Imides asymmetric aldol reactions

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

Chiral amides (222) and (223) and imides (224) and (225) have also been studied as reagents for asymmetric aldol reactions. These reagents show excellent diastereofacial preferences as their boron and zirconium enolates, but generally show poor selectivity as their lithium enolates. The reader is referred to other chapters in this volume for a discussion of these and related reagents. 

Asymmetric aldolization of a-isocyanoacetamide and fluorinated benzaldehydes has been realized with a gold(I) salt and a ferrocenyl amine-phosphine ligand. (Salen)-Ti complexes serve well in catalyzing the condensation of diketene with aldehydes. " A camphor lactam is an adequate chiral auxiliary as its derived imide undergoes asymmetric aldol reactions. 

The asymmetric aldol reaction using the Evans oxazolidinone auxiliary has been used in a number of syntheses. Suggest reagents for the preparation of the imide 2, used in a synthesis of cytovaricin and explain the stereoselectivity of this reaction. Suggest how you would obtain the other syn aldol product and explain the difference in the stereoselectivity. 

Since its discovery in 1974, more than 180 papers have been published on the use of the Overmann rearrangement to prepare allylic amines and their analogs from their allylic alcohols. For example, a recent synthesis of the fluoroalkene peptidomimetic precursor of A -acetyl-Z,-glutamyI-Z.-alanine involves the Overman rearrangement of the imidate derived from the allylic alcohol 60. ° This alcohol is readily prepared through Evans asymmetric aldol reaction of oxozolidinone with an aldehyde. 

One of the most attractive options for asymmetric aldol reactions available to the synthetic chemist is to use enolates of carboxylic acid derivatives (inter alia ester, amide, or imide) with an appended chiral auxiliary (alcohol, amine, urethane). An early example of this approach dates back to 1938, when McKenzie reported that benzaldehyde undergoes addition by (-)-menthyl malonate (42) to give propanoic acid derivative 43 in 21 % ee (Equation 4) [43]. The modest selectivity was attributed to the conformational flexibility of ester enolates (cf. 44). 

In addition to these examples of alkylations that employ chelate-enforced intraannular asymmetric induction, Evans s imides are useful in asymmetric aldol (Section 5.2.2 and 5.2.3), and Michael additions (Section 5.3.2), Diels-Alder reactions (Section 6.2.2), and enolate oxidations (Section 8.4), making this one of the most versatile auxiliaries ever invented. 

Asymmetric Evans aldol reaction (11,379—381).2 The boron cnolatc of the Iivans imide 1 is widely used for preparation of chiral syn-aldols 2. However, if the boron enolate is generated at —78° and then treated with the aldehydes prccomplexcd... 

Kobayashi et al. reported that a chiral barium complex prepared from a 3,3 -disilyl-substituted BINOF derivative was promising in asymmetric reactions [23]. By using the barium catalyst, direct-type aldol reactions of imides were investigated. Basically, a stereocontrolled direct-type aldol reaction between an... 

SCHEME 2.69 Thiourea-catalyzed asymmetric aldol/O-C cyclization reaction of a-isothiocyanato imide and aldehydes. 

From the illustrated (S)-valinol imide (175), the derived dibutylboryl enolates undergo condensation with a broad range of aldehydes in greater than 99% asymmetric induction for both newly formed asymmetric centers 180). Evans et al. have shown that the propionyl sidely chain in (175) may be replaced by other alkanoyl substituents without loss of stereoselectivity in the aldol type reaction 180). 

The first catalytic asymmetric Michael addition of an mygen-centred addition of salicylaldoxime to a,p-unsaturated imides was achieved by the Jacobsen group in 2004 (Scheme 19.34). With p-oxo dimer catalyst [r,R)-[(salan)Al]20 5 as the catalyst, a series of a,p-unsaturated imides worked well. It should be noted that this method could tolerate ester, acetal, and silyl ether functionality, allowing its potential application as an acetate aldol alternative in polyketide natural product synthesis. When combined with efficient N-O bond hydrogenolysis, this (salen)aluminium-catalysed reaction enables the net enantioselective hydration of electron-deficient olefins with no need for purification of the intermediate oxime ethers. 

A remarkable case of remote asymmetric induction was observed by Kobayashi and coworkers when they extended the Evans method to protocol for a vinylogous aldol addition (Scheme 4.59). For this purpose, the alkenoic imides 251 and 254 were converted into vmylketene sUyl N,0-acetals 252 and 255, respectively. When these silicon enolates, whose fr 5-configuration was assigned based upon NOE experiments, were submitted to a vinylogous Mukaiyama reaction, the adducts 253 and 256 were obtained with excellent diastereoselectivity [131]. 

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