The synthesis and biological evaluation of novel eunicellin analogues

Article abstract of DOI:10.1055/s-2004-825627

The intramolecular Diels-Alder reaction of a 2,9-disubstituted hexahydro-Δ^5.6-oxonin derivative 14 afforded two diastereomeric tricyclic eunicellin analogues 15 and 16, which were desilylated to produce the alcohols 17 and 3; these were found t

Full text of DOI:10.1055/s-2004-825627

1434
LETTER
The Synthesis and Biological Evaluation of Novel Eunicellin Analogues
Synthesis
aand Biolog
m
ical Evaluation of
N
e
ovel Eunic
s
ellin Analogues E. P. Davidson,a Ryan Gilmour,a Sylvie Ducki,b John E. Davies,a Richard Green,c Jonathan W. Burton,*a
Andrew B. Holmes*a
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)334866; E-mail: abh1@cam.ac.uk
b
Centre for Molecular Drug Design, Cockcroft Building, University of Salford, Salford, M5 4WT, UK
c
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
Received 15 March 2004
Dedicated to Professor Clayton H. Heathcock for his inspiration and example in organic chemistry
Abstract: The intramolecular Diels–Alder reaction of a 2,9-disub-
stituted hexahydro-D5,6-oxonin derivative 14 afforded two diastere-
omeric tricyclic eunicellin analogues 15 and 16, which were
desilylated to produce the alcohols 17 and 3; these were found to be
microtubule stabilising agents with activity in the micromolar
range.
O
O
OH
O
OH
O
O
H
H
H
H
OTBDPS
OTBDPS
O
3
4
5
Key words: eunicellin, cycloaddition, lactone, microtubules
Scheme 1 Retrosynthetic analysis of the eunicellin skeleton 3
Eunicellin (1) and related diterpenoid marine natural
products such as the antineoplastic sclerophytin A (2) membered lactone precursor 5 which we have previously
have attracted considerable attention owing to their gener- described.9,10
al cytotoxic properties.1,2 A number of different synthetic
strategies have been employed, ranging from the pioneer-
ing Prins-pinacol condensation-rearrangement combined
Petasis methylenation11 of the lactone 59,10 (Scheme 2) af-
forded the enol ether 6. The enol ether was efficiently con-
verted into the aldehyde 9 by a method adapted from that
with Nozaki–Hiyama–Kishi ring closure approach of
used in the synthesis of octahydrodeacetyldebromolau-
Overman3 to the furanone annelation combined with ring
rencin.12 Addition of phenylselenyl chloride to the enol
closing metathesis approach of Paquette4 and the Lewis
ether 6 and subsequent reduction with lithium aluminium
hydride gave a mixture of the phenylselenomethyl deriv-
atives 7. Selenoxide formation followed by Pummerer re-
arrangement and methoxide cleavage of 8 afforded the
cis-2,9-disubstituted unsaturated oxonane 9. The cis-con-
figuration is predicted by molecular modelling to be the
acid-mediated [4+3]-annulation of Molander.5 Other im-
portant contributions have been made by Rainier,6 Jung7
and McIntosh.8 The importance of synthesis in the revi-
sion of certain structures in this family has been demon-
strated on several occasions.
thermodynamically preferred, and was confirmed by
AcO
HO
NOE measurements, which are consistent with previous
experience regarding the base-catalysed equilibration of
related 2,9-disubstituted oxonane derivatives.13
HO
O
O
OAc
OH
H
H
H
H
H
H
H
H
i
ii
O
O
O
AcO
AcO
OTBDPS
OTBDPS
OTBDPS
OTBDPS
OTBDPS
OTBDPS
O
2
1
PhSe
5
6
7
Figure 1 Eunicellin (1) and sclerophytin A (2)
iii
iv
Our strategy for the synthesis of the skeleton 3 (Scheme 1)
represented by 1 and 2 (Figure 1) is based on the use of an
intramolecular Diels–Alder reaction of a 2,9-disubstituted
nine-membered ether derivative 4 which should be readily
accessible from the corresponding D5,6-unsaturated 9-
O
O
OTBDPS
OTBDPS
OTBDPS
OTBDPS
H
H
PhSe
O
OAc
9
8
Scheme 2 Synthesis of the 2,9-cis-disubstituted D5,6-oxonane.
