Synthesis of Octahydro- and Decahydroquinolines by a One-Pot Cascade Reaction of Tetrasubstituted Enecarbamate

Article abstract of DOI:10.1021/acs.orglett.7b02122

A transition-metal-catalyzed cyclopropanation followed by ring opening was investigated for the synthesis of octahydroquinolines 4 and decahydroquinolines 5 having a quaternary carbon center at the angular position, which are core structures of the fawcettimine-type alkaloids. A tandem reaction was also established for the synthesis of decahydroquinolines 5 and the tricyclic compound 6 through an iminium ion intermediate, readily produced by acidic treatment of cyclopropane 2.

Full text of DOI:10.1021/acs.orglett.7b02122

Letter
pubs.acs.org/OrgLett
Synthesis of Octahydro- and Decahydroquinolines by a One-Pot
Cascade Reaction of Tetrasubstituted Enecarbamate
Tomohiro Kurose, Chihiro Tsukano,* and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
S
* Supporting Information
ABSTRACT: A transition-metal-catalyzed cyclopropanation followed by ring opening was investigated for the synthesis of
octahydroquinolines 4 and decahydroquinolines 5 having a quaternary carbon center at the angular position, which are core
structures of the fawcettimine-type alkaloids. A tandem reaction was also established for the synthesis of decahydroquinolines 5
and the tricyclic compound 6 through an iminium ion intermediate, readily produced by acidic treatment of cyclopropane 2.
awcettimine, isolated from Lycopodium fawcettii by Burnell
various alkaloids such as fendleridine.9 Therefore, the develop-
ment of a concise synthetic method for these skeleta would
contribute to the synthesis of not only fawcettimine-type
alkaloids but also related natural products.
F
and co-workers in 1959, is one of the representative
Lycopodium alkaloids (Figure 1).1 It is one of more than 80
Considering a synthesis of various analogues, we envisioned
that an intramolecular cyclopropanation of tetrahydropyridine 1
followed by a ring opening would give both octa- and
decahydroquinoline 4 and 5, respectively (Scheme 1). That is,
Scheme 1. Synthetic Strategy for Diverse Decahydro- and
Octahydroquinolines
Figure 1. Fawcettimine-type alkaloids and a natural product containing
both octa- and decahydroquinoline skeletons.
congeners reported to date, which include fawcettidine,1,2
macleanine,3 and squarrosusine B,4 each of which belong to
the fawcettimine class of alkaloids. Recently, new members of
this alkaloid class, such as lyconesidines,5 have been found in
related species. Among these compounds, a complex tetracyclic
skeleton is common, and the structural diversity mainly derives
from the oxidation level and substituents on the B and D rings.6
Because of its unique tetracyclic structure, many groups are
engaged in synthetic studies of the fawcettimine-type alkaloids.7,8
The main focus of these studies has been the synthesis of the
hydrindane skeleton (B and D rings), and they are based on
Heathcock and Inubushi’s pioneering work.8p,q As an exceptional
strategy, Dake and Kozak reported Pt(II)-catalyzed cyclization to
construct an octahydroquinoline skeleton having a quaternary
carbon (C and D rings),8n while Dake’s synthesis proposed the
possibility of an octahydroquinoline skeleton as a useful
intermediate. Additionally, the skeleton has been found in
by introducing an electron-withdrawing group as a substituent
(R3 = EWG), a ring-opening of cyclopropane 2 would readily
produce an iminium intermediate 3,10 which would be converted
to 4 and 5 by a proton transfer and stereoselective reduction,
respectively. It was expected that various substituents could be
introduced into the obtained compounds 4 and 5 by using
ketone functionality for the synthesis of fawcettimine-type
alkaloids. Moreover, the iminium intermediate 3, derived from a
substrate having a hydroxyethyl group (R2 = CH2CH2OH),
would be intramolecularly trapped with an alcohol to give a
Received: July 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02122
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tricyclic compound 6, which can be found in a fendleridine
skeleton. While there are many reports about cyclopropanation
of monosubstituted enamides and ene carbamates,11,12 the
number of reports decreases as the number of substituents
increases. In the case of tetrasubstituted enamides and ene
carbamates, pyrolysis of tosylhydrazone13a and formation of
carbene from chloroform via treatment of a strong base13b were
only employed for cyclopropanation.14 Thus, there is no example
of the use of a transition-metal−carbene complex. Herein, we
report synthesis of octahydroquinolines 4, decahydroquinolines
5, and tricyclic compound 6 having a quaternary carbon center at
the angular position via a transition-metal-catalyzed cyclo-
propanation of tetrasubstituted ene carbamate and a ring-
opening.
