Palladium(II)-catalyzed enantio- and diastereoselective synthesis of pyrrolidine derivatives

Article abstract of DOI:10.1021/ol3016989

A palladium-catalyzed enantio- and diastereoselective synthesis of pyrrolidine derivatives is described. Initial intramolecular nucleopalladation of the tethered protected amine forms the pyrrolidine moiety and a quinone methide intermediate. A second nucleophile adds intermolecularly to afford diverse products in high enantio- and diastereoselectivity.

Full text of DOI:10.1021/ol3016989

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4074–4077
Palladium(II)-Catalyzed Enantio- and
Diastereoselective Synthesis of
Pyrrolidine Derivatives
Ranjan Jana, Tejas P. Pathak, Katrina H. Jensen,† and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City,
Utah 84112, United States
sigman@chem.utah.edu
Received June 20, 2012
ABSTRACT
A palladium-catalyzed enantio- and diastereoselective synthesis of pyrrolidine derivatives is described. Initial intramolecular nucleopalladation of
the tethered protected amine forms the pyrrolidine moiety and a quinone methide intermediate. A second nucleophile adds intermolecularly to
afford diverse products in high enantio- and diastereoselectivity.
The strategic generation and interception of Pd(II)-alkyl
species is an attractive approach for the development of
alkene difunctionalization reactions.1 A major challenge in
this pursuit is to suppress β-hydride elimination of the
Pd(II)-alkyl species, which would result in Heck2 or Wack-
er-type products.3 To avoid β-hydride elimination, Pd(II)-
alkyl intermediates derived from initial addition of a
nucleophile may be stabilized via π-allyl4 and π-benzyl5
formation, or the Pd(II)-alkyl may be further oxidized
prior to functionalization.6
€
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Soc. 2010, 132, 10209. (h) Kalyani, D.; Satterfield, A. D.; Sanford, M. S.
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† Current address: Black Hills State University, 1200 University St.,
Spearfish, SD 57799.
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r
10.1021/ol3016989
Published on Web 08/08/2012
2012 American Chemical Society

