A new approach to the synthesis of cross-conjugated cyclopentenone prostaglandins. Synthesis of (±)-15-deoxy-Δ12,14-prostaglandin J2methyl ester

Article abstract of DOI:10.1016/j.tetlet.2014.08.096

A new approach to 15-deoxy-Δ^12,14-prostaglandin J₂and related structures based on the (±)-Corey lactone diol has been developed. The key stage of this approach involves building the structure of a prostaglandin (PG) derivative with l

Full text of DOI:10.1016/j.tetlet.2014.08.096

Tetrahedron Letters 55 (2014) 5622–5624
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Tetrahedron Letters
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A new approach to the synthesis of cross-conjugated cyclopentenone
prostaglandins. Synthesis of ( )-15-deoxy-
methyl ester
D
12,14-prostaglandin J2
⇑
N. S. Vostrikov , I. F. Lobko, M. S. Miftakhov
Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, Pr. Oktyabrya 71, Ufa, Russian Federation
a r t i c l e i n f o
a b s t r a c t
A new approach to 15-deoxy-D
12,14-prostaglandin J2 and related structures based on the ( )-Corey
Article history:
Received 20 May 2014
Revised 8 August 2014
Accepted 26 August 2014
Available online 29 August 2014
lactone diol has been developed. The key stage of this approach involves building the structure of a pros-
taglandin (PG) derivative with leaving groups at positions 9, 13, and 15, followed by elimination of these
groups by treatment with an organic base.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopentenone prostaglandins
Corey lactone
Total synthesis
15-Deoxy-D
12,14-PGJ2 methyl ester
In the series of cyclopentenone prostaglandins (PG),1 15-deoxy-
removed without affecting the other groups. The protecting groups
and substituents R1, R2, and R3 should be chosen from among inher-
ently good leaving groups, such as acetates, tosylates, mesylates,
carbonates, etc. In the next stage, ketone 3, which can be formed
by oxidation of the C-11 hydroxyl should undergo stepwise decom-
position under the reaction conditions or with the aid of promoters
to eventually give the target prostaglandin 2 (Scheme 1).
Standard prostaglandin techniques and synthons were used in a
previous synthesis of one representative of compounds 4.6 The
Corey ( )-lactone diol 5 was used as the starting compound, which
was obtained according to a described procedure.7 The synthesis of
key prostaglandin intermediate 14 is shown in Scheme 2. Lactone
diol 5 was converted into fully protected lactone 7 by selective
D
12,14-PGJ2 (1),2 with a cross-conjugated trienone moiety on the
ring is of great interest due to its unique mechanism of action3
and prospects for its practical applications.4 15-Deoxy-D12,14
PGJ2 is a selective ligand for PPAR (peroxisome proliferator-acti-
-
c
vated receptor
c)—nucleus receptors that directly regulate gene
transcription and are responsible for initiation of inflammatory
processes, apoptosis, inhibition of virus replication, etc.4 Many
reports on the biological properties of 15-deoxy-D
12,14-PGJ2 are
available. However, syntheses of compound 1 reported in the liter-
ature are quite limited.5
CO2R
O
OR 1
1
2
R = H
R = CH3
CO2CH3
CO2CH3
In this Letter we describe a new approach to prostaglandin 1 and
related structures with the example of the synthesis of the title
compound 2. The key stage of this approach involves the synthesis
of orthogonally protected derivatives of F-series prostaglandins,
that is, compounds with the general formula 4 in which the
protecting group (R) of the C-11 hydroxyl can be selectively
O
O
3
2
OR3
R2
OR1
O
O
CO2CH3
RO
OH
HO
4
OR3
R2
5
⇑
Corresponding author.
E-mail address: bioreg@anrb.ru (N.S. Vostrikov).
