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Synthesis, Stereochemistry, Structural Classification, and Chemical Reactivity of Natural Pterocarpans Atul Goel,* Amit Kumar, and Ashutosh Raghuvanshi Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India 6.3.1. Asymmetric Synthesis from 2H-Chromenes 6.3.2. Asymmetric Synthesis of cis- and transPterocarpins 6.3.3. Asymmetric Synthesis of cis- and transPterocarpans 6.3.4. Asymmetric Synthesis of (−)-Cabenegrin A-I 6.3.5. Asymmetric Synthesis of (+)-Pisatin 6.3.6. Asymmetric Synthesis of (+)-Variabilin and (−)-Variabilin 6.3.7. Asymmetric Synthesis of (−)-Glyceollin I and (+)-Glyceollin I 6.3.8. Asymmetric Synthesis of (−)-Glycinol 7. Chemical Reactivity of Pterocarpans 7.1. Oxidation of Pterocarpans 7.2. Reduction of Pterocarpans 7.3. Reactions of Pterocarpans with Acids 7.4. Reactions of Pterocarpans with Bases 7.5. Photochemical Transformations of Pterocarpans 8. Conclusions Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Characteristics of Pterocarpans (UV, Mass, and NMR) 3. Conformational Analysis of Pterocarpans 4. Optical Resolution and Absolute Configuration of Pterocarpans by Online HPLC-CD Analysis 5. Classification of Naturally Occurring Pterocarpans 5.1. Pterocarpans Containing Core Skeleton 5.2. O-Glycosylated Pterocarpans 5.3. Dimethylpyranopterocarpans 5.4. Furanopterocarpans 5.5. 6a-Hydroxypterocarpans Containing the Core Skeleton 5.5.1. Dimethylpyrano-6a-hydroxypterocarpans 5.5.2. Furano-6a-hydroxypterocarpans 6. Syntheses of Pterocarpans 6.1. Biosynthesis of Pterocarpans 6.2. Syntheses of (±)-Pterocarpans 6.2.1. Synthesis from 2′-Hydroxyisoflavones and 2′-Hydroxyisoflavanones 6.2.2. Synthesis from pterocarpene 6.2.3. Synthesis from 2′-Hydroxyisoflavans 6.2.4. Synthesis via Heck Arylation of 2HChromenes 6.2.5. Synthesis via [3 + 2] Cycloaddition Reaction of 2H-Chromenes 6.2.6. Synthesis via Claisen Rearrangement 6.2.7. Synthesis via 1,3-Michael−Claisen Annulation 6.2.8. Synthesis via Aldol Condensation 6.2.9. Synthesis via Radical Cyclization 6.2.10. Synthesis via Alkene Metathesis 6.3. Asymmetric Syntheses © XXXX American Chemical Society

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1. INTRODUCTION Nature is a phenomenal source of biologically active simple and complex molecules having oxygen heterocyclic scaffolds such as flavonoids, isoflavonoids, pyranones, coumarins, and their benzannulated compounds. These oxygen heterocyclic compounds are originated from eclectic array of plants and marine sources through various de novo selective enzymatic reactions in a combinatorial fashion. Isoflavonoids are biogenetically related to flavonoids but constitute a distinctly separate class in which they contain a rearranged C15 skeleton and may be regarded as derivatives of 3-phenylchroman. Architecturally, isoflavonoids may be subdivided into several classes according to the heterocyclic subunits present in the molecular framework and the complexity of the skeleton, for instance, formation of further oxygen heterocyclic ring systems. One such biologically relevant and chemically interesting scaffold is pterocarpan (6a,11a-dihydro-6H-benzofuro[3,2-c]chromene), which was

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Received: June 1, 2012

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dx.doi.org/10.1021/cr300219y | Chem. Rev. XXXX, XXX, XXX−XXX

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named by Harper et al.,1 because of the first two isolated compounds, the pterocarpin and the homopterocarpin in 1874 from a Pterocarpus species.2 Since then, tremendous work has been done in isolation, characterization, biological evaluations, and synthesis of this class of compounds. A literature search on the pterocarpan scaffold revealed the existence of large number of structurally diverse compounds in nature with a broad range of biological activities. However there is a paucity of reviews on this topic. A few book chapters and old reviews are available on isolation and characterization of natural pterocapans, which are now out dated.3−5 Recently RodríguezGarcía and co-workers6 published an interesting review on biological properties of natural pterocarpans covering phytochemical studies published from 1950 until 2006. To date, no review is available that deals with stereochemical aspects, chemical reactivity, or total syntheses of natural pterocarpans. To our surprise, many reports are published with ambiguous stereochemistry at positions 6a and 11a of pterocarpans. Considering the importance of the unique conformations of the pterocarpans and their biological activities, this review is concerned with conformational studies, assignment of absolute configurations, and state-of-the-art methodologies for their syntheses. It covers the period from the 1940s until March 2012. Based on five- or six-membered heterocyclic ring-fused systems, the natural pterocarpans have been categorized in section 5 of the review. Biosynthetic pathways, total syntheses including asymmetric methods, and chemical reactivity of pterocarpans are discussed in sections 6 and 7, respectively. Natural or synthetic compounds having a C6−C3−C6 fundamental ring system of either coumarono[3,2-c]chromane (1, 2) or its oxidized forms pterocarpene (3) and coumestone (4) are collectively called pterocarpanoids, a class of naturally occurring isoflavonoids (Figure 1). The 6a,11a-dihydro systems

Figure 2. Four isomers of pterocarpan (1).

for improving bone health and also hold therapeutic promise in postmenopausal osteoporosis. Recently Erhardt and co-workers14 developed biomimetic route for the synthesis of racemic and enantiomerically pure pterocarpans and demonstrated antiproliferative activities in various human cancer cell lines.

2. CHARACTERISTICS OF PTEROCARPANS (UV, MASS, AND NMR) The structures of the pterocarpan class of compounds have been assigned by UV, mass, and NMR spectroscopy and by circular dichroism studies. The UV spectra15,16 of subsituted pterocarpans show three characteristic absorption peaks in the range of 280−335 nm. 6a,11a-Unsubsituted pterocarpans are, in general, stable to electron impact (EI) and electrospray ionization (ESI) mass spectrometry wherein they show intense molecular ion peaks.17−22 However pterocarpans having a 6ahydroxy group (2) can readily lose a molecule of water during electron impact and thus display a parent ion peak that is indistinguishable from the analogous pterocarpenes (3). The mass fragmentation studies on 18O-labeled 6a-hydroxypterocarpans have confirmed the evidence of the loss of water molecule by the elimination of 6a-hydroxy group.22 Therefore, soft ionization techniques are often applied to obtain a molecular ion peak in the case of 6a-hydroxy-substituted pterocarpans. The mass spectrum of pterocarpan 1 displayed an intense molecular ion peak at 224 as the base peak. The mass fragmentation patterns of the selected pterocarpans by electron impact (EI) and electrospray ionization (ESI) mass spectrometry are shown in Figure 3.20,21 Recently Manickavasagam et al.23 analyzed the mass fragmentation of 3-hydroxypterocarpan (6) using both positive and negative ion electrospray ionization and atmospheric

Figure 1. Structures of pterocarpanoid class of compounds.

such as 6a,11a-dihydro-6H-benzofuro[3,2-c]chromene (1) and 6a,11a-dihydro-6H-benzofuro[3,2-c]chromen-6a-ol (2), are called pterocarpans. The main structural feature of pterocarpan 1 is the presence of the two fused chromophores, chromane and 2,3dihydrobenzo[b]furan, that give rise to the two asymmetric centers at 6a and 11a positions leading to the four possible isomers, two cis, (−)-(6aR,11aR)-1 and (+)-(6aS,11aS)-1, and two trans, (−)-(6aR,11aS)-1 and (+)-(6aS,11aR)-1, as represented in the Figure 2. Pterocarpans, apart from the isoflavones, represent the second largest group of natural isoflavanoids with medicarpin and maackiain occurring almost ubiquitously in nature.3−5 They are potent phytoalexins, defensive substances produced by plants in response to biotic and abiotic elicitors.7 Pterocarpans and their related compounds have been reported to exhibit antitoxin,8 anti-snake venom,8 antiviral,8 antibacterial,9 and antiosteoporotic activities.10,11 Recently pterocarpans have shown stimulation of osteoblast differentiation and enhancement of peak bone mass (PBM) in growing female rats.12,13 Owing to their unique osteogenic properties and the lack of estrogen-like effect, pterocarpans may be used as prophylactics

Figure 3. Mass fragmentation pattern of pterocarpans 1 and 5 in positive ionization mode. B


