Stereoselective formal synthesis of (-)-mesembrane by intramolecular condensation of chiral amide and 1,3-cyclohexanedione moiety

Article abstract of DOI:10.1016/j.tetlet.2010.02.136

A new stereoselective formal synthesis of (-)-mesembrane has been achieved by intramolecular condensation of chiral amide and 1,3-cyclohexanedione moiety. The precursor amide was readily prepared by condensation of the corresponding chiral amine and acid.

Full text of DOI:10.1016/j.tetlet.2010.02.136

Tetrahedron Letters 51 (2010) 2354–2355
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Tetrahedron Letters
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Stereoselective formal synthesis of (ꢀ)-mesembrane by intramolecular
condensation of chiral amide and 1,3-cyclohexanedione moiety
Le Anh Tuan a,b, Guncheol Kim a,
*
a Department of Chemistry, College of Natural Science, Chungnam National University, Daejon 305–764, Republic of Korea
b Institute of Chemistry, Vietnamese Academy of Science and Technology (VAST), Hanoi, Viet Nam
a r t i c l e i n f o
a b s t r a c t
Article history:
A new stereoselective formal synthesis of (ꢀ)-mesembrane has been achieved by intramolecular conden-
sation of chiral amide and 1,3-cyclohexanedione moiety. The precursor amide was readily prepared by
condensation of the corresponding chiral amine and acid. Condensation provided moderate ratios of
ene-amide derivatives and the following transformation of functional groups has yielded the known pre-
cursor for (ꢀ)-mesembrane, resulting in formal synthesis.
Received 30 January 2010
Revised 18 February 2010
Accepted 23 February 2010
Available online 1 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Mesembrane 1 is a member of the Sceletium alkaloids,1 which
has the basic structural element of cis-3a-aryloctahydroindole
skeleton 3. Crinine 2 is also a prototype of the alkaloids.2 These
alkaloids containing quaternary center at C3a constitute a large
family of products that have attracted considerable attention over
the years due to their diverse and interesting structures,3 and sev-
eral asymmetric approaches have also been suggested (Fig. 1).4
Initially, as a new effort toward the asymmetric synthesis of
mesembrane, we tried to apply desymmetrization of enantiotopic
1,3-dicarbonyl groups of compound 45 by condensation with chiral
phenylglycinol (Scheme 1).7
Conversion of compound 7a to the known intermediate 10 for
(ꢀ)-mesembrane has been carried out by reducing the carbonyl
to alcohol and transforming the alcohol to xanthate 8 in 95% in
two steps.9 Reduction of the xanthate to inseparable hexahydroin-
dol-2-ones 9 by Bu3SnH/AIBN was achieved in 84% yield. Fortu-
nately, each reaction provided the inseparable products in good
MeO
O
OMe
MeO
OMe
Ph
O
H2N
OH
- H2O
However, the chiral induction obtained under various dehydra-
tion conditions was found to be only ca. 1:1, and the diastereomers
of 5 were not separable.
COOH
N
O
O
O
Ph
4
5
In order to improve the selectivity in the cyclization step, we
decided to attempt an intramolecular amide-carbonyl condensa-
tion. Chiral amide precursors 6 have been prepared by coupling 4
with the commercially available chiral amines using 2-chloro-
4,6-dimethoxy-1,3,5-triazine (CDMT)/N-methylmorphorine N-
oxide (NMM) in good yields.8 The following asymmetric cycliza-
tion to 7 has been found to be optimal 65 °C in benzene in the pres-
ence of catalytic amount of TsOH. Higher temperature reduced the
selectivity and even yields due to some decomposition, and the
lower temperature showed only retarded reaction process without
enhancing the selectivity. 1-(1-Naphthyl)ethyl group on the nitro-
gen provided the best ratio 3:1 in quantitative yield, however, as
an inseparable diastereomeric mixture. It seems that steric interac-
tion between dimethoxyphenyl group and bulkier aromatic groups
of amide would play a role for differentiating the two carbonyl
groups in the reaction with the amide (Table 1).
Scheme 1.
O
OMe
O
OMe
HO
N
N
H
H
CH3
1: (-)-mesembrane
2: crinine
Ar
H
3a
N
R
3: cis-3a-aryloctahydroindole
ring skeleton
* Corresponding author. Tel.: +82 42 821 5475; fax: +82 42 821 8896.
E-mail address: guncheol@cnu.ac.kr (G. Kim).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.136

