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 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 R 1 H R 2 R 1 R 2 OH OO R 1 R 2 R 2 R 1 R 2 OH - H+ HX R 1 R 2 OH X O OMe Ph Me Me Me O Ph - Cl 4 SnO O Ph - Cl 4 SnO O Ph O + The Prins Reaction R 1 CHO X - + + Lewis Acid >95% ee Prins pinacol Prins-Pinacol: Prins: 32C-01 1/19/00 8:15 PM OHR 1 R OH OR 1 R OH OHR 1 R O R 2 R 2 O OR R 2 R 1 OR1 R2 O R H + H + Stereoelectronic Aspects of the Prins Reaction from MacMillan Seminar, 1996 + + R 2 CHO - H + Cannot undergo cyclization Can undergo cyclization OLAMe O R OLAMe OR O R LAO O LAO R O R OLAMe 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 O OMe Ph Me Me Me O Me Me Ph Me O Me O O O Ph - Cl 4 SnO O Ph - Cl 4 SnO Ph - Cl 4 SnO - Cl 4 SnO O Ph Ph O O Ph O Evidence for Prins-Pinacol Mechanism from MacMillan Seminar, 1996 + + + + SnCl 4 , CH 2 Cl 2 -78 °C → -23 °C >95% ee enantiopure racemic Prins [3,3] fast pinacol aldol O OMe Me OMe Me MeHO OH OMe O Me O OMe Me Me Me Me Me Me Me O Me OMe Me Me O Me Ph Examples of Stereoselective THF Formation SnCl 4 , CH 2 Cl 2 -70 → -23 °C 82% 7:1 anti:syn BF 3 ?OEt 2 (E)-CH=CHPhCHO CH 2 Cl 2 , -55 °C 97% SnCl 4 , CH 2 Cl 2 -70 → -23 °C 82% anti syn from MacMillan Seminar, 1996 32C-03 3/18/99 9:51 PM 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.) CH 2 Cl 2 , 98% 1. SnCl 4 (2 equiv.), 0 °C, CH 2 Cl 2 2. TBAF 37% yield, one isomer, 4 g scale OH 1. (+)-DET, Ti(OiPr) 4 , tBuOOH 4 ? sieves, 78% 2. Et 3 NHCl, Ti(OiPr) 4 , CH 2 Cl 2 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, CH 2 Cl 2 3. TMSOTf, Et 3 N, 0 °C, Pd(OAc) 2 , CH 3 CN 56% 1. DIBAL 2. MsCl, Et 3 N 3. NaBH 4 , 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 JACS, 1991, 113, 5365 O R H H O RCHO, H + -H 2 O O ( ) n R + OH OH ( ) n OH -H + ( ) n OH OH O O R 1 O R 1 O R 1 CHO 52-85 % SnCl 4 , -70 °C, 1 h 48-76% OH OH O O Me SnCl 4 , -70 → -23 °C 75-93% MeCHO O Me O R 2 R 2 R 3 R 4 R 3 R 4 R 2 R 3 R 4 Overman: Ring-Enlarging THF annulations JACS, 1991, 113, 5365 OH O O RCHO RSO 3 H 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 JACS, 1991, 113, 5365 OH OH PTSA or BF 3 ?OEt 2 40 -70% O O + R 1 CHO SnCl 4 , -70 °C → rt 80% O O O O O O R 1 O O Me Ph Lewis Acid no desired product some epimerization of acetal carbon X R 1 R 1 Me Ph O O OH R HO R + + cis-only cis-fused trans-fused Overman: Ring-Enlarging THF annulations JACS, 1991, 113, 5365 R 3 OH OH O R 1 R 2 BF 3 ?OEt 2 or PTSA 45-74% O O R 2 R 1 R 3 ? 