Enantioselective Ring Opening of meso‐Epoxides with Silicon Tetrachloride Catalyzed by Pyridine N‐Oxides Fused with the Bicyclo[3.3.1]nonane Framework

Abstract

The synthesis of new chiral Lewis basic organocatalysts that contain pyridine N-oxide moieties fused with the bicyclo-[3.3.1]nonane framework is reported. The obtained pyridine N-oxides were employed as catalysts in the enantioselective ring opening of meso-epoxides with silicon tetrachloride. Derivative 1b endowed with two 2,4-diaryl-substituted pyridine N-oxide moieties proved to be a particularly effective cata-6359 lyst for desymmetrization of norbornene oxide 16i to furnish Wagner-Meerwein rearrangement product 20i in unprecedented 96 % ee. Difunctional congener 3, which is striped of the 4-aryl substituents, exhibited moderate to high levels of asymmetric induction (47-88 % ee) with alicyclic epoxide substrates.N,NЈ-dioxide L3, [8] helical chiral N-oxide L4, [9] bipyridine N-monooxide L5 (PINDOX), [10] as well as dipyridylmethane, [11] bis(tetrahydroisoquinoline) [12] and bipyridine [13] N,NЈ-dioxides promote enantioselective chlorohydrin formation. Figure 1. Selected Lewis basic pyridine-type N-oxide and phosphine oxide organocatalysts.Chiral phosphine oxides, such as axially chiral L6 (BI-NAPO), [14] its heteroaromatic congeners, [15] or allene-derived bisphosphine oxide L7, [16] have been also shown to A. Neniškis, S. Stončius FULL PAPERcatalyze enantioselective ring-opening of meso-epoxides with SiCl 4 . Nevertheless, the Lewis basic catalysts developed so far proved to be rather fastidious with respect to the epoxide substrate. As a rule, the ability to impart high levels of enantioselection is limited to the derivatives of cisstilbene oxide (87-97 % ee with catalysts L1-L4, L6, and L7), whereas in the case of the less sterically demanding aliphatic substrates and, in particular, with cyclic epoxides, the enantioselectivity drops to moderate levels. Pinene-derived N-monooxide PINDOX [10] (L5; Figure 1), which is most effective with saturated cyclic substrates that contain more than seven carbon atoms and norbornene oxide (87-90 % ee) but inefficient with cis-stilbene oxide (16 % ee), is a notable exception.Desymmetrization of meso-epoxides is an attractive strategy for asymmetric synthesis as two contiguous stereogenic centers can be unveiled through a single transformation. [17] Therefore further development, which enhances the catalyst efficiency and broadens the scope of such reactions is desirable. Herein we present the synthesis of new Lewis bases that feature a pyridine N-oxide fragment attached to a chiral bicyclo[3.3.1]nonane backbone, and their application in enantioselective ring opening of meso-epoxides with silicon tetrachloride. www.eurjoc.org 6361 Scheme 2. Reagents and conditions: (a) TiCl 4 , Cl(CH 2 ) 2 COCl, 1,2-DCE; (b) TEA, CH 2 Cl 2 (18-43 %); (c) (i) DMF, POCl 3 , 0°C (98 %), (ii) H 2 C=CHMgBr, THF, 0°C (80 %); (d) IBX, THF/ DMSO, room temp. (67 %); (e) Me 2 NH 2 Cl, iPrOH, Δ (91 %); (f) 4, TEA, 180°C, then NH 2 OH·HCl, EtOH, Δ (30 %); (g) m-CPBA, K 2 CO 3 , CH 2 Cl 2 , room temp. (38 %).