Synthesis and endothelin receptor binding activity of synthetic analogues of RES-1149-2

Article abstract of DOI:10.1016/S0960-894X(00)00136-0

A direct synthesis of analogues 6 and 7 is described. The key transformations are the addition of dibromomethyl lithium to a ketone and the subsequent mild hydrolysis to a hemiacetal. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00136-0

Bioorganic & Medicinal Chemistry Letters 10 (2000) 895±897
Synthesis and Endothelin Receptor Binding Activity of Synthetic
Analogues of RES-1149-2
George A. Kraus* and Xuemei Wang
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 11 January 2000; accepted 14 February 2000
AbstractÐA direct synthesis of analogues 6 and 7 is described. The key transformations are the addition of dibromomethyl lithium
to a ketone and the subsequent mild hydrolysis to a hemiacetal. # 2000 Elsevier Science Ltd. All rights reserved.
Drimane sesquiterpenes have been reported to exhibit a
broad range of useful biological activities, including
anticancer, antiviral and anti-in¯ammatory activity.
RES-1149-2 (1) and related lactols 2 and 3 were isolated
from the fungus Aspergillus ustus var. pseudo¯ectus in
1995.1 Pereniporin A (4) and B (5) were isolated as
metabolites from microorganisms Perreniporia medul-
laepanis Aj 8345.2 Compounds 1±3 exhibit endothelin
receptor binding activity at the mg/mL level in the rabbit
ETA assay and at the mg/mL level in the human ETA
assay. Alcohols 4 and 5 show antibiotic activity against
Bacillus subtilis Aj 1316 and exhibit cytotoxicity against
the Friend leukemia virus at the mg/mL level.
dimethylcyclohexanone.6 However, no synthesis or syn-
thetic approaches to 1±3 have been communicated. As
part of a program to identify and synthesize sesqui-
terpene antiviral agents that exert useful biological
activity,7 we have developed direct preparations of ana-
logues 6 and 7 from ketone 8. Compounds 6 and 7
represent bicyclic analogues that possess most of the key
functionality contained in compounds 1±3.
The key transformation is the direct installation of the
hemiacetal and lactone carbonyl carbon atom via the
addition of dibromomethyl lithium followed by the
high-yield conversion of the dibromomethyl group into
a lactol. The hydrolysis of dibromomethyl groups to
aldehydes has been reported to proceed in modest yield.
We attribute the successful conversion to neighboring
group participation by the alkoxide of the primary
allylic alcohol.
Syntheses and synthetic approaches to pereniporin A
and B have been reported. Urones and co-workers pre-
pared 4 by modifying 12-acetoxy-7,9(11)-drimadiene.3
Burke and co-workers synthesized 5 via a clever vinyl
silane intermediate.4 Vidari and co-workers converted
cinnamodial into 4.5 Mori and Takaishi produced both
4 and 5 by a 33-step synthesis from (S) 3-hydroxy-2,2-
The synthetic route begins with bicyclic ketone 8, read-
ily available from 1.3-cyclohexanedione and formalde-
hyde.8 Ketone 8 was converted into silyl ether 9 in 83%
yield over two steps by treatment with lithium diiso-
propylamide (LDA) and trimethylchlorosilane at
20 ꢀC followed by oxidation with MCPBA. Desilylation
using potassium carbonate in methanol provided
alcohol 10. The reaction of 9 with LAH followed by
*Corresponding author. Tel.: +1-515-294-7794; fax: +1-515-294-
0105; e-mail: gakraus@iastate.edu
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00136-0

