An expeditious total synthesis of (±)-jamtine using condensation between imine and acid anhydride

Article abstract of DOI:10.1016/j.tetlet.2009.10.091

A totally convergent and very short (three steps) synthesis of (±)-jamtine was described. The key step of this sequence was the condensation of 6,7-dimethoxy-3,4-dihydroisoquinoline and tetrahydrophthalic anhydride under microwave activation which occurred in good yield and high diastereomeric selectivity.

Full text of DOI:10.1016/j.tetlet.2009.10.091

Tetrahedron Letters 51 (2010) 96–98
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An expeditious total synthesis of ( )-jamtine using condensation between
imine and acid anhydride
*
Joelle Pérard-Viret, Florence Souquet, Marie-Line Manisse, Jacques Royer
Synthèse et Structure de Molécules d’Intérêt Pharmacologique, UMR 8638 CNRS-Université Paris Descartes, 4 Avenue de l’Observatoire, 75270 Paris Cedex 06, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A totally convergent and very short (three steps) synthesis of ( )-jamtine was described. The key step of
this sequence was the condensation of 6,7-dimethoxy-3,4-dihydroisoquinoline and tetrahydrophthalic
anhydride under microwave activation which occurred in good yield and high diastereomeric selectivity.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 October 2009
Revised 15 October 2009
Accepted 19 October 2009
Available online 23 October 2009
Keywords:
Natural product synthesis
Microwave-assisted synthesis
Pyrroloisoquinoline
Isoquinoline alkaloid
Jamtine
Imine condensation
Acid anhydride condensation
1. Introduction
We want to report herein our own efforts towards the synthesis
of jamtine which allowed us to achieve an expeditious synthesis of
Our general interest in the synthesis of diversely substituted
pyrrolidine derivatives1 led us to launch a study on the total syn-
thesis of jamtine (1). This compound is one of the medicinal alka-
loids isolated from the climbing shrub Cocculus hirsutus which
originates from Pakistan and India.2 This plant is renowned for
its therapeutic properties and is used in folk medicine. Jamtine to-
gether with other extracted substances was found to have signifi-
cant antihyperglycemic activity.3
this alkaloid.6 During the redaction of this Letter we were aware
from a recent paper of Shaw7 which described the condensation
reaction we used as a key step, with the same substrates and
experimental conditions along a methodological study.
2. Results and discussion
2.1. First synthetic plan: dimethoxydihydrofuran condensation
We already reported on the condensation of a primary amine
with dimethoxydihydrofuran to prepare pyrrolidones.1 The
reaction was applied to the preparation of several pyrrolidine
derivatives but also to polycyclic compounds including pyrroloiso-
quinolines.1b We thought that this condensation could be extended
to adequately substituted dimethoxydihydrofuran to prepare pyr-
roloisoquinoline ester 4 as a precursor of jamtine (1) (Scheme 1).
We thus prepared dimethoxydihydrofuran methyl ester 2 accord-
ing to the literature8 and engaged this compound in the condensa-
tion with 2-(3,4-dimethoxyphenyl)ethylamine.9 The reaction
provided pyrrolidone 3 (50% yield) which was treated with TFA
at rt for 2 h to give the pyrroloisoquinoline 49 in 76% yield as a sin-
gle diastereomer.
MeO
N
MeO
H
MeOOC
jamtine 1
Up to now, only two total syntheses have been reported: the
first one was based on a thionium/N-acyliminium ion cascade by
Padwa and Danca4 and the second was an asymmetric synthesis
using a chiral base desymmetrisation by Simpkins and Gill.5
Though this condensation gave a rapid access to the tricyclic
intermediate 4, the rest of the synthesis to jamtine (1) would con-
sist in the introduction of the cyclohexene D-ring which would
probably hamper the overall sequence by the further use of some
* Corresponding author.
E-mail address: jacques.royer@parisdescartes.fr (J. Royer).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.091

J. Pérard-Viret et al. / Tetrahedron Letters 51 (2010) 96–98
97
MeO
MeO
Cl
MeO
NH3
TFA
MeO
MeO
citric acid
H2O-CCl4
O
OMe
MeO
N
2h, rt
N
O
O
MeO
MeOOC
H
MeOOC
MeOOC
2
3
4
Scheme 1. Substituted dimethoxydihydrofuran condensation.
