Synthesis of a Bicyclo [ 6 . 3 . 0 ] undecene Skeleton Characteristic of Some Cyclooctanoids by an Intramolecular Reductive Coupling of Carbonyls Promoted by Low-Valent Titanium

A síntese do esqueleto biciclo[6.3.0]undeceno, característico de um grande número de ciclooctanóides naturais é descrita neste trabalho. A metodologia aplicada na construção do sistema ciclooctanóide está baseada na reação intramolecular de acoplamento redutivo de dialdeídos promovida por titânio em baixa valência (reação de McMurry). O dialdeído 15, pre cur sor do sistema bicíclico [6.3.0]undeceno, foi preparado em 5 etapas com um rendimento global de 40% a partir da 2-metóxicarbonil-ciclopentanona como ma te rial de partida. O uso de C8K-TiCl3 como agente alternativo para efetuar o acoplamento redutivo intramolecular do dialdeído 15 também foi investigado. O acoplamento redutivo do dialdeído 15 para gerar o anel ciclooctânico ocorreu em baixos rendimentos (~10%) apesar de diversas alterações nas condições de reação visando melhorar sua eficiência.

Nat u rally oc cur ring cyclooctanoid com pounds bear ing an eight-membered ring fused to a five-membered ring form a grow ing fam ily of nat u ral prod ucts that has been attract ing much at ten tion from the chem i cal com mu nity over the last fif teen years 1 .Ex am ples of these cyclooctanoids are il lus trated in the Fig ure be low: i) the sesquiterpenes dactylol 1 2 , and asteriscanolide 2 3 ; ii) the diterpenes pleuromutilin 3, pos sess ing an ti bi otic ac tiv ity 4 , and the fusicoccin H 4 ex hib it ing phytohormone ac tiv ity 5 ; iii) the sesterterpenoids, such as variecolin 5 with antihypertensive prop er ties 6 ; and iv) the lignans rep resented by steganacin 6 pos sess ing antileukemic ac tiv ity 7 .
The pres ence of a carbocyclic eight-membered ring as the main struc tural fea ture of these com pounds has posed a sig nif i cant syn thetic chal lenge since these are con sid ered to be the most dif fi cult me dium-sized rings to pre pare 8 .It was the syn thetic chal lenge in the con struc tion of an eight-membered ring in con junc tion with the in ter est ing bio log i cal ac tiv i ties of sev eral of these cyclooctanoids that prompted the nu mer ous syn thetic stud ies de scribed in the lit er a ture 1 .
Among the sev eral meth od ol o gies now avail able to pre pare an eight-membered ring the reductive cou pling of car bon yls pro moted by low-valent ti ta nium (McMurry reac tion) ap pears to be one of the most prom is ing 9 .Re markably, ap pli ca tions of this meth od ol ogy in the con struc tion of more densely functionalized in ter me di ates are few 10 .
Con sidering the stra te gic ef fec tive ness of the McMurry trans for ma tion we de cided some time ago to ap ply this trans for ma tion as the key step in the con struc tion of cyclooctanoid com pounds.Our ini tial tar get was the structur ally ir reg u lar cyclooctanoid dactylol 2 .The en vi sioned syn thetic strat egy is de picted in Scheme 1.
Al though the car bonyl cou pling rep re sented in Scheme 1 ap pears di rect, the po ten tial lability of the β-hydroxy ketone moi ety could prove trou ble some in the reductive cou pling pro cess.This per cep tion prompted us to ini ti ate our stud ies more cau tiously by first in ves ti gat ing the McMurry trans for ma tion on a model sub strate.Thus, the prep a ra tion of the bicyclo[6.3.0]undecene 9 was conceived as shown in Scheme 2 where dialdehyde 8 is the sub strate that un der goes an intramolecular McMurry reductive cou pling.
The work pre sented in this pa per de scribes our re sults con cern ing the im ple men ta tion of this pre lim i nary study.

