Taxane diterpene synthesis studies. Part 2: Towards taxinine - enantiospecific construction of an AB-ring substructure incorporating both quaternary carbon centres and attempts to annulate the C-ring

Article abstract of DOI:10.1071/CH03161

In connection with efforts to develop an efficient total synthesis of the biologically active natural product taxinine 1, the enzymatically-derived and monochiral cis-1,2-dihydrocatechol 7 was converted, over several steps including a Diels-Alder cycloadd

Full text of DOI:10.1071/CH03161

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 53–66
Taxane Diterpene Synthesis Studies. Part 2: Towards
Taxinine—Enantiospecific Construction of an AB-ring Substructure
Incorporating both Quaternary Carbon Centres and Attempts to
Annulate the C-ring*
Martin G. Banwell,A,B Malcolm D. McLeod,A and Andrew G. RichesA
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).
In connection with efforts to develop an efficient total synthesis of the biologically active natural product taxinine 1,
the enzymatically-derived and monochiral cis-1,2-dihydrocatechol 7 was converted, over several steps including a
Diels–Alder cycloaddition reaction, into the bicyclo[2.2.2]octan-2-one 18. Reaction of the last compound with the
organocerium reagent 22 afforded the 1,5-diene 23 which engaged in an anionic oxy-Cope rearrangement reaction
to give, after C-methylation of the product enolate 25, bicyclo[5.3.1]undecenone 27 embodying theAB-ring system
of target 1. Two methods for allylic oxidation of such products were developed and several unsuccessful attempts
to effect a cyclization reaction so as to establish the taxane C-ring are described.
Manuscript received: 30 June 2003.
Final version: 28 August 2003.
O
AcO
AcO
Introduction
H
O
5
OAc
H
14
4
Ph
2
The crystalline taxane diterpene taxinine 1 (Diagram 1)
was first isolated by ethanol extraction of the needles of
the Japanese yew around 1925.[1] This compound has since
been identified in the needles, fruits, seeds, twigs, bark, and
heartwood of many Taxus species. Its structure was estab-
lished through a combination of NMR and chemical studies
over 30 years ago[2] and subsequently confirmed by X-ray
crystallographic methods.[3] As such taxinine was the first
natural taxoid to be obtained in pure form and structurally
characterized. Various studies have revealed that, unlike its
structurally more complex and well known congener Taxol,
compound 1 is a weakly cytotoxic agent.[4] Significantly,
however, taxinine has been shown, among others, to increase
the cellular accumulation of vincristine in multi-drug resis-
tant tumour cells and must, therefore, be regarded as having
therapeutic potential for resensitizing tumour cells to vari-
ous anti-cancer agents.[4,5] As a consequence taxinine has
attracted some attention as a synthetic target[6] although
no total synthesis has been reported to date. That having
been said, the preparation of closely related taxoids such as
taxusin have been described by several groups.[7] Herein we
detail an approach to the enantiomer of the natural product,
namely ent-1 (Diagram 1), that has culminated in the stereo-
controlled synthesis of AB-ring substructures incorporating
1
13
3
B
6
O
7
O
15
10
8
A
C
12
Ph
11
9
H
H
OAc
O
AcO
AcO
O
1
ent-1
Diagram 1.
the synthetically demanding C8 quaternary carbon centre[8]
as well as that at C15.
The retrosynthetic analysis of target ent-1 employed in the
present work is shown in Fig. 1 and exploits results detailed in
Part 1 of this series.[9] It requires, in the closing stages, annu-
lation of the taxane C-ring onto a bicyclo[5.3.1]undecenyl
framework 2 incorporating the pivotal quaternary carbon
centre C8 (taxane numbering). This centre was to be con-
structed by C-methylation of the enolate 3 which should,
in turn, be accessible via anionic oxy-Cope rearrangement
of the bicyclo[2.2.2]octane 4, itself likely to be available
through nucleophilic addition of an appropriately metallated
alkene 5 to ketone 6. Based on our earlier studies,[9,10] we
anticipated that the bicyclo[2.2.2]octan-2-one 6 would be
obtained by engaging cis-1,2-dihydrocatechol 7 in a Diels–
Alder cycloaddition reaction with an appropriate dienophile.
*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/CH03161
0004-9425/04/010053

54
M. G. Banwell, M. D. McLeod and A. G. Riches
The monochiral (>99.8% e.e.) diene 7 is readily generated
by enzymatic dihydroxylation of toluene[11] and has already
proven to be an important building block in the synthesis
of terpenoids.[12] Since the enantiomeric form of diene 7 is
also available[13] the successful implementation of the strat-
egy defined here would provide, in a formal sense, access to
substructures of the naturally occurring form, 1, of taxinine.
Additionally, we have described ‘enantiomeric switching’
regimes[9] which could well be employed here so as to pro-
vide access to precursors of taxinine 1 from diene 7. The
proposed use of the anionic oxy-Cope rearrangement 4 → 3
was inspired by the work of Martin et al.[14] who have high-
lighted the utility of this process in gaining access to the
AB-ring system of taxanes, albeit in racemic form.
both hydrogen. Once proof-of-concept was obtained then
appropriate variation of these substituents would be exam-
ined so as to enable introduction of the C9 and C10 acetate
groups associated with target ent-1.
The synthesis of an ‘operational’ version of the generic
structure 6, namely bicyclo[2.2.2]octan-2-one 18, is shown
in Scheme 1 and this starts with the conversion of diol 7 into
the corresponding p-methoxyphenyl (PMP) acetal 8 (53%)
under conventional conditions. The product of this reaction
was obtained as a single diastereomer and the stereoselective
nature of this conversion most likely arises from the opera-
tion of a kinetically controlled process.[15] Reaction of diene
8 with α-chloroacrylonitrile, a well-known ketene equivalent
used in Diels–Alder reactions,[16] provided a ca. 4 : 1 mixture
of cycloadducts 9 and 10 which was immediately subjected to
hydrolysis with potassium hydroxide in t-butanol, thus pro-
viding the ketone 11 as a white crystalline solid in 86%
yield. gem-Dimethylation of compound 11 was achieved
under standard conditions and the resulting product hydro-
genated to give the saturated equivalent 12 (88% over two
steps). Methylenation of this last ketone, as necessary for
installation of one of the two double bonds required for the
foreshadowed and pivotal anionic oxy-Cope rearrangement,
proved somewhat problematic because of the hindered nature
of the carbonyl group which is flanked by quaternary carbon
centres. After considerable experimentation, two means for
effecting this conversion were identified. The first involved
using Cristau’s diphenylphosphonium dimethyldiylide[17]
which is much more reactive than the more commonly used
‘parent’ triphenylphosphonium methylide and under appro-
priate conditions the target methylenated product 13 was
obtained in 99% yield. An alternate approach to this com-
pound simply involved using the aforementioned parent ylide
at 19 kbar. Under such conditions alkene 13 was obtained in
88% yield. The operational simplicity of the former pro-
cess meant this was favoured in supporting the preparative
work described from this point. Reductive ring-opening of
the PMP-acetal unit within compound 13 could be achieved
with diisobutylaluminium hydride (Dibal-H) to give a ca. 1 : 8
Results and Discussion
In our initial attempts to implement the synthetic plan implied
by Fig. 1 we elected, for the sake of simplicity, to target
intermediates 5 and 6 wherein substituents X and Y are
HO
OP'
OP'
H
H
O
O
OP"
PO
ent-1
8
Y
Y
X
X
2
3
Y
X
M
OP"
5
Y
X
ꢁ
OP"
OP'
HO
OH
OH
4
OP'
X ꢀ Y ꢀ OAc or equivalent
O
7
6
P, P', P" ꢀ OH protecting groups
Fig. 1.
X
X
Y
p-MBDMA
(ꢁ)-CSA (cat.)
NaHMDS
O
NC
Cl
MeI
PMP
7
1
O
then H2
Pt on C
∆
O
O
H
3
H
O
O
2
PMP
PMP
XꢀCl, YꢀCN
10 XꢀCN, YꢀCl
11 X,YꢀO
8
12 XꢀO
13 XꢀCH2
9
Ph2P
CH2Li
Dibal-H
KOH
ButOH
BnBr, NaH
Bu4NI
TPAP
NMO
ꢁ
OBn
O
OBn
OH
OPMB
RO
PMBO
HO
16 RꢀPMB
17 RꢀH
DDQ
18
15
14
Scheme 1.

Taxane Diterpene Synthesis Studies—Part 2
55
9-Br-9-BBN
then AcOH
compound 18
OTBDPS
OTBDPS
OTBDPS
X
OTBDPS
OBn
OTBDPS
HO
20 X ꢀ Br
21 X ꢀ Li
19
ButLi
23
base
(see text)
CeCl3
22 X ꢀ CeCl2
OBn
H
OBn
H
O
O
OTBDPS
OTBDPS
Hꢁ
3
4
H
OBn
O
26
25
24
MeI
MeI
OBn
H
O
OTBDPS
3
4
13
OBn
MeO
27
28
Scheme 2.
H
H
H
H
addition to the adjacent carbonyl moiety in substrate 18.
The assignment of stereochemistry follows from the success-
ful participation of this compound in the anionic oxy-Cope
rearrangement reaction (see below). Thus, on subjecting
compound 23 to reaction with KH so as to form oxyan-
ion 24 then warming the reaction mixture, so as to effect
conversion of this species into the isomeric anion 25, fol-
lowed by quenching with ammonium chloride, afforded
bicyclo[5.3.1]undecenone 26 (88%). This material was
obtained as a single diastereoisomer and, based upon pre-
vious observations,[21] it is assumed that the side-chain has
the α-configuration which arises through kinetically con-
trolled exo-or β-face protonation of the precursor enolate 25.
Unfortunately, all attempts to alkylate ketone 26 by depro-
tonation to regenerate enolate 25 followed by trapping the
latter with methyl iodide, so as to form the target dialkyl
ketone 27, failed. This outcome is attributed to an inabil-
ity to regenerate the enolate 25 from 26, a situation which
is ascribed to the unfavourable orbital overlap between the
α-hydrogen and the carbonyl group in the preferred confor-
mation (Fig. 2) of ketone 26.[22] This explanation is sup-
ported by the observation that quenching anion 25 (derived
by rearrangement of isomer 24) with methyl iodide does
indeed provide the desired dialkyl ketone 27 although only
as a 1 : 10 mixture with the chromatographically insepara-
ble protio-counterpart 26. Rigorous exclusion of moisture
failed to reduce the observed amount of the latter prod-
uct, leading to speculation that deprotonation of alcohol 23
by the added hydride is rather slow with the result that
this compound can protonate enolate 25 thus affording
undesired non-methylated material 26. To circumvent such
difficulties an ‘internal quenching’ experiment was carried
out wherein methyl iodide was present before the base was
added to deprotonate alcohol 23. Under such conditions (and
BnO
BnO
R
R
O
O
R = (CH2)4OTBDPS
Fig. 2.
mixture of the chromatographically separable diol mono-
ethers 14 (10%) and 15 (83%). The regioselectivity of this
reaction is attributed to the preferential co-ordination of the
reducing agent to that acetal oxygen remote from the bridge-
head methyl group in substrate 13. As a consequence the
O1–C2 bond is cleaved preferentially. Conversion of the free
hydroxy group within compound 15 into the corresponding
benzyl ether 16 (92%) followed by 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) mediated oxidative cleavage of the
p-methoxybenzyl (PMB) moiety within the latter provided
alcohol 17 (97%) which was oxidized to the ketone 18 in
98% yield using the Ley–Griffith reagent.[18]
The specific form, 22 (Scheme 2), of the generic
nucleophile 5 (Fig. 1) required for addition to the
bicyclo[2.2.2]octan-2-one 18 was prepared by adding 9-
bromo-9-borabicyclo[3.3.1]nonane (BBN)[19] to the known
terminal alkyne 19[20] and subjecting the resulting adduct to
successive treatment with acetic acid then alkaline hydro-
gen peroxide. In this manner the bromoalkene 20 was
obtained in 83% yield. Compound 20 could be lithiated using
t-butyllithium and the resulting alkenyllithium transmetalled
with anhydrous cerium trichloride to give compound 22
which was treated with ketone 18 at −78◦C. After warming
the reaction mixture to 18˚C and quenching with ammo-
nium chloride the anticipated 3◦-alcohol 23 was obtained
as a single diastereoisomer in 84% yield. The stereoselec-
tivity of this conversion is attributed to the steric demands
of the benzyloxy group which inhibits α-face nucleophilic

