Synthesis of spirocycles via ring closing metathesis of heterocycles carrying gem-diallyl substituents obtained via ring opening of (halomethyl)cyclopropanes with allyltributyltin

Article abstract of DOI:10.1039/b300314k

In the presence of allyl tri-n-butyltin-AlBN, cyclopropylmethyl bromides/xanthates undergo ring-opening reaction with concomitant formation of geminal diallyl derivatives in good yields. The ring closing metathesis reactions on geminal diallyl derivatives with Grubbs' catalyst provided spirocyclopentenyl products. Combination of these two methodologies has been applied to the synthesis of mono-, bis-cyclopentyl-carbohydrates as well as spirocyclopentylproline derivatives.

Full text of DOI:10.1039/b300314k

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Synthesis of spirocycles via ring closing metathesis of heterocycles
carrying gem-diallyl substituents obtained via ring opening of
(halomethyl)cyclopropanes with allyltributyltin
Mukund K. Gurjar,*a Somu V. Ravindranadh,a Kuppusamy Sankar,a Sukhen Karmakar,a
Joseph Cheriana and Mukund S. Chorghadeb
a National Chemical Laboratory, Pune, 411 008, India
b Chorghade Enterprises, 14 Carlson Circle, Natick, MA 01760, USA
Received 9th January 2003, Accepted 10th February 2003
First published as an Advance Article on the web 20th March 2003
In the presence of allyl tri-n-butyltin–AIBN, cyclopropylmethyl bromides/xanthates undergo ring-opening reaction
with concomitant formation of geminal diallyl derivatives in good yields. The ring closing metathesis reactions
on geminal diallyl derivatives with Grubbs’ catalyst provided spirocyclopentenyl products. Combination of these
two methodologies has been applied to the synthesis of mono-, bis-cyclopentyl-carbohydrates as well as
spirocyclopentylproline derivatives.
Introduction
Interest in developing new protocols that can give rise to spiro
derivatives has risen considerably, primarily due to the inherent
rigidity displayed by the spiro functionality.1 Molecules con-
taining a spiro group find innumerable applications particularly
in peptides,2 nucleosides3 and carbohydrates.4 The synthesis of
spiro derivatives was difficult until the advent of novel catalysts
by Schrock5 and Grubbs6 used in ring closing metathesis
(RCM). The RCM based approaches7 have made the introduc-
tion of a spiro group in the structural framework of an organic
molecule an easy proposition.8 For instance, gem-diallyl con-
taining substrates undergo RCM to produce spirocyclopentene
derivatives.9
The synthesis of gem-diallyl derivatives can be realized by
double alkylation of an active methylene group.10 We realized
that the introduction of a gem-diallyl functionality on a carbon
Scheme 1
atom not activated by any electron-withdrawing group, is a
difficult proposition. The problem becomes insurmountable
when a carbohydrate precursor is involved because base cata-
lysed reactions lead to tandem elimination of water molecules,
resulting in the formation of a mixture of compounds.
Some years ago, we observed interesting reactions11 with
carbohydrate cyclopropyl precursors. For example, the radical
mediated cyclopropyl scission of the spirocyclopropyl bromide
1 with n-Bu3SnH gave the C-allyl derivative 2 in a stereo-
controlled fashion. On the other hand, hydrogenation of the
cyclopropyl-aldehyde derivative 3 over Pd/C provided 4 with a
quaternary chiral center (Scheme 1).
and catalytic AIBN to give the gem-diallyl derivative 5 in 76%
yield (Scheme 2). The structure of 5 was proven, beyond any
doubt, by 1H, 13C, mass spectroscopy and elemental analysis.
We were particularly impressed by the radical ring opening
reaction as described above because we envisaged that in situ
quenching of the homoallyl radical formed (Fig. 1) with allyl-
tri-n-butyltin12 should lead to the formation of a gem-diallyl
derivative. This study forms the main objective of this
manuscript.13
Scheme 2 Reagents and conditions: (a) allyltri-n-butyltin, C6H6, AIBN,
80 ЊC, 76%.
In order to establish the versatility of this reaction, a number
of spirocyclopropylmethyl bromides were prepared (Table 1),
according to the general strategy depicted in Scheme 3. The
carbonyl derivative was subjected to the Wittig reaction with
Ph P᎐CHCO Et in refluxing benzene. For entries 1–3, the
᎐
3
2
resulting unsaturated ester was cyclopropanated14 with Me3-
S(O)I–NaH in DMSO and then reduced with DIBAL-H in
CH2Cl2 at Ϫ78 ЊC to afford the cyclopropylmethanol deriv-
atives. For entry 4, the unsaturated ester was first reduced with
DIBAL-H in CH2Cl2 at Ϫ78 ЊC to provide an allylic alcohol
which was subsequently cyclopropanated (entry 5 as well)
using the modified Simmons–Smith method15 by using Et2Zn–
CH2I2 in CH2Cl2 at Ϫ20 ЊC. Conversion of the cyclopropyl-
Fig. 1
Results and discussion
The requisite precursor 1, earlier reported11 from our labora-
tory, was treated with allyltri-n-butyltin in refluxing benzene
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 6 6 – 1 3 7 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Scheme 3 Reagents and conditions: (a) PPh3᎐᎐CHCO2Et, C6H6, 80 ЊC; (b) Me3SOI, DMSO, NaH; (c) DIBAL-H, CH2Cl2, Ϫ78 ЊC; (d) CBr4, PPh3,
CH2Cl2, py or NaH, CS2, MeI, THF; (e) Et2Zn, CH2I2, CH2Cl2, Ϫ20 ЊC.
Table 1 Synthesis of gem-diallyl compounds from (halomethyl)cyclopropanes
Entry
1
Substrate
Product
Yield (%)
76
2
44
3
4
81
60
5
6
53
62
methanol to the corresponding cyclopropylmethyl bromide was
accomplished with CBr4–Ph3P–pyridine in CH2Cl2 at room
temperature.
The preparation of the xanthate derivative (entry 6) from the
cyclopropylmethanol was accomplished using a well-defined
protocol using CS2–NaH–MeI in THF. The bromoxanthate
derivatives (entries 1–6) were treated with allyltri-n-butyltin–
AIBN in refluxing benzene to provide the gem-diallyl product
in good yields. The diallyl derivatives were fully characterized
by spectroscopic methods.
Application of this concept to install two different allylic
functionalities on the same carbon was also explored when
methallyltri-n-butyltin was treated with 1 to give rise to 3-
deoxy-3-C-allyl-3-C-methallyl derivative 20 (Scheme 4). The
absolute stereochemistry of 20 was established by NOE studies
as indicated in Fig. 2.
Scheme 4 Reagents and conditions; (a) methallyltributyltin, C6H6,
AIBN, 80 ЊC, 12 h, 52%.
was to perform ring closing metathesis reactions7 in order to
convert them to novel spirocyclopentyl derivatives. For
instance, compound 5 was treated with Grubbs’ catalyst in
CH2Cl2 at room temperature to provide the spirocyclopentenyl
derivative 21 whose structure was supported by spectroscopic
data. Interestingly the RCM reaction of 20 gave 22 in 75% yield
(Scheme 5).
