Organocatalyzed, enantioselective synthesis of bicyclo-[2.2.2]-octanes containing benzylic, all-carbon quaternary centers

Article abstract of DOI:10.1016/j.tet.2010.01.094

Proline aryl sulfonamide-catalyzed, multi-component couplings have been developed for accessing densely functionalized [2.2.2] bicyclic ketones containing up to four contiguous chiral centers including an all-carbon benzylic quaternary center in high enan

Full text of DOI:10.1016/j.tet.2010.01.094

Tetrahedron 66 (2010) 4854–4859
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalyzed, enantioselective synthesis of bicyclo-[2.2.2]-octanes containing
benzylic, all-carbon quaternary centers
*
Hua Yang, Rich G. Carter
Department of Chemistry, 153 Gilbert Hall, Oregon State University, Corvallis, OR 97331, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2010
Received in revised form 25 January 2010
Accepted 26 January 2010
Available online 1 February 2010
Proline aryl sulfonamide-catalyzed, multi-component couplings have been developed for accessing
densely functionalized [2.2.2] bicyclic ketones containing up to four contiguous chiral centers including
an all-carbon benzylic quaternary center in high enantio- and diastereoselectivity. Application to the
bicyclic core of the recently isolated alkaloid kopsonoline is illustrated.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Organocatalysis
Quaternary center
Asymmetric synthesis
1. Introduction
non-polar solubility properties of sulfonamide 5 provides access to
reaction protocols that may not be readily accessible through other
Bicyclo-[2.2.2]-octane ring systems are found in numerous
natural products, which have attracted considerable synthetic
attentiondfrom maoecrystal V1 to vinigrol.2 An important sub-
class of this skeleton in which stereogenic, all-carbon quaternary
centers are embedded within one of the non-bridgehead carbons
are particularly challenging to addressddespite their presence in
several natural product skeletons. For example, Kam and co-
workers have recently reported the isolation and structural de-
termination of kopsijasminine (1) and kopsonoline (2)dboth of
which contain this key combination of motifs (Fig. 1).3
catalyst systems. For example, we have recently disclosed a orga-
nocatalyzed protocol for accessing bicyclo-[2.2.2]-octanes through
the use of
a,a
-disubstituted aldehydes (Scheme 1).5 This trans-
formation is uniquely facilitated through use of our proline sul-
fonamide derivative 5. These reactions proceeded in modest to
good chemical yield with good endo/exo selectivity (>10:1 in each
case). These transformations were performed in the absence of
solvent and generally proceeded to completion in between 2 and 4
days. The overall scope of these reactions was modest. The chemical
yield of the transformation was sensitive to steric effects. For ex-
ample, use of 3-pentyl compound 4b instead of isopropyl com-
pound 4a led to a noticeable drop in chemical efficiency (34% vs 62%
20
O
21
2
yield). Aldehydes not containing
a-branching (e.g., R–CH2CHO)
7
proved poor substrates in these transformationsdlikely due to
slow rate of enamine formation under the reaction conditions. It is
important to note in three of the four examples shown in Scheme 1,
products 6a–6c do not contain a stereogenic quaternary center. In
a single case, we were able to access a stereogenic quaternary
center-containing product 4d in modest chemical yield (27%) and
good enantioselectivity (95.5:4.5 er). Prior to this work, we are
N
N
MeO2C
HN
HN
kopsonoline (2)
kopsijasminine (1)
Figure 1. Select examples of bicyclo-[2.2.2]-octane, quaternary center-containing
alkaloids.
aware of only a single case, which exploits an
a,a-disubstituted
Our research group has recently developed a novel proline aryl
sulfonamide containing a lipophilic, dodecyl sidearm (catalyst 5),
which has proven effective in a range of reaction pathways.4,5 The
aldehyde as the nucleophile in this transformation.6
While product 6d was an encouraging result, a higher yielding
transformation with improved substrate scope is necessary to
provide access to biologically relevant scaffolds such as alkaloids 1
and 2. We attribute the challenges in the above reaction to the
nature of the imine substituent R and the protecting group on the
* Corresponding author. Tel.: þ1 541 737 9486; fax: þ1 541 737 9496; e-mail
address: rich.carter@oregonstate.edu (R.G. Carter).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.094

H. Yang, R.G. Carter / Tetrahedron 66 (2010) 4854–4859
4855
Table 1
imine nitrogen. In the four cases shown above, we employed
Optimization of three-component coupling with cyclohexenone
a preformed imine derived from p-methoxyaniline (PMP) under
neat reaction conditions. These PMP-based imines often provide
good levels of enantioselectivity, but at the cost of poor overall
chemical yield. The high stereoselectivity in these reactions may be
attributed to the structural rigidity of the aniline-derived imines,
while the lower chemical yields are a function of the poorer sta-
bility of PMP-containing iminesdlikely due to their electron-rich
nature. Additionally, a PMP-protecting group is not ideal as its re-
moval can require harsh conditions (e.g., CAN).7 We hoped that an
alternate protecting group could address the poor chemical effi-
ciency of these transformations in several cases while not com-
promising enantioselectivity and generating a readily removable
moiety on the product amine.
CHO
O
5 (30 mol %)
O
H
Ph
NHR
RNH2
+
See Table
13
3
14a R = Bn
14b R = PMP
Entry
R
Conditions
Yield (%)
71
53
76
31
48
72
era (dr)b
a
b
c
d
e
f
Bn
PMP
Bn
Bn
Bn
DCE, 1 d, rt
DCE, 3 d, rt
PhMe, 1 d, rt
DCE, 2 d, rt, mol. sieves
PhMe, 3 d, rt, mol. sieves
PhMe, 3 d, 4 ꢀC
92.2:7.8 (>20:1)
98.3:1.7 (>20:1)
90.4:9.6 (>20:1)
79.9:20.1 (>20:1)
96.0:4.0 (>20:1)
93.3:6.7 (>20:1)
Bn
a
O
O
Determined by chiral HPLC analysis.
Determined by 1H NMR analysis.
