New β-ketophosphonates for the synthesis of prostaglandin analogues. 2 Phosphonates with bicyclo[3.3.0]octene and bicyclo[3.3.0]octane scaffolds linked to the β-keto group

Article abstract of DOI:10.1039/d0nj04594b

β-Ketophosphonates, with the keto group linked to a bicyclo[3.3.0]oct(a)ene fragment, were synthesized starting from two diacids. These diacids were first transformed into internal anhydrides and one into a diester. The anhydrides and the diester were reacted with the lithium salt of dimethyl methanephosphonate to give two carboxy β-ketophosphonates, an ester β-ketophosphonate and a bis β-ketophosphonate in good yield. The ester β-ketophosphonate, obtained by two routes was used in the E-HEW selective olefination of a prostaglandin aldehyde with an α-side chain to give the 15-keto prostaglandin analogue in good yield. The compounds were characterized by elemental analysis, IR and high resolution 1H- A nd 13C-NMR spectroscopies. This journal is

Full text of DOI:10.1039/d0nj04594b

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DOI: 10.1039/D0NJ04594B
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ARTICLE
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introduced in the molecule by an E-selective Horner-Emmons-
Wadsworth (HEW) olefination of an aldehyde, with a δ-lactone, -
lactone and cyclopentane structure (at different steps of the
reaction sequence), with a β-ketophosphonate, in the presence of a
base. Therefore, the design of the -side chain of the target
prostaglandin molecule is integrated in the design of the β-
Received 00th January 20xx,
Accepted 00th January 20xx
ketophosphonate
intermediate
to
be
synthesized.
A
DOI: 10.1039/x0xx00000x
bicyclo[3.3.0]octane fragment is encountered in many natural
products, some of them with anticancer activity [1], however, as far
www.rsc.org/
as we know, there is no mention in the literature of
a
bicyclo[3.3.0]octane (octahydropentalene) or bicyclo[3.3.0]octene
(hexahydropentalene) fragment used in prostaglandin analogues.
In our works in the field we aim to create new prostaglandin
analogues with this fragment in the -side chain and the first step
in this direction is to synthesize the key β-ketophosphonates
intermediates, used in their convergent synthesis.
New
β-ketophosphonates
for
the
synthesis of prostaglandin analogues. 2.
Phosphonates with bicyclo[3.3.0]octene
and bicyclo[3.3.0]octane scaffolds linked to
the β-ketone group.
Previously we synthesized β-ketophosphonates with
a
bicyclo[3.3.0]octene scaffold spaced by a methylene group
from the β-ketone [1] to obtain prostaglandin analogues of
type I in which "the bicyclo[3.3.0]octene fragment is spaced far
enough from C15, not to hinder the access of the PG-receptor
to the functional group linked to C15 carbon atom; at the same
time, the new bicyclo[3.3.0]octene fragment is enough spaced
to contribute to the biological activity of the new
prostaglandin analogues" [1].
Constantin I. Tănase,a* Constantin Drăghicib, Miron Teodor
Caproiub
β-Ketophosphonates, with the keto group linked to
a
bicyclo[3.3.0]oct(a)ene fragment, were synthesized starting from
two diacids. These diacids were first transformed into internal
anhydride and one into diester. The anhydrides and the diester were
reacted with the lithium salt of dimethyl methanephosphonate to
give two carboxy β-ketophosphonates, an ester β-ketophosphonate
COOR1
COOR1
OH
OH
R
and
a
bis β-ketophosphonate in good yield. Ester β-
R
Ketophosphonate, obtained by two routes, was used in a E-HEW
selective olefination of a prostaglandin aldehyde with α-side chain
to give the 15-keto prostaglandin analogue in good yield. The
compounds were characterized by elemental analysis, IR and high
resolution 1H- and 13C-NMR spectroscopy.
R2 R3
R2 R3
OH
OH
II. Prostaglandin analogues with a
bicyclo[3.3.0]oct(a)ene fragment in the
-side chain linked to C15 carbon atom
I. Prostaglandin analogues with a
bicyclo[3.3.0]octene fragment
in the -side chain
Figure 1. Prostaglandin analogues with a bicyclo[3.3.0]octene
fragment spaced from the C15 carbon atom by a methylene group (I)
and a bicyclo[3.3.0]oct(a)ene fragment linked to the C15 carbon
atom (II).
1. Introduction
The vast family of prostaglandins is defined by the structural
elements of the cyclopentane ring and the two α- and -side
chains. The modifications of the α-side chain, the -side chain or
both were done for designing new prostaglandin analogues, but the
most beneficial modifications to the associated biological activities
were performed on the -side chain. In the total stereo-controlled
Corey convergent synthesis of prostaglandins, the -side chain is
In this paper we present the synthesis of new β-ketophosphonates
with bicyclo[3.3.0]octene and bicyclo[3.3.0]octane scaffolds linked
to the β-ketone group, to give more restricted access to the C15
carbon atom from the -side chain of the prostaglandin analogues
of type II, and the synthesis of one prostaglandin analogue with this
fragment in the -side chain. The main theme of the work is to
search for new metabolically and chemically more stable and active
analogues of prostaglandins.
