Novel synthesis of heterocycles having a functionalized carbon center via nickel-mediated carboxylation: Total synthesis of erythrocarine

Article abstract of DOI:10.1021/ol034670w

(Matrix presented) Novel synthetic procedure of heterocycles was developed using nickel-mediated alkylative carboxylation, and the total synthesis of erythrocarine was achieved using this method and RCM of dienyne as the key steps.

Full text of DOI:10.1021/ol034670w

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2323-2325
Novel Synthesis of Heterocycles Having
a Functionalized Carbon Center via
Nickel-Mediated Carboxylation: Total
Synthesis of Erythrocarine
Kazuya Shimizu, Masanori Takimoto, and Miwako Mori*
Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity,
Sapporo 060-0812, Japan
mori@pharm.hokudai.ac.jp
Received April 21, 2003
ABSTRACT
Novel synthetic procedure of heterocycles was developed using nickel-mediated alkylative carboxylation, and the total synthesis of erythrocarine
was achieved using this method and RCM of dienyne as the key steps.
Carbon dioxide is a useful carbon 1-unit source for synthetic
organic chemistry, and the reaction of Grignard reagent and
carbon dioxide has been used as a method for converting an
aryl or alkyl halide into carboxylic acid. Transition-metal-
mediated or -catalyzed carboxylation is a promising reaction
because carbon-carbon bond formation is induced between
carbon-oxygen double bond of carbon dioxide and multiple
bonds by the transition metals.1 Recent reports2 of nickel-
mediated and -catalyzed carboxylation reactions to alkyne
are very interesting because the reaction conditions are very
mild. During the course of our study3 of nickel-mediated
carboxylation to alkyne,3b we planned for the synthesis of
heterocycles using this method. Our plan is shown in Scheme
1. If alkyne 1 having a heteroatom in a tether is treated with
Ni(0) under carbon dioxide, oxanickelacycle 4 should be
formed.
Transmetalation of an alkyl group of a zinc reagent into
nickel4 followed by reductive elimination should give trisub-
Scheme 1. Plan for Synthesis of Heterocycles
(1) Reviews: (a) Behr, A. Angew. Chem., Int. Ed. Engl. 1988, 27, 661.
(b) Braunstein, P.; Matt, D.; Nobel, D. Chem. ReV. 1988, 88, 747. (c) Gibson,
D. H. Chem. ReV. 1996, 96, 2063. (d) Leitner, W. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2207.
(2) (a) Hoberg, H.; Burkhart, G. Angew. Chem., Int. Ed. Engl. 1982, 21,
76. (b) Hoberg, H.; Schaefer, D. J. Organomet. Chem. 1982, 238, 383. (c)
Hoberg, H.; Schaefer, D.; Burkhart, G.; Kru¨ger, C.; Romao, M. J. J.
Organomet. Chem. 1984, 266, 203. (d) Saito, S.; Nakagawa, S.; Koizumi,
T.; Hirayama, K.; Yamamoto, Y. J. Org. Chem. 1999, 64, 3975. Recent
reports of catalytic reactions involving a related coupling process: (e) Inoue,
Y.; Itoh, Y.; Kazama, H.; Hashimoto, H. H. Bull. Chem. Soc. Jpn. 1980,
53, 3329. (f) Tsuda, T.; Morikawa, S.; Hasegawa, N.; Saegusa, T. J. Org.
Chem. 1990, 55, 2978. (g) De`rien, S.; Clinet, J.-C.; Dun˜ach, E.; Pe`richon,
J. J. Am. Chem. Soc. 1991, 113, 8447. (h) Louie, J.; Gibby, J. E.; Farnworth,
M. V.; Tekavec, T. N.; J. Am. Chem. Soc. 2002, 124, 15189.
10.1021/ol034670w CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/31/2003