56
M. G. Banwell, M. D. McLeod and A. G. Riches
with KH as base) formation of compound 26 was completely
suppressed but the target ketone 27 (45%) was accompanied
by large quantities of the chromatographically separable O-
methyl ether 28 (20%) arising from reaction of the methyl
iodide with oxyanion 24. Various adjustments to the base and
solvent used in this conversion (Table 1) ultimately lead to
the identification of conditions (Entry 4, Table 1)[23] wherein
the desired compound 27 was the major product (84%).
Once again, the assignment of stereochemistry at C4 in
compound 27 follows from previous observations[21] that
reactions of enolate anions such as 25 with electrophiles
occurs selectively at the exo- or β-face, thus affording an
α-configured side-chain.
With significant quantities of compound 27 to hand efforts
could be directed towards achieving allylic oxidation of this
species so as to establish the C13 oxygen of taxinine.To these
ends (Scheme 3) alkene 27 was treated with the CrO3/3,5-
dimethylpyrazole (DMP) complex,[24] a species known for
its capacity to effect the desired conversion. Indeed, under
appropriate conditions the target enone 29 was obtained
albeit in low yield (17%) and accompanied by the rear-
ranged allylic alcohol 30 (11%). As a consequence, a more
circuitous but higher yielding method for forming com-
pound 29 was developed (Scheme 4). In keeping with the
behaviour of a related system,[21] compound 27 engaged in
an SnCl2-mediated transannular ‘cycloaddition’ of the C3
carbonyl group to the bridgehead alkene to give the oxe-
tane 31 in 93% yield.[25] However, in contrast to earlier
work involving a related system,[21] the latter could not be
converted into the isomeric (and required) homoallylic alco-
hol 32 on exposure to various Brønsted or Lewis acids.
Such difficulties could be circumvented by subjecting com-
pound 27 to a thermally induced carbonyl-ene reaction[26]
thus affording the tricyclic target 32 directly and in 96%
yield. Subjection of the latter to epoxidation with dimethyl
dioxirane (DMDO)[27] at 15◦C afforded the unstable oxi-
rane 33 which was not isolated but, rather, allowed to engage
in a very facile and thermally promoted Eschenmoser–Grob
fragmentation.[28] This afforded the target allylic alcohol 34
but it was accompanied by varying amounts of the ben-
zoate 35 and diol 36 depending on the reaction stoichiometry,
temperature and time (Table 2). Compound 35 presumably
arises through DMDO-promoted benzylic oxidation of the
benzyl ether moiety within 32, 33, and/or 34. Co-product
36 may be generated through hydrolysis of benzoate 35 or
Table 1. Product distributions arising from use of inter-
nal quench/alkylation regime during the anionic oxy-Cope
rearrangement of compound 23
Entry
Scale [mmol]
Base/Solvent
27
28
1
2
3
4
0.047
0.047
0.15
KH/THF
37%
57%
45%
84%
51%
17%
20%
trace
KH/DME
KH/DME
KOBut/Et2O
1.11
OBn
O
H
OTBDPS
3
4
13
O
29
CrO3 ⋅ DMP
27
ꢁ
OBn
O
H
OTBDPS
HO
30
Scheme 3.
H
OBn
SnCl2
OTBDPS
O
31
27
X
Hꢁ
H
H
OBn
OH
OR
∆
OH
OTBDPS
DMDO
O
OTBDPS
32
33
R = Bn, H, or Bz
∆
OBn
O
OBz
OH
H
H
H
O
O
OTBDPS
HO
OTBDPS
OTBDPS
TPAP
NMO
HO
HO
ꢁ
ꢁ
29
34
35
Scheme 4.
36

Taxane Diterpene Synthesis Studies—Part 2
57
a hemi-acetal derived from ether 34. Oxidation of allylic
alcohol 34 with the Ley–Griffith reagent afforded the corre-
sponding enone 29 in 97% yield and which proved identical,
in all respects, with the material obtained by the more direct
(but less efficient) route described immediately above.
The efficiencies of the reaction sequences leading to
compounds 27 and 29 were such that many hundreds of mil-
ligrams of these materials were available. As a consequence,
the identification of methods for construction of the taxi-
nine C-ring via cyclization between the C3 ketone and the
terminus of the butyl side-chain attached at C4 of such sub-
strates was pursued. Our initial approaches were very much
influenced by Kajiwara’s report[29] that SmI2-mediated pina-
colic coupling reactions can be used to effect formation of
the C-ring of taxoids. To such ends, the TBDPS-ether within
bicyclo[5.3.1]octenone 27 was cleaved using tetrabutylam-
monium fluoride (TBAF) and the ensuing alcohol 37 (99%)
oxidized to the corresponding aldehyde 38 (84%) using the
Dess–Martin periodinane (DMP) (Scheme 5).[30] With the
requisite dicarbonyl compound in hand the foreshadowed
reductivecouplingreactionwaspursuedbutexposureofcom-
pound 38 to samarium(ii) iodide/lithium bromide[31] only
providedthereducedanddeoxygenatedproduct39(12%)and
the tricyclic diol 40 (63%). When samarium(ii) iodide alone
was employed then a 1 : 1 mixture of these same products
was observed. The tricyclic product presumably arises via
one electron reduction of the ketone carbonyl within precur-
sor 38 followed by cyclization of the resulting ketyl radical
anion onto the transannularly disposed double bond. Accom-
panying this process is the reduction of the aldehyde carbonyl
so as to establish the 1◦-alcohol unit observed in the final
product 40.
In the first step of efforts to form the C-ring through an
intramolecular benzoin-type condensation reaction,[32] the
keto-aldehyde was treated with trimethylsilylcyanide in the
presence of triethylamine. However, the resulting material,
tentatively identified as ca. 1 : 1 mixture of the diastereoiso-
meric cyanohydrin ethers 41 (69%), failed to engage in the
desired cyclization reaction (which would have led to acyloin
42) on exposure to a range of relevant conditions including
those involving successive use of lithium diisopropylamide
(LDA) then a fluoride ion source. Under such conditions only
complex mixtures of products were obtained.
Intramolecular Wittig reactions involving treatment of a
ketone with a suitably tethered ylide have proven useful in
the formation of cyclohexenes.[33] In efforts to exploit such
a process here, the TBDPS-ether 29 was deprotected using
TBAF and the ensuing 1◦-alcohol 43 (93%) (Scheme 6) then
converted into the corresponding bromide 44 (96%) using
Ph3P · Br2.[34] Interestingly, when the equivalent conversion
was attempted, directly,[35] on the TBDPS-ether 27 lacking
an allylic oxygen at C13 (taxane numbering) only the previ-
ously observed oxetane 31 was obtained. Since reaction of
bromide 44 with triphenylphosphine proved sluggish it was
first converted, under Finkelstein conditions, into the cor-
responding iodide 45 (91%). Reaction of the latter halide
with triphenylphosphine proceeded rapidly and the presumed
phosphonium salt so formed was immediately treated with
potassium tert-butoxide in an effort to generate the corre-
sponding ylide which, of course, it was hoped would engage
BnO
OBn
H
H
O
X
KOBut
O
O
X
Compound 46
Table 2. Product distributions observed in the DMDO-
mediated epoxidation of tricyclic alkene 32
47
29 XꢀOTBDPS
43 XꢀOH
44 XꢀBr
45 XꢀI
46 XꢀPPh3I
TBAF
NaI
Ph3P⋅Br2
Entry
eq. DMDO
Temp/Time
34
35
36
1
2
3
3
5
10
−20◦C/8 h
0◦C/24 h
0◦C/20 h
61%
10%
25%
–
15%
–
30%
65%
57%
Ph3P
Scheme 6.
H
O
OH
OBn
H
OBn
H
39
O
O
OH
O
SmI2
DMP
TBAF
ꢁ
27
H
OBn
OH
37
38
OH
Me3SiCN
O
40
BnO
H
OBn
O
OSiMe
H
3
base,
then Fꢂ
X
CN
OH
42
41
Scheme 5.

58
M. G. Banwell, M. D. McLeod and A. G. Riches
OH
H
O
OH
TBAF
36
HO
48
DMP
O
H
OH
OH
H
H
O
O
O
O
O
OH
O
O
O
ꢁ
ꢁ
49
50
51
SmI
X
LiHMDS
2
Li
OH
OH
O
O
H
H
OH
O
?
O
O
53
Scheme 7.
52
in the desired intramolecular olefination reaction. Unfortu-
nately, noevidencefortheformationofthetargetcyclohexene
47 could be obtained.
in an intramolecular carbonyl ene reaction has been exploited
in the installation of the C13 oxygen (taxane numbering)
required in the target natural product. Further development
of this approach requires the identification of an effective
strategy for annulation of the taxoid C-ring onto the AB-ring
systems such as 27 and 29. Work directed towards such ends
is now underway in these laboratories.
Our final efforts to effect C-ring annulation involved
attempts to exploit aldol condensation processes (Scheme 7).
To such ends the TBDPS-ether 36 was desilylated using
TBAF so as to generate triol 48 (95%). Reaction of the lat-
ter compound with one molar equivalent of DMP afforded a
chromatographically separable mixture of diketone 49 (18%)
and the tricarbonyl system 50 (46%). Use of two equiva-
lents of DMP afforded compounds 49 and 50 in 21% and
68% yields, respectively. Increasing the mole ratio of oxi-
dant to substrate to ca. 3.5 : 1 resulted in the tetracarbonyl
system 51 (36%) being obtained as the only isolable reac-
tion product. Attempts to effect a samarium iodide-mediated
pinacolic coupling within polycarbonyl compound 51 and
thereby form diol 52 were also unsuccessful.[36] A more
tantalizing result was observed during efforts to effect an
intramolecular aldol reaction of compound 50. Thus, this tri-
carbonyl species was reacted with LiHMDS in the hope that
the resulting acyloin-derived enolate 53 might engage in an
aldol process to generate, after acidic work-up, the keto-diol
52. Indeed, small amounts (11%) of a product isomeric (as
judged by mass spectral analysis) with the starting material
was obtained but the quantities of material obtained did not
permit accumulation of sufficiently convincing NMR data to
allow for unequivocal assignment of structure.
Experimental
General
General procedures and protocols have been described in Part 1[9] of
this series.
Synthetic Studies
(2S,3aR,7aS)-3a,7a-Dihydro-2-(4-methoxyphenyl)-4-methyl-
1,3-benzodioxole 8
A magnetically stirred suspension of diol 4 (5.00 g, 39.6 mmol) in
dichloromethane (150 mL) was treated with p-methoxybenzaldehyde
dimethyl acetal (7.47 mL, 43.6 mmol) and the resulting mixture cooled
to−20◦C. (–)-Camphorsulfonicacidmonohydrate(99 mg, 0.396 mmol)
was then added in one portion which resulted in the rapid dissolu-
tion of suspended material. After 10 min the reaction mixture was
quenched with NaHCO3 (150 mL of a 5% w/v aqueous solution), the
layers separated, and the aqueous phase extracted with dichloromethane
(1 × 150 mL). The combined organic extracts were washed with brine
(1 × 100 mL), then dried (MgSO4), filtered, and concentrated under
reduced pressure to give an oily solid. Recrystallization (petroleum
spirit, 2 crops) of this material afforded acetal 8 (5.18 g, 53%) as pale-
brown crystals, mp 101–102◦C, [α]D+118 (c 2.0), Rf 0.4 (15 : 85 v/v
ethyl acetate/hexane), (Found: M+• 244.1101, C 73.7, H 6.8. C15H16O3
requires M+• 244.1099, C 73.7, H 6.6%). νmax/cm−1 1664, 1613, 1585,
1519. δH (300 MHz) 7.39 (2 H, m), 6.88 (2 H, m), 6.02 (1 H, dd, J 9.8
and 5.6), 5.87 (1 H, dd, J 9.8 and 3.9), 5.78 (1 H, d, J 5.2), 5.68 (1 H, s),
4.70 (1 H, dd, J 9.3 and 3.9), 4.52 (1 H, dd, J 9.3), 3.80 (3 H, s), 1.95
(3 H, s). δC (75 MHz) 160.6, 133.8, 129.0, 128.4, 124.9, 121.5, 119.3,
113.7, 99.1, 75.0, 72.2, 55.2, 20.3. m/z (EI, 70 eV) 244 (M+•, 32%),
198 (68), 183 (13), 165 (13), 135 (100), 121 (21), 108 (51), 79 (48),
77 (49).
Summary and Conclusions
The work detailed here demonstrates that the enantiomeri-
cally pure and readily accessible cis-1,2-dihydrocatechol 7
can be elaborated, via Diels–Alder and anionic oxy-Cope
rearrangement reactions, into the AB-ring substructure, for
example 27, associated with ent-taxoids such as ent-taxinine.
The propensity for such bicyclo[5.3.1]undecenones to engage

