研究者詳細 - 須貝　威

論文 - 須貝　威

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Semisynthesis of prunetin, a bioactive O-methylated isoflavone from naringenin, by the sequential deacetylation of chalcone intermediates and oxidative rearrangement

T. Sugai, K. Hanaya, S. Higashibayashi

Bioscience, Biotechnology and Biochemistry 85 143 - 147 2021年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09168451

Theoretical Analysis of the Heterocyclic [4+2] Cycloaddition Between Pyridinium Ion and Enol Ether

Nakahara M., Hanaya K., Sugai T., Higashibayashi S.

ChemistryOpen （ChemistryOpen） 10 （ 6 ） 627 - 629 2020年12月

研究論文（学術雑誌）, 共著, 査読有り

Dearomative heterocyclic [4+2] cycloaddition between the N-(2,4-dinitrophenyl)pyridinium ion of nicotinamide and an enol ether was analyzed by Density Functional Theory (DFT) calculations. The calculation revealed that the reaction undergoes stepwise bond formation rather than occurring in a concerted manner. The experimental products were found to be both kinetically and thermodynamically favored. The calculated transition states and intermediate suggested that the high diastereoselectivity is derived from the electrostatic interaction between the 2-nitro group of the pyridinium ion and the hydrogen of the enol ether.

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Improved preparation of vitexin from hot water extract of Basella alba, the commercially available vegetable Malabar spinach (“Tsurumurasaki” in Japanese) and the application to semisynthesis of chafuroside B

Kurahayashi K., Hanaya K., Higashibayashi S., Sugai T.

Bioscience, Biotechnology and Biochemistry 84 1554 - 1559 2020年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09168451

Hot water extraction of D-arabinofuranosylvitexin from the raw leaves of commercially available Basella alba “Tsurumurasaki” and subsequent acidic hydrolysis was improved to be a procedure using a high-pressure steam sterilizer to afford vitexin. The amount was estimated to be 14.1 mg from 1 g of dry weight of the raw leaves, whose recovery was calculated to be 95% based on the estimated content of D-arabinofuranosylvitexin in B. alba raw leaves. The product was dehydratively cyclized between hydroxy groups on the carbohydrate and flavone skeletons under modified Mitsunobu reaction conditions in N,N-dimethylformamide to give chafuroside B, which is known to be a bioactive Oolong tea polyphenol. Through these transformations, 10.2 mg of chafuroside B could be semisynthesized from 1 g of dry weight of the raw leaves, and the efficiency was improved compared to that from the extraction from Oolong tea (3.4 μg from 1 g of dry weight).

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Comprehensive semisyntheses of catathelasmols C, D, and E from D-glutamic acid, utilizing lipase-catalyzed site-selective reactions on intermediates

Hashiba R., Hashimoto R., Nishiguchi M., Kobayashi T., Hanaya K., Higashibayashi S., Sugai T.

Bioscience, Biotechnology and Biochemistry 84 1339 - 1344 2020年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09168451

Catathelasmols C, D, and E, which had been isolated from Catathelasma imperiale as inhibitors for 11-hydroxysteroid dehydrogenases, were comprehensively semisynthesized from commercially available D-glutamic acid. The key synthetic intermediate, (R)-pentane-1,2,5-triol, was site-selectively acetylated by treatment with vinyl acetate and Candida antarctica lipase B (Novozym 435) in tetrahydrofuran (THF) at 25°C to furnish 1,5-diacetate (catathelasmol E, quantitative). The acetylation occurred site-selectively on the primary alcohols at the C-1 and C-5 positions over the secondary alcohol at the C-2 position. Dichromic acid oxidation provided 2-oxopentane-1,5-diyl diacetate (catathelasmol C, 78%). Burkholderia cepacia lipase-catalyzed transesterification with methanol in THF at–5°C proceeded preferentially on the acetate at C-1 located adjacent to the C-2 carbonyl group over the other terminal acetate at the C-5 position. 5-Hydroxy-4-oxopentyl acetate (catathelasmol D) was obtained in 53% yield.

