Synthesis of the necine bases (±)-macronecine and (±)-supinidine via an aza-ene reaction and allylsilane induced ring closure

Article abstract of DOI:10.1016/j.tet.2004.11.046

An aza-ene reaction has been used for the first time for the synthesis of two 5-membered lactam-hydrazides, each with a built-in allylsilane terminator for further elaboration. One of the lactam-hydrazides was transformed via an allylsilane-hydrazonium io

Full text of DOI:10.1016/j.tet.2004.11.046

Tetrahedron 61 (2005) 1155–1165
Synthesis of the necine bases (G)-macronecine and
(G)-supinidine via an aza-ene reaction and allylsilane induced
ring closure
a
a
a
b
Tarun K. Sarkar,a, Anindya Hazra, Pulak Gangopadhyay, Niranjan Panda, Zdenek Slanina,
*
Chun-Cheng Linc and Hui-Ting Chenc
aDepartment of Chemistry, Indian Institute of Technology, Kharagpur-721302, India
bInstitute for Molecular Science, Okazaki, Japan
cInstitute of Chemistry, Academia Sinica, Taipei, Taiwan
Received 27 July 2004; revised 1 November 2004; accepted 18 November 2004
Available online 15 December 2004
Abstract—An aza-ene reaction has been used for the first time for the synthesis of two 5-membered lactam-hydrazides, each with a built-in
allylsilane terminator for further elaboration. One of the lactam-hydrazides was transformed via an allylsilane-hydrazonium ion ring closure
to a fused tetrahydropyrazole which may be considered as a mono-nitrogen analog of the biologically significant necine bases. A density
functional theoretical study (B3LYP/6-21G*) was undertaken to provide insight into the factors that favor a synclinal transition structure of
the hydrazonium ion intermediate leading to the tetrahydropyrazole. This stereocontrolled synthesis served as a model for the multi-step
conversion of the other lactam-hydrazide, the substituted 2-pyrrolidinone, to necine bases (G)-supinidine and (G)-macronecine. An
allylsilane-aldehyde ring closure formed the key step in the synthesis of these natural products.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Over the past several decades the pyrrolizidine alkaloids
have continued to attract significant interest from synthetic
and medicinal chemists alike partly because of their diverse
Figure 1.
biological activities which allow their utility as research
tools in pharmacology, but also because they provide
pyrrolizidine-3-one synthesis reported in the literature
challenging targets for testing new synthetic method-
involving intramolecular cyclization (C7–C7a bond for-
ologies.1 Necine bases, having a 1-hydroxymethyl group
mation) of an acyl iminium ion with an allylsilane
in the pyrrolizidine ring system, comprise the majority of
(Scheme 1).3
the pyrrolizidine alkaloids. Many approaches to these
pyrrolizidine alcohols converge on building a second five-
membered ring on to a preformed, functionalized 2-
pyrrolidinone, though the final bond formed in the synthesis
can be N–C5, C6–C7 or C7–C7a (Fig. 1).1a
Although allylsilanes have been widely recognized as
intermediates for many applications, especially in the area
of natural products synthesis, it is surprising that they have
found only limited use in the synthesis of necine bases.2
Indeed, to our knowledge there is only one example of a
Scheme 1.
We have previously described the use of 3-cyclopentyl
Keywords: Aza-ene reaction; Heterocyclic allylsilanes; Fused tetrahydro-
allylsilanes to form a range of bicyclo-[3.3.0]octanes
pyrazole; Necine bases; Supinidine; Macronecine.
including a demonstration in the stereoselective construc-
* Corresponding author. Tel.: C91 3222 283330; fax: C91 3222 255303;
e-mail: tksr@chem.iitkgp.ernet.in
tion of various natural products.4 The 3-cyclopentyl
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.046

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T. K. Sarkar et al. / Tetrahedron 61 (2005) 1155–1165
allylsilane intermediates are available in near quantitative
yields by 5-(3,4) ene cyclization5 of activated 1,6-dienes
containing a homoallylsilane unit as ene donor (1/2,
Scheme 2).
Figure 2.
In this paper we report the full details8 of our efforts in this
area which culminated in the synthesis of necine bases, e.g.
(G)-supinidine (8)9 and (G)-macronecine (9)10 (Fig. 2).
2. Results and discussion
Scheme 2.
2.1. Synthesis of cyclic hydrazide 14
The foregoing work prompted us to examine a related aza-
ene reaction6 and subsequent allylsilane chemistry to gain
entry into necine bases. Our retrosynthetic analysis towards
this end is outlined in Scheme 3. Thus, 7-substituted
pyrrolizidinones, e.g. 7, precursor to various necine bases,
could be accessed from compound 6 by an allylsilane–
aldehyde ring closure. Compound 6, in turn, could be
obtained from the cyclic hydrazide 5 via reductive cleavage
of the N–N bond and alkylation of the resulting pyrrolidi-
none with a two-carbon electrophile. Compound 5 was
imagined to be accessed via an aza-ene reaction of the
reactive azodicarbonyl intermediate 4 which may be
generated by mild oxidation of the readily available acyl
hydrazide 3. It should be mentioned here that several
7-substituted pyrrolizidinones, reducible to necine bases at a
late stage of the synthesis, were synthesized earlier either by
nucleophilic substitution or radical cyclization of 5-sub-
stituted 1-halogenoethyl pyrrolidin-2-ones.7
The synthesis of the substrate for the aza-ene reaction began
with the silylated carbinol 10, obtainable by addition of
vinylmagnesium bromide to 3-(trimethylsilyl)propanal,11
which on orthoester Claisen rearrangement gave the g,
d-unsaturated ester 11 (Scheme 4); the configuration of the
double bond in this case was tentatively assigned E on the
basis of literature precedent. Saponification of 11 gave 12
which was next converted into the crystalline acyl hydrazide
13 in high yield via the acid chloride. Based on the original
work of Vedejs and Meier,6a it was envisaged that oxidants
capable of converting hydrazides into azo compounds (cf. 4)
would convert 13 into the cyclic hydrazide 14. It was also
deemed necessary to make use of neutral or slightly basic
oxidants to ensure that the acid labile allylsilane function-
ality of 14 survived. Two different oxidizing agents, silver
carbonate impregnated celite12 and activated manganese
dioxide,6a,13 were initially selected for optimum results.
Scheme 3.
Scheme 4. (a) CH3C(OEt)3, HC, toluene, 81%; (b) KOH, MeOH, 91%; (c) NaH, (COCl)2, benzene; (d) NH2NHCO2Me, Et3N, CH2Cl2, 88% from 12;
(e) MnO2, ClCH2CH2Cl, 15 8C, 89%; (f) Ag2CO3-celite, benzene, 38%.

T. K. Sarkar et al. / Tetrahedron 61 (2005) 1155–1165
1157
amount of Z-isomer contaminated with the E-isomer in one
run was found to be as high as 30%. The structural and
stereochemical assignment of 14 followed from analysis of
its 1H and 13C NMR spectroscopic data. Sonicating 13 with
10 equiv of Ag2CO3/celite reagent12 followed by chroma-
tography of the crude product also gave a semisolid material
(38%) as a mixture (the isomers do not resolve on TLC) of
E-14 and Z-15 in a ratio of 4.5:1, respectively. It is our
experience that MnO2 oxidation generally gives a purer ene
product 14 in consistently good yields.
2.2. Synthesis of fused pyrazole 17a
With compound 14 in hand we were in a position to effect
reductive cleavage of the N–N bond and elaborate the
resulting 2-pyrrolidone for the synthesis of necine bases.
However, before embarking on this work, we felt it
important to study the efficacy of the allylsilane function-
ality to take part in some Lewis acid catalyzed ring closure
reactions, such as the formation of the fused pyrazole 17a
(Scheme 5). The diastereoselectivity of this reaction which
creates two adjacent stereogenic centers is important in light
of possible application to the synthesis of necine bases.
Additionally, the cyclic hydrazide derivative 17a belongs to
a class of compounds which are attractive objects of study in
their own right and as analogs of bioactive mono-nitrogen
compounds.14 In the event, exposure of 14 to 1 equiv of
Scheme 5. (a) NaH, THF, and then MOMCl; (b) BF3$OEt2, CH2Cl2, 51%
from 14.