Taxane Diterpene Synthesis Studies—Part 2
59
(2S,3aS,4R,7S,7aR,8R)-8-Chloro-3a,4,7,7a-tetrahydro-2-(4-methoxy-
phenyl)-7-methyl-4,7-ethano-1,3-benzodioxole-8-carbonitrile 9
and (2S,3aS,4R,7S,7aR,8S)-8-Chloro-3a,4,7,7a-tetrahydro-
2-(4-methoxyphenyl)-7-methyl-4,7-ethano-1,3-benzodioxole-
8-carbonitrile 10
(1 H, d, J 8.1), 5.68 (1 H, s), 4.79 (1 H, dd, J 7.6 and 3.4), 4.13 (1 H, d,
J 6.8), 3.81 (3 H, s), 3.07, (1 H, m), 1.37 (3 H, s), 1.17 (3 H, s), 1.09 (3 H,
s). δC (75 MHz) 214.0, 160.7, 135.4, 130.1, 128.8, 128.1, 113.7, 104.2,
79.5, 77.4, 55.3, 55.2, 46.4, 41.7, 28.4, 23.3, 14.6. m/z (EI, 70 eV) 314
(M+•, 13%), 198 (14), 178 (23), 163 (12), 149 (40), 136 (100), 121
(23), 109 (22).
Amagneticallystirredsolutionofdiene8(1.88 g, 7.69 mmol)inbenzene
(15 mL) was treated with 2-chloroacrylonitrile (1.84 mL, 23.1 mmol)
and the resulting mixture heated at reflux for 48 h then cooled and con-
centrated under reduced pressure to afford a brown solid. This material
was subject to flash chromatography (1 : 4 v/v ethyl acetate/hexane elu-
tion) to give, after concentration of the appropriate fractions (Rf 0.3), a
4 : 1 mixture of the title compounds 9 and 10 (2.55 g, 100%) as a light-
yellow oil (Found: C 65.5, H 5.4, N 4.5, Cl 10.4. C8H8NO3Cl requires
C 65.2, H 5.5, N 4.2, Cl 10.7%). δH (300 MHz) (major) 7.38 (2 H, m),
6.89 (2 H, m), 6.38 (1 H, dd, J 8.1 and 6.6), 5.90 (1 H, d, J 8.1), 5.65
(1 H, s), 4.35 (2 H, s), 3.81 (3 H, s), 3.13 (1 H, m), 2.56 (1 H, dd, J 15.3
and 1.9), 2.25 (1 H, dd, J 15.3 and 4.0), 1.67 (3 H, s). δH (minor) 7.38
(2 H, m), 6.89 (2 H, m), 6.47 (1 H, app. t, J 7.4), 6.04 (1 H, d, J 8.2),
5.61 (1 H, s), 4.47 (1 H, dd, J 7.3 and 1.2), 4.40 (1 H, m), 3.81 (3 H, s),
3.13 (1 H, m), 2.68 (1 H, dd, J 14.9, 4.1), 2.19 (1 H, dd, J 14.9, 1.9),
1.68 (3 H, s). δC (75 MHz, CDC13) (major) 160.8, 132.2, 131.6, 128.8,
127.7, 118.7, 113.7, 103.9, 79.5, 78.0, 58.7, 55.3, 47.0, 42.3, 34.0, 17.5.
δC (minor) 160.8, 134.5, 133.7, 128.8, 127.7, 119.2, 113.7, 103.2, 78.2,
77.9, 60.1, 55.2, 46.4, 42.4, 34.8, 17.2.
(2S,3aR,4S,7S,7aS)-Tetrahydro-2-(4-methoxyphenyl)-4,6,6-trimethyl-
4,7-ethano-1,3-benzodioxol-5(4H)-one 12
A solution of (2S,3aS,4S,7S,7aR)-3a,4,7,7a-tetrahydro-2-(4-methoxy-
phenyl)-7,9,9-trimethyl-4,7-ethano-1,3-benzodioxol-8-one (18.6 g,
59.1 mmol) in ethanol (180 mL) was purged with nitrogen and 10%
platinum on carbon (5.87 g) was added. The atmosphere was exchanged
for hydrogen (1 atmosphere) and the resulting mixture stirred at 18◦C
for 7 h then purged with nitrogen, filtered through a pad of Celite and the
filtrate evaporated to give a white solid. This material was recrystallized
(hexane) to afford ketone 12 (18.5 g, 99%) as colourless crystals, mp
127–128◦C, [α]D −21.8 (c 1.1), Rf 0.4 (1 : 4 v/v ethyl acetate/hexane),
(Found: [M – H•]+ 315.1596, C 72.1, H 7.8. C19H24O4 requires
[M – H•]+ 315.1596, C 72.1, H 7.7%). νmax/cm−1 1717, 1612, 1585,
1516. δH (300 MHz) 7.51 (2 H, m), 6.95 (2 H, m), 5.78 (1 H, s), 4.58
(1 H, m), 3.96 (1 H, m), 3.82 (3 H, s), 2.30–2.05 (3 H, complex m),
1.70 (1 H, m), 1.30 (1 H, m), 1.23 (3 H, s), 1.12 (3 H, s), 1.07 (3 H, s). δC
(75 MHz) 218.7, 160.6, 128.2, 113.8, 103.8, 76.9, 74.0, 55.2, 48.0, 43.9,
41.5, 25.0, 23.4, 23.1, 17.0, 14.7 (one signal obscured or overlapping).
m/z (EI, 70 eV) 316 (M+•, 45%), 315 (60), 285 (12), 135 (100), 121
(33), 108 (28), 94 (69).
(2S,3aS,4R,7S,7aR)-3a,4,7,7a-Tetrahydro-2-(4-methoxyphenyl)-
7-methyl-4,7-ethano-1,3-benzodioxol-8-one 11
A magnetically stirred suspension of a mixture of α-chloronitriles 9
and 10 (2.27 g, 6.84 mmol) in tert-butanol (68 mL) was treated with
ground potassium hydroxide (1.92 g, 34.2 mmol), and the resulting mix-
ture stirred at 70◦C for 1.5 h. The cooled reaction was then quenched
with water (70 mL) and extracted with diethyl ether (3 × 50 mL). The
combined organic extracts were washed with brine (1 × 50 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure to give an
off-white solid. Subjection of this material to flash chromatography
(1 : 3 v/v ethyl acetate/hexane elution) and concentration of the appro-
priate fractions (Rf 0.3) afforded a white solid which was recrystallized
(ether) to give the title ketone 11 (1.69 g, 86%) as white, crystalline
masses, mp 136–137◦C, [α]D +257 (c 2.1), (Found: M+• 286.1214,
νmax/cm−1 1726, 1613, 1585, 1519. δH (300 MHz) 7.43 (2 H, m), 6.89
(2 H, m), 6.49 (1 H, app. t, J 7.1), 5.88 (1 H, d, J 8.3), 5.72 (1 H, s)
4.52 (1 H, dd, J 7.3 and 3.8), 4.09 (1 H, d, J 6.9), 3.80 (3 H, s), 3.32
(1 H, m), 2.20 (1 H, dd, J 18.7 and 3.9), 1.95 (1 H, dd, J 18.7 and 2.1),
1.39 (3 H, s). δC (75 MHz) 209.8, 160.8, 134.0, 131.7, 128.7, 128.0,
113.7, 104.6, 79.9, 79.6, 55.2, 54.7, 35.2, 35.0, 14.3. m/z (EI, 70 eV)
286 (M+•, 18%), 198 (17), 149 (17), 136 (100), 121 (32), 108 (32),
91 (27), 77 (40).
(2S,3aR,4R,7S,7aS)-Hexahydro-2-(4-methoxyphenyl)-4,6,6-trimethyl-
5-methylene-4,7-ethano-1,3-benzodioxole 13
Method A
A magnetically stirred suspension of dimethyl diphenylphosphonium
iodide (2.05 g, 5.99 mmol) in THF (20 mL) maintained at −10◦C
(ice/salt bath) was treated with n-butyllithium (9.86 mL of a 1.58 M
in THF, 15.6 mmol) resulting in the formation of a yellow solution. This
was stirred at −10◦C for 0.5 h and then at 18◦C for 1.5 h whereupon it
was re-cooled to 0◦C and a solution of ketone 12 (1.26 g, 3.99 mmol) in
THF(5 mL + 2 × 2.5 mLwashings)wasaddedviacannula.Thereaction
mixture was stirred for 0.5 h then t-butanol (1.91 mL, 20.0 mmol) was
added dropwise producing a white precipitate. Stirring was continued
for 0.5 h after which time the reaction mixture was quenched by the addi-
tion of water (40 mL) and extracted with diethyl ether (3 × 40 mL). The
combined organic extracts were washed with brine (1 × 40 mL), then
dried (MgSO4), filtered, and concentrated under reduced pressure to
give a light-yellow oil. Subjection of this material to flash chromatogra-
phy (7.5 : 92.5 v/v ethyl acetate/hexane elution) gave, after concentration
of the appropriate fractions (Rf 0.6 in 1 : 4 v/v ethyl acetate/hexane), a
white solid. Recrystallization of this material (hexane) afforded alkene
13 (1.25 g, 99%) as crystalline masses, mp 62–64◦C, [α]D +29.3 (c 1.2),
(Found: [M – H•]+ 313.1807, C 76.7, H 8.0. C20H26O3 requires
[M – H•]+ 313.1804, C 76.4, H 8.3%). νmax/cm−1 1641, 1615, 1588,
1518. δH (300 MHz) 7.52 (2 H, m) 6.95 (2 H, m), 5.72 (1 H, s), 4.94
(2 H, s), 4.46 (1 H, m), 3.83 (3 H, s), 3.75 (1 H, dd, J 8.7 and 1.5), 2.08
(1 H, m), 1.93 (1 H, m), 1.77 (1 H, m), 1.63 (1 H, m), 1.26 (3 H, s),
1.19–1.09 (1 H, partially obscured complex m), 1.17 (3 H, s), 1.10 (3 H,
s). δC (75 MHz) 161.2, 160.5, 129.0, 128.4, 113.8, 106.2, 102.9, 79.4,
74.6, 55.3, 41.5, 39.7, 36.6, 30.8, 29.5, 24.8, 20.9, 15.1. m/z (EI, 70 eV)
314 (M+•, 47%), 313 (55), 163 (34), 162 (32), 149 (22), 147 (20),
145 (17), 135 (100), 121 (77), 119 (49), 107 (56), 105 (48), 93 (52),
91 (56), 77 (55).
•
C 71.5, H 6.3. C17H8O4 requires M+ 286.1205, C 71.3, H 6.3%).
(2S,3aS,4S,7S,7aR)-3a,4,7,7a-Tetrahydro-2-(4-methoxyphenyl)-
7,9,9-trimethyl-4,7-ethano-1,3-benzodioxol-8-one
A magnetically stirred solution of ketone 11 (3.26 g, 11.4 mmol) in
THF (45 mL) maintained at 0◦C (ice bath) was treated with sodium
hexamethyldisilazide (22.8 mL, 22.8 mmol) followed by methyl iodide
(1.42 mL, 22.8 mmol). The reaction mixture was stirred for 6 h at 0◦C
with the addition of further sodium hexamethyldisilazide (22.8 mL,
22.8 mmol) and methyl iodide (1.42 mL, 22.8 mmol) after 2 and 4 h.The
reaction mixture was then quenched with water (100 mL) and extracted
with ether (3 × 100 mL). The combined organic extracts were washed
with brine (1 × 100 mL), then dried (MgSO4), filtered, and concen-
trated under reduced pressure to give an orange solid. Subjection of
this material to flash chromatography (1 : 4 v/v ethyl acetate/hexane elu-
tion) and concentration of the appropriate fractions (Rf 0.3) afforded
a white solid which was recrystallized (ether) to give the title ketone
(3.20 g, 89%) as white, crystalline masses, mp 117–118◦C, [α]D +230
Method B
A solution of ketone 12 (0.050 g, 0.158 mmol) and methyltriphenyl-
phosphonium bromide (0.0847 g, 0.237 mmol) in THF (1.58 mL)
contained in a polyethylene pipette bulb was treated with sodium hexa-
methyldisilazide (237 µL, 0.237 mmol) and the pipette bulb neck was
secured firmly with a brass clamp. This vessel was subjected to 19 kbar
for 2 h and then removed from the high pressure reactor. The contents
•
(c 2.0), (Found: M+• 314.1517, C 72.3, H 7.0. C19H22O4 requires M+
314.1518, C 72.6, H 7.1%). νmax/cm−1 1722, 1614, 1586, 1519. δH
(300 MHz) 7.43 (2 H, m), 6.89 (2 H, m), 6.46 (1 H, app. t, J 8.1), 5.80

