Production and Synthetic Modifications of Shikimic Acid - Chemical

Review pubs.acs.org/CR

Cite This: Chem. Rev. 2018, 118, 10458−10550

Production and Synthetic Modifications of Shikimic Acid Nuno R. Candeias,*,† Benedicta Assoah,† and Svilen P. Simeonov*,‡ †

Laboratory of Chemistry and Bioengineering, Tampere University of Technology, Korkeakoulunkatu 8, 33101 Tampere, Finland Laboratory Organic Synthesis and Stereochemistry, Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bontchev str. Bl. 9, 1113 Sofia, Bulgaria

Chem. Rev. 2018.118:10458-10550. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 11/10/18. For personal use only.

‡

ABSTRACT: Shikimic acid is a natural product of industrial importance utilized as a precursor of the antiviral Tamiflu. It is nowadays produced in multihundred ton amounts from the extraction of star anise (Illicium verum) or by fermentation processes. Apart from the production of Tamiflu, shikimic acid has gathered particular notoriety as its useful carbon backbone and inherent chirality provide extensive use as a versatile chiral precursor in organic synthesis. This review provides an overview of the main synthetic and microbial methods for production of shikimic acid and highlights selected methods for isolation from available plant sources. Furthermore, we have attempted to demonstrate the synthetic utility of shikimic acid by covering the most important synthetic modifications and related applications, namely, synthesis of Tamiflu and derivatives, synthetic manipulations of the main functional groups, and its use as biorenewable material and in total synthesis. Given its rich chemistry and availability, shikimic acid is undoubtedly a promising platform molecule for further exploration. Therefore, in the end, we outline some challenges and promising future directions.

CONTENTS 1. Introduction 2. Isolation and Purification from Plant Sources 3. Synthesis of Shikimic Acid 3.1. Chemical Methods 3.1.1. Synthesis from (−)-Quinic Acid 3.1.2. Synthesis via Diels−Alder Cyclization 3.1.3. Synthesis from Carbohydrates 3.1.4. Synthesis via Kinetic Resolution 3.1.5. Other Methods 3.2. Microbial Production 4. Synthetic Applications of Shikimic Acid 4.1. Synthesis of Oseltamivir Phosphate (Tamiflu) 4.2. Reactions of Shikimic Acid and Applications in Synthesis 4.2.1. Reactions of Carboxyl Group 4.2.2. Oxidation of Shikimic Acid to 3-Dehydroshikimic Acid and Other Oxidations 4.2.3. Enzymatic Acylation 4.2.4. Protection of Vicinal Diols 4.2.5. Transformations at Hydroxyl Groups 4.2.6. Epoxidation by Ring Closure 4.2.7. Halogenation of Shikimic Acid 4.2.8. Shikimic Acid Ring Opening 4.2.9. Conjugate Addition 4.3. Use as Biorenewable Material 4.4. Use in Total Synthesis 5. Miscellaneous Applications of Shikimic Acid 6. Conclusion Author Information Corresponding Authors ORCID © 2018 American Chemical Society

Notes Biographies References

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10538 10538 10539

1. INTRODUCTION (−)-Shikimic acid (Figure 1) is a natural product abundant in the plant kingdom. It is a metabolite involved in the shikimate

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Figure 1. (−)-Shikimic acid derived antiviral oseltamivir phosphate.

pathway (Scheme 73, section 3.2) responsible for the biosynthesis of aromatic amino acids in plants and microorganisms.1 Shikimic acid came into the spotlight during the avian flu outbreak in the 2000s as a result of its use as a precursor in the synthesis of the antiviral Tamiflu2 (Figure 1). It is nowadays produced in multihundred-ton amounts3 by extraction of star anise (Illicium verum) and by a fermentation process using a genetically engineered Escherichia coli strain.4 Received: May 30, 2018 Published: October 11, 2018 10458

DOI: 10.1021/acs.chemrev.8b00350 Chem. Rev. 2018, 118, 10458−10550

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Figure 2. Representative examples of important products available from shikimic acid.

oils;51−58 (ii) shikimic acid extraction after degreasing of the plant material;59−62 (iii) membrane separation by ultrafiltration63,64 or osmosis;65 (iv) ion exchange resin purification;66−71 (v) isolation with imprinted polymers;72,73 (v) ultrasonic− microwave synergic extraction.74 Shikimic acid is usually extracted from the plant material with polar protic organic solvents or hot water. Ionic liquids have also been successfully applied as extraction solvents. Isolation of shikimic acid from the fruits of I. religiosum75 in yields of 16.5% involves extraction with refluxing EtOH, followed by treatment with 40% formaldehyde and purification by ion-exchange chromatography on Amberlite IR-4B (Table 1, entry 1). Later, shikimic acid was isolated from I. verum76,77 in up to 7% yield after Soxhlet extraction with 95% EtOH and purification by ionexchange chromatography (Table 1, entries 2 and 3). Isolation of shikimic acid in 5.5% yield from I. verum used extraction with 95% aqueous i-PrOH (Table 1, entry 4).78 The use of semibatch flow apparatus in hot water extraction of shikimic acid from Chinese star anise79 allowed recoveries of 100% and rapid separation from the plant material at temperatures above 120 °C. A pressurized hot water extraction of multigram quantities of shikimic acid from star anise was achieved using an unmodified household espresso machine as the extraction apparatus (Table 1, entry 5).80 The isolation of shikimic acid from the fruits of I. grif f ithii in yields of 12−18% entails defattation of the plant material prior to extraction with MeOH and does not require the use of chromatography (Table 1, entry 6).81 L. styracif lua (sweetgum) has been reported as an alternative source of shikimic acid.82 Hot water extraction of sweetgum seeds gives shikimic acid in comparable amounts to that of I. verum (Table 1, entry 7). Scots pine (P. sylvestris) is also considered as a source of shikimic acid.41 The hot water extraction of Scots pine needles provided crystals of shikimic acid with different purity (Table 1, entry 8). The classical extraction techniques usually do not provide good access to the shikimic acid embedded in the biopolymer matrix. Hence, several strategies which seek to improve extraction of shikimic acid have been reported.83 Sun et al.84 carried out ultrasound-assisted and microwave-assisted water extraction of Chinese star anise, where several variables, such as applied power, ratio of solvent to material, and extraction time, were investigated. Under ultrasound-assisted extraction up to 1.367% yield of shikimic acid could be obtained, while microwave-assisted extraction produced up to 2.75% yield. The unsatisfactory results, compared to other reports, were attributed to the significant effect of the temperature of the extraction water over the yield. Zhou et al.85 developed a GC−

Shikimic acid is mainly utilized industrially for the synthesis of oseltamivir. Its chemical scaffold provided extensive use as a versatile chiral precursor in the synthesis of bioactive substances and natural products (Figure 2). Shikimic acid has also been explored in the synthesis of biorenewable aromatics, stabilization of metal nanoparticles, and other applications. Epimers of shikimic acid have been synthetically prepared and used as substrates in organic synthesis. The chemistry of shikimic acid was first reviewed in 1965 by Bohm.5 The chemical synthesis of shikimic acid and its analogues has been reviewed later on.6 Recent reviews deal with the production of shikimic acid7−10 and its use in medicinal chemistry11−13 and pharmacy.14,15 However, the majority of reviews are outdated or devoted to specific topics. Despite the extensive research on the chemistry of shikimic acid, no recent comprehensive reviews are available on this subject. Given the utility of shikimic acid in organic synthesis, a systematic review covering both the preparation and synthetic modifications of this compound is timely and desirable. This review aims to cover two main aspects: (i) the main methods available for production of shikimic acid and its epimers, including synthetic methods, extraction from plants and microbial production, and (ii) synthetic modifications and related applications, including synthesis of Tamiflu and derivatives, synthetic manipulations of the main functional groups, its use in green chemistry, and in total synthesis.

2. ISOLATION AND PURIFICATION FROM PLANT SOURCES Shikimic acid was first isolated in 1885 from I. religiosum.16 It is found in a variety of plants,9,11,17−31 and its distribution in distinct plant tissues9,32,33 depends on the metabolic processes that are taking place. Typically, shikimic acid is accumulated in storage tissue of seeds and fruits where metabolic processes are inhibited.9 The amount of shikimic acid increases rapidly in plant tissues upon treatment with the herbicide glyphosate,34−37 which inhibits the biosynthesis of aromatic amino acids.38 Plant treatment with glyphosate improves the production of shikimic acid.36,39,40 Trees such as Pinus sylvestris,41,42 Liquidambar styracif lua,43−45 Eichhornia crassipes, 46 pine and cedar plant tissues,43,47,48 and palm oil materials and wastes49,50 are sources of shikimic acid. The fruits of Illicium genus present the highest amount of shikimic acid (up to 24% on a dry basis), which forms the major source of shikimic acid.17 Procedures for the isolation of shikimic acid include the following: (i) isolation from star anise residues and waste waters after separation of essential 10459


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L. styraciflua seeds

Scots pine (P. sylvestris) dry needles

782

841

I. grif fithii dried fruits

681

I. verum seeds

478

I. verum seeds

I. verum seeds

377

580

I. verum seeds and carpels

276

plant

I. religiosum

175

entry

1.0 kg

35 g

54 g

40 g

400 g

25 g

900 g

27 g

amount

three separate water extractions (5 L each) at 45 °C for 2

refluxed over 6 h in 2 L of 95% aq i-PrOH; residual seeds again refluxed for 4 h in 95% aq i-PrOH ground star anise (20 g) packed in the portafilter (sample compartment) of an espresso machine and extracted (approximately 2 min) with a 30% EtOH/ water solution (200 mL) powdered fruits extracted with 150 mL of hexane with a Soxhlet apparatus; defatted plant material then extracted with 150 mL of CHCl3; defatted plant material extract in CHCl3 again extracted with 150 mL of MeOH stirred overnight in 400 mL of deionized water at 65 °C

Soxhlet extraction with 95% EtOH (125 mL) for 2 h

four extractions (20 min) with refluxing EtOH (70 mL) Soxhlet extraction with 95% EtOH (4 L) for 24 h

extraction

The extracts were subjected to three treatments with Norit activated charcoal, followed by filtration and concentration under reduced pressure until approximately 50 mL of liquid remained. After allowing the solution to cool, 75 mL of i-PrOH was added to each solution to precipitate a white solid. The mixture was heated to boiling and passed through a preheated, medium porosity fritted filter. The filtrate was concentrated under reduced pressure to yield a clear, yellow syrup. The syrup reconstituted with water was chromatographed on an Amberlite IRA-400 (acetate) column. Water (20 mL) and 25% aq AcOH (125 mL) in their respective amounts were used as eluent. The AcOH fractions were concentrated under reduced pressure to obtain the amorphous free acid.a The water extract was concentrated by a factor of 2. In the condensed extract, 20 g of activated charcoal was added and the temperature was kept at 80 °C for 10 min under stirring. The solid materials were then removed by filtration. Shikimic and other organic acids were adsorbed on the resin through anion-exchange when the water extract was passed through the separation column, which contained 650 mL of Amberlite IRA 900 in Ac−1 format. The separation column was

The extracted MeOH solution was distilled under reduced pressure to obtain the crude shikimic acid. Twenty mL of MeOH was added to the solid material containing mostly shikimic acid, and the mixture was refluxed for 30 min, cooled to 0 °C, and maintained for 2 h. The precipitated crystalline shikimic acid was then isolated by filtration.

The combined extracts were evaporated and residue dissolved in 90 mL of hot water. Aqueous formaldehyde was then added and the solution was refluxed for few minutes. The resulting precipitate was removed by filtration, and the filtrate was passed down an anion exchange column of Amberlite IR-4b (10 g). The column was washed with 25 mL of water and then eluted with 45 mL 25% of aq AcOH followed by 25 mL of water. After evaporation of the resulting solution to dryness, shikimic acid was obtained by crystallization from MeOH. The extract was evaporated to dryness in vacuo to give a thick green oil that gave off a strong smell of aniseed. This oil was warmed (ca. 80 °C) in water (5 L) and a dark green oil, which formed on the surface, removed by pipet, and discarded. To the hot solution was added 37/40% aq formaldehyde (5 mL) and set to boil for 5 min, then allowed to cool. The precipitate formed was filtered and the clear amber filtrate passed down an anion exchange column of Amberlite IRA-400 (CI) anion exchange resin (standard grade, 500 g, as the acetate). After washing with water (3 L), the product was eluted with aq AcOH (25% v/v, 4 L). The resulting orange solution was evaporated to dryness in vacuo to yield the crude product as an orange-red solid that was taken up into the minimum volume of water and applied to a column of “Solka Floc” in water. Elution with water afforded a pale yellow solution that was evaporated to dryness in vacuo to afford the product as white prisms after crystallization from toluene and MeOH. Evaporation of EtOH from the brown colored filtrate under reduced pressure afforded a thick brown oil (approximately 8.5 g), which was redissolved in water (145 mL) and warmed to 80 °C. Any dark green oil that formed on the surface of the aqueous solution was removed by Pasteur pipet. Approximately five drops of 37−40% formaldehyde solution was added to the hot solution; the aqueous solution was set to boil for 5 min and then allowed to cool. The resulting precipitate was removed by passing the solution through a glass filter funnel containing a layer of Celite to afford a clear orange solution. The solution was passed through an anion exchange column (Amberlite IRA-400, in acetate form, dry weight 25 g). The column was then washed with water (100 mL) and the water discarded. The column was then eluted with 25% aq AcOH (185 mL) and the yellow eluent was collected. Removal of AcOH by rotary evaporator and high vacuum pump afforded an orange colored solid (approximately 3.0 g). The solid was dissolved in MeOH and heated for 10 min with activated charcoal (three spatulas). Filtration and subsequent removal of the MeOH under reduced pressure afforded an off-white solid (approximately 2.0 g). The solid was then recrystallized from MeOH and toluene (or EtOAc) to afford the desired shikimic acid as a bright white crystalline solid. The extracts were combined and concentrated to dryness. The residue was dissolved in 900 mL of water. The oily layer formed was separated and the aqueous layer washed four times with EtOAc (1.2 L) followed by treatment with 37% aq formaldehyde. The precipitated impurities were removed by filtration. The filtrate was treated with activated charcoal (60 g), and the water distilled out completely. MeOH (50 mL) was added and distilled to remove traces of water. Finally, MeOH (40 mL) was added and the mixture heated to reflux for 30−45 min, cooled to 0 °C, and maintained for 2 h. The precipitated shikimic acid was collected by filtration. The extracts from two extractions were combined, silica gel (20 g) was added, and evaporated to dryness. The ensuing solid was washed with DCM and EtOAc before extraction with a 10% AcOH/EtOAc solution. The solvent was evaporated, and the residue washed with DCM, which was then dried to provide shikimic acid as an off-white solid.

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Table 1. Organic Chemist’s Guide to Shikimic Acid: Selected Methods for Isolation from Available Plant Sources yield

b

1.1 g, 3.23%

10 g, 18.5%

2.21 g, 5.5%

20 g, 5%

0.6−1.74 g, 2.4−7%

50−60 g, 6−7%

4.44 g, 16.5%

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MS method with selected ion monitoring for quantitative determination of shikimic acid and compared the extraction efficiency of ultrasound-assisted and Soxhlet extraction. Ultrasonic extraction was as efficient as Soxhlet extraction but was more rapid and simpler. Sadaka and Garcia86,87 studied the forward/back extraction of shikimic acid and reported that the forward extraction with tridodecylamine/1-heptanol was favored at low temperature. In back extraction, higher temperatures and the addition of oleic acid as a competitive displacer provided 80% recovery for shikimic acid. Ionic liquids have also been successfully applied as extraction solvents. Bica et al.88 studied the reactive dissolution of star anise in acidic functionalized ionic liquids. The extraction of shikimic acid was coupled with in situ conversion to shikimic acid ethyl ester, an important precursor of oseltamivir phosphate, that was achieved in up to 12.7% yield. Later on, the same authors89 studied different imidazolium-based ionic liquids for their capacity to extract shikimic acid from star anise pods. Up to 11 wt % extraction efficiency under microwave-assisted dissolution was achieved. The extraction yield was correlated with the hydrogen-bonding properties. Polarizable molecular dynamics simulations indicated that the hydrogen bonding of the ionic liquid anion to shikimic acid is responsible for the good extraction performance. The isolation of (−)-shikimic acid from the ionic liquid extract was accomplished with complete recovery of the ionic liquid by ion-exchange chromatography on Amberlite-400 resin. Usuki et al.90,91 extracted shikimic acid from Ginkgo biloba leaves utilizing the cellulose-dissolving ionic liquid [bmim]Cl2. At 150 °C, a yield of 2.3% w/w was obtained, which was significantly higher compared to MeOH extraction at 80 °C (0.93% w/w). In one instance, the authors achieved the isolation of pure shikimic acid from the undistillable ionic liquid extracts by ion-exchange chromatography, though in the very low amount of 6.2 mg.90 Yang et al.92 carried out ultrasoundassisted extraction of shikimic acid from conifer needles with ionic liquid solutions. The structure of the ionic liquids, especially the cations, had significant impact on the extraction yield. [Bzmim]Br 0.5 mol/L and liquid−solid ratio of 8.3:1 (mL/g) was the most efficient extraction system. Aldous et al.93 used solid-state NMR spectroscopy to quantify precisely the shikimic acid content present in whole biomass samples and to compare the efficiencies of different extraction techniques. The classical Soxhlet extraction with MeOH was incomplete even after 72 h (6.6%), while the use of cellulose-dissolving aqueous tetrabutylammonium hydroxide led to quantitative extraction and isolation of 14.0 ± 0.6 wt % shikimic acid.

mp 184.7 °C; ATR-IR 3482, 3380, 3222, 1682, 1646, 1445, 1384, 1286, 1267, 1121, 1113, 1070 cm−1. 1H NMR (D2O, 300 MHz) δ 2.20 (1H, dd) 2.74 (1H, dd) 3.77 (1H, dd) 4.04 (1H, td) 4.45 (1H, dd) 4.88 (3H, s) 6.83 (1H, t); 13C NMR (D2O, 75 MHz) δ 32.62, 67.96, 68.73, 73.30, 131.89, 139.42, 172.18; HRMS-DCI m/z 192.0871 [M + NH4]+ calcd for C7H14NO5 192.0866. bAfter crystallization and recrystallization, 5.7 g of coarse crystal with a purity of 93.6% and 4.0 g of white crystal with a purity of 98.5% were obtained. Repeated crystallization of the mother liquid gave an additional 1.5 g of shikimic acid with a purity of 98.3%.

purification

Review

3. SYNTHESIS OF SHIKIMIC ACID 3.1. Chemical Methods

Synthesis of shikimic acid and its epimers via several routes has been reviewed although not extensively.5,6,8,14,94 Its racemic synthesis and the construction of the six-membered ring by Diels−Alder reaction have been reported in several instances. Natural chiral compounds with a suitable chemical structure such as (−)-quinic acid and sugars have been intensively used for the stereoselective synthesis of shikimic acid and its epimers, while more recent methods include asymmetric catalysis and kinetic resolution. 3.1.1. Synthesis from (−)-Quinic Acid. (−)-Quinic acid is available in bulk quantities from various plants and microorganism sources. Albeit (−)-quinic acid is not an intermediate in the shikimate pathway, its structure, similar to the naturally

a

h under continuous stirring

extraction amount plant entry

Table 1. continued

then washed in turn with water and MeOH after it was saturated, followed by washing with a 2N aq AcOH in order to desorb shikimic acid from the column. The resulting solution was then condensed under vacuum until a yellow solid material was obtained. The resulting material was dissolved in 95% MeOH at 50−60 °C, followed by an addition of 2−5 g of activated charcoal and boiling for 20 min with a condenser. After filtration, the clear solution was condensed into a lightly viscous liquid and cooled down. A yellowish crystal was obtained within a period of a few hours to overnight, depending on the concentration and purity of the extracted material. The coarse crystal was filtered and dissolved in 95% EtOH while heating. The colorless solution was then cooled down overnight in a recrystallization process. The resulting white crystal was filtered, dried in a vacuum oven at 60 °C for 8 h, and the remaining liquid was again condensed for crystallization to recover any residual shikimic acid.

yield

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against previous reports (Scheme 3). The dehydration of 12 produced exclusively shikimate 13, which was later reconsidered and proved to be incorrect.98

occurring (−)-shikimic acid, provided its extensive use as a precursor. The first synthesis of (−)-shikimic acid from (−)-quinic acid was reported by Dangschat and Fischer.95 The (−)-quinic acid derivative 1 was converted to nitrile 2 by dehydration of the amide function and simultaneous elimination of the alongside formed p-toluenesulfonate ester. Hydrolysis of 2 furnished 4-Omethyleneshikimic acid 3, which was further deprotected to (−)-shikimic acid (Scheme 1).

