Diastereoselective synthesis of a highly substituted cis-decahydroquinoline via a Knoevenagel condensation

Article abstract of DOI:10.1016/j.tet.2008.04.073

A diastereoselective approach to 3,7,8-trisubstituted cis-decahydroquinolines is described. This ring system forms the core of rings B and E of the norditerpenoid alkaloid methyllycaconitine. This approach starts with a known disubstituted cyclohexene. The remaining carbons are attached via a Knoevenagel condensation followed by an intramolecular lactam formation. The stereochemistry of the substituents is controlled by the cis-substitution of the starting cyclohexene ring.

Full text of DOI:10.1016/j.tet.2008.04.073

Tetrahedron 64 (2008) 6434–6439
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselective synthesis of a highly substituted cis-decahydroquinoline
via a Knoevenagel condensation
*
Junfeng Huang, Stephen C. Bergmeier
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A diastereoselective approach to 3,7,8-trisubstituted cis-decahydroquinolines is described. This ring
system forms the core of rings B and E of the norditerpenoid alkaloid methyllycaconitine. This approach
starts with a known disubstituted cyclohexene. The remaining carbons are attached via a Knoevenagel
condensation followed by an intramolecular lactam formation. The stereochemistry of the substituents is
controlled by the cis-substitution of the starting cyclohexene ring.
Received 21 February 2008
Received in revised form 17 April 2008
Accepted 17 April 2008
Available online 24 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
disubstituted ring system (e.g., cis-195A, Lepadins).36–38 These
methods are not well suited for the synthesis of the desired 3,7,8-
Methyllycaconitine (MLA), a norditerpenoid alkaloid isolated
trisubstituted ring system 1. Many of these methods are focused on
carbon substitution at the 2- and 5-position as seen in natural
products such as cis-195A and Lepadin A. For the synthesis of our
required bicyclic amine 1, we need a carbon substituent at position
3 and the ability to introduce hydroxyl groups at positions 7 and 8.
from plants of the genera Aconitum and Delphinium,1,2 is the most
potent nonpeptide antagonist at the
a7 nicotinic acetylcholine
receptors (nAChRs).3,4 The interesting structure and biological
activities of methyllycaconitine have stimulated numerous
synthetic efforts in the past decades.5–25 In our efforts to identify
structure–activity relationships of methyllycaconitine, we have
synthesized numerous simple analogues of methyllycaconitine,
which contain only the E ring and the succinimidoylanthranilate
ester.26–29 All of the simple E-ring analogues have been shown to be
OMe
OMe
H
OH
C
D
MeO
N
OH
OMe
noncompetitive antagonists to the
the agonist binding sites of either
a
3
b
a
4
*
nAChR, with no affinity to
B
nAChRs.30 We
N
F
a
7,
4b
2, or
a
3
b4
*
A
N
hoped that introducing a more rigid conformation to our previous
E-ring analogues might provide a selective and competitive ligand
O
O
O
to the a7 nAChR. A simple removal of the A, C, D, and F rings of MLA
provides a BE-ring analogue. This analogue should thus be available
from the cis-decahydroquinoline core structure (Fig. 1).
E
O
Methyllycaconitine
In addition, the cis-decahydroquinoline ring system is an
essential component of many interesting and pharmacologically
useful compounds. These include amphibian alkaloids such as cis-
195A, isolated from the skin extract of the Panamanian frog
Dendrobates pumilio in 1969.31 Since that time, over 50 cis-deca-
hydroquinoline alkaloids have been isolated from amphibian
sources.32 Moreover, this cis-fused heterocyclic ring system fre-
quently occurs as a subunit of many polycyclic natural alkaloids,
such as huperzine B33 and cylindricines A–K.34,35
OH
OH
H
H
N
OH
O
O
3
O
N
7
8
HO
N
H
HO
O
Much of the methodology for the synthesis of the cis-decahy-
droquinoline ring system has focused on the synthesis of the 2,5-
cis-decahydroquinoline
core structure
BE-ring analogues of
methyllycaconitine
* Corresponding author. Tel.: þ1 740 517 8462; fax: þ1 740 593 0148.
E-mail address: bergmeis@ohio.edu (S.C. Bergmeier).
Figure 1. Methyllycaconitine and necessary decahydroquinoline core structure.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.073

J. Huang, S.C. Bergmeier / Tetrahedron 64 (2008) 6434–6439
6435
Table 1
H
H
H
H
H
COOMe
O
Comparison of Knoevenagel reaction conditions
OH
MeO2C
CO2Me
MeO2C
CO2Me
H
N
N
H
O
O
H
O
O
CHO
H
1
2
NHCbz
NHCbz
NHCbz
H
H
H
H
COOMe
4
8
9
CHO
NHCbz
COOMe
Entry
Conditions
10 mol % piperidine, 10 mol % HOAc, rt, 8 h
10 mol % piperidine, 10 mol % HOAc, 4 Å MS, 0 ꢀC, 4 h
Pyridine (solvent), 100 mol % HOAc, rt, 20 h
200 mol % Et3N, 200 mol %, HOAc, rt, 8 h
Product ratio
O
NH2
H
O
(8/9)a (yield, %)b
1
2
3
4
5
1:1 (95)
4:1 (90)
1:0 (80)
1:0 (70)
1:0 (80)
3
4
Scheme 1. Retrosynthesis of the cis-decahydroquinoline core structure 1.
