Synthesis of an isomer of the oxaspirobicyclic tetronic acid unit of the CCK-B receptor antagonist tetronothiodin

Article abstract of DOI:10.1055/s-2003-39287

An isomer of the oxaspirobicyclic tetronic acid unit of the CCK-B Receptor antagonist tetronothiodin, diastereoisomeric at the spiro centre, has been synthesized in five steps from dienol 4.

Full text of DOI:10.1055/s-2003-39287

1022
LETTER
Synthesis of an Isomer of the Oxaspirobicyclic Tetronic Acid Unit of the
CCK-B Receptor Antagonist Tetronothiodin
Synthesis of
a
h
t
i
l
spirobi
icyclic
T
p
etronic
A
cid C. Bulman Page,*a Hooshang Vahedi, Kevin J. Batchelor, Stephen J. Hindley, Mark Edgar, Paul Beswickb
a
Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
Fax +44(1509)223926; E-mail: p.c.b.page@lboro.ac.uk
b
Department of Medicinal Chemistry, Neurology & GI Centre of Excellence for Drug Discovery, Glaxo SmithKline, Medicines Research
Centre, Gunnells Wood Road, Stevenage, Herts SG2 2NY
Received 10 February 2003
Abstract: An isomer of the oxaspirobicyclic tetronic acid unit of
the CCK-B Receptor antagonist tetronothiodin, diastereoisomeric
at the spiro centre, has been synthesized in five steps from dienol 4.
HO
HO
O
Key words: tetronothiodin, Diels–Alder, Dieckmann, spiro tetron-
ic acid, CCK
H
O
O
HO2C
S
Cholecystokinin (CCK) is a 33 amino acid peptide that
functions as a gastrointestinal hormone having a variety of
effects including pancreatic exocrine secretion, stimula-
tion of gut motility, and gallbladder contraction.1 There
are two types of CCK receptor: CCK-A receptors,2 found
in the periphery and in discrete regions of the central ner-
vous system, and responsible for the satiety actions of pe-
ripherally administered CCK; and CCK-B receptors,
widely distributed in the brain, which have been shown to
cause appetite,3 pain,4 and anxiety.5
O
1
H
H
O
HO
X
H
X
O
HO
MeO2C
O
HO2C
S
Y
O
O
Tetronothiodin (1) is a novel brain-type CCK receptor an-
tagonist isolated from Streptomyces sp. NR0489.6 The
structure is claimed on the basis of detailed spectroscopic
analysis and is not supported by crystallography. The rel-
ative stereochemistry therefore remains unconfirmed at
any of the asymmetric centers, and indeed none is yet pro-
posed for two of the eight.
Scheme 1
HO
HO
O
Our synthetic approach is designed around a flexible and
convergent route, with the target molecule split into
three zones: The oxaspirobicyclic unit, the unsaturated
macrocycle framework, and the tetrahydrothiophene
(Scheme 1).
O
O
O
2
Figure 1
We report herein the stereoselective synthesis in five steps
of oxaspirobicycle 2, a diastereoisomer of the proposed
structure of the oxaspirobicyclic unit of 1, suitably func-
tionalized with hydroxyethyl and ester substituents for
further elaboration (Figure 1).
PPh3
HO
PPh3
Br
HO
Br
Toluene
97%
3
The synthesis of 2 began with the preparation of the Wit-
tig salt 3 from 3-bromopropanol and triphenyl phosphine
in dry toluene under reflux, which afforded the phospho-
nium salt in 96% yield. Treatment of 3-hydroxypropyl
phosphonium salt 3 with n-butyllithium at 0 °C followed
by trans-2-methyl butenal gave (E,E)-5-methylhepta-3,5-
dien-1-ol (4) in 84% yield (Scheme 2).7
1) n-BuLi
2) trans-2-methyl-2-butenal
74%
HO
4
Synlett 2003, No. 7, Print: 02 06 2003.
