Total synthesis of (±)-martinelline

Article abstract of DOI:10.1016/S0040-4039(02)02331-6

The squaric acid-catalyzed imino-Diels-Alder reaction of enamine 4 with the imine 5 provides the pyrroloquinolines 6 and 7, which were converted to the triamine 3 using regioselective reduction and a Wittig reaction as the key steps. Guanylation of 3 foll

Full text of DOI:10.1016/S0040-4039(02)02331-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9405–9409
Total synthesis of ( )-martinelline
Chengfeng Xia,a Linshen Hengb and Dawei Maa,*
aState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, 354 Fenglin Lu,
Shanghai 200032, China
bDepartment of Chemistry, Daxian Normal College, Sichuan 635000, China
Received 27 August 2002; revised 30 September 2002; accepted 11 October 2002
Abstract—The squaric acid-catalyzed imino-Diels–Alder reaction of enamine 4 with the imine 5 provides the pyrroloquinolines 6
and 7, which were converted to the triamine 3 using regioselective reduction and a Wittig reaction as the key steps. Guanylation
of 3 followed by coupling with the alcohol 19 furnished the total synthesis of ( )-martinelline. © 2002 Elsevier Science Ltd. All
rights reserved.
The Martinella are a family of tropical plants contain-
ing two species, M. iquitosensis A. Sampaio and M.
obovata (HBK.) Bur. & K. Schum. Preparations from
the root bark of Martinella species have been used as
an eye medication in over 13 different ethnolinguistic
groups from eight South American countries. In 1995,
scientists at Merck reported the isolation of two alka-
loids from an organic extract of M. iquitosensis roots
named as martinelline 1 and martinellic acid 2 (Scheme
1). The presence of alkaloids 1 and 2 in Martinella
could be used to explain partially its therapeutic prop-
erties.1 Further biological evaluation indicated that
martinelline was an effective inhibitor for several G-
protein coupled receptor systems including bradykinin
(BK), histaminergic, a-adrenergic, and muscarinic
receptors. This is the first example of a nonpeptide
natural product being identified as a BK receptor
antagonist. In addition, both alkaloids contain a
pyrroloquinoline skeleton that is unprecedented in
nature. Therefore, it is not surprising that synthetic
interest in these targets has been considerable. To date,
a number of synthetic efforts have been disclosed.2–6 In
a previous report, we described the first total synthesis
of martinellic acid using a CuI-catalyzed coupling of an
enantiopure b-amino ester as a key step.4 Herein we
wish to report the total synthesis of ( )-martinelline
through triamine 3, a key intermediate obtained this
time by a squaric acid-catalyzed Diels–Alder reaction of
the enamine 4 with the imine 5.
Using an imino-Diels–Alder strategy to assemble the
core structure of martinellic acid and martinelline was
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02331-6

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C. Xia et al. / Tetrahedron Letters 43 (2002) 9405–9409
initially studied by Stevenson’s and Batey’s groups.2
The advantage of this approach was that all three chiral
centers present in the hexahydropyrroloquinone core
were generated in one synthetic operation. In fact, the
triamine 3 has been successfully obtained utilizing an
InCl3-catalyzed cycloaddition (Scheme 2) of a trans-cin-
namaldehyde derived imine with an electron-rich olefin
as the key step.2b However, this step gave the desired
exo-product A in 40% yield, together with an almost
equal amount of the endo-product, which was useless
for further transformations. Stevenson and co-workers
also found that the Diels–Alder reaction of a methyl
glyoxalate derived imine provided B as a mixture of
exo- and endo-isomers in rather low yields.2a,c After
careful analysis of this reaction, we realized that the
endo-product or its derivative C might be converted to
the thermodynamically stable exo-isomer D under basic
conditions. If this idea worked, and the reaction yield
in the Diels–Alder cycloaddition of glyoxalate-derived
imine could be improved, we would be able to develop
a very efficient protocol to martinellic acid and
martinelline.
Regioselective reduction of the diester 6 was achieved
with NaBH4/LiCl in a mixture of 1/10 methanol–THF
at room temperature to afford the alcohol 8 (Scheme
4). In order to attach the side chain by a Wittig
reaction, we had to protect the 1-amino group. This
was found to be a challenging task because many
methods such as direct acylation with acetic anhydride
or trifluoroacetic anhydride followed by release of the
hydroxyl group under basic conditions were not suit-
able. This problem resulted from the facile deprotection
of the 1-acyl group under basic conditions presumably
assisted by the adjacent free hydroxyl group. After
many experiments, we found that the following reaction
sequence met our requirements: (1) protection of the
hydroxyl group as a silyl ether; (2) treatment of the silyl
ether with acetic anhydride at 100°C to protect the
amino group; (3) removal of the silyl group through the
action of TsOH in methanol. Next, a Swern oxidation
of 9 gave the corresponding aldehyde as a mixture of
trans- and cis-isomers, which showed that isomeriza-
tion had occurred at the 2-position as we suspected.
Without further purification, this aldehyde mixture was
condensed directly with (carbethoxymethylene)-
triphenylphosphorane giving diester 108 (85% yield)
as the major product, together with a small amount of
the 2-epimer 11 (6% yield). This result indicated that
during the Swern oxidation and subsequent Wittig reac-
tion the cis-aldehyde intermediate was isomerized to its
thermodynamically more stable trans-isomer. Thus,
in this manner we had successfully changed the
stereochemistry of the major product from the imino-
Diels–Alder reaction to that required for synthesis
of martinellic acid and martinelline. Following the
same procedure, we transformed the exo-isomer 7 to
the diester 10 in 61% overall yield. Overall, the
With the above idea in mind, we investigated the
cycloaddition reaction of the imine with the enamine 4
and found that an unusual catalyst, squaric acid, was
an effective catalyst for this transformation. Thus,
treatment of a mixture of 4-methoxycarbonylaniline,
ethyl glyoxalate and the enamine 4 with 5 mol% of
squaric acid in acetonitrile provided the addition prod-
ucts 6 and 7 in a ratio of 2:1 and >92% yield (Scheme
3).7 Other catalysts we examined such as Lewis acids2d,e
also worked for this reaction but lower yields were
observed. For example, in the case of Sc(OTf)3 as the
catalyst, 6 and 7 was obtained in a ratio of 1:2 and 72%
yield.
Scheme 2.
Scheme 3.