60
M. G. Banwell, M. D. McLeod and A. G. Riches
were concentrated under reduced pressure and the residue subjected
to purification by flash chromatography and then recrystallization,
as defined in Method A, thus providing the title ketone 13 (43 mg,
88%) identical, in all respects, with the material obtained as described
immediately above.
78.6, 73.5, 70.8, 55.2, 40.8, 36.5, 30.7, 29.3, 25.6. 21.0, 15.7 (two
signals obscured or overlapping). m/z (EI, 70 eV) 406 (M+•, 3%),
315 (7), 285 (13), 179 (12), 162 (20), 137 (15), 135 (25), 121 (100),
105 (13), 91 (68).
(1R,2R,3S,4S)-1,5,5-Trimethyl-6-methylene-3-(phenylmethoxy)-
bicyclo[2.2.2]octan-2-ol 17
(1R,2R,3S,4S)-3-[(4-Methoxyphenyl)methoxy]-1,5,5-trimethyl-
5-methylenebicyclo[2.2.2]octan-2-ol 14
and (1S,2S,3R,4R)-3-[(4-Methoxyphenyl)methoxy]-4,6,6-trimethyl-
5-methylenebicyclo[2.2.2]octan-2-ol 15
A
rapidly stirred mixture of ether 16 (2.05 g, 5.04 mmol),
dichloromethane (45 mL) and water (5 mL) was treated with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (1.72 g, 7.56 mmol). The ensu-
ing deep-green suspension was stirred for 0.25 h then quenched with
NaHCO3 (50 mL of a saturated aqueous solution), the layers were
separated, and the aqueous phase was extracted with dichloromethane
(1 × 50 mL). The combined organic extracts were washed with brine
(1 × 50 mL), then dried (MgSO4), filtered, and concentrated under
reduced pressure. The resulting light-yellow oil was subject to flash
chromatography (1 : 9 v/v ethyl acetate/hexane elution) and concen-
tration of the appropriate fractions (Rf 0.4) gave alcohol 17 (1.40 g,
A magnetically stirred solution of acetal 13 (80 mg, 0.255 mmol)
in a mixture of dichloromethane (0.63 mL) and pentane (0.63 mL)
was cooled to −60◦C then treated with diisobutylaluminium hydride
(1.27 mL of a 1 M solution in hexane, 1.27 mmol). The resulting mix-
ture was stirred at −60◦C for 4 h then −40◦C for 1.5 h after which
it was carefully quenched with tartaric acid (10 mL of a 1 M aque-
ous solution) and the resulting biphasic mixture was stirred vigorously
for 0.25 h then extracted with dichloromethane (3 × 10 mL). The com-
bined organic extracts were washed with brine (1 × 30 mL), then dried
(MgSO4), filtered, and concentrated under reduced pressure to give
a light-yellow oil. Subjection of this material to flash chromatography
(13 : 87 v/v ethyl acetate/hexane) afforded two fractions, A and B.
Concentration of fraction A [Rf 0.5(3)] afforded compound 14
(7.9 mg, 10%) as a clear colourless oil, [α]D +14.8 (c 1.5), (Found:
•
97%) as a clear, colourless oil, [α]D +14.0 (c 2.2), (Found: M+
•
286.1934. C19H26O2 requires M+ 286.1933). νmax/cm−1 3516, 1638.
δH (300 MHz) 7.38–7.32 (5 H, complex m), 4.89 (1 H, s), 4.85 (1 H, s),
4.64 (1 H, d, J 11.6), 4.58 (1 H, d, J 11.6), 3.92 (1 H, m), 3.46 (1 H,
dd, J 8.5 and 1.7), 3.40 (1 H, broad s), 1.88–1.70 (2 H, complex m),
1.65–1.57 (2 H, complex m), 1.20 (3 H, s), 1.10 (1 H, partially obscured
m), 1.10 (3 H, s), 1.04 (3 H, s). δC (75 MHz) 162.0, 137.8, 128.5, 127.9,
127.7, 105.6, 73.1, 72.0, 70.6, 41.5, 40.9, 36.5, 30.5, 29.2, 24.5, 20.6,
15.4. m/z (EI, 70 eV) 286 (M+•, 4%), 195 (21) 180 (12), 178 (27), 162
(23), 159 (18), 149 (18), 135 (64), 121 (32), 107 (27), 91 (100).
•
•
M+ 316.2036. C20H28O3 requires M+ 316.2038). νmax/cm−1 3508,
1638, 1613, 1586, 1514. δH (300 MHz) 7.28 (2 H, m), 6.89 (2 H, m),
4.88 (1 H, s), 4.84 (1 H, s), 4.56 (1 H, d, J 11.2), 4.48 (1 H, d, J 11.2),
3.89 (1 H, m), 3.81 (3 H, s), 3.41 (1 H, m), 1.90–1.65 (2 H, complex m),
1.65–1.50 (2 H, complex m), 1.18 (3 H, s), 1.11–1.05 (1 H, partially
obscured complex m), 1.09 (3 H, s), 1.02 (3 H, s) (signal due to
hydroxyl proton not observed). δC (75 MHz) 162.1, 159.3, 129.9.
129.4, 113.9, 105.6, 72.8, 71.8, 70.6, 55.3, 41.6, 40.9, 36.5, 30.5, 29.2,
24.5, 20.6, 15.5. m/z (EI, 70 eV) 316 (M+•, 6%), 195 (5), 135 (12),
121 (100).
(1R,3S,4S)-1,5,5-Trimethyl-6-methylene-3-(phenylmethoxy)bicyclo-
[2.2.2]octan-2-one 18
A magnetically stirred solution of alcohol 17 (1.39 g, 4.85 mmol)
in dichloromethane (48 mL) was treated with 4-methylmorpholine
N-oxide (1.71 g, 14.6 mmol) and powdered 4 Å molecular sieves (2.4 g)
then tetrapropylammonium perruthenate (85 mg, 0.243 mmol). The
resulting mixture was stirred at 18◦C for 2.5 h then filtered through
a pad of TLC-grade silica (dichloromethane washing), and the filtrate
concentrated under reduced pressure to give a brown oil. Subjection
of this material to flash chromatography (1 : 9 v/v diethyl ether/hexane
elution) and concentration of the appropriate fractions (Rf 0.4) afforded
ketone 18 (1.36 g, 98%) as a clear, colourless oil, [α]D −70.2 (c 2.0),
(Found [M + H]+ 285.1858. C19H24O2 requires [M + H]+ 285.1855).
νmax/cm−1 1729, 1637, 1607, 1586. δH (300 MHz) 7.40–7.28 (5 H, com-
plex m), 4.94 (1 H, s), 4.93 (1 H, s), 4.91 (1 H, partially obscured d), 4.76
(1 H, d, J 12.0), 3.84 (1 H, m), 2.04 (1 H, m), 1.93–1.66 (4 H, complex
m), 1.29 (3 H, s), 1.11 (6 H, s). δC (75 MHz) 212.5, 156.3, 138.0, 128.3,
127.8, 127.6, 108.0, 77.6, 72.4, 51.4, 44.3, 37.0, 32.1, 30.6, 28.8, 16.7,
16.4. m/z (EI, 70 eV) 285 ([M + H]+, 8%), 179 (17), 178 (48), 165
(29), 163 (49), 147 (17), 137 (55), 135 (40), 123 (20), 121 (33), 119
(15), 109 (33), 107 (22), 105 (30), 95 (63), 91 (100).
Concentration of fraction B [Rf 0.4(7)] afforded compound 15
(66.5 mg, 83%) as a clear colourless oil, [α]D +18.4 (c 2.1), (Found:
•
•
M+ 316.2035. C20H28O3 requires M+ 316.2038). νmax/cm−1 3499,
1637, 1613, 1586, 1515. δH (300 MHz) 7.31 (2 H, m), 6.91 (2 H, m),
4.87 (1 H, s), 4.85 (1 H, s), 4.59 (1 H, d, J 11), 4.52 (1 H, d, J 11),
4.13 (1 H, m), 3.82 (3 H, s), 3.35 (1 H, d, J 6.5), 3.26 (1 H, br. d,
J 7.2), 1.82–1.49 (4 H, complex m), 1.17 (3 H, s), 1.15 (3 H, s), 1.09
(1 H, partially obscured m), 1.04 (3 H, s). δC (75 MHz) 162.2, 159.4,
129.8, 129.7, 113.9, 105.6, 79.5, 75.1, 64.8, 55.2, 44.5, 40.7, 36.5, 30.7,
29.1, 25.2, 21.1, 14.7. m/z (EI, 70 eV) 316 (M+•, 6%), 195 (4), 135 (10),
121 (100).
(1R,4S,5S,6R)-6-[(4-Methoxyphenyl)methoxy]-1,3,3-trimethyl-
2-methylene-5-(phenylmethoxy)bicyclo[2.2.2]octane 16
A magnetically stirred suspension of sodium hydride (462 mg,
19.3 mmol), tetrabutylammonium iodide (203 mg, 0.550 mmol), and
benzyl bromide (1.31 mL, 11.0 mmol) in dimethylformamide (50 mL)
was treated with a solution of alcohol 15 (1.74 g, 5.50 mmol) in
dimethylformamide (3 mL + 2 × 1 mL washings), and the resulting
mixture stirred at 18◦C for 5 h then quenched (CAUTION!) by the
addition of water (100 mL) and extracted with ether (3 × 50 mL). The
combined organic extracts were washed with water (1 × 50 mL) and
brine (1 × 50 mL), then dried (MgSO4), filtered, and concentrated
under reduced pressure. Purification of the resulting light-yellow oil
by flash chromatography (1 : 9 v/v ethyl acetate/hexane elution) and
concentration of the appropriate fractions (Rf 0.4) gave benzyl ether
16 (2.05 g, 92%) as a clear colourless oil, [α]D +98.5 (c 0.9), (Found:
2-Bromo-6-(tert-butyldiphenylsilyloxy)hex-1-ene 20
A magnetically stirred solution of 9-Br-9-BBN (1.23 g, 6.12 mmol) in
dry dichloromethane (30 mL) and maintained under nitrogen was cooled
to 0◦C then 6-tert-butyldiphenylsilanyloxyhex-1-yne 19[20] (1.72 g,
5.10 mmol) was added dropwise. Stirring was continued at 0◦C for 3 h
then glacial acetic acid (3.4 mL) was added and stirring continued at 0◦C
for a further 1 h before the addition of NaOH (140 mL of a 3 M aqueous
solution) and hydrogen peroxide solution (6.8 mL of a 30% aqueous
solution). Stirring was continued at 18◦C for 0.5 h then the mixture
was extracted with hexane (2 × 75 mL). The combined extracts were
washed successively with water (1 × 150 mL), NaHCO3 (1 × 150 mL
of a saturated aqueous solution), and brine (1 × 150 mL), then dried
(MgSO4), filtered, and concentrated under reduced pressure. Subjec-
tion of the resulting light-yellow oil to flash chromatography (3 : 97 v/v
ethyl acetate/hexane elution) gave the alkenyl bromide 20 (1.77 g, 83%)
•
•
M+ 406.2503. C27H34O3 requires M+ 406.2508). νmax/cm−1 1637,
1613, 1586, 1514. δH (300 MHz) 7.39–7.21 (7 H, complex m), 6.82
(2 H, m), 4.81 (1 H, s), 4.78 (1 H, s), 4.78 (1 H, d, J 11.5), 4.66 (1 H,
d, J 12.1), 4.43 (1 H, d, J 12.1), 4.35 (1 H, d, J 11.5), 3.89 (1 H, dt, J
8.1 and 2.0), 3.79 (3 H, s), 3.19 (1 H, d, J 8.2), 2.05 (1 H, m), 1.87 (1 H,
td, J 12.1 and 3.0), 1.67–1.54 (2 H, complex m), 1.14 (3 H, s), 1.12
(1 H, partially obscured m), 1.08 (3 H, s), 0.95 (3 H, s). δC (75 MHz)
162.5, 158.9, 138.9, 131.4, 129.5, 128.2, 127.9, 127.4, 113.4, 105.1,