Scheme 2
Art Id.1437-2096,E;2003,0,07,1022,1024,ftx,en;D0303ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of an Isomer of the Oxaspirobicyclic Tetronic Acid
1023
The preparation of diene 4 allowed the study of Diels–
Alder reactions with suitable dienophiles, chosen to pro-
vide appropriate functionality in the adduct for elabora-
tion into the spirotetronic acid moiety. Successful
cycloadditions were observed with nitroethylene at room
temperature in toluene (64%), phenyl vinyl sulfone at
170 °C in toluene (36%), and 2-chloroacrylonitrile at
110 °C in toluene (40%), giving 5, 6, and 7 respectively
(Figure 2).
Propenal (5.0 equiv)
H2O, r.t., 2 days
76%
CHO
HO
HO
4
H
H
O
OH
10
Cl CN
NO2
SO2Ph
Scheme 4
HO
HO
HO
7
6
5
tion is presumably facilitated by interaction between the
hydroxy group of 4 and the aldehyde carbonyl group.
Figure 2
Lactol 10 was oxidized to the corresponding lactone 11
with pyridinium dichromate in N,N-dimethylformamide
(Scheme 5). Introduction of the oxygen atom of the
spirotetronic acid unit was accomplished by oxygenation
of the enolate derived from lactone 11. Deprotonation of
11 with sodium bis(trimethylsilyl)amide at –78 °C for 1
hour to generate the corresponding enolate, followed by
treatment with (1S)-(+)-(10-camphorsulfonyl) oxaziri-
dine,10,11 afforded the hydroxylactone 12 as a single dia-
stereoisomer in 57% yield (Scheme 5).
Construction of the spirotetronic acid requires introduc-
tion of acyl and oxygen substituents into the new six-
membered ring at the pro-spiro centre. Unfortunately we
were unable to achieve a Nef reaction with adduct 5 to
generate a carbonyl group at the pro-spiro position, as in
compound 8 (R = H), ready for functionalization as a cy-
anohydrin or through Wittig or similar homologation.
Compound 8 (R = TBDPS) was, however, eventually pre-
pared using an intramolecular Diels–Alder reaction of
triene 9 (95%),8 followed by Tamao-type oxidation
(78%), protection of the primary alcohol, for example as
a TBDPS ether (86%), and oxidation to the ketone with
pyridinium dichromate (89%) (Scheme 3).
H
PDC (3.0 equiv)
H
DMF, overnight
64%
H
H
O
O
OH
Toluene
170 °C
O
10
H
11
96 h, 95%
H
1) NaHMDS (3.0 equiv)
2) (1S)-(+)-(Camphorsulfonyl)
SiPh2
SiPh2
O
O
oxaziridine (3.0 equiv), –78 °C
9
1) KHCO3, thf-MeOH,
H2O2, 2, 4 h, 78%
2) TBDPSCl, imid,DMF,
r.t., 16 h, 86%
57%
H
OH
O
PDC, CH2Cl2
r.t., 16 h, 89%
O
12
O
OH
RO
Scheme 3
RO
Scheme 5
8
The stereochemistry of 12 was unambiguously verified by
single crystal X-ray analysis, and shown to be isomeric at
this centre with the proposed structure of the natural prod-
uct. Use of lithium bis(trimethylsilyl)amide gave 12 in
only 31% yield, in accordance with the reported observa-
tions of Davis.10 Hydroxylactone 12 was also derived
from 11 by hydroxylation of the enolate with 2-(phenyl-
sulfonyl)-3-phenyloxaziridine in 46% yield. Hydroxyla-
tion of the enolate derived from a chiral lactone by
treatment with oxygen, to yield a 1:1 mixture of stereoiso-
mers, has been reported;12 similar treatment of 11, howev-
er, provided 12 as a single isomer in 20% yield.
