A Practical Method for the Synthesis of Highly Enantioenriched trans-1,2-Amino Alcohols

Abstract

A highly enantioselective addition of phenyl carbamate to meso-epoxides has been developed to efficiently generate protected trans-1,2-amino alcohols. This transformation is promoted by an oligomeric (salen)Co–OTf catalyst and has been used to prepare two useful 2-aminocycloalkanol hydrochlorides in enantiopure formon a multigram scale from commercially-available starting materials.

Enantioenriched trans-1,2-amino alcohols are useful building blocks for the preparation of complex molecules and chiral catalysts as well as ligands and auxiliaries for asymmetric synthesis.¹ Catalytic asymmetric approaches to synthesize this class of compounds have been developed, but their applicaton on a preparative scale has been limited.² A chief concern in known methods is the use of hydrazoic acid as an ammonia equivalent,^2a–b since this reagent is potentially dangerous and requires special safety measures. Bartoli has demonstrated that carbamates can be employed successfully in (salen)Co(III)-catalyzed kinetic resolutions of terminal epoxides.³ However, there are no known examples of enantioselective carbamate additions to meso epoxides, which are intrinsically much less reactive than terminal epoxides in (salen)Co(III)-catalyzed reactions.

Bimetallic mechanisms have been established for (salen)metal-catalyzed nucleophilic ring-opening of both terminal and meso-epoxides,⁴ and polymer-supported, dendrimeric, and oligomeric (salen)Co(III) complexes have been developed to facilitate cooperativity between metal centers.⁵ These multimeric complexes have been shown to display striking improvements in both rate and selectivity in relation to their monomeric equivalents.⁶ Herein we report the use of an oligomeric (salen)Co–OTf complex^5e–f,7 to catalyze the highly enantioselective addition of phenyl carbamate to meso-epoxides (Scheme 1). This reaction enables an efficient, operationally-simple, and scaleable approach to protected trans-1,2-amino alcohols in high enantiomeric excess from commercially available starting materials.

Scheme 1.

Oligomeric (salen)Co(III)-Catalyzed Carbamate Addition to meso-Epoxides

In preliminary studies, we found that oligomeric (salen)Co–OTf complexes provide marked improvements in reactivity in the kinetic resolution of 1,2-epoxyhexane with tert-butyl carbamate.^5f For example, only 0.2 mol % of the oligomeric complex 3 was needed to effectively catalyze this reaction whereas under similar conditions 4.4 mol % of a related monomeric (salen)Co(III) was required.^3a

The addition of carbamates to cyclohexene oxide was selected as a model reaction, and it was found that phenyl carbamate was particularly effective as a nucleophlic reacting partner.^8,9 Clean addition to cyclohexene oxide with subsequent intramolecular cyclization was observed to afford trans-4,5-disubstituted oxazolidinone product 1 (Table 1).¹⁰ The cyclization appears to be relatively rapid, as the initial addition intermediate is not detectable. While both monomeric and oligomeric (salen)Co–OTf complexes were found to catalyze this transformation, both the rate and enantioselectivity were far superior with the oligomeric catalyst 3 (entry 3). The best balance of rate and enantioselectivity was achieved in reactions carried out at 50 °C, with oxazolidinone 1 obtained in 91% yield and 95% ee after 24 h (entry 4).

Table 1.

Catalyst and Reaction Optimization

entrya	catalyst (mol %)	temperature (°C)	yieldb (%)	eec (%)
1	2 (5)	23	3	n.d.
2	2 (5)	50	33	21
3	3 (1)	23	21	97
4	3 (1)	50	91	95

^aReactions run on a 0.5 mmol scale.

^bYield determined by ¹H NMR analysis relative to p-xylene as internal standard.

^cEnantiomeric excess determined by GC analysis using commercial chiral columns.

The addition of phenyl carbamate to a variety of meso-epoxides was evaluated under the optimized reaction conditions (Table 2). Epoxides with unsaturation in the ring were viable substrates, but underwent reaction with slower rates than cyclohexene oxide (entries 2–3). Carbamate addition to five-membered ring epoxide derivatives proceeded with very high enantioselectivity (entries 4–5). The products from these reactions did not undergo intramolecular cyclization, presumably due to the unfavorable strain in trans-fused 5–5 ring systems.¹¹ Instead, the monomeric additon product was generated together with carbamate-bridged oligomers (Scheme 2). However, this mixture could be subjected to hydrolysis by treatment with base to liberate the trans-1,2-amino alcohol in high overall yield (see below).

Table 2.

Substrate Scope

entrya	substrate	product	catalyst loading (mol %)	time (h)	yieldb (%)	eec (%)
1			1	24	94	96
2			2	48	84	96
3			2	48	63	95
4			1	24	66	>99
5			1	24	49	>99

^aReactions run on a 1.0 mmol scale.

^bIsolated yield of purified product.

^cEnantiomeric excess determined by GC or HPLC analysis on commercial chiral columns.

Scheme 2.

(salen)Co(III)-Catalyzed Carbamate Addition to Cyclopentene Oxide

The practical applicability of the carbamate addition protocol is illustrated in the preparation of trans-2-aminocyclohexanol hydrochloride (6) and trans-2-aminocyclopentanol hydrochloride (7) on a multigram scale using 0.5 and 1 mol % of catalyst, respectively (Scheme 3).^12,13 Following the catalytic reaction, the reaction mixture was subjected to basic deprotection conditions and the products recrystallized as the hydrochloride salts in >99% ee. These amino alcohols are versatile building blocks for organic synthesis and can readily be transformed into a variety of valuable chiral products.^{13a, 14}

Scheme 3.

Preparative-Scale Reactions

In summary, we have developed an efficient protocol for the catalytic enantioselective synthesis of protected trans-1,2-amino alcohols in high yield and enantiomeric excess. Crucial to this development was the use of an oligomeric (salen)Co–OTf complex as the catalyst and aryl carbamate nucleophiles. This method is amenable to large-scale synthesis due to the low catalyst loadings and high concentration used, its operational simplicity, and the use of inexpensive, commercially-availalable starting materials.