The first total synthesis of (+)-(Z)-laureatin

Article abstract of DOI:10.1016/j.tetlet.2006.12.082

The stereoselective total synthesis of (+)-(Z)-laureatin is described. The 3,8-dioxabicyclo[5.1.1]nonane skeleton possessing trans-orientated alkyl substituents at the α,α′-positions to the ether linkage was stereoselectively constructed via formation of

Full text of DOI:10.1016/j.tetlet.2006.12.082

Tetrahedron Letters 48 (2007) 1109–1112
The first total synthesis of (+)-(Z)-laureatin
Masashi Sugimoto,a Toshio Suzuki,b,* Hisahiro Hagiwaraa and Takashi Hoshib
aGraduate School of Science and Technology, Niigata University, 2-Nocho, Ikarashi, Niigata 950-2181, Japan
bFaculty of Engineering, Niigata University, 2-Nocho, Ikarashi, Niigata 950-2181, Japan
Received 26 October 2006; revised 11 December 2006; accepted 14 December 2006
Available online 8 January 2007
Abstract—The stereoselective total synthesis of (+)-(Z)-laureatin is described. The 3,8-dioxabicyclo[5.1.1]nonane skeleton possess-
ing trans-orientated alkyl substituents at the a,a0-positions to the ether linkage was stereoselectively constructed via formation of the
oxetane arising from 4-exo cyclization of hydroxy epoxide existing on the oxocene core.
Ó 2006 Elsevier Ltd. All rights reserved.
Red algae of the genus Laurencia produce a wide variety
of medium-sized cyclic ethers as distinctive members of
marine natural products.1 Among them, eight-mem-
bered cyclic ethers are abundant constituents, and are
divided into two subclasses, the lauthisan type and the
laurenan type, in view of the structural features arising
from the biogenetic pathway.2 Much synthetic effort
has been directed toward these compounds. As a result,
several successful total syntheses of the lauthisan struc-
tural class exemplified by (+)-laurencin have been
reported so far.3 In contrast, there have been few
reports4,5 on synthetic studies of the laurenan com-
pounds, such as (+)-prelaureatin (1),6 (+)-laurallene
(2),7 (+)-(Z)-laureatin (3),8 (+)-(Z)-isolaureatin (4),8
and geometric isomers regarding the enyne moieties of
(+)-3 and (+)-4 (Fig. 1).9 This is due to certain problems
incurred in assembling eight-membered cyclic ether sys-
tems as well as the stereoselective introduction of alkyl
substituents into the a- and a0-positions of a cyclic ether
with trans-orientation. Particularly in the synthesis of
bicyclic compounds such as (+)-2, (+)-(Z)-3, and (+)-
(Z)-4, a crucial problem, regio- and stereocontrolled
construction of bicyclic skeletons is included.
OH
O
H
Br
H
C
O
H
O
H
H
H
H
Br
Br
(+)-prelaureatin (1)
(+)-laurallene (2)
Br
Br
O
O
O
H
O
H
Br
H
Br
H
(+)-(Z)-isolaureatin (4)
(+)-(Z)-laureatin (3)
Figure 1.
converted to bicyclic compounds, (+)-laurallene (2),
(+)-(Z)-laureatin (3), (+)-(Z)-isolaureatin (4) and their
geometric isomers, via the subsequent bromo-cationic
cyclization.2 According to the biogenetic pathway, we
accomplished the total synthesis of (+)-2 via a two-step
cyclization sequence (Scheme 1).4a The a,a0-trans-oxo-
cene core 6, structural equivalent of (+)-1, was stereo-
selectively constructed via 8-exo cyclization of hydroxy
epoxide 5 promoted by Eu(fod)3,5a and the subsequent
5-exo cyclization between the C7 hydroxy group and
the epoxide installed on the alkyl substituent provided
the dioxabicyclic skeleton of (+)-2. In this Letter, we
examined the availability of the synthetic strategy to-
ward other bicyclic laurenan compounds, (+)-(Z)-3
and (+)-(Z)-4 via the a,a0-trans-oxocene core 6 along
the biogenetic pathway. For the successful synthesis of
Intensive biogenetic studies by the Ishihara and Murai
group led to a proposal of the biogenetic pathway of
laurenan compounds; the bromo-cationic cyclization
of an acyclic precursor, (6S,7S)-laurediol, affords (+)-
prelaureatin (1) and its geometric isomer which were
Keywords: (+)-Laureatin; Oxocenes; Medium-ring heterocycles; Cycli-
zation; Hydroxy epoxides.
*
Corresponding author. Tel./fax: +81 25 262 6780; e-mail: suzuki@
eng.niigata-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.082

