Confirmation of the Stereostructure of (+)‐Cytostatin by Fluorous Mixture Synthesis of Four Candidate Stereoisomers

Abstract

Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthdayCytostatin (1) is a potent and selective inhibitor of protein phosphatase 2A that was isolated from the cultured broth of Streptomyces sp. by Ishizuka and co-workers (Scheme 1).[1] It inhibits lung metastasis of melanoma cells in mice and displays potent cytotoxic activity toward leukemia cell lines (inhibitory concentration; IC 50 = 42-65 nm). Ishizuka and coworkers assigned the two-dimensional structure (constitution) of cytostatin (1) by analysis of 1D and 2D NMR spectra. The relative configurations of C4-C6 and C9-C11 of cytostatin were assigned as syn at C4/C5 and C9/C10 and as anti at C5/C6 and C10/C11 by the research groups of Waldmann and Boger by comparison of key features of the 1 H NMR spectra of cytostatin with those of relevant models. [2,3] This approach lowered the number of structure candidates down to four, namely: 1 ss, 1 rs, 1 sr, and 1 rr.[4]Based on an analogy to fostriecin 2 [5] and related compounds (which share three stereocenters with 1), the research groups of Waldmann and Boger independently synthesized (4S,5S,6S,9S,10S,11S)-1 (hereafter called 1 ss), and concluded, by comparison of spectroscopic, physical, and biological properties, that this was the natural product.We have recently commented on the logic of proof and disproof of stereostructures by comparison of synthetic and natural samples.[6] If two or more stereoisomers of a natural product can reasonably be expected to have substantially identical spectra, then a rigorous assignment of the structure should include proof that the candidate isomer matches the natural product and, more importantly, proof that the other isomers do not. Acetogenins, such as the murisolins have very remote groups of stereocenters (10 or more methylene groups apart), so it can be expected that diastereomers might exhibit substantially identical spectra.[6] In contrast, the two groups of stereocenters in cytostatin (1) are only insulated by an ethylene group. Will enantiomers 1 ss and 1 rr have different spectra from their diastereomers 1 rs and 1 sr? To answer this question, and thereby to prove which three isomers were not cytostatin, we undertook the fluorous mixture synthesis [7,8] of all four isomers of 1.The fluorous mixture synthesis (FMS) strategy to make the four isomers of cytostatin is briefly outlined in Scheme 2. Late introduction of the triene is dictated by its chemical instability, so we followed the strategy of Bialy and Waldmann [2d] by planning to prepare four individual vinyl iodides 3 by coupling with alkenyl stannane 4.These four isomers are made over several steps from a single four-compound mixture of fluorous-tagged quasiisomers M-5 [9] ("quasi" because the compounds have different fluorous tags and are not true isomers [10] ). In turn, M-5 is made by coupling between fluorous-tagged quasiracemic aldehydes M-6 with quasiracemic keto phosphonates M-7 by a Horner-Wadsworth-Emmons (HWE) reaction.From the FMS standpoint, the configurations of the stereocenters ...

Bare-Minimum Fluorous Mixture Synthesis of a Stereoisomer Library of 4,8,12-Trimethylnonadecanols and Predictions of NMR Spectra of Saturated Oligoisoprenoid Stereoisomers

“…2 Recent work has had a dual focus of introducing more efficient tagging strategies and solving structure problems by characterizing the natural product stereoisomer library members. 3 For example, we introduced a new double-tagging method to make macrosphelide stereoisomers that allows more compounds to be tagged with fewer fluorine atoms compared to prior tagging schemes. 4 And by characterizing the library members, we confirmed the structures of macrosphelides E and M and corrected the structure of macrosphelide D.…”

Structure-Activity Relationship Studies of Fostriecin, Cytostatin, and Key Analogs, with PP1, PP2A, PP5, and (β12–β13)-Chimeras (PP1/PP2A and PP5/PP2A), Provide Further Insight into the Inhibitory Actions of Fostriecin Family Inhibitors

“…Following the first total synthesis of fostriecin (Boger et al, 2001), at least nine total or formal syntheses have been reported (Chavez and Jacobsen, 2001;Esumi et al, 2002;Reddy and Falck, 2002;Miyashita et al, 2003;Maki et al, 2005;Trost et al, 2005). The total synthesis of cytostatin (Bialy and Waldmann, 2004;Lawhorn et al, 2006;Jung et al, 2008) and cytostatin analogs (Lawhorn et al, 2006;Jung et al, 2008) have also been reported. These studies have sparked renewed interest in the potential for development of more stable derivatives that may have utility as novel antitumor drugs.…”

Hypervalent iodine reagents in the total synthesis of natural products

“…77,78 The oxidation of a complex substrate bearing a primary alcohol has been described by Hirama and co-workers (Scheme 5). ROMPM, 114,115,118,183 ROBn, 80,90,104,106,110,124,191,192 ROTr, 180 ROMe, 94,101,107,113,192 RONPhth, 88 RON=CMe 2 , 88 ArOAllyl, 193 ArOMe, 108,130,131,192,194,195 ArOBn, 127,131 ArOTBS, 174 R 2 NBoc, 174,[194][195][196][197] 208 This IBX analogue generates only water during the oxidation, while DMP releases acetic acid. When DMP was applied the required keto ester was obtained in only 60%, with 40% of the starting lactone recovered (Scheme 6).…”