Scheme 3. Géro et al.97 Synthesis of (−)-Methyl Shikimate

Scheme 1. Dangschat and Fischer95 Synthesis of (−)-Shikimic Acid

Snyder and Rapoport98 prepared the stereochemically intact ketone 14 by Hunsdiecker degradation of the tetraacetate derivative of (−)-quinic acid 4. Cyanide addition afforded cyanohydrin 15 as an epimeric mixture. In contrast to the previous reports, the dehydration of 15 in the presence of POCl3 or SO2Cl2 was not regioselective and resulted in a nearly 1:1 mixture of nitriles 16 and 17. Nitrile 16 spontaneously crystallized from the reaction mixture, while 17 remained as an oil, a possible cause for the previous omission of 17 by other authors. Nitriles 16 and 17 were separated and hydrolyzed in the presence of KOH to give (−)-shikimic acid or 4-epi(−)-shikimic acid, respectively (Scheme 4). Lesuisse and Berchtold99 also prepared (−)-4-epi-shikimic acid from (−)-quinic acid (Scheme 5). Benzylidenation of (−)-quinic acid followed by intramolecular esterification furnished lactone 18 as a 3:1 mixture of diastereomers. The major isomer obtained in crystalline form was assigned an S configuration at the acetal carbon based on steric arguments. Cleavage of the lactone afforded methyl ester 19. Based on previous reports,98 the authors expected the direct dehydration of 19 to produce a mixture of regioisomers. Therefore, 19 was subjected to a Swern oxidation. Regioselective dehydration of

Another synthesis96 was initiated with full acetylation of (−)-quinic acid followed by treatment with SO2Cl2 to afford the acid chloride 5. NaBH(OMe)3 promoted reduction of 5 with concomitant acetyl group migration furnished tetraacetate 6 with free hydroxyl group at C-1, which was regioselectively dehydrated to olefin 7. Full deacetylation and selective protection with trityl chloride afforded trityl ether 8, which was acetylated and selectively detritylated to afford alcohol 9. The oxidation of 9 with CrO3 followed by acid-catalyzed esterification with MeOH furnished (−)-methyl shikimate (Scheme 2). Géro et al.97 described a three-step synthesis of (−)-methyl shikimate from (−)-methyl quinate 11. The selective benzoylation of 11, which occurred only at the secondary hydroxyl groups, makes this protocol significantly simple as

Scheme 2. Grewe et al.96 Synthesis of (−)-Methyl Shikimate from (−)-Quinic Acid

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Gotor et al.103 prepared (−)-methyl 4-epi-shikimate in similar fashion to Lesuisse and Berchtold.99 This protocol features the advantage of the diastereoselective NaBH(OAc)3 reduction of ketone 30, which leads to an exclusive formation of the desired (−)-methyl 4-epi-shikimate (Scheme 7). Ventura et al.104 prepared (−)-methyl shikimate and (−)-methyl 3-epi-shikimate from (−)-quinic acid derivative 31 which is protected at the vicinal trans hydroxyl groups. Swern oxidation of 31 afforded ketone 32, which was subjected to a regioselective dehydration to give enone 33, with a rigid decaline-like structure. The reduction of 33 with DIBAL-H gave two diastereoisomers 34 and 35 with diastereomeric ratio (dr) 14.6:1, respectively. Diastereoisomer 34 was obtained in 73% yield after recrystallization. The relative energies of the two aluminum alkoxide product-like transition states control the hydride attack. In this case, the more stable equatorial aluminum alkoxide predominates and accounts for the high yield of 34 over 35. The reduction of 33 with L-selectride, on the other hand, furnished exclusively diastereoisomer 35. In this instance, the high 1,2-cis stereoselectivity is due to the steric bulk of the reducing agent inducing attack at the side opposite to the vicinal group. Both 34 and 35 were separately deprotected to afford (−)-methyl 3-epi-shikimate and (−)-methyl shikimate, respectively (Scheme 8). (−)-Shikimic acid labeled with deuterium at C-2 was prepared from the readily available form (−)-quinic acid,105 3dehydroquinic acid. The α-carbonyl position of 3-dehydroquinic acid was equilibrated in D2O at pH 7.0, and deuterium was partially but selectively incorporated in the C-2 position. The deuterated ketone was then subjected to enzymatic dehydration and reduction to afford partially C-2 deuterated (−)-shikimic acid.106 Banwell et al.107 described the utilization of (−)-3dehydroshikimic acid 36 available from (−)-quinic acid. The initial efforts in this work were focused on a concise route to (+)-shikimic acid via direct conversion of (−)-36 into (+)-36 by Mitsunobu reaction. However, under various conditions, only aromatic products resulting from elimination reactions were

Scheme 4. Snyder and Rapoport98 Synthesis of (−)-Shikimic Acid and 4-epi-(−)-Shikimic Acid

the resulting ketone 20 in the presence of POCl3 afforded enone 21, which was subjected to NaBH4 reduction to give shikimate 22. The inversion of the stereochemistry at C-3 under Mitsunobu conditions followed by full deprotection of shikimate 23 furnished (−)-4-epi-shikimic acid in 18% overall yield from (−)-quinic acid. Later on, this approach was used by Shing and Tang100,101 in their synthesis of pseudosugars from quinic acid. Following the pioneer work of Lesuisse and Berchtold,99 Hanessian et al.102 prepared (−)-methyl 3,4-O-isopropylidene5-epi-shikimate 28 from (−)-quinic acid (Scheme 6). A noteworthy feature of this work was the conversion of shikimate 27 to the more stable 5-epi-shikimate shikimate 28 via thermodynamically controlled isopropylidenation.

Scheme 5. Lesuisse and Berchtold99 Synthesis of 4-epi-(−)-Shikimic Acid

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Scheme 6. Hanessian et al.102 Synthesis of (−)-Methyl 3,4-O-Isopropylidene-5-epi-shikimate 28

Scheme 7. Gotor et al.103 Synthesis of (−)-Methyl 4-epi-Shikimate

Scheme 8. Ventura et al.104 Synthesis of (−)-Methyl Shikimate and (−)-Methyl 3-epi-Shikimate

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Scheme 9. Banwell et al.107 Synthesis of (−)-Methyl 3-epi-Shikimate

Scheme 10. Banwell et al.107 Synthesis of (−)-Methyl 3-epi-Shikimate via Modified Ventura et al.104 Protocol

deprotected in the presence of aqueous TFA to (−)-methyl shikimate. In another work, Whitehead et al.111 carried out regioselective Martin’s sulfurane promoted dehydration of (−)-quinic acid derivative 55 and achieved exclusively 56 in 97% yield (Scheme 14). Bianco et al.112 described a concise route to (−)-methyl shikimate in only four steps from (−)-quinic acid (Scheme 15). Central in this synthesis stands the exclusive formation of shikimate 58 by SOCl2 promoted regioselective dehydration of the triacetyl derivative 57. The role of the substituents at C-3 and C-5 accounts for the regioselectivity of this transformation. The tertiary hydroxyl group at C-1 takes an axial orientation to undergo the elimination with the anti-proton. Based on the NMR couplings, the acetoxy group at C-3 was found to adopt equatorial orientation, while the one at C-5 adopts axial orientation. Hence, the transition state, which corresponds to the dehydration that produces 58, was more energetically favored than the one which would produce the opposite regioisomer. Two patents from 1999113 and 2000114 described the synthesis of (−)-shikimic acid via Vilsmeier reagent promoted dehydration of (−)-quinic acid (Scheme 16). In this example, a suitably protected quinic acid ester 59 was subjected to a reaction with DMF and POCl3. The formed intermediate 60 was converted in situ into protected (−)-shikimic acid 61 with a regioselectivity of 50:1. 3.1.2. Synthesis via Diels−Alder Cyclization. Diels− Alder cycloadditions have proved to be a powerful tool for construction of unsaturated six-membered rings. They have been extensively explored in initial attempts to access racemic shikimic acid until more recently, upon the development of asymmetric versions, in the synthesis of its enantiopure forms. The synthesis of (±)-shikimic acid via Diels−Alder cyclization was first achieved in the early 1960s when Smissman et al.115 and Raphael et al.116 reported similar synthetic routes. Raphael et al.116 described the formation of Diels−Alder adduct 64 via cyclization of (1E,3E)-buta-1,3-diene-1,4-diyl diacetate 62 with acrylic acid 63, while methyl acrylate was used by Smissman et al.115 Raphael et al. also succeeded in achieving (−)-shikimic acid by selective crystallization of (±)-tri-O-acetyl derivative 68 with (−)-quinine, though in low overall yield of 15% (Scheme 17). Later, Abell et al.117 used this synthetic route in their synthesis of deuterium labeled (±)-shikimic acid (Scheme 18). The

observed. For this reason, the authors concluded that the desired “enantiomeric switching” would require operating at a lower and, therefore, less sensitive oxidation level with shikimates rather than dehydroshikimates. This consideration evolved into a strategy wherein reduction of (−)-36 to (−)-methyl 3-epishikimate followed by oxidation of the hydroxyl at C-5 would allow migration of the double bond to the desired isomer. (−)-36 was converted into (−)-methyl 3-epi-shikimate as shown in Scheme 9. Alternatively, the authors obtained (−)-methyl 3epi-shikimate from (−)-quinic acid using the Ventura et al.104 protocol, where the only difference was the use of Luche conditions instead of DIBAL-H for the reduction of enone 33 to alcohol 34 (Scheme 10). A slightly better yield of 87% was achieved together with 7% of the other readily separable isomer 35. Protection of the obtained (−)-methyl 3-epi-shikimate with bipyran 39 in the presence of (+)-CSA afforded a regioisomeric mixture of dispiroketals 40 and 41. The presence of allylic hydroxyl moiety within the undesired regioisomer 40 allowed selective oxidation with MnO2 to ketone 42 and consequent chromatographic purification of the desired isomer 41. PDC or Swern oxidation of 41, followed by DBU promoted isomerization, afforded the conjugated isomer 44. Luche reduction of 44 produced an 84:16 mixture of separable epimers 45 and 46. Reduction with the bulky K-selectride led to 1,2-cis stereoselectivity and the exclusive formation of isomer 46. Hydrolysis of each of the bis-acetals 45 and 46 afforded (+)-methyl 3-epishikimate and (+)-methyl shikimate, respectively (Scheme 11). Ohfune et al.108 described a synthetic route from (−)-quinic acid to (−)-shikimic acid wherein the regioselectivity of the key dehydration step was not controlled via formation of a conjugated enone as in most of the previous reports.99 Instead, the authors prepared the protected (−)-methyl quinate 31 as reported by Frost et al.109 Subsequent silylation and reduction afforded diol 50. Regioselective dehydration of 50 via in situ generated thiiranium ion 51 afforded exclusively the desired olefin 52, which was transformed to (−)-shikimic acid in four steps (Scheme 12). More recently, Whitehead et al.110 carried out direct dehydration of 49 (Scheme 13) under various conditions and achieved varying levels of regioselectivity. Martin’s sulfurane proved to be the optimum reagent for generation of the desired regioisomer 53. After purification by chromatography and crystallization, pure 53 was obtained in 83% yield and 10465


Chemical Reviews

Review

Scheme 11. Synthesis of (+)-Methyl Shikimate and (+)-Methyl 3-epi-Shikimate

AcOH and subsequent deacetylation afforded (±)-methyl 5-epishikimate as the major product, while the use of KOAc furnished (±)-methyl 4-epi-shikimate as the predominant product. Epimerization of (±)-4-epi-shikimic acid triacetate 81 in the presence of liquid HF furnished (±)-methyl shikimate, which after saponification afforded (±)-shikimic acid in 41% overall yield (Scheme 20). In another synthesis120 72 was epoxidized to 82, which after treatment with DBN furnished alcohol 83. Epoxidation of 83 followed by solvolysis afforded (±)-methyl 4-epi-shikimate in only five steps (Scheme 21), though in low overall yield of 20%. Bartlett and McQuaid121 prepared (±)-methyl shikimate from the Diels−Alder adduct 85 in a remarkable overall yield of 50%. Iodolactonization of 85 furnished lactone 86, which was treated with DBU. The resulting olefin 87 was readily converted into (±)-methyl shikimate (Scheme 22).

Diels−Alder cycloaddition was reinvestigated, and it was found to result in the formation of a mixture of diastereoisomers in an approximately 80:20 endo:exo ratio, which was in accordance with the earlier evidence for the predominant endo addition.116 Grewe and Hinrichs118 prepared (±)-methyl shikimate and (±)-methyl 3-epi-shikimate from the Diels−Alder adduct 72 (Scheme 19). Epoxidation of 72 followed by in situ ring opening furnished diacetate 73. Because of the lack of both stereoselectivity and regioselectivity, the bromination of 73 resulted in a mixture of products 74 and 75. The mixture was treated with AgOAc, followed by acid-catalyzed hydrolysis to give another mixture of products wherein (±)-methyl shikimate was the predominant one. In a later version of this synthesis, Grewe and Kersten119 used the Woodward reaction to produce syn-diacetate 78, which was subjected to regioselective bromination to give an epimeric mixture of 79 and 80. Treatment of this mixture with AgOAc in 10466


Chemical Reviews

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Scheme 12. Synthesis of (−)-Shikimic Acid via Thiiranium Ion Controlled Dehydration

Scheme 13. Whitehead et al.110 Synthesis of (−)-Methyl Shikimate via Martin’s Sulfurane Promoted Dehydration

58 in 29% overall yield (Scheme 23). The ester 98 could be further hydrolyzed under alkaline conditions to free (±)-shikimic acid in ∼80% yield. Koreeda et al.123 revealed that, at the time, majority of the synthetic routes to (±)-shikimic acid involved hydrolysis of the acetyl and methyl ester groups of methyl shikimate and produced m-hydroxybenzoic acid as a side product. Therefore, the authors developed a strategy wherein the use of 2(trimethylsilyl)ethyl acrylate instead of methyl acrylate allowed the final deprotection to be carried out under milder desilylation conditions (Scheme 24). A stereocontrolled route from the Diels−Alder adduct 106a to (±)-methyl 5-epi-shikimate (Scheme 25) was described by Campbell et al.124 The Diels−Alder reaction resulted in an endo/ exo mixture, which was treated with OsO4 to yield the diol 107. Central in this synthesis stands the lithium hexamethyldisilazide promoted ring opening of acetonide 108 that allowed direct entry into the desired cyclohexene system in shikimate 109. The authors also attempted the synthesis of (±)-methyl shikimate via

Scheme 14. Improved Martin’s Sulfurane Promoted Dehydration

Koreeda and Ciufolini122 prepared (±)-shikimic acid from the Diels−Alder adduct 93 obtained in 9:1 endo:exo ratio from the reaction of methyl acrylate 92 and diene 91. Dihydroxylation of 93 furnished the corresponding diol 94, which was subjected to an acid-catalyzed elimination to olefin 95. Stereoselective epoxidation of 95 with MCPBA afforded epoxide 96, which after hydrolysis followed by acetylation afforded γ-lactone triacetate 97. Acid-catalyzed lactone ring opening followed by acetylation and treatment with DBU afforded (±)-methyl triacetylshikimate 10467


Chemical Reviews

Review

Scheme 15. Bianco et al.112 Synthesis of (−)-Methyl Shikimate

Scheme 16. Synthesis of (−)-Shikimic Acid via Vilsmeier Reagent Promoted Dehydration

Scheme 17. Raphael et al.116 Synthesis of (−)-Shikimic Acid

deprotection furnished (±)-methyl shikimate in low overall yield of 2.7%. Later, the same authors reported more concise route from 106 to (±)-methyl shikimate (Scheme 26). In this example, the basepromoted ring opening of 106 was carried out prior to the dihydroxylation, thus leading to intermediate 83, previously proposed by McGowan and Berchtold.120 The direct dihydroxylation of 83 afforded a separable mixture of (±)-methyl shikimate and (±)-methyl 5-epi-shikimate in 5:1 ratio. However, the presence of a bulky tert-butyldimethylsilyl protecting group allowed stereoselective dihydroxylation with exclusive formation of (±)-methyl shikimate.125−127

Scheme 18. Synthesis of Deuterium Labeled (±)-Shikimic Acid

inversion of the stereochemistry at C-5 by Mitsunobu reaction, but only a product of dehydration 110 was obtained in low yield. However, hydroboration−oxidation125 of 110 and further 10468


Chemical Reviews

Review

Scheme 19. Grewe and Hinrichs118 Synthesis of (±)-Methyl Shikimate and (±)-Methyl 3-epi-Shikimate

Scheme 20. Grewe and Kersten119 Synthesis of (±)-Shikimic Acid via Woodward Reaction

Scheme 21. McGowan and Berchtold120 Synthesis of (±)-Methyl 4-epi-Shikimate

Rodrigo and co-workers128 reported the synthesis of (±)-shikimic acid from cycloadduct 114. A strategy similar to

that discussed previously was adopted, wherein early stage basepromoted ring opening of 114 followed by diastereoselective dihydroxylation of 115, controlled by the presence of bulky protecting group, furnished (±)-shikimic acid in 31% overall yield from 113 (Scheme 27). In another synthesis,129 the troublesome diastereoselective dihydroxylation was omitted by the use of furan 117 owning two latent hydroxyls. Diels−Alder reaction with methyl acrylate furnished cycloadduct 118 in 15.3:1 endo/exo ratio (Scheme 28). Catalytic hydrogenation of endo-118 resulted in the exclusive formation of the desired syn-product 119. Ring opening of 119 in the presence of lithium hexamethyldisilazide followed by debenzylation and acetylation furnished 58 in 63.9% overall yield. Choy et al.130 accomplished stereoselective synthesis of (−)-shikimic acid. The asymmetric induction in this early example was achieved from dienophile 121 owning chiral auxiliary (Scheme 29). The obtained intermediate 122 was further converted to (−)-shikimic acid analogous to the Smissman synthesis.115 However, the authors did not report the overall yield. Some years later, Koizumi et al.131 described the synthesis of (+)-methyl 5-epi-shikimate using asymmetric Diels−Alder 10469


Chemical Reviews

Review

Scheme 22. Bartlett and McQuaid121 Synthesis of (±)-Methyl Shikimate

Scheme 23. Koreeda and Ciufolini122 Synthesis of (±)-Shikimic Acid

Scheme 24. Synthesis of (±)-Shikimic Acid Employing Fleming Oxidation

Hayashi et al.133 prepared the previously described124 adduct (+)-106b in its enantiopure form by highly diastereoselective Diels−Alder reaction of furan (105) and acrylate ester 139 derived from Corey’s chiral auxiliary ((−)-(1R,2R)-2-(naphthalene-2-sulfonyl)cyclohexanol). Treatment of (+)-106 with I2 furnished iodolactone 140. One-pot hydrolysis and epoxidation followed by esterification afforded epoxy ester 141, which was subjected to base promoted β-elimination to give epoxyshikimate 142 (Scheme 32). Posner and Wettlaufer134 prepared cycloadduct (−)-145 by inverse-electron-demand asymmetric Diels−Alder reaction between vinyl ether 143 and pyranone 144 and converted it to 3,4,5-tri-O-acetyl-4-epi-shikimate 81 in 15 steps (Scheme 33).

reaction of S8-3-(2-pyridylsulfinyl)acrylate (−)-123 and furan (105). The predominantly formed optically pure endo-adduct 124 was transformed to (+)-methyl 5-epi-shikimate in seven steps as shown in Scheme 30. Cabrejas et al.132 prepared (+)-shikimic acid and (+)-5-epishikimic acid via high pressure asymmetric Diels−Alder reaction of (S)-α-p-tolylsulfinyl acrylate 131 and furan (105). The reaction provided moderate selectivity, and a mixture of all four possible adducts, predominantly the endo ones, was obtained. The authors succeeded in isolating the two major adducts, endo132 and endo-133, which were further converted to (+)-shikimic acid and (+)-5-epi-shikimic acid, respectively (Scheme 31). 10470


Chemical Reviews

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Scheme 25. Campbell et al.124 Synthesis of (±)-Methyl 5-epi-Shikimate

Scheme 26. Synthesis of (±)-Methyl Shikimate Controlled by the Presence of a Bulky Protecting Group125