1110
M. Sugimoto et al. / Tetrahedron Letters 48 (2007) 1109–1112
OBn
O
MPMO
OTBDPS
OH
5
Eu(fod)3
8-exo
ref. 4(a)
OBn
O
H
Br
H
7
5-exo
OTBDPS
C
O
H
O
H
H
H
ref. 4(a)
H
Br
HO
6
(+)-laurallene (2)
5-endo
4-exo
Br
Br
Br
O
O
O
H
H
O
H
H
Br
(+)-(Z)-laureatin (3)
(+)-(Z)-isolaureatin (4)
Scheme 1.
them, a crucial problem, regio- and stereocontrolled
conversion of 6 to bicyclic skeletons, must be resolved.
bromo-cationic cyclization analogously to the biogenetic
pathway (Scheme 2). The requisite intermediate 7 was
derived from 6 through bromination of a hydroxy group
followed by deprotection of a benzyl group. Treatment
In an initial attempt, we examined the conversion of
oxocene 6 to bicyclic skeleton(s) 9 and/or 10 via the
of
7
with 2,4,6,6-tetrabromo-2,5-cyclohexadienone
OBn
OH
a,b
OTBDPS
OTBDPS
O
H
O
H
H
HO
Br
H
6
7
TBCO
or
NBS
H
Br
H
H
H
Br
Br
O H
H
R2
O
OTBDPS
H
O
B
R1
Br+
O
O
H
H
H
path C
5.4%
H
Br
H
OTBDPS
path A
and/or B
C
H
H
H
O
9
H
11
H
A
and/or
8
Br
1.8%
H
4.7%
O
NOEs
O
H
Br
OTBDPS
H
O
H
Br
H
OTBDPS
O
H
H
10
Br
12
Scheme 2. Reagents and conditions: (a) P(oct)3, CBr4, 1-methyl-1-cyclohexene, Py, toluene, 70 °C, 90%; (b) DDQ, pH = 7.5 buffer, CH2ClCH2Cl,
35 °C, 62%.

