Stereoselective synthesis of cis-2,5-disubstituted pyrrolidines via Wacker-type aerobic oxidative cyclization of alkenes with tert-butanesulfinamide nucleophiles

Article abstract of DOI:10.1021/ol3000519

Palladium(II)-catalyzed aerobic oxidative cyclization of alkenes with tethered tert-butanesulfinamides furnishes enantiopure 2,5-disubstituted pyrrolidines, originating from readily available and easily diversified starting materials. These reactions are the first reported examples of metal-catalyzed addition of sulfinamide nucleophiles to alkenes.

Full text of DOI:10.1021/ol3000519

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1242–1245
Stereoselective Synthesis of
cis-2,5-Disubstituted Pyrrolidines via
Wacker-Type Aerobic Oxidative
Cyclization of Alkenes with
tert-Butanesulfinamide Nucleophiles
Joanne E. Redford, Richard I. McDonald, Matthew L. Rigsby, Joshua D. Wiensch, and
Shannon S. Stahl*
University of WisconsinÀMadison, 1101 University Avenue, Madison, Wisconsin 53706,
United States
stahl@chem.wisc.edu
Received January 10, 2012
ABSTRACT
Palladium(II)-catalyzed aerobic oxidative cyclization of alkenes with tethered tert-butanesulfinamides furnishes enantiopure 2,5-disubstituted
pyrrolidines, originating from readily available and easily diversified starting materials. These reactions are the first reported examples of metal-
catalyzed addition of sulfinamide nucleophiles to alkenes.
2,5-Disubstituted pyrrolidines are an important class
of heterocycles featured in numerous natural products,
pharmaceuticals, ligands for transition metals, and
organocatalysts.1 PdII-catalyzed aerobic oxidative cycliza-
tion reactions provide efficient routes to pyrrolidines
(eq 1);2,3 however, few of these methods enable stereo-
selective CÀN bond formation. The first examples of
enantioselective oxidative cyclization have been reported
only recently.4À6 Here, we show that chiral γ-amino-
alkene substrates bearing a tBu-sulfinyl auxiliary undergo
efficient PdII-catalyzed aerobic oxidative cyclization
to afford enantiopure 2,5-disubstituted pyrrolidines.7
tBu-Sulfinamides have been widely used for the
(1) (a) Ronzani, N.; Lajat, M. Bioorg. Med. Chem. Lett. 1995, 5,
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r
10.1021/ol3000519
Published on Web 02/21/2012
2012 American Chemical Society

