Gold catalysis in organic synthesis: Efficient cycloisomerization of α-aminoallenes to 3-pyrrolines

Article abstract of DOI:10.1021/ol0481838

(Chemical Equation Presented) The gold(III) chloride-catalyzed cycloisomerization of various α-aminoallenes gave the corresponding 3-pyrrolines in good to high chemical yields. An interesting dependence of the chirality transfer and reactivity on the N-pr

Full text of DOI:10.1021/ol0481838

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4121-4123
Gold Catalysis in Organic Synthesis:
Efficient Cycloisomerization of
r
-Aminoallenes to 3-Pyrrolines
Nobuyoshi Morita and Norbert Krause*
Organic Chemistry II, Dortmund UniVersity, D-44221 Dortmund, Germany
norbert.krause@uni-dortmund.de
Received September 8, 2004
ABSTRACT
The gold(III) chloride-catalyzed cycloisomerization of various
r-aminoallenes gave the corresponding 3-pyrrolines in good to high chemical
yields. An interesting dependence of the chirality transfer and reactivity on the N-protecting group was observed. The 3-pyrrolines are highly
useful intermediates for the synthesis of functionalized pyrrolines, pyrrolidines, and other natural products.
Functionalized pyrrolines and pyrrolidines are of great
importance in natural product synthesis because of their high
and diverse biological activities (Figure 1).1 These include
Thus, it is not surprising that numerous pathways for the
synthesis of substituted pyrrolines and pyrrolidines have been
developed, and in recent years much work has focused on
metal-mediated approaches. To control the relative and
absolute configuration of stereogenic centers in position 2
and/or 5 of the heterocycles, the cyclization/cyloisomerization
of sterically defined R-aminoallenes is particularly promising,
and metals such as Pd(0 or II),4 Ag(I),5 and Hg(II)6 as well
as organolanthanides7 have been used for this purpose.
(2) (a) Schwartz, R. E.; Liesch, J. Hensens, O.; Zitano, L.; Honeycutt,
S.; Garrity, G.; Fromtling, R. A.; Onishi, J.; Monaghan, R. J. Antibiot. 1988,
41, 1774. (b) Johnson, J. H.; Phillipson, D. W.; Kahle, A. D. J. Antibiot.
1989, 42, 1184. (c) Hulme, A. N.; Rosser, E. M. Org. Lett. 2002, 4, 265.
(d) Overhand, M.; Hecht, S. M. J. Org. Chem. 1994, 59, 4721. (e) Deng,
W.; Overman, L. E. J. Am. Chem. Soc. 1994, 116, 11241. (f) McGrane, P.
L.; Livinghouse, T. J. Am. Chem. Soc. 1993, 115, 11485. (g) Pak, C. S.;
Lee, G. H. J. Org. Chem. 1991, 56, 1128.
(3) (a) Matkhalikova, S. F.; Malikov, V. M.; Yunusov, S. Y. Khim. Prir.
Soedin 1969, 5, 607. (b) Matkhalikova, S. F.; Malikov, V. M.; Yunusov,
S. Y. Khim. Prir. Soedin 1969, 5, 30. (c) Severino, E. A.; Correia, C. R. D.
Org. Lett. 2000, 2, 3039. (d) Yoda, H.; Nakajima, T.; Takabe, K.
Tetrahedron Lett. 1996, 37, 5531. (e) Wang, C.-H. J.; Calabrese, J. C. J.
Org. Chem. 1991, 56, 4341. (f) Iida, H.; Yamazaki, N.; Kibayashi, C. J.
Org. Chem. 1987, 52, 1956.
(4) (a) Ma, S.; Yu, F.; Gao, W. J. Org. Chem. 2003, 68, 5943. (b) Dieter,
R. K.; Yu, H. Org. Lett. 2001, 3, 3855. (c) Kang, S.-K.; Kim, K.-J. Org.
Lett. 2001, 3, 511. (d) Karstens, W. F. J.; Klomp, D.; Rutjes, F. P. J. T.;
Hiemstra, H. Tetrahedron 2001, 57, 5123. (e) Ohno, H.; Toda, A.; Miwa,
Y.; Taga, T.; Osawa, E.; Yamaoka, Y.; Fijii, N.; Ibuka, T. J. Org. Chem.
1999, 64, 2992. (f) Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H.
Tetrahedron Lett. 1997, 35, 6257. (g) Davis, I. W.; Scopes, D. I.; Gallagher.
Synlett 1993, 85. (h) Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J.
Org. Chem. 1992, 57, 6377. (i) Prasad, J. S.; Liebeskind, L. S. Tetrahedron
Lett. 1988, 29, 4257.
Figure 1. Naturally occurring pyrrolidines.
antifungal compounds (e.g., preussin, anisomycin2), hypoten-
sive activity (codonopsinine3), anti-HIV activity, as well as
various enzyme inhibitors such as lentiginosine, swainsonine,
and alexine.1
(1) (a) O’Hagen, D. Nat. Prod. Rep. 2000, 17, 435. (b) Mauger, A. B.
J. Nat. Prod. 1996, 59, 1205. (c) Huwe, C. M.; Blechert, S. Tetrahedron
Lett. 1995, 36, 1621. (d) Anderson, W. K.; Milowsky, A. S. J. Med. Chem.
1987, 30, 2144.
10.1021/ol0481838 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/08/2004

