NOEs between 30-H/32-H and 32-H/33-H.10 Removal of
the benzyl group by hydrogenolysis provided alcohol 11
(97%), which was then converted into dibromoolefin 12 in
two steps (85% yield).11 Finally, sequential treatment with
NaHMDS and n-BuLi afforded the desired alkyne 5 in 90%
yield.12
Scheme 4. Synthesis of Model Compounds 3a and 3ba
For the construction of the FG ring aldehyde 6, we used
ketone 77 as the same starting material, which was converted
to exo-methylene 13 through Peterson olefination13 (Scheme
3). This olefin was subjected to hydrogenation/hydrogenoly-
Scheme 3. Synthesis of the FG Ring Fragmenta
a Reagents and conditions: (a) TMSCH2MgCl, THF, 0 °C; (b)
HOAc, 120 °C, 55% (two steps); (c) H2, Pd/C, EtOAc, rt, 50%;
(d) SO3‚pyr, Et3N, DMSO, CH2Cl2, 0 °C, 85%.
a Reagents and conditions: (a) 5, n-BuLi, THF, -78 °C, CeCl3,
then 6, 93%; (b) H2, Pd/C, MeOH, rt; (c) TPAP, NMO, 4 Å MS,
CH2Cl2, rt, 80% (two steps); (d) 6 M HCl, THF, 0 f 30 °C, 89%;
(e) p-TsOH‚H2O, MeOH, rt, 44% (92% based on recovered 4a);
(f) Et3SiH, BF3‚OEt2, CH2Cl2/MeCN, 0 °C, 83%; (g) Ac2O, DMAP,
CH2Cl2, rt, quant.
sis to produce an approximately 2:1 mixture of reduced
products, from which the desired alcohol 14 was separated
by column chromatography on silica gel in 50% yield.14 The
stereochemistry of the axial-oriented methyl group at C39
was confirmed by NOE between 39-Me and 41-H.10 Oxida-
tion of 14 gave aldehyde 6 in 85% yield.
alcohol 15 together with recovered 5 and 6. However, a less
basic alkynylcerium reagent15 prepared from the lithium
acetylide and cerium(III) chloride was more satisfactory and
added successfully to aldehyde 6 to give 15 as an ap-
proximately 7:3 diastereomeric mixture in high yield.
Hydrogenation of the triple bond followed by oxidation of
the secondary alcohol with TPAP/NMO provided ketone 16
in 80% yield over the two steps. The acetonide group was
removed by treatment with 6 M HCl (89%), and the obtained
keto diol 4a was then treated with p-toluenesulfonic acid in
methanol to yield methyl ketal 17 in 44% yield along with
recovered 4a (52%).16 Finally, reduction of 17 with tri-
ethylsilane in the presence of BF3‚OEt2 furnished the CDE/
FG ring model 3a in 83% yield.17 The stereochemistry of
3a was unambiguously established by NOE and coupling
constant data. Similarly, the diastereomeric model 3b was
prepared from alkyne 5 and aldehyde ent-6.18
With the desired 5 and 6 in hand, we next focused our
attention on their coupling (Scheme 4). An initial attempt to
couple the lithium acetylide generated from 5 (n-BuLi, THF,
-78 °C) with 6 gave a poor yield of the desired propargylic
(5) (a) Sasaki, M.; Nonomura, T.; Murata, M.; Tachibana, K. Tetrahedron
Lett. 1994, 35, 5023-5026. (b) Sasaki, M.; Nonomura, T.; Murata, M.;
Tachibana, K. Tetrahedron Lett. 1995, 36, 9007-9010. (c) Sasaki, M.;
Matsumori, N.; Murata, M.; Tachibana, K.; Yasumoto, T. Tetrahedron Lett.
1995, 36, 9011-9014. (d) Sasaki, M.; Matsumori, N.; Maruyama, T.;
Nonomura, T.; Murata, M.; Tachibana, K.; Yasumoto, T. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1782-1785. (e) Nonomura, T.; Sasaki, M.;
Matsumori, N.; Murata, M.; Tachibana, K.; Yasumoto, T. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1786-1789. For the work from Kishi’s
group, see: (f) Zheng, W.; DeMattei, J. A.; Wu, J.-P.; Duan, J. J.-W.;
Cook, L. R.; Oinuma, H.; Kishi, Y. J. Am. Chem. Soc. 1996, 118, 7946-
7968.
(6) Sasaki, M.; Shida, T.; Tachibana, K. Tetrahedron Lett. 2001, 42,
5725-5728.
(7) Mori, Y.; Yaegashi, K.; Furukawa, H. Tetrahedron Lett. 1999, 40,
7239-7242.
The two diastereomeric CDE/FG ring models 3a and 3b
were subjected to the NMR study, and the 1H and 13C NMR
(8) Mori, Y.; Yaegashi, K.; Furukawa, H. Tetrahedron 1997, 53, 12917-
12932.
(9) For similar stereoselective introduction of a hydroxy group into a
seven-membered ether, see: Tsukano, C.; Sasaki, M. J. Am. Chem. Soc.
2003, 125, 14294-14295.
(10) Numbering of all compounds in this paper corresponds to that of
prymnesins.
(11) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769-
3772.
(15) (a) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita,
T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904-3912. (b)
Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984, 25, 4233-
4236. (c) Fox, C. M. J.; Hiner, R. N.; Warrier, U.; White, J. D. Tetrahedron
Lett. 1988, 29, 2923-2926. (d) Molander, G. A. Chem. ReV. 1992, 92,
29-68.
(16) Direct treatment of 16 with excess amounts of p-toluenesulfonic
acid in methanol resulted in a low yield of methyl ketal 17.
(17) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976-4978.
(18) Synthesis of compounds ent-6 and 3b are included in Supporting
Information.
(12) Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett. 1994, 35,
3529-3530.
(13) Boeckman, R. K., Jr.; Silver, S. M. Tetrahedron Lett. 1973, 14,
3497-3500.
(14) For similar face-selective hydrogenation, see: (a) Wipf, P.; Uto,
Y.; Yoshimura, S. Chem. Eur. J. 2002, 8, 1670-1681. (b) Ireland, R. E.;
Daub, J. P. J. Org. Chem. 1981, 46, 479-485.
Org. Lett., Vol. 6, No. 9, 2004
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