Chelation-controlled facially selective cyclocondensation reactions of chiral alkoxy aldehydes: syntheses of a mouse androgen and of a carbon-linked disaccharide

Abstract

Magnesium bromide in tetrahydrofuran catalyzes the cycloaddition of a variety of chiral alkoxy aldehydes with activated butadienes. The stereochemistry of these products is such that they can be rationalized as arising from a reacting conformer in which the alkoxy group is syn to the carbonyl function. The C=0 bond is attacked from its less hindered face.That chelation of the magnesium is involved in these reactions is indicated by a striking change from endo to exo topology as alkoxy functionality is introduced on the aldehyde. Titanium tetrachloride catalysis also provides excellent chelation-control stereoselectivity. The application of these findings to the synthesis of bridged ketals including the mouse androgen dehydrobrevicomin is described. Another application allows for the synthesis of carbon-linked disaccharides. BackgroundThe issue of diastereotopic preferences in the reactions of carbon nucleophiles with aldehydes or ketones has provoked considerable research1 and interpretation.2-6 Of course, nucleophilic addition to carbonyl groups is a central reaction type in organic chemistry.Thus, an insight into the relationship of chirality generated through such additions, with preexisting dissymmetry, is crucial to achieving stereochemical control in synthesis.

Pre-mRNA Splicing-Modulatory Pharmacophores: The Total Synthesis of Herboxidiene, a Pladienolide–Herboxidiene Hybrid Analog and Related Derivatives

“…43 The MgBr 2 mediated inverse electron-demand Diels-Alder reaction of diene 8a or 8b and ( S )-2-(benzyloxy)propanal ( 7 ) then provided dihydropyranones 9a and 9b as single diastereomers. 42 The reduction of the ketone moiety was achieved under Luche conditions to selectively provide the alcohols 10a and 10b .…”

Experiments Directed Towards the Synthesis of Anthracyclinones. XXXIV Hetero-Diels - Alder Reactions Using Chiral Boron and Titanium Reagents

“…protocols to establish the enantiopurity of this compound. Togni 2 has obtained the same dihydropyrone (22) in 18% e.e. in favour of the (R)-(-) enantiomer from the (+)-VO(hfc) 2 catalysed hetero-Diels-Alder reaction of benzaldehyde and (12) but did not report the magnitude of the specific rotation.…”

“…The dihydropyrone (22) had a specific rotation of -52.2°r evealing that the reaction proceeded with some degree of enantioselection. However, the lack of a methoxy group on (22) precluded use of the usual chiral solvating agent-1 H n.m.r. protocols to establish the enantiopurity of this compound.…”

“…The use of chiral titanium complexes to catalyse or promote hetero-Diels-Alder reactions between aldehydes and silyloxy dienes has received little attention, despite the pioneering work of Danishefsky,22,23 which showed that simple titanium Lewis acids such as titanium(IV) chloride are efficient catalysts of such reactions. Two reports have appeared which suggest that chiral titanium(IV) complexes have potential for the catalysis of enantioselective hetero-Diels-Alder reactions.…”

Titanocene-Catalyzed Pinacol Couplings: Reagent-ControlledTransition-Metal-Catalyzed Radical Reactions

“…Homogeneous solutions of the salt could only be obtained when about 10% of benzene was added to the mixture. [13] Otherwise phase separation was observed. In this manner 2.5Ϫ3.0  solutions of magnesium bromide in diethyl ether could be readily obtained.…”