Elsevier

Tetrahedron

Volume 59, Issue 20, 12 May 2003, Pages 3649-3663
Tetrahedron

Remote substituent effect favoring the formation of syn-adducts in the chelation controlled radical reactions of γ-benzyloxy-α-methylenecarboxylic acid esters

https://doi.org/10.1016/S0040-4020(03)00421-6Get rights and content

Abstract

The chelation controlled radical reactions of ethyl γ-benzyloxy-α-methylenecarboxylates bearing a bulky γ-substituent, such as CHMe2, CHPh2, c-C6H11 and CH(Ph)OTBDMS, with alkyl iodides gave the syn-adducts with high diastereoselectivities. However, the diastereoselectivity for the substrates bearing a γ-substituent CH(i-Pr)OTBDMS depended critically on the configuration of the substituent; the substrate bearing the OTBDMS group anti to the γ-benzyloxy group showed poor diastereoselectivity, but its diastereomer gave syn-adduct exclusively. The high syn-selectivitiy is referred to the H-atom transfer to the outside face of radical center in the sharply folded seven-membered chelate intermediate bearing the ethoxy group with Z-geometry. The corner flapping of the radical center atom of the global minimum energy conformer generates a local minimum conformer and the H-atom transfer to the outside face of the radical center of the newly formed structure gives the anti-adduct. The poor diastereoselectivity is due to the very small energy difference between the two conformers and consequently both the syn- and anti-adducts are yielded in nearly equal amounts.

Introduction

During the past decade the stereochemical control of acyclic radical reactions has been received considerable attention and significant levels of diastereoselectivity have been achieved when they adopt preferred conformations.1 The use of Lewis acids offers the possibility to regulate conformations and improve the stereoselectivity in acyclic radical reactions.2 The bulk of substituents at the stereogenic center is, as well, an important factor controlling the stereoselectivity as represented by the exocyclic effect in 1,2-asymmetric induction.3

We have recently reported the chelation-controlled 1,3-asymmetric induction in the radical-mediated additions to α-methylene-γ-oxycarboxylic acid esters I (Scheme 1).4., 5. The diastereoselectivity depended on the substituents R1 and R2 and the alkyl iodides R3I. The radical reactions of γ-hydroxy, γ-methoxy and γ-methoymethoxy esters with methyl, ethyl or isopropyl iodide (R3=Me, Et or i-Pr) performed in the presence of Lewis acid gave syn-II predominantly. In the addition of bulky tert-butyl radical, however, the selectivity was reversed and the major product was anti-II. In contrast to the substrates mentioned above, γ-benzyloxy esters I (R2=Bn) showed syn-selectivity irrespective of the bulk of alkyl iodides. Furthermore, we have reported the origin of diastereoselectivities based on the conformational analysis of the chelated radical intermediates obtained by combination of CONFLEX and PM3 calculations.4., 6. The H-atom transfer reaction to the sharply folded seven-membered chelate intermediate4., 7., 8. bearing an ethoxy group with Z-geometry (dihedral angle OC–O–C of ester moiety: ca. 0°) and CH2–R3 bond parallel to the radical face occurs exclusively on the exposed outside face of radical center to afford the highest syn-selectivity.

In the radical reactions of the steroidal γ-benzyloxy-α-methylenecarboxylic acid esters 1 and 2 with alkyl iodides R3I performed in the presence of MgB2·OEt2, we have observed that the diastereoselectivity depends on the configuration at C-22 (i.e. the relative stereochemistry of γ- and δ-substituents) and the bulk of R3 group (Scheme 2).4c,d The results suggest that there may exist stereochemical relationships between the γ- and δ-substituents that exert either complementary or opposing influences on the facial bias of the radical center.

We report herein the effect of substituents at the δ-position and their configurations affecting the diastereoselectivity in the chelation controlled radical addition reactions to γ-benzyloxy-α-methylenecarboxylic acid esters 8, 9 and 1525 (Scheme 4 and Table 1, Table 2). This work was performed to find out the radical reactions with reliably high level of diastereoselectivity.

Section snippets

Preparation of 9, 10 and 1517

Substrates 9 and 10 were prepared from octanal and ethyl 2-(bromomethyl)propenoate following the procedures reported previously.4d Substrates 1517 were prepared from isobutyl aldehyde, diphenylacetaldehyde, and cyclohexylcarbaldehyde, respectively, following the procedures reported previously.4c

Preparation of 18 and 22

The alcohol 469 was transformed to the silyl ether 47 with tert-butyldimethylsilyl chloride and imidazole in 47% yield (Scheme 3). The oxidative cleavage of the thioacetal 47 with N-bromosuccimide in

Conclusion

In summary, we have shown that the chelation controlled radical reactions of γ-benzyloxy-α-methylenecarboxylic acid esters bearing a bulky γ-substituent14 with alkyl iodides gave the adducts with high syn-selectivities. The selectivity is referred to the H-atom transfer to the outside face of radical center in the sharply folded seven-membered chelate intermediate A bearing the ethoxy group with Z-geometry. However, the reaction of 18 showed poor diastereoselectivity despite the presence of a

General

1H NMR spectra were recorded on a JEOL GSX-270 (270 MHz) or GSX-400 (400 MHz) spectrometer with CDCl3 as the solvent and tetramethylsilane as an internal standard. 13C NMR spectra were recorded on the instruments operating at 67.9 or 100.5 MHz with CDCl3 as the solvent and internal standard (δ 77.0). Mass spectra (EI+) were obtained on a JEOL JMS-700 mass spectrometer. Precoated Merck Kieselgel 60 F254 and Kanto silica gel 60 (spherical neutral) were used for thin layer chromatography and flash

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