Taxane diterpene synthesis studies. Part 1: Chemoenzymatic and enantiodivergent routes to AB-ring substructures of taxoids and ent-taxoids

Article abstract of DOI:10.1071/CH03164

The microbially derived cis-1,2-dihydrocatechol 2 has been converted, via reaction sequences including Diels-Alder cycloaddition and anionic oxy-Cope rearrangement steps, into enantiopure bicyclo[5.3.1]undecenes 21 and 34, which correspond to AB-ring subs

Full text of DOI:10.1071/CH03164

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 41–52
Taxane Diterpene Synthesis Studies. Part 1: Chemoenzymatic and
Enantiodivergent Routes to AB-ring Substructures of Taxoids and
ent-Taxoids*
Martin G. Banwell,A,B Penny Darmos,A and David C. R. HocklessA
A
Research School of Chemistry, Institute of Advanced Studies, The Australian National University,
Canberra ACT 0200, Australia.
B Author to whom correspondence should be addressed (e-mail: mgb@rsc.anu.edu.au).
The microbially derived cis-1,2-dihydrocatechol 2 has been converted, via reaction sequences including Diels–
Alder cycloaddition and anionic oxy-Cope rearrangement steps, into enantiopure bicyclo[5.3.1]undecenes 21 and
34, which correspond to AB-ring substructures of ent-taxoids and taxoids, respectively.
Manuscript received: 30 June 2003.
Final version: 28 August 2003.
O
Introduction
OAc
H
O
Ph
N
O
The taxane diterpeneshaveattracted enormousattention from
synthesis chemists because of their challenging molecular
architectures and because certain members of this class of
compound, mostnotablyTaxol(paclitaxel, 1, Diagram1), dis-
play clinically useful anti-tumour properties.[1] Many elegant
approaches to and several total syntheses of taxoid natural
products have been developed in recent years.[2,3] Martin
and co-workers have demonstrated,[4] using racemic mate-
rials, that anionic oxy-Cope rearrangement[5] of 2-alkenyl-
6-methylenebicyclo[2.2.2]octan-2-ols provides an especially
attractive means for preparing the bicyclo[5.3.1]undecenyl-
or AB-ring system associated with taxoids. However, this
approach is limited by a paucity of monochiral bicyclo-
[2.2.2]octanyl systems[6] which would allow for the synthesis
of enantiopure bicyclo[5.3.1]undecenes. Since monochiral
cis-1,2-dihydrocatechols[7] such as 2 (Diagram 1) engage,
as the 4π-component, in diastereofacially selective Diels–
Alder cycloaddition reactions with the resultant forma-
tion of bicyclo[2.2.2]octenes,[7,8] we have investigated the
possibility of converting these adducts into enantiomeri-
cally pure bicyclo[5.3.1]undecenones via anionic oxy-Cope
rearrangement chemistry. We now report that by such means
the cis-1,2-dihydrocatechol 2, which is available in quantity
via microbial oxidation of toluene,[7] can be readily elabo-
rated to the AB-ring system associated with either taxoids
or ent-taxoids.
OH
OH
OH
O
B
8
Ph
O
15
A
C
OH
HO
H
BzO
OAc
1
2
Diagram 1.
2-alkenyl-6-methylenebicyclo[5.3.1]undecenes 4 and ent-4,
respectively. As the labelling implies, each of these pairs
of compounds is enantiomerically related if they possess
the mirror-image stereochemistry at the hydroxy-bearing
centre, namely C2 in 3/ent-3 and C3 in 4/ent-4, and pseudo-
enantiomerically related if they possess the same configu-
ration at these stereogenic centres. Compounds 4 and ent-4
should be accessible from a common precursor 5 through
appropriatemanipulationofeitherthedioloralkenylmoieties
as well as methylenation of the ketone carbonyl. Compound
5 could, in a formal sense at least, be generated via a Diels–
Alder reaction between diene 2 and a ketene equivalent. The
successful implementation of these ideas is detailed below.
Results and Discussion
Initial efforts were focussed, for reasons of simplicity, on
that route leading to an AB-ring substructure of ent-taxoids
as exemplified by the O-benzyl derivative of ent-3. The
reaction sequence (Scheme 1) begins with a Diels–Alder
reaction between α-chloroacrylonitrile, a well known ketene
The retrosynthetic analysis employed in the present work
is shown in Fig. 1 and hinges on the idea that the target
bicyclo[5.3.1]undecenes 3 and ent-3 could be generated
via anionic oxy-Cope rearrangement of the corresponding
*Certain aspects of this work have been reported in preliminary form: M. G. Banwell, P. Darmos, M. D. McLeod, D. C. R. Hockless, Synlett
1998, 897. doi:10.1055/S-1998-1801
© CSIRO 2004
10.1071/CH03164
0004-9425/04/010041

42
M. G. Banwell, P. Darmos and D. C. R. Hockless
equivalent used in such cycloaddition processes, and the ace-
tonide derivative, 6,[8b] of diol 2 (the use of a diol protecting
group was required because of the lack of participation of
compound 2 itself in the equivalent Diels–Alder reaction
with α-chloroacrylonitrile under conventional conditions).
By such means a chromatographically separable mixture of
the epimeric adducts 7 (70%) and 8 (18%) was obtained and
the structure of the latter was established by single-crystal
X-ray analysis (see Fig. 2 and Experimental section). Reac-
tion of the mixture of compounds 7 and 8 with aqueous
KOH provided ketone 9 (81%) which was converted into its
saturated analogue 10 (96%) under standard hydrogenation
conditions. Acid-catalyzed hydrolysis of the acetonide group
within this latter compound provided the corresponding diol
11 (67% at 86% conversion) which, because of a need to
protect the C3 hydroxy whilst leaving its counterpart free
for oxidation, was re-protected as its p-methoxybenzylidene
acetal 12 (100%) by reaction with p-methoxybenzaldehyde
dimethylacetal (p-MBDMA) in the presence of catalytic
amounts of p-toluenesulfonic acid (p-TsOH). Compound 12,
representing a protected and saturated form of intermedi-
ate 5 associated with the retrosynthetic analysis (Fig. 2),
was obtained as a single diastereoisomer in which the p-
methoxyphenyl residue assumes the endo-configuration (as
determined by nuclear Overhauser effect (nOe) NMR experi-
ments) at the acetal carbon atom, presumably by virtue of the
producing reaction proceeding under conditions of kinetic
control.[9] It should also be noted that the need to effect
OH
H
O
2
A
B
2
O
H
OH
ent-3
3
anionic
oxy-Cope
rearrangement
HO
3
3
OH
HO
OH
4
ent-4
FGIs
O
Diels–Alder
reaction
OH
OH
2
5
Fig. 1.
O
Ar
OH
14
O
X
X
Y
H2
Pd on C
O
O
NC
Cl
DDQ
3
2
∆
O
O
OR'
OR
6
10 RR' ꢀ C(CH3)2, X ꢀ O
11 R ꢀ R' ꢀ H, X ꢀ O
12 RR' ꢀ CHAr, X ꢀ O
13 RR' ꢀ CHAr, X ꢀ CH2
7 X ꢀ Cl, Y ꢀ CN
8 X ꢀ CN, Y ꢀ Cl
9 X ꢀ Y ꢀ O
H3Oꢁ
Ph3P ꢀ CH2
p-MBDMA
p-TsOH
aq. KOH
OH
O
Ar
15
O
Ar ꢀ p-MeOC6H4
Swern
oxidation
OBn
H
O
OBn
H
O
NH4Cl
H2C ꢀ CHMgBr
KHMDS
O
ꢁ
8
Ar
O
7
OR
OH
Ar
O
O
O
18 R ꢀ H
19 R ꢀ Bn
O
21
20
17
16
BnBr, NaH
Scheme 1.

Taxane Diterpene Synthesis Studies—Part 1
43
Cl
N
O
O
O
Fig. 3. CS Chem3D Pro drawing of 1,5-diene-diol 18 generated using
data derived from an X-ray crystallographic study (H atoms omitted for
clarity).
O
manner, with carbon-centred electrophiles. Furthermore,
subsequent work in these laboratories (see following paper)
has revealed similar possibilities. The structure of the non-
crystalline bicyclo[5.3.1]undecenone 21 follows from spec-
tral data. In particular, a comparison of the 1H NMR spectrum
of this compound with that of precursor 19 reveals that the
former lacks any resonances due to alkenic protons whilst
the latter exhibits five such signals. In the 13C NMR spec-
trum of compound 21 a signal due to a ketone carbonyl is
observed at δ 211.2 and a carbonyl stretching band appears
at 1713 cm−1 in the infra-red spectrum. Signals due to three
quaternary and sp2-hybridized carbons are observed in the
former spectrum and two of these are assigned to C7 and
C8 in 21 whilst the third arises from C1ꢀ of the aromatic
ring associated with the benzyl ether moiety. Similarly, only
two resonances due to oxygenated sp3-hybridized carbons
are observed in the 13C NMR spectrum of compound 21
whilst three such signals appear in the equivalent spectrum
of precursor 19. Such data when taken together with our
recentacquisition[10] ofanX-raycrystalstructureonaclosely
related bicyclo[5.3.1]undecenone obtained by anionic oxy-
Cope rearrangement of a more extensively C-methylated
analogue of compound 19 allows for confident assignment
of structure 21.
The reaction sequence shown in Scheme 1 provides
a means for converting cis-1,2-dihydrocatechol 2 into a
product, 21, which embodies the AB-ring system associ-
ated with ent-taxoids. Since the enantiomer of compound
2, namely ent-2, is also available (in about 98% e.e.),
via a two-step sequence involving microbial oxidation of
p-iodotoluene and reductive de-iodination of the resulting
cis-1,2-dihydrocatechol,[11] then the enantiomer of com-
pound 21 must also be accessible by this same pathway.
However, as noted earlier (Fig. 1), by proper positioning
of the vinyl group within a bicyclo[2.2.2]octanyl frame-
work, for example 5, derived from compound 2 it is pos-
sible to imagine producing compounds, for example 4,
that, upon anionic oxy-Cope rearrangement, deliver bicyclo-
[5.3.1]undecenones corresponding to the natural series of
taxoids. Such potential for the enantiodivergent synthesis of
the AB-ring substructures of taxoids from a common and
enantiomericallypureprecursor, namely2, hasnowbeenreal-
ized through successful prosecution of the reaction sequence
shown in Scheme 2.
Fig. 2. CS Chem3D Pro drawing of Diels–Alder adduct 8 gener-
ated using data derived from an X-ray crystallographic study (H atoms
omitted for clarity).
this exchange of diol protecting groups has been overcome
by using the p-methoxybenzylidene acetal moiety from the
beginning of the synthesis, as demonstrated in the following
paper.
Methylenation of compound 12 with the Wittig reagent
gave alkene 13 (89%), thus installing one of the two dou-
ble bonds required for the anionic oxy-Cope rearrangement
reaction. In anticipation of installing the second such moiety,
compound 13 was treated with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) thus providing a 1:1 and rapidly
interconverting mixture of diol mono-ester 14 and its regio-
isomer 15 (99% combined yield). These were completely
characterized as their individual and stable acetate deriva-
tives. Swern oxidation of the mixture of free alcohols 14
and 15 gave ketone 16 (30%) and its regioisomer 17 (53%)
which could be separated from one another by flash chro-
matography. The assignment of structure to each of these
ketones follows from an X-ray analysis of a vinylated deriva-
tive of the later product. Thus, reaction of compound 17 with
vinylmagnesium bromide then KOH to give diol 18 (92%
from 17). The stereochemical relationship between the two
double bonds within this last compound was established by
single-crystal X-ray analysis (see Fig. 3 and Experimental
section) and is as required for anionic oxy-Cope rearrange-
ment. However, prior to effecting this key reaction, the
less hindered 2◦-hydroxy group was protected as its ben-
zyl ether 19 (74%) so as to avoid having to effect a double
deprotonation in order to initiate the anionic oxy-Cope
process.