Having in hand the gem-diallyl derivatives, our next target
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 6 6 – 1 3 7 3
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Fig. 2
Scheme 7 Reagents and conditions; (a) (EtO)2P(O)CH2COOEt, NaH,
THF, 0 ЊC
rt, 80%; (b) DIBAL-H, CH2Cl2, Ϫ78 ЊC, 0.5 h, 88%;
(c) Et2Zn, CH2I2, CH2Cl2, Ϫ20 ЊC, 14 h, 60%; (d) NaH, CS2, MeI, THF,
0.5 h, 90%; (e) allyltributyltin, C6H6, AIBN, 80 ЊC, 34%; (f ) Grubbs’
catalyst, CH2Cl2, rt, 4 h, 88%; (g) 10% Pd/C–H2, MeOH, 82%.
In a similar manner, the other isomer (24) was also converted
to the diallyl derivative 29 and the bis-spiro-derivative 30
(Scheme 8).
Scheme 5 Reagents and conditions; (a) Grubbs’ catalyst, CH2Cl2, rt,
80%; (b) Grubbs’ catalyst, CH2Cl2, rt, 75%.
Our next plan was to adopt an iterative approach of the
above two strategies and prepare some novel bis-spirocyclo-
pentyl derivatives of carbohydrates. For this endeavor, com-
pound 21was subjected to hydroboration–oxidation reaction,
which led to the formation of a complex mixture of dia-
stereomers (Scheme 6). The mixture as such was oxidized under
Swern oxidation conditions to give two products (23 and 24),
separated by silica gel chromatography. The correct assignment
of the structures of 234 and 24 was performed by NOE experi-
ments (Fig. 3).
Scheme 8
Spiroproline derivatives are of interest in biological studies
with potential applications as an inhibitor and mechanistic
probe of prolyl-4-hydroxylase.20 In pursuit of the development
of potent inhibitors of angiotensin converting enzyme (ACE),
lipophilic and sterically hindered spiroproline derivatives have
been substituted in the structural framework of peptides.
In addition, spiroprolines could offer interesting scaffold pre-
cursors, particularly in the synthesis of combinatorial libraries
of peptides. The earlier synthetic efforts aimed at spiroproline
analogues involved building the proline nucleus on the struc-
tural backbone of the alicyclic system followed by resolution.
We decided to try to expand the potential of our synthesis of
spirocyclic compounds to proline derivatives, with the hitherto
unknown 2-azaspiro[4.4]nonanecarboxylic acid derivative 39 as
the target.
Scheme 6 Reagents and conditions; (a) BH3ؒSMe2, NaOAc, 30% H2O2,
THF, 0 ЊC, 1 h; (b) (COCl)2, Me2SO, CH2Cl2, Et3N, Ϫ78 ЊC, 2 h, 56%.
The known trans-N-(p-toluenesulfonyl)-4-hydroxy--prolinol
(31)21 was converted into 4,4Ј-cyclopentyl--proline derivative
by essentially following the route already discussed and shown
in Scheme 9. The purity of the final product was determined by
chiral HPLC (95%). The structure of 39 was supported by its
1H-NMR, 13C-NMR, and mass spectral data.
Conclusions
We have derived a simple protocol to introduce a gem-diallyl
group. The RCM reaction provided a strategy for the prepar-
ation of spirocyclopentyl derivatives of sugars and -proline.
Fig. 3
Compound 23 was subjected to the following sequence of
reactions: Wittig olefination with (EtO)2P(O)CH2CO2Et, reduc-
tion of ester group with DIBAL-H to obtain 25, Simmons–
Smith cyclopropanation and the corresponding xanthate
preparation with NaH–CS2–MeI in THF (Scheme 7).
The radical induced diallylation of xanthate gave 26 whose
RCM reaction and catalytic hydrogenation produced the bis-
spiro-derivative 28.
Experimental
NMR spectra were recorded on Bruker AC 200, MSL 300 or
DRX 500 MHz instruments in CDCl3 or acetone-D6 using
TMS as internal standard. IR spectra were recorded on a Per-
kin–Elmer 16 PC–FT IR spectrometer. Electron impact mass
spectra (EIMS) were recorded on a Finnigan MAT–1020.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 6 6 – 1 3 7 3
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under N2 followed by CH3I (5.0 eq.). After 30 min the reaction
was quenched with saturated aq. NH4Cl, extracted with CH2Cl2
and washed with water, brine and dried. The crude product was
purified by column chromatography on silica gel.
General procedure for diallylation
A solution of the cyclopropylmethyl bromide/xanthate, allyltri-
n-butyltin (2.0 eq.) and AIBN (cat.) in benzene was degassed
and refluxed under argon for 12 h. The reaction mixture was
concentrated, diluted with ether and stirred with an aq. solu-
tion of KF for 3 h and then filtered. The filtrate was washed
with water, dried (Na2SO4), concentrated and the residue puri-
fied by column chromatography on silica gel.
General procedure for RCM
A solution of the gem-diallyl compound and Grubbs’ catalyst
(5 mol%) in CH2Cl2 was stirred at rt for 3 h. Solvent was
removed and the crude product purified by column chromato-
graphy on silica gel.
3-Deoxy-1,2:5,6-di-O-isopropylidene-3,3-C-diallyl-ꢀ-D-ribo-
hexofuranose (5)
Scheme 9 Reagents and conditions: (a) TBDPSCl, imidazole, DMF, rt,
overnight; (b) PDC, 4 Å mol sieves, CH2Cl2, 4 h, 60%; (c) Ph3P᎐
᎐
Following the general procedure for diallylation, compound 111
(0.19 g, 0.52 mmol), allyltri-n-butyltin (0.35 mL, 1.0 mmol) and
AIBN (10 mg) in benzene (6 mL) gave compound 5 (0.13 g,
76%); [α]D ϩ 36 (c 2.1 in CHCl3); δH (300 MHz; CDCl3) 1.27,
1.33, 1.45, 1.50 (4 s, 12 H), 2.15–2.45 (m, 4 H), 3.72 (m, 1H),
3.78 (m, 1 H), 4.09 (m, 2 H), 4.24 (d, 1 H, J 3.4 Hz), 5.03 (m,
4 H), 5.57 (d, 1 H, J 3.4 Hz), 5.90 (m, 2 H); δC (50 MHz; CDCl3)
25.5, 26.4, 26.8, 27.1, 36.1, 37.0, 50.6, 69.0, 73.5, 85.2, 86.0,
104.4, 109.5, 111.3, 117.6, 134.8, 135.5 (Found: C, 66.46; H,
8.92. C18H28O5 requires C, 66.64; H, 8.70%).
CHCO2Et, C6H6, 80 ЊC, 24 h; (d) DIBAL-H, CH2Cl2, Ϫ78 ЊC, 45 min,
85%; (e) Et2Zn, CH2I2, CH2Cl2, overnight, 78%; (f ) Ph3P, CBr4, CH2Cl2,
pyridine, 0 ЊC, 30 min.; (g) allyltri-n-butyltin, AIBN, C6H6, 8 h, 66%;
(h) Grubbs’ catalyst, CH2Cl2, rt, 1.5 h, 96%; (i) TBAF, THF, rt, 2 h,
93%; (j) Pd/C, H2, MeOH, 3 h, 96%; (k) RuCl3ؒ(H2O)n, NaIO4, CCI4,
CH3CN, H2O, rt, 2 h, 77%.
