Synthesis of a tetraoxy-bis-nortaxadiene, en route to taxol, using a cascade radical cyclisation sequence

Article abstract of DOI:10.1016/j.tet.2009.04.021

Concise syntheses of the substituted enynediones 28a, 33b and 36 starting from the cyclohexenealdehyde 18, corresponding to ring A in the taxanes, and the vinylstannane 24, are described. Treatment of 36 with Bu₃SnH-AIBN did not lead to the oxy

Full text of DOI:10.1016/j.tet.2009.04.021

Tetrahedron 65 (2009) 6670–6681
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Synthesis of a tetraoxy-bis-nortaxadiene, en route to taxol, using a cascade
radical cyclisation sequence
*
William P.D. Goldring, Gerald Pattenden , Stuart L. Rimmington
School of Chemistry, The University of Nottingham, Nottingham NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Concise syntheses of the substituted enynediones 28a, 33b and 36 starting from the cyclo-
hexenealdehyde 18, corresponding to ring A in the taxanes, and the vinylstannane 24, are described.
Treatment of 36 with Bu3SnH–AIBN did not lead to the oxy-substituted taxadiene 37 expected from
a tandem radical macrocyclisation–radical transannulation sequence; instead, a mixture of unidentified
products resulted. When the PMB ether 33b corresponding to the alcohol 36 was treated with Bu3SnH–
AIBN under similar conditions, p-anisaldehyde was isolated, as a major by-product, but no evidence for
the formation of a taxadiene could be observed. In contrast, the iododienynedione 41, i.e., deoxy 36,
underwent a tandem radical macrocyclisation–transannulation sequence, when treated with Bu3SnH–
AIBN, leading to the tetraoxy-bis-nortaxadiene 42 in 44% yield. Attempts to synthesise the alcohol 28b
from the silyl ether 28a en route to the iodide 28c instead gave the substituted tetrahydrofuran 29 via an
intramolecular oxy-Michael reaction.
Received 26 February 2009
Received in revised form 3 April 2009
Accepted 6 April 2009
Available online 16 April 2009
Keywords:
Taxanes
Radical cascades
Taxoids
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
transannular cyclisations from geranylgeranylpyrophosphate
(GGPP) 3.12 A series of cytochrome P450-mediated oxidations then
The natural product taxol (paclitaxel or TaxolÔ) 1, isolated from
the Pacific yew tree Taxus brevifolia,1 has been the focus of intense
interest amongst chemists and biologists ever since its pronounced
anti-cancer properties were revealed some 30 years ago.2 After
a further period of research studying its mode of action, followed by
chemical trials, Taxol and its semi-synthetic analogue Taxotere 2
entered the clinic in the early 1990s as drugs for the treatment of
ovarian and breast cancer.3 With its availability from natural
sources very limited, taxol became one of the most challenging
targets for total synthesis throughout the late 1980s and the early
1990s. These efforts culminated in two independent syntheses of
taxol, published simultaneously by the research groups led by
Holton4 and by Nicolaou5 in 1994, closely followed by distinctly
different total syntheses by Danishefsky et al. (1996),6 Wender et al.
(1997),7 Kuwajima et al. (1998)8 and by Mukaiyama et al. (1999).9
Needless to say, however, over the past 20 years, a wide range of
ingenious synthetic designs towards the unique tricyclic ring sys-
tem in taxol have emerged, some of which may also yet lead to
further total syntheses.10,11
enter the arena to decorate the taxadiene hydrocarbon 5 with its
oxygenation pattern.13 In 1984, and before taxol became such a re-
vered compound, we synthesised the 6,12-bicyclic hydrocarbon 4,
known as verticillene, which was a purported biosynthetic in-
termediate between GGPP and taxadiene.14 We also examined
electrophilic transannular cyclisations from verticillene 4 but, un-
fortunately, we were not able to convert it into the 6,8,6-tricyclic
taxadiene 5. Interestingly, Croteau et al.15 were also unable to ob-
tain taxadiene 5 when verticillene 4 was added to incubations
containing the taxadiene synthase enzyme.16
AcO
O
OH
Ph
O
NH
O
O
O
H
Ph
O
HO OBz OAc
OH
Taxol (1)
Nature elaborates the 6,8,6-tricyclic ring system in taxanes us-
ing a sequence of electrophilic macrocyclisation followed by two
HO
O
OH
Ot-Bu
O
NH
O
H
Ph
O
HO OBz OAc
OH
* Corresponding author. Tel.: þ44 (0)115 951 3530; fax: þ44 (0)115 951 3535.
E-mail address: gerald.pattenden@nottingham.ac.uk (G. Pattenden).
Taxotere (2)
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.021

W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
6671
coupling to the substituted vinylstannane 24. The vinylstannane 24
was prepared in five steps from commercial (S)-1,2,4-butanetriol
19. Thus, protection of the triol 19 as its p-methoxybenzylidene
acetal followed by oxidation of the primary alcohol group in 20
using Swern conditions, first gave the aldehyde 21. A modified Takai
olefination reaction24 next gave the E-vinylstannane 22, which was
then reduced, using DIBAL, leading to the primary alcohol 23. Fi-
nally, treatment of 23 with TBS chloride gave the differentially
protected 1,3-diol substituted vinylstannane 24.
H
OPP
3
H
4
H
5
Over the past decade and more, our research group has exam-
ined a range of carbon-centred radical-mediated cascade cyclisa-
tions to access a variety of ring-fused systems found in natural
products.17 These studies also included a synthetic approach to the
taxane ring system,18 which distinguished itself from all other ap-
proaches, whereby the 8,6-(BC) fused ring system in the natural
product was elaborated in a single step via a tandem radical cascade
sequence from a substituted A-ring precursor, viz. 6/7.19 We have
now investigated this approach to taxanes using a more oxygen-
substituted ring A precursor, i.e., 8, with the aim of producing an
advanced taxadiene, viz. 9, towards taxol itself.
O
O
H
H
O
O
R
R
H
H
10
11
O
2. Results and discussion
O
H
An important limitation in the radical cascade sequence, 6/7,
to the tricyclic ring system in the taxanes was found when pre-
cursors carrying methyl group substitutions at C8 on their C8–C9
alkene bonds were used, i.e., 6c. In these instances, only the
products 11 resulting from intramolecular 1,5-H abstraction in-
volving the first-formed alkyl radical centre and the vinyl methyl
group, via 10, were isolated, rather than the anticipated angular
methyl substituted tricycles 12.19 Accordingly, our synthesis design
towards taxol necessitated that we introduce the (angular) C8-
methyl group after elaborating any oxygenated taxane tricycle.
12
O
O
OR''
OR''
RO
RO
O
O
OR'
13
OR'
14
Addition of the cyclohexenealdehyde 18 to the vinyllithium
species produced from the stannane 24, using n-BuLi, followed by an
aqueous work-up, gave a mixture of diastereoisomers of the adduct
25, resulting from simultaneous removal of the benzoate group in 18
(Scheme 2). Oxidation of the primary and secondary hydroxyl
groups in 25 next led to the ketoaldehyde 26, which reacted
O
O
R
H
7
C
4
9
6
5
Bu3SnH
AIBN
8
8
B
R'
A
3
I
A
O
O
H
H
6
7
OTBS
OTBS
a, R = H; R' = CH=CH2
b, R = H; R' =C CH
a, Δ3,4-dihydro
b, Δ3,4-dehydro
a
HO
MOMO
c, R = Me; R' = CH=CH2/C CH
HO
15
OBz
MOMO
16
OBz
O
O
OR''
OR''
7
H
O
CH2OH
OBz
CHO
I
b
c
RO
RO
O
OR'
8
OR'
9
MOMO
MOMO
MOMO
MOMO
OBz
17
18
A number of sequences were considered, however, whereby an
angular methyl group could be introduced at C8 in an appropriately
oxygenated taxadiene intermediate, i.e., 9. These included using
a C–H insertion reaction at C8 from a diazo ester intermediate as-
sociated with the C7 hydroxy group in 9,20 or by Michael addition of
an appropriate methylcuprate to the conjugated enone 13 derived
from 9,21 and/or via cleavage of the cyclopropane ring in a cyclo-
propyl ketone intermediate viz. 14.22 In spite of all these plausible
considerations, however, we first needed to prepare the oxygen-
ated taxadiene 9 from the radical cascade precursor 8!
PMP
PMP
O
O
O
OH OH
O
d
e
OH
OH
O
19
20
21
PMP
O
O
OPMB
g,h
f
To achieve the aforementioned objective, we began by synthe-
sising the fully oxygen-substituted chiral A-ring compound 15,
starting from 2,2-dimethyl-cyclohexan-1,3-dione using a sequence
we had already developed and published in full.11a,23 Protection of
the secondary and tertiary hydroxyl groups in 15 as their MOM
ethers, followed by deprotection of the silyl ether group in the
product 16 first gave the primary alcohol 17 (Scheme 1). Oxidation
of 17 next gave the corresponding aldehyde 18 in readiness for
Bu3Sn
Bu3Sn
23, R = H
24, R = TBS
OR
22
Scheme 1. Reagents and conditions: (a) TBAI, DIPEA, MOMCl, CH2Cl2, 83%; (b) TBAF,
THF, 60%; (c) Dess–Martin periodinane, NaHCO3, CH2Cl2, 82%; (d) p-methox-
ybenzaldehyde dimethyl acetal, CH2Cl2, 40 ꢀC, 77%; (e) (COCl)2, DMSO, then NEt3,
CH2Cl2, ꢁ78 ꢀC, 82%; (f) CrCl2, DMF, Bu3SnCHBr2, LiI, THF, 48%; (g) DIBAL, CH2Cl2, 67%;
(h) NEt3, DMAP, TBSCl, 95%.

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W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
HO
O
OPMB
OPMB
a
b
18 + 24
OTBS
OTBS
26
MOMO
MOMO
OH
O
MOMO
OPMB
MOMO
25
PMBO
O
O
O
OPMB
O
e
c
d
OH
O
OTBS
R'
MOMO
MOMO
MOMO
MOMO
MOMO
O
MOMO
29
27
28
a, R' = OTBS
b, R' = OH
c, R' = I
Scheme 2. Reagents and conditions: (a) 24, n-BuLi, THF, ꢁ78 ꢀC, then 18, 92%; (b) Dess–Martin periodinane, NaHCO3, CH2Cl2, 85%; (c) HCCMgBr, THF, 0 ꢀC; (d) Dess–Martin pe-
riodinane, NaHCO3, CH2Cl2, 98% (over two steps); (e) TBAF, THF, 55%.
selectively with acetylenemagnesium bromide producing the
propargylic alcohol 27. Oxidation of 27, using Dess–Martin period-
inane, then gave the ynone 28a in 98% yield over two steps. Our plan
now was to remove the silyl ether protecting group in 28a and then
convert the resulting alcohol 28b into the corresponding iodide 28c,
in readiness for the proposed radical cascade to a taxane, viz. 9.
Unfortunately, when the silyl ether 28a was treated with TBAF, the
resulting alcohol 28b underwent immediate intramolecular oxy-
Michael cyclisation producing the tetrahydrofuran 29 instead.
To overcome the above problem, we first converted the diol 25
into its bis-p-nitrobenzyl derivative 30 and then removed the TBS
protection producing the alcohol 31a (Scheme 3). The alcohol 31a
was next converted into the bromide 31b, via its mesylate. The ester
groups in 31b were saponified and the resulting diol was then
oxidised to the ketoaldehyde 32. Finally, the ketoaldehyde 32 was
converted into the enynone 33a using procedures described earlier
in the conversion of 26 into 28. Interchange of bromide for iodide in
33a, using Finkelstein conditions, then gave the radical precursor
33b. Much to our chagrin, when the iodide 33b was treated with
Bu3SnH–AIBN, the only ‘product’ isolated was p-anisaldehyde. We
believe the p-anisaldehyde originates from cleavage of the benzyl
ether group at C7 in 33b via a process involving 1,5-H abstraction by
the alkyl radical intermediate 34, leading to the benzyl radical 35,
which then undergoes a precedented fragmentation as shown in
Scheme 4.25 Unfortunately, no products, resulting from the antici-
pated radical cascade, were isolated.
produced from the PMB ether 33b after treatment with DDQ in
CH2Cl2–H2O at 0 ꢀC (Scheme 5). Subsequent treatment of the io-
dide 36a with Bu3SnH–AIBN led to a mixture of products, but we
were baffled to find that not only did none of them correspond to
the substituted taxane ring system 37, but also none of them
contained any alkene unsaturation on analysis of their NMR
spectroscopic data! A similar fate was met by the corresponding
TBS ether (36b).
At this point in time in our studies, we asked ourselves whether
it was simply the oxy-substitution at C7, which was affecting the
attempted radical cascade reactions from the iodides 33b and 36, or
perhaps it had something to do with the oxy-substitutions in the A-
rings of the same precursors. To answer this question we decided to
examine a radical cascade from the substituted iodide 41, which
lacked any oxy-functionality at C7, but contained a fully oxy-
substituted A-ring. The iodoenynedione 41 was produced from
the aldehyde 18 and the vinylstannane 38 derived from pent-4-yn-
1-ol26 using procedures and reagents, which were identical to those
used previously in the syntheses of the analogous compounds 28,
33 and 36 from 18 (Scheme 6).
We were gratified to find that when the iodide 41 was treated
with Bu3SnH–AIBN, it underwent alkyl radical formation, followed
by a tandem 12-endo-dig macrocyclisation and 6-exo-trig cyclisa-
tion leading to the 6,8,6-tricyclic dienedione 42, in 44% yield after
purification by chromatography. The structure and stereochemistry
of the tricycle 42 followed from analysis of its 1H–1H COSY NMR
spectroscopic data together with comparison of its spectroscopic
data with those of the analogue 7a devoid of oxy-substitution in the
A-ring, prepared by us in early work.19
Almost as a last resort we then attempted to carry out a radical
cascade from the substrate 36a containing no protecting group
associated with the C7 hydroxy group. This alcohol was easily
PNBO
PNBO
PNBO
OPMB
OPMB
OPMB
b
c,d
MOMO
a
25
OTBS
OH
Br
MOMO
MOMO
OPNB
30
OPNB
31a
OPNB
31b
MOMO
MOMO
MOMO
O
O
O
OPMB
OPMB
OPMB
I
g,h
i
e,f
O
O
Br
Br
MOMO
MOMO
MOMO
O
MOMO
MOMO
33a
MOMO
32
33b
Scheme 3. Reagents and conditions: (a) PNBCl, NEt3, DMAP, CH2Cl2, 97%; (b) HF$Py, Py, 84%; (c) MsCl, NEt3, CH2Cl2; (d) LiBr, THF, 56 ꢀC, 73% (over two steps); (e) K2CO3, MeOH, 86%;
(f) Dess–Martin periodinane, NaHCO3, CH2Cl2; (g) HCCMgBr, THF, 0 ꢀC; (h) Dess–Martin periodinane, NaHCO3, CH2Cl2, 67% (over three steps); (i) NaI, butan-2-one, 80 ꢀC, 95%.

