Enantioselective thiourea-catalyzed intramolecular cope-type hydroamination

Article abstract of DOI:10.1021/ja402893z

Catalysis of Cope-type rearrangements of bis-homoallylic hydroxylamines is demonstrated using chiral thiourea derivatives. This formal intramolecular hydroamination reaction provides access to highly enantioenriched α-substituted pyrrolidine products and represents a complementary approach to metal-catalyzed methods.

Full text of DOI:10.1021/ja402893z

Communication
pubs.acs.org/JACS
Enantioselective Thiourea-Catalyzed Intramolecular Cope-Type
Hydroamination
Adam R. Brown, Christopher Uyeda, Carolyn A. Brotherton, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
(Figure 1).8,9 Protic solvents have been shown to accelerate the
Cope-type hydroamination,10 and computational studies have
ABSTRACT: Catalysis of Cope-type rearrangements of
bis-homoallylic hydroxylamines is demonstrated using
chiral thiourea derivatives. This formal intramolecular
hydroamination reaction provides access to highly
enantioenriched α-substituted pyrrolidine products and
represents a complementary approach to metal-catalyzed
methods.
identified specific stabilizing H-bonding interactions in the
polar cyclization transition structure to account for this effect.11
We considered whether ureas and thioureas,12 which have
demonstrated utility as enantioselective dual hydrogen-bond
donor catalysts, could facilitate the Cope-type hydroamination
in a similar manner.13 In order to evaluate this hypothesis, we
analyzed the effect of a simple thiourea on the reaction
coordinate for the Cope reaction using DFT methods (Figure
1). This analysis predicts that the thiourea lowers the activation
barrier for the cyclization by 3.1 kcal/mol, thereby supporting
the hypothesis that this family of H-bond donors could serve as
viable catalysts for the hydroamination reaction. We report here
the development of chiral thiourea derivatives bearing electron
rich aromatic components that catalyze highly enantioselective
Cope-type hydroaminations, providing access to enantioen-
riched α-substituted pyrrolidine products.
nantioselective intramolecular olefin hydroamination
Eaffords a direct and atom-economical synthetic approach
to chiral nitrogen heterocycles with useful properties as
biologically active compounds,1 small-molecule catalysts,2 and
ligands.3 Significant advances in metal-catalyzed asymmetric
intramolecular hydroaminations have relied mostly on highly
air- and moisture-sensitive lanthanide, group 4 metal (Zr, Ti),
or highly electropositive main-group metal (Mg, Li) com-
plexes.4 Late transition metal-catalyzed hydroamination4s,t and
carboamination4a,5 reactions have been identified that hold
promise for broader functional group tolerance and concom-
itant substrate generality.6,7
The retro-Cope elimination reaction (Figure 1) represents a
mechanistically distinct alternative to metal-catalyzed processes
for alkene hydroamination. In this type of transformation, a
hydroxylamine undergoes reaction with an olefin in a pericyclic
pathway involving concerted C−H and C−N bond formation
The principle we applied to the design of chiral catalysts for
the Cope hydroamination is outlined in Scheme 1. In prior
Scheme 1. Design Strategy for Enantioselective Cope-Type
Hydroamination Catalyst
work on enantioselective catalytic Claisen rearrangements,14
the combined effect of hydrogen-bonding and secondary
stabilization in the dipolar transition structure was shown to
underlie the observed rate acceleration and asymmetric
induction.15 We reasoned that the polar character of the
Cope-type hydroamination transition structure might render it
susceptible to analogous cooperative, attractive, non-covalent
interactions with the appropriate polyfunctional catalyst
framework.
The cyclization of hydroxylamine 1a was evaluated in the
presence of a variety of thiourea catalysts bearing polarizable
and conformationally constrained aromatic components (Table
1). While catalysts 3a and 3b (Table 1, entries 2 and 3)
provided modest acceleration over the background, uncatalyzed
reaction, catalysts containing electron-rich π-systems, such as
Figure 1. Calculated electronic energies for the optimized structures of
the substrate, transition state, N-oxide intermediate, and product for
both an uncatalyzed (black, top) and an N,N′-dimethylthiourea-
catalyzed (blue, bottom) Cope hydroamination reaction (B3LYP/6-
311+G(d,p) level of DFT). Relative energies are in kcal/mol and key
hydrogen bonding distances are shown in angstroms.