Taxane Diterpene Synthesis Studies—Part 2
61
as a clear, colourless oil. δH (300 MHz) 7.75–7.66 (4 H, complex m),
7.46–7.34 (6 H, complex m), 5.54 (1 H, m), 5.39 (1 H, d, J 1.6), 3.68
(2 H, t, J 6.1), 2.42 (2 H, t, J 6.7), 1.69–1.52 (4 H, complex m), 1.06
(9 H, s).
(1S,2S,4S)-4-[4-(tert-Butyldiphenylsilyloxy)butyl]-4,8,11,11-
tetramethyl-2-(phenylmethoxy)bicyclo[5.3.1]undec-7-en-3-one 27
Amagneticallystirredsolutionoffreshlysublimedpotassium t-butoxide
(540 mg, 4.816 mmol) in dry ether (10 mL) was treated with a mix-
ture of methyl iodide (stored over CaCl2) (300 µL, 4.816 mmol) and
alcohol 23 (600 mg, 0.963 mmol). The resulting mixture was stirred at
18◦C for 5 h during which time the formation of a white precipitate was
observed. The mixture was then poured into NH4Cl (20 mL of a sat-
urated aqueous solution). The separated aqueous phase was extracted
with ether (2 × 10 mL) and the combined organic extracts were washed
with brine (1 × 30 mL), then dried (MgSO4), filtered, and concentrated
under reduced pressure. Subjection of the ensuing light-yellow oil to
flash chromatography (5 : 95 v/v ethyl acetate/hexane elution) and con-
centration of the appropriate fractions (Rf 0.2) afforded the bicyclic
ketone 27 (505 mg, 84%) as a clear, colourless syrup, [α]D −39.5◦
(1R,2S,3S,4S)-2-{1-[4-(tert-Butyldiphenylsilyloxy)butyl]vinyl}-1,5,5-
trimethyl-6-methylene-3-(phenylmethoxy)bicyclo[2.2.2]octan-2-ol 23
Anhydrous cerium trichloride (1.413 g, 5.732 mmol; prepared by heat-
ing the heptahydrate at 150–160◦C and 1 mmHg for 12 h) maintained
under argon was treated with dryTHF (14 mL). The resulting slurry was
stirred at 18◦C for 2 h then sufficient tert-butyllithium (ca. 5 drops of
a 1.8 M solution in pentane) was added dropwise until an orange colour
persisted. The resulting mixture was cooled to −78◦C. In a separate
flask, a solution of the alkenyl bromide 20 (2.393 g, 5.732 mmol) in
dry THF (10 mL) was cooled to −78◦C and tert-butyllithium (5.92 mL
of a 1.8 M solution, 10.65 mmol) was added dropwise. After 0.33 h this
solution was rapidly cannulated into the stirred slurry of CeCl3. Stirring
was continued at −78◦C for 0.5 h before dropwise addition of a solution
of the ketone 18 (1.164 g, 4.09 mmol) in THF (4 mL). The mixture was
stirred at −78◦C for 2 h then allowed to warm to 18◦C over 1 h before
being poured into NH4Cl (50 mL of a saturated aqueous solution) and
extracted with ether (2 × 50 mL). The combined extracts were washed
with brine (1 × 100 mL), then dried (MgSO4) and evaporated to give
a pale-yellow residue. Subjection of this material to flash chromato-
graphy (hexane to 5 : 95 v/v ethyl acetate/hexane gradient elution) gave,
after concentration of the appropriate fractions (Rf 0.25, 2.5 : 97.5 v/v
ethyl acetate/hexane), the title alcohol 23 (1•.82 g, 71%) as a colour-
less syrup, [α]D −22.1◦ (c 0.8), (Found: M+ 622.3849. C41H54O3Si
•
•
(c 1.4), (Found: M+ 636.3987. C42H56O3Si requires M+ 636.3999).
νmax/cm−1 2930, 1692, 1427, 1110, 700. δH (300 MHz) 7.68–7.65 (4 H,
complex m), 7.45–7.26 (11 H, complex m), 4.43 (1 H, d, J 11.8), 4.35
(1 H, d, J 3.4), 4.32 (1 H, d, J 11.8), 3.69 (2 H, t, J 6.4), 2.43–2.27 (2 H,
complex m), 2.15 (1 H, dd, J 7.6 and 3.2), 2.10–1.93 (3 H, complex m),
1.85–1.50 (7 H, complex m), 1.46 (3 H, s), 1.40 (3 H, s), 1.30–1.18 (2 H,
complex m), 1.05 (12 H, m), 0.84 (3 H, s). δC (75 MHz) 212.3, 138.4,
136.7, 135.6, 134.3, 134.1, 129.5, 128.3, 127.7, 127.6, 127.5, 76.9, 70.4,
63.8, 54.1, 49.7, 36.4, 35.1, 33.4, 31.5, 29.7, 27.5, 26.9, 25.1, 24.6, 24.2,
21.9, 19.7, 19.2, 15.9. m/z (EI, 70 eV) 636 (M+•, 1%), 604 (1), 579 (3),
565 (3), 471 (35), 199 (51), 135 (28), 91 (100).
(1R,2S,3S,4S)-[5-(2-methoxy-1,5,5-trimethyl-6-methylene-
3-(phenylmethoxy)bicyclo[2.2.2]oct-2-yl)-hex-5-enyloxy]-
tert-butyldiphenylsilane 28
•
requires M+ 622.3842). νmax/cm−1 3522, 2960, 2931, 2869, 1471,
1461, 1427, 1110, 700. δH (300 MHz) 7.71–7.67 (4 H, complex m),
7.45–7.27 (11 H, complex m), 4.90 (1 H, broad s), 4.86 (1 H, broad s),
4.80 (1 H, s), 4.74 (1 H, s), 4.52 (2 H, s), 3.75 (1 H, t, J 1.8), 3.66 (2 H,
m), 2.15 (1 H, m), 2.02–1.80 (2 H, complex m), 1.66–0.80 (9 H, complex
m), 1.18 (3 H, s), 1.13 (3 H, s), 1.06 (9 H, s), 0.84 (3 H, s). δC (75 MHz)
160.5, 154.4, 137.8, 135.5, 134.1, 129.5, 128.3, 127.9, 127.8, 127.6,
A solution of alcohol 23 (92 mg, 0.148 mmol), which had been dried
azeotropically using toluene, in anhydrous DME (2 mL) was treated
with methyl iodide (14 µL, 0.222 mmol) and the resulting mixture
transferred, via cannula, into a sealable vial fitted with a septum and
containing KH (7.1 mg, 0.177 mmol). The vial was sealed and the mix-
ture heated at 50◦C for 2 h. After cooling, the mixture was poured
into NH4Cl (10 mL of a saturated aqueous solution) and extracted
with ether (2 × 10 mL). The combined extracts were washed with brine
(1 × 20 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The resulting light-yellow residue was subjected to flash
chromatography (5 : 95 v/v to 1 : 9 ethyl acetate/hexane gradient elution)
thus affording two fractions, A and B.
110.5, 106.8, 78.5, 71.9, 64.0, 45.0, 44.5, 42.3, 37.1, 32.9, 32.7, 32.1,
•
29.4, 28.2, 26.9, 25.6, 19.2, 18.9, 16.4. m/z (EI, 70 eV) 622 (M+
,
0.6%), 605 (1), 604 (2), 565 (12), 457 (23), 241 (27), 199 (56), 135
(58), 91 (100).
Concentration of fractionA (Rf 0.2 in 5 : 95 v/v ethyl acetate/hexane
elution) gave the C-alkylated compound 27 (42 mg, 45%) which was
identical, in all respects, with the material obtained as described above.
Concentration of fraction B (Rf 0.33 in 5 : 95 v/v ethyl acetate/
hexane) gave the title ether 28 (19 mg, 20%) as a clear, colourless syrup,
(1S,2S,4S)-4-[4-(tert-Butyldiphenylsilyloxy)butyl]-8,11,11-trimethyl-
2-(phenylmethoxy)bicyclo[5.3.1]undec-7-en-3-one 26
A solution of the alcohol 23 (16 mg, 0.026 mmol) in dry THF (1 mL)
was cannulated into a flask containing KH (2 mg, 0.051 mmol) main-
tained under nitrogen and the resulting mixture heated at reflux for
0.5 h after which time TLC analysis indicated complete consumption
of starting material had occurred. As a consequence, the reaction mix-
ture was cooled to 18◦C then poured into NH4Cl (10 mL of a saturated
aqueous solution) and extracted into ether (2 × 10 mL). The combined
extracts were washed with brine (2 × 15 mL), then dried (MgSO4), fil-
tered, and concentrated under reduced pressure to give a light-yellow
oil. Subjection of this material to flash chromatography (5 : 95 v/v ethyl
acetate/hexane) afforded, after concentration of the appropriate frac-
tions (Rf 0.2), the title ketone 26•(14 mg, 88%) as a clear colourless oil,
•
•
[α]D −8.4◦ (c 1.0), (Found: M+ 636.3988. C42H56O3Si requires M+
636.3999). νmax/cm−1 2958, 2931, 1471, 1462, 1427, 1110, 1100, 700.
δH (300 MHz) 7.70–7.67 (4 H, complex m), 7.44–7.26 (11 H, complex
m), 5.09 (1 H, broad s), 4.87 (1 H, broad s), 4.76 (1 H, s), 4.59 (1 H, s),
4.57 (1 H, d, J 12.0), 4.40 (1 H, d, J 12.0), 3.91 (1 H, broad s), 3.66
(2 H, t, J 6.2), 3.48 (3 H, s), 2.06 (1 H, m), 2.00–1.43 (10 H, complex
m), 1.18 (3 H, s), 1.12 (3 H, s), 1.07 (9 H, s), 0.85 (3 H, s). δC (75 MHz)
160.9, 148.4, 139.1, 135.6, 134.1, 129.5, 128.1, 127.8, 127.6, 127.4,
114.1, 106.8, 84.8, 78.5, 71.3, 63.9, 57.3, 45.9, 41.6, 36.9, 33.1, 32.8,
•
31.7, 29.6, 28.4, 26.9, 25.4, 20.0, 19.2, 16.3. m/z (EI, 70 eV) 636 (M+
,
•
[α]D −1.8 (c 1.06), (Found: M+ 622.3850. C41H54O3Si requires M+
3%), 604 (3), 199 (58), 183 (23), 135 (41), 91 (100).
622.3842). νmax/cm−1 3400, 2931, 2858, 1702, 1460, 1427, 1111, 701.
δH (300 MHz) 7.75–7.63 (4 H, complex m), 7.45–7.20 (11 H, complex
m), 4.43 (1 H, d, J 11.8), 4.22 (1 H, d, J 11.8), 4.20 (1 H, d, J 5.5),
3.61 (2 H, t, J 6.5), 2.55 (1 H, m), 2.40–2.24 (3 H, complex m), 2.18–
0.80 (12 H, complex m), 1.43 (3 H, s), 1.41 (3 H, s), 1.08 (3 H, s), 1.04
(9 H, s). δC (75 MHz) 216.0, 138.1, 136.1, 135.5, 134.9, 134.0, 129.5,
128.2, 127.6(3), 127.5(9), 127.5(2), 84.7, 71.1, 63.7, 55.4, 51.1, 36.1,
34.0, 33.5, 32.8, 30.0, 28.4, 27.3, 26.9, 25.4, 23.9, 20.4, 19.2, 15.6. m/z
(EI, 70 eV) 622 (M+•, 3%), 604 (13), 514 (31), 487 (30), 458 (49), 457
(100), 445 (38), 397 (40), 389 (41), 241 (30), 199 (50), 185 (20), 135
(26), 91 (100).
(1S,2S,4S)-4-[4-(tert-Butyldiphenylsilyloxy)butyl]-4,8,11,11-tetra-
methyl-2-(phenylmethoxy)bicyclo[5.3.1]undec-7-ene-3,9-dione 29
and (1S,2S,4S,7S)-4-[4-(tert-Butyldiphenylsilyloxy)butyl]-7-hydroxy-
4,8,11,11-tetramethyl-2-(phenylmethoxy)bicyclo[5.3.1]undec-8-en-3-
one 30
A magnetically stirred suspension of chromium trioxide (53 mg,
0.534 mmol) in dry dichloromethane (4 mL) was cooled to −20◦C and
3,5-dimethylpyrazole (58 mg, 0.534 mmol) was added. After stirring
the reaction mixture for 0.33 h at −20◦C it had become homogeneous