Reagents and conditions: i, Cp2TiMe2, toluene, 110 °C, 0.5 h, 83%;
ii, PhSeCl, THF, then LiAlH4, –78 °C, 52%; iii, m-CPBA, THF,
NaOAc, Ac2O, –78 °C → reflux; iv, MeOH, CH2Cl2, K2CO3, 16 h,
88% over two steps.
SYNLETT 2004, No. 8, pp 1434–1436
Advanced online publication: 08.06.2004
DOI: 10.1055/s-2004-825627; Art ID: Y02204ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
7.
2
0
0
4

LETTER
Synthesis and Biological Evaluation of Novel Eunicellin Analogues
1435
Synthesis of the diene component of the Diels–Alder pre- eunicellin configuration, arising from one of the two
cursor is illustrated in Scheme 3. The aldehyde 9 was con- possible endo transition states.
verted by Wittig reaction into the E-enal 10; Petasis
The parent natural products (1 and 2) possess a cis-anti-
cis-relative stereochemistry of the bridgehead hydrogens
methylenation11 of the enal proved unsatisfactory, giving
a mixture of products that were inseparable by HPLC.
in relation to the hydrogens at the angular positions that
However, Wittig methylenation yielded the diene 11 in
would arise from an exo transition state. Detailed 1H NMR
quantitative yield. This was deprotected to the alcohol and
analysis15 of the minor product 16 and comparison with
the data for 15 suggests that the structure of 16 corre-
oxidised with perruthenate14 to the aldehyde 13.
sponds to the required natural configuration of the euni-
cellin skeleton, and efforts are in hand to adjust the
diastereoselectivity of the intramolecular cycloaddition
reaction.
O
O
O
i
ii
OTBDPS
OTBDPS
OTBDPS
OTBDPS
OTBDPS
OTBDPS
O
O
9
10
11
O
O
iii
iv
OTBDPS
OH
OTBDPS
O
12
13
Scheme 3 Synthesis of the aldehyde 13. Reagents and conditions: i,
2-(Triphenylphosphoranylidene)propanal, toluene, 110 °C, 62%; ii,
Ph3PCH3Br, n-BuLi, –78 °C, 2 h, 100%; iii, HF–pyridine, THF, 3 h,
89%; iv, TPAP, NMO, 4 Å molecular sieves, CH2Cl2, 0.5 h, 100%.
Figure 2 X-ray crystal structure of the alcohol 1716,17
The aldehyde 13 was converted into the enone 14 by a
Wittig reaction. Under the conditions employed the prod-
uct 14 underwent an in situ intramolecular Diels–Alder
reaction to afford two diastereomeric tricyclic adducts
15 and 16 in a 3:1 ratio and a combined overall yield of
84% (Scheme 4). Finally, cleavage of the silyl ether with
HF–pyridine furnished the diastereomeric eunicellin ana-
logues 17 and 3 in 77% and 64% yield, respectively.
The effect of the new analogues 17 and 3 on the assembly
of tubulin to form microtubules was assessed using pacli-
taxel™ as a reference (Table 1).18 Both compounds were
shown to induce microtubule assembly and stabilise them
in the presence of CaCl2.19
Table 1 Comparison of Tubulin Assembly Properties of 17 and 3
with that of Paclitaxel™.
The alcohol 17 derived from the major adduct 15 afforded
crystals suitable for X-ray crystal structure analysis which
revealed (Figure 2) that it corresponded to a non-natural
Compound
ED90 (mM)a
Paclitaxel™
<0.5
3
3
7
0.6
1.4
17
ii
O
O
O
OTBDPS
O
OTBDPS
O
OTBDPS
+
a ED90: Effective dose required to induce 90% tubulin assembly.18
H
H
H
H
H
H
H
H
O
The lower ED90 of 3 compared with 17 (Table 1), corre-
lates with a more potent microtubule stabilising activity.
