Versatile construction of functionalized tropane ring systems based on lactam activation: Enantioselective synthesis of (+)-pervilleine B

Article abstract of DOI:10.1039/c3cc43665a

The halo-assisted intramolecular addition of silyl enol ethers with in situ activated lactams yielded (hydroxylated) 1-halo-8-azabicyclo[3,2,1]octane and 1-halo-9-azabicyclo[3,3,1]nonane ring systems, which provided an easy enantioselective access to 6β-s

Full text of DOI:10.1039/c3cc43665a

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Versatile construction of functionalized tropane ring
systems based on lactam activation: enantioselective
synthesis of (+)-pervilleine B†
Cite this: Chem. Commun., 2013,
49, 7088
Received 15th May 2013,
Accepted 13th June 2013
Su-Yu Huang, Zong Chang, Shi-Chuan Tuo, Long-Hui Gao, Ai-E Wang and
Pei-Qiang Huang*
DOI: 10.1039/c3cc43665a
www.rsc.org/chemcomm
The halo-assisted intramolecular addition of silyl enol ethers
with in situ activated lactams yielded (hydroxylated) 1-halo-8-
azabicyclo[3,2,1]octane and 1-halo-9-azabicyclo[3,3,1]nonane
ring systems, which provided an easy enantioselective access to
6b-silyloxytropane-3-one, 3a,6b-dihydroxytropane, and pervilleine
B. The absolute configuration of the natural (ꢀ)-pervilleine B was
determined to be 1R,3R,5S,6R.
Recently more and more dihydroxytropane alkaloids derived
from 3a,6b-tropanediol (1) have been isolated in forms of mono
and di-esters.1,2 For example, eleven such alkaloids have been
isolated from the roots of Erythroxylum pervillei Baillon,
collected in southern Madagascar.2 Among them, pervilleines
B, C and F (Fig. 1, 3–5) displayed promising MDR-inhibitory
activities,3 and were selected for further development through a
Fig. 1 Structures of some tropane alkaloids and the parent molecules.
special program.2c In addition, 3a,6b-dihydroxytropane
1
(ref. 4a) and O-protected 6b-hydroxytropan-3-ones such as 2
(ref. 4b and c) have been used to develop highly active analogs
of the muscarinic agonists,4a cocaine antagonists/partial
agonists,4b and potent and selective M2-receptor agonists.4c
The bioactivities of this class of alkaloids have been shown to
be highly enantiomer-dependent.4 However, little attention has
been paid to the enantioselective synthesis of dihydroxy-
tropanes5 although that of other tropane alkaloids and analogs
has attracted considerable attention.6
In a program on the asymmetric synthesis of bioactive
N-heterocycles and alkaloids,7 we recently disclosed enantio-
selective synthesis of (ꢀ)-Bao Gong Teng A.6a As a continuation
of that study, and on the basis of our development of the amide
activation-based C–C bond formation reactions,8 we envisaged
that intramolecular cyclization of ketone–lactams A through
addition of silyl enol ethers with in situ activated lactams could
build the hydroxytropane-3-one ring systems B (Scheme 1). The
compatibility of silyl enol ethers with amide activation conditions
Scheme 1 A new approach to hydroxylated tropan-3-ones.
9
´
has been nicely demonstrated by Belanger et al., while hydroxy-
lactams A are easily available from chiral pools such as malic
acid10 via a-amidoalkylation. Herein we communicate the
results of this investigation.
