The Gabosine and Anhydrogabosine Family of Secondary Metabolites

Review pubs.acs.org/CR

The Gabosine and Anhydrogabosine Family of Secondary Metabolites Pau Bayón and Marta Figueredo* Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain There are also some known epoxyquinone derivatives, most of them isolated from fungi, with anhydrogabosine structure. Formally, the hydrolysis of the epoxide functionality on one of these compounds should furnish a gabosine, although this transformation is generally less straightforward than expected. In the past decades, many research groups have revealed active in the synthesis of gabosines and anhydrogabosines, and new articles on the topic are appearing regularly. One of the reasons for the interest of synthetic chemists in this field is most probably related to the known or expected biological activities of some of these compounds. Yet, undoubtedly, another reason comes from the fact that the extremely crowded functionalization of these small molecules makes them highly challenging synthetic targets. This extensive work has CONTENTS contributed to confirm the structure and absolute configuration of most gabosines. 1. Introduction 4680 In this Review, we summarize the information available in the 2. Origin and Structure 4680 literature until March 2011 concerning the natural occurrence, 3. Biological Activity 4683 biogenetic origin, and biological properties of all of these 4. Biogenetic Studies 4683 compounds, along with the synthetic efforts devoted to their 5. Synthetic Approaches 4684 preparation. This latter aspect constitutes the main focal point 5.1. Biomimetic Approaches 4685 of this Review. Even though the biogenetic origins of gabosines 5.2. Diels−Alder Strategies 4686 and anhydrogabosines are not related, their structural similarity 5.3. From Benzene Derivatives 4690 propitiates synthetic connections, thus making it advisable to 5.4. From Carbohydrates 4693 analyze their syntheses simultaneously. Moreover, although the 5.5. From Other Chiral Pool Materials 4698 synthetic approaches to the different gabosines and anhy5.6. From Cyclohexanones 4701 drogabosines, which have so far been published, come from a 6. Conclusions and Perspectives 4705 variety of laboratories, a detailed analysis of the different Author Information 4705 syntheses allows classifying and discussing them in terms of Corresponding Author 4705 general strategies. Therefore, and for a better understanding of Notes 4705 the difficulties associated with the preparation of these densely Biographies 4705 functionalized molecules, the syntheses have been organized Acknowledgments 4705 attending to the strategy used instead of considering the References 4705 specific target or the chronological order. To the best of our knowledge, a review on gabosines has never been published yet. The compounds with anhydrogabosine structure are included in the wider category of epoxyquinols, a subject on which a 1. INTRODUCTION general review was published in 2004.3 The term gabosines was first used in the literature in 1993 to describe a family of secondary metabolites isolated from various 2. ORIGIN AND STRUCTURE Streptomyces strains.1 The gabosine family comprises a group of The gabosine family comprises a group of secondary carbasugars that presents a polyhydroxylated methyl cyclometabolites isolated from various Streptomyces strains with a hexane system as the common constitutional feature. Their closely related carba-sugar structure. In 1993, Thiericke, Zeeck, structural diversity is originated by differences in the substituent and co-workers isolated 11 compounds that were named positions, unsaturation degree, and/or relative and absolute gabosines A−K and classified them into four different structural configuration of their stereogenic centers.1,2 Before they were types, I−IV (Figure 1).1 In 2000, the same authors disclosed named gabosines, some of these compounds were already the isolation of three additional members of the family, known, and, in some cases, the same compound was given two different names. Several other secondary metabolites, whose isolation from natural sources is described in the literature, Received: April 12, 2012 present also a structural pattern within the gabosine family. Published: April 18, 2013 © 2013 American Chemical Society

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dx.doi.org/10.1021/cr300150w | Chem. Rev. 2013, 113, 4680−4707

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Figure 1. The gabosine family of secondary metabolites.

gabosines L, N, and O.2 All of the gabosines present a polyhydroxylated methyl cyclohexane system as the common constitutional feature. Their structural diversity is originated by differences in the substituent positions, unsaturation degree, and/or relative and absolute configuration of their stereogenic centers. In gabosines A, B, C, D, E, F, N, and O, the carbon substitution is located at the α-carbonyl position, while in gabosines G, H, I, and J it is located at the β-carbonyl position. Gabosine B had been formerly isolated from Actinomycetes strains.4 Gabosine C is identical to the previously known antibiotic KD16-U1, which was first isolated from Streptomyces filipinensis,5 and its crotonyl ester, named COTC, is a recognized antitumor agent that was extracted from the cultured broth of Streptomyces griseosporeus6,7 and other Streptomyces strains.8 The absolute configurations of natural gabosines A, F, and L were determined by the Helmchen method,1 as was that of gabosine N, which was then confirmed by X-ray analysis.2 The absolute configuration of gabosine B, which is the enantiomer of gabosine F, was established by degradation to (+)-(R)-methylsuccinic acid4 and later confirmed by chemical correlation to gabosine A.1 The absolute stereochemistry of gabosine C was also determined by correlation to gabosine A, while that of its crotonyl ester, COTC, had been previously established by X-ray analysis of the addition product of p-bromothiophenol.6b The absolute configurations of gabosines D and E were deduced from their correlation to gabosine F,1 and those of gabosines I,9 O,10 and G11 were established by total synthesis. The relative stereochemistry of natural gabosines H and J was deduced from their NMR data, and their absolute configurations remain unknown. Synthetic studies indicated that the structure originally assigned to gabosine K was incorrect.12 Some other compounds, whose isolation from natural sources is described in the literature, present also a structural pattern within the gabosine family (Figure 2). Thus, compound (−)-1 was isolated from the fungus Phyllostica sp., the “Kurohagare” disease of red clover,13 and from the endophytic fungus Phoma sp. 8889 of the plant Salsola oppostifoli, along

Figure 2. Other secondary metabolites with gabosine structural pattern.

with the related compound (−)-epoxydine B.14 An undefined stereoisomer of (−)-1 was also found in Ophiosphaerella herpotricha, a cause of spring dead spot of bermuda grass.15 Compound (+)-2 was identified as the major component of a mixture of isomers extracted from the marine fungus Aspergillus varians KMM 4630.16 Streptol (also named valienol) was isolated from a culture filtrate of an unidentified Streptomyces sp. No 1409 17 and, more recently, from Streptomyces xanthochromogenes ID-4017418 and from Streptomyces lincolnensis DSM 40 355.19 (+)-MK7607, the C-4 epimer of streptol, was isolated from the fermentation broth of Curvularia eragrostidis D2452.20 Rosevionol and dehydrorosevionol, two compounds isolated from Streptomyces roseoviolaceus for which no stereochemical assignment was given,21 are isomers of streptol and (+)-2, respectively. Nigrospoxydons A, B, and C were recently isolated from the marine fungus Nigrospora sp. PSU-F5.22 The absolute configuration of (−)-1 was established 4681


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Table 1. Occurrence of Gabosines and Other Closely Related Carbasugars compound gabosine A

gabosine B

gabosine C ((−)-KD16-U1)

gabosine D gabosine E

gabosine F

gabosine G gabosine H gabosine I (valienone)

gabosine gabosine gabosine gabosine

J K L N

gabosine O

COTC

1

rosevionol dehydrorosevionol 2 streptol (valienol)

(+)-MK7607 nigrospoxydon A nigrospoxydon B nigrospoxydon C epoxydine B

[α]D

configuration

−132 (c = 1, MeOH)1 −131 (c = 0.27, MeOH)23 −125 (c = 0.8, CD3OD)24 −91 (c = 1.5, MeOH)1 −106 (c = 0.45, MeOH)4 −88 (c = 0.51, MeOH)25 −168 (c = 1, H2O)5 −166 (c = 0.2, H2O)1 −170 (c = 1.0, H2O)6b −166 (c = 0.13, H2O)26,27 +86 (c = 1, MeOH)1 +71 (c = 0.54, MeOH)28 +148 (c = 0.95, MeOH)1 +152 (c = 1, H2O)1 +136 (c = 0.46, MeOH)28 +94 (c = 1.0, MeOH)1 +88 (c = 0.69, MeOH)29 +89 (c = 0.32, MeOH)25 +42 (c = 1.34, MeOH)11 −68 (c = 0.58, MeOH)1 −61 (c = 1.0, MeOH)1 −40 (c = 1.0, MeOH)9 −59 (c = 0.79, MeOH)11

absolute

Streptomyces strains1,2

1993

absolute

Actinomycetes strains4 Streptomyces strains1 Actinomycetes strains2 Streptomyces filipinensis5 Streptomyces strains1

1986 1993 2000 1974 1993

absolute

Streptomyces strains1

1993

absolute


1993

absolute

Streptomyces strains1,2

1993

absolute relative absolute

Streptomyces Streptomyces Streptomyces Streptomyces

strains1 strains1 strains1 lincolnensis DSM 40 35519

1993 1993 1993 2009

relative relative12 absolute absolute

Streptomyces Streptomyces Streptomyces Streptomyces

strains1 strains1 strains2 strains2

1993 1993 2000 2000

absolute


2000

absolute

Streptomyces griseosporeus6,7 Streptomyces strains8 Streptomyces griseosporeus7

1975 1982 2000

absolute

absolute

Phyllostica sp.13a Phyllostica sp.13b Phoma sp. 888914 Streptomyces roseoviolaceus21 Streptomyces roseoviolaceus21 Aspergillus varians KMM 463016 Streptomyces sp. No 140917 Streptomyces xanthochromogenes ID-4017418 Streptomyces lincolnensis DSM 40 35521 Curvularia eragrostidis D245220

1971 1975 2010 1974 1974 2005 1987 2005 2009 1994

absolute absolute absolute absolute

Nigrospora sp. PSU-F522 Nigrospora sp. PSU-F522 Nigrospora sp. PSU-F522 Phoma sp. 888914

2008 2008 2008 2010

−13 (c = 0.10, MeOH)2 −152 (c = 0.89, H2O)2 −150 (c = 0.30, CD3OD)24 −142 (c = 0.16, MeOH)10 −21 (c = 0.1, MeOH)2 −11 (c = 0.15, MeOH)30 −11 (c = 0.38, MeOH)10 −109 (c = 1.5, MeOH)6 −108 (c = 0.23, MeOH)31 −106 (c = 0.6, MeOH)32 −111 (MeOH)28 −181 (c = 1, EtOH)13a

+76 (c = 0.25, EtOH)16 +92 (c = 0.25, H2O)33 +88 (c = 0.3, H2O)34 +96 (c = 0.45, MeOH)35 +210 (c = 0.55, H2O)20 +201 (c = 0.4, H2O)34 +10 (c = 0.06, EtOH)22 +39 (c = 0.31, EtOH)22 +24 (c = 0.25, EtOH)22 −73 (c = 1.1, CHCl3)14

absolute

not given not given relative absolute

source

year

confirmed by total synthesis of its enantiomer.12b The absolute configurations of nigrospoxydons A, B, and C were assumed to be the same as in some accompanying known metabolites.22 Table 1 summarizes the origin and optical rotation values of the natural products with gabosine structural pattern. Several known epoxyquinone natural products possess anhydrogabosine structure3 (Figure 3). Most of these compounds are phytotoxins. Among them, the first structural

by chemical correlation to the known phytotoxin (+)-epoxydon,13 while that of (+)-2 was not determined. Considering their close biogenetic relationship and the likewise negative optical rotation value, the absolute configuration of epoxydine B and (−)-1 was assumed to be the same.14 The absolute stereochemistry of streptol was deduced from the circular dichroism (CD) spectrum of the benzoate of its hydrogenation product.17 The absolute configuration of (+)-MK7607 was 4682


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The absolute configuration of natural theobroxide was established by 1H NMR analysis of the Mosher esters of a derivative57a and confirmed by total synthesis.59 The absolute configuration of epoformin was established by chemical correlation52 and total synthesis.60 Table 2 summarizes the origin and optical rotation values of the natural products with anhydrogabosine structural pattern.

3. BIOLOGICAL ACTIVITY Gabosines A−K exhibit no significant activity in the fundamental antibacterial, antifungal, antiviral, herbicidal, and insecticidal assays, but they showed a weak antiprotozoal activity when the test organism Trichomonas vaginalis was used. Gabosine E showed a weak inhibitory effect on the cholesterol biosynthesis in cell line tests with HEP-G2 live cells.1 Gabosines A, B, F, N, and O present DNA-binding properties.2,68 As already mentioned, gabosine C is the known antibiotic KD16-U1,5 and its crotonyl ester, COTC, is an antitumor agent.6a It has been long assumed that the activity of COTC was the result of glyoxalase I inhibition,7,8 and its effects in macromolecular synthesis, mitosis, and membrane functions have been attributed to the interaction with the sulphydryl group of various enzymes, but a more recent hypothesis proposes that COTC is an enzyme-activated product in which the crotonate ester serves as a leaving group, in a process triggered by glutathionyl transferase, which produces a transient, highly electrophilic glutathionated 2-exomethylenecyclohexanone that can covalently modify proteins and nucleic acids.69 It has been reported that compound (+)-2 is a cytotoxic and potential contraceptive agent,16 streptol is a plant growth regulator,17 and nigrospoxydon A shows activity against Staphylococcus aureus ATCC 25923.22 It has also been published that the closely related esters (−)-1 and epoxydine B display antibacterial, antifungal, and antialgal activities.14 Among the epoxide derivatives, epoxydon has been the most extensively investigated. It showed antiobiotic activity against Phycomycetes and Gram-negative bacteria70 and the methicillinresistant and multidrug-resistant Staphylococcus aureus,22,42 and it presented antitumor,37 radical scavenging42 and antiauxin activities, showing efficiency against clubroot of cruciferous crops caused by Plasmodiophora brassicae.41 Some of these activities were also described for the epoxydon monoacetate (+)-4.42 Epiepoxydon showed antibiotic and antifungal activity,46a,47 β-1,3-glucan inhibition,63 and it is strongly cytotoxic against HM02, HepG2, and MCF7 human cancer cell lines.50 Moreover, epoxydon, epiepoxydon, and epiepoformin inhibited the germination of lettuce seeds,45 and the first also reduced growth in rice seedings.70 Phyllostine is a tumor inhibitor,51 dihydroepiepoformin is an antagonist for the interleukin-1 receptor,54 and theobroxide is a potato microtuber inducing substance and causes growth inhibitory effects on seedlings of Nicotiana tabacum.57 The synthetic compound (+)-RKTS-33 has inhibitory activity toward death receptormediated apoptosis.56,71 The racemate of a synthetic compound with the structure misassigned to parasitenone is a nuclear factor-κB inhibitor and therefore a suitable candidate as antiinflammatory and anticancer agent.72

Figure 3. Epoxyquinone natural products with anhydrogabosine structure.

