Organocatalytic asymmetric mannich cyclization of hydroxylactams with acetals: Total syntheses of ( )-epilupinine, ( )-tashiromine, and ( )-trachelanthamidine

Article abstract of DOI:10.1002/anie.201407185

An asymmetric, organocatalytic, one-pot Mannich cyclization between a hydroxylactam and acetal is described to provide fused, bicyclic alkaloids bearing a bridgehead N atom. Both aliphatic and aromatic substrates were used in this transformation to furnish chiral pyrrolizidinone, indolizidinone, and quinolizidinone derivatives in up to 89% yield and 97% ee. The total syntheses of (-)-epilupinine, (-)-tashiromine, and (-)-trachelanthamidine also achieved to demonstrate the generality of the process.

Full text of DOI:10.1002/anie.201407185

Angewandte
Chemie
DOI: 10.1002/anie.201407185
Organocatalysis
Organocatalytic Asymmetric Mannich Cyclization of Hydroxylactams
with Acetals: Total Syntheses of (ꢀ)-Epilupinine, (ꢀ)-Tashiromine, and
(ꢀ)-Trachelanthamidine**
Dipankar Koley,* Yarkali Krishna, Kyatham Srinivas, Afsar Ali Khan, and Ruchir Kant
Abstract: An asymmetric, organocatalytic, one-pot Mannich
cyclization between a hydroxylactam and acetal is described to
provide fused, bicyclic alkaloids bearing a bridgehead N atom.
Both aliphatic and aromatic substrates were used in this
transformation to furnish chiral pyrrolizidinone, indolizidi-
none, and quinolizidinone derivatives in up to 89% yield and
97% ee. The total syntheses of (ꢀ)-epilupinine, (ꢀ)-tashir-
omine, and (ꢀ)-trachelanthamidine also achieved to demon-
strate the generality of the process.
N
aturally occurring izidine alkaloids (pyrrolizidine, indoli-
zidine, and quinolizidine; Figure 1A) and their synthetic
variants are of considerable importance because of their
diverse biological activities.[1] While the polyhydroxylated
izidines inhibit glycosidase and glycosyl-transfer enzymes,
and show anti-HIV, anti-dengue virus, anticancer, anti-
inflammatory, and antidiabetic activities,[2] the alkylated
izidines are noncompetitive blockers of nicotinic acetylcho-
line receptors and are known as defense chemicals used by
hosts against predators.[3]
Figure 1. A) Izidine alkaloids. B) Asymmetric bioinspired approach for
the synthesis of the skeletons of izidine alkaloids.
Although chiral-pool[4,5] and chiral-auxiliary-mediated[4,6]
approaches have been described for the asymmetric synthesis
of various izidine derivatives, they are often target directed.
In contrast, approaches for the catalytic asymmetric synthesis
of these skeletons are limited and izidine specific. These
include chiral-rhodium-catalyzed[7] [2+2+2], [3+3], and 1,3-
dipolar cycloadditions for indolizidine and quinolizidine
derivatives, asymmetric hydrogenation of dihydro-b-carbo-
lines,[8] organocatalytic cascade cyclizations,[9] formal aza-
hetero-Diels–Alder reactions,[10] intramolecular annulation of
oxo-isoquinolinium[11] for quinolizidine derivatives, chiral-
silver-catalyzed one-pot double 1,3-dipolar cycloaddition for
pyrrolizidines,[12] and asymmetric hydrogenation of indolizine
by a chiral-ruthenium-catalyst[13] for indolizidine derivatives.
