The synthesis of 2-oxyalkyl-cyclohex-2-enones, related to the bioactive natural products COTC and antheminone A, which possess anti-tumour properties

Article abstract of DOI:10.1016/j.tet.2010.08.072

The syntheses of five novel 2-oxyalkyl-cyclohex-2-enones, structurally related to the natural products COTC and antheminone A, are described. The target structures were selected in order to probe the influence of several key structural parameters on in vi

Full text of DOI:10.1016/j.tet.2010.08.072

Tetrahedron 66 (2010) 9049e9060
Contents lists available at ScienceDirect
Tetrahedron
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The synthesis of 2-oxyalkyl-cyclohex-2-enones, related to the bioactive natural
products COTC and antheminone A, which possess anti-tumour properties
Claire L. Arthurs a, Gareth A. Morris a, Michela Piacenti a, Robin G. Pritchard a, Ian J. Stratford b,
,
a
b
Tanja Tatic a, Roger C. Whitehead a , Katharine F. Williams , Natasha S. Wind
*
a School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
b School of Pharmacy and Pharmaceutical Sciences and Manchester Cancer Research Centre, University of Manchester, Oxford Road, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 April 2010
Received in revised form 10 August 2010
Accepted 31 August 2010
Available online 9 September 2010
The syntheses of five novel 2-oxyalkyl-cyclohex-2-enones, structurally related to the natural products
COTC and antheminone A, are described. The target structures were selected in order to probe the in-
fluence of several key structural parameters on in vitro anti-cancer bioactivity. The results of a cyto-
toxicity bioassay of the compounds against non-small-cell lung cancer cell lines A549 and H460 are
reported. The biological data provides useful information, which will help guide the future design of
compounds in this class with enhanced anti-cancer activity.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
of the cyclohexenones which is depicted for (1) in Scheme 1.6,7
According to this mechanism, conjugate addition of glutathione
The 2-oxyalkyl-cyclohex-2-enone moiety is a common struc-
tural feature in many natural products, including keto-carbasugars
such as 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-
2-enone (COTC, 1)1 and gabosine E (2),2 as well as a variety of ter-
penoids including antheminone A (3)3 and phorbasin B (4)4 (Fig. 1).
Of these, (1) and (3) have been shown to display notable toxicity
towards a range of different cancer cell lines3,5da finding that has
stimulated much interest from both chemists and biologists in
compounds of this type.
(g-L-glutamyl-L-cysteinylglycine, GSH) to the enone moiety of (1)
gives enol (6), which undergoes expulsion of crotonic acid to gen-
erate a glutathionylated exocyclic enone (7); the formation of enol
(6) is facile but the rate of reaction in cells is substantially increased
by enzymatic catalysis via glutathione transferase (GST).6 Alkyl-
ation of intracellular proteins and/or nucleic acids by (7) is believed
to then lead to cell death.
Other processes may also contribute to the anti-cancer activity
of the cyclohexenones. Thus, GSH conjugate (9), derived by trap-
HO
HO
O
O
O3
O
O
O
O
2
1
O
HO
OH
HO
5
HO
OH
X
6 X
4
OH
X
OH
Antheminone A
1 COTC (X = OH)
5 COMC (X = H)
Gabosine E
Phorbasin B
2
3
4
Fig. 1.
Extensive investigations into the anti-tumour properties of
COTC, and its non-hydroxylated analogue, 2-crotonyloxymethyl-
cyclohex-2-enone (COMC, 5), by Creighton, Ganem and others have
delineated a plausible general mechanism for anti-cancer activity
ping the exocyclic enone (7) with GSH, has been shown to be
a competitive inhibitor of human glyoxalase 1 (Glo1):7 this enzyme
(inhibitors of which have previously been demonstrated to have
anti-cancer properties) is vital for cell survival as part of a de-
toxification system for cytotoxic 2-oxoaldehydes such as methyl-
glyoxal.8 Furthermore, general depletion of intracellular GSH
resulting from formation of (9), or indeed the bis-GSH adduct (10),
may also contribute to anti-cancer activity due to a resulting
* Corresponding author. Tel.: þ44 161 275 7856; fax: þ44 161 275 4939; e-mail
address: roger.whitehead@manchester.ac.uk (R.C. Whitehead).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.072

9050
C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
1
2
R R N
O
DNA/
RC(=O)O
RC(=O)O
protein
HO
OH
GS
OH
OH
O
GS
HO
O
OH
8
- RCO H
GSH/GST
2
HO
HO
R =
OH
OH
GS
HO
GS
GS
OH
6
OH
1
OH
7
GSH
O
O
GSH
OH
HO
OH
OH
9
OH
10
Scheme 1.
increase in concentration of 2-oxoaldehydes or other toxic species.
A consequence of these mechanisms of action is the probability that
cells, which require high levels of GSH/GST compared with normal
cells (e.g., many inherently drug-resistant tumour cells) may
exhibit enhanced sensitivity towards compounds containing the
2-oxyalkyl-cyclohex-2-enone moiety.
Prompted by the findings described above, one focus of our
current research concerns the preparation of analogues of com-
pounds (1e4) having generic structure (11) wherein there are five
loci for diversification: the acyl substituent R1, the side-chain
branching substituent R2 and the C4, C5 and C6 substituents on the
cyclohexenone core (X, Y and Z).9e11 In this paper, we provide full
details of the syntheses of five novel 2-oxyalkyl-cyclohex-2-enones
(12e16) (Fig. 2) as well as the results of their bioassay against GSH-
rich lung cancer cell lines, A549 and H460.
itself. We felt that a key intermediate in the synthesis of (12) would
be the hydroxyl-protected derivative of (4S)-4-hydroxycyclohex-2-
enone (17), which could be converted to the target compound via
a three-step reaction sequence of MoritaeBayliseHillman re-
action,12 esterification and deprotection (Scheme 2).
A large-scale synthesis of TBS-ether (17) from (ꢀ)-quinic acid
(20) has been described by Danishefsky and co-workers during the
course of which isopropylidene protection was employed for the
vicinal cis-diol moiety of (20).13 In our hands, although this
synthetic route was successful, it proved to be a little capricious
with regard to reproducibility of yields as well as ease of isolation
of some intermediates (e.g., the isopropylidene analogue of triol
(22)). We opted, therefore, to modify the route to (17) and to
utilise cyclohexylidene protection for the cis-diol moiety in (20)
(Scheme 3).
1
2
O
O
O
O
R
O R
O
O
O
O
O
O
O
F
O
O
O
O
6Z
O
O
X4
11
HO
5
HO
HO
14
HO
15
HO
OH
OH
Y
12
13
16
Fig. 2.
HO
O
O
O
O
O
O
O
O
Morita-Baylis-Hillman
reaction
esterification
deprotection
TBSO
TBSO
TBSO
HO
17
18
19
12
Scheme 2.
The selection of the target molecules was initiated by an early
observation made by Douglas and co-workers that the non-hy-
droxylated synthetic compound COMC (5) was generally more toxic
towards cancer cell lines than the tri-hydroxylated natural product
COTC (1).5 Thus, compounds (12), (13) and (14) were chosen in
order to probe the importance of the extent of hydroxylation, as
well as absolute configuration, on anti-cancer activity. Compound
(15) was selected in order to examine the biological effect of
incorporation of an activating and lipophilic fluorine atom adjacent
to the carbonyl group and compound (16) was chosen in order to
discover whether incorporation of a second electrophilic site into
Using an adaptation of a published procedure, cyclohexylidene
quinide (21) was prepared in excellent yield from (20).14 Reductive
ring-opening of the
under mild conditions (NaBH4) and subsequent oxidative cleavage
of the vicinal diol moiety in (22) gave -hydroxyketone (23) in
acceptable overall yield from (21).15 In a similar manner to the work
reported by Danishefsky, dehydration of (23) to give -enone (24)
g-lactone moiety in (21) proceeded smoothly
b
a,b
could be achieved using methanesulfonyl chloride and Et3N. This
reaction, however, was sluggish even at elevated temperature and
the transformation was better accomplished at room temperature
via an intermediate triflate and in the presence of pyridine. Cata-
lytic hydrogenation of (24) proceeded with good chemoselectivity
to give cyclohexanone (25) and subsequent base-mediated elimi-
nation of the cyclohexylidene protecting group with concomitant
O-silylation gave (17), which was identical in all respects to the
material reported by Danishefsky and co-workers.13
the structures
(a,b-cyclopropyl ketones are pseudo-Michael
acceptors) would result in enhanced biological potency.
2. Results and discussion
2.1. Mono-hydroxylated analogues of COTC (12) and (13)
The MoritaeBayliseHillman reaction represents a powerful
procedure for the introduction of a hydroxyalkyl group at the
The first objective of our research programme was the prepa-
ration of enantiomerically pure mono-hydroxylated analogue (12),
which possesses the same absolute configuration at C4 as COTC
a-position of a,b-unsaturated carbonyl compounds however, with
cyclic enone substrates, the reaction can be quite unpredictable
with regard to reaction time as well as isolated yield.12 We were

C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
9051
OH
CO H
OH
OH
OH
OH
HO
O
O
O
O
O
O
i)
ii)
iii)
2
O
O
22
HO
O
OH
OH
iv)
21
23
_
( )-quinic acid
20
O
O
O
24
v)
O
O
O
O
O
O
O
vii), viii), ix)
vi)
TBSO
HO
12
17
25
Scheme 3. Reagents: (i) cyclohexanone, DMF/C6H6 (1:1), Amberlite IR 120 (H)Ò, reflux (Dean and Stark), 5 h, 92%; (ii) NaBH4, CH3OH, 0 ꢁC to rt, 24 h; (iii) NaIO4, H2O, CH3OH, 0 ꢁC,
1.5 h, 58% from 21; (iv) (CF3SO2)2O, pyridine, CH2Cl2, 0 ꢁC to rt, 12 h, 82%; (v) H2, 10% Pd on C, EtOAc, rt, 17 h, 92%; (vi) DBU, TBSCl, C6H6, reflux, 6 h, 80%; (vii) DMAP (cat.), H2CO, THF/
H2O (1:1), 40 ꢁC, 24 h, 52%; (viii) crotonic anhydride, pyridine, DMAP (cat.), CH2Cl2, rt, 1.5 h, 68%; (ix) TFA/H2O (7:1), 0 ꢁC, 1 h, 98%.
pleased, therefore, to discover that treatment of (17) with aqueous
formaldehyde and a catalytic amount of DMAP for 24 h furnished
hydroxymethyl compound (18) in an acceptable yield (52%).16
Finally, crotonylation of the primary hydroxyl group of (18) and
acid-mediated removal of the silyl protecting group both
proceeded smoothly to give target compound (12), the enantio-
meric purity of which was confirmed by chiral GC analysis using an
essentially racemic sample for comparison (vide infra).
The synthesis of analogue (13) was achieved in a similar fashion
to (12) via racemic silyl-ether (29), which in turn was prepared in
five synthetic operations from commercially available 1,3-cyclo-
hexadiene (26). Thus, using the excellent protocol described by
2.2. Dihydroxylated analogues of COTC (14) and (15)
The key intermediate in our approach to dihydroxylated ana-
logue (14) was butane-diacetal (BDA) protected dihydroxy-
cyclohexenone (33), the cyclohexane-diacetal (CDA) protected
variant of which was first described in 1996 by Brückner and
Gebauer.21 Using a variation of the synthetic sequence reported by
these authors, (33) was prepared in four steps from (ꢀ)-quinic acid
(20) in an overall yield of 79% (Scheme 5). Accordingly, using
a modification of the procedure described by Frost and co-workers,
BDA-protected methyl quinate (30) was prepared from (20) in al-
most quantitative yield.22,23 Reduction of the
a-hydroxy ester
€
Backvall, palladium-catalysed cis-1,4-diacetoxylation of (26) pro-
moiety of (30) was initially carried out using a large excess of NaBH4
in aqueous methanol, however mass-recovery of the highly polar
and partially water-soluble triol (31) using this procedure was quite
variable. A more reliable procedure was developed, therefore,
whereby treatment of (30) with 2 equiv of LiBH4 in THF resulted in
a good recovery of crude triol (31) after 90 min and subsequent
oxidative cleavage, using the silica-supported NaIO4 reagent
vided the meso-diacetate (27).17 In accordance with the observa-
tions of Kazlauskas and co-workers,18 enzymatic de-symmetrisation
of (27) using electric eel cholinesterase19 then gave essentially
21
racemic mono-acetate (28) (synthetic (28): [
CH2Cl2); (ꢀ)-(28): [
a
]
ꢀ1.8 (c 2.21,
D
a
]D ꢀ100.0 (c 1.3, CH2Cl2)). Subsequent silylation
of the free hydroxyl of (28) with TBSOTf followed by methanolysis of
the allylic acetate and oxidation using the LeyeGriffith reagent
(TPAP)20 gave enone (29) in acceptable yield. Conversion of (29) to
mono-hydroxylated analogue (13) was then accomplished using an
identical three-step sequence to that described for the preparation
of (12) (Scheme 4).
described by Shing and Zhong,24 gave
b-hydroxyketone (32) in
excellent yield over two steps from (30). Dehydration of (32) to give
enone (33) was then accomplished, via an intermediate mesylate,
using similar conditions to those described by the original
authors.21
Similarly to the mono-hydroxylated series (vide supra), treat-
ment of (33) with formaldehyde in the presence of a catalytic
amount of DMAP, under the ‘aqueous’ conditions described by
Rezgui and El Gaied,16 furnished hydroxymethyl compound (34) in
excellent yield (Scheme 6). Alternative conditions for this reaction,
including the use of DABCO as a nucleophilic catalyst25 and the use of
surfactant additives,26 were less successful with regard to both the
isolated yield of (34) as well as reproducibility. Crotonylation
of the free hydroxyl of (34) and subsequent acid-mediated removal
of the BDA protecting group both proceeded smoothly to give the
dihydroxylated target compound (14), which was purified by reverse
phase HPLC.
OAc
OAc
i)
ii)
AcO
HO
26
27
28
iii) - v)
O
O
O
O
TBSO
HO
13
29
Scheme 4. Reagents: (i) MnO2, LiCl, p-benzoquinone, Pd(OAc)2, LiOAc$2H2O, AcOH, rt,
3 d, 69%; (ii) electric eel cholinesterase, NaN3, phosphate buffer (pH 6.85), 20 ꢁC, 30 h,
63%; (iii) TBSOTf, Et3N, DMAP, CH2Cl2, 0 ꢁC, 1 h, 82%; (iv) K2CO3, CH3OH, rt, 3 h, 88%; (v)
Unambiguous confirmation of the structure of the product of the
MoritaeBayliseHillman reaction was gained by X-ray analysis of
a crystal of (34) obtained from petroleum ether/ethyl acetate (Fig. 3).
ꢀ
TPAP, NMO, 4 A mol. sieves, CH2Cl2, rt, 7 h, 65%.
2
OH
CO CH
OH
1
HO
O
O
O
OH
CO H
HO
O
HO
O
3
HO
HO
i)
ii)
H CO
3
iii)
OH
iv)
4
6
2
3
5
2
O
H CO
H CO
3
H CO
3
3
O
O
O
O
OH
20
OCH
OCH
3
OCH
OCH
3
3
3
30
31
32
33
Scheme 5. Reagents and conditions: (i) butan-2,3-dione, (CH3O)3CH, camphorsulfonic acid, CH3OH,
over two steps from 30; (iv) Et3N, CH3SO2Cl, CH2Cl2, 3 h, 98%.
D, 12 h, 98%; (ii) LiBH4, THF, rt, 1.5 h; (iii) NaIO4 on silica gel, CH2Cl2, 1.5 h, 82%

