Total synthesis of leustroducsin B

Article abstract of DOI:10.1021/ja0340679

A convergent total synthesis of leustroducsin B (1), which is known to exhibit a variety of biological activities, was successfully carried out. Notable features of our synthesis include construction of the C8 stereocenter by lipase-mediated desymmetrizat

Full text of DOI:10.1021/ja0340679

Published on Web 03/15/2003
Total Synthesis of Leustroducsin B
Kousei Shimada, Yosuke Kaburagi, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received January 7, 2003; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Scheme 1. Synthetic Plan for LSN-B (1)
Leustroducsin B (LSN-B, 1) is a potent colony-stimulating factor
inducer isolated from the culture broth of Streptomyces platensis
SANK 60191 by Sankyo’s groups.1,2 LSN-B is known to exhibit a
variety of biological activities3 and is likely to be developed as a
new drug candidate. Recent studies suggest that LSN-B induces
cytokine productions via NF-κB activation at the transcription level
as well as at the posttranscription level.4 These interesting biological
activities coupled with its unique structural features have attracted
our attention as a target for total synthesis.
As illustrated in Scheme 1, we designed the construction of a
carbon framework of LSN-B by coupling the aldehyde 2 and the
enyne 3. The stereochemistry of C8 of 2 was to be controlled by
lipase-mediated desymmetrization of the meso-diol 4.
Scheme 2. Desymmetrization of meso-Diol 4a
Our total synthesis commenced with the preparation of â-keto-
ester 5 by treatment of ethyl 4-chloroacetoacetate with thiophenol
(Scheme 2). Conversion of 5 to 1,3-dioxolane 6, and subsequent
transformations involving oxidation of the sulfide and the Pummerer
reaction, afforded aldehyde 7. Upon treatment with (HCHO)n and
K2CO3, aldehyde 7 underwent aldol and Cannizzaro reactions to
give meso-diol 4. Desymmetrization of meso-diol 4 with Lipase
AK in n-hexane-vinyl acetate furnished the optically active acetate,5
and the remaining alcohol was immediately protected as its TBS
ether 8. This method for preparing the chiral building block 8 is
operationally simple and amenable to scale-up. The enantiomeric
purity of 8 was determined to be 90.2% ee by converting the acetate
to the modified Mosher’s ester.6 Removal of the acetyl group of 8,
oxidation of the alcohol to the corresponding aldehyde,7 and Wittig
reaction with Ph3PdCHCO2Et furnished the R,â-unsaturated ester
(Scheme 3). Reduction of the ethyl ester followed by deprotection
of the TBS group gave a diol whose less-hindered allyl alcohol
was selectively protected as the TIPS ether. The remaining alcohol
was oxidized to aldehyde 9.7 Chelation-controlled addition of
allylmagnesium bromide to the aldehyde in Et2O at -78 °C afforded
the sec-alcohol 10 as a single diastereomer. Changing the protecting
groups at this stage was necessary to construct the dihydropyranone
moiety and to protect the diol at C8 and C9 together. The acetonide
on 10 was deprotected, and the primary alcohol of the resultant
triol was selectively protected to give trityl ether 11. The remaining
diol was then protected as the p-TBSO-benzylidene acetal 13.8
Because both acetonide and p-methoxybenzylidene acetal protecting
groups for the C8,C9-diol could not be removed at the last stage
of the synthesis, we devised this new benzylidene group which can
be deprotected safely under weakly acidic conditions from densely
functionalized substrates.
a Reagents and conditions: (a) Et3N, CH2Cl2, 0 °C; (b) NaBH4, EtOH,
0 °C; (c) LAH, Et2O, 0 °C; (d) (MeO)2CMe2, CSA, DMF, room temperature;
(e) O3, CH2Cl2, -78 °C; TFAA, Et3N, 0 °C; (f) (HCHO)n, K2CO3, MeOH,
reflux (71%, six steps); (g) Lipase AK, vinyl acetate, n-hexane, room tem-
perature; (h) TBSCl, imidazole, DMF, room temperature (86%, two steps).
according to Ando’s method.11 Selective deprotection of the TES
group with PPTS afforded the hydroxy ester 17, which, upon
treatment with a catalytic amount of Ti(Oi-Pr)4 in refluxing benzene,
underwent smooth cyclization to give lactone 18. The terminal
alkene was converted into aldehyde 19 by osmium-catalyzed
oxidation12 followed by cleavage of the diol with Pb(OAc)4.
The relative configuration of 18 was determined to be the desired
C8-C9 anti form by the NOE studies,13 and the absolute config-
uration was confirmed by the modified Mosher’s method.6
The next step was to construct the C11 stereocenter. After
extensive studies, it was found that Zn reagents proved to be very
effective.14 Thus, the alkynylzinc bromide 2015 underwent smooth
addition to 19 in toluene-Et2O to give the desired adduct 21 as a
single diastereomer. Partial reduction of the conjugated triple bond
was best carried out with Zn/LiCuBr2 according to the method of
Brandsma16 to yield the Z,Z-diene 22, which was subsequently
converted to phenoxyacetate 23. It should be noted that the
attempted reduction of 21 with the Lindlar catalyst as well as
diimide resulted in the formation of the overreduced products.
