Strategies for Stereocontrolled Synthesis

Transcription

1 Chemistry. Synthetic rganic Chemistry II Lecture 3 March, 2007 Rick L. Danheiser Massachusetts Institute of Technology! Thermodynamic Control Strategies! Kinetic Control Strategies! Strategies for the of Acyclic Target Molecules: " Glycinoeclepin A Intermediate (Danheiser) " Prostaglandins from Sugars (Stork)

2 General Strategies for the Stereocontrolled of Acyclic Target Molecules " Chiron Approach " Ring Template Approach " Chirality Transfer " Acyclic Asymmetric! Thermodynamic Control Strategies! Kinetic Control Strategies! Strategies for the of Acyclic Target Molecules: " Glycinoeclepin A Intermediate (Danheiser) " Prostaglandins from Sugars (Stork)

3 General Strategies for the Stereocontrolled of Acyclic Target Molecules " Chiron Approach " Ring Template Approach " Chirality Transfer " Acyclic Asymmetric C 2 C 2 G. Stork and S. Raucher J.. Chem. Soc. 17,, 3 G. Stork, T. Takahashi, I. Kawamoto, and T. Suzuki J.. Chem. Soc. 17, 100, 272 For discussions of the use of chiral natural products as starting materials for the synthesis of complex molecules, see (1) S. anessian "Total of Natural Products: The 'Chiron Approach' ", Pergamon Press: xford, 13. (2) T.-L. o "Enantioselective : Natural Products from Chiral Terpenes", W iley Interscience: New York, 12.

4 G. Stork and S. Raucher J.. Chem. Soc. 17,, 3 G. Stork, T. Takahashi, I. Kawamoto, and T. Suzuki J.. Chem. Soc. 17, 100, 272 (2) Prostaglandins from Sugars (Stork) C 2

5 C 2! Install C- side chain by enolate alkylation! Thermodynamic control of stereochemistry at C- X C 2 R C 2! Install C- side chain by enolate alkylation! Thermodynamic control of stereochemistry at C-! [For PGF 2! ] C- stereochemistry by steric approach substrate control X C 2 R R

6 ! Form cyclopentanone from acyclic precursor by nucleophilic cyclization C 2 X EWG or X R umpolung New Subtargets C ( ) C 2 R X ( ) C 2 R R R R! The sugar connection : requires translation of C- stereogenic centers into C-C centers C 2 New Subtargets C ( ) C 2 R X ( ) C 2 R R R R C n Sugars as starting materials

7 ! Set C- stereochemistry by chirality transfer via [3,3] sigmatropic rearrangement C 2 Subtargets C ( ) C 2 R X ( ) C 2 R R R R Z Z (R)! (R) " # $ " $ # Retron for [3,3] sigmatropic shift: #,$-unsaturated carbonyl compound! Set C- stereochemistry by chirality transfer via [3,3] sigmatropic rearrangement C 2 Previous subtargets C ( ) C 2 R X ( ) C 2 R R R R New Subtargets C R X R R

8 ! Set C- stereochemistry by chirality transfer via [3,3] sigmatropic rearrangement top face attack Z Z CZ bottom face attack Z Z CZ! Set C- stereochemistry by chirality transfer via [3,3] sigmatropic rearrangement C 2 Previous subtargets C ( ) C 2 R X ( ) C 2 R R R R New Subtargets C R X R R

9 C 2 For PGA 2 C " # R [3,3] C + Bu 2 CuLi C C Ts L-erythrose C 2 For PGF 2! R X R R R R R 1,2-deoxygenation (both! or ") D-Glycero-D-guloheptono-1,4-lactone ne step from D-glucose

10 C 2 Total of PGA 2 2 C=CMgCl TF-C 2 Cl h % ClC 2 Me pyr, -30!0 C 2 Me 10 eq C 3 C(Me) 3 cat EtC h Me 2 C C 2 Me 2% aq Ac 0 1 h Me 2 C C 2 Me 3% C 2 Total of PGA 2 1 eq Et 3 N C 2 Cl 2 rt 1 h Me 2 C C 2 Me Me 2 C 2 eq (Me) 3 C xyl 10 1 h C 2 Me 0.1 eq K 2 C 3 Me rt 30 min % overall Me 2 C Me 2 C 1:1 C 2 Me

11 C 2 Total of PGA 2 Me 2 C Me 2 C 1:1 C 2 Me 1) 2, Pd-BaS 4 Me 2) TsCl, pyr d 3) EVE Me 2 C Me 2 C Ts C(Me)Et C 2 Me 7% eq Bu 2 CuLi Et h C(Me)Et C 2 0. N Na! 10 min 77% 10 eq Kt-Bu TF rt 4 min Me 2 C Me 2 C C(Me)Et C 2 Me 7% C 2 Total of PGA 2 C eq LDA TF 3 eq PhSeCl 4 eq NaI 4 Me rt 3 + C 2 C(Me)Et 1 steps in the longest linear sequence

12 Total of PGF 2! C 2 D-glucose CN 10 NaB 4 aq 10% 2 S 4 acetone + 0% 7% commercially available D-Glycero-D-guloheptono-1,4-lactone NaB 4 Me 10 C 1. h Ac 2, pyr C 2 Cl 2-7 C 1 h 1) K 2 C 3, Me 2) ClC 2 Me, pyr 3) CuS 4, aq Me 4) Ph,! Ac 1) Me 2 NC(Me) 2 2) Ac 2,! 40% overall Ac Total of PGF 2! C 2 acetone cat 2 S 4 4% overall C 3 (Me) 3 cat EtC 2! 0% C 2 Me 1) K 2 C 3, Me 2) TsCl, pyr 3) EVE C 2 Me R Ts R Sit-BuPh 2 R R = C()MeEt LiMDS RBr TF-MPA 71% EVE 1) 10 eq Bu 2 CuLi Et 2, -40 C 2 h 2) aq 2 S 4 TF, rt h 3% overall

13 Total of PGF 2! C 2 R R Sit-BuPh 2 R = C()MeEt DIBAL CN Et -10 C 0% aq Ac TF, 3 C NC SiR 3 1. eq TsCl pyr, - C R NC R R Sit-BuPh 2 eq KMDS benzene! h 72% EVE Ts NC 37% overall SiR 3 Total of PGF 2! C 2 NC R Sit-BuPh 2 R R 1) TBAF, TF 2) Collins x 3) AgN 3, K aq Et R = C()MeEt 31 steps in the longest linear sequence R NC R C 2 Ac 2 -TF 40 C h Lis-Bu 3 B TF, -7 C 1. h 73% C 2 R

14 [1,3] $C Chirality Transfer X Y * * C 2 R X Y [1,3] $N Chirality Transfer X Y * * N X Y Review of chirality transfer via sigmatropic rearrangements ill, R. K. In Asymmetric ; Morrison, J. D., Ed.; Academic Press: rlando, 14; Vol. 3, pp [1,3] $N Chirality Transfer X Y * * N X Y verman Rearrangement of Allylic Trihaloacetimidates Bn K, CCl 3 CN Et 2 Bn N CCl 3 0 C xylene 4% overall Bn N CCl 3 Bu SiR 3 1) DBU, CCl 3 CN C 2 Cl 2 Bu SiR 3 2) 1% PdCl 2 (PhCN) 2 benzene, rt 72% NCCCl 3 Review: verman, L. E.; Carpenter, N. E. rg. React. 200,, 1