Solid-phase synthesis of diverse E- and F-series prostaglandins

Full text of DOI:10.1021/jo9800762

2066
J . Org. Chem. 1998, 63, 2066-2067
Sch em e 1a
Solid -P h a se Syn th esis of Diver se E- a n d
F -Ser ies P r osta gla n d in s
Lorin A. Thompson,† Frederick L. Moore,
Young-Choon Moon, and J onathan A. Ellman*
Department of Chemistry, University of California,
Berkeley, California 94720
Received J anuary 15, 1998
The naturally occurring prostaglandins have important
and wide-ranging biological activities, and many synthetic
analogues have been developed as drugs and as pharmaco-
logical tools. Prostaglandins (PGs) are complex structures
that display functionality of defined stereochemistry about
a cyclopentane core. They are also delicate structures that
are often sensitive to both acidic and basic reaction condi-
tions. Thus, the general synthesis of these molecules
continues to provide a standard for demonstrating the
versatility of new synthesis methods.1 In this paper, we
describe general solid-phase methods for the rapid prepara-
tion of members of several of the structurally distinct PG
classes.2
a
Reagents and conditions: (a) Br2, CH2Cl2, 0 °C; then Et3N, 0 °C
to rt; (b) CeCl3, NaBH4, CH3OH, -78 °C; (c) TMT-Cl, pyridine, DMAP,
50 °C; (d) TBAF, THF, rt; (e) t-BuLi, CuCN, (Z)-1,3-dibromo-1-propene,
-78 °C.
Sch em e 2a
A common synthesis sequence has been devised that
provides access to both 1- and 2-series PGs as either E or F
derivatives. The common synthesis sequence is based upon
the display of functionality about two central cyclopentane
core structures. Core structure 3 provides access to 1-series
PGs, while core structure 5 provides access to 2-series
derivatives (Scheme 1).
The core structures are synthesized from TBS-protected
(R)-4-hydroxycyclopenten-2-one (Scheme 1). The R-bromine
atom is introduced using bromine and Et3N in CH2Cl2.
Reduction under Luche conditions with NaBH4 and CeCl3
then provides the monoprotected diol with 6:1-8:1 selectivity
favoring the cis epimer.3 The diastereomerically pure cis
isomer can be obtained by crystallization from pentane at
-20 °C.4 Protection with the trimethoxytrityl (TMT) group
(TMT-Cl, pyridine, DMAP, 50 °C) and desilylation (TBAF,
THF) then provides 3, the core alcohol for the 1-series PGs.
Halogen-metal exchange on 2 with t-BuLi followed by the
addition of CuCN and then (Z)-1,3-dibromo-1-propene pro-
vides 4. The TBS group is then removed using TBAF in
THF to provide 5, the core alcohol for synthesis of the
2-series PGs.
To load alcohols 3 and 5 onto the solid support, we employ
a dibutylsilyl chloride-substituted resin that is prepared
according to the general procedure of Farrall and Frechet.5
Reaction of the dibutylsilyl chloride resin with alcohol 3 or
5 in CH2Cl2 with imidazole provides the support-bound
alcohol. The alcohol loading levels are rapidly and precisely
determined by acid-mediated TMT cleavage (1 M formic acid
in CH2Cl2, 5 min) followed by spectrophotometric quantita-
tion of the released TMT cation. The loading levels range
from 0.35 to 0.45 mmol/g over multiple runs.
a
Reagents and conditions: (a) 1 M HCOOH/CH2Cl2, rt; (b) alkyl-
9-BBN derivative, Pd(PPh3)4, 2 M Na2CO3, THF 65 °C; (c) Dess-Martin
peridinane, CH2Cl2, 45 °C; (d) alkyne, Cp2ZrHCl, CuCN, 3 equiv of
CH3Li, THF, -78 to -20 °C; (e) L-Selectride, THF, -78 °C; (f) 17.5%
HF/pyridine, THF, rt.
Our initial work was carried out using the dimethoxytrityl
(DMT) protecting group on the core structures and using
diisopropylsilyl chloride substituted resin.6 However, we
found that alcohols linked through the diisopropylsilyl linker
do not cleave readily in dilute HF/pyridine, one of the few
cleavage reagents compatible with the â-hydroxy ketone E
series PGs.1a In contrast, with the dibutylsilyl linker,
complete release from support is observed in less than 2 h
using dilute HF/pyridine. Replacement of the DMT group
with the more labile TMT protecting group is necessary to
minimize cleavage from support (<5%) during alcohol depro-
tection.
