The total synthesis of the annonaceous acetogenin, muricatetrocin C

Article abstract of DOI:10.1002/1521-3765(20020402)8:7<1621::AID-CHEM1621>3.0.CO;2-8

The total synthesis of the potential antitumour agent muricatetrocin C has provided an ideal stage for the exploitation and development of new chemistry. A convergent synthetic strategy has been realised incorporating three distinct pieces of methodology, these include a highly diastereoselective hetero-Diels -Alder reaction to construct the butenolide terminus, an oxygen to carbon rearrangement to install the trans-2,5-disubstituted tetrahydrofuran ring and a spatial desymmetrisation process to afford the anti-diol unit.

Full text of DOI:10.1002/1521-3765(20020402)8:7<1621::AID-CHEM1621>3.0.CO;2-8

FULL PAPER
The Total Synthesis of the Annonaceous Acetogenin, Muricatetrocin C
Darren J. Dixon, Steven V. Ley,* and Dominic J. Reynolds[a]
Dedicated to Professor Jean-FranÁois Normant on the occasion of his 65th birthday
Abstract: The total synthesis of the potential antitumour agent muricatetrocin C has
provided an ideal stage for the exploitation and development of new chemistry. A
convergent synthetic strategy has been realised incorporating three distinct pieces of
methodology, these include a highly diastereoselective hetero-Diels Alder reaction
to construct the butenolide terminus, an oxygen to carbon rearrangement to install
the trans-2,5-disubstituted tetrahydrofuran ring and a spatial desymmetrisation
process to afford the anti-diol unit.
Keywords: antitumor agents ¥ cy-
cloaddition ¥ natural products ¥ total
synthesis
rated g-lactone ring, whilst the other side is simply aliphatic.
The largest site of variation in the acetogenins is the central
core, where the ring(s) can be cis- or trans-disubstituted,
adjacent or nonadjacent, flanked by one or two hydroxyl
groups or incorporate other functionality such as a ketone,
epoxide or THP ring.
Introduction
In their quest for novel lead structures Cole and co-workers in
1982 isolated a new natural product, uvaricin (1), from the
dried roots of Uvaria accuminta (Figure 1).[1] This was the first
member of a family of natural products that has since come to
be known as the annonaceous acetogenins and which now
features over 350 members, isolated from 37 different species
These compounds are known to exhibit a broad range of
biological activities, the precedent for which came from early
South American populations, who used extracts of Annona-
ceae plants as pesticidal and antiparasitic agents.[3] The tested
activities of the acetogenins now include, but are not limited
to: pesticidal, antifeedant, antiprotozoal, immunosuppressive
and probably most importantly, antitumour.[4] In this respect
they are known to be very potent cytotoxic compounds,
targeting the reduced nicotinamide adenine dinucleotide
(NADH), ubiquinone oxidoreductase in complex I, which is
a membrane bound protein of the mitochondrial electron
transport system, and the ubiquinone linked NADH oxidase
in the plasma membrane of cancerous cells.[5, 6] Inhibition by
these mechanisms results in ATP deprivation, which leads to
apoptosis of the high energy demanding tumour cells.[7] The
acetogenins are now considered as the most potent (effective
in nanomolar concentrations) known inhibitors of mitochon-
drial complex I.[5, 8] More recently the annonaceous acetoge-
nins have also been shown to overcome resistance in multi-
drug resistant (MDR) tumours.[9] Thus, for the above reasons
and by virtue of their limited availability from natural sources,
these compounds have been targeted for total synthesis by a
O
O
O
O
3
OH
OH
Uvaricin 1
OH
OH
O
O
OH
OH
O
Muricatetrocin C 2
Figure 1. Uvaricin (1) and muricatetrocin C (2).
of Annonaceae.[2] The structure of 1 can be taken as typical of
the annonaceous acetogenins. They are a series of C-35/C-37
natural products, usually characterised by a central polyoxy-
genated core comprising one, two or three tetrahydrofuranyl
(THF) rings along with a number of flanking hydroxyl groups.
Either side of this core unit is substituted with a long carbon
chain, one bearing a terminal methyl substituted a,b-unsatu-
15]
number of research groups.[10
Muricatetrocin C (2) was isolated in 1996 by McLaughlin
et al. from the leaves of Rollina mucosa, a tropical fruit tree
native to the West Indies and parts of Central America.[16] Our
specific interest in this molecule stemmed from two factors.
Firstly, the isolation group showed that 2 exhibits potent
[a] Prof. Dr. S. V. Ley, Dr. D. J. Dixon, Dr. D. J. Reynolds
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax : (‡44)1223-336442
E-mail: svl1000@cam.ac.uk
Chem.Eur.J. 2002, 8, No. 7
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S. V. Ley et al.
FULL PAPER
inhibitory action against PC-3 prostatic adenocarcinoma,
PACA-2 pancreatic carcinoma and A-549 lung carcinoma
cell lines, making it a potential antitumour agent. Unfortu-
nately, the limited supply of the natural product (15mg from
1.63 kg of dried leaves) restricted further investigation, high-
lighting the need for total synthesis in this area.[16] The second
level of interest arose due to the structural features present in
the molecule: namely seven stereogenic centres, compart-
mentalised into three distinct structural motifs. It was
envisaged that 2 would provide an excellent platform for
both the evolution of existing group methodology and the
potential development of new synthetic tools. This was
compounded by the fact that no synthesis of 2 had previously
been reported in the literature.[17]
the hydroxy-butenolide terminus 5, using a hetero-Diels
Alder (HDA) reaction with diene 8 to simultaneously install
the 1,5-stereochemical relationship and mask the butenolide
double bond.
With regard to the later stages of the synthesis, addition of
the alkynyl lithium reagent derived from 3 to the anomerically
disposed aldehyde 4, was envisaged to introduce the remain-
ing stereogenic centre at C-16. Subsequent manipulation to
unmask a terminal alkyne, would then allow for a Sonogashira
coupling with 5 to complete the carbon skeleton. The
À
formation of this C7 C8 bond and the subsequent selective
hydrogenation of the resulting enyne in the presence of the
butenolide is supported by good precedent from previous
work carried out in this area.[20]
Synthetic plan: The strategy towards 2 centred on the
enantioselective preparation of fragments 3, 4 and 5, and
their subsequent coupling to realise an overall convergent
route (Scheme 1). The plan incorporates some well-estab-
lished endgame chemistry based on the large literature
precedent in the area, whilst also generating three evenly
Results and Discussion
The anti-diol fragment: The synthesis commenced with the
preparation of 3 wherein the anti-diol arises from the chemical
desymmetrisation of a meso-dimethyltartrate derivative, fol-
lowing a modification of the previously reported process.[21]
Thus 2,3-butanediacetal (BDA) protected (R,R)-dimethyl
tartrate 9 was converted to the corresponding (R,S)-diol 6
exploiting the local chirality contained within the BDA
protecting group (Scheme 2). Terminal differentiation of 6
by successive treatment with sodium hydride (1.1 equiv) then
tert-butyldimethylchlorosilane (TBSCl) afforded 10 and 11 in
a 5:1 ratio of easily separable diastereoisomers, favouring the
axial silyl ether 10. In order to achieve this bias towards axial
protection it was critical to observe precipitation of the
initially formed mono-anion. Presumably the nature of this
precipitate is such that the sodium cation is positioned
OH
OH
O
O
OH
OH
2
O
Sonogashira
coupling
Addition
to aldehyde
34
OMe
TBSO
OBn
16
I
O
O
O
O
4
9
7
O
O
OMe
Single
inversion
3
4
5
HO
OMe
OMe
O
a
MeO
MeO
O
O
O
O
HO
O
OMe
OMe
HO
9
6
OMe
via:
HO
O
OMe
O
O
O
O
Na
b
O
TBSO
HO
BnO
HO
OMe
OMe
O
TBDPSO
SnBu3
O
OMe
O
O
O
O
O
OMe
HO
TBSO
6
7
8
12
OMe
OMe
Scheme 1. Synthetic plan for 2. Bn ˆ benzyl, TBS ˆ tert-butyldimethylsilyl,
TBDPS ˆ tert-butyldiphenylsilyl.
10
11
c-e
Br
RO
functionalised fragments that it was hoped would allow either
the utilisation of existing methodology from our laboratories
or the development and application of new chemistry. Thus
the key features of the approach are: the application of the
recently reported (R',R',R,S)-2,3-butanediacetal-protected
butane tetrol 6 as a building block for the anti-1,2-diol
containing component 3 through selective chemical differ-
entiation of the incongruous hydroxyl termini;[18] the use of
the recently developed anomeric oxygen to carbon rearrange-
ment of alkynyl stannanes such as 7 for the stereoselective
construction of the 2,5-trans-disubstituted THF ring compo-
nent 4;[19] and finally the implementation of a new approach to
OMe
Br
OMe
g,h
O
O
O
O
OMe
OMe
R = TBS 13
R = H 14
15
f
Scheme 2. Synthesis of gem-dibromo olefin 15. a) ref. [21]; b) NaH; THF/
pentane, 08C ! rt, 30 min, then TBSCl, 40 min (72%); c) DMSO, (COCl)2,
CH2Cl2, À788C; NEt3, À78 ! rt; d) CH3(CH2)10PPh3I, n-BuLi, THF,
À788C, 30 min (92%, two steps; Z/E 8:1); e) Raney nickel, H2, EtOH;
rt, 30 min (90%); f) TBAF, THF, rt, 2 h; g) DMSO, (COCl)2, CH2Cl2,
À788C; NEt3, À78 ! 08C; h) PPh3, CBr4, CH2Cl2, 08C, 30 min, (88%,
three steps). TBAF ˆ tetra-n-butylammonium fluoride, TBSCl ˆ tert-bu-
tyldimethylsilyl chloride.
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Muricatetrocin C
1621 1636
between the axial oxy-anion and a donating lone pair from
one of the two oxygen atoms of the BDA dioxane ring. In this
event a kinetic trap of the anion 12 with TBSCl prior to
equilibration in solution would lead to the observed result.
More conventional silylation conditions (namely TBSCl,
imidazole, THF) afforded the expected equatorial silyl ether
11 with high diastereoselectivity (11/10 17:1).[18b]
Chain extension to build the twelve-carbon terminus was
the first homologation that was required to progress towards
fragment 3. Oxidation of 10 to the equatorial aldehyde
proceeded smoothly using the Swern conditions. This crude
material underwent Wittig reaction with the phosphorus ylid
derived from 1-iodoundecane at À788C in THF, to form an
inseparable mixture of olefins (Z/E 8:1) in good yield. For
ease of subsequent characterisation, the resulting olefin was
saturated using hydrogen and Raney nickel in ethanol, to
afford 13. Reduction with hydrogen in the presence of other
metal additives such as palladium on carbon and platinum
dioxide were far less efficient, producing significant decom-
position of the starting material. This was perhaps a result of
competing hydrogenolysis at the allylic position.
The known lactol 17 was readily prepared in three high
yielding steps from (R)-glycidol (Scheme 4). Consequently,
formation of the tert-butyldiphenylsilyl (TBDPS) ether 16,
opening of this epoxide with allyl magnesium bromide in the
presence of catalytic dilithium tetrachlorocuprate [Li2CuCl4],
and then ozonolysis of the resulting alkenol with in situ ring
closing afforded 17 in 70% overall yield, as a 3:2 mixture of
anomers. Subsequent treatment of this material with excess
propargylic alcohol and catalytic Amberlyst A-15in benzene
at reflux delivered the propargylic ether 18 in excellent yield,
again as a 3:2 mixture of anomers.
b,c
d
TBDPSO
TBDPSO
RO
R = H
R = TBDPS 16
OH
O
O
O
O
17
18
a
e
f
TBDPSO
TBDPSO
7
O
g
O
OH
OH
19
20
Deprotection of the silyl group using tetra-butylammonium
fluoride (TBAF) in THF furnished 14, then Swern oxidation
of the resulting alcohol afforded the axial aldehyde. Con-
version to a suitable coupling partner required a one-carbon
homologation reaction. Thus,
h
TBDPSO
HO
X
O
O
[O]
failed
OBn
OBn
O
21
23
addition of the crude aldehyde
3.9%
i,j
to a solution of CBr4 and Ph3P
in CH2Cl2 at 08C, afforded
O
OBn
Br
O
O
OBn
H
Br
OMe
24
4
gem-dibromo olefin 15 in good
yield.[22] Compound 15 was
subjected to a NOE study in
order to ascertain whether any
epimerisation had occurred ei-
ther in the oxidation step or in
the presence of the in situ
generated (dibromomethyle-
O
O
Scheme 4. Synthesis of tetrahydrofuran 4. a) TBDPSCl, NEt3, DMAP,
CH2Cl2, rt, 24 h (85%); b) allylMgBr, CuLi2Cl4, (10 mol%), THF, À308C
2 h (89%); c) O3, CH2Cl2, À788C, 20 min; PPh3, À788C ! rt, 14 h (93%);
d) prop-2-yn-1-ol, Amberlyst A-15, benzene, reflux, 15 min (91%); e) n-
BuLi, THF, À788C, 30 min; Bu3SnCl, À788C ! rt, 30 min; f) BF3 ¥ OEt2,
CH2Cl2, À108C, 10 min [85%, two steps (5.5:1, 19/20)]; g) KHMDS,
À788C, 30 min, then BnBr, THF, À788C ! rt (78%); h) TBAF, THF, rt,
3 h (95%); i) Raney nickel, H2, EtOH; rt, 30 min (70%); j) DMSO,
(COCl)2, CH2Cl2, À788C; NEt3, À78 ! rt (used crude). TBDPSCl ˆ tert-
butyldiphenylsilylchloride, DMAP ˆ dimethylaminopyridine, KHMDS ˆ
potassium hexamethyldisilazide.
OMe
15
Figure 2. NOE to confirm ax-
ial disposition of the gem-di-
bromo olefin 15.
ne)triphenylphosphorane. The important effect was observed
between the olefin proton and the proximal axial methoxy
substituent (Figure 2). The conversion of 15 to the alkynyl
lithium derivative of 3 is described in the coupling section.
Subjection to the rearrangement protocol by deprotonation
of the alkyne 18 with n-butyllithium in THF at À788C,
followed by treatment with tributyltin chloride and warming
to room temperature afforded, after aqueous work up, the
crude tributylstannylated material 7. This was not purified, but
simply dissolved in dichloromethane, cooled to À108C and
then treated with boron trifluoride etherate for ten minutes
before the reaction mixture was quenched with sodium
hydroxide. Aqueous work up and inspection of the crude
1H NMR indicated that the reaction had proceeded to give the
carbon linked products 19 and 20 in a ratio of 5.5:1 favouring
the trans-product 19 in good overall yield. Benzylation of the
released primary hydroxyl by treatment with potassium
hexamethyldisilazide (KHMDS) followed by benzyl bromide
allowed chromatographic separation of the diastereoisomers
to afford 21 [along with minor isomer (not shown) 22], which
underwent analysis by NOE to corroborate the predicted
trans-relationship of the major component (Figure 3).[23]
The central fragment: The trans-relationship across the
disubstituted tetrahydrofuran ring 4 was expected to arise
from a Lewis acid mediated rearrangement of alkynyl
stannane 7, with the approach of the tributylstannane being
directed by the pendant bulky tert-butyldiphenylsilyloxymeth-
yl group (Scheme 3).
O-C
rearrangement
OBn
TBDPSO
SnBu3
O
O
O
O
4
7
Bu3Sn
OBF3
H
O
O
Si
Hindered
approach
Scheme 3. Synthetic plan towards tetrahydrofuran 4.
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S. V. Ley et al.
FULL PAPER
1.4%
the facial selectivity of the reaction, and secondly in the case
of X=O; the desired frontier orbital coefficients to force the
regioselective delivery of oxygen atom to C-4.
0.3%
H
H
O
TBDPSO
H
OBn
OBn
With these criteria in mind the obvious choice of dien-
ophile, singlet oxygen (X ˆ O), which avoids any regiochem-
ical issues was considered unsuitable due to the lack of any
steric component to direct the diastereoselectivity. A search
for more appropriate alternatives indicated nitroso dieno-
philes as potential reagents. In particular nitrosobenzene,
which along with the evident steric properties, had been
shown by Kresze and Firl to exhibit promising regioselectivity,
albeit in combination with the much simpler 2-cyanobuta-
diene 25, affording 26 in 70% yield (Scheme 6).[24] With this
initial precedent in hand, molecular orbital calculations were
performed in an attempt to predict if the more complicated
diene 8 would exhibit the same regiochemical preferences
(Figure 4). The resulting frontier orbital coefficients implied
that the reaction should proceed with normal electron
demand to favour the desired regioisomer.[25]
O
H
TBDPSO
21
22
À
Figure 3. NOE values to confirm the stereochemical outcome of the O C
rearrangement reaction.
After the successful introduction of the C-12 stereogenic
centre, 21 needed to be prepared for coupling with the
metallated fragment 3. Given that this coupling produces a
further propargylic triple bond requiring reduction, it was
thought that both these hydrogenation steps would be
performed simultaneously, at a later stage in the synthesis.
Therefore TBAF mediated removal of the silyl protecting
group proceeded smoothly to afford 23. However, trial
reactions with a variety of common oxidation procedures
revealed that the desired aldehyde 24, was unstable and
extremely difficult to isolate. Surprisingly, after much exper-
imentation, it was found that removal of the triple bond by
hydrogenation over Raney nickel allowed Swern oxidation to,
and isolation of, essentially pure aldehyde 4.
PhNO
NC
NC
N
O
MeOH, rt
25
26
Scheme 6. Reaction of nitrosobenzene with 2-cyanobutadiene (25).
The butenolide terminus: The synthetic strategy towards 5
centred on the idea of utilising the C-34 methyl substituent of
diene 8 to influence the introduction of the C-4 stereogenic
centre–a formal 1,5-induction process (Scheme 5). This
approach offers a significant departure from the previous
work in the area, the majority of which concentrates on the
union of two chiral fragments or the employment of more
than one source of chirality.
The heterodienophile requires two distinct properties in
order to render the reaction successful namely the necessary
steric bulk to develop the unfavourable, nonbonding inter-
action with the C-34 methyl substituent and therefore control
0.428
E
LUMO
0.027
O
N
—0.046
—0.308
LUMO
HOMO
—0.266
—0.302
0.283
—0.330
O
O
BnO
HOMO
8
Figure 4. Results of the frontier orbital calculations.
Subsequent to the HDA reaction, two events are required,
firstly elimination of the aryl amine portion to re-introduce
the unsaturation to the g-lactone, and then manipulation of
the primary benzyl ether to allow one carbon homologation to
a vinyl iodide. The important issue is that the cleavage of the
Masked
α,β-unsaturation
i)
X
34
TBSO
TBSO
I
O
O
4
BnO
H
O
O
5
Masked
vinyl iodide
Acid labile
protecting group
À
N O bond must be performed selectively in the presence of
the benzyl group and more importantly the a,b-unsaturation,
which is required to protect against the possibility of internal
translactonisation. However, the synthetic ordering of the
above events was considered interchangeable and this inher-
ent flexibility was found to be an important benefit of the
synthesis plan.
X
O
HDA
X
O
O
O
O
BnO
BnO
O
8
The synthesis began with 1,4-butanediol, which was mono-
protected to give the primary benzyl ether 27, then a tandem
Swern Wittig reaction afforded the a,b-unsaturated tert-
butyl ester 28 in excellent yield (Scheme 7). Then, in a three
step procedure with no isolation of intermediates, 28 was
treated with LDA in the presence of HMPA followed by the
addition of (S)-2-(tert-butyldimethylsilyloxy)propanal, de-
rived from (S)-ethyl lactate.[26] This crude material was stirred
O
Me
ii)
O
4
34
BnO
Directs
stereocontrol
Frontier orbitals
direct regiocontrol
O X
R
Steric bulk
Scheme 5. i) Synthetic plan towards fragment 5; ii) requirements of the
dienophile for the successful induction of stereochemistry.
1624
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Muricatetrocin C
1621 1636
freshly prepared [Mo(CO)3(MeCN)3] in the presence of water
could effect this transformation at ambient temperature,
affording 33 in 70% yield (Scheme 8).[30] Interestingly the
direct use of [Mo(CO)6] in refluxing acetonitrile (the pre-
cursor to [Mo(CO)3(MeCN)3]) resulted in thermal decom-
position of the HDA adduct to afford diene 8–probably the
result of a retro-Diels Alder process. Subsequent silylation
of the resultant secondary hydroxyl with TBSCl proceeded
smoothly in 83% yield to afford 34. With the potential for
translactonisation alleviated, the a,b-unsaturation was cleanly
and efficiently removed by hydrogenation over catalytic
platinum dioxide to afford 35. This reduction step furnished
a single diastereoisomer, which was subsequently shown by
NOE analysis to have the (R)-configuration at C-2, with the
important enhancement occurring between H-2 and H-34.
c-e
b
BnO
O
f
OH
BnO
O
RO
O
R = H
a
28
29
O
O
R = Bn 27
[E/Z 1:6]
N
O
O
g
N
+
O
O
BnO
BnO
BnO
O
8
O
O
31
30
[E/Z >20:1]
HPLC
3%
Important NOE's
H
H
H
4
H
N
O
BnO
33
N
Me
O
O
H
O
O
H
BnO
4
O
10%
32
32
Scheme 7. Synthesis of the hetero-Diels Alder adduct 32. a) NaH; BnBr,
DMF, 08C (82%); b) DMSO, (COCl)2, CH2Cl2, À788C; NEt3, À78 ! rt,
HN
HN
then
(tert-butoxycarbonylmethylene)triphenylphosphorane,
CH2Cl2,
N
a
c
RO
TBSO
34
O
08C ! rt, 14 h (96%); c) LDA/HMPA/THF, À788C, 30 min, then (S)-2-
(tert-butyldimethylsilyloxy)propanal, À78 ! 08C; d) MeOH/HCl (sat.), rt,
5min, (repeat); e) MsCl, NEt 3, CH2Cl2, 08C, 30 min (E/Z 1:6); f) I2
(5mol%), sunlamp irradiation, rt, 4 h (56%, four steps; E/Z, >20:1);
g) PhNO, MeOH/CH2Cl2 (1:1), 08C, 21 h [91% (30/31 7:3)]; DMF ˆ N,N-
dimethylformamide, LDA ˆ lithium diisopropylamide, HMPA ˆ hexa-
methyl phosphoramide, MsCl ˆ methanesulfonyl chloride.
2
O
O
O
BnO
BnO
BnO
H
O
O
O
32
35
R = H 33
b
R = TBS 34
d
O
O
F3C
TBSO
N
H
F3C
TBSO
TBSO
N
H
f,g
h
I
O
I
O
O
RO
e
O
in an acidic methanol solution to effect deprotection of both
the TBS group and the tert-butyl ester allowing cyclisation to
the g-lactone. b-Elimination was then achieved by treatment
of the crude material with methanesulfonyl chloride and
triethylamine to afford 29 and 8 as a mixture (E/Z 1:6) of
geometric isomers at the external olefin position in 56% over
the three steps.[27] The desired E-isomer 8 was then accessed
with a ratio of greater than 20:1 by sunlamp irradiation in the
presence of a catalytic amount of iodine.[28]
O
5
38
O
R = Bn 36
R = H 37
Scheme 8. Synthesis of the butenolide fragment 5. a) [Mo(CO)6], MeCN,
reflux, 4 h; then 32, H2O, rt, 15min (70%); b) TBSCl, imidazole, DMF, rt,
14 h (83%); c) PtO2 (33 mol%), H2, MeOH; rt, 90 min (98%); d) TFAA,
H¸nig×s base, CH2Cl2, 08C, 30 min; e) Pd(OH)2 (20 mol%), H2, MeOH; rt,
48 h (90% two steps); f) DMSO, (COCl)2, CH2Cl2, À788C; NEt3,
À788C ! 08C; g) CrCl2, CHI3, THF, 08C ! rt, 14 h (80% two steps, E/Z
4:1); h) DBU, CH2Cl2, 08C, 60 min (91%). TFAA ˆ trifluoroacetic anhy-
dride, DBU ˆ 1,8-diazobicyclo[5.4.0]undec-7-ene.
With 8 now readily available, the key HDA reaction was
investigated. It was found that overnight stirring of a
methanol/dichloromethane (1:1) solution of 8 with nitro-
sobenzene at 08C afforded a mixture of regioisomers (30/31
7:3), favouring the desired adduct 30, in overall 89% yield.
At this stage in the synthesis several options were
investigated towards the elimination of the aryl amine portion
to re-introduce the unsaturation to the g-lactone ring. After
experimentation involving N-quaternisation, N-oxidation
(followed by Cope elimination) and N-sulfonylation, we
found that the optimum activation allowing facile elimination
of the aryl amine was trifluoroacetamide formation. The
eventual path to 5 actually involved ™protection∫ of 35 as its
trifluoroacetamide 36 using trifluoroacetic anhydride and
H¸nig×s base followed by a three-step process to form the
desired vinyl iodide. Thus hydrogenation of the benzyl ether
over Pd(OH)2 gave 37, then Swern oxidation of the released
hydroxyl group followed by one carbon homologation ac-
cording to the Takai procedure[31] provided 38 as a 4:1 ratio of
inseparable isomers in overall 64% yield (four steps),
favouring the E-geometry. Subsequent elimination of the
trifluoroacetamide was effected using DBU at 08C, to afford 5
in 91% yield with no epimerisation of the C-34 methyl
substituent.
1
Pleasingly, inspection of the crude H NMR showed that the
major regioisomer 30 had been formed with a diastereoiso-
meric ratio of greater than 20:1–thus the observed diaster-
eoselection appeared to be limited only by the original
geometry of the external olefin in the diene precursor. The
required diastereomerically pure regioisomer 32 was obtained
in 55% yield following separation by HPLC; the slightly
diminished yield perhaps reflecting the propensity for retro-
DA reaction on silica that has been previously documented
for this class of compounds.[29] Extensive NOE studies were
undertaken on the major isolated product 32 with the
important enhancements being found between H-34 and the
ortho-protons of the aryl amine portion, and between H-33
and the C-34 methyl substituent to confirm the regioselectiv-
ity and diastereoselectivity, respectively.
After screening a variety of standard conditions for the
À
cleavage of N O bonds with little success, it was found that
Chem.Eur.J. 2002, 8, No. 7
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1625