With the relevant substrate, 19, to hand this pivotal rear-
rangement reaction could be investigated. In the event,
treatment of compound 19 with potassium hexamethyl-
disilazide (KHMDS) between −78 and 18◦C resulted
in a smooth conversion into the enolate 20 which was
quenched with ammonium chloride to provide the bicyclo-
[5.3.1]undecenone 21 in 73%. No attempt has been made
to intercept intermediate 20 with anything other than a pro-
ton source. However, Martin et al. have shown[4] that closely
related enolates can be trapped, in a highly stereoselective

44
M. G. Banwell, P. Darmos and D. C. R. Hockless
HO
O
Ar
Ar
O
O
O
O
O
O
O
O
X
25
27
OsO4
Swern
oxidation
RO
RO
DDQ
TMANO
ꢁ
9
O
O
O
O
O
O
Ar HO
Ar
p-MBDMA
p-TsOH
22 R ꢀ H,
23 R ꢀ CHAr, X ꢀ O
24 R ꢀ CHAr, X ꢀ CH2
X ꢀ O
O
O
O
O
O
Ph3P ꢀ CH2
28
26
H2C ꢀ CHMgBr
then NaOH
KOH
Ar ꢀ p-MeOC6H4
HO
HO
HO
HO
BnO
BnBr
NaH
ꢁ
ꢁ
O
O
O
O
O
O
O
HO
O
HO
O
32
31
30
29
KHMDS
H2C ꢀ CHMgBr
NH4Cl
O
O
O
O
O
O
H
H
OBn
OBn
33
34
Scheme 2.
cis-Dihydroxylation (Scheme 2) of alkene 9 was effected
(and stable) acetate derivatives, were immediately subjected
to Swern oxidation and the resulting ketones 27 (46% from
24) and 28 (46% from 24) separated by column chromato-
graphy. This oxidation reaction could also be carried out
using the operationally more straightforward Ley–Griffith
protocol[13] but yields were lower (38% of each ketone).
Reaction of compound 28 with vinylmagnesium bromide fol-
lowed by treatment with sodium hydroxide led to acyloin 29
(11%) together with a ca. 1 : 3 mixture of vinylated prod-
ucts 30 (34%) and 31 (11%). These products were readily
separated by column chromatography and the structure of
the predominant but undesired vinylated material 30 was
confirmed by single crystal X-ray analysis (see Fig. 4 and
Experimental section). A more selective route to compound
31 involved KOH-promoted hydrolysis of ester 28 to the
corresponding α-hydroxyketone 29 (95%) which was then
reacted with vinylmagnesium bromide in a ligand assisted
using Matteson’s procedure[12] and this reaction pro-
ceeded with high diastereofacial selectivity to give diol 22
(89%) which was then converted into the corresponding
p-methoxybenzylidene acetal 23 (79%). As observed in the
earlier conversion 11 → 12 (Scheme 1), compound 23 was
produced as a single epimer and this is attributed to the
acetalization reaction proceeding under conditions of kinetic
control and thus affording (as confirmed by nOe studies)
an endo-configured p-methoxyphenyl group. Methylenation
of ketone 23 was readily achieved using the Wittig reagent
and the product of this reaction, alkene 24 (90%), was then
subjected to DDQ-promoted oxidative cleavage of the acetal
moiety.As a result, and as observed before for compounds 14
and 15, an inseparable 1 : 1 mixture of diol mono-benzoate 25
and regio-isomer 26 was produced. These materials, which
were comprehensively characterized as their corresponding

Taxane Diterpene Synthesis Studies—Part 1
45
on a Perkin–Elmer 241 polarimeter, in spectroscopic grade chloroform
at 20–25◦C. Melting points were recorded on a Reichert hot-stage
apparatus and are uncorrected. Elemental analyses were carried out
by the Australian National University Microanalytical Service on a
Carbo–Erba EA 1106 CHN-O elemental analyzer. A titrometric method
using mercury nitrate was employed for halogen analyses. Analytical
thin layer chromatography (TLC) was conducted on aluminium-backed
0.2 mm thick silica gel 60 GF254 plates (supplied by Merck) and the
chromatograms were visualized under a 254 nm UV lamp and/or by
treatment with anisaldehyde/sulfuric acid/ethanol (2 : 5 : 93 v/v/v mix-
ture) reagent dip or phosphomolybdic acid/cesium(iv) sulfate/sulfuric
acid/water (37.5 g : 7.5 g : 37.5 mL : 720 mL) reagent dip, followed by
heating. Flash chromatography was conducted according to the method
of Still and coworkers[16] using Merck silica gel 60 (230–400 mesh) and
AR grade solvents.
Many reagents were available from the Aldrich Chemical Com-
pany and were used as supplied. Certain solvents and reagents were
purified according to well-established procedures.[17] Thus, tetrahydro-
furan (THF) and benzene were purified by distillation from sodium
benzophenone ketyl. Ethanol was distilled from magnesium ethoxide.
Dimethylformamide (DMF) and dichloromethane were distilled from
CaH2. Pyridine and triethylamine were distilled from potassium hydrox-
ide pellets. Dimethyl sulfoxide (DMSO) was distilled from CaH2 at
reduced pressure (ca. 15 mmHg) and the initial 20% of the distillate
was discarded before collection began. Sodium and potassium hydrides
were washed with hexane, then dried under high vacuum and stored
in a desiccator. 4 Å Molecular sieves were dried by heating under high
vacuum above 150◦C for at least 24 h in a drying pistol charged with
P2O5 or by heating in a 1000W microwave oven (running at full power
for 5 min) and transferring the sieves to a new and open container and
repeating this process for 0.5 h.
O
O
O
O
Fig. 4. CS Chem3D Pro drawing of diol 30 generated using data
derived from an X-ray crystallographic study (H atoms omitted for
clarity).
nucleophilic addition (LANA) reaction.[14] In this manner a
ca. 1 : 10 mixture 30 and 31 was obtained (55% combined
yield). The mono-benzyl ether 32 (53%) derived from 31
underwent smooth anionic oxy-Cope rearrangement upon
treatment with KH/[18]crown-6 at 0–18◦C and after quench-
ing the intermediate enolate anion 33 with saturated aqueous
ammonium chloride the bicyclo[5.3.1]undecenone 34 (47%),
which embodies theAB-ring system associated with taxoids,
was obtained as a clear, colourless oil. As with congener 21,
the spectral data derived from compound 34 are fully con-
sistent with the assigned structure. Interestingly, the specific
rotations of compounds 21 and 34 are of almost equal value
but opposite sign, namely +37 and −33 respectively.
Unless otherwise specified, reactions were carried out under an
atmosphere of dry, oxygen-free nitrogen.Those reactions employing air-
and/or moisture-sensitive reagents were performed in oven- or flame-
dried apparatus. In those instances requiring the use of oil or graphite
heating baths, the bath temperatures were monitored with an IKATRON
ETS D3 temperature regulator. When low temperature (<0◦C) reactions
were involved the internal reaction temperature was monitored using an
alcohol thermometer. After normal work-up procedures, solutions were
concentrated under reduced pressure on a rotary evaporator with the
bath temperature generally not exceeding 30◦C. Residual solvent was
then removed using a JAVAC Double Stage high vacuum pump.
Conclusions
On the basis of the foregoing it is clear that by appro-
priate choice of reaction pathways usefully functionalized
AB-ring sub-structures (such as 21 and 34) associated with
both taxoids and ent-taxoids are accessible from the same
readily available chiron, namely the toluene-derived cis-1,2-
dihydrocatechol 2. While compounds 21 and 34 lack the two
quaternary carbon centres, at C8 and C15 (for taxane num-
bering see structure 1), associated with taxoids the strategy
described above does allow for the introduction of these struc-
turally demanding features. Thus, the following paper[15]
detailsahighlyefficientsynthesisofcompoundswhichincor-
porate these centres and the novel chemistry that follows from
their presence.
Synthetic Studies
(3aS,4R,7S,7aR,8S)-8-Chloro-3a,4,7,7a-tetrahydro-
2,2,7-trimethyl-4,7-ethano-1,3-benzodioxole-8-carbonitrile 7
and (3aS,4R,7S,7aR,8R)-8-Chloro-3a,4,7,7a-tetrahydro-
2,2,7-trimethyl-4,7-ethano-1,3-benzodioxole-8-carbonitrile 8
A magnetically stirred solution of diene 6 (8.66 g, 52.1 mmol) and
α-chloroacrylonitrile (12.5 mL, 156 mmol) in benzene (100 mL) was
heated at reflux for 21 h while being maintained under a nitrogen
atmosphere. The cooled reaction mixture was then concentrated under
reduced pressure to give a 4 : 1 mixture (as judged by 1H NMR and
HPLC analysis) of the expected Diels–Alder adducts as a pale-yellow
oil (11.6 g) which crystallized upon standing. Subjection of this mixture
to flash chromatography (silica, 1 : 4 v/v ethyl acetate/hexane elution)
gave two fractions, A and B.
Experimental
General Procedures and Protocols
1H and 13C NMR spectra were recorded on a Varian Gemini-300
spectrometer. All 1H NMR spectra were recorded in CDCl3 and refer-
enced to the signal arising from residual CHCl3 (7.26 ppm). 13C NMR
spectra were also recorded in CDCl3 and referenced to the central
line of the CDCl3 triplet (77.0 ppm). Infrared spectra were recorded
on a Perkin–Elmer 683 Infrared Spectrometer or a Perkin–Elmer 1800
Fourier transform infrared spectrometer. Samples were analyzed either
as thin films on NaCl or KBr plates (for liquids) or as KBr discs (for
solids). Low and high resolution electron impact (EI, 70 eV electron
beam) mass spectra were recorded on an AUTOSPEC spectrometer.
Optical rotations were measured at the wavelength of the sodium d-line,
Concentration of fraction A [Rf 0.5(4)] afforded a colourless,
crystalline solid. Recrystallization (ethanol) of this material afforded
Diels–Alder adduct 7 (9.28 g, 70%) as colourless cubes, mp 144–146◦C,
•
[α]D +47◦ (c 0.6) (Found: M+ 253.0874, C 61.4, H 6.4, N 5.4, Cl
14.0. C13H16N35ClO2 requires M+• 253.0870, C 61.5, H 6.4, N 5.5, Cl
14.0%). νmax/cm−1 3383, 2974, 2933, 2883, 2234, 1496, 1213, 1087,
1032, 745. δH (300 MHz) 6.24 (1 H, t, J 7), 5.75 (1 H, dd,J 7 and 1),
4.31 (2 H, m), 2.96 (1 H, m), 2.51 (1 H, dd, J 16 and 3), 2.24 (1 H, dd, J
16 and 5), 1.59 (3 H, s), 1.34 (3 H, s), 1.29 (3 H, s). δC (75 MHz) 131.9
(CH), 131.1 (CH), 118.9 (C), 110.0 (C), 79.1 (CH), 77.7 (CH), 59.0 (C),
46.9 (C), 42.1 (CH2), 34.1 (CH), 25.4 (CH3), 25.0 (CH3), 17.5 (CH3).