W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
6673
C6H4OMe
H
C6H4OMe
H
C6H4OMe
33b
O
O
O
R
R
R
34
35
Scheme 4. Fragmentation of the alkyl radical centre produced from the iodide 33b, leading to p-anisaldehyde.
the same oxidation level, and of similar constitution, to the ad-
vanced intermediate 43 used by Kuwajima et al.8 in their synthesis
of taxol. Thus, a synthetic sequence involving 1,2-carbonyl group
transposition, i.e., C10 to C9, and oxidative dehydrogenation of the
C7 to C8 bond in 42, as key steps, could have provided access to the
compound 43 from 42.
O
O
OR
OH
a
33b
O
I
MOMO
MOMO
O
37
MOMO
MOMO
36a, R = H
b
36b, R = TBS
3. Conclusions
Scheme 5. Reagents and conditions: (a) DDQ, CH2Cl2–H2O, 87%; (b) TBSOTf, 2,6-luti-
dene, CH2Cl2, 56%.
The approach to complex polycyclic structures involving cas-
cades of radical cyclisations is a powerful strategy, which is now
widely applied in contemporary organic synthesis. Protagonists of
the applications of this novel radical chemistry will emphasise its
special benefits when compared with corresponding ionic re-
actions. For our own part, we have shown here, and elsewhere, how
powerful radical cascade reactions can be in accessing a variety of
complex ring-fused systems, not just taxanes, but steroids and
a multitude of polycyclic terpenoids.17 We would also emphasise
that when these same radical cascades do not proceed according to
plan, they can always be relied upon to produce new chemistry and
interesting new chemical structures.
The successful outcome of the cascade cyclisation from 41 to 42
demonstrated that the oxy-substituents in the A-ring of the pre-
cursor 41 had no effect on the outcome of the cascade. With the
benefit of hindsight, the failure of the C7 oxy-substituted enyne-
diones 36 to undergo the anticipated cascade radical sequence,
leading to 37, could be due to an unforeseen, competitive, H-radical
abstraction process involving the C7–H centre. Thus, the alkyl
radical centre 44 produced from 36 would be expected to undergo
a 12-endo-dig cyclisation leading to the vinylic radical species 45
(Scheme 7). Instead of undergoing the expected 6-exo-trig cycli-
sation, leading to 37, the vinylic radical 45 could then undergo 1,5-H
abstraction leading to the new radical centre 46, which is stabilised
by both the neighbouring oxy-centre and the conjugated enone
unit. The radical centre 46 could then undergo fragmentation,
producing a new carbonyl group at C7, i.e., 48, or it could take part
in a variety of alternative cyclisation and/or H-abstraction pro-
cesses from the delocalised radical species 47, leading to a plethora
of products. Interesting as these suggestions may be, we have no
experimental evidence to support them and they must therefore
remain as speculation for the time being.
Our synthesis of the tetraoxy-bis-nortaxadiene 42 is distin-
guished from other approaches to the taxane ring system, in that
the B and C rings are produced in a single step from a substituted A-
ring precursor. In the syntheses of taxol 1 developed by Holton4 and
Wender7 and their respective colleagues, the A,B-ring system was
produced first, to which the C-ring was later annulated. By contrast,
the research groups led by Nicolaou,5 Danishefsky,6 and Kuwajima8
all prepared ring A and ring C precursors as a prelude to making the
eight-membered B-ring. Finally, Mukaiyama et al.9 synthesised
their taxol, by first preparing the B-ring and then annulating the C
(first) and the A-ring. Although our own synthetic approach to taxol
was eventually thwarted by the lack of sufficient quantities of the
taxadiene 42 to continue with, it is gratifying to note that 42 is at
4. Experimental
4.1. General details
For general experimental details see Ref. 27.
4.1.1. [(S)-2-(4-Methoxy-phenyl)-[1,3]dioxan-4-yl]-methanol (20)
4-Methoxybenzaldehyde dimethyl acetal (2.00 mL, 11.7 mmol)
was added dropwise over 5 min to a stirred solution of (S)-1,2,4-
butanetriol 19 (1.01 g, 9.5 mmol) in dichloromethane (30 mL) at
room temperature. p-Toluenesulfonic acid (0.13 g, 0.60 mmol) was
added in one portion and the mixture was then heated at 40 ꢀC for
20 h under a nitrogen atmosphere. The mixture was cooled and
then concentrated in vacuo. The residue was purified by flash col-
umn chromatography on silica, using 40% ethyl acetate in petro-
leum ether as eluent, to give the alcohol (1.64 g, 77%) as a colourless
23
oil; [a
]
þ7.2 (c 1.3, CHCl3); nmax (film)/cmꢁ1 3595, 3491, 2936 and
D
2865; dH (360 MHz, CDCl3) 1.38 (1H, br d, J 13.2, OCH2CHHCH),1.76–
1.90 (1H, m, OCH2CHHCH), 2.76 (1H, br s, OH), 3.59 (2H, br d, J 5.4,
CHOCH2OH), 3.78 (3H, s, ArOCH3), 3.87–3.96 (2H, m, CH2CHO), 4.24
(1H, ddd, J 1.0, 5.0 and 11.3, CH2CHO), 5.46 (1H, s, CHAr), 6.89 (2H, d,
J 8.8, 2ꢂArH), 7.42 (2H, d, J 8.8, 2ꢂArH); dC (90 MHz, CDCl3) 26.7 (t),
O
O
a,b
c,d
18
+
Bu3Sn
O
Br
Br
40
Br
O
MOMO
f
MOMO
O
MOMO
MOMO
38
39
O
O
O
H
e
I
MOMO
MOMO
TBSO
O
OH
43
MOMO
MOMO
HO
41
42
Scheme 6. Reagents and conditions: (a) 38, n-BuLi, THF, ꢁ78 ꢀC, then 18; (b) Dess–Martin periodinane, NaHCO3, CH2Cl2, 86% (over two steps); (c) HCCMgBr, THF, 0 ꢀC; (d) Dess–
Martin periodinane, NaHCO3, CH2Cl2, 64% (over two steps); (e) NaI, butan-2-one, 80 ꢀC, 58%; (f) Bu3SnH, AIBN, PhH, 80 ꢀC, 44%.

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W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
O
O
OR
OR
H
12-endo-dig
36
O
MOMO
O
MOMO
OR
O
44
45
MOMO
OR
MOMO
O
O
O
1,5-H
abstraction
MOMO
MOMO
MOMO
O
O
O
46
47
48
MOMO
MOMO
MOMO
Scheme 7. Possible 1,5-H abstraction from the vinylic radical 45.
55.2 (q), 65.4 (t), 66.5 (t), 77.5 (d),101.0 (d),113.5 (2ꢂd),127.4 (2ꢂd),
130.9 (s), 159.9 (s); m/z (ES) 247.0931 (MþþNa, 100%, C12H16NaO4
requires 247.0946).
3ꢂCH2CH3, 3ꢂCH2CH3), 1.26–1.40 (6H, m, 3ꢂCH2CH2CH3), 1.45–
1.59 (6H, m, 3ꢂSnCH2), 1.63 (1H, br dd, J 1.3 and 13.0, CHHCHO),
1.94 (1H, dtd, J 5.0, 11.7 and 130, CHHCHO), 3.81 (3H, s, ArOCH3),
4.00 (1H, dt, J 2.5 and 11.5, CH2CHO), 4.29 (1H, ddd, J 0.9, 5.0 and
11.5, CH2CHO), 4.32–4.39 (1H, m, CH2CHO), 5.55 (1H, s, CHAr), 6.12
(1H, dd, J 4.9 and 19.3, CH]CHSn), 6.29 (1H, dd, J 1.2 and 19.3,
CH]CHSn), 6.92 (2H, d, J 8.8, 2ꢂArH), 7.48 (2H, d, J 8.8, 2ꢂArH); dC
(90 MHz, CDCl3) 7.6 (3ꢂt),13.7 (3ꢂq), 27.3 (3ꢂt), 29.1 (3ꢂt), 31.3 (t),
55.2 (q), 67.0 (t), 79.9 (d), 101.1 (d), 113.6 (2ꢂd), 127.5 (2ꢂd), 129.1
(d), 131.1 (s), 147.5 (d), 159.9 (s); m/z (ES) 511.2252 (MþþH, 20%,
C25H43O3Sn requires 511.2234).
4.1.2. (S)-2-(4-Methoxy-phenyl)-[1,3]dioxane-4-carbaldehyde (21)
A solution of DMSO (0.9 mL, 12.6 mmol) in dichloromethane
(10 mL) was added dropwise over 15 min to a stirred solution of
oxalyl chloride (0.62 mL, 7.13 mmol) in dichloromethane (10 mL)
at ꢁ78 ꢀC under a nitrogen atmosphere. The solution was stirred at
ꢁ78 ꢀC for 20 min and then a solution of the alcohol 20 (1.01 g,
4.50 mmol) in dichloromethane (10 mL) was added dropwise over
15 min. The solution was stirred at ꢁ78 ꢀC for 25 min, then trie-
thylamine (2.00 mL, 27.7 mmol) was added dropwise over 5 min
and the mixture was allowed to warm to room temperature over
1 h. Water (20 mL) was added and the separated aqueous phase
was then extracted with dichloromethane (2ꢂ20 mL). The com-
bined organic extracts were washed with brine (20 mL), then dried
over magnesium sulfate and concentrated in vacuo. The residue
was purified by flash column chromatography on silica, using 40%
ethyl acetate in petroleum ether as eluent, to give the aldehyde
(0.817 g, 82%) as a colourless oil; nmax (film)/cmꢁ1 2934, 2860 and
1738; dH (360 MHz, CDCl3) 1.78 (1H, dtd, J 1.5, 2.7 and 13.4,
OCH2CHHCH), 1.95 (1H, dtd, J 5.0, 11.9 and 13.4, OCH2CHHCH),
3.78–3.80 (1H, m, CH2CHO), 3.81 (3H, s, ArOCH3), 3.99 (1H, ddd, J
2.7, 11.7 and 11.9, CH2CHO), 4.28–4.37 (1H, m, CH2CHO), 5.56 (1H, s,
CHAr), 6.93 (2H, d, J 8.7, 2ꢂArH), 7.46 (2H, d, J 8.7, 2ꢂArH), 9.71
(1H, s, CHO); dC (90 MHz, CDCl3) 25.9 (t), 55.3 (q), 66.4 (t), 80.3 (d),
101.1 (d), 113.7 (2ꢂd), 127.4 (2ꢂd), 130.2 (s), 160.2 (s), 200.6 (d),
m/z (ES) 277.1069 (MþþMeOHþNa, 100%, C13H18NaO5 requires
277.1052).
4.1.4. (E)-(S)-3-(4-Methoxy-benzyloxy)-5-tributylstannanyl-
pent-4-en-1-ol (23)
A solution of DIBAL (1.0 M) in hexanes (2.10 mL, 2.10 mmol) was
added dropwise over 5 min to a stirred solution of the stannane 22
(0.53 g, 1.04 mmol) in dichloromethane (20 mL) at 0 ꢀC under a ni-
trogen atmosphere. The solution was stirred at room temperature
for 1 h and then a saturated solution of aqueous Rochelle’s salt
(5 mL) was added at 0 ꢀC. The mixture was warmed to room tem-
perature over 20 min and then extracted with diethyl ether
(3ꢂ20 mL). The combined organic extracts were dried over mag-
nesium sulfate and then concentrated in vacuo. The residue was
purified by flash column chromatography on silica, using 20% ethyl
acetate in petroleum ether (bp 40–60 ꢀC) as eluent, to give the al-
cohol (0.36 g, 67%) as a colourless oil; nmax (film)/cmꢁ1 3626, 3507,
2929, 1613 and 1514; dH (360 MHz, CDCl3) 0.83–0.97 (15H, m,
3ꢂCH2CH3, 3ꢂCH2CH3), 1.24–1.39 (6H, m, 3ꢂCH2CH2CH3), 1.46–
1.58 (6H, m, 3ꢂSnCH2), 1.72–1.93 (2H, m, CH2CHOPMB), 2.57 (1H, br
s, OH), 3.68–3.85 (2H, m, CH2OH), 3.81 (3H, s, ArOCH3), 3.96 (1H, dt,
J 4.6 and 7.4, CH2CHOPMB), 4.30 (1H, d, J 11.4, OCHHAr), 4.50 (1H, d,
J 11.4, OCHHAr), 5.91 (1H, dd, J 7.4 and 19.1, CH]CHSn), 6.20 (1H,
dd, J 0.7 and 19.1, CH]CHSn), 6.88 (2H, d, J 8.7, 2ꢂArH), 7.24 (2H, d, J
8.7, 2ꢂArH); dC (90 MHz, CDCl3) 9.6 (3ꢂt), 13.8 (3ꢂq), 27.3 (3ꢂt),
29.2 (3ꢂt), 37.8 (t), 55.3 (t), 61.0 (q), 70.0 (t), 82.8 (d), 113.9 (2ꢂd),
129.5 (2ꢂd), 130.5 (s), 132.0 (d), 148.1 (d), 159.3 (s); m/z (ES)
513.2441 (MþþH, 100%, C25H44O3Sn requires 513.2391).
4.1.3. Tributyl-{(E)-2-[(S)-2-(4-methoxy-phenyl)-[1,3]dioxan-
4-yl]-vinyl}-stannane (22)
N,N-Dimethylformamide (3 mL) was added dropwise to a stir-
red solution of chromium(II) chloride (2.5 g, 20 mmol, weighed out
in a glove bag under an argon atmosphere) in THF (60 mL) at room
temperature under an argon atmosphere. The solution was stirred
at room temperature for 20 min and then a solution of Bu3SnCHBr2
(3.6 g, 7.8 mmol) and the aldehyde 21 (0.46 g, 2.0 mmol) in THF
(30 mL) was added dropwise over 10 min via cannula. The reaction
flask was covered with aluminium foil and then a solution of
lithium iodide (2.26 g, 16.9 mmol) in THF (30 mL) was added
dropwise via cannula over 10 min. The mixture was stirred at room
temperature for 17 h, then water (50 mL) was added and the
aqueous layer was extracted with diethyl ether (2ꢂ50 mL). The
combined organic extracts were dried over magnesium sulfate and
then concentrated in vacuo. The residue was purified by flash
column chromatography on silica, using 10% diethyl ether in pe-
4.1.5. tert-Butyl-[(E)-(S)-3-(4-methoxy-benzyloxy)-5-tributyl-
stannanyl-pent-4-enyloxy]-dimethyl-silane (24)
N,N-Dimethylaminopyridine (6.6 mg, 0.054 mmol) was added
in one portion to a stirred solution of the alcohol 23 (0.25 g,
0.48 mmol), triethylamine (0.15 mL, 1.08 mmol) and tert-butyl-
dimethylsilyl chloride (0.12 g, 0.76 mmol) in dichloromethane
(1.5 mL) at room temperature. The solution was stirred at room
temperature for 4 h and then a saturated solution of aqueous so-
dium hydrogencarbonate (5 mL) was added. The separated aqueous
phase was extracted with dichloromethane (3ꢂ5 mL) and the
combined organic extracts were then dried over magnesium sulfate
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography on silica using 10% diethyl ether in petroleum
ether (bp 40–60 ꢀC) as eluent to give the silyl ether (0.29 g, 95%) as
troleum ether (bp 40–60 ꢀC) as eluent, to give the stannane (0.5 g,
23
48%) as a colourless oil; [
a
]
ꢁ5.7 (c 0.98, CDCl3). (Found: C, 58.7;
D
H, 8.3. C25H42O3Sn requires C, 58.8; H, 8.3%.) nmax (film)/cmꢁ1 2937,
2851, 1615 and 1518; dH (360 MHz, CDCl3) 0.83–1.04 (15H, m,