the intramolecular nucleophile would allow facile access to
pyrrolidines8 which are privileged structures in biology9
and catalysis.10 Phenol bearing pyrrolidines are also im-
portant analogs in ongoing biological investigations in our
laboratories. Herein, we report thesuccessful identification
of a suitable intramolecular nitrogen nucleophile that
expands the substrate scope to enable the enantioselective
construction of complex pyrrolidine small molecules bear-
ing a diverse array of heterocycles.
Scheme 1. Proposed Mechanism for Pd(II)-Catalyzed Alkene
Difunctionalization via a Putative Quinone Methide Inter-
mediate
In addition to these strategies, our group has accom-
plished alkene difunctionalization reactions of a specific
alkene class, namely ortho-vinyl phenols (e.g., 1, Scheme 1),
wherein the Pd(II)-alkyl intermediate derived from nucleo-
palladation of A is proposed to undergo a redox reaction,
forming Pd(0) and an ortho-quinone methide intermediate
(BfC).7 This intermediate can be trapped by various
exogenous nucleophiles. Our group has developed highly
diastereoselective and enantioselective variants of this reac-
tion using a pendant alcohol nucleophile to form an oxygen-
containing heterocycle.7e,g A broad scope of exogenous
alcohol- and indole-based nucleophiles may be added to
the quinone methide. Of particular importance, certain pro-
ducts accessible using this route, particularly those featuring
an indole, have been identified to have not only differential
activity toward breast cancer cell lines but also unique
cellular targets based on initial biological investigations
(Figure 1).7g Therefore, we became interested in expanding
this reaction manifold to nitrogen-based intramolecular
nucleophiles, a substrate class that had previously performed
poorly. A successful variant employing a tethered amine as
Figure 1. Substrate optimization Reaction conditions: (a) 4 mol %
Pd(CH3CN)2Cl2, 8 mol % CuCl, 14 mol % iPrQuinox, 40 mol %
KHCO3, 50 equiv of MeOH, O2 balloon, rt, toluene/THF, 4:1, 24 h.
In our early attempts to form pyrrolidine derivatives
with nitrogen-based intramolecular nucleophiles, tosyl car-
bamate 2 (Figure 1) was prepared and submitted to our
previous reaction conditions, but unfortunately, no desired
product formation was observed. In contrast, methyl car-
bamate protected substrate 3 did afford the desired product
4, albeit in low yield and moderate enantioselectivity. The
relatively low observed enantioselectivity may be the result
of the Lewis basic carbamate displacing the chiral quinox
ligand during the reaction. Therefore, lowering the Lewis
basicity and simultaneously the pKa of the nucleophile was
thought to be a prudent approach to facilitate this reaction.
As such, tosylamide 5a was prepared and, after exporsure to
(7) (a) Zhang, Y.; Sigman, M. S. Org. Lett. 2006, 8, 5557. (b) Gligorich,
K. M.; Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2006, 128, 2794.
(c) Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2006, 128, 1460.
(d) Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 3076. (e) Jensen,
K. H.;Pathak, T. P.;Zhang, Y.;Sigman, M. S.J. Am. Chem. Soc. 2009, 131,
17074. (f) Jensen, K. H.; Webb, J. D.; Sigman, M. S. J. Am. Chem. Soc.
2010, 132, 17471. (g) Pathak, T. P.; Gligorich, K. M.; Welm, B. E.; Sigman,
M. S. J. Am. Chem. Soc. 2010, 132, 7870. (h) Pathak, T. P.; Sigman, M. S.
Org. Lett. 2011, 13, 2774. (i) Pathak, T. P.; Sigman, M. S. J. Org. Chem.
2011, 76, 9210.
Table 1. Conditions Optimization
(8) For Pd-catalyzed variants of pyrrolidine synthesis, see: (a) Tsujihara,
T.; Shinohara, T.; Takenaka, K.; Takizawa, S.; Onitsuka, K.; Hatanaka,
M.; Sasai, H. J. Org. Chem. 2009, 74, 9274. (b) Mai, D. N.; Wolfe, J. P.
J. Am. Chem. Soc. 2010, 132, 12157. (c) McDonald, R. I.; White, P. B.;
Weinstein, A. B.; Tam, C. P.; Stahl, S. S. Org. Lett. 2011, 13, 2830.
(9) (a) Cole, D. C.; Lennox, W. J.; Lombardi, S.; Ellingboe, J. W.;
Bernotas, R. C.; Tawa, G. J.; Mazandarani, H.; Smith, D. L.; Zhang, G.;
Coupet, J.; Schechter, L. E. J. Med. Chem. 2005, 48, 353. (b) Borthwick,
A. D. Med. Res. Rev. 2005, 25, 427.
(10) For classic examples, see: (a) Kagan, H. B. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1985; Vol. 5,
Chapter 1. (b) Doyle, M. P.; Pieters, R. J.; Martin, S. F.; Austin, R. E.;
Oalmann, C. J.; Miiller, P. J. Am. Chem. Soc. 1991, 113, 1423. For a
review of proline derivatives, see: (c) Mukherjee, S.; Yang, J. W.;
Hoffman, S.; List, B. Chem. Rev. 2007, 107, 5471.
Org. Lett., Vol. 14, No. 16, 2012
4075

