Asymmetric synthesis of mercaptoalcohols - Matrix metalloproteinase inhibitors

Article abstract of DOI:10.1055/s-1999-2858

A novel approach has been developed for the preparation of all of the possible diastereoisomers of mercaptoalcohol 1, a potent matrix metalloproteinase (MMP) inhibitor, with easy access to various P1' substituents. Readily available chiral epoxides have b

Full text of DOI:10.1055/s-1999-2858

LETTER
1371
Asymmetric Synthesis of Mercaptoalcohols – Matrix Metalloproteinase
Inhibitors
K. Paulvannan*, Tao Chen
Affymax Research Institute, 3410 Central Expressway, Santa Clara, CA 95051. USA
Fax +1 408 481-9558: E-mail: kumar_paulvannan@affymax.com
Received 27 June 1999
wanted to study the influence of the relative and absolute
stereochemistry of the –OH group and the P1’ substituent
on the inhibition of the MMPs.
Abstract: A novel approach has been developed for the preparation
of all of the possible diastereoisomers of mercaptoalcohol 1, a po-
tent matrix metalloproteinase (MMP) inhibitor, with easy access to
various P1’ substituents. Readily available chiral epoxides have
been used as the starting materials to control the stereochemistry of
the –OH group.
The previously reported route to 1 utilized the Evan’s
chiral auxiliary to establish the P1’ stereochemistry and
the –OH functionality was introduced via an iodolacton-
ization approach.2a In an effort to introduce the P1’ diver-
sity using readily available diverse alkyl halides, we
wished to develop an alternative synthetic route. In this
communication we report a novel approach to prepare an-
alogs of 1 from an advanced key intermediate 5 via six
simple chemical steps. The P1’ substituents are efficiently
introduced via a malonate alkylation/decarboxylation ap-
proach, and readily available chiral epoxides are used to
introduce the –OH group with desired stereochemistry.
The utility of this approach is demonstrated by preparing
all of the possible isomers of 1, keeping the P2’ moiety in-
tact.
Key words: Mercaptoalcohol, MMP inhibitor, malonate alkylation,
epoxide opening, decarboxylation
The matrix metalloproteinases (MMPs) are a family of
zinc dependent enzymes, which play an important role in
normal matrix remodeling.1 Overproduction of these en-
zymes can lead to a range of biological pathologies, such
as arthritis, tumor metastasis, periodontal disease, and
multiple sclerosis. Thus, the identification of potent and
selective inhibitors of MMPs would be highly desirable as
potential therapeutic agents for controlling pathological
processes. A standard approach to design an MMP inhib-
itor involves the incorporation of a zinc binding group
such as a thiol,2 hydroxamate,3 or carboxylate4 into a
pseudopeptide capable of binding to a subset of enzyme’s
specificity pockets, usually on the P’ side. Recent commu-
nication from these laboratories and Wyeth-Ayerst Re-
search laboratories has shown that mercaptoalcohols 1a,
1b, 1c and 1d inhibit MMPs (Figure 1) in the nanomolar
range.2a As part of our program directed toward the iden-
tification of potent and selective MMP inhibitors, we were
interested in the preparation of analogs of mercaptoalco-
hol 1 with varying P1’ substituents. In addition, we also
Preparation of mercaptoalcohols 1a and 1b, and their di-
astereoisomers 13 and 14, respectively, from (R)-epoxide
2, is shown in Scheme 1. Treatment of 2 with triphenylm-
ethyl mercaptan (Trt-SH) in the presence of KF in MeOH
provided, after epoxide opening, the desired alcohol 3 in
63% yield and 99.7 % ee.5 Use of bases other than KF re-
sulted in the formation of complex product mixtures. Al-
cohol 3 was then protected as the TBS ether 4 under
standard conditions (TBSCl/ imidazole/ CH2Cl2). Alkyla-
tion of sodium diallylmalonate with tosylate 4 in the pres-
o
ence of KI or TBAI at 80 C afforded the desired mono-
alkylation product 5 in 53% yield. In this approach, the
malonate derivative 5 serves as the key intermediate for
the preparation of analogs of 1 with desired alkyl P1’ sub-
stituents.
