One-pot organocatalytic enantioselective domino double-michael reaction and Pictet-Spengler-Lactamization reaction. a facile entry to the inside yohimbane system with five contiguous stereogenic centers

Article abstract of DOI:10.1021/ol3032329

An expedited method was developed for the enantioselective synthesis of dodecahydrobenz[a]indolo[3,2-h]quinolizine containing five contiguous stereogenic centers with high enantioselectivities (>99% ee). The methodology comprises a domino organocatalytic double Michael reaction and Pictet-Spengler-lactamization reaction. The structures and absolute configurations of the appropriate products were confirmed by X-ray analysis.

Full text of DOI:10.1021/ol3032329

ORGANIC
LETTERS
2013
Vol. 15, No. 3
468–471
One-Pot Organocatalytic Enantioselective
Domino Double-Michael Reaction and
Pictet-SpenglerÀLactamization Reaction.
A Facile Entry to the “Inside Yohimbane”
System with Five Contiguous Stereogenic
Centers
Bor-Cherng Hong,* Wei-Kai Liao, Nitin S. Dange, and Ju-Hsiou Liao
Department of Chemistry and Biochemistry, National Chung Cheng University,
Chia-Yi, 621 Taiwan, R.O.C.
chebch@ccu.edu.tw
Received November 23, 2012
ABSTRACT
An expedited method was developed for the enantioselective synthesis of dodecahydrobenz[a]indolo[3,2-h]quinolizine containing five con-
tiguous stereogenic centers with high enantioselectivities (>99% ee). The methodology comprises a domino organocatalytic double Michael reactionand
Pictet-SpenglerÀlactamization reaction. The structures and absolute configurations of the appropriate products were confirmed by X-ray analysis.
The quinolizidine alkaloids represent an important class
of alkaloids with a wide spectrum of biological activities
and have long attracted extensive pharmacological, chem-
ical, and synthetic interests.1 Among these compounds,
the dodecahydrobenz[a]indolo[3,2-h]quinolizine, the
so-called “inside yohimbane”, emerged as a preeminent
member of this alkaloid category. Examples of natural and
synthetic compounds bearing the dodecahydrobenz-
[a]indolo[3,2-h]quinolizine skeleton have shown various
biological activities (Figure 1). Manadomanzamine A
and manadomanzamine B have anti HIV, antifungal,
antimycobacterial, and cytotoxic activities;2 21a-homo-
14-nor-yohimba-15,17,19-triene has high affinity for the R1
adrenergic receptors;3 2,3,4,4aβ,5,6,7,8,13,13bβ-decahydro-
1H-6a,13-diazaindeno[1,2-c]phenanthren-13cβ-ol has high
affinity for the R2C-adrenoceptor;4 pentacyclic benzindo-
loquinolizine has been reported to have antiserotoninergic
effects.5 The inside R-yohimbine intermediates have been
prepared following the method for the total synthesis of
reserpine and R-yohimbane.6 Although several synthetic
approaches toward the “inside yohimbane” skeleton have
(3) (a) Hoefgen, B.; Decker, M.; Mohr, P.; Schramm, A. M.; Rostom,
S. A. F.; El-Subbagh, H.; Schweikert, P. M.; Rudolf, D. R.; Kassack,
M. U.; Lehmann, J. J. Med. Chem. 2006, 49, 760–769. (b) Abadi, A. H.;
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Hill, R. T.; Franzblau, S. G.; Zhang, F.; Schinazi, R. F.; Wirtz, S. S.;
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Chem. Soc. 2003, 125, 13382–13386. (b) Rao, K. V.; Donia, M. S.; Peng,
J.;Garcia-Palomero, E.;Alonso, D.;Martinez, A.;Medina, M.;Franzblau,
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M. T. J. Nat. Prod. 2006, 69, 1034–1040.
(4) Orion Corporation, WO2003/82866 A1, 2003.
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K.; Lehmann, J. Bioorg. Med. Chem. Lett. 2007, 17, 1399–1402. (b)
Enzensperger, C.; Lehmann, J.; Schroetter, K.; Riyazi, A.; Verspohl,
E. J. Arzneimittelforschung 2010, 60, 544–552.
r
10.1021/ol3032329
Published on Web 01/11/2013
2013 American Chemical Society