62
M. G. Banwell, M. D. McLeod and A. G. Riches
and brick-red in colour. A solution of the bicyclic ketone 26 (17 mg,
0.0267 mmol) in dry dichloromethane (1 mL) was then added dropwise
and the temperature maintained between −15 and −10◦C for 5 h, after
which time most of the starting material had been consumed as judged
by TLC analysis. Consequently, the reaction mixture was quenched, at
−15 to −20◦C, by addition of NaOH (2 mL of a 5 M aqueous solution)
with vigorous stirring of the resultant mixture in an ice-bath for 0.5 h.
The separated aqueous phase was extracted with ether (3 × 5 mL) and
the combined organic phases was washed with HCl (1 × 15 mL of a 1 M
aqueous solution) and brine (1 × 15 mL), then dried (MgSO4), filtered,
and concentrated under reduced pressure. The residue was subjected to
flash chromatography (3 : 97 to 1 : 4 v/v ethyl acetate/hexane gradient
elution) affording two fractions, A and B.
tricyclic alcohol 32 (231 mg, 96%) as a colourless syrup, [α]D −7.8◦
•
•
(c 1.2), (Found: M+ 636.3991. C42H56O3Si requires M+ 636.3999).
νmax/cm−1 3540 (br), 2930, 1471, 1453, 1428, 1101, 700. δH (300 MHz)
7.69–7.66 (4 H, complex m), 7.41–7.26 (11 H, complex m), 5.34 (1 H,
broad m), 4.55 (1 H, d, J 11.5), 4.44 (1 H, d, J 11.5), 4.13 (1 H, d, J 5.6),
3.67 (2 H, t, J 6.3), 3.10 (1 H, broad s), 2.36 (1 H, broad d, J 17.1), 2.05–
1.89 (2 H, complex m), 1.88–1.67 (2 H, complex m), 1.63–1.20 (11 H,
complex m), 1.04 (12 H, s), 1.02 (3 H, s), 0.99 (3 H, s). δC (75 MHz)
141.5, 138.4, 135.6, 134.2, 129.4, 128.3, 127.7, 127.5, 120.4, 92.3, 81.1,
71.9, 66.2, 64.1, 47.7, 46.8, 39.8, 39.5, 38.5, 33.9, 27.6, 26.9, 25.3, 24.4,
23.0, 22.9, 22.7, 22.4, 19.2 (one resonance obscured or overlapping).
m/z (EI, 70 eV) 636 (M+•, 2.5%), 618 (1), 579 (5), 528 (50), 471 (52),
459 (34), 411 (31), 403 (24), 199 (63), 135 (64), 91 (100).
Concentration of the fraction A (Rf 0.5) gave the endione 29
(3 mg, 17%) as a clear, colourless syrup, [α]D −76.3◦ (c 0.9), (Found:
M+• 650.3797. C42H54O4Si requires M+• 650.3791). νmax/cm−1 2929,
1695, 1668, 1111, 701. δH (300 MHz) 7.68–7.64 (4 H, complex m),
7.45–7.25 (11 H, complex m), 4.50 (1 H, d, J 3.4), 4.41 (1 H, d, J 11.5),
4.27 (1 H, d, J 11.5), 3.69 (2 H, t, J 6.3), 3.11 (1 H, d, J 19.5), 2.63 (1 H,
dd, J 19.5, 6.6), 2.60–2.45 (2 H, complex m), 2.28 (1 H, d, J 13.6), 2.13
(1 H, m), 1.81 (1 H, m), 1.75–0.80 (6 H, complex m), 1.67 (3 H, s), 1.50
(3 H, s), 1.30 (1 H, m), 1.14 (3 H, s), 1.05 (9 H, s), 0.92 (3 H, s). δC
(75 MHz) 212.8, 198.6, 157.3, 137.8, 135.8, 135.5(5), 135.5(2), 134.0,
129.6, 128.4, 127.8, 127.7, 127.6, 75.7, 70.5, 63.5, 50.0, 49.9, 37.3,
35.1, 33.8, 33.2, 31.9, 31.5, 26.9, 26.1, 24.9, 24.5, 19.5, 19.2, 14.6. m/z
(EI, 70 eV) 650 (M+•, 2%), 607 (3), 593 (32), 270 (24), 199 (44), 179
(32), 135 (32), 91 (100).
(1S,2S,4S,9R)-4-[4-(tert-Butyldiphenylsilyloxy)butyl]-9-hydroxy-
4,8,11,11-tetramethylbicyclo[5.3.1]undec-7-en-3-one 34,
(1S,2S,4S,9R)-4-[4-(tert-Butyldiphenylsilyloxy)butyl]-9-hydroxy-4,8,-
11,11-tetramethyl-2-oxobicyclo[5.3.1]undec-7-en-2-yl Benzoate 35,
and (1S,2S,4S,9R)-4-[4-(tert-Butyldiphenylsilyloxy)butyl]-2,9-
dihydroxy-4,8,11,11-tetramethylbicyclo[5.3.1]undec-7-en-3-one 36
Method A
A mixture of tricyclic alcohol 32 (106 mg, 0.166 mmol) and anhydrous
potassium carbonate (50 mg) was cooled in an ice-salt bath and an
ice-cold solution of dimethyldioxirane (ca. 0.01 M in acetone, 5.0 mL,
0.499 mmol) was added slowly. The resulting mixture was stirred at ca.
−20◦C for 8 h then warmed to 18◦C, filtered, and the filtrate concen-
trated under reduced pressure. The residue was taken up in dry toluene
(5 mL) and the resulting solution heated at reflux for 2 h. The cooled
reaction mixture was then subjected to flash chromatography (1 : 4 to
1 : 1 v/v ethyl acetate/hexane gradient elution) affording two fractions,
A and B.
Concentration of fraction B (Rf 0.4) afforded compound 30
•
(2 mg, 11%) as a clear colourless oil (Found: [M − H2O]+ 634.3849.
C42H56O4Si requires [M − H2O]+• 634.3842). νmax/cm−1 3540, 2929,
1703, 1111, 701. δH (300 MHz) 7.67–7.64 (4 H, complex m), 7.42–7.26
(11 H, complex m), 5.32 (1 H, broad m), 4.70 (1 H, d, J 1.8), 4.44 (1 H,
d, J 11.8), 4.21 (1 H, d, J 11.8), 3.69 (2 H, t, J 6.3), 2.50 (1 H, m),
Concentration of fraction A (Rf 0.3 in 1 : 4 v/v ethyl acetate/ hex-
ane) gave compound 34 (66 mg, 61%) as a clear, colourless syrup,
2.20–0.80 (3 H, complex m), 1.72 (3 H, broadened s), 1.28 (3 H, s), 1.08
•
[α]D −6.6◦ (c 0.8), (Found: M+ 652.3930. C42H56O4Si requires
•
(3 H, s), 1.04 (9 H, s), 0.87 (3 H, s). m/z (EI, 70 eV) 634 ([M − H2O]+
,
•
M+ 652.3948). νmax/cm−1 3535, 2930, 1682, 1454, 1110, 701. δH
0.3%), 595 (0.5), 409 (10), 199 (40), 135 (22), 133 (21), 91 (100).
(300 MHz) 7.67–7.62 (4 H, complex m), 7.45–7.24 (11 H, complex m),
4.41 (1 H, d, J 11.8), 4.41 (1 H, d, J 3.3), 4.35 (1 H, d, J 11.8), 4.03
(1 H, broad d, J 10.2), 3.70 (2 H, t, J 6.2), 2.60 (1 H, m), 2.43–0.80
(3 H, complex m), 1.70 (3 H, s), 1.39 (3 H, s), 1.05 (9 H, s), 0.93 (3 H,
s), 0.84 (3 H, s). δC (75 MHz) 217.9, 137.9, 137.4, 135.5, 134.0, 129.5,
128.4, 127.7(8), 127.7(5), 127.6, 70.5, 67.3, 63.6, 50.6, 50.3, 36.4, 33.3,
33.2, 31.5, 30.4, 30.3, 29.3, 26.9, 24.9, 24.7, 24.4, 19.6, 19.2, 17.5 (one
resonance obscured or overlapping). m/z (EI, 70 eV) 652 (M+•, 0.7%),
634 (2.4), 593 (3), 577 (6), 543 (7), 487 (26), 459 (40), 295 (21), 233
(27), 199 (66), 164 (40), 135 (81), 91 (100).
(1R,3aS,4R,7S,8S,8aR)-1-[(4-tert-Butyldiphenylsilyloxy)butyl]-
hexahydro-1,4,9,9-tetramethyl-8-(phenylmethoxy)-
1H-3a,7-methanoazulen-4,8a-oxide 31
A
magnetically stirred solution of the silyl ether 27 (15 mg,
0.0235 mmol) in CDCl3 (0.5 mL) was treated with SnCl2 · 2H2O
(0.3 mg, 0.0012 mmol) and the resulting mixture stirred at 18◦C for 1 h
after which time 1H NMR analysis showed efficient formation of the
oxetane 31. No further change was observed on standing at 18◦C for
48 h. At this time the reaction mixture was poured into NaHCO3 (10 mL
of a saturated aqueous solution) and extracted with diethyl ether
(2 × 10 mL). The combined extracts were washed with brine (2 ×
10 mL), then dried (MgSO4), filtered, and concentrated under reduced
pressure to give essentially pure oxetane 31 (14 mg, 93%) as a clear,
colourless syrup, [α]D 0.0◦ (c 1.0), Rf 0.25 (1 : 9 v/v ethyl acetate/hex-
ane). δH (300 MHz) 7.74–7.71 (4 H, complex m), 7.46–7.26 (11 H, com-
plex m), 4.66 (1 H, d, J 12.0), 4.37 (1 H, d, J 12.0), 3.99 (1 H, d, J 5.6),
3.69 (2 H, m), 2.40–2.26 (3 H, complex m), 1.93–1.87 (2 H, complex
m), 1.73 (2 H, m), 1.66–1.05 (8 H, complex m), 1.24 (3 H, s), 1.10 (9 H,
s), 1.01 (3 H, s), 0.94 (3 H, s), 0.77 (3 H, s). δC (75 MHz) 138.4, 135.6,
134.3(1), 134.2(6), 129.4, 128.5, 128.1, 127.5, 96.9, 84.3, 75.8, 71.5,
64.1, 63.1, 50.7, 45.3, 44.2, 37.4, 35.0, 34.1, 33.6, 27.3, 26.9, 2•3.4, 21.4,
21.3, 20.9, 20.5, 19.2, 17.2. m/z (EI, 70 eV) 579 ([M − C4H9 ]+, 1%),
561(2), 528 (2), 501 (2), 471 (38), 411 (24), 255 (18), 199 (50), 91 (100).
Concentration of fraction B (Rf 0.1 in 1 : 4 v/v ethyl acetate/hexane)
gave compound 36 (28 mg, 30%) as a clear, colourless syrup,
•
+
[α]D + 9.1◦ (c 1.2), (Found: [M − C4H9
]
505.2772. C35H50O4Si
•
requires [M − C4H9
]
+ 505.2774). νmax/cm−1 3536, 3434, 2931, 1673,
1111, 701. δH (300 MHz) 7.69–7.65 (4 H, complex m), 7.45–7.26 (6 H,
complex m), 4.62 (1 H, d, J 3.7), 4.03 (1 H, broad d, J 10.6), 3.71 (2 H,
t, J 6.3), 2.60 (1 H, m), 2.38 (1 H, m), 2.20–1.05 (13 H, complex m),
1.71 (3 H, s), 1.47 (3 H, s), 1.06 (9 H, s), 0.96 (3 H, s), 0.94 (3 H, s). δC
(75 MHz) 222.7, 138.4, 135.5, 135.0, 134.0, 129.5, 127.6, 70.2, 67.1,
63.6, 53.0, 50.5, 36.6, 33.3, 32.8, 31.0, 30.2, 28.7, 26.8, 24.8, 24.6, 19.5,
19.2, 17.5 (one resonance obscured or overlapping). m/z (EI, 70 eV) 505
•
([M − C4H9 ]+, 12%), 487 (66), 409 (28), 295 (32), 271 (37), 233 (35),
199 (100), 135 (81).
Method B
(1R,3aR,7S,8S,8aR)-1-[4-(tert-Butyldiphenylsilyloxy)butyl]-
2,3,7,8-tetrahydro-1,4,9,9-tetramethyl-8-(phenylmethoxy)-
1H-3a,7-methanoazulen-8a(6H)-ol 32
A mixture of the tricyclic alcohol 32 (216 mg, 0.339 mmol) and anhy-
drous potassium carbonate (200 mg) was cooled in an ice-salt bath
then an ice-cold solution of dimethyldioxirane (ca. 0.01 M in acetone,
17.0 mL, 1.69 mmol) was added slowly. The resulting mixture was
stirred at 0◦C for 24 h then filtered, and the filtrate concentrated under
reduced pressure. The ensuing residue was taken up in toluene (10 mL)
and the resulting solution heated at reflux for 2 h then cooled to 18◦C and
concentrated under reduced pressure. The resulting yellow residue was
A solution of the bicyclic silyl ether 27 (240 mg, 0.377 mmol) in sodium-
dried xylene (3 mL) was heated at reflux for 3 h then cooled to 18◦C
and concentrated under reduced pressure. Subjection of the resulting
yellow oil to flash chromatography (5 : 95 v/v ethyl acetate/hexane elu-
tion) and concentration of the appropriate fractions (Rf 0.4) gave the

