Stereodivergent approach to enantiopure hydroxyindolizidines through 1,3-dipolar cycloaddition of 3-hydroxypyrroline N-oxide derivatives

Article abstract of DOI:10.1002/1099-0690(200206)2002:12<1941::AID-EJOC1941>3.0.CO;2-T

The (3S)-3-alkoxypyrroline N-oxides 7 and 27 were easily prepared from 1-malic acid and used as starting materials for enantiospecific syntheses of stereo differentiated polyhydro-xyindolizidines. Selection of the appropriate modality (inter or intramolec

Full text of DOI:10.1002/1099-0690(200206)2002:12<1941::AID-EJOC1941>3.0.CO;2-T

FULL PAPER
Stereodivergent Approach to Enantiopure Hydroxyindolizidines Through
1,3-Dipolar Cycloaddition of 3-Hydroxypyrroline N-Oxide Derivatives
Franca M. Cordero,*[a] Federica Pisaneschi,[a] Martina Gensini,[a] Andrea Goti,[a] and
Alberto Brandi*[a]
Keywords: Cycloaddition / Diastereoselectivity / Nitrogen heterocycles / Nitrones / Protecting groups
The (3S)-3-alkoxypyrroline N-oxides 7 and 27 were easily
prepared from -malic acid and used as starting materials for
tected hydroxy nitrone during the introduction of the di-
polarophile moiety. Protection/deprotection were achieved
l
enantiospecific syntheses of stereodifferentiated polyhydro- by cycloaddition/retro-cycloaddition reactions. The different
xyindolizidines. Selection of the appropriate modality (inter-
or intramolecular) for 1,3-dipolar cycloaddition of the cyclic
nitrone with 5-hydroxypentenoic acid derivatives gave ac-
propensity of some pyrrolo[1,2-b]isoxazolidines to undergo
retro-cycloaddition with regeneration of the nitrone func-
tionality was investigated both experimentally and by semi-
cess to either [1,8a]-trans- or -cis-hydroxyindolizidines 31 empirical and ab initio calculations on model compounds.
and 24, respectively, through elaboration of the primary
cycloadducts. Moreover, the choice of the esterification con-
ditions (Ph3P/DEAD or DIC/DMAP) used in linking the
nitrone and the dipolarophile moieties in the intramolecular
approach determined the absolute configuration of the final
product, allowing the selective synthesis of both enanti-
omers, (−)-24 and (+)-24. This strategy required protection of
the nitrone functionality to avoid racemization of the unpro-
The relative calculated activation energies were qualitatively
in good agreement with the experimental observations. Fum-
aronitrile was found to be a convenient protecting reagent
for the nitrone moiety and could be removed by retro-cyclo-
addition at lower temperatures than styrene and ethyl acryl-
ate.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
The 1,3-dipolar cycloaddition of enantiomerically pure
nitrones and alkenes is a powerful synthetic device that al-
lows up to three new stereogenic centers to be assembled
in a stereospecific manner in a single step.[1] The resulting
isoxazolidine cycloadducts can be further elaborated to pro-
vide polyfunctionalized compounds with preservation of
optical purity.
In recent years we have applied the cycloaddition strategy
to the synthesis of several natural and unnatural pyrrolizid-
ines and indolizidines by employing a variety of enantio-
merically pure mono- and dialkoxypyrroline N-oxides
derived from malic acid and tartaric acid, respectively (Fig-
ure 1).[2]
Figure 1. Synthesis of polyhydroxy-indolizidines and -pyrrolizid-
ines
polarophiles towards the nitrone. An attack anti to the alk-
oxy group vicinal to the nitrone moiety produces a cis rela-
tionship of the OR group and the bridgehead H atom in
the final product. The opposite trans relationship can only
be achieved by a syn approach of the reagents, but this ap-
proach is usually highly hindered by unfavorable steric in-
teractions between the dipolarophile and the alkoxy sub-
stituent (Figure 2). A good to excellent selectivity is in fact
observed in favor of the anti product.[2]
The process allows control over the relative and absolute
configuration of three (or more) stereocenters in the final
product, resulting with high efficiency in highly func-
tionalized compounds. The configuration of the bridgehead
carbon atom is dictated by the mode of approach of di-
[a]
Dipartimento di Chimica Organica ‘‘Ugo Schiff’’, and Centro
di Studio sulla Chimica e la Struttura dei Composti Eterociclici
`
e loro Applicazioni-CNR, Universita degli Studi di Firenze,
Polo Scientifico,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Fax: (internat.) ϩ 39-055/457-3531
E-mail: franca.cordero@unifi.it
Figure 2. Modes of approach between the cyclic nitrone and
alkenes
Eur. J. Org. Chem. 2002, 1941Ϫ1951  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0612Ϫ1941 $ 20.00ϩ.50/0
1941

F. M. Cordero, F. Pisaneschi, M. Gensini, A. Goti, A. Brandi
FULL PAPER
The only possible means to induce a syn approach of the
The novel THP-protected nitrone 7 was prepared on a
reagent, in order to achieve a trans (OR, bridgehead H) multigram scale from diethyl (2S)-malate in five steps, with
relationship in the products, relies on forcing the cycloaddi- only one, final purification and in 44% overall yield. This
tion to occur in an intramolecular mode. The success of synthetic methodology had previously been used to make
this alternative approach can expand the usefulness of this other optically pure pyrroline N-oxides,[7] and consists of
strategy in accessing all the broad range of natural and un- protection of hydroxy ester 5 with a suitable group, followed
natural pyrrolizidines and indolizidines, the most represent- in sequence by reduction with LiAlH4, mesylation with
ative of which are shown in Scheme 1.[3]
methanesulfonyl chloride (MsCl), and cyclization to N-hy-
droxypyrrolidine with NH2OH in triethylamine (TEA) as
solvent. The final oxidation step, carried out with HgO, af-
forded the THP-protected nitrone 7 and its regioisomer 8
in a 10:1 ratio. As recently reported, use of more environ-
[8]
mentally friendly MnO2
as oxidant afforded the two
nitrones 7 and 8 in comparable ratio (each of them as a
pair of diastereoisomers), which were easily separated by
silica gel chromatography (Scheme 3).
Scheme 1. Some representative natural polyhydroxypyrrolizidines
and -indolizidines
In this paper we demonstrate the feasibility of this gen-
eral strategy applied to the stereocontrolled synthesis of
several configurationally differentiated polyhydroxyindolizi-
dines.[4] The dipolarophile chosen for this study contains a
carboxylate moiety that plays a double role. It is able to
steer the regioselectivity in the intermolecular reaction, and
can serve as a removable tether to connect the dipolarophile
Scheme 3. a: i) 2H-dihydropyran, Amberlyst 15, pentane, room
temp.; ii) LiAlH4, diethyl ether, reflux temperature; iii) MsCl,
TEA, CH2Cl2, 0 °C; b) i) NH2OH HCl, TEA, reflux temperature;
ii) HgO or MnO2, CH2Cl2, 0 °C Ǟ room temp.
temporarily to the nitrone for the intramolecular reaction. Intramolecular Cycloadditions
For this purpose, a new tetrahydropyranyl-protected (THP-
To connect the dipolarophile 4 to the cyclic nitrone it was
protected) nitrone was synthesized, to allow the deprotec-
tion of the hydroxy functionality under milder conditions.
Moreover, the abilities of three different dipolarophiles Ϫ
styrene, ethyl acrylate and fumaronitrile Ϫ for protection
of the nitrone moiety were evaluated both experimentally
and computationally.
necessary to remove the THP protecting group. Unfortu-
nately, although the THP could be removed under very mild
conditions, such as by treatment with an acidic resin (Am-
berlyst 15) in methanol at 40 °C, the nitrone 9 turned out
to be configurationally unstable and could not be obtained
enantiomerically pure.[9] Partial loss of optical activity was
also observed during purification of 9 by silica gel chroma-
tography or recrystallization from ethyl acetate.
Results and Discussion
A thorough analysis of the crude deprotection mixture
showed the presence of small amounts of the methylated
nitrone 10 (Scheme 4). The racemization process of 9, as
well as the formation of 10, might be explained by the exist-
ence of the transient bicyclic intermediate I, which could
undergo a nucleophilic attack by H2O or CH3OH under
the reaction conditions (Scheme 5). On the other hand, the
hypothesis that 9 could racemize through the occurrence of
fast nitrone/hydroxy enamine tautomerism[10] was dis-
carded, as no H/D exchange of 3-H was observed when the
deprotection of 8 was run in CD3OD (Scheme 5).
The preparation of the previously unknown 5-PMBO-2-
pentenoic acid (4) (PMB: p-methoxybenzyl) was carried out
starting from 1,3-propanediol (1) through slight modifica-
tion of published procedures.[5] The monoprotected diol
2[5a,5b] was subjected to Swern oxidation,[6] followed by
HornerϪWadsworthϪEmmons olefination to afford the
pentenoate 3[5c,5d] in very good overall yield (Scheme 2).
The ester 3 was then hydrolyzed with NaOH to afford the
acid 4, required to connect the dipolarophile with the
nitrone.
Scheme 2. (a) i) p-Anisaldehyde, cat. pTsOH, toluene, 110 °C; ii)
DIBAL, toluene, 0 °C, 91%; (b) i) (COCl)2, DMSO, TEA, CH2Cl2;
ii) trimethyl phosphonoacetate, K2CO3, H2O, 98%; (c) i) 1 
NaOH, THF; ii) HCl, 72%
Scheme 4. a: Amberlyst 15, CH3OH, 40 °C
Eur. J. Org. Chem. 2002, 1941Ϫ1951
1942

Stereodivergent Approach to Enantiopure Hydroxyindolizidines
FULL PAPER
Scheme 5
Protection of the nitrone functionality might circumvent
the problem of the racemization.[11] The only practical
method for nitrone protection available to date consists of
the formation of an isoxazolidine, provided that the nitrone
functionality can later be restored by retro-cycloaddition.
The method was originally reported by Tufariello, who ap-
plied it to the synthesis of (Ϯ)-cocaine,[11g] and was recently
also successfully employed by Holmes for the synthesis of
(Ϫ)-histrionicotoxine.[11e]
Nitrone 7 was therefore converted into an isoxazolidine
before the removal of the THP group. Styrene (11),[4][11e]
ethyl acrylate (12), and fumaronitrile (13) were used as di-
polarophiles to create the temporary isoxazolidines 14Ϫ16.
After deprotection, which occurred on the isoxazolidine
without any problem, the hydroxy group was connected to
the dipolarophile 4.
