Improved synthetic route to enantiomerically pure samples of the tetrahydropyran-2-ylacetic acid core associated with the phytotoxic polyketide herboxidiene

Article abstract of DOI:10.1071/CH00083

The phosphine oxide (2), which embodies the tetrahydropyran-2-ylacetic acid core associated with the phytotoxic polyketide herboxidiene (1) and which is a key intermediate in a projected synthesis of this natural product, has been prepared in a highly enantio- and diastereo-selective manner. The pivotal steps in this new and improved synthesis of compound (2) involve Katsuki-Sharpless asymmetric epoxidation of the allylic alcohol (4) to give epoxide (7) and subsequent ring-cleavage of the latter compound with trimethylaluminium to give diol (9). The derived acetate (10) is then readily ozonolysed to give the previously reported aldehyde (11), although now in high enantiomeric excess. Compound (11) can be elaborated, by established chemistry, to the target oxide (2). CSIRO 2000.

Full text of DOI:10.1071/CH00083

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 53, 2000
© CSIRO 2000
A journal for the publication of original research
in all branches of chemistry and chemical technology
w w w. p u b l i s h . c s i ro . a u / j o u rn a l s / a j c
All enquiries and manuscripts should be directed to
The Managing Editor
Australian Journal of Chemistry
CSIRO PUBLISHING
PO Box 1139 (150 Oxford St)
Collingwood
Vic. 3066
Australia
Telephone: 61 3 9662 7630
Facsimile: 61 3 9662 7611
Email: john.zdysiewicz@publish.csiro.au
Published by CSIRO PUBLISHING
for CSIRO and
the Australian Academy of Science

Aust. J. Chem., 2000, 53, 659–664
Improved Synthetic Route to Enantiomerically Pure Samples
of the Tetrahydropyran-2-ylacetic Acid Core Associated
with the Phytotoxic Polyketide Herboxidiene
Martin G. Banwell,A,B Malcolm D. McLeod,A,C Rajaratnam PremrajA and
Gregory W. SimpsonD
A Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, A.C.T. 0200.
B To whom correspondence should be addressed.
C School of Chemistry, F11, University of Sydney, Camperdown, N.S.W. 2006.
D CSIRO Molecular Science, Bag 10, Clayton South, Vic. 3169.
The phosphine oxide (2), which embodies the tetrahydropyran-2-ylacetic acid core associated with the phytotoxic
polyketide herboxidiene (1) and which is a key intermediate in a projected synthesis of this natural product, has
been prepared in a highly enantio- and diastereo-selective manner. The pivotal steps in this new and improved syn-
thesis of compound (2) involve Katsuki–Sharpless asymmetric epoxidation of the allylic alcohol (4) to give epoxide
(7) and subsequent ring-cleavage of the latter compound with trimethylaluminium to give diol (9). The derived
acetate (10) is then readily ozonolysed to give the previously reported aldehyde (11), although now in high enan-
tiomeric excess. Compound (11) can be elaborated, by established chemistry, to the target oxide (2).
Keywords. Dess–Martin oxidation; Michaelis–Arbuzov reaction; Mosher esterification; Parikh–Doering oxida-
tion; Katsuki–Sharpless asymmetric epoxidation; Still oxidation; Still–Gennari olefination; synthesis.
Introduction
associated with compound (1). However, a deficiency asso-
ciated with our synthesis of (2) is the need to carry out, at the
initial stage, a Katsuki–Sharpless asymmetric epoxidation of
nerol (3) which delivers the corresponding epoxy alcohol in
only c. 50% enantiomeric excess (e.e.).9 Since, with the
exception of target (2), all the compounds in the reaction
sequence, including the initially formed epoxy alcohol, are
oils the only opportunity to obtain enantiopure phosphine
oxide (2) was by repeated recrystallization of this compound.
However, the attendant loss of material was significant thus
prompting us to examine alternative routes to this com-
In 1992 a group at Monsanto (U.S.A.) detailed1 the near
complete structural elucidation of the polyketide herboxidi-
ene (1) (also known as TAN-1609) which the researchers had
isolated from Streptomyces chromofuscus A7847. The same
group also revealed1 that the molecule displays potent and
highly selective phytotoxic properties so that at application
rates of 35 g/acre it selectively controls various crop pests
such as oilseed rape, wild buckwheat and morning glory
while being harmless to wheat. Such properties, which are
remarkable for a polyketide, prompted efforts by Edmunds’s
group at Novartis AG2 to reisolate herboxidiene and then,
through a combination of X-ray crystallographic, chemical
degradation and chemical synthesis studies, to establish the
full stereochemistry associated with compound (1). Several
Japanese groups3–5 have also isolated herboxidiene and one
has determined5 that the compound up-regulates the gene
expression of the low-density lipoprotein receptor while
another has reported (Horiguchi et al.3) that it inhibits the
growth of various murine and human tumour cell lines. The
interesting biological profile of this natural product has
prompted various attempts to effect its preparation by total
synthesis.2,6–9 In connection with our own efforts in this
area8,9 we have reported9 a 12-step route to phosphine oxide
(2) which embodies the tetrahydropyran-2-ylacetic acid core
Manuscript received 26 June 2000
© CSIRO 2000
10.1071/CH00083
0004-9425/00/080659

660
M. G. Banwell et al.
pound. As a consequence, we now describe a new synthesis,
of phosphine oxide (2), that circumvents the above-men-
tioned problems.
