A novel synthesis of β-sulfinyl- and β-sulfonyl-hydroxamic acids via CsF-mediated ring opening of substituted β-lactones

Article abstract of DOI:10.1055/s-2001-12311

The ring-opening reaction of 3-substituted β-lactones with thiols was achieved using CsF in DMF as promoter. The resulting β-sulfanyl-carboxylic acid intermediates were coupled to hydroxylamine-Wang resin and the sulfur atom was selectively oxidized to afford β-sulfinyl- and β-sulfonyl-hydroxamic acid libraries.

Full text of DOI:10.1055/s-2001-12311

538
LETTER
A Novel Synthesis of -Sulfinyl- and -Sulfonyl-Hydroxamic Acids via CsF-
Mediated Ring Opening of Substituted -Lactones
Gérard Rossé,* Fernand Gerber, Jean-Luc Specklin, Christian Hubschwerlen*
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
E-mail: gabriela.haenggi@roche.com
Received 5 January 2001
O
R1
Abstract: The ring-opening reaction of 3-substituted -lactones
R2
C
S
O
with thiols was achieved using CsF in DMF as promoter. The result-
ing -sulfanyl-carboxylic acid intermediates were coupled to hy-
droxylamine-Wang resin and the sulfur atom was selectively
oxidized to afford -sulfinyl- and -sulfonyl-hydroxamic acid
libraries.
i
ii
C
O
Me3 S
i
R1
OH
O
1
2
3
Scheme 1 i. BF3 OEt2 (0.01 equiv), R1CHO (0.9 equiv), CH2Cl2,
-15°C, 1h. ii. CsF (2 equiv), R2SH (2 equiv, DMF, 30 °C, 1h.
Key words: combinatorial chemistry, solid-phase synthesis,
cycloaddition, ring opening, oxidation
Table 1 CsF-mediated ring-opening of -lactones
The elaboration of selective methods to generate rapidly
combinatorial libraries of small molecules useful in me-
dicinal chemistry programs represents a challenge for
modern synthetic chemists.1 Substituted hydroxamic ac-
ids are found both in natural and synthetic products that
exhibit for example, antibiotic,2 antiinflammatory3 or
anticancer4 activities. Due to their broad biological activ-
ities hydroxamic acids have motivated the development of
a variety of synthetic methodologies to produce combina-
torial libraries.5 We report herein a novel approach to syn-
thesize -sulfanyl-carboxylic acids 3 from 3-substituted
-lactones 2 using CsF in DMF as promoter and its use to
generate -sulfinyl-hydroxamic acids 5 and -sulfonyl-
hydroxamic acids 6 libraries. These compounds have re-
cently been described to inhibit matrix metalloprotein-
ases, phosphodiesterase3a and bacterial peptide deform-
ylase.2b
b-lactone
thiol
product yielda purityb
3a
57
70
O
O
2a
SH
H2N
2a
3b
3c
25
92
70
78
SH
Cl
Cl
2a
SH
The synthesis started with the BF3 OEt2-catalyzed [2+2]
cycloaddition of trimethylsilylketene 1 with aldehydes6 to
afford 3-substituted -lactones 2 in good yields (Scheme
1). Whilst the reaction proceeded well with non-aromatic
aldehydes, the cycloaddition with aromatic aldehydes
gave the corresponding , -unsaturated carboxylic acids
as major product.7 The ring opening reaction of 2 with thi-
ols was examined using either i-Pr2NEt or CsF as activat-
ing agents. CsF has been described to promote efficiently
the SN2 reaction of secondary mesylates.8 The reaction
promoted by CsF furnished products in higher yield and
purity and the undesired , -unsaturated carboxylic acids
were not observed.
3d
84
88
SH
O
O
2b
MeO
2b
3e
89
95
95
50
SH
Br
3f
65
O
SH
The mild CsF method allowed the introduction of a vari-
ety of thiols and the products were obtained by simple fil-
tration of the reaction mixture over silica gel (Table 1).
The reaction is expected to be promoted by a composite
formed between CsF and DMF.8 Synthesis of the acids 3
through the base catalyzed Michael addition of thiols with
, -unsaturated carboxylic acids at elevated temperature9
gave inferior results.
O
2c
N
2c
3g
n.d.
N
SH
a Yield in% after filtration of the products over silica gel. b Purity in%
determined by HPLC at 254 nm.