H
H
b
O
C12H25
NHPMP
NHPMP
of transformationsdlikely due to the increased localization of the
lone pair on nitrogen as compared to anilines. Our initial conditions
utilized DCE as the solvent of choice5,8 (entry a) to generate the
desired [2.2.2] bicycle 14a in good levels of enantioselectivity and
diastereoselectivity. In contrast, use of p-methoxyaniline yielded
a noticeable drop in chemical yield of 14b and rate of reaction
(entry b). Product 14b did provide us with the opportunity to es-
tablish relative stereochemistry through X-ray crystallographic
analysis (Fig. 2).ySubstitution of DCE for toluene led to comparable
levels of stereoselectivity with slightly improved chemical yield.
Interestingly, addition of molecular sieves had a dramatic impact of
the reaction performance. This transformation generates an
equivalent of water during initial enamine formation. In the case of
DCE (entry d), a dramatic reduction in chemical yield (31%) and
enantioselectivity was observed. Use of molecular sieves with tol-
uene as the solvent (entry e) also led to a significant reduction in
the chemical efficiency of the reaction (48%). Ultimately, the use of
toluene without molecular sieves with a reaction temperature of
4 ꢀC proved to be the optimum conditions (entry f). It is important
to note that this transformation generates four contiguous stereo-
genic centers including an all-carbon quaternary center. This
compound 14 contains the central bicyclic core and benzylic qua-
ternary center of kopsonoline (2).
6a
6b
O
62% yield
34% yield
14:1 endo:exo
14:1 endo:exo
N
H
HN SO2
93.5:6.5 er
93.3:6.7 er
3
5 (30 mol%)
O
H
O
H
PMP
neat, rt
2-4 d
N
Ar
NHPMP
NH
R
PMP
H
4a R = CH(Me)2
4b R = CH(Et)2
4c R = CH(CH2)5
6d
6c
Ar = 4-i-Pr-C6H4
27% yield
55% yield
>20:1 endo:exo
93.4:6.6 er
>20:1 dr
4d R = CH(Me)(CH2Ar)
95.5:4.5 er
Scheme 1. Prior published work toward accessing [2.2.2] bicycles.5
The performance of the reaction detailed in Scheme 1 is also
a function of the equilibrium between the starting imines 8 and 11
and the necessary enamines 7/9 and 10/12 (Scheme 2, Eq. 1). In
cases where the imine is substituted with two alkyl substituents
(e.g., 8), the rate of this equilibrium is likely slow and favors rela-
tively the imine tautomer. In contrast, if the imine was substituted
with at least one aryl ring (e.g., 11), the rate of enamine/imine
tautomerization as well as the equilibrium concentration of the
enamines 10 and 12 are likely increased (Eq. 2). This modification of
the starting imine would also nicely provide access to the benzylic,
all-carbon quaternary center present in both kopsijasminine (1)
and kopsonoline (2). Herein, we provide a full account of the syn-
thesis of the bicyclo-[2.2.2]-octane core of kopsonoline including
the stereogenic, all-carbon benzylic stereocenter through the use of
a cascading, organocatalyzed transformation.
R
H
R
H
H
R
H
H
N
R'
N
N
Eq. 1
Eq. 2
R'
7
8
9
R'
R
R
H
R
H
N
N
N
Figure 2. ORTEP representation of bicycle 14b.
Ar
H
H
H
Ar
Ar
We next sought to probe the scope of the aldehyde component
15 with the optimized conditions (Table 2). These aldehydes 15 can
be readily synthesized from the corresponding benzylic nitrile or
methyl ketone through a two-step sequence.9 A range of electron-
donating and electron-withdrawing groups was tolerated on the
aromatic ring (entries a–e). Increasing in the electron-withdrawing
10
11
12
Scheme 2. Comparisons of likely equilibriums between different imine substitution
patterns.
2. Results
Based on our prior work,5 we envisioned that
a multi-
component coupling between aldehyde 13, 2-cyclohexenone (3),
and an amine could be facilitated via proline sulfonamide catalyst 5
(Table 1). Benzyl amines should be particularly useful in these types
y
CCDC-765,281 (14b) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

4856
H. Yang, R.G. Carter / Tetrahedron 66 (2010) 4854–4859
nature of the arene appeared to lead to a modest increase in
enantioselectivity. Use of alternate groups at R1 was also feasi-
bledalbeit with slightly reduced enantioselectivity (entries f and
g). It should be noted that more sterically congested aldehydes
enantioselectivity as compared to the PMP-derived example (27%
yield, >20:1 dr, 95.5:4.5 er, see Scheme 1). We hope that we can
address this shortcoming through modification of the catalyst
structure. Such findings will be reported in due course.
3. Discussion and conclusion
Table 2
Exploration of scope of multi-component coupling with cyclohexenone
R1
CHO
We are currently working to gain a better understanding of
the controlling elements in this transformation; however, a ten-
tative explanation for the observed stereochemical outcome is
presented in Scheme 4. After formation of iminium ion A, we
hypothesize that the enamine B hydrogen bonds with the sul-
fonamide nitrogen to preorganize the nucelophile as drawn in
intermediate C. Conjugate addition by the enamine would es-
tablish the stereogenic quaternary center present in imine D. The
nature of the stereochemical outcome is dependent on both the
enamine geometry and facial approach of the enamine (re or si)
R2
R3
O
5 (30 mol %)
O
H
R4NH2
+
R3
NHR4
See Table
R1
R2
3
16
15
Entry R1
R2 R3 R4
Conditions
Yield era (dr)b
(%)
a
b
c
d
e
f
Me
Me
Br
Br
Cl
H
H
H
H
Bn
Bn
PMP
Bn
PhMe, 4 ꢀC, 3 d 65
PhMe, 4 ꢀC, 5 d 52
DCE, rt, 3 d
PhMe, 4 ꢀC, 3 d 69
PhMe, 4 ꢀC, 5 d 53
DCE, rt, 3 d
PhMe, 4 ꢀC, 6 d 46
PhMe, 4 ꢀC, 3 d 66
92.2:7.8 (>20:1)
94.6:5.4 (>20:1)
95.4:4.6 (>20:1)
94.3:5.7 (>20:1)
95.8:4.2 (>20:1)
90.6:9.4 (>20:1)
88.0:12.0 (>20:1)
88.8:11.2 (>20:1)
92.8:7.2 (>20:1)
Me
Me
Me
Me
Allyl Br
Allyl Br
on the
b-carbon of the conjugated iminium ion. We have
53
attempted to characterize the enamine B by NMR; however,
spectroscopic analysis of the compound generated upon mixing
benzyl amine and aldehyde 13 revealed a complex mixtur-
edlikely indicated a dynamic equilibrium is present. After in-
terconversion between enamine D and enamine F, intramolecular
Mannich cyclization could be facilitated by sulfonamide N–H
activation to provide the bicyclic intermediate H. Finally, hydro-
lysis of the pyrrolidine moiety would regenerate 5 and provide
the product 14/16.
