Fast and efficient synthesis of novel fumagillin analogues

Article abstract of DOI:10.1016/S0040-4020(02)00514-8

A novel class of non-carbocyclic ring analogues of the potent angiogenesis inhibitors fumagillin and TNP-470 have been enantioselectively and efficiently synthesised starting from pyridine-2-thiol in 10 steps in excellent overall yield.

Full text of DOI:10.1016/S0040-4020(02)00514-8

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 5441±5452
Fast and ef®cient synthesis of novel fumagillin analogues
p
Jack E. Baldwin, Paul G. Bulger and Rodolfo Marquez
Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford OX1 3QY, UK
Received 18 March 2002;revised 23 April 2002;accepted 16 May 2002
AbstractÐA novel class of non-carbocyclic ring analogues of the potent angiogenesis inhibitors fumagillin and TNP-470 have been
enantioselectively and ef®ciently synthesised starting from pyridine-2-thiol in 10 steps in excellent overall yield. q 2002 Elsevier Science
Ltd. All rights reserved.
Fumagillin 1, isolated in 1951 by Elbe and Hanson from the
microbial organism Aspergillus fumigatus, was originally
described as an anti-microbial agent. However, in 1990,
the spiro epoxide of fumagillin, resulting in irreversible
inhibition.
8
1
Folkman and co-workers discovered that fumagillin
potently and selectively inhibits angiogenesis (the growth
of blood vessels). Angiogenesis inhibitors are of great
2
3
potential therapeutic use and as a result of this discovery
a considerable effort was made to explore the biological
activity of fumagillin and its synthetic analogues.
4
Thus, based on an analysis of the reported biological data
and structural studies, a series of novel ring oxygenated
analogues have been designed and synthesised.
It was expected that replacing the methoxy-substituted C5
atom with an oxygen atom would result in an increase in the
rigidity of the cyclohexyl ring core, due to the anomeric
The compound TNP-470 2, a semi-synthetic derivative of
fumagillin, has become one of the most promising small
molecule cancer treatment candidates to date, and is
currently in phase III clinical trials for the treatment of a
effect at the C position. This would possibly result in a
6
better ®t within the MetAP-2 active site, as the cyclohexyl
ring in fumagillin appears to be somewhat ¯attened upon
binding within the active site.
5
variety of cancers. Unfortunately, though more potent than
fumagillin, TNP-470 has shown low half-life values, neuro-
toxic side effects (fatigue, vertigo, ataxia and loss of concen-
tration) and possible disruption of normal angiogenic
processes (female reproductive system, wound healing),
Furthermore, the introduced oxygen atom should also main-
tain the electrostatic interaction between the trisubstituted
epoxide of the C side-chain and the water556 molecule in
4
the active site. It is believed that this interaction may play a
6
which limit the available patient dosage.
Fumagillin 1 and its analogues have been shown to bind
very selectively to the protein methionine aminopeptidase
crucial role in the correct orientation of the C
within the active site.
side-chain
4
7
type 2 (MetAP-2). X-Ray crystal data has shown the mode
of biological action to involve covalent bond formation by
attack of the His231 residue in the MetAP-2 active site on
Keywords: fumagillin;TNP-470;angiogenesis inhibitors;analogues;furan
rearrangement.
p
Corresponding author. Tel.: 144-1865-275670;fax: 144-1865-275632;
e-mail: jack.baldwin@chem.ox.ac.uk
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00514-8

5442
J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
Scheme 1.
Herein we describe a fast and ef®cient synthesis of this new
class of oxygenated fumagillin analogues, beginning with
cheap and readily available starting materials.
yield, and as a 1.5:1 mixture of diastereomers at the newly
formed anomeric position.
With the six-membered ring core in place, we then turned
our attention to the introduction of the required spiro
epoxide functionality at C . Thus, protection of the ano-
We proposed that the six-membered ring core could be
constructed by the well-known oxidative rearrangement of
furyl carbinol 5 to pyranone 4 (Scheme 1). Appropriate
functional-group transformations would then give the
desired targets 3. Furyl carbinol 5 could in turn be obtained
by chelation-controlled addition of 2-furyllithium 6 to
epoxy aldehyde 7. Finally, the chiral epoxy aldehyde
intermediate could be obtained by Sharpless epoxidation
of allylic alcohol 8 (Scheme 1).
3
9
meric hydroxyl group as the acetate, followed by catalytic
hydrogenation of the enone double bond proceeded cleanly
to afford the desired ketone 14 in good yield. However,
conversion of ketone 14 into the spiro epoxide 15 proved
to be extremely challenging, as previously reported epoxi-
1
2
dation conditions were met with a complete lack of
success. It was not until the epoxidation was attempted
1
3
using the highly nucleophilic bromomethyllithium, gener-
ated in situ, that the desired spiro epoxide was obtained.
Although the yield was only moderate, most likely due to
competing attack of the bromomethyl anion on the acetate
group, the product was formed as a single diastereomer,
with the initial attack being on the less hindered face of
the ketone.
Our synthesis began with commercially available 3-buten-
1-ol 9, which was readily silyl protected and then ozono-
lysed to afford the desired aldehyde adduct (Scheme 2).
1
0
Wittig ole®nation, followed by ester reduction, generated
the expected allylic alcohol 10 in good yield. Epoxidation
1
1
of alcohol 10 under racemic conditions, followed by
Swern oxidation of the resulting epoxy alcohol intermediate
afforded the corresponding aldehyde 11 in excellent yield
for both steps.
Removal of the silyl protecting group afforded alcohol
15, which was then oxidised to the corresponding alde-
hyde. However, ole®nation of the aldehyde failed to
produce any of the desired alkene, instead yielding
enal 16 as the sole product, which arose as a result of
b-elimination of the side-chain epoxide rather than ole®-
nation. This elimination, while easily explained, was
nevertheless extremely disappointing, considering
previous reports that indicated that such an ole®nation,
Alkylation of epoxy aldehyde 11 with 2-furyllithium
proceeded cleanly to yield the desired secondary alcohol
1
2 in reasonable yield and as a 4:1 mixture of separable
diastereomers at the newly formed stereocentre, with the
main addition product being formed via a Cram chelation-
controlled transition state. Treatment of alcohol 12 with
mCPBA resulted in oxidative rearrangement to produce
1
2
as was used in a total synthesis of fumagillin itself,
would be successful.
enone 13 with the correct stereochemistry at C in good
4
Scheme 2. Reagents and conditions: (a) TBSCI, Imid.;(b) O
then 11;(h) mCPBA;(i) Ac O;Py;(j) H , Pd/C;(k) CH Br
3
, DMS;(c) PPh C(Me)CO
, nBuLi;(l) TBAF;(m) Swern;(n) NaH, (CH
3
2
Et;(d) Dibal-H;(e) VO(acac) , TBHP;(f) Swern;(g) furan, nBuLi,
3
CHPPh Br.
2
2
2
2
2
3
)
2

J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
5443
Scheme 5.
lytic hydrogenation was unsatisfactory, as the side chain
double bond was reduced preferentially, and it was only
after considerable experimentation that the appropriate
conditions were found, namely the use of Raney-Nickel in
THF. However, while the silyl 23, methyl 24 and ethoxy-
ethyl 25 protected lactols produced the desired saturated
ketones 27±29, acetate 22 underwent concomitant hydro-
genolysis to afford pyran 26 as the sole product.
Scheme 3. Reagents and conditions: (a) 3-chloro-2-methyl-propene,
NaOEt;(b) prenyl bromide, nBuLi;(c) mCPBA;(d)Et NH;(e) d-(2)-
nBuLi, then 19;(g)
, TBHP;(h) RX, base or ethylvinyl ether, PPTS.
2
i
DIPT, Ti(O Pr)
4
, TBHP;(f) Swern;(g) furan,
1
6
VO(acac)
2
The inability to prevent this elimination from occurring in
the last step of this route prompted us to modify our
approach, namely to introduce the complete side chain at
the beginning of the synthetic sequence.
Epoxidation of ketones 27±29 was again only possible
using bromomethyllithium, and with mixed results (Scheme
5). Thus, while the methyl 28 and ethoxyethyl 29 protected
The modi®ed approach (Scheme 3) began with commer-
cially available 2-mercaptopyridine 17 which, following
compounds were cleanly converted into spiro epoxides 30
and 31 in good yield and as single diastereomers at the newly
formed stereocentre, silyl ether 27 failed to undergo any
reaction, and most of the starting material could invariably
be recovered unchanged.
1
4
the procedure of Mori and Ueda, was converted in four
steps in good yield to the unconjugated dienol 18. Sharpless
epoxidation followed by Swern oxidation gave epoxy
aldehyde 19 in good yield and excellent enantiomeric
1
5
excess (ee.98%).
The ®nal steps of the synthesis were then deprotection
followed by acylation of the anomeric hydroxyl group.
Unfortunately, hydrolysis of the methyl ether protecting
group under a variety of conditions proved unsuccessful in
both the 30a and 30b anomeric series. However treatment
of compound 31 with PPTS in acetone/water (4:1 v/v) at
458C resulted in clean removal of the ethoxyethyl group,
forming lactol 32 in excellent yield (Scheme 6).
Addition of 2-furyllithium again proceeded cleanly to yield
the secondary alcohol as a 3.5:1 mixture of diastereomers,
with the desired product 20 being isolated in 59% yield after
chromatographic separation. Oxidative rearrangement of
the furan ring was ®rst attempted using mCPBA as before,
but this led to preferential epoxidation of the trisubstituted
double bond. However, treatment of furan 20 under
hydroxyl-directed epoxidation conditions (VO(acac)2/
Once synthesised, the key lactol 32 allowed us to easily
install various side chains at the C position by simple acyl-
1
1
t-butylhydroperoxide) produced the desired enone 21 in
reasonable yield and as a 1.5:1 mixture of diastereomers at
the anomeric position.
6
ation. Thus, treatment of lactol 32 with chloroacetyl iso-
cyanate or acetic anhydride generated the desired
carbamate and acetate analogues 33 and 34, respectively
(a/b ratios typically .10:1). The absolute stereochemistry
of the ®nal products was con®rmed through nOe analysis.
A variety of protecting groups were then investigated for the
protection of the anomeric hydroxyl group, with protection
as the acetate ester and the TBS, methyl and ethoxyethyl
ethyl ethers under standard conditions to afford the desired
protected hemiketals 22±25 in good yields.
Chemoselective reduction of the enone double bond in
hemiketals 22±25 was then performed (Scheme 4). Cata-
In conclusion, we have rapidly and ef®ciently completed the
enantioselective synthesis of the ®rst non-carbocyclic ana-
logues of fumagillin and TNP-470 in ten ¯exible and easily
modi®able steps staring from commercially available
2-mercaptopyridine. We hope that this novel class of
compounds will shed further light into the mechanism of
fumagillin's anti-angiogenic activity, while at the same time
addressing some of the toxicity side effects.
Scheme 4.

