A-Benzyloxy aldehydes

The class of 3-silyl-substituted reagents provides, upon addition with aldehydes, allylic silanes that offer many options for further derivatization. Oxidative processes are described in previous sections (see the sections on Preparation of 1,2-Diols and 1,4-Diols). If the appropriate silicon substituents are chosen, formal [3+2] cycloadditions with aldehydes can be promoted under Lewis acid catalysis. For example, the mismatched addition of the Z-3-propyl-3-benzhydryldimethyl allylsilane 183 to an a-benzyloxy aldehyde proceeds with low diastereofacial selectivity in favor of product 184 however, after protection of the secondary alcohol, an efficient [3+2] annulation provides the polysubsubstituted furan 185 in good yield and acceptable stereoselectivity (Scheme 24). ° The latter is brought forward to a tricyclic unit found in the antitumor natural product angelmicin B. 

Allylation of a-methylthio aldehydes.1 This reaction, when catalyzed by a Lewis acid, particularly SnCl4, proceeds with high anti-selectivity. In contrast, the reaction with a-benzyloxy aldehydes is highly syn-selective. 

Scheme 8C.27. Asymmetric carbonyl-ene rr. aldol-type reaction of a-benzyloxy aldehyde.

Keck [63] and Carreira [64] have independently reported catalytic asymmetric Mukaiyama aldol reactions. Keck et al. also reported the aldol reaction of an a-benzyloxy aldehyde with a Danishefsky s diene. The aldol product was transformed to the corresponding HDA-type product through acid-catalyzed cyclization. In these reactions, the catalyst that is claimed to... 

Enders and Bhushan reported the preparation of a-benzyloxy aldehydes and a-acetoxy ketones 6 of high enantiomeric purity and in good overall yield by oxygenation of the azaenolates of chiral hydrazone 4 with 3-phenyl-2-(phenylsulfonyl)oxaziridine 282. The chiral auxiliary was removed without racemization by ozonolysis of the a-hydroxy hydrazone 5 at — 78 °C. 

A parallel trend is observed for MgBr2-promoted additions of cis- and trans-crotyl tributylstannanes to a-benzyloxy aldehydes but the effect is much smaller (Table 9) [18], In such reactions the orientation of the allylic stannane and the chelated aldehyde is governed by steric effects in which the vinylic y-hydrogen orients over the five-membered chelate (Fig. 4). Support for this picture is provided by competition experiments in which y3,)8-dimethylallyl tributyltin was found to be markedly slower than the crotyl or allyl derivatives in additions to a-benzyloxypropanal. The observed rate decrease was attributed to the disfavored relationship of a vinylic methyl substituent with the chelate ring resulting in unfavorable steric interactions. 

The MgBr2-promoted additions to the (5)-a-benzyloxy aldehyde proceed via a chelation-controlled transition state (Fig. 18). Approach to the carbonyl face of the nearly planar five-membered magnesium chelate is directed by the methyl substituent resulting in re attack by the allenylstannane through the antiperiplanar geometry for the (P) stannane and the synclinal geometry for the (M) stannane. An antiperiplanar orientation of the (A/) stannane would place the vinylic methyl substituent in close proximity to the chelate ring. 

Figure 18. Transition states for MgBr2-promoted addition of (/ )- and (Af)-allenylstannanes to an (5)-a-benzyloxy aldehyde.

Useful levels of stereoselectivity were obtained in intermolecular addition reactions of C(3)-sub-stituted allylsilanes to chiral aldehydes. Lewis acids that are capable of chelating to heteroatoms have been used to direct the stereochemical course of allylsilane a itions to a-alkoxy and a, -dialkoxy carbonyl compounds. The allylation of a-benzyloxy aldehyde (94) in the presence of TiCU and SnCl4 furnished products with high levels of syn stereoselection (. n-9. In contrast, under nonchelation-controlled reaction conditions (BF3-OEt2) allyltrimethylsilane reacted to form predominantly the anti-1,2-diol product (onri-95), as shown in Scheme 4S. 

Scheme 1-8. Reaction of silyl enol ether complex 23 with a-benzyloxy aldehydes.

Mikami and Keck have each demonstrated that a-alkoxy aldehydes can also undergo highly selective chelate-controlled additions with crotyltri-n-butylstannane [53, 57]. The MgBr2-OEt2-promoted reaction of the a-benzyloxy aldehyde 55 with crotyltri- -butylstannane 10 gave predominantly the 5yn,5yn-adduct 121, whose stereochemistry is consistent with the antiperiplanar, chelate transition state 122 (Eq. (11.4)). 