20 mol % Et3N, 20 mol % HOAc, 4 Å MS, rt, 4 h
a
Determined by 1H NMR.
Isolated yield of an inseparable mixture of 8 and 9.
Equally important is the ability to control the relative stereo-
chemistry at position 3. While some of the known methods for the
synthesis of the cis-decahydroquinoline ring system might be
adapted by omitting a carbon chain or two, they lack a method to
control the newly instituted stereocenter at position 3. Herein, we
wish to describe a diastereoselective route to this cis-decahy-
droquinoline ring core, which includes five stereocenters. The
cis-decahydroquinoline system 1 can be obtained via the reduction
of the lactam-ester 2 (Scheme 1). This bicycle can be formed from
an intramolecular cyclization reaction of diester-amine 3. The
diester compound 3 can be obtained from aldehyde 4 via a Knoe-
venagel condensation. The starting aldehyde 4 is known39 and can
be readily prepared via a Diels–Alder cycloaddition.40–44
b
provides the expected product and its diastereomer in a 1:1 ratio.
While the yield of the product was excellent, the large amount of
epimerization was unacceptable for the preparation of our target
compounds. Adding 4 Å molecular sieves to the reaction and de-
creasing the reaction temperature to 0 ꢀC reduce the amount of
trans-product 9, giving a cis/trans ratio of 4:1. While considering
the reaction mechanism, we hypothesized that the piperidine first
reacted with aldehyde 4 to form an iminium salt.49 This iminium
salt can subsequently tautomerize to form an enamine50 and then
tautomerization again provides the more stable trans-isomer. To
avoid this epimerization, we changed the secondary amine catalyst
to tertiary amine such as Et3N or pyridine to preclude iminium ion
formation (and the subsequent epimerization). We believe that the
change in base from piperidine to Et3N may shift the mechanism
from the Knoevenagel mechanism (iminium formation) to the
2. Results and discussion
As outlined in Scheme 2, our synthesis of aldehyde 4 follows the
previously published method of Overman and co-workers. We have
made slight changes in the procedure that have improved the yield
of diene 7.44–46 Reaction of acid 6 with diphenyl phosphoryl azide47
provides the intermediate acylazide. In the original procedure,45,46
the acylazide was prepared in situ by using ethyl chloroformate and
sodium azide. Our modification avoids any formation of ethanol,
a good nucleophile that can react with the acylazide in the work-up
process and lower the overall yield. The acylazide was sufficiently
stable at rt that was quickly chromatographed to remove the very
polar by-product formed in the reaction. Curtius rearrangement of
the acylazide in the presence of benzyl alcohol provides diene 7 in
70% yield from acid 6. The Diels–Alder reaction of 7 with acrolein
was carried out in a sealed tube and provided an 80% yield of
predominantly cis-compound 4 (cis/trans¼10:1). cis-Compound 4
can be further purified via recrystallization from a 20% EtOAc/
hexane solution.
Hann–Lapworth mechanism (b
-hydroxy ester formation).49 This
shift in mechanistic pathway should eliminate the possibility for
enamine formation and consequently epimerization. We were
pleased to see that reaction using either pyridine or Et3N provided
solely the cis-diastereomer. Decreasing the amount of Et3N and
adding molecular sieves decrease the reaction time while retaining
the good yields and excellent diastereoselectivity. Decreasing the
amount of Et3N to 10 mol % did provide similar levels of diaster-
eoselectivity, however, the reaction took over 24 h to provide
an 80% yield. Compared with the only 2 h required with 20 mol %
of Et3N, this seemed to be as low as was practical for this
transformation.
The next step was to carry out a selective dihydroxylation of the
cyclohexene double bond. The use of catalytic OsO4/NMO provided
an excellent yield of diol 10.51 Our expectation was that diol 10
would be the preferred product with osmylation occurring from the
least hindered face of the molecule. An examination of the coupling
constants between Hb and Hc showed the expected large diaxial
coupling constant (Scheme 3 inset). The corresponding all cis
product would not have any diaxial couplings. The relatively polar
diol was converted to the acetonide in 85% yield by treatment with
2,2-dimethoxypropane. The relative stereochemistry of 10 was
further confirmed by single crystal X-ray of acetonide 11 as shown
in Figure 2.52
The synthetic approach was designed to use the Knoevenagel
condensation for the installation of the remaining carbons of the
decahydroquinoline ring system. The Knoevenagel condensation is
a well known method for the synthesis of alkylidine malonates.48,49
As shown in Table 1, the use of standard reaction conditions
b, c
a
HOOC
COOH
COOH
6
5
Our plan for the conversion of 11 to 2 required the selective
removal of the carbobenzyloxy group followed by an intra-
molecular cyclization to lactam 2. Reduction of the double bond at
this stage would generate a 1,3-dicarbonyl compound (12), which
would likely readily epimerize. As shown in Table 2, the use of
standard deprotection conditions provided over-reduced com-
pound 12 as the sole product in excellent yield. The use of different
hydrogen sources (Table 1, entries 2 and 3) such as cyclohexadiene
or ammonium formate also provided only the over-reduced
H
H
CHO
d
NHCbz
NHCbz
7
4
Scheme 2. (a) Acrolein, pyridine, rt, 3 h, 50%; (b) Et3N, (PhO)2P(O)N3, CH2Cl2, rt, 1 h; (c)
PhCH2OH, toluene, 0.5 h, 110 ꢀC, 70% over two steps; (d) acrolein, toluene, 110 ꢀC,
90 min, 80%.