M. Sugimoto et al. / Tetrahedron Letters 48 (2007) 1109–1112
1111
OR
OTBDPS
a
6
O
H
H
SEMO
13 : R = Bn
14 : R = H
b
c
O
HO
OH
H
10
d
O
OR
OTBDPS
12 O
H
NOE
O
H
H
H
SEMO
SEMO
16 : R = H
17 : R = Piv
15
e
Scheme 3. Reagents and conditions: (a) SEMCl, i-Pr2NEt, n-Bu4NI, CH2ClCH2Cl, 94%; (b) DDQ, pH = 7.46 buffer, CH2ClCH2Cl, 45 °C, 85%; (c)
MCPBA, CH2Cl2, 0 °C to rt, 96%; (d) aq KOH, DMSO, 80 °C, 97%; (e) PivCl, TEA, CH2Cl2, 80%.
(TBCO) or NBS provided no trace of 4-exo and/or 5-
endo cyclized product(s) 9 and/or 10. In these reactions,
the tetrahydrofuran derivative 12 was mainly obtained.
The stereochemistries on the tetrahydrofuran ring were
determined by NOE correlations. Conformation analy-
sis of 7 by MM2 calculation predicted to generate b-bro-
monium ion 8 in the conformation as shown in Scheme
1. Transannular attack of the etherial oxygen via path C
prior to attack of the hydroxy group via path A and/or
B followed by pinacol-type rearrangement of the resul-
tant oxonium ion 11 would result in the formation of 12.
AcO
10
a,b
O
OPiv
17
O
H
H
SEMO
18
c,d
HO
Br
Br
e
O
O
OPiv
OPiv
O
O
H
H
H
The entirely unexpected result led our turning attention
to the approach including cyclization of hydroxy epox-
ide (Scheme 3). Epoxidation of SEM ether 13, derived
from 6, was expected to proceed mainly from b-phase
in the conformation analogous to that of 8 described
above. Actually, treatment of 13 with MCPBA provided
b-epoxide along with its a-isomer with a ratio of 80:20 in
a combined yield of 97%. When 14, obtained by depro-
tection of the benzyl group in 13, was used for the epox-
idation substrate, the b-selectivity was interestingly
improved up to 96% and the desired epoxide 15 was
obtained in an isolated yield of 96%. It was presumably
due not to a directive effect of the hydroxy group but
a slight change of the conformation. The stereochemis-
try of epoxide 15 was confirmed by an NOE correlation
between C10–H and C12–H. With the key intermediate
15 in hand, we examined cyclization reaction toward the
laureatin and/or isolaureatin bicyclic skeleton(s). Treat-
ment of 15 with several Lewis acids (e.g., Zn(OTf)2; Eu-
(fod)3) gave a complex mixture, whereas exposure to
aqueous KOH in DMSO10 resulted in regioselective 4-
exo cyclization to provide the laureatin bicyclic system
16 in 97% yield along with simultaneous deprotection
of the TBDPS group. In the reaction, formation of the
isolaureatin bicyclic system arising from the alternative
5-endo cyclization was not detected. Protection of the
resulting hydroxy group as its pivaloyl ester afforded
17 in 80% yield.
HO
H
19
20
f,g,h,i,j
Br
Br
O
H
k
(+)-(Z)-3
O
H
TBS
21
Scheme 4. Reagents and conditions: (a) MsCl, TEA, DMAP, CH2Cl2,
100%; (b) CsOAc, 18-crown-6, xylene, 110 °C, 88%; (c) guanidine,
EtOH–CH2Cl2 (5:1), 92%; (d) MeSTMS, ZnI2, n-Bu4NI,
CH2ClCH2Cl, 0 °C, 99%; (e) P(oct)3, CBr4, TEA, toluene, 80 °C,
82%; (f) DIBAL, toluene, ꢀ78 °C to ꢀ30 °C, 96%; (g) Dess–Martin
periodinane, CH2Cl2, 93%; (h) HMPT, CBr4, THF, 0 °C, 93%; (i)
Bu3SnH, Pd(PPh3)4, benzene, 82%; (j) (t-butyldimethylsilyl)acetylene,
Pd(PPh3)4, CuI, i-Pr2NH, benzene, 90%; (k) TBAF, THF, 93%.
next task was the stereoselective introduction of the bro-
mine moiety at the C10 position. Although the direct
bromination of 17 using SO2Br2 in CH2Cl211 with reten-
tion of configuration was unsuccessful, the targeted
reaction was realized via the following stepwise process.
Namely, mesylation of 17 (100%) followed by treatment
with CsOAc and 18-crown-6 in toluene12 provided
acetate 18 in 88% yield with complete inversion.
After deprotection of the acetyl and SEM groups, the
With 17 successfully in hand, our attention was focused
on the synthesis of (+)-(Z)-laureatin (3) (Scheme 4). The

