Letter pubs.acs.org/OrgLett
Total Synthesis and Stereochemical Revision of 4,8-Dihydroxy-3,4dihydrovernoniyne Suresh Kanikarapu,† Kanakaraju Marumudi,‡ Ajit C. Kunwar,‡ Jhillu S. Yadav,† and Debendra K. Mohapatra*,† †
Natural Products Chemistry Division and ‡Centre for NMR and Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India S Supporting Information *
ABSTRACT: The first asymmetric total synthesis of two possible diastereomers (4S,5R)-4,8-dihydroxy-3,4-dihydrovernoniyne 5 and (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a is accomplished. Salient features of the synthesis involve Cadiot− Chodkiewicz coupling and Sonogashira cross-coupling of terminal acetylenes. Detailed comparison of the 1H and 13C NMR data and specific rotation with that of the natural product led to the revision of the absolute stereochemistry of the natural product as (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a.
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The retrosynthetic route for the synthesis of (4S,5R)-4,8dihydroxy-3,4-dihydrovernoniyne 5 is illustrated in Scheme 1. We envisioned a convergent strategy based on the coupling of functionalized alkyne in 9 and bromodiyne 10 either by a Cadiot−Chodkiewicz7 cross-coupling reaction or by Sonogashira8 coupling reaction. The functionalized alkyne in 9 could be synthesized from homopropargyl alcohol 12 using Jin’s onestep dihydroxylation−oxidation protocol,9 which in turn could be accessible from commercially available D-mannitol 14. Similarly, the bromodiyne 10 can be obtained from readily available propargyl alcohol 15. Thus, the synthesis began with the preparation of bromodiyne 10 and diyne 11, which were easily prepared from commercially available propargyl alcohol 15 (Scheme 2). Conversion of the propargyl alcohol 15 to the PMB ether following a mild one-step heterogeneous protocol10 and further reaction with NBS and AgNO3 afforded bromoacetylene 1311 in 97% yield. Coupling of bromoalkyne 13 with TMS-acetylene under Cadiot−Chodkiewicz conditions7 provided the crosscoupling product 17 (62%) along with the dimer resulting from the homocoupling in 23% yield. Formation of the dimer resulting from the TMS-acetylene was investigated by performing the coupling reaction. Interestingly, under Sonogashira conditions (Pd(PPh3)2Cl2, CuI, i-Pr2NH, THF)8 (Table 1,
atural products bearing a polyacetylenic group with varied and diverse substitutions are unique structural motifs displaying several bioactivity profiles.1 Among them, unsymmetrical 1,3-diynes have received considerable attention. Over 1000 polyacetylenic natural products have been isolated to date from organisms such as plants, mosses and lichens, fungi, bacteria, insects, algae, sponges, and tunicates.2 These natural products are relatively unstable and reactive due to their potential to undergo oxidative, photolytic, or pH-dependent decomposition.3 Their unique rodlike structure and often conjugated character is responsible for the cytotoxic, antibacterial, antiparasitic, insecticidal, antitumor, anti-inflammatory, antiviral, and phytotoxic activities.4 Recently, Biavatti and co-workers5 isolated eight polyacetylene-containing butyrolactone natural products 1−8, seven of which are new, from the leaves of Vernonia scorpioides (Asteraceae) (Figure 1). This herb is used in folk medicine for the treatment of several skin diseases, such as allergies, skin parasites, irritation, chronic skin injuries (ulcers), and itching. Their structures were established by 1D and 2D NMR spectroscopy and MS analysis. We recently accomplished the total synthesis of the diynecontaining natural product ivorenolide A.6 In continuation of our efforts, we report herein the first asymmetric total synthesis of (4S,5R)-4,8-dihydroxy-3,4-dihydrovernoniyne and revision of its absolute stereochemistry based on the synthesis. © XXXX American Chemical Society
Received: June 1, 2017
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DOI: 10.1021/acs.orglett.7b01620 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
a
entry
cross-coupling conditions
17a (%)
1 2
CuCl, NH2OH·HCl, n-BuNH2, ether, 0 °C, 30 min CuI, (Ph3P)2PdCl2, DIPA, THF, 0 °C, 1 h
62 85
Isolated yield.
in quantitative yield.12 Reaction of compound 17 with K2CO3 in MeOH furnished the diyne 11 in 96% yield (Scheme 2). Synthesis of the lactone 9 commenced from a known homoallylic alcohol 18, which was synthesized from D-mannitol following a procedure described in the literature.13 Modified Mosher’s ester method14 was applied to assign the stereocenter at C4 bearing the secondary hydroxyl group, and the center was found to have an S configuration. The secondary alcohol group present in 18 was protected as its MOM-ether 19 in good yield. Compound 19 was treated with 1 M HCl in acetonitrile to obtain the diol 20 in 92% yield. Treatment of the diol 20 with trisylimidazole in the presence of NaH in THF furnished the epoxide 21. Regioselective opening of the epoxide ring using the Yamaguchi−Hirao alkynylation protocol15 afforded the βhydroxy alkyne 22 in 85% yield. At this stage, the absolute stereochemistry at C5 was determined as R based on a modified Mosher’s ester method. Removal of the TMS group under anhydrous K2CO3 in MeOH conditions furnished the homopropargyl alcohol 12 in quantitative yield. The terminal double bond was selectively oxidized following Jin’s one-step dihydroxylation−oxidation protocol9 to obtain the desired lactol 23 in 82% yield. The lactol 23 was oxidized with PCC in CH2Cl2 to afford lactone 9 in 90% yield. The alkyne group was converted to bromoalkyne 24 by using NBS and a catalytic amount of AgNO3 in 97% yield (Scheme 3).11 With the requisite fragments in hand, coupling of the alkyne 9 with bromodiyne 10 was investigated under Cadiot−
Figure 1. Structures of polyacetylenes 1−8.