5444
J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
2 2
Scheme 6. Reagents and conditions: (a) PPTS, acetone, water;(b) ClCH COCNO;(c) Ac O, Py.
All reactions were performed in oven-dried (24 h at 1108C)
glassware under inert (Ar or N ) atmosphere. Anhydrous
2
THF and Et O were obtained by distillation from sodium
2
benzophenone ketyl under N . Anhydrous DCM was
2
obtained by distillation from CaH under N . `40/60 Petrol'
2
2
refers to that fraction of light petroleum ether boiling at
40±608C and was distilled before use.
The carbamate 33, acetate 34 and both a- and b-methoxy
analogues 30a and 30b analogues have been submitted for
biological testing and the results will be reported shortly.
1.2. Experimental procedures
1. Experimental
1.2.1. (2E)-2-Methyl-5-[((1,1-dimethyl)ethyl)dimethyl-
1
.1. General methods
silylsilyloxy] pent-2-en-1-ol (10). To a stirred solution of
-buten-1-ol (4.93 g, 68.4 mmol, 1.0 equiv.) in dry DCM
(70 ml) was added imidazole (5.12 g, 75.2 mmol,
1.1 equiv.) and TBSCl (11.7 g, 75.2 mmol, 1.1 equiv.) at
rt. After 90 min, the mixture was partitioned between
3
1
H NMR spectra were recorded on Bruker DPX250
250 MHz), DPX400 (400 MHz), DRX500 (500 MHz) or
(
1
3
AMX500 (500 MHz) spectrometers. C NMR spectra
were recorded on Bruker DPX250 (63 MHz), DPX400
Et
washed with 10% HCl (70 ml), brine (70 ml), dried
(MgSO ), ®ltered and concentrated to afford the crude
O (200 ml) and H O (100 ml). The organic layer was
2
2
(
100 MHz) or AMX500 (125 MHz). Chemical shifts (d)
are reported in ppm, and are referenced to the residual
solvent peak. Coupling constants (J) are quoted to the
nearest 0.1 Hz.
4
silyl ether (13.23 g) as a colourless oil, which was used
without further puri®cation in the next step.
IR spectra were recorded as a thin ®lm between NaCl plates
on a Perkin±Elmer 1750 FTIR spectrometer. Only selected
peaks are reported, absorption maxima being recorded in
Ozone was bubbled through a solution of the crude silyl
ether (13.23 g) in DCM (80 ml) at 2788C until a pale
blue colour developed. Oxygen was bubbled through the
solution for 5 min to remove the excess ozone, followed
by argon for another 5 min. Dimethyl sulphide (200 ml)
was added, and the mixture was allowed to warm to rt and
stirred for 24 h. The mixture was concentrated, then par-
2
1
cm .
Low-resolution mass spectra (m/z) were recorded on V. G.
Masslab (CI), Micromass Platform 1 (APCI) or V. G. Trio 1
(
GCMS) spectrometers. m/z values of major peaks are
titioned between Et
aqueous layer was extracted with Et
the combined organic layers were washed with brine
(100 ml), dried (MgSO ), ®ltered and concentrated to afford
the aldehyde (12.75 g) as a colourless oil which was used
without further puri®cation in the next step.
2
O (150 ml) and H
2
O (150 ml). The
reported in Daltons, with intensities quoted as percentages
of the base peak. High-resolution mass spectra were
recorded on a V. G. Autospec chemical ionisation mass
spectrometer.
2
O (2£100 ml), and
4
1
4
TLC was performed on Merck aluminium foil-backed
sheets precoated with 0.2 mm Kieselgel 60 F254. Product
spots were visualised by the quenching of UV ¯uorescence
To a stirred solution of the crude aldehyde (12.75 g) in tolu-
ene (230 ml) was added (1-ethoxycarbonylethylidene)tri-
phenylphosphorane (25 g, 69 mmol, ca. 1.0 equiv.) in one
portion at rt. The mixture was re¯uxed for 18 h, then cooled
to rt and concentrated. The residue was dissolved in hexane
(200 ml), and the precipitated triphenylphosphine oxide
(
lmax, 254 nm), or by staining with a solution of 5% (w/v)
dodecamolybdophosphoric acid in EtOH followed by
heating. Flash column chromatography was performed
using silica gel (Sorbisile C60 40±60 mm).

J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
5445
®ltered off. The ®ltrate was then concentrated. Puri®cation
by ¯ash column chromatography (47:3 30/40 petrol/Et O)
DMSO (2.4 ml, 33.4 mmol, 4.0 equiv.) in dry DCM (5 ml)
dropwise at 2788C. After 10 min a solution of the epoxy
alcohol (2.06 g, 8.35 mmol, 1.0 equiv.) in dry DCM (10 ml)
2
gave ethyl (2E)-2-methyl-5-[((1,1-dimethyl)ethyl)dimethyl-
silyloxy]pent-2-enoate (13.43 g, 72%) as a colourless oil: R
was added dropwise. After 20 min Et N (9.3 ml, 66.8 mmol,
3
f
2
.24 (47:3 30/40 petrol/Et O); nmax(®lm) (cm ) 2956,
1
0
2
0
8.0 equiv.) was added, and the mixture allowed to warm to
rt. After 1 h the mixture was poured into H O (50 ml). The
2
859, 1714, 1653, 1472, 1257, 837; d (400 MHz;CDCl )
H
.04 (6H, s), 0.88 (9H, s), 1.27 (3H, t, Jˆ7.1 Hz), 1.83 (3H,
3
2
aqueous layer was extracted with DCM (2£40 ml), and the
d, Jˆ0.9 Hz), 2.35±2.40 (2H, m), 3.69 (2H, t, Jˆ6.7 Hz),
combined organic layers were dried (MgSO ), ®ltered and
4
4
CDCl ) 25.38, 12.48, 14.21, 18.25, 25.83, 32.32, 60.34,
.17 (2H, t, Jˆ7.1 Hz), 6.72±6.76 (1H, m); d (100 MHz;
concentrated. Puri®cation by ¯ash column chromatography
(6:1 40/60 petrol/Et O) gave the title compound (1.877 g,
C
3
2
61.68, 129.18, 138.45, 167.99; m/z (GCMS) 290 (95%,
MNH ), 273 (100, MH ), 215 (42), 141 (31);HRMS:
92%) as a colourless oil: R 0.55 (1:1 40/60 petrol/Et O);
2
f
1
1
21
nmax(®lm)/cm 2957, 2931, 1732, 1472, 1257, 1099, 837;
d (500 MHz;CDCl ) 0.07 (6H, s), 0.89 (9H, s), 1.41 (3H,
4
1
Found 273.1886 (MH ). C H O Si requires 273.1886.
1
4
29
3
H
3
s), 1.81±1.91 (2H, m), 3.32 (1H, t, Jˆ5.8 Hz), 3.82 (2H, dd,
To a stirred solution of the ester (1.074 g, 3.9 mmol,
.0 equiv.) in dry Et O (20 ml) at 2788C was added Dibal
Jˆ6.9, 5.1 Hz), 8.87 (1H, s); d (126 MHz;CDCl ) 25.56,
C
3
1
10.11, 18.13 25.73, 31.13, 57.76, 59.85, 62.02, 199.94; m/z
(GCMS) 246 (100%, MH ), 229 (79), 171 (57), 83 (65);
2
1
(
3
7.8 ml of a 1.5 M solution in toluene, 11.7 mmol,
.0 equiv.) dropwise over 5 min. The mixture was stirred
1
HRMS: Found 247.1737 (MH ). C H O Si requires
247.1729.
1
2
27
3
at 2788C for 1 h, then at 08C for 1 h, then quenched by
the cautious addition of MeOH (5 ml). 3 M Sodium potas-
sium tartrate tetrahydrate (50 ml) was added, and the
mixture stirred for 3 h. The layers were separated, and
the aqueous layer extracted with EtOAc (3£30 ml). The
combined organic layers were washed with brine (50 ml),
dried (MgSO ), ®ltered and concentrated. Puri®cation by
4
1.2.3. (^)-(1R){(2R,3R)-2-Methyl-3-[2-[((1,1-dimethyl)-
ethyl)dimethylsilyloxy]ethyl]oxiran-2-yl}-22-furyl-
methan-1-ol (12). To a stirred solution of furan (freshly
¯
gave the title compound (0.87 g, 96%) as a colourless oil:
ash column chromatography (3:2 30/40 petrol/Et O)
2
2
1
R 0.31 (3:2 30/40 petrol/Et O); nmax(®lm)/cm
2
CDCl ) 0.06 (6H, s), 0.89 (9H, s), 1.68 (3H, s), 2.24±2.30
3350,
897, 2858, 1671, 1473, 1256, 1095; d (400 MHz;
distilled from CaCO , 0.64 ml, 8.83 mmol, 1.3 equiv.) in
3
f
2
H
dry THF (40 ml) was added nBuLi (3.8 ml of a 2.33 M
solution in hexane, 8.83 mmol, 1.3 equiv.) dropwise at
2788C. The mixture was stirred at 2788C for 20 min, at
258C for 3 h, at rt for 10 min, and was then recooled to
2788C before a solution of aldehyde (11) (1.66 g,
6.79 mmol, 1.0 equiv.) in dry THF (8 ml) was added drop-
wise. The mixture was stirred at 2788C for 2 h then allowed
to warm to rt overnight. The mixture was quenched with sat.
3
(
(
2H, m), 3.60 (2H, t, Jˆ7.0 Hz), 3.99 (1H, br s), 5.38±5.40
1H, m); d (100 MHz;CDCl ) 25.41, 13.75, 18.33, 25.91,
C
3
1
1.40, 62.71, 68.77, 122.05, 136.59; m/z (CI ) 248 (28%,
3
MNH ), 231 (27, MH ), 213 (100), 132 (24), 99 (25).
1
4
1
aq. NH Cl (50 ml). The layers were separated, and the
4
aqueous layer extracted with Et O (3£30 ml). The
2
1
.2.2. (^)-{(2S,3R)-3-[2-[((1,1-Dimethyl)ethyl)dimethyl-
silyloxy)ethyl] oxiran-2-methyloxirane-2-carbaldehyde
11). To a stirred solution of alcohol (10) (0.4 g,
.74 mmol, 1.0 equiv.) in benzene (15 ml) was added
combined organic layers were dried (MgSO ), ®ltered and
4
1
concentrated. H NMR analysis of the crude product
mixture indicated a 4:1 mixture of diastereomers. Puri®-
cation by ¯ash column chromatography (23:2 DCM:EtOAc)
gave the title compound (1.389 g, 65%) as a pale yellow oil:
(
1
VO(acac) (18 mg, 0.05 mmol, 0.03 equiv.) then tert-butyl-
2
hydroperoxide (0.42 ml of a 5 M solution in decane,
2
1
R
1472, 1257, 1097, 835; d (400 MHz;CDCl ) 0.07 (6H, s),
0.29 (23:2 DCM:EtOAc); nmax(®lm)/cm 3436, 2885,
f
2
.08 mmol, 1.2 equiv.) at rt. After 3 h more tert-butylhydro-
peroxide (0.1 ml) was added. After another 2 h, the mixture
H
3
0.90 (9H, s), 1.24 (3H, s), 1.76±1.86 (2H, m), 2.60 (1H, d,
Jˆ6.8 Hz), 3.27 (1H, dd, Jˆ6.7, 5.6 Hz), 3.79 (1H, m), 4.49
(1H, d, Jˆ6.7 Hz), 6.34±6.36 (2H, m), 7.39 (1H, m);
was concentrated. The residue was dissolved in Et O,
2
®
tion by ¯ash column chromatography (1:1 30/40 petrol/
ltered through a pad of Florisil, and concentrated. Puri®ca-
d (100 MHz;CDCl ) 12.85, 18.30, 25.89, 31.62, 58.22,
C 3
Et O) gave (^)-{(2S,3R)-2-methyl-3-[2-[((1,1-dimethyl)-
2
60.27, 62.24, 71.58, 107.26, 110.22, 142.19, 153.37.
ethyl)dimethylsilyloxy)ethyl]oxiran-2-yl}methan-1-ol (0.41 g,
9
nmax(®lm)/cm
6%) as a colourless oil: R 0.32 (1:1 30/40 petrol/Et O);
f 2
2
1
3436, 2930, 1472, 1256, 1098, 836;
d (400 MHz;CDCl ) 0.06 (6H, s), 0.89 (9H, s), 1.29 (3H,
H
3
s), 1.74±1.83 (2H, m), 1.97 (1H, dd, Jˆ8.4, 4.7 Hz), 3.16
(
1H, t, Jˆ6.3 Hz), 3.56 (1H, dd, Jˆ12.2, 8.4 Hz), 3.69 (1H,
dd, Jˆ12.2, 4.7 Hz), 3.76±3.80 (2H, m); d (63 MHz;
C
CDCl ) 25.06, 14.69, 18.63, 26.25, 31.95, 58.40, 60.70,
3
1.2.4. (^)-2-{(3R)-2-Methyl-3-[2-[(1,1-dimethyl)ethyldi-
methylsilyloxy]ethyl]oxiran-2-yl}(6S,2R)-6-hydroxy-6-
hydro-2H-pyran-3-one (13). To a stirred solution of furan
1
4
6
MH ), 229 (100), 189 (65), 171 (34), 97 (58).
1.57, 66.02; m/z (CI) 264 (18%, MNH ), 247 (96,
1
(
12) (1.382 g, 4.42 mmol, 1.0 equiv.) in dry DCM (35 ml)
To a stirred solution of oxalyl chloride (1.46 ml, 16.7 mmol,
2
was added mCPBA (55% purity, 1.526 g, 4.87 mmol,
1.1 equiv.) in one portion at 08C. The mixture was allowed
.0 equiv.) in dry DCM (30 ml) was added a solution of