assignment corresponded to (+)-epoxydon (also named phyllosinol), which presents an oxymethyl substituent at the α-carbonyl position, as in gabosines C, D, and E. (+)-Epoxydon was first isolated in 1965 from a Phoma sp.36 and then found in several other fungi like Phyllostica sp.,37 Mycosphaerella ligulicola, which is a disease of the chrysantenum flowers,38 a rhubarb pathogen agent,39 Phoma sorghina,40 Phoma glomerata,41 the marine fungus Aspergillus,42 Nigrospora sp. PSU-F5,22 and also in the persimmon fruits Diospyrous kaki L.,43 in the liquid culture of Ophiosphaerella herpotricha,15 and in the Phoma sp. 8889 isolated from Solsola oppostifolia.14 (+)-Epoxydon was also isolated from the marine-derived fungus culture of Aspergillus parasiticus,44 and named parasitenone after a structural misassignment, as it was demonstrated by total synthesis.33 The C-4 epimer of (+)-epoxydon, (+)-epiepoxydon (also named isoepoxydon), is as well a secondary metabolite that was originally found in an unidentified fungus from the diseased leaf of crapemyrtle (Lagerstroemia indica L.)45 and later extracted from Penicillium urticae,46 the liquid cultures of Poronia punctata (NRRL 6457), a fungal colonist of cattle dung,47 the tea gray blight fungi Pestalotiopsis longireta and Pestalotiopsis theae,48 and from marine fungi of the algae Enteromorpha intestinalis49 and Polysiphonia violacea.50 Other phytotoxins closely related to (+)-epoxydon and (+)-epiepoxydon are (−)-phyllostine, which has been isolated from common sources,15,40,46b,51 and the epoxydon monoacetates 3 and (+)-4, respectively, isolated from Mycosphaerella ligulicola38 and a marine Aspergillus.42 There are also several anhydrogabosines with a methyl group at the α-carbonyl position as in gabosines A and N. (+)-Epoformin (also named desoxyepoxydon) was first isolated from Penicillium claviforme52 and found also in a fungus of Lagerstroemia indica L.,45 in Phoma sp.,39,40 in Ophiosphaerella herpotricha,15 and Penicillium vulpinum.53 (+)-Epiepoformin was isolated from Lagerstroemia indica L.,45 and dihydroepiepoformin was extracted from Penicillium patulum.54 Three additional related natural products are (+)-isoepiepoformin, which presents a methyl substituent at the β-carbonyl position as in gabosine H and was isolated from a culture of Myrothecium roridum grown in rice substrate,55 (+)-RKTS-33,56 with a hydroxymethyl substituent at the βcarbonyl position as in gabosines I and J, and (−)-theobroxide, isolated from Lasidiplodia theobromae IFO31059.57 The absolute configurations of natural (+)-epoxydon,37 (+)-epiepoxydon,45,46a (+)-epiepoformin,45 and (+)-isoepiepoformin55 were established from CD studies, and that of (−)-phyllostine was determined by chemical correlation to (+)-epoxydon.58

4. BIOGENETIC STUDIES Biosynthetic studies on gabosines A, B, and C, extracted from Streptomyces cellulosae subsp. griseorubiginosus (strain S 1096), with 13C-labeled precursors indicated that their origin is 4683


Chemical Reviews

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Table 2. Occurrence of Epoxyquinone Derivatives with Anhydrogabosine Structure compound epoxydon (phyllosinol) (parasitenone)44

[α]D

configuration

source

year

+93 (c = 0.29, MeOH)36 +102 (c = 1, EtOH)37 +92 (c = 0.123, EtOH)38 +72 (c = 0.3, MeOH)42,44 +98 (c = 0.1, EtOH)34 +98 (c = 1, EtOH)61

absolute

absolute

Phoma sp.36 Phyllostica sp.37 Diospyrous kaki L.43 Mycosphaerella ligulicola38 Phoma sp.39 Phoma sorghina40 Ophiosphaerella herpotricha15 Phoma glomerata JCM997241 Aspergillus parasiticus44 Aspergillus42 Nigrospora sp. PSU-F522 Phoma sp. 888914 Lagerstroemia indica L. fungus45 Penicillium urticae46a Penicillium urticae NRRL 2159A46b Poronia punctata NRRL 645747 Pestalotiopsis longireta and P. theae48 unspecified fungi63 Penicillium sp. from Enteromorpha intestinalis49 Apiospora montagnei50 Phyllostica sp.51 Penicillium urticae NRRL 2159A46b Phoma sorghina40 Ophiosphaerella herpotricha15 Mycosphaerella ligulicola38 Aspergillus42 Penicillium claviforme52 Lagerstroemia indica L. fungus45 Phoma sp.39 Phoma sorghina40 Ophiosphaerella herpotricha15 Penicillium vulpinum53 Lagerstroemia indica L. fungus45

1965 1969 1979 1981 1992 1994 1994 1999 2002 2005 2008 2010 1978 1979 1979 1988 1992 1993 1999 2004 1971 1979 1994 1994 1981 2005 1973 1978 1992 1994 1994 1998 1978

absolute absolute

Penicillium patulum54 Myrothecium roridum55

1995 1986

absolute

Lasidiplodia theobromae IFO3105957

1994

absolute

synthetic56

2003

epiepoxydon (Isoepoxydon)

+194 +206 +192 +261 +114 +256 +250

(c (c (c (c (c (c (c

= = = = = = =

1.57, EtOH)45 0.17, MeOH)46a 7.5, MeOH)47 1.00, MeOH)48 0.92, MeOH)49 0.8, EtOH)58,62 1.4, EtOH)61

absolute

phyllostine

−106 −120 −108 −116

(c (c (c (c

= = = =

1, EtOH)51,59,62 0.28, EtOH)64 1.61, EtOH)61 1.00, EtOH)35

absolute

3 4 epoformin (desoxyepoxydon)

epiepoformin (desoxyepiepoxydon)

dihydroepiepoformin isoepiepoformin theobroxide

RKTS-33

+66 (c = 0.5, MeOH)42 +114 (EtOH)52 +109 (c = 0.2, EtOH)25,60

+221 (c = 0.83, EtOH)45 +316 (c = 0.37, EtOH)59 +310 (c = 0.46, EtOH)65 +314 (c = 0.49, EtOH)66 +320 (c = 0.06, EtOH)58 +303 (c = 1.1, EtOH)30 +315 (c = 1.1, EtOH)25 +22 (c = 0.1, acetone)30 +36 (c = 0.50, CHCl3)55 +430 (c = 0.6, CHCl3)67 −6.12 (c = 0.20, EtOH)57a −6.25 (c = 0.40, EtOH)59 −6.18 (c = 0.35, EtOH)66 −8.0 (c = 0.10, EtOH)30 −276 (c = 0.26, EtOH)33

absolute

different from the shikimate pathway.73 The observed labeling pattern suggests that the biosynthesis of gabosines follows a pentose phosphate pathway in which sedoheptulose 7phosphate (S-7-P) is a key intermediate (Scheme 1). S-7-P is originated from glyceraldehyde 3-phosphate (G-3-P) by transfer of a C2 fragment from fructose 6-phosphate (F-6-P) by a transketolase. The resulting xylulose 5-phosphate (X-5-P) can be converted into ribose 5-phosphate (R-5-P) by isomerization. In the next step, a second C2 fragment transfer from X-5-P to R-5-P occurs to form S-7-P. It is assumed that S7-P cyclizes by an aldol reaction between C-2 and C-7.

The biosyntheses of the anhydrogabosines epoxydon and theobroxide were also investigated.57b,74 Their origin was established by performing biogenetic studies with labeled acetates. Epoxydon was obtained from Phyllostica sp., a fungus that also produces 6-methylsalicylic acid, 6, and gentisyl alcohol, 7, and theobroxide was isolated from Lasidiplodia theobromae. It was concluded that both metabolites derive from a tetraketide chain 5 (Scheme 2).

5. SYNTHETIC APPROACHES An analysis of the published work devoted to the synthesis of compounds with gabosine and anhydrogabosine structure 4684


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Scheme 1. Biosynthetic Pathway of Gabosines

Scheme 3. Syntheses of (±)-Phyllostine and (±)-Epoxydon from Gentisyl Alcohola

Scheme 2. Biosyntheses of Epoxydon and Theobroxide a

Reagents and conditions: (a) PbAcO4; (b) DHP, PTSA (100%); (c) NaBO3, AcOH, EtOH/H2O (pH = 8) (40%); (d) PTSA, EtOH (78%); (e) NaBH4 (63%); (f) Ac2O, pyridine (100%); (g) PTSA, MeOH (70%); (h) KHCO3, H2O; (i) TrCl, pyridine (60%, two steps); (j) MnO2 (88%); (k) PTSA, MeOH (51%).

as a sole diastereoisomer probably by epimerization of C-4 during the oxidation process. Treatment of 20 with ptoluenesulfonic acid gave (±)-epoxydon in 10 steps from gentisyl alcohol and ca. 1% overall yield. Recently, Nishiyama and co-workers reported that the reduction of (±)-phyllostine with sodium triacetoxyhydroborate proceeded stereoselectively to produce a compound with the structure misassigned to parasitenone.72 The first intermediate in their sequence (Scheme 4) is also a derivative Scheme 4. Syntheses of (±)-Phyllostine and Putative (±)-Parasitenonea

discloses common trends between the approaches developed in different laboratories. Moreover, quite often the synthetic pathway splits into two or more parallel or alternative routes leading to different targets. It is also noticeable that some early syntheses have been later modified to improve them in terms of chemical yield and selectivity or to develop an enantioselective version. In the next discussion, the syntheses have been organized attending to the strategy used instead of considering the specific target or the chronological order. 5.1. Biomimetic Approaches

Pioneer syntheses of (±)-phyllostine and (±)-epoxydon were reported by Ichihara and co-workers.75 In their biomimetic approach (Scheme 3), the starting material was gentisyl alcohol, 7, which was oxidized to the hydroxymethyl-p-benzoquinone 12. After protecting the hydroxyl group, a regioselective epoxidation of the quinone with sodium perborate afforded 14, and subsequent hydrolysis of the acetal protection delivered (±)-phyllostine. Alternatively, the reduction of diketone 14 with sodium borohydride furnished a mixture of epoxydiols 15, which were acetylated to 16. Hydrolysis of the acetal, followed by regioselective base-promoted deacetylation by neighboring group participation, furnished the diol 18. The primary alcohol of 18 then was protected as the trityl ether, and the free secondary alcohol was oxidized with manganese dioxide to the corresponding α,β-unsaturated ketone 20, which was obtained

Reagents and conditions: (a) (i) NaBH4, CH3OH, 0 °C, (ii) TBDPSCl, imidazole, DMF, rt (98%, two steps); (b) (i) C.P.E. (1.15 V vs SCE), 1% KOH/CH3OH, Pt wire (cathode)−Pt net (anode), 0 °C, (ii) 5% AcOH, acetone, (quant., two steps); (c) propane-1,3-diol, PPTS, benzene, reflux (90%); (d) (i) tBuOOH (TBHP), tBuOK, THF, −78 °C to −35 °C (57%), (ii) HF-pyr, CH3CN; (e) NaBH(AcO)3, CH3OH, 0 °C (43%, two steps). a

of gentisyl alcohol, 22, which was converted into the dimethylacetal 23 through anodic oxidation in 1% KOH− MeOH followed by regioselective monohydrolysis. It was necessary to perform an unplanned transketalization step to accomplish the epoxidation that, after deprotection of the 4685


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Scheme 5. Syntheses of (±)-Phyllostine, (±)-Epoxydon, (±)-Epiepoxydon, (±)-Epoformin, and (±)-Epipoformina

Reagents and conditions: (a) 5 °C; (b) H2O2; (c) H2CO, DBU, THF (29, 65%), (32a, 90%), (32b, 86%), (33a, 91%), (33b, 92%); (d) 140 °C (73%); (e) NaBH4, THF; (f) Ac2O, pyridine; (g) (i) tBuOK, DMF, (ii) CH3I; (h) KOH, H2O; (i) Δ, EtOAc.

a

Scheme 6. Syntheses of (+)- and (−)-Theobroxide, (+)-Epiepoformin, (+)-Epiepoxydon, and (−)-Phyllostinea

a Reagents and conditions: (a) lipase-mediated desymmetrization (79%); (b) (i) TBSCl, imidazole, DMF (88%), (ii) K2CO3, CH3OH, (iii) PDC (87% from (+)-41), (iv) 30% H2O2, Triton B, THF (88%); (c) KH, CH3I, THF (90%); (d) Ph2O, reflux (95%); (e) (i) NaBH4, CeCl3·7H2O, (ii) HF, CH3CN (82%); (f) (i) Piv2O, TEA, DMAP, DCM, (ii) K2CO3, CH3OH, (iii) TBSOTf, TEA (89%); (g) (i) CH3Li, THF, (ii) PDC, DCM (95%); (h) 30% H2O2, Triton B (80%); (i) KH, CH3I, THF (87%); (j) Ph2O, reflux (94%); (k) (i) NaBH4, CeCl3·7H2O, (ii) HF, CH3CN (80%); (l) HF, CH3CN (93%); (m) (i) TMSCl, TEA, THF, (ii) RhI-(S)-BINAP, DCE, (iii) TBAF, H2O (96%); (n) (i) NBS, (ii) TMSOTf, DIPEA, (iii) (AcO)2Pd, (iv) NaBH4, CeCl3·7H2O, (v) Ac2O, TEA, DMAP, (vi) Zn, AcOH, CH3OH (49% from 40); (o) (i) TBSCl, imidazole, (ii) K2CO3, (iii) 30% H2O2, Triton B, THF (80%); (p) H2CO, DBU (98%); (q) (i) Ph2O, reflux (87%), (ii) 46% HF−MeCN (86%); (r) PDC, DMF (37%).

alcohol, provided (±)-phyllostine. The overall yield from 21 to (±)-parasitenone was 22%.

ydon, (±)-epiepoxydon, (±)-epoformin, and (±)-epipoformin (Scheme 5),76 improving notably their previous syntheses. The cycloaddition of p-benzoquinone to dimethylfulvene delivered a 1:1 mixture of the endo and exo Diels−Alder adducts that, without isolation, were oxidized to the corresponding anti epoxides 28. These epoxides reacted with formaldehyde in the presence of diazabicycloundecene (DBU) to furnish the hydroxymethylated compound 29. The retro-Diels−Alder reaction of 29 afforded (±)-phyllostine. The syntheses of (±)-epoxydon and (±)-epiepoxydon were accomplished from the alcohols 30a,b and 31a,b, which were obtained by reduction of 28. These alcohols were treated with formaldehyde and converted into 32a,b and 33a,b that after the retro-Diels−Alder

5.2. Diels−Alder Strategies

Several successful approaches to gabosines and anhydrogabosines rely on Diels−Alder methodologies. In some cases, a Diels−Alder adduct derived from p-benzoquinone is conveniently elaborated, and then a retro-Diels−Alder process allows recovering the cyclohexene moiety. In other cases, both the diene and the dienophile are incorporated in the final compound. Ichihara and co-workers were the first to report a strategy based on Diels−Alder/retro-Diels−Alder processes to synthesize the anhydrogabosines (±)-phyllostine, (±)-epox4686


