Total synthesis of grandisine d

Article abstract of DOI:10.1021/ol900032h

Total synthesis of grandisine D (5) was achieved by a Bronsted acid mediated Morita-Baylis-Hillman (MBH) ring-closure reaction and stereoselective aldol condensation with (S)-5-methylcyclohexenone (9) as key steps. The MBH approach was also applicable for

Full text of DOI:10.1021/ol900032h

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1179-1181
Total Synthesis of Grandisine D
Haruaki Kurasaki,† Iwao Okamoto,‡ Nobuyoshi Morita,‡ and Osamu Tamura*,‡
DiscoVery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi,
Nogi-Machi, Shimotsuga-Gun, Tochigi 329-0114, Japan, and Showa Pharmaceutical
UniVersity, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan
tamura@ac.shoyaku.ac.jp
Received January 8, 2009
ABSTRACT
Total synthesis of grandisine D (5) was achieved by a Brønsted acid mediated Morita-Baylis-Hillman (MBH) ring-closure reaction and
stereoselective aldol condensation with (S)-5-methylcyclohexenone (9) as key steps. The MBH approach was also applicable for the construction
of the aza-fused bicyclic systems of pyrrolizidine and stemona alkaloids.
Opioid receptors have been classified into three subtypes,
µ, κ, and δ, and activation of µ-opioid receptor is known
to cause dependence, respiratory depression, and muscle
rigidity. Therefore, a selective agonist of δ-opioid receptor
is a promising lead for development of new analgetics
with few side effects. Grandisines A-G (1-7) are
indolizidine alkaloids isolated by Carroll and co-workers
from the leaves of the Australian rain forest tree Elaeo-
carpus grandis, and these alkaloids display selective
human δ-opioid receptor affinity (Figure 1).1,2 Despite their
attractive biological profiles, only grandisine A (1) has been
synthesized so far.3 In this paper, we describe the first total
synthesis of grandisine D (5), which was proposed to be a
biogenetic precursor of grandisines B (2) and F (4) and (-)-
Figure 1. Structure of grandisines.
isoelaeocarpiline,1,2 by means of a Brønsted acid mediated
Morita-Baylis-Hillman (MBH) reaction4 and a stereose-
lective aldol reaction with (S)-5-methylcyclohexenone (9).
The retrosynthetic analysis is as follows (Scheme 1).
Grandisine D (5) would be obtained by an aldol reaction of
8-formylindolizidine 10 with (S)-5-methylcyclohexenone (9),
readily prepared from (S)-pulegone,5 followed by reduction
of amide 8. 8-Formylindolizidine 10 would be synthesized
by an MBH ring-closure reaction via acyl iminium ion6
generated from aminal 11, which can be derived from (S)-
malic acid.
† Kyorin Pharmaceutical Co., Ltd.
‡ Showa Pharmaceutical University.
(1) Carroll, A. R.; Arumugan, G.; Quinn, R. J.; Redburn, J.; Guymer,
G.; Grimshaw, P. J. Org. Chem. 2005, 70, 1889–1892
(2) Katavic, P. L.; Venables, D. A.; Forster, P. I.; Guymer, G.; Carroll,
A. R. J. Nat. Prod. 2006, 69, 1295–1299
.
.
(3) Maloney, D. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007,
46, 7789–7792.
(5) (a) Katsuhara, J. J. Org. Chem. 1967, 32, 797–799. (b) Mutti, S.;
Daubie´, C.; Decalogne, F.; Fournier, R.; Rossi, P. Tetrahedron Lett. 1996,
37, 3125–3128. (c) Caine, D.; Procter, K.; Cassell, R. A. J. Org. Chem.
1984, 49, 2647–2648. (d) Oppolzer, W.; Petrzilka, M. HelV. Chim. Acta
1978, 61, 2755–2762.
(4) For reviews on MBH reaction, see: (a) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. ReV. 2003, 103, 811–891. (b) Basavaiah, D.; Rao,
K. V.; Reddy, R. J. Chem. Soc. ReV. 2007, 36, 1581–1588.
10.1021/ol900032h CCC: $40.75
Published on Web 02/09/2009
2009 American Chemical Society