5446
J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
to warm to rt over 22 h, then partitioned between 50% sat.
aq. Na S O (60 ml) and DCM (40 ml). The layers were
2
2
3
separated, and the organic layer was washed with sat. aq.
NaHCO3 (40 ml). The combined aqueous layers were
extracted with DCM (3£40 ml). The combined organic
layers were dried (MgSO ), ®ltered and concentrated to
4
afford the crude product (1.36 g, 94%) as a pale yellow oil
and as a 1:1.5 mixture of anomers. This material was used
without further puri®cation in the next step: R 0.27 (21:4
1.2.6. (^)-4-[(3R)-3-(2-Hydroxyethyl)-2-methyloxiran-2-
yl](3S,4S,6R)-1,5-dioxaspiro[2.5]oct-6-yl acetate (15). To
a stirred solution of ketone (14) (68 mg, 0.18 mmol,
1.0 equiv.) and dibromomethane (15 ml, 0.22 mmol,
f
DCM:EtOAc).
1.2 equiv.) in dry THF (2 ml) was added nBuLi (84 ml of
a 2.32 M solution in hexanes, 0.19 mmol, 1.05 equiv.) drop-
wise at 2788C. The mixture was allowed to warm to rt, and
stirred for 18 h. The mixture was partitioned between Et O
2
(10 ml) and sat. aq. NH Cl (10 ml). The aqueous layer was
4
extracted with Et O (3£10 ml), dried (MgSO ), ®ltered and
2
4
concentrated. Puri®cation by ¯ash column chromatography
(14:11 40/60 petrol/Et O) gave (^)-4-[(3R)-3-[2-[((1,1-di-
methyl)ethyl)dimethylsilyloxy]ethyl]-2-methyloxiran-2-yl]-
1
.2.5. (^)-6-{(3R)-2-Methyl-3-[2-[((1,1-dimethyl)ethyl)-
2
dimethylsilyloxy]ethyl]oxiran-2-yl}(2R,6R)-5-oxo-3,4,6-
trihydro-2H-pyran-2-yl acetate (14). To a stirred solution
of pyranone (13) (80 mg, 0.24 mmol, 1.0 equiv.) in dry
DCM (6 ml) was added pyridine (160 ml, 1.95 mmol,
(3S,4S,6R)-1,5-dioxaspiro[2.5]oct-6-yl acetate (30 mg,
42%) as a pale yellow oil: R
0.16 (3:2 40/60 petrol/Et
2955, 1749, 1372, 1204, 1096;
(400 MHz;CDCl ) 0.08 (6H, s), 0.91 (9H, s), 1.25±
O);
f
2
2
1
n
d
max(®lm)/cm
8
5
.0 equiv.), acetic anhydride (110 ml, 1.22 mmol,
.0 equiv.) and DMAP (45 mg) at 08C. After 90 min H O
H
3
1.32 (1H, m), 1.29 (3H, s), 1.71±1.79 (2H, m), 1.86 (1H,
dt, Jˆ13.9, 1.6 Hz), 2.10 (3H, s), 2.22±2.27 (1H, m), 2.34±
2.39 (1H, m), 2.56 (1H, d, Jˆ4.3 Hz), 2.86 (1H, t, Jˆ
6.0 Hz), 3.02 (1H, d, Jˆ4.3 Hz), 3.76 (1H, s), 3.77±3.80
2
(
10 ml) was added. The layers were separated, and the
aqueous layer extracted with DCM (3£10 ml). The
combined organic layers were washed with brine
(
1£20 ml), dried (MgSO ), ®ltered and concentrated. Puri-
(2H, m), 6.35 (1H, s); d (100 MHz;CDCl ) 12.79, 18.29,
C 3
4
®cation by ¯ash column chromatography (27:23 40/60
petrol/Et O) gave (^)-6-{(3R)-2-methyl-3-[2-[((1,1,-di-
21.24, 25.88, 26.37, 26.92, 31.25, 50.34, 56.02, 58.45,
59.30, 60.18, 78.39, 91.93, 125.50, 169.40; m/z (CI) 404
2
1
1
methyl)ethyl)dimethylsilyloxy] ethyl]oxiran-2-yl}(2R,6R)-
-oxo-6-hydro-2H-pyran-2-yl acetate (55 mg, 61%) as a
(4%, MNH
(50), 95 (57).
), 387 (3, MH ), 309 (100), 195 (47), 165
4
5
pale yellow 1oil: Rf 0.27 (1:1 40/60 petrol/Et O);
2
2
nmax(®lm)/cm
2956, 2868, 1759, 1699, 1462, 1213,
100; d (400 MHz;CDCl ) 0.09 (6H, s), 0.91 (9H, s),
To a stirred solution of the spiro epoxide (80 mg,
0.21 mmol, 1.0 equiv.) in dry THF (4 ml) was added
TBAF (0.25 ml of a 1 M solution in THF, 0.25 mmol,
1.2 equiv.) dropwise at rt. After 1 h more TBAF (0.1 ml)
was added. After another 90 min, the mixture was par-
1
1
H
3
.27 (3H, s), 1.71±1.80 (1H, m), 1.90±1.99 (1H, m), 2.13
(
4
3H, s), 3.14 (1H, dd, Jˆ7.2, 5.1 Hz), 3.81±3.88 (2H, m),
.13 (1H, s), 6.23 (1H, d, Jˆ10.3 Hz), 6.60 (1H, d,
Jˆ3.7 Hz), 6.94 (1H, dd, Jˆ10.3, 3.7 Hz); d (100 MHz;
titioned between EtOAc (10 ml) and H O (10 ml). The
2
C
CDCl ) 25.38, 12.36, 18.27, 20.92, 25.88, 31.38, 58.56,
3
aqueous layer was extracted with EtOAc (3£10 ml). The
5
1
9.67, 60.11, 81.78, 86.73, 128.44, 142.18, 169.28,
92.46; m/z (CI) 311 (100%, [M2OAc] ), 293 (46), 253
combined organic layers were washed with brine
(1£10 ml), dried (MgSO
1
), ®ltered and concentrated. Puri-
4
(
61).
®cation by ¯ash column chromatography (EtOAc) gave the
title compound (45 mg, 80%) as a colourless oil: R 0.22
f
2
1
To a solution of the acetate (51 mg, 0.14 mmol, 1.0 equiv.)
in EtOAc (6 ml) was added 10% Pd/C (15 mg). The mixture
was degassed and ¯ushed with H three times, then placed
(EtOAc); nmax(®lm)/cm 3462, 2936, 1748, 1205, 1010;
(250 MHz;CDCl ) 1.31 (3H, s), 1.78±1.89 (3H, m),
d
H
3
2.09 (3H, s), 2.16±2.33 (3H, m), 2.62 (1H, d, Jˆ4.2 Hz),
2.90 (1H, t, Jˆ5.8 Hz), 2.94 (1H, d, Jˆ4.2 Hz), 3.75 (1H, s),
3.80±3.86 (2H, m), 6.33±6.35 (1H, m); d (63 MHz,CDCl )
C 3
2
under H (balloon) and stirred for 22 h. The mixture was
2
®ltered through Celite, and the ®ltrate concentrated. Puri®-
cation by ¯ash column chromatography (27:23 40/60 petrol/
13.26, 21.62, 26.73, 27.37, 30.81, 50.97, 56.57, 58.99,
59.75, 60.45, 78.55, 92.23, 169.89; m/z (CI) 290 (31%,
Et O) gave the title compound (43 mg, 86%) as a colourless
2
2
1
1
oil: R 0.23 (27:23 40/60 petrol/Et O); nmax(®lm)/cm
f
MNH
(100), 123 (98);HRMS: Found: 295.1166 (MNa ).
4
), 255 (19), 230 (36), 213 (80), 195 (94), 183
2
1
2
957, 1750, 1472, 1224, 1098, 836; d (400 MHz;CDCl )
H
3
2
3
0
.07 (6H, s), 0.89 (9H, s), 1.25 (3H, s), 1.69±1.74 (1H,
C H O Na requires 295.1158.
13 20 6
m),1.86±1.91 (1H, m), 2.06±2.10 (1H, m), 1.90 (3H, s),
.42±2.47 (1H, m), 2.52±2.57 (2H, m), 3.12 (1H, dd,
2
Jˆ7.1, 5.1 Hz), 3.78±3.82 (2H, m), 3.91 (1H, s), 6.37
(
1
5
1H, t, Jˆ4.7 Hz); d (400 MHz;CDCl ) 25.40, 12.86,
C
3
8.29, 21.14, 25.76, 25.90, 27.23, 31.39, 33.58, 58.03,
9.60, 60.16, 82.00, 90.56, 169.40, 206.01; m/z (CI) 390
1
1
(
(
28, MNH ), 373 (8, MH ), 355 (67), 313 (100), 295
4
66), 1821 (52);HRMS: Found 395.1864 (MNa
1.2.7. (^)-4-((2E)-1-Hydroxy-1-methyl-4-oxobut-2-enyl)-
(3S,4R,6R)-1,5-dioxaspiro[2.5]oct-6-yl acetate (16). To a
stirred solution of oxalyl chloride (49 ml, 0.56 mmol,
1
).
3
C H O NaSi requires 395.1866.
1
8
32
6