Cl
Cl Bn
H
H
H
H
PMP
Bn
Allyl
31
gc
hc
ic
Me
Me
H
H
Propargyl PhMe, 4 ꢀC, 3 d 63
a
Determined by chiral HPLC analysis.
Determined by 1H NMR analysis.
Reaction was performed at rt.
b
c
O
Bn
H
O
N
Ar
O
N
H
Ar
HN SO2
O
N
HN SO2
N
N
N
O
B
Ar
SO2
Bn
N
H
N
S
O
5
Ar
+
O
H
Me Ar
H
Bn
N
Ph
C
Ar
A
D
3
‡
O
O
Ar
N
Ar
H
N
N
H
N
HN SO2
N
SO2
Ar
Ar
N
O
N
ArO2S
O
H
N
N
H
Bn
H
Bn
H
Bn
Bn
ArO2S
N
N
H
Ar
Ar
E
F
G
5
14/16
Scheme 4. Possible mechanistic explanation for [2.2.2] bicycle formation.
[e.g., 2-(o,o-dichlorophenyl)-propanal] were unreactive under the
reaction conditions. We were pleased to see that alternate amines
could also be used in this transformationdwith propargyl amine
giving particularly useful levels of stereoselectivity and chemical
yield (entry i).
In summary, a rapid, multi-component coupling method has
been developed for accessing all-carbon quaternary centers in
a highly enantio- and diastereoselective fashion. The importance of
substitution on nitrogen and on the aldehyde moiety has been
demonstrated. Further applications of this technology will be
reported in due course.
We also explored the possibility of using these new optimized
conditions on
a,a-dialkylsubstituted aldehydes (Scheme 3). Un-
fortunately, the benzyl amine derived product was formed in
modestly better chemical yield but reduced diastereo- and
4. Experimental section
4.1. General
5
(30 mol %)
O
R'
Infrared spectra were recorded neat unless otherwise indicated
and are reported in cmꢁ1. 1H NMR spectra were recorded in deu-
terated solvents and are reported in parts per million relative to
tetramethylsilane and referenced internally to the residually pro-
tonated solvent. 13C NMR spectra were recorded in deuterated
solvents and are reported in parts per million relative to
O
BnNH2
18
R'
39% yield
H
PhMe, rt
9:1 dr, 88.3:11.7 er
NHBn
17
R' = 4-i-Pr-C6H4
Scheme 3. Exploration of alkyl,alkyl disubstituted aldehydes.

H. Yang, R.G. Carter / Tetrahedron 66 (2010) 4854–4859
4857
tetramethylsilane and referenced internally to the residually pro-
4.5. 2-(4-Methylphenyl)-propanal (15a)9c
tonated solvent. Chiral HPLC was performed with chiral columns
[Chirapak AD, OD, OJ, AS-H columns, (Daicel Chemical Ind., Ltd.)].
Routine monitoring of reactions was performed using EM Sci-
ence DC-Alufolien silica gel, aluminum-backed TLC plates. Flash
chromatography was performed with the indicated eluents on EM
Science Gedurian 230–400 mesh silica gel.
Air and/or moisture sensitive reactions were performed under
usual inert atmosphere conditions. Reactions requiring anhydrous
conditions were performed under a blanket of argon, in glassware
dried in an oven at 120 ꢀC or by flame, then cooled under argon. Dry
THF and CH2Cl2 were obtained via a solvent purification system. All
other solvents and commercially available reagents were either
purified via literature procedures or used without further purifi-
cation. 2-(4-Bromophenyl)-propanal 15b and 2-(4-chlorophenyl)-
propanal 15d were prepared according to the reported procedure.9d
To a stirred solution of 199b (1.12 g, 7.71 mmol) in CH2Cl2 (25 mL)
at ꢁ78 ꢀC was added DIBAL-H (8.48 mL, 8.48 mmol, 1.0 M in
CH2Cl2) dropwise. After stirring at ꢁ78 ꢀC to rt for 3 h, the reaction
was quenched with satd aq NH4Cl (50 mL) and extracted with Et2O
(3ꢂ40 mL). The dried (Na2SO4) extract was concentrated in vacuo
and purified by chromatography over silica gel, eluting with 0.5–1%
ether/pentane, to give aldehyde 15a (0.731 g, 4.93 mmol, 64%) as
a colorless oil; 1H NMR (400 MHz, CDCl3) 9.701–9.704 (m, 1H), 7.23
(d, J¼8.0 Hz, 2H), 7.14 (d, J¼8.0 Hz, 2H), 3.63 (q, J¼6.8 Hz, 1H), 2.39
(s, 3H), 1.46 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 201.2,
137.3, 134.7, 129.8, 128.2, 52.6, 21.0, 14.6.