The challenging aspect in the final stage involves a series of
functional group manipulations without disturbing the other delicate
functionalities. The allyl carbamate 24 was synthesized from the
trityl ether 23 in a four-step sequence involving removal of the
trityl group,17 conversion of the resultant alcohol to the azide,18
reduction of the azide by Staudinger reaction,19 and protection of
the amine with an Alloc group.1d Deprotection of the arylidene
group required a mild two-stage procedure. Thus, the TBS group
of 24 was first deprotected with (HF)3‚Et3N, and the more acid-
The allyl alcohol moiety of 13 was oxidized to the R,â-
unsaturated aldehyde 14 in a three-step sequence. The boron-
mediated asymmetric aldol reaction between 14 and n-butyric acid
derivative 15 proceeded smoothly to afford the syn-product 16.9
Protection of the secondary alcohol as the TES ether, removal of
the chiral auxiliary with LiSEt, and reduction of the resultant
thiolester with DIBAL10 furnished the corresponding aldehyde,
which was subsequently converted to the (Z)-R,â-unsaturated ester
9
4048
J. AM. CHEM. SOC. 2003, 125, 4048-4049
10.1021/ja0340679 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Total Synthesis of Leustroducsin B (1)a
a Reagents and conditions: (a) K2CO3, MeOH, room temperature; (b) TPAP, NMO, MS 4 Å, CH2Cl2, room temperature; (c) Ph3PdCHCO2Et, toluene,
100 °C (84%, three steps); (d) DIBAL, CH2Cl2, -78 °C; (e) TBAF, THF, room temperature; (f) TIPSCl, imidazole, CH2Cl2, 0 °C (83%, three steps); (g)
TPAP, NMO, MS 4 Å, CH2Cl2, room temperature; (h) AllylMgBr, Et2O, -78 °C (80%, two steps); (i) PPTS, MeOH, room temperature; (j) TrCl, DMAP,
pyridine, 50 °C; (k) 12, CSA, DMF, 50 °C; (l) TBAF, THF, room temperature (88%, four steps); (m) MnO2, CH2Cl2, room temperature; (n) TBSCl,
imidazole, CH2Cl2, room temperature (48%, two steps); (o) 15, n-Bu2BOTf, i-Pr2NEt, CH2Cl2, -78 °C; (p) TESCl, imidazole, DMF, room temperature; (q)
LiSEt, THF, 0 °C (72%, three steps); (r) DIBAL, toluene, -78 °C; (s) (PhO)2P(O)CH2CO2Et, (n-Bu)4N‚OH, THF, -78 °C; (t) PPTS, MeOH-THF, room
temperature (73%, three steps); (u) Ti(Oi-Pr)4, benzene, reflux (99%); (v) K2OsO4‚2H2O, (DHQD)2PHAL, K3Fe(CN)6, NaHCO3, t-BuOH-H2O, room
temperature (62%); (w) Pb(OAc)4, K2CO3, benzene, room temperature; (x) 20, toluene-Et2O, -78 °C to -10 °C (77%, two steps); (y) Zn, BrCH2CH2Br,
LiCuBr2, EtOH, reflux; (z) PhOCH2COCl, pyridine, CH2Cl2, 0 °C (86%, two steps); (aa) ZnBr2, Et3SiH, CH2Cl2, -18 °C; (bb) PPTS, MeOH-THF, room
temperature (68%, two steps); (cc) HN3, PPh3, DEAD, toluene, 0 °C (73%); (dd) PPh3, THF-H2O, room temperature; AllocCl, pyridine, room temperature
(78%); (ee) (HF)3‚NEt3, THF, room temperature; (ff) AcOH-THF-H2O, room temperature (57%, two steps); (gg) N-trimethylsilylimidazole, pyridine,
room temperature; (hh) (HF)3‚NEt3, THF, room temperature (51%, two steps); (ii) (AllylO)2PN(i-Pr)2, 1H-tetrazole, MeCN-CH2Cl2, room temperature;
t-BuOOH, 0 °C (79%); (jj) CAN, THF-H2O, 0 °C (82%); (kk) 6-(S)-methyloctanoic acid, DCC, DMAP, toluene, room temperature (92%); (ll) Er(OTf)3,
MeOH, room temperature (68%); (mm) Pd(PPh3)4, HCO2H, Et3N, THF, 50 °C (51%). AOM ) p-anisyloxymethyl.