The first element of diversity is introduced by a Suzuki
cross-coupling reaction as is shown in Scheme 2 for 1-series
PG derivatives. The Suzuki reaction is particularly appeal-
ing because functionality may be directly incorporated from
the large number of available terminal alkenes by in situ
hydroboration.7 The use of a Suzuki coupling approach was
inspired by the elegant chemistry that J ohnson and Braun
have developed for 1-series PG synthesis in solution, where
Suzuki cross-coupling reactions were carried out upon
2-iodo-4-(silyloxy)cyclopent-2-enone at room temperature
using PdCl2(dppf) with Ph3As as the catalyst.1b We chose
to employ cyclopentenol cores 3 and 5 because we found that
the conditions required to ensure complete Suzuki cross-
coupling for diverse alkylboranes on support resulted in
decomposition of the corresponding base-labile â-alkoxy
ketones for some derivatives.
Both the acid-labile TMT protecting group and the nature
of the alkyl groups on silicon required careful optimization.
† The DuPont Merck Pharmaceutical Co., Wilmington, DE 19880.
(1) (a) Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533. (b)
J ohnson, C. R.; Braun, M. P. J . Am. Chem. Soc. 1993, 115, 11014. (c)
Lipshutz, B. H.; Wood, M. R. J . Am. Chem. Soc. 1994, 116, 11689.
(2) The synthesis of a prostaglandin (prostaglandin E2 methyl ester) in
37% overall yield was recently reported using a soluble polymer. Chen, S.;
J anda, K. D. J . Am. Chem. Soc. 1997, 119, 8724.
(3) Nakazawa, M.; Sakamoto, Y.; Takahashi, T.; Tomooka, K.; Ishikawa,
K.; Nakai, T. Tetrahedron Lett. 1993, 34, 5923.
(4) The mixture of diastereomers is usually used directly as the second
stereocenter is later destroyed in the oxidation step.
(5) Farrall, M. J .; Frechet, J . M. J . J . Org. Chem. 1976, 41, 3877.
(6) Danishefsky, S. J .; McClure, K. F.; Randolph, J . T.; Ruggeri, R. B.
Science 1993, 260, 1307.
(7) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
S0022-3263(98)00076-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/12/1998

Communications
J . Org. Chem., Vol. 63, No. 7, 1998 2067
Sch em e 3a
Ta ble 1. P r osta gla n d in s Syn th esized on Su p p or t
entry
cmpd
class
series
R1 or Z-R3
yielda (%)
1
2
3
4
5
6
7
8
9
14a
14a
14a
14b
10a
10b
18a
18a
18a
18b
18b
E
E
E
F
E
F
E
E
E
F
F
2
2
2
2
1
1
1
1
1
1
1
CH2CH2OCH3
(CH2)3CH3
CH2CH2OCH3
CH2CH2OCH3
(CH2)3CH3
(CH2)3CH3
NHSO2Ph
NHCH2Ph
OCH2CH3
OCH3
52
54
50
54
60
54
55
58
55
49
57
b
10
11
OCH(CH3)2
a
Yields of analytically pure material based upon the TMT
b
quantitation of support-bound core 3 or 5. This derivative was
a
synthesized using TES-protected (()-4,4′dimethyl-1-octyn-3-ol. For
Reagents and conditions: (a) alkyl-9-BBN derivative, Pd(PPh3)4,
all other derivatives, R2 ) (CH2)4CH3.
2 M Na2CO3, THF 65 °C; (b) 1 M HCOOH/CH2Cl2, rt; (c) Dess-Martin
periodinane, CH2Cl2, 45 °C; (d) alkyne, Cp2ZrHCl, CuCN, 3 equiv of
CH3Li, THF, -78 to -20 °C; (e) L-Selectride, THF, -78 °C; (f) 17.5%
HF/pyridine, THF, rt.
Suzuki coupling reactions are accomplished using stan-
dard conditions [Pd(PPh3)4 as catalyst with 2 M Na2CO3 as
the base in refluxing THF] and with 5 equiv of an alkyl
9-BBN derivative prepared by in situ hydroboration of an
alkene (Scheme 2). The secondary alcohol is then oxidized
using 3 equiv of Dess-Martin periodinane in refluxing CH2-
Cl2 for 2 h to provide enones 8. A number of other oxidants
were explored but either did not result in complete oxidation
or resulted in some cleavage of the intermediate from the
support.