P1'
R1
P2'
Treatment of 5 with 1.5 equivalents of NaH followed by
the addition of isobutyl bromide or heptyl bromide pro-
vided the corresponding alkylation products 6a and 6b in
89% and 91% yields, respectively. The alkylation reaction
was very efficient with most of the primary alkyl and aryl
alkyl bromides we examined, and provided the desired
alkylation products in high yields. Treatment of 6a and 6b
with catalytic amount of (Ph3P)4Pd followed by the addi-
tion of morpholine at room temperature yielded the corre-
sponding diacids. The crude diacids were immediately
taken in dioxane and heated at reflux for 3 h to provide the
decarboxylation products 7a and 7b as an inseparable
equal mixture of diastereoisomers in 68% and 78% yields,
respectively. Formation of two diastereoisomers in equal
O
R3
R2
H
N
HS
Me
N
H
O
P3'
1
IC50 (nM)
MMP-1 MMP-3
R2 R3
MMP-9
8
1a R1 = i-Bu
11
5
470
9
OH
H
1b R1 = Heptyl
0.14
250
12
OH
H
H
OH
1c R1 = i-Bu
46
140
3700
430
1d R1 = Heptyl
H
OH
Figure 1
Synlett 1999, No. 9, 1371–1374 ISSN 0936-5214 © Thieme Stuttgart · New York

1372
K. Paulvannan, T. Chen
LETTER
O
O
OH
OTBS
O
b
c
a
d
OTs
TrtS
OTs
TrtS
OTs
OAll
AllO
53%
88%
63%
TBSO
3
4
5
2
TrtS
O
O
O
R1
TBSO
TBSO
O
R1 R2
H
N
g
e,f
H2N
Me
AllO
OAll
TrtS
OH
+
TrtS
Me
N
H
R1
N
H
TBSO
O
O
TrtS
9a R1 = i-Butyl ;
9b R1 = H ;
R2 = H 38%
R2 = i-Butyl 45%
8
7a R1 = i-Butyl
7b R1 = Heptyl
68%
78%
6a R1 = i-Butyl
89%
6b R1 = Heptyl 91%
R2 = H
R1 = Heptyl;
90%
10
R2 = Heptyl
R1 = H ;
R2
O
HO
O
R2
R1
HO
O
H
N
R1
H
N
i
h
HS
Me
TrtS
Me
N
H
N
H
O
1a R1 = i-Butyl ;
13 R1 = H ;
R2 = H 65%
11a R1 = i-Butyl ;
11b R1 = H ;
R2 = H 81%
R2 = i-Butyl 59%
R2 = i-Butyl 84%
R2 = H 66%
1b R1 = Heptyl;
R2 = H 39%
12a R1 = Heptyl;
R2 = Heptyl 64%
14 R1 = H ;
R2 = Heptyl 45%
12b R1 = H ;
Reaction Conditions: (a) Trt-SH, KF, MeOH, 36 h, rt; (b) TBSCl, imidazole, CH2Cl2, rt, 12 h; (c) Diallylmalonate, NaH, TBAI, DMF,
80 °C, 18 h; (d) NaH, Heptyl bromide or i-Butyl bromide, KI, DMF, 50 °C, 12 h; (e) Pd(Ph3P)4, morpholine, THF rt, 3 h; (f) Dioxane,
reflux, 3 h; (g) EDC/ HOBt/ DIEA, 12 h; (h) TBAF, 12 h; (I) TFA, TES.