9052
C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
The facial selectivity of the reaction of (36) with SelectFluorÒ, to
give axially fluorinated compound (37), was confirmed by the use
of 2D heteronuclear Overhauser effect spectroscopy (HOESY) of the
hydroxymethylated compound (38). Figure 4 compares the normal
HO
O
O
i)
O
H CO
3
O
O
H CO
3
O
proton spectrum (top) of (38) for the region around d 4.8 ppm with
OCH
3
OCH
ii)
33
34
3
a cross-section (bottom) through the F2 dimension of a 2D gradient
HOESY spectrum at the fluorine chemical shift. As expected a strong
NOE is seen to the geminal proton C(6)H (53 Hz doublet, one half of
O
O
which overlaps the vicinal proton resonance C(4)H at
and a weaker transannular NOE to C(4)H.
d 4.84 ppm),
O
O
O
O
O
iii)
H CO
3
HO
14
O
OH
OCH
35
3
Scheme 6. (i) DMAP (cat.), H2CO, THF/H2O (1:1), 40 ꢁC, 24 h, 80%; (ii) crotonicanhydride,
pyridine, DMAP (cat.), CH2Cl2, rt, 1.5 h, 67%; (iii) TFA/H2O (7:1), 0 ꢁC, 30 min, then HPLC,
75%.
Fig. 4.
Fig. 3. Crystal structure of (34) with ellipsoids at 50% probability.
2.3.
a,
b-Cyclopropyl ketone (16)
Incorporation of a highly electronegative and lipophilic fluorine
atom into natural products can have a profound and often benefi-
cial effect on their bioactivity. We were interested, therefore, to
discover whether incorporation of a fluorine atom adjacent to the
ketone carbonyl of dihydroxylated analogue (14) would have
a positive influence on anti-cancer activity. It was envisaged that
It is well documented that
a,b
-cyclopropyl ketones can react as
pseudo-Michael acceptors towards a range of different nucleo-
philes and this observation prompted our interest in the prepara-
tion of COTC analogue (16). This compound possesses both
a conjugated ketone and an
a,b-cyclopropyl ketone moiety and
might, therefore, be expected to display enhanced GSH/GST-me-
diated anti-cancer activity. As a prequel to the synthesis of com-
pound (16), a pertinent observation was made during earlier
the synthesis of the target a-fluoro ketone (15) may be achievable
via quenching an enolate derived from enone (33) with an elec-
trophilic source of fluorine. In this regard, we were particularly
encouraged by results communicated by O’Brien and co-workers
who reported a procedure for introduction of a bromine atom at C6
of (33), via the intermediate generation of trimethylsilylenol-ether
(36).27 After much experimental investigation, it was gratifying to
find that, using a modification of these workers’ procedure, enol-
ether (36) could be quenched with the ‘Fþ-source’, SelectFluorÒ,28
to give a single fluorine-containing compound (37) in acceptable
yield (Scheme 7). MoritaeBayliseHillman reaction of (37) with
formaldehyde then proceeded in excellent yield to give allylic al-
cohol (38), which was converted in the usual manner to fluorinated
COTC analogue (15).
investigations into the reactivity of b-silyloxy ketone (40) towards
a variety of nucleophiles: thus, exposure of the latter compound to
dimethylsulfoxonium methylide (Corey’s ylid)29 resulted in face-
selective formation of cyclopropane (41) as the only isolable
product (rather than the spiro-epoxide (42)) (Scheme 8). The for-
mation of (41) can be rationalised as arising from base-mediated
elimination of tert-butyldimethylsilanoxide to generate enone (33),
followed by stereoelectronically favoured ‘axial attack’ at C3 by the
ylid. In accord with this suggestion, treatment of enone (33) with
a slight excess of Corey’s ylid furnished cyclopropane (41) in very
good yield.
Scheme 7. Reagents and conditions: (i) KHMDS (0.75 M in toluene), TMSCl, THF, ꢀ78 ꢁC to 0 ꢁC, 1 h then SelectFluorÒ, CH3CN, 0 ꢁC, 30 min, 57%; (ii) DMAP (cat.), H2CO, THF/H2O
(1:1), 40 ꢁC, 24 h, 94%; (iii) crotonic anhydride, pyridine, DMAP (cat.), CH2Cl2, rt, 1.5 h, 39%; (iv) TFA/H2O (7:1), rt, 3 h, then HPLC, 95%.

C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
9053
TBSO
O
O
i)
i)
2
1
O
3
1
H CO
TBSO
O
O
O
6
3
O
ii)
5
5
OCH
3
40
O
O4
H CO
H CO
H CO
3
3
3
O
O
O
O
OCH
3
OCH
OCH
42
43
41
3
3
O
H CO
3
O
OCH
3
33
Scheme 8. Reagents and conditions: (i) trimethylsulfoxonium iodide, NaH, DMSO, rt, 1.5 h, 56% from 40, 87% from 33; (ii) SmI2, THF, DMPU, rt, 15 min, 54%.
Initially, the stereochemical assignment of (41) was based on the
observation of a significant NOE from the axially located hydrogen
by Ganem and co-workers.6 These cell lines were chosen because
they showed the highest level of GSH from among a panel of human
tumour cell lines used in chemosensitivity testing.32 Intracellular
GSH concentrations are 16.9 and 22.3 mM, respectively. Further-
at C5 (
1.48 ppm). Further evidence was gained from spectroscopic
analysis of -methylcyclohexanone (43), the product of reductive
ring-opening of
-cyclopropyl ketone (41):30 a significant NOE
d 3.87 ppm) to the cyclopropyl methylene endo hydrogen (d
b
more, the A549 cells show high levels of cytosolic pGST. The
a
,b
cytotoxicity assays were carried out by exposing cells to varying
concentrations of each compound for 4 days. The number of sur-
viving cells was then determined by the use of the MTT assay.33
Values of IC50 are the drug concentrations required to reduce cell
number by 50% relative to untreated, control cells.
between the axially located hydrogen at C5 and the methyl
hydrogens together with a small vicinal coupling constant between
C(4)H and C(3)H of 4.6 Hz are both in accord with an axial location
for the C3 substituent in this compound.
Conversion of
a
,
b
-cyclopropyl ketone (41) to the target analogue
The bioassay results allow several conclusions to be reached
regarding the structural features that influence the toxicity of this
class of compounds towards the two lung cancer cell lines:
(16) was accomplished in five synthetic operations. Thus, pro-
longed exposure of (41) to aqueous acidic conditions resulted in
sequential removal of the BDA protecting group and elimination of
a molecule of water to generate
g
-hydroxy-enone (44) (Scheme 9).
ꢂ incorporation of a single hydroxyl group at C4 results in
a significant improvement in potency over the non-hydroxy-
lated compound, COMC (5) (data for (12), (13) and (16) vs data
for (5));
Protection of the allylic hydroxyl of (44) then proceeded smoothly
to give TBS-ether (45) and subsequent incorporation of a hydroxy-
methyl group at C2 was best accomplished, albeit in very disap-
pointing yield, via an imidazole-mediated MoritaeBayliseHillman
reaction with formaldehyde.31 Conversion of (46) to target struc-
ture (16) was then accomplished in the usual manner.
ꢂ the absolute configuration at C4 has little influence on potency
(data for (12) vs data for (13));
ꢂ incorporation of a second hydroxyl group at C5 results in
a significant erosion of potency (data for (14) and (15) vs data
for (5), (12), (13) and (16));
ꢂ incorporation of a lipophilic and activating fluorine atom ad-
jacent to the carbonyl group has no beneficial influence on
bioactivity (data for (15) vs data for (14));
ꢂ incorporation of an additional electrophilic site into the COTC
analogues has no beneficial influence on bioactivity (data for
(16) vs data for (12) and (13));
O
O
i)
HO
O
ii)
iii)
41
TBSO
TBSO
44
45
46
OH
iv)
O
O
v)
HO
TBSO
O
R
16
47
The enhanced potency of the mono-hydroxylated analogues
compared to COMC (5) prompted us to investigate the toxicity of
compounds (12) and (16) towards a small panel of human cancer
cell lines (Table 2).
The data presented here clearly demonstrate that both mono-
hydroxylated compounds display significant toxicity towards all of
O
R
O
O
R = CH CH=CH
3
Scheme 9. Reagents and conditions: (i) TFA/H2O (7:1), rt, 12 h, then K2CO3, H2O,
CH3OH, rt, 30 min, 99%; (ii) TBSCl, DMAP (cat.), Et3N, CH2Cl2, rt, 6 d, 78%; (iii) imidazole
(cat.), H2CO, THF, Na2CO3 (aq), 40 ꢁC, 7 d, 23%; (iv) crotonic anhydride, pyridine, DMAP
(cat.), CH2Cl2, rt, 24 h, 48%; (v) TFA/H2O (7:1), 0 ꢁC, 1 h, 94%.
the cell lines investigated with the
a,b-cyclopropyl ketone (16)
being between two and five times less potent than (12).
2.4. Toxicity of COTC analogues (12e16) towards cancer cell
lines
3. Conclusion
The results of toxicity bioassays of the five novel analogues of
COTC against two lung cancer cell lines (A549 and H460) are shown
in Table 1 together with the corresponding data for COMC (5),
which was prepared according to a two-step procedure described
In conclusion, five novel 2-oxyalkyl-cyclohex-2-enones (12e16),
which are structurally related to the natural products COTC (1) and
antheminone A (3), have been prepared. The target compounds
were selected in order to probe the influence of several key struc-
tural parameters on the cytoxicity of this structural class towards
non-small-cell lung cancer cell lines. Four of the compounds (12
and 14e16) were enantiomerically pure and were synthesised from
the ‘chiral pool’ material (ꢀ)-quinic acid. The remaining compound
(13), a racemate, was synthesised from cyclohexa-1,3-diene.
Cytotoxicity bioassay of the new compounds against non-small-
cell lung cancer cell lines, A549 and H460, was carried out and the
results of this allow several general conclusions to be made:
Table 1
IC50 values (mM) of compounds (12e16) towards lung cancer cell lines A549 and
H460. Experiments were repeated twice and data within individual experiments
were derived from four separate observations: average values are given in the table
Compound
COMC (5)
(12)
(13)
(14)
(15)
163.7
>200
(16)
Cell line
A549
H460
54.5
40.4
16.7
10.9
23.6
10.5
147.4
158.0
18.1
20.4

