Asymmetric total synthesis of octalactin B using a new and rapid lactonization

Article abstract of DOI:10.1016/j.tetlet.2003.10.213

A method for the synthesis of octalactin B is established via a new and quite effective mixed-anhydride lactonization for the synthesis of an eight-membered ring moiety using 2-methyl-6-nitrobenzoic anhydride with DMAP. Both an optically active linear pre

Full text of DOI:10.1016/j.tetlet.2003.10.213

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 543–547
Asymmetric total synthesis of octalactin B
using a new and rapid lactonization
Isamu Shiina,* Hiromi Oshiumi, Minako Hashizume, Yu-suke Yamai and
Ryoutarou Ibuka
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 24 September 2003; revised 29 October 2003; accepted 31 October 2003
Abstract—A method for the synthesis of octalactin B is established via a new and quite effective mixed-anhydride lactonization for
the synthesis of an eight-membered ring moiety using 2-methyl-6-nitrobenzoic anhydride with DMAP. Both an optically active
linear precursor of the lactone and a side chain of octalactins are prepared by the enantioselective aldol reaction of ketene silyl
acetals with aldehydes.
Ó 2003 Elsevier Ltd. All rights reserved.
Octalactin B (2) was isolated from the marine bacterium
Streptomyces sp. together with a related cytotoxic active
compound octalactin A (1).1 Synthesis of this unique
complex structure has been one of the more interesting
topics in organic chemistry (Scheme 1). There are cur-
rently three total syntheses of octalactins accomplished
by two groups;2 besides, some formal syntheses and
related synthetic studies of octalactins have also been
reported3.
eight-membered ring lactone moiety was obtained by the
efficient cyclization of the seco acid via a novel mixed-
anhydride method using (4-trifluoromethyl)benzoic
anhydride (TFBA) with Hf(OTf)4.4;6
As our continuous effort for the synthesis of medium-
sized natural compounds,7 the total synthesis of the
octalactins was planned using a very effective and con-
venient lactonization for producing the eight-membered
ring part of the octalactins using 2-methyl-6-nitroben-
zoic anhydride (MNBA) with DMAP.8 An optically
active seco acid of the eight-membered ring lactone
might also be constructed according to the enantio-
selective aldol reaction of a ketene silyl acetal with
aldehydes promoted by Sn(OTf)2 coordinated with a
chiral diamine.
In 1998, the total synthesis of cephalosporolide D (3), an
eight-membered ring lactone similar to the octalactins
was attained by our group,4 and the exact stereochem-
istry of this compound was determined through a chiral
induction technology for producing optically active
compounds;5 that is, both asymmetric carbons were
constructed by the asymmetric aldol reaction of 1-
ethylthio-1-(trimethylsiloxy)ethene with aldehydes in the
presence of a chiral catalyst. Furthermore, the desired
Because the synthetic intermediates similar to 4 have
already been prepared and the transformations of these
O
O
O
HO
HO
HO
O
O
OH
O
O
H
O
OH
H
O
Octalactin A (1)
Octalactin B (2)
Cephalosporolide D (3)
Scheme 1. Structure of octalactins A and B, and a similar lactone, cephalosporolide D.
* Corresponding author. Tel.: +81-3-3260-4271; fax: +81-3-3260-5609; e-mail: shiina@ch.kagu.sut.ac.jp
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.213

544
I. Shiina et al. / Tetrahedron Letters 45 (2004) 543–547
O
BnO
O
O
H
O
known
coupling
H
BnO
5
+
O
H
OH
OTBS
1 and 2
OTBS
I
4
6
O
OH
OBn O
lactonization
BnO
O
5
TBDPSO
PMP
OH
OTBDPS
H
8
7
Wittig
coupling
OBn
O
O
+
I
OTBS
O
9
10
two carbons
elongation
OTBS
O
OH
known route
6
EtS
11
Scheme 2. Retrosynthesis of octalactins from optically active linear compounds.
