Highly stereoselective and scalable synthesis of trans -fused octahydrocyclohepta[ b ]pyrrol-4(1 H)-ones via the aza-Cope-Mannich rearrangement in racemic and enantiopure forms

Article abstract of DOI:10.1021/jo301762a

We have developed an efficient and stereoselective route to trans-fused octahydrocyclohepta[b]pyrrol-4(1H)-ones. The key features of our synthesis include the regioselective epoxide ring-opening of alkynyl oxiranes and a stereoselective aza-Cope-Mannich r

Full text of DOI:10.1021/jo301762a

Article
pubs.acs.org/joc
Highly Stereoselective and Scalable Synthesis of trans-Fused
Octahydrocyclohepta[b]pyrrol-4(1H)‑ones via the Aza-Cope−
Mannich Rearrangement in Racemic and Enantiopure Forms
Dmitry S. Belov, Evgeny R. Lukyanenko, Alexander V. Kurkin,* and Marina A. Yurovskaya
Department of Chemistry, Lomonosov Moscow State University, 1/3 Leninsky Gory, Moscow, 119991, Russia
S
* Supporting Information
ABSTRACT: We have developed an efficient and stereo-
selective route to trans-fused octahydrocyclohepta[b]pyrrol-
4(1H)-ones. The key features of our synthesis include the
regioselective epoxide ring-opening of alkynyl oxiranes and a
stereoselective aza-Cope−Mannich reaction. The target com-
pounds were prepared in 3−6 steps from commercially available starting materials (61−75% overall yield) with minimal
chromatographic purification. We have devised an stereoselective route to target compounds using Shi epoxidation or (R)-1-
phenylethylamine as a source of chirality.
INTRODUCTION
■
Recently, most players in the pharmaceutical industry working
on small molecule drug discovery have focused their efforts on
enriching the newly designed drug prototype with sp3-
hybridized carbon atoms, as their goal was to bring the
chemotypes closer to natural products and to boost chemo-
types’ three-dimensional properties.1
However, the reaction portfolio currently available to the
pharmaceutical industry lacks solid synthetic methodologies to
produce compound libraries of natural product-like molecules
for screening purposes.2 Furthermore, the synthetic approaches
commonly used for small molecule compound libraries often
miss a stereocontrolled bond formation. Conversely, most
natural products do have well stereodefined structural features.
Hence, the implementation of a robust and stereocontrolled
methodology to build a saturated heterocyclic fused system
such as the cycloalkano[b]fused pyrrolidines may serve to
improve the reaction tools available to a chemist, as these
scaffolds are well represented among drugs and natural
products (Figure 1).3
Figure 1. Representative examples of cycloalkano[b]pyrrolidine-
containing natural products.
Since Overman’s first report in 1979, the aza-Cope−Mannich
rearrangement has become a powerful tool for the construction
of various substituted pyrrolidines including complex natural
products.3,4 If the starting amino alcohol is cyclic, this
transformation provides ring-enlarged pyrrolidine annulated
products (Figure 2).5−7 Because of the restricted conforma-
tional freedom in the transition state, this variant of the aza-
Cope−Mannich reaction occurs without loss of enantiomeric
purity of the starting amino alcohol and typically exhibits
excellent stereoselectivity.7e
Although the preparation of octahydrocyclohepta[b]pyrrol-
4(1H)-ones with cis-fused seven-membered and pyrrolidine
rings has been studied in great detail,7 few analogues with trans-
stereochemistry at the ring junction have been reported.
Overman described the preparation of trans-octahydro-
cyclohepta[b]pyrrol-4(1H)-ones as mixtures with the cis-
Figure 2. General scheme for cycloalkano[b]fused pyrrolidine
formation via the aza-Cope−Mannich reaction (* chiral center).
isomers.6b,e,7a,c This stereochemistry can also be accessed via
the selective epimerization of the C-3a stereocenter (Figure
3).7e The major drawbacks of these methods are the need for
the laborious chromatographic separation of diastereomeric
mixtures and the low overall efficiency.
In an earlier study, we found that the treatment of
unsaturated amino alcohols 1a and 1b with CH2O at ambient
temperature results in a mixture of oxazolidine 2 and trans-
Received: August 17, 2012
Published: October 31, 2012
© 2012 American Chemical Society
10125
dx.doi.org/10.1021/jo301762a | J. Org. Chem. 2012, 77, 10125−10134

The Journal of Organic Chemistry
Article
Scheme 1. Construction of Cyclohepta[b]pyrrol Core via the Aza-Cope−Mannich Reaction8
Scheme 2. Rationalization of the trans-Cyclohepta[b]pyrrol Formation
such systems, most of these methods are based either on the
reactions between α-amino ketones and vinyl lithium6,10 or
cerium3d,e,8 reagents or are based on vinyl epoxide ring-
openings.3a,b,4,6c,9 However, in general, organometallic addition
favors cis-amino alcohols,3 and vinyl epoxide ring-openings tend
to give allyl amines rather than allyl alcohols.11,12 To develop a
general method for this class of compounds, we proposed that
2-vinyl amino alcohols 9 could arise from the reduction of 1-
alkynyl 2-amino alcohols 10. In turn, 10 could be easily
prepared by the Lewis acid-promoted, regioselective epoxide
ring-opening of known oxiranes 11 (Figure 4).12−15
To test the viability of this method, we synthesized alkynyl
oxirane 14 using a previously described three-step procedure.13
The addition of a lithium phenylacetylenide species to
cyclohexanone smoothly delivered the propargyl alcohol 12
(82%), which was then dehydrated through the action of
POCl3 in pyridine to afford alkene 13 in 90% yield. The
Figure 3. Earlier work on the syntheses of trans-octahydrocyclohepta-
[b]pyrrol-4(1H)-ones.
fused β-amino ketone 3a (Scheme 1).8 Given that the ratio of 2
to 3a is also that of 1a to 1b and pure 1a only yielded 2 under
these conditions, we deduced that that the β-amino ketone 3a
arose from the trans-amino alcohol 1b. The observed
stereoselectivity was attributed to the preferred transition
state 5, which minimizes unfavorable interactions between the
N-alkyl substituent and the cyclohexane ring (Scheme 2). This
result and the mechanistic considerations suggest that an
appropriately substituted trans-amino alcohol 4 would lead
exclusively to trans-amino ketone 7. Herein, we report the
concise and highly stereocontrolled synthesis of trans-
octahydrocyclohepta[b]pyrrol-4(1H)-ones.
RESULTS AND DISCUSSION
■
Preparation of trans-3a-Phenyloctahydrocyclohepta-
[b]pyrrol-4(1H)-ones. Our synthetic studies began by
preparing the starting amino cyclohexanol with the requisite
trans relationship between the amino and alcohol groups.
Although many methods are available for the construction of
Figure 4. Retrosynthetic analysis.
10126
dx.doi.org/10.1021/jo301762a | J. Org. Chem. 2012, 77, 10125−10134

The Journal of Organic Chemistry
Article
Scheme 3
epoxidation of 13 with mCPBA in dichloromethane at 0 °C
furnished epoxide 14 in quantitative yield (67% overall yield
from the starting cyclohexanone). Using a cerium(III)-
mediated addition in the first step16 and MsCl-Et3N17 for
dehydration in the second step allowed us to increase the
overall yield of 14 to 95% (Scheme 3).
The reaction of 17 with an excess of formalin and 0.9 equiv
of camphorsulfonic acid (CSA) in methylene chloride at room
temperature gave 18 in a quantitative yield as the sole product
(Scheme 3). The structure of 18 was unambiguously confirmed
by X-ray crystallographic analysis.19 Reducing the amount of
CSA to 0.3 equiv increased the reaction time only slightly and
did not change the yield. After the addition of all the reactants,
TLC indicates the immediate consumption of the starting
material 17 and only a slow formation of 18. This result led us
to propose an open hemiaminal as the intermediate, in contrast
to the stable oxazolidine, which is formed with cis-amino
alcohols.3b,8 Debenzylation under hydrogenolytic conditions
furnished β-amino ketone 19 as HCl salt.
We next examined various factors that may influence the
stereochemical outcome of the aza-Cope−Mannich reaction.
The nature of the solvent affects the stereoselection in this type
of a molecular rearrangement.6c,e,7c However, 18 was the only
product formed in polar, aprotic solvents (CH2Cl2, DMSO,
DMF and THF). Running the reaction in solvents with low
dielectric conductivity (benzene, dioxane, EtOAc) or EtOH
resulted in complex mixtures containing varying amounts of the
starting material and the products of its dehydration.
The LiClO4-meditated epoxide ring-opening15 of 14 using 2
equiv of benzylamine gave amino cyclohexanol 15 and a small
amount of regioisomeric product 16 (8−10%). Pure 15 was
isolated in 65% yield following the recrystallization of its HBr
salt from ethanol:methyl tert-butyl ether (MTBE) 1:1 mixture.
Initial attempts to reduce propargyl alcohol 15 using LiAlH4
in THF resulted in a mixture containing the desired product 17,
overreduced product 17a and pyrrole 17b, the product of 5-
endo-dig cyclization (Scheme 4). Alternatively, employing
NaAlH2(OCH2OCH3)2 (Red-Al) in Et2O gave E-alkene 17
in a 90% yield after chromatographic purification (Scheme 3).18
Scheme 4
We further investigated whether the stereochemical outcome
of the reaction could be controlled by the size of the substituent
on nitrogen6c,7c (Scheme 2). N-Allyl and N-Me 22 and 23
amino alcohols were prepared by the epoxide ring-opening of
14 followed by alkyne reduction (Scheme 5). Amino alcohol
24, containing an unsubstituted nitrogen functionality, was
prepared by the Pd-catalyzed deallylation20 of 22 in 80% yield.
The aza-Cope−Mannich rearrangement of 22 under the
same conditions as for 17 (0.3 equiv of CSA, CH2O, DCM)
gave trans-amino ketone 25 in an 82% yield. N-Me amino
alcohol 23 could be completely consumed only after using 0.9
equiv of CSA, furnishing pure N-Me amino ketone 26 in 90%
yield. N-Unsubstituted amino alcohol 24 produced a complex
mixture under the reaction conditions (0.9 equiv of CSA,
CH2O, CH2Cl2 or HBr salt, CH2O, DMSO), which contained a
small amount of trans-ketone 19 (LC−MS and 13C NMR). The
formation of the trans-fused product was confirmed by a
comparison of the NMR spectra of 25 and 26 with those of 18
For large-scale preparations of 17 (>10 g), this two-step
procedure was simplified to avoid column chromatography.
