Enantioselective Intramolecular Openings of Oxetanes Catalyzed by (salen)Co(III) Complexes: Access to Enantioenriched Tetrahydrofurans

Abstract

The catalytic enantioselective intramolecular ring-opening of oxetanes with alcohols is catalyzed by (salen)Co(III) complexes. Either a monomeric or oligomeric catalyst can be used successfully in this transformation, providing 3-substituted tetrahydrofurans in both high yield and enantioselectivity. This methodology extends the range of electrophiles that can be activated toward highly enantioselective addition reactions by (salen)metal catalysts to an important new class.

Oxetanes are receiving increased attention as intermediates in organic synthesis and drug discovery, thanks in part to the development of new methods for their preparation.^1,2 At this stage, few enantioselective reactions of oxetanes have been realized; these include ring expansions catalyzed by chiral copper complexes³ and ring openings with organolithium reagents promoted by a chiral boron reagent.⁴ We became intrigued by the possibility of activating oxetanes with (salen)Co(III) complexes for enantioselective ring opening (e.g., eq 1), given the successful application of these catalysts in the asymmetric ring-opening of epoxides.^5,6 Herein, we describe intramolecular openings of oxetanes catalyzed by (salen)Co(III) complexes 1 and 2 to afford functionalized tetrahydrofurans in high yields and enantioselectivities.

(1)

Lewis acid catalysis represents a viable approach to enantioselective ring opening of oxetanes, given that oxetanes possess lower ring strain⁷ but superior Lewis basicity⁸ relative to epoxides. Mechanistic studies of (salen)Co(III)-catalyzed reactions have established that epoxide ring-openings occur through cooperative bimetallic mechanisms involving simultaneous activation of nucleophile and Lewis acid activation of epoxide.⁹ By enforcing cooperative interactions between (salen)Co units, oligomeric catalysts such as 2 have been shown to provide greatly enhanced reactivity compared with monomeric catalysts.¹⁰

We chose to examine achiral 3-substituted oxetanes as potential reacting partners, as these substrates are readily accessed from malonate esters or 3-oxetanone,¹¹ and are susceptible, in principle, to enantioselective ring-opening with nucleophiles other than water. Intermolecular additions to 3-butyloxetane were studied using nucleophiles proven effective in (salen)Co(III)-catalyzed epoxide ring-opening reactions, such methanol,^10c,e 4-methoxyphenol^10c,e,12 and tert-butyl carbamate.^13,10e However, no desired ring-opened product was obtained in any case using either 10 mol% monomeric (salen)Co(III) complex 1 or 2 mol% of the oligomeric complex 2.

Encouraged by the excellent reactivity and enantioselectivity obtained in intramolecular epoxide openings with alcohols using monomeric (salen)Co(III),¹⁴ we examined intramolecular opening of oxetanes as a potential route to pharmacologically active and synthetically useful 3-substituted heterocycles (Table 1).^15–17 A variety of oxetane-containing tethered nucleophiles were prepared and treated with catalytic levels of (salen)Co(III) complexes 1 and 2. Cyclization to provide tetrahydrofuran 4a proceeded in excellent enantioselectivity and yield using either the monomeric or oligomeric catalyst. Cyclization of 5 to tetrahydropyran 6 proceeded substantially more slowly, yet with high enantioselectivity and yield using oligomeric catalyst 2, whereas cyclizations to provide seven-membered ring oxepanes were unsuccessful. Oxetane 7 bearing carbamate nucleophilic component underwent ring-opening with diminished yield and enantioselectivity.

Table 1.

Representative Intramolecular Oxetane Ring-Openings

entry	substrate	product	catalyst (mol%)	time (h)	yielda (%)	eeb (%)
1	3a	4a	1 (1)	1	92d	98
2			2 (0.01)	2	93e	96
3	5	6	1 (10)	96	38d	7
4			2 (0.1)	96	89e	96
7	7	8	1 (10)	72	72f	50c
8			2 (10)	72	70e	10c

^aIsolated yield after flash chromatography on SiO₂.

^bDetermined by chiral HPLC analysis of the benzoylated product unless noted otherwise.

^cDetermined by chiral GC analysis of the trifluoroacetylated product.

^dReaction carried out in the absence of solvent.

^eReaction carried out in MeCN (6 M).

^fReaction carried out in TBME (6 M).

The scope of the intramolecular opening of oxetanes with O-centered nucleophiles was examined with a variety of achiral oxetane substrates bearing nucleophilic appendages (Table 2). A series of substituted ethanol derivatives underwent ring opening with high enantioselectivity and yield (entries 3–10). Alkyl (3b–c, 3i) and phenyl (3d) substitution at the 3-position of the oxetane was tolerated, affording products bearing quaternary stereocenters.¹⁸ Incorporation of a fluorine substituent in the substrate provided tetrahydrofuran 4e, which contains an interesting fluorine-bearing stereocenter. Ring-opening of phenolic substrates (3f–h) provided enantioenriched dihyrobenzofurans; however, higher catalyst loadings were required to attain high levels of enantioselectivity.

Table 2.

Enantioselective Tetrahydrofuran and Benzodihydrofuran Synthesis

entry	substrate	product	catalyst (mol%)	time (h)	yielda (%)	eeb (%)
1	3a	4a	1 (1.0)	1	92c	98h
2			2 (0.01)	2	93d	96h
3	3b	4b	1 (1.0)	6	87c	99
4			2 (0.01)	6	88d	96
5	3c	4c	1 (1.0)	24	96e	98
6			2 (0.01)	24	98d	99
7	3d	4d	1 (1.0)	2	93c	99
8			2 (0.01)	12	97d	99
9	3e	4e	1 (1.0)	7	87c	97h
10			2 (0.01)	7	76d	98h
11	3f	4f	1 (5)	8	94e	93
12			2 (0.01)	6	89d	98
13	3g	4a	1 (10)	8	77e	96
14			2 (1)	8	95d	98
15	3h	4h	1 (10)	96	79f	84
16			2 (1)	6	94g	88
17	3i	4i	1 (1)	5	88c	97
18			2 (0.01)	5	98d	99

^aIsolated yield, after flash chromatography on SiO₂.

^bDetermined by chiral HPLC analysis of the benzoylated product unless noted otherwise.

^cReaction carried out in the absence of solvent.

^dReaction carried out in MeCN (6 M).

^eReaction carried out in TBME (6 M).

^fTBME (1 M).

^gMeCN (1 M).

^hDetermined by chiral GC analysis of the trifluoroacetylated product.

Both monomeric and oligomeric complexes proved to be efficient catalysts for the enantioselective ring-opening of oxetanes, providing access to a wide variety of tetrahydrofurans in high enantioselectivity and yield. Monomeric catalyst 1 is easily accessed from the commercially available (salen)Co(II) complex by treatment with TfOH.¹⁹ Reactions using this catalyst can be carried out either solvent-free or with small amounts of TBME, and catalyst loadings as low as 1 mol%. Oligomeric catalyst 2 displays enhanced efficiency, and can be used in loadings as low as 0.01 mol%, often with improved enantioselectivity. We are now pursuing synthetic applications and mechanistic studies of the oxetane ring-opening reaction.

Supplementary Material

1_si_001. Supporting Information.

Representative experimental procedures, characterization data, and chiral chromatographic analyses of racemic and enantiomerically enriched products. This material is available free of charge via the Internet at http://pubs.acs.org