on the basis that the product epoxide would be obtained in high
e.e. In addition, it was expected that nucleophilic methylation
of the product epoxide could be achieved in a regio- and
diastereo-selective manner so as to install the methyl group
required at C 6 in the target molecule (2). The pivotal alkene (4)
was readily prepared (Scheme 1) by a one-pot procedure
involving initial oxidation of commercially available (Aldrich)
alcohol (5) to the corresponding aldehyde. Using a modifica-
tion of procedures reported by Barrett,11 Lee12 and Taylor,13 this
latter compound was subjected to in situ Wittig olefination with
(methoxycarbonylmethylidene)triphenylphosphorane. In this
manner the , -unsaturated ester (6) (98%) was obtained and
the illustrated (E)-configuration about the 2-double bond was
established by 1H n.m.r. analysis (JH2,H3 15.6 Hz). DIBAL-H-pro-
moted 1,2-reduction of compound (6) proceeded smoothly to
give the target alcohol (4) in 85% yield and the various spec-
troscopic data derived from this material were in full accord
with the assigned structure. Katsuki–Sharpless asymmetric
epoxidation of compound (4) was effected under standard con-
ditions by using catalytic quantities of diethyl D-(–)-tartrate and
in this manner the expected epoxy alcohol (7) (70%) was
obtained. This latter material was converted, under standard
conditions, into the corresponding Mosher ester (8) (42%)
which was obtained as a single diastereoisomer (as determined
Results and Discussion
In contrast to the situation with (Z)-1,2,2-trisubstituted
alkenes (e.g. nerol), the Katsuki–Sharpless asymmetric epoxi-
dation of allylic alcohols proceeds in high enantiomeric excess
when (E)-1,2-disubstituted alkenes are employed as sub-
strates.10 Consequently, the allylic alcohol (4) was chosen as
the substrate for Katsuki–Sharpless asymmetric epoxidation
1
by H n.m.r. analysis) and thus suggesting that the precursor
alcohol was of >95% e.e. This interpretation was confirmed by,
inter alia, converting the racemic modification of epoxide (7)
[prepared by treating alkene (4) with m-chloroperbenzoic acid]
into the corresponding 1 : 1 mixture of compound (8) and its
diastereoisomer and observing that these Mosher esters were
readily differentiated from one another by 300 MHz 1H n.m.r.
spectroscopy (see Experimental section).
Treatment of epoxy alcohol (7) with 3 mol. equiv. of
trimethylaluminium14 in CH2Cl2 at 18°C for 10 h resulted in
its smooth conversion into diol (9) (83%) the structure of
which follows from its transformation into the previously
reported9 aldehyde (11). Thus, twofold acetylation of com-
pound (9) was achieved under standard conditions and the
resulting diacetate (10) (96%) was subjected to ozonolytic
cleavage followed by reductive workup with triphenylphos-
phine to give the aldehyde (11) (79%). This last compound
1
proved identical (as judged by H n.m.r., 13C n.m.r., i.r. and
mass spectral analysis) with the samples of the aldehyde
obtained by our previous route.9 As expected, however, the
specific rotation of the material generated by the present route
was effectively double {[ ]D +7.3 versus [ ]D +3.8} that
observed for the sample of aldehyde (11) obtained earlier.9
The completion of the synthesis of the target phosphine
oxide (2) followed the route established earlier, although
various minor modifications to the previously reported
methods9 are detailed herein. Thus, subjection of compound
(11) to Still–Gennari modification15 of the Wadsworth–
Emmons reaction afforded the alkene (12) (80%) as the only
isolable product of reaction. The (Z)-configuration about the
double bond in this product follows from the magnitude of the
vicinal spin–spin coupling (J 11.5 Hz) observed between H 2
and H 3 in the 1H n.m.r. spectrum of this material. Treatment
of compound (12) with potassium carbonate in methanol

Route to Tetrahydropyran-2-ylacetic Acid Core of Herboxidiene
661
recorded with a Varian Gemini 300 spectrometer operating at 300 MHz
for proton and 75 MHz for carbon. All such spectra were recorded in
(D)chloroform solution at 22°C. The protonicities of the carbon atoms
observed in 13C n.m.r. spectra were determined by attached proton test
(a.p.t.) experiments. Infrared spectra ( max) were recorded with either a
Perkin–Elmer 983G infrared spectrophotometer or a Perkin–Elmer
1800 Fourier-transform infrared spectrophotometer. Unless otherwise
specified, samples were analysed as thin liquid films on potassium
bromide plates. Low-resolution electron-impact mass spectra (m/z)
were recorded at 70 eV on a VG Micromass 7070F mass spectrometer.
High-resolution mass spectra were recorded with the same instrument.
Unless otherwise stated, optical rotations were measured in spectro-
scopic grade chloroform at 22°C by means of a Perkin–Elmer 241
polarimeter. Diethyl ether (Et2O) and tetrahydrofuran (thf) were dis-
tilled under nitrogen from sodium benzophenone ketyl.
Dichloromethane (CH2Cl2), ethyl acetate (EtOAc) and hexane were
each distilled from calcium hydride. Ethanol and methanol (MeOH)
were distilled from their respective magnesium alkoxide salts.
Ozonolyses were performed using a Wallace and Tiernan Ozonator with
the oxygen flow rate and power set at approximately 25 l/h and 200 V,
respectively. Flash chromatographic separations were conducted
according to the method of Still et al.18
resulted in removal of the acetate groups and a subsequent
intramolecular Michael addition reaction to give the tetrahy-
dropyran-2-ylacetic acid ester (13) which was accompanied
by varying quantities of the corresponding acid. Consequently,
the crude reaction mixture was treated with acidic methanol
and in this manner compound (13) was obtained in 71% yield.
Oxidation of hydroxy ester (13) under Parikh–Doering condi-
tions (pyridine–SO3 activated Me2SO)16 afforded the cor-
responding aldehyde (14) (60%) which proved spectro-
scopically identical with the sample we had obtained by our
previous route. In addition, the optical rotation of this material
effectively matched that reported2 by Edmunds for enan-
tiomerically pure material. The conversion of aldehyde (14)
into methyl ketone (15) proved especially troublesome and,
thus far, we have not been able to satisfactorily resolve these
difficulties. After considerable experimentation with a range
of nucleophilic methylating agents, methylmagnesium chlo-
ride proved to be most effective in adding to the aldehyde
moiety associated with compound (14). The resulting mixture
of diastereoisomeric secondary alcohols was immediately oxi-
dized with the Dess–Martin periodinane17 and the correspond-
ing methyl ketone (15) thereby obtained albeit in only 17%
yield. Nevertheless, the optical rotation of this compound
matched that reported for a sample obtained by ozonolytic
cleavage of herboxidiene itself.2
Ethyl (E)-Hepta-2,6-dienoate (6)
Dimethyl sulfoxide (23.7 ml, 334 mmol) was added to a magneti-
cally stirred solution of oxalyl chloride (13.4 ml, 153 mmol) in CH2Cl2
(480 ml) maintained under a nitrogen atmosphere at –78°C. After 0.1 h,
pent-4-en-1-ol (5) (12.0 g, 139 mmol, ex Aldrich) was added, dropwise,
followed, after a further 0.25 h, by triethylamine (134 ml, 961 mmol).
