Iridium Catalyzed anti-Diastereo- and Enantioselective Carbonyl (Trimethylsilyl)allylation from the Alcohol or Aldehyde Oxidation Level

Abstract

Using the ortho-cyclometallated π-allyl iridium precatalyst (R)-I derived from [Ir(cod)Cl]₂, 4-cyano-3-nitrobenzoic acid, (R)-SEGPHOS and allyl acetate, enantioselective transfer hydrogenation of α-(trimethylsilyl)allyl acetate in the presence of aldehydes 2a–2i mediated by isopropanol delivers products of (trimethylsilyl)allylation 4a–4i in good isolated yields and with exceptional levels of anti-diastereoselectivity and enantioselectivity (90–99% ee). In the absence of isopropanol, but under otherwise identical reaction conditions, carbonyl (trimethylsilyl)allylation is achieved directly from alcohol oxidation level to furnish an equivalent set of adducts 4a–4i with roughly equivalent isolated yields and stereoselectivities. To evaluate the synthetic utility of the reaction products 4a–4i, adduct 4g was converted to the 1,4-ene-diol 5g via dioxirane mediated oxidative desilylation with allylic transposition, the allylic alcohol 6g via protodesilylation with allylic transposition, and the γ-lactam 7g via chlorosulfonyl isocyanate mediated cycloaddition.

Introduction

In connection with studies aimed at the discovery of hydrogen-mediated reductive C-C bond formations beyond hydroformylation, we recently uncovered a broad family of C-C bond forming transfer hydrogenations promoted by iridium and ruthenium catalysts.¹ A remarkable feature of these processes resides in the ability to achieve carbonyl addition from the aldehyde or alcohol oxidation level. In the former case, isopropanol or formic acid mediate reductive C-C coupling. In the latter case, dehydrogenation of the primary alcohol reactants generates aldehyde electrophiles, while simultaneously driving reductive generation of nucleophilic organometallics from unsaturated reactants. Using ortho-cyclometallated iridium catalysts, highly enantioselective protocols for carbonyl allylation,2a,b,e–h,j crotylation2c,f,j and tert-prenylation2d,f,j from the alcohol or aldehyde oxidation level were devised. More recently, related catalytic enantioselective methods carbonyl (hydroxy)allylation and (hydroxymethyl)allylation were developed.³ Unlike conventional methods for carbonyl allylation,⁴ these processes circumvent use of premetallated nucleophiles and metallic reductants.^1–3

Here, using the isolated ortho-cyclometallated π-allyl iridium precatalyst derived from [Ir(cod)Cl]₂, 4-cyano-3-nitrobenzoic acid, (R)-SEGPHOS⁵ and allyl acetate, we report that α-(trimethylsilyl)allyl acetate⁶ 1a couples to carbonyl compounds from the aldehyde or alcohol oxidation level, respectively, with exceptional levels of regio-, anti-diastereo- and enantioselectivity (Scheme 1). In this fashion, α-(trimethylsilyl)allyl acetate serves as a alternative to previously reported silicon-containing 1,3- or 1,1-bimetallic allyl transfer agents.^7–11 As demonstrated in the case of adduct 4g, the products of (trimethylsilyl)allylation are readily converted to 1,4-ene-diols upon DMDO oxidation.^8h,i Additionally, conditions for proto-desilylation with allylic transposition have been identified in the absence of a hydroxyl protecting group. Finally, upon exposure to chlorosulfonyl isocyanate, formal [3+2] cycloaddition occurs to deliver γ-lactams possessing 3 contiguous stereogenic centers as single diastereomers.

Scheme 1.

Iridium catalyzed anti-diastereo- and enantioselective carbonyl (trimethylsilyl)allylation from the alcohol or aldehyde oxidation Level.

Results and Discussion

Our study began with the attempted (trimethylsilyl)allylation of benzyl alcohol 3a. Using the ortho-cyclometallated catalyst generated in situ from [Ir(cod)Cl]₂, 4-cyano-3-nitrobenzoic acid, (R)-SEGPHOS⁵ and allyl acetate, neither the desired (trimethylsilyl)allylation product 4a or resulting Peterson olefination product were detected. Using the isolated π-allyl iridium precatalyst (R)-I in the presence of cesium carbonate, the desired (trimethylsilyl)allylation product 4a was formed along with substantial quantities Peterson olefination product. After screening various inorganic bases, it was found that Peterson olefination is suppressed using K₃PO₄ (1.0 equiv.) in the presence of water (5.0 equiv.) for reactions conducted at 70 °C. Under these conditions, α-(trimethylsilyl)allyl acetate 1a was coupled to a structurally diverse set of aldehydes 2a–2i (Table 1). In each case, good isolated yields were accompanied by exceptional levels of diastereo- and enantioselectivity. In the absence of isopropanol, but under otherwise identical conditions, (trimethylsilyl)allylation occurs directly from the alcohol oxidation level to furnish an identical set of adducts 4a–4i (Table 2). Again, good isolated yields were accompanied by exceptional levels of diastereo- and enantioselectivity. Thus, unlike corresponding protocols involving allylmetal reagents,^7–11 carbonyl (trimethylsilyl)allylation occurs with equal facility from the alcohol or aldehyde oxidation level.