The cycloaddition of 7 to 11 took place at 80 °C to give
a mixture of two diastereomeric pairs of anti-exo and anti-
endo adducts in a 4:1 ratio and 89% overall yield. The re-
moval of the THP protecting group was achieved with pyri-
dinium p-toluenesulfonate (PPTS) in refluxing dry EtOH,
and afforded the two diastereomeric isoxazolidines 14 in
89% yield (Scheme 6). The two diastereomeric adducts 14
Scheme 6. (a) R ϭ Ph, RЈ ϭ H: toluene, 80 °C, 10 h, 89%; R ϭ
CO2Et, RЈ ϭ H: CH2Cl2, room temp., 87%; R ϭ RЈ ϭ CN:
CH2Cl2, room temp., 86%; (b) R ϭ Ph, RЈ ϭ H: PPTS, EtOH,
reflux, 3 h, 89%; R ϭ CO2Et, RЈ ϭ H and R ϭ H, RЈ ϭ CO2Et:
Amberlyst 15, EtOH, reflux, 91%; R ϭ RЈ ϭ CN: Amberlyst 15,
MeOH, 55 °C, 97%: (c) 4, DIC, DMAP, CH2Cl2 (17: 70%; 18:
94%, 19: 76%); (d) 17: o-dichlorobenzene, reflux, 14 h, 31%; 18: o-
dichlorobenzene, 150 °C, 3 h, 51%; 19: o-xylene, reflux, 1 h, 84%;
(e) DDQ, H2O, CH2Cl2, 82%; (f) i): MsCl, TEA, CH2Cl2, 0 °C;
ii): H2, Pd/C, MeOH; iii): Ambersep 900 OH, 77%; (g) Red-Al,
THF, reflux, 3 h, 78%
The two isoxazolidines 16 were similarly obtained from
could easily be separated by chromatography on silica gel 7 and fumaronitrile (13) in high yields after deprotection
and fully characterized, but they were utilized as a mixture (Scheme 6). In this case the removal of THP was achieved
in the following synthesis, since both of them afforded the with Amberlyst 15 in MeOH at 55 °C and afforded the two
same nitrone intermediate 20 after retro-cycloaddition.
diastereoisomers 16 in 97% yield (Scheme 6). When the
The isoxazolidines 14 were treated with acid 4 in the pres- THP deprotection in the dicyanoisoxazolidines was per-
ence of 1,3-diisopropylcarbodiimide (DIC) and 4-(di- formed in refluxing EtOH, the formation of small amounts
methylamino)pyridine (DMAP) to give the two (4S)-esters of 13, 7, and 9 attested to a promising propensity of the
17 in 70% yield (Scheme 6). The refluxing temperature of dicyano adducts to undergo thermally induced retro-cyclo-
o-dichlorobenzene (180 °C)[11e] was necessary to induce the addition. The activating effect, exerted on isoxazolidine
thermal retro-cycloaddition reaction of phenylisoxazolid- cycloreversion by electron-withdrawing groups in general
ines 17 to the nitrone 20, which immediately underwent in- and cyano groups in particular, has been already reported,
tramolecular cycloaddition under the reaction conditions. albeit with different nitrones.[11c][11d] In contrast to the re-
The tricyclic isoxazolidine (ϩ)-21 was obtained with com- ported instability of fumaronitrile cycloadducts even at
plete diastereoselectivity, through the syn-TS A, in 31% room temperature,[11d] no retro-cycloaddition was observed
yield (Scheme 6).
by us when the dicyanoisoxazolidines were treated at a tem-
The efficiencies of ethyl acrylate (12) and fumaronitrile perature below 50 °C, which was of extreme importance for
(13) as protecting dipolarophiles for the nitrone moiety in the general application of our process.
the process were also evaluated. Ethyl acrylate (12) reacted
The isoxazolidines 15 and 16 were then acylated as previ-
with the nitrone 7 at room temperature to give a mixture of ously (4, DIC, DMAP) to give the corresponding esters 18
adducts composed, after removal of the THP group, of two and 19, respectively, in good yields (Scheme 6). The esters
pairs of regioisomers, 15a and 15b, in a 6:1 ratio (79% over- 18 and 19 underwent the domino retro-cycloaddition/intra-
all yield).
molecular cycloaddition process under rather easier condi-
Eur. J. Org. Chem. 2002, 1941Ϫ1951
1943

F. M. Cordero, F. Pisaneschi, M. Gensini, A. Goti, A. Brandi
FULL PAPER
tions than 17 and were completely converted at 145Ϫ150 ature, to the best of our knowledge, and certainly needs
°C after 3 and 1 h, respectively (Scheme 6), to afford (ϩ)- further investigation.
21 in reasonable to good yields.
The tricyclic isoxazolidine (Ϫ)-21 (Scheme 7) was ob-
Isoxazolidines 19 underwent retro-cycloaddition even at tained from 25 and 26 by heating at 180 °C and 150 °C,
100 °C, but at that temperature the intramolecular cycload- respectively, and was converted into (Ϫ)-24 by treatment
dition was sluggish and afforded (ϩ)-21 in very low yields. with trifluoroacetic acid (TFA) to remove the PMB group
In contrast, the domino retro-cycloaddition/intramolecular and mesylation by the same procedure as used to obtain
cycloaddition process in refluxing o-xylene was fast and (ϩ)-24. The optical rotation of (Ϫ)-24 ([α] ϭ Ϫ57.6) proved
(ϩ)-21 was recovered in high yield (84%) (Scheme 6). The that the Mitsunobu reaction occurred with complete inver-
identity of the optical rotatory power in (ϩ)-21 deriving sion of configuration in both isoxazolidines 14 and 15.
from the three different isoxazolidines 17, 18, and 19 at-
tested to the generality of the process and its ability to in-
duce transformations with complete stereocontrol.
Intermolecular Cycloaddition
As previously pointed out, the intermolecular 1,3-dipolar
cycloaddition of 3-alkoxy nitrones occurs preferentially
with anti diastereofacial selectivity to afford the adduct
characterized by a trans (OR, bridgehead H) relationship.
The C-1 epimer of indolizidine (Ϫ)-24 was therefore ex-
pected to be easily available from the same starting mat-
erials and through the same methodology, just switching
from the intra- to the intermolecular mode in the cycloaddi-
tion step.
In this case the OH protecting group had to be removed
only in the last step. The tert-butyl-protected nitrone 27 was
therefore used instead of 7, in order to avoid the formation
of diastereomers.
The intermolecular cycloaddition of 27, obtained from -
malic acid,[7a] with 5-hydroxypentenoate 28, obtained from
3 by treatment with ceric ammonium nitrate (CAN)
(Scheme 8), was carried out at 60 °C and was completely
regio- and diastereoselective. As expected,[14] the sole cyclo-
adduct 29, deriving from an anti(OtBu)-endo(CO2CH3) ap-
proach of the two reagents (TS B, Scheme 8), was formed.
(2S,3R,3aS,4S)-Pyrrolo[1,2-b]isoxazolidine 29 was sequen-
tially mesylated and hydrogenated on Pd/C to give the indo-
lizidine 30 in 83% overall yield. Reduction of the ester moi-
ety with Red-Al, followed by hydrolysis of the tert-butyl
ether with TFA, afforded the enantiomerically pure indoliz-
idine (ϩ)-31, a diastereoisomer of 24, in high yields (85%)
(Scheme 8).
Removal of PMB from (ϩ)-21 with 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (DDQ) afforded the alcohol (ϩ)-22,
which was subsequently mesylated, and then directly hydro-
genated, in the presence of catalytic amounts of Pd/C, to
give the indolizidine (ϩ)-23 (77% yield) through a domino
isoxazolidine ring-opening/intramolecular nucleophilic sub-
stitution.[12] Reduction of the lactone moiety with Red-Al
afforded the final trihydroxyindolizidine (ϩ)-24 in 78%
yield ([α] ϭ ϩ57.8) (Scheme 6).
Its enantiomer (Ϫ)-24 could be synthesized from nitrone
7, in an enantiodivergent approach, by condensing the same
intermediate isoxazolidine alcohols 14Ϫ15[4] with penteno-
ate 4 under Mitsunobu esterification conditions,[13] which
cause the inversion of configuration at C-4 (see below). The
mixture of adducts 14 was treated with the pentenoate 4
in the presence of diethyl azodicarboxylate (DEAD) and
polymer-supported Ph3P, to give the esters 25 with clean
inversion of configuration at C-4 (59% yield) (Scheme 7).
Analogously, adducts 15 gave the esters 26 under the clas-
sical Mitsunobu reaction conditions (82% yield based on
50% conversion) (Scheme 7).
Scheme 7. (a) 14: 4, PPh3 (polystyrene-supported), DEAD,
CH2Cl2, 59%; 15: 4, PPh3, DEAD, THF, 82% (50% conversion);
(b) 25: o-dichlorobenzene, reflux, 64 h, 62%;. 26: o-dichloroben-
zene, 150 °C, 3 h, 74%; (c) TFA, CH2Cl2, room temp., 70%; (d) i):
MsCl, TEA, CH2Cl2, 0 °C; ii): H2, Pd/C, MeOH; iii): Ambersep
900 OH, 77%; (e) Red-Al, THF, reflux, 3 h, 91%
Unfortunately, any attempt to run the Mitsunobu reac-
tion with 16 as the β-dinitrile moiety proved to be affected
under Mitsunobu conditions, affording mainly decomposi-
tion products. The use of the Mitsunobu reaction with sim-
Scheme 8. (a) CAN, CH3CN/H2O or TFA, CH2Cl2; 66%; (b) tolu-
ene, 60 °C, 1 d, 77%; (c) i): MsCl, TEA, CH2Cl2, 0 °C; ii: H2, Pd/
C, MeOH; iii): Ambersep 900 OH, 83%; (d) Red-Al, THF, reflux,
ilar dinitrile compounds is very little addressed in the liter- 89%; (e) i): TFA, H2O; ii): Ambersep 900 OH, 95%
1944
Eur. J. Org. Chem. 2002, 1941Ϫ1951

Stereodivergent Approach to Enantiopure Hydroxyindolizidines
FULL PAPER
Computational Data
These data support the experimental results, indicating
that fumaronitrile (13) is in general the most suitable re-
agent for protection of the nitrone moiety under mild reac-
tion conditions, through a cycloaddition-cycloreversion
process. In the cases reported in this study its convenience
was partially limited by the lack of stability of the two vi-
cinal nitrile groups under Mitsunobu reaction conditions.
Semiempirical and ab initio calculations were performed
on model cycloreversion reactions I and II of anti and syn
adducts 32 and 33, respectively, in order to explain the dif-
ferent propensities of pyrrolo[1,2-b]isoxazolidines 17, 18,
19, 25, and 26 to undergo retro-cycloaddition (Scheme 9).
All calculations were performed with a Silicon Graphics O2
R10000, by using the Spartan software package (SPAR-
TAN, SGI Version 5.1.1, Wavefunction, Inc., 1991؊1998).
The structures of 32, 33, and transition states (TSs) were
fully optimized at RHF/AM1, PM3, STO3G, and 3-21G*
Conclusion
This study has established the high flexibility of applica-
levels in the gas phase. Each TS showed only one imaginary tion of the cycloaddition approach to enantiomerically pure
frequency, the corresponding vibration being associated OR-substituted pyrroline N-oxides for the synthesis of sub-
with the nuclear motion along the reaction coordinates.
stituted polyhydroxyindolizidines.