46
M. G. Banwell, P. Darmos and D. C. R. Hockless
•
m/z 255 and 253 (M+•, 1 and 3%), 240 and 238 ([M – CH3 ]+, 29 and
77), 197 and 195 (15 and 43), 160 (87), 127 (77), 121 (100), 100 (33).
Concentration of fraction B (Rf 0.5) provided a colourless, crys-
talline solid. Recrystallization (ethanol) of this material afforded Diels–
ethyl acetate (2 × 50 mL) and the combined organic phases were then
washed with water (1 × 50 mL) and NaHCO3 (1 × 50 mL of a 10% w/v
aqueous solution) before being dried (MgSO4), filtered, and concen-
trated under reduced pressure to afford a pale-yellow oil. Subjection of
this material to flash chromatography (silica, 1 : 1 ethyl acetate/petrol
elution) afforded two fractions, A and B.
Concentration of fraction A (Rf 0.6) afforded the starting acetonide
10 (69 mg, 14% recovery) which was identical, in all respects, with an
authentic sample.
Alderadduct 8(2.32 g, 18%)ascolourlessneedles, mp178–180◦C, [α]D
•
+83◦ (c 0.2) (Found: [M − CH3
]
+ 238.0637, C 61.1, H 6.4, N 5.4, Cl
•
13.8. C13H16N35ClO2 requires [M − CH3
]
+ 238.0635, C 61.5, H 6.4,
N 5.5, Cl 14.0%). νmax/cm−1 3001, 2973, 2922, 2243, 1460, 1258,
1211, 1083, 1047, 879. δH (300 MHz) 6.34 (1 H, t, J 7), 5.89 (1 H,
dd, J 7 and 1), 4.39 (2 H, m), 2.97 (1 H, m), 2.62 (1 H, dd, J
15 and 4), 2.12 (1 H, dd, J 15 and 2), 1.61 (3 H, s), 1.33 (3 H,
s), 1.30 (3 H, s). δC (75 MHz) 134.1 (CH), 133.3 (CH), 119.3 (C),
109.1 (C), 77.9 (CH), 77.5 (CH), 60.2 (C), 46.2 (C), 42.1 (CH2),
34.8 (CH), 25.4 (CH3), 24.9 (CH3), 17.2 (CH3). m/z 255 and 253
Concentration of fraction B (Rf 0.2) afforded compound 11 (229 mg,
67% at 86% conversion) as a colourless solid, mp 156–157◦C, [α]D +4◦
•
(c 0.55), (Found: M+• 170.0942, C 63.2, H 8.0. C9H14O3 requires M+
170.0943, C 63.5, H 8.3%). νmax/cm−1 3355, 2933, 2907, 1714, 1401,
1076, 1002, 982, 951, 433. δH (300 MHz) 3.97 (1 H, ddd, J 8, 3 and 2),
3.61 (1 H, dd, J 8 and 2), 3.17 (2 H, br s), 2.36 (1 H, dd, J 19 and 3),
2.29–1.92 (4 H, complex m), 1.47 (1 H, m), 1.28 (1 H, m), 1.02 (3 H, s).
δC (75 MHz) 215.3 (C), 68.3 (CH), 67.6 (CH), 48.9 (C), 41.7 (CH2),
33.8 (CH), 22.9 (CH2), 18.0 (CH2), 16.5 (CH3). m/z 170 (M+•, 89%),
(M+•, <1 and <1%), 240 and 238 ([M – CH3 ]+, 33 and 64), 195
•
([M – CH3CO•]+, 21), 160 (78), 121 (100).
(3aS,4R,7S,7aR)-3a,4,7,7a-Tetrahydro-2,2,7-trimethyl-
4,7-ethano-1,3-benzodioxol-8-one 9
•
152 ([M – H2O]+•, 22), 137 ([M – H2O – CH3 ]+, 47), 110 (100), 109
(89), 95 (72), 69 (75).
A magnetically stirred and ice-cold solution of potassium hydroxide
(120 g in 150 mL of water, 14.3 M) was added to a 250 mL round-bottom
flask containing compounds 7 and 8 (5.41 g, 21.3 mmol) and the result-
ing mixture was heated at reflux for 16 h. The cooled reaction mixture
was then poured into ether (100 mL) and the separated aqueous layer
was treated with potassium carbonate (ca. 2 g) then extracted with ether
(3 × 100 mL). The combined organic phases were dried (MgSO4), fil-
tered, and concentrated under reduced pressure to afford a colourless
solid. Subjection of this material to flash chromatography (silica, 1 : 4
v/v ethyl acetate/hexane elution) afforded, after concentration of the
appropriate fractions (Rf 0.3), the ketone 9 (3.61 g, 81%) as colour•-
less, crystalline plates, mp 81–82◦C, [α]D +334◦ (c 0.7), (Found: M+
(2S,3aR,4S,7S,7aS)-Hexahydro-2-(4-methoxyphenyl)-4-methyl-
4,7-ethano-1,3-benzodioxol-5-one 12
A magnetically stirred solution of the diol 11 (200 mg, 1.18 mmol) and
p-methoxybenzaldehyde dimethyl acetal (303 µL, 321 mg, 1.77 mmol)
in THF (5 mL) was cooled to 0◦C then treated with p-toluenesulfonic
acid monohydrate (10 mg, 4 mol %). After stirring at 0◦C for 2 h, the
reaction mixture was quenched with triethylamine (0.5 mL) and con-
centrated under reduced pressure to afford a pale-yellow solid which
was dissolved in dichloromethane (50 mL). The resulting solution was
treated with NaOH (1 × 50 mL of a 1 M aqueous solution) and the sep-
arated aqueous layer was extracted with dichloromethane (3 × 50 mL).
The combined organic phases were washed with brine (1 × 50 mL), then
dried (MgSO4), filtered, and concentrated under reduced pressure to
give a yellow solid. Subjection of this material to flash chromatography
(silica, dichloromethane elution) and concentration of the appropriate
fractions(Rf 0.3)affordedthetitleacetal 12(339 mg, 100%)•asacolour-
less solid, mp 162–163◦C, [α]D −22◦ (c 2.8), (Found: M+ 288.1351,
•
208.1101, C 69.4, H 7.7. C12H16O3 requires M+ 208.1099, C 69.2,
H 7.7%). νmax/cm−1 2970, 2880, 1729, 1382, 1273, 1253, 1201, 1094,
1049, 877. δH (300 MHz) 6.36 (1 H, t, J 7), 5.74 (1 H, d, J 7), 4.51
(1 H, dd, J 6 and 4), 4.06 (1 H, dd, J 6 and 2), 3.18 (1 H, m), 2.14 (1 H,
dd, J 19 and 4), 1.89 (1 H, dd, J 19 and 2), 1.38 (3 H, s), 1.32 (6 H, s).
δC (75 MHz) 210.2 (C), 133.4 (CH), 131.3 (CH), 110.6 (C), 79.6 (CH),
79.1 (CH), 54.5 (C), 35.3 (CH), 35.0 (CH2), 25.3 (CH3), 24.9 (CH3),
•
14.3 (CH3). m/z 208 (M+•, 18%), 193 ([M – CH3 ]+, 21), 161 (27),
•
C 70.5, H 6.8. C17H20O4 requires M+ 288.1362, C 70.8, H 7.0%).
150 ([M – (CH3)2CO]+•, 57), 121 (75), 108 (100), 100 (68).
νmax/cm−1 2924, 1717, 1615, 1518, 1313, 1254, 1170, 1063, 1021,
843. δH (300 MHz) 7.51 (2 H, d, J 8), 6.95 (2 H, d, J 8), 5.82 (1 H,
s—shows 20%, 9% and 4% nOe to signals at δH 7.51, 4.32, and 3.94,
respectively), 4.32 (1 H, ddd, J 8, 4 and 1), 3.94 (1 H, dd, J 8 and 2),
3.83 (3 H, s), 2.50 (1 H, m), 2.41 (1 H, dd, J 19 and 4), 2.32–2.12 (3 H,
complex m), 1.53–1.25 (2 H, complex m), 1.09 (3 H, s). δC (75 MHz)
214.0 (C), 160.8 (C), 128.3 (2 × CH), 128.2 (C), 113.9 (2 × CH), 104.3
(CH), 76.6 (CH), 76.0 (CH), 55.3 (CH3), 47.6 (C), 40.2 (CH2), 31.0
(CH), 23.3 (CH2), 18.3 (CH2), 16.7 (CH3). m/z 288 (M+•, 42%), 287
([M – H•]+, 53), 257 ([M – CH3O•]+, 8), 135 (100), 121 (31), 108 (39),
94 (73).
(3aS,4R,7S,7aR)-3a,4,5,6,7,7a-Hexahydro-2,2,7-trimethyl-
4,7-ethano-1,3-benzodioxol-8-one 10
A solution of alkene 9 (6.11 g, 29.4 mmol) in ethanol (100 mL) was
treated with 10% palladium on carbon (8.63 g) and the resulting sus-
pension stirred at 18◦C under a hydrogen atmosphere (1 atm) for 16 h
then filtered through a 0.5 cm deep pad of Celite placed atop a 7 cm deep
plug of silicagel.Theretainedsolids were washed with ethanol (100 mL)
and the combined filtrates were concentrated under reduced pressure to
give compound 10 (5.91 g, 96%) as a colourless, crystalline solid, mp
•
50–51◦C, [α]D −35◦ (c 0.55), (Found: M+ 210.1253, C 68.3, H 8.9.
C12H18O3 requires: M+• 210.1256, C 68.6, H 8.6%). νmax/cm−1 2972,
2936, 1727, 1384, 1374, 1266, 1208, 1085, 1062, 1020. δH (300 MHz)
4.29 (1 H, dd, J 8, 4 and 2), 3.90 (1 H, dd, J 8 and 2), 2.39–2.31 (2 H,
complex m), 2.18–1.94 (3 H, complex m), 1.57 (3 H, s), 1.44 (1 H, m),
1.37 (3 H, s), 1.23 (1 H, m), 1.02 (3 H, s). δC (75 MHz) 214.4 (C), 110.2
(C), 76.1 (CH), 75.1 (CH), 47.5 (C/CH2), 40.1 (C/CH2), 31.2 (CH),
25.7 (CH3), 24.2 (CH3), 23.0 (CH2), 18.1 (CH2), 16.7 (CH3). m/z 210
(2S,3aR,4R,7S,7aS)-Hexahydro-2-(4- methoxyphenyl)-4-methyl-
5-methylene-4,7-ethano-1,3-benzodioxole 13
A magnetically stirred suspension of sodium hydride (208 mg,
8.68 mmol) in DMSO (7.5 mL) was heated at 78◦C for 1 h while being
maintained under a nitrogen atmosphere. The resulting green solu-
tion was cooled to 0◦C then treated with a warm solution of methyl-
triphenylphosphonium bromide (3.10 g, 8.68 mmol) in DMSO (10 mL).
The caramel-coloured reaction mixture was stirred at 18◦C for 0.25 h
then treated with ketone 12 (500 mg, 1.74 mmol). After stirring the
resulting mixture at 18◦C for 1 h it was poured into water/pentane
(200 mL of a 1 : 1 v/v mixture). The separated aqueous layer was
extracted with pentane (3 × 100 mL) and the combined organic phases
were washed with NaHCO3 (1 × 100 mL of a saturated aqueous solu-
tion) and brine (1 × 100 mL), then dried (MgSO4), filtered, and con-
centrated under reduced pressure to afford a colourless, waxy solid.
