Synthesis of novel prostaglandins containing a boronate in the α chain

Article abstract of DOI:10.1016/S0040-4039(00)00973-4

A novel class of prostaglandins containing a boronate in the α chain have been synthesized. The key steps in the synthesis were the preparation of the ylide containing the boronate and the subsequent Wittig reaction using the ylide. (C) 2000 Elsevier Scie

Full text of DOI:10.1016/S0040-4039(00)00973-4

Tetrahedron Letters 41 (2000) 5813±5816
Synthesis of novel prostaglandins containing a boronate in
the a chain
Zixia Feng* and Mark Hellberg
Alcon Research Ltd., Fort Worth, TX 76134, USA
Received 22 February 2000; revised 1 June 2000; accepted 2 June 2000
Abstract
A novel class of prostaglandins containing a boronate in the a chain have been synthesized. The key
steps in the synthesis were the preparation of the ylide containing the boronate and the subsequent Wittig
reaction using the ylide. # 2000 Elsevier Science Ltd. All rights reserved.
Many prostaglandin derivatives have been synthesized in an attempt to develop therapeutic
agents during the past decades. Recently, much of this e€ort has centered on the identi®cation of
prostaglandin derivatives as ocular hypotensives for the use in the treatment of glaucoma.1 In this
paper, we report the successful synthesis of a novel class of prostaglandin in which the carboxylic
acid is replaced by boronic acid ester (Scheme 1).
Scheme 1.
The strategy was to synthesize the ylide precursor 8 containing a boronate moiety and to treat
8 with the intermediate 14 under the conditions of the Wittig reaction.2 Compounds 2 and 3 were
obtained by an analogous synthetic sequence.
* Corresponding author. Tel: 817 551 6983; fax: 817 615 3396; e-mail: zixia.feng@alconlabs.com
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00973-4

5814
The ®rst intermediate, catechol-4-bromo-butylboronate 6, was obtained by hydroboration3 of
4-bromo-butene 4 with catecholborane 5 at 95ꢀC for 18 h (Scheme 2). Distillation gave boronate
6, which was then transesteri®ed4 with pinacol in THF to give pinacol-4-bromo-butylboronate 7.
The boronate was heated with triphenylphosphine in xylene at 120ꢀC for 24 h to provide the ylide
precursor 8,10 which was recrystallized from diethyl ether and was stable if stored in a refrig-
erator. This type of boronate has not been reported previously.
Scheme 2.
Scheme 3.

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The intermediate 14 was synthesized starting from commercially available Corey lactone5 9 and
dimethyl(2-cyclohexyl-2-oxo)ethylphosphonate 10, which was synthesized from dimethyl
methylphosphonate and methyl cyclohexanecarboxylate (Scheme 3). The phosphonate 10 was
treated with lithium chloride and triethylamine in THF followed by Horner±Emmons reaction
with the Corey lactone aldehyde 9 to give the corresponding enone 11.6 Reduction of the
carbonyl group of 11 with sodium borohydride and cerium(III) chloride in methanol a€orded a
mixture (1:1) of the two diastereomeric allyl alcohols, which were separated by HPLC.7 Cleavage
of the benzoate ester of the alcohol 12 followed by protection of the resulting diol a€orded the
THP-ether diol 13. Reduction of the lactone 13 with diisobutylaluminum hydride (DIBAL-H) in
toluene and treatment of the resulting lactol 14 with the ylide precursor 8 in potassium tert-
butoxide in THF gave the boronate 15. Treatment of boronate 15 with methanesulfonyl chloride
in pyridine and then with tetrabutylammonium chloride in toluene provided the chloride 16.8 The
cleavage of the THP-ethers under mildly acidic conditions gave the ®nal product 1,10 which was
puri®ed by HPLC. Compounds 210 and 310 were synthesized using a similar method.
Compounds 1 and 2 showed the DP receptor binding anities9 of 61 and 55 mM respectively.
Compound 3 exhibited FP receptor binding anity9 of 8.7 mM. Further biological studies are in
progress.
Acknowledgements
We thank Peter Klimko and Paul Zinke for synthetic assistance, Naj Sharif's group for binding
anity tests, Hans Moll and Karen Haggard for HPLC puri®cation, Glen Dillow and Liang Xue
for performing and discussing mass and NMR spectrometry data, and David Belanger for useful
suggestions during the preparation of the manuscript.
References
1. Dean, T. R.; Hellberg, M.; Sallee, V. L. Patent WO 9723225 A1, US 95-577039 951222.
2. For a review, see: Maryano€, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863±927.
3. Brown, H. C.; Mandal, A. K.; Kulkarni, S. M. J. Org. Chem. 1977, 1392.
4. Kettner, C.; Mersinger, L.; Knabb, R. J. Biol. Chem. 1990, 265(30), 18289±18297.
5. Bindra, J. S.; Bindra, R. Prostaglandin Synthesis; Academic Press: New York, 1977; p. 187.
6. Resul, B.; Stjernschantz, J.; No, K.; Liljebris, C.; Selen, G.; Astin, M.; Karlsson, M. and Bito, L. Z. J. Med. Chem.
1993, 36, 243±248.
7. Klimko, P. G.; Bishop, J.; Desantis Jr., L.; Sallee, V. L. EP 639563 A2 950222, US 93-101598 930803.
8. Klimko, P. G.; Selliah, R. D.; Dean, T. R.; Hellberg, M. R.; Bishop, J. E. US 5807892 A 980915, US 95-480706
950607.
9. Sharif, N. A.; Xu, S. X.; Williams, G. W.; Crider, J. Y.; Grin, B. W.; Davis, T. L. J. Pharmacol. Exp. Ther. 1998,
286(2), 1094±1102.
1
10. All compounds were fully characterized by H and 13C NMR (600 MHz) and mass spectroscopy. Characteristic
1
data for ®nal compounds and a key intermediate are given as follows. Compound 1: H NMR (CDCl3) ꢀ 5.51±
5.49 (m, 1H), 5.41±5.39 (m, 1H), 4.09 (s, 1H), 4.04 (s, 1H), 2.30±2.28 (m, 2H), 2.15±2.12 (m, 2 H), 2.09±2.05 (m,
3H), 1.81±1.47 (m, 15H), 1.34±1.30 (m, 1H), 1.24 (s, 12H), 1.21±1.01 (m, 5H), 0.81±0.78 (m, 2H); 13C NMR
(CDCl3) ꢀ 132.14 (CH), 125.97 (CH), 82.94 (C), 76.34 (CH), 76.07 (CH), 60.84 (CH), 54.36 (CH), 51.77 (CH),
44.56 (CH2), 43.48 (CH), 31.83 (CH2), 30.0 (CH2), 29.88 (CH2), 29.23 (CH2), 27.98 (CH2), 26.49 (CH2), 26.28
(CH2), 26.12 (CH2), 24.81 (CH3), 24.07 (CH2); ESMS 469 (M+H+), HR-FABMS calcd for M+H+ C26H47ClBO4
1
469.3260, found 469.3260. Compound 2: H NMR (CDCl3) ꢀ 5.55±5.41 (m, 4H), 4.20±4.13 (m, 1H), 3.81±3.80 (s,