The two enantiomerically pure hydroxyindolizidines
(1S,7R,8R,8aS)-24 and (1R,7S,8S,8aR)-24 were synthesized
starting from -malic acid derivative 7 by an efficient en-
antiodivergent process, and their diastereoisomer
(1S,7S,8S,8aR)-31 was similarly obtained from 27
(Scheme 10). Complete control over the relative configura-
tions of the three new stereocenters was achieved by carry-
ing out the cycloadditions either intra- or intermolecularly.
Both the enantiomers (ϩ)-24 and (Ϫ)-24 could be obtained
by proper selection of the esterification mode when assem-
bling the substrate for intramolecular cycloaddition. Ana-
logously, inversion of configuration prior to execution of
the intermolecular cycloaddition[2e] might furnish access to
the enantiomeric (Ϫ)-31.
Scheme 9. Model retro-cycloaddition reactions I and II
The
4-unsubstituted
pyrrolo[1,2-b]isoxazolidines
32bϪ32g showed increasing activation energy (∆Ea) values
in the order CN Ͻ CO2Me Ͻ Ph at all the calculation levels
(Table 1). The same trend was found for the semiempirical
∆Ea values of the corresponding OMe-anti and OMe-syn
adducts 32hϪ32m and 33hϪ33m.
Table 1. Calculated activation energies (∆Ea, kcal/mol)for model
reactions I and II
R
R1 R2 R3 R4 AM1 PM3 STO3G 3-21G*
[a]
∆Ea
∆Ea ∆Ea
∆Ea
32a
32b
32c
32d
32e
32f
32g
H
H
H
H
H
H
H
H
H
H
H
H
H
60.9
49.2
68.0 139.8
57.0 119.8
56.2 120.0
61.8 132.0
62.5 134.2
63.5 134.9
64.0 136.2
56.7
56.2
62.3
62.1
64.6
64.5
57.5
55.8
60.3
62.4
63.8
64.3
65.3
49.5
51.5
57.8
61.4
67.8
69.4
CN CN
CN
H
H
H
H
H
H
H
CN 47.6
E[b]
H
H
H
H
H
H
54.1
54.5
57.0
57.0
49.4
E[b]
H
Ph
H
CN CN
Ph
H
32h OMe
Scheme 10
32i OMe CN
32j OMe
32k OMe E[b]
32l OMe
32m OMe Ph
33h OMe
33i OMe CN
33j OMe
33k OMe E[b]
H
H
H
H
H
H
CN 48.3
E[b]
H
H
H
H
H
H
54.5
54.9
57.5
57.3
51.0
The performances of three different dipolarophiles Ϫ
styrene, ethyl acrylate, and fumaronitrile Ϫ as protecting
reagents for the nitrone moiety were also evaluated. Both
experimental and computational studies proved that the di-
pole could be regenerated from the fumaronitrile cycload-
ducts more easily and quickly than from the other adducts.
The whole process featured complete stereocontrol over
four contiguous stereogenic centers in the final products
and appears to be of general application for structurally
related 1,3-dipoles and dipolarophiles, which will be the ob-
ject of further studies in our group.
H
H
Ph
H
CN CN
H
H
H
H
H
H
H
CN 48.4
H
E[b]
H
H
H
H
H
55.3
55.5
57.5
58.4
33l OMe
33m OMe Ph
H
Ph
H
[a]
∆Ea ϭ E(TS) Ϫ E(lowest energy conformer of 32 or 33).[15]
[b] E ϭ CO2Me.
The experimentally determined thermal stability of pyr-
rolo[1,2-b]isoxazolidines was qualitatively well reproduced
by both semiempirical and ab initio calculations on the
model reactions I and II.
Experimental Section
General Remarks: All reactions requiring anhydrous conditions
were carried out under nitrogen and the solvents were appropriately
Eur. J. Org. Chem. 2002, 1941Ϫ1951
1945

F. M. Cordero, F. Pisaneschi, M. Gensini, A. Goti, A. Brandi
Horner؊Wadsworth؊Emmons Reaction: Trimethyl phos-
phonoacetate (1.1 mL, 6.76 mmol) was added to a solution of
K2CO3 (2.0 g, 13.5 mmol) in water (2 mL), cooled at 0 °C. The
FULL PAPER
dried before use. Rf values refer to TLC on 0.25-mm silica gel plates
(Merck F254). Melting points (m.p.) were determined with an RCH
Kofler apparatus. Polarimetric measures were performed with a JA-
SCO DIP-370 or a PerkinϪElmer 241 polarimeter. NMR spectra reaction mixture was stirred for 15 min, and a solution of the crude
were recorded with Varian Gemini (1H, 200 MHz), VXR 300 (1H,
aldehyde (1.0 g, 5.2 mmol) in diethyl ether (1.5 mL) was then ad-
300 MHz), or Bruker DRX 500 (1H, 500 MHz) instruments, the ded. The heterogeneous mixture was stirred overnight at room
NMR spectroscopic data are reported in δ (ppm) from TMS at 25
°C. IR spectra were recorded with a PerkinϪElmer 881 spectropho-
tometer. Mass spectra were recorded with a QMD 1000 Carlo Erba
instrument by GC or direct inlet; relative percentages are shown in
brackets. Elemental analyses were performed with a PerkinϪElmer
240 C or a PerkinϪElmer 2400 analyzer.
temp. and then extracted with diethyl ether. The organic phase was
dried with anhydrous Na2SO4 and concentrated to give the ester 3
(1.28 g, 98%) as a yellow oil, sufficiently pure to be used in the next
step without further purification. A sample purified by chromato-
graphy on silica gel (eluent: petroleum ether/ethyl acetate, 5:1) af-
forded analytically pure 3.
Compound 3: Rf ϭ 0.33 (petroleum ether/ethyl acetate, 5:1). 1H
NMR (200 MHz, CDCl3): δ ϭ 7.28Ϫ7.23 (m, 2 H, Ar), 6.99 (dt,
J ϭ 15.7, 6.8 Hz, 1 H, 3-H), 6.91Ϫ6.87 (m, 2 H, Ar), 5.90 (dt, J ϭ
15.7, 1.5 Hz, 1 H, 2-H), 4.46 (s, 2 H, CH2Ar), 3.81 (s, 3 H,
CH3OAr), 3.73 (s, 3 H, CO2CH3), 3.56 (t, J ϭ 6.6 Hz, 2 H, 5-H),
2.50 (qd, J ϭ 6.6, 1.5 Hz, 2 H, 4-H) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 166.7 (s, C-1), 159.2 (s, Ar), 145.9 (d, C-3), 130.1 (s,
Ar), 129.2 (d, 2 C Ar), 122.3 (d, C-2), 113.7 (d, 2 C Ar), 72.6 (t,
CH2Ar), 67.8 (t, C-5), 55.1 (q, CH3OAr), 51.3 (q, CO2CH3), 32.5
(t, C-4) ppm. IR (CDCl3): ν˜ ϭ 3008, 2954, 2862, 1712, 1656, 1610,
1511, 1246, 1171, 1080 cmϪ1. MS (70 eV, EI): m/z (%) ϭ 250 (1)
[Mϩ], 190 (6), 135 (20), 121 (100), 122 (89), 114 (39). C14H18O
(250.29): calcd. C 67.18, H 7.25; found C 67.11, H 7.29.
3-(4-Methoxybenzyloxy)-1-propanol (2):[5a][5b] A solution of 1,3-
propanediol (1, 24 mL, 0.33 mol) and p-anisaldehyde (40 mL, 0.33
mol) in toluene (41 mL) was treated with a catalytic amount of p-
toluenesulfonic acid monohydrate (100 mg) and then heated under
reflux in a DeanϪStark apparatus for 11 h. The solvent was evap-
orated and the resulting crude acetal (64 g, quantitative yield) was
directly reduced to propanol 2.
2-(4-Methoxyphenyl)-1,3-dioxane: Rf ϭ 0.68 (petroleum ether/ethyl
acetate, 2:1). 1H NMR (200 MHz, CDCl3): δ ϭ 7.44Ϫ7.40 (m, 2
H, Ar), 6.92Ϫ6.87 (m, 2 H, Ar), 5.47 (s, 1 H, 2-H), 4.25 (m, 2 H,
4-Ha, 6-Ha) , 3.99 (m, 2 H, 4-Hb, 6-Hb), 3.80 (s, 3 H, CH3O),
2.35Ϫ2.10 (m, 1 H, 5-Ha), 1.50Ϫ1.40 (m, 1 H, 5-Hb) ppm. The
crude acetal was dissolved in toluene (100 mL) and the solution
was cooled in an ice/salt bath. Diisobutylaluminium hydride (DI-
BAL, 275 mL, 1.5  in toluene) was added dropwise at such a rate
as to maintain the mixture temperature at 0 °C. The reaction mix-
ture was stirred overnight at room temp., diluted with toluene
(80 mL), and cooled in an ice/water bath. Methanol (45 mL) was
added dropwise at such a rate as to keep the temperature below 40
°C. Water (40 mL) was then added dropwise and the reaction mix-
ture was stirred at room temp. for 1 h. The white precipitate was
filtered through a short pad of Celite and thoroughly washed with
toluene. The filtrate was concentrated to give the crude monopro-
tected propanol 2 (59.2 g, 91%) as a yellow oil, which was used in
the next step without further purification.
(2E)-5-(4-Methoxybenzyloxy)-2-pentenoic Acid (4): A solution of 3
(12.0 g, 48 mmol) in THF (22.5 mL) was treated with a 1  aque-
ous solution of NaOH (72 mL). The resulting mixture was stirred
at room temp. for 5 h and diluted with diethyl ether (60 mL). The
layers were separated, and the aqueous layer was acidified with 6
 HCl and extracted with CH2Cl2 (6 ϫ 90 mL). The combined
extracts were dried with Na2SO4, filtered, and concentrated. The
crude product was washed with diisopropyl ether to give 4 (8.15 g,
72%) as a pure, colorless solid.
Compound 4: Rf ϭ 0.18 (CH2Cl2/MeOH, 30:1); m.p. 65Ϫ67 °C. 1H
NMR (200 MHz CDCl3): δ ϭ 7.29Ϫ7.24 (m, 2 H, Ar), 7.09 (dt,
J ϭ 15.7, 6.8 Hz, 1 H, 3-H), 6.91Ϫ6.87 (m, 2 H, Ar), 5.91 (dt, J ϭ
15.7, 1.5 Hz, 1 H, 2-H), 4.46 (s, 2 H, CH2Ar), 3.82 (s, 3 H, CH3O),
3.58 (t, J ϭ 6.4 Hz, 2 H, 5-H), 2.54 (qd, J ϭ 6.6, 1.5 Hz, 2 H, 4-
H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 171.7 (s, C-1), 159.2 (s,
Ar), 148.6 (d, C-3), 130.0 (s, Ar), 129.3 (d, 2 C, Ar), 122.2 (d, C-
2), 113.8 (d, 2 C, Ar), 72.7 (t, CH2Ar), 67.6 (t, C-5), 55.2 (q,
CH3O), 32.6 (t, C-4) ppm. IR (CDCl3): ν˜ ϭ 3001, 2940, 2865, 1695,
1512, 1246, 1171, 1086 cmϪ1. MS (70 eV, EI): m/z (%) ϭ 236 (5)
[Mϩ], 190 (4), 163 (3), 137 (27), 121 (100), 100 (22), 77 (20).