Scheme 27. Rodrigo et al.128 Synthesis of (±)-Shikimic Acid

Evans and Barnes136,137 were the first to describe catalytic asymmetric Diels−Alder cyclization toward production of enantiopure shikimic acid (Scheme 35). Diels−Alder reaction of furan (105) and acrylamide 168 catalyzed by Cu chiral complex 167 afforded an 80:20 endo:exo mixture of isomers. The desired endo isomer 169 was isolated via recrystallization in 67% yield. Initially, the authors attempted to generate the cyclohexene ring by reverse-Michael ring opening of the cycloadduct 169, which was unsuccessful under a variety of conditions. Therefore, 169 was converted to methyl ester 170 and was

A stereoselective Diels−Alder reaction between maleic anhydride and D-glucose substituted diene 157135 afforded a mixture of isomers 158 and 159 in 86:14 ratio. The mixture was subjected to Upjohn dihydroxylation with the desired syn-diol 160 isolated by selective crystallization and acetylated to anhydride 161. Treatment of 161 with benzyl alcohol afforded benzyl ester 162, which was transformed in two steps into acid 163. The latter underwent Hunsdiecker reaction to give a 62:38 mixture of bromides 164 and 165, which was converted to (−)-4-epi-shikimate 166. Acid hydrolysis of 166 furnished enantiopure (−)-4-epi-shikimic acid (Scheme 34). 10471


Chemical Reviews

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Scheme 28. Koreeda et al.129 Synthesis of (±)-Methyl 3,4,5-Triacetylshikimate

Scheme 29. Choy et al.130 Synthesis of (−)-Shikimic Acid via Enantioselective Diels−Alder Reaction

Scheme 30. Koizumi et al.131 Synthesis of (+)-Methyl 5-epi-Shikimate

further transformed into (+)-shikimic acid under Campbell conditions.125−127 Ryu et al.138 achieved the synthesis of the adduct 106c in a 91:9 endo:exo ratio with remarkable enantioselectivity of above 99% enantiomeric excess (ee) (endo). The endo isomer 106c was separated and converted to ethyl ester 106d, which was further transformed into (−)-shikimic acid under Campbell conditions (Scheme 36). 3.1.3. Synthesis from Carbohydrates. Sugars have been reported as suitable naturally occurring starting materials for the synthesis of enantiopure shikimic acid. Heid et al.139 took advantage of the stereochemistry of D-arabinose and were the first to report stereospecific synthesis of (−)-shikimic acid from the sugar platform (Scheme 37). Later, Kitagawa et al.140

demonstrated the synthesis of the key intermediate 14 from Dmannose (Scheme 38). However, these early attempts involve multistep synthesis and produce low yields of (−)-shikimic acid. Suami et al.141,142 achieved shorter synthesis of (−)-methyl shikimate from diethyl dithioacetal derivatized D-lyxose143 194 (Scheme 39). Central in this synthesis stands the concomitant formation of the two new C−C bonds during the reaction of the mesylated aldehyde 197 with the dianion of dimethyl malonate. Therefore, this protocol features the advantage over the previously reported methods in that the introduction of the carboxyl side chain was achieved simultaneously with the cyclohexane ring formation. The reaction provided a mixture of C-2 stereoisomers 198 and 199, which was not problematic because the newly formed stereogenic center was lost during the 10472


Chemical Reviews

Review

Scheme 31. Cabrejas et al.132 Synthesis of (+)-Shikimic Acid and (+)-5-epi-Shikimic Acid

Scheme 32. Hayashi et al.133 Synthesis of Epoxyshikimate 154

subsequent decarboxymethylation accompanied by β-elimination of the 2-acetoxy group. However, the two stereoisomers 198 and 199 were reported to exhibit different reactivities (Scheme 39). Later on, the same authors prepared (+)-methyl 3,4,5-Otribenzyl-4-epi-shikimate from L-arabinose in a similar manner.144 In a modified procedure, the two C−C bond formation was achieved in a two-step protocol,145 which allowed also the synthesis of (−)-methyl 3,4,5-O-tribenzyl-5-epi-shikimate from D-ribose. Fleet et al.146 reported high yield synthesis of (−)-shikimic acid from D-mannose using intramolecular Wadsworth− Emmons olefination as a key step (Scheme 40). The synthesis was initiated from the D-mannose derived intermediate 202, which was converted to phosphonate 204. Debenzoylation of 204 followed by intramolecular Wadsworth−Emmons olefina-

tion of the resulting lactol 205 furnished shikimate 206. Hydrolysis of the acetonide protection, followed by saponification of the methyl ester, afforded (−)-shikimic acid. Soon after, the authors described a modified procedure147 where the two-carbon chain extension was carried out with sodium tert-butyl dimethoxyphosphoryl acetate. The resulting intermediate 207 was subjected to a reductive debenzoylation to yield shikimate 209. Finally, in the hydrolysis step, the use of tert-butyl ester featured an advantage over methyl ester and allowed a one-step full deprotection in the presence of aqueous TFA (Scheme 41). Fleet’s strategy was used by Floss et al.148 in their synthesis of 13 D-(−)-[1,7- C2]shikimic acid (Figure 3). The authors carried out Wadsworth−Emmons olefination with tert-butyl dimethylphosphono[1,2-13C2]acetate and claimed that this 10473


Chemical Reviews

Review

Scheme 33. Posner and Wettlaufer134 Synthesis of 3,4,5-Tri-O-acetyl-4-epi-shikimate 81

diastereoisomers. The mixture was deprotected to the corresponding hemiacetals, which upon treatment with base underwent intramolecular olefination to form shikimate 206. Deacetonation of 206 furnished (−)-methyl shikimate in 38% overall yield from D-ribose (Scheme 44). Synthesis of (−)-shikimic acid and (−)-5-epi-shikimic acid from D-ribose involving intramolecular [3 + 2] nitrone cycloaddition to establish the carbocyclic ring was reported by Wightman et al.153,154 In their first work,153 2,3-O-isopropylidene-D-ribose 225 was reacted with diallyl zinc to give D-allotriol 226 in very high diastereoselectivity. Quantitative periodate cleavage of 226 and treatment with N-methylhydroxylamine furnished nitrone 228. Thermolysis of 228 afforded cycloadduct 229 with minor traces of an isomer. 229 was converted to (−)-5epi-shikimic acid in five steps wherein the desired cyclohexene system was achieved by Swern oxidation of alcohol 231 accomplished with concomitant β-elimination to give aldehyde 232 (Scheme 45). The authors also attempted to prepare (−)-shikimic acid by inversion of the stereochemistry of the hydroxyl group in alcohol 229. However, this attempt was unsuccessful under a variety of conditions. Therefore, an alternative synthetic route was initiated from the D-ribonolactone derivative 234, which was treated with allyl magnesium chloride to give lactol 235 as an anomeric mixture. Reduction of 235 produced a single diol 236. Desilylation of 236, followed by periodate cleavage, furnished

route provides reproducibly good yields, making it suitable for isotopic synthesis. Mirza et al.149 prepared (−)-shikimic acid from D-mannose derived lyxo-aldehyde 210. In this example, the two-carbon chain extension was achieved by Knoevenagel condensation of 210 with triethyl phosphonoacetic acid (Scheme 42). The resulting vinyl phosphonate 211 was subjected to catalytic hydrogenation with concomitant removal of the benzyl ether to give hemiacetal 212. Intramolecular olefination in a similar manner as reported by Fleet et al.146 furnished shikimate 213, which after deprotection afforded (−)-shikimic acid in 26−29% from D-mannose. More recently, Hilvert et al.150,151 used the same strategy for the production of various isotopically labeled shikimates 217a− 217c, which were further used as intermediates for enzymatic synthesis of chorismic acids (Scheme 43). Mirza and Vasella152 described two-carbon chain extension of the 1-deoxy-1-nitro derivatized D-ribose 218 by Michael addition with diethyl vinylphosphonate 219. The resulting 5.5:1 anomeric mixture of phosphonates 220 was reduced with NaBH 4 to give a mixture of diastereoisomeric diols. Detritylation of the predominantly formed diol 221 followed by treatment with periodate furnished lyxo-phosphonate 222 as a 4.9:1 mixture of anomers. TBS protection of 222 followed by treatment with BuLi and methyl chloroformate furnished ester 224 as a mixture of anomers each containing a 1:1 mixture of 10474


Chemical Reviews

Review

Scheme 34. Stoodley et al.135 Synthesis of (−)-4-epi-Shikimic Acid

Scheme 35. Evans and Barnes136,137 Synthesis of (+)-Shikimic Acid

hemiacetals 238. Treatment with N-methylhydroxylamine, followed by thermolysis of the obtained nitrone 239, gave the cycloaduct 240 with the desired stereochemistry (Scheme 46). Later, the same authors154 reinvestigated their synthesis (Scheme 47) and instead of diallylzinc used allylmagnesium chloride in the first step to produce a 5:1 mixture of inseparable diastereoisomers 226 and 237. However, downstream separation of the cycloaducts 230 and 241 by crystallization and column chromatography allowed the synthesis of both (−)-5-

epi-shikimic acid and (−)-shikimic acid in overall yields of 16 and 3%, respectively. Mukaiyama-type intramolecular aldolization was used by Dong et al.155 as a key step in their synthesis of (−)-methyl shikimate from D-arabinose. In this example, the two-carbon chain extension of D-arabinose was achieved by Wittig olefination. The resulting unsaturated ester 242 was hydrogenated to ester 243 and selectively tritylated to 244. Treatment of 244 with allyl bromide in the presence of NaH resulted in a lactonization with concomitant allylation of both secondary 10475


Chemical Reviews

Review

Scheme 36. Ryu et al.138 Synthesis of (−)-Shikimic Acid

Scheme 37. Heid et al.139 Synthesis of (−)-Shikimic Acid from D-Arabinose

Scheme 38. Kitagawa et al.140 Synthesis of (−)-Shikimic Acid from D-Mannose

hydroxyl groups to form lactone 245. Deprotection of 245 followed by Swern oxidation furnished the key intermediate in

this synthesis, the aldehyde 246. Cyclization of 246 via Mukaiyama-type aldolization generated the desired carbocyclic 10476


Chemical Reviews

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Scheme 39. Suami et al.141 Synthesis of (−)-Methyl Shikimate from D-Lyxopyranose

Scheme 40. Synthesis of (−)-Shikimic Acid by Intermolecular Wadsworth−Emmons Olefination

ring in 247. The authors reported that the diastereoselectivity of the intramolecular aldolization was very high due to the favored re/si face attack during the nucleophilic cycloaddition, though this was not particularly useful in the synthesis of (−)-methyl shikimate (Scheme 48). Kiessling et al.156 described the synthesis of (−)-4-epishikimic acid in 32% overall yield from D-arabinose (Scheme 49). In this work, the pyranose form of D-arabinose was subjected to a high yielding acid-catalyzed ring contraction to give furanose 249, which was further converted to the iodosugar derivative 250. Zinc-mediated reductive ring opening of 250 produced an intermediate aldehyde, which was trapped in situ by a Barbier reaction with bromide 251 and afforded a 2.2:1 mixture of diastereomers 252 and 253. The major diastereomer 252 was isolated and, after deprotection, subjected to a ring-

closing metathesis (RCM) to produce (−)-4-epi-methyl shikimate. Finally, as a proof of the adaptability of their strategy, the authors described the synthesis of (+)-3-epi-shikimic acid from the minor diastereomer 253. Chen et al.157 described the synthesis of ketals 259 and 261 (Scheme 50), the latter being a key intermediate for Tamiflu synthesis. The D-ribose derived intermediate 257 was transformed in a one-pot synthesis into bis-olefin 258, and then subjected to RCM to give 5-epi-shikimic acid derivative 259.Treatment of the triflate 260 with sodium nitrite gave the desired inversion of the stereochemistry at the free hydroxyl group and furnished 261. The synthesis of (−)-shikimic acid and (−)-5-epi-shikimic acid from D-ribose derived158 aldehyde 262 with Barbier reaction and RCM as key steps has been accomplished by 10477


Chemical Reviews

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Scheme 41. Fleet et al.147 High Yield Synthesis of (−)-Shikimic Acid from D-Mannose

enantioselective hydrolysis of the corresponding (±)-277 from their earlier work.163 Hydroxyl group elimination under Mitsunobu conditions followed by hydrolysis of the ester afforded cyclohexenol 279. PMB protection of 279 and epoxidation from the exo-face afforded epoxide 281. Regioselective opening of the epoxide with 2-lithio-1,3-dithiane in the presence of HMPA furnished 282 as a sole product. Hydrolysis of the thioacetal followed by hydroxyl group elimination afforded aldehyde 284, which was readily converted into (+)-methyl shikimate (Scheme 54). Johnson et al.164,165 described the synthesis of (+)- and (−)-methyl shikimate from a single enantiomer of alcohol (−)-286 obtained by asymmetric enzymatic resolution.72 Central in this synthesis stands the use of 2-furyl group in 289 as a carboxylate surrogate. The initial plan involved direct carbonylation of α-iodoenone 288 in the presence of CO, MeOH, and Pd0, which failed. As an alternative, the authors obtained furan 289 under Stille conditions. The attempts to conjugatively reduce the enone 289 under a variety of conditions failed. Therefore, 289 was subjected to Luche reduction, which furnished a mixture of separable epimeric allylic alcohols in a 6:1 ratio. The major isomer 290 was isolated and hydrogenated in the presence of Pd/C to produce the alcohol 291 as a single diastereoisomer, which was acylated to yield diacetate 292. The furan group of 292 was oxidized with RuO2, and the crude acid was esterified with diazomethane. Elimination of the α-acetate group in the presence of DBU furnished the desired α,β-unsaturated ester 68, which was subjected to a concomitant deprotection of the three hydroxyl groups to deliver (−)-methyl shikimate. This strategy allowed also the synthesis of the unnatural (+)-methyl shikimate as shown in Scheme 55.

Figure 3. D-(−)-[1,7-13C2]Shikimic Acid.

Vankar et al.159 (Scheme 51). The low stereoselectivity of the Barbier reaction resulted in the formation of bis-olefin 264 as an inseparable mixture of two diastereomers in 2:1 ratio. Separation was however achieved, after transformation of 264 into the PNB esters 267 and 268. The major isomer 267 was converted to (−)-5-epi-shikimic acid, and the minor 268 was converted to (−)-shikimic acid. The enantiomers of (−)-5-epi-shikimic acid and (−)-shikimic acid can be synthesized from aldehyde 269. The syntheses of (+)-methyl shikimate and (+)-methyl 5-epishikimate160 have been accomplished from the D-mannose derivative 270. Subjection of 270 to ring opening and in situ Nozaki−Hiyama−Kishi coupling with vinyl chromium gave an inseparable mixture of diastereomers 271 and 272 in 1:1 ratio. RCM of the mixture in the presence of Hoveyda−Grubbs II catalyst furnished shikimates 273 and 130, which were converted to (+)-methyl shikimate and (+)-methyl 5-epishikimate, respectively (Scheme 52). 3.1.4. Synthesis via Kinetic Resolution. Pawlak and Berchtold161 described an enzymatic kinetic resolution of the racemic epoxy ester (±)-274. The desired enantiomer (−)-274 was achieved in 97% ee and readily converted to (−)-shikimic acid in three steps (Scheme 53). Vandewalle et al.162,163 prepared (+)-methyl shikimate from the enantiopure alcohol (+)-277 obtained by lipase-catalyzed

Scheme 42. Mirza et al.149 Synthesis of (−)-Shikimic Acid via Knoevenagel Condensation

10478


Chemical Reviews

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Scheme 43. Hilvert et al.150,151 Synthesis of Isotopically Labeled Shikimate Esters

Scheme 44. Mirza and Vasella152 Synthesis of (−)-Methyl Shikimate

Shoji et al.168 reported a chemo-enzymatic enantioconvergent approach toward (−)-ethyl shikimate. In this work, racemic shikimate (±)-305 was prepared in a very similar manner as described by Campbell et al.124 Lipase-catalyzed acetylation of (±)-305 provided enantiomers (−)-306 and (+)-305 in excellent yields and ee. Both enantiomers were transformed into (−)-ethyl shikimate via regioselective inversion of the stereochemistry at C-5 in (+)-305 and at C-3 and C-4 in (−)-306 (Scheme 58). Kamikubo and Ogasawara169 described the stereoselective construction of (−)-shikimic acid from the chiral alcohol (+)-313, accessible via enzymatic resolution.170 The correct absolute stereochemistry at C-3 and C-4 for (−)-shikimic acid was established at an early stage via convex face stereoselective dihydroxylation of the obtained olefin 315 in 2 steps from (+)-313 olefin 315. Subjection of the resulting diol 316 to MOM protection and a subsequent reductive regeneration of the olefin functionality gave 318. Retro Diels−Alder reaction of

The readily available from the commercial 3-cyclohexane carboxylic acid, lactone121 (±)-300, was recognized by Kiyota et al.166 as a suitable starting material for the synthesis of (−)-methyl shikimate. Acetylation of (±)-300 followed by enzymatic hydrolysis in the presence of lipase YM furnished (−)-300 in 54% yield and >99% ee. Finally, epoxidation of (−)-300 and subsequent alkaline hydrolysis afforded enantiomerically pure (−)-methyl shikimate in 80% yield from (−)-300 (Scheme 56). Enzymatic hydrolysis of the largely available (±)-303 was employed by Sugai et al.167 as a key step in the synthesis of (−)-3-epi-shikimic acid (Scheme 57). In this example, pig liver esterase (PLE) catalyzed the hydrolysis of (±)-303 and afforded (−)-303 in nearly 43% and 99.4% ee. LiHMDS mediated βelimination furnished epoxide 304. The alkaline hydrolysis of 304 proceeded with stereoselective epoxide ring opening to give (−)-3-epi-shikimic acid. 10479


Chemical Reviews

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Scheme 45. Wightman et al.153 Synthesis of (−)-5-epi-Shikimic Acid via Intramolecular [3 + 2] Nitrone Cycloaddition

Scheme 46. Wightman et al.153 Synthesis of (−)-Shikimic Acid via Intramolecular [3 + 2] Nitrone Cycloaddition

diol 329 was the predominant product. Protection of 329 as an acetonide and reduction of the ketone furnished alcohol 330, after which elimination and full deprotection afforded (−)-shikimic acid (Scheme 60). Yoshida and Ogasawara172 described the synthesis of (−)-shikimic acid from the readily available (±)-333 which possessed a carboxylic function. (±)-333 was resolved under lipase-mediated transesterification conditions to give the alcohol (+)-333 and acetate (+)-334, which were both separately converted into (−)-shikimic acid. Central in this synthesis stands the formation of cyclohexanones 337 and 344 via palladium-mediated elimination of acetic acid involving a suprafacial 1,4-hydrogen shift. Stereoselective epoxidation of 337 and 344 furnished epoxides 338 and 345, respectively.