been reported,7 the construction of this pentacyclic ring
system with five stereogenic centers in a cascade strategy
with high enantioselectivity remains elusive. An efficient
synthetic methodology toward this system with suitable
functionality is certainly attractive and would be useful for
discovering pharmaceutical lead compounds.
Table 1. Screening of the Catalysts, Solvents, and Reaction
Conditions for the Stereoselective Double Michael Reactiona
entry
cat.Àadditive
solvent
CHCl3
time (h)
yieldb,c (%)
1
2
IÀDABCO
7
96
96
44
96
96
19
41
96
64
72
10
96
61
96
43
39
18
39
39
84
IIÀDABCO
IIIÀDABCO
IVÀDABCO
VÀDABCO
VIÀDABCO
VIIÀDABCO
VIIIÀDABCO
IVÀDABCO
IVÀDABCO
IVÀDABCO
IVÀDABCO
IVÀDABCO
IVÀDABCO
IVÀDABCO
IVÀEt3N
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
CH2Cl2
THF
50
3
nr
4
83d
0
5
6
56
7
15
8
trace
41
9
10
11
12
13
14
15
16
17
18
19
20
89d
80
EtOHe
DMF
90d,f
71
CH3CN
1,4-dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
90d,g
59
68
IVÀNaOAc
IVÀDBU
62
65
IVÀ2,6-lutidine
IVÀHOAc
65
Figure 1. Select examples of the biologically active natural prod-
ucts and synthetic compounds with dodecahydrobenz[a]indolo-
[3,2-h]quinolizine skeleton.
41
a Unless otherwise noted, the reactions were performed on a 0.1 mmol
scale of 3a and 4a (1.2 equiv) using 20 mol % of the catalyst and additive at
ambient temperature in a vial containing the appropriate solvent. b Isolated
yields of 5a. c Unless otherwise noted, diastereomeric ratio >20:1, deter-
mined by 1H NMR of the reaction mixture. d >99% ee of 5a, determined
by HPLC with chiral column Chiralpak IA. e 99% ethanol. f Diastereo-
meric ratio 16:1. g Diastereomeric ratio 17:1, nr = no reaction.
Scheme 1. Retrosynthetic Analysis of Dodecahydrobenz-
[a]indolo[3,2-h]quinolizine
Prompted by the above background and in the context
of our ongoing investigations in organocatalyzed annula-
tions,8,9 we envisioned that the lactamization and PictetÀ
Spengler10 transformation of the “inside yohimbane” system
(8) For a recent review of organocatalyzed cycloadditions, see: Hong,
B.-C. In Enantioselective Organocatalyzed Reactions II; Mahrwald, R.,
Ed.; Springer: Dordrecht, 2011; Chapter 3, pp 187À244.
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Org. Lett. 2012, 14, 5346–5349. (b) Hong, B.-C.; Chen, P.-Y.; Kotame,
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7792. (c) Hong, B.-C.; Dange, N. S.; Ding, C.-F.; Liao, J.-H. Org. Lett.
2012, 14, 448–451. (d) Hong, B.-C.; Hsu, C.-S.; Lee, G.-H. Chem.
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G.-H. Org. Lett. 2011, 13, 5758–5761. (f) Hong, B.-C.; Dange, N. S.;
Hsu, C.-S.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2011, 13, 1338–1341. (g)
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Org. Lett., Vol. 15, No. 3, 2013
469