Microanalysis was carried out on a Carlo–Elba elemental
analyzer. Melting points were measured on a Buchi B-540
apparatus and are uncorrected. Optical rotations were recorded
on a JASCO DIP-1020 digital polarimeter. Solvents were dis-
tilled over drying agents under argon or nitrogen. All reactions
were monitored by thin-layer chromatography carried out on
0.25 m E. Merck silica gel plates (60F–254) using UV light as
visualizing agent and anisaldehyde in ethanol as developing
agent. Silica gel (60–120) was purchased from Acme Chemical
Company.
Methyl 3-O-benzyl-5,6-O-cyclohexylidene-2-deoxy-2,2-C-
[(hydroxymethyl)ethylene]-ꢁ-D-arabino-hexofuranoside (8)
A mixture of compound 716 (3.6 g, 10.0 mmol) and PPh ᎐
᎐
3
CHCO2Et (5.2 g, 15.0 mmol) was refluxed in benzene (20 mL)
for 4 h and concentrated. The residue was purified by passing
through a bed of silica gel (light petroleum–EtOAc 20 : 1) to
afford the unsaturated ester (3.2 g) which was treated with
Me3S(O)I (3.2 g, 14.8 mmol) and NaH (0.6 g, 14.8 mmol) in
dry DMSO (10 ml), as per general procedure, to give the
cyclopropyl derivative (1.3 g). It was dissolved in dry CH2Cl2
(10 mL) and cooled to Ϫ78 ЊC. DIBAL-H solution (2.0 molar
solution, 3.7 mL, 7.4 mmol) was introduced, stirred for 1 h,
and treated with saturated solution of sodium potassium
tartrate. The organic layer was separated, dried (Na2SO4) and
evaporated. The resulting residue was purified on silica gel with
ethyl acetate–light petroleum (2 : 3) to give methyl 3-O-benzyl-
5,6-cyclohexylidene-2-deoxy-2,2-[(hydroxymethyl)ethylene]-β-
-arabino-hexofuranoside 8 (0.93 g, 23%); [α]D ϩ 82 (c 0.5 in
CHCl3); δH (200 MHz; CDCl3) 0.75 (dd, 1 H, J 5.8, 8.8 Hz),
0.9 (t, 1 H, J 5.8 Hz), 1.39–1.75 (m, 11 H), 2.31 (br s, 1 H), 3.26
(dd, 1 H, J 8.8, 11.7 Hz), 3.34 (s, 3 H), 3.59 (d, 1 H, J 3.8 Hz),
3.71 (dd, 1 H, J 5.9, 11.7 Hz), 3.97–4.21 (m, 4 H), 4.38 (m, 1 H),
4.64 (d, 1 H, J 11.6 Hz), 4.79 (d, 1 H, J 11.6 Hz), 4.86 (s, 1 H),
7.32 (m, 5 H) (Found: C, 68.40; H, 7.68. C23H32O6 requires C,
68.29; H, 7.97%).
General procedure for cyclopropanation with Me3S(O)I
To the mixture of Me3S(O)I (2.0 eq.) and NaH (2.0 eq.) in
DMSO at 0 ЊC was added a solution of α,β-unsaturated ester in
dry DMSO under argon. After 2 h, the reaction was quenched
with water and extracted with ether, washed with brine, dried
and concentrated. The residue was purified by column chrom-
atography on silica gel.
General procedure for cyclopropanation with Et2Zn
To a solution of the allylic alcohol in dry CH2Cl2 under argon
at Ϫ20 ЊC was added a 1 M solution of Et2Zn (3.0 eq.) and
CH2I2 (6.0 eq.). After 12 h, the reaction was quenched with ice
and partitioned between CH2Cl2 and water. The organic layer
was dried, concentrated and the residue passed through a short
column of silica gel.
General procedure for the preparation of cyclopropylmethyl
bromides
To the stirred solution of the cyclopropylmethanol in dry
CH2Cl2 at rt was added pyridine, triphenylphosphine (2.2 eq.)
and CBr4 (1.1 eq.) successively. After 30 min solvent was
removed in vacuo and the residue was passed through a short
bed of silica gel.
Methyl 3-O-benzyl-5,6-O-cyclohexylidene-2-deoxy-2,2-C-dial-
lyl-ꢁ-D-arabino-hexofuranoside (9)
Following the general procedure, compound
8 (1.6 g,
4.0 mmol), PPh3 (2.3 g, 8.8 mmol), CBr4 (1.5 g, 4.4 mmol)
and pyridine (0.3 mL) gave the corresponding cyclopropyl-
methylbromide (purified by passing through a short bed of
silica gel, eluting with ethyl acetate-light petroleum-1:9, 1.3 g).
Following the general procedure for diallylation, the cyclo-
General procedure for the preparation of xanthates
CS2 (4.0 eq.) was added to a previously stirred solution of the
cyclopropylmethanol and NaH (2.0 eq.) in dry THF at 0 ЊC
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 6 6 – 1 3 7 3
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propylmethyl bromide (1.3 g, 2.8 mmol), allyltri-n-butyltin
(1.8 ml, 5.6 mmol) and AIBN (10 mg) gave 9 (0.75 g, 44%);
[α]D ϩ 66 (c 0.41 in CHCl3); δH (500 MHz; CDCl3) 1.58 (m,
10 H), 2.05–2.40 (m, 4 H), 3.31 (s, 3 H), 3.90 (d, 1 H, J 4.4 Hz),
3.95 (dd, 1 H, J 5.9, 8.3 Hz), 4.08 (m, 2 H), 4.31 (m, 1 H), 4.49
(d, 1 H, J 11.0 Hz), 4.71 (s, 1 H), 4.74 (d, 1 H, J 11.0 Hz), 5.06
(m, 4 H), 5.77 (m, 2 H), 7.31 (m, 5 H); δC (125 MHz; CDCl3)
23.9, 24.1, 25.2, 35.0, 35.3, 36.5, 52.6, 55.9, 67.2, 73.2, 74.2,
80.4, 84.4, 109.2, 109.6, 117.5, 117.7, 127.6–128.3, 135.0, 138.5
(Found: C, 72.73; H, 8.44. C26H36O5 requires C, 72.87; H,
8.47%).
1.6 mmol) and pyridine (0.5 mL) gave the corresponding cyclo-
propylmethyl bromide (0.27 g). As per general procedure, the
cyclopropylmethyl bromide (0.27 g, 1.2 mmol), allyltri-n-butyl-
tin (0.7mL, 2.4 mmol) and AIBN (20 mg) gave 15 (0.17 g, 60%);
δH (200 MHz; CDCl3) 1.10–1.80 (m, 8 H), 1.92–2.30 (m, 4 H),
2.94 (dd, 1 H, J 3.4, 7.8 Hz), 3.27 (s, 3 H), 4.94 (m, 4 H), 5.77
(m, 2 H); δC (50 MHz; CDCl3) 21.0, 22.9, 24.1, 31.4, 36.8, 39.8,
40.9, 56.3, 82.3, 117.0, 117.2, 135.1; MS (EI) m/z 194 (Mϩ)
(Found: C, 80.62; H, 11.53. C13H22O requires C, 80.35; H,
11.41%).