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Stepwise approach for sterically hindered C<inf>sp<sup>3</sup></inf>-C<inf>sp<sup>3</sup></inf> bond formation by dehydrogenative: O -alkylation and Lewis acid-catalyzed [1,3]-rearrangement towards the arylalkylcyclopentane skeleton of sesquiterpenes

Fujitani B., Hanaya K., Sugai T., Higashibayashi S.

Chemical Communications （Chemical Communications） 56 （ 25 ） 3621 - 3624 2020年03月

研究論文（学術雑誌）, 査読有り, ISSN 13597345

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Syntheses of Indirubins by Aldol Condensation of Isatins with Indoxyl Anion Generated in situ by Lipase-Catalyzed Deacetylation of Indoxyl Acetate

Sugai, T.; Hanaya K., Higashibayashi S.

Heterocycles （Heterocycles） 100 （ 1 ） 129 - 136 2019年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03855414

© 2019 The Japan Institute of Heterocyclic Chemistry. The syntheses of indirubin (76% yield), 6-bromoindirubin (82% yield), and 6-bromoindirubin-3′-oxime (78% yield in two steps) were achieved via the lipase-triggered aldol condensation between isatins and an indoxyl anion in tetrahydrofuran under anhydrous and anaerobic conditions as the key step. The aldol donor was generated in situ by Burkholderia cepacia lipase (Amano PS-IM)-catalyzed deacetylation of commercially available and stable indoxyl acetate in the presence of triethylamine and with 2-propanol as the transesterification reagent. The scale-up of the presently developed reactions is easier than that in the previously reported chemical aldol condensations, because of the simplicity of the isolation procedure and suppression of the oxidative byproduct formation from indoxyl acetate.

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Chemoenzymatic synthesis of hydroxytyrosol monoesters and their suppression effect on nitric oxide production stimulated by lipopolysaccharides

Sakakura A., Pauze M., Namiki A., Funakoshi-Tago M., Tamura H., Hanaya K., Higashibayashi S., Sugai T.

Bioscience, Biotechnology and Biochemistry （Bioscience, Biotechnology and Biochemistry） 83 （ 2 ） 185 - 191 2019年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09168451

© 2018 Japan Society for Bioscience, Biotechnology, and Agrochemistry. Fatty acid monoesters of hydroxytyrosol [2-(3,4-dihydroxyphenyl)ethanol] were synthesized in two steps from tyrosol (4-hydroxyphenylethanol) by successive Candida antarctica lipase B-catalyzed chemoselective acylation on the primary aliphatic hydroxy group over phenolic hydroxy group in tyrosol, and 2-iodoxybenzoic acid (IBX)-mediated hydroxylation adjacent to the remaining free phenolic hydroxy group. Examination of their suppression effects on nitric oxide production stimulated by lipopolysaccharides in RAW264.7 cells showed that hydroxytyrosol butyrate exhibited the highest inhibition (IC 50 7.0 μM) among the tested compounds.

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Synthesis of 5-Hydroxy-3′,4′,7-trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2-Mediated Anticancer Drug Resistance

Tsunekawa R., Katayama K., Hanaya K., Higashibayashi S., Sugimoto Y., Sugai T.

ChemBioChem （ChemBioChem） 20 （ 2 ） 210 - 220 2019年01月

ISSN 14394227

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3′,4′,7-Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C-5 and several kinds of capping moiety at the C-7 hydroxy group, on the same 3′,4′-dimethoxy-substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP-expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI 50 ). Of the synthesized compounds, the reversal effect of 5-hydroxy-3′,4′,7-trimethoxyflavone (HTMF, RI 50 7.2 nm) towards 7-ethyl-10-hydroxycamptothecin (SN-38) was stronger than that of TMF (RI 50 18 nm). Fluoro-substituted 5-fluoro-3′,4′,7-trimethoxyflavone (FTMF, RI 50 25 nm) and monoglycosylated 7-(β-glucosyloxy)-5-hydroxy-3′,4′-dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di- and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01–10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP-mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.

