Synthesis of alexine-like compounds from chiral five-membered endocyclic enecarbamates

Article abstract of DOI:10.1016/j.tetlet.2008.01.098

Stereoselective syntheses of enantiomerically enriched trihydroxy pyrrolizidine and indolizidines were accomplished from a common chiral endocyclic enecarbamate. The synthetic strategy features an efficient [2+2] cycloaddition of ketenes to the endocyclic enecarbamate and a highly regioselective Baeyer-Villiger oxidation of the intermediate azabicyclic-cyclobutanones. These new heterocycles are compounds structurally related to the alexines.

Full text of DOI:10.1016/j.tetlet.2008.01.098

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Tetrahedron Letters 49 (2008) 1957–1960
Synthesis of alexine-like compounds from chiral
five-membered endocyclic enecarbamates
a
b
a,
*
Marcelo Siqueira Valle , Pascal Retailleau , Carlos Roque Duarte Correia
a
Institute of Chemistry, State University of Campinas—UNICAMP, PO Box 6154, CEP 13084-971, Campinas-SP, Brazil
b
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 20 December 2007; revised 19 January 2008; accepted 21 January 2008
Available online 30 January 2008
Abstract
Stereoselective syntheses of enantiomerically enriched trihydroxy pyrrolizidine and indolizidines were accomplished from a common
chiral endocyclic enecarbamate. The synthetic strategy features an efficient [2+2] cycloaddition of ketenes to the endocyclic enecarbamate
and a highly regioselective Baeyer–Villiger oxidation of the intermediate azabicyclic-cyclobutanones. These new heterocycles are
compounds structurally related to the alexines.
Ó 2008 Elsevier Ltd. All rights reserved.
2
c,d
Polyhydroxylated indolizidines and pyrrolizidines form
an important and diversified class of alkaloids. The struc-
tural complexity and the wide range of biological activity
displayed by these natural compounds constitute one of
the major impetus for their chemical synthesis. Alexine
inhibitors of several glycosidases,
ral activity.
also possessing antivi-
1
e
Endocyclic enecarbamates are versatile and useful build-
ing blocks, which have been extensively used in the synthe-
3
,4
sis of N-heterocycles and alkaloids. In particular, the
five-membered endocyclic enecarbamates, bearing an elec-
tron-rich enamine functionality can undergo efficient
[2+2] cycloaddition to ketenes to produce azabicyclic
cyclobutanones. These compounds are key intermediates
in the synthesis of a number of biologically active natural
1
a
1b
1c
1
,
australine 2 and casuarine 3 are polyhydroxylated
pyrrolizidine alkaloids exhibiting potent glucosidase inhi-
1
d,e
bitory action and anti-HIV activity (Fig. 1).
In a similar
manner, polyhydroxylated indolizidines alkaloids, such as
2
a
2b
swainsonine 4 and castanospermine 5, act as effective
3
a–c,e,g
products.
In view of the great interest in the pharmacological
properties of polyhydroxylated alkaloids, we decided to
apply the [2+2] cycloaddition reaction of 5-membered
endocyclic enecarbamates to ketenes as a direct access to
novel polyhydroxylated N-heterocycles. Our synthetic
strategy is illustrated in Figure 2 in which we demonstrate
the synthesis of the new alexine-like compounds 6 and 7,
structurally related to alkaloids 1–5. One of the key steps
in this strategy involves a stereocontrolled [2+2] cycloaddi-
tion of haloalkylketenes to chiral endocyclic enecarbamate
to form alkyl substituted azabicyclic cyclobutanones.
The required starting endocyclic enecarbamate 10 was
synthesized in multigram scale following a protocol previ-
HO
OH
HO
OH
HO
OH
OH
H
H
H
OH
OH
OH
HO
OH
OH
N
N
N
OH
OH
1
3
2
OH
OH
H
H
HO
HO
OH
N
N
4
5
Fig. 1. Polyhydroxylated pyrrolizidine and indolizidine alkaloids.
*
Corresponding author. Tel.: +55 19 3521 3086; fax: +55 19 3521 3023.
E-mail address: roque@iqm.unicamp.br (C. R. D. Correia).
3
i
ously developed by us. The choice for a tert-butyl ester
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.098

