A new, enantioselective synthesis of (+)-isolaurepan

Article abstract of DOI:10.1016/j.tetlet.2009.07.041

A highly enantioselective synthesis of 2,6-syn-disubstituted tetrahydropyrans from commercially available tri-O-acetyl-d-glucal, based on a thermal Claisen rearrangement, allows enantioselective synthesis of (+)-isolaurepan when combined with a ring expan

Full text of DOI:10.1016/j.tetlet.2009.07.041

Tetrahedron Letters 50 (2009) 5285–5287
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new, enantioselective synthesis of (+)-isolaurepan
*
*
Gonzalo Pazos, Manuel Pérez, Zoila Gándara, Generosa Gómez , Yagamare Fall
Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo, 36200 Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective synthesis of 2,6-syn-disubstituted tetrahydropyrans from commercially avail-
able tri-O-acetyl- -glucal, based on a thermal Claisen rearrangement, allows enantioselective synthesis
of (+)-isolaurepan when combined with a ring expansion reaction using trimethylsilyldiazomethane.
Received 2 June 2009
Revised 2 July 2009
Accepted 7 July 2009
Available online 22 July 2009
D
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Marine toxins
Enantioselective synthesis
Claisen rearrangement
26-syn-Disubstituted tetrahydropyrans
Polycyclic ether toxins are potent bioactive agents with skele-
tons consisting of ladder-like chains of fused, mostly 6–9-mem-
bered oxacycles; many are found in marine organisms.1 The
synthesis of these unique structures constitutes a considerable
challenge for organic chemists.2 (+)-Isolaurepinnacin (1)3 and (+)-
neoisoprelaurefucin (2),4 which were both isolated from species
of the genus Laurencia and contain a 2,7-disubstituted oxepane
core (Fig. 1), have received much attention as intermediate syn-
thetic targets. (+)-Isolaurepan (3) is a fully saturated analogue of
1 and of other chiral oxepene and oxepane derivatives.5
Br
H
O
H
H
O
H
Br
Cl
O
(+)-isolaurepinnacin (1)
H
Br
(+)-neoisoprelaurefucin (2)
Several reports of the stereoselective construction of racemic
cis-2,7-disubstituted oxepanes have appeared,2e,6 but very few
syntheses of nonracemic species such as (+)-isolaurepan.7 A gen-
eral strategy for enantioselective functionalisation of the oxepane
ring is lacking.
O
(+)-isolaurepan (3)
Figure 1. Structures of representative Laurencia acetogenin metabolites.
Here we describe the new, enantioselective synthesis of (+)-iso-
laurepan that is outlined retrosynthetically in Scheme 1. We antic-
ipated that the latent allylic alcohol of tri-O-acetyl-D-glucal (6)
would undergo a thermal Claisen rearrangement,8 to 2,6-cis-disub-
stituted tetrahydropyran 5, which would afford oxepane 4 by ring
expansion with trimethylsilyldiazomethane.9 A subsequent Wolf-
Kishner reaction and side chain manipulation would then afford
(+)-isolaurepan (3).
O
3
O
Following the procedure described by Mori and Hayashi,10 com-
pound 7 was prepared in two steps from 611 in 85% yield (Scheme 2).
The preparation of aldehyde 5 from allylic alcohol 7 via ester 8
was at first frustrated by the yield of 8 being only 30% when ob-
OTBDPS
O
4
OAc
O
OAc
OAc
O
Si
O
H
O
O
5
6
* Corresponding authors. Tel.: +34 986 812320; fax: +34 986 81 22 62 (Y.F.).
E-mail addresses: ggomez@uvigo.es (G. Gómez), yagamare@uvigo.es (Y. Fall).
Scheme 1. Retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.041

