Dedicated to Professor Albert Eschenmoser on the occasion of his 75th birthday for his outstanding contributions to organic and bioorganic chemistry
The total synthesis of plakosides A (1) and B (2), and their designed analogs 3 ± 10 was accomplished. The convergent strategy employed involved construction of the individual building blocks employing the Sharpless asymmetric dihydroxylation and the Charette asymmetric cyclopropanation reactions to introduce the desired configuration, followed by their couplings and final elaboration. Thus, key intermediates 12 ± 14 were prepared in their optically active forms and joined through a glycosidation reaction and amide-bond formation to yield the target molecules after appropriate elaboration and final deprotection. The synthesized compounds 1 ± 10 were evaluated for their immunosuppressive properties in vitro and found to be only modestly active.
Helvetica Chimica Acta ± Vol. 83 (2000) of the THP group from 37 (PPTS, 100% yield), followed by Swern oxidation (97% yield), led to aldehyde 39 via alcohol 38.
The required C 1 homologation of aldehyde 39 was accomplished by a Wittig olefination (CH 2 PPh 3 , 40, 97% yield), followed by regioselective hydroboration [19] (9-BBN, 41, 84% yield). Swern oxidation of the resulting primary alcohol 41 furnished aldehyde 42 (97% yield). Olefination of 42 with (EtO) 2 P(O)CH 2 CO 2 Et and NaH gave the a,b-unsaturated ester 43 in 96% yield ((E)/(Z) ca. 98 : 2). Asymmetric dihydroxylation of 43 with AD-mix b and MeSO 2 NH 2 gave the syn-dihydroxy ester 44 (97% yield), which was selectively and quantitatively hydrogenated (H 2 , Lindlar catalyst) to afford 45. Selective nosylation of 45 (nosyl chloride, pyridine, 46, 84% yield), followed by reaction with NaN 3 in DMF, furnished azide 47 (95% yield), from which silyl ether 48 was generated quantitatively (TBDMSOTf, 2,6-lutidine). The targeted a-azido-b-(silyloxy)sphingosine 14 was then obtained in 92% yield by LiBH 4 reduction of 48. Synthesis of a-Hydroxy Carboxylic Acid 12. The construction of the remaining fragment, a-hydroxy acid 12, proceeded as shown in Scheme 4. Thus, asymmetric dihydroxylation of the intermediate 40 with ((DHQD) 2 AQN, K 2 Os 2 (OH) 4 , K 2 Fe(CN) 6 , and K 2 CO 3 ) resulted in the formation of diol 49 in 91% yield [26]. Selective pivaloate formation proceeded smoothly with 49 in the presence of stoichiometric amounts of freshly distilled PivCl in pyridine at 08, leading to 50 (91% yield) [21]. The secondary OH group in 50 was silylated (TBDMSOTf, 2,6-lutidine, 51, 100% yield), and the pivaloate group was cleaved by treatment with DIBAL, Helvetica Chimica Acta ± Vol. 83 (2000) 1983 Scheme 4. Synthesis of a-Hydroxy Acid 12 a) (DHQD) 2 AQN (0.01 equiv.), K 2 Fe(CN) 6 (3.0 equiv.), K 2 Os 2 (OH) 4 (0.004 equiv.), K 2 CO 3 (3.0 equiv.), t-BuOH/H 2 O 1:1 (v/v), 08, 8 h; 91%. b) PivCl (1.0 equiv.), pyridine, 08, 40 min; 91%. c) TBDMSOTf (1.01 equiv.), 2,6-lutidine (2.5 equiv.), CH 2 Cl 2 , À 78 3 258, 30 min; 100%. d) DIBAL (2.0 equiv.), CH 2 Cl 2 , À 788, 20 min; 100%. e) Lindlar cat. (0.1 equiv.), H 2 (1 atm), EtOH, 258, 30 min; 100%. f) Dess-Martin periodinane (1.2 equiv.), CH 2 Cl 2 , 0 3 258, 40 min; 96%. g) NaClO 2 (2.5 equiv.), NaH 2 PO 4 (12.0 equiv.), 2methylbut-2-ene (20.0 equiv.), t-BuOH/H 2 O 5 :1 (v/v), 08, 30 min; > 95%. Abbreviations: AD-mix b reagent for Sharpless AD, in this case containing 1,4-bis(dihydroquinidinyl)anthraquinone ((DHQD) 2 AQN) ligand, DIBAL diisobutylaluminium hydride, Piv pivaloyl, TBDMS (t-Bu)Me 2 Si.