Sch em e 4a
Diversity in the lower side chain is readily introduced by
the addition of vinyl cuprates, which are prepared in situ
from readily accessible terminal alkynes by hydrozirconation
followed by transmetalation using the chemistry developed
by Lipshutz and co-workers. After investigating a number
of hydrozirconation/transmetalation procedures,8 we found
that the use of 5 equiv of a vinyl cuprate prepared by the
procedure of Babiak and co-workers8b gives the best results.
The PGE derivative 10a may be cleaved from the support
using 17.5% HF/pyridine at 0.2 M in THF for 2 h. Alter-
natively, the PGF derivative 10b can be prepared by
reduction of the support-bound PGE derivative 9a with 10
equiv of L-Selectride at -78 °C for 1 h and subsequent
cleavage from support. As shown in entries 5-11 in Table
1, the final 1-series PGs are isolated in analytically pure
form in 49-60% overall yields after purification by filtration
through silica gel. All of the prostaglandin products were
obtained in greater than 95% diastereomeric purity as would
be expected on the basis of analogous cuprate addition
chemistry in solution.
The synthesis of the 2-series PGs is shown in Scheme 3.
The steps are almost identical to the 1-series derivatives;
however, the TMT group may be removed either before or
after the Suzuki coupling step. As shown in entries 1-4 of
Table 1, the pure 2-series derivatives are isolated in com-
parable 50-54% overall yields after filtration through silica
gel.
All naturally occurring PGs and many synthetic deriva-
tives incorporate carboxylic acids or acid derivatives in the
upper side chain. To introduce diverse functionality at this
a
Reagents and conditions: (a) L-Selectride, THF, -78 °C; (b) 1 M
BrCH2CN, 0.5 M i-Pr2EtN, NMP, rt; (c) 1 M amine, NMP, rt; or 2 M
alcohol, DMAP, NMP, 50 °C; (d) 17.5% HF/pyridine, THF, rt.
site, we chose to incorporate carboxylic acid functionality
protected as an N-acylbenzenesulfonamide. N-Acylsulfona-
mides are stable to all of the reaction conditions in the
synthetic sequence, including the reduction with L-Selectride
that provides the F-series PGs. Sulfonamides 15a or 15b
(Scheme 4) are prepared according to the general procedures
to obtain 1-series PGs (Scheme 2). Activation is then
accomplished by treatment with 1 M bromoacetonitrile and
0.5 M i-Pr2EtN.9 The activated sulfonamides 16a or 16b
are displaced with an amine nucleophile or an alcohol using
DMAP as catalyst. Representative PG esters and amides
synthesized by this method are isolated in 49-58% overall
yields after release from support as shown in entries 8-11,
Table 1.
In conclusion, we have developed general and efficient
methods for the synthesis of a variety of PG derivatives on
solid support. We are currently using this chemistry for the
parallel synthesis of PG derivatives to identify novel PGs
for use as pharmacological tools.
Ack n ow led gm en t. We thank the NIH (GM-50353) and
Proctor and Gamble for funding. L.A.T. is grateful to Glaxo-
Wellcome for a graduate fellowship.
(8) (a) Lipshutz, B. H.; Ellsworth, E. L. J . Am. Chem. Soc. 1990, 112,
7440. (b) Babiak, K. A.; Behling, J . R.; Dygos, J . H.; McLaughlin, K. T.; Ng,
J . S.; Kalish, V. J .; Kramer, S. W.; Shone, R. L. J . Am. Chem. Soc. 1990,
112, 7441. (c) Dygos, J . H.; Adamek, J . P.; Babiak, K. A.; Behling, J . R.;
Medich, J . R.; Ng, J . S.; Wieczorek, J . J . J . Org. Chem. 1991, 56, 2549. (d)
Lipshutz, B. H.; Keil, R. J . Am. Chem. Soc. 1992, 114, 7919.
(9) Backes, B. J .; Virgilio, A. A.; Ellman, J . A. J . Am. Chem. Soc. 1996,
118, 3055.
Su p p or tin g In for m a tion Ava ila ble: Experimental details for
the synthesis and characterization of all compounds (32 pages).
J O9800762