Studies toward the synthesis of natural and unnatural dienediynes. Part 2: A practical approach to functionalised cyclopentenones

Article abstract of DOI:10.1016/S0040-4020(00)00846-2

The dienediyne natural products contain a functionalised dihydroxylated cyclopentane motif. A critical evaluation of the methods for the preparation and rearrangements of pyranones to give 4,5-dihydroxylated cyclopentenones is presented. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00846-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8953±8958
Studies Toward the Synthesis of Natural and Unnatural
Dienediynes. Part 2: A Practical Approach to
Functionalised Cyclopentenones
a
a
a
a
b
S. Caddick,a, S. Khan, L. M. Frost, N. J. Smith, S. Cheung and G. Pairaudeau
*
aCentre for Biomolecular Design and Drug Development, The Chemistry Laboratory, University of Sussex, Falmer, Brighton BN1 9QJ, UK
bAstraZeneca Pharmaceuticals, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK
Received 29 June 2000; revised 29 August 2000; accepted 14 September 2000
AbstractÐThe dienediyne natural products contain a functionalised dihydroxylated cyclopentane motif. A critical evaluation of the
methods for the preparation and rearrangements of pyranones to give 4,5-dihydroxylated cyclopentenones is presented. q 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
Background
Our ®rst synthetic objective became the synthesis of a
dihydroxylated cyclopentenone derivative which could be
used to prepare both functionalised monocyclic NCS
analogues6 and the natural product chromophores
(Scheme 2).
The dienediyne chromoprotein antibiotics have been the
subject of signi®cant scienti®c interest.1 In particular,
interest in these molecules arises from their unusual
synthetically challenging, molecular structure and their
potent biological activity.2 Members of this class include
Neocarzinostatin (NCS), Kedarcidin, C-1027 and Maduro-
peptin which are all isolated from natural sources, and each
comprise a 1:1 complex of an apoprotein and a chromo-
phore.3 The structures of the chromophores are depicted in
Scheme 1. Much effort has been directed toward the
chemical synthesis of natural and unnatural dienediyne
chromophores and numerous elegant studies have been
described including the ®rst completed synthesis of a
dienediyne chromoprotein natural product (NCS Chrom).4
Despite numerous methods available for the synthesis of
cyclopentane derivatives we felt that very few offered the
simplicity and practicality required for our work. The result
of our studies led us to identify and optimise a rearrange-
ment reaction which delivers large quantities of cyclo-
pentenone 1 in good yield.
Results and Discussion
Our own work in this area has focused on NCS and Kedar-
cidin, and in particular we have been interested in designing
synthetic approaches to compounds which can ®nd common
use in total synthesis and provide functionalised analogues.5
From our perspective, a particularly attractive and compel-
ling synthetic objective was the identi®cation of a suitable
cyclopentane building block which could be readily
prepared on large scale. This paper describes in full a
study we have carried out which has led to the identi®cation
of a practical procedure for the preparation of functionalised
cyclopentenone derivatives which we have routinely used as
starting materials for our work in this area.
Formation of 6-acetoxy-2,3-dihydro-6H-pyrano-3-one 4
The classical approach for the preparation of 6-acetoxy-2,3-
dihydro-6H-pyran-3-ones is through the preparation of the
a,a0-dimethoxydihydroderivative 2 by treating furfuryl
alcohol with an excess of bromine in methanol.7 This
reaction has shown great utility for our work as the furan
can be formed in up to 100 g quantities (Scheme 3).
Mild hydrolysis of 2 brings about the cleavage of the acetal
bonds, leading to the formation of 3. This hydroxypyranone
derivative exhibits low stability in aqueous solutions at
ambient temperatures and undergoes rapid decomposition
under basic conditions, but can be stored at reduced
temperatures without signi®cant decomposition. The
workup procedure for this reaction is laborious and
problematic. The reaction conditions require an aqueous
Keywords: cyclopentenones; diynes; isomerisation; pyrones; rearrange-
ment.
