Angewandte
Chemie
Reaction of 15: A mixture of 15 (3 mmol) and [PdCl2(CH3CN)2]
(0.45 mmol) in THF (60 mL) was stirred for 1 h at ꢀ58C. After
addition of benzoquinone (0.9 mmol), the mixture was stirred for
2 days at room temperature. The mixture was diluted with hexane
(70 mL), and NaBH4 (1 mmol) was added to decompose the
remaining benzoquinone. The standard workup and purification by
silica-gel column chromatography eluted with EtOAc in hexane
(10%) gave (R)-16 as a colorless oil in 60% yield. Rf = 0.76 (30%
EtOAc in hexane); [a]D24 = ꢀ29.5 (c = 0.74, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 0.97 (3H, d, J = 6.8 Hz), 1.23 (1H, ddd, J =
14.1, 9.5, and 3.5 Hz), 1.71 (1H, ddd, J = 14.1, 9.7, and 4.2 Hz), 1.89–
2.13 (5H, m), 3.24 (1H, dd, J = 9.1 and 6.5 Hz), 3.33 (1H, dd, J = 9.1
and 6.0 Hz), 3.75–3.82 (1H, m), 3.79 (3H, s), 4.38–4.52 (3H, m), 4.43
(2H, s), 5.68–5.73 (1H, m), 5.82–5.88 (1H, m), 6.86 (2H, d, J =
6.8 Hz), 7.25 (2H, d, J = 8.6 Hz), 7.40–7.45 (2H, m), 7.52–7.57 (1H,
m), 8.02–8.06 ppm (2H, m); 13C NMR (100 MHz, CDCl3): d = 16.8,
29.7, 31.3, 33.0, 39.4, 55.3, 61.9, 65.2, 69.2, 72.5, 75.9, 113.7, 124.8,
128.3, 129.0, 129.1, 129.6, 130.4, 130.9, 132.9, 159.0, 166.5 ppm; IR
(neat): n˜ = 2955, 2930, 1716, 1613, 1513, 1276, 1249, 1112, 1036 cmꢀ1
;
MS (20 eV): m/z (%): 424 (2) [M+], 303 (2), 285 (3), 204 (11), 181 (44),
121 (100); HR-MS (20 eV): calcd for C26H32O5: 424.2250; found:
424.2249. (S)-16: 56% yield; its physical and spectroscopic data is
described in the Supporting Information.
Scheme 7. Coupling of 2 and 3 and synthesis of 1. Reagents and con-
ditions: a) SnCl4, CH2Cl2, ꢀ788C, 86%; b) DMP, 86%; c) BH3·THF
complex, (R)-CBS, THF, ꢀ408C, 92%; d) TBDMSCl, imidazole, DMF,
room temperature, 95%; e) K2CO3, MeOH/THF (3:1), room tempera-
ture, 93%; f) 1. DMP; 2. DDQ, CH2Cl2/buffer(pH 7) (2:1), 08C, 80%;
g) NaClO2, 2-methyl-2-butene, NaH2PO4, THF/tBuOH (1:2), 08C, 98%;
h) Yamaguchi lactonization, 88%; i) HF·py, CH3CN, room temperature,
quant. j) Lindlar cat., H2, quinoline, EtOAc/1-hexene (1:1), room tem-
perature, 77%; k) Sharpless epoxidation conditions, (+)-diisopropyl
tartrate, 80%.
Received: January 5, 2005
Published online: March 30, 2005
Keywords: diastereoselectivity · macrocycles · natural products ·
.
palladium · total synthesis
[1] a) E. Quinoa, Y. Kakou, P. Crews, J. Org. Chem. 1988, 53, 3642 –
3644; b) D. G. Corley, R. Herb, R. E. Moore, P. J. Scheuer, V. J.
Paul, J. Org. Chem. 1988, 53, 3644 – 3646; c) C. W. Jefford, G.
Bernardinelli, J. Tanaka, T. Higa, Tetrahedron Lett. 1996, 37,
159 – 162.
the natural product as well as those previously reported.[5a–c,h]
In conclusion, we have completed the asymmetric total
synthesis of (ꢀ)-laulimalide based on the novel PdII- and Pd0-
catalyzed stereospecific ring formation of a 3,6-dihydro[2H]-
pyran system. We believe that this method should be useful
for the synthesis of not only 1 but also of a variety of other
marine natural products that contain the 3,6-dihydro[2H]-
pyran unit.
[2] S. L. Mooberry, G. Tien, A. H. Hernandez, A. Plubrukarn, B. S.
Davidson, Cancer Res. 1999, 59, 653 – 660.