Table 1. Transition-Metal-Catalyzed Cyclopropanation of
Tetrasubstituted Enecarbamate 1a
a
yield (%)
entry
cat.
time
10 h
2a
4a
12
1
2
3
4
5
Cu(OTf)2
Cu(hfacac)2
Rh2(cap)4
Rh2(OAc)4
0
13
42
52
57
0
33
0
70
0
b
24 h
2.5 h
0
Initially, cyclization precursors 1a−h were synthesized from 2-
piperidone in six to eight steps including Heck or Suzuki−
Miyaura coupling, 1,4-reduction,15 and diazotransfer16 (Scheme
2). We then investigated transition-metal-catalyzed cyclo-
30 min
15 min
0
0
c
Rh2(esp)2
0
0
a
b
c
Isolated yield. 60 mol %. 0.1 mol %. Tf = triflate, hfacac =
hexafluoroacetylacetonato, cap = caprolactamate, esp = α,α,α′,α′-
tetramethyl-1,3-benzenedipropionic acid.
Scheme 2. Synthesis of Tetrasubstituted Enecarbamate 1
Table 2. Selective Formation of Octahydroquinoline 4a and
Decahydroquinoline 5a
a
yield (%)
entry Lewis acid or H+
reductant
none
time
4a
5a
b
1
TFA
30 min
30 min
2 h
96
95
56
40
17
0
b
2
BF3·OEt2
TFA
none
0
0
0
3
Et3SiH
4
TFA
Ph3SiH
5 h
5
TFA
NaBH3CN
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
NaBH(OAc)3
2 h
0
c
c
6
TFA
2 h
22
72
d
e
c
c
7
BF3·OEt2
11 h
15 min
3 h
23
31
f
8
Ti(OiPr)4
AlCl3
29
0
0
0
9
59
28
60
10
11
Sc(OTf)3
2 h
MgBr2·OEt2
3 h
0
d
a
b
c
1
Isolated yield. 1 equiv. The yield was calculated by H NMR.
equiv. 10 equiv. The starting material was recovered (31%). TFA =
6
propanation of tetrasubstituted ene carbamate 1a. When
compound 1a was treated with Cu(OTf)2, diketone 12 was
obtained in 70% yield via a ring-opening of cyclopropane
followed by hydrolysis (Table 1, entry 1). Although Cu(hfacac)2
could be used for suppressing a ring-opening of cyclopropane, a
part of the desired product 2a was converted to octahydroquino-
line 4a, which was a mixture of keto and enol tautomers owing to
the presence of an acidic proton (entry 2). In contrast, the use of
rhodium catalysts, including Rh2(OAc)4, Rh2(cap)4,17 and
Rh2(esp)2,18 was effective for suppressing the undesired side
reactions (entries 3−5). Specifically, Rh2(esp)2 gave hexasub-
stituted cyclopropane 2a in 57% yield without compounds 4a
and 12 (entry 5). For reproducible isolation of the product 2a,
addition of triethylamine into an eluent for silica gel column
chromatography was important because 2a was not stable on
silica gel.
e
f
trifluoroacetic acid.
These results indicated that cyclopropane 2a was readily cleaved
to produce an iminium ion such as 3. Thus, reduction of the
iminium ion was examined for obtaining decahydroquinoline 5a.