The crude mixture containing 15 was separated from the
benzylamine using a short silica pad and subsequently reduced
using Red-Al (Et2O, −10 °C). Following an aqueous workup,
the crude residue was dissolved in ethanol−MTBE (1:1) and
acidified with aqueous HBr to pH 5. Pure 17 (>95%) was
crystallized out as its HBr salt with a 65% yield in two steps.
Thus, the final optimized route to 17, the starting material for
the aza-Cope−Mannich rearrangement, furnished the target
compound in five steps from cyclohexanone with only one
chromatographic purification step in 61% overall yield. The
experimental simplicity of this route allowed us to prepare 17
on a half-mole scale.
10127
dx.doi.org/10.1021/jo301762a | J. Org. Chem. 2012, 77, 10125−10134

The Journal of Organic Chemistry
Article
a
Scheme 5
a
Reagents and conditions: (a) AllylNH2, LiClO4, MeCN, 65 °C, 87%; (b) MeNH2, MeOH−H2O, 50 °C, 92%; (c) [Pd(PPh3)2]Cl2 1%, N,N′-
dimethylbarbituric acid, CH2Cl2, 61%.
and 19. In particular, the 1H NMR spectra displayed
characteristic signals at ∼3.2 ppm (dd, H-3a), ∼3.9 ppm
(ddd, H-3) and 2.0−2.6 ppm (ddd, H-8a) with typical coupling
constant values of 9.6−10.8 Hz for H-3a−H-8a and 5.5−6.9 Hz
for the H-3−H-3a pair. Additionally, the reductive amination
(CH2O, HCOOH) of 19 gave 26 as the only product.
These results indicate that the nature of the solvent or the
substituent at the nitrogen atom has little impact on the
stereochemical outcome of the aza-Cope−Mannich reaction
(Scheme 2, Path A). However we show that bulky alkyl groups
greatly simplify the purification of amino ketones and increase
their stability (e.g., pure 18 was obtained on the 0.5 molar scale
following an aqueous 5% K2CO3 workup of the reaction
mixture). Also benzyl N-protecting group was chosen because
of the ease of its installation and removal.
conditions, likely as a result of the steric shielding of the C3a α-
ketone center by the neighboring phenyl group.
Preparation of Enantiomerically Pure trans-3a-
Phenyloctahydrocyclohepta[b]pyrrol-4(1H)-one Deriva-
tives. Since in natural products and drug synthesis, it is often
necessary to access single enantiomers, stereoselective routes
are highly desirable.
The epoxide ring-opening of 14 by chiral (R)-1-phenyl-
ethylamine3b,22 resulted in a ∼1:1 mixture of diastereomers 32
and 33 in a 78% combined yield (Scheme 7), which were
readily separable by column chromatography and were
characterized by X-ray crystallographic analysis (as HBr
salts).23 In cases of incomplete chromatographic separation,
pure 32 and 33 could be obtained following recrystallizations of
To test the versatility of our approach, we synthesized amino
ketone 31 without the C3 phenyl group (Scheme 6). The ring-
Scheme 7. Stereoselective Synthesis Using a Chiral
Auxiliary
a
Scheme 6
opening of the commercially available oxirane 28 furnished
amino alcohol 29 in 80% yield. The Red-Al18 reduction of 29 in
THF resulted in 30, albeit in low yield (10−15%). Hydro-
genation using the Lindlar catalyst significantly improved the
yield of 30. Treatment of 30 with formalin in the presence of
CSA (0.9 equiv) gave the desired trans-amino ketone 31 in a
93% yield. A comparison of the 1H NMR spectrum of crude 31
and a separately prepared cis-isomer21 of 31 indicated that no
cis-isomer is formed during the aza-Cope−Mannich rearrange-
ment of 30. These transformations (28 to 31) were routinely
performed on a 1 molar scale.
In addition, amino ketones 31 and 18 do not epimerize
under the reaction conditions or upon storage. However, under
the action of strong base (NaOMe in MeOH), enantiopure 31
was converted to a 5:2 mixture of its cis/trans-isomers.7e
Compound 18 was recovered unchanged under the same
a
Reagents and conditions: (a) NaAlH2(OCH2OCH3)2, THF, 0 °C;
(b) CSA, 2.2 equiv CH2O, CH2Cl2, Na2SO4; (c) H2, 1 atm, 10% Pd/
C, EtOH, HCl.
10128
dx.doi.org/10.1021/jo301762a | J. Org. Chem. 2012, 77, 10125−10134

The Journal of Organic Chemistry
Article
their HBr salts from ethanol-MTBE (1:1). Additionally, no
product of the C-1 epoxide ring-opening was observed, which is
attributed to the increased steric bulk surrounding the amine.
The reduction of 32 and 33 using Red-Al furnished allyl
alcohols 34 (93%) and 35 (90%), which were readily
crystallized from ethanol−MTBE as their HBr salts. A
subsequent aza-Cope−Mannich reaction gave ketones 36 and
37 in a quantitative yield. Their configurations were verified by
X-ray analysis and matched those predicted by the mecha-
nism.24,25 The hydrogenation of 36 and 37 under acidic
conditions completed the preparation of enantiopure ketones
19 in 83 and 93% yields after recrystallization (ee >95%, as
determined by 19F NMR of (R)-Mosher amide). These
compounds exhibit opposite signs of optical rotations with
EXPERIMENTAL SECTION
■
Compounds 12−14 were synthesized using procedures from ref 13.
For modified procedures, see ref 8 (CeCl3) and ref 17 (MsCl−Et3N).
1-(Phenylethynyl)cyclohexanol (12). Data: mp = 61.0−61.6 °C
(hexane); 1H NMR (CDCl3, 400 MHz) δ = 1.22−1.36 (m, 1H),
1.54−1.79 (m, 7H), 1.96−2.07 (m, 2H), 2.18 (br. s., 1H), 7.26−7.36
(m, 3H), 7.40−7.48 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ = 23.4
(2 C), 25.2, 40.1 (2C), 69.1, 84.4, 92.8, 122.9, 128.2 (2 C), 128.3,
131.7 (2C). Anal. Calcd for C14H16O: C, 83.96; H, 8.05. Found: C,
84.25; H, 8.18.
(Cyclohex-1-en-1-ylethynyl)benzene (13). Data: bp = 130 °C
1
(1 Torr.); H NMR (CDCl3, 400 MHz) δ = 1.62−1.74 (m, 4H),
2.13−2.21 (m, 2H), 2.22−2.29 (m, 2H), 6.21−6.27 (m, 1H), 7.27−
7.36 (m, 3H), 7.42−7.47 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ =
21.5, 22.4, 25.8, 29.3, 86.8, 91.3, 120.7, 123.8, 127.7, 128.2 (2C), 131.4
(2C), 135.2. Anal. Calcd for C14H14: C, 92.26; H, 7.74. Found: C,
92.32; H, 7.63.
the same magnitude ([α]D23
=
2.3, c = 1, MeOH).
Thus, the routes to both enantiomers of 19 consist of 7 steps
from the starting cyclohexanone with only one chromato-
graphic purification to furnish the desired products with 18−
19% overall yields. The bottleneck of this sequence is the
epoxide ring-opening and subsequent separation of the
diastereomers; however, it was routinely performed on a 100
mM scale.
1
1-(Phenylethynyl)-7-oxabicyclo[4.1.0]heptane (14). Data: H
NMR (CDCl3, 400 MHz) δ = 1.26−1.52 (m, 4H), 1.95−2.01 (m,
2H), 2.09−2.17 (m, 1H), 2.23−2.31 (m, 1H), 3.47 (t, J = 2.4 Hz, 1H),
7.29−7.34 (m, 3H), 7.44−7.47 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ = 18.9, 19.5, 24.2, 29.8, 50.7, 60.4, 82.0, 89.7, 122.3, 128.3
(2C), 128.5, 131.8 (2C). Anal. Calcd for C14H14O: C, 84.81; H, 7.12.
Found: C, 84.61; H 7.28.
General Procedure for Epoxide Opening (Procedure A). To a
vigorously stirred solution of epoxide (14 or 28) (10 mmol) and
amine (15−30 mmol) in MeCN (10 mL), LiClO4 (15 mmol) was
added in one portion. The reaction mixture was warmed at 50−60 °C
until the consumption of the starting epoxide occurred (reaction
monitored by TLC, typically 5−10 h). The reaction mixture was then
allowed to cool to ambient temperature, poured into water (50 mL)
and extracted with CH2Cl2 (3 × 50 mL). The combined extracts were
dried over Na2SO4 and concentrated. The residue was purified by
column chromatography (10:1 hexane−EtOAc) to give colorless or
slightly yellow oils.
Next we investigated the preparation of the enantiopure
ketone 31. Initial attempts to use the same method as for 19
failed. The epoxide opening of 28 followed by reduction using a
Lindlar catalyst and the aza-Cope−Mannich reaction produced
a 1:1 mixture of inseparable diastereomers for all three steps.
However, epoxide 28 could be readily accessed by an
asymmetric Shi epoxidation of the respective alkene in 98%
ee,26 which in turn arose from the commercially available
propargyl alcohol 27 (Scheme 6).14 Employing the reaction
conditions used for rac-31 synthesis resulted in (−)-31 without
loss of optical purity. This method allows only moderate scaling
up of the reaction (up to several grams of (−)-31), as Shi
epoxidation requires high dilution and long reaction times to
reach full conversion.27
General Procedure for the Synthesis of HBr Salts of
Aminoethanols. To a solution of compound 15 (17 or 32−35) (1
g) in ethanol (5 mL), aqueous HBr (48 wt %) was added until the pH
was ∼4 (∼0.42 mL). The mixture was left undisturbed until the first
crystallization occurred (0.5−1 h). Then, 15 mL of MTBE was added,
and the resulting suspension was cooled in the freezer for 24 h. The
precipitate was filtered and subsequently washed with 20 mL of
MTBE:EtOH 10:1 mixture and 20 mL of MTBE. Yield 90−100%.
