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J. Am . Chem. SOC.1993,115, 4 1 9 - 4 4 2 0 4419

Total Synthesis o RapamycinK. C . Nicolaou, T. K. Chakraborty,+A. D . Piscopio,*N. Minowa,f and P. Bertinato

Departments of ChemistryUniversity of California San Diego9500 Gilman DriveLa Jolla California 92093The Scripps Research Institute10666 North Torrey Pines RoadLa Jolla California 92037Received February 1 I993

Rapamycin (1) lJ is a novel, naturally occurring substance,with poten t antibiotic, cytotoxic, and imm unosuppressive activity.Isolated from Streptomyces hygroscopicus found in an EasterIsland soil sample, this synthetically challenging molecule iscurrently under intense investigation as a rival to the immuno-suppressive agents FK506 and c yc lo~ po rin .~ erein we reportthe first total synthesis of rapamycin 1) in its naturally o ccurringenantiomeric forms4Rapamycin 1) with its 31-membered ring, plethora ofasymmetric a nd geometrical centers, and sensitive functionalitypresents to thesynthe ticchemist a formidab lechallenge . A ratherdaring approac h o this target is outlined in Scheme I. Accordingto this strategy, rapamycin 1) was to be constructed by a singleoperation from a fully functionalized acyclic precursor 2), viaa stitching-cyclization process tha t would bring in the twomissing carbons as th e central olefinic unit (C1 942 0)of the trienemoiety. The bridging unit, enedistannane 3,5 was expected tobring together the two termin al vinyl iodides of precursor 2 in aS t i l l e - t~pe6.~oupling-cyclization reaction to furnish the natur alproduc t in a single step. Suc h a stra teg y would ensure a directapproach to 1an d avoid instability problems, depro tection steps,and late stage oxidation state adjustments. Precursor 2 wasexpected to be derived from advanced key intermediates 4 and

5 (Scheme I).Coupling of advanced intermediates 48 and 59 n th e presenceof 1 hydroxybenzotriazolean d diisopropylcarbodiimide proceededHyderabad, India, 1992-1993.ng Scientist from the Indian Institute of Chemical Technology,NIH Fellow 1990-1992. Present address: Pfizer Co., Groton, CT.Visiting Scientist from Meiji Seika Kaisha, LTD., Japan, 1991-1993.1) Isolation: Vtzina, C.; Kudelski, A.; Sehgal, S.N . J Anribiot. 1975,28, 721; Sehgal, S. N.; Baker, H.; Vtzina, C. J Anribiot. 1975, 28, 727.2) Structure: Swindells, D. C. N.; White, P. S.; Findlay, J. A. Can. JChem. 1978, 56 2491. Findlay, J. A ; Radics, L. Can. J Chem. 1980, 58579.3) Schreiber,S. . Chem. Eng. News 1992,70 (Oct. 26), 22. Rosen, M.K.; Schreiber, S.L. Angew. Chem. Int . Ed. Engl. 1992, 31, 384.4) Previous synthetic studies on rapamycin: Yohannes, D.; Danishefsky,S. J . TefruhedronLerr. 1992,33,7469. Fisher, M. J.; Myers, C. D.; Joglar,J.; Ch en, S.-H.; Danishefsky, S . J . J Org. Chem. 1991, 56 5826. Chen,S.-H.; Horvath, R. F.; Joglar, J ; Fisher, M. J.; Danishefsky, S. . J Urg.Chem. 1991, 56 5834. Hale, M. R.; Hoveyda, A. H. J Org. Chem. 1992,57 1643. Meyers, S.D.; Miwa, T.; Nakatsuka, M.; Schreiber, S . L. J . Org.Chem. 1992, 57, 5058. Romo, D.; Johnson, D. D.; Plamonodon, L.; Miwa,T.; Schreiber, S. L. J Org. Chem. 1992, 57, 5060.5) Corey, E. J.; Wollenberg, R. H . J Am . Chem. SOC 974, 96 5581.6) Stille, J. K.; Groh, B. L. J Am . Chem. SOC.1987, 109 813. For areview, see: Mitchell, T. N . Synthesis 1992, 803.7) For some recent applicationsof theStillecouplingusingenedistannaneJand the corresponding butadienediyldistannane, ee: Barrett, A . G. M.;Edmunds, J. J.; Horita, K .; Parkinson, C. J. J Chem.Soc. Chem. Commun.1992, 1236. Barrett, A . G. M.; Edmunds, J. J.; Hendrix, J. A.; Horita, K .;Parkinson, C. J. J Chem. SOC. hem. Commun. 1992, 1238. Kiehl, A.;Eber hard t, A.; Adam, M.; En kelmann, V.; Mlillen, K. Angew. Chem . nr.E d.Engl. 1992, 31, 1588.8) Piscopio, A. D.; Minowa, N.;Cha kra bor ty, T. K.; Koide, K.; Bertinato,P.; Nicolaou, K. C. J . Chem. SOC. hem. Commun. 1993, 617.9) Nicolaou. K. C.; Bertinato, P.; Piscopio, A. D.; Chakraborty, T. K.;Minowa, N. J Chem. SOC. hem. Commun. 1993,619.

