A silicon-tethered tandem radical cyclisation-trapping strategy to the fully substituted cyclopentene ring in viridenomycin

Article abstract of DOI:10.1016/j.tet.2008.05.027

Treatment of α-bromosilyl ether 27 derived from the substituted cyclopentenol 26 and (bromomethyl)chlorodimethylsilane, with 1,1′-azobis(cyclohexanecarbonitrile) in n-heptane at 100 °C, in the presence of allyltri-n-butylstannane leads to the silicon heterocycle 28 by way of a stereocontrolled tandem radical cyclisation (to 11)-trapping process. Oxidative cleavage of the carbon-silicon bond in 28, using H₂O₂-KF in THF-MeOH, next led to the corresponding cyclopentane diol 29a, which was then elaborated to the β-hydroxy ester 30b using five steps. Oxidation of 30b using Moffatt conditions, followed by methylation of the resulting enol ester 32a gave the fully functionalised cyclopentene ring in the antitumoural antibiotic substance viridenomycin 1 isolated from Streptomyces viridochromogenes and Streptomyces gannmycicus.

Full text of DOI:10.1016/j.tet.2008.05.027

Tetrahedron 64 (2008) 7400–7406
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A silicon-tethered tandem radical cyclisation–trapping strategy to the fully
substituted cyclopentene ring in viridenomycin
*
Nicholas P. Mulholland, Gerald Pattenden
School of Chemistry, The University of Nottingham, Nottingham NG7 2RD, England, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of
a-bromosilyl ether 27 derived from the substituted cyclopentenol 26 and (bromome-
thyl)chlorodimethylsilane, with 1,10-azobis(cyclohexanecarbonitrile) in n-heptane at 100 ꢀC, in the
presence of allyltri-n-butylstannane leads to the silicon heterocycle 28 by way of a stereocontrolled
tandem radical cyclisation (to 11)–trapping process. Oxidative cleavage of the carbon–silicon bond in 28,
using H2O2–KF in THF–MeOH, next led to the corresponding cyclopentane diol 29a, which was then
Received 5 March 2008
Received in revised form 23 April 2008
Accepted 8 May 2008
Available online 11 May 2008
elaborated to the b-hydroxy ester 30b using five steps. Oxidation of 30b using Moffatt conditions, fol-
lowed by methylation of the resulting enol ester 32a gave the fully functionalised cyclopentene ring in
the antitumoural antibiotic substance viridenomycin 1 isolated from Streptomyces viridochromogenes and
Streptomyces gannmycicus.
Ó 2008 Published by Elsevier Ltd.
1. Introduction
H
N
Ph
NH
O
H
HO
MeO
Viridenomycin 1 is an unusual macrocyclic antitumoural anti-
biotic compound, isolated from Streptomyces viridochromogenes
and Streptomyces gannmycicus.1,2 It is cytotoxic against Gram-pos-
itive bacteria and the parasitic protozoa Trichomonas vaginalis,
which is responsible for the sexually transmitted disease TV. Vir-
idenomycin is also capable of prolonging the life span of various
transgenic mice expressing P388 leukaemia and B16 melanoma.
The compound has a structure based on a polyene macrolactam
O
O
O
MeO
O
OH
OH
HO
2
1
OH
O
O
O
HO
HO
HO
HO
HO
core linked via an enolised
b-keto ester unit and a quaternary
centre to an oxygenated cyclopentane. Viridenomycin is related
structurally to the polyene macrolactam hitachimycin 2,3 and to the
less-adorned oxygenated cyclopentenones terrein 3,4 pentenomy-
cin 4,5 and xanthocidin 5.6
HO
i-Pr CO2H
3
4
5
It is likely that viridenomycin and the aforementioned relatives
share a related biosynthetic origin involving cyclisations of modi-
Neither the absolute stereochemistry nor the stereochemistry at
the benzylic centre in viridenomycin 1 is known, and no total
synthesis of the natural product has been forthcoming. Meyers
et al.11 were the first to describe a synthesis of the substituted
cyclopentene 6 with the correct structural and stereochemical
features in viridenomycin, which was closely followed by a syn-
thesis of the related substituted cyclopentene 7 by Tadano et al.12
During our own studies Trost and Jiang13 presented a synthesis of
substituted cyclopentene 8.
fied poly-b
-ketide precursors,7 in some instances with ring con-
traction of 6-ring aromatic/quinonoid intermediates.8 These
biosynthetic interrelationships, in combination with the striking
structural features and interesting biological properties of vir-
idenomycin, have combined to make the metabolite a challenging
target for synthesis. In this paper we present a synthetic route to
the fully substituted cyclopentene ring in viridenomycin based on
a concise tandem radical cyclisation–trapping strategy.9,10
Our own synthetic approach to the cyclopentene ring system 9
(cf. 6) in viridenomycin uses an intramolecular radical cyclisation
from a silicon-tethered 2-cyclopentenol, i.e., 12, in tandem with in
situ trapping of the product radical 11 with allyltri-n-butyl-
stannane, leading to 10 as the key stratagem (Scheme 1). The
* Corresponding author.
E-mail address: gp@nottingham.ac.uk (G. Pattenden).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.05.027

N.P. Mulholland, G. Pattenden / Tetrahedron 64 (2008) 7400–7406
7401
OMe
CO2Me
OPiv
CO2Me
OAc
OMe
Si
MeO
MeO
MeO
O
Si
O
OH
CO2Et
i
Br
ii
TBSO
TBSO
TBSO
OTBS
I
14
13
15
6
7
8
OH
O
Si
OH
general scope for tandem silicon-tethered radical cyclisation–
trapping sequences in the synthesis of substituted cyclopentanes
was first highlighted by Stork et al.14 in their beautiful studies of
iii
prostaglandin synthesis.15 Keck et al.16 later extolled the use of
b-
16
17
stannyl substituted enones as versatile radical trapping agents in
similar tandem processes, and other researchers have since used
alternative radical trapping agents,17 including allyltri-n-
butylstannane.18
Scheme 2. Reagents and conditions: (i) (BrCH2)SiMe2Cl, Et3N, DMAP, 0 ꢀC (96%); (ii)
(Bu3Sn)2, PhH, allyltri-n-butylstannane, hn; (iii) H2O2, KF, KHCO3, reflux (45% over two
steps).
acetonide group in 19, using EtOH–HCl, next gave the cyclic acetal
20a as a mixture of anomers, which was then converted into the
corresponding benzyl ether 20b (Scheme 3). Hydrolysis of the ac-
etal 20b in the presence of 75% acetic acid, followed by oxidation of
the intermediate cyclic hemiacetal, using DMSO–Ac2O, now gave
the lactone 21 in an excellent 89% yield over the two steps. Addition
of methyllithium to a solution of 21 in THF at ꢁ78 ꢀC next gave rise
to a mixture of anomers of the corresponding cyclic hemiketal 22
together with the ketone tautomer 23a.24 The mixture was treated
immediately with t-BuMe2SiCl and imidazole leading to the dif-
2. Results and discussion
We assessed the viability of the tandem radical cyclisation–
trapping strategy shown in Scheme 1 by first conducting a model
study with the less sophisticated substrate 14 produced from
silylation of the cyclopentenol 13 using (bromomethyl)-
chlorodimethylsilane in the presence of DMAP and Et3N. To our
satisfaction when a solution of the bromide 14 and allyltri-n-
butylstannane in benzene was irradiated with UV light,19 followed
by in situ oxidative cleavage of the silacycle intermediate 1620 using
H2O2, KF, KHCO3,21 the required 1,3-diol 17 was isolated in an
unoptimised 45% yield over the two steps. The relative stereo-
chemistry of the substituents about the cyclopentane ring in the
product 17 followed from NOE experiments in the 1H NMR spec-
trum.22 These data confirmed that, as anticipated, the allylstannane
reagent was trapped from the least hindered (convex) face of the
bicyclic radical intermediate 15 in the overall sequence (Scheme 2).
ferentially protected triol substituted d-unsaturated methyl ketone
23b in a modest 54% yield over the two steps.
Methylenation of the methyl ketone 23b, using Nysted’s re-
agent25 and TiCl4 in THF, next gave the corresponding 1,6-diene 24
with no evidence of any racemisation at the neighbouring a-chiral
centre. Finally, treatment of a solution of the 1,6-diene 24 in ben-
zene at 80 ꢀC with 20 mol % of Grubbs’ second generation cata-
lyst,26 dropwise over 30 h, led to the cyclopentene 25 in 90% yield.