Received: March 21, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja402893z | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Catalyst Evaluationa
Table 2. Scope of Enantioselective Hydroaminationa
extended arenes or arylpyrroles, led to more significant rate
enhancements. For catalysts 3b−3e (Table 1, entries 3−6), an
increase in yield and enantioselectivity was observed as the
expanse of the α-aryl group of the pyrrolidine was increased.
Comparable correlations between arene expanse and rate and
enantioselectivity have been observed previously for this class
of catalysts (3c−3e) in the context of polyene cyclizations and
episulfonium ion ring-openings.16 In these systems, stabilizing
cation−π interactions between the catalyst arene and the
cationic transition state were identified.
Catalysts bearing arylpyrrole components capable of similar
interactions15 were also found to be effective and highly
enantioselective catalysts for the model transformation (Table
1, compare entries 2 and 7). For catalysts containing both a
pyrrole and an α-arylpyrrolidine moiety, the level of
enantioinduction was relatively insensitive to the size of the
aryl group on the pyrrolidine portion of the catalyst (Table 1,
entries 8−11). These results suggest that catalyst−transition
state interactions with the arylpyrrole are stronger than those
with the arylpyrrolidine for this class of catalysts. After extensive
optimization of these structural motifs, thiourea 5 was identified
as the optimal catalyst for the hydroamination.17
With the optimal catalyst identified, the substrate scope of
the hydroamination reaction was evaluated. Several 4-alkenyl-1-
hydroxylamines bearing electronically diverse (E)-styryl groups
underwent cyclization in the presence of thiourea 5 in good
yields and moderate to excellent enantioselectivities (Table 2,
entries 1−10). Ortho, meta, and para substitution on the arene
were all well tolerated (Table 2, entries 3, 6 and 7), as were
halogen- and oxygen-containing functionality (Table 2, entries
3 and 5). Substrates with geminal disubstitution at the 2-
position reacted more rapidly and with higher enantioselectivity
than substrates lacking such groups (Table 2, entries 1, 8, and
9), presumably as a result of a favorable Thorpe−Ingold effect
in the cyclization reaction.18 Terminal olefin substrate 1j also
underwent cyclization to the desired pyrrolidine product, albeit
with slightly lower enantioselectivity than the corresponding
styrenyl analogues (Table 2, entries 11 and 12). The catalytic
efficiency of the system is also notable, as the catalyst loading
could be decreased from 10 to 2 mol% with only slight
diminution of enantioselectivity (Table 2, entry 2).19
In conclusion, we have developed a highly enantioselective
thiourea-catalyzed Cope-type hydroamination that provides
access to a variety of pyrrolidine products under mild reaction
conditions. Thiourea catalysts capable of stabilizing the dipolar
transition structure in the pericyclic reaction via multiple non-
covalent interactions were found to be most effective for
catalysis and enantioinduction. Elucidation of the specific
catalyst−substrate interactions at play is the focus of ongoing
study, and will be applied to future catalyst design strategies.
B
dx.doi.org/10.1021/ja402893z | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Soc. 2010, 132, 12157. (e) Liwosz, T. W.; Chemler, S. R. J. Am. Chem.
Soc. 2012, 134, 2020. (f) Hopkins, B. A.; Wolfe, J. P. Angew. Chem., Int.
Ed. 2012, 51, 9886.
ASSOCIATED CONTENT
* Supporting Information
Complete experimental procedures and characterization data
for products and all isolated intermediates. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(6) Asymmetric hydroaminations of allenes and dienes have also
been identified that proceed under mild reaction conditions:
(a) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science
2007, 317, 496. (b) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F.
D. J. Am. Chem. Soc. 2007, 129, 2453. (c) Zhang, Z.; Bender, C. F.;
Widenhoefer, R. A. Org. Lett. 2007, 9, 2887. (d) Zhang, Z.; Bender, C.
F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2007, 129, 14148. (e) Kanno,
O.; Kuriyama, W.; Wang, Z. J.; Toste, F. D. Angew. Chem., Int. Ed.
2011, 42, 9919. (f) Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu,
J.; Toste, F. D. Nature 2011, 470, 245.