4.6. 6-(Benzylamino)-5-methyl-5-(4-methylphenyl)-
bicyclo[2.2.2]octan-2-one (16a)
Reaction time 3 d, 4 ꢀC. Purified by chromatography over silica
gel, eluting with 2–6% EtOAc/hexanes, to give the bicycle 16a
(54.2 mg, 65%, 92.2:7.8 er, >20:1 dr, colorless oil). Enantiomeric ex-
cess was determined by chiral HPLC [4.6ꢂ250 mm Daicel OD col-
4.2. General procedure for three-component formal aza-
Diels–Alder reaction with cyclohexenone (30 mol % catalyst)
umn, 95:5 hexanes/i-PrOH, 1.0 mL minꢁ1, retention times 10.5 min
The aldehyde (0.25 mmol) and amines (0.25 mmol) were dis-
solved in toluene (0.26 mL). After stirring at rt for 30 min, cyclo-
23
(major) and 12.7 min (minor)] to be 92.2:7.8 er: [
a]
D
þ34.2 (c 2.5,
CHCl3); IR (neat) 3341, 2943, 2867, 1718, 1457, 1113, 819, 700 cmꢁ1
;
hexenone (0.24 mL, 10 equiv) and sulfonamide
9 (31.7 mg,
0.75 mmol) were added to it at 4 ꢀC or rt. After stirring for the
prescribed time, reaction mixture was loaded directly onto silica gel
and was purified by chromatography, eluting with 2–15% EtOAc/
hexanes, to give the corresponding product.
1H NMR (400 MHz, CDCl3)
d
7.43 (d, J¼7.2 Hz, 2H), 7.37 (t, J¼7.2 Hz,
2H), 7.29–7.32 (m, 3H), 7.10 (d, J¼8.0 Hz, 2H), 4.09 (d, J¼13.2 Hz, 1H),
3.76 (d, J¼13.2 Hz, 1H), 3.50 (d, J¼2.0 Hz, 1H), 2.64–2.71 (m, 3H),
2.26–2.38 (m, 5H), 1.46–1.86 (m, 4H), 1.21 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 216.6,147.3,140.2,135.4,129.0,128.6,128.4,127.1,
125.6, 66.1, 51.5, 46.6, 44.3, 41.1, 37.2, 25.4, 21.7, 21.2, 20.9; HRMS
4.3. 6-(Benzylamino)-5-methyl-5-phenyl-bicyclo[2.2.2]octan-
2-one (14a)
(CIþ) calcd for C23H27NO (Mþ), 333.2093, found 333.2086.
4.7. 6-(Benzylamino)-5-(4-bromophenyl)-5-methyl-
bicyclo[2.2.2]octan-2-one (16b)
Reaction time 3 d, 4 ꢀC. Purified by chromatography over silica
gel, eluting with 2–6% EtOAc/hexanes, to give the bicycle 14a
(57.5 mg, 72%, 93.3:6.7 er, >20:1 dr, colorless oil). Enantiomeric ex-
cess was determined by chiral HPLC [4.6ꢂ250 mm Daicel OD col-
The starting aldehyde 15b was prepared in accord with literature
procedure.9d Reactiontime5 d, 4 ꢀC. Purified bychromatographyover
silica gel, eluting with 2–7% EtOAc/hexanes, to give the bicycle 16b
(51.9 mg,52%,94.6:5.4er, >20:1dr, colorlessoil). Enantiomericexcess
was determined bychiral HPLC [4.6ꢂ250 mmDaicelODcolumn, 95:5
umn, 99:1 hexanes/i-PrOH, 1.0 mL minꢁ1, retention times 16.6 min
23
(major) and 20.8 min (minor)] to be 93.3:6.7 er: [
a
]
þ40.1 (c 1.7,
D
CHCl3); IR (neat) 3330, 2949, 2867, 1718, 1495, 1457, 1113, 765,
694 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
7.41–7.42 (m, 4H), 7.37 (t,
hexanes/i-PrOH, 1.0 mL minꢁ1, retention times 14.2 min (major) and
J¼7.6 Hz, 2H), 7.26–7.31 (m, 3H), 7.20 (t, J¼7.2 Hz, 1H), 4.09 (d,
J¼13.2 Hz, 1H), 3.76 (d, J¼13.2 Hz, 1H), 3.51 (d, J¼2.0 Hz, 1H), 2.70–
2.71 (m, 3H), 2.29 (dd, J¼19.6, 3.2 Hz, 1H), 1.37–1.86 (m, 5H), 1.22 (s,
23
19.3 min (minor)] to be94.6:5.4 er: [
a
]
þ34.4(c 1.2, CHCl3);IR (neat)
D
3342, 2945, 2875,1719,1490,1451,1112,1077, 820, 727, 704 cmꢁ1; 1H
NMR (400 MHz, CDCl3)
3H); 13C NMR (100 MHz, CDCl3)
d 216.5, 150.3, 140.2, 128.6, 128.4,
d
7.26–7.42 (m, 9H), 4.08 (d, J¼12.8 Hz, 1H),
3.74 (d, J¼13.2 Hz,1H), 3.40–3.41 (m,1H), 2.62–2.73 (m, 3H), 2.30 (dd,
128.3, 127.1, 125.9, 125.7, 66.1, 51.5, 46.5, 44.7, 41.2, 37.1, 25.4, 21.7,
J¼18.4,1.2 Hz,1H),1.46–1.88 (m, 5H),1.19 (s, 3H); 13C NMR (100 MHz,
21.2; HRMS (CIþ) calcd for C22H25NO (Mþ), 319.1936, found 319.1926.
CDCl3) d 216.1, 149.4, 139.9, 131.3, 128.6, 128.4, 127.6, 127.3, 119.7, 66.0,
51.3, 46.2, 44.5, 41.1, 37.0, 25.1, 21.6, 21.1; HRMS (CIþ) calcd for
C22H24ONBr (Mþ), 397.1041, found 397.1028.
