Stereocontrolled Synthesis of β‐Amino Alcohols from Lithiated Aziridines and Boronic Esters

Abstract

From natural products to ligands for asymmetric catalysis, the b-amino alcohol motif is ubiquitous.[1] The importance of this motif to such a broad spectrum of chemistry has prompted the development of a range of methodologies for its synthesis which include Sharpless aminohydroxylation [2] as well as the addition of nucleophiles to aminocarbonyls, [3] imines, [4] epoxides, and aziridines.[5] We considered a conceptually different route to prepare this class of compound: namely, the lithiation/borylation [6] of aziridines [7] (Scheme 1, pathway a).This route was attractive because: 1) it combines readily available aziridines 1 and boronic esters 2, and creates a C À C bond, 2) high stereoselectivity for the overall process could be expected since lithiation of N-Boc [8] (tert-butoxycarbonyl) and N-Bus [9] (tert-butylsulfonyl) aziridines [10] had been shown to occur trans to the aziridine substituent, and the subsequent steps (3 ! 4 ! 5 ! 6) were expected to be stereospecific, 3) there existed the potential to create quaternary stereogenic centers through lithiation at the internal position. [11] Although most studies have focused on lithiation and trapping of N-sulfonyl aziridines, [9,12] we were attracted to the N-Boc aziridines because: 1) they could be easily prepared in enantiomerically enriched form (either from the corresponding amino acid [13] or by Jacobsens kinetic resolution of terminal epoxides [14] using Boc-NH 2 [15] ), and 2) the N-Boc amino alcohol products provide more useful functionality for further manipulation downstream. However previous studies had shown that lithiated aziridines bearing an N-Boc group undergo a rapid intramolecular [1,2] anionic rearrangement to give aziridinyl esters 7, a useful reaction in its own right (Scheme 1, pathway b).[8] This rearrangement pathway made it virtually impossible to trap the C-lithiated aziridine with any external electrophile, including MeOD. However, if the electrophile was already present during the deprotonation step, it would be theoretically possible to trap the lithiated aziridine prior to the migration of the Boc group.[16] As we believed that most boronic esters/boranes would also be compatible with the hindered base (LTMP) required for deprotonation, this provided the possibility of using N-Boc aziridines in the lithiation-borylation reaction, without migration of the Boc group. This analysis gave us the motivation to embark on the following study.To maximize the rate of the bimolecular trapping (and therefore minimize the migration rate of the Boc group), the reactions were conducted at the maximum concentration that was practical. Thus, slow addition of a THF solution of LTMP to a solution of N-Boc aziridine 1 a and ethyl boronic ester 2 a (1.5 equiv) at À78 8C followed by warming to 0 8C and oxidative workup gave a mixture of amino alcohol 6 and the aziridine 7, in 40 % and 20 % yield, respectively (Scheme 1). This result showed that the rates of trapping and of rearrangement of the lithiated aziridine were similar, even at high conce...

Reagent-Controlled Lithiation–Borylation

“…Lithiation of N-Boc-protected aziridines 96 with LTMP followed by electrophilic quench with boronic esters gave the intermediate boronate complexes 97 that rearranged to give, after oxidation, various 1,2-aminoalcohols 98 in very high selectivity [57]. This methodology was then extended by using the enantioenriched N-Bus-phenyl aziridine 99.…”

“…The choice of the Bus as the N-protecting group was required as when N-Boc-phenyl aziridine was used a N ! C migration of the Boc group was observed [57]. Scheme 21 Synthesis of (R)-4-ethyl-4-methyloctane via lithiation-borylation…”

Investigation of Functionalized α‐Chloroalkyllithiums for a Stereospecific Reagent‐Controlled Homologation Approach to the Analgesic Alkaloid (−)‐Epibatidine

“…Iteration allows for an “assembly‐line” style synthesis of complex polysubstituted alkyl moieties wherein stereochemical and constitutional features are directly programmed by the carbenoid presentation sequence. Since the first demonstration of StReCH of boronic esters with α‐chloroalkylmagnesium chlorides,6a the concept has been better realized with other carbenoid types, including α‐chloroalkyllithiums,6 α‐[(diisopropylamino)carbonyloxy]alkyllithiums,9 α‐[(2,4,6‐triisopropylbenzoyl)oxy]alkyllithiums,10 oxiranyllithiums,11 aziridinyllithiums,12 and α‐lithiated N ‐Boc amines 13. Of these findings, the fact that StReCH can be effected with species as chemically labile as α‐chloroalkyllithiums is arguably the most surprising result 14.…”

Synthesis ofcis-C-Iodo-N-Tosyl-Aziridines using Diiodomethyllithium: Reaction Optimization, Product Scope and Stability, and a Protocol for Selection of Stationary Phase for Chromatography

“…20 Deprotonation of unstabilized monosubstituted aziridines can occur regio- and stereoselectively: occurring trans to the substituent at the least hindered position for alkyl-aziridines, or at the benzylic position for aryl-aziridines. 21 Functional group exchange has also been demonstrated to be an effective method for generating aziridinyl anions, which react with electrophiles at the predefined position. 13,22 In addition, the palladium-catalyzed cross-coupling of intact aziridines has recently been achieved; separately Vedejs, 23 and ourselves 24 have reported the cross-coupling of aryl halides with aziridine metal species formed by Bu 3 Sn–Li exchange and TolSO–Mg exchange respectively.…”