molecules Article Hydroboration-Oxidation of (±)-(1α,3α,3aβ,6aβ) -1,2,3,3a,4,6a-Hexahydro-1,3-pentalenedimethanol and Its O-Protected Derivatives: Synthesis of New Compounds Useful for Obtaining (iso)Carbacyclin Analogues and X-ray Analysis of the Products Constantin I. Tănase 1,* ID , Florea G. Cocu 1, Miron Teodor Căproiu 2, Constantin Drăghici 2 and Sergiu Shova 3 1 National Institute for Chemical-Pharmaceutical Research and Development, Department of bioactive substances and pharmaceutical technologies, 112 Vitan Av., 031299, Bucharest-3, Romania; [email protected] 2 Organic Chemistry Center “C.D.Nenitescu”, Spectroscopy Laboratory, 202 B Splaiul Independentei, 060023 Bucharest, Romania; [email protected] (M.T.C.); [email protected] (C.D.) 3 Institute of Macromolecular Chemistry “Petru Poni”, Crystallography Department, 700478 Iasi, Romania; [email protected] * Correspondence: [email protected]; Tel.: +40-21-321-2117; Fax: +40-21-322-2917 Received: 22 October 2017; Accepted: 16 November 2017; Published: 24 November 2017 Abstract: Hydroboration-oxidation of 2α,4α-dimethanol-1β,5β-bicyclo[3.3.0]oct-6-en dibenzoate (1) gave alcohols 2 (symmetric) and 3 (unsymmetric) in ~60% yield, together with the monobenzoate diol 4a (37%), resulting from the reduction of the closer benzoate by the intermediate alkylborane. The corresponding alkene and dialdehyde gave only the triols 8 and 9 in ~1:1 ratio. By increasing the reaction time and the temperature, the isomerization of alkylboranes favours the un-symmetrical triol 9. The PDC oxidation of the alcohols gave cleanly the corresponding ketones 5 and 6 and the deprotection of the benzoate groups gave the symmetrical ketone 14, and the cyclic hemiketal 15, all in high yields. The ethylene ketals of the symmetrical ketones 11 and 13 were also obtained. The compounds 5, 6, 11, 13, 14 could be used for synthesis of new (iso)carbacyclin analogues. The structure of the compounds was established by NMR spectroscopy and confirmed by X-ray crystallography. Keywords: hydroboration-oxidation; borane; sodium acetoxyborohydride; hexahydro-1,3-pentalenedimethanol; octahydropentalene-triols; octahydropentalene-ketones; X-ray analysis 1. Introduction The synthesis of hydrogenated pentalene ketone intermediates has found applications in obtaining new drugs, of which the best known are carbacyclin [1] and isocarbacyclin [2–8] analogues, cioctol [9] and a few antibacterial [10] and antitumor natural products [11,12]. In carbacyclin synthesis, the standard key intermediate I has a symmetric ketone for linking the α-side chain by a Wittig E-olefination (at the !-side chain) and a R group which finally is transformed into an aldehyde used to introduce the !-side chain by a stereoselective Wardworth-Emmons E-olefination with a phosphonate (Figure1)[13–16]. In the synthesis of isocarbacyclin analogues, a few pentalene intermediates with different structures have been used to build the α-side chain (Figure1). The type II intermediate contains Molecules 2017, 22, 2032; doi:10.3390/molecules22122032 www.mdpi.com/journal/molecules Molecules 2017, 22, 2032 2 of 18 an exocyclic allylic aldehyde for building the α-side chain [17], while the type III intermediate has an allylicMolecules alcohol 2017, 22, or 2032 ester for introducing the α-side chain by a regioselective SN2’ alkylation2 of 17 with zinc-copper organic reagents [18–20], and the unsymmetric ketone intermediate of type IV links the zinc-copper organic reagents [18–20], and the unsymmetric ketone intermediate of type IV links the α-sideMolecules chain 2017 by, different22, 2032 methods [21–24]. 2 of 17 α-side chain by different methods [21–24]. The synthesis of new carbacyclin and isocarbacyclin analogs requires new key intermediate zinc-copperThe synthesis organic of reagents new carbacyclin [18–20], and and th eisocarbacy unsymmetricclin ketoneanalogs intermediate requires new of keytype intermediateIV links the octahydropentaleneoctahydropentaleneα-side chain by different ketones. ketones. methods In In this this paper, [21–24].paper, we we describe describe the synt synthesishesis of of the the ketone-o ketone-octahydropentalenesctahydropentalenes of typesof typesVTheand V synthesis andVI usefulVI useful of fornew for obtaining carbacyclinobtaining new new and carbacyclin carbacyclin isocarbacy clinand and isocarbacyclinanalogs isocarbacyclin requires analogues. analogues.new key intermediate octahydropentalene ketones. In this paper, we describe the synthesis of the ketone-octahydropentalenes α-Side chain of types V and VI useful for obtaining new carbacyclinSteps and isocarbacyclinα analogues. O COOH -Side chain O α-Side chain CHO COOH O StepsO α COOH R'O -Side chain Steps Steps R' R CHO O ω-Side chain ω-SideCOOH chain V R'O O O R R R R Steps OH OH Steps R' R OH OH OH OH OH OH ω-Side chain ω-Side chain V I II III IV Isoarbacyclin Carbacyclin O R and analogues R RSteps R and analogues R' R OH OH VI OH OH OH OH OH OH I II III IV Isoarbacyclin FigureCarbacyclin 1. Key intermediates for synthesis of carbacyclin and isocarbacyclin analogues. Figure 1.andKey analogues intermediates for synthesis ofSteps carbacyclin and isocarbacyclinand analogues analogues.R' R VI 2. Results andFigure Discussion 1. Key intermediates for synthesis of carbacyclin and isocarbacyclin analogues. 