Scheme 1. Retrosynthetic analysis of ( )-2.
http://dx.doi.org/10.1016/j.tetlet.2014.08.096
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

N.S. Vostrikov et al. / Tetrahedron Letters 55 (2014) 5622–5624
5623
O
O
OH
to be the simplest and most convenient approach. Thus adduct 15
was reduced with NaBH4 to give alcohol 16 in high yield. This was
acylated and the resulting compound 17 was oxidized with H2O2
under catalysis with an Mo(VI) salt to give sulfone 18. Removal
of the THP protecting group in 18, followed by oxidation of the
resulting alcohol 19 with PCC gave ketone 20. Elimination of the
leaving groups in compound 20 under acidic conditions failed. In
addition, ketone 208 remained unchanged after refluxing in ben-
zene containing an equivalent amount of benzoic acid for half an
hour. However, it was smoothly converted into compound 28 in
32% yield on stirring in benzene with DBU at room temperature.
During the reaction minor amounts of by-products were formed
which were removed by column chromatography. In particular,
1H NMR analysis of the crude reaction mixture showed the pres-
O
O
O
a,b
c
d
OTBDPS
OH
OTBDPS
RO
HO
THPO
OR
(
)-5
6 R=H
8
7
R=THP
OH
CO2CH3
g
CO2H
e,f
THPO
OTBDPS
10 R=H
11 R=Ac
OTBDPS
THPO
9
OAc
OAc
CO2CH3
CO2CH3
h
OH
O
THPO
12
THPO
13
ence of 13,14-cis-isomers of 2, 15a,b-acetate methyl ester 12-
PGJ2 among others, which were not isolated.
OAc
Stereochemistries of the E,E-olefinic double bonds of 2 at C14–
15 and C12–13 were confirmed from their coupling constants
[J14,15 = 14.9 Hz and J13,14 = 11.3 Hz (d13-H = 6.96 ppm), respec-
tively], which are consistent with those reported earlier for 1.5a,5b
i
CO2CH3
TBDPS - tert-butyldiphenylsilyl
THPO
THP - tetrahydropyranyl
14
O
Hence, the methyl ester of ( )-D
12,14-PGJ2 2 has been obtained in
Scheme 2. Reagents and conditions: (a) t-BuPh2SiCl (1.2 equiv), imidazole, CH2Cl2,
85%; (b) DHP, CH2Cl2, PPTS (cat.), 95%; (c) i-Bu2AlH, CH2Cl2, À70 °C, 95% (crude); (d)
BrÀPh3P+(CH2)4CO2H, NaHMDS, THF; (e) CH2N2; (75% overall two steps, d and e); (f)
Ac2O, Py, 83%; (g) Bu4NF, THF, 85%; (h) CrO3–Py, CH2Cl2, 90%; (i) (MeO)2P(O)CH2-
C(O)C5H11, Et4N+BrÀ, NaOH, CH2Cl2/H2O, 80%.
16 steps and 4% overall yield starting from Corey lactone diol 5.
The hydrolysis of the base sensitive ester 2 has been accomplished
previously by using lipases and esterases.9
In conclusion, the developed method to synthesize compound 2
based on readily available traditional prostaglandin building blocks
(Corey lactone diol 5 and 15-oxoprostadienoic acid derivative 14)
can be implemented in the chiral version and can be varied in
terms of the analogues that can be obtained.
protection of the primary hydroxyl group as a tert-butyldiphenylsi-
lyl ether and subsequent blocking of the secondary hydroxyl of 6
with dihydropyran. Reduction of 7 with i-Bu2AlH at À70 °C in CH2-
Cl2 and olefination of unstable lactol 8 with the in situ generated
ylide [Ph3P@CH(CH2)3CO2Na] led to hydroxyl acid 9. This was trans-
formed in three steps into alcohol 12, and then converted into the
aldehyde 13. Emmons–Horner condensation of aldehyde 13 with
dimethyl 2-oxo-heptylphosphonate gave the key enone 14.