After considerable experimentation it was found that the
aza-ene reaction could be run with only 12 equiv of MnO2
(instead of 25–30 equiv as reported by Vedejs and Meier6)
and sonication somewhat accelerated the reaction com-
pared to mechanical stirring to give 14 containing 5–10%
of the Z-isomer in high yield. However, the percentage of
Z-isomer varied from batch to batch and the maximum
Figure 3.

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T. K. Sarkar et al. / Tetrahedron 61 (2005) 1155–1165
Table 1. Relative energies in kcal/mol
Activated complex
B3LYP/3-21G*
MP2/6-31G*
MP2/6-311CCG*
MP2/6-311CCG(2df,p)
A
B
C
D
0.0
3.49
0.0
0.0
3.12
0.0
0.0
3.27
0.0
0.0
2.57
0.0
7.24
5.49
5.55
5.12
All computations were carried out in the B3LYP/3-21G* optimized geometries; MP2 done as MP2ZFC.
sodium hydride in THF followed by treatment with
methoxymethyl chloride (MOMCl) gave 15 (Scheme 5)
which without further purification was treated with
BF3$OEt2 (2.5 equiv) in CH2Cl2 to give the fused
tetrahydropyrazole 17a in good yield. Careful GC–MS
analysis of the crude product showed total absence of the
other diastereomer 17b. Incidentally, 17a had some nagging
impurity which could not be removed by preparative layer
chromatography. For analytical purposes, however, it could
be readily purified by preparative HPLC. The structure and
disposition of the group at C2 could not be clearly predicted.
In the event, N-alkylation with methyl bromoacetate gave
20 in good yield. However, attempts to selectively reduce
the ester group with DIBAL-H yielded only traces of 23 and
a lot of polar compounds which were not further
investigated. In view of these difficulties, a somewhat
roundabout route was followed which involved transform-
ation of 19 to thioester 22 via the acid 21 and reduction of
the thioester to the aldehyde 23 following the procedure
reported by Fukuyama et al.18 The thioester reduction was
initially plagued by the formation of a substantial amount of
the overreduced aldehyde 25. Hence, optimum conditions
had to be worked out which delivered 23 uncontaminated
with any of 25. With sufficient quantities of 23 in hand, the
stage was set to build up the second 5-membered ring. Thus,
when 23 was exposed to BF3$OEt2 in methylene chloride,
24 was formed as the major product along with three minor
diastereomers in a moderate yield. LCMS of the crude
product showed that the four diastereomers were present in
a relative ratio of 86.4: 5.8: 3.4: 4.4. Since the diastereomers
do not resolve on TLC (silica gel), the major product 24 was
purified by preparative HPLC. The structure and stereo-
chemistry of 24 rest on a full complement of NMR
spectroscopic data including those from NOE experiments,
stereochemistry of 17a were confirmed from its 1H and 13
C
NMR, COSY, HMQC and NOE-difference spectra.
In order to understand the high stereoselectivity in the
reactions of E and Z-15 to 17a where the reactions obviously
involve intramolecular trapping of the N-acyl hydrazonium
ion intermediate 16 by the allylsilane terminator, ab initio
calculations15 were carried out to arrive at the four
optimized activated complexes A–D (Fig. 3). The torsion
angles (B3LYP/3-21G*) between the C,C and N,C double
bonds in the synclinal transition structures A and C are 98.3
and 106.58, respectively, whereas in the antiperiplanar
transition structures B and D, they are 163.6 and 171.98,
respectively. The relative energies are shown in Table 1.
Clearly, A (from E-16) and C (from Z-16) which give rise to
17a are favored over B (from E-16) and D (from Z-16)
which might have led to 17b. These findings are in line with
previous work on allylsilane-iminium ion ring closure
reactions where useful selectivity compatible with synclinal
transition structures has been found for the formation of
five-membered rings, when either both double bonds are
exocyclic to the ring being formed or when one of them is
endocyclic.16
2.3. Synthesis of 7-vinyl substituted pyrrolizidinone 24
The synthesis began with the ene adduct 14 which gave
2-pyrrolidinone 19 via a two-step alkylation reduction
sequence (Scheme 6). Thus, N-methylation gave a rota-
meric mixture of 18 whose N–N bond could be cleaved to
give 19 in high yield using Li/NH3 in the presence of excess
ethanol for 1 min. If the alcohol was omitted, or if longer
reaction were used, the yield and purity of the product
decreased dramatically. Incidentally, in a selective mono-N-
debenzylation of a substituted allylsilane using Li/NH3 a
similar observation including total loss of the silyl group
was made by Weinreb et al.17 Our plan at this stage was to
attach a 2-carbon electrophile at the nitrogen atom in 19 and
effect an allylsilane induced ring closure leading to a
7-substituted pyrrolizidinone (cf. 7). Based on our model
study on the synthesis of fused tetrahydropyrazole 17a, we
expected that the vinyl side chain at C1 in this case would be
cis with respect to C7a–H, although the stereochemical
Scheme 6. (a) NaH, THF; then CH3I, 86%; (b) Li/NH3/EtOH, 96%;
(c) BuLi/THF; then BrCH2CO2Me, HMPA, 74%; (d) NaOH/MeOH, 85%;
(e) EtSH, DCC, cat. DMAP, CH2Cl2, 76%; (f) Et3SiH, Pd–C (10%),
CH2Cl2, 94%; (g) BF3$OEt2, CH2Cl2, 44% (contains 3 other minor
diastereomers).

T. K. Sarkar et al. / Tetrahedron 61 (2005) 1155–1165
1159
complication in this reaction was the similar polarity of the
substitution product and triphenylphosphine oxide, requir-
ing multiple purification21 by silica gel chromatography to
obtain 26 in a pure form. For confirmation that 24 had,
indeed, undergone invertive substitution and was not simply
acylated in the Mitsunobu reaction, the pyrrolidinone 24
was treated with 4-nitrobenzoyl chloride to obtain the
epimeric 4-nitrobenzoate 27. Comparison of 1H NMR
spectra of the two esters confirmed that the Mitsunobu
reaction had occurred with inversion.
2.5. Synthesis of (G)-supinidine (8) and
(G)-macronecine (9)
With ready access to substantial quantities of 26, studies
were next directed to the synthesis of the target natural
product (G)-macronecine (9). Ozonolysis of 26 followed by
reduction of the resulting ozonide gave none of the desired
aldehyde 28; instead the a, b-unsaturated aldehyde 29 was
Figure 4. ORTEP perspective view of 24 with the numbering structure.
1
obtained as a crystalline solid (Scheme 9). The H NMR
and finally confirmed by X-ray crystal structure determi-
nation (CCDC 251447, Fig. 4).
data of 29 completely match with those reported for the
same compound by Chamberlin et al.9g as well as Tsai and
Ke.7d As one would expect, the diastereomeric pyrrolizidi-
none 27 under similar conditions yielded the identical
aldehyde, e.g. 29. The structure of 29 was best confirmed by
its ready conversion to (G)-supinidine (8) by reduction with
excess Red-Al in THF. The 1H NMR of our synthetic
product is superimposable with those of the racemic product
reported by Hart et al.9e Since the aldehyde 28, an
intermediate for the synthesis of (G)-macronecine (9) was
not available via the usual ozonolysis route, the experimen-
tal conditions were modified so as to reach the targeted
natural product directly in one pot. Thus, ozonolysis of 26
was carried out as before in methylene chloride at K78 8C,
then the bulk of the solvent was removed in vacuo at
K30 8C and replaced by THF followed by the addition of
excess Red-Al. This protocol effected reduction of the
ozonide, the lactam carbonyl group and the ester in one pot
to yield (G)-macronecine (9) whose 1H and 13C NMR data
Based on the work of Tokoroyama et al.19 on the
stereoselective cyclization of (E)- and (Z)-5,6-dimethyl-8-
trimethylsilyl-6-octenals and also based on our own
theoretical analysis in the case of 15/17a, a chair like
transition state is proposed to account for the formation of
the major diastereomer 24 (Scheme 7).
2.4. Correction of configuration at C2
The pyrrolizidinone 24 possessed all the correct features of
(G)-macronecine (9). However, to convert it to the natural
molecule, inversion of configuration at C2 was required. The
configuration at C2 was now corrected under standard
Mitsunobu reaction conditions20 on the crude product 24
(contaminated with three other minor diastereomers) using
4-nitrobenzoic acid as the nucleophile (Scheme 8). The only
Scheme 7.
