Two-directional synthesis and stereochemical assignment toward a C₂ symmetric oxasqualenoid (+)-intricatetraol

Abstract

The asymmetric synthesis of tetraol (+)-3, a degradation product derived from a C₂ symmetric oxasqualenoid intricatetraol 1, has been achieved through the two-directional synthesis starting from diol 7, realizing the further additional assignment of the incomplete stereostructure of 1, the stereochemistry of which is difficult to determine otherwise.

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Recently, highly oxidized and structurally diverse triterpene polyethers, which are thought to be biogenetically squalene-derived natural products (oxasqualenoids), have been isolated from both marine and terrestrial organisms.¹ Among them was intricatetraol 1 isolated from the red alga Laurencia intricata by Suzuki et al. in 1993, and a crude fraction including intricatetraol 1 as the major component exhibited cytotoxic activity against P388 with an IC₅₀ of 12.5 μg mL⁻¹.² The structural analysis was mainly carried out by NMR methods. Although it has been found that the molecule has C₂ symmetry, cis configuration within the THF ring, and R configuration at the C11 (C14) position, the stereochemistries between C6 and C7 (C18 and C19) and C10 and C11 (C14 and C15) and at the bromine-attached C3 (C22) position remain to be determined (Fig. 1). There have also been many other types of oxasqualenoids; however, it is often difficult to determine their stereostructures even by the current, highly advanced spectroscopic methods, especially in acyclic systems including stereogenic quaternary carbon centers such as C6–C7 (C18–C19) and C10–C11 (C14–C15) in 1. These contexts have prompted synthetic organic chemists to determine the stereostructures of oxasqualenoids by chemical synthesis.³ Suzuki et al. have suggested a stereostructure 2 except for the C3 (C22) position as the possible one based on the hypothetical biogenesis.² In this paper, we report that the possible stereostructure 2 proposed for intricatetraol 1 is correct through the two-directional synthesis of the degradation product (+)-3 derived from the natural product 1.

Fig. 1 Stereostructures 1 and 2 of intricatetraol based on NMR data and biogenesis.

The retrosynthetic analysis of the possible stereostructure 2 for (+)-intricatetraol is depicted in Scheme 1. It was envisioned that a two-directional synthetic strategy⁴ could be efficient to synthesize the C₂ symmetric molecule 2. The vicinal bromochloro functionality might be introduced by manipulation of the alkene in 3, where the THF ring would be constructed in a two-directional manner through a Shi asymmetric epoxidation⁵ of bishomoallylic alcohol 4 followed by the 5-exo-tet epoxide-opening reaction.⁶ The diol 4 would, in turn, be derived from diepoxide 5 by extending both side chains with the C₁₀ unit 6, still in the two-directional mode. Thus, we planned to prepare the C₂ symmetric chiral diepoxide 5 from the readily available diol 7via the established Sharpless asymmetric dihydroxylation.⁷

Scheme 1 Retrosynthetic analysis of possible stereostructure 2.

Preparation of the diepoxide 5 began with protection of the known diol 7 ^3b as a benzyl ether (Scheme 2). Sharpless asymmetric dihydroxylation of the diene 8 using AD-mix-β ⁷ afforded an inseparable mixture of diastereomeric tetraols in quantitative yield. Subsequent selective TIPS protection of the secondary hydroxy groups in the mixture resulted in separation of the diastereomers to provide diols 11 and 12 in 67 and 28% yields, respectively, after column chromatography on silica gel. Both symmetric diols 11 ‡ and 12 were assigned to C₂ and meso isomers, respectively, by their optical rotations, 11: [α]²⁶_D +4.8 (c 1.03, CHCl₃); 12: [α]²²_D 0 (c 0.95, CHCl₃). Deprotection of the benzyl ether in the desirable major diol 11, mesylation of both primary hydroxy groups in the resulting tetraol 13, and subsequent basic treatment of the dimesylate gave diepoxide 15 in good overall yield. Replacement of the bulky TIPS ether in 15 with a relatively small MOM ether yielded the requisite diepoxide 5.§

Scheme 2 Two-directional synthesis of diepoxide 5.

The lithiation of the known allylic sulfide 6 ^3f and alkylation of the lithio derivative with the diepoxide 5 were carried out in the presence of TMEDA, and the resulting disulfide as a mixture of diastereomeric sulfides was desulfurized under Bouvault–Blanc conditions⁸ to yield the expected diol 4 (Scheme 3). Shi asymmetric epoxidation of the bishomoallylic alcohol 4 catalyzed by chiral ketone 17 ⁵ followed by treating the resulting labile bishomoepoxy alcohol with (±)-10-camphorsulfonic acid (CSA) in dichloromethane brought about a regioselective 5-exo-tet oxacyclization^6b to produce diol 18 in 50% yield over two steps. The C₂ symmetric structure and the cis stereochemistry of the THF ring in 18 (C₄₀H₇₄O₁₂) could be confirmed by the observation of only 20 signals in the ¹³C NMR spectrum and NOE shown in 18, respectively.

Scheme 3 Two-directional synthesis of tetraol 3.