a. National Institute for Chemical-Pharmaceutical Research and Development, 112
Vitan Av., 031299, Bucharest-3, Romania
b. Organic Chemistry Center “C.D.Nenitescu”, 202 B Splaiul Independentei, 060023
Bucharest, Romania
See DOI: 10.1039/x0xx00000x
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Synthesis of the unsaturated β-ketophosphonate 10 started from
2. Results and discussion
the diacid 5, obtained by oxidativDeOI: 10.1039/D0NJ04594B
cleavage of
View Article O5nl,in6e-
dihydroxydicyclopentadiene 1 to dialdehyde 3 [9] followed by Jones
oxidation, in 72.5 % yield on two steps. Anhydride 7 was obtained
by a published procedure [10] in 81.3 % yield. In the final step,
anhydride 7 reacted with the lithium salt of DMPh, which had been
obtained by the reaction of DMPh with n-BuLi at a reduced
For the synthesis of new β-ketophosphonates, we choose as a key
step the reaction of an ester with dimethyl methanephosphonate
(DMPh) in the presence of n-butyllithium at a reduced temperature
(<-70˚C) in anh. THF and the reaction of an anhydride with dimethyl
methanephosphonate in the same conditions [2]. The first method
is usually used in the Corey procedure of prostaglandin synthesis to
obtain the β-ketophosphonates for manufacturing new
prostaglandin analogues (for ex.: [3-8]); we used this procedure in
the micro-production of prostaglandin analogues and also for
obtaining the β-ketophosphonates with a bicyclo[3.3.0]octene
fragment in the molecule, which we described in a previous paper
[1].
temperature (below -70C), giving the unsaturated
ketophosphonate 10, mp, 113-114C, in 73.5 % yield.
β-
10
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The synthesis of the saturated β-ketophosphonates 11, 12 and 13
started from the same 5,6-dihydroxydicyclopentadiene 1, which
was first hydrogenated (10 % Pd/C, 10 atm. H2, rt, 97 % yield) to 2.
The synthesis of new β-ketophosphonates, with a double bond and
a single bond in the cyclopentane ring, is presented in Scheme 1:
O
CHO
COOH
7a
3a)
2a)
HO
HO
7
8
4
1
4)
6
5
O
2
3a
3
CHO
COOH
O
6)
COCH P(O)(OCH )
1
3
5
7
1)
8
CHO
COOH
2
3 2
3a
2b)
3
4
3b)
HO
HO
5
2
1
6
6a
COOH
7
CHO
COOH
10
2
5)
4
6
O
O
4)
COCH P(O)(OCH )
8
COOCH3
2
3 2
3a
6)
3
4
O
5
2
1
6
6a
COOH
COOCH3
7
8
11
9
6)
COCH P(O)(OCH )
8
7
2
3 2
COCH P(O)(OCH )
8
7
2
3 2
3a
3a
7)
3
4
3
4
5
+
2
5
2
1
6
1
6
6a
6a
COOCH
3
COCH P(O)(OCH )
2
3 2
13
12
Scheme 1. Synthesis of β-ketophosphonates 10-13 from di-acids 5 and 6.
1) H2 (10 atm), 10% Pd/C, EtOAc, 97%; 2a) NaIO4, EtOH-water, 0-5˚C; 3a) 2.44 M Jones reagent, acetone, 0-10˚C, 72.5 % on two steps; 2b)
NaIO4, EtOH-water, 0-5˚C; 3b) 2.44 M Jones reagent, acetone, 0-10˚C, 72.5 % on two steps; 78.0 %; 4) Ac2O, 80-90˚C, 9 h, 81.3 % for 7,
quantitative for 8; 5) MeOH, TsOH, overnight, 91.3 %; 6) dimethyl methanephosphonate, n-BuLi, < -65˚C with 7, 73.5 % 10; with 8, 84.1 %
11; with 9, 42.0 % 12 and 47.4 % 13; 7) CH2N2 chloroform-ethyl ether, 92%.
2 | NJC., 2020, 00, 1-6
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New Journal of Chemistry
New Journal of Chemistry
The oxidative cleavage of diol 2, followed by Jones oxidation of the
dialdehyde intermediate 4, gave the saturated diacid 6 in 78 % yield
over two steps. The saturated anhydride 8 was obtained in the
same conditions as for 7 in almost quantitative yield. Finally, the
reaction of this anhydride with the lithium salt of DMPh gave the
crystallized (mp 148-150C) saturated β-ketophosphonates 11 in
84.1% yield.
ARTICLE
1
2
3
4
5
6
7
8
H3COOC
1
COOCH3
View Article Online
DOI: 10.1039/D0NJ04594B
2
3
4
C6H5COO
5
OOCC6H5
6
8
7
9
10
11
12
13
14
15
9
C6H5COO
10
11
12
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For the synthesis of the β-ketophosphonates 12 and 13, we
followed a reaction sequence where we use the diester compound
9 in the final step, as in our previous paper [1]. So, the diacid 6 was
esterified with methanol in the presence of TsOH as acid catalyst to
the crystallized diester (mp 71-73.0C) 9 in 91.3 % yield. Then the
diester was reacted with 2.05 equivalents of lithium salt of DMPh,
giving pure mono β-ketophosphonate 13 in 47.4% yield and bis β-
ketophosphonate 12 in 42.0% yield.