Scheme 8. (a) Ph3P/DEAD/4-NO2C6H4CO2H/THF, 53%; (b) 4-NO2C6H4COCl/4-DMAP/CH2Cl2, 70%.

1160
T. K. Sarkar et al. / Tetrahedron 61 (2005) 1155–1165
1.3 M in THF, 161 mmol) at K20 8C under argon was
added a solution of 3-(trimethylsilyl)propanal11 (18.90 g,
145 mmol) in THF (75 mL) over a period of 30 min. The
reaction mixture was stirred at room temperature overnight
and quenched by the addition of ammonium chloride
solution (150 mL, sat. aq) at 0 8C. The organic layer was
separated and the aqueous layer was extracted with ether
(200 mL). The combined ether extract was washed with
brine (50 mL), dried (Na2SO4) and concentrated in vacuo.
Distillation of the crude product afforded the title compound
10 (18.4 g, 80.6%) as a colorless oil; bp 97–98 8C/5 Torr;
mp (3,5-dinitrobenzoate) 53–54 8C; [Found: C, 51.01; H,
5.63; N, 8.01. C15H20N2O6Si requires C, 51.12; H, 5.72; N,
7.95%]; Rf [2% EtOAc/petroleum ether (60–80 8C)] 0.38;
nmax (liquid film) 3360, 2960, 2930, 1420, 1250, 920, 860,
835 cmK1; dH NMR (200 MHz, CDCl3) 5.93–5.76 (1H, m),
5.23–5.09 (2H, m), 4.00 (1H, td, JZ12.2, 6.2 Hz), 1.60–
1.57 (1H, br s), 1.53–1.47 (2H, m), 0.60–0.44 (2H, m), 0.00
(9H, s); dC (50 MHz, CDCl3) 140.8 (CH), 114.7 (CH2), 75.3
(CH), 32.1 (CH2), 12.1 (CH2), K1.9 (3 CH3).
Scheme 9. (a) O3, CH2Cl2, K78 8C, then Ph3P, 50%; (b) Red-Al, THF,
reflux (3 h), 76% (c) O3, CH2Cl2, K78 8C; then excess Red-Al, THF, reflux
(3 h), 33%.
were very close to those of the natural product reported in
the literature.10a,10d
4.1.2. (E)-7-(Trimethylsilyl)-4-heptenoic acid (12). A
stirred mixture of 10 (18 g, 113.9 mmol), triethyl ortho-
acetate (22.9 g, 141.5 mmol) and a catalytic amount of
propionic acid (0.30 mL) in toluene (150 mL) was heated at
reflux for 8 h in an oil bath under argon. Toluene was
removed by distillation and the temperature of oil bath
gradually increased to 155 8C over a period of 1.5 h. The
reaction mixture was cooled to room temperature and
distilled to give ethyl (E)-7-(trimethylsilyl)-4-heptenoate
(11) (21 g, 81%) as a colorless oil; bp 88 8C/0.2 Torr; Rf
[petroleum ether (60–80 8C)] 0.87; nmax (liquid film) 2980,
2950, 2900, 1745, 1450, 1375, 1250, 1180, 970, 860,
835 cmK1; dH (200 MHz, CDCl3) 5.60–5.33 (2H, m), 4.11
(2H, q, JZ7.2 Hz), 2.36–2.23 (4H, m), 2.06–1.86 (2H, m),
1.25 (3H, t, JZ7.2 Hz), 0.57–0.51 (2H, m), K0.03 (9H, s);
dC (50 MHz, CDCl3) 173.1 (C), 134.3 (CH), 126.3 (CH),
60.1 (CH2), 34.3 (CH2), 27.7 (CH2), 26.6 (CH2), 16.3 (CH2),
14.1 (CH3), K1.7 (3 CH3). To a stirred solution of 11 (20 g,
87.7 mmol) in methanol (80 mL) was added a solution of
10% methanolic sodium hydroxide (30 mL) dropwise at
room temperature. After 2 h the reaction mixture was
concentrated in vacuo and diluted with water (30 mL). The
aqueous layer was cooled in ice bath, acidified with dilute
hydrochloric acid and extracted with ether (150 mL). The
combined ether extract was washed with brine (50 mL),
dried (Na2SO4) and concentrated in vacuo. Distillation of
the residue gave the title compound 12 (16 g, 91%) as a
colorless thick oil; bp 135 8C (bath) / 0.5 Torr; [Found: C,
60.03; H, 9.95. C10H20O2Si requires C, 59.94; H, 10.06%];
nmax (liquid film) 2960, 2920, 1715, 1410, 1250, 970, 860,
835 cmK1; dH (200 MHz, CDCl3) 5.58–5.28 (2H, m), 2.45–
2.26 (4H, m), 2.02–1.94 (2H, m), 0.60–0.52 (2H, m), K0.02
(9H, s); dC (50 MHz, CDCl3) 179.8 (C), 134.7 (CH), 126.0
(CH), 34.1 (CH2), 27.4 (CH2), 26.7 (CH2), 16.3 (CH2),
K1.6 (3 CH3).
3. Conclusion
A 5-membered cyclic hydrazide containing an allylsilane
functionality was readily synthesized by a facile, but rarely
used aza-ene reaction. The allylsilane terminator allowed its
further elaboration to a fused tetrahydropyrazole which may
be regarded as a mono-nitrogen analog of the biologically
potent necine bases. An in-depth analysis of the stereo-
chemistry of the allylsilane-hydrazonium ion ring closure
leading to the fused pyrazole was made possible by use of
density functional theoretical study (B3LYP/6-21G*). The
stereochemical information gathered from this work proved
useful in the multi-step synthesis of two pyrrolizidine
natural products (G)-supinidine and (G)-macronecine
starting from a substituted 2-pyrrolidinone, readily available
from the 5-membered cyclic hydrazide via an alkylation–
reduction sequence.
4. Experimental
4.1. General
All melting points are uncorrected. Unless otherwise noted,
all reactions were carried out under an inert atmosphere in
flame-dried flasks. Solvents and reagents were dried and
purified by distillation before use as follows: tetrahydro-
furan, toluene, and benzene from sodium benzophenone
ketyl; dichloromethane from P2O5; DMSO from CaH2;
Et3N, pyridine from solid KOH; and MeOH, EtOH from
Mg. After drying, organic extracts were evaporated under
reduced pressure and the residue was chromatographed on
silica gel (Acme’s, particle size 100–200 mesh) using
EtOAc, petroleum ether (60–80 8C) mixture as eluent unless
specified otherwise. TLC was recorded using precoated
plate (Merck, silica gel 60 F254).
4.1.3. Methyl (E)-7-(trimethylsilyl)-4-heptenoylhydrazo-
carboxylate (13). To a mixture of sodium hydride (7 g,
82.5 mmol, 28% dispersion in oil) in benzene (100 mL) at
0 8C was added a solution of 12 (15 g, 75 mmol) in benzene
(50 mL). The mixture was stirred for 30 min before addition
of oxalyl chloride (8.16 mL, 93.2 mmol) at 0 8C, followed
4.1.1. 5-(Trimethylsilyl)-3-hydroxy-1-pentene (10). To a
stirred solution of vinylmagnesium bromide (124 mL of

T. K. Sarkar et al. / Tetrahedron 61 (2005) 1155–1165
1161
by pyridine (4 drops). After 3.5 h, the reaction mixture was
filtered through a sintered filter under argon and the filtrate
was concentrated in vacuo. The residue was diluted with
dichloromethane (50 mL) and was slowly added to a stirred
solution of methyl hydrazinocarboxylate (8.80 g,
97.5 mmol), Et3N (10.6 g, 105.9 mmol) in dichloromethane
(100 mL). After 12 h, the reaction mixture was poured into
water (150 mL) and extracted with ether (200 mL). The
combined ether extract was washed with water (30 mL),
brine (60 mL), dried (Na2SO4) and concentrated in vacuo to
give the title compound 13 (18 g, 88%) as a white
crystalline solid, mp 76 8C [ether–pet.ether (40–60 8C)];
[Found: C, 52.74; H, 8.88; N, 10.25. C12H24N2O3Si requires
C, 52.94; H, 8.88; N, 10.28%]; Rf [40% EtOAc/petroleum
ether (60–80 8C)] 0.53; nmax (film) 3285, 3170, 3020, 2940,
2895, 1715, 1655, 1520, 1430, 1300, 1280, 1260, 1245,
1235, 1050, 970, 865, 840 cmK1; dH (300 MHz, CDCl3)
7.34 (1H, br s), 6.71 (1H, br s), 5.60–5.53 (1H, m), 5.46–
5.39 (1H, m), 3.78 (3H, s), 2.38–2.27 (4H, m), 2.06–1.98
(2H, m), 0.60–0.55 (2H, m), 0.00 (9H, s); dC (50 MHz,
CDCl3) 172.2 (C), 156.9 (C), 135.1 (CH), 126.1 (CH), 53.1
(CH3), 34.0 (CH2), 27.9 (CH2), 26.7 (CH2), 16.3 (CH2),
K1.6 (3 CH3).
