Asymmetric construction of nitrogen-containing [2.2.2] bicyclic scaffolds using N-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide

Article abstract of DOI:10.1021/jo9009062

(Chemical Equation Presented) An organocatalyzed approach to enantioenriched isoquinuclidines and bicyclo[2.2.2]octanes via a p-dodecylphenylsulfonamide-modified proline catalyst has been developed. A series of aromatic imines have been explored for the f

Full text of DOI:10.1021/jo9009062

pubs.acs.org/joc
Asymmetric Construction of Nitrogen-Containing [2.2.2] Bicyclic
Scaffolds Using N-( p-Dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide
Hua Yang and Rich G. Carter*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon 97331
rich.carter@oregonstate.edu
Received May 1, 2009
An organocatalyzed approach to enantioenriched isoquinuclidines and bicyclo[2.2.2]octanes via a
p-dodecylphenylsulfonamide-modified proline catalyst has been developed. A series of aromatic
imines have been explored for the formation of isoquinuclidines with high levels of enantioselectivity
and diastereoselectivity, strongly favoring the exo product. A series of aliphatic imines has also been
explored, which provide access to bicyclo[2.2.2]octanes through a novel mechanistic pathway in high
levels of enantioselectivity and diastereoselectivity, favoring the endo product.
Introduction
principally focused on conversion of the carboxylic acid
moiety into an alternate functional group (e.g., tetrazoles
and sulfonamides3-5) to improve catalyst performance.
Over the past decade, a renaissance in the field of enantio-
selective organocatalysis has emerged.1 Driven by the
potential practicality of the chemistry and the use of non-
toxic reagents, a wealth of research has been directed toward
the optimization of standard transformations and the
development of new mechanistic pathways.2 Proline and
its derivatives have been particularly successful as organo-
catalysts. Modifications of the amino acid scaffold have
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DOI: 10.1021/jo9009062
r
Published on Web 06/11/2009
J. Org. Chem. 2009, 74, 5151–5156 5151
2009 American Chemical Society

Yang and Carter
JOCFeatured Article
Recently, our laboratory developed p-dodecylphenylsulfo-
namide-based catalysts 1 and ent-1 (Figure 1).6 These
catalysts are readily available from inexpensive starting
materials and can be prepared in large quantities.7 One
major advantage to 1 and ent-1 is their greatly improved
solubility properties, particularly in nonpolar media.8 We
have previously demonstrated the utility of these catalysts
for facilitating enantioselective aldol6 and Mannich reac-
tions.9 Herein, we disclose a full account of the highly
enantioselective and diastereoselective construction of aza-
bicyclo[2.2.2]octane and bicyclo[2.2.2]octane scaffolds
using our proline p-dodecylphenylsulfonamide-based cata-
lyst system 1.
FIGURE 1. N-( p-Dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide
(1) and (ent-1).
Diels-Alder strategies15 involving dihydropyridines have been
employed with good levels of asymmetric induction.16,17
Results
Azabicyclo[2.2.2]octanes (or isoquinuclidines) have gen-
erated considerable synthetic attention due to their pre-
sence in numerous alkaloid natural products,10,11 including
the iboga alkaloids.12 Enantioselective syntheses of these
azabicycles have been investigated using primarily enan-
tioenriched BINOL-derived phosphoric Brønsted acids.13
Use of these types of catalysts typically generate modestly
endo-selective products (typically 3-4:1 endo/exo selectiv-
ity) in reasonable enantioselectivities (typically 76-88% ee).
