An efficient synthesis of 3-hetero-13,14-dihydro prostaglandin F1α analogues

Article abstract of DOI:10.1021/ol015613a

Matrix presented A new class of 3-hetero-13,14-dihydro prostaglandin F_1α analogues was synthesized from a common intermediate. The latter was constructed via a two-step, three-component process. The lower chain, containing the 15-(phenoxymethyl

Full text of DOI:10.1021/ol015613a

ORGANIC
LETTERS
2001
Vol. 3, No. 5
791-794
An Efficient Synthesis of
3-Hetero-13,14-dihydro Prostaglandin F1r
Analogues
Jianxin Gu,† Michelle J. Dirr,‡ Yili Wang,‡ David L. Soper,‡ Biswanath De,‡
,†
John A. Wos,‡ and Carl R. Johnson*
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489,
and Procter & Gamble Pharmaceuticals, 8700 Mason-Montgomery Road,
Mason, Ohio 45040-8006
crj@chem.wayne.edu
Received January 24, 2001
ABSTRACT
A new class of 3-hetero-13,14-dihydro prostaglandin F1r analogues was synthesized from a common intermediate. The latter was constructed
via a two-step, three-component process. The lower chain, containing the 15-(phenoxymethyl) group, was synthesized in enantiopure form
using Jacobsen’s (salen)Co-catalyzed kinetic resolution of a terminal epoxide with phenol.
The identification and cloning of multiple prostaglandin
receptor subtypes1 has resulted in renewed enthusiasm for
the development of highly receptor-selective prostaglandin
derivatives. Ideally, such compounds would exhibit desirable
activity without the side effects associated with indiscriminate
binding to multiple receptors. As a part of research program
in designing highly receptor-selective PGF2R analogues as
potential bone anabolic agents for the treatment of os-
teoporosis,2 we disclose an efficient synthesis of a novel class
of saturated PGF analogues 1a-g from a common interme-
diate, 2 (Scheme 1).
Scheme 1
† Wayne State University.
‡ Procter & Gamble Pharmaceuticals.
(1) Coleman, R. A.; Smith, W. L.; Narumiya, S. Pharmacol. ReV. 1994,
46, 205-229.
(2) Wang, Y.; Wos, J. A.; Dirr, M. J.; Soper, D. L.; DeLong, M. A.;
Mieling, G. E.; De, B.; Amburgey, J. S.; Suchanek, E. G.; Taylor, C. J. J.
Med. Chem. 2000, 43, 945-952.
Many interesting synthetic methods have been developed
for the synthesis of prostaglandins, including Corey’s 2-fold
Wittig approach,3 the two-component process,4 the three-
component coupling methodology,5,6 and, recently, an ap-
proach based on ring closing alkyne metathesis or alkyne
cross metathesis.7 The overall strategy of our syntheses is
based on the three-component, two-step process developed
in our laboratories (Scheme 2)6 which has a convergent
(3) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am.
Chem. Soc. 1969, 91, 5675.
(4) Sih, C. J.; Price, P.; Sood, R.; Salomon, R. G.; Peruzzotti, G.; Casey,
M. J. Am. Chem. Soc. 1972, 94, 3643.
(5) Noyori, R.; Suzuki, M.; Chemtracts: Org. Chem. 1990, 173.
(6) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014-
11015.
(7) (a) Furstner, A.; Grela, K.; Mathes, C.; Lehmann, C. W. J. Am. Chem.
Soc. 2000, 122, 11799-11805. (b) Furstner, A.; Grela, K. Angew. Chem.,
Int. Ed. 2000, 39, 1234-1235.
10.1021/ol015613a CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/15/2001