9054
C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
Table 2
IC50 values (
m
M) of compounds (12) and (16) towards an array of human cancer cell lines. Experiments were repeated three times and data within individual experiments were
derived from four separate observations: average values are given in the table
Cell line
MDA231 (breast)
T47D (breast)
HCT116 (colon)
HT29 (colon)
RT112 (bladder)
HT1080 (fibrosarcoma)
Compound
(12)
(16)
5.4ꢄ2.7
10.0ꢄ0.9
20.1ꢄ2.3
6.4ꢄ2.4
8.3ꢄ3.0
3.7ꢄ0.5
4.5ꢄ0.4
18.8ꢄ5.0
12.4ꢄ2.2
12.2ꢄ4.4
14.2ꢄ2.2
24.2ꢄ5.9
ꢂ analogues possessing a single free hydroxyl group (e.g., (12),
(13) and (16)) display the greatest anti-cancer activity
ꢂ the absolute configuration at C4 has little influence on
bioactivity
71.9 (C(4)H), 72.1 (C(3)H), 76.3 (C(1)), 110.9 (acetal C), 178.9 (C]O);
m/z (CI/NH3) 272 ([MþNH4]þ, 100%), 255 ([MþH]þ, 30), 211 (10);
(Found: 255.1213. C13H19O5 ([MþH]þ) requires 255.1227).
ꢂ an additional electrophilic moiety (
a,b-cyclopropyl ketone)
4.2.2. 3-O,4-O-Cyclohexylidene-(3R,4S,5R)-trihydroxycyclohexan-1-
one (23). The lactone quinide (21) (0.87 g, 3.43 mmol) was stirred in
methanol (60 mL) at 0 ꢁC and sodium borohydride (1.29 g,
34.3 mmol) was carefully added portionwise. Once effervescence
had ceased, the reaction mixture was stirred for a further 24 h at
room temperature when it was quenched by the addition of a satu-
rated aqueous solution of ammonium chloride (40 mL). Organic
material was extracted into ethyl acetate (3ꢃ40 ml) and the com-
bined organic extracts were dried (MgSO4) and concentrated in
vacuo to yield the crude triol (22) as a colourless solid (0.88 g).
Methanol (80 mL) was added to the solid and the resulting disper-
sion was stirred at 0 ꢁC. A saturated aqueous solution of sodium
periodate (19.6 mL) was added to the dispersion and stirring was
continued at 0 ꢁC for 1.5 h. The reaction was quenched by the ad-
dition of brine (20 mL) and organic material was then extracted into
ethyl acetate (2ꢃ20 mL) and diethyl ether (2ꢃ20 mL). The combined
organic extracts were washed with brine (10 mL), dried (MgSO4) and
concentrated in vacuo to yield the crude product as a clear oil. Pu-
rification by flash column chromatography (SiO2; petroleum ether/
diethyl ether, 1:1) furnished the title compound as a colourless solid
(0.45 g, 58% from (21)); Rf 0.12 (petroleum ether/diethyl ether, 1:1);
does not enhance biological potency
The synthetic chemistry described herein, coupled with the
results of cytotoxicity bioassay, will provide useful information to
guide the future design and synthesis of novel compounds of this
class with enhanced anti-cancer activity.
4. Experimental
4.1. General
Solvents were dried and distilled before use. Chromatography
was performed over Merck silica gel 60 (40e63 mm). IR spectra were
recorded on a PerkineElmer 881 spectrometer or an AT1-Mattson
Genesis Series FTIR spectrometer or a JASCO FT/IR-4100 spectro-
meter. 1H, 13C and 19F spectra were recorded on a Varian Inova
400 MHz spectrometer, a Varian Inova 300 MHz spectrometer or
a Bruker AMX 500 MHz spectrometer. Chemical shifts are refer-
enced to the residual solvent peak. Mass spectra were recorded on
Micromass Trio 2000 quadrupole (EI/CI, low resolution), Thermo
Finnigan MAT 95 XP (EI/CI, high resolution), Micromass Platform
(electrospray) spectrometers. Melting points were recorded using
a Sanyo Gallenkamp MPD350 heater and are uncorrected.
mp 94e95 ꢁC [lit.15 mp 97e98 ꢁC]; [
a]
D
20 þ98.2 (c 0.88, CH2Cl2) [lit.15
[a]
þ100.3 (c 0.44, CH3OH)]; nmax (film)/cmꢀ1 3419br (OeH),
D
2935w (CeH), 1700s (C]O); dH (300 MHz; CDCl3) 1.39e1.62 (10H,
m, 5ꢃCH2 of cyclohexane), 2.44 (1H, ddd, J 18.0, 3.0, 2.0, C(6)Ha),
2.63e2.71 (2H, m, C(2)Hb and C(6)Hb), 2.81 (1H, dd, J 18.0, 3.0, C(2)
Ha), 3.17 (1H, br s, OH), 4.22e4.24 (1H, m, C(5)H), 4.32 (1H, dt, J 9.0,
3.0, C(4)H), 4.70 (1H, dt, J 9.0, 3.0, C(3)H); dC (75 MHz; CDCl3) 23.7,
24.1, 25.4, 33.5 and 36.5 (5ꢃCH2 of cyclohexane), 30.6 (C(6)H2), 40.5
(C(2)H2), 68.3 (C(5)H), 71.9 (C(4)H), 74.8 (C(3)H), 109.7 (acetal C),
209.5 (C(1)O); m/z (CI/NH3) 244 ([MþNH4]þ, 100%), 227 ([MþH]þ,
40); (Found: 227.1277. C12H19O4 ([MþH]þ) requires 227.1278).
4.2. Preparation of mono-hydroxylated compound (12)
4.2.1. (1S,3R,4R,5R)-3-O,4-O-Cyclohexylidene-7-oxo-6-oxabicyclo
[3.2.1]octan-1,3,4-triol (21)14. A mixture of (ꢀ)-quinic acid (40.0 g,
208 mmol), cyclohexanone (140 mL, 1.35 mol), DMF (170 mL) and
benzene (160 mL) was heated under reflux in a flask fitted with
a Dean and Stark trap and condenser until no more water was
collected. After cooling to room temperature, AmberliteÒ resin IR
120 (H) (35 g) was added. The suspension was heated at reflux for
a further 5 h (until no more water was collected) and then allowed
to cool to room temperature. The resin was removed by filtration
and the excess solvent removed in vacuo. Toluene (150 mL) was
added and the mixture washed with a saturated aqueous solution
of sodium bicarbonate (2ꢃ100 mL), followed by water (2ꢃ100 mL).
The combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo to give the crude product as a waxy solid. Petroleum
ether (200 mL) was added and the mixture was cooled in ice for 1 h.
The solid was collected by filtration, washed with cold petroleum
ether and dried under vacuum to afford the title compound as
colourless crystals (49.1 g, 92%); mp 140.8e141.3 ꢁC [lit.14 mp
4.2.3. (4R,5S)-4-O,5-O-Cyclohexylidene-4,5-dihydroxycyclohex-2-
en-1-one (24). A solution of
b-hydroxyketone (23) (1.00 g,
4.43 mmol) in dichloromethane (22 mL) was stirred at ꢀ10 ꢁC un-
der an atmosphere of N2. Pyridine (0.43 mL, 5.31 mmol) and tri-
fluoromethanesulfonic anhydride (0.87 mL, 5.31 mmol) were
added dropwise to the stirred solution, which was then allowed to
warm to room temperature. After 3 h, a further portion of pyridine
(0.43 mL, 5.31 mmol) was added and the reaction mixture was
stirred overnight. The reaction was quenched by the careful addi-
tion of a saturated aqueous solution of sodium bicarbonate (10 mL)
and the organic phase was collected. The aqueous phase was
extracted with a further portion of dichloromethane (10 mL) and
the combined organic extracts were washed sequentially with
a saturated aqueous solution of sodium bicarbonate (10 mL) and
brine (10 mL), dried (MgSO4) and concentrated in vacuo to yield the
crude product as an orange oil. Purification by flash column chro-
matography (SiO2; petroleum ether/diethyl ether, 2:1) provided
22
22
139e141 ꢁC]; [
a
]
ꢀ36.0 (c 0.60, CH2Cl2) [lit.14
[
a
]
ꢀ33.0 (c 1.05,
D
D
CHCl3)]; nmax (film)/cmꢀ1 3434br (OeH), 2930s (CeH), 1795s (C]
O); dH (300 MHz; CDCl3) 1.40e1.80 (10H, m, 5ꢃCH2 of cyclohexane),
2.21 (1H, dd, J 14.5, 3.0, one of C(2)H2), 2.28e2.45 (2H, m, one of C
(2)H2 and one of C(6)H2), 2.76 (1H, br d, J 11.5, one of C(6)H2), 4.38
(1H, ddd, J 6.5, 2.5, 1.0, C(4)H), 4.48e4.56 (1H, m, C(3)H), 4.80 (1H,
dd, J 6.0, 2.5, C(5)H); dC (75 MHz; CDCl3) 23.8, 24.2, 25.3, 33.9, 37.1
(5ꢃCH2 of cyclohexane), 34.7 (C(6)H2), 38.8 (C(2)H2), 71.3 (C(5)H),
enone (24) as a colourless solid (0.75 g, 82%); Rf 0.20 (petroleum
20
ether/diethyl ether, 2:1); mp 50e51 ꢁC [lit.34 mp 55e58 ꢁC]; [
a]
D
þ113 (c 1.81, CH2Cl2) [lit.34
[
a
]
D
þ135 (c 1.0, CHCl3)]; nmax (film)/

