Direct and Asymmetric Aldol Reactions of N‐Azidoacetyl‐1,3‐thiazolidine‐2‐thione Catalyzed by Chiral Nickel(II) Complexes. A New Approach to the Synthesis of β‐Hydroxy‐α‐Amino Acids

Abstract

A direct and asymmetric triisopropylsilyltrifluoromethanesulfonate (TIPSOTf) mediated aldol reaction of N‐azidoacetyl‐1,3‐thiazolidine‐2‐thione with aromatic aldehydes catalyzed by a chiral nickel(II)‐Tol‐BINAP complex has been developed (BINAP=2,2’‐bis(diphenylphosphino)‐1,1’‐binaphthyl). The catalytic protocol gives the corresponding anti α‐azido‐β‐silyloxy adducts with outstanding stereocontrol and in high yields. Theoretical calculations account for the stereochemical outcome of the reaction and lay the foundations for a mechanistic model. In turn, the easy removal of the thiazolidinethione yields a wide array of enantiomerically pure derivatives in a straightforward and efficient manner. Such a noteworthy character of the heterocyclic scaffold together with the appropriate manipulation of the azido group open a new route to the synthesis of di‐ and tripeptide blocks containing a β‐aryl‐β‐hydroxy‐α‐amino acid.

Direct, Stereodivergent, and Catalytic Michael Additions of Thioimides to α,β‐Unsaturated Aldehydes – Total Synthesis of Tapentadol

“…Other substrates with less sterically hindered substituents performed better and gave the corresponding enantiomerically pure syn stereoisomers 14 a – 15 a in good yields. In turn, the results achieved with α‐azidoacetyl thiazolidinethione 10 [29] were particularly noteworthy, as the expected syn diastereomer 16 a was obtained with excellent stereocontrol (dr 90 : 10, ee 99 %) and an isolated yield of 66 %.…”

Stereocontrolled Aldol-Like Reactions Involving Oxocarbenium Intermediates

“…To our pleasure, the TIPS-mediated aldol reaction of 168 with aromatic aldehydes, catalyzed by 2–6 mol% of nickel complex 169 produced a single enantiomer ( ee 99%) of the protected anti aldol products 168a – i in diastereoselectivities normally higher than dr 93:7 and in yields of up to 95% (Eq 21 in Scheme 47 ). 66 In particular, the reaction with benzaldehyde catalyzed by 4 mol% of ent -169 furnished enantiomerically pure anti aldol ent -168c (dr 93:7, ee 99%) in an 89% yield through a mechanism like that represented in Scheme 20 . Displacement of the thiazolidinethione with H-Pro-O t -Bu led quantitatively to 183 , and appropriate manipulation of the azido group, followed by a further coupling with Fmoc-Asn-OH and standard removal of the Fmoc group from the resulting product afforded tripeptide 185 containing a β-hydroxy phenylalanine residue (Scheme 47 ).…”

“…To our pleasure, the TIPS-mediated aldol reaction of 168 with aromatic aldehydes, catalyzed by 2-6 mol% of nickel complex 169 produced a single enantiomer (ee 99%) of the protected anti aldol products 168ai in diastereoselectivities normally higher than dr 93:7 and in yields up to 95% (Eq 21 in Scheme 47). 66 The direct reaction of oxocarbenium intermediates from acyclic dimethyl acetals was also exploited by Liu to get access to anti αalkyl or α-aryl-β-methoxy thioimides (Eq 22 in Scheme 48). 67 Indeed, the addition of N-acyl oxazolidinethiones to dimethyl acetals activated by BF3 with oxocarbenium XXXII, generated from benzaldehyde dimethyl acetal and BF3•OEt2, to produce XXXIV.…”

“…Displacement of the thiazolidinethione with H-Pro-Ot-Bu led quantitatively to 183, and appropriate manipulation of the azido group, followed by a further coupling with Fmoc-Asn-OH and standard removal of the Fmoc group from the resulting product afforded tripeptide 185 containing a -hydroxy phenylalanine residue (Scheme 47). 66 The direct reaction of oxocarbenium intermediates from acyclic dimethyl acetals was also exploited by Liu to gain access to anti -alkyl or -aryl--methoxy thioimides (Eq 22 in Scheme 48). 67 Indeed, the addition of N-acyl oxazolidinethiones to dimethyl acetals activated by BF 3 •OEt 2 and catalyzed by 10 mol% of the chiral nickel triflate 153 provided mixtures of aldol adducts in high overall yields, from which the anti stereoisomers 186-194 were mainly obtained with remarkable enantioselectivities (ee 88-99%).…”

Protected syn-Aldol Compounds from Direct, Catalytic, and Enantioselective Reactions of N-Acyl-1,3-oxazinane-2-thiones with Aromatic Acetals

“…In this context, we recently reported a direct and enantioselective TIPSOTf-mediated aldol addition of a wide array of N -acyl thioimides to aromatic aldehydes that is catalyzed by small amounts of a [Tol-BINAP]­Ni­(II) complex and produces the protected anti -aldol derivatives with high yields (Scheme ). , In view of that accomplishment and the importance of general procedures leading to the complementary syn -aldol counterparts, − we have striven to unveil the keys that determine the diastereo- and enantiocontrol of such transformations and thus to obtain any of the four possible protected stereoisomers at will. Herein, we disclose our findings on a direct, catalytic, and enantioselective syn -aldol reaction of N -acyl thioimides with aromatic acetals based on the use of a new oxazinanethione scaffold and a [DTBM-SEGPHOS]­Ni­(II) chiral complex that leads to enantiomerically pure O -alkyl-protected syn products and hence paves the way for the synthesis of any of the aldol stereoisomers (Scheme ).…”