Deprotection of the silyl ether group in 25, then led to the cyclo-
pentenol 26 in readiness for further elaboration to the substituted
cyclopentane ring in viridenomycin, via our tandem radical cycli-
sation–trapping strategy (cf. Scheme 1).
We next examined
a synthesis of the more elaborately
substituted cyclopentenol 26, corresponding to 13 in order to
pursue our proposed synthesis of the fully substituted cyclo-
pentene ring 9 in viridenomycin (Scheme 1). The high density of
stereo-defined hydroxyl group functionality in 26 suggested that
a sugar derivative, i.e., the commercially available glucofuranose 18,
would be an ideal starting material. Our plan then was to elaborate
the glucofuranose 18 to the 1,6-diene 24 via the known tetrahy-
drofuran 19,23 and then to convert 24 into the cyclopentene 25
using ring closure metathesis.
Treatment of the cyclopentenol 26 with (bromomethyl)-
chlorodimethylsilane gave the a-bromosilyl ether 27 in good yield
(Scheme 4). However, when 27 was irradiated with UV light in the
presence of allyltri-n-butylstannane and hexa-n-butyldistannane,
under the conditions used successfully to convert 14 into 16, only
starting material was recovered. This problem was eventually
overcome using the alternative radical initiator 1,10-azobis(cyclo-
hexanecarbonitrile) in n-heptane at 100 ꢀC,27 described by Zard
et al.18 in their synthesis of the pleuromutilin ring system. The
Thus, the substituted tetrahydrofuran 19 was first produced
from 1,2,5,6-di-O-isopropylidene-a-D-glucofuranose 18, using the
procedures described by Josan and Eastwood.23 Deprotection of the
OMe
OMe
O
Si
MeO
RO
MeO
RO
MeO
RO
Cleavage
CO2Me
OH
10
9
OH
O
O
Si
Si
MeO
RO
MeO
RO
MeO
RO
Radical
cyclisation
Bu3Sn
Br
Radical
trap
11
12
Scheme 1. Retrosynthetic analysis of the substituted cyclopentene 9.

7402
N.P. Mulholland, G. Pattenden / Tetrahedron 64 (2008) 7400–7406
O
O
O
O
O
ref. 23
i
OEt
OR
O
O
HO
MeO
MeO
MeO
O
O
18
19
20
a, R = H
b, R = CH2Ph
ii
MeO
O
O
O
iii, iv
OH
v
O
MeO
OBn
OBn
OR OBn
21
23
22
a, R = H
vi
b, R = TBS
TBSO
MeO
OTBS
OH
MeO
BnO
MeO
BnO
ix
vii
viii
BnO
24
26
25
Scheme 3. Reagents and conditions: (i) EtOH, HCl in dioxane, 60 ꢀC (91%); (ii) BnBr, NaH, DMF, 0 ꢀC (89%); (iii) AcOH, H2O (98%); (iv) DMSO, Ac2O (91%); (v) MeLi, THF, ꢁ78 ꢀC; (vi)
TBSCl, imidazole, DMF (54% over 2 steps); (vii) {cyclo-dibromodi-m-methylene[m
-(tetrahydrofuran)] trizinc}, TiCl4 THF, 0 ꢀC/rt (98%); (viii) 1,3-(bis(mesityl)-2-imidazolidinylidene)-
dichloro-(phenylmethylene)(tricyclohexylphosphine)ruthenium, benzene, 80 ꢀC (90%); (ix) TBAF, THF (80%).
crude product, containing the silacycle 28, was subjected to the
Tamao–Fleming oxidation conditions21 to give the cyclopentane-
substituted diol 29a containing five contiguous chiral centres in
50% overall yield. The stereochemistry of 29a followed un-
ambiguously from NOE studies in the 1H NMR spectrum (see Sec-
tion 4).
The 1,3-diol unit in the cyclopentane 29a was converted into the
methyl enol ether of the corresponding b-keto ester residue in the
target, i.e., 32b, by initial protection of the secondary hydroxyl
group in 29a as its TBS ether followed by oxidation of the primary
alcohol group in 29b to the corresponding methyl ester 30a, using
a three-step sequence (Scheme 4). The oxidation of the secondary
contains all the necessary functionalisation with the correct ste-
reochemistry for elaboration to an appropriate intermediate, cf. 6,
en route to viridenomycin.
Comparison of the 1H NMR spectroscopic data for 32a with
those of natural viridenomycin showed excellent correlation in
their chemical shift and coupling data for resonances associated
with the cyclopentene ring units. For completeness, the enol ester
32a was converted into the corresponding methyl ether 32b, using
Me2SO4/K2CO3. The chemical shift and coupling data in the 1H NMR
spectrum of 32b showed close agreement with similar data pub-
lished for the substituted cyclopentenes 6 and 7 synthesised by
Meyers et al.11 and Tadano et al.,12 respectively (Table 1).
alcohol 30b derived from 30a to the corresponding b-keto ester 31
turned out to be problematic. Eventually, however, use of a modi-
fied Pfitzner–Moffatt oxidation (DMSO, EDC, C5H5N, TFA)28 con-
verted the alcohol 30b into 31, which existed exclusively as the enol
ester tautomer 32a, in 89% yield. The substituted cyclopentene 32a
3. Summary and conclusion
In summary, we have developed an intramolecular, silicon-
tethered, 5-exo-trig radical cyclisation, followed by in situ trapping
OR
Si
O
O
Si
MeO
BnO
MeO
BnO
MeO
BnO
Br
i
ii
iii
26
OH
27
29
28
a, R = H
iv-v
b, R = TBS
OR
OR
O
MeO
BnO
MeO
BnO
MeO
iv-viii
x
3
4
CO2Me
CO2Me
CO2Me
BnO
30
31
32
a, R = H
a, R = TBS
b, R = H
ix
xi
b, R = Me
Scheme 4. Reagents and conditions: (i) Et3N, (CH3)2Si(CH2Br)Cl, DMAP, CH2Cl2 (80%); (ii) ACCN, n-heptane, 100 ꢀC, allyltri-n-butylstannane; (iii) H2O2, KF, KHCO3, MeOH, THF, 80 ꢀ
C
(50% over two steps); (iv) TBSCl, imidazole, DMF (92%); (v) PPTS, EtOH (71%, based on recovered starting material); (vi) Dess–Martin periodinane, pyridine, CH2Cl2; (vii) NaClO2,
KH2PO4, H2O, t-BuOH, 2-methyl-2-butene; (viii) TMSCHN2, benzene, MeOH; (ix) TBAF, THF (69% over four steps); (x) EDC, DMSO, Py$TFA, DMAP (89%); (xi) Me2SO4, DMSO, K2CO3 (97%).

N.P. Mulholland, G. Pattenden / Tetrahedron 64 (2008) 7400–7406
7403
(CHCl3) 2979, 2931, 2902, 1454, 1375, 1351, 1099, 1043 cmꢁ1
NMR (360 MHz, CDCl3) 7.37–7.27 (5H, m, ArH), 6.05 (1H, ddd,
;
1H
Table 1
Relevant comparative 1H NMR spectroscopic data for the substituted cyclopentenes
d
6, 7 and 32ba
J¼7.9, 10.3, 17.2 Hz, CH]CH2), 5.38 (1H, br d, J¼17.2 Hz, CH]CHH),
5.28 (1H, br d, J¼10.3 Hz, CH]CHH), 5.02 (1H, d, J¼2.2 Hz, CHOEt),
4.65–4.61 (3H, m, CH2Ph, OCH), 4.02 (1H, dd, J¼2.2, 3.6 Hz, CHOBn),
3.88 (1H, dd, J¼3.6, 6.0 Hz, CHOMe), 3.85 (1H, qd, J¼7.0, 9.2 Hz,
OCHHCH3), 3.54 (1H, qd, J¼7.0, 9.2 Hz, OCHHCH3), 3.36 (1H, s,
OCH3), 1.23 (3H, t, J¼7.0 Hz, CH2CH3); 13C NMR (90 MHz, CDCl3)
6
7
32b
C3–H
C4–H
d
d
4.31 d (J¼6.3 Hz)
4.07 d (J¼6.3 Hz)
d
d
4.32 d (J¼6.7 Hz)
4.10 d (J¼6.7 Hz)
d
d
4.47 d (J¼5.5 Hz)
3.87 d (J¼5.5 Hz)
Corresponding 1H NMR spectroscopic data for the cyclopentene 8, described by
a
Trost and Jiang,13 are C3–H
d
3.74 d (J¼9.8 Hz) and C4–H
d
3.35 d (J¼9.8 Hz). The
large vicinal coupling (J¼9.8 Hz) reported between C3–H and C4–H in 8 is more
consistent with a syn-relationship between these hydrogen atoms.