4.4. 6-(p-Methoxyphenylamino)-5-methyl-5-phenyl-
bicyclo[2.2.2]octan-2-one (14b)
4.8. 5-Methyl-5-(4-bromophenyl)-6-(4-
Reaction time 3 d. Purified by chromatography over silica gel,
eluting with 2–10% EtOAc/hexanes, to give the bicycle 14b
(40.6 mg, 53%, 98.3:1.7 er, >20:1 dr, colorless crystal). Enantiomeric
excess was determined by chiral HPLC [4.6ꢂ250 mm Daicel OD
methoxyphenylamino)-bicyclo[2.2.2]octan-2-one (16c)
The starting aldehyde 15b was prepared in accord with litera-
ture procedure.9d Reaction time 3 d, rt. Purified by chromatography
over silica gel, eluting with 2–10% EtOAc/hexanes, to give the bi-
cycle 16c (51.9 mg, 51%, 95.4:4.6 er, >20:1 dr, colorless oil). Enan-
tiomeric excess was determined by chiral HPLC [4.6ꢂ250 mm
column, 92:8 hexanes/i-PrOH, 1.0 mL minꢁ1
, retention times
15.9 min (major) and 13.1 min (minor)] to be 98.3:1.7 er: mp: 138–
23
139 ꢀC; [
1462, 1228, 1103, 1032, 819, 765, 705 cmꢁ1
CDCl3)
a
]
þ7.7 (c 1.0, CHCl3); IR (neat) 3379, 2943, 1718, 1511,
D
;
1H NMR (400 MHz,
Daicel OD column, 95:5 hexanes/i-PrOH, 1.0 mL minꢁ1, retention
23
d
7.53 (d, J¼7.6 Hz, 2H), 7.36 (t, J¼7.2 Hz, 2H), 7.26 (t,
times 17.2 min (major) and 21.8 min (minor)] to be 95.4:4.6 er: [a]
D
J¼7.2 Hz, 1H), 6.81–6.84 (m, 2H), 6.66–6.68 (m, 2H), 4.24 (d,
J¼8.4 Hz, 1H), 3.79 (s, 3H), 3.66 (br s, 1H), 2.70–2.79 (m, 2H), 2.54 (s,
1H), 2.35 (dd, J¼18.4, 2.0 Hz, 1H), 1.61–1.88 (m, 4H), 1.33 (s, 3H); 13C
ꢁ3.0 (c 1.0, CHCl3); IR (neat) 3370, 2949, 1715, 1513, 1233, 1007, 824,
754, 719 cmꢁ1 1H NMR (400 MHz, CDCl3)
7.40 (d, J¼8.8 Hz, 2H), 6.82 (d, J¼8.8 Hz, 2H), 6.64 (d, J¼8.8 Hz, 2H),
4.13 (d, J¼10.0 Hz, 1H), 3.77 (s, 3H), 3.60 (d, J¼11.2 Hz, 1H), 2.29–
2.71 (m, 4H), 1.61–1.83 (m, 4H), 1.28 (s, 3H); 13C NMR (100 MHz,
;
d
7.46 (d, J¼8.8 Hz, 2H),
NMR (100 MHz, CDCl3)
d 215.9, 152.7, 149.9, 140.2, 128.6, 126.2,
125.6, 115.7, 115.1, 63.4, 55.8, 47.6, 44.3, 41.2, 36.7, 25.1, 21.7, 21.1;
HRMS (CIþ) calcd for C22H25NO2 (Mþ), 335.1885, found 335.1874.
CDCl3)
d 215.4, 152.9, 149.0, 139.9, 131.7, 127.5, 120.1, 115.8, 115.1,

4858
H. Yang, R.G. Carter / Tetrahedron 66 (2010) 4854–4859
63.5, 55.8, 47.5, 44.1, 41.1, 36.6, 24.9, 21.7, 21.1; HRMS (CIþ) calcd for
C22H24NO2Br (Mþ), 413.0990, found 413.0989.
4.12. 6-(Benzylamino)-5-(3,4-dichlorophenyl)-5-methyl-
bicyclo[2.2.2]octan-2-one (16e)
Reaction time 5 d, 4 ꢀC. Purified by chromatography over silica
gel, eluting with 2–20% EtOAc/hexanes, to give the bicycle 16e
(51.5 mg, 53%, 95.8:4.2 er, >20:1 dr, colorless oil). Enantiomeric
excess was determined by chiral HPLC [4.6ꢂ250 mm Daicel OD
4.9. 6-(Benzylamino)-5-(4-chlorophenyl)-5-methyl-
bicyclo[2.2.2]octan-2-one (16d)
The starting aldehyde 15d was prepared in accord with literature
procedure.9d Reaction time 3 d, 4 ꢀC. Purified bychromatographyover
silica gel, eluting with 2–6% EtOAc/hexanes, to give the bicycle 16d
(61.1 mg, 69%,94.3:5.7er, >20:1dr, colorlessoil). Enantiomericexcess
was determined by chiral HPLC [4.6ꢂ250 mm DaicelODcolumn, 92:8
column, 95:5 hexanes/i-PrOH, 1.0 mL minꢁ1
, retention times
23
15.9 min (major) and 23.2 min (minor)] to be 95.8:4.2 er: [
þ26.4 (c 0.7, CHCl3); IR (neat) 3341, 2949, 1718, 1473, 1457, 1135,
1026, 819, 705 cmꢁ1; 1H NMR (400 MHz, CDCl3)
7.57 (s, 1H), 7.27–
a]
D
d
hexanes/i-PrOH, 1.0 mL minꢁ1, retention times 11.7 min (major) and
7.41 (m, 6H), 7.21 (d, J¼8.4 Hz, 1H), 4.07 (d, J¼12.8 Hz, 1H), 3.74 (d,
J¼12.8 Hz, 1H), 3.33 (br s, 1H), 2.59–2.74 (m, 3H), 2.29 (d, J¼18.4 Hz,
1H), 1.49–1.90 (m, 6H), 1.18 (s, 3H); 13C NMR (100 MHz, CDCl3)
23
15.4 min (minor)] to be94.3:5.7er: [
a
]
þ44.8 (c1.5, CHCl3);IR(neat)
D
3324, 2943,1718,1484,1451,1092,1010, 825, 732, 705 cmꢁ1; 1H NMR
(400 MHz, CDCl3)
d
215.7, 150.7, 139.6, 132.3, 130.1, 129.8, 128.7, 128.5, 128.2, 127.3,
d
7.28–7.43 (m, 7H), 7.23 (d, J¼8.8 Hz, 2H), 4.09 (d,
125.2, 65.9, 51.2, 45.9, 44.5, 41.0, 36.9, 25.0, 21.6, 21.1; HRMS (CIþ)
calcd for C22H23NOCl2 (Mþ), 387.1157, found 387.1152.
