Communications
removal of all protecting groups under Birch
conditions,[8g] provided the pentaol 17. Following
the protection of all five hydroxy groups of 17 as
their TES ethers, selective cleavage of the
primary allylic TES ether with AcOH–H2O–
THF afforded the corresponding allylic alcohol,
which was oxidized with MnO2 in 97% yield. A
Roush asymmetric anti crotylation[10] then gave
the desired left-hand fragment 12 in 89% yield
with d.r. 4.7:1 (the minor diastereomer was
separated by silica-gel column chromatography).
Next, we focused on the synthesis of the
right-hand fragment 13 (Scheme 6). The syn-
thesis commenced with a VMAR between the
N,O-acetal 3 and methacrolein (14). Under
standard conditions (TiCl4 in CH2Cl2, 2.0 equiv-
alents of 14), the aldol adduct 18 was formed in
low yield (23%), presumably as a result of
polymerization of 14. During an extensive survey
of reaction conditions, we improved the yield of
Scheme 7. Completion of the total synthesis of (+)-TMC-151C (1): a) 13 (1.5 equiv),
Et2NPh2SiCl, Et3N, DMAP (cat.), then 12, DMAP, CH2Cl2, 08C!RT, 54% (81% from
12 on the basis of recovered starting material); b) Hoveyda–Grubbs second-generation
catalyst (20 mol%), p-benzoquinone, xylene, reflux, 87% (E/Z>20:1); c) HF–pyridine,
pyridine, then aqueous HF, THF–MeCN, 08C!RT, 54%.
tethered RCM[11,12] of 21 under the previously reported
conditions[7] (with the Hoveyda–Grubbs second-generation
catalyst[13] in the presence of p-benzoquinone[14] in xylene at
reflux) provided the desired E olefin 22 in 87% yield with
high stereoselectivity (E/Z > 20:1). The configuration of the
E olefin 22 was determined by NOE experiments.[9] Finally,
desilylation by the sequential treatment of 22 with HF·pyr-
idine and aqueous HF completed the total synthesis of
(+)-TMC-151C.[15] The spectroscopic data (1H NMR,
13C NMR, and IR spectra, HRMS) of synthetic (+)-1 were
identical to those of natural (+)-1.[1a]
Scheme 6. Synthesis of the right-hand fragment 13: a) TiCl4, methacro-
lein (14; 4.0 equiv), toluene, ꢀ78!ꢀ508C, 65% (d.r.>20:1);
b) PMBOC(NH)CCl3, CSA (cat.), CH2Cl2, 08C!RT, 68%; c) LiOH·H2O,
H2O2, THF–H2O, 08C, 83%; d) Piv2O, Et3N, CH2Cl2, 08C; e) 20,
DMAP, toluene, room temperature, 60% (over 2 steps); f) DDQ,
CH2Cl2–buffer (pH 7.5), 08C, 93%. PMB=p-methoxybenzyl,
In conclusion, we have completed the first total synthesis
of (+)-TMC-151C by a highly convergent synthetic route.
Characteristic features of the present synthesis include the
construction of the C1–C5 and C9–C13 units by vinylogous
Mukaiyama aldol reactions and the use of a silicon-tethered
diene for the stereoselective formation of the C6–C7 double
bond by our recently developed E-selective RCM reaction to
give an eight-membered ring. This synthetic strategy should
provide efficient access to a range of related naturally
occurring polyketides containing pent-2-ene-1,5-diol units.
CSA=camphorsulfonic acid, DDQ=2,3-dichloro-5,6-dicyano-1,4-ben-
zoquinone, DMAP=N,N-4-dimethylaminopyridine, Piv=pivaloyl.
18 to 65% with greater than 20:1 diastereoselectivity by using
toluene as the solvent and 4.0 equivalents of 14. The major by-
products were
Received: October 5, 2010
Published online: December 22, 2010
1,4-addition adducts (15% yield) as a mixture of diastereo-
mers. After protection of the secondary alcohol with
PMBOC(NH)CCl3, the chiral auxiliary was removed with
LiOH and H2O2 to provide the carboxylic acid 19. Esterifi-
cation of the unsaturated acid 19 (as the mixed anhydride
formed by treatment with Piv2O) with the alcohol 20[9]
afforded the corresponding ester in 60% overall yield for
the two steps. Cleavage of the PMB ether gave the right-hand
fragment 13.
With both fragments in hand, we proceeded to the final
stage of the total synthesis of (+)-1 (Scheme 7). Our silicon-
tethering method with Et2NPh2SiCl/Et3N/DMAP[7] was used
successfully for the connection of 12 and 13 to afford silylene
acetal 21 in 54% yield (81% from 12 as calculated on the
basis of recovered starting material). The crucial silicon-
Keywords: aldol reaction · natural products · polyketides ·
.
ring-closing metathesis · total synthesis
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Kishi, T. Okuda, S. Komatsubara, J. Antibiot. 2000, 53, 1301 –
1304; c) T. Okuda, J. Kohno, N. Kishi, Y. Asai, M. Nishio, S.
[2] J. Kohno, Y. Asai, M. Nishio, M. Sakurai, K. Kawano, H.
Hiramatsu, N. Kameda, N. Kishi, T. Okuda, S. Komatsubara, J.
Antibiot. 1999, 52, 1114 – 1123.
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Angew. Chem. Int. Ed. 2011, 50, 680 –683