6436
J. Huang, S.C. Bergmeier / Tetrahedron 64 (2008) 6434–6439
MeO2C
OH
CO2Me
MeOOC
COOMe
H
a
HO
NHCbz
NHCbz
8
10
MeO2C
CO2Me
H
b
NHCbz
11
O
O
OH
Hb
NH
Ja,b = 3.5 Hz
Jb,c = 12 Hz
Jc,d = 5.5 Hz
Hd
Ha
HO
Hc
CO2Me
CO2Me
Cbz
10
Scheme 3. (a) OsO4 (5 mol %), NMO, acetone/H2O (3:1), 8 h, rt, 85%; (b)
(CH3)2C(OCH3)2, 2 mol % p-TSA, 6 h, rt, 95%.
product 12. Interestingly, decreasing the amount of catalyst and
reducing the reaction time (entry 4) provided 13 as the major
product. Sakaitani and Ohfune described the conversion of a Cbz
group into a triethylsilyl carbamate (NH–CO2SiEt3), which is
converted to the corresponding carbamic acid in situ and decar-
boxylated to give the free amine.53 Applying these conditions to our
substrate provided no product at all (entry 5). Using the Coleman
modification of a stoichiometric amount of Pd salt to significantly
increase the reaction rate54,55 (entry 6) provided some of the
desired product. We thus increased the loading of Pd(OAc)2 to
300 mol % and found that the deprotection and cyclization reaction
occurred in only 30 min (entry 7). In addition to the changes in
catalyst loading, we also changed the solvent to the more polar
EtOAc/EtOH mixture.56 We were then able to decrease the Pd(OAc)2
to only 30 mol %, which provided the desired product in acceptable
yield without using a large excess of the palladium salt (entry 8).
With lactam 2 in hand, we need to reduce either the lactam or
the ester without reducing the double bond. Upon reduction of one
of these carbonyl moieties, the double bond can be stereo-
selectively reduced and the final stereocenter introduced into the
molecule. The reaction of 2 with a slight excess of DIBAL cleanly
provided the alcohol with no concomitant 1,4-reduction of the
double bond. The double bond was then stereoselectively reduced
with 10% Pd/C and H2 to provide 14 as a single diastereomer.
Figure 2. Perspective view of the molecular structure of 11 with the atom labeling
scheme. The thermal ellipsoids are scaled to enclose 30% probability.
Compound 14 was unfortunately too polar to readily purify and we
thus converted it directly to the target compound 1. The lactam of
14 was reduced with LiAlH4 to the amine and then alkylated with
ethyl iodide to provide 1 in 45% overall yield from 2. With com-
pound 1 in hand, we were now able to confirm the relative ste-
reochemistry that was set in the hydrogenation of 2. A NOESY
experiment with compound 1 clearly showed NOE crosspeaks be-
tween H-3 and H-9 as well as between H-9 and H-10 (Scheme 4,
inset). This confirms the hydrogenation occurring from the less
hindered face of the bicycle 2 as one would predict.
In summary, we have developed an efficient and highly dia-
stereoselective approach to the cis-fused 3,7,8-trisubstituted dec-
ahydroquinoline 1. The epimerization in the Knoevenagel
condensation was prevented by using a tertiary amine catalyst. The
removal of the Cbz group and subsequent intramolecular cycliza-
tion was accomplished using catalytic Pd(OAc)2 and triethylsilane.