OOCC6H5
O
O
III, 15-keto-pseudo-Prostaglandin analogue
Figure 2. 15-Keto-pseudo-prostaglandin analogue III should be
obtained from bis-β-ketophosphonate 12.
4. Experimental
Finally, the carboxylic β-ketophosphonate 11 was esterified with
diazomethane to the ester phosphonate 13, obtained previously
from diester 9, giving another confirmation of the structure of both
compounds.
Melting points (uncorrected) were determined in open capillary on
an OpiMelt melting point apparatus. The progress of the reactions
was monitored by TLC on Merck silica gel 60 or 60F254 plates eluted
with the solvent systems: I, benzene-ethyl acetate-hexane, 5:3:2, II,
ethyl acetate-hexane-acetic acid, 5:4:0.1, III, ethyl acetate-hexane-
acetic acid, 5:1:0.1, IV, hexane-ethyl acetate-acetic acid, 5:2:0.1.
Spots were developed in UV and with 15% H2SO4 in MeOH (heating
at 110˚C, 10 min.). IR spectra were recorded on FT-IR Perkin Elmer
spectrometer. 1H-NMR and 13C-NMR spectra were recorded on
Varian 300 MHz spectrometer, chemical shifts are given in ppm
relative to TMS as internal standard. Complementary spectra: 2D-
NMR and decoupling were done for the correct assignment of the
NMR signals. The numbering of the atoms in the compounds is
presented in Scheme 1 and Scheme 2. Dialdehyde 3 was obtained
as we described in our previous paper [11].
We then tested the E-HEW selective olefination of the
prostaglandin aldehyde intermediate 15, obtained by trans-
ketalyzation of the dimethylaketal intermediate 14 in acetone, in
the presence of 70% HClO4 as catalyst, with the mono β-
ketophosphonate 13 (Scheme 2) and obtained the new
prostaglandin analogue 16 in 71.3 % yield, as an oil.
C6H5COO
C6H5COO
COOCH3
COOCH3
HCO4
OCH3
OCH3
Acetone
CH
CHO
C6H5COO
C6H5COO
14
15
COCH P(O)(OCH )
8'
3 2
2
1. Synthesis of compound 2.
3a'
3'
2'
1'
4'
5'
6'
1
6a'
2
COOCH3
3
100 g (0.6016 mol), (3aS,4R,7S,7aR)-3a,4,5,6,7,7a-hexahydro-1H-
4,7-methanoindene-5,6-diol, dissolved in ethyl acetate (1L) were
hydrogenated on 10% Pd/Cat 10 atmosphere H2, monitoring the
4
COOCH
7'
C6H5COO
3
5
6
13
8
7
9
10
11
12
13
16
14
NaH, THF, ice-bath, 5 h, 71.3 %
15
end of the reaction by H- and 13C-NMR. The catalyst was filtered
1
COOCH3
C6H5COO
off, washed with ethyl acetate used to wash autoclave (TLC
monitoring on catalyst washing), the filtrate was concentrated to
dryness under reduced pressure, the concentrate co-evaporated
with benzene, resulting 97 g (97 %) of crystallized compound 2 in
mass. A sample of 11 g was crystallized from benzene-hexane,
resulting 9.35 g of pure product 2, (3aR,4S,7R,7aS)-octahydro-1H-
4,7-methanoindene-5,6-diol, crystallized as needles, mp 67.0-68.0
˚C, 1H-NMR (DMSO-d6,  ppm, J Hz):4.47 (s, 2H, OH), 3.73 (m, 2H, H-
5, H-6), 2.31 (m, 2H, H-3a, H-7a), 1.90 (dt, 2H, H-4, H-7, 1.5, 5.4),
1.77 (dt, 1H, H-8, 1.7, 9.7), 1.59-1.52 (m, 3H, H-1, H-2, H-3), 1.47-
1.21 (m, 3H, H-1, H-2, H-3), 1.15 (dqv, 1H, H-8, 1.5, 9.7), 1H-NMR
(DMSO-d6 +TFA,  ppm, J Hz): 7.45 (OH moved from 4.47), 3.73 (d,
2H, H5, H-6, 1.9), 2.30 (m, 2H, H-3a, H-7a), 1.90 (dt, 2H, H-4, H-7,
1.5, 5.4), 1.77 (dt, 1H, H-8, 1.7, 9.7), 1.59-1.49 (m, 3H, H-1, H-2, H-
3), 1.46-1.20 (m, 3H, H-1, H-2, H-3), 1.14 (dqv, 1H, H-8, 1.5, 9.7), 13C-
RMN (DMSO-d6,  ppm): 68.68 (C-5, C-6), 48.32 (C-4, C-7), 43.38 (C-
3a, C-7a), 36.41 (C-8), 28.32 (C-2), 26.37 (C-1, C-3).
O
Scheme 2. Synthesis of prostaglandin analogue 16 with β-
ketophosphonate 13.