stereoselective synthesis of amines, as summarized in an
extensive recent review by Ellman;8 however, the present
reactions are the first use of sulfinamides in metal-catalyzed
nucleophilic functionalization of alkenes.9
Table 1. Optimization of a Catalyst System for Diastereoselec-
tive Oxidative Cyclizationa
Our strategy to prepare 2,5-disubstituted pyrrolidines is
illustrated in Scheme 1 and begins with readily available
cis-4-hexen-1-ols.10 Aerobic oxidation of the alcohol11
entry
1
[PdII]/additives
solvent
DMSO
yieldc
87
t
and condensation of the resulting aldehyde with Bu-
Pd(OAc)2/2 equiv of NaOAc,
sulfinamide8,12 furnish the sulfinyl imine derivative 1.
Methods for stereoselective addition of nucleophiles to
chiral sulfinyl imines provide access to a variety of enan-
tiopure R-substituted sulfinamides 2.8 PdII-catalyzed
aerobic oxidative cyclization of 2 affords the desired 2,5-
disubstituted pyrrolidines.
˚
no 3 A MS
2
3
Pd(OAc)2/20 mol % pyridine
Pd(TFA)2/40 mol % pyridine,
toluene
toluene
38
8
˚
2 equiv of Na2CO3, no 3 A MS
4
Pd(TFA)2/20 mol % DMSO,
1 equiv of LiOAc
THF
83
5
6
Pd(TFA)2/no base
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6
The enantiopure R-Me-substituted sulfinamide 3 was
used as the substrate in the development of a suitable
heterocyclization catalyst (Table 1).13 Testing of catalyst
systems that have been shown previously to promote aero-
bic oxidative cyclization of γ-aminoalkene derivatives led
Pd(TFA)2/1 equiv of NaOAc
Pd(TFA)2/1 equiv of NaOBz
Pd(TFA)2/1 equiv of LiOAc
Pd(TFA)2/1 equiv of Na2CO3
PdCl2/1 equiv of LiOAc
Pd(OPiv)2/1 equiv of LiOAc
81
79
92
14
81
13
7
8
9
10
11
a Conditions: substrate (0.08 mmol), PdII (0.008 mmol), 3 A MS
(40 mg), O2 (1 atm), solvent (0.8 mL), 50 °C, 14 h. b Diastereomeric ratio
determined by 1H NMR spectroscopy. c Yield determined by 1H NMR
spectroscopy, int. std. = PhSiMe3.
˚
Scheme 1. Stereoselective Synthesis of 2,5-Disubstituted Pyr-
rolidines
to mixed results (Table 1, entries 1À4).3,14 Good product
yields were obtained with PdII catalysts in which DMSO
was used as a solvent and/or ligand (entries 1 and 4),3a,14
while PdII/pyridine-based catalyst systems (entries 2
and 3)3b,c afforded low yields. Further screening of anionic
base additives, the PdII source, and solvents (Table 1, entries
5À11; Table S1) revealed that optimal results were obtained
with Pd(TFA)2 (TFA = trifluoroactate) as the PdII source,
1 equiv of LiOAc, and DMSO as the solvent. All conditions
tested led to formation of a single diastereomeric product
(>20:1 dr), affording the cis disubstituted pyrrolidine 4.
The sulfinamide group is readily removed upon treatment of
4 with 4 M HCl,15 affording the HCl salt of the unprotected
pyrrolidine in 95% yield.16
(5) For a review of stereoselective nucleopalladation reactions, in-
cluding oxidative cyclizations, see: McDonald, R. I.; Liu, G.; Stahl, S. S.
Chem. Rev. 2011, 111, 2981–3019.
(6) For leading references to other enantioselective metal-catalyzed
aminocyclization reactions, see: (a) Hong, S.; Tian, S.; Metz, M. V.;
Marks, T. J. J. Am. Chem. Soc. 2003, 125, 14768–14783. (b) Wood,
M. C.; Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew.
Chem., Int. Ed. 2007, 46, 354–358. (c) Chemler, S. R. Org. Biomol. Chem.
2009, 7, 3009–3019. (d) Fuller, P. H.; Kim, J.-W.; Chemler, S. R. J. Am.
Chem. Soc. 2008, 130, 17638–17639. (e) Shen, X.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2010, 49, 564–567. (f) Mai, D. N.; Wolfe, J. P.
J. Am. Chem. Soc. 2010, 132, 12157–12159.
(8) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600–3740.
(9) For alternative heterocyclization methods using tBu-sulfinamides
in the stereoselective formation of CÀN bonds, see: (a) Brinner, K. M.;
Ellman, J. A. Org. Biomol. Chem. 2005, 3, 2109–2113. (b) Li, Y.; Ni, C.;
Liu, J.; Zhang, L.; Zheng, J.; Zhu, L.; Hu, J. Org. Lett. 2006, 8, 1693–
1696. (c) Reddy, L. R.; Das, S. G.; Lui, Y.; Prashad, M. J. Org. Chem.
2010, 75, 2236–2246.
(7) For leading references on the synthesis of 2,5-disubstituted
pyrrolidines, see: (a) Pichon, M.; Figadere, B. Tetrahedron: Asymmetry
1996, 7, 927–964. (b) Rudolph, A. C.; Machauer, R.; Martin, S. F.
Tetrahedron Lett. 2004, 45, 4895–4898. (c) Hussaini, S. R.; Moloney,
(10) Wenkert, E.; Micheloti, E. L.; Swindell, C. S.; Tingoli, M. J. Org.
Chem. 1984, 49, 4894–4899.
(11) Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901–
16910.
(12) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278–1284.
(13) Additional reaction optimization data are provided in the
Supporting Information.
(14) McDonald, R. I.; Stahl, S. S. Angew. Chem., Int. Ed. 2010, 49,
5529–5532.
ꢀ
M. G. Org. Biomol. Chem. 2006, 4, 2600–2615. (d) Llamas, T.; Arrayas,
R. G.; Carretero, J. C. Org. Lett. 2006, 8, 1795–1798. (e) Wang, P.-A.;
Xu, Z.-S.; Chen, C.-F.; Gao, X.-G.; Sun, X.-L.; Zhang, S.-Y. Chirality
2007, 19, 581–588. (f) Zhang, S.; Xu, L.; Miao, L.; Shu, H.; Trudell,
M. L. J. Org. Chem. 2007, 72, 3133–3136. (g) Paderes, M. C.; Chemler,
S. R. Org. Lett. 2009, 11, 1915–1918. (h) Lygo, B.; Beynon, C.; McLeod,
M. C.; Roy, C.-E.; Wade, C. E. Tetrahedron 2010, 66, 8832–8836. (i)
Lemen, G. S.; Wolfe, J. P. Org. Lett. 2010, 12, 2322–2325. (j) Lemen,
G. S.; Wolfe, J. P. Org. Lett. 2011, 13, 3218–3221.
(15) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883–
8904.
Org. Lett., Vol. 14, No. 5, 2012
1243