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(J6aH,11aH) of the aliphatic protons 6aH and 11aH determines the conformation of the heterocyclic rings. The coupling constant (J6aH,11aH) for the cis-conformation24,27 of the pterocarpans ranges between 5.0 and 7.0 Hz, while for the transconformation,31−33 it ranges between 12.0 and 14.0 Hz. Similarly in 13C NMR spectra of cis-pterocarpans (1,7), chemical shifts for C-11a range from 77 to 78, for C-6 from 66 to 67, and for C-6a from 40 to 41 ppm, while in the case of trans-pterocarpans (1,7), C-11a carbon ranges from 83 to 84, C-6 from 68 to 69, and C-6a from 44 to 46. The structure assignment of an isolated unknown natural substance is not an easy task for natural product chemists. Therefore, background information on a required scaffold is very useful. In order to get insight in this context, Chalmers et al.34 undertook a study of the 13C NMR of medicarpin 5, neodunol 8, neodulin 9, ficinin 10, neorautenol 11, neorautenane 12, edunol 13, and acetoxypterocarpin 14. Chemical shifts of the compounds 5 and 8−14 are shown in Tables 2 and 3. Based on the reported chemical shifts of these compounds, the data has now been compiled as shown in Figure 6.

pressure chemical ionization (APCI) mode. They observed high sensitivity in the negative ion mode. The mass spectrum of 3-hydroxypterocarpan 6 showed a molecular ion peak at m/z 239 corresponding to [M − H]− as depicted in Figure 4. The

Figure 4. Mass fragmentation pattern of pterocarpan 6 in negative ionization mode of ESI.

MS/MS fragmentation of 3-hydroxypterocarpan (6) revealed the prominent product ion peak at m/z 169 generated by the loss of CO2 and C2H2 units from the parent molecule. The 1H NMR spectra of pterocarpans revealed a unique pattern for protons at positions 6, 6a, and 11a due to the presence of two asymmetric centers.24−30 The chemical shifts31−33 and coupling constants of the cis-pterocarpans 1 and 7 and transpterocarpans 1 and 7 (Figure 5) are summarized in Table 1.

3. CONFORMATIONAL ANALYSIS OF PTEROCARPANS Conformational analysis of pterocarpans considering chromane and 2,3-dihydrobenzo[b]furan chromophores as two subunits has been extensively studied by 1H NMR spectroscopy and by various computational models.3 The 1H NMR spectra of the natural pterocarpans revealed the presence of a cis-fused B/C-ring system.3,24,35 The cis-conformation of pterocarpans is energetically more favorable than the trans-fused ring conformation as demonstrated by theoretical studies.36−39 This led to only one possible diastereomer of (±)-pterocarpans, with its two enantiomeric forms, cis-(6aR,11aR)- and cis-(6aS,11aS)enantiomer. Interestingly for each enantiomer that is, cis(6aR,11aR)-1, two strain-free conformations (X, Y) may exist (Figure 7). The standard projections of the six-membered O-heterocycle with helicity7 in the cis-(6aR,11aR) configuration are shown in Figure 7. The five-membered O-heterocyclic ring (lower part of Figure 7) fused to the six-membered one has opposite helicity with respect to them. The cis-(6aR,11aR)-pterocarpan 1 skeleton in which O11 is pseudoaxially oriented with respect to the hydrogen at C6

Figure 5. Structures of cis- and trans-pterocarpans (1, 7).

The 1H NMR spectra of pterocarpans cis-1,7 and trans-1,7 exhibit four characteristic signals corresponding to the four aliphatic protons (Table 1). Because these compounds possess two asymmetric centers, C-6a and C-11a, coupling constant

Table 1. Chemical Shifts (δ Values) of the Heterocyclic Ring Protons and the Carbon Atoms δ-values (ppm) chemical shifts of proton

δ-values (ppm) chemical shifts of carbon

compound

11a

6eq

6ax

6a

coupling constants, J6a,11a (Hz)

C-11a

C-6

C-6a

cis-1 trans-1 cis-7 trans-7

5.55 5.12 5.52 5.19

4.30 4.85 4.29 4.88

3.20 4.45 3.68 4.47

3.14 3.55 3.64 3.63

6.0 13.4 6.6 13.4

77.61 83.51 77.98 83.99

66.34 68.58 66.41 68.33

40.36 44.96 40.89 45.61

Table 2. 13C NMR Data for cis-Pterocarpans in CDCl3 compd

C-1

C-1a

C-2

C-3

C-4

C-4a

C-6

C-6a

C-7a

C-7

C-8

C-9

C-10

C-10a

C-11a

5 8 9 10 11 12 13 14

132 123.1 122.9 116.2 128.5 128.4 130.8 124.2

111.3 117.2 117.2 118.6 113 113 110.7 112.1

109.7 121.8 121.8 122.8 115.6 115.6 121.6 133.9

158.7 154.8 154.7 146.7 156 156 155.9 152

102.9 99 98.9 133.3 103.7 103.7 102.4 101.4

156.4 153.3 153.3 144.9 153.7 153.7 153.9 154

65.5 66.5 66.4 66.7 66 65.8 65.6 66

39.3 39.4 39.9 39.9 38.8 39.6 39.6 39.6

119.4 119.7 118 118 117.3 118.1 118.2 118.1

125 124.9 104.9 105.1 124.9 105 104.9 105.3

106 106.1 141.1 141.1 107.4 141.1 140.8 141.2

160.6 160.5 147.3 147.4 158.4 147.5 147.2 147.5

96.3 96.2 92.8 92.9 97.4 93 92.9 93.2

160.4 160.2 153.5 153.6 159.7 153.7 153.6 153.6

78.1 78.5 78.3 78.5 77.4 77.7 78 77.4

C


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Table 3. 13C NMR Data for cis-Pterocarpans in CDCl3 compd 5 8 9 10 11 12 13 14

C-1′

27.2

C-2′ 145.6 145.6 145.8 76.2 76.2 122.8

C-3′ 106.1 106.1 106.6 129 129 130.8

C-4′

C-5′

C-6′

OCH2O

OMe

CO

Me

168.7

20.8

55.3 55.2

121 121 25.2

27.7 27.6 17.3

27.7 27.6

100.8 100.9

60.4

100.9 100.8 101.1

56

exist40 (Figure 8); of these, the structure in which 6a-H is oriented anti relative to one of the hydrogen atoms at C-6

Figure 8. Two strain free conformations of cis-medicarpin 5.40 Reprinted with permission from ref 40. Copyright 2012 Royal Society of Chemistry.

Figure 6. Structures of functionalized pterocarpans 8−14 and their range of chemical shifts in 13C NMR.

(Hanti, ΔE = 0.00 kcal mol−1) is energetically favored compared with that having 6a-H anti to the ring oxygen O-5 and, thus, gauche to both hydrogens at C-6 (Oanti, ΔE = 1.88 kcal mol−1). For trans-configurations, only Ht arrangements have been located with their possible helicity, shown in the Figure 9. Trans-configurations are about 10 kcal mol−1 less favorable than cis-configurations.30,36,37

4. OPTICAL RESOLUTION AND ABSOLUTE CONFIGURATION OF PTEROCARPANS BY ONLINE HPLC-CD ANALYSIS CD spectroscopy provides a powerful tool to determine the absolute configuration of the naturally occurring compounds. It has been widely utilized for configurational assignments41−44 of pterocarpans, which exhibited CD bands of the chromane and the 2,3-dihydrobenzo[b]furan chromophores being cisannulated in natural pterocarpans. The projections shown in Figures 7 and 9 are particularly useful for the correlation between helicity and CD bands.31 Antus and co-workers43 successfully performed HPLC-CD analysis on cis-pterocarpans with different substitution patterns and explained the rule between the signs of the characteristic CD bands and the absolute configurations of the annulation points. The CD spectra of cis-pterocarpans were considered the sum of two chirally perturbed achiral chromophores, the chromane and the 2,3-dihydrobenzo[b]furan. According to the rule, the measured negative 1Lb band of the chromane chromophore and positive one of the 2,3-dihydrobenzo[b]furan derives from M helicity of the chromane and P helicity of the 2,3-dihydrobenzo[b]furan in the unsubstituted cis-pterocarpan [(+)-1], which correspond to 6aS,11aS absolute configuration, and vice versa for 6aR,11aR configuration (Table 4). From the online HPLC-CD data,31,43,44

Figure 7. Possible conformations of chromane and 2,3-dihydrobenzo[b]furan chromophores with their helicity for cis-(6aR,11aR)-1.

is the most stable conformation (Figure 7, structure I). When both H’s at C6 are gauche with respect to the H at C6a (Figure 7, structure II), the corresponding backbone structure is about 2 kcal mol−1 less favorable than the structure I, whereas in aqueous solution their energy gap is nearly conserved (Figure 7).36−39 For example, in the case of enantiomers of the cis-(6aS,11aS)medicarpin 5, two strain-free conformations V and VI may D


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Figure 9. Possible conformations of chromane and 2,3-dihydrobenzo[b]furan chromophores with their helicity for trans-(6aR,11aS)-1 and trans(6aS,11aR)-1.