* Corresponding author. Tel.: 11273-678734; fax: 11273-678734;
e-mail: s.caddick@sussex.ac.uk
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00846-2

8954
S. Caddick et al. / Tetrahedron 56 (2000) 8953±8958
Scheme 1.
Scheme 2.
solution of sulfuric acid, which must be removed at the end
of the reaction in vacuo maintaining a water bath tempera-
ture below 308C. Following the removal of the water a
standard aqueous extraction with ethyl acetate may be
carried out. Although this route yields the required pyranone
in good yield (80% from furfuryl alcohol), this workup
procedure, and the instability of the isolated intermediates
limits the scale on which the reaction can be carried out.
Activation of the hemiacetal hydroxy functionality was
achieved through formation of the acetoxypyranone 4 with
acetic anhydride and sodium acetate affording the corre-
sponding acetate in 60±70% yield. This activation step
was deemed necessary as the corresponding hydroxypyran-
one 3 is unreactive to ring contraction conditions.
An alteration to the above method involves addition of a
catalytic amount of tri¯uoromethane sulfonic acid to the
furan intermediate 2 (Scheme 4).8 This alteration removes
the need for the laborious aqueous extraction as the reaction
is carried out in wet THF. A further advantage of this route
Scheme 3. Reagents and conditions: (a) Br2, MeOH:Et2O, 2408C; NH3 2408CÐrt; (b) 2% H2SO4, NaHCO3, rt, 4 h; (c) Ac2O, NaOAc, 08CÐrt 18 h.

S. Caddick et al. / Tetrahedron 56 (2000) 8953±8958
8955
Scheme 6. Reagents and conditions: SnCl4 (5 mol%), ClCH2CH2Cl, ROH,
rt.
Scheme 4. Reagents and conditions: TfOH (15%), THF:H2O, Ac2O,
NaOAc.
can be used to remove some of the benzoic acid, which is
only sparingly soluble in dichloromethane. The remaining
benzoic acid persists and co-elutes with acetoxypyranone 4
on silica-gel. The incorporation of an aqueous extraction
can remove the residual benzoic acid. However, the
instability of hydroxypyranone 3 to aqueous and basic
conditions precludes the incorporation of such conditions.
Scheme 5. Reagents and conditions: (a) NBS, NaHCO3, THF:H2O, Ac2O;
(b) mCPBA, DCM, 08C, AcCl, pyridine, 2 h.
In conclusion, our method of choice for the production of
acetoxypyranones is the tri¯ic acid mediated hydrolysis and
ring expansion procedure. Although the NBS and mCPBA
mediated reactions appear to offer simple procedures they
produce less of the required acetoxypyranone. Moreover,
the Lewis acid mediated reactions are sensitive to impurities
which are dif®cult to remove from the acetoxypyranone 4
derived from these procedures.
is that the highly unstable hydroxypyranone 3 is never
isolated as the reaction is carried out in the presence of
acetic anhydride and sodium acetate, which yields the
required acetoxypyranone 4 in 70% yield from furfuryl
alcohol.
The instability of the intermediates in the synthesis of
6-acetoxy-2,3-dihydro-6H-pyrano-3-one 4 makes the idea
of a one-pot synthesis very appealing (Scheme 5). One
such method utilises N-bromosuccinimide in the presence
of sodium bicarbonate and acetic anhydride to functionalise
furfuryl alcohol.9 Although this self-indicating reaction
affords the required acetoxypyranone 4 in moderate yield
(57%) from furfuryl alcohol, problems are encountered
during scale-up. Whereas the acid hydrolysis reactions can
both be carried out using 70 g of furfuryl alcohol, the NBS
cannot be effectively carried out above 20 g scale.
Ring contraction to polyfunctionalised cyclopentenones
There are relatively few procedures for the conversion of a
hemiacetal hydroxy of 3 into its corresponding glycosidic
function, and many methods are unsuitable for our purpose
due to scale up problems. One report ef®ciently demon-
strated the conversion via acetate 4 into various ethers
using catalytic Lewis acid conditions.11 Using these condi-
tions we were able to effectively transform acetate 4 into the
corresponding tert-butyl 5a and benzyl 5b derivatives in 89
and 82% yield respectively (Scheme 6).