d
137.7 (s), 134. 7 (d), 128.4 (d)ꢂ2, 127.8 (d)ꢂ2, 127.7 (d), 118.3 (t),
106.6 (d), 87.0 (d), 85.3 (d), 82.0 (d), 72.2 (t), 63.8 (t), 58.1 (q), 15.1
(q); m/z (ES) found 301.1433 (MþNa, 16H22O4Na requires
301.1416); and (ii) the -anomer of the benzyl ether (combined yield
13.10 g, 89%) as a pale yellow oil. [
(CHCl3) 2979, 2931, 1454, 1374, 1096, 1053, 989 cmꢁ1
(360 MHz, CDCl3)
C
of the product radical centre to install the quaternary carbon centre,
in addition to the four contiguous chiral centres, in the cyclo-
pentene unit 32 in viridenomycin. The silicon-tethered radical
cyclisation precursor 27 was conveniently produced from the
commercially available glucofuranose 18 via the cyclopentenol 26
whose synthesis featured ring-closing metathesis from the 1,6-
diene intermediate 24.
a
23
a
]
þ99.4 (c 1.0, CHCl3); nmax
D
;
1H NMR
7.43–7.30 (5H, m, ArH), 5.94 (1H, ddd, J¼7.1,10.3,
d
17.2 Hz, CH]CH2), 5.37 (1H, br d, J¼17.2 Hz, CH]CHH), 5.31 (1H, br
d, J¼10.3 Hz, CH]CHH), 4.95 (1H, d, J¼4.3 Hz, CHOEt), 4.67–4.64
(3H, m, CH2Ph, OCH), 4.10 (1H, dd, J¼6.1, 6.3 Hz, CHOMe), 3.82 (1H,
dd, J¼4.3, 6.3 Hz, CHOBn), 3.82 (1H, qd, J¼7.1, 9.9 Hz, OCHHCH3),
3.53 (1H, qd, J¼7.1, 9.9 Hz, OCHHCH3), 3.40 (1H, s, OCH3), 1.29 (3H, t,
4. Experimental
J¼7.1 Hz, CH2CH3); 13C NMR (90 MHz, CDCl3)
d 137.8 (s), 133.9 (d),
4.1. General details
128.3 (d)ꢂ2, 128.1 (d)ꢂ2, 127.7 (d), 118.3 (t), 99.2 (d), 84.5 (d), 83.4
(d), 78.3 (d), 72.5 (t), 63.5 (t), 58.2 (q), 15.2 (q); m/z (ES) found
301.1409 (MþNaþ, C16H22O4Na requires 301.1416).
For general details see Ref. 29.
4.1.1. 1,2-O-Isopropylidene-3-O-methyl-
enofuranose (19)
a-D
-xylo-hex-5-
4.1.3. (2R,3S,4R)-2-Benzyloxy-3-methoxy-4-vinyl-dihydro-furan-1-
one (21)
The substituted tetrahydrofuran was prepared from the
a
[a]
-
D
-
A solution of the ethyl glycoside anomer 20b (4.44 g, 16.0 mmol)
in acetic acid–water (3:1, 100 mL) was stirred at 65 ꢀC for 3 days.
The mixture was concentrated in vacuo and the residue was then
azeotroped with toluene. The residue was dried under vacuum to
leave the corresponding hemiacetal (4.0 g, 98%) as a yellow oil,
which was used in the next reaction without further purification.
A solution of the hemiacetal (1.50 g 6.0 mmol) in anhydrous
DMSO (16 mL) and acetic anhydride (9.6 mL) was stirred at room
temperature for 18 h under a nitrogen atmosphere. The mixture
was quenched with water (60 mL) and was then stirred at room
temperature for a further 15 min during which time the product
precipitated. The mixture was diluted with dichloromethane
(20 mL) and the separated aqueous phase was then extracted with
dichloromethane (2ꢂ20 mL). The combined organic extracts were
washed with water (2ꢂ20 mL) and brine (20 mL), then dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
23
glucofuranose 18 according to the literature procedures.23
D
23
ꢁ85.0 (c 1.0, CHCl3) (lit.23
[
a
]
D
ꢁ70 (c 1.0, CHCl3)); nmax (CHCl3)
2984, 2937, 1646, 1455, 1384, 1376, 1134, 1074 cmꢁ1 1H NMR
;
(360 MHz, CDCl3)
d
5.98 (1H, ddd, J¼6.8, 10.5, 17.5 Hz, CH]CH2),
5.97 (1H, d, J¼3.8 Hz, OCH), 5.47 (1H, d, J¼17.5 Hz, CH]CHH), 5.32
(1H, d, J¼10.5 Hz, CH]CHH), 4.64 (1H, dd, J¼6.8, 3.2 Hz, OCH), 4.63
(1H, d, J¼3.8 Hz, OCH), 3.70 (1H, d, J¼3.2 Hz, CHOMe), 3.44 (3H, s,
OCH3), 1.54 (3H, s, CH3), 1.35 (3H, s, CH3); 13C NMR (90 MHz, CDCl3)
dC 131.9 (d), 118.7 (t), 111.4 (s), 104.3 (d), 85.8 (d), 82.0 (d), 81.2 (d),
58.1 (q), 26.7 (q), 26.1 (q); m/z (ES) found 223.0955 (MþNaþ,
C
10H16O4Na requires 223.0946).
4.1.2. (2R,3S,4R)-2-Benzyloxy-1-ethoxy-3-methoxy-4-vinyl-
tetrahydro-furan (20b)
Hydrochloric acid (4 M in dioxane, 3 mL) was added in one
portion to a stirred solution of the acetonide 19 (2.00 g, 10.0 mmol)
in absolute ethanol (30 mL). The mixture was heated to 60 ꢀC and
stirred at this temperature for 15 h, then cooled to room tempera-
ture. Saturated aqueous sodium bicarbonate (20 mL) was added and
the resulting suspension was concentrated in vacuo to approxi-
mately 20 mL. The aqueous residue was extracted with ethyl acetate
(2ꢂ60 mL) and the combined organic extracts were then washed
with brine (10 mL), dried over MgSO4 and concentrated in vacuo to
leave the ethyl glycoside 20a (1.71 g, 91%) as a mixture of anomers.
Sodium hydride (3.83 g, 97.8 mmol, 60% in mineral oil) was added in
one portion to a stirred solution of the ethyl glycoside (9.96 g,
52.9 mmol) in anhydrous DMF (175 mL) at 0 ꢀC under a nitrogen
atmosphere. The mixture was stirred at 0 ꢀC for 20 min and then
benzyl bromide (13.1 g, 76.7 mmol) was added in one portion. The
mixture was stirred at 0 ꢀC for 2 h, methanol (5 mL) was then added
and the solution was stirred at room temperature for a further
30 min. The mixture was poured into diethyl ether (500 mL) and the
solutionwas thenwashed with water (2ꢂ400 mL) followed by brine
(50 mL). The combined organic extracts were dried over MgSO4 and
concentrated in vacuo to leave the crude benzyl ether as a yellow oil,
which was purified by flash chromatography, using diethyl ether–
flash chromatography, using ethyl acetate–pentane (1:7) as eluent,
27
to give the lactone (1.36 g, 91%) as a colourless oil. [
a
]
þ153.8 (c
D
1.0, CHCl3); nmax (CHCl3) 2937, 2886, 1790 cmꢁ1; 1H NMR (360 MHz,
CDCl3)
d
7.42–7.30 (5H, m, ArH), 5.95 (1H, ddd, J¼6.4, 10.3, 17.2 Hz,
CH]CH2), 5.46 (1H, app. dt, J¼1.2, 17.2 Hz, CH]CHH), 5.39 (1H,
app. dt, J¼1.2, 10.3 Hz, CH]CHH), 5.07 (1H, ddt, J¼1.2, 6.2,
6.4 Hz, OCH), 5.03 (1H, d, J¼11.5 Hz, CHHPh), 4.76 (1H, d, J¼11.5 Hz,
CHHPh), 4.18 (1H, d, J¼6.2 Hz, CHOBn), 4.08 (1H, app. t, J¼6.2 Hz,
CHOMe), 3.41 (1H, s, OCH3); 13C NMR (90 MHz, CDCl3)
d 175.5 (s),
136.6 (s), 130.9 (d),128.5 (d)ꢂ2,128.2 (d)ꢂ2,128.1 (d),119.7 (t), 82.0
(d), 79.5 (d), 76.4 (d), 72.5 (t), 58.2 (q); m/z (ES) found 271.0970
(MþNaþ, C14H16O4Na requires 271.0970).