C13H16O4 (236.26): calcd. C 66.09, H 6.83; found C 66.15, H 6.99.
Compound 2: Rf ϭ 0.50 (petroleum ether/ethyl acetate, 9:1). 1H
NMR (200 MHz, CDCl3): δ ϭ 7.26Ϫ7.22 (m, 2 H, Ar), 6.89Ϫ6.85
(m, 2 H, Ar), 4.45 (s, 2 H, CH2Ar), 3.80 (s, 3 H, CH3O), 3.76 (t,
J ϭ 5.8 Hz, 2 H, 3-H), 3.63 (t, J ϭ 5.5 Hz, 2 H, 1-H), 1.86 (quint,
J ϭ 5.6 Hz, 2 H, 2-H) ppm.
Methyl (2E)-5-(4-Methoxybenzyloxy)-2-pentenoate (3): Swern Ox-
idation: A solution of DMSO (20.3 mL, 286 mmol) in CH2Cl2
(42 mL) was added to a solution of oxalyl chloride (10.6 mL,
122 mmol) in CH2Cl2 (125 mL), cooled at Ϫ65 °C. After 5 min, a
solution of 2 (20.0 g, 102 mmol) in CH2Cl2 (83 mL) was added
dropwise to the cold mixture over 5 min. After 20 min, NEt3
(71 mL, 0.510 mol) was added. The mixture was allowed to warm
to room temp. and poured into water (125 mL). The organic phase
was separated and the aqueous phase was extracted twice with
CH2Cl2 (2 ϫ 100 mL). The collected organic phases were washed
with brine, dried with anhydrous Na2SO4, and concentrated to give
the crude aldehyde (19.8 g, quantitative yield) as a yellow oil, which
was used in the next step without further purification.
(3S)-3-[(Tetrahydro-2H-pyran-2-yl)oxy]pyrroline 1-Oxide (7): A so-
lution of diethyl (S)-malate (5, 15.0 g, 79 mmol) and 2H-dihydropy-
ran (8.6 mL, 95 mmol) in pentane (22 mL) was added to a suspen-
sion of Amberlyst 15 (1.97 g) in pentane (10 mL). The reaction
mixture was stirred at room temp. for 1.5 h, filtered through Celite,
and concentrated. The mixture of the two diastereoisomeric tetra-
hydropyranyl ethers was diluted with diethyl ether (80 mL) and ad-
ded dropwise to a suspension of LiAlH4 (6.84 g, 180 mmol) in di-
ethyl ether (220 mL). The white suspension was vigorously stirred
and heated under reflux for 6 h. A saturated aqueous Na2SO4 solu-
tion (80 mL) was slowly added to the reaction mixture. The suspen-
3-(4-Methoxybenzyloxy)propionaldehyde: 1H NMR (200 MHz,
CDCl3): δ ϭ 9.78 (t, J ϭ 1.8 Hz, 1 H, 1-H), 7.30Ϫ7.24 (m, 2 H, sion was then filtered through Celite, and the salts were washed
Ar), 6.98Ϫ6.66 (m, 2 H, Ar), 4.47 (s, 2 H, CH2Ar), 3.82 (s, 3 H, thoroughly with diethyl ether. The ethereal filtrate was dried with
CH3O), 3.80 (t, J ϭ 6.8 Hz, 2 H, 3-H), 2.70 (td, J ϭ 6.8, 1.8 Hz, 2 Na2SO4, filtered, and concentrated. The crude diols were dissolved
H, 2-H) ppm.
in CH2Cl2 (85 mL) and NEt3 (30.6 mL, 221 mmol). Methanesul-
1946
Eur. J. Org. Chem. 2002, 1941Ϫ1951

Stereodivergent Approach to Enantiopure Hydroxyindolizidines
FULL PAPER
fonyl chloride (MsCl, 14.2 mL, 184 mmol) was added dropwise to
the solution at 0 °C, and the mixture was stirred at room temp. for
1 h, cooled to 0 °C, and treated with ice (50 mL) and an aqueous
saturated K2CO3 solution (50 mL). The two phases were separated
and the aqueous phase was extracted with CH2Cl2 (50 mL). The
collected organic phases were washed with saturated Na2CO3
(50 mL) and brine (50 mL), dried with K2CO3, and filtered. The
solvent was removed to give product 6 as a mixture of two diaster-
eoisomers. A suspension of crude 6 and hydroxylamine hydro-
chloride (21.0 g, 300 mmol) in NEt3 (200 mL) was heated at reflux
temperature for 5 h. The solvent was then evaporated and the re-
sulting yellow solid was washed thoroughly with diethyl ether. The
ethereal extracts were concentrated to give the crude N-hydroxypyr-
rolidine as a mixture of two diastereoisomers. The crude product
was dissolved in CH2Cl2 (250 mL) and cooled to 0 °C, and yellow
Figure 3. Determination of the configurations of adducts 14 by
NOESY
Isomer (2R,3aR,4S)-14: Colorless solid; Rf ϭ 0.16 (ethyl acetate).
[α]1D9ϭ Ϫ6.9 (c ϭ 1.0 in CHCl3); m.p. 118Ϫ119 °C. 1H NMR
mercury oxide (17.8 g, 82 mmol) was added in small portions. The (200 MHz, CDCl3): δ ϭ 7.40Ϫ7.30 (m, 5 H, Ph), 4.98 (dd, J ϭ 8.2,
green suspension was stirred at room temp. for 3 h, filtered through
Celite, and concentrated. Purification and separation of the two
regioisomeric nitrones 7 and 8 (each of them as a mixture of two
diastereoisomers) by chromatography on silica gel (eluent: ethyl
6.8 Hz, 1 H, 2-H), 4.26 (dt, J ϭ 5.8, 3.5 Hz, 1 H, 4-H), 3.75 (m, 1
H, 3a-H), 3.59Ϫ3.45 (m, 1 H, 6-Ha), 3.40Ϫ3.30 (m, 1 H, 6-Hb),
2.50Ϫ2.45 (m, 2 H, 3-H), 2.37Ϫ2.20 (m, 1 H, 5a-H), 1.88Ϫ1.74
(m, 1 H, 5b-H), 1.74 (br. s, 1 H, OH) ppm. 13C NMR (50 MHz,
acetate/MeOH, 10:1) gave 7 (6.46 g, 44% overall yield from the CDCl3): δ ϭ 139.1 (s, Ph), 128.5 (d, 2 C, Ph), 128.0 (d, Ph), 126.4
starting diester 5) as a colorless oil and 8 (678 mg, 4%) as a color-
less oil.
(d, 2 C Ph), 79.2, 77.1 (d, C-2, C-4), 74.0 (d, C-3a), 55.7 (t, C-6),
42.6 (t, C-3), 33.8 (t, C-5) ppm. IR (CDCl3): ν˜ ϭ 3658, 3323 br,
3071, 2949, 1491, 1445 cmϪ1. MS (70 eV, EI): m/z (%) ϭ 205 (7)
[Mϩ], 188 (8), 161 (5), 144 (30), 115 (15), 104 (100), 91 (11).
C12H15NO2 (205.26): calcd. C 70.22, H 7.37, N 6.82; found C
70.04, H 7.51, N 6.63.
Compound 7: Mixture of two diastereoisomers in a 1.3:1 ratio: Rf ϭ
0.20 and 0.13 (ethyl acetate/MeOH, 10:1). 1H NMR (200 MHz,
CDCl3): δ ϭ 7.02Ϫ6.98 (m, 1 H, 2-H), 5.00Ϫ4.96 (m, 1 H, OCHO
THP, major isomer), 4.87Ϫ4.84 (m, 1 H, OCHO THP, minor iso-
mer), 4.75Ϫ4.68 (m, 1 H, 3-H), 4.24Ϫ4.06 (m, 1 H, 5-Ha),
3.92Ϫ3.78 (m, 2 H, 5-Hb, OCHHCH2 THP), 3.57Ϫ3.48 (m, 1 H,
OCHHCH2 THP), 2.70Ϫ2.49 (m, 1 H, 4-Ha), 2.37Ϫ2.15 (m, 1 H,
4b-H), 1.91Ϫ1.53 (m, 6 H, CH2 THP) ppm. 13C NMR (50 MHz,
CDCl3): major isomer: δ ϭ 132.5 (d, C-2), 97.2 (d, OCHO THP),
74.9 (d, C-3), 61.5, 60.4 (t, C-5, OCH2 THP), 29.4 (t, C-4), 27.3,
24.1, 18.3 (t, CH2 THP) ppm; minor isomer: δ ϭ 133.9 (d, C-2),
97.6 (d, OCHO THP), 76.1 (d, C-3), 61.2, 59.8 (t, C-5, OCH2
THP), 29.4 (t, C-4), 26.5, 24.1, 18.2 (t, CH2 THP) ppm. IR
(CDCl3): ν˜ ϭ 2900, 1590, 1450, 1380, 1280 cmϪ1. MS (70 eV, EI):
m/z (%) ϭ 185 (2) [Mϩ], 179 (6), 169 (15), 85 (100). C9H15O3
(185.22): calcd. C 58.36, H 8.16, N 7.56; found C 58.07, H 8.20,
N 7.29.
Isomer (2S,3aR,4S)-14: Colorless solid; Rf ϭ 0.27 (ethyl acetate).
[α]1D9ϭ ϩ18.3 (c ϭ 1.0 in CHCl3); m.p. 161Ϫ163 °C. 1H NMR
(200 MHz, CDCl3): δ ϭ 7.42Ϫ7.26 (m, 5 H, Ph), 5.03 (dd, J ϭ 9.4,
5.8 Hz, 1 H, 2-H), 4.31 (dt, J ϭ 5.5, 4.2 Hz, 1 H, 4-H), 3.82 (ddd,
J ϭ 8.8, 5.5, 1.8 Hz, 1 H, 3a-H), 3.35Ϫ3.27 (m, 2 H, 6-H), 2.95
(br. s, 1 H, OH), 2.81 (ddd, J ϭ 12.2, 5.8, 1.8 Hz, 1 H, 3-Ha), 2.19
(ddd, J ϭ 12.2, 9.4, 8.8 Hz, 1 H, 3-Hb), 2.05Ϫ1.94 (m, 2 H, 5-H)
ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 139.8 (s, Ph), 128.3 (d, 2
C, Ph), 127.7 (d, Ph), 126.5 (d, 2 C, Ph), 79.3, 71.4 (d, C-2, C-4),
69.5 (d, C-3a), 53.5 (t, C-6), 38.4 (t, C-3), 34.1 (t, C-5) ppm. IR
(CDCl3): ν˜ ϭ 3624, 3032, 2950, 1490, 1438 cmϪ1. MS (70 eV, EI):
m/z (%) ϭ 205 (9) [Mϩ], 188 (10), 161 (3), 144 (32), 115 (14), 104
(100), 77 (26). C12H15NO2 (205.26): calcd. C 70.22, H 7.37, N 6.82;
found C 70.42, H 7.45, N 6.66.