Table 4. Cotton Effects (CE) of cis-Pterocarpan 1 with Their Respective Helicities 2,3-dihydrobenzo[b]furan chromophore

chromane chromophore CE at 1Lb (260−310 nm)

helicity

CE at 1Lb (260−310 nm)

helicity

negative positive

M P

positive negative

P M

CE at 1La (220−250 nm) elution order in RP-HPLC positive negative

1 2

[α]D absolute configuration + −

(6aS,11aS) (6aR,11aR)

assignment of the (6aS,11aS)-configuration to the faster eluting enantiomer of 5 and, consequently, the (6aR,11aR)-configuration to the more slowly eluting stereoisomer of 5.40 Similarly the comparison of the CD spectrum simulated for (6aS,11aS)-6 and (6aR,11aR)-6 with the experimental CD for peak 1 and peak 2, respectively, was found in agreement with the proposed absolute configuration.40

it may be concluded that the CD bands of the second eluted levorotatory enantiomers between 220 and 250 nm were assigned as the 1La ones and the bands between 260 and 310 nm belonged to 1Lb transitions. While the 1La band appeared as an intense negative peak in all the second eluted levorotatory enantiomers, the 1Lb band had a positive cotton effect (CE) in (−)-(6aR,11aR)-pterocarpans. Counter to this, the 1La band showed as an intense positive peak in all the first eluted dextrorotatory enantiomers, and the 1Lb band had a negative CE in (+)-(6aS,11aS)-pterocarpans. Recently an improved method40 for the resolution of the racemic medicarpin (5) was developed using cellulose tris(3,5dimethylphenylcarbamate) as the stationary phase in reversephase HPLC conditions, and a direct correlation between experimental and computationally predicted CD spectra was demonstrated as a tool for the determination of the absolute configurations of natural and synthetic pterocarpans. An attribution of the absolute configuration to the respective enantiomer of medicarpin (5) and its demethoxy derivative (6) was achieved by the combination of online HPLC-CD measurements with the quantum-chemical calculation of the CD spectra of the respective enantiomers as shown in Figure 10. Quantum chemical calculations were carried out using Grimme’s double hybrid TDB2GP-PLYP45−47 functional with Ahlrich’s TZVP basis set and furthermore by a combined approach of DFT (B3LYP/SVP) and MRCI (CAS 12,12) methods.48 After UV correction, the predicted CD spectra were compared with the experimental CD curves of the two resolved enantiomers.49 Due to the strong similarity of the experimental CD curves of the corresponding peaks of 5 and 6 with the calculated ones; only the calculated curves of 5 are shown exemplarily in Figure 10, for reasons of clarity. The comparison of the CD spectrum simulated for (6aS,11aS)-5 and (6aR,11aR)-5 with the experimental CD for peak 1 and peak 2 revealed a good agreement, thus permitting

5. CLASSIFICATION OF NATURALLY OCCURRING PTEROCARPANS This section deals with the listing of pterocarpans with their trivial names. Due to a large number of natural pterocarpans isolated from an eclectic array of natural sources, the details of the plants of these pterocarpans have not been included in this section, and it has been restricted only to their structures and their respective references as depicted in Table 5. 5.1. Pterocarpans Containing Core Skeleton

Table 5 provides structures and references for pterocarpans containing the core skeleton. 5.2. O-Glycosylated Pterocarpans

In view of a large number of structurally diverse pterocarpans present in nature, there is a great paucity of references in the literature for O-glycosylated pterocarpans. Naturally occurring glucosides include glucose and galactose as sugar moieties attached to the natural pterocarpans mainly medicarpin (5) and maackiain (54) as the aglycone residue as shown in Figure 11. 5.3. Dimethylpyranopterocarpans

The dimethylpyran ring fused pterocarpans are an important class of biologically active molecules, which are enzymatically formed by isoprenylation followed by intramolecular cyclization. Various dimethylpyranopterocarpans are represented in Figure 12. E


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carpans are mainly formed involving the 3-hydroxyl group of 6a-hydroxypterocarpans (Figure 16). To the best of our knowledge, the furan ring-fused 6a-hydroxypterocarpans involving the 9-hydroxyl group are yet unknown in the literature.

6. SYNTHESES OF PTEROCARPANS 6.1. Biosynthesis of Pterocarpans

Pterocarpans and isoflavones play an important role in plant− microbe interaction.156−159 Pterocarpans are frequently produced after exposure to environmental factors such as wound, oxidative, and herbicide stress, pathogen challenge, or shortwave UV radiation. Induction of pterocarpans has been achieved in various tissues of the plant, among which seedlings and cell suspension cultures are particularly useful for the characterization and isolation of enzymes of this pathway. Remarkable progress has been made in the elucidation of pterocarpan biosynthesis.3,35,78,79,131,150,154−163 Pterocarpans possess two asymmetric centers, which leads to the possibility of the four stereoisomers, but only two stereoisomers are known to exist in nature. Plant systems frequently used for biosynthesis studies are Cicer arietinum,161 Glycine max,162 Medicago sativa,131 and Pisum sativum (Figures 17 and 18).163,164 Literature on biosynthetic pathways revealed that the biosynthesis of (+)-pisatin (111) proceeded via intermediates such as (+)-sophorol (132) and (+)-maackiain (54), which have stereogenic centers with the same configuration as that found in (+)-pisatin (111) (Figure 17).3,35,78,79,131,150,154−166 However, recent studies as shown in Figure 18 have suggested that the pathway up to the (−)-7,2′-dihydroxy4′,5′-methylenedioxyisoflavanol [(−)-DMDI (138)] intermediate involves a chiral intermediate with the opposite absolute configuration, which then becomes carbon 6a in (+)-pisatin (111).167,168 The administration of the radiolabeled intermediates has demonstrated that (−)-sophorol (132) was converted into (+)-pisatin (111) more efficiently from either (+)-sophorol (132) or (+)-maackiain (54) (Figure 18).167 These results supported a (+)-pisatin (111) biosynthetic pathway that proceeded through chiral intermediates with a configuration opposite to that found in (+)-pisatin (111).

Figure 10. Stereochemical assignment of the two enantiomers of medicarpin (5) and 9-demethoxy-medicarpin (6) by online LC-CD coupling in combination with quantum-chemical CD calculations.40 Reprinted with permission from ref 40. Copyright 2012 Royal Society of Chemistry.

6.2. Syntheses of (±)-Pterocarpans

6.2.1. Synthesis from 2′-Hydroxyisoflavones and 2′-Hydroxyisoflavanones. Numerous synthetic methodologies are reported in the literature for the synthesis of the pterocarpan class of compounds. One of the simplest synthetic routes to pterocarpan is by the sodium borohydride reduction of 2′-hydroxy-isoflavones. This reaction proceeds via 1,4-reduction to an isoflavanone, then further reduction to the isoflavan-4-ol. The first synthesis of a natural pterocarpan, (±)-homopterocarpin (15) was accomplished by Suginome and Iwadare.169 They used tetrahydropyranyl-protected 2′-hydroxyisoflavones for reduction with NaBH4. The resulting isoflavan-4-ols on treatment with 50% acetic acid removed the protecting group and underwent cyclization. Seshadri et al.170 independently carried out this transformation of 2′-hydroxy-4′,7-dimethoxyisoflavone (139) into (±)-homopterocarpin171 (15) in one step by direct reduction with sodium borohydride without protecting the 2′-hydroxyl group (Scheme 1). They had confirmed the findings of Miyano and Matsui172 on the reduction of dehydrorotenone and related compounds. The reduction of isoflavones and isoflavanones has been extensively explored to prepare various pterocarpan derivatives.173

5.4. Furanopterocarpans

Compared with pyranopterocarpans, furan ring fused natural pterocarpans are fewer in number. Structures of some of the furanopterocarpans are shown in Figure 13. 5.5. 6a-Hydroxypterocarpans Containing the Core Skeleton

Another important subclass of pterocarpan is 6a-hydroxypterocarpans, which play a unique role in medicinal chemistry.14 According to the literature survey, it was observed that naturally occurring 6a-hydroxypterocarpans are functionalized with hydroxy, methoxy and methylenedioxy substituents at all the available positions onto the benzene rings as shown in Figure 14. 5.5.1. Dimethylpyrano-6a-hydroxypterocarpans. 3Hydroxy- and 9-hydroxy-substituents in 6a-hydroxypterocarpans are susceptible to prenylation. These prenylated pterocarpans may intramolecularly cyclize at the positions available adjacent to the hydroxyl group. Some of the structures related to dimethylpyrano6a-hydroxypterocarpans are depicted in Figure 15. 5.5.2. Furano-6a-hydroxypterocarpans. In contrast to pyrano-6a-hydroxypterocarpans, furan ring fused pteroF