J¼12.8 Hz, 1H), 3.74 (d, J¼13.2 Hz, 1H), 3.40 (d, J¼2.0 Hz, 1H), 2.62–
2.73 (m, 3H), 2.30(d, J¼18.4 Hz,1H),1.52–1.89 (m, 5H),1.18 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 216.1, 148.8, 139.9, 131.6, 129.1, 128.6, 128.4,
128.3,127.2, 66.0,51.3, 46.3, 44.4,41.1, 37.0, 25.2, 21.6, 21.1;HRMS(CIþ)
calcd for C22H24NOCl (Mþ), 353.1546, found 353.1536.
CN
CN
Cl
Cl
4.13. 4-Bromo-a
-2-propen-1-yl-benzeneacetonitrile (23)10
Cl
20
Cl
21
To a stirred solution of nitrile 22 (1.96 g, 10 mmol) in THF
(50 mL) at ꢁ78 ꢀC was added LiHMDS (10 mL, 10 mmol, 1.0 M in
THF) dropwise. After 1 h, a solution of allyl bromide (1.21 g,
0.866 mL, 10 mmol) was added dropwise to the reaction solution at
ꢁ78 ꢀC. After stirring at ꢁ78 ꢀC for 1 h, the reaction mixture was
removed from the cooling bath, quenched with water (50 mL), and
extracted with Et2O (2ꢂ50 mL). The dried (Na2SO4) extract was
concentrated in vacuo and purified chromatography over silica gel,
eluting with 1–5% ether/hexanes, to give nitrile 23 (2.12 g,
8.98 mmol, 90%) as a colorless oil; IR (neat) 3085, 2987, 2241, 1489,
4.10. 2-(3,4-Dichlorophenyl)-propionitrile (21)10
To a stirred solution of nitrile 20 (1.86 g, 10 mmol) in THF
(50 mL) at ꢁ78 ꢀC was added LiHMDS (10 mL, 10 mmol, 1.0 M in
THF) dropwise. After 1 h, a solution of iodomethane (1.42 g,
0.63 mL, 10 mmol) was added dropwise to the reaction solution at
ꢁ78 ꢀC. After stirring at ꢁ78 ꢀC for 1 h and then at rt for 2 h, the
reaction mixture was removed from the cooling bath, quenched
with water (40 mL) and extracted with Et2O (3ꢂ30 mL). The dried
(Na2SO4) extract was concentrated in vacuo and purified chroma-
tography over silica gel, eluting with 1–4% Ether/hexanes, to give
nitrile 21 (1.62 g, 8.10 mmol, 81%) as a colorless oil; 1H NMR
(400 MHz, CDCl3) 7.49–7.51 (m, 2H), 7.24 (dd, J¼8.4, 2.0 Hz, 1H),
3.90 (q, J¼7.2 Hz, 1H), 1.67 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
1408, 1075, 1010, 923, 814 cmꢁ1 1H NMR (400 MHz, CDCl3) 7.50–
;
7.53 (m, 2H), 7.21–7.24 (m, 2H), 5.73–5.81 (m, 1H), 5.16–5.21 (m,
2H), 3.85 (d, J¼7.2 Hz, 1H), 2.56–2.68 (m, 2H); 13C NMR (100 MHz,
CDCl3)
d 134.3, 132.22, 132.17, 129.1, 122.2, 119.9, 119.8, 39.6, 37.0.
CDCl3)
d 137.1, 133.4, 132.5, 131.2, 128.9, 126.1, 120.5, 30.5, 21.2.
4.14. 4-Bromo-a-2-propen-1-yl-benzeneacetaldehyde (15f)
4.11. 2-(3,4-Dichlorophenyl)-propanal (15e)
To a stirred solution of 23 (1.11 g, 4.70 mmol) in CH2Cl2 (14 mL)
at ꢁ78 ꢀC was added DIBAL-H (5.17 mL, 5.17 mmol, 1.0 M in CH2Cl2)
dropwise. After stirring at ꢁ78 ꢀC to rt for 3 h, the reaction mixture
was quenched with satd aq NH4Cl (20 mL) and extracted with Et2O
(3ꢂ30 mL). The dried (Na2SO4) extract was concentrated in vacuo
and purified chromatography over silica gel, eluting with 1–5%
Ether/pentane, to give aldehyde 15e (0.890 g, 3.72 mmol, 79%) as
a light yellow oil; IR (neat) 3248, 2922, 1723, 1680, 1582, 1489, 1075,
To a stirred solution of 21 (1.62 g, 8.11 mmol) in CH2Cl2 (16 mL)
at ꢁ78 ꢀC was added DIBAL-H (8.92 mL, 8.92 mmol, 1.0 M in
CH2Cl2) dropwise. After stirring at ꢁ78 ꢀC for 2 h, the reaction
mixture was warmed to rt. After 8 h, the reaction was quenched
with satd aq NH4Cl (20 mL) and extracted with Et2O (3ꢂ30 mL).
The dried (Na2SO4) extract was concentrated in vacuo and purified
chromatography over silica gel, eluting with 0.5–2% ether/pentane,
to give aldehyde 15e (1.23 g, 7.04 mmol, 87%) as a colorless oil; 1H
NMR (400 MHz, CDCl3) 9.68 (d, J¼1.2 Hz, 1H), 7.46 (d, J¼8.4 Hz, 1H),
7.33 (d, J¼2.0 Hz, 1H), 7.07 (dd, J¼8.4, 2.0 Hz, 1H), 3.63 (qd, J¼7.2,
1.2 Hz, 1H), 1.46 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
1010, 917, 825, 721 cmꢁ1 1H NMR (400 MHz, CDCl3) 9.68 (d,
;
J¼2.0 Hz, 1H), 7.49–7.54 (m, 2H), 7.06–7.12 (m, 2H), 5.63–5.75 (m,
1H), 5.00–5.10 (m, 2H), 3.58–3.63 (m, 1H), 2.46–2.89 (m, 2H); 13C
NMR (100 MHz, CDCl3)
d 199.5, 134.7, 134.4, 132.2, 130.6, 121.8,
117.6, 94.9, 58.1, 33.9; HRMS (EIþ) calcd for C11H11OBr (Mþ),
d
199.7, 137.9, 133.1, 131.8, 130.9, 130.3, 127.6, 52.0, 14.0.
237.9993, found 237.9985.