chloride solution (5 mL, sat. aq) and extracted with ether
(15 mL). The combined ether extract was washed with brine
(5 mL), dried (Na2SO4) and concentrated in vacuo to afford
N-carbomethoxy, N-methoxyamino-5-[3-(trimethylsilyl)-1-
propenyl]-2-pyrrolidinone (15) (210 mg, 90%) as a light
yellow thick oil; dH (200 MHz, CDCl3) 5.70–5.50 (1H, m),
5.30–4.55 (3H, m), 4.30–4.18 (1H, m), 3.70–3.68 (3H, m),
3.37 (3H, br s), 2.50–2.10 (3H, m), 1.90–1.60 (1H, m), 1.50–
1.30 (2H, m), K0.02 (9H, s). To a stirred solution of 15
(210 mg, 0.67 mmol) in dichloromethane (5 mL), BF3$OEt2
(0.2 mL, 1.68 mmol) was added at K20 8C under argon and
stirred for 1 h and then it was allowed to attain room
temperature. After 4 h, the reaction mixture was poured into
brine (5 mL) and extracted with dichloromethane (15 mL).
The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The residue after preparative layer
chromatography on silica gel [10% EtOAc/petroleum ether
(60–80 8C)] afforded the title compound 17a (72 mg, 51%)
as a light yellow thick oil. For analytical purpose, this
compound was further purified by preparative HPLC
[Lichrosob (R) Si 60 (7 mm) column (Merc), ethyl
acetate–hexane solvent system]; nmax GC-FTIR (270 8C)
2964, 1772, 1737, 1450, 1366, 1176, 925 cmK1; dH
(400 MHz, CDCl3) 5.70–5.61 (1H, m, C10–H), 5.25–5.19
(2H, m, C20-2H), 3.84–3.79 (1H, m, C2–HH), 3.79 (3H, s,
OCH3), 3.60–3.54 (2H, m, C3a–H, C2–HH), 2.67–2.64 (1H,
m, C5–HH), 2.56–2.51 (1H, m, C3–H), 2.46–2.38 (2H, m,
C5–HH, C4–HH), 2.01–1.91 (1H, m, C4–HH); dC
(100 MHz, CDCl3) 178.7 (C), 157.3 (C), 133.3 (CH),
119.2 (CH2), 62.7 (CH), 53.9 (CH2), 53.7 (CH3), 50.3 (CH),
27.9 (CH2), 18.8 (CH2); m/z [GC–MS (JLB.COL. SPB1
30M PRG: 130–240 10/MN)] 210 (34 MC), 155 (35), 151
(30), 127 (100), 123 (48), 101 (38), 68 (35), 59 (39), 55 (38),
41 (47%).
4.1.4. N-Carbomethoxyamino-5-[3-(trimethylsilyl)-1-
propenyl]-2-pyrrolidinone (14). To a stirred suspension
of active MnO2 (38.8 g, 0.40 mol) in dichloroethane
(100 mL) was slowly added a solution of 13 (8.4 g,
30.8 mmol) in dichloroethane (50 mL) at 0 8C under argon
and the resulting suspension was sonicated (using
BRANSONIC (R) 5210 E-MTH, frequency 47 KHz) for
4 h. The reaction mixture was then filtered through sintered
filter and the residue washed with hot ethyl acetate
(150 mL). The filtrate was concentrated in vacuo to give
the title compound 14 (7.5 g, 89%), which was sufficiently
pure for the next step. A part of this solid was recrystallized
[Et2O/petroleum ether (40–60 8C)] for analytical purpose,
mp 89 8C; [Found: C, 53.36; H, 8.08; N, 10.37.
C12H22N2O3Si requires C, 53.30; H, 8.20; N, 10.36%]; Rf
[40% EtOAc/petroleum ether (60–80 8C)] 0.34; nmax (KBr)
3170, 3000, 2950, 2900, 1720, 1695, 1650, 1540, 1455,
1430, 1410, 1315, 1295, 1280, 1250, 1230, 1180, 1145,
1095, 1060, 1040, 1020, 980, 970, 865, 855 cmK1; dH
(300 MHz, CDCl3) 6.41 (br s); 5.69 (1H, dt, JZ15.0,
8.2 Hz), 5.13 (1H, dd, JZ15.0, 8.8 Hz), 4.69–4.55 (0.3!1
H for Z-isomer, m), 4.21–4.05 (0.7!1H, m), 3.73 (3H, s),
2.47–2.39 (2H, m), 2.32–2.24 (1H, m), 1.81–1.74 (1H, m),
1.50 (2H, d, JZ6.9 Hz), 0.00 (9H, s); dC (75 MHz, CDCl3)
for E-isomer 173.7 (C), 155.6 (C), 133.2 (CH), 126.3 (CH),
62.0 (CH3), 52.6 (CH), 28.0 (CH2), 24.7 (CH2), 22.8 (CH2),
K2.1 (CH3); dC for Z-isomer (partial): 131.8 (CH), 125.5
(CH), 55.6 (CH), 24.4 (CH2), 18.7 (CH2); m/z (ES) 271.1
(100 MHC), 293.1 (56% MNaC).
4.1.6. 5-[3-(Trimethylsilyl)-1-propenyl]-2-pyrrolidinone
(19). To a mixture of sodium hydride (2.1 g, 24.50 mmol,
28% dispersion in oil) in THF (20 mL) at 0 8C was added a
solution of 14 (5.5 g, 20.4 mmol) in THF (20 mL). The
mixture was stirred for 1 h at room temperature before
addition of methyl iodide (6.37 mL, 102.2 mmol, freshly
distilled) at 0 8C and stirring was continued for 30 min at
that temperature. After 2 h at room temperature the reaction
mixture was quenched by addition of ammonium chloride
solution (30 mL, sat. aq) and extracted with ether (90 mL).
The combined ether extract was washed with brine (30 mL),
dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by silica gel chromatography [10%
EtOAc/petroleum ether (60–80 8C)] to afford N-carbo-
methoxy, N-methylamino-5-[3-(trimethylsilyl)-1-propenyl]-
2-pyrrolidinone (18) (5 g, 86%) as a light yellow thick oil;
Rf [10% EtOAc/petroleum ether (60–80 8C)] 0.58;
nmax(CHCl3): 3480, 3285, 2956, 2888, 1688, 1500, 1399,
1251, 1399, 1251, 1150, 1064, 1021, 970, 851 cmK1; dH
(300 MHz, CDCl3) 5.74–5.54 (1H, m), 5.19–5.03 (1H, m),
4.34–4.22 (0.3!1H, m, for Z-isomer), 4.14– 4.01(0.7!1H,
m), 3.74–3.60 (3H, m), 3.14–3.00 (3H, m), 2.40–2.10 (3H,
m), 1.90–1.60 (1H, m), 1.52–1.40 (2H, m), K0.04 (9H, s).