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Preparation of menisdaurigenin and related compounds

Shirakawa R., Ishikawa S., Takahasi M., Ueno Y., Uekusa Y., Narukawa Y., Sugai T., Kiuchi F.

Journal of Natural Medicines （Journal of Natural Medicines） 73 （ 1 ） 236 - 243 2019年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13403443

© 2018, The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature. Menisdaurin (1), a cyano glucoside, was first isolated in 1978 from Menispermum dauricum (Menispermaceae) and named after the plant. It has been also isolated from several plant sources. The stereochemistry of the aglycone part was first reported as (Z,4R,6S)-enantiomer of (4,6-dihydroxy-2-cyclohexen-1-ylidene)acetonitrile based on the CD spectrum of menisdaurilide (2), the α,β-unsaturated γ-lactone obtained by an acid hydrolysis of menisdaurin. Later, the absolute stereochemistry was revised as (Z,4S,6R) by X-ray crystal analysis of 1 isolated from Saniculiphyllum guangxiens. The aglycone part of menisdaurin (1) has not been obtained from 1, because an acid hydrolysis of 1 gave menisdaurilide (2), and enzymatic hydrolysis with emulsin did not give the aglycone. On the other hand, a compound named coculauril (3) was isolated from Cocculus lauriforius. This compound has the same planner structure corresponding to the aglycone of 1, but the stereochemistry was reported to be (E,4R,6S). Here, we confirmed the absolute stereochemistry of 1 by Mosher’s method to be (Z,4S,6R), and prepared the aglycone of 1, i.e., menisdaurigenin (4) by an enzymatic hydrolysis of 1. We also revealed that 4 is a different compound from 3 and unstable in water and MeOH.

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Dearomative Oxidative Rearrangement of [3]Cyclo-1,8-carbazolylene

Yasui M., Ohtsu H., Kawano M., Hanaya K., Sugai T., Higashibayashi S.

Chemistry Letters （Chemistry Letters） 47 （ 11 ） 1357 - 1359 2018年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03667022

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Synthesis of trilobatin from naringin via prunin as the key intermediate: Acidic hydrolysis of the α-rhamnosidic linkage in naringin under improved conditions

Kurahayashi K., Hanaya K., Higashibayashi S., Sugai T.

Bioscience, Biotechnology and Biochemistry （Bioscience, Biotechnology and Biochemistry） 82 （ 9 ） 1463 - 1467 2018年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09168451

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Synthesis of oroxylin A starting from naturally abundant baicalin

Fujita R., Hanaya K., Higashibayashi S., Sugai T.

Heterocycles （Heterocycles） 97 （ 2 ） 1165 - 1174 2018年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03855414

© 2018 The Japan Institute of Heterocyclic Chemistry – A new approach to oroxylin A, a monomethylated trihydroxyflavone, is described. The starting material was baicalin, a representative naturally abundant flavonoid glucuronide. First, conditions for the cleavage of the glycosidic bond were established, using a mixture of water and conc. sulfuric acid (5:2) at 121 °C for 40 min. The hydrolysis was performed in a high-pressure steam sterilizer so that the temperature and reaction time were precisely controlled. Subsequent acetylation of the crude material furnished baicalein 6,7-diacetate on a preparative scale and in a reproducible manner. Next, the C-7 position was protected site-selectively with a methoxymethyl (MOM) group, taking advantage of an unexpected sequential migration of the two acetyl groups among the C-5, C-6, and C-7 positions under basic conditions. The removal of the two remaining acetyl groups followed by site-selective methylation of the C-6 position furnished 5-hydroxy-6-methoxy-7-methoxymethoxyflavone (oroxylin A C-7 MOM ether). Finally, by the deprotection of the MOM ether, oroxylin A was obtained in 6 total steps and 62% overall yield from baicalin.

