The syn-selective conjugate addition of amines to enoates derived from d-mannitol

The syn-selective conjugate addition of neat amines to enoates Z-1 and E-1, prepared from d-(+)-mannitol, is reported. The reactions with benzyl and allylamine 2a,d at −50 °C or 2e at −25 °C in the absence of a solvent led to syn-adducts in moderate to good chemical yields and good syn/anti ratios, and were accelerated in the presence of DBU. Enoate Z-1 was more reactive than E-1, leading to products with better syn-selectivity. The syn-selectivity slightly decreased for reactions at rt. The reaction of both enoates with primary amines 2c,d (Ph changed by 2- and 3-pyridyl) only occurred at rt, leading to adducts in good chemical yields and with moderate to good syn-selectivities. Secondary acyclic amine 2f showed very low reactivity (rt, DBU, several hours) and led to the adduct in moderate chemical yields and with low syn-stereoselectivity while higher reactivity and moderated yields and syn-selectivities were observed for cyclic secondary amines 2g–i.

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Ethyl (4S,5)-O-isopropyliden-(3R)-benzylaminopentanoateC17H25NO4[α]D25 = +15.7 (c 0.8, Chloroform P.A)Absolute configuration: (S), (R)Source of chirality: d-(+)-Mannitol

Ethyl (4S,5)-O-isopropyliden-(2R)-pyridin-3-ylmethylaminopentanoateC16H24N2O4[α]D27 = −3.85 (c 1.65, Chloroform P.A)Absolute configuration: (S), (R)Source of chirality: d-(+)-Mannitol

Ethyl (4S,5)-O-isopropyliden-(3R)-pyridin-3-ylmethylaminopentanoateC16H24N2O4[α]D27 = −2.2 (c 2.24, Chloroform P.A)Absolute configuration: (S), (R)Source of chirality: d-(+)-Mannitol

Ethyl (4S,5)-O-isopropyliden-(3R)-allylaminopentanoateC13H23NO4[α]D25 = +19.1 (c 0.5, Chloroform P.A)Absolute configuration: (S), (R)Source of chirality: d-(+)-Mannitol

Ethyl (4S,5)-O-isopropyliden-(3R)-(2-morpholinoethylamino)pentanoateC16H30N2O5[α]D27 = +6.9 (c 0.8, Chloroform P.A)Absolute configuration: (S), (R)Source of chirality: d-(+)-Mannitol

Ethyl (4S,5)-O-isopropyliden-(3R)-pirrolidi-1-nylpentanoateC14H25NO4[α]D25 = +4.45 (c 0.4, Chloroform P.A)Absolute configuration: (S), (R)Source of chirality: d-(+)-Mannitol

Ethyl (4S,5)-O-isopropyliden-(3R)-piperidi-1-nylpentanoateC15H27NO4[α]D27 = +3.4 (c 0.8, Chloroform P.A)Absolute configuration: (S), (R)Source of chirality: d-(+)-Mannitol

Ethyl (4S,5)-O-isopropyliden-(3R)-morpholi-1-nylpentanoateC14H25NO4[α]D27 = +4.0 (c 1.4, Chloroform P.A)Absolute configuration: (S), (R)Source of chirality: d-(+)-Mannitol

Ethyl (4S,5)-O-isopropyliden-(3R)-(allyl(benzyl)amino)pentanoateC20H29NO4[α]D27 = +10.3 (c 4.38, Chloroform P.A)Absolute configuration: (S), (R)Source of chirality: d-(+)-Mannitol