The resulting mixture was stirred for 0.5 h at –78°C, then warmed to
room temperature and treated with (ethoxycarbonylmethylidene)triph-
enylphosphorane19 (72.8 g, 209 mmol) in dry CH2Cl2 (110 ml). After
2 h at 18°C the reaction mixture was quenched with water (200 ml) and
the separated aqueous layer was extracted with CH2Cl2 (3×100 ml). The
combined organic layers were washed with brine (1×75 ml), then dried
(MgSO4), filtered and concentrated under reduced pressure to give a
light-yellow oil. An ethyl acetate/hexane (1: 9 v/v) solution of this
material was filtered through a short pad of t.l.c. grade silica gel to
afford, after concentration of the filtrate, the title ester (6)12,20 (21.0 g,
Elaboration of ketone (15) to the target phosphine oxide
(2) followed previously established procedures9 and involved
initial reaction of the former compound with vinylmagnesium
bromide. This resulted in generation of the desired tertiary
alcohol (60%) which was treated with phosphorus tribromide
to afford the allylic bromide (16) (93%). The latter compound
engaged in a Michaelis–Arbuzov reaction with ethoxy-
diphenylphosphine to deliver the target compound (2) (85%)
as a crystalline solid after flash chromatography. The melting
point (125–126°C) of this compound matched that reported
for the multiply recrystallized material obtained by the previ-
ous route.9 However, the specific rotation of compound (2)
produced by the method described here was much lower
{[ ]D –0.4 versus [ ]D –33} than that reported9 for material
generated by the earlier route. Fortunately a sample of com-
pound (2) derived by the earlier sequence was still available
and a redetermination of the specific rotation resulted in a
value identical to that observed for the newly prepared
sample. Consequently, we believe our earlier determination9
of the optical rotation for compound (2) to be in error. Given
the absence of any racemization pathways in the synthetic
sequence just described as well as the high levels of enantio-
selectivity obtained in the Katsuki–Sharpless asymmetric
epoxidation reaction leading to compound (7) we conclude
that phosphine oxide (2) produced by the method described
here has been obtained in >95% e.e.
98%) as a light-yellow oil.
3078, 2980, 2933, 1721, 1655, 1446,
max
1367, 1315, 1266, 1206, 1176, 1044, 989, 914, 852 cm–1. H n.m.r.
6.93, dt, J 15.6 and 5.7 Hz, 1H; 5.84–5.73, complex m, 2H; 5.06–4.96,
complex m, 2H; 4.15, q, J 7.1 Hz, 2H; 2.32–2.17, complex m, 4H; 1.26,
t, J 7.1 Hz, 3H. 13C n.m.r. 166.5 (C), 148.2 (CH), 137.0 (CH), 121.6
(CH), 115.4 (CH2), 60.1 (CH2), 32.0 (CH2), 31.4 (CH2), 14.2 (CH3).
Mass spectrum m/z 154 (6%, M+ ), 109 [30, (M–C2H5O )+], 81 [100,
(M–C2H5OCO )+]. This material was of sufficient purity for use in the
next step of the reaction sequence.
1
(E)-Hepta-2,6-dien-1-ol (4)
Diisobutylaluminium hydride (325 ml of a 1.0 M solution in hexane,
325 mmol, ex Aldrich) was added dropwise (via syringe) to a magneti-
cally stirred solution of ethyl (E)-hepta-2,6-dienoate (6) (20.0 g, 130
mmol) in CH2Cl2 (650 ml) maintained under a nitrogen atmosphere at
–78°C. The resulting mixture was stirred for 2 h at –78°C then warmed
to 18°C and quenched with tartaric acid (200 ml of a 1 M aqueous solu-
tion). Stirring was continued until two distinct layers were observed
(0.25 h). The separated aqueous layer was extracted with CH2Cl2
(3×200 ml) and the combined organic phases were washed with brine
(1×200 ml), then dried (MgSO4), filtered and concentrated under
reduced pressure. Subjection of the material thus obtained to flash chro-
matography (silica gel, 1: 4 v/v ethyl acetate/hexane elution) and con-
centration of the appropriate fractions (RF 0.25) afforded the title
compound (4)12,21 (12.4 g, 85%) as a light-yellow oil. max 3326, 2923,
1641, 1437, 1087, 1000, 970, 911 cm–1. 1H n.m.r. 5.85–5.65, complex
m, 3H; 5.04–4.94, complex m, 2H; 4.07, d, J 4.4 Hz, 2H; 2.15–2.13,
complex m, 4H; 1.67, s, 1H. 13C n.m.r. 138.0 (CH), 132.4 (CH), 129.3
(CH), 114.8 (CH2), 63.7 (CH2), 33.2 (CH2), 31.5 (CH2). Mass spectrum
m/z 111 [1%, (M –H )+], 94 [13, (M–H2O)+ ], 79 (100).
Efforts are now under way to exploit compound (2) as a
key building block in the total synthesis of herboxidiene.8
Results will be described in due course.
Experimental
Melting points were recorded with a Kofler hot-stage apparatus and
are uncorrected. Proton (1H) and carbon (13C) n.m.r. spectra were

662
M. G. Banwell et al.
(2R-trans)-2,3-Epoxyhept-6-en-1-ol (+)-(7)
tion with (+)- -methoxy- -(trifluoromethyl)phenylacetyl chloride
under the conditions described immediately above. 1H n.m.r. analysis of
this material revealed it to be a 1: 1 mixture of compound (8) and the
Katsuki–Sharpless asymmetric epoxidation of allylic alcohol (4), so
as to afford epoxide (+)-(7), was carried out according to the method of
ref. 22. Thus, a magnetically stirred suspension of finely powdered and
activated 4 Å molecular sieves (1.0 g) in dry CH2Cl2 (137 ml) was
cooled to –40°C then treated, sequentially, with diethyl D-(–)-tartrate
(0.92 ml, 5.38 mmol), Ti(OPri)4 (1.32 ml, 4.50 mmol) and t-butyl
hydroperoxide (17.2 ml of a 5.2 M solution in isooctane, 89 mmol—pre-
pared by extraction of 70% aqueous t-butyl hydroperoxide ex
Aldrich22). The resulting mixture was stirred at –40°C for 0.5 h then a
solution of compound (4) (5.0 g, 44.6 mmol) in CH2Cl2 (20 ml) was
added, via cannula, at such a rate as to maintain the reaction tempera-
ture below –20°C. After an additional 3 h at –20°C the reaction mixture
was warmed to 0°C then treated with water (26 ml). The reaction
mixture was then warmed to 18°C and after a further 1 h treated with
NaOH (6.0 ml of a 30% aqueous solution saturated with sodium chlo-
ride) and stirred vigorously. After c. 0.2 h of stirring, the mixture was
filtered through a small pad of Celite™ then the separated aqueous
layer was extracted with CH2Cl2 (3×150 ml). The combined organic
layers were dried (MgSO4), filtered and concentrated under reduced
pressure to give a light-yellow oil. Subjection of this material to flash
chromatography (silica gel, 3: 7 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (RF 0.3) afforded the title
compound (7) (4.00 g, 70%) as a clear colourless oil, [ ]D +33 (c, 1.2).
