Synthesis of (+)-laurencin via ring expansion of a C-glycoside derivative

Article abstract of DOI:10.1016/j.tetlet.2005.08.024

Laurencin was efficiently synthesized from a C-glycoside derivative based on ring expansion of the oxane part of the starting compound into an eight-membered cyclic ether via a ring-cleavage/ring-closing olefin metathesis process, stereoselective introduc

Full text of DOI:10.1016/j.tetlet.2005.08.024

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6819–6822
Synthesis of (+)-laurencin via ring expansion of a
C-glycoside derivative
Kenshu Fujiwara,* Saori Yoshimoto, Ayumi Takizawa, Shin-ichiro Souma,
Hirofumi Mishima, Akio Murai, Hidetoshi Kawai and Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 27 July 2005; revised 3 August 2005; accepted 4 August 2005
Abstract—Laurencin was efficiently synthesized from a C-glycoside derivative based on ring expansion of the oxane part of the start-
ing compound into an eight-membered cyclic ether via a ring-cleavage/ring-closing olefin metathesis process, stereoselective intro-
duction of a bromo group at C4, and convergent construction of the side-chain part using a lithiated enyne unit.
Ó 2005 Elsevier Ltd. All rights reserved.
The lauthisan1 and trans-laurenan2 families of bromo-
ether compounds, represented by (+)-laurencin (1)3 and
(+)-prelaureatin (2),4 respectively, were isolated from
some local species of the red algae Laurencia5 in the sea
around the Japanese islands and were hypothesized to
be biosynthesized from a common precursor, laurediol.6
The hypothesis has inspired us to design a divergent
chemical synthesis of 1 and 2 from common C-glycoside
substrate 3 by ring expansion of the oxane part of 3 into
eight-membered ring systems corresponding to 1 and 2
through a common ring-cleavage/ring-closing olefin
metathesis (RCM)7 process (Scheme 1).8 Although quite
many synthetic approaches to lauthisan and trans-laure-
nan natural compounds and several total syntheses were
reported so far,9,10 there were only a few synthetic meth-
ods appropriate for both of them.9i–l,10a,c,11 Recently, we
have synthesized 2 through a route involving site-selec-
tive RCM reaction of triene 4 according to our sche-
me.10b Here, the successful synthesis of 1 from 3, the
other goal of our divergent plan, based on the RCM reac-
tion of 5 and convergent construction of the C10–C15
side-chain part using a lithiated enyne unit is described.
First, the ethyl side-chain part of 1 was constructed at the
initial stage (Scheme 2). The substrate 3, prepared from b-
D-galactose pentaacetate (6) according to our previously
reported procedure,10b was transformed into 8 (overall
81%) by a two-step process [(i) protection with PMBBr
and (ii) removal of the TBDPS group]. Alcohol 8 was con-
verted to 10 via triflate 9 by the Kotsuki procedure (over-
all 95%),12 thereby providing the ethyl side-chain part.
Then, an eight-membered ring ether 14 was synthesized
by ring expansion of 10 via a ring-cleavage/RCM
Ring-Closing
Olefin Metathesis
Previous Work
Ring-Cleavage
OTBDPS
This Work
Ring-Closing Olefin
Metathesis
H
H
TBSO
Br
OH
O
H
H
9
H
H
Me
O
3
11
9
O
4
4
4
Br
O
H
O
3
O
H
3
Br
HO
H
Br
OAc
Me
H
15
O
OH
O
Me
Me
1
15
Me
O
Br
Me
Me
1
Laurencin (1)
Scheme 1.
5
3
4
Prelaureatin (2)
Me
Keywords: Marine natural product; Total synthesis; Medium-ring ether; Ring-closing olefin metathesis; (+)-Laurencin.