J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
5447
4
.0 equiv.) in dry DCM (3 ml) was added a solution of
(55.5 ml, 0.48 mol, 1.08 equiv.) added dropwise. The
mixture was stirred at 2788C for 1 h, 2458C for 1 h, then
allowed to warm to rt over 3 h. The reaction was quenched
DMSO (74 ml, 1.12 mmol, 8.0 equiv.) in dry DCM (1 ml)
dropwise at 2788C. After 10 min a solution of alcohol (15)
(
added dropwise. After 20 min Et N (0.31 ml, 2.24 mmol,
38 mg, 0.14 mmol, 1.0 equiv.) in dry DCM (1 ml) was
with sat. aq. NH Cl (400 ml). The layers were separated,
4
and the aqueous layer extracted with Et O (3£300 ml).
3
2
1
to rt. After 1 h the mixture was poured into H O (50 ml).
6.0 equiv.) was added, and the mixture allowed to warm
The combined organic layers were washed with brine
(1£300 ml), dried (MgSO ), ®ltered and concentrated.
2
4
The aqueous layer was extracted with DCM (2£40 ml), and
Puri®cation by vacuum distillation gave 2-[(3Z)-4-Methyl-
1-(1-methylvinyl)pent-3-enylthio]pyridine (80.4 g, 76%) as
a pale yellow oil: R 0.3 (13:1 40/60 petrol/Et O);bp 125±
the combined organic layers were dried (MgSO ), ®ltered
4
and concentrated to afford the crude product as a colourless
oil, which was used without further puri®cation in the next
step.
f
2
1
4
1308C/1.1 mmHg (lit. 110±120/1 mmHg); d (500 MHz;
H
CDCl ) 1.70 (3H, s), 1.74 (3H, d, Jˆ1.0 Hz), 1.88 (3H, s),
3
2
.27±2.52 (1H, m), 2.58±2.63 (1H, m), 4.46 (1H, dd, Jˆ9.0
nBuLi (67 ml of a 2.3 M solution in hexanes, 0.15 mmol,
and 6.5 Hz), 4.90 (1H, q, Jˆ1.0 Hz), 5.04 (1H, s), 5.20 (1H,
m), 7.02 (1H, ddd, Jˆ8.0, 5.0, 0.5 Hz), 7.22 (1H, d, Jˆ
8.0 Hz), 7.51 (1H, app dt, Jˆ8.0, 8.0, 1.5 Hz), 8.48 (1H,
ddd, Jˆ5.0, 1.5, 0.5 Hz).
1.1 equiv.) was added to a suspension of isopropyltriphenyl-
phosphonium iodide (73 mg, 0.17 mmol, 1.2 equiv.) in dry
THF (3 ml) at 08C. After 15 min the mixture was cooled to
2
(
2
788C, and a solution of the crude aldehyde in dry THF
2 ml) was added dropwise. The mixture was stirred at
788C for 1 h then at 08C for 2 h. The mixture was par-
To a stirred solution of the sulphide (16.18 g, 69.3 mmol,
1.0 equiv.) in DCM was added a solution of mCPBA (77%
purity, 16.3 g, 72.8 mmol, 1.05 equiv.) in DCM (300 ml)
over 1 h at 2258C. The mixture was allowed to warm to
rt over 3 h. The mixture was washed with sat. aq. Na CO
titioned between EtOAc (10 ml) and H O (10 ml). The
2
aqueous layer was extracted with EtOAc (3£10 ml), and
the combined organic layers were washed with brine
1£10 ml), dried (MgSO ), ®ltered and concentrated. Puri-
2
3
(
(500 ml). The aqueous layer was extracted with DCM
(2£300 ml), and the combined organic layers were dried
4
®
Et O) gave the title compound (9 mg, 24%) as a yellow oil:
cation by ¯ash column chromatography (1:4 40/60 petrol/
(MgSO ), ®ltered and concentrated. The residue was
4
2
R 0.17 (1:4 40/60 petrol/Et O); d (500 MHz;CDCl ) 1.43
f
dissolved in MeOH (150 ml), and diethylamine (150 ml)
was added in one portion at rt. After 20 h the mixture was
concentrated, and the residue partitioned between Et O
2
H
3
(
(
3H, s), 1.61±1.64 (1H, m), 1.83±1.87 (1H, m), 1.96±2.00
1H, m), 2.18 (3H, s), 2.33±2.39 (1H, m), 2.68 (1H, d,
2
Jˆ5.0 Hz), 3.20 (1H, d, Jˆ5.0 Hz), 4.13 (1H, s), 6.32
(200 ml) and H O (200 ml). The aqueous layer was
2
(
1H, m), 6.37 (1H, dd, Jˆ16.0, 7.5 Hz), 7.14 (1H, d, Jˆ
extracted with Et O (3£150 ml), and the combined organic
2
1
2
1
6.0 Hz), 9.66 (1H, d, Jˆ7.5 Hz); d (125 MHz;CDCl )
layers were washed with 2 M HCl (2£200 ml), brine
C
3
1.5, 27.5, 27.5, 27.8, 30.8, 53.5, 58.2, 74.9, 76.1, 92.0,
29.6, 160.2, 194.4. Sample decomposed before IR, m/z
(1£200 ml), dried (MgSO ), ®ltered and concentrated. Puri-
4
®cation by ¯ash column chromatography (3:2 40/60 petrol/
Et O) gave the known compound (18) (7.06 g, 73%) as a
1
4
and HRMS could be recorded.
2
colourless oil: Rf 0.33 (1:1 40/60 petrol/Et O);
2
d (500 MHz;CDCl ) 1.70 (3H, s), 1.75 (6H, s), 2.79 (2H,
H
3
t, Jˆ7.0 Hz), 4.06 (2H, d, Jˆ6.0 Hz), 5.15±5.18 (1H, m),
1
4
1
.2.8. (5Z,2E)-2,6-Dimethylhepta-2,5-dien-1-ol (18).
5.43±5.46 (1H, m).
Freshly cut sodium (11.26 g, 0.49 mol, 1.05 equiv.) was
slowly added to absolute EtOH (600 ml) at 08C. Once all
the sodium had dissolved, 2-mercaptopyridine (17)
(
51.84 g, 0.47 mol, 1.0 equiv.) was added in one portion at
0
0
8C. After 10 min 3-chloro-2-methylpropene (53 ml,
.54 mol, 1.15 equiv.) was added. After 3 h the mixture
1.2.9. (2S,3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methylox-
1
5
irane-2-carbaldehyde (19). To a stirred suspension of
powdered 4A molecular sieves (0.1 g) in dry DCM (5 ml)
was added (2)-diethyl tartrate (61 ml, 0.36 mmol,
0.25 equiv.). The mixture was cooled to 2228C (dry ice/
was concentrated;the residue was partitioned between
Et O (300 ml) and H O (300 ml). The aqueous layer was
2
2
extracted with Et O (3£200 ml), and the combined organic
2
i
layers were washed with 5% aq. NaOH, brine, dried
(MgSO ), ®ltered and concentrated. Puri®cation by vacuum
distillation
CCl ), Ti(OPr ) (85 ml, 0.29 mmol, 0.2 equiv.) was added
4
4
and the mixture stirred vigorously for 25 min. tert-Butyl-
hydroperoxide (0.57 ml of a 5 M solution in decane,
2.85 mmol, 2.1 equiv.) was added, and stirring continued
for 25 min. A solution of alcohol (18) (0.2 g, 1.43 mmol,
1.0 equiv.) in dry DCM (2 ml) was added, and after 30 min
the mixture was placed in the freezer (2258C) for 16 h. The
4
gave 2-(2-methylprop-2-enylthio)pyridine
73.12 g, 95%) as a yellow oil: R 0.37 (7:1 40/60 petrol/
(
f
1
4
EtOAc);bp 84±87 8C/0.9 mmHg (lit. 90±928C/1 mmHg);
d (250 MHz;CDCl ) 1.88 (3H, t, Jˆ1.1 Hz), 3.88 (2H, d,
H
3
Jˆ0.9 Hz), 4.89 (1H, m), 5.05 (1H, m), 7.00 (1H, ddd,
Jˆ8.2, 7.2, 1.0 Hz), 7.22 (1H, dt, Jˆ8.2, 1.0 Hz), 7.50
mixture was diluted with Et O (15 ml), and ®ltered through
2
(
1H, m), 8.47 (1H, ddd, Jˆ5.0, 1.9, 1.0 Hz).
a pad of Celite on top of a pad of silica, washing thoroughly
with Et O. The ®ltrate was then concentrated. Puri®cation
2
To a stirred solution of the sulphide (73.7 g, 0.45 mol,
.0 equiv.) in dry THF (500 ml) was added nBuLi (190 ml
of a 2.5 M solution in hexanes, 0.48 mol, 1.07 equiv.) drop-
wise at 2458C (dry ice/MeCN). After 30 min the mixture
was cooled to 2788C and 4-bromo-2-methyl-2-butene
by ¯ash column chromatography (12:13 40/60 petrol/Et O)
2
1
gave [(2S,3R)-3-((2Z)-3-methylbut-2-enyl)-2-methyloxi-
ran-2-yl]methan-1-ol (0.2 g, 90%, 98% ee) as a colourless
2
2
5
oil: R 0.18 (1:1 40/60 petrol/Et O);[ a] ˆ12.9 (cˆ1.5,
f
2
D
1
5
CHCl3) (lit.
12.6 (cˆ2.13, CHCl3); d (250 MHz;
H