Chemical Reviews

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Scheme 7. Synthesis of (+)-Phyllostinea

reactions yielded (±)-epoxydon and (±)-epiepoxydon, respectively. The syntheses (±)-epoformin was completed starting from 30a. To avoid O-methylation of the free hydroxyl group, 30a was transformed into the acetate 34 before treatment with methyl iodide in the presence of potassium tert-butoxide to yield 36, which after saponification delivered the corresponding alcohol 37. The retro-Diels−Alder reaction of 37 furnished (±)-epoformin. A parallel sequence starting from 31b led to (±)-epiepoformin. Some years later, Ogasawara and co-workers developed an enantioselective version of Ichihara strategy and accomplished the syntheses of (+)- and (−)-theobroxide, (+)-epiepoformin, (+)-epiepoxydon, and (−)-phyllostine (Scheme 6). In a first publication,59 the enantioselectivity was originated by a lipasemediated desymmetrization of the tricyclic diol 40. Protection of the free hydroxyl group of the enantiomerically pure monoacetate (+)-41, followed by saponification, oxidation to the corresponding ketone, and then epoxidation from the less hindered exo face of the tricyclic system led to (+)-42, which was α-methylated to furnish (−)-43. The retro-Diels−Alder reaction of (−)-43 gave the epoxyketone (−)-44 that was stereoselectively reduced to the alcohol and, finally, desilylated to deliver (+)-theobroxide in eight steps from (+)-41 and 47% overall yield. A convenient modification of the hydroxyl protections allowed the preparation of the enantiomeric intermediates (−)-42 and (+)-44, which served as the precursors for the preparation of (−)-theobroxide and (+)-epiepoformin. In a second publication,62 the resolution of the meso 1,4-enediol 40 was performed in a different manner, by the RhI-(S)-BINAP-catalyzed asymmetrization of its bistrimethylsilyl ether. This alternative gave access to the monoacetate (−)-41, which was processed to the tetracyclic ketone (−)-42. Ketone (−)-42 was converted into (+)-epiepoxydon by α-hydoxymethylation, followed by retro-Diels− Alder reaction. The selective oxidation of (+)-epiepoxydon by treatment with pyridinium dichromate (PDC) in DMF yielded (−)-phyllostine. Recently, Ryu and co-workers reported a new and very efficient preparation of the key intermediate (−)-42 through the use of a catalytic asymmetric Diels−Alder reaction (Scheme 7).77a The cycloaddition of cyclopentadiene to 2-iodo-1,4quinone monoketal 50 in the presence of the oxazaborolidinium catalyst (S)-51 provided exclusively the endo adduct 52 with excellent enantioselectivity. Removal of the iodo group and then Luche reduction generated the alcohol 53, which was hydrolyzed to the corresponding free ketone 54. Conversion of ketone 54 in (−)-42 was accomplished by silylation and subsequent base promoted epoxidation. The overall yield for the sequence was 60%. In a second report of the same authors,77b the Diels−Alder adduct 52 was elaborated to (+)-phyllostine in five conventional steps, including reduction of the C−I bond, nucleophilic epoxidation, hydroxymethylation at the α-carbonyl position, ketal hydrolysis, and retro-Diels− Alder reaction. The overall yield from the starting diene was 72%. An analogous sequence was applied to the synthesis of the natural antipode, (−)-phyllostine, by using the R enantiomer of the catalyst in the initial cycloaddition process. In 2002, the group of Taylor described a new synthesis of racemic epiepoxydon, where the most significant feature was the use of a Baylis−Hillman reaction to introduce the hydroxymethyl substituent (Scheme 8).78 The key epoxyquinol 60 was prepared through a modified version of a route previously developed by Ogasawara.79 Thus, the endo cyclo-

Reagents and conditions: (a) DCM, −78 °C, (95%); (b) (i) Bu3SnH, benzene, 80 °C (88%), (ii) CeCl3·7H2O, NaBH4, CH3OH, −78 °C (92%); (c) 1 N H2SO4, acetone−THF (1:1), rt (92%); (d) (i) TBSCl, imidazole, DMF, 0 °C (90%), (ii) 30% H2O2, DBU, CH3CN, 0 °C (86%); (e) (i) nBu3SnH, benzene, 80 °C (88%), (ii) 30% H2O2, DBU, CH3CN, 0 °C (92%); (f) 37% formaldehyde, DBU, THF, 0−25 °C (98%); (g) (i) 1 N H2SO4, acetone−THF, 60 °C (98%), (ii) Ph2O, 230 °C (98%). a

n

Scheme 8. Synthesis of (±)-Epiepoxydona

Reagents and conditions: (a) CH3OH, 0 °C (74%); (b) TBHP, TBD, CH3CN (85%); (c) L-Selectride, THF (52%); (d) Ph2O, reflux (94%); (e) TESCl, imidazole (86%); (f) (CH2O)n, Et3Al, nBu3P, DCM (44%); (g) HF·pyridine, CH3OH (70%). a

adduct 57 resulting from the Diels−Alder reaction of cyclopentadiene and p-benzoquinone was epoxidized with complete exo selectivity, using tert-butyl hydroperoxide and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). The reduction of the diketoepoxide 58 with L-Selectride or Superhydride furnished the hydroxyketone 59, which upon thermolysis delivered 60. It was necessary to protect the hydroxyl group before performing the hydroxymethylation step, and, among all of the silylether protections assayed, the triethylsilyl (TES) derivative 61 gave the best results. The optimal conditions for the Baylis−Hilman reaction were established after extensive experimentation, and moderate yields of 62 were only obtained by using triethylaluminum/trin-butylphosphine catalysis under very strict control of the reaction conditions. After desilylation, the synthesis of (±)-epiepoxydon was completed in 6.7% overall yield from p-benzoquinone. Metha and co-workers, making use of a lipase-catalyzed acetylation of a compound derived from the cyclopentadiene and p-benzoquinone Diels−Alder adduct 57 previously used by Taylor in his synthesis of (±)-epoxydon, accomplished the syntheses of (+)-epiepoxydon, (+)-epoxydon, (−)-phyllostine, 4687


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Scheme 9. Syntheses of (+)-Epiepoxydon, (+)-Epoxydon, (−)-Phyllostine, (+)-Streptol, (−)-RKTS-33, and Putative (−)-Parasitenonea

a

Reagents and conditions: (a) 30% H2O2, Na2CO3, acetone (96%); (b) HCHO, DBU, THF (95%); (c) TBSCl, imidazole, DMAP, DMF (92%); (d) NaBH4, CH3OH (81%); (e) lipase PS-D (Amano), AcOCHCH2 ((−)-65, 45%/(+)−66, 46%); (f) Ph2O, reflux (93%); (g) LiOH, CH3OH (75%); (h) HF·pyridine, THF (80%); (i) (i) Ph3P, DIAD, PNBA, THF, (ii) LiOH, CH3OH (65%, two steps); (j) HF·pyridine, THF (76%); (k) (i) PDC, DCM (89%), (ii) HF·pyridine, THF (72%); (l) BF3·OEt2, toluene (62%); (m) Ac2O, pyridine, DCM (quant.); (n) Ph2O, reflux (91%); (o) (i) NaBH4, CeCl3·7H2O, CH3OH (80%), (ii) HF·pyridine, THF (83%), (iii) CH3ONa, CH3OH (96%); (p) NaBH4, CH3OH (87%); (q) TBSOTf, 2,6-lutidine, DCM (83%); (r) (i) LiOH, CH3OH (70%), (ii) MnO2, DCM (83%); (s) HF, CH3CN (80%); (t) (i) LiOH, CH3OH (68%), (ii) MnO2, DCM (86%); (u) HF, CH3CN (80%).

(+)-streptol, (−)-RKTS-33, and the putative (−)-parasitenone (Scheme 9).33,61 Epoxidation of (±)-57 and further reaction with formalin in the presence of DBU led stereoselectively to the hydroxymethyl derivative (±)-63, which was protected as the corresponding tert-butyldimethylsilyl (TBS) ether (±)-64. Sodium borohydride reduction of (±)-64 afforded regio- and stereoselectively the endo alcohol (±)-65. Exposure of (±)-65 to lipase PS-D in vinyl acetate led to the isolation of (−)-65 and the acetate (+)-66, with excellent yield and enantioselectivity. On thermal activation, the acetate (+)-66 underwent a retro-Diels−Alder reaction to deliver the epoxyquinol (+)-67, which was hydrolyzed to (+)-68. From alcohol (+)-68, the syntheses of (+)-epiepoxydon and (−)-phyllostine were immediately completed, while the synthesis of (+)-epoxydon required a stereochemical inversion that was accomplished following the Mitsunobu protocol. For the synthesis of (+)-streptol, the enantiopure acetate (+)-66 was subjected to BF3-mediated and acetate-assisted regioselective cleavage of the epoxide to furnish the trans diol (+)-70, which was protected as the diacetate previous to the retro-Diels−Alder process. The syntheses of the epimeric compounds (−)-RKTS-33 and putative (−)-parasitenone were completed from the epoxyenone (+)-67 in a stereodivergent manner after few easy transformations. It was detected that the spectroscopic data of

the synthetic sample with the structure assigned to parasitenone did not match those of the natural compound, being established that the natural product named parasitenone was in fact (+)-epoxydon. In the other reported syntheses based on Diels−Alder reactions, the formed cyclohexene ring is incorporated in the final product. An early example of this type was described by Suami and co-workers in 1983. These authors obtained racemic streptol together with other products in the course of a study related to the bromination reaction of a polyacetoxylated, conjugated methylenecyclohexene (Scheme 10).80 Thus, the triacetate 80 was prepared in several steps from the Diels− Alder adduct of furan and acrylic acid 77. Bromination of 80 in acetic acid−acetic anhydride furnished the dibromo derivative 81, among other products. A mixture of tetraacetates 82/83 was isolated as major product from the reaction of 81 with silver acetate in acetic acid. Acetylation of this mixture delivered a sole pentaacetate, which was converted into (±)-streptol by methanolysis under basic conditions. Alternatively, treatment of dibromide 81 with silver acetate in acetic acid−acetic anhydride gave mainly the pentaacetate 84, with retention of configuration at the allylic stereocenter, whose methanolysis produced (±)-4-epi-streptol. The overall yield from 78 was 4688


Chemical Reviews

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anhydride gave the crotonate 90. Reoxidation of the sulfide to sulfoxide followed by treatment with trifluoroacetic acid delivered (−)-COTC in eight steps and 30% overall yield from 85, after deprotection of the ketal group and spontaneous β-elimination of the sulfoxide. Some years later, as part of their investigations devoted to the study of the high-presure-mediated asymmetric Diels−Alder reaction of chiral sulfinylacrylate derivatives, Takahashi and coworkers reported an almost identical sequence toward (−)-gabosine C and (−)-COTC (Scheme 12).81 To assess

Scheme 10. Syntheses of (±)-Streptol and (±)-4-epiStreptola

Scheme 12. Syntheses of (−)-Gabosine C and (−)-COTCa

Reagents and conditions: (a) 15% HBr, AcOH, 75 °C (70%); (b) DBU, toluene (45%); (c) 5% Br2, AcOH−Ac2O (3:1) CCl4 (45%); (d) AcOAg, 90% AcOH, 90 °C (56%); (e) (i) Ac2O, H2SO4 cat. (95%), (ii) MeONa, CH3OH, 0−5 °C (87%); (f) AcOAg, 90% AcOH−Ac2O, 90 °C (73%); (g) MeONa, CH3OH, 0−5 °C (98%). a

7% and 22% for (±)-streptol and (±)-4-epi-streptol, respectively. In 1986, Koizumi and co-workers reported the first enantioselective synthesis of (−)-COTC. The sequence started from reaction of 2-methoxyfuran, 86, as the diene, and a chiral arylsulfinylacrylate 85 as the dienophile (Scheme 11).31 The Scheme 11. Synthesis of (−)-COTC

a

Reagents and conditions: (a) DCM, 1.2 GPa; (b) OsO4, (CH3)3NO, acetone (53% from 92); (c) 2,2-dimethoxypropane, PTSA, acetone (64%); (d) LiAlH4, THF; (e) TFA, H2O (51%); (f) crotonic anhydride, pyridine, DMAP, benzene (43% from 95); (g) TFA, H2O (29%).

a

the absolute configuration of 93, the unstable cyclohexene that was the major product of the corresponding endo stereoselective cycloaddition between 86 and the chiral acrylate 92, the adduct was converted to (−)-gabosine C and (−)-COTC. To this aim, the carbon−carbon double bond of 93 was dihydroxylated affording 94 in 53% yield for the two steps. Acetonide formation and then reduction with lithium aluminum hydride gave alcohol 96, which was esterified with crotonic anhydride to furnish 97. Treatment of 96 and 97 with trifluoroacetic acid gave (−)-gabosine C and (−)-COTC, in overall yields from 92 of 17% and 4%, respectively. In 2001, Okamura and co-workers described the preparation of compound (+)-44, the ultimate precursor of (−)-theobroxide and (+)-epiepoformin in Ogasawara’s syntheses, through a different pathway involving also the use of a chiral auxiliary in a Diels−Alder cycloaddition (Scheme 13).65 Thus, the basecatalyzed Diels−Alder reaction between the optically active oxazolidinone acrylamide derivative 98 and 3-hydroxy-2pyrone, 99, took place quantitatively with excellent diastereoselectivity. The cycloadduct 100 was converted into the αhydroxymetylcyclohexenone (−)-102 in four trivial steps and 53% total yield. The epoxidation of (−)-102 with hydrogen peroxide and Triton B occurred stereoselectively, furnishing a mixture of epimeric epoxides 103, which were dehydrated to the exocyclic olefin (−)-104. The isomerization to the endocyclic position of the double bond in (−)-104 delivered

a Reagents and conditions: (a) toluene; (b) (i) OsO4, Me3NO, (ii) 2,2dimethoxypropane, PTSA (72% from 85); (c) (i) TiCl3, EtOH, (ii) LiAlH4, THF (78%, two steps); (d) crotonic anhydride, pyridine (quant.); (e) MCPBA, DCM, NaHCO3 aq (85%); (f) TFA, H2O (62%).

chiral acrylate 85 was prepared in three steps from menthyl (Men) propiolate. The Diels−Alder reaction between 85 and 86 took place with high endo selectivity to furnish the cycloadduct 87. The double bond in 87 was dihydroxylated, and subsequent protection of the diol as the acetonide afforded 88. The sulfoxide and ester groups in 88 were successively reduced with TiCl3 and LiAlH4, respectively, affording the sulfide 89. Esterification of 89 by treatment with crotonic 4689


Chemical Reviews

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Scheme 13. Syntheses of (+)-Epiepoformin and (−)-Phyllostinea

Scheme 14. Syntheses of (±)-Gabosine B and Putative (±)-Gabosine Ka

a

Reagents and conditions: (a) cinchonidine, iPrOH, H2O (quant.); (b) (i) CH3ONa, CH3OH, (ii) TBSCl, imidazole; (c) (i) LiAlH4, THF, (ii) NaIO4, THF, H2O (53% from 100); (d) 30% H2O2, Triton B, THF (92%); (e) TsCl, TEA, DMAP (94%); (f) Pd/C (70%); (g) HF·CH3CN (99%); (h) OsO4, NMO, THF, H2O (99%); (i) Im2CO, DMAP, DCM (84%); (j) (i) CSA, CH3OH (82%), (ii) CrO3, H2SO4, acetone (76%).

