Structure and Absolute Configuration of Ginkgolide B Characterized by IR- and VCD Spectroscopy NIELS H. ANDERSEN, 1 NIELS JOHAN CHRISTENSEN, 2 PETER R. LASSEN, 1 TERESA B.N. FREEDMAN, 3 LAURENCE A. NAFIE, 3 KRISTIAN STRØMGAARD, 4 AND LARS HEMMINGSEN 5 * 1 Department of Physics, Quantum Protein Center (QuP), Technical University of Denmark, Kgs. Lyngby, Denmark 2 Department of Food Science, Quality and Technology, Faculty of Life Sciences, University of Copenhagen, Frederiksberg, Denmark 3 Department of Chemistry, Syracuse University, New York 4 Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark 5 Department of Basic Sciences and Environment, Faculty of Life Sciences, University of Copenhagen, Frederiksberg, Denmark ABSTRACT Experimental and calculated (B3LYP/6-31G(d)) vibrational circular dichroism (VCD) and IR spectra are compared, illustrating that the structure and abso- lute configuration of ginkgolide B (GB) may be characterized directly in solution. A con- formational search for GB using MacroModel and subsequent DFT optimizations (B3LYP/6-31G(d)) provides a structure for the lowest energy conformer which agrees well with the structure determined by X-ray diffraction. In addition, a conformer at an energy of 7 kJ mol 21 (B3LYP/6-3111G(2d,2p)) with respect to the lowest energy con- former is predicted, displaying different intramolecular hydrogen bonding. Differences between measured and calculated IR and VCD spectra for GB at certain wavenumbers are rationalized in terms of interactions with solvent, intermolecular GB-GB interactions, and the potential presence of more than one conformer. This is the first detailed investi- gation of the spectroscopic fingerprint region (85021300 cm 21 ) of the natural product GB employing infrared absorption and VCD spectroscopy. Chirality 22:217–223, 2010. V V C 2009 Wiley-Liss, Inc. KEY WORDS: ginkgolides; vibrational circular dichroism; DFT calculations; conformational analysis; fingerprint region INTRODUCTION The interest in the medical effects of the Ginkgo tree has persisted since ancient time in Eastern Asia. A stand- ardized extract from the Ginkgo tree (Egb761) contains ginkgolides GA, GB, GC, GJ, and GM. It appears that GM is only found in the root bark and GJ only in the leaves whereas the other ginkgolides can be isolated from all parts of the tree. 1 The ginkgo tree itself is remarkable in being a specimen that has survived since the Jurassic era. 1,2 In 1932 ginkgolides were discovered as the bitter chemicals produced by Ginkgo biloba, and later structure elucidation revealed that these compounds are complex terpene trilactones. Discovery of their ability to interact with the platelet activating factor (PAF) receptor in 1985 markedly increased the attention on ginkgolides. Among the ginkgolides, ginkgolide B (GB) is found to be the most potent PAF receptor antagonist. 1 Recently, a new tar- get for ginkgolides was discovered, as it was found that they bind to and block glycine receptors in the brain. 3,4 The overall IR spectral features of ginkgolides comprise characteristics of alcohols, ethers, esters and aliphatic hydrocarbons, which are all strongly entangled due to sharing of many atoms in the ring, see Figure 1. 5 The fingerprint spectral region (850–1300 cm 21 ) is therefore highly complex, and many spectral bands should rather be assigned to the vibrational character of the whole molecular frame than to specific groups. Addition or removal of OHÀÀ than to specific groups or inversions of chiral centers are therefore expected to have a consider- able effect on both IR and vibrational circular dichroism (VCD) spectra. The number of chiral centers for GA, GB, GC, GJ, and GM are 10, 11, 12, 11, and 12, respectively. However, three of these (C 4 ,C 5 , and C 9 ) cannot contribute to the number of possible diastereomers without rupture of the 5-ring structure, and four (C 2 ,C 3 ,C 6 , and C 12 ) will severely alter the overall shape of the molecular frame. Inversion of C 8 or C 14 implies change of the t-butyl or methyl group orientation. Thus, we have limited our inves- tigations of GB only to include diastereomers with inver- sions at C 1 and C 10 (denoted GB-C 1 i and GB-C 10 i, respec- tively). These isomers are relevant for total synthesis of *Correspondence to: Lars Hemmingsen, Department of Basic Sciences and Environment (IGM), Faculty of Life Sciences, University of Copenha- gen, Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark. E-mail: lhe@life.ku.dk Additional Supporting Information may be found in the online version of this article. Contract grant sponsor: The Lundbeck Foundation Received for publication 27 November 2008; Accepted 25 February 2009 DOI: 10.1002/chir.20730 Published online 19 May 2009 in Wiley InterScience (www.interscience.wiley.com). CHIRALITY 22:217–223 (2010) V V C 2009 Wiley-Liss, Inc.