W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
6675
23
a colourless oil; [
a]
ꢁ30.3 (c 1.15, CHCl3). (Found: C, 59.6; H, 9.4.
OCHCHH), 2.46 (1H, dd, J 3.5 and 14.3, OCHCHH), 3.27 (3H, s, OCH3),
3.34 (3H, s, OCH3), 4.04 (1H, dd, J 3.5 and 5.5, OCHCH2), 4.14 (1H, d, J
11.7, CHHOH), 4.21 (1H, d, J 7.1, OCHHO), 4.21 (1H, d, J 11.7, CHHOH),
4.38 (1H, d, J 11.9, CHHOBz), 4.56 (1H, d, J 11.9, CHHOBz), 4.69 (1H,
d, J 7.1, OCHHO), 4.88 (1H, d, J 7.4, OCHHO), 4.97 (1H, d, J 7.4,
OCHHO), 7.42 (2H, t, J 7.6, 2ꢂArH), 7.54 (1H, t, J 7.4, ArH), 8.03 (2H,
d, J 8.5, 2ꢂArH); dC (90 MHz, CDCl3) 16.4 (q), 21.2 (q), 23.6 (q), 27.9
(t), 41.6 (s), 55.6 (q), 55.8 (q), 58.9 (t), 68.2 (t), 73.0 (d), 78.3 (s), 91.7
(t), 94.7 (t), 128.5 (2ꢂd), 129.4 (2ꢂd), 130.3 (s), 131.6 (s), 132.9 (d),
140.0 (s), 166.1 (s); m/z (ES) 431.2065 (MþþNa, 100%, C22H32NaO7
requires 431.2046).
D
C31H58O3SnSi requires C, 59.4; H, 9.3%.) nmax (film)/cmꢁ1 2931,
2856, 1613 and 1514; dH (360 MHz, CDCl3) 0.04 (6H, s, 2ꢂSiCH3),
0.84–0.95 (24H, m, 3ꢂCH2CH3, 3ꢂCH2CH3, 3ꢂSiC(CH3)3), 1.47–1.58
(6H, m, 3ꢂCH2CH2CH3), 1.33 (6H, ttd, J 7.3, 7.3 and 7.3, 3ꢂSnCH2),
1.70 (1H, tdd, J 6.5, 12.3 and 13.4, CHHCH2OTBS), 1.86 (1H, tdd, J 6.2,
7.2 and 12.3, CHHCH2OTBS), 3.64 (1H, td J 6.2 and 10.1, CHHOTBS),
3.72 (1H, td, J 6.5 and 10.1, CHHOTBS), 3.81 (3H, s, ArOCH3), 3.87
(1H, dd, J 7.2 and 13.4, CH2CHOPMB), 4.28 (1H, d, J 11.3, OCHHAr),
4.52 (1H, d, J 11.3, OCHHAr), 5.86 (1H, dd, J 7.2 and 19.1, CH]CHSn),
6.14 (1H, dd, J 0.7 and 19.1, CH]CHSn), 6.87 (2H, d, J 8.7, 2ꢂArH),
7.25 (2H, d, J 8.7, 2ꢂArH); dC (90 MHz, CDCl3) ꢁ5.2 (2ꢂq), 9.6 (3ꢂt),
13.8 (3ꢂq), 18.4 (s), 26.0 (3ꢂq), 27.3 (3ꢂt), 29.2 (3ꢂt), 38.7 (t), 55.3
(q), 59.6 (t), 69.9 (t), 80.1 (d), 113.8 (2ꢂd), 129.4 (2ꢂd), 131.1 (d),
131.3 (s), 149.0 (d), 159.0 (s); m/z (ES) 627.3294 (MþþH, 95%,
C31H58O3SnSi requires 627.3287), 649.3107 (MþþNa, 100%,
C31H58NaO3SiSn requires 649.3075).
4.1.8. Benzoic acid (1S,5S)-3-formyl-1,5-bis-methoxymethoxy-
2,2,4-trimethyl-cyclohex-3-enylmethyl ester (18)
Sodium hydrogencarbonate (150 mg, 1.79 mmol) and Dess–
Martin periodinane (148 mg, 0.35 mmol) were added to a stirred
solution of the alcohol 17 (65.8 mg, 0.161 mmol) in dichloromethane
(10 mL) at room temperature. The mixture was stirred at room
temperaturefor 1 h, and then saturated solutions of aqueous sodium
hydrogencarbonate (5 mL) and aqueous sodium thiosulfate (5 mL)
were added. The biphasic mixture was stirred at room temperature
for 5 min, and then diethyl ether (10 mL) was added. The separated
aqueous phase was extracted with diethyl ether (2ꢂ10 mL) then the
combined organic extracts were then dried over magnesium sulfate
and concentrated in vacuo. The residue was purified by flash column
chromatography on silica, using 40% ethyl acetate in petroleum
4.1.6. Benzoic acid (S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-
1,5-bis-methoxymethoxy-2,2,4-trimethyl-cyclohex-3-enyl ester (16)
Tetrabutylammonium iodide (0.83 g, 2.26 mmol) was added in
one portion to a stirred solution of the diol 15 (0.30 g, 0.64 mmol)23
in dry dichloromethane (10 mL) at room temperature. Diisopropy-
lethylamine (5.5 mL, 31.6 mmol) was added dropwise over 2 min
and then methyloxymethyl chloride (1.8 mL, 23.7 mmol) was added
over 2 s at room temperature. The mixture was stirred at room
temperature for 17 h and then more tetrabutylammonium iodide
(0.52 g,1.41 mmol), diisopropylethylamine (3.6 mL, 20.7 mmol) and
methyloxymethyl chloride (1.2 mL, 14.7 mmol) were added. The
mixture was then stirred at room temperature for a further 4 h.
Water (5 mL) was added and the separated aqueous phase was then
extracted with dichloromethane (2ꢂ5 mL). The combined organic
extracts were dried over magnesium sulfate and then concentrated
in vacuo. The residue was purified by flash column chromatography
ether (bp 40–60 ꢀC) as eluent, to give the aldehyde (54 mg, 82%) as
23
a colourless oil; [
a]
þ2.3 (c 1.0, CHCl3); nmax (film)/cmꢁ1 2952,1719
D
and 1682; dH (360 MHz, CDCl3) 1.35 (3H, s, C(CH3)2), 1.38 (3H, s,
C(CH3)2), 2.13 (3H, s, C]C(CH3)), 2.26 (1H, dd, J 5.6 and 14.4,
OCHCHH), 2.38 (1H, dd, J 5.6 and 14.4, OCHCHH), 3.34 (3H, s, OCH3),
3.37 (3H, s, OCH3), 4.16 (1H, t, J 5.6, OCHCH2), 4.36 (1H, d, J 7.1,
OCHHO), 4.42 (1H, d, J 12.2, CHHOBz), 4.46 (1H, d, J 12.2, CHHOBz),
4.74 (1H, d, J 7.1, OCHHO), 4.92 (1H, d, J 7.4, OCHHO), 4.95 (1H, d, J 7.4,
OCHHO), 7.43–7.49 (2H, m, 2ꢂArH), 7.55–7.61 (1H, m, ArH), 8.03–
8.07 (2H, m, 2ꢂArH),10.20 (1H, s, CHO); dC (90 MHz, CDCl3) 15.6 (q),
22.1 (q), 22.5 (q), 28.3 (t), 41.7 (s), 55.9 (q), 56.1 (q), 67.4 (t), 73.8 (d),
78.8 (s), 91.7 (t), 95.5 (t),128.6 (2ꢂd),129.5 (2ꢂd),130.1 (s),133.1 (d),
140.5 (s), 148.5 (s), 166.1 (s), 193.7 (d); m/z (ES) 429.1991 (MþþNa,
100%, C22H30NaO7 requires 429.1889).
on silica, using 20% ethyl acetate in petroleum ether (bp 40–60 ꢀC)
as eluent, to give the protected diol (0.28 g, 83%); [
23
a
]
ꢁ3.4 (c 1.1,
D
CHCl3); nmax (film)/cmꢁ1 2954 and 1716; dH (360 MHz, CDCl3) 0.09
(6H, s, 2ꢂSiCH3), 0.91 (9H, s, 3ꢂSiC(CH3)3), 1.19 (6H, s, 2ꢂC(CH3)2),
1.80 (3H, s, C]C(CH3)), 2.15 (1H, dd, J 5.6 and 14.3, OCHCHH), 2.52
(1H, dd, J 2.9 and 14.3, OCHCHH), 3.27 (3H, s, OCH3), 3.35 (3H, s,
OCH3), 4.06 (1H, dd, J 2.9 and 5.6, OCHCH2), 4.17 (2H, s, CH2OSi), 4.20
(1H, d, J 7.1, OCHHO), 4.40 (1H, d, J 11.9, CHHOBz), 4.56 (1H, d, J 11.9,
CHHOBz), 4.71 (1H, d, J 7.1, OCHHO), 4.87 (1H, d, J 7.4, OCHHO), 5.00
(1H, d, J 7.4, OCHHO), 7.43 (2H, t, J 7.6, 2ꢂArH), 7.54 (1H, t, J 7.4, ArH),
8.05 (2H, d, J 7.1, 2ꢂArH); dC (90 MHz, CDCl3) ꢁ5.4 (2ꢂq), 16.6 (q),
18.3 (s), 20.9 (q), 23.9 (q), 25.8 (3ꢂq), 27.7 (t), 42.6 (s), 55.6 (q), 55.8
(q), 59.3 (t), 68.4 (t), 73.2 (d), 78.5 (s), 91.7 (t), 94.5 (t), 128.5 (2ꢂd),
129.5 (2ꢂd),130.2 (s),130.5 (s),132.8 (d),139.3 (s),166.1 (s); m/z (ES)
545.2878 (MþþNa, 100%, C28H46NaO7Si requires 545.2911).
4.1.9. (E)-(S)-6-(tert-Butyl-dimethyl-silanyloxy)-1-((3S,5S)-5-
hydroxymethyl-3,5-bis-methoxymethoxy-2,6,6-trimethyl-cyclohex-
1-enyl)-4-(4-methoxy-benzyloxy)-hex-2-en-1-ol (25)
A solution of n-BuLi (2.5 M) in hexanes (1.6 mL, 2.5 mmol) was
added dropwise over 2 min to a stirred solution of the vinyl-
stannane 24 (1.7 g, 2.7 mmol) in dry THF (4 mL) at ꢁ78 ꢀC. The
solution was stirred at ꢁ78 ꢀC for 1 h and then a solution of the
aldehyde 18 (290 mg, 0.71 mmol) in dry THF (10 mL) was added
dropwise over 2 min at ꢁ78 ꢀC. The mixture was warmed to room
temperature over 17 h, and then water (30 mL) and diethyl ether
(30 mL) were added. The separated aqueous phase was extracted
with diethyl ether (3ꢂ30 mL) and the combined organic extracts
were dried then over magnesium sulfate and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica, using 20% ethyl acetate in petroleum ether (bp 40–60 ꢀC)
as eluent, to give: (i) diastereoisomer A (177 mg, 39%); (eluted first)
nmax (film)/cmꢁ1 3609, 2954, 1612 and 1514; dH (360 MHz, CDCl3)
0.04 (6H, s, 2ꢂSiCH3), 0.89 (9H, s, 3ꢂSiC(CH3)3), 1.03 (3H, s,
C(CH3)2), 1.20 (3H, s, C(CH3)2), 1.62–1.73 (2H, m, CH2CH2OTBS), 1.93
(3H, s, C]C(CH3)), 2.04 (1H, dd, J 5.3 and 14.5, OCHCHH), 2.34 (1H,
d, J 14.5, OCHCHH), 3.43 (3H, s, OCH3), 3.44 (3H, s, OCH3), 3.60–3.75
(4H, m, CH2CH2OTBS and CH2OH), 3.80 (3H, s, ArOCH3), 3.89–3.95
(1H, m, OCHCH2), 3.99 (1H, dd, J 7.9 and 13.1, CHOPMB), 4.29 (1H, d,
J 11.2, OCHHArOMe), 4.50 (1H, d, J 11.2, OCHHArOMe), 4.68 (1H, d, J
6.8, OCHHO), 4.83 (1H, d, J 6.8, OCHHO), 4.90 (1H, s, C]
4.1.7. Benzoic acid (S)-3-hydroxymethyl-1,5-bis-methoxymethoxy-
2,2,4-trimethyl-cyclohex-3-enyl ester (17)
Tetrabutylammonium fluoride (0.411 g, 0.613 mmol) was added
in one portion to a stirred solution of the silyl ether 16 (0.320 g,
0.613 mmol) in dry THF (10 mL) at room temperature, and the
mixture was then stirred at room temperature for 2 h. A saturated
solution of aqueous ammonium chloride (10 mL) followed by
diethyl ether (10 mL) were added, and the separated aqueous
phase was then extracted with diethyl ether (2ꢂ10 mL). The
combined organic extracts were dried over magnesium sulfate and
then concentrated in vacuo. The residue was purified by flash
column chromatography on silica, using 50% ethyl acetate in pe-
troleum ether (bp 40–60 ꢀC) as eluent, to give the alcohol (0.15 g,
60%) as a colourless oil; nmax (film)/cmꢁ1 3614, 3501 (br), 2952 and
1716; dH (360 MHz, CDCl3) 1.16 (3H, s, C(CH3)2), 1.21 (3H, s,
C(CH3)2), 1.85 (3H, s, C]C(CH3)), 2.14 (1H, dd, J 5.5 and 14.3,