Table 1.

Enantioselective α-(trimethylsilyl)allylation from the aldehyde oxidation level.^a

^aYields are of material isolated by silica gel chromatography. Enantiomeric excess was determined by chiral stationary phase HPLC analysis. See Supporting Information for further details.

Table 2.

Enantioselective α-(trimethylsilyl)allylation from the alcohol oxidation level.^a

^aAs described for Table 1.

^bThe complex modified by (R)-C3-TUNEPHOS was used as precatalyst.

The mechanism for catalytic carbonyl (trimethylsilyl)allylation is analogous to that previously proposed for related crotylations.^2c However, complete levels of anti-diastereoselectivity are observed in nearly all cases, suggesting carbonyl addition occurs exclusively from the (E)-σ-allyl through a chair-like transition structure. Notably, although the catalyst dehydrogenates primary alcohols 2a-2i, the reaction products 4a–4i, which are homo-allylic alcohols, are not oxidized under the coupling conditions and, hence, do not experience any erosion of enantiomeric purity by way of redox equilibration. This result is remarkable as 2-propanol, a secondary alcohol, is oxidized under the coupling conditions when aldehydes 3a–3i are employed as reactants. As indicated in the proposed catalytic mechanism (Scheme 2), coordination of iridium to the homoallylic olefin of reaction products 4a–4i provides a hexa-coordinate, 18-electron complex that cannot engage in β-hydride elimination due to the absence of an open coordination site.

Scheme 2.

Proposed catalytic mechanism and stereochemical model for carbonyl (trimethylsilyl)allylation from the alcohol or aldehyde oxidation level.

To evaluate the utility of the coupling products 4a–4i, adducts 4a, 4f, 4g and 4i were subjected to DMDO-mediated oxidative elimination.^8h,i The 1,4-ene-diols 5a, 5f, 5g and 5i were produced in excellent yield with high levels of E:Z selectivity (Scheme 3). Proto-desilylation was attempted next. Under nearly all conditions assayed, exclusive formation of Peterson olefination products was observed. However, upon exposure of adduct 4g to TiCl₄ in the presence of exogenous aldehyde, the product of proto-desilylation 6g is generated in 73% yield with complete E:Z selectivity (Scheme 3). In the absence of aldehyde, Peterson olefination is again the exclusive reaction product, suggesting exogenous aldehyde protects the hydroxyl moiety of 4g through formation of a titanium bound hemi-acetal. Notably, compound 6g was previously prepared in 7-steps from malic acid.¹² Thus far, the protodesilylation is most efficient for the benzyl-ether containing adduct 4g (Scheme 4).

Scheme 3.

Dioxirane mediated oxidative desilylation of adducts 4a, 4f, 4g and 4i to furnish the corresponding 1,4-ene-diols 5a, 5f, 5g and 5i.

Scheme 4.

Protodesilylation of 4g requires exogenous aldehyde to suppress Peterson olefination.

Finally, under conditions similar to those described by Woerpel,¹³ exposure of 4g-OAc to chlorosulfonyl isocyanate delivers the product of [3+2] cycloaddition, the 4,5-trans-disubstituted pyrrolidinone 7g, as a single diastereomer. Lactone formation was not observed. Formation of the 7g suggests a mechanism involving stereoselective addition of chlorosulfonyl isocyanate to the allylsilane anti-periplanar with respect to the silyl group to generate the indicated β-silyl carbocation. Exclusive N-cyclization accompanied by 1,2-silyl migration delivers the 4,5-trans-substituted pyrrolidinone 7g. In the absence of NaHCO₃, a mixture of lactone and lactam products are observed. These data suggest that partitioning of the N- and O-cyclization pathways is not dictated primarily by steric factors as proposed by Woerpel,^13b but that the acidity of the medium plays a dominant role (Scheme 5).

Scheme 5.

Reaction of adduct 4g with chlorosulfonyl isocyanate to furnish the product of formal [3+2] cycloaddition 7g.

Summary

In summary, we report a highly anti-diastereo- and enantioselective carbonyl (trimethylsilyl)allylation under the conditions of iridium catalyzed transfer hydrogenation employing a single-component catalyst, the ortho-cyclometallated complex (R)-I. Notably, identical sets of adducts 4a–4i are formed with comparable levels of selectivity from the aldehyde or alcohol oxidation level in the absence of Peterson olefination. Oxidative desilylation of adducts 4a, 4f, 4g and 4i employing DMDO provides access to highly enantiomerically enriched 1,4-ene-diols 5a, 5f, 5g and 5i.^8h,i Conditions for proto-desilylation with allylic transposition have been identified for adduct 4g in the absence of a hydroxyl protecting group. Finally, exposure of adduct 4g to chlorosulfonyl isocyanate delivers 4,5-trans-disubstituted pyrrolidinone 7g as a single diastereomer. Future studies will focus on the development of related alcohol-unsatruate C-C couplings and related imine additions from the amine oxidation level.