A simple, enantiocontrolled and efficient route to an intermediate containing carbons 18 to 35 of the macrocyclic immunosuppressant FK-506 (1) is described which depends on a sequence of three enantioselective C-C bond forming reactions. Research in our group has recently led to the development of new and highly effective enantioselective versions of such major synthetic processes as the Diels-Alder, aldol and carbonyl allylation reactions.Ipz In this paper we demonstrate the power of this methodology as applied to the construction of a key intermediate for the synthesis of the novel immunosuppressant FK-506 (1). The structuml novelty and biological potency of FK-506 have made this substance a popular target for synthesis despite a level of toxicity which discourages clinical use. 3 One line of retrosynthetic analysis which leads to effective structural simplification of FK-5064 is shown below. Clearance of the ally1 appendage and stereocenter from C(21) (triethylsilane reduction, a-allylation transform) leads to 2, with reliance on macroring geomet@ to ensure stereoselectivity at C(21) and C(19) -C(20). Macroring disconnection to 3 and Wittig disconnection to 4 are among several possible further retrosynthetic disconnections. Described herein is a simple synthesis of 4 and its elaboration to 3, R=i-F'r, to validate the Wittig step (which might also be used for macroring closure). Dienone 3 corresponds to the C(18) -C(35) segment of FK-506.