Diastereoselective Synthesis of trans-1,2-Dialkylcyclopropanols by the Kulinkovich Hydroxycyclopropanation of Homoallylic Alcohols This work was supported by the National Institutes of Health (GM35956) and National Science Foundation (CHE98-13975).

Abstract

The hydroxy group regulates the stereoselectivity in a modification of the titanium‐mediated Kulinkovich cyclopropanation procedure (see scheme). This method provides a diastereoselective synthesis of trans‐1,2‐dialkylcyclopropanols, which starts with homoallylic alcohols and proceeds via a bicyclic titanacyclopropane intermediate. Enantiopure products may also be obtained if the corresponding chiral alcohols are used.

Enantioselective preparation of (+)- and (–)-Z-2-hydroxyethyl-1-methylcyclopropan-1-ol

“…The intramolecular cyclopropanation reactions of esters of homoallylic alcohols were shown by us, along with other laboratories, to proceed in excellent yields to give trans-dialkyl cyclopropanols, albeit with low 1,3-diastereoselectivity. 4,8 Indeed, the hydroxyl-directed cyclopropanation of 5 afforded both trans-dialkyl isomers 6 and 8 in good (83%) yield. Following separation by column chromatography, the nonselective formation of 6 and 8 was taken advantage of to develop an enantiodivergent route to both antipodes of 1 by straightforward elaboration of the side chain functionalities (vide infra).…”

“…The stereochemistry of 6 and 7 was assigned on the basis of 1 H NMR analysis and also by analogy to related examples. 4 Formation of the cis-dialkyl isomer 7 in surprisingly significant amounts was attributed to the presence of the benzyloxy moiety. 7 In order to preclude the undesirable formation of 7, we opted to rely on an intramolecular cyclopropanation of 5.…”

“…To a solution of (+)-5 (10 g, 40.3 mmol) and Ti(O-i-Pr) 4 (13 mL, 44.3 mmol) in THF (300 mL) was added over 1 h (syringe pump) a 2 M solution of cyclohexylmagnesium chloride (81 mL) in THF. The reaction mixture was stirred for an additional 30 min and quenched by addition of water (40 mL) at 0 o C. The reaction mixture was stirred for an additional 1 h at rt, dried over anhydrous Na 2 SO 4 and filtered.…”

“…Excess m-CPBA was quenched by addition of saturated aqueous Na 2 S 2 O 3 and the resulting mixture was extracted with ether. The combined organic layers were washed with saturated aqueous NaHCO 3 and brine, dried over anhydrous Na 2 SO 4 , and then concentrated under reduced pressure. The crude product was directly used without further purification for next step.…”

“…3 Of particular significance is the lack of a stereoselective route to the (S,R,R)-stereoisomers typified by 2, whereas the hydroxycyclopropanation of homoallylic alcohols gives convenient access to the alternate trans-dialkyl stereochemistry present in 3. 4,5 Thus, chiral building blocks (+)-and (-)-1 promises to be of considerable utility in providing an expedient method for stereoselectively preparing 2 and its derivatives, as well as 3. We report herein an enantioselective preparation of (+)-and (-)-1 starting from an inexpensive lactate derivative.…”