5448
J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
CDCl ) 1.34 (3H, s), 1.67 (3H, s), 1.75 (3H, d, Jˆ0.8 Hz),
1.2.11.
2-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
3
2
.15±2.26 (1H, m), 2.36±2.48 (1H, m), 3.07 (1H, t,
oxiran-2-yl](6S,2R)-6-hydroxy-6-hydro-2H-pyran-3-one
(21). To a stirred solution of furan (20) (7.50 g, 33.7 mmol,
Jˆ6.5 Hz), 3.56±3.75 (2H, m), 5.15±5.22 (1H, m).
1.0 equiv.) in dry DCM (250 ml) was added VO(acac)2
To a stirred solution of oxalyl chloride (1.67 g, 19.2 mmol,
(1.18 g, 3.37 mmol, 0.1 equiv.) and tert-butylhydroperoxide
(9.44 ml of a 5 M solution in decane, 47.2 mmol, 1.4 equiv.)
at rt. After 2.5 h, the mixture was concentrated;the residue
2
.0 equiv.) in dry DCM (20 ml) was added a solution of
DMSO (2.72 ml, 58.4 mmol, 4.0 equiv.) in dry DCM
5 ml) dropwise at 2788C. After 10 min a solution of the
(
was dissolved in Et O and ®ltered through a pad of Florisil.
2
alcohol (1.5 g, 9.6 mmol, 1.0 equiv.) in dry DCM (10 ml)
was added dropwise. After 20 min Et N (10.7 ml,
The ®ltrate was concentrated, dissolved in the minimum
amount of Et O and passed through a pad of silica (6 cm
3
2
7
to warm up to rt. After 1 h the mixture was poured into H O
6.8 mmol, 8.0 equiv.) was added, and the mixture allowed
length), eluting with Et O. The ®ltrate was concentrated to
2
afford the title compound (4.02 g, 51%) as an orange oil,
which was used without puri®cation in the next step: R 0.26
(22:3 DCM:EtOAc).
2
(
(
(
50 ml). The aqueous layer was extracted with DCM
2£40 ml), and the combined organic layers were dried
f
MgSO ), ®ltered and concentrated. Puri®cation by ¯ash
4
column chromatography (6:1 40/60 petrol/Et O) gave the
2
title compound (1.2 g, 81%) as a colourless oil: R 0.32
f
2
D
5
(
(
4:1 40/60 petrol/Et O);[ a] ˆ251.9 (cˆ1.01, CH Cl )
2
2
2
1
5
25
lit. [a]D ˆ252.2 (cˆ0.985, CH Cl ); d (500 MHz;
2 2 H
CDCl ) 1.49 (3H, s), 1.71 (3H, s), 1.79 (3H, d, Jˆ1.0 Hz),
3
2
.28±3.33 (1H, m), 2.53±2.60 (1H, m), 3.20 (1H, t,
1.2.12.
oxiran-2-yl](2R,6R)-5-oxo-6-hydro-2H-pyran-2-yl acetate
22a). To a stirred solution of pyranone (21) (1.397 g,
.86 mmol, 1.0 equiv.) in dry DCM (20 ml) was added
pyridine (3.8 ml, 46.90 mmol, 8.0 equiv.), acetic anhydride
2.8 ml, 29.31 mmol, 5.0 equiv.) and DMAP (1.1 mg) at
8C. After 90 min H O (30 ml) was added. The layers
6-[3-((2E)-3-Methylbut-2-enyl)(3R)-2-methyl-
Jˆ6.5 Hz), 5.17±5.21 (1H, m), 8.90 (1H, s).
(
5
(
0
2
were separated, and the aqueous layer extracted with
DCM (3£20 ml). The combined organic layers were washed
1
methyloxiran-2-yl]-2-furylmethan-1-ol (20). To a stirred
solution of furan (freshly distilled from CaCO , 2.27 ml,
3
.2.10.
(1R)[(2S,3R)-3-((2Z)-3-Methylbut-2-enyl)-2-
with brine (1£20 ml), dried (MgSO ), ®ltered and concen-
4
trated. Puri®cation by ¯ash column chromatography (27:23
40/60 petrol/Et O) gave the title compound (1.117 mg,
3
1.17 mmol, 1.35 equiv.) in dry THF (40 ml) was added
nBuLi (13.6 ml of 2.3 M solution in hexane,
1.17 mmol, 1.35 equiv.) dropwise at 2788C. The mixture
was stirred at 2788C for 20 min, at 258C for 3 h, at rt for
0 min, and was then recooled to 2788C before a solution of
aldehyde (19) (3.56 g, 23.09 mmol, 1.0 equiv.) in dry THF
8 ml) was added dropwise. The mixture was stirred at
788C for 2 h, then allowed to warm to rt overnight. The
2
a
68%) as a pale yellow oil: R 0.29 (1:1 40/60 petrol/Et O);
f
2
2
5
21
3
[a]D ˆ118.7 (cˆ0.78, CHCl ); nmax(®lm)/cm
2979,
1756, 1698, 1635, 1370, 1213, 948; d (500 MHz;CDCl )
3
H
3
1
1.30 (3H, s), 1.67 (3H, s), 1.77 (3H, s), 2.13 (3H, s), 2.30±
2.39 (2H, m), 3.01 (1H, t, Jˆ6.5 Hz), 4.12 (1H, s), 5.28±
5.31 (1H, m), 6.27 (1H, d, Jˆ10.5 Hz), 6.61 (1H, d, Jˆ
(
2
3.5 Hz), 6.96 (1H, dd, Jˆ10.5, 3.5 Hz); d (125 MHz;
C
mixture was quenched with sat. aq. NH Cl (50 ml). The
4
CDCl ) 12.6, 18.4, 21.3, 26.1, 27.4, 60.4, 61.4, 82.3, 87.2,
3
layers were separated, and the aqueous layer extracted
with Et O (3£30 ml). The combined organic layers were
118.8, 128.9, 135.0, 142.7, 169.7, 193.0; m/z (CI) 263
(20%), 221 (100, [M2OAc] ), 203 (28), 125 (23).
1
2
1
dried (MgSO ), ®ltered and concentrated. H NMR analysis
4
of the crude product mixture indicated a 3.5:1 mixture
of diastereomers. Puri®cation by ¯ash column chroma-
tography (47:3 DCM:EtOAc) gave the title compound
(
3.02 g, 59%) as a pale yellow oil: R 0.30 (23:2 DCM:E-
f
2
5
21
tOAc);[ a]D ˆ129.3 (cˆ1.04, CHCl ) nmax(®lm)/cm
1.2.13.
oxiran-2-yl](2R)-4,5,6-trihydro-2H-pyran-3-one
2-[3-((2E)-3-Methylbut-2-enyl)(3R)-2-methyl-
(26).
3
3
1
2
430, 2916, 1674, 1385, 1052, 735; d (400 MHz;CDCl )
H 3
.25 (3H, s), 1.65 (3H, s), 1.74 (3H, s), 2.12±2.24 (1H, m),
.36±2.44 (1H, m), 2.58 (1H, d, Jˆ6.7 Hz), 3.15 (1H, t,
To a stirred solution of acetate (22a) (30 mg, 0.11 mmol,
1.0 equiv.) in THF (3 ml) was added Raney-Ni (130 mg of a
suspension in water) in one portion at rt. After 5 h the
Jˆ6.5 Hz), 4.49 (1H, d, Jˆ6.7 Hz), 5.14±5.19 (1H, m),
6.32±6.38 (2H, m), 7.39±7.40 (1H, m); d (100 MHz;
CDCl ) 12.57, 17.93, 25.70, 27.27, 60.13, 62.37, 71.62,
mixture was diluted with Et
a pad of silica, washing with Et
2
O (10 ml) and ®ltered through
O. The ®ltrate was then
C
3
2
1
07.14, 110.22, 118.33, 134.64, 142.15, 153.43; m/z (CI)
concentrated. Puri®cation by ¯ash column chromatography
(DCM) gave the title compound (16 mg, 67%) as a pale
1
23 (27%, MH ), 205 (100), 149 (34), 125 (43);HRMS:
2
Found 223.1332 (MH ). C H O requires 223.1334.
1
25
yellow oil: R
CHCl ); nmax(®lm)/cm 2926, 1723, 1449, 1384, 1090;
0.17 (DCM);[ a]
ˆ18.04 (cˆ0.95,
1
3
19
3
f
D
2
1
3
d (500 MHz;CDCl ) 1.58 (3H, s), 1.94 (3H, s), 2.04 (3H,
H
3
s), 2.34±2.36 (1H, m), 2.43±2.56 (2H, m), 2.65±2.76 (2H,
m), 2.84±2.92 (1H, m), 3.20 (1H, t, Jˆ6.5 Hz), 3.79 (1H, s),
3.99±4.04 (1H, m), 4.42±4.45 (1H, m), 5.53±5.56 (1H, m);
d (125 MHz;CDCl ) 13.2, 18.4, 26.2, 27.5, 30.8, 38.6,
C
3

