Stereoselective synthesis of the cyclic ether core of (+)-laurenyne

Article abstract of DOI:10.1016/j.tetlet.2004.09.160

A concise enantioselective synthesis of the cyclic ether core of the marine natural product (+)-laurenyne has been accomplished using ring-closing metathesis for medium-ring construction.

Full text of DOI:10.1016/j.tetlet.2004.09.160

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8639–8642
Stereoselective synthesis of the cyclic ether core of (+)-laurenyne
a
a
b
J. Stephen Clark,a, Rebecca P. Freeman, Monica Cacho, Andrew W. Thomas,
*
´
Steven Swallowc and Claire Wilsona
aSchool of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
bF. Hoffmann-LaRoche AG, Discovery Chemistry, Pharmaceuticals Division, Bldg. 92-6.88, 4070 Basel, Switzerland
cRoche Products Limited, 40 Broadwater Road, Welwyn Garden City, Herts AL7 3AY, UK
Received 6 September 2004; accepted 23 September 2004
Available online 12 October 2004
Abstract—A concise enantioselective synthesis of the cyclic ether core of the marine natural product (+)-laurenyne has been accom-
plished using ring-closing metathesis for medium-ring construction.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Laurenyne was first isolated from a sample of the alga
Laurencia obtusa collected in the Aegean Sea off the
coast of Turkey by Thomson and co-workers in 1980.1
It is one of a large number of C15 medium-ring ether
metabolites to have been isolated from Laurencia algae
and organisms that feed on them.2 The prototypical
member of the family, laurencin, was isolated from
Laurencia glandulifera in 1965 and has been the subject
of several successful total syntheses.3,4
ether intermediate. A second total synthesis of laurenyne
has been reported recently by Boeckman and co-work-
ers; in this case, a retro-Claisen rearrangement was
employed to assemble the medium-ring ether core of
the natural product.5b
In our retrosynthetic analysis of laurenyne, we envisaged
initial disconnection by cleavage of the enyne side chain
and replacement of the chlorine substituent with a
masked hydroxyl group (Scheme 1). Disconnection of
the enyne side chain across the alkene revealed the
aldehyde i and the acetylenic Wittig reagent ii as
7
Cl
8
Br
O
O
2
H
H
H
H
OAc
laurencin
Cl
laurenyne
O
H
H
laurenyne
OR
OR
OX
The structure of laurenyne was established by Thomson
and co-workers using X-ray crystallography, and the
absolute configuration was incorrectly assigned to be
2S,7S,8S on the basis of their X-ray data.1 The absolute
configuration was corrected to 2R,7R,8R following the
landmark synthesis of (ꢀ)-laurenyne by Overman and
Thompson in 1988,5a in which an intramolecular
Prins-type reaction was used to construct the key cyclic
O
O
O
H
H
H
H
i
iii
SiR3
SiR3
Ph3P
LnM
PMP
ii
iv
H
H
O
O
O
H
v
Keywords: Marine natural product; Cyclic ether; Ring-closing
metathesis.
H
RO
*
Corresponding author. Tel.: +44 0115 9513542; fax: +44 0115
9513564; e-mail: j.s.clark@nottingham.ac.uk
Scheme 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.160