Table 2. Substrate Scopea
a All reactions were carried out on 0.50 mmol scale. Yields refer to the average of at least two reactions.
the optimal conditions, the desired product 6a was observed
in modest yield (43%) and high enantioselectivity, albeit in
low diastereoselectivity.
alkene isomerization modestly improved the yield when
using the enriched E-alkene (37%, entry 3) as compared to
reacting at room temperature (entry 1). Under these con-
ditions, the use of the predominantly Z-alkene resulted
in synthetically useful yields of the desired product with
only a slight reduction in enantioselectivity (entry 4).
Of note, poor mass balance is believed to arise from
oligomerization of the proposed quinone methide
intermediate.
Under these conditions, the substrate scope for this
reaction was explored (Table 2). Several N-protected in-
doles underwent the reaction to yield the desired products
in high enantioselectivity and diastereoselectivity (7aÀ7g).
Modest changes to the electronic nature of the phenol did
not affect the reaction outcome (7g). However, highly
electron-rich phenols (X = OMe) do not undergo the
reaction due to rapid decomposition (not depicted). In
addition to indoles, substituted furans (7h, 7i) and indoli-
zines (7jÀ7o) are highly effective reaction partners; these
reactants have not been evaluated previously in this reac-
tion class and lead to new pharmacophores in the
products.11 Although an excess (15 equiv) of the external
nucleophile is required, it can be effectively recovered after
the reaction.
Considering our standing interest in the products de-
rived from indole additions to the generated quinone
methides and the improved diastereoselectivity typically
observed when using these nucleophiles, we evaluated
N-methyl indole with substrate 5a (Table 1).7g Initially,
we found considerable variation in reaction yield. A
possible origin for this result is the stereoisomeric purity
of 5a, which was found to be dependent on how long the
Wittig reaction used to prepare 5a was allowed to stir (see
Supporting Information). To probe this hypothesis, a
sample of 5a with >95% E geometry was submitted
to the reaction (entry 1). A low yield of 7a was observed
with excellent enantio- and diasteroselectivity. However,
significant amounts of remaining starting material was
isolated. In contrast, an evaluation of ∼80% Z-sample of
5a resulted in significantly improved yields and the same
high levels of selectivity (entry 2). Of particular impor-
tance, only the E-isomer of 5a (25%) was isolated (entry 2,
the starting material only contained 20%), indicating that
the Z-isomer isomerizes to the thermodynamically more
stable E-isomer under the reaction conditions. Addition-
ally, the results suggest that the E-isomer reacts faster than
the Z-isomer, which is consistent with previous mechan-
istic studies on this reaction type in that the Z-alkene is
proposed to undergo trans-nucleopalladation to achieve
the observed stereochemical outcome as depicted in
Scheme 1.7f Therefore, heating of the reaction to facilitate
To further explore the scope of the intramolecular
nucleophile, substrate 8 with a pendant carboxylic acid
was prepared and evaluated. An excellent yield of the desired
lactone product was observed (Figure 2A). Surprisingly, the
product of this reaction is racemic, albeit isolated as
a single diastereomer. One mechanistic hypothesis to
4076
Org. Lett., Vol. 14, No. 16, 2012

reaction has been proposed to proceed through a trans-
nucleopalladation of the bidentate Z-alkene and phenol to
account for the stereoinduction (Scheme 1).7f However, the
nature of the nucleophile has been reported to strongly
influence the stereochemical course of nucleopalladation.12
In this case, an alkeneÀPdÀcarboxylate complex likely
forms preferentially due to the higher acidity of the acid
(as compared to the relatively high pKa’s of both alcohol
and sulfonamide nucleophiles) resulting in cis-nucleopalla-
dation (Figure 2C, II). To acount for the loss of enantios-
electivity, either the chiral ligand is displaced due to the
presumed change in mechanism or the enantioselectivity is
lost if the phenol is not engaged in this key step.
In conclusion, we have expanded the scope of enantio-
selective alkene difunctionalization reactions to include
amine nucleophiles through modest, but mechanistically
guided, changes to the reaction conditions. The diverse
products incorporate vetted pharmacophores in unique
structures. Current efforts are focused on exploring the
biological properties of these compounds and will be
reported in due course.
Figure 2. Evaluation of lactone formation.
Acknowledgment. This research was supported by
the National Institutes of Health (RO1GM3540 and
R01CA140296).
account for this observation is a reversible nucleopallada-
tion step, as a carboxylate is a better leaving group than
an alkoxide, which could lead to an erosion of enantio-
selectivity (Figure 2B). Alternatively, the significant change
in the pKa of the nucleophile may lead to a change in
mechanism (Figure 2C). The nucleopalladation step of this
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data, and chiral separations
for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) (a) Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.;
Murakami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.; Ueno, M.;
Chikazawa, Y.; Yamada, K.; Ono, T.; Teshirogi, I.; Ohtani, M. J. Med.
Chem. 1996, 39, 3636. (b) Sonnet, P.; Dallemagne, P.; Guillon, J.;
Enguehard, C.; Stiebing, S.; Tanguy, J.; Bureau, R.; Rault, S.; Auvray,
(12) The nature of the nucleophile strongly influences the stereoche-
€
mical outcome of nucleopalladation; see: (a) Backvall, J. E.; Nordberg,
R. E. J. Am. Chem. Soc. 1981, 103, 4959. (b) McDonald, R. I.; Liu, G.;
Stahl, S. S. Chem. Rev. 2011, 111, 2981.
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8, 945.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
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