A general asymmetric route for the synthesis of the alexine and australine family of pyrrolizidine alkaloids. The first asymmetric synthesis of 1,2-diepi-alexine and 1,2,7-triepi-australine

Article abstract of DOI:10.1016/j.tetlet.2005.10.074

The first asymmetric synthesis of 1,2-diepi-alexine and 1,2,7-triepi-australine (both are unknown at present) is described, which utilized the regioselective asymmetric aminohydroxylation (RAA) reaction of the achiral olefin VI, the cross metathesis (CM)

Full text of DOI:10.1016/j.tetlet.2005.10.074

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8865–8868
A general asymmetric route for the synthesis of the alexine and
australine family of pyrrolizidine alkaloids. The first
asymmetric synthesis of 1,2-diepi-alexine and 1,2,7-triepi-australine
Dinesh Chikkanna, Om V. Singh, Suk Bin Kongꢀ and Hyunsoo Han*
Department of Chemistry, The University of Texas at San Antonio, 6900 N. Loop 1604 West, San Antonio, TX78249, USA
Received 12 September 2005; revised 12 October 2005; accepted 18 October 2005
Available online 2 November 2005
Abstract—The first asymmetric synthesis of 1,2-diepi-alexine and 1,2,7-triepi-australine (both are unknown at present) is described,
which utilized the regioselective asymmetric aminohydroxylation (RAA) reaction of the achiral olefin VI, the cross metathesis (CM)
reaction of the terminal olefin 8, and the formation and subsequent intramolecular double cyclization (DC) reactions of the epoxides
10 and 11. The C1 stereocenter was diastereoselectively introduced by the reaction of the aldehyde 7 with vinylmagnesium bromide.
Ó 2005 Elsevier Ltd. All rights reserved.
HO
HO
HO
HO
HO
HO
Alexine (1) and australine (2) were isolated from Alexa
leiopetala and Castanospermum australe, respectively,
in 1988, and were shown to be potent glycosidase inhibi-
tors.1 Since glycosidases are involved in many vital bio-
logical processes and also believed to be implicated in
human diseases such as diabetes,2 cancers,3 malaria,4
and viral infection,5 a plethora of research activities
have been directed to find or prepare the other stereoiso-
mers and derivatives of alexine and australine with such
activities.6 So far, 13 stereoisomers of 1 and 2 (out of 32
possible isomers) are known from natural sources1,7 and
syntheses.8 These compounds have indeed proved to be
selective glycosidase inhibitors,7 and further some of
them have been reported to exhibit antiviral and retro-
viral activities9 (Fig. 1).
HO
HO
N
N
N
N
H
H
H
OH
H
OH
OH
OH
HO
HO
HO
HO
4, 1,2,7-triepi-
1, (+)-alexine 2, (+)-australine 3, 1,2-diepi-alexine
australine
Figure 1. Structure of alexine, australine, 1,2-diepi-alexine, and 1,2,7-
triepi-australine.
lation of the substituents and the stereoselective con-
struction of the pyrrolizidine ring are required for any
successful asymmetric synthesis. A number of methodolo-
gies have been devised for the asymmetric synthesis of
this family, most of which have employed chiral carbo-
hydrates and amino acids as starting materials.8,10 To
the best of our knowledge, only two true asymmetric
methodologies have been reported to date, in which
achiral starting materials were used and all stereocenters
were introduced either by asymmetric induction or
enzymatic reaction. Denmark utilized tandem chiral
auxiliary based intermolecular [4+2] and inter-/intra-
molecular [3+2] nitroalkene cycloaddtion reactions fol-
lowed by a stereoselective dihydroxylation reaction to
introduce all five stereocenters.11 Wong used Sharpless
asymmetric epoxidation/enzymatic aldol reaction/bis-
reductive amination for the stereochemical control in
their synthesis.12 Herein, we report an efficient and
highly flexible asymmetric approach for the synthesis
of the alexine and australine family of pyrrolizidine
Besides their profound biological activities, the alexine
and australine family of pyrrolizidine alkaloids repre-
sent interesting and challenging synthetic targets. They
are densely functionalized by the hydroxyl and amino
groups, and have five contiguous stereocenters as well
as a pyrrolizidine ring. Thus, both stereoselective instal-
Keywords: Pyrrolizidine alkaloids; Regioselective asymmetric amino-
hydroxylation; Olefin cross metathesis; Epoxidation; Double
cyclization.
*
Corresponding author. Tel./fax: +1 210 458 4958; e-mail:
hyunsoo.han@utsa.edu
ꢀ Address: Department of Chemistry, University of The Incarnate
Word, San Antonio, TX 78209, USA.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.074