5286
G. Pazos et al. / Tetrahedron Letters 50 (2009) 5285–5287
OH
t-Bu
t-Bu
(a)
t-Bu
t-Bu
OAc
O
O
O
Si
O
t-Bu
O
OAc
OAc
(a)
Si
O
O
t-Bu
O
H
O
O
7
O
85%
80%
5
11
(b)
(c)
X
99%
6
(b)
30%
OH
t-Bu
O
Si
t-Bu
(c)
O
t-Bu
OTBDPS
OTBDPS
O
Si
O
O
n-Hex
O
t-Bu
t-Bu
t-Bu
O
n-Hex
O
12
O
Si
O
13
Me2N
O
9
92%
EtO
O
80%
O
(d)
8
O
(e)
OTBDPS
OTBDPS
n-Hex
O
4
t-Bu
60%
O
n-Hex
n-Hex
O
14
O
H
Si
O
t-Bu
(f)
O
58%
5
(g)
Scheme 2. Reagents and conditions: (a) (i) K2CO3, MeOH; (ii) t-Bu2Si(OTf)2, DMF,
Pyr; (b) MeC(OMe)3, TMBA, 160 °C; (c) MeC(OMe)2NMe2, toluene, 120 °C.
OH
O
16
n-Hex
O
15
95%
(h)
76%
tained by acid-catalysed orthoester Claisen rearrangement.12 The
Eschenmoser [3,3]-sigmatropic rearrangement of alcohol 7 to
amide 913 was also unsuccessful.
As the Johnson orthoester rearrangement and the Eschenmoser
variant involve the in situ generation of an allyl vinyl ether, we
decided to change our strategy and use the classical Claisen rear-
rangement following preparation of allyl vinyl ether 10 (Scheme 3).
Thorough investigation of the latter step showed that reaction
(i)
TMS
n-Hex
O
n-Hex
O
17
3
79%
Scheme 4. Reagents and conditions: (a) n-BuPPh3Br, n-BuLi, THF, 0 °C; (b) H2, Pd/C
(10%), MeOH; (c) (i) TBAF, THF, rt; (ii) TBDPSCl, imidazole, DMAP, DMF; (d) TPAP,
NMO, CH2Cl2, molecular sieves; (e) (i) TMSCHN2, BF3ÁOEt2, CH2Cl2, À78 °C; (ii) PPTS,
MeOH; (f) (i) NH2NHTs, MeOH, 70 °C, molecular sieves; (ii) NaBH3CN, DMF, 130 °C;
(g) TBAF, THF; (h) (i) Tf2O, CH2Cl2, pyridine, À15 °C; (ii) TMSCCH, n-BuLi, THF/
DMPU, 0 °C; (i) (i) TBAF, THF; (ii) H2, Pd/C(10%), MeOH.
of allylic alcohol 7 with ethyl vinyl ether could give enolether 10
14
in 80% and 72% yields when catalysed by Hg(OAc)2
and
Pd(OAc)2,15 respectively.
Following purification by column chromatography, compound
10 underwent a Claisen rearrangement when heated in toluene
at 185 °C, giving aldehyde 5 in 95% yield. The stereochemistry of
5 was determined by NOE experiments.
With aldehyde 5 in hand, we addressed the transformation of
its side chains and the expansion of its ring (Scheme 4).
Wittig reaction of 5 afforded an 80% yield of diene 11, which
upon hydrogenation on Pd/C gave 12 in nearly quantitative yield.
Removal of the silyl protecting group of 12, followed by selective
protection of the primary alcohol of the resulting diol, then pro-
vided alcohol 13, which was converted into ketone 14 in 80% yield.
The crucial oxepane formation was accomplished by reaction of 14
with trimethylsilyldiazomethane in the presence of BF3OEt2 in
CH2Cl2 at À78 °C, which gave the seven-membered ketone 4 in
60% yield along with an 8% yield of its isomeric ketone after acidic
hydrolysis of the intermediary trimethylsilyl enol ether. Wolf-
Kishner reaction of 4 then afforded oxepane 15 in 58% yield,16
and removal of the silyl protecting group of 15 with TBAF gave
the known alcohol 16,7a,c which was transformed into alkyne 17
by alkylation of the corresponding triflate. Finally, alkyne 17 was
uneventfully converted into the target (+)-isolaurepan 3 in 79%
yield. All attempts to obtain 3 directly from alcohol 16 by the
method described in the literature7a were unsuccessful.
In conclusion, we have achieved a new and enantioselective
synthesis of (+)-isolaurepan. Furthermore, intermediate 5 is a valu-
able building block. It will allow us not only to synthesise (À)-iso-
laurepan, the enantiomer of 3, by sequential side chain
modification, but also to extend our work on racemic polyoxacyclic
compounds17 to the enantioselective synthesis of polyoxacycles
with trans–cis–trans stereochemistry. These developments are
currently underway in our laboratories.
Acknowledgements
This work was financially supported by the Spanish Ministry of
Education and Science (CTQ2007-61788) and the Xunta de Galicia
(INCITE08PXIB314253PR, INCITE08ENA314019ES and INCITE08P-
XIB314255PR). The work of the NMR and MS divisions of the
research support services of the University of Vigo (CACTI) is also
gratefully acknowledged.
(a)
OH
O
t-Bu
O
t-Bu
t-Bu
80%
O
Si
O
Si
O
t-Bu
O
7
O
(b)
10
72%
(c)
Supplementary data
95%
t-Bu
t-Bu
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.041.
O
O
Si
O
H
O
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vinyl ether, Pd(OAc)2, bipyridine, CF3CO2H, Et3N, 80 °C; (c) toluene, 185 °C, 5 h.

G. Pazos et al. / Tetrahedron Letters 50 (2009) 5285–5287
5287
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