6676
W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
CCH(O)CH]CH), 4.91 (1H, d, J 7.2, OCHHO), 4.96 (1H, d, J 7.2,
OCHHO), 5.64 (1H, ddd, J 1.0, 7.9 and 15.7, CH]CHCH(OPMB)), 5.88
(1H, dd, J 4.7 and 15.7, CH]CHCH(OPMB)), 6.87 (2H, d, J 8.5,
2ꢂArH), 7.24 (2H, d, J 8.5, 2ꢂArH); dC (90 MHz, CDCl3) ꢁ5.3 (2ꢂq),
17.7 (q), 18.3 (s), 23.3 (q), 26.0 (3ꢂq), 28.6 (t), 29.8 (q), 39.0 (t), 42.9
(s), 55.3 (q), 55.5 (q), 56.4 (q), 59.4 (t), 65.9 (t), 69.8 (d), 70.2 (t), 75.6
(d), 76.0 (d), 80.0 (s), 91.6 (t), 96.8 (t),113.8 (2ꢂd),129.4 (2ꢂd),130.8
(s), 131.0 (s), 131.6 (d), 134.0 (d), 142.2 (s), 159.1 (s); m/z (ES)
661.3727 (MþþNa, 100%, C34H58NaO9Si requires 661.3748); and (ii)
diastereoisomer B (208 mg, 46%); (eluted second) nmax (film)/cmꢁ1
3607, 2955, 1602 and 1514; dH (360 MHz, CDCl3) 0.04 (2ꢂ3H, s,
2ꢂSiCH3), 0.89 (9H, s, 3ꢂSiC(CH3)3), 1.12 (3H, s, C(CH3)2), 1.19 (3H, s,
C(CH3)2), 1.75–1.81 (1H, m, CHHCH2OTBS), 1.89–2.02 (1H, m,
CHHCH2OTBS), 1.89 (3H, s, C]C(CH3)), 2.10 (1H, dd, J 5.8 and 14.6,
OCHCHH), 2.23 (1H, dd, J 5.8 and 14.6, OCHCHH), 3.43 (3H, s, OCH3),
3.44 (3H, s, OCH3), 3.75–3.83 (4H, m, CH2CH2OTBS and CH2OH),
3.80 (3H, s, ArOCH3), 3.91 (1H, t, J 5.8, OCHCH2), 3.97–4.03 (1H, m,
CHOPMB), 4.28 (1H, d, J 11.2, OCHHArOMe), 4.50 (1H, d, J 11.2,
OCHHArOMe), 4.68 (1H, d, J 6.9, OCHHO), 4.82 (1H, d, J 6.9, OCHHO),
4.83 (1H, d, J 7.4, OCHHO), 4.94 (1H, d, J 7.4, OCHHO), 4.96 (1H, br d, J
4.2, C]CCH(O)CH]CH), 5.63 (1H, ddd, J 1.7, 8.0 and 15.6, CH]
CHCH(OPMB)), 5.89 (1H, dd, J 4.2 and 15.6, CH]CHCH(OPMB)),
6.86 (2H, d, J 8.7, 2ꢂArH), 7.23 (2H, d, J 8.7, 2ꢂArH); dC (90 MHz,
CDCl3) ꢁ5.3 (2ꢂq), 17.6 (q), 18.3 (s), 22.7 (q), 26.0 (3ꢂq), 28.5 (t),
30.4 (q), 39.0 (t), 42.9 (s), 55.3 (q), 55.5 (q), 56.2 (q), 59.4 (t), 65.6 (t),
69.9 (d), 70.0 (t), 75.6 (d), 76.1 (d), 80.7 (s), 91.3 (t), 96.6 (t), 113.8
(2ꢂd), 129.4 (2ꢂd), 130.8 (s), 131.2 (d), 131.4 (s), 134.6 (d), 142.2 (s),
159.1 (s); m/z (ES) 661.3798 (MþþNa, 100%, C34H58NaO9Si requires
661.3748).
the aldehyde 26 (21.8 mg, 0.034 mmol) in dry THF (1.5 mL) at 0 ꢀC.
The mixture was warmed to room temperature over 17 h and then
water (5 mL) and diethyl ether (10 mL) were added. The separated
aqueous phase was extracted with diethyl ether (3ꢂ10 mL) and the
combined organic extracts were then dried over magnesium sulfate
and concentrated in vacuo to leave the propargyl alcohol 27 as an
oil. Sodium hydrogencarbonate (21.9 mg, 0.261 mmol) and Dess–
Martin periodinane (13.2 mg, 0.0311 mmol) were added in one
portion to a stirred solution of 27 in dichloromethane (4 mL) at
room temperature. The mixture was stirred at room temperature
for 3.5 h, and then saturated solutions of aqueous sodium hydro-
gencarbonate (5 mL) and aqueous sodium thiosulfate (5 mL) were
added. The biphasic mixture was stirred at room temperature for
5 min and then diethyl ether (10 mL) was added. The separated
aqueous phase was extracted with diethyl ether (2ꢂ10 mL), and the
combined organic extracts were then dried over magnesium sulfate
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography on silica, using 20% ethyl acetate in petro-
leum ether (bp 40–60 ꢀC) as eluent, to give the ynone (13.3 mg, 98%)
as a colourless oil; dH (360 MHz, CDCl3) 0.04 (6H, s, 2ꢂSiCH3), 0.89
(9H, s, 3ꢂSiC(CH3)3), 1.17 (3H, br s, C(CH3)2), 1.20 (3H, br s, C(CH3)2),
1.67 (3H, s, C]C(CH3)), 1.97–2.08 (1H, m, CHHCH2OTBS), 2.09–2.19
(1H, m, CHHCH2OTBS), 2.22–2.27 (1H, m, OCHCHH), 2.41–2.48 (1H,
m, OCHCHH), 3.40 (3H, s, OCH3), 3.44 (3H, s, OCH3), 3.48 (1H, s,
C^CH), 3.81 (3H, s, ArOCH3), 3.83 (2H, m, CH2CH2OTBS), 4.02–4.08
(1H, m, OCHCH2), 4.20–4.29 (1H, m, CHOPMB), 4.34 (1H, d, J 11.2,
OCHHArOMe), 4.48 (1H, d, J 11.2, OCHHArOMe), 4.64 (1H, d, J 6.9,
OCHHO), 4.71 (1H, d, J 7.2, OCHHO), 4.76 (1H, d, J 6.9, OCHHO), 4.90
(1H, d, J 7.2, OCHHO), 6.32 (1H, d, J 16.1, CH]CHCH(OPMB)), 6.78
(1H, dd, J 6.8 and 16.1, CH]CHCH(OPMB)), 6.89 (2H, d, J 8.9,
2ꢂArH), 7.23 (2H, d, J 8.9, 2ꢂArH).
4.1.10. (1S,5S)-3-[(E)-(S)-6-(tert-Butyl-dimethyl-silanyloxy)-4-(4-
methoxy-benzyloxy)-hex-2-enoyl]-1,5-bis-methoxymethoxy-2,2,4-
trimethyl-cyclohex-3-enecarbaldehyde (26)
4.1.12. 1-((1S,5S)-3-{2-[(S)-3-(4-Methoxy-benzyloxy)-
Sodium hydrogencarbonate (95.4 mg, 1.14 mmol) and Dess–
Martin periodinane (153 mg, 0.36 mmol) were added in one por-
tion to a stirred solution of a mixture of diastereoisomers of the
alcohol 25 (72.0 mg, 0.113 mmol) in dichloromethane (4 mL) at
room temperature. The mixture was stirred at room temperature
for 2 h, and then saturated solutions of aqueous sodium hydro-
gencarbonate (5 mL) and aqueous sodium thiosulfate (5 mL) were
added. The biphasic mixture was stirred at room temperature for
5 min and then diethyl ether (10 mL) was added. The separated
aqueous phase was extracted with diethyl ether (3ꢂ10 mL), and the
combined organic extracts were then dried over magnesium sulfate
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography on silica, using 20% ethyl acetate in petro-
leum ether (bp 40–60 ꢀC) as eluent, to give the ketoaldehyde
(60.7 mg, 85%) as a colourless oil; dH (360 MHz, CDCl3) 0.04 (6H, s,
2ꢂSiCH3), 0.88 (9H, s, 3ꢂSiC(CH3)3),1.16 (3H, br s, C(CH3)2),1.19 (3H,
br s, C(CH3)2), 1.66 (3H, s, C]C(CH3)), 1.98–2.09 (1H, m,
CHHCH2OTBS), 2.09–2.21 (1H, m, CHHCH2OTBS), 2.23–2.27 (1H, m,
OCHCHH), 2.40–2.47 (1H, m, OCHCHH), 3.41 (3H, s, OCH3), 3.42
(3H, s, OCH3), 3.79 (3H, s, ArOCH3), 3.82 (2H, m, CH2CH2OTBS),
4.04–4.08 (1H, m, OCHCH2), 4.21–4.29 (1H, m, CHOPMB), 4.36
(1H, d, J 11.4, OCHHArOMe), 4.52 (1H, d, J 11.4, OCHHArOMe), 4.64
(1H, d, J 6.8, OCHHO), 4.72 (1H, d, J 7.4, OCHHO), 4.75 (1H, d, J 6.8,
OCHHO), 4.89 (1H, d, J 7.4, OCHHO), 6.33 (1H, d, J 15.9, CH]
CHCH(OPMB)), 6.77 (1H, dd, J 6.5 and 15.9, CH]CHCH(OPMB)),
6.90 (2H, d, J 8.7, 2ꢂArH), 7.22 (2H, d, J 8.7, 2ꢂArH), 9.77 (1H,
s, CHO).
tetrahydrofuran-2-yl]-acetyl}-1,5-bis-methoxymethoxy-2,2,4-
trimethyl-cyclohex-3-enyl)-propynone (29)
Tetrabutylammonium fluoride (15 mg, 0.05 mmol) was added in
one portion to a stirred solution of the silyl ether 28a (13.3 mg,
0.02 mmol) in dry THF (2 mL) at room temperature. The mixture
was stirred at room temperature for 1 h and then water (5 mL) and
diethyl ether (10 mL) were added. The separated aqueous phase
was extracted with diethyl ether (3ꢂ10 mL) and the combined or-
ganic extracts were then dried over magnesium sulfate and con-
centrated in vacuo. The residue was purified by flash column
chromatography on silica, using 10% ethyl acetate in petroleum
ether (bp 40–60 ꢀC) as eluent, to give the substituted tetrahydro-
furan (6.0 mg, 55%) as a colourless oil; dH (360 MHz, CDCl3) 1.16 (3H,
br s, C(CH3)2), 1.19 (3H, br s, C(CH3)2), 1.68 (3H, s, C]C(CH3)), 1.86–
2.22 (4H, m, (C]O)CH2CH and CH(OPMB)CH2CH2), 2.23–2.27 (1H,
m, OCHCHH), 2.40–2.46 (1H, m, OCHCHH), 3.39 (3H, s, OCH3), 3.42
(1H, s, C^CH), 3.48 (3H, s, OCH3), 3.70–3.76 (1H, m, (C]O)CH2
-
CHOCH2), 3.74 (3H, s, ArOCH3), 3.97–4.09 (3H, m, OCHCH2 and
CH(OPMB)CH2CH2OCH), 4.14–4.19 (1H, m, CHOPMB), 4.33 (1H, d, J
11.6, OCHHArOMe), 4.52 (1H, d, J 11.6, OCHHArOMe), 4.63 (1H, d, J
6.4, OCHHO), 4.69 (1H, d, J 7.1, OCHHO), 4.74 (1H, d, J 6.4, OCHHO),
4.89 (1H, d, J 7.1, OCHHO), 6.88 (2H, d, J 9.0, 2ꢂArH), 7.21 (2H, d, J 9.0,
2ꢂArH).
4.1.13. [(E)-(S)-6-[(3S,5S)-3,5-Bis-methoxymethoxy-2,6,6-
trimethyl-5-(4-nitrophenoxymethyl)-cyclohex-1-enyl]-3-(4-
methoxy-benzyloxy)-6-(4-nitrophenoxy)-hex-4-enyloxy]-tert-
butyl-dimethyl-silane (30)
4.1.11. (E)-(S)-1-((3S,5S)-3,5-Bis-methoxymethoxy-2,6,6-trimethyl-
5-propynoyl-cyclohex-1-enyl)-6-(tert-butyl-dimethyl-silanyloxy)-
4-(4-methoxy-benzyloxy)-hex-2-en-1-one (28a)
A solution of ethynylmagnesium bromide (0.5 M) in THF (1 mL,
0.50 mmol) was added dropwise over 5 min to a stirred solution of
Triethylamine (0.31 mL, 2.22 mmol) and N,N-dimethylamino-
pyridine (13 mg, 0.11 mmol) were added to a stirred solution of
diastereoisomer A of the diol 25 (142.6 mg, 0.224 mmol) in dry
dichloromethane (10 mL) at room temperature. para-Nitrobenzoyl
chloride (266 mg, 1.43 mmol) was added, in one portion, and the