Taxane Diterpene Synthesis Studies—Part 2
63
subject to flash chromatography (1 : 4 to 2 : 3 v/v ethyl acetate/hexane
gradient elution) thus giving three fractions A–C.
Concentration of fraction A [Rf 0.3(2) in 1 : 4 v/v ethyl acetate/
hexane] afforded the allylic alcohol 34 (22 mg, 10%) identical, in all
respects, with the material obtained as described above.
398.2821). δH (300 MHz) 7.33–7.26 (5 H, complex m), 4.42 (1 H, d, J
11.8), 4.35 (1 H, d, J 3.9), 4.32 (1 H, d, J 11.8), 3.68 (2 H, t, J 6.5), 2.38
(2 H, m), 2.16 (1 H, m), 2.08–1.94 (2 H, complex m), 1.83–1.15 (11 H,
complex m), 1.51 (3 H, s), 1.40 (3 H, s), 1.06 (3 H, s), 0.88 (3 H, s). δC
(75 MHz) 212.4, 138.3, 136.7, 134.4, 128.3, 127.7, 127.6, 76.9, 70.4,
62.8, 54.0, 49.6, 36.3, 35.7, 33.4, 31.8, 29.7, 27.5, 25.0, 24.5, 24.2, 21.8,
19.9, 15.9. m/z (EI, 70 eV) 398 (M+•, 3%), 307 (7), 290 (18), 165 (53),
137 (67), 135 (53), 121 (38), 109 (38), 105 (38), 95 (71), 91 (100).
Concentration of fraction B (Rf 0.3 in 1 : 4 v/v ethyl acetate/hexane)
afforded the benzoate 35 (34 mg, 15%) as a clear colourless oil,
•
[α]D +8.3◦ (c 0.94), (Found: [M − H2O]+ 648.3637. C42H54O5Si
•
requires [M − H2O]+ 648.3635). νmax/cm−1 3541, 2931, 1720, 1688,
1272, 1111, 707. δH (300 MHz) 8.08 (2 H, m), 7.69–7.65 (4 H, complex
m), 7.58 (1 H, m), 7.47–7.34 (8 H, complex m), 6.03 (1 H, d, J 3.4), 4.10
(1 H, broad m), 3.69 (2 H, t, J 6.4), 2.69 (1 H, m), 2.50–2.12 (5 H, com-
plex m), 1.85–0.82 (8 H, complex m), 1.75 (3 H, s), 1.58 (3 H, s), 1.04
(9 H, s), 1.03 (3 H, s), 0.97 (3 H, s). δC (75 MHz) 215.0, 165.1, 137.5,
135.9, 135.6, 134.0, 134.1, 133.3, 129.8, 129.5, 128.4, 127.6, 71.6, 67.1,
63.6, 50.9, 50.8, 36.7, 33.4, 33.3, 31.8, 30.2, 29.7, 26.9, 24.9, 24.7, 24.6,
19.6, 19.2, 17.6. m/z (EI, 70 eV) 648 ([M − H2O]+•, 0.4%), 609 (2),
591 (3), 588 (3), 531 (5), 487 (24), 469 (15), 303 (26), 199 (39), 135
(25), 105 (100).
(1S,2S,4S)-4-{4,10,11,11-Tetramethyl-5-oxo-6-
(phenylmethoxy)bicyclo[5.3.1]undec-7-en-4-yl}butyraldehyde 38
A magnetically stirred solution of alcohol 37 (269 mg, 0.675 mmol) in
drydichloromethane(60 mL)wastreatedwithDess–Martinperiodinane
(429 mg, 1.012 mmol) and the resulting mixture stirred at 18◦C for 2 h
then treated with NaHCO3 (50 mL of a saturated aqueous solution) and
Na2S2O3 (50 mL of a saturated aqueous solution). The resulting mix-
ture was stirred vigorously until all suspended solids were dissolved.
The organic layer was then separated and the aqueous phase extracted
with dichloromethane (2 × 50 mL). The combined organic phases were
washed with brine (2 × 100 mL), then dried (MgSO4), filtered, and con-
centrated under reduced pressure. The resulting light-yellow oil was
subjected to flash chromatography (1 : 3 v/v ethyl acetate/hexane elu-
tion) and concentration of the appropriate fractions (Rf 0.4) gave the
aldehyde 38 (224 mg, 84%) as a colourless, crystalline solid, mp 78–
80◦C, [α]D −87.4◦ (c 0.9), (Found: M+• 396.2662. C26H36O3 requires
Concentration of fraction C (Rf 0.1 in 1 : 4 v/v ethyl acetate/hexane)
afforded the diol 36 (124 mg, 65%) identical, in all respects, with the
material obtained as described above.
Method C
Treatment of the tricyclic alcohol 32 (76 mg, 0.119 mmol) with
dimethyldioxirane (ca. 0.01 M in acetone, 11.6 mL, 1.162 mmol) in the
presence of dry potassium carbonate (200 mg) at 0◦C for 20 h followed
by thermolysis in boiling toluene, as above, gave a light-yellow oil on
work-up. Subjection of this material to flash chromatography (1 : 4 to
1 : 1 v/v ethyl acetate/hexane gradient elution) afforded two fractions
A and B.
Concentration of fractionA (Rf 0.3 in 1 : 4 v/v ethyl acetate/hexane)
gave compound 34 (19 mg, 25%) which was identical, in all respects,
with the material obtained as described above.
•
M+ 396.2664). νmax/cm−1 2931, 1724, 1693, 1455, 1101, 734. δH
(300 MHz) 9.80 (1 H, t, J 1.4), 7.33–7.25 (5 H, complex m), 4.42 (1 H,
d, J 11.9), 4.35 (1 H, d, J 2.9), 4.33 (1 H, d, J 11.9), 2.57–2.30 (4 H,
complex m), 2.18–1.92 (4 H, complex m), 1.73–1.20 (7 H, complex m),
1.47 (3 H, s), 1.40 (3 H, s), 1.05 (3 H, s), 0.88 (3 H, s). δC (75 MHz)
212.0, 202.6, 138.3, 136.7, 134.5, 128.3, 127.7, 127.6, 76.8, 70.5, 54.0,
49.6, 44.6, 36.3, 35.5, 31.7, 29.7, 27.4, 25.0, 24.4, 24.1, 21.9, 16.4, 15.9.
m/z (EI, 7 eV) 396 (M+•, 4%), 305 (7), 288 (20), 256 (28), 165 (64),
137 (65), 135 (51), 121 (40), 109 (32), 95 (80), 91 (100).
Concentration of fraction B (Rf 0.1 in 1 : 4 v/v ethyl acetate/hexane)
gave compound 36 (37 mg, 57%) which was identical, in all respects,
with the material obtained as described above.
(1S,4R)-4-(4-Hydroxybutyl)-4,8,11,11-tetramethylbicyclo[5.3.1]-
undec-7-en-3-one 39
and (1R,3aR,7S,8S,8aR)-(4-Hydroxybutyl)-1,4,9,9-tetramethyl-2,3,7,8-
tetrahydro-8-(phenylmethoxy)-1H-3a,7-methanoazulen-8a(6H)-ol 40
(1S,2S,4S)-4-[4-(tert-Butyldiphenylsilyloxy)butyl]-
4,8,11,11-tetramethyl-2-(phenylmethoxy)bicyclo[5.3.1]-
undec-7-ene-3,9-dione 29 (from 34)
Lithium bromide (42 mg), which had been dried at 18◦C and 1 mm Hg
for 5 h, was dissolved in dry THF (200 mL) and the resulting solution
was deoxygenated by the freeze-pump-thaw method (3 cycles and using
nitrogen as replacement gas). Freshly prepared SmI2 (611 µL of a 0.1 M
solution in THF, 0.061 mmol) was added, followed by a deoxygenated
solution of the keto-aldehyde 38 (11 mg, 0.0278 mmol). Since the blue
colour of SmI2 was discharged before addition of the substrate was
complete additional quantities of this reagent (2 mL of a 0.1 M solu-
tion in THF, 0.2 mmol) were added until a blue colour persisted. The
resulting mixture was allowed stir for 16 h at 18◦C then quenched by
addition of Na2S2O3 (3 mL of a 2 M aqueous solution) and extracted
with ether (2 × 10 mL). The combined organic phases was washed with
brine (2 × 20 mL), then dried (MgSO4), filtered, and concentrated under
reduced pressure. The resulting light-yellow oil was subjected to flash
chromatography (1 : 4 to 2 : 3 v/v ethyl acetate/hexane gradient elution)
thus giving two fractions, A and B.
A magnetically stirred solution of the alcohol 34 (66 mg, 0.101 mmol)
in dry dichloromethane (10 mL) was treated with N-methylmorpholine-
N-oxide (18 mg, 0.152 mmol) and 4 Å molecular sieves (50 mg). The
resulting mixture was stirred at 18◦C for 0.25 h then treated with
tetrapropylammonium perruthenate (3.6 mg, 0.0101 mmol). The ensu-
ing mixture was stirred at 18◦C for 3 h then filtered through a pad
of TLC-grade silica gel and the solids thus retained washed with
ethyl acetate (10 mL). The combined filtrates were concentrated under
reduced pressure and the residue subject to flash chromatography
(1 : 4 v/v ethyl acetate/hexane elution). Concentration of the appropriate
fractions (Rf 0.3) gave the enone 29 (64 mg, 97%) as a clear, colourless
syrup which was identical, in all respects, with the material obtained
previously.
(1S,2S,4S)-4-(4-Hydroxybutyl)-4,8,11,11-tetramethyl-
2-(phenylmethoxy)bicyclo[5.3.1]undec-7-en-3-one 37
Concentration of fractionA (Rf 0.5 in 1 : 4 v/v ethyl acetate/hexane)
gave a clear colourless oil tentatively identified as compound 39 (1 mg,
•
•
A magnetically stirred solution of the silyl ether 27 (474 mg,
0.761 mmol) in dry THF (35 mL) was treated with TBAF (1.52 mL of
a 1.0 M in THF, 1.52 mmol) and the resulting mixture stirred at 18◦C
for 3 h. The reaction mixture was poured into NH4Cl (50 mL of a sat-
urated aqueous solution) and extracted with ether (2 × 100 mL). The
combined organic extracts were washed with brine (2 × 50 mL), then
dried (MgSO4), filtered, and concentrated under reduced pressure. The
light-yellow residue thus obtained was subjected to flash chromatogra-
phy (2 : 3 v/v ethyl acetate/hexane elution) giving, after concentration of
the appropriate fractions (Rf 0.5), the title alcohol 37 (301 mg, 99%) as
12%) (Found: M+ 292.2395. C19H32O2 requires M+ 292.2402).
νmax/cm−1 3400, 2980, 1676, 1459, 1373, 1039. δH (300 MHz) 3.67
(2 H, m), 2.92 (1 H, dd, J 11.9 and 2.6), 2.38 (1 H, m), 2.24–0.80 (16 H,
complex m), 1.48 (3 H, s), 1.39 (3 H, s), 1.04 (3 H, s), 0.92 (3 H, s). m/z
(EI, 70 eV) 292 (M+•, 47%), 274 (11), 220 (37), 219 (38), 201 (33), 178
(100), 163 (50), 135 (66), 121 (76), 107 (60), 91 (49).
Concentration of fraction B (Rf 0.3 in 1 : 4 v/v ethyl acetate/hexane)
gave compound 40 (7 mg, 63%) as a clear, colourless syrup,
•
+
[α]D + 36.7◦ (c 0.55), (Found: [M − CH3
]
385.2730. C26H38O3
•
+
requires [M − CH3
]
385.2743). νmax/cm−1 3400, 2942, 1464, 1067.
δH (300 MHz) 7.38–7.26 (5 H, complex m), 4.58 (1 H, d, J 11.4), 4.52
•
•
a clear, colourless oil (Found: M+ 398.2824. C26H38O3 requires M+

64
M. G. Banwell, M. D. McLeod and A. G. Riches
(1 H, d, J 11.4), 4.07 (1 H, d, J 5.0), 3.66 (3 H, m), 3.40 (1 H, broad s),
2.40 (1 H, m), 2.03 (1 H, m), 1.90–0.80 (12 H, complex m), 1.13 (3 H,
s), 1.01 (3 H, s), 0.99 (3 H, s), 0.89 (3 H, s). δC (75 MHz) 138.2, 128.6,
128.1, 90.9, 80.5, 71.7, 62.8, 61.6, 47.2, 47.1, 41.6, 38.7, 38.0, 34.9, 33.4,
29.2, 28.5, 26.2, 25.7, 22.9, 22.1, 20.6, 18.7 (on•e resonance obscured or
overlapping). m/z (EI, 70 eV) 385 ([M − CH3 ]+, 2%), 309 (31), 294
(26), 292 (29), 279 (29), 149 (23), 109 (30), 107 (31), 95 (35), 91 (100).
3.24 (2 H, t, J 6.6), 3.11 (1 H, d, J 19.5), 2.68–2.49 (3 H, complex m),
2.33 (1 H, broad d, J 14.2), 2.17 (1 H, m), 1.90–1.20 (7 H, complex m),
1.72 (3 H, s), 1.51 (3 H, s), 1.15 (3 H, s), 0.95 (3 H, s).
(1S,2S,4S,9R)-2,9-Dihydroxy-4-(4-hydroxybutyl)-
4,8,11,11-tetramethylbicyclo[5.3.1]undec-7-en-3-one 48
A magnetically stirred solution of the diol 36 (60 mg, 0.107 mmol) in
dryTHF (5 mL) was treated withTBAF (1.0 M solution inTHF, 320 µL,
0.320 mmol), the resulting mixture stirred at 18◦C for 5 h then poured
into ammonium chloride (10 mL of a saturated aqueous solution) and
extracted with ethyl acetate (4 × 20 mL). The combined extracts were
washed with brine (1 × 15 mL), then dried (MgSO4), filtered, and con-
centrated under reduced pressure. The residue was subjected to flash
chromatography (ethyl acetate elution) to give, after concentration of
the appropriate fractions (Rf 0.4), the triol 48 (33 mg, 95%) as a clear,
(1S,2S,4S)-4-(4-Hydroxybutyl)-4,8,11,11-tetramethyl-
2-(phenylmethoxy)bicyclo[5.3.1]undec-7-ene-3,9-dione 43
A
magnetically stirred solution of the silyl ether 29 (15 mg,
0.0235 mmol) in dry THF (2 mL) was treated with TBAF (35 mL
of a 1.0 M solution in THF, 0.035 mmol) and the resulting mixture
stirred at 18◦C for 1 h then poured into NH4Cl (5 mL of a saturated
aqueous solution) and extracted twice with ether (3 × 10 mL). The com-
bined organic extracts were washed with brine (2 × 30 mL), then dried
(MgSO4), filtered, and concentrated under reduced pressure.The result-
ing light-yellow oil was subjected to flash chromatography (4 : 1 v/v
ethyl acetate/hexane elution) and concentration of the appropriate frac-
tions (Rf 0.4) gave the alcohol 43 (9 mg, 93%) as a clear, colourless
•
colourless oil, [α]D +17.8◦ (c 1.4), (Found: M+ 324.2302. C19H32O4
•
requires M+ 324.2301). νmax/cm−1 3400, 2940, 1675, 1461, 1408,
1011, 731. δH (300 MHz) 4.60 (1 H, d, J 3.7), 4.01 (1 H, broad d,
J 10.6), 3.67 (2 H, t, J 6.5), 2.59 (1 H, m), 2.43–1.20 (5 H, complex
m), 1.72 (3 H, s), 1.45 (3 H, s), 0.97 (3 H, s), 0.92 (3 H, s). δC (75 MHz)
222.5, 138.4, 135.0, 70.2, 67.1, 62.6, 53.0, 50.4, 36.6, 33.3, 33.0, 31.2,
30.1, 28.6, 24.7, 24.6, 19.7, 17.5, 17.4. m/z (EI, 70 eV) 324 (M+•, 3%),
306 (6), 291 (10), 233 (17), 211 (23), 149 (26), 137 (35), 136 (32), 135
(100), 133 (46), 121 (45).
•
oil, [α]D −16.0◦ (c 1.06), (Found: M+ 412.2610. C26H36O4 requires
•
M+ 412.2614). νmax/cm−1 3402, 2924, 1693, 1662, 1454, 1072. δH
(300 MHz) 7.36–7.26 (5 H, complex m), 4.50 (1 H, d, J 3.2), 4.41 (1 H,
d, J 11.6), 4.28 (1 H, d, J 11.6), 3.68 (2 H, t, J 6.3), 3.12 (1 H, d, J 19.5),
2.67–2.47 (3 H, complex m), 2.30 (1 H, broad d, J 14.3), 2.16 (1 H, m),
1.83 (1 H, m), 1.75–0.80 (7 H, complex m), 1.71 (3 H, s), 1.50 (3 H, s),
1.14 (3 H, s), 0.95 (3 H, s). δC (75 MHz) 212.9, 198.6, 157.4, 137.7,
Oxidations of Triol 54. Formation of (1S,2S,4S)-2-Hydroxy-
4-(4-hydroxybutyl)-4,8,11,11-tetramethylbicyclo[5.3.1]undec-7-
ene-3,9-dione 49
and (1S,2S,4R)-4-{2-Hydroxy-4,8,11,11-tetramethyl-
5,9-dioxobicyclo[5.3.1]undec-7-en-4-yl}butyraldehyde 50
135.8, 128.4, 127.8, 127.7, 75.7, 70.6, 62.5, 50.0, 49.8, 37.3, 35.0, 33.7,
•
33.2, 32.2, 31.8, 26.1, 24.7, 24.5, 19.7, 14.6. m/z (EI, 70 eV) 412 (M+
,
0.8%), 369 (0.8), 321 (7), 293 (13), 270 (30), 179 (51), 91 (100).
(1S,2S,4S)-4-(4-Bromobutyl)-4,8,11,11-tetramethyl-2-
(phenylmethoxy)bicyclo[5.3.1]undec-7-ene-3,9-dione 44
Method A
A magnetically stirred solution of the triol 48 (11 mg, 0.0339 mmol)
in dry dichloromethane (2 mL) maintained at 0◦C was treated with
the Dess–Martin periodinane (14.4 mg, 0.0339 mmol) and the result-
ing mixture stirred at 0◦C for 1 h. The reaction mixture was then
quenched by the successive addition of Na2S2O3 (2 mL of a satu-
rated aqueous solution) then NaHCO3 (2 mL of a saturated aqueous
solution) and the resulting slurry stirred vigorously for 0.5 h. The sepa-
rated aqueous phase was extracted with dichloromethane (2 × 5 mL) and
the combined organic phases washed with brine (2 × 10 mL), then
dried (MgSO4) filtered, and concentrated under reduced pressure.
Subjection of the resulting light-yellow oil to flash chromatography
(2 : 3 v/v ethyl acetate/hexane to ethyl acetate gradient elution) gave two
fractions, A and B.
A magnetically stirred solution of the alcohol 43 (9 mg, 0.0218 mmol)
in dry dichloromethane (2 mL) was treated with Ph3P · Br2 (327 µL of a
0.1 M solution in dichloromethane, 0.0327 mmol) and the resulting mix-
ture was stirred at 18◦C for 1 h and then poured into water and extracted
with dichloromethane (2 × 10 mL).The combined organic extracts were
washed with brine (2 × 40 mL), then dried (MgSO4), filtered, and con-
centrated under reduced pressure. The ensuing light-yellow oil was
subjected to flash chromatography (1 : 3 v/v ethyl acetate/hexane elu-
tion) and concentration of the appropriate fractions (Rf 0.5) afforded the
•
alkyl bromide 44 (10 mg, 96%) as a clear, colourless oil (Found: M+
•
474.1767. C26H3579BrO3 requires M+ 474.1770). νmax/cm−1 2924,
1694, 1666, 1454, 1098, 1068. δH (300 MHz) 7.37–7.27 (5 H, complex
m), 4.50 (1 H, d, J 3.3), 4.41 (1 H, d, J 11.5), 4.29 (1 H, d, J 11.5), 3.46
(2 H, t, J 6.4), 3.12 (1 H, d, J 19.5), 2.68–2.48 (3 H, complex m), 2.33
(1 H, broad d, J 14.3), 2.17 (1 H, m), 1.95–1.79 (3 H, complex m), 1.72
(3 H, s), 1.72–0.80 (4 H, m), 1.51 (3 H, s), 1.15 (3 H, s), 0.95 (3 H, s). δC
(75 MHz) 212.7, 198.5, 157.3, 137.7, 135.8, 128.4, 127.9, 127.7, 75.6,
70.6, 49.9, 49.8, 37.3, 35.1, 33.9, 33.7, 32.9, 32.1, 30.9, 26.1, 24.8, 24.5,
21.7, 14.6. m/z (EI, 70 eV) 476 and 474 (M+•, both 3%), 433 (3) and
431 (3), 385 (32) and 383 (32), 357 (97) and 355 (100), 270 (40), 179
(61), 91 (100).
Concentration of fraction A (Rf 0.3, 4 : 1 v/v ethyl acetate/hexane)
yielded compound 49 (2 mg, 18%) as a clear colourless oil, [α]D −73.4◦
•
•
(c 1.0), (Found: M+ 322.2141. C19H30O4 requires M+ 322.2144).
νmax/cm−1 3400, 2926, 1685 (sh), 1654, 1460, 1058. δH (300 MHz)
4.69 (1 H, dd, J 8.3 and 3.7), 3.69 (2 H, t, J 6.3), 3.16 (1 H, broad d, J
8.3), 2.64–2.53 (3 H, complex m), 2.43–2.17 (3 H, complex m), 2.00–
1.20 (8 H, complex m), 1.72 (3 H, s), 1.57 (3 H, s), 1.17 (3 H, s), 1.03
(3 H, s). δC (75 MHz) 217.8, 197.7, 159.0, 135.6, 69.3, 62.6, 51.8, 50.2,
37.6, 35.1, 33.2, 32.8, 31.8, 31.1, 26.1, 25.5, 24.3, 19.5, 14.6. m/z (EI,
70 eV) 323 ([M + H]+, 35%), 322 (M+•, 7), 279 (20), 238 (35), 203
(20), 180 (100), 165 (34), 151 (43), 137 (37), 121 (62).
(1S,2S,4S)-4-(4-Iodobutyl)-4,8,11,11-tetramethyl-2-
(phenylmethoxy)bicyclo[5.3.1]undec-7-ene-3,9-dione 45
Concentration of fraction B (Rf 0.6, 4 : 1 v/v ethyl acetate/hexane)
yielded compound 50 (5 mg, 46%) as a clear, colourless syrup, [α]D
A magnetically stirred solution of the alkyl bromide 44 (9 mg,
0.0189 mmol) in acetone (2 mL) was treated with anhydrous sodium
iodide (11 mg, 0.0757 mmol) and the resulting mixture heated at reflux
for 4 h. The cooled reaction mixture was concentrated under reduced
pressure and the residue partitioned between ether (5 mL) and Na2S2O3
(5 mL of a ca. 0.1 M aqueous solution).The separated organic phase was
washed with brine (1 × 5 mL), then dried (MgSO4), filtered, and con-
centrated under reduced pressure to give alkyl iodide 45 (9 mg, 91%) as
a clear, colourless, but unstable oil. δH (300 MHz) 7.37–7.25 (5 H, com-
plex m), 4.51 (1 H, d, J 3.3), 4.41 (1 H, d, J 11.5), 4.29 (1 H, d, J 11.5),
•
•
−103.0◦ (c 1.0), (Found: M+ 320.1988. C19H28O4 requires M+
320.1988). νmax/cm−1 3411, 2924, 1720, 1687, 1662, 1461, 1058. δH
(300 MHz) 9.81 (1 H, t, J 1.1), 4.69 (1 H, m), 3.14 (1 H, d, J 8.7), 2.70–
2.20 (5 H, complex m), 1.94 (1 H, m), 1.70–0.80 (7 H, complex m), 1.68
(3 H, s), 1.57 (3 H, s), 1.16 (3 H, s), 1.04 (3 H, s). δC (75 MHz) 217.4,
201.9, 197.6, 158.8, 135.6, 69.3, 51.8, 50.1, 44.2, 37.6, 35.0, 32.8, 31.7,
30.9, 26.0, 25.2, 24.2, 15.7, 14.6. m/z (EI, 70 eV) 320 (M+•, 6%), 305
(8), 248 (55), 236 (37), 231 (26), 180 (67), 165 (21), 151 (28), 149 (34),
142 (100), 121 (38), 100 (27), 84 (42).