{2-(Benzyloxymethyl)cyclopropyl}methanol (17)
Cyclopropanation of 1619 (1.4 g, 7.8 mmol) was achieved by
following the general procedure using Et2Zn (1 M solution,
23.5 mL, 23.5 mmol) and CH2I2 (3.8 mL, 47.2 mmol) in CH2Cl2
(50 mL) at Ϫ20 ЊC to yield 17 (0.79 g, 52%); δH (300 MHz;
CDCl3) 0.20 (dd, 1 H, J 2.9, 7.0 Hz), 0.8 (m, 1 H), 1.33 (m, 2 H),
2.96 (s, 1 H), 3.14 (m, 2 H), 3.90 (m, 2 H), 4.55 (m, 2 H), 7.33
(m, 5 H); δc (50 MHz; CDCl3) 8.6, 14.8, 18.5, 62.9, 70.7, 73.1,
127.9, 128.5, 137.5; MS (EI) m/z 161 (Mϩ Ϫ CH2OH), 101 (Mϩ
Ϫ OBn).
(E )-5-O-(tert-Butyldiphenylsilyl)-3-deoxy-1,2-O-isopropylidene-
3,3-C-[(hydroxymethyl)ethylene]-ꢀ-D-threo-pentofuranose (11)
Cyclopropanation of 1017 (3.5 g, 7.0 mmol) was carried out as
per the general procedure using NaH (0.56 g, 14.1 mmol) and
Me3S(O)I (3.1 g, 14.1 mmol) in DMSO (10 mL). The cyclo-
propanated product (2.1 g, 4.2 mmol) was reduced with
DIBAL-H (2 M solution, 4.7 mL, 9.4 mmol) at Ϫ78 ЊC as
reported before to obtain 11 (1.6 g, 48%); [α]D ϩ 11.1 (c 2.1in
CHCl3); δH (300 MHz; CDCl3) 0.5 (t, 1H, J 5.1 Hz), 0.97 (s,
9H), 1.08 (m, 2H), 1.26, 1.52 (2s, 6H), 3.16 (t, 1H, J 11.4 Hz),
3.29 (dd, 1H, J 6.2, 10.6 Hz), 3.56 (dd, 1H, J 4.7, 10.6 Hz), 4.36
(m, 2H), 5.79 (d, 1H, J 3.6 Hz), 7.40 (m, 5H), 7.65 (m, 5H);
δC (75 MHz; CDCl3) 12.5, 19.1, 20.7, 26.6, 26.8, 27.1, 33.8, 63.5,
65.1, 78.5, 86.4, 104.6, 111.7, 127.7, 129.8, 133.0, 135.6; MS
(EI) m/z 255 (Mϩ Ϫ OtBuSiPh2) (Found: C, 68.96; H, 7.87.
C27H36O5Si requires C, 69.20; H, 7.74%).
2-Allylpent-4-enyl benzyl ether (18)
Compound 17 (0.4 g, 2.1 mmol) was treated with PPh3 (1.2 g,
4.6 mmol), CBr4 (0.76 g, 2.3 mmol) and pyridine (1.5 mL) in
CH2Cl2 (10 mL) as per the general procedure for bromination.
The resulting cyclopropylmethyl bromide derivative (0.4 g,
1.6 mmol) was reacted with allyltri-n-butyltin (1.0 mL, 3.2
mmol) according to the general procedure for diallylation, to
give 18 (0.24 g, 53%); δH (200 MHz; CDCl3) 1.76 (m, 1 H), 2.10
(m, 4 H), 3.33 (dd, 2 H, J 5.9, 11.2 Hz), 4.46 (d, 2 H, J 11.7 Hz),
5.00 (m, 4 H), 5.73 (m, 2 H), 7.26 (m, 5 H); δC (50 MHz; CDCl3)
35.4, 38.3, 72.4, 73.1, 116.3, 127.5, 128.3, 136.7; MS (EI)
m/z 216 (Mϩ) (Found: C, 83.35; H, 9.47. C15H20O requires C,
83.29; H, 9.32%).
5-O-(tert-Butyldiphenylsilyl)-3-deoxy-3,3-C-diallyl-1,2-O-iso-
propylidene-ꢀ-D-threo-pentofuranose (12)
As per the general procedure, 11 (0.6 g, 1.3 mmol) was con-
verted to the corresponding cyclopropylmethyl bromide using
Ph3P (0.7 g, 2.8 mmol), CBr4 (0.5 g, 1.4 mmol) and pyridine
(0.5 mL) in CH2Cl2 (25 mL). The cyclopropylmethyl bromide
thus obtained (0.61 g, 1.2 mmol) was treated with allyltri-n-
butyltin (0.74 mL, 2.4 mmol) and AIBN (5 mg) by following the
general procedure for diallylation, to afford 12 (0.45 g, 81%);
[α]D ϩ 22 (c 1.0 in CHCl3); δH (200 MHz; CDCl3) 1.08 (s,
9 H), 1.29 (s, 3 H), 1.54 (s, 3 H), 1.87–2.54 (m, 4 H), 3.82 (m,
2 H), 4.03 (t, 1 H, J 6.5 Hz), 4.25 (d, 1 H, J 3.4 Hz), 5.0 (m, 4 H),
5.70 (d, 1 H, J 3.4 Hz), 5.80 (m, 2 H), 7.35–7.77 (m, 10 H);
δC (50 MHz; CDCl3) 19.3, 26.5, 27.0, 35.6, 36.5, 50.0, 62.9, 84.7,
85.6, 104.2, 111.0, 117.7, 127.8, 129.8, 133.3–135.7; MS (EI)
m/z 257 (Mϩ Ϫ t-BuSiPh2) (Found: C, 73.19; H, 8.28. C30H40-
O4Si requires C, 73.13; H, 8.18%).
3-Deoxy-1,2:5,6-di-O-isopropylidene-3,3-C-[S-methyldithio-
carbonylmethylethylene]-ꢀ-D-ribo-hexofuranose (19)
Following the general procedure for the preparation of
xanthate, 6 (0.22 g, 0.73 mmol), NaH (0.059 g, 1.5 mmol) and
CH3I (0.3 ml, 4.9 mmol) gave compound 19 (0.26 g, 92%);
[α]D ϩ 97 (c 1.0 in CHCl3); δH (200 MHz; CDCl3) 0.71 (t, 1 H,
J 5.6 Hz), 1.27 (s, 6 H), 1.33 (m, 1 H), 1.36, 1.52 (2 s, 6 H), 1.81
(m, 1 H), 2.57 (s, 3 H), 3.72 (ddd, 1 H, J 9.3, 5.2, 6.4 Hz), 3.92
(dd, 1 H, J 5.2, 8.8 Hz), 4.05 (dd, 1 H, J 6.4, 8.8 Hz), 4.16
(d, 1 H, J 9.3 Hz), 4.32 (d, 1 H, J 3.9 Hz), 4.48 (dd, 1 H, J 9.3,
11.8 Hz), 4.97 (dd, 1 H, J 5.4, 11.8 Hz), 5.97 (d, 1 H, J 3.9 Hz);
δC (50 MHz; CDCl3) 13.7, 16.4, 18.8, 25.3, 26.7 (2C), 27.0, 34.5,
68.1, 75.0, 75.5, 79.0, 86.3, 104.7, 109.5, 111.9, 215.7 (Found: C,
52.23; H, 6.87; S, 16.63. C17H26O6S2 requires C, 52.29; H, 6.71;
S, 16.42%).
