A new strategy for stereocontrol of cation-olefin cyclization. The first chemical emulation of the A/B-trans-9,10-syn-folding pathway of steroid biosynthesis from 2,3-oxidosqualene
A new strategy for stereocontrol of cation-olefin cyclization. The first chemical emulation of the A/B-trans-9,10-syn-folding pathway of steroid biosynthesis from 2,3-oxidosqualene
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DOI：
10.1021/ja9632926
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发表时间：
1996-11-27
影响因子：
15
通讯作者：
Wood, HB
中科院分区：
文献类型：
--
作者：
Corey, EJ;Wood, HB
The enzymic cyclization of (S)-2, 3-oxidosqualene (1) to the protosterol cation (2) 1, 2 has never been emulated in a chemical system, in part because the A/B-trans, 9, 10-syn, B/C-trans stereochemistry of 2, which requires boat geometry for the B ring, is several kcal/mol less stable than the alternative transanti-trans A/B/C arrangement. In general, chemically conducted cation-olefin cyclizations have led to trans-anti-trans type fused ring systems (triterpene folding) exclusively. 1a, 3 We report herein on a substrate design which favors cyclization to A/B-trans, 9, 10-syn product (steroid numbering) and which suggests a new approach to the control of stereochemistry and olefinic face selectivity in cation-olefin cyclizations. The specific substrate that was the focus of this investigation was the chiral oxirane 4, which was synthesized as a 1: 1 mixture of E-and Z-isomers4, 5 at the vinyl trifluoroethyl ether subunit by Wittig olefination of the corresponding ketone (3)(Ph3P+-CH2OCH2CF3 Br-, potassium tert-amyl oxide, C7H8, 25 C, 4.5 h). Treatment of the 1: 1 mixture of E-and Z-4 with MeAlCl2 (2 equiv) in CH2Cl2 at-95 C for 1 h produced a single tetracyclic hydroxy R,-enone (5) which was obtained pure in 40% yield after flash column chromatography on silica gel. The structure of 5 was determined unambiguously as described below. 6 It is likely that 5 arises from the E-form of 4 because of the correspondence of vinyl ether geometry. It may also be that tetracyclic products are not formed from the Z-form of 4 because such structures would be severely destabilized by steric repulsion between C (15) of the D-ring and the trifluoroethoxy group. On the basis of this assumption, the yield of the cyclization product would be 80%. The oily cyclization product 5 was converted to the crystalline tetracyclic ketone bis-silyl ether 7, mp 145.5-146 C, by the following sequence:(1) silylation of the 3-hydroxyl group (1.3 equiv of tert-butyldimethylsilyl triflate, TBSOTf, and 2.3 equiv of 2, 6-lutidine in THF at-78 C for 1 h),(2) selective hydrogenation of the 14, 15-double bond (H2, Pd-C, EtOH, 25 C, 3 h),(3) oxidative cleavage of the C (7) exocyclic vinyl ether to form 6 (0.05 equiv of RuCl3, 4 equiv of NaIO4 in CCl4-CH3CN-H2O at 25 C for 1.5 h), and (4) transformation of ketone 6 to the enol ether 7 (1.3 equiv of TBSOTf and 2 equiv of KHMDS in THF at-78 C for 45 min). A crystal of 7 was subjected to X-ray crystallographic analysis which revealed the three-dimensional structure shown in Figure 1. 7 The structure of 7 involves the syn-relationship between the H at C (9) and the CH3 at C (10) and A/B-trans geometry in common with the protosterol system. The formation of 7 therefore must involve the same olefinic face selectivity (ie, substrate folding) which is involved in forming the A-and B-rings during sterol biosynthesis. To the best of our knowledge this is the first time that this stereochemical pathway has been demonstrated for a non-enzymic cation-olefin cyclization. The cis-fusion of the B-and C-rings, which provides a clear indication that C-ring formation is not concerted with B-ring closure, reflects the preferred face selectivity for cation-olefin closure to form the C-ring in this particular system. Evidently, the bicyclic B-ring cation 8 is a discrete intermediate, and attack by the terminating π-system occurs preferentially at the R-face of C (8) of the bicyclic oxaallylic cation. That mode of closure also controls the C/D-ring fusion of 7 to be cis.