It is worth mentioning that the reduction of the 15-ketone group
with aluminium diisobornyloxyisopropoxyde, a reagent used in the
selective reduction of 16-aryloxy intermediates (15-keto
intermediates for obtaining cloprostenol, fluprostenol, travoprost),
gives no 15-allylic alcohol. This shows that the bicyclo[3.3.0]octane
skeleton, linked to the C15 carbon atom, is bulky enough to block
the access of the also bulky reducing reagent. This first reduction of
16 predicts that the usual enzymatic inactivation of prostaglandins,
by transforming 15α-OH into 15-keto group, will be hindered by the
bulky bicyclo[3.3.0]octane fragment, as we initially assumed.
The use of bis β-keto-phosphonate 12 in the usual HEW olefination
conditions should give the pseudo-prostaglandin compoud III, like
we mentioned in the previous paper [1]:
2.
Synthesis
of
saturated
diacid
6,(1R,3S,3aR,6aS)-
octahydropentalene-1,3-dicarboxylic acid
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The hydrogenated compound 2 (91.35 g, 0.543 mol) was dissolved 4. Synthesis of saturated anhydride 8
in ethanol (380 mL), the resulting solution was cooled below 0˚C on
View Article Online
DOI: 10.1039/D0NJ04594B
an ice-salt bath and a solution of NaIO4 (124 g, 0.567 mol) in water
(1.05 L) was added dropwise under intense mechanical stirring.
Ethanol (190 mL) was added, the stirring was continued on the
cooling bath, monitoring the end of the reaction by TLC (I, Rf 2= 0,40,
Rf 4= 0,64). NaIO3 was filtered off, washed on filter with ethanol (190
mL) and then with chloroform (3×140 mL). The ethanol solutions
were concentrated to dryness, the concentrate was dissolved in
chloroform used in washings of sodium iodate precipitate, washed
with brine (140 mL), dried (Na2SO4) and half of the solution was
used in the next step for the oxidation of dialdehyde 4 to diacid 6.
The diacid 6 (7.45 g, 37.6 mmol) was added to acetic anhydride (150
mL) and stirred at 80-90˚C for 9 h, monitoring the end of the
reaction by TLC (II, Rf 6 = 0.51, Rf 8 = 0.75). The reaction mixture was
concentrated under reduced pressure, co-evaporated with toluene,
the concentrate was taken in toluene (200 mL), the solution was
washed with 10 % KHCO3 (250 mL), brine (30 mL), dried (Na2SO4)
and concentrated, resulting 6.77 g (quantitative) of anhydride, 8. A
sample was crystallized from toluene-hexane, mp 155.8-157.3˚C,
1H-NMR (CDCl3,  ppm, J Hz): 3.24 (m, 2H, H-1, H-3), 2.97 (m, 2H, H-
3a, H-6a), 2.34 (d, 1H, H-2, 12.6), 2.00 (dt, 1H, H-2, 4.0, 12.6), 1.78
(m, 2H, H-4, H-6), 1.67 (m, 2H, H-5), 1.49 (m, 2H, H-4, H-6), 13C-NMR
(CDCl3,  ppm): 168.86 (COO), 46.62 (C-1, C-3), 46.06 (C-3a, C-6a),
34.05 (C-2), 27.66 (C-4, C-6), 27.45 (C-5).
5
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The crude aldehyde solution was concentrated under reduced
pressure, the concentrate was dissolved in acetone (500 mL), the
solution was cooled on an ice-salt bath and then 2.44 M Jones
solution (222.5 mL, 0.543 mol) were added dropwise. TLC (I, Rf 4
=
5. Synthesis of un-saturated anhydride 7
0.64, Rf 6 = 0.11; the diacid was hardly visualized with iodine and
H2SO4 reagent) confirmed the consumption of the dialdehyde after
3 h and then isopropanol (30 mL) was added. After stirring for 1 h,
the reaction mixture was filtered off, washed with acetone (2×300
mL) and the filtrates were concentrated under reduced pressure.
The concentrate was extracted with ethyl ether (3×300 mL). The
salts were dissolved in brine and extracted with ethyl ether (3×300
mL). The unified ether solutions were extracted with a solution of
KOH (51.45 g) in water (400 mL) in three portions and concentrated
to dryness, resulting 3.5 g of neutral secondary compounds. The
alkaline solutions were acidified to pH 5.5 with con. HCl,
concentrated under reduced pressure, the concentrate was
extracted with ethyl ether (4×300 mL), the ether solution dried
(Na2SO4) and concentrated to dryness, resulting 51 g of crude
diacid 6. By crystallization from ethyl acetate, 41.97 g (78 %) of
crystallized compound 6 were obtained, mp 218.0-221.0˚C, 1H-NMR
(DMSO-d6,  ppm, J Hz): 2.75 (dd, 2H, H-1, H-3, 5.9, 8.8), 2.66 (m,
2H, H-3a, H-6a), 1.80 (q, 1H, H-2, 12.5), 1.66 (m, 3H, H-2, 2H-4), 1.57
(dq, 1H, H-5, 2.8, 5.6), 1.21 (m, 1H, H-5), 1.05 (m, 2H, H-4, H-6), 13C-
NMR (DMSO-d6,  ppm): 173.63 (COO), 46.10 (C-1, C-3), 44.01 (C-
3a, C-6a), 30.05 (C-4, C-6), 28.04 (C-2), 26.89 (C-5), M = 198.21, M-1
=197.2.