(4-Methoxyspiro[2.5]octan-1-yl)methanol (14)
To a solution of 1318 (0.6 g, 3.0 mmol) in dry CH2Cl2 (25 mL)
under argon atmosphere at Ϫ78 ЊC was added a 2.1 M solution
of DIBAL-H (3.6 mL, 7.6 mmol). After stirring for 1 h at
Ϫ78 ЊC, the reaction mixture was worked up in the usual
fashion to give a residue, which was purified by silica gel
chromatography (EtOAc–light petroleum 1 : 9) to give 2-(2-
methoxycyclohexylidene)ethanol (0.4 g). Following the general
3-Deoxy-1,2:5,6-di-O-isopropylidene-3-C-allyl-3-C-methallyl-ꢀ-
D-ribo-hexofuranose (20)
By following the general procedure for diallylation, compound
1
11 (0.2 g, 0.55 mmol), methallyltri-n-butyltin (0.5 g, 1.4 mmol)
procedure
for
cyclopropanation,
2-(2-methoxycyclo-
and AIBN (5 mg) gave 20 (97 mg, 52%); [α]D ϩ 57 (c 0.7 in
CHCl3); δH (200 MHz; CDCl3) 1.32 (s, 3 H), 1.36 (s, 3 H), 1.43
(s, 3 H), 1.54 (s, 3 H), 1.86 (s, 3 H), 2.10 (d, 1 H, J 13.3 Hz),
2.35 (d, 1 H, J 13.3 Hz), 2.47 (d, 2 H, J 7.8 Hz), 3.89 (m, 2 H),
4.09–4.33 (m, 2 H), 4.49 (d, 1 H, J 3.9 Hz), 4.76 (s, 1 H), 4.91
(s, 1 H), 5.05 (s, 1 H), 5.11 (m, 1 H), 5.61 (d, 1 H, J 3.5 Hz), 6.02
(m, 1 H); MS (EI) m/z 338 (Mϩ) (Found: C, 67.51; H, 8.90.
C19H30O5 requires C, 67.43; H, 8.93%).
hexylidene)ethanol (0.4 g, 2.6 mmol), a 1 M solution of Et2Zn
(7.8 mL, 7.8 mmol) and CH2I2 (1.2 mL, 15.6 mmol) in dry
CH2Cl2 (25 mL) gave 14 (0.29 g, 56%); δH (200 MHz; CDCl3)
0.14 (t, 1 H, J 5.1 Hz), 0.47 (dd, 1 H, J 5.1, 8.8 Hz), 1.25–1.95
(m, 9 H), 2.53 (s, 1 H), 2.96 (br s, 1 H), 3.34 (s, 3 H), 3.53
(dd, 1 H, J 8.8, 11.0 Hz), 3.68 (m, 1 H); δC (50 MHz; CDCl3)
13.7, 21.0, 24.9, 25.4, 25.9, 26.0, 28.7, 56.1, 62.2, 83.9; MS (EI)
m/z 170 (Mϩ).
3-Deoxy-1,2:5,6-di-O-isopropylidene-ꢀ-D-ribo-hexofuranose-3-
spiro-3-cyclopentene (21)
1,1-Diallyl-2-methoxycyclohexane (15)
Following the general procedure of bromination, compound 14
(0.25 g, 1.5 mmol), Ph3P (0.85 g, 3.2 mmol), CBr4 (0.54 g,
Following the general procedure for RCM, compound 5 (0.10 g,
0.3 mmol) and Grubbs’ catalyst (5 mg) in CH2Cl2 (8 mL) gave
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21 (73 mg, 80%), [α]D ϩ 43 (c 0.9 in CHCl3); δH (200 MHz;
CDCl3) 1.31 (s, 6 H), 1.40 (s, 3 H), 1.50 (s, 3 H), 1.79 (m, 1 H),
2.57 (m, 3 H), 3.96 (m, 2 H), 4.10 (m, 2 H), 4.24 (d, 1 H, J 3.7
Hz), 5.69 (m, 3 H); δC (50 MHz; CDCl3) 25.4, 26.4, 26.7, 27.0,
34.9, 36.3, 55.1, 68.3, 74.5, 81.6, 87.2, 103.9, 109.2, 111.7, 127.3,
130.2; MS (EI) m/z 281 (M Ϫ Me) ϩ (Found: C, 64.75; H, 8.23.
C16H24O5 requires C, 64.84; H, 8.16%).
petroleum–EtOAc (3 : 2). The resulting product (0.32 g) was
added to DIBAL-H (2 M solution in toluene, 1.0 mL, 2 mmol)
in CH2Cl2 (8 mL) at Ϫ78 ЊC. After 0.5 h, saturated aq. NH4Cl
was added at Ϫ78 ЊC and the product diluted with CH2Cl2,
washed with brine, dried and evaporated. The residue was
passed through a short bed of silica gel eluting with EtOAc–
light petroleum (1 : 1) to give 25 (0.26 g, overall yield for two
steps 77%); δH (200 MHz; CDCl3) 1.30, 1.32, 1.40, 1.52 (4 s,
12 H), 1.88–2.07 (m, 3 H), 2.29–2.60 (m, 3 H), 3.85–4.17 (m,
7 H), 5.58 (m, 1 H), 5.70 (m, 1 H); δC (50 MHz; CDCl3)
25.2, 25.9, 26.3, 26.6, 26.8, 27.2, 27.5, 30.2, 32.6, 37.4, 55.0,
55.8, 59.9, 60.1, 68.4, 74.2, 81.1, 85.2, 85.4, 103.9, 109.2, 111.5,
121.5, 143.6; MS (EI) m/z 340 (Mϩ) (Found: C, 63.59; H, 8.13.
C18H28O6 requires C, 63.51; H, 8.29%).
3-Deoxy-1,2:5,6-di-O-isopropylidene-ꢀ-D-ribo-hexofuranose-3-
spiro-3-(3-methylcyclopentene) (22)
Following the general procedure for RCM, compound 20 (75
mg, 0.22 mmol) and Grubbs’ catalyst (5 mg) in CH2Cl2 (5 mL)
gave 22 (52 mg, 75%) [α]D ϩ 46 (c 0.45 in CHCl3); δH (200 MHz;
CDCl3) 1.25 (s, 3 H), 1.32 (s, 3 H), 1.41 (s, 3 H), 1.53 (s, 3 H),
1.73 (s, 3 H), 2.57 (m, 4 H), 3.97 (m, 2 H), 4.12 (m, 2 H), 4.26
(d, 1 H, J 3.4 Hz), 5.31 (br s, 1 H), 5.70 (d, 1 H, J 3.4 Hz);
δC (50 MHz; CDCl3) 25.4, 26.4, 26.7, 27.0, 29.7, 34.9, 40.7, 55.8,
68.2, 74.7, 81.8, 87.4, 104.1, 109.3, 111.8, 123.6, 136.9; MS (EI)
m/z 295 (M Ϫ Me)ϩ (Found: C, 65.82; H, 8.63. C17H26O5
requires C, 65.78; H, 8.44%).