4.1.4. (3R,4R,5R)-3-Benzyloxy-5-(tert-butyl-dimethyl-silanyloxy)-
4-methoxy-hept-6-en-2-one (23b)
A solution of methyllithium (2.1 mL, 3.4 mmol, 1.6 M in diethyl
ether) was added dropwise over 5 min to a stirred solution of the
lactone 21 (0.5 g, 1.9 mmol) in anhydrous THF (20 mL) at ꢁ78 ꢀC
under a nitrogen atmosphere. The mixture was stirred at ꢁ78 ꢀC for
15 min, then a saturated solution of aqueous ammonium chloride
(20 mL) was added and the mixture was allowed to warm gradually
to room temperature. The mixture was diluted with dichloro-
methane (40 mL) and the separated aqueous phase was extracted
pentane (1:12) as eluent, to give: (i) the
b
-anomer of the benzyl ether
23
(eluted first) as a pale yellow oil. [
a]
ꢁ30.1 (c 1.0, CHCl3); nmax
D

7404
N.P. Mulholland, G. Pattenden / Tetrahedron 64 (2008) 7400–7406
with dichloromethane (2ꢂ20 mL). The combined organic extracts
were washed with brine (10 mL), then dried over MgSO4 and
concentrated in vacuo to leave the crude lactol 22 as a mixture of
anomers, together with the ketone tautomer 23a.
tert-Butyldimethylsilyl chloride (0.3 g, 2.2 mmol) and imidazole
(0.3 g, 4.4 mmol) were added in one portion to a stirred solution of
22/23a in anhydrous DMF (1.7 mL) at room temperature under an
argon atmosphere. The mixture was stirred at room temperature
for 24 h, then the reaction mixture was purified directly by flash
chromatography, using diethyl ether–pentane (1:10) as eluent, to
to room temperature. Silica was added and the mixture was con-
centrated in vacuo. The residue was purified by flash chromatog-
raphy, using diethyl ether–pentane (1:15) as eluent, to give the
21
cyclopentene (415 mg, 90%) as a colourless oil; [
CHCl3); nmax (CHCl3) 2953, 2930, 2857 cmꢁ1
CDCl3) 7.40–7.27 (5H, m, ArH), 5.40 (1H, br s, ]CH), 4.70 (1H, d,
a
]
ꢁ47.6 (c 1.10,
D
;
1H NMR (360 MHz,
d
J¼11.9 Hz, CH2Ph), 4.67 (1H, d, J¼11.9 Hz, CH2Ph), 4.50 (1H, br s,
CHOTBS), 4.16 (1H, br s, CHOBn), 3.83 (1H, app. t, J¼3.9 Hz, CHOMe),
3.50 (3H, s, OCH3), 1.76 (3H, d, J¼1.1 Hz, CCH3), 0.90 (9H, s,
SiC(CH3)3), 0.11 (3H, s, Si(CH3)(CH3)), 0.09 (3H, s, Si(CH3)(CH3)); 13
C
give the methyl ketone (370 mg, 54% over two steps) as a colourless
NMR (90 MHz, CDCl3)
d
140.6 (s), 138.7 (s), 128.8 (d), 128.2 (d)ꢂ2,
24
oil. [
a
]
D
þ62.9 (c 1.3, CHCl3). (Found: C, 66.5; H, 9.1; C21H34O4Si
127.5 (d)ꢂ2, 127.4 (d), 96.2 (d), 87.2 (d), 78.9 (d), 71.0 (t), 58.0 (q),
25.7 (q)ꢂ3, 17.9 (s), 14.1 (q), ꢁ4.2 (q), ꢁ4.8 (q); m/z (ES) found
371.1946 (MþNaþ, C20H32NaO3Si requires 371.2018).
requires: C, 66.6; H, 9.1); nmax (CHCl3) 2954, 2930, 1710 cmꢁ1
;
1H
NMR (400 MHz, CDCl3) 7.36–7.31 (5H, m, ArH), 5.79 (1H, ddd,
d
J¼6.7, 10.4, 17.3 Hz, CH]CH2), 5.63 (1H, d, J¼17.3 Hz, CH]CHH),
5.09 (1H, d, J¼10.4 Hz, CH]CHH), 4.57 (1H, d, J¼11.5 Hz, CHHPh),
4.41 (1H, d, J¼11.5 Hz, CHHPh), 4.42–4.37 (1H, m, CHOTBS), 3.85
(1H, d, J¼2.6 Hz, CHOBn), 3.44 (1H, s, OCH3), 3.42 (1H, dd, J¼2.6,
7.3 Hz, CHOMe), 2.23 (3H, s, COCH3), 0.90 (9H, s, SiC(CH3)3), 0.10
(3H, s, Si(CH3)(CH3)), 0.05 (3H, s, Si(CH3)(CH3)); 13C NMR (90 MHz,
4.1.7. (1R,4S,5R)-4-Benzyloxy-5-methoxy-3-methyl-cyclopent-2-
enol (26)
A solution of tetrabutylammonium fluoride (3.6 mL, 3.6 mmol,
1.0 M solution in THF) was added dropwise over 5 min to a stirred
solution of the TBS ether 25 (0.4 g, 1.2 mmol) in anhydrous THF
(5 mL) at room temperature under a nitrogen atmosphere. The
mixture was stirred at room temperature for 16 h, then diluted with
diethyl ether (20 mL) and quenched with water (5 mL). The sepa-
rated aqueous layer was extracted with diethyl ether (3ꢂ20 mL),
and the combined organic extracts were then dried over MgSO4
and concentrated in vacuo. The residue was purified by flash
CDCl3)
d
212.0 (s), 137.6 (d), 137.1 (s), 128.5 (d)ꢂ2, 128.3 (d)ꢂ2, 128.1
(d), 116.6 (t), 86.2 (d), 84.5 (d), 74.2 (d), 73.7 (t), 61.0 (q), 27.6 (d),
25.9 (q)ꢂ3, 18.2 (s), ꢁ4.5 (q), ꢁ4.8 (q); m/z (ES) found 401.2086
(MþNaþ, C21H34O4NaSi requires 401.2124). Some of the lactone 21
(85 mg, 34%) was also recovered.
4.1.5. (3R,4R,5R)-3-Benzyloxy-5-(tert-butyl-dimethyl-silanyloxy)-
4-methoxy-2-methyl-hepta-1,6-diene (24)
chromatography, using diethyl ether–petrol (1:2) as eluent, to give
24
the alcohol (222 mg, 80%) as a colourless oil; [
a]
ꢁ3.2 (c 1.3,
D
A solution of titanium(IV) tetrachloride (2.0 mL, 2.0 mmol, 1.0 M
in dichloromethane) was added dropwise over 5 min to a stirred
solution of the Nysted reagent25 (4.7 mL, 2.4 mmol, 20% in THF) in
anhydrous THF (15 mL) at 0 ꢀC under a nitrogen atmosphere. The
resulting slurry was stirred at 0 ꢀC for 5 min and then a solution of
the methyl ketone 23b (0.4 g, 1.0 mmol) in anhydrous THF (20 mL,
5 mL wash) was added via cannula. The mixture was allowed to
gradually warm to room temperature and held at this temperature
for 5 h. The reaction mixture was cooled to 0 ꢀC, and then quenched
and neutralised with saturated aqueous sodium hydrogen car-
bonate solution. The mixture was filtered through a pad of Celite
and the separated aqueous phase was then extracted with diethyl
ether (3ꢂ40 mL). The combined organic extracts were dried over
MgSO4, then concentrated in vacuo to leave a colourless oil, which
was purified by flash chromatography, using diethyl ether–pentane
CHCl3); nmax (CHCl3) 3593 (br), 2934, 1602 cmꢁ1
;
1H NMR
(360 MHz, CDCl3) 7.40–7.27 (5H, m, ArH), 5.50 (1H, br s, ]CH),
d
4.72 (1H, d, J¼11.8 Hz, CHHPh), 4.62 (1H, d, J¼11.8 Hz, CHHPh), 4.48
(1H, br s, CHOH), 4.15 (1H, br s, CHOBn), 3.78 (1H, app. t, J¼3.5 Hz,
CHOMe), 3.52 (3H, s, OCH3), 1.78 (3H, d, J¼1.6 Hz, CCH3); 13C NMR
(90 MHz, CDCl3)
d
142.8 (s), 138.4 (s), 128.4 (d), 128.3 (d)ꢂ2, 127.7
(d)ꢂ2, 127.6 (d), 95.7 (d), 87.7 (d), 78.9 (d), 71.1 (t), 57.8 (q), 14.2 (q);
m/z (ES) found 217.1240 (MꢁOHꢁ, C14H17O2 requires 217.1229).