Scheme 1
amounts during decarboxylation was an advantage allow- from an advanced common intermediate 5, a feature that
ing us to prepare both diastereoisomers from a common would readily allow us to prepare large numbers of ana-
starting material. Acids 7a and 7b were then coupled with logs of 1 in a short period of time.
t-butylglycine-N-methylamide 8, prepared in two steps
The above approach was then extended to the preparation
from Boc-t-butylglycine-OH and methylamine, under
of 1c and 1d, and their diastereoisomers 18a and 18b re-
standard coupling conditions (EDC, DIEA). In the case of
spectively. Mercaptoalcohols 1c, 1d, 18a and 18b were
7a, diastereoisomers 9a and 9b were readily separated by
prepared from (S)-glycidyl tosylate (15) using similar re-
flash column chromatography, and isolated in 38% and
action sequence (Scheme 2).5 As before, the relative ste-
45% yields, respectively. On the other hand, 7b provided
reochemistry of -OH and the P1’ substituent in 1c, 1d, 18a
the corresponding amides 10 as an inseparable mixture of
and 18b were determined by comparing with the 1H NMR
diastereoisomers in 90% combined yield. Deprotection of
of the authentic samples 1c and 1d.
9a and 9b with tetrabutylammonium fluoride (TBAF)
provided the alcohols 11a and 11b in 81% and 84%
yields, respectively. Under TBS deprotection condition,
10 yielded the diastereoisomers 12a and 12b in 39% and
45% yields, respectively, after chromatographic separa-
tion. Treatment of 11a, 11b, 12a, and 12b with trifluoro-
acetic acid (TFA) in dichloromethane containing
triethylsilane (TES) provided the corresponding mercap-
toalcohols 1a, 13, 1b, and 14, respectively.
OH
O
TrtS
OTs
OTs
15
16
O
O
R2
O
HO R1
O
OAll
AllO
H
HS
N
Me
TBSO
N
1
All the mercaptoalcohols were fully characterized by H
H
17
and 13C NMR and mass spectrometry. The relative stereo-
chemistry of -OH and the P1’ substituent in 1a, 1b, 13 and
14 was determined by comparing with the 1H NMR of the
authentic samples 1a and 1b. It is important to point out
that the reaction sequence illustrated in this work requires
six simple steps to prepare the desired mercaptoalcohols
TrtS
R1 = iButyl
R1 = Heptyl
R2 = iButyl
1c
1d
18a
18b
R2 = Heptyl
Scheme 2
Synlett 1999, No. 9, 1371–1374 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Mercaptoalcohols – Matrix Metalloproteinase Inhibitors
1373
In conclusion, we have developed a novel synthetic route in THF) and the reaction mixture was stirred at r.t. for
to prepare analogs of mercaptoalcohol 1 with any desired 12 h. The reaction mixture was diluted with EtOAc and
stereochemical combination. Since preparation of 5 in- washed with sat. NH4Cl. The organic layer was washed
volved simple chemical transformations, the synthetic with sat. aq NaCl (1x), dried, concentrated, and purified
route was amenable to scaleup. Construction of libraries (hexane: EtOAc 3:1 to 2:1) to give 12a and 12b in 39%
of mercaptoalcohols on solid support and their biological and 45% yields, respectively. To a solution of 12a (0.73
activity will be reported in due course.
mmol) in CH2Cl2 (30 mL) purged with N2 was added TFA
(5 mL) and TES (0.32 mL) and the reaction mixture was
stirred at r.t. for 20 min. Solvent was removed, and the res-
idue was purified (CH2Cl2:EtOAc 1:1 to 2:1) to give 1b in
66% yield.