C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
9055
cmꢀ1 3143m (CeH), 1659s (C]O); dH (300 MHz; CDCl3) 1.41e1.68
temperature. Formaldehyde (37% aqueous solution) (115 mL,
(10H, m, 5ꢃCH2 of cyclohexane), 2.71 (1H, dd, J 17.7, 3.9, one of C(6)
H2), 2.98 (1H, dd, J 17.7, 2.7, one of C(6)H2), 4.68e4.77 (2H, m, C(4)H
and C(5)H), 6.04 (1H, dt, J 10.5, 1.2, C(2)H), 6.68 (1H, ddd, J 10.5, 2.7,
2.1, C(3)H); dC (75 MHz; CDCl3) 24.0, 24.1, 25.2, 36.5 and 37.7
(5ꢃCH2 of cyclohexane), 39.1 (C(6)H2), 70.9 (C(4)H or C(5)H), 72.1 (C
(4)H or C(5)H), 110.8 (acetal C), 128.9 (C(2)H), 146.5 (C(3)H), 195.9 (C
(1)O); m/z (CI/NH3) 226 ([MþNH4]þ, 50%), 209 ([MþH]þ, 100);
(Found: 208.1099. C12H16O3 (Mþ) requires 208.1094).
1.55 mmol) and a crystal of 4-dimethylaminopyridine were added
and the reaction mixture was stirred at 40 ꢁC for 24 h. The reaction
mixture was then acidified with 1.5 M aqueous hydrochloric acid
and extracted with dichloromethane (2ꢃ10 mL). The combined or-
ganic extracts were washed sequentially with brine (2ꢃ10 mL) and
saturated aqueous sodium bicarbonate solution (2ꢃ10 mL), dried
(MgSO4) and concentrated in vacuo to yield the crude product as
a yellow oil. Purification by flash chromatography (SiO2; petroleum
ether/diethyl ether, 1:1) yielded the title compound as a colourless
20
4.2.4. (3R,4S)-3-O,4-O-Cyclohexylidene-3,4-dihydroxycyclohexanone
(25). A solution of the enone (24) (352 mg, 1.69 mmol) in ethyl
acetate (13 mL) was stirred at room temperature and palladium on
carbon (10%, 35 mg) was added. The reaction vessel was flushed
several times with hydrogen and the reaction mixture was then
stirred under an atmosphere of hydrogen for 17 h. After this time,
the reaction mixture was filtered through a pad of CeliteÒ, eluting
with ethyl acetate, and concentration of organic solvents in vacuo
then yielded the crude product as a yellow oil. Purification by flash
column chromatography (SiO2; diethyl ether/petroleum ether, 1:1)
furnished the title compound as a colourless solid (329 mg, 92%); Rf
0.22 (diethyl ether/petroleum ether, 7:3); mp 84.6e85.7 ꢁC [lit.34
mp 86e87 ꢁC]; nmax (film)/cmꢀ1 3169s (CeH), 2070w (CeH),
1649s (C]O); dH (300 MHz; CDCl3) 1.40e1.65 (10H, m, 5ꢃCH2 of
cyclohexane),1.88 (1H, wtdd, J 15.0, 6.0, 3.0, C(5)Ha), 2.09e2.17 (1H,
m, C(5)Hb), 2.22e2.30 (1H, m, one of C(6)H2), 2.47 (1H, ddd, J 15.0,
6.0, 3.0, one of C(2)H2), 2.54 (1H, ddd, J 12.0, 6.0, 3.0, one of C(6)H2),
2.71 (1H, dd, J 15.0, 3.0, one of C(2)H2), 4.56e4.60 (1H, m, C(4)H),
4.65e4.69 (1H, m, C(3)H); dC (75 MHz; CDCl3) 23.8, 24.2, 25.5, 25.9
and 33.5 (5ꢃCH2 of cyclohexane), 33.8 (C(6)H2), 36.0 (C(5)H2), 42.3
(C(2)H2), 71.3 (C(4)H), 72.6 (C(3)H), 108.6 (acetal C), 210.3 (C(1)O);
m/z (CI/NH3) 211 ([MþH]þ, 100%), 210 (Mþ, 20); (Found: 210.1253.
C12H18O3 (Mþ) requires 210.1256).
oil (82 mg, 52%); Rf 0.18 (petroleum ether/diethyl ether, 3:1); [a]
D
ꢀ50.5 (c 1.14, CH2Cl2); nmax (film)/cmꢀ1 3425br (OeH), 2932m
(CeH), 1675s (C]O); dH (300 MHz; CDCl3) 0.16 (3H, s, SiCH3), 0.17
(3H, s, SiCH3), 0.95 (9H, s, C(CH3)3),1.96e2.69 (4H, m, C(5)H2 andC(6)
H2), 4.23 (1H, d, J 13.5, CHaHbOH), 4.35 (1H, d, J 13.5, CHaHbOH),
4.56e4.63 (1H, m, C(4)H), 6.79e6.82 (1H, m, C(3)H); dC (75 MHz;
CDCl3) ꢀ4.5 (SiCH3), ꢀ4.4 (SiCH3), 26.0 (C(CH3)3), 33.3 (C(5)H2 or C
(6)H2), 36.1 (C(5)H2 or C(6)H2), 61.7 (CH2OH), 67.3 (C(4)H), 137.1 (C
(2)), 151.1 (C(3)H), 200.0 (C(1)O); m/z (CI/NH3) 257 ([MþH]þ, 10%);
(Found: 257.1572. C13H25O3Si ([MþH]þ) requires 257.1567).
4.2.7. (4S)-2-((E)-Crotonyloxymethyl)-4-O-tert-butyldimethylsilyl-
cyclohex-2-en-1-one-4-ol (19). A solution of hydroxymethyl com-
pound (18) (81.9 mg, 0.32 mmol) in dichloromethane (5 mL) was
stirred at room temperature under an atmosphere of N2. Crotonic
anhydride (104 mL, 0.70 mmol), a crystal of 4-dimethylaminopyr-
idine and pyridine (0.23 mL, 2.84 mmol) were added and the
reaction mixture was left to stir for 24 h. The reaction was quenched
by the addition of a saturated aqueous solution of sodium bicar-
bonate (5 mL) and organic material was extracted into dichloro-
methane (2ꢃ10 mL). The combined organic extracts were then
washed with saturated aqueous sodium bicarbonate solution
(10 mL), dried (MgSO4) and concentrated in vacuo to yield the crude
product as a yellow oil. Purification by flash chromatography (SiO2;
petroleum ether/diethyl ether, 6:1) furnished the title compound as
4.2.5. (4S)-4-O-tert-Butyldimethylsilyl-cyclohex-2-en-1-one-4-ol
(17)13. tert-Butyldimethylsilyl chloride (0.30 g, 1.99 mmol) and
DBU (0.28 mL, 1.86 mmol) were added at room temperature to
a solution of ketone (25) (0.35 g, 1.66 mmol) in benzene (14 mL).
The reaction mixture was stirred at room temperature for 10 min
and then heated under reflux for 3 h. After cooling to room tem-
a colourless oil (70 mg, 68%); Rf 0.13 (petroleum ether/diethyl ether,
20
6:1); [
a
]
ꢀ45.9 (c 0.75, CH2Cl2); nmax (film)/cmꢀ1 2955m (CeH),
D
1725m (C]O, ester),1650s (C]O, enone); dH (300 MHz; CDCl3) 0.15
(3H, s, SiCH3), 0.16 (3H, s, SiCH3), 0.95 (9H, s, C(CH3)3), 1.92 (3H, dd, J
6.9, 1.8, CH3CH]CH), 1.98e2.70 (4H, m, C(5)H2 and C(6)H2),
4.57e4.64 (1H, m, C(4)H), 4.79 (1H, d, J 13.8, CHaHbOC(]O)), 4.87
(1H, d, J 13.8, CHaHbOC(]O)), 5.91 (1H, dq, J 15.3, 1.8, CH3CH]CH),
6.83e6.84 (1H, m, C(3)H), 7.05 (1H, dq, J 15.3, 6.9, CH3CH]CH); dC
(75 MHz; CDCl3) ꢀ4.4 (SiCH3), ꢀ4.3 (SiCH3), 18.3 (CH3CH]CH), 26.0
(C(CH3)3), 33.2 (C(5)H2 or C(6)H2), 35.9 (C(5)H2 or C(6)H2), 60.7
(CH2OC(]O)), 67.4 (C(4)H), 122.5 (CH3CH]CH), 133.8 (C(2)), 145.6
(CH3CH]CH), 150.9 (C(3)H), 166.3 (CH2OC(]O)), 197.5 (C(1)O); m/z
(CI/NH3) 342 ([MþNH4]þ, 40%), 325 ([MþH]þ, 60%); (Found:
325.1826. C17H29O4Si ([MþH]þ) requires 325.1830).
perature, a second portion of DBU (70 mL, 0.46 mmol) was added
and heating under reflux was continued for a further 3 h. The re-
action mixture was then allowed to cool to room temperature and
diethyl ether (15 mL) was added. The resulting organic phase was
washed sequentially with water (10 mL), 1 M aqueous HCl (10 mL),
saturated aqueous sodium bicarbonate solution (10 mL) and brine
(10 mL). The organic layer was dried (MgSO4) and concentrated in
vacuo to yield the crude product as a yellow oil. Purification by flash
column chromatography (SiO2; petroleum ether/diethyl ether, 9:1)
furnished the title compound as a colourless oil (0.30 g, 80%); Rf
20
0.22 (petroleum ether:diethyl ether, 9:1); [
a
]
ꢀ111.6 (c 0.81,
4.2.8. (4S)-2-((E)-Crotonyloxymethyl)-4-hydroxycyclohex-2-en-1-
one-4-ol (12). Silyl-ether (19) (36 mg, 0.11 mmol) was stirred in
a mixture of TFA and H2O (7:1, 0.8 mL) at 0 ꢁC for 1 h, after which
time the solvents were removed in vacuo to give the crude product
as a yellow oil. Purification by flash chromatography (SiO2; petro-
leum ether/diethyl ether, 3:1) provided the title compound as
D
20
CH2Cl2) [lit.13
[
a]
ꢀ115.9 (c 1.06, CHCl3); nmax (film)/cmꢀ1 2940w
D
(CeH), 2920s (CeH), 1675s (C]O); dH (300 MHz; CDCl3) 0.15 (3H, s,
SiCH3), 0.16 (3H, s, SiCH3), 0.95 (9H, s, C(CH3)3), 2.03 (1H, tdd, J 12.9,
9.2, 4.5, C(5)Ha), 2.24 (1H, dqd, J 12.9, 4.5,1.8, C(5)Hb), 2.38 (1H, ddd,
J 16.8, 12.9, 4.5, C(6)Hb), 2.61 (1H, br dt, J 16.8, 4.5, C(6)Ha), 4.56 (1H,
ddt, J 9.2, 4.5, 1.8, C(4)H), 5.96 (1H, d, J 10.2, C(2)H), 6.86 (1H, dt, J
10.2,1.8, C(3)H); dC (75 MHz; CDCl3) ꢀ4.9 (SiCH3), ꢀ4.3 (SiCH3), 26.0
(C(CH3)3), 33.2 (C(5)H2 or C(6)H2), 35.8 (C(5)H2 or C(6)H2), 67.3 (C
(4)H), 128.9 (C(2)H), 154.2 (C(3)H), 199.2 (C(1)O); m/z (CI/NH3) 244
([MþNH4]þ, 100%), 227 ([MþH]þ, 20); (Found: 244.1736.
C12H26NO2Si ([MþNH4]þ) requires 244.1727).
a colourless oil (23 mg, 98%); Rf 0.17 (petroleum ether/diethyl ether,
20
3:1); [
a]
ꢀ23.0 (c 0.45, CH2Cl2); nmax (film)/cmꢀ1 3434br (OeH),
D
2361w (CeH), 1716s (C]O, ester), 1658s (C]O, enone); dH
(300 MHz; CDCl3) 1.93 (3H, dd, J 6.0,1.5, CH3CH]CH),1.98e2.73 (4H,
m, C(5)H2 and C(6)H2), 4.62e4.70 (1H, m, C(4)H), 4.78e4.92 (2H, m,
CH2OC(]O)), 5.91 (1H, dq, J 15.0, 1.5, CH3CH]CH), 6.92e6.93 (1H,
m, C(3)H), 7.06 (1H, dq, J 15.0, 6.0, CH3CH]CH); dC (75 MHz; CDCl3)
18.4 (CH3CH]CH), 32.5 (C(5)H2 or C(6)H2), 35.7 (C(5)H2 or C(6)H2),
60.7 (CH2OC(]O)), 66.7 (C(4)H), 122.3 (CH3CH]CH), 134.5 (C(2)),
146.4 (C(3)H), 149.2 (CH3CH]CH), 166.6 (CH2OC(]O)), 197.7 (C(1)
4.2.6. (4S)-2-Hydroxymethyl-4-O-tert-butyldimethylsilyl-cyclohex-
2-en-1-one-4-ol (18). The enone (17) (140 mg, 0.62 mmol) was
stirred in a mixture of tetrahydrofuran/water (1:1) (8 mL) at room