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 R 3 HO + O R R 3 HO + O R HO R 3 X O O R 3 or R X = F or SO 2 R 32C-06 3/22/99 9:31 AM Overman: Possible [3,3] rearrangement JACS, 1991, 113, 5365 Ph OH OH O HPh 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 + ab O O XR XR Prins OTMS OMe OMe TMSOTf, DTBMP CH 2 Cl 2 , rt, 82% O RuCl 3 ?3H 2 O NaIO 4 , CCl 4 MeCN, H 2 O 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 Tetrahedron, 1997, 53, 8927 TMSOTf, DTBMP CH 2 Cl 2 , rt, 70% RuCl 3 ?3H 2 O NaIO 4 , CCl 4 MeCN, H 2 O 68-71% OTMS OMe OMe OTMS MeO OMe OMe OO O TMSOTf, DTBMP CH 2 Cl 2 , rt, 28% RuCl 3 ?3H 2 O NaIO 4 , CCl 4 MeCN, H 2 O 68-77% O OTMS SEt SEt Me 2 SSMeBF 4 CH 2 Cl 2 , 0 → 23 °C 63% O SEt NNHC(S)NH 2 SEt NH 2 NHC(S)NH 2 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 HR 1 + X H R 1 + OR + XR 1 a b OR + XR 1 a b XR 1 O XR 1 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: 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 O BnOCH 2 CHO RSO 3 H, rt 69% m-CPBA 72% 4:1 regioselectivity 1. H 2 , Pd-C, 88% 2. Swern, 100% O H H O O Me TMS BF 3 ?OEt 2 -78 °C → rt 73% 1. 2. TBSCl O H H O O Et OTBS O 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 SnCl 4 conditions no reaction under a variety of conditions O TMS Cl OSitBuMe 2 OEt 2-propyl 2-propenyl 30% under SnCl 4 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 MeEtO O TMS Cl OTBS MeEtO + 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 Overman: Magellanine Synthesis JACS, 1993, 115, 2992 TESO CH(OMe) 2 O OMe H SnCl 4 , (1.1 equiv.) CH 2 Cl 2 , -78 → -23 °C 57% N O OMe H 1. OsO 4 (cat.), NaIO 4 dioxane-H 2 O, rt 2. Ph 2 CHNH 3 Cl NaBH 3 CN i-PrOH, rt, 60% CHPh 2 1. Cl 3 SiMe, NaI MeCN, 80 °C 2. TBSCl, imidazole DMF, rt, 76% 3. H 2 , Pd(OH) 2 , EtOAc 4. (BOC) 2 O, Et 3 N DMAP, 89% N O H BOC Me N O Me OH H (-)-Magellanine OTBS OTES O R + 1. LDA, TMSCl, THF, -78 °C, 85% 2. LiMe 2 Cu, TMEDA, TMSCl -78 → -23 °C Pd(OAc) 2 , MeCN, CF 3 CO 2 H Overman: Synthesis of trans-Kumausyne JACS, 1991, 113, 5378 O AcO Et Br trans-Kumausyne O HO Et OTBS H O 1. TMSOTf, Et 3 N 2. Pd(OAc) 2 , 53% 3. O TMSO Et OTBS - 100 °C → 0 °C 88% Cl Cl 1. n-BuLi, NH 4 Cl, 98% 2. citric acid, MeOH 3. Ac 2 O, pyr., 92% (EtO) 2 PLi O Cl Cl O AcO Et OTBS 1. HF-pyr., 100% 2. PPh 3 , CBr 4 2,6-di-t-butyl pyridine benzene, 40 °C, 40% trans-Kumausyne 32C-10 3/18/99 10:41 PM Overman and MacMillan: Synthesis of a Eunicellin Diterpene JACS, 1995, 117, 10391 O HH Me AcOHO (-)-7-Deacetoxy-alcyonin acetate TMSOH OH ds = 9:1 O OTIPS TMS CHOH BF 3 ?OEt 2 (3 equiv.) CH 2 Cl 2 , -55→ -20 °C 79% OHC OTIPS Me OHC TMSO OMe Me Me I 1. t-BuLi, THF, -78 °C 2. PPTS, MeOH 64% O OPiv + single stereoisomer O Me Me Me R 1 R 2 + HO 6 steps, 39% yield from (S)-carvone Overman: Laurencin Model Studies JACS, 1995, 117, 5958 SPh O OPiv OMe O Me PhS PivO O Et Br OAc BF 3 ?OEt 2 (2 equiv.) t-BuOMe, 0.05M -78 → -30 °C, 5h (+)-Laurencin O SPh RMe BF 3 ?OEt 2 (3.5 equiv.) t-BuOMe, 0.2M -78 → -10 °C, 4h + Me 2 BBr (2.5 equiv.) CH 2 Cl 2 , 0.05M -78 → o °C, 4h 87% 40% trace 4% 7% - O SPh RMe - - trace O Me R RO PhS H + 32C-11 3/22/99 9:42 AM Overman: Laurencin Synthesis SPh OAc O Me OPiv OMe O OAc Et PhS PivO O Et Br OAc BF 3 ?OEt 2 (3 equiv.) t-BuOMe, 0.05M -78 → -40 °C, 7h 57% ( 5 g scale) (+)-Laurencin (+)-Laurencin 24 steps, 2% yield from allyl alcohol JACS, 1995, 117, 5958 SPh OAc O Me OPiv + SPh OAc OBF 3 - Me OPiv MeOBF 3 - MeO + desired product SPh OR 1 OR 2 A: R 1 = H, R 2 = Ac B: R 1 = Ac, R 2 = H By products include the THP product (7%), internal vinyl sulfide acetals (18%) and hydroxy vinyl sulfide acetates A and B Overman: Trisubstituted Tetrahydropyrans JACS, 1999, 121, 1092 Ph OH OH + RCHO (2 equiv.) SnCl 4 (0.5 equiv.) MeNO 2 , -25 °C 25 mM OORR CHO PhPh racemic Yield of A + B 65 50 58 32 34 RCHO PhCH 2 CH 2 CHO PhCH2CHO i-PrCHO (E)-PhCH=CHCHO PhCHO B A CHO 7:3 mixture of epimers ORPh O CHOPh n Yields were considerably lower due to the formation of oligomers: 32C-12 3/18/99 10:55 PM Overman: Trisubstituted Tetrahydropyrans JACS, 1999, 121, 1092 Ph OH OHMe + RCHO CF 3 SO 3 H or SnCl 4 MeNO 2 , -25 °C OO O COMe RR R X Me OH COMe PhPh Ph racemic GC ratio of A:B 18:1 11:1 6:1 14:1 9:1 6:1 8:1 Yield of A 81 73 61 65 76 68 61 RCHO PhCH 2 CH 2 CHO MeCHO PhCH 2 CHO i-PrCHO t-BuCHO (E)-PhCH=CHCHO PhCHO with TfOH Yield of A 65 66 56 68 50 59 76 GC ratio of A:B 10:1 10:1 8:1 12:1 10:1 8:1 6:1 with SnCl 4 B C A Reaction of enantiopure starting material with isobutyraldehyde gives a 68% yield of A with >99% ee Taddei: Synthesis of 4-Halo-Tetrahydropyrans Taddei, TL, 1987, 28, 973 JOC, 1988, 53, 911 Chan,TL, 1987, 28, 3441 TMS + 2 RCHO O X RR X = Cl, BrAlX 3 R 1 CHO R 1 OTMS R 2 CHO R 1 OTMSO R 2 ? Aldehydes: acetaldehyde, propanal, hexanal, benzaldehyde Yields: 43 - 86% ? Consecutive addition of different aldehydes gives unsymmetrical products. The use of TiCl 4 minimizes the formation of symmetrical halotetrahydropyrans. Yields of unsymmetrical THPs = 41-62% ? Chan developed a similar reaction using alkoxy-allylsilanes and AlCl 3 , TiCl 4 , and SnCl 4 . -AlX 2 OTMS O R 1 + X - R 2 32C-13 3/18/99 11:01 PM Markó: Spiroketal Formation TL, 1997, 38, 2895 O RH TMS O OEt O Cl R OH ( ) n TiCl 4 CH 2 Cl 2 , 0 °C RCHO C 6 H 13 CHO (C 2 H 5 ) 2 CHCHO C 6 H 13 CHO (C 2 H 5 ) 2 CHCHO ( ) n n 1 1 2 2 Yield (%) 62 77 60 60 OR O ( ) n 1. NaBH 4 , HMPA, ? 