General Procedure for the Preparation of Compound
1b
(2R)-(-)-Glycidyl tosylate (2) (15 g, 65.7 mmol), triphe-
nylmethyl mercaptan (27.24 g, 98.6 mmol) and potassium
fluoride (7.64 g, 131.4 mmol) ) were taken in MeOH (330
mL) and stirred at r.t. for 36 h. The reaction mixture was
filtered, concentrated, and the crude was purified (hexane:
EtOAc 5:1 to 2:1) to yield 3 in 63% yield. Alcohol 3 (21
g, 41.7 mmol), imidazole (5.7 g, 83.3 mmol),TBSCl (6.9
g, 45.8 mmol) and DMAP (catalytic) were stirred in
CH2Cl2 (200 mL) for 12 h. The reaction mixture was
washed with sat. aq NaHCO3, dried (MgSO4), concentrat-
ed, and purified (hexane: EtOAc 95:5 to 90:10) to yield 4
in 88% yield. To a suspension of NaH (1.3 equiv) in DMF
was slowly added diallyl malonate (1.3 equiv) at 0 oC and
the reaction mixture was stirred at r.t. for 1 h. A solution
of tosylate 4 (1 equiv) in DMF was added followed by
NMR data for selected compounds. Compound 5: 1H NMR
(400 MHz, CDCl3) d 0.16 (s, 6H), 0.95 (s, 9H), 2.09-2.16
(m, 1H), 2.33-2.48 (m, 3H), 3.65 (dd, J = 9.2, 4.6 Hz, 1H),
3.80-3.84, (m, 1H), 4.70-4.83 (m, 4H), 5.37-5.50 (m, 4H),
5.99-6.09 (m, 2H), 7.34-7.57 (m, 15H); 13C NMR (100
MHz, CDCl3) d 4.9, 4.3, 18.1, 25.9, 35.6, 38.8, 48.0, 65.9,
66.6, 68.9, 118.4, 118.6, 126.5, 127.7, 129.4, 131.4,
144.5, 168.5, 168.9.
Compound 13: 1H NMR (400 MHz, CDCl3) d 0.89 (d, J =
6.4 Hz, 3H,), 0.94 (d, J = 6.4 Hz, 3H), 1.00 (s, 9H), 1.14-
1.23 (m, 1H), 1.50 (t, J = 8.6 Hz, 1H), 1.53-1.67 (m, 3H),
1.74-1.82 (m, 1H), 2.49-2.64 (m, 3H), 2.78 (d, J = 4.8 Hz,
3H), 3.62-3.69 (m, 1H), 4.33 (d, J = 9.2 Hz, 1H), 6.86 (b,
1H); 13C NMR (100 MHz, CDCl3) d 22.0, 23.5, 25.9, 26.2,
26.8, 32.1, 34.1, 39.2, 42.4, 42.8, 60.9, 72.1, 171.7, 176.6.
TBAI (0.3 equiv) and imidazole (0.1 equiv), and the reac-
o
tion mixture was stirred at 80 C for 18 h. The reaction Compound 14: 1H NMR (400 MHz, CDCl3) d 0.87 (t, J =
was quenched with H2O, and extracted with EtOAc (2x). 7.0 Hz, 3H), 1.01 (s, 9H), 1.23-1.30 (m, 12H), 1.47 (t, J =
The combined organic layers were washed with sat. aq 8.8 Hz, 1H), 1.60-1.66 (m, 1H), 1.76-1.84 (m, 1H), 2.32-
NaCl, dried, concentrated, and purified (hexane: EtOAc 2.38 (m, 1H), 2.47-2.54 (m, 1H), 2.60-2.66 (m, 1H), 2.79
98:2 to 95:5) to give 5 in 53% yield. To a suspension of (d, J = 4.8 Hz, 3H), 3.59-3.65 (m, 1H), 4.24 (d, J = 9.2 Hz,
NaH (1.5 equiv) in DMF at 0 oC was slowly added a solu- 1H), 6.31 (b, 1H), 6.50 (bd, 1H); 13C NMR (100 MHz,
tion of diallyl malonate 5 (1 equiv) in DMF and the mix- CDCl3) d 14.1, 22.6, 26.1, 26.8, 27.4, 29.2, 29.6, 31.8,
ture was stirred at r.t. for 30 min. Heptyl bromide (2 32.0, 33.0, 34.1, 38.9, 44.0, 60.4, 71.4, 171.7, 176.2.
equiv) and KI (1 equiv) were then added and the reaction
Compound 18a: 1H NMR (400 MHz, CDCl3) d 0.88 (d, J
mixture was stirred at 50 oC for 12 h. The reaction mixture
= 6.6 Hz, 3H), 0.91 (d, J = 6.2 Hz, 3H), 0.99 (s, 9H), 1.11-
was carefully quenched with H2O and extracted with
EtOAc (2x). The organic layers were washed with H2O
(2x), sat. aq NaCl (1x), dried, concentrated, and purified
1.17 (m, 1H), 1.49 (t, J = 8.6, 1H), 1.52-1.70 (m, 4H),
2.42-2.57 (m, 2H), 2.66-2.73 (m, 1H), 2.81 (d, J = 4.8 Hz,
3H), 3.35-3.41 (m, 1H), 4.33 (d, J = 9.5 Hz, 1H), 6.67 (d,
(hexane: EtOAc 98:2 to 90:10) to give 6b in 91% yield.
J = 9.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 22.1, 23.4,
To a suspension of 6b (1 equiv) and tetrakis(triphe-
26.2, 26.7, 32.2, 33.9, 39.7, 41.6, 42.0, 60.3, 69.8, 171.8,
176.2.
Compound 18b: 1H NMR (400 MHz, CDCl3) d 0.87 (t, J
= 7.0 Hz, 3H), 1.00 (s, 9H), 1.24-1.30 (m, 12H), 1.46 (t, J
nylphosphine)palladium (0.1 equiv) in THF was added
morpholine (3 equiv) and the reaction mixture was stirred
at r.t. for 3 h. Solvent was removed, and the residue was
taken in dioxane and heated at reflux for 3 h. Solvent was
= 8.6 Hz, 1H), 1.55-1.71 (m, 2H), 2.43-2.60 (m, 3H), 2.82
removed and the residue was purified (hexane:
(d, J = 4.8 Hz, 3H,), 3.37-3.43 (m, 1H), 4.24 (d, J = 9.2 Hz,
EtOAc:HOAc 97:3:1.0 to 90:10:1.0) to give 7b in 78%
3H), 6.17 (b, 1H), 6.55 (d, J = 9.2 Hz, 1H); 13C NMR (100
yield.
MHz, CDCl3) d 14.1, 22.6, 26.1, 26.7, 27.7, 29.2, 29.6,
31.8, 32.2, 33.1, 33.9, 39.4, 43.5, 60.3, 69.8, 171.8, 176.1.
A mixture of 7b (1 equiv), amine 8 (1.5 equiv), DIEA (3
equiv), HOBt (1.2 equiv) and EDC (1.2 equiv) were taken
in CH2Cl2 and stirred at rt for 12 h. The reaction mixture
was diluted with EtOAc, and washed with saturated aque-
ous NaHCO3 (2 x) and NaCl (1 x), dried, and concentrated
to give a residue, which was purified (hexane: EtOAc 4:1
Acknowledgement
We thank Mr. Satoru Ida for providing NMR spectral data of the au-
thentic samples and helpful suggestions. We also thank Dr. David
to 2:1) to give 10 in 90% yield. To a solution of 10 (1 Campbell, Dr. Marc Navre, Dr. Dennis Solas, Dr. Ron Hale and
Professor Gregory Cook, NDSU, for helpful discussions.
equiv) in THF was added TBAF (1.5 equiv, 1M solution
Synlett 1999, No. 9, 1371–1374 ISSN 0936-5214 © Thieme Stuttgart · New York

1374
K. Paulvannan, T. Chen
LETTER
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Article Identifier:
1437-2096,E;1999,0,09,1371,1374,ftx,en;S00599ST.pdf
Synlett 1999, No. 9, 1371–1374 ISSN 0936-5214 © Thieme Stuttgart · New York