To liquid NH3 (w140 mL) was added Li metal (200 mg,
28.57 mmol) and stirred. Within 2 min the color of the
solution became blue. To this solution was added a solution
of 18 (2.40 g, 8.45 mmol) in ether (12 mL). The color of the
solution became grey within 1 min. It was quenched
4.1.5. Methyl (3S*, 3aS*)-3-ethenylhexahydro-6-oxo-1H-
pyrrolo-[1,2-b]pyrazole-1-carboxylate (17a). To a mix-
ture of sodium hydride (92 mg, 1.16 mmol, 28% dispersion
in oil) in THF (5 mL) at 0 8C was added a solution of 14
(200 mg, 0.74 mmol) in THF (2 mL). The mixture was
stirred for 1 h at room temperature before addition of
methoxymethyl chloride (0.3 mL, 3.98 mmol) at 0 8C and
stirring was continued for 30 min at 0 8C. After 2 h, the
reaction mixture was quenched by addition of ammonium

1162
T. K. Sarkar et al. / Tetrahedron 61 (2005) 1155–1165
immediately with dry ethanol (12 mL). The reaction
mixture was left for hours so as to allow ammonia to
evaporate and then ethanol was removed in vacuo. It was
then diluted with water (20 mL) and extracted with ether
(60 mL). The combined organic layers were concentrated in
vacuo. The residue after silica gel chromatography [20%
EtOAc/petroleum ether (60–80 8C)] afforded the title
compound 19 (1.6 g, 96%) as a light yellow oil; Rf [10%
EtOAc/petroleum ether (60–80 8C)] 0.32; nmax (liquid film)
3788, 3215, 3094, 2957, 2893, 1698, 1416, 1344, 1255,
1152, 970, 852 cmK1; dH (300 MHz, CDCl3) 5.65–5.57
(1H, m), 5.26–5.18 (1H, m), 4.13–4.06 (0.83!1H, m),
2.36–2.27 (2H, m), 1.81–1.72 (2H, m), 1.48 (2H, dd, JZ8.1,
1.1 Hz), 0.00 (9H, s); for Z-isomer (partial) 4.50–4.40
(0.17!1H, m); dC for E-isomer (75 MHz, CDCl3) 178.1
(C), 129.3 (CH), 128.9 (CH), 56.7 (CH), 30.1 (CH2), 28.8/
28.7 (CH2), 22.5 (CH2), K2.0 (CH3); for Z-isomer (partial)
127.8 (CH), 50.8 (CH), 30.4 (CH2), 28.8/28.7 (CH2), 19.0
(CH2); m/z (EI) 197 (9.6, MC), 182 (17.5), 166 (5.0), 110
(5.3), 97 (6.0), 84 (15.7), 82 (9.4), 80 (7.4), 75 (25.1), 74
(13.3), 73 (100%, Me3Si); HRMS (ES): MHC, found
198.1309. C10H20NOSi requires 198.1308.
aqueous layer was cooled and acidified with dilute
hydrochloric acid and extracted with ether (60 mL). The
combined ether layer was washed with brine (20 mL), dried
(Na2SO4) and concentrated in vacuo to give the title
compound 21 (3.40 g, 85%) as a white crystalline solid; mp
100 8C, [50% EtOAc/petroleum ether (60–80 8C)]; [Found:
C, 56.45; H, 8.28; N, 5.46. C12H21NO3Si requires C, 56.44;
H, 8.29; N, 5.84%]; nmax (KBr) 3879, 3823, 3722, 3628,
3437, 3378, 3253, 2964, 2708, 1749, 1640, 1556, 1455,
1410, 1340, 1259, 1187, 1035, 978 cmK1; dH (300 MHz,
CDCl3) 6.39 (1H, br s), 5.71 (1H, dt, JZ15.0, 8.2 Hz), 5.06
(1H, dd, JZ15.0, 9.1 Hz), 4.29 (1H, d, JZ17.7 Hz), 4.14
(0.86!1H, td, JZ8.1, 7.3 Hz), 3.67 (1H, d, JZ17.7 Hz),
2.51– 2.42 (2H, m), 2.32–2.21 (1H, m), 1.80–1.67 (1H, m),
1.50 (2H, d, JZ8.1 Hz), 0.0 (9H, s); For Z-isomer (partial)
4.59–4.56 (0.14!1H, m), 4.26 (d, JZ17.7 Hz); dC
(50 MHz, CDCl3: CCl4, 3:1) 176.2 (C), 171.6 (C), 133.3
(CH), 127.0 (CH), 61.9 (CH), 41.8 (CH2), 29.9 (CH2), 26.5
(CH2), 22.9 (CH2), K1.9 (3 CH3); dC for Z-isomer (partial)
132.3 (CH), 125.9 (CH), 55.2 (CH), 18.9 (CH2); HRMS
(ES): MHC, found 256.1362. C12H22NO3Si requires
256.1363.
4.1.7. Methyl 2-[2-oxo-5-[3-(trimethylsilyl)-1-pro-
penyl]tetrahydro-1H-pyrrolyl]ethanoate (20). To a stir-
red solution of 19 (3.9 g, 19.7 mmol) in THF (40 mL) was
added BuLi (7.5 mL of 2.5 M, 18.76 mmol) at K78 8C and
stirred for 30 min. Then it was allowed to attain room
temperature and stirring was continued for an additional 1 h.
Then methyl bromoacetate (1.86 mL, 19.7 mmol) was
added followed by HMPA (2 mL). After 4 h, the reaction
mixture was quenched with ammonium chloride solution
(10 mL, sat. aq) and extracted with ether (30 mL). The
combined ether extracts were washed with brine, dried
(Na2SO4) and concentrated in vacuo. Purification of the
crude residue by column chromatography [15% EtOAc/
petroleum ether (60–80 8C)] gave the title compound 20
(3.5 g, 74%, based on recovered starting material) as a pale
yellow thick oil; Rf [5% EtOAc/petroleum ether (60–80 8C)]
0.32; nmax (liquid film) 3477, 2956, 2893, 1751, 1702, 1547,
1427, 1254, 1208, 1063, 1016, 978, 850 cmK1; dH
(300 MHz, CDCl3) 5.67 (1H, dt, JZ15.0, 8.2 Hz), 5.06
(1H, dd, JZ15.0, 9.0 Hz), 4.30 (1H, d, JZ17.5 Hz), 4.14–
4.12 (0.85!1H, td, JZ8.0, 7.4 Hz), 3.71 (3H, s), 3.65 (1H,
d, JZ17.5 Hz), 2.45–2.39 (2H, m), 2.32–2.23 (1H, m),
1.79–1.67 (1H, m), 1.49 (2H, d, JZ8.2 Hz), 0.00 (9H, s); for
Z-isomer (partial) 4.62–4.50 (0.15!1H, m), 3.63 (1H, d,
JZ17.5 Hz); dC for E-isomer (50 MHz, CDCl3:CCl4, 3:1)
175.1 (C), 169.1 (C), 132.8 (CH), 127.4 (CH), 61.5 (CH),
51.8 (CH3), 41.5 (CH2), 30.0/29.9 (CH2), 26.5 (CH2), 22.8
(CH2), K2.0 (3 CH3); for Z-isomer (partial) 175.2 (C),
169.3 (C), 131.8 (CH), 126.3 (CH), 54.7 (CH), 30.0/29.9
(CH2), 26.1 (CH2), 18.8 (CH2); HRMS (ES): MHC, found
270.1521. C13H24NO3Si requires 270.1520.
4.1.9. Ethyl 2-[2-oxo-5-[3-(trimethylsilyl)-1-propenyl]-
tetrahydro-1H-pyrrolyl]ethanethioate (22). To a stirred
solution of 21 (1.48 g, 5.8 mmol) in dichloromethane
(15 mL) was added DMAP (64 mg), ethanethiol (1.72 mL,
23.28 mmol) and DCC (2.4 g, 11.64 mmol) at 0 8C. After
5 min it was warmed to room temperature and stirred for
3 h. Then the precipitated urea derivative was filtered off
and the filtrate was concentrated to one fourth of the total
volume in vacuo. The precipitate reappeared, was filtered
again to make it free from any further precipitate of urea
derivative. The filtrate was then diluted with dichloro-
methane (20 mL), washed twice with 0.5 N hydrochloric
acid followed by sodium bicarbonate (30 mL, sat. aq) and
dried (Na2SO4). The solvent was removed in vacuo. The
crude product was purified by column chromatography
[10% EtOAc/petroleum ether (60–80 8C)] to give the title
compound 22 (1.32 g, 76%) as a colorless thick oil; Rf [10%
EtOAc/petroleum ether (60–80 8C)] 0.3; nmax(CHCl3) 3509,
3137, 2942, 2857, 2132, 1699, 1451, 1636, 1354, 1305,
1254, 1139, 1151, 1081, 1039, 955, 891, 848 cmK1; dH
(200 MHz, CDCl3) 5.65 (1H, dt, JZ15.0, 8.2 Hz), 5.05 (1H,
dd, JZ15.0, 9.0 Hz), 4.42 (1H, d, JZ17 Hz), 4.20–4.0 (1H,
m), 3.74 (1H, d, JZ17 Hz), 2.89 (2H, q, JZ7.4 Hz), 2.50–
2.20 (3H, m), 1.85–1.65 (1H, m), 1.48 (2H, d, JZ8.1 Hz),
1.25 (3H, t, JZ7.4 Hz), 0.00 (9H, s); For Z-isomer (partial)
