Absolute Configuration and Total Synthesis of (+)-Epolactaene, a Neuritogenic Agent from Penicillium sp. BM 1689-P Active in Human Neuroblastoma Cells

Full text of DOI:10.1021/jo980087v

2068
J . Org. Chem. 1998, 63, 2068-2069
Sch em e 1
Absolu te Con figu r a tion a n d Tota l Syn th esis
of (+)-Ep ola cta en e, a Neu r itogen ic Agen t
fr om P en icilliu m sp . BM 1689-P Active in
Hu m a n Neu r obla stom a Cells†
Shinji Marumoto, Hiroshi Kogen,* and Shunji Naruto*
Exploratory Chemistry Research Laboratories, Sankyo Co.,
Ltd. 2-58, Hiromachi 1-chome,
Shinagawa-ku Tokyo, 140-8710 J apan
Received J anuary 20, 1998
Neurotrophic factors including nerve growth factor (NGF)1
stimulate the proliferation and differentiation of neuroblasts
during their development and trigger adaptive plasticity
responses in the mature nervous system. The ability of
neurotrophic factors to control developmental neuronal
survival and adult nervous system plasticity suggests the
use of these molecules to treat neurodegeneration associated
with human diseases.2
Sch em e 2a
Epolactaene (1) was isolated as a diastereomeric mixture
at the C-15 position (ca. 5:1 ratio) from the culture broth of
Penicillium sp. BM 1689-P in 1995 by Osada et al.3 The
compound shows potent neurite outgrowth activity in the
human neuroblastoma cell line SH-SY5Y.4 Therefore, this
natural product is noteworthy in the context of new drug
development for various neurodegenerative diseases such as
dementia.5
The gross structure of 1 was deduced by Osada using
extensive NMR studies including 1H-1H COSY and HMBC.
However, the initial structural assignment did not specify
the absolute stereochemistry of the epoxy moiety, although
it did establish the (E,E,E) geometry of the conjugated triene
and the (E) configuration of the R,â-unsaturated ketone. We
describe here the asymmetric total synthesis of (+)-epolac-
taene via a convergent approach that utilizes epoxyamide
2, which is derived from D-(+)-lactic acid, C6 unit 3, and
Wittig reagent 4 (Scheme 1), followed by cyclization to form
the lactam.
a
Readily available aldehyde (+)-56 ([R]22 +14.4° (c 0.50,
Reagents and conditions: (a) (i) ZnCl2, (ii) LiCH(CO2-t-Bu)2, THF,
D
-78 °C (53%); (b) CF3CO2H, CH2Cl2, 0 °C (80%); (c) Me3SiCl, imidazole,
DMF, 0 °C (94%); (d) (i) LHMDS, (ii) I2, -78 °C; (e) TBAF, THF, -45
to -15 °C (52% two steps); (f) HCO2H, rt; (g) Me(MeO)NH‚HCl, PyBOP,
i-Pr2NEt, CH2Cl2, 0 °C (69% from 8); (h) NH3, MeOH, rt; (i) TBDMSCl,
imidazole, DMF, 0 °C to rt (93% from 10); (j) (Z)-Br(CH3)CdCH-
(CH2)3OH, t-BuLi, THF, -78 °C (83%); (k) Dess-Martin reagent,
CH2Cl2, rt (81%).
CHCl3)) derived from D-(+)-lactic acid was subjected to
stereoselective aldol reaction with malonate anion to intro-
† With regard to this investigation, a patent application was filed before
J apanese Patent Office on Oct 30, 1997, as patent filing no. H9-297983.
(1) (a) Barde, Y, A.; Neuron 1989, 2, 1525-1535. (b) Ross, R. A.; Biedeler,
J . L. Cancer Res. 1985, 45, 1628-1632.
(2) Hefti, F. J . Neurobiol. 1994, 25, 1418-1435.
(3) Kakeya, H.; Takahashi, I.; Okada, G.; Isono, K.; Osada, H. J . Antibiot.
1995, 48, 733-735.
duce a chiral center at the C-13 position of epolactaene
(Scheme 2). The diastereoselective aldol reaction7 was
achieved by treating the aldehyde 5 with lithium malonate
(4) Kakeya, H.; Onozawa, C.; Sato, M.; Arai, K.; Osada, H. J . Med. Chem.
1997, 40, 391-394.