896
G. A. Kraus, X. Wang / Bioorg. Med. Chem. Lett. 10 (2000) 895±897
work up with 3 N HCl a€orded diol 11 in 73% yield by
a sequence involving reduction of the ketone and acid-
mediated rearrangement. Monosilylation of diol 11
using 1 equiv of tert-butyldimethylchlorosilane (TBSCl)
with triethylamine and dimethylaminopyridine in
methylene chloride generated alcohol 12 in 87% yield.
Monosilylation favored the less sterically hindered
alcohol. The use of 2 equiv of TBSCl provided 13.
The reaction of 12 with dibromomethyl lithium, pre-
pared by a modi®cation of Taguchi's procedure,9 at
78 ꢀC provided a 91% yield of 14a and 14b in a ratio
of 1.5:1. The addition of dibromomethyl lithium to 13
provided 15a and 15b in 91% yield in a 15:1 ratio of
diastereomers.
Table 1. The IC50 values of natural products and analogues
Compound Rabbit ETA Rabbit ETB Human ETA Human ETB
(mM)
(mM)
(mM)
(mM)
1
2
3
155
65
50
50
21
70
135
62
>250
73
41
148
>25
>25
>25
6
2.5
7
18
2.6
8.2
The binding activity of analogues 6, 7, and 18 is depic-
ted above in Table 1. All three compounds exhibit sub-
stantial endothelin receptor binding activity in the
human ETA assay. Interestingly, the analogues appear
to be more e€ective than the natural products at the
ETA receptor.10
The direct synthesis of 6 and 7 illustrates the synthetic
utility of the dibromomethyl lithium addition/hydrolysis
sequence.11 The mild methodology for the introduction
of a hemiacetal carbon should have broad utility in
synthesis. Analogues 6 and 7 may stimulate the devel-
opment of novel synthetic probes for the endothelin
receptor site, since a majority of the endothelin receptor
antagonists that have been reported are peptide-based
compounds. In recent years a number of heterocyclic
aromatic endothelin receptor antagonists have also been
developed.12
The reaction of 15a and 15b with HF in acetonitrile
a€orded a triol in 97% yield that, without puri®cation,
was treated with potassium carbonate in aqueous
isopropanol to a€ord lactol 16 in 93% yield. The excel-
lent yield in the hydrolysis of the dibromomethyl group
is likely due to neighboring group participation from
the alkoxide of the primary allylic alcohol. The reaction
of 16 with trimethyl orthoformate and a catalytic
amount of PTSA produced diols 17 in 86% yield as a
3:1 mixture at the anomeric center.
Acknowledgements
We thank the Center for Advanced Technology Devel-
opment at Iowa State for partial support of this
research. We thank Steven Haleen and Kathleen Welch
of Park-Davis for performing the receptor binding
assays.
References and Notes
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A.; Matsuda, Y. J. Antibiot. 1996, 49, 168. Ogawa, T.; Ando,
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1. Uosaki, Y.; Yoshida, M.; Ogawa, T.; Saitoh, Y. J. Antibiot.
1996, 49, 6. Hayes, M. A.; Wrigley, S. K.; Chetland, I.;
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P.; Moro, R. F. J. Chem. Soc., Perkin Trans. 1 1997, 1815.
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The acylation of diol 17 using either the acid chloride of
sorbic acid or sorbic acid and dimethylaminopyridine
produced the desired ester along with elimination pro-
ducts and some aromatized products. However, the
reaction of 17 with the anhydride of sorbic acid and
triethylamine and dimethylaminopyridine in methylene
chloride at 0 ꢀC gave the ester 18 in 75% yield which
could be hydrolyzed to hemiacetal 6 in 88% yield using
aqueous HCl in THF at 50 ꢀC. Compound 6 was a single
stereoisomer. Lactone 7 was synthesized from 6 using
N-iodo succinimide (NIS) and tetrabutylammonium
iodide in 91% yield.
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11. Experimental and spectra: To a solution of ketone (10
mmol) and CH2Br2 (50 mmol) in THF (50 mL), 3 to 5 equiv
of LiTMP (30 mmol, prepared from tetramethylpiperidine
(4.23 g, 30 mmol) and n-butyllithium (12 mL of 2.5 M solution
in hexanes)), were added slowly at 78 ꢀC. The reaction was
stirred at 78 ꢀC for 3 h and monitored by TLC. Saturated
NH4Cl solution (15 mL) was added at 78 ꢀC. The mixture
was then extracted with ether, washed with brine, dried over
MgSO4, and concentrated. The residue was puri®ed by sgc,
eluting with hexanes and ethyl acetate, to give dihalomethyl
carbinol. To the dihalomethyl carbinol (100 mg) in a mixture
of i-PrOH (5 mL) and water (5 mL), K2CO3 (100 mg) was
added. It was stirred at rt for 1 to 12 h (TLC). The i-PrOH was
removed in vacuo. The aqueous solution was saturated with
NaCl and extracted with ethyl acetate. The organic layers were
dried over MgSO4 and concentrated. The residue was puri®ed
by sgc (eluting with hexanes and ethyl acetate) to give the
lactol. 16: 1H NMR (acetone-d6, d): 5.64 (s, 1H), 5.10 (m, 1H),
4.2±4.5 (m, 3H), 3.5±3.9 (m, 3H), 2.0 (m, 2H). 13C NMR
(acetone-d6, d): 140.8, 128.3, 123.2, 102.9, 75.9, 67.6, 27.0,
23.9. IR (neat) cm 1: 3540, 1627, 1604. MS m/z (CI): 172, 154.
HRMS m/z (M H2O): 154.0631 for C8H10O3: 154.0630. 6: 1H
NMR (CDCl3, d): 7.12±7.29 (m, 1H), 6.13±6.19 (m, 2H), 5.75
(dd, J=15, 1.5 Hz, 2H), 5.49 (d, J=16 Hz, 1H), 5.26 (s, 1/2H),
4.93 (s, 1/2H), 4.59 (dt, J=16, 2.4 Hz, 1H), 4.34 (dt, J=16, 2.4
Hz, 1H), 1.5±2.0 (m, 4H). 13C NMR (CDCl3, d): 167.1, 145.8,
142.5, 140.1, 129.8, 123.4, 118.8, 102.4, 76.4, 70.3, 67.5, 29.7,
24.0, 18.8. IR (neat) cm 1: 3450, 3368, 2959, 2921, 1716, 1616,
1558, 1539 ,1050, 1018. MS m/z (CI±NH3): 252, 110.
12. Rosendor€, C. Cardiovasc. Drugs Ther. 1997, 10, 795.
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Kusumoto, K.; Itoh, Y.; Ohtaki, T. Watanabe, T.; Furuya, S.
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