In constructing compounds with general formula 4, enone 14
appears to be a rational building block for introducing the C-13
leaving group by Michael reaction with O-, N-, or S-nucleophiles
(Scheme 3). At first, considering that base-catalyzed addition of
mercaptans to enones occurs readily, we studied the 1,4-conjugate
addition of ethanethiol to enone 148 in THF. This reaction
promoted by NaH occurred quickly to give adduct 15 in high yield.
The next stage of this work involved the conversion of the substit-
uents and functional groups at C-13 and C-15 in 15 into good
leaving groups. As a first approximation, we introduced the sulfone
and acetate functions, respectively, at these centers which seemed
Supplementary data
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2014.08.096.
References and notes
1. (a) Straus, D. S.; Glass, C. K. Med. Res. Rev. 2001, 21, 185; (b) Roberts, S. M.;
Santoro, M. G.; Sickle, E. S. J. Chem. Soc., Perkin Trans. 1 2002, 1735.
2. Fitzpatrick, F. A.; Wynalda, M. A. J. Biol. Chem. 1983, 258, 11713.
3. Suzuki, M.; Mori, M.; Niwa, T.; Hirata, R.; Furuta, K.; Ishikawa, T.; Nojori, R. J. Am.
Chem. Soc. 1997, 119, 2376.
4. (a) Uchida, R.; Shibata, T. Chem. Res. Toxicol. 2008, 21, 138; (b) Paune, V.; Rawes,
M. J. Bioorg. Med. Chem. Lett. 2005, 15, 4057; (c) Cox, B.; Murphey, L. J.; Zackert,
W. E.; Chinery, R.; Yraves-Deal, R.; Boutand, O.; Oates, J. A.; Coffey, R. J.; Merrow,
J. D. Biochim. Biophys. Acta 2002, 37, 1584.
5. (a) Brummond, K. M.; Sill, P. C.; Chen, H. Org. Lett. 2004, 6, 149; (b) Acharya, H.;
Kobayshi, Y. Tetrahedron Lett. 2004, 45, 1199; (c) Acharya, H.; Kobayashi, Y.
Tetrahedron 2006, 62, 3329; (d) Bickley, J. F.; Jadhav, V.; Roberts, S. M.; Santoro,
M. G.; Steiner, A.; Sutton, P. W. Synlett 2003, 1170.
6. Mitra, A. The Synthesis of Prostaglandins; Wiley Interscience: New York, 1977; p
414.
OAc
OAc
CO2CH3
CO2CH3
a
THPO
THPO
7. Tolstikov, G. A.; Miftakhov, M. S.; Valeev, F. A.; Vostrikov, N. S.; Akhmetvaleev, R.
R. Zh. Org. Chem. 1984, 20, 1672 (in Russian).
O
S
O
14
1
5
8. Spectral data for selected compounds: ( )-(3a a
R⁄,4S⁄,5R⁄,6 S⁄)-4-({[tert-
butyl(diphenyl)silyl]oxy}methyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-
one (6): Colorless crystals, mp 95–97 °C; Rf 0.22 (PE–EtOAc, 7:3). IR (KBr)
OAc
OAc
max = 3456, 3070, 1749, 1458, 1375, 1357, 1114, 1033, 707 cmÀ1 1H NMR
.
CO2CH3
m
CO2CH3
b,c
d,e
(300 MHz, CDCl3): d 7.63 (d, J = 6.0 Hz, 4H); 7.45–7.37 (m, 6H); 4.87 (td, J = 6.9,
2.9 Hz, 1H), 4.20–4.13 (m, 1H), 3.71 (dd, J = 10.5, 5.2 Hz, 1H), 3.61 (dd, J = 10.5,
6.7 Hz, 1H), 2.69 (dd, J = 17.7, 9.9 Hz, 1H), 2.60–2.55 (m, 1H), 2.42–2.38 (m, 2H),
2.10 (br s, 1H), 2.01–1.95 (m, 2H), 1.05 (s, 9H). 13C NMR (75 MHz, CDCl3):
177.20, 135.44, 132.79, 129.90, 127.78, 83.65, 74.95, 64.18, 55.30, 40.54, 39.34,
35.21, 26.80, 19.06 ppm. MS (ESI): m/z (%): 411 [M+H]+ (20.6), 393 [M–H2O]+
(5.9), 365 (82.4), 333 [M–PhH]+ (100).