1958
M. S. Valle et al. / Tetrahedron Letters 49 (2008) 1957–1960
Stereoselective
2+2]cycloadditon
5-chlorovaleryl
chloride, Et N,
O
H
[
mCPBA, NaHCO3,
CH Cl , rt, 30 min
O
H
3
cyclohexane, 65 °C
2
2
Cl
1
0
(
)
n
CO t-Bu
2
COCl, Et
3
N
*
*
N
75%
H
81%
CO R
*
2
2
CO R
N
Boc
N
Boc
H
(
)
12
n
Boc
n = 1, 2
Cl
1. TFA, Et
Cl
Chiral endocyclic
O
3
SiH,
CH Cl , reflux, 8 h
enecarbamate
O
1
. LiAlH4,
H
2
2
O
THF, reflux
2. HCl 2N
OH
OH
HO
OH
2. NaHCO , 1h,
3
H
HO
O
H
H
0
°Cthen HCl 2.5N
.
( HCl)
7
CO2
t-Bu
N
N
70%
H
75%, 2 steps
N
N
7
Boc
.
13
HCl
14
CO H
2
6
OH
Cl
New trihydroxylated
pyrrolizidine and indolizidine
compounds
Scheme 2. Synthesis of trihydroxylated indolizidine 7.
Fig. 2. Synthetic strategy to alexine-like compounds.
O
H
in the enecarbamate 10 was made to guarantee high facial
O
C
N
H
R
O
C
H
R
stereoselectivity during the [2+2] cycloaddition to alkylket-
O
3
i
N
enes. The proline derivative 8 was readily prepared from
L-proline (69% over two steps) as depicted in Scheme 1.
Compound 8 was then oxidized with sodium periodate in
the presence of a catalytic amounts of ruthenium to furnish
O
H
O
O
t
-Bu
O
-Bu
O
12
t
-Bu
O
t
t
-Bu
5
Fig. 3. Approach of the olefin and the ketene during cycloaddition
R = CH CH CH Cl).
pyroglutamic derivative 9 in 70–96% yields. The lactam
(
2
2
2
moiety of 9 was next reduced to the corresponding lacta-
mol using diisopropylaluminum hydride (DIBAL-H) in
THF at ꢀ78 °C. The resulting mixture of hemiacetals was
then submitted to dehydration using trifluoroacetic anhy-
dride (TFAA) and 2,4-lutidine in toluene to provide endo-
cyclic enecarbamate 10 in 75% yield (over two steps; 44%
overall yield over five steps). Alternatively, endocyclic
enecarbamate 10 can be prepared with the same overall
yield of 44% by esterification and Boc protection of L-pyro-
glutamic acid as depicted in Scheme 1.
Baeyer–Villiger oxidation of 12, using mCPBA led to
lactone 13 in 81% yield. As described in the previous work
from our laboratory, ring expansion is exceptionally regio-
selective in such systems, producing a single isomeric
3
a,b,e,g–i
lactone.
Therefore, we hypothesize that the steric
strain built into the Criegee’s intermediate is the regio con-
trolling element during oxidation, overriding stereoelec-
3
g
tronic bias for the ring expansion.
Conversion of
lactone 13 to the tricyclic intermediate 14 was performed
using a two-step procedure encompassing: (i) removal of
the Boc group and cleavage of tert-butyl ester to the corre-
sponding carboxylic acid with trifluoroacetic acid, and (ii)
neutralization with sodium bicarbonate to promote intra-
molecular cyclization, followed by acidification with
With the endocyclic enecarbamate 10 in hand, we
started the synthesis aiming at the construction of the tri-
hydroxy indolizidine 7. [2+2] Cycloaddition of enecarba-
mate 10 to chloroalkylketene (generate in situ from
5
-chlorovaleryl chloride in presence of Et N) in cyclo-
3
hexane as a solvent provided the endo-cycloadduct 12, as
the exclusive diastereoisomer in 75% yield (Scheme 2).
Gratifyingly, the bulk t-butoxycarbonyl group at C-2 pro-
vided excellent stereocontrol during cycloaddition with the
endo preference for the alkyl group arising from the mini-
2
(
.5 mol/L HCl to form the rather stable hydrochloride 14
we observe decomposition of this compound as free-base).
Finally, the reduction of tricyclic lactone 14 with LiAlH in
4
THF under reflux resulted in the desired trihydroxy indo-
lizidine 7 in 70% yield after purification using DOWEX-
6
mum energy approach of the olefin and the ketene (Fig. 3).
50W-X8. The synthesis of trihydroxy indolizidine 7 was
accomplished in an overall yield of 32% after five steps
from endocyclic enecarbamate 10.
A similar strategy was employed for the synthesis of the
trihydroxylated pyrrolizidine 6 (Scheme 3). However,
1. (t-BuO C) O,
2 2
NaHCO3,
dioxane/H
NaIO
RuCl ,
3
4
,
2
O 1:1
L-Proline
CO2
t
-Bu
O
CO2
t-Bu
N
N
2.
t
-BuOH, DIC,
EtOAc
85%
DMAP, CH Cl2
Boc
8
Boc
9
2
6
9%, 2 steps
1. DIBAL-H,
78 °C, toluene
. 2,4-lutidine,
TFAA, toluene,
-
Boc O, DMAP,
3
2
2
CH CN, 30 min.
4-chlorobutyryl
chloride,
O
H
recristalization
in EtOAc/
hexane
quant.
O
0
°C
reflux.
H
Et N,c-hexane,
3
75%, 2 steps
AcO
t
-Bu,
2
reflux, 4 h
HClO .2H O
10
CO t-Bu
4
2
N
Boc
15
CO t-Bu
2
3
days
51%
H
N
H
L
-Piroglutamic
O
CO2
t
-Bu
N
H
CO2
Boc 10
t
-Bu
Cl
Cl
Boc
endo-15
acid
N
4
4%
1
1
exo (Hα /endo (Hβ) 1:1.2
Scheme 1. Synthesis of endocyclic enecarbamate 10.
Scheme 3. Preparation of cyclobutanones 15-endo/exo.

