Synthesis of Acyclic Insect Pheromones from Cycloalkanones via Acetylenic Lactones

A Fig. 1 des cre ve um mé to do ge ral para pre pa ra ção de fe ro mô ni os de in se tos. Vá ri os com po nen tes de fe ro mô ni os de in se tos, jun to de seus isô me ros ge o mé tri cos e/ou po si ci o na is, fo ram pre pa ra dos a par tir de Z-lactonas 2a-d, que são fa cil men te aces sí ve is pela hi dro ge na ção es te re os se le ti va (Lind lar Pd, H2) dos pre cur so res ace ti lê ni cos 1a-d, sen do es tes já sin te ti za dos a par tir de ci clo al ca no nas. A iso me ri za ção de ace ta tos de Z-alquenilas 6a-d aos res pec ti vos es te res de E-alquenilas 8a-d, foi re a li za da tan to pela téc ni ca ca ta lí ti ca (NaNO2, HNO3, ∆) como pelo mé to do de in ver são quí mi ca (NBS, TFA; NaI, DMF, ∆). O ál co ol (E)-6-decenílico (7b) foi tam bém pre pa ra do di re ta men te do es ter ace ti lê ni co (15b) pela re du ção, em trans, com hi dre to de lí tio-alumínio (LiAlH4), por re flu xo em di gli ma. Os ace ta tos de de ci la (18) e he xa de ci la (19), com po nen tes dos fe ro mô ni os de ma ri po sa do nabo (Agro tis se ge tum; tur nip moth) e da bor bo le ta Lyco rea ce res ce res, res pec ti va men te, fo ram ob ti dos pela hi dro ge na ção ca ta lí ti ca (Pd, H2) dos ace ta tos de Z-alquenilas cor res pon den tes.


Intro duc ti on
Phe ro mo nes are an im por tant and a ra pidly gro wing class of bi o lo gi cally ac ti ve or ga nic com pounds.A lar ge pro por ti on of phe ro mo nes iso la ted from a va ri ety of in sects exem pli fi es di ver sely func ti o nal li zed acy clic com pounds, which have been synthe si zed by se ve ral rou tes [1][2][3] .Whi le ear li er met ho do lo gi es em plo yed for the cons truc ti on of the acy clic ske le ton in vol ved ma inly the acety le nic che mistry and ole fin for ma ti on by the Wit tig or re la ted re ac ti ons 1 .More re cently, the re has been an in cre a sing emp ha sis on the use of di ver se met hods for im pro ved iso me ric pu rity of the E or Z pro duct and for tho se le a ding to the op ti cally ac tive phe ro mo nes 2,3 .
We have re cently ini ti a ted a dif fe rent ap pro ach to the se acy clic com pounds by the syste ma tic ela bo ra ti on of cycloal ka no nes, whe re the va ri a ble size of the star ting ke to ne is ex plo i ted to ge ne ra te the tri ple or the dou ble bond of the desi red pro duct in a re gi os pe ci fic and ste re o se lec ti ve manner 4 (Sche me 1).
We have al re ady re por ted our pre li mi nary re sults on the con ver si on of cyclo he xa no ne, in vol ving the trans for ma tion of an α-chlo ro ke to ne func ti on into an acety le nic lin ka ge (RCHClCOR → RC ≡CR), to both the Z and E se ri es of C 9 phe ro mo nes 5 .A re cent pu bli ca ti on 6 des cri bed the pre pa rati on of Z and E ma cro li des from the acety le nic lac to nes 7 1a-d , whilst we re port the ir trans for ma ti on into se ve ral Ar ti cle mem bers of the ti tle com pounds and the ir ge o me tric or posi ti o nal iso mers, as il lus tra ted in Sche me 2.