9056
C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
O); m/z (CI/NH3) 228 ([MþNH4]þ, 50%), 211 ([MþH]þ,100%); (Found:
228.1238. C11H18NO4 ([MþNH4]þ) requires 228.1230).
m, C(1)H or C(2)H); dC (75 MHz; CDCl3) ꢀ4.4 (SiCH3), ꢀ4.3 (SiCH3),
18.4 (C(CH3)3) 21.6 (OC(]O)CH3), 25.6 (C(4)H2 or C(5)H2), 26.1 (C
(CH3)3), 28.7 (C(4)H2 or C(5)H2), 66.6 (C(6)H), 67.3 (C(3)H), 126.5 (C
(1)H or C(2)H), 136.7 (C(1)H or C(2)H), 170.6 (C]O); m/z (CI/NH3)
288 ([MþNH4]þ, 10%), 271 ([MþH]þ, 5); (Found: 288.1997.
C14H30NO3Si ([MþNH4]þ) requires 288.1998).
4.3. Preparation of racemic enone (29)
4. 3.1. meso-3, 6-Di-O-acetyl-cyclohex-1 -en e-3, 6-dio l
(27)17. Manganese(IV) oxide (2.72 g, 31.3 mmol) was added to
a stirred solution of lithium chloride (207 mg, 4.9 mmol), p-ben-
zoquinone (640 mg, 5.9 mmol), palladium(II) acetate (280 mg,
1.25 mmol) and lithium acetate dihydrate (8.60 g, 84.3 mmol) in
acetic acid (40 mL). 1,3-Cyclohexadiene (2.4 mL, 25.0 mmol) in
pentane (50 mL) was then added to the reaction mixture and the
resulting solution was stirred at room temperature for 3 days. Brine
(50 mL) was added to dilute the mixture, which was extracted
sequentially with pentane (3ꢃ100 mL) and pentane/diethyl ether
(1:1 mixture, 3ꢃ80 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo to yield the crude product as an
orange oil. Purification by flash column chromatography (SiO2;
petroleum ether/ethyl acetate, 9:1) furnished the title compound as
a yellow oil (3.42 g, 69%); Rf 0.18 (petroleum ether/ethyl acetate,
9:1); nmax (film)/cmꢀ1 2953s (CeH), 1736s (C]O); dH (300 MHz;
CDCl3) 1.73e1.88 (4H, m, C(4)H2 and C(5)H2), 1.97 (6H, s, 2ꢃCH3),
5.13 (2H, br s, C(3)H and C(6)H), 5.80 (2H, s, C(1)H and C(2)H); dC
(75 MHz; CDCl3) 21.3 (2ꢃCH3), 25.0 (C(4)H2 and C(5)H2), 67.4 (C(3)
H and C(6)H), 130.4 (C(1)H and C(2)H), 170.5 (2ꢃC]O); m/z (CI/
NH3) 216 ([MþNH4]þ, 90%), 199 ([MþH]þ, 10), 139 (100); (Found:
216.1226. C10H18NO4 ([MþNH4]þ) requires 216.1230).
4.3.4. (3S,6R/3R,6S)-6-O-tert-Butyldimethylsilyl-cyclohex-1-ene-3,6-
diol. Potassium carbonate (150 mg, 1.05 mmol) was added por-
tionwise, at room temperature, to a stirred solution of racemic
3-O-acetyl-6-O-tert-butyldimethylsilyl-cyclohex-1-ene-3,6-diol
(284 mg, 1.05 mmol) in methanol (10 mL) and stirring was con-
tinued for 3 h. The reactionwas quenched by the addition of water
(10 mL) and organic components were extracted into ethyl ace-
tate (2ꢃ20 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo to yield the crude product as
a pale yellow oil. Purification by flash column chromatography
(SiO2; petroleum ether/diethyl ether, 3:1) provided the title
compound as a colourless oil (210 mg, 88%); Rf 0.11 (petroleum
ether/diethyl ether, 3:1); nmax (film)/cmꢀ1 3400br (OeH), 2953w
(CeH), 2856w (CeH); dH (300 MHz; CDCl3) 0.01 (6H, s, Si(CH3)2),
0.92 (9H, s, C(CH3)3), 1.67e1.88 (4H, m, C(4)H2 and C(5)H2),
4.09e4.18 (2H, m, C(3)H and C(6)H), 5.75e5.84 (2H, m, C(1)H and
C(2)H); dC (75 MHz; CDCl3) ꢀ4.4 (SiCH3), ꢀ4.3 (SiCH3), 26.1 (C(4)
H2 or C(5)H2), 28.5 (C(4)H2 or C(5)H2), 28.7 (C(CH3)3), 65.1 (C(3)H
or C(6)H), 66.6 (C(3)H or C(6)H), 130.8 (C(1)H or C(2)H), 134.5 (C
(1)H or C(2)H); m/z (ESIþ) 251 ([MþNa]þ,100%), 229 ([MþH]þ,10).
4.3.2. (3S,6R/3R,6S)-3-O-Acetyl-cyclohex-1-ene-3,6-diol (28)19. The
meso-diacetate (27) (300 mg, 1.51 mmol) was stirred in aqueous
phosphate buffer (0.58 M, pH¼6.85, 50 mL) together with sodium
azide (2 mg, 0.03 mmol) and electric eel cholinesterase (1 mg, 292
units) at 20 ꢁC for 30 h. Organic material was then extracted into
a mixture of ethyl acetate and diethyl ether (1:1, 3ꢃ20 mL) and the
combined organic extracts were dried (MgSO4) and concentrated in
vacuo to yield the crude product as a red oil. Purification by flash
column chromatography (SiO2; petroleum ether/ethyl acetate, 3:1)
furnished the title compound as a clear oil (149 mg, 63%); Rf 0.11
(petroleum ether/ethyl acetate, 3:1); nmax (film)/cmꢀ1 3402br
(OeH), 2950s (CeH), 1735s (C]O); dH (300 MHz; CDCl3) 1.70e1.98
(4H, m, C(4)H2 and C(5)H2), 2.04 (3H, s, OC(]O)CH3), 2.60 (1H, br,
OH), 4.18e4.20 (1H, m, C(6)H), 5.15e5.18 (1H, m, C(3)H), 5.77 (1H,
br dd, J 10.2, 3.6, C(1)H), 5.95 (1H, br dd, J 10.2, 2.9, C(2)H); dC
(75 MHz; CDCl3) 21.5 (OC(]O)CH3), 25.3 (C(4)H2 and C(5)H2, sig-
nals coincident), 65.5 (C(6)H), 67.6 (C(3)H), 127.8 (C(1)H), 135.3 (C
(2)H), 171.1 (C]O); m/z (CI/NH3) 174 ([MþNH4]þ, 100%), 139 (100);
(Found: 174.1136. C8H16NO3 ([MþNH4]þ) requires 174.1125).
4.3.5. (4S/R)-4-O-tert-Butyldimethylsilyl-cyclohex-2-en-1-one-4-ol
(29). A solution of racemic 6-O-tert-butyldimethylsilyl-cyclohex-1-
ene-3,6-diol (200 mg, 0.88 mmol) in dichloromethane (15 mL) was
stirred at room temperature. Molecular sieves (1.5 g), 4-methyl-
morpholine N-oxide (130 mg, 0.97 mmol) and TPAP (15.5 mg,
0.04 mmol) were added and stirring was continued at room tem-
perature for 7 h. The reaction mixture was filtered through a pad of
silica, eluting successively with dichloromethane (20 mL) and ethyl
acetate (20 mL) and the eluate was concentrated in vacuo to yield
the crude product as a brown oil. Purification by flash column
chromatography (SiO2; petroleum ether/diethyl ether, 5:1) fur-
nished the title compound as a pale yellow oil (130 mg, 65%); an-
alytical data as for compound (17) (vide supra).
4.4. Preparation of dihydroxylated compound (14)
4.4.1. (20S,30S)-Methyl-4-O,5-O-(20,30-dimethoxybutane-20,30-diyl)-
quinate (30). Prepared as described previously.35
4.4.2. (20S,30S,3R,4R,5R)-4-O,5-O-(20,30-Dimethoxybutane-20,30-diyl)-
cyclohexan-1-one-3,4,5-triol (32). Lithium borohydride (0.68 g,
31.2 mmol) was stirred in freshly distilled THF (30 mL) at room
temperature under an atmosphere of N2 for 15 min. A solution of
BDA-protected methyl quinate (30) (5.0 g, 15.6 mmol) in THF
(30 mL) was added at 0 ꢁC and the reaction mixture was stirred at
room temperature for 1.5 h. The reaction mixture was then poured
into a saturated aqueous solution of ammonium chloride (60 mL).
Water and THF were removed in vacuo to yield a colourless solid to
which ethyl acetate (200 mL) was added. The resulting mixture was
filtered to remove the suspended solid, which was washed re-
peatedly with ethyl acetate (3ꢃ40 mL). The combined washings
were dried (MgSO4) and concentrated in vacuo to yield the crude
triol (31) as a colourless solid (4.48 g).
4.3.3. (3S,6R/3R,6S)-3-O-Acetyl-6-O-tert-butyldimethylsilyl-cyclo-
hex-1-ene-3,6-diol. A stirred solution of allylic acetate (28)
(200 mg, 1.28 mmol) in dichloromethane (10 mL) was cooled to
0 ꢁC. A crystal of 4-dimethylaminopyridine was added, followed by
triethylamine (0.27 mL, 1.92 mmol) and a solution of TBDMSeOTf
(0.32 mL, 1.41 mmol) in dichloromethane (10 mL). The reaction
mixture was stirred for 1 h at 0 ꢁC when it was quenched by the
careful addition of water (20 mL). The organic phase was collected
and combined with two further dichloromethane extracts
(2ꢃ20 mL). The combined organic extracts were washed with brine
(20 mL), dried (MgSO4) and concentrated in vacuo to yield the
crude product as a yellow oil. Purification by flash column chro-
matography (SiO2; petroleum ether/ethyl acetate, 15:1) provided
the title compound as a colourless oil (284 mg, 82%); Rf 0.26 (pe-
troleum ether/diethyl ether, 15:1); dH (300 MHz; CDCl3) 0.01 (6H, s,
(Si(CH3)2)), 0.92 (9H, s, C(CH3)3), 1.72e1.97 (4H, m, C(4)H2 and C(5)
H2), 2.07 (3H, s, OC(]O)CH3), 4.16e4.22 (1H, m, C(6)H), 5.15e5.19
(1H, m, C(3)H), 5.75e5.77 (1H, m, C(1)H or C(2)H), 5.89e5.91 (1H,
Sodium periodate (8.20 g, 38.3 mmol) was dissolved in water
(30 mL) with gentle warming. To the resulting solution, silica gel
(20.5 g) was carefully added with vigorous stirring to produce silica-
supported sodium periodate as a free flowing powder. A solution of
the crude triol (31) in dichloromethane (60 mL) was added to