This methodology provides synthetic flexibility and opens the door
for the controlled construction of more complex alkaloids with
cis-decahydroquinoline subunits. The conversion of 1 to MLA
Table 2
Conditions for selective removal of a Cbz group from 11
MeOOC
COOMe
MeOOC
COOMe
H
H
H
H
CO2Me
O
CO2Me
O
conditions
N
H
N
H
O
O
NHCbz
11
NHCbz
13
O
O
O
O
O
O
2
12
Entry
Conditions
Product
Yield (%)
1
2
3
4
5
6
7
8
10 mol % of 10% Pd/C, H2, MeOH, 8 h
12
12
12
13
90
80
70
10 mol % of 10% Pd/C, 1,4-cyclohexadiene, solvent, 8 h
10 mol % of 10% Pd/C, HCO2NH4, solvent, 8 h
3 mol % of 10% Pd/C, H2, MeOH, solvent, 2 h
400 mol % Et3SiH, 10 mol % Pd(OAc)2, 100 mol % Et3N, CH2Cl2, rt, 16 h
120 mol % Et3SiH, 100 mol % Pd(OAc)2, 120 mol % Et3N, EtOAc, rt, 6 h
50 (þ20% of 11)a
NR
10
50
2
2
2
120 mol % Et3SiH, 300 mol % Pd(OAc)2, 120 mol % Et3N, EtOAc/EtOH (1:1), rt, 0.5 h
120 mol % Et3SiH, 30 mol % Pd(OAc)2, 120 mol % Et3N, EtOAc/EtOH (1:1), rt, 4 h
50 (þ10% of 11)
Isolated yield of an inseparable mixture of 13 and 11, ratio of 13 to 11 determined by 1H NMR.
a

J. Huang, S.C. Bergmeier / Tetrahedron 64 (2008) 6434–6439
6437
H
H
H
H
H
to rt and concentrated to afford a brown semisolid residue, which
was purified immediately by chromatography (10% EtOAc in
hexanes) to give 4 g (79%) of 7 as a white solid, mp 70–73 ꢀC. Rf 0.7
(20% EtOAc in hexanes), which matched the reported analytical
data.45
CO2Me
O
OH
a, b
O
N
H
N
H
O
O
d
O
O
2
14
3.3. Carbamic acid, [(1R
*
,6S )-6-formyl-2-cyclohexen-1-yl]-,
*
H
H
c
phenylmethyl ester (4)
OH
N
O
H
A solution of 7 (3 g, 14.8 mmol), acrolein (1.1 mL, 14.8 mmol),
and 2,6-di-tert-butyl-4-methylphenol (10 mg) in toluene (10 mL)
was placed in an Ace glassware resealable sealed tube (Cat. #
8648–86). The tube was degassed with three freeze/thaw cycles
and then filled with Ar. The tube was heated to 110 ꢀC for 90 min,
then cooled, concentrated, and chromatographed (15% EtOAc in
hexanes) to give 2.9 g (80% considering recovered 7) of 4 as
a white solid, mp 80–82 ꢀC. Rf 0.4 (20% EtOAc in hexanes); 1H NMR
H
O
15
H
H
H9
H3
OH
OH
H10
O
N
N
O
H
O
(CDCl3, 300 MHz)
J¼9.8 Hz, 1H), 5.12 (m, 3H), 4.75 (br s, 1H), 2.80 (br s, 1H), 1.92–2.15
(m, 3H), 1.58–1.80 (m, 1H); 13C NMR (CDCl3, 70 MHz)
202.7,
d 9.80 (s, 1H), 7.35 (m, 5H), 5.90 (m, 1H), 5.72 (d,
O
1
1
d
Scheme 4. (a) DIBAL-H, THF, 0 ꢀC, 4 h; (b) 10 mol % of 10% Pd/C, H2 (1 atm), MeOH, rt,
4 h; (c) LiAlH4, THF, rt, 24 h; (d) iodoethane, K2CO3, acetone, rt, 16 h, 45% over four
steps. Inset: observed NOE crosspeaks from NOESY spectra of 1.
136.2, 135.8, 130.7, 128.6, 128.2, 128.1, 126.3, 67.0, 51.0, 45.6, 23.4,
18.6; HRMS calcd for C15H17NO3Naþ 282.1101, found 282.1105
(1.4 ppm).
analogues and subsequent pharmacological assays are underway
and will be reported in due course.
3.4. Benzyl (1R
*
,6R )-6-(2,2-di(methoxycarbonyl)vinyl)-
*
cyclohex-2-enylcarbamate (8)
Et3N (0.43 mL, 3.1 mmol) and HOAc (0.18 mL, 3.1 mmol) were
simultaneously added by syringe to a vigorously stirred EtOH
(50 mL) solution of methyl malonate (1.94 mL, 17.0 mmol), alde-
hyde 4 (4.0 g, 15.4 mmol), and 4 Å molecular sieves (5.0 g). After
stirring for 6 h at rt, the solvent was removed by rotary evaporator
at rt. The resulting slurry was diluted with Et2O and filtered. The
filtrate was washed with 1 N HCl, saturated aqueous NaHCO3, and
brine, dried over MgSO4, filtered, concentrated, and chromato-
graphed (20% EtOAc in hexanes) to provide 4.6 g (80%) of 8 as
a white solid, mp 92–94 ꢀC. Rf 0.3 (20% EtOAc in hexanes); 1H NMR
3. Experimental
3.1. General
All reagents used were purchased from commercial sources or
prepared according to standard literature methods using references
given in the text and purified as necessary prior to use by standard
literature procedures. THF and CH2Cl2 were dried using a Solv-Tek
solvent purification system. Dry DMF was distilled from calcium
hydride and degassed for 10 min prior to use. Dry toluene was
distilled from calcium hydride prior to use. Column chromatogra-
phy was performed using ICN silica gel 60A. Proton (1H) and carbon
(CDCl3, 300 MHz)
d
7.36 (m, 5H), 7.04 (d, J¼10.8 Hz, 1H), 5.89 (m,
1H), 5.62 (d, J¼9.6 Hz, 1H), 5.12 (m, 2H), 4.75 (d, J¼8.9 Hz, 1H), 4.46
(
13C) magnetic resonance spectra (NMR) were recorded on a Bruker
300 MHz spectrometer, and chemical shift values are expressed in
parts per million ( ) relative to tetramethylsilane (TMS, 0 ppm) as
(br s, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.05 (br s, 1H), 2.12 (br s, 2H),
1.60–1.92 (m, 2H); 13C NMR (CDCl3, 70 MHz)
d 165.7, 164.1, 155.8,
148.5, 136.4, 130.2, 129.6, 128.5, 128.1, 127.9, 126.4, 66.9, 52.4, 48.7,
38.1, 24.8, 22.6; HRMS calcd for C20H23NO3Naþ 396.1418, found
396.1408 (2.3 ppm).