8640
J. S. Clark et al. / Tetrahedron Letters 45 (2004) 8639–8642
synthetic intermediates, whereas disconnection of the
entire enyne unit suggested the activated alcohol deriva-
tive iii and the vinylic organometallic reagent iv as late
stage intermediates. The first disconnection implies a
Wittig reaction of an aldehyde and the phosphonium
ylide ii late in the synthesis, and is attractive because
both previous syntheses of laurenyne have used this cou-
pling reaction to construct the enyne side chain at a late
stage.5 Disconnection of laurenyne into the intermedi-
ates iii and iv suggests a more adventurous and conver-
gent alternative strategy involving displacement of a
suitable leaving group (e.g., X is a triflate or tosylate)
to install the enyne side chain in a single operation. Both
the eight-membered cyclic ethers i and iii can be discon-
nected to reveal the acyclic diene precursor v by a retro-
synthetic operation that implies ring-closing metathesis
be used for construction of the eight-membered cyclic
ether core of laurenyne. It should be noted that Crim-
mins has used an analogous ring-closing metathesis
reaction for the total synthesis of laurencin and other
Laurencia metabolites.4h,6,7
Scheme 1) required to explore the key ring-closing
metathesis reaction were prepared from the alcohol 1
in just four or five steps using Myers auxiliary method-
ology to control the configuration of the remote stereo-
genic centre (Scheme 2).10 The alcohol
1 was
deprotonated and the resulting alkoxide was alkylated
using methyl bromoacetate in the presence of tetra-n-
butylammonium iodide.10 The chiral auxiliary was then
introduced in high yield by treatment of the methyl ester
with (+)-pseudoephedrine and sodium methoxide. The
resulting amide 2 was deprotonated with LDA in the
presence of lithium chloride and then alkylated with
allyl iodide at 0ꢁC, following the Myers protocol for
related substrates.10 Subsequent reductive removal of
the chiral auxiliary using lithium amidotrihydroborate
delivered the alcohol 3 in excellent yield and NMR analy-
sis confirmed that a single diastereoisomer was present
at this stage.11
The key ring-closing metathesis reaction to give the
eight-membered cyclic ether was then explored. Ring-
closing metathesis of the diene 3 using the Grubbs first
generation ruthenium catalyst 7a (5mol%) delivered
the cyclic ether 6 in 48% yield. Increasing the amount
of catalyst used and adding it to the diene in a por-
tion-wise manner (5 · 2mol%) resulted in an improve-
ment in yield (63%), but prolonged reaction times
(several days) were necessary.12 When the reaction was
performed using the ruthenium catalyst 7b, the yield of
the cyclic ether 6 increased to 75% and the reaction time
was reduced to 1h. To improve the yield of the RCM
reaction further, we protected the free primary hydroxyl
group as its t-butyldiphenylsilyl ether giving the diene 4
in excellent yield. The ring-closing metathesis reaction of
the diene 4 mediated by the Grubbs second generation
ruthenium catalyst 7b proceeded to give the cyclic ether
5 in essentially quantitative yield, and high-yielding
removal of the t-butyldiphenylsilyl group then delivered
the alcohol 6. Thus, the overall yield for the three-step
route to the alcohol 6 from the diene 3 was significantly
higher than the yield obtained by direct RCM of the
diene 3.
Our synthesis of the eight-membered cyclic ether core of
laurenyne commenced with the alcohol 1 (Scheme 2).
We have previously employed the alcohol 1 and homolo-
gous compounds as the key starting materials for the
construction of medium-ring ethers by ring-closing
metathesis during our work concerning the synthesis
of marine polyether toxins.7,8 The alcohol 1 is a versatile
intermediate and can be prepared in three steps and on
large scale from (R)isopropylideneglyceraldehyde.9 The
diene precursors 3 and 4 (analogous to the diene v in
O
Me
H
H
OH
O
Ph
O
H
O
H
N
a, b
Me OH
PMP
PMP
O
O
PMP
PMP
O
O
H
1
H
2
c, d
OTBDPS
OH
H
H
H
H
O
O
O
H
f
O
H
Rapid access to the cyclic ether 6 on multi-gram scale
allowed us to explore side chain functionalisation (Scheme
3). Introduction of the propenyl side chain was investi-
gated first and proved to be more problematic than
anticipated. Oxidation of the free hydroxyl group to give
the required aldehyde was performed using the Parikh–
Doering oxidation protocol.13 At this stage, we expected
to be able to introduce the propenyl side chain using a
Wittig or Julia olefination reaction. However, standard
Wittig or Julia coupling conditions (including the
Kocienski variant)14 either failed to give acceptable
product yields or delivered inseparable mixtures of iso-
meric alkene products with poor selectivity. Ultimately,
we installed the propenyl side chain by first converting
the aldehyde derived from the alcohol 6 into the boronic
ester 8 using the chromium-mediated reaction developed
by Takai et al.15 The crystalline boronic ester 8 was
obtained in excellent yield and with high stereoselectivity
(>10:1) for the E-alkene isomer. Crystals of the boronic
ester 8 suitable for X-ray analysis were obtained upon
H
4
H
3
e
g
OTBDPS
OH
H
H
H
H
O
O
h
O
H
O
H
PMP
O
PMP
O
H
5
H
6
X
Ph
Cl
Cl
X = PCy
7a
7b X =
3
Ru
MesN
NMes
PCy3
Scheme 2. Reagents and conditions: (a) NaH, n-Bu4NI,
BrCH2CO2Me, THF, 0ꢁC ! rt (81%); (b) (+)-pseudoephedrine,
NaOMe, THF, rt (84%); (c) (i) LDA, LiCl, THF, ꢀ78ꢁC, (ii)
CH2CHCH2I, 0ꢁC (75%); (d) LDA, NH3–BH3, THF, 0ꢁC (88%); (e)
7a (5mol%), CH2Cl2, rt (48%)/7a (5 · 2mol%), CH2Cl2, rt (63%)/7b
(5mol%), PhMe, 80ꢁC (75%); (f) t-BuPh2SiCl, imidazole, DMF, rt
(98%); (g) 7b (2mol%), PhMe, 80ꢁC (99%); (h) TBAF, THF, rt (91%).