4.60–4.40 (m), 4.41 (d, JZ17 Hz), 3.71 (d, JZ17 Hz); dC
(50 MHz, CDCl3/CCl4 3:1) 195.7 (C), 175.0 (C), 133.0
(CH), 127.0 (CH), 61.7 (CH), 49.8 (CH2), 29.7 (CH2), 26.4
(CH2), 22.9 (CH2), 22.9 (CH2), 14.6/ 14.5 (CH3), K1.9
(3 CH3); dC for Z-isomer (partial) 132.1 (CH), 125.9 (CH),
54.9 (CH), 34.9 (CH2), 29.9 (CH2), 26.2 (CH2), 25.4 (CH2),
18.9 (CH2), 14.6/14.5 (CH3); HRMS (ES): MHC, found
300.1448. C14H26NO2SiS requires 300.1448.
4.1.8. 2-[2-Oxo-5-[3-(trimethylsilyl)-1-propenyl]tetra-
hydro-1H-pyrrolyl]ethanoicacid (21). To a stirred sol-
ution of 20 (4.2 g, 15.6 mmol) in methanol (90 mL) was
slowly added a solution of 10% methanolic sodium
hydroxide (9 mL) at room temperature. After 2.5 h the
reaction mixture was concentrated in vacuo and diluted with
water (20 mL). The aqueous layer was washed with ether
(20 mL) to remove any organic impurities and then the
4.1.10. (1S*, 2S*, 7aS*)-1-Ethenyl-2-hydroxy-5-oxo-
hexahydro-1H-pyrrolizine (24). To a stirred solution of
22 (440 mg, 1.47 mmol) and 10% Pd–C (120 mg) in
dichloromethane (50 mL) was added Et3SiH (0.70 mL,
4.42 mmol) at room temperature under argon atmosphere.
Stirring was continued for 25 min. The catalyst was filtered

T. K. Sarkar et al. / Tetrahedron 61 (2005) 1155–1165
1163
off through a sintered funnel and the residue washed with
dichloromethane (10 mL). The filtrate was concentrated in
vacuo and purified quickly by chromatography [50%
EtOAc/petroleum ether (60–80 8C)] to give 2-[2-oxo-5-[3-
(trimethylsilyl)-1-propenyl]tetrahydro-1H-pyrrolyl]ethanal
(23) (330 mg, 94%) as a colorless thick oil; nmax (liquid
8.20–8.14 (2H, m), 5.89–5.71 (2H, m), 5.28–5.19 (2H, m),
4.27–4.11(1H, m), 4.04 (1H, dd, JZ13.8, 5.3 Hz), 3.27 (1H,
d, JZ13.8 Hz), 2.83–2.70 (1H, m), 2.56–2.31 (2H, m),
1.94–1.78 (2H, m); dC (50 MHz, CDCl3) 175.2 (C), 163.6
(C), 150.7 (C), 134.9 (C), 130.6 (2 CH), 123.6 (CH), 119.6
(CH2), 79.0 (CH), 63.1 (CH), 54.3 (CH), 49.0 (CH2), 33.9
(CH2), 24.8 (CH2); HRMS (EI): MC, found 316.1051.
C16H16N2O5 requires 316.1059.
film) 2946, 2623, 1707, 1666, 1548, 1451, 1251, 1156 cmK1
;
dH (200 MHz, CDCl3) 9.54 (1H, m), 5.65 (1H, dt, JZ15.0,
7.9 Hz), 5.06 (1H, dd, JZ15.0, 9.0 Hz), 4.25 (1H, d, JZ
18.4 Hz), 4.15–4.00 (1H, m), 3.82 (1H, d, JZ18.4), 2.5–2.2
(3H, m), 1.90–1.60(1H, m), 1.50(2H,d,JZ8.2 Hz), 0.02(9H,
s). To a stirred solution of 23 (130 mg, 0.54 mmol) in
dichloromethane (2 mL) was added BF3$OEt2 (0.20 mL,
1.63 mmol) at K20 8C. The mixture was stirred for 1 h and
then it was allowed to attain room temperature. After 4 h, the
mixture was poured into brine (2 mL) and extracted with
dichloromethane (15 mL). The combined organic layers were
dried (Na2SO4) and concentrated in vacuo. The residue was
purified by preparative thin layer chromatography [25%, 50%
EtOAc/petroleum ether (60–80 8C)] to afford the title
compound 24 (40 mg, 44%) contaminated with three other
diastereomers (LCMS) as a semi solid mass. Preparative
HPLC [Lichrosob (R) Si 60 (7 mm) column (Merc), (50%
EtOAc/hexaneC2% MeOH)] gave pure 24 as a white solid,
mp 100.2 8C (MeOH); Rf (EtOAc) 0.15; nmax (KBr) 3667,
3083, 2929, 1673, 1428, 1292, 1211, 1174, 1091, 931, 864,
790, 668, 574 cmK1; dH (500 MHz, D2O) 5.62 (1H, ddd, JZ
17, 10, 8 Hz, C10–H), 5.09 (1H, d, JZ17 Hz, C20–HH), 5.05
(1H, d, JZ10 Hz, C20–HH), 4.28–4.20 (1H, m, C2–H), 3.74–
3.67 (1H, m, C7a–H), 3.37 (1H, dd, JZ11.5, 8.5 Hz, C3–HH),
3.03 (1H, dd, JZ11.5, 7 Hz, C3–HH), 2.61–2.51 (1H, m, C6–
HH), 2.30–2.23 (1H, m, C6–HH), 2.15–2.10 (1H, m, C7–HH),
2.09–2.07 (1H, m, C1-H), 1.78–1.69 (1H, m, C7-HH);
dC (125 MHz, D2O) 177.7 (C, C-5), 134.7 (CH, C-10),
119.0 (CH2, C-20), 77.1 (CH, C-2), 64.6 (CH, C-7a), 57.6
(CH, C-1), 47.7 (CH2, C-3), 33.9 (CH2, C-6), 25.3 (CH2, C-7);
HRMS (FAB): MHC, found 168.1029. C9H14NO2 requires
168.1025.
4.1.12. (1S*, 2R*, 7aS*)-5-Oxo-1-vinylhexahydro-1H-
pyrrolizine-2yl 4-nitrobenzoate (27). To a stirred solution
of 24 (crude product containing three other diastereomers,
30 mg, 0.179 mmol) in dichloromethane (5 mL) was added
DMAP (11 mg, 0.09 mmol), pyridine (0.06 mL,
0.776 mmol) and 4-nitrobenzoyl chloride (109.3 mg,
0.55 mmol) and stirred for 5 h at room temperature. Then
it was poured into dichloromethane (50 mL), washed with
sodium bicarbonate solution (30 mL, sat. aq), 1 N hydro-
chloric acid (30 mL) and brine (20 mL). The organic layer
was dried (Na2SO4) and concentrated in vacuo. The crude
product was then purified by preparative thin layer
chromatography [40% EtOAc/petroleum ether (60–80 8C)]
to afford the title compound 27 (40 mg, 70.5%) as a
yellowish white solid; mp 101–102 8C [50% EtOAc/
etroleum ether (60–80 8C)]; Rf [40% EtOAc/petroleum
ether (60–80 8C)] 0.66; nmax (KBr pellet) 3071, 2959,
2896, 1727, 1684, 1605, 1524, 1461, 1404, 1352,
1279,1167, 114, 1006, 931, 871 cmK1; dH (200 MHz,
CDCl3) 8.29 (2H, d, JZ8.6 Hz), 8.15 (2H, d, JZ8.7 Hz),
5.94–5.64 (1H, m), 5.59–5.41 (1H, m), 5.38–5.19 (2H, m),
3.95–3.77 (1H, m), 3.75–3.65 (2H, m), 2.85–2.32 (4H, m),
2.05–1.70 (1H, m); dC (50 MHz, CDCl3) 175.2 (C), 164.0
(C), 150.7 (C), 134.5 (C), 133.5 (CH), 130.7 (CH), 123.5
(CH), 119.0 (CH2), 80.3 (CH), 63.2 (CH), 55.6 (CH), 46.9
(CH2), 32.8 (CH2), 24.9 (CH2); HRMS (EI): MC, found
316.1053. C16H16N2O5 requires 316.1059.
4.1.13. (7aS*)-3-Oxo-1-2,3,5,7a-tetrahydro-1H-pyrroli-
zine-7-carbaldehyde (29). To a stirred solution of olefin
26 (50 mg, 0.158 mmol) in dichloromethane (10 mL) ozone
was bubbled at K78 8C until a faint blue color persisted.