W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
6677
mixture was then stirred at room temperature for 1.5 h. Water
(10 mL) was added and the separated aqueous phase was then
extracted with dichloromethane (2ꢂ10 mL). The combined organic
extracts were dried over magnesium sulfate and then concentrated
in vacuo. The residue was purified by flash column chromatography
on silica, using 30% ethyl acetate inpetroleum ether (bp 40–60 ꢀC) as
eluent, to give the bis-benzoate (203 mg, 97%) as a colourless oil;
nmax (film)/cmꢁ1 2955, 1725, 1610 and 1531; dH (360 MHz, CDCl3)
0.01–0.04 (6H, m, 2ꢂSiCH3), 0.87 (9H, s, 3ꢂSiC(CH3)3), 1.26 (6H, s,
2ꢂC(CH3)2), 1.69 (1H, td, J 6.1 and 13.4, CHHCH2OTBS), 1.84 (1H, td, J
5.7 and 13.4, CHHCH2OTBS), 2.05 (3H, s, C]C(CH3)), 2.31 (1H, br d, J
6.3, OCHCHH), 2.58 (1H, br d, J 14.3, OCHCHH), 3.32 (3H, s, OCH3),
3.34 (3H, s, OCH3), 3.63 (1H, td, J 5.3 and 9.1, CH2CHHOTBS), 3.69–
3.76 (1H, m, CH2CHHOTBS), 3.79 (3H, s, ArOCH3), 4.02–4.09 (2H, m,
OCHCH2 and CHOPMB), 4.24 (1H, d, J 6.9, CHHOBzpNO2), 4.31 (1H, d,
J 11.5, OCHHArOMe), 4.47–4.53 (1H, m, OCHHO), 4.50 (2H, d, J 11.5,
OCHHArOMe), 4.58–4.63 (1H, m, CHHOBzpNO2), 4.73 (1H, d, J 6.9,
OCHHO), 4.91 (2H, s, OCHHO), 5.74 (1H, ddd, J 1.2, 7.5 and 15.6,
CH]CHCH(OPMB)), 5.92 (1H, dd, J 4.0 and 15.6, CH]CHCH(OPMB)),
6.43 (1H, d, J 4.0, C]CCH(O)CH]CH), 6.85 (2H, d, J 8.7, 2ꢂArH), 7.23
(2H, d, J 8.7, 2ꢂArH), 8.20–8.25 (4H, m, ArH), 8.28–8.34 (4H, m, ArH);
dC (90 MHz, CDCl3) ꢁ5.4 (2ꢂq), 14.1 (q), 18.2 (q), 18.4 (s), 23.3 (q),
25.9 (3ꢂq), 29.6 (t), 38.7 (t), 43.5 (s), 55.3 (q), 55.8 (q), 56.1 (q), 59.2
(t), 68.8 (t), 70.4 (t), 72.2 (d), 72.7 (d), 75.6 (d), 78.1 (s), 91.2 (t), 94.7
(t), 113.8 (2ꢂd), 123.7 (4ꢂd), 123.8 (4ꢂd), 129.4 (2ꢂd), 130.2 (s),
130.5 (d),130.8 (d),135.7 (2ꢂs),135.8 (s),137.3 (s),150.5 (s),150.6 (s),
159.1 (s), 163.5 (s), 164.1 (s); m/z (ES) 960.4101 (MþþHþNa, 100%,
C48H65N2NaO15Si requires 960.4101).
The diastereoisomer B of the diol 25 (224 mg, 0.35 mmol) was
treated under the same conditions to give the corresponding di-
astereomeric bis-benzoate (314 mg, 95%) as a colourless oil; nmax
(film)/cmꢁ1 2930, 1726, 1610 and 1531; dH (360 MHz, CDCl3) 0.02
(3H, s, SiCH3), 0.03 (3H, s, SiCH3), 0.87 (9H, s, 3ꢂSiC(CH3)3),1.26 (6H,
s, 2ꢂC(CH3)2), 1.69 (1H, td, J 5.9 and 13.6, CHHCH2OTBS), 1.84 (1H,
td, J 5.9 and 13.6, CHHCH2OTBS), 2.04 (3H, s, C]C(CH3)), 2.32
(2H, br d, J 5.5, OCHCH2), 3.34 (3H, s, OCH3), 3.35 (3H, s, OCH3), 3.62
(1H, td, J 5.9 and 10.0, CH2CHHOTBS), 3.73 (1H, td, J 5.9 and 10.0,
CH2CHHOTBS), 3.78 (3H, s, ArOCH3), 4.01–4.09 (2H, m, OCHCH2 and
CHOPMB), 4.31 (1H, d, J 11.7, OCHHArOMe), 4.41 (1H, d, J 7.0,
OCHHO), 4.50 (1H, d, J 11.7, CHHOBzpNO2), 4.51 (1H, d, J 11.7,
CHHOBzpNO2), 4.61 (1H, d, J 11.7, OCHHArOMe), 4.74 (1H, d, J 7.0,
OCHHO), 4.86 (1H, d, J 7.6, OCHHO), 4.94 (1H, d, J 7.6, OCHHO),
5.75 (1H, ddd, J 1.2, 7.5 and 15.6, CH]CHCH(OPMB)), 5.94
(1H, dd, J 4.5 and 15.6, CH]CHCH(OPMB)), 6.44 (1H, d, J 4.5,
C]CCH(O)CH]CH), 6.85 (2H, d, J 8.7, 2ꢂArH), 7.23 (2H, d, J 8.7,
2ꢂArH), 8.21 (2H, d, J 6.6, 2ꢂArH), 8.23 (2H, d, J 6.6, 2ꢂArH), 8.30
(2H, d, J 5.5, 2ꢂArH), 8.32 (2H, d, J 5.5, 2ꢂArH); dC (90 MHz, CDCl3)
ꢁ5.3 (2ꢂq), 14.2 (q), 18.3 (s), 18.6 (q), 23.5 (q), 26.0 (3ꢂq), 29.8 (t),
38.8 (t), 43.5 (s), 55.3 (q), 55.9 (q), 56.1 (q), 59.2 (t), 68.4 (t), 70.5
(t), 72.9 (d), 74.3 (d), 75.8 (d), 79.0 (s), 91.7 (t), 95.6 (t), 113.9 (2ꢂd),
123.7 (4ꢂd), 123.8 (4ꢂd), 129.4 (2ꢂd), 129.7 (s), 130.5 (d), 130.9 (d),
135.6 (2ꢂs), 135.7 (s), 137.0 (s), 150.6 (2ꢂs), 159.2 (s), 163.6 (s), 164.3
(s); m/z (ES) 959.3951 (MþþNa, 100%, C48H64N2NaO15Si requires
959.3974).
a saturated solution of aqueous copper(II) sulfate (15 mL). The or-
ganic layer was dried over magnesium sulfate and then concen-
trated in vacuo to leave the alcohol (11.3 mg, 84%) as a colourless oil,
which was used without further purification; nmax (film)/cmꢁ1
3606, 2931, 1724, 1610 and 1531; dH (360 MHz, CDCl3) 1.23 (3H, s,
C(CH3)2), 1.25 (3H, s, C(CH3)2), 1.72–1.95 (2H, m, CH2CH2OH), 2.04
(3H, s, C]C(CH3)), 2.25–2.40 (1H, m, OCHCHH), 2.59 (1H, br d, J 6.3,
OCHCHH), 3.00 (3H, s OCH3), 3.35 (3H, s, OCH3), 3.71–3.80 (2H, m,
CH2CH2OH), 3.78 (3H, s, ArOCH3), 4.05–4.13 (2H, m, OCHCH2 and
CHOPMB), 4.20 (1H, d, J 6.9, OCHHO), 4.32 (1H, d, J 11.3, OCHHAr-
OMe), 4.45 (1H, d, J 11.8, CHHOBzpNO2), 4.53 (1H, d, J 11.3, OCH-
HArOMe), 4.63 (1H, d, J 11.8, CHHOBzpNO2), 4.71 (1H, d, J 6.9,
OCHHO), 4.90 (1H, d, J 7.7, OCHHO), 4.93 (1H, d, J 7.7, OCHHO), 5.79
(1H, app dddd, J 1.1, 3.5, 7.4 and 15.6, CH]CHCH(OPMB)), 5.96 (1H,
dd,
J 5.2 and 15.6, CH]CHCH(OPMB)), 6.41 (1H, d, J 4.9,
C]CCH(O)CH]CH), 6.85 (2H, d, J 8.7, 2ꢂArH), 7.22 (2H, d, J 8.7,
2ꢂArH), 8.22 (2H, d, J 9.0, 2ꢂArH), 8.23 (2H, d, J 9.0, 2ꢂArH),
8.30 (2H, d, J 9.0, 2ꢂArH), 8.31 (2H, d, J 9.0, 2ꢂArH); dC (90 MHz,
CDCl3) 14.2 (q), 18.6 (q), 23.6 (q), 29.8 (t), 37.8 (t), 43.5 (s), 55.3 (q),
55.9 (q), 56.2 (q), 60.4 (t), 68.9 (t), 70.4 (t), 72.3 (d), 72.8 (d), 78.1
(s), 77.9 (d), 91.9 (t), 94.8 (t), 114.0 (2ꢂd), 123.7 (4ꢂd), 123.8
(4ꢂd), 129.5 (2ꢂd), 130.0 (s), 130.5 (d), 130.8 (d), 134.5 (s), 135.7
(2ꢂs), 137.4 (s), 150.6 (s), 150.7 (s), 159.4 (s), 163.6 (s), 164.3 (s);
m/z (ES) 845.3076 (MþþNa, 100%, C42H50N2NaO15 requires
845.3109).
The diastereoisomer B of the silyl ether 30 (380 mg, 0.41 mmol)
was treated under the same conditions to give the corresponding
diastereomeric alcohol (324 mg, 97%) as a colourless oil; nmax (film)/
cmꢁ1 3519, 2936, 1724, 1610 and 1531; dH (360 MHz, CDCl3) 1.26
(6H, s, 2ꢂC(CH3)2), 1.72–1.89 (2H, m, CH2CH2OH), 2.05 (3H, s,
C]C(CH3)), 2.28–3.36 (2H, m, OCHCH2), 3.35 (6H, s, 2ꢂOCH3),
3.69–3.75 (2H, m, CH2CH2OH), 3.80 (3H, s, ArOCH3), 4.08–4.15 (2H,
m, OCHCH2 and CHOPMB), 4.32 (1H, d, J 11.3, OCHHArOMe), 4.39
(1H, d, J 7.0, OCHHO), 4.50 (1H, d, J 12.2, CHHOBzpNO2), 4.54 (1H, d, J
11.3, OCHHArOMe), 4.61 (1H, d, J 12.2, CHHOBzpNO2), 4.73 (1H, d, J
7.0, OCHHO), 4.87 (1H, d, J 7.6, OCHHO), 4.94 (1H, d, J 7.6, OCHHO),
5.77 (1H, ddd, J 1.4, 7.5 and 15.7, CH]CHCH(OPMB)), 5.97 (1H, dd, J
4.4 and 15.7, CH]CHCH(OPMB)), 6.46 (1H, d,
J 4.4, C]
CCH(O)CH]CH), 6.87 (2H, d, J 8.7, 2ꢂArH), 7.73 (2H, d, J 8.7, 2ꢂArH),
8.21 (2H, d, J 8.9, 2ꢂArH), 8.24 (2H, d, J 8.9, 2ꢂArH), 8.31 (2H, d, J 7.6,
2ꢂArH), 8.33 (2H, d, J 7.6, 2ꢂArH); dC (90 MHz, CDCl3) 14.2 (q), 18.6
(q), 22.9 (q), 29.8 (t), 37.9 (t), 43.5 (s), 55.3 (q), 55.8 (q), 56.0 (q), 60.3
(t), 68.3 (t), 70.4 (t), 72.7 (d), 74.1 (d), 78.0 (d), 78.8 (s), 91.6 (t), 95.4
(t), 114.0 (2ꢂd), 123.8 (4ꢂd), 123.9 (4ꢂd), 129.5 (2ꢂd), 130.1 (s),
130.5 (d), 130.8 (d), 133.8 (s), 135.5 (2ꢂs), 136.8 (s), 150.7 (2ꢂs),
159.4 (s), 163.7 (s), 164.3 (s); m/z (ES) 845.3155 (MþþNa, 100%,
C42H50N2NaO15 requires 845.3109).
4.1.15. (E)-(S)-6-[(3S,5S)-3,5-Bis-methoxymethoxy-2,6,6-trimethyl-
5-(4-nitrophenoxymethyl)-cyclohex-1-enyl]-1-bromo-3-
(4-methoxy-benzyloxy)-6-(4-nitrophenoxy)-hex-4-ene (31b)
Triethylamine (7 mL, 0.05 mmol) was added dropwise to a stir-
red solution of diastereoisomer A of the alcohol 31a (29.8 mg,
0.04 mmol) in dry dichloromethane (4 mL) at ꢁ20 ꢀC. Meth-
anesulfonyl chloride (3 mL, 0.04 mmol) was added dropwise and
4.1.14. (E)-(S)-6-[(3S,5S)-3,5-Bis-methoxymethoxy-2,6,6-trimethyl-
5-(4-nitrophenoxymethyl)-cyclohex-1-enyl]-3-(4-methoxy-
benzyloxy)-6-(4-nitrophenoxy)-hex-4-en-1-ol (31a)
the mixture was then stirred at room temperature for 1 h. A solu-
tion of lithium bromide (31.3 mg, 0.36 mmol) in THF (2 mL) was
added dropwise via cannula over 1 min, and the mixture was
heated to 56 ꢀC for 17 h and then cooled to room temperature. A
saturated solution of aqueous sodium hydrogencarbonate (10 mL)
and ethyl acetate (10 mL) were added, and the separated aqueous
phase was then extracted with ethyl acetate (3ꢂ15 mL). The com-
bined organic extracts were dried over magnesium sulfate and then
concentrated in vacuo. The residue was purified by flash column
chromatography on silica, using 50% ethyl acetate in petroleum
ether (bp 40–60 ꢀC) as eluent, to give the bromide (23.4 mg, 73%) as
A solution of hydrogen fluoride (70% solution) in pyridine
(0.1 mL) was added dropwise over 1 min to a stirred solution of
diastereoisomer A of the silyl ether 30 (15.3 mg, 0.016 mmol) in
pyridine (0.5 mL, 6.2 mmol) at 0 ꢀC. The solution was stirred at
room temperature for 1.5 h and then poured onto a saturated so-
lution of aqueous sodium hydrogencarbonate (20 mL). The result-
ing biphasic mixture was extracted with ethyl acetate (3ꢂ15 mL),
and the combined organic extracts were then washed with

