HETEROCYCLES

Communication | Special issue | Vol. 82, No. 2, 2011, pp. 1163-1170
Received, 24th August, 2010, Accepted, 2nd November, 2010, Published online, 18th November, 2010.
DOI: 10.3987/COM-10-S(E)111

■ [2,3] Wittig Rearrangement of β’-Hydroxyethyl Bis-Allylic Ethers: Highly Regiospecific Entry to Singly Dehydroxylated 19-Nor-1(or 3),25-dihydroxy-vitamin D3

Koichi Mikami,* Kumiko Fujita, Kazuki Wakabayashi, and Shigekazu Ito

Department of Applied Chemistry, Graduate School of Science and Technology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552, Japan

Abstract

A conceptually new approach to regiospecific deprotonation at the α-position of β'-hydroxyethyl bis-allylic ethers is shown on the basis of the dianion repulsion with the β'-alkoxy anion, of which the [2,3]Wittig rearrangement product can be transformed to the A-rings of singly dehydroxylated 1(or 3),25-dihydroxy-19-nor-vitamin D3 analogues to stimulate apoptosis or differentiation of HL-60 cancer cell.

Recently, the [2,3] Wittig rearrangement1 of unsymmetrical bis-allylic ethers has enjoyed wide synthetic applications via highly regioselective deprotonation of an α- and/or a γ-substituted bis-allylic ether.2 However, a β,β'-unsymmetrically substituted bis-allylic ether has still challenged regioselective α- or α'-deprotonation; We have already reported that the introduction of an anion stabilizing trialkylsilyl group at the γ-position leads to the highly regiocontrol in α-deprotonation3 and that the introduction at the β-position has, however, essentially no effect4 in regioselective deprotonation. Herein, we report a conceptually new approach to regiospecific deprotonation at the α-position by β'-hydroxyethyl bis-allylic ether (1) on the basis of the dianion repulsion with the “β'-alkoxy anion” (Scheme 1). The present synthetic method based on the highly regiospecific [2,3] Wittig rearrangement of unsymmetrical β'-hydroxyethyl bis-allylic ether can eventually lead to the A-rings of singly dehydroxylated5 1 (or 3),25-dihydroxy-19-nor6-vitamin D37 analogues which stimulate apoptosis or differentiation of cancer cell line of HL-60, depending on the regio- and stereo-chemistries of the 1- or 3-hydroxy groups.

Prior to the base treatment of the β'-hydroxyethyl unsymmetrical bis-allylic ether (1), the regioselectivity in deprotonation was deduced by DFT (RB3LYP) calculations implemented in GAUSSIAN 038 program package. The extended structures were calculated at the HF/6-31G(d,p) (ab initio) levels and DFT [RB3LYP/6-311+G(d,p)] method (Figure 1). Highly α-regioselective deprotonation is preferred over the regioisomeric α’-deprotonation by 19.74 kcal/mol energy difference, depending on the dianion repulsion in deprotonation at the α'-position of unsymmetrical bis-allylic ether substituted by β'-hydroxyethyl (alkoxy anion) group.

In order to examine the regiochemistry in deprotonation of the unsymmetrical bis-allylic ether (1), the various combination of metal/base species was scrutinized (Table 1). n-Butyllithium, the commonly employed base for the [2,3] Wittig rearrangement, did not give the highly regiospecific α-deprotonation/ rearrangement product but rather the regioisomeric mixture (entry 1: 60% α'-regioselectivity); The α’-[2,3] Wittig product was obtained via an α'-deprotonation, presumably via six-membered chelate with the lithiated β’-alkoxyethyl anion (Figure 2, A). Indeed, β'-hydroxypropyl substituent (1”) gave, in turn, the α-regioselective deprotonation/rearrangement product (entry 9: 81% α-regioselectivity), via dianion repulsion with the β'-“alkoxypropyl anion” (B), because seven-membered chelate (C) was less favorable than the six-membered chelate (A).

