Total synthesis of the natural (-)-205B alkaloid and its activity toward α7 nAChRs.

A new approach to the synthesis of the (-)-205B alkaloid is described in this paper. This work is characterised by the development of an efficient chirality transfer through a silyl tethered intramolecular alkylation reaction, an unprecedented tandem highly selective iridium catalyzed partial reduction of lactam coupled with an acid promoted aza-Prins reaction, and an almost complete stereochemical control in Shenvi's radical hydrogen atom transfer on an exocyclic methylene. The second part of this work demonstrates the positive allosteric behavior of this natural alkaloid toward α7 nAChRs, in contrast to the reported inhibitory effect of the unnatural enantiomer.

Diverse Natural Products from Dichlorocyclobutanones: An Evolutionary Tale.

11-Nor PGE2 was prepared in our laboratory several years ago and used to obtain the corresponding ring-expanded γ-butyrolactam, γ-butyrolactone, and cyclopentanone derivatives. The conversion of a cyclobutanone into a cyclopentanone had relatively little precedent and merited further study. It was soon found that the presence of a single chlorine adjacent to the carbonyl not only greatly accelerated the reaction with ethereal diazomethane, but also substantially enhanced its regioselectivity; not surprisingly, a second chlorine further increased both. The confluence of this finding and the discovery by Krepski and Hassner that the presence of phosphorus oxychloride significantly improved the Zn-mediated dehalogenation procedure for the preparation of α,α-dichlorocyclobutanones from olefins provided the starting point for decades' worth of exciting adventures in natural product synthesis. A wide variety of naturally occurring 5-membered carbocycles (e.g., hirsutanes, cuparenones, bakkanes, guaianolides, azulenes) could thus be prepared by using dichloroketene-olefin cycloaddition, followed by regioselective one-carbon ring expansion with diazomethane. Importantly, it was also found that natural γ-butyrolactones (e.g., ß-oxygenated γ-butyrolactones, lactone fatty acids) could be secured through regioselective Baeyer-Villiger oxidation of cycloadducts with m-CPBA and that naturally occurring γ-butyrolactam derivatives (e.g., amino acids, pyrrolidines, pyrrolizidines, indolizidines) could be efficiently obtained by regioselective Beckmann ring expansion of the adducts with O-(mesitylenesulfonyl)hydroxylamine (Tamura's reagent). These 5-membered carbocycles, γ-butyrolactones, and γ-butyrolactam derivatives were generally secured in enantiopure form through the use of either intrinsically chiral olefins or olefins bearing Stericol, a highly effective chiral auxiliary developed specifically for this "three-atom olefin annelation" approach. In addition, considerable useful chemistry has been developed in the context of this synthesis program. This includes new methods for olefin vicinal dicarboxylation, ß-methylene-γ-butyrolactonization, γ-butyrolactone and δ-valerolactone α-methylenations, transesterification, angelic ester synthesis, chiral enol and ynol ether preparations, dichloroacetylene synthesis, and trans, trans hydroxy triad introduction. This versatile dichlorocyclobutanone-centered approach to natural product synthesis, together with the attendant new methods that have been developed, forms the basis of this Account, which is presented as an evolutionary tale. It is hoped that the Account will stimulate other research groups to seek to exploit the rich chemistry of dichlorocyclobutanones for possible solutions to problems in organic synthesis.

A new approach to the 8b-azaacenaphthylene ring system.

A stereoselective approach to the 8b-azaacenaphthylene ring system is described. This new route features a dichloroketene-enol ether [2 + 2] cycloaddition, a vinylogous Mannich reaction, and an aza-Prins cyclization as key stereoselective transformations.

Asymmetric approach to hyacinthacines B1 and B2.

Naturally occurring hyacinthacines B1 and B2 have been prepared from a common, easily available, advanced intermediate. The approach features several highly stereoselective transformations: inter alia, a dichloroketene-enol ether [2 + 2] cycloaddition, a Bruylants alkylation, and an amino-nitrile alkylation-reduction.

Dichloroketene-chiral olefin-based approach to pyrrolizidines: highly stereocontrolled synthesis of (+)-amphorogynine A.

[reaction: see text] A highly stereoselective route to (+)-amphorogynine A, a novel pyrrolizidine recently isolated from the New Caledonian plant Amphorogynine spicata, has been realized. The key step in the approach is a diastereoselective [2 + 2] dichloroketene-chiral enol ether cycloaddition (dr >or= 93:7) to access a dichlorocyclobutanone intermediate, which is converted into the alkaloid natural product via a pyrrolidinone derivative.

Approach to the hyacinthacines: first non-chiral pool synthesis of (+)-hyacinthacine A1.

The first non-chiral pool total synthesis of (+)-hyacinthacine A(1) is described. This synthesis is based on an effective [2 + 2] cycloaddition of dichloroketene to a Stericol-based enol ether, a diastereoselective dihydroxylation, and an efficient Tamao-Fleming oxidation.

1-(2,4,6-triisopropylphenyl)ethylamine: a new chiral auxiliary for the asymmetric synthesis of gamma-amino acid derivatives.

The title compound has proven to be an excellent chiral auxiliary for nitrones in SmI2-mediated reductive coupling with alpha,beta-unsaturated esters. A variety of such nitrones, prepared from aldehydes and enantiopure N-hydroxy-1-(2,4,6-triisopropylphenyl)ethylamine, afforded gamma-N-hydroxyamino esters in high yields and diastereomeric purity. These adducts, readily available as either enantiomer, could be transformed into gamma-N-acetoxyamino esters, N-Boc-gamma-amino esters, and gamma-lactams.

New asymmetric approach to natural pyrrolizidines: synthesis of (+)-amphorogynine A, (+)-amphorogynine D, and (+)-retronecine.

Three natural pyrrolizidines, (+)-amphorogynines A and D and (+)-retronecine, have been prepared from a common lactam intermediate. This central compound, in turn, was synthesized in diastereomerically enriched form through a highly selective [2 + 2]-cycloaddition of dichloroketene with a chiral enol ether, followed by Beckmann ring expansion and reduction. Subsequent stereocenters were then cleanly introduced through internal induction.