L. A. Tuan, G. Kim / Tetrahedron Letters 51 (2010) 2354–2355
2355
Table 1
We have tried to differentiate the enantiotopic 1,3-dicarbonyl
groups of 1,3-cyclohexanedione by asymmetric cyclodehydration
process for the synthesis of chiral mesembrane. In the intramolec-
ular condensation process, marginal selectivity has been found,
and the subsequent conversion to the known intermediates
confirmed each of the structures and ensued the formal synthesis
of (ꢀ)-mesembrane.
OMe
OMe
OMe
OMe
O
O
TsOH, benzene
65oC, 2h
CONHR
N
R
O
O
6
7
Acknowledgment
Entry
1
R
Yield (%)
Ratio of 7a
This work was supported by the Korea Research Foundation
Grant funded by Korean Government (MOEHRD, Basic Research
Promotion Fund) (KRF-2008–313-C00461).
99
97
82
3:1
1-Naph
Me
H
References and notes
2
3
2.4:1
1.2:1
Me
H
Ph
1. Jeffs, P. W.. In The Alkaloids; Rodrigo, R. G. A., Ed.; Academic Press: New York,
1981; Vol. 19, p 1.
2. Lewis, J. R. Nat. Prod. Rep. 1998, 15, 107.
C6H11
Me
H
3. (a) Hoshino, O.. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York,
1987; Vol. 51, p 323; (b) Pearson, W. H.; Szura, D. P.; Postich, M. J. J. Am. Chem.
Soc. 1992, 114, 1329; (c) Iwamatsu, S. I.; Matsubara, K.; Nagashima, H. J. Org.
Chem. 1999, 64, 9625; (d) Padwa, A.; Brodney, M. A.; Dimitroff, M.; Liu, B.; Wu,
T. J. Org. Chem. 2001, 66, 3119; (e) Bru, C.; Guillou, C. Tetrahedron 2006, 62,
9043; (f) Bohno, M.; Imase, H.; Chida, N. Chem. Commun. 2004, 1086; (g)
Pearson, W. H.; Lovering, F. E. J. Org. Chem. 1998, 63, 3607; (h) Martin, S. F.;
Campbell, C. L. J. Org. Chem. 1988, 53, 3184.
H
Me
4
83
1.1:1
Me Me
Ratios were detected by 1H NMR.
a
4. For the asymmetric syntheticapproaches, see: (a) Solé, D.; Bonjoch, J. Tetrahedron
Lett. 1991, 32, 5183; (b) Mori, M.; Kuroda, S.; Zhang, C. S.; Sato, Y. J. Org. Chem.
1997, 62, 3263; (c) Saito, M.; Matsuo, J. I.; Ishibashi, H. Tetrahedron 2007, 63, 4865.
5. Compound 4 has been prepared by modifying the known process4a,6 coupling
1,3-cyclohexadione with 4-bromoveratrole in the presence of Pd(OAc)2
(0.01 equiv) and (2-biphenyl)di-tert-butylphosphine (0.02 equiv) (81% yield),
O-allylation with allylbromide followed by Claisen rearrangement (86% yield),
and oxidative cleavage to carboxylic acid 4 by NaIO4/KMnO4 (65% yield): 1H
NMR (400 MHz, CDCl3) d 6.81 (1H, d, J = 8.4 Hz), 6.63–6.55 (2H, m), 3.86 (3H, s,
OMe), 3.83 (3H, s, OMe), 3.22 (2H, s), 2.78–2.62 (4H, m br), 1.98–1.84 (2H, m
br); 13C NMR (100 MHz, CDCl3) d 207.2, 177.0, 149.7, 148.9, 126.8, 119.1, 111.7,
109.3, 69.9, 55.9, 55.8, 40.6, 38.6, 17.0; IR (neat, cmꢀ1) 2940, 1716, 1697, 1516,
1261, 1150, 1022, 669.
OMe
OMe
