Acid-Mediated Intermolecular [3 + 2] Cycloaddition toward Pyrrolo[2,1-a]isoquinolines: Total Synthesis of the Lamellarin Core and Lamellarin G Trimethyl Ether

Article abstract of DOI:10.1021/acs.orglett.7b00769

A novel one-pot reaction has been developed for the efficient synthesis of pyrrolo[2,1-a]isoquinolines and 1-dearyllamellarin core from (E)-(2-nitrovinyl)benzenes and azomethine ylides generated in situ. This strategy provides a concise total synthesis of

Full text of DOI:10.1021/acs.orglett.7b00769

Letter
pubs.acs.org/OrgLett
Acid-Mediated Intermolecular [3 + 2] Cycloaddition toward
Pyrrolo[2,1‑a]isoquinolines: Total Synthesis of the Lamellarin Core
and Lamellarin G Trimethyl Ether
Kai-Lu Zheng, Min-Qi You, Wen-Ming Shu, Yan-Dong Wu,* and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan, Hubei 430079, P. R. China
S
* Supporting Information
ABSTRACT: A novel one-pot reaction has been developed for the efficient synthesis of pyrrolo[2,1-a]isoquinolines and 1-
dearyllamellarin core from (E)-(2-nitrovinyl)benzenes and azomethine ylides generated in situ. This strategy provides a concise
total synthesis of the lamellarin core and lamellarin G trimethyl ether using electrophilic substitution and palladium-catalyzed
Suzuki−Miyaura cross-coupling reactions.
yrrolo[2,1-a]isoquinoline scaffolds form the core of the
Plamellarin alkaloids, which are natural products that were
first isolated from the prosobranch mollusk Lamellaria sp. by
Faulkner and co-workers in 1985.1 Since then, more than 50
lamellarins have been isolated, mainly from marine organisms
such as mollusks, ascidians, and sponges.2 These alkaloids exhibit
a wide spectrum of biological activities;3 for example, lamellarin I
reverses multidrug resistance by direct inhibition of P-
glycoprotein-mediated drug efflux at noncytotoxic doses,4
whereas lamellarin K and L have immunomodulatory effects in
the micromolar range.5 Furthermore, lamellarin D has been
reported to be an inhibitor of human topoisomerase I,4b,6 and
lamellarin α-20-sulfate is a drug candidate for the inhibition of
HIV integrase7 (Figure 1).
The novel structures and intriguing biological properties of the
lamellarin alkaloids have garnered considerable attention, and
the diverse approaches to their synthesis and their biological
activities have been reviewed.2b,3,8 We anticipated that the
Figure 1. Molecular structures of lamellarin I, K, L, and G trimethyl
ether.
lamellarin core could be synthesized from compound 6 by
hydrolysis and subsequent oxidative ring closure with Pb(OAc)4.
Compound 6 was prepared by palladium-catalyzed cross-
coupling of 5, which was synthesized through electrophilic
substitution of key intermediate pyrrolo[2,1-a]isoquinoline 4. In
fact, several important strategies, including transition metal-
catalyzed, photocatalyzed, or other oxidation reaction have been
reported for the construction of C1-substituted pyrrolo[2,1-
a]isoquinolines9 (Scheme 1). However, it is difficult to
synthesize the lamellarins from those C1-substituted skeletons.
Fortunately, we found that C1-unsubstituted pyrrolo[2,1-
a]isoquinoline 4 could be obtained by intermolecular cyclo-
addition of 3 with azomethine ylide generated in situ from 1 and
2. This novel reaction holds promise for the total synthesis of
lamellarins, and our retrosynthetic strategy is depicted in Scheme
1.
We initially investigated the reaction conditions using 1,2,3,4-
tetrahydroisoquinoline (THIQ) 1a, phenylglyoxal monohydrate
2a, and (E)-(2-nitrovinyl)benzene 3a as model substrates.
Received: March 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00769
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
when we performed the reaction at temperatures between rt and
110 °C (entries 14−18). The optimized reaction conditions were
thus identified as 1.0 equiv of 1a, 2a, and 3a with 2.0 equiv of
PhCO2H in toluene at 100 °C for 2.5 h.