1
diastereoisomeric ester derived from ent-(7). The most diagnostic H
n.m.r. signals due to the (R)-MTPA ester derivative of ent-(7) appear (in
C6D6) at 4.14 (dd, J 12.2 and 3.2 Hz, 1H) and 3.90 (dd, J 12.2 and
5.8 Hz, 1H) [the corresponding signals for (8) appear at 4.30 and 3.80
respectively (see preceding paragraph)].
(2S,3S)-3-Methylhept-6-ene-1,2-diol (9)
Trimethylaluminium (131 ml of a 2.0 M solution in hexane, 262
mmol, ex Aldrich) was added, dropwise, to a magnetically stirred solu-
tion of epoxide (7) (11.15 g, 87 mmol) in CH2Cl2 (90 ml) maintained at
0°C under a nitrogen atmosphere. After addition was complete, the
reaction mixture was stirred at 18°C for 10 h and then chilled (0°C) and
quenched (CAUTION) with HCl (75 ml of 1 M aqueous solution). The
aqueous layer was extracted with CH2Cl2 (3×150 ml) and the combined
organic layers were washed with water (1×100 ml) then dried (MgSO4),
filtered and concentrated under reduced pressure to give a light-yellow
oil. Subjection of this material to flash chromatography (silica gel, 1: 1
v/v ethyl acetate/hexane elution) and concentration of the appropriate
fractions (RF 0.4) afforded the title compound (9) (10.4 g, 83%) as a
clear, colourless oil, [ ]D –5.7 (c, 1.2) [Found: (M–H )+, 143.1070.
C8H16O2 requires (M –H )+, 143.1072].
3368, 3077, 2962, 2928,
max
3401, 3078, 2979, 2928, 1641, 1449, 1088, 1030, 997, 914, 882,
1640, 1458, 1380, 1073, 995, 909, 880 cm–1. 1H n.m.r. 5.78, m, 1H;
5.03–4.88, complex m, 2H; 3.70–3.60, complex m, 1H; 3.53–3.40,
complex m, 2H; 3.20, br s, 2H; 2.20–2.08, complex m, 1H; 2.05–1.90,
complex m, 1H; 1.70–1.54, complex m, 2H; 1.29–1.18, complex m,
1H; 0.88, d, J 7.0 Hz, 3H. 13C n.m.r. 138.8 (CH), 114.5 (CH2), 76.1
(CH), 64.6 (CH2), 35.5 (CH), 31.6 (CH2), 31.1 (CH2), 15.1 (CH3). Mass
spectrum m/z 145 [3%, (M+H)+], 144 (3, M+ ), 143 [2, (M – H )+], 95
(100), 71 (53).
max
642 cm–1. 1H n.m.r. 5.90–5.73, complex m, 1H; 5.10–4.95, complex
m, 2H; 3.94–3.88, complex m, 1H; 3.66–3.58, m, 1H; 3.01–2.90,
complex m, 2H; 2.20, m, 2H; 1.76, t, J 6.5 Hz, 1H; 1.71–1.64, complex
m, 2H. 13C n.m.r. 137.4 (CH), 115.3 (CH2), 61.7 (CH2), 58.6 (CH),
55.4 (CH), 30.8 (CH2), 30.1 (CH2). Mass spectrum m/z 97 [18%,
(M–HOCH2 )+], 67 (100).
(±)-trans-2,3-Epoxyhept-6-en-1-ol (±)-(7)
(2S,3S)-3-Methylhept-6-ene-1,2-diol Diacetate (10)
A magnetically stirred solution of allylic alcohol (4) (50 mg, 0.45
mmol) in CH2Cl2 (2.5 ml) was treated, portionwise, with m-chloroper-
benzoic acid (132 mg of technical grade material containing c. 70%
peracid, c. 0.54 mmol). After 2 h the reaction mixture was quenched
with Na2S2O5 (5 ml of a 1 M aqueous solution). The separated organic
phase was washed with NaHCO3 (1×5 ml) and water (1×5 ml) then
dried (MgSO4), filtered and concentrated under reduced pressure to
give a light-yellow oil. Subjection of this material to flash chromato-
graphy (silica gel, 1 : 4 v/v ethyl acetate/hexane elution) followed by
concentration of the appropriate fractions (RF 0.3) then afforded the title
compound (±)-(7) (25 mg, 44%) as a clear, colourless oil. This material
A magnetically stirred solution of diol (9) (5.54 g, 38.5 mmol) in
pyridine (21 ml) was treated with acetic anhydride (12.7 ml, 134 mmol)
and 4-(dimethylamino)pyridine (10 mg, 0.08 mmol). The resulting
mixture was stirred at 18°C for 3 h then poured onto ice (c. 50 g) and
extracted with ether (1×100 ml). The separated organic phase was
washed with HCl (2×20 ml of a 1 M aqueous solution), NaHCO3
(2×20 ml of a saturated aqueous solution) and brine (1×20 ml) then
dried (MgSO4), filtered and concentrated under reduced pressure to
give a light-yellow oil. Subjection of this material to flash chromato-
graphy (silica gel, 3: 7 v/v ethyl acetate/hexane elution) and concentra-
tion of the appropriate fractions (RF 0.7) afforded the title compound
(10) (8.40 g, 96%) as a clear, colourless oil, [ ]D +5.24 (c, 1.3) [Found:
1
was identical, as judged by H n.m.r., 13C n.m.r., mass spectral and
infrared analysis, with the material obtained using the Katsuki–
Sharpless asymmetric epoxidation protocol described above.
(M+H)+, 229.1440. C12H20O4 requires (M+H)+, 229.1440].