Re sults and Dis cus si on
Met ha noly sis of the Z-lactones 6 2a-d gave the cor respon ding hydroxy-esters 3a-d, which on mesy la ti on 8 fur nished the res pec ti ve mesy la tes 4a-d.Lit hi um alu mi num hydri de re duc ti on of the lat ter in et her af for ded the Z-alkenols 5a-d, which were acety la ted to the cor res ponding ace ta tes 6a-d.Of the se, (Z)-5-decenyl ace ta te (6a) is the phe ro mo ne com po nent of the tur nip moth ( Agro tis sege tum ) 3 , whi le (Z)-8-dodecenyl ace ta te (6c) cons ti tu tes the sex phe ro mo ne of the ori en tal fru it moth ( Grap ho li ta moles ta ) 3 .The se two com pounds have been synthe si zed ear lier 3 .
Both the ca taly tic iso me ri za ti on (NaNO 2 , HNO 3 ) 9 and the che mi cal in ver si on (TFA, NBS; NaI, DMF, ∆) 10 of the Z al kenyl ace ta tes 6a-d wor ked well with the se acy clic com pounds, le a ding to the cor res pon ding E ace ta tes 8a-d in good (90-95%) yi eld.Ne vert he less, the ca taly tic tech nique 9 (2M NaNO 2 , 2M HNO 3 , 70-75 °C, 1 h) is far more con ve ni ent and eco no mi cal.Among the E com pounds 8a-d , only (E)-8-dodecenyl ace ta te ( 8c ) is a mi nor com ponent of the phe ro mo ne of the ori en tal fru it fly ( Grap ho li ta mo les ta ), men ti o ned ear li er 3 .
We would like to stress here that the al ter na ti ve rou te to the se E al kenyl ace ta tes 8a-d , through the res pec ti ve transfor ma ti ons of the E lac to nes (das hed ar rows in Sche me 2-A), is rat her li mi ted and less at trac ti ve, be ca u se the Z to E iso me ri za ti on works bet ter in the acy clic com pounds as com pa red with the cyclic ones (lac to nes), as dis cus sed elsew he re 6 .
Anot her path was tes ted with the ope ning of the acetyle nic lac to ne 1b .Ho we ver, re duc ti on of the me si loxy-ester 13b , with LiAlH 4 in et her, re qui red a much lo wer ini ti al reac ti on tem pe ra tu re (-100 °C as com pa red with the usu al -15 °C), but still gave a mix tu re of the de si red al co hol 14b and the un wan ted diol 16b .The lat ter could be se pa ra ted by column chro ma to graphy of the cor res pon ding ace ta tes 15b and 17b .Des pi te this draw back, this path has the ad van ta ge of le a ding to both the Z and E iso mers di rectly from the acety le nic pre cur sor.Thus, se mi-hydrogenation (H 2 , Lindlar cat.) of 15b fur nis hed (Z)-6-decenyl ace ta te ( 6b ), whi le its trans re duc ti on with LiAlH 4 in re flu xing digl yme 11 a : m = n = 1 ; b -d : m = 0 ; b : n = 2 ; c : n = 4 ; d : n = 8 .i -v i i i : 9 0 -9 5 % c r u d e y i e l d s , s e e t e x t .

b
Fi gu re 1.
Apart from fur nis hing the acety le nic in ter me di a tes as well as both the Z and E al kenyl al co hols and the ir es ters, the pre sent met ho do logy also opens an ac cess to the sa tu rated phe ro mo nes, eit her by the full hydro ge na ti on of the un -sa tu ra ted pre cur so res or by the syste ma tic ela bo ra ti on of the sa tu ra ted lac to nes.We cho se to pre pa re decyl ace ta te (18 ) and he xa decyl ace ta te ( 19 ), phe ro mo ne com po nents of the tur nip moth ( Agro tis se ge tum ) 12 and the male butterfly Lyco rea ce res ce res 13 , res pec ti vely, from the cor respon ding Z-alkenyl ace ta tes (Sche me 2-C).Sche me 2. Pre pa ra ti on of Z & E Phe ro mo nes from Acety le nic Lac to nes.Re a gents : i) Lind lar cat., H 2 ; ii) MeOH, MeO Na, re flux, 20-24 h; iii) MsCl, Et 3N, CH 2Cl 2, -15 °C, 3 h; iv) LiAlH 4, et her, -15 °C to re flux, 14-16 h; v) Ac 2O, Py (cat.), 80-90 °C, 3 h; vi) NaNO 2, HNO 3, 70-75 °C, 1 h; vii) NBS, TFA, 0 °C, 30 min; NaI, DMF, 90 °C, 20-22 h; viii) LiAlH 4, digl yme, re flux, 24 h; ix) Pd-C, H 2. All re ac ti ons gave 90-95% cru de yi elds (see Expe ri men tal).
The in fra red and 90 MHz 1 H NMR spec tra do not clearly dif fe ren ti a te bet we en the Z and E al kenyl ace ta tes (6a-d / 8a-d ).Con se quently, we re sor ted to the ir 200/50 MHz 1 H-and 13 C-spec tra (PND, DEPT, 1 H x 1 H and 1 H x 13 C COSY, etc.), whe re the most evi dent dis tin guishing fe a tu re, as ex pec ted, was the che mi cal shift of the allylic car bon atoms, which are 4 to 6 ppm up fi eld in the Z com pounds as com pa red with the res pec ti ve atoms in the E iso mers (Ta bles 1 and 2) 14 .Mo re o ver, clo se exa mi na ti on of the ole fi nic car bon atoms in the PND spec tra re ve a led that all the E al kenyl ace ta tes ( 8a-d ) were con ta mi na ted with 5-10% of the cor res pon ding Z iso mer, whi le only the (Z)-8-dodecenyl ace ta te ( 6c ) and (Z)-12-hexadecenyl aceta te ( 6d ) con ta i ned 5-10% of the res pec ti ve E com pound, as also pre sent in the pre cur sor Z-lactones 6 2c,d .