(1RS,2SR)- 2-(Benzylamino)-1-(phenylethynyl)cyclohexanol
(15). Compound 15 was synthesized by the general procedure A
from epoxide 14 (32.0 g) and benzylamine (2 equiv) at 60 °C, and
isolated as yellow oil (38.5 g, 78%) alone with a small amount of 16
(8%, 3.9 g) and then recrystallized as as a HBr salt (40.5 g, 65%). Rf =
0.6 (hexane−EtOAc, 5:1). Free base: 1H NMR (CDCl3, 400 MHz) δ
= 1.23−1.47 (m, 3H), 1.52−1.63 (m, 1H), 1.65−1.89 (m, 3H), 2.23
(td, J = 13.6, 2.0 Hz, 1H), 2.49 (dd, J = 11.0, 3.3 Hz, 1H), 3.77 (d, J =
13.1 Hz, 1H), 4.07 (d, J = 13.1 Hz, 1H), 4.45 (br. s., 1H), 7.27−7.50
(m, 10H); 13C NMR (CDCl3, 100 MHz) δ = 23.4, 25.3, 29.0, 38.2,
50.8, 65.1, 72.3, 86.2, 90.4, 122.9, 127.1, 128.2 (2C), 128.3 (2C), 128.5
(2C), 131.7 (2C), 140.4; IR νmax (KBr) 3464, 3060, 3028, 2933, 2856,
1490, 1452, 1371, 1070, 756, 694 cm−1; m/z (Irel, %) 305 (M+, 7), 129
(38), 115 (25), 92 (28), 91 (100), 65 (41).
CONCLUSION
■
Thus, we developed a simple high stereoselectivity and high
efficiency synthesis of trans-fused octahydrocyclohepta[b]-
pyrrol-4(1H)-ones. Its key processes are as follows: (1) high
efficiency 3−5 step preparation of N-benzyl-trans-1-alkenyl-2-
aminocyclohexanones from commercially available reagents via
1-alkynyl-oxirane ring-opening with appropriate amines fol-
lowed by partial reduction of the triple bond (61−75% overall
yield with one chromatographic purification for all the steps);
and (2) the aza-Cope−Mannich reaction of these compounds
with formalin proceeding in very high yields and complete
stereoselectivity. All the steps of this synthesis are simple and
easily scalable up to 0.5−1 mol with the use of standard
laboratory equipment. We showed the possibility of applying
this technology for obtaining individual enantiomers with the
use of chiral 1-phenylethylamine at the epoxide ring-opening
step followed by chromatographic separation of the diastereo-
meric alcohols. In cases where using the chiral 1-phenylethyl-
amine is ineffective due to inseparability of the diastereomeric
mixtures of the intermediate amino alcohols, the developed
approach enables obtaining small amounts (up to several
grams) of individual enantiomers by using the Shi asymmetric
epoxidation. To the best of our knowledge, this is the only
example of a completely trans-selective aza-Cope−Mannich
reaction.
1
HBr salt: mp = 194.2−194.6 °C (Ethanol); H NMR (DMSO-d6,
400 MHz) δ = 1.03−1.21 (m, 1H), 1.38−1.55 (m, 2H), 1.55−1.69 (m,
2H), 1.69−1.81 (m, 1H), 1.97−2.10 (m, 1H), 2.10−2.24 (m, 1H),
2.71 (d, J = 10.5 Hz, 1H), 4.27 (s, 2H), 6.50 (br.s., 1H), 7.35−7.51 (m,
6H), 7.51−7.68 (m, 4H), 8.70 (br.s., 1H), 9.02 (br.s., 1H); 13C NMR
(DMSO-d6, 100 MHz) δ = 23.2, 23.8, 25.8, 40.3, 48.7, 63.0, 69.8, 88.0,
88.2, 122.2, 129.1 (2C), 129.3 (2C), 129.5, 129.6, 130.8 (2C), 131.7,
132.2 (2C); m/z (Irel, %) 305 (MH+, 5), 258 (6), 214 (5), 196 (5),
132 (5), 129 (12), 115 (8), 92 (7), 91 (100), 77 (7), 65 (16), 56 (5),
41 (8), 39 (7); IR νmax (KBr) 3325 (br.), 2935, 2864, 2808, 1564,
1425, 1404, 1070, 1034, 752, 702, 688 cm−1. Anal. Calcd for
C21H24NOBr: C, 65.29; H, 6.26; N, 3.63. Found: C, 65.23; H, 6.17; N,
3.70.
10129
dx.doi.org/10.1021/jo301762a | J. Org. Chem. 2012, 77, 10125−10134

The Journal of Organic Chemistry
Article
(1RS,2SR)-2-(Benzylamino)-2-(phenylethynyl)cyclohexanol
z (Irel, %) 319 (M+, 18), 304 (11), 214 (17), 197 (11), 196 (23), 169
(31), 156 (12), 129 (26), 115 (13), 105 (100), 103 (15), 91 (13), 79
(20), 77 (24); IR νmax (KBr) 3456, 2931, 1491, 1450, 1369, 1117,
1063, 756, 704 cm−1. Anal. Calcd for C22H25NO: C, 82.72; H, 7.89; N,
4.38. Found: C, 82.92; H, 8.14; N, 4.44.
1
(16). Data: H NMR (DMSO-d6, 400 MHz) δ = 1.26−1.48 (m, 2H),
1.60−1.85 (m, 4H), 1.92−2.00 (m, 1H), 2.19 (br.s., 2H), 2.24−2.31
(m, 1H), 3.51 (dd, J = 11.2, 4.1 Hz, 1H), 3.90 (d, J = 12.1 Hz, 1H),
4.09 (d, J = 12.1 Hz, 1H), 7.24−7.56 (m, 10H); 13C NMR (DMSO-d6,
100 MHz) δ = 22.7, 24.3, 32.1, 35.5, 48.0, 62.0, 65.0, 76.2, 88.0, 89.3,
123.0, 127.0, 128.3, 128.4 (2C), 128.5 (4C), 131.8 (2C), 140.8.
(1RS,2SR)-2-(Allylamino)-1-(phenylethynyl)cyclohexanol
(20). Compound 20 was synthesized by the general procedure A from
epoxide 14 (4.40 g) and allyl amine (3 equiv) at 50 °C, and isolated as
HBr salt: mp = 258.9−259.6 °C; [α]2D3 = −75.5 (c = 1.0, MeOH);
1H NMR (DMSO-d6, 400 MHz) δ = 0.96−1.12 (m, 1H), 1.29−1.40
(m, 1H), 1.55−1.78 (m, 3H), 1.68 (d, J = 6.7 Hz, 3H), 2.03 (d, J =
12.3 Hz, 1H), 2.09−2.19 (m, 1H), 2.50−2.56 (m, 1H), 3.35 (s, 1H),
4.60−4.71 (m, 1H), 6.37 (s, 1H), 7.40−7.50 (m, 6H), 7.54−7.60 (m,
2H), 7.61−7.66 (m, 2H), 8.63 (br. s, 1H), 8.79 (br. s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ = 20.4, 23.2, 24.0, 25.8, 40.4, 56.2, 63.4, 69.6,
87.9, 88.3, 122.3, 128.4 (2 C), 129.1 (2 C), 129.5 (2 C), 132.2 (2 C),
137.4. Anal. Calcd for C22H26NOBr: C, 66.00; H, 6.55; N, 3.50.
Found: C, 66.02; H, 6.48; N, 3.55.
1
colorless oil (4.90 g, 87%): H NMR (CDCl3, 400 MHz) δ = 1.12
(br.s., 1H), 1.27−1.36 (m, 2H), 1.56 (td, J = 12.2, 4.8 Hz, 1H), 1.66−
1.87 (m, 3H), 2.07−2.19 (m, 1H), 2.24 (dq, J = 8.1, 3.0 Hz, 1H), 2.41
(dd, J = 11.1, 3.8 Hz, 1H), 3.22 (ddt, J = 14.3, 5.9, 1.4 Hz, 1H), 3.51
(ddt, J = 14.3, 5.9, 1.4 Hz, 1H), 4.41 (br.s., 1H), 5.12 (dq, J = 10.2, 1.4
Hz, 1H), 5.23 (dq, J = 17.2, 1.6 Hz, 1H), 5.93 (dddd, J = 17.1, 10.3,
6.0, 6.0 Hz, 1H), 7.30−7.35 (m, 3H), 7.43−7.49 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ = 23.4, 25.2, 29.1, 38.1, 49.4, 65.0, 72.7, 86.1,
90.3, 115.9, 122.9, 128.2 (2 C), 128.2 (2 C), 131.7, 137.3; IR νmax
(KBr) 3437 (br), 2933, 2858, 1489, 1444, 1369, 1072, 918, 756, 692
cm−1; m/z (Irel, %) 255 (M+, 19), 214 (25), 196 (50), 129 (50), 115
(43), 96 (42), 83 (30), 82 (44), 70 (65), 68 (87), 56 (52), 55 (33), 41
(100), 39 (50). Anal. Calcd for C17H21NO: C, 79.96; H, 8.29; N, 5.49.
Found: C, 80.01; H, 8.01; N, 5.50.
(1S,2R)-2-{[(1R)-1-Phenylethyl]amino}-1-(phenylethynyl)-
cyclohexanol (33) Free base. Colorless viscous oil: [α]2D3 = +33.6 (c
= 0.72, MeOH); Rf 0.55 (hexane−EtOAc, 5:1); 1H NMR (CDCl3, 400
MHz) δ = 0.86−0.95 (m, 1H), 1.23−1.35 (m, 3H), 1.39 (d, J = 6.2
Hz, 3H), 1.55−1.84 (m, 4H), 1.90−2.00 (m, 1H), 2.22−2.33 (m, 1H),
2.50−2.65 (m, 1H), 3.98 (q, J = 6.4 Hz, 1H), 7.25−7.47 (m, 10H);
13C NMR (CDCl3, 100 MHz) δ = 23.4, 23.6, 25.4, 29.7, 38.3, 55.1,
63.7, 72.3, 86.2, 90.4, 122.9, 126.5 (2C), 127.2, 128.2 (2C), 128.6
(2C), 131.8 (2C), 146.6; m/z (Irel, %) 319 (M+, 18), 304 (10), 301
(16), 214 (16), 197 (27), 196 (24), 169 (37), 129 (31), 115 (15), 105
(100), 103 (22), 91 (16), 79 (29), 77 (34), 56 (12); IR νmax (KBr)
3456 (br), 2931 (br), 2856, 1491, 1444, 1371, 1109, 1057, 756, 700
cm−1. Anal. Calcd for C22H25NO: C, 82.72; H, 7.89; N, 4.38. Found:
C, 82.65; H, 7.95; N, 4.29.
