Enantioselective construction of lactone[2,3-b]piperidine skeletons via organocatalytic tandem reactions

Article abstract of DOI:10.1039/b922053d

A highly enantioselective construction of δ- and γ-lactone[2,3- b]piperidine skeletons was accomplished by tandem aza-Diels-Alder reaction-hemiacetal formation-oxidation from N-Tos-1-aza-1,3-butadienes and aliphatic dialdehydes. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b922053d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective construction of lactone[2,3-b]piperidine skeletons via
organocatalytic tandem reactions†
Zhao-Quan He,a,b Bo Han,b Rui Li,*a Li Wub and Ying-Chun Chen*a,b
Received 21st October 2009, Accepted 2nd December 2009
First published as an Advance Article on the web 14th December 2009
DOI: 10.1039/b922053d
A highly enantioselective construction of d- and c-lactone[2,3-
b]piperidine skeletons was accomplished by tandem aza-
Diels–Alder reaction–hemiacetal formation–oxidation from
N-Tos-1-aza-1,3-butadienes and aliphatic dialdehydes.
Recently we have developed the asymmetric inverse electron
demand aza-Diels–Alder reaction (ADAR) of N-sulfonyl-1-aza-
1,3-butadienes and aldehydes or a,b-unsaturated aldehydes by
the catalysis of chiral secondary amines, providing efficient
protocols to access highly enantioenriched piperidine derivatives.5
We envisaged that a bicyclic compound bearing adjacent aminal–
hemiacetal structures would be generated from N-Tos-1-aza-1,3-
butadienes and an aliphatic dialdehyde,6 via a tandem ADAR–
intramolecular cyclisation process.7 Thus, the desired chiral
lactone[2,3-b]piperidine skeletons could be obtained by a subse-
quent oxidation reaction (Scheme 1).
The lactone[2,3-b]piperidine structures are key units in some
biologically important natural products. For example, the dimeric
indole alkaloid haplophytine (Fig. 1), isolated from the leaves of
Haplophyton cimicidum, and its biosynthetic precursor aspidophy-
tine, contain a g-lactone[2,3-b]piperidine motif. Their total syn-
thesis has triggered considerable attention owing to the appealing
complex structures.1 Zoanthamines, a family of marine alkaloids
isolated from the zoanthid Zoanthus, possess a d-lactone[2,3-
b]piperidine structure, and have an array of important biological
activities.2 In addition, lycojapodine A, a novel alkaloid recently
obtained from Lycopodium japonicum with an unprecedented
tetracyclic ring system, exhibit significant inhibitory activities
on acetylcholinesterase and HIV-1.3 The lactone[2,3-b]piperidines
are also interesting intermediates in organic synthesis.4 However,
currently there are few reports concerning the facile catalytic
asymmetric synthesis of lactone[2,3-b]piperidine skeletons.
Scheme
1 Tandem aza-Diels–Alder reaction-hemiacetal formation-
oxidation reaction to access lactone[2,3-b]piperidine skeletons.
Based on these considerations, we initially investigated the
reaction of aqueous glutaraldehyde 2a (50% in water) and N-Tos-
1-aza-1,3-butadiene 3a in MeCN at room temperature catalysed by
a chiral a,a-diphenylprolinol O-TMS ether 1 (Scheme 1, 10 mol%)
and benzoic acid (10 mol%).8 Upon the complete consumption of
diene 3a, the bicyclic hemiacetal 4a was isolated in 90% yield
as a diastereomeric mixture, which was further oxidised with 2-
iodoxybenzoic acid (IBX)9,10 to afford 5a in excellent stereocontrol
(Table 1, entry 1, dr > 99 : 1, >99% ee). Similar results were
obtained in other solvents such as MeOH, toluene and DCM
(entries 2–4). However, very sluggish reactivity was observed in
THF and the product 4a was isolated in low yield (entry 5). High
yield and outstanding enantioselectivity were also attained using
acetic acid as the additive (entry 6).
Fig. 1 Natural products containing lactone[2,3-b]piperidine structures.
