Silicon-Tethered reactions B A-B Duke m. fitch Evans Group Seminar March 15. 1996 Bols, M; Skrydstrup, T. Chem. Rev. 1995, 95, 1253-1277 Cycloadditions A. 5-Atom Tether Ring 2.区2 3.[5+2] B. 6-Atom Tether Ring C 7-Atom Tether Ring 1. Type I and ll Diels-Alder D. 8-Atom and Larger Tether Rings 1. Type Il Diels-Alder Radical reactions A. 5-EXo-and 6-Endo- Ring Formations 1. Trig-Cyclizations 2. Dig-Cyclizations B. 6-EXo-and 7-Endo-Ring Formations lIL Silicon Addition to double bonds A. Addition to c=c Bonds 1. Hydrosilylation Bis-silylation B. Addition to c=o bonds Ⅳ. Nucleophile Delivery 33A-013/149611:15PM
A + B A + B A B Si A Silicon-Tethered Reactions B Si Duke M. Fitch Evans' Group Seminar March 15, 1996 Review: Bols, M.; Skrydstrup, T. Chem. Rev. 1995, 95, 1253-1277. I. Cycloadditions A. 5-Atom Tether Ring 1. [4 + 2] 2. [2 + 2] 3. [5 + 2] B. 6-Atom Tether Ring C. 7-Atom Tether Ring 1. Type I and II Diels-Alder D. 8-Atom and Larger Tether Rings 1. Type II Diels-Alder II. Radical Reactions A. 5-Exo- and 6-Endo- Ring Formations 1. Trig-Cyclizations 2. Dig-Cyclizations B. 6-Exo- and 7-Endo- Ring Formations C. Others III. Silicon Addition to Double Bonds A. Addition to C=C Bonds 1. Hydrosilylation 2. Bis-silylation B. Addition to C=O Bonds IV. Nucleophile Delivery 33A-01 3/14/96 11:15 PM
Why use a silicon tether? Intramolecularity offers reduced entropic factors Higher yields Certain reactions that could not be carried out intermolecularly are possible u High Regioselectivity Function of tether length Certain cases offer route to opposite regioisomer obtained from intermolecular variant u Increased Stereoselectivity Function of tether length and steric bulk of alkyl substituents on silicon u Functional Group Protection Serves as protecting group before and after reaction Protodesilylation, Tamao oxidation, allylsilane additions, and transmetallations are possible Diels-Alder To Form 5-Atom Tether Ring 60-170°c favors exo-cyclization ieburth S M. Fensterbank, L.J. Org. Chem. 1992, 57, 5279 33A-023/149611:14PM
OH SiR2Cl O Si R R Si O R R Si O R R OH SiR2Cl O Si R R ❏ Increased Reactivity ❏ High Regioselectivity ❏ Increased Stereoselectivity ❏ Functional Group Protection ❏ Facile Refunctionalization H O Si Why use a silicon tether? - Intramolecularity offers reduced entropic factors - Higher yields - Certain reactions that could not be carried out intermolecularly are possible - Function of tether length - Certain cases offer route to opposite regioisomer obtained from intermolecular variant - Function of tether length and steric bulk of alkyl substituents on silicon - Serves as protecting group before and after reaction - Protodesilylation, Tamao oxidation, allylsilane additions, and transmetallations are possible Et3N H O Si 160 - 170 °C + R = Me 2 : 1 R = Ph R = t-Bu 1 : 4 Note: Bulkier substituent favors exo-cyclization Et3N 190 °C + R = Me 4 : 1 R = Ph R = t-Bu >20 : 1 R R R 10 : 1 Sieburth, S. M.; Fensterbank, L. J. Org. Chem. 1992, 57, 5279. 1 : 1 R Diels-Alder To Form 5-Atom Tether Ring: 33A-02 3/14/96 11:14 PM
Trans ition States Further Transformations TBAF or Occus with re entin f cefic steps Tamao oxidation: Organometallics 1983, 2, 1694 Meli R=Me, 75% over 2 steps Occurs with retention of co Stereoselectivity and Regioselectivity 80% 60: 40 mixture of isomers 1 isomer SiMex 160°c75% 2. TBAF-DMF 85% 2. TBAF-DMF 8 Stork, G: Chan, T.Y., Breault, G. A.J. Am. Chem. Soc. 1992, 114. 7578 33A-033/14965:30PM
O H H Si R R H H O Si R R Si O R R OH OH OH OH SiMe3 O SiMe2 exo SiMe2 O endo Transition States: Me Me OH vs. Further Transformations: TBAF TBAF or KF then H2O2 MeLi R = Me or Ph, 71-85% over 2 steps Occurs with retention of configuration O Ph SiMe2 R = Me, 75% over 2 steps Ph OH Tamao oxidation: Organometallics 1983, 2, 1694. R = Me, 75% over 2 steps Occurs with retention of configuration 60:40 mixture of isomers 160 °C 80% TBAF-DMF, 75 °C 65% O SiMe2 Stereoselectivity and Regioselectivity: OH 1. 160 °C 75% 2. TBAF-DMF 85% 1. 180 °C 80% Ph 2. TBAF-DMF 85% Stork, G.; Chan, T. Y.; Breault, G. A. J. Am. Chem. Soc. 1992, 114, 7578. Ph 1 isomer 33A-03 3/14/96 5:30 PM
Stork Delivers more siMe, TBAF-DMF °c75% then H2O2 80% TBAF-DMF TBAF-DMF CO Et CO,Et hen H2O2 CoEt Note ed compound is epimerized by fluoride ion in the course of desilylation other Interesting Examples from Sieburth KE.Ho 1: 1 mixture of diastereomers 46%2s06 33A-043/149611:31PM
O SiMe2 CO2Et SiMe2 O CO2Et SiMe2 O CO2Et O SiMe2 CO2Et OH CO2Et OH OH CO2Et OH CO2Et OH CO2Et OH 80 °C 90% O O O SiPh2 O O H Si Ph Ph O SiPh2 O H H O OH OH H Stork Delivers More: TBAF-DMF then H2O2 80% TBAF-DMF then H2O2 TBAF-DMF 60 °C 75% O SiMe2 Note: Selectivity in each case results from endo-addition with respect to the ester, even when the product contains four contigous cis stereocenters. This highly strained compound is epimerized by fluoride ion in the course of desilylation. 190 °C retro-Diels-Alder Bu TBAF-DMF 60 °C ‡ SiMe2 O hetero-Diels-Alder 1 isomer Bu KF, H2O2 75%, 2 steps Other Interesting Examples from Sieburth: SiMe2 O 190 °C 1:1 mixture of diastereomers Bu DDQ 46%, 2 steps 33A-04 3/14/96 11:31 PM
Silicon Connected to Diene 1 mol% Ni(acac)2 2 mol% DIBAK-H H-SiMez(NEt2) 52% z·E=94:6 1n1 KF, H2O2 ' ph Tamao, K; Kobayashi, K; Ito, Y J. Am. Chem. Soc. 1989, 111, 6478 Photochemical [2+2 Note: Similar results were obtained with a four s necessary to prevent Baeyer-