This may be consistent with the fact that the minor adduct
corresponds to the natural eunicellin configuration.
15
16
14
iii
i
O
O
OH
H
OH
H
H
+
H
H
H
H
O
H
Acknowledgment
O
13
We thank EPSRC for financial support, provision of the Swansea
National Mass Spectrometry Service, assistance with the purchase
of the Rigaku AFC7R diffractometer, and a doctoral training award
(RG). We thank GSK for the award of a studentship (JEPD), The
Royal Society (University Research Fellowship to Dr J. W. Burton)
and Dr S. J. Conway for helpful discussions. R. A. Robinson made
early suggestions in this project.
17
3
Scheme 4 Tandem Wittig/Diels–Alder sequence to prepare adducts
15 and 16. Reagents and conditions: i, 1-Triphenylphosphoranylide-
ne-2-propanone, toluene, 110 °C, 2 h, 84%; ii, heat; iii, HF (40% aq),
MeCN, 48 h, 17 (77%), 3 (64%).
Synlett 2004, No. 8, 1434–1436 © Thieme Stuttgart · New York

1436
J. E. P. Davidson et al.
LETTER
2859 (m), 1713 (s) (CO), 1473 (m), 1428 (m), 1358 (m),
References
1111 (s), 1089 (m), 1043 (s), 1021 (m), 943 (w), 823 (m),
610 (w) cm–1. 1H NMR (500 MHz, CDCl3): d = 7.64–7.71 (4
H, m, Ar), 7.33–7.44 (6 H, m, Ar), 5.55–5.64 (1 H, m, H-6),
5.30–5.50 (1 H, br s, H-5), 5.20–5.24 (1 H, m, H-12), 4.65 (1
H, dd, J = 8.4 and 1.1 Hz, H-2), 3.95–4.03 (1 H, m, H-9),
3.48 (1 H, d, J = 8.4 Hz, H-3), 2.72–2.81 (1 H, m, H-10), 2.54
(1 H, dt, J = 11.0 and 6.8 Hz, H-14), 2.10–2.47 (4 H, m,
H-1, H-4, H-13 and H-7), 2.02–2.11 (2 H, m, H-4 and H-8),
1.87–1.96 (1 H, m, H-13), 1.79 (3 H, s, CH3CO), 1.67–1.75
(1 H, m, H-8), 1.66 (3 H, s, CH3C=C) and 1.04 [9 H, s,
C(CH3)3]. 13C NMR (62.5 MHz, CDCl3): d = 209.2 (C=O),
136.0, 136.0, 134.8, 134.6, 130.9, 129.5, 129.5, 127.6 and
127.47 (Ar), 133.7 (C-11), 130.9 (C-6), 127.3 (C-5), 120.5
(C-12), 84.6 (C-2), 80.4 (C-9), 71.8 (C-3), 48.9 (C-14), 45.9
(C-1), 43.6 (C-10), 31.9 (C-4), 30.8 (C-13), 27.8 (CH3CO),
27.5 (C-8), 27.0 [C(CH3)3], 21.4 (C-7), 21.2 (CH3C=C) and
19.2 [C(CH3)3]. MS (EI): m/z (%) = 514 (20) [M+], 491 (15),
472 (10), 457 (100) [M – t-Bu]+, 215 (10), 199 (85), 135 (40)
and 77 (20). C33H42O3Si requires [M]: 514.2903; found
[M+]: 514.2884.