A few other examples of enantioselective organocatalytic
reactions are also known for the synthesis of indolizidine-
based alkaloids.[14] However, a general method for the
catalytic asymmetric synthesis of all the izidine skeletons is
rare. Herein, we report the development of an asymmetric
organocatalytic Mannich cyclization for the synthesis of the
bicyclic skeleton of izidine alkaloids and its application to the
total syntheses of (ꢀ)-epilupinine,[15] (ꢀ)-tashiromine,[16] and
(ꢀ)-trachelanthamidine.[17]
Inspired by the biosynthetic pathway of pyrrolizidine
alkaloids (1a!1b; Figure 1B),[18] we recently reported the
Brønsted acid catalyzed Mannich cyclization between
a hydroxylactam and acetal (2a!(rac)-2b; Figure 1B).[19]
This reaction led us to realize that an asymmetric version of
such a cyclization might be possible by using a suitable chiral
catalyst. Although various chiral Brønsted acid[20] catalyzed
enantioselective reactions of N-acyliminium[20,21] ions with
various aromatic and heteroaromatic C nucleophiles[20,22]
have been reported, these processes are unable to introduce
chirality at C1. We realized that a nucleophilic addition of an
asymmetric enamine[23] (generated at C1) onto an N-acylimi-
nium ion should resolve the issue. Our efforts to remove the
acetal of 2a under various reaction conditions gave either
very low yield of the linear aldehyde along with the cyclized
product, or led to decomposed products. We hypothesized
that a one-pot catalytic acetal removal/enamine formation/N-
[*] Dr. D. Koley, Y. Krishna, K. Srinivas, A. A. Khan
Medicinal and process Chemistry Division,
CSIR-Central Drug Research Institute, Lucknow, 226031 (India)
E-mail: dkoley@cdri.res.in
R. Kant
Molecular and Structural Biology Division
CSIR-Central Drug Research Institute, Lucknow, 226031 (India)
[**] This work was supported by CSIR-GenCODE (BSC0123), New Delhi.
We are thankful to SAIF, CSIR-CDRI, for providing the analytical
facilities, R. K. Purshottam for assistance with HPLC, Dr. Tejender S.
Thakur, Molecular and Structural Biology, CSIR-CDRI for supervising
the X-ray data collection and structure determination of the
compound 4m, and the Director of the Centre of Biomedical
Research, Lucknow, 226014, (India) for allowing us to measure
optical rotations. Y.K., K.S. thank CSIR for SRF. This is CSIR-CDRI
communication no 8778.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407185.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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Table 1: Optimization of the enantioselective cyclization of 3a[a]
acyliminium formation using 2a might be possible and
provide 2c by using a chiral amine in cooperation[24] with
a Brønsted acid and water. Such a strategy, if successful,
would then provide enantioenriched 2d, from 2c, after
cyclization. However, the main challenges were to identify
1) a suitable Brønsted acid which would only catalyze the
acetal removal and N-acyliminium formation, but not pro-
mote the background reaction to deliver racemic products[19]
and 2) a chiral amine catalyst that will simultaneously
perform cyclization via an enamine. To the best of our
knowledge, an acetal has not been reported as a direct
precursor to a chiral enamine, although List et al. have
developed[25] the chiral Brønsted acid catalyzed asymmetric
transketalization of acetals.
Given the versatile performance of pyrrolidine-[20] and
imidazolidinone-based[20,26] substrates as enamine catalysts,
we screened the catalysts I–V using 3a[19] as a model substrate
(Table 1). While the pyrrolidine-based catalysts I–IV (free
amine) did not lead to the desired cyclization, only traces of
4a were formed when HCl was used as an additive (see
Table S1 in the Supporting Information). In contrast,
although the imidazolidinone-based catalyst V (free amine)
failed to promote the cyclization (entry 1), the salt V·HCl
catalyzed the desired transformation enantioselectively
(46%) to furnish 4a in 74% yield after six days (entry 2).
Despite having a low ee value, this result clearly validated our
hypothesis of using an acetal and hydroxylactam as a pro-
nucleophile and pro-electrophile, respectively. Surprisingly,
V, better known as a LUMO-lowering catalyst[27] via iminium-
ion formation, performed much better than IV. Thus, a series
of Brønsted acid salts (with different pKa) of the MacMillan
catalyst were screened against 3a in acetonitrile (entries 3–8).
The salt of the strongest Brønsted acid (TfOH) provided good
yields of 4a with very good enantioselectivity (entry 8). This
increase in the enantioselectivity could be rationalized on the
basis of the strength of Brønsted acidity of the cocatalyst. A
stronger acid cocatalyst facilitates a higher equilibrium
content of 2c, thereby increasing the rate of asymmetric
cyclization. Notably, this result indicates that despite using
a strong Brønsted acid, the desired asymmetric pathway out-
competes the undesired racemic cyclization process. Solvent
screening (entries 9–13) showed acetone to be the most
suitable solvent, thus allowing 90% ee of 4a, presumably by
favoring the transacetalization (entry 13). An additional
increase in enantioselectivity was observed (entry 14) in the
absence of water at 188C. Addition of excess water disfavored
the enamine formation, and therefore decreased both the
yield and enantioselectivity (entries 15 and 16). However, in
the presence of 4 ꢀ molecular sieves, only traces of the
cyclized product were obtained (entry 17; see Figure S2).
