Abstract

Epoxidation of racemic trans-2-(N,N-dibenzylamino)cyclohex-3-en-1-ol, upon treatment with Cl₃CCO₂H then m-CPBA, proceeded with poor diastereoselectivity (ca. 60:40 dr), whilst epoxidation of racemic trans-2-(N-benzylamino)cyclohex-3-en-1-ol under the same conditions proceeded with high diastereoselectivity (>95:5 dr) and was followed by completely regioselective and stereospecific ring-opening in situ to give, after methanolysis of the intermediate trichloroacetate ester, (1RS,2SR,3SR,4SR)-2-(N-benzylamino)cyclohexane-1,3,4-triol. Use of aq HBF₄ as the acid protecting agent gave the amino triol directly. The differing diastereoselectivities of these epoxidation reactions may be due to a predilection towards formation of an intramolecular hydrogen-bond in the former substrate disrupting the ability of the in situ formed ammonium moiety to act as a directing group for the incoming oxidant; the presence of two potential hydrogen-bond donors (i.e., two N–H bonds) in the latter substrate circumvents this limitation. With the criterion for a highly diastereoselective (ammonium-directed) epoxidation in this system established, a synthesis of enantiopure trans-2-(N-benzylamino)cyclohex-3-en-1-ol (>99% ee) was developed and the ammonium-directed epoxidation was then employed as a key synthetic step to facilitate the asymmetric syntheses of enantiopure dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3 (>98% ee in each case) from 1,3-cyclohexadiene.

Epoxidation of racemic trans-2-(N,N-dibenzylamino)cyclohex-3-en-1-ol, upon treatment with Cl₃CCO₂H then m-CPBA, proceeded with poor diastereoselectivity (ca. 60:40 dr), whilst epoxidation of racemic trans-2-(N-benzylamino)cyclohex-3-en-1-ol under the same conditions proceeded with high diastereoselectivity (>95:5 dr) and was followed by completely regioselective and stereospecific ring-opening in situ to give, after methanolysis of the intermediate trichloroacetate ester, (1RS,2SR,3SR,4SR)-2-(N-benzylamino)cyclohexane-1,3,4-triol. Use of aq HBF₄ as the acid protecting agent gave the amino triol directly. The differing diastereoselectivities of these epoxidation reactions may be due to a predilection towards formation of an intramolecular hydrogen-bond in the former substrate disrupting the ability of the in situ formed ammonium moiety to act as a directing group for the incoming oxidant; the presence of two potential hydrogen-bond donors (i.e., two N–H bonds) in the latter substrate circumvents this limitation. With the criterion for a highly diastereoselective (ammonium-directed) epoxidation in this system established, a synthesis of enantiopure trans-2-(N-benzylamino)cyclohex-3-en-1-ol (>99% ee) was developed and the ammonium-directed epoxidation was then employed as a key synthetic step to facilitate the asymmetric syntheses of enantiopure dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3 (>98% ee in each case) from 1,3-cyclohexadiene.

中文翻译：

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二氢conduramines（–）-A-2，（–）-B-2，（–）-C-3和（+）-F-3不对称合成中的立体选择性铵导向的环氧化

摘要

外消旋的反式-2-（N，N-二苄氨基）环己-3-烯-1-醇的环氧化，先用Cl ₃ CCO ₂ H然后用m -CPBA进行，非对映选择性差（约60:40 dr），外消旋的反式-2-（N-苄氨基）环己-3-烯-1-醇在相同条件下进行环氧化时，具有高非对映选择性（> 95：5 dr），然后完全原位选择性和立体选择性开环在甲醇水解中间体三氯乙酸酯后，得到（1 RS，2 SR，3 SR，4 SR）-2-（N-苄氨基）环己烷-1,3,4-三醇。使用HBF ₄水溶液作为酸保护剂直接得到氨基三醇。这些环氧化反应的非对映选择性不同，可能是由于倾向于在前一种底物中形成分子内氢键，从而破坏了原位形成的铵部分作为传入氧化剂的导向基团的能力。在后一种底物中存在两个潜在的氢键供体（即两个N–H键）可以规避这一限制。建立了该系统中高度非对映选择性（铵离子定向）环氧化的标准，合成了对映体反式-2-（N-苄基氨基）环己-3-烯-1-醇（> 99％ee）被开发出来，然后采用铵导向的环氧化作为关键的合成步骤，以促进对映纯二氢conduramines（–）-A-2的不对称合成， （–）-B-2，（–）-C-3和（+）-F-3（每种情况下> 98％ee）来自1,3-环己二烯。

外消旋的反式-2-（N，N-二苄氨基）环己-3-烯-1-醇的环氧化，先用Cl ₃ CCO ₂ H然后用m -CPBA进行，非对映选择性差（约60:40 dr），外消旋的反式-2-（N-苄氨基）环己-3-烯-1-醇在相同条件下进行环氧化时，具有高非对映选择性（> 95：5 dr），然后完全原位选择性和立体选择性开环在甲醇水解中间体三氯乙酸酯后，得到（1 RS，2 SR，3 SR，4 SR）-2-（N-苄氨基）环己烷-1,3,4-三醇。使用HBF ₄水溶液作为酸保护剂直接得到氨基三醇。这些环氧化反应的非对映选择性不同，可能是由于倾向于在前一种底物中形成分子内氢键，从而破坏了原位形成的铵部分作为传入氧化剂的导向基团的能力。在后一种底物中存在两个潜在的氢键供体（即两个N–H键）可以规避这一限制。建立了该系统中高度非对映选择性（铵离子定向）环氧化的标准，合成了对映体反式-2-（N-苄基氨基）环己-3-烯-1-醇（> 99％ee）被开发出来，然后采用铵导向的环氧化作为关键的合成步骤，以促进对映纯二氢conduramines（–）-A-2的不对称合成， （–）-B-2，（–）-C-3和（+）-F-3（每种情况下> 98％ee）来自1,3-环己二烯。