Taxane Diterpene Synthesis Studies—Part 2
65
Method B
[6] (a) J. D. Winkler, S. K. Bhattacharya, R. A. Batey, Tetrahedron
Lett. 1996, 37, 8069. doi:10.1016/0040-4039(96)01841-2
(b) A. J. Phillips, J. C. Morris, A. D. Abell, Tetrahedron Lett.
2000, 41, 2723. doi:10.1016/S0040-4039(00)00248-3
[7] For useful reviews by key contributors to this area see:
(a) I. Kuwajima, H. Kusama, Synlett 2000, 1385. doi:10.1055/S-
2000-7619
Treatment of triol 48 (34 mg, 0.105 mmol) with Dess–Martin period-
inane (89 mg, 0.210 mmol) at 0◦C for 4 h as described above gave diol
49 (7 mg, 21%) and the aldehyde 50 (23 mg, 68%).
(1S,4S)-4-{4,8,11,11-Tetramethyl-5,6,9-trioxobicyclo[5.3.1]undec-7-
en-4-yl}butyraldehyde 51
(b) L. A. Paquette, M. Zhao, F. Montgomery, Q. Zeng, T. Z.
Zhong, S. Elmore, K. Combrink, H.-L. Wang, S. Bailey, Z. Su,
Pure Appl. Chem. 1998, 70, 1449.
A magnetically stirred solution of triol 48 (14 mg, 0.0431) in
dichloromethane (2 mL) was treated with the Dess–Martin periodinane
(60 mg, 0.141 mmol) and the resulting mixture stirred at 18◦C for 4 h.
The reaction mixture was then worked up as described above and the
resulting light-yellow oil subject to flash chromatography (3 : 7 v/v ethyl
acetate/hexane elution). Concentration of the appropriate fractions (Rf
0.5) then gave the title compound 51 (5 mg, 36%) as a clear, colourless
syrup, [α]D −97.7◦ (c 0.4), (Found: M+• 318.1834. C19H26O4 requires
[8] W. Bauta, J. Booth, M. E. Bos, M. DeLuca, L. Diorazio,
T. Donohoe, N. Magnus, P. Magnus, J. Mendoza, P. Pye,
J. Tarrant, S. Thom, F. Ujjainwalla, Tetrahedron Lett. 1995,
36, 5327.
[9] M. G. Banwell, P. Darmos, D. C. R. Hockless, Aust. J. Chem.
2004, 57, 41. doi:10.1071/CH03164
•
M+ 318.1831). νmax/cm−1 2938, 1722, 1696, 1677, 1462, 1376, 875.
[10] (a) M. G. Banwell, J. R. Dupuche, Chem. Commun. 1996, 967.
(b) M. G. Banwell, J. R. Dupuche, R. W. Gable, Aust. J. Chem.
1996, 49, 639. (c) M. G. Banwell, C. Chun, A. J. Edwards,
M. Vögtle, Aust. J. Chem. 2003, 56, 861. doi:10.1071/CH03112
[11] For a very useful review on the generation and synthetic utility
of this and related cis-1,2-dihydrocatechols see: T. Hudlicky,
D. Gonzalez, D. T. Gibson, Aldrichimica Acta 1999, 32, 35.
[12] M. G. Banwell, A. J. Edwards, G. J. Harfoot, K. A. Jolliffe,
M. D. McLeod, K. J. McRae, S. G. Stewart, M. Vögtle, Pure
Appl. Chem. 2003, 75, 223.
[13] D. R. Boyd, N. D. Sharma, S. A. Barr, H. Dalton, J. Chima,
G. Whited, R. Seemayer, J. Am. Chem. Soc. 1994, 116, 1147.
[14] S. F. Martin, J.-M. Assercq, R. E. Austin, Tetrahedron 1995,
51, 3455. doi:10.1016/0040-4020(95)00095-P
[15] Y. Oikawa, T. Nishi, O. Yonemitsu, Tetrahedron Lett. 1983,
24, 4037. doi:10.1016/S0040-4039(00)88256-8
[16] For a review of ketene equivalents see: S. Ranganathan,
D. Ranganathan, A. K. Mehrotra, Synthesis 1977, 289.
doi:10.1055/S-1977-24362
[17] H.-J. Cristau, Y. Ribeill, L. Chiche, F. Plénat, J. Organomet.
Chem. 1988, 352, C47. doi:10.1016/0022-328X(88)83131-0
[18] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
1994, 639. doi:10.1055/S-1994-25538
δH (300 MHz) 9.81 (1 H, t, J 1.1), 3.06–2.34 (7 H, complex m), 2.13
(1 H, m), 1.94 (1 H, m), 1.77 (3 H, s), 1.74–1.10 (4 H, complex m),
1.42 (3 H, s), 1.28 (3 H, s), 1.23 (3 H, s). δC (75 MHz) 210.6, 207.6,
201.9, 196.2, 157.3, 137.6, 59.4, 48.4, 44.1, 35.8, 33.5, 32.2, 31.3, 26.0,
24.8, 24.5, 15.3, 15.0 (one resonance obscured or overlapping). m/z
(EI, 70 eV) 318 (M+•, 12%), 290 (17), 222 (64), 221 (59), 203 (55), 178
(100), 150 (46), 135 (71), 122 (41), 107 (80), 91 (32).
Attempted Cyclization of Compound 50
A magnetically stirred solution of the compound 50 (9 mg, 0.0281) in
THF (2 mL) was cooled to −78◦C and LiHMDS (56 µL of a 1.0 M solu-
tion in THF) was added dropwise. Stirring was continued at −78◦C for
0.25 h then the reaction mixture was allowed to warm to 18◦C over 0.5 h,
before quenching with NH4Cl (5 mL of a saturated aqueous solution).
The resulting mixture was extracted with ethyl acetate (2 × 10 mL) and
the combined extracts were washed with brine (2 × 10 mL), then dried
(MgSO4), filtered, and concentrated under reduced pressure. Subjection
of the resulting light-yellow oil to flash chromatography (ethyl acetate)
gave, after concentration of the appropriate fractions (Rf 0.2), ca. 1 mg
of a•colourless syrup that is isomeric with the starting material (Found:
•
M+ 320.1986. C19H28O4 requires M+ 320.1988). νmax/cm−1 3424,
2924, 1662, 1603, 1461, 1302, 1058, 731. m/z 321 ([M + H]+, 7%),
320 (M+•, 8), 305 (18), 291 (10), 236 (70), 180 (100), 165 (37), 151
(47), 137 (26), 135 (24), 121 (61), 91 (24), 67 (28).
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Acknowledgements
[22] For related examples of this phenomenon see: R. A. Holton,
C. Somoza, H.-B. Kim, F. Liang, R. J. Biediger, P. D. Boatman,
M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki,
C. Tao, P. Vu, S. Tang, P. Zhang, K. K. Murthi, L. N. Gentile,
J. H. Liu, J. Am. Chem. Soc. 1994, 116, 1597.
[23] Potassium t-butoxide has been used previously as the base to
effect anionic oxy-Cope rearrangement reactions (L. A. Paquette,
S. Nakatani, T. M. Zydowsky, S. D. Edmondson, L.-Q. Sun,
R. Skerlj, J. Org. Chem. 1999, 64, 3244) but we are not aware
of any prior examples of the ‘internal quench’ procedure
employed here. doi:10.1021/JO9825254
We thank the Institute of Advanced Studies for providing
post-doctoral Fellowships to M.D.M. and A.G.R. Dr Gregg
Whited (Genencor International Inc., Palo Alto) as well
as Professor Tomas Hudlicky (University of Florida at
Gainesville) are warmly thanked for providing generous
quantities of the cis-1,2-dihydrocatechol 7.
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66
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