Chemistry 206 Advanced Organic Chemistry Handout -32C Recent applications of the Prins Reaction in Stereoselective Synthesis Eileen Shaughnessy Evans Group seminar March 19. 19 9 9 Matthew d. shair Monday December 9. 2002
Chemistry 206 Advanced Organic Chemistry Handout–32C Recent Applications of the Prins Reaction in Stereoselective Synthesis Matthew D. Shair Monday , December 9, 2002 Eileen Shaughnessy Evans Group Seminar March 19, 1999
Recent applications of the Prins Reaction in Stereoselective Synthesis Eileen Shaughnessy Evans Group Seminar larch 19 1999 Prins-Pinacol methodology Il. Prins-Pinacol synthese IlL Tetrahydropyran synthesis IV. Other uses of the Prins reaction in synthesis Prins reaction: Adams, D.R.; Bhaynagar, S. D. Synthesis 1977, 661 Prins and carbonyl ene reactions: Snider, B. B, Comprehensive Organic Synthesis, 1991, Vol. 2 Bicyclic THF synthesis: Dave MacMillan, Evans Group Seminar, 1996 Approaches to 2, -6-Disubstituted THP Derivatives: Duke Fitch, Evans Group Seminar, 1997 The Prins reaction X RICHO Lewis Ad Prins AlSo 32C-011/19/008:15PM
Prins-Pinacol methodology Prins-Pinacol syntheses Tetrahydropyran synthesis Other uses of the Prins reaction in synthesis I. II. III. IV. Recent Applications of the Prins Reaction in Stereoselective Synthesis Eileen Shaughnessy Evans Group Seminar March 19, 1999 Prins reaction: Adams, D.R.; Bhaynagar, S. D. Synthesis 1977, 661 Prins and carbonyl ene reactions: Snider, B. B., Comprehensive Organic Synthesis, 1991, Vol. 2 Bicyclic THF synthesis: Dave MacMillan, Evans Group Seminar, 1996 Approaches to 2,-6-Disubstituted THP Derivatives: Duke Fitch, Evans Group Seminar, 1997 O R1 H R2 R1 R2 OH O O R1 R2 R2 R1 R2 OH - H+ HX R1 R2 OH X O Me O Ph Me Me Me O Ph - Cl4SnO O Ph - Cl4SnO O Ph O + The Prins Reaction R1CHO X- + + Lewis Acid >95% ee Prins pinacol Prins-Pinacol: Prins: 32C-01 1/19/00 8:15 PM
Stereoelectronic Aspects of the Prins Reaction Can undergo cy from Mac ian seminar. 1996 Oxocarbenium Ion formation 32C-023/18999:41PM
R1 OH R OH R1 O R OH R1 OH R O R2 R2 O R O R2 R1 R1 O R2 O R H+ H+ Stereoelectronic Aspects of the Prins Reaction from MacMillan Seminar, 1996 + + R2CHO - H+ Cannot undergo cyclization Can undergo cyclization Me OLA O R Me OLA O R O LAO R O LAO R O R Me OLA O R O Oxocarbenium Ion Formation + + 10 - 14 kcal/mol + + (E)-Oxocarbenium ion (Z)-Oxocarbenium Ion + Prins pinacol 32C-02 3/18/99 9:41 PM
Evidence for prins-Pinacol mechanism nCle. CH2Cl2 >95% 78°c→-23°c om MacMillan Seminar. 1996 Examples of Stereoselective THF Formation hcHO 32C-033/1899951PM from MacEWan Seminar. 1996
O Me O Ph Me Me Me O Me Me Ph Me O Me O O O Ph - Cl4SnO O Ph - Cl4SnO Ph - Cl4SnO - Cl4SnO O Ph Ph O O Ph O Evidence for Prins-Pinacol Mechanism from MacMillan Seminar, 1996 + + + + SnCl4, CH2Cl2 -78 °C → -23 °C >95% ee enantiopure racemic Prins [3,3] fast pinacol aldol O Me O Me Me O Me HO Me OH Me O O Me O Me O Me Me Me Me Me Me Me O Me Me O Me Me O Me Ph Examples of Stereoselective THF Formation SnCl4, CH2Cl2 -70 → -23 °C 82% 7:1 anti:syn BF3•OEt2 (E)-CH=CHPhCHO CH2Cl2, -55 °C 97% SnCl4, CH2Cl2 -70 → -23 °C 82% anti syn from MacMillan Seminar, 1996 32C-03 3/18/99 9:51 PM
Overman: Laurenyne Synthesis ()-Laurenyne 1.(+)-DET, Ti(OiPr)4. IBuoOH 4A sieves.78% 3:1 regioselectivity, 92% 3. TsCl, pyridine, 88 H2 C2,98% OTBDPS 2equv).0°c,cH2Cl2 48 1. HF, pyridine, rt PCC, NaOAC, CHzClz 1-3 NaCN.DMso.95°c 32C-043/18999:54PM JAcs,1988,110.2248
Overman: Laurenyne Synthesis JACS, 1988, 110, 2248 O Cl Me (-)-Laurenyne O Cl OTs HO Cl OTs O TMS Cl OTs EtO OTBDPS TBDPSO OEt TBDPSO PPTS (cat.) CH2Cl2, 98% 1. SnCl4 (2 equiv.), 0 °C, CH2Cl2 2. TBAF 37% yield, one isomer, 4 g scale OH 1. (+)-DET, Ti(OiPr)4, tBuOOH 4 Å sieves, 78% 2. Et3NHCl, Ti(OiPr)4, CH2Cl2 3:1 regioselectivity, 92% 3. TsCl, pyridine, 88% TMS TMS Overman: Laurenyne Synthesis JACS, 1988, 110, 2248 O Cl Me (-)-Laurenyne O Cl OTs TBDPSO O Cl OTs O H O Cl OTs Me 1. HF, pyridine, rt 2. PCC, NaOAc, CH2Cl2 3. TMSOTf, Et3N, 0 °C, Pd(OAc)2, CH3CN 56% 1. DIBAL 2. MsCl, Et3N 3. NaBH4, HMPA 65% 1. NaCN, DMSO, 95 °C 2. DIBAL 3. TIPS TIPS n-BuLi, HMPA THF, -78 °C 3:1 E:Z 4. TBAF 20 steps, 0.6% yield from 1,1-TMS-Br-ethylene 32C-04 3/18/99 9:54 PM