C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
9057
a vigorously stirred suspension of the silica-supported sodium
periodate reagent in dichloromethane (120 mL). The heterogeneous
reaction mixture was stirred at room temperature for 1.5 h then
filtered and the silica-residue washed repeatedly with dichloro-
methane (3ꢃ50 mL). The filtrate was dried (MgSO4) and concen-
trated in vacuo to yield the title compound as a pale yellow solid
2.58 (1H, dd, J 16.5, 15.0, C(6)Hb), 2.80 (1H, dd, J 16.5, 4.8, C(6)Ha),
3.30 (3H, s, OCH3), 3.38 (3H, s, OCH3), 4.09 (1H, ddd, J 15.0, 9.3, 4.8, C
(5)H), 4.25 (1H, d, J 14.4, CHaHbOH), 4.36 (1H, d, J 14.4, CHaHbOH),
4.58 (1H, dd, J 9.3, 1.8, C(4)H), 6.88 (1H, d, J 1.8, C(3)H); dC (75 MHz;
CDCl3) 17.9 (butyl CH3), 18.0 (butyl CH3), 42.4 (C(6)H2), 48.4 (OCH3),
48.5 (OCH3), 61.1 (CH2OH), 68.3 (C(5)H), 69.3 (C(4)H), 100.0 (acetal
C), 101.1 (acetal C), 139.3 (C(2)), 144.7 (C(3)H), 197.5 (C(1)O); m/z (CI/
NH3) 290 ([MþNH4]þ, 40%), 273 (10), 258 (90); (Found: 290.1597.
C13H24NO6 ([MþNH4]þ) requires 290.1598).
(3.34 g, 82%); Rf 0.26 (ethyl acetate/40e60 petroleum ether,1:1); mp
24
167.9e169.7 ꢁC [lit.36 mp 163e165 ꢁC]; [
a
]
þ147 (c 1.0, CH2Cl2)
D
[lit.36
[a
]
20 þ159.8 (c 0.59, CH2Cl2)]; nmax (film)/cmꢀ1 3442br (OeH),
D
2991w (CeH), 2948w (CeH), 2991w (CeH), 2834w (CeH), 1721s
(C]O); dH (400 MHz; CDCl3) 1.32 (3H, s, butyl CH3),1.35 (3H, s, butyl
CH3), 2.40 (1H, s, OH), 2.47e2.54 (2H, m, one of C(2)H2 and one of C
(6)H2), 2.64e2.70 (2H, m, one of C(2)H2 and one of C(6)H2), 3.24 (3H,
s, OCH3), 3.32 (3H, s, OCH3), 3.90 (1H, dd, J 10.1, 2.5, C(4)H), 4.25e4.32
(2H, m, C(3)H and C(5)H); dC (100 MHz; CDCl3) 17.6 (butyl CH3), 17.7
(butyl CH3), 44.7 (C(2)H2 or C(6)H2), 46.1 (C(2)H2 or C(6)H2), 48.0
(OCH3), 48.1 (OCH3), 63.2 (C(3)H or C(5)H), 67.7 (C(3)H or C(5)H),
72.2 (C(4)H), 99.2 (acetal C), 100.3 (acetal C), 205.5 (C(1)O); m/z (CI/
NH3) 278 ([MþNH4]þ, 60%), 246 (90), 229 (60), 214 (50); (Found:
278.1606. C12H24NO6 ([MþNH4]þ) requires 278.1598).
4.4.5. (20S,30S,4R,5R)-2-((E)-Crotonyloxymethyl)-4-O,5-O-(20,30-di-
methoxybutane-20,30-diyl)-4,5-dihydroxycyclohex-2-en-1-one
(35). A solution of hydroxymethyl compound (34) (175 mg,
0.73 mmol) in dichloromethane (20 mL) was stirred under an at-
mosphere of N2 at room temperature. Crotonic anhydride (0.24 mL,
1.60 mmol), a crystal of 4-dimethylaminopyridine and pyridine
(0.52 mL, 6.45 mmol) were added sequentially and the reaction
mixture was then left to stir for 1.5 h at room temperature. The re-
actionwas quenched by the addition of a saturated aqueous solution
of sodium bicarbonate (20 mL) and organic material was then
extracted into dichloromethane (2ꢃ20 mL). The combined organic
extracts were washed with saturated sodium bicarbonate solution
(10 mL), dried (MgSO4) and concentrated in vacuo to yield the crude
product as a yellow solid. Purification by flash column chromatog-
raphy (SiO2; petroleum ether/ethyl acetate, 5:1) yielded the title
compound as a colourless solid (165 mg, 67%); Rf202.22 (petroleum
4.4.3. (20S,30S,4R,5R)-4-O,5-O-(20,30-Dimethoxybutane-20,30-diyl)-
4,5-dihydroxycyclohex-2-en-1-one (33). A solution of hydroxy-
ketone (32) (1.0 g, 3.8 mmol) in dichloromethane (20 mL) was stir-
red under an atmosphere of N2 at 0 ꢁC and methanesulfonyl chloride
(0.36 mL, 4.61 mmol), followed by triethylamine (1.55 mL,
11.2 mmol) were carefully added. The reaction mixture was allowed
to warm to room temperature and it was then stirred at that tem-
perature for a further period of 3 h. The reaction was quenched by
the addition of water (20 mL). The organic phase was collected and
combined with two subsequent dichloromethane extracts
(2ꢃ20 mL). The combined organic extracts were dried (MgSO4)
and concentrated in vacuo to yield the title compound as a slightly
off-white solid (0.91 g, 98%); (Found: C, 59.61; H, 7.47. C12H18O5 re-
quires C, 59.49; H, 7.49%); mp 181.8e183.0 ꢁC [lit.36 mp 182e184 ꢁC];
ether/ethyl acetate, 5:1); mp 76.2e76.8 ꢁC; [
a
]
þ72.3 (c 0.6,
D
CH2Cl2); nmax (film)/cmꢀ1 2854m (CeH),1720m (C]O, ester),1685w
(C]O, enone); dH (300 MHz; CDCl3) 1.38 (3H, s, butyl CH3),1.40 (3H,
s, butyl CH3),1.95 (3H, dd, J 6.9,1.8, CH3CH]CH), 2.58 (1H, dd, J 16.5,
13.5, C(6)Hb), 2.82 (1H, dd, J 16.5, 4.8, C(6)Ha), 3.30 (3H, s, OCH3), 3.38
(3H, s, OCH3), 4.01 (1H, ddd, J 13.5, 9.3, 4.8, C(5)H), 4.58 (1H, dd, J 9.3,
1.5, C(4)H), 4.76 (1H, d, J 14.4, CHaHbOC]O), 4.81 (1H, d, J 14.4,
CHaHbOC]O), 5.90 (1H, dq, J 15.6,1.8, CH3CH]CH), 6.84 (1H, d, J 1.5,
C(3)H), 7.05 (1H, dq, J 15.6, 6.9, CH3CH]CH); dC (75 MHz; CDCl3) 17.9
(butyl CH3), 18.0 (butyl CH3), 18.3 (CH3CH]CH), 42.3 (C(6)H2), 48.4
(OCH3), 48.5 (OCH3), 60.3 (CH2OC]O), 68.2 (C(5)H), 69.4 (C(4)H),
99.9 (acetal C), 101.1 (acetal C), 109.9 (CH3CH]CH), 122.4 (CH3CH]
CH),135.8 (C(2)),145.1 (C(3)H),166.1 (CH2OC]O),195.4 (C(1)O); m/z
(CI/NH3) 358 ([MþNH4]þ, 70%), 341 (60), 326 (40); (Found:
358.1866. C17H28NO7 ([MþNH4]þ) requires 358.1860).
22
20
[
a]
þ68.8 (c 1.2, CH2Cl2) [lit.36
[
a]
þ64.4 (c 0.39, CH2Cl2)]; nmax
D
D
(film)/cmꢀ1 3054w (CeH), 2854s (CeH), 1685 (m, C]O); dH
(300 MHz; CDCl3) 1.38 (3H, s, butyl CH3),1.40 (3H, s, butyl CH3), 2.52
(1H, dd, J 16.5,13.2, C(6)Hb), 2.80 (1H, dd, J 16.5, 4.8, C(6)Ha), 3.30 (3H,
s, OCH3), 3.38 (3H, s, OCH3), 4.08 (1H, ddd, 13.2, 9.3, 4.8, C(5)H), 4.55
(1H, dt, J 9.3,1.8, C(4)H), 6.05 (1H, dd, J 10.2,1.8, C(2)H), 6.92 (1H, dd, J
10.2, 1.8, C(3)H); dC (75 MHz; CDCl3) 17.9 (butyl CH3), 18.0 (butyl
CH3), 42.3 (C(6)H2), 48.4 (OCH3), 48.5 (OCH3), 68.4 (C(5)H), 69.5 (C(4)
H),100.0 (acetal C),101.1 (acetal C),130.4 (C(3)H),148.8 (C(2)H),197.5
(C(1)O); m/z (CI/NH3) 260 ([MþNH4]þ, 10%), 228 (90); (Found:
260.1491. C12H22NO5 ([MþNH4]þ) requires 260.1492).
4.4.6. (4R,5R)-2((E)-Crotonyloxymethyl)-4,5-(dihydroxy)-cyclohex-
2-en-1-one (14). Removal of the BDA protecting group from (35)
was accomplished using trifluoroacetic acid in the same manner as
deprotection of silyl-ether (19). Purification by reverse phase HPLC
eluting with acetonitrile/water (20:80) afforded the title compound
4.4.4. (20S,30S,4R,5R)-2-Hydroxymethyl-4-O,5-O-(20,30-dimethoxy-
butane-20,30-diyl)-4,5-dihydroxycyclohex-2-en-1-one (34). A solu-
tion of the enone (33) (300 mg, 1.24 mmol) was stirred in a mixture
of tetrahydrofuran and water (1:1, 10 mL) at room temperature.
as a paleyellowoil (75%); [
a]
18 þ11.7 (c 2.5, CH2Cl2); nmax (film)/cmꢀ1
D
3402br (OeH), 2963w (CeH), 2362w (CeH), 1719m (C]O, ester),
1678m (C]O, enone); dH (300 MHz; CDCl3) 1.94 (3H, dd, J 6.9, 1.8,
CH3CH]CH), 2.52 (1H, dd, J 16.5, 12.3, C(6)Hb), 2.92 (1H, dd, J 16.5,
4.8, C(6)Ha), 4.01 (1H, ddd, J 12.3, 8.4, 4.8, C(5)H), 4.58 (1H, dd, J 8.4,
2.4, C(4)H), 4.80e4.90 (2H, m, CH2OC]O), 5.90 (1H, dq, J 15.6, 1.8,
CH3CH]CH), 6.84 (1H, d, J 2.4, C(3)H), 7.05 (1H, dq, J 15.6, 6.9,
CH3CH]CH); dC (75 MHz; CDCl3) 18.4 (CH3CH]CH), 44.8 (C(6)H2),
60.3 (CH2OC]O), 72.9 (C(5)H), 73.3 (C(4)H), 122.2 (CH3CH]CH),
135.2 (C(2)), 146.4 (C(3)H), 146.8 (CH3CH]CH), 166.4 (CH2OC]O),
195.8 (C(1)O); m/z (CI/NH3): 244 ([MþNH4]þ, 90%), 227 ([MþH]þ,
20); (Found: 244.1181. C11H18NO5 ([MþNH4]þ) requires 244.1179).
Formaldehyde (37%) (0.19 mL, 2.49 mmol) and
a crystal of
4-dimethylaminopyridine (15 mg, 0.12 mmol) were added and the
reaction mixture was warmed and stirred at 40 ꢁC for 24 h. The
reaction mixture was then acidified with 1.5 M aqueous hydro-
chloric acid and extracted with dichloromethane (3ꢃ10 mL). The
combined organic extracts were washed sequentially with brine
(2ꢃ10 mL) and a saturated aqueous solution of sodium bicarbonate
(2ꢃ10 mL), dried (MgSO4) and concentrated in vacuo to yield the
crude product as a yellow solid. Purification by flash chromatog-
raphy (SiO2; petroleum ether/ethyl acetate, 1:1) furnished the title
compound as a colourless solid (270 mg, 80%). Found: C, 57.24; H,
7.51. C13H20O6 requires C, 57.34; H, 7.40%; Rf 0.36 (petroleum ether/
4.5. Preparation of fluorinated compound (15)
4.5.1. (20S,30S,4R,5S,6S)-6-Fluoro-4-O,5-O-(20,30-dimethoxybutane-
20,30-diyl)-4,5-dihydroxycyclohex-2-en-1-one (37). A solution of the
enone (33) (200 mg, 0.83 mmol) in tetrahydrofuran (5 mL) was
added, via cannula and under an atmosphere of N2, to a stirred
ethyl acetate, 1:1); mp 179.8e181.2 ꢁC; [
a
]
22 þ34.5 (c 0.9, CH2Cl2);
D
nmax (film)/cmꢀ1 3435br (OeH), 3054m (CeH), 1677m (C]O); dH
(300 MHz; CDCl3) 1.38 (3H, s, butyl CH3), 1.40 (3H, s, butyl CH3),