2973,
max
2937, 1744, 1641, 1458, 1371, 1227, 1048, 1020, 913, 605 cm–1. H
n.m.r. 5.76, m, 1H; 5.03–4.90, complex m, 3H; 4.27, dd, J 12.0 and
3.0 Hz, 1H; 4.05, dd, J 12.0 and 4.2 Hz, 1H; 2.15–1.90, complex m, 2H;
2.06, s, 3H; 2.03, s, 3H; 1.85–1.73, complex m, 1H; 1.50, m, 1H; 1.23,
m, 1H; 0.92, d, J 6.9 Hz, 3H. 13C n.m.r. 170.8 (C), 170.6 (C), 138.2
(CH) 114.8 (CH2), 74.9 (CH), 63.6 (CH2), 33.6 (CH), 31.3 (CH2), 31.0
(CH2), 21.0 (CH3), 20.9 (CH3), 15.0 (CH3). Mass spectrum m/z 229
[2%, (M+H)+], 213 [24, (M–H3C )+], 115 (76), 114 (78), 108 (90), 95
(100), 93 (96), 79 (70).
1
Mosher Ester Analysis of Epoxides (+)-(7) and (±)-(7). Formation of
Ester (8) and a Diastereoisomer Thereof
A nitrogen atmosphere was established over a magnetically stirred
solution of 4-(dimethylamino)pyridine (18 mg, 0.15 mmol) and tri-
ethylamine (0.1 ml) in CH2Cl2 (0.5 ml) which was then treated with
epoxide (+)-(7) (19.2 mg, 0.15 mmol) and (+)- -methoxy- -(trifluo-
romethyl)phenylacetyl chloride22 (0.04 ml, 0.20 mmol). The resulting
solution became warm and turned orange in colour. After 0.1 h the reac-
tion mixture was treated with NaHCO3 (5 ml of a saturated aqueous
solution) and extracted with CH2Cl2 (2×10 ml). The combined organic
extracts were washed with brine (1×5 ml) then dried (MgSO4), filtered
and concentrated under reduced pressure to afford a pale-yellow oil
which was subjected to flash chromatography (silica, 1: 4 v/v ethyl
acetate/hexane elution). Concentration of the appropriate fractions (RF
0.4) afforded Mosher ester (8) (22 mg, 42%) as a clear, colourless oil.
1H n.m.r. (C6D6) 7.82, d, J 7.6 Hz, 2H; 7.35–7.05, complex m, 3H;
5.69, m, 1H; 5.00, m, 2H; 4.30, dd, J 12.2 and 3.2 Hz, 1H; 3.80, dd, J
12.2 and 5.8 Hz, 1H; 3.54, s, 3H; 2.63, m, 1H; 2.53, m, 1H; 1.97, m, 2H;
1.32, m, 2H.
[S-(R*,R*)]-5,6-Bis(acetyloxy)-4-methylhexanal (11)
A magnetically stirred solution of diacetate (10) (10.50 g, 45.65
mmol) in CH2Cl2 (575 ml) was cooled to –78°C then treated with a
stream of ozone gas until a blue colour persisted. The reaction mixture
was then warmed to –30°C and triphenylphosphine (12.0 g, 45.65
mmol) was carefully added in portions. After the addition was com-
plete, the reaction mixture was allowed to warm to room temperature.
The solvent was then removed under reduced pressure and the residue
thereby obtained was subjected to flash chromatography (silica gel, 3: 7
v/v ethyl acetate/hexane elution). Concentration of the appropriate frac-
tions (RF 0.3) gave the title compound (11)9 (8.40 g, 79%) as a pale-
yellow oil, [ ]D +7.3 (c, 2.0 in MeOH) [Found: (M+H)+, 231.1232.
The racemic epoxide (±)-(7) (25 mg, 0.20 mmol) was converted into
the corresponding mixture of diastereoisomeric Mosher esters by reac-

Route to Tetrahydropyran-2-ylacetic Acid Core of Herboxidiene
663
Calc. for C11H18O5: (M+H)+, 231.1232]. max 2967, 2727, 1744, 1371,
1227, 1048, 959, 605 cm–1. 1H n.m.r. 9.77, s, 1H; 4.94, m, 1H; 4.31,
dd, J 12.1 and 2.9 Hz, 1H; 4.05, dd, J 12.1 and 6.8 Hz, 1H; 2.60–2.30,
complex m, 2H; 2.07, s, 3H; 2.04, s, 3H; 1.90–1.72, complex m, 2H;
1.54–1.44, complex m, 1H; 0.93, d, J 6.8 Hz, 3H. 13C n.m.r. 201.8
(CH), 170.8 (C), 170.6 (C), 74.5 (CH), 63.4 (CH2), 41.2 (CH2), 33.5
(CH), 24.1 (CH2), 21.0 (CH3), 20.8 (CH3), 15.1 (CH3); Mass spectrum
m/z 231 [15%, (M+H)+], 115 (60), 103 (53), 97 (100), 84 (48).
Methyl [2R-(2 ,5 ,6 )]-6-Formyl-5-methyltetrahydro-2H-pyran-2-
acetate (14)
A solution of alcohol (13) (1.0 g, 4.95 mol) and triethylamine
(4.5 ml, 32.1 mmol) in CH2Cl2 (14.2 ml) was added, dropwise, to a
magnetically stirred solution of sulfur trioxide/pyridine complex
(2.52 g, 15.8 mmol, exAldrich) in Me2SO/CH2Cl2 (15.6 ml of a 3 : 2 v/v
mixture) maintained at 0°C (icebath) under a nitrogen atmosphere. The
reaction mixture was warmed to 18°C and after stirring for a further 1 h
it was treated with water (130 ml) then extracted with hexane (3×7 ml).