The un-saturated diacid 5 (7.77 g, 39.6 mmol) was stirred in acetic
anhydride (150 mL) at 70-80˚C as in example 4. TLC (II, Rf 5 = 0.39, Rf
7 = 0.73). After similar work-up, 5.74 g (81.3 %) of compound 7 were
1
otained, H-NMR (CDCl3,  ppm, J Hz): 5.78 (dq, 1H, H-6, 2.2, 5.8),
5.64 (dq, 1H, H-5, 2.2, 5.8), 3.43 (m, 1H, H-6a), 3.46 (ddt, 1H, H-1,
1.1, 4.0, 7.3), 3.31 (dt, 1H, H-3, 3.7, 7.1), 3.15 (m, 1H, H-3a), 2.59 (m,
1H, H-4), 2.33 (m, 2H, H-2, H-4), 1.97 (dt, 1H, H-2, 4.0, 12.6), 13C-
NMR (CDCl3,  ppm): 168.45, 168.19 (COO), 133.21 (C-6), 128.33 (C-
5), 52.66 (C-6a), 46.96, 46.90 (C-1, C-3), 42.35 (C-3a), 33.25 (C-4),
32.21 (C-2).
6. Synthesis of β-ketophosphonates 12 and 13
To a solution of DMPh (14.5 g, 0.113 mol) in THF (300 mL), cooled
below -65˚C, in inert anh. atmosphere (Ar), a solution of 1.7 M n-
BuLi in hexanes (73 mL) was added dropwise, stirred for 15 min.
and then a solution of diester 9 (12.5 g, 55.2 mmol) in THF (85 mL)
was added dropwise during 30 min. The temperature of the
reaction mixture was slowly increased to -30˚C in 2.5 h, monitoring
the end of the reaction by TLC (II, Rf 9 = 0,75, Rf 13 = 0.40, Rf 12 = 0.09;
III, Rf = 0.51, Rf
= 0.11). Acid acetic (15 mL) was added to
13
12
neutralize the base, stirring was continued for 5 min. and the
solvents were distilled under reduced pressure. The residue was
taken in water (50 mL) and ethyl acetate (150 mL), phases were
separated (aqueous phase extracted with 3×150 mL ethyl acetate),
organic phases washed with 30% NaHPO4 soln. (30 mL), brine (30
mL), dried (MgSO4) and concentrated to dryness. The crude product
(24.5 g) was purified by LPC (eluent: ethyl acetate-hexane, 1:1),
resulting two pure fractions of β-ketophosphonates 12 and 13:
-5.91 g (33.5 %) mono β-ketophosphonate 13, as an oil, 1H-NMR
(CDCl3,  ppm, J Hz): 3.80 (d, 3H, OCH3, JHP =11.3), 3.79 (d, 3H, OCH3,
The diacid 5 was obtained in 72.5 % yield by the same procedure,
starting from 1.
3. Synthesis of diester 9.
Diacid 6 (22.8 g, 0.115 mol) was added to a solution of TsOH (2 g) in
methanol (250 mL) and stirred overnight at rt, monitoring the end
of the reaction by TLC (II, Rf 6 = 0.51, Rf 9 = 0.78). NaHCO3 (3 g) was
added, the solution was concentrated under reduced pressure, the
concentrate was taken in ethyl acetate (150 mL), the solution was
washed with sat. soln. NaHCO3 (50 mL), brine (30 mL), dried
(Na2SO4), concentrated, coevaporated with benzene, resulting 25 g
of crystallized crude diester. By crystallization from ethyl acetate-
hexane, we obtained 23.3 g (91.1 %) of pure product, mp 71.0-73.1
˚C, 1H-NMR (CDCl3,  ppm, J Hz): 3.68 (s, 6H, CH3O), 2,80 (m, 4H, H-
1, H-3, H-3a, H-6a), 2.14 (q, 1H, H-2, 12.8), 1.91 (m, 1H, H-2), 1.72
(m, 2H, H-4, H-6), 1.66 (tt, 1H, H-5, 2.3, 5.8), 1.27 (m, 1H, H-5), 1.11
(m, 2H, H-4, H-6), 13C-NMR (CDCl3,  ppm): 173.72 (COO), 51.29
(CH3O), 46.55 (C-1, C-3), 44.51 (C-3a, C-6a), 30.24 (C-4, C-6), 27.78
(C-2), 27.10 (C-5).
JHP =11.3), 3.67 (s, 3H, OCH3), 3.29 (dd, 1H, CH2P, JHP = 22.7, Jgem
=
14.0), 3.20 (m, 1H, H-3), 2.99 (dd, 1H, CH2P, JHP = 22.7, Jgem = 14.0),
2.90-2.78 (m, 2H, H1, H-3a), 1.83-1.61 (m, 4H, H-2, H-4, H-6, H-6a),
1.35-0.85 (m, 5H, H-2, H-4, 2H-5, H-6), 13C-NMR (CDCl3,  ppm):
201.36 (d, CO, 6.2), 173.69 (COOCH3), 55.16 (C-3), 53.21 (d, POCH3,
JCP = 6.5), 52.97 (d, POCH3, JCP = 6.5), 51.36 (COOCH3), 46.28 (C-1),
44.96 (C-6a), 44.07 (C-3a), 40.55 (d, CH2P, JCP = 129.3), 29.97 (C-6 or
C-4), 29.78 (C-4 or C-6), 27.30 (C-5), 26.63 (C-2).
