LETTER
Improved Synthesis of (–)-Martinellic Acid
895
K.; Pal, S.; Rama Rao, A. V. Heterocycles 1997, 45, 231.
(c) Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287.
(d) Hadden, M.; Stevenson, P. J. Tetrahedron Lett. 1999, 40,
1215. (e) Lovely, C. J.; Mahumud, H. Tetrahedron Lett.
1999, 40, 2079. (f) Snider, B. B.; Ahn, Y.; Foxman, B. M.
Tetrahedron Lett. 1999, 40, 3339. (g) Frank, K. E.; Aube, J.
J. Org. Chem. 2000, 65, 655. (h) Nieman, J. A.; Ennis, M.
D. Org. Lett. 2000, 2, 1395. (i) Nyerges, M.; Fejes, I.; Toke,
L. Tetrahedron Lett. 2000, 41, 7951. (j) Snider, B. B.;
O’Hare, S. M. Tetrahedron Lett. 2001, 42, 2455.
(k) Mahmud, H.; Lovely, C. J.; Rasika, D. H. V. Tetrahedron
2001, 57, 4095. (l) Batey, R. A.; Powell, D. A. Chem.
Commun. 2001, 2362. (m) Hamada, Y.; Kunimune, I.; Hara,
O. Heterocycles 2002, 56, 97. (n) He, Y.; Mahmud, H.;
Wayland, B. R.; Rasika Dias, H. V.; Lovely, C. J.
Tetrahedron Lett. 2002, 43, 1171. (o) Malassene, R.;
Sanchez-Bajo, L.; Toupet, L.; Hurvois, J.-P.; Moinet, C.
Synlett 2002, 1500. (p) Nyerges, M.; Fejes, I.; Toke, L.
Synthesis 2002, 1823. (q) Hara, O.; Sugimoto, K.; Makino,
K.; Hamada, Y. Synlett 2004, 1625. (r) Hara, O.; Sugimoto,
K.; Hamada, Y. Tetrahedron 2004, 60, 9381. (s) Yadav, J.
S.; Subba, R. B. V.; Sunitha, V.; Srinivasa, R. K.;
ester 20 was converted to the desired a,b-unsaturated ester
5 (82% from 20). We next carried out the RACE reaction
of ester 5 which proceeded smoothly to give the desired
3aR,3bS,11bS-dipyrroloquinoline (6a) and its stereoiso-
mers in 45% combined yield.9
We next investigated the chemoselective reduction of 6a
carrying three different types of carbonyl groups such as
the ester, N-arylpyrrolidinone, and N-norpyrrolidinone. In
order to reduce selectively the carbonyl group of N-
arylpyrrolidinone, the dipyrroloquinoline 6a was treated
with LiBH4 in the presence of MeOH in THF to afford
the desired amino alcohol 2110 in 76% yield. Finally, the
reduction of lactam 21 with borane–THF followed by
acylation of the resulting amine with trifluoroacetic anhy-
dride gave the desired trifluoroacetamide 711 (79% yield
from 21), which is the key intermediate for synthesis of
(–)-martinellic acid.
In conclusion, we have newly developed an 11-step syn-
thesis (10% overall yield) of the optically active key inter-
mediate for synthesis of (–)-martinellic acid. Key steps
include the RACE reaction of oxime ether and chemo-
selective reductions of three carbonyl groups.
Ramakrishna, K. V. S. Tetrahedron Lett. 2004, 45, 7947.
(t) Nyerges, M. Heterocycles 2004, 63, 1685.
(5) Danishefsky, S.; Singh, R. K. J. Org. Chem. 1975, 40, 3807.
(6) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 7421. (b) Yin, J.; Buchwald, S. L. Org. Lett.
2000, 2, 1101. (c) Browning, R. G.; Badarinarayaha, V.;
Mahmud, H.; Lovely, C. J. Tetrahedron 2004, 60, 359.
(7) Keusenkothen, P. F.; Smith, M. B. J. J. Chem. Soc., Perkin
Trans. 1 1994, 2485.
(8) In addition to 15a, three stereoisomers, which are
(3aR,3bS,11bR)-15b (12%), (3aS,3bS,11bS)-15c (9%), and
(3aS,3bS,11bR)-15d (6%) were obtained after purification of
the reaction mixture by column chromatography.
Acknowledgment
We are grateful to Prof. D. Ma, Shanghai Institute of Organic Che-
mistry, Chinese Academy of Sciences, for kindly providing the
spectra of authentic sample of 7.
We acknowledge Grants-in-Aid for Scientific Research (B) (T.N.)
and Scientific Research (C) (O.M.) from Japan Society for the
Promotion of Science, Scientific Research on Priority Areas (A)
(T.N.) from the Ministry of Education, Culture, Sports, and
Technology. This work was supported in part by the Second Project
for Advanced Research and Technology by Kobe Pharmaceutical
University.