2. HgO, I 2 CCl 4 , ?, hν 64 - 77% O H R H OTiX 3 Cl - + Markó: Synthesis of Okadaic Acid Model Fragment TL, 1997, 38, 2895 Me CHO Me Me TMS OOEt TiCl 4 , CH 2 Cl 2 , rt 59% O Me Cl Me Me OH O Me Me Me O O Me Me Me OH NaBH 4 HMPA 97% + + HgO, I 2 CCl 4 , ?, hν 61% O Me O O MeOH O O OH H H O Me H OHO 2 C Me OH Me OH H H Okadaic Acid 32C-14 3/18/99 11:06 PM Li: InCl 3 -catalyzed Prins Cyclizations TL, 1999, 54, 1627 RH O R OH InCl 3 CH 2 Cl 2 O Cl RR R Ph 4-Me-Ph 3-Me-Ph 2-Me-Ph 4-Cl-Ph 4-F-Ph 4-Et-Ph CH 3 (CH 2 ) 6 Yield (%) 81 79 76 88 70 78 73 73 ? This reaction compliments the TiCl 4 /AlCl 3 mediated reactions which give very low yields with aromatic aldehydes. Li: Sc(OTf) 3 -catalyzed Prins Cyclizations Chem.Comm., 1999, 291 RH OOH Sc(OTf) 3 CHCl 3 O OH R R Ph 4-Me-Ph 3-Me-Ph 2-Me-Ph 4-Cl-Ph 4-F-Ph 4-Et-Ph 2-F-Ph 3-F-Ph 2-Cl-Ph 3, 4-Cl-Ph 3-Br-Ph 1-napth Yield A(%) 14 18 13 20 15 16 10 19 12 13 17 14 9 O O R A B Yield B (%) 63 64 62 58 68 69 56 50 57 71 49 72 70 ? Aliphatic aldehydes are less effective in this reaction. 32C-15 3/18/99 11:10 PM Jung: Prins Reaction Catalyzed by Silyl Triflates JOC, 1997, 62, 9182 R 2 R 3 R 1 OH OH R 2 R 3 R 1 CHO OH O TBSO H R 2 R 1 Swern TBSOTf DTBMP CH 2 Cl 2 R 1 = R 2 = R 3 = Me R 1 = R 2 = Me, R 3 = Et R 1 = H, R 2 = Ph, R 3 = Me R 2 R 3 R 1 CHO OTES R 2 R 3 R 1 CHO OH TBSOTf DTBMP CH 2 Cl 2 no reaction Me Me Me OH OH Me Me Me CHO OH TBSOTf DTBMP CH 2 Cl 2 no reaction Swern TBAF R 1 = H, R 2 = R 3 = Me R 1 = R 2 = Me, R 3 = Ph 89% 84% 92% DTBMP = 2,6-di-t-butyl-4-methylpyridine Paquette: Studies toward Trixikingolide JOC, 1989, 54, 3334 H O H H OH Cl H SnCl 4 CH 2 Cl 2 , 0 °C H H OH Ph H Cl OH H OH Cl H 25% 23% 4.4% Phenylation occurred when the reaction was performed in benzene: H O H 1. Na, NH 3 , THF 2. PCC, 3? sieves "high yield" R 2 Me H R 1 Me ++ 32C-16 3/18/99 11:15 PM Paquette: Unsuccessful ring closure JOC, 1989, 54, 3334 H OMe O O H 7300 atm, 57% Me 2 AlCl, CH 2 Cl 2 H O O Me Me Me H H OMe O Me Br O O OMe O Me H O CO 2 CH 3 Me Br conformation adopted in the solid-state ? There was no reaction at atmospheric pressure using a variety of Lewis acids. ? Reaction at high pressure with stannic chloride polymerized the starting material. ? Conformation needed for