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706 4924; e-mail: fjwkn@sci.hokudai.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.024

6820
K. Fujiwara et al. / Tetrahedron Letters 46 (2005) 6819–6822
OR2
O
Me
Me
HO
Me
Me
OAc
H
H
H
H
H
H
O
O
O
O
O
O
O
OAc
OAc
O
ref. 10b
e, f
g
h
d
3
3
OHC
OR1
OPMB
OPMB
O
HO
AcO
O
O
O
OH
11
O
OAc
Me
Me
Me
Me
Me
Me
Me
12
Me
6
3: R1=H, R2=TBDPS
10
13
a
b
c
7: R1=PMB, R2=TBDPS
8: R1=PMB, R2=H
i
9: R1=PMB, R2=Tf
Me
H
H
O
m
l
k
j
3
4
4
4
4
4
Br
HO
O
HO
O
O
O
O
O
H
O
O
O
H
O
H
O
H
H
HO
O
O
O
Me
Me
Me
Me
O
Me
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
17
16
15
14
5
n
p
s
q
11
11
1
Br
Br
Me
Br
OR
Bu3Sn
O
O
O
H
H
H
O
OH
OR1
R2
Me
Me
H
H
H
21
TMS
18: R=H
19: R=Tf
20
22: R1=H, R2=TMS
23: R1=R2=H
o
r
Scheme 2. Reagents and conditions: (a) NaH, PMBBr, Bu4NI, THF, 23 °C, 1.5 h, 88%; (b) Bu4NF, THF, 25 °C, 3.5 h, 92%; (c) Tf2O, 2,6-lutidine,
CH2Cl2, 0 °C, 10 min; (d) MeMgBr, CuI (cat.), THF–Et2O, 4 °C, 38 h, 95% from 8; (e) 2 M HCl aq–THF (1:1), 22 °C, 9 h, 100%; (f) NaIO4,
t-BuOH–pH 7 buffer (3:1), 0 °C, 3 h, then NaBH4, MeOH, 0 °C, 15 min, 100%; (g) DDQ, CH2Cl2, 26 °C, 15 min, then TsOH–H2O, acetone, 26 °C,
1 h; 79%; (h) (COCl)2, DMSO, CH2Cl2, ꢀ78 °C, 15 min, then Et3N, ꢀ78 to 0 °C, 15 min; (i) CH2@CHCH2MgCl, THF, ꢀ78 °C, 15 min, 100% from
12; (j) (H2IMes)(PCy3)Cl2RuCHPh (0.1 equiv), CH2Cl2, reflux, 45 min, 81%; (k) (COCl)2, DMSO, CH2Cl2, ꢀ78 °C, 15 min, then Et3N, ꢀ78 to 0 °C,
10 min, 90%; (l) LS-SelectrideÒ, THF, ꢀ78 °C, 10 min, 16: 91%, 4-epi-16: 5%; (m) Ph3P, CBr4, toluene, 70 °C, 1.5 h, 90%; (n) HS(CH2)2SH, Zn(OTf)2,
NaHCO3, CH2Cl2, 0 °C, 1 h, 86%; (o) Tf2O, 2,6-lutidine, CH2Cl2, ꢀ78 °C, 10 min; (p) K2CO3, MeOH, 23 °C, 30 min, 94% from 18; (q) 21, BuLi, THF,
ꢀ30 °C, 1 h, then 20, then Et2OÆBF3, ꢀ30 °C, 30 min, 73%; (r) Bu4NF, THF, 23 °C, 5 min, 87%; (s) AcCl, pyridine, CH2Cl2, 0 °C, 1 h, 87%.
process. After acidic hydrolysis of 10 (100%), the result-
ing diol was cleaved with NaIO4 into a dialdehyde, which
was immediately reduced by one-pot treatment with
NaBH4 to give 11 (100%). Although the reaction of 11
with DDQ under anhydrous conditions afforded a
p-methoxybenzylidene acetal, it was so unstable as to
decompose gradually during purification and could not
be used for further synthesis. Therefore, 11 was
converted to 12 by the reaction with DDQ and the sub-
sequent one-pot acetal exchange reaction (79%). While
alcohol 12 could be facilely oxidized to aldehyde 13,
rapid epimerization at C3 of 13 was observed during
the work-up and purification. After several attempts,
we found that one-pot treatment of the reaction solution
obtained just after Swern oxidation13 of 12 with large
excess of allyl magnesium chloride provided 5 in excel-
lent yield (overall 100%) without epimerization at C3
though it was given as a 1:1 mixture of diastereomers
at C4.14 The diene 5 was cyclized with second-generation
Grubbsꢀ catalyst15 into 14 in good yield (81%). Thus, the
eight-membered ring ether part of 1 was successfully
constructed.
