Stereoselective Vinylogous Mukaiyama Aldol Reaction of .ALPHA.-Haloenals

Abstract

We previously reported a highly stereoselective vinylogous Mukaiyama aldol reaction (VMAR) using vinylketene silyl N,O-acetal 1 and 2, which provides a unique and remarkable entry to a remote asymmetric induction (Chart 1).1-3) From a synthetic point of view, this method can directly afford the anti-d-hydroxy-a,g-dimethyl-a,b-unsaturated carbonyl unit which is seen in many naturally occurring products. Indeed, VMAR has successfully been utilized in natural product syntheses by many groups [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] including ourselves. [21][22][23][24][25] However, a,b-unsaturated aldehyde is not generally a good substrate for VMAR in terms of yield (i.e., low to moderate). High yield could be achieved by the addition of a catalytic amount of water, 3) or by carrying out the reaction for a prolonged period of time. 5,11) In this context, we became interested in the employment of a-haloenals as substrates which are considered to be much more reactive compared to simple enals. We also reasoned that the VMAR products from ahaloenals could serve as versatile intermediates for introducing a variety of substituents using well-established Pd-mediated methodologies. Herein, we report a high-yielding and stereoselective VMAR of a-haloenals achieved under standard conditions (TiCl 4 in CH 2 Cl 2 , 2.0 eq of aldehyde). Some transformations of VMAR products from a-haloenals by Pdcatalyzed cross-coupling are also described.In this study, we examined VMAR of a-iodoenal 3a, 26) abromoenal 3b, 27) and a-chloroenal 3c 28,29) (Table 1). According to the established protocol, VMAR of a-iodoenal 3a (2.0 eq) with the vinylketene silyl N,O-acetal 2 using TiCl 4 (1.0 eq) afforded the corresponding anti-aldol adduct 4a in excellent yield with high diastereoselectivity (entry 1). In addition, VMAR of a-bromoenal 3b and a-chloroenal 3c also provided anti-adducts 4b and 4c 30) in excellent yield, respectively (entries 2, 3). Notably, a-halo substituents improved the yields of aldol adducts and shortened the reaction time compared with VMAR of tiglic aldehyde 3d (entry 4). Independently, Hosokawa and Tatsuta et al. reported that the VMAR of ent-2 and tiglic aldehyde 3d afforded ent-4d in good yield (82%) over a prolonged reaction time (4 d) at low temperature (Ϫ60°C). 5,11)Stereochemical determination of the aldol adducts 4a and 4b were easily achieved by Stille cross-coupling using a catalytic amount of Pd(dba) 2 and Me 4 Sn to convert the antiadduct 4d (Chart 2). The spectroscopic data of synthetic 4d We have developed a high-yielding and stereoselective vinylogous Mukaiyama aldol reaction (VMAR) of a ahaloenals. Contrary to the simple a a,b b-unsaturated aldehyde, a a-haloenals were found to be reactive affording the corresponding VMAR adducts in excellent yields. Some transformations of VMAR adducts by Pd-mediated cross-coupling were also examined in order to demonstrate the synthetic utility of VMAR of a a-haloenals.

New Developments of the Principle of Vinylogy as Applied to π-Extended Enolate-Type Donor Systems

“…Going on in investigating the exploitation of silyl ketene acetals of type 807 in asymmetric VMAR, Kobayashi et al explored the use of α-haloenals 808 ( Scheme 206 , n = 1, R 1 = Hal, R 2 = R 3 = H) as acceptors to overcome the low reactivity of α,β-unsaturated aldehydes such as tiglic aldehyde ( 808 , n = 1, R 1 = Me, R 2 = R 3 = H). 532 According to the established protocol, dienolate 807 reacted with two equivalents of haloenals 808 and TiCl 4 affording anti -aldols of type 809 endowed with versatile δ-hydroxy-ε-halo functionalities along with two versatile double bonds. As previously demonstrated, even in this case, high yields could be obtained by prolonging reaction times or by adding a catalytic amount of water.…”

The vinylogous Mukaiyama aldol reaction (VMAR) in natural product synthesis

“…84). 94 Different a-haloenals require different reaction times and give yields up to 95% with >20 : 1 dr. It should be pointed out that those a-haloenals can be used as substrates for Pdmediated cross coupling reactions in further transformations.…”

Selective Formation of a Trisubstituted Alkene Motif by trans‐Hydrostannation/Stille Coupling: Application to the Total Synthesis and Late‐Stage Modification of 5,6‐Dihydrocineromycin B

“…[35,36] Instead, indirect solutionsp revail in the literature,i nw hich an alkenylstannane is first converted into the corresponding iodide,which is then treated with astoichiometric amount of Me 2 CuLi [37] or cross-coupled with an appropriate methyl donor. [38] Alternatively,transmetalation strategies were exercised that rely on the initial transformation of the alkenyltin species into am ore reactive organolithium or organocopper reagent which is then trapped with MeX. [39] In the present case,however, an organolithium intermediate is excluded by the presence of the lactone group in 16,w hereas aS n!…”