4.1.8. ((1R,4S,5R)-4-Benzyloxy-5-methoxy-3-methyl-cyclopent-2-
enyloxy)-bromomethyl-dimethyl-silane (27)
(Bromomethyl)chlorodimethylsilane (80 mL, 0.6 mmol) was
added in one portion to a stirred solution of the alcohol 26 (69 mg,
0.3 mmol), triethylamine (0.2 mL, 1.2 mmol) and DMAP (3.5 mg,
30 m
mol) in anhydrous dichloromethane (2 mL) at 0 ꢀC. The mix-
(1:10) as eluent, to give the 1,6-diene (266 mg, 98%) as a colourless
ture was allowed to warm to room temperature over 12 h and then
washed with water (8 mL). The separated aqueous phase was
extracted with dichloromethane (3ꢂ8 mL) and the combined or-
ganic extracts were then dried over MgSO4 and concentrated in
vacuo. The residue was purified by flash chromatography, using
20
oil. [
a
]
þ37.5 (c 0.95, CHCl3). (Found: C, 70.2; H, 9.6; C22H36O3Si
D
requires C, 70.2; H, 9.6); nmax (CHCl3) 2953, 2929, 2857, 1643,
1455 cmꢁ1 1H NMR (360 MHz, CDCl3)
;
d
7.34–7.27 (5H, m, ArH),
5.77 (1H, ddd, J¼6.7, 10.5, 17.2 Hz, CH]CH2), 5.08–5.00 (4H, m,
]CH2, CH]CH2), 4.54 (1H, d, J¼11.6 Hz, CHHPh), 4.28 (1H, app. tt,
J¼1.1, 6.3 Hz, CHOTBS), 4.20 (1H, d, J¼11.6 Hz, CHHPh), 3.84 (1H, d,
J¼3.2 Hz, CHOBn), 3.50 (3H, s, OCH3), 3.10 (1H, dd, J¼3.2, 6.3 Hz,
CHOMe), 1.81 (3H, br s, C(CH3)]CH2), 0.90 (9H, s, SiC(CH3)3), 0.08
(3H, s, Si(CH3)(CH3)), 0.03 (3H, s, Si(CH3)(CH3)); 13C NMR (90 MHz,
diethyl ether–pentane (1:9) as eluent, to give the silyl ether (79 mg,
21
80%) as a colourless oil; [
a
]
D
ꢁ44.0 (c 0.55, CHCl3). (Found: C, 52.9;
H, 6.4; C17H25BrO3Si requires C, 53.0; H, 6.5); nmax (CHCl3) 2936,
2356, 1662 cmꢁ1 1H NMR (360 MHz, CDCl3)
;
d
7.40–7.29 (5H, m,
ArH), 5.43 (1H, br s, ]CH), 4.68 (1H, d, J¼11.8 Hz, CHHPh), 4.62 (1H,
d, J¼11.8 Hz, CHHPh), 4.58 (1H, br s, CHOSiR3), 4.17 (1H, br s,
CHOBn), 3.84 (1H, app. t, J¼3.8 Hz, CHOMe), 4.50 (3H, s, OCH3), 2.51
(2H, s, Si(CH3)2CH2Br), 1.76 (3H, d, J¼1.1 Hz, CCH3), 0.32 (3H, s,
Si(CH3)(CH3)), 0.31 (3H, s, Si(CH3)(CH3)); 13C NMR (90 MHz, CDCl3)
CDCl3)
d
142.8 (s), 138.5 (d), 137.1 (s), 128.3 (d)ꢂ2, 128.2 (d)ꢂ2,127.4
(d), 115.7 (t), 114.0 (t), 86.9 (d), 81.2 (d), 74.8 (d), 70.6 (t), 61.3 (q),
25.9 (q)ꢂ3, 19.0 (q), 18.2 (s), ꢁ4.4 (q), ꢁ4.8 (q); m/z (ES) found
399.2357 (MþNaþ, C22H36O3SiNa requires 399.2331).
d
144.8 (s), 138.6 (s), 128.3 (d)ꢂ2, 128.2 (d), 127.6 (d)ꢂ2, 127.5 (d),
4.1.6. ((1R,4S,5R)-4-Benzyloxy-5-methoxy-3-methyl-cyclopent-2-
enyloxy)-tert-butyl-dimethylsilane (25)
A solution of 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-
(phenylmethylene)(trichlorohexenylphosphine)ruthenium (84 mg,
95.6 (d), 87.3 (d), 79.4 (d), 79.1 (t), 57.9 (t), 16.2 (t), 14.2 (q), ꢁ2.4
(q)ꢂ2; m/z (ES) found 217.1214 (MꢁOSi(CH3)2CH2Brꢁ, C14H17O2
requires 217.1229).
9.3
m
mol) in dry degassed benzene (7 mL) was added over 30 h to
4.1.9. (1R,2S,3R,4S,5S)-3-Allyl-4-benzyloxy-2-hydroxymethyl-5-
methoxy-3-methyl-cyclopentanol (29a)
Azobis(cyclohexanecarbonitrile) (41.0 mg, 0.17 mmol) was
added in one portion to a degassed solution of the a-bromosilyl
a stirred solution of the 1,6-diene 24 (0.5 g, 1.3 mmol) in dry
degassed benzene (27 mL) at 80 ꢀC under an argon atmosphere.
The mixture was stirred at 80 ꢀC for a further 14 h and then cooled

N.P. Mulholland, G. Pattenden / Tetrahedron 64 (2008) 7400–7406
7405
ether 27 (128 mg, 0.33 mmol) and allyltri-n-butylstannane (311 mg,
1.00 mmol) in n-heptane. The mixture was heated at 100 ꢀC for
24 h, then cooled to room temperature and concentrated in vacuo.