Gen eral
Nu clear mag netic res o nance spec tra (NMR) were recorded as so lu tions in the in di cated sol vents on Gem ini 200 MHz or Varian 60 MHz spec trom e ters.Chem i cal shifts are re ported in parts per mil lion ( δ units) rel a tive to tetramethylsilane or CDCl 3 as in ter nal stan dard.Cou pling con stants are re ported in hertz (Hz).The in fra red spec tra were re corded on a Perkin-Elmer 783 spec trom e ter.The mass spec tra were ob tained from an VG Autospec In strument, and the data are re ported as m/z (abun dance).All solvents used were re agent grade and were dis tilled prior to use.DME used in the car bonyl cou pling ex per i ments was dis tilled from po tas sium metal un der Ar, fol lowed by deoxygenation with a steady flow of Ar un der ul tra sound  for 0.5 h.Un less in di cated oth er wise, all re agents used were at least re agent grade and used as re ceived.MgCl 2 (Aldrich) was treated with thionyl chlo ride for 10 h, ro tary evap o rated (heat ing bath at 60-70 °C), and kept under N 2 .The Zn-Cu al loy and the C 8 K were pre pared ac cording to lit er a ture pro ce dures and kept un der N 2 . 11-Carbomethoxycy-clopentanone, 6-methylhept-5-ene-2-one and TiCl 3 were pur chased from Aldrich Co. TiCl 3 is a pyrophoric solid.Un less oth er wise noted, all re ac tions were car ried out un der a dry ni tro gen atmo sphere us ing oven or flame-dried glass ware.Cap il lary gas chro ma tog ra phy (GC) anal y ses were per formed on a Varian 1400 chromatograph equipped with a flame ion ization de tec tor and OV-101 col umn (25 m x 0.32 mm) or on a HP 5890 gas chromatograph in ter faced to the above mass spec trom e ter.Flash chro ma tog ra phy was per formed as pre vi ously de scribed 12 on E. Merck sil ica gel 60 (230-400 mesh).All re ac tions were mon i tored by thin layer chro matog ra phy (TLC) or cap il lary GC.All com pounds sub mit ted to spec tro scopic anal y ses were shown to be ho mo ge neous by TLC.

Alkenyl-keto es ter 11
To a sus pen sion of K 2 CO 3 (9.1 g, 66 mmol) in ac e tone (20  mL), was added a so lu tion of 2-carbomethoxy-cyclopentanone (2.3 g, 16.5 mmol) in ace tone (13 mL).Af ter 15 min the bro mide 10 (4.9 g, 27.9 mmol) was added.The re sult ing mix ture was stirred un der re flux for 60 h, af ter which it was par ti tioned be tween wa ter (30 mL) and CH 2Cl 2 (3 x 30 mL).The com bined or ganic phase was dried (Na 2SO 4) and con cen trated in vac uum.Dis til la tion of the res i due at low pres sure (0.

Cyclopentanone 7
To a so lu tion of KCN (2.27 g, 35.0 mmol) in DMSO (14 mL) was added a so lu tion of the keto es ter 11 (2.08 g, 8.74 mmol) in DMSO (15 mL).The mix ture turned from col orless to pale brown.The flask was placed into a pre-heated oil bath at 150 °C.Af ter 2 h the mix ture was cooled to room tem per a ture; then di luted with wa ter (40 mL) (exo thermic!), and ex tracted with hex ane (4 x 40 mL).The combined or ganic phase was washed with brine (50 mL), dried (Na 2 SO 4 ) and con cen trated in vac uum to give 1.19 g (76%) of the cyclopentanone 7 in pure enough form to be used directly in the next step.IR (film): ν = 2960, 2920, 2850, 1730, 1450, 1420, 1380, 1160, 830 cm -1 .