MeO
O
O
O
+
MeO
MeO
12b
N
O
H
MeO
H
N
12a
ROOC
8a
5
6
7a,b,c R = H
8a,b,c
TMS-CHN2
R = Me
Scheme 2. Castagnoli condensation with 1,2-cyclohexanedicarboxylic anhydride (6).
days, 29% of diastereomeric mixture of the expected carboxylic
acid 7 was isolated.
Table 1
Condensation of imine 5 with anhydride 6
It was rapidly found that the condensation could be dramati-
cally improved by the use of microwave activation13 since 70%
yield was obtained after a 45-min irradiation at 150 °C in toluene
(Table 1, entry 2).14
Entry
Solvent
Experimental
conditions
7 yield (%)
Diastereomeric
ratioa a/b/c (%)
1
2
3
4
5
Toluene
Toluene
ClCH2CH2Cl
DMF
Reflux, three days
29
70
20
33
75
68/5/27
53/30/17
61/36/3
50/50/—
60/32/8
l
l
l
l
Wb, 45 min, 150 °C
W, 45 min, 150 °C
W, 45 min, 150 °C
W, 45 min, 150 °C
Nevertheless, this better yield was accompanied by a lower dia-
stereoselectivity. Then the effect of the solvent on the reaction was
briefly examined. Toluene or acetonitrile was found to give the
best yields while with similar and poor diastereoselectivity (Table
1, entries 2 and 5). In any cases, three isomers were detected
among the four theoretically possible. The major isomer 8a15 could
be easily isolated after esterification (TMSCHN2,16 88–100% yield).
This compound was not identical with that described by Simpkins
(epimeric at C8a), but it possessed the required syn (C12a–C12b) con-
figuration17 and thus could be transformed to jamtine through the
already-described synthesis.5 Ester 8b exhibited a reverse anti
(C12a–C12b) configuration.18
CH3CN
a
Estimated by NMR on the crude reaction mixture.
Microwaves reactor.
b
tedious steps. We then looked for a more convergent approach and
turned our attention to the Castagnoli10 reaction which should of-
fer a better solution to our synthetic task.
2.2. Second synthetic plan: Castagnoli condensation
Despite this success, we anticipated that the use of unsaturated
anhydride 9 instead of 6 should provide a more convergent approach
giving an intermediate possessing the required double bond. Indeed,
Forty years ago, Castagnoli described a reaction between imines
and cyclic anhydrides to form lactams. This process could be used
to achieve convergent syntheses of natural or biologically active
products.11 We thought that this cycloaddition could be the exact
answer to the synthesis of jamtine (1) allowing the installation of
the four rings of the natural product in a single step as well as
the carboxylic acid function.
under similar experimental conditions (CH3CN,
lW reactor, and
150 °C for 45 min) it was our delight to find that isoindoloisoquino-
line acid 1014 was formed in a nice 78% yield and a 1:1 mixture of two
diastereomers (Scheme 3, Table 2, entry 1).
By analogy with the previous study, we reasoned that the dia-
stereomeric ratio might be modified by varying the experimental
conditions (Table 2). We then investigated the reaction of 9 in
different solvents (Table 2, entries 1–4). Using the same irradiation
The reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline (5)12
with 1,2-cyclohexanedicarboxylic anhydride (6) was first investi-
gated in refluxing toluene (Scheme 2, Table 1, entry 1). After three
MeO
MeO
MeO
O
O
O
+
MeO
MeO
N
N
O
O
MeO
H
H
+
N
ROOC
ROOC
5
9
10a (R = H)
10b (R = H)
TMSCHN2
TMSCHN2
11a (R = Me)
11b (R = Me)
Scheme 3. Castagnoli condensation with tetrahydrophthalic anhydride (9).

98
J. Pérard-Viret et al. / Tetrahedron Letters 51 (2010) 96–98
Synth. Commun. 1997, 27, 2817–2824; (c) Halie, D.; Pérard-Viret, J.; Dufour, S.;
Table 2
Royer, J. Tetrahedron 2009, 65, 1402–1414.
Condensation of imine 5 with anhydride 9
2. (a) Ahmad, V. U.; Rahman, A.; Rasheed, T.; Rehman, H. Heterocycles 1987, 26,
1251–1255; (b) Rasheed, T.; Khan, M. N. I.; Zhadi, S. S. A.; Durrani, S. J. J. Nat.
Prod. 1991, 54, 582–584.