The residue, containing the silacycle 28, was dissolved in metha-
nol–tetrahydrofuran (14 mL, 1:1) and the solution was treated with
potassium hydrogen carbonate (670 mg, 6.67 mmol), potassium
fluoride (390 mg, 6.67 mmol) and aqueous hydrogen peroxide so-
lution (7 mL, 35%) at room temperature. The mixture was heated at
80 ꢀC for 3 h, then cooled to room temperature and concentrated in
vacuo. The residue was diluted with ethyl acetate (30 mL) and the
solution was filtered through Celite. The separated aqueous layer
was extracted with ethyl acetate (2ꢂ10 mL), and the combined
organic extracts were dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash chromatography, using ethyl ac-
diethyl ether (3ꢂ8 mL). The combined organic extracts were dried
over MgSO4 and concentrated in vacuo. The residue was purified by
flash chromatography, using diethyl ether–petrol (1:9) as eluent, to
28
give the alcohol (53.7 mg, 58%) as a colourless oil; [
a]
ꢁ6.8 (c 0.15,
D
CHCl3); nmax (CHCl3) 3626, 3521, 2930, 2858, 1602 cmꢁ1
;
1H NMR
(360 MHz, CDCl3)
d
7.36–7.27 (5H, m, ArH), 5.82 (1H, dddd, J¼7.1,
7.7, 10.2, 17.3 Hz, CH]CH2), 5.07 (1H, br d, J¼10.2 Hz, CH]CHH),
5.02 (1H, br d, J¼17.3 Hz, CH]CHH), 4.68 (1H, d, J¼11.8 Hz, CHHPh),
4.59 (1H, d, J¼11.8 Hz, CHHPh), 4.17 (1H, dd, J¼3.4, 6.8 Hz, CHOTBS),
3.88 (1H, dd, J¼8.4, 11.0 Hz, CH2OH), 3.71 (1H, dd, J¼3.9, 6.8 Hz,
CHOMe), 3.70 (1H, dd, J¼4.3, 8.4 Hz, CH2OH), 3.45 (1H, d, J¼3.9 Hz,
CHOBn), 3.44 (3H, s, OCH3), 2.17 (1H, dd, J¼7.7, 14.1 Hz,
CHHCH]CH2), 2.08 (1H, dd, J¼7.1, 14.1 Hz, CHHCH]CH2), 1.94 (1H,
ddd, J¼3.4, 4.3, 11.0 Hz, CHCH2OH), 1.06 (3H, s, CCH3), 0.90 (9H, s,
etate–pentane (1:9) then ethyl acetate as eluent, to give the diol
SiC(CH3)3), 0.14 (3H, s, Si(CH3)(CH3)), 0.13 (3H, s, Si(CH3)(CH3)); 13
C
23
(51 mg, 50%) as a colourless oil; [
a]
ꢁ4.46 (c 1.53, CHCl3); nmax
NMR (90 MHz, CDCl3)
d
138.8 (s), 134.5 (d), 128.4 (d)ꢂ2, 127.5 (d),
D
(CHCl3) 3615, 3413, 2930, 1454, 1097 cmꢁ1
;
1H NMR (360 MHz,
127.4ꢂ2, 118.2 (t), 94.1 (d), 88.7 (d), 77.2 (d), 72.6 (t), 59.0 (t), 57.7
(q), 48.3 (s), 45.2 (d), 44.4 (t), 25.9 (q)ꢂ3, 18.1 (s), 17.3 (q), ꢁ4.4 (q),
ꢁ5.0 (q); m/z (ES) found 443.2536 (MþNaþ, C24H40NaO4Si requires
443.2594).
CDCl3)
d
7.36–7.27 (5H, m, ArH), 5.74 (1H, dddd, J¼4.8, 7.4, 10.2,
17.1 Hz, CH]CH2), 5.06 (1H, dd, J¼1.2, 10.2 Hz, CH]CHH), 5.01 (1H,
dd, J¼1.2, 17.1 Hz, CH]CHH), 4.76 (1H, d, J¼11.8 Hz, CHHPh),
4.57 (1H, d, J¼11.8 Hz, CHHPh), 4.26 (1H, dd, J¼3.6, 7.8 Hz, CHOH),
3.87 (1H, dd, J¼7.5, 11.2 Hz, CH2OH), 3.78 (1H, dd, J¼4.8, 11.2 Hz,
CH2OH), 3.74 (1H, dd, J¼3.6, 5.0 Hz, CHOMe), 3.47 (3H, s, OCH3),
3.44 (1H, d, J¼5.0 Hz, CHOBn), 2.12–2.04 (3H, m, CHCH2OH,
4.1.11. (1R,2R,3S,4S,5R)-2-Allyl-3-benzyloxy-5-hydroxy-4-meth-
oxy-2-methyl-cyclopentanecarboxylic acid methyl ester (30b)
Dess–Martin periodinane (81.3 mg, 0.19 mmol) was added to
a stirred solution of the alcohol 29b in anhydrous dichloromethane
CH2CH]CH2), 1.03 (3H, s, CCH3); 13C NMR (90 MHz, CDCl3)
d 138.3
(s), 134.0 (d), 128.4 (d), 128.3 (d)ꢂ2, 127.6 (d)ꢂ2, 118.3 (t), 95.1 (d),
87.0 (d), 76.8 (d), 72.2 (t), 59.0 (t), 57.7 (q), 48.3 (d), 45.0 (s), 43.5 (t),
17.3 (q); m/z (ES) found 329.1707 (MþNaþ, C18H26O4Na requires
329.1729). In an NOE experiment (1H NMR, 360 MHz, CDCl3) irra-
(2.6 mL) and pyridine (260 mL), and the suspension was then stirred
at room temperature for 4 h. The mixture was diluted with diethyl
ether, then saturated aqueous solutions of sodium thiosulfate
(2.5 mL) and sodium hydrogen carbonate (2.5 mL) were added and
the mixture was stirred at room temperature for a further 0.5 h. The
separated aqueous layer was extracted with diethyl ether (3ꢂ5 mL),
and the combined ether extracts were then dried over MgSO4 and
concentrated in vacuo to leave the corresponding aldehyde, which
was used without further purification.
Sodium chlorite (58.0 mg, 0.64 mmol) and a solution of potas-
sium dihydrogen phosphate (87.0 mg, 0.64 mmol) in water (0.6 mL)
were added to a stirred solution of the crude aldehyde in tert-bu-
tanol (2.5 mL) and 2,3-dimethylbut-2-ene (2.5 mL). The mixture
was stirred at room temperature for 15 h, and was then diluted
with dichloromethane (14 mL) and water (7 mL). The separated
aqueous layer was extracted with dichloromethane (2ꢂ7 mL), and
the combined organic extracts were dried over MgSO4 and con-
centrated in vacuo to leave the corresponding carboxylic acid. A
diation at
and 5.3% at
(CHCH2OH) gave an enhancement of 2.1% at
d
1.03 (CMe) gave enhancements of 5.1% at
3.87 (CH2OH). In addition, irradiation at
2.1 (CH2CH]CH2).
d
3.78 (CH2OH)
d
d
4.26
d
4.1.10. [(1S,2R,3S,4R,5R)-2-Allyl-3-benzyloxy-5-(tert-butyl-
dimethyl-silanyloxy)-4-methoxy-2-methyl-cyclopentyl]-
methanol (29b)
tert-Butyldimethylsilyl chloride (60 mg, 0.4 mmol) and imidaz-
ole (50 mg, 0.8 mmol) were added portionwise to a stirred solution
of the diol 29a (28 mg, 91 mmol) in anhydrous DMF (200 mL) at room
temperature under an argon atmosphere. The mixture was stirred at
room temperature for 2 days and then more tert-butyldimethylsilyl
chloride (60 mg, 0.4 mmol) and imidazole (50 mg, 0.8 mmol) were
added and the solution was stirred for a further 3 days. The mixture
was purified directly by flash chromatography, using diethyl ether–
solution of trimethylsilyldiazomethane (100 mL, 200 mmol, 2 M in
petrol (1:30) as eluent, to give the corresponding bis-silyl ether
dichloromethane) was added dropwise to a stirred solution of the
carboxylic acid in dry methanol–benzene (1:2, 3 mL), under a ni-
trogen atmosphere. The mixture was stirred at room temperature
for 1 h, and then concentrated in vacuo to leave the crude methyl
ester 30a, which was used without further purification. Tetrabu-
tylammonium fluoride (81.0 mg, 0.26 mmol) was added to a stirred
solution of the methyl ester in anhydrous THF (2.6 mL) at room
temperature under an argon atmosphere. The mixture was stirred
at room temperature for 26 h, and then diluted with diethyl ether
(12 mL) and water (3 mL). The separated aqueous layer was
extracted with diethyl ether (3ꢂ12 mL) and the combined organic
extracts were then dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash chromatography, using diethyl
24
(45 mg, 92%) as a colourless oil; [
a
]
D
þ16.9 (c 0.7, CHCl3); nmax
(CHCl3) 2955, 2856, 1602 cmꢁ1
;
1H NMR (360 MHz, CDCl3)
d 7.40–
7.27 (5H, m, ArH), 5.82 (1H, dddd, J¼7.0, 7.7, 10.2, 17.0 Hz, CH]CH2),
5.03 (1H, dd, J¼1.2, 10.2 Hz, CH]CHH), 4.96 (1H, dd, J¼1.2, 17.0 Hz,
CH]CHH), 4.69 (1H, d, J¼11.9 Hz, CHHPh), 4.60 (1H, d, J¼11.9 Hz,
CHHPh), 4.04 (1H, dd, J¼1.5, 6.2 Hz, CHOTBS), 3.79 (1H, dd, J¼7.9,
10.2 Hz, CHHOTBS), 3.67 (1H, dd, J¼6.0, 10.2 Hz, CHHOTBS), 3.63
(1H, dd, J¼1.5, 5.4 Hz, CHOMe), 3.46 (1H, d, J¼5.4 Hz, CHOBn), 3.42
(3H, s, OCH3), 2.17–2.11 (2H, m, CH2CH]CH2), 1.65 (1H, ddd, J¼6.0,
6.2, 7.9 Hz, CHCH2OTBS), 1.03 (3H, s, CCH3), 0.90 (9H, s, SiC(CH3)3),
0.89 (9H, s, SiC(CH3)3), 0.05 (3H, s, Si(CH3)), 0.04 (3H, s, Si(CH3)); 13
NMR (90 MHz, CDCl3)
C
d
139.2 (s),135.2 (d),128.3 (d)ꢂ2,127.5 (d)ꢂ2,
127.4 (d),117.6 (t), 95.0 (d), 89.2 (d), 77.3 (d), 72.2 (t), 59.0 (t), 57.7 (q),
48.3 (s), 45.0 (d), 43.5 (t), 26.1 (q)ꢂ3, 26.0 (q)ꢂ3,18.3 (s),18.2 (s),17.3
(q), ꢁ4.4 (q), ꢁ4.9 (q), ꢁ5.2 (q)ꢂ2; m/z (ES) found 535.3644 (MþHþ,
ether–petrol (2:1) as eluent, to give the
69% over four steps) as a colourless oil; [
b
-hydroxy ester (29.5 mg,
26
a
]
þ37.6 (c 0.17, CHCl3);
D
nmax (CHCl3) 3483 (br), 2934, 2902, 1708 cmꢁ1; 1H NMR (360 MHz,
C
30H55O4Si2 requires 535.3634).