J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
5449
2
D
5
6
(
2
0.8, 60.9, 66.1, 88.6, 119.0, 134.9, 206.9; m/z (APCI) 225
17%, MH ), 207 (75), 149 (100), 125 (53);HRMS: Found
colourless oil: R 0.29 (5:3 30/40 petrol/Et O);[ a]
f
ˆ
2
1
21
118.2 (cˆ1.01, CHCl ); nmax(®lm)/cm
2916, 1728,
1676, 1450, 1055; d (400 MHz;CDCl ) 1.30 (3H, s), 1.65
H 3
3
1
25.1495 (MH ). C H O requires 225.1491.
1
3
21
3
(
3H, s), 1.75 (3H, d, Jˆ0.9 Hz), 1.94±2.02 (1H, m), 2.26±
1
.2.14.
2-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
2.34 (3H, m), 2.40±2.56 (2H, m), 2.94 (1H, t, Jˆ6.5 Hz),
3.44 (3H, s), 3.71 (1H, s), 4.97 (1H, t, Jˆ4.3 Hz), 5.24±5.28
(1H, m); d (100 MHz;CDCl ) 12.51, 17.95, 25.73, 27.05,
oxiran-2-yl](6S,2R)-6-methoxy-6-hydro-2H-pyran-3-one
24a) and 2-[(3R)-3-((2Z)-3-methylbut-2-enyl)-2-methyl-
oxiran-2-yl](2R,6R)-6-methoxy-6-hydro-2H-pyran-3-one
(
C
3
28.55, 34.09, 55.29, 59.86, 60.81, 80.55, 97.36, 118.54,
134.47, 207.49; m/z (CI) 255 (18%, MH ), 237, (46), 223
1
(
24b). To a stirred solution of the crude pyranone (21)
1
(100), 125 (91);HRMS: Found 255.1595 (MH ). C H O
requires 255.1596.
(
Ag O (375 mg, 1.57 mmol, 5.0 equiv.) in one portion a rt.
75 mg, 0.32 mmol, 1.0 equiv.) in MeI (3 ml) was added
1
4
23
4
2
The mixture was stirred in the dark for 40 h, diluted with
Et O (15 ml), ®ltered through a pad of silica and concen-
2
trated. Puri®cation by ¯ash column chromatography (16:9
4
0/60 petrol/Et O) gave the desired products (21a) (30 mg,
2
3
8%) followed by compound (21b) (37 mg, 46%).
1.2.16. 2-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
oxiran-2-yl](2R,6R)-6-methoxy-4,5,6-trihydro-2H-pyran-
3-one (28b). To a stirred solution of enone (24b) (804 mg,
3.19 mmol, 1.0 equiv.) in THF (15 ml) was added Raney-Ni
(4.0 g of a suspension in water) in one portion at rt, and the
mixture stirred for 3 h. The mixture was diluted with Et O
Data for compound (24a): R 0.30 (2:1 40/60 petrol/Et O);
f
2
2
2
5
21
(30 ml), ®ltered through a pad of silica and concentrated.
Puri®cation by ¯ash column chromatography (5:3 30/40
petrol/Et O) gave the title compound (716 mg, 89%) as a
[
1
a]D ˆ133.1 (cˆ1.21, CHCl ); nmax(®lm)/cm
2930,
698, 1633, 1453, 1049; d (400 MHz;CDCl ) 1.29 (3H,
H 3
3
s), 1.66 (3H, s), 1.76 (3H, d, Jˆ0.9 Hz), 2.31±2.36 (2H,
2
2
D
5
colourless oil: R 0.15 (5:3 30/40 petrol/Et O);[ a]
f
16.6 (cˆ0.89, CHCl ); nmax(®lm)/cm 2967, 1727,
451, 1386, 1054; d (400 MHz;CDCl ) 1.32 (3H, s), 1.65
ˆ
m), 2.97 (1H, t, Jˆ6.4 Hz), 3.53 (3H, s), 3.99 (1H, s),
2
2
1
1
1
5
.19 (1H, d, Jˆ3.5 Hz), 5.27±5.32 (1H, m), 6.09 (1H, d,
3
Jˆ10.3 Hz), 6.89 (1H, dd, Jˆ10.3, 3.5 Hz); d (100 MHz;
H
3
C
(
2
3H, s), 1.74 (3H, d, Jˆ0.9 Hz), 2.10±2.18 (2H, m), 2.22±
CDCl ) 12.14, 17.96, 25.73, 27.04, 56.71, 59.96, 61.27,
3
.29 (1H, m), 2.32±2.42 (2H, m), 2.63 (1H, dt, Jˆ17.2,
8
0.24, 93.94, 118.49, 127.63, 134.51, 143.81, 193.71; m/z
CI) 253 (48%, MH ), 235 (83), 221 (83), 125 (100), 103
1
7.3 Hz), 2.86 (1H, t, Jˆ6.4 Hz), 3.54 (3H, s), 3.57 (1H, s),
(
1
91);HRMS: Found 253.1440 (MH ). C H O requires
4.86±4.88 (1H, m), 5.23±5.27 (1H, m); d (100 MHz;
C
(
1
4
21
4
CDCl ) 12.55, 17.94, 25.70, 27.08, 28.72, 34.33, 56.31,
3
2
53.1440.
6
(
0.09, 60.74, 85.00, 99.53, 118.45, 134.44, 206.47; m/z
1
CI) 255 (20%, MH ), 237 (62), 223 (100), 205 (42), 125
Data for compound (24b): R 0.22 (2:1 40/60 petrol/Et O);
f
2
1
2
5
21
(72);HRMS: Found 255.1597 (MH ). C H O requires
14 23 4
[
1
a]D ˆ127.5 (cˆ0.97, CHCl ); nmax(®lm)/cm
2932,
698, 1628, 1389, 1209, 1058; d (400 MHz;CDCl ) 1.33
H 3
3
255.1596.
(
(
3H, s), 1.65 (3H, s), 1.75 (3H, d, Jˆ1.0 Hz), 2.28±2.39
2H, m), 2.93 (1H, t, Jˆ6.4 Hz), 3.60 (3H, s), 3.67 (1H,
s), 5.26±5.31 (2H, m), 6.14 (1H, dd, Jˆ10.4, 1.7 Hz),
6
1
9
2
.90 (1H, dd, Jˆ10.4, 1.4 Hz); d (100 MHz;CDCl
)
3
C
2.68, 18.42, 26.18, 27.51, 56.92, 60.54, 61.66, 85.03,
7.56, 118.91, 129.79, 134.9, 148.30, 193.63; m/z (CI)
1
53 (6%, MH ), 235 (44), 221 (100), 125 (26);HRMS:
1.2.17.
4-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
1
Found 253.1440 (MH ). C H O requires 253.1440.
1
oxiran-2-yl](3S,4S,6S)-6-methoxy-1,5-dioxaspiro[2.5]-
octane (30a). To a stirred solution of ketone (28a)
4
21
4
(
(
325 mg, 1.28 mmol, 1.0 equiv.) and dibromomethane
108 ml, 1.54 mmol, 1.2 equiv.) in dry THF (5 ml) was
added nBuLi (0.63 ml of a 2.45 M solution in hexanes,
.54 mmol, 1.2 equiv.) dropwise at 2788C. The mixture
was stirred at 2788C for 2 h, then allowed to warm to rt
1
over 16 h, then quenched with sat. aq. NH Cl (10 ml). The
4
1
oxiran-2-yl](6S,2R)-6-methoxy-4,5,6-trihydro-2H-pyran-
.2.15.
2-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
layers were separated, and the aqueous layer extracted with
Et
(MgSO
column chromatography (49:1 DCM:EtOAc) gave the title
compound (282 mg, 82%) as a pale yellow oil: R 0.25 (16:9
ˆ157.2 (cˆ1.62, CHCl );
2934, 1674, 1444, 1218, 1020, 965;
(400 MHz;CDCl ) 1.13±1.18 (1H, m), 1.42 (3H, s),
O (3£10 ml). The combined organic layers were dried
2
3
1
-one (28a). To a stirred solution of enone (24a) (425 mg,
.69 mmol, 1.0 equiv.) in THF (7 ml) was added Raney-Ni
4
), ®ltered and concentrated. Puri®cation by ¯ash
(
mixture stirred for 3 h. The mixture was diluted with Et O
1.8 g of a suspension in water) in one portion at rt, and the
f
2
5
40/60 petrol/EtOAc);[ a]
2
D
3
2
1
(30 ml), ®ltered through a pad of silica and concentrated.
Puri®cation by ¯ash column chromatography (5:3 30/40
n
d
max(®lm)/cm
H
3
petrol/Et O) gave the title compound (391 mg, 92%) as a
2
1.64 (3H, s), 1.76 (3H, d, Jˆ1.0 Hz), 1.78±1.80 (1H, m),