Additionally, Cordova has shown that formaldehyde-based
and glycolate-based imines can undergo this type of trans-
formation using proline catalysis in good levels of enantioselec-
tivity (up to 99% ee using DMSO as solvent).14 Alternatively,
We became intrigued by the possibility that our p-dode-
cylphenylsulfonamide-based catalyst
1 might be able
to improve the observed levels of diastereoselectivity and
enantioselectivity while expanding the reaction scope to
include alkyl- and aryl-substituted imines. To this end, we
selected 4-chlorophenyl imine 3 as the prototypical substrate
(Table 1). Use of our previously reported DCE conditions6,9
proved modestly effective, generating the desired product in
34% yield with 92% ee (entry a). It should be noted that the
endo/exo selectivity for this transformation is completely
reversed as compared to the chiral phosphoric acids-catalyst
1 favored exclusively the exo product (>99:1). Addition of 1
equiv of EtOH led to an improvement in chemical yield
(48%) for this transformation (entry b). Use of a purely
protic solvent (IPA) proved similarly effective (entry c).
Interestingly, omission of the solvent led to an improved
chemical yield with now excellent enantioselectivity (entry d).
In contrast, use of proline (30 mol %) in place of catalyst 1
under otherwise identical conditions resulted in greatly re-
duced yield (22%) and lower enantioselectivity (93% ee)
(entry e). We attribute this reactivity difference to the greatly
improved solubility properties of the catalyst 1 as well as the
increased steric component and the modulated pKa of the
sulfonamide moiety (as compared to a carboxylic acid). The
substitution on the imine nitrogen also appeared to have a
noticeable impact on the reaction (entries f-i). Substitution
of the PMP moiety for a 3,4-dimethoxyphenyl led to further
improvement in the chemical yield without sacrificing en-
antioselectivity or the exo/endo ratio (entry f ). In contrast,
use of the more sterically encumbered 2,4-dimethoxyphenyl
group was deleterious to the reaction yield and enantioselec-
tivity (entry g). Both electronically neutral (phenyl) and
electron deficient (4-chlorophenyl) moieties were tolerated,
albeit with reduced chemical efficiency (entries h and i).
Based on these results, it was determined that the 4-methoxy-
phenyl and the 3,4-dimethoxyphenyl moieties were optimal
for substitution on the imine nitrogen.
(6) Yang, H.; Carter, R. G. Org. Lett. 2008, 10, 4649–4652.
(7) These catalysts will be available for purchase from Sigma-Aldrich
Chemical Co. later this year.
(8) For a more detailed discussion of the advantages of catalyst 1 over
other proline-derived organocatalysts, see ref 6.
(9) Yang, H.; Carter, R. G. J. Org. Chem. 2009, 74, 2246–2249.
(10) (a) Khan, M. O. F.; Levi, M. S.; Clark, C. R.; Ablordeppey, S. Y.;
Law, S.-J.; Wilson, N. H.; Borne, R. Stud. Nat. Prod. Chem. 2008, 34
(Bioactive Natural Products-Part N), 753-787. (b) Sundberg, R. G.; Smith,
S. Q. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: new York, 2002;
Vol. 59, p 261.
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The scope of this reaction on a series of aromatic imines
was also explored (Table 2). We were pleased to observe a
good tolerance for a range of aryl substituents. In general,
electron-withdrawing groups were well-tolerated; however,
ortho-substitution did appear to dramatically reduce the
reaction rate (entry b). Resonance electron-donating groups
also have a negative impact on the reaction yield and
€
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Chem. Soc. 1966, 88, 3099–3109.
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2006, 8, 6023–6026.
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Mi, A.; Jiang, Y.; Gong, L. Org. Lett. 2006, 8, 6023-6026. (c) Costantino, U.;
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10572.
5152 J. Org. Chem. Vol. 74, No. 15, 2009

Yang and Carter
JOCFeatured Article
TABLE 1. Optimization of Aniline Substituent in Enantioselective Azabicyclo[2.2.2]octane Formation
entry
conditions
Ar
yield (%)
eea (%)
exo/endob
a
b
c
d
e
f
g
h
i
1 (20 mol %), DCE (2 M), rt, 4 d
1 (20 mol %), DCE (2 M), EtOH (1 equiv. rt, 4 d)
1 (20 mol %), IPA (2 M), rt, 4 d
1 (30 mol %), neat, rt, 4 d
D-proline (30 mol %), neat, rt, 4 d
1 (30 mol %), neat, rt, 4 d
1 (30 mol %), neat, rt, 4 d
4-MeO-C6H4-
4-MeO-C6H4-
4-MeO-C6H4-
4-MeO-C6H4-
4-MeO-C6H4-
3,4-(MeO)2-C6H3-
2,4-(MeO)2-C6H3-
C6H5-
34
48
5
57
22
63
24
36
43
92
92
91
99
93
99
84
98
99
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
1 (30 mol %), neat, rt, 4 d
1 (30 mol %), neat, rt, 4 d
4-Cl-C6H4-
a ee was determined by chiral HPLC analysis. b Exo/endo ratios were determined by 1H NMR analysis.