5816
1H), 3.79±3.77 (s, 1H), 2.44±2.07 (m, 7H), 1.87±1.38 (m, 13 H), 2.09±2.05 (m, 2H), 1.24±1.21 (m, 12H), 1.14±1.13
(m, 2H), 0.98±0.94 (m, 2H), 0.80±0.78 (m, 2H); 13C NMR (CDCl3) ꢀ 133.68 (CH), 133.50 (CH), 130.95 (CH),
128.09 (CH), 83.01 (C), 78.12 (CH), 72.98 (CH), 56.08 (CH), 50.48 (CH), 43.55 (CH), 42.72 (CH2), 29.76 (CH2),
28.84 (CH2), 26.53 (CH2), 26.10 (CH2), 26.03 (CH2), 25.63 (CH2), 24.80 (CH3), 24.05 (CH2); ESMS 466
(M+NH4)+; HR-FABMS calcd for (M^H) C26H44BO5 447.3282, found 447.3282. Compound 3: 1H NMR
(CDCl3) ꢀ 7.30±7.18 (m, 5H), 5.64±5.61 (m, 1H), 5.54±5.50 (m, 1H,), 5.43±5.40 (m, 2H), 4.20 (s, 1H), 4.12±4.11
(m, 1H), 3.94 (s, 1H), 2.72±2.70 (m, 2H), 2.34±1.77 (m, 13H), 1.54±1.46 (m, 2H), 1.24±1.22 (m, 12H), 0.81±0.77 (m,
2H); 13C NMR (CDCl3) ꢀ 141.84 (CH), 134.52 (CH), 132.77 (CH), 128.42 (CH), 128.04 (C), 125.82 (CH), 83.04
(C), 73.23 (CH), 72.08 (CH), 56.05 (CH), 50.63 (CH2), 42.75 (CH2), 38.83 (CH2), 31.80 (CH2), 29.79 (CH2), 25.70
(CH2), 24.79 (CH3), 24.04 (CH2); ESMS 488 (M+NH4)+; HR-FABMS calcd for (M^H) C26H42BO5 469.3126,
1
found 469.3126. Compound 8: H NMR (CD3OD) ꢀ 7.78±7.62 (m, 15H), 3.42±3.25 (m, 2H), 1.60±1.59 (m, 4H),
1.14±1.10 (m, 12H), 0.82±0.75 (m, 2H); 13C NMR (CDCl3) ꢀ 136.22 (CH), 134.85 (CH), 134.65 (CH), 131.58 (CH),
131.33 (CH), 120.92 (C), 119.21 (C), 26.28 (CH2), 25.85 (CH2), 24.71 (CH3), 23.23 (CH2), 22.22 (CH2); ESMS 445
(M+).