CDCl3)
d
7.38–7.27 (5H, ArH), 5.71 (1H, dddd, J¼4.8, 7.5,10.2,17.0 Hz,
A solution of pyridinium para-toluenesulphonate (11.2 mg,
CH]CH2), 5.06 (1H, dd, J¼2.3, 10.2 Hz, CH]CHH), 4.76 (1H, br d,
J¼17.0 Hz, CH]CHH), 4.76 (1H, d, J¼12.0 Hz, CHHPh), 4.57 (1H, d,
J¼12.0 Hz, CHHPh), 4.19 (1H, dd, J¼2.1, 6.2 Hz, CHOH), 3.78 (1H,
dd, J¼2.1, 6.2 Hz, CHOMe), 3.77 (3H, s, CO2CH3), 3.50 (1H, d,
J¼6.2 Hz, CHOBn), 3.44 (3H, s, OCH3), 2.70 (1H, d, J¼6.2 Hz,
44.0
m
mol) in water (220
m
L) was added in one portion to a stirred
mol) in ethanol
solution of the bis-silyl ether (119 mg, 220
m
(2.2 mL). The mixture was stirred at room temperature for 60 h,
then brine was added (4 mL) and the mixture was extracted with

7406
N.P. Mulholland, G. Pattenden / Tetrahedron 64 (2008) 7400–7406
CHCO2Me), 2.26–2.18 (2H, m, CH2CH]CH2), 0.93 (3H, s, CCH3); 13
NMR (90 MHz, CDCl3)
127.7 (d)ꢂ2, 127.5 (d), 119.1 (t), 93.1 (d), 85.5 (d), 74.2 (d), 72.2 (t),
57.6 (q), 51.9 (q), 49.6 (d), 46.8 (s), 42.5 (t), 18.9 (q); m/z (ES) found
357.1649 (MþNaþ, C19H26NaO5 requires 357.1678).
C
References and notes
d
173.8 (s), 138.9 (d), 133.8 (s), 128.3 (d)ꢂ2,
1. Hasegawa, T.; Kamiya, T.; Henmi, T.; Iwasaki, H.; Yamatodani, S. J. Antibiot. 1975,
28, 167–175.
2. Nakagawa, M.; Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron Lett. 1991, 32,
659–662.
3. (a) Omura, S.; Nakagawa, A.; Shibata, K.; Sano, H. Tetrahedron Lett. 1982, 23,
4713–4716; (b) Umezawa, I.; Takeshima, H.; Komiyama, K.; Koh, Y.; Yamamoto,
H.; Komiyama, M. J. Antibiot. 1981, 34, 259–265.
4. (a) Raistrick, H.; Smith, G. Biochem. J. 1935, 29, 606–611; (b) Grove, J. F. J. Chem.
Soc. 1954, 4693–4694; (c) Barton, D. H. R.; Miller, E. J. Chem. Soc. 1955, 1028–
1029.
4.1.12. (3R,4S,5R)-5-Allyl-4-benzyloxy-2-hydroxy-3-methoxy-5-
methyl-cyclopent-1-enecarboxylic acid methyl ester (32a)
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
5. (a) Umino, K.; Furama, T.; Matzuzawa, N.; Awataguchi, Y.; Ito, Y.; Okuda, T.
J. Antibiot. 1973, 26, 506–512; (b) Umino, K.; Takeda, N.; Ito, Y.; Okuda, T. Chem.
Pharm. Bull. 1974, 22, 1233–1238.
ride (12 mg, 61
DMAP), then pyridine trifluoroacetate (7.9 mg, 41
added to a stirred solution of the -hydroxy ester 30b (3.4 mg,
10 mol) in dry DMSO (300 L) at room temperature under an ar-
gon atmosphere. The mixture was stirred at room temperature for 3
days, then water (500 L) was added and the mixture was extracted
L). The combined organic extracts were
m
mol), 4-dimethyl aminopyridine (1.2 mg, 10
mmol,
mmol) were
b
´
6. Martınez, A. G.; Vilar, E. T.; Fraile, A. G.; Cerero, S. M.; Osuna, S. O.; Maroto, B. L.
Tetrahedron Lett. 2001, 42, 7795–7799 and references cited therein.
7. cf. Hill, R. A.; Carter, R. H.; Staunton, J. J. Chem. Soc., Perkin Trans. 1 1981, 2570–
2576.
8. See for example: Birch, A. J.; Elliott, P. Aust. J. Chem. 1956, 9, 95–104; Liu, S.-Y.;
Ogihara, Y. J. Pharm. Soc. Jpn. 1975, 95, 1114–1118; Lee, H. H.; Tan, C. H. J. Chem.
Soc. C 1967, 1583–1585 and also see Ref. 7.
m
m
m
with diethyl ether (5ꢂ500
m
dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash chromatography, using diethyl ether–pentane
9. Preliminary communication: Mulholland, N. P.; Pattenden, G. Tetrahedron Lett.
2005, 46, 937–939.
(1:6) as eluent, to give the enol ester (3.0 mg, 89%) as a colourless
10. For a complementary, alternative, synthesis of the cyclopentane unit in vir-
idenomycin from our laboratory, based on an intramolecular rhodium-cata-
lysed C–H insertion reaction, see: Pattenden, G.; Blake, A. J.; Constandinos, L.
Tetrahedron Lett. 2005, 46, 1913–1915.
20
film; [
a
]
D
þ52.6 (c 0.19, CHCl3); nmax (CHCl3) 2977, 2874, 1661,
1619 cmꢁ1 1H NMR (360 MHz, CDCl3)
; d 10.55 (1H, s, OH), 7.42–
7.27 (5H, m, ArH), 5.59 (1H, dddd, J¼6.2, 8.5, 10.1, 16.4 Hz,
CH]CH2), 4.99 (1H, br d, J¼10.1 Hz, CH]CHH), 4.85 (1H, br
d, J¼16.4 Hz, CH]CHH), 4.78 (1H, d, J¼11.9 Hz, CHHPh), 4.68 (1H,
d, J¼11.9 Hz, CHHPh), 4.37 (1H, d, J¼6.5 Hz, CHOMe), 3.83 (1H, d,
J¼6.5 Hz, CHOBn), 3.82 (3H, s, CO2CH3), 2.52 (1H, dd, J¼6.2,
14.0 Hz, CHHCH]CH2), 2.23 (1H, dd, J¼8.5, 14.0 Hz, CHHCH]CH2),
11. (a) Arrington, M. P.; Meyers, A. I. Chem. Commun. 1999, 1371–1372; (b) Kruger,
A. W.; Meyers, A. I. Tetrahedron Lett. 2001, 42, 4301–4304; (c) Waterson, A. G.;
Kruger, A. W.; Meyers, A. I. Tetrahedron Lett. 2001, 42, 4305–4308.