As a model study, racemic keto-lactam 6 was treated with
TBDMSOTf–NEt3,11 and the resulting silyl enol ethers, formed as
regioisomeric mixtures [SL1a (terminal) : SL1b (internal) = 6.4 : 1],
were used directly in the cyclization reaction under the previously
established lactam activation conditions (Tf2O,12 DTBMP, CH2Cl2,
ꢀ78 1C) (Scheme 2).8a To our disappointment, the desired product
9 was not observed. Addition of Lewis acid such as BF3ꢁEt2O or
TMSOTf did not yield any product. However, use of 1.0 equiv. of
TMSCl as a Lewis acid produced a 6-enolendo13 cyclization
product (7a) bearing a chlorine atom at the bridgehead carbon
in 12% yield, instead of compound 9. Other halo-containing
Lewis acids including TiCl4, AlCl3, SnCl4, ZnBr2, and ZnCl2 were
Department of Chemistry, College of Chemistry and Chemical Engineering, and
Fujian Provincial Key Laboratory of Chemical Biology, Xiamen University, Xiamen,
Fujian 361005, China. E-mail: pqhuang@xmu.edu.cn; Tel: +86-592-2182240
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc43665a
c
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Table 1 Lactam activation-based cyclization reaction of keto-lactams via silyl
enol ethers
Entry
1a
Silyl enol etherc
Cyclization product (yield)d
2a
3a
4a
Scheme 2 The halo-assisted intramolecular addition of silyl enol ethers with
in situ activated lactam. DTBMP = 2,6-di-tert-butyl-4-methylpyridine.
thus surveyed. The best result was obtained with the use of
1.2 equiv. of ZnCl2 (86% yield based on the major regioisomer
of the silyl enol ether). In all cases, no 4-enolexo cyclization
product from the internal silyl enol ether SL1b was observed.
The optimal conditions for the cyclization of silyl enol ether–
lactams SL1a,b were thus established to be: Tf2O (1.2 equiv.),
DTBMP (1.2 equiv.), ZnCl2 or ZnBr2 (1.2 equiv.).
We then proceeded to investigate the reactions of other
keto-lactams (cf. ESI†). All the silyl enol ethers, formed as regio-
isomeric mixtures, were directly used in the cyclization. The
results are summarized in Table 1. As observed with silyl enol
ethers SL1a,b (entry 1), the cyclization of SL3a,b (entry 3) led only
to the formation of the 8-azabicyclo[3,2,1]octane ring system 11b
(isolated as a single diastereomer in 75% yield based on SL3b).
From the cyclization of silyl enol ethers SL2a,b, the seven-
membered (10a) and five-membered products were obtained only
in trace amounts (entry 2) which precluded the full characteriza-
tion of the products. Subjection of the regioisomeric mixture
SL4a,b (ratio = 3.8 : 1) to the cyclization conditions produced the
9-azabicyclo [3,3,1]nonane ring system 12a in 65% yield (entry 4).
The cyclization reactions of the enantiomeric keto-lactams 13
(cis-diastereomer) and 14 (trans-diastereomer), easily available
from (S)-malic acid, were also investigated. The reaction of
keto-lactam 13 with TMSOTf (NEt3, CH2Cl2) yielded the terminal
silyl enol ether SL5a in excellent regioselectivity (>20 :1), which
upon treatment with Tf2O, DTBMP and ZnBr2 cyclized to produce
the 1-bromo-tropan-3-one 15 in 50% yield from keto-lactam 13
(entry 5). For trans-keto-lactam 14, the terminal silyl enol ether
SL6a was also formed in excellent regioselectivity (>20: 1), which
5b
6b
a
Method A: (1) TBDMSOTf, Et3N, CH2Cl2, 0 1C; (2) Tf2O, DTBMP, ZnCl2,
b
ꢀ78 1C–rt. Method B: (1) TMSOTf, Et3N, CH2Cl2, 0 1C; (2) Tf2O, DTBMP,
(internal), regioisomeric ratio determined using 1H NMR. Isolated yield
c
was subjected to the cyclization conditions to give the expected ZnBr2, ꢀ78 1C–rt. Combined isolated yield of SLXa (terminal) and SLXb
1-bromo-tropan-3-one 16 in 23% yield from 14, along with the
tetracyclic compound 17 in a yield of 30% (from 14).
d
obtained from the corresponding regioisomers of silyl enol ethers.