AUTHOR INFORMATION
Corresponding Author
jacobsen@chemistry.harvard.edu
Notes
■
The authors declare no competing financial interest.
(7) For asymmetric intermolecular hydroaminations, see: (a) Dorta,
R.; Egli, P.; Zurcher, F.; Togni, A. J. Am. Chem. Soc. 1997, 119, 10857.
(b) Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 12220.
(c) Zhang, Z.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009,
131, 5372.
ACKNOWLEDGMENTS
This work was supported by the NIH (GM-43214).
■
REFERENCES
■
(8) For a review on the transformation, see: (a) Copper, N. J.;
Knight, D. W. Tetrahedron 2004, 60, 243. See also: (b) House, H. O.;
Manning, D. T.; Melillo, D. G.; Lee, L. F.; Haynes, O. R.; Wilkes, B. E.
J. Org. Chem. 1976, 41, 855. (c) House, H. O.; Lee, L. F. J. Org. Chem.
1976, 41, 863. (d) Black, D.; St, C.; Doyle, J. E. Aust. J. Chem. 1978,
31, 2317. (e) Oppolzer, W.; Siles, S.; Snowden, R. L.; Bakker, B. H.;
Petrzilka, M. Tetrahedron Lett. 1979, 20, 4391. (f) Oppolzer, W.;
Spivey, A. C.; Bochet, C. G. J. Am. Chem. Soc. 1994, 116, 3139.
(g) Krenske, E. H.; Davison, E. C.; Forbes, I. T.; Warner, J. A.; Smith,
A. L.; Holmes, A. B.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 2434.
(9) For an elegant catalytic tethering approach to asymmetric
intermolecular Cope-type hydroaminations, see: (a) MacDonald, M.
J.; Schipper, D. J.; Ng, P. J.; Moran, J.; Beauchemin, A. M. J. Am. Chem.
Soc. 2011, 133, 20100. (b) Guimond, N.; MacDonald, M. J.; Lemieux,
V.; Beauchemin, A. M. J. Am. Chem. Soc. 2012, 134, 16571.
(1) (a) Hensler, M. E.; Bernstein, G.; Nizet, V.; Nefzi, A. Biorg. Med.
Chem. Lett 2006, 16, 5073. (b) Li, X.; Li, J. Mini-Rev. Med. Chem. 2010,
10, 794. (c) Lexa, K. W. Proteins 2011, 79, 2282. (d) Galliford, C. V.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748. (d) Cole, D. C.;
Lennox, W. J.; Lombardi, S.; Ellingboe, J. W.; Bernotas, R. C.; Tawa,
G. J.; Masandarani, H.; Smith, D. L.; Zhang, G.; Coupet, J.; Schechter,
L. E. J. Med. Chem. 2005, 48, 353.
(2) (a) Zhang, S.; Wang, W. Privileged Chiral Ligands and Catalysts;
Zhou, Q.-L., Ed.; Wiley-VCH: Weinheim, Germany, 2011; pp 409−
439. (b) Watson, A. J. B.; MacMillan, D. W. C. Enantioselective
Organocatalysis Involving Iminium, Enamine SOMO and Photoredox
Activation. In Catalystic Asymmetric Synthesis, 3rd ed.; Ojima, I., Ed.;
Wiley & Sons: Hoboken, NJ, 2010; pp 39−57.
(3) For a review of chiral amine ligands, see: Caputo, C. A.; Jones, N.
D. Dalton Trans. 2007, 4627.
(4) For recent reviews on hydroamination, see: (a) Chemler, S. R.
́
(10) (a) Beauchemin, A. M.; Moran, J.; Lebrun, M.-E.; Seguin, C.;
Dimitrijevic, E.; Zhang, L.; Gorelsky, S. I. Angew. Chem., Int. Ed. 2008,
47, 1410. (b) Moran, J.; Gorelsky, S. I.; Dimitrijevic, E.; Lebrun, M.-E.;
Org. Biomol. Chem. 2009, 7, 3009. (b) Muller, T. E.; Hultzsch, K. C.;
̈
Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. For
asymmetric intramolecular hydroaminations with lanthanide com-
plexes, see: (c) Giardello, M. A.; Conticello, V. P.; Brard, L.; Gagne, M.
R.; Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10241. (d) Hong, S.;
Tian, S.; Metz, M. V.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 14768.