Reagents and conditions: (a) (i) Δ, (ii) H2SO4, CH3OH, (iii) Na, NH3, EtOH (80% from 108), (iv) TsCl, pyridine, DMAP, DCM (90%), (v) OsO4, NMMNO, acetone, H2O (84%), (vi) Amberlyst-15, acetone, H2O (90%); (b) CH3ONa, CH3OH (70%); (c) OsO4, NMMNO (95%); (d) Amberlyst-15, 4 Å MS, acetone (85%); (e) (i) LiAlH4 (82%), (ii) TsCl, pyridine (94%); (f) (i) NaI, acetone (92%), (ii) tBuOK, tBuOH (70%); (g) RhCl3, NaHCO3, EtOH (60%); (h) 5% HCl, Et2O, H2O (90%); (i) OsO4, NMMNO, acetone, H2O (95%); (j) (i) Ac2O, DMAP (100%), (ii) SOCl2, pyridine; (k) Amberlyst-15, THF, H2O (85%); (l) 5% HCl, rt (>95%). a

(+)-44. In a complementary manner, the exocyclic enone was dihydroxylated and converted in the carbonate 106, which was deprotected and then oxidized to furnish (−)-phyllostine.64 Through these sequences, the total syntheses of (+)-epiepoformin and (−)-phyllostine were accomplished in 9 and 11 steps in 32% and 24% overall yields, respectively. In 2000, Mehta and Lakshminath reported an original route to polyoxygenated cyclohexenoids,12a,82 in which the key step was a fragmentation of a norbornane derivative, involving a carbon−carbon bond scission (Scheme 14). The starting norbornenone 109 was prepared in several steps from the inverse-demand Diels−Alder adduct of vinyl acetate, 107, and the cyclopentadiene derivative 108. The sodium methoxydepromoted fragmentation of 109 provided a dioxycyclohexenecarboxylate 111, which was further elaborated to the tetroxymethylenecyclohexane 112. In five simple steps, compound 112 was converted into the exocyclic olefin 115. A rhodium trichloride-promoted isomerization of the exocyclic double bond in 115, followed by simple hydrolysis, concluded the first total synthesis of (±)-gabosine B in nine steps and 15% overall yield from 109. Alternatively, the diol 117, obtained by stereoselective dihydroxylation of the double bond in 115, was acetylated, with concomitant elimination at the endocyclic position, to give the allylic acetate 118. Full hydrolysis of 118 produced the natural metabolite (±)-MK7607, while selective hydrolysis of the acetal groups resulted in the formation of a compound with the structure previously assigned to gabosine K, but its physical data did not match those of the natural product. In 2003, Kakeya, Osada, and co-workers, as part of a study directed to the design of nonpeptide inhibitors of Fas-mediated apoptosis,56 described, among others, the first synthesis of RKTS-33 (Scheme 15). The Diels−Alder adduct of furan and

acryloyl chloride, 119, was submitted to hydrolysis followed by iodolactonization to afford 121. 83 Conversion of the iodolactone to cyclohexenol (±)-122 occurred through a sequential process involving opening of the lactone ring, intramolecular substitution, and methyl ester formation followed by E1CB elimination with simultaneous opening of the tetrahydrofuran ring. A kinetic resolution of (±)-122 by Pseudomonas stutzeri lipase (Meito TL) afforded (+)-122 and the acetate (−)-123. Epoxidation of alcohol (+)-122 proceeded diastereoselectively to provide the bis-epoxide (+)-124. The reduction of the ester in (+)-124 and TBS protection of the generated primary alcohol afforded the silyl ether (+)-125. The oxidation of (+)-125 with the Dess−Martin periodinane (DMPI), followed by isomerization with silica gel, produced the enone (+)-126. Deprotection of the alcohol gave (+)-RKTS-33. The overall yield from (+)-122 was 55%. 5.3. From Benzene Derivatives

In a few approaches, the precursor of the cyclohexene core of the target compound is a benzene derivative, which is submitted to an oxidative desymmetrization. The first synthesis of (±)-epiepoxydon reported belongs to this category (Scheme 16). It was published in 1980 by Ganem and co-workers as part of a study devoted to the biosynthesis of patulin.84 Their synthesis started from 1,4-dihydrobenzoic acid, 127, which was 4690


Chemical Reviews

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Scheme 15. Synthesis of RKTS-33a

(Scheme 17) starting from the cis-1,2-dihydrocatechol 137, a material readily prepared in enantiopure form by toluene Scheme 17. Synthesis of (−)-Gabosine Aa

a

Reagents and conditions: (a) NaOH aq; (b) (i) I2, DCM, (ii) Na2S2O3 aq (55% from 119); (c) (i) KOH, DMF, then CH3I (94%), (ii) LDA, THF (92%); (d) Meito TL (lipase), AcOCHCH2 ((+)-122, 50%/(−)-123, 50%); (e) VO(acac)2, TBHP, DCM (96%); (f) (i) NaBH4, CH3OH, (ii) TBS, TEA, DMAP, DCM (81%, two steps); (g) (i) DMPI, DCM, (ii) SiO2, toluene (quant., two steps); (h) Amberlyst-15, iPrOH (71%).

Reagents and conditions: (a) TBDPS, imidazole, DCM (97%); (b) OsO4, NMMNO, acetone, H2O (98%); (c) 2,2-dimethoxypropane, PTSA, TEA (85%); (d) (COCl)2, DMSO, TEA (90%); (e) CH3MgCl, FeCl3, NMP, THF (94%); (f) (i) HCl aq CH3OH, (ii) (Me2N)3S+F2SiMe3−, THF (85%).

Scheme 16. Synthesis of (±)-Epiepoxydona

dioxygenase-mediated dihydroxylation of iodobenzene. The less sterically hindered hydroxyl group of 137 was selectively protected, and the silyl ether 138 was converted into the acetonide (+)-140, via the triol 139 resulting from the selective dihydroxylation of the more nucleophilic double bond. Swern oxidation of alcohol (+)-140 gave the corresponding ketone (+)-141, in which the iodine was replaced by a methyl group by reaction with methylmagnesium chloride in the presence of iron(III) chloride under very mild conditions. Treatment of (−)-142 with methanolic HCl followed by desilylation provided (−)-gabosine A in 58% overall yield from 137. Some years later, Whitehead and co-workers described the synthesis of (−)-6-epi-COTC85 using a strategy similar to that of Banwell. The synthetic route was first set up for the racemic target (Scheme 18). The choice of the appropriate protecting groups was crucial for the success of every individual step. Thus, the acetonide of the meso diol 143, derived from enzymatic dihydroxylation of benzene, was stereoselectively dihydroxylated to (±)-144. The allylic hydroxyl group was selectively protected as its 2-naphtylmethyl (Napht) ether via an intermediate stannylene acetal, the acetonide was hydrolyzed, and the vicinal trans-diequatorial hydroxyl groups were subsequently protected as their butane methyl mixed diacetal derivative 146. PCC oxidation of the secondary carbinol led to the cyclohexenone 147 whose imidazole-mediated Morita− Baylis−Hillman reaction permitted the introduction of the αhydroxymethyl chain. The resulting alcohol (±)-148 was then esterified with crotonic anhydride leading to (±)-149. Full deprotection of the masked functionalities delivered the racemic target in 2.7% overall yield from 143. The asymmetric synthesis of (−)-6-epi-COTC required the preparation of enantiopure diol (−)-144. This was accomplished from the enantiomerically pure iododiol 137. Formation of the acetonide derivative of 137 followed by cis-dihydroxylation gave diol (+)-150, and subsequent chemoselective reduction of the C−I bond yielded (−)-144. As part of these studies, other COTCanalogues were also prepared, and their activity as antitumor agents was investigated.86

a

a

Reagents and conditions: (a) Br2, DCM (62%); (b) NaHCO3 aq (65%); (c) NBS, CCl4 (70%); (d) AcONa, HMPA (43%); (e) 10% H2SO4, THF (80%); (f) CF3CO3H, DCE (92%); (g) (i) TMSCl, TEA (91%), (ii) LiBH4, THF (97%); (h) (ClCH2CO)2O, pyridine, DCM (95%); (i) CrO3 (98%); (j) NaHCO3, CH3OH (68%).

converted in the key lactone intermediate 132 in five steps involving bromine addition, base-promoted cyclization, allylic bromination, syn-SN2′ substitution of the bromine by acetate, and hydrolysis. The overall transformation from 127 to 132 was accomplished in ca. 10% yield. Lactone 132 was stereoselectively epoxidized to 133, which, after silylation and subsequent reduction with lithium borohydride, furnished the bromodiol 134. The diol 134 was converted into the bis(αchloroacetyl) derivative 135, which, exposed to Jones reagent, was hydrolyzed and oxidized in one step to the ketodiester 136. Alcoholysis of the crude oxidation product furnished (±)-epiepoxydon in 52% overall yield from 132. In 2001, Banwell and co-workers reported the first synthesis of (−)-gabosine A through a very short and efficient sequence23 4691


Chemical Reviews

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Scheme 18. Synthesis of (−)-6-epi-COTCa

met with failure, and it was necessary to modify the hydroxylic protection. Finally, the methyl derivative could be prepared from the TES ether 155 albeit in only 37% yield, and then desilylation provided (−)-epiepoformin. More recently, they reported the first synthesis of (+)-isoepiepoformin, the α-methylated congener of (+)-epiepoformin, from the same starting material and through a similar sequence based on the same strategy (Scheme 20).67 In Scheme 20. Synthesis of (−)-Isoepiepoformina

Reagents and conditions: (a) (i) p-MBDMA, PTSA·H2O, THF, 0 °C (97%), (ii) DIBALH, TBME, −78° to 0 °C; (b) NBS, H2O−THF, 18 °C (11%, two steps); (c) NaOMe, THF, 18 °C (99%); (d) DMPI, DCM, 18 °C (92%); (e) Me4Sn, Pd2(dba)3, Ph3As, NMP, 18 °C (63%); (f) (i) DDQ, H2O−DCM, 18 °C (48%); (ii) ClCH2COOH, DBAD, Ph3P, THF, 18 °C (73%); (g) Zn(AcO)2, CH3OH, 18 °C (66%). a

a

Reagents and conditions: (a) (i) 2,2-dimethoxypropane, PTSA, (ii) OsO4, NMO, tBuOH, H2O (57%, two steps); (b) Bu2SnO, toluene, CH3OH, 2-bromoethylnaphtalene, Bu4NI (76%); (c) H2O, TFA, THF, then butan-2,3-dione, (CH3O)3CH, CSA, CH3OH, (46%); (d) PCC, DCM (76%); (e) H2CO, imidazole, NaHCO3 aq (68%); (f) crotonic anhydride, pyridine, DMAP, DCM (50%); (g) (i) DDQ, DCM, CH3OH (66%), (ii) TFA, H2O (98%); (h) (i) 2,2dimethoxypropane, PTSA, (ii) OsO4, NMO, tBuOH, H2O (81%, two steps); (i) H2, Pd/C, TEA, CH3OH (71%).

this case, the vicinal diol in 137 was converted into the corresponding p-methoxybenzyl (PMB) acetal by acidcatalyzed reaction with p-methoxybenzaldehyde dimethyl acetal (p-MBDMA), which upon treatment with diisobutylaluminium hydride (DIBALH) furnished a 2.5:1 inseparable mixture of the two possible p-methoxybenzyl (PMB) ethers, where the regioisomer 156 predominated. Treatment of this mixture with NBS provided the bomohydrine 157, as the only isolable product in 11% yield. The bromohydrine was selectively converted into the epoxide 158 with the exclusive participation of the non allylic hydroxyl group. The remaining steps to the target parallelized totally those of the above synthesis of (−)-epiepoformin: oxidation to ketone 159, Stille crosscoupling reaction to furnish 160, deprotection followed by Mitsunobu inversion to 161, and, finally, hydrolysis of the ester to deliver (+)-isoepiepoformin in a total of nine steps and 1.5% yield from 137. In 2003, Müller and co-workers described an efficient microbial access to (2S,3S)-2,3-dihydroxy-2,3-dihydrobenzoic acid, (+)-162, with engineered cells of Escherichia coli.88 Diol (+)-162 was used as the starting material for the preparation of (−)-streptol, the enantiomer of the naturally occurring metabolite (Scheme 21). The synthesis allowed establishing the absolute configuration of (+)-162. The acid (+)-162 was transformed in its methyl ester, which was then converted in the bis-TBS ether (+)-163. The good face selectivity accomplished in the next dihydroxylation step was favored by the bulky TBS protecting groups. The ester group in (−)-164 was reduced to the primary alcohol (+)-165 by treatment with DIBALH, and subsequent deprotection gave (−)-streptol in 28% overall yield from (+)-162.

In subsequent studies, the group of Banwell extended the applicability of the enantiomerically pure iododihydrocatechol 137 as a key synthon for the preparation of other epoxyquinol derivatives. In particular, (−)-epiepoformin was prepared from 137 in eight steps and 4% total yield (Scheme 19).87 Treatment of 137 with N-bromosuccinimide (NBS) and water in THF produced the bromohydrine 151, which was converted in the epoxide 152. Selective inversion of the alcohol remote from the iodine by a Mitsunobu reaction furnished the monoacetate 153, which was oxidized to the α-iodoenone 154. The intended Stille cross-coupling reaction of 154 with tetramethylstannane Scheme 19. Synthesis of (−)-Epiepoformina

Reagents and conditions: (a) NBS, H2O−THF, 20 °C (66%); (b) NaOMe, THF, 20 °C (79%); (c) (tBuOCON)2, PPh3, ClCH2COOH, THF, 20 °C (77%); (d) PDC, AcOH, DCM, 20 °C (75%); (e) (i) Zn(AcO)2, CH3OH, 20 °C (87%), (ii) TESCl, 2,6-lutidine, DCM, 0− 20 °C, (55%); (f) (i) Me4Sn, Pd0, Ph3As, CuI, THF, 80 °C (37%), (ii) HF·pyridine, CH3CN, 20 °C (78%). a

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Scheme 21. Synthesis of (−)-Streptola

Scheme 23. Syntheses of (+)-Gabosine C and (+)-Gabosine Ea

a

Reagents and conditions: (a) (i) HCl, CH3OH, (ii) TBSOTf, TEA, DCM (57%, two steps); (b) NMO, MeSO3NH2, KOsO4, acetone, n BuOH, H 2 O (56%); (c) DIBALH, DCM (92%); (d) (Me2N)3S+F2SiMe3− (96%).