S. V. Ley et al.
FULL PAPER
The final steps: The convergent assembly of muricatetrocin C
from the three fragments 3, 4 and 5 involves two key bond-
forming events. The first coupling reaction between 3 and 4
forms the final C-16 stereogenic centre then, after manipu-
lation to unmask a terminal alkyne, the second coupling
event, to attach 5, completes the carbon skeleton.
Treatment of the gem-dibromoalkene 15 with n-butyllithi-
um in THF at À788C, followed by quenching of the resulting
anion 39 with crude aldehyde 4, proceeded in good yield to
give the propargylic alcohols 40 and 41 (Scheme 9). Inspec-
tion of the crude 1H NMR spectrum indicated that the
reaction had proceeded with poor selectivity to afford 40 and
41 in a ratio of 1.8:1; tentatively assigned as favouring 40,
which is the product of Felkin Anh control. Unfortunately
the two epimers were inseparable at this stage. The yield of
the coupling reaction was generally dependent on the quality
of the crude aldehyde, and the poor diastereoselectivity was as
expected based upon literature precedent.[32] Consequently an
oxidation reduction sequence was sought in order to estab-
lish the correct stereochemistry at C-16.
Reduction of the alkyne with hydrogen in the presence of
Raney nickel proceeded smoothly to afford 42 and 43, which
were separable by column chromatography. Analysis of the
13C NMR spectra of the two epimers, provided further
evidence supporting the original stereochemical assignment
of the major and minor products. By analogy with previous
studies, the chemical shift of C-16 is dependent on the
configuration of the adjacent THF ring, with the erythro-
product 42, having a lower chemical shift.[13a] In this instance,
the difference between the two resonances was d ˆ 3.2, which
is typical for these systems.
After separation of the minor isomer 43, the remaining
material was oxidised using the Swern reagent to afford 44 in
good yield. Several reducing agents were investigated in an
attempt to develop a diastereoselective recycling protocol. l-
Selectride in THF at À1008C, was found to deliver the best
selectivity, providing 43 and 42 in excellent yield as a 4:1 ratio
favouring 43; this result is consistent with those previously
observed in the literature.[13b] Interestingly when Superhy-
dride was used under the same conditions, the reduction
favoured formation of the erythro-isomer (43/42 1:2), whereas
sodium borohydride provided no diastereoselection in meth-
anol at 08C.
Using achiral reducing reagents, a 4:1 ratio favouring the
desired threo-isomer was the best result obtained. Reduction
using the enantiopure (R)-CBS reagent (CBS: Corey Bak-
shi Shibata) was also performed on the ketone 44, which
delivered a significantly higher ratio (43/42 9:1) of the C-16
epimers.[33] Furthermore, the stereochemical outcome, pre-
dicted using the mnemonic for reductions of this type, was in
agreement with the stereochemistry previously assigned using
the 13C NMR chemical shift data, providing further proof of
the configuration at C-16.
Protection of the free secondary alcohol was effected by
treatment of 43 with TBSCl and imidazole in DMF in good
yield to afford the silyl ether 45, which then underwent de-
benzylation using hydrogen in the presence of catalytic
palladium hydroxide to give 46 (Scheme 10). Oxidation to
the corresponding aldehyde oc-
curred in excellent yield using
O
OBn
the Dess Martin periodinane
O
reagent in dichloromethane at
08C.[34] Initial attempts at the
HO
OBn
4
O
16
Li
OMe
one carbon homologation to-
O
OMe
O
wards 47 focussed on the
a
OMe
Corey Fuchs procedure which
O
O
15
had been successfully used ear-
erythro C-16 (R) 40
threo C-16 (S) 41
OMe
lier in the synthesis.[22] Howev-
er, on reaction with in situ
generated (dibromomethyle-
ne)triphenylphosphorane,
39
b
complete decomposition of the
starting material was observed.
This disappointing result
may be attributed to competing
acetal deprotection, which is
known to be effected by the
phosphorane reagent.[35] In ad-
dition, the small scale of the
reaction may also have been a
contributing factor. An alter-
native, well established proce-
dure, for the conversion of
aldehydes to terminal alkynes
is the Colvin Gilbert Sey-
ferth reagent, diethyl(diazo-
methyl)phosphonate.[36] In this
case, owing to the greater nu-
HO
OBn
HO
O
OBn
O
OMe
OMe
threo
erythro
O
O
O
C-16, δC = 74.9
O
C-16, δC = 71.7
OMe
OMe
43
42
c
Reagent
Ratio 43/42
L-Selectride
LiBHEt3
4:1
1:2
OBn
O
O
NaBH4
1:1
9:1
OMe
(R)-CBS
O
O
OMe
44
Scheme 9. Coupling fragments 39 and 4. a) n-BuLi, THF, À78 ! 08C, 30 min; À788C then 4 (63% two steps; 40/
41, 1.8:1); b) Raney nickel, H2, EtOH; rt, 60 min (43 18%, 42‡43 71%); c) DMSO, (COCl)2, CH2Cl2, À788C;
NEt3, À78 ! rt (80%).
1626
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Chem.Eur.J. 2002, 8, No. 7

Muricatetrocin C
1621 1636
Conclusion
TBSO
e
RO
O
OR'
c,d
O
5
In summary, the first total synthesis of 2 has been achieved by
implementing new methods for the stereoselective prepara-
tion of each of the three coupling fragments. The route
described here, has a longest linear sequence of 22 steps, and
prepares muricatetrocin C in overall 2.8% yield at average
yield of 85% per step. Thus our anti-diol building block,
(R',R',R,S)-2,3-BDA-protected butane tetrol 6 has found
further utility in total synthesis, the recently developed
OMe
OMe
O
O
O
O
OMe
OMe
47
R = H, R' = Bn 43
a
R = TBS, R' = Bn 45
b
R = TBS, R' = H 46
TBSO
TBSO
O
O
À
OMe
anomeric O C rearrangement methodology has been used
O
O
to install the 2,5-trans-disubstituted THF moiety 4 and a new
approach to the hydroxy-butenolide terminus 5, employing a
highly diastereoselective HDA reaction, has been developed.
Further studies aimed at expanding our synthetic approach to
other members of this family of bioactive natural products are
currently underway, and progress will be reported in due
course.
O
OMe
48
f,g
OH
OH
O
O
OH
OH
O
muricatetrocin C 2
Experimental Section
Scheme 10. Second coupling reaction and final steps. a) TBSCl, DMF,
imidazole, 458C, 14 h (87%); b) Pd(OH)2 (20 mol%), H2, EtOH; rt, 12 h
(94%); c) DMP, py, CH2Cl2, 08C ! rt, 45min (96%); d) diethyl(diazo-
methyl)phosphonate, tBuOK, THF, À788C, 16 h; then rt, 4 h (76%);
e) [(PPh3)2PdCl2] (10 mol%), CuI (30 mol%), NEt3, rt, 3 h (81%);
f) [Rh(PPh3)3Cl], H2, benzene/EtOH 1:1, rt, 11 h (76%); g) TFA/H2O
9:1, rt, 30 s; repeat (82%). DMP ˆ Dess Martin periodinane, TFA ˆ tri-
fluoroacetic acid.
General: All reactions were carried out under an atmosphere of argon, and
those not involving aqueous reagents were carried out in oven-dried
glassware, cooled under vacuum. Diethyl ether and tetrahydrofuran were
distilled over sodium/benzophenone; dichloromethane, methanol, benzene
and toluene were distilled over calcium hydride; pentane was distilled over
sodium; and triethylamine from potassium hydroxide. Petroleum ether 40/
60 was used for chromatography. All other solvents and reagents were used
as supplied unless otherwise stated. Flash column chromatography was
carried out using Merck Kieselgel (230 400 mesh) under pressure unless
otherwise stated. High performance liquid chromatography (HPLC) was
performed using a Waters Delta Prep machine using a multiwave detector
set at 205nm using silica gel as the stationary phase with the mobile phases
and flow rate as described. Analytical thin layer chromatography (TLC)
was performed on glass plates pre-coated with Merck Kieselgel 60F254,
and visualised by UV irradiation (254 nm), or by staining with aqueous
acidic ammonium molybdate, or aqueous acidic potassium permanganate
solutions as appropriate. Melting points were measured on a Reichert hot
stage apparatus, and are uncorrected. Optical rotations were measured on
an Optical Activity AA-1000 polarimeter, and [a]D values are reported in
10À1 degcm2 gÀ1; concentration (c) is in g per 100 mL. Infrared spectra were
obtained on Perkin Elmer 983G or FTIR 1620 spectrometers, from a thin
cleophilicity of the phosphonate anion, the reaction condi-
tions are considerably milder and, perhaps more importantly,
basic. Pleasingly, on reaction with the potassium anion of the
phosphonate, the aldehyde afforded terminal alkyne 47 in
good yield. This transformation completed the preparation of
the coupling partner required for the Sonogashira reaction
with fragment 5.
According to the method of Hoye et al., alkyne 47 was
added to
a triethylamine solution of vinyl iodide 5,
[Pd(PPh3)2Cl2] and copper iodide at room temperature and
stirred for two hours to afford, after purification by column
chromatography, enyne 48 in good (81%) yield.[20a] There was
considerable literature precedent for the selective hydro-
genation of the resulting enyne moiety in the presence of the
a,b-unsaturated g-lactone. According to this precedent,
reduction of 48 with hydrogen in ethanol/benzene in the
presence of Wilkinson×s catalyst gave, after eleven hours, fully
protected 2 in good (76%) yield with no reduction of the
butenolide portion.[20b] Both BDA and TBS groups are known
to be acid labile, which was important in order to maintain the
stereochemical integrity of the butenolide methyl substituent.
Global deprotection was therefore achieved by treatment
with aqueous trifluoroacetic acid for 30 seconds followed by
concentration in vacuo. This process was repeated, then
column chromatography afforded 2, as a white amorphous
solid in 82% yield. The spectroscopic data for synthetic 2
(1H NMR, 13C NMR, IR, m.p. and specific rotation) were all
in excellent agreement with those reported for the naturally
occurring muricatetrocin C.[16]
film deposited onto
a NaCl plate or mixed with KBr as a tablet.
Microanalyses were performed in the microanalytical laboratories at the
Department of Chemistry, Lensfield Road, Cambridge. Mass spectra and
accurate mass data were obtained on a Micromass Platform LC-MS, Kratos
MS890MS or Bruker BIOAPEX 4.7 T FTICR spectrometer, by electron
ionisation, chemical ionisation or fast atom/ion bombardment techniques
at the Department of Chemistry, Lensfield Road, Cambridge. 1H NMR
spectra were recorded in CDCl3, at ambient temperature on AM-200, AM-
400, DPX-400 or DRX-600 Bruker spectrometers, at 200, 400 or 600 MHz,
with residual protic solvent CHCl3 as the internal reference (dH ˆ 7.26);
Chemical shifts (d) are given in parts per million (ppm), and coupling
constants (J) are given in Hertz (Hz). The proton spectra are reported as
follows d (multiplicity, coupling constant J, number of protons, assignment).
13C NMR spectra were recorded in CDCl3 at ambient temperature on the
same spectrometers at 50, 100 or 150 MHz, with the central peak of CHCl3
as the internal reference (dC ˆ 77.0). DEPT135and two dimensional
(COSY, HMQC, HMBC) NMR spectroscopy were used where appropri-
ate, to aid in the assignment of signals in the 1H and 13C NMR spectra;
gradient NOE experiments were also performed in certain cases and their
salient results are detailed in the text. Where a compound has been
characterised as an inseparable mixture of diastereoisomers, the NMR data
for each individual isomer has been reported as far as was discernible from
the spectrum of the mixture. Where coincident coupling constants have
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1627

