Enantioselective synthesis of Indolizidines bearing quaternary substituted stereocenters via rhodium-catalyzed [2 + 2 + 2] cycloaddition of alkenyl Isocyanates and terminal alkynes

Article abstract of DOI:10.1021/ol800086s

An enantioselective synthesis of Indolizidines bearing quaternary substituted stereocenters by way of a rhodium-catalyzed [2 + 2 + 2] cycloaddition of substituted alkenyl Isocyanates and terminal alkynes Is described. The reaction provides lactam products using aliphatic alkynes, whereas aryl alkynes give rise to vlnylogous amide products. Through modification of the phosphoramldlte llgand, high levels of enantloselectlvlty, regloselectlvlty, and product selectivity are obtained for both products.

Full text of DOI:10.1021/ol800086s

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1231-1234
Enantioselective Synthesis of
Indolizidines Bearing Quaternary
Substituted Stereocenters via
Rhodium-Catalyzed [2
Cycloaddition of Alkenyl Isocyanates
and Terminal Alkynes
+ 2 + 2]
Ernest E. Lee and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
roVis@lamar.colostate.edu
Received January 17, 2008
ABSTRACT
An enantioselective synthesis of indolizidines bearing quaternary substituted stereocenters by way of a rhodium-catalyzed [2
+ 2 + 2]
cycloaddition of substituted alkenyl isocyanates and terminal alkynes is described. The reaction provides lactam products using aliphatic
alkynes, whereas aryl alkynes give rise to vinylogous amide products. Through modification of the phosphoramidite ligand, high levels of
enantioselectivity, regioselectivity, and product selectivity are obtained for both products.
Transition-metal-catalyzed [m + n + o]-type cycloaddition
reactions have proven to be efficient methods for the
construction of complex polycyclic carbocycles and hetero-
cycles.1 Of the functional groups that participate in these
cycloadditions, isocyanates2 have played an increasingly
important role due to their reactivity and embedded nitrogen-
containing functionality.3 Indeed, the [2 + 2 + 2] cycload-
dition of isocyanates with diynes to generate 2-pyridones
has been demonstrated with Co(I), Ru(II), Ni(0), and Rh-
(I).4 Our group has recently demonstrated5 that the [2 + 2
+ 2] cycloaddition of unsubstituted pentenyl isocyanate 1
with alkynes 2 could be accomplished in the presence of a
rhodium(I) catalyst to form either lactam 3 or vinylogous
amide 4, the result of an apparent CO migration.6 Moreover,
the reaction of 1 with terminal aryl alkynes in the presence
(4) With Co: (a) Earl, R. A.; Vollhardt, K. P. C. J. Org. Chem. 1984,
49, 4786. (b) Hong, P.; Yamazaki, H. Tetrahedron Lett. 1977, 1333. (c)
Bonaga, L. V. R.; Zhang, H.-C.; Moretto, A. F.; Ye, H.; Gauthier, D. A.;
Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem. Soc. 2005, 127, 3473.
With Ru: (d) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 3,
2117. (e) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda,
S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605. With Ni:
(f) Hoberg, H.; Oster, B. W. Synthesis 1982, 324. (g) Duong, H. A.; Cross,
M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438. With Rh: (h) Tanaka,
K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737.
(5) (a) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782. (b) Yu,
R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370.
(6) Barnhart, R. W.; Bosnich, B. Organometallics 1995, 14, 4343. (b)
Tanaka, K.; Fu, G. C. Chem. Commun. 2002, 684.
(1) (a) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813.
(b) Murakami, M. Angew. Chem., Int. Ed. 2003, 42, 718. (c) Nakamura, I.;
Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (d) Gandon, V.; Aubert, C.;
Malacria, M. Chem. Commun. 2006, 2209. (e) Witulski, B.; Alayrac, C.
Angew. Chem., Int. Ed. 2002, 41, 3281. (f) Tanaka, K. Synlett 2007, 1977.
(2) Braunstein, P.; Nobel, D. Chem. ReV. 1989, 89, 1927.
(3) (a) Hoberg, H.; Hernandez, E. Angew. Chem., Int. Ed Engl. 1985,
24, 961. (b) Hoberg, H. J. Organomet. Chem. 1988, 358, 507. (c) Hoberg,
H.; Ba¨rhausen, D.; Mynott, R.; Schroth, G. J. Organomet. Chem. 1991,
410, 117.
10.1021/ol800086s CCC: $40.75
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Published on Web 02/20/2008