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Table 5. Pterocarpans 5 and 15−64

compd no.

name

R1

R2

R3

R4

R5

R6

5 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

medicarpin homopterocarpin demethylmedicarpin isomedicarpin sophoracarpan A 3,8-dihydroxy-9-methoxypterocarpin 8-hydroxy-3,9-dimethoxypterocarpin 3,4-dihydroxy-9-methoxypterocarpan melilotocarpan A 4-methoxymedicarpin prostratol D prostratol E phaseollidin sandwicensin 1-methoxyphaseollidin kanzonol P erybraedin A erybraedin C calopocarpin erythrabyssin II erycristin vesticarpan nissolin methylnissolin sparticarpin 2-methoxy-homopterocarpin 2,8-dihydroxy-homopterocarpin mucronucarpan 2,8-dihydroxy-10-methoxyhomopterocarpin 4-hydroxy- demethylmedicarpin 4-hydroxymedicarpin 4-hydroxy- homopterocarpin 4-methoxyhomopterocarpin 8-hydroxy,4,10-dimethoxy-homopterocarpin 4-hydroxy-2-methoxy homopterocarpin 2,8-dihydroxy-4,9-dimethoxy-homopterocarpin homoedudiol edudiol edulenol lespedezin maackiain pterocarpin 4-hydroxymaackiain 4-methoxymaackiain 4-hydroxy-2-methoxypterocarpin sophoracarpan B 4-hydroxypterocarpin trifolian nitiducol neoraucarpanol neoraucarpan

H H H H H H H H H H H H H H OMe OMe H H H H H H H H H H H H H H H H H H H H H OMe OMe H H H H H H H H OH H H H

H H H H H H H H H H H H H H H Pr H H Pr Pr Pr H H H OMe OMe OH OH OH H H H H H OMe OH Pr Pr Pr H H H H H OMe H H OMe H Pr Pr

OH OMe OH OMe OH OH OMe OH OMe OH OH OH OH OH OH OMe OH OH OH OH OH OH OH OH OMe OMe OMe OMe OMe OH OH OMe OMe OMe OMe OMe OH OH OH OH OH OMe OH OH OMe OH OMe OH OH OH OMe

H H H H H H H OH H OMe H H H H H H Pr Pr H H H H H H H H H H H OH OH OH OMe OMe OH OMe H H H H H H OH OMe OH H OH H DPr OMe OMe

H H H H OMe H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H OMe H H H H H

H OMe H OMe H OH H OH H OMe OH OMe OH OMe H OMe H OMe H OMe Pr OMe DPr OMe H OH H OMe H OH H OH H OH Pr OH H OH H OH H OMe H OMe H OH H OMe H OH H OMe OH OMe H OMe OH OMe H OH H OMe H OMe H OMe OH OMe H OMe OH OMe H OH H OH H OMe H OH O−CH2−O O−CH2−O O−CH2−O O−CH2−O O−CH2−O O−CH2−O O−CH2−O O−CH2−O O−CH2−O O−CH2−O O−CH2−O

G

R7

R8

ref

H H H H H H H H H H H H Pr Pr Pr H Pr H H Pr Pr OH OMe OMe H H H OH OMe H H H H OMe H OMe H H H DPr H H H H H H H H H H H

50−79 73, 80, 81 82−87 88 89 90 90 91 92 93 94 94 83, 84, 88, 95, 96 97 98 99 97, 100, 101 97 102, 103 97, 100, 104, 105 104 66, 74 63 63 106 93 107 81 107 108 108 108 109 107 93 107 110 111 111, 112 113 55−58, 75−78, 114−117 108 57 57 118 19, 89, 119−122 57 123 124 111 111


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Figure 11. Structures of O-glycosylated pterocarpans 67−72.

The method was subsequently used for the synthesis of (±)-maackiain (54),174 (±)-pterocarpin (55),175 (±)-medicarpin (5),176,177 (±)-isomedicarpin (17),177 and analogues of neodulin (9).178 (±)-4-Methoxymedicarpin (23)179 and (±)-3,4,9-trimethoxypterocarpan (46)82,179 were also synthesized in multisteps by this method as described in Scheme 2. Farkas et al.180 developed the synthesis of (±)-2-hydroxy-3methoxy-8,9-methylenedioxypterocarpan (160) and (±)-philenopteran (161),42 exploring the synthetic utility of chalcones by oxidative rearrangement with thallium(III) nitrate (TTN) to isoflavones (Scheme 3). This route to isoflavones has advantages over previous methods (phenylacetic acid precursors) due to easy accessibility of benzaldehydes and mild reactions conditions (Scheme 3). (±)-Leiocarpin (76) was synthesized by TTN oxidation of the appropriate chalcone to isoflavone followed by reduction and acid catalyzed cyclization.181 Prasad et al.182 synthesized (±)-isomedicarpin (17) by the hydrogenation of the isoflavone 166 in acetone (or methanol) in the presence of 10% palladium on charcoal together with a mixture of 2′,4′-dihydroxy-7-methoxyisoflavone (167) and 2,4-dihydroxy-7-methoxyisoflavanone (168) (Scheme 4). The mixture of 167 and 168 on rehydrogenation furnished the (±)-isomedicarpin (17) (Scheme 4). Methylation of 17 afforded (±)-homopterocarpin 15 in good yield. 2-Substituted pterocarpans and their benzannulated analogues 172 have also been synthesized efficiently by the reaction of salicylaldehydes 169 with o-methoxymethoxylphenylacetylene (170) catalyzed by gold(I) to afford isoflavanones (171) followed by one-pot reduction with NaBH4 in a mixture of THF/MeOH at room temperature (Scheme 5).183 Recently Goel et al.40 developed an expeditious synthesis of medicarpin (5) by reacting resorcinol with substituted phenyl acetic acid 142 in the presence of Lewis acid followed by selective demethylation to afford isoflavone 134 (Scheme 6). This intermediate 134 on reduction with sodium borohydride in ethanol at room temperature furnished medicarpin in good

Figure 13. Structures of furan ring fused pterocarpans.

yield. An expeditious synthesis of 3,4,9-trimethoxypterocarpan (46) has been accomplished through the methodology described in Scheme 6.40 6.2.2. Synthesis from pterocarpene. Fukui et al.184,185 used readily available pterocarpones (175), which may undergo smooth reductive ring-opening with lithium aluminum hydride and subsequent cyclization to give pterocarpene (177). Finally catalytic reduction with hydrogen in the presence of Pd or Rh yielded pterocarpans (Scheme 7). The pterocarpans synthesized by this method are (±)-pterocarpin (55),184,185 (±)-maackiain (54),186 (±)-4-methoxypterocarpin (178),187−189 (±)-3,8,9trimethoxypterocarpan (179),187−189 and (±)-3-hydroxy-8,9dimethoxypterocarpan (180).187−189 For the synthesis of (±)-4-methoxypterocarpin (178), Bouwer et al.190 employed diborane in THF to reduce the lactone carbonyl group of the pterocarpone 181 into a methylene moiety without opening of the lactone ring (Scheme 8). Miki et al.191 synthesized the (±)-homopterocarpin (15) by catalytic hydrogenation of 6a,11a-dehydrohomopterocarpin (187). They treated chalcone 183 with phenyliodine(III) bis(trifluoroacetate) (PIFA) 184 to produce 1,2-bis(2′-benzyloxy4′-methoxyphenyl)-3,3-dimethoxypropan-1-one 185, which was subsequently converted into (±)-homopterocarpin (15) as shown in Scheme 9. 6.2.3. Synthesis from 2′-Hydroxyisoflavans. Cornia et al.192 suggested oxidative conversion of 2′-hydroxyisoflavans, as a possible chemical analogy for the biosynthetic pathway, to pterocarpans by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). (±)-Medicarpin (5) and (±)-maackiain (54) have been synthesized by mild oxidation of the 2′-hydroxyisoflavans 188 with DDQ in benzene.192 The reaction probably proceeded through a quinone methide intermediate 189, which underwent a nucleophilic addition by the 2′-OH group

Figure 12. Structures of dimethylpyran ring fused pterocarpans 11, 12, and 73−88. H


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Review

Figure 14. Structures of 6a-hydroxypterocarpans 96−113 containing the core skeleton.

