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
Overman: Ring-Enlarging THF annulations RCHO.H 48-76% MeCHo sncl4,-70→-23 P 75-93% JAcs,1991,1135365 Overman: Ring-Enlarging THF annulations JAcs,1991,113.5365 32C-053/22999:30AM
Overman: Ring-Enlarging THF annulations JACS, 1991, 113, 5365 O R H H O RCHO, H+ -H2O O ( )n R + OH OH ( )n OH -H+ ( )n OH OH O O R1 O R1 O R1CHO 52-85 % SnCl4, -70 °C, 1 h 48-76% OH OH O O Me SnCl4, -70 → -23 °C 75-93% MeCHO O Me O R2 R2 R3 R4 R3 R4 R2 R3 R4 Overman: Ring-Enlarging THF annulations JACS, 1991, 113, 5365 OH O O RCHO RSO3H OH O R + HO O OH R + O HO + O OH R + O O O O R R R R 32C-05 3/22/99 9:30 AM
Overman: Ring- Enlarging THF annulations PTSA or + R,CHO° R 一m Lewis Acid Overman: Ring-Enlarging THF annulations PTsa In reactions with ketones, only substrates with nucleophilic alkene substituents rearrange successfuly. Acetals derived from the cis-12-cyclobutandiols do not undergo ring-enlarging furan annulation under a vanety of conditions F or So.R 32C-063/22999:31AM
Overman: Ring-Enlarging THF annulations JACS, 1991, 113, 5365 OH OH PTSA or BF3•OEt2 40 -70% O O + R1CHO SnCl4, -70 °C → rt 80% O O O O O O R1 O O Me Ph Lewis Acid no desired product some epimerization of acetal carbon X R1 R1 Me Ph O O OH R HO R + + cis-only cis-fused trans-fused Overman: Ring-Enlarging THF annulations JACS, 1991, 113, 5365 R3 OH OH O R1 R2 BF3•OEt2 or PTSA 45-74% O O R2 R1 R3 • In reactions with ketones, only substrates with nucleophilic alkene substituents rearrange successfully. • Acetals derived from the cis-1,2-cyclobutandiols do not undergo ring-enlarging furan annulation under a variety of conditions. O R R3 HO + O R R3 HO + O HO R R3 X O O R3 or R X = F or SO2R 32C-06 3/22/99 9:31 AM
Overman: Possible [3, 3] rearrangement 2: 1 mixture of epimers Two possible mechanisms explain the formation of the minor diastereomer: 得年”,一改 Overman: Spiroannulations 人 1.5: 1 mixture Tetrahedron, 1997. 53. 8927 32C-073/189910:27PM
Overman: Possible [3,3] rearrangement JACS, 1991, 113, 5365 Ph OH OH O H Ph O O Ph Ph 2:1 mixture of epimers O OH Ph Ph + O Ph OH + or O Ph HO Ph + O O Ph Ph Ph O Ph OH + Ph O Ph H OH [3,3] Two possible mechanisms explain the formation of the minor diastereomer: Overman: Spiroannulations Tetrahedron, 1997, 53, 8927 OTMS XR + XR OTMS + b a O O XR XR Prins OTMS OMe OMe TMSOTf, DTBMP CH2Cl2, rt, 82% O RuCl3•3H2O NaIO4, CCl4 MeCN, H2O 68-88% O O bond a bond b 1.5:1 mixture DTBMP = 2,6-t-butyl-4-methylpyridine OMe 32C-07 3/18/99 10:27 PM
Overman: Spiroannulations DuChy TMSOTf. DTBMP CCl4 CH2Cl, rt, 70% by X-ray structure TMSOTf. DTBMP Naco: c ai CH2Clz, rt, 28% 68-77% 1.5:1 moxture NH2 NHC(S)NH cHzC2,0→23°c relative stereochemistry Overman: Spiroannulations "xR, Axial orientation of the side chain gives good overlap in either the anti or synclinal trajectories If pinacol rearrangement occurs rapidly, only A and B will be formed. Destabilizing interactions between the SEt and the axial C-8 hydrogen in the synclinal trajectory result in the exclusive formation of the A epim 32C-083/22999:47AM Tetrahedron, 1997, 53, 89
Overman: Spiroannulations Tetrahedron, 1997, 53, 8927 TMSOTf, DTBMP CH2Cl2, rt, 70% RuCl3•3H2O NaIO4, CCl4 MeCN, H2O 68-71% OTMS OMe OMe OTMS MeO OMe OMe O O O TMSOTf, DTBMP CH2Cl2, rt, 28% RuCl3•3H2O NaIO4, CCl4 MeCN, H2O 68-77% O OTMS SEt SEt Me2SSMeBF4 CH2Cl2, 0 → 23 °C 63% O SEt NNHC(S)NH2 SEt NH2NHC(S)NH2 HOAc, rt, 80% one isomer relative stereochemistry established by X-ray structure 1.4:1 mixture OMe O stereochemistry determined by X-ray structure 1.5:1 mixture Overman: Spiroannulations Tetrahedron, 1997, 53, 8927 X H R1 + X H R1 + OR + XR1 a b OR + XR1 a b XR1 O XR1 O • Axial orientation of the side chain gives good overlap in either the anti or synclinal trajectories. • If pinacol rearrangement occurs rapidly, only A and B will be formed. • Destabilizing interactions between the SEt and the axial C-6 hydrogen in the synclinal trajectory result in the exclusive formation of the A epimer. OR A B O 6 32C-08 3/22/99 9:47 AM
Overman: Limitations 2-propyl 18-24% under Sncl conditions 2-propyl 30% under SnCl4 conditions 。ms retro-Aldol LOTS % Unsaturation or heteroatoms at the B or y positions of the acetal initiator are not tolerated in these reactions. JACS, 1988, 110, 2248 Overman: Synthesis of trans-Kumausyne trans-Kumausyne 4:1 regioselectivity 1. H2, Pd-c *CHO OTES 32C-093/22999:40AM 4cs,1991,113537
Overman: Synthesis of trans-Kumausyne JACS, 1991, 113, 5378 O AcO Et Br trans-Kumausyne OH OH O H H O OBn O H H OBn O BnOCH O 2CHO RSO3H, rt 69% m-CPBA 72% 4:1 regioselectivity 1. H2, Pd-C, 88% 2. Swern, 100% O H H O O Me TMS BF3•OEt2 -78 °C → rt 73% 1. 2. TBSCl O H H O O Et O OTBS HO Et OTBS H O DIBAL -78 °C 97% CHO Overman: Limitations JACS, 1988, 110, 2248 O Cl Me (-)-Laurenyne Cl TMS O O 2 2-propyl 2-propenyl 18-24% under SnCl4 conditions no reaction under a variety of conditions O TMS Cl OSitBuMe2 OEt 2-propyl 2-propenyl 30% under SnCl4 conditions gives only acetal cleavage O TMS Cl OR Et EtO X X = Br X = SMe X = OAc X = Me R = TBS R = TBS R = TBS R = Me decomposition, acetal cleavage O TMS Cl OTBS EtO EtO Me O TMS Cl OTBS EtO Me + O TMS Cl OTBS 2 O OTBS Me • Unsaturation or heteroatoms at the β or γ positions of the acetal initiator are not tolerated in these reactions. 24% retro-Aldol Cl 32C-09 3/22/99 9:40 AM