A Tandem Semipinacol Rearrangement/Alkylation of a-epoxy Alcohols: An Efficient and Stereoselective Approach to Multifunctional 1,3-Diols B() 2 H H B() 2 H H Hu, X.-D.; Fan, C.-A.; Zhang, F.-M.; Tu, Y. Q. Angew. Chem., Int. Ed. Engl. 2004, 43, 1702 Michel Grenon @ Wipf Group 1 3/31/04
Presentation utline Semipinacol rearrangement of a-epoxy silyl ethers Semipinacol rearrangement of a-epoxy alcohols Lewis acids used Migrating groups Substrates scope Halonium ion induced semipinacol rearrangement Reductive rearrangement of a-epoxy alcohols (tandem semipinacol/mvp reduction) Tandem semipinacol rearrangement/tishchenko reduction of a-epoxy alcohols Tandem semipinacol rearrangement/alkylation of a-epoxy alcohols Allylation with allyl boronic acid Reaction with allenyl boronic acid Proposed transition states Michel Grenon @ Wipf Group 2 3/31/04
Semipinacol Rearrangement of a-epoxy Alcohols H H + 4 R R 5 -H 2 Lewis acid S N 2-like 1,2-migration Classical Pinacol H 3 R R 5 Semipinacol Aldol-type products are obtained, some of which are difficult or impossible to obtain according to the classical aldol reaction Highly stereoselective, the migrating group attacking anti to the epoxide The stereochemistry of the hydroxy-bearing carbon center is not important, since both diastereoisomers afford the same product Although originally developed for a-epoxy silyl ethers, work has mostly been focused on the free a-epoxy alcohols Michel Grenon @ Wipf Group 3 3/31/04
Semipinacol Rearrangement of a-epoxy Alcohols First Report TMS 4 R R 5 TiCl 4 (1.1 equiv) CH 2 Cl 2, -78 C, 10-30 min H 3 R R 5 TMS TMS H 95% and 79% TMS H 81% TMS H 79% TMS 89% BF 3 Et 2 can be used for the free alcohols Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.; Shimazaki, M.; Tsuchihashi, G.-I. J. Am. Chem. Soc. 1986, 108, 3827 Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G.-I. Tetrahedron Lett. 1987, 28, 5891 Michel Grenon @ Wipf Group 4 3/31/04
BF 3 Et 2 Promoted Semipinacol Rearrangement of a-epoxy Alcohols BF 3 Et 2 (2 equiv), -50 C to rt 70-89% C 5 H 11 Et C 5 H 11 Et H S NH HN S catalyst ZnEt 2 or ZnMe 2 (3 equiv) Ti( i Pr) 4 (1.2 equiv), cat (10 mol%) Hexanes/Toluene, rt, 40 h = Me, Et 50-65%, 96-99% ee Diastereoselective epoxydation performed with m-cpba or 2 Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9545 Michel Grenon @ Wipf Group 5 3/31/04
Semipinacol Rearrangement of a-epoxy Alcohols: Use of SnCl 4 and Reaction Scope n CH 2 Cl 2, SnCl 4 (2 equiv), 0 C n For = Me and n = 1 Migrating group ( ) Me, 56% Vinyl, 95%, 99% t-bu, 75% 2-Furyl, 75% c-c 3 H 5, 88% -C C, 58% -CH 2 CH 2, 78% Relative order of migrating ability, vinyl >> alkynyl, cyclopropyl, t-bu, alkyl > Me > H Marson, C. M.; Walker, A. J.; Pickering, J.; Hobson, A. D.; Wrigglesworth, R.; Edge, S. J. J. rg. Chem. 1993, 58, 5944 Michel Grenon @ Wipf Group 6 3/31/04
TMSTf Catalyzed Semipinacol Rearrangement of a-epoxy Silyl Ethers TMS TMS 2 R TMS H TMS TMSTf (5 mol%) CH 2 Cl 2, -78 C to -10 C 99%(91%) TMS H H 72%(12%) Bn TMS Bn TMS C 8 H 17 H C 8 H 17 TMS 92%(100%) Pr TMS H Pr 76%(62%) TMSI works also (yields in parenthesis), but is less effective for terminal epoxydes because of competitive ring-opening TMSBr can be used (1 example, 93%), but not TMSCl (17%) Suzuki, K.; Miyazawa, M.; Tsuchihashi, G.-I. Tetrahedron Lett. 1987, 28, 3515 Michel Grenon @ Wipf Group 7 3/31/04