Although the yield of the reaction was reduced in compari-
son to the two acid catalysed reactions, the NBS method is
simple and, unlike the acid hydrolysis routes does not
involve the bromine addition step which is highly sensitive
to temperature. An interesting point to note is that if the
reaction is carried out over two steps with isolation of the
intermediate hydroxypyranone 3, the limiting step in this
sequence is found to be the acetylation reaction which
occurs in 48% yield.
The isomerisation reaction of pyranones to a give a dihy-
droxylated cyclopentenone has previously been reported
using a palladium catalysed procedure.12 We were able to
devise a modi®ed procedure which could be carried out on
preparative scale (ca. 50 g) without the requirement of
metal catalysts, instead using an amine base to give cyclo-
pentenones 1a and 1b. (Scheme 7).13
It can be seen from Table 1 that the isomerisation reaction
occurs under a variety of basic conditions. A study on the
rearrangement of pyranone 5a is presented in Table 1. As
previously reported by this group, the optimum conditions
involve treatment of the pyranone 5a or 5b with 5 equiv. of
triethylamine in hot DMF over a 24 h period which leads to
cyclopentenone 1a and 1b in good yield.14 More impor-
tantly, the reaction is stereoselective, forming exclusively
the 1,2-trans product.
Alternatively, it is possible to form acetoxypyranone 4 via a
mCPBA mediated ring expansion.10 Again, this method
avoids the temperamental low temperature bromine addi-
tion. The m-chloroperoxybenzoic acid is added to furfuryl
alcohol in portions at reduced temperature yielding
hydroxypyranone 3. A by-product from this reaction is
benzoic acid, the removal of which is problematic. Filtration
Scheme 7. Reagents and conditions: NEt3, DMF, 808C, 24 h.

8956
S. Caddick et al. / Tetrahedron 56 (2000) 8953±8958
Table 1. Variation of basic conditions in the isomerisation reaction of
pyranone 5a
spectrometer. Analytical thin layer chromatography was
carried out using SIL G/UV254 plates and visualised using
standard procedures. Melting points are uncorrected.
o
Temperature C
Entry
Base
Solvent
Yield %
1
2
3
4
5
6
7
8
Et3Na
DMF
DMF
DMF
DMF
DMF
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
80
80
80
80
80
80
30
30
30
30
70
54
76
16
29
11
11
11
±
19
10
37 (6)
2-Hydroxymethyl-2,5-dimethoxy-3,4-dihydrofuran (2).7,16
A solution of bromine (136.9 g, 0.86 mol) in methanol
(239 mL) was slowly added via addition funnel to a stirred
solution of distilled furfuryl alcohol (70.4 g, 0.718 mol) in
dry diethyl ether (239 mL) and methanol (239 mL) main-
taining an internal temperature between 235 and 2458C.
Upon addition completion, stirring was continued for a
further 2 h at reduced temperature. The resulting light
yellow solution was saturated with gaseous ammonia to
pH 8 and allowed to warm to an ambient temperature.
The resulting yellow suspension was ®ltered, removing
ammonium bromide and concentrated in vacuo. Further
®ltration removed the white solid formed upon concentra-
tion of the yellow oil. The oil was diluted in benzene
(500 mL) and ®ltered through neutral alumina. Evaporation
of the solvent yielded a yellow oil (102.6 g, 90.4%) which
was seen to be of suf®cient purity for use in further stages.
nmax 3473, 2988, 2837, 1632, 1266, 995 cm21; dH
(300 MHz, CDCl3) 1.95 (1H, br s), 3.09 (3H, s), 3.38 (3H,
s), 3.52±3.69 (2H, m), 5.48 (1H, d Jˆ0.9 Hz), 5.93 (1H, d
Jˆ4.7 Hz), 6.04 (1H, d Jˆ4.7 Hz); dC (75 MHz, CDCl3)
50.4, 56.2, 66.6, 107.3, 112.9, 131.3, 132.2; HRMS (EI)
[M2OH]1, found 143.0699. C7H11O3 requires 143.0708.