for the side-chain construction. Deprotection18 of 17
(86%) followed by regioselective formation of triflate
19 and the subsequent basic treatment afforded epoxide
20 (94% for two steps). After treatment of 2119 with
BuLi, the resulting E-1-lithio-4-(trimethylsilyl)but-1-en-
3-yne was treated first with 20 and then with Et2OÆBF3
at ꢀ30 °C to provide 22 (73%),20,21 which was trans-
formed into 1 through a two-step desilylation/acetyla-
tion process (76% for two steps). The spectral data
(1H and 13C NMR as well as IR) and optical rotation
23
27
{½aꢁD +69.6 (c 0.093, CHCl3); Lit.3b: ½aꢁD +70.2 (c
1.0, CHCl3)} of the resulting 1 agreed well with those
of the literature.3 Thus, the synthesis of 1 was achieved
in 16% overall yield for total 21 steps including three
one-pot, two-step processes from 3.
In conclusion, laurencin (1) was efficiently synthesized
from C-galactoside derivative 3, the common substrate
of our previous synthesis of prelaureatin (2), based
on ring expansion of 3 into eight-membered ring ether
14 via a ring-cleavage/RCM process, stereoselective
introduction of a bromo group at C4, and coupling
reaction of epoxide 20 with a lithiated enyne unit,
thereby achieving the divergent synthesis of 1 and 2
from 3.
Next, stereoselective bromination at C4 was performed.
Oxidation of 14 followed by reduction with LS-Select-
rideÒ selectively gave 16 (91%),16 which was treated with
Ph3P and CBr4 in toluene at 70 °C to produce 17 (90%)
with complete inversion of configuration at C4.17
Acknowledgements
At the last stage of the synthesis, a convergent method
using a lithiated enyne unit was efficiently employed
We thank Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC–MS and NMR Laboratory, Graduate School of

K. Fujiwara et al. / Tetrahedron Letters 46 (2005) 6819–6822
6821
1999, 1, 2029; (m) Kadota, I.; Uyehara, H.; Yamamoto,
Y. Tetrahedron 2004, 60, 7361; (n) Baek, S.; Jo, H.;
Kim, H.; Kim, H.; Kim, S.; Kim, D. Org. Lett. 2005, 7,
75.
Agriculture, Hokkaido University) for the measure-
ments of mass spectra. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology
of Japanese Government.
10. For the syntheses of prelaureatin and laurallene, see: (a)
Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000,
122, 5473; (b) Fujiwara, K.; Souma, S.; Mishima, H.;
Murai, A. Synlett 2002, 1493; (c) Saitoh, T.; Suzuki, T.;
Sugimoto, M.; Hagiwara, H.; Hoshi, T. Tetrahedron Lett.
2003, 44, 3175; See, also: (d) Edwards, S. D.; Lewis, T.;
Taylor, R. J. K. Tetrahedron Lett. 1999, 4267.
11. Stereoselective syntheses of 2,8-cis and 2,8-trans eight-
membered cyclic ethers: (a) Kotsuki, H.; Ushio, Y.;
Kadota, I.; Ochi, M. J. Org. Chem. 1989, 54, 5153; (b)
Hoffmann, H. M. R.; Brandes, A. Tetrahedron 1995, 51,
155.
12. Here, CuI was employed instead of CuBr, used in the
original procedure. Original reports: (a) Kotsuki, H.;
Kadota, I.; Ochi, M. Tetrahedron Lett. 1989, 30, 1281; (b)
Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1989,
30, 3999.
References and notes
1. The lauthisan compounds have a common cis-2-ethyl-8-
hexyloxocane skeleton: (a) Blunt, J. W.; Lake, R. J.;
Munro, M. H. G.; Yorke, S. C. Aust. J. Chem. 1981, 34,
2393; (b) Blunt, J. W.; Lake, R. J.; Munro, M. Aust. J.