S. V. Ley et al.
FULL PAPER
been observed in the NMR spectrum, the apparent multiplicity of the
proton resonance concerned has been reported.
(10:1) afforded the corresponding olefin (5.26 g, 92%), an oil, as an
inseparable mixture of geometric isomers which was used without further
purification in the subsequent step [Z/E 8:1; assigned by integration of the
The anti-diol fragment
ˆ
peaks at dH (major) ˆ 4.94 (dd, J ˆ 8.8, 4.2 Hz, 1H; C CHCH) and dH
(2S,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethyl-2-hydroxymethyl-5,6-
ˆ
(minor) ˆ 4.49 (dd, J ˆ 8.8, 4.2 Hz, 1H; C CHCH)]. Rf ˆ 0.45(petroleum
dimethoxy-5,6-dimethyl-[1,4]-dioxane (10):
A solution of 6 (3.86 g,
ether/diethyl ether 10:1); 1H NMR (400 MHz; CDCl3): d (major) ˆ 5.52
16.3 mmol) in THF (5mL) was added dropwise through a syringe to a
stirred suspension of sodium hydride (60% dispersion in mineral oil,
720 mg, 18.0 mmol) in THF (10 mL) at 08C. After warming to rt over
30 min, pentane (15mL) was added and the solution stirred for a further
30 min. tert-Butyldimethylchlorosilane (2.45g, 16.3 mmol) in pentane
(5mL) was then added and the reaction mixture stirred for a further
40 min. The solution was then poured onto diethyl ether (250 mL), water
(200 mL) was added and the organic phase separated. The aqueous layer
was re-extracted with diethyl ether (100 mL) and the combined organic
phase was washed with saturated NaCl solution (150 mL), dried (MgSO4),
filtered and concentrated in vacuo. Purification by flash column chroma-
tography eluting with petroleum ether/diethyl ether (2:1‡1% triethyl-
amine) afforded mono-silylated diol 10 (4.13 g, 72%) as white cubes which
were further recrystallised frm pentane/diethyl ether 10:1. M.p. 798C; Rf ˆ
0.14 (petroleum ether/diethyl ether 2:1); [a]D29 ˆ À118 (c ˆ 1.00 in CH2Cl2);
1H NMR (400 MHz; CDCl3): d ˆ 4.35(t, J ˆ 9.9 Hz, 1H; CHHOSi), 4.26
4.21 (m, 1H; CHCH2OH), 3.73 (dt, J ˆ 9.9, 2.4 Hz, 1H; CHCH2OSi), 3.66
(dd, J ˆ 7.1, 2.9 Hz, 2H; CH2OH), 3.57 (dd, J ˆ 9.9, 2.4 Hz, 1H; CHHOSi),
3.24 (s, 3H; OCH3), 3.22 (s, 3H; OCH3), 2.96 (t, J ˆ 7.1 Hz, 1H; OH), 1.26
(s, 3H; CCH3), 1.25(s, 3H; CC H3), 0.88 (s, 9H; C(CH3)3), 0.08 (s, 6H;
Si(CH3)2); 13C NMR (100 MHz; CDCl3): d ˆ 99.2 (OCCH3), 98.1 (OCCH3),
72.8 (CHCH2OSi), 67.9 (CHCH2OH), 62.3 (CH2OSi), 61.7 (CH2OH), 49.3
(OCH3), 47.9 (OCH3), 25.8 (C(CH3)3), 18.2 (C(CH3)3), 18.1 (CCH3), 17.9
(CCH3), À5.5 (SiCH3), À5.6 (SiCH3); IR (KBr): nmax ˆ 3489 (br, O-H),
2924, 2854 cmÀ1 (C-H); elemental analysis calcd (%) for C16H34O6Si: C
54.8, H 9.78; found: C 54.8, H 9.56.
ˆ
(dt, J ˆ 11.1, 7.4 Hz, 1H; CH2CH C), 5.42 (dd, J ˆ 11.1, 8.8 Hz, 1H;
ˆ
ˆ
C CHCH), 4.94 (dd, J ˆ 8.8, 4.2 Hz, 1H; C CHCH), 4.05(dd, J ˆ 10.5,
6.7 Hz, 1H; CHHOSi), 3.86 (dd, J ˆ 10.5, 5.8 Hz, 1H; CHHOSi), 3.63 3.59
(m, 1H; CHCH2OSi), 3.31 (s, 3H; OCH3), 3.26 (s, 3H; OCH3), 2.14 2.03
ˆ
(m, 2H; CH2C C), 1.31 1.23 (m, 16H; (CH2)8), 1.29 (s, 3H; CCH3), 1.28 (s,
3H; CCH3), 0.88 0.85(m, 12H; C(C H3)3, CH2CH3), 0.03 (s, 3H; SiCH3),
0.02 (s, 3H; SiCH3); 1H NMR (400 MHz; CDCl3): d (minor, selected
ˆ
peaks) ˆ 5.71 (dt, J ˆ 15.3, 6.6 Hz, 1H; CH2CH C), 4.49 (dd, J ˆ 8.8,
ˆ
4.2 Hz, 1H; C CHCH), 4.08 4.01 (m, 1H; CHHOSi), 3.75(dd, J ˆ 10.4,
4.9 Hz, 1H; CHHOSi), 3.27 (s, 3H; OCH3), 3.22 (s, 3H; OCH3); 13C NMR
ˆ
ˆ
(100 MHz; CDCl3): d (major) ˆ 133.4 (C CCH), 125.7 (C CCH), 99.7
ˆ
(OCCH3), 97.9 (OCCH3), 75.3 (C CCH), 64.9 (CHCH2OSi), 62.1 (CH2O-
ˆ
Si), 49.3 (OCH3), 47.9 (OCH3), 30.3 (CH2C C), 29.6 (5 Â CH2), 29.3 (CH2),
28.1 (CH2), 25.8 (C(CH3)3), 22.7 (CH2), 18.5(C CH3), 18.4 (C(CH3)3), 18.1
(CCH3), 14.1 (CH2CH3), À5.4 (SiCH3), À5.4 (SiCH3); 13C NMR
ˆ
ˆ
(100 MHz; CDCl3): d (minor) ˆ 133.8 (C CCH), 125.8 (C CCH), 99.6
ˆ
(OCCH3), 97.9 (OCCH3), 75.6 (C CCH), 70.0 (CHCH2OSi), 62.2 (CH2O-
ˆ
Si), 49.2 (OCH3), 47.8 (OCH3), 31.9 (CH2C C), 29.6 (5xCH2), 29.3 (CH2),
28.1 (CH2), 25.8 (C(CH3)3), 22.7 (CH2), 18.4 (CCH3), 18.4 (C(CH3)3), 18.1
(CCH3), 14.1 (CH2CH3), À5.4 (SiCH3), À5.4 (SiCH3).
3) Olefin reduction: A slurry of Raney nickel (50% in water, 6.0 g), was
washed successively with 95% ethanol (3 Â 15mL) and absolute ethanol
(3 Â 15mL). Absolute ethanol (8 mL) was then added and the suspension
placed under a hydrogen atmosphere. The above olefin (1.20 g, 2.47 mmol)
in absolute ethanol (5mL) was added dropwise through a syringe and the
reaction stirred vigorously for 30 min. Filtration through a short plug of
silica eluting with diethyl ether, concentration in vacuo and purification by
flash column chromatography (petroleum ether/diethyl ether 15:1) afford-
ed silyl ether 13 (1.08 g, 90%) as an oil. Rf ˆ 0.39 (petroleum ether/diethyl
ether 10:1); [a]D29 ˆ À85( c ˆ 0.65in CH 2Cl2); 1H NMR (600 MHz; CDCl3):
d ˆ 4.14 (dd, J ˆ 10.2, 8.2 Hz, 1H; CHHOSi), 4.06 4.04 (m, 1H;
CHCH2CH2), 3.69 (dd, J ˆ 10.2, 3.8 Hz, 1H; CHHOSi), 3.58 (dt, J ˆ 8.2,
3.8 Hz, 1H; CHCH2OSi), 3.26 (s, 3H; OCH3), 3.24 (s, 3H; OCH3), 1.52
1.43 (m, 2H; CH2CH), 1.28 1.20 (m, 23H; (CH2)10, CCH3), 1.27 (s, 3H;
CCH3), 0.88 (s, 9H; C(CH3)3), 0.88 (t, J ˆ 7.0 Hz, 3H; CH2CH3), 0.04 (s,
6H; Si(CH3)2); 13C NMR (100 MHz; CDCl3): d ˆ 99.5(O CCH3), 98.0
(OCCH3), 75.3 (CHCH2OSi), 68.6 (CH2CH), 62.3 (CH2OSi), 49.3 (OCH3),
47.7 (OCH3), 31.9 (CH2CH), 30.8 (CH2), 29.6 (6 Â CH2), 29.3 (CH2), 26.2
(CH2), 25.8 (C(CH3)3), 22.7 (CH2), 18.3 (CCH3), 18.1 (C(CH3)3), 18.1
(2S,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethyl-5,6-dimethoxy-5,6-di-
methyl-2-dodecane-[1,4]-dioxane (13)
1) Oxidation to the aldehyde: A solution of dimethyl sulfoxide (1.84 mL,
26.0 mmol) in dichloromethane (5mL) was added to a vigorously stirred
solution of oxalyl chloride (2.10 mL, 23.6 mmol) in dichloromethane
(30 mL) at À788C. After 30 min, 10 (4.13 g, 11.8 mmol) in dichloro-
methane (15mL) was added dropwise through a syringe and the temper-
ature maintained at À788C for 1 h. Triethylamine (9.87 mL, 70.8 mmol)
was then added and the solution allowed to warm to rt over 1 h. The
reaction mixture was diluted with diethyl ether (300 mL), washed with
phosphate buffer solution (pH 7.2, 150 mL) and saturated NaCl solution
(100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude oil
solidified on standing to afford the aldehyde (4.1 g, >98%) which was used
in the subsequent step without further purification. M.p. 49 508C; Rf ˆ
0.41 (petroleum ether/diethyl ether 2:1); [a]D29 ˆ À122 (c ˆ 1.10 in CH2Cl2);
1H NMR (400 MHz; CDCl3): d ˆ 9.49 (s, 1H; CHO), 4.49 (d, J ˆ 4.0 Hz,
1H; CHCHO), 4.30 (t, J ˆ 9.9 Hz, 1H; CHHOSi), 4.10 (dt, J ˆ 9.9, 4.0 Hz,
1H; CHCH2OSi), 3.62 (dd, J ˆ 9.9, 4.0 Hz, 1H; CHHOSi), 3.24 (s, 3H;
OCH3), 3.18 (s, 3H; OCH3), 1.35(s, 3H; CC H3), 1.26 (s, 3H; CCH3), 0.84 (s,
9H; C(CH3)3), 0.01 (s, 3H; SiCH3), 0.01 (s, 3H; SiCH3); 13C NMR
(100 MHz; CDCl3): d ˆ 195.6 (CHO), 100.4 (OCCH3), 98.5(O CCH3), 74.3
(CHCH2OSi), 72.0 (CHCHO), 61.0 (CH2OSi), 48.6 (OCH3), 48.2 (OCH3),
25.7 (C(CH3)3), 18.4 (CCH3), 18.1 (C(CH3)3), 17.9 (CCH3), À5.6 (SiCH3),
À5.7 (SiCH3).
(CCH3), 14.1 (CH2CH3), À5.4 (SiCH3), À5.4 (SiCH3); IR (film): nmax
ˆ
2925, 2854 cmÀ1 (C-H); elemental analysis calcd (%) for C27H56O5Si: C
66.3, H 11.55; found: C 66.5, H 11.51.
(2S,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-hydroxymethyl-2-dodec-
ane-[1,4]-dioxane (14): TBAF (1.0m in THF, 4.40 mL, 4.40 mmol) was
added in one portion to a solution of 13 (1.08 g, 2.21 mmol) in THF
(4.4 mL) at rt and the reaction stirred for 2 h. Removal of the volatiles in
vacuo and filtration through a pad of silica, eluting with diethyl ether
afforded primary alcohol 14 (810 mg, 99%) as an oil. Rf ˆ 0.12 (petroleum
ether/diethyl ether 2:1); [a]D29 ˆ À104 (c ˆ 1.10 in CH2Cl2); 1H NMR
(400 MHz; CDCl3): d ˆ 4.05(dt, J ˆ 8.9, 4.3 Hz, 1H; CH2CH2CH), 3.80
(brs, 2H; CH2OH), 3.67 (brs, 1H; OH), 3.55 3.53 (m, 1H; CHCH2OH),
3.35(s, 3H; OC H3), 3.21 (s, 3H; OCH3), 1.78 1.70 (m, 1H; CH2CHH),
1.56 1.44 (m, 2H; CH2), 1.31 (s, 3H; CCH3), 1.29 1.20 (m, 19H; (CH2)9,
CHH), 1.26 (s, 3H; CCH3), 0.85(t, J ˆ 6.8 Hz, 3H; CH2CH3); 13C NMR
(100 MHz; CDCl3): d ˆ 99.3 (OCCH3), 97.8 (OCCH3), 74.2 (CHCH2OH),
68.2 (CH2CH2CH), 63.1 (CH2OH), 49.0 (OCH3), 47.7 (OCH3), 31.9
(CH2CH2CH), 30.2 (CH2), 29.6 (6 Â CH2), 29.3 (CH2), 26.1 (CH2), 22.6
(CH2), 18.2 (CCH3), 18.0 (CCH3), 14.0 (CH2CH3); IR (film): nmax ˆ 3480
(br, O-H), 2924, 2853 cmÀ1 (C-H); elemental analysis calcd (%) for
C21H42O5: C 67.3, H 11.30; found: C 67.2, H 11.07.
2) Wittig reaction: 1-Iodoundecane (6.20 g, 22.0 mmol), was added drop-
wise through a syringe to a solution of Ph3P (5.48 g, 20.9 mmol) in toluene
(6 mL). The reaction mixture was heated at reflux for 4 h and then cooled
to rt. Concentration in vacuo afforded a pale yellow gum that was used
without further purification (11.68 g, quant).
n-Butyllithium (1.6m in hexanes, 12.6 mL, 20.2 mmol) was added dropwise
through a syringe to the phosphonium salt (11.0 g, 20.2 mmol) in THF
(30 mL) at 08C. After stirring at 08C for 30 min, the deep red solution was
transferred dropwise via cannular to a solution of the aldehyde (prepared
as above, 4.10 g, 11.8 mmol) in THF (15mL) at À788C. The reaction
mixture was warmed to 08C over 30 min, and phosphate buffer solution
(pH 7.2, 10 mL) was then added. After dilution with diethyl ether (250 mL)
the organic phase was separated, washed with saturated NaCl solution
(100 mL), dried (MgSO4), filtered and concentrated in vacuo. Filtration
through a short pad of silica gel eluting with petroleum ether/diethyl ether
(2S,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-2-dodecane-3-(2',2'-gem-di-
bromo)ethenyl-[1,4]-dioxane (15)
1) Oxidation to the aldehyde: A solution of dimethyl sulfoxide (0.34 mL,
4.77 mmol) in dichloromethane (5mL) was added dropwise through a
syringe to a vigorously stirred solution of oxalyl chloride (0.38 mL,
1628
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1628 $ 20.00+.50/0
Chem.Eur.J. 2002, 8, No. 7

Muricatetrocin C
1621 1636
4.34 mmol) in dichloromethane (10 mL) at À788C. After stirring for
30 min, 14 (810 mg, 2.17 mmol) in dichloromethane (5mL) was added
dropwise through a syringe. After stirring at À788C for 1 h, triethylamine
(1.80 mL, 13.0 mmol) was added dropwise through a syringe and the
solution warmed to rt over 1 h. The reaction mixture was diluted with
diethyl ether (100 mL) and washed with phosphate buffer solution (pH 7.2,
50 mL) and saturated NaCl solution (50 mL), dried (MgSO4), filtered and
concentrated in vacuo. This afforded the aldehyde (810 mg, >98%), an oil,
which was used with no further purification. Rf ˆ 0.50 (petroleum ether/
diethyl ether 2:1); 1H NMR (400 MHz; CDCl3): d ˆ 9.96 (d, J ˆ 3.0 Hz, 1H;
CHO), 4.11 4.07 (m, 1H; CH2CH), 3.56 (t, J ˆ 3.0 Hz, 1H; CHCHO), 3.26
(s, 3H; OCH3), 3.17 (s, 3H; OCH3), 1.72 1.68 (m, 1H; CHH), 1.53 1.41
(m, 2H; CH2), 1.33 (s, 3H; CCH3), 1.31 (s, 3H; CCH3), 1.29 1.21 (m, 19H;
(CH2)9, CHH), 0.87 (t, J ˆ 6.8, 3H; CH2CH3); 13C NMR (100 MHz;
CDCl3): d ˆ 200.7 (CHO), 99.7 (OCCH3), 98.8 (OCCH3), 76.1 (CHCHO),
67.3 (CH2CH), 49.1 (OCH3), 47.9 (OCH3), 31.9 (CH2CH), 29.6 (7 Â CH2),
29.4 (CH2), 25.8 (CH2), 22.6 (CH2), 18.0 (CCH3), 17.4 (CCH3), 14.1
(CH2CH3).
column chromatography, eluting with petroleum ether/diethyl ether (6:1)
gave the secondary alcohol (20.1 g, 89%) as an oil. Rf ˆ 0.27 (petroleum
ether/diethyl ether 4:1); [a]D29 ˆ À7.8 (c ˆ 2.3 in CH2Cl2); 1H NMR
(400 MHz; CDCl3): d ˆ 7.73 7.71 (m, 4H; Ph), 7.47 7.41 (m, 6H; Ph),
ˆ
ˆ
5.89 5.78 (m, 1H; CH CH2), 5.06 4.97 (m, 2H; CH CH2), 3.82 3.75(m,
1H; CHOH), 3.72 (dd, J ˆ 10.1, 3.4 Hz, 1H; CHHOSi), 3.56 (dd, J ˆ 10.1,
7.3 Hz, 1H; CHHOSi), 2.57 (d, J ˆ 3.7 Hz, 1H; OH), 2.27 2.09 (m, 2H;
ˆ
CH2CH CH2), 1.64 1.47 (m, 2H; CH2CHOH), 1.13 (s, 9H; C(CH3)3);
13C NMR (100 MHz; CDCl3): d ˆ 138.3 (Ph), 135.6 (Ph), 133.2 (ipso C-Si),
ˆ
ˆ
129.9 (CH CH2), 127.8 (Ph), 114.8 (CH CH2), 71.4 (CHOH), 68.0
(CH2OSi), 32.0 (CH2), 29.8 (CH2), 26.9 (C(CH3)3), 19.3 (C(CH3)3); IR
(film): nmax ˆ 3430 (br, OH), 3072, 2931, 2858 (C-H), 1640 cmÀ1 (C C);
ˆ
elemental analysis calcd (%) for C22H30O2Si: C 74.5, H 8.53; found: C 74.6,
‡
‡
H 8.48; EI-MS: m/z (%): 337.2 (33) [M À OH] , 297.1 (52) [M À C4H9] ,
‡
199.1 (100) [M À 2 Â Ph] .
2) Ozonolysis: Sodium bicarbonate (1.50 g) was added to a stirred solution
of the above secondary alcohol (10.1 g, 28.7 mmol) in dichloromethane
(250 mL) at À788C. O3 (2 LsÀ1) was then bubbled through until the
reaction mixture became light blue (about 20 min). Ph3P (9.00 g,
34.4 mmol) was added to the reaction mixture, which was warmed to rt
and stirred for 14h; at which point the solvent was removed in vacuo.
Purification by flash column chromatography, eluting with petroleum
ether/diethyl ether (10:1 ! 2:1) afforded lactol 17 (9.47 g, 93%), an oil, as
an inseparable, 3:2 mixture of anomers [assigned by integration of the
peaks at dH (major) ˆ 5.59 (brt, J ˆ 3.2 Hz, 1H; H-2) and dH (minor) ˆ 5.48
(dd, J ˆ 6.6, 3.6 Hz, 1H; H-2)]. Rf ˆ 0.25(petroleum ether/diethyl ether
1:1); 1H NMR (400 MHz; CDCl3): d (major) ˆ 7.73 7.69 (m, 4H; Ph),
7.45 7.37 (m, 6H; Ph), 5.59 (brt, J ˆ 3.2 Hz, 1H; H-2), 4.41 4.35(m, 1H;
H-5), 3.66 (d, J ˆ 4.7 Hz, 2H; CH2OSi), 3.27 (d, J ˆ 2.3 Hz, 1H; OH), 2.20
1.70 (m, 4H; H2-3, H2-4), 1.08 (s, 9H; C(CH3)3); 1H NMR (400 MHz;
CDCl3): d (minor) ˆ 7.73 7.69 (m, 4H; Ph), 7.45 7.37 (m, 6H; Ph), 5.48
(dd, J ˆ 6.6, 3.6 Hz, 1H; H-2), 4.27 4.22 (m, 1H; H-5), 3.84 (dd, J ˆ 10.8,
3.6 Hz, 1H; CHHOSi), 3.63 (dd, J ˆ 10.8, 3.8 Hz, 1H; CHHOSi), 3.53 (d,
J ˆ 6.6 Hz, 1H; OH), 2.20 1.70 (m, 4H; H2-3, H2-4), 1.11 (s, 9H; C(CH3)3);
13C NMR (100 MHz; CDCl3): d (major) ˆ 135.6 (Ph), 133.6 (ipso C-Si),
129.6 (Ph), 127.7 (Ph), 99.0 (C-2), 79.0 (C-5), 66.2 (CH2OSi), 32.8 (C-3), 26.9
(C(CH3)3), 25.4 (C-4), 19.3 (C(CH3)3); 13C NMR (100 MHz; CDCl3): d
(minor) ˆ 135.7 (Ph), 132.9 (ipso C-Si), 129.8 (Ph), 127.8 (Ph), 98.6 (C-2),
80.3 (C-5), 66.5 (CH2OSi), 34.6 (C-3), 26.8 (C(CH3)3), 24.1 (C-4), 19.2
(C(CH3)3); IR (film): nmax (mixture) ˆ 3404 (br, OH), 3070, 2930, 2857 cmÀ1
(C-H); elemental analysis calcd (%) for C21H28O3Si: C 70.7, H 7.92; found:
2) Homologation to the gem-dibromo olefin: Ph3P (2.28 g, 8.68 mmol) was
added portionwise to a solution of CBr4 (1.44 g, 4.34 mmol) in dichloro-
methane (10 mL) at 08C. After 30 min, the above aldehyde (810 mg,
2.17 mmol), as a solution in dichloromethane (6 mL), was added dropwise
through a syringe. After stirring at 08C for a further 30 min the reaction
mixture was poured onto petroleum ether (100 mL) and the yellow
precipitate was removed by filtration under reduced pressure. Concen-
tration in vacuo and purification by flash column chromatography eluting
with petroleum ether/diethyl ether (15:1) afforded gem-dibromo olefin 15
(0.98 g, 88%) as an oil. Rf ˆ 0.36 (petroleum ether/diethyl ether 15:1);
1
ˆ
H NMR (400 MHz; CDCl3): d ˆ 7.05(d, J ˆ 9.4 Hz, 1H; CH CBr2), 4.16
ˆ
(dd, J ˆ 9.4, 3.6 Hz, 1H; CHCH CBr2), 4.07 4.03 (m, 1H; CHCH2), 3.24
(s, 3H; OCH3), 3.19 (s, 3H; OCH3), 1.48 1.37 (m, 2H; CH2), 1.29 (s, 3H;
CCH3), 1.29 1.21 (m, 23H; (CH2)10, CCH3), 0.88 (t, J ˆ 6.7 Hz, 3H;
CH2CH3); 13C NMR (100 MHz; CDCl3): d ˆ 136.4 (CHCBr2), 99.6
ˆ
ˆ
(OCCH3), 98.5(O CCH3), 93.1 (CH CBr2), 73.4 (CHCH CBr2), 67.9
(CHCH2), 48.4 (OCH3), 47.8 (OCH3), 31.9 (CH2CH), 30.2 (CH2), 29.6 (6 Â
CH2), 29.3 (CH2), 25.3 (CH2), 22.7 (CH2), 18.0 (CCH3), 17.9 (CCH3), 14.1
(CH2CH3); IR (film): nmax ˆ 2925, 2853 (C-H), 1612 cmÀ1 (C C); ES-MS:
ˆ
m/z (%): calcd for C22H40O479Br2: 526.1293; found: 526.1326.
The central fragment
(2S)-1-(tert-Butyldiphenylsilyloxy)prop-2-enoxide (16):[37] Triethylamine
(16.8 mL, 121 mmol), TBDPSCl (21.5mL, 82.9 mmol) and dimethylami-
nopyridine (2.80 g, 22.6 mmol) were added to a stirred solution of (R)-(‡)-
glycidol (5.60 g, 75.3 mmol) in dichloromethane (150 mL), and the reaction
mixture was stirred for 24 h. HCl solution (1.5n, 100 mL) was added and
the organic phase separated. The aqueous layer was re-extracted with
dichloromethane (2 Â 100 mL), and the combined organic phase was
washed with saturated sodium bicarbonate solution (150 mL), saturated
NaCl solution (100 mL), dried (MgSO4), filtered and concentrated in
vacuo. Purification by flash column chromatography eluting with petro-
leum ether/diethyl ether (20:1 ! 10:1) gave the TBDPS ether 16 (20.0 g,
85%) as an oil. Rf ˆ 0.34 (petroleum ether/diethyl ether 10:1); [a]D29 ˆ À2.1
(c ˆ 1.8 in CH2Cl2); 1H NMR (400 MHz; CDCl3): d ˆ 7.75 7.73 (m, 4H;
Ph), 7.49 7.41 (m, 6H; Ph), 3.90 (dd, J ˆ 11.8, 3.1 Hz, 1H; CHHOSi), 3.76
(dd, J ˆ 11.8, 4.7 Hz, 1H; CHHOSi), 3.18 3.14 (m, 1H; CHCH2OSi), 2.77
(t, J ˆ 4.3 Hz, 1H; CHHCHCH2OSi), 2.66 2.63 (m, 1H; CHHCHCH2O-
Si), 1.12 (s, 9H; C(CH3)3); 13C NMR (100 MHz; CDCl3): d ˆ 135.7 (Ph),
135.6 (Ph), 133.3 (ipso C-Si), 129.8 (Ph), 127.8 (Ph), 127.7 (Ph), 64.3
(CH2CHCH2OSi), 52.3 (CHCH2OSi), 44.5( CH2OSi), 26.8 (C(CH3)3), 19.3
(C(CH3)3); elemental analysis calcd (%) for C19H24O2Si: C 73.0, H 7.74;
found: C 72.9, H 7.67.
‡
C 70.4, H 7.81; EI-MS: m/z (%): 339.3 (77) [M À OH] , 117.1 (100) [M À
‡
C16H19Si] .
(2R/S,5S)-5-(tert-Butyldiphenylsilyloxymethyl)-2-(prop-2-yne-1-oxy)-tet-
rahydrofuran (18): Amberlyst A-15(100 mg) was added to a stirred
solution of 17 (7.20 g, 20.2 mmol) and prop-2-yn-1-ol (30 mL, 0.50 mol) in
benzene (100 mL) in a round bottomed flask fitted with a distillation head
and condenser. The reaction mixture was heated to 808C and 20 mL of
benzene/water azeotrope removed through distillation. The reaction was
then cooled to rt, filtered and the volatiles removed in vacuo. Filtration
through a short pad of silica gel, eluting with petroleum ether/diethyl ether
(6:1) yielded propargylic ether 18 (7.20 g, 91%) an oil, as an inseparable,
3:2 mixture of anomers [assigned by integration of the peaks at dH
(major) ˆ 5.34 (d, J ˆ 4.2 Hz, 1H; H-2) and dH (minor) ˆ 5.30 (d, J ˆ
3.7 Hz, 1H; H-2)]. Rf ˆ 0.60 (petroleum ether/diethyl ether 1:1); 1H NMR
(400 MHz; CDCl3): d (major) ˆ 7.72 7.70 (m, 4H; Ph), 7.46 7.38 (m, 6H;
Ph), 5.34 (d, J ˆ 4.2 Hz, 1H; H-2), 4.27 4.22 (m, 3H; CH2OCH, H-5),
ꢀ
3.70 3.67 (m, 2H; CH2OSi), 2.41 (t, J ˆ 2.3 Hz, 1H; C CH), 2.13 1.75(m,
4H; H2-3, H2-4), 1.09 (s, 9H; C(CH3)3); 1H NMR (400 MHz; CDCl3): d
(minor) ˆ 7.72 7.70 (m, 4H; Ph), 7.46 7.38 (m, 6H; Ph), 5.30 (d, J ˆ
3.7 Hz, 1H; H-2), 4.27 4.22 (m, 1H; H-5), 4.16 (d, J ˆ 2.3 Hz, 2H;
(2R/S,5S)-5-(tert-Butyldiphenylsilyloxymethyl)-tetrahydrofuran-2-ol
(17)[38]
ꢀ
CH2OCH), 3.70 3.67 (m, 2H; CH2OSi), 2.37 (t, J ˆ 2.3 Hz, 1H; C CH),
2.13 1.75(m, 4H; H2-3, H2-4), 1.10 (s, 9H; C(CH3)3); 13C NMR (100 MHz;
CDCl3): d (major) ˆ 135.7 (Ph), 134.0 (ipso C-Si), 129.6 (Ph), 127.7 (Ph),
1) Allylation of 16: Dilithium tetrachlorocuprate (0.10m in THF, 15mL,
1.5mmol) followed by allyl magnesium bromide (1.0 m in THF, 76.8 mL,
76.8 mmol) was added at À308C to a stirred solution of 16 (20.0 g,
64.0 mmol) in THF (100 mL). After 15min at À308C, saturated ammo-
nium chloride solution (100 mL) was added and the suspension warmed to
rt. Water (100 mL) was then added and the reaction mixture extracted with
diethyl ether (2 Â 100 mL). The combined organic phase was dried
(MgSO4), filtered and the solvent removed in vacuo. Purification by flash
ꢀ
ꢀ
102.8 (C-2), 80.4 (C CH), 79.0 (C-5), 73.7 (C CH), 66.0 (CH2OCH), 53.8
(CH2OSi), 32.0 (C-3), 26.8 (C(CH3)3), 25.3 (C-4), 19.3 (C(CH3)3); 13C NMR
(100 MHz; CDCl3): d (minor) ˆ 135.6 (Ph), 134.0 (ipso C-Si), 129.6 (Ph),
ꢀ
ꢀ
127.6 (Ph), 102.3 (C-2), 81.3 (C-5), 80.3 (C CH), 73.7 (C CH), 67.5
(CH2OCH), 53.5 (CH2OSi), 32.8 (C-3), 26.8 (C(CH3)3), 25.9 (C-4), 19.3
ꢀ
(C(CH3)3); IR (film): nmax ˆ 3293 (C C-H), 3070, 2930, 2857 (C-H), 2118
À1
ꢀ
(C C), 1589 cm (Ph); elemental analysis calcd (%) for C24H30O3Si: C
Chem.Eur.J. 2002, 8, No. 7
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1629 $ 20.00+.50/0
1629

