On the Conformations of Halichlorine and the Pinnaic Acids: Nitrogen Inversion as a Possible Determinant of Biological Profile

Abstract

Dedicated to Professor Albert Eschenmoser on the occasion of his 75th birthday 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.Halichlorine (1) [1] and the pinnaic acids (2a, 2b) [2], marine alkaloids recently isolated by Uemura and co-workers, exhibit considerable structural homology. Halichlorine was found to selectively inhibit the induced expression of VCAM-1 (Vascular Cell Adhesion Molecule-1) [3]. By contrast, pinnaic acid and tauropinnaic acid were identified in an assay aimed at the identification of specific inhibitors of cytosolic phospholipase A 2 (cPLA 2 ). Since both VCAM-1 and cPLA 2 play key roles in the inflammatory cascade, such agents might be useful in the discovery and development of novel drugs against various diseases, including autoimmunity disorders and cancer. The value of such compounds as leads could be much enhanced through a clearer understanding of their solution conformations. In the course of our recent total synthesis of ()-halichlorine [4], we came upon several interesting findings in this regard. We noticed that crucial NMR-spectral features of a series of advanced intermediates incorporating the spiroquinolizidine framework (3a ± 3e, 4a ± 4b) bore little resemblance to those of halichlorine itself. In particular, the chemical shifts and the coupling patterns observed for the bridgehead H-atoms at C(5) (e.g., for compound 3a: d 2.37 ppm, dddd, J 3.6, 3.8, 10.5, 11.3 Hz) clearly differ from the corresponding ones found in halichlorine (d 3.18 ppm, dddd, J 1.5, 2.0, 6.5, 13.0 Hz) [1]. Since extensive NMR studies and an X-ray crystal structure of a subsequent derivative (vide infra) allowed us to unambiguously assign the configuration of our intermediate spiroquinolizidines 3 ± 4, a rationale for these strikingly different spectroscopic features was sought.Quinolizidines can exist as cisoid or transoid invertomers [5]. We propose that halichlorine adopts a cisoid conformation (see 5). This perception is at some variance

Total synthesis of (±)-halichlorine, (±)-pinnaic acid, and (±)-tauropinnaic acid

“…3 shows the crystal structure of (Ϯ)-halichlorine. The crystal structure demonstrates the cis ring fusion in the dehydroquinolizidine system, which was predicted by Trauner et al (46).…”

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

“…This set of preferences coincides, in the case of 6 , with an anti relationship of the hydrogen atoms at C13 and C14. Such an anti preference of the corresponding hydrogens is seen in the one known X‐ray crystal structure, currently available, of a seco ‐halichlorine 4c. The synergy of these conformational preferences is suggested by the MM2 model depicted in Figure 1.…”

Concise Stereoselective Routes to Advanced Intermediates Related to Natural and Unnatural Pinnaic Acid

“…Thus, pinnaic acid inhibits cPLA 2 in vitro (IC 50 0.2 mm) whereas halichlorine is a vascular cell-adhesion molecule-1 (VCAM-1) antagonist. [9] To further our program, which seeks to gain access to natural product inspired non-steroidal privileged structures of potential interest with respect to inflammation, we embarked on the total synthesis of pinnaic acid (see 1). Not surprisingly, these compounds have garnered much attention from the synthetic community.…”