Compound 15a: mp >260 °C (acetone, MeOH). IR: nmax
=
1694, 3433 cm–1. 1H NMR (500 MHz): d = 1.72–1.80 (1 H,
m), 2.22 (1 H, d, J = 17.0 Hz), 2.40–2.71 (4 H, m), 2.80 (1
H, dd, J = 17.0, 7.5 Hz), 3.71 (1 H, dt, J = 11.5, 7.5 Hz), 4.83
(1 H, d, J = 5.5 Hz), 6.48 (1 H, br s), 7.16 (1 H, td, J = 8.0,
2.0 Hz), 7.29 (1 H, dd, J = 8.0, 2.0 Hz), 7.37 (1 H, td, J = 8.0,
2.0 Hz), 8.50 (1 H, dd, J = 8.0, 2.0 Hz). 13C NMR (125
MHz): d = 22.8, 31.2, 34.1, 40.5, 53.4, 55.8, 120.2, 123.8,
124.5, 129.22, 129.24, 135.7, 173.2, 175.1. HRMS: m/z
calcd for C14H14N2O2 [M+]: 242.1055; found: 242.1067;
Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56.
Found: C, 69.16; H, 5.80; N, 11.48. [a]D27 +44.5 (c 0.26,
CHCl3).
References and Notes
(1) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard,
A. M.; Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.;
Pitzenberger, S. M.; Varga, S. L. J. Am. Chem. Soc. 1995,
117, 6682.
(2) Total synthesis of (–)-martinellic acid: (a) Ma, D.; Xia, C.;
Jiang, J. Org. Lett. 2001, 3, 2189. (b) Ma, D.; Xia, C.; Jiang,
J.; Zhang, J.; Tang, W. J. Org. Chem. 2003, 68, 442.
(3) Total synthesis of ( )-martinelline and martinellic acid:
(a) Xia, C.; Heng, L.; Ma, D. Tetrahedron Lett. 2002, 43,
9405. (b) Snider, B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett.
2001, 3, 4217. (c) Powell, D. A.; Batey, R. A. Org Lett.
2002, 4, 2913. (d) Takeda, Y.; Nakabayashi, T.; Shirai, A.;
Fukumoto, D.; Kiguchi, T.; Naito, T. Tetrahedron Lett.
2004, 45, 3481. (e) Hadden, M.; Nieuwenhuyzen, M.;
Osborne, D.; Stevenson, P. J.; Thompson, N. Tetrahedron
Lett. 2001, 42, 6417. (f) He, Y.; Moningka, R.; Lovely, C. J.
Tetrahedron Lett. 2005, 46, 1251. (g) Ikeda, S.; Shibuya,
M.; Iwabuchi, Y. Tennen Yuki Kagobutsu Toronkai Koen
Yoshishu 2005, 47, 589.
(9) Column chromatography of the reaction mixture gave
(3aR,3bS,11bS)-dipyrroloquinoline 6a (29%),
(3aR,3bS,11bR)-6b (8%), (3aS,3bS,11bS)-6c (4%), and
(3aS,3bS,11bR)-6d (4%), respectively.
Compound 6a: mp 165–168 °C (acetone, MeOH). IR: nmax
=
1702, 3428 cm–1. 1H NMR (500 MHz): d = 1.75–1.83 (1 H,
m), 2.26 (1 H, d, J = 17.0 Hz), 2.45–2.56 (2 H, m), 2.59–2.74
(2 H, m), 2.82 (1 H, dd, J = 17.0, 7.5 Hz), 3.77 (1 H, td,
J = 11.0, 7.5 Hz), 3.93 (3 H, s), 4.86 (1 H, d, J = 5.5 Hz),
5.93 (1 H, br s), 7.99 (1 H, d, J = 2.0 Hz) 8.02 (1 H, dd,
J = 8.5, 2.0 Hz), 8.67 (1 H, d, J = 8.5 Hz). 13C NMR (125
MHz): d = 23.1, 31.4, 34.0, 40.3, 52.3, 53.2, 55.8, 119.6,
123.5, 125.7, 130.7, 131.1, 139.8, 166.2, 173.8, 174.6.
HRMS: m/z calcd for C16H16N2O4 [M+]: 300.1110; found:
300.1128. Anal. Calcd for C16H16N2O4: C, 63.99; H, 5.37;
N, 9.33. Found: C, 63.85; H, 5.25; N, 9.25. [a]D28 +100.7
(c 0.235, CHCl3).
(4) Synthesis of tricyclic pyrroloquinoline core: (a) Hadden,
M.; Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J.;
Thompson, N. Tetrahedron 2001, 57, 5615. (b) Gurjar, M.
Synlett 2006, No. 6, 893–896 © Thieme Stuttgart · New York