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Site-selective synthesis of acacetin and genkwanin through lipase-catalyzed deacetylation of apigenin 5,7-diacetate and subsequent methylation

Fujita R., Mandal S., Hanaya K., Shoji M., Higashibayashi S., Sugai T.

Heterocycles （Heterocycles） 99 （ 1 ） 638 - 648 2018年08月

研究論文（学術雑誌）, 査読有り, ISSN 03855414

Candida antarctica lipase B-catalyzed deacetylation proceeded with high site-selectivity on the C-4′ acetyl group in apigenin triacetate to give apigenin 5,7-diacetate. Methylation of the liberated hydroxy group with the combination of trimethyloxonium tetrafluoroborate (Meerwein reagent) and 1,8-bis(dimethylamino)naphthalene (proton sponge) in CH2Cl2 proceeded in a quantitative manner to give the product methylated at the C-4′ hydroxy group (acacetin 5,7-diacetate). Even with the same precursor, a different methylation product at the C-7 hydroxy group (genkwanin 4′,5-diacetate) was obtained in 86% yield by applying iodomethane and Cs2CO3 in dimethyl sulfoxide (DMSO). The methylated products were deprotected to form acacetin and genkwanin. We inferred that the latter unexpected methylation was ascribable to the intermolecular migration of an acetyl group from C-7 to C-4′. DFT calculations indicated that the C-7 phenoxide ion was 12.6 kJ/mol more stable than the initially formed C-4′ phenoxide ion.

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Synthesis and Properties of Hydrazine-Embedded Biphenothiazines and Application of Hydrazine-Embedded Heterocyclic Compounds to Fluorescence Cell Imaging

Shindo Y., Nomura S., Saikawa Y., Nakata M., Tanaka K., Hanaya K., Sugai T., Higashibayashi S.

Asian Journal of Organic Chemistry （Asian Journal of Organic Chemistry） 7 （ 9 ） 1797 - 1801 2018年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 21935807

© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Hydrazine-embedded unsubstituted butterfly-shaped biphenothiazine and its sulfoxides were synthesized by dimerization of 1,9-dibromophenothiazine, which was prepared by realizing selective debromination at the 3,7-positions of 1,3,7,9-tetrabromophenothiazine. cis/trans-Biphenothiazine sulfoxide was selectively prepared by changing the oxidation temperature to control the inversion rate of the butterfly shape of the intermediate. Their butterfly-shapes, conformations, photophysical properties (UV-vis absorption, fluorescence), and redox properties were elucidated by X-ray analysis, DFT calculations, spectral and electrochemical measurements. Fluorescent hydrazine-embedded biphenothiazine sulfoxides and bicarbazoles were applied to cell imaging of HeLa cells. The bicarbazoles exhibited high fluorescence signals in the cells with low toxicity.

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Lipase-catalyzed site-selective deacetylation of sterically hindered naphthohydroquinone diacetate and its application to the synthesis of a heterocyclic natural product

Hashimoto R., Sakakura A., Hanaya K., Higashibayashi S., Sugai T.

Heterocycles （Heterocycles） 99 （ 1 ） 625 - 632 2018年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03855414

Lipase-catalyzed site-selective deacetylation of 2,5-dimethylnaphthalene-l,4-diol diacetate was examined. With Candida antarctica lipase B, the suppressing effect of a methyl substituent at the peri-position of the a-naphthyl ester over that at the ortho-position was significant. This site-selectivity was in contrast to that of chemical hydrolysis reported to date. From the resulting monoacetate, mansonone F, a physiologically active heterocyclic orthoquinone, was synthesized in 38% yield in as few as three steps.

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Effect of hesperetin derivatives on the development of selenite-induced cataracts in rats

Nakazawa Y., Pauze M., Fukuyama K., Nagai N., Funakoshi-Tago M., Sugai T., Tamura H.