Cyanohydrin formation from 8 proved poorly stereoselec-
tive, and other methods of functionalization were low-
yielding. In addition, this route was rather lengthy, and we
sought a more efficient approach. Attempted cycloaddi-
tion of diene 4 with ethyl acrylate had proved unsuccess-
ful, and we were therefore delighted to discover that
Diels–Alder reaction of 4 with acrolein, performed in wa-
ter at room temperature, afforded the lactol endo-cycload-
duct 10 in 76% yield,9 in a diastereoisomeric ratio of 2:1
at the hydroxy group (Scheme 4). The Diels–Alder reac-
Synlett 2003, No. 7, 1022–1024 ISSN 1234-567-89 © Thieme Stuttgart · New York

1024
P. C. B. Page et al.
LETTER
(2) (a) Dourish, C. T.; Hill, D. R. Trends Pharmacol. Sci. 1987,
8, 207. (b) Moran, T.; Robinson, P.; Goldrich, M. S.;
McHuge, P. Brain Res. 1986, 362, 175.
(3) Dourish, C. T.; Rycroft, W.; Iversen, S. D. Science 1989,
245, 1509.
Formation of the spirotetronic acid requires acylation of
the newly-introduced hydroxy group. We envisaged that
acylation of this hydroxy group as a malonyl ester and
subsequent deprotonation of the malonyl moiety might
lead to intramolecular Dieckmann cyclization13 by nu-
cleophilic attack at the lactone carbonyl group, so gener-
ating the spirotetronic acid unit of 1/2, complete with a
pendant ester group for attachment to the macrocycle
(Scheme 6). Hydroxylactone 12 was thus treated with ex-
cess (2.5 equiv) ethyl malonyl chloride in the presence of
2,6-di-t-butyl-6-methylpyridine (2.5 equiv), in dichlo-
romethane as solvent. The acylated product 13 was ob-
tained after a five-hour reaction time in excellent yield
(98%).
(4) Dourish, C. T.; O’Neil, M. F.; Coughlan, J.; Kitchener, S. J.;
Hawley, D.; Iversen, S. D. Eur. J. Pharmacol. 1990, 176, 35.
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Nakano, A.; Ohtsuka, T.; Yoshizaki, H.; Arisawa, M. Eur. J.
Pharmacol. 1992, 221, 99. (b) Ohtsuka, T.; Kudoh, T.;
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Fujisaki, N.; Watanabe, J.; Yokose, K.; Seto, H. J. Antibiot.
1992, 45, 140. (c) Watanabe, J.; Fujisaki, N.; Fujimori, K.;
Anzai, Y.; Oshima, S.; Sano, T.; Ohtsuka, T.; Watanabe, K.;
Okuda, T. J. Antibiot. 1993, 46, 1. (d) Ohtsuka, T.; Kotaki,
H.; Nakayama, N.; Itezono, Y.; Shimma, N.; Kudoh, T.;
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46, 11. (e) Ohtsuka, T.; Nakayama, N.; Itezono, Y.;
Shimma, N.; Kuwahara, T.; Yokose, K.; Seto, H. J. Antibiot.
1993, 46, 18. (f) Kuwahara, T.; Kudoh, T.; Nakano, A.;
Yoshizaki, H.; Takamiya, M.; Nagase, H.; Arisawa, M.
Neurosci. Lett. 1993, 158, 1. (g) Murayama, T.; Matsumori,
Y.; Iwata, N.; Ito, M.; Taniguchi, T.; Chihara, K.; Matsui, T.
Jap. J. Cancer Res. 1996, 87, 743.
Ethyl malonyl
chloride (2.5 equiv)
H
H
O
O
2,6-di-t-butyl-4-methyl
pyridine (2.5 equiv)
CH2Cl2 , 5 h
OH
O
O
O
O
O
O
12
13
98%
KHMDS (2.0 equiv)
–78 °C then r.t.
overnight
91%
(7) The stereochemical assignment for diene 4 was based on the
coupling constant between H-3 and H-4 (J = 18 Hz),
consistent with the E isomer.
(8) Triene 9 was prepared in 82% yield by reaction of alcohol 4
with diphenylvinylsilyl chloride in dichloromethane at r.t. in
the presence of triethylamine.