Table 2. Substrate Effects on the Diastereoselectivity of PdII-
Table 3. Stereoselective Oxidative Cyclization of Alkenes
Bearing Tethered R-Substituted tBu-Sulfinamide Nucleophilesa
Catalyzed Oxidative Cyclizationa
a Conditions: substrate (0.07 mmol), Pd(TFA)2 (0.007 mmol), 3 A
MS (35 mg), O2 (1 atm), DMSO-d6 (0.7 mL), 50 °C, 24 h. b Yield
determined by 1H NMR spectroscopy, int. std. = PhSiMe3. c Diaster-
˚
1
eomeric ratio determined by H NMR spectroscopy of crude reaction
mixture.
The presence of two stereocenters in 3, one associated
with the sulfinyl group and the other R to the nitrogen
atom, raises fundamental questions concerning the origin
of stereocontrol in these reactions. The optimized catalyst
system was used to probe these issues (Table 2). Substrate 5,
which lacks a stereocenter adjacent to nitrogen, underwent
cyclization with 7:1 dr (68% yield, entry 1), demonstrating
that the tBu-sulfinyl group could be used as an auxiliary to
achieve stereocontrol when no other stereocenters are
present in the substrate. The influence of the R-Me group
on diastereoselectivity was evaluated by performing
a
t
˚
Conditions: substrate (0.5 mmol), Pd(TFA)2 (0.05 mmol), 3 A MS
the cyclization of 6, in which the Bu-sulfinyl group
(250 mg), O2 balloon, DMSO (5 mL), 50 °C, 24 h. c Isolated yield.
b Diastereomeric ratio determined by 1H NMR spectroscopy of crude
reaction mixture. d Performed at 70 °C, 3 atm of O2.
was replaced with an achiral toluenesulfonyl (Ts) group.
This reaction afforded the cis-pyrrolidine product
with moderate diastereoselectivity (6:1 dr, entry 2). The
cooperative effect of the two stereocenters is evident
from the improved yield and diastereoselectivity in the
(16) See Supporting Information for further information.
1244
Org. Lett., Vol. 14, No. 5, 2012