During the studies of isoflavan−pterocarpan interconversion, Merwe et al.194 found that the photochemical fission of the C11a−O11 bond of the pterocarpans at 300 nm in MeOH afforded the 3,4-trans-2′-hydroxy-4-methoxyisoflavans (191). One of the 3,4-trans-2′-hydroxy-4-methoxyisoflavans left in MeOH at ambient temperatures slowly reverted to 192, while conversion was completed within 1 h at 50 °C. Partial conversions were also obtained for neodulin 9, 193, and 194, when 3,4-trans-2′-hydroxy-4-methoxyisoflavans 191 was heated under the same conditions. These cyclizations to pterocarpans were enhanced dramatically in the presence of an acid (3 N HCl), running to completion within 30 min in all cases. Similar results were observed with the 3,4-trans-2′,4-dihydroxyisoflavans 195 to furnish pterocarpan 196 (Scheme 11). 6.2.4. Synthesis via Heck Arylation of 2H-Chromenes. A new route to pterocarpans was accomplished195 by Heck arylation strategy. (±)-Pterocarpin (55) and other pterocarpans 1, 199, and 200 were synthesized in a single step by the reaction of 2H-chromenes 197 with o-chloromercuriphenols 198 in the presence of lithium chloropalladite (Li2PdCl4) and acetonitrile at room temperature196,197 (Scheme 12). Ishiguro et al.199 developed an efficient route for the synthesis of (±)-cabenegrins A-I (65) and (±)-cabenegrins A-II (66), both having the skeleton of (±)-maackiain (54) with isoprenyl side chains (Scheme 13). They coupled chromene 203, derived from sequential reactions of resorcinol 201 with o-chloromercuriphenols in the presence of Li2PdCl4 in acetone to yield pterocarpans 204 and 210. Pterocarpan 204 on debenzylation gave (±)-maackiain (54), which on allylation

Figure 15. Structures of dimethylpyran ring fused 6a-hydroxypterocarpans 114−117.

Figure 16. Structures of furan ring fused 6a-hydroxypterocarpans 118−124.

(Scheme 10). Breytenbach et al.193 oxidized the 2′,7dihydroxyisoflavans with DDQ in benzene or methanol solutions under nitrogen to furnish pterocarpans 5, 6, 54, and 190 (Scheme 10). I


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Figure 17. The pathway to 6a-hydroxypterocarpans from flavanones. The left-hand column includes metabolites formed via 3R-isoflavanones as present in Cicer arietinum, Glycine max, and Medicago sativa. The right-hand column includes metabolites formed via 3S-isoflavanones as present in Pisum sativum.

found that the palladium chloride-catalyzed coupling reaction between 225 and 198 did not proceed regioselectively to give the pterocarpan 226, but it also furnished another O-heterocyclic compound 227 as a side product (Scheme 15). These observations were in the agreement with their previous findings toward the Heck-type oxyarylation of 3-chromene derivatives.203 Costa and co-workers204,205 exploited the Heck arylation reaction for the synthesis of pterocarpans 232 and transformed them to coumestans 233 for pharmacological evaluation (Scheme 16). Costa et al.206 also synthesized (±)-maackiain (54), (±)-3,4dihydroxy-8,9-methylenedioxypterocarpan (56), and (±)-2,3dihydroxy-8,9-methylenedioxypterocarpan (237) natural products with other analogues to test their cytotoxic effects on human leukemia cell lines (Scheme 17). Antus et al.207 have described a convenient synthesis of pteorocarpan 240 through modification of the Heck oxyarylation step by the replacement of the toxic chloromercuriophenol derivatives with 2-iodophenol (239), which allowed them to considerably decrease the amount of the expensive palladium(II) salt from 100 to 10 mol % in the presence of triphenylphosphine and silver carbonate in acetone207 or in ionic liquids such as

followed by Claisen rearrangement afforded 206. The compound 206 on oxidation using Upjohn method yielded 1,2-diol 207, which on further oxidation with sodium metaperiodate furnished hemiacetal 208. Treatment of 208 with α-ethoxycarbonylethyl triphenylphosphorane in DMSO afforded 209. The pterocarpan 209 on reduction with LiAlH4 in THF gave (±)-cabenegrin A-I (65). Similarly 210 on treatment with LiAlH4 in THF gave benzyl alcohol 211, which on oxidation by MnO2 yielded aldehyde 212. The pterocarpan 212 was reacted with phosphorane (prepared from 3-bromo-2methyl propanol and triphenylphosphine) and subsequent treatment with n-butyl lithium in THF, afforded the E-olefin 213. Hydrogenation of 213 on 10% Pd−C furnished (±)-cabenegrins A-II (66) (Scheme 13). Narkhede et al.200 also utilized the Heck arylation strategy to prepare (±)-leiocarpin (76) and isohemileiocarpin (224) (Scheme 14).195,199 In order to unambiguously determine the absolute configuration of (−)-cabenegrin A-I (65) and to examine its biological activity in comparison with that of its racemate, Antus et al. developed its total synthesis via (±)-maackiain (54).201,202 The strategy used by them was based on the well-documented synthetic availability of racemic maackiain (54).70,195 They J


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As an application of this methodology, Engler et al.216−219 treated 7-methoxy-2H-chromene (252) with a variety of Lewis acids, such as BF3−OEt2, TiCl4, and SnCl4, in DCM at −78 °C followed by addition of monoimides 253 and 255 to give sulfonamide-substituted pterocarpans 254 and 256, which possess interesting antimicrobial214 and anti-HIV214,215 properties (Scheme 20). In continuation of the synthesis of novel pterocarpans, Murugesh et al.220 utilized Engler’s [3 + 2] cycloaddition reaction methodology212 for the regioselective synthesis of various substituted pterocarpenes 259 and pterocarpans 260 (Scheme 21). In order to suppress the formation of pterocarpene, the reactions were carried out under a variety of conditions, and the best results were obtained by quenching the reaction for a minute after the addition of chromene. Total synthesis of (±)-edulane (85) and its angular analogue from phloroglucinol were also carried out by the group (Scheme 21).221 They found that the [3 + 2] cycloaddition reactions of 2H-chromenes 261 with 2-methoxy-1,4-benzoquinone 262 proceeded efficiently in the presence of ZnCl2.222 Evangelista et al.223 also synthesized derivatives of pterocarpans by the [3 + 2] cycloaddition reactions of 2H-chromenes with 2-alkoxy-1,4-benzoquinone in the presence of ZnCl2. 6.2.6. Synthesis via Claisen Rearrangement. A new route to pterocarpans from the Claisen rearrangement of aryl allyl ethers was developed by Thyagarajan et al.224,225 They refluxed a solution of 1,4-bis-(p-chlorophenoxy)-2-butyne (264) in diethyl aniline for 10 h to yield 2,8-dichloro-11amethylpterocarpan (265) following the mechanism based on literature report226−228 as shown in Scheme 22. Later on, Bates et al.229 suggested that 1,4-bis(aryloxy)-2butynes 266 may be converted into 4-(aryloxymethyl)-2Hchromenes 268 and 6H-benzofuro[3,2-c]-6a,11a-dihydro-11amethylbenzopyrans 267 by treating a dichloromethane solution of 266 with mercuric trifluoroacetate, silver trifluoroacetate, or silver tetrafluoroborate (Scheme 23). They found that the product obtained from 1,4-bis-(aryloxy)2-butynes 266 to 267 was a function of both the aryl group and the reaction time. With activated aromatic rings, 266 rearranged within 1 h into 267, while with less activated ones it rearranged more slowly. Thus, for moderately activated compounds, they had chosen a new path through 4-(aryloxymethyl)-2Hchromenes (268), which was converted into 267 by heating (Scheme 23). Various heterocyclic scaffolds were explored by this useful transformation strategy.230−234 Chattopadhyay et al.235 developed synthesis of pterocarpan derivatives 272 on a carbazole scaffold by cascade sigmatropic rearrangements of 1-aryloxy-4carbazolyloxybut-2-yne (271). Accordingly, when compound 271 was refluxed in N,N-diethylaniline, a slow conversion to a new compound, benzofuropyranocarbazole 272, was observed (Scheme 24). 6.2.7. Synthesis via 1,3-Michael−Claisen Annulation. A new synthetic route to the pterocarpans via a [3C + 3C] annulation was developed by Ozaki et al.236,237 1,3-Michael− Claisen condensation of γ-butyrolactones with substituted ketones delivered six-membered rings, which was converted into the pterocarpan framework by aromatization (Scheme 25). The lactone 280 used as a precursor for the synthesis of (±)-sophorapterocarpan A (287) was prepared from 7-hydroxychroman-4-one (273) via seven steps. The ketone 283 was obtained from 1-(phenylthio)propan-2-one via two steps. The [3C + 3C] annulation was achieved by condensation of 280 with 283 in dimethoxyethane (DME) in the presence of NaH at room temperature. The acetate 285 obtained from 284

Figure 18. Biosynthesis of the major pterocarpans of Cicer arietinum, Medicago sativa, and Pisum sativum. Solid arrows represent the steps in which enzymes have been identified for the biosynthesis of (+)-pisatin in pea, (−)-medicarpin in alfalfa, and (−)-maackiain in chickpea, while dashed arrows131 represent a proposal for the biosynthesis of (+)-pisatin through (+)-sophorol and for (+)-6a-hydroxymaackiain. The dotted lines are the steps at which it is proposed that intermediates are formed so that the oxygen in the 6a hydroxy group of (+)-pisatin is derived from water.