Et3Nb
iPr2Neta
iPr2Netb
Pyridinea
Pyridineb
DBNa
DBNb
9
10
11
DBUa
DBUb
Et3Nb
a Method a: 1.5 equiv. base.
a Method b: 5 equiv. base.
These results are noteworthy because it can be seen that we
can deliver good quantities of substituted cyclopentenones
under basic conditions (entry 2). The conditions used for
this transformation are similar to those used by a number
of workers to generate oxidopyrilium species from related
acetoxy pyranone derivatives (i.e. 4).15 It is clear that the
reactivity of a pyranone is sensitive to substrate structure
and/or reaction conditions and we found that the nature of
the amine base can have a profound and detrimental impact
on the reactivity of pyranone 5a (entry 3 onwards). Solvent
can also play a role and in particular we found that when we
carried out the reaction in methanol we isolated 3-t-butoxy-
2-hydroxy-cyclopent-2-enone 6 which we assume is derived
from isomerisation of the initially formed cyclopentenone
5a. In order to further support this assumption we stirred
cyclopentenone 5a with Et3N and obtained 6 (entry 11).
6-Hydroxy-2,3-dihydro-6H-pyrano-3-one (3).17 To
2
(102.6 g, 0.64 mol) was added a 2% v:v solution of aqueous
sulfuric acid (200 mL, 2 mL/g). The reaction was stirred at
ambient temperature for 4 h. whereupon solid sodium
hydrogen carbonate was added until the solution reached
pH 4. The residue was extracted into ethyl acetate
(3£750 mL), dried over MgSO4, ®ltered and concentrated
in vacuo maintaining the water bath temperature below
358C to yield the title compound as a yellow oil (65.3 g,
89.5%). nmax 3417, 3055, 1708, 1630, 1266, 978 cm21; dH
(300 MHz, CDCl3) 3.49 (bs, 1H), 4.14 (1H, d Jˆ17 Hz),
4.58 (1H, d Jˆ17 Hz), 5.64 (1H, dd Jˆ5.4, 3.0 Hz), 6.17
(1H, d Jˆ10.4 Hz), 6.97 (1H, dd Jˆ10.4, 1.5 Hz); dC
(75 MHz, CDCl3) 66.5, 88.1, 127.7, 146.1, 194.8; HRMS
(EI) [M]1, found 114.0306. C5H6O3 requires 114.0316.
In conclusion, we have devised a new practical procedure
for the preparation of functionalised cyclopentenones. This
method relies on a new base mediated isomerisation
reaction which proceeds in good yield on large scale.
However, this methodology is limited to availability of
precursors and after extensive evaluation we have identi®ed
what we believe to be the optimum method for the prepara-
tion of pyranone precursors in good yield on large scale. We
believe that these features make this procedure attractive to
synthetic chemists and we have found this methodology
ideal for our work in the dienediyne area.