C. Xia et al. / Tetrahedron Letters 43 (2002) 9405–9409
9407
Scheme 4.
yield of intermediate 10 from the imino-Diels–Alder
tion was carried out to remove the Cbz group and
reduce the azide moiety to provide 3 as its hydrochlo-
ride salt. Condensation of the triamine 3 with S-
methylisothiourea 15 gave the guanylation product 16
in 68% yield.4
reaction was 54%.
Hydrogenation of 10 afforded the diester 12, which was
reduced with NaBH4/LiCl in a mixture of 1/10
methanol–THF at 50°C to give the alcohol 13 (Scheme
5). Reprotection of the amino group with (CF3CO)2O
followed by conversion of the hydroxyl to the azido
group provided the azide 14. After hydrolysis of 14
with K2CO3 in methanol, Pd/C catalyzed hydrogena-
In order to introduce the ester moiety of martinelline,
we required a functionalized alcohol 20, which was
synthesized as outlined in Scheme 6. This synthesis
started from 1-hydroxyacetone and utilized a Wittig
Scheme 5.

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C. Xia et al. / Tetrahedron Letters 43 (2002) 9405–9409
Scheme 6.
Scheme 7.
reaction and a guanylation9 with N,N-di-Boc-triflyl-
guanidine as the key steps.
Thompson, N. Tetrahedron Lett. 2001, 42, 6417; (c)
Hadden, M.; Nieuwenhuyzen, M.; Potts, D.; Stevenson,
P. J.; Thompson, N. Tetrahedron 2001, 57, 5615; (d)
Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.;
Lough, A. J. Chem. Commun. 1999, 651; (e) Batey, R. A.;
Powell, D. A. Chem. Commun. 2001, 2362.
After hydrolysis of 16 with NaOH in methanol, the
resultant acid was coupled with 19 mediated with EDCI
to provide the ester 2110 in 80% yield (Scheme 6).
Finally, treatment of 21 with 5% TFA under the assis-
tance of anisole afforded martinelline 1, which showed
identical analytical data with those reported. Thus, the
total synthesis of ( )-martinelline was achieved in 17
linear steps and 8% overall yield (Scheme 7).
3. By intermolecular [3+2] cycloaddition strategy, see:
Nyerges, M.; Fejes, I.; Toke, L. Tetrahedron Lett. 2000,
41, 7951.
4. By CuI-catalyzed coupling strategy, see: Ma, D.; Xia, C.;
Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189.
5. By intramolecular [3+2] cycloaddition strategy, see: (a)
Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron Lett.
1999, 40, 3339; (b) Snider, B. B.; O’Hare, S. M. Tetra-
hedron Lett. 2001, 42, 2455; (c) Snider, B. B.; Ahn, Y.;
O’Hare, S. M. Org. Lett. 2001, 3, 4217; (d) Lovely, C. J.;
Mahmud, H. Tetrahedron Lett. 1999, 40, 2079; (e) Mah-
mud, H.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2001,
57, 4095; (f) Ho, T. C. T.; Jones, K. Tetrahedron 1997,
53, 8287.
6. By other strategies, see: (a) Kim, S. S.; Cheon, H. G.;
Kang, S. K.; Yum, E. K.; Choi, J. K. Heterocycles 1998,
48, 221; (b) Gurjar, M. K.; Pal, S.; Rao, A. V. R.
Heterocycles 1997, 45, 231; (c) Ho, T. C. T.; Jones, K.
Tetrahedron 1997, 53, 8287; (d) Frank, K. E.; Aube, J. J.
Org. Chem. 2000, 65, 655. (e) Nieman, J. A.; Ennis, M.
D. Org. Lett. 2000, 2, 1395.
Acknowledgements
The authors are grateful to the Chinese Academy of
Sciences, National Natural Science Foundation of
China (grant 20132030), and the Qiu Shi Science &
Technologies Foundation for their financial support.
We thank Dr. K. M. Witherup of Merck research
laboratories for providing NMR spectra of natural
martinelline.
References
1. Witherup, K. M.; Ransom, R. W.; Graham, A. C.;
Bernard, A. M.; Salvatore, M. J.; Lumma, W. C.; Ander-
son, P. S.; Pitzenberger, S. M.; Varga, S. L. J. Am. Chem.
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7. Typical procedure: A mixture of 4-methoxycarbonylani-
line (1 mmol), ethyl glyoxalate (1 mmol) and the enamine
4 (1.05 mmol) in 5 mL of acetonitrile was stirred for 40
min at rt. After squaric acid (0.05 mmol) was added, the
solution was stirred for 2 h at rt. The mixture was
concentrated and chromatographed to afford 6 and 7.