12
compounds to 1 and/or 2 were also described in previous
papers,2a;b 4 was determined to be our target precursor
for the synthesis of the octalactins as shown in Scheme
2. It is assumed that the allyl alcohol 4 could be pre-
pared by the nucleophilic addition of a metallic species
generated from 6 to aldehyde 5 according to literature
methods.2a;b The synthesis of the eight-membered ring
lactone part 7 was planned by starting from a linear
compound 8, which could be obtained from two seg-
ments 9 and 10. Preparation of both optically active
anti-b-hydroxy-a-methyl units 9 and 10 might be
attained according to the enantioselective aldol addition
of the tetra-substituted ketene silyl acetal derived from
ethyl 2-methylthiopropanoate to aldehydes and succes-
sive stereoselective desulfurization. On the other hand,
aldol 12 was chosen as an intermediate of the sil-
oxyalkyne 11, which could be converted to the side
chain 6.2a
First, an optically active aldol 16 was synthesized with
high stereoselectivity by the asymmetric aldol reaction
of tetra-substituted ketene silyl acetal 13 with b-siloxy-
aldehyde 14 using a chiral Lewis acid consisting of
Sn(OTf)2, chiral diamine 15 and n-Bu3SnF (Scheme 3).
The ee was determined by the HPLC analysis of 16
referenced to the corresponding racemic sample. Direct
acetalyzation of 16 with benzaldehyde dimethyl acetal in
the presence of p-toluenesulfonic acid afforded a cyclic
compound 17. Desulfurization of 17 using n-Bu3SnH
was carried out according to the similar reactions
reported by Guindon et al. and Kiyooka and Shahid to
give the desired anti-b-hydroxy-a-methyl unit 18 with
high diastereoselectivity.9;10 Successive reductive cleav-
age of the benzylidene acetal and protection of the pri-
mary alcohol gave the corresponding silyl ether. The
ester group was reduced by LiAlH4 and halogenation of
the formed primary alcohol afforded the desired right
O
OH
OTMS
a
O
SMe
+
EtO
MeS
EtO
OTIPS
OTBS
H
OTIPS
Ph
13 (E/Z=12/88)
14
16
N
H
N
Me
OBn
b
d
15
O
O
O
X
EtO
R
X = I; 9
R = MeS; 17
R = H; 18
e
c
X = I–Ph3P+; 19
Scheme 3. Reagents and conditions: (a) Sn(OTf)2, n-Bu3SnF, chiral diamine 15, CH2Cl2, )78 °C (56%, syn/anti ¼ 96/4, 87% ee for syn);
(b) PhCH(OMe)2, TsOH, CH2Cl2, 0 °C (64% from syn-16); (c) n-Bu3SnH, AIBN, benzene reflux (quant, anti/syn ¼ 95/5); (d) 1. LiAlH4, THF, 0 °C
(47% from anti-18); 2. TsCl, Et3N, DMAP, CH2Cl2, 0 °C (96%); 3. NaI, acetone, reflux (97%); 4. DIBAL, CH2Cl2, 0 °C (94%); 5. TBSCl, imidazole,
i
DMF, 0 °C (96%); (e) PPh3, Pr2NEt, CH3CN, reflux (84%).

I. Shiina et al. / Tetrahedron Letters 45 (2004) 543–547
545
O
OH
OTMS
SMe
a
O
OTIPS
+
OTIPS
20
EtO
EtO
H
SMe
21
13 (E/Z=12/88)
N
H
N
PMP
Me
d
b
O
O
ent -15
O
O
O
O
EtO
R
10
R = MeS; 22
R = H; 23
c
Scheme 4. Reagents and conditions: (a) Sn(OTf)2, n-Bu3SnF, chiral diamine ent-15, CH2Cl2, )78 °C (50%, syn/anti ¼ 87/13, 69% ee for syn); (b) 1.
TBAF, AcOH, THF, 0 °C (91% from syn-21); 2. Me2C(OMe)2, MsOH, CH2Cl2, rt (96%); (c) n-Bu3SnH, AIBN, benzene reflux (92%, anti/syn ¼ 97/3);
(d) 1. LiAlH4, THF, 0 °C (82% from anti-23); 2. PPTS, MeOH; 3. PMPCH(OMe)2, PPTS, CH2Cl2, rt (96%, two steps); 4. PhSNHtBu, NCS, K2CO3,
ꢀ
MS 4 A, CH2Cl2, 0 °C to rt (99%).
hand 9, which was further converted to the phospho-
nium salt 19 by conventional method.