6-Acetoxy-2,3-dihydro-6H-pyrano-3-one 4 from (3).18 To
a cold solution (08C) of 3 (65.3 g, 0.57 mol) in THF
(600 mL) was added acetic anhydride (234 g, 2.29 mol)
and sodium acetate (188 g, 2.29 mol). The slurry was stirred
for 18 h at ambient temperature, following which, the result-
ing orange solution was ®ltered under pressure to remove
any residual solid and concentrated in vacuo. The reaction
was quenched by addition of saturated sodium bicarbonate
solution (1 L) and additional solid sodium hydrogen carbon-
ate until effervescence ceased. The organic portions were
extracted into diethyl ether (2£1 L), dried over MgSO4,
®ltered and concentrated in vacuo (cold bath) to yield an
orange oil. Puri®cation of this oil was achieved by column
chromatography on silica gel with petrol: diethyl ether (1:4
v:v) as the eluent to give the required product as a yellow oil
(59.6 g, 67%); nmax 2979, 1707, 1700, 1630, 1264,
998 cm21; dH (300 MHz, CDCl3) 2.15 (3H, s), 4.23 (1H, d
Jˆ1.7 Hz), 4.51 (1H, d Jˆ17 Hz), 6.18 (1H, d Jˆ11 Hz),
6.47 (1H, d Jˆ3.6 Hz), 6.95 (1H, dd Jˆ11, 3.6 Hz); dC
Experimental
General
All glassware was oven or ¯ame dried prior to use. All
reagents and solvents were purchased from commercial
sources and used as supplied or puri®ed using standard
methods. Preparations were performed under an inert
1
atmosphere unless stated otherwise. H NMR spectra were
recorded on a Bruker spectrometer at 300 MHz operating at
ambient probe temperature. Coupling constants were
measured in hertz (Hz). 13C NMR spectra were recorded
at 75 MHz in CDCl3 using residual CHCl3 as internal
reference. Infra red spectra were recorded on a Perkin±
Elmer 1710 FTIR spectrometer as thin ®lms, solutions or
KBr discs. Mass spectra were recorded on a Kratos MS25

S. Caddick et al. / Tetrahedron 56 (2000) 8953±8958
8957
(75 MHz, CDCl3) 21.3, 67.8, 87.0, 129.2, 142.7, 169.9,
193.8; HRMS (EI) [M]1, found 156.0419, C7H8O4 requires
156.0422.
6-t-Butoxy-2,3-dihydro-6H-pyrano-3-one (5a).19 A solu-
tion of tin (IV) chloride (6 mL of a 1 M in dichloromethane,
5.6 mmol) was slowly added to a stirred solution of 4
(17.6 g, 0.113 mol) in dichloroethane (10 mL) and tert-
butanol (53 mL, 0.55 mol). Stirring was continued at
ambient temperature for 5 h, after which, the reaction was
quenched with saturated sodium bicarbonate solution
(150 mL) and the resulting oil was extracted into ethyl
acetate (500 mL). The organics were washed with saturated
sodium bicarbonate solution (50 mL) and water (40 mL),
dried (MgSO4), ®ltered under reduced pressure and concen-
trated in vacuo to yield an orange oil which, was puri®ed by
chromatography on silica with petrol:ethyl acetate (7:1 v:v)
as the eluent to yield the title compound as a colourless
liquid (17.1 g, 89%). nmax 3056, 2979, 1707, 1630, 1392,
1266, 998 cm21; dH (300 MHz, CDCl3) 1.17 (9H, s), 3.91
(1H, d Jˆ16.9 Hz), 4.39 (1H, d Jˆ16.9 Hz), 5.33 (1H, d
Jˆ3.4 Hz), 5.95 (1H, d Jˆ10.2 Hz), 6.64 (1H, dd Jˆ10.2,
3.4 Hz); dC (75 MHz, CDCl3) 28.9, 66.5, 88.3, 127.6, 146.6,
195.9; HRMS (EI) [M2CH3]1 found 155.0703. C8H11O3
requires 155.0708.
6-Acetoxy-2,3-dihydro-6H-pyrano-3-one (4) from (2). To
2 (71.4 g, 0.717 mol) in THF (700 mL) and water (25 mL)
cooled to 08C was added tri¯ic acid (16.6 g, 0.107 mol)
producing a dark colouration. The reaction mixture was
stirred at 08C for 3 h, after which acetic anhydride (292 g,
2.87 mol) and sodium acetate (235 g, 2.87 mol) were added.
The reaction was allowed to warm to room temperature for
18 h, after which the solid was removed via ®ltration under
reduced pressure. The resulting brown liquid was washed
with saturated sodium bicarbonate solution (500 mL) and
the organic layer was extracted into ethyl acetate
(3£400 mL), dried over MgSO4, ®ltered and concentrated
in vacuo. The resulting brown liquid was passed through a
short plug of silica with petrol:ethyl acetate (5:1 v:v) as the
eluent to yield the title compound as a yellow low melting
point solid (77.4 g, 69%).