8866
D. Chikkanna et al. / Tetrahedron Letters 46 (2005) 8865–8868
alkaloids, which not only resulted in the first asymmetric
synthesis of 1,2-diepi-alexine and 1,2,7-triepi-australine
(two unknown members of this family until now) from
the readily available achiral olefin VI, but also implies
the potential to synthesize other stereoisomers of this
family from the same olefin.
O
Ac
OEt
NH
O
a
O
PMPO
OEt
OEt
5
OH
OMe
VI
b
Boc
Boc
NH
O
NH O
c
Shown in Figure 2 is the retrosynthetic analysis for the
alexine and australine family of pyrrolizidine alkaloids.
In designing the synthetic strategy, emphasis has been
put on the stereochemical predictability as well as the
flexibility and overall efficiency of the synthesis. Thus,
the fully functionalized pyrrolizidine ring (I) can be de-
rived from the SN2-type double cyclization (DC)8f of the
epoxyamine II, which itself would be generated through
the allylic epoxidation13 of the alkenylalcohol III. The
sequential epoxidation and double cylization reactions
set the C7a and C7 stereocenters of the alexine and aus-
traline family. Compound III can be prepared by the
cross metathesis (CM) reaction14 of the terminal olefin
IV. A nucleophilic addition reaction between the alde-
hyde V and vinyl metals should give IV, establishing
the C1 stereocenter. Finally, V would be prepared
through the regioselective asymmetric aminohydroxyla-
tion (RAA) reaction15 of the readily available a,b-
unsaturated ester VI, which installs the C2 and C3
stereocenters in a syn-fashion.
PMPO
PMPO
H
7
6
OBn
OBn
d
TsO
NH
Boc
Boc
PMPO
NH
e
PMPO
OH
OH
OBn
9
OBn
8
Scheme 1. Reagents and conditions: (a) K2OsO4Æ2H2O, (DHQD)2-
PHAL, LiOH, N-bromoacetamide, t-BuOH–H2O 2:1, 4 °C, 8 h, 70%;
(b) (i) NaH, BnCl, DMF, 0 °C, 10 h; 78%; (ii) (Boc)2O, DMAP, THF,
reflux, 4 h, then NH2NH2, MeOH, 4 h, 85%; (c) DIBAL, CH2Cl2,
À78 °C, 3 h, 90%; (d) vinylmagnesium bromide, THF, À50 °C, 1 h
then rt, 1 h, 85%; (e) RCM, Grubbsꢁ second generation catalyst,
4-butenol p-tolylsulfonate, CH2Cl2, 65%.
7.18 The reaction of 7 with vinylmagnesium bromide at
À50 °C in THF generated the allylic alcohol 8 with 4:1
diastereoselectivity. Other reaction conditions involving
different vinyl anion sources, solvents, and temperatures
did not improve diastereoselectivity much. The cross
metathesis reaction14d of 8 with 4-butenol p-tolyl-
sulfonate in the presence of the second generation
Grubbsꢁ catalyst {tricyclohexylphosphine[1,3-bis(2,4,6-
trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzyl-
idine]ruthenium (IV) dichloride} provided the trans-olefin
9 almost exclusively.
Our synthesis of 1,2-diepi-alexine and 1,2,7-triepi-austra-
line started with the readily available a,b-unsaturated
ester VI (Scheme 1). The RAA reaction of VI using
the (DHQD)2PHAL as a ligand and N-bromoacetamide
as a nitrogen source/oxidant afforded the syn-amino-
alcohol 5 with an excellent regio- (>20:1) and enantio-
selectivity (>99% after one recrystallization from ethyl
acetate).15a,b,c The protection of the hydroxyl group by
benzylchloride and sodium hydride in DMF gave the
benzyl ether,16 the N-acetyl group of which was con-
verted to the N-Boc group to give the carbamate 6.
The protection group intercoversion was accomplished
by employing the Burkꢁs protocol: (Boc)2O, DMAP,
then NH2NH2.17 The partial reduction of the ester 6
by slow addition of DIBAL at À78 °C gave the aldehyde
Scheme 2 depicts the latter stage of the synthesis. The
allylic alcohol 9 was subjected to the epoxidation condi-
tions involving VO(acac)2/ROOH.19 After some experi-
TsO
NH
TsO
NH
O
Boc
PMPO
Boc
a
O
OH
+
9
PMPO
3
OH
10 OBn
11 OBn
:
2
HO
TsO
DC
N
NH2
b
HO
O
OH
PGO
PMPO
PMPO
OH
HO
OPG
II
I
N
N
+
BnO
BnO
H
H
OH
OH
OH
12
13
HO
HO
HO
TsO
NH
PG
C M
PG
PGO
NH
c
c
PGO
OH
HO
HO
.
.
OH
HCl
HCl
OPG
IV
OPG
III
N
N
HO
HO
O
H
H
OH
3
PG
4
HO
OEt
VI
OMe
O
R AA
NH
O
PGO
Scheme 2. Reagents and conditions: (a) VO(acac)2, TBHP, toluene,
74%; (b) (i) 3 N HCl, MeOH, (ii) K2CO3, MeOH, 83%; (c) (i) CAN,
CH3CN–H2O 4:1, 4 °C; (ii) H2, Pd/C, MeOH, 72% for 3 and 80% for
4.
H
V
OPG
Figure 2. Retrosynthetic analysis of pyrrolizidine alkaloids.