Scheme 1
Table 1. Morita-Baylis-Hillman Reaction of 11
yield (%)
(trans-14:
cis-14)b
entry
reagentsa
solvent
CH2Cl2
temp
1
2
3
4
5
6
7
TMSOTf, Me2S
TMSOTf, Me2S
TMSOTf, Me2S
TMSOTf, Me2S
BF3·OEt2, Me2S
Tf2NH, Me2S
-78 °C to rt 32 (96:4)
CH3NO2 -15 °C to rt 26 (97:3)
toluene
CH3CN
CH3CN
CH3CN
-60 °C to rt 28 (92:8)
-35 °C to rt 56 (94:6)
-35 °C to rt 61 (81:19)
-35 °C to rt 64 (95:5)
-35 °C to rt 65 (94:6)
TfOH, tetrahydro- CH3CN
thiophene
8
TfOH, Me2S
CH3CN
-35 °C to rt 67 (96:4)
a Aminal 11 (1.0 equiv), Lewis acid or Brønsted acid (2.5 equiv), and
Our synthetic study was initiated by synthesis of aminal
11 from imide 12 prepared by Lee’s method7 from (S)-malic
acid (Scheme 2). Regioselective reduction of 12 with NaBH4,
immediately followed by ethanolysis, produced ethoxy
lactam 13.8 Cross-metathesis of 13 with acrolein was
achieved using the Grubbs-Hoveyda catalyst to give the
MBH-precursor 11.9
sulfide (1.5 equiv) were used. b The ratios of products trans-14 and cis-14
1
were estimated by the H NMR spectra.
the best yield (entry 4). The effects of Lewis and Brønsted
acids were next examined. When BF3·OEt2 instead of
TMSOTf was used, the stereoselectivity was slightly de-
creased (entry 5). After experimentation, the use of a
Brønsted acid such as Tf2NH or TfOH was found to give
good yield with high stereoselectivity (entries 6-8).10 The
configuration of the resulting stereocenter C-8a of MBH
product 14 was confirmed, after conversion into 15, by the
observation of convincing differences in NOE effects
between trans-15 and cis-15.
Scheme 2
We have also partially examined the scope of the Brønsted
acid mediated MBH ring-closure reaction, particularly with
respect to ring size, because aza-fused bicyclic systems, such
as those of the pyrrolizidine, indolizidine, and stemona
alkaloids, possess biological activities and have attracted
considerable attention in organic synthesis.11 Aminals 16 and
17, obtained from (S)-malic acid, smoothly cyclized to afford
the 5/5-bicyclic lactam 189 in 36% yield (trans:cis ) 91:9)
and the 5/7-bicyclic lactam 19 in 64% yield (trans:cis )
66:34), respectively (Scheme 3). The stereochemistry of the
resulting stereocenter C-9a of the MBH product 19 was also
confirmed, after conversion into 20, by the observation of
convincing differences in NOE effects between trans-20 and
cis-20.
We next examined the MBH ring-closure reaction of 11.
Initial investigations were focused on the solvent effect using
TMSOTf and Me2S.9 Although the stereoselectivities were
high, the chemical yield was fairly low in CH2Cl2, CH3NO2,
or toluene (Table 1, entries 1-3). When acetonitrile was used
as the solvent, the desired indolizidine 14 was obtained in
Completion of the total synthesis of 5 is depicted in
Scheme 4. Removal of the acetoxy group of trans-15 was
conducted by using the Barton-McCombie deoxygenation
protocol.12 Thus, lactam 21 obtained by deacetylation of
trans-15 was transformed to thionocarbonate, which was then
(10) For recent applications in asymmetric MBH reactions catalyzed
by chiral Brønsted acids, see: (a) Yamada, Y. M. A.; Ikegami, S.
Tetrahedron Lett. 2000, 41, 2165–2169. (b) McDougal, N. T.; Schaus, S. E.
J. Am. Chem. Soc. 2003, 125, 12094–12095. (c) McDougal, N. T.; Trevellini,
W. L.; Rodgen, S. A.; Kliman, L. T.; Schaus, S. E. AdV. Synth. Catal. 2004,
346, 1231–1240. (d) Matsui, K.; Tanaka, K.; Horii, A.; Takizawa, S.; Sasai,
H. Tetrahedron: Asymmetry 2006, 17, 578–583. (e) Matsui, K.; Takizawa,
S.; Sasai, H. Synlett 2006, 5, 761–765.
(6) For Brønsted acid catalyzed MBH reaction, see: (a) Wijnberg, B. P.;
Speckamp, W. N. Tetrahedron Lett. 1981, 22, 5079–5082. (b) Melching,
K. H.; Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. Tetrahedron Lett.
1986, 27, 4799–4802. (c) Taber, D. F.; Hoerrner, R. S.; Hagen, M. D. J.
Org. Chem. 1991, 56, 1287–1289. (d) Koseki, Y.; Fujino, K.; Takeshita,
A.; Sato, H.; Nagasaka, T. Tetrahedron: Asymmetry 2007, 18, 1533–1539.
(7) Lee, Y. S.; Lee, J. Y.; Kim, D. W.; Park, H. Tetrahedron 1999, 55,
4631–4636.
(11) (a) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773–781. (b) Michael,
J. P. Nat. Prod. Rep. 2002, 19, 719–741. (c) Pilli, R. A.; Ferreira de Oliveira,
M. C. Nat. Prod. Rep. 2000, 17, 117–127.
(8) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc.
1989, 111, 2588–2595.
(9) Myers, E. L.; de Vries, J. G.; Aggarwal, V. K. Angew. Chem., Int.
Ed. 2007, 46, 1893–1896.
(12) Barton, D. H. R.; Dorchak, J.; Jaszberenyi, J. C. Tetrahedron 1992,
48, 7435–7446.
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Org. Lett., Vol. 11, No. 5, 2009