(1RS,2SR)-2-(Methylamino)-1-(phenylethynyl)cyclohexanol
(21). Epoxide 14 (1.00 g) was dissolved in methanol (10 mL), and
aqueous methylamine was added (10 mL). The reaction mixture was
warmed at 50 °C until the consumption of the starting epoxide
occurred (reaction monitored by TLC, 10 h). The reaction mixture
was evaporated and purified via silica gel flash column chromatography
using DCM:EtOH (20:1). Yield: 92%, 1.06 g (sum of regioisomers,
HBr salt: mp = 193.3−193.7 °C; [α]2D3 = +33.8 (c = 1.0, MeOH);
1H NMR (DMSO-d6, 400 MHz) δ = 1.03−1.19 (m, 1H), 1.41−1.57
1
∼5:1 in favor to desired); mp = 82−83 °C; H NMR (CDCl3, 400
(m, 1H), 1.57−1.73 (m, 5H), 1.70 (d, J = 6.8 Hz, 3H), 2.10 (d, J =
12.5 Hz, 1H), 3.01−3.10 (m, 1H), 3.36 (s, 1H), 4.52 (q, J =6.1 Hz,
1H), 6.42 (s, 1H), 7.38−7.48 (m, 6H), 7.51−7.55 (m, 1H), 7.68−7.73
(m, 2H), 8.64 (br. s, 1H), 8.93 (br. s, 1H); 13C NMR (DMSO-d6, 100
MHz) δ = 19.9, 23.2, 24.0, 27.9, 40.5, 59.3, 65.9, 70.2, 88.0, 88.3,
122.3, 128.9 (2C), 129.1 (2C), 129.2 (2C), 129.4, 129.5, 132.1 (2C),
138.1. Anal. Calcd for C22H26NOBr: C, 66.00; H, 6.55; N, 3.50.
Found: C, 66.25; H, 6.40; N, 3.42.
MHz) δ = 1.20−1.33 (m, 2 H), 1.51−1.85 (m, 4 H), 2.10−2.25 (m, 2
H), 2.49 (s, 3 H), 2.51 (CH3 signal of minor isomer), 3.45 (br. s., 1
H), 7.23−7.33 (m, 3 H), 7.40−7.48 (m, 2 H); 13C NMR (CDCl3, 100
MHz) δ = 23.4, 25.1, 28.2, 33.5, 38.5, 67.5, 72.1, 86.2, 90.1, 122.8,
128.2 (3C), 131.7 (2C); IR νmax (KBr) 3062, 2937, 2856, 2802, 1488,
1452, 1103, 1072, 752, 690 cm−1; m/z (Irel, %) 229 (M+, 16), 183
(59), 170 (36), 70 (56), 57 (100), 44 (68), 42 (41). Anal. Calcd for
C15H19NO: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.23; H, 8.22; N,
5.96.
General Procedure for Alkyne Reduction (Procedure B). A
mixture of the amino alcohol 15 (20, 21, 32 or 33) (10 mmol) and 25
mL of Et2O was added dropwise to a solution of RedAl (8.6 mL, 30
mmol) in 25 mL of Et2O at 0 °C. After gas evolution subsided, the
mixture was allowed to warm to room temperature and stirred for 2 h.
Excess hydride was quenched by successive dropwise addition 1 mL of
water, 1.5 mL of 10% NaOH and 1 mL of water to reaction mixture at
−10 °C. The reaction was allowed to warm to room temperature,
stirred for an hour and filtered through a thin pad of silica gel. The
precipitate was washed with THF. The organic layer was then
concentrated to give an oil, which was purified by column
chromatography or redissolved in EtOH to be precipitated as the
HBr salt (see above procedure).
(1RS,2SR)-2-(Benzylamino)-1-[(E)-2-phenylethenyl]-
cyclohexanol (17). Compound 17 was synthesized by the general
procedure B from propargyl alcohol 15 (38.48 g), and isolated as
colorless oil (33.25 g, 86%) or as a white solid (HBr salt, 44.0 g, 90%).
HBr salt: mp = 194.2−194.6 °C; 1H NMR (DMSO-d6, 400 MHz) δ =
1.10−1.24 (m, 1H), 1.45−1.68 (m, 4H), 1.73−1.86 (m, 2H), 2.03−
2.13 (m, 1H), 2.74−2.86 (m, 1H), 4.21 (s, 2H), 5.66 (s, 1H, OH),
6.68 (d, J = 15.8 Hz, 1H), 6.90 (d, J = 15.8 Hz, 1H), 7.22−7.31 (m,
1H), 7.31−7.48 (m, 5H), 7.51−7.63 (m, 4H), 8.17 (br.s., 1H, NH),
8.81 (br.s., 1H, NH); 13C NMR (DMSO-d6, 100 MHz) δ = 22.4, 24.4,
24.7, 40.4, 48.3, 63.8, 72.6, 127.4 (2C), 128.16, 128.22, 129.0 (2 C),
129.2 (2 C), 129.5, 130.8 (2 C), 131.8 (2 C), 137.10; m/z (Irel, %) 307
(MH, 5), 198 (13), 146 (18), 132 (16), 131 (33), 120 (34), 115 (12),
106 (44), 92 (23), 91 (100), 82 (15), 80 (16), 79 (12), 77 (29), 65
(46), 56 (22), 55 (13), 51 (14), 43 (15), 41 (21), 39 (20); IR νmax
(KBr) 3330 (br.), 2943, 2910, 2871, 2802, 1568, 1452, 1425, 978, 970,
746, 702, 688 cm−1. Anal. Calcd for C21H26NOBr: C, 64.95; H, 6.75;
N, 3.61. Found: C, 65.11; H, 6.77; N, 3.75.
(1RS,2SR)-2-(Benzylamino)-1-ethynylcyclohexanol (29).
Compound 29 was synthesized by the general procedure A from
epoxide 28 (20.0 g) and benzylamine (2 equiv) at 60 °C, and isolated
as colorless oil (34.0 g, 91%). For (1R,2S)-2-(benzylamino)-1-
ethynylcyclohexanol: [α]2D3 = +31.1 (c = 1, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ = 1.18−1.52 (m, 4H), 1.55−1.82 (m, 3H),
2.09−2.21 (m, 2H), 2.38 (dd, J = 11.3, 3.8 Hz, 1H), 2.45 (s, 1H), 3.71
(d, J = 13.0 Hz, 1H), 4.01 (d, J = 13.0 Hz, 1H), 4.33 (br. s., 1H),
7.24−7.29 (m, 1H), 7.31−7.38 (m, 4H); 13C NMR (CDCl3, 100
MHz) δ = 23.1, 25.1, 28.7, 37.8, 50.8, 64.7, 71.8, 74.1, 85.2, 127.2,
128.2 (2C), 128.5 (2C), 140.3; IR νmax (KBr) 3465 (br), 3296, 2935,
2858, 1452, 1369, 1095, 1072, 1032, 741, 700 cm−1; m/z (Irel) 229(2
MH+), 138 (9), 132 (11), 120 (9), 92 (12), 91 (100), 65 (26), 53
(18), 53 (18), 41 (14), 39 (18%). Anal. Calcd for C15H19NO: C,
78.56; H, 8.35; N, 6.11. Found: C, 78.47; H, 8.17; N, 6.00.
Compounds 32 and 33 were synthesized by the general procedure
A from epoxide 14 (10.0 g) and (1R)-1-phenylethanamine (1.5 equiv)
at 65 °C, and isolated by means of column chromatography (eluent:
hexane−EtOAc 30:1) as white solid and colorless oil (6.60 g, 41%;
5.97 g, 37%), respectively.
(1R,2S)-2-{[(1R)-1-Phenylethyl]amino}-1-(phenylethynyl)-
cyclohexanol (32). Free base: mp = 85−87 °C; [α]2D3 = −41.9 (c =
1
0.96, MeOH); Rf 0.65 (hexane−EtOAc, 5:1); H NMR (CDCl3, 400
MHz) δ = 1.11−1.22 (m, 1H), 1.26−1.46 (m, 3H), 1.40 (d, J = 6.6
Hz, 3H), 1.61−1.71 (m, 2H), 1.72−1.80 (m, 1H), 2.12−2.23 (m, 3H),
4.04 (q, J = 6.5 Hz, 1H), 4.31 (br. s., 1H), 7.26−7.31 (m, 1H), 7.33−
7.38 (m, 7H), 7.48−7.53 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ =
23.3, 25.1, 25.8, 28.8, 37.9, 54.0, 62.1, 72.2, 86.2, 90.5, 123.0, 126.9
(2C), 127.2, 128.25, 128.29 (2C), 128.6 (2C), 131.8 (2C), 145.10; m/
10130
dx.doi.org/10.1021/jo301762a | J. Org. Chem. 2012, 77, 10125−10134

The Journal of Organic Chemistry
Article
1
Free base: H NMR (CDCl3, 400 MHz) δ = 1.16−1.33 (m, 2H),
(1RS,2SR)-2-(Benzylamino)-1-ethenylcyclohexanol (30). To
an ethanolic solution of 29 (10.10 g), Lindlar catalyst was added
(1.00 g), and the resulting mixture was degassed and stirred under 1
atm of hydrogen until the complete consumption of the starting
material occurred (reaction was monitored by TLC every 30 min,
hexane:EtOAc 1:1, typically 2 h). The catalyst was then removed by
filtration, and the filtrate was concentrated under reduced pressure to
give a colorless oil (9.83 g, 96%). The product usually contains 5−10
mol % inseparable overreduced product ((1RS,2SR)-2-(benzylamino)-
1-ethylcyclohexanol). For (1R,2S)-2-(benzylamino)-1-ethenylcyclo-
hexanol: [α]2D3 = +34.7 (c = 1, CHCl3); 1H NMR (CDCl3, 400
MHz) δ = 1.06−1.19 (m, 1H), 1.33−1.41 (m, 1H), 1.45−1.60 (m,
2H), 1.54−1.73 (m, 1H), 1.81−1.92 (m, 2H), 2.09−2.16 (m, 1H),
2.51 (dd, J =11.7, 3.9 Hz, 1H), 3.53 (br.s., 1H), 3.68 (d, J = 13.1 Hz,
1H), 3.97 (d, J = 13.1 Hz, 1H), 5.25 (dd, J = 10.8, 2.0 Hz, 1H), 5.49
(dd, J = 17.0, 2.0 Hz, 1H), 6.24 (dd, J = 17.0, 10.8 Hz, 1 H), 7.24−7.31
(m, 1H), 7.31−7.39 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ = 22.8,
25.3, 28.2, 38.2, 50.8, 64.6, 73.9, 115.4, 127.0, 128.1 (2 C), 128.4 (2
C), 138.6, 140.6; IR νmax (KBr) 3473 (br), 2933, 2860, 1454, 1119,
926, 739, 698 cm−1; m/z (Irel) 231 (4 MH+), 146 (26), 133 (19), 120
(17), 105 (25), 91 (100), 65 (33), 55 (44), 41 (25), 39 (24%). Anal.
Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 78.02; H,
9.17; N, 6.24.
1.35−1.48 (m, 1H), 1.54−1.67 (m, 2H), 1.67−1.77 (m, 1H), 1.86−
1.95 (m, 1H), 1.95−2.02 (m, 1H), 2.13−2.21 (m, 1H), 2.57 (dd, J =
11.7, 3.9 Hz, 1H), 3.70 (d, J = 13.1 Hz, 1H), 3.74 (br.s., 1H), 3.97 (d, J
= 13.1 Hz, 1H), 6.62 (d, J = 15.9 Hz, 1H), 6.86 (d, J = 15.9 Hz, 1H),
7.21−7.29 (m, 2H), 7.30−7.37 (m, 6H), 7.40−7.46 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ = 22.9, 25.4, 28.3, 38.6, 50.9, 65.1, 74.0,
126.6 (2C), 127.1, 127.4, 128.1 (2C), 128.5 (2C), 128.6 (2C), 130.40,
130.45, 137.3, 140.6.
(1RS,2SR)-2-(Benzylamino)-1-(2-phenylethyl)cyclohexanol
(17a). Data: H NMR (CDCl3, 400 MHz) δ = 1.08−1.95 (m, 10H),
2.04−2.12 (m, 2H), 2.49 (dd, J = 11.5, 3.9 Hz, 1H), 2.61 (td, J = 12.8,
5.1 Hz, 1H), 2.83 (dd, J = 12.8, 4.1 Hz, 1H), 3.68 (d, J = 12.7 Hz, 1H),
3.97 (d, J = 12.7 Hz, 1H), 7.18−7.44 (m, 10H); 13C NMR (CDCl3,
100 MHz) δ = 22.3, 25.2, 28.1, 29.0, 34.2, 34.4, 52.2, 65.9, 73.3, 125.7,
127.1, 128.2 (2C), 128.4 (2C), 128.5 (4C), 140.7, 143.3.
1
(1RS,2SR)-1-[(E)-2-Phenylethenyl]-2-(prop-2-en-1-ylamino)-
cyclohexanol (22). Compound 22 was synthesized by the general
procedure B from propargyl alcohol 20 (3.11 g), and isolated as
slightly yellow solid (2.43 g, 78%): mp = 71−72 °C; 1H NMR
(CDCl3, 400 MHz) δ = 0.75 (br.s., 1H), 1.16 (ddd, J = 24.9, 12.9, 3.9
Hz, 1H), 1.35−1.48 (m, 1H), 1.54−1.69 (m, 2H), 1.69−1.77 (m, 1H),
1.84−1.93 (m, 1H), 1.95−2.02 (m, 1H), 2.07−2.15 (m, 1H), 2.51 (dd,
J = 11.7, 3.9 Hz, 1H), 3.16 (ddt, J = 13.9, 5.9, 1.4 Hz, 1H), 3.43 (ddt, J
= 13.9, 5.9, 1.4 Hz, 1H), 3.78 (br.s., 1H), 5.07 (dq, J = 10.2, 1.4 Hz,
1H), 5.19 (dq, J = 17.2, 1.8 Hz, 1H), 5.88 (dddd, J = 17.1, 10.3, 6.0,
6.0 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.85 (d, J = 15.9 Hz, 1H),
7.22−7.28 (m, 1H), 7.31−7.36 (m, 2H), 7.42−7.45 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ = 22.9, 25.4, 28.4, 38.6, 49.5, 65.0, 73.9,
115.7, 126.5 (2C), 127.4, 128.5 (2C), 130.29, 130.34, 137.28, 137.35;
IR νmax (KBr) 3435 (br), 3303 (br), 2931, 2860, 1450, 974, 920, 748,
694 cm−1; m/z (Irel, %) 257 (M+, 32), 198 (44), 131 (91), 115 (46),
109 (41), 105 (35), 103 (67), 96 (99), 91 (77), 82 (36), 77 (43), 70
(91), 68 (51), 56 (48), 41 (100). Anal. Calcd for C17H23NO: C, 79.33;
H, 9.01; N, 5.44. Found: C, 79.19; H, 8.82; N, 5.33.
(1RS,2SR)-2-(Methylamino)-1-[(E)-2-phenylvinyl]cyclo-
hexanol (23). Compound 23 was synthesized by the general
procedure B from propargyl alcohol 21 (1.00 g), and isolated as
slightly yellow solid (0.82 g, 81%): mp = 117−8 °C; 1H NMR
(CDCl3, 400 MHz) δ = 1.14 (dq, J = 12.8, 3.6 Hz, 1 H), 1.20−1.48 (m
+ br. s., 2 H), 1.49−1.70 (m, 3 H), 1.70−1.78 (m, 1 H), 1.85−1.93 (m,
1 H), 1.94−2.01 (m, 1 H), 2.10−2.19 (m, 1 H), 2.40 (dd, J = 11.9, 3.9
Hz, 1 H), 2.43 (s, 3 H), 6.59 (d, J = 15.9 Hz, 1 H), 6.83 (d, J = 15.9
Hz, 1 H), 7.21−7.27 (m, 1 H), 7.30−7.37 (m, 2 H), 7.40−7.46 (m, 2
H); 13C NMR (CDCl3, 100 MHz) δ = 22.9, 25.3, 27.5, 33.7, 38.7,
67.6, 74.0, 126.5 (2C), 127.4, 128.5 (2C), 130.2, 130.3, 137.2; IR νmax
(KBr) 3057, 2931, 2858, 1467, 1448, 1109, 968, 856, 746, 694 cm−1;
m/z (Irel, %) 231 (M+, 11), 96 (15), 91 (11), 83 (32), 77 (13), 70
(59), 57 (50), 56 (15), 44 (100), 42 (21). Anal. Calcd for C15H21NO:
C, 77.88; H, 9.15; N, 6.05. Found: C, 77.60; H, 9.06; N, 6.03.
(1RS,2SR)-2-Amino-1-[(E)-2-phenylethenyl]cyclohexanol
(24). To a solution containing 3.74 g of 22 (14.5 mmol) and 4.50 g of
N,N′-dimethylbarbituric acid (29.0 mmol, 2 equiv) in 140 mL of
CH2Cl2, 0.16 g of [Pd(PPh3)2]Cl2 (1 mol. %) was added under argon.
The mixture was stirred for 2−4 h under reflux (reaction monitored by
TLC). After cooling, the CH2Cl2 was extracted twice with 5% aqueous
K2CO3 to remove the unreacted NDMBA. The organic phase was
dried over Na2SO4 and concentrated. Purification by flash column
chromatography (20:1 CH2Cl2:MeOH) gave an oil, which solidified
(1R,2S)-2-{[(1R)-1-Phenylethyl]amino}-1-[(E)-2-phenyl-
ethenyl]cyclohexanol (34). Compound 34 was synthesized by the
general procedure B from propargyl alcohol 32 (1.00 g), and isolated
as slightly yellow oil (0.94 g, 93%). Free base: Colorless viscous oil;
yield 93%; [α]2D3 = −97.3 (c = 1.1, CH2Cl2); H NMR (CDCl3, 400
1
MHz) δ = 0.79−0.95 (m, 1H), 1.02−1.52 (m, 6H), 1.22 (d, J = 6.7
Hz, 3H), 1.54−1.61 (m, 1H), 1.72−1.86 (m, 2H), 2.03−2.12 (m, 1H),
2.21 (dd, J = 10.1, 4.0 Hz, 1H), 3.60 (br.s., 1H), 3.90 (q, J = 6.6 Hz,
1H), 6.57 (d, J = 15.8 Hz, 1H), 6.83 (d, J = 15.8 Hz, 1H), 7.15−7.45
(m, 10H); 13C NMR (CDCl3, 100 MHz) δ = 22.9, 25.3, 25.8, 28.0,
38.5, 54.0, 62.0, 73.8, 126.7 (2C), 126.9 (2C), 127.2, 127.5, 128.7
(4C), 130.5, 130.6, 137.5, 145.3; m/z (Irel, %) 321 (MH, 13), 216
(17), 198 (24), 131 (44), 120 (21), 105 (100), 104 (12), 103 (30), 91
(22), 84 (17), 79 (23), 77 (28), 69 (14), 56 (18), 43 (12); IR νmax
(KBr) 3469 (br.), 3026, 2931, 2860, 1493, 1450, 1369, 1120, 975, 733,
700, 519 cm−1.
HBr salt: [α]2D3 = −121.3 (c = 1.0, MeOH); mp = 205−210 °C
1
(decomp.); H NMR (DMSO-d6, 400 MHz) δ = 0.97−1.13 (m, 1H),
1.36−1.56 (m, 3H), 1.64 (d, J = 6.7 Hz, 3H), 1.67−1.83 (m, 3H),
2.09−2.19 (m, 1H), 2.52−2.62 (m, 1H), 4.61−4.70 (m, 1H), 5.61 (br.
s., 1H), 6.73 (d, J = 15.9 Hz, 1H), 6.92 (d, J = 15.9 Hz, 1H), 7.25−
7.31 (m, 1H), 7.34−7.48 (m, 5 H), 7.57−7.64 (m, 4H), 8.12 (br. s.,
1H), 8.69 (br. s., 1H); 13C NMR (DMSO-d6, 100 MHz) δ = 20.3,
22.4, 24.47, 24.51, 40.7, 55.4, 63.8, 72.5, 127.4 (2C), 128.2, 128.3
(2C), 128.5, 129.0 (2C), 129.44, 129.48 (2C), 131.6, 137.2, 137.4; IR
νmax (KBr) 3342, 2981, 2949, 2829, 1556, 1454, 1350, 1088, 1065, 970,
756, 754, 700 cm−1; m/z (Irel, %) 321 (9 MH+), 198 (17), 131 (32),
105 (100), 103 (35), 79 (28), 77 (32%). Anal. Calcd for C22H28NOBr:
C, 65.67; H, 7.01; N, 3.48. Found: C, 65.67; H, 6.90; N, 3.43.