Screening of additives (entry 18) and additional imidazolidi-
none catalysts (VI and VII) did not improve the enantiose-
lectivity of the process (entries 19 and 20). Surprisingly, VII,
having a bulky tert-butyl group, showed substantially low
enantioselectivity (entry 20). Presumably, VII could not
surpass the background reaction because of the steric factor.
After establishing the optimal reaction conditions, the
scope and generality of this cyclization reaction were inves-
tigated (Table 2). The yields of the six-membered ring-closed
Entry Catalyst
Solvent
t
Yield[b]
[%]
d.r.[c]
ee [%][d]
[days]
(trans/cis) (trans/cis)
1[e]
2[e]
3[e]
4[e]
5[e]
6[e]
7[e]
8[e]
9
10
11
12
13
14[f]
V
CH3CN
CH3CN
CH3CN
10
6
5
6
6
5
5
5
5
5
7
7
5
5
5
5
7
5
5
4
trace
74
69
55
52
68
85
71
42
56
27
15
78
77
70
62
trace
72
–
–
V·HCl
V·TFA
V·(+)CSA CH3CN
V·(ꢀ)CSA CH3CN
12:1
9:1
4:1
4:1
3:1
3:1
5:1
5:1
3:1
4:1
2:1
5:1
4:1
5:1
6:1
–
46:03
60:72
76:77
76:80
80:77
82:74
86:76
90:82
86:78
88:80
42:32
90:82
92:82
86:76
86:80
–
V·PTSA
V·HClO4
V·TfOH
V·TfOH
V·TfOH
V·TfOH
V·TfOH
V·TfOH
V·TfOH
CH3CN
CH3CN
CH3CN
THF
CH2Cl2
DMF
toluene
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
15[f,g] V·TfOH
16[f,h] V·TfOH
17[f,i]
18[f,j]
19
V·TfOH
V·TfOH
VI·TfOH
6:1
4:1
3:1
86:74
84:72
46:38
66
79
20[f,k] VII
[a] Reaction conditions: 0.21 mmol of 3a, 30 mol% catalyst, 1.5 mL of
solvent at 258C. [b] Combined yield of the isolated 4a (two diastereo-
mers are inseparable by silica gel column chromatography for most of
the substrates). [c] Determined by 1HNMR analysis of the crude alcohol.
[d] Determined by HPLC analysis of the benzoyl ester of 4a using a chiral
stationary phase. [e] 10 mol% of H2O was added. [f] Carried out at 188C.
[g] 1 equiv of H2O was used. [h] 4 equiv of H2O was used. [i] Carried out
in presence of 4 ꢀ molecular sieves. [j] 30 mol% of AgSbF6 was used as
additive. [k] 20 mol% of TfOH was added. DMF=N,N-dimethylforma-
mide, ee=enantiomeric excess, PTSA=para-toluenesulfonic acid,
TFA=trifluoroacetic acid, TfOH=trifluoromethanesulfonic acid,
THF=tetrahydrofuran, TMS=trimethylsilyl.
products (4b–g) were in the good to very good range (63–
88%) with excellent ee values (up to 97%). gem-Dialkyl-
substituted substrates (3c–e) and sterically hindered acetals
(3 f,g) tethered with cyclopentyl and cyclohexyl groups also
afforded 4c–g with good yield and excellent ee values (up to
97%). The process has also been found useful for five-
membered and seven-membered rings and provided the
corresponding izidinone derivatives (4h–k) in very good
yields with very good ee values (up to 87%). Interestingly,
when 3i was treated with V·HCl, the opposite sense of
diastereoinduction was observed and 4i’ was obtained in good
yield with good ee value. Although the reason is unclear to us,
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Table 2: Scope with respect to 3 in the enantioselective cyclization.[a]
Scheme 1. Total syntheses of (ꢀ)-epilupinine, (ꢀ)-tashiromine, and
(ꢀ)-trachelanthamidine. Reaction conditions: a) LiAlH4, THF, reflux;
b) PhCOCl, Et3N, DMAP, CH2Cl2, 08C. DMAP=4-(N,N-dimethylami-
no)pyridine.