9058
C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
solution of potasium bis(trimethylsilyl)amide (3.3 mL of a 0.75 M
solution in toluene, 2.48 mmol) in tetrahydrofuran (5 mL) at ꢀ78 ꢁC
in a two-neck round bottom flask attached to a high vacuum Büchi
rotary evaporator (no vacuum applied). The resulting solution was
stirred for 1 h at ꢀ78 ꢁC. Freshly distilled trimethylsilyl chloride
(0.52 mL, 4.13 mmol) was added dropwise and the reaction mixture
was stirred for 30 min at ꢀ78 ꢁC, and then at 0 ꢁC for a further
30 min. After being allowed to warm to room temperature the
solvents were removed in vacuo and the crude trimethylsilylenol-
ether (36) was stored under vacuum. A solution of SelectFluorÒ
(0.59 g, 1.65 mmol) in acetonitrile (10 mL) was then added via sy-
ringe to the crude enol-ether at 0 ꢁC and the resulting solution was
stirred at 0 ꢁC for 30 min. The reaction mixture was quenched by
the addition of a saturated aqueous solution of ammonium chloride
(20 mL), ethyl acetate (20 mL) was added and the organic phase
was collected and combined with two subsequent ethyl acetate
extracts (2ꢃ20 mL). The combined organic extracts were washed
with brine (2ꢃ10 mL), dried (MgSO4) and concentrated in vacuo to
give the crude product as a yellow solid. Purification by flash col-
umn chromatography (SiO2; petroleum ether/ethyl acetate, 9:1)
CH2OC]O), 4.90 (1H, dd, J 51.0, 3.0, C(6)HF), 4.94 (1H, dq, J 9.0, 3.0, C
(4)H), 5.91 (1H, dq, J 15.0, 3.0, CH3CH]CH), 7.00 (1H, q, J 3.0, C(3)H),
7.08 (1H, dq slightly obscured, J 15.0, 9.0, CH3CH]CH); dC (75 MHz;
CDCl3) 17.7 (butyl CH3), 19.9 (butyl CH3), 18.4 (CH3CH]CH), 48.6
(2ꢃOCH3, coincident), 59.9 (CH2OC]O), 64.0 (d, J 7.4, C(4)H), 71.1 (d,
J 17.7, C(5)H), 89.9 (d, J 182.0, C(6)HF),100.8 (acetal C),101.2(acetal C),
122.2 (CH3CH]CH),133.9 (C(2)),146.2 (C(3)H or CH3CH]CH),146.6
(C(3)H or CH3CH]CH),165.9 (CH2OC]O),189.2 (d, J 17.1, (C(1)O)); dF
(282 MHz; CDCl3) ꢀ29.5 (dd, J 51.0, 33.0, C(6)HF); m/z (CI/NH3) 376
([MþNH4]þ, 50%), 359 ([MþH]þ, 10), 344 (20); (Found: 376.1773.
C17H27FNO7 ([MþNH4]þ) requires 376.1766).
4.5.4. (4R,5S,6S)-(2(E)-Crotonyloxymethyl)-6-fluoro-4,5-(dihy-
droxy)-cyclohex-2-en-1-one (15). Removal of the BDA protecting
group from (39) (43 mg, 0.12 mmol) was accomplished using
trifluoroacetic acid in the same manner as for deprotection of
silyl-ether (19). Purification by reverse phase HPLC eluting with
acetonitrile/water (20:80) afforded the title compound as a clear
oil (95%); [
a
]
18 ꢀ4.4 (c 1.36, H2O); nmax (film)/cmꢀ1 3402br (OeH),
D
2900w (CeH), 1708s (C]O, ester), 1680s (C]O, enone); dH
(400 MHz; CDCl3) 1.74 (1H, br, OH), 1.91 (3H, d, J 6.8, CH3CH]
CH), 3.10 (1H, br, OH), 4.30 (1H, wd, J 18.4, C(5)H), 4.67 (1H, br s,
C(4)H), 4.86 (1H, d, J 14.8, CHaHbOC]O), 4.90 (1H, d, J 14.8,
CHaHbOC]O), 5.22 (1H, wd, J 50.0, C(6)HF), 5.89 (1H, d, J 14.0,
CH3CH]CH), 6.86 (1H, br s, C(3)H), 6.99e7.09 (1H, m, CH3CH]
CH); dC (100 MHz; CDCl3) 18.1 (CH3CH]CH), 59.7 (CH2OC]O),
68.1 (d, J 7.6, C(4)H), 74.1 (d, J 17.5, C(5)H), 90.7 (d, J 182.8, C(6)
HF), 121.8 (CH3CH]CH), 134.0 (C(2)), 143.0 (C(3)H), 146.2
(CH3CH]CH), 165.9 (CH2OC]O), 190.7 (C(1)O); dF (376 MHz;
CDCl3) ꢀ206.8 (dd, J 50.0, 18.4, C(6)HF); m/z (CI/NH3): 262
([MþNH4]þ, 100%), 245 ([MþH]þ, 30); (Found: 262.1077.
C11H17FNO5 ([MþNH4]þ) requires 262.1085).
yielded the title compound as a colourless solid (123 mg, 57%); Rf
22
0.28 (petroleum ether/ethyl acetate, 9:1); mp 170e171 ꢁC; [
a]
D
ꢀ45.0 (c 1.2, CH2Cl2); nmax (film)/cmꢀ1 3003w (CeH), 2948s (CeH),
1688s (C]O); dH (300 MHz; CDCl3) 1.38 (3H, s butyl CH3), 1.40 (3H,
s, butyl CH3), 3.38 (3H, s, OCH3), 3.40 (3H, s, OCH3), 4.05 (1H, ddd, J
35.1, 8.7, 2.4, C(5)H), 4.84 (1H, wdt, J 51.9, 2.4, C(6)HF), 4.93 (1H,
wdq slightly obscured, J 8.7, 1.8, C(4)H), 6.12 (1H, dq, J 10.2, 1.8, C(2)
H), 7.03 (1H, dd, J 10.2, 1.8, C(3)H); dC (75 MHz; CDCl3) 17.8 (butyl
CH3), 17.9 (butyl CH3), 48.5 (OCH3), 48.6 (OCH3), 64.2 (d, J 7.2, C(4)
H), 71.4 (d, J 18.2, C(5)H), 89.9 (d, J 182.3, C(6)HF), 91.1 (acetal C),
100.8 (acetal C), 127.9 (C(2)H), 150.3 (C(3)H), 190.7 (d, J 16.9, C(1)O);
dF (282 MHz; CDCl3) ꢀ20.0 (dd, J 51.9, 35.1, C(6)HF); m/z (CI/NH3)
278 ([MþNH4]þ, 80%), 246 (60), 214 (40); (Found: 278.1393.
C12H21FNO5 ([MþNH4]þ) requires 278.1398).
4.6. Preparation of a,b-cyclopropyl ketone (16)
4.5.2. (20S,30S,4R,5S,6S)-6-Fluoro-2-hydroxymethyl-4-O,5-O-(20,30-
dimethoxybutane-20,30-diyl)-4,5-dihydroxycyclohex-2-en-1-one
(38). MoritaeBayliseHillman reaction of enone (37) (123 mg,
0.47 mmol) was carried out in a similar manner to that described for
(33) (vide infra). Purification by flash chromatography (SiO2; petro-
leum ether/ethyl acetate, 3:1) provided the hydroxymethyl com-
4.6.1. (20S,30S,2S,3R,4S,5R)-2,3-Cyclopropyl-4-O,5-O-(20,30-dimethoxy-
butane-20,30-diyl)-cyclohexan-1-one-4,5-diol (41). A solution of the
enone (33) (1.50 g, 6.19 mmol) in a 1:1 mixture of DMSO and THF
(75 mL) was added carefully at room temperature to neat sodium
hydride (0.19 g, 7.9 mmol) and trimethylsulfonium iodide (1.71 g,
8.38 mmol). The resulting orange slurry was stirred under a ni-
trogen atmosphere, becoming homogeneous within 5 min. Stir-
ring was continued for 1 h when THF was removed in vacuo and
the residue was quenched by the careful addition of brine
(50 mL). The organic components were extracted into dichloro-
methane (3ꢃ50 mL) and the combined organic extracts were
washed with brine (50 mL), dried (MgSO4) and concentrated in
vacuo to yield the crude product as a yellow oil. Purification by
flash chromatography (SiO2; petroleum ether/diethyl ether, 3:2)
pound (38) as a colourless oil (94%); Rf 0.16 (petroleum ether/ethyl
20
acetate 3:1); [
a
]
ꢀ53.4 (c 0.75, CH2Cl2); nmax (film)/cmꢀ1 3435br
D
(OeH), 2361w (CeH),1636w (C]O); dH (300 MHz; CDCl3) 1.40 (3H, s,
butyl CH3),1.42 (3H, s, butyl CH3),1.60 (1H, br, OH), 3.38 (3H, s, OCH3),
3.40 (3H, s, OCH3), 4.04 (1H, ddd, J 35.1, 8.1, 2.1, C(5)H), 4.37 (2H, s,
CH2OH), 4.88 (1H, dd, J 52.2, 2.1, C(6)HF), 4.94 (1H, dt slightly ob-
scured, J 8.1, 1.8, C(4)H), 7.04 (1H, q, J 1.8, C(3)H); dC (75 MHz; CDCl3)
17.4 (butyl CH3), 17.9 (butyl CH3), 48.5(OCH3), 48.6 (OCH3), 60.5
(CH2OH), 63.9 (d, J 7.2, C(4)H), 71.1 (d, J 18.1, C(5)H), 90.0 (d, J 181.4, C
(6)HF), 100.8 (acetal C), 101.1 (acetal C), 137.5 (C(2)), 145.7 (C(3)H),
190.7 (d, J 16.9, (C(1)O)); dF (282 MHz; CDCl3) ꢀ29.0 (dd, J 52.2, 35.1, C
(6)HF); m/z (CI/NH3) 308 ([MþNH4]þ, 100%), 290 (20), 276 (80);
(Found: 308.1501. C13H23FNO6 ([MþNH4]þ) requires 308.1504).
afforded the title compound as a colourless solid (1.38 g, 87%); Rf
22
0.21 (petroleum ether/diethyl ether, 3:2); mp 160e161 ꢁC; [
a]
D
þ123.1 (c 1.0, CH2Cl2); nmax (film)/cmꢀ1 2950w (CeH), 1685s (C]
O); dH (300 MHz; CDCl3) 1.15e1.25 (1H, m, cyclopropyl CHexo),
1.30 (3H, s, butyl CH3), 1.37 (3H, s, butyl CH3), 1.43e1.52 (1H, m,
cyclopropyl CHendo), 1.75e1.86 (1H, m, C(3)H), 1.93e2.01 (1H, m, C
(2)H), 2.30 (1H, dd, J 18.3, 12.0, C(6)Hb), 2.59 (1H, dd, J 18.3, 6.2, C
(6)Ha), 3.25 (3H, s, OCH3), 3.31 (3H, s, OCH3), 3.89 (1H, ddd, J 12.0,
9.8, 6.2, C(5)H), 4.19 (1H, dd, J 9.8, 3.7, C(4)H); dC (75 MHz; CDCl3)
9.9 (cyclopropyl CH2), 17.9 (butyl, CH3), 18.1 (butyl, CH3), 18.9 (C
(3)H), 26.9 (C(2)H), 41.8 (C(6)H2), 48.3 (2ꢃOCH3 coincident), 61.8
(C(5)H), 67.6 (C(4)H), 99.7 (acetal C), 100.3 (acetal C), 205.5 (C(1)
O); m/z (CI/NH3) 274 ([MþNH4]þ, 20%), 225 (100); (Found:
274.1647. C13H24NO5 ([MþNH4]þ) requires 274.1649).
4.5.3. (20S,30S,4R,5S,6S)-2((E)-Crotonyloxymethyl)-6-fluoro-4-O,5-O-
(20,30-dimethoxybutane-20,30-diyl)-4,5-dihydroxycyclohex-2-en-1-
one (39). Crotonylation of hydroxmethyl compound (38) (125 mg,
0.43 mmol) was carried out in a similar manner to that used for (34).
Purification by flash chromatography (SiO2; petroleum ether/ethyl
acetate, 9:1) provided the title compound as a colourless oil (39%); Rf
0.18 (petroleum ether/ethyl acetate, 9:1); [
a
]
22 ꢀ2.8 (c 1.1, CH2Cl2);
D
nmax (film)/cmꢀ1 2952m (CeH), 1726s (C]O, ester), 1695s (C]O,
enone); dH (300 MHz; CDCl3) 1.39 (3H, s, butyl CH3),1.41 (3H, s, butyl
CH3),1.93 (3H, dd, J 9.0, 3.0, CH3CH]CH), 3.35 (3H, s, OCH3), 3.38 (3H,
s, OCH3), 4.04 (1H, ddd, J 33.0, 9.0, 3.0, C(5)H), 4.87e4.88 (2H, m,
4.6.2. (20S,30S,3R,4S,5R)-3-Methyl-4-O,5-O-(20,30-dimethoxybutane-
20,30-diyl)-cyclohexan-1-one-4,5-diol (43). To a stirred solution of