Scheme 1. Retrosynthetic Approach and Precious Reports
With the optimized reaction conditions in hand, we proceeded
to examine the scope of the reaction using a variety of substituted
nitro olefins. As shown in Scheme 2, nitro olefins bearing
a
Scheme 2. Scope of Nitroolefin
Compound 4a was obtained in 34% yield when the reaction was
performed in toluene at 80 °C for 2.5 h without any additives
(entry 1). Encouraged by this result, various acids, solvents, and
temperatures were screened for the reaction, and the results are
summarized in Table 1. We were pleased to find that the addition
a
Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: 1a (1 mmol, 1.0 equiv), 2a (1 mmol, 1.0 equiv),
3 (1 mmol, 1.0 equiv), PhCO2H (2 mmol, 2.0 equiv), and solvent (5
mL). The reaction was performed for 2−8 h.
b
entry
solvent
toluene
acid
temp (°C)
yield (%)
1
80
80
80
80
80
80
80
80
80
80
80
80
80
rt
34
75
72
trace
trace
69
64
70
41
0
electron-neutral (H), electron-donating (4-Me, 4-OMe, 3,4-
2OMe), or electron-withdrawing (4-CN) groups reacted
smoothly to afford the corresponding products in excellent
yields (62−79%; 4a−4e). Halogen-substituted substrates (4-F,
4-Br) also reacted well to give the desired product 4f−4g in 65%
and 67% yields. (E)-2-(2-Nitrovinyl)thiophene and (E)-1-(2-
nitrovinyl)naphthalene reacted as anticipated to give the
corresponding products 4h−4i in 80% and 72% yields,
respectively. Aliphatic nitro alkenes were not compatible in this
reaction (see the Supporting Information (SI)).
The scope of this reaction was subsequently expanded to
arylglyoxal monohydrates, as shown in Scheme 3. The
phenylglyoxal monohydrate bearing electron-donating (4-Me,
4-OMe) groups was smoothly transformed into corresponding
products in good to excellent yields (72−82%; 4j−4k).
Satisfactory yields were also observed with halogen-substituted
(4-Cl, 4-Br) groups attached to the benzene ring (68−70%; 4l−
4m). The desired products could be obtained in moderate yield
from electron-withdrawing (4-NO2) substrates (47%, 4n). In
addition, the heteroaromatic and sterically hindered substrate
proceeded well to afford the expected product in good yield (69−
73%; 4o−4p). Additionally, the use of ethyl 2-oxoacetate 2i as a
substrate gave 4q in 61% yield. We also reacted 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline with 2i and (E)-1,2-dimethoxy-4-
(2-nitrovinyl)benzene, and corresponding product 4r was
obtained in 51% yield. The structure of 4q was confirmed by
X-ray crystallographic analysis (see the SI).
2
toluene
toluene
toluene
toluene
toluene
DMSO
DMF
PhCO2H
AcOH
3
4
TsOH
5
TfOH
6
TFA
7
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
8
9
DCE
10
11
12
13
14
15
16
17
18
NMP
EG
60
52
50
0
EA
1,4-dioxane
toluene
toluene
toluene
toluene
toluene
70
90
100
110
71
72
79
71
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0
equiv), 3a (0.1 mmol, 1.0 equiv), acid (0.2 mmol, 2.0 equiv), and
solvent (3 mL). The reaction was performed for 2.5 h. Isolated yields.
b
of 2.0 equiv of PhCO2H remarkably improved the yield (entry
2). A variety of acids, including AcOH, TsOH, TfOH, and TFA,
were screened to investigate their effect on the reaction, but there
was no further improvement in the yield (entries 3−6). Solvent
screening identified toluene as the optimum choice, and other
solvents (DMSO, DMF, DCE, NMP, EG, EA, and 1,4-dioxane)
gave lower yields (entries 7−13). The optimal reaction
temperature for this protocol was determined to be 100 °C
These results prompted us to attempt the synthesis of the
lamellarin core, and the reaction scheme is shown in Scheme 4.
Reaction of compound 4q with NBS in DMF yielded C1-bromo-
B
DOI: 10.1021/acs.orglett.7b00769
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Letter
a
droisoquinoline and 2i to give the corresponding products in
moderate yields (42%−60%; 4t−4u), as shown in Scheme 5.
This methodology was further utilized for the total synthesis of
lamellarin G trimethyl ether with an overall yield of 24.5% in
three steps.
Scheme 3. Scope of Arylglyoxal Monohydrates
Scheme 5. Synthetic Application
a
Reaction conditions: 1 (1 mmol, 1.0 equiv), 2 (1 mmol, 1.0 equiv), 3
(1 mmol, 1.0 equiv), PhCO2H (2 mmol, 2.0 equiv), and solvent (5
mL). The reaction was performed for 2−8 h.