S. V. Ley et al.
FULL PAPER
ꢀ
73.1, H 7.66; found: C 73.2, H 7.75; EI-MS: m/z (%): 281.1 (100) [M À
80.4 (CHC C), 79.3 (C-2), 71.6 (PhCH2), 68.7 (C-5), 66.0 (CH2OSi), 57.5
‡
ꢀ
(C4H9‡C3H3O)] , 225.1 (58), 199.1 (55).
(C CCH2), 33.5( C-4), 27.4 (C-3), 26.8 (C(CH3)3), 19.3 (C(CH3)3); IR
(film): nmax (major) ˆ 3070, 2929, 2856 (C-H), 1589 cmÀ1 (Ph); elemental
(2R/S,5S)-2-(tert-Butyldiphenylsilyloxymethyl)-5-(1-hydroxyprop-2-ynyl)
tetrahydrofuran 19 (2S) and 20 (2R): n-Butyllithium (1.6m in hexanes,
2.50 mL, 4.00 mmol) was added dropwise through a syringe to a solution of
18 (1.45g, 3.7 mmol) in THF (2.5mL) at À788C. The solution was stirred at
À788C for 30 min then tributyltinchloride (1.00 mL, 3.90 mmol) was added
dropwise through a syringe and the reaction warmed to rt. Following
dilution with diethyl ether (50 mL), washing with water (30 mL) and
saturated NaCl solution (30 mL), drying (MgSO4) and evaporation of
volatiles in vacuo gave the stannylated material 7 as a viscous oil, which was
used without purification in the next step.
analysis calcd (%) for C31H36O3Si: C 76.8, H 7.49; found (major): C 76.5, H
‡
‡
7.48; LREI-MS (major): m/z: 507 (52) [M‡Na] , 427 (30) [M À C4H9] , 281
(100).
(2S,5S)-2-(Hydroxymethyl)-5-(1-benzyloxyprop-2-ynyl)tetrahydrofuran
(23): TBAF (1.0m in THF, 5.20 mL, 5.20 mmol) was added to a solution of
21 (500 mg, 1.03 mmol) in THF (5 mL) at rt and the reaction stirred for 3 h.
Subsequent removal of all volatiles in vacuo followed by filtration through
a small pad of silica eluting with diethyl ether afforded primary alcohol 23
(242 mg, 95%) as an oil. Rf ˆ 0.33 (diethyl ether); [a]D29 ˆ À13.4 (c ˆ 1.00 in
CH2Cl2); 1H NMR (400 MHz; CDCl3): d ˆ 7.35 7.26 (m, 5H; Ph), 4.76
(brt, J ˆ 6.0 Hz, 1H; H-5), 4.58 (s, 2H; PhCH2), 4.27 4.23 (m, 1H; H-2),
Boron trifluoride etherate (1.40 mL, 11.0 mmol) was added dropwise
through a syringe to a solution of 7 (2.64 g) in dichloromethane (1 mL) with
vigorous stirring at À108C. The reaction was stirred for 10 min at À108C
and then quenched by the addition of NaOH solution (10%, 2 mL).
Following dilution with dichloromethane (30 mL), the organic phase was
separated, washed with saturated NaCl solution (20 mL), dried (MgSO4),
filtered and concentrated in vacuo. Purification by flash column chroma-
tography eluting with petroleum ether/diethyl ether (20:1 then 2:1 ! 1:2).
The oil resulting from evaporation of the fractions containing a mixture of
cis and trans isomers was further purified by flash column chromatography
eluting with petroleum ether/diethyl ether (20:1 then 1:1) to give 19 and 20
(1.16 g, 85%) as an oil, as an inseparable mixture of trans and cis isomers
[19/20, 5.5:1; assigned by integration of the peaks at dH (major) ˆ 4.74 (t,
J ˆ 6.2 Hz, 1H; H-5) and dH (minor) ˆ 4.64 4.61 (m, 1H; H-5)]. Rf ˆ 0.18
(petroleum ether/diethyl ether 1:1); 1H NMR (400 MHz; CDCl3): d
(major) ˆ 7.72 7.67 (m, 4H; Ph), 7.45 7.37 (m, 6H; Ph), 4.74 (t, J ˆ
6.2 Hz, 1H; H-5), 4.31 (dd, J ˆ 5.9, 1.3 Hz, 2H; CH2OSi), 4.28 4.23 (m,
ꢀ
4.21 (d, J ˆ 1.2 Hz, 2H; C CCH2), 3.70 (dd, J ˆ 11.7, 3.2 Hz, 1H; CHHOSi),
3.51 (dd, J ˆ 11.7, 5.5 Hz, 1H; CHHOSi), 2.27 2.18 (m, 1H; H-3), 2.16
1.99 (m, H-3, 3H; H-4, OH), 1.79 1.69 (m, 1H; H-4); 13C NMR (100 MHz;
CDCl3): d ˆ 137.42 (ipso C-C), 128.4 (Ph), 128.0 (Ph), 127.8 (Ph), 86.1
ꢀ
ꢀ
(CHC C), 80.8 (CHC C), 79.4 (C-2), 71.6 (CH2Ph), 68.6 (C-5), 64.5
ꢀ
(CH2OH), 57.4 (C CCH2), 33.6 (C-4), 26.8 (C-3); elemental analysis calcd
(%) for C15H18O3: C 73.1, H 7.37; found: C 72.6, H 7.39; FAB-MS: m/z:
calcd for C15H18O3Na: 269.1154; found: 269.1161; EI-MS: m/z: 269.0 (100)
[M‡Na] , 154 (55) [M À C7H7] .
‡
‡
(2S,5R)-2-(Carboxymethyl)-5-(1-benzyloxypropyl)tetrahydrofuran (4)
1) Saturation of the alkyne 23: A slurry of Raney nickel (1.2 g, 50% in
H2O), was washed successively with 95% ethanol (3 Â 10 mL) and absolute
ethanol (3 Â 10 mL). Absolute ethanol (5mL) was then added and the
suspension was placed under
a hydrogen atmosphere. 23 (328 mg,
1.33 mmol) was added in one portion through a syringe in absolute ethanol
(5mL) and the solution stirred vigorously for 30 min. Filtration through a
pad of silica eluting with diethyl ether, concentration in vacuo and
purification by flash column chromatography (petroleum ether/diethyl
ether 1:2) gave the primary alcohol (230 mg, 70%) as an oil. Rf ˆ 0.29
(diethyl ether); [a]2D9 ˆ À8.6 (c ˆ 1.00 in CH2Cl2); 1H NMR (400 MHz;
CDCl3): d ˆ 7.36 7.32 (m, 4H; Ph), 7.31 7.26 (m, 1H; Ph), 4.51 (s, 2H;
CH2Ph), 4.13 4.07 (m, 1H; H-2), 4.01 3.93 (m, 1H; H-5), 3.64 3.60 (m,
1H; CHHOH), 3.53 3.46 (m, 3H; CHHOH, CH2OBn), 2.07 1.93 (m,
3H; H-3, H-4, OH), 1.74 1.51 (m, 6H; CH2CH2CH2OBn, H-3, H-4);
13C NMR (100 MHz; CDCl3): d ˆ 138.6 (ipso C-C), 128.3 (Ph), 127.6 (Ph),
127.5(Ph), 79.2 ( C-2), 78.8 (C-5), 72.9 (CH2Ph), 70.3 (CH2OBn), 65.1
ꢀ
1H; H-2), 3.71 3.63 (m, 2H; C CCH2), 2.27 1.88 (m, 4H; H2-3, H2-4),
1.06 (s, 9H; C(CH3)3); 1H NMR (400 MHz; CDCl3): d (minor) ˆ 7.72 7.67
(m, 4H; Ph), 7.45 7.37 (m, 6H; Ph), 4.64 4.61 (m, 1H; H-5), 4.21 (dd, J ˆ
6.1, 1.3 Hz, 2H; CH2OSi), 4.10 (m, 1H; H-2), 3.79 (dd, J ˆ 10.5, 4.7 Hz, 1H;
ꢀ
ꢀ
C CCHH), 3.71 3.63 (m, 1H; C CCHH), 2.27 1.88 (m, 4H; H2-3, H2-4),
1.07 (s, 9H; C(CH3)3); 13C NMR (100 MHz; CDCl3): d (major) ˆ 135.7
ꢀ
(Ph), 133.7 (ipso C-Si), 129.6 (Ph), 127.7 (Ph), 85.8 (CHC C), 82.7
ꢀ
ꢀ
(CHC C), 79.4 (C-2), 68.6 (C-5), 66.0 (CH2OSi), 51.1 (C CCH2), 33.4 (C-
4), 27.4 (C-3), 26.8 (C(CH3)3), 19.2 (C(CH3)3); 13C NMR (100 MHz;
CDCl3): d (minor) ˆ 135.6 (Ph), 133.8 (ipso C-Si), 129.6 (Ph), 127.7 (Ph),
ꢀ
ꢀ
85.8 (CHC C), 82.7 (CHC C), 80.3 (C-2), 68.6 (C-5), 66.5 (CH2OSi), 51.2
(CH2OH), 32.3 (C-3), 32.0 (C-4), 27.5( CH2), 26.5( CH2); IR (film): nmax
ˆ
ꢀ
(C CCH2), 33.1 (C-4), 28.1 (C-3), 26.8 (C(CH3)3), 19.2 (C(CH3)3); IR
3427 (br, O-H), 3070, 2933, 2867 (C-H), 1589 cmÀ1 (Ph); elemental analysis
calcd (%) for C15H22O3: C 72.0, H 8.86; found: C 71.6, H 8.98; EI-MS: m/z:
calcd for C15H22O3: 250.1569; found: 250.1556.
(film): nmax ˆ 3406 (br, O-H), 3070, 2930, 2857 (C-H), 1589 cmÀ1 (Ph);
elemental analysis calcd (%) for C24H30O3Si: C 73.1, H 7.66; found: C 73.5,
H 7.63; FAB-MS: m/z (%): calcd for C24H30O3SiNa: 417.1862; found:
‡
417.1848; EI-MS: m/z (%): 338 (12) [M À C4H9] , 199 (66), 135(100).
2) Swern oxidation: A solution of DMSO (0.22 mL, 3.10 mmol) in
dichloromethane (6 mL) was added dropwise through a syringe to a
vigorously stirred solution of oxalyl chloride (0.24 mL, 2.80 mmol) in
dichloromethane at À788C. After 30 min, a solution of the above primary
alcohol (350 mg, 1.4 mmol) in dichloromethane was added dropwise
through a syringe and the reaction mixture stirred at À788C for a further
30 min. Triethylamine (1.20 mL, 8.40 mmol) was added, then the reaction
mixture was stirred at À788C for 20 min before warming to rt over 30 min.
The reaction mixture was poured onto phosphate buffer solution (10 mL,
pH 7.2) and diethyl ether (25mL). The organic layer was separated, dried
(Na2SO4) and concentrated in vacuo to afford aldehyde 4 as a yellow oil
which was used without further purification in the coupling step with
fragment 3. Rf ˆ 0.11 (petroleum ether/diethyl ether 1:1); 1H NMR
(400 MHz; CDCl3): d ˆ 9.65(d, J ˆ 1.6 Hz, 1H; CHO), 7.37 7.31 (m, 4H;
Ph), 7.30 7.27 (m, 1H; Ph), 4.51 (s, 2H; PhCH2), 4.31 (td, J ˆ 8.3, 1.6 Hz,
1H; H-2), 4.07 4.01 (m, 1H; H-5), 3.56 3.47 (m, 2H; CH2OBn), 2.22
2.15(m, 1H; H-3), 2.06 1.91 (m, 2H; H-3, H-4), 1.79 1.54 (m, 5H; H-4,
CH2CH2); 13C NMR (100 MHz; CDCl3): d ˆ 203.1 (CHO), 138.6 (ipso C-
C), 128.3 (Ph), 127.6 (Ph), 127.5(Ph), 82.4 ( C-2), 80.9 (C-5), 72.9 (CH2Ph),
70.1 (CH2OBn), 32.0 (C-3), 31.1 (C-4), 27.2 (CH2), 26.4 (CH2).
(2S,5S)-2-(tert-Butyldiphenylsilyloxymethyl)-5-(1-benzyloxyprop-2-ynyl)-
tetrahydrofuran (21): KHMDS (0.5m in toluene, 6.50 mL, 3.20 mmol) was
added dropwise through a syringe to a solution of 19 and 20 (1.16 g,
2.90 mmol) in THF (6.5mL) at À788C. The solution was stirred at À788C
for 30 min and then benzyl bromide (1.0 mL, 8.8 mmol) was added
dropwise through a syringe. The reaction was then allowed to warm to rt
and stirred for a further 2 h. The reaction mixture was diluted with diethyl
ether (100 mL), then quenched by the addition of water (5mL). The
organic phase was separated, washed with aqueous HCl solution (3n, 2 Â
30 mL) and saturated NaCl solution (30 mL), dried (MgSO4) and the
volatiles removed in vacuo. The resulting mixture of 5.5:1 diastereoisomers
[assigned by integration of the peaks at dH (major) ˆ 4.81 4.79 (m, 1H; H-
1
5) and dH (minor) ˆ 4.70 4.68 (m, 1H; H-5) in the crude H NMR] could
be separated by MPLC chromatography eluting with petroleum ether/
diethyl ether (9:1) to afford 21 (1.11 g, 78%) and the minor cis-isomer 22
(200 mg, 14%). Rf (major) ˆ 0.25(petroleum ether/diethyl ether 4:1); Rf
(minor) ˆ 0.20 (petroleum ether/diethyl ether 4:1); [a]D29 (major) ˆ À17.3
(c ˆ 0.95in CH 2Cl2); 1H NMR (600 MHz; CDCl3): d (major) ˆ 7.73 7.70
(m, 4H; Ph), 7.46 7.36 (m, 10H; Ph), 7.33 7.31 (m, 1H; Ph), 4.81 4.79 (m,
1H; H-5), 4.64 (d, J ˆ 11.9 Hz, 1H; PhCHH), 4.62 (d, J ˆ 11.9 Hz, 1H;
The butenolide terminus
1-Benzyloxy-butan-4-ol (27): A solution of 1,4-butanediol (3.90 mL,
44.0 mmol) in DMF (8 mL) was added to a suspension of sodium hydride
(880 mg, 22.0 mmol) in DMF (25mL) at 0 8C. After 1 h at 08C,
benzylbromide (2.60 mL, 22.0 mmol) was added dropwise via syringe.
The solution was stirred for a further 15min then diluted with diethyl ether
(250 mL) and poured onto a saturated ammonium chloride solution
ꢀ
PhCHH), 4.32 4.28 (m, 1H; H-2), 4.25(d, J ˆ 1.5Hz, 2H; C CCH2), 3.73
(dd, J ˆ 10.8, 4.7 Hz, 1H; CHHOSi), 3.70 (dd, J ˆ 10.8, 4.2 Hz, 1H;
CHHOSi), 2.29 2.24 (m, 1H; H-4), 2.19 2.14 (m, 1H; H-3), 2.06 2.01
(m, 1H; H-4), 1.99 1.93 (m, 1H; H-3), 1.10 (s, 9H; C(CH3)3); 13C NMR
(100 MHz; CDCl3): d (major) ˆ 137.5( ipso C-C), 135.6 (Ph), 133.8 (ipso C-
ꢀ
Si), 129.7 (Ph), 128.4 (Ph), 128.1 (Ph), 127.8 (Ph), 127.7 (Ph), 86.6 (CHC C),
1630
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1630 $ 20.00+.50/0
Chem.Eur.J. 2002, 8, No. 7

