Diastereoselective pyrrolidine synthesis via copper promoted intramolecular aminooxygenation of alkenes: Formal synthesis of (+)-monomorine

Article abstract of DOI:10.1021/ol9003492

The diastereoselectivity of the copper-promoted intramolecular aminooxygenation of various alkene substrates was investigated. a-Substituted 4-pentenyl sulfonamides favor the formation of 2,5-c/s-pyrrolidines (dr > 20:1) giving excellent yields which range from 76-97% while y-substituted substrates favor the 2,3-trans pyrrolidine adducts with moderate selectivity (ca. 3:1). A substrate whose N-substituent was directly tethered to the a-carbon exclusively yielded the 2,5-trans pyrrolidine. The synthetic utility of the method was demonstrated by a short and efficient formal synthesis of (+)-monomorine.

Full text of DOI:10.1021/ol9003492

ORGANIC
LETTERS
2009
Vol. 11, No. 9
1915-1918
Diastereoselective Pyrrolidine Synthesis
via Copper Promoted Intramolecular
Aminooxygenation of Alkenes: Formal
Synthesis of (+)-Monomorine
Monissa C. Paderes and Sherry R. Chemler*
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
618 Natural Sciences Complex, Buffalo, New York 14260
schemler@buffalo.edu
Received February 18, 2009
ABSTRACT
The diastereoselectivity of the copper-promoted intramolecular aminooxygenation of various alkene substrates was investigated. r-Substituted
4-pentenyl sulfonamides favor the formation of 2,5-cis-pyrrolidines (dr >20:1) giving excellent yields which range from 76-97% while γ-substituted
substrates favor the 2,3-trans pyrrolidine adducts with moderate selectivity (ca. 3:1). A substrate whose N-substituent was directly tethered
to the r-carbon exclusively yielded the 2,5-trans pyrrolidine. The synthetic utility of the method was demonstrated by a short and efficient
formal synthesis of (+)-monomorine.
Pyrrolidine moieties are frequently found in biologically
active molecules.1 These include glycosidase inhibitors such
as alexine2 and australine,3 antiviral agents such as preussin,4
antileukemia agents such as harringtonine5 and crambesci-
din,6 and the angiotensin-converting enzyme (ACE) inhibitor
ramipril.7 Due to the therapeutic importance of these
pyrrolidine alkaloids, considerable effort has been devoted
to the stereoselective synthesis of substituted pyrrolidines.8
In this paper, we report a copper(II) promoted diastereose-
lective synthesis of disubstituted pyrrolidines via an intramo-
lecular aminooxygenation of alkenes.
The intramolecular aminooxygenation of alkenes can be cata-
lyzed and promoted using a number of reagents and catalysts,
but few result in the stereoselective synthesis of pyrrolidines.9-12
Donohoe has reported a diastereoselective osmium-catalyzed
aminohydroxylation that results in the synthesis of 2,5-cis-
(1) (a) Lewis, J. R. Nat. Prod. Rep. 2001, 18, 95–128. (b) O’Hagan, D.
Nat. Prod. Rep. 2000, 17, 435–446.
(2) (a) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.; Derome,
A. E.; Hamor, T. A.; Scofield, A. M.; Watkin, D. J. Tetrahedron Lett. 1988,
29, 2487–2490. (b) Scofield, A. M.; Rossiter, J. T.; Witham, P.; Kite, G. C.;
Nash, R. J.; Fellows, L. E. Phytochemistry 1990, 29, 107–109.
(3) (a) Kato, A.; Kano, E.; Adachi, I.; Molyneux, R. J.; Watson, A. A.;
Nash, R. J.; Fleet, G. W. J.; Wormald, M. R.; Kizu, H.; Ikeda, K.; Asano,
N. Tetrahedron: Asymmetry 2003, 14, 325–331. (b) Molyneux, R. J.;
Benson, M.; Wong, R. Y.; Tropea, J. E.; Elbein, A. D. J. Nat. Prod. 1988,
51, 1198–1206.
(5) Powell, R. G.; Weisleder, D.; Smith, C. R., Jr.; Rohwedder, W. K.
Tetrahedron Lett. 1970, 11, 815–818.
(6) Chang, L. C.; Whittaker, N. F.; Bewley, C. A. J. Nat. Prod. 2003,
66, 1490–1494.
(7) Warner, G. T.; Perry, C. M. Drugs 2002, 62, 1381–1405.