8
(5) Lactacystin has also been reported as the same neurite outgrowth
activity. Isolation: (a) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki,
K.; Moriguchi, R.; Tanaka, H.; Sasaki, Y. J . Antibiot. 1991, 44, 113-116.
(b) Omura, S.; Matsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita,
S.; Nakagawa, A. J . Antibiot. 1991, 44, 117-118. Synthesis: (c) Corey, E.
J .; Reichard, G. A. J . Am. Chem. Soc. 1992, 114, 10677-10678. (d) Corey,
E. J .; Reichard, G. A., Kania, R. Tetrahedron Lett. 1993, 34, 6977-6980.
(e) Sunazuka, T.; Nagamitsu, T.; Matsuzaki, K.; Tanaka, H.; Omura, S.;
Smith, A. B., III. J . Am. Chem. Soc. 1993, 115, 5302. (f) Uno, H.; Baldwin,
J . E.; Russell, A. T. J . Am. Chem. Soc. 1994, 116, 2139-2140. (g) Chida,
N.; Takeoka, J .; Tsutsumi, N.; Ogawa, S. J . Chem. Soc., Chem. Commun.
1995, 793-794.
in the presence of ZnCl2 at -78 °C to give the desired syn
product 6 as 9:1 diastereomeric mixture in 53% yield9 (85%
yield based on 62% conversion of the aldehyde 5 by 1H NMR
analysis). After deprotection (80%) and silylation (94%) of
6, the resulting bissilyl ether was purified by silica gel flash
column chromatography to remove the minor anti isomer
and then iodinated to obtain the R-iodo compound 7.
Subsequent desilylation with tetrabutylammonium fluoride
(TBAF) gave the epoxide 8 in 52% yield (two steps). Treat-
ment of this compound with formic acid provided epoxy
lactone 9, diastereoselectively generating a chiral center at
the C-13 position. The lactone 9 was converted to the
Weinreb amide10 10 by treating with (1H-benzotriazol-1-
(6) Aldehyde (-)-5 ([R]24D -14.4° (c 1.14, CHCl3)) was synthesized by Mori
et al.: Mori, K.; Kikuchi, H. Liebigs. Ann. Chem. 1989, 963-967.
(7) For a review of stereoselective aldol reactions, see: (a) Franklin, A.
S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317-338. (b) Heathcock, C.
H. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 181-238. (c) Heathcock, C. H. In
Asymmetric Synthesis; Morrison, J . D., Eds.; Academic Press: New York,
1984; Vol. 3, pp 111-212. (d) Evans, D. A.; Nelson, J . V.; Taber, T. R. In
Topics in Stereochemistry; Allinger, N. L., Eliel, E. L., Wilen, S. H., Eds.;
J ohn Wiley & Sons: New York, 1982; Vol. 13, pp 1-115.
(8) No aldol product was obtained in the absence of ZnCl2.
(9) The detailed study on this reaction will be described elsewhere.
(10) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
S0022-3263(98)00087-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/11/1998

Communications
J . Org. Chem., Vol. 63, No. 7, 1998 2069
Sch em e 3a
Sch em e 4a
a
Reagents and conditions: (a) 17, 18-crown-6, t-BuOK, THF, -78
to -40 °C (69%); (b) 3HF‚Et3N, DMF, rt (96%); (c) Dess-Martin
reagent, CH2Cl2, rt (74%).
a
Reagents and conditions: (a) t-BuPh2SiCl, imidazole, DMF, rt
(96%); (b) (i) t-BuLi, THF, - 78 °C, (ii) Me3SnCl, THF, -78 °C; (c)
(Z)-MeO2C(Br)CdCHCH3, Pd(Ph3P)4, toluene, reflux (47% from 14);
(d) TBAF, THF, 0 °C to rt (86%); (e) CBr4, Ph3P, THF, 0 °C (95%); (f)
n-Bu3P, CH3CN, reflux (quantitative).
studies. The silyl group of 16 was removed with TBAF
(86%), and the resulting alcohol was transformed to the
corresponding bromide with CBr4 and triphenylphosphine
(95%) followed by a treatment with tributylphosphine19 to
yield the desired Wittig reagent 17 in quantitative yield.
yloxy)tripyrrolidinophosphonium hexafluorophosphate11 (Py-
BOP) and N,O-dimethylhydroxylamine in 69% overall yield
from 8. The absolute stereochemistry of C-13-C-14 epoxide
and C-15 was assumed to be cis because the methine proton
of the C-14 position of lactone 9 was observed as a doublet
(J ) 1.2 Hz).12 The structure of 10 was firmly established
by X-ray crystallographic analysis.13 Exposure of 10 to
ammonia in methanol followed by protection of alcohol with
the tert-butyldimethylsilyl group provided the lactam pre-
cursor 11 in 93% yield from 10. Coupling of vinyllithium,
derived from (Z)-5-bromo-4-hexen-1-ol14 with tert-butyl-
lithium, with 11, afforded the enone in 83% yield, which was
then converted by Dess-Martin periodinane oxidation15 to
aldehyde 12 in 81% yield.