Subjection of this material to flash chromatography (silica, 1 : 19
v/v ethyl acetate/hexane elution) and concentration of the appropriate
•
•
(M+•, 5%), 195 ([M – CH3 ]+, 100), 153 ([M – CH3 – CH2CO]+, 99),
109 (48), 93 (80), 81 (59), 69 (61).
(1S,4S,5S,6R)-5,6-Dihydroxy-1-methylbicyclo-
[2.2.2]octan-2-one 11
A magnetically stirred solution of acetonide 10 (490 mg, 2.33 mmol) in
acetic acid/water (250 mL of a 4 : 1 v/v solution) was heated at 80◦C
for 18 h. The cooled reaction mixture was concentrated under reduced
pressure and the resulting oil partitioned between water (50 mL) and
ethyl acetate (50 mL). The separated aqueous layer was extracted with

Taxane Diterpene Synthesis Studies—Part 1
47
fractions (Rf 0.3) afforded compound 13 (445 mg, 89%) as a colour-
Concentration of the fractions containing the less mobile
component [Rf 0.1(6)] afforded (1R,2R,3S,4S)-3-acetoxy-1-methyl-
6-methylenebicyclo[2.2.2]octan-2-yl 4-methoxybenzoate, the acetate
derivative of compound 15, (93 mg, 37%), as a clear, colourless oil
(Found: M+• 344.1621. C20H24O5 requires M+• 344.1624). νmax/cm−1
1746, 1719, 1607, 1512, 1282, 1258, 1238, 1168, 1103, 788. δH
(300 MHz) 8.03 (2 H, d, J 9), 6.95 (2 H, d, J 9), 5.04 (1 H, dd, J 8
and 2), 4.98–4.87 (3 H, complex m), 3.87 (3 H, s), 2.43 (2 H, br s),
2.11–1.93 (3 H, complex m), 1.80 (3 H, s), 1.54 (1 H, m), 1.35 (1 H, m),
1.04 (3 H, s). δC (75 MHz) 170.0 (C), 165.6 (C), 163.4 (C), 148.8 (C),
131.6 (2 × CH), 122.6 (C), 113.7 (2 × CH), 108.4 (CH2), 72.3 (CH),
70.0 (CH), 55.4 (CH3), 38.4 (C/CH2), 33.0 (C/CH2), 30.7 (CH3), 26.7
(CH2), 20.7 (CH3), 19.9(9) (CH3), 19.9(5) (CH2). m/z 344 (M+•, 4%),
284 ([M – CH3CO2H]+•, 25), 243 (16), 242 (16), 135 (100), 107 (19),
92 (27), 77 (24).
•
less solid, mp 41–42◦C, [α]D +47◦ (c 1.3), (Found: M+ 286.1557.
C18H22O3 requires M+• 286.1569). νmax/cm−1 2934, 2912, 1616, 1519,
1402, 1249, 1074, 1030, 1009, 831. δH (300 MHz) 7.51 (2 H, d, J 9),
6.93 (2 H, d, J 9), 5.73 (1 H, s), 4.92 (1 H, br s), 4.89 (1 H, br s), 4.15
(1 H, dd, J 8 and 4), 3.82 (3 H, s), 3.73 (1 H, dd, J 8 and 2), 2.48 (1 H,
ddd, J 19, 8 and 3), 2.28 (1 H, dm, J 19), 2.17–1.94 (3 H, complex m),
1.40 (1 H, m), 1.20 (1 H, m), 1.10 (3 H, s). δC (75 MHz) 160.6 (C), 150.2
(C), 129.0 (C), 128.4 (CH), 113.8 (CH), 107.7 (CH2), 103.0 (CH), 80.0
(CH), 76.9 (CH), 55.3 (CH3), 38.3 (C), 32.2•(CH2), 30.2 (CH), 25.7
(CH2), 20.3 (CH3), 19.2 (CH3). m/z 286 (M+ , 60%), 285 ([M – H•]+,
55), 257 (21), 137 (66), 135 (100), 121 (98), 107 (48), 91 (C7H+7 , 47).
(1R,2R,3S,4S)-2-Hydroxy-1-methyl-6- methylenebicyclo-
[2.2.2]octan-3-yl 4-Methoxybenzaote 14
and (1R,2R,3S,4S)-3-Hydroxy-1-methyl-6-methylenebicyclo-
[2.2.2]octan-2-yl 4-Methoxybenzaote 15
(1S,2R,4R)-4-Methyl-5-methylene-2-oxobicyclo[2.2.2]octan-3-yl
4-Methoxybenzoate 16
A magnetically stirred solution of compound 13 (445 mg, 1.56 mmol)
in dichloromethane/water (20 mL of a 17 : 1 v/v mixture) was treated
with DDQ (530 mg, 2.33 mmol, 1.5 mole equiv.). After 4 h at 18◦C the
reaction mixture was poured into NaHCO3 (50 mL of a 5% w/v
aqueous solution) and the separated aqueous layer was extracted with
dichloromethane (3 × 50 mL). The combined organic phases were
washed with NaHCO3 (1 × 100 mL of a 5% w/v aqueous solution), then
dried (MgSO4), filtered, and concentrated under reduced pressure to
give a colourless solid. Subjection of this material to flash chromato-
graphy (silica, 1 : 4 ethyl acetate/petrol elution) afforded two fractions,
A and B.
Concentration of fractionA (Rf 0.4) afforded compound 14 (236 mg,
50%) as a colourless solid. 1H NMR analysis of this material indicated
that it was contaminated with ca. 0.5% of its regioisomer 15.
Concentration of fraction B containing the less mobile component
(Rf 0.2) afforded compound 15 (230 mg, 49%) as a colourless solid. 1H
NMR analysis of this material indicated that it was contaminated with
ca. 2% of compound 14.
and (1R,3S,4S)-1-Methyl-6-methylene-2-oxobicyclo[2.2.2]octan-3-yl
4-Methoxybenzoate 17
Trifluoroacetic anhydride (234 µL, 1.67 mmol, 1.5 mole equiv.) was
added dropwise to a magnetically stirred solution of DMSO (157 µL,
2.19 mmol, 2 mole equiv.) in dichloromethane (6 mL) maintained at
−60◦C (dry ice/chloroform bath) under a nitrogen atmosphere. The
resulting solution was stirred at −60◦C for 10 min before a solu-
tion of a 1 : 1 mixture of compound 14 and regioisomer 15 (334 mg,
1.11 mmol) in dichloromethane (1 mL) was added dropwise. After
stirring for 3 h at −60◦C, triethylamine (1 mL) was added and the
mixture then warmed to 18◦C. The orange solution thus obtained was
poured into HCl (1 × 50 mL of a 2 M aqueous solution) and extracted
with dichloromethane (3 × 50 mL). The combined organic phases were
washed with water (1 × 50 mL), then dried (MgSO4), filtered, and
concentrated under reduced pressure to afford an orange oil (332 mg).
Subjection of this material to flash chromatography (silica, 1 : 4 ethyl
acetate/petrol elution) provided two fractions, A and B.
Concentration of fractionA (Rf 0.4) afforded compound 16 (100 mg,
Compounds 14 and 15 interconvert on standing. Consequently, no
attempt was made to characterize them in a comprehensive manner.
Rather, the crude mixture of these compounds was acetylated (see
below) and the derived acetates were then separated and characterized
spectroscopically.
•
30%) as a pale-yellow oil, [α]D +164◦ (c 2.8), (Found: M+ 300.1358.
C18H20O4 requires M+• 300.1362). νmax/cm−1 1719, 1606, 1512, 1325,
1257, 1168, 1100, 1027, 847, 767. δH (300 MHz) 8.03 (2 H, d, J 8), 6.94
(2 H, d, J 8), 5.25 (1 H, d, J 2), 5.11 (1 H, br s), 5.02 (1 H, br s), 3.86
(3 H, s), 2.70 (2 H, m), 2.60 (1 H, m), 2.09–1.82 (3 H, br m), 1.50 (1 H,
m), 1.10 (3 H, s). δC (75 MHz) 211.0 (C), 165.1 (C), 163.4 (C), 147.0
(C), 131.8 (CH), 121.6 (C), 113.5 (CH), 109.0 (CH2), 76.4 (CH), 55.2
(CH3), 43.1 (C), 42.8 (CH), 31.3 (CH2), 27.2 (CH2), 25.5 (CH2), 18.5
(CH3). m/z 300 (M+•, 15%), 135 (100), 107 (12), 92 (7), 77 (10).
Concentration of the fraction B (Rf 0.5) gave a colourless solid.
Recrystallization (CHCl3/hexane) of this material afforded compound
17 (175 mg, 53%) as colourless needles, mp 78–79◦C, [α]D +44◦
(1R,2R,3S,4S)-2-Acetoxy-1-methyl-6-methylenebicyclo-
[2.2.2]octan-3-yl 4-Methoxybenzoate
and (1R,2R,3S,4S)-3-Acetoxy-1-methyl-6-methylenebicyclo-
[2.2.2]octan-2-yl 4-Methoxybenzoate
A solution of a ca. 1 : 1 mixture of compounds 14 and 15 (219 mg,
0.725 mmol) in pyridine (2 mL) was treated with acetic anhydride
(630 µL, 6.62 mmol) and the resulting mixture stirred at 18◦C for 16 h
then concentrated under reduced pressure to give a pale-yellow oil. This
material was subjected to flash chromatography (silica, 1 : 4 v/v ethyl
acetate/hexane elution) thus affording two fractions, A and B.
(c 2.2), (Found: M+• 300.1360, C 71.8, H 6.6. C18H20O4 requires M+
•
300.1362, C 72.0, H 6.7%). νmax/cm−1 1739, 1711, 1607, 1510, 1304,
1260, 1176, 1118, 1026, 767. δH (300 MHz) 8.02 (2 H, d, J 9), 6.92
(2 H, d, J 9), 5.30 (1 H, t, J 2), 4.97 (2 H, dt, J 6 and 2), 3.86 (3 H, s),
2.77–2.68 (2 H, complex m), 2.47 (1 H, m), 2.05 (1 H, m), 1.87 (2 H, m),
1.72 (1 H, m), 1.19 (3 H, s). δC (75 MHz) 208.8 (C), 165.3 (C), 163.5
(C), 143.9 (C), 131.9 (CH), 122.0 (C), 113.6 (CH), 110.0 (CH2), 75.6
(CH), 55.4 (CH3), 50.3 (C), 33.7 (CH2), 33.2(2) (CH), 33.1(9) (CH2),
20.4 (CH2), 15.8 (CH3). m/z 300 (M+•, 17%), 135 (100), 107 (6), 92
(9), 77 (12).
Concentration of fractionA (Rf 0.2) gave a colourless solid. Recrys-
tallization (hexane) of this material afforded (1R,2R,3S,4S)-2-acetoxy-
1-methyl-6-methylenebicyclo[2.2.2]octan-3-yl 4-methoxybenzoate, the
acetate derivative of compound 14, (100 mg, 40%) as colourless,
crystalline needles, mp 73–74◦C (Found: M+• 344.1631, C 69.6, H 7.0.