Synlett 2001, No. 4, 538–540 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Novel Synthesis of -Sulfinyl- and -Sulfonyl-Hydroxamic Acids
539
The carboxylic acids 3 were then preactivated by addition Cleavage from the resin with TFA:H2O:CH2Cl2 70:2:28
of N-[(dimethylamino)-1H-1,2,3-triazolo[4,5,b]-pyridin- afforded the hydroxamic acids 5 and 6. These compounds
1-ylmethylmethaminium hexafluorophosphate N-oxide were purified by preparative reverse-phase HPLC and ob-
(HATU)10 and i-Pr2NEt in N,N-dimethylacetamide tained in satisfactory yields (Table 2). All new com-
1
(DMA) and reacted with hydroxylamine-Wang resin pounds were characterized by HPLC, ESIMS and H
(Scheme 2). The resin-bound -sulfanyl hydroxamic ac- NMR analysis.12 The use of hydroxylamine trityl5d or N-
ids 4 were selectively oxidized into their corresponding tethered, O-protected alkoxyamine5e resins instead of hy-
sulfoxides with 1.1 equiv of N-(phenylsulfonyl)-3- droxylamine-Wang resin failed to give the desired prod-
phenyloxaziridine11 in CH2Cl2. Sulfur oxidation of 4 with uct in satisfactory yields and purity.
4 equiv MCPBA in CH2Cl2 furnished the corresponding
resin-bound sulfones.
In summary, we have developed a novel and straightfor-
ward approach to synthesize -sulfinyl-hydroxamic acids
5 and -sulfonyl-hydroxamic acids 6 combinatorial librar-
ies. We have demonstrated for the first time known to us
that CsF in DMF is an excellent reagent for the clean ring
opening of -lactones with thiols. The combination of
both solution-phase and solid-phase chemistry was partic-
ularly useful for rapidly generating the libraries 5 and 6 in
sufficient amounts for biological screening.
O-
R2
Acids 3
+
S
O
ii, iii
i
R1
N
H
OH
R2
R1
5
S
O
N
H
O
4
Acknowledgement
O
R2
R1
S
O O
We gratefully thank our colleagues from the Central Units for spec-
troscopic measurements.
iv, iii
N
H
OH
6
References and Notes
Scheme 2 i. HATU, i-Pr2NEt, DMA, hydroxylamine-Wang resin,
r.t., 2 h. ii. N-(phenylsulfonyl)-3-phenyloxaziridine (1.1 equiv),
CH2Cl2, r.t., 10 h. iii. TFA:H2O:CH2Cl2 70:2:28, 3 h. iv. MCPBA (4
equiv), CH2Cl2, r.t., 4 h.
(1) (a) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D.
Tetrahedron 1996, 52, 4527. (b) Hermkens, P. H.; Ottenheijm,
H. C.; Rees, D. C. Tetrahedron 1997, 53, 5643. (c) Obrecht,
D.; Villalgordo, J. M. Solid-Supported Combinatorial and
Parallel Synthesis of Small-Molecular-Weight Compound
Libraries; Elsevier Science Ltd: Oxford, 1998. (d) Bunin, B.
A.; Dener, J. M.; Livingston, D. A. Annu. Rep. Med. Chem.
1999, 34, 267. (e) Guillier, F.; Orain, D.; Bradley, M. Chem.
Rev. 2000, 100, 2091.
Table 2 Solid-phase synthesis of -sulfinyl- (5a-5e) and -sulfo-
nyl-hydroxamic acids (6a-6f)
(2) (a) Broughton, B. J.; Chaplen, P.; Freeman, W. A.; Warren, P.
J.; Wooldridge, K. R. H.; Wright, D. E. J. Chem. Soc., Perkin
Trans. 1 1975, 857. (b) Apfel, C. W.; Banner, D. W.; Bur, D.;
Dietz, M.; Hirata, T.; Hubschwerlen, C.; Locher, H.; Page, M.
G. P.; Pirson, W.; Rossé, G.; Specklin, J.-L. J. Med. Chem.
2000, 43, 2324.
(3) (a) Groneberg, R. D.; Burns, C. J.; Morrissette, M. M.; Ullrich,
J. W.; Morris, R. L.; Darnbrough, S.; Djuric, S. W.; Condon,
S. M.; McGeehan, G. M.; Labaudiniere, R.; Neuenschwander,
K.; Scotese, A. C.; Kline, J. A. J. Med. Chem. 1999, 42, 541.
(b) Pikul, S.; Dunham, K. L. M.; Almstead, N. G.; De, B.;
Natchus, M. G.; Anastasio, M. V.; McPhail, S. J.; Snider, C.
E.; Taiwo, Y. O.; Chen, L.; Dunaway, C. M.; Gu, F.; Mieling,
G. E. J. Med. Chem. 1999, 42, 87.
(4) (a) Young, C. W.; Schachetman, C. S.; Hodas, S.; Bolis, M. C.
