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The Lewis acid catalyzed asymmetric synthesis of bamino-cyclohexyl sulfonates via aza-Michael addition is reported.As key step the addition of (S)-1-amino-2-methoxymethyl-pyrrolidine (SAMP) or (R,R,R)-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]-octane (RAMBO) to alkenyl-cyclohexyl sulfonates is applied, to give b-hydrazino sulfonates in moderate to good yields and diastereomeric excesses (yield = 41-85%, de = 55-90%). The epimers are separated by preparative HPLC, followed by reductive N-N bond cleavage with BH 3 ×THF and protection of the resulting amines with CbzCl to afford NCbz-protected-b-amino-cyclohexyl sulfonates in moderate to good yields (38-68%, 2 steps) and enantiomeric excesses (ee) of ³96%.The synthesis of unnatural amino acids is still of great importance, since these compounds can be utilized for example in the preparation of new peptides with a high potential for biological activities. In recent years 2-substituted taurines were used in the synthesis of b-amino sulfonopeptides. 1 White et al. designed b-sulfonopeptides as inhibitors of D-alanyl-D-alanine transpeptidases containing a taurine instead of a penultimate amino acid. 2 Furthermore, Liskamp et al. synthesized oligopeptido sulfonamides on solid phase in order to analyze their three-dimensional structure and biological activity. 3In addition to the peptides, the b-amino-sulfonates themselves are of great interest. The best known b-amino-sulfonic acid is taurine, but there are also other interesting derivatives like 2-amino-2-phenylethanesulfonic acid 4 as a potential GABA B receptor antagonist or flavocristamide 5 A and B, which have inhibitory activity against DNA polymerase a.The Michael reaction can provide an efficient access to the desired taurine derivatives. The first published azaMichael addition to alkenyl-sulfonates is dated to 1970, when Dumaitre et al. reacted primary and secondary amines with ethene-sulfonates. 6 During the following years, considerable attention towards the aza-Michael addition to alkenyl-sulfonates 7 has been shown, but to our knowledge enantioselective 1,4-additions with enantiopure nitrogen-nucleophiles have not been described.Scheme Reagents and conditions: a) ZnBr 2 (0.2 equiv), MeOH, add 3, add (S)-1 or (R,R,R)-2 (3.0 equiv), r.t., 7-14 d. b) BH 3 ×THF (10 equiv, 1.0 M in THF), THF, reflux, 5 h; r.t., add MeOH, reflux, 1 h. c) CbzCl (3.0 equiv), Na 2 CO 3 (6.0 equiv), CH 2 Cl 2 -H 2 O (4:1), reflux, 1-3 d.

A s y m m e t r i c S y n t h e s i s o f S u l f o n a t e s , b-Sultams a n d g-Sult o n e s Abstract: An efficient asymmetric synthesis of b-aminocyclohexyl sulfonates, b-sultams and g-sultones has been developed. The key step of the synthesis is the Lewis acid catalyzed aza-Michael addition of the enantiopure hydrazines SAMP [(S)-1] or RAMBO [(R,R,R)-2] to alkenylcyclohexyl sulfonates 3. This leads to b-hydrazino sulfonates 4a-k in moderate to good yields (41-85%) and diastereomeric excesses (de = 44-90%). The epimers were separated by preparative HPLC. Subsequent reductive N-N bond cleavage with BH 3 ·THF and protection of the resulting amines with CbzCl gave N-Cbz-protected b-aminocyclohexyl sulfonates 6a-k in moderate to good yields (38-68% over 2 steps) and high enantiomeric excesses (ee ³ 96%). a-Alkylation of 6 with various electrophiles afforded a-alkyl-b-aminocyclohexyl sulfonates 10a-g in good to excellent yields (67-92%) and moderate to high diastereomeric excesses (de = 71-93%). After alkylation with allyl iodide, the first asymmetric iodosultonization was achieved with high selectivities. Compounds 6g-k were also cyclized in a four-step synthesis to highly enantio-enriched 3-substituted-1,2-thiazetidine 1,1-dioxides (b-sultams) 9a-e.There is constant need for the synthesis of unnatural amino acids, since these compounds can provide new biological activities and their peptides are attractive targets for drug discovery. The best-known b-aminosulfonic acid is taurine, which is important for the evolution of the central nervous system of many mammals. Moreover, derivatives like 2-amino-2-phenylethanesulfonic acid, 1 a potential GABA B receptor antagonist or flavocristamides A and B, 2 which have inhibitory activity against DNA polymerase a, demonstrate the demanding interest for the asymmetric synthesis of taurine derivatives. Furthermore, the exchange of a-or b-amino acids in peptides for b-aminosulfonic acids or the synthesis of b-sulfonopeptides have drawn great attention. 3 White et al. designed b-sulfonopeptides as inhibitors of D-alanyl-Dalanine transpeptidase containing taurine instead of a penultimate amino acid. 4 Liskamp et al. synthesized oligo-petido sulfonamides on solid-phase starting from a-amino acids in order to analyze their secondary and tertiary structure as well as their biological activity. 5As we have described in a previous communication, the aza-Michael addition provides an efficient access to taurine derivatives. 6 As shown in Scheme 1, the reaction starts with 1,4-addition of enantiopure nitrogen nucleophiles to alkenyl sulfonates, followed by cleavage of the chiral auxilaries. This leads to chiral b-amino sulfonates, which can be used in the synthesis of 3-substituted 1,2-thiazetidine 1,1-dioxides (b-sultams) and g-sultones.Scheme 1 Asymmetric synthesis of b-aminocyclohexyl sulfonates, g-sultones and b-sultams by aza-Michael addition b-Sultams are the sulfonyl analogues of b-lactams. Therefore, they are interesting building blocks for the synthesis of new antibiotics, corre...

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