6678
W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
a colourless oil; nmax (film)/cmꢁ1 2934, 1725, 1610 and 1631; dH
(360 MHz, CDCl3) 1.26 (6H, br s, 2ꢂC(CH3)2), 2.01–2.21 (2H, m,
CH2CH2Br), 2.06 (3H, s, C]C(CH3)), 2.29–2.35 (1H, m, OCHCHH),
2.58 (1H, br d, J 13.7, OCHCHH), 3.32 (3H, s, OCH3), 3.36 (3H, s,
OCH3), 3.41–3.48 (1H, m, CH2CHHBr), 3.49–3.57 (1H, m,
CH2CHHBr), 3.80 (3H, s, ArOCH3), 4.05–4.11 (2H, m, OCHCH2 and
7.8 and 15.5, CH]CHCH(OPMB)), 5.90 (1H, dd, J 4.5 and 15.5,
CH]CHCH(OPMB)), 6.87 (2H, d, J 8.6, 2ꢂArH), 7.23 (2H, d, J 8.6,
2ꢂArH); dC (90 MHz, CDCl3) 17.7 (q), 23.3 (q), 28.1 (t), 29.9 (t), 30.3
(q), 38.7 (t), 42.9 (s), 55.3 (q), 55.8 (q), 56.5 (q), 65.9 (t), 69.5 (d),
70.4 (t), 75.8 (d), 77.0 (d), 79.8 (s), 91.3 (t), 97.2 (t),113.9 (2ꢂd),125.5
(s), 129.5 (2ꢂd), 130.3 (d), 131.0 (s), 134.8 (d), 142.1 (s), 159.3 (s); m/z
(ES) 609.2018 (MþþNa, 100%, C28H43BrNaO8 requires 609.2039).
CHOPMB), 4.23 (1H, d,
J 6.9, OCHHO), 4.33 (1H, d, J 11.1,
CHHOBzpNO2), 4.45 (1H, d, J 11.7, OCHHArOMe), 4.52 (1H, d, J 11.1,
CHHOBzpNO2), 4.63 (1H, d, J 11.7 ꢀCHHArOMe), 4.72 (1H, d, J 6.9,
OCHHO), 4.91 (1H, s, OCHHO), 4.92 (1H, s, OCHHO), 5.73 (1H, ddd,
J 1.5, 7.5 and 15.4, CH]CHCH(OPMB)), 5.99 (1H, dd, J 5.0 and 15.4,
CH]CHCH(OPMB)), 6.43 (1H, d, J 4.2, C]CCH(O)CH]CH), 6.87 (2H,
d, J 8.7, 2ꢂArH), 7.24 (2H, d, J 8.7, 2ꢂArH), 8.23 (2H, d, J 9.0, 2ꢂArH),
8.24 (2H, d, J 9.0, 2ꢂArH), 8.32 (2H, d, J 9.0, 2ꢂArH), 8.33 (2H, d, J 9.0,
2ꢂArH); dC (90 MHz, CDCl3) 14.2 (q), 18.6 (q), 28.4 (t), 29.7 (t), 31.6
(q), 37.9 (t), 43.4 (s), 55.3 (q), 55.9 (q), 56.0 (q), 68.3 (t), 70.3 (t), 72.8
(d), 74.1 (d), 77.9 (d), 78.9 (s), 91.7 (t), 95.5 (t), 113.9 (2ꢂd), 123.7
(8ꢂd), 129.4 (2ꢂd), 130.1 (s), 130.5 (d), 130.9 (d), 133.6 (s), 135.5
(2ꢂs), 136.8 (s), 150.6 (s), 150.7 (s), 159.3 (s), 163.6 (s), 164.3 (s); m/z
(ES) 907.2247 (MþþNa, 100%, C42H49BrN2NaO14 requires 907.2247).
The diastereoisomer B of the alcohol 31a (14.4 mg, 0.02 mmol)
was treated under the same conditions to give the corresponding
diastereomeric bromide (13.2 mg, 83%) as a colourless oil; dH
(360 MHz, CDCl3) 1.26 (6H, br s, 2ꢂC(CH3)2), 1.98–2.02 (1H, m,
CHHCH2Br), 2.03 (3H, s, C]C(CH3)), 2.11–2.20 (1H, m, CHHCH2Br),
2.32 (2H, br s, OCHCH2), 3.35 (6H, s, 2ꢂOCH3), 3.44 (1H, td, J 6.2 and
10.0, CH2CHHBr), 3.54 (1H, td, J 6.0 and 10.0, CH2CHHBr), 3.81 (3H, s,
ArOCH3), 4.06–4.14 (2H, m, 2H, m, OCHCH2 and CHOPMB), 4.33 (1H,
d, J 11.6, OCHHArOMe), 4.40 (1H, d, J 7.1, OCHHO), 4.50 (1H, d, J 6.6,
CHHOBzpNO2), 4.53 (1H, d, J 6.6, CHHOBzpNO2), 4.62 (1H, d, J 11.6,
OCHHArOMe), 4.73 (1H, d, J 7.1, OCHHO), 4.86 (1H, d, J 7.6, OCHHO),
4.94 (1H, d, J 7.6, OCHHO), 5.73 (1H, ddd, J 1.6, 7.6 and 15.7,
CH]CHCH(OPMB)), 6.01 (1H, dd, J 4.5 and 15.7, CH]CHCH(OPMB)),
6.45 (1H, d, J 4.5, C]CCH(O)CH]CH), 6.87 (2H, d, J 8.7, 2ꢂArH), 7.24
(2H, d, J 8.7, 2ꢂArH), 8.22 (2H, d, J 9.0, 2ꢂArH), 8.24 (2H, d, J 9.0,
2ꢂArH), 8.32 (2H, d, J 9.0, 2ꢂArH), 8.34 (2H, d, J 9.0, 2ꢂArH); dC
(90 MHz, CDCl3) 14.2 (q), 18.6 (q), 28.5 (t), 29.7 (t), 30.3 (q), 38.5 (t),
43.5 (s), 55.3 (q), 55.9 (q), 56.0 (q), 68.3 (t), 70.7 (t), 72.7 (d), 74.2 (d),
76.7 (d), 78.9 (s), 91.6 (t), 95.5 (t), 113.9 (2ꢂd), 123.7 (8ꢂd), 129.4
(2ꢂd), 130.0 (s), 130.5 (d), 130.9 (d), 133.5 (s), 135.5 (s), 135.6 (s),
136.8 (s), 150.6 (s), 150.7 (s), 159.3 (s), 163.6 (s), 164.2 (s).
The diastereoisomer B of the bis-benzoate 31b (97.4 mg,
0.11 mmol) was treated under the same conditions to give the
corresponding diastereomeric diol (61.4 mg, 95%); dH (360 MHz,
CDCl3) 1.13 (3H, br s, C(CH3)2), 1.20 (3H, br s, C(CH3)2), 1.88 (3H, s,
C]C(CH3)), 1.96–2.06 (2H, m, CH2CH2Br), 2.11–2.25 (2H, m,
OCHCH2), 3.43 (3H, s, OCH3), 3.45 (3H, s, OCH3), 3.40–3.49 (1H, m,
CH2CHHBr), 3.50–3.59 (1H, m, CH2CHHBr), 3.64–3.72 (1H,
m, CHHOH), 3.76–3.83 (1H, m, CHHOH), 3.81 (3H, s, ArOCH3), 3.89–
3.93 (1H, m, OCHCH2), 4.04 (1H, dt, J 4.4 and 8.0, CHOPMB), 4.30 (1H,
d, J 11.2, OCHHArOMe), 4.52 (1H, d, J 11.2, OCHHArOMe), 4.68 (1H, d,
J 6.9, OCHHO), 4.82 (1H, d, J 6.9, OCHHO), 4.83 (1H, d, J 7.4, OCHHO),
4.94 (1H, d, J 7.4, OCHHO), 4.96–4.99 (1H, m, C]CCH(O)CH]CH),
5.65 (1H, ddd, J 1.8, 8.0 and 15.5, CH]CHCH(OPMB)), 5.95 (1H, dd, J
4.3 and 15.5, CH]CHCH(OPMB)), 6.88 (2H, d, J 8.6, 2ꢂArH), 7.24 (2H,
d, J 8.6, 2ꢂArH); dC (90 MHz, CDCl3) 17.5 (q), 22.7 (q), 28.5 (t), 30.0 (t),
30.3 (q), 38.8 (t), 42.9 (s), 55.3 (q), 55.6 (q), 56.2 (q), 65.5 (t), 69.7 (d),
70.2 (t), 75.6 (d), 77.1 (d), 80.6 (s), 91.2 (t), 96.6 (t), 113.9 (2ꢂd), 129.3
(s), 129.5 (2ꢂd), 129.9 (s), 130.3 (d), 135.6 (d), 142.1 (s), 159.2 (s).
Sodium hydrogencarbonate (29 mg, 0.34 mmol) and Dess–
Martin periodinane (31.4 mg, 0.074 mmol) were added in one
portion to a stirred solution of diastereoisomer A of the above diol
(13.8 mg, 0.023 mmol) in dichloromethane (2.3 mL) at 0 ꢀC. The
mixture was stirred at 0 ꢀC for 30 min and then allowed to warm to
room temperature over 5 h. Saturated solutions of aqueous sodium
hydrogencarbonate (1 mL) and aqueous sodium thiosulfate (1 mL)
were added to the mixture, which was stirred at room temperature
for 5 min and then diethyl ether (5 mL) was added. The separated
aqueous phase was extracted with diethyl ether (3ꢂ5 mL), and the
combined organic extracts were then dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica, using 30% ethyl acetate in pentane as
eluent, to give the ketoaldehyde (11.3 mg, 84%) as a colourless oil;
nmax (film)/cmꢁ1 2937, 1727, 1613 and 1514; dH (360 MHz, CDCl3)
1.15 (3H, br s, C(CH3)2), 1.20 (3H, br s, C(CH3)2), 1.65 (3H, s,
C]C(CH3)), 1.98–2.09 (1H, m, CHHCH2Br), 2.09–2.20 (1H, m,
CHHCH2Br), 2.26 (1H, dd, J 6.8 and 15.0, OCHCHH), 2.43 (1H, dd,
J 6.4 and 15.0, OCHCHH), 3.38–3.49 (1H, m, CH2CHHBr), 3.40 (3H, s,
OCH3), 3.43 (3H, s, OCH3), 3.54 (1H, ddd, J 5.9, 8.8 and 10.1,
CH2CHHBr), 3.81 (3H, s, ArOCH3), 4.06–4.12 (1H, m, OCHCH2), 4.21–
4.29 (1H, m, CHOPMB), 4.35 (1H, d, J 11.0, OCHHArOMe), 4.52 (1H, d,
J 11.0, OCHHArOMe), 4.66 (1H, d, J 7.0, OCHHO), 4.73 (1H, d, J 7.4,
OCHHO), 4.77 (1H, d, J 7.0, OCHHO), 4.84 (1H, d, J 7.4, OCHHO), 6.35
(1H, d, J 16.0, CH]CHCH(OPMB)), 6.75 (1H, dd, J 6.5 and 16.0,
CH]CHCH(OPMB)), 6.89 (2H, d, J 8.6, 2ꢂArH), 7.24 (2H, d, J 8.6,
2ꢂArH), 9.79 (1H, s, CHO); dC (90 MHz, CDCl3) 17.3 (q), 21.9 (q), 25.4
(q), 27.9 (t), 29.1 (t), 37.9 (t), 40.6 (s), 55.3 (q), 56.0 (q), 56.1 (q), 71.5
(t), 73.2 (d), 75.8 (d), 85.1 (s), 92.6 (t), 96.3 (t), 114.0 (2ꢂd), 129.5 (s),
129.6 (2ꢂd), 130.6 (s), 132.8 (d), 140.6 (s), 149.3 (d), 159.5 (s), 199.1
(s), 202.5 (d); m/z (ES) 605.1736 (MþþNa, 100%, C28H39BrNaO8 re-
quires 605.1726).
4.1.16. (1S,5S)-3-[(E)-(S)-6-Bromo-4-(4-methoxy-benzyloxy)-
hex-2-enoyl]-1,5-bis-methoxymethoxy-2,2,4-trimethyl-cyclohex-
3-enecarbaldehyde (32)
Potassium carbonate (104 mg, 0.75 mmol) was added in one
portion to a stirred solution of diastereoisomer A of the bis-ben-
zoate 31b (11.2 mg, 0.13 mmol) in methanol (2 mL) at room tem-
perature. The mixture was stirred at room temperature for 1 h and
then concentrated in vacuo. Water (5 mL) and ethyl acetate (5 mL)
were added to the residue and the separated aqueous phase was
then extracted with ethyl acetate (3ꢂ10 mL). The combined organic
extracts were dried over magnesium sulfate and then concentrated
in vacuo. The residue was purified by flash column chromatography
on silica, using 70% ethyl acetate in petroleum ether (bp 40–60 ꢀC)
as eluent, to give the corresponding diol (6.4 mg, 86%) as a colour-
less oil; nmax (film)/cmꢁ1 3606, 2954, 1612 and 1514; dH (360 MHz,
CDCl3) 1.02 (3H, br s, C(CH3)2), 1.16 (3H, br s, C(CH3)2), 1.92 (3H, s,
C]C(CH3)), 1.86–2.06 (2H, m, CH2CH2Br), 2.09–2.20 (1H, m,
OCHCHH), 2.47 (1H, d, J 14.3, OCHCHH), 3.38–3.56 (2H, m,
CH2CH2Br), 3.44 (3H, s, OCH3), 3.49 (3H, s, OCH3), 3.69–3.77 (2H,
m, CH2OH), 3.79 (3H, s, ArOCH3), 3.88–3.96 (1H, m, OCHCH2), 4.01
(1H, dt, J 4.5 and 8.0, CHOPMB), 4.30 (1H, d, J 11.1, OCHHArOMe),
4.50 (1H, d, J 11.1, OCHHArOMe), 4.72 (1H, d, J 6.8, OCHHO), 4.77
(1H, d, J 7.6, OCHHO), 4.87 (1H, d, J 6.8, OCHHO), 4.91 (1H, br d, J 3.3,
C]CCH(O)CH]CH), 5.15 (1H, d, J 7.6, OCHHO), 5.63 (1H, ddd, J 1.5,
4.1.17. (E)-(S)-1-((3S,5S)-3,5-Bis-methoxymethoxy-2,6,6-trimethyl-
5-propynoyl-cyclohex-1-enyl)-6-bromo-4-(4-methoxy-benzyl-
oxy)-hex-2-en-1-one (33a)
A
solution of ethynylmagnesium bromide (0.5 M) in THF
(2.8 mL, 1.4 mmol) was added dropwise over 5 min to a stirred
solution of the ketoaldehyde 32 (61 mg, 0.09 mmol) in dry THF
(2 mL) at 0 ꢀC, and the mixture was then warmed to room tem-
perature over 17 h. Water (2 mL) and 2 M hydrochloric acid (2 mL)