Scheme 2. Synthesis of Isobenzofuran
Scheme 3. Retrosynthetic Analysis of Erythrina Alkaloid
stituted alkene 2 after hydrolysis. Michael addition of a
heteroatom in a tether of 2 to an R,â-unsaturated carboxyl
moiety would give heterocycles 3.
On the basis of this idea, a THF solution of compound 1a
was stirred in the presence of Ni(cod)2 (1.1 equiv) and DBU
(2.2 equiv) under carbon dioxide (1 atm) at 0 °C for 1 h,
and then Me2Zn was added. The solution was stirred at 0
°C for 5 h, and after hydrolysis, the crude product was treated
with CH2N2 to give ester 2a in 81% yield. Deprotection of
a silyl group afforded the desired isobenzofuran 3a in 81%
yield (Scheme 2).
Table 1. Synthesis of Heterocycles Using Nickel-Mediated
Carboxylation Followed by Michael Reaction
Subsequently, alkyne 1b, whose one carbon in a tether
was elongated, was treated in a similar manner to give ester
2b, which was treated with TBAF at room temperature to
give isobenzopyran 3b in 81% yield (Table 1, run 1).
Synthesis of isoindoline 3c or isoquinoline derivative 3d was
also achieved in a similar manner in high yield (runs 2 and
3). Furthermore, alkynylzinc reagent 5 could be used as a
zinc reagent for this reaction, and isoindoline 3e having a
highly functionalized carbon center could be synthesized (run
4).
Encouraged by these results, we planned for the synthesis
of erythrina alkaloid,5 which is a widely distributed family
of structurally interesting and biologically active natural
products that each possess a tetracyclic framework. Our
retrosynthetic analyses of erythraline 6a6a-c and erythrocarine
6b6d are shown in Scheme 3. They would be synthesized
from dienyne 7 by a ruthenium-catalyzed metathesis reaction.
(3) (a) Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2001, 123, 2895. (b)
Takimoto, M.; Shimizu, K.; Mori, M. Org. Lett. 2001, 3, 3345. (c) Takimoto,
M. Mori, M. J. Am. Chem. Soc. 2002, 124, 10008.
(4) Transmetalation of alkylzinc reagent to nickel, See: (a) Ikeda, S.;
Kondo, K.; Sato, Y. Chem. Lett. 1999, 1227. (b) Ikeda, S.; Kondo, K.;
Sato, Y. J. Org. Chem. 1996, 61, 8248. (c) Oblinger, E.; Montgomery, J.
J. Am. Chem. Soc. 1997, 119, 9065. (d) Sato, Y.; Takanashi, T.; Mori, M.
Organomet. 1999, 18, 4891.
(5) (a) Hill, R. K. The Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, 1967; Vol. 9, p 281. (b) Dyke, S. F.; Quessy, S. N. The
Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1981; Vol.
18, p 1.
(6) Isolation of erythraline: (a) Folkers, K.; Koniuszy, F. J. Am. Chem.
Soc. 1940, 62, 436. Total synthesis of erythraline: (b) Sano, T.; Toda, J.;
Heterocycles 1982, 18, 229. (c) Sano, T.; Toda, J.; Kashiwaba, N.; Ohshima,
T.; Tsuda, Y. Chem. Pharm. Bull. 1987, 35, 479. Erythrocarine, isolation:
(d) Chawla, A. S.; Redha, F. M. J.; Jackson, A. H. Phytochemistry 1985,
24, 1821.
a Treatment of 2b with TBAF at room temperature for 3 h. b A CH2Cl2
solution of 2c was refluxed in the presence of CF3CO2H for 2 h. c A CH2Cl2
solution of 2d was refluxed in the presence of CF3CO2H for 1 h, and then
a MeOH solution of amine was refluxed for 2 h. d A CH2Cl2 solution of 2e
was refluxed in the presence of CF3CO2H for 5 h, and then a MeOH solution
of amine was refluxed for 14 h.
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Org. Lett., Vol. 5, No. 13, 2003