The combined organic phases were washed with brine (1×50 ml) then
dried (MgSO4), filtered and concentrated under reduced pressure. The
light-yellow oil thus obtained was subjected to flash chromatography
(silica gel, 3: 7 v/v ethyl acetate/hexane elution) and concentration of
the appropriate fractions (RF 0.4) then afforded the title compound (14)9
(594 mg, 60%) as a clear colourless oil, [ ]D –65 (c, 0.45) {lit.2 [ ]D –62
(c, 0.5 in CHCl3)} [Found: (M–CHO )+, 171.1020. Calc. for C10H16O4:
(M–CHO )+, 171.1021). max 2932, 1740, 1437, 1200, 1090, 1021,
857 cm–1. 1H n.m.r. 9.51, d, J 2.3 Hz, 1H; 3.80, m, 1H; 3.67, s, 3H;
3.41, dd, J 10.6 and 2.3 Hz, 1H; 2.61, dd, J 15.4 and 7.6 Hz, 1H; 2.44,
dd, J 15.4 and 5.4 Hz, 1H; 1.88, m, 1H; 1.70, m, 1H; 1.64–1.50,
Methyl {S-[R*,R*-(Z)]}-7,8-Bis(acetyloxy)-6-methyloct-2-
enoate (12)
KN(SiMe3)2 (73.0 ml of a 0.5 M solution in toluene, 36.5 mmol)
was added, dropwise, to a magnetically stirred solution of bis(2,2,2-tri-
fluoroethyl) (methoxycarbonylmethyl)phosphonate (7.73 ml, 36.5
mmol) and 18-crown-6/MeCN complex23 (48.3 g, 183 mmol) in dry thf
(140 ml) maintained at –78°C under an atmosphere of nitrogen. The
reaction mixture was stirred at –78°C for 0.5 h then treated with alde-
hyde (11) (8.4 g, 36.52 mmol). After 1 h at this temperature, the reac-
tion mixture was quenched with NH4Cl (60 ml of a saturated aqueous
solution) then allowed to warm to room temperature. The resulting
mixture was extracted with ether (3×50 ml) and the combined organic
phases were washed with water (1×100 ml) then dried (MgSO4), fil-
tered and concentrated under reduced pressure. Subjection of the mate-
rial thus obtained to flash chromatography (silica gel, 3 : 7 v/v ethyl
acetate/hexane elution) and concentration of the appropriate fractions
(RF 0.4) afforded the title ester (12)9 (8.35 g, 80%) as a pale-yellow oil,
[ ]D +9.9 (c, 5.4) [Found: (M+H)+, 287.1495. Calc. for C14H22O6:
complex m, 1H; 1.45–1.20, complex m, 2H; 0.91, d, J 6.6 Hz, 3H. 13
C
n.m.r. 200.6 (CH), 171.4 (C), 86.7 (CH), 73.5 (CH), 51.7 (CH3), 41.0
(CH2), 32.1 (CH2), 30.8 (CH2), 30.5 (CH), 16.3 (CH3). Mass spectrum
m/z 201 [14%, (M+H)+], 171 [100, (M–CHO )+], 139 (88), 127 (52),
111 (57), 97 (88), 81 (57), 69 (59).
Methyl [2R-(2 ,5 ,6 )]-6-Acetyl-5-methyltetrahydro-2H-pyran-2-
acetate (15)
(M+H)+, 287.1495].
2953, 1743, 1645, 1439, 1371, 1226, 1176,
Methylmagnesium chloride (0.83 ml of a 3 M solution in thf, 2.5
mmol) was added, dropwise, to a magnetically stirred solution of alde-
hyde (14) (500 mg, 2.5 mmol) in thf (12.5ml) maintained at –78°C under
a nitrogen atmosphere. After addition was complete the reaction mixture
was allowed to warm to 0°C, stirred at this temperature for a further 1 h
then poured onto a mixture of ice (c. 20 g) and NH4Cl (20 ml of a satu-
rated aqueous solution). The resulting mixture was extracted with ether
(3×20 ml) and the combined organic phases were washed with water
(1×30 ml) then dried (MgSO4), filtered and concentrated under reduced
pressure to afford a light-yellow oil (190 mg). Subjection of this material
to flash chromatography (silica gel, 3 :7 v/v ethyl acetate/hexane elution)
and concentration of the appropriate fractions (RF 0.3) afforded the
expected mixture of diastereoisomeric secondary alcohols as a clear,
colourless oil. This material was dissolved in CH2Cl2 (8.0 ml) and the
resulting solution treated with the Dess–Martin periodinane17 (560 mg,
1.32 mmol). The mixture thus obtained was stirred at 18°C for 1 h then
diluted, successively, with diethyl ether (10 ml), NaHCO3 (5 ml of a sat-
urated aqueous solution) and Na2S2O3 (5 ml of a 1 M aqueous solution).
Stirring was continued until two layers became apparent. The separated
aqueous phase was extracted with diethyl ether (3×10 ml) and the com-
bined organic phases were washed with brine (1×10 ml) then dried
(MgSO4), filtered and concentrated under reduced pressure. The resulting
light-yellow oil was subjected to flash chromatography (silica gel, 3 :7
v/v ethyl acetate/hexane elution) and concentration of the appropriate
fractions (RF 0.3) then afforded the title compound (15)9 (90 mg, 17%) as
a clear colourless oil [ ]D –91 (c, 1.2) {lit.2 [ ]D –95 (c, 1.5 in CHCl3)}
max
1048, 821 cm–1. 1H n.m.r. 6.18, m, 1H; 5.78, br d, J 11.5 Hz, 1H; 4.95,
td, J 6.8 and 2.9 Hz, 1H; 4.29, dd, J 12.0 and 2.9 Hz, 1H; 4.06, dd, J
12.0 and 7.1 Hz, 1H; 3.70, s, 3H; 2.68, m, 2H; 2.07, s, 3H; 2.04, s, 3H;
1.82, m, 1H; 1.65–1.50, complex m, 1H; 1.35–1.20, complex m, 1H;
0.96, d, J 7.0 Hz, 3H. 13C n.m.r. 170.8 (C), 170.6 (C), 166.7 (C),
149.8 (CH), 119.7 (CH), 74.9 (CH3), 63.5 (CH2), 51.0 (CH), 33.9
(CH), 31.3 (CH2), 26.3 (CH2), 21.0 (CH3), 20.8 (CH3), 15.0 (CH3).
Mass spectrum m/z 287 [5%, (M+H)+], 166 (52), 153 (70), 139 (100),
107 (74), 81 (90).
Methyl [2R-(2 ,5 ,6 )]-6-(Hydroxymethyl)-5-methyltetrahydro-2H-
pyran-2-acetate (13)
A mixture of methyl ester (12) (8.35 g, 29.20 mmol), K2CO3 (20.2
g, 146 mmol) and methanol (42 ml) was stirred at 18°C for 24 h then
filtered through a sintered glass funnel. Water (100 ml) was added to the
filtrate which was acidified to pH 2–3 with HCl (concentrated aqueous
solution). The resulting mixture was extracted with diethyl ether
(3×50 ml) and the combined extracts were dried (MgSO4), filtered and
then concentrated under reduced pressure. The light-yellow oil obtained
in this manner was suspended in methanol (50 ml) containing H2SO4 (6
drops of 98% acid) and the resulting mixture stirred at 18°C for 16 h
then poured onto ice (50 g) and extracted with diethyl ether (3×50 ml).