TABLE 2. Exploration of Scope in Enantioselective Synthesis of Aza-
bicyclo[2.2.2]octanes
SCHEME 1. Exploration of Alternate Enone Systems in the
Bicycle Formation
entry
Ar
PG
yield (%) eea (%) exo/endob
a
b
c
d
e
f
g
h
i
3-Cl-C6H4-
2-Cl-C6H4-
4-pyridyl-
4-CF3-C6H4-
C6H5-
PMPc
PMP
PMP
PMP
PMP
54
19
52
54
51
25
58
49
53
61
53
99
96
99
99
91
80
98
99
99
94
92
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
4-MeO-C6H4- PMP
3-Cl-C6H4-
4-CF3-C6H4-
4-Br-C6H4-
C6H5-
DMPd
DMP
DMP
DMP
DMP
j
k
4-Me-C6H4-
a ee was determined by chiral HPLC analysis. b Exo/endo ratios were
determined by 1H NMR analysis. c PMP is defined as 4-MeO-C6H4.
d DMP is defined as 3,4-(MeO)2-C6H3.
good chemical yield (64%) and diastereoselectivity (>20:1 dr),
but with essentially no enantioselectivity. We are unsure at this
juncture as to the rational for the absence of asymmetric
induction in product 11. Replacement of the enone substrate
for an ynone substrate (e.g., 4-TMS-3-butyn-2-one, 4-phenyl-3-
butyn-2-one) led to a complex mixture of products.
enantioselectivity (entry f ), presumably due to the reduced
electrophilicity of the imine. More electron-neutral examples
(entries e and i-k) performed well. The absolute configura-
tion of 6a was established through X-ray crystallographic
analysis (see the Supporting Information). While the yields
for many of these transformations are modest, the inexpen-
sive starting materials and the highly functionalized products
demonstrate the value of this protocol. Furthermore, all of
these reactions are performed in the absence of solvent
because of the favorable solubility profile of 1, further
adding to the scalability and practicality of this chemistry.
We also explored variation of the enone component in this
reaction (Scheme 1). Not surprisingly, use of cyclopentenone
(7) in place of cyclohexenone (2) completely suppressed pro-
duct formation. The use of the acyclic enone 8 led to a complex
mixture of products. Use of 4-phenyl-3-buten-2-one (9) with
known imine 1018 did provide the desired ring system 11 in
When our exploration was extended to include aliphatic
imine structures, a divergent reaction pathway was observed
(Scheme 2). For example, treatment of imine 12a under the
standard conditions did not result in the formation of the
corresponding azabicyclo[2.2.2]octane product. Instead, the
all-carbon bicyclo[2.2.2]octane variant 13a was produced.
The use of benzyl-protected imine 12 dramatically improved
the rate and overall yield of the process; however, reduced
levels of diastereoselectivity and enantioselectivity were ob-
served. The 4-chloro product 13c allowed for the determina-
tion of the absolute configuration in this transformation via
X-ray crystallographic analysis (see the Supporting Infor-
mation). Use of the isopropyl imine 14 cleanly provided the
gem-dimethyl product 15. The analogous diethyl product 17
could also be prepared. Reaction of imine 18 generated
(18) Grigg, R.; Stevenson, P. J. Synthesis 1983, 1009–1010.