THPO
RO
S
OR
16
R = H
17 R = Ac
S
OAc 18
R = THP
O
O
19 R = H
OAc
CO2CH3
f
CO2CH3
Methyl
yloxy)prosta-5,13-dien-1-oate (14): Colorless oil, Rf 0.7 (PE–EtOAc, 1:1). IR
(KBr) max = 2950 (s), 2934 (s), 1735 (s), 1700 (w), 1680 (w), 1620 (w), 1242
(s) cmÀ1
( )-(5Z,9a,11a,13E)-9-(acetyloxy)-15-oxo-11-(tetrahydro-2H-pyran-2-
g
O
O
m
S
OAc
20
2
O
O
.
1H NMR (300 MHz, CDCl3): d 6.68 (m, 1H, C-13–H), 6.18 (dt, J = 1.7, 15.9 Hz, 1H,
H-14), 5.35–5.20 (m, 2H, CH@CH), 5.00 (br s, 1H, H-9), 4.55 (br s, 0.5H) and 4.50
(br s, 0.5H) (H-1, THP), 4.10–3.90 (m, 2H, H-11, H-5, THP), 3.75–3.65 (m, 1H,
H-5, THP), 3.60 (s, 3H, OCH3), 3.40–3.30 (m, 1H, H-12), 2.75–2.60 (m, 1H),
2.55–2.45 (m, 2.5H), 2.30–2.40 (m, 0.5H), 2.22 (t, J = 6.9 Hz, 2H, H-2), 2.15–2.05
Scheme 3. Reagents and conditions: (a) EtSH, THF, NaH, 95%; (b) NaBH4, MeOH,
90%; (c) Ac2O, Py, 98%; (d) 30% H2O2, (NH4)6Mo7O24Á7H2O, 73%; (e) 30% AcOH, 60 °C,
82%; (f) PCC, CH2Cl2, 86%; (g) DBU, C6H6, 20 °C, 32%.

5624
N.S. Vostrikov et al. / Tetrahedron Letters 55 (2014) 5622–5624
(m, 1H), 2.01, 2.00 (s, 3H, OAc), 2.00–1.90 (m, 2H), 1.80–1.40 (m, 10H), 1.35–
46.52 and 46.39 (CH2SO2), 45.38 and 43.29 (C-8), 43.31 and 37.75 (C-10), 34.85
and 34.74 (C-16), 33.48 and 33.44 (C-2), 33.13 and 32.74 (C-14), 31.62 and 31.57
(C-18), 26.83 and 26.81 (C-4), 26.64 and 26.59 (C-7), 24.81, 24.76 and 24.71 (C-
3, C-17), 22.47 (C-19), 21.31, 21.20, 21.13, 21.07, 21.01 and 20.97 (OAc), 13.98
(CH3), 6.59 and 6.24 (CH3) ppm.
1.25 (m, 5H), 0.85 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): 200.42 and
200.28 (C-15), 173.82 (C-1), 170.53 and 170.43 (OAc), 146.95 (C-13), 131.77 and
131.56 (C-5), 130.03 (C-14), 127.73 and 127.71 (C-6), 99.18 and 96.61 (C-1–
THP), 81.02 and 78.78 (C-11), 74.48 and 74.18 (C-9), 62.68 and 61.69 (C-5–THP),
53.54 and 52.99 (C-12), 51.42 (OCH3), 47.37 and 47.30 (C-8), 40.42 and 40.23 (C-
16), 40.12 and 38.47 (C-10), 33.32 (C-8), 31.42 and 31.40 (C-2–THP), 30.66 (C-
18), 26.55 (C-4), 25.33 and 25.27 (C-7), 25.07 and 25.02 (C-4–THP), 24.62 (C-3),
23.95 and 23.92 (C-17), 22.43 (C-19), 21.19 and 21.18 (Ac), 19.60 and 19.01 (C-
3–THP), 14.14 and 13.88 (CH3) ppm.