5.4. From Carbohydrates

Most successful syntheses of gabosines have been accomplished starting from carbohydrates. Pioneer among them were the syntheses of (−)-gabosine C and (−)-COTC developed by Vasella and co-workers (Scheme 22).26 The pseudolactone Scheme 22. Syntheses of (−)-Gabosine C and (−)-COTCa Reagents and conditions: (a) CH2CHMgBr, THF (90%); (b) (i) TBSCl, pyridine, DMAP, (ii) BzCl, pyridine, (iii) 2,3-DHF, PPTS, DCM (73%, three steps); (c) (i) TBAF, THF, (ii) (COCl)2, DMSO, TEA, THF, (iii) HCl·H2NOH, pyridine, CH3OH (81%, three steps); (d) NaClO, TEA, DCM (60%); (e) H2, Ni-Raney, EtOH, AcOH (89%); (f) DABCO, THF (80%); (g) TFA, DCM (95%); (h) TFA, DCM (100%). a

highly diastereoselective manner. Conversion to the cycloaddition precursor required oxidation of the primary hydroxyl group and formation of the corresponding oxime. To accomplish this, the primary hydroxyl was protected as the TBS ether, then the most reactive allylic secondary hydroxyl was selectively transformed into its benzoate, and, finally, the remaining hydroxyl group was protected as the tetrahydrofuranyl (THF) derivative. Compound 172 was converted to the oxime 173 using standard procedures. With this combination of protecting groups, the INOC reaction took place in an acceptable 60% yield. Conversion of the cycloadduct 174 into gabosines C and E involved reductive cleavage of the isoxazole ring and elimination of benzoic acid. This elimination could be effected in good yield by treatment of 175 with 1,4diazabicyclo[2.2.2]octane (DABCO), but epimerization at C6 occurred more rapidly and the product was obtained as a mixture of the two epimeric enones 176a and 176b. The conversion of these enones into (+)-gabosines C and E was achieved by treatment with trifluoroacetic acid. More recently, Shing and co-workers employed also an INOC reaction to form the cyclohexane ring in the syntheses of other gabosines starting from sugars (Scheme 24).29 In their approach, the dipolarophile moiety was introduced by addition of allylmagnesium bromide to the protected carbohydrate, and the aldehyde precursor of the oxime was formed by oxidative cleavage. Thus, oxime 179, prepared from D-mannose, produced a mixture of the two epimeric cycloadducts 180 in 79% overall yield. Reductive cleavage of the heterocyclic ring delivered the corresponding ketodiols 181, which could be converted into the unstable exocyclic olefin 182 by treatment with bis[α,α-bis(trifluoromethyl)benzyloxy]diphenylsulfur (Martin’s sulfurane). In situ hydrogenation of 182 proceeded stereoselectively to furnish the β-methylketone 183, the

a

Reagents and conditions: (a) CH3PO(OCH3)2, nBuLi, THF (62%); (b) PhSH, HCHO, Al(CH3)3, DCM (66%); (c) MCPBA, DCM (91%); (d) TFA, H2O (100%); (e) (i) crotonic acid, DCC, CH3CN, (ii) TFA, H2O (82%, two steps).

(−)-166 was prepared from methyl α-D-mannopyranoside and was reacted with dimethyl methylphosphonate lithium anion, leading, in an intramolecular Horner−Wadsworth−Emmons (H−W−E) reaction, to the protected trihydroxycyclohexenone (−)-167. Treatment of (−)-167 with dimethylaluminium phenylsulfide and then formaldehyde furnished the hydroxymethylketone (−)-168, whose oxidation and subsequent elimination delivered the conjugated olefin (−)-169. Deprotection of (−)-169 led to (−)-gabosine C in 18% overall yield from methyl α-D-mannopyranoside. Esterification of (−)-gabosine C gave (−)-COTC. Alternatively, (−)-COTC was obtained in higher yield by esterification of (−)-169, followed by deprotection of the hydroxyl groups. In 1994, Lygo and co-workers described the synthesis of unnatural (+)-gabosine C, along with that of its epimer at C-6, (+)-gabosine E, starting from D-ribose (Scheme 23).89 The carba-sugar skeleton was formed through an intramolecular nitrile oxide cycloaddition (INOC), the success of which depends of the correct choice of the protecting groups. The monoacetonide 170, derived from D-ribose, was treated with an excess of vinylmagnesium bromide to give the olefin 171 in a 4693


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Scheme 25. Synthesis of (+)-Gabosine Fa

Scheme 24. Syntheses of (−)-Gabosine O and (+)-4-epiGabosine Oa

a Reagents and conditions: (a) (i) BnOH, H+, rt (91%), (ii) 2,2,3,3tetramethoxybutane, (±)CSA, CH3OH, reflux (77%); (b) (i) 10% Pd/ C, H2, EtOH, rt, (ii) allyl magnesium bromide, THF, −78 °C to rt (49% from 186); (c) (i) NaIO4, silica gel, DCM, rt, (ii) NH2OH, CH3OH, rt (98% from 187); (d) Chloramine-T, silica gel, EtOH, rt (94%); (e) H2, Raney Ni, AcOH, EtOH−H2O−dioxane, rt (90%); (f) (i) AcCl, 2,4,6-collidine, DCM, −78 °C (87%), (ii) Et3N, DCM; (g) H2, Raney Ni, AcOH, EtOH−H2O−dioxane, rt (84% from 190); (h) TFA, H2O, DCM, rt (100%).

a

Reagents and conditions: (a) (i) acetone, H+, rt (92%), (ii) allyl magnesium bromide, THF, −78 °C to rt (83%); (b) (i) H5IO6, Et2O, rt (79%), (ii) NH2OH, CH3OH, rt (100%); (c) chloramine-T, silica gel, EtOH, rt (79%); (d) H2, Raney Ni, AcOH, EtOH−H2O−1,4dioxane, rt (97%); (e) Martin’s sulfurane, THF, −78 °C; (f) H2, Raney Ni, AcOH, EtOH−H2O−1,4-dioxane, −78 °C; (g) TFA, H2O, DCM, rt (89% from 181); (h) (i) PPh3, DIAD, p-NO2BzOH, (ii) LiOH (aq) (98%).

Scheme 26. Synthesis of (−)-ent-Gabosine Ea

ultimate precursor of (−)-gabosine O.90 A parallel sequence of reactions applied to 184, the Mitsunobu inversion product of 180, ended with (+)-4-epigabosine O. The overall yields from D-mannose to (−)-gabosine O and (+)-4-epigabosine O were 41% and 38%, respectively. In the same article, they also described the synthesis of (+)-gabosine F in 12 steps from L-arabinose, 185, and 23% total yield, following a similar pathway (Scheme 25). This synthesis differs from the previous ones in the C2−C3 glycol protective group and the method employed to generate the conjugated double bond of the enone 191, which is formed by acetylation of the primary alcohol in 190 and then treatment with triethylamine. Notably, the INOC reaction (188→189) proceeds in this case with complete diastereoslectivity, although this fact is inconsequential for the synthesis, and no explanation is given by the authors. In a contemporary article, Gallos and co-workers disclosed a synthesis of ent-gabosine E starting from D-mannose and including also an intramolecular dipolar cycloaddition to generate the cyclohexane as the key step, although in this case the 1,3-dipole was a nitrone (Scheme 26).91 The commercially available mannopyranoside 193 was converted into the tribenzyl derivative 194 by standard protocols. Next, the primary alcohol was oxidized to the aldehyde, followed by Wittig olefination and then hydrolysis that furnished the hemiacetal 195. Treatment of this intermediate with Nmethylhydroxylamine led to a mixture of two epimeric cycloadducts 196 in 80% combined yield and 2:1 ratio. The synthesis was continued from the major adduct by cleavage of the N−O bond, followed by silylation of the primary alcohol. The enone moiety was generated from 197 by quaternization of the amino group and subsequent oxidative elimination that delivered the protected gabosine 198. Removal of the protecting groups was accomplished by reaction with BBr3,

Reagents and conditions: (a) (i) TrCl, pyridine, 20 °C (84%), (ii) BnCl, NaH, DMF, 20 °C (90%); (iii) H2SO4, CH3OH, 20 °C (84%); (b) (i) (COCl)2, DMSO, Et3N, DCM, −60 °C then Ph3P+CH3Br−, n BuLi 1.6 M in hexanes, THF, −70 °C (72%), (ii) H2SO4, Ac2O, 0 °C, then EtONa, EtOH, 0 °C (91%); (c) MeNHOH·HCl, EtONa, EtOH, 20 °C (53%); (d) (i) separate diastereomers, (ii) Zn, AcOH, reflux, (iii) TBSOTf, 2,6-lutidine, DCM, −78 °C (77%) ; (e) (i) excess MeI, K2CO3, THF, (ii) DMPI, DCM, 20 °C, (80% from 197); (f) BBr3, DCM, −78 °C (85%). a

completing the synthesis of ent-gabosine E in 11 steps and 12% total yield from the starting mannose derivative 193. In 1998, Tatsuta and co-workers disclosed new syntheses of (−)-gabosine C and (−)-COTC starting from a D-ribose derivative (Scheme 27).92 The O-trityl derivative of Dribonolactone 199 was silylated, followed by reductive Odetritylation to give the alcohol 200. Oxidation and acetal formation gave 201, which upon reaction with lithiated methyl phenyl sulfone afforded the furanose 202. This compound was silylated to produce the labile enol silyl ether 203. The SnCl4promoted cyclization of 203 furnished the cyclohexenone 204. 4694


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Scheme 27. Syntheses of (−)-Gabosine C and (−)-COTCa

aldehyde 211. The Cr/Ni-catalyzed N−H−K reaction smoothly promoted the cyclization of the vinyl bromide 211 and furnished 212 in 61% yield. Oxidation of the allylic alcohol 212 with pyridinium chlorochromate (PCC) in the presence of sodium acetate delivered the enone 213 that was debenzylated to give (−)-gabosine I in nine steps and 15% overall yield. The absolute configuration of natural gabosine I had not been previously reported. The negative value of the specific rotation of the synthesized material indicated that the natural compound has the gluco configuration. In a new synthesis of (−)-gabosine C reported by Ramana and Rao in 2005, a crucial step was also the N−H−K reaction, in this case through an intermolecular process (Scheme 29).27 Scheme 29. Synthesis of (−)-Gabosine Ca

a Reagents and conditions: (a) (i) TBSOTf, 2,6-lutidine, (ii) H2, Pd/C (82%, two steps); (b) (i) DCC, pyridine·TFA, DMSO, Et2O, (ii) HC(OCH3)3, CSA, CH3OH (79%, two steps); (c) CH3SO2Ph, nBuLi, THF (90%); (d) TBSOTf, 2,6-lutidine (74%); (e) SnCl4, DCM (85%); (f) (i) nBu3SnLi, HCHO, (ii) SiO2, toluene (70%, two steps); (g) TFA, H2O (86%); (h) crotonic acid, BF3·OEt2, CH3CN (71%).

A Michael-type addition of tributylstannyllithium followed by trapping with formaldehyde and desulfonylation by treatment with silica gel afforded the hydroxymethylcyclohexenone 205. Desilylation of 205 led to (−)-gabosine C that was esterified to (−)-COTC with overall yields of 22% and 16%, respectively. A contemporary publication of Lubineau and Billault reported a concise synthesis of (−)-gabosine I starting from a D-glucose derivative and using an intramolecular Nozaki− Hiyama−Kishi (N−H−K) reaction as the key step (Scheme 28).9 The silylated D-glucitol 207 was prepared from tetra-O-

a Reagents and conditions: (a) CH2CHMgBr, THF (70%); (b) (i) PivCl, 2,6-lutidine, DMAP, DCM (74%), (ii) MOMCl, Bu4NI, DIPEA, DCM (83%); (c) (i) CH3ONa, CH3OH (75%), (ii) (COCl)2, DMSO, TEA, DCM; (d) CrCl2, NiCl2, DMF (84%, two steps); (e) Grubbs II, DCM (56%); (f) PDC, DCM (78%); (g) Amberlyst-15, THF, H2O (50%).

The sequence started with a vinyl Grignard reaction on 2,3-Oisopropylidene-L-erythronolactol 214 derived from D-ribose that afforded diol 215 as the major isomer. Selective protection of the primary alcohol as the pivaloyl (Piv) ester and then the secondary alcohol as the methoxymethyl (MOM) ether gave 216. Removal of the Piv group followed by Swern oxidation furnished the aldehyde 217, whose treatment with the iodide 218 in the presence of CrCl2 and NiCl2 produced a diastereomeric mixture of dienes 219. Ring-closing metathesis (RCM) of these dienes furnished the cyclohexenes 220 in 56% yield. Oxidation of 220 with PDC and removal of the protecting groups delivered (−)-gabosine C in 6% total yield from 214. Later, these authors extended their strategy to the synthesis of (+)-gabosines N and O using the D-ribofuranose derivative 222 as starting material (Scheme 30).93 Olefin 223 was obtained by one carbon homologation of 222 through a Wittig reaction and the secondary alcohol protected as MOM ether. Desilylation of the primary hydroxyl group, followed by Swern oxidation, furnished an aldehyde, which was submitted to nucleophilic addition to install the second olefin moiety. Thus, the reaction with 2-bromopropene under N−H−K conditions delivered a mixture of the two epimers 225a and 225b in 1:3.8 ratio, while under Grignard conditions the ratio was reversed to 4:1. The mixture of dienes was subjected to RCM, and oxidation of the resulting allylic alcohols delivered enone 226. Removal of all of the protecting groups in compound 226 gave (+)-gabosine N, whereas catalytic hydrogenation and then

Scheme 28. Synthesis of (−)-Gabosine Ia

a Reagents and conditions: (a) (i) NaBH4, THF, H2O (98%), (ii) TBSCl, pyridine (97%); (b) PCC, AcONa, 4 Å MS, DCM (89%); (c) Ph3P+CH2Br Br−, tBuOK, THF (74%); (d) TBAF, THF (80%); (e) (COCl)2, DMSO, DCM (89%); (f) CrCl2, NiCl2, DMF (61%); (g) PCC, AcONa, 4 Å MS, DCM (76%); (h) BCl3, DCM (74%).

benzyl-D-glucose, 206, upon sodium borohydride reduction followed by silylation. Oxidation of 207 gave the L-sorbose derivative 208. This ketone reacted with bromomethylenetriphenylphosphorane to give exclusively the Z isomer of the Wittig reaction product 209. The vinyl bromide 209 was desilylated to afford the alcohol 210, which was oxidized to the 4695


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the epimers 225a and 225b were separated and independently elaborated to the tetrols (−)-227 and (−)-228. The syntheses of (+)-MK7607 and its C-1 epimer reported in 2009 by Kim and co-workers also made use of a RCM reaction for the construction of the cyclohexene ring (Scheme 31).94 The commercially available galactose derivative 229 was converted in ketone 230 by a four-step procedure including a one-carbon Wittig homologation. Nucleophilic addition of a vinyl fragment under Grignard conditions afforded the diene 231, which was submitted to the RCM process. A crucial step of the sequence was the next 1,3-rearrangement of the tertiary allylic alcohol 232. This transformation was accomplished under palladium catalysis on the corresponding acetate 233, whose preparation required treatment of 232 with LHMDS and acetyl chloride. The stereochemical course of the rearrangement was explained by a [3,3]-sigmatropic reaction through a transition state in which Pd(II) coordinates to the double bond by the less hindered face opposite to the acetate group. To facilitate the isolation of the hydrophilic target product, the protecting benzyl groups were replaced with acetates, and, finally, methanolysis and purification on a resin column afforded 1-epi-(+)-MK7607 in 11 steps from 229 and 29% overall yield. The synthesis of the natural epimer was accomplished from the tetraacetate 236 prepared from the common intermediate 232. Treatment of 236 with PBr3 led to the stereoselective formation of the rearranged allylic bromide 237, through a SNi′ mechanism involving neighboring group participation. Heating of bromide 237 in wet ethanol in the presence of Ag2CO3 afforded a mixture of regioisomeric acetates that were converted in (+)-MK7607 by methanolysis as above. The overall yield of (+)-MK7607 from 229 was 24%. A last example relying on RCM chemistry was described by Madsen and co-workers, in their short synthesis of the two epimeric gabosines A and N starting from D-ribose (Scheme 32).24 The furanoside 239, easily available in two steps from the