Wittig reagent 17 corresponding to the C-1 to C-6 unit
was synthesized as shown in Scheme 3. (E)-3-Iodo-2-methyl-
2-propen-1-ol (13)16 was protected as the tert-butyldiphen-
ylsilyl (TBDPS) ether to obtain 14 in 96% yield. Lithiation
of 14 with tert-butyllithium followed by trapping with
trimethyltin chloride afforded vinylstannane 15, which was
subjected to Stille coupling reaction17 with methyl (Z)-2-
bromo-2-butenoate18 to furnish diene 16 in 47% yield. The
stereochemistry of 16 was confirmed by NOE 1H NMR
Generation of the ylide from phosphonium salt 17 using
potassium tert-butoxide in the presence of 18-crown-6 in
THF followed by addition of aldehyde 12 resulted in the
formation of the desired (E)-olefin 18 in high stereoselectivity
(69% yield, E:Z ) 10:1). The (E)-isomer was purified by
silica gel flash column chromatography (Scheme 4), and its
stereochemistry was confirmed by the large coupling con-
stant (J 6-7 ) 15 Hz) observed in the 1H NMR spectrum.
Removal of the silyl group from 18 with triethylamine
trihydrofluoride in N,N-dimethylformamide afforded alcohol
19 in 96% yield. Dess-Martin periodinane oxidation of 19
followed by spontaneous cyclization gave (+)-epolactaene (1)
as an ca. 5:1 diastereomeric mixture at C-15, as with the
natural product [[R]22D +37° (c 0.2, MeOH) (lit.3 [R]22D +32°
(c 0.1, MeOH))] in 74% yield. Synthetic (13R,14R)-(+)-
epolactaene (1) exhibited physical and spectroscopic data (1H
NMR, 13C NMR) identical with those of an authentic sample.
Ack n ow led gm en t. We thank Dr. Hiroyuki Osada, The
Institute of Physical and Chemical Research (RIKEN), for
copies of the NMR spectra of (+)-epolactaene. We also
thank Dr. Tadashi Hata and Mr. Youji Furukawa, Analyti-
cal and Metabolic Research Laboratories, Sankyo Co. Ltd.,
for X-ray crystallographic analysis. This paper is dedicated
to Prof. Isao Kuwajima (Tokyo Institute of Technology) on
the occasion of his 60th birthday.
(11) Coste, J .; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31, 205-
208.
(12) Nishide, K.; Aramata, A.; Kamanaka, T.; Inoue, T.; Node, M.
Tetrahedron 1994, 50, 8337.
(13) Crystal data: colorless prisms, orthorhombic P212121, a ) 9.577(2)
Å, b ) 15.361(1) Å, c ) 6.609(2) Å, Z ) 4, R ) 0.041, RW ) 0.063. For full
X-ray data, see the Supporting Information.
Su p p or tin g In for m a tion Ava ila ble: Experimental details for
the syntheses and spectroscopic data including a listing of crystal-
lographic details for 10 (23 pages).
(14) This compound was synthesized from readily available (E)-3-bromo-
2-buten-1-ol as follows: (a) MsCl, Et3N, CH2Cl2, 0 °C; (b) NaH, CH2(CO2-
Et)2, THF, 0 °C; (c) NaOH, EtOH, rt; (d) DMF, 100 °C; (e) K2CO3, MeI,
DMF, rt; (f) LiAlH4, THF, -78 °C (45% in overall yield). Corey, E. J .; Bock,
M. G.; Kozikowski, A. P.; Rama Rao, A. V.; Floyd, D.; Lipshutz, B.
Tetrahedron Lett. 1978, 19, 1051-1054.
(15) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-4156.
(16) Baker, R.; Castro, J . L. J . Chem. Soc., Perkin. Trans. 1 1990, 47-
65.
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Soc. 1991, 113, 3, 5085-5086. (b) Hagiwara, H.; Abe, F.; Uda, H. J . Chem.
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