The addition of MeLi to boron enolates produced by the 1,4-addition of Ar2Cu(CN)Li2 to BF3·OEt2-activated enones was followed by the reaction with ClP(O)(OEt)2 to afford the corresponding enol phosphates in moderate to good yields. The scope of this method was examined with sterically hindered or electronically biased enones and/or reagents. This activation of boron enolates was successfully applied to the synthesis of the methyl ether of Δ(9)-tetrahydrocannabinol.
Allylic substitution of esters derived from 2-bromocyclohex-2-enol with PhMgBr-based copper reagent was investigated to find high anti S N 2′ selectivity with the diethyl phosphate, whereas other esters such as picolinate, acetate, and mesylate resulted in partial racemization or recovery of the starting esters. This protocol was applied to the copper reagent derived from 2-Me-4-MeOC 6 H 3 MgBr and CuBr·SMe 2 and the olefin part of the anti S N 2′ product was cleaved for a synthesis of patchouli alcohol.2-Bromocyclohex-2-enol (1), available as an enantiomerically enriched form by the Corey-Bakshi-Shibata (CBS) reduction of 2-bromocyclohexen-1-one, 1 is a functionalgroup-rich compound, and has been utilized for organic synthesis. 1,2 To expand a scope of utilization we envisioned allylic substitution of esters 2 with aryl reagents followed by cleavage of the olefinic C(Br)-C(H) bond to produce 4 (Scheme 1), in which functional groups X and Y are differentiated to facilitate further transformation toward several biologically active compounds such as curcumenes, heliannuols, etc. 3 In addition, coupling reactions of 3a (Ar = Ph) were studied to compare the reactivity of 3a with that of the corresponding iodide. 4 Several allylic esters 2A-E were prepared from 1 (R isomer, 94-98% ee) 1 by esterification, and allylic substitution with phenyl copper reagents derived from PhMgBr/CuBr·SMe 2 in various ratios was evaluated by chirality transfer (CT) defined as (% ee of 3a) × 100/(% ee of 2) and by yield of 3a (or conversion of the substrate). First, picolinate 2A was chosen as a substrate on the basis of the previous results from our laboratory. 5 The reaction with Ph 2 CuMgBr·MgBr 2 , however, resulted in almost complete racemization (Table 1, entry 1). On the other hand, the substitution with PhCu·MgBr 2 gave 3a through the anti S N 2′ pathway (vide infra) with 73% CT (Table 1, entry 2). To suspect a reason for the low enantiomeric excess, a structurally related picolinate 5 (94% ee) was synthesized from 1 in 87% yield by iron-catalyzed coupling 6 with MeMgBr [Fe(acac) 3 (0.5 equiv), NMP (9 equiv), THF] followed by esterification with PyCO 2 H (DCC, DMAP).As delineated in Scheme 2, the substitution of 5 proceeded with substantial racemization as in the case of 2A. These results suggest that the substituent (Br, Me) on the ring is responsible for the racemization through syn S N 2′ and/or S N 2-type mechanism or through the π-allyl copper intermediate. In relation to these results, the substitution of the iodoacetate 7a with the mixed cuprates 8 gives the S N 2 products 9a highly stereoselectively according to Knochel, who mentioned that the substitution of 7b with the Scheme 1 Aim of the research and compounds possessing the framework of 4 Br L Ar Br 3 1 (L = OH) 2A-E (L = leaving group) allylic substitution Y Ar 4 X cleavage X, Y = CH 2 OH, CHO, CO 2 Me, etc. curcumene (R = H) xanthorrhizol (R = OH) R Me OMe patchouli alchohol intermediate O OH heliannuol A OH Scheme 2 Substitution of the methyl-substituted allylic pic...
A 1,4-addition strategy using an enone and a copper reagent was studied for the synthesis of (-)-piperitylmagnolol. A MOM-protected biphenol copper reagent was added to BF3·OEt2-activated 4-isopropylcyclohexenone, whereas 1,4-addition of protected monophenol reagents possessing an allyl group was found to be unsuccessful. The allyl group was later attached to the p-,p'-diiodo-biphenol ring by Pd-catalyzed coupling with allylborate. The aforementioned iodide was synthesized using a new method for ortho-selective deiodination of o-,p-diiodophenols.
trans-2,6-Disubstituted cyclohexanones were synthesized with high regio- and stereoselectivity by allylic substitution followed by ozonolysis. Both alkyl and aryl groups were successfully installed to the cyclohexane ring. The stereochemistry of the SN2' products was determined to be controlled by the pre-existing chirality on the ring. The present method is highlighted by the synthesis of enantiomerically enriched cyclohexanones.
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