Scheme 1. Synthesis of (±)-Homopterocarpin (15)

1-butyl-3-methylimidazolium hexafluorophosphate [[bmim][PF6]](Scheme 18).208−210 6.2.5. Synthesis via [3 + 2] Cycloaddition Reaction of 2H-Chromenes. Engler et al.211,212 accomplished a new route to pterocarpans, which includes [3 + 2] cycloaddition reactions of 2H-chromenes 241 and 2-alkoxy-l,4-benzoquinones 242 using titanium(IV) as a catalyst.213 Titanium(IV) was employed in the form of a premixed combination of titanium(IV) chloride and titanium(IV) isopropoxide, and the ratio of the products 243 and 244 depends upon the ratio of TiC14 to Ti(OiPr)4 and the reaction temperature (Scheme 19). At −78 °C with 1−2 equiv of Ti(IV) as catalyst, formal [2 + 2] adduct 243 was formed exclusively. However, upon warming of the reaction mixture or utilization of catalyst systems with >2 equiv of Ti(IV) enriched in TiCl4, the formal [3 + 2] adduct 244 was the major product. Cyclobutane derivatives 243 were converted to pterocarpans 244 upon treatment with protic acids at room temperature via the shown intermediates 245 and 246 (Scheme 19). (±)-Homopterocarpin (15) and (±)-pterocarpin (55) were synthesized by this method.212 K


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Scheme 2. Synthesis of (±)-3-Hydroxy-4,9-dimethoxypterocarpan (23) and (±)-3,4,9-Trimethoxypterocarpan (46)

A (287) (Scheme 25). Similarly maackiain (54) was synthesized by the annulations using the lactone 280 and 1,1-bis(ethylthio)propan-2-one (288). Reaction of 280 with 288 in DME in the presence of NaH at room temperature gave tautomers 289, which on treatment with mercuric perchlorate in CHC13−THF followed by refluxing in acetic acid afforded the pterocarpan 290. Methylenation of 290 with dibromomethane in the presence of CsF in DMF at 110 °C unexpectedly gave pterocarpene 291, which was further converted into (±)-maackiain (54) by the earlier methods196−198 (Scheme 26). 6.2.8. Synthesis via Aldol Condensation. van Aardt et al.238,239 opted for a direct synthetic approach, which is based on Aldol condensation between phenylacetates and benzaldehydes with a view to expand the protocol to address the issue of stereocontrol at C-6a and C-11a of the pterocarpan framework. The Aldol condensation between esters 294 and the benzaldehydes 295 was done by lithium diisopropylamide (LDA) to afford the 2,3-diaryl-3-hydroxypropanoates 296. The cleavage of the C3−OH bond of 296 was achieved by the

Scheme 3. Synthesis of (±)-2-Hydroxy-3-methoxy-8,9methylenedioxypterocarpan (160) and (±)-Philenopteran (161)

was debenzylated by treatment with trichloroborane in DCM at −50 °C for 5 min to afford the phenol 286. Hydrolysis of 286 with NaOH in MeOH−H2O produced (±)-sophorapterocarpan L


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Scheme 4. Synthesis of (±)-Homopterocarpin (15) and (±)-Isomedicarpin (17)

Scheme 5. Synthesis of (±)-Subsituted Pterocarpans (172)

Scheme 8. Synthesis of (±)-4-Methoxypterocarpin (178)

Scheme 6. Synthesis of (±)-Medicarpin (5) Scheme 9. Synthesis of (±)-Homopterocarpin (15)

Scheme 7. Synthesis of (±)-Maackiain (54), (±)-Pterocarpin (55), and (±)-4-Methoxypterocarpin (178)

Scheme 10. Synthesis of (±)-Medicarpin (5), (±)-9-Demethoxymedicarpin (6), (±)-Maackiain (54), and Analogues (6, 190)

thermodynamically more stable trans-fused 2,3-dihydrobenzofuran intermediate 305 by treating with AgBF4. Subsequent reduction of 305 into 306 by LiAlH4 followed by cyclization of diols 306 under Mitsunobu conditions afforded 6a,11a-transpterocarpan (1) (Scheme 28). 6.2.9. Synthesis via Radical Cyclization. A synthetic route to pterocarpans based on a 5-endo−trig radical cyclization reaction has been accomplished by Balasubramanian et al.240,241 The precursor 4-(2″-bromoaryloxy)-2H-chromene 313 was synthesized from aryl propynyl ether 307 as shown in Scheme 29. Pterocarpan derivatives 314 were prepared by the reaction of 313 with tributyltin hydride in refluxing benzene through radical cyclization. They have also developed a novel route to 4-(2′-bromoaryloxy)-2H-chromene 318 through Mitsunobu

powerful nucleophile benzylthiol in the presence of Lewis acid, which on subsequent removal of the methoxymethyl group afforded ester 297. The reduction of 297 into corresponding diol followed by Mitsunobu cyclization provided 4-benzylthio3-arylchroman 299. Subsequent cleavage of the silyl ether 299 by TBAF on silica in THF at room temperature, followed by treatment with Lewis acids dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) or silver trifluoromethanesulfonate (CF3SO3Ag) afforded pterocarpans 1 and 15 (Scheme 27). van Aardt et al.32 also synthesized racemic trans-pterocarpan (1) for the first time exploiting their previous findings.238,239 2,3-Diaryl-3-benzylsulfanylpropanoates (304) was synthesized as described in Scheme 28, which was then cyclized into M


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Scheme 11. Synthesis of (±)-Pterocarpans Analogues 9, 192−194, and 196

Scheme 14. Synthesis of (±)-Leiocarpin (76) and Related (±)-Pterocarpan (224)

Scheme 12. Synthesis of (±)-Pterocarpan (1), (±)-Pterocarpin (55), and Analogues (199, 200)

of the dihydrobenzopyran ring, followed by intramolecular cyclization with dihydrobenzofuran ring. This pathway only allows the formation of the cis-fused system, which is the most stable. Jiménez-González et al.33 have developed a new protocol to accessing cis- and trans-pterocarpans as shown in Scheme 30. Treatment of 322 with a base promoted migration of the

reaction, which on treatment with tributyltin hydride furnished cis-pterocarpans 319 (Scheme 29). 6.2.10. Synthesis via Alkene Metathesis. The general existing methodologies to pterocarpans involve the formation

Scheme 13. Synthesis of (±)-Cabenegrins A-I (65) and (±)-Cabenegrins A-II (66)