•
C20H24O5 requires M+ 344.1624, C 69.8, H 7.0%). νmax/cm−1 1741,
1723, 1607, 1286, 1267, 1237, 1168, 1125, 1100, 1020. δH (300 MHz)
7.99 (2 H, d, J 9), 6.92 (2 H, d, J 9), 5.21 (1 H, ddd, J 8, 3 and 2),
4.94 (1 H, br s), 4.88 (1 H, br s), 4.85 (1 H, dd, J 8 and 2), 3.86
(3 H, s), 2.44 (2 H, br s), 2.15–2.03 (2 H, complex m), 1.98–1.88 (1
H, complex m), 1.93 (3 H, s), 1.50 (1 H, m), 1.30 (1 H, m), 0.98 (3
H, s). δC (75 MHz) 170.2 (C), 165.2 (C), 163.4 (C), 149.0 (C), 131.5
(2 × CH), 122.6 (C), 113.6 (2 × CH), 108.2 (CH2), 71.9 (CH), 69.8
(CH), 55.4 (CH3), 38.1 (C/CH2), 32.8 (C/CH2), 30.7 (CH), 26.6 (CH2),
20.6 (CH3), 20.1 (CH2), 19.6 (CH3). m/z 344 (M+•, 17%), 150 (24),
135 (100), 108 (18), 77 (16).
(1R,2R,3S,4S)-2-Ethenyl-1-methyl-6-methylenebicyclo-
[2.2.2]octane-2,3-diol 18
Amagneticallystirredsolutionofketone17(61 mg, 0.203 mmol)inTHF
(3 mL) maintained at 0◦C under a nitrogen atmosphere was treated, in
one portion, with vinylmagnesium bromide (0.55 mL of a 1.2 M solu-
tion in THF, 0.660 mmol, 3.25 mole equiv.). After stirring the resulting
mixture at 0◦C for 3 h, NH4Cl (10 mL of a saturated aqueous solu-
tion) was added and the resulting suspension partitioned between water
(20 mL) and ethyl acetate (50 mL). The separated aqueous layer was

48
M. G. Banwell, P. Darmos and D. C. R. Hockless
extracted with ethyl acetate (2 × 50 mL), and the combined organic
phases dried (MgSO4), filtered, and concentrated under reduced pres-
sure to give a yellow oil. A solution of this material in methanol (2 mL)
was treated with potassium hydroxide (ca. 1 g) and after stirring the reac-
tion mixture at 18◦C for 0.33 h it was poured into water (10 mL) and
extracted with ethyl acetate (3 × 50 mL). The combined organic phases
were dried (MgSO4), filtered, and concentrated under reduced pressure
to provide an orange oil. Subjection of this material to flash chromato-
graphy (silica, 3 : 17 v/v ethyl acetate/hexane elution) and concentration
of the appropriate fractions (Rf 0.2) afforded an oil which solidified
upon standing. Recrystallization (hexane) of this solid afforded com-
pound 18 (36 mg, 92%) as colourless needles, mp 97–98◦C, [α]D –18◦•
(c 2.1), (Found: M+• 194.1306, C 74.0, H 9.6. C12H18O2 requires M+
194.1307, C 74.2, H 9.3%). νmax/cm−1 3311, 2958, 2946, 2915, 1644,
1082, 1072, 984, 921, 894. δH (300 MHz) 5.83 (1 H, dd, J 17 and 11),
5.26 (1 H, dd, J 17 and 2), 5.07 (1 H, dd, J 11 and 2), 4.83 (2 H, m),
3.50 (1 H, br s), 2.79 (1 H, br s), 2.65 (1 H, br m), 2.44 (1 H, ddd, J 17,
5 and 3), 2.32 (1 H, dddd, J 17, 7, 3 and 2), 2.01–1.79 (3 H, complex
m), 1.40 (1 H, m), 1.22 (1 H, ddd, J 18, 12 and 6), 0.89 (3 H, s). δC
(75 MHz) 141.7 (C), 111.6 (C/CH2), 110.5 (C/CH2), 107.6 (C/CH2),
74.0 (CH), 44.4 (CH), 44.3 (C), 33.6 (CH2), 33.2 (C), 27.8 (CH2), 18.8
(C), 133.9 (C), 129.9 (C), 128.3 (2 × CH), 127.8 (CH), 127.6 (2 × CH),
84.5 (CH), 70.7 (CH2), 43.1 (CH2), 40.0 (CH), 31.9 (CH2), 31.6 (CH2),
28.4 (CH2), 24.8 (CH2), 19.0 (CH2), 18.1 (CH3). m/z 284 (M+•, 3%),
193 (23), 176 (28), 175 (27), 107 (22), 91 (100), 55 (26).
(3aR,4S,7R,7aS,8S,9R)-Tetrahydro-8,9-dihydroxy-
2,2,4-trimethyl-4,7-ethano-1,3-benzodioxol-5(4H)-one 22
A magnetically stirred mixture of alkene 9 (7.86 g, 37.8 mmol),
t-butanol (152 mL), water (47.4 mL), pyridine (6.4 mL), and
trimethylamine-N-oxide (9.20 g) maintained under a nitrogen atmo-
sphere was treated, in one portion, with osmium tetroxide (3.2 mL of
2.5 wt-% solution in t-butanol). The resulting pale-brown solution was
heated at reflux for 5 h then cooled and treated with Na2S2O5 (200 mL
of a 20% w/v aqueous solution). The ensuing mixture was concentrated
under reduced pressure and the residue acidified to pH 2 with H2SO4
(6wt-%solutioninwater)thentheseparatedaqueouslayerwasextracted
with ether (4 × 250 mL). The combined organic phases were washed
with brine (1 × 250 mL), then dried (MgSO4), filtered, and concentrated
under reduced pressure to give a pale-yellow solid. Recrystallization
(ethyl acetate/hexane) of this material afforded diol 22 (8.16 g, 89%)
as colourless needles, mp 182–182.5◦C, [α]D −38◦ (c 1.0), (Fou•nd:
•
(CH2), 17.8 (CH3). m/z 194 (M+ , 0.2%), 176 ([M – H2O]+•, 4), 161
•
+
[M – CH3
]
+ 227.0920, C 59.3, H 7.7. C12H18O5 requires [M – CH3
]
(13), 118 (27), 108 (100), 93 (45), 91 (28), 79 (24), 55 (30).
227.0920, C 59.5, H 7.5%). νmax/cm−1 3512, 3456, 1726, 1377, 1210,
1158, 1083, 1053, 1040, 858. δH (300 MHz) 4.51 (1 H, m), 4.33 (1 H,
dd, J 8 and 4), 4.18 (1 H, dm, J 8), 3.93 (1 H, d, J 8), 2.80–2.53 (4 H,
complex m), 1.98 (1 H, dt, J 19 and 2), 1.50 (3 H, s), 1.32 (3 H, s), 1.27
(3 H, s). δC (75 MHz) 210.7 (C), 110.3 (C), 76.8 (CH), 74.8 (CH), 69.2
(CH), 62.6 (CH), 54.5 (C), 38.8 (CH), 3•4.1 (CH2), 25.5 (CH3), 23.6
(CH3), 14.1 (CH3). m/z 227 ([M – CH3 ]+, 13%), 209 ([M – H2O –
(1R,2R,3S,4S)-2-Ethenyl-1-methyl-6-methylene-
3-(phenylmethoxy)bicyclo[2.2.2]octan-2-ol 19
Sodium hydride (66 mg, 2.75 mmol, 3 mole equiv.) was added to a mag-
netically stirred and ice-cold solution of diol 18 (180 mg, 0.927 mmol)
in benzyl bromide (10 mL of a 0.1 M solution in DMF, 1.00 mmol) main-
tained under a nitrogen atmosphere. After stirring the resulting mixture
at 0◦C for 2 h it was quenched with water (50 mL) (CAUTION) then
extracted with ethyl acetate (3 × 50 mL). The combined organic phases
were dried (MgSO4), filtered, and concentrated under reduced pressure
to provide a yellow oil. Subjection of this material to flash chromato-
graphy (silica, 1 : 9 v/v ethyl acetate/hexane elution) and concentra-
tion of the appropriate fractions (Rf 0.3) then gave the benzyl ether 19
•
CH3 ]+, 14), 149 (30), 125 (50), 124 (45), 121 (100), 109 (41), 85 (42).
(3aS,4R,4aS,6S,7aR,8S,8aR)-Hexahydro-6-(4-methoxyphenyl)-2,2,8-
trimethyl-4,8-ethanobenzo[1,2-d:4,5-dꢀ]bis[1,3]-dioxol-9-one 23
A magnetically stirred solution of diol 22 (677 mg, 2.78 mmol) and
p-methoxybenzaldehyde dimethyl acetal (0.7 mL, 4.17 mmol, 1.5 mole
equiv.) in THF (10 mL) maintained under a nitrogen atmosphere was
cooled to 0◦C and treated with p-toluenesulfonic acid monohydrate
(25 mg, 5 mol %). The resulting mixture was warmed to 18◦C, stirred
for 16 h then quenched with triethylamine (1 mL) and concentrated
under reduced pressure. The residue was dissolved in dichloromethane
(50 mL) and the resulting solution treated with NaOH (1 × 50 mL of
a 1 M aqueous solution). The separated aqueous phase was extracted
with dichloromethane (3 × 50 mL), and the combined organic phases
were washed with brine (1 × 50 mL), then dried (MgSO4), filtered, and
concentrated under reduced pressure to afford a yellow oil (1.32 g).
Subjection of this material to flash chromatography (silica, 3 : 7 ethyl
acetate/hexane elution) and concentration of the appropriate fractions
(Rf 0.4) gave compound 23 (792 mg, 79%) as a colourless, crystalline
•
(194 mg, 74%) as a pale-yellow oil, [α]D −23◦ (c 3.2), (Found: M+
•
284.1772. C19H24O2 requires M+ 284.1776). νmax/cm−1 3508, 2936,
1642, 1455, 1402, 1348, 1135, 1094, 1074, 697. δH (300 MHz) 7.32
(5 H, m), 5.83 (1 H, dd, J 17 and 10), 5.36 (1 H, dd, J 17 and 2), 5.03
(1 H, dd, J 10 and 2), 4.80 (2 H, br s), 4.59 (2 H, s), 3.55 (1 H, s), 3.30
(1 H, br s), 2.44 (1 H, ddd, J 17, 6 and 1), 2.26 (1 H, br d, J 17), 1.99
(1 H, m), 1.95 (2 H, m), 1.39 (1 H, ddd, J 10, 8 and 3), 1.16 (1 H, m), 0.88
(3 H, s). δC (75 MHz) 150.6 (C), 142.9 (CH), 137.8 (C), 128.4 (CH),
127.8 (2 × CH), 127.7 (2 × CH), 112.2 (CH2), 107.6 (CH2), 81.2 (CH),
73.8 (C), 72.6 (CH2), 42.0 (C), 33.5 (CH2), 30.5 (CH), 28.1 (CH2), 19.3
(CH2), 17.6 (CH3). m/z 284 (M+•, 0.4%), 229 (4), 176 (85), 107 (96),
91 (100), 77 (23).
•
solid, mp 118.5–119.5◦C, [α]D +18◦ (c 1.3), (Found: M+ 360.1563,
(1S,2S)-8-Methyl-2-(phenylmethoxy)bicyclo[5.3.1]undec-
7(8)-en-3-one 21
•
C 66.6, H 6.8. C20H24O6 requires M+ 360.1573, C 66.7, H 6.7%).