(8) For reviews, see: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571–
582. (b) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213–7256. (c)
Coldham, I.; Hufton, R. Chem. ReV. 2005, 105, 2765–2810. (d) Mitchinson,
A.; Nadin, A. J. Chem. Soc., Perkin Trans. I 2000, 2862–2891. (e) Pichon,
M.; Figade`re, B. Tetrahedron: Asymmetry 1996, 7, 927–964.
(4) (a) Kinzy, T. G.; Harger, J. W.; Carr-Schmid, A.; Kwon, J.; Shastry,
M.; Justice, M.; Dinman, J. D. Virology 2002, 300, 60–70. (b) Achenbach,
T. V.; Slater, P. E.; Brummerhop, H.; Bach, T.; Mu¨ller, R. Antimicrob.
Agents Chemother. 2000, 44, 2794–2801.
10.1021/ol9003492 CCC: $40.75
Published on Web 03/30/2009
 2009 American Chemical Society

pyrrolidines.9a However, Donohoe’s reaction requires two
coordinating groups in the substrate, the sulfonamide nitrogen
that forms the C-N bond and an additional vicinal alcohol,
to achieve high diastereoselectivity.
Table 1. Effects of Varying the Amount of Cu(R)2, Ligand,
Temperature, and Solventa
The diastereoselective copper-promoted aminooxygenation
reactions reported in this paper do not require additional
coordinating groups to provide high levels of 2,5-cis-
pyrrolidine selectivity. Furthermore, analysis of the confor-
mational factors that control the diastereoselectivity in these
reactions led to the development of a 2,5-trans-pyrrolidine
selective reaction as well (vide infra).
Recent reports from our group showed that the copper(II)-
promoted synthesis of 2,5-disubstituted pyrrolidines via
intramolecular alkene carboamination occur in high diaste-
reoselectivity with predominating cis stereochemistry (Scheme
1).13a Mechanistic studies of these reactions13a revealed a
temp yield
(°C)
entry R (equiv)
ligand (equiv)
solvent
(%)b
1c
2c
3
OTf (0.2) 2,2′-dipyridyl (0.2)
OTf (0.2) (R,R)-Ph-box (0.2)
EH (3)
xylenes
xylenes
DMF
130
130
160
160
130
130
120
130
120
120
130
20d
60d
80
40
94
-
-
-
-
-
-
-
-
-
4
EH (1.5)
EH (1.5)
EH(1.5)
EH (1.5)
EH (1.5)
EH (1.5)
EH (1.0)
EH (1.0)
DMF
5
xylenes
xylenes
xylenes
DMF
CF3Ph
CF3Ph
xylenes
6e
7
78
54d
40d
63d
38d
68d
Scheme 1. Copper(II) Promoted Diastereoselective Formation of
8
9
10
11
2,5-cis-Pyrrolidines and TEMPO Trapping of Radical
Intermediate
a All reactions were run in pressure tubes at 0.1 M w/r to 1. b Yield
refers to amount of product isolated after purification by flash chromatog-
raphy on silica gel. c Reaction was run under O2 (1 atm). d Remainder of
the material is the starting olefin 1. e Reaction was run using 1.5 equiv of
TEMPO. EH ) 2-ethylhexanoate, PMBS ) p-methoxybenzenesulfonyl.
quite operationally simple, not requiring an O2 atmosphere,
we concluded that the stoichiometric reaction provides an
acceptable solution until superior catalytic conditions are
identified.
(9) For intramolecular osmium-catalyzed aminooxygenation reactions,
see: (a) Donohoe, T. J.; Churchill, G. H.; Wheelhouse, K. M. P.; Glossop,
P. A. Angew. Chem., Int. Ed. 2006, 45, 8025–8028. (b) Donohoe, T. J.;
Chughtai, M. J.; Klauber, D. J.; Griffin, D.; Campbell, A. D. J. Am. Chem.
Soc. 2006, 128, 2514–2515. (c) Donohoe, T. J.; Bataille, C. J. R.; Gattrell,
A.; Kloeges, J.; Rossignol, E. Org. Lett. 2007, 9, 1725–1728.
(10) For intramolecular Pd-catalyzed aminooxygenation reactions, see:
(a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127,
7690–7691. (b) Szolcsanyi, P.; Gracza, T. Chem. Commun. 2005, 3948–
3950. (c) Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46,
5737–5740.
pathway involving a primary carbon radical intermediate that
was trapped efficiently with 2,2,6,6-tetramethylpiperidine-
N-oxyl radical (TEMPO), a standard carbon radical trapping
agent (Scheme 1).13b These results led us to investigate the
diastereoselectivity of this net alkene aminooxygenation
reaction using substrates bearing substituents R as well as γ
to the sulfonamide unit.