(2R,3aR,4S)- and (2S,3aR,4S)-Hexahydro-2-phenylpyrrolo[1,2-b]i-
soxazol-4-ol (14): A solution of nitrone 7 (2.23 g, 12 mmol) and
styrene (11, 2.77 mL, 24 mmol) in toluene (12 mL) was heated at
80 °C for 10 h and then concentrated. Purification by chromato-
graphy on silica gel (eluent: ethyl acetate/petroleum ether, 2:3) gave
a mixture of four diastereoisomeric adducts (2.76 g, 89%), which
was diluted with EtOH (60 mL) and treated with pyridinium p-
toluenesulfonate (PPTS, 3.6 g, 14.4 mmol). The mixture was heated
under reflux for 3 h and concentrated under reduced pressure. The
crude product was dissolved in MeOH (60 mL), stirred in the pres-
ence of Ambersep 900 OH, filtered, and concentrated. The two
diastereomeric isoxazolidines 14 (2.19 g, 10.7 mmol, 89% based on
7) were obtained in a 4:1 ratio as a colorless solid. Separation by
flash column chromatography on silica gel (eluent: ethyl acetate)
afforded the two isomers 14. The relative configurations of the two
pure compounds 14 were deduced by analysis of NOESY spectra.
The cis relationship between 2-H (δ ϭ 4.98 ppm) and 4-H (δ ϭ
4.26 ppm) in the major isomer (deriving from an anti-exo TS), was
confirmed by the presence of a significant cross-peak (Figure 3).
No NOE peak was detected between the corresponding 2-H (δ ϭ
5.03 ppm) and 4-H (δ ϭ 4.31 ppm) in the spectrum of the minor
(3aR,4S)-Hexahydro-4-hydroxypyrrolo[1,2-b]isoxazole-2-carboxylic
Acid and Ethyl (3aR,4S)-Hexahydro-4-hydroxypyrrolo[1,2-b]isox-
azole-3-carboxylate (15): A solution of nitrone 7 (1.0 g, 5.64 mmol)
and ethyl acrylate (12, 797 µL, 7.33 mmol) in CH2Cl2 (6 mL) was
stirred at room temp. for 1 d and then concentrated. Purification
of the residue by chromatography on silica gel (eluent: ethyl acet-
ate) gave a mixture of cycloadducts (1.4 g, 87%) that was diluted
with EtOH (25 mL) and treated with Amberlyst 15 (300 mg). The
mixture was heated at reflux for 1 h, filtered, and concentrated.
The crude product was filtered through a small pad of silica gel
(eluent: ethyl acetate; then ethyl acetate/MeOH, 1:1) to give a mix-
ture of the two regioisomers 15 (each as a pair of diastereoisomers)
(895 mg, 91%, 15a/15b, 6:1 ratio) that was used in the next step
without further purification and separation.
Isomer 15a: Major isomer; colorless oil; Rf ϭ 0.17 (ethyl acetate).
1H NMR (200 MHz, CDCl3): δ ϭ 4.52 (dd, J ϭ 8.4, 4.4 Hz, 1 H,
2-H), 4.28Ϫ4.16 (m, 3 H, 4-H, CH2CH3), 3.68Ϫ3.60 (m, 1 H, 3a-
H), 3.45Ϫ3.35 (m, 2 H, 6-H), 2.87 (ddd, J ϭ 12.8, 8.8, 4.4 Hz, 1
H, 3-Ha), 2.34 (ddd, J ϭ 12.8, 8.1, 4.8 Hz, 1 H, 3-Hb), 2.33Ϫ2.22
isomer (deriving from an anti-endo TS), in agreement with the as- (m, 1 H, 5-Ha), 2.00 (br. s, 1 H, OH) 1.80Ϫ1.70 (m, 1 H, 5-Hb),
signed configuration (Figure 3).
1.30 (t, J ϭ 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz,
Eur. J. Org. Chem. 2002, 1941Ϫ1951
1947

F. M. Cordero, F. Pisaneschi, M. Gensini, A. Goti, A. Brandi
FULL PAPER
CDCl3): δ ϭ 171.4 (s, CO), 78.3, 75.3 (d, C-2, C-4), 73.7 (d, C-3a), 3 H, CH3O), 3.65Ϫ3.43 (m, 1 H, 3a-H), 3.54 (t, J ϭ 6.2 Hz, 2 H,
61.5 (t, CH2CH3), 55.3 (t, C-6), 37.9 (t, C-3), 33.7 (t, C-5), 14.1 (q, CH2CH2O), 3.33Ϫ3.15 (m, 1 H, 6-Ha), 3.03Ϫ2.86 (m, 1 H, 6-Hb),
CH2CH3) ppm. IR (CDCl3): ν˜ ϭ 3615, 2945, 1730, 1263, 1205 2.64Ϫ2.28 (m, 3 H, 3-H, 5-Ha), 2.48 (qd, J ϭ 6.5, 1.5 Hz, 2 H,
cmϪ1. MS (70 eV, EI): m/z (%) ϭ 201 (4) [Mϩ], 158 (3), 128 (3), CH2CH2O), 1.93Ϫ1.80 (m, 1 H, 5-Hb), 1.29 (t, J ϭ 7.1 Hz, 3 H,
83 (100).
CH2CH3) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 171.0 (s, CO2Et),
165.7 (s, COCHϭ), 158.9 (s, Ar), 146.4 (d, ϭCHCH2), 129.8 (s,
Ar), 128.9 (d, 2 C Ar), 122.0 (d, COCHϭ), 113.5 (d, 2 C Ar),
80.5, 75.0 (d, C-2, C-4), 72.4 (t, CH2Ar), 71.8 (d, C-3a), 67.5 (t,
CH2CH2O), 61.1 (t, CH2CH3), 55.3 (q, CH3O), 55.0 (t, C-6), 37.9
(t, C-3), 32.4, 30.2 (t, C-5, CH2CH2O), 13.9 (q, CH2CH3) ppm.
(4S)-2,3-Dicyanohexahydropyrrolo[1,2-b]isoxazol-4-ol (16): A solu-
tion of nitrone 7 (1.0 g, 5.64 mmol) and fumaronitrile (13, 570 mg,
7.30 mmol) in CH2Cl2 (6 mL) was stirred at room temp. for 1 d
and concentrated. The residue was filtered through a small pad of
silica gel (eluent: petroleum ether/ethyl acetate, 1:1) to give a mix-
ture of cycloadducts (1.3 g, 86%) that was diluted with MeOH
(50 mL) and treated with a catalytic amount of Amberlyst 15. The
mixture was stirred at 55 °C for 1 h, filtered, and concentrated. A
(4S)-2,3-Dicyanohexahydropyrrolo[1,2-b]isoxazol-4-yl
(2E)-5-(4-
Methoxybenzyloxy)-2-pentenoate (19): 76% yield; colorless oil.
Major isomer: Rf ϭ 0.31 (petroleum ether/ethyl acetate, 1:1). 1H
mixture of three isomers 16 (919 mg, 97%) was obtained and was NMR (200 MHz, CDCl3): δ ϭ 7.30Ϫ7.23 (m, 2 H, Ar), 7.03 (dt.
used in the next step without further purification and separation.
J ϭ 15.6, 6.9 Hz, 1 H, ϭCHCH2), 6.90Ϫ6.81 (m, 2 H, Ar), 5.88
(dt, J ϭ 15.7, 1.6 Hz, 1 H, COCHϭ), 5.32 (dt, J ϭ 7.1, 2.0 Hz, 1
H, 4-H), 5.07 (d, J ϭ 1.1 Hz, 1 H, 2-H), 4.45 (s, 2 H, CH2Ar), 4.18
(dd, J ϭ 9.5, 1.6 Hz, 1 H, 3-H), 4.00 (dd, J ϭ 9.5, 2.6 Hz, 1 H, 3a-
H), 3.81 (s, 3 H, CH3O), 3.72Ϫ3.53 (m, 1 H, 6-Ha), 3.57 (t, J ϭ
6.2 Hz, 2 H, CH2CH2O), 3.36 (ddd, J ϭ 14.3, 11.7, 6.2 Hz, 1 H,
6-Hb), 2.52 (qd, J ϭ 6.5, 1.5 Hz, 2 H, CH2CH2O), 2.46Ϫ2.37 (m,
1 H, 5-Ha), 2.08 (ddt, J ϭ 14.1, 6.3, 1.8 Hz, 1 H, 5-Hb) ppm. 13C
NMR (50 MHz, CDCl3): δ ϭ 165.6 (s, CO), 159.0 (s, Ar), 147.7
(d, ϭCHCH2), 129.9 (s, Ar), 129.1 (d, 2 C Ar), 121.4 (d, COCHϭ
), 115.5 (s, CN), 115.3 (s, CN), 113.6 (d, 2 C Ar), 77.6 (d,), 72.5 (t,
CH2Ar), 72.3 (d, C-2 or C-4), 68.3 (d, C-3a), 67.5 (t, CH2CH2O),
55.1 (q, CH3O), 55.0 (t, C-6), 42.9 (t, C-3), 32.5, 30.5 (t, C-5,
CH2CH2O).
Compound 16: Major isomer; Rf ϭ 0.40 (petroleum ether/ethyl acet-
1
ate, 1:1). H NMR (200 MHz, CD3OD): δ ϭ 5.46 (d, J ϭ 2.3 Hz,
1 H, 2-H), 4.56Ϫ4.49 (m, 1 H, 4-H), 4.49 (dd, J ϭ 9.0, 2.2 Hz, 1
H, 3a-H), 3.93 (dd, J ϭ 9.0, 2.3 Hz, 1 H, 3-H), 3.54Ϫ3.34 (m, 2
H, 6-H), 2.40Ϫ2.22 (m, 1 H, 5-Ha), 1.94Ϫ1.81 (m, 1 H, 5-Hb) ppm.
13C NMR (50 MHz, CD3OD): δ ϭ 117.3 (s, CN), 117.2 (s, CN),
75.7, 74.9 (d, C-2, C-4), 69.6 (d, C-3a), 55.6 (t, C-6), 43.5 (d, C-3),
34.2 (t, C-5) ppm. IR (CDCl3): ν˜ ϭ 3612, 2928, 2252, 1117 cmϪ1
.
MS (70 eV, EI): m/z (%) ϭ 152 (3) [Mϩ Ϫ HCN], 85 (25), 78 (100),
77 (66).
Synthesis of Esters 17, 18, and 19
General Procedure: A solution (0.1 ) of isoxazolidines 14, 15, or
16 in CH2Cl2 (14 and 15) or THF (16) was treated with 4 (2.3
equiv.) and 4-(dimethylamino)pyridine (DMAP, 0.25 equiv.), and
1,3-diisopropylcarbodiimide (DIC, 2.5 equiv.) was then added
dropwise at room temp. The mixture was stirred for 1 d at room
temp., concentrated, and filtered through a short pad of silica gel.
The products 17, 18, and 19 were obtained as mixtures of isomers
and were used in the next step without further purification and
separation.