Cyclopentanol 12
To a 300 mL flask con tain ing dry MgCl 2 (8.1 g, 86 mmol) un der ar gon was added THF (65 mL) fol lowed by small pieces of freshly cut po tas sium (4.4 g, 115 mmol).The het er o ge neous mix ture was stirred un der a gen tle reflux un til a dark sus pen sion is formed.Abrupt heat ing should be avoided at this stage since it may lead to in tense foam for ma tion re sult ing in pro jec tion of the re ac tion medium.Af ter 2 h the heat ing bath was re moved and the result ing sus pen sion was stirred at room tem per a ture for 0.5 h.Allyl bro mide (2.5 mL, 29 mmol) was then added in such a rate to avoid the re flux of THF.Af ter an ad di tional 0.5 h the re ac tion mix ture was cooled to -10 °C.A so lu tion of 7 (1.2 g, 7.1 mmol) in THF (12 mL) was added over 1 h with the aid of a sy ringe-pump.Af ter 0.5 h the re ac tion was quenched by the ad di tion of a sat u rated aque ous NH 4 Cl solu tion (~30 mL).The cool ing bath was re moved and upon warm ing to room tem per a ture a 5% aque ous HCl so lu tion was added un til the pH = 8.The mix ture was ex tracted with ethyl ac e tate (4 x 50 mL).The com bined or ganic phase was washed with brine (80 mL), dried (Na 2 SO 4 ) and con centrated in vac uum.Flash-chromatography of the res i due (5.0 x 9.0 cm, EtOAc/Hex ane 5%) af forded 1.2 g (77%) of the ter tiary al co hol 12 as a col or less oil in a 3:1 diastereomeric ra tio.IR (film): ν = 3460, 3080, 2920, 2860, 1640, 1445, 1350, 1080, 990, 910 cm -1 .

Gen eral pro ce dure for the ozonolysis of 13 and 14
A 0.25 M so lu tion of the pro tected diene in CH 2 Cl 2 at -78 °C was treated with a di luted stream of ozone in ox ygen.When the so lu tion turned light blue, it was flushed with ni tro gen un til the blue color dis ap peared.The cool ing bath was re moved and the re ac tion mix ture was warmed to room tem per a ture, di luted with CH 2 Cl 2 (10 mL) and hy dro -ge nated for 4 h at 60 psi over 10% pal la dium on car bon (15% by weight).The re ac tion mix ture was fil tered through Celite, and the sol vent re moved in vac uum to give the cor re spond ing dialdehyde (93-97% yield), which was shown to be ho mo ge neous by TLC.(5), 211 (28), 197 (2), 189 (18), 147 (56), 119 (14), 103 (18), 75 (100).

Bicyclo[6.3.0]undecene 17 (i) Prep a ra tion of C 8K 11b
A flask con tain ing pow dered graph ite (4.9 g, 411,3 mmol) and freshly cut po tas sium (2.0 g, 51 mmol) was immersed in a pre-heated oil bath at 140 °C and stirred vig orously un der a stream of ar gon for 0.5 h.A finely pow dered golden solid re sulted, which was cooled to room tem per ature un der dry ar gon.
(ii) Prep a ra tion of low-valent ti ta nium Into a glovebag un der dry ar gon were com bined TiCl 3 (2.6 g, 17 mmol) and the freshly pre pared C 8K.The flask was equipped with a re flux con denser.The ap pa ra tus was re moved from the glovebag and DME (145 mL) was added.The mix ture was stirred un der re flux with a stream of dry ar gon for 2 h.The re sult ing black sus pen sion was cooled to room tem per a ture.

(iii) Reductive cou pling
A so lu tion of the dialdehyde 15 (300 mg, 1 mmol) in DME (8.0 mL) was placed in a gas-tight sy ringe (10 mL ca -pac ity) and added at room tem per a ture to the sus pen sion of the low valent ti ta nium over a 40 h pe riod with the aid of a sy ringe-pump.A slight pos i tive pres sure of pure and dry Ar was kept through out the ad di tion.Af ter com plete ad di tion of the dialdehyde 15 the mix ture was stirred for an ad ditional 6 h at room tem per a ture, fol lowed by 5 h un der reflux.The re ac tion was quenched by the ad di tion of MeOH (2 mL), and cooled to room tem per a ture.The mix ture was then fil tered on Florisil ® (3 x 8 cm) un der ni tro gen.The column was washed with more DME (80 mL) and EtOAc (150 mL).The com bined fil trate was then con cen trated in vacuum and flash-chromatographed (1.5 x 10 cm col umn; slurry of sil ica in hex ane with 1% of triethyl amine; eluant gra di ent from hex ane to EtOAc/hex ane 5%-all the eluant con tain ing 1% of triethyl amine) to pro vide 26