We first investigated the aminooxygenation reaction of
4-pentenyl sulfonamide 1 using catalytic amounts of copper(II)
salts (Table 1).11f,g The use of the bisoxazoline ligand [(R,R)-
Ph-box] gave better conversion than the 2,2′-dipyridyl ligand
under catalytic conditions using O2 (1 atm) (Table 1, entries
1 and 2). The (R,R)-Ph-box ligand and substrate 1 both favor
formation of the C2(S) stereocenter (the reaction is
matched).11f We have previously used these conditions to
catalyze the aminooxygenation reactions of slightly more
reactive achiral substrates.11f,g However, neither reaction of
sulfonamide 1 went to completion. While the catalytic reac-
tion shows promise (yield ) 60%, Table 1, entry 2), its opti-
mization is ongoing. On the other hand, we were able to
rapidly identify a highly efficient and operationally simple
reaction process by use of a slight excess (1.5 equiv) of a
readily available and inexpensive copper(II) carboxylate,
copper(II) 2-ethylhexanoate [Cu(EH)2]. Because Cu(EH)2 is
neither very expensive nor toxic and since the reaction is
(11) For other intramolecular aminooxygenation reactions, see: (a)
Noack, M.; Gottlich, R. Chem. Commun. 2002, 536–537. (b) Chikkana,
D.; Han, H. Synlett 2004, 2311–2314. (c) Correa, A.; Tellitu, I.; Dominguez,
E.; SanMartin, R. J. Org. Chem. 2006, 71, 8316–8319. (d) Cochran, B. M.;
Michael, F. E. Org. Lett. 2008, 10, 5039–5042. (e) Mahoney, J. M.; Smith,
C. R.; Johnson, J. N. J. Am. Chem. Soc. 2005, 127, 1354–1355. (f) Fuller,
P. H.; Kim, J. W.; Chemler, S. R. J. Am. Chem. Soc. 2008, 130, 17638–
17639. (g) Sherman, E. S.; Chemler, S. R. AdV. Synth. Catal. 2009, 351,
467–471.
(12) For intermolecular aminohydroxylation of alkenes, see: (a) O’Brien,
P. Angew. Chem., Int. Ed. 1999, 38, 326–329. (b) Bolm, C.; Hildebrand,
J. P.; Muniz, K. Catalytic Asymmetric Synthesis, 2nd ed; Ojima, I., Ed.;
Wiley-VCH: New York, 2000; pp 412-424. (c) Schlingloff, G.; Sharpless,
B. K. Asymmetric Oxidation Reactions; Katsuki, T., Ed.; Oxford University
Press: Cambridge, 2001; pp 104-114. (d) Nilov, D.; Rieser, O. AdV. Synth.
Catal. 2002, 344, 1169. (e) Bodkin, J. K.; McLeod, M. D. J. Chem. Soc.,
Perkin Trans. 1 2002, 2733. (f) Michaelis, D. J.; Ischay, M. A.; Yoon,
T. P. J. Am. Chem. Soc. 2008, 130, 6610–6615. (g) Michaelis, D. J.; Shaffer,
C. J.; Yoon, T. P. J. Am. Chem. Soc. 2007, 129, 1866–1867. (h) Liu, G.;
Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179–7181. (i) Michaelis, D. J.;
Williamson, K. S.; Yoon, T. P. Tetrahedron 2009, doi:10.1016/
j.tet.2009.03.012.
(13) (a) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org.
Chem. 2007, 72, 3896–3905. (b) Vogler, T.; Studer, A. Synthesis 2008,
1979–1993.
