Enantioselective Syntheses of Insect Pheromones with a Methyl-branched Skeleton Verified by Chiral HPLC Analyses

Transcription

1 29 th ISCE Annual eting lbourne, Australia (August 20, 2013) Enantioselective Syntheses of Insect Pheromones with a thyl-branched Skeleton Verified by Chiral PLC Analyses Ts T. Ando, T. Taguri, Y. Muraki, T. Fujii and M. Yamamoto Graduate School of BASE, Tokyo University of Agriculture and Technology, Tokyo antetsu@cc.tuat.ac.jp

2 Lepidopteran Sex Pheromones Type I Silkworm moth bombykol Type II Giant looper Photos from Diamondback moth Tussock moth posticlure Lichen moths inhabiting in Iriomote Island Adachi et al J. Chem. Ecol., 36, 814 Lyclene dharma Yamakawa et al Tetrahedron Lett., 52, 5808 Miltochrista calamina

3 Lepidopteran Sex Pheromones with a Branched Skeleton Including Stereogenic Center(s) Leafminer moths (Lyonetiidae) peach leafminer Sugiei et al AEZ, 36, 814 Gries et al JCE, 23, 1119 emlock looper (Geometridae) apple leafminer Bagworm moth (Psychidae ) Gries et al Naturwiss.., 78, 315 Gries et al JCE, 19, 1501 mountain-ash bentwing Francke et al Naturwiss., 74, 143 Gries et al JCE, 32, 1673 Lichen moths inhabiting in Iriomote Island Adachi et al J. Chem. Ecol., 36, 814 Lyclene dharma Yamakawa et al Tetrahedron Lett., 52, 5808 Miltochrista calamina

4 Synthetic Strategy for 5,9-Dimethyl Compounds S N 2 reaction between a secondary tosylate and a carbanion associated with stereospecific inversion Ts Ts: leaving group : nucleophile (carbanion) Ts Block A Block B S N 2 S N 2 X Y Ts + C 1 + C 2 + C 7 + C 3 2 C Tamagawa et al., 1999 EJC, 973

5 Synthetic Strategy for 5,9-Dimethyl Compounds S N 2 reaction between a secondary tosylate and a carbanion associated with stereospecific inversion Ts Complete inversion?? With racemization Ts: leaving group : nucleophile (carbanion) (C 8 17 ) 2 CuLi Ts Bn / Et Bn 2, -70ºC 99% ee 71 % ee Larcheveque & Sanner, 1988 Tetrahedron, 44, 6407 Ms C 2 Et 99% ee NaC(C 2 Et) 2 / DMF, 50ºC Et 2 C Et 2 C C 2 Et 74% ee Sato & tera, 1995 JC, 60, 2627 Without racemization Ms NaC(C 2 Et) 2 / DME, 85ºC Et 2 C >99% ee Et 2 C >99% ee Sorger & Stohrer, 2007 US Patent A1

6 Synthesis of the Chiral Block A Block A Block B (5S.9)-1 1) n-c 3 7 MgBr 2) TsCl, Et 3 N Ts NaC(C 2 ) 2 / DME ()-2 ()-3 (S)-4 C 2 C 2 LiCl / DMS ºC LiAl C 2 4 I 2, PPh 3 / TF imidazole / TF (S)-5 (S)-6 (S)-A I Chiral PLC Analysis Chiralpak AS- (S)-3 ()-3 10% IPA in hexane UV 254 nm Chiralpak AY- ()-6 (S) % IPA in hexane I detector t (min) t (min)

7 Synthesis of the Chiral Block B Block A (5S.9)-1 Block B (S)-2 1) n-c 7 15 MgBr 2) TsCl, Et 3 N Ts (S)-7?? Ts ()-B p-tol S 2 C 2 C 2 / base or p-tolsc 2 C 2 / base Ts ()-8 C 2 S p-tol C 2 ()-9 Ts = S