saturated eight-membered ring lactone 7 was obtained in
84% yield within 13 h.12 Buszek et al. reported the suc-
cessful lactonization of a similar seco acid, which has the
PMB group instead of the Bn group in 8 using the S-Py
ester method.2a;13;14 It is reported that the cyclization
requires a high reaction temperature and longer reaction
time (96 h); nevertheless, the reaction is accelerated by
AgBF4. Although our desired lactone 7 could also be
obtained from 8 by the S-Py ester method, the reaction
sluggishly proceeded even under very severe conditions
(96 h in refluxing toluene with AgBF4). Furthermore, it
was revealed that this reaction did not take place at all
at room temperature. The conversion of the formed 7 to
the eight-membered ring lactone aldehyde 5 was then
carried out through deprotection of the TBDPS group
and successive oxidation.
Second, the left-hand segment 10 was also prepared as
shown in Scheme 4. The optically active aldol 21 gen-
erated from 13 with a-siloxyaldehyde 20 was trans-
formed to the cyclic acetal 22, and the diastereoselective
desulfurization of 22 smoothly took place to preferen-
tially yield the desired anti-b-hydroxy-a-methyl unit 23.
Successive reduction of the ester group, formation of
p-methoxybenzylidene acetal, and oxidation of the
intermediary primary alcohol produced the corre-
sponding optically active aldehyde 10.11
These two segments 10 and 19 were coupled in the
presence of NaHMDS to produce a linear polyoxy
compound 24 in good yield (Scheme 5). Reductive
cleavage of the acetal moiety followed by protection of
the resulted primary alcohol afforded the disilyl ether 25.
Deprotection of the TBS group and stepwise oxidation
of the formed primary alcohol gave the corresponding
carboxylic acid 26. The desired chiral linear seco acid 8
was then obtained by deprotection of the PMB group
and hydrogenation of the double bond.
Next, the side chain 6 was prepared from an optically
active aldol 12, which was generated by the asymmetric
aldol reaction of 1-ethylthio-1-(trimethylsiloxy)ethene
(27) with 2-methylpropionaldehyde (28) as shown in
Scheme 6.5c The protection of 12 and the successive
reduction using Et3SiH with Pd/C afforded the chiral
aldehyde 30.15 According to BuszekÕs synthesis of the
side chain,2a 30 was transformed into the desired vinyl
iodide 6 through the siloxyalkyne 11. The side chain 6
was finally introduced to the aldehyde 5 using the
method reported by McWilliams and Clardy2b to give
the multi-oxygenated eight-membered ring lactone 4, a
precursor of the octalactins. Both diastereomers were
This seco acid 8 was eventually cyclized to form the
eight-membered ring lactone using a new effective
mixed-anhydride method involving MNBA with DMAP
as shown in Scheme 5. Actually, the reaction proceeded
quite smoothly at room temperature and the desired
OBn
OBn
a
b
TBDPSO
+
10
19
OTBS
OTBS
O2 O2
O
O
OPMB
N
N
24
25
PMP
O
Me
O
O
Me
OBn O
MNBA
c
d
e
f
TBDPSO
8
7
5
OH
OPMB
26
Scheme 5. Reagents and conditions: (a) NaHMDS, toluene, )78 °C to rt (80%, >97% ee); (b) 1. DIBAL, CH2Cl2, 0 °C (79%); 2. TBDPSCl, Et3N,
DMAP, CH2Cl2, rt (84%); (c) 1. 1 M HCl, THF, rt (95%); 2. DMP, CH2Cl2, rt; 3. NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH, H2O, rt (94%, two
steps); (d) 1. DDQ, H2O, CH2Cl2, rt (81%); 2. H2, Pd/C, AcOEt, rt (83%); (e) MNBA, DMAP, toluene, rt (84%); (f) 1. TBAF, AcOH, THF, rt (86%);
ꢀ
2. TPAP, NMO, MS 4 A, CH2Cl2, 0 °C (quant).

546
I. Shiina et al. / Tetrahedron Letters 45 (2004) 543–547
O
O
OH
OTMS
a
+
H
EtS
N
H
EtS
N
Me
27
28
OTBS
12
29
O
OTBS
b
c
d
e
f
6
4
2
H
30
11
Scheme 6. Reagents and conditions: (a) Sn(OTf)2, chiral diamine 29, CH2Cl2, )78 °C (48%, 90% ee); (b) 1. TBSCl, imidazole, DMF, rt (93%); 2.