Scheme 4. Suzuki Coupling and Attempted Oxidative Ring
Closure
In conclusion, we have developed a novel and efficient
intermolecular [3 + 2] cycloaddition for the directed synthesis of
pyrrolo[2,1-a]isoquinolines and 1-dearyllamellarin core from
available starting materials with simple reaction conditions. This
methodology was extended to the three-step synthesis of the type
Ia lamellarin core, which contains five fused rings, with an overall
yield of 50.7%. In addition, we successfully achieved the total
synthesis of lamellarin G trimethyl ether in three steps with an
overall yield of 24.5%. To the best of our knowledge, this method
represents the shortest access to the core of type Ia lamellarins
with high yield.7,8,9c,k,11,12,14 Further studies on lamellarin
synthesis using this methodology are in progress in our
laboratory.
substituted compound 5 in 97% yield.10 Then, palladium-
catalyzed Suzuki−Miyaura coupling of 5 with phenylboronic acid
under standard conditions [Pd(dba)2 (10 mol %), Na2CO3,
H2O, DME, reflux, 18 h] afforded compound 6 in 85% yield.11
Subsequent base-mediated hydrolysis of 6 provided compound 7
in 96% yield.12 Unfortunately, reaction of 7 with Pb(OAc)4 in
refluxing EtOAc failed to furnish the lamellarin core but instead
gave lactam 8, which was confirmed by X-ray crystallographic
analysis (see the SI). We reasoned that this behavior was caused
by the larger electron density in the pyrrole ring.13
We next attempted to apply this reaction to 1a, 2i, and (E)-2-
(2-nitrovinyl)phenol 3j, hoping to synthesize ethyl 2-(2-
hydroxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-car-
boxylate because intermolecular lactonization would be easier
than oxidative ring closure. Much to our delight, we obtained
compound 4s in 63% yield. The bromination proceeded cleanly
to furnish compound 5a in 97% yield. The final Suzuki−Miyaura
coupling with phenylboronic acid under standard conditions
proceeded as planned to afford the lamellarin core in an overall
yield of 50.7%.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00769.
Crystallographic data of 4q (CIF)
Crystallographic data of 8 (CIF)
Experimental procedures, product characterizations, and
copies of the 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: chwuyd@mail.ccnu.edu.cn.
*E-mail: chwuax@mail.ccnu.edu.cn.
ORCID
An-Xin Wu: 0000-0001-7673-210X
Notes
In addition, 3j and (E)-4,5-dimethoxy-2-(2-nitrovinyl)phenol
3k each reacted smoothly with 6,7-dimethoxy-1,2,3,4-tetrahy-
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b00769
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Banwell, M. G. Eur. J. Org. Chem. 2011, 2011, 88−99. (d) Ueda, K.;
Amaike, K.; Maceiczyk, R. M.; Itami, K.; Yamaguchi, J. J. Am. Chem. Soc.
2014, 136, 13226−13232.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21602070, 21472056) and the Fundamental
Research Funds for the Central Universities (CCNU15ZX002
and CCNU16A05002) for financial support. We acknowledge
the graduate student educational innovation grant from Central
China Normal University (2016CXZZ64). This work was also
supported by the 111 Project B17109. We also thank Dr.
Chuanqi Zhou, Hebei University, for analytical support.
REFERENCES
■
(1) Andersen, R. J.; Faulkner, D. J.; He, C. H.; Van Duyne, G. D.;
Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492−5495.
(2) (a) Davis, R. A.; Carroll, A. R.; Pierens, G. K.; Quinn, R. J. J. Nat.
Prod. 1999, 62, 419−424. (b) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. F.
Chem. Rev. 2008, 108, 264−287.
(3) Bailly, C. Mar. Drugs 2015, 13, 1105.
(4) (a) Boger, D. L.; Soenen, D. R.; Boyce, C. W.; Hedrick, M. P.; Jin,
Q. J. Org. Chem. 2000, 65, 2479−2483. (b) Vanhuyse, M.; Kluza, J.;
Tardy, C.; Otero, G.; Cuevas, C.; Bailly, C.; Lansiaux, A. Cancer Lett.
2005, 221, 165−175.
(5) Malla Reddy, S.; Srinivasulu, M.; Satyanarayana, N.; Kondapi, A. K.;
Venkateswarlu, Y. Tetrahedron 2005, 61, 9242−9247.