d
an internal reference. All high-resolution mass spectra (HRMS)
were acquired using positive electrospray ionization (ESI) at the
Mass Spectrometry Center of the University of Tennessee. The rel-
ative stereochemistry of all compounds is noted using the R
*
or S
*
3.5. Benzyl (1S
*
,2R
*
,3S
*
,4R )-4-(2,2-di(methoxy-
*
notation.57
carbonyl)vinyl)cyclohexyl-1,2-diol-3-enylcarbamate (10)
3.2. Benzyl trans-1,3-butadiene-
L
-carbamate (7)
To a 0 ꢀC solution of 8 (5.7 g, 15.2 mmol) and NMO (3.6 g,
30.7 mmol) in acetone/water (3:1, 100 mL) was added OsO4 (7.0 mL
of a 2.5% solution in H2O, 0.7 mmol). The reaction mixture was
warmed to rt and stirred for 8 h. A solution of Na2S2O4 (1 g) in H2O
(10 mL) was added to the reaction mixture and stirred for 20 min.
The reaction mixture was extracted with EtOAc (3ꢁ50 mL) and the
combined organic layers were washed with brine, dried over
MgSO4, filtered, concentrated, and chromatographed (50% EtOAc in
hexanes) to provide 5.3 g (85%) of 10 as a colorless oil. Rf 0.3 (50%
To a solution of trans-2,4-pentadienoic acid 6 (2.45 g, 25 mmol)
in Et2O (50 mL) at 0 ꢀC was added Et3N (3.8 mL, 27.5 mmol) fol-
lowed by diphenyl phosphoryl azide (6.0 mL, 27.5 mmol). The re-
action mixture was warmed to rt and stirred for 30 min. The
mixture was cooled to 0 ꢀC, and saturated aqueous NaHCO3 and
Et2O were added. The aqueous layer was separated and extracted
with Et2O, and the combined organic layers were dried over MgSO4,
filtered, and concentrated. Chromatography (15% EtOAc in hexane)
of the residue with a short column to remove the polar impurity
provided 3.0 g of the acylazide as a brown oil. The acylazide was
diluted with dry toluene (10 mL), and was then added over 30 min
to a vigorously stirred solution of benzyl alcohol (2.4 mL, 23 mmol)
and 2,6-di-tert-butyl-4-methylphenol (20 mg) in dry toluene
(30 mL) while a rapid reflux was maintained. Reflux was continued
for an additional 30 min, and then the reaction mixture was cooled
EtOAc in hexanes); 1H NMR (CDCl3, 500 MHz)
d 7.35 (m, 5H), 7.05
(d, J¼11.5 Hz, 1H), 5.30 (d, J¼9.6 Hz, 1H), 5.11 (m, 2H), 4.10 (ddd,
J¼12.2, 9.5, 3.5 Hz, 1H), 4.04 (br s, 1H), 3.79 (s, 6H), 3.72 (dd, J¼12.2,
4.5 Hz, 1H), 3.10 (m, 1H), 2.05 (br s, 1H), 1.84 (br s, 1H), 1.75 (t,
J¼12.5 Hz, 1H), 1.46 (dd, J¼14.0, 4.5 Hz, 1H); 13C NMR (CDCl3,
70 MHz)
d 165.7, 163.8, 157.7, 145.9, 136.1, 130.8, 128.6, 128.3, 71.7,
68.8, 67.3, 53.5, 52.7, 38.5, 25.8, 23.5; HRMS calcd for
C
20H23NO8Naþ 430.1472, found 430.1476 (1.0 ppm).