6-Acetoxy-2,3-dihydro-6H-pyrano-3-one (4) from fur-
furyl alcohol using m-CPBA
6-Benzyloxy-2,3-dihydro-6H-pyrano-3-one (5b).17±19
A
solution of tin (IV) chloride (3.46 mL of a 1 M in dichloro-
methane, 5.6 mmol) was slowly added to a stirred solution
of 4 (10.8 g, 69.2 mmol) in 1,2-dichloroethane (180 mL)
and benzyl alcohol (8.59 mL, 83 mmol). Stirring was
continued at ambient temperature for 5 h, after which, the
reaction was quenched with saturated sodium bicarbonate
solution (150 mL) and the resulting oil was extracted into
ethyl acetate (500 mL). The organics were washed with
saturated sodium bicarbonate solution (50 mL) and water
(40 mL), dried (MgSO4), ®ltered under reduced pressure
and concentrated in vacuo to yield an orange oil which,
was puri®ed by chromatography on silica with petrol:
ethyl acetate (7:1 v:v) as the eluent to yield the title
compound as a colourless liquid (11.65 g, 82%). nmax
3064, 2881, 1707, 1630, 1265, 854 cm21; dH (300 MHz,
CDCl3) 4.13 (1H, d, Jˆ16.8 Hz), 4.50 (1H, d,
Jˆ16.8 Hz), 4.68 (1H, d, Jˆ11.7 Hz), 4.87 (1H, d, Jˆ
11.7 Hz), 5.30 (1H, d, Jˆ3.6 Hz), 6.16 (1H, d, Jˆ
10.3 Hz), 6.91 (1H, dd, Jˆ10.3, 3.4 Hz), 7.30±7.39 (5H,
m); dCH (75 MHz, CDCl3) 66.3, 70.7, 92.1, 127.9, 128.1,
128.4, 128.5, 136.8, 144.3, 194.7; HRMS (EI) [M]1, found
204.0795. C12H12O3 requires 204.0786.
To a cooled solution of furfuryl alcohol (20 g, 0.21 mol) in
dichloromethane (800 mL) was added 3-chloroperoxy-
benzoic acid (53 g, 0.31 mol) in 5 g portions. The reaction
²
mixture was allowed to stir at 08C for 6 h, during which a
white solid was generated. The white solid was removed by
®ltration leaving a yellow liquid, which upon concentration
yielded more of the white solid. The residual oil was diluted
with dichloromethane (300 mL) and cooled to 08C, where-
upon pyridine (28 mL, 0.35 mol) and acetyl chloride
(25 mL, 0.35 mol) were added and stirring continued for
2 h. The resulting brown liquid was poured into saturated
sodium bicarbonate solution (150 mL) and the organics
were extracted into dichloromethane (2£100 mL). The
organics were washed with saturated copper sulfate solution
(2£50 mL), dried (MgSO4), ®ltered and concentrated in
vacuo to yield a brown oil. Puri®cation of this oil was
attempted using chromatography on silica gel with diethyl
ether:petrol (4:1 v:v) as the eluent to yield the title
compound as a yellow solid contaminated with residual
benzoic acid (24.27 g, 74%)
6-Acetoxy-2,3-dihydro-6H-pyran-3-one (4) from fur-
furyl alcohol using NBS
General method for the ring contraction reaction
Triethylamine (5 equiv.) was added to a stirred solution of
the alkoxypyranone (1 equiv.) in DMF (2.5 mL/mmol). The
reaction mixture was allowed to stir at 808C for 24 h, after
which, the DMF was removed under reduced pressure to
yield a brown oil. This oil was puri®ed by chromatography
on silica with petrol:ethyl acetate (2:1 v:v) as the eluent to
yield a yellow oil which crystallised on standing to yield the
corresponding cyclopentenone as a white solid.