(3R)-3-Deoxy-1,2;5,6-di-O-isopropylidene-ꢀ-D-ribo-hexofuran-
ose-3-spiro(3,3-diallylcyclopentane) (26)
Following the general procedure for cyclopropanation, 25
(0.13 g, 0.38 mmol), a 1 M solution of Et2Zn (1.1 mL,
1.14 mmol) and CH2I2 (0.18 mL, 2.28 mmol) in dry CH2Cl2
(5 mL) gave the cyclopropylmethanol derivative (85 mg) which
was converted into the xanthate derivative with NaH (19 mg,
0.48 mmol), CS2 (0.06 mL, 0.96 mmol) and MeI (0.08 mL,
1.2 mmol). By following the general procedure for diallylation,
the xanthate derivate (90 mg, 0.3 mmol), allyltri-n-butyltin
(0.2 mL, 0.6 mmol) and AIBN (5 mg) gave 26 (26 mg, overall
yield 19%), [α]D ϩ22.8 (c 1.1 in CHCl3); δH (200 MHz; CDCl3)
0.97 (d, 1 H, J 14.4 Hz), 1.32, 1.34, 1.40, 1.50 (4 s, 12 H), 1.55–
1.67 (m, 2 H), 1.75 (d, 1 H, J 14.4 Hz), 1.83–2.03 (m, 2 H), 2.15
(d, 4 H, J 6.4 Hz), 3.80–3.93 (m, 2 H), 4.01–4.20 (m, 2 H), 4.26
(d, 1 H, J 3.4 Hz), 4.94–5.10 (m, 4 H), 5.62 (d, 1 H, J 3.4 Hz),
5.66–5.92 (m, 2 H); δC (50 MHz; CDCl3) 25.5, 26.5, 26.8, 27.1,
27.9, 35.5, 39.2, 43.3, 43.9, 45.7, 56.2, 69.1, 74.0, 82.8, 87.8,
104.1, 109.4, 111.9, 117.4, 135.4 (Found: C, 70.03; H, 9.13.
C22H34O5 requires C, 69.81; H, 9.05%).
(3R)-3-Deoxy-1,2:5,6-di-O-isopropylidene-ꢀ-D-ribo-hexofuran-
ose-3-spiro(3-oxocyclopentane) (23) and (3S )-3-deoxy-1,2:5,6-
di-O-isopropylidene-ꢀ-D-ribo-hexofuranose-3-spiro-(3-oxocyclo-
pentane) (24)
To a solution of compound 21 (1.8 g, 6.1 mmol) in THF
(10 mL) under N2, was added BH3ؒSMe2.(0.6 mL, 6.7 mmol) at
0 ЊC. After 2 h, a saturated aq. solution of sodium acetate and
H2O2 (30% solution, 0.8 mL, 7.3 mmol) were added at Ϫ15 ЊC.
Solvent was removed and the residue extracted with EtOAc,
washed with brine, dried (Na2SO4), and concentrated. The
crude product was purified on silica gel using light petroleum–
EtOAc (3 : 2) to give a residue (1.6 g, 5.1 mmol) which was
added to a solution of (COCl)2 (1.0 mL,10.2 mmol) and Me2SO
(1.6 mL, 20.4 mmol) in CH2Cl2 (10 mL) under nitrogen at Ϫ78
ЊC. After 1 h at Ϫ78 ЊC, Et3N (4.4 mL, 30.6 mmol) was added
and allowed to attain rt. The reaction mixture was diluted with
CH2Cl2, washed with water, brine, dried (Na2SO4) and con-
centrated. The crude product was purified on silica gel with
light petroleum–EtOAc (5 : 1) to afford 23 (0.59 g), [α]D ϩ89.11
(c 1.0 in CHCl3); δH (500 MHz; CDCl3) 1.33 (s, 6 H), 1.42,1.55
(2 s, 6 H), 1.95 (d, 1 H, J 17.8 Hz), 2.17–2.32 (m, 2 H), 2.35–2.47
(m, 2 H), 2.50 (d, 1 H, J 17.8 Hz), 3.88 (dt, 1 H, J 8.9,3.2 Hz),
3.95 (m, 2 H), 4.16 (m, 1 H), 4.24 (d, 1 H, J 3.7 Hz), 5.73 (d,
1 H, J 3.7 Hz); δC (50 MHz; CDCl3) 25.1, 26.4, 26.7, 26.9, 36.4,
43.0, 53.1, 68.8, 74.2, 82.2, 86.1, 104.1, 109.7, 112.2, 216.2; MS
(EI) m/z 297 (Mϩ Ϫ CH3) (Found: C, 61.65; H, 7.46. C16H24O6
requires C, 61.52; H, 7.74%). Further elution afforded com-
pound 24 (0.7 g), [α]D ϩ 32.3 (c 1.0 in CHCl3); δH (500 MHz;
CDCl3) 1.31 (s, 6 H), 1.38 (s, 3 H), 1.52 (s, 3 H), 1.65 (m, 1 H),
2.17–2.32 (m, 2 H), 2.46 (m, 1 H), 2.54 (ABq, 2 H, J 17.5 Hz),
3.87 (d, 1 H, J 9.4 Hz), 3.95 (dd, 1 H, J 5.2, 8.6 Hz), 4.07 (ddd,
1 H, J 9.4, 5.2, 6.2 Hz), 4.18 (dd, 1 H, J 6.2, 8.6 Hz), 4.30 (d,
1 H, J 3.2 Hz), 5.79 (d, 1 H, J 3.2 Hz); δC (50 MHz; CDCl3)
24.9, 25.5, 26.1, 26.4, 26.6, 36.7, 41.8, 52.6, 68.6, 73.8, 81.8,
86.6, 103.9, 109.6, 111.9, 215.8; MS (EI) m/z 297 (Mϩ Ϫ CH3)
(Found: C, 61.38; H, 7.54. C16H24O6 requires C, 61.52; H,
7.74%).
(3R)-3-Deoxy-1,2;5,6-di-O-isopropylidene-ꢀ-D-ribo-hexofuran-
ose-3-spirocyclopentane-3-spiro(3-cyclopentene) (27)
Following the general procedure for RCM, compound 26
(22 mg, 0.06 mmol), and Grubbs’ catalyst (3 mg) in CH2Cl2
(5 mL) gave 27 (18 mg, 88%), [α]D ϩ22.7 (c 0.5 in CHCl3);
δH (200 MHz; CDCl3) 1.22 (d, 1 H, J 15.1 Hz), 1.32, 1.35, 1.41,
1.51 (4 s, 12 H), 1.55–1.74 (m, 2 H), 1.82–2.13 (m, 3 H), 2.34
(m, 4 H), 3.88 (m, 2 H), 4.11 (m, 2 H), 4.29 (d, 1 H, J 3.5 Hz),
5.62 (d, 1 H, J 3.5 Hz), 5.65 (s, 2H); δC (50 MHz; CDCl3) 25.6,
26.6, 26.8, 27.2, 28.8, 39.5, 43.7, 47.0, 47.3, 50.3, 55.9, 69.1,
74.2, 83.1, 88.4, 104.3, 109.4, 111.8, 129.5, 130.0 (Found: C,
68.30; H, 8.69. C20H30O5 requires C, 68.55; H, 8.63%).