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M. Sugimoto et al. / Tetrahedron Letters 48 (2007) 1109–1112
Topics in Heterocyclic Chemistry; Kiyota, H., Ed.;
Springer: Berlin, 2006; Vol. 5, pp 97–148; Total synthesis
of (+)-laurencin: (b) Fujiwara, K.; Yoshimoto, S.; Taki-
zawa, A.; Souma, S.; Mishima, H.; Murai, A.; Kawai, H.;
Suzuki, T. Tetrahedron Lett. 2005, 46, 6819–6822; (c)
Baek, S.; Jo, H.; Kim, H.; Kim, H.; Kim, S.; Kim, D. Org.
Lett. 2005, 7, 75–77; (d) Crimmins, M. T.; Choy, A. L. J.
resulting two hydroxy groups were simultaneously bro-
minated via the SN2 process under Murai’s conditions13
to afford dibromide 20 in high yield.
With 20 in hand, the stage was set for the installation of
the Z-enyne moiety. The pivaloyl group in 20 was reduc-
tively deprotected (96%), and the resulting alcohol was
converted by the following sequence similar to that
reported by the Murai group:14 (i) oxidation with Dess–
Martin periodinane (93%), (ii) treatment with CBr4 and
HMPT in THF (93%),15 (iii) stereoselective hydrogenol-
ysis of 1,1-dibromoalkene by Uenishi’s method (82%),16
(iv) Sonogashira coupling of the resulting Z-1-bromo-
alkene with (t-butyldimethylsilyl)acetylene (90%).17 Finally,
deprotection of the TBS group in 21 led to the comple-
tion of (+)-(Z)-laureatin (3). The optical rotation of syn-
thetic (+)-(Z)-3 ½½aꢁ2D0 +103 (c 0.35, CCl4)] coincided with
that of the natural product [[a]D +96 (c 2.00, CCl4)].8
The comparison of the spectral data of synthetic (+)-
(Z)-3 (1H, 13C NMR,18 and IR) with those of the natural
product revealed that they were identical.
Am. Chem. Soc. 1999, 121, 5653–5660; (e) Kruger, J.;
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Hoffmann, R. W. J. Am. Chem. Soc. 1997, 119, 7499–
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4. (a) Saitou, T.; Suzuki, T.; Sugimoto, M.; Hagiwara, H.;
Hoshi, T. Tetrahedron Lett. 2003, 44, 3175–3178; (b)
Fujiwara, K.; Souma, S.; Mishima, H.; Murai, A. Synlett
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5. For the selective synthesis of a,a0-trans-8-membered cyclic
ethers, see: (a) Saitou, T.; Suzuki, T.; Onodera, N.;
Sekiguchi, H.; Hagiwara, H.; Hoshi, T. Tetrahedron Lett.
2003, 44, 2709–2712; (b) Mujica, M. T.; Afonso, M. M.;
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1991, 32, 5597–5598.
7. Fukuzawa, A.; Kurosawa, E. Tetrahedron Lett. 1979,
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In conclusion, the first total synthesis of (+)-(Z)-laurea-
tin (3) was accomplished with high stereoselectivity.
Although the bromo-cationic cyclization of the oxocene
derivative 7 according to the biogenetic pathway for the
stereoselective construction of the bicyclic skeleton gave
unsuccessful result, the purpose was indigenously
achieved via a sequence of stereoselective epoxidation
of 14 followed by regioselective 4-exo cyclization.
8. (a) Irie, T.; Izawa, M.; Kurosawa, E. Tetrahedron 1970,
26, 851–870; (b) Izawa, M.; Kurosawa, E. Tetrahedron
Lett. 1968, 2735–2738; (c) Irie, T.; Izawa, M.; Kurosawa,
E. Tetrahedron Lett. 1968, 2091–2096.
Acknowledgments
9. Suzuki, M.; Kurosawa, E. Bull. Chem. Soc. Jpn. 1987, 60,
3791–3792.
10. Murai, A.; Ono, M.; Masamune, T. Bull. Chem. Soc. Jpn.
1977, 50, 1226–1231.
We thank Professor J. Ishihara (University of Nagasaki)
and Professor T. Suzuki (Hokkaido University of Edu-
1
cation) for providing us H and 13C NMR spectra of
natural (+)-(Z)-3, respectively. This work was partially
supported by Grant-in-Aid for Scientific Research on
Priority Area (18032031 for H.H.) from The Ministry
of Education, Culture, Sports, Science and Technology
(MEXT).
11. Chlorination with retention of configuration using SO2Cl2
was reported. See: Kozikowski, A. P.; Lee, J. Tetrahedron
Lett. 1988, 29, 3053–3056.
12. Torisawa, Y.; Okabe, H.; Ikegami, S. Chem. Lett. 1984,
1555–1556.
13. Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33,
4345–4348.
References and notes
14. Fujiwara, K.; Akakura, D.; Tsunashima, M.; Nakamura,
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1. For reviews, see: (a) Moore, R. E. In Marine Natural
Products; Scheuer, P. J., Ed.; Academic Press: New York,
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New York, 1983; Vol. 5, pp 131–257; (c) Faulkner, D. J.
Nat. Prod. Rep. 2001, 18, 1–49, see also his previous
reviews in Nat. Prod. Rep.
18. In the 13C NMR spectrum, the C6 signal of the natural
product was reported to appear at 75.7 ppm (see Ref. 9),
whereas the corresponding signal was observed at
77.6 ppm in that provided by Professor Suzuki as the
natural product data. Including this signal, the 13C
spectral data of synthetic sample was identical with that
provided by Professor Suzuki.
2. (a) Ishihara, J.; Shimada, Y.; Kanoh, N.; Takasugi, Y.;
Fukuzawa, A.; Murai, A. Tetrahedron 1997, 53, 8371–
8382; (b) Ishihara, J.; Kanoh, N.; Murai, A. Tetrahedron
Lett. 1995, 36, 737–740; (c) Fukuzawa, A.; Takasugi, Y.;
Murai, A. Tetrahedron Lett. 1991, 32, 5597–5598.
3. For a review on the total synthesis of medium-sized cyclic
ethers from Lurencia red algae, see: (a) Fujiwara, K. In