Cancer Res. 1967, 27, 535. (b) Patel, D. V.; Young, M. G.;
Robinson, S. P.; Hunihan, L.; Dean, B. J.; Gordon, E. M. J.
Med. Chem. 1996, 39, 4197.
(5) (a) Floyd, C. D.; Lewis, C. N.; Patel, S. R.; Whittaker, M.
Tetrahedron Lett. 1996, 37, 8045. (b) Bauer, U.; Ho, W.-B.;
Koskinen, A. M. P. Tetrahedron Lett. 1997, 38, 7233. (c)
Sophiamma, P. N.; Sreekumar, K. Indian J. Chem. Sect. B
1997, 36, 995. (d) Mellor, S. L.; McGuire, C.; Chan, W. C.
Tetrahedron Lett. 1997, 38, 3311. (e) Ngu, K.; Patel, D. V. J.
Org. Chem. 1997, 62, 7088. (f) Kahn, S. I.; Grinstaff, M. W.
Tetrahedron Lett. 1998, 39, 8031. (g) Dankwardt, S. M.
Synlett 1998, 761.
a Yields in% of purified products are based on the initial loading of
hydroxylamine-Wang resin (1.0 mmol/g). b Purity in % was deter-
mined by HPLC, detecting at 254 nm. c Purity in % was determined
by 1H NMR.
Synlett 2001, No. 4, 538–540 ISSN 0936-5214 © Thieme Stuttgart · New York

540
G. Rossé et al.
LETTER
were added. After 5 min shaking at r.t., the light yellow
(6) (a) Ruden, R. A. J. Org. Chem. 1974, 39, 3607. (b) Yang, H.
W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877.
(7) Black, T. H.; Zhang, Y.; Huang, J.; Smith, D. C.; Yates, B. E.
Synth. Commun. 1995, 25, 15.
(8) Otera, J.; Nakazawa, K.; Sekoguchi, K.; Orita, A. Tetrahedron
1997, 53, 13633.
(9) Burns, C. J.; Groneberg, R. D.; Salvino, J. M.; McGeehan, G.;
Condon, S. M.; Morris, R.; Morrissette, M.; Mathew, R.;
Darnbrough, S.; Neuenschwander, K.; Scotese, A.; Djuric, S.
W.; Ullrich, J.; Labaudiniere, R. Angew. Chem., Int. Ed. 1998,
37, 2848.
(10) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
(11) Davis, A. F.; Stringer, O. D. J. Org. Chem 1982, 47, 1774.
(12) The synthesis of 5a and 6a are representative of the procedure
used for the parallel synthesis of the libraries.
solution was added to the hydroxylamine-Wang resin. The
reaction mixture was shaken for 2 h, filtered off, washed three
times with DMA (4 mL) and three times with i-PrOH (3 mL)
each. A sample of the resin was dried under high vacuum:
77% conversion based on elemental analysis. ATR
(attenuated total reflection) FTIR: 1670 cm-1. Anal. Found:
N, 1.21; S, 1.93.
5,5-Dimethyl-3-(naphthalene-2-sulfinyl)-hexanoic acid
hydroxyamide (5a): A portion of resin 4a (0.25 mmol) was
washed three times with CH2Cl2 (4 mL) and then a solution of
N-phenylsulfonyl-3-phenyloxaziridine (2.8 mL, 0.1 M, 0.28
mmol) in CH2Cl2 was added. The reaction mixture was shaken
for 10 h, filtered off, washed three times with CH2Cl2 (4 mL),
three times with i-PrOH (3 mL) and again three times with
CH2Cl2 (4 mL). A solution of TFA/H2O/CH2Cl2 70:2:28
(4 mL) was added to the resin and the reaction mixture was
shaken for 3 h. This eluate and one subsequent wash with
TFA/H2O/CH2Cl2 70:2:28 were collected and combined. The
solvent was evaporated and the residue was purified by
preparative HPLC (YMC Pack Pro C18 column, 5 , 120 Å,
50 20 mm) using a gradient of H2O and MeCN (in 3.3 min
from 20%MeCN to 95% MeCN, 1.2 min at 95% MeCN, in 0.1
min from 95% MeCN to 20% MeCN, 0.1 min at 20% MeCN,
flow: 35 mL/min). 35 mg (41%) of 5a: ESIMS m/z 332.3
([M-], 100). 1H NMR (250 MHz, DMSO-d6): 10.4 (s, 1H,
NH), 8.21 (s, 1H), 8.02-8.19 (m, 3H), 7.63-7.70 (m, 3H), 3.12-
3.24 (m, 1H), 1.81-2.22 (m, 3H), 1.23-1.31 (m, 1H), 0.93 (s,
9H).