J. S. Clark et al. / Tetrahedron Letters 45 (2004) 8639–8642
8641
H
H
H
H
H
H
O
O
O
O
B
HO
a
O
OH
H
H
PMBO
PMBO
H
H
O
O
H
O
H
O
H
a, b
11
12
b
PMP
O
PMP
PMP
O
O
H
H
H
6
8
H
H
O
O
O
MeO
PMBO
c
c
H
H
H
H
PMBO
O
O
H
H
TsO
HO
O
H
d, e
14
13
˚
Scheme 4. Reagents and conditions: (a) PCC, NaOAc, 4A sieves,
CH2Cl2, rt (66%); (b) Ph3P+CH2OMeClꢀ, KHMDS, THF, ꢀ78ꢁC
(67%); (c) Hg(OAc)2, THF–H2O, rt (78%).
H
H
10
9
f
H
H
O
HO
PMBO
enol ether 13 as a mixture of E and Z isomers and finally
mercuric acetate mediated hydrolysis to give the alde-
hyde 14 (Scheme 4). The aldehyde 14 can be regarded
as the synthetic equivalent of the intermediate i shown
in the retrosynthetic analysis (Scheme 1).
H
11
Scheme 3. Reagents and conditions: (a) SO3, pyridine, Et3N, DMSO,
rt (81%); (b) Cl2CHB(OCMe2CMe2O), CrCl2, LiI, THF, rt (75%, E:
Z > 10:1); (c) Pd(PPh3)4, K3PO4, MeI, dioxane, 60ꢁC (51%); (d) PPTS,
MeOH, rt (84%); (e) p-MeC6H4SO2Cl, DMAP, Et3N, CH2Cl2, rt
(71%); (f) i-Bu2AlH, CH2Cl2, ꢀ78ꢁC (68%).
In summary, we have prepared advanced intermediates
(10 and 14) for the synthesis of (+)-laurenyne using a
route in which ring-closing metathesis is employed to
construct the eight-membered cyclic ether core in excel-
lent yield. The tosylate 10 and the aldehyde 14 have been
synthesised in a highly stereoselective and concise man-
ner (10 and 12 steps, respectively) from the readily avail-
able alcohol 1. Both late stage intermediates possess the
functionality required for completion of the synthesis of
(+)-laurenyne by installation of the enyne side chain and
chlorination.
recrystallisation and this confirmed its structure and
stereochemistry.16 (Fig. 1) Assembly of the propenyl
side chain was then completed by Suzuki coupling of
the boronic ester 8 and methyl iodide. Although the
yield of the coupled product 9 was modest (ꢁ50%),
the Suzuki reaction delivered a single alkene isomer.17
Further functionalisation of the medium-ring ether core
in preparation for installation of the enyne side chain
was explored (Scheme 3). Acid mediated removal of
the p-methoxybenzylidene acetal and selective conver-
sion of the resulting 1,3-diol into the primary tosylate
delivered the alcohol 10, which would serve as the inter-
mediate iii shown in Scheme 1. Regioselective ring open-
ing of the p-methoxybenzylidene acetal using diisobut-
ylaluminium hydride at ꢀ78ꢁC delivered the alcohol
11 in reasonable yield.18 The alcohol 11 was then sub-
jected to side chain homologation by sequential oxida-
tion to give aldehyde 12, Wittig reaction with
(methoxymethylene)triphenylphosphorane to give the
Acknowledgements
We thank the EPSRC and the University of Nottingham
for financial support.
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