J. zyxwvuts Org. Chem. 1989, zyxwvut 54, 15-16 15 7916210. Many stimulating conversations with Professor Stuart Schreiber are recalled. Supplementary Material Available: zyxwvut 'H NMR spectra for 4,5,26, and 27 (4 pages). Ordering information is given on any current masthead page. Anabella Villalobos,' Samuel J. Danishefsky* Department of Chemistry Yale University z New Haven, Connecticut zy 0651 1 Received October 18, 1988 Studies Relating to the Synthesis of the Immunosuppressive Agent FK-506: Application of the Two-Directional Chain Synthesis Strategy to the Pyranose Moiety Summary: The asymmetric synthesis of the Clo-C1g fragment of FK-506 is reported. The two-directional cham synthesis strategy resulted in a considerable degree of double processing along the nascent chain. Sir: As part of a program aimed a t a modular synthesis of the potent immunosuppressive agent FK-506,' we re- quired an efficient synthesis of the phosphine oxide 3 (Figure 1). Our plan entails the utilization of this com- pound as a synthon for the ClO-Cl9 chain of the natural product. The synthesis allows the incorporation of in- termediates into other targets whose structures have been formulated to elucidate the structural requirements for binding to cellular mediators and suppression of immune systems.2 The two-directional chain synthesis strategy offers certain advantages over conventional chain synthesis strategies provided the problem of terminus differentiation of the two-directionally homologated chain can be sur- m~unted.~ The synthesis of the target chain 3 illustrates the efficiency of the double processing that is characteristic of the strategy and a solution to the problem of terminus differentiation that entails the use of a diastereotopic group-selective reaction. The two stereocenters of commercially available arabitol (1) correspond to those at C13and C15of FK-506 (Scheme I). Treatment of the tetraol with the acid chloride reagent developed by Moffatt4 provided the crude dichloro di- acetate 4, which was converted to the bisepoxide benzyl ether 5 in 45% overall yield by saponification with sodium methoxide and alkylation with benzyl bromide. The bis- epoxide was simultaneously homologated in two directions by reaction with 1-lithio-2-ethoxyacetylene in the presence of boron trifluoride etherate5 to give the hydrolytically labile bisalkyne diol 6, which was directly transformed into the bislactone 7 by treatment with methanolic HC1. The dilactone 7 was isolated as a crystalline solid (mp 65-68 "C, [.Iz2D zyxwvutsrqponmlk = +2.6", c = 1.0, CHC1,) after silica gel chro- matography in 62% overall yield from the bisepoxide. Formation of the bisenolate with 2.2 equiv of LDA and alkylation with excess iodomethane provided a mixture of products, from which the desired dimethyl bislactone 8 (mp 76-77 "c, [(YIzD = +23.6", zyxwvuts c = 1.1, CHC1,) was isolated in 54% yield after careful chromatography.6 A sequence consisting of saponification of the lactone, removal of water (1) See: (a) Accompanying papers in this issue. (b) Askin, D.; Volante, R. P.; Reamer, R. A.; Ryan, K. M.; Shinkai, I. Tetrahedron Lett. 1988, 29,277. (c) Mills, S.; Desmond, R.; Reamer, R. A.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1988, 29,281. (2) For a discussion of natural products binding and scaffolding do- mains, see: Schreiber, S. L.; Anthony, N. J.; Dorsey, B. D.; Hawley, R. C. Tetrahedron Lett. In press. (3) Schreiber, S. L. Chem. Scr. 1987,27, 563. (4) Greenberg, S.; Moffatt, J. G. J. Am. Chem. SOC. 1973,95,4016. (5) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24,391. (6) Takano, S.; Chiba, K.; Yonaga, M.; Ogasawara, K. J. Chem. SOC., Chem. Commun. 1980,616. two-directional chain synthesis - Me0,C C0,Me (simultaneous 2 OH chrmtopic nonstereogenic arab/to/ 1 Me ye QMe OMe Me terminus differentiation -* PhLp (diastereotopic II group selectivity) 0 3 OTBS Figure 1. Two-directionalchain synthesis: class C chain. to leave the solid bis(sodium carboxylate), and exhaustive alkylation with methyl iodide in DMF in the presence of sodium hydride produced the desired dimethyl ester di- methyl ether 9 [((uIz2D = -37.5", c = 1.6, CHC1,) in 51% yield following chromatography. Analysis by 'H NMR revealed that the compound so obtained consisted of >90% of a single diastereomer, indicating that negligible epimizeration had occurred during the methylation pro- cess. Following removal of the benzyl protecting group by hydrogenolysis in the presence of Pearlman's catalyst, differentiation of the termini of the resulting hydroxy bis(methy1 ester) 2 ([CY]~~D = -24.2", c = 1.8, CHCl,) was required. A similar problem had been encountered by Hoye in the course of a different synthetic objective.' A solution to the present problem follows closely the method employed in that earlier work. A group-selective lacton- ization of 2 with pyridinium p-toluenesulfonate* in meth- ylene chloride gave rise to a 6:l mixture of lactones with 10 as the dominant isomer in 65% yield, together with 25% recovered starting material. Attempts to drive the reaction to completion by prolonged treatment under these conditions or use of stronger acids led to unsatisfactory diastereomer ratios. Selective reduction of the lactone in the presence of the methyl ester was achieved with L-Se- lectride (Aldrich) to provide a 1:l mixture of lactol anomers 11 in 99% yield. Installation of the dithiane protecting group under standard conditions resulted in concomitant lactonization to generate the highly crystalline lactone dithiane 12 in 90% yield (mp 126-127 "C, [.]22D = -21.7", c = 0.5, CHCl,). Reduction of 12 to the corresponding diol ([.I2'D = +2.7", c = 1.7, CHCl,), selective conversion of the primary alcohol to the corresponding iodide, and protection of the secondary alcohol delivered 13, which was readily extended to the target phosphine oxide. Addition of an excess of the lithio salt of diphenylethylphosphine oxide (formed by treatment of diphenylethylphosphine oxide with n-butyllithium at 0 "C in THF)g to the iodide ~~ (7) Hoye, T. R.; Peck, D. R.; Swanson, T. A. J. Am. Chem. SOC. 1984, (8) Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977, (9) Buss, A. D.; Warren, S. J. Chem. Soc., Perkin Tram. I 1985,2307. 106, 2738. 42, 3772. 0022-3263/89/1954-0015$01.50/0 0 1989 American Chemical Society