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J. Huang, S.C. Bergmeier / Tetrahedron 64 (2008) 6434–6439
3.6. Benzyl (1S
*
,2R
*
,3S
*
,4R
*
)-4-(2,2-di(methoxycarbonyl)-
1 as a yellow oil. Rf 0.35 (10% MeOH in CH2Cl2); 1H NMR (CDCl3,
300 MHz) 4.21 (m, 2H), 3.38 (m, 2H), 2.82 (m, 3H), 2.53 (m, 1H),
vinyl)cyclohexyl-1,2-diol-1,2-O-isopropylidine-
d
3-enylcarbamate (11)
2.17 (m, 1H), 1.80 (m, 6H), 1.44 (m, 4H), 1.25 (m, 5H), 1.02 (t,
J¼14.2 Hz, 3H); 13C NMR (CDCl3, 70 MHz)
d 107.4, 74.2, 71.7, 68.0,
The diol 10 (5.0 g, 12.3 mmol) was dissolved in a 2,2-dime-
thoxypropane/acetone (2:1) solution (60 mL), then TsOH$H2O
(25 mg, 0.13 mmol) and MgSO4 (5.0 g) were added. The reaction
mixture was stirred for 6 h at rt, filtered, concentrated, and chro-
matographed (30% EtOAc in hexane) to provide 5.2 g of 11 (95%) as
a white solid, mp 143–146 ꢀC. Rf 0.7 (50% EtOAc in hexanes); 1H
60.1, 49.2, 48.8, 38.1, 33.6, 28.3, 28.2, 28.1, 24.9, 13.4; HRMS (ESI)
C
15H27NO3 m/z calculated MþHþ 270.2069, measured MþHþ
270.2067 (0.7 ppm).
Acknowledgements
NMR (CDCl3, 300 MHz)
d
7.35 (m, 5H), 6.94 (d, J¼11.5 Hz, 1H), 5.15
This work was supported by grant DA13939 (SCB) from the
National Institutes on Drug Abuse at the National Institutes of
Health. We would also like to acknowledge the support of the
NanoBioTechnology Initiative funded by the office of the Vice
President for Research at Ohio University. We thank Judith Galluci
(Ohio State University Crystallography Laboratory) for the X-ray
structural determination of compound 11.
(m, 2H), 4.98 (d, J¼7.9 Hz, 1H), 4.33 (br s, 1H), 3.95 (m, 2H), 3.78 (s,
3H), 3.71 (s, 3H), 3.15 (dd, J¼11.1, 3.4 Hz, 1H), 2.05 (m, 3H), 1.54 (m,
4H), 1.36 (s, 3H); 13C NMR (CDCl3, 70 MHz)
d 166.0, 164.5, 156.7,
145.8, 136.9, 131.8, 129.1, 128.9, 128.8, 109.5, 76.2, 73.9, 67.6, 54.4,
53.4, 53.3, 39.0, 28.8, 26.8, 23.1, 21.7; HRMS calcd for C23H29NO8Naþ
470.1785, found 470.1788 (1.0 ppm).
3.7. (4aR
*
,7S
*
,8R
*
,8aR )-Methyl 1,2,4a,5,6,7,8,8a-octahydro-2-
*
References and notes
oxoquinoline-7,8-diol-7,8-O-isopropylidine-3-carboxylate (2)
1. Manske, R. H. Can. J. Res., B 1938, 16, 57.
2. Goodson, J. A. J. Chem. Soc. 1943, 139.
3. Macallan, D. R. E.; Lunt, G. G.; Wonnacott, S.; Swanson, K. L.; Rapoport, H.;
Albuquerque, E. X. FEBS Lett. 1988, 226, 357.
4. Ward, J. M.; Cockcroft, V. B.; Lunt, G. G.; Smillie, F. S.; Wonnacott, S. FEBS Lett.
1990, 270, 45.
5. Kraus, G. A.; Dneprovskaia, E. Tetrahedron Lett. 1998, 39, 2451.
6. Trigg, W. J.; Grangier, G.; Lewis, T.; Rowan, M. G.; Potter, B. V. L.; Blagbrough, I. S.
Tetrahedron Lett. 1998, 39, 893.
7. Grangier, G.; Trigg, W. J.; Lewis, T.; Rowan, M. G.; Potter, B. V. L.; Blagbrough, I. S.
Tetrahedron Lett. 1998, 39, 889.
8. Davies, A. R.; Hardick, D. J.; Blagbrough, I. S.; Potter, B. V. L.; Wolstenholme, A. J.;
Wonnacott, S. Biochem. Soc. Trans. 1997, 25, 545S.
9. Callis, D. J.; Thomas, N. F.;Pearson, D. P. J.; Potter, B. V. L. J. Org. Chem.1996, 61, 4634.
10. Coates, P. A.; Blagbrough, I. S.; Rowan, M. G.; Pearson, D. P. J.; Lewis, T.; Potter,
B. V. L. J. Pharm. Pharmacol. 1996, 48, 210.
11. Coates, P. A.; Blagbrough, I. S.; Rowan, M. G.; Potter, B. V. L.; Pearson, D. P. J.;
Lewis, T. Tetrahedron Lett. 1994, 35, 8709.