N


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(252, 330) and 2-methoxy-l,4-benzoquinone (262) using chiral titanium(IV) complex as a catalyst (Scheme 31). As observed in the reactions promoted by simple mixtures of TiCl4/Ti(Oi-Pr)4,212 reactions of 252 bearing a C-7 methoxy substituent provided the pterocarpan products (+)-20, whereas reactions of 330 at low temperatures yielded the cyclobutane product (+)-332. Treatment of the latter with protic acids effected its rearrangement to pterocarpan (+)-333 without loss of enantiomeric purity. 6.3.2. Asymmetric Synthesis of cis- and transPterocarpins. Jiménez-González et al.33 developed a new protocol to accessing cis- and trans-pterocarpan as discussed in Scheme 30. In continuation of these studies, they investigated the possibility of using a chiral Lewis acid to perform an asymmetric condensation between 334 and 335. The reaction was completely diastereoselective with (+)-TolBINAP/Ag+, but only the trans-diastereoisomer (+)-336 was obtained in 84% ee (Scheme 32).244 The diastereoselectivity of the reaction was found to be opposite that observed using BF3·Et2O.33 The total synthesis of natural (−)-pterocarpin (55) was achieved as shown in Scheme 32 by the ring closure of the intermediate 336 through the double-bond degradation (catalytic osmium tetroxide in excess of NaIO4), followed by aldehyde reduction (LiAlH4) and Mitsunobu cyclization (DIAD/PPh3) of the dihydroxy derivative 337. The trans-pterocarpin (55) was isomerized into the more stable natural cis-pterocarpin (55) through treatment with camphor sulfonic acid (CSA). 6.3.3. Asymmetric Synthesis of cis- and transPterocarpans. Kiss et al.31 developed a new method to synthesize enantiopure trans-(6aS,11aR)-pterocarpan [(+)-1] and convert it to cis-(6aS,11aS)-pterocarpan [(+)-1] for the first time starting from racemic 2′-benzyloxyflavanone (rac-338) and chiral auxiliary as (2R,3R)-butanediol (Scheme 33). The diastereomeric ketal of rac-338 to rac-339 was prepared with acid catalyst using (2R,3R)-butanediol and then debenzylation to afford rac-340, which on crystallization in hexane/benzene 15:1 gave the diasteromerically pure (−)-340. The benzylation of (−)-340 to (+)-339 and removal of the chiral auxiliary afforded the optically active flavanone (+)-338. The optically active flavanone (+)-338 on treatment with thallium-trinitrate gave ring contracted product (+)-341 with retention of the absolute configuration (R) at C-2. The compound (+)-341 on reduction, tosylation, deprotection, and ring closure furnished trans-pterocarpan (6aS,11aR). The trans-pterocarpan (+)-1 was converted to its cis-isomer (+)-1 by treating it with p-toluenesulfonic acid, which experimentally proved that the trans-pterocarpan is the less stable isomer. 6.3.4. Asymmetric Synthesis of (−)-Cabenegrin A-I. Tő kés et al.201 synthesized (−)-cabenegrin A-I [(−)-65] by a very similar method used for its racemates by Ishiguro et al.199 The total synthesis of (−)-cabenegrin A-I [(−)-65] in five steps via intermediates 346−350 was achieved from (−)-(6aR,11aR)maackiain [(−)-54], which was prepared by the optical resolution of racemic maackiain (54) using S-(−)-α-methylbenzyl isocyanate as the chiral auxiliary (Scheme 34). 6.3.5. Asymmetric Synthesis of (+)-Pisatin. An asymmetric total synthesis of (+)-pisatin (111) was developed by Pinard et al.245 involving a Sharpless asymmetric dihydroxylation and a hydrogenative cyclization as key steps. Aldehyde 352 was synthesized by o-benzylation of sesamol (351) followed by formylation in the presence of α,α-dichloromethyl methyl ether-TiCl4. Homologation of 352 into acid 354 was achieved using methyl(methylthio)methyl sulfoxide (Tsuchihashi’s reagent) and powdered KOH, then treatment with an ethanolic

Scheme 15. Synthesis of (±)-Pterocarpan Analogue 226


Scheme 17. Synthesis of Natural and Synthetic (±)-Pterocarpans 54, 56, 237, and 238


double bond, and further silylation of 323 gave the desired diolefin 324 as a mixture of geometrical isomers. Ring closing metathesis of 324 in the presence of the Grubb’s catalyst furnished 325. At this point, the second aromatic ring of the pterocarpan was introduced through a modified Sakurai− Hosomi condensation of 325 with aldehyde 326 in the presence of BF3·Et2O. Oxidation of 327 with catalytic osmium tetroxide in an excess of NaIO4 yielded an aldehyde, which on further reduction with LiAlH4 in Et2O or THF gave cis-328 with retention of configuration. The compound 327 was transformed into alcohol trans-329 with NaBH4 in MeOH, a reagent that reduced the aldehyde and at the same time promoted complete epimerization of C-3. Both pterocarpans cis-7 and trans-7 were prepared by treatment with PPh3 and diisopropyl azodicarboxylate (DIAD) from the corresponding alcohols. 6.3. Asymmetric Syntheses

6.3.1. Asymmetric Synthesis from 2H-Chromenes. Engler et al.242,243 developed asymmetric synthesis of pterocarpans by [3 + 2] cycloaddtion reactions212 of 2H-chromenes O


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Scheme 19. Synthesis of (±)-Homopterocarpin (15) and (±)-Pterocarpin (55)

Scheme 20. Synthesis of (±)-Substituted Pterocarpans 254 and 256

Scheme 22. Synthesis of (±)-Substituted Pterocarpan 265

acid activating agent and DBU as the base to afford coumarin 355. After reduction of 355 with DIBAH into diol 356, cyclization through Mitsunobu reaction afforded benzopyran 357 (Scheme 35). Further, compound 357 was subjected to the catalytic Sharpless asymmetric dihydroxylation using a stoichiometric

solution of HCl and catalytic amount of CuCl2 followed by saponification. The compound 354 was coupled with 2-hydroxy-4benzyloxybenzaldehyde using phenyl dichlorophosphate as an

Scheme 21. Synthesis of (±)-Edulane (85) and (±)-Substituted Pterocarpan 263

P


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Scheme 26. Synthesis of (±)-Maackiain (54)


Scheme 27. Synthesis of (±)-Substituted Pterocarpans 1 and 15 Scheme 25. Synthesis of (±)-Sophorapterocarpan A (287)

Scheme 28. Synthesis of (±)-trans-Pterocarpan (1)

dihydroquinine p-chlorobenzoate (DHQ-CLB), 362, afforded (−)-(3R,4S)-syn-diols 364 or 365 in more than 99% enantiomeric excess (Scheme 36).221 In the same way, when 360 and 361 were treated with stoichiometric amounts of OsO4 in the presence of the chiral catalyst dihydroquinidine p-chlorobenzoate (DHQD-CLB), 363, (+)-(3S,4R)-syn-diols 364 or 365 were isolated in more than 99% enantiomeric excesses. Deprotection of (−)-(3R,4S)syn-diols 364 and 365 by TBAF suspended on silica yielded (−)-(3R,4S)-2′-hydroxyisoflavan-3,4-diols 366 and 367, respectively, which on reaction with Ms2O/pyridine afforded the requisite (+)-(6aR,11aR)-cis-6a-variabilin 99 and (+)-(6aR,11aR)-cis-6a-hydroxy-3,9,10-trimethoxypterocarpan 368, respectively, in more than 99% enantiomeric excess. Similarly, under same reaction conditions isomers (+)-(3S,4R)364 and -365 afforded (−)-(6aS,11aS)-variabilin 99 and

amount of OsO4 and dihydroquinine p-chlorobenzoate in toluene at room temperature, which furnished the desired diol 358 in 80% ee. Moreover in CH2Cl2 at −78 °C, the enantiomeric excess reached up to 94%. Optically pure diol 358 was transformed into 6a-hydroxymaackiain 110 in a single step by a large excess of Pd/C (10%) under H2 (1 atm). Finally, 110 was methylated in the presence of dimethylsulfate and K2CO3 to provide optically pure (+)-pisatin, 111 (Scheme 35). 6.3.6. Asymmetric Synthesis of (+)-Variabilin and (−)-Variabilin. In regard to the asymmetric synthesis of 6a-hydroxy pterocarpans, van Aardt et al.32 developed a new protocol for cis- as well as for trans-conformations. First of all, they synthesized isoflav-3-enes 360 and 361. The treatment of isoflav-3-enes 360 and 361 in DCM at −78 °C with stoichiometric amounts of OsO4 in the presence of the chiral catalyst Q


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Review

Scheme 33. Synthesis of cis- and trans-Pterocarpan (1)

Scheme 29. Synthesis of (±)-Pterocarpans 319

Scheme 34. Synthesis of (−)-Cabenegrin A-I (65) Scheme 30. Synthesis of (±)-cis- and trans-Pterocarpans 7

Scheme 31. Synthesis of (+)-Pterocarpans 20 and 333 “interrupted” Feist−Benary reaction (IFB) as the key transformation to introduce chirality into the target molecule rather than using osmium tetroxide in the presence of chiral catalysts (Scheme 37). The IFB reaction for the synthesis of (−)-variabilin 99 involved the attack of the nucleophile dithiane-based diketone 370 to the electrophile β-bromo-α-ketoester 369 in the presence of a chiral catalyst monoquinidine pyrimidinyl ether 371, which afforded a mixture of diastereoisomers 372. The synthesis of (−)-variabilin was accomplished by the aromatization of 372 into the phenol 374 followed by tosylation and double reduction to afford 1,2-diol 376 (Scheme 37). Intramolecular Buchwald−Hartwig cyclization on the diol 376 in the presence of chiral ferrocene ligand 377 afforded dihydrobenzopyran 378 in high diastereopurity. The reduction of 378 using THF-soluble LiBH4 in the presence of NiCl2 furnished (−)-variabilin (99) in 5.7% overall yield. 6.3.7. Asymmetric Synthesis of (−)-Glyceollin I and (+)-Glyceollin I. The first total synthesis of racemic glyceollin I (115) and its enantiomers was developed by Erhardt and co-workers.247 They utilized a Wittig olefination reaction as a consequence of the ring closure to the appropriately substituted isoflav-3-ene 387, so that an osmium tetroxide-mediated asymmetric dihydroxylation could be deployed for stereospecific introduction of the 6a-hydroxy group. The synthetic route to isoflav-3-ene 387 is depicted in Scheme 38.