In the complementary chelate-controlled reaction of the a-benzyloxy aldehyde 127 with the (y-silyloxyallyl)stannane 113, the. s yn,.sy -adduct 128 arises as the major adduct, presumably through transition state 129 (Eq. (11.6)) [90]. 

The synthesis of 145 (Scheme 11-4) began with the allylation adduct 121, obtained through a chelate-controlled addition of crotyltri- -butylstannane to the a-benzyloxy aldehyde 55 (see Eq. (11.4)). Adduct 121 was converted in five steps to aldehyde 146, which subsequently underwent a highly diastereoselective chelate-controlled allylation reaction with allyltri-n-butylstannane 98. The stereochemistry of the resulting adduct, 147, is consistent with formation through a chelate transition state analogous to 101 (Table 11-7). 

Panek and Cirillo demonstrated that the -methyl chiral crotylsilane (5)-217b favors formation of the 5,6-anti diastereomer in the chelate-controlled reaction with the achiral a-benzyloxy aldehyde 353 (Eq. (11.26)) [57, 58]. Here, the synclinal transition state 355 best explains the stereochemistry of the major adduct. 

Double asymmetric reactions between [7-(alkoxy)allyl]stannanes 230 and the a-benzyloxy aldehyde 55 exhibited clear matched and mismatched behavior [168]. With BF3 OEt2 catalysis, the matched double asymmetric reaction between (R)-230a and aldehyde (S)-55 generates exclusively the syn,anti adduct 425 (Eq. (11.40)). Formation of 425 can be rationalized through either the antiperipla-nar, Felkin transition state 426 (as proposed by Marshall) or the synclinal Felkin transition state 427. 

Scheme 5.2.13 Chelation-controlled addition of E- and Z-crotyltri-n-butylstannanes to a-benzyloxy-aldehyde 51...

Keck25 also examined the behavior of four Lewis acids in one of the first examples of allylations with a-benzyloxy aldehyde 59. The chelation-controlled pathway is most selective with MgBra OEta producing the expected syn, syn-product 61 via 63. The use of Znla or TiCU led to mixtures of 61 and 62, owing to the competing pathway proceeding via the synclinal transition state 64 (Scheme 5.2.15). 

The diastereoselectivity of the allylation of a-benzyloxy aldehyde 23 was studied70 (equation 64). It was found that under chelation control a very high percentage of the syn adduct is formed whereas under non-chelation control the anti product is favored. 

The stereoselectivity of the reaction of 1 -alkynylzinc bromides 130 (R == heptyl or Ph) with various chiral a-benzyloxy aldehydes 131 (R = Me, /-Pr or PhCH20CH2) to yield the alcohols 132 depends on the nature of the substituents R and R Regiospecific propargylation with acylsilanes is exemplified by the reaction of the organozinc bromide 133 (from 2-octynyl bromide and zinc dust in THF) with benzoyltrimethylsilane, followed by desilylation, to yield only the alcohol 134 . 

The homologation of D-glyceraldehyde acetonide (2) serves to illustrate the method. This consists of two sequential operations first, addition of 2-(trimethylsilyl)thiazole (1) to the aldehyde (2) followed by in situ desilylation and protection as the O-benzyl derivative (3) (eq 6) secondly, aldehyde release in the resultant adduct by a three-step sequence involving methylation of the thiazole ring to the iV-methylthiazolium salt reduction to thiazo-lidine hydrolysis to a-benzyloxy aldehyde (4) (eq 7). 

The p-lactone cyclization precursors come from Romo and Yang s tandem Mukaiyama aldol lactonization (TMAL) process (Scheme 7) [10]. As an example of this, lactone 25 was the product of the ZnCl2-mediated cyclization of a-benzyloxy aldehyde 24 with thio-ketene acetal 23. Ozonolytic cleavage of the alkene gave 26. 

Use of y-alkoxy-substituted allylic stannane reagents with a-benzyloxy aldehydes provides convenient access to 1,2,3-triol subunits (Equation 8) [92]. Keck reported the chelation-controlled formation of 113 as a single dia-stereomer and suggested that this product is the result of the intermediacy of transition state structure 112, analogous to 100. 

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