Scheme 1. Retrosynthetic Analysis
Scheme 3. Synthesis of the Alkyne Fragment 9 and Bromoalkyne Fragment 24
Scheme 2. Synthesis of Bromodiyne 10 and Diyne 11
entry 2), the required cross-coupling product 17 was obtained in 85% yield along with homocoupled dimer in 5% yield were obtained. Upon treatment with NBS and AgNO3, compound 17 underwent in situ deprotection of the C-silyl group followed by bromination of the terminal alkyne to obtain bromodiyne 10 B
DOI: 10.1021/acs.orglett.7b01620 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Chodkiewicz reaction conditions. While performing the reaction in diethyl ether was futile (Table 2, entry 1), the
Scheme 5. Synthesis of (4S,5S)-4,8-Dihydroxy-3,4dihydrovernoniyne 5a
Table 2. Optimization of the Reaction Conditions for Cadiot−Chodkiewicz and Sonogashira Cross-Coupling entry
R1
R2
cross-coupling conditions
yield (%)
1 2 3 4 5
H H H Br Br
Br Br Br H H
CuCl, NH2OH·HCl, n-BuNH2, Et2O, 0 °C CuCl, NH2OH·HCl, n-BuNH2, CH2Cl2, 0 °C CuI, (Ph3P)2PdCl2, DIPA, THF, rt CuI, (Ph3P)2PdCl2, DIPA, THF, rt CuCl, NH2OH·HCl, n-BuNH2, CH2Cl2, 0 °C
0 60 75 55 90
reaction in dichloromethane afforded the product in 60% yield (Table 2, entry 2). Performing the reaction under Sonogashira conditions furnished the product in 75% yield. Interestingly, reaction of the bromoalkyne 24 (derived from 9) with the diyne 11 gave the required product 25 in 90% yield (Table 2, entry 5) (Scheme 4). These reactions are summarized in Table 2.
Table 3. Comparison of 13C NMR of Natural Product with Synthetic 5 and 5a in Acetone-d6 (400 MHz)
Scheme 4. Synthesis of (4S,5R)-4,8-Dihydroxy-3,4dihydrovernoniyne 5
The PMB group in compound 25 was selectively deprotected with DDQ under standard reaction conditions to furnish the primary alcohol 26 in 92% yield. Deprotection of the MOM ether in 26 with BF3·OEt2 in dimethyl sulfide at −40 °C provided (4S,5R)-4,8-dihydroxy-3,4-dihydrovernoniyne 5 in 70% yield.16 The specific rotation of the synthetic sample had opposite sign [[α]D25 +4.61 (c 0.76, EtOH)] compared to that reported for the natural product [lit.5 [α]D25 −2.16 (c 0.74, EtOH)]. Moreover, the 1H and 13C NMR spectral data of synthetic 5 were not in agreement with those reported (see the Supporting Information). As both the spectral data and sign of optical rotation for synthetic sample were not matched with those reported for the natural product, we surmised that the isolated compound might be diastereomer of 5. Therefore, we undertook the total synthesis of the other diastereomer of 5 (i.e., 5a) by following a route similar to that described (Scheme 5 and Supporting Information for further details). Gratifyingly, compound 5a displayed 1H and 13C NMR spectral data identical to those reported for the natural product (4S,5R)-4,8dihydroxy-3,4-dihydrovernoniyne 5 (Table 3). The structures of 5 and 5a were further confirmed by detailed 2D NMR
experiments in two different solvents, acetone-d6 and acetonitrile-d3. The presence of medium range characteristic NOE correlations: H3a/4-OH, H4/(H1′a-H1′b) and 4-OH/ H5 in 5 supported an “R” configuration at C5 whereas H3a/4OH and 4-OH/(H1′a-H1′b) in 5a are consistent with the configuration at C5 to be “S”. The specific rotation of (4S,5S)-5a showed [[α]D25 −61.5 (c 0.94, EtOH)], however, did not match in magnitude with the value that reported for the natural product [lit.5 [α]D25 −2.16 (c 0.74, EtOH)], a plausible reason for the discrepancy is either an impure sample of the natural products or the unstable nature of the polyene compounds, which is reflected in the NMR spectra of the natural product.5 Therefore, the results led to the revision of the configuration at C-5 to be “S”. In summary, first stereoselective total synthesis of two isomers of 4,8-dihydroxy-3,4-dihydrovernoniyne 5 and 5a was accomplished in 11 steps with 28% overall yield starting from known intermediate 18. The salient features of this synthesis include Cadiot−Chodkiewicz coupling, Pd-catalyzed crossC
DOI: 10.1021/acs.orglett.7b01620 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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coupling of terminal acetylenes and optimization of their reaction conditions. The 1H and 13C NMR data as well as spectral data of the synthetic 5 and 5a were compared with those reported for the natural product. On the basis of the data, stereostructure of the natural product was reassigned to (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01620. Experimental procedure and characterization of new compounds (1H, 13C NMR spectra, 2D-NMR spectra) (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Debendra K. Mohapatra: 0000-0002-9515-826X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Council of Scientific and Industrial research (CSIR), New Delhi, India, for financial support as part of the XII Five Year Plan Programme under the title ORIGIN (CSC0108). S.K. and K.M. thank CSIR, and UGC, New Delhi, India, for financial assistance in the form of fellowships.
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DOI: 10.1021/acs.orglett.7b01620 Org. Lett. XXXX, XXX, XXX−XXX