(1S,2R)-2-{[(1R)-1-Phenylethyl]amino}-1-[(E)-2-phenyl-
ethenyl]cyclohexanol (35). Compound 35 was synthesized by the
general procedure B from propargyl alcohol 33 (1.00 g), and isolated
as slightly yellow oil (0.91 g, 90%). Free base: Colorless viscous oil;
yield 90%; [α]2D3 = +34.3 (c = 0.82, CH2Cl2); H NMR (CDCl3, 400
1
MHz) δ = 0.91−1.20 (br. s., 1H), 1.12 (dq, J = 12.7, 3.7 Hz, 1H), 1.84
(d, J = 6.5 Hz, 3H), 1.34−1.48 (m, 1H), 1.48−1.62 (m, 1H), 1.63−
1.78 (m, 2H), 1.80−1.89 (m, 1H), 1.91−1.99 (m, 1H), 1.99−2.07 (m,
1H), 2.66 (dd, J = 11.9, 3.9 Hz, 1H), 3.87 (br. s., 1H), 3.93 (q, J = 6.5
Hz, 1H), 6.60 (d, J = 15.9 Hz, 1H), 6.87 (d, J = 15.9 Hz, 1H), 7.21−
7.29 (m, 2H), 7.29−7.38 (m, 6H), 7.40−7.44 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ = 22.9, 23.6, 25.7, 29.0, 38.7, 55.0, 63.5, 73.8,
126.4 (2C), 126.5 (2C), 127.1, 127.3, 128.5 (4C), 130.45, 130.53,
137.4, 146.8; IR νmax (KBr) 3467 (br), 3026, 2931, 2860, 1493, 1450,
1367, 1119, 1063, 972, 748, 700, 544 cm−1; m/z (Irel, %) 321 (M+, 29),
306 (24), 223 (18), 216 (48), 199 (14), 198 (58), 173 (17), 160 (13),
134 (16), 132 (13), 131 (74), 120 (30), 105 (100), 104 (19), 103
(38), 91 (33), 84 (17), 79 (24), 77 (30), 69 (14), 56 (16), 43 (12).
1
upon standing (1.92 g, 61%): mp = 118−119 °C; H NMR (CDCl3,
400 MHz) δ = 1.25−2.03 (m, 11H), 2.70 (dd, J = 11.4, 3.9 Hz, 1H),
6.57 (d, J = 15.9 Hz, 1H), 6.84 (d, J = 16.0 Hz, 1H), 7.23−7.30 (m,
1H), 7.31−7.38 (m, 2H), 7.41−7.46 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ = 23.3, 25.2, 33.6, 38.7, 59.2, 75.0, 126.5 (2C), 127.5, 128.6
(2C), 129.7, 130.9, 137.2; m/z (Irel, %) 217 (7 MH+), 73 (15), 69
(46), 56 (58), 43 (73), 32 (38), 30 (100%); IR νmax (KBr) 3176 (br.),
2933, 2862, 1595, 1460, 1446, 1333, 1103, 1065, 976, 933, 750, 696
cm−1. Anal. Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found:
C, 76.92; H, 8.42; N, 6.23.
10131
dx.doi.org/10.1021/jo301762a | J. Org. Chem. 2012, 77, 10125−10134

The Journal of Organic Chemistry
Article
HBr salt: mp = 185−7 °C; [α]2D3 = +56.2 (c = 1, MeOH); 1H NMR
(DMSO-d6, 400 MHz) δ = 1.21−1.35 (m, 1H), 1.41−1.79 (m, 5H),
1.63 (d, J = 6.8 Hz, 3H), 1.86−1.96 (m, 2H), 3.06−3.15 (m, 1H),
4.47−4.55 (m, 1H), 5.71 (br. s., 1H), 6.61 (d, J = 15.9 Hz, 1H), 6.90
(d, J = 15.9 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.5 H, 2H),
7.38−7.46 (m, 3H), 7.51 (d, J = 7.3 Hz, 2H), 7.65 (d, J = 6.8 Hz, 2H),
8.00 (br., 1H), 8.59 (br., 1H); 13C NMR (DMSO-d6, 100 MHz) δ =
19.5, 22.7, 24.6, 26.0, 40.7, 57.7, 66.0, 72.8, 127.2 (2C), 128.1, 128.4,
128.8 (2C), 129.0 (2C), 129.2 (2C), 129.4, 131.5, 137.2, 138.4; IR
νmax (KBr) 3321, 3194, 2945, 2887, 2870, 2756, 2692, 1554, 1450,
1390, 1020, 972, 762, 752, 702, 607 cm−1; m/z (Irel, %) 321 (6 MH+),
198 (20), 131 (40), 105 (100), 103 (33), 79 (32), 77 (37%). Anal.
Calcd for C22H28NOBr: C, 65.67; H, 7.01; N, 3.48. Found: C, 66.12;
H, 7.24; N, 3.46.
General Procedure for Aza-Cope−Mannich Reaction (Pro-
cedure C). To a vigorously stirred mixture of 6 (10 mmol), anhydrous
Na2SO4 (70 mmol), camphorsulfonic acid (3 mmol) and CH2Cl2 (50
mL), 1.64 mL of formalin (37% in water, 22 mmol) was rapidly added
at room temperature. The reaction mixture was vigorously stirred
overnight. The mixture was washed with saturated NaHCO3 solution
(50 mL) and dried over Na2SO4. The concentration yields products
that are usually pure; however, when necessary, the products were
purified via silica gel flash column chromatography using petroleum/
EtOAc (10:1) or recrystallized as a free bases or as the HBr salts.
(3RS,3aSR,8aRS)-1-Benzyl-3-phenyloctahydrocyclohepta[b]-
pyrrol-4(1H)-one (18). Compound 18 was synthesized by the
general procedure C from 17 (10.0 g), and isolated as white solid
(10.4 g, 100%): mp = 106.2−106.7 °C; Rf 0.55 (Hexane:EtOAc, 10:1);
1H NMR (CDCl3, 400 MHz) δ = 1.29−1.44 (m, 1H), 1.57−1.80 (m,
2H), 1.86−1.98 (m, 1H), 2.06−2.15 (m, 1H), 2.26 (td, J = 10.3, 2.8
Hz, 1H, C(8a)H), 2.33−2.48 (m, 2H), 2.52−2.60 (m, 2H), 3.05 (dd, J
= 9.8, 2.2 Hz, 1H), 3.18 (d, J = 13.2 Hz, 1H), 3.23 (dd, J = 9.9, 6.0 Hz,
1H, C(3a)H), 3. 89 (ddd, J = 8.6, 6.0, 2.2 Hz, 1H, C(3)H), 4.15 (d, J =
13.1 Hz, 1H), 7.13−7.19 (m, 1H), 7.21−7.29 (m, 3H), 7.29−7.43 (m,
6H); 13C NMR (CDCl3, 100 MHz) δ = 23.2, 26.8, 35.1, 40.7, 43.7,
58.1, 60.9, 67.4, 68.7, 126.0, 126.9, 127.5 (2C), 128.3 (2C), 128.5
(2C), 128.6 (2C), 139.3, 147.4, 210.4; IR νmax (KBr) 3369 (br.), 3032,
2933, 2912, 2777, 1693, 1495, 1452, 1136, 760, 742, 700 cm−1; m/z
(Irel, %) 333 (3, MH), 277 (7), 144 (3), 131 (3), 129 (5), 128 (4), 117
(4), 115 (10), 104 (5), 103 (3), 92 (8), 91 (100), 77 (4), 65 (15), 55
(11), 43 (4), 44 (10), 41 (12), 40 (6), 39 (7). Anal. Calcd for
C22H25NO: C, 82.72; H, 7.89; N, 4.38. Found: C, 82.97; H, 7.88; N,
4.35.
7.17−7.23 (m, 1 H), 7.26−7.33 (m, 2 H), 7.36−7.42 (m, 2 H); 13C
NMR (CDCl3, 100 MHz) δ = 23.1, 26.7, 34.7, 40.5, 40.8, 43.7, 63.9,
67.7, 70.4, 126.1, 127.5 (2C), 128.5 (2C), 147.3, 210.3; IR νmax (KBr)
2929, 2854, 2775, 1703, 1454, 702 cm−1; m/z (Irel, %) 243 (M+, 31),
201 (37), 159 (37), 158 (52), 82 (44), 70 (38), 55 (39), 42 (100), 41
(50%). Anal. Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found:
C, 78.87; H, 8.73; N, 5. 63.
(3aRS,8aSR)-1-Benzyloctahydrocyclohepta[b]pyrrol-4(1H)-
one (31). Compound 31 was synthesized by the general procedure C
1
from 30 (10.00 g), and isolated as colorless oil (9.78 g, 93%): H
NMR (CDCl3, 400 MHz) δ = 1.30−1.45 (m, 1H), 1.49−1.62 (m,
1H), 1.63−1.78 (m, 1H), 1.75−1.88 (m, 1H), 1.89−2.00 (m, 1H),
2.00−2.18 (m, 3H), 2.30−2.46 (m, 3H), 2.58−2.67 (m, 1H), 2.93 (td,
J = 9.1, 1.8 Hz, 1H), 3.10 (d, J = 12.7 Hz, 1H), 3.24 (td,, J = 10.2, 5.5
Hz, 1H), 3.10 (d, J = 12.7 Hz, 1H), 7.23−7.38 (m, 5H); 13C NMR
(CDCl3, 100 MHz) δ = 21.8, 23.4, 27.1, 34.8, 43.6, 53.2, 56.5, 58.3,
67.9, 127.0, 128.3 (2C), 129.0 (2C), 138.8, 211.6; IR νmax (KBr)
2929, 2858, 2790, 1703, 1452, 1356, 1147, 735, 700 cm−1; m/z (Irel)
244 (10 MH+), 201 (32), 186 (11), 159 (26), 91 (100), 65 (18), 55
(19), 42 (14), 41 (33), 39 (19), 29 (13%). Anal. Calcd for C16H21NO:
C, 78.97; H, 8.70; N, 5.76. Found: C, 78.73; H, 8.80; N, 5.50. For
(3aR,8aS)-1-benzyloctahydrocyclohepta[b]pyrrol-4(1H)-one: [α]D23
+44.2 (c = 1, CHCl3).