Entry
Solvent
Experimentala
conditions
10 yield (%)
Diastereomeric ratiob
a (syn)/b (anti) (%)
3. Badole, S.; Patel, N.; Bodhankar, S.; Jain, B.; Bhardwaj, S. Indian J. Pharmacol.
2006, 38, 49–53.
1
2
3
4
5
6
7
CH3CN
Toluene
THF
CHCl3
CH3CN
CH3CN
CH3CN
45 min, 150 °C
45 min, 150 °C
45 min, 150 °C
45 min, 150 °C
90 min, 150 °C
90 min, 160 °C
45 min, 180 °C
78
62
84
62
84
76
48
43/57
25/75
20/80
36/64
62/38
83/17
95/5
4. (a) Padwa, A.; Danca, M. D. Org. Lett. 2002, 4, 715–717; (b) Padwa, A.; Danca, M.
D.; Hardcastle, K. I.; McClure, M. S. J .Org. Chem. 2003, 68, 929–941.
5. (a) Simpkins, N. S.; Gill, C. D. Org. Lett. 2003, 5, 535–537; (b) Gill, C. D.;
Greenhalgh, D. A.; Simpkins, N. S. Tetrahedron 2003, 59, 9213–9230.
6. Preliminary Communication at the XIIth ICSN Symposium: ‘From Organic
Chemistry to Chemical Biology’, July 11–12th, 2009. Gif-sur-Yvette, France.
7. Tang, Y.; Fettinger, J. C.; Shaw, J. T. Org. Lett. 2009, 11, 3802–3805.
8. Stibor, I.; Srogl, J.; Janda, M.; Piricova, N.; Vlazny, K. Collect. Czech. Chem.
Commun. 1982, 47, 3261–3267.
a
All the reactions were performed under microwave activation.
Estimated by NMR.
b
9. To 2-(3,4-dimethoxyphenyl)ethylamine–HCl (2.17 g, 10 mmol) and citric
acid (3.84 g, 20 mmol) in H2O (80 mL) was added
2 (2.0 g, 10 mmol) in
CCl4 (35 mL). The solution was vigorously stirred under reflux for 8 h. The
organic layer was washed with satd NaHCO3 soln, dried with MgSO4,
concentrated in vacuo and the residue was purified by flash column
time and temperature, it appeared that when acetonitrile or tetra-
hydrofuran was employed, highest yields were observed, but vary-
ing diastereomeric ratios were found. With THF (Table 2, entry 3), a
clean and high yielding reaction was observed but unfortunately
the anti diastereoisomer 10b was the major isomer.
In order to reverse the diastereomeric ratio, we focussed on the
reaction in acetonitrile and changed the irradiation time and the
temperature (Table 2, entries 1, 5–7)). It was then found that a
longer reaction time led predominantly to 10a. In the same way,
a slight increase in the temperature (Table 2, entry 6) led to a
76% yield and a good 83:17 ratio in favour of the syn diastereomer.
Eventually higher temperature (Table 2, entry 7) gave a 95:5 ratio
albeit in lower yield (some degradation occurred).
chromatography (SiO2, CH2Cl2/AcOEt 80:20), to give
3 (1.59 g, 50%). A
solution of 3 (1 g, 3.3 mmol) in TFA (4 mL) was stirred at rt for 2 h. After
concentration, the residue was extracted with CH2Cl2 and washed with satd
NaHCO3 soln. After solvent evaporation, the residue was purified by flash
column chromatography (SiO2, CH2Cl2/AcOEt 70:30) to lead to 4 (770 mg,
76%). Mp 125 °C; 1H NMR (CDCl3, 300 MHz): d (ppm): 2.35–2.62 (4H, m);
2.68–2.86 (2H, m); 3.53 (3H, s, OCH3); 3.55 (3H, s, OCH3); 3.59 (3H, s,
OCH3); 3.89 (1H, m); 4.68 (1H, d, J = 7.5 Hz, CHN); 6.34 (1H, s, Har); 6.49
(1H, s, Har); 13C NMR (75 MHz, CDCl3) (ppm) :27.7 (CH2); 35.1 (CH2); 36.9
(CH2); 45.4 (CH); 52.3 (COOMe); 55.4 (OMe); 55.5 (OMe); 58.4 (CH); 107.6
(CHar); 111.5 (CHar); .125.6 (Car); 127.7 (Car); (147.8 (Car); 147.9 (Car); 169.7
(CO); 173.4 (CO).
