Novel 13,14-Dehydro Analogs of Prostaglandins of the 11-Deoxy Series
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l 13,14-Dehydro Analogs of Prostaglandins of the 11-Deoxy Series N. A. Ivanovaa,*, G. A. Shavaleevaa, and M. S. Miftakhova a
Ufa Institute of Chemistry, Ufa Research Center, Russian Academy of Sciences, Ufa, 450054 Russia *e-mail: [email protected] Received February 16, 2020; revised February 22, 2020; accepted February 28, 2020
Abstract—A convergent cuprate synthesis of 11,15-dideoxy-13-dehydro-16-hydroxy-16-methylprostaglandin E1 and its 17-phenoxy derivative, involving 1,4-conjugation of corresponding copper acetylides to 2-(6-ethoxycarbonylhexyl)cyclopent-2-en-1-one, was implemented. The products were obtained in good yields as a mixture of the 8,12-trans- and 8,12-cis-isomers with a predominant proportion of the trans-isomers. Keywords: cuprate synthesis, 13,14-dehydro prostaglandin analogs, 4-hydroxy-4-methyl-5-phenoxypent-1-yne
DOI: 10.1134/S1070428020080035 Prostaglandins (PG) are known to be rapidly metabolized in living organisms (oxidation of the α- and ω-chains, oxidation of С15, and saturation of the ∆13-double bond) and lose activity [1]. One of the important directions in the search for more active and selective PG analogs is the design and synthesis of their modifiers containing an acetylenic unit in the lower side chain [1]. The aim of PG modification is to prepare analogs resistant to the destructive action of enzymes in vivo [2]. Thus, the replacement of the 13,14-trans-double bond in a native PG containing an acetylic bond does not affect the biological activity but imparts to the resulting analog resistance to 15-prostaglandin dehydrogenase and prevents decomposition in this direction [1].
The most important representatives of acetylenic PG analogs is Alfaprostol (1), a PGF-type derivative, used in veterinary medicine as a luteolytic agent [3], as well as Cicaprost ( 2), a prostacyclin I analog, used for treatment of pulmonary arterial hypertensions [4, 5] (Fig. 1). Proceeding with search for pharmacologically perspective analogs of 11-deoxymisoprostol 3 [6, 7] and aimed at studying structure–activity correlations, in the present work we synthesized novel 13,14-acetylenic derivatives 4. In the synthesis of compounds 4, we made us key stage (Scheme 1) of which involves conjugated 1,4-addition to cyclopentenone 5 of acetylenic reagents 6a and 6b [8]. O
CO2H
HO CO2Me HO HO
HO
Alfaprostol 1
HO Cicaprost 2
Fig. 1. Structures of ω-acetylenic analogs of PGF2α 1 and prostacyclin 2.
1347
1348
IVANOVA et al. Scheme 1.
O
O
CO2Me
CO2Me
OH
R 4a, 4b
3 O
(a),
R=
(CH2)6CO2Et
HO (b).
OPh
HO
+ R
CuLn
5
Conjugated addition of alkyl, alkenyl, and aryl cuprates is widely used in organic synthesis [9, 10], and, therewith, the activity of lithium organocuprates in conjugated 1,4-addition reactions is strongly dependent on the structure of the its organic radical and decreases in the series R = alkyl > alkenyl > alkynyl. The inactive alkynyl radical (as pentynylcopper) was initially used as a “nontransportable” ligand in mixed alkenyl/alkynyl cuprates with the aim to “save” more valuable alke
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