Scheme 2. Postulated mechanism for cyclization.
With regard to the mechanism, first the acetal removal for
3b provides the aldehyde 8 (Scheme 2; see the Supporting
Information). We assume that the reaction of 8 with the
imidazolidinone catalyst V results in the E-enamine A.[27a]
Upon protonation, A loses a water molecule and furnishes the
intermediate N-acyliminium-enamine ion which cyclizes
through the Si face of the enamine, preferably via the
transition-state TSchair (B1, more favored; TSboat B2 less
favored) conformation to afford the trans-configured major
product (cis/trans descriptors are with respect to the H1 and
H9a). A similar hypothesis also explains why the cis deriva-
tive was formed as the major product in the case of the five-
membered ring cyclization (see Figure S8).
In summary, we have demonstrated a mild, step-eco-
nomic, catalytic enantioselective intramolecular Mannich
reaction between acetals and hydoxylactams to provide N-
bridgehead bicyclic scaffolds by employing MacMillanꢁs
catalyst. Our method has been generalized for the asymmetric
synthesis of the entire izidine skeleton and utilized for the
total synthesis of izidine alkaloids. We hope that the concept
of using an acetal as the precursor to an enamine in one pot
will be useful towards designing new organocatalytic cascade
reactions for the synthesis of complex polycyclic scaffolds. We
aim to explore this strategy further and studies are currently
ongoing.
[a] Reaction conditions: 0.21 mmol of 3b–3o, 30 mol% catalyst, 1.5 mL
of solvent, 188C. Yield is that of the two isolated diastereomers. The
d.r. value was determined by 1H NMR spectroscopy. The ee values
(mentioned for both the diastereomers) were determined by HPLC
analysis of the benzoyl ester (4-nitrobenzoyl ester for 4i and 4i’) of the
substrates using a chiral stationary phase. [b] Performed on 2.04 mmol
of 3b. [c] 30 mol% of AgSbF6 was used as additive. [d] Performed at 48C.
[e] Performed using 30 mol% V·HCl in THF (see Scheme S1). Ts=4-
toluenesulfonyl.
such a counteranion-directed switch in diastereoselectivity
was reported earlier by MacMillan et al.[28] Pleasingly, sub-
strates with heteroatom-containing acetals afforded pyrazi-
nopyrrolidinone (4l), pyrazinopiperidinone (4m), and oxazi-
nopyrrolidinone (4n) derivatives with very good ee values (up
to 86%). The arene substrate 3o afforded 4o in 72% yield in
93% ee, and there was no isolable product corresponding to
the intramolecular Friedel–Crafts reaction.
A larger scale (500 mg, 2.04 mmol) reaction of 3b also
furnished 4b in 82% yield with 88% ee (Table 2). In addition,
the total syntheses of (ꢀ)-tashiromine (5), (ꢀ)-epilupinine
(6), and (ꢀ)-trachelanthamidine (7) [representative natural
products of the indolizidine, quinolizidine, and pyrrolizidine
alkaloids, respectively; Scheme 1] were also achieved by using
our method. The absolute configuration of 4m was deter-
mined by X-ray crystallography[29] (see Figure S9). The
optical rotation of 6 (see the Supporting Information) also
matched the literature value for the natural product.[15]
Received: July 14, 2014
Published online: && &&, &&&&
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Keywords: acetals · alkaloids · cyclization · natural products ·
organocatalysis
.
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Angewandte
Communications
Communications
Organocatalysis
D. Koley,* Y. Krishna, K. Srinivas,
A. A. Khan, R. Kant
&&&& — &&&&
Organocatalytic Asymmetric Mannich
Cyclization of Hydroxylactams with
Acetals: Total Syntheses of (ꢀ)-
Epilupinine, (ꢀ)-Tashiromine, and (ꢀ)-
Trachelanthamidine
Double bonanza: The title reaction in the
presence of an imidazolidinone-based
catalyst furnished N-bridgehead bicyclic
alkaloids bearing [3.3.0], [3.4.0], [4.4.0],
and [4.5.0] skeletons. By using this pro-
tocol, the total syntheses of (ꢀ)-epilupi-
nine, (ꢀ)-tashiromine, and (ꢀ)-trache-
lanthamidine were achieved.
6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!