C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
9059
cyclopropyl ketone (41) (0.5 g, 1.95 mmol) in a mixture of anhydrous
DMPU (4.5 mL) and dry THF (35 mL) (degassed with N2 for an hour
prior to use), was added dropwise a 0.1 M solution of samarium
iodide in THF (39.0 mL, 3.90 mmol) at room temperature under a ni-
trogen atmosphere. After w15 min the reaction mixture underwent
a colour-change from blue to yellow and a saturated aqueous solution
of sodium hydrogen carbonate solution (30 mL) was added. The or-
ganic components were extracted into diethyl ether (3ꢃ30 mL), dried
(MgSO4) and volatile solvents then removed in vacuo to give the
crude product as a viscous orange oil. Purification by flash chroma-
tography (SiO2; petroleum ether/diethyl ether, 1:1) afforded the title
(cyclopropyl CH2), 19.1 (C(5)H or C(6)H), 23.9 (C(5)H or C(6)H), 26.9
(C(CH3)3), 65.4 (C(4)H), 125.1 (C(2)H), 147.3 (C(3)H), 197.2 (C(1)O);
m/z (CI/NH3) 256 ([MþNH4]þ, 40%), 239 ([MþH]þ, 100); (Found:
238.1380. C13H22NO2Si (Mþ) requires 238.1384).
4.6.5. (4S,5R,6S)-5,6-Cyclopropyl-2-hydroxymethyl-4-O-tert-butyldi-
methylsilyl-cyclohex-2-en-1-one-4-ol (46). MoritaeBayliseHillman
reaction of enone (45) (123 mg, 0.47 mmol) using imidazole as
nucleophilic catalyst was carried out in a similar manner to that
described for the preparation of (34) to give hydroxymethyl com-
pound (46) as a colourless oil (23%); nmax (film)/cmꢀ1 3053s (CeH),
1667s (C]O); dH (300 MHz; CDCl3) 0.18 (6H, s, Si(CH3)2), 0.97 (9H, s,
C(CH3)3), 1.15e1.30 (2H, m, cyclopropyl CH2), 1.85e2.00 (2H, m, C(5)
H and C(6)H), 2.53 (1H, dd, J 7.3, 5.5, CH2OH), 4.15 (1H, dd, J 13.3, 7.3,
CHaHbOH), 4.30 (1H, dd, J 13.3, 5.5, CHaHbOH), 4.95e5.00 (1H, m, C
(4)H), 6.19e6.23 (1H, m, C(3)H); dC (75 MHz; CDCl3) ꢀ4.5 (SiCH3),
ꢀ4.2 (SiCH3), 12.2 (cyclopropyl CH2), 18.5 (C(CH3)3), 19.0 (C(5)H or C
(6)H), 24.4 (C(5)H or C(6)H), 26.1 (C(CH3)3), 62.1 (CH2OH), 65.3 (C(4)
H), 133.4 (C(2)), 143.1 (C(3)H), 199.0 (C(1)O); m/z (CI/NH3) 286
([MþNH4]þ, 35%), 269 ([MþH]þ, 100), 137 (30); (Found: 268.1496.
C14H24O3Si (Mþ) requires 268.1489).
compound as a colourless oil (0.27 g, 54%); Rf 0.35 (ethyl acetate/
29
40e60 petroleum ether, 1:7); mp 79.3e79.9 ꢁC; [
a]
D
þ151.2 (c 1.0,
CH2Cl2); nmax (film)/cmꢀ1 2987w (CeH), 2957m (CeH), 2904w
(CeH), 2831w (CeH), 1720s (C]O); dH (400 MHz; C6D6) 0.91 (3H, d, J
7.5, C(3)HCH3), 1.30 (3H, s, butyl CH3), 1.33 (3H, s, butyl CH3),
1.89e2.06 (3H, m, C(2)H2 and C(3)H), 2.30(1H, wt, J 13.1, C(6)Hb), 2.63
(1H, ddd, J 13.1, 5.5, 2.5, C(6)Ha), 2.93 (3H, s, OCH3), 3.11 (3H, s, OCH3),
3.83(1H, dd, J 10.0, 4.5, C(4)H), 3.98(1H, ddd, J 13.1,10.0, 5.5, C(5)H); dC
(100 MHz; C6D6) 13.9 (C(3)HCH3), 18.3 (butyl CH3), 18.4 (butyl CH3),
31.8 (C(3)H), 45.7 (C(6)H2), 47.0 (C(2)H2), 47.9 (OCH3), 48.0 (OCH3),
64.8 (C(5)H), 72.1 (C(4)H), 99.6 (acetal C),100.4 (acetal C), 205.8 (C(1)
O); m/z (EI) 227 ([MꢀOCH3]þ, 8%), 127 (12), 110 (65), 101 (45), 68
(100); (Found: 227.1272. C12H19O4 ([MꢀOCH3]þ) requires 227.1278).
4.6.6. (4S,5R,6S)-2-Crotonyloxymethyl-5,6-cyclopropyl-4-O-tert-
butyldimethylsilyl-cyclohex-2-en-1-one-4-ol (47). Crotonylation of
hydroxmethyl compound (46) was carried out in a similar manner to
that used for the preparation of (35) to give crotonate ester (47) as
a colourless oil (48%); nmax (film)/cmꢀ1 2951s (CeH), 2857m (CeH),
1726s (ester C]O), 1674s (enone C]O); dH (300 MHz; CDCl3) 0.19
(6H, s, (SiCH3)2), 0.97 (9H, s, C(CH3)3), 1.15e1.29 (2H, m, cyclopropyl
CH2), 1.92 (3H, dd, J 6.9, 1.5, CH3CH]CH), 1.90e2.02 (2H, m, C(5)H
and C(6)H), 4.76e4.79 (2H, m, CH2OH), 4.95e4.99 (1H, m, C(4)H),
5.90 (1H, br d, J 15.6, CH3CH]CH), 6.23e6.26 (1H, m, C(3)H), 7.03
(1H, dq, J 15.6, 6.9, CH3CH]CH); dC (75 MHz; CDCl3) ꢀ4.5 (SiCH3),
ꢀ4.2 (SiCH3), 11.9 (cyclopropyl CH2), 18.3 (C(5)H or C(6)H), 18.5 (C
(CH3)3), 19.0 (CH3CH]CH), 24.3 (C(5)H or C(6)H), 26.1 (C(CH3)3), 60.9
(CH2OC]O), 65.4 (C(4)H), 122.5 (CH3CH]CH), 130.1 (C(2)), 144.0 (C
(3)H), 145.6 (CH3CH]CH), 166.2 (CH2OC]O), 195.9 (C(1)O); m/z (CI/
NH3) 354 ([MþNH4]þ, 8%), 337 ([MþH]þ, 100), 311 (35), 251 (40), 205
(32); (Found: 337.1835. C18H29O4Si ([MþH]þ) requires 337.1830).
4.6.3. (4S,5R,6S)-5,6-Cyclopropyl-cyclohex-2-en-1-one-4-ol (44). The
a,b-cyclopropane (41) (0.24 g, 0.94 mmol) was stirred in a mixture of
TFA and H2O (7:1, 4 mL) at room temperature overnight. The reaction
mixture was then concentrated in vacuo to give an oily residue,
which was re-dissolved in methanol (20 mL) and the resulting so-
lution was cooled to 0 ꢁC. Potassium carbonate (0.13 g, 0.94 mmol)
was added in one portion and the dispersion was stirred for 30 min
at 0 ꢁC. Water (20 mL) was added and organic components were
extracted into ethyl acetate (3ꢃ10 mL). The combined organic ex-
tracts were dried (MgSO4) and concentrated in vacuo to yield the
crude product as an orange oil. Purification by flash column chro-
matography (SiO2; petroleum ether/ethyl acetate, 1:1) furnished the
22
title compound as a viscous oil (0.12 g, 99%); [
a
]
ꢀ130.2 (c 1.3,
D
CH2Cl2); nmax (film)/cmꢀ1 3499br (OeH), 2351s (CeH), 1660s (C]O);
dH (300 MHz; CDCl3) 1.13e1.18 (1H, m, one of cyclopropyl CH2),
1.26e1.33 (1H, m, one of cyclopropyl CH2), 1.98e2.13 (2H, m, C(5)H
and C(6)H), 4.96 (1H, wdt, J 6.0, 3.0, C(4)H), 5.77 (1H, wdt, J 12.0, 3.0,
C(2)H), 6.40 (1H, wdt, J 12.0, 3.0, C(3)H); dC (75 MHz; CDCl3) 11.6
(cyclopropyl CH2), 18.9 (C(5)H or C(6)H), 23.9 (C(5)H or C(6)H), 64.7
(C(4)H), 125.4 (C(2)H), 146.8 (C(3)H), 197.5 (C(1)O); m/z (CI/NH3) 142
([MþNH4]þ, 100%), 125 ([MþH]þ, 100).
4.6.7. (4S,5R,6S)-2-Crotonyloxymethyl-5,6-cyclopropyl-cyclohex-2-
en-1-one-4-ol (16). Removal of the silyl protecting group in (47) was
accomplished in the same manner as deprotection of silyl-ether (19)
to give the title compoundasa colourless oil(94%);[
a
]
20 ꢀ84.2(c 0.57,
D
CH2Cl2); nmax (film)/cmꢀ1 3424 (br, OH), 1713 (s, ester C]O), 1666 (s,
enone C]O); dH (300 MHz; CDCl3) 1.11e1.34 (2H, m, cyclopropyl
CH2),1.93 (3H, dd, J 6.0, 3.0, CH3CH]CH), 2.07e2.12 (2H, m, C(5)H and
C(6)H), 2.60 (1H, br, OH), 4.72e4.87 (2H, m, CH2OC]O), 4.96e4.98
(1H, m, C(4)H), 5.90 (1H, dq, J 15.0, 3.0, CH3CH]CH), 6.35e6.36 (1H,
m, C(3)H), 7.05 (1H, dq, J 15.0, 6.0, CH3CH]CH); dC (75 MHz; CDCl3)
11.3 (cyclopropyl CH2), 18.4 (CH3CH]CH), 18.9 (C(5)H or C(6)H), 24.3
(C(5)H or C(6)H), 60.7 (CH2OC]O), 64.9 (C(4)H),122.3 (CH3CH]CH),
130.7 (C(2)), 141.9 (C(3)H), 146.1 (CH3CH]CH), 166.3 (CH2OC]O),
195.6 (C(1)O);m/z (CI/NH3) 240([MþNH4]þ,15%), 223 ([MþH]þ,100);
(Found: 223.0969. C12H15O4 ([MþH]þ) requires 223.0965).
4.6.4. (4S,5R,6S)-5,6-Cyclopropyl-4-O-tert-butyldimethylsilyl-cyclo-
hex-2-en-1-one-4-ol (45). A solution of the allylic alcohol (44)
(0.96 g, 0.77 mmol) in dichloromethane (8 mL) was stirred at 0 ꢁC
under a nitrogen atmosphere. Triethylamine (0.80 mL) and a crystal
of 4-dimethylaminopyridine were added followed by TBDMSeCl
(0.14 g, 0.92 mmol) and the resulting solution was stirred at room
temperature for 96 h. The reaction was quenched by the addition of
water (8 mL) and organic components were extracted into
dichloromethane (3ꢃ10 mL). The combined organic extracts were
washed with brine (10 mL), dried (MgSO4) and concentrated in
vacuo to yield the crude product as a yellow oil. Purification by flash
column chromatography (SiO2; petroleum ether/diethyl ether, 5:1)
4.7. X-ray crystallographic analysis of (34)
afforded the title compound as a colourless oil (0.14 g, 78%); Rf 0.30
The selected crystal was an extremely thin, easily distorted
blade, which was mounted along a glass fibre for support. All
measurements were carried out on an Enraf-Nonius Kappa CCD
22
(petroleum ether:diethyl ether, 5:1); [
a]
ꢀ50.5 (c 1.1, CH2Cl2);
D
nmax (film)/cmꢀ1 2351w (CeH), 1680s (C]O); dH (300 MHz; CDCl3)
0.16 (6H, s, Si(CH3)2), 0.94 (9H, s, C(CH3)3), 1.13e1.28 (2H, m,
cyclopropyl CH2), 1.81e1.96 (2H, m, C(5)H and C(6)H), 4.91e4.95
(1H, m, C(4)H), 5.68 (1H, br d, J 10.4, C(2)H), 6.24 (1H, br d, J 10.4, C
(3)H); dC (75 MHz; CDCl3) ꢀ4.6 (SiCH3), ꢀ4.2 (SiCH3), 11.8
diffractometer employing graphite monochromated, Mo Ka radia-
ꢀ
tion,
l
¼0.71073 A. Crystal data is as follows.
C13H20O6 Mr¼272.29, Dx¼1.377 Mg mꢀ3
,
Monoclinic P21,
ꢀ
a¼6.8277(7), b¼6.9460(7), c¼14.0151(14) A,
b
¼98.995(5)ꢁ,

9060
C.L. Arthurs et al. / Tetrahedron 66 (2010) 9049e9060
3
¼0.11 mmꢀ1, T¼100(2) K, crystal
References and notes
ꢀ
V¼656.49(11) A , Z¼2, F000¼292,
dimensions 0.3ꢃ0.8ꢃ0.03 mm.
m
1. Takeuchi, T.; Chimura, H.; Hamada, M.; Umezawa, H.; Yoshioka, O.; Oguchi, N.;
Takahashi, Y.; Matsuda, A. J. Antibiot. 1975, 28, 737.
2. (a) Bach, G.; Breiding, M. S.; Grabley, S.; Hammann, P.; Hütter, K.; Thiericke, R.;
The structure was solved by direct methods using SHELXS and
subjected to full-matrix least-squares refinement using SHELXL.37
The final R values were R[F2>2
s
(F2)]¼0.063 and wR(F2)¼0.152 for
Uhr, H.; Wink, J.; Zeeck, A. Liebigs Ann. Chem. 1993, 241; (b) Tang, Y. Q.; Maul, C.;
€
Hofs, R.; Sattler, I.; Gabley, S.; Feng, X.-Z.; Zeeck, A.; Thiericke, R. Eur. J. Org.
1520 unique reflections. All non-hydrogen atoms were subjected to
anisotropic refinement and hydrogen atoms were constrained to
chemically reasonable positions.
Crystallographic data (excluding structure factors) for (34) have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 764787. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: þ44 (0)1223336033 or e-
mail: deposit@ccdc.cam.ac.uk].
Chem. 2001, 1, 149.
3. Collu, F.; Bonsignore, L.; Casu, M.; Floris, C.; Gertsch, J.; Cottiglia, F. Bioorg. Med.
Chem. Lett. 2008, 18, 1559.
4. McNally, M.; Capon, J. R. J. Nat. Prod. 2001, 64, 645.
5. Aghil, O.; Bibby, M. C.; Carrington, S. J.; Double, J.; Douglas, K. T.; Phillips, R. M.;
Shing, T. K. M. Anti-Cancer Drug Des. 1992, 7, 67.
6. Hamilton, D. S.; Ding, Z.; Ganem, B.; Creighton, D. J. Org. Lett. 2002, 4, 1209.
7. Joseph, E.; Eiseman, J. L.; Hamilton, D. S.; Wang, H.; Tak, H.; Ding, Z.; Ganem, B.;
Creighton, D. J. J. Med. Chem. 2003, 46, 194.
8. Douglas, K. T.; Shinkai, S. Angew. Chem., Int. Ed. Engl. 1985, 24, 31.
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Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.08.072.