J. Org. Chem. Vol. 74, No. 15, 2009 5153

Yang and Carter
JOCFeatured Article
SCHEME 2. Enantioselective Synthesis of All-Carbon [2.2.2]
Bicyclesa
A reasonable mechanistic explanation for the [2.2.2] all-
carbon bicycle formation is provided in Scheme 4. Imine 12a
is in equilibrium with its enamine tautomer 25. Upon suitable
activation of cyclohex-2-enone (2), conjugate addition of the
enamine would provide intermediate 27. The facial selecti-
vity for conjugate addition may be controlled via a hydrogen
bonding interaction between the enamine and the sulfona-
mide as shown in compound 26. After enamine isomeriza-
tion, intramolecular Mannich cyclization would generate
zwitterion 29. Inspection of models indicates that the sulfo-
namide is well-positioned to direct the facial attack on the
imine in intermediate 28. Subsequent hydrolysis would
regenerate the catalyst 1 and reveal the product 13a. It should
be noted that a somewhat related transformation has been
reported by Cordova and co-workers involving R,β-unsatu-
rated nitro compounds;20 however, those examples involve 2
acting as the initial nucleophile in the transformation.
In conclusion, an organocatalyzed method has been de-
veloped for accessing nitrogen-containing [2.2.2]-bicyclic
scaffolds in a highly enantioselective and diastereoselective
manner. The p-dodecylphenylsulfonamide catalyst 1 allows
for the scope of this formal aza-Diels-Alder process to be
expanded to include aryl imines. Additionally, alkyl imines
proceed with a divergent and novel reaction pathway, further
demonstrating the utility of this technology. Subsequent
application of these protocols will be reported in due course.
Experimental Section
General Procedure for Formal Aza-Diels-Alder Reaction with
Cyclohexenone (30 mol % of Catalyst). To a solution of cyclo-
hex-2-enone (2) (1.25 mmol, 0.12 mL, 10 equiv) was added
the corresponding imine 3/5 (0.125 mmol) and sulfonamide 1
(15.8 mg, 0.0375 mmol) at room temperature. After being stirred
at the same temperature for the denoted time, the reaction
mixture was loaded directly onto silica gel and purified by
chromatography, eluting with 2-20% EtOAc/hexanes, to give
the corresponding product.
3-(4-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-2-azabicyclo-
[2.2.2]octan-5-one (4f). Reaction time 4 d. Purified by chromato-
graphy over silica gel, eluting with 2-20% EtOAc/hexanes, to give
the bicycle 4f (29.1 mg, 63%, 99% ee,>99:1 dr, white solid). En-
antiomeric excess was determined by chiral HPLC [4.6ꢀ250 mm
Daicel OD column, 90:10 hexanes/i-PrOH, 1.0 mL min-1, retention
times 30.5 min (major) and 38.0 min (minor)] to be 99% ee: mp 42-
43 °C; [R]23D=-86.4 (c=0.8, CHCl3); IR (neat) 2943, 2867, 1729,
1511, 1244, 1026, 814, 759, 732 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.36-7.41 (m, 4H), 6.73 (d, J=8.8 Hz, 1H), 6.20 (d, J=2.8 Hz,
1H), 6.13 (dd, J=8.4, 2.4 Hz, 1H), 4.73 (br s, 1H), 4.45 (br s, 1H),
3.79 (s, 3H), 3.68 (s, 3H), 2.79 (dt, J=19.2, 2.4 Hz, 1H), 2.64-2.66
(m, 1H), 2.42 (dd, J=18.4, 1.6 Hz, 1H), 2.27-2.32 (m, 1H), 1.62-
1.97 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 213.2, 149.9, 143.0,
141.9, 139.0, 133.2, 129.1, 127.7, 113.1, 104.7, 99.4, 62.2, 56.5, 55.7,
50.9, 49.1, 42.1, 26.4, 16.2; HRMS (EI+) calcd for C21H22NO3Cl
(M+) 371.1288, found 371.1281.
a ee was determined by chiral HPLC analysis. Exo/endo ratios were
determined by 1H NMR analysis.
bicycle 19, which contains four contiguous stereogenic cen-
ters, including an all-carbon quaternary center. The relative
stereochemistry in compound 19 was assigned via a NOE
between the quaternary center methyl group and the endo
R-keto hydrogen.
