Unexpected dramatic substituent effect for tuning the selectivity in the double ring-closing metathesis reaction of N-containing tetraenes. An efficient synthesis of bicyclic izidine alkaloid skeletons

Article abstract of DOI:10.1021/ol0172673

(equation presented) A double ring-closing metathesis reaction for the efficient construction of the fused bicyclic izidine alkaloid skeleton was developed. In this reaction, high selectivity was realized by tuning of electronic and steric effects of substituents in the N-containing tetraenes. It was observed that the reactivity of electron-rich carbon-carbon double bonds is higher than that of electron-deficient ones. A brief mechanistic study is also discussed.

Full text of DOI:10.1021/ol0172673

ORGANIC
LETTERS
2002
Vol. 4, No. 4
639-641
Unexpected Dramatic Substituent Effect
for Tuning the Selectivity in the Double
Ring-Closing Metathesis Reaction of
N-Containing Tetraenes. An Efficient
Synthesis of Bicyclic Izidine Alkaloid
Skeletons
Shengming Ma* and Bukuo Ni
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032,
P. R. China
masm@pub.sioc.ac.cn
Received December 19, 2001
ABSTRACT
A double ring-closing metathesis reaction for the efficient construction of the fused bicyclic izidine alkaloid skeleton was developed. In this
reaction, high selectivity was realized by tuning of electronic and steric effects of substituents in the N-containing tetraenes. It was observed
that the reactivity of electron-rich carbon−carbon double bonds is higher than that of electron-deficient ones. A brief mechanistic study is
also discussed.
Recently, we have demonstrated that a protocol of bicyclic
carbopalladation can be efficiently applied to the synthesis
of fused bicyclic compounds.1 In principle, this paradigm
can be realized with any reaction, provided that a good
selectivity can be realized. Here, we wish to report our recent
results on the double ring-closing metathesis for the efficient
construction of bicyclic izidine alkaloid skeletons, in which
the selectivity was tuned by the electronic and steric effects
of the substituents of the N-containing tetraenes.
compounds can usually be synthesized via a sequential ring
formation approach4-6 (Scheme 1).
We envisioned that it would be possible to construct both
rings via a double RCM protocol in just “one shot” (Scheme
1).6-8 Here, the key point would be the control of the RCM
mode (ab/cd mode Vs ac/bd mode, Scheme 2).
(2) Wro´bel, J. T. In The Alkaoids; Brossi, A., Ed.; Academic Press: San
Diego, 1985; Vol. 26, pp 327-384. (b) Numata, A.; Ibuka, T. In The
Alkaloids; Brossi, A., Ed.; Academic Press: San Diego, 1987; Vol. 31, pp
193-315. (c) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: San Diego, 1993; Vol. 43, pp 185-
288; (d) Alkaliods: Chemical and Biological PerspectiVes; Pelletier, S. W.,
Ed.; Wiley: New York, 1997; Vol. 5.
Bicyclic izidine alkaloid skeletons are structural units
commonly observed in many important compounds.2,3 These
(3) Michael, J. P. Nat. Prod. Rep. 1997, 14, 21-41. (b) Michael, J. P.
Nat. Prod. Rep. 1994, 11, 639-657. (c) Liddell, J. R. Nat. Prod. Rep. 1997,
14, 653-660. (d) Fuji, K.; Yamada, T.; Fujita, E.; Murata, H. Chem. Phar.
Bull. 1978, 26, 2515-2521. (e) Jain, P.; Garraffo, H. M.; Yeh, H. J. C.;
Spande, T. F.; Daly, J. W. J. Nat. Prod. 1996, 59, 1174-1178.
* Fax: (+86) 21-64166128.
(1) Ma, S.; Xu, B. J. Org. Chem. 1998, 63, 9156-9157. (b) Ma, S.; Xu,
B.; Ni, B. J. Org. Chem. 2000, 65, 8532-8543.
10.1021/ol0172673 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/30/2002