W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
6679
were added and the separated aqueous phase was then extracted
4.1.19. (E)-(S)-1-((3S,5S)-3,5-Bis-methoxymethoxy-2,6,6-trimethyl-
with diethyl ether (3ꢂ15 mL). The combined organic extracts were
dried over magnesium sulfate and concentrated in vacuo. Sodium
hydrogencarbonate (142 mg, 1.69 mmol) and Dess–Martin peri-
odinane (108 mg, 0.254 mmol) were added in one portion to
a stirred solution of the residue in dichloromethane (2 mL) at
room temperature. The mixture was stirred at room temperature
for 1 h, and then saturated solutions of aqueous sodium hydro-
gencarbonate (2 mL) and aqueous sodium thiosulphate (2 mL)
were added. The biphasic mixture was stirred at room tempera-
ture for 5 min and then diethyl ether (5 mL) was added. The
separated aqueous phase was extracted with diethyl ether
(3ꢂ15 mL), and the combined organic extracts were then dried
over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography on silica, using 30% ethyl
acetate in petroleum ether (bp 40–60 ꢀC) as eluent, to give the
ynone (69 mg, 67%) as a colourless oil; nmax (film)/cmꢁ1 3297,
2936, 2097, 1645, 1613 and 1514; dH (360 MHz, CDCl3) 1.17 (3H, br
s, C(CH3)2), 1.24 (3H, br s, C(CH3)2), 1.64 (3H, s, C]C(CH3)), 1.99–
2.07 (1H, m, CHHCH2Br), 2.12–2.20 (1H, m, CHHCH2Br), 2.54 (2H, t,
J 7.2, OCHCH2), 3.41 (3H, s, OCH3), 3.38–3.45 (1H, m, CH2CHHBr),
3.43 (3H, s, OCH3), 3.47 (1H, s, C^CH), 3.50–3.57 (1H, m,
CH2CHHBr), 3.81 (3H, s, ArOCH3), 4.22–4.29 (2H, m, OCHCH2 and
CHOPMB), 4.43 (1H, d, J 11.0, OCHHArOMe), 4.42 (1H, d, J 11.0,
OCHHArOMe), 4.67 (1H, d, J 7.2, OCHHO), 4.76 (1H, d, J 5.7,
OCHHO), 4.78 (1H, d, J 5.7, OCHHO), 4.83 (1H, d, J 7.2, OCHHO),
6.34 (1H, d, J 16.0, CH]CHCH(OPMB)), 6.83 (1H, dd, J 6.6 and 16.0,
CH]CHCH(OPMB)), 6.89 (2H, d, J 8.7, 2ꢂArH), 7.23 (2H, d, J 8.7,
2ꢂArH); dC (90 MHz, CDCl3) 17.3 (q), 21.8 (q), 26.6 (q), 29.2 (t), 30.8
(t), 38.0 (t), 41.3 (s), 55.4 (q), 56.0 (q), 56.6 (q), 71.5 (t), 73.5 (d),
75.8 (d), 81.9 (d), 82.6 (s), 88.7 (s), 94.0 (t), 96.5 (t), 114.0 (2ꢂd),
129.4 (s), 129.6 (2ꢂd), 130.5 (s), 132.0 (d), 140.7 (s), 149.6 (d), 159.5
(s), 189.0 (s), 199.5 (s); m/z (ES) 629.1721 (MþþNa, 100%,
C30H39BrNaO8 requires 629.1726).
5-propynoyl-cyclohex-1-enyl)-4-hydroxy-6-iodo-
hex-2-en-1-one (36a)
2,3-Dichloro-5,6-dicyanobenzoquinone
(DDQ)
(25.0 mg,
0.11 mmol) was added in one portion to a stirred solution of the
iodide 33b (36.6 mg, 0.06 mmol) in dichloromethane (3.5 mL) and
water (0.5 mL) at room temperature. The mixture was stirred at
room temperature for 2 h and then an extra portion of DDQ
(25.0 mg, 0.11 mmol) was added in one portion at room tempera-
ture. The mixture was stirred at room temperature for a further 2 h,
and then
a saturated solution of aqueous sodium hydro-
gencarbonate (5 mL) was added. The separated aqueous phase was
extracted with dichloromethane (4ꢂ5 mL) and the combined or-
ganic extracts were dried over sodium sulfate and then concen-
trated in vacuo. The residue was purified by flash column
chromatography on silica, using 30% ethyl acetate in petroleum
ether (bp 40–60 ꢀC) as eluent, to give the alcohol (25.8 mg, 87%) as
23
a colourless oil; [
a]
ꢁ1.0 (c 0.24, CHCl3); nmax (film)/cmꢁ1 3604,
D
3297, 2935, 2096, 1725 and 1675; dH (360 MHz, CDCl3) 1.15 (3H, s,
C(CH3)2), 1.22 (3H, s, C(CH3)2), 1.61 (3H, s, C]C(CH3)), 1.98–2.10 (2H,
m, CH2CH2I), 2.51 (2H, t, J 7.5, OCHCH2), 3.26–3.36 (2H, m, CH2CH2I),
3.42 (3H, s, OCH3), 3.43 (3H, s, OCH3), 3.47 (1H, s, C^CH), 4.23 (1H,
t, J 7.5, OCHCH2), 4.49–4.57 (1H, m, CHOH), 4.66 (1H, d, J 7.4,
OCHHO), 4.76 (1H, d, J 6.8, OCHHO), 4.77 (1H, d, J 6.8, OCHHO), 4.83
(1H, d, J 7.4, OCHHO), 6.36 (1H, d, J 15.9, CH]CHCH(OH)), 6.89 (1H,
dd, J 4.9 and 15.9, CH]CHCH(OH)); dC (90 MHz, CDCl3) 1.5 (t), 17.3
(q), 21.8 (q), 26.6 (q), 30.8 (t), 39.6 (t), 41.3 (s), 56.0 (q), 56.6 (q), 71.0
(d), 73.5 (d), 81.9 (d), 82.5 (s), 88.6 (s), 93.9 (t), 96.5 (t), 130.4 (s),
130.9 (d), 140.8 (s), 151.0 (d), 189.0 (s), 199.6 (s); m/z (ES) 573.0775
(MþþK, 100%, C22H31IKO7 requires 573.0752).
4.1.20. (E)-(S)-1-((3S,5S)-3,5-Bis-methoxymethoxy-2,6,6-
trimethyl-5-propynoyl-cyclohex-1-enyl)-4-(tert-butyl-dimethyl-
silanyloxy)-6-iodo-hex-2-en-1-one (36b)
tert-Butyl-dimethylsilyl triflate (50
dropwise over 10 s to a stirred solution of the alcohol 36a (18.1 mg,
0.034 mmol) and 2,6-lutidine (40 L, 0.34 mmol) in dry dichloro-
mL, 0.22 mmol) was added
4.1.18. (E)-(S)-1-((3S,5S)-3,5-Bis-methoxymethoxy-2,6,6-trimethyl-
5-propynoyl-cyclohex-1-enyl)-6-iodo-4-(4-methoxy-benzyloxy)-
hex-2-en-1-one (33b)
m
methane (2 mL) at ꢁ20 ꢀC. The mixture was warmed to room
temperature over 17 h and then water (5 mL) was added. The
separated aqueous phase was extracted with dichloromethane
(3ꢂ5 mL) and the combined organic extracts were then dried over
magnesium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography on silica using 20% ethyl
Sodium iodide (26 mg, 0.17 mmol) was added in one portion to
a stirred solution of the bromide 33a (69 mg, 0.113 mmol) in
butan-2-one (2 mL) at room temperature and the mixture was
then heated under reflux for 16 h. The mixture was allowed to cool
to room temperature and then water (2 mL) and diethyl ether
(2 mL) were added. The separated aqueous phase was extracted
with diethyl ether (2ꢂ5 mL), and the combined organic extracts
were then dried over sodium sulfate and concentrated in vacuo.
The residue was purified by flash column chromatography on
acetate in petroleum ether (bp 40–60 ꢀC) as eluent to give the silyl
23
ether (12.3 mg, 56%); [
a
]
þ3.7 (c 0.60, CHCl3); nmax (film)/cmꢁ1
D
3297, 2931, 2096, 1711 and 1676; dH (360 MHz, CDCl3) 0.04 (3H, s,
SiCH3), 0.12 (3H, s, SiCH3), 0.90 (9H, s, 3ꢂSiC(CH3)3), 1.14 (3H, s,
C(CH3)2), 1.22 (3H, s, C(CH3)2), 1.61 (3H, s, C]C(CH3)), 1.97–2.10 (2H,
m, CH2CH2I), 2.39–2.47 (2H, m, OCHCH2), 3.13–3.25 (2H, m,
CH2CH2I), 3.42 (3H, s, OCH3), 3.43 (3H, s, OCH3), 3.46 (1H, s, C^CH),
4.13–4.20 (1H, m, OCHCH2), 4.39–4.47 (1H, m, CHOTBS), 4.66 (1H, d,
J 6.8, OCHHO), 4.76 (1H, d, J 7.2, OCHHO), 4.77 (1H, d, J 6.8, OCHHO),
4.83 (1H, d, J 7.2, OCHHO), 6.28 (1H, d, J 15.8, CH]CHCH(OTBS)),
6.86 (1H, dd, J 5.7 and 15.8, CH]CHCH(OTBS)); dC (90 MHz, CDCl3)
ꢁ4.3 (q) ꢁ4.6 (q), 1.2 (t), 17.3 (q), 18.2 (s), 21.8 (q), 25.9 (3ꢂq), 26.7
(q), 30.8 (t), 40.6 (t), 41.3 (s), 56.0 (q), 56.6 (q), 71.8 (d), 73.5 (d), 81.9
(d), 82.6 (s), 88.8 (s), 94.0 (t), 96.5 (t), 130.3 (s), 131.0 (d), 140.9 (s),
151.6 (d), 189.1 (s), 199.6 (s); m/z (ES) 671.1889 (MþþNa, 60%,
C28H45INaO7Si requires 671.1877).
silica, using 30% ethyl acetate in petroleum ether (bp 40–60 ꢀC) as
23
eluent, to give the iodide (70 mg, 95%) as a colourless oil; [a]
D
ꢁ17.4 (c 0.84, CHCl3); nmax (film)/cmꢁ1 3298, 2935, 2096, 1726,
1613 and 1515; dH (360 MHz, CDCl3) 1.26 (6H, s, 2ꢂC(CH3)2), 1.65
(3H, s, C]C(CH3)), 1.98–2.13 (2H, m, CH2CH2I), 2.52 (1H, d, J 7.9,
OCHCHH), 2.54 (1H, d, J 7.9, OCHCHH), 3.21–3.31 (2H, m, CH2CH2I),
3.42 (3H, s, OCH3), 3.43 (3H, s, OCH3), 3.46 (1H, s, C^CH), 3.82 (3H,
s, ArOCH3), 4.21–4.19 (1H, m, CHOPMB), 4.25 (1H, dd, J 7.9 and 7.9,
OCHCH2), 4.34 (1H, d, J 11.0, OCHHArOMe), 4.52 (1H, d, J 11.0,
OCHHArOMe), 4.68 (1H, d, J 7.2, OCHHO), 4.77 (1H, d, J 5.7,
OCHHO), 4.79 (1H, d, J 5.7, OCHHO), 4.83 (1H, d, J 7.2, OCHHO), 6.34
(1H, d, J 16.0, CH]CHCH(OPMB)), 6.83 (1H, dd, J 6.6 and 16.0,
CH]CHCH(OPMB)), 6.89 (2H, d, J 8.7, 2ꢂArH), 7.24 (2H, d, J 8.7,
2ꢂArH); dC (90 MHz, CDCl3) 1.5 (t), 17.3 (q), 21.8 (q), 26.7 (q), 30.8
(t), 38.7 (t), 41.3 (s), 55.4 (q), 56.0 (q), 56.7 (q), 71.4 (t), 73.5 (d),
77.7 (d), 81.9 (d), 82.6 (s), 88.7 (s), 94.0 (t), 96.5 (t), 114.0 (2ꢂd),
129.5 (s), 129.6 (2ꢂd), 130.5 (s), 133.1 (d), 140.7 (s), 149.4 (d), 159.5
(s), 189.0 (s), 199.5 (s); m/z (ES) 677.1530 (MþþNa, 100%,
C30H39INaO8 requires 677.1587).
4.1.21. (1S,5S)-3-((E)-6-Bromo-hex-2-enoyl)-1,5-bis-methoxy-
methoxy-2,2,4-trimethyl-cyclohex-3-enecarbaldehyde (39)
A solution of n-BuLi (2.5 M) in hexanes (0.65 mL, 1.6 mmol) was
added dropwise over 2 min to a stirred solution of the vinyl-
stannane 38 (715 mg, 1.63 mmol)19 in dry THF (10 mL) at ꢁ78 ꢀC.
The mixture was stirred at ꢁ78 ꢀC for 1 h and then a solution of the

6680
W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
aldehyde 18 (132 mg, 0.32 mmol) in dry THF (5 mL) at ꢁ78 ꢀC was
added dropwise over 2 min. The mixture was warmed to room
temperature over 17 h, and then water (10 mL) and diethyl ether
(10 mL) were added. The separated aqueous phase was extracted
with diethyl ether (3ꢂ10 mL), and the combined organic extracts
were then dried over magnesium sulfate and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica, using 30% ethyl acetate in petroleum ether (bp 40–60 ꢀC)
as eluent, to give the corresponding diol analogue of 25 (79.6 mg,
53%) as a mixture of diastereoisomers. Sodium hydrogencarbonate
(142 mg, 1.69 mmol) and Dess–Martin periodinane (146 mg,
0.344 mmol) were added to a stirred solution of the diol in
dichloromethane (10 mL) at room temperature. The mixture was
stirred at room temperature for 2 h, and then a saturated solution
of aqueous sodium thiosulfate (5 mL) was added. The biphasic
mixture was stirred at room temperature for 5 min and then diethyl
ether (5 mL) was added. The separated aqueous phase was
extracted with diethyl ether (3ꢂ10 mL), and the combined organic
extracts were then dried over sodium sulfate and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica, using 30% ethyl acetate in petroleum ether (bp 40–60 ꢀC)
(C]O)CH]CHCH2), 6.89 (1H, dt, J 7.0 and 15.8, (C]O)CH]CHCH2);
dC (90 MHz, CDCl3) 17.2 (q), 21.8 (q), 26.6 (q), 30.7 (t), 30.9 (2ꢂt),
32.5 (t), 41.2 (s), 56.5 (q), 56.0 (q), 73.6 (d), 82.0 (d), 82.6 (s), 88.6 (s),
93.9 (t), 96.4 (t), 130.1 (s), 133.6 (d), 140.8 (s), 149.7 (d), 189.0 (s),
199.8 (s); m/z (ES) 493.1210 (MþþNa, 100%, C22H31BrNaO6 requires
493.1202).
4.1.23. (E)-1-((3S,5S)-3,5-Bis-methoxymethoxy-2,6,6-trimethyl-5-
propynoyl-cyclohex-1-enyl)-6-iodo-hex-2-en-1-one (41)
Sodium iodide (66 mg, 0.43 mmol) was added in one portion to
a stirred solution of the bromide 40 (45.0 mg, 0.093 mmol) in
butan-2-one (3 mL) at room temperature. The mixture was heated
under reflux for 16 h and then allowed to cool to room temperature.
Water (2 mL) and diethyl ether (2 mL) were added and the sepa-
rated aqueous phase was extracted with diethyl ether (3ꢂ5 mL).
The combined organic extracts were dried over sodium sulfate and
concentrated in vacuo to leave a residue, which was purified by
flash column chromatography on silica, using 30% ethyl acetate in
petroleum ether (bp 40–60 ꢀC) as eluent, to give the iodide (29 mg,
23
58%) as a colourless oil; [
a
]
þ5.6 (c 1.0, CHCl3); nmax (film)/cmꢁ1
D
3295, 2938, 2096, 1728, 1675 and 1644; dH (400 MHz, CDCl3) 1.15
(3H, br s, C(CH3)2), 1.22 (3H, br s, C(CH3)2), 1.61 (3H, s, C]C(CH3)),
1.95–2.03 (2H, m, CH2CH2I), 2.36–2.43 (2H, m, C]CCH2), 2.51 (2H,
app. dd, J 7.9 and 9.6, OCHCH2), 3.20 (2H, t, J 6.8, CH2CH2I), 3.42 (3H,
s, OCH3), 3.43 (3H, s, OCH3), 3.43 (1H, s, C^CH), 4.23 (1H, t, J 7.9,
OCHCH2), 4.66 (1H, d, J 7.2, OCHHO), 4.76 (1H, d, J 3.3, OCHHO), 4.77
(1H, d, J 3.3, OCHHO), 4.83 (1H, d, J 7.2, OCHHO), 6.18 (1H, dt, J 1.4
as eluent, to give the ketoaldehyde (67.5 mg, 86%) as a colourless oil;
23
[
a]
þ8.0 (c 1.0, CHCl3); nmax (film)/cmꢁ1 2953 and 1726; dH
D
(360 MHz, CDCl3) 1.12 (3H, br s, C(CH3)2), 1.29 (3H, br s, C(CH3)2),
1.62 (3H, s, C]C(CH3)), 1.99–2.09 (2H, m, CH2CH2Br), 2.25 (1H, dd,
J
7.5 and 15.0, OCHCHH), 2.36–2.49 (3H, m, OCHCHH and
C]CCH2CH2), 3.40–3.44 (2H, m, CH2CH2Br), 3.41 (3H, s, OCH3), 3.43
(3H, s, OCH3), 4.08 (1H, t, J 7.5, OCHCH2), 4.66 (1H, d, J 7.1, OCHHO),
4.74 (1H, d, J 7.4, OCHHO), 4.77 (1H, d, J 7.1, OCHHO), 4.84 (1H, d,
J 7.4, OCHHO), 6.19 (1H, dt, J 1.3 and 15.9, (C]O)CH]CHCH2), 6.83
(1H, dt, J 7.0 and 15.9, (C]O)CH]CHCH2), 9.79 (1H, s, CHO); dC
(90 MHz, CDCl3) 17.3 (q), 22.0 (q), 25.3 (q), 28.0 (t), 30.8 (t), 30.9 (t),
32.5 (t), 40.5 (s), 56.0 (q), 56.1 (q), 73.4 (d), 85.1 (s), 92.6 (t), 96.4 (t),
130.3 (s), 133.5 (d), 140.9 (s), 149.5 (d), 199.4 (s), 202.8 (d); m/z (ES)
469.1169 (MþþNa, 100%, C20H31BrNaO6 requires 496.1202).
and 15.8, (C]O)CH]CHCH2), 6.87 (1H, dt,
J 7.0 and 15.8,
(C]O)CH]CHCH2); dC (100 MHz, CDCl3) 5.2 (t), 17.2 (q), 21.8 (q),
26.7 (q), 30.8 (t), 31.6 (t), 33.2 (t), 41.3 (s), 56.6 (q), 56.0 (q), 73.5 (d),
82.0 (d), 82.5 (s), 88.6 (s), 93.9 (t), 96.5 (t), 130.1 (s), 133.6 (d), 140.9
(s), 149.3 (d), 189.1 (s), 199.6 (s); m/z (ES) 541.1076 (MþþNa, 100%,
C22H31INaO6 requires 541.1063).
4.1.24. (1S,8R,13S)-1,13-Bis-methoxymethoxy-12,15,15-
trimethyltricyclo[9.3.1.03,8]pentadeca-3,11-diene-2,10-dione (42)
4.1.22. (E)-1-((3S,5S)-3,5-Bis-methoxymethoxy-2,6,6-trimethyl-
A solution of tributyltin hydride (20 mL, 0.074 mmol) and AIBN
5-propynoyl-cyclohex-1-enyl)-6-bromo-hex-2-en-1-one (40)
(0.5 mg) in dry, degassed benzene (5 mL) was added dropwise over
4 h to a solution of the iodide 41 (28.6 mg, 0.055 mmol) and 2,2-
azo-bis-isobutyronitrile (0.5 mg) in dry, degassed benzene (18 mL)
at 80 ꢀC under an argon atmosphere. The mixture was stirred at
80 ꢀC for 3 h and then allowed to cool to room temperature. The
mixture was concentrated in vacuo and the residue was purified by
flash column chromatography on silica, using 30% ethyl acetate in
A
solution of ethynylmagnesium bromide (0.5 M) in THF
(1.5 mL, 0.75 mmol) was added dropwise over 5 min to a stirred
solution of the aldehyde 39 (67.5 mg, 0.15 mmol) in dry THF (3 mL)
at 0 ꢀC. The mixture was warmed to room temperature over 17 h
and then water (5 mL) and 2 M hydrochloric acid (0.5 mL) were
added. The separated aqueous phase was extracted with diethyl
ether (3ꢂ10 mL), and the combined organic extracts were then
dried over sodium sulfate and concentrated in vacuo. Sodium
hydrogencarbonate (123 mg, 1.46 mmol) and Dess–Martin period-
inane (124 mg, 0.29 mmol) were added to a stirred solution of the
residue in dichloromethane (5 mL) at room temperature. The
mixture was stirred at room temperature for 2 h and then a satu-
rated solution of aqueous sodium thiosulfate (2 mL) was added. The
biphasic mixture was stirred at room temperature for 5 min and
then diethyl ether (5 mL) was added. The separated aqueous phase
was extracted with diethyl ether (3ꢂ15 mL), and the combined
organic extracts were then dried over sodium sulfate and concen-
trated in vacuo. The residue was purified by flash column chro-
matography on silica, using 30% ethyl acetate in petroleum ether
petroleum ether (bp 40–60 ꢀC) as eluent, to give the tricycle
23
(9.6 mg, 44%) as a colourless oil; [
a]
ꢁ9.2 (c 0.5, CHCl3); nmax
D
(film)/cmꢁ1 2931, 1694 (br); dH (500 MHz, CDCl3) 1.17 (3H, s,
C(CH3)2), 1.40 (3H, s, C(CH3)2), 1.65 (3H, br s, C]C(CH3)), 1.67–1.72
(3H, m, C]CCH2CH2 and C]OCH2CHCHH), 2.13–2.19 (3H, m,
C]CCH2 and C]OCH2CHCHH), 2.44 (1H, dd, J 9.3 and 13.7,
OCHCHH), 2.47–2.51 (1H, m, C]CCH), 2.54 (1H, dd, J 3.4 and 19.1,
(C]O)CHHa), 2.85 (1H, dd, J 12.9 and 19.1, (C]O)CHHb), 2.99 (1H,
dd, J 1.9 and 13.7, OCHCHH), 3.40 (3H, s, OCH3), 3.44 (3H, s, OCH3),
4.38 (1H, d, J 9.3, OCHCH2), 4.62 (1H, d, J 6.8, OCHHO), 4.65 (1H, d, J
7.1, OCHHO), 4.85 (1H, d, J 6.8, OCHHO), 4.85 (1H, d, J 7.1, OCHHO),
5.69 (1H, t, J 3.6, C]CH); dC (125 MHz, CDCl3) 16.3 (q), 21.6 (q), 24.4
(t), 26.4 (q), 29.6 (t), 33.0 (t), 33.4 (d), 34.1 (t), 38.3 (s), 50.6 (t), 56.0
(q), 56.1 (q), 70.8 (d), 85.0 (s), 92.7 (t), 95.6 (t), 128.8 (d), 135.8 (s),
142.2 (s), 144.7 (s), 206.6 (s), 209.0 (s); m/z (ES) 415.2107 (MþþNa,
100%, C22H32NaO6 requires 415.2097).
(bp 40–60 ꢀC) as eluent, to give the ynone (44.9 mg, 64%) as a col-
23
ourless oil; [
a]
þ3.4 (c 1.0, CHCl3); nmax (film)/cmꢁ1 3296, 2945,
D
2096, 1704, 1674, 1651 and 1616; dH (360 MHz, CDCl3) 1.14 (3H, br s,
C(CH3)2), 1.21 (3H, br s, C(CH3)2), 1.60 (3H, s, C]C(CH3)), 1.98–2.07
(2H, m, CH2CH2I), 2.40–2.47 (2H, m, C]CCH2), 2.51 (2H, t, J 7.9,
OCHCH2), 3.38–3.44 (2H, m, CH2CH2I), 3.42 (3H, s, OCH3), 3.43 (3H,
s, OCH3), 3.47 (1H, s, C^CH), 4.23 (1H, t, J 7.9, OCHCH2), 4.66 (1H, d, J
6.9, OCHHO), 4.76 (1H, d, J 7.3, OCHHO), 4.77 (1H, d, J 6.9, OCHHO),
Acknowledgements
We thank the EPSRC (studentship to S.L.R.) and The University of
Nottingham (fellowship to W.P.D.G.) for support of this work.
4.82 (1H, d,
J 7.3, OCHHO), 6.17 (1H, dt, J 1.2 and 15.8,