-7.27 g (32.1 %) bis β-ketophosphonate 12, 1H-NMR (CDCl3,  ppm, J
Hz): 3.80 (d, 6H, POCH3, JHP =11.3), 3.79 (d, 6H, OCH3, JHP =11.3),
3.30 (d, 2H, CH2P, JHP = 22.8), 3.29 (d, 1H, CH2P, JHP = 22.7), 3.10-2.80
4 | NJC., 2020, 00, 1-6
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New Journal of Chemistry
ARTICLE
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9
(m, 4H, H-1, H-3, H-3a, H-6a), 2.15-1.90 (m, 2H, 2H-2), 1.75-1.63 (m, In the reaction conditions presented at the example 7V, isetwaArtrtiinclge Ofrnolinme
2H, H-4, H-6), 1.50-1.30 (m, 2H, H-5), 1.10-0.85 (m, 2H, H-4, H-6), 3.56 g (20 mmol) 7 in 25 mL THF, 5.6 g DMPh (44 mmol) in 110 mL
DOI: 10.1039/D0NJ04594B
13C-NMR (CDCl3,  ppm): 201.18 (d, CO, JCP = 6.7), 54.76 (C-1, C-3),
53.18 (d, POCH3, JCP = 6.5), 53.00 (d, POCH3, JCP = 6.5), 44.45 (C-3a,
THF, 27 mL 1.7 M n-BuLi solution in hexanes, TLC (II, Rf 7 = 0.71, Rf 10
=0.11), 4.44 g (73.5 %) of pure β-ketophosphonate 10 were
C-6a), 40.59 (d, CH2P, JCP = 128.4), 29.47 (C-4, C-6), 27.46 (C-5), obtained, mp 113-114C (acetone), IR (KBr): 3250-2300 large band
25.57 (C-2). The fraction with the mixture of the phosphonates 12
and 13 (6.6 g) was repurified, resulting 2.46 g of mono β-
ketophosphonate 13 (total yield, 47.4%) and 2.25 g of bis β-
ketophosphonate 12 (total yield, 42.0%).
(with peaks at 2954s, 2911s), 1715vs (C=O), 1705 (COOH), 1375m,
1289vs (P=O), 1210s, 1201s, 1053vs (P-O-C), 1032vs, 910m, 866vs,
807s (P-O-C), H-NMR (CDCl3,  ppm, J Hz): 12.16 (COOH), 5.69 (dq,
1H, H-6, 2.1, 5.8), 5.37 (dq, 0.5H, H-5, 2.3, 5.8), 5.30 (dq, 0.5H, H-5,
2.3, 5.8), 3.67 (d, 3H, OCH3, JHP = 11.2), 3.65 (d, 3H, OCH3, JHP = 11.2),
3.53 (dd, 0.5H, CH2P, JHP = 22.1, Jgem = 14.4), 3.51 (dd, 0.5H, CH2P, JHP
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
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51
52
53
54
55
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59
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7. Synthesis of β-ketophosphonate 11
= 22.1, Jgem = 14.4), 3.48 (m, 1H, H-6a), 3.24 (dd, 0.5H, CH2P, JHP
=
A solution of 1.7 M n-BuLi in hexanes (48.1 mL, 81.7 mmol) was
added dropwise under mechanical stirring to a solution of DMPh 97
% (9.95 g, 8.6 mL, 77.77 mmol) in anh. THF (200 mL), which had
been cooled to < -70C in an inert anh. atmosphere (Ar). After 40
min of stirring, a solution of saturated anhydride 8 (6.37 g, 35.35
mmol) in THF (40 mL) was added dropwise. Stirring was continued
for 100 min at a temperature below -60C, then the temperature
was allowed to increase to -35C, monitoring the end of the
reaction by TLC (I, Rf 8 = 0.77, Rf 11 =0.13 ). TLC showed the end of
the reaction after 30 min. Acetic acid was added, stirred for 5 min.
and the solvents were distilled under pressure. The residue was
taken in water (100mL) and ethyl acetate (150 mL), phases were
separated (aqueous phase extracted with 3×150 mL ethyl acetate),
organic phases were extracted with 10 % KHCO3 (3×75 mL), brine
(25 mL), dried and concentrated. The aqueous phases were
acidified to pH 3, extracted with ethyl acetate (100 mL ×, control
TLC), organic phases washed with brine (20 mL), dried (MgSO4) and
concentrated to dryness. The residue was taken in warm toluene
and the β-ketophosphonate 11 crystallized at rt, resulting 3.70 g
(34.4 %), mp 148-150C, IR (KBr): 3250-2500 large band (with peaks
at: 2967s, 2935s, 2865s), 1724vs (C=O), 1706 (COOH), 1393m,
21.8, Jgem = 14.5), 3.21 (dd, 0.5H, CH2P, JHP = 21.8, Jgem = 14.5), 3.13
(m, 1H, H-3, 5.4, 8.7), 3.03 (dq, 1H, H-3a, 4.4, 8.4), 2.85 (m, 1H, H-1),
2.41 (m, 1H, H-4), 1.98 (m, 1H, H-4), 1.78-1.50 (m, 2H, H-2), 13C-
NMR (CDCl3,  ppm): 202.79, 201.75 (CO), 174.49, 173.97 (COOH),
132.57, 132.42 (C-6), 129.32, 129.01 (C-5), 55.80, 55.76, 55.72 (C-
6a), 52.69 (d, OCH3, JCP = 6.8), 52.57 (d, OCH3, JCP = 6.0), 51.69, 51.42
(C-3), 47.34, 46.89 (C-1), 41.04 (C-3a), 40.87 (d, CH2P, JC P = 128.8) in
DMSO, 36.24, 35.85 (C-4), 26.84 (C-2).