Scheme 4. Synthesis of Alkyne 1fa
Scheme 5. Total Synthesis of Erythrocarinea
a Key: (i) trimethylsilylacetylene, PdCl2(PhCN)2, PPh3, Et3N,
reflux, 30 min, quant; (ii) CH3NO2, NH4OAc, AcOH, 100 °C, 7 h,
85%; (iii) LiAIH4, THF-Et2O (1:1), rt, 3 h; (iv) (Boc)2O, Et3N,
61% from 10.
Synthesis of isoquinoline 7 should be achieved from 3f,
which would be obtained from 1f by our novel synthesis of
heterocycles via nickel-mediated carboxylation. For the
synthesis of 1f, commercially available 8 was chosen as a
starting material.
a Key: (i) CO2, Ni(cod)2 (1.1 equiv), DBU (3.3 equiv), THF, 0
°C , 1 h, then 5 (3 equiv), 0 °C, 24 h; (ii) CH2N2, 69% from 1f;
(iii) CF3CO2H, rt, 3 h; (iv) MeOH, reflux, 18 h; (v) TBAF, 76%
from 2f; (vi) allyl bromide, K2CO3; (vii) LiAIH4; (viii) (COCl)2,
DMSO, Et3N and then vinylmagnesium bromide; (ix) Ac2O, Et3N,
DMAP, 70% from 3f; (x) HCl then 10 mol % of 16 in CH2Cl2, rt,
18 h, quant; (xi) K2CO3, MeOH, 93%.
Reaction of 8 with trimethylsilylacetylene in the presence
of a palladium catalyst afforded alkyne 9,7 which was
condensed with nitromethane to give 10. Treatment of 10
with LiAlH4 followed by protection with the butyloxycar-
bonyl group gave alkyne 1f (Scheme 4).
t
Carboxylation into alkyne 1f using a nickel complex
proceeded smoothly, and then alkynylzinc reagent 5 was
added. After hydrolysis of the reaction mixture and then
treatment with diazomethane, ester 2f was obtained in 69%
carine (6b) reported in the literature.6d,10 Thus, the total
synthesis of erythrocarine was achieved from commercially
available 6-bromopiperonal 8 via 15 steps using our novel
isoquinoline synthesis and ruthenium-catalyzed dienyne
metathesis as the key steps.
The remarkable features of our synthetic method of
heterocycles having a highly functionalized carbon center
are as follows. An atmospheric pressure of carbon dioxide
can be used. Carboxylation proceeds at 0 °C. Various
substituents could be introduced on the heterocycles using a
zinc reagent. Cyclization using Michael addition smoothly
proceeded to give various heterocycles in high yields. Further
studies are in progress.
t
yield (Scheme 5). Deprotection of the butyloxycarbonyl
group followed by Michael addition and then deprotection
of the silyl group afforded 3f in high yield. Allylation of
secondary amine followed by Swern oxidation and then
addition of vinylmagnesium bromide afforded a diastereo-
meric mixture of alcohol 12, whose hydroxyl group was
protected with the acetyl group to give 13. For the dienyne
metathesis, 13 was treated with HCl in Et2O because the
nitrogen would coordinate to ruthenium metal.8
When a CH2Cl2 solution of dienyne hydrochloride 13‚HCl
was stirred in the presence of 10 mol % of first-generation
ruthenium carbene complex 169 at room temperature for 18
h, the reaction proceeded smoothly, and we were very
pleased to find that tetracyclic compounds 14a and 14b were
obtained in quantitative yields in a ratio of 1 to 1. After
separation of them, the NOE experiments were carried out.
The results of the NOE experiment between the protons of
C3 and C14 of each compound 14a or 14b indicate that the
C3 proton of the less polar product 14a on TLC is placed at
the â-position. Treatment of 14a with K2CO3 in MeOH gave
alcohol, whose spectral data agreed with those of erythro-
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research on Priority Areas (A)
“Exploitation of Multi-Element Cyclic Molecules” from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan.
Supporting Information Available: Experimental details
and the spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL034670W
(7) Grotjahn, D. B.; Vollhardt, K. P. C. Synthesis 1993, 579.
(8) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993,
115, 9856.
(9) Kim, S.-H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc. 1994,
116, 10801.
(10) The protons of the lower field (the vinyl, aromatic ring and
methylene dioxy protons) agree with those of erythrocarine reported in the
literature, but those of higher field do not agree.
Org. Lett., Vol. 5, No. 13, 2003
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