=
(3S,3aR,8aS)-3-Phenyl-1-[(1R)-1-phenylethyl]octahydro-
cyclohepta[b]pyrrol-4(1H)-one (36). Compound 36 was synthe-
sized by the general procedure C from 36 (1.00 g), and isolated as
colorless oil (1.04 g, 100%). Colorless viscous oil: Rf 0.55
(Hexane:EtOAc, 10:1); [α]2D3 = +1.03 (c = 1.0, CH2Cl2); H NMR
1
(CDCl3, 400 MHz) δ = 1.25−1.37 (m, 1H), 1.55 (d, J = 7.0 Hz, 3H),
1.57−1.68 (m, 1H), 1.68−1.79 (m, 1H), 1.84−1.94 (m, 1H), 2.06−
2.16 (m, 1H), 2.21−2.37 (m, 2H), 2.45−2.57 (m, 1H), 2.57−2.69 (m,
1H), 2.81 (t, J = 9.1 Hz, 1H), 3.16−3.25 (m+dd, J = 9.9, 6.7 Hz, 2H,
C(3a)H), 3.74 (ddd, J = 8.6, 6.7, 3.7 Hz, 1H, C(3)H), 4.23 (q, J = 7.0
Hz, 1H), 7.21−7.30 (m, 3H), 7.30−7.43 (m, 5H), 7.43−7.49 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ = 19.7, 23.3, 26.6, 35.2, 40.5, 43.6,
53.7, 56.5, 64.0, 66.6, 126.1, 127.2, 127.6 (2C), 128.1 (2C), 128.3
(2C), 128.5 (2C), 138.9, 146.8, 210.7; IR νmax (KBr) 2931, 1701,
1493, 1452, 1128, 910, 758, 733, 702 cm−1; m/z (Irel) 333 (9 MH+),
318 (21), 291 (15), 144 (16), 115 (17), 105 (100), 103 (20), 79 (25),
77 (29), 41 (15%). Anal. Calcd for C23H27NO: C, 82.84; H, 8.16; N,
4.20. Found: C, 82.70; H, 8.02; N, 4.20.
(3S,3aR,8aS)-3-Phenyl-1-[(1R)-1-phenylethyl]octahydro-
cyclohepta[b]pyrrol-4(1H)-one (37). Compound 37 was synthe-
sized by the general procedure C from 35 (1.00 g), and isolated as
colorless oil (1.04 g, 100%). Colorless viscous oil. Yield: 100%; Rf 0.50
(Hexane:EtOAc, 10:1); mp = 60−61 °C; [α]2D3 = −24.4 (c = 1.0,
CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ = 1.23−1.34 (m, 1 H), 1.37
(d, J = 6.9 Hz, 3 H), 1.47−1.64 (m, 1 H), 1.70−1.84 (m, 1 H), 1.84−
1.97 (m, 1 H), 2.02−2.11 (m, 1 H), 2.27−2.36 (m, 1 H), 2.36−2.48
(m, 1 H), 2.50−2.60 (m, 1 H), 2.63 (td, J = 10.3, 3.0 Hz, 1 H, C(8a)H),
2.78 (dd, J = 9.7, 4.0 Hz, 1H), 3.01 (t, J =9.3 Hz, 1 H), 3.29 (dd, J =
9.7, 6.9 Hz, 1 H, C(3a)H), 3.84 (ddd, J = 8.8, 6.9, 4.0 Hz, 1H, C(3)H),
4.15 (q, J = 6.8 Hz, 1 H), 7.16−7.22 (m, 1 H), 7.24−7.31 (m, 3 H),
7.33−7.40 (m, 4 H), 7.49−7.53 (m, 2 H); 13C NMR (CDCl3, 100
MHz) δ = 11.6, 23.1, 26.5, 35.5, 41.0, 43.8, 53.4, 55.9, 65.8, 66.6,
126.1, 126.6, 127.49 (2C), 127.53 (2C), 128.1 (2C), 128.4 (2C),
144.7, 146.5, 210.9; IR νmax (KBr) 3475 (br.), 3059, 3028, 2968, 2922,
2856, 2802, 1705, 1697, 1603, 1450, 1375, 1219, 1165, 1134, 1082,
1032, 783, 760, 700, 526 cm−1; m/z (Irel, %) 333 (29, MH+), 319 (24),
318 (98), 291 (36), 131 (26), 117 (22), 115 (26), 105 (100), 104
(24), 103 (34), 97 (25), 79 (27), 77 (47), 55 (30), 43 (28), 41 (37),
39 (20). Anal. Calcd for C23H27NO: C, 82.84; H, 8.16; N, 4.20.
Found: C, 82.93; H, 8.31; N, 4.24.
(3RS,3aSR,8aRS)-3-Phenyl-1-prop-2-en-1-yloctahydrocyclo-
hepta[b]pyrrol-4(1H)-one (25). Compound 25 was synthesized by
the general procedure C from 22 (0.50 g), and isolated as colorless oil
1
(0.43 g, 82%): H NMR (CDCl3, 400 MHz) δ = 1.24−1.38 (m, 1H),
1.49−1.60 (m, 1H), 1.66−1.79 (m, 1H), 1.84−1.95 (m, 1H), 2.02−
2.13 (m, 1H), 2.18 (td, J = 10.3, 2.9 Hz, 1H, C(8a)H), 2.33−2.44 (m,
2H), 2.51−2.61 (m, 1H), 2.62 (t, J = 9.6 Hz, 1H), 2.73 (dd, J = 13.5,
7.8 Hz, 1H), 3.20 (dd, J = 10.2, 6.4 Hz, 1H, C(3a)H), 3.23 (dd, J = 10.4,
2.5 Hz, 1H), 3.56−3.63 (m, 1H), 3.91 (ddd, J = 9.1, 6.4, 2.7 Hz, 1H,
C(3)H), 5.13 (d, J = 9.4 Hz, 1H), 5.24 (d, J = 17.0 Hz, 1H), 5.93
(dddd, J = 17.0, 10.2, 7.7, 4.9 Hz, 1H), 7.17−7.23 (m, 1H), 7.27−7.33
(m, 2H), 7.37−7.41 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ = 23.1,
26.6, 34.9, 40.7, 43.7, 56.6, 60.7, 67.2, 68.3, 117.0, 126.1, 127.5, 128.5,
135.5, 147.0, 210.4; IR νmax (KBr) 2929, 2858, 2789, 1703, 1493, 1454,
1371, 1346, 1219, 1163, 1134, 920, 762, 702 cm−1; m/z (Irel, %) 269
(5 MH+), 115 (34), 91 (67), 77 (24), 70 (24), 56 (20), 55 (33), 43
(24), 42 (33), 39 (31%). Anal. Calcd for C18H23NO: C, 80.26; H,
8.61; N, 5.20. Found: C, 79.94; H, 8.44; N, 5.15.
(3RS,3aSR,8aRS)-1-Methyl-3-phenyloctahydrocyclohepta[b]-
pyrrol-4(1H)-one (26). The title compound was prepared by general
procedure C from 23, but using 0.90 equiv of CSA (0.10 g scale).
(3RS,3aSR,8aRS)-3-Phenyloctahydrocyclohepta[b]pyrrol-
4(1H)-one HCl salt (19). A suspension of 10.00 g of 18 in EtOH
(100 mL) was acidified with aqueous HCl to pH ∼3 (approximately
2.6 mL needed). Pd/C (l0%, 1 g) was added, and the mixture was
degassed and stirred under 1 atm of hydrogen gas for 2 h. The catalyst
was then removed by filtration, and the filtrate was concentrated under
reduced pressure. Recrystallization from ethanol gave white solid (7.91
1
Chromatography CH2Cl2:EtOH 10:1. Yield: 90%; H NMR (CDCl3,
400 MHz) δ = 1.24−1.39 (m, 2 H), 1.46−1.58 (m, 1 H), 1.65−1.78
(m, 1 H), 1.84−1.94 (m, 1 H), 1.95 (td, J = 10.6, 2.9 Hz, 1 H, C(8a)H),
2.03−2.14 (m, 1 H), 2.30−2.43 (m+s, 2 + 3 H), 2.50−2.60 (m, 1 H),
2.63 (t, J = 9.6 Hz, 1 H), 3.17 (dd, J = 9.8, 2.2 Hz, 1 H), 3.19 (dd, J =
10.0, 6.1 Hz, 1 H, C(3a)H), 3.94 (ddd, J = 9.2, 6.1, 2.2 Hz, 1 H, C(3)H),
10132
dx.doi.org/10.1021/jo301762a | J. Org. Chem. 2012, 77, 10125−10134

The Journal of Organic Chemistry
Article
g, 95%). 36 and 37 were debenzylated in a similar fashion: mp = 225−
(b) Overman, L. E.; Humphreys, P. G.; Welmaker, G. S. Org. React.
2011, 75, 747−820.