νmax/cm−1 3425, 2932, 1734, 1615, 1381, 1257, 1210, 1170, 1071,
1033, 998. δH (300 MHz) 7.30 (2 H, d, J 9), 6.87 (2 H, d, J 9), 5.60
(1 H, s—shows 23%, 3% and 7% nOe to signals at δ 7.30, 4.72 and 4.44,
respectively), 4.72 (1 H, ddd, J 8, 3 and 1), 4.50 (1 H, dd, J 8 and 4),
4.44 (1 H, d, J 8), 3.97 (1 H, d, J 8), 3.78 (3 H, s), 2.91 (1 H, m), 2.75
(1 H, dd, J 19 and 4), 1.95 (1 H, br d, J 19), 1.52 (3 H, s), 1.36 (3 H, s),
1.34 (3 H, s). δC (75 MHz) 209.7 (C), 160.7 (C), 128.3 (2 × CH), 127.5
(CH), 113.9 (2 × CH), 110.4 (C), 102.2 (CH), 77.4 (CH), 76.5 (CH),
75.1 (CH), 71.6 (CH), 55.3 (CH3), 52.9 (C), 35.5 (CH), 34.8 (CH2),
25.4 (CH3), 23.3 (CH3), 13.8 (CH3). m/z 360 (M+•, 54%), 359 ([M –
A solution of compound 19 (22 mg, 0.0775 mmol) in THF (1 mL) main-
tained at −78◦C (dry ice/acetone bath) under a nitrogen atmosphere
was treated with potassium hexamethyldisilazane (0.5 mL of a 0.5 M
solution in toluene, 0.250 mmol, 3 mole equiv.). After stirring at −78◦C
for 0.26 h, the reaction mixture was warmed to 18◦C then treated with
NH4Cl (10 mL of a saturated aqueous solution). The resulting suspen-
sion was treated with water (5 mL) and the separated aqueous layer
extracted with dichloromethane (2 × 20 mL). The combined organic
phases were dried (MgSO4), filtered, and concentrated under reduced
pressuretoaffordapale-yellowoil(20 mg). Subjectionofthismaterialto
flash chromatography (silica, 1 : 9 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf 0.4) afforded compound
21 (16 mg, 73%) as a clear, colourless oil, [α]D –33◦ (c 1.7), (Found:
•
H•]+, 78), 345 ([M – CH3 ]+, 4), 329 ([M – CH3O•]+, 15), 149 (28),
135 (100), 108 (67).
(3aR,4S,4aR,6S,7aS,8R,8aS)-Hexahydro-6-(4-methoxyphenyl)-
2,2,4-trimethyl-10-methylene-4,8-ethanobenzo[1,2-d:4,5-dꢀ]-
bis[1,3]dioxole 24
•
•
M+ 284.1769. C19H24O2 requires M+ 284.1776). νmax/cm−1 2937,
2871, 1713, 1452, 1257, 1113, 1062, 1027, 786, 761. δH (300 MHz)
7.31 (5 H, m), 4.53 (1 H, d, J 12), 4.25 (1 H, d, J 12), 4.16 (1 H, d,
J 5), 2.71 (1 H, br m), 2.47 (1 H, m), 2.31 (1 H, m), 2.20–1.76 (9 H,
complex m), 1.60 (1 H, m), 1.54 (3 H, s). δC (75 MHz) 211.2 (C), 138.0
A
magnetically stirred suspension of sodium hydride (1.30 g,
54.3 mmol) in DMSO (30 mL), maintained under a nitrogen atmosphere

Taxane Diterpene Synthesis Studies—Part 1
49
was heated at 78◦C for 1 h. The resultant green solution was
then chilled to 0◦C and treated with a warm solution of methyl-
triphenylphosphonium iodide (21.9 g, 54.3 mmol) in DMSO (85 mL).
The ensuing caramel-coloured mixture was stirred at 18◦C for 0.25 h
then treated with ketone 23 (9.78 g, 27.2 mmol).After stirring the result-
ing mixture at 65◦C for 16 h,TLC analysis (1 : 4 v/v ethyl acetate/hexane
elution) indicated that starting material (Rf 0.2) remained. Conse-
quently, another portion of triphenylphosphonium methylide (2 mole
equiv.) was prepared (as described above) and added (via cannula) to the
hot reaction mixture which was stirred at 78◦C for 3 h. The cooled reac-
tion mixture was then poured (CAUTION!) into pentane/water (200 mL
of a 1 : 1 v/v mixture) and the separated aqueous layer was extracted
with pentane (4 × 100 mL). The combined organic phases were washed
with NaHCO3 (1 × 200 mL of a saturated aqueous solution) and brine
(1 × 200 mL) before being dried (MgSO4), filtered, and concentrated
under reduced pressure to afford a viscous, golden oil (19.1 g). Sub-
jection of this material to flash chromatography (silica, 1 : 4 v/v ethyl
acetate/hexane elution) and concentration of the appropriate fractions
(Rf 0.4) provided compound 24 (8.78 g, 90%) as a clear, colourless
16 h then concentrated under reduced pressure to an orange oil. Sub-
jection of this material to flash chromatography (silica, 1 : 4 v/v ethyl
acetate/hexane elution) afforded two fractions, A and B.
Concentration of the fractions containing the less mobile
component [Rf 0.1(8)] gave a colourless solid. Recrystallization
(ether) of this material afforded (3aR,4R,5R,6S,7R,7aS)-hexahydro-
6-acetoxy-2,2, 4-trimethyl-9-methylene-4,7-ethano-1,3-benzodioxol-5-
yl-4-methoxybenzoate, the acetate derivative of compound 25, (280 mg,
37%) as colourless needles, mp 107–108◦C, [α]D +28◦ (c 2.9), (Found:
•
•
M+ 416.1835, C 66.1, H 6.9. C23H28O7 requires M+ 416.1835,
C 66.3, H 6.8%). νmax/cm−1 2984, 1732, 1709, 1604, 1284, 1257, 1243,
1209, 1169, 1064. δH (300 MHz) 7.94 (2 H, d, J 9), 6.90 (2 H, d, J 9),
5.49 (1 H, dt, J 8 and 2), 5.41 (1 H, d, J 8), 5.10 (1 H, br s), 5.03 (1 H,
br s), 4.23 (1 H, dd, J 8 and 4), 3.86 (1 H, d, J 8), 3.84 (3 H, s), 2.81
(1 H, ddd, J 17, 5 and 3), 2.31 (1 H, m), 2.19 (1 H, dt, J 17 and 2),
1.76 (3 H, s), 1.59 (3 H, s), 1.33 (3 H, s), 1.21 (3 H, s). δC (75 MHz)
169.7 (C), 165.4 (C), 163.3 (C), 144.1 (C), 131.6 (2 × CH), 122.3 (C),
113.6 (2 × CH), 111.2 (C/CH2), 109.2 (C/CH2), 79.4 (CH), 75.1 (CH),
69.4 (CH), 65.1 (CH), 55.4 (CH3), 43.9 (C), 35.8 (CH), 26.1 (CH2),
25.8 (CH3), 23.8 (CH3), 20.6 (CH3), 17.1 (CH3). m/z 416 (M+•, 1%),
•
oil, [α]D +84◦ (c 1.4), (Found: M+• 358.1776. C21H26O5 requires M+
•
358.1780). νmax/cm−1 2936, 1616, 1519, 1398, 1383, 1250, 1209, 1171,
1072, 1037. δH (300 MHz) 7.42 (2 H, d, J 8), 6.88 (2 H, d, J 8), 5.60
(1 H, s), 5.07 (1 H, br s), 5.03 (1 H, br s), 4.51 (1 H, ddd, J 8, 4 and 1),
4.36 (1 H, dd, J 8 and 4), 4.24 (1 H, d, J 8), 3.87 (1 H, d, J 8), 3.80 (3 H,
s), 2.83 (1 H, ddd, J 18, 5 and 2), 2.60 (1 H, m), 2.04 (1 H, br d, J 18),
1.49 (3 H, s), 1.35 (3 H, s), 1.33 (3 H, s). δC (75 MHz) 160.6 (C), 144.1
(C), 128.9 (C), 128.8 (2 × CH), 113.7 (2 × CH), 111.6 (C/CH2), 108.5
(C/CH2), 102.2 (CH), 78.6 (CH), 76.8 (CH), 75.7 (CH), 72.1 (CH), 55.2
(CH3), 43.5 (C), 34.4 (CH), 25.8 (CH2), 25.5 (CH3), 23.4 (CH3), 17.1
(CH3). m/z 358 (M+•, 22%), 300 (20), 148 (59), 135 (100), 119 (35),
107 (42), 100 (41).
401 ([M – CH3 ]+, 6), 358 (7), 257 (11), 147 (25), 135 (100), 92 (6),
77 (11).
Concentration of fraction
B (Rf 0.2) gave a colourless
solid. Recrystallization (ethyl acetate/hexane) of this material
afforded (3aS,4S,5S,6R,7S,7aR)-hexahydro-6-acetoxy-2,2,7- trimethyl-
8-methylene-4,7-ethano-1,3-benzodioxol-5-yl 4-methoxybenzoate, the
acetate derivative of compound 26, (350 mg, 49%) as long, colourless
•
prisms, mp 117–118◦C, [α]D +64◦ (c•2.4), (Found: M+ 416.1839,
C 66.2, H 6.6. C23H28O7 requires M+ 416.1835, C 66.3, H 6.8%).
νmax/cm−1 1739, 1709, 1605, 1377, 1278, 1259, 1240, 1126, 1064,
1048. δH (300 MHz) 7.96 (2 H, d, J 9), 6.90 (2 H, d, J 9), 5.60 (1 H,
ddd, J 8, 3 and 2), 5.37 (1 H, d, J 8), 5.08 (1 H, br s), 5.00 (1 H, br s),
4.26 (1 H, dd, J 8 and 4), 3.86 (1 H, d, J 8), 3.85 (3 H, s), 2.85 (1 H, ddd,
J 17, 5 and 3), 2.45 (1 H, m), 2.19 (1 H, br d, J 17), 1.84 (3 H, s), 1.60
(3 H, s), 1.34 (3 H, s), 1.16 (3 H, s). δC (75 MHz) 170.2 (C), 164.9 (C),
163.3 (C), 143.8 (C), 131.5 (2 × CH), 122.5 (C), 113.6 (2 × CH), 111.4
(C/CH2), 109.3 (C/CH2), 79.5 (CH), 75.0 (CH), 69.0 (CH), 65.3 (CH),
55.4 (CH3), 43.6 (C), 35.8 (CH), 26.3 (CH2), 25.8 (CH3), 23.9•(CH3),
20.6 (CH3), 16.8 (CH3). m/z 416 (M+•, 3%), 401 ([M – CH3 ]+, 5),
264 (6), 135 (100).
(3aR,4R,5R,6S,7R,7aS)-Hexahydro-6-hydroxy-2,2,4-trimethyl-
9-methylene-4,7-ethano-1,3-benzodioxol-5-yl 4-Methoxybenzoate 25
and (3aS,4S,5S,6R,7S,7aR)-Hexahydro-6-hydroxy-2,2,7-trimethyl-
8-methylene-4,7-ethano-1,3-benzodioxol-5-yl 4-Methoxybenzoate 26
A magnetically stirred solution of compound 24 (8.23 g, 23.0 mmol)
in dichloromethane/water (90 mL of a 17 : 1 v/v mixture) was treated
with DDQ (7.83 g, 34.5 mmol, 1.5 mole equiv.). After 5 h at 18◦C
the reaction mixture was poured into NaHCO3 (100 mL of a 5% w/v
aqueous solution) and the separated aqueous layer was extracted with
dichloromethane (3 × 300 mL).The combined organic phases were then
washed with NaHCO3 (2 × 100 mL of a 5% w/v aqueous solution)
before being dried (MgSO4), filtered, and concentrated under reduced
pressure to afford an orange oil (12.5 g). Subjection of this material to
flash chromatography (silica, 3 : 7 ethyl acetate/hexane elution) afforded
two fractions, A and B.