M. S. Valle et al. / Tetrahedron Letters 49 (2008) 1957–1960
1959
somewhat surprisingly, [2+2] the cycloaddition of enecar-
bamate 10 to the alkylketene derived from 4-chlorobutyryl
O
H
a: 1. TFA, Et
CH Cl , reflux, 18 h
2. NaHCO or
3
SiH,
m-CPBA, NaHCO
3
,
2
2
O
CH
2
Cl
2
, 30 min
3
chloride (Et N, cyclohexane as solvent at reflux) resulted in
15 -endo
2
CO t-Bu
3
N
9
9%
H
b: 1. 10% HCl, 8 h
2. 5% NaOH, 2 h
a mixture of endo and exo cycloadducts 15 (1.2:1 ratio) in a
moderate yield of 51%. The reasons for this drastic reduc-
tion in yields and stereoselectivity are not clear at present.
Previous results from our laboratory using simpler endo-
cyclic enecarbamates provided higher yields and higher
stereoselectivity for endo cycloadduct on similar [2+2] cyc-
Boc
1
Cl
6
O
O
1.LiAlH , T HF,
O
O
4
H
H
2
SO
4
, MeOH,
H
reflux,12 h
reflux, 12 h
2.HCl 2N
.
( HCl)
6
N
H
1
N
6
1% (2 steps)
Cl
CO H
2
2
CO Me
7
19
3
b,g–i
loadditions.
out to be straightforward. The desired cycloadduct endo-
5 could be easily separated from the cycloadduct exo-15
by recrystallization in a solvent mixture of EtOAc/hexane
1:1). The structure of the key cycloadduct endo-15 was
Separation of the diastereomers turned
LiAlH
4
or AlH
3
OH
1
HO
H
+
17
N
H
1
8
H
(
7
Cl
CO
2
then confirmed by the X-ray analysis (Fig. 4).
As expected cycloadduct endo-15 underwent a clean
Baeyer–Villiger oxidation (mCPBA, NaHCO in CH Cl )
Scheme 4. Synthesis of trihydroxylated deoxyalexine 6.
3
2
2
to provide lactone 16 in almost quantitative yield (99%)
as a single regioisomer. Simultaneous cleavage of the tert-
butyl ester and Boc protecting groups of lactone 16 was
1
0 in a concise manner. Synthesis of indolizidine 7 was
accomplished in an overall yield of 32% after six steps,
whereas pyrrolizidine 6 was prepared in 22% overall yield
after 5 steps. These total syntheses feature a selective
carried out using excess of TFA, in the presence of Et SiH
3
in dichloromethane to furnish the corresponding tricyclic
amino acid 17 (trifluoroacetate salt) in only 22% yield (con-
dition a, Scheme 4). Much higher yields of amino acid 17
were obtained when using stronger acid/neutralization
conditions (HCl 10% then NaOH 5%) to provide hydro-
chloride 17 in 71% yield (condition b, Scheme 4). Reduc-
tion of lactone moiety of 17 with LiAlH4 or AlH3
[
2+2] cycloaddition of alkylketenes generated in situ to
endocyclic enecarbamate 10, which can be efficiently syn-
thesized from L-proline or pyroglutamic acid with an over-
all yield of 44%. The capacity of these new alexine-like
compounds to inhibit glucosidases is being evaluated and
the results of these assays will be reported in due course.
(
generated in situ) gave an inseparable mixture of the start-
Acknowledgments
ing lactone 17 and the dihydroxy amino acid 18 instead of
the expected triol 6. To obtain the desired triol 6 the amino
acid hydrochloride 17 was first reacted with MeOH/H SO
We thank the Research Support Foundation of the State
of S a˜ o Paulo (FAPESP) for financial support of this work
2
4
to generate amino ester 19, which was then reduced with
(Grants 02/03431-8 and 05/00721-3) and for a doctoral fel-
LiAlH to yield the corresponding trihydroxy pyrrolizidine
4
lowship to M.S.V. We also thank the Brazilian National
Research Council (CNPq) for a research fellowship to
C.R.D.C. and the ICSN-CNRS, France for complemen-
tary analyses.
6
in 61% yield from hydrochloride 17, after purification by
DOWEX-50W-X8.
In conclusion, trihydroxy pyrrolizidine 6 and tri-
hydroxy indolizidine 7 were synthesized as alexine-like
8
9
compounds from the common endocyclic enecarbamate
References and notes
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Fig. 4. Ortep drawing of cycloadduct endo-15.