W.P.D. Goldring et al. / Tetrahedron 65 (2009) 6670–6681
6681
Williams, R. M.; Croteau, R. Chem. Biol. 2004, 11, 379–387; (c) Jennewein, S.;
Rithner, C. D.; Williams, R. M.; Croteau, R. Arch. Biochem. Biophys. 2003, 413,
262–270; (d) Chau, M.; Jennewein, S.; Walker, K.; Croteau, R. Chem. Biol. 2004,
11, 663–672.
References and notes
1. Wani, M. C.; Wall, M. E.; Taylor, H. L.; Coggan, P.; McPhail, A. T. J. Am. Chem. Soc.
1971, 93, 2325–2327.
2. Horwitz, S. B.; Fant, J.; Schiff, P. B. Nature 1979, 277, 665–667.
14. (a) Jackson, C. B.; Pattenden, G. Tetrahedron Lett. 1985, 26, 3393–3396; (b)
Begley, M. J.; Jackson, C. B.; Pattenden, G. Tetrahedron Lett. 1985, 26, 3397–
3400; (c) Begley, M. J.; Jackson, C. B.; Pattenden, G. Tetrahedron 1990, 46,
4907–4924.
15. (a) Lin, X.; Hezari, M.; Koepp, A. E.; Floss, H. G.; Croteau, R. Biochemistry 1996,
35, 2968–2977; (b) Jin, Q.; Williams, D. C.; Hezari, M.; Croteau, R.; Coates, R. M.
J. Org. Chem. 2005, 70, 4667–4675.
16. Goldring, W. P. D.; Pattenden, G. Acc. Chem. Res. 2006, 39, 354–361; see also:
Tokiwano, T.; Endo, T.; Tsukagoshi, T.; Goto, H.; Fukushi, E.; Oikawa, H. Org.
Biomol. Chem. 2005, 3, 2713–2722.
17. See for example: (a) Chen, L.; Gill, G. B.; Pattenden, G. Tetrahedron Lett. 1994, 35,
2593–2596; (b) Handa, S.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 843–
845; (c) Pattenden, G.; Smithies, A. J.; Walter, D. S. Tetrahedron Lett. 1994, 35,
2413–2416; (d) Begley, M. J.; Pattenden, G.; Smithies, A. J.; Walter, D. S. Tetra-
hedron Lett. 1994, 35, 2417–2420; (e) Brennan, C. J.; Pattenden, G.; Rescourio, G.
Tetrahedron Lett. 2003, 44, 8757–8760; (f) Pattenden, G.; Gonzalez, M. A.;
McCulloch, S.; Walter, A.; Woodhead, S. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
12024–12029; (g) Hayes, C. J.; Herbert, N. M. A.; Harrington-Frost, N. M.; Pat-
tenden, G. Org. Biomol. Chem. 2005, 3, 316–327; (h) de Boeck, B.; Harrington-
Frost, N. M.; Pattenden, G. Org. Biomol. Chem. 2005, 3, 340–347; (i) Mulholland,
N. P.; Pattenden, G. Tetrahedron Lett. 2005, 46, 937–939; (j) Cases, M.; Gonzalez-
Lopez de Turiso, F.; Hadjisoteriou, M. S.; Pattenden, G. Org. Biomol. Chem. 2005,
3, 2786–2804; (k) Pattenden, G.; Stoker, D. A.; Thomson, N. M. Org. Biomol.
Chem. 2007, 5, 1776–1788.
18. Hitchcock, S. A.; Pattenden, G. Tetrahedron Lett. 1992, 33, 4843–4846.
19. Hitchcock, S. A.; Houldsworth, S. J.; Pattenden, G.; Pryde, D. C.; Thomson, N. M.;
Blake, A. J. J. Chem. Soc., Perkin Trans. 1 1998, 3181–3206.
20. cf. Taber, D. F.; Joshi, P. V. J. Org. Chem. 2004, 69, 4276–4278.
21. For some discussion on the issue of installing the angular methyl at C8 in the
taxanes see: (a) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, K.;
Nishimura, T.; Ohkawa, N.; Sakoh, H.; Saitoh, K. Chem. Lett. 1996, 483–484; (b)
Kuwajima, I.; Kusama, H. Synlett 2000, 1385–1401.
3. For commentary and reviews see: (a) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K.
Angew. Chem., Int. Ed. Engl. 1994, 33, 15–44; (b) Goodman, J.; Walsh, V. The Story
of Taxol, 1st ed.; Cambridge University Press: Cambridge, UK, 2001; part 1,
Chapter 1, p 10; (c) Kingston, D. G. I. Chem. Commun. 2001, 867–880.
4. (a) Holton, R. A.; Somoza, C.; Kim, H. B.; Liang, F.; Biediger, R. J.; Boatman, P. D.;
Shindo, M.; Smith, C. C.; Kim, S. C.; Nadizadeh, H.; Suzuki, Y.; Tao, C. L.; Vu, P.;
Tang, S. H.; Zhang, P. S.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc.
1994, 116, 1597–1598; (b) Holton, R. A.; Kim, H. B.; Somoza, C.; Liang, F.; Bie-
diger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S. C.; Nadizadeh, H.;
Suzuki, Y.; Tao, C. L.; Vu, P.; Tang, S. H.; Zhang, P. S.; Murthi, K. K.; Gentile, L. N.;
Liu, J. H. J. Am. Chem. Soc. 1994, 116, 1599–1600.
5. (a) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.; Couladoros, E. A.;
Sorensen, E. J. J. Am. Chem. Soc. 1995, 117, 624–633; (b) Nicolaou, K. C.; Liu, J. J.;
Yang, Z.; Ueno, H.; Sorensen, E. J.; Claiborne, C. F.; Guy, R. K.; Hwang, C. K.;
Nakada, M.; Nantermet, P. G. J. Am. Chem. Soc. 1995, 117, 634–644; (c) Nicolaou,
K. C.; Yang, Z.; Liu, J. J.; Nantermet, P. G.; Claiborne, C. F.; Renaud, J.; Guy, R. K.;
Shibayama, K. J. Am. Chem. Soc. 1995, 117, 645–652; (d) Nicolaou, K. C.; Ueno, H.;
Liu, J. J.; Nantermet, P. G.; Yang, Z.; Renaud, J.; Paulvannan, K.; Chadha, R. J. Am.
Chem. Soc. 1995, 117, 653–659; (e) Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.;
Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.;
Paulvannan, K.; Sorensen, E. J. Nature 1994, 367, 630–634.
6. Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T.
V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Di
Grandi, M. J. J. Am. Chem. Soc. 1996, 118, 2843–2859.
7. Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.; Houze, J. B.;
Krauss, N. E.; Lee, D. S.; Marguess, D. G.; McGrane, P. L.; Meng, W.; Natchus, M. G.;
Shuker, A. J.; Sutton, J. C.; Taylor, R. E. J. Am. Chem. Soc. 1997, 119, 2757–2758.
8. (a) Morihira, K.; Hara, R.; Kawahara, S.; Nishimora, T.; Nakamura, N.; Kusama;, H.;
Kuwajima, I. J. Am. Chem. Soc. 1998, 118, 12980–12981; (b) Kusama, H.; Hara, R.;
Kawahara, S.; Nishimora, T.; Kashima, H.; Nakamura, N.; Morihira, K.; Kuwajima, I.
J. Am. Chem. Soc. 2000, 122, 3811–3820.
22. Kuwajima et al. used this approach in their synthesis of taxol. See Ref. 8.
23. Roy, O.; Pattenden, G.; Pryde, D. C.; Wilson, C. Tetrahedron 2003, 59, 5115–5121;
Also see: Pryde, D. C. Ph.D. Thesis, University of Nottingham, 1994. For some
other earlier approaches to the fully substituted A-ring in taxol see: (a) Pet-
tersson, L.; Frejd, T.; Magnusson, G. Tetrahedron Lett. 1987, 28, 2753–2756; (b)
Pettersson, L.; Frejd, T. J. Chem. Soc., Perkin Trans. 1 2001, 789–800; (c) Doi, T.;
Robertson, J.; Stork, G.; Yamashita, A. Tetrahedron Lett. 1994, 35, 1481–1484; (d)
Winkler, J. D.; Bhattacharya, S. K.; Liotta, F.; Batey, R. A.; Heffernan, G. D.;
Cladingboel, D. E.; Kelly, R. C. Tetrahedron Lett. 1995, 36, 2211–2214; (e) Tjep-
kema, M. W.; Wilson, P. D.; Wong, T.; Romero, M. A.; Audrain, H.; Fallis, A. G.
Tetrahedron Lett. 1995, 36, 6039–6042; (f) Tjepkema, M. W.; Wilson, P. D.;
Audrain, H.; Fallis, A. G. Can. J. Chem. 1997, 75, 1215–1224.
24. Hodgson, D. M. Tetrahedron 1995, 51, 3713–3724.
25. Curran, D. P.; Yu, H. Synthesis 1992, 1, 123–127.
26. Leusink, A. J.; Budding, H. A. J. Organomet. Chem. 1968, 11, 533–539 See also
Ref. 19.
27. Foote, K. M.; Hayes, C. J.; John, M. P.; Pattenden, G. Org. Biomol. Chem. 2003, 1,
3917–3948.
9. Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.;
Sakoh, H.; Nishimura, K.; Tani, Y.; Hasegawa, M.; Yamada, K.; Saitoh, K.
Chem.dEur. J. 1999, 5, 121–161.
10. For some early examples see: (a) Funk, R. L.; Yost, K. J. J. Org. Chem. 1996, 61,
2598–2599; (b) Yadav, J. S.; Srinivas, D. Tetrahedron Lett. 1997, 38, 7789–7792;
(c) Crich, D.; Natarajan, S.; Crich, J. Z. Tetrahedron 1997, 53, 7139–7158; (d)
Wennerberg, J.; Polla, M.; Frejd, T. J. Org. Chem. 1997, 62, 8735–8740.
11. For more recent examples see: (a) To¨rma¨kangas, O. P.; Toivola, R. J.; Karvinen, E.
K.; Koskinen, A. M. P. Tetrahedron 2002, 58, 2175–2181; (b) Enomoto, T.;
Morimoto, T.; Ueno, M.; Matsukubo, T.; Shimada, Y.; Tsutsumi, K.; Shirai, R.;
Kakiuchi, K. Tetrahedron 2008, 64, 4051–4059; (c) Bre´mond, P.; Audran, G.;
Monti, H. J. Org. Chem. 2008, 73, 6033–6036; (d) Ma, C.; Schiltz, S.; Le Goff, X. F.;
Prunet, J. Chem.dEur. J. 2008, 14, 7314–7323.
12. (a) Harrison, J. W.; Scrowston, R. M.; Lythgoe, B. J. Chem. Soc. C 1966, 1933–
1945; (b) Koepp, A. E.; Hezari, M.; Zajicek, J.; Vogel, B. S.; LaFever, R. E.; Lewis,
N. G.; Croteau, R. J. Biol. Chem. 1995, 270, 8686–8690.
13. (a) Hefner, J.; Rubenstein, S. M.; Williams, R. M.; Ketchum, R. E. B.; Gibson, D.
M.; Croteau, R. Chem. Biol. 1996, 3, 479–489; (b) Jennewein, S.; Long, R. M.;