of phosphoramidite ligand L17 affords vinylogous amide 4
products with high levels of enantioenrichment (up to 94%
ee), whereas reaction with terminal aliphatic alkynes in the
presence of ligand L2 affords lactam products 3 with only
moderate enantioenrichment (76-87% ee).5b
Figure 1. Indolizidines bearing quaternary substituted stereo-
centers.
a 1:8 mixture of lactam 6a and vinylogous amide 7a (58%
combined yield) as single regioisomers with good enanti-
oselectivities (eq 2). The major byproduct in this reaction
was 2-pyridone 8a, the result of cycloaddition between the
isocyanate and 2 equiv of alkyne. Using more dilute
conditions ([5a] ) 0.04 M), the formation of pyridone 8a
could be suppressed, leading to the desired cycloadducts as
a 1:7 mixture of 6a:7a with similar ee’s.
We envisioned that this reaction would provide an expedi-
ent entry into a variety of indolizidine and quinolizidine
natural products.8 We further noted that a number of these
natural products possess additional substitution at various
positions around the core, including carbon groups at the
bridgehead position (a quaternary substituted stereocenter).9
Two specific examples of such natural products include the
marine alkaloids cylindricines A-F10 and the immunosup-
pressant FR901483 (Figure 1).11 We thus endeavored to
extend this cycloaddition reaction to incorporate polysub-
stituted alkenes, despite considerable literature precedent
which suggested that more substituted alkenes provide less
stable alkene/metal complexes.12 For example, ethylene binds
to Rh(I) 13 times stronger than propylene, and isobutylene
binds 200 times less strongly than propylene.13 Indeed, the
substitution of disubstituted alkenes in place of terminal
olefins in catalytic reactions is not trivial.14 In light of these
potential problems, it is particularly notable that a Rh(I)‚
phosphoramidite catalyst system has proven to be very
accommodating of 1,1-disubstituted alkenes as partners in
this chemistry. The development of this transformation is
described herein.
The reaction was further optimized by lowering the
rhodium dimer catalyst loading to 2.5 mol %, a change that
results in only a minor decrease in yield (Table 1, entry 1).
Table 1. Alkyne Scope
In preliminary tests, we were pleased to discover that the
methyl-substituted isocyanate 5a (0.12 M in toluene) reacts
with phenylacetylene (2 equiv) in the presence of [Rh(C2H4)2-
Cl]2 (5 mol %) and phosphoramidite L3 (10 mol %) to give
(7) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (b) Alexakis, A.;
Burton, J.; Vastra, J.; Benhaim, C.; Fournioux, X.; van den Heuvel, A.;
Leveque, J.; Maze, F.; Rosset, S. Eur. J. Org. Chem. 2000, 4011. (c) Panella,
L.; Feringa, B. L.; de Vries, J. G.; Minnaard, A. J. Org. Lett. 2005, 7, 4177.
(d) Woodward, A. R.; Burks, H. E.; Chan, L. M.; Morken, J. P. Org. Lett.
2005, 7, 5505.
(8) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191.
(9) Quaternary Stereocenters; Christoffers, J., Baro, A., Eds.; Wiley-
VCH: Weinheim, 2005.
(10) Weinreb, S. M. Chem. ReV. 2006, 106, 2531.
(11) Asymmetric syntheses: (a) Snider, B. B.; Lin, H. J. Am. Chem.
Soc. 1999, 121, 7778. (b) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew.
Chem., Int. Ed., 2000, 39, 4593. (c) Ousmer, M.; Braun, N. A.; Ciufolini,
M. A. Org. Lett. 2001, 3, 765. Racemic syntheses: (d) Maeng, J.-H.; Funk,
R. L. Org. Lett. 2001, 3, 1125. (e) Kan, T.; Fujimoto, T.; Ieda, S.; Asoh,
Y.; Kitaoka, H.; Fukuyama, T. Org. Lett. 2004, 6, 2729. (f) Brummond, K.
M.; Hong, S.-P. J. Org. Chem. 2005, 70, 907.
a Product selectivity determined by 1H NMR of the unpurified mixture.
b Determined by HPLC using a chiral stationary phase. c Alkyne and product
E:Z ) 97:3. d Absolute stereochemistry determined by X-ray.
(12) Tolman, C. A. J. Am. Chem. Soc. 1974, 96, 2780.
(13) Cramer, R. J. Am. Chem. Soc. 1967, 89, 4621.
A series of terminal alkynes were subjected to reaction with
isocyanate 5a using the optimized conditions (Table 1).
Comparing the lactam to vinylogous amide (6:7) selectivity
obtained with phenylacetylene 2a (1:8), p-methoxy-pheny-
(14) For an example of the problem, see: (a) Ohno, H.; Miyamura, K.;
Mizutani, T.; Kadoh, Y.; Takeoka, Y.; Hamaguchi, H.; Tanaka, T. Chem.
Eur. J. 2005, 11, 3728. For successful solutions, see: (b) Evans, P. A.;
Lai, K. W.; Sawyer, J. R. J. Am. Chem. Soc. 2005, 127, 12466. (c) Shibata,
T.; Arai, Y.; Tahara, Y.-K. Org. Lett. 2005, 7, 4955.
1232
Org. Lett., Vol. 10, No. 6, 2008