The combined organic extracts were washed with NaHCO3 (1×50 ml of
a saturated aqueous solution) then dried (MgSO4), filtered and concen-
trated under reduced pressure to afford a light-yellow oil. Subjection of
this material to flash chromatography (silica gel, 3: 7 v/v ethyl
acetate/hexane elution) and concentration of the appropriate fractions
(RF 0.25) afforded the title compound (13)9 (4.18 g, 71%) as a clear
colourless oil, [ ]D +9.8 (c, 1.0) {lit.2 [ ]D +9.4} [Found: (M–H2O)+ ,
184.1097. Calc. for C10H18O4: (M–H2O)+ , 184.1099). max 3458, 2928,
2873, 1738, 1437, 1199, 1087, 1019 cm–1. 1H n.m.r. 3.80–3.63,
complex m, 2H; 3.65, s, 3H; 3.47, ddd, J 11.4, 7.1 and 4.3 Hz, 1H; 3.10,
ddd, J 9.8, 7.1 and 2.7 Hz, 1H; 2.53, dd, J 15.2 and 7.7 Hz, 1H; 2.40,
dd, J 15.2 and 5.4 Hz, 1H; 2.21, dd, J 8.2 and 4.4 Hz, 1H; 1.80–1.72,
complex m, 1H; 1.70–1.60, complex m, 1H; 1.48–1.12, complex m, 3H;
0.80, d, J 6.5 Hz, 3H. 13C n.m.r. 171.6 (C), 83.5 (CH), 74.0 (CH), 63.7
(CH2), 51.6 (CH3), 41.1 (CH2), 32.1 (CH2), 31.5 (CH2), 31.1 (CH), 17.1
(CH3). Mass spectrum m/z 203 [26%, (M+H)+], 171 [100,
(M– H3CO )+], 139 (73), 129 (57), 97 (54).
[Found: (M+H)+, 215.1282. Calc. for C11H18O4:(M+H)+, 215.1283].
max
2931, 1741, 1719, 1437, 1354, 1199, 1083, 1022, 894 cm–1. 1H n.m.r.
3.78, m, 1H; 3.67, s, 3H; 3.41, d, J 10.2 Hz, 1H; 2.57, dd, J 15.1 and 7.6
Hz, 1H; 2.44, dd, J 15.1 and 5.4 Hz, 1H; 2.14, s, 3H; 1.87, m, 1H;
1.72–1.67, complex m, 1H; 1.60–1.18, complex m, 3H; 0.82, d, J 6.6 Hz,
3H. 13C n.m.r. 207.9 (C), 171.5 (C), 89.0 (CH), 73.7 (CH), 51.7 (CH3),
41.1 (CH2), 32.2 (CH2), 31.8 (CH3), 31.1 (CH2), 25.8 (CH), 16.9 (CH3).
Mass spectrum m/z 215 [5%, (M+H)+], 171 [100, (M–CH3CO )+], 139
(95), 111 (61), 97 (92).
Methyl {2R-[2 ,5 ,6 (E)]}-6-(3-Bromo-1-methylprop-1-enyl)-5-
methyltetrahydro-2H-pyran-2-acetate (16)
Vinylmagnesium bromide (1.6 ml of a 1 M solution in thf,
1.58 mmol, ex Aldrich) was added, dropwise, to a magnetically stirred
solution of ketone (15) (339 mg, 1.58 mmol) in thf (65 ml) maintained

664
M. G. Banwell et al.
at –78°C under a nitrogen atmosphere. The resulting mixture was
stirred at –78°C for a further 1 h then warmed to 0°C, poured into
NH4Cl (25 ml of a saturated aqueous solution) and extracted with
diethyl ether (3×50 ml). The combined organic extracts were dried
(MgSO4), filtered and concentrated under reduced pressure to give a
light-yellow oil (203 mg) which was subjected to flash chromatography
(silica gel, 1 : 4 v/v ethyl acetate/hexane elution). Concentration of the
appropriate fractions (RF 0.3) then afforded the expected vinyl alcohol
which was immediately subjected to the brominative rearrangement
reaction. Thus, PBr3 (50 l, 0.5 mmol) was injected, via syringe, into a
magnetically stirred solution of the vinyl alcohol (100 mg, 0.41 mmol)
in diethyl ether (10 ml) maintained at 0°C under a nitrogen atmosphere.
After the addition was complete, the reaction mixture was stirred at 0°C
for a further 1 h and then poured onto ice (c. 10 g). The resulting
mixture was extracted with diethyl ether (1×30 ml) and the separated
organic phase dried (MgSO4), filtered and concentrated under reduced
pressure to give a light-yellow oil. Subjection of this material to flash
chromatography (silica gel, 1: 4 v/v ethyl acetate/hexane elution)
afforded, after concentration of the appropriate fractions (RF 0.3), the
title bromide (16)9 (117 mg, 93%) as a clear, colourless oil, [ ]D –29 (c,
2.1) {lit.9 [ ]D –5.2 (c, 1.5 in CHCl3)} [Found: (M –Br )+, 225.1495.
Acknowledgments
The Institute of Advanced Studies and Dunlena Pty Ltd
are thanked for generous financial support. R.P. thanks the
Australian Research Council for the provision of an APA(I)
Ph.D. Scholarship.
References
1
Miller-Wideman, M., Makkar, N., Tran, M., Isaac, B., Biest, N., and
Stonard, R., J. Antibiot., 1992, 45, 914; Isaac, B. G., Ayer, S. W.,
Elliott, R. C., and Stonard, R. J., J. Org. Chem., 1992, 57, 7220.
2
Edmunds, A. J. F., Trueb, W., Oppolzer, W., and Cowley, P.,
Tetrahedron, 1997, 53, 2785.
3
Tanida, S., Shirasaki, M., and Horiguchi, T., Jpn Kokai Tokkyo
Koho JP 06 22,770 [94 22,770] (Chem. Abstr., 1994, 121, 33284r);
Horiguchi, T., Shirasaki, M., and Tanida, S., Takeda Kenkyushoho,
1996, 55, 149 (Chem. Abstr., 1996, 125, 185223r).
4
Mizukami, T., Sakai, Y., Yoshida, T., Uosaki, Y., Ochiai, K., and
Akinaga, S., Eur. Pat. Appl. EP 781,772 (Chem. Abstr., 1997, 127,
108054a).