was observed that the monocyclic intermediate 5c was
formed highly selectively, suggesting that the ab-mode RCM
reaction may be much faster than those of ac, bd, and cd
modes, which may account for the highly selective formation
of fused bicyclic product 2c. Upon treating of 5c with 5 mol
% of (Cy3P)2Cl2RudCHPh, 2c was formed exclusively in
89% yield (Scheme 4).
Scheme 1
Scheme 4
As expected, the reaction of 1a and 1b did afford a mixture
of ab/cd-mode and ac/bd-mode products with the dumbell-
type products 3 as the major products (Scheme 3).
To investigate the possibility of fast conversion of the in
situ formed dumbell-type product 3c to 2c, N-(4-(1,6-
heptadienyl))propenamide 6c, precursor to 1c, was synthe-
sized.9 The reaction of 6c afforded monocyclic products 7c
and 8c in 79% and 10% yields, respectively. Here, the RCM
reaction of the bd mode is much faster than that of the cd
mode. Monocyclic product 7c can be further converted to
9c, which upon treatment with 5 mol % of (PCy3)2Cl2Rud
CHPh afforded 3c and 2c in 62% and 13% yields, respec-
tively (Scheme 5). Treatment of isolated pure dumbell-type
product 3c under the catalysis of (Cy3P)2Cl2RudCHPh in
CH2Cl2 did not afford the fused bicyclic product 2c,
indicating that 2c was formed directly via the double RCM
reaction of 1c (Scheme 5).
Scheme 2. Double RCM Strategy for N-Containing Bicycles
Furthermore, it is interesting to note that by starting from
1d (a methyl group was introduced into the terminal position
To our surprise, the reaction of 1c9 afforded the corre-
sponding products with a ratio of fused bicyclic compound
2c to dumbell-type bicyclic compound 3c as high as 21:1 in
a combined yield of 88% (Scheme 3). The structure of 2c
was unambiguously determined by its conversion to the trans
dibromide 4c, which was characterized by an X-ray diffrac-
tion study.10 When we followed this reaction carefully, it
(4) Pearson, W. H.; Suga, H. J. Org. Chem. 1998, 63, 9910-9918. (b)
Michel, P.; Rassat, A. J. Chem. Soc., Chem. Commum. 1999, 2281-2282.
(c) Takahata, H.; Kubota, M.; Ihara, K.; Okamoto, N.; Momose, T.; Azer,
N.; Eldefrawi, A. T.; Eldefrawi, M. E. Tetrahedron: Asymmetry 1998, 9,
3289-3301. (d) Comins, D. L.; Lamunyon, D. H. J. Org. Chem. 1992, 57,
5807-5809.
(5) Alkene Metathesis in Organic Synthesis; Topics in Organometallic
Chemistry; Fu¨rstner, A., Ed.; Springer: Germany, 1998. For an account on
Ru complex-catalyzed RCM reaction, see: Grubbs, R. H.; Miller, S.; Fu,
G. C. Acc. Chem. Res. 1995, 28, 446-452. For a seminal paper of Ru-
catalyzed double RCM reaction, see: Fu, G. C.; Nguyen, S. B. T.; Grubbs,
R. H. J. Am. Chem. Soc. 1993, 115, 9856-9857.
(6) For reports on the synthesis of izidine alkaloid skeletons through the
ring by ring approach via a RCM reaction, see: (a) Paolucci, C.; Musiani,
L.; Venturelli, F.; Fava, A. Synthesis 1997, 1415-1417. (b) Arisawa, M.;
Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa, M. Synlett 1997, 1179-
1180. (c) Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles, M. R.;
Marshall, E. L.; Procopiou, P. A. J. Chem. Soc., Chem. Commun. 1997,
155-156.
Scheme 3
(7) For the formation of spirocyclic compounds via double or triple RCM,
see: (a) Baylon, C.; Heck, M. P.; Mioskowski, C. J. Org. Chem. 1999, 64,
3354-3360. (b) Bassindale, M. J.; Hamley, P.; Leitner, A.; Harrity, J. P.
A. Tetrahedron Lett. 1999, 40, 3247-3250; (c) Wallace, D. J.; Cowden,
C. J.; Kennedy, D. J.; Ashwood, M. S.; Cottrell, I. F.; Dolling, U. H.
Tetrahedron Lett. 2000, 41, 2027-2029. (d) Heck, M. P.; Baylon, C.; Nolan,
S. P.; Mioskowski, C. Org. Lett. 2001, 3, 1989-1991.
640
Org. Lett., Vol. 4, No. 4, 2002

Scheme 5
Scheme 7
the selectivity of the double RCM reaction leading to a highly
selective synthesis of izidine alkaloid skeleton:11 (1) Intro-
duction of a substituent at the CdC bond increases the ab/
cd vs ac/bd selectivity (Scheme 2). (2) Introduction of an
alkyl group to the secondary carbon center next to the
nitrogen atom may make the CdC bonds b and d relatively
closer, which increases the possibility of the bd-mode RCM
reaction leading to the dumbell-type product 3. Further
studies on this reaction including the scope and the synthetic
application are being carried out in our laboratory.
Acknowledgment. Financial support from the Major
State Basic Research Development Program (Grant
G2000077500) and National NSF of China are greatly
appreciated. Shengming Ma is the recipient of 1999 Qiu Shi
Award for Young Scientific Workers issued by Hong Kong
Qiu Shi Foundation of Science and Technology (1999-
2003).
of the CdC bond a in 1c (Scheme 2)), 2c was formed as the
only product in 86% yield, indicating an interesting sub-
stituent effect on the selectivity of the cyclization. This
reaction can be extended to the synthesis of substituted 6,6-
bicyclic lactam 2e (Scheme 6).
Supporting Information Available: Typical experimen-
tal procedure and analytical data for all the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 6
OL0172673
(9) As a typical example, 1c was prepared according to the following
scheme:
For the synthesis of 7,7-bicyclic lactam 2f, the introduction
of a methyl group at the terminal position of the CdC bond
increased the selectivity of 2f/3f increased from 8.9:1 to 20:1
(Scheme 7)!
In conclusion, we have observed interesting steric and
electronic effects of substituents in tetraenes 1 for tuning
(10) Crystal Data for 4c: C9H11NOBr, MW ) 309.01, triclinic, space
group P-1, Mo KR, final R indices [I > 2σ(I)], R1 ) 0.0571, wR2 ) 0.1570,
a ) 7.7149(10) Å, b ) 8.1119(10) Å, c ) 8.6994(11) Å, R ) 94.146 (2)°,
â ) 103.579 (2)°, â ) 95.786 (2)°, V ) 523.92 (11) Å3, T ) 293 K, Z )
2, reflections collected/unique: 5210/1945 (Rint ) 0.1721), no observation
[I > 2σ(I)] 1658, parameters 163.
(11) For a study on the relative reaction rate of olefin substrates with
Ru carbenes see: Ulman, M.; Grubbs, R. H. Organometallics 1998, 17,
2484-2489.
(8) For the formation of fused carbobicyclic or polycyclic compounds
via double RCM reaction, see:(a) Lautens, M.; Hughes, G. Angew. Chem.,
Int. Ed. 1999, 38, 129-131. (b) Clark, J. S.; Hamelin, O. Angew. Chem.,
Int. Ed. 2000, 39, 372-374.
Org. Lett., Vol. 4, No. 4, 2002
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