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Data for 16: Rf = 0.55 (CH2Cl2), [a]D25 +0.8 (c 0.76 in
CHCl3). IR (CHCl3): νmax = 2931 (s), 2859 (s), 1709 (s)
(CO), 1472 (w), 1428 (m), 1170 (w), 1112 (s), 1071 (s), 999
(w), 824 (m), 612 (m) cm-1. 1H NMR (500 MHz, CDCl3):
d = 7.68–7.73 (4 H, m, Ar), 7.34–7.45 (6 H, m, Ar), 5.51–
5.59 (1 H, m, H-6), 5.40–5.50 (1 H, m, H-5), 5.31 (1 H, br s,
H-12), 4.03 (1 H, t, J = 6.2 Hz, H-9), 3.84 (1 H, d, J = 5.8 Hz,
H-2), 3.78 (1 H, dd, J = 9.0 and 2.9 Hz, H-3), 2.38–2.73 (4
H, m, H-4, H-10, H-7 and H-1), 2.20–2.28 (1 H, m, H-4),
2.07–2.20 (2 H, m, H-7 and H-8), 1.96–2.05 (1 H, m, H-13),
1.94 (3 H, s, CH3CO), 1.84–1.92 (2 H, m, H-14 and H-13),
1.58–2.66 (1 H, m, H-8), 1.59 (3 H, s, CH3C=C) and 1.07
[9 H, s, C(CH3)3]. 13C NMR (62.5 MHz, CDCl3): d = 210.2
(C=O), 136.1, 136.0, 135.5, 130.8 and 127.5 (Ar), 134.1
(C-11), 129.6 (C-6), 126.4 (C-5), 118.7 (C-12), 90.3 (C-2),
84.5 (C-9), 74.1 (C-3), 48.5 (C-14), 45.5 (C-10), 41.5 (C-1),
31.2 (C-8), 30.6 (C-4), 28.7 (CH3CO), 27.1 [C(CH3)3], 25.2
(C-13), 22.7 (CH3C=C), 21.7 (C-7) and 19.3 [C(CH3)3]. MS
(CI, NH3): m/z (%) = 532 (10) [M + NH4]+, 515 (2) [M + H]+,
437 (15), 259 (100). C33H46NO3Si requires [M]: 532. 3247.
Found [M + NH4]+: 532.325.
(16) Crystal data for 17: C17H24O3, M = 276.36, trigonal, space
group P31, (no. 144), a = b = 10.041 (3), c = 12.585 (5) Å,
a = b = 90o, g = 120o, U = 1098.8 (6) Å3, Z = 3,
(14) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
Chem. Commun. 1987, 1625.
m(MoKa) = 0.084 mm–1, 1450 reflections measured at 150
(2) K using an Oxford Cryosystems Cryostream cooling
apparatus, 1332 unique (Rint = 0.039); R1 = 0.073,
(15) Wittig Elaboration of 13 and Intramolecular
Cycloaddition of 14 to Give 15 and 16. To a stirred solution
of the aldehyde 13 (93 mg, 0.2 mmol) in toluene (15 mL)
was added 1-triphenylphosphoranylidene-2-propanone (187
mg, 0.59 mmol). The resultant mixture was heated to reflux
for 2 h 15 min, and then allowed to cool to ambient
temperature. The solvent was removed in vacuo and
purification by flash chromatography (CH2Cl2) yielded the
title compounds 15 (64 mg, 63%) and 16 (21.4 mg, 21%) as
colourless oils.
wR2 = 0.189 [I>2s(I)]; goodness-of-fit on F2, S = 1.030. The
structure was solved with SHELXS-97 and refined with
SHELXL-9717 (CCDB 233639).
(17) Sheldrake, G. M. SHELXS-97/SHELXL-97; University of
Göttingen: Germany, 1997.
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Sirtori, F. R.; Telser, J.; Gennari, C. Tetrahedron 2003, 59,
8803.
Data for 15: Rf = 0.41 (CH2Cl2); [a]D25 –24.6 (c 0.65 in
CHCl3). IR (CHCl3): nmax = 3022 (w), 3019 (m), 2932 (s),
(19) Microtubules did not depolymerise at 10 °C.
Synlett 2004, No. 8, 1434–1436 © Thieme Stuttgart · New York