Syn the sis of the dialdehyde pre cur sor
A rather straight for ward route was de vised to pre pare the dialdehyde in ter me di ate 8 from 2-carbomethoxy-cyclopentanone as start ing ma te rial (Schemes 3 and 4).The bro mide 10 was pre pared in good over all yield from the com mer cially avail able 6-methyl-5-hepten-2-one in four steps as fol lows (frame in set in Scheme 3): i) bromoform ox i da tion 13 of 6-methyl-5-hepten-2-one to furnish the cor re spond ing carboxylic acid (NaOBr, NaOH, dioxane/H 2O, 4 °C, 1 h, 64% yield); ii) re duc tion of the carboxylic acid to the pri mary al co hol (LiAlH 4, THF, reflux, 3 h, 90-93% yield); iii) for ma tion of the cor re sponding mesylate 14 (MsCl, Et 3N, CH 2Cl 2, -10 °C, 5-10 min, 97-99% yield), and iv) con ver sion of the mesylate into the pri mary bro mide 10 (LiBr, THF, re flux, 3 h, 86-89% yield).The over all yield for bro mide 10 af ter these four steps was usu ally very good, rang ing from 48% to 52% for the pu ri fied prod uct.
Once 6-bromo-2-methyl-2-hexene was avail able, we turned our at ten tion to the prep a ra tion of the 2-(5-methyl-4-hexenyl)-cyclopentanone 7.As il lus trated in Scheme 3, com pound 7 was ef fi ciently pre pared by a sequence of two trans for ma tions.Alkylation of 2-carbomethoxy-cyclopentanone with un sat u rated bromide 10 in the pres ence of K 2CO 3 as base 15 yielded the alkenyl-keto-ester 11 in 73-78%, af ter dis til la tion.Sur prisingly, at tempted decarbomethoxylation us ing the stan dard Krapcho con di tions (NaCl, DMSO, re flux) 16 did not af ford the de sired elim i na tion.Af ter some ex per i men ta tion, decarbomethoxylation of 11 was fi nally achieved us ing KCN in DMSO (150 °C, 2 h) 17 to af ford the ex pected cyclopentanone 7 in 72-76% yield.
We next turned our at ten tion to the stereoselective instal la tion of an al lyl ic frag ment at C-1, which af ter ozonolysis should pro duce the dicarbonyl es sen tial for the reductive cou pling.Ad di tion of the al lyl ic moi ety was initially planned as an ad di tion of an al lyl ic Grig nard re - agent 18 .The trans stereochemistry was an tic i pated based on the 1,2 in ter ac tion caused by the side chain dur ing nucleophilic at tack of the Grig nard re agent on the carbonyl 19 .Con trary to our ini tial ex pec ta tions, ad di tion of allylmagnesium bro mide to cyclopentanone 7 re sulted in a small con ver sion of the start ing ketone.The ex pected adduct, diene-alcohol 12 was iso lated from the re ac tion me dium in low yield.More over, the stereoselectivity of ad di tion was only mod er ate rang ing from a trans:cis ra tio of 2:1 (0 °C) to 3:1 (-10 °C) by GC anal y sis.The first at tempts to per form this allylation step led mainly to the re cov ery of the start ing cyclopentanone 7, even in the pres ence of a large ex cess of allylmagnesium bro mide.We rea soned that a mag ne sium enolate was formed dur ing the re ac tion, thus pre vent ing nucleophilic ad di tion of the Grig nard re agent to the car bonyl group.
The pro pen sity of cyclopentanones to enolize in the presence of Grig nard re agents was rec og nized ear lier by Paquette 20 .To cir cum vent this prob lem a sys tem atic in ves tiga tion of the Grig nard re ac tion was un der taken.The use of ad di tives such as CeCl 3 , MgCl 2 and changes in the stoichiometry of the re ac tion were exhaustively in ves ti gated based on the work of Paquette and Imamoto 20,21 .Af ter much ex per i men ta tion, the best con di tions found to carry out nucleophilic ad di tion of allylmagnesium bro mide re quired four equiv a lents of the Grig nard re agent and four equiv a lents of MgCl 2 as ad di tives.Also, the mag ne sium metal had to be gen er ated im me di ately be fore use by re duc tion of MgCl 2 with po tas sium metal (Rieke's mag ne sium) 22 .Thus, the op ti mum stoichiometry for con ver sion of cyclopentanone 7 into diene-alcohol 12 was de ter mined as 1:4:4 (7:CH 2=CHCH 2MgBr:MgCl 2).Un der these con di tions cyclopentanone 7 was to tally con verted in the re ac tion medium to gen er ate a 3:1 mix ture (as de ter mined by cap il lary GC) of diastereomeric ter tiary diene-alcohols 12 iso lated in 75-78% yield (Scheme 4).The stereochemical as sign ment of the trans -diene-alcohol as the ma jor prod uct was based on pre vi ous pre ce dents in the lit er a ture 19 and on the anal y sis of the 13 C-NMR spec tra (SFORD and DEPT).The trans -diene CH showed a sig nal at 48 ppm ( γ-syn -ef fect) when com pared to the cis -diene CH at 50 ppm ( γ-anti -ef fect) 23 .
Diastereomeric diene-alcohols 12 were not sep a ra ble by flash chro ma tog ra phy and were used as a mix ture through out this model study (for sim plic ity only the ma jor diastereomer, the trans , is shown in the syn thetic schemes).Ozonolysis of diene 12 was per formed un der sev eral dif fer ent re ac tion condi tions (Scheme 4): O 3 in MeOH or O 3 in CH 2 Cl 2 and worked-up em ploy ing reductive con di tions (Me 2S or H 2, Pd/C).On all oc ca sions only small amounts (10-20% yield) of dialdehyde 8 were ob tained from the re ac tion me dium as an un sta ble oil.In view of the low yields and in sta bil ity of dialdehyde 8, the diene-alcohol 12 was pro tected in the ex pecta tion of ob tain ing a better yield of the cor re spond ing dialdehyde.
Pro tec tion of ter tiary al co hols is not an easy task in chem ical syn the sis.For this rea son, pro tec tion of diene-alcohol 12 was ex e cuted us ing pro to cols based on solid lit er a ture pre cedents for this type of trans for ma tion.Two such pro to cols employ MEMCl and TBDMSOTf to form the cor re spond ing ethers from an al co hol 24 .As ex pected, pro tec tion of the al cohol 12 went smoothly in both cases af ford ing the ter tiary MEM-ether 13 or silyl ethers 14 as sta ble com pounds in high yields (Scheme 5).The pro tected dienes were once again submit ted to ozonolysis un der the con di tions de tailed in the exper i men tal sec tion.To our sat is fac tion dialdehydes 15 and 16 could be iso lated in high yields from the re ac tion mix ture (93-97%).These al de hydes could be stored at 4 °C, un der nitro gen, for sev eral days.How ever, they were shown to be unsta ble to sil ica-gel col umn chro ma tog ra phy.Thus, dialdehydes 15 and 16 were al ways pre pared prior to use in the reductive cou pling with low-valent ti ta nium.