Triphenylphosphine (50 mg, 0.190 mmol, 1.2 equiv) was
then added at that temperature, and the reaction mixture was
allowed to attain room temperature. After 12 h, the mixture
was concentrated in vacuo and crude product was purified
by preparative thin layer chromatography [EtOAc] to afford
the title compound 29 (12 mg, 50%) as a white crystalline
solid; mp 106–107 8C [EtOAc/petroleum ether (60–80 8C)];
Rf (EtOAc) 0.14; nmax (CH2Cl2) 3812, 3748, 3379, 2925,
1678, 1411, 1230, 1062, 802, 658, 552 cmK1; dH (CDCl3,
200 MHz) 9.78 (1H, br s), 6.88 (1H, br s), 4.84 (1H, br s),
4.66 (1H, br d, JZ18.8 Hz), 3.87 (1H, br d, JZ18.8 Hz),
2.85–2.60 (2H, m), 2.42–2.20 (1H, m), 2.10–1.75 (1H, m);
dC (50 MHz, CDCl3) 187.0, 178.4, 146.3, 146.2, 65.0, 50.3,
33.3, 29.2; HRMS (EI): MC found 151.0629. C8H9NO2
requires 151.0633.
4.1.11. (1S*, 2S*, 7aS*)-5-Oxo-1-vinylhexahydro-1H-
pyrrolizine-2yl 4-nitrobenzoate (26). To a stirred solution
of 24 (crude product containing three other diastereomers,
120 mg, 0.718 mmol), triphenylphosphine (756.0 mg,
2.88 mmol) and 4-nitrobenzoic acid (478 mg, 2.85 mmol)
in THF (20 mL) was added slowly a solution of diethyl
azodicarboxylate (DEAD, 0.45 mL, 2.80 mmol) at 0 8C.
The resulting yellow solution was allowed to attain to room
temperature, stirred in an aluminum foil-covered flask for
30 h and then concentrated in vacuo. The resulting thick oil
was diluted with dichloromethane (30 mL), washed with
sodium bicarbonate solution (20 mL, sat. aq), brine (20 mL)
and dried (Na2SO4). Solvent was removed under reduced
pressure and the crude product was purified by column
chromatography [20%, 40% EtOAc/petroleum ether (60–
80 8C)] to afford 190 mg of solid product, which was further
purified by preparative thin layer chromatography [40%
EtOAc/petroleum ether (60–80 8C)] to give the title
compound 26 (120 mg, 53%) as a yellowish white solid;
mp 103–104 8C [EtOAc/petroleum ether (60–80 8C)]; Rf
[40% EtOAc/petroleum ether (60–80 8C)] 0.69; nmax (liquid
film) 3439, 3075, 2934, 2886, 2732, 1723, 1688, 1602,
1524, 1414, 1347, 1276, 1113, 1059, 1002, 931, 852, 772,
749, 712 cmK1; dH (200 MHz, CDCl3) 8.33–8.26 (2H, m),
4.1.14. Supinidine (8). To a stirred solution of 29 (10 mg,
0.066 mmol) in THF (5 mL) was added Red-Al (65C wet%
in toluene, 1 mL, excess) slowly at K78 8C. After 5 min the
clear solution was allowed to attain room temperature and
stirred for 0.5 h, during which the color changed from
yellow to red. The resulting solution was then heated at

1164
T. K. Sarkar et al. / Tetrahedron 61 (2005) 1155–1165
reflux for 3 h. The mixture was cooled to room temperature
and quenched with water (0.4 mL), 2 N sodium hydroxide
(0.3 mL) and water (0.6 mL) and then it was diluted with
THF (3 mL) and stirred for 5 min. The resulting solution
was filtered, concentrated and crude product was purified by
preparative thin layer chromatography [SiO2, 10/10/1
CH2Cl2 /MeOH/NH4OH] to give the title compound (8)
(7 mg, 76%) as yellow oil, mp (picrate) 123–124 8C
[ethanol] (lit.9e 124.5–125 8C); Rf (CH2Cl2: MeOH:
NH4OH, 10:10:1) 0.25; nmax (CH2Cl2) 3371, 3300, 2957,
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2004.11.
046
1613, 1455, 1338, 1193, 1087, 1050, 894, 857, 800 cmK1
;
References and notes
dH (200 MHz, CDCl3) 5.48 (1H, br s), 4.25–4.07 (3H, m),
3.86 (1H, d, JZ15 Hz), 3.30 (1H, br d, JZ15 Hz), 3.11–
3.01 (1H, m), 2.74 (1H, OH, br s), 2.57–2.45 (1H, m), 2.03–
1.88 (1H, m), 1.80–1.67 (2H, m), 1.57–1.41 (1H, m); dC
(50 MHz, CDCl3) 144.2, 120.7, 70.9, 61.8, 59.6, 56.4, 30.2,
25.7.
1. For reviews see: (a) Despinoy, X. L. M.; McNab, H.
Tetrahedron 2000, 56, 6359. (b) Liddell, J. R. Nat. Prod.
Rep. 1999, 16, 499. (c) Casiraghi, G.; Zanardi, F.; Rassu, G.;
Pinna, L. Org. Prep. Proc. Int. 1996, 28, 643. (d) Liddell, J. R.
Nat. Prod. Rep. 1996, 13, 187. (e) Robins, D. J. Nat. Prod. Rep.
1995, 12, 413. (f) Robins, D. J. Nat. Prod. Rep. 1992, 9, 313.
2. Langkopf, E.; Schinzer, D. Chem. Rev. 1995, 95, 1375.
3. (a) Hiemstra, H.; Sno, M. H. A. M.; Vijn, R. J.; Speckamp,
W. N. J. Org. Chem. 1985, 50, 4014. (b) Hiemstra, H.;
Speckamp, W. N. Tetrahedron Lett. 1983, 24, 1407.
4.1.15. Macronecine (9). To a stirred solution of olefin 26
(80 mg, 0.253 mmol) in dichloromethane (10 mL) ozone
was bubbled at K78 8C until a faint blue color persisted.
Then solvent was removed at K30 8C; THF (8 mL) was
added to it at K78 8C and was followed by Red-Al (65C
wet% in toluene, 5 mL, excess) and the cold bath was
allowed to attain room temperature. The resulting reaction
mixture was stirred at room temperature for 0.5 h during
which time the solution color changed from yellow to red.
The red solution was heated to reflux for 3 h. The mixture
was cooled to room temperature, quenched with water
(0.6 mL), 2 N sodium hydroxide (0.5 mL) and water
(1 mL). Then the reaction mixture was diluted with THF
(3 mL) and stirred for 5 min. The resulting solution was
filtered, concentrated to 2 mL and the crude product was
purified by preparative thin layer chromatography [SiO2,
10/10/1 CH2Cl2/MeOH/NH4OH as developing solvent] to
give the title compound (9) (13 mg, 33%) as a white solid,
mp 107–108 8C (lit.10a 109–110 8C); Rf (10/10/1 CH2Cl2/
MeOH /NH4OH,) 0.18; nmax (CH2Cl2) 3356, 2949, 1452,
1319, 1091, 1037, 764, 613, 564 cmK1; dH (CDCl3,
200 MHz) 4.54–4.36 (1H, m), 4.11 (2H, br s), 3.85–3.71
(2H, m), 3.60–3.39 (1H, m), 3.18 (1H, d, JZ11 Hz), 3.04–
2.80 (1H, m), 2.73–2.40 (2H, m), 2.04–1.63 (4H, m), 1.63–
1.39 (1H, m); dC (50 MHz, CDCl3) 75.1, 63.9, 63.0, 60.4,
54.9, 52.5, 31.2, 25.4; HRMS (ES): MHC found 158.1175.