Molecular Medicine Reports （Molecular Medicine Reports） 18 （ 1 ） 1043 - 1050 2018年07月

ISSN 17912997

Copyright © Spandidos Publications 2017. All rights reserved. Cataracts are a major cause of blindness worldwide. As anti-cataract pharmaceutical therapies require long-term treatment, identifying anti-cataract compounds that are ubiquitous in the human diet, have no adverse effects and are affordable, is of paramount importance. The present study focused on hesperetin and its derived compounds, hesperetin stearic acid ester (Hes-S) and hesperetin oleic acid ester (Hes-O), in order to investigate their therapeutic potential to treat cataracts in a selenite animal model. Thirteen-day-old Sprague Dawley rats were divided into 12 groups. Animals in groups 1 and 7 were subcutaneously injected with vehicle, those in groups 2 and 8 were administered hesperetin, those in groups 3 and 9 received stearic acid, those in groups 4 and 10 were injected with oleic acid, those in groups 5 and 11 were administered Hes-S, and those in groups 6 and 12 received Hes-O (10 nmol/kg body weight on days 0, 1 and 2). Animals in groups 7 to 12 were treated with sodium selenite (20 µmol/kg body weight given 4 h following the test compound treatment on day 0) to induce cataract. On day 6, rats had less severe central opacities and lower stage cataracts than rats in the selenite treatment-only control groups. The levels of glutathione (GSH) and ascorbic acid (AsA) in lenses with selenite-induced cataracts declined to one-third of that of controls, and the reduction in GSH and AsA levels was rescued following hesperetin, Hes-S or Hes-O treatment, with concentrations remaining to 70-80% of that of controls. However, there were no changes in the plasma levels of GSH and AsA following treatments. Administration of either hesperetin or hesperetin-derived compounds prevented the reduction of chaperone activity in the lens, and rats treated with Hes-S or Hes-O treatment had significantly greater chaperone activity than hesperetin-treated rats. Collectively, these results suggested that hesperetin and hesperetin-derived compounds may be novel drug compounds that have the potential to prevent or delay the onset of cataracts.

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Hydroxytyrosol butyrate inhibits 6-OHDA-induced apoptosis through activation of the Nrf2/HO-1 axis in SH-SY5Y cells

Funakohi-Tago M., Sakata T., Fujiwara S., Sakakura A., Sugai T., Tago K., Tamura H.

European Journal of Pharmacology （European Journal of Pharmacology） 834 246 - 256 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00142999

© 2018 Elsevier B.V. Hydroxytyrosol (HT) is a polyphenol contained in olives and exhibits antioxidant activity. We herein investigated the effects of HT and its derivatives, hydroxytyrosol acetate (HT-A) and hydroxytyrosol butyrate (HT-B), on the protection of neuronal cells against apoptosis induced by the Parkinson's disease-related neurotoxin 6-hydroxydopamine (6-OHDA). The pretreatment of SH-SY5Y cells with HT-B, but not HT or HT-A significantly reduced the 6-OHDA-induced generation of reactive oxygen species, activation of caspase-3, and subsequent cell death. HT-B also induced the protein expression of the transcription factor, NF-E2-related factor-2 (Nrf2) and its transcriptional activation, resulting in the up-regulated expression of heme oxygenase-1 (HO-1), which conferred neuroprotection against 6-OHDA-induced oxidative damage. Furthermore, three cysteine residues, Cys151, Cys273, and Cys288 in Kelch-like ECH-associated protein 1 (Keap1) were necessary for the HT-B-induced activation of Nrf2. Collectively, the present results demonstrated that HT-B, harboring higher fat solubility than HT and HT-A, effectively elicited adaptive responses to oxidative stress by activating the Nrf2/HO-1 axis in neuronal cells.

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Synthesis of enantiomerically enriched drug precursors and an insect pheromone via reduction of ketones using commercially available carbonyl reductase screening kit “Chiralscreen® OH”

Nagai T., Sakurai S., Natori N., Hataoka M., Kinoshita T., Inoue H., Hanaya K., Shoji M., Sugai T.

