Natural Products Synthesis DOI: 10.1002/anie.200700321 Synthesis and Stereochemical Assignment of FR252921, a Promising Immunosuppressant** J. Russell Falck,* Anyu He, Hiroki Fukui, Hideyuki Tsutsui, and Akella Radha Dedicated to Professor Koichi Narasaka FR252921, an unusual 19-membered lactone– dilactam distinguished by a lipophilic C 12 appendage, was isolated from the culture broth of Pseudomonas fluorescens by Fujine et al., who published its structure without characterization of its three stereogenic cen- ters. [1] Interest in FR252921 from this [2] and other [3,4] laboratories stems in large part from its unique pharmacological profile. In contrast with other immunosuppressants, FR252921 potently inhibits both lipopolysaccharide- (LPS)-stimulated and anti-CD3 mAb-stimu- lated splenocyte proliferation in vitro without blocking T-cell activation. [5] It also decreases transcription regulated by activating protein 1 (AP-1) despite a null effect on the transcription factors NF-AT and NF-kB. Notably, FR252921 synergizes strongly the effects of FK506 in vitro and in vivo. [6] To expedite current studies into the site of action of FR252921 and conclude the complete assignment of its structure, we describe herein the asymmetric total synthesis of FR252921 and three diastereomers by a versatile, convergent strategy. Retrosynthetic analysis dissected FR252921 into segments A–C (Scheme 1), which were chosen to provide convenient access to the minimum stereoarray [7] needed to establish the relative and absolute configuration of the natural product as well as to support future structure–activity-relationship studies. [8,9] The segments would be assembled by following a sequence C !BC !ABC, which postponed the macrolacto- nization of the labile C18 OH group to the final stages of the synthesis to minimize opportunities for b elimination. The route to both enantiomers of segment A (Scheme 2) commenced with (E)-2-decenal (1), which was homologated with commercial ethyl 2-(diethylphosphono)propionate to give a chromatographically separable 12:1 mixture of the 2E,4E diene ester 2 and its 2Z,4E isomer. A routine reduc- tion–oxidation sequence from 2 with DIBAL-H and MnO 2 led to alcohol 3 and then dienal 4 [10] in excellent overall yield. Alternatively, 4 could be obtained in a single step by the CrCl 2 -induced condensation of 1 with 2,2-dichloropropanal (OMM Scientific). [11] The samarium-mediated Reformatsky addition of (S)-4-benzyl-3-(2-bromoacetyl)oxazolidin-2- one [12] (9) to 4 at low temperature produced predominately the 3R alcohol 5 (81%), which was hydrolyzed smoothly to the free acid 7. Hydrolysis of the minor 3S diastereomer 6, isolated in 10% yield, gave 8. Segment B (Scheme 3) was quickly stitched together by hydrozirconation of homopropargyl tosylate [13] (10) and cross-coupling with the E vinylzirconocene derived from (E)-3-(tert-butyldimethylsilyloxy)-1-iodopropene [14] (14) at room temperature in the presence of Pd(OAc) 2 and 2’-(dicyclohexylphosphanyl)-N,N-dimethyl-(1,1’-biphenyl)-2- amine [15] (DPBA). The resulting E,E diene 11, which was Scheme 1. Retrosynthetic analysis of FR252921. Scheme 2. Synthesis of carboxylic acids 7 and 8 : a) (EtO) 2 P(O)CH- (CH 3 )CO 2 Et, NaH, THF, 0 8C,2h,92%(Z,E/E,E 1:12); b) DIBAL-H, CH 2 Cl 2 ,0 8C, 20 min; c) MnO 2 /MgSO 4 , CH 2 Cl 2 , 23 8C, 2 days, 93% for two steps; d) H 3 CCCl 2 CHO, CrCl 2 , BF 3 ·Et 2 O, THF/DMF (2:1), 23 8C, 14h,74%(Z,E/E,E 1:10); e) 9, SmI 2 , THF, 86 8C,14h,91% combined; f) LiOH, H 2 O 2 , THF/H 2 O, 4 8C, 2.5 h, 97%. DIBAL-H = di- isobutylaluminum hydride, DMF = N,N-dimethylformamide. [*] Prof. J. R. Falck, Dr. A. He, Dr. H. Fukui, Dr. H. Tsutsui, Dr. A. Radha Departments of Biochemistry and Pharmacology University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas, TX 75390-9038 (USA) Fax: (+ 1)214-648-6455 E-mail: j.falck@utsouthwestern.edu [**] Dr. NoriakiInamura (Astellas Pharma, Inc.) and Dr. Kiyotaka Fujine (Fujisawa Pharmaceutical, Inc.) graciously provided a sample of the natural material and spectra. We thank Dr. ThomasG. LaCour and Dr. Suju Joseph for preliminary experiments. We are grateful for financial support from the Robert A. Welch Foundation and NIH (GM31278, DK38226). Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 4527 Angew. Chem. Int. Ed. 2007, 46, 4527 –4529 # 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim