A general synthesis of dioxolenone prodrug moieties

Article abstract of DOI:10.1016/S0040-4039(01)02386-3

A general method for the synthesis of dioxolenone prodrug moieties from appropriately substituted β-ketoesters is described. This novel and versatile sequence allows for the synthesis of alkyl- or aryl-substituted dioxolenone alcohols 8 or bromides 9. Coupling of the bromides 9 to prepare bis-dioxolenone phosphonate prodrug esters is also presented.

Full text of DOI:10.1016/S0040-4039(01)02386-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1161–1164
A general synthesis of dioxolenone prodrug moieties
Chong-Qing Sun,* Peter T. W. Cheng,* Jay Stevenson, Tamara Dejneka, Baerbel Brown,
Tammy C. Wang, Jeffrey A. Robl and Michael A. Poss
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA
Received 21 November 2001; revised 7 December 2001; accepted 14 December 2001
Abstract—A general method for the synthesis of dioxolenone prodrug moieties from appropriately substituted b-ketoesters is
described. This novel and versatile sequence allows for the synthesis of alkyl- or aryl-substituted dioxolenone alcohols 8 or
bromides 9. Coupling of the bromides 9 to prepare bis-dioxolenone phosphonate prodrug esters is also presented. © 2002 Elsevier
Science Ltd. All rights reserved.
Esters are the most commonly employed prodrug moi-
eties for acid-derived drugs (e.g. carboxylate, phospho-
nate and phosphinate) due to the ubiquitous
distribution of esterases in the blood, liver and other
organs and tissues.1 However, simple aliphatic or aro-
matic esters are often insufficiently labile in vivo (due
primarily to the resulting steric hindrance at the acid
functionality) to ensure the desired rate and extent of
prodrug conversion to drug. This limitation can be
overcome by the use of double esters such as
(acyloxy)alkyl esters2 in which the terminal ester moiety
is more sterically accessible to esterases, as illustrated in
Fig. 1 for phosphonic acids. Although the double ester
prodrug approach has been widely used in solving
delivery problems for drugs with poor absorption
(notably in the case of fosinopril3), two significant
problems are encountered using this type of prodrug.
First, synthetic complications are introduced since a
new asymmetric center is generated in the case where
R%"H. This becomes especially problematic in the case
of phosphonate bis(acyloxy)alkyl esters (where R%"H),
which now contain multiple chiral centers both at phos-
phorus and on the prodrug moieties. Secondly, for the
most simple case of (acyloxy)alkyl esters (where R%=
R'
O
O
O
Drug
RCO2H
P
(OH)2
R'CHO
+
+
Drug
P O
O
R
2
Enzyme/H2O
(Acyloxy)alkyl Ester Prodrugs
R' = alkyl or H
O
R
O
Drug
P O
R
Drug
P
(OH)2
+
CO2
O
+
O
O
O
2
O
Dioxolenone Ester Prodrugs
Enzyme/H2O
Figure 1.
Keywords: dioxolenone prodrug moieties; phosphonate prodrugs; squalene synthase inhibitors.
* Corresponding authors. Fax: 609-818-3460; e-mail: chongqing.sun@bms.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02386-3

1162
C.-Q. Sun et al. / Tetrahedron Letters 43 (2002) 1161–1164
H), concerns regarding the potential toxicity associated
with the formaldehyde by-product after bioconversion
of the prodrug will always need to be addressed. Diox-
olenone esters4 comprise a different class of masked
double-ester prodrug moiety which offer potential
advantages over (acyloxy)alkyl esters because: (1) no
asymmetric centers are present, and (2) enzymatic
hydrolysis of dioxolenone esters releases relatively non-
toxic carbon dioxide and a-dicarbonyl derivatives5
rather than formaldehyde as by-products.
As part of a program to identify suitable prodrugs of
the novel squalene synthase inhibitor BMS-187745,8 we
wished to investigate modifications of the substituents
(with diverse steric and electronic properties) at the
5-position of dioxolenone prodrug moieties as a means
of modulating their susceptibility to enzymatic hydroly-
sis. Therefore, a general and efficient synthesis of 5-
alkyl and 5-aryl substituted dioxolenones was required.
The general synthetic sequence which we developed9 is
shown in Scheme 2. The requisite benzyl b-ketoesters 2
(R=alkyl or aryl) were readily available through
acylation of ethyl malonate monoester with an acid
chloride10 and subsequent transesterification with ben-
zyl alcohol.11 Diazotization of b-ketoester 2 furnished
the a-diazo b-keto ester 3, which was then subjected to
rhodium-mediated a,a-insertion of water to provide a
key intermediate, the a-hydroxy b-keto ester 4. Treat-
ment of 4 with phosgene or a suitable synthetic equiva-
lent (such as carbonyldiimidazole or triphosgene) in the
presence of base furnished the corresponding dioxo-
The variety of dioxolenones that could be used as
prodrug moieties has to date been limited by available
synthetic methods.6 The literature synthetic sequence
summarized in Scheme 1 relies upon allylic bromination
of the dioxolenone intermediate A for the preparation
of dioxolenone bromides B. Thus, this synthetic method
is feasible with only a limited subset of substituents (i.e.
R=H, CH3, t-Bu or aryl). Dioxolenone alcohols C are
obtained from bromides B by formate displacement
followed by acid-catalyzed hydrolysis.7
O
O
O
1) COCl2/PhCH3
Me2NPh/CH2Cl2
1) NBS/AIBN
CCl4
(60-70%)
2) HCO2H/Et3N
MeCN
O
O
O
O
O
O
O
CH3
OH
R
2) heat/distillation
(30-50%)
R
Br
R
CH3
R
OH
3) MeOH
(80%)
C
B
R = H, Me, t-Bu, Ph
A
Scheme 1.
O
O
O
O
O
R
c
a
b
Cl
R
EtO
R
BnO
O
1
2
O
O
R
X
O
O
O
e
d
BnO
O
BnO
R
f
R
OH
N2
4
5
CO2Bn
3
O
O
O
O
O
O
g
h
O
O
O
O
O
O
R
R
R
R
CO2H
9
8
CO2Bn
6
7
Br
HO
O
i
BMS-187745
O
O
O
P
O
O
PO3H2
SO3H
O
R
HO3S
10
2
Scheme 2. Reaction conditions: (a) KO2CCH2CO2Et, MgCl2, Et3N/CH3CN; (b) PhCH2OH, DMAP (cat.), toluene/D; (c)
4-N-acetyl phenylsulfonylazide, Et3N/CH3CN; (d) Rh2(OAc)4 (cat.), THF/H2O (2:1)/reflux; (e) COCl2, iPr2NEt; toluene OR
carbonyldiimidazole, iPr2NEt (cat.), CH2Cl2; (f) H2, Pd(OH)2, EtOH; (g) i. (COCl)2, DMF (cat.), CH2Cl2, ii. Bu4NBH4, CH2Cl2;
(h) Ph3P, CBr4, CH2Cl2; (i) iPr2NEt, CH3CN.

C.-Q. Sun et al. / Tetrahedron Letters 43 (2002) 1161–1164
1163
lenone ester 6 in good yield. The reaction presumably
occurs via the initial O-acylation intermediate 5, then
undergoes enolization and subsequent cyclization to
afford 6. Hydrogenolysis of benzyl ester 6 provided the
acid 7, which was converted to the primary alcohol 8 via
acid chloride formation followed by reduction (Table 1).
Dioxolenone bromides 9 (obtained from bromination of
alcohols 8) were then successfully used to prepare the
corresponding dioxolenone phosphonate prodrug esters
10 of BMS-187745 as shown in Scheme 2. The use of these
carefully defined reaction conditions is necessary in order
to avoid the racemization of the highly sensitive chiral
center of BMS-187745. Di-esters 10 represent a unique
phosphonate prodrug that has not been previously
described.
EtOAc/hexane) to provide compound 3c as an oil (12.79
g, 96% yield); 1H NMR (400 MHz, CDCl3): l 0.91 (t, 3H,
J=7.3 Hz), 1.34 (m, 2H), 1.62 (m, 2H), 2.85 (m, 2H), 5.26
(s, 2H), 7.37 (s, 5H); 13C NMR (100 MHz, CDCl3): l
193.3, 161.7, 135.6, 129.1, 129.1, 128.8, 67.3, 40.4, 26.8,
22.7, 14.2. Anal. calcd for C14H16N2O3: C, 64.60; H, 6.20;
N, 10.76. Found: C, 64.70; H, 6.10; N, 11.02.
Compound 4c: A solution of the diazo compound 3c (12.7
g, 48.7 mmol) in THF (250 mL) and H2O (120 mL) was
refluxed with Rh2(OAc)4 (165 mg, 0.37 mmol) for 5 h and
allowed to cool to room temperature. The mixture was
concentrated in vacuo and the aqueous residue was
extracted with EtOAc (3×). The combined organic
extracts were washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo to provide crude 4c
1
In conclusion, the synthetic sequence described in this
paper allows for the preparation of a wide variety of
5-substituted dioxolenone alcohols 8 and bromides 9
which are suitable as penultimate intermediates for the
synthesis of carboxylic acid and phosphonic acid pro-
drugs. These novel substituted dioxolenone prodrugs
should display a wide range of susceptibility to enzymatic
hydrolysis as required. The utility of these substituted
dioxolenones as prodrug moieties for acid-containing
drugs, particularly phosphonic acids, will be reported in
due course.
(12.04 g) as a yellow oil; H NMR (400 MHz, CDCl3):
l 0.84 (t, 3H, J=7.3 Hz), 1.21 (m, 2H), 1.52 (m, 2H),
2.53 (m, 2H), 4.81 (s, 1H), 5.24 (m, 2H), 7.36 (s, 5H); 13
C
NMR (100 MHz, CDCl3): l 204.1, 168.1, 134.6, 128.7,
128.6, 128.5, 77.7, 67.9, 38.3, 25.3, 21.9, 13.6. Anal. calcd
for C14H18O4·0.5H2O: C, 64.83; H, 7.39. Found: C, 64.84;
H, 7.11.
Compound 6c: A 0°C solution of alcohol 4c (11.76 g, 46.9
mmol) in dry THF (230 mL) was treated with carbonyldi-
imidazole (15.3 g, 94.4 mmol) followed by iPr2NEt (336
mL, 1.9 mmol). After stirring at 0°C for 5 h and room
temperature overnight, the mixture was concentrated in
vacuo and the residue was partitioned between EtOAc
and 5% aqueous KHSO4. The separated organic layer was
washed with H2O and brine, dried over Na2SO4, filtered
and concentrated in vacuo to give an oily residue, which
was chromatographed (SiO2, 15:85 EtOAc/hexane) to
provide pure 6c (9.99 g, 77% yield from 3c) as a colorless
A representative set of experimental procedures for the
preparation of dioxolenone alcohol 8c, bromide 9c, and
the corresponding phosphonate prodrug 10c is as follows:
Compound 3c: To a 0°C solution of b-keto ester 2c (12.0
g, 51.3 mmol) and p-toluenesulfonylazide (12.3 g, 51.3
mmol) in CH3CN (420 mL) was added Et3N (21.4 mL,
15.4 mmol). The resulting yellow suspension was stirred
at 0°C for 30 min, then at room temperature for 4 h. The
mixture was concentrated in vacuo, and the solid residue
was triturated with 2:1 ethyl ether and petroleum ether
(2×150 mL). The filtrate was concentrated in vacuo to give
an oily residue, which was chromatographed (SiO2, 15:85
1
oil; H NMR (400 MHz, CDCl3): l 0.90 (t, 3H, J=7.3
Hz), 1.35 (m, 2H), 1.60 (m, 2H), 2.80 (t, 2H, J=7.6 Hz),
5.13 (s, 2H), 7.39 (s, 5H); 13C NMR (100 MHz, CDCl3):
l 156.8, 152.9, 150.1, 134.5, 129.4, 128.8, 128.8, 128.6,
67.5, 28.5, 24.6, 22.0, 13.5. Anal. calcd for C15H16O5: C,
65.21; H, 5.84. Found: C, 65.30; H, 6.07.
Table 1.
O
O
O
O
O
O
O
O
BnO
R
R
R
2
Br
HO
9
8
Entry
R
% yield of 8 from 2
% yield of 9 from 8
a
b
c
d
e
f
Et
53
31
52
44
54
34
41
63
87
79
86
84
51
74
n-Pr
n-Bu
i-Pr
t-Bu
4-CF3-C6H4-
4-CH3O-C6H4-
g
All new compounds gave satisfactory spectroscopic data (1H NMR, 13C NMR, MS).

1164
C.-Q. Sun et al. / Tetrahedron Letters 43 (2002) 1161–1164
Compound 7c: A solution of compound 6c (9.98 g, 36.1
mmol) was stirred with Pd(OH)2 on carbon (20%, 490 mg)
in absolute EtOH (230 mL) under an atmosphere of
hydrogen (balloon) for 70 min. Filtration and removal
of volatiles in vacuo provided 7c (6.56 g, 98%) as an
off-white solid: mp 59–61°C; 1H NMR (400 MHz,
CDCl3): l 0.96 (t, 3H, J=7.3 Hz), 1.41 (m, 2H), 1.68 (m,
2H), 2.86 (t, 2H, J=7.5 Hz); 13C NMR (100 MHz,
CDCl3): l 162.1, 155.5, 150.4, 129.3, 28.9, 25.3, 22.5, 14.0.
Anal. calcd for C8H10O5: C, 51.61; H, 5.41. Found: C,
51.61; H, 5.73.
A (B=95% CH3CN/5% H2O; A=95% H2O/5% CH3CN;
A is buffered with 0.04 M NH4OAc/acetic acid to pH 5.5).
The desired fractions were combined and lyophilized to
give 10c (ammonium salt) as a clear gum (925 mg, 61%
yield); MS: [M+H]+=695; 1H NMR (400 MHz, CD3OD):
l 0.92 (m, 6H), 1.36 (m, 4H), 1.54 (m, 4H), 1.93–2.21 (m,
4H), 2.52 (m, 4H), 2.61 (m, 2H), 3.32–3.45 (m, 1H), 4.92
(d, 2H, J=8.6 Hz), 4.98 (d, 2H, J=8.6 Hz), 6.75 (m, 1H),
6.84 (s, 1H), 6.95 (d, 3H, J=8.5 Hz), 7.06 (m, 1H), 7.20
(m, 1H), 7.32 (m, 2H); 13C NMR (100 MHz, CD3OD):
l 158.9, 158.7, 153.8, 145.5, 145.2, 135.5, 135.4, 130.8,
130.7, 124.6, 124.2, 120.1, 119.8, 117.3, 60.8, 59.4, 58.0,
57.2, 36.5, 30.9, 29.7, 28.7, 24.1, 23.0, 14.0. Anal. calcd
for C32H42NO13PS·0.11H2O: C, 53.86; H, 5.96; N, 1.96;
P, 4.34; S, 4.49. Found: C, 53.78; H, 6.03; N, 2.04; P, 4.40;
S, 4.40.
Compound 8c: To a 0°C solution of acid 7c (6.47 g, 34.7
mmol) and anhydrous DMF (350 mL) in dry CH2Cl2 (150
mL) was added dropwise oxalyl chloride (3.33 mL, 38.2
mmol). After addition was complete, the mixture was
stirred at 0°C for 30 min, then at room temperature for
1 h before being concentrated and dried in vacuo. The
residue was dissolved in dry CH2Cl2 (200 mL) and cooled
to −78°C. To this solution was then added dropwise a
solution of Bu4NBH4 (9.86 g, 38.3 mmol) in CH2Cl2 (60
mL) over 15 min (exothermic reaction). After stirring at
−78°C for 1 h, the mixture was cautiously quenched with
0.1N aqueous HCl (100 mL) and allowed to warm up to
room temperature. Volatiles were removed in vacuo and
the residue was partitioned between EtOAc (200 mL) and
H2O (50 mL). The separated aqueous layer was saturated
with NaCl and extracted with EtOAc (100 mL). The
combined organic extracts were washed with brine, dried
over Na2SO4, filtered and concentrated in vacuo to give
an oily residue, which was chromatographed (SiO2, 4:6
EtOAc/hexane) to provide pure 8c as an oil (4.25 g) in
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1
69% yield; H NMR (400 MHz, CDCl3): l 0.94 (t, 3H,
J=7.5 Hz), 1.37 (m, 2H), 1.59 (m, 2H), 2.38 (t, 1H, J=6.2
Hz), 2.45 (t, 2H, J=7.5 Hz), 4.41 (d, 2H, J=6.0 Hz); 13
C
NMR(100MHz, CDCl3):l152.9, 141.3, 137.1, 53.4, 28.8,
23.5, 22.0, 13.7. Anal. calcd for C8H12O4: C, 55.81; H,
7.02. Found: C, 56.11; H, 7.34.
Compound 9c: To a 0°C solution of alcohol 8c (2.00 g,
11.6 mmol) in CH2Cl2 (150 mL) were successively added
CBr4 (4.62 g, 13.9 mmol) and Ph3P (3.35 g, 12.8 mmol).
After stirring for 30 min at 0°C and 1 h at room
temperature, volatiles were removed in vacuo and the
residue was chromatographed (SiO2, 2:8 EtOAc/hexane)
to provide 9c (2.15 g, 79%); 1H NMR (400 MHz, CDCl3):
l 0.95 (t, 3H, J=7.5 Hz), 1.39 (m, 2H), 1.60 (m, 2H),
2.45 (t, 2H, J=7.5 Hz), 4.19 (s, 2H); 13C NMR (100 MHz,
CDCl3): l 151.7, 141.6, 134.4, 28.3, 23.6, 21.9, 17.8, 13.6.
Anal. calcd for C8H11BrO3: C, 40.88; H, 4.72; Br, 33.99.
Found: C, 40.90; H, 4.71; Br, 33.93.
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Compound 10c: A solution of the triacid BMS-187745 (830
mg, 2.15 mmol) and iPr2NEt (1.27 mL, 7.34 mmol) in
anhydrous CH3CN (10 mL) was treated with bromide 9c
(1.73 g, 7.33 mmol) in anhydrous CH3CN (8 mL). After
stirring at room temperature for 5 days, the mixture was
diluted with EtOAc (100 mL) and successively washed
with 5% KH2PO4 buffer (pH 2, 3×40 mL), 5% KH2PO4
buffer (pH 6, 40 mL) and saturated aqueous KCl (40 mL),
dried over Na2SO4, filtered and concentrated in vacuo to
give an oily residue. This crude product was purified using
preparative HPLC (2-EM Merck, RP Select B column
(5×50 cm) eluting with 57% isocratic solvent B: solvent
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