ZnBr 2 Catalyzed Semipinacol Rearrangement of a-epoxy Alcohols ZnBr 2 (2-8 mol%) CH 2 Cl 2, rt, 0.5-14 h n n major n 94% 64% (78:22) 91% 41% (77:23) ZnCl 2 works, but AlCl 3 too reactive Formation of syn-isomer probably arises from migration onto the carbocation 60% (64:36) 55% (84:16) Tu, Y. Q.; Fan, C. A.; Ren, S. K.; Chan, A. S. C. J. Chem. Soc., Perkin Trans. 1 2000, 3791 Michel Grenon @ Wipf Group 8 3/31/04
Lanthanide Catalyzed Semipinacol Rearrangement of a-epoxy Alcohols H Yb(Tf) 3 (20 mol%) CH 2 Cl 2, rt 99% 82% Bn 100% 97% Sc(Tf) 3 and La(Tf) 3 are also effective, but longer reaction times are needed urea:h 2 2, DBU, THF, rt Si 2 :poly-l-leucine Bickley, J. F.; Hauer, B.; Pena, P. C. A.; Roberts, S. M.; Skidmore, J. J. Chem. Soc., Perkin Trans 1. 2001, 1253 Michel Grenon @ Wipf Group 9 3/31/04
Halonium Ion Induced Semipinacol Rearrangement: Synthesis of b-haloketones S N Cl Na ZnBr 2, CH 3 CN, rt, 1 min 94% Br Ar H Br Br Br 85-87% 75% 92% ther solvents: Et 2, CH 2 Cl 2, Acetone Work equally well with the cyclopentene alcohols ZnCl 2 and ZnI 2 can also be used to prepare the chloro and iodo derivatives Wang, B. M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Chen, W. M. Synlett 2003, 1497 Michel Grenon @ Wipf Group 10 3/31/04
Reductive Rearrangement of a-epoxy Alcohols Al( i Pr) 3, i-pr or THF D, 4-8 h 25-98% 80:20 to >98:2 de major minor R Al R1 H R Al H MPV Best results R H 2 Works also for cyclopentyl derivatives Side-products Tu, Y. Q.; Sun, L. D.; Wang, P. Z. J. rg. Chem. 1999, 64, 629 Michel Grenon @ Wipf Group 11 3/31/04
SmI 2 Catalyzed Tandem Semipinacol Rearrangement/ Tishchenko Reduction = Mostly SmI 2, (10-30 mol%) CH (4-8 equiv) Toluene, 80-85 C, 4-8 h 70-96% C only isomer C M H R2 M M pposite relative stereochemistry for the reduction was obtained (compared to reduction with Al( i Pr) 3 ) H M I 2 Sm SmI 2 M = Fan, C.-A.; Wang, B.-M.; Tu, Y.-Q.; Song, Z.-L. Angew. Chem., Int. Ed. Engl. 2001, 40, 3877 Michel Grenon @ Wipf Group 12 3/31/04
A Tandem Semipinacol Rearrangement/Alkylation of a-epoxy Alcohols: An Efficient and Stereoselective Approach to Multifunctional 1,3-Diols B() 2 H H B() 2 H H Key feature: Boronic acids acts as a Lewis acid in the first step, and as a nucleophile in the second Hu, X.-D.; Fan, C.-A.; Zhang, F.-M.; Tu, Y. Q. Angew. Chem., Int. Ed. Engl. 2004, 43, 1702 Michel Grenon @ Wipf Group 13 3/31/04
Allylation of a-epoxy Alcohols with Allylboronic Acid B() 2 H R 1 DCE, rt, 6 to 18 h A H B Entry Substrate Ratio Product A:B Yield (%) 1 70:30 H >99:1 75 H 2 >99:1 81 S H S 3 88:12 >99:1 69 4 85:15 80 Michel Grenon @ Wipf Group 14 3/31/04
Allylation of a-epoxy Alcohols with Allylboronic Acid B() 2 H R 1 DCE, rt, 6 to 18 h A H B Entry Substrate Ratio Product A:B Yield (%) 5 71:29 99 6 99:1 91 H 7 78:22 31:69 71 H 8 69:31 1:99 61 Michel Grenon @ Wipf Group 15 3/31/04
Reaction of a-epoxy Alcohols with Allenylboronic Acid B() 2 H R 1 DCE, rt A H B Entry Substrate Ratio Time (h) Product A:B Yield (%) 1 70:30 70 H >99:1 55 2 78 H >99:1 40 3 4 69:31 65 96 H >99:1 50:50 Michel Grenon @ Wipf Group 16 3/31/04 74 48
Proposed Transition States for the Tandem Semipinacol Rearrangement/Alkylation of a-epoxy Alcohols RB() 2 -H 2 H B R Allylation R1 Allenation H major H B R 2 4 R H R B R 2 4 R H B R 2 4 R H major H minor 1 R R 2 H B 1 R R 2 H B R 1 R R 2 H B H minor Michel Grenon @ Wipf Group 17 3/31/04
Tandem Semipinacol Rearrangement/Alkylation of a- Epoxy Alcohols: ther Applications? Extend to other allyl boronic acids B 4 R R 5 Preparation of 1,3-amino alcohols N H Nu NH Nu H Extend to oxetane alcohols R1 Michel Grenon @ Wipf Group 18 3/31/04