cyclization of the parent substrate 3 (98% yield, >20:1 dr;
entry 3). The pairwise influence of the sulfur- and carbon-
based stereocenters was analyzed further by testing the
reaction of epi-3, in which the stereochemical configura-
tion R to nitrogen is inverted (entry 4). This substrate
afforded the corresponding cis-pyrrolidine16 as a single
diastereomer, but with moderately reducedyield relative to
the reaction of 3. This observation suggests that rotation
about the NÀS bond enables the sulfinamide to act
cooperatively with either epimeric form of the substrate
to enforce highly diastereoselective CÀN bond formation.
Finally, analysis of the alkene stereochemistry revealed
that a significantly lower yield and diastereoselectivity
was observed with substrate 7, bearing a trans-alkene (cf.
entries 3 and 5).17
With these results in hand, we investigated the reactivity
of a number of different substrates (Table 3). A benzyl-
substituted alkene underwent cyclization in 85% yield to
provide the stryenyl product (entry 1). Each of the other
substrates, bearing diverse functional groups in the R
position, was readily obtained by stereoselective addition
of the appropriate nucleophile to the sulfinylimine pre-
cursor (cf. Scheme 1).8,16 Oxidative cyclization of these
substrates proceeded with excellent diastereoselectivity, in
most cases affording a single detectable diastereomer
(Table 3). All of the reactions proved to be operationally
straightforward, with substrates and reagents weighed and
combined in a flask open to the air and stirred under a
balloon of O2. Substrates with relatively large R substitu-
ents, including isopropyl and aryl groups, proceeded effec-
tively, albeit with a somewhat lower yield relative to the
R-Me derivative 3 (61À74% yield, entries 2À4). Subtrates
featuring an aryl chloride (entry 4), phosphonate (entry 5),
carboxylic ester (entry 6), or acetal (entry 7) also under-
went successful cyclization. The latter functional groups
are appealing because they are readily amenable to further
functional-group manipulations to prepare more complex
molecules.
Scheme 2. Synthesis of a Common Precursor for the Synthesis of
Tropane Alkaloids
azabicyclic tropene 10 in 82% yield (Scheme 2).16 Tropane
alkaloids have received substantial attention in recent
years due to the effect of these molecules on the central
nervous system,18 and tropene derivatives directly analo-
gous to 10 have been converted by straightforward meth-
ods to various alkaloid products.18d
In summary, we have developed catalytic conditions
that enable Wacker-type aerobic oxidative cyclization of
t
alkenes bearing tethered Bu-sulfinamide nucleophiles.
These reactions benefit from efficient access to the enan-
tiopure substrates and highly diastereoselective cycliza-
tion, and they enable modular, stereocontrolled synthesis
of a diverse collection of cis-2,5-disubstituted pyrrolidines.
These results highlight the prospective utility of tBu-sulfi-
namides as chiral nitrogen nucleophiles in metal-catalyzed
additions to alkenes and related electrophiles.
Acknowledgment. We thank the NIH (R01 GM67163)
and Abbott Laboratories (graduate fellowship for R.I.M.)
for financial support. Spectroscopic instrumentation was
partially funded by the NSF (CHE-9208463, CHE-
0342998, CHE-9629688, CHE-9974839), and high-pressure
instrumentation was funded by the NSF (CHE-0946901).
Substrate 8, which contains an R-propenyl substituent,
cyclized in good yield with increased temperature and
O2 pressure (Table 3, entry 8). Alkene metathesis of the
diene product 9 using the Grubbs II catalyst yielded the
Supporting Information Available. Experimental pro-
1
ceedures, H and 13C NMR spectra, and methods for
determination of configuration. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Recent studies suggest that CÀN bond formation could proceed
via cis or trans aminopalladation of the alkene, and further work will be
needed to resolve this issue for the present reactions. Nevertheless, the
results in Tables 2 and 3 demonstrate that the diastereoselectivity of
these reactions is predictable from the substrate structure. For consider-
iation of the factors that influence cis vs trans aminopalladation of
alkenes, see ref 5 and the following leading references: (a) Nakhla, J. S.;
Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 2893–2901. (b)
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328–6335. (c) Sibbald,
P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc.
2009, 131, 15945–15951.
(18) (a) Aggarwal, V. K.; Astle, C. J.; Rogers-Evans, M. Org. Lett.
2004, 6, 1469–1471. (b) Mans, D. M.; Pearson, W. H. Org. Lett. 2004, 6,
3305–3308. (c) Grynkiewicz, G.; Gadzikowska, M. Pharmacol. Rep.
2008, 60, 439–463. (d) Cheng, G.; Wang, X.; Zhu, R.; Shao, C.; Xu, J.;
Hu, Y. J. Org. Chem. 2011, 76, 2694–2700. (e) Schultz, D. M.; Wolfe,
J. P. Org. Lett. 2011, 13, 2962–2965.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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