2. Results and Discussion Retrosynthetic analysis of the key intermediates 5 and 6 (Scheme 1), indicates that these Retrosyntheticcompounds2. Results and could Discussion analysis be obtained of by the a sequence key intermediates of two reactions:5 and hydration6 (Scheme of the 1double), indicates bond of thatalkene these compounds1 to anRetrosynthetic alcohol, could be followed obtained analysis by by theof a theoxidation sequence key intermediates of of the two alcohol reactions: 5 to and the hydration 6corresponding (Scheme of 1), the indicatesketone. double The bondthat starting these of alkene 1 to ancompounds alcohol, followedcould1 were be previously obtained by the by oxidation synthesized a sequence of of[25] the two alcoholand reactions: have to already thehydration corresponding been of usedthe double for ketone. the bond synthesis of The alkene starting of compounds“pseudocarbacyclin”1 to an alcohol,1 were followed previously type compoundby the synthesized oxidations [26,27], of [of 25the the] andalcohol corresponding have to the already corresponding diols by been hydroxylation used ketone. for thewithThe synthesisstartingKMnO4 of [28], of the corresponding α and β-epoxides, by epoxidation of the double bond with MPBA [29], and of “pseudocarbacyclin”compounds 1 were type previously compounds synthesized [26,27 [25]], of and the have corresponding already been diols used byfor hydroxylationthe synthesis of with pentalenofuranic“pseudocarbacyclin” compounds type compound by regis oselective[26,27], of thereactions corresponding [30]. Follow diolsing by our hydroxylation retrosynthetic with analysis, KMnO4 KMnO [28], of the corresponding α and β-epoxides, by epoxidation of the double bond with we[28],4 decided of the corresponding to hydrate αthe and double β-epoxides, bond byof epoxidationalkene 1 by of thehydroboration-oxidation double bond with MPBA with [29], sodium and of MPBA [29], and of pentalenofuranic compounds by regioselective reactions [30]. Following our acetoxyborohydridepentalenofuranic compounds and with byborane. regioselective reactions [30]. Following our retrosynthetic analysis, retrosyntheticwe decided analysis, to hydrate we decided the double to hydrate bond of the alkene double 1 bondby hydroboration-oxidation of alkene 1 by hydroboration-oxidation with sodium with sodium acetoxyborohydride and with borane. acetoxyborohydrideCH2OR and with borane.8 CH2OR CH2OR CH2OR 1 1 1). 8 CH6a OR6 CH OR CH OR CH2OR 2 2 5 OH + 2 + 2 343a 3 4 OH 1). 1 6a 6 1 5 72 OH + 7CH OR OH + CH2OR CH343a2OR 3 2 4 CH2OH OH 1 2 3 4 7CH OR 7CH OR OH CH OH a).CH R2 OR= Bz 2 2 2 2). 2). b). R1 = Ac 2 3 4 a). R = Bz b). R = Ac 2). 2). CH2OR CH2OR CH2OR O CH2OR O CH2OR CH2OR O 5 6 CH2OR CH2OR O Scheme 1. Hydroboration-oxidation of the compounds 1 for obtaining the octahydro-pentalenofurane 5 6 ketones 5 and 6. Reagents and Conditions: (1) (a) Sodium acetoxyborohydride or BH3·THF, r.t, 24 h; (b) 30% H2O2/3 M AcONa or 3 M NaOH, 5 °C, ~35 min. (2) PDC/molecular sieves, r.t., overnight. SchemeScheme 1. Hydroboration-oxidation 1. Hydroboration-oxidation of of the thecompounds compounds 11 forfor obtaining obtaining the the octahydro-pentalenofurane octahydro-pentalenofurane ketonesketones5 and 5 and6. Reagents 6. Reagents and and Conditions: Conditions: ((11)) (a)(a) Sodium acetoxyborohydride acetoxyborohydride or BH or3 BH·THF,·THF, r.t, 24 r.t, h; 24 h; Hydroboration-oxidation of alkene 1a with sodium acetoxyborohydride [31] resulted3 in the (b) 30% H2O2/3 M AcONa or 3 M NaOH, 5 °C,◦ ~35 min. (2) PDC/molecular sieves, r.t., overnight. (b)formation, 30% H2 Oin2 /3a non-regioselective M AcONa or 3 M NaOH,manner, 5 ofC, both ~35 alcohols min. (2) PDC/molecular2a (34%) and 3a sieves,(25%), r.t.,slightly overnight. in favor Hydroboration-oxidation of alkene 1a with sodium acetoxyborohydride [31] resulted in the formation, in a non-regioselective manner, of both alcohols 2a (34%) and 3a (25%), slightly in favor Molecules 2017, 22, 2032 3 of 18 Hydroboration-oxidation of alkene 1a with sodium acetoxyborohydride [31] resulted in the formation,Molecules in 2017 a,non-regioselective 22, 2032 manner, of both alcohols 2a (34%) and 3a (25%), slightly3 of in 17 favor of the symmetrical alcohol 2. In the reaction, the monobenzoate-triol 4a was also formed in a great of the symmetrical alcohol 2. In the reaction, the monobenzoate-triol 4a was also formed in a great quantityquantity (38%) (38%) (Scheme (Scheme1). 1). Browsing Browsing the the literature, literature, we we found found that in that the incase the of casethe unsaturated of the unsaturated esters estersVV, by, by forming forming a acyclic cyclic intermediate intermediate with with 5 or 5 or6 atoms 6 atoms VIIVII, hydroboration, hydroboration of the of double the double bond bond proceededproceeded with with concomitant concomitant reduction reduction of of the the ester ester groupgroup (Scheme (Scheme 2)2 )[[32].32].