Scheme 30. Syntheses of (+)-Gabosine N, (+)-Gabosine O, (−)-227, and (−)-228a

a Reagents and conditions: (a) Ph3PCH2, THF, −78 °C to rt (76%); (b) (i) MOMCl, DIPEA, cat. DMAP, DCM, −15 °C to rt (93%), (ii) TBAF, THF (95%); (c) (i) (COCl)2, DMSO, DCM, Et3N, −78 °C, (ii) 2-bromopropene, CrCl2, cat. NiCl2, DMF (72%) or 2bromopropene, Mg, THF, −78 °C (85%); (d) (i) 10 mol % Grubbs II, toluene, reflux (85%), (ii) PDC, DCM, 4 Å MS (82%); (e) Amberlyst-15, THF−H2O (2:1), 70 °C (75%); (f) (i) H2, Pd/C, CH3OH (95%), (ii) Amberlyst-15, THF−H2O (2:1), 70 °C (85%); (g) (i) 10% Grubbs II, toluene, reflux (85%), (ii) H2, PtO2, CH3OH (90%), (iii) aq 6 M HCl, CH3OH, rt (80%).

deprotection furnished (+)-gabosine O. The overall yields from 222 were 30% and 31%, respectively. As part of the same work, Scheme 31. Syntheses of (+)-MK7607 and 1-epi-(+)-MK7607a

a Reagents and conditions: (a) (i) NaH, BnBr, DMF, (ii) AcOH, H2SO4 3 M, (iii) Ph3PCH3Br, nBuLi, THF, −78 °C to rt, (iv) PCC, AcONa, 4 Å MS, DCM (44%, four steps); (b) vinyl magnesium bromide, THF, −78 °C (91%); (c) Grubbs II, DCM, rt (92%); (d) LHMDS, AcCl, THF, 0 °C (89%); (e) (MeCN)2PdCl2, EtOAc, reflux (74%); (f) (i) BCl3, DCM, −78 °C to rt, (ii) Ac2O, pyridine, rt (90%, two steps); (g) Et3N, CH3OH, 40 °C (98%); (h) (i) BCl3, DCM, −78 °C to rt, (ii) Ac2O, pyridine, rt (86%, two steps); (i) PBr3, DCM, 0 °C to rt (98%); (j) Ag2CO3, 5% H2O in EtOH, reflux (80%); (k) Et3N, CH3OH, 40 °C (97%).

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Scheme 32. Syntheses of (−)-Gabosines A and Na

free OH to give 250. The cyclopropane 250 was treated with mercuric trifluoroacetate in dry methanol to give, after exchange with NaCl, the organomercuric compound 251, which was treated with LiAlH4 to afford the bisglycoside 252. When compound 252 was submitted to hydrolysis, the 2methyl cyclohexenone 254 was isolated in 65% yield, along with a minor quantity of its C-4 epimer. It was assumed that enone 254 was formed with the intermediacy of the dicarbonylic compound 253 by means of a fast acid-promoted intramolecular aldol reaction and subsequent loss of water. The reduction of 254 with hydrogen and Pd/C furnished compound 255, a diastereoisomer of the natural gabosines B, F, and O. In 2007, Shing and Cheng reported a new synthesis of (−)-gabosine I11 starting from a D-glucose derivative, as in the previous approach of Lubineau and Billault.9 The sequence was extremely short and relied on an intramolecular H−W−E reaction for the formation of the cyclohexenone core, like in the pioneer work of Vasella.26 In that synthesis, they employed a mixed acetal as the protective group for C-1 and C-2. Because these acetals are very unstable to acidic media, in posterior works of the same laboratory,35,96 they improved the performance of the synthetic approach by using a more robust alternative. The best performance was achieved with the stable ethoxymethylether (EOM) group for the hydroxyl protection (Scheme 34). Total alkylation of δ-D-gluconolactone, 256, with EOM chloride followed by nucleophilic addition of lithiated dimethyl metylphosphonate afforded lactol 257. Because the direct oxidation of 257 to the diketone suitable for the H−W− E cyclization did not work, the elaboration to enone 258 was accomplished through a three-step protocol involving reduction

a Reagents and conditions: (a) Zn, THF, H2O, sonication (57%); (b) Grubbs II, DCM (97%); (c) DHP, PPTS, DCM (75%); (d) CH3ONa, CH3OH (83%); (e) PDC, DCM (71%); (f) AcOH, H2O (88%); (g) Tf2O, pyridine, DCM, NaNO2, DMF (52%); (h) (i) DHP, PPTS, DCM (85%), (ii) CH3ONa, CH3OH (90%); (i) PDC, DCM (86%); (j) AcOH, H2O (96%).

parent pentose, was treated with zinc and the bromide 240 to afford a 2:1 mixture of dienes epimeric at the alcohol position, from which 241 was separated in 57% yield. The RCM of 241 gave the cyclohexenol 242. To complete the synthesis of gabosine N, the homoallylic alcohol was protected as the THP ether, the benzoate was then hydrolyzed to the allylic alcohol 244, and subsequent PDC oxidation furnished ketone 245. Finally, deprotection under acidic conditions led to (−)-gabosine N in 15% overall yield from 239. The synthesis of the epimeric (−)-gabosine A was achieved by a similar sequence, after inverting the hydroxyl group in 242, in 13% overall yield. In 2006, Corsaro and co-workers described a procedure for the conversion of a cyclopropyl derivative of a pyranoside into gabosine type compounds.95 The sequential transformations are illustrated in Scheme 33. A highly stereoselective Simmons−Smith cyclopropanation of the 4-hydroxypyranoside 249 derived from lactose occurred from the face of the vicinal

Scheme 34. Syntheses of (−)-Gabosine I, Streptol, and 1-epiStreptola

Scheme 33. Synthesis of the Gabosine-type Compound 255a

a

Reagents and conditions: (a) (i) EOMCl, 2,6-lutidine, (93%), (ii) CH3PO(OCH3)2, nBuLi, THF, −78 °C (95%); (b) (i) NaBH4, CH3OH (96%), (ii) TFAA, DMSO, DCM, −78 °C, (iii) Et3N, −78 °C to rt (80%, two steps); (c) TFA, H2O, rt (96%); (d) AcCl, 2,4,6collidine (65%); (e) K-Selectride, −78 °C (259a (86%), 259b (6%)); (f) NaBH4, CeCl3·7H2O, CH3OH (259a (9%), 259b (82%)); (g) TFA, H2O (92%); (h) TFA, H2O (89%); (i) AcCl, 2,4,6-collidine, DCM, −30 °C (80%).

a Reagents and conditions: (a) CH2I2, ZnEt2, Et2O (quant.); (b) Hg(CF3CO2)2, CH3OH (98%); (c) LiAlH4, THF (96%); (d) TFA, CH3CN, H2O (65%); (e) H2, Pd/C, CH3OH (92%).

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to a diol, followed by Swern oxidation and then basic treatment. Complete deprotection of 258 by acid hydrolysis provided (−)-gabosine I in 65% overall yield. In a previous work, (−)-gabosine I had been regioselectively acetylated to (−)-gabosine G in 65% yield.11 The hydride reduction of enone 258 to the allylic alcohols 259a and 259b with KSelectride or NaBH4 was accomplished with good yields and complementary stereoselectivities. Independent acid hydrolysis of all of the EOM ethers in 259a and 259b gave (+)-streptol and 1-epi-streptol, respectively. The acetylation of the primary alcohol of 1-epi-streptol furnished a compound, 260, with spectral data identical to those previously reported for gabosine K,1 whose relative configuration had been originally misassigned. Because the specific rotation of natural gabosine K is unknown yet, its absolute configuration remains undefined. In parallel to these last reports, the same authors disclosed new syntheses of various gabosines from the common intermediate 265, produced by L-proline-catalyzed intramolecular aldol reaction of diketone 264, followed by POCl3promoted dehydration. Diketone 264 was prepared from Dglucose, 262, in six steps and 31% yield (Scheme 35) including anomeric allylation, protection of the 1,2-trans diol and 1,3-diol, deallylation, methyl Grignard addition, and oxidation.12c,28 The reduction of enone 265 with K-Selectride proceeded stereoselectively to furnish exclusively the α-alcohol, which, after silylation and selective hydrolysis, delivered diol 266. For the synthesis of (+)-gabosine A, the primary alcohol of 266 was

mesylated, followed by displacement of the mesylate group by Super hydride, PDC oxidation of the secondary alcohol, and, finally, deprotection of the C4−C5 glycol unit. For the syntheses of (+)-gabosines D and E, the primary alcohol was converted either into the corresponding acetate or silyl ether, respectively, before performing the oxidation of the secondary alcohol, and then the protective groups were removed. The synthesis of (−)-gabosine K, 260, was accomplished from enone 265 in seven steps. Luche reduction of 265 furnished a mixture of epimeric alcohols, which could only be separated after conversion into the corresponding acetates. Silylation of the major epimeric alcohol delivered 267, where a selective hydrolysis of the acetonide was performed by treatment with 80% AcOH. Regioselective acetylation provided the primary acetate, and unraveling of the protected hydroxyl groups completed the sequence. Alcohol 266 was also elaborated to 4epi-gabosine K, 261, by acetylation, followed by acid hydrolysis. An iron-catalyzed tandem isomerization−intramolecular aldolization was the key step in the synthesis of gabosine analogues reported by Yadav, Grée, and co-workers in 2009 (Scheme 36).97 These authors prepared the vinylpyranose 271 Scheme 36. Syntheses of 4-epi-Gabosine A and 4-epiGabosine Ba

Scheme 35. Syntheses of (+)-Gabosine A, (+)-Gabosine D, (+)-Gabosine E, (+)-4-epi-Gabosine K, and (−)-Gabosine Ka

Reagents and conditions: (a) (i) TMSOTf (cat.), Ac2O, DCM, −50 °C (83%), (ii) BnBr, NaH, DMF, rt (quant.); (b) (i) NaOMe, CH3OH (quant.), (ii) PCC, 4 Å MS, DCM (83%); (c) (i) BuLi, Ph3PCH3Br, THF, −78 °C to rt (86%); (ii) TfOH−AcOH−H2O, 80 °C (72%); (d) Fe(CO)5, hν, THF (95%); (e) MsCl, Et3N, DCM, rt (69%); (f) FeCl3, DCM, rt (55%); (g) H2, Pd/C, EtOH, rt (85%). a

from methyl β-D-glucopyranoside, 268, through a previously described six-step protocol98 and treated it with with Fe(CO)5 under irradiation. This key reaction produced ketone 272, as a mixture of epimers, which was dehydrated to enone 273 through the corresponding mesylates. Enone 273 was converted into 4-epi-gabosines A and B, 274 and 275, by treatment with FeCl3 or catalytic hydrogenation, respectively. The overall yield from 268 was 15% for 274 and 24% for 275.

Reagents and conditions: (a) (i) allyl alcohol, BF3·OEt2, (ii) 2,3butadione, CH(OMe)3, CH3OH, (iii) (CH3)2C(OCH3)2, acetone (43%, three steps); (b) (i) Pd(PPh3)4, K2CO3, CH3OH (82%), (ii) MeMgBr, THF (95%), (iii) PDC, 3 Å MS, DCM (92%); (c) (i) Lproline, DMSO (82%), (ii) POCl3, pyridine (99%); (d) (i) KSelectride, THF, −78 °C (99%), (ii) TBSCl, imidazole, DMF (95%), (iii) AcOH (88%); (e) (i) MsCl, 2,4,6-collidine, DCM, −78 °C, (ii) LiEt3BH, THF, −78 °C (84%, two steps), (iii) PDC, 3 Å MS, DCM (92%), (iv) TFA, H2O, DCM (90%); (f) (i) AcCl, 2,4,6-collidine, DCM, −78 °C (94%), (ii) PDC, 3 Å MS, DCM (91%), (iii) TFA, H2O, DCM (89%); (g) (i) TBSCl, imidazole, DCM (97%), (ii) PDC, 3 Å MS, DCM (100%), (iii) TFA, H2O, DCM (87%); (h) (i) AcCl, 2,4,6-collidine, DCM, −30 °C (94%), (ii) TFA, H2O, DCM (81%); (i) (i) NaBH4, CeCl3·7H2O, CH3OH, (ii) Ac2O, DMAP, Et3N, DCM (82%, two steps), (iii) K2CO3, CH3OH (99%), (iv) TBSCl, imidazole, DCM (100%); (j) (i) 80% AcOH (84%), (ii) AcCl, 2,4,6-collidine, DCM, −30 °C (92%), (iii) TFA, H2O, DCM (86%). a

5.5. From Other Chiral Pool Materials

Complementary to carbohydrates, other chiral pool materials have been employed in several successful syntheses of gabosines and anhydrogabosines. Among them, the most frequently used has been (−)-quinic acid. The pioneer work within this group was that reported by Shing and Tang in 1990 (Scheme 37).32 Acetalization of (−)-quinic acid, 276, with cyclohexanone proceeded with concomitant lactonization to give 277. The lactone ring was cleaved with NaOMe, and Swern oxidation of the secondary alcohol followed by β4698


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Scheme 37. Synthesis of (−)-COTCa

Scheme 38. Synthesis of (+)-Epiepoformina

a

Reagents and conditions: (a) (i) BzCl, pyridine (82%), (ii) DMPI, pyridine, DCM (88%); (b) CH3CeCl2, THF (90%); (c) NaIO4, H2O; (d) NaOH, THF (60% from 284); (e) TBSCl, imidazole, DMF (79%); (f) H2O2, Triton B, THF (92%); (g) Tf2O, DIPEA, DMAP, DCM (57%); (h) (i) L-Selectride, THF, (ii) Ac2O, DIPEA, DMAP (73% from 290), (iii) TBAF, THF (98%); (i) (i) DMPI, pyridine, DCM (99%), (ii) KOH, THF (95%).

alcohol, and, finally, acetate hydrolysis, (+)-epoformin was obtained in 14 steps and 12.5% overall yield from 283. The synthesis of (+)-epiepoformin (Scheme 39) started from the

a

Reagents and conditions: (a) cyclohexanone, benzene, DMF, DOWEX 50WX8 (79%); (b) (i) CH3ONa, CH3OH (96%), (ii) (COCl)2, DMSO, TEA, (iii) POCl3, pyridine (76%, two steps); (c) (i) NaBH4, CH3OH (82%), (ii) TBSCl, imidazole, DMAP, DCM (96%), (iii) OsO4, TMANO, tBuOH (82%); (d) (i) Ac2O, pyridine, DMAP, DCM (100%), (ii) (TfO)2O, pyridine, DMAP, DCM (86%), (iii) TEA, DBU, DCM (71%); (e) (i) DIBALH, THF (75%), (ii) crotonic anhydride, pyridine, DMAP, DCM (95%); (f) PCC, 3 Å MS, DCM (80%); (g) TFA, H2O (100%).