12. Ishihara, J.; Hagihara, K.; Chiba, H.; Ito, K.; Yanagisawa, Y.; Totani, K.; Tadano, K.
Tetrahedron Lett. 2000, 41, 1771–1774.
13. Trost, B. M.; Jiang, C. H. Org. Lett. 2003, 5, 1563–1564.
14. (a) Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303–304; (b) Stork, G.; Sher,
P. M.; Chen, H.-L. J. Am. Chem. Soc. 1986, 108, 6384–6385.
15. For reviews on silicon-tethered reactions see: (a) Gauthier, D. R., Jr.; Zandi, K. S.;
Shea, K. J. Tetrahedron 1998, 54, 2289–2338; (b) Fensterbank, L.; Malacria, M.;
Sieburth, S. M. Synthesis 1997, 813–854; (c) For other earlier examples of sili-
con-tethered cyclisation reactions see: Fleming, I.; Barbero, A.; Walter, D. Chem.
Rev. 1997, 97, 2063–2192; (d) Nishiyama, H.; Kitajima, T.; Matsumoto, M.; Itoh,
K. J. Org. Chem. 1984, 49, 2298–2300; (e) Stork, G.; Kahn, M. J. Am. Chem. Soc.
1985, 107, 500–501; (f) Stork, G.; Sofia, M. J. J. Am. Chem. Soc. 1986, 108, 6826–
6828; (g) Crimmins, M. T.; O’Mahony, R. J. Org. Chem. 1989, 54, 1157–1161; (h)
Journet, M.; Malacria, M. J. Org. Chem. 1992, 57, 3085–3093; (i) Vandewalle, M.
Synlett 1994, 228–230; (j) Jenkins, P. R.; Wood, A. J. Tetrahedron Lett. 1997, 38,
1853–1856.
1.16 (3H, s, CCH3); 13C NMR (90 MHz, CDCl3)
d 170.8 (s), 169.9 (s),
138.5 (d), 135.1 (s), 128.2 (d)ꢂ2, 127.7 (d)ꢂ2, 127.5 (d), 117.7 (t),
85.7 (d), 84.1 (d), 77.2 (d), 72.6 (t), 58.5 (q), 51.2 (q), 44.4 (t), 42.1
(s), 21.7 (q); m/z (ES) found 355.1573 (MþNaþ, C19H24NaO5
requires 355.1521).
4.1.13. (3R,4S,5R)-5-Allyl-4-benzyloxy-2,3-dimethoxy-5-methyl-
cyclopent-1-enecarboxylic acid methyl ester (32b)
Potassium carbonate (13 mg, 95
(9.5 mg, 76 mol) were added portionwise to a stirred solution of the
enol ester 32a (6.3 mg, 19 mol) in dry DMSO (300 L) at room
temperature under an argon atmosphere. The mixture was stirred at
room temperature for 16 h, then water (300 L) was added and the
L). The combined
mmol) and dimethyl sulfate
16. Keck, G. E.; Burnett, D. A. J. Org. Chem. 1987, 52, 2958–2960.
17. Nagano, H.; Seko, Y.; Nakai, K. J. Chem. Soc., Perkin Trans. 1 1991, 1291–1295.
m
´
18. Bacque, E.; Pautrat, F.; Zard, S. Z. Org. Lett. 2003, 5, 325–328.
m
m
19. The use of AIBN in place of Bu6Sn2, using either heat or light, in this reaction
was unsuccessful, returning only starting material.
20. Bols, M.; Skrydstrup, T. Chem. Rev. 1995, 95, 1253–1277.
21. (a) Fleming, I. Chemtracts: Org. Chem. 1996, 9, 1–64; (b) Jones, G. R.; Landais, Y.
Tetrahedron 1996, 52, 7599–7662; (c) Tamao, K.; Nakajima, T.; Sumiya, R.; Arai,
H.; Higuchi, N.; Ito, Y. J. Am. Chem. Soc. 1986, 108, 6091–6093.
m
mixture was extracted with diethyl ether (5ꢂ500
m
organic extracts were dried over MgSO4 and then concentrated in
22. A similar outcome was obtained when acrylonitrile was used as the trapping
agent, i.e., treatment of 14 with n-Bu3SnCl, CH2]CH–CN, NaBH3CN, AIBN,
reflux, then Tamao oxidation.
23. (a) Josan, J. S.; Eastwood, F. W. Carbohydr. Res. 1968, 7, 161–166; (b) Yan, S.;
Klemm, D. Tetrahedron 2002, 58, 10065–10071; (c) Gurjar, M. K.; Patil, V. J.;
Pawar, S. M. Carbohydr. Res. 1987, 165, 313–317.
vacuo to leave the methyl enol ether (6.4 mg, 97%) as a colourless
22
film;
[
a]
þ35.5 (c 0.58, CHCl3); nmax (CHCl3) 2949, 1698,
D
1627 cmꢁ1
;
1H NMR (360 MHz, CDCl3)
d
7.42–7.27 (5H, m, ArH),
5.59 (1H, dddd, J¼6.1, 8.6, 10.1, 17.1 Hz, CH]CH2), 5.00 (1H, br d,
J¼10.1 Hz, CH]CHH), 4.87 (1H, br d, J¼17.1 Hz, CH]CHH), 4.73
(1H, d, J¼11.7 Hz, CHHPh), 4.67 (1H, d, J¼11.7 Hz, CHHPh), 4.47 (1H,
d, J¼5.5 Hz, CHOMe), 3.89 (3H, s, OCH3), 3.87 (1H, d, J¼5.5 Hz,
CHOBn), 3.73 (3H, s, CO2CH3), 3.40 (3H, s, OCH3), 2.55 (1H, dd,
J¼6.1, 14.0 Hz, CHHCH]CH2), 2.22 (1H, dd, J¼8.6, 14.0 Hz,
CHHCH]CH2), 1.16 (3H, s, CCH3); 13C NMR (90 MHz, CDCl3)
24. Lay, L.; Nicotra, F.; Panza, L.; Russo, G.; Caneva, E. J. Org. Chem. 1992, 57, 1304–
1306.
25. Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313–315.
26. (a) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc.
2000, 122, 3783–3784; (b) Chauvin, Y. Angew. Chem., Int. Ed. 2006, 45, 3740–
3747; (c) Schrock, R. R. Angew. Chem., Int. Ed. 2006, 45, 3748–3759; (d) Grubbs,
R. H. Angew. Chem., Int. Ed. 2006, 45, 3760–3765; (e) Nicolaou, K. C.; Bulger,
P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527; (f) Aburel, P. S.;
Romming, C.; Ma, K.; Undheim, K. J. Chem. Soc., Perkin Trans. 1 2001, 1458–1472;
d
165.30 (s), 161.8 (s), 138.5 (s), 135.5 (d), 128.2 (d)ꢂ2, 127.7 (d)ꢂ2,
117.9 (t), 112.7 (s), 85.5 (d), 84.1 (d), 77.3 (d), 72.7 (t), 58.3 (q), 56.1
(q), 51.2 (q), 46.6 (q), 42.8 (t), 21.8 (q); m/z (ES) found 369.1677
(MþNaþ, C20H26NaO5 requires 369.1678).
´
(g) Ovaa, H.; Lastdrager, B.; Codee, J. D. C.; van der Marel, G. A.; Overkleeft, H. S.;
van Boom, J. H. J. Chem. Soc., Perkin Trans. 1 2002, 2370–2377.
27. ACCN has two advantages over AIBN. Firstly it is more soluble in the preferred
solvent n-heptane and, secondly, it has a longer half-life in solution, thus
producing a more constant source of initiating radical species. n-Heptane is the
preferred solvent over the more traditional solvents such as benzene and tol-
uene, as these solvents are known to participate in a number of side reactions,
for example, hydrogen abstraction.
Acknowledgements
28. (a) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85, 3027–3028; (b)
Hanessian, S.; Lavellee, P. Can. J. Chem. 1981, 59, 870–877.
29. Bennett, N. J.; Prodger, J. C.; Pattenden, G. Tetrahedron 2007, 63, 6216–6231.
We thank AstraZeneca for financial support (studentship to
N.P.M.) and Dr. Iain Walters for his interest in this project.