[3] a) D. E. Pryor, A. OꢀBrate, G. Bilcer, J. F. Diaz, Y. Wang, Y.
Wang, M. Kabaki, M. K. Jung, J. M. Andreu, A. K. Ghosh, P.
Giannakakou, E. Hamel, Biochemistry 2002, 41, 9109 – 9115;
b) E. J. Gapud, R. Bai, A. K. Ghosh, E. Hamel, Mol. Pharmacol.
2004, 66, 113 – 121; c) O. Pineda, J. Farras, L. Maccari, F. Manetti,
M. Botta, J. Vilarrasa, Bioorg. Med. Chem. Lett. 2004, 14, 4825 –
4829.
[4] An excellent review for (ꢀ)-laulimalide; see, J. Mulzer, E. ꢁhler,
Chem. Rev. 2003, 103, 3753 – 3786.
[5] Total syntheses; see, a) A. K. Ghosh, Y. Wang, J. Am. Chem. Soc.
2000, 122, 11027 – 11028; b) I. Paterson, C. De Savi, M. Tudge,
Org. Lett. 2001, 3, 3149 – 3152; c) J. Mulzer, E. ꢁhler, Angew.
Chem. 2001, 113, 3961 – 3964; Angew. Chem. Int. Ed. 2001, 40,
3842 – 3846; d) P. A. Wender, S. G. Hegde, R. D. Hubbard, L.
Zhang, J. Am. Chem. Soc. 2002, 124, 4956 – 4957; e) M. T.
Crimmins, M. G. Stanton, S. P. Allwein, J. Am. Chem. Soc. 2002,
124, 5958 – 5959; f) D. R. Williams, L. Mi, R. J. Mullins, R. E.
Stites, Tetrahedron Lett. 2002, 43, 4841 – 4844; g) S. G. Nelson,
W. S. Cheung, A. J. Kassick, M. A. Hilfiker, J. Am. Chem. Soc.
2002, 124, 13654 – 13655; h) B. M. Gallagher, Jr., F. G. Fang,
C. W. Johannes, M. Pesant, M. R. Tremblay, H. Zhao, K.
Akasaka, X. Li, J. Liu, B. A. Littlefield, Bioorg. Med. Chem.
Lett. 2004, 14, 575 – 579.
[6] J. Uenishi, M. Ohmi, K. Matsui, M. Iwano, Tetrahedron 2005, 61,
1971 – 1979.
[7] The compound 7a was unreactive under these (and even
harsher) conditions.
[8] A. Pfaltz, M. Lautens in Comprehensive Asymmetric Catalysis,
Vol. II (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Experimental Section
3,6-Dihydro[2H]pyran formation (representative reaction): A mix-
ture of 10 (1 mmol) and [PdCl2(CH3CN)2] (0.1 mmol) in THF
(10 mL) was stirred for 3 h at 08C. After concentration, the residue
was purified by chromatography on silica gel, eluted with EtOAc in
hexane (20%) to give (S)-8 as a colorless oil in 89% yield. Rf = 0.36
(20% EtOAc in hexane); [a]2D4 = ꢀ61.8 (c = 0.11, MeOH); H NMR
1
(400 MHz, CDCl3): d = 1.40 (3H, s), 1.40 (3H, s), 1.69 (3H, brs),
1.77–1.95 (3H, m), 1.99–2.08 (1H, m), 3.51–3.63 (2H, m), 3.80 (3H, s),
3.83 (1H, td, J = 8.2 and 4.0 Hz), 4.00–4.09 (2H, m), 4.11–4.22 (2H,
m), 4.43 (2H, s), 5.41 (1H, brs), 5.70 (1H, ddd, J = 15.6, 7.5, and
1.3 Hz), 5.87 (1H, ddd, J = 15.6, 5.4, and 0.5 Hz), 6.86 (2H, d, J =
8.8 Hz), 7.25 ppm (2H, d, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3):
d = 22.9, 26.9, 27.2, 32.0, 35.6, 55.2, 65.6, 66.7, 72.6, 73.1, 77.8, 81.9,
108.6, 113.7, 119.6, 127.4, 129.2, 130.5, 131.3, 135.4, 159.1 ppm; IR
(neat): n˜ = 1613, 1514 cmꢀ1; MS (20 eV): m/z (%): 388 (0.4) [M+], 370
(1), 209 (6), 160 (10), 136 (36), 121 (100); HRMS (20 eV): calcd for
C23H32O5: 388.2250, found: 388.2251. (R)-8: 77% yield; its physical
and spectroscopic data is described in the Supporting Information.
Angew. Chem. Int. Ed. 2005, 44, 2756 –2760
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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