Chem. 1984, 37, 1545.
2. The trivial name laurenan describes the basic skeleton of
laurenyne. See: (a) Carling, R. W.; Clark, S. J.; Holmes, A.
B. J. Chem. Soc., Chem. Commun. 1986, 565. Although the
original laurenan was designated for cis-2-pentyl-8-prop-
yloxocane by Holmes, the name was also used for
describing prelaureatin-type compounds that have a com-
mon trans-2-pentyl-8-propyloxocane skeleton by Murai.
See: (b) Ishihara, J.; Kanoh, N.; Fukuzawa, A.; Murai, A.
Chem. Lett. 1994, 1563. For clarity, ꢁtrans-laurenanꢀ is
adopted here to explain the prelaureatin skeleton.
3. (a) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett.
1965, 1091; (b) Irie, T.; Suzuki, M.; Masamune, T.
Tetrahedron 1968, 24, 4193; (c) Cameron, A. F.; Cheung,
K. K.; Ferguson, G.; Robertson, J. M. J. Chem. Soc. B
1969, 559; (d) Cameron, A. F.; Cheung, K. K.; Ferguson,
G.; Robertson, J. M. J. Chem. Soc., Chem. Commun. 1965,
638.
4. (a) Fukuzawa, A.; Takasugi, Y.; Murai, A. Tetrahedron
Lett. 1991, 32, 5597; (b) Fukuzawa, A.; Takasugi, Y.;
Murai, A.; Nakamura, M.; Tamura, M. Tetrahedron Lett.
1992, 33, 2017.
5. For a review: Erickson, K. L. In Marine Natural Products,
Chemical and Biological Perspectives; Scheuer, P. J., Ed.;
Academic Press: New York, 1983; Vol. 5, p 131.
13. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2048.
14. The C4-diastereomers of 5 could be separated facilely by
flash silica gel column chromatography (hexane/
AcOEt = 12:7), and no C3-epimers were observed. 1H
NMR data of the less polar C4-diastereomer of 5:
(300 MHz, CDCl3) d 0.94 (3H, t, J = 7.3 Hz), 1.35 (3H,
s), 1.39–1.63 (2H, m), 1.42 (3H, s), 2.04–2.37 (4H, m), 2.26
(1H, d, J = 3.7 Hz), 3.44 (1H, br-ddd, J = 3.3, 4.0,
8.1 Hz), 3.56 (1H, ddd, J = 3.3, 6.6, 8.8 Hz), 3.72–3.79
(1H, m), 3.77 (1H, dd, J = 6.6, 8.3 Hz), 3.99 (1H, dd,
J = 6.6, 8.3 Hz), 4.12 (1H, q, J = 6.6 Hz), 5.07–5.20 (4H,
m), 5.77–5.95 (2H, m); 1H NMR data of the polar C4-
diastereomer of 5: (300 MHz, CDCl3) d 0.92 (3H, t,
J = 7.4 Hz), 1.35 (3H, s), 1.38–1.73 (2H, m), 1.42 (3H, s),
2.13–2.41 (4H, m), 2.48 (1H, d, J = 4.6 Hz), 3.38 (1H, q,
J = 5.4 Hz), 3.54–3.66 (2H, m), 3.75 (1H, dd, J = 6.6,
8.3 Hz), 3.99 (1H, dd, J = 6.6, 8.3 Hz), 4.12 (1H, q,
J = 6.6 Hz), 5.01–5.12 (4H, m), 5.81–5.95 (2H, m). For
convenience, the diene 5 was used without diastereomer
separation for the next RCM step, where the product 14
also displayed a 1:1 diastereomer ratio. From the fact that
oxidation of 14 gave 15 as a single product, no epimer-
ization at C3 during the transformation from 12 to 15 was
confirmed.
6. For reviews: (a) Murai, A. In Comprehensive Natural
Products Chemistry; Barton, D., Nakanishi, K., Meth-
Cohn, O., Eds.; Elsevier: Amsterdam, 1999; Vol. 1, p 303;
(b) Ishihara, J.; Murai, A. J. Synth. Org. Chem. Jpn. 2001,
59, 1181; Oka, T.; Murai, A. Chem. Lett. 1994, 1611.
7. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinhem, 2003.
15. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
8. Related work, see: Fujiwara, K.; Koyama, Y.; Doi, E.;
Shimawaki, K.; Ohtaniuchi, Y.; Takemura, A.; Souma, S.;
Murai, A. Synlett 2002, 1496, See, also Ref. 9h and 9i.
9. For the synthesis of laurencin, see: (a) Murai, A.; Murase,
H.; Matsue, H.; Masamune, H. Tetrahedron Lett. 1977,
2507; (b) Masamune, T.; Matsue, H.; Murase, H. Bull.
Chem. Soc. Jpn. 1979, 52, 127–134; (c) Masamune, T.;
Murase, H.; Matsue, H.; Murai, A. Bull. Chem. Soc. Jpn.
1979, 52, 135–141; (d) Tsushima, K.; Murai, A. Tetra-
hedron Lett. 1992, 33, 4345; (e) Brats, M.; Bullock, W. H.;
Overman, L. E.; Takemoto, T. J. Am. Chem. Soc. 1995,
117, 5958; (f) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork,
T. C.; Bendall, J. G.; Holmes, A. B. J. Am. Chem. Soc.
16. In the reaction, 4-epi-16 was afforded in 5% yield (16: 4-
epi-16 = 18:1). When L-SelectrideÒ was used in the
reduction of 15, the stereoselectivity was moderate
(4.4:1). The stereoselectivity tended to increase with
increasing bulkiness of the reductant. The details will be
disclosed elsewhere in the future.
17. Calzada, J. G.; Hooz, J. Org. Synth. Coll. 1988, 6, 634, and
the references cited therein.
18. Ethanedithiol–Zn(OTf)2 for removal of an acetal protec-
tive group: (a) Takemura, A.; Fujiwara, K.; Shimawaki,
K.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron 2005,
61, 7392; See, also: (b) Nocolaou, K. C.; Veale, C. A.;
Hwang, C.-K.; Hutchinson, J.; Prasad, C. V. C.; Ogilvie,
W. W. Angew. Chem., Int. Ed. Engl. 1991, 30, 299.
19. (a) Burke, S. D.; Piscopio, A. D.; Kort, M. E.; Matulenko,
M. A.; Parker, M. H.; Armistead, D. M.; Shankaran, K. J.
Org. Chem. 1994, 59, 332; (b) Wender, P. A.; Sieburth, S.
M.; Petraitis, J. J.; Singh, S. K. Tetrahedron 1981, 37,
3967.
1997, 119, 7483; (g) Kruger, J.; Hoffmann, R. W. J. Am.
¨
Chem. Soc. 1997, 119, 7499; (h) Mujica, M. T.; Afonso, M.
M.; Galindo, A.; Palenzuela, J. A. Synlett 1996, 983; (i)
Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J.
A. J. Org. Chem. 1998, 63, 9728; (j) Suzuki, T.; Matsu-
mura, R.; Nagai, K.; Sato, H.; Sekiguchi, H.; Hagiwara,
H.; Ando, M. Symposium papers, 39th Symposium on
the Chemistry of Natural Products, Sapporo; 1997; pp 97.
(k) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999,
121, 5653; (l) Crimmins, M. T.; Emmitte, K. A. Org. Lett.
20. The combination of Et2OÆBF3 and an organolithium
reagent for epoxide ring-opening, see: (a) Eis, M. J.;

6822
K. Fujiwara et al. / Tetrahedron Letters 46 (2005) 6819–6822
Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984, 106,
21. The reaction of 20 with the premixture of Et2OÆBF3 and E-
1-lithio-4-(trimethylsilyl)but-1-en-3-yne resulted only in
the recovery of 20. The use of CuI or CuCN instead of
Et2OÆBF3 gave a complex mixture of products.
3693; (b) Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.;
Skalitzky, D. J. J. Org. Chem. 1991, 56, 5161; (c)
Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.