Expe ri men tal
Re a gent gra de che mi cals and sol vents were used as rece i ved from the com mer ci al sup pli ers, un less no ted ot herwi se.All re ac ti ons were mo ni to red rou ti nely by thin la yer chro ma to graphy (TLC: si li ca gel, re ve a led by I 2 va pours).Orga nic ex tracts were dri ed over anhydrous Na 2SO 4 and eva po ra ted un der re du ced pres su re on a ro tary eva po ra tor.IR spec tra of all li quid sam ples were re cor ded on a Ni co let 5ZDX-FT spec tro me ter as neat films.Rou ti ne 1 H-NMR spec tra, re por ted in the ex pe ri men tal text, were ob ta i ned on a Va ri an EM-390 (90 MHz) ins tru ment as CCl 4 so lu ti ons, whi le the high re so lu ti on 1 H-and 13 C-spec tra (PND, DEPT, 1 Hx 1 H and 1 Hx 13 C COSY, etc.) for the Z-and E-alkenyl ace ta tes (Ta bles 1 and 2) were re cor ded in CDCl 3 on a Bru ker AC-200 (200/50 MHz) spec tro me ter.Bran sonic ul tra so nic cle a ner (Mo del 1210 or 2210; 47 ± 6 KHz) was used to con duct the se mi-hydrogenations.Tem pe ra tures in the short path dis til la ti ons re fer to the air bath.Other ex pe ri men tal de ta ils are gi ven be low.

Met ha noly sis of Z-Lactone s 2a-d . Ge ne ral pro ce du re
A so lu ti on of 2a-d (5 mmol) in MeOH (20 ml), con ta ining NaO Me (10 mL, 0.13 mM) and pro tec ted with a CaCl 2 tube, was re flu xed (N 2 ) for 20-24 h.After eva po ra ting excess of the sol vent, dis til led wa ter (20 ml) was ad ded and the mix tu re ex trac ted with ethyl ace ta te (3 x 30 ml).The com bi ned ex tract was was hed with wa ter (20 ml) and bri ne (2 x 20 mL).Drying and eva po ra ti on of the sol vent fur nished the cru de hydroxy-esters 3a-d as yel lo wish li quids (~4.5 mmol; ~90%), prac ti cally pure by TLC , which were used in the next step, af ter the usu al spec tral iden ti fi ca ti on.

Mesy la ti on of the Hydroxy-Esters 3a-d . Ge ne ral pro ce dure
To a stir red so lu ti on of the hydroxy-ester 3a-d (4.5 mmol) and tri eth yla mi ne (0,95 mL, 690 mg, 6.83 mmol) in CH 2Cl 2 (20 mL), co o led to -15 °C and un der anhydrous con di ti ons, was ad ded slowly a so lu ti on of H 3CSO 2Cl (0.4 mL, 592 mg, 5.17 mmol) in CH 2Cl 2 (10 mL).The re acti on mix tu re was stir red for 3 h, when it was di lu ted with more CH 2Cl 2 (50 mL) and was hed with wa ter (3 x 20 mL) and bri ne (20 mL).Drying and eva po ra ti on of sol vent gave yel lo wish, vis cous li quids 4a-d (4.0-4.3 mmol; 90-95%), sho wing one spot on TLC pla tes.A ra pid pas sa ge through a small co lumn of Flo ri sil (3-5 g), in CH 2 Cl 2 (20-30 mL), affor ded pu rer sam ples which were cha rac te ri zed by the ir spec tra and sub se quently re du ced with LiAlH 4 .