Synthesis of Esters 25 and 26
General Procedure: A 0.2  solution of isoxazolidines 14 or 15 (1
equiv.), 4 (1.2 equiv.), and PPh3 (polystyrene-supported PPh3 was
used with 14) (3 equiv.) in CH2Cl2 (14) or in THF (15) was cooled
at 0 °C, and DEAD (3 equiv.) was added dropwise. The reaction
mixture was stirred at 0 °C for 2 h and then at room temp. for 3 d.
The polymeric reagent, when present, was filtered off through Cel-
ite and the solvent was evaporated. The residue was purified by
chromatography on silica gel. The products 25 and 26 were ob-
tained as mixtures of isomers and were used in the next step with-
out further purification and separation.
(3aR,4S)-Hexahydro-2-phenylpyrrolo[1,2-b]isoxazol-4-yl (2E)-5-(4-
Methoxybenzyloxy)-2-pentenoate (17): 70% yield; colorless oil.
1
Major isomer: Rf ϭ 0.27 (diisopropyl ether). H NMR (200 MHz,
CDCl3): δ ϭ 7.44Ϫ7.25 (m, 7 H, Ar), 7.10Ϫ6.86 (m, 3 H, Ar, ϭ
CHCH2), 5.90 (dt, J ϭ 15.7, 1.5 Hz, 1 H, COCHϭ), 5.18Ϫ5.03 (m,
2 H, 2-H, 4-H), 4.47 (s, 2 H, CH2Ar), 3.83 (s, 3 H, CH3O),
3.72Ϫ3.41 (m, 3 H, 3a-H, 6-H), 3.58 (t, J ϭ 6.4 Hz, 2 H,
CH2CH2O), 2.77Ϫ2.35 (m, 3 H, 3-H, 5-Ha), 2.52 (qd, J ϭ 6.8,
1.5 Hz, 2 H, CH2CH2O), 2.00Ϫ1.80 (m, 1 H, 5-Hb) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 166.2 (s, CO), 159.4 (s, Ar), 146.9 (d, ϭ
CHCH2), 140.3 (s, Ph), 130.2 (s, Ar), 129.4 (d, 2 C Ar). 128.6 (d,
2 C Ph), 127.9 (d, Ph), 126.2 (d, 2 C Ph), 122.5 (d, COCHϭ), 113.9
(d, 2 C Ar), 80.0, 79.3 (d, C-2, C-4), 72.8 (t, CH2Ar), 72.5 (d, C-
3a), 67.9 (t, CH2CH2O), 56.2 (t, C-6), 55.4 (q, CH3O), 43.1 (t, C-
3), 32.8, 30.4 (t, C-5, CH2CH2O) ppm.
(3aR,4R)-Hexahydro-2-phenylpyrrolo[1,2-b]isoxazol-4-yl (2E)-5-(4-
Methoxybenzyloxy)-2-pentenoate (25): 59% yield; colorless oil.
Major isomer: Rf ϭ 0.40 (ethyl acetate). 1H NMR (200 MHz,
CDCl3): δ ϭ 7.40Ϫ7.21 (m, 7 H, Ar), 7.06 (dt, J ϭ 15.8, 6.6 Hz, 1
H, ϭCHCH2), 6.90Ϫ6.80 (m, 2 H, Ar), 5.95 (dt, J ϭ 15.8, 1.8 Hz,
1 H, COCHϭ), 5.35 (q, J ϭ 5.0 Hz, 1 H, 4-H), 5.03 (dd, J ϭ 9.1,
6.2 Hz, 1 H, 2-H), 4.50 (s, 2 H, CH2Ar), 4.04 (td, J ϭ 6.6, 1.8 Hz,
1 H, 3a-H), 3.77 (s, 3 H, CH3O), 3.58 (t, J ϭ 6.3 Hz, 2 H,
CH2CH2O), 3.38Ϫ3.32 (m, 2 H, 6-H), 2.59Ϫ2.50 (m, 3 H, 3-Ha,
CH2CH2O), 2.30Ϫ2.20 (m, 3 H, 3-Hb, 5-H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 165.2 (s, CO), 159.0 (s, Ar), 146.8 (d, ϭ
CHCH2), 139.8 (s, Ph), 133.4 (s, Ar), 129.0 (d, 2 C Ar), 128.3 (d,
2 C Ph), 127.0 (d, Ph), 126.1 (d, 2 C Ph), 122.1 (d, COCHϭ), 113.6
(d, 2 C Ar), 79.1, 73.9 (d, C-2, C-4), 72.6 (t, CH2Ar), 67.8 (d, C-
3a), 67.6 (t, CH2CH2O), 55.1 (q, CH3O), 53.7 (t, C-6), 39.1 (t, C-
3), 32.6, 31.2 (t, C-5, CH2CH2O) ppm.
Ethyl (3aR,4S)-Hexahydro-4-{[(2E)-5-(4-methoxybenzyloxy)-1-oxo-
2-pentenyl]oxy}pyrrolo[1,2-b]isoxazole-2-carboxylate (18a) and
Ethyl (3aR,4S)-Hexahydro-4-{[(2E)-5-(4-methoxybenzyloxy)-1-oxo-
2-pentenyl}oxy]pyrrolo[1,2-b]isoxazole-3-carboxylate (18b): 94%
yield; colorless oil. Major diastereoisomer 18a: Rf ϭ 0.15 (petro-
leum ether/ethyl acetate, 2:1). 1H NMR (200 MHz, CDCl3): δ ϭ
7.30Ϫ7.20 (m, 2 H, Ar), 6.96 (dt, J ϭ 15.7, 6.8 Hz, 1 H, ϭCHCH2)
6.90Ϫ6.81 (m, 2 H, Ar), 5.85 (dt, J ϭ 15.7, 1.6 Hz, 1 H, COCHϭ
(؉)-(2aS,3R,6aS,6bS)- and (؊)-(2aR,3S,6aR,6bR)-Hexahydro-3-{2-
[(4-methoxyphenyl)methoxy]ethyl}-2H-1,4-dioxa-4a-azacyclo-
penta[cd]pentalen-2-one (21)
), 5.05Ϫ4.95 (m, 1 H, 4-H), 4.54 (dd, J ϭ 8.3, 4.1 Hz 1 H, 2-H), From 17 and 25: A 0.02  solution of 17 (75 mg, 0.18 mmol) or 25
4.44 (s, 2 H, CH2Ar), 4.21 (q, J ϭ 7.1 Hz, 2 H, CH2CH3), 3.79 (s, (1.046 g, 2.47 mmol) in o-dichlorobenzene (9 or 123.5 mL) was
1948
Eur. J. Org. Chem. 2002, 1941Ϫ1951

Stereodivergent Approach to Enantiopure Hydroxyindolizidines
heated at reflux for 14 h or 64 h, respectively. The solution was 1180, 1053 cmϪ1. MS (70 eV, EI): m/z (%) ϭ 199 (5) [Mϩ], 149 (5),
FULL PAPER
filtered through silica gel, eluting first with petroleum ether and
then with MeOH. The alcohol solution was concentrated and the
residue was purified by chromatography on silica gel (eluent: ethyl
acetate) to give (ϩ)-21 (18 mg, 31%) or (Ϫ)-21 (560 mg, 71%), re-
spectively.
127 (27), 110 (5), 84 (100), 79 (16). C9H13NO4 (199.21): calcd. C
54.26, H 6.58, N 7.03; found C 54.66, H 6.73, N 7.00.
(؊)-(2aR,3S,6aR,6bR)-Hexahydro-3-(2-hydroxyethyl)-2H-1,4-
dioxa-4a-azacyclopenta[cd]pentalen-2-one [(؊)-22]: A solution of
(Ϫ)-21 (575 mg, 1.8 mmol) in TFA/CH2Cl2 (10:90, 100 mL) was
stirred at room temp. for 45 min, concentrated, diluted with
CH2Cl2, and treated with Amberlyst A-21. The mixture was
stirred for 30 min, filtered through Celite, and concentrated. Puri-
fication of the residue by chromatography on silica gel (eluent: ethyl
acetate/MeOH, 10:1) gave the deprotected alcohol (Ϫ)-22 (250 mg,
70%) as a white solid.
From 18 and 26: A 0.02  solution of 18 (374 mg, 0.89 mmol) or
26 (50 mg, 0.12 mmol) in o-dichlorobenzene (44.5 or 6 mL) was
heated at 150 °C for 3 h. The solution was filtered through silica
gel, eluting first with petroleum ether and then with MeOH. The
alcohol solution was concentrated and the residue was purified by
chromatography on silica gel (eluent: ethyl acetate) to give (ϩ)-21
(151 mg, 53%) and (Ϫ)-21 (28 mg, 73%), respectively.
Compound (؊)-22: The spectroscopic data are identical to those
reported for (ϩ)-22. [α]1D9 ϭ Ϫ15.5 (c ϭ 0.5, CHCl3). C9H13NO4
(199.21): calcd. C 54.26, H 6.58, N 7.03; found C 54.29, H 6.62,
N 6.84.
From 19: A solution of 19 (47.3 mg, 0.12 mmol) in o-xylene (6 mL)
was heated at reflux for 1 h. The solution was filtered through silica
gel, eluting first with petroleum ether and then with MeOH. The
alcohol solution was concentrated and the residue was purified by
chromatography on silica gel (eluent: ethyl acetate) to give (ϩ)-21
(32.1 mg, 84%).
(؉)-(2aS,3R,8aS,8bS)-2a,3,4,5,7,8,8a,8b-Octahydro-3-hydroxy-2H-
furo[4,3,2-h,i]indolizin-2-one [(؉)-23]: Cold MsCl (45 µL,
0.58 mmol) was added dropwise to a solution of alcohol (ϩ)-22
(105.4 mg, 0.53 mmol) and NEt3 (102 µL, 0.79 mmol) in CH2Cl2
(distilled from P2O5, 1.8 mL) at 0 °C. The mixture was stirred for
1 h at 0 °C, diluted with THF (2 mL), and concentrated. The
residue was dissolved in MeOH (9 mL), treated with a catalytic
amount of 10% Pd/C, and treated under H2 (1 atm) for 12 h. The
mixture was filtered through a column of Ambersep 900 OH and
concentrated. The crude product was purified by chromatography
on silica gel (eluent: ethyl acetate/MeOH/NEt3, 10:1:0.1) to give
(ϩ)-23 (74.3 mg, 77%) as a white solid.
Compound (؉)-21: White solid; Rf ϭ 0.23 (ethyl acetate); m.p.