5,5-Dimethyl-3-(naphthalene-2-sulfonyl)-hexanoic acid
hydroxyamide (6a): A portion of resin 4a (0.2 5 mmol) was
washed three times with CH2Cl2 (4 mL) and then of a solution
of MCPBA (4.0 mL, 0.25 M, 1.0 mmol) in CH2Cl2 was added.
The suspension was shaken at r.t. for 4 h. Washing of the resin,
cleavage of the compound from the resin and purification
using preparative HPLC were performed as described for 5a.
25 mg (29%) of 6a: ESIMS m/z 348.3 ([M-], 100). 1H NMR
(250 MHz, DMSO-d6): 10.5 (s, 1H, NH), 8.57 (s, 1H), 8.25
(d, J = 7.6 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 7.6
Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.68-7.79 (m, 2H), 3.56-
3.72 (m, 1H), 2.67 (dd, J = 6.8 Hz, 16.1 Hz, 1H), 2.24 (dd,
J = 4.4 Hz, 16.1 Hz, 1H), 1.85 (d, J = 13.1 Hz, 1H), 1.32 (dd,
J = 7.4 Hz, 14.6 Hz, 1H), 0.72 (s, 9H).
4-(2,2-Dimethyl-propyl)-oxetan-2-one (2a): A solution of
BF3 OEt2 (1 mL, 0.5 M, 0.5 mmol) in CH2Cl2 was slowly
added at -15 °C to a solution of 3,3-dimethyl-butyraldehyde
(3.9 g, 39 mmol) in CH2Cl2 (50 mL) and then trimethylsilyl
ketene (6 mL, 43 mmol) was added at -15 °C over 30 min. The
reaction was stirred for 3 h at -15 °C, two drops of H2O were
added and stirring was continued for 1 h at r.t. After
evaporation of the solvent, MeCN (30 mL) and potassium
fluoride dihydrate (3 g, 19 mmol) were added. The mixture
was stirred overnight, filtered off, evaporated and the residue
was chromatographed on SiO2 eluting with hexane/CH2Cl2/
Et2O (6:2:1) affording 2a: 4.4 g (80%). 1H NMR (250 MHz,
DMSO-d6): 4.66-4.71 (m, 1H), 3.56-3.72 (m, 1H), 3.64 (dd,
J = 5.7 Hz, 16.3 Hz, 1H), 3.19 (dd, J = 4.3 Hz, 16.2 Hz, 1H),
1.75 (dd, J = 7.1 Hz, 14.3 Hz, 1H), 1.66 (dd, J = 5.8 Hz, 14.3
Hz, 1H), 0.93 (s, 9H).
5,5-Dimethyl-3-(naphthalene-2-sulfanyl)-hexanoic acid
(3a): Naphthalene-2-thiol (352 mg, 2.2 mmol) was added to
CsF (334 mg, 2.2 mmol) in DMF (4 mL), and the suspension
was stirred for 10 min at r.t. Then, 2a (203 mg, 1.1 mmol) was
added and the suspension was stirred for 1 h at 30 °C. After
filtration of the CsF, the solvent was evaporated, the residue
was dissolved in CH2Cl2/MeOH (95:5) and filtered through
silica gel. 189 mg (57%) of 3a: ESIMS m/z 301.1 ([M-], 100).
1H NMR (250 MHz, DMSO-d6): 7.88-7.95 (m, 4H), 7.50-
7.53 (m, 3H), 3.59-3.63 (m, 1H), 2.45-2.54 (m, 2H), 1.56-1.61
(m, 2H), 0.93 (s, 9H).
Synthesis of resin 4a: Hydroxylamine-Wang resin (500 mg,
0.5 mmol, 1% crosslinking, 38-75 , 1 mmol/g, from Bachem,
Switzerland) was swollen once with DMA (5 mL). To a
solution of acid 3a (226 mg, 0.75 mmol) in DMA (0.75 mL),
a solution of HATU in DMA (1.5 mL, 0.5 N, 0.75 mmol) and
a solution of i-Pr2NEt in DMA (1.5 mL, 1.5 N, 2.25 mmol)
Article Identifier:
1437-2096,E;2001,0,04,0538,0540,ftx,en;G00101ST.pdf
Synlett 2001, No. 4, 538–540 ISSN 0936-5214 © Thieme Stuttgart · New York