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T. Hamada, Y. Kobayashi / Tetrahedron Letters 44 (2003) 4347–4350
Scheme 2. Synthesis of C1–C7 segment 5. Reagents and conditions: (a) Benzyl trichloroacetimidate, hexane–CH2Cl2 (2:1), 0–20°C,
3 h; (b) LiAlH4, Et2O, 0°C, 1.5 h; (c) (COCl)2, DMSO, Et3N, CH2Cl2, −70 to −60°C, 1 h; (d) crotyltri-n-butylstannane,
MgBr2OEt2, CH2Cl2, −30°C, 4 h; (e) DMPMCl, KH, 18-crown-6, 25°C, 3 h; (f) OsO4, NMO, acetone–H2O (10:1), 25°C, 20 h;
(g) NaIO4, acetone–H2O (4:1), 25°C, 20 h; (h) crotyltri-n-butylstannane, BF3OEt2, CH2Cl2, −90 to −30°C, 6 h; (i) 2,2-
dimethoxypropane, TsOH, benzene, 25°C, 14 h; (j) OsO4, NMO, acetone–H2O (10:1), 25°C, 20 h; (k) NaIO4, acetone–H2O (4:1),
rt, 1 h; (l) LiAlH4, Et2O, 0°C, 15 min; (m) TBDPSCl, imidazole, CH2Cl2, 25°C, 1 h; (n) Raney Ni (W-2), H2, EtOH, 25°C, 120
h; (o) TsCl, pyridine, DMAP, CH2Cl2, 20°C, 20 h; (p) NaI, NaHCO3, 2-butanone, 60°C, 20 h.
Scheme 3. Synthesis of C8–C16 fragment. Reagents and conditions: (a) BOMCl (benzyloxymethyl chloride), i-Pr2NEt, CH2Cl2,
0°C to rt, 4 h; (b) LiAlH4, Et2O, 0°C, 15 min; (c) (COCl)2, DMSO, Et3N, CH2Cl2, −78 to −50°C, 4 h; (d) Me2CuLi, Et2O, −78°C,
3 h; (e) BnBr, NaH, THF–DMSO (1:1), 20°C, 15 h; (f) 4N HCl, THF, reflux, 18 h; (g) (COCl)2, DMSO, Et3N, CH2Cl2, −78 to
−50°C, 1 h; (h) crotyltri-n-butylstannane, BF3OEt2, CH2Cl2, −85°C, 1 h; (i) MPMCl, NaH, THF–DMSO (1:1), rt, 15 h; (j) OsO4,
NMO, acetone–H2O (10:1), rt, 12 h; (k) NaIO4, acetone–H2O (4:1), rt, 1.5 h; (l) crotyltri-n-butylstannane, MgBr2OEt2, CH2Cl2,
−30°C to rt, 8 h; (m) TESCl, imidazole, CH2CH2, rt, 4 h; (n) OsO4, NMO, acetone–H2O (10:1), rt, 20 h; (o) PivCl, pyridine,
DMAP, CH2CH2, rt, 3.5 h; (p) TESCl, imidazole, CH2CH2, rt, 1 h; (q) DIBAH, CH2Cl2, −78°C, 0.5 h; (r) (COCl)2, DMSO, Et3N,
CH2Cl2, −78°C, 0.5 h.
Oxidation of the secondary alcohol to ketone followed
by Wittig reaction and deprotection of TBDPS and
TES to give triol. TBDMS protection of the primary
alcohol of the triol followed by acetalization of the
resultant diol with mesytaldehyde dimethyl acetal and
deprotection of TBDPS afforded 21. Jones oxidation of
the primary alcohol and deprotection of MPM7 by
DDQ formed seco-acid 3.
undesired products was 3:1). MPM (4-methoxybenzyl)
protection of the primary alcohol of 16 formed 17.
Oxidative degradation of 17 to form an aldehyde, fol-
lowed by chelation-controlled crotyl addition, afforded
18 (the ratio of desired 18 to undesired products was
6:1). TES protection and dihydroxylation and pivaroyl
(Piv) protection of the resulting primary alcohol gave
19, although the face selectivity of osmylation was not
so high (2R:3S=3:1). TES protection, followed by
deprotection of the pivaroyl group and Swern oxidation
gave C8–C16 fragment 4.
The cyclization of the seco-acid 3 is summarized in
Table 1. Because of the crowded surroundings of the
alcohol reaction site,8 cyclization proceeded sluggishly
to give lactone 22 in low yield. The best result (22%
based on recovered 3) by the improved Yamaguchi
method was obtained under the high dilution condition
and xylene reflux (Table 1), and in other solvents
Synthesis of lactone 22 via seco-acid 3 is shown in
Scheme 4. Aldehyde 4 was added to a solution of
methylene lithium prepared by lithium halogen
exchange2 of iodide 5 with t-butyl lithium to afford 20.