5
Koguchi, Y., Nishio, M., Kotera, J., Omori, K., Ohnuki, T., and
Calc. for C13H21BrO3: (M–Br )+, 225.1491].
2951, 2926, 1740,
max
Komatsubara, S., J. Antibiot., 1997, 50, 970.
1
1436, 1200, 1069, 1019, 865 cm–1. H n.m.r. 5.69, t, J 9.0 Hz, 1H;
4.00, m, 2H; 3.80–3.70, complex m, 1H; 3.66, s, 3H; 3.35, d, J 9.8 Hz,
1H; 2.58, dd, J 15.2 and 6.5 Hz, 1H; 2.40, dd, J 15.2 and 6.5 Hz, 1H;
1.90–1.80, complex m, 1H; 1.69, s, 3H; 1.70–1.65, complex m, 1H;
1.62–1.47, complex m, 1H; 1.40–1.15, complex m, 2H; 0.71, d, J 6.7
Hz, 3H. 13C n.m.r. 171.7 (C), 141.5 (C), 123.9 (CH), 89.5 (CH), 73.8
(CH), 51.6 (CH3), 41.2 (CH2), 32.3 (CH), 32.2 (CH2), 31.5 (CH2),
28.2 (CH2), 17.4 (CH3), 11.5 (CH3). Mass spectrum m/z 224 [8%,
(M–HBr)+ ], 121 (100).
6
Smith, N. D., Kocienski, P. J., and Street, S. D. A., Synthesis, 1996,
652.
7
Blakemore, P. R., Kocienski, P. J., Morley, A., and Muir, K., J.
Chem. Soc., Perkin Trans. 1, 1999, 955.
8
Banwell, M. G., Bui, C. T., Hockless, D. C. R., and Simpson, G. W.,
J. Chem. Soc., Perkin Trans. 1, 1997, 1261.
9
Banwell, M. G., Bui, C. T., and Simpson, G. W., J. Chem. Soc.,
Perkin Trans. 1, 1998, 791.
10
Pfenninger, A., Synthesis, 1986, 89.
11
Barrett, A. G. M., Hamprecht, D., and Ohkubo, M., J. Org. Chem.,
Methyl {2R-[2 ,5 ,6 (E)]}-6-[3-(Diphenylphosphinoyl)-1-methyl-
prop-1-enyl]-5-methyltetrahydro-2H-pyran-2-acetate (2)
1997, 62, 9376.
12
Lee, E., Yoon, C. H., Lee, T. H., Kim, S. Y., Ha, T. J., Sung, Y-s.,
A magnetically stirred solution of bromide (16) (100 mg, 0.33
mmol) and ethoxydiphenylphosphine (143 l, 0.66 mmol, ex Aldrich)
in thf (10 ml) was heated at reflux until the starting materials had been
consumed (c. 2 h). The cooled reaction mixture was concentrated under
reduced pressure and the resulting solid recrystallized (diethyl ether) to
give the phosphine oxide (2)9 (119 mg, 85%) as a fine white powder,
m.p. 125–126°C (lit.9 125–126°C), [ ]D –0.4 (c, 1.4) {lit.9 [ ]D –32.8
(c, 0.5 in CHCl3)—see text} (Found: M+ , 426.1962. Calc. for
Park, S.-H., and Lee, S., J. Am. Chem. Soc., 1998, 120, 7469.
13
Wei, X., and Taylor, R. J. K., Tetrahedron Lett., 1998, 39, 3815; J.
Org. Chem., 2000, 65, 616.
14
Suzuki, T., Saimoto, H., Tomioka, H., Oshima, K., and Nozaki, H.,
Tetrahedron Lett., 1982, 23, 3597; Roush, W. R., Adam, M. A., and
Peseckis, S. M., Tetrahedron Lett., 1983, 24, 1377.
15
Still, W. C., and Gennari, C., Tetrahedron Lett., 1983, 24, 4405.
16
Parikh, J. R., and Doering, W. von E., J. Am. Chem. Soc., 1967, 89,
C25H31O4P: M+ , 426.1960).
(KBr disk) 2924, 2847, 1736, 1437,
5505.
1180, 1120, 1069, 1018, 745, 7m1a9x, 697, 555, 512 cm–1. 1H n.m.r. 7.74,
m, 4H; 7.50, m, 6H; 5.50, m, 1H; 3.72–3.60, complex m, 1H; 3.63, s,
3H; 3.26, d, J 9.7 Hz, 1H; 3.23–3.10, complex m, 2H; 2.54, dd, J 15.1
and 6.5 Hz, 1H; 2.37, dd, J 15.1 and 6.4 Hz, 1H; 1.75, dm, J 13.5 Hz,
1H; 1.63, dm, J 13.5 Hz, 1H; 1.47, br s, 3H; 1.45–1.10, complex m, 3H;
0.42, d, J 6.6 Hz, 3H. 13C n.m.r. 171.7 (C), 140.0 (d, C), 133.2 (d, C),
131.9 (CH), 131.0 (d, CH), 128.5 (d, CH), 116.9 (d, CH), 90.0 (CH),
73.8 (CH), 51.5 (CH3), 41.3 (CH2), 32.1 (CH2), 32.0 (CH3), 31.5 (CH2),
30.7 (d, CH2), 17.2 (CH), 12.2 (CH3) [d denotes doublet due to 13C–31P
coupling]. 31P n.m.r. 31.0. Mass spectrum m/z 426 (51%, M+ ), 202
[100, (Ph2POH)+ ], 201 [94, (Ph2PO)+].
17
Boeckman, R. K., Shao, P., and Mullins, J. J., Org. Synth., 1999, 77,
141.
18
Still, W. C., Kahn, M., and Mitra, A., J. Org. Chem., 1978, 43, 2923.
19
Denney, D. B., and Ross, S. T., J. Org. Chem., 1962, 27, 998.
20
Booker-Milburn, K. I., Barker, A., Brailsford, W., Cox, B., and
Mansley, T. E., Tetrahedron, 1998, 54, 15321.
21
Colonge, J., and Poilane, G., Bull. Soc. Chim. Fr., 1955, 953.
22
Gao, Y., Hanson, R. M., Klunder, J. M., Ko, S. Y., Masamune, H.,
and Sharpless, K. B., J. Am. Chem. Soc., 1987, 109, 5765.
23
Gokel, G. W., Cram, D. J., Liotta, C. L., Harris, H. P., and Cook, F.
L., J. Org. Chem., 1974, 39, 2445.