Muricatetrocin C
1621 1636
(100 mL). The organic phase was separated and washed with water (2 Â
100 mL), saturated NaCl solution (80 mL), dried (MgSO4), filtered and
concentrated in vacuo. Purified by flash column chromatography eluting
with petroleum ether/diethyl ether (3:1 ! 1:1) afforded alcohol 27 (6.50 g,
82%) as an oil. Rf ˆ 0.13 (petroleum ether/diethyl ether 1:1); 1H NMR
(200 MHz; CDCl3): d ˆ 7.35 7.31 (m, 5H; Ph), 4.52 (s, 2H; PhC H2), 3.52 (t,
J ˆ 4.2 Hz, 2H; PhCH2OCH2), 3.64 3.61 (m, 2H; CH2OH), 2.46 (brs, 1H;
OH), 1.72 1.65(m, 4H; C H2CH2CH2OH); 13C NMR (50 MHz; CDCl3):
d ˆ 138.3 (ipso C-C), 128.3 (Ph), 127.6 (Ph), 127.6 (Ph), 72.9 (PhCH2), 70.3
solution of 29 in chloroform (100 mL) at rt. The red solution was stirred for
4 h under irradiation (250 W sunlamp bulb), then concentrated in vacuo.
Purification by flash column chromatography eluting with petroleum ether/
diethyl ether (6:1 ! 2:1) afforded diene 8 (1.15g, 56%), an oil, as an
inseparable mixture of geometric isomers at the external olefin [E/Z,
>95:5; assigned by integration of the peaks at dH (major) ˆ 5.02 (brq, J ˆ
6.8 Hz, 1H; CHCH3) and dH (minor) ˆ 5.06 (m, 1H; CHCH3)]. Rf ˆ 0.57
(petroleum ether/diethyl ether 1:1); [a]D29 ˆ ‡27.4 (c ˆ 0.31 in CH2Cl2);
1H NMR (200 MHz; CDCl3): d ˆ 7.35 7.31 (m, 5H; Ph), 7.05(d, J ˆ 1.7 Hz,
ˆ
(CH2OH), 62.2 (CH2OCH2Ph), 29.7 (CH2), 26.4 (CH2); IR (film): nmax
ˆ
1H; CHCHO), 6.80 (dt, J ˆ 15.9, 7.0 Hz, 1H; CH2CH CH), 6.20 (brd, J ˆ
3381 cmÀ1 (br, O-H); elemental analysis calcd (%) for C11H16O2: C 73.3, H
8.90; found: C 72.9, H 8.99.
15.9 Hz, 1H; CH2CH CH), 5.02 (brq, J ˆ 6.8 Hz, 1H; CHCH3), 4.53 (s,
ˆ
2H; PhCH2), 3.57 (t, J ˆ 6.7 Hz, 2H; PhCH2OCH2), 2.50 (brq, J ˆ 6.8 Hz,
2H; CH2C C), 1.42 (d, J ˆ 6.8 Hz, 3H; CHCH3); 13C NMR (50 MHz;
ˆ
(E)-tert-Butyl-6-benzyloxy-hex-2-enoate (28):
A solution of dimethyl
CDCl3): d ˆ 171.8 (CO2), 147.5( CHCHO), 138.3 (ipso C-C), 134.8
sulfoxide (25.6 mL, 361 mmol) in dichloromethane (140 mL) was added
dropwise through a syringe over a period of 30 min to a vigorously stirred
solution of oxalyl chloride (14.9 mL, 171 mmol) in dichloromethane
(470 mL) at À788C. The resulting mixture was stirrred for a further
30 min at À788C, then a solution of 27 (21.2 g, 118 mmol) in dichloro-
methane (70 mL) was added slowly through a syringe. The reaction mixture
stirred at À788C for 1 h then triethylamine (67.8 mL, 487 mmol) was added
slowly through a syringe. After a further 20 min at À788C, the reaction
mixture warmed to rt and stirred for 1 h. The mixture was then poured onto
saturated NaCl solution (300 mL), the aqueous layer separated, and
extracted with diethyl ether (4 Â 100 mL). The organic layers were
combined, dried (MgSO4), filtered and concentrated in vacuo to give the
crude aldehyde.
ˆ
ˆ
(CH2CH CH), 129.2 (CH2CH CH), 128.4 (Ph), 127.7 (Ph), 127.6 (Ph),
120.2 (CCO2), 76.9 (CHCH3), 73.0 (PhCH2), 69.1 (PhCH2OCH2), 33.8
ˆ
ˆ
ˆ
(CH2C C), 19.1 (CHCH3); IR (film): nmax ˆ 1753 (C O), 1662 (C C),
1496 cmÀ1 (Ph); FAB-MS: m/z: calcd for C16H18O3: 259.1334; found:
259.1334.
(3S,6R,9R)-6-(2'-Benzyloxy)-ethyl-3-methyl-4-phenyl-1,3,4,5,6,9-hexahy-
dro-4-aza-5-oxo-isobenzofuran-1-one (32): Nitrosobenzene (2.92 g,
27.3 mmol) was added in one portion to a stirred solution of 8 (3.52 g,
13.6 mmol) in methanol/dichloromethane (1:1, 30 mL) at 08C. The solution
turned aqua blue and was stirred at 08C for 21 h. Concentration in vacuo
and purification by flash column chromatography eluting with petroleum
ether/diethyl ether (4:1 ! 2:1) afforded a yellow oil (4.57 g, 91%), as a
mixture of regioisomers (7:3, 30/31) and diastereoisomers [>95:5 d.r. for
the major regioisomer 30, tentatively assigned by integration of the peaks
(tert-Butoxycarbonylmethylene)triphenylphosphorane (44.4 g, 118 mmol)
was added in several portions to a stirred solution of the crude aldehyde in
dichloromethane (300 mL) at 08C. The reaction mixture was stirred for
14 h at rt, concentrated in vacuo and passed through a short pad of silica
eluting with petroleum ether/diethyl ether (4:1) to afford enoate 28 (31.3 g,
96%) an oil, as an inseparable mixture of geometric isomers [E/Z, >15:1;
assigned by integration of the peaks at dH (major) ˆ 6.87 (dt, J ˆ 15.6,
ˆ
at dH (major) ˆ 6.96 (t, J ˆ 2.7 Hz, 1H; CH C) and dH (minor) ˆ 7.07 (brs,
ˆ
1H; CH C)]. Further purification of the mixture of regio- and diaster-
eoisomers by HPLC (hexane/THF 98:2; flow rate 40 mLminÀ1) afforded
HDA adduct 32 (2.75g, 55%, >98:2 d.r.). Retention time 30 min; Rf ˆ 0.30
(petroleum ether/diethyl ether 1:1); [a]D29 ˆ À69 (c ˆ 0.46 in CH2Cl2);
1H NMR (600 MHz; CDCl3): d ˆ 7.40 (t, J ˆ 7.8 Hz, 2H; NPhCH-meta),
ˆ
ˆ
6.9 Hz, 1H; CH2CH CH) and dH ˆ 6.15(minor) (m, 1H; CH 2CH CH)]
which was used in the subsequent step without further purification. Rf ˆ
0.52 (petroleum ether/diethyl ether 1:1); 1H NMR (200 MHz; CDCl3): d ˆ
ˆ
7.30 (m, 8H; Ph), 6.96 (t, J ˆ 2.7 Hz, 1H; CH C), 4.82 4.78 (m, 1H;
CHN), 4.48 (d, J ˆ 12.1 Hz, 1H; PhCHH), 4.46 (d, J ˆ 12.1 Hz, 1H;
PhCHH), 4.32 4.28 (m, 1H; CHCH3), 3.97 (dt, J ˆ 7.7, 2.7 Hz, 1H;
CHON), 3.60 3.56 (m, 1H; OCHHCH2), 3.56 3.50 (m, 1H; OCHHCH2),
2.28 2.22 (m, 1H; OCH2CHH), 2.05 1.96 (m, 1H; OCH 2CHH), 0.98 (d,
J ˆ 6.3 Hz, 3H; CHCH3); 13C NMR (100 MHz; CDCl3): d ˆ 167.3 (CO2),
ˆ
7.35 7.31 (m, 5H; Ph), 6.87 (dt, J ˆ 15.6, 7.0 Hz, 1H; CH2CH CH), 5.75
ˆ
(dt, J ˆ 15.6, 1.4 Hz, 1H; CH2CH CH), 4.50 (s, 2H; PhCH2), 3.49 (t, J ˆ
ˆ
6.3 Hz, 2H; PhCH2OCH2), 2.28 (qd, J ˆ 7.0, 1.4 Hz, 2H; CH2CH CH), 1.76
(m, 2H; CH2CH2CH), 1.49 (s, 9H; C(CH3)3); 13C NMR (50 MHz; CDCl3):
ˆ
148.4 (ipso C-N), 138.2 (ipso C-C), 137.6 (CH CCO2), 129.2 (NPhCH-
ˆ
d ˆ 165.9 (CO2), 147.2 (CH2CH CH), 138.4 (ipso C-C), 128.3 (Ph), 127.5
ˆ
meta), 129.1 (Ph), 128.3 (Ph), 127.9 (2 Â Ph), 127.5(Ph), 123.7 (CH CCO2),
ˆ
(Ph), 127.5(Ph), 123.3 (CH CH CH), 79.9 (C(CH3)3), 72.9 (PhCH2), 65.8
2
78.0 (CHON), 74.3 (PhCH2), 73.0 (CHOCH3), 69.8 (CHN), 66.3
(OCH2CH2), 33.5(OCH 2CH2), 19.3 (CHCH3); IR (film): nmax ˆ 1771
(PhCH2OCH2), 28.7 (CH2), 28.2 (CH2), 28.1 (C(CH3)3); IR (film): nmax
1713 (C O), 1653 (C C), 1496 cmÀ1 (Ph); elemental analysis calcd (%) for
C17H24O3: C 73.9, H 8.75; found: C 74.1, H 8.86.
ˆ
ˆ
ˆ
(C O), 1595 (C C), 1490 cmÀ1 (Ph); ES-MS: m/z: calcd for C22H23NO4Na:
ˆ
ˆ
388.1543; found: 388.1525.
(5S)-3-[(E)-4-Benzyloxy-but-1-enyl]-2,5-dihydro-5-methyl-furan-2-one
(8): n-Butyllithium (1.6m in hexanes, 5.41 mL, 8.67 mmol) was added
dropwise through a syringe to a solution of diisopropylamine (1.33 mL,
9.46 mmol) in THF (8.7 mL) at À788C. After 5min at À788C, the solution
was warmed to 08C over 10 min, then re-cooled to À788C. HMPA
(1.57 mL, 9 mmol) was added in one portion through a syringe and the
solution stirred at À788C for 30 min. A solution of 28 (2.18 g, 7.88 mmol) in
THF (3 mL) was then added dropwise through a cannula to the lithium
amide solution. Stirring was maintained at À788C for 1 h, then (S)-2-(tert-
butyldimethylsilyloxy)propanal (1.63 g, 8.67 mmol) in THF (2 mL) was
added dropwise through a cannula. After a further 10 min at À788C,
phosphate buffer solution (pH 7.2, 10 mL) was added and the reaction
mixture warmed to rt. Following dilution with diethyl ether (200 mL), the
organic phase was separated and washed with water (2 Â 100 mL) and
saturated NaCl solution (100 mL), dried (MgSO4), filtered and concen-
trated in vacuo to give the crude aldol product. This crude material was
dissolved in a saturated solution of HCl in methanol (100 mL), stirred at rt
for 5min, then concentrated in vacuo. This process was repeated twice to
afford the crude cyclised product. Methanesulfonyl chloride (0.91 mL,
11.8 mmol) was added dropwise through a syringe to a solution of this crude
material and triethylamine (3.30 mL, 23.64 mmol) in dichloromethane
(30 mL) at 08C. After 30 min at rt, the reaction mixture was diluted with
dichloromethane (200 mL) and washed with HCl solution (1m, 2 Â 50 mL),
saturated sodium hydrogen carbonate solution (50 mL) and saturated NaCl
solution (50 mL), then dried (MgSO4), filtered and concentrated in vacuo
to give the crude diene 29. Iodine (50 mg, 0.20 mmol) was added to a
(2'R,4R,5S)-3-(4'-Benzyloxy-2'-hydroxy-butylidene)-4-N-phenylamino-di-
hydro-5-methyl-furan-2-one (33):
A solution of [Mo(CO)6] (1.45g,
5.48 mmol) in anhydrous acetonitrile (14 mL) was heated at reflux under
argon for 4 h, then allowed to cool to rt. A solution of 32 (1.00 g, 2.74 mmol)
in acetonitrile (3 mL) was added dropwise through a syringe and the
reaction mixture stirred at rt for 15min, then water (2 mL) was added.
After stirring for
a further 45min at rt, the reaction mixture was
concentrated in vacuo and passed through a short pad of silica eluting
with petroleum ether/diethyl ether (1:2) to afford a pale purple oil. This was
further purified by flash column chromatography eluting with dichloro-
methane/diethyl ether (95:5) to afford amino alcohol 33 (650 mg, 70%) as
an oil that solidified on standing. The solid could be recrystallised from
dichloromethane/ether/pentane to give fine white needles. M.p. 828C; Rf ˆ
0.41 (diethyl ether); [a]2D9 ˆ ‡79 (c ˆ 0.50 in CH2Cl2); 1H NMR (200 MHz;
CDCl3): d ˆ 7.34 7.25(m, 5H; Ph), 7.21 (brt, J ˆ 7.7 Hz, 2H; NPhCH-
ˆ
meta), 6.99 (dd, J ˆ 6.3, 1.6 Hz, 1H; CH CCO2), 6.84 (brt, J ˆ 7.7 Hz, 1H;
NPhCH-para), 6.61 (brd, J ˆ 7.7 Hz, 2H; NPhCH-ortho), 4.76 (q, J ˆ
ˆ
6.3 Hz, 1H; CHCH C), 4.60 4.54 (brm, 1H; CHN), 4.54 4.48 (m, 1H;
CHCH3), 4.48 (q (AB), J ˆ 11.9 Hz, 2H; PhCH2), 4.40 3.80 (brm, 2H;
OH, NH), 3.70 3.55 (m, 2H; OCH2CH2), 1.97 1.87 (m, 2H; OCH2CH2),
1.38 (d, J ˆ 6.4 Hz, 3H; CHCH3); 13C NMR (50 MHz; CDCl3): d ˆ 169.9
ˆ
(CO2), 147.6 (ipso C-N), 145.5 (CH CCO2), 137.7 (ipso C-C), 129.6 (Ph),
ˆ
128.5(Ph), 127.8 (Ph), 127.8 (Ph), 127.6 (Ph), 119.7 (CH CCO2), 114.7
ˆ
(NPhC-ortho), 80.5(O CHC C), 73.2 (PhCH2), 68.5( CHCH3), 67.2,
(OCH2CH2), 57.2 (CHN), 36.2 (OCH2CH2), 21.0 (CHCH3); IR (KBr):
Chem.Eur.J. 2002, 8, No. 7
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1631 $ 20.00+.50/0
1631