1 would lead to the precursor, cyclohexylcarbaldehyde 2,
which could be efficiently prepared via a domino organo-
catalyzed double Michael reaction11 of the suitable nitro
alkenoate 3 and R,β-unsaturated aldehyde 4 (Scheme 1).
We report herein the development of a one-pot organoca-
talytic enantioselective domino double-Michael reaction
and PictetÀSpenglerÀlactamization reaction sequence
leading to dodecahydrobenz[a]indolo[3,2-h]quinolizines
in good yields and excellent diastereoselectivities and en-
antioselectivities (up to >99% ee).
with >99% ee for the reaction in CH2Cl2 (Table 1, entries
9À15 and entry 10). The reactions in 99% EtOH or CH3CN
gave slightly lower diastereoselectivity (Table 1, entries 12
and 14). Reactions performed with catalysts IV and other
additives were not promising and provided lower yields
(Table 1, entries 16À20).
The PictetÀSpengler reaction and lactamization was
achieved by the reaction of 5a, isolated from the reaction
depicted in Table 1, and 1.5 equiv of 2-(1H-indol-3-yl)-
ethanamine (6a) with 1.4 equiv of trifluoroacetic acid
(TFA) in refluxing toluene for 1 h to give 73% yield of
7a. Notably, the domino reaction sequence, the double-
Michael, and the PictetÀSpengler reactions could be
achieved in one pot without the need to isolate the double
Michael adducts 5a. The one-pot reaction strategy was
achieved via the addition of toluene in the reaction mix-
tures after the completion of double Michael reaction in
CH2Cl2, followed by treatment with 6a and TFA, to
provide 77% yield of 7a with >99% ee. In addition, the
one-pot process provided a slightly better yield than that
obtained with the isolation of 5a and the resubmission
sequence of the PictetÀSpenglerÀlactamization reaction
(Table 2, entry 1). With the optimized conditions in hand, the
one-pot domino-reaction protocol was applied in the reaction
with various R,β-unsaturated aldehydes 4, and the results
were promising and general with high yields and stereoselec-
tivities (Table 2). Usually, the reaction was completed in 2
days, but a much longer reaction time was required in the case
with 4h bearing the ortho-substituent. The steric bulkiness so
close to the conjugate addition center may encumber the
reactions (Table 2, entry 8). The structures of the adducts
were assigned on the basis of the X-ray analysis of a single
crystal of (À)-7a (Figure 1).12 In particular, the absolute
configurations of the products were unambiguously deter-
mined by the X-ray analysis of (À)-7c (Figure 2).13
Table 2. Scope of Organocatalytic Double-MichaelÀPictetÀ
Spengler Reactionsa
entry
R1
R2
timeb (h) yieldc,d (%) eee (%)
1
2
7a, C6H5
H
34
36
25
36
26
36
31
168
25
44
38
77
82
83
62
77
82
84
76
83
65
86
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
7b, 4-FC6H4
7c, 4-ClC6H4
7d, 4-BrC6H4
7e, 4-NO2C6H4
7f, 4-MeOC6H4
7g, 4-NMe2C6H4
7h, 2-MeC6H4
7i, 4-MeC6H4
7j, 2-furyl
H
3
H
4
H
5
H
6
H
7
H
8
H
9
H
10
11
H
7k, C6H5
OMe
a Unless otherwise noted, the reactions were performed on a 0.2 mmol
scale of 3 and 4, in a ratio of 1:1.2, using 20 mol % of the catalyst IV and
DABCO at room temperature in a vial containing the appropriate solvent.
b Time required for 1stÀdouble Michael reaction. c Isolated yield of 7.
d Diastereomeric ratio >20:1, determined by 1H NMR of crude reaction
mixture. e The ee of 7, determined by HPLC with Chiralpak IA.
Initially, the double Michael reaction of nitroalkenoate
3 and cinnamaldehyde 4a was performed with pyrrolidine
(I)ÀDABCO in CHCl3 at ambient temperature for 7 h and
provided the cyclohexylcarbaldehyde 5a in 84% yield
(Table 1, entry 1). After the reactions were screened with
other catalysts, e.g., IIÀVIII, the best result was obtained
with the condition of IVÀDABCO for 44 h reaction to give
83% yield of 5a with >99% ee (Table 1, entry 4). The
reactions with other catalysts afforded much lower yield,
or there was no observation of product 5a (Table 1, entries
1À8). Further optimization of the double-Michael reac-
tion with IVÀDABCO in various solvents was conducted,
and the optimal yield of 5a was obtained in 89% yield
Figure 2. Stereoplots of the X-ray crystal structures of (À)-7a
and (À)-7c: C, gray; O, red; N, blue; Cl, green.
(12) X-ray crystal structure analysis of (À)-7a: C25H25N3O3, weight
415.48 g molÀ1, colorless crystal. CCDC-909086 contains the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
(13) X-ray crystal structure analysis of (À)-7c: C25H24ClN3O3,
weight 449.92 g molÀ1, colorless crystal. CCDC-909087 contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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470
Org. Lett., Vol. 15, No. 3, 2013