Discussion
A possible mechanism for the azabicyclo[2.2.2]octane
formation is presented in Scheme 3. The initial Mannich
reaction should proceed via the accepted transition state put
forth by Houk.19 The resultant syn stereochemistry illu-
strated in zwitterions 21/22 ultimately governs the subse-
quent aza-Michael cyclization to produce enamine 24. This
mechanism provides a reasonable explanation for the strong
exo preference in these organocatalyzed reactions. In con-
trast, the chiral phosphoric acid catalyst systems likely
generate modest anti selectivity in the initial Mannich reac-
tion leading to modest endo selectivity in those cases.13 The
slow cleavage of the enamine 24 (due increased steric con-
gestion) is likely the cause for the higher catalyst loading (30
mol %) as compared to standard aldol and Mannich reac-
tions.6,9 A similar catalyst loading was required in Cordova’s
examples with the formaldehyde-based and glycolate-based
imines.14
3-(4-Chlorophenyl)-2-(2,4-dimethoxyphenyl)-2-azabicyclo-
[2.2.2]octan-5-one (4g).15a Reaction time 4 d. Purified by
chromatography over silica gel, eluting with 2-20% EtOAc/
hexanes, to give the bicycle 4g (10.2 mg, 24%, 84% ee,>99:1 dr,
colorless crystal). Enantiomeric excess was determined by chiral
ꢀ
ꢀ
(20) (a) Sunden, H.; Rios, R.; Xu, Y.; Eriksson, L.; Cordova, A. Adv.
Synth. Catal. 2007, 349, 2549–2555. For related examples with nitroso
electrophiles, see: (b) Momiyama, N.; Yamamoto, Y.; Yamamoto, H. J. Am.
Chem. Soc. 2007, 129, 1190–1195. (c) Yamamoto, Y.; Momiyama, N.;
Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962–5963.
(19) Bahmanyar, S.; Houk, K. N. Org. Lett. 2003, 5, 1249–1251.
5154 J. Org. Chem. Vol. 74, No. 15, 2009

Yang and Carter
JOCFeatured Article
SCHEME 3. Possible Mechanistic Hypothesis for Formation of Amines 4 and 6
SCHEME 4. Possible Mechanistic Hypothesis for Formation of
Amine 13a
11.6 Hz, 1H) 4.01 (dd, J=3.2, 11.6 Hz, 1H), 3.08 (dd, J=6.4,
15.2 Hz, 1H), 2.75-3.00 (m, 3H), 2.50-2.65 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 205.9, 150.2, 147.5, 141.9, 130.1, 129.0, 128.3,
128.0, 127.3, 124.3, 120.2, 64.4, 63.8, 51.7, 50.6, 50.2; HRMS (EI+)
calcd for C20H20N2O3 (M+H) 337.1552, found 337.1549.
3-(4-Methoxyphenylamino)spiro[bicyclo[2.2.2]octane-2,10-cyclo-
hexan]-5-one (13a). Reaction time 48 h. Purified by chromatogra-
phy over silica gel, eluting with 2-20% EtOAc/hexanes, to give the
bicycle 13a (21.5 mg, 55%, 88% ee,>20:1 dr, light yellow oil).