Methyl ( )-(5Z,12E,14E)-11-oxoprosta-5,12,14-trien-1-oate (2): Yellow oil, Rf 0.55
(PE–EOAc, 7:3). IR (KBr) m .
max = 2954, 2928, 2856, 1738, 1695, 1634 cmÀ1 1H
NMR (300 MHz, CDCl3): d 7.47 (dd, J = 1.9, 6.0 Hz, 1H, H-9), 6.95 (d, J = 11.3 Hz,
1H, H-13), 6.36 (dd, J = 1.8, 6.1 Hz, 1H, H-10), 6.32 (dd, J = 11.4, 15.0 Hz, 1H, H-
14), 6.25 (dt, J = 6.9, 14.9 Hz, 1H, H-15), 5.48–5.43 (m, 1H, H-5), 5.39–5.33 (m,
1H, H-6), 3.65 (s, 3H, OCH3), 3.55–3.60 (m, 1H, H-8), 2.60 (dt, J = 14.5, 6.3 Hz, 1H,
H-7), 2.33–2.28 (m, 1H, H-7), 2.28 (t, J = 7.5 Hz, 2H, H-2), 2.23 (q, J = 7.3 Hz, 2H,
H-16), 2.20 (q, J = 7.3 Hz, 2H, H-4), 1.65 (quin, J = 7.5 Hz, 2H, H-3), 1.45 (quin,
J = 7.2 Hz, 2H, H-17), 1.33 –1.25 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H, CH3). 13C NMR
(75 MHz, CDCl3): 197.43, 173.94, 160.69, 146.96, 135.38, 135.06, 131.72, 131.50,
125.99, 125.67, 51.56, 43.51, 33.50, 33.43, 31.45, 30.76, 28.50, 26.69, 24.72,
Methyl ( )-(5Z)-9a,15a,b-bis(acetyloxy)-13a,b-(ethylsulfonyl)-11-oxoprost-5-en-
1-oate (20): Colorless oil, Rf 0.3 (PE–EtOAc, 7:3). 1H NMR (300 MHz, CDCl3): d
5.45–5.35 (m, 2.5H, CH@CH, H-9), 5.10 (br s, 0.5H, H-9), 4.95–4.85 (m, 1H, H-
15), 3.87–3.82 (m, 1H, H-13), 3.65 (s, 3H, OCH3), 3.10 (dd, J = 7.3, 15.2 Hz, 1H, H-
10), 2.98 (dd, J = 7.7, 15.2 Hz, 1H, H-10), 2.50–2.20 (m, 3H), 2.30 (t, J = 6.5 Hz, 2H,
H-2), 2.07 s, 2.03 s, 1.98 s (6H, 2OAc), 1.70–1.50 (m, 4H), 1.38 (t, J = 7.5 Hz, 3H,
CH3), 1.30 (br s 7H), 0.85 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3):
212.76 (C-11), 173.96 and 173.91 (C-1), 171.46, 170.86, 170.56, 170.52 and
170.27 (OAc), 131.42, 130.69 (C-5), 127.18 and 126.17 (C-6), 77.96 and 76.17(C-
9), 71.42, 71.35, 70.54 and 70.31 (C-15), 56.30 (C-12), 49.37 and 49.15 (C-13),
22.51, 14.05 ppm. MS (ESI): m/z (%): 330.3 [M]+ (90), 299 [M–OCH3]+ (10), 259
+
[M–C5H11
]
(100). HRMS (ESI): calcd for C21H30O3: 330.2231, found: 330.2209.
9. (a) Rodrigues, A. R.; Spur, B. W. Tetrahedron Lett. 2002, 43, 9249; (b) Rodrigues, A.
R.; Spur, B. W. Tetrahedron Lett. 2003, 44, 7411.