To a stirring solution of furfuryl alcohol (26 g, 0.27 mmol)
in THF:water (104 mL:26 mL) cooled to 08C, was added
portion wise a ®nely ground mixture of NBS (52 g,
0.29 mol) and sodium bicarbonate (44 g, 0.53 mol). To the
resulting solution was added acetic anhydride (54 g,
0.53 mol) and stirring was continued at ambient temperature
for 18 h. To the resulting orange solution was added enough
solid sodium bicarbonate and saturated sodium bicarbonate
solution to neutralise the solution. The organics were
extracted from ethyl acetate (5£100 mL), dried (MgSO4),
®ltered and concentrated in vacuo to yield the title
compound as an orange oil. Yield (24.25 g, 57%).
trans-4-t-Butoxy-5-hydroxy-2-cyclopenten-1-one (1a).12,20
The general method was employed for the preparation of
1a. The quantities of reagents used were as follows:
triethylamine (146.1 g, 1.45 mol), 5a (49.4 g, 0.29 mol),
DMF (750 mL). (38.4 g, 78%) mp 61±638C. nmax 3430,
2979, 1719, 1615, 1393, 1266, 922 cm21; dH (300 MHz,
²
57±85% in water.

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S. Caddick et al. / Tetrahedron 56 (2000) 8953±8958
2. Goldberg, I. H. Frontiers in Pharmacology and Therapeutics,
Cancer Chemotherapy, Blackwell: Oxford, 1992.
3. For isolation of Kedarcidin, C-1027 and Maduropeptin see:
Kawata, S.; Ashizawa, J.; Hirama, M. J. Am. Chem. Soc. 1997,
119, 12012; Yoshida, K.-I.; Minami, Y.; Azuma, R.; Saeki, M.;
Otani, T. Tetrahedron Lett. 1993, 34, 2637; Schroeder, D. R.;
Colson, K. L.; Klohr, S. E.; Zein, N.; Langley, D. R.; Lee, M. S.;
Matson, J. A.; Doyle, T. W. J. Am. Chem. Soc. 1994, 116, 9351;
Edo, K.; Mizugaki, M.; Koide, Y.; Seto, H.; Furihata, K.; Otake,
N.; Ishida, N. Tetrahedron Lett. 1985, 26, 331.
CDCl3) 1.25 (9H, s), 2.81 (1H, br s), 4.01 (1H, d Jˆ2.3 Hz),
4.53±4.56 (1H, m), 6.17 (1H, d Jˆ6.1 Hz), 7.29 (1H, dd
Jˆ6.1, 1.8 Hz); dC (75 Hz, CDCl3) 28.2, 75.1, 76.4, 80.7,
131.3, 161.5, 205.0; HRMS (EI) [M2CH3]1 found
155.0703. C8H11O3 requires 155.0708.
trans-4-Benzyloxy-5-hydroxy-2-cyclopenten-1-one (1b).12
The general method was employed for the preparation of
1b. The quantities of reagents used were as follows: triethyl-
amine (14.4 g, 142 mmol), 5b (5.8 g, 28.4 mmol), DMF
(70 mL). (4.55 g, 78%), mp 55±568C. nmax 3424, 3056;
2871, 1724, 1627, 896 cm21; dH (300 MHz, CDCl3)
2.85 (1H, br s), 4.28 (1H, d, Jˆ2.2 Hz), 4.55 (1H, s), 4.74
(1H, d, Jˆ11.7 Hz), 4.88 (1H, d, Jˆ11.7 Hz), 6.30 (1H, d,
Jˆ6.1 Hz), 7.32±7.42 (5H, m), 7.48 (1H, d, Jˆ6.1 Hz); dC
(75 MHz, CDCl3) 72.4, 80.4, 82.5, 128.0, 128.1, 128.5,
132.1, 137.2, 159.0, 204.2; HRMS (EI) [M]1 found
204.0790. C12H12O3 requires 204.0786.
4. Myers, A. G.; Liang, J.; Hammond, M.; Harrington, P. M.; Wu,
Y. S.; Kuo, E. Y. J. Am. Chem. Soc. 1998, 120, 2103.
5. Caddick, S.; Delisser, V. M. Tetrahedron Lett. 1997, 38, 2355.
6. Caddick, S.; Khan, S.; Smith, N. J.; Barr, D. M.; Delisser, V. M.
Tetrahedron Lett. 1997, 38, 5035.