Enantiomeric excess was determined by chiral HPLC [4.6ꢀ250
mm Daicel OD column, 90:10 hexanes/i-PrOH, 1.0 mL min-1
,
retention times 17.4 min (major) and 23.1 min (minor)] to be 88%
ee: mp 117-118 °C; [R]23D=+40.9 (c=1.4, CHCl3); IR (neat) 3374,
2856, 1723, 1511, 1462, 1239, 1184, 1043, 814, 765, 727 cm-1
;
1H NMR (400 MHz, CDCl3) δ 6.77-6.79 (m, 2H), 6.56-6.59 (m,
2H), 3.76 (s, 3H), 3.32 (s, 1H), 3.24 (br s, 1H), 2.51 (dt, J=18.8, 2.8
Hz, 1H), 2.38-2.43 (m, 2H), 2.15 (dd, J=18.8, 2.4 Hz, 1H), 1.98-
2.03 (m, 1H), 1.82-1.90 (m, 3H), 1.28-1.69 (m, 10H); 13C NMR
(100 MHz, CDCl3) δ 216.6, 152.2, 141.5, 115.2, 115.0, 64.2, 55.8,
49.4, 41.2, 39.1, 37.2, 32.1, 30.0, 25.9, 22.7, 22.1, 21.6, 20.2; HRMS
(EI+) calcd for C20H27NO2 (M+) 313.2042, found 313.2031.
3-(Benzylamino)spiro[bicyclo[2.2.2]octane-2,10-cyclohexan]-5-one
(13b). Reaction time 8 h. Purified by chromatography over silica
gel, eluting with 2-10% EtOAc/hexanes, to give the bicycle 13b
(29.1 mg, 78%, 71% ee, 6:1 dr, colorless oil). Enantiomeric excess
was determined by chiral HPLC [4.6 ꢀ250 mm Daicel OD column,
99:1 hexanes/i-PrOH, 1.0 mL min-1, retention times 14.3 min
(major) and 16.4 min (minor)] to be 71% ee: [R]23D=+21.2 (c=
1.9, CHCl3); IR (neat) 3336, 2927, 2851, 1723, 1446, 1097, 738,
689 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.24-7.39 (m, 5H), 3.95
(d, J=13.2 Hz, 1H), 3.59 (d, J = 13.2 Hz, 1H), 2.50-2.62 (m, 3H),
1.24 (br s, 1H), 2.06 (dd, J =18.8, 2.8 Hz, 1H), 1.76-1.95 (m, 3H),
1.28-1.67 (m, 11H); 13C NMR (100 MHz, CDCl3) δ 216.9, 140.4,
128.3, 128.2, 126.9, 65.8, 51.5, 47.8, 41.0, 38.4, 37.6, 30.1, 26.1, 22.8,
22.7, 21.1, 20.6; HRMS (EI+) calcd for C20H27NO (M+)
297.2093, found 297.2098.
3-(4-Chlorophenylamino)spiro[bicyclo[2.2.2]octane-2,10-cyclohex-
an]-5-one (13c). Reaction time 5 d. Purified by chromatography
over silica gel, eluting with 2-20% EtOAc/hexanes, to give the
bicycle 13c (18.6 mg, 47%, 87% ee,>20:1 dr, colorless crystal).
Enantiomeric excess was determined by chiral HPLC [4.6ꢀ250 mm
Daicel OD column, 90:10 Hexanes/i-PrOH, 1.0 mL min-1, reten-
tion times 9.6 min (major) and 10.7 min (minor)] to be 87% ee: Mp:
139-141 °C; [R]23D=+56.7° (c=0.9, CHCl3); IR (neat) 3374,
2927, 2862, 1718, 1593, 1489, 1315, 1097, 808 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.12 (d, J=8.8 Hz, 2H), 6.51 (d, J=8.8 Hz, 2H),
3.56 (d, J=10.0 Hz, 1H), 3.37 (dd, J=10.0, 2.4 Hz, 1H), 2.51 (dt,
J=19.2, 3.2 Hz, 1H), 2.395-2.402 (m, 2H), 2.17 (dd, J=19.2,
2.8 Hz, 1H), 1.83-2.06 (m, 4H), 1.28-1.67 (m, 10H); 13C NMR
(100 MHz, CDCl3) δ 216.2, 145.9, 129.2, 121.9, 114.4, 62.7, 49.6,
HPLC [4.6ꢀ250 mm Daicel OD column, 95: 5 hexanes/i-PrOH,
1.0 mL min-1, retention times 14.3 min (major) and 12.9 min
(minor)] to be 84% ee: [R]23D=+41.2 (c=1.1, CHCl3); IR (neat)
2943, 1723, 1500, 1206, 836, 803, 738 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.40 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 6.87 (d,
J=8.4 Hz, 1H), 6.49 (d, J=2.8 Hz, 1H), 6.31 (dd, J=8.8, 2.8 Hz,
1H), 5.18 (br s, 1H), 3.90 (s, 3H), 3.79 (br s, 1H), 3.74 (s, 3H), 2.79 (dt,
J=18.8, 3.2 Hz, 1H), 2.46-2.55 (m, 2H), 2.24 (dd, J=18.8, 2.0 Hz,
1H), 1.84-1.90 (m, 1H), 1.59-1.71 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ215.3, 156.2, 154.7, 139.4, 132.7, 131.0, 128.5, 128.4, 121.7,
103.4, 100.2, 58.8, 55.5, 55.4, 55.0, 51.9, 42.4, 27.5, 16.4; HRMS
(EI+) calcd for C21H22NO3Cl (M+) 371.1288, found 371.1290.