lacetylene 2b (<1:20), and p-bromo-phenylacetylene 2c (1:
3), it is evident that electron-rich alkynes favor formation
of vinylogous amide products 7, whereas electron-poor
alkynes increase the formation of lactam products 6, a
situation we had also noted in our work with terminal alkynes
and pentenyl isocyanate.5b Unlike the product selectivity in
entries 1-3, the yield (76-80%) and enantioselectivity (88-
91% ee) remain relatively unchanged with shifting alkyne
electronics. The reaction also proceeds smoothly with vinyl
ether 2d to yield vinylogous amide product in good yield
and excellent enantioselectivity (91% ee).15
in the reaction with 2e (entry 2). Further modification of
the ligand led to phosphoramidite L5, which affords the
lactam in good product selectivity (6.5:1) and enantioselec-
tivity (91% ee). A variety of terminal aliphatic alkynes,
including those bearing silyl ethers, an ester, and alkyl
chloride (entries 4-8), are tolerated under the optimized
conditions (60-83% yield, 92-95% ee). The generally high
enantioselectivity and product selectivity obtained with ligand
L5 represents a marked improvement over the selectivity
previously reported with L3.5b
The range of alkenyl isocyanate substitution was also
explored using p-methoxy-phenylacetylene 2b as the alkyne
(Table 3). The ratio of lactam to vinylogous amide products
Terminal aliphatic alkynes also participate in the cycload-
dition with isocyanate 5a, albeit with a reversal in product
selectivity (Table 2). With 1-octyne 2e, a modest 2:1 ratio
Table 3. Alkenyl Substitution Scope
Table 2. Aliphatic Alkyne Scope
a Determined by HPLC using a chiral stationary phase. b Major product
isolated is pyridone (48% yield).
obtained remains independent of the alkene substitution (<1:
20 in all cases). The reaction proceeds in a consistent manner
with alkyl substituents such as butyl, isobutyl, and benzyl
(71-80% yield, 92-94% ee). As the steric size of the
substituent is increased, as in the case with isopropyl and
cyclohexyl isocyanates, an increase in pyridone byproduct
and a corresponding decrease in vinylogous amide yield are
observed (entries 4, 5). We presume that the increased steric
demand about the alkene decreases the rate of coordination
and/or insertion of the alkene to the extent where intermo-
lecular insertion of a second alkyne is competitive even under
dilute conditions. Benzyl ethers 5g, silyl ethers 5h, and
terminal alkenes 5i17 are all tolerated under these reaction
conditions (74-77% yield, 88-92% ee).
a Product selectivity determined by 1H NMR of the unpurified mixture.
b Determined by HPLC using a chiral stationary phase.
of lactam 6e (84% ee) and vinylogous amide 7e (71% ee) is
obtained in 82% combined yield. Interestingly, phosphora-
midite ligand L4 (a ligand with little effect on the reaction
of phenylacetylene16) greatly improves the enantioselectivity
(15) Attempts at generating quinolizidine systems using homologous
substituted isocyanates resulted in exclusive formation of pyridone.
(16) With L4, 6a:7a (1:7) are obtained in 76% combined yield (83%
and 90% ee, respectively).
Org. Lett., Vol. 10, No. 6, 2008
1233

We have shown that 1,1-disubstituted alkenes are com-
petent partners in the Rh-catalyzed [2 + 2 + 2] cycloaddition
reaction leading to the generation of tetrasubstituted carbino-
lamine stereocenters. We have also identified a new phos-
phoramidite ligand that provides improved product selectivity
and enantioselectivity in the cycloaddition of aliphatic
alkynes.18 Efforts aimed at understanding the subtle ligand
effects and applications in total synthesis are currently
underway.
Acknowledgment. We thank NIGMS (GM080442), Eli
Lilly, Boehringer Ingelheim, and Johnson & Johnson for
support. T.R. is a fellow of the Alfred P. Sloan Foundation
and thanks the Monfort Family Foundation for a Monfort
Professorship.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) We have observed no evidence to suggest the terminal olefin
participates in this reaction. Homologous systems were not examined.
(18) Internal alkynes also participate in this cycloaddition reaction but
provide higher selectivities using a different ligand. These studies are
currently ongoing.
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