10. Synthesis of prostaglandin analogue 16
a) 70 % HClO4 (0.25 mL) was added to a solution of prostaglandin
intermediate 14 (2.63 g, 5 mmol) in acetone (130 mL) and the
solution was stirred overnight at rt, monitoring the end of the
reaction by TLC (IV, Rf 14 = 0.46, Rf 15 = 0.40). HClO4 was neutralized
with KHCO3 solid, the acetone was distilled under reduced pressure,
the residue was taken in benzene (100 mL), the benzene solution
was washed with 10 % KHCO3 soln. (20 mL), brine (20 mL), dried
(MgSO4), concentrated, and co-evaporated with anh. benzene to
about 20 mL. The solution was used as such in the next reaction.
1240vs (P=O), 1207s, 1165s, 1106m, 1036vs (P-O-C), 1024m, 895m, b) A solution of β-ketophosphonate 13 (1.59 g, 5 mmol) in THF (20
1
mL) was added dropwise in inert anh. atmosphere (Ar) to a
suspension of NaH (hexane washed) (123 mg, 5.1 mmol) in THF (20
mL), cooled to an ice bath, and stirred for 30 min. Then the solution
of aldehyde 15 in benzene was added dropwise and stirred for 5 h,
860s, 832vs (P-O-C), 674m, H-NMR (CDCl3,  ppm, J Hz): 3.66 (d,
3H, OCH3, JHP = 11.1), 3.65 (d, 3H, OCH3, JHP = 11.1), 3.50 (dd, 1H,
CH2P, JHP = 22.0, Jgem = 14.3), 3.12 (dd, 1H, CH2P, JHP = 22.0, Jgem
=
14.3), 3.06 (t, 1H, H-3, 6.3), 2.86 (qv, 1H, H-3a, 8.5), 2.77 (m, 1H, H-
1, 5.9, 9.1), 2.70 (m, 1H, H-6a, 5.9, 9.1, 12.0), 1.81 (q, 1H, H-2, 12.6),
1.72-1.59 (m, 2H, H-4, H-6), 1.59-1.49 (m, 2H, H-2, H-5), 1.18 (dq,
1H, H-5, 5.8, 11.8), 1.00 (m, 1H, H-6, 5.9, 8.3, 12.0), 0.78 (m, 1H, H-
4, 5.9, 9.1, 12.0), 13C-NMR (CDCl3,  ppm): 202.26 (CO), 174.41
(COOH), 54.52, 54.49 (C-3), 52.62 (d, OCH3, JCP = 5.8), 52.51 (d,
OCH3, JCP = 5.8), 45.81 (C-1), 44.11 (C-6a), 43.55 (C-3a), 40,05 (d,
CH2P, JC P = 129) in DMSO, 29.77 (C-6), 29.32 (C-4), 26.92 (C-5), 26.59
(C-2). M = 304.27, M-1 = 303.22, fragment: 269. By LPC purification
of the mother liquors, another 5.35 g of the β-ketophosphonate 11
were obtained (total yield, 84.1 %).
monitoring the end of the reaction by TLC (II, Rf 15 = 0.40, Rf 16
=
0.25, Rf = 0.51). Acetic acid (1.5 mL) was added, the
phosphonate 13
solvents were distilled under reduced pressure and the residue was
purified by LPC (eluent, ethyl acetate-hexane, 1:1), resulting 2.39 g
1
(71.3 %) prostaglandin compound 16, as an oil, H-NMR (CDCl3, 
ppm, J Hz): 8.10-8.06 (2m, 2H, H-o), 7.93-7.86 (2m, H-o), 7.60 (tt,
1H, H-p, 7.4, 1.3), 7.51 (tt, 1H, H-p, 7.5, 1.4), 7.46 (tl, 2H, H-m,7.3),
7.33 (tl, 2H, H-m, 7.4), 6.92 (dd, 0.5H, H-13, 15.8, 2.1), 6.89 (dd,
0.5H, H-13, 15.8, 2.1), 5.52-5.35 (m, 4H, H-5, H-6, H-9, H-11), 3.68
(s, 3H, CH3O-BC), 3.61 (s, 3H, CH3O-C1), 3.20-2.64 (m, 6H), 2.42-2.00
(m, 2H), 1.42-1.92 (m, 2H), 1.30-0.80 (m, 2H), 13C-NMR (CDCl3, 
ppm): 199.45, 199.32 (CO), 174.06, 173.92 (COO), 165.97, 165.70
(COO-Ph), 145.10 (C-13), 133.19, 133.09 (2C-p), 131.52, 131.45 (d,
C-14), 130.69 (C-5 or C-6), 130.17, 129.66 (Cq, Bz), 129.56, 129.52
(C-o), 128.45, 128.27 (CH, C-m), 127.06 (C-6 or C-5), 78.19, 78.14 (d,
C-11), 75.21 (C-9), 53.42, 53.28 (d, C-12), 52.33, 52.25 (d, C-1'),
51.42 (2CH3O), 48.63, 48.53 (CH, C-), 46.39 (2C, C-1, C-3), 45.19,
44.80 (CH, C-), 39.20, 39.13 (C-10), 33.25 (C-2), 30.05, 29.82 (C-4', C-
6'), 27.28 (C-2'), 26.63 (C-5', C-4), 25.55, 25.47 (CH2, C-), 24.56 (CH2,
C-).