OMe
OMe
MeS
S
O
O
AIBN, Bu3SnH
i) NaBH4, THF/MeOH
toluene, reflux, 4h
84%
N
H
O
ii) NaH, CS2, MeI, THF
48h, 95% (2 steps)
N
H
O
Me
1-Naph
Me
1-Naph
8
7a
6. Liang, Z.; Hou, W.; Du, Y.; Zhang, Y.; Pan, Y.; Mao, D.; Zhao, K. Org. Lett. 2009, 11,
4978.
7. Amat, M.; Cantó, M.; Llor, N.; Ponzo, V.; Pérez, M.; Bosch, J. Angew. Chem., Int.
Ed. 2002, 41, 335.
OMe
OMe
OMe
OMe
OMe
OMe
8. Garrett, C. E.; Jiang, X.; Prasad, K.; Repic, O. Tetrahedron Lett. 2002, 43, 4161.
9. Huang, Q.; Wang, Q.; Zheng, J.;Zhang, J.; Pan, X.;She, X. Tetrahedron2007, 63, 1014.
10. Compound 10: ½a D30
ꢁ
64.2 (c 1.45, CHCl3); 1H NMR (400 MHz, CDCl3) d 8.22 (1H,
TFA, Et3SiH
2h, 91%
d, J = 8.0 Hz), 7.83 (1H, d, J = 8.0 Hz), 7.77 (1H, m), 7.58–7.38 (4H, m), 6.98 (1H,
dd, J = 2.0, 8.4 Hz), 6.92 (1H, d, J = 2.0 Hz), 6.85 (1H, d, J = 8.4 Hz), 6.06 (1H, q,
J = 6.8 Hz), 3.94 (3H, s, OMe), 3.89 (3H, s, OMe), 3.53 (1H, dd, J = 5.6, 8.4 Hz),
2.80 (1H, d, J = 16.4 Hz), 2.61 (1H, d, J = 16.4 Hz), 1.80–1.60 (2H, m), 1.43–1.36
(1H, m), 1.2–1.1 (1H, m), 1.11 (3H, d, J = 6.8 Hz), 0.95–0.68 (3H, m), 0.53–0.47
(1H, m); 13C NMR (100 MHz, CDCl3) d 173.1, 148.8, 147.7, 139.1, 136.5, 133.4,
132.3, 128.6, 128.5, 126.7, 125.8, 124.8, 124.0, 123.6, 118.6, 110.8, 110.2, 61.6,
56.2, 55.9, 45.28, 45.26, 39.8, 35.5, 29.1, 22.1, 21.6, 15.6; IR (neat, cmꢀ1) 3048,
2935, 2859, 1675, 1520, 1453, 1416, 1255, 1027, 808, 780, 731. Compound 11:
N
H
O
N
H
O
1-Naph
N
O
Me
1-Naph
Me
Me
1-Naph
H
H
H
10
9
(68%)
11
(23%)
Scheme 2.
½
a 3D0
ꢁ
ꢀ71.4 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.76 (1H, d, J = 8 Hz),
7.72 (1H, d, J = 8 Hz), 7.54 (1H, d, J = 6.8 Hz), 7.43 (1H, m), 7.36–7.29 (2H, m),
7.02 (1H, m), 6.36 (1H, dd, J = 2.8, 8.4 Hz), 6.26 (1H, d, J = 8.4 Hz), 6.10 (1H, d,
J = 2.8 Hz), 5.98 (1H, q, J = 7.2 Hz), 3.76 (3H, s, OMe), 3.45 (3H, s, OMe), 2.97
(1H, dd, J = 6, 9.2 Hz), 2.80 (1H, d, J = 16.4 Hz), 2.67 (1H, d, J = 16.4 Hz), 2.05 (1H,
m), 1.72 (3H, d, J = 6.8 Hz), 1.72–1.16 (7H, m); 13C NMR (100 MHz, CDCl3) d
173.1, 148.1, 147.1, 138.2, 134.4, 133.3, 131.6, 128.6, 127.9, 126.1, 125.4, 124.4,
123.8, 123.0, 117.2, 109.9, 108.7, 61.5, 55.5, 55.3, 46.3, 44.5, 39.8, 36.4, 31.0,
22.6, 21.9, 18.5; IR (neat, cmꢀ1) 2932, 2857, 1678, 1520, 1411, 1254, 1151,
1028, 804, 779.
yields without change of the diastereomeric ratio. Reduction of 9
with Et3SiH4c provided octahydroindol-2-one 10 as a major prod-
uct (68%) and its isomer 11 as a minor product (23%). The spectral
data10 of these compounds were identical to those published in the
literature4c {10: ½a D30
ꢁ
64.2, lit. ½a 2D6
ꢁ
65.6; 11: ½a 3D0
ꢁ
ꢀ71.4, lit. ½a 2D6
ꢁ
ꢀ73.0} (Scheme 2).