Recently, we reported a highly efficient gold(III)-
catalyzed8 cycloisomerization of R-hydroxyallenes that pro-
vides 2,5-dihydrofurans with complete axis to center chirality
transfer.9 This method is compatible with various functional
groups present in the substrate and therefore highly suitable
for application in natural product chemistry.10 We anticipated
that a similar reaction with an R-aminoallene would bring
about an efficient cycloisomerization to afford a 3-pyrroline,
the double bond of which can then be utilized for further
transformations, e.g., reductions, oxidations, etc. (Scheme
1).
Scheme 2
Scheme 1
by the solvent or temperature (entries 2-5). This effect was
even more pronounced for the acylated aminoallenes 4d and
4e (entries 6 and 7). Only the unprotected aminoallene 4a
afforded the diastereomerically pure 3-pyrroline (entry 1).
The synthesis of the starting materials, the diastereomeri-
cally pure aminoallenes 4a-e, is shown in Scheme 2.
Epoxidation of enyne 1, followed by benzylation gave a 70%
yield of oxirane 2. The corresponding hydroxyallene 3 was
prepared via anti-selective SN2′ substitution reaction of
oxirane 2 with a magnesium cyanocuprate in the presence
of n-Bu3P.9,10 The R-aminoallene 4a was prepared from 3
via Mitsunobu reaction with phthalimide, followed by
hydrazinolysis.11 For an initial screening of the effect of
various N-protecting groups in the gold-catalyzed cyclization,
aminoallene 4a was reacted with a selection of acylating and
sulfonylating agents.
Treatment of the diastereomerically pure R-aminoallenes
4a-e with 2 mol % of AuCl3 in dry CH2Cl2 at room
temperature gave the corresponding 3-pyrrolines 5a-e in
good to excellent yields (Table 1).
The reactions were complete after 30 min at room
temperature for the N-protected aminoallenes 4b-e (entries
2-7), whereas the unprotected substrate required a much
longer reaction time (entry 1). A slight erosion of the
stereoselectivity was observed in the cycloisomerization of
the sulfonylated substrates 4b and 4c which was not affected
Table 1. AuCl3-Catalyzed Cycloisomerization of
R-Aminoallenes 4 to 3-Pyrrolines 5
entry
4
PG solvent T (°C)
time
5 (yield, %)
dr
1
2
3
4
5
6
7
4a
H
CH2Cl2
rt
rt
rt
0
rt
rt
rt
5 days
30 min
30 min
1 h
1.5 h
30 min
30 min
5a (74)
5b (77)
5c (93)
5c (95)
5c (95)
5d (80)
5e (69)
>99:1
94:6
95:5
96:4
93:7
4b Ms CH2Cl2
4c Ts
4c Ts
4c Ts
4d Ac CH2Cl2
4e Boc CH2Cl2
CH2Cl2
CH2Cl2
THF
70:30
46:54
To further examine the scope of the gold-catalyzed
cycloisomerization of R-aminoallenes, we prepared the
substrates 6a-c with a variable substituent pattern. These
were efficiently converted into the corresponding 3-pyrrolines
7a-c in good yields with complete chirality transfer (Table
2).
A plausible mechanism of the gold(III) chloride-catalyzed
cycloisomerization of R-aminoallenes is shown in Scheme
3. Thus, coordination of the carbophilic gold catalyst to an
allenic double bond (complex A) would be followed by
formation of the metallacyclopropane B. As a consequence
of the increased electrophilicity, cyclization via an SN2-type
transition state and subsequent proton transfer would produce
the 3-pyrroline with complete axis-to-center chirality transfer.
(5) (a) Amombo, M. O.; Hausherr, A.; Reissig, H.-U. Synlett 1999, 1871.
(b) Davis, I, W.; Gallagher, T.; Lamont, R. B.; Scopes, I. C. J. Chem. Soc.
Chem. Commun. 1992, 335. (c) Kinsman, R.; Lathbury, D.; Vernon, P.;
Gallagher, T. J. Chem. Soc., Chem. Commun. 1987, 243.
(6) (a) Fox, D. N. A.; Lathbury, D.; Mahon, M. F.; Molly, K. C.;
Gallagher, T. J. Chem. Soc., Chem. Commun. 1989, 1073.
(7) Arrendondo, V. M.; Mcdonald, F. E.; Marks, T. J. J. Am. Chem.
Soc. 1998, 120, 4871.
(8) Recent reviews on gold catalysis in organic synthesis: (a) Hashmi,
A. S. K. Gold Bull. 2004, 37, 51. (b) Arcadi, A.; Di Giuseppe, S. Curr.
Org. Chem. 2004, 8, 795.
(9) Hoffmann-Ro¨der, A.; Krause, N. Org. Lett. 2001, 3, 2537.
(10) Krause, N.; Hoffmann-Ro¨der, A.; Canisius, J. Synthesis 2002, 1759.
(11) Roush, W. R.; Straud, J. A.; Brown, R. T. J. Org. Chem. 1987, 52,
5127.
4122
Org. Lett., Vol. 6, No. 22, 2004