When compound 2 was treated with Et3SiH, Ph3SiH, or
NaBH3CN under acidic conditions (TFA), these reductions
did not proceed (entries 3−5). In sharp contrast, use of
NaBH(OAc)3 was effective, and the reaction gave the desired
product 5a in 72% yield along with a small amount of 4a (entry
6). Several Lewis acids were also examined instead of TFA. In the
case of BF3·OEt2, the reaction gave 5a, but the yield was low
(31%, entry 7). In contrast, a combination of NaBH(OAc)3 and
other Lewis acids, including Ti(OiPr)4, AlCl3, Sc(OTf)3, and
MgBr2·OEt2, gave only octahydroquinoline 4a in low to
moderate yields (entries 8−11). Therefore, BF3·OEt2 was
employed for opening the cyclopropane ring to access
compound 4, and a combination of TFA and NaBH(OAc)3
was determined to provide the best conditions for the synthesis
of compound 5. Reduction of the iminium intermediate 3a
We next focused on the selective transformation of the
hexasubstituted cyclopropane 2a into octahydroquinoline 4a and
decahydroquinoline 5a. When compound 2a was treated with
trifluoroacetic acid (TFA) or BF3·OEt2, ring-opening of
cyclopropane was followed by a proton transfer to give
compound 4a in excellent yields (Table 2, entries 1 and 2).
B
DOI: 10.1021/acs.orglett.7b02122
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Organic Letters
Letter
proceeded with excellent stereoselectivity because the reductant
attacked from the less hindered face (Scheme 3). Because 5a was
Table 3. Scope and Limitations of Synthesis of
Octahydroquinoline 4
Scheme 3. Stereoselectivity of the Reduction of Iminium
Intermediate 3a
a mixture of keto and enol tautomers, the stereochemistry of the
trans-fused ring system was determined by NOESY experiments
after formation of tert-butyldimethylsilyl (TBS) enol ether 13a
(Scheme 3). For the synthesis of compound 5a, compound 4a
was also treated under the optimized reduction conditions (TFA
and NaBH(OAc)3, rt). However, the reaction did not proceed to
give 5a. This result indicated that the iminium ion 3a was not
produced from compound 4a under these mild conditions.
To determine the scope and limitations, the optimized
conditions were applied for the synthesis of several octahy-
droquinolines 4b−h (Table 3). Cyclopropanation of substrates
1b and 1c having CO2Me and Boc groups as protecting groups
gave compounds 2b and 2c in moderate yields, respectively
(entries 1 and 2). Compound 2b readily converted to
octahydroquinoline 4b when treated with BF3·OEt2. In the
case of 2c, MgBr2·OEt2 was used instead of BF3·OEt2 for
suppressing the undesired deprotection of the Boc group.
Compound 4c was obtained in excellent yield. Interestingly, the
reaction of 1d with its tosyl group gave 4d in 76% yield without
acidic treatment, as the corresponding cyclopropane 2d was
easily cleaved (entry 3). The reaction of β-keto-α-diazoester 1e
did not give compound 2e. Thus, a nitrile group is essential for
this cyclopropanation (entry 4). The reaction of 1f did not give
cyclopropane 2f because C−H insertion was competitive (entry
5). Benzyl (Bn) and TBS groups were compatible under these
reactions, and octahydroquinolines 4g and 4h were obtained in
80% and quantitative yields, respectively (entries 6 and 7).
Because compound 2 was not stable as described above, a one-
pot cyclopropanation/reductive ring-opening was attempted for
the synthesis of decahydroquinolines 5. Treatment of 1a with
Rh2(esp)2 was followed by reductive ring opening using TFA and
NaBH(OAc)3 to give decahydroquinoline 5a in 48% yield, which
was comparable to the yield of the stepwise procedure (Table 4,
entry 1). Methoxycarbonyl and Boc groups were compatible
under these conditions (entries 2 and 3). In the case of substrates
having Bn and TBS groups, the desired decahydroquinolines 5g
and 5h were obtained as major products, respectively, while the
reductive ring opening competed with formation of octahy-
droquinolines 4g and 4h.
a
b
c
Isolated yield. MgBr2·OEt2 was used instead of BF3·OEt2. Without
d
acidic treatment. The reaction time was 35 min. Bn = benzyl, TBS =
tert-butyldimethylsilyl.
