We report an enantioselective Ni-catalyzed cross coupling of arylzinc reagents with pyridiniumions formed in situ from pyridine and a chloroformate. This reaction provides enantioenriched 2-aryl-1,2-dihydropyridine products that can be elaborated to numerous piperidine derivatives with little or no loss in ee. This method is notable for its use of pyridine, a feedstock chemical, to build a versatile, chiral heterocycle in a single synthetic step.

A nickel for your thoughts …︁ An enantioselective nickel‐catalyzed cross‐coupling between N‐acylpyridinium salts and organozinc reagents is reported. The catalytic system, which is comprised of an air‐stable NiII source and a chiral phosphoramidite ligand, affords 2‐substituted‐2,3‐dihydro‐4‐pyridones with up to >99 % ee.

Die enantioselektive Kreuzkupplung zwischen N‐Acylpyridinium‐Salzen und Organozinkreagentien nutzt ein Katalysatorsystem aus einer luftbeständigen Nickel(II)‐Quelle und einem chiralen Phosphoramiditliganden für die Synthese von 2‐substituierten 2,3‐Dihydro‐4‐pyridonen mit bis >99 % ee.

The C16-C28 fragment common to the cytotoxic macrolide ammocidin D has been prepared by a stereospecific 5-exo opening of a γ,δ-epoxyketone followed by a rearrangement to a pyran acetal. The reaction pathway was traced by 18 O labeling of the keto carbonyl and observation of 18 O induced 13 C shifts in the pyran acetal product. NMR data of the synthetic C16-C28 fragment compared favorably to the natural product providing support of the assigned stereochemistry.During the course of screening extracts for apoptosis inducers in Ras-dependent Ba/F3-V12 cells, Hayakawa and co-workers identified the macrolide ammocidin A (Figure 1) from the culture broth of Sacchaarothrix ap. AJ9571.1 In 2009 the same research group reported on the isolation and antiproliferative properties of ammocidins B-D.2 Structurally, ammocidins A-D share a common 20-membered macrolactone and differ primarily in glycosylation at C24. For example, ammocidin A incorporates a β-D-olivomycose-β-D-digitoxose disaccharide at C24 while ammocidin D is devoid of sugars at this position (Figure 1). Only the two-dimensional structure of the common aglycone (ammocidinone) was assigned by NMR analysis with degradation by acidic methanolysis providing full assignment of the deoxy sugars by isolation of the derived methyl acetals. Hayakawa has noted that the structure of ammocidin A bears a resemblance to apoptolidin A,3 a macrolide of fully assigned stereochemistry.1b Among the common structural features shared by these polyketides are a central 20-membered macrolactone, a 28-carbon seco-acid incorporating a C21-C25 cyclic acetal ( Figure 1) and 6-deoxy glucose at C9. Based on comparison to apoptolidin A and analysis of nOe data, the stereochemistry of ammocidin A/D was tentatively assigned as shown in Figure 1.4 Given the significant antiproliferative properties of ammocidins A-D, we initiated a program directed toward the total synthesis of ammocidin D in order to assign the full structure and subsequently advance biological studies. Herein we describe synthetic and mechanistic studies leading to a stereocontolled assembly of the C16-C28 fragment of ammocidin D. When compared to the apoptolidins, a distinguishing structural feature of ammocidins A-D is incorporation of a tertiary alcohol at C24. The C24 hydroxyl group and substitution pattern of the pyran-acetal spanning the C21-C25 region suggested the synthetic strategy shown in Figure 2 beginning with a 5-exo opening of the neighboring methyl substituted epoxide by the C21 keto group (I).5 When accompanied by hydration, the 5-exo cyclization of I would afford furan acetal II that we anticipated would isomerize to the ammocidin pyran-acetal III.6Our first evaluation of this proposal examined cyclization of the epoxy alcohol derived from aldol adduct 2, the C20-C28 fragment of ammocidin D (Scheme 1). Oxazolidone 1 was obtained by an Evans asymmetric glycolate aldol starting from (E)-6-methoxy-2-methylhexenal, prepared in four steps from 4-methoxy methyl butanoate.7 Conversion of 1 to a Weinreb ami...