C8H16NO2 requires 158.1175.
4. (a) Sarkar, T. K.; Ghosh, S. K.; Subba Rao, P. S. V.; Satapathi,
T. K. Tetrahedron Lett. 1990, 31, 3461. (b) Sarkar, T. K.;
Ghorai, B. K.; Nandy, S. K.; Mukherjee, B. Tetrahedron Lett.
1994, 35, 6903. (c) Sarkar, T. K.; Ghosh, S. K.; Subba Rao,
P. S. V.; Mamdapur, V. R. Tetrahedron Lett. 1990, 31, 3456.
(d) Sarkar, T. K.; Ghosh, S. K.; Subba Rao, P. S. V.;
Mamdapur, V. R. Tetrahedron 1992, 48, 6897. (e) Sarkar,
T. K.; Ghorai, B. K.; Banerji, A. Tetrahedron Lett. 1994, 35,
6907. (f) Sarkar, T. K.; Ghorai, B. K.; Nandy, S. K.;
Mukherjee, B.; Banerji, A. J. Org. Chem. 1997, 62, 6006.
(g) Sarkar, T. K.; Mukherjee, B.; Ghosh, S. K. Tetrahedron
1998, 54, 3243. (h) Sarkar, T. K.; Gangopadhyay, P.; Ghorai,
B. K.; Nandy, S. K.; Fang, J-M. Tetrahedron Lett. 1998, 39,
8365.
5. For the use of this terminology in ene reactions, see: (a)
Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021. (b)
Sarkar, T. K. J. Ind. Inst. Sci. 1994, 74, 329.
6. (a) Vedejs, E.; Meier, G. P. Tetrahedron Lett. 1979, 20, 4185.
(b) Scartozzi, M.; Grondin, R.; Leblanc, Y. Tetrahedron Lett.
1992, 33, 5717.
7. (a) Kraus, G. A.; Neuenschwander, K. Tetrahedron Lett. 1980,
21, 3841. (b) Nagao, Y.; Dai, W. M.; Ochiai, M.; Shiro, M.
Tetrahedron 1990, 46, 6361. (c) Keusenkothen, P. F.; Smith,
M. B. J. Chem. Soc., Perkin Trans. 1 1994, 2485. (d) Tsai,
Y.-M.; Ke, B.-W. J. Chin. Chem. Soc. 1993, 40, 641. (e) Tsai,
Y. M.; Ke, B.-W.; Yang, C. T.; Lin, C.-H. Tetrahedron Lett.
1992, 33, 7895.
8. For a preliminary communication, see: Sarkar, T. K.; Gang-
opadhyay, P.; Satapathi, T. K. Tetrahedron Lett. 1999, 40, 395.
9. For synthesis of (G)-supinidine, see: (a) Tsai, Y.-M.; Ke,
B.-W.; Yang, C.-T.; Lin, C.-H. Tetrahedron Lett. 1992, 33,
7895. (b) Keck, G. E.; Cressman, E. N. K.; Enholm, E. J.
J. Org. Chem. 1989, 54, 4345. (c) Pearson, W. H. Tetrahedron
Lett. 1985, 26, 3527. (d) Hudlicky, T.; Frazier, J. O.; Kwart,
L. D. Tetrahedron Lett. 1985, 26, 3523. (e) Burnett, D. A.;
Choi, J.-K.; Hart, D. J.; Tsai, Y.-M. J. Am. Chem. Soc. 1984,
106, 8201. (f) Kametani, T.; Higashiyama, K.; Otomasu, H.;
Honda, T. Heterocycles 1984, 22, 729. (g) Chamberlin, A. R.;
Nguyen, H. D.; Chung, J. Y. L. J. Org. Chem. 1984, 49, 1682.
(h) Hart, D. J.; Yang, T.-K. Tetrahedron Lett. 1982, 23, 2761.
(i) Chamberlin, A. R.; Chung, J. Y. L. Tetrahedron Lett. 1982,
Acknowledgements
Financial support from DST, Government of India is
gratefully acknowledged. A. H. and N. P. thank CSIR,
Government of India for a Senior Research Fellowship.
Z. S. acknowledges support from the Japan Society for the
Promotion of Science. We thank Professor S. E. Denmark
for providing us with copies of 1H and 13C NMR spectra of
(K)-macronecine. We also thank Professor D. Hart for
sending us the copy of 1H NMR of (G)-supinidine.
Professor D. L. J. Clive is thanked for help with X-ray
crystallographic work. Dr. S. K. Ghosh (BARC, India) is
especially thanked for continued help.

T. K. Sarkar et al. / Tetrahedron 61 (2005) 1155–1165
1165
23, 2619. (j) Robins, D.; Sakdarat, S. J. Chem. Soc. Perkin
Trans. 1 1979, 1734. (k) Tufariello, J. J.; Tette, J. P. J. Org.
Chem. 1975, 40, 3866. (l) See also Ref. 7(d). For synthesis of
(K)-supinidine, see: (m) Boynton, C. M.; Hewson, A. T.;
Mitchell, D. J. Chem. Soc., Perkin Trans. 1 2000, 3599. (n)
Andersson, P. G.; Baeckvall, J. E. J. Am. Chem. Soc. 1992,
114, 8696. (o) Takahata, H.; Banba, Y.; Momose, T.
Tetrahedron 1991, 47, 7635. (p) Nagao, Y.; Dai, W. M.;
Ochiai, M.; Shiro, M. Tetrahedron 1990, 46, 6361. (q) Nagao,
Y.; Dai, W. M.; Ochiai, M.; Shiro, M. Tennen Yuki Kagobutsu
Toronkai Koen Yoshishu 1988, 30, 468. (r) Nagao, Y.; Dai,
W. M.; Ochiai, M. Tetrahedron Lett. 1988, 29, 6133. (s)
Robins, D.; Sakdarat, S. J. Chem. Soc. Perkin Trans. 1 1980,
909.
Speckamp, W. N. Tetrahedron Lett. 1988, 29, 6975. (b) Rutjes,
F. P. J. T.; Teerhuis, N. M.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron 1993, 49, 8605.
15. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.;
Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;
Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.;
Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford,
S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B.
B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.;
Replogle, E. S.; Pople, J.A. Gaussian 98 revision A.5:
Gaussian Inc., Pittsburgh, PA, 1998, USA.
10. For synthesis of (G)-macronecine, see: (a) Aasen, A. J.;
Culvenor, C. C. J. J. Org. Chem. 1969, 34, 4143. (b) Aasen,
A. J.; Culvenor, C. C. J. Chem. Commun. 1969, 1, 34. For
synthesis of (K)-macronecine, see: (c) Ha, D.-C.; Ahn, J.-B.;
Kwon, Y.-E. Bull. Kr. Chem. Soc. 1998, 19, 514. (d) Denmark,
S. E.; Hurd, A. R. J. Org. Chem. 1998, 63, 3045. (e) Ito, H.;
Ikeuchi, Y.; Taguchi, T.; Hanzawa, Y.; Shiro, M. J. Am. Chem.
Soc. 1994, 116, 5469.
16. Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97,
2063.
17. Sisko, J.; Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1993, 58,
4945.
11. (a) Sarkar, T. K.; Ghosh, S. K. Tetrahedron Lett. 1987, 28,
2061. (b) Sarkar, T. K.; Ghosh, S. K.; Satapathi, T. K.
Tetrahedron 1990, 46, 1885.
18. Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112,
7050.
12. Fetizon, M.; Golfier, M.; Milcent, R.; Papadakis, I.
Tetrahedron 1975, 31, 165.
19. Asao, K.; Iio, H.; Tokoroyama, T. Tetrahedron Lett. 1989, 30,
6397.
13. Attenburrow, J.; Cameron, A. F. B.; Chapman, J. H.; Evans,
R. M.; Hems, B. A.; Jansen, A. B. A.; Walker, T. J. Chem. Soc.
1952, 1094.
20. Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994,
59, 234.
21. Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J. Am.
Chem. Soc. 1996, 118, 8266.
14. (a) Rutjes, F. P. J. T.; Hiemstra, H.; Mooiweer, H. H.;