Bioorganic and Medicinal Chemistry （Bioorganic and Medicinal Chemistry） 26 （ 7 ） 1304 - 1313 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09680896

© 2017 Elsevier Ltd Commercially available “Chiralscreen® OH” starter kit containing five types of carbonyl reductases (E001, E007, E031, E039, and E078) was used for the reduction of several aromatic and aliphatic ketones to obtain enantiomerically enriched drug precursors and an insect pheromone. Almost stereochemically pure secondary alcohols, used in the synthesis of drugs such as (R)-rasagiline mesylate, (S)-rivastigmine, (R)-chlorphenesin carbamate, and (R)-mexiletine, and the insect pheromone (4S,5R)-sitophilure, were conveniently obtained. The enzymes worked well with ketones containing at least one non-bulky substituent at the carbonyl group. The diverse stereochemical preference of the above five carbonyl reductases was clarified.

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Synthesis of 3β-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene and Reductive Nucleophilic Attack on a Branched Aliphatic Aldehyde

Nagai T., Hanaya K., Higashibayashi S., Shoji M., Sugai T.

Chemical and Pharmaceutical Bulletin （Chemical and Pharmaceutical Bulletin） 64 （ 3 ） 334 - 338 2018年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00092363

© 2018 The Pharmaceutical Society of Japan. 3β-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene, which has a double bond between C-9 and C-11 and a phenylsulfenyl group on the terminus of the side chain, is a potential synthetic intermediate for steroids with 9,11-unsaturation or 9,11-seco skeletons. We describe here the synthesis of the title compound from 17-ethylenedioxy-3-acetoxyandrosta-3,5-dien-11-one. The introduction of an ethylene unit to 3β-tert-butyldimethylsiloxyandrosta-5,9(11)-dien-17-one by the action of ethyltriphenylphosphonium bromide under basic conditions resulted in an inseparable mixture of two stereoisomeric products (5 : 1). However, in the subsequent step, only the (Z)-isomer was susceptible to the Lewis acid-catalyzed ene reaction with formaldehyde, giving a stereochemically pure product with the desired configuration. Within three steps, the ene-product was derivatized to the title compound, with a total yield of 53% over seven steps. Reductive terminal anion formation by treatment with lithium di-tert-butylbiphenyl (LiDBB) and subsequent nucleophilic attack on a branched aliphatic aldehyde was demonstrated, with an eye toward the introduction of side chains, especially for steroids with oxygen functionality at C-23.

Formal total synthesis of (−)-hamigeran B from a chemo-enzymatically prepared building block with quaternary chiral center

Kuwata K., Fujita R., Hanaya K., Higashibayashi S., Sugai T.

Tetrahedron （Tetrahedron） 74 （ 7 ） 740 - 745 2018年02月

ISSN 00404020

© 2017 Elsevier Ltd A formal total synthesis of (−)-hamigeran B was achieved in 17 steps from commercially available ethyl 2-oxocyclopentanecarboxylate. Carbonyl reductase-catalyzed asymmetric reduction and the subsequent chemical transformations furnished an enantiomerically pure synthetic intermediate, (R)-5-formyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate. Suzuki-Miyaura coupling with Gao's arylboronate [2-(2-formyl-3-methoxy-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane], under PdCl2(dppf)•CH2Cl2 catalysis, and the subsequent cyclization by way of intramolecular reductive SmI2-mediated 1,2-diol formation provided a tricyclic skeleton with a tetrasubstituted double bond between C-1 and C-9b. Upon hydrogenation of this double bond, the proper stereochemistry of the remaining chiral centers was established. Exclusive addition of the hydrogen atom from the β-face occurred, owing to the shielding of the α-face with a bulky TBS protective group on the C-4 alcohol. The hydrogenation products were transformed into Clive's synthetic precursor for (−)-hamigeran B.

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