Re duc ti on of Mesy loxy-esters 4a-d. Ge ne ral pro ce du re
To a stir red sus pen si on of LiAlH4 (608-646 mg, 16-17 mmol) in et her (40-50 mL), co o led to -15 °C, was ad ded drop wi se a so lu ti on of the mesy loxy-ester 4a-d (4.0-4.3 mmol) in the same sol vent (10 mL).The re ac ti on mix tu re was stir red un til it at ta i ned r. t. (2-3 h), when it was gently re flu xed for 14-16 h.After co o ling, it was ca re fully de com po sed with small pi e ces of ice and ex trac ted with ethyl ace ta te (3 x 30 mL), the com bi ned ex tract be ing succes si vely was hed with dil.HCl (20 mL), satd.so lu ti on of NaHCO 3 (20 mL) and bri ne (20 mL).Drying and eva po rati on fur nis hed yel lo wish li quids (3.6-3.8 mmol; 90-95%), which were acety la ted af ter spec tral cha rac te ri za ti on.

Acety la ti on of Z-Alkenols 5a-d. Ge ne ral pro ce du re
A so lu ti on of 5a-d (3.6-3.8 mmol) in ace tic anhydri de (3.2-3.4 mL, 3.5-3.7 g, 34-36 mmol), con ta i ning 6-7 drops of pyri di ne and pro tec ted with a CaCl 2 tube, was he a ted on a wa ter bath (80-90 °C) for 3 h, af ter which wa ter (15-20 mL) was ad ded and the co o led re ac ti on mix tu re ex trac ted with he xa ne (3 x 30 mL).The com bi ned ex tract was washed with dil.HCl (10 mL), satd.so lu ti on of NaHCO 3 (10 mL), and bri ne (20 mL).Drying and eva po ra ti on gave the de si red ace ta tes 6a-d, as co lor less li quids, pos ses sing ple asant odor.Short path dis til la ti on (6a-c: 110-120 °C/5 Torr; 6d: 110-120 °C/0.5 Torr) fur nis hed the pure sam ples in 85-90% yi eld.
200/50 MHz spec tra of the se ace ta tes are shown in Table 1.

Ca taly tic Iso me ri za ti on of Z Ace ta tes 6a-d into E Iso mers 8a-d. Ge ne ral pro ce du re
So di um ni tri te so lu ti on (2M, 0.1mL) and 2M HNO 3 (0.2 mL) were ad ded to the Z ace ta te 6a-d (1 mmol), kept un der N2 at mosp he re.The re sul ting yel lo wish mix tu re was stir red vi go rously and he a ted to 70-75 o C for 1 h.After co oling and di lu ti on with wa ter (10 mL), it was ex trac ted with he xa ne (3 x 20 mL), the com bi ned ex tract be ing was hed with satd.soln. of NaHCO 3 (10 mL) and bri ne (10 mL).Drying and eva po ra ti on gave yel lo wish li quids in 95-100% yi eld.Short path dis til la ti on ( 8a-c : 110-120 °C/5 Torr; 8d : 110-120 °C/0.5 Torr) af for ded co lor less li quids (90-95%).

Che mi cal Inver si on of Z Ace ta tes ( 6a-d ) to E Iso mers (8a-d ). Ge ne ral pro ce du re
Com pound 6a-d (0.5 mmol) was ad ded slowly to a cold (0 °C) and stir red so lu ti on of NBS (107 mg, 0.6 mmol) in TFA (0.75 mL, 1.1 g, 9.74 mmol), pro tec ted with a drying tube.After stir ring for 30 min, the re ac ti on mix tu re was dilu ted with wa ter (10 mL) and ex trac ted with he xa ne (3 x 10 mL), the ex tract be ing was hed with wa ter (5 x 10 mL) and bri ne (10 mL).Usu al work-up fur nis hed the cru de ad ducts, in al most quan ti ta ti ve yi eld, sho wing cha rac te ris tic ab sorpti ons around 1785 and 1740 cm -1 .
The cru de pro duct dis sol ved in DMF (2 mL) and con tai ning NaI (338 mg, 2.25 mmol) was he a ted at 90 °C for 20-22 h.After co o ling, a dil.so lu ti on of NaHSO 3 (10 mL) was ad ded and the who le ex trac ted with he xa ne (3 x 10 mL).Usu al work-up gave brown li quids, which on short path dis til la ti on fur nis hed the E ace ta tes 8a-d , in Ta ble 1. 13 C-and 1 H-spec tra # of Z-Alkenyl Ace ta tes 6a-d .