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Scheme I. Retrosynthetic Analysis of Rapamycin 1)m e

1

2

Me Me OHI / 8 OH

8

4

5a TI PS triisopropylsilyl; TE S triethylsilyl; TBD PS rerr-butyldiphenylsilyl.

smoothly to afford the amid e 6 in 95% yield (Sch eme 11). Swernoxidation of dihydroxy amide 6 fforded the pale yellow diketoamide 7 in high yield. This compound was then subjected toselective desilylation with HF-pyr leading to the correspondingdiol intermediate. A second Swern oxidation furnishes thehexacarbonyl compound 8. Finally, removal of the remainingsilyl groups und er th e influence of aqueous HF in acetonitrile ledto the desired precursor, divinyl diiodide 2, in 70 overall yieldfrom compound 6.The crucial stitching of the long chain precursor 2 with themissing two-carbon o lefinic segmen t C19-c20) was accomplishedby utilizing vinylenedistannane 35 n the presence of Pd(CH3-CN)2C12 and Hunigs base in DM F/ TH F according to the Stillemethod6 (Scheme 11). Rapamycin 1) was obtained from thisreaction in 28% yield together with unreacted startin g material(ca. 30 ) and an iodo-stannane intermed iatelo (ca. 30% yield).1993 American Chemical Society

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4420 J . Am . Chem. SOC. Vol. 115 No. IO, 1993Scheme 11. Total Synthesis of R apamycin 1)

Communications to the Editor

QP *OTBDPS

Me OMe Me Me TES6

TIPSOa TIPSOMe

I

OTES ?TIPSe,...*OTBDPS

Me OMe Me Me TES7 8

a Reagent s and conditions: ( a) 4 2 equiv), 1-hydroxybenzotriazole (2 equiv), diisopropylcarbodiimide (2 equiv), CH2C12,O O C 0.5 h, and then 5(1 equiv), 0-25 O C 2 h, 95%; (b) (COC1)2 (10 equiv), DM SO (32 equiv), CH2C12, -78 OC, 15 min, th en 6 1 equiv), -78 O C 0.5 h followed by Et,N(50 equiv), -78 to -10 OC, 1 h; (c) excess HF/pyridi ne, THF , 25 OC, 2 h; (d) aqueous H F in CH N (lo% ), 25 OC, 60 h, overall 70% yield in foursteps from 6; (e) 3 (1.2 equiv), diisopropylethylamine (1.5 equiv), Pd(CH3CN)2C12 (20 m ol ), D M F / T H F ( 1 :l ) (0.003 M), 25 OC, 24 h, 28% [plusrecovered starting mate rial (ca. 30%) and interm ediate iodostannane precursor (c a. 30%)].

This intermediate was converted to rapamycin 1) (ca. 60 )undersimilar conditions,as expected. Sy nthe tic apamycin 1)exhibitedphysical and spectroscopic data (TLC, HPLC, [ C Y I ~ ~ ~H andI3C N M R, mass, IR, and UV spectra) identical with those of anauthentic sample.

The described total synthesis of rapamycin 1) is distinctlydirect, represents a new approach to complex polyene macrocyclicstructures, and provides an entry in to a wide variety of designedimmunophilin ligands for biological studies.12IO) This iodc-stannane interm ediate was not fully characterized, but itwas presumed to be the one form ed by initia l coupling at the less substitute dC:,-C?: vinyl iodide.(11) We thank Dr. J. Meier (Sandoz Pharma., Basel, Switzerland) andDr. N. Jensen (Wyeth-Ayerst, Princeton, NJ) for generous samples ofrapamycin.

Acknowledgment. We wish to express our many thanks toDrs. Gary Siuzdak and Dee H. Huang for mass spectrometricand N M R spectroscopic assistance, respectively. This work wasfinancially supported through an N I H fellowship (to A.D.P.,1990-1992), a visiting scientist fellowship from Meiji SeikaKaisha, LTD., Japan (toN .M.) , the National Institutes of Health,the University of California, San Diego, and T he Scripps ResearchInstitute.

SupplementaryMaterialAvailable: A listing of selected physicaldata for compounds2,4,5, and 6 5 pages). Orderinginformationis given on any current masthead page.1 2) New compoundsexhibited satisfactory spectral and exact mass data .Yields refer to spectroscopically and chromatographically homogeneousmaterials.