318 under thermolysis allowed the entry into the six-member carbocyclic system in 319. Finally, 319 was further elaborated to (−)-shikimic acid via a complex sequence of transformations as shown in Scheme 59. In a subsequent paper, Ogasawara et al.171 described the diastereoselective conversion of keto silyl ether (−)-324 into (−)-shikimic acid. In this work, the carboxylic function of shikimic acid was introduced at an early stage by the formation of the α,β-dihydroxy ester 326, which was obtained as a single stereoisomer in two steps. After acetylation of 326, subjection of the resulting tertiary acetate 327 to retro Diels−Alder reaction gave cyclohexenone 328. Diastereoselective osmylation of 328 directed by the axially disposed acetoxy group gave a readily separable 15:1 mixture of diastereoisomers from which the syn10480


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Scheme 47. Wightman et al.154 Synthesis of both (−)-5-epiShikimic Acid and (−)-Shikimic Acid from 2,3-OIsopropylidene-D-ribose

morpholine-dione 351 was transformed in two steps into the dialkylated glycolamide derivative 353 obtained as a single diastereoisomer. Treatment of 353 with the Grubbs I catalyst furnished spiro-morpholine 354 owning the key α-hydroxy acid functionality and the right carbon backbone. Reductive cleavage of the ephedrine portion led to hydroxy amide 355, which was converted to bromolactone 356 analogous to the iodolactone 86 obtained by Bartlett and McQuaid121 (Scheme 22). This formed the basis to claim formal synthesis of shikimic acid by the authors, which is achievable in both enantiomeric forms due to the commercial availability of both enantiomers of ephedrine. Sudalai et al.176 reported the synthesis of (−)-methyl 3-epishikimate from the monoprotected cis-2-butene-1,4-diol 357 (Scheme 64). The desired stereochemistry in this example was established by an early stage asymmetric Sharpless epoxidation of 357. The resulting epoxy alcohol (−)-358 was obtained in 93% yield and 96% ee. Oxidation of (−)-358 gave the aldehyde 359, which was subjected to Barbier allylation with acrylate 263 to afford the homoallylic alcohol syn-360 in dr = 4:1. Protection of 360, followed by deprotection of the TBS group furnished alcohol 361. The hydroxyl group of 361 was oxidized and the resulting aldehyde was subjected to Seyferth−Gilbert homologation, which afforded terminal alkyne 362 with a completely transesterified methyl ester. Partial hydrogenation of the terminal alkyne in the presence of Lindlar’s catalyst afforded bis-olefin 363 that allowed the generation of the cyclohexene core by RCM in the presence of Grubbs II catalyst. The obtained epoxide 364 was hydrolyzed and deprotected to give (−)-methyl 3-epi-shikimate in 16% overall yield and 96% ee. In a patent from 2012177 was described the synthesis of highly enantiopure (−)-shikimic acid from the Diels−Alder adduct 366. Central in this synthesis stands the simultaneous kinetic resolution/asymmetric epoxidation of 366 under Sharpless conditions that produced enantiopure epoxide 367, which was then readily transformed to (−)-shikimic acid (Scheme 65). Mehta and Mohal178 described the synthesis of shikimic derivative 374 starting from the readily available endo-hydroxy-

Retro Diels−Alder reactions of 339 and 345 led to direct entry to the desired cyclohexene structures in 340 and 346, respectively (Scheme 61). 3.1.5. Other Methods. Ganem et al. 173 prepared (±)-shikimic acid from the readily available from 1,4dihydrobenzoic acid, alcohol 348.174 Stereoselective epoxidation of 348 furnished epoxide 349, which was subjected to debromination to give the corresponding epoxyol 350. Finally, saponification with KOH furnished (±)-shikimic acid (Scheme 62). Pansare and Adsool175 reported an enantioselective route to (−)-quinic acid that is extendable to shikimic acid derivatives (Scheme 63). The ephedrine-derived enantiomerically pure

Scheme 48. Synthesis of (−)-Methyl Shikimate via Mukaiyama-Type Intramolecular Aldolization

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Scheme 49. Synthesis of (−)-4-epi-Shikimic Acid and (+)-3-epi-Shikimic Acid via RCM

Scheme 50. Chen et al.157 Synthesis of Tamiflu Precursor 261

378, which was then transformed into iodide 379. Treatment of 379 with Zn/AcOH induced reductive cleavage to yield the hemiacetal 380, followed by immediate reduction with LiAlH4 to give the divinyl diol 381. The key RCM reaction of 381 in the presence of Grubbs catalyst furnished cyclohexenol 382. Diastereoselective epoxidation of 382 with MCPBA from the same face to the allylic hydroxyl functionality produced epoxide 384, with subsequent transformation into (−)-shikimic acid (Scheme 67). Recently, Yan et al.181 reported a common chiral pool based synthetic strategy that leads from the readily available L-tartaric acid to both enantiomers of shikimic acid and 4-epi-shikimic acid. Central in this strategy stands the remarkable one-pot conversion of the readily prepared from L-tartaric acid chiral synthon 389 into allylic epoxide 390 accomplished with retention of the configuration. Three different synthetic routes furnished (−)-shikimic acid, (+)-shikimic acid, and (−)-4-epishikimic acid from the single enantiomer of 390. The authors achieved also the synthesis of ent-390 in good yields from 389

7-norbornenone ketal 368. This was accomplished by transformation to the ketone 371 through a three-step sequence that involved O-methylation, dihydroxylation from the exo-face, and a single-pot deprotection−protection of the 7-keto and dihydroxy functionalities, respectively. Baeyer−Villiger oxidation of 371 gave an 80:20 regioisomeric mixture of lactones 372 and 373. The mixture was separated and the minor regioisomer 373 was elaborated to shikimate 374 (Scheme 66). The authors claimed that this route allows fast entry to shikimic acid and carbasugars. However, considering the former, the poor regioselectivity of the Baeyer−Villiger oxidation was a major drawback. Ogasawara et al.179 reported a diastereocontrolled synthesis of (−)-shikimic acid using RCM as a key step. This synthesis was initiated from the furfural-derived chiral building block180 (+)-375, which was subjected to convex-face selective 1,4addition of a vinyl group to give olefin 376. Reduction of the ketone in 376 under Luche conditions generated the desired alcohol diastereoisomer as a major product, which was isolated as MOM ether 377. TBDMS deprotection furnished alcohol 10482


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Scheme 51. Vankar et al.159 Synthesis of (−)-5-epi-Shikimic Acid, (+)-5-epi-Shikimic Acid, (+)-Shikimic Acid, and (−)-Shikimic Acid

Scheme 52. Kumar et al.160 Synthesis of (+)-Methyl Shikimate and (+)-Methyl 5-epi-Shikimate

69). Treatment of the complex (+)-399 with aqueous NaHCO3 yielded alcohol complex 400, followed by protection with TBDMSCl to give 401. Decomplexation of 401 with anhydrous Me3NO furnished bulky group protected diene 111. The synthesis of (−)-methyl shikimate from 111 was achieved in 67% yield by a slight modification of the procedure reported by Campbell et al. (Scheme 26).

and converted it into (+)-4-epi-shikimic acid as shown in Scheme 68. Weerasuria et al.182 prepared enantiopure shikimic acid from tricarbonyliron complexes of methyl dihydrobenzoate. In this example, tricarbonyliron was used as a lateral control group which allowed the synthesis of both enantiomeric forms of shikimic acid starting from either (+)-399 or (−)-399 (Scheme 10483


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hydroxyl group of 405 was first oxidized to a carbonyl with Dess−Martin periodinane. Reduction of the ketone with NaBH4 from the less hindered β-face afforded exclusively alcohol 406, which delivered the (−)-methyl 5-epi-shikimate upon cleavage of the ketal protecting group.

Scheme 53. Pawlak and Berchtold161 Synthesis of (−)-Shikimic Acid via Enzymatic Hydrolysis

3.2. Microbial Production

The shikimate pathway (Scheme 73) is distributed in plants and microorganisms and links carbohydrate metabolism to the biosynthesis of aromatic compounds. Shikimic acid is the main precursor for the biosynthesis of primary metabolites such as aromatic amino acids and many aromatic compounds. Since this pathway is absent in animals, the essential aromatic amino acids for humans have to be taken from their diet.185 The shikimic pathway in microorganisms produces shikimic acid in abundance from carbon glucose or other carbon sources. Metabolic engineering of several bacteria that aims to partly block the biochemical mechanisms that consume shikimic acid, and overexpresses the enzymes responsible for its synthesis, has been performed. Condensation of PEP and E4P that is obtained upon metabolization of glucose or other carbohydrate begins the shikimic acid pathway. The aldol-type reaction between PEP and E4P is catalyzed by the enzyme DAHP synthase. This enzyme is inhibited by the three aromatic amino acids that can be ultimately formed by this pathway. A remarkable sequence of oxidation, β-elimination of phosphate, reduction, ring opening, and intramolecular aldol condensation catalyzed by a single enzyme, 3-DHQ synthase, converts DAHP into 3-dehydroquinic acid. 3-Dehydroquinic acid can be reversibly transformed into quinic acid and shikimic acid by dehydration and reduction catalyzed by DHQ dehydratase and shikimate dehydrogenase, respectively. Consumption of shikimic acid occurs when shikimate kinase phosphorylates the 3-OH group of shikimic acid and forms S3P, which reacts with another PEP molecule to provide EPSP. The final step of the shikimate pathway is the

The synthesis of natural (−)-shikimic acid was achieved not only directly from (+)-399 as shown in Scheme 69 but also indirectly from (−)-399 by inversion of the configuration as shown in Scheme 70. Gotor et al.183 described the conversion of the natural (−)-shikimic acid into its C-3 epimer. Simultaneous trans-1,2 diol protection and esterification of (−)-shikimic acid furnished the protected ester 35. The inversion of the stereochemistry at C-3 of 35 occurred quantitatively under Mitsunobu conditions to give p-nitrobenzoate ester 404. Deprotection of the pnitrobenzoate ester and subsequent removal of the diacetal moiety furnished (−)-methyl 3-epi-shikimate (Scheme 71). The same group reported the synthesis of (−)-methyl 5-epishikimate from (−)-methyl shikimate 3,4-ketal derivative 405 prepared from (−)-quinic acid (Scheme 72).184 After several unsuccessful attempts to invert the chirality of the C-5 center of 405 by Mitsunobu reaction and other methods, the free

Scheme 54. Enantioselective Synthesis of Unnatural (+)-Methyl Shikimate

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Scheme 55. Johnson and Co-Workers164 Synthesis of (+)- and (−)-Methyl Shikimates

Scheme 56. Kiyota et al.166 Synthesis of (−)-Methyl Shikimate

Researchers have developed several metabolic engineering approaches for the overproduction of shikimic acid by E. coli. The shikimic acid pathway depends on the glycolytic and the pentose phosphate pathways to provide the two starting materials. Thus, genetic modifications have been made at the central carbon metabolism and shikimic acid pathways. The carbon flux from the central carbon metabolism can be increased by overexpressing the feedback-resistant 3-deoxy-D-arabinoheptulosonate-7-phosphate (DAHP) synthases (coded by aroFf br or aroGfb and aroHf br), shikimate dehydrogenase (coded by aroE), transketolase (coded by tktA), and DHQ synthase enzymes (coded by aroB).4,188,189,193−196 The carbon flux can be redirected by zwf removal to channel the carbon flux to quinic acid, gallic acid, and shikimic acid.197 The consumption of shikimic acid and subsequent accumulation in the aromatic amino acid pathway can be achieved by deleting the aroK and aroL genes, encoders of shikimate kinase I and II. The first enzyme in the aromatic amino acid pathway (DAHP synthase) is regulated by the production of phenylalanine, tryptophan, and tyrosine. Due to this, plasmid-coded feedback resistant (f br) aroF or aroG genes have been expressed.188,198 The intracellular accumulation of shikimic acid can revert the reduction of 3dehydroshikimic acid into shikimic acid which results in “hydroaromatic equilibration” and formation of byproducts as

trans-1,4-elimination of phosphate catalyzed by chorismate synthase to yield chorismic acid that can be further transformed into the aromatic amino acids. E. coli has been the focus of several bioengineering studies for industrial production of shikimic acid.186 Genetically engineered E. coli solved the supply problem of shikimic acid needed for the massive production of Tamiflu in the 2000s.4,187−190 Many other bacteria have been studied in the production of shikimic acid, but E. coli stands prominent.7−10,191,192 10485


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Scheme 57. Sugai et al.167 Synthesis of (−)-3-epi-Shikimic Acid

Scheme 58. Shoji et al.168 Synthesis of (−)-Ethyl Shikimate

quinic acid and gallic acids. Inactivation of the shikimic acid transport gene (shiA) prevents its cellular reuptake.4,7,189,195,198 The inactivation of ydiB, a paralog of aroE, also increases the accumulation of shikimic acid by inhibiting the consumption of 3-dehydroquinic acid into quinic acid.198,199 However, the effect observed by activation of ydiB is considerably more pronounced on the accumulation of quinic acid than the effect observed in the accumulation of shikimic acid by inactivation of the same gene.200 Deletion of genes for shikimate kinase, aroK and aroL, usually requires the fermentation medium to be supplemented with aromatic amino acids to facilitate growth. Recently, an Esa quorum sensing device was developed to integrate a circuit variant that switches off gene expression at desired times and cell densities. This dynamic pathway modulation allowed the accumulation of shikimic acid in a modest 105 mg/L titer without the addition of aromatic amino acids to the medium.201

Although glucose is the main carbon source for bacterial production of shikimic acid, other carbon sources have been studied. The carbohydrate phosphotransferase system has been displaced with other transport systems, such as by expression of galactose permease (coded by galP) and glucokinase (coded by glk).194,202,203 Sorbitol, glycerol, maltose, fructose, and gluconate are some of the carbon sources tested for several E. coli strains (Table 2). Growing genetically modified E. coli in carbonlimited conditions has been reported to favor the production of the shikimic acid pathway byproducts such as 3-dehydroshikimic acid, 3-dehydroquinic acid, and quinic acid. Conversely, phosphorus limitation resulted in the major production of shikimic acid together with 3-dehydroshikimic acid as the only byproduct.195,198,204−206 Other bacteria have been recently considered for the production of shikimic acid as documented in Table 3. A 10486


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Scheme 59. Kamikubo and Ogasawara169 Synthesis of (−)-Shikimic Acid via Stereoselective Dihydroxylation

Scheme 60. Ogasawara et al.171 Synthesis of (−)-Shikimic Acid via Acetoxy Group Directed Diastereoselective Osmylation

another microorganism generally recognized as safe, has been studied for production of shikimic acid.211,220,221 However, 3dehydroshikimic acid was always obtained as the major product, upon deactivation of pyruvate and shikimate kinases.220 Knockout of aroK in B. megaterium increased the production

remarkable titer of 93 g/L of shikimic acid produced by Corynecaterium glutamicum fermentation has been reported. Although glucose was the substrate used for this fermentation process, other carbon sources such as mixed sugars derived from lignocellulosic biomass were demonstrated.219 Bacillus subtilis, 10487


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Scheme 61. Yoshida and Ogasawara172 Synthesis of (−)-Shikimic Acid via Palladium-Mediated Elimination

Scheme 62. Ganem et al.173 Synthesis of (±)-Shikimic Acid

of shikimic acid by 6 times in flask culture when compared with the wild type.222 Fermentation of a different strain of the same bacterium allowed accumulation of shikimic acid in 12.5 g/L titer with fructose as the carbon source, which was obtained in 89% purity upon further purification of the fermentation broth.222 Although fermentation of mutated strains of Citrobacter f reundii resulted in production of shikimic acid in 10 g/L titer in flask culture,223 wild type strains isolated from soil were reported to provide the same compound in 22.3 g/L in a fed-batch bioreactor after culture conditions optimiza-

tion.224−227 A process involving Gluconobacter oxidans growing cells, resting cells, dried cells, and cell membrane was reported to biotransform quinic acid to 3-dehydroshikimate.228 This oxidative fermentation step, catalyzed by cytoplasmic membranes located on the bacterial outer surface, was coupled with the reduction of 3-dehydroshikimate to shikimic acid. The reduction step occurs in the cytoplasm and is catalyzed by shikimate dehydrogenase in the presence of NADP-dependent D-glucose dehydrogenase and excess D-glucose as an NADPH regenerating system. The best performance of shikimate 10488


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Scheme 63. Pansare and Adsool175 Formal Synthesis of Shikimic Acid and Its Derivatives

Scheme 64. Sudalai et al.176 Synthesis of (−)-Methyl 3-epi-Shikimate via Sharpless Epoxidation

Scheme 65. Synthesis (−)-Shikimic Acid via Simultaneous Kinetic Resolution/Asymmetric Epoxidation

established with ionic-liquid-treated switchgrass as the carbon substrate identified the presence of shikimic acid in the supernatant. Although this compound was one among many others in the supernatant (over 25), its accumulation was not observed in the individual cultures.232

dehydrogenase to catalyze the reduction of 3-dehydroshikimate to shikimic acid was achieved at pH 7, while the reversible transformation was observed to be better achieved at pH 10.229 Saccharomyces cerevisiae was recently engineered to accumulate shikimic acid by overexpressing a mutant version of Aro1 enzyme with disrupted activity in the shikimate kinase subunit. Although modest shikimic acid accumulation levels were observed, this was the first example of production of this compound by a yeast,230 that was later improved to 2.5 g/L titer by further manipulation of the aromatic amino acid pathway.231 A recent exometabolomic analysis of microbial consortia composed of Cellulomonas f imi and Yarrowia lipolytica

4. SYNTHETIC APPLICATIONS OF SHIKIMIC ACID Shikimic acid has been recognized as an interesting chiral block in organic synthesis for many years now. However, the recent outbreaks of influenza have elevated the interest in shikimic acid by the synthetic organic community. This synthetic precursor of antiviral Tamiflu has triggered not only the development of 10489


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Scheme 66. Mehta and Mohal178 Norbornyl Route toward Shikimic Acid

Scheme 67. Ogasawara et al.179 Synthesis of (−)-Shikimic Acid via RCM

influenza” since 2004 have been also of major concern due to the high mortality rate over 50%.241 Two main antiviral neuraminidase inhibitors (Figure 4) have been used to treat and prevent influenza A and B virus strains: zanamivir (GSK’s Relenza) reached the market in July 1999 and oseltamivir phosphate (Gilead’s Tamiflu) reached the market in October of the same year.242 The higher bioavailabilty of oseltamivir phosphate, the prodrug of potent inhibitor GS-4071,243 compared with zanamivir allows Tamiflu to be administered to patients as capsules, while Relenza is administered by inhalation. Oseltamivir phosphate was patented by Gilead in 1995,244 and licensed to Roche in 1996, and after only 2 1/2 years of development time, a new drug application was filed with the U.S. Food and Drug Administration for the use of this compound in the treatment of influenza infections. Many synthetic paths for the preparation of oseltamivir phosphate have been developed after introduction of Tamiflu into the market;245 however, the initial manufacturing process adopted by Hoffmann-La Roche started either from quinic acid and its transformation into shikimic acid or from shikimic acid

Tamiflu synthetic processes and their optimization for industrial scale-up, but also its use in the total synthesis of natural products and biologically active compounds. The supply problem of shikimic acid that resulted in the shortage of production of Tamiflu during influenza peak seasons led many researchers to develop other synthetic methods for shikimic acid preparation and processes that overcame its use in the production of Tamiflu. As shikimic acid is now available in multihundred-ton amounts for production of Tamiflu, there is an opportunity to explore this densely functionalized molecule as a biorenewable platform in green chemistry. 4.1. Synthesis of Oseltamivir Phosphate (Tamiflu)

Influenza is a major threat to human health and spreads worldwide in yearly outbreaks, which causes approximately, 250 000−500 000 deaths and 3−5 million cases of severe illness.237,238 Mankind has witnessed four influenza pandemics in the last century: “Spanish influenza” (1918), “Asian influenza” (1957), “Hong Kong influenza” (1968), and “swine influenza” (2009). 239,240 Additionally, several outbreaks of “avian 10490


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Scheme 68. Yan et al.181 Common Chiral Pool Based Synthetic Strategy toward Shikimic and 4-epi-Shikimic Acids

retrosynthetic strategies as pointed out by Voglmeir.12 Namely, they are the following: from shikimic acid or other sixmembered rings; through a Diels−Alder cycloaddition with acrylic acid; by construction of cyclohexane ring via intramolecular metathesis, Horner−Wadsworth−Emmons reaction, or aldol condensation reactions; from nitroalkenes by Curtius rearrangement; or by Claisen rearrangement of D-glucal. In this section, only the reports on preparation of oseltamivir using shikimic acid as initial building block or as intermediate will be covered. Several excellent and comprehensive literature reviews on the synthesis of oseltamivir phosphate have been published.2,12,13,247−249 Preparation of oseltamivir was first described in the literature in 1997 (Scheme 74).250 After prior studies on the influenza

Scheme 69. Weerasuria et al.182 Synthesis of (−)-Methyl Shikimate Using Tricarbonyliron as a Lateral Control Group

directly.246The several synthetic routes for synthesis of oseltamivir currently available can be divided into five

Scheme 70. Weerasuria et al.182 Synthesis of (−)-Methyl Shikimate via Inversion of the Configuration

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Scheme 71. Gotor et al.183 Conversion of the Natural (−)-Shikimic Acid into Its C-3 Epimer

raphy and encompassed three isolated crystalline intermediates, was developed by Rohloff and co-workers (Scheme 75).252 The challenging introduction of the 3-pentyl ether group was accomplished by reductive opening of 3,4-pentylidene ketal 413 upon treatment with trimethylsilyl trifluoromethanesulfonate and BH3·Me2S to afford 414 as a mixture of ethers. Selective conversion of ether 414a into epoxide 415 was obtained after treatment with potassium bicarbonate in aqueous ethanol. The introduction of the trans C-4 and C-5 diamine groups was accomplished by epoxide ring opening with sodium azide and ammonium chloride followed by reductive aziridine ring closing promoted by trimethylphosphine, and aziridine ring opening with sodium azide. Aziridine 417 formation was also reported to be successfully promoted by triphenylphosphine, although removal of corresponding phosphine oxide proved to be more challenging. Crystallized oseltamivir phosphate was eventually obtained after N-acetylation, reduction of the azide with Raney nickel, and acidification with phosphoric acid, in 21% overall yield from (−)-shikimic acid. Faced with the demand for a larger scale production of oseltamivir phosphate, due to entering in phase II and phase III trials, Roche scientists developed a second-generation largescale synthesis of epoxide 415 (50−250 kg batches).246 In order to cope with the very different impurity profiles of shikimic acid which arise from the sources, the previously established method via pentylideneketal 413 was compared with another one that included preparation of acetonide 419 (Scheme 76). This last method allowed formation of solid compounds in higher yields that could be efficiently purified by crystallization, which contrasted with the oily molecules obtained in the pentylideneketal route although it was one step longer compared to the former route. To make the process more amenable for industrial scale, the reductive ketal opening originally performed with trimethylsilyl trifluoromethanesulfonate and BH3·Me2S was modified. The combination of triethylsilane and TiCl4 in dichloromethane allowed predominant formation of intermediate 414a that was further epoxidized to 415 under aqueous basic conditions. Control of reaction temperature at −34 °C was determined to be pivotal to achieve high regioselectivity and suppression of diol 414c. This synthetic route was recently improved by the formation of the pentylideneketal directly from ethyl shikimate, which employed triethyl orthoformate and 3pentanone for in situ formation of 3,3-diethoxypentane. The transketalization reaction followed by mesylation of hydroxyl group at C-3 afforded 413 in only three steps from shikimic acid.253,254 The several synthetic azide intermediates on the synthetic path demanded further inspection into the reactions used. Two different methods to eliminate the use of azides were further reported by two different teams at Roche.255,256 The industrial process was optimized to handle the azides, after safety tests (Scheme 77). Treatment of a mixture of azides 416a and 416b obtained upon epoxide 415 opening, with triphenylphosphine in the presence of triethylamine and methanesulfonic acid, allowed

neuraminidase inhibitory activity of zanamivir, and in order to develop a more bioavailable molecule, researchers at Gilead Sciences engaged in a rational drug design program that ultimately led to the preparation of several carbocyclic sialic acid analogues including oseltamivir. Despite the structural similarities of (−)-shikimic acid and the targeted molecule, a stereochemical inversion of trans C-4 and C-5 hydroxyl groups of the natural product into the trans C-4 and C-5 amino groups was required. In order to obviate this problem, (−)-shikimic acid methyl ester was transformed into epoxide 407 by a method previously established by Berchtold251 to selectively activate the C-5 hydroxyl group with triphenylphosphine and dimethyl azodicarboxylate. A series of two regio- and stereospecific nucleophilic attacks of azide, first to open the epoxide 407 and then to open the aziridine 409 formed upon reduction, resulted in formation of synthetic intermediate 410 with the desired tridimensional arrangement of the nitrogen atoms. The high selectivities observed for opening of the three membered ring intermediates is a consequence of the steric and electronegative inductive influence of the methoxymethyl (MOM) group. The trans amino alcohol 410 was then protected on the nitrogen with a trityl group and aziridine 411 formed upon mesylation of the hydroxyl group. Treatment of the aziridine with 3-pentanol in the presence of BF3·Et2O, followed by N-acetylation, reduction of the azide, and saponification delivered the carboxylic acid 412 derivative of oseltamivir. When confronted with the need for multikilogram preparation of oseltamivir, scientists at Gilead Sciences developed an alternative scale-up route to avoid the use of scarcely available shikimic acid. Starting from (−)-quinic acid, Kim and co-workers first prepared the acetone-derived acetonide, which after tosylation of the C-5 hydroxyl group and acetal cleavage, provided the unprotected precursor of epoxide 407.250 In an attempt to develop a method suitable for the multikilogram synthesis of oseltamivir, a 10-step synthesis from shikimic acid, which overcame the need for chromatog-

Scheme 72. Gotor et al.184 Conversion of the (−)-Methyl Shikimate into Its C-5 Epimer

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Scheme 73. Biosynthetic Pathway of Shikimic Acida

a

Abbreviations: PEP, phosphoenolpyruvate; E4P, erythrose-4-phosphate; DAHP, 3-deoxy-D-arabino-heptulosomate-7-phosphate; DHQ, 3dehydroquinic acid; S3P, shikimate-3-phosphate; EPSP, 5-enolpyruvylshikimate-3-phosphate. Enzymes encoding genes in E. coli are colored in blue.

the reaction temperature to remain below 60 °C. This minimized the aziridine 417 decomposition. Aziridine ring opening with sodium azide was achieved with the use of dimethyl sulfoxide as solvent in the presence of sulfuric acid at 35 °C. This again decreased the decomposition of the alkyl azide. N-Acetylation of the azide was achieved upon treatment with acetic anhydride in dibutylether. A final Staudinger type phosphine reduction was attained using tri-n-butylphosphine in an aqueous ethanolic solution,257 followed by crystal seeding with orthophosphoric acid in ethanol to induce crystallization of oseltamivir phosphate.258 The attempts to design a new synthetic route that would avoid the use of azides was first developed at Roche in Basel (Scheme 78). This protocol relied on the 415 epoxide ring opening with allyl amine catalyzed by MgBr2·OEt2, followed by Pd/Ccatalyzed deallylation to the amino alcohol 422. A cascade reaction that involved a domino sequence via a transient imino protection allowed the ingenious conversion of the aminoalcohol into the vicinal diamine 424. Selective acetylation of 424 followed by deallylation and acidification with phosphoric acid afforded crystalline oseltamivir phosphate. Introduction of ethanolamine into the reaction mixtures in both deallylation steps led to improved selectivity and reduced reaction times.255,259 Another synthetic route that overcomes the manipulation or use of azides was also developed by Harrington and co-workers in RocheColorado (Scheme 79).256 This high yielding multigram synthesis allowed the conversion of epoxide 415 into the desired oseltamivir phosphate in 61% overall yield in six

steps. Epoxide 415 ring opening was performed with a tertbutylamine-magnesium complex to give aminoalcohol 426, and transformed into aziridine upon mesylation of the hydroxyl group. Aziridine 427 ring opening was achieved by the use of benzenesulfonic acid and diallylamine, and after acetylation, the tert-butyl group of the alkylamine was cleaved with trifluoroacetic acid in a surprisingly highly efficient process. The deallylation process was achieved by allyl transfer to 1,3dimethylbarbituric acid (NDMBA) in ethanol in a palladiumcatalyzed process. Chemists at Roche continued to improve their synthesis of oseltamivir starting from shikimic acid, as this natural product became widely abundant.3 The RocheBasel group further developed an eight-step synthesis, which required only three workups and purifications (Scheme 80).3,260 This new process started from mesylation of ethyl shikimate followed by regioand stereoselective nucleophilic substitution of the O-mesylate at C-3. Treatment of 432 with triethyl phosphite gave a new aziridine intermediate 433. The initial strategy used by medicinal chemists at Gilead was used to introduce the 3-pentyl ether group in 434, by a reaction of aziridine 433 with 3pentanol in the presence of BF3·(OEt)2 Lewis acid. Nucleophilic substitution of the O-mesylate with azide introduced the vicinal nitrogen atom in 418, after N−P cleavage of 434 and acetylation of the primary amine. Staudinger reduction of the azide 418 followed by acidification with H3PO4 led to formation of the desired prodrug in 20% overall yield. This synthetic route was recently reviewed by Kalashnikov and co-workers, with slight improvements at the multigram scale.261 For instance, the 10493


10494

lack of PEP:carbohydrate phosphotransferase system; deletion of aroK and aroL; transformation with plasmids carrying aroGfbr, tktA, aroB, and aroE genes overexpression of ppsA inclusion of glf-encoded glucose facilitator inactivation of PTS and tktA overexpression overexpression of tktA insertion of aroB into serA locus and disruption of aroL and aroK

PB12.SA22

a

66 70 84 52 27.2

5.11 7.05

fructose glucose glucose glucose glucosed glucose glucose

6.54 6.79 3.50 7.00 5.10 3.58 1.48

1.85 1.07 0.47 0.22 5.33

glucose glucose gluconate glycerol xylose fructose glucose

glycerol glycerol maltose glucose glycerol

43.3

3.12

20.26 8.00 20.64 27.41 13.15 0.89 0.20 1.08

SA titer (g/L)

fed batch fed batch fed batch fed batch fed batch

− 0.33 0.15 0.17 0.19 − − − − − − − − −

− − − − − − − − 29 23 24 33 18 15

batch batch

− − − − −

− 43c 16c 9c −

batch batch batch batch batch batch batch

fed batch flask culture flask culture flask culture flask culture

1.44

42

batch

flask culture

−

33

fed batch fed batch fed batch fed batch fed batch flask culture flask culture flask culture

0.28 0.33 0.43 0.57 − − − −

− − − − − − 500).314 Mixtures of monopalmityloxy shikimic acids were obtained in 70% when reacted with shikimic acid with palmitic acid in tert10507


Chemical Reviews

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Table 5. Regioselective Enzymatic Acylation of Methyl Shikimate with Divinyl Esters

yield entry

n

enzyme

solvent

conv (%)

518

519

1 2 3 4 5

6 6 6 6 6

CAL-B CAL-B MML MML MML

acetone acetonitrile THF acetone dioxane

88.7 55.4 79.1 82.4 75.9

8 2.3 71.4 76.1 69.7

74.9 45.2 3.2 5.4 1.7

Scheme 102. Cyclic Sulfite Intermediated Epoxy Shikimate Synthesis from Methyl Shikimate

Scheme 103. Epoxy Shikimate Synthesis from Cyclic Sulfite Intermediate

tetramethoxybutane (TMB) in the presence of camphorsulfonic acid (Scheme 104).325 TMB can also be prepared in situ by a reaction of trimethylorthoformate with butane-2,3-dione.183 Higher temperatures and longer reaction times were identified to be determinant for the reaction selectivity, as protection of the cis hydroxyl groups arises as a side reaction. When the protection reaction was run in refluxing methanol, short reaction times led

intermediate 526 that ring closes to epoxide 275 in the presence of base. The allyl hydroxyl group of diol 525 can be selectively benzoylated yielding 527, prone for mesylation and epoxide ring closure upon cleavage of the esters under earlier mentioned basic conditions.324 The trans-4,5-diol unit can be protected in the form of 1,2diacetal, upon reaction of a shikimate ester with 2,2,3,310508


Chemical Reviews

Review

Scheme 104. trans Vicinal Diol Protection of Methyl Shikimate

Scheme 105. Dirhodium(II) Catalyzed O−H insertion of Epoxy Shikimate

Scheme 106. Synthesis of Shikimate 3-Phosphate

Scheme 107. Synthesis of (−)-5-Enolpyruvylshikimic Acid

85 °C with catalytic amounts of CSA, 35 can be obtained in 80% isolated yield after 9 h.183

mainly to formation of 530 that isomerizes to 35 upon longer reaction times.325 Alternatively, in a reaction in a sealed tube at 10509


Chemical Reviews

Review

Scheme 108. Dirhodium(II) Catalyzed O−H Insertion of Ketal Shikimate

Scheme 109. O-Alkylation of Shikimate Derivatives with Methyl Pyruvates

4.2.5. Transformations at Hydroxyl Groups. Dirhodium(II)-catalyzed OH insertion of shikimic acid derivative 529 was used in the preparation of phosphonate analogue of chorismic acid 532 (Scheme 105). Reaction of epoxide 529 with tetramethyl methylenediphosphonate in the presence of dirhodium(II) tetraoctanoate in a very slow process leads to isolation of ether 531 in only 40% yield after 4 days in refluxing benzene. The epoxide moiety remained intact despite the long reaction times, and no dimerization of the diazo compound or cyclopropanation was observed when using model substrate 2cyclohexenol.326 Introduction of phosphate group in the C-3 hydroxyl position of shikimic acid was achieved in 32% overall yield after a series of OH protection and deprotection reactions (Scheme 106). Cleavage of acetonide 68 and reaction with dibutyltin oxide formed O-stannylene acetal 533.This was further reacted with dimethoxytrityl chloride to yield 534, selectively protected in the C-3 hydroxyl group. Acetylation of C-4 hydroxyl and removal of dimethoxytrityl provided alcohol 535 prone for phosphorylation and oxidation with m-CPBA to give phosphonate 536, which was then transformed into the desired product 537.320 A more straightforward method was later reported by Wu, with the use of 2,2,3,3-tetramethoxybutane as the protecting agent of methyl shikimate; phosphorylation of the C-3 position of 35 followed by oxidation, debenzylation, and deprotection afforded the

shikimate-3-phosphate 537 in 42% overall yield after three steps.325 The introduction of enolpyruvyl moiety in the C-5 hydroxyl position was reported by McGowan and Berchtold in their synthesis of (−)-5-enolpyruvylshikimic acid 542 (Scheme 107).120 Initial protection of the vicinal cis diol functionality was accomplished by a reaction of methyl shikimate with carbonyldiimidazole into a carbonate. Reaction of carbonate 538 with dimethyl oxomalonate followed by nucleophilic substitution of the hydroxyl by chlorine and reduction with zinc in acetic acid resulted in formation of diester 539. Alkylation of the α-dicarbonyl position with Mannich base resulted in formation of tertiary amine 540, further quaternized with methyl iodide and fragmented in DMSO to afford 541. Final basic hydrolysis and acidification yielded (−)-5-enolpyruvylshikimic acid 542. 5-Enolpyruvylshikimate 3-phosphate (EPSP) and its analogues have been synthesized starting from modification of the C-5 hydroxyl group of ketal shikimate 206 (Scheme 108). Dimethyl diazomalonate327 and methyl(dibenzylphosphono)diazoacetate328 can undergo a dirhodium(II) catalyzed O−H insertion with the free hydroxyl group of 206 to afford the corresponding ethers in reasonable yields. Further removal of the acetonide group and phosphorylation of intermediate 10510


Chemical Reviews

Review

Scheme 110. O-Benzylation of Shikimate Acetonide

Scheme 111. Synthesis of Conformationally Restricted Shikimic Acid Derivatives

lactones led to formation of EPSP from 543 and EPSP synthase inhibitor 545 from 544. Other analogues of EPSP have been obtained starting from reaction of ketal shikimate 206 or orthoester 546 with methyl pyruvates to yield hemiketal 547 (Scheme 109), prone for reaction with PCl3, 2-(p-nitrophenyl) ethanol, and oxidation with m-CPBA of the phosphite to phosphate 548 in one pot. Despite the success of this methodology when trifluoro-, difluoro-,329 and dibromopyruvates330 were used, reaction with methyl fluoropyruvate proved unsuccessful. O-Benzylation of shikimic acid at the C-5 hydroxyl group has been recently reported on preparation of shikimate kinase inhibitors (Scheme 110).331 Alkylation of acetonide protected shikimic ester 206 gave modest yields with several benzyl bromide derivatives in the presence of sodium iodide and diisopropylethylamine at 150 °C. After removal of the ketal protecting group, several carboxylic acids or its sodium salts 551

were obtained upon hydrolysis of the methyl ester. Sequential Mitsunobu and Staudinger reactions and hydrolysis of the ester led to the conversion of the intermediate ether 550 into amine 553. Conformationally restricted shikimic acid derivatives that contain an ether bridge from the oxygen at C-5 were prepared332 starting from the previously reported enone 33, which in turn can be prepared from quinic acid (Scheme 111).104 Formation of the ether bridge key step was accomplished by ring-closing metathesis of triene 556 in 80% yield with the use of a secondgeneration Grubbs catalyst. Diasteroselective addition of ethynyl magnesium bromide to the enone, followed by partial reduction to the olefin 555, was achieved in only moderate yields. Suprisingly, the introduction of the acetonide protecting group in 554 was reported to proceed in a yield as low as 48%. Introduction of the allyl moiety was accomplished by reaction of the alcohol 555 with allyl methyl carbonate catalyzed by 10511


Chemical Reviews

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Scheme 112. Epoxidation of Methyl Shikimate by Ring Closure of 3-Bromo Methyl Shikimate

Scheme 113. Split-Pool Synthesis of Compounds Reminiscent of Natural Products

Pd2(dba)3/dppb, which provided the skeleton needed for the ring-closing step. The ether formed was also chemoselectively hydrogenated to the cyclic ether 559 in the presence of Lindlar catalyst. Final deprotection and hydrolysis of the esters afforded carboxylic acids 558 and 560. 4.2.6. Epoxidation by Ring Closure. Methyl shikimate reacts with triphenylphosphine/diethyl azodicarboxylate to provide epoxide 276 in 77% isolated yield, after selective activation of the C-5 hydroxyl group.251 This method was later used in the first reported preparation of oseltamivir (Scheme 74).250 This provided a way to introduce an amine functionality at C-5 by reaction with sodium azide followed by hydrogenation that allowed the building up of a glyphosate unit.333 Wood and Ganem reported the preparation of 3,4-epoxyol 142 and its equilibration to epoxyol 529 by Payne rearrangement (Scheme 112).334 Epoxy-shikimates 142 and 529 were prepared by an initial reaction with trans-bromoacetate 561, derived from reaction of methyl shikimate with 2-acetoxyisobutyryl bromide, with sodium methoxide. Epoxy-shikimate 142 was obtained quantitatively, although when in the presence of sodium methoxide equilibration to a mixture of 142:529 in a 1:3 ratio was observed. Further optimization of the reaction conditions to increased temperatures allowed preparation of epoxide 529 in 46% yield. When bromoacetate 561 was treated with DBU, an acyl migration followed by cyclization led to formation of acetylated analogue of epoxy-shikimate 142. The use of the above-mentioned methods for preparation of both enantiomers of epoxycyclohexenol 529 and 524, with further hydrolysis to the corresponding carboxylic acids 562 and

563, led to development of a remarkable split-pool synthesis of complex small molecules by Schreiber and co-workers.335,336 A library of over 2 million compounds reminiscent of natural products and compatible with miniaturized assays was achieved (Scheme 113). Both enantiomers of epoxycyclohexanol were first attached to a photocleavable linker on solid support, having ω-aminocaproic acid and glycine as spacers or without any spacer. The resin-bound epoxycyclohexenol 564 was treated with several nitrone carboxylic acids 565 in the presence of PyBroP, DIPEA, and DMAP to generate the highly functionalized tetracycle 566 with complete regio- and stereoselectivities via tandem acylation/1,3-dipolar cycloaddition. The rigid, densely functionalized tetracycles could undergo Sonogashira/ Castro−Stephens cross-coupling by the iodoaryl groups, nucleophilic lactone and epoxide opening, and reductive N−O bond cleavage. After preliminary assessment of several synthetic transformations regarding the purity of the compounds obtained, the authors optimized a sequence of palladium catalyzed cross-coupling with alkynes, followed by lactone aminolysis and esterification. The use of three libraries of building blocks (50 alkynes, 87 amines, and 98 carboxylic acids), together with six resin-bound epoxycyclohexenols with different spacers and three nitrone carboxylic acids, resulted in a collection of compounds calculated to contain an astonishing amount of 2.18 million chemical entities. Recently, the epoxycyclohexanol 570 was attached to a solid support and further reacted with iodophenol derivatives 572 by a Mitsunobu reaction (Scheme 114).337,338 The solid phase supported epoxides 573 were then reacted with amines by a 10512


Chemical Reviews

Review

Scheme 114. Shikimic Acid Based Library Synthesis

methyl esters 582, 585, and 589 furnished the corresponding carboxylic acids or its sodium salts in over 90% yields. 4.2.7. Halogenation of Shikimic Acid. The introduction of halogens such as bromine in shikimic acid has been extensively used as a way to prepare synthetic intermediates for further use, and for preparation of halogenated mimetics of shikimic acid as in the case of fluorinated analogues. Dibromination of methyl shikimate’s double bond can be achieved by the classical methods,75 which leads to formation of 2-bromoquinic acid upon treatment with water or the lactone after heating. On the other hand, when treated with Ba(OH)2, 2bromoquinic acid leads to formation of 1,2-epoxyshikimic acid.340 Introduction of halides in the C-2 position of shikimic acid derivatives that retains the unsaturation of the cyclohexene skeleton demands indirect methods, resulting in multistep synthetic routes. Bartlett and co-workers reported the stereoselective preparation of (−)-2-chloro-341 and (−)-2-fluoroshikimic acids.342 Introduction of chlorine in shikimic acid core (Scheme 116) was achieved by the transformation of the olefin into the C-2 sulfide 590 by Michael addition of pmethoxybenzenethiol in the presence of catalytic amounts of lithium thiolate. Further reaction of the diastereomeric mixture of sulfides 590 with thionyl chloride and oxidation of the chlorine derivative with MCPBA led to formation of the sulfoxide 591. This underwent elimination in refluxing toluene, to afford the triacetylated chloro derivative of shikimic acid 592