75Ϫ76 °C. [α]2D6 ϭ ϩ24.5 (c ϭ 0.5 in CHCl3). 1H NMR (200 MHz,
CDCl3): δ ϭ 7.28Ϫ7.24 (m, 2 H, Ar), 6.92Ϫ6.86 (m, 2 H, Ar), 5.03
(q, J ϭ 5.9 Hz, 1 H, 6a-H), 4.64 (dt, J ϭ 9.2, 2.6 Hz, 1 H, 3-H),
4.45 (s, 2 H, CH2Ar), 4.35 (dd, J ϭ 8.6, 6.4 Hz, 1 H, 6b-H), 3.81
(s, 3 H, CH3O), 3.61 (dd, J ϭ 6.8, 5.3 Hz, 2 H, CH2CH2OPMB),
3.46 (dd, J ϭ 8.8, 2.6 Hz, 1 H, 2a-H), 3.40Ϫ3.31 (m, 1 H, 5-Ha),
3.18Ϫ3.09 (m, 1 H, 5-Hb), 2.30Ϫ2.21 (m, 2 H, 6-H), 2.13Ϫ1.95 (m,
2 H, CH2CH2OPMB) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ
176.7 (s, CO), 159.2 (s, Ar), 130.4 (s, Ar), 129.3 (d, 2 C Ar), 113.8
(d, 2 C Ar), 82.4, 80.9 (d, C-3, C-6a), 72.8 (t, CH2Ar), 70.7 (d, C-
6b), 66.2 (t, CH2CH2OPMB), 55.2 (q, CH3O), 54.9 (d, C-2a), 52.3
(t, C-5), 34.0, 31.9 (t, C-6, CH2CH2OPMB) ppm. IR (CDCl3): ν˜ ϭ
2934, 1770, 1510, 1245, 1173, 1085 cmϪ1. MS (70 eV, EI): m/z
(%) ϭ 319 (0.1) [Mϩ], 198 (5), 183 (4), 154 (10), 137 (18), 121 (100),
84 (16). C17H21NO5 (319.35): calcd. C 63.94, H 6.63, N 4.39; found
C 64.24, H 6.65, N 4.22.
Compound (؉)-23: Rf ϭ 0.23 (ethyl acetate/MeOH/NEt3, 10:1:0.1);
m.p. 59Ϫ61 °C. [α]2D8 ϭ ϩ73.5 (c ϭ 0.8 in CHCl3). 1H NMR
(500 MHz, CDCl3): δ ϭ 5.06 (t, J ϭ 4.2 Hz, 1 H, 8a-H), 3.97Ϫ3.95
(m, 1 H, 3-H), 3.93 (dd, J ϭ 6.3, 4.3 Hz, 1 H, 8b-H), 3.13 (dt, J ϭ
14.5, 3.2 Hz, 1 H, 5-Ha), 2.97Ϫ2.83 (m, 4 H, 2a-H, 5-Hb, 7-H),
2.20 (dd, J ϭ 13.6, 4.8 Hz, 1 H, 8-Ha), 2.05Ϫ1.97 (m, 1 H, 8b-H),
1.75Ϫ1.72 (m, 1 H, 4-Ha), 1.67 (br. s, 1 H, OH), 1.55 (qd, J ϭ 12.6,
3.6 Hz, 1 H, 4-Hb) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 178.1
(s, CO), 84.2 (d, C-8a), 68.2 (d, C-3), 60.8 (d, C-8b), 48.3, 45.5 (t,
C-5, C-7), 42.7 (d, C-2a), 31.8, 28.2 (t, C-4, C-8) ppm. IR (CDCl3):
ν˜ ϭ 3493 (br), 2926, 1744, 1342, 1176 cmϪ1. MS (70 eV, EI): m/z
(%) ϭ 183 (11) [Mϩ], 120 (33), 112 (13), 95 (100), 84 (30).
C9H13NO3 (183.21): calcd. C 59.00, H 7.15, N 7.65; found C 58.80,
H 7.33, N 7.37.
Compound (؊)-21: The spectroscopic data are identical to those
reported for (ϩ)-21, apart from traces of inseparable unidentified
impurities.
(؉)-(2aS,3R,6aS,6bS)-Hexahydro-3-(2-hydroxyethyl)-2H-1,4-dioxa-
4a-azacyclopenta[cd]pentalen-2-one [(؉)-22]: DDQ (251 mg,
1.10 mmol) in CH2Cl2 (32 mL) was added dropwise to a solution of
(ϩ)-21 (270 mg, 0.85 mmol) in CH2Cl2 (180 mL) and water (6 mL),
cooled at 0 °C. The mixture was stirred at 0 °C for 3 h, and Na2SO4
was added. After the mixture had stirred for 1 h, Na2SO4 was fil-
tered off and the solvent was evaporated. The crude product was
purified by chromatography on silica gel (eluent: ethyl acetate; then
ethyl acetate/MeOH, 1:1) to give the deprotected alcohol (ϩ)-22
(139 mg, 82%) as a white solid.
(؊)-(2aR,3S,8aR,8bR)-2a,3,4,5,7,8,8a,8b-Octahydro-3-hydroxy-
2H-furo[4,3,2-h,i]indolizin-2-one [(؊)-23]: The tricyclic compound
(Ϫ)-22 (104.0 mg, 0.52 mmol) was converted into (Ϫ)-23 (74 mg,
77%) by the same procedure as described for the synthesis of (ϩ)-
23 starting from (ϩ)-22.
Compound (؊)-23: The spectroscopic data are identical to those
reported for (ϩ)-23. [α]2D5 ϭ Ϫ73.3 (c ϭ 1.0 in CHCl3). C9H13NO3
(199.21): calcd. C 59.00, H 7.15, N 7.65; found C 59.04, H 7.03,
N 7.98.
Compound (؉)-22: White solid; Rf ϭ 0.16 (ethyl acetate/MeOH,
10:1); m.p. 114Ϫ116 °C. [α]2D1 ϭ ϩ18.1 (c ϭ 0.6 in CHCl3). 1H
NMR (200 MHz, CDCl3): δ ϭ 5.07 (dt, J ϭ 6.6, 5.0 Hz, 1 H, 6a-
(؉)-(1S,7R,8R,8aS)-8-(Hydroxymethyl)indolizidine-1,7-diol [(؉)-
H), 4.65 (dt, J ϭ 6.2, 2.6 Hz, 1 H, 3-H), 4.42 (dd, J ϭ 8.6, 6.2 Hz, 24]: Red-Al (0.33 mL, 1.11 mmol) was added dropwise to a solu-
1 H, 6b-H), 3.87Ϫ3.69 (m, 2 H, CH2CH2OH), 3.45 (dd, J ϭ 8.6,
3.1 Hz, 1 H, 2a-H), 3.44Ϫ3.33 (m, 1 H, 5-Ha), 3.19Ϫ3.06 (m, 1 H,
tion of (ϩ)-23 (33.8 mg, 0.18 mmol) in THF (10 mL), and the mix-
ture was heated at reflux for 3 h. The mixture was treated sequen-
5-Hb), 2.06 (br. s, 1 H, OH), 2.34Ϫ2.22 (m, 2 H, 6-H), 2.09Ϫ1.92 tially with H2O (200 µL), NaOH (2 , 180 µL), and H2O (400 µL),
(m, 1 H, CH2CH2OH) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ
diluted with THF, and stirred for 30 min. The solvent was removed
176.9 (s, CO), 82.6, 82.0 (d, C-3, C-6a), 70.9 (d, C-6b), 59.3 (t, at reduced pressure and the crude product was purified by chroma-
CH2CH2OH), 54.8 (d, C-2a), 52.0 (t, C-5), 36.6, 31.83 (t, C-6, tography on silica gel (eluent: CHCl3/MeOH/NH3, 10:5:1). The in-
CH2CH2OH) ppm. IR (CDCl3): ν˜ ϭ 3629 (br), 2931, 1770, 1357,
dolizidine (ϩ)-24 (26.7 mg, 78%) was obtained as a colorless oil.
Eur. J. Org. Chem. 2002, 1941Ϫ1951
1949

F. M. Cordero, F. Pisaneschi, M. Gensini, A. Goti, A. Brandi
FULL PAPER
Compound (؉)-24: Rf ϭ 0.12 (CHCl3/MeOH/NH3, 10:5:1). [α]2D3
ϩ57.8 (c ϭ 0.7 in MeOH). H NMR (500 MHz, CDCl3): δ ϭ 4.30 tBu), 73.0 (d, C-3a), 59.5, 55.5 (t, C-6, CH2CH2OH), 55.2 (q,
(ddd, J ϭ 6.2, 4.1, 1.7 Hz, 1 H, 1-H), 3.99Ϫ3.93 (m, 1 H, CH3O), 51.9 (d, C-3), 35.6, 34.4 (t, C-5, CH2CH2OH), 28.5 (q, 3
ϭ
CDCl3): δ ϭ 170.8 (s, CO), 77.3, 74.8 (d, C-2, C-4), 73.8 (s, Cq
1
CHHOH), 3.90 (dd, J ϭ 11.0, 3.7 Hz, 2 H, CHHOH), 3.82Ϫ3.77
C CH3 tBu) ppm. IR (CDCl3): ν˜ ϭ 3600 br, 2973, 1730, 1434, 1363,
(m, 1 H, 7-H), 3.19Ϫ3.11 (m, 2 H, 3-Ha, 5-Ha), 2.38Ϫ2.18 (m, 5 1170, 1059 cmϪ1. MS (70 eV, EI): m/z: 287 (5) [Mϩ], 230 (34), 214
H, 2-Ha, 3-Hb, 5-Hb, 8-H, 8a-H), 1.90Ϫ1.81 (m, 1 H, 2-Hb), (4), 198 (4), 186 (9), 86 (49), 84 (85), 57 (100). C14H25NO5 (287.35):
1.75Ϫ1.60 (m, 1 H, 6-H) ppm. 13C NMR (50 MHz, CD3OD): δ ϭ calcd. C 58.52, H 8.77, N 4.87; found C 58.39, H 8.99, N 5.22.
72.2 (d, C-1), 69.5 (d, C-7), 58.0 (t, CH2OH), 52.7 (t, C-3), 50.8 (t,
(2S,3R,3aR,4S)-1-tert-Butoxy-7-hydroxy-8-(methoxycarbonyl)-
indolizidine (30): The same procedure as reported for the synthesis
of indolizidines 23 was used.
C-5), 45.3 (d, C-8), 34.0 (t, C-2), 31.3 (t, C-6) ppm. MS (70 eV, EI):
m/z ϭ 187 (0.6) [Mϩ], 186 (1), 169 (13), 143 (16), 126 (13), 112
(100), 100 (12), 82 (25). C9H17NO3 (187.24): calcd. C 57.73, H 9.15,
N 7.48; found C 57.44, H 9.23, N 7.21.
Compound 30: 83% yield; colorless oil; Rf ϭ 0.29 (CH2Cl2/MeOH/
NH3, 10:1:0.01). [α]2D8 ϭ ϩ39.6 (c ϭ 0.7, in CHCl3). 1H NMR
(500 MHz, CDCl3): δ ϭ 4.32 (td, J ϭ 8.3, 3.2 Hz, 1 H, 1-H), 3.76
(s, 3 H, CH3O), 3.75Ϫ3.69 (m, 1 H, 7-H), 3.19 (t, J ϭ 3.7 Hz, 1 H,
8-H), 3.09Ϫ3.06 (m, 1 H, 5-Ha), 2.99 (t, J ϭ 8.3 Hz, 1 H, 3-Ha),
2.74 (br. s, 1 H, OH), 2.27Ϫ2.12 (m, 2 H, 3-Hb, 6-Ha), 2.11Ϫ2.04
(m, 3 H, 2-Ha, 6-Hb, 8a-H), 1.85 (m, 1 H, 5-Hb), 1.61Ϫ1.57 (m, 1
H, 2-Hb), 1.18 (s, 9 H, CH3 tBu) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 172.2 (s, CO), 73.4 (s, Cq tBu), 72.3 (d, C-1), 71.3 (d,
C-8a), 70.7 (d, C-7), 52.8 (t, C-3), 51.3 (q, CH3O), 51.1 (t, C-5),
46.8 (d, C-8), 33.5 (t, C-2), 30.5 (t, C-6), 28.6 (q, 3 C CH3 tBu)
(؊)-(1R,7S,8S,8aR) 8-(Hydroxymethyl)indolizidine-1,7-diol [(؊)-
24]: Indolizidine (Ϫ)-23 (49.7 mg, 0.27 mmol) was reduced to (Ϫ)-
24 (46 mg, 91%) by the same procedure as described for the syn-
thesis of (ϩ)-24 starting from (ϩ)-23.