Scheme 39. Syntheses of (+)-Epiepoformin and (−)-Theobroxidea

elimination provided the enone 278. Face selective reduction of the keto group in 278 with NaBH4 furnished the corresponding alcohol, which was silylated, and then dihydroxylation gave the diol 279. This compound was regioselectively acetylated at the secondary hydroxyl group, and afterward the tertiary alcohol was esterified with triflic anhydride. Base-mediated βelimination furnished the eneoate 280. Reduction of the diester was followed by selective crotonylation of the primary alcohol to afford 281. Oxidation of the allylic alcohol provided an enone, which was hydrolyzed to (−)-COTC. The overall yield from quinic acid was 13%. Around one decade later, the group of Maycock and Barros described the syntheses of (+)-epoformin, (+)-epiepoformin, and (−)-theobroxide also employing (−)-quinic acid as the starting material.60,66 The synthesis of (+)-epoformin (Scheme 38) started from the derivative of (−)-quinic acid 283. Selective benzoylation of the primary alcohol and then Dess−Martin oxidation of the secondary one furnished the ketone 284. Treatment of this ketone with MeCeCl2 gave the mixture of diols 285 that was submitted to oxidative cleavage to deliver the corresponding mixture of ketones 286. After base-catalyzed elimination carried out on this mixture, alcohol 287 was isolated as the sole product in 60% yield from 284. Selective protection of the secondary hydroxyl group was followed by epoxidation with H2O2 and Triton B to give exclusively the epoxide 289, most probably by the directing effect of the unprotected tertiary hydroxyl group. Elimination of water gave the enone 290. The reduction of 290 with L-Selectride afforded a single alcohol, which was protected to the corresponding acetate. After desilylation, periodinane oxidation of the free

a

Reagents and conditions: (a) TBSCl, imidazole, DMF (98%); (b) NaOH, THF (294a, 41%/294b, 41%); (c) 30% H2O2, Triton B, THF (89%); (d) (i) Ac2O, DIPEA, DMAP, DCM (44%), (ii) I2, DMAP, pyridine, CCl4 (93%); (e) (CH3)4Sn, AsPh3, Pd(dba)3, CuI, THF (91%); (f) HF, CH3CN, H2O (99%); (g) NaBH4, CeCl3·7H2O, CH3OH (92%); (h) HF, CH3CN, H2O (84%).

acetonide 292, available from (−)-quinic acid in three steps. Silylation of 292 afforded the protected compound 293, which upon treatment with NaOH furnished a mixture of the expected enone 294a and its isomer 294b, in approximately a 1:1 ratio. After separation and one recycling, enone 294b was obtained in 75% yield. Hydroxyl directed epoxidation of 294b with H2O2 and Triton B furnished epoxide 295. Elimination of water in compound 295 led to the corresponding enone, which upon α-iodination furnished 296. A Stille cross-coupling reaction was used to introduce the methyl group into αiodoenone 296, furnishing (+)-44. Desilylation of (+)-44 gave 4699


Chemical Reviews

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(+)-epiepoformin. Reduction of the α,β-unsaturated ketone with NaBH4 in the presence of CeCl3 produced 297, along with its C-1 epimer. Desilylation of 297 delivered (−)-theobroxide. From 292, the overall yield for the synthesis of (+)-epiepoformin was 24%, and that of (−)-theobroxide was 19%. Also in 2000, Ganem and co-workers disclosed their synthesis of (−)-gabosine C and (−)-COTC starting from the cyclohexylidene acetal 298 of (−)-methyl quinate (Scheme 40).99 The bis-triflate of 298 spontaneously formed 299 on

and D, which are the enantiomers of the naturally occurring metabolites, were prepared from enone 310 by conjugated addition of water or acetic acid, respectively, followed by TFA hydrolysis of the protecting groups. For the syntheses of (−)-gabosines A and B, the allylic alcohols 311 were converted into the endocyclic enone 316 by a sequence of reactions involving catalytic hydrogenation, Dess−Martin oxidation, and β-elimination of the MOMoxy group. Hydrolysis of 316 gave (−)-gabosine A. Alternatively, compound 316 was hydrogenated to give a mixture of α-methylcyclohexanones, from which the less stable isomer was epimerized with DBU to furnish exclusively 317 and, upon deprotection with TFA, (−)-gabosine B. In 2001, Singh and co-workers published the first enantioselective synthesis of MK7607 starting from (−)-shikimic acid (Scheme 42).12b The methyl ester of shikimic acid was prepared and converted into the corresponding acetonide 319. Treatment of 319 with triflic anhydride followed by elimination of the triflate group furnished diene 320, which was unstable and prone to aromatization. Dihydroxylation of 320 gave an almost equimolar mixture of the two possible cis diols, among which 321 was protected as the acetonide and then reduction furnished the allylic alcohol 322. Full deprotection of 322 produced (−)-MK7607, while acetylation and subsequent smooth hydrolysis delivered a compound with the structure misassigned to gabosine K. Tartaric acid was used as the staring material for the synthesis of gabosine type compounds in two examples, both of them employing a RCM reaction for the construction of the cyclohexene ring. The first example was the synthesis of 1epi-(+)-MK7607, reported by Enders and Grondal in 2006, where the other crucial step was a proline-catalyzed aldol addition (Scheme 43).101 Thus, the reaction of aldehyde 324, prepared from (S,S)-tartaric acid in four steps, with dioxanone 323 in the presence of (R)-proline furnished the heptulose derivative 325 with very high diastereomeric excess. The secondary alcohol in 325 was protected as the MOM ether, and then debenzylation followed by Dess−Martin oxidation delivered the aldehyde 326. Conversion of aldehyde 326 in the bisolefin 327 met with difficulties, due to a competitive elimination reaction occurring under strong basic conditions, but a double Wittig reaction was accomplished in a moderate yield using Ph3PCH3Br and tBuOK as the base. The bisolefin 327 was converted in the cyclohexene 328 via RCM employing Grubbs’ second generation catalyst, and full deprotection gave 1-epi-(+)-MK7607. The overall yield from 324 was 24%. The second example was reported by Krishna and Kadiyala in 2010.34 In this case, the synthesis started from epoxide 329, which had been previously prepared from (R,R)-tartaric acid (Scheme 44). The epoxide was transformed into the allylic alcohol 330 through the sodium-induced ring-opening of the corresponding epoxy chloride. After protecting the hydroxyl functionality as the MOM ether, the benzyl group was removed, and Swern oxidation of the resulting primary alcohol provided aldehyde 331. The Baylis−Hillman reaction of ethyl acrylate with aldehyde 331 furnished the adduct 332 as a mixture of two inseparable epimers. The RCM of this mixture employing Hoveyda−Grubbs second generation catalyst afforded the corresponding mixture of cyclohexenes, 333a/b, which were separated and independently elaborated to the final targets. Thus, reduction of 333a with DIBALH followed by global deprotection rendered (+)-MK7607, while the same protocol, when applied to 333b, furnished (+)-streptol. The

Scheme 40. Synthesis of (−)-Gabosine C and (−)-COTCa

a

Reagents and conditions: (a) Tf2O, pyridine, DCM (65%); (b) AcOCs, DMF; (c) NBS, H2O, DMF (72% from 299); (d) DIBALH, benzene, toluene (65%); (e) LiHMDS, THF (87%); (f) CH3SO3H, DMSO then TEA (71%); (g) TFA, H2O (88%); (h) crotonic anhydride, DCC, DMAP, THF (54%); (i) TFA, H2O (73%).

stirring at room temperature. When treated with cesium acetate, the unsaturated ester 299 furnished diene 300, which underwent face-selective addition of Br+ giving the bromoformate 301. Reduction of both ester groups delivered the diol 302, which was transformed to the epoxide 303 in the presence of LiHMDS. The oxidative opening of 303 was accomplished by treatment with methanesulfonic acid/DMSO, followed by an excess of triethylamine. Direct hydrolysis of the acetal 304 furnished (−)-gabosine C, while crotonylation and then hydrolysis led to (−)-COTC. The overall yields were 16.5% and 7.5%, respectively. In 2002, Shinada, Ohfume, and co-workers published the syntheses of (−)-gabosines A, B, D, and E starting from the allyl sulfide 306 derived from (−)-quinic acid (Scheme 41).100 The key step of their approach was the conversion of the allylic sulfide moiety into the required cyclohexenone. Oxidation of 306 with m-chloroperbenzoic acid (MCPBA) furnished a mixture of sulfoxides 307, which, upon heating in the presence of (EtO)3P, provided the allylic alcohol 308 as a single isomer through a sulfoxide sulfenate [2,3]-sigmatropic rearrangement and sulfenate cleavage by the thiophilic agent. This alcohol was protected as the MOM ether 309. Allylic oxidation of 309 with SeO2/pyridine N-oxide gave a mixture of the α,β-unsaturated enone 310 and two epimeric alcohols 311 in variable yields and ratios depending on the reaction conditions. (−)-Gabosines E 4700


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Scheme 41. Syntheses of (−)-Gabosines A, B, D, and Ea

a

Reagents and conditions: (a) MCPBA, DCM (90%); (b) (EtO)3P, EtOH (98%); (c) MOMCl, DIPEA, DCM (90%); (d) SeO2, pyridine-N-oxide, dioxane (310, 27%/311, 54%); (e) NaOH, THF (68%); (f) TFA, H2O, DCM (59%); (g) AcONa, AcOH (71%); (h) TFA, H2O, DCM (64%); (i) H2, Pd/C, CH3OH (60%); (j) DMPI, DCM (67%); (k) NaOH, H2O, THF (81%); (l) TFA, H2O, DCM (90%); (m) (i) H2, Pd/C, CH3OH (60%), (ii) DBU, benzene (89%); (n) TFA, H2O (68%).

Scheme 43. Synthesis of 1-epi-(+)-MK7607a

Scheme 42. Syntheses of (−)-MK7607 and Misassigned Gabosine Ka

a

Reagents and conditions: (a) (R)-proline, DMF, rt (69%); (b) (i) MOMCl, 2,6-lutidine, Me4NI, DCM, rt (99%), (ii) H2, Pd/C (99%), (iii) DMPI, DCM, 0 °C (90%); (c) Ph3PCH3+Br−, tBuOK, THF, −78 °C (48%); (d) Grubbs II, DCM, reflux (90%); (e) DOWEX, CH3OH, 70 °C (90%). a

building block 335 (Scheme 45).58 The hydroxyester 335 is available in large quantities via the enantioselective reduction of 334 with baker yeast. Hydrolysis of 335, followed by acetylation, gave the carboxylic acid 336. Oxidative decarboxylation with iodobenzene diacetate and iodine afforded iodide 337 as a mixture of diastereomers. Dehydroiodination with DBU and subsequent hydrolysis gave the allylic alcohol 338. After TBS protection of the hydroxyl group, the resulting silyl ether was hydrolyzed to produce the enone 339. Reaction of 339 with H2O2 and Triton B provided epoxide 340. Prior to the attachment of the methyl chain, ketone 340 was activated by introduction of a phenylseleno group at the α-carbonyl position. The phenylseleno derivative 341, which was a mixture of two epimers, was either methylated or hydroxymethylated to furnish compounds 342 and 343, respectively. Successive oxidative elimination of the phenylselenyl group gave the

Reagents and conditions: (a) (i) CSA, CH3OH, reflux (96%), (ii) (CH3)2C(OCH3)2, CSA, rt (95%); (b) (i) Tf2O, DMAP, pyridine, DCM, −20 °C (98%), (ii) CsOAc, DMF, rt (81%); (c) OsO4, NMO, t BuOH−H2O, 20 °C (38%); (d) (i) (CH3)2C(OCH3)2, CSA, rt (95%), (ii) DIBALH, THF, −10 °C (99%); (e) TFA−H2O, rt (92%); (f) (i) Ac2O, DMAP, pyridine, rt (93%), (ii) 80% AcOH aq, 60 °C (66%).

overall yields from 329 were 21% and 11% for (+)-MK7607 and (+)-streptol, respectively. 5.6. From Cyclohexanones

Three reported approaches to enantiomerically pure gabosines and anhydrogabosines make use of enantioselective transformations on monoketals derived from cyclohexan-1,4-diones. In 2003, Kitahara and Tachihara published the syntheses of (+)-epiepoformin and (+)-epiepoxydon starting from the chiral 4701


Chemical Reviews

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Scheme 44. Syntheses of (+)-MK7607 and (+)-Streptola

synthesized in 13 steps from 335 and 10% and 8% overall yield, respectively. More recently, Carreño and co-workers disclosed their approach to the synthesis of this kind of polyoxygenated methylcyclohexanes.30,102 Their strategy involved the use of the chiral (p-tolylsulfinyl)-methyl-p-quinols (R)- or (S)-345 as starting materials (Scheme 46). These quinols are readily prepared by reaction of p-benzoquinone dimethyl monoacetal 344 with the lithium anion derived from (R)- or (S)-methyl ptolylsulfoxide, followed by the hydrolysis of the acetal group using oxalic acid. The stereoselective addition of AlMe3 to (S)345 gave exclusively cyclohexenone 346. Oxidation to sulfone and then reduction of the carbonyl group with DIBALH delivered the cyclohexendiol 347. Protection of the carbinol at C-4 of 347 followed by Cs2CO3-promoted elimination of methyl p-tolylsulfone furnished cyclohexenone (−)-348 in optically pure form. The best conditions found for the stereoselective epoxidation of the double bond (Ph3COOH and Triton B) afforded epoxide 349 along with the opposite stereoisomer in a 3:1 ratio. Desilylation of 349 furnished (+)-dihydroepiepoformin in 32% overall yield from (S)-345. The synthesis of (+)-epiepoformin started from the enantiomeric quinol (R)-345. The stereoselective addition of AlMe3 followed by trapping of the enolate intermediate with Nbromosuccinimide (NBS) furnished the α-bromoketone 350. Elimination of HBr afforded dienone 351, which was submitted to MCPBA oxidation delivering the sulfone 352. The epoxidation of 352 was accomplished with TBHP and Triton B, giving rise to epoxide 353 as the unique isomer. Conversely, the DIBALH reduction of 353 gave a mixture of the two possible diasteromeric carbinols from which 354 was isolated in 67% yield. Elimination of methyl p-tolylsulfone gave (+)-epiepoformin in 12% total yield from (R)-345. Deprotection of the hydroxyl group in (+)-348 and then dihydroxylation furnished (−)-gabosine O in seven steps from (R)-345 and 25% overall yield. The reduction of (+)-epiepoformin with NaBH4 in the presence of CeCl3 gave (−)-theobroxide in quantitative yield. Heating of (+)-epiepoformin with an aqueous solution of NaOAc allowed the isolation of a 45% yield of 4-epi-gabosine A. In 2006, Figueredo and co-workers reported the synthesis of several gabosines and analogues by a stereodivergent and enantioselective strategy starting from a common intermediate (Scheme 47).10 A crucial point for the success of their approach was the preparation of enones (4R,6RS)- and (4S,6RS)-359 with absolute stereochemical control at C4. Thus, enone 356 can be readily prepared in two steps from p-methoxyphenol, by treatment with phenyliodonium bis-(trifluoroacetate) (PIFA) and ethylene glycol, followed by conjugate addition of thiophenol.103 The reduction of enone 356 with NaBH4 yielded the corresponding cis alcohol, which when treated with vinyl acetate and a catalytic amount of Novozyme435 in diisopropyl ether furnished the acetate (−)-358 and the unreacted alcohol (+)-357. Methanolysis of the acetate (−)-358 led to recovering of the levorotatory alcohol (−)-357. Silylation of alcohol (+)- or (−)-357 followed by hydrolysis of the acetal furnished the α-phenylthioketone (4R)or (4S)-359, respectively. The synthetic design from 359 to gabosine type compounds involved alkylation of the doubly activated C-6 position, dihydroxylation or epoxidation of the double bond, and oxidative or reductive elimination of the sulfanyl residue. As the first application, they completed the synthesis of (+)- and (−)-gabosine N, (+)- and (−)-gabosine

a

Reagents and conditions: (a) (i) Ph3P, CCl4, cat. NaHCO3, reflux (93%), (ii) Na, Et2O, 0 °C to rt (85%); (b) (i) MOMCl, DIPEA, DCM, 0 °C (90%), (ii) DDQ, DCM−H2O, reflux (75%), (iii) (COCl)2, DMSO, Et3N, DCM (87%); (c) DABCO, ethyl acrylate, DMF (80%); (d) Hoveyda−Grubbs II, toluene, reflux (83%); (e) (i) DIBALH, THF, −10 °C (99%), (ii) DOWEX, CH3OH, 70 °C (90%); (f) (i) DIBALH, THF, −10 °C (98%), (ii) DOWEX, CH3OH, 70 °C (90%).