S. V. Ley et al.
FULL PAPER
À1
ˆ
ˆ
nmax ˆ 3375(br, O-H and N-H), 1752 (C O), 1680 (C C), 1601, 1497 cm
C-C), 130.4 (Ph), 130.2 (Ph), 130.0 (Ph), 129.9 (Ph), 128.4 (Ph), 127.7 (Ph),
127.6 (Ph), 76.2 (CHCH3), 73.1 (PhCH2), 67.1 (CHOSi), 66.7 (OCH2CH2),
65.5 (CHN), 39.4 (CHCO2), 37.1 (OCH2CH2), 36.2 (CH(O)CH2), 25.9
(C(CH3)3), 19.3 (CHCH3), 18.0 (C(CH3)3), À4.2 (SiCH3), À4.6 (SiCH3); IR
(Ph); elemental analysis calcd (%) for C22H25NO4: C 71.9, H 6.86, N 3.8;
found: C 71.8, H 6.87, N 3.8.
(2'R,4R,5S)-3-(4'-Benzyloxy-2'-(tert-butyldimethylsilyloxy)-butylidene)-4-
N-phenylamino-dihydro-5-methyl-furan-2-one (34): tert-Butyldimethyl-
chlorosilane (590 mg, 3.92 mmol) was added in one portion to a solution
of 33 (480 mg, 1.30 mmol) and imidazole (440 mg, 6.53 mmol) in DMF
(2.5mL) at rt. After stirring for 14 h at rt, the reaction mixture was diluted
with diethyl ether (75mL), washed with water (30 mL) and saturated NaCl
solution (30 mL), dried (MgSO4), filtered and concentrated in vacuo.
Purification by flash column chromatography eluting with petroleum ether/
diethyl ether (9:1 ! 2:1) afforded silyl ether 34 (520 mg, 83%) as an oil.
Rf ˆ 0.70 (petroleum ether/diethyl ether 1:1); [a]D29 ˆ ‡86 (c ˆ 0.49 in
CH2Cl2); 1H NMR (200 MHz; CDCl3): d ˆ 7.33 7.24 (m, 5H; Ph), 7.16
(brt, J ˆ 7.5Hz, 2.0H; NPhC H-meta), 6.98 (dd, J ˆ 7.1, 1.9 Hz, 1H;
ˆ
ˆ
(film): nmax ˆ 2930, 2857 (C-H), 1782 (OC O), 1699 (PhNC O), 1596, 1537,
1493 cmÀ1 (Ph); ES-MS: m/z: calcdc for C30H40F3NO5SiNa: 602.2526;
found:602.2523.
(2'S,3R,4R,5S)-3-(4'-Hydroxy-2'-tert-butyldimethylsilyloxy)-butyl-4-N-
phenyl-N-trifluoroacetamido-2,3,4,5-tetrahydro-5-methyl-furan-2-one
(37): Methanol (3 mL) was added to a mixture of 36 (92 mg, 0.163 mmol)
and palladium hydroxide (40 mg, 40%), and the reaction mixture was
placed under a hydrogen atmosphere. After stirring at rt for 48 h, the
catalyst was removed by filtration through a small pad of silica eluting with
diethyl ether and all volatiles were removed in vacuo. Purification by flash
column chromatography eluting with petroleum ether/diethyl ether (1:2)
afforded alcohol 37 (76 mg, 95%) as an oil. Rf ˆ 0.16 (petroleum ether/
diethyl ether 1:2); [a]2D9 ˆ ‡30.6 (c ˆ 1.87 in CH2Cl2); 1H NMR (400 MHz;
CDCl3): d ˆ 7.54 7.50 (m, 3H; N-Ph), 7.29 (brd, J ˆ 6.4 Hz, 1H; N-Ph), 7.16
(brd, J ˆ 6.4 Hz, 1H; N-Ph), 4.85(dd, J ˆ 9.7, 8.3 Hz, 1H; CHN), 4.47 4.43
(m, 1H; CHOSi), 4.43 4.38 (m, 1H; CHCH3), 3.77 (brs, 2H; CH2OH),
2.73 2.69 (m, 1H; CHCO2), 2.10 (brs, 1H; OH), 2.02 1.94 (m, 2H;
CH2CHCO2), 1.80 1.75(m, 1H; CH 2CHH), 1.68 1.63 (m, 1H;
CH2CHH), 1.55 (d, J ˆ 6.3 Hz, 3H; CHCH3), 0.91 (s, 9H; C(CH3)3), 0.13
(s, 3H; SiCH3), 0.12 (s, 3H; SiCH3); 13C NMR (150 MHz; CDCl3): d ˆ 174.6
(CO2), 158.1 (q, J ˆ 36, F3CCO2), 138.8 (ipso C-N), 130.5(Ph), 130.0 (Ph),
130.0 (Ph), 129.8 (Ph), 129.7 (Ph), 75.6 (CHCH3), 71.1 (CHOSi), 68.2
(CHN), 65.7 (CH2OH), 39.7 (CHCO2), 37.5(OCH 2CH2), 36.2
(CH2CHCO2), 25.8 (C(CH3)3), 19.0 (CHCH3), 17.9 (C(CH3)3), À4.3
ˆ
CH CCO2), 6.77 (brt, J ˆ 7.5Hz, 1H; NPhC H-para), 6.45(brd, J ˆ
ˆ
7.5Hz, 2H; NPhC H-ortho), 4.84 (q, J ˆ 7.1 Hz, 1H; CHCH C), 4.55 (qd,
J ˆ 6.5, 2.0 Hz, 1H; CHCH3), 4.50 (s, 2H; PhCH2), 4.47 (m, 1H; CHN),
3.91 (d, J ˆ 5.6 Hz, 1H; NH), 3.58 (t, J ˆ 6.1 Hz, 2H; OCH2CH2), 2.06 1.97
(m, 1H; OCH2CHH), 1.97 1.90 (m, 1H; OCH2CHH), 1.38 (d, J ˆ 6.5Hz,
3H; CHCH3), 0.85(s, 9H; C(C H3)3), À0.03 (s, 3H; SiCH3), À0.05(s, 3H;
SiCH3); 13C NMR (50 MHz; CDCl3): d ˆ 169.7 (CO2), 149.1 (ipso C-N),
ˆ
145.4 (CH CCO2), 138.0 (ipso C-C), 129.5(Ph), 128.4 (Ph), 127.6 (Ph),
ˆ
127.5(Ph), 126.2 (Ph), 118.7 (CH CCO2), 113.5(NPh C-ortho), 79.9
(CHCH C), 72.9 (PhCH2), 66.9 (CHCH3), 65.9, (OCH2CH2), 56.1
(CHN), 37.5(OCH CH2), 25.7 (C(CH3)3), 20.7 (CHCH3), 18.0 (C(CH3)3),
ˆ
2
ˆ
À4.5(Si CH3), À5.1 (SiCH3); IR (film): nmax ˆ 3354 (br, N-H), 1754 (C O),
À1
ˆ
1680 (C C), 1601, 1489 cm (Ph); elemental analysis calcd (%) for
(SiCH3), À4.7 (SiCH3); IR (film): nmax ˆ 3480 (br, O-H), 2931, 2858 (C-
C28H39NO4Si: C 69.8, H 8.16, N 2.9; found: C 69.8, H 8.14, N 3.0.
À1
ˆ
ˆ
H), 1779 (OC O), 1698 (PhNC O), 1596, 1493 cm (Ph); elemental
analysis calcd (%) for C23H34F3NO5Si: C 56.4, H 6.99, N 2.9; found: C 56.6,
H 6.86, N 3.0; ES-MS: m/z: calcd for C23H34F3NO5SiNa: 512.2056; found:
512.2027.
(2'S,3R,4R,5S)-3-(4'-Benzyloxy-2'-tert-butyldimethylsilyloxy)-butyl-4-N-
phenylamino-2,3,4,5-tetrahydro-5-methyl-furan-2-one (35): Methanol
(3 mL) was added to a mixture of 34 (85mg, 0.176 mmol) and PtO 2
(30 mg, 33 mol%), and the reaction was placed under an hydrogen
atmosphere. After stirring at rt for 90 min, the catalyst was removed by
(Z/E)-(2'S,3R,4R,5S)-3-(5'-Iodo-2'-tert-butyldimethylsilyloxy)-pent-4'-en-
yl-4-N-phenyl-N-trifluoroacetamido-2,3,4,5-tetrahydro-5-methyl-furan-2-
one (38)
filtration through
a small pad of silica eluting with diethyl ether.
Concentration in vacuo afforded amine 35 (83 mg, 98%) an oil, as a single
diastereoisomer, which required no further purification. Rf ˆ 0.24 (petro-
leum ether/diethyl ether 1:1); [a]D29 ˆ À30.5( c ˆ 0.49 in CH2Cl2); 1H NMR
(200 MHz; CDCl3): d ˆ 7.37 7.27 (m, 5H; Ph), 7.16 (dd, J ˆ 8.6, 7.4 Hz, 2H;
NPhCH-meta), 6.74 (brt, J ˆ 7.4 Hz, 1H; NPhCH-para), 6.56 (brd, J ˆ
8.6 Hz, 2H; NPhCH-ortho), 4.46 (s, 2H; PhCH2), 4.20 4.14 (m, 2H;
CHOSi, CHCH3), 3.77 3.47 (m, 4H; CHN, NH, OCH2CH2), 2.66 (dt, J ˆ
9.2, 6.5Hz, 1H; C HCO2), 2.11 1.97 (m, 1H; CH(O)CHH), 1.86 1.73 (m,
3H; OCH2CH2, CH(O)CHH), 1.46 (d, J ˆ 6.3 Hz, 3H; CHCH3), 0.88 (s,
9H; C(CH3)3), 0.03 (s, 6H; 2  SiCH3); 13C NMR (50 MHz; CDCl3): d ˆ
176.3 (CO2), 146.3 (ipso C-N), 138.4 (ipso C-C), 129.4 (Ph), 128.3 (Ph),
127.6 (Ph), 127.5(Ph), 118.5(Ph), 113.2 (Ph), 80.8 ( CHCH3), 73.0 (PhCH2),
67.2 (CHOSi), 66.5(O CH2CH2), 62.6 (CHN), 44.1 (CHCO2), 36.6
(OCH2CH2), 36.5(CH(O) CH2), 25.9 (C(CH3)3), 19.4 (CHCH3), 18.0
(C(CH3)3), À4.4 (SiCH3), À4.6 (SiCH3); IR (film): nmax ˆ 3373 (br, N-H),
1) Oxidation of 37 to the aldehyde: A solution of dimethyl sulfoxide
(36 mL, 0.512 mmol) in dichloromethane (1 mL) was added dropwise
through a syringe to a vigorously stirred solution of oxalyl chloride (41 mL,
0.465mmol) in dichloromethane (2 mL) at À788C. After 30 min at À788C,
a solution of 37 (75mg, 0.155mmol) in dichloromethane (2 mL) was added
dropwise through a syringe. The temperature was maintained at À788C for
a further 30 min, then triethylamine (0.2 mL, 1.40 mmol) was added
dropwise through a syringe. After warming to rt over 45min, the reaction
mixture was diluted with diethyl ether (100 mL), washed with phosphate
buffer solution (pH 7.2, 20 mL) and saturated NaCl solution (20 mL), dried
(MgSO4), filtered and concentrated in vacuo. The oil was passed through a
small pad of silica eluting with diethyl ether, to afford after removal of
volatiles, the aldehyde (73 mg, 96%) which was used in the subsequent step
without further purification. Rf ˆ 0.34 (petroleum ether/diethyl ether 1:2);
1H NMR (400 MHz; CDCl3): d ˆ 9.79 (d, J ˆ 3.0 Hz, 1H; CHO), 7.55 7.49
(m, 3H; Ph), 7.34 7.28 (brs, 1H; Ph), 7.15(brd, J ˆ 6.2 Hz, 1H; Ph), 4.89
(dd, J ˆ 9.9, 8.3 Hz, 1H; CHN), 4.79 4.74 (m, 1H; CHOSi), 4.38 (dq, J ˆ
8.3, 6.3 Hz, 1H; CHCH3), 2.74 (dd, J ˆ 9.9, 4.2 Hz, 1H; CHCO2), 2.68 (dd,
J ˆ 15.6, 4.3 Hz, 1H; CHHCHO), 2.46 (ddd, J ˆ 15.6, 5.7, 3.0 Hz, 1H;
CHHCHO), 2.06 (ddd, J ˆ 14.2, 9.4, 4.7 Hz, 1H; CHHCHCO2), 1.93 (ddd,
J ˆ 14.2, 7.8, 4.2 Hz, 1H; CHHCHCO2), 1.55 (d, J ˆ 6.3 Hz, 3H; CHCH3),
0.89 (s, 9H; C(CH3)3), 0.11 (s, 3H; SiCH3), 0.11 (s, 3H; SiCH3); 13C NMR
(100 MHz; CDCl3): d ˆ 201.5( CHO), 174.5( CO2), 158.0 (q, J ˆ 36,
F3CCO2), 134.3 (ipso C-N), 130.6 (Ph), 130.2 (Ph), 129.8 (Ph), 75.4
(CHCH3), 65.4 (CHOSi), 65.3 (CHN), 49.5( CH2CHO), 39.2 (CHCO2),
36.5( CH2CHCO2), 25.8 (C(CH3)3), 18.8 (CHCH3), 18.0 (C(CH3)3), À4.4
(SiCH3), À4.8 (SiCH3).
À1
ˆ
1770 (C O), 1601, 1497 cm (Ph); elemental analysis calcd (%) for
C28H41NO4Si: C 69.5, H 8.54, N 2.9; found: C 69.0, H 8.76, N 3.0.
(2'S,3R,4R,5S)-3-(4'-Benzyloxy-2'-tert-butyldimethylsilyloxy)-butyl-4-N-
phenyl-N-trifluoroacetamido-2,3,4,5-tetrahydro-5-methyl-furan-2-one
(36): Trifluoroacetic anhydride (74 mL, 0.516 mmol) was added dropwise
through a syringe to a solution of 35 (83 mg, 0.172 mmol) and H¸nig×s base
(123 mL, 0.704 mmol) in dichloromethane (4 mL) at 08C. After 30 min at
08C, the reaction mixture was diluted with diethyl ether (50 mL), washed
with water (30 mL) and saturated NaCl solution (30 mL), dried (MgSO4),
filtered and concentrated in vacuo. Purification by flash column chroma-
tography eluting with petroleum ether/diethyl ether (1:1) afforded
trifluoroacetamide 36 (92 mg, 95%) as an oil. Rf ˆ 0.43 (petroleum ether/
diethyl ether 1:1); 1H NMR (400 MHz; CDCl3): d ˆ 7.51 7.43 (m, 3H;
N-Ph), 7.35 7.26 (m, 5H; Ph), 7.13 (brd, J ˆ 5.9 Hz, 2H; NPhCH-ortho),
4.85(dd, J ˆ 9.0, 7.7 Hz, 1H; CHN), 4.50 (d, J ˆ 11.9 Hz, 1H; PhCHH), 4.45
(d, J ˆ 11.9 Hz, 1H; PhCHH), 4.39 (qn, J ˆ 6.7 Hz, 1H; CHOSi), 4.37
4.31, (m, 1H; CHCH3), 3.61 3.52 (m, 2H; OCH2CH2), 2.73 2.67 (m, 1H;
CHCO2), 2.02 1.94 (m, 1H; CHHCHCO2), 1.94 1.87 (m, 2H;
OCH2CH2), 1.81 1.68 (m, 1H; CH(O)CHH), 1.53 (d, J ˆ 6.3 Hz, 3H;
CHCH3), 0.88 (s, 9H; C(CH3)3), 0.08 (s, 3H; SiCH3), 0.07 (s, 3H; SiCH3);
13C NMR (50 MHz; CDCl3): d ˆ 175.0 (CO2), 138.4 (ipso C-N), 134.5( ipso
2) Homologation to the vinyl iodide: A solution of the above aldehyde
(73 mg, 0.150 mmol) and iodoform (181 mg, 0.465 mmol) in THF (3 mL)
was added via cannular to a rapidly stirred slurry of chromium dichloride
(191 mg, 1.55 mmol) in THF at 08C. A deep red colouration was observed
after complete addition. After stirring for 14 h, the reaction mixture was
diluted with diethyl ether (60 mL), washed with water (2 Â 30 mL) and
saturated NaCl solution (30 mL), dried (MgSO4), filtered and concentrated
in vacuo. Purification by flash column chromatography eluting with
1632
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1632 $ 20.00+.50/0
Chem.Eur.J. 2002, 8, No. 7