Lewis acid catalyzed epoxide ring opening and further acylated. Survey of the reaction conditions identified the use of 20 equiv of amine and 1.1 equiv of MgBr2·OEt2 in acetonitrile as the best conditions regarding selectivity toward epoxide ring opening products 574. The installation of the aryl iodide allowed the intramolecular Heck reaction that provided tricyclic products 578 after resin cleavage with HF·pyridine followed by treatment with ethoxytriethylsilane. Among several palladium sources tested for the Heck cyclization, palladium acetate together with 1,2-(dicyclohexylphosphine)ethane (dcpe) led to the best outcome when the reaction was run in dioxane at 80 °C for 24 h. The addition of tetrabutylammonium acetate allowed cleaner reaction mixtures after 12 h at lower temperatures. In order to develop selective shikimic acid mimetics for inhibition of shikimate kinase, González-Bello and co-workers explored the preparation of shikimic acid derivatives decorated with different nitrogen moieties at C-5 (Scheme 115). Opening of epoxide 276 with sodium azide under acidic conditions was achieved regioselectively to provide the azide 581 which could be transformed into 4-substituted triazole derivatives 582 in good yields.331 Transformation of the azide by Staudinger reaction into the primary amine 584, allowed for double alkylation with several alkyl bromides on the nitrogen, in low yields (23−32%). Preparation of secondary amines 585 via reductive amination was achieved after protection of the vicinal diol moiety and reduction of the azide.339 Hydrolysis of the 10513


Chemical Reviews

Review

Scheme 115. Preparation of Shikimic Acid Derived Amines

Scheme 116. Synthesis of (−)-2-Chloroshikimic Acid

conditions.342 A different strategy based on introduction of a keto group in the C-2 position of shikimic acid, prone for reaction with (diethylamino) sulfur trifluoride (DAST), was considered (Scheme 117). However, the highly enolic nature of the β-keto ester prevented the desired reaction, and reduction of

that was readily hydrolyzed to afford the desired (−)-2chloroshikimic acid 593.341 To adapt the above-mentioned process to the preparation of (−)-2-fluoroshikimic acid, fluorination of sulfide 590 resulted in formation of elimination products due to the harsh reaction 10514


Chemical Reviews

Review

Scheme 117. Synthesis of (−)-2-Fluoroshikimic Acid

Scheme 118. C3 Halogenation of Shikimic Acid Derivatives with N-Halosuccinimides

Scheme 119. Preparation of 3-Fluoroshikimic Acid

was easily achieved by acid hydrolysis, removal of the methylene acetal required prolonged heating. Bromination and chlorination of the C-3 position of shikimic acid was achieved via protected shikimate 602 through a radical process with corresponding N-halosuccinimides (Scheme 118).76,319,343 Bromination reaction with molecular bromine

the carboxylate functionality was needed to achieve efficient reaction with the DAST fluorinating agent. Fluorination of intermediate 597 led to a mixture of mono- and difluorinated compounds. After separation and deprotection of the primary hydroxyl group, oxidation gave the vinyl fluoride 598 with further oxidation to 599. While methoxymethyl ether removal 10515


Chemical Reviews

Review

Scheme 120. Synthesis of 5-Deoxyshikimate

Scheme 121. Synthesis of (6S)-6-Fluoroshikimic Acid

resulted in formation of C-3 fluorinated shikimic acids 608 in 96% as a 1:18 mixture of epimers.322,343 Introduction of bromine in the C-5 position of shikimic acid has been used as a way to deoxygenate the C-5 position by reduction of the halide diol with tri-n-butyltin hydride (Scheme 120). Reaction of 4,5-epoxyshikimate 276 with dilithiotetrabromonickelate rendered halogenated diol 609 that was transformed to a ketal prior to reduction of the halide. Reaction of epoxyshikimate 276 with sodium azide followed by hydrogenation provided a method for installation of a primary amine in the C-5 position of methyl shikimate.344 Antibacterial 6-fluoroshikimic acid has been prepared starting from shikimic acid, upon dehydration to form diene 110 (Scheme 121). While elimination of triflate with cesium acetate in DMF allowed for formation of unsaturated product 110 in 81% yield after 2 h, the mesylate analogue did not eliminate under the same reaction conditions. Harsher elimination reaction conditions of both sulfonates, such as increased temperatures, resulted in formation of methyl 3-hydroxybenzoate. Treatment of diene 110 with osmium tetroxide and Nmethylmorpholine N-oxide resulted in its nonregioselective dihydroxylation to afford a mixture of 1:1 isomeric diols 613 and 614. Fluorination at the C-6 position with stereogenic inversion was achieved by C5 hydroxyl protection with silyl ether and efficient reaction of 615 with DAST. Removal of the protecting group and ester hydrolysis afforded the desired (6S)-6fluoroshikimic acid 617.345,346 4.2.8. Shikimic Acid Ring Opening. Although the cyclic skeleton of shikimic acid is mostly used in preparation of cyclohexane derivatives, ring opening can be a useful strategy in the preparation of enantiomerically pure acyclic compounds or in the construction of other cyclic derivatives. For instance, the allyl alcohol 469 formed by reduction of shikimate esters can

leads to formation of desired product 603a, but in low selectivity due to formation of products derived from benzoyl migration or epoxide ring closure. Introduction of bromine via slower bromination with N-bromosuccinimide resulted in formation of product 603a in 62% yield after 24 h reflux. Use of radical initiators such as AIBN or dibenzoyl peroxide did not increase the reaction rate. The bromination of the acetylated derivative 602 under reflux resulted in formation of 603b as a mixture of C3 epimers due to a triple inversion mechanism, which was overcome when the reaction was run at room temperature for longer times. Reaction of 603a with sodium azide in warm methanol delivered a mixture of isomeric azides that, after controlled removal of benzoyl protecting group, were reduced via Staudinger reaction, which completed the first reported synthesis of 3-aminoshikimic acid.76 Attempts to introduce the nitrogen functionality by reaction of the allyl bromides 603 with amines resulted in formation of aromatic products.76 Despite the success of the chlorination reaction of 602, attempts to remove the benzoyl group of 604 resulted in formation of decomposition products due to the high reactivity of the allylic chlorine. An alternative method for preparation of 3chloroshikimic acid, although in low yields due to formation of aromatized products, was achieved via epoxide cleavage of epoxyol 142. The epoxide cleavage with hydrochloric acid at 60−70 °C occurred in low yields that lead to formation of the desired chlorinated compound in 13% together with 12% of the 3,4-epoxyshikimic acid.343 The above-mentioned epoxide ring opening with halogens was used in the preparation of C-3 fluorinated derivatives of shikimic acid (Scheme 119). Treatment of the benzoylated epoxide 605 with Olah’s reagent (polyhydrogen fluoride in pyridine) at 0 °C yielded a mixture of both C-3 epimers 606 and vicinal diol 607. Acidic hydrolysis of the mixture of diesters 606 10516


Chemical Reviews

Review

Scheme 122. Preparation of Azepane-3,4,5-triol through Ozonolysis of a Shikimic Acid Derivative

Scheme 123. Lemieux−Johnson Oxidative Cleavage of Shikimic Acid Derivatives

Scheme 124. Conjugate Addition of Thiophenate to Shikimic Ester

several shikimate ester derivatives 621, decorated with various protecting groups in the hydroxyl, as well as in the oxidation of several allyl alcohols 623 derived from shikimate esters. A similar reactivity toward ring opening with this method was observed for shikimic acid derivatives protected in the form of 1,2-diacetal as well as in the ozonide form (protection of C-3 and C-4 hydroxyls).348 4.2.9. Conjugate Addition. The C-2 position of shikimic acid can be modified through conjugate addition of nucleophiles to the α,β-unsaturated carbonyl moiety. This approach has been explored in several reports through use of sulfides as nucleophiles, for instance, in the introduction of halides in the C-2 position (Scheme 116) or in the construction of glycomimetic libraries starting from amides (Scheme 90). Campbell, Sainsbury, and co-workers have demonstrated that Michael addition of sodium thiophenate to acetonide protected

undergo ozonolysis to reveal 1,6-dicarbonyl derivatives. Such a strategy was explored in the preparation of azepanes (Scheme 122), in which the dicarbonyl compound was used in a double reductive amination.347 Selective formation of the azepane single diastereoisomer 619 was achieved upon protection of the primary and secondary hydroxyl groups of the allyl alcohol with bulky TBDMS. Despite the high yields observed for the ozonolysis step of the allyl alcohol 469, the aldehyde was obtained as a mixture with the cyclized furanose derivates. The double reductive amination step also resulted in a mixture of azepane diastereomers. Alternatively, the alkene functionality of shikimic acid derivatives can undergo a Lemieux−Johnson oxidation, with the use of K2OsO4·2H2O and NaIO4 in a CH2Cl2/tert-butanol/ water (1:2:2) mixture at room temperature (Scheme 123). This procedure was exemplified in the oxidative ring opening of 10517


Chemical Reviews

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Scheme 125. Conjugate Addition of Nitromethane to a Shikimic Ester Derivative

Scheme 126. Frost et al.351 Dehydration of Shikimic Acid

shikimic ester 109 occurred slowly at room temperature to afford a 2:1 mixture of C-1 epimers of hydroxysulfides 625 in 73% yield after 18 h reaction. Extension of reaction times led to formation of the corresponding lactone 626 (Scheme 124).349 The conjugate addition of nitromethane to shikimic ester derivatives has been recently explored as a way to introduce a γamino functionality in the shikimic core (Scheme 125).350 Protection of the hydroxyl group with TBS was used in order to avoid the formation of the lactone species formed upon conjugate addition of nitromethane to shikimate 206. Despite the poor diastereoselectivity observed in the addition of nitromethane to silyl ether 332, formation of single transdiastereoisomer was observed with treatment of 206 with nitromethane in TBAF solution in THF. The first peptide coupling step was performed after conversion of the methyl ester 627a to the perfluororophenyl ester 628. Other coupling agents tested (EDCI, TBTU, HATU, and PyBOP) promoted the retroMichael reaction with carboxylic acid. The reduction of the nitro group after hydrolysis of 627a led to considerable formation of the corresponding lactam, even in the presence of Boc2O. The desired shikimic acid based 2-aminocyclohexanecarboxylic acids were obtained after hydrogenation of the nitro group and further coupling with the activated glycine methyl ester hydrochloride in similar yields starting from either nitro derivatives 627.

Formic acid mediated dehydration of quinic and shikimic acids to benzoic acid 635 was reported.352 In order for shikimic acid to be soluble in a reaction media, the solvent must be high boiling, chemically and thermally stable with high polarity. Thus, sulfolane 634 was a suitable reaction media. Under the optimized conditions, the dehydration of shikimic acid furnished 635 in 89% yield (Scheme 127). However, similar yield of 92% could be achieved from the more readily available quinic acid. The ability of the, readily available from natural (−)-shikimic acid, methyl 3-dehydroshikimate 497 to aromatize in the presence of amines has been reported in several instances. Gorrichon and co-workers353 were the first to report the formation of arylamines by reaction of 497 with methyl glycinate. More recently, the Zou group further explored the utility of this transformation and reported that, in the presence of p-toluenesulfonic acid as catalyst, primary arylamines could be efficiently condensed with 497 to yield secondary arylamines 636 (Scheme 128). Electron-rich arylamines were better partners than electron-poor ones, although the process seems somewhat sensitive to sterically hindered amines. Interestingly,

4.3. Use as Biorenewable Material

The production of aromatic hydrocarbons, which are among the most important raw materials in the chemical industry, is based largely on fossil resources. In several instances, shikimic acid served as an alternative source and was used in the production of biorenewable aromatic compounds. In 2001 Frost et al.351 reported the synthesis of phenol 631 by dehydration of natural (−)-shikimic acid. Under acid catalysis in refluxing aqueous HCl, only m-hydroxybenzoic acid 632 and phydroxybenzoic acid 633 were formed in yields of 13 and 40%, respectively. The formation of phenol as predominant product in 53% yield was achieved only under near critical water conditions at 350 °C. However, the formation of side products 632 and 633, although in low yields, was also observed (Scheme 126). 10518


Chemical Reviews

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carboxylic acids 639 or 642 under microwave (MW) irradiation in the presence of CuO2 afforded triarylamine derivatives 640 and 643. Intramolecular lactonization of 640 and 643 with bis(trichloromethyl)carbonate (BTC) furnished seven- or eight-membered-ring lactones 641 and 645, respectively. BF3· Et2O promoted intramolecular acylation furnished six- or sevenmembered-ring ketones 648 and 649. The aromatization of methyl 3-dehydroshikimate upon reaction with arylamines was utilized by the Zou group for the preparation of N-substituted dihydrobenzoxazines 650356 and N-aryl-1,4-benzoxazin-3-ones 651.308 This synthesis involves one-pot aromatization under microwave irradiation followed by addition of vicinal dihalides or α-chloro esters (Scheme 132). The presence of an electron-donating substituent in the arylamine was beneficial for the reactions outcome. Albeit, moderate yields were obtained upon the use of deactivated anilines. Interestingly, the 2-aminophenol intermediate 636 was determined to be O-alkylated prior to amine nucleophilic attack on the vicinal dihalide. Nonvicinal dihalides such as 1,3dichloropropane failed to provide the desired products. Under the same conditions, the cyclization with 1,2dichloropropane resulted in the formation of two regioisomers 653 and 654 in moderate to very good yields and regioselectivity that ranged from 0.9 to 1.5 molar ratio.356 However, predominant formation of regioisomer 654 was mostly observed. Both electron-rich and electron-poor aryl amines were applicable to this transformation (Scheme 133). Knoevenagel condensation and aromatization of methyl 3dehydroshikimate 497 with malononitrile in water under microwave irradiation produced 2-amino-3-cyanobenzofurans, which were mono or bis N-alkylated upon in situ addition of bromoalkanes (Scheme 134). This transformation features broad substrate scope; however, sterically hindered cycloalkyl bromides failed to provide the desired products.357 The intensive research on this subject by the Zou group recently led to a shikimic acid based strategy for the synthesis of EGFR tyrosine kinase inhibitors.358 In this work, the highly reactive intermediate 658 was obtained from the previously reported methyl 2-amino-3-cyanobenzofuran-5-carboxylate 657357 and triethyl orthoformate. The treatment of 658 with primary arylamines furnished N-substituted benzofuro[2,3d]pyrimidine-4-amines 659 (Scheme 135). The electronic

Scheme 127. Formic Acid Mediated Conversion of Shikimic to Benzoic Acid

the condensation with alkylamines led to the formation of 3,4dihydroxy-5-alkylamine 637.307 Additionally, the primary alkylamines were more efficient in the acceleration of the aromatization; thus the reactions were carried out at ambient temperature in DCM. However, the products were obtained in only moderate to good yields. Contrary to primary alkyl and aryl amines, the secondary ones did not provide the desired products, which indicates that the primary amine moiety is essential for the aromatization process. The formation of different products that arise from primary alkylamines vs arylamines was attributed to be probably due to an oxidation process that only took place during the condensation with the former (Scheme 129). In one instance, the condensation of aniline and 497 was carried out in the presence of Cu(OAc)2 (Scheme 130). The reaction afforded 3,4-dihydroxy-5-anilinebenzoate derivative 638, which indicates that the presence of an oxidant (including oxygen distributed in the reaction mixture) is responsible for the different outcome. In another work, the same group reported the use of α-amino esters hydrochlorides354 as partners (Scheme 128). In this case, no oxidation took place; thus only secondary arylamines 638 were obtained in very good yields. The reaction tolerates the presence of other functional groups, such as additional esters, thioethers, and alcohols. The use of microwave heating significantly shortened the reaction time compared to conventional heating; however, the yield was not determined.354 More recently, the Zou group described the synthesis of novel six-, seven-, or eight-membered benzo-fused N-heterocycles from the previously reported N-aryl 2-aminophenols 636 (Scheme 131).355 N-Arylation with halogenated aromatic

Scheme 128. Secondary Aryl Amines from Methyl 3-Dehydroshikimate

10519


Chemical Reviews

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Scheme 129. Plausible Mechanisms for the Reaction of 497 with Primary Aryl or Alkyl Amines

properties of the arylamines did not significantly affect the formation of 659, and generally, good to excellent yields were achieved. Primary aliphatic amines were also compatible with this transformation. However, secondary aryl and alkyl amines failed to afford the corresponding products.

Scheme 130. Reaction of Aniline and 497 in the Presence of Cu(OAc)2 as an External Oxidant

4.4. Use in Total Synthesis

In order to understand the stereochemistry of the reaction catalyzed by homocitrate synthase and by the protein from the nif V gene, isotopically labeled trimethyl homocitrates and Scheme 131. Synthesis of Six- to Eight-Membered, Benzo-Fused N-Heterocycles355

10520


Chemical Reviews

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Scheme 132. Two-Step, One-Pot Reaction of Methyl 3-Dehydroshikimate and Arylamines with Bifunctional Reagents

Scheme 133. Synthesis of N-Aryl-3,4-dihydro-2H-1,4-benzoxazines with 1,2-Dichloropropane as Bifunctional Substrate

Scheme 134. 2-(Alkylamino)-3-cyanobenzofurans from Methyl 3-Dehydroshikimate

in turn obtained from D-mannose via labeled protected lyxofuranoside derivative 668 (Scheme 137). The synthesis of quinic acid from shikimic acid has been reported in the literature in several instances. The first report was a synthesis via a dibromo derivative by Grewe and Lorenzen75 and reviewed by Bohm some years later.5 In order to prepare isotopically labeled [14C]quinic acid, Tamm developed a synthetic route to be applied on modification of commercially available [14C]shikimic acid (Scheme 138).323 The 5-OH group of shikimate ester was protected in the form of silyl ether and the allyl hydroxyl group in 112 was used to orient the Sharpless epoxidation with high stereoselectivity. A reaction of the epoxide formed with sodium thiophenolate opened the epoxide, which provided the thioether 670 in 84% yield, despite formation of lactones derived from migration of the silyl group to hydroxyl groups in C-3 and C-4. Removal of the phenylthio group by reduction with Raney Ni and H2, followed by protecting group removal, resulted in formation of quinic acid in

homocitric lactones were prepared from shikimic acid and its (−)-[2-2H] derivative (Scheme 136).359,360 Ketal protected shikimate ester 206 acid was first deoxygenated at C-5 through a Barton−McCombie deoxygenation to yield 610. Upon ketal deprotection, the allyl and homoallyl hydroxyl groups were shown to be suitable for direct Sharpless epoxidation of the double bond from the lower face of the molecule. After protection of the glycol functionality, the epoxide 663 was opened with lithium aluminum deuteride, which also resulted in the intended reduction of the carboxylic ester. Since an isotope effect hampered further oxidation of the deuterated primary alcohol, the carboxylic ester in 662 was reduced with NaBH4 prior to epoxide opening with deuteride. Oxidation of the primary alcohol followed by ketal removal afforded 665, which underwent glycol oxidative cleavage to yield a mixture of the methylated esters 666a and 667a upon reaction with methanol and Amberlite-120 (H+). Epimers of 666a and 667a were prepared from (−)-[2-2H]shikimate derivative 206b, which was 10521


Chemical Reviews

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Scheme 135. Synthesis of N-Substituted Benzofuro[2,3-d]pyrimidine-4-amines

Scheme 136. Total Synthesis of Trimethyl (2S,3R)-[2-2H1]Homocitrate and Dimethyl (2S,3R)-[2-2H1]Homocitric Lactone

21−25% overall yield from shikimic acid. The attempted opening of the epoxide after silylation of C-3 and C-5 hydroxyl groups resulted in opposite regioselectivity, with attack of the thiophenolate ion at C-1 instead of C-2. A higher yielding synthesis of quinic acid from shikimic acid was recently reported by Shi and co-workers (Scheme 139).361 The use of N-bromosuccinimide through a cascade benzylic oxidation and allylic bromination led to the conversion of the 3OH group of shikimic acid derivative 672 into the bromine derivative 673. The 5-OH acetylated derivative underwent ruthenium-catalyzed dihydroxylation to afford exclusively diol 678. According to the authors, the stereospecificity of the dihydroxylation step was a consequence of the bromine bulkiness at the C-3 position. Treatment of the bromine derivative 678 with base furnished epoxide 679 and further

transformed into iodine derivative 680, as a mixture of separable regioisomers. Chelation of the phosphine to C-1 hydroxyl and epoxide’s oxygen favored an iodide nucleophilic attack at the axial position at C-2, which accounts for the regioselectivity of the transformation. Iodine removal upon catalytic hydrogenation, followed by protecting groups removal, resulted in formation of quinic acid in 38% overall yield after 10 steps. Both enantiomers of zeylenone have been synthesized from (−)-shikimic acid (Scheme 140). While the nonnatural (+)-zeylenone could be prepared directly from the shikimic acid skeleton,362,363 the natural enantiomer (−)-zeylenone required the inversion of the C-3 stereogenic center through a Mitsunobu reaction.364 The introduction of the cis vicinal diol at C-1 and C-2 was achieved through stereoselective dihydroxylation of 682 and 689 with OsO4 to yield the protected polyols 10522