C. Xia et al. / Tetrahedron Letters 43 (2002) 9405–9409
9409
1
8. Selected data for 10: H NMR (300 MHz, CDCl3) l 8.56
1H), 7.67 (d, J=8.1 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H),
6.08 (br s, 1H), 5.75 (d, J=7.2 Hz, 1H), 5.56 (t, J=7.0
Hz, 1H), 5.28 (t, J=6.8 Hz, 1H), 5.20 (t, J=6.7 Hz, 1H),
4.87 (m, 2H), 4.65 (q, J=3.6 Hz, 2H), 4.09 (m, 2H), 3.87
(m, 1H), 3.75 (m, 2H), 3.46–3.29 (m, 3H), 3.15 (m, 1H),
2.36 (m, 2H), 2.13–2.05 (m, 4H), 1.75 (s, 3H), 1.73 (s,
3H), 1.70 (s, 3H), 1.67 (s, 3H), 1.63 (s, 3H), 1.49 (s, 36H);
13C NMR (75 MHz, CHCl3) l 166.3, 163.5, 155.9, 153.2,
146.7, 137.8, 137.5, 135.4, 131.4, 130.3, 122.4, 119.7,
119.1, 117.8, 113.9, 83.1, 79.3, 68.6, 50.5, 47.3, 44.6, 40.0,
38.9, 38.6, 32.5, 31.9, 31.2, 29.7, 29.6, 28.3, 28.2, 28.1,
27.4, 26.2, 25.6, 22.7, 22.5, 22.4, 18.1, 18.0, 14.2, 14.1;
ESI-MS m/z 1021 (M+H+); HRMS calcd for
C53H84N10O10: 1021.6372 (M+H+). Found: 1021.6407.
(s, 0.6H), 8.31 (s, 0.4H), 7.94 (d, J=8.2 Hz, 1H), 7.37–
7.25 (m, 6H), 6.72 (d, J=14.8 Hz, 1H), 5.78 (d, J=15.7
Hz, 1H), 5.61 (m, 1H), 5.20 (m, 3H), 4.10 (q, J=7.1 Hz,
2H), 3.90 (s, 3H), 3.64 (m, 1H), 3.43 (m, 1H), 2.82 (m,
1H), 2.30 (s, 3H), 2.19 (m, 1H), 1.85 (m, 1H), 1.22 (t,
J=7.1 Hz, 3H); HRMS calcd for C28H30N2O7 (M+)
506.2053. Found: 506.2082.
9. (a) Feichtinger, K.; Sings, H. L.; Baker, T. J.; Matthews,
K.; Goodman, M. J. Org. Chem. 1998, 63, 8432; (b)
Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J.
Org. Chem. 1998, 63, 3804.
10. Selected data for 21: 1H NMR (300 MHz, CDCl3) l
11.49 (br s, 1H), 9.00 (br s, 1H), 8.25 (m, 1H), 7.94 (s,