H. Yang, R.G. Carter / Tetrahedron 66 (2010) 4854–4859
4859
4.15. 5-Allyl-5-(4-bromophenyl)-6-(4-methoxyphenylamino)-
bicyclo[2.2.2]octan-2-one (16f)
CDCl3)
d
7.55 (d, J¼7.6 Hz, 2H), 7.36 (t, J¼7.6 Hz, 2H), 7.23 (t,
J¼7.2 Hz, 1H), 3.81 (d, J¼2.0 Hz, 1H), 3.60 (qd, J¼17.2, 2.4 Hz, 2H),
2.67–2.71 (m, 2H), 2.57–2.58 (m, 1H), 2.24–2.31 (m, 2H), 1.54–1.83
Reaction time 3 d, rt. Purified by chromatography over silica gel,
eluting with 2–15% EtOAc/hexanes, to give the bicycle 16f (34.6 mg,
31%, 90.6:9.4 er, >20:1 dr, colorless crystal). Enantiomeric excess was
determined by chiral HPLC [4.6ꢂ250 mm Daicel AD column, 99:1
(m, 5H), 1.20 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 216.2, 149.9,
128.4, 126.0, 125.8, 81.7, 72.0, 64.1, 46.0, 44.2, 41.1, 37.6, 35.6, 25.6,
21.28, 21.26; HRMS (CIþ) calcd for C18H21NO (Mþ), 267.1623, found
267.1621.
hexanes/i-PrOH, 0.8 mL minꢁ1, retention times 60.9 min (major) and
23
55.7 min (minor)] to be 90.6:9.4 er: mp: 68–69 ꢀC; [
a]
D
þ3.4 (c 1.0,
4.19. 6-(Benzylamino)-5-(4-isopropylbenzyl)-5-methyl-bi-
cyclo[2.2.2]octan-2-one (18)
CHCl3); IR (neat) 3363, 2949, 1718, 1598, 1506, 1446, 1228, 1043, 863,
814, 727 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.47 (d, J¼8.7 Hz, 2H), 7.41
Reaction time 7 d, 4 ꢀC. Purified by chromatography over silica
gel, eluting with 2–10% EtOAc/hexanes, to give the bicycle 18
(36.6 mg, 39%, 88.3:11.7 er, 9:1 dr, colorless oil). Enantiomeric
excess was determined by chiral HPLC [4.6ꢂ250 mm Daicel AD
(d, J¼8.7 Hz, 2H), 6.82 (d, J¼8.7 Hz, 2H), 6.67 (d, J¼9.0 Hz, 2H), 5.31–
5.38 (m, 1H), 4.96–5.00 (m, 2H), 4.07 (d, J¼12.6 Hz, 1H), 3.84 (s, 3H),
3.62 (d, J¼12.6 Hz,1H), 2.28–2.76 (m, 6H),1.75–1.90 (m, 4H); 13C NMR
(100 MHz, CDCl3) d 215.4,153.2, 146.6,140.0,133.4,131.4, 128.5,120.3,
column, 99:1 Hexanes/i-PrOH, 1.0 mL minꢁ1
, retention times
118.1, 116.3, 115.2, 65.9, 55.8, 47.8, 46.5, 40.5, 40.4, 32.1, 22.0, 20.8;
HRMS (CIþ) calcd for C24H26NO2Br (Mþ), 439.1147, found 439.1139.
23
14.0 min (major) and 10.9 min (minor)] to be 88.3:11.7 er: [a]
D
¼ꢁ20.5ꢀ (c¼ 2.5, CHCl3); IR (neat) 3341, 2960, 2927, 1713, 1451,
1112, 825, 738, 700 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.22–7.34
4.16. 5-Allyl-6-(benzylamino)-5-(4-bromophenyl)-
bicyclo[2.2.2]octan-2-one (16g)
(m, 4H), 7.17 (d, J¼8.0 Hz, 2H), 7.10 (d, J¼8.0 Hz, 2H), 3.90 (d,
J¼13.2 Hz, 1H), 3.57 (d, J¼13.2 Hz, 1H), 2.92 (p, J¼6.8 Hz, 1H) 2.86
(d, J¼2.0 Hz, 1H), 2.79 (d, J¼13.2 Hz, 1H), 2.72 (d, J¼13.2 Hz, 1H),
2.58 (q, J¼2.4 Hz, 1H), 2.48 (dt, J¼18.8, 3.2 Hz, 1H), 2.23–2.31 (m,
1H), 2.09 (dd, J¼18.8, 1.6 Hz, 1H), 1.88–1.93 (m, 3H), 1.64–1.69 (m,
1H), 1.28 (d, J¼6.8 Hz, 6H), 0.93 (s, 3H); 13C NMR (100 MHz, CDCl3)
Reaction time 6 d, rt. Purified by chromatography over silica gel,
eluting with 2–8% EtOAc/hexanes, to give the bicycle 16g (48.8 mg,
46%, 88.0:12.0 er, >20:1 dr, colorless oil). Enantiomeric excess was
determined by chiral HPLC [4.6ꢂ250 mm Daicel AS-H column, 96:4
hexanes/i-PrOH, 1.0 mL minꢁ1, retention times 31.8 min (major)
d
216.8, 146.8, 140.3, 135.6, 130.4, 128.27, 128.23, 126.9, 126.0, 66.9,
23
and 15.1 min (minor)] to be 88.0:12.0 er: [
a
]
þ48.6 (c 1.8, CHCl3);
51.7, 47.1, 46.0, 41.9, 40.6, 36.8, 33.7, 24.1, 21.9, 20.9, 19.4; HRMS
D
(CIþ) calcd. for C26H34NO (Mþ1), 376.2640 found 376.2644.
IR (neat) 3327, 2945, 1719, 1486, 1455, 1112, 1007, 910, 863, 735,
700 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.28–7.43 (m, 9H), 5.27–5.37
(m, 1H), 4.89–4.93 (m, 2H), 4.09 (d, J¼12.8 Hz, 1H), 3.71 (d,
J¼12.8 Hz, 1H), 3.32 (d, J¼2.0 Hz, 1H), 2.53–2.71 (m, 4H), 2.22–2.29
Acknowledgements
(m, 2H), 1.40–1.92 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 216.1, 147.0,
Financial support was provided by the Oregon State University
(OSU) Venture Fund. National Science Foundation (CHE-0722319)
and the Murdock Charitable Trust (2005265) are acknowledged
for their support of the NMR facility. We thank We thank Dr. Lev
N. Zakharov (OSU and University of Oregon) for X-ray crystallo-
graphic analysis of compound 14b Professor Max Deinzer and Dr.