Scheme 32. Synthesis of (−)-cis- and (−)-trans-Pterocarpins (55)

(−)-(6aS,11aS)-cis-6a-hydroxy-3,9,10-trimethoxypterocarpan 368, respectively, in 99% ee (Scheme 36). Calter and Li246 have recently developed a new unique protocol for the synthesis of (−)-variabilin 99 via an R


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Scheme 35. Synthesis of (+)-Pisatin (111)

Scheme 36. Synthesis of 6a-Hydroxypterocarpans 99 and 368

Scheme 37. Synthesis of (−)-Variabilin (99)

The aldol approach was used for condensing the tautomeric keto-form of the phenol with the unsaturated aldehyde masked as its acetal 391 under refluxing p-xylene by using picoline as a base with continuous removal of the liberated alcohol into 392 and its regioisomer 393 (precursor to glyceollin II, 116). Separation of these regioisomers was accomplished by using silica column chromatography. At the end, NEt3·3HF was utilized for the transformation of 392 into (−)-glyceollin I (115). In the same way, unnatural (+)-glyceollin I (115) was synthesized from the enantiomer of 388 having (6aR,11aR) stereochemistry (Scheme 39). Racemic glyceollin I was also synthesized without using chiral catalyst by dihydroxylation with osmium tetroxide in large quantities. Erhardt asymmetric synthesis247 is highly efficient for the synthesis of rac- and enantiomerically pure glyceollin I and related molecules prepared through one set of protocols. The procedure has been successfully scaled up by Erhardt and co-workers in order to supply multigram quantities of (−)-glyceollin I (115) needed for in vivo biological studies.250

Distinct stereochemistry was established during the osmium tetroxide dihydroxylation step.245,248,249 Using stoichiometric amounts of (DHQD)2-PHAL as a chiral catalyst and OsO4 led it to be delivered from the β-face so as to provide the (6aS,11aS) stereochemistry desired for the natural (−)-glyceollin I (115), while (DHQ)2-PHAL provided the (6aR,11aR) stereochemistry desired for the unnatural (+)-enantiomer, each enantiomer in greater than 95% ee (Scheme 39). The next step involved debenzylation of diol 388 to the tetrol 389 by hydrogenation with 10% Pd−C. Polymer-bound 1,3,4,6,7,8-hexahydro-2Hpyrimido[1,2-a]pyrimidine was deployed as a base in anhydrous ethanol over molecular sieves for the cyclization through quinine−methide intermediate into 390. S


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Scheme 38. Synthesis of Isoflavenes (387)

Scheme 40. Synthesis of (−)-Glycinol (96)

Scheme 41. Synthesis of (−)-Glycinol (96)

6.3.8. Asymmetric Synthesis of (−)-Glycinol. 3,6a,9Trihydroxypterocarpan (glycinol, 96) is a key biochemical intermediate of the glyceollin family of natural products. Owing to interesting biological activities associated with the 6ahydroxypterocarpan class of compounds, an efficient synthesis of (−)-glycinol has been reported starting from the phenolic group protected isoflav-3-ene 387. A Sharpless dihydroxylation strategy was used to introduce enantiomeric 6a-hydroxy group of pterocarpan 390 as shown in Scheme 39. The synthesis of (−)-glycinol was accomplished by the deprotection of the masked phenolic group of 390 using a mild acidic reagent, NEt3·3HF, buffered with excess pyridine (Scheme 40).251 Recently Calter and Li246 developed an efficient synthesis of (−)-glycinol (96) in high enantio- and diastereoselectivity with 3% overall yield (Scheme 41). The “interrupted” Feist−Benary (IFB) reaction was employed as the key step to introduce both stereogenic centers simultaneously. A reaction of the electrophile β-bromo-α-ketoester 394 with the nucleophile dione 395 in the presence of a catalyst monoquinidine pyrimidinyl ether 371 afforded a mixture of E/Z isomer 396. After chromatographic separation of the E-isomer of 396, aromatization with t-BuOK followed by tosylation and twostage reduction furnished diol 399. The diol 399 was then

converted to (−)-glycinol 96 under modified Buchwald− Hartwig conditions followed by oxidation and subsequent hydrogenation (Scheme 41).

7. CHEMICAL REACTIVITY OF PTEROCARPANS Pterocarpans are biologically interesting and chemically reactive compounds, which possess three sp3-hybridized carbons with two stereogenic centers. These centers are highly reactive and susceptible to various oxidizing and reducing agents. Due to conformational flexibility at C6−C6a−C11a centers and the presence of a benzylic ether bond, various organic reactions have been performed under acidic or basic conditions, which furnished useful synthetic intermediates. Some of the important reactions are described in this section.

Scheme 39. Synthesis of (−)-Glyceollin I (115)

T


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7.1. Oxidation of Pterocarpans

Scheme 46. Oxidation of Pterocarpans 411

In order to generate resistance to microbial invasion, many plants produce pterocarpan derivatives as phytoalexins, which are toxic to fungi. However some fungal enzymes such as cytochrome P450 monooxygenase have the ability to neutralize the toxicity of phytoalexins by oxidation of the pterocarpans.252 For example, (−)-maackiain 54 can be oxidized at the 6a and 6 positions by the broad host-range pathogen Colletotrichum gloeosporioides to produce both (−)-6a-hydroxymaackiain 110 and 6,6a-dihydroxymaackiain 403 (Scheme 42).253

7.2. Reduction of Pterocarpans

Catalytic hydrogenation of pterocarpans is an efficient route to the synthesis of isoflavans. Since pterocarpans possess a benzylic ether group, they can undergo hydrogenolysis. For example, reduction of homopterocarpin 15 to isoflavan 413 was accomplished either with hydrogen in the presence of Pd on charcoal or with zinc amalgam and hydrochloric acid (Scheme 47).206,256 Reduction of medicarpin 5 was carried out in the presence of sodium cyanoborohydride [Na(CN)BH3] in TFA, which furnished (+)-vestitol 414 in good yield (Scheme 47).257−259

Scheme 42. Enzymatic Oxidation of Maackiain

Pterocarpans 404 are considered to be useful precursors to prepare coumestan derivatives 405 via oxidation with DDQ (Scheme 43).204,254,255 A natural product tuberostan (407) was

Scheme 47. Hydrogenation of Pterocarpans

Scheme 43. Reaction of Pterocarpan 404 or 406 with DDQ

The allylic and benzylic ether bonds in dimethylpyranopterocarpans are susceptible to catalytic hydrogenation and can be cleaved to provide prenylated isoflavans, which are presumably a key intermediate in the biosynthesis of pterocarpans. The reduction of phaseollin 73 using liquid ammonia and lithium metal afforded phaseollidin isoflavan 415 (Scheme 48).260

synthesized from a prenylated pterocarpan 406 utilizing this approach.182 In the presence of excess of DDQ in DCM, 3,4-dihydroxypterocarpan 56 was transformed into ortho-quinone 408 (Scheme 44).206

Scheme 48. Reduction of Phaseeollin 73

Scheme 44. Reaction of Pterocarpans 56 with DDQ

7.3. Reactions of Pterocarpans with Acids

It was found that reaction of pterocarpan 409 with CH2I2 in K2CO3 led to the (±)-pterocarpin 55 in 46% yield together with its oxidized product anhydropisatin, a pterocarpene 410 in 6% yield (Scheme 45).212

Pterocarpans are sensitive to acids yielding generally resinous products, presumably due to intermediate formation of isoflav3-enes.261,262 Pterocarpans may undergo ring opening at C11a−O11 in the presence of acidic reagents to form the corresponding isoflav-3-enes 416 (Scheme 49).263−266 A similar

Scheme 45. Oxidation of Pterocarpan 409 Scheme 49. Reaction of Pterocarpans with Acids

In an individual oxidation reaction, (±)-neorautane 411 was converted into pterocarpene 412 by the reaction of N-bromosuccinimide (NBS) followed by dehydrobromination in the presence of pyridine (Scheme 46).254

type of isoflav-3-enes have been reported to degrade into multiple side products in the presence of trifluoroacetic acid or with boron tribromide.267 U


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Erhardt and co-workers250 thoroughly studied the stability of glyceollin I under acidic conditions using a HPLC technique and proposed that cis-ring fusion collapsed in a E2 type fashion in a concerted manner. 6a-Hydroxypterocarpan glyceollin I was found to be unstable in acidic medium at pH < 4 and at pH > 10; however, it may be stable at pH > 4 and

Synthesis, Stereochemistry, Structural ... - ACS Publications

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