Aldehydes asymmetric vinylation

Another landmark development in the area of hDA chemistry is the emergence of the tridentate chromium complexes 194 that can catalyze the reaction of njl-unsaturatcd aldehydes with vinyl ethers to afford dihydropyrans with high diastereo- and enantioselectivity (Equation 91) <2002AGE3059>. The same catalytic system can be used for the asymmetric synthesis of the 3,4-dihydropyran 195 from 3-boronoacrolein pinacolate and ethyl vinyl ether in quantitative yield (Equation 92) <2003JA9308, 2005JA1628>. 

Alexakis et al. proposed in 2010 the use of aminals deriving from 4-hydroxyproline for the asymmetric addition of aliphatic aldehydes to vinyl sulfones." " The idea that a fluorine atom at the C4 position of these pyrrolidine-based organocatalysts could be used to favour one single reactive enamine conformation was further exploited by the same authors in 2011, designing a catalyst (28) able to afford excellent yields and enantioselec-tivities (Scheme 11.24). ... 

Scheme 11.24 Asymmetric addition of aliphatic aldehydes to vinyl sulfones catalysed by 28.

Lately, sulfones have become especially important substrates in organocatalysis [87]. First studies on the asymmetric conjugate addition of aldehydes to vinyl sulfones were carried out by Alexakis and Mossd employing as catalyst bipyrrolidine 30 (25 mol%) for the addition of linear and a-branched aldehydes to l,l-bis(benzenesulfonyl)ethylene [88], Large excess of aldehyde (10 equivalents) was required and moderate levels of enantioselection were obtained for linear aldehydes (53-80% ee), while reactions with a-branched nucleophiles led to racemic or very low selectivities (0-12% ee). With respect to the mechanism, the acyclic synclinal model proposed by Seebach and GoUnski [70] involving a trans enamine intermediate was postulated. 

Soon afterward, the same group accomplished the first asymmetric organo-SOMO a-vinylation of aldehydes using vinyl trifluoroborate salts (Scheme 8.30) [137]. Broad functional groups tolerance, high reaction efficiency, trawi-olefin selectivity, and enantioselectivity were obtained under optimized reaction conditions in the presence of imidazolidinone catalyst LXIV. Moreover, the steric demands of the aldehyde substrate have little influence on efficiency and enantiocontrol. This reported transformation also represents the first use of boron salts as coupling reagents for radical-based processes. 

Toward this end, aldehyde 2.188 was protected as the acetal, which was followed by oxidative removal of PMB group and subsequent TPAP oxidation of resulting alcohol to deliver the aldehyde 2.212. Gratifyingly, the subjection of 2.212 to the (-)-MlB-catalyzed asymmetric vinylation reaction (4-methyl-1-pentyne, Cy2BH, Et2Zn, (-)-MlB, toluene, -5 °C, 1.5 h) afforded the desired (17/f)-alcohol 2.213 with excellent stereoselectivity (dr = 32 1) as determined by HPLC. 

Mosse and Alexakis reported on the first asymmetric direct Michael addition of aldehydes to vinyl sulfones... 

Organo-SOMO catalysis has been successfully exploited to achieve the first asymmetric a-vinylation of aldehydes using vinyl trifluoroborate salts and the commercial Kim and MacMillan catalyst 191. " ° Vinyl potassium trifluoroborate salts participate in enantioselective and regioselec-tive carbon-carbon bond formation with the aldehyde-derived radical cation 192 to form a (3-borato-stabilized radical 193 (Scheme 25.90), which in the presence of a suitable oxidant will undergo rapid electron transfer to render the (3-cation (not shown). Subsequent Peterson elimination of the trifluoroborate group with tran.s-selectivity followed by iminium hydrolysis of 194 would then reveal an optically enriched R-( )-vinyl aldehyde (e.g., 195). 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

A valuable feature of the Nin/Crn-mediated Nozaki-Takai-Hiyama-Kishi coupling of vinyl iodides and aldehydes is that the stereochemistry of the vinyl iodide partner is reflected in the allylic alcohol coupling product, at least when disubstituted or trans tri-substituted vinyl iodides are employed.68 It is, therefore, imperative that the trans vinyl iodide stereochemistry in 159 be rigorously defined. Of the various ways in which this objective could be achieved, a regioselective syn addition of the Zr-H bond of Schwartz s reagent (Cp2ZrHCl) to the alkyne function in 165, followed by exposure of the resulting vinylzirconium species to iodine, seemed to constitute a distinctly direct solution to this important problem. Alkyne 165 could conceivably be derived in short order from compound 166, the projected product of an asymmetric crotylboration of achiral aldehyde 168. 

The asymmetric Baylis-Hillman reaction of sugar-derived aldehydes as chiral electrophiles with an activated olefin in dioxane water (1 1) proceeded with 36-86% de and in good yields of the corresponding glycosides (Eq. 10.47).104 The use of chiral /V-mcthylprolinol as a chiral base catalyst for the Baylis-Hillman reaction of aromatic aldehydes with ethyl acrylate or methyl vinyl ketone gave the adducts in good yields with moderate-to-good enantioselectivities in l,4-dioxane water (1 1, vol/vol) under ambient conditions.105... 

Various catalytic or stoichiometric asymmetric syntheses and resolutions offer excellent approaches to the chiral co-side chain. Among these methods, kinetic resolution by Sharpless epoxidation,14 amino alcohol-catalyzed organozinc alkylation of a vinylic aldehyde,15 lithium acetylide addition to an alkanal,16 reduction of the corresponding prochiral ketones,17 and BINAL-H reduction18 are all worth mentioning. 

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

Chiral alkenes derived from ot,p-unsaturated aldehydes have also been applied in asymmetric 1,3-dipolar cycloadditions (142). Soucy et al. (142) used (—)-8-(benzylamino)menthol (94) and acrolein for the exclusive formation of 95 having an equatorial C(2) vinyl group (Scheme 12.31). The 1,3-dipolar cycloaddition of acetonitrile oxide with 95 gave 96 with a selectivity of > 90% de. 

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