In a combination of n-butyllithium with sodium hydride, potassium tert-butoxide, or potassium hydride, the α-[2,3] Wittig rearrangement product was obtained in good-to-moderate (97-60%) combined yields via the α-deprotonation/rearrangement with n-BuLi, however, still as a regioisomeric mixture with α'-regioisomer (83:17 - 61:39) (entries 2, 3 and 4). Sterically demanding lithium amides in a combination with potassium hydride afford the α-carbanion in a regiospecific manner (entry 5) by virtue of the (1) dianion repulsion and (2) highly sterically demanding nature of lithium amides/potassium alkoxides (vide infra). Among the lithium bases employed, the lithium dialkylamides gave the rearrangement product (2) in highly regiospecific manner. Significantly, lithium dicyclohexylamide (LDCHA) in a combination with potassium hydride gave the rearrangement product (2) in high yield and regiospecific manner (entry 5). However, LDCHA itself was totally ineffective (entry 6).

The characteristic feature of Schlosser’s superbase in a combination of lithium amides with potassium alkoxides9 affects the reactivity and regioselectivity of unsymmetrically substituted bis-allylic ethers in the [2,3] Wittig rearrangement (Scheme 2). By virtue of the sterically demanding nature of lithium amides/potassium hydride (eventually as Schlosser’s mixed-metal amide base showed in Scheme 2), the high yielding and regiospecific [2,3] Wittig rearrangement takes place (entry 5).

The employment of highly sterically demanding and less nucleophilic lithium dialkylamides rather than the alkyllithium bases in a combination with β-potassium alkoxide (eventually as Schlosser’s mixed-metal amide base) is thus the key for the highly α-regiospecific deprotonation/rearrangement sequence.
In sharp contrast to the highly regioselective α’-deprotonation of a γ-methyl substituted bis-allylic ethers,2 β'-hydroxyethyl γ-methyl bis-allylic ether gave the deprotonation at the α-position of unsymmetrical bis-allylic ethers, though in 33% regioselectivity and 42% combined yield (entry 11); the SN2' displacement product with base10 was obtained due to the less favorable α-deprotonation process in the γ-methyl allylic ether. Indeed, β'-hydroxyethyl α-methyl bis-allylic ether gave the α'-[2,3] Wittig rearrangement product regioselectively in 92% yield (entry 13).
The highly regiospecific α-[2,3] Wittig rearrangement is, in principle, extended to the tandem anionic oxy-Cope rearrangement11 of the α-[2,3] Wittig dianion rearrangement product (2) (Scheme 3); the tandem product (3) can be employed for the asymmetric catalytic ene cyclization7e-f leading to the A-ring of 19-nor-vitamin D3 (Scheme 4). However, an attempted anionic oxy-Cope rearrangement of the α-[2,3] Wittig product in THF, DME, and DMSO with or without 18-crown-6 had not yet provided the oxy-Cope rearrangement aldehyde (3).12 Simply upon isolation of the α-[2,3] Wittig rearrangement alcohol (2) followed by microwave-assisted thermal oxy-Cope rearrangement13 in N-methyl-2-pyrrolidinone (NMP), the rearranged aldehyde (3) was obtained in 48% yield within only 10 min. Without microwave irradiation, the oxy-Cope rearrangement took 1 h in NMP to give lower (40%) yield (Scheme 3). The oxy-Cope rearrangement aldehyde (3) has already been reported via the BINOL-Ti-catalyzed ene cyclization14,15 to give the A-ring of 1β-epi- or 3α-epi-19-nor-vitamin D3 that stimulate apoptosis of leukemia HL-60 cell and 1α- or 3β-19-nor analogues as potent differentiators of cancer cell line of HL-60 (Scheme 4).15

We have thus developed the new route to regiospecific deprotonation at the α-position of β'-hydroxyethyl bis-allylic ether by the dianion repulsion with the β'-alkoxy anion. The [2,3] Wittig rearrangement product can be transformed to the A-rings of singly dehydroxylated 1(or 3),25-dihydroxy-19-nor-vitamin D3 analogues.


References 12

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