229 °C (MeOH); [α]D23
=
2.3 (c = 0.5, MeOH); 1H NMR (DMSO-
d6, 400 MHz) δ = 1.18−1.37 (m, 1H), 1.70−1.89 (m, 2H), 1.89−2.06
(m, 1H), 2.06−2.26 (m, 2H), 2.26−2.40 (m, 1H), 2.40−2.63 (m, 1H),
3.12−3.28 (m, 1H), 3.28−3.52 (m, 1H) 3.52−3.72 (m, 2H), 3.72−
3.88 (m, 1H), 7.16−7.26 (m, 1H), 7.26−7.36 (m, 2H), 7.36−7.48 (m,
2H), 9.90 (br., 1H), 10.20 (br., 1H); 13C NMR (DMSO-d6, 100 MHz)
δ = 22.0, 25.5, 32.5, 43.7, 44.3, 49.7, 61.0, 61.2, 127.4, 128.5 (2C),
128.9 (2C), 140.1, 207.7; IR νmax (KBr) 3384 (br.), 3053, 2937, 2875,
2721, 2652, 1703, 1454, 1400, 1169, 762, 708, 515 cm−1; m/z (Irel, %)
229 (16, MH+), 172 (13), 145 (11), 144 (20), 129 (11), 128 (11), 120
(10), 119 (100), 115 (17), 104 (13), 91 (21), 83 (29), 77 (12), 70
(27), 68 (19), 57 (13), 56 (26), 55(13), 41 (22), 39 (14), 38 (13), 36
(37). Anal. Calcd for C15H20NClO: C, 67.79; H, 7.58; N, 5.27. Found:
C, 67.42; H, 7.37; N, 5.03. Free base: 1H NMR (CDCl3, 400 MHz) δ
= 1.25−1.40 (m, 1 H), 1.64 (qd, J = 13.1, 3.3 Hz, 1 H), 1.76 (qd, J =
12.3, 3.3 Hz, 1 H), 1.86−1.97 (m, 1 H), 2.00−2.11 (m, 1 H), 2.28−
2.42 (m, 2 H), 2.48−2.48 (m, 1H), 2.94 (td, J = 10.6, 3.1 Hz, 1 H),
3.13 (dd, J = 9.7, 8.0 Hz, 1 H), 3.17 (dd, J = 10.8, 5.5 Hz, 1 H, C(3a)H),
3.37 (dd, J = 11.0, 8.2 Hz, 1 H), 3.98 (td, J = 8.5, 5.5 Hz, 1 H, C(3)H),
7.16−7.23 (m, 1 H), 7.29 (d, J = 4.50 Hz); 13C NMR (CDCl3, 100
MHz) δ = 23.2, 26.6, 37.3, 43.8, 45.7, 53.9, 64.2, 66.9, 126.3, 127.3
(2C), 128.6 (2C), 145.0, 210.2.
(5) Cyclopenta[b]pyrrolidines (a) Overman, L. E.; Okazaki, M. E.;
Jacobsen, E. J. J. Org. Chem. 1985, 50, 2403−2405.
(6) Octahydroindols (a) Overman, L. E.; Sworin, M.; Bass, L. S.;
Clardy, J. Tetrahedron 1981, 37, 4041−4045. (b) Overman, L. E.;
Mendelson, L. T. J. Am. Chem. Soc. 1981, 103, 5579−5581.
(c) Overman, L. E.; Mendelson, L. T.; Flippin, L. A. Tetrahedron
Lett. 1982, 23, 2733−2740. (d) Overman, L. E.; Sworin, M.; Burk, R.
M. J. Org. Chem. 1983, 48, 2685−2690. (e) Overman, L. E.;
Mendelson, L. T.; Jacobsen, E. J. J. Am. Chem. Soc. 1983, 105, 6629−
6637. (f) Overman, L. E.; Sugai, S. Helv. Chim. Acta 1985, 68, 745−
749. (g) Overman, L. E.; Wild, H. Tetrahedron Lett. 1989, 30, 647−
650. (h) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Org.
Chem. 1989, 54, 1236−1238. (i) Fevig, J. M.; Marquis, R. W., Jr.;
Overman, L. E. J. Am. Chem. Soc. 1991, 113, 5085−5086. (j) Overman,
L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113,
2598−2610.
(7) Cyclohepta[b]pyrrols (a) Overman, L. E.; Jacobsen, E. J.
Tetrahedron Lett. 1982, 23, 2737−2740. (b) Overman, L. E.;
Jacobsen, E. J. Tetrahedron Lett. 1982, 23, 2741−2744. (c) Overman,
L. E.; Jacobsen, E. J.; Doedens, R. J. J. Org. Chem. 1983, 48, 3393−
3400. (d) Earley, W. G.; Oh, T.; Overman, L. E. Tetrahedron Lett.
1988, 29, 3785−3788. (e) Jacobsen, E. J.; Levin, J.; Overman, L. E. J.
ASSOCIATED CONTENT
Am. Chem. Soc. 1988, 110, 4329−4336. (f) Bruggemann, M.;
̈
■
McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink, L.; Scott,
J. P. J. Am. Chem. Soc. 2003, 125, 15284−15285. (g) Earley, W. G.;
Jacobsen, J. E.; Madin, A.; Meier, G. P.; O’Donnell, C. J.; Oh, T.; Old,
D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127,
18046−18053. (h) Madin, A.; Meier, G. P.; O’Donnell, C. J.; Oh, T.;
Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127,
18054−18065. (i) Dunn, T. B.; Ellis, J. M.; Kofink, C. C.; Manning, J.
R.; Overman, L. E. Org. Lett. 2009, 11, 5658−5661.
S
* Supporting Information
1H NMR and 13C NMR spectra for new compounds and CIF
files for 18, 32·HBr, 33·HBr, ent-32, and 36·HBr. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kurkin@direction.chem.msu.ru.
(8) Belov, D. S.; Lukyanenko, E. R.; Kurkin, A. V.; Yurovskaya, M. A.
Tetrahedron 2011, 67, 9214−9218.
Notes
(9) Overman, L. E.; Kakimoto, M.; Okazaki, M. E.; Meier, G. P. J.
Am. Chem. Soc. 1983, 105, 6622−6629.
The authors declare no competing financial interest.
(10) Deng, W.; Overman, L. E. J. Am. Chem. Soc. 1994, 116, 11241−
11250.
ACKNOWLEDGMENTS
■
(11) Lindstrom, U. M.; Olofsson, B.; Somfai, P. Tetrahedron Lett.
̈
This study was supported by the Russian Foundation for Basic
Research (RFBR), Russia (Grant No. 11-03-00444a).
1999, 40, 9273−9276.
(12) Olofsson, B.; Somfai, P. J. Org. Chem. 2002, 67, 8574−8583.
(13) Yoshida, M.; Hayashi, M.; Shishido, K. Org. Lett. 2007, 9, 1643−
1646.
REFERENCES
■
(14) Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F.
(1) (a) Schneider, G.; Neidhart, W.; Giller, T.; Schmid, G. Angew.
Chem., Int. Ed. Engl. 1999, 38, 2894−2896. (b) Andrews, K. M.;
Cramer, R. D. J. Med. Chem. 2000, 43, 1723−1740. (c) Mason, J. S.;
Morize, I.; Menard, P. R.; Cheney, D. L.; Hulme, C.; Labaudiniere, R.
F. J. Med. Chem. 1999, 42, 3251−3264. (d) Lovering, F.; Bikker, J.;
Humblet, C. J. Med. Chem. 2009, 52, 6752−6756. (e) Yang, Y.;
Tetrahedron 1991, 47, 1677−1696.
(15) Andreev, I. A.; Ryzhkov, I. O.; Kurkin, A. V.; Yurovskaya, M. A.
Chem. Heterocycl. Compd. 2012, 48, 715−719.
(16) (a) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett.
1984, 25, 4233−4236. (b) Imamoto, T.; Takiyama; Nakamura, K.
Tetrahedron Lett. 1985, 26, 4763−4766. (c) Imamoto, T.; Sugiura, Y.;
Takiyama, N.; Hatojima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111,
4392−4398.
(17) Nicolaou, K. C.; Montganon, T.; Ulven, T.; Baran, P. S.; Zhong,
Y.-L.; Sarabia, F. J. Am. Chem. Soc. 2002, 124, 5718−5728.
(18) Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H. J. Am. Chem.
Soc. 1967, 89, 4245−4247.
(19) The X-ray CIF file for this structure has been deposited at the
Cambridge Crystallographic Data Center (CCDC), deposition
number: 855659 (18). Copies of these data can be obtained free of
charge on application to the CCDC; e-mail: deposit@ccdc.cam.ac.uk.
The CIF is also included in the Supporting Information.
(20) Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58,
6109−6113.
̀
Engkvist, O.; Llinas, A.; Chen, H. J. Med. Chem. 2012, 55, 3667−3677.
(2) For reviews, see: (a) Bunib, B. A.; Dener, J. M.; Livingston, D. A.
Annu. Rep. Med. Chem. 1999, 34, 267−286. (b) Baldwin, J. J. Comb.
Chem. Mol. Diversity Drug Discovery 1998, 181−188. (c) Oliver, S. F.;
Abell, C. Curr. Opin. Chem. Biol. 1999, 3, 299−306. (d) Ellingboe, J.
W. Med. Chem. Res. 1998, 8, 181−186. (e) Nicolaou, K. C.;
Pfefferkorn, J. A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.; Cao,
G.-Q. J. Am. Chem. Soc. 2000, 122, 9968−9976.
(3) Some representative examples of natural products synthesis:
Strychnine (a) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am.
Chem. Soc. 1993, 115, 9293−9294. (b) Knight, S. D.; Overman, L. E.;
Pairaudeau, G. J. Am. Chem. Soc. 1995, 117, 5776−5788. Pancracine
(c) Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56, 5005−5007.
(d) Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662−4672.
Actinophyllic acid (e) Martin, C. L.; Overman, L. E.; Rohde, J. M. J.
Am. Chem. Soc. 2008, 130, 7568−7569. (f) Martin, C. L.; Overman, L.
E.; Rohde, J. M. J. Am. Chem. Soc. 2010, 132, 4894−4906.
(21) The cis-isomer was prepared using procedures from ref 6;
vinylmagnesium bromide was employed instead of lithium phenyl-
acetelenide. See the Supporting Information for NMR spectra of both
compounds.
(4) For a seminal publication: (a) Overman, L. E.; Kakimoto, M.-A. J.
Am. Chem. Soc. 1979, 101, 1310−1312. For a recent review:
(22) Overman, L. E.; Sugai, S. J. Org. Chem. 1985, 50, 4154−4155.
10133
dx.doi.org/10.1021/jo301762a | J. Org. Chem. 2012, 77, 10125−10134

The Journal of Organic Chemistry
Article
(23) Deposition numbers: 720940 (32·HBr), 720939 (33·HBr),
855658 (ent-32).
(24) Deposition number: 885117 (36·HBr).
(25) Rybakov, V. B.; Belov, D. S.; Lukyanenko, E. R.; Kurkin, A. V.;
Yurovskaya, M. A. Acta Crystallogr. 2012, E68, o2227.
(26) (a) Taber, D. F.; He, Y.; Xu, M. J. Am. Chem. Soc. 2004, 126,
13900−13901. (b) Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999,
64, 7646−7650.
(27) Peng, X.; Li, P.; Shi, Y. J. Org. Chem. 2012, 77, 701−703.
10134
dx.doi.org/10.1021/jo301762a | J. Org. Chem. 2012, 77, 10125−10134