Stereoselective Synthesis of Allylic Sulfoximines fromS-(Chloromethyl)-N-methyl-S-phenylsulfoximine and Alkenyl Cuprates

Abstract

Enantio-and diastereomerically pure acyclic and cyclic allylic sulfoximines have been obtained by the reaction of (+)-(S)-S-(chloromethyl)-N-methyl-S-phenylsulfoximine with alkenyl cuprates of the type R 2 CuLi . LiCN.Allylic sulfoximines 4 (Scheme 1) are receiving currently much attention. In particular their hydroxyalkylation, 1-4 substitution by cuprates, 5-7 Pd-catalyzed rearrangement 8 and conjugate addition to enones 9 offer interesting possibilities for asymmetric synthesis. Prerequisite to the synthetic application of 4 is their accessibility in an enantio-and diastereomerically pure form. Existing methods 4-7,10 provide only for an access to enantiomerically pure cyclic allylic sulfoximines and acyclic allylic sulfoximines having the (E) configuration. Acyclic allylic sulfoximines having the (Z) configuration were so far accessible only in isolated cases as side products in the synthesis of the (E) isomers from aldehydes (ketones) and S-(lithiomethyl)-N-methyl-S-phenylsulfoximine. 7 It occurred to us that this void could be filled and a general route to 4 could be opened by the substitution 11 of α-halo sulfoximines 2 with 1-alkenyl cuprates 3. The α-chloro sulfoximine 2a is easily accessible in 75% yield by the chlorination of N,S-dimethyl-S-phenylsulfoximine 1 with tert-butyl hypochlorite. 12 The α-iodo sulfoximine 2b was prepared from 1 following the procedure described for the synthesis of the corresponding N-tosyl derivative 13 which gave 2b 14 in 44% yield (cf. Scheme 1). The sulfoximine 1 in turn can be obtained enantiomerically pure on a large scale via a racemate separation. 15 Configurationally stable cuprates of the type 3 16-18 are available from the corresponding (E)-and (Z)-1-alkenyllithium reagents which can be synthesized by various methods in quite a large structural variety. 19 Scheme 1Herein we describe the application of this methodology 11,16,17 to the stereoselective synthesis of acyclic and cyclic allylic sulfoximines.The alkenyl cuprates 3a-d were prepared from (Z)-1-propenyllithium, (E)-1-propenyllithium, (Z)-1-styryllithium and 1-cyclohexenyllithium, 20,21 respectively, by transmetallation with 0.5 equivalents CuCN in THF. 18 The reaction of 3a-d with 1 equivalent of the enantiomerically pure α-chloro sulfoximine 2a 12 at −78°C to −5°C led to the isolation of the allylic sulfoximines 4a, 2,14 4b, 2,14 4c and 4d, 6,14 respectively, in acceptable yields (Table 1, entries 1-4). The diastereomeric purity of 4a-c was shown to be ≥98% by 1 H NMR spectroscopy. We observed, however, that in the case of 4c a delay in the isolation of the sulfoximine from the quenched reaction mixture resulted in its partial isomerization to the (E) isomer. The synthesis of 4d (Table 1, entry 4) shows that cyclic allylic sulfoximines can be obtained by this route, too.The usefulness of the new route to 4 is exemplified by the synthesis of 4c which could not be obtained by the previously existing methods. The (E) isomer of 4c is readily available diastereomerically pure from phenyl acetaldehyde and lithiat...

Sulfoximine‐Directed Single and Double ortho‐Lithiation: Stereoselective Rearrangements of o,o′‐Dilithiophenylsulfoximines to o,N‐Dilithiosulfinylanilines through Anionic Fries Rearrangements of o,o′‐Dilithiophenylsulfinamides

“…[15] Similar alkylation of 10 with ClCH 2 SiMe 3 gave the sulfoximine 6 with Ն98 % de and in 97 % yield. Treatment of the methyl-substituted sulfoximines 11 [15] and 12 [15] with nBuLi at -50°C gave the corresponding α-lithiosulfoximines 13 [22] and 14, [22] methylation of which with MeI afforded the corresponding dimethyl-substituted sulfoximines 1 and 2 in 54 % and 52 % yields, respectively. Similarly, the sulfoximine ent-2 was synthesized by starting from ent-12.…”

“…The enantiopure sulfoximines 3-5 were synthesized in high yields from the starting S-configured sulfoximine 9, [15] through a highly diastereoselective alkylation of the α-lithiosulfoximine 10 [22] (Scheme 1). [15] Similar alkylation of 10 with ClCH 2 SiMe 3 gave the sulfoximine 6 with Ն98 % de and in 97 % yield.…”

“…Some time ago we developed an efficient synthesis of the α-substituted cyclic sulfoximines 1-6 ( Figure 2), in which the SN moieties are incorporated in rings, [15] and so the phenylsulfoximines 1-6 were selected as substrates for the present study. Whereas the sulfoximines 1-3 have no H atoms at their α-positions, the sulfoximines 4-6 each have one H atom at the α-position.…”

“…The sulfoximines 4-6 should thus be particularly valuable probes because any persisting or transient lithiation at their α-positions should manifest itself in inversion of configuration at these stereogenic C atoms upon treatment with an electrophile. [15] Figure 2. Cyclic and acyclic phenylsulfoximines.…”

A Method for the Conversion of Sulfoximines to Sulfones: Application to Polymer-Bound Sulfoximines and to the Synthesis of Chiral Sulfones

“…[21] Oxidative cleavage of 20 gave the sulfone 16 in 98% yield (Scheme 6). A similar treatment of sulfoximine rac-21, [22] which carries a tosyloxypropyl group at the N atom, with m-chloroperbenzoic acid, cleanly furnished sulfone 16 in 98% yield. Next we studied the cleavage of the N-benzylsulfoximine 22 [23] as a model compound for Merrifield resin-bound sulfoximines.…”