Asymmetric Synthesis of β-AminoCyclohexyl Sulfonates, β-Sultams and γ-Sultones

Abstract

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...

A Versatile Synthesis of Various Substituted Taurines from Vicinal Amino Alcohols and Aziridines

“…[16] Enders and co-workers reported an efficient asymmetric synthesis of 2-substituted and 1,2-disubstituted taurine derivatives through aza-Michael addition of enantiopure hydrazines to α,β-unsaturated sulfonates in the presence of Lewis acid catalysts. [17] They also further converted substituted taurine derivatives into substituted β-sultams and γ-sultones.…”

[2 + 2] Annulation of Aldimines with Sulfonic Acids: A Novel One‐Pot cis‐Selective Route to β‐Sultams

“…From a chemical viewpoint, β‐sultams can act as peptidomimetics in sulfonyl transfer reactions and as potent sulfonating agents for a variety of nucleophiles6–8 to afford a wide range of important chemicals. Page et al have exhaustively studied the reactivity of β‐sultams with nucleophiles and found that it depends on the N ‐substituent 9.…”

“…The [2 + 2] cycloaddition reported for β‐sultam synthesis utilizes mainly sulfene intermediates with imines,10 mesyl chloride with chiral imines,11 or alkenes with N ‐sulfonylamines 12. The intramolecular cyclization strategy involves use of amino acids followed by introduction of the sulfur moiety,13 β‐amino sulfonic acids,6 heterocyclic sulfonates14 or β‐aminosulfonyl chlorides,15 for diastereo‐ and enantioselective synthesis of β‐sultams 6,8,16…”

Five‐Membered Heterocycles with Two Heteroatoms: O and S Derivatives

“…Full details of the asymmetric synthesis of chiral c-sultones 281 have been described [236]. The direct reaction of cyclopropanes 282 with SO 2 in TFA to give 1,2-oxathiolane-2-oxides 283 and 284 has been studied extensively to determine the regioselectivity of this reaction (Scheme 11.90) [237].…”