Scheme 2
Scheme 4a
nature and synthetic flexibility, especially in the introduction
of diverse R-chains.
The preparation of enantiopure lower chain precursor 3
was essential for the construction of common intermediate
2. This was accomplished using Jacobsen methodology8 by
mixing 1 equiv of phenol and 2.2 equiv of epoxide 4 in the
presence of (S,S)-(salen)Co[OC(CF3)3]. The resulting kinetic
resolution provided 5 in nearly quantitative yield on the basis
of phenol with an ee greater than 98%.9 The required lower
chain precursor (+)-3 was then synthesized from (+)-5 in
two steps (Scheme 3).10
a (a) Benzyl 3-butenyl ether (1.5 equiv), 9-BBN (0.5 M in THF,
1.5 equiv), PdCl2(dppf) (5 mol %), K3PO4 (2 equiv), DMF-THF-
H2O, rt; (b) 3 (1.3 equiv), tert-BuLi (2.7 equiv), ThCu(CN)Li (1.1
equiv), pentane-Et2O, -78 to -20 °C; (c) L-Selectride (1.2 equiv),
THF, -78 °C; (d) TBSCl, imidazole, DMF, rt.
R-alcohol with good enantioselectivity (92:8 R/â). Protection
of the three hydroxyl groups as TBS ethers under standard
conditions and subsequent purification by silica gel chro-
matography provided the enantiopure intermediate 2.13
The late stage of the synthesis involved the transformation
of 2 in a series of steps into a variety of prostaglandin
analogues incorporating glycine or mercaptoacetic acid into
the upper chain. For the introduction of the mercaptoacetic
acid moiety, the benzyl protecting group in compound 2 was
first removed by hydrogenation on 5% Pd/C in 89% yield
(Scheme 5). The resulting hydroxyl was converted to the
Scheme 3
Scheme 5a
Synthesis of common intermediate 2 is outlined in Scheme
4. The upper chain bearing a benzyl-protected hydroxyl
functionality was installed via a Suzuki cross-coupling
reaction between a 9-BBN derivative generated in situ from
benzyl 3-butenyl ether and iodoenone 66 catalyzed by PdCl2-
(dppf); the coupling product 7 was isolated in 72% yield.
Conjugate addition of the lower chain component was
successfully achieved by treatment of enone 7 with a high-
order cuprate generated by lithiation of iodide 3 with tert-
butyllithium11 in combination with lithium 2-thienylcyano-
cuprate12 to give 8 in 83% yield. Reduction of 8 with
L-Selectride at -78 °C proceeded smoothly to provide the
a (a) H2, 5% Pd/C, EtOAc, rt; (b) MsCl, Et3N, CH2Cl2,0 °C; (c)
mercaptoacetic acid, NaH, DMSO, rt; (d) H2SiF6, CH3CN, rt; (e)
Bu4NIO4, CH2Cl2-MeOH, rt.
(8) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 6086-
6087.
(9) The enantiopurity was determined via NMR analysis of its corre-
sponding Mosher ester. 5 exhibited the following physical data: colorless
needles, mp 40-41 °C, [R]23 ) 8.5 (c 1.0, CHCl3).
D
corresponding mesylate; subsequent nucleophilic displace-
ment with the disodium salt of mercaptoacetic acid in DMSO
afforded 10 in 80% yield (two steps). The DeShong protocol
(H2SiF6/CH3CN)14 was the most effective and convenient
way to remove all TBS protecting groups in the present case
(10) (+)-3: colorless needles, mp: 28 °C, [R]23D ) 19.3 (c 1.16, CHCl3).
(11) (a) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
(b) Negishi, E.; Swanson, D. R.; Rousset, C. R. J. Org. Chem. 1990, 55,
5406.
(12) Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett. 1987,
28, 945-948.
792
Org. Lett., Vol. 3, No. 5, 2001

