Generation of Stereochemically Defined Tetrasubstituted Enolborinates by 1,4‐Hydroboration of α,β‐Unsaturated Morpholine Carboxamides with (Diisopinocampheyl)borane

Abstract

The enantioselective synthesis of acyclic all-carbon quaternary centers remains a significant challenge in organic synthesis. [1] In view of the tremendous utility of enantioselective aldol reactions in organic synthesis, extension of this reaction to the enantioselective synthesis of all-carbon quaternary centers from stereochemically defined tetrasubstituted enolates would be highly valuable. [2,3] However, attempts to generate such enolates or enolate equivalents by deprotonation of acyclic carbonyl compounds in most cases lead to geometric mixtures, which translates to poor diastereoselectivity in the subsequent aldol reaction. [3, 4] Thus, alternative methods for generation of acyclic tetrasubstituted enolates or their synthetic equivalents have been developed. [5][6][7][8] Noteworthy among these, a highly stereoselective carbocupration of chiral ynamides followed by oxidation of the resultant vinylcuprate has been developed by Marek and co-workers. [8] Nevertheless, the development of a simple, highly stereocontrolled method for synthesis of stereochemically defined tetrasubstituted enolates from readily available achiral starting materials remains an important objective. Toward this end, we report herein a simple procedure by which stereodefined tetrasubstituted enolborinates are generated with exceptional stereoselectivity by 1,4-hydroboration reactions [9,10] of unsaturated morpholine carboxamides with (diisopinocampheyl)borane [(Ipc) 2 BH], and demonstrate that the tetrasubstituted enolborinates undergo highly enantio-and diastereoselective aldol reactions with representative achiral aldehydes.We recently reported that the 1,4-hydroboration of the morpholine acrylamide 1 with ( l Ipc) 2 BH provides the enolborinate Z(O)-2 via TS-I (Scheme 1, where R 2 = R 3 = H). [11a] Treatment of Z(O)-2 with aldehydes provided the syn-aldol products 3 with exceptional diastereo-and enantioselectivity (! 20:1 d.r. and 96-98 % ee). By virtue of the transition state TS-I proposed for the 1,4-hydroboration reaction, [9,12] we anticipated that this procedure could be used to generate stereodefined tetrasubstituted enolborinates (5) from substi-tuted a,b-unsaturated amides (4). Subsequent aldol reactions of 5 should faithfully relay the enolborinate geometry to the all-carbon quaternary stereocenter in 6 via the transition state TS-II. [2] To the best of our knowledge, stereodefined tetrasubstituted enolates have not been successfully generated with high stereochemical control by using alternative reductive aldol procedures, [9,10,12,13] but several have been generated by 1,4-addition of organometallic reagents to unsaturated carbonyl derivatives. [5a,m,q,r, 14] We began by using the a-methylacryl carboxamide 7 as the substrate to probe the effect of an a substituent on the 1,4hydroboration and the subsequent aldol reaction. Compounds bearing a a,a-dimethyl-b-hydroxy quaternary center are often generated by using Mukaiyama aldol methods. [15] 1,4-Hydroboration of 7 (1.1 equiv) with ( d Ipc) 2 BH (1 equiv) in Et 2 O a...

Enantioselective Construction of Quaternary Stereogenic Carbon Atoms by the Lewis Base Catalyzed Additions of Silyl Ketene Imines to Aldehydes

“…A simple and effective method for controlling enolate geometry in tetrasubstituted enol borinates was recently described by Roush and co-workers (Scheme 5). [13] The enol borinates (18) are generated in situ by the 1,4-hydroboration of a,b-unsaturated morpholine carboxamides (17) with (diisopinocampheyl)borane (( l Ipc) 2 BH). Subsequent aldol addition reactions of Scheme 3.…”