7. Achmatowicz Jr., O.; Bukowski, P.; Szechner, B.;
Zwierzchowska, Z.; Zamoiski, A. Tetrahedron 1971, 27, 1973±
1996.
8. Weeks, P. D.; Kuhla, D. E.; Allingham, R. P.; Watson Jr., H. A.
Carbohydr. Res. 1977, 56, 195±199.
3-t-Butoxy-2-hydroxy-cyclopent-2-enone (6). To a stirred
solution of trans-4-t-butoxy-5-hydroxy-2-cyclopenten-1-
one (0.3071 g, 1.81 mmol, 1 equiv.) in anhydrous methanol
(5 mL), was added NEt3 (1.26 mL, 9.03 mmol, 5.0 equiv.)
via syringe and heated at 608C for 23 h. The reaction was
concentrated in vacuo to give a brown oil. Puri®cation of
this oil was achieved by ¯ash chromatography on silica gel
eluting with petrol:ethyl acetate (3:1 v:v) as the eluent yield-
ing the title compound as a pale yellow oil (113 mg, 37%).
nmax 3306, 2978, 1728, 1615 cm21; dH (300 MHz, CDCl3)
1.47 (9H, s), 2.31±2.34 (2H, m), 2.38±2.41 (2H, m), 6.38
(1H, br s); dC (75 MHz, CDCl3) 25.1, 28.1, 28.7, 81.2,
129.9, 160.0, 200.2; HRMS (EI) [M]1 found 170.0959,
C9H14O3 requires 170.0943.
9. Formation of the hydroxypyranone has been achieved using this
method: Shanmugam, Ponnusamy; Nair, Vijay Synth. Commun.
1996, 3007±3014.
10. Formation of the corresponding hydroxypyranone achieved
using this method; Laliberte, R., et al. J. Med. Chem. 1973, 16,
1084±1089.
11. Mucha, B.; Hoffmann, H. M. R. Tetrahedron Lett. 1989, 30,
4489±4492.
12. Kolb, H. C.; Hoffmann, H. M. R. Tetrahedron 1990, 46, 5127±
5144.
13. Caddick, S.; Khan, S. J. Chem. Soc., Chem. Commun. 1995,
1971±1972.
14. Prolonged heating (.24 h) leads to a dramatic reduction in the
yield of desired product and the formation of 3-t-butoxy-2-
hydroxy-cyclopent-2-enone.
Acknowledgements
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We thank AstraZeneca and the Association for International
Cancer Research for their support of this work. We also
thank BBSRC, EPSRC, GlaxoWellcome, SmithKline
Beecham and Novartis for support of our programme. We
thank the University of Sussex for providing the funds to
establish the Centre for Biomolecular Design and Drug
Development. We are grateful to Drs Abdul-Sada, Avent
and Hitchcock (Sussex) for assistance and the EPSRC
Mass Spectrometry Service (Swansea) for mass spectra.
17. Kuo, Yueh-Hsiung; Shih, Kae-Shyang Heterocycles 1990, 31,
1941±1949; Constantinou-Kokotou, V.; Couladouros, E. A.;
Georgiadis, M. P.; Kokotos, G.; Georgiadis, T. M. Carbohydr.
Res. 1991, 222, 163±172; Hoffmann, H. M. R.; Krumwiede, D.;
Mucha, B.; Oehlerking, H. H.; Prahst, G. W. Tetrahedron 1993, 49,
8999±9018.
18. Constantinou-Kokotou, V.; Kokotos, G.; Georgiadis, M. P.
Liebigs Ann. Chem. 1991, 2, 151±154.
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