5450
J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
2
.06±2.14 (2H, m), 2.33±2.43 (2H, m), 2.52 (1H, d,
To a stirred solution of the crude enone in THF (10 ml) was
added Raney-Ni (2.5 g of a suspension in H O) in one
portion at rt. After 4 h the mixture was diluted with Et O
2
Jˆ4.4 Hz), 2.63±2.67 (1H, m), 2.81 (1H, d, Jˆ4.4 Hz),
2
3
5
2
1
2
.39 (3H, s), 3.57 (1H, s), 4.90 (1H, d, Jˆ2.5 Hz), 5.14±
.18 (1H, m); d (100 MHz;CDCl ) 12.71, 17.96, 25.70,
C
(30 ml), ®ltered through a pad of silica and concentrated.
Puri®cation by ¯ash column chromatography (22:3 40/60
petrol/Et O) gave the desired products (27a) (171 mg,
3
6.85, 27.92, 50.07, 54.85, 56.45, 60.44, 75.59, 97.95,
18.03, 135.22; m/z (GCMS) 269 (4%, MH ), 221 (23),
1
2
1
05 (50), 127 (100);HRMS: Found 269.1752 (MH ).
23%) followed by (27b) (367 mg, 49%) as colourless oils.
C H O requires 269.1753
1
5
25
4
Data for compound (27a): R 0.28 (22:3 40/60 petrol/Et O);
f
2
2
5
21
[
a]D ˆ191.9 (cˆ1.05, CHCl ); nmax(®lm)/cm
2930,
728, 1463, 1254, 1047; d (500 MHz;CDCl ) 0.19 (6H,
3
1
s), 0.94 (9H, s), 1.32 (3H, s), 1.70 (3H, s), 1.79 (3H, d,
H 3
Jˆ0.5 Hz), 1.98±2.04 (1H, m), 2.27±2.32 (2H, m), 2.38±
2
3
.47 (2H, m), 2.64±2.68 (1H, m), 2.98 (1H, t, Jˆ6.5 Hz),
.92 (1H, s), 5.29±5.32 (1H, m), 5.49 (1H, t, Jˆ3.5 Hz);
1
.2.18.
4-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
d (125 MHz;CDCl ) 25.1, 24.0, 13.4, 18.4, 26.1, 26.2,
C
3
oxiran-2-yl](3S,4S,6R)-6-methoxy-1,5-dioxaspiro[2.5]-
octane (30b). To a stirred solution of ketone (28b)
2
2
7.6, 31.9, 34.3, 60.3, 60.8, 81.0, 91.6, 119.1, 134.7,
07.9; m/z and HRMS: molecular ions could not be found
(
(
630 mg, 2.48 mmol, 1.0 equiv.) and dibromomethane
0.19 ml, 2.73 mmol, 1.1 equiv.) in dry THF (10 ml) was
under any ionisation conditions.
added nBuLi (1.1 ml of a 2.45 M solution in hexanes,
.73 mmol, 1.1 equiv.) dropwise at 2788C. The mixture
was stirred at 2788C for 2 h, then allowed to warm to rt
Data for compound (27b): R 0.16 (22:3 40/60 petrol/Et O);
f
2
2
2
5
21
[
1
a]D ˆ111.5 (cˆ1.3, CHCl ); nmax(®lm)/cm
2957,
731, 1676, 1387, 1175, 1056, 839; dH(500 MHz;CDCl )
3
3
over 16 h, then quenched with sat. aq. NH Cl (10 ml). The
4
0.20 (3H, s), 0.21 (3H, s), 0.95 (9H, s), 1.36 (3H, s), 1.69
layers were separated, and the aqueous layer extracted with
Et O (3£10 ml). The combined organic layers were dried
(
3
6
(
3H, s), 1.79 (3H, d, Jˆ1.0 Hz), 2.11±2.22 (2H, m), 2.28±
2
.35 (1H, m), 2.38±2.45 (2H, m), 2.67 (1H, dt, Jˆ17.0,
.5 Hz), 2.89 (1H, t, Jˆ6.5 Hz), 3.58 (1H, s), 5.29±5.35
(
column chromatography (3:2 40/60Petrol/Et O) gave the
MgSO ), ®ltered and concentrated. Puri®cation by ¯ash
4
2
2H, m); d (125 MHz, CDCl ) 24.7, 23.6, 13.1, 18.4,
C
3
title compound (532 mg, 80%) as a pale yellow oil: R
f
2
5
26.2, 27.5, 32.3, 35.2, 60.4, 61.1, 85.8, 94.4, 119.0, 134.8,
206.7; m/z and HRMS: molecular ions could not be found
under any ionisation conditions.
0
CHCl ); nmax(®lm)/cm 2934, 1673, 1450, 1380, 1041,
.11 (16:9 40/60 petrol/EtOAc);[ a] ˆ142.6 (cˆ1.0,
D
2
1
3
931; d (400 MHz;CDCl ) 1.33±1.39 (1H, m), 1.36 (3H,
H 3
s), 1.65 (3H, s), 1.74 (3H, s), 1.85±1.89 (2H, m), 2.08±
2
2
.17 (2H, m), 2.39±2.46 (1H, m), 2.56 (1H, d, Jˆ4.4 Hz),
.66 (1H, dd, Jˆ7.3, 5.7 Hz), 2.84 (1H, d, Jˆ4.4 Hz), 3.30
(1H, s), 3.55 (3H, s), 4.49±4.52 (1H, m), 5.14±5.18 (1H, m);
d (100 MHz;CDCl ) 12.74, 17.95, 25.70, 26.87, 29.30,
C
3
3
1
2
0.57, 49.55, 55.73, 56.30, 59.65, 60.36, 82.21, 102.72,
17.93, 135.48; m/z (APCI) 269 (18%, MH ), 237 (69),
19 (24), 169 (21).
1
1.2.20.
2-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
oxiran-2-yl](6S,2R)-6-((1-ethoxyethyl)ethyl)-6-hydro-2H-
pyran-3-one (25a). To a stirred solution of crude alcohol
(
21) (100 mg, 0.42 mmol, 1.0 equiv.) in dry DCM (4 ml)
was added ethyl vinyl ether (0.9 ml, 9.4 mmol,
2.5 equiv.) and PPTS (ca. 10 mg) at 08C. The mixture
2
was warmed to rt, stirred for 4 h, then partitioned between
DCM (10 ml) and sat. aq. NaHCO (15 ml). The aqueous
1
.2.19.
2-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-methyl-
3
oxiran-2-yl](2R,6S)-6-[((1,1-dimethyl)ethyl)dimethylsilyl-
oxy]-4,5,6-trihydro-2H-pyran-3-one (27a) and 2-[(3R)-
layer was extracted with DCM (3£10 ml), and the combined
organic layers were dried (MgSO ), ®ltered and concen-
4
3
6
2
-((2Z)-3-methylbut-2-enyl)-methyloxiran-2-yl](2R,6R)-
-[((1,1-dimethyl)ethyl)dimethylsilyloxy]-4,5,6-trihydro-
H-pyran-3-one (27b). To a stirred solution of alcohol (21)
trated. Puri®cation by ¯ash column chromatography (18:7
40/60 petrol/Et O) gave the title compound (69 mg, 53%) as
2
a colourless oil (ca. 1:1 mixture of diastereomers): R 0.28
f
2
D
5
(
500 mg, 2.1 mmol, 1.0 equiv.) in dry DCM (6 ml) was
(1:1 40/60 petrol/Et O);[ a] ˆ15.9 (cˆ0.39, CHCl );
2
3
2
1
added imidazole (429 mg, 6.3 mmol, 3.0 equiv.) and
TBSCl (633 mg, 4.2 mmol, 2.0 equiv.) at rt. After 2 h the
mixture was partitioned between DCM (10 ml) and H O
nmax(®lm)/cm 2980, 1698, 1632, 1385, 1009, 877;
d (250 MHz;CDCl ) 1.19±1.25 (6H, m), 1.27 (6H, s),
H
3
1.37 (3H, d, Jˆ5.3 Hz), 1.43 (3H, d, Jˆ5.4 Hz), 1.65(6H,
s), 1.75 (6H, d, Jˆ0.8 Hz), 2.27±2.38 (4H, m), 2.94 (2H, t,
Jˆ6.4 Hz), 3.46±3.60 (2H, m), 3.68±3.82 (2H, m), 3.99
(1H, s), 4.11 (1H, s), 4.97 (1H, q, Jˆ5.4 Hz), 5.05 (1H,
q, Jˆ5.3 Hz), 5.26±5.32 (2H, m), 5.57 (1H, d, Jˆ3.6 Hz),
5.61 (1H, d, Jˆ3.6 Hz), 6.07 (1H, d, Jˆ10.2 Hz), 6.11
(1H, d, Jˆ10.2 Hz), 6.82 (1H, dd, Jˆ10.2, 3.6 Hz), 6.89
(1H, dd, Jˆ10.2, 3.6 Hz); d (63 MHz;CDCl ) 12.54,
2
(
(
15 ml). The aqueous layer was extracted with DCM
2£10 ml), and the combined organic layers were washed
with brine (1£15 ml), dried (MgSO ), ®ltered and concen-
4
trated to afford a yellow oil, which was used without further
puri®cation in the next step: m/z (CI) 353 (35%, MH ), 335
1
(
(
34), 221 (100), 211 (46), 127 (37);HRMS: Found 353.2145
MH ). C H O Si requires 353.2148.
1
1
9
33
4
C
3