would proceed with partial isomerization (via single bond
rotation) to complex D, leading to a diminished diastereo-
selectivity.
Table 2. AuCl3-Catalyzed Cycloisomerization of
R-Aminoallenes 6 to 3-Pyrrolines 7
In conclusion, we have developed a new efficient gold-
(III)-catalyzed cycloisomerization reaction of various R-ami-
noallenes to the corresponding 3-pyrrolines. An interesting
dependence of the chirality transfer and reactivity on the
N-protecting group was observed. Compared to the corre-
sponding Ag(I)-catalyzed cyclization of aminoallenes,5 our
catalytic system is advantageous in terms of a very low
catalyst loading (2 mol %), which renders the method much
more economical.
entry
6
R
R′
Bn
n-hexyl TBS
Ph
dr
7 (yield, %)
dr
1
2
3
6a
6b
6c
Me
90:10
85:15
TBS >99:1
7a (71)
7b (82)
7c (79)
90:10
85:15
>99:1
We are now searching for more active and selective gold
catalysts, which should allow for shorter reaction times in
case of the unprotected R-aminoallenes, and for higher
stereoselectivities in case of the N-protected substrates.
Furthermore, application of the method to the synthesis of
functionalized pyrrolines, pyrrolidines, and other natural
products is actively pursued.
In the case of the N-protected aminoallenes 4b-e, however,
an oxygen atom of the protecting group could stabilize the
zwitterionic complex C by coordination, and the cyclization
Scheme 3
Acknowledgment. Continuous support of our work by
the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie is gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedure and H and 13C NMR data of 3-pyrrolines. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0481838
Org. Lett., Vol. 6, No. 22, 2004
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