(3aR,4R,5R,7S,7aS)-Hexahydro-2,2,4- trimethyl-9-methylene-
6-oxo-4,7-ethano-1,3-benzodioxol-5-yl 4-Methoxybenzoate 27
and (3aS,4S,5S,7R,7aR)-Hexahydro-2,2,7-trimethyl-8-methylene-
6-oxo-4,7-ethano-1,3-benzodioxol-5-yl 4-Methoxybenzoate 28
Method A
Trifluoroacetic anhydride (3.5 mL, 24.7 mmol) was added dropwise
to a magnetically stirred solution of DMSO (2.3 mL, 32.4 mmol) in
dichloromethane (50 mL) maintained at −60◦C (dry ice/chloroform
bath) under a nitrogen atmosphere. The ensuing mixture was stirred
for 10 min at −60◦C then treated, dropwise, with a solution of a ca. 1 : 1
mixture of alcohols 25 and 26 (3.06 g, 8.18 mmol) in dichloromethane
(20 mL). After stirring for 4 h at −60◦C, the reaction mixture was
quenched with triethylamine (1 mL) then slowly warmed to 18◦C.
The resulting orange solution was poured into HCl (100 mL of a 2 M
aqueous solution), and the separated aqueous layer was extracted with
dichloromethane (3 × 100 mL). The combined organic phases were
washed with water (1 × 100 mL), then dried (MgSO4), filtered, and con-
centrated under reduced pressure to give an orange oil. Subjection of this
material to flash chromatography (silica, 1 : 4 v/v ethyl acetate/hexane
elution) afforded two fractions, A and B.
Concentration of fraction A (Rf 0.3) afforded compound 25
(3.43 g, 40%) as a clear, colourless oil. 1H NMR analysis of this
material indicated that it was contaminated with ca. 1% of the
regioisomer 26.
Concentration of fraction B (Rf 0.5) afforded compound 26
(3.47 g, 40%) as a clear, colourless oil. 1H NMR analysis of this
material indicated that it was contaminated with ca. 0.5% of the
regioisomer 25.
Compounds 25 and 26 interconvert on standing. Consequently,
no attempt was made to characterize them in a comprehensive man-
ner. Rather, the crude mixture of these compounds was acetylated
(see below) and the derived acetates separated and characterized
spectroscopically.
(3aR,4R,5R,6S,7R,7aS)-Hexahydro-6-acetoxy-2,2,4-trimethyl-
9-methylene-4,7-ethano-1,3-benzodioxol-5-yl 4-Methoxybenzoate
and (3aS,4S,5S,6R,7S,7aR)-Hexahydro-6-acetoxy-2,2,7-trimethyl-
8-methylene-4,7-ethano-1,3-benzodioxol-5-yl 4-Methoxybenzoate
Concentration of fractionA (Rf 0.4) gave a colourless solid. Recrys-
tallization (ethyl acetate–hexane) of this material afforded compound
27 (1.40 g, 46%) as colourless plates, mp 154–156◦C, [α]D –38◦ (c
•
•
0.50), (Found: M+ 372.1567, C 67.5, H 6.5. C21H24O6 requires M+
A magnetically stirred and 1 : 1 mixture of compounds 25 and 26
(685 mg, 1.83 mmol) in pyridine (5 mL) was treated with acetic anhy-
dride (1.7 mL, 18.3 mmol) and the resulting solution kept at 18◦C for
372.1573, C 67.7, H 6.5%). νmax/cm−1 1747, 1718, 1606, 1512, 1256,
1210, 1168, 1098, 1045, 767. δH (300 MHz) 7.95 (2 H, d, J 9), 6.89
(2 H, d, J 9), 5.68 (1 H, s), 5.18 (2 H, m), 4.51 (1 H, dd, J 8 and 4), 4.09

50
M. G. Banwell, P. Darmos and D. C. R. Hockless
•
•
(1 H, d, J 8), 3.84 (3 H, s), 3.01 (1 H, dd, J 7 and 4), 2.73 (1 H, m),
2.60 (1 H, m), 1.55 (3 H, s), 1.37 (3 H, s), 1.21 (3 H, s). δC (75 MHz)
206.8 (C), 165.3 (C), 163.5 (C), 141.2 (C), 131.9 (2 × CH), 121.7 (C),
113.6 (2 × CH), 113.1 (C/CH2), 109.6 (C/CH2), 78.7 (CH), 74.9 (CH),
73.0 (CH), 55.4 (CH3), 47.8 (CH), 47.1 (C), 29.4 (CH2), 25.6•(CH3),
23.8 (CH3), 15.1 (CH3). m/z 372 (M+•, 7%), 357 ([M – CH3 ]+, 2),
221 (29), 163 (37), 135 (100), 107 (11), 77 (15).
(Found: M+ 238.1203, C 65.7, H 7.9. C13H18O4 requires M+
238.1205, C 65.5, H 7.6%). νmax/cm−1 3461, 1738, 1379, 1267, 1210,
1164, 1142, 1063, 1032, 890. δH (300 MHz) 5.02 (2 H, dt, J 7 and 2),
4.35 (1 H, dd J 8 and 4), 4.22 (1 H, dd, J 4 and 2), 4.00 (1 H, dd,
J 8 and 1), 3.01 (1 H, br s), 2.74 (1 H, ddd, J 18, 5 and 3), 2.56 (1 H,
m), 2.22 (1 H, ddd, J 18 and 3 and 2), 1.38 (3 H, s), 1.29 (3 H, s),
1.27 (3 H, s). δC (75 MHz) 211.7 (C), 142.0 (C), 112.5 (C/CH2), 109.2
(C/CH2), 79.2 (CH), 74.9 (CH), 69.8 (CH), 55.8 (C), 37.8 (CH), 25.8
(CH2), 25.4 (CH3), 23.7 (CH3), 12.8 (CH3). m/z 238 (M+•, 56%), 223
Concentration of the fraction B (Rf 0.5) gave a colourless oil which
solidified on standing. Recrystallization (ethyl acetate–hexane) of this
material afforded compound 28 (1.40 g, 46%)aslong, colourless prisms,
•
([M – CH3 ]+, 85), 181 (50), 180 ([M – (CH3)2CO]+•, 58), 163 (80),
152 (83), 151 (98), 134 (80), 123 (100), 107 (43).
•
mp 156–157◦C, [α]D –37◦ (•c 2.4), (Found: M+ 372.1570, C 67.5, H
6.7. C21H24O6 requires M+ 372.1573, C 67.7, H 6.5%). νmax/cm−1
1744, 1725, 1604, 1283, 1255, 1209, 1170, 1115, 1093, 1059. δH
(300 MHz) 7.98 (2 H, d, J 9), 6.90 (2 H, d, J 9), 5.75 (1 H, t, J 2),
5.13 (2 H, m), 4.44 (1 H, dd, J 8 and 4), 4.09 (1 H, d, J 8), 3.85 (3
H, s), 2.82 (1 H, ddd, J 18, 5 and 2), 2.72 (1 H, m), 2.38 (1 H, dt,
J 18 and 2), 1.53 (3 H, s), 1.35 (3 H, s), 1.34 (3 H, s). δC (75 MHz)
205.2 (C), 165.0 (C), 163.5 (C), 141.3 (C), 131.9 (2 × CH), 121.9 (C),
113.6 (2 × CH), 113.1 (C/CH2), 109.6 (C/CH2), 79.9 (CH), 74.9 (CH),
70.5 (CH), 56.5 (C), 55.4 (CH3), 37.0 (CH), 26.5 (CH2), 25.6 •(CH3),
23.9 (CH3), 13.1 (CH3). m/z 372 (M+•, 0.6%), 357 ([M – CH3 ]+, 3),
314 ([M – (CH3)2CO]+•, 3), 162 (46), 135 (100).
Concentration of fraction B (Rf 0.3) afforded diene 30 (170 mg,
34%)asacolourless, crystallinesolid, mp138–139◦C, [α]D –49◦ (c 2.4),
•
•
(Found: M+ 266.1517, C 67.9, H 8.2. C15H22O4 requires M+
266.1518, C 67.7, H 8.3%). νmax/cm–1 3516, 3402, 2945, 1645, 1385,
1280, 1210, 1073, 1051, 1033, 889. δH (300 MHz) 6.27 (1 H, dd, J 17
and 11), 5.33 (1 H, dd, J 17 and 2), 5.12 (1 H, dd, J 11 and 2), 5.04 (2 H,
m), 4.15 (1 H, dd, J 8 and 3), 4.02 (1 H, br m), 3.80 (1 H, d, J 8), 2.88 (1
H, br d, J 6), 2.73 (1 H, ddd, J 17. 5 and 3), 2.55 (1 H, s), 2.16–2.07 (2
H, complex m), 1.53 (3 H, s), 1.30 (3 H, s), 1.14 (3 H, s). δC (75 MHz)
146.5 (C), 142.8 (CH), 113.1 (C/CH2), 111.4 (C/CH2), 108.9 (C/CH2),
80.0 (CH), 75.7 (CH), 74.3 (C), 67.4 (CH), 47.5 (C), 38.2 (CH), 25.8
(CH2), 25.5 (CH3), 23.4 (CH3), 15.8 (CH3). m/z 266 (M+•, 6%), 251
•
([M – CH3 ]+, 33), 208 ([M – (CH3)2CO]+•, 44), 190 (45), 161 (33),
135 (81), 123 (99), 122 (90), 107 (100), 91 (52), 79 (41).
Method B
Concentration of fraction C (Rf 0.2) gave a clear, colourless oil
which solidified upon refrigeration. Recrystallization (pentane) of this
Solid tetrapropylammonium perruthenate (7.5 mg, 0.0213 mmol) was
added in one portion to a magnetically stirred mixture of compounds 27
and 28 (402 mg, 1.07 mmol), N-methylmorpholine-N-oxide (879 mg,
7.50 mmol, 7 mole equiv.) and powdered 4 Å molecular sieves (537 mg)
in acetonitrile (5 mL) maintained under a nitrogen atmosphere. The
resultingmixturewasstirredat18◦Cfor16 hthenfilteredthrougha7 cm
deep pad of TLC-grade silica gel. The retained solids were washed with
dichloromethane (80 mL) and the combined filtrates concentrated under
reduced pressure to give a colourless solid. Subjection of this material to
flash chromatography (silica, 1 : 4 ethyl acetate/petrol elution) provided
two fractions, A and B.
Concentration of fractionA (Rf 0.4) afforded compound 27 (152 mg,
38%) as a colourless solid which was identical, in all respects, with the
material obtained as described above.
Concentration of fraction B (Rf 0.5) afforded compound 28 (152 mg,
38%) as a colourless solid which was identical, in all respects, with the
material obtained as described above.
material afforded diene 31 (56 mg, 11%) as col•ourless cubes, mp 72–
+
73◦C, [α]D −25◦ (c 0.95), (Found: [M – CH3
]
251.1287, C 67.5,
•
+
H 8.6. C15H22O4 requires [M – CH3
]
251.1283, C 67.7, H 8.3%).