J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
5451
1
2
8
1
2.65, 15.58, 15.69, 18.36, 21.31, 21.43, 26.13, 27.48,
7.52, 60.19, 60.27, 61.42, 61.62,.62.48, 63.94, 80.88,
0.90, 88.74, 90.06, 118.96, 127.77, 128.05, 134.76,
34.85, 144.43, 144.87, 193.97, 194.21; m/z (CI) 328 (7%,
79%) as a pale yellow oil: R 0.33 (2:1 40/60 petrol/
f
2
5
EtOAc);[ a] ˆ158.5 (cˆ0.395, CHCl ); nmax(®lm)/
D
3
2
cm 2977, 2934, 1673, 1381, 1133, 973; d (250 MHz;
1
H
CDCl ) 1.21 (3H, t, Jˆ7.0 Hz), 1.22 (3H, t, Jˆ7.1 Hz),
3
1
1
MNH ), 311 (12, MH ), 293 (66), 267 (51), 221 (100), 125
(
1.31 (6H, s), 1.36 (3H, d, Jˆ5.2 Hz), 1.37 (3H, d, Jˆ
5.3 Hz), 1.65 (6H, s), 1.75 (6H, s), 1.81±2.00 (2H, m),
2.03±2.22 (4H, m), 2.35±2.50 (4H, m), 2.53 (2H, d, Jˆ
4
1
37);HRMS: Found 311.1850 (MH ). C H O requires
17 27 5
3
11.1858.
4
.4 Hz), 2.6±2.68 (2H, m), 2.82 (1H, d, Jˆ4.4 Hz), 2.83
(1H, d, Jˆ4.4 Hz), 2.95±3.06 (2H, m), 3.42±3.68 (2H,
m), 3.63 (1H, s), 3.65±3.91 (2H, m), 3.78 (1H, s), 4.87±
4
1
1
2
5
.98 (2H, m), 5.16 (2H, t, Jˆ7.4 Hz), 5.24 (1H, d, Jˆ
.9 Hz), 5.29 (1H, d, Jˆ2.1 Hz); d (63 MHz;CDCl
)
3
C
3.15, 13.18, 15.68, 18.35, 21.23, 21.87, 21.13, 27.23,
7.25, 27.38, 28.23, 28.95, 50.59, 50.65, 56.94, 57.02,
9.82, 59.86, 60.68, 60.80, 62.66, 64.07, 76.47, 76.56,
1
.2.21.
2-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
92.78, 95.14, 99.08, 99.53, 118.47, 135.60, 135.64; m/z
(CI) 344 (6%, MNH
(100).
1
oxiran-2-yl](6S,2R)-6-((1-ethoxy)ethyl)-4,5,6-trihydro-2H-
pyran-3-one (29a). To a stirred solution of enone (25a)
), 281 (9), 237 (82), 219 (23), 73
4
(
Raney-Ni (300 mg of a suspension in H O) in one portion
67 mg, 0.22 mmol, 1.0 equiv.) in THF (3 ml) was added
2
at rt, and the mixture stirred for 3 h. The mixture was diluted
with Et O (10 ml), ®ltered through silica, and concentrated.
2
Puri®cation by ¯ash column chromatography (18:7 40/60
petrol/Et O) gave the title compound (62 mg, 92%) as a
2
2
D
5
pale yellow oil; R 0.20 (2:1 40/60 petrol/Et O);[ a]
f
153.9 (cˆ0.41, CHCl ); nmax(®lm)/cm 2978, 1732,
675, 1380, 1142, 860; d (250 MHz;CDCl ) 1.16±1.26
ˆ
2
2
1
1.2.23.
4-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
1
1
3
oxiran-2-yl](3S,4S)-1,5-dioxaspiro[2.5]octan-6-ol (32).
To a stirred solution of epoxide (31a) (19.5 mg, 0.06
mmol) in 4:1 acetone/water (1.5 ml) was added PPTS (ca.
H
3
(
6H, m), 1.28 (6H, s), 1.35 (3H, d, Jˆ5.3 Hz), 1.39 (3H,
d, Jˆ5.3 Hz), 1.65 (6H, s), 1.75 (6H, s), 1.91±2.08 (2H, m),
3
mg) at 458C. After 90 min more PPTS (ca. 3 mg) and
2
6
3
.20±2.42 (6H, m), 2.45±2.62 (4H, m), 2.92 (1H, t, Jˆ
.4 Hz), 2.93 (1H, t, Jˆ6.4 Hz), 3.48±3.57 (2H, m), 3.66±
.82 (2H, m), 3.77 (1H, s), 3.89 (1H, s), 4.94 (1H, q,
solvent (0.5 ml) were added, and the mixture stirred for
another 90 min. The mixture was then partitioned between
EtOAc (10 ml) and sat. aq. NaHCO (10 ml). The aqueous
3
Jˆ5.3 Hz), 5.00 (1H, q, Jˆ5.3 Hz), 5.22±5.28 (2H, m),
.33 (1H, t, Jˆ4.8 Hz), 5.39 (1H, t, Jˆ4.7 Hz);
dC(63 MHz;CDCl 3) 12.89, 13.30, 15.61, 15.70, 18.36,
layer was extracted with EtOAc (3£10 ml), and the
5
combined organic layers were dried (MgSO ), ®ltered and
4
concentrated to afford the crude product (13 mg, 85%) as a
yellow oil, which was used without further puri®cation in
the next step: R 0.21 (40/60 petrol/EtOAc).
2
6
9
2
1.36, 21.54, 26.14, 27.47, 28.71, 29.15, 34.51, 34.62,
0.17, 60.20, 60.97, 61.18, 62.40, 63.86, 81.32, 92.45,
3.82, 98.72, 99.81, 118.95, 134.78, 134.85, 207.82,
f
1
4
1
08.09; m/z (CI) 330 (7%, MNH ), 313 (8, MH ), 295
(100), 223 (58), 73 (32);HRMS: Found 313.2011 (MH 1).
C H O requires 313.2015.
1
7
29
5
1
.2.24.
oxiran-2-yl](3S,4S,6R)-1,5-dioxaspiro[2.5]oct-6-yl acetate
33a). To a stirred solution of the crude lactol (32) (12 mg,
.05 mmol, 1.0 equiv.) in dry DCM (4 ml) was added
4-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
(
0
pyridine (38 ml, 0.5 mmol, 10.0 equiv.), Ac O (35 ml,
2
1
oxiran-2-yl](3S,4S,6S)-6-((1-ethoxy)ethyl)-1,5-dioxaspiro-
.2.22.
4-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
0.4 mmol, 8.0 equiv.) and DMAP (9 mg, 0.08 mmol,
1.5 equiv.) at 08C. The mixture was allowed to warm to rt
[
(
(
2.5]octane (31a). To a stirred solution of ketone (29a)
61 mg, 0.2 mmol, 1.0 equiv.) and dibromomethane
19 ml, 0.26 mmol, 1.35 equiv.) in dry THF (3 ml) was
over 2 h, then partitioned between DCM (10 ml) and H O
2
(10 ml). The aqueous layer was extracted with DCM
(3£10 ml), and the combined organic layers were dried
(MgSO ), ®ltered and concentrated. Puri®cation by ¯ash
4
added nBuLi (110 ml of a 2.4 M solution in hexanes,
.26 mmol, 1.35 equiv.) dropwise at 2788C. The mixture
was stirred at 2788C for 2 h, then allowed to warm to rt over
6 h, then quenched with sat. aq. NH Cl (10 ml). Et O
0
column chromatography (12:13 40/60 petrol/Et
the title compound (10 mg, 72%) as a colourless oil: R
O) gave
2
f
2
5
1
0.25 (2:3 40/60 petrol/Et
2
O);[ a]
D
ˆ126.4 (cˆ0.315,
); nmax(®lm)/cm 2964, 2933, 1749, 1673, 1372,
3
4
2
2
1
(
10 ml) was added, the layers were separated, and the
CHCl
1204, 1008, 945; d
aqueous layer extracted with Et O (3£10 ml). The
H
(500 MHz;CDCl
3
) 1.34 (1H, dt, Jˆ
2
combined organic layers were dried (MgSO ), ®ltered and
4
13.6, 4.0 Hz), 1.37 (3H, s), 1.71 (3H, s), 1.80 (3H, s),
1.89±1.1.93 (1H, m), 2.14 (3H, s), 2.14±2.19 (1H, m),
2.28 (1H, ddt, Jˆ13.6, 4.0, 4.0 Hz), 2.40 (1H, dt, Jˆ13.5,
concentrated. Puri®cation by ¯ash column chromatography
(
18:7 40/60Petrol/Et O) gave the title compound (50 mg,
2

5452
J. E. Baldwin et al. / Tetrahedron 58 (2002) 5441±5452
4
.5 Hz), 2.45±2.50 (1H, m), 2.62 (1H, d, Jˆ4.4 Hz), 2.72
References
(
1H, dd, Jˆ7.3, 5.7 Hz), 2.92 (1H, d, Jˆ4.4 Hz), 3.76 (1H,
s), 5.22 (1H, t Jˆ7.5 Hz), 6.40 (1H, s); d (125 MHz;
1. (a) Elbe, T. E.;Hanson, F. R. Antibiot. Chemother. 1951, 1,
54. (b) McCorkindale, N. J.;Sime, J. G. Proc. Chem. Soc.
1961, 331.
C
CDCl ) 13.02, 18.38, 21.62, 26.13, 26.87, 27.33, 27.41,
3
5
1
0.71, 56.41, 59.74, 60.59, 78.69, 92.35, 118.42, 135.80,
69.77; m/z (CI) 314 (17%, MNH ), 297 (7, MH ), 237
1
2. (a) Ingber, D.;Fujita, T.;Kishimoto, S.;Sudo, K.;Kanamaru,
T.;Brem, H.;Folkman, J. Nature 1990, 348, 555. (b) Folkman,
J. Nature Med. 1995, 1, 27.
4
1
(
(
100), 219 (62), 177 (36), 125 (48);HRMS: Found 314.1966
MNH ). C H NO requires 314.1967.
1
4
16 28
5
3
. Liekens, S.;DeClercq, E.;Neyts, J. Biochem. Pharmacol.
001, 61, 253.
2
4
. (a) Han, C. K.;Ahn, S. K.;Choi, N. S.;Hong, R. K.;Moon,
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Yoon, J. K.;No, K. T. Bioorg. Med. Chem. Lett. 2000, 10, 39.
(
b) Marui, S.;Yamamoto, T.;Sudo, K.;Akimoto, H.;
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J. Haematol. 1997, 58, 293.
1
.2.25. {4-[(3R)-3-((2Z)-3-Methylbut-2-enyl)-2-methyl-
oxiran-2-yl](3S,4S,6R)-1,5-dioxaspiro[2.5]oct-6-yloxy}-
N-(2-chloroacetyl)carboxamide (34a). To a stirred solu-
tion of the crude lactol (32) (88 mg, 0.35 mmol, 1.0 equiv.)
in dry DCM (4 ml) was added chloroacetyl isocyanate
(
7
(
60 ml, 0.7 mmol, 2.0 equiv.) dropwise at 08C. After
0 min at 08C the mixture was partitioned between EtOAc
15 ml) and H O (15 ml). The aqueous layer was extracted
5. (a) Taunton, J. Chem. Biol. 1997, 4, 493. (b) Borman, S. Chem.
Eng. News 1997, 16, 39. (c) Hawkins, M. J. Curr. Opin. Oncol.
1995, 7, 90. (d) Twardowski, P.;Gradishar, W. J. Curr. Opin.
Oncol. 1997, 9, 584.
2
with EtOAc (3£10 ml), and the combined organic layers
were washed with brine (1£15 ml), dried (MgSO ), ®ltered
6. Dai, X. B.;Grif®th, E. C.;Liu, J. O. Abstracts of Papers. 219th
National Meeting of the American Chemical Society, San
Francisco, CA;American Chemical Society: Washington,
DC, 2000 MEDI-061.
4
and concentrated. Puri®cation by ¯ash column chroma-
tography (14:11 40/60 petrol/EtOAc) gave the title com-
pound (82 mg, 64%) as a colourless paste: R 0.32 (1:1 40/
f
2
5
6
d (500 MHz;CDCl ) 1.29 (3H, s), 1.63 (3H, s), 1.72 (3H,
0
petrol/EtOAc);[ a]D ˆ120.4 (cˆ0.28, CHCl3);
7. Lowther, W. T.;McMillen, D. A.;Orville, A. M.;Matthews,
B. W. Proc. Natl Acad. USA 1998, 95, 12153.
8. Liu, S.;Widom, J.;Kemp, C. W.;Crews, C. M.;Clardy, J.
Science 1998, 282, 1324.
H
3
s), 1.90±1.94 (1H, m), 2.03±2.11 (2H, m), 2.21±2.28 (1H,
m), 2.39 (2H, dt, Jˆ13.7, 4.6 Hz), 2.58 (1H, d, Jˆ4.3 Hz),
2
(
(
2
1
.65 (1H, dd, Jˆ7.3, 5.7 Hz), 2.85 (1H, d, Jˆ4.3 Hz), 3.72
9. Sammes, P. G.;Street, L. J.;Kirby, P. J. Chem. Soc. Perkin
Trans. 1 1983 (11), 2729.
1H, s), 4.50 (2H, s), 5.11±5.14 (1H, m), 6.33 (1H, s), 8.62
1H, br s); d (125 MHz;CDCl ) 12.39, 17.86, 25.57, 26.01,
C
3
10. Pirrung, M. C.;Webster, N. J. G. J. Org. Chem. 1987, 52,
3603.
6.72, 43.80, 50.15, 55.65, 59.29, 60.21, 78.46, 94.31,
17.59, 135.58, 150.01, 167.16, 200.42; m/z (CI) 393 (3%,
11. Martin, S. F.;Zinke, P. W. J. Am. Chem. Soc 1989, 111, 2311.
12. Taber, D. F.;Christos, T. E.;Rheinhold, A. L.;Guzei, I. A.
J. Am. Chem. Soc. 1999, 121, 5589.
1
37
1 35
4
MNH , Cl), 391 (10, MNH , Cl), 331 (9), 237 (43),
4
2
19 (25), 95 (100).
1
1
3. Michnick, T. J.;Matteson, D. S. Synlett 1991, 631.
4. Mori, K.;Ueda, H. Tetrahedron 1981, 37, 2581.
Acknowledgements
15. Jung, M. E.;D'Amico, D. C. J. Am. Chem. Soc. 1995, 117,
379±7384.
16. Barrero, A. F.;Alvarez-Manzaneda, E. J.;Charboun, R.;
7
We thank Dr R. M. Adlington for fruitful discussions. P. G.
B. also thanks the EPSRC for a graduate fellowship.
Meneses, R. Synlett 1999, 1663.