D. Chikkanna et al. / Tetrahedron Letters 46 (2005) 8865–8868
8867
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using two fold excess of t-BuOOH in the presence of
4 mol % of VO(acac)2 in toluene solvent at ambient tem-
perature were optimal for the epoxidation of 9, which
produced an inseparable mixture of the epoxides 10
and 11 in a 2:3 ratio and 74% yield. Treatment of the
mixture of 10 and 11 with 3 N HCl in MeOH followed
by the addition of solid K2CO3 in one pot operation
effected the double cyclization to yield the fully function-
alized alexine 12 and australine 13. After column separa-
tion, a sequential deprotection of PMP and benzyl
group by CAN20 and hydrogenation, respectively, con-
verted 12 to 1,2-diepi-alexine (3),21 which was isolated
as a HCl salt. Similarly 1,2,7-triepi-australine (4)21 was
obtained from 13, the spectral data (1H and 13C
NMR) of which were consistent with those of its enan-
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In summary, the first asymmetric synthesis of 1,2-diepi-
alexine and 1,2,7-triepi-australine was accomplished
from the simple olefin VI in only 10 steps by using the
regioselective asymmetric aminohydroxylation, olefin
cross metathesis, and double cyclization reactions as
key steps. Currently, we are persuing the asymmetric
synthesis of the other stereoisomers and derivatives of
alexine and australine by modifying the present method-
ology slightly.
Acknowledgement
Financial support from National Institute of Health
(GM 08194) and The Welch Foundation (AX-1534) is
gratefully acknowledged.
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21. Characterization data: 1,2-diepi-alexine hydrochloride:
[a]D +33.0 (c 0.1, H2O); 1H NMR (500 MHz, D2O): d
4.62–4.58 (1H, m), 4.37 (1H, br s), 4.32 (1H, br s), 4.12–
3.98 (3H, m), 3.80 (1H, d, J = 5.8 Hz), 3.75–3.60 (2H, m),
2.51–2.44 (1H, m), 2.04–1.96 (1H, m). 13C NMR (75 MHz,
D2O): d 81.8, 79.4, 78.9, 74.8, 69.8, 57.6, 50.3, 34.9. 1,2,7-
triepi-australine hydrochloride: [a]D +49.0 (c 0.1, H2O);
1H NMR (500 MHz, D2O): d 4.69 (1H, br s), 4.43–4.41
(1H, m), 4.35 (1H, br s), 4.30 (1H, d, J = 4.8 Hz), 4.07
(1H, dd, J = 7.8 and 4.8 Hz), 4.01 (1H, dd, J = 12.7 and
7.8 Hz), 2.42–2.34 (1H, m), 2.15–2.10 (1H, m); 13C NMR
(75 MHz, D2O): d 80.7, 79.3, 75.6, 72.7, 71.6, 59.8, 54.7,
36.3.