Muricatetrocin C
1621 1636
petroleum ether/diethyl ether (2:1) afforded vinyl iodide 38 (68 mg, 75%),
an oil, as an inseparable mixture of geometric isomers [E/Z 4:1; assigned by
integration of the 1H NMR peaks at dH (major) ˆ 6.09 (d, J ˆ 14.5Hz, 1H;
dimethoxy-34,35-dimethyl-19-(12-(9-benzyloxypropyl)-15-(16-hydroxy-
prop-17-ynyl)tetrahydrofuran)-20-dodecanyl-[33,36]-dioxane (41): n-Bu-
tyllithium (1.6m in hexanes, 2.35mL, 3.76 mmol) was added dropwise
through a syringe to a solution of 15 (970 mg, 1.88 mmol) in THF (2.4 mL)
at À788C. After 30 min at À788C, a solution of 4 (350 mg, 1.40 mmol) in
THF (2.5mL) was added dropwise via cannular. The reaction was warmed
to À208C over 30 min, then saturated ammonium chloride solution (2 mL)
was added. Once at rt, the reaction mixture was diluted with diethyl ether
(100 mL), washed with water (50 mL) and saturated NaCl solution
(50 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification
by flash column chromatography eluting with petroleum ether/diethyl
ether (10:1 ! 1:2) afforded propargylic alcohols 40 and 41 (540 mg, 63%)
an oil, as an inseparable mixture of C-16 epimers [40/41 1.8:1; assigned by
integration of the peaks at dH (major) ˆ 3.36 (s, 3H; C34OCH3) and dH
(minor) ˆ 3.35(s, 3H; C 34OCH3)]. Rf ˆ 0.14 (petroleum ether/diethyl ether
1:1); 1H NMR (600 MHz; CDCl3): d (mixture) ˆ 7.34 7.33 (m, 3H; Ph),
7.29 7.26 (m, 2H; Ph), 4.50 [brs, 3H; PhCH2, H-16 (major)], 4.38 4.37 (m,
1H; H-19), 4.26 [d, J ˆ 6.1 Hz, 1H; H-16 (minor)], 4.14 (dt, J ˆ 7.5, 3.4 Hz,
1H; H-15), 4.09 4.06 (m, 1H; H-12), 3.99 3.94 (m, 1H; H-20), 3.51 3.47
(m, 2H; H2-9), 3.36 [s, 3H; C34OCH3 (major)], 3.35[s, 3H; C 34OCH3
(minor)], 3.24 (s, 3H; C35OCH3), 2.40 (brs, 1H; OH), 2.09 2.05(m, 1H;
H-13), 2.02 1.99 (m, 2H; H2-14), 1.74 1.69 (m, 1H; H-10), 1.68 1.61 (m,
4H, H-10; H2-11, H-21), 1.58 1.52 (m, 1H; H-13), 1.48 1.45(m, 1H; H-
21), 1.31 (s, 3H; C34CH3), 1.30 1.23 (m, 20H; H2-22 ! H2-31), 1.27 (s, 3H;
C35CH3), 0.88 (t, J ˆ 7.0 Hz, 3H; H3-32); 13C NMR (150 MHz; CDCl3): d
(mixture) ˆ 138.6 (ipso C-C), 128.3 (Ph), 127.6 (Ph), 127.5(Ph), 99.4 ( C-34),
98.2 (C-35), 83.7 [C-17 (minor)], 83.5[ C-17 (major)], 82.8 [C-18 (major)],
82.6 [C-18 (minor)], 81.5[ C-12 (minor)], 80.8 [C-15(major)], 80.6 [ C-12
(major)], 79.7 [C-15(minor)], 72.8 (Ph CH2), 70.3 [C-9 (major)], 70.2 [C-9
(minor)], 67.7 (C-20), 65.4 [C-16 (minor)], 64.7 [C-16 (major)], 63.8 (C-19),
49.6 (C34OCH3), 47.9 (C35OCH3), 32.3 [C-13 (major)], 32.2 [C-13 (minor)],
32.0 [C-11 (minor)], 31.9 [C-11 (major)], 31.5[ C-21 (minor)], 30.3 [C-21
(major)], 29.7 29.6 (7 Â CH2), 29.3 (CH2), 26.6 (C-14), 26.4 (C-10), 25.2
(CH2), 22.7 (CH2), 18.3 (C35CH3), 18.0 (C34CH3), 14.1 (C-32); IR (film):
nmax ˆ 3443 (br, O-H), 2921, 2856 (C-H), 1588 cmÀ1 (Ph); ES-MS: m/z:
calcd for C37H60O7Na: 639.4237; found: 639.4267.
ˆ
CHI) and dH (minor) ˆ 6.38 6.32 (m, 2H; CHI, CH CHI)]. Rf ˆ 0.42
(petroleum ether/diethyl ether 1:1); 1H NMR (400 MHz; CDCl3): d
(major) ˆ 7.53 7.50 (m, 3H; Ph), 7.23 (brs, 1H; Ph), 7.16 (brs, 1H; Ph),
ˆ
6.55 (dt, J ˆ 14.5, 7.5 Hz, 1H; CH CHI), 6.09 (d, J ˆ 14.5Hz, 1H; C HI),
4.79 (dd, J ˆ 9.4, 8.0 Hz, 1H; CHN), 4.48 4.41 (m, 1H; CHOSi), 4.31 4.27
(m, 1H; CHCH3), 2.77 2.72 (m, 1H; CHCO2), 2.29 2.23 (m, 1H;
CHHCHCO2), 2.20 2.13 (m, 1H; CHHCHCO2), 1.95 1.83 (m, 2H;
ˆ
CH2CH C), 1.54 (d, J ˆ 6.3 Hz, 3H; CHCH3), 0.90 (s, 9H; C(CH3)3), 0.09
(s, 3H; SiCH3), 0.08 (s, 3H; SiCH3); 1H NMR (400 MHz; CDCl3): d
(minor) ˆ 7.53 7.50 (m, 3H; Ph), 7.23 (brs, 1H; Ph), 7.16 (brs, 1H; Ph),
ˆ
6.38 6.32 (m, 2H; CHI, CH CHI), 4.91 4.87 (m, 1H; CHN), 4.41 4.36
(m, 1H; CHOSi), 4.31 4.27 (m, 1H; CHCH3), 2.77 2.72 (m, 1H;
CHCO2), 2.33 (t, J ˆ 5.7 Hz, 1H; CHHCHCO2), 2.29 2.23 (m, 1H;
ˆ
CHHCHCO2), 1.95 1.83 (m, 2H; C H2CH C), 1.55 (d, J ˆ 6.3 Hz, 3H;
CHCH3), 0.90 (s, 9H; C(CH3)3), 0.10 (s, 3H; SiCH3), 0.09 (s, 3H; SiCH3);
13C NMR (100 MHz; CDCl3): d (major) ˆ 174.4 (CO2), 158.0 (q, J ˆ 36,
ˆ
F3CCO2), 142.3 (CH CHI), 134.9 (ipso C-N), 130.5(Ph), 130.1 (Ph), 129.8
ˆ
(Ph), 77.4 (CH CHI), 75.7 (CHCH3), 67.9 (CHOSi), 66.2 (CHN), 42.5
ˆ
(CH2CH C), 39.3 (CHCO2), 36.3 (CH2CHCO2), 25.9 (C(CH3)3), 19.1
(CHCH3), 18.0 (C(CH3)3), À4.4 (SiCH3), À4.5(Si CH3); 13C NMR
(100 MHz; CDCl3): d (minor) ˆ 174.6 (CO2), 158.0 (q, J ˆ 36, F3CCO2),
ˆ
137.2 (CH CHI), 134.9 (ipso C-N), 130.5(Ph), 130.1 (Ph), 129.7 (Ph), 84.7
ˆ
ˆ
(CH CHI), 75.8 (CHCH3), 67.9 (CHOSi), 65.6 (CHN), 41.6 (CH2CH C),
39.6 (CHCO2), 36.6 (CH2CHCO2), 25.9 (C(CH3)3), 19.1 (CHCH3), 18.0
(C(CH3)3), À4.4 (SiCH3), À4.5(Si CH3); IR (film): nmax ˆ 2929, 2856 (C-H),
1780 (OC O), 1698 (PhNC O), 1596, 1492 cmÀ1 (Ph); ES-MS: m/z: calcd
ˆ
ˆ
for C24H33F3INO4SiNa: 634.1073; found: 634.1069.
(Z/E)-(2'R,5S)-3-(5'-Iodo-2'-tert-butyldimethylsilyloxy)-pent-4'-enyl-2,5-
dihydro-5-methyl-furan-2-one (5): 1,8-Diazabicyclo[5.4.0]undec-7-ene
(36 mL, 0.24 mmol) was added dropwise through a syringe to a solution
of 38 (67 mg, 0.11 mmol) in dichloromethane (2 mL) at 08C. After stirring
at 08C for 1 h, saturated ammonium chloride (1 mL) was added, and then
the reaction mixture was poured onto diethyl ether (50 mL). The organic
phase was separated, washed with water (20 mL) and saturated NaCl
solution (20 mL), dried (MgSO4), filtered and concentrated in vacuo.
Purification by flash column chromatography eluting with dichlorome-
thane afforded butenolide 5 (42 mg, 91%) an oil, as in separable mixture of
geometric isomers [E/Z 4:1; tentatively assigned by integration of the
1H NMR peaks at dH (major) ˆ 6.07 (d, J ˆ 14.4 Hz, 1H; CHI) and dH
(12R,15S,16R,19R,20S,34R,35R)-34,35-Dimethoxy-34,35-dimethyl-19-(12-
(9-benzyloxypropyl)-15-(16-hydroxypropyl)tetrahydrofuran)-20-dodecan-
yl-[33,36]-dioxane (42) and (12R,15S,16S,19R,20S,34R,35R)-34,35-dime-
thoxy-34,35-dimethyl-19-(12-(9-benzyloxypropyl)-15-(16-hydroxypropyl)-
tetrahydrofuran)-20-dodecanyl-[33,36]-dioxane (43): A slurry of Raney
nickel (50% in water, 2.0 g), was washed successively with 95% ethanol
(3 Â 5mL) and absolute ethanol (3 Â 5mL), then suspended in absolute
ethanol (3 mL) and placed under an hydrogen atmosphere. A solution of 40
and 41 (490 mg, 0.790 mmol) in absolute ethanol (3 mL) was added
dropwise through a syringe and the reaction stirred vigorously for 1 h at rt.
Filtration through a short plug of silica eluting with diethyl ether and
concentration in vacuo afforded alcohols 42 and 43 (440 mg, 89%), an oil,
as a mixture of C-16 epimers (42/43 1.8:1; assigned by integration of the
peaks at dH (major) ˆ 3.31 (s, 3H; C34OCH3) and dH (minor) ˆ 3.28 (s, 3H;
C34OCH3) in the crude 1H NMR). Further purification by flash column
chromatography eluting with petroleum ether/diethyl ether (1:1) afforded
43 (90 mg, 18%) and a mixture of 42 and 43 (350 mg, 71%). Rf ˆ 0.33
(major; petroleum ether/diethyl ether 2:1); [a]D29 (major) ˆ À38 (c ˆ 0.85in
CH2Cl2); 1H NMR (600 MHz; CDCl3): d(major) ˆ 7.35 7.33 (m, 4H; Ph),
7.29 7.27 (m, 1H; Ph), 4.50 (s, 2H; PhCH2), 4.08 4.06 (m, 1H; H-20),
3.99 3.97 (m, 1H; H-12), 3.91 3.88 (m, 1H; H-15), 3.80 3.78 (m, 1H; H-
16), 3.52 3.48 (m, 3H; H2-9, H-19), 3.31 (s, 3H; C34OCH3), 3.24 (s, 3H;
C35OCH3), 2.17 2.14 (m, 1H; H-18), 2.02 2.07 (m, 2H; H-13, OH), 1.87
1.82 (m, 2H; H2-14), 1.75 1.67 (m, 2H; H-10, H-17), 1.67 1.61 (m, 2H; H-
10, H-11), 1.56 1.43 (m, 5H; H-11, H-13, H-17, H-18, H-21), 1.33 1.21 (m,
21H; H-21, H2-22 ! H2-31), 1.29 (s, 3H; C34CH3), 1.27 (s, 3H; C35CH3), 0.88
(t, J ˆ 7.0 Hz, 3H; H3-32); 13C NMR (150 MHz; CDCl3): d (major) ˆ 138.6
(ipso C-C), 128.3 (Ph), 127.6 (Ph), 127.5(Ph), 99.7 ( C-34), 98.7 (C-35), 81.5
(C-15), 79.8 (C-12), 74.3 (C-19), 72.8 (PhCH2), 71.7 (C-16), 70.3 (C-9), 68.8
(C-20), 49.7 (C35OCH3), 47.8 (C34OCH3), 32.6 (C-11), 32.2 (C-13), 31.9
(CH2), 31.4 (C-17), 30.0 (CH2), 29.7 29.6 (6 Â CH2), 29.3 (CH2), 26.4
(CH2), 26.0 (C-10), 25.1 (C-14), 24.7 (C-18), 22.7 (CH2), 18.8 (C34CH3), 18.2
(C35CH3), 14.1 (C-32); IR (film): nmax (major) ˆ 3445(br, O-H), 2920,
2850 cmÀ1 (C-H). Rf ˆ 0.29 (minor; petroleum ether/diethyl ether 2:1);
[a]D29 (minor) ˆ À42 (c ˆ 0.95in CH 2Cl2); 1H NMR (600 MHz; CDCl3): d
ˆ
(minor) ˆ 6.34 6.30 (m, 2H; CHI, CH CHI)]. Rf ˆ 0.45(dichlorome-
1
ˆ
thane); H NMR (600 MHz; CDCl3): d (major) ˆ 7.11 (brs, 1H; C CH),
ˆ
6.53 (dt, J ˆ 14.4, 7.4 Hz, 1H; CHC CHI), 6.07 (d, J ˆ 14.4 Hz, 1H; CHI),
5.02 (brq, J ˆ 7.0 Hz, 1H; CHCH3), 4.06 (qn, J ˆ 5.7 Hz, 1H; CHOSi),
ˆ
2.46 2.40 (m, 2H; CH2CCO2), 2.26 2.17 (m, 2H; CH2CH C), 1.42 (d, J ˆ
7.0 Hz, 3H; CHCH3), 0.88 (s, 9H; C(CH3)3), 0.06 (s, 3H; SiCH3), 0.03 (s,
3H; SiCH3); 1H NMR (600 MHz; CDCl3): d (minor) ˆ 7.15(brs, 1H;
ˆ
ˆ
C CH), 6.34 6.30 (m, 2H; CHI, CH CHI), 4.99 (brq, J ˆ 6.9 Hz, 1H;
CHCH3), 4.16 (qn, J ˆ 5.7 Hz, 1H; CHOSi), 2.46 2.40 (m, 1H;
CHHCCO2), 2.36 2.31 (m, 1H; CHHCCO2), 2.26 2.17 (m, 2H;
ˆ
CH2CH C), 1.43 (d, J ˆ 6.9 Hz, 3H; CHCH3), 0.87 (s, 9H; C(CH3)3),
0.09 (s, 3H; SiCH3), 0.05(s, 3H; SiC H3); 13C NMR (150 MHz; CDCl3): d
ˆ
ˆ
ˆ
(major) ˆ 173.7 (CO2), 151.9 (C CH), 142.3 (CH CHI), 130.4 (C CH),
ˆ
ˆ
77.5( CHCH3), 77.2 (CH CHI), 68.6 (CHOSi), 43.4 (CH2CH C), 33.0
(CH2CCO2), 25.8 (C(CH3)3), 18.9 (CHCH3), 18.0 (C(CH3)3), À4.5(Si CH3),
À4.6 (SiCH3); 13C NMR (150 MHz; CDCl3): d (minor) ˆ 173.7 (CO2),
ˆ
ˆ
ˆ
ˆ
152.1 (C CH), 137.2 (CH CHI), 130.4 (C CH), 84.7 (CH CHI), 77.7
(CHCH3), 68.4 (CHOSi), 43.6 (CH2CH C), 32.8 (CH2CCO2), 25.8
ˆ
(C(CH3)3), 19.1 (CHCH3), 18.0 (C(CH3)3), À4.6 (SiCH3), À4.8 (SiCH3);
À1
ˆ
ˆ
IR (film): nmax ˆ 2928, 2855 (C-H), 1754 (C O), 1604 cm (C C); ES-MS:
m/z: calcd for C16H27O3ISiNa: 445.0672; found: 445.0680.
The final steps: Detailing the synthesis of muricatetrocin C from fragments
3, 4 and 5. In this section the compounds are discussed in terms of the
numbering system used for this family of natural products. Thus, the
butenolide carbonyl carbon is C-1, and the terminal methyl group of the
aliphatic chain is C-32.
(12R,15S,16R,19R,20S,34R,35R)-34,35-Dimethoxy-34,35-dimethyl-19-(12-
(9-benzyloxypropyl)-15-(16-hydroxyprop-17-ynyl)tetrahydrofuran)-20-do-
decanyl-[33,36]-dioxane (40) and (12R,15S,16S,19R,20S,34R,35R)-34,35-
Chem.Eur.J. 2002, 8, No. 7
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1633 $ 20.00+.50/0
1633

S. V. Ley et al.
FULL PAPER
(minor) ˆ7.35 7.33 (m, 4H; Ph), 7.29 7.27 (m, 1H; Ph), 4.50 (s, 2H;
PhCH2), 4.07 4.04 (m, 1H; H-20), 3.91 (qn, J ˆ 6.0 Hz, 1H; H-12), 3.80 (q,
J ˆ 7.0 Hz, 1H; H-15), 3.51 3.46 (m, 3H; H2-9, H-19), 3.38 3.36 (m, 1H;
H-16), 3.28 (s, 3H; C34OCH3), 3.24 (s, 3H; C35OCH3), 2.42 (d, J ˆ 3.5Hz,
1H; OH), 2.04 1.98 (m, 3H; H-13, H-14, H-18), 1.81 1.50 (m, 10H; H2-10,
H2-11, H-13, H-14, H2-17, H-18, H-21), 1.32 1.23 (m, 21H; H-21, H2-22 !
H2-31), 1.29 (s, 3H; C34CH3), 1.27 (s, 3H; C35CH3), 0.88 (t, J ˆ 7.0 Hz, 3H;
H3-32); 13C NMR (150 MHz; CDCl3): d(minor) ˆ 138.6 (ipso C-C), 128.3
(Ph), 127.6 (Ph), 127.5(Ph), 99.7 ( C-34), 98.9 (C-35), 82.0 (C-15), 79.0 (C-
12), 75.2 (C-19), 74.9 (C-16), 72.9 (PhCH2), 70.2 (C-9), 68.9 (C-20), 49.6
(C35OCH3), 47.7 (C34OCH3), 32.4 (CH2), 32.3 (CH2), 31.9 (CH2), 31.3 (CH2),
31.2 (CH2), 29.7 29.6 (6 Â CH2), 29.3 (CH2), 28.6 (CH2), 26.5( CH2), 26.1
(CH2), 25.3 (CH2), 22.7 (CH2), 18.8 (C34CH3), 18.2 (C35CH3), 14.1 (C-32);
IR (film): nmax (minor) ˆ 3442 (br, O-H), 2921, 2845cm À1 (C-H); ES-MS:
m/z (minor): calcd for C37H64O7Na: 643.4550; found: 643.4539.
flash column chromatography eluting with petroleum ether/diethyl ether
(5:1 ! 1:1) afforded TBS ether 45 (92 mg, 87%) as an oil. Rf ˆ 0.54
(petroleum ether/diethyl ether 1:1); [a]D29 ˆ À36 (c ˆ 0.50 in CH2Cl2);
1H NMR (400 MHz; CDCl3): d ˆ 7.35 7.31 (m, 4H; Ph), 7.29 7.26 (m, 1H;
Ph), 4.50 (s, 2H; PhCH2), 4.06 4.04 (m, 1H; H-20), 3.91 3.86 (m, 2H; H-
12, H-15), 3.57 3.54 (m, 1H; H-16), 3.51 3.43 (m, 3H; H2-9, H-19), 3.28 (s,
3H; C34OCH3), 3.23 (s, 3H; C35OCH3), 1.99 1.95(m, 1H; H-14), 1.94 1.84
(m, 3H; H-14, H-17, H-18), 1.76 1.44 (m, 8H; H2-10, H2-11, H2-13, H-18,
H-21), 1.33 1.22 (m, 22H; H-17, H-21, H2-22 ! H2-31), 1.29 (s, 3H;
C34CH3), 1.26 (s, 3H; C35CH3), 0.88 0.86 (m, 12H; H3-32, C(CH3)3), 0.08 (s,
3H; SiCH3), 0.05(s, 3H; SiCH ); 13C NMR (100 MHz; CDCl3): d ˆ 138.7
3
(ipso C-C), 128.3 (Ph), 127.6 (Ph), 127.4 (Ph), 99.6 (C-34), 98.7 (C-35), 81.7
(C-15), 79.0 (C-12), 75.8 (C-16), 75.4 (C-19), 72.8 (PhCH2), 70.4 (C-9), 68.9
(C-20), 49.6 (C35OCH3), 47.7 (C34OCH3), 32.4 (CH2), 32.3 (CH2), 31.9
(CH2), 31.6 (CH2), 30.7 (CH2), 29.7 (CH2), 29.6 (4 Â CH2), 29.5( CH2), 29.3
(CH2), 27.8 (CH2), 26.6 (CH2), 26.0 (CH2), 26.0 (C(CH3)3), 25.7 (CH2),
22.7 (CH2), 18.8 (C34CH3), 18.2 (C35CH3) 18.2 (C(CH3)3), 14.1 (C-32), À4.1
(SiCH3), À4.7 (SiCH3); IR (film): nmax ˆ 2924, 2853 cmÀ1 (C-H); elemen-
tal analysis calcd (%) for C43H78O7Si: C 70.3, H 10.69; found: C 70.5, H
10.48.
(12R,15S,19R,20S,34R,35R)-34,35-Dimethoxy-34,35-dimethyl-19-(12-(9-
benzyloxypropyl)-15-(propan-16-onyl)tetrahydrofuran)-20-dodecanyl-
[33,36]-dioxane (44): A solution of dimethyl sulfoxide (63 mL, 0.89 mmol)
in dichloromethane (2 mL) was added dropwise through a syringe to a
vigorously stirred solution of oxalyl chloride (71 mL, 0.81 mmol) in
dichloromethane (2 mL) at À788C. After 30 min at À788C a solution of
42 and 43 (250 mg, 0.41 mmol) in dichloromethane (2 mL) was added
dropwise via syringe and the temperature was maintained at À788C for a
further 30 min, then triethylamine (0.34 mL, 2.43 mmol) was added
dropwise through a syringe. The reaction warmed to rt over 1 h, and then
was diluted with diethyl ether (100 mL), washed with phosphate buffer
solution (pH 7.2, 50 mL) and saturated NaCl solution (50 mL), dried
(MgSO4), filtered and concentrated in vacuo. Purification by flash column
chromatography eluting with petroleum ether/diethyl ether (3:1) to
afforded ketone 44 (200 mg, 80%) as an oil. Rf ˆ 0.57 (petroleum ether/
diethyl ether 1:2); [a]2D9 ˆ À5 8 (c ˆ 0.99 in CH2Cl2); 1H NMR (400 MHz;
CDCl3): d ˆ 7.34 7.32 (m, 4H; Ph), 7.28 7.25(m, 1H; Ph), 4.50 (s, 2H;
PhCH2), 4.36 (t, J ˆ 7.7 Hz, 1H; H-15), 4.06 4.02 (m, 2H; H-12, H-20),
3.52 3.46 (m, 2H; H2-9), 3.43 (dt, J ˆ 11.7, 3.3 Hz, 1H; H-19), 3.26 (s, 3H;
C34OCH3), 3.23 (s, 3H; C35OCH3), 2.83 2.72 (m, 2H; H2-17), 2.25 2.15
(m, 2H; H-14, H-18), 2.14 1.97 (m, 1H; H-13), 1.92 1.85(m, 1H; H-14),
1.83 1.48 (m, 7H; H2-10, H2-11, H-13, H-18, H-21), 1.40 1.34 (m, 1H; H-
21), 1.34 1.21 (m, 20H; H2-22 ! H2-31), 1.28 (s, 3H; C34CH3), 1.26 (s, 3H;
C35CH3), 0.88 (t, J ˆ 6.8 Hz, 3H; H3-32); 13C NMR (100 MHz; CDCl3): d ˆ
(12R,15S,16S,19R,20S,34R,35R)-34,35-Dimethoxy-34,35-dimethyl-19-(12-
(9-hydroxypropyl)-15-(16-tert-butyldimethylsilyloxypropyl)tetrahydrofur-
an)-20-dodecanyl-[33,36]-dioxane (46): Ethanol (7 mL) was added to a
mixture of 45 (100 mg, 0.136 mmol) and palladium hydroxide (20 mg,
20%), and the reaction placed under a hydrogen atmosphere. After 12 h at
rt, the reaction mixture was passed through a small pad of Celite and
concentrated in vacuo to afford alcohol 46 (82 mg, 94%), as an oil, which
was used in the subsequent step without further purification. Rf ˆ 0.44
(petroleum ether/diethyl ether 1:2); [a]D29 ˆ À44 (c ˆ 0.65in CH 2Cl2);
1H NMR (400 MHz; CDCl3): d ˆ 4.06 4.03 (m, 1H; H-20), 3.97 3.93 (m,
2H; H-12, H-15), 3.68 3.61 (m, 2H; H2-9), 3.61 3.56 (m, 1H; H-16),
3.47 3.43 (m, 1H; H-19), 3.28 (s, 3H; C34OCH3), 3.24 (s, 3H; C35OCH3),
2.14 (brs, 1H; OH), 2.01 1.96 (m, 1H; H-13), 1.96 1.84 (m, 3H; H-14, H-
17, H-18), 1.73 1.46 (m, 8H; H2-10, H2-11, H-13, H-14, H-18, H-21), 1.33
1.23 (m, 22H; H-17, H-21, H2-22 ! H2-31), 1.29 (s, 3H; C34CH3), 1.26 (s,
3H; C35CH3), 0.88 0.86 (m, 12H; H3-32, C(CH3)3), 0.07 (s, 3H; SiCH3),
0.06 (s, 3H; SiCH3); 13C NMR (100 MHz; CDCl3): d ˆ 99.6 (C-34), 98.7 (C-
35), 81.5 (C-15), 79.4 (C-12), 75.4 (C-16), 75.3 (C-19), 68.9 (C-20, 62.9 (C-9),
49.6 (C35OCH3), 47.7 (C34OCH3), 32.5( CH2), 32.4 (CH2), 31.9 (CH2), 31.6
(CH2), 30.7 (CH2), 29.8 (CH2), 29.7 (CH2), 29.6 (4 Â CH2), 29.5( CH2), 29.3
(CH2), 27.5( CH2), 26.0 (C(CH3)3), 25.9 (CH2), 25.6 (CH2), 22.6 (CH2), 18.8
(C34CH3), 18.2 (C35CH3) 18.2 (C(CH3)3), 14.1 (C-32), À4.1 (SiCH3), À4.6
(SiCH3); ES-MS: m/z: calcd for C36H72O7SiNa: 667.4945; found: 667.4966.
ˆ
212.9 (C O), 138.6 (ipso C-C), 128.3 (Ph), 127.6 (Ph), 127.5(Ph), 99.7 ( C-
34), 98.8 (C-35), 83.2 (C-15), 80.7 (C-12), 73.7 (C-19), 72.9 (PhCH2), 70.2
(C-9), 68.7 (C-20), 49.5(C 35OCH3), 47.8 (C34OCH3), 34.8 (C-17), 32.1
(CH2), 31.9 (CH2), 31.3 (CH2), 31.2 (CH2), 29.6 (6 Â CH2), 29.3 (CH2), 29.2
(CH2), 26.4 (CH2), 26.0 (CH2), 22.7 (CH2), 21.6 (CH2), 18.8 (C34CH3), 18.1
(C35CH3), 14.1 (C-32); IR (film): nmax ˆ 2925, 2853 (C-H), 1714 cmÀ1
(12R,15S,16S,19R,20S,34R,35R)-34,35-Dimethoxy-34,35-dimethyl-19-(12-
(but-9-ynyl)-15-(16-tert-butyldimethylsilyloxypropyl)tetrahydrofuran)-20-
dodecanyl-[33,36]-dioxane (47)
ˆ
(C O); ES-MS: m/z: calcd for C37H62O7Na: 641.4393; found: 641.4334.
(12R,15S,16S,19R,20S,34R,35R)-34,35-Dimethoxy-34,35-dimethyl-19-(12-
(9-benzyloxypropyl)-15-(16-hydroxypropyl)tetrahydrofuran)-20-dodecan-
yl-[33,36]-dioxane (43) and (12R,15S,16R,19R,20S,34R,35R)-34,35-dime-
thoxy-34,35-dimethyl-19-(12-(9-benzyloxypropyl)-15-(16-hydroxypropyl)-
tetrahydrofuran)-20-dodecanyl-[33,36]-dioxane (42): l-Selectride (1.0m in
THF, 0.64 mL, 0.64 mmol) was added dropwise through a syringe to a
vigorously stirred solution of 44 (200 mg, 0.330 mmol) in THF (6.4 mL) at
À1008C. After 10 min at À1008C, methanol (1 mL) was added dropwise
through a syringe, then the reaction mixture was warmed to rt, and passed
through a small pad of silica eluting with diethyl ether. Concentration in
vacuo, then purification by flash column chromatography eluting with
petroleum ether/diethyl ether (2:3) afforded alcohol 43 (140 mg, 70%), as
an oil, along with a mixture of alcohols 42 and 43 (55 mg, 27%) also as an
oil. The diastereoisomeric ratio (43/42 4:1) was assigned by integration of
the peaks at dH (major) ˆ 3.28 (s, 3H; C34OCH3) and dH (minor) ˆ 3.31 (s,
3H; C34OCH3) in the crude 1H NMR. All data for the major and minor
epimers was identical to that previously obtained for 43 and 42 respectively.
1) Oxidation of 46 to the aldehyde: Dess Martin periodinane (33 mg,
0.078 mmol) was added in one portion to a solution of 46 (25mg,
0.039 mmol) and pyridine (17 mL, 0.23 mmol) in dichloromethane (1 mL)
at 08C. The resulting suspension was stirred for 3 h at 08C, then diluted with
dichloromethane (25mL) and poured onto a mixture of sodium thiosulfate
solution (20%, 4 mL) and saturated sodium bicarbonate solution (4 mL).
The organic phase was separated, and the aqueous phase re-extracted with
dichloromethane (3 Â 10 mL). The combined organic phases were washed
with saturated NaCl solution (20 mL), dried (MgSO4), filtered and
concentrated in vacuo. Filtration through a short pad of silica gel eluting
with petroleum ether/diethyl ether (2:1) afforded the aldehyde (24 mg,
96%) as an oil. Rf ˆ 0.47 (petroleum ether/diethyl ether 1:2); [a]D29 ˆ À42
(c ˆ 0.92 in CH2Cl2); 1H NMR (400 MHz; CDCl3): d ˆ 9.77 (brs, 1H; H-9),
4.06 4.03 (m, 1H; H-20), 3.96 3.89 (m, 1H; H-12), 3.88 (q, J ˆ 7.0 Hz, 1H;
H-15), 3.56 3.51 (m, 1H; H-16), 3.46 3.41 (m, 1H; H-19), 3.27 (s, 3H;
C34OCH3), 3.23 (s, 3H; C35OCH3), 2.60 2.40 (m, 2H; H2-10), 2.03 1.74
(m, 5H; H2-11, H-13, H-14, H-18), 1.74 1.55 (m, 2H; H-14, H-18), 1.54
1.40 (m, 3H; H-13, H-17, H-21), 1.33 1.19 (m, 22H; H-17, H-21, H2-22 !
H2-31), 1.29 (s, 3H; C34CH3), 1.26 (s, 3H; C35CH3), 0.88 0.86 (m, 12H; H3-
32, C(CH3)3), 0.07 (s, 3H; SiCH3), 0.05(s, 3H; SiCH 3); 13C NMR
(100 MHz; CDCl3): d ˆ 202.1 (C-9), 99.7 (C-34), 98.7 (C-35), 81.9 (C-15),
78.1 (C-12), 75.7 (C-16), 75.4 (C-19), 68.9 (C-20), 49.6 (C35OCH3), 47.7
(C34OCH3), 40.8 (C-10), 32.5( CH2), 32.4 (CH2), 31.9 (CH2), 31.6 (CH2),
30.9 (CH2), 29.7 (CH2), 29.6 (3 Â CH2), 29.5( CH2), 29.3 (CH2), 28.1 (CH2),
27.8 (CH2), 27.7 (CH2), 26.0 (C(CH3)3), 25.9 (CH2), 22.7 (CH2), 18.8
(12R,15S,16S,19R,20S,34R,35R)-34,35-Dimethoxy-34,35-dimethyl-19-(12-
(9-benzyloxypropyl)-15-(16-tert-butyldimethylsilyloxypropyl)tetrahydro-
furan)-20-dodecanyl-[33,36]-dioxane (45): TBSCl (110 mg, 0.73 mmol) was
added in one portion to a solution of 43 (90 mg, 0.145mmol) and imidazole
(70 mg, 1.01 mmol) in DMF (0.6 mL). After heating at 458C for 14 h, the
reaction mixture was diluted with diethyl ether (100 mL), washed with
phosphate buffer solution (pH 7.2, 40 mL) and saturated NaCl solution
(40 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by
1634
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1634 $ 20.00+.50/0
Chem.Eur.J. 2002, 8, No. 7