The C–Cl bond was cleaved by heating a mixture of 1-chloro-
tropan-3-one 7a, 1,10-azobis(cyclohexanecarbonitrile) (ACCN) regioselectivity (terminal : internal > 20 : 1), which without
and Bu3SnH in toluene at 85 1C for 3.0 h, which gave 18 in purification was treated with Tf2O, DTBMP, and ZnCl2 (CH2Cl2,
90% yield (Scheme 3).
ꢀ78 1C to rt) to produce (ꢀ)-21 in 65% yield (from 19) as a
We next turned to the enantioselective synthesis of pervil- single diastereomer. Radical de-chlorination (ACCN, Bu3SnH,
leine B (3). Since the absolute configuration of this alkaloid is toluene, 85 1C) of 21 afforded (+)-(1R,5R,6S)-6b-silyloxytropane-
unknown, we decided to synthesize pervilleine B with the 3-one 2 in 80% yield (Scheme 4).
absolute configuration displayed in Fig. 1. The requisite keto-
By stereoselective hydrogenation5c (PtO2, H2, 50 atm, EtOH),
lactam (+)-(4S,5R)-19 was synthesized in 29% overall yield from de-silylation (TsOH, acetone, 50 1C), and esterification of the
(S)-malic acid (see ESI†). Treatment of 19 with TBDMSOTf–NEt3 resulting 3a,6b-dihydroxytropane 1 (TmcCl, Et3N, tol., refl.), the
(CH2Cl2, 0 1C) yielded the silyl enol ether 20 in excellent key intermediate 2 was transformed into monoester 22 in 90%
c
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MOST of China (Grant No. 2010CB833200), the NSF of China
(20832005, 21072160) and the Program for Changjiang Scholars
and Innovative Research Team in University of the MOE, China.
Notes and references
Scheme 3 Radical de-chlorination of 1-chloro-tropane derivative 7a.
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Scheme 4 The construction of (1R,5R,6S)-tropan-3-one 2.
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Scheme 5 Final synthesis of (+)-(1S,3S,5R,6S)-pervilleine B, and the determined
absolute configuration of the natural (ꢀ)-pervilleine B.
´
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overall yield. Further esterification (TmbCl, NEt3, DMAP, tol., refl.)
of the sterically more hindered axial C-3 hydroxyl group of (+)-22
furnished (+)-pervilleine B (3) in 94% yield. The spectroscopic data
of our product matched those reported for the natural one,2a except
for the sense of optical rotation {[a]2D0 +27 (c 1.0, CHCl3); lit.2a [a]2D0
ꢀ22.5 (c 0.25, CHCl3)}. Our synthetic product is thus the antipode
of the natural (ꢀ)-pervilleine B and the absolute configuration of
the latter is determined to be 1R,3R,5S,6R (Scheme 5).
In summary, a versatile method for construction of hydroxyl-
ated 8-azabicyclo[3,2,1]octane and 9-azabicyclo[3,3,1]nonane
ring systems from keto-lactams has been disclosed. Based on
this methodology, the enantioselective syntheses of (+)-6b-silyl-
oxytropane-3-one 2 and 3a,6b-dihydroxytropane 1, two versatile
key intermediates for the synthesis of tropane alkaloids and
highly bioactive analogs, were performed. The first enantio-
selective synthesis of pervilleine B (3) allowed determining the
´
9 (a) G. Belanger, M. Dupuis and R. Larouche-Gauthier, J. Org. Chem.,
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absolute configuration of natural pervilleine
B to be
1R,3R,5S,6R. In addition, compounds 11b and 12a are valuable
advanced intermediates for the syntheses of ferruginine6h and
9-azabicyclo[3.3.1]nonane type alkaloids such as euphococcinine6j
and adaline,6j respectively.
The authors are grateful for financial support provided by
the National Basic Research Program (973 Program) of the
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c
7090 Chem. Commun., 2013, 49, 7088--7090
This journal is The Royal Society of Chemistry 2013