Scheme 3
Scheme 4
treated with tributyltin hydride and a catalytic amount of
AIBN to afford deoxygenated lactam 22 in 94% yield from
21. Deprotection of the acetal of 22 by acid hydrolysis gave
aldehyde 10 in 97% yield. The crucial aldol reaction of enone
95 with aldehyde 10 was accomplished by employing boron-
enolate methodology to furnish 23 in quantitative yield as a
single isomer. The stereochemistry at the C-10 position of
23 was confirmed by means of the modified Mosher’s
method (see Supporting Information).13 Treatment of alcohol
23 with Dess-Martin periodinane gave 8, in which the
stereochemistry of C-11 was deduced from the large vicinal
1
coupling constants (JH11-H16 ) 11.2 Hz) in the H NMR
spectrum. R,ꢀ-Unsaturated ketone of 8 was protected as the
thiophenol adduct 24,14 which was converted into the
corresponding thioamide 25 by treatment with Lawesson’s
reagent. Finally, synthesis of grandisine D (5) was ac-
complished by elimination of the phenylthio group15 and
reduction of thioamide to grandisine D (5) with Meerwein’s
salt and NaBH3CN,16 in 63% yield from 25. The spectral
data were identical in all respects with the literature data.2
In summary, we have successfully completed the total
synthesis of grandisine D (5) from (S)-malic acid, featuring
Brønsted acid mediated MBH ring-closure reaction of 11
and stereoselective aldol reaction with (S)-5-methylcyclo-
hexenone (9). This compound 5 is thought to be a biogenetic
precursor of grandisines B (2) and F (4) and (-)-isoelaeo-
carpiline.1,2 This cyclization was also shown to be an efficient
strategy for the construction of aza-fused bicyclic systems,
such as those of pyrrolizidines and stemona alkaloids. Further
application of this strategy to the synthesis of grandisines
and other natural products is under investigation.
Acknowledgment. We are grateful to Dr. T. Ishizaki of
Kyorin Pharmaceutical Co., Ltd. for extensive support and
Dr. Y. Fukuda of Kyorin Pharmaceutical Co., Ltd. for his
encouragement and support of this project.
Note Added after ASAP Publication. BF3·OEt2 was
incorrectly shown as BF3·Et2 in the version published ASAP
February 9, 2009; the corrected version was published on
the Web February 12, 2009.
(13) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Khan, A. T.; Ghosh, S.; Choudhury, L. H. Eur. J. Org. Chem. 2006,
2226–2231.
(15) Treatment of 25 (1.0 equiv) with Meerwein’s salt (3.0 equiv) caused
methylation of thioamide group as well as phenylthio group, which
subsequently underwent elimination to regenerate enone moiety.
(16) Sundberg, R. J.; Amat, M.; Fernando, A. M. J. Org. Chem. 1987,
52, 3151–3159.
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