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(Scheme 143).367 The nucleophilic substitution at C-5 by azide was observed to occur either with or without inversion, depending on the reaction conditions employed. While a typical SN2 reaction was observed toward 700 with 2.0 equiv of sodium azide in the presence of 0.5 equiv of acetic acid in DMSO, the use of refluxing ethanol in the absence of acid led to formation of the organic azide 701 with retention of configuration. This aspect was rationalized by the possibility for the 4-OH to assist the mesylate extrusion through epoxide 702 formation when in basic medium, followed by azide nucleophilic attack at C-5. L-α-Phosphatidyl-D-myo-inositol 4,5-biphosphate 711, a minor constituent of membrane phospholipids, and its 3,4,5triphosphate analogue 712 were synthesized from 3-dehydroshikimic acid (Scheme 144). The stereoselective reduction of the ketone in preparation of 38 was achieved with lithium tritert-butoxyaluminohydride, which contrasted with the poor selectivities observed with sodium borohydride. The double bond of the fully protected triol was then dihydoxylated exclusively from the less hindered face to afford 703. The exclusive etherification of the secondary hydroxyl group allowed the one-pot degradation of the α-hydroxy ester through sequential reduction of the ester and glycol oxidative cleavage with periodate. Ketone 704 was transformed into the rather stable epoxide 705, which could be rearranged in situ to another ketone to pursue the synthesis of triphosphate 712 after nine synthetic high-yielding steps.368 The formation of epoxide 705 was achieved through oxidation of the silyl enol ether with MCPBA or dimethyldioxirane. Further rearrangement of the epoxide to a ketone underwent stereoselective reduction with sodium borohydride to yield 706, with hydride delivery at the less hindered face, assisted by the vicinal hydroxyl group. Sequential protection and deprotection of the alcohol functional groups, followed by phosphorylation with different phosphoramidites and phosphorus oxidation provided several glyceryl ether analogues of L-α-phosphatidyl-D-myo-inositol phosphates 711.369 The antipode of the naturally occurring herbicide MK7607 was synthesized from shikimic acid321 (Scheme 145), and only later, the naturally occurring (+)-MK7607 enantiomer was prepared for the first time, starting from galactose.370 The key step in the total synthesis of (−)-MK7607 was the OsO4catalyzed dihydroxylation of the diene 110, as shown in Scheme 121. Protection of the isolated diol 613 followed by reduction of the ester to the primary alcohol and removal of the protection groups furnished the desired herbicide. Despite the bottleneck of the synthesis in the dihydroxylation step, the authors reported

Scheme 137. Total Synthesis of Trimethyl (2R,3R)[2-2H1]Homocitrate and Dimethyl (2R,3R)[2-2H1]Homocitric Lactone

with the desired stereochemistry. The removal of the trans vicinal diol groups at C-4 and C-5 was achieved through conversion into the olefin with triphenylphosphine, iodine, and imidazole. Despite the excellent yields in every other steps, the allylic oxidation with selenium oxide was the bottleneck of the described routes, which led to the enone 687 formation in only up to 40% yield. C7N aminocyclitols such as (+)-valiolamine and (+)-valienamine are known to be strong inhibitors of glucosidases and structural components of several active pharmaceutical ingredients. Their total syntheses from shikimic acid have been reported by Shi and co-workers as well as the synthesis of (−)-1epi-valiolamine.365−367 The seminal 12-step synthesis of (+)-valiolamine from shikimic acid367 was refined by the same group365 in order to improve its practicality regarding the reactants. This resulted in an increase of the overall yield from 35 to 40% with the same number of steps. The new synthesis (Scheme 141) consisted of (i) inversion of the C-3 stereogenic center, (ii) stereoselective dihydroxylation of the alkene 693, and (iii) regioselective reduction of the C-1 carboxylic ester 694 with NaBH4 upon boron complexation with the tertiary alcohol, followed by (iv) introduction of the nitrogen at C-5 through organic azide intermediate 697. Faced with a chemoselective acetylation of the primary and hydroxyl groups of 695, the tertiary alcohol functionality of 696 was dehydrated with thionyl chloride, to afford alkene 698 prone for usage in the total synthesis of (+)-valienamine (Scheme 142). Shikimate ester derivative 693 was shown to serve as a precursor of both (+)-valiolamine and (−)-1-epi-valiolamine Scheme 138. Tamm’s Quinic Acid Synthesis from Shikimic Acid

10523


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Scheme 139. Shi’s361 Quinic Acid Synthesis from Shikimic Acid

dehydration with cesium acetate as a base in DMF. A one-pot conversion of 405 to that diene was later reported in 65% yield under microwave irradiation with the use of trifluoroacetic anhydride, pyridine, and excess of DMAP after 30 min.378 The bromohydrination of (+)-718 with NBS was examined in detail in order to diminish the formation of side products which included the formation of another bromohydrin isomer and a cycloaddition byproduct. The product distribution was observed to be dependent on the composition of the aqueous solvent used in which acetonitrile was determined to be superior to other water-miscible solvents. Conversion of bromohydrin 719 after epoxidation through treatment with LHMDS afforded chlorohydrin 721 in good yields. Coupling of both synthetic fragments was accomplished with 10 mol % BF3·Et2O, which provided 723 and underwent an oxidation−reduction sequence to invert the secondary hydroxyl group and ultimately led to the formation of the desired (−)-pericosine E after protecting group removal. The (+)-pericosine E enantiomer was later reported to be obtained in a similar fashion, where the enantiomers of 721 and 722 were prepared from quinic acid and shikimic acids, respectively.379 Although only recently Usami and co-workers reported the preparation of diene (+)-718 from shikimic acid,377,378 it has previously been prepared from quinic acid. This diene was used in the total synthesis of (−)-pericosine B380 (antipode of the natural product) and (−)-pericosine D381 (Scheme 148), despite the low selectivities achieved in the epoxidation step with MCPBA which rendered 724 and 725 as a 3:2 mixture. Dimethyldioxirane (DMDO) and methyl(trifluoromethyl)dioxirane (TFDO) were tested as oxidants for such a transformation, in which the latter provided the exclusive formation of the desired epoxide 724 in 72% yield.377 Nevertheless, the mixture of epoxides was further used for the preparation of (−)-pericosine D in only 1% yield upon opening of the epoxide with hydrochloric acid, and in the preparation of ether 727 for the total synthesis of (−)-pericosine B. Shikimic acid was used in the convergent synthesis of a locked previtamin D3 analogue 1α,25-dihydroxy-19-norvitamin D3 734 (Scheme 149), as the absence of the C-19 methyl group

the transformation of the diols into other related carbasugars from either 613 or 614. Pericosines A−E are metabolites of the fungus Periconia byssoides OUPS-N133 originally isolated from the sea hare Aplysia kurodai.371,372 The total syntheses of some of these carbasugars have been accomplished by Usami and coworkers373 after a revision of the original structure of pericosine A374 reported by Numata et al.372 The first total syntheses of (+)- and (−)-pericosine A have been achieved starting from either quinic or shikimic acid, respectively.375,376 Shikimic acid was used as a starting material in the preparation of the (−)-antipode of the natural product (Scheme 146), starting from methylation of the carboxylic acid and formation of the ketal 405. Oxidation of the free hydroxyl with Dess−Martin periodinane followed by stereoselective reduction of the ketone with sodium borohydride resulted in the inversion of the C-5 stereogenic center. After protection, 714 was dihydroxylated and the secondary hydroxyl group formed protected in the acetate form. Oxidation of 715 followed by dehydration with trifluoroacetic anhydride and pyridine led to the formation of enone 716. The use of sodium borohydride in anhydrous THF resulted in stereoselective reduction of the enone back to the alcohol in 95% yield. Reduction in methanol gave only 10% yield of product, while DIBAL-H failed to provide the desired compound. The introduction of chlorine was achieved in 42% yield by addition of excess thionyl chloride to 717 which after deprotection resulted in isolation of the desired (−)-pericosine A. Several attempts to improve the rather low chlorination yield using other chlorinating agents failed to provide the desired product. Recently the same authors reported the total synthesis of more challenging (−)-pericosine E377 (Scheme 147), apparently formed in nature by connection of (−)-pericosine A and (+)-pericosine B. Shikimic acid was initially transformed into the synthetic diene intermediate (+)-718, while its enantiomer (−)-718 could be obtained from quinic acid. Both enantiomers of the diene were transformed into ketals 721 and 722 and further coupled to 723. Preparation of diene (+)-718 was originally accomplished in 78% yield through a two-step 10524


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Scheme 140. Synthesis of (+)- and (−)-Zeylenones from Shikimic Acid

precludes the isomerization to the vitamin D triene system.382 The key steps in the synthesis of the A-ring of the hormone analogue (in 25% overall yield from shikimic acid) were the Barton deoxygenation of thionocarbonate ester 729, as other deoxygenation methods were less satisfactory, and the chain extension to enyne 732 through formation of a vinyl dibromide. A similar strategy was applied by Ferrero and Gotor for the preparation of other previtamin D3 analogues with A-ring modifications. Use of shikimic acid or its epi isomers resulted in preparation of several 6-s-cis analogues of 1α,25-dihydroxyvitamin D3.383,384 Recently, this was expanded to the preparation of 2-hydroxyethylidene previtamin D3 analogues 745 and 746 (Scheme 150).385 The oxidation of the free OH group at C-4 of the shikimic acid skeleton in 736 with Dess−Martin periodinane to the corresponding ketone 737 was followed by cyanomethylation to provide 738 as a mixture of isomers. Reduction of the nitrile to the allyl alcohol 739 and further protection led to formation of the synthon 740. Separation by preparative HPLC of 740 and coupling with triflate 744 through the Sonogashira

reaction eventually afforded 745 after hydrogenation and protecting group removal. During scale-up preparation of compound 736, migration of the silyl group to form 741 as a side product was observed. The 736/741 ratios were determined to be dependent on the batch of the n-BuLi used, and postulated to depend on the amount of lithium hydroxide present in the solution. With 741 in hand, the allyl hydroxyl was transformed into the ketone with MnO2 and further reacted with the ylide generated from (cyanomethyl)phosphonate to provide the nitrile 742 as a single isomer. The allyl alcohol 743 formed upon reduction of the nitrile was also coupled with triflate 744 to afford 746 after a similar procedure as described for 745. In an attempt to reach the total synthesis of the neuropoison tetrodotoxin, Keana and co-workers synthesized lactone 752 from shikimic acid (Scheme 151).386,387 Treatment of shikimate derivative 747 with diazomethane in methanol−ether resulted in formation of pyrazoline 748, presumably after purification with silica gel where isomerization of the double bond from the Δ1 to the Δ2 position of pyrazoline took place. Reaction of the 10525


Chemical Reviews

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Scheme 141. Total Synthesis of (+)-Valiolamine

time by Kishi and co-workers 1 year after,388 and different synthetic routes were later reported.389,390 The preparation of the 14-epi-hydrophenanthrene core of morphine alkaloids was reported391 as one example of the pattern recognition in retrosynthetic analysis created by Danishefsky392 (Scheme 152). Initial conversion of protected shikimic acid derivative 35 into the allyl bromide 753 was achieved through formation of the mesylate and further reaction with lithium bromide. A second SN2 reaction was used to install the aryl ether in the allyl position, for which the use of silver(I) oxide was determinant to afford the desired compound 755 as a single isomer, since a reversible bromide displacement was observed in its absence. Cyclization of the aryl ether 755 was achieved by Heck reaction, for which Pd(PPh3)4 was identified as the best catalyst among several tested, in combination with potassium carbonate as base in toluene at 90 °C. In order to avoid overreduction of the aldehyde group, ammonia was used as an additive in the hydrogenation reaction. This led to

Scheme 142. Total Synthesis of (+)-Valienamine

acyl chloride derivative of 749 with methylisocyanide followed by hydrolysis of the imidoyl chloride led to formation of ketoamide 750 that was further reduced and cyclized to lactone 752 as a mixture of epimers. Eventually the total synthesis of the highly complex and intricate tetrodotoxin was achieved the first

Scheme 143. Intermediate Step in Synthesis of (+)-Valienamine and (−)-1-epi-Valiolamine from a Common Intermediate

10526


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Scheme 144. Synthesis of L-α-Phosphatidyl-D-myo-inositol Phosphates

Scheme 145. Synthesis of (−)-MK7607 from (−)-Shikimic Acid

oxidation of the allyl alcohol and further reduction under Luche’s conditions. The α-bromoethyl ether side chain was introduced by reaction of the alcohol with in situ formed 1,2dibromoethyl ethyl ether (from Br2 and ethyl vinyl ether) in the presence of dimethylaniline. This led to formation of bromo acetal 753 as a mixture of inseparable diastereoisomers. According to the authors, an intramolecular radical cyclization with Et3B/Bu3SnH delivered the desired product 754 in 52% yield as a single diastereomer. Both enantiomers of β,γ-unsaturated ketone 756 were prepared from (−)-quinic acid, for which the two diastereomers

formation of benzyl alcohol 757, further reduced with DIBAL-H followed by oxidation to the dialdehyde 758 with Dess−Martin periodinane. The final cyclization step to 759 was accomplished through McMurry coupling with titanium(IV) chloride and zinc dust. In an attempt to achieve the total synthesis of (−)-reserpine, shikimic acid was used as a starting material for the construction of its E-ring core containing five contiguous stereocenters (Scheme 153).393 The disilyl ether 728 was first converted to the diol 751 after methylation of the free hydroxyl group. The inversion of the allyl stereogenic center was achieved by 10527


Chemical Reviews

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Scheme 146. Synthesis of (−)-Pericosine A from (−)-Shikimic Acid

Scheme 147. Synthesis of (−)-Pericosine E from (−)-Shikimic and Quinic Acids

of the acetylene unit by a reaction of the β,γ-unsaturated ketone 756 with cerium reagent derived from lithium(trimethylsilyl)acetylene, followed by C-desilylation and O-silylation, which afforded ketal 758 in high yield. A Sonogashira coupling of 758

of ketal shikimate 755 and 405 were synthetic intermediates and explored as fragments for the total synthesis of antibiotic esperamicin-A1 (Figure 6; Scheme 154).394,395 The construction of the enediyne bridge started with the regiospecific installation 10528


Chemical Reviews

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Scheme 148. Synthesis of (−)-Pericosines B and D from Common Epoxide 724

via stepwise functionalization of shikimic acid, with two of the stereocenters from the starting material, which served as central features of the fragment. An additional stereocenter was created by stereoselective conjugate addition to the enone 770. The silyl enol ether intermediate formed was converted to the less substituted enone by Saegusa oxidation and epoxidized to a single stereoisomer 771 with the use of NaBO3·H2O and H2O2. The Eschenmoser−Tanabe fragmentation was achieved through activated hydrazone intermediate 773 formed after reaction of the epoxy ketone with racemic aziridinyl hydrazine 772. Further treatment with cyclohexylamine afforded 774 as a mixture of diastereomers. The linear fragment 774 was then used in the synthesis of 776, which contained an amine in the ansa-chain. Baeyer−Villiger oxidation followed by reduction of the intermediate formate ester with DIBAL-H led to the preparation of the primary alcohol 775. The latter was then used for the syntheses of ethers 777 and 778 by a sequence of benzylation, metallacycle-mediated cross-coupling, saponification, macrolactamization, Sharpless asymmetric dihydroxylation, and carbamate formation.

with 759 resulted in the installation of the acyclic enediyne unit to be further cyclized after transformation of the carboxylic ester to the aldehyde by a reduction−oxidation sequence and Cdesilylation. The aldehyde 762 cyclized to 763 in 60% yield when treated with KHMDS and the alkoxide trapped with MeI. The removal of the cyclohexylidene moiety was achieved by treatment with EtSH in neat trifluoroacetic acid and the allyl alcohol formed oxidized to the enone with MnO2 to yield 764. With the installation of the urethane precursor in mind at C-10, aziridine 765 was synthesized by a reaction of enone 764 with S,S-diphenylsulfilimine monohydrate, which resulted also in the TBS migration to the secondary hydroxy group. Further efforts from the same group were aimed at the stereoselective introduction of the allyl trisulfide system, for which the enol silyl ether 768 was prepared and transformed into lactone 769.395,396 However, the total synthesis of this natural antitumoral agent remains an open issue. LoGrasso, Micalizio, and co-workers, inspired by benzoquinone ansamycins such as geldanamycin and macbecin, synthesized three macrocylic lactams 776−778 from shikimic acid (Scheme 155).397,398 The synthetic fragment 775 was built 10529


Chemical Reviews

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Scheme 149. Synthesis of a Previtamin D3 Analogue from Shikimic Acid

5. MISCELLANEOUS APPLICATIONS OF SHIKIMIC ACID With shikimic acid being a natural product of extreme importance in biological processes of plants and microorganisms but absent in animals, the use of shikimic acid in medicine and drug development is highly attractive. Although the importance of shikimic acid in biological processes has been acknowledged for many decades, its biological properties have only recently gathered the interest of medicinal chemists after the development of Tamiflu. Since then, shikimic acid and some simple derivatives have been reported to encompass many interesting biological properties such as high antioxidant activity,399−401 antibacterial,402−404 antiviral,405 anti-inflammatory,401,406−408 and antithrombotic.315,409−411 Notwithstanding this, shikimic acid was indicated as being toxic and carcinogenic in rats412 though these claims were not confirmed by more recent studies.413−415 Water-soluble extract from pine needle extracts of Cedrus deodara was reported to have antibacterial properties against foodborne bacteria such as E. coli, Proteus vulgaris, Staphylococcus aureus, B. subtilis, and B. cereus.403 Shikimic acid was identified as the main antibacterial component of the mixture and was observed to act on the cell membrane of S. aureus which increases cell membrane permeability, destroys membrane integrity, and ultimately causes growth inhibition and bacterial death.402 Previously, shikimic acid was disclosed as the chemical constituent of fungus strain Trichoderma ovalisporum, isolated from Panax notoginseng with the strongest antibacterial properties against Micrococcus luteus, S. aureus, B. cereus, and E. coli.404 The ability of shikimic acid to scavenge peroxyl radicals or quench hydroxyl radicals at concentrations as high as 10 mM was recently reported. At the same concentration, nitrite

production was also reduced, which indicates its ability to limit inflammatory actions of reactive species in biological systems. Moreover, shikimic acid inhibited the effect of toxic concentration of H2O2 after 1 h of treatment of human neuronallike SH-SY5Y cells while no cytotoxic effect was observed after 24 h treatment with the same concentration of only shikimic acid.399 The cellular protective properties of coconut water concentrate against H2O2-induced hepatotoxicity was assigned to the presence of shikimic acid, and was suggested to reduce apoptosis.400 With the aim to explore the mentioned free radical scavenging properties of shikimic acid, this compound was recently tested for the development of skin-whitening agents for the cosmetics industry. The melanin-inhibition assay of the embryo zebrafish animal model demonstrated a decrease of 79% melanin after treatment with shikimic acid with such an effect being suggested to originate from its inhibitory potential on tyrosinase activity.416 Hair growth effect is another property of shikimic acid that can lead to another potential use in the field of cosmetics. The water-soluble extract of I. anisatum (Japanese star anise) was demonstrated to stimulate mouse vibrissae follicle growth. Further experiments identified shikimic acid as one of the main components responsible for such an effect to promote hair growth through an increase in subcutaneous blood flow.417 The ingestion of shikimic acid by rats 3 days prior to induction of middle cerebral artery thrombosis by FeCl3 was observed to attenuate the neurologic deficit, reduce infarct size, and increase cerebral blood flow after ischemia. Such a neuroprotective role was suggested to be related to shikimic acid inhibition of thrombosis formation and platelet aggregation.410 The antithrombotic effects of shikimic acid were later confirmed in models of carrageenan-induced tail thrombosis, collagen and 10530