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2
ꢀ1
Cl
2
/MeOH/NH
4
OH
2
0
14:5:1); ½aꢁ +9.20 (c 0.5, H
2
O); IR (film, cm ): 3304, 2947 2284,
D
1
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2
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4.1 Hz, J 2.5 Hz, 1H), 3.87 (m, 1H), 3.90 (m, 1H), 3.94 (m, 2H), 3.97
(m, 2H), 4.09 (dd, J 3.5 Hz, J 8.5 Hz, 1H), 4.65 (br dd, J 2.5 Hz, J
1
3
2
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2.8 Hz, 1H); C NMR (125 MHz, D
61.1, 69.8, 73.8, 76.4; TOF MS ES+ calcd for C9H18NO3 : 188.1,
found 188.1; HRMS m/z calcd for C9H18NO3 : 188.1287, found
2
O): d 30.2, 35.4, 40.4, 54.2, 59.8,
þ
þ
5
6
1986, 34, 3873.
188.1264.
2
D
0
. For a comprehensive review on [2+2] cycloadditions, see: Tidwell, T.
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3
/MeOH 1:1); ½aꢁ
ꢀ1
ꢀ8.75 (c 0.1, H
2
O); IR (film, cm ): 3310, 2952, 2889, 1597, 1455,
1
1368, 1339, 1115, 1083, 1049; H NMR (300 MHz, CDCl
3
): d 1.62–
1.77 (m, 2H), 1.85–2.20 (m, J 3.66 Hz, J 5.13 Hz, 4H), 2.61 (m, J
7.32 Hz, 1H), 3.17 (td, J 3.66 Hz, 13.18, 1H), 3.51 (br td, 1H), 3.58 (br
dd, J 1.41 Hz, 1H), 3.72–4.00 (m, J 2.93 Hz, 3H), 3.80 (t, J 2.20 Hz,
1
3
122; (d) Snider, B. B. ChemTracts-Org. Chem. 1991, 4, 403; (e) Tidwell,
1H), 4.30 (br s, 1 H); C NMR (75 MHz, CDCl
3
): d 13.8 (CH), 28, 2
), 59.8 (CH ), 62.6
T. T. Acc. Chem. Res. 1990, 23, 273; (f) Ghosez, L.; O’Donnell, M. J. In
Pericyclic Reactions; Marchand, A. P., Lehr, R. E., Eds.; Academic
Press: New York, 1977; pp 79–140.
(CH ), 28.6 (CH ), 40.8 (CH), 46.4 (CH ), 58.8 (CH
(CH), 63.1 (CH), 65.8 (CH); ESI-MS calcd for [M+H] : 202.2, found
202.2.
2
2
2
2
2
+