10. Castagnoli, N. J. Org. Chem. 1969, 34, 3187–3189.
11. (a) Cushman, M.; Castagnoli, N. J. Org. Chem. 1971, 36, 3404–3406; (b)
Cushman, M.; Gentry, J.; Dekow, F. W. J. Org. Chem. 1977, 42, 1111–1116; (c)
Gonzalez-Lopez, M.; Shaw, J. T. Chem. Rev. 2009, 109, 164–189.
12. Warrener, R. N.; Liu, L.; Russel, R. A. Tetrahedron 1998, 54, 7485–7496.
13. Bose, A. K.; Manhas, M. S.; Ghosh, M.; Raju, V. S.; Tabei, K.; Urbanczyk-
Lipkowska, Z. Heterocycles 1990, 30, 741–744.
14. General procedure: Imine 5 (96 mg; 0.5 mmol) and anhydride 6 or 9 (0.5 mmol)
in 2 mL of solvent were heated in a microwave reactor under stirring. The
solution was concentrated in vacuo, extracted with NaOH 1 M and washed
twice with CH2Cl2. The aqueous layer was acidified by concentrated HCl and
extracted with CH2Cl2 (3 Â 15 mL). The organic layers were dried with
anhydrous MgSO4 and concentrated in vacuo.
The supposed thermodynamic control of the reaction was
checked. On heating (lW reactor, 150 °C, 90 min), the 20:80 mixture
of syn/anti diastereomers 10(arising from THF experiment)was con-
verted into a 50:50 mixture in 80% yield. The reaction was thus
reversible and an acyliminium intermediate could be invoked. This
clearly suggested that the syn isomer should be the thermodynamic
product of this condensation as proposed by Shaw,7 on the basis of
theoretical calculations. Nevertheless, this author did not experi-
mentally verify his proposal and suggested an inverse diastereo-
meric ratio according to the presence, or not, of Et3N, Et3N–HCl.
The syn methyl ester 11a was obtained in 56% from 5 after
treatment of the crude mixture (83:17) of acids 10 with trimethyl-
silyl diazomethane and separation on silica gel column chromatog-
raphy. The reduction of the amide function following the published
method5 (Et3OBF4 then NaBH4, 64%) gave jamtine (1).
15. Analytical data for 8a: 1H NMR (CDCl3, 300 MHz): d (ppm): 1.15–1.35 (3H, m);
1.60–1.85 (3H, m); 2.06 (1H, m); 2.35 (1H, m); 2.47 (1H, m); 2.65–2.76 (3H, m);
3.16 (3H, s, COOMe); 3.80 (3H, s, OCH3); 3.84 (3H, s, OCH3); 4.33 (1H, m); 4.62
(1H, s, CHN); 6.53 (1H, s, Har); 6.59 (1H, s, Har); 13C NMR (75 MHz, CDCl3)
(ppm): 21.9 (CH2); 23.0 (CH2); 25.1 (CH2); 28.1 (CH2); 32.4 (CH2); 36.5 (CH2);
51.1 (CH); 51.2 (COOMe); 55.8 (OMe); 56.0 (OMe); 58.8 (Cq); 64.4 (CHN); 111.4
(CHar); 109.5 (CHar); .123.5 (Car); 127.2 (Car); (147.6 (Car); 148.1 (Car); 171.3
(CO); 173.4 (CO).
16. Presser, A.; Hüfner, A. Monatsh. Chem. 2004, 135, 1015–1022.
17. The syn isomer is characterized by a strong upfield shift of the methyl group of
the ester; see Ref. 2a.
18. Compound 8c has not been obtained in pure form, its configuration was
tentatively assigned as anti (C12a–C12b) after examination of the NMR spectra of
the mixture 8a–c.
In summary, we described an efficient and highly convergent
synthesis of ( )-jamtine (1)19 in three steps and 36% overall yield.
References and notes
19. The analytical data of our synthetic material were identical with those
described by Padwa4 and Simpkins5 who mentioned some doubt on the
structure of the natural product.
1. (a) Baussanne, I.; Dudot, B.; Pérard-Viret, J.; Planas, L.; Royer, J. Arkivoc 2006, 7,
57–66. and references cited herein; (b) Fontaine, H.; Baussanne, I.; Royer, J.