The intramolecular reductive cou pling pro moted by low-valent Ti ta nium to pro duce the Bicyclo[6.3.0] undecene skel e ton
With a re li able route to the dialdehydes 15 and 16 on hand, we be gan to eval u ate the key step for the con struc tion of the bicyclo[6.3.0]undecenesys tem.Ini tial at tempts em ployed the tra di tional McMurry con di tions to ef fect cou pling, low-valent ti ta nium be ing gen er ated by re duc ing a TiCl 3 (DME) 1.5 complex with Zn-Cu al loy un der refluxing DME 25 .In our case, these con di tions led in vari ably to com plex mix tures of products. 1H-NMR spec tra of the crude mix tures dis played a large peak be tween 1 and 2 ppm, with out any ev i dence of olefinic hy dro gens.TLC of the re ac tion mix ture dis played a com plex pat tern in di cat ing the pres ence of a large num ber of prod ucts.Some mod i fi ca tions of the re ac tion con di tions were ex am ined (time of ad di tion of sub strate and tem per a ture of re ac tion) with dis ap point ing re sults.Aiming to pre pare the in ter me di ate pinacol, which could be later con verted into the de sired cyclooctene, car bonyl cou pling of 15 and 16 was car ried out using TiCl 3/Zn-Cu at room tem per a ture 26 .These ex per i ments resulted in com plex mix tures, and no glycols could be de tected by IR or 1 H-NMR spec tros copy.In ter est ingly, TLC of these re actions was very sim i lar to that ob tained for the car bonyl cou pling of 15 and 16 per formed un der re flux con di tions.More over, vary ing the time of ad di tion of dialdehyde 15 or 16 to the Ti(0) slurry from the usual 40 h (as in di cated in the lit er a ture) to 8 h (shorter re ac tion time), 60 h or 72 h (lon ger re ac tion times) did not sig nif i cantly change the re ac tion out come; in all in stances a com plex mix ture re sulted as in di cated by the 1 H-NMR or TLC of the crude mix tures.Pre sum ably, the ZnCl 2 formed dur ing reduc tion of TiCl 3 (DME) 1.5 com plex (17 to 20 equiv a lents employed in each re ac tion) led to de com po si tion of the dialdehydes 15 / 16 .Thus, we then de cided to use reductive agents which would al low the re ac tion to be run un der neu tral con di tions.For this pur pose, C 8K (po tas sium on graph ite) was cho sen as the re ducing agent to gen er ate the low-valent ti ta nium in the re ac tion me dium 27 .
The choice of C 8K as the re duc ing agent proved cor rect and reductive cou pling was fi nally achieved (al beit in low yield) when the MEM-protected dialdehyde 15 was sub jected to a slurry of TiCl 3 -C 8 K in DME un der high di lu tion con di tions for 40 h at room tem per a ture (Scheme 6) to yield the bicyclo[6.3.0]undecene 17 .Al though the yields ob tained for 17 were low (~10%) we be lieve the milder re ac tion con di tions em ployed in this pro to col were in stru men tal in ef fect ing carbonyl cou pling.The use of C 8K to con vert Ti(III) into low-valent ti ta nium did not pro duce any Lewis acid in the medium (McMurry's pro to col pro duced con sid er able amounts of ZnCl 2 ), and so no del e te ri ous ef fects were caused to ei ther the start ing dialdehyde or the fi nal un sat u rated bicyclic ether product.The re main ing ma te rial, af ter iso la tion of the bicyclic system, seemed to be poly meric by 1 H-NMR anal y sis.At tempts to im prove the yields for the reductive car bonyl cou pling step were fruit less.
TBDMS-protected dialdehyde 16 failed to pro vide any of the cyclized prod uct even un der the TiCl 3-C 8K pro to col.Complex mix tures were ob tained in all ex per i ments car ried out 28 .