Table 4. One-Pot Cyclopropanation and Reductive Ring-
Opening for Synthesis of Decahydroquinoline 5
yield
a
(%)
b
of
ratio
entry
R1
Cbz
R2
time
product 5 + 4 of 5:4
c
1
Et
Et
Et
2 h
50 min
45 min
8 h
5a
5b
5c
5g
5h
48
64
77
47
43
4.0:1
7.3:1
6.5:1
3.3:1
3.8:1
d
2
CO2Me
Boc
d
3
4
Cbz
CH2CH2OBn
d
5
Cbz
CH2CH2OTBS
2 h
a
b
c
1
Isolated yield. The ratio was calculated by H NMR. 0.1 mol % of
d
Rh2(esp)2 was used. Rh(OAc)2 was used instead of Rh2(esp)2.
This one-pot procedure for decahydroquinolines 5 was
extended to a one-pot synthesis of tricyclic compound 6
(Scheme 4). Treatment of β-keto-α-diazonitrile 1i with
Rh2(esp)2 followed by BF3·OEt2 gave compound 6 via
cyclopropanation in 66% yield. It is interesting that the
cyclopropanation was the preferable process rather than O−H
insertion in the first step, and an iminium ion could be trapped
without formation of ene carbamate in the second step. It was
difficult to obtain compound 6 from octahydroquinoline 4i
C
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Organic Letters
Letter
(7) For recent reviews of synthesis of fawcettimine-type alkaloids, see:
(a) Murphy, R. A.; Sarpong, R. Chem. - Eur. J. 2014, 20, 42.
(b) Nakayama, A.; Kitajima, M.; Takayama, H. Synlett 2012, 23, 2014.
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Scheme 4. One-Pot Synthesis of Tricyclic Compound 6
(8) For selected examples of synthesis of fawcettimine-type alkaloids,
see: (a) Tanimura, S.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2017, 19,
3684. (b) Hong, B.; Li, H.; Wu, J.; Zhang, J.; Lei, X. Angew. Chem., Int.
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under mild conditions including treatment with BF3·OEt2 or
CSA.
In summary, we have investigated a concise synthesis of
octahydroquinolines 4 and decahydroquinolines 5 having a
quaternary carbon center at the angular position via a one-pot
reaction involving cyclopropanation and ring opening. The use
of Ts-protected ene−sulfonamide 1d was found to be effective
for direct access to 4. One-pot procedures for the synthesis of
decahydroquinolines 5 and tricyclic compound 6 were also
established. These methods would be powerful because a
quaternary carbon center and a six-membered carbocycle were
constructed at once. Synthesis of related alkaloids based on the
developed strategy for decahydroquinolines 5 is now underway.
ASSOCIATED CONTENT
* Supporting Information
■
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02122.
(10) For recent reviews of ring-opening of aminocyclopropane with an
electron-withdrawing group, see: (a) Grover, H. K.; Emmett, M. R.;
Kerr, M. A. Org. Biomol. Chem. 2015, 13, 655. (b) Schneider, T. F.;
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Experimental procedures and spectral data (1H and 13C
NMR, IR, and HRMS) (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tsukano@pharm.kyoto-u.ac.jp.
*E-mail: takemoto@pharm.kyoto-u.ac.jp.
ORCID
Chihiro Tsukano: 0000-0002-9361-0857
Yoshiji Takemoto: 0000-0003-1375-3821
Notes
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Rashatasakhon, P.; Ozdemir, A. D.; Willis, J. J. Org. Chem. 2005, 70, 519.
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indole ring having two substituents at the C2 and C3 positions; see:
(a) Huang, H.-X.; Jin, S.-J.; Gong, J.; Zhang, D.; Song, H.; Qin, Y. Chem.
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Chem. Soc. 2009, 131, 6013. (e) Salim, M.; Capretta, A. Tetrahedron
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the JSPS KAKENHI (Grant No.
JP17H05051), the Platform Project for Supporting Drug
Discovery and Life Science Research from Japan Agency for
Medical Research and Development (AMED).
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DOI: 10.1021/acs.orglett.7b02122
Org. Lett. XXXX, XXX, XXX−XXX