Compound (؊)-24: The spectroscopic data are identical to those
reported for (ϩ)-24. [α]2D9 ϭ Ϫ57.6 (c ϭ 0.8 in MeOH). C9H17NO3
(187.24): calcd. C 57.73, H 9.15, N 7.48; found C 57.48, H 9.31,
N 7.53.
Methyl (2E)-5-Hydroxy-2-pentenoate (28)
ppm. IR (CDCl3): ν˜ ϭ 3600, 2975, 1721, 1438, 1364, 1195 cmϪ1
.
MS (70 eV, EI): m/z (%) ϭ 214 (75) [Mϩ Ϫ tBu], 196 (15), 170 (8),
112 (10), 83 (100), 57 (42). C14H25NO4 (271.36): calcd. C 61.97, H
9.29, N 5.16; found C 61.97, H 9.69, N 5.23.
Method A: (NH4)2Ce(NO3)6 (CAN, 3.34 g, 6.8 mmol) was added
to a solution of 3 (762 mg, 3.2 mmol) in CH3CN/H2O (9:1). The
mixture was stirred at room temp. for 1 h, diluted with CH2Cl2
(40 mL), and washed with a saturated aqueous NaHCO3 solution.
The two phases were separated and the aqueous phase was ex-
tracted with CH2Cl2. The combined organic phases were dried with
Na2SO4, filtered, and concentrated. The crude product was purified
by chromatography on silica gel (eluent: petroleum ether/ethyl acet-
ate, 1:1) to give 28 (260 mg, 66%) as a yellow oil.
Synthesis of (1S,7S,8S,8aR)-1,7-Dihydroxy-8-(2-hydroxyethyl)indol-
izidine [(؉)-31]
Reduction of the Methoxycarbonyl Functionality: The same proced-
ure as reported for the synthesis of indolizidines 21 was used.
(1S,7S,8S,8aR)-1-tert-Butoxy-7-hydroxy-8-(2-hydroxyethyl)-
indolizidine: 89% yield, yellow solid, Rf ϭ 0.09 (CH2Cl2/MeOH,
Method B: Compound 3 (700 mg, 2.8 mmol) was dissolved in
CH2Cl2 (140 mL), and TFA (14 mL) was added dropwise. After 5
min, the mixture was concentrated and the crude product was puri-
fied by chromatography on silica gel (eluent: petroleum ether/ethyl
acetate, 1:1) to give 28 (238.2 mg, 66%) as a yellow oil.
10:1); m.p. 84Ϫ86 °C. [α]2D0 ϭ ϩ48.1 (c ϭ 0.6, CHCl3). H NMR
1
(500 MHz, CDCl3): δ ϭ 4.24 (td, J ϭ 8.0, 3.5, 1 H, 1-H), 4.12Ϫ4.04
(m, 2 H, CH2OH), 3.87Ϫ3.80 (m, 1 H, 7-H), 3.08Ϫ2.88 (m, 3 H,
3-Ha, 5-Ha and OH), 2.26Ϫ2.01 (m, 7 H, 2-Ha, 3-Hb, 5-Hb, 6-Ha,
8-H, 8a-H and OH), 1.90Ϫ1.80 (m, 1 H, 6-Hb), 1.70Ϫ1.60 (m, 1
H, 2-Hb) 1.19 (s, 9 H, CH3 tBu) ppm. 13C NMR (50 MHz, CDCl3):
δ ϭ 73.6 (s, Cq tBu), 72.1, 71.8, 71.2 (d, C-1, C-7, C-8a), 59.0 (t,
CH2OH), 52.6, 51.2 (t, C-3, C-5), 39.5 (d, C-8), 33.7, 31.5 (d, C-2,
C-6), 28.6 (q, 3 C CH3 tBu) ppm. IR (CDCl3): ν˜ ϭ 3689,
3600Ϫ3100, 2977, 2871, 1446, 1363, 1187 cmϪ1. MS (70 eV, EI):
m/z (%) ϭ 243 (1.5) [Mϩ], 196 (2), 187 (25), 186 (100), 168 (45),
138 (29), 112 (73), 100 (28), 84 (41), 57 (77). C13H25NO3 (243.34):
calcd. C 64.16, H 10.36, N 5.76; found C 63.96, H 10.14, N 5.83.
Compound 28: Rf ϭ 0.28 (petroleum ether/ethyl acetate, 1:1). 1H
NMR (200 MHz, CDCl3): δ ϭ 6.98 (dt, J ϭ 15.4, 7.3 Hz, 1 H, 3-
H), 5.94 (dt, J ϭ 15.7, 1.4 Hz, 1 H, 2-H), 3.78 (t, J ϭ 6.4 Hz, 2 H,
5-H), 3.74 (s, 3 H, CH3O), 2.48 (dq, J ϭ 6.2, 1.4 Hz, 2 H, 4-H)
ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 166.9 (s, CO), 145.8 (d, C-
3), 122.8 (d, C-2), 60.7 (t, C-5), 51.4 (q, CH3O), 35.3 (t, C-4) ppm.
IR (CDCl3): ν˜ ϭ 3627, 2957, 1714, 1659, 1438, 1275, 1199, 1031
cmϪ1. MS (70 eV, EI): m/z (%) ϭ 112 (1) [Mϩ Ϫ H2O], 100 (64),
99 (26), 81 (7), 68 (100).
Deprotection of tert-Butyl Ether: A solution of protected indolizidi-
netriol (38.5 mg, 0.16 mmol) in trifluoroacetic acid (1 mL) and
water (0.1 mL) was stirred at room temp. for 3 h. The TFA was
removed at reduce pressure, and the crude product was dissolved
in MeOH, filtered through a short column of Ambersep 900 OH,
and concentrated to give pure 31 (28 mg, 95%) as a colorless oil.
Methyl
(2S,3R,3aR,4S)-4-tert-Butoxy-2-(2-hydroxyethyl)-
2,3,3a,4,5,6-hexahydropyrrolo[1,2-b]isoxazole-3-carboxylate (29): A
solution of nitrone 27 (87.9 mg, 0.56 mmol) and alcohol 28
(73.2 mg, 0.56 mmol) in toluene (1.1 mL) was heated at 60 °C for
1 d. The solvent was evaporated at reduced pressure, and the crude
adduct was purified by chromatography on silica gel (eluent: petro-
leum ether/ethyl acetate, 1:1; then ethyl acetate) to give 29
(124.4 mg, 77%) as a colorless oil.
Compound (؉)-31: [α]2D8 ϭ ϩ15.1 (c ϭ 0.5, in MeOH). 1H NMR
(200 MHz, D2O): δ ϭ 4.29 (td, J ϭ 8.2, 3.9 Hz, 1 H, 1-H),
3.87Ϫ3.76 (m, 2 H, 7-H and CHHOH), 3.65 (dd, J ϭ 11.4, 5.2 Hz,
Compound 29: Rf ϭ 0.26 (ethyl acetate). [α]2D1 ϭ Ϫ28.7 (c ϭ 0.9 in
CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ 4.39 (ddd, J ϭ 8.4, 6.6, 1 H, CHHOH), 2.92Ϫ2.77 (m, 2 H, 3-Ha, 5-Ha), 2.30Ϫ1.98 (m, 5
5.1 Hz, 1 H, 2-H), 4.04 (dt, J ϭ 7.0, 3.6 Hz, 1 H, 4-H), 3.79Ϫ3.69 H, 2-Ha, 3-Hb, 5-Hb, 8-H, 8a-H); 1.73Ϫ1.34 (m, 3 H, 2-Hb, 6-H)
(m, 3 H, 3a-H, CH2CH2OH), 2.73 (s, 3 H, CH3O), 3.41 (t, J ϭ
ppm; (500 MHz, CD3OD): δ ϭ 4.39 (ddd, J ϭ 8.9, 7.6, 4.1 Hz, 1
8.6 Hz, 1 H, 3-H), 3.36Ϫ3.17 (m, 2 H, 6-H), 2.41 (br. s, 1 H, OH), H, 1-H), 3.99 (dd, J ϭ 11.2, 4.8 Hz, 1 H, CHHOH), 3.94 (dd, J ϭ
2.14 (m, 1 H, 5-Ha), 1.90Ϫ1.80 (m, 2 H, CH2CH2OH), 1.78Ϫ1.63 11.2, 4.3 Hz, 1 H, CHHOH), 3.82Ϫ3.76 (m, 1 H, 7-H), 3.02 (ddd,
(m, 1 H, 5-Hb), 1.29 (s, 9 H, CH3 tBu) ppm. 13C NMR (50 MHz, J ϭ 11.0, 4.3, 3.9 Hz, 1 H, 5-Ha), 2.95 (td, J ϭ 8.6, 1.9, 1 H, 3-
1950
Eur. J. Org. Chem. 2002, 1941Ϫ1951

Stereodivergent Approach to Enantiopure Hydroxyindolizidines
FULL PAPER
T. Oka, A. Murai, Tetrahedron 1998, 54,
W. H. Pearson, B. W. Lian, Angew. Chem. Int. Ed.
[5c]
9, 1351Ϫ1358.
1Ϫ20.
Ha), 2.33Ϫ2.07 (m, 5 H, 2-Ha, 3-Hb, 5-Hb, 8-H, 8a-H), 1.83Ϫ1.71
(m, 2 H, 2-Hb, 6-Ha), 1.63 (dddd, J ϭ 12.7, 8.6, 4.3, 2.1 Hz, 1 H,
6-Hb) ppm. 13C NMR (50 MHz, D2O): δ ϭ 72.5, 71.3, 71.2 (d, C-
1, C-7, C-8a), 57.8 (t, CH2OH), 52.3, 50.6 (t, C-3, C-5), 42.7 (d, C-
8), 32.2, 29.3 (t, C-2, C-6) ppm. MS (70 eV, EI): m/z (%) ϭ 187 (3)
[Mϩ], 186 (5), 169 (33), 143 (29), 112 (100), 82 (31). C9H17NO3
(187.12): calcd. C 57.73, H 9.15, N 7.48; found C 57.69, H 9.25,
N 7.30.
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or TBDMS-protected 3-hydroxy-1-pyrroline N-oxide was erro-
neously reported as giving enantiopure 9.
Acknowledgments
We thank the MIUR (Ministry of Instruction, University and
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1951