Stereoselective Formation of Fully Substituted Ketone Enolates

“…[5,6] However,t he generation of as tereodefined fully substituted enolate precursor as as ingle isomer in acyclic systems is not atrivial task, especially for ketone enolates,a nd therefore all the enolization reactions leading to stereodefined a,a-disubstituted enolates were restricted to esters and amides.F or instance, a,a-acyclic disubstituted esters require ap erfect conformational control for the abstraction of the a-hydrogen, [3] and this control can only be achieved by deprotonation of diastereomerically pure a,a-acyclic dialkylated amides, [7] enantiomerically pure a,a-acyclic dialkylated esters with chiral bases (Scheme 1, Path B), [8] or through conjugate additions. [9] As we have been involved over the last few years in the development of synthetic strategies leading to the creation of several carbon-carbon bonds in acyclicsystems and as inglepot operation, including the formation of quaternary carbon stereocenters, [5,10] we reported adirect access to the formation of a,a-disubstituted enolates of amides by carbocupration of ynamides followed by selective oxidation of the resulting alkenyl cuprates species (Scheme 1, Path C). [11,12] Despite all these efforts,t he stereoselective formation of a,a-disubstituted enolate of ketones is still very challenging and remains in its complete infancy, as the regioselectivity and the E/Zselectivity of the enolization need to be concomitantly controlled (Scheme 1, Path A).…”

Stereodefined Acyclic Polysubstituted Silyl Ketene Aminals: Asymmetric Formation of Aldol Products with Quaternary Carbon Stereocenters

“…[3] Themain problem that limits the formation of this stereocenter is the difficulty to prepare stereodefined trisubstituted enolates with different alkyl groups in an acyclic system ( Figure 1). [7] These three original methods require the preparation of enantiomerically pure sp 3 stereocenters that are subsequently enolized into stereodefined disubstituted enolates of amides and esters.T he conjugate addition (not shown) or the deprotonation of a,b-unsaturated amides (path D, Scheme 1) [5c,8] and the 1,4-hydroboration reaction of a,b-unsaturated morpholine carboxamides (path E, Scheme 1) [9] constitute alternative approaches to prepare stereodefined disubstituted enolates of amides. [7] These three original methods require the preparation of enantiomerically pure sp 3 stereocenters that are subsequently enolized into stereodefined disubstituted enolates of amides and esters.T he conjugate addition (not shown) or the deprotonation of a,b-unsaturated amides (path D, Scheme 1) [5c,8] and the 1,4-hydroboration reaction of a,b-unsaturated morpholine carboxamides (path E, Scheme 1) [9] constitute alternative approaches to prepare stereodefined disubstituted enolates of amides.…”

“…Whereas Lewis base catalyzed additions of silyl ketene imines to aliphatic aldehydes proceed with good results, [15] in all other cases,u seful yields and diastereoselectivities were only achieved by using a,b-unsaturated aldehydes which could eventually serve as surrogates for saturated aldehyde substrates through hydrogenation. [7,9,13] Thed evelopment of an ew approach to aldol products by reaction of stereodefined trisubstituted acyclic enolates with aliphatic aldehydes leading to the expected quaternary carbon stereocenters was therefore needed.…”

“…[4] Them ost prominent examples reported to date for the formation of disubstituted enolates of amides and esters, although rarely used for aldol transformations,a re the stereospecific enolization of enantiomerically enriched starting materials such as acyclic a-alkylbutyramides (path A, Scheme 1), [5] the double stereodifferentiation in the deprotonation of enantiomerically enriched a-branched esters with enantiomerically pure chiral lithium amides (path B, Scheme 1), [6] and ring-opening of chiral bicyclicthioglycolate lactams (path C, Scheme 1). [7] These three original methods require the preparation of enantiomerically pure sp 3 stereocenters that are subsequently enolized into stereodefined disubstituted enolates of amides and esters.T he conjugate addition (not shown) or the deprotonation of a,b-unsaturated amides (path D, Scheme 1) [5c,8] and the 1,4-hydroboration reaction of a,b-unsaturated morpholine carboxamides (path E, Scheme 1) [9] constitute alternative approaches to prepare stereodefined disubstituted enolates of amides.…”