N-Allyl-2-(4-nitrophenyl)-6-phenyl-4-piperidinone (11). Reac-
tion time 72 h in DCE (125 μL). Purified by chromatography
over silica gel, eluting with 2-20% EtOAc/hexanes, to give the
bicycle 11 (26.7 mg, 64%, 0% ee,>20:1 dr, light yellow solid):
IR (neat) 3077, 3027, 2976, 2933, 2851, 1719, 1603, 1517, 1349,
704 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.4 Hz, 2H),
7.68 (d, J = 8.4 Hz, 2H), 7.25-7.70 (m, 5H), 5.70-5.80 (m, 1H),
5.09 (d, J=10.4 Hz, 1H), 4.65 (d, J=16.8 Hz, 1H), 4.11 (dd, J=3.6,
J. Org. Chem. Vol. 74, No. 15, 2009 5155

Yang and Carter
JOCFeatured Article
41.2, 39.2, 37.5, 32.1, 30.1, 25.8, 22.6, 22.1, 21.5, 20.2; HRMS (EI+)
calcd. for C19H24NOCl (M+), 317.1546 found 317.1556.
5-(4-Isopropylbenzyl)-5-methyl-6-(4-methoxyphenylamino)bi-
cyclo[2.2.2]octan-2-one (19). Reaction time 4 d. Purified by
chromatography over silica gel, eluting with 2-20% EtOAc/
hexanes, to give the bicycle 19 (13.2 mg, 27%, 91% ee,>20:1 dr,
colorless oil). Enantiomeric excess was determined by chiral
HPLC [4.6ꢀ250 mm Daicel OD column, 90:10 hexanes/i-PrOH,
1.0 mL min-1, retention times 11.6 min (major) and 16.2 min
(minor)] to be 91% ee: [R]23D=-18.6 (c=1.2, CHCl3); IR (neat)
3363, 2954, 1713, 1506, 1233, 1108, 1037, 814 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.15 (d, J=8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz,
2H), 6.79 (d, J=8.8 Hz, 2H), 6.59 (d, J=8.8 Hz, 2H), 3.77 (s,
3H), 3.52 (br s, 1H), 2.99 (d, J=13.2 Hz, 1H), 2.87 (d, J=13.2
Hz, 1H), 2.87-2.94 (m, 1H), 2.37-2.46 (m, 3H), 2.12 (dd,
J=18.4, 2.0 Hz, 1H), 1.71-2.05 (m, 4H), 1.26 (d, J=7.2 Hz,
6H), 0.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 216.5, 152.6,
146.9, 141.0, 135.1, 130.4, 126.0, 115.9, 115.0, 65.0, 55.8, 48.3,
45.8, 41.9, 40.9, 35.3, 33.7, 24.0, 22.0, 20.8, 19.4; HRMS (EI+)
calcd for C26H33NO2 (M+) 391.2511, found 391.2517.