Com
#: Ba sed on PND, DEPT, 1 H x 1 H and 1 H x 13 C COSY Spec tra at 200/50 MHz in CDCl 3. *: Allylic C; i: Inter chan ge a ble as sign ment; s, m, t : Usu al mul ti pli city of pe aks .
90-95% yi eld, as co lor less li quids, iden ti cal (IR and 1 H-NMR) with the res pec ti ve pro ducts ob ta i ned ear li er by the ca taly tic pro ce du re.

Re duc ti on of the Mesy loxy-Ester 13b
A so lu ti on of es ter 13b (1.2 g; 4.5 mmol) in anhydrous et her (40 mL) was ad ded slowly to a stir red sus pen si on of LiAlH 4 (684 mg, 18 mmol) in et her (10 mL), kept at -100 °C (li quid N 2 and EtOAc).After al lo wing the re ac ti on mix tu re to at ta in r. t. (2-3 h), it was gently re flu xed for 14-16 h.Usu al work-up, as des cri bed in the ear li er ca ses, fur nis hed a yel lo wish li quid (770 mg), sho wing two prin cipal spots on TLC pla te.Spec tral analy sis re ve a led the se as the de si red al co hol 14b and un wan ted diol 16b .IR ( ν): 3349, 1161, 1073, 1052 cm -1 .The abo ve mix tu re was acety la ted with Ac 2 O (4.3 mL) and pyri di ne (8 drops), un der the usu al con di ti ons, and the re sul ting pro duct (1.1 g) chro ma to grap hed, un der re du ced pres su re, 15 over si li ca gel 60G (15 g), elu ted with he xane-EtOAc (98:2), ob ta i ning the acety le nic mo no a ce ta te 15b (690 mg; 70%) and di a ce ta te 17b (340 mg; 27%).

Se mi-hydrogenation 6 of 6-Decynyl Ace ta te ( 15b )
Com pound 15b (196 mg, 1 mmol), Lind lar ca talyst (60 mg) and he xa ne (10 mL) were put in a pe ar-shaped flask, which was con nec ted to a bal lo on fil led with H 2 (~500 mL).After the usu al pur ging with H 2 (3 ti mes) the re ac ti on flask was pla ced in the cen ter of an ul tra sound bath and ir ra di ated for 4 h, when the re was no more star ting alk yne 15b , as de tec ted by GC analy sis (FFAP co lumn, 200 °C).Fil tra ti on of the ca talyst and eva po ra ti on of the sol vent gave a co lorless li quid, which on short path dis til la ti on (110-120 °C/5 Torr) fur nis hed an analy ti cal sam ple (194 mg; 98%), identi cal in all res pects (TLC, IR, 1 H-NMR) with (Z)-6-decenyl ace ta te ( 6b ), pre pa red ear li er by an al ter na ti ve rou te.

Re duc ti on of 6-Decynyl Ace ta te ( 15b ) to (E)-6-Decenyl Alco hol ( 7b )
A so lu ti on of com pound 15b (196 mg, 1 mmol) in diglyme (5 mL) was ad ded drop wi se to a mag ne ti cally stir red suspen si on of LiAlH 4 (152 mg, 4 mmol) in digl yme (10 mL), co o led to 0 °C.After at ta i ning r. t., the re ac ti on mix tu re was re flu xed gently for 24 h, when it was co o led and de com po sed ca re fully with small pi e ces of ice.Extrac ti on with he xa ne (3 x 20 mL) and usu al work-up af for ded the (E)-6-decenol (7b ), which was acety la ted to the cor res pon ding ace ta te un der the usu al con di ti ons des cri ded ear li er.Short path dis til la ti on (110-120 °C/5 Torr) gave the pure com pound 8b (190 mg; 95%), iden ti cal (TLC, IR, 1 H-NMR) with the pro duct ob ta ined ear li er by the iso me ri za ti on of Z iso mer 6b .
He xa decyl Ace ta te 13

Sche me 1 .
a c t o n e s Z & E A c y c l i c P h e r o m o n e s n : V a r i a b l e ; X = C l , B r , Ge ne ral Stra te gi es for the Synthe sis of Acyclic Phe ro mo nes from Cyclo al ka no nes.t y l e n i c L a c t o n e s 1 a -d
*: Allylic C; i: Inter chan ge a ble as sign ment; s, m, t : Usu al mul ti pli city of sig nals .