Et3SiH, Pd/C, acetone, rt (85%); (c) 1. CBr4, PPh3, CH2Cl2, )78 to 0 °C (81%); 2. n-BuLi, MeI, THF, )78 °C to rt (88%); (d) Cp2ZrHCl, benzene,
t
ꢀ
sun-lamp, 35 °C, then I2, 7 °C (86%, E/Z ¼ 51/49); (e) E-6, BuLi, 5, Et2O, )78 °C (27%, a=b ¼ 48=52); (f) 1. TPAP, NMO, MS 4 A, CH2Cl2, 0 °C
(75%); 2. 46% HF, CH3CN, 0 °C (93%); 3. BBr3, CH2Cl2, )45 °C (68%).
4. (a) Shiina, I.; Fukuda, Y.; Ishii, T.; Fujisawa, H.;
Mukaiyama, T. Chem. Lett. 1998, 831–832; (b) Shiina,
I.; Fujisawa, H.; Ishii, T.; Fukuda, Y. Heterocycles 2000,
52, 1105–1123.
oxidized to generate the corresponding enone, and suc-
cessive deprotections of the TBS and Bn groups fur-
nished the targeted compound 2.16
5. (a) Mukaiyama, T.; Kobayashi, S.; Uchiro, H.; Shiina, I.
Chem. Lett. 1990, 129–132; (b) Kobayashi, S.; Uchiro, H.;
Fujishita, Y.; Shiina, I.; Mukaiyama, T. J. Am. Chem. Soc.
1991, 113, 4247–4252; (c) Kobayashi, S.; Furuya, M.;
Ohtsubo, A.; Mukaiyama, T. Tetrahedron: Asymmetry
1991, 2, 635–638; (d) Kobayashi, S.; Uchiro, H.; Shiina, I.;
Mukaiyama, T. Tetrahedron 1993, 49, 1761–1772; (e) See
also: Mukaiyama, T.; Uchiro, H.; Shiina, I.; Kobayashi, S.
Chem. Lett. 1990, 1019–1022; (f) Mukaiyama, T.; Shiina,
I.; Kobayashi, S. Chem. Lett. 1991, 1901–1904; (g)
Kobayashi, S.; Shiina, I.; Izumi, J.; Mukaiyama, T. Chem.
Lett. 1992, 373–376; (h) Mukaiyama, T.; Shiina, I.; Izumi,
J.; Kobayashi, S. Heterocycles 1993, 35, 719–724; (i)
Mukaiyama, T.; Shiina, I.; Uchiro, H.; Kobayashi, S. Bull.
Chem. Soc. Jpn. 1994, 67, 1708–1716; (j) Shiina, I.; Ibuka,
R. Tetrahedron Lett. 2001, 42, 6303–6306.
6. (a) Shiina, I.; Miyoshi, S.; Miyashita, M.; Mukaiyama, T.
Chem. Lett. 1994, 515–518; (b) Shiina, I.; Mukaiyama, T.
Chem. Lett. 1994, 677–680; (c) See also: Ishihara, K.;
Kubota, M.; Kurihara, H.; Yamamoto, H. J. Am. Chem.
Soc. 1995, 117, 4413–4414, 6639 (correction); (d) Ishihara,
K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org.
Chem. 1996, 61, 4560–4567.
Thus, an efficient method for the synthesis of octalactin
B (2) was established via the enantioselective aldol
reaction and a new and quite effective lactonization
using MNBA. It is already known that ent-2 could be
converted to ent-1 by nonselective epoxidation,2b there-
fore, the present report showed the related formal syn-
thesis of octalactin A (1). An advanced investigation of
the alternative highly stereoselective synthesis of 1 is
now in progress in this laboratory.
Acknowledgements
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Science, Sports and Culture, Japan.
References and Notes
7. (a) Shiina, I.; Iwadare, H.; Sakoh, H.; Hasegawa, M.;
Tani, Y.; Mukaiyama, T. Chem. Lett. 1998, 1–2; (b)
1. Tapiolas, D. M.; Roman, M.; Fenical, W.; Stout, T. J.;
Clardy, J. J. Am. Chem. Soc. 1991, 113, 4682–4683.