5,5-Dimethyl-6-(4-methoxyphenylamino)bicyclo[2.2.2]oc-
tan-2-one (15). Reaction time 46 h. Purified by chromatography
over silica gel, eluting with 2-20% EtOAc/hexanes, to give the
bicycle 15 (21.2 mg, 62%, 87% ee, 14:1 dr, colorless crystal).
Enantiomeric excess was determined by chiral HPLC [4.6 ꢀ
250 mm Daicel OD column, 95:5 hexanes/i-PrOH, 1.0 mL min-1
,
retention times 16.2 min (major) and 17.9 min (minor)] to be 87%
ee (time 46 h, 2-20% EtOAc/hexanes, 21.2 mg, 62%, 87% ee, 14:1
dr, light yellow solid): mp 59-60 °C; [R]23D=+47.9 (c=0.8,CHCl3);
IR (neat) 3385, 2954, 2894, 1713, 1511, 1467, 1233, 1097, 1037,
819 cm-1;1H NMR (400 MHz, CDCl3)δ6.76-6.80 (m, 2H), 6.55-
6.58 (m, 2H), 3.76 (s, 3H), 3.43 (d, J=2.0 Hz, 1H), 3.33 (br s, 1H),
2.60 (dt, J = 18.8, 3.2 Hz, 1H), 2.39-2.40 (m, 1H), 2.10-2.18
(m, 2H), 1.81-1.98 (m, 3H), 1.58-1.65 (m, 1H), 1.13 (s, 3H), 1.03
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 216.3, 152.2, 141.5, 115.1,
114.9, 63.4, 55.8, 49.2, 42.2, 40.3, 36.9, 29.6, 22.7, 21.8, 21.1; HRMS
(EI+) calcd for C17H23NO2 (M+) 273.1729, found 273.1719.
5,5-Diethyl-6-(4-methoxyphenylamino)bicyclo[2.2.2]octan-2-one (17).
Reaction time 4 d. Purified by chromatography over silica gel,
eluting with 2-20% EtOAc/hexanes, to give the bicycle 17 (12.8 mg,
34%, 87% ee, 14:1 dr, white solid). Enantiomeric excess was
determined by chiral HPLC [4.6 ꢀ 250 mm Daicel OD column,
90:10 hexanes/i-PrOH, 1.0 mL min-1, retention times 11.1 min
Acknowledgment. Financial support was provided by
the Oregon State University (OSU) Venture Fund. We
thank Dr. Lev N. Zakharov (OSU and University of
Oregon) for X-ray crystallographic analysis of compounds
ꢀ
6a and 13c and Professor Max Deinzer and Dr. Jeff Morre
(major) and 27.5 min (minor)] to be 87% ee: mp 88-90 °C; [R]23
=
D
(OSU) for mass spectra data. Finally, we are grateful to
Dr. Roger Hanselmann (Rib-X Pharmaceuticals) and
Dr. “Paul” Ha-Yeon Cheong (University of California at
Los Angeles and OSU) for their helpful discussions.
+62.7 (c=1.0, CHCl3); IR (neat) 3379, 2960, 1718, 1506, 1239,
1032, 819 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.76-6.79 (m, 2H),
6.55-6.58 (m, 2H), 3.76 (s, 3H), 3.45 (br s, 1H), 3.29 (br s, 1H), 2.52
(dt, J=18.8, 3.2 Hz, 1H), 2.40-2.41 (m, 1H), 2.13 (dd, J=19.2, 2.4
Hz, 1H), 2.01-2.05 (m, 2H), 1.54-1.90 (m, 6H), 1.27-1.31 (m, 1H),
0.92 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 216.5, 152.4, 140.8, 115.5, 115.0, 63.7, 55.8,
48.8, 42.0, 40.9, 35.1, 29.8, 21.8, 20.9, 20.4, 8.55, 8.18; HRMS (EI+)
calcd for C19H27NO2 (M+) 301.2042, found 301.2047.
Supporting Information Available: Complete experimental
procedures for all remaining compounds are provided,
including 1H and 13C spectra, of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
5156 J. Org. Chem. Vol. 74, No. 15, 2009