1916
Org. Lett., Vol. 11, No. 9, 2009

Using the optimized reaction conditions (Table 1, entry
5), the reactions of a number of R and γ-substituted 4-
pentenyl sulfonamides were examined (Table 2). Similar to
the diastereoselectivity results in the analogous copper(II)
promoted carboamination reaction of 4-pentenyl sulfona-
mides (Scheme 1), substrates 1, 3, 5, 7, and 9 generated the
2,5-cis-pyrrolidines 2, 4, 6, 8, and 10 in excellent yields with
>20:1 selectivity (Table 2, entries 1-5). Gratifyingly, no
hydroamination side products were observed in these reac-
tions. The crystal structure of 2 indicated cis stereochemistry
with an absolute configuration of C2(S), C5(R) (see Sup-
porting Information).15 The relative configurations of pyr-
rolidines 4, 6, 8, and 10 were assigned by analogy and by
NOE experiments. Upon changing the nitrogen protecting
group from tosyl (Ts) or p-methoxybenzenesulfonyl (PMBS)
to 4-nitrophenyl sulfonyl (Ns), there was a slight decrease
in the yield, but a high level of stereocontrol was still
observed (Table 2, entry 6). The Ns group is usually more
easy to remove.16 γ-Substituted 4-pentenyl sulfonamides 13
and 16 gave only moderate selectivity (3:1 for 13 and 2:1
for 16) favoring the trans pyrrolidine adducts (Table 2, entries
7 and 8). Little difference between the electron-donating
OMe and electron-withdrawing CF3 benzyl substituents was
observed. The relative configurations of the cis and trans
isomers were assigned by X-ray crystallography and NOE
experiments (see Supporting Information). The trans pyrro-
lidine is presumably favored due to equatorial placement of
the γ-substituent in the cyclic transition state (see Supporting
Information). It was not clear if substrate 19, with an internal
disubstituted olefin, would favor aminooxygenation (20) or
oxidative amination (21). In the carboamination series13a only
21 was obtained. To our delight, the aminooxygenation
product 20 was isolated as the major product with >20:1
diastereoselectivity and 7:1 aminooxygenation:oxidative ami-
nation selectivity. The stereochemistry of 20 was determined
by X-ray crystallography (see Supporting Information).15
The mechanism illustrated in Scheme 2 provides a
rationalization for the high degree of cis stereoselectivity
observed in the aminooxygenation reaction of the R substi-
tuted substrates. It was reasoned that this reaction underwent
a mechanism similar to the copper(II) promoted intramo-
lecular carboamination reaction.13a The first C-N bond is
proposed to form in a stereoselective manner via syn
aminocupration through the chairlike transition state 23 or
possibly the boat-like transition state 24, generating an
Table 2. Diastereoselective Aminooxygenation of Alkenesa
a R ) 2,2,6,6-tetramethylpiperidine, Reaction conditions: 1.5 equiv of
Cu(EH)2, 3 equiv of TEMPO, 1 equiv of Cs2CO3, xylenes (0.1 M), 130 °C,
24 h, pressure tube. b Yield refers to amount of product isolated upon
purification by column chromatography on SiO2. c Yield refers to the sum
of the products isolated by chromatography on SiO2. d Diastereomeric ratio
was determined by analysis of the crude 1H NMR spectrum. e Reaction
was run at 140 °C. f Yield refers to amount of 20 isolated.
Copper(II) 2-ethylhexanoate is more reactive than many
copper carboxylates owing to its high solubility in organic
solvents.13a,14 Among the solvents (DMF, xylenes, CF3Ph)
and temperatures (120-160 °C) surveyed, we found that
xylenes at 130 °C provided the optimal yield (94%, Table
1, entry 5). Slightly more than 1 equiv of Cu(EH)2 (1.5 equiv)
was also required for optimal yield, and the reaction was
complete within 24 h. Lower TEMPO amounts (1.5 equiv)
gave slightly lower yield (entry 6), so the reactions were
run using 3 equiv of TEMPO.
Scheme 2
.
Proposed Mechanism for the Formation of
2,5-cis-Pyrrolidine
(14) (a) Fuller, P. H.; Chemler, S. R. Org. Lett. 2007, 9, 5477–5480.
(b) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077–2079. (c) Baran,
P. S.; Richter, P. S. J. Am. Chem. Soc. 2004, 126, 7450–7451
.
Org. Lett., Vol. 11, No. 9, 2009
1917

unstable organocopper(II) species 25. This organocopper(II)
species then undergoes homolysis, forming a primary carbon
radical intermediate which is trapped by the TEMPO
radical,11f,13 forming the cis aminooxygenation product 2.