(6) (a) Tardy, C.; Facompre,
Gravalos, D.; Francesch, A.; Mateo, C.; Pastor, A.; Jimen
́
M.; Laine, W.; Baldeyrou, B.; García-
ez, J. A.;
́
Manzanares, I.; Cuevas, C.; Bailly, C. Bioorg. Med. Chem. 2004, 12,
1697−1712. (b) Marco, E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.;
Ishibashi, F.; Bailly, C.; Gago, F. J. Med. Chem. 2005, 48, 3796−3807.
(7) Yamaguchi, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. Tetrahedron Lett.
2006, 47, 3755−3757.
(8) Imbri, D.; Tauber, J.; Opatz, T. Mar. Drugs 2014, 12, 6142.
(9) (a) Banwell, M. G.; Flynn, B. L.; Hockless, D. C. R. Chem. Commun.
1997, 33, 2259. (b) Ishibashi, F.; Miyazaki, Y.; Iwao, M. Tetrahedron
1997, 53, 5951. (c) Heim, A.; Terpin, A.; Steglich, W. Angew. Chem., Int.
Ed. Engl. 1997, 36, 155−156. (d) Banwell, M. G.; Flynn, B. L.; Stewart, S.
G. J. Org. Chem. 1998, 63, 9139. (e) Boger, D. L.; Boyce, C. W.; Labroli,
M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54.
(f) Ruchirawat, S.; Mutarapat, T. Tetrahedron Lett. 2001, 42, 1205.
́
(g) Cironi, P.; Manzanares, I.; Albericio, F.; Alvarez, M. Org. Lett. 2003,
5, 2959. (h) Ploypradith, P.; Mahidol, C.; Sahakitpichan, P.;
Wongbundit, S.; Ruchirawat, S. Angew. Chem., Int. Ed. 2004, 43, 866.
(i) Ploypradith, P.; Petchmanee, T.; Sahakitpichan, P.; Litvinas, N. D.;
Ruchirawat, S. J. Org. Chem. 2006, 71, 9440. (j) Su, S.; Porco, J. A. J. Am.
Chem. Soc. 2007, 129, 7744−7745. (k) Ohta, T.; Fukuda, T.; Ishibashi,
F.; Iwao, M. J. Org. Chem. 2009, 74, 8143−8153. (l) Yu, C.; Zhang, Y.;
Zhang, S.; Li, H.; Wang, W. Chem. Commun. 2011, 47, 1036−1038.
(m) Zou, Y. Q.; Lu, L. Q.; Fu, L.; Chang, N. J.; Rong, J.; Chen, J. R.; Xiao,
W. J. Angew. Chem., Int. Ed. 2011, 50, 7171−7175. (n) Wang, H. T.; Lu,
C. D. Tetrahedron Lett. 2013, 54, 3015. (o) Huang, L.; Zhao, J. Chem.
Commun. 2013, 49, 3751−3753. (p) Guo, S.; Zhang, H.; Huang, L.;
Guo, Z.; Xiong, G.; Zhao, J. Chem. Commun. 2013, 49, 8689−8691.
(q) Huang, H. M.; Li, Y. J.; Ye, Q.; Yu, W. B.; Han, L.; Jia, J. H.; Gao, J. R.
J. Org. Chem. 2014, 79, 1084−1092. (r) Fujiya, A.; Tanaka, M.;
Yamaguchi, E.; Tada, N.; Itoh, A. J. Org. Chem. 2016, 81, 7262−7270.
(10) Handy, S. T.; Zhang, Y.; Bregman, H. J. Org. Chem. 2004, 69,
2362−2366.
(11) Komatsubara, M.; Umeki, T.; Fukuda, T.; Iwao, M. J. Org. Chem.
2014, 79, 529−537.
(12) Gupton, J. T.; Giglio, B. C.; Eaton, J. E.; Rieck, E. A.; Smith, K. L.;
Keough, M. J.; Barelli, P. J.; Firich, L. T.; Hempel, J. E.; Smith, T. M.;
Kanters, R. P. F. Tetrahedron 2009, 65, 4283−4292.
(13) (a) Li, Q.; Jiang, J.; Fan, A.; Cui, Y.; Jia, Y. Org. Lett. 2011, 13,
312−315. (b) Liermann, J. C.; Opatz, T. J. Org. Chem. 2008, 73, 4526−
4531.
(14) (a) Manjappa, K. B.; Syu, J.-R.; Yang, D.-Y. Org. Lett. 2016, 18,
́
332−335. (b) Pla, D.; Marchal, A.; Olsen, C. A.; Albericio, F.; Alvarez,
M. J. Org. Chem. 2005, 70, 8231−8234. (c) Hasse, K.; Willis, A. C.;
D
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