and did not introduce byproducts that are difficult to remove.
After simple workup, analogue 1a was obtained in 94%
yield; the second analogue, the corresponding sulfoxide 1b,
was synthesized by oxidation of 1a with Bu4NIO4 in 86%
yield.
Scheme 7a
Incorporation of the glycine moiety into the upper chain
in intermediate 2 is depicted in Scheme 6. Reductive
Scheme 6a
a (a) 1. R ) Me: formaldehyde (37% in H2O), NaCNBH3,
MeOH, 98%; 2. R ) Ac: Ac2O, Et3N, DMAP, CH2Cl2, 99%; 3. R
) Ms: Ms2O, Et3N, CH2Cl2, 93%; (b) H2SiF6, CH3CN; (c) 1,4-
cyclohexadiene, 10% Pd/C, EtOH.
a (a) NH2CH2CO2Bn‚HCl, Et3N, NaCNBH3, MeOH, rt; (b)
H2SiF6, CH3CN, rt; (c) 1,4-cyclohexadiene, 10% Pd/C, EtOH, rt.
conditions. In a manner identical to that described in Scheme
6, two deprotection steps led to analogues 1d-f in excellent
yields.
A two-step sequence was used to synthesize the N-benzyl-
protected analogue 1g (Scheme 8). Treatment of aldehyde
amination of aldehyde 11 with glycine benzyl ester using
NaCNBH3 in the presence of Et3N provided 12 in 66% yield.
Aldehyde 11 was available from the standard Swern oxida-
tion of alcohol 9. A key requirement for the success of this
reductive amination reaction was that an equimolar amount
of Et3N and glycine ester hydrochloride salt be premixed
with the aldehyde in MeOH prior to the addition of
NaCNBH3. Without the presence of Et3N, the corresponding
dimethyl ketal of aldehyde 11 was the sole product recovered.
With H2SiF6, three TBS groups were removed in quantitative
yield and subsequent catalytic transfer hydrogenation15
quantitatively afforded analogue 1c.
Scheme 8a
The syntheses of analogues incorporating various substit-
uents at the secondary amine in compound 1c started with
intermediate 12 (Scheme 7). For the synthesis of the
N-methyl derivative, reductive amination was used to
introduce the N-methyl substitution. The Ac2O/Et3N/DMAP
combination was used to install the N-acetyl group. The
mesyl group was introduced with Ms2O/Et3N under standard
a (a) BnNHCH2CO2H‚HCl, NaCNBH3, Et3N, MeOH-Et2O, rt;
(13) Optical and spectral data for 2: colorless oil, [R]23D ) 11.1 (c 3.2,
CHCl3); 1H NMR(CDCl3) δ 7.35-7.25 (m, 7H), 6.96-6.86 (m, 3H), 4.50
(s, 2H), 4.08-4.03 (m, 1H), 4.01-3.95 (m, 1H), 3.86-3.74 (m, 3H), 3.49-
3.44 (m, 2H), 2.16-2.07 (m, 1H), 1.77-1.21 (m, 13H), 0.9 (s, 9H), 0.88
(s, 9H), 0.87 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.04 (s, 6H), 0.02 (s, 3H),
0.01 (s, 3H); 13C NMR (CDCl3) δ 158.50, 138.66, 129.36, 128.29, 127.54,
127.39, 120.49, 114.28, 76.80, 72.80, 71.94, 71.62, 71.39, 70.58, 49.77,
47.91, 44.50, 31.63, 30.21, 27.21, 26.65, 25.93, 25.86, 25.83, 24.48, 18.18,
18.00, 17.85, -4.07, -4.19, -4.23, -4.68, -4.79, -5.10; HRMS calcd
for C44H78O5Si3, (M+) 770.5157, (M - C4H9) 713.4453, found 713.4455.
(14) Pilcher, A. S.; Hill, D. K.; Shimshock, S. J.; Waltermire, R. E.;
DeShong, P. J. J. Org. Chem. 1992, 57, 2492..
(b) H2SiF6, CH3CN, rt.
11 with N-benzylglycine using NaCNBH3 in the presence
of Et3N gave 15 in 56% yield. Deprotection of 15 using H2-
SiF6 in CH3CN afforded the target compound 1g in 95%
yield.
The receptor binding affinities of these saturated PG
analogues, 1a-g, were then measured by their abilities to
displace various radiolabeled PG ligands in COS-7 cells
(15) Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.;
Meienhofer, J. J. Org. Chem. 1978, 43, 4194.
Org. Lett., Vol. 3, No. 5, 2001
793

transiently transfected with human prostaglandin membrane.2
enantiopure form and to install it efficiently. Preliminary
biological results suggested that analogues of this type may
be useful as agents in cases where metabolism concerns such
as â-oxidation may prevent use of more traditional FP
agonists due to shorter half-lives.17
Data for compounds 1a and 1c16 are shown in Table 1.
Table 1. Binding Affinity of 1a and 1c [IC50 (nM)]
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
1H and 13C NMR spectra for intermediate 2. This material
is available free of charge via the Internet at http://pubs.acs.org.
entry hFP hEP1 hEP2 hEP3 hEP4 hTP hDP
hIP
1a
1c
137 1000 >104
>104
760
>104 >104 >104 >104
OL015613A
(16) The binding affinity of compound 1c for the other prostaglandin
receptors was not further tested as it showed poor activity toward hFP
receptor [IC50 >104 (nM)]. Compounds 1b and 1d-g showed a biological
profile similar to that exhibited by 1c.
(17) For a review on the metabolism of PGF2R, see: Roberts, L. J., II;
CRC Handbook of Eicosanoids: Prostaglandins and Related Lipids, Vol.
1, part A; 1987; pp 233-244.
In conclusion, a very efficient process was developed for
the synthesis of advanced intermediate 2. From this common
precursor, a total of seven novel prostaglandin analogues
were synthesized. A method was developed to make the
lower chain precursor containing a phenoxy group in
794
Org. Lett., Vol. 3, No. 5, 2001