2. (a) Buszek, K. R.; Sato, N.; Jeong, Y. J. Am. Chem. Soc.
1994, 116, 5511–5512; (b) McWilliams, J. C.; Clardy, J. J.
Am. Chem. Soc. 1994, 116, 8378–8379; (c) Buszek, K. R.;
Sato, N.; Jeong, Y. Tetrahedron Lett. 2002, 43, 181–184.
3. Formal syntheses: (a) Buszek, K. R.; Jeong, Y. Tetrahe-
dron Lett. 1995, 36, 7189–7192; (b) Kodama, M.; Matsu-
shita, M.; Terada, Y.; Takeuchi, A.; Yoshio, S.;
Fukuyama, Y. Chem. Lett. 1997, 117–118; (c) Inoue, S.;
Iwabuchi, Y.; Irie, H.; Hatakeyama, S. Synlett 1998, 735–
736; (d) Partial syntheses: Andrus, M. B.; Argade, A. B.
Tetrahedron Lett. 1996, 37, 5049–5052; (e) Bach, J.;
Garcia, J. Tetrahedron Lett. 1998, 39, 6761–6764; (f)
Other synthetic studies: Bach, J.; Berenguer, R.; Garcia, J.;
Vilarrasa, J. Tetrahedron Lett. 1995, 36, 3425–3428; (g)
Hulme, A. N.; Howells, G. E. Tetrahedron Lett. 1997, 38,
8245–8248; (h) Shimoma, F.; Kusaka, H.; Wada, K.;
Azami, H.; Yasunami, M.; Suzuki, T.; Hagiwara, H.;
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R.; Holmes, A. B.; Collins, I. Synlett 1999, 972–974; (j)
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ꢁ
Shiina, I.; Saitoh, K.; Frechard–Ortuno, I.; Mukaiyama,
T. Chem. Lett. 1998, 3–4; (c) Mukaiyama, T.; Shiina, I.;
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Yamada, K.; Saitoh, K. Chem. Eur. J. 1999, 5, 121–161.
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dron Lett. 2002, 43, 7535–7539.
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12. Experimental procedure for the synthesis of the eight-
membered ring lactone moiety of octalactins: To a

I. Shiina et al. / Tetrahedron Letters 45 (2004) 543–547
547
solution of MNBA (6.9 mg, 0.020 mmol) and DMAP
(11.3 mg, 0.092 mmol) in toluene (5.3 mL) at room tem-
perature was added 8 (8.7 mg, 0.015 mmol) in toluene
(2.4 mL). After the reaction mixture had been stirred for
13 h at room temperature, saturated aqueous sodium
hydrogen carbonate was added at 0 °C. The mixture was
extracted with ethyl acetate and the organic layer was
washed with brine, and dried over sodium sulfate. After
filtration of the mixture and evaporation of the solvent,
the crude product was purified by preparative thin
layer chromatography (AcOEt/hexane ¼ 1/5) to afford 7
(7.1 mg, 84%) as a colorless oil.
14. Original S-Py ester methods for the synthesis of macro-
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Helv. Chim. Acta 1974, 57, 2661–2663; (c) Corey, E. J.;
Brunelle, D. J. Tetrahedron Lett. 1976, 17, 3409–3412; (d)
See also the synthesis of unsaturated eight-membered ring
lactones using S-Py ester method: Nicolaou, K. C.;
McGarry, D. G.; Somers, P. K.; Kim, B. H.; Ogilvie, W.
W.; Yiannikouros, G.; Prasad, C. V. C.; Veale, C. A.;
Hark, R. R. J. Am. Chem. Soc. 1990, 112, 6263–6276.
15. Fukuyama, T.; Lin, S.-C.; Li, L.-P. J. Am. Chem. Soc.
1990, 112, 7050–7051.
23
D
13. Buszek, K. R.; Jeong, Y.; Sato, N.; Still, P. C.; Muino,
P. L.; Ghosh, I. Synth. Commun. 2001, 31, 1781–
1791.
16. ½aꢀ
)124° (c 0.42, CHCl3) (>99% ee), cf. )123°
24
(revised),1;2b )126°,2a ½aꢀ +132° (c 1.00, CHCl3) (enantio-
D
morph).2b