139.8, 134.1, 130.9, 128.64, 128.59, 128.46, 127.3, 119.9, 117.6, 68.5,
51.7, 47.0, 46.5, 40.44, 40.35, 32.1, 21.8, 20.9; HRMS (CIþ) calcd for
C24H26BrNO (Mþ), 423.1198, found 423.1217.
4.17. 6-(Allylamino)-5-methyl-5-phenyl-bicyclo[2.2.2]octan-
2-one (16h)
´
Jeff Morre (OSU) for mass spectra data. Finally, we are grateful to
Dr. Roger Hanselmann (Rib-X Pharmaceuticals) and Dr. Paul
Ha-Yeon Cheong (OSU) for their helpful discussions.
Reaction time 3 d, rt. Purified by chromatography over silica gel,
eluting with 2–7% EtOAc/hexanes, to give the bicycle 16h (44.6 mg,
66%, 88.8:11.2 er, >20:1 dr, colorless oil). Enantiomeric excess was
determined by chiral HPLC [4.6ꢂ250 mm Daicel OD column, 98:2
Supplementary data
hexanes/i-PrOH, 0.8 mL minꢁ1, retention times 14.5 min (major)
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.01.094.
23
and 16.1 min (minor)] to be 88.8:11.2 er: [
a]
ꢁ9.5 (c 1.5, CHCl3); IR
D
(neat) 3330, 2949, 1718, 1440, 1233, 1108, 923, 754, 700 cmꢁ1
;
1H
7.53 (d, J¼7.6 Hz, 2H), 7.35 (t, J¼7.6 Hz,
NMR (400 MHz, CDCl3)
d
References and notes
2H), 7.23 (t, J¼7.2 Hz, 1H), 5.94–6.04 (m, 1H), 5.24 (d, J¼17.2 Hz, 1H),
5.14 (d, J¼10.0 Hz, 1H), 3.53 (dd, J¼13.6, 5.6 Hz, 1H), 3.49 (d,
J¼1.6 Hz, 1H), 3.25 (dd, J¼13.6, 6.0 Hz, 1H), 2.59–2.69 (m, 3H), 2.27
(dd, J¼19.6, 2.8 Hz, 1H), 1.40–1.83 (m, 5H), 1.20 (s, 3H); 13C NMR
1. Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.; Sun, H.-D.; Li, M.-L. l;
Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org. Lett. 2004, 6, 4327–4330.
2. Uchida, I.; Ando, T.; Fukami, N.; Yoshida, K.; Hashimoto, M.; Tada, T.; Koda, S.;
Morimoto, Y. J. Org. Chem. 1987, 52, 5292–5293.
3. Lim, S.-H.; Sim, K.-M.; Abdullah, Z.; Hiraku, O.; Hayashi, M.; Komiyama, K.; Kam,
T.-S. J. Nat. Prod. 2007, 70, 1380–1383.
(100 MHz, CDCl3)
d 216.6, 150.3, 136.9, 128.4, 125.9, 125.7, 116.3,
66.1, 50.1, 46.5, 44.5, 41.2, 37.1, 25.2, 21.6, 21.2; HRMS (CIþ) calcd for
C18H24NO (Mþ1), 270.1858, found 270.1849.
4. (a) Yang, H.; Carter, R. G. Org. Lett. 2008, 10, 4649–4652; (b) Yang, H.; Carter, R.
G. J. Org. Chem. 2009, 74, 2246–2249.
5. Yang, H.; Carter, R. G. J. Org. Chem. 2009, 74, 5151–5156.
6. Otani, G.; Yamada, S.-I. Chem. Pharm. Bull. 1973, 21, 2112–2118.
7. (a) Zheng, H.-J.; Chen, W.-B.; Wu, Z.-J.; Deng, J.-G.; Lin, W.-Q.; Yuan, W.-C.;
Zhang, X.-M. Eur. J. Chem. 2008, 14, 9864–9867; (b) Fukuyama, T.; Frank, R. K.;
Jewell, C. F., Jr. J. Am. Chem. Soc. 1980, 102, 2122–2123.
4.18. 5-Methyl-5-phenyl-6-(propargylamino)-
bicyclo[2.2.2]octan-2-one (16i)
8. (a) Li, H.; Wang, J.; E-Nunu, T.; Zu, L.; Jiang, W.; Wei, S.; Wang, W. Chem.
Commun. 2007, 507–509; (b) Carlson, E. K.; Rathbone, L. K.; Yang, H.; Collett, N.
D.; Carter, R. G. J. Org. Chem. 2008, 73, 5155–5158.
9. (a) Zdansky, G. Arkiv foer Kemi 1955, 7, 577–581; (b) Selva, M.; Tundo, P. J. Org.
Chem. 1998, 63, 9540–9544; (c) Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem.
Soc. 2006, 128, 13074–13075; (d) Baumann, T.; Vogt, H.; Bra¨se, S. Eur. J. Org.
Chem. 2007, 266–282.
Reaction time 3 d, rt. Purified by chromatography over silica gel,
eluting with 2–8% EtOAc/hexanes, to give the bicycle 16i (42.2 mg,
63%, 92.8:7.2 er, >20:1 dr, colorless oil). Enantiomeric excess was
determined by chiral HPLC [4.6ꢂ250 mm Daicel AD column, 98:2
hexanes/i-PrOH, 1.0 mL minꢁ1, retention times 16.3 min (major)
23
and 19.6 min (minor)] to be 86% er: [
a
]
ꢁ29.2 (c 1.4, CHCl3); IR
D
10. Hobbs, D. W.; Guo, T.; Hunter, R. C.; Gu, H. Application: WO 2002-US8300
20020319.
(neat) 2943, 2878, 1718, 1113, 765, 705 cmꢁ1 1H NMR (400 MHz,
;