Treatment of adduct 5a with tryptamines 6a and TFA
afforded the PictetÀSpengler adducts (E or/and F)
(Scheme 3). Since the stereogenic center formed in the
PictetÀSpengler reaction is well-known to be subject to
epimerization,14 thehighdiastereoselectivity of thecascade
PictetÀSpenglerÀlactamization is probably governed by
the differential rates of lactamization of intermediates E
and F. As such, the predominate formation of 7a arose
from E via the lesser sterically bulky transition state T1,
while another pathway from F toward 8a was encumbered
owing to the significant steric hindrance in transition state T2.
In summary, we have achieved an organocatalytic double-
Michael reaction and PictetÀSpenglerÀlactamization of
(E)-ethyl 6-nitrohex-2-enoate, R,β-unsaturated aldehydes,
and 2-(1H-indol-3-yl)ethanamine and provided a facile entry
to the dodecahydrobenz[a]indolo[3,2-h]quinolizine system
with five contiguous stereogenic centers. The mild reaction
conditions at ambient temperatures as well as the one-pot
operation further manifest the merit of this strategy. The
highly enantioselective transformation and the highly func-
tionalized pentacyclic benzindolo-quinolizine products ren-
der this reaction sequence as a potential protocol for future
synthetic applications. The structures as well as the absolute
configurations of the products were unambiguously con-
firmed by X-ray crystallographic analysis of the appropriate
adducts. Further work is underway to elaborate the synthetic
applications of this procedure.
Scheme 2. Plausible Reaction Mechanism for the
Double-Michael Reaction
Scheme 3. Plausible Reaction Mechanism for the
PictetÀspengler Reaction
Acknowledgment. We acknowledge the financial sup-
port for this study from the National Science Council,
Taiwan, ROC. Thanks to the instrument center of the
National Science Council for analyses of compounds.
Supporting Information Available. Experimental pro-
cedures and characterization data for the new compounds
and X-ray crystallographic data for compounds (À)-7a
and (À)-7c (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) (a) Van Linn, M. L.; Cook, J. M. J. Org. Chem. 2010, 75, 3587.
(b) Fang, H.; Wu, X.; Nie, L.; Dai, X.; Chen, J.; Cao, W.; Zhao, G. Org.
Lett. 2010, 12, 5366–5369. (c) Zhang, W.; Franzen, J. Adv. Synth. Catal.
2010, 352, 499–518. (d) Shi, X. X.; Liu, S. L.; Xu, W.; Xu, Y. L.
To explain the stereoselectivity of the reactions, plausi-
ble mechanisms were proposed as shown in Scheme 2 and
Scheme 3. Initially, iminium formation of 4a with catalyst
IV provide the iminium intermediate A, followed by the
nitro-Michael addition of the nitroalkane 3, triggered by
DABCO, from the re face under the control of the catalyst
to give intermediate B, which could then undergo the
subsequent Michael reaction to provide 5a (Scheme 2).
€
Tetrahedron: Asymmetry 2008, 19, 435. (e) Han, D. M.; Forsterling,
F. H.; Deschamps, J. R.; Parrish, D.; Liu, X. X.; Yin, W. Y.; Huang,
S. M.; Cook, J. M. J. Nat. Prod. 2007, 70, 75. (f) Jiang, W. Q.; Sui, Z. H.;
Chen, X. Tetrahedron Lett. 2002, 43, 8941. (g) Cox, E. D.; Hamaker,
L. K.; Li, J.; Yu, P.; Czerwinski, K. M.; Deng, L.; Bennett, D. W.; Cook,
J. M. J. Org. Chem. 1997, 62, 44.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
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