(3S )-3-Deoxy-1,2;5,6-di-O-isopropylidene-ꢀ-D-ribo-hexofuran-
ose-3-spiro-(3,3-diallylcyclopentane) (29)
Compound 29 was prepared from (24) (overall yield 8%) by
following the same procedure described for 23, [α]D ϩ 47.5
(c 1.0 in CHCl3); δH (200 MHz; CDCl3) 1.31, 1.33, 1.39, 1.49
(4 s, 12 H), 1.57 (m, 3 H), 1.76–1.92 (m, 3 H), 2.11 (d, 4 H, J 7.3
Hz), 3.75–3.93 (m, 2 H), 3.98– 4.17 (m, 3 H), 4.98–5.08 (m,
4 H), 5.63 (d, 1 H, J 3.4 Hz), 5.72–5.93 (m, 2 H); δC (50 MHz;
CDCl3) 25.7, 26.5, 26.8, 27.2, 29.0, 35.9, 38.0, 43.9, 44.1, 44.3,
55.9, 69.1, 74.2, 82.6, 87.7, 104.4, 109.4, 111.6, 117.0, 117.3,
135.7, 135.9 (Found: C, 69.82; H, 9.15. C22H34O5 requires C,
69.81; H, 9.05%).
(3R)-3-Deoxy-1,2:5,6-di-O-isopropylidene-ꢀ-D-ribo-hexofuran-
ose-3-spiro[3-(hydroxyethylidene)cyclopentane] (25)
Compound 23 (0.31 g, 1.0 mmol) in THF (4 mL) was added to
a previously stirred solution of triethyl phosphonoacetate
(0.25 mL, 1.3 mmol) and NaH (0.048 g, 1.2 mmol) in THF
(5 mL) at 0 ЊC under N2. After 0.5 h at rt, saturated aq. NH4Cl
was added and the solvent removed. The residue was extracted
with EtOAc, washed with water, brine, dried and concentrated.
The crude product was purified on silica gel by using light
(3S )-3-Deoxy-1,2;5,6-di-O-isopropylidene-ꢀ-D-ribo-hexofuran-
ose-3-spirocyclopentane-3-spiro(3-cyclopentene) (30)
Following the general procedure for RCM, compound 29
(30 mg, 0.08 mmol) and Grubbs’ catalyst (4 mg) in CH2Cl2
(5 mL) gave 30 (24 mg, 87%), [α]D ϩ 38.9 (c 0.85 in CHCl3);
δH (200 MHz; CDCl3) 1.32, 1.34, 1.40, 1.49 (4 s, 12 H), 1.55–
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 6 6 – 1 3 7 3
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1.87 (m, 4 H), 1.93 (d, 1 H, J 14.2 Hz), 2.11 (d, 1 H, J 14.2 Hz),
2.20–2.41 (m, 4 H), 3.79–3.94 (m, 2 H), 4.04–4.20 (m, 3 H), 5.63
(m, 3 H); δC (50 MHz; CDCl3) 25.6, 26.5, 26.8, 27.1, 30.0, 39.9,
42.2, 46.6, 47.3, 49.0, 55.5, 69.0, 74.1, 82.9, 88.8, 104.3, 109.4,
111.6, 129.4, 130.0 (Found: C, 68.80; H, 8.78. C20H30O5 requires
C, 68.55; H, 8.63%).
(3S )-[2-(Toluene-4-sulfonly)-2-azaspiro[4.4]non-7-en-3-yl]-
methanol (37)
Compound 35 was subjected to RCM reaction to afford 36
(0.31 g, 96%); {δH (200 MHz; CDCl3) 1.06 (s, 9 H), 1.7–2.3
(m, 6 H), 2.43 (s, 3 H), 3.19 (ABq, 2 H, J 9.5 Hz), 3.60 (m, 1 H),
3.69 (t, 1 H, J 9.5 Hz), 4.11 (dd, 1 H, J 3.2, 9.5 Hz), 5.50 (m,
2 H), 7.2–7.7 (m, 14 H); δC (50 MHz; CDCl3) 19.8, 22.1, 27.5,
42.6, 43.8, 44.8, 48.0, 61.2, 61.7, 67.0, 128.1–136.1, 141.7} and
then treated with n-Bu4NF (1 M solution in THF, 1.5 mL,
1.5 mmol) in THF (5 mL) at rt for 1 h. Solvent was removed
and the residue purified on a short silica gel column using light
petroleum–ethyl acetate (4 : 1) to give 37 (0.16 g, 93%), [α]D Ϫ38
(c 0.7 in CHCl3); δH (200 MHz; CDCl3) 1.5–2.0 (m, 4 H), 2.32
(m, 2 H), 2.48 (s, 3 H), 3.32 (ABq, 2 H, J 9.7 Hz), 2.64 (m, 1 H),
2.76 (br d, 2 H), 5.42 (m, 1 H), 5.58 (m, 1 H), 7.35 (d, 2 H, J 7.7
Hz), 7.74 (d, 2 H, J 7.7 Hz); δC (50 MHz; CDCl3) 21.3, 42.1,
42.5, 43.4, 46.8, 61.4, 62.1, 65.5, 127.4–129.4, 143.4; MS (EI)
m/z 292 (Mϩ Ϫ 1) (Found: C, 62.70; H, 7.02; N, 4.19; S, 10.26.
C16H21NO3S requires C, 62.51; H, 6.89; N, 4.56; S, 10.43%).
(5S )-(5-tert-Butyldiphenylsilyloxymethyl)-1-(toluene-4-
sulfonyl)pyrrolidin-3-one (32)
A mixture of compound 31 (2.3 g, 8.5 mmol), TBDPSCl
(2.4 mL, 9.35 mmol) and imidazole (0.64 g, 9.35 mmol) in
DMF (15 mL) was stirred overnight. The reaction mixture was
diluted with water, extracted with EtOEt, dried (Na2SO4) and
concentrated. The residue was passed through a short column
of silica gel with light petroleum–ethyl acetate (4 : 1). The
product (3.0 g, 5.9 mmol) was treated with PDC (3.0 g,
8.0 mmol) and powdered molecular sieves 4 Å (3.0 g) in CH2Cl2
(100 mL). After stirring at rt for 4 h, the mixture was filtered
through a bed of silica gel with EtOEt as eluent. The filtrate was
concentrated and crystallized from CHCl3 to give 32 (2.6 g,
60%); mp 144 ЊC; [α]D ϩ 34 (c 1.0 in CHCl3); IR (CHCl3) 1764
cmϪ1 (C᎐O); δ (200 MHz; CDCl3) 1.00 (s, 9 H), 2.3 (m, 2 H),
(3S )-[2-(Toluene-4-sulfonyl)-2-azaspiro[4.4]nonan-3-yl]-
methanol (38)
᎐
H
2.42 (s, 3 H), 3.58 (dd, 1 H, J 2.3, 10.3 Hz), 3.82 (ABq, 2 H,
J 18.7 Hz), 4.00 (dd, 1 H, J 3.3, 10.3 Hz), 4.32 (m, 1 H), 7.55
(m, 14 H); δC (50 MHz; CDCl3) 19.0, 21.5, 26.6, 40.0, 54.0, 58.0,
67.9, 127.0–143.8, 208.6; MS (EI) m/z 450 (Mϩ Ϫ tBu) (Found:
C, 66.03; H, 6.68; N, 2.66; S, 6.46. C28H33NO4SSi requires C,
66.24; H, 6.55; N, 2.76; S, 6.32%).