Having established the optimal reaction conditions, the sub-
strate scope of this reaction was investigated. The hemiacetal
intermediates 4 were directed converted to the corresponding
lactone[2,3-b]piperidine derivatives 5 by IBX oxidation. The
results are summarised in Table 2. For the reactions of glutaralde-
hyde 2a, a few N-Tos-1-aza-1,3-butadienes bearing an ester group
at the 4-position were successfully applied, and the d-lactone
products 5a–5e were smoothly obtained in excellent enantioselec-
tivities with fair isolated yields via a two-step procedure (Table 2,
aState Key Laboratory of Biotherapy, West China Hospital, Sichuan
University, Chengdu, 610041, China
bKey Laboratory of Drug-Targeting and Drug Delivery System of Educa-
tion Ministry, Department of Medicinal Chemistry, West China School
of Pharmacy, Sichuan University, Chengdu, 610041, China. E-mail:
ycchenhuaxi@yahoo.com.cn; Fax: +86 28 85502609
† Electronic supplementary information (ESI) available: Experimental
procedures, structural proofs, NMR spectra and HPLC chromatograms
of the products. See DOI: 10.1039/b922053d
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Table 1 Screening studies on tandem ADAR–hemiacetal formation–
Table 2 Synthesis of d-lactone[2,3-b]piperidine derivativesa
oxidation reactiona
Entry R1
R2
Time/h
Yield b(%) ee c(%)
1
2
3
4
Ph
p-ClC6H4
p-BrC6H4
COOEt
COOEt
COOEt
2
5
5
8
5
22
24
26
36
230
5a, 51
5b, 53
5c, 54
5d, 46
5e, 51
5f, 50
5g, 45
5h, 42
5i, 47
5j, 45
99
99
99
99
97
99
98
99
98
90
p-MeOC6H4 COOEt
5
2-Thienyl
COOEt
COOEt
COOEt
Ph
COOEt
Ph
p-BrC6H4
p-MeOC6H4
p-BrC6H4
Me
6d
7d
8d
9
Entry
Solvent
Time/h
Yield b(%)
ee c(%)
1
2
3
4
5
6d
MeCN
MeOH
Toluene
DCM
THF
MeCN
2
5
2
2
96
2
90
83
81
81
30
89
99
99
99
99
99
99
10
Ph
a Unless noted otherwise, the reaction was conducted with 2a (0.2 mmol),
3 (0.1 mmol), catalyst 1 (0.01 mmol) and PhCOOH (0.01 mmol) in MeCN
(1.0 mL) at rt. b Isolated yield for two steps. c Determined by chiral HPLC
analysis, dr > 99 : 1. The absolute configuration of the products was
proposed based on the similarity as what was previously reported, see
ref. 5a. d 100 mol% of PhCOOH was used in DCM.
a Unless noted otherwise, the reaction was conducted with catalyst 1
(0.01 mmol), 2a (0.2 mmol), 3a (0.1 mmol) and PhCOOH (0.01 mmol)
in solvent (1.0 mL) at rt. b Isolated yield for 4a. c Determined by chiral
HPLC analysis of 5a, dr > 99 : 1. d CH3COOH was used.
applications in the synthesis of compounds with medicinal impor-
tance.
entries 1–5). Nevertheless, when N-Tos-1-aza-1,3-butadienes with
an ester substituent at the 2-position were used, much lower
reactivity was observed in MeCN. Fortunately, the reaction could
be greatly accelerated by using DCM as the solvent and more
benzoic acid (100 mol%) was required. The yields were acceptable
and the stereoselectivities were also remarkable (entries 6–8).
Moreover, two N-Tos-1-aza-1,3-butadienes without activating
substituents were tested. Although the cycloaddition reaction
turned out to be more sluggish, good conversions could be ensured
by extending the reaction time, especially for an alkyl-substituted
substrate. The enantioselectivities were still satisfactory (entries 9
and 10).
On the other hand, succinaldehyde 2b was employed with
N-Tos-1-aza-1,3-butadiene 3a for the synthesis of g-lactone[2,3-
b]piperidine derivative. As illustrated in Scheme 2, the expected
target compound 6 was similarly afforded, also in excellent
stereoselectivity.
We are grateful for the financial support from the National
Natural Science Foundation of China (20972101), PCSIRTC
(IRT0846) and National Basic Research Program of China (973
Program) (2010CB833303).
Notes and references
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Scheme 2 Synthesis of g-lactone[2,3-b]piperidine skeleton.
In conclusion, we have developed a tandem inverse elec-
tron demand aza-Diels–Alder reaction–intramolecular hemiacetal
formation–oxidation reaction to construct d- and g-lactone[2,3-
b]piperidine skeletons. This tandem process exhibited good effi-
ciency and excellent stereocontrol under environmentally friendly
and mild reaction conditions, utilising readily available N-Tos-
1-aza-1,3-butadienes and aliphatic dialdehydes as the starting
materials. These enantiomerically pure heterocycles might find
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756 | Org. Biomol. Chem., 2010, 8, 755–757
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10 The utilisation of PCC (pyridinium chlorochromate) as the oxidant
resulted in much lower yield. In addition, the current attempt to remove
the hydroxyl group of 4a using the Et3SiH–BF3·OEt2 system also gave
messy products due to some over-reduction reactions.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 755–757 | 757
©