Chemical Reviews

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Scheme 150. Synthesis of Previtamin D3 Analogues with A-Ring Modifications from Shikimic Acid

and peripheral vascular diseases and acute coronary syndromes after determination of its in vivo activity as a thrombus and platelet aggregation inhibitor without perturbation of systemic homeostasis in rats.411 The acetonide derivative of shikimic acid 747 has also demonstrated a protective effect due to its antioxidant action. The regular administration of this compound to rats for 12 days before ulcerative colitis induced by 2,4,6-trinitrobenzenesulfonic acid resulted in reduced colon weight/length ratios. Moreover, the alteration of several biochemical parameters related to anti-inflammatory effects suggested that the protective effect of this molecule relates to its antioxidative properties.408 Similar findings were reported for rats treated for 6 days with the acetonide prior to colitis induction by acetic acid.408 Other in vivo tests have recently demonstrated reduction of inflammations in mouse ear edema induced by xylene and carrageenaninduced rat paw edema upon administration of the acetonide 30

epinephrine-induced pulmonary thromboembolism in mice, and FeCl3-induced carotid arterial thrombus.409 The biological properties of shikimic acid were recently expanded to include antinociceptive effects verified in a mice model. The ability of shikimic acid to decrease the pro-inflammatory cytokine production downregulates pain and suggests this molecule as a novel analgesic for treatment of a broad spectrum of inflammatory painful conditions. 406 Upon revelation of wound-healing properties of extracts of Hypericum androsaemum L., shikimic acid, as one of the main components of the extracts, was determined to have a pronounced effect to promote migration and proliferation of human fibroblasts.418 On the other hand, shikimic acid alone does not possess antiviral activity although its combination with quercitin may affect the modulation of innate immunity, namely leukocyte activity.405 Triacetylshikimic acid 68 was suggested as a possible therapeutic for treatment of cardiovascular, cerebrovascular, 10531


Chemical Reviews

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Scheme 151. Attempted Use of Shikimic Acid in the Synthesis of Tetrodotoxin

Scheme 152. Synthesis of 14-epi-Hydrophenanthrene Core of Morphine Alkaloids

inhibition, leukocyte infiltration and its antioxidant properties, and the peripheral analgesic effect by inhibition of chemical mediators and/or cytokine release.401 747 was also reported to have a protective effect on treatment of cerebral ischemic injury in rats and to attenuate cerebral ischemic damage.419−422 747

min prior to induction of inflammation. Better analgesic activities of this compound than shikimic acid alone were observed in mice exposed to the hot-plate test and acetic acid induced writhing. The anti-inflammatory properties of this compound were suggested to derive from vasodilatation 10532


Chemical Reviews

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Scheme 153. Synthesis of E-Ring of (−)-Reserpine from Shikimic Acid

trinitrobenzenesulfonic acid.407 In order to find a shikimic acid delivery method devoid of initial burst release, phospholipidcoated, shikimic acid loaded polylactic acid submicrometer particles were prepared by the coaxial electrospray technique and their pharmacokinetics profile was studied. A sustained shikimic acid release profile from the core−shell of shikimic acid loaded coaxial electrospray submicrometer particles was observed with shikimic acid being released in less than 70% after 2 h and 95% after 12 h in vitro in HCl solution (pH 1.2).425 Monopalmityloxy shikimic acid was reported to have anticoagulation activity in vivo with very little toxicity via oral administration that inhibits generation of thrombin through intrinsic and extrinsic pathways.315 Stimulated by the widely explored antitumor properties of the platinum complex cisplatin, shikimic acid complexes of this metal were prepared and assessed for their antitumor activity. The platinum complex of shikimic acid and R,R-1,2diaminocyclohexane (dach) were prepared by a conversion of PtCl2(dach)2 to the sulfate complex followed by reaction with barium salt of shikimic acid. Although highly soluble in water, complex Pt(dach)(shik)2 780 is hydrolyzed at room temperature with a half-life of initial hydrolysis of 2.6 h. The suggested complex 781 (Figure 8) formed upon hydrolysis was determined to be cytotoxic against L1210 leukemia. In vivo tests of 780 showed highly schedule-dependent activity against L1210, P388 leukemia, and B16 melanoma.426 Other Pt(II) complexes with shikimic acid based ligands depicted above (Scheme 86) were observed to have low cytotoxicity against BEL7404 cell due to their ability to block DNA synthesis and replication upon covalent binding.277 After the parallel synthesis of glycomimetic libraries derived from shikimic acid (Scheme 90),287,288 Kiessling and co-workers demonstrated the use of shikimic acid as a non-carbohydrate building block and scaffold in the development of compounds able to function as mannoside or fucoside surrogates in the interaction with lectin. DC-SIGN, a C-type lectin present in dendritic cells, mediates interactions with other host cells, bacterial pathogens, or viral pathogens and is involved in immune responses. The agonist effect of a shikimic acid derived glycomimetic was determined by NMR HSQC measurements in

Figure 6. Esperamicin-A1.

precondition on ischemic rats inhibited the inflammation, which partially reversed the inhibitory effects of ischemia on neurons and astrocytes and scaveged reactive oxygen species.423 The same compound was also suggested to be implicated in cognitive enhacement due to stimulation of adipokines during adipocyte differentitation.424 The use of shikimic acid as anti-inflammatory and anticoagulant agent for the potential therapeutic treatment of ulcerative colitis is hindered by its short half-life of oral administration. Xing and co-workers observed that the tributyryl ester of shikimic acid 779 (Figure 7), prepared by sulfuric acid catalyzed esterification of shikimic acid, was easily hydrolyzed in the upper gastrointestinal tract of mice. A colon-targeting resin microcapsule loaded with this prodrug was engineered to increase its potency. The sodium salt of shikimic acid triester was first loaded in Amberlite 717, an ion-exchange resin mainly composed of styrene−divinylbenzene copolymer and then encapsulated in Eudragit S100, a methyl acrylic acid−methyl methacrylate copolymer. The final particles displayed drug release behavior responsive to pH that allowed a colon target delivery. This showed a similar therapeutic effect as compared to dexamethasone on experimental colitis mouse induced by 2,4,610533


Chemical Reviews

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Scheme 154. Synthesis of Bicyclic Core and Allyltrisulfide Structures of Esperamicin-A1 from Quinic Acid

endometrial, and others.428 Radiolabeled bombesin analogues were glycated by insertion of carbohydrate linkers between the stabilized binding sequence and the Nα-histidine chelator. The introduction of shikimic acid moiety into the linker sequence reduced the abdominal accumulation, increased tumor uptake, and improved the tumor-to-background ratios in vivo, while no effect was observed on internalization, efflux, or metabolic stability in vitro. Nevertheless, the radiolabeled triazole coupled glucose analogue showed a more pronounced tumor-to-tissue ratio in vivo and improved biodistribution profile.429−431 The ability of shikimic acid to mimic carbohydrates was also explored in the development of ligands targeted at the mannose receptor in dendritic cells. Grandjean and co-workers have demonstrated that lysine based clusters of shikimic and quinic acids were effective ligands for the mannose receptor of dendritic cells280,432 and later demonstrated it with a model lipopeptide vaccine derived from quinic acid.433 Later on, Chaudhuri and co-workers developed cationic amphiphiles,

which compound 782 was observed to occupy the same carbohydrate recognition domain of DC-SIGN.288,427 Neurotensin receptors are absent in normal pancreas tissues and are highly overexpressed in ductal pancreatic carcinoma cells, which makes these receptors attractive targets in the diagnosis of pancreatic cancer. In an attempt to increase the pharmacokinetic profile of 99mTc-labeled neuropeptide neurotensin analogues, Tourwé and co-workers explored the effect of conjugating shikimic acid in a previously reported 99mTc(CO)3labeled analogue. Despite the success of the approach that resulted in an analogue with higher hydrophilicity and lower kidney and liver accumulation due to the enhanced excretion kinetics and blood clearance, the tumor uptake and receptor affinity was reduced.286 A similar approach was taken for the development of 99mTc(CO)3-labeled bombesin analogues. Bombesin was observed to have high affinity for the mammalian gastrin-releasing peptide receptor highly expressed in many tumor cells such as human prostate, breast, lung, ovarian, 10534


Chemical Reviews

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Scheme 155. Synthesis of Ansamycin-Inspired Macrocyclic Lactams 776−778

which contained shikimic and quinic acid headgroups to target DNA vaccines to antigen presenting cells via its mannose receptors.284 The dendritic cells-transfection efficiencies of shikimic acid directly conjugated to the hydrophobic residues of the amphiphile were 3−4%, and effective antimelanoma immune response was observed only for 30 days and all the immunized rats died after 49 days.284,285 A second generation of cationic amphiphiles in which a lysine spacer between the

Figure 7. Bioactive carboxylic acids derived from shikimic acid.

Figure 8. Bioactive derivatives of shikimic acid. 10535


Chemical Reviews

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Scheme 156. Preparation of H2O2-Sensitive Multilayer Film Coated Magnetic Particles and Release of Fluorescent Probe

Figure 9. Reversible competitive inhibitors of M. tuberculosis shikimic kinase (Mt-SK).

mannose-mimicking headgroup and the hydrophobic residues was introduced (465, Scheme 88) presented a longer-lasting immune response.283,434 Additionally, pharmaceutical formulations that comprise polypeptides such as human insulin were observed to be stabilized by the addition of shikimic acid.435 Interaction of shikimic and boric acids in basic water was observed through 11B NMR. Although not fully elucidated, esterification of cyclic ate complexes were suggested to be formed at different rates depending on the mixture composition stoichiometry.436 The ability of boronic acids to complex with shikimic acid was explored in the development of H2O2 and glucose-sensitive drug delivery systems. Sato and co-workers developed polymer-coated magnetic particles, by layer-by-layer deposition of shikimic acid appended poly(allylamine hydrochloride) and poly(styrenesulfonate) on the surface of gold magnetic particles followed by loading of 3-(dansylamino)phenylboronic acid (784) (Scheme 156). The engineered magnetic particles were evaluated for their ability to release 784 in response to H2O2 upon oxidation to the phenol counterpart 787. Although 784 release was observed in H2O2-free solutions, the system responded linearly to H2O2 concentrations in the 0− 0.5 mM range within 30 min to reach a plateau in the 0.5−5 mM range. Despite the interference of D-fructose that caused 784 release from the particles, negligible release was observed in the presence of up to 10 mM D-glucose. The particles were then modified to introduce glucose oxidoreductase prior to addition of 784 as this enzyme catalyzes the oxidation reaction of Dglucose to generate D-glucono-δ-lactone and H2O2. Even though fluorescence of glucose-free solution was observed, this increased upon 0.1 and 1 mM glucose addition due to 787 release.437

Considering the lack of the shikimic acid pathway in mammals and its vital nature in some microorganisms, its target can be attractive for the development of new antimicrobial agents.438 Shikimate kinase, the fifth enzyme of the aromatic amino acid biosynthesis, is responsible for the stereospecific phosphorylation of the C-3 hydroxyl group of shikimic acid by ATP (Scheme 73). In an attempt to identify new targets in the development of antibacterials, and ultimately develop chemical agents that avoid bacterial resistance, the inhibition of shikimate kinase has been studied. The several reported crystal structures of this enzyme, either as binary complexes with ATP, ADP, or shikimic acid in the active site, or as ternary complexes, have allowed the structure-base design of inhibitors. Although several classes of inhibitors have been reported,438−444 only substrate mimetics will be herein considered due to their structural similarities with shikimic acid. Shikimic acid binds to its natural enzyme in an unstable conformation, that places the two hydroxyl groups at C-4 and C5 in axial positions, thus forcing the C-3 hydroxyl group to remain at the equatorial position for the selective phosphoryltransfer reaction.438 The transition state for the phosphoryltransfer process has recently been analyzed by computational methods, and was demonstrated to be the rate-limiting step and a concerted one that proceeds via a loose transition state.445 This structural aspect in conjugation with additional ligand−receptor interaction features led to the development of several shikimic acid derivatives (Figure 9), some of them conformationally restricted such as 558 and 560 that were reported to be reversible competitive inhibitors of the Mycobacterium tuberculosis shikimic kinase (Mt-SK).332 Shikimate kinase is a magnesium-dependent enzyme with two recognition centers: one for shikimic acid and another for the 10536


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Figure 10. Reversible competitive inhibitors of M. tuberculosis (Mt-SK) and H. pylori (Hp-SK) shikimic kinases.

potency for both enzymes, while introduction of a primary amine at the same position allowed the development of selective inhibitors 791 for H. pylori shikimic kinase.339 Shikimic acid has also found its use in material science as an additive in the stabilization of metal nanoparticles446 and crosslink collagen for use in tissue engineering applications.447 Banach and Pulit-Prociak prepared a series of metal nanoparticles by chemical reduction with tannic and shikimic acids, sodium salicylate, or sodium potassium tartrate as reducing and stabilizing agents. The stabilizing properties of shikimic acid in the silver nanoparticles resulted in fabrication of nanoparticles in 90−105 nm size, while smaller gold nanoparticles were obtained in 60−80 nm sizes.446 During the addition of shikimic acid in the breakdown of silver hydroxide to silver oxide, the acid gets caged on the silver nanoparticles and prevents their aggregation. Silver nanoparticles of 220 nm average size, uniform in shape and size, are thus obtained. When compared with native collagen, collagen cross-linked with shikimic acid caged silver nanoparticles was determined to have increased tensile strength, elongation at break and viscosity, as well as relatively higher thermal stability. Additionally, shikimic acid caged silver nanoparticle stabilized collagen showed cell proliferative and antimicrobial properties. Surprisingly, even though shikimic acid is engineered and produced in E. coli, its conjugation with silver nanoparticles resulted in microbial growth inhibition.447

ATP cofactor. The enzyme has three regions: (1) the cofactor binding site composed of CORE domain and the P-loop; (2) the LID domain, that closes over the shikimic acid binding site and has residues crucial for ATP binding; and (3) the substrate binding (SB) domain, responsible for recognition and binding of shikimic acid. While the reversible competitive inhibitor of shikimic kinase 558 developed by González-Bello and coworkers was shown to provide a well-ordered closed form of the active site and prevent the opening of the substrate binding site, the targeting of the inactive open form conformation of the enzyme was recently explored.331,339 The introduction of different substituents in the C-5 position of shikimic acid proved to be a suitable strategy to block the appropriate closed form of the enzyme for catalysis. Different inhibitory activitivities of the newly developed compounds were observed for shikimic kinases, from Mycobacterium tuberculosis and Helicobacter pylori (Figure 10). The presence of an O-benzyl moiety at C-5 of shikimic acid allowed a strong interaction of compounds 551 with the open form of the enzyme, specifically at the LID and SB domains.331 Upon extensive studies on the essential motion of the two enzymes by molecular dynamics simulations of the enzyme−product complexes, the same authors observed significant differences in opening of the SB domain between the two enzymes. The replacement of the Obenzyl moiety at C-5 by secondary benzyl amines, as depicted in Scheme 115, resulted in several inhibitors 790 of increased 10537


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of valuable secondary targets that would fill the low-volume, high-value void. Some of the potential of shikimic acid as an element of the chiral pool has been exploited in the total synthesis of many natural products, stretching from simpler C7N aminocyclitols365−367 to more challenging esperamicin-A1,395,396 even though the total synthesis of this natural antitumoral agent remains unforeseen. The comprehensive works of Usami and co-workers 377,379 on the synthesis of several cytotoxic pericosines from shikimic acid stand as examples of successful uses of this natural product in total synthesis. Being highly rich in its biological properties, it comes as no surprise that shikimic acid has served as an inspiration in the drug development, and might serve this role over a long period. For instance, the recently reported inhibition of bacterial shikimate kinases by C-5 substituted shikimic acid derivatives331,339 is a promising application of shikimic acid in the antibiotic drug discovery. The several reports on the antiinflammatory, analgesic, and antioxidant activities of shikimic acid and derivatives399,401,406 suggest future uses of the shikimic acid core in the development of new biologically active entities. Besides being a topic of research of many studies in chemistry, shikimic acid has been recently exploited in cosmetics and material sciences, such as skin whitening416 or stabilizer of metal nanoparticles446 and unforeseen uses of this compound in upcoming years in very different fields of science are anticipated.

6. CONCLUSION Despite the long journey to develop an economically viable and easy method for the acquisition of shikimic acid, its rich structural properties have been widely explored in many fields of science. When putting this topic into an historical perspective, synthetic chemists focused on the synthetic preparation of this highly functionalized molecule from quinic acid and sugars. The interest in this compound by the synthetic chemistry community has been rejuvenated at later periods, namely when boosted by the development of asymmetric methodologies, hauled by the development of Tamiflu, and on the total synthesis of complex natural products. Consequently, there are now ways to prepare both enantiomeric forms of shikimic acid, its diastereoisomers, and their isotopically labeled congeners. Interestingly, a high yielding and practical method to convert quinic acid into shikimic acid remains an open issue, despite the structural similarities between the two carboxylic acids. Notwithstanding the rather huge efforts made for the development of efficient methods for isolation of shikimic acid from star anise or other plant sources, the microbial production stands as a more attractive strategy, and the method developed by Frost296 for the microbial production of shikimic acid stands as a landmark in the field. Many other bioengineering strategies have been developed and will likely result in even more competitive ways to produce this compound or other derivatives of the shikimate pathway in upcoming years. The carbon source or supplements or the type of microorganisms used are some of the aspects that are likely to become landmarks in the production of shikimic acid. The recently reported use of Cor. glutamicum for production of shikimic acid from lignocellulosic feedstocks219 and the dynamic regulation of metabolic flux from biomass formation to chemical synthesis in engineered E. coli as developed by Prather201 are some examples. Being a highly functionalized molecule, shikimic acid has been synthetically modified through a plethora of reactions. For instance, functional group interconversions of the carboxylic acid, alcohol, or alkene functional groups or installation of other functionalities such as nitro, thioethers, or halides have all been well documented. Undoubtedly, the conversion of this molecule into epoxides have been one of the most explored transformations, serving the preparation of Tamiflu and other biologically relevant molecules such as aminocyclitols. Nevertheless, the diversity of molecules derived from this natural carboxylic acid is enormous, and its potential as a molecular scaffold was exemplified by the impressive library of over 2 million compounds reported by Schreiber and co-workers.335 The utilization of shikimic acid in the field of biorenewables has again brought this compound into the spotlight, where it has been explored as a way to prepare aromatic hydrocarbons as an alternative to petrol manufacture regardless of its inherent chirality. Namely, several recent works from Zou document the valorization of (−)-methyl 3-dehydroshikimate through preparation of arylamines and aromatic heterocycles.355,358 Despite the many synthetic manipulations of shikimic acid, the selective removal of the hydroxyl functionalities has been only scarcely explored and the development of methods for its efficient deoxygenation is still an open issue. This can be seen as an opportunity for future works on increasing the potential of this molecule as a biorenewable carbon source, particularly if some of the chiral elements are kept in the products and extensive use of protecting groups can be avoided. Although not likely to turn into a bulk commodity, shikimic acid could become the source

AUTHOR INFORMATION Corresponding Authors

*E-mail: nuno.rafaelcandeias@tut.fi. *E-mail: [email protected]. ORCID

Nuno R. Candeias: 0000-0003-2414-9064 Benedicta Assoah: 0000-0001-5877-2749 Svilen P. Simeonov: 0000-0002-6824-5982 Notes

The authors declare no competing financial interest. Biographies Nuno R. Candeias, born in Lisbon, Portugal, in 1981, graduated in applied chemistry from New University of Lisbon (2004) and received his Ph.D. in chemistry from Technical University of Lisbon, under the supervision of Prof. Carlos A. M. Afonso (2008). After 6 months as an invited assistant professor at Cooperativa de Ensino Egas Moniz, he took his postdoc at the Pharmacy Faculty of the Lisbon University under the supervision of Dr. Pedro M. P. Góis for 3 years and at Scripps Research Institute under the supervision of Prof. Carlos F. Barbas III for 1 year. In 2012 he moved to Tampere University of Technology in Finland as university lecturer, where he was later appointed adjunct professor. In 2015 he was awarded with an Academy of Finland Research Fellowship. His current research interests are the modification of bioderived raw materials for synthetic purposes and preparation of bioactive molecules through use of Petasis borono−Mannich multicomponent reaction. Benedicta Assoah completed her bachelor’s degree at the University of Education, Winneba (UEW), in 2012 and received a M.Sc. in research chemistry from University of Eastern Finland (UEF) in 2015. Benedicta is currently a Ph.D. student under the supervision of Nuno R. Candeias at Tampere University of Technology. Her research involves mainly Lewis base hydrosilylation protocols and synthesis of novel organic compounds. 10538


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Svilen P. Simeonov graduated from Sofia University in 2004 and joined the Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, as a research fellow. In 2010 he moved to the University of Lisbon and received his Ph.D. in 2014 under the supervision of Prof. Carlos A. M. Afonso. Afterward, he returned to Sofia and currently holds an associate professor position at the Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences. His research interests are mainly focused on green chemistry methodologies, flow chemistry, valorization of natural resources, and asymmetric catalysis.

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Production and Synthetic Modifications of Shikimic Acid - Chemical

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