νmax/cm−1 3490, 2987, 1643, 1423, 1377, 1331, 1260, 1210, 1167,
1064, 1021. δH (300 MHz) 5.62 (1 H, dd, J 17 and 10), 5.49 (1 H, dd, J
17 and 3), 5.27 (1 H, dd, J 9 and 3), 4.99 (2 H, br d, J 9), 4.48 (1 H, br
s), 4.24 (1 H, t, J 2), 4.21 (1 H, d, J 3), 3.86 (1 H, d, J 8), 2.70 (1 H, ddd,
J 17, 8 and 2), 2.24 (1 H, m), 2.09 (1 H, ddd, J 17, 3 and 2), 1.80 (1 H,
br s), 1.57 (3 H, s), 1.32 (3 H, s), 1.17 (3 H, s). δC (75 MHz) 145.8 (C),
136.7 (CH), 116.5 (CH2), 111.6 (C/CH2), 109.1 (C/CH2), 80.9 (CH),
79.2 (C), 75.9 (CH), 75.6 (CH), 46.5 (C), 37.3 (CH), 25.6 (CH3), 25.5
•
(CH2), 23.1 (CH3), 14.4 (CH3). m/z 251 ([M – CH3 ]+, 12%), 208
([M – (CH3)2CO]+•, 30), 190 (30), 161 (30), 135 (78), 123 (90), 122
(86), 107 (100), 91 (71).
(3aR,4R,6S,7S,7aR)-Tetrahydro-6-hydroxy-2,2,4-trimethyl-
9-methylene-4,7-ethano-1,3-benzodioxol-5(4H)-one 29
(3aR,4R,6S,7R,7aS)-Tetrahydro-6-hydroxy-2,2,4-
trimethyl-9-methylene-4,7-ethano-1,3-benzodioxol-5(4H)-one 29,
(3aR,4R,5R,6S,7R,7aS)-5-Ethenylhexahydro-2,2,4-
trimethyl-9-methylene-4,7-ethano-1,3-benzodioxole-5,6-diol 30,
and (3aR,4R,5S,6S,7S,7aS)-5-Ethenylhexahydro-2,2,4-
trimethyl-9-methylene-4,7-ethano-1,3-benzodioxole-5,6-diol 31
A magnetically stirred solution of compound 28 (320 mg, 0.860 mmol)
in methanol (50 mL) maintained at 18◦C under a nitrogen atmosphere
was treated with powdered potassium hydroxide (150 mg, 2.68 mmol).
The reaction mixture was stirred at 18◦C for 1 h then poured into water
(50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined
organic phases were dried (MgSO4), filtered, and concentrated under
reduced pressure to give a pale-yellow oil (336 mg). Subjection of this
material to flash chromatography (silica, 1 : 4 v/v ethyl acetate/hexane
elution) and concentration of the appropriate fractions (Rf 0.2) afforded
the title acyloin 29 (192 mg, 95%) as a colourless solid which was
identical, in all respects, with the material obtained as described
above.
Amagneticallystirredsolutionofketone28(703 mg, 1.89 mmol)inTHF
(7 mL) maintained at 0◦C under a nitrogen atmosphere was treated, in
one portion, with vinylmagnesium bromide (7.9 mL of a 1.2 M solu-
tion in THF, 9.48 mmol, 5 mole equiv.). The resulting mixture was
stirred at 0◦C for 0.5 h then warmed to 18◦C. After 16 h the reac-
tion mixture was re-cooled to 0◦C and treated with NH4Cl (30 mL of
a saturated aqueous solution) and water (50 mL) then extracted with
ethyl acetate (3 × 100 mL). The combined organic phases were dried
(MgSO4), filtered, andconcentratedunderreducedpressuretoanorange
oil (895 mg). This material was dissolved in methanol (15 mL) and the
resulting solution treated with potassium hydroxide (1.06 g), allowed to
stand at 18◦C for 16 h then poured into water (50 mL) and extracted
with ethyl acetate (3 × 100 mL). The combined organic phases were
dried (MgSO4), filtered, and concentrated under reduced pressure to an
orange oil (1.25 g). Subjection of this material to flash chromatography
(silica, 3 : 17 v/v ethyl acetate/dichloromethane elution) afforded three
fractions, A–C.
(3aR,4R,5R,6S,7R,7aS)-5-Ethenylhexahydro-2,2,4-trimethyl-
9-methylene-4,7-ethano-1,3-benzodioxole-5,6-diol 30
and (3aR,4R,5S,6S,7S,7aS)-5-Ethenylhexahydro-2,2,4-trimethyl-
9-methylene-4,7-ethano-1,3-benzodioxole-5,6-diol 31
A magnetically stirred solution of acyloin 29 (82 mg, 0.344 mmol) in
THF (5 mL) maintained at 0◦C under a nitrogen atmosphere was treated,
in one portion, with vinylmagnesium bromide (2.9 mL of a 1.2 M solu-
tion inTHF, 3.48 mmol, 10 mole equiv.) and the resulting mixture stirred
at 0◦C for 0.5 h then warmed to 18◦C. After 5 days the reaction mixture
was re-cooled to 0◦C and NH4Cl (5 mL of a saturated aqueous solu-
tion) then water (20 mL) were carefully added. The resulting mixture
was extracted with ethyl acetate (3 × 20 mL) and the combined organic
Concentration of fraction A (Rf 0.4) afforded acyloin 29 (56 mg,
11%) as a colourless, crystalline solid, mp 52–53◦C, [α]D –30◦ (c 2.4),

Taxane Diterpene Synthesis Studies—Part 1
51
phases were dried (MgSO4), filtered, and concentrated under reduced
pressure to give an orange oil (90 mg). Subjection of this material to
flash chromatography (silica, 3 : 17 v/v ethyl acetate/dichloromethane
elution) afforded two fractions, A and B.
Concentration of fraction A (Rf 0.3) afforded diol 30 (5 mg, 5%)
which was identical, in all respects, with the material obtained as
described above.
Concentration of fraction B (Rf 0.2) afforded compound 31 (46 mg,
50%) which was identical, in all respects, with the material obtained as
described above.
unique data (2θmax 120.0◦), 1079 with I > 3σ(I); R 0.023, wR 0.023,
GoF 2.76.
Crystal data for compound 18: C12H18O2, M 194.27, T 296(1) K,
orthorhombic, space group P212121,
a 6.689(3), b 12.000(2),
c 13.904(2) Å, V 1116.1(5) Å3, Dc (Z 4) 1.156 g cm−3, F(000) 424,
µ(CuKα) 5.76 cm−1, semi-empirical absorption correction; 1013
unique data (2θmax 120.1◦), 395 with I > 3σ(I); R 0.039, wR 0.046,
GoF 1.47.
Crystal data for compound 30: C15H22O4, M 266.34, T 296(1) K,
tetragonal, space group P43212,
a 11.058(2), c 23.818(3) Å,
V 2912(1) Å3, Dc (Z 8) 1.215 g cm−3, F(000) 1152, µ(MoKα
)
0.87 cm−1, semi-empirical absorption correction; 2032 unique data
(2θmax 55.0◦), 1268 with I > 3σ(I); R 0.043, wR 0.040, GoF 2.65.
Intensity data were collected on a Rigaku AFC6R diffractometer
using the ω–2θ scan technique to a maximum 2θ value of 120◦ (for
30: 55◦).
Three representative reflections were measured after every 150
reflections which revealed that no decay correction was required for
8 and 30, however a correction was required for the crystal of 18
which decayed rapidly. An empirical absorption correction based on
azimuthal scans was applied and the data were corrected for Lorentz
and polarization effects.
(3aR,4R,5R,6S,7S,7aS)-5-Ethenylhexahydro-2,2,4-trimethyl-
9-methylene-6-(phenylmethoxy)-4,7-ethano-1,3-benzodioxol-5-ol 32
A magnetically stirred and ice-cooled solution of compound 31 (100 mg,
0.376 mmol) in benzyl bromide (0.4 mL of a 1.0 M solution in DMF,
0.400 mmol) maintained under a nitrogen atmosphere was treated with
sodium hydride (29 mg, 1.21 mmol, 3.2 mole equiv.). After 5 h at 0◦C
the reaction mixture was quenched with water (20 mL) (CAUTION)
then extracted with ethyl acetate (3 × 50 mL). The combined organic
phases were dried (MgSO4), filtered, and concentrated under reduced
pressure to give a pale-yellow oil (57 mg). Subjection of this material to
flash chromatography (silica, 1 : 19 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf 0.1) provided compound
32 (72 mg, 53%) as a clear, colourless oil, [α]D –35◦ (c 1.9), (Found:
The structures were solved by direct methods[18] and expanded using
Fourier techniques. The non-hydrogen atoms were refined anisotrop-
ically. Hydrogen atoms were included at geometrically determined
positions which were periodically recalculated but were not refined.
The rapid decay of 18 compromised the number of observed reflec-
tions. Although the identity of the molecule has been unambiguously
determined, the data to parameter ratio is low which results in the
bond distances and angles having poor precision. All calculations were
performed using the teXsan[19] crystallographic software package.
Atomic coordinates, bond lengths, and angles, together with
displacement parameters have been deposited with the Cambridge
Crystallographic Data Centre (deposition nos: 8 210946, 18 210947,
30 101611).
•
•
+
+
341.1753).
[M – CH3
]
341.1748. C22H28O4 requires [M – CH3
]
νmax/cm−1 3494, 3019, 2989, 1643, 1456, 1375, 1213, 1069, 1026, 756.
δH (300 MHz) 7.35–7.20 (5 H, complex m), 6.22 (1 H, dd, J 17 and 11),
5.41 (1 H, dd, J 17 and 2), 5.09 (1 H, dd, J 11 and 2), 4.95 (2 H, m),
4.75 (1 H, d, J 16), 4.48 (1 H, d, J 16), 4.45 (1 H, s), 4.14 (1 H, dd, J8
and 3), 3.84 (1 H, br s), 3.76 (1 H, d, J 8), 2.81 (1 H, ddd, J 17, 6 and 1),
2.25 (1 H, br m), 2.06 (1 H, br d, J 17), 1.46 (3 H, s), 1.29 (3 H, s), 1.13
(3 H, s). δC (75 MHz) 145.9, 138.7, 137.4, 128.1, 127.7, 127.3, 114.5,
111.3, 109.0, 82.6, 80.9, 7•9.0, 75.8, 72.2, 46.9, 36.9, 26.1, 25.6, 23.3,
13.9. m/z 341 ([M – CH3 ]+, 5%), 298 ([M – (CH3)2CO]+•, 4), 192
(22), 189 (22), 135 (38), 107 (40), 105 (40), 91 (C7H+7 , 100).
Acknowledgments
(3aS,4S,5S,11aR)-4,5,7,8,9,11a-Hexahydro-2,2,11-trimethyl-
5-(phenylmethoxy)-4,10-methanocyclodeca-1,3-dioxol-6(3aH)one 34
Financial support from the Institute of Advanced Studies
(ANU) and the Department of Industry, Science andTourism
(in the form of a Bilateral Science and Technology Program
Grant) is gratefully acknowledged. We thank Dr Gregg
Whited (Genencor International Inc., PaloAlto) for providing
generous quantities of compound 2.
A magnetically stirred solution of compound 32 (17 mg, 0.0478 mmol)
and [18]crown-6 (39 mg, 0.148 mmol) in THF (1 mL) maintained under
nitrogen atmosphere at 0◦C was treated, in one portion, with potassium
hydride (10 mg, 0.250 mmol). The resulting mixture was stirred at 0◦C
for 1 h then warmed to 18◦C over a period of 0.5 h.After this time NH4Cl
(10 mL of a saturated aqueous solution) was slowly added to the reaction
mixture which was then diluted with water (5 mL) and extracted with
dichloromethane (3 × 20 mL). The combined organic phases were dried
(MgSO4), filtered, and concentrated under reduced pressure to give a
pale-yellow oil (26 mg). Subjection of this material to flash chromato-
graphy (silica, 1 : 19 v/v ethyl acetate/hexane elution) and concentration
of the appropriate fractions (Rf 0.2) afforded compound 34 (8 mg, 47%)
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