Con clu sions
The bicyclo[6.3.0]undecenesys tem found in a num ber of cyclooctanoid nat u ral prod ucts was ob tained through an intramolecular cou pling of car bon yls pro moted by low valent ti ta nium from dialdehyde in ter me di ate 15 con tain ing a protected β-hydroxy car bonyl group.The trou ble some nucleophilic ad di tion of an allyl group to the readily enolizable cyclopentanone 7 was achieved in good yields (75-78%) by the use of an ex cess of the Grig nard re agent in the pres ence of the ad di tive MgCl 2 , and these con di tions might prove use ful for other enolizable ke tones.The key dialdehydes 15 and 16 for the cou pling stud ies were pre pared in a con ve nient and con cise man ner from 2-carbomethoxy-cyclopentanone in 5 steps, in an over all yield of ap prox i mately 40%.
De spite the lim ited suc cess, to the best of our knowl edge this is the first time a cyclooctenoid ring has been ob tained by the intramolecular cou pling of a pro tected β-hydroxy-aldehyde group with a non-conjugated al de hyde group us ing low-valent ti ta nium.Af ter com ple tion of this study we ini ti ated an approach to the to tal syn the sis of the cyclooctanoid dactylol as planned in Scheme 1. Hope fully, a more ex ten sive in ves ti gation into Clive's con di tions to ef fect car bonyl cou pling or the ap pli ca tion of the more re cent ole fin me tath e sis ap proaches devel oped by Grubbs 29 and Nu gent 30 could re sult in a better yield of the cyclooctenoid sys tem, thus mak ing it a more vi a ble transfor ma tion for our pur poses.Fur ther re sults con cern ing these stud ies will be pub lished in due course.