Total Synthesis and Proof of Stereochemistry of Natural and Unnatural Pinnaic Acids: A Remarkable Long-Range Stereochemical Effect in the Reduction of 17-Oxo Precursors of the Pinnaic Acids This work was supported by the National Institutes of Health (Grant Numbers: CA28824). Postdoctoral Fellowship support is gratefully acknowledged by M.W.C. (U.S. Army BCRP, DAMD17-98-1-8154). We thank Dr. George Sukenick of the MSKCC NMR Core Facility for NMR and mass spectral analyses. We would like to thank professor
Abstract:Build ‘em up and knock ‘em down: natural pinnaic acid and three of its stereoisomers were synthesized from the aldehydes described in the preceding communication. A key step in the synthesis of natural pinnaic acid was a highly stereoselective reduction of ketone 1. The stereochemistry was determined by means of degradation studies of the synthetic material; TBS=tert‐butyldimethylsilyl.
“…The compound was converted into its sodium carboxylate. The zwitterionic and sodium salt forms had very similar 1 H NMR spectra to those obtained with natural material; consequently, this synthesis confirms the stereochemical assignment made by the Danishefsky group. , 19 20 …”
Section: 2 Synthesis Of (±)-Pinnaic Acid By a Methods That Merges Wit...supporting
confidence: 75%
“…Olefination of 8.6 with 66.8 (Scheme ) again gave rise to a mixture of the desired product ( 11.1 ) and starting aldehyde, and as before, reduction afforded a separable mixture . This sequence gave alcohols 11.2 [a 1.7:1 ratio of C(17) epimers] together with the alcohol derived from 8.6 .…”
Section: 2 First Total Synthesis Of Pinnaic Acid and
Assignment Of C(...mentioning
confidence: 79%
“…Once again, the amine cyclized by Michael addition in the presence of DBU and the product ( 8.5 ) was elaborated into 8.6 , so that at this stage both the 14- R ( 7.7 ) and 14- S ( 8.6 ) aldehydes were at hand. The 14- R isomer was elaborated first (Scheme ) 9 …”
Section: 2 First Total Synthesis Of Pinnaic Acid and
Assignment Of C(...mentioning
“…The compound was converted into its sodium carboxylate. The zwitterionic and sodium salt forms had very similar 1 H NMR spectra to those obtained with natural material; consequently, this synthesis confirms the stereochemical assignment made by the Danishefsky group. , 19 20 …”
Section: 2 Synthesis Of (±)-Pinnaic Acid By a Methods That Merges Wit...supporting
confidence: 75%
“…Olefination of 8.6 with 66.8 (Scheme ) again gave rise to a mixture of the desired product ( 11.1 ) and starting aldehyde, and as before, reduction afforded a separable mixture . This sequence gave alcohols 11.2 [a 1.7:1 ratio of C(17) epimers] together with the alcohol derived from 8.6 .…”
Section: 2 First Total Synthesis Of Pinnaic Acid and
Assignment Of C(...mentioning
confidence: 79%
“…Once again, the amine cyclized by Michael addition in the presence of DBU and the product ( 8.5 ) was elaborated into 8.6 , so that at this stage both the 14- R ( 7.7 ) and 14- S ( 8.6 ) aldehydes were at hand. The 14- R isomer was elaborated first (Scheme ) 9 …”
Section: 2 First Total Synthesis Of Pinnaic Acid and
Assignment Of C(...mentioning
“…Danishefsky and Trauner were the rst to report the synthesis of (+)-halichlorine in 1999 309 followed by a synthesis of pinnaic acid in 2001 (Scheme 48). 310,311 They used Meyers' lactam 217 as a chiral precursor, which was combined with allyltrimethylsilane in a Sakurai reaction to install the ATA in 218. Intermediate 219 could be diversied to reach both halichlorine and pinnaic acid.…”
Section: Indolizidine and Quinolizidine Alkaloidsmentioning
Alkaloids account for some of the most beautiful and biologically active natural products. Although they are usually classified along biosynthetic criteria, they can also be categorized according to certain structural motifs. Amongst these, the α-tertiary amine (ATA), i.e. a tetrasubstituted carbon atom surrounded by three carbons and one nitrogen, is particularly interesting. A limited number of methods have been described to access this functional group and fewer still are commonly used in synthesis. Herein, we review some approaches to asymmetrically access ATAs and provide an overview of alkaloid total syntheses where those have been employed.
“…Spirocyclic amines are present in several natural products, such as pinnaic acid and halichlorine, and the lepadiformines and cylindricines . Spirocycles are desirable scaffolds for drug discovery due to their 3D conformational structures and rigidity that reduces the loss of entropy upon ligand–protein binding .…”
Aliphatic ketones containing a chloride and alkene were heated with hydroxylamine to promote cascade, tandem condensation to oximes, cyclization to nitrones, and 1,3-dipolar cycloaddition to tricyclic isoxazolidines as single stereoisomers. Single regioisomers were obtained when three atoms linked the ketone and dipolarophile to give five-membered rings but mixtures resulted with four atoms in the tether unless a terminal ester was located on the alkene. The N-O bond in the products could be reduced to give spirocyclic amines and diamines.
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