Scheme 45. Syntheses of (+)-Epiepoformin and (+)-Epiepoxydona

a

Reagents and conditions: (a) Dry baker’s yeast (74%); (b) (i) LiOH, CH3OH, H2O, (ii) Ac2O, pyridine (87%, two steps); (c) IBDA, I2, CCl4, hν (91%); (d) (i) DBU, toluene, (ii) KCO3, CH3OH (78%, two steps); (e) (i) TBSCl, imidazole, DMF (98%), (ii) PPTS, acetone, H2O (90%); (f) H2O2, Triton B, THF (80%); (g) (i) LiHMDS, TMSCl, (ii) PhSeCl, DCM; (h) NaH, CH3I, THF; (i) 35% H2O2, NaHCO3, THF (50% from 340); (j) HF, CH3CN (62%); (k) DBU, HCHO, THF; (l) 35% H2O2, NaHCO3, THF (45% from 340); (m) HF, CH3CN (53%).

silylated precursors of the target compounds (+)-44 and (+)-103. Both (+)-epiepoformin and (+)-epiepoxydon were 4702


Chemical Reviews

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Scheme 46. Syntheses of (+)-Dihydroepiepoformin, (+)-Epiepoformin, (−)-Gabosine O, (+)-4-epi-Gabosine A, and (−)-Theobroxidea

a

Reagents and conditions: (a) (i) (S)-p-TolSOCH3, LDA, THF, (ii) (COOH)2, H2O (76%, two steps); (b) Al(CH3)3, DCM (65%); (c) (i) MCPBA, DCM (98%), (ii) DIBALH, THF (99%); (d) (i) TBSOTf, 2,6-lutidine, DCM, (ii) Cs2CO3, CH3CN (87%, two steps); (e) Ph3COOH, Triton B, THF (99%); (f) TBAF, THF (61%); (g) (i) Al(CH3)3, DCM, (ii) NBS, THF (53%, two steps); (h) Li2CO3, LiBr, DMF (86%); (i) MCPBA, DCM (99%); (j) tBuOOH, Triton B, THF (72%); (k) DIBALH, THF (67%); (l) Cs2CO3, CH3CN (54%); (m) TBAF, THF (80%); (n) OsO4, TMEDA (60%); (o) NaBH4, CeCl3·7H2O (99%); (p) AcONa, H2O (45%).

Scheme 47. Syntheses of (−)-Gabosine N, (−)-Gabosine O, (−)-Epigabosine N, and (−)-Epigabosine Oa

a Reagents and conditions: (a) (i) NaBH4, DCM, CH3OH (93%), (ii) Novozyme 435, AcOCHCH2, iPr2O ((+)-357, 45%/(−)-358, 48%); (b) (i) TBS-Im, DCM, (ii) montmorillonite K10, DCM (62%, two steps); (c) (i) tBuOK, THF, CH3I ((+)-360, 30%/(+)-361, 67%); (d) OsO4, NMO, acetone, H2O (62%); (e) Bu3SnH, AIBN, toluene (53%); (f) MCPBA, CHCl3 (60%); (g) TBAF, THF (51%); (h) TBAF, THF (83%); (i) OsO4, NMO, acetone, H2O (70%); (j) Bu3SnH, AIBN, toluene (83%); (k) MCPBA, CHCl3 (84%); (l) TBAF, THF (66%); (m) TBAF, THF (73%).

converted to (−)-gabosine O by desilylation. The oxidationpyrolysis protocol applied to a mixture of (−)-362 and (−)-363 furnished a mixture of enones, from where the major isomer (−)-366 was separated in 60% yield and converted to (−)-gabosine N. Starting from (−)-357 and applying the same sequences of reactions, they accomplished the syntheses of the corresponding enantiomeric gabosines. The previously unknown absolute configuration of natural gabosine O was established as 2R,3R,4R,6S. In a second publication, the same group described the synthesis of (+)-gabosine A, the enantiomeric gabosines B and F, (+)-epiepoformin, and (+)-epoformin (Scheme 48).25 The epoxidation of enone (−)-360 with TBHP and Triton B

O, (+)- and (−)-4-epi-gabosine N, and (+)- and (−)-4-epigabosine O. Treatment of (4R)-359 with potassium tertbutoxide and methyl iodide furnished a mixture of ketones (+)-360 and (+)-361 in 97% total yield. The reaction of ketone (+)-360 with N-methylmorpholine N-oxide (NMO) in the presence of osmium tetroxide delivered diols (−)-362 and (−)-363 in ca. 3:1 ratio, while dihydroxylation of ketone (+)-361 furnished exclusively diol (+)-364. Standard desulfuration of (+)-364 followed by desilylation gave (−)-4-epigabosine O, whereas the sulfide oxidation followed by pyrolysis of the sulfoxide and desilylation furnished (−)-4-epi-gabosine N. Desulfuration of the mixture of diols (−)-362 and (−)-363 provided ketone (−)-365 as the major product, which was 4703


Chemical Reviews

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Scheme 48. Syntheses of (+)-Epiepoformin, (+)-Gabosine A, (+)-Gabosine F, and (+)-Epoformina

a Reagents and conditions: (a) tBuOOH, Triton B, THF, 0 °C to rt (96%); (b) (i) MCPBA, 0 °C, (ii) CHCl3, reflux (87%, two steps); (c) Et3N·HF, THF, rt (86%); (d) Ac2O, DMAP, CH3CN, 0 °C to rt (89%); (e) (i) BF3·OEt2, toluene, 0 °C, (ii) NaOMe, CH3OH, rt (87%, two steps); (f) Bu3SnH, AIBN, toluene, reflux (89−90%); (g) (i) Et3N·HF, THF, rt (80%), (ii) Ac2O, DMAP, CH3CN, 0 °C to rt (82%); (h) (i) BF3·OEt2, toluene, 0 °C, (ii) NaOMe, CH3OH, rt (88%, two steps); (i) H2O2, Triton B, THF, 0 °C to rt (78%, (−)-374:(−)-369, 5:1); (j) (i) MCPBA, 0 °C, (ii) CHCl3, reflux (72%, two steps); (k) Et3N·HF, THF, rt (87%).

produced exclusively epoxide (+)-369. The elimination of thiophenol from (+)-369, following an oxidation-pyrolysis protocol, gave a mixture of the two regioisomeric enones 370a/ b that, without separation, was converted into (+)-epiepoformin by treatment with Et3N·3HF. The conversion of (+)-epiepoformin into (+)-gabosine A required the intermediacy of the acetate (+)-371, because the presence of the vicinal acetate proved to be decisive for the cleavage of the epoxide. On the other hand, radical-mediated desulfuration of (+)-369 delivered ketone 372, as a mixture of epimers, which was converted in the corresponding mixture of acetates 373. The subsequent epoxide opening and methanolysis gave gabosine F. The same sequence starting from to (+)-360 furnished gabosine B. The synthesis of epoformin was completed taking advantage of the fact that the epoxidation of enone (+)-360 using hydrogen peroxide instead of TBHP occurred with opposite diastereoselectivity furnishing mainly oxirane (−)-374, which was converted to the target compound by elimination of thiophenol and then deprotection. The first step in the syntheses of (±)-MK7607, (±)-streptol, and some other related carba-pyranoses published by Leermann and co-workers in 2010 was a regioselective bromination of the substituted p-benzoquinone 376 (Scheme 49). 104 The bromination took place exclusively at the unsubstituted double bond, and the reduction with NaBH4 gave mainly the all trans diastereomer, which was then acetylated. The total yield from 376 to the dibromotriacetate 377 was 41%. The reaction of 377 with silver acetate in dry acetic acid provided the all-trans pentaacetate 378, which methanolysis afforded (±)-4-epistreptol. Alternatively, pentaacetate 379 with the cis,trans,cis configuration was prepared from intermediate 377 by conversion with silver acetate in 90% aqueous acetic acid followed by acetylation with acetic anhydride. Cleavage of the protecting groups gave (±)-MK7607. The stereochemistry of the bromine substitutions may be explained by considering the formation of a cyclic oxonium intermediate with the participation of the neighbor acetate group in the elimination of the bromide. Under dry conditions (377→378), this cyclic intermediate is opened by a molecule of acetic acid, resulting in overall retention of configuration. On the contrary, if water is present (377→379), the cyclic intermediate is hydrolyzed and the configuration is inverted, and then treatment with acetic

Scheme 49. Syntheses of (±)-epi-Streptol, (±)-MK7607, (±)-Streptol, and 385a

Reagents and conditions: (a) (i) Br2, DCM, 5−10 °C (98%), (ii) NaBH4, Et2O−H2O, −15 °C (82%), (iii) Ac2O, pyridine, 0 °C to rt (51%); (b) AgOAc, AcOH, Ac2O, reflux (71%); (c) NaOMe, CH3OH, 0−5 °C (100%); (d) AgOAc, 90% AcOH, reflux, then Ac2O, pyridine (35%); (e) NaOMe, CH3OH, 0−5 °C (82%); (f) LiOH, Et2O− CH3OH, −15 to 10 °C (83%); (g) PTSA, H2O, 0 °C to rt, then Ac2O, pyridine (51%); (h) AgOAc, 90% AcOH, reflux, then Ac2O, pyridine (71%); (i) NaOMe, CH3OH, 0−5 °C (81%); (j) (i) K2CO3, CH3OH, 0 °C (100%), (ii) 2,2-dimethoxypropane, PTSA, acetone (100%); (k) (i) NaOH, Et2O−H2O, rt, (ii) AcOH, H2O, then Ac2O, pyridine, rt (52%); (l) AgOAc, 90% AcOH, reflux, then Ac2O, pyridine (54%); (m) NaOMe, CH3OH, 0−5 °C (79%). a

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anhydride furnishes the corresponding tetracetate. Additionally, epoxide 380 was regioselectively prepared from dibromide 377 by treatment with lithium hydroxide. Nucleophilic ring-opening with water and subsequent peracetylation delivered bromide 381. The bromide 381 was transformed in the cis,trans,trans pentaacetate 382 by reaction with silver acetate in 90% aqueous acetic acid and subsequent acetylation as above, and then full deprotection furnished (±)-streptol. To synthesize the diastereomer with the trans,trans,cis configuration, the acetonide 383 was prepared in two steps from dibromotriacetate 377 and converted into the bromotriacetate 384 through an intermediate epoxide. Reaction of 384 with silver acetate in 90% aqueous acetic acid followed by acetylation with acetic anhydride delivered pentaacetate 385, the ultimate precursor of (±)-1-epi-MK7607. The overall yields of (±)-4-epi-streptol, (±)-MK7607, (±)-streptol, and (±)-1-epi-MK7607 from the common intermediate 377 were 71%, 29%, 22%, and 22%, respectively.

Pau Bayón studied Chemistry at the Universitat Autònoma de Barcelona (UAB), Spain, where he earned his B.Sc. degree in 1994 and his Ph.D. degree in 1999 working with Prof. Josep Font on enantioselective catalysis in 1,3-dipolar cycloadditions. He was a postdoctoral fellow at the University of Aarhus, Denmark, in the Center for Catalysis with Prof. Karl Anker Jørgensen working on enantioselective catalysis in imine addition reactions. In 2001, he joined Prof. Cesare Gennari at Milan University, Italy, as a Marie Curie postdoctoral fellow working on the synthesis of microtubule stabilizing agents. Back to the UAB, he was appointed Lector Professor in 2005. In 2010, he achieved a position of Associated Professor of Organic Chemistry at the UAB. His research interest is focused on the stereoselective synthesis of molecules with potential or recognized biological activity.

6. CONCLUSIONS AND PERSPECTIVES The information summarized in the above sections illustrates that the isolation, structural determination, biogenetic studies, biological evaluation, and synthesis of gabosine and anhydrogabosine type compounds is an active area of interest among organic chemists. Although the earliest synthetic efforts toward these small compounds were reported in the 1970s, their densely functionalized architecture still leaves large space for improvement. The enantio- and diastereoselective construction of the central cyclohexane-core decoration required for each target is undoubtedly the main synthetic challenge. As compared to chiral pool strategies, the use of kinetic resolution methodologies presents the advantage of providing access to either enantiomer of the target compound. Many other natural products, which were not considered here, display structures similar to those of gabosines with larger substituents instead of the typical methyl or hydroxymethyl chain. The advances in the synthesis of gabosines and anhydrogabosines will therefore contribute to facilitate the access to other more intricate compounds.

Marta Figueredo was trained in Chemistry at the Universitat Autònoma de Barcelona (UAB), Spain, where she obtained her B.Sc. degree in 1978, her Ph.D. in 1983, working with Prof. Pelayo Camps on the synthesis of polyquinanes, and then she collaborated, as a postdoctoral fellow in the laboratory of Prof. Marcial Moreno-Mañas, on the development of new photoaffinity probes. Following a period as a NATO-SERC postdoctoral fellow in the group of Prof. Michael Jung at the University of California Los Angeles, working on stereoselective synthesis of biologically active compounds, she returned to the UAB and joined the group directed by Prof. Josep Font. In 1988, she accessed a position of Associated Professor of Organic Chemistry at the UAB, and in 2006 she was promoted to Full Professor. Her main research interest is focused on the stereoselective synthesis of compounds with potential or recognized biological activity.

AUTHOR INFORMATION Corresponding Author

*E-mail: marta.fi[email protected].

ACKNOWLEDGMENTS We acknowledge financial support from DGI (projects CTQ2007-60613 and CTQ2010-15380). We acknowledge the contributions of past and present graduate students in our laboratory who were involved in the development of the research described in a significant portion of this Review, including Dr. Georgina Marjanet, Dr. Gladis Toribio, and Miguel Á ngel Fresneda.

Notes

The authors declare no competing financial interest. Biographies

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