Pd(OAc)2 (68 mg, 0.3 mmol) was added to a solution of 11
(450 mg, 1.0 mmol) in dry EtOAc (6 mL). Dry EtOH (6 mL) was then
added and the reaction mixture stirred for 5 min, and then freshly
distilled triethylsilane (0.19 mL, 1.2 mmol) was added, immediately
followed by the addition of dry Et3N (0.17 mL, 1.2 mmol). The
reaction mixture was stirred for an additional 30 min (until TLC
indicated the starting material was consumed) and the reaction
mixture was diluted with CH2Cl2, filtered through a Celite pad,
washed with saturated aqueous NaHCO3 and brine, dried over
MgSO4, filtered, concentrated, and chromatographed (5% MeOH in
CH2Cl2) to provide 140 mg (50%) of 2 as a brown oil. Rf 0.2 (50%
EtOAc in hexanes); 1H NMR (CDCl3, 300 MHz)
d
6.90 (d, J¼11.5 Hz,
1H), 6.45 (d, J¼10.5 Hz, 1H), 4.09 (m, 1H), 3.85 (s, 3H), 3.78 (m, 2H),
3.50 (m, 1H), 1.98 (m, 3H), 1.36 (m, 4H), 1.20 (m, 3H); 13C NMR
12. Baillie, L. C.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc., Chem. Commun. 1994,
2487.
13. Doisy, X.; Blagbrough, I. S.; Wonnacott, S.; Potter, B. V. L. Pharm. Pharmacol.
Commun. 1998, 4, 313.
14. Baillie, L. C.; Bearder, J. R.; Sherringham, J. A.; Whiting, D. A. J. Chem. Soc., Perkin
Trans. 1 1997, 7687.
(CDCl3, 70 MHz)
d 166.7, 160.5, 143.8, 131.0, 109.5, 75.5, 73.6, 54.4,
52.5, 38.4, 28.2, 26.2, 22.4, 21.1; HRMS (ESI) C14H19NO5 m/z calcu-
lated MþHþ 282.1341, measured MþHþ 282.1346 (1.8 ppm).
15. Simoni, D.; Rossi, M.; Rondanin, R.; Baruchello, R.; Grisolia, G.; Eleopra, M.;
Giovannini, R.; Bozzoli, A.; Davalli, S.; Di Fabio, R.; Daniele, D. Tetrahedron Lett.
2005, 46, 759.
16. Carroll, F. I.; Ma, W.; Navarro, H. A.; Abraham, P.; Wolckenhauer, S. A.; Damaj,
M. I.; Martin, B. R. Bioorg. Med. Chem. 2007, 15, 678.
3.8. ((3S
*
,4aR
*
,7S
*
,8R
*
,8aR )-1-Ethyl-decahydroquinolin-7,8-
*
diol-7,8-O-isopropylidine-3-yl)methanol (1)
Compound 2 (310 mg, 1.1 mmol) was dissolved in THF (20 mL)
and cooled to 0 ꢀC. DIBAL-H (1.3 mL of a 1.0 M solution in hexane,
1.3 mmol) was added and the reaction mixture stirred for 4 h. The
reaction was quenched with MeOH until no additional gas (H2)
release was observed and then NaF (50 mg, 1.19 mmol) was added.
The mixture was stirred for 2 h at rt, filtered, and concentrated to
provide the crude allylic alcohol. The crude alcohol was dissolved in
MeOH (20 mL) and then 10% Pd/C (106 mg) was added. The reaction
mixture was then stirred under an H2 atmosphere (balloon) for 4 h.
The reaction mixture was filtered through a Celite pad and con-
centrated to give 216 mg (77%) of crude 14, which was used directly
in next step. Crude compound 14 (216 mg, 0.85 mmol) was dis-
solved in THF (10 mL) and cooled to 0 ꢀC, followed by the addition
of LiAlH4 (100 mg, 2.6 mmol). The reaction mixture was warmed to
rt and stirred for 24 h. The reaction mixture was then diluted with
Et2O. To this mixture was sequentially added H2O (0.11 mL), 15%
aqueous NaOH (0.11 mL), and H2O (2.6 mL). The reaction mixture
was stirred for an additional 30 min at rt, filtered, and concentrated
to give 144 mg (0.6 mmol, 70% yield) crude 15 as a colorless oil.
Amine 15 was dissolved in acetone (8 mL), then iodoethane
(0.06 mL, 0.72 mmol) and K2CO3 (332 mg, 2.4 mmol) were added,
and the reaction mixture was stirred for 16 h at rt. The reaction
mixture was then filtered, concentrated, and chromatographed (5%
MeOH in CH2Cl2) to provide 133 mg (81%, 45% from compound 2) of
17. Lin, D. S. H.; Chebib, M.; McLeod, M. D. Acta Pharmacol. Sinica 2006, 27, 390.
18. Lehmann, A.; Brocke, C.; Barker, D.; Brimble, M. A. Eur. J. Org. Chem. 2006, 3205.
19. Goodall, K. J.; Barker, D.; Brimble, M. A. Synlett 2005, 1809.
20. Barker, D.; Lin, D. H. S.; Carland, J. E.; Chu, C. P. Y.; Chebib, M.; Brimble, M. A.;
Savage, G. P.; McLeod, M. D. Bioorg. Med. Chem. 2005, 13, 4565.