(e) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737. (f) Collin, J.;
Daran, J.; Jacquet, O.; Schulz, E.; Trifonov, A. Chem.Eur. J. 2005, 11,
3455. (g) Riegert, D.; Collin, J.; Meddour, A.; Schulz, E.; Trifonov, A.
J. Org. Chem. 2006, 71, 2514. (h) Gribkov, D. V.; Hultzsch, K. C.;
Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748. (i) Chapurina, Y.;
Ibrahim, H.; Guillot, R.; Kolodziej, E.; Collin, J.; Trifonov, A.; Schulz,
E.; Hannedouche, J. J. Org. Chem. 2011, 76, 10163. For asymmetric
intramolecular hydroamination with group 4 complexes, see:
(j) Knight, P. D.; Munslow, I.; O’Shaughnessy, P. N.; Scott, P.
Chem. Commun. 2004, 894. (k) Watson, D. A.; Chiu, M.; Bergman, R.
G. Organometallics 2006, 25, 4731. (l) Wood, M. C.; Leitch, D. C.;
Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem., Int. Ed. 2007,
46, 354. (m) Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P.
Organometallics 2007, 26, 1729. (n) Zi, G.; Liu, X.; Xiang, L.; Song, H.
Organomettalics 2009, 28, 1127. (o) Manna, K.; Xu, S.; Sadow, A. D.
Angew. Chem., Int. Ed. 2011, 50, 1865. For asymmetric intramolecular
hydroamination with main-group metals, see: (p) Martinez, P. H.;
Hultzsch, K. C.; Hampel, F. Chem. Comm 2006, 2221. (q) Ogata, T.;
Ujihara, A.; Tsuchida, S.; Shimizu, T.; Kaneshige, A.; Tomioka, K.
Tetrahedron Lett. 2007, 48, 6648. (r) Zhang, X.; Emge, T. J.; Hultzsch,
K. C. Angew. Chem., Int. Ed. 2012, 51, 394. For asymmetric
intramolecular hydroamination with late transition metals, see:
(s) Shen, X.; Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49, 564.
(t) Turnpenny, B. W.; Hyman, K. L.; Chemler, S. R. Organometallics
2012, 31, 7819.
Bed
130, 17893.
́ ́
ard, A.-C.; Seguin, C.; Beauchemin, A. M. J. Am. Chem. Soc. 2008,
(11) Acevedo, O.; Jorgensen, W. L. J. Am. Chem. Soc. 2006, 128,
6141.
(12) (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006,
45, 1520. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713.
(13) For acceleration of the Claisen rearrangement by a similar
strategy, see: (a) Curran, D. P.; Kuo, L. H. Tetrahedron Lett. 1995, 36,
6647−6650. (b) Kirsten, M.; Rehbein, J.; Hiersemann, M.; Strassner,
T. J. Org. Chem. 2007, 72, 4001−4011.
(14) (a) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130,
9228. (b) Uyeda, C.; Rotheli, A. R.; Jacobsen, E. N. Angew. Chem., Int.
̈
Ed. 2010, 49, 9753.
(15) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062.
(16) (a) Knowles, R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc.
2010, 132, 5030. (b) Lin, S.; Jacobsen, E. N. Nat. Chem. 2012, 4, 817.
(17) See Supporting Information for complete catalyst optimization.
(18) For a review on the Thorpe−Ingold effect, see: Jung, M. E.;
Pizzi, G. Chem. Rev. 2005, 105, 1735.
(19) In order to prevent racemic cyclization of any unreacted
hydroxylamine during workup, the catalytic reactions were quenched
by the addition of p-nitrobenzoyl chloride. The resultant O-
benzoylated products can be reduced to the corresponding pyrrolidine
in good yield and without erosion of enantiomeric excess. See
Supporting Information for further details.
(5) For example: (a) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.;
Yang, D. J. Am. Chem. Soc. 2006, 128, 3130. (b) Zeng, W.; Chemler, S.
R. J. Am. Chem. Soc. 2007, 129, 12948. (c) Zeng, W.; Chemler, S. R. J.
Org. Chem. 2008, 73, 6045. (d) Duy, M. N.; Wolfe, J. P. J. Am. Chem.
C
dx.doi.org/10.1021/ja402893z | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX