Faculty Bibliography

The development of new reactions that facilitate the creative and efficient synthesis of molecular structures with desirable properties continues to fascinate chemists. The test of a significant contribution is its acceptance over time by the scientific community. The B-alkyl Suzuki-Miyaura cross-coupling reaction appears to be one such reaction. Since its disclosure by Suzuki and Miyaura in 1986, this reaction has been an attractive solution to challenging synthetic problems.

This review covers recent developments in the area of morphine synthesis and biosynthesis. Literature is reviewed since the publication of the last major review. The first part of the chapter discusses recent advancements in biosynthesis of morphine alkaloids. Total syntheses published since 1996 are reviewed next and the third section discusses all published approaches to morphine skeleton. At the end of the of the chapter, an additional reference list is provided for synthesis of medicinally important derivatives, improvements in alkoloid interconversion, as well as a list of all dissertations dealing with morphine synthesis.

Although the marine alkaloids halichlorine (1) and the pinnaic acids 2, which contain a quinolizidine ring system, exhibit considerable structural homology, they act upon different biological targets (VCAM-1 and cPLA(2), respectively). Quinolizidines can exist as cisoid or transoid invertomers. In the recently reported total synthesis of (+)-halichlorine, it was determined by NMR that advanced intermediates 3 and 4, containing the spiroquinolizidine core, exhibit the transoid conformation, while the macrolactone-containing halichlorine has the cisoid conformation We conclude that constraints imposed upon closure of the macrolactone ring force adoption of the cisoid conformation The major conformational reorganization upon macrolactonization has implications for the design of pharmacophors and anticipated structure-activity relationships in their action on biological targets.

The diastereoselective addition of the highly functionalized organozinc compound 1 to the aldehyde 2 in the presence of the chiral amino alcohol 3 (-->4) is a key step in the first total synthesis of (+)-halichlorine. A series of protections/deprotections and a macrolaconization complete the synthesis. Halichlorine selectively inhibits the expression of the cell adhesion molecule VCAM-1. TBS=tert-butyldimethylsilyl.

The C1-C15 spiroquinolizidine subunit (cf. 2) of the marine natural product halichlorine (1) was prepared in 12 steps starting from the known 'Meyers-lactam' 5. The synthesis involves a B-alkyl-Suzuki coupling followed by a highly stereoselective intramolecular Michael addition and an intramolecular Mannich ring closure. (C) 1999 Elsevier Science Ltd. All rights reserved.

The hydrophenanthrenone approach to the synthesis of morphinane alkaloids such as (-)-dihydrocodeinone (16) is described, Optical activity is achieved by chiral resolution of the hydrophenanthrenone derivative 6 on cellulose triacetate. Key steps of the thirteen-step synthesis are the conjugate addition of vinyl cuprate to 6, which generates the crucial benzylic quaternary center and the demethylative cycloetherification step that transforms bromoketone 8 into morphinane 9. Chirality 11: 475-482, 1999. (C) 1999 Wiley-Liss, Inc.

A concise, linear, total synthesis of (-)-dihydrocodeinone-a close synthetic precursor of (-)-codeine and (-)-morphine-has been achieved. The carbocyclic core of the alkaloid was provided in the form of a phenanthrenone, which was resolved by chromatography on cellulose triacetate. A cuprate conjugate addition was used to establish the crucial benzylic quaternary stereocenter and to introduce the C(2)-side chain. Dimeric byproducts provide evidence for a single electron transfer (SET) mechanism. Unusual S(N)2 and radical cyclizations were employed for the formation of the dihydrobenzofuran and the piperidine ring, respectively.