Compound 37 (0.155 g, 0.5 mmol) and 10% Pd/C (0.02 g) in
methanol (5 mL) were stirred under hydrogen atmosphere at
normal temperature and pressure (ntp) for 3 h. The catalyst was
filtered and the filtrate concentrated to give 38 (0.15 g, 96%);
[α]DϪ15 (c 0.7 in CHCl3); δH (200 MHz; CDCl3) 0.86 (m, 2 H),
1.52 (m, 6 H), 1.75 (m, 2 H), 2.46 (s, 3 H), 3.23 (ABq, 2 H, J 9.5
Hz), 3.58 (m, 1 H), 3.78 (br s, 2 H), 7.35 (d, 2 H, J 7.6 Hz), 7.73
(d, 2 H, J 7.6 Hz); δC (50 MHz; CDCl3) 21.3, 24.1, 35.9, 36.4,
41.2, 48.0, 60.5, 62.2, 65.7, 127.3, 129.4, 133.9, 143.5 (Found: C,
61.93; H, 7.76; N, 4.39; S, 10.39. C16H23NO3S requires C, 62.11;
H, 7.49; N, 4.53; S, 10.36%).
(5S,2E,Z )[(5-tert-Butyldiphenylsilyloxymethyl)-1-(toluene-4-
sulfonyl)pyrrolidin-3-ylidene]ethanol (33)
A solution of compound 32 (4.0 g, 7.9 mmol), Ph P᎐CHCO Et
᎐
3
2
(5.48 g, 15.8 mmol) in benzene (25 mL) was heated under reflux
for 24 h. Solvent was removed and the residue passed through
a short column of silica gel with light petroleum–ethyl acetate
(19 : 1) to give the α,β-unsaturated ester (4.18 g) which was
taken in CH2Cl2 (50 mL) and cooled to Ϫ78 ЊC. DIBAL-H
(2 M solution in toluene, 8.3 mL, 16.6 mmol) was introduced.
After stirring at Ϫ78 ЊC for 45 min., excess DIBAL was
quenched by addition of saturated solution of sodium
potassium tartrate. The mixture was stirred at rt for 3 h, filtered,
and concentrated. The product was purified on silica gel by
using light petroleum–ethyl acetate (4 : 1) to give 33 (3.6 g,
85%); δH (200 MHz; CDCl3) 1.08 (s, 9 H), 2.14–2.69 (m, 2 H),
2.43 (s, 3 H), 3.48–4.0 (m, 7 H), 5.43 (m, 1 H), 7.20–7.74 (m,
14 H); δC (50 MHz; CDCl3) 19.0, 21.2, 26.6, 30.2, 34.6. 49.1,
52.7, 59.6, 60.6, 65.7, 66.1, 121.5–137.4, 143.1; MS (EI) m/z 478
(3S )-2-(Toluene-4-sulfonyl)-2-azaspiro[4.4]nonane-3-carboxylic
acid (39)
A mixture of 38 (0.13 g, 0.42 mmol), CH3CN (2 mL), CCl4
(2 mL), H2O (2 mL), NaIO4 (0.1g, 1.32 mmol) and RuCl3(H2O)n
(0.02 g) was vigorously stirred at rt for 2 h. The reaction mixture
was filtered through a pad of celite, the filtrate concentrated
and the residue purified on silica gel by using ethyl acetate
afforded 39 (0.1 g, 77%); [α]D Ϫ67 (c 0.7 in CHCl3); IR (CHCl3)
1726 (C᎐O), 3012 cmϪ1 (OH); δH (200 MHz; CDCl3) 1.18 (m,
᎐
2 H), 1.52 (m, 6 H), 2.05 (m, 2 H), 2.41 (s, 3 H), 3.18 (ABq, 2 H.
J 9.1 Hz), 4.20 (t, 1 H, J 8.2 Hz), 7.29 (d, 2 H, J 9.1 Hz), 7.73
(d, 2 H, J 9.1 Hz), 10.7 (br. s, 1 H); δC (50 MHz; CDCl3) 21.4,
24.3, 24.5, 35.8, 36.3, 42.5, 49.7, 59.1, 60.4, 127.6, 129.6, 134.7,
143.6, 177.0; MS (EI) m/z 278 (Mϩ Ϫ CO2) (Found: C, 59.06;
H, 6.80; N, 4.15; S, 9.63. C16H21NO4S requires C, 59.42; H, 6.54;
N, 4.33; S, 9.91%).
t
(Mϩ Ϫ Bu) (Found: C, 67.59; H, 7.12; N, 2.44; S, 5.78.
C30H37NO4SSi requires C, 67.25; H, 6.96; N, 2.61; S, 5.98%).
(2S )-(2-tert-Butyldiphenylsilyloxymethyl)-4,4Ј-diallyl-1-
(toluene-4-sulfonyl)pyrrolidine (35)
Acknowledgements
Cyclopropanation of 33 was done as described earlier using
Et2Zn–CH2I2 to give 34 (0.8 g, 78%); δH (200 MHz; CDCl3)
0.10 (m, 1 H), 0.45 (m, 1 H), 0.75–2.0 (m, 3 H), 1.11 (s, 9 H),
2.44 (s, 3 H), 3.0–4.25 (m, 7 H), 7.30 (m, 14 H); δC (50 MHz;
CDCl3) 19.0, 21.2, 24.1, 24.6, 26.8, 30.6, 37.0, 51.0, 56.6, 60.5,
60.7, 62.5, 63.1, 65.5, 127.5–135.4, 143.0; MS (EI) m/z: 548
(Mϩ Ϫ 1). Subsequent bromination and allylation reactions as
per general procedure, afforded 35 (0.55 g, 66%) (contaminated
with trace amount of tin reagent and used as such for the next
reaction); δH (200 MHz; CDCl3) 1.05 (s, 9 H), 1.59 (m, 3 H),
1.81 (dd, 1 H, J 3.1, 6.3 Hz), 2.06 (d, 2 H, J 6.3 Hz), 2.38 (s,
3 H), 3.16 (ABq, 2 H, J 10.9 Hz), 3.66 (m, 1 H), 3.79 (dd, 1 H,
J 6.7, 10.1 Hz), 4.01 (dd, 1 H, J 3.3, 10.1 Hz), 4.8 (m, 4 H), 5.7
(m, 2 H), 7.1–7.6 (m, 14 H); δC (75 MHz; CDCl3) 19.25, 21.4,
26.9, 38.85, 39.4, 40.7, 43.7, 58.2, 60.0, 66.3, 118.2, 127.3–136.0,
142.9; MS (EI) m/z 516 (Mϩ Ϫ tBu).
SVR, KS, JC and SK are grateful to CSIR, New Delhi for the
award of research fellowships.
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