8 Synthesis of the Chiral Block B Block A (5S.9)-1 Block B (S)-2 1) n-c 7 15 MgBr 2) TsCl, Et 3 N Ts (S)-7 TsC 2 Li / TF Ts ()-B TsC 3 [p-(c 6 4 )S 2 ] methyl p-tolyl sulfone + base (S)-8 ()-11 2 C 2 C ()-B Br n-c 7 15 MgBr 1) LiAl 4 2) I 2, PPh 3, imidazole 3) p-(c 6 4 )S 2 Na Base Solvent Temp (ºC) Yield BuLi TF 55 72% (>99% ee) BuLi TF 20 none BuLi TF-MPA 55 none LDA TF 55 18% NaMDS TF 55 30% Chiral PLC Analysis Chiralpak AS- 10% IPA in hexane UV 254 nm (S)-B ()-B t (min)

9 Coupling of Two Blocks for 1,5-Dimethyl Compounds 1) Female pheromone of the mountain-ash bentwing (S)-A + Ts I Mg / ()-B BuLi / TF-MPA (5S.9)-1 Ts (5S.9)-12 Taguri et al Tetra. Asym., 23, 852 2) Female pheromone of the apple leafminer Block A (3-methyl) Block B (2-methyl) 3) Male pheromone of the stink bug, Pallantia macunaima 1 Ts X Block A (3-methyl) Y Block B (2-methyl) Muraki et al EJC,,2209 Ts 2 The secondary tosylates are useful precursors for building blocks with a methyl branch at the 2- or 3-position.

10 Application of the S N 2 eaction for 1,11-Dimethyl Compounds Sex pheromone of the bagworm moth S N 2 S 2 Ph Ts A + C 1 (S)-2 Taguri et al EJC, in press. (3,13,3'S)-1 2 N C 2 (S)-valine I B C S N 2 + C 2 Ms or Ts- A useful chiral building block including a methyl branch between two functionalities ()-2

11 Application of the S N 2 eaction for 1,11-Dimethyl Compounds Chiral PLC Analysis Chiralpak AY- 0.3 % IPA in hexane UV 254 nm Carlsen et al JC, 46, 3936 ucl 3, NaI 4 / CCl 4 -CN- 2 (Yield 63%) ()-C (S)-C C t (min) S N 2 reaction between a sulfonate of Block C and NaC(C 2 ) 2 Sulfonate Temp After 24 hr (ºC) Yield E 1 -product Ts 85 54% 10% Ms The benzyl group is bulky and activates methylene protons. A mesylate is superior to the corresponding tosylate. C S N 2 + C 2 Ms or Ts- A useful chiral building block including a methyl branch between two functionalities ()-2

12 Application of the S N 2 eaction for 1,11-Dimethyl Compounds Sex pheromone of the bagworm moth Taguri et al EJC, in press. 1) ucl 3, NaI 4 2) SCl 2 3) (S)-alcohol (3,13,3'S)-1 2 N C 2 1) NaN 2, Cl K 2) LiAl 4 Cl Li / CuCN (S)-valine Carlseo et al. 1981JC, 46, C NM of (S)-AP Esters Ac (S)-alcohol (S)-alcohol

13 Enantioselective Syntheses of Insect Pheromones with a thyl-branched Skeleton S N 2 reaction of secondary sulfonates, which were synthesized from a chiral propylene oxide, formed a new C-C bond with complete inversion of configuration. The inversion was confirmed by a chiral PLC analysis. NaC(C 2 ) 2 and LiC 2 S 2 Ph were ideal nucleophiles to increase two and one carbon(s), respectively. The reaction could be utilized as a key step for synthesis of chiral building blocks with a methyl group at the 3- or 2-position. The two blocks were available for the synthesis of not only 1,5-dimethyl compounds but also other dimethyl compounds, such as 3,13-dimethylpentadecanoate. Ts