Muricatetrocin C
1621 1636
(C34CH3), 18.2 (C35CH3) 18.2 (C(CH3)3), 14.1 (C-32), À4.1 (SiCH3), À4.6
(4R,12R,15S,16S,19R,20S,34S)-Muricatetrocin C (2)
À1
ˆ
(SiCH3); IR (film): nmax ˆ 2927, 2854 (C-H), 2780 (H-C O), 1728 cm
1) Reduction of the enyne 48: Wilkinson×s catalyst (3 mg, 0.0032 mmol)
was added in one portion to a solution of 48 (15mg, 0.016 mmol) in
benzene/ethanol (1:1, 1 mL), and the reaction was placed under a hydrogen
atmosphere. After 11 h at rt, all volatiles were removed in vacuo. Filtration
through a short pad of silica gel eluting with petroleum ether/diethyl ether
(3:1) afforded fully protected muricatetrocin C (11 mg, 76%) as an oil.
Rf ˆ 0.29 (petroleum ether/diethyl ether 2:1); [a]D29 ˆ À31 (c ˆ 0.38 in
CH2Cl2); 1H NMR (400 MHz; CDCl3): d ˆ 7.11 (brs, 1H; H-33), 5.02 (brq,
J ˆ 6.2 Hz, 1H; H-34), 4.06 4.03 (m, 1H; H-20), 3.95(qn, J ˆ 5.4 Hz, 1H;
H-4), 3.89 (dt, J ˆ 7.6, 6.5Hz, 1H; H-15), 3.87 3.82 (m, 1H; H-12), 3.53
3.58 (m, 1H; H-16), 3.46 4.42 (m, 1H; H-19), 3.28 (s, 3H; BDA-OCH3),
3.23 (s, 3H; BDA-OCH3), 2.42 (d, J ˆ 5.4 Hz, 2H; H2-3), 2.00 1.93 (m, 1H;
H-13), 1.93 1.83 (m, 3H; H-14, H-17, H-18), 1.72 1.65(m, 1H; H-18),
1.65 1.59 (m, 1H; H-14), 1.55 1.47 (m, 2H; H-13, H-21), 1.46 1.36 (m,
4H; H2-5, H2-11), 1.41 (d, J ˆ 6.8 Hz, 3H; H3-35), 1.33 1.19 (m, 32H; H-17,
H-21, H2-6 ! H2-10, H2-22 ! H2-31), 1.29 (s, 3H; BDA-CCH3), 1.26 (s, 3H;
BDA-CCH3), 0.89 0.84 (m, 21H; H3-32, 2 Â C(CH3)3), 0.08 (s, 3H;
ˆ
(HC O); ES-MS: m/z: calcd for C36H70O7SiNa: 665.4783; found:
665.4765.
2) Homologation to the terminal alkyne: Diethyl(diazomethyl)phospho-
nate (6.2 mg, 0.041 mmol) in THF (0.2 mL) was added dropwise to a slurry
of potassium tert-butoxide (4.6 mg, 0.041 mmol) in THF (0.2 mL) at
À788C. After 10 min at À788C, a pale yellow colour was observed to form,
and a solution of the above aldehyde (22mg, 0.034 mmol) in THF (0.5mL)
was added dropwise through a syringe. On addition of the aldehyde the
solution turned a bright yellow colour and was left to stir at À788C for 16 h,
before being warmed to rt and stirred for a further 4 h. After this period,
water (1 mL) was added, and the reaction mixture was extracted with
dichloromethane (3 Â 15mL). The combined organic phases were washed
with saturated NaCl solution (20 mL), dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column chromatography
eluting with petroleum ether/diethyl ether (6:1 ! 3:1) afforded alkyne 47
(16.6 mg, 76%) as an oil. Rf ˆ 0.40 (petroleum ether/diethyl ether 4:1);
[a]D29 ˆ À39 (c ˆ 0.65in CH 2Cl2); 1H NMR (400 MHz; CDCl3): d ˆ 4.07
4.03 (m, 1H; H-20), 4.03 3.96 (m, 1H; H-12), 3.89 (dt, J ˆ 8.2, 6.4 Hz, 1H;
H-15), 3.59 3.54 (m, 1H; H-16), 3.44 (dt, J ˆ 6.8, 4.0 Hz, 1H; H-19), 3.29
(s, 3H; C34OCH3), 3.23 (s, 3H; C35OCH3), 2.32 2.22 (m, 2H; H2-10), 2.04
1.96 (m, 1H; H-13), 1.95 1.82 (m, 3H; H-14, H-17, H-18), 1.92 (t, 1H; J ˆ
2.5, H-8), 1.76 1.59 (m, 4H; H2-11, H-14, H-18), 1.55 1.41 (m, 2H; H-13,
H-21), 1.33 1.18 (m, 22H; H-17, H-21, H2-22 ! H2-31), 1.29 (s, 3H;
C34CH3), 1.26 (s, 3H; C35CH3), 0.88 0.86 (m, 12H; H3-32, C(CH3)3), 0.08 (s,
3H; SiCH3), 0.06 (s, 3H; SiCH3); 13C NMR (100 MHz; CDCl3): d ˆ 99.7 (C-
34), 98.7 (C-35), 84.3 (C-9), 81.8 (C-15), 77.8 (C-12), 75.8 (C-16), 75.4 (C-
19), 68.9 (C-20), 68.2 (C-8), 49.6 (C35OCH3), 47.7 (C34OCH3), 34.6 (C-11),
32.2 (C-13), 31.9 (CH2), 31.6 (CH2), 30.8 (C-17), 29.7 (CH2), 29.6 (4 Â CH2),
29.5( CH2), 29.3 (CH2), 27.8 (C-14), 26.0 (C(CH3)3), 26.0 (CH2), 25.7 (C-18),
22.7 (CH2), 18.8 (C34CH3), 18.2 (C35CH3) 18.2 (C(CH3)3), 15.6 (C-10), 14.1
SiCH3), 0.05(s, 6H;
2
 SiCH3), 0.02 (s, 3H; SiCH3); 13C NMR
(100 MHz; CDCl3): d ˆ 174.0 (C-1), 151.4 (C-33), 130.9 (C-2), 99.7
(BDA-CO2), 98.7 (BDA-CO2), 81.6 (C-15), 79.4 (C-12), 77.4 (C-34), 75.8
(C-16), 75.4 (C-19), 70.2 (C-4), 68.9 (C-20), 49.6 (BDA-OCH3), 47.7 (BDA-
OCH3), 36.9 (C-5), 35.9 (C-11), 32.7 (C-3), 32.4 (C-13), 31.9 (CH2), 31.6
(CH2), 30.9 (C-17), 29.7 (2 Â CH2), 29.6 (5 Â CH2), 29.5(2 Â CH2), 29.3
(CH2), 27.8 (C-14), 26.3 (CH2), 26.0 (C(CH3)3), 26.0 (CH2), 25.8 (C(CH3)3),
25.7 (C-18), 25.1 (CH2), 22.6 (CH2), 18.9 (CHCH3), 18.8 (BDA-CCH3), 18.2
(C(CH3)3), 18.2 (BDA-CCH3), 18.0 (C(CH3)3), 14.1 (C-32), À4.0 (SiCH3),
À4.5(Si CH3), À4.5(Si CH3), À4.7 (SiCH3); IR (film): nmax ˆ 2928, 2855 (C-
H), 1760 cmÀ1 (C O); ES-MS: m/z: C53H102O9Si2Na: 961.6955; found:
961.6970.
ˆ
2) Global deprotection: Trifluoroacetic acid/water (9:1, 0.5mL) was added
in one portion to fully protected 2 (8.0 mg, 0.0085mmol). The solution was
swirled manually for 30 s, then all volatiles were removed in vacuo. This
process was repeated then purification by flash column chromatography
eluting with chloroform/methanol (99:1 ! 96:4) afforded muricatetrocin C
(2; 4.2 mg, 82%) as a white amorphous solid. M.p. 65 67 8C (m.p. 65
668C)[5]; Rf ˆ 0.08 (EtOAc); [a]2D9 ˆ ‡5.8 (c ˆ 0.38 in CH2Cl2), [a]2D9 ˆ ‡6.3
(in CH2Cl2)[5]; 1H NMR (600 MHz; CDCl3): d ˆ 7.18 (d, J ˆ 1.1 Hz, 1H; H-
33), 5.06 (qd, J ˆ 6.8, 1.1 Hz, 1H; H-34), 3.89 3.87 (m, 1H; H-12), 3.87
3.83 (m, 1H; H-4), 3.82 (q, 1H; J ˆ 7.2, H-15), 3.63 3.60 (m, 2H; H-19, H-
20), 3.47 3.43 (m, 1H; H-16), 2.90 (brs, 2H; OH), 2.53 (dt, J ˆ 15.1, 1.6 Hz,
1H; H-3), 2.40 (dd, J ˆ 15.1, 8.3 Hz, 1H; H-3), 2.04 2.01 (m, 1H; H-13),
2.00 1.97 (m, 1H; H-14), 1.70 1.40 (m, 6H; H2-17, H2-18, H2-21), 1.60
1.40 (m, 3H; H2-11, H-13), 1.62 1.55 (m, 1H; H-14) 1.50 1.40 (m, 2H; H2-
5), 1.43 (d, J ˆ 6.8 Hz, 3H; H3-35), 1.40 1.20 (m, 32H; H2-6 ! H2-10, H2-
22 ! H2-31, 2  OH), 0.88 (t, J ˆ 6.9 Hz, 3H; H3-32); 13C NMR (150 MHz;
CDCl3): d ˆ 174.5( C-1), 151.7 (C-33), 131.2 (C-2), 81.7 (C-15), 79.3 (C-12),
77.9 (C-34), 74.7, 74.4 (C-20, C-19), 74.3 (C-16), 70.0 (C-4), 37.4 (C-5), 33.5
22.7 (C-6 ! C-11, C-17, C-18, C-21 ! C-31), 33.4 (C-3), 32.4 (C-13), 28.4 (C-
14), 19.1 (C-35), 14.1 (C-32); IR (film: nmax ˆ 3422 (br, O-H), 2928, 2855 (C-
ꢀ
(C-32), À4.1 (SiCH3), À4.7 (SiCH3); IR (film): nmax ˆ 3315(C C-H), 2926,
2855 (C-H), 2118 cmÀ1 (C C); ES-MS: m/z: calcd for C37H70O6SiNa:
ꢀ
661.4834; found: 661.4817.
(E/Z)-(4R,12R,15S,16S,19R,20S,34S)-4,16-di-tert-Butyldimethylsilyloxy-
19,20-butanediacetal-6-en-8-yne-muricatetrocin C (48): A solution of 47
(15.5 mg, 0.024 mmol) in triethylamine (0.6 mL) was added dropwise
through a syringe to a solution of 5 (15.0 mg, 0.036 mmol), copper iodide
(2.0 mg, 0.010mmol) and [PdCl2(PPh3)2] (1.5mg, 0.002 mmol) in triethyl-
amine at rt. After 3 h at rt, all volatiles were removed in vacuo. Purification
by flash column chromatography eluting with dichloromethane/diethyl
ether (100:0 ! 95:5) afforded enyne 48 (18.0 mg, 81%), an oil, as an
inseparable mixture of olefin isomers [E/Z, 7.5:1; assigned by integration of
the peaks at dH (major) ˆ 6.02 (dt, J ˆ 15.8, 7.7 Hz, 1H; H-6) and dH
(minor) ˆ 5.89 (dt, J ˆ 10.8, 7.4 Hz, 1H; H-6). Rf ˆ 0.20 (dichlorome-
thane/diethyl ether 95:5); [ a]D29 ˆ À27 (c ˆ 0.60 in CH2Cl2); 1H NMR
(400 MHz; CDCl3): d (major) ˆ 7.09 (brs, 1H; H-33), 6.02 (dt, J ˆ 15.8,
7.7 Hz, 1H; H-6), 5.47 (d, J ˆ 15.8 Hz, 1H; H-7), 5.00 (brq, J ˆ 6.3 Hz, 1H;
H-34), 4.07 4.01 (m, 2H; H-20, H-4), 4.00 3.92 (m, 1H; H-12), 3.88 (dt,
J ˆ 7.9, 6.4 Hz, 1H; H-15), 3.58 3.51 (m, 1H; H-16), 3.45 3.41 (m, 1H; H-
19), 3.28 (s, 3H; BDA-OCH3), 3.23 (s, 3H; BDA-OCH3), 2.42 (d, J ˆ
5.7 Hz, 2H; H2-3), 2.39 2.30 (m, 2H; H2-10), 2.29 2.21 (m, 2H; H2-5),
2.04 1.97 (m, 1H; H-13), 1.95 1.81 (m, 3H; H-14, H-17, H-18), 1.76 1.60
(m, 4H; H2-11, H-14, H-18), 1.55 1.44 (m, 2H; H-13, H-21), 1.41 (d, J ˆ
6.8 Hz, 3H; H3-35), 1.29 (s, 3H; BDA-CCH3), 1.28 1.23 (m, 25H; H-17, H-
21, H2-22 ! H2-31, BDA-CCH3), 0.90 0.85(m, 21H; H3-32, 2 Â C(CH3)3),
0.08 (s, 3H; SiCH3), 0.06 (s, 6H; 2 Â SiCH3), 0.01 (s, 3H; SiCH3); 1H NMR
(400 MHz; CDCl3): d (minor, selected peaks) ˆ 7.13 (brs, 1H; H-33), 5.89
(dt, J ˆ 10.8, 7.4 Hz, 1H; H-6), 5.54 (d, J ˆ 10.8 Hz, 1H; H-7); 13C NMR
(100 MHz; CDCl3): d (major) ˆ 173.7 (C-1), 151.7 (C-33), 138.2 (C-6), 130.7
(C-2), 112.9 (C-7), 99.7 (BDA-CO2), 98.7 (BDA-CO2), 89.0 (C-9), 81.8 (C-
15), 79.1 (C-8), 78.0 (C-12), 77.5( C-34), 75.9 (C-16), 75.4 (C-19), 69.3 (C-4),
68.9 (C-20), 49.6 (BDA-OCH3), 47.7 (BDA-OCH3), 40.8 (C-5), 35.0 (C-11),
32.8 (C-3), 32.2 (C-13), 31.9 (CH2), 31.6 (CH2), 30.9 (C-17), 29.7 (CH2), 29.6
(4 Â CH2), 29.5( CH2), 29.3 (CH2), 27.8 (C-14), 26.0 (C(CH3)3), 26.0 (CH2),
25.8 (C(CH3)3), 25.7 (C-18), 22.7 (CH2), 18.9 (CHCH3), 18.8 (BDA-CCH3),
18.3 (C(CH3)3), 18.2 (BDA-CCH3), 18.0 (C(CH3)3), 16.6 (C-10), 14.1 (C-
H), 1733 (C O), 1675cm À1 (C C); FAB-MS: m/z (%): calcd for
C35H64O7Na: 619.4544; found: 619.4522; EI-MS: m/z (%): 597.6 (100)
ˆ
ˆ
‡
‡
[M] , 525.81 (25) [M À C2H4O À CO] .
Acknowledgement
We thank the EPSRC (to D.J.D. and D.J.R.), the Novartis Research
Fellowship (to S.V.L.) and the BP Research Endowment (to S.V.L.) for
generous financial support for this work.
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32), À4.0 (SiCH3), À4.5(Si CH3), À4.6 (SiCH3), À4.7 (SiCH3); IR (film):
À1
ˆ
ˆ
nmax ˆ 2927, 2855 (C-H), 1760 (C O), 1600 cm (C C); ES-MS: m/z: calcd
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Chem.Eur.J. 2002, 8, No. 7
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0807-1635 $ 20.00+.50/0
1635

S. V. Ley et al.
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À
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Received: September 5, 2001 [F3534]
1636
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0947-6539/02/0807-1636 $ 20.00+.50/0
Chem.Eur.J. 2002, 8, No. 7