The remaining task is the generation of trisubstituted double bonds. Selective deprotection of the acetonide group in diol 18 and subsequent cleavage of the resultant vicinal diol with sodium metaperiodate afforded tetraTHF ether 19, which was found to be present mostly as a hemiacetal in the ¹H NMR spectrum, in 91% yield over two steps. The Wittig olefination of the hemiacetal 19 with an excess of isopropylidene triphenylphosphorane provided the desired diene 20 in 63% yield. Removal of the MOM protective group in the diene 20 furnished tetraol 3. The spectral characteristics (¹H and ¹³C NMR) of the synthetic 3, [α]²⁹_D +11.5 (c 0.175, CHCl₃), were identical to those reported for the dehalogenated product 3, [α]²⁰_D +13.6 (c 0.77, CHCl₃), derived from the natural intricatetraol 1 by Suzuki et al.² Thus, it has been found that the possible stereostructure 2 proposed for (+)-intricatetraol based on the hypothetical biogenesis is correct.¶

In conclusion, we have accomplished the asymmetric synthesis of tetraol (+)-3, a degradation product derived from the natural product, through a two-directional strategy that takes its intrinsic molecular symmetry into consideration. The synthesis has realized the further additional assignment of the incomplete stereostructure of intricatetraol 1, the stereochemistry of which is difficult to determine otherwise. The total synthesis and complete assignment of the stereostructure of (+)-intricatetraol 2 are currently under investigation in our laboratory.

This work was supported by the Novartis Foundation (Japan) for the Promotion of Science, the Saneyoshi Scholarship Foundation, and Grant-in-Aids for Scientific Research on Basic Research (C) from the Japan Society for the Promotion of Science and Priority Areas 17035071 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

Notes and references

1. For reviews, see: J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Northcote and M. R. Prinsep, Nat. Prod. Rep., 2004, 21, 1–49; J. D. Connolly and R. A. Hill, Nat. Prod. Rep., 2003, 20, 640–660.
2. M. Suzuki, Y. Matsuo, S. Takeda and T. Suzuki, Phytochemistry, 1993, 33, 651–656.
3. For stereochemical assignments of oxasqualenoids by total synthesis, see: (a) H. Kigoshi, M. Ojika, Y. Shizuri, H. Niwa and K. Yamada, Tetrahedron, 1986, 42, 3789–3792; (b) Y. Morimoto, T. Iwai and T. Kinoshita, J. Am. Chem. Soc., 2000, 122, 7124–7125; (c) Z. Xiong and E. J. Corey, J. Am. Chem. Soc., 2000, 122, 9328–9329; (d) H. Kigoshi, T. Itoh, T. Ogawa, K. Ochi, M. Okada, K. Suenaga and K. Yamada, Tetrahedron Lett., 2001, 42, 7461–7464; (e) Y. Morimoto, M. Takaishi, T. Iwai, T. Kinoshita and H. Jacobs, Tetrahedron Lett., 2002, 43, 5849–5852; (f) Y. Morimoto, Y. Nishikawa and M. Takaishi, J. Am. Chem. Soc., 2005, 127, 5806–5807.
4. For reviews, see: C. S. Poss and S. L. Schreiber, Acc. Chem. Res., 1994, 27, 9–17; S. R. Magnuson, Tetrahedron, 1995, 51, 2167–2213.
5. Z.-X. Wang, Y. Tu, M. Frohn, J.-R. Zhang and Y. Shi, J. Am. Chem. Soc., 1997, 119, 11 224–11 235.
6. (a) J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734–736; (b) Y. Morimoto, Y. Nishikawa, C. Ueba and T. Tanaka, Angew. Chem., Int. Ed., 2006, 45, 810–812.
7. H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev., 1994, 94, 2483–2547; K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu and X.-L. Zhang, J. Org. Chem., 1992, 57, 2768–2771.
8. M. Hashimoto, H. Harigaya, M. Yanagiya and H. Shirahama, J. Org. Chem., 1991, 56, 2299–2311; Y. Morimoto, T. Iwai and T. Kinoshita, J. Am. Chem. Soc., 1999, 121, 6792–6797.

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Footnotes

† Electronic supplementary information (ESI) available: experimental procedures for synthesis of 3 and characterizations of 3 and the synthetic intermediates. See DOI: 10.1039/b608098g

‡ The optical purity of 11 was determined to be >95% ee by derivatization of debenzylated tetraol 13 to diMTPA ester 14 [MTPA = α-methoxy-α(trifluoromethyl)phenylacetyl] and integration of the signals in the ¹H NMR spectrum (J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 1969, 34, 2543–2549).

§ The replacement of the protective group of the C11 and C14 hydroxy groups was necessary to bring about Shi epoxidation which is sensitive to steric factors in 4 – Shi epoxidation of 4 where it is protected by a bulky TIPS group instead of the MOM group resulted in no reaction. At the stage of tetraols after the Sharpless asymmetric dihydroxylation, we could not selectively protect the secondary hydroxy groups as MOM ethers.

¶ Independently of us, Dr K. Ujihara, Sumitomo Chemical, has also reported the same partial stereochemistry of (+)-intricatetraol as ours through the synthesis of diacetate 21 derived from the natural product (K. Ujihara, Ph.D. Thesis, The University of Tokyo, Tokyo, Japan, 2004).

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