21. Kraus, G. A.; Kesavan, S. Tetrahedron Lett. 2005, 46, 1111.
22. Barker, D.; Brimble, M. A.; McLeod, M. D. Tetrahedron 2004, 60, 5953.
23. Barker, D.; Brimble, M. A.; McLeod, M. D.; Savage, G. P. Org. Biomol. Chem. 2004,
2, 1659.
24. Barker, D.; McLeod, M. D.; Brimble, M. A.; Savage, G. P. Tetrahedron Lett. 2002,
43, 6019.
25. Barker, D.; Brimble, M. A.; McLeod, M.; Savage, G. P.; Wong, D. J. J. Chem. Soc.,
Perkin Trans. 1 2002, 924.
26. Bergmeier, S. C.; Lapinsky, D. J.; Free, R. B.; McKay, D. B. Bioorg. Med. Chem. Lett.
1999, 9, 2263.
27. Bryant, D. L.; Free, R. B.; Thomasy, S. M.; Lapinsky, D. J.; Ismail, K. A.; McKay,
S. B.; Bergmeier, S. C.; McKay, D. B. Neurosci. Res. 2002, 42, 57.
28. Bryant, D. L.; Free, R. B.; Thomasy, S. M.; Lapinsky, D. J.; Ismail, K. A.; Arason, K.
M.; Bergmeier, S. C.; McKay, D. B. In Chromaffin Cell: Transmitter Biosynthesis,
Storage, Release, Actions, and Informatics; New York Academy of Sciences: New
York, NY, 2002; pp 139.
29. Bergmeier, S. C.; Ismail, K. A.; Arason, K. M.; McKay, S.; Bryant, D. L.; McKay, D.
B. Bioorg. Med. Chem. Lett. 2004, 14, 3739.
30. McKay, D. B.; Chang, C.; Gonzalez-Cestari, T. F.; McKay, S. B.; El-Hajj, R. A.;
Bryant, D. L.; Zhu, M. X.; Swaan, P. W.; Arason, K. M.; Pulipaka, A. B.; Orac, C. M.;
Bergmeier, S. C. Mol. Pharmacol. 2007, 71, 1288.
31. Daly, J. W.; Tokuyama, T.; Habermehl, G.; Karle, I.; Witkop, B. Liebigs Ann. Chem.
1969, 729, 198.
32. Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556.
33. Xu, H.; Tang, X. C. Acta Pharmacol. Sinica 1987, 8, 18.
34. Li, C. P.; Blackman, A. J. Aust. J. Chem. 1995, 48, 955.

J. Huang, S.C. Bergmeier / Tetrahedron 64 (2008) 6434–6439
6439
35. Blackman, A. J.; Li, C. P.; Hockless, D. C. R.; Skelton, B. W.; White, A. H. Tetra-
hedron 1993, 49, 8645.
49. Tietze, L. F.; Beifuss, U. Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; p 341.
36. Neidhofer, J.; Blechert, S. Synthesis 2004, 3047.
37. Ozawa, T.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 2001, 66, 3338.
38. Pu, X.; Ma, D. J. Org. Chem. 2006, 71, 6562.
50. Alt, G. H.; Gallegos, G. A. J. Org. Chem. 1971, 36, 1000.
51. Frasier-Reid, B.; Molino, B. F.; Magdzinski, L.; Mootoo, D. R. J. Org. Chem. 1987, 52,
4495.
39. Wipf, P.; Wang, X. Tetrahedron Lett. 2000, 41, 8747.
52. Crystallographic data (excluding structure factors) for compound 11 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 677136. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-
(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
53. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
54. Coleman, R. S. Synlett 1998, 1031.
55. Coleman, R. S.; Carpenter, A. J. Tetrahedron 1997, 53, 16313.
56. Reding, M. T.; Fukuyama, T. Org. Lett. 1999, 1, 973.
40. Overman, L. E.; Lesuisse, D.; Hashimoto, M. J. Am. Chem. Soc. 1983, 105, 5373.
41. Overman, L. E.; Taylor, G. F.; Houk, K. N.; Domelsmith, L. N. J. Am. Chem. Soc.
1978, 100, 3182.
42. Overman, L. E.; Clizbe, L. A. J. Am. Chem. Soc. 1976, 98, 2352.
43. Overman, L. E.; Jessup, P. J. Tetrahedron Lett. 1977, 1253.
44. Overman, L. E.; Taylor, G. F.; Jessup, P. J. Tetrahedron Lett. 1976, 3089.
45. Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. Org. Synth. 1979, 59, 1.
46. Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. Org. Chem. 1978, 43, 2164.
47. Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203.
48. Jones, G. Org. React. 1967, 15, 204.
57. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds;
Wiley: New York, NY, 1994; p 1260.