8. Esterification of β-ketophosphonate 11 to β-ketophosphonate 13
with diazomethane
20 mL Of a solution of diazomethane in ethyl ether were added to a
solution of 100 mg β-ketophosphonate 11 in 5 mL chloroform, and
stirred at rt (the yellow color to persist at the end of the reaction),
monitoring the end of the reaction by TLC (II, Rf 11 = 0.29, Rf 13
=
0.40). The solvents were distilled and the product, though almost
pure, was purified by LPC, resulting 95 mg (92%) β-
ketopphosphonate 13, with NMR identical to that of β-
ketopphosphonate 13.
9. Synthesis of β-ketophosphonate 10
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New Journal of Chemistry
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A patent request [12] with the synthesis of β-ketophosphonates
having functionalized hexahydro-and octahydropentalene
fragment linked to the ketone group was submitted to OSIM,
Romania.
8. M. Harre, J. Westermann, K. Nickish, H. Rewinkel, DE
View Article Online
a
4028864/1992.
DOI: 10.1039/D0NJ04594B
9. Tolstikov, G.A., Miftakov, M. S., Danilova, N. A., Sitikova, O.
V. Zhur. Org. Khim., 1985, XXI (3), 675.
10. Starck, G. P., Golobish, T. D., Aboud-Gharbia, M. A.-M. EP
0286263/1988.
11. C. Tănase, F., Cocu, C. Drăghici, M.T. Căproiu, Rev. Roum.
Chim., 2008, 53(3), 195.
Conclusions
β-Ketophosphonates, with the keto group linked to the
bicyclo[3.3.0]oct(a)ene fragment, were synthesized. Diacids 5 and 6
were transformed into internal anhydrides 7 and 8, which were
reacted with lithium salt of dimethyl methanephosphonate to
obtain the acid phosphonates 10 and 11. The saturated di-acid was
esterified to the dimethyl ester 9 which was reacted with lithium
salt of dimethyl methanephosphonate to obtain the mono β-
ketophosphonates 13 and bis β-ketophosphonates 12. The acid β-
ketophosphonate 11 was esterified with diazomethane to the ester
β-ketophosphonate 13, and the synthesis of 13 from anhydride 8
and from diester 9, confirmed the structure of both compounds. A
E-HEW selective olefination of the prostaglandin aldehyde 15
having an α-side chain, with the β-ketophosphonate 13 was realized
to give the 15-keto prostaglandin analogue 16 in good yield. The
following step, that is, the selective reduction of the 15-ketone
group with aluminium diisobornyloxyisopropoxyde, gave no 15-
allylic alcohol. This shows that the bicyclo[3.3.0]octane skeleton,
linked to the C15 carbon atom, is bulky enough to block the access
of the also bulky reducing reagent and this fact predicts that the
access of the prostaglandin receptor(s) to the 15α-OH active form
of the prostaglandin will be diminished. The compounds, all
obtained in good yields, were characterized by elemental analysis,
(a few by MS), IR and high resolution 1H- and 13C-NMR
spectroscopy.
10
11
12
13
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12. C. Tănase, M.T. Căproiu, C. Drăghici, Patent request
A/00517/14.08.2020.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We acknowledge the Ministry of Education and Research for the
grant Orizont-2000, 45/1999/1
Notes and references
1. Tănase, C., Căproiu, M. T., Drăghici, C. New β-
ketophosphonates for synthesis of prostaglandin
analogues. 1. Phosphonates with a bicyclo[3.3.0]octene
scaffold separated by a methylene group to β-ketone,
Submited for publication.
2. L. Delmarche, P. Mosset, J. Org. Chem., 1994, 59, 5453.
3. E.J., Corey, G.T. Kwiatkowski, J. Am. Chem. Soc., 1966, 88,
23, 5654.
4. G.A. Tolstikov, M. S. Miftakhov, M. E. Adler, V. E. Platonov,
Kh. F. Sagitdinova, L. M. Khalilov, Zhur. Org. Khim. 1990,
26, 1, 119.
5. I. Szekely, M. Lovasz, S. Botar, K. Dolgosne Kekesi, B. Bertok,
A. Gajary, T. Szabolcsi, G. Kovacs, WO 1983/004021.
6. I. Kalder, V. Simonidesz, P. Gyory, F. Szabo, J. Oery,
WO8807537/1988.
7. J.S. Bindra, M.R. Johnson, US4024179/1977.
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