To demonstrate the synthetic utility of the method, we
performed a short and efficient formal synthesis of (+)-
monomorine (28). (+)-Monomorine is an indolizidine alka-
loid that is known to be a trail pheromone of a health hazard
pharaoh ant Monomorium pharaonis L.17 Along with the
other indolizidine alkaloids, (+)-monomorine has been the
target of many organic chemists for some time. As a result,
a number of different ways of synthesizing it have been
reported.18 Particularly relevant to this study was the
synthesis reported by Ba¨ckvall and co-workers19 wherein
they used aldehyde 27 as an intermediate in their synthesis
of (+)-monomorine. Utilizing our method, aldehyde 27 was
synthesized in 6 steps and 40% overall yield. Our route to
27 is 3 steps shorter than Ba¨ckvall’s approach. The 2,5-cis-
pyrrolidine 8 was formed from substrate 7 in 94% yield and
high selectivity (>20:1) (Table 2, entry 4). Substrate 7 was
readily synthesized from commercially available D-norleucine
(see Supporting Information). The TEMPO adduct 8 was
oxidized to aldehyde 27 using mCPBA in 68% yield (Scheme
3).20 We have previously also demonstrated that dissolving
metal reduction can chemoselectively reveal one or both of
the free amine and free alcohol functionalities.11f
for this copper(II) promoted aminooxygenation, it produced
the trans pyrrolidine 31 in poor yield but with high
diastereoselectivity (>20:1). We hypothesized that addition
of excess TEMPO (3 equiv) caused the decomposition of
the starting material via benzylic oxidation. When the amount
of TEMPO was decreased to 1.5 equiv, we were able to
increase the yield to 59% with the same level of selectivity.
The trans configuration of pyrrolidines 31 was confirmed
by X-ray crystallography (Figure 1).15 We have previously
demonstrated that the SO2 moiety in sultams such as 31 can
be removed by dissolving metal reduction.13a,21
Figure 1. Crystal structure of 31.
In conclusion, we have developed a high yielding route
for the synthesis of disubstituted pyrrolidines via the in-
tramolecular copper promoted aminooxygenation of alkenes.
These reactions afford the 2,3-trans-pyrrolidines in moderate
selectivity and both the 2,5-cis- and 2,5-trans-pyrrolidines
in excellent diastereoselectivity. The efficiency of this
approach was demonstrated with the formal synthesis of (+)-
monomorine. More efforts to apply this method to the total
synthesis of interesting biologically active nitrogen hetero-
cycles and further investigations into substrate scope and
catalytic methods are currently underway.
Scheme 3. Formal Synthesis of (+)-Monomorine
Acknowledgment. We thank the National Institutes of
Health (NIGMS) for financial support of this work (R01
GM078383). We also gratefully acknowledge Dr. Shao-
Liang Zheng, Dr. Mateusz Pitak, and Dr. Stephan Scheins
(SUNY, Buffalo X-ray crystallography facility) for obtaining
crystal structures of compounds 2, 17, 20, and 31.
On the basis of the proposed transition state for the R
substituted 4-pentenyl sulfonamides (Scheme 2), we pre-
dicted that if the N-substituent was directly tethered to the
R-carbon (e.g., substrate 29), the reaction would occur via
transition state 30, which places the R-substitutent in a
pseudoequatorial position, thereby favoring the formation of
the 2,5-trans pyrrolidine adduct (Scheme 4). When sulfon-
amide 29 was subjected to the optimized reaction conditions
Supporting Information Available: Procedures and
characterization data and NMR spectra for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL9003492
(15) CCDC 696031 (2), 711960 (17), 714177 (20), and 704323 (31)
contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Scheme 4
. Diastereoselective Aminooxygenation of
Sulfonamide 29 Forming the trans Pyrrolidine 31
(16) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353–359
.
(17) Ritter, F. J.; Rotgans, I. E. M.; Tulman, E.; Verweil, P. E.; Stein,
F. Experientia 1973, 29, 530–531
.
(18) (a) Toyooka, N.; Zhou, D.; Nemoto, H. J. Org. Chem. 2008, 73,
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A.; Silvani, A. J. Org. Chem. 2009, 74, 590–596
.
(19) (a) Riesinger, S. W.; Lo¨fstedt, J.; Petterson-Fasth, H.; Ba¨ckvall, J.
Eur. J. Org. Chem. 1999, 3277–3280. (b) Petterson-Fasth, H.; Riesinger,
S. W.; Ba¨ckvall, J. J. Org. Chem. 1995, 60, 6091–6096
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(20) Inokuchi, T.; Kawafuchi, H. Tetrahedron 2004, 60, 11969–11975
(21) Evans, P.; McCabe, T.; Morgan, B. S.; Reau, S. Org. Lett. 2005,
7, 43–46
.
.
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