Shimazu, A.; Seto, H. J. Antibiot. 1989, 42, 1019. (b) Fushimi, S.; Furihata,
sensitive p-hydroxybenzylidene group was subjected to acid hy-
K.; Seto, H. J. Antibiot. 1989, 42, 1026.
drolysis under mild conditions to give the diol 25. The subsequent
(3) (a) Kohama, T.; Maeda, H.; Imada Sakai, J.; Shiraishi, A.; Yamashita, K.
J. Antibiot. 1996, 49, 91. (b) Koishi, R.; Serizawa, N.; Kohama, T. J.
protection-deprotection scheme furnished the free secondary
Interferon Cytokine Res. 1998, 18, 863.
alcohol at C9, which was phosphorylated to give rise to the
(4) Koishi, R.; Yoshimura, C.; Kohama, T.; Serizawa, N. J. Interferon
phosphate triester.1d,20 After removal of the AOM group with
CAN,21 the resultant alcohol was acylated with 6-(S)-methyl-
octanoic acid1d to yield 26. Finally, removal of the phenoxyacetyl
group on C11-OH with Er(OTf)3 in MeOH followed by treatment
with Pd(PPh3)4, HCO2H, and Et3N furnished leustroducsin B (1),1d
which was in all respects identical to natural LSN-B.1
Cytokine Res. 2002, 22, 343.
(5) (a) Akai, S.; Naka, T.; Fujita, T.; Takebe, Y.; Tsujino, T.; Kita, Y. J.
Org. Chem. 2002, 67, 411. (b) Fadel, A.; Arzel, P. Tetrahedron:
Asymmetry 1997, 8, 283.
(6) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
(7) (a) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639. (b) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J.
Chem. Soc., Chem. Commun. 1987, 1625.
(8) Sabitha, G.; Babu, R. S.; Reddy, E. V.; Yadav, J. S. Chem. Lett. 2000,
1074.
Acknowledgment. We thank Dr. Takafumi Kohama (Sankyo,
Co., Ltd.) for providing us with a sample of natural LSN-B, and
Dr. Yoshihiko Hirose (Amano Enzyme, Inc.) for providing Lipase
AK. K.S. thanks Dr. Hiroaki Yanagisawa (Sankyo, Co., Ltd.) for
constant encouragement and Dr. Hayao Matsuhashi (GlaxoSmith-
Kline) for helpful discussions. This work was financially supported
by CREST, JST, and JSPS (predoctoral fellowship to Y.K.).
(9) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
(10) Evans, D. A.; Trotter, B. W.; Coˆte´, B.; Coleman, P. J. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2741.
(11) Ando, K. J. Org. Chem. 1997, 62, 1934.
(12) Oi, R.; Sharpless, K. B. Org. Synth. Collect. Vol. IX 1998, 251.
(13) NOE between H-9 and H-7, H-10 was observed. NOE between H-7 and
the benzylidene acetal proton indicated that the stereochemistry of the
benzylidene group is S.
(14) For examples of the chelation-controlled addition of Zn reagents, see:
(a) Soucy, R. L.; Kozhinov, D.; Behar, V. J. Org. Chem. 2002, 67, 1947.
(b) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.
(15) See Supporting Information for the preparation of 20.
(16) Aerssens, M. H. P. J.; van der Heiden, R.; Heus, M.; Brandsma, L. Synth.
Commun. 1990, 20, 3421.
Supporting Information Available: Experimental details and
spectroscopic data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) The triethylsilyl ether, formed partially under the deprotection conditions,
was subjected to methanolysis to give the desired alcohol.
(18) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org. React. 1992,
42, 335.
(19) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635.
(20) (a) Hayakawa, Y.; Wakabayashi, S.; Kato, H.; Noyori, R. J. Am. Chem.
Soc. 1990, 112, 1691. (b) Hayakawa, Y.; Wakabayashi, S.; Nobori, T.;
Noyori, R. Tetrahedron Lett. 1987, 28, 2259.
References
(1) (a) Kohama, T.; Enokita, R.; Okazaki, T.; Miyaoka, H.; Torikata, A.;
Inukai, M.; Kaneko, I.; Kagasaki, T.; Sakaida, Y.; Satoh, A.; Shiraishi,
A. J. Antibiot. 1993, 46, 1503. (b) Kohama, T.; Nakamura, T.; Kinoshita,
T.; Kaneko, I.; Shiraishi, A. J. Antibiot. 1993, 46, 1512. Structure
determination: (c) Shibata, T.; Kurihara, S.; Yoda, K.; Haruyama, H.
Tetrahedron 1995, 51, 11999. (d) Matsuhashi, H.; Shimada, K. Tetra-
hedron 2002, 58, 5619.
(21) Masaki, Y.; Iwata, I.; Mukai, I.; Oda, H.; Nagashima, H. Chem. Lett.
1989, 659.
(2) Seto reported the isolation and structure determination of phoslactomycins,
similar 2-pyranone compounds. See: (a) Fushimi, S.; Nishikawa, S.;
JA0340679
9
J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003 4049