Aldehydes allenylzinc reagent addition

Table 9.48 Additions of non-racemic silylated allenylzinc reagents to racemic silylated mandelic aldehyde.

A related allenylzinc reagent was prepared by the addition of LDA to a solution of trimethylsilylpropargyl chloride and ZnBr2 in THF at -78°C (Eq. 9.128) [107], Anti propargylic chlorohydrins adducts were obtained when aldehydes were allowed to react with this reagent. Subsequent treatment with DBU gave the alkynyloxiranes (Eq. 9.129). 

Additions of enantioenriched allenylzinc reagents to chiral aldehydes provide intermediates that can be employed in the synthesis of polyketide natural products. Matched and mismatched pairing of reagent and substrate can result in enhanced or diminished diastereoselectivity (Eqs. 9.132 and 9.133) [114]. 

The factors that control the stereochemical outcome of such rections can be illustrated by additions of enantiomeric allenylzinc reagents to (S)-lactic aldehyde derivatives [114]. The matched S/S pairing proceeds via the cyclic transition state A in which addition to the aldehyde carbonyl assumes the Felkin-Anh orientation with an anti arrangement of the allenyl methyl and aldehyde substituents (Scheme 9.29). The alternative arrangement B is disfavored both by the anti-Felkin-Anh arrangement and eclipsing of the allenylmethyl and aldehyde substituents. 

Table 9.50 Additions of butyl-allenylzinc reagents to aldehydes.

Additions of Transient Allenylzinc Reagents to Representative Achiral Aldehydes ... 

The earliest studies on allenylzinc reagents were mainly concerned with the regioselec-tivity of addition reactions to aldehydes and ketones. Moreau and Gaudemar converted... 

In their quest for alkynyl-substituted 1,2-diols, Epsztein and workers examined additions of alkoxy allenylzinc reagents to aldehydes (Table 4)5. The reagents were prepared from various propargylic ethers by lithiation with BuLi followed by addition of Znl2. Although exact ratios were not determined, the major propargylic products were surmised to be the anti isomers based on spectral data and comparison with authentic samples. 

Zweifel and Hahn found that deprotonation of terminal allenes with -BuLi and subsequent addition of ZnCb leads to terminal allenylzinc reagents, which afford anti adducts upon addition to various aldehydes (Table 5)7. Branching in the aldehyde and allene substituents enhanced the anti syn ratio of adducts, in keeping with the previously proposed cyclic transition state for such additions. 

Additions of the chiral allenylzinc reagents to enantiomeric -methyl-/ -OBn aldehyde substrates proceeded with a high degree of reagent control to afford anti,syn or anti,anti adducts (equations 23 and 24). In these additions, the preferred anti orientation of the allenyl methyl and the aldehyde substituents requires the reaction to proceed by the normally less-favored anti Felkin-Anh pathway (equation 25). 

When they subjected the allenylzinc reagent to the Hoffmann test for configurational stability,29 Poisson, Chemla and Normant found that at — 50 °C, racemization does not occur at a significant rate (equation 36)30,31. Accordingly, when the racemic allenylzinc reagent was added slowly to the /V-benzy limine of (R)-mandehc aldehyde at — 50 °C, a 1 1 mixture of the anti,syn and anti,anti adducts was isolated in 65% yield. However, when the addition process was reversed, a 3 1 mixture favoring the matched anti,anti adduct was formed in 53% yield, suggestive of a partial kinetic resolution. 

Addition of an excess of the racemic allenylzinc reagent to the /V-benzylimine of (S)-malic aldehyde TBS ether yielded the matched anti,anti adduct of >95% enantiomeric purity derived from the (M)-enantiomer of the reagent (equation 37)31. 

TABLE 17. Addition of TMS allenylzinc reagents to silyl-protected mandelic aldehydes... 

Under carefully controlled conditions, the reaction proceeds with excellent stereocontrol. Addition of the allenylzinc reagent derived from the (i )-mesylate 101 to (i )-aldehyde 100 proceeded at -20 °C to give the anti-anti triad 102 in 70 % yield with a small amount of the anti-syn isomer [30], As an intramolecular version, the propargyl benzoate 103 attacked the methyl ketone to afford the cyclopentanol 104 using Et2Zn and an Lewis acid with high stereocontrol. The most effective Lewis acid was Yb(OTf)3. A good catalyst was Pd(OAc)2-P(n-Bu)3 [31]. 

Propargylic zinc derivatives react with aldehydes or ketones with variable selectivity affording a mixture of allenic and homopropargylic alcohols [135]. However, under appropriate reaction conditions, high enantioselectivities and diastereo-selectivities can be achieved. Marshall and coworkers have shown that chiral propargylic mesylates such as 188 are converted to allenylzinc reagents 189 through treatment with a Pd(0)-catalyst. Their addition to an aldehyde such as 190... 

Reactions of allenylzinc bromide reagents with aldehydes afford increased amounts of propargyl adducts compared to analogous additions to ketones (Table 3). Presumably, diminished steric interactions render the aldehyde propargylic adducts more stable than their ketone counterparts. Alternatively, equilibration of the kinetic propargylic adducts with the allenyl isomers is slower for the adducts of aldehydes. 

Normant and Poisson prepared allenylzinc bromide reagents from TMS acetylenes along the lines of Epsztein and coworkers5, by sequential lithiation with s-BuLi to yield a lithiated species, and subsequent transmetallation with ZnBr2 (equation 35)27,28. Additions to racemic /J-silyloxy aldehydes proceed with low diastereoselectivity to afford mixtures of the anti,anti and anti,syn adducts (Table 17). The latter adducts are formed via an anti Felkin-Anh transition state. Additions to the racemic IV-benzylimine analogs, on the other hand, proceed with nearly complete Felkin-Anh diastereoselectivity to yield the anti,anti amino alcohol adducts (Table 18). 

Marshall and co-workers have demonstrated that allenylindium [277] and allen-ylzinc [276] reagents can be formed in situ from propargyl mesylate 389 and that these reagents react enantioselectively with aldehydes without additional Lewis acid catalysis (Scheme 11-28). The allenylzinc and allenylindium reagents 392 and 391 are derived from the allenylpalladium intermediate 390 via metathesis with Et2Zn and Ini, respectively. Allenylpalladium intermediate 390 in turn is derived from (7 )-389 via invertive displacement of the mesylate functionality of 389 with Pd(0). 

The addition of a chiral allenyl metal to an aldehyde generating a 2-substituted butynyl structure is named Marshall-Tamaru MT) reaction (Scheme 5-13). An allenyl palladium species is generated via a formal Sn2 substitution of the mesylate, which in turn undergoes a transmetalation with diethylzinc yielding a nucleophilic species (Scheme 5-13). The reaction of the electrophile proceeds via a similar -ester enolate transition state as depicted in Scheme 5-13. Corresponding allenylindium reagents can also be used instead of allenylzinc intermediates. ... 

Use of these chiral allenyl metal reagents for the introduction of a propar-gyl group allows the synthesis of all four diastereomeric permutations of dipropionate subunits. The propargyl unit also provides a convenient handle for further elaboration, as demonstrated in Marshall s synthesis of the cytotoxic polyketide discodermolide (182, Scheme 5.30) [115]. Propargylation of aldehyde 177 with an allenylzinc species derived from mesylate 172 furnishes anti product 178 in 90 10 dr. The addition of allenylstannane 180 to aldehyde 179 affords the syn product 181 in an impressive 97% yield and >95 5 dr. 

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