desired cyclization: ? Aldol ring closure was also unsuccessful. Me CO 2 Me O H - MX n X + 32C-17 3/22/99 9:25 AM Rychnovsky: Cyclization of 4-Allyl-1,3-Dioxanes TL, 1996, 37, 8679 TiCl 4 (2 equiv.), CH 2 Cl 2 , -98 °C 95%, 95:5 i-Pr OAc O OAc i-Pr Other conditions: 1. BF 3 ?OEt 2 , HOAc, cyclohexane 2. Ac 2 O, Et 3 N, DMAP Yields: 41 - 95%, > 67:33 C 6 H 13 OAc O OAc Me Me i-Pr OH O X i-Pr X = Ph 60% X = F 26%, 2:1 1. BF 3 ?OEt 2 , HOAc, benzene 2. Ac 2 O, Et 3 N, DMAP C 6 H 13 OO C 6 H 13 OAc O Cl i-Pr i-Pr Rychnovsky: Desymmetrization of C 2 -Symmetric Diol JOC, 1997, 62, 3022 OO 1. VinylMgBr, CuI 2. CSA, CH 2 Cl 2 BnO OMe OMe 80% OO OBn OOAc OBn OAc 1. BF 3 ?OEt 2 , HOAc cyclohexane, rt 2. Ac 2 O, DMAP, Et 3 N 42-51% OO Me OOAc Me OAc 1. BF 3 ?OEt 2 , HOAc cyclohexane, rt 2. Ac 2 O, DMAP, Et 3 N 80% OOAc OBn OAc OAc Br 1. (DHQD) 2 -PYR OsO 4 , K 3 Fe(CN) 6 2. AcO Br O 67% Me O H OHOHOHOHOH OH OH O O Me Me Me OH 17-Deoxyroflamycoin no antifungal activity 17 17 11 Influence of acetal substituent: 32C-18 3/19/99 10:12 AM Rychnovsky: Hemiacetal Cyclizations TL, 1998, 39, 7271 R O O R 1 1. DIBAL 2. Ac 2 O, pyr. DMAP 80-96% CH 2 Bn O OAc R 1 O Cl CH 2 Bn I Lewis Acid O Cl C 6 H 13 OCF 3 OMeC 6 H 13 OC 6 H 13 O OH MeC 6 H 13 O OH C 6 H 13 OMe Cl Cl Ph ClCl Cl O X R 1 R 80% 79% 80% 8:1 95% 7:1 65% 1:1.5 90% 97% 3:1 91% 5:1 Using TiCl 4 , CH 2 Cl 2 , -78 °C: Using 1. TFAA, HOAc, CH 2 Cl 2 , 0 °C to rt 2. K 2 CO 3 , MeOH Cl R OH R 1 CO 2 H couple X- Rychnovsky: Synthesis of Model Phorboxazole Fragment TL, 1998, 39, 7271 Ph OH OC 5 H 11 HO O DCC, DMAP 80% OC 5 H 11 O O Ph 1. DIBAL 2. Ac 2 O, pyr DMAP, 81% OC 5 H 11 OPh OAc SnBr 4 CH 2 Cl 2 , -78 °C 75%OC5H11OPh Br + O O N O O O O Me Me Me N O O OH OMe OH R 1 R 2 R 32C-19 3/19/99 10:14 AM Mikami: Siloxy Effect Tetrahedron, 1996, 52, 7287 OSiMe 2 i-Pr Me O MeMeO 2 C OH OP O MeO 2 CH SnCl 4 , CH 2 Cl 2 -78 °C O MeO 2 C OH Me P dimethylthexylsilyl TIPS DIMS benzyl Yield (%) 48 33 67 32 R 3 SiO O O MeO H Me SnCl 4 + Proposed Transition State: O MeO 2 CH SnCl 4 , CH 2 Cl 2 -78 °C 64% yield, 4:1 cis selective R 3 SiO O O MeO H Me SnCl 4 + OP Me O MeO 2 CH SnCl 4 , CH 2 Cl 2 -78 °C P = 2,6-dichlorobenzyl MeO 2 C OH Me OP Mikami: Siloxy Effect Tetrahedron, 1996, 52, 7287 OSiMe 2 i-Pr O MeO 2 C OH O MeO 2 CH SnCl 4 , CH 2 Cl 2 -78 °C 67% yield, 3:1 cis selective Me Me Me O OMe mostly ene product OSiMe 2 i-Pr O MeO 2 CH SnCl 4 , CH 2 Cl 2 -78 °C O MeO 2 C OH 69% yield, >95% anti selective O MeO 2 CH SnCl 4 , CH 2 Cl 2 -78 °C 32C-20 3/19/99 10:19 AM