(9) The stereochemical assignment for lactol 10 was based on
NOE data and on the coupling constant between the
hydrogen atoms at the ring junction positions (J = 4.5 Hz),
consistent with the cis isomer.
HO
HO
O
O
O
O
2
Scheme 6
(10) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919.
(11) (a) Davis, F. A.; Mancinelli, P. A.; Balasubramanian, K.;
Nadir, U. J. Am. Chem. Soc. 1979, 101, 1044. (b) Davis, F.
A.; Stringer, O. D. J. Org. Chem. 1982, 47, 1744. (c)Davis,
F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org.
Chem. 1984, 49, 3241. (d) Davis, F. A.; Lamendale, J.;
Nadir, U.; Kluger, E. W.; Sedergran, T. C.; Panunto, T. W.;
Billmers, R.; Jenkins, R.; Turchi, I. J.; Watson, W. H.; Chen,
J. S.; Kimura, M. J. Am. Chem. Soc. 1980, 102, 2000.
(e) Glinski, M. B.; Freed, J. C.; Durst, T. J. Org. Chem.
1987, 52, 2749.
(12) Belletire, J. L.; Fry, D. K. J. Org. Chem. 1988, 53, 4724.
(13) (a) Ireland, R. E.; Thompson, W. J. J. Org. Chem. 1979, 44,
3041. (b) Roush, W. R.; Sciotti, R. J. J. Org. Chem. 1998,
63, 5473. (c) Roush, W. R.; Reilly, M. L.; Koyama, K.;
Brown, B. B. J. Org. Chem. 1997, 62, 8708.
Treatment of malonate derivative 13 with lithium bis(tri-
methylsilyl)amide (2.0 equiv) overnight at room tempera-
ture did not induce product formation. Ishihara has
reported that potassium bis(trimethylsilyl)amide is a
much more effective reagent for Dieckmann cyclization
than are the corresponding lithium or sodium deriva-
tives.14 We were gratified to find that the desired Dieck-
mann cyclization to give 2 proceeded smoothly in 91%
yield upon exposure of 13 to potassium bis(trimethyl-
silyl)amide at –78 °C, allowing the mixture to reach room
temperature, and stirring overnight.15 The driving force is
presumably the formation of the highly conjugated five-
membered ring in place of the six-membered ring lac-
tone.
(14) Ishihara, J.; Nonaka, R.; Terasawa, Y.; Tadano, K.; Ogawa,
S. Tetrahedron: Asymmetry 1994, 5, 2217.
(15) Analytical data: IR(neat): nmax = 3378, 2923, 1782, 1613
cm–1. 1H NMR (400 MHz, CDCl3): d = 0.74–0.84 (1 H, m),
1.1 (3 H, d, J = 5.2 Hz), 1.19 (1 H, s), 1.31 (3 H, t, J = 8.0
Hz), 1.41–1.49 (1 H, m), 1.60 (3 H, s), 1.76–1.79 (2 H, m),
1.97–2.03 (1 H, m), 2.33–2.40 (2 H, m), 3.59–3.71 (2 H, m),
4.3 (2 H, q, J = 8.0 Hz), 5.3 (1 H, s). 13C NMR (100.6 MHz,
CDCl3): d = 194, 167, 166, 138, 121, 95, 85, 62, 60, 41, 36,
35, 31, 23, 19, 15. MS (EI): m/z (%) = 310 (100) [M+] , 199,
134, 120, 91, 60. Found: 310.14124; C16H22O6 requires
310.14164.
Acknowledgment
This investigation has enjoyed the support of Loughborough
University, Glaxo SmithKline, and the Leverhulme Trust.
References
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Nakano, A.; Ohtsuka, T.; Yoshizaki, H.; Arisawa, M. Eur. J.
Pharmacol. 1992, 221, 99.
Synlett 2003, No. 7, 1022–1024 ISSN 1234-567-89 © Thieme Stuttgart · New York