Details of the total synthesis of rapamycin (1) are reported. The synthesis required the preparation of intermediates 4-9 in nonracemic form; key coupling reactions included a chromium-mediated addition of vinyl iodide 8 to aldehyde 7 and an Evans aldol reaction to couple fragments 62 and 9. Intermediates 4 and 6 were joined through an amide bond formation to afford advanced intermediate 71. Swern oxidation of the diol in 71 was (USA) 0 V C H Verlugsgesellsrhufr mbH. 049451 Weinhrim. 1995 OS?OO833/95~0SO5-03~8 $ SO.W+ .25/0 Chem. Eur. 1 1995. I, No. S
318-333macrolactamization or macrolactonization strategies as demonstrated in the synthesis of the related natural product FK506 by the MerckI"] and the Harvard[''] groups. However, careful inspection of the structure of rapamycin suggested to us the possibility of constructing the macrocyclic ring by inserting a C 19-C20 ethene unit between two terminal vinyl iodides to form simultaneously the triene ahd the 31 -membered macrocyclic systems (Scheme 1). It was also anticipated that this "stitching cyclization" could be achieved after removal of all protecting groups and adjustment of oxidation states; this last step would then deliver rapamycin (1) directly.Disconnection of the triene system in 1 (Scheme 1, Stille palladium-catalyzed coupling[' 91) suggests bis(viny1 iodide) 2 and distannylethene 3 I 2 O * 211 (C 19-C20 fragment) as potential precursors. Further disconnection of the indicated amide and ester bonds in 2 and opening of the lactol ring reveals, upon appropriate functional group adjustments, compounds 4-6 as advanced key intermediates. The most complex of the latter three fragments, compound 6 was then dissected (Evans aldol reaction for the C 34-C 35 bond and a chromium -nickel coupling[221 for the C 28 -C 29 bond) to afford, after functional group manipulations, compounds 7-9 as potential building blocks. Thus a strategy was devised entailing construction and coupling of intermediates 7-9 and final elaboration to rapamycin.Total Synthesis of Rapamycin: The first task in the projected total synthesis of rapamycin was the construction of the key building blocks 4, 7, 8, and 9. These compounds were synthesized from readily available starting materials and by means of highly stereocontrolled sequences. istry. Nicolaou's research interests focus on chemical synthesis, molecular design and molecular recognition, and the biological acrions ofmolecules. He is the author or co-author of over 330 publications, 45 patents, and two books. Nicolaou's current research includes chemical synthesis. molecular design, and biological evaluation of compounds,from the areas of taxoids, enediynes. carbohydrates, D N A interacting molecules, DNA replication, zaragozic acids, and brevetoxins. Chem. Eiir. J. 1995. I. No. 5 j) 0,. MeOH/CH,CI, (1:l). -78°C. then Me,S (5.0equiv), -78-25"C. 16h, 88%; k) 57 (1.5 equiv), LiCl (2.0 equiv). N.N-diisopropylethylamine (2.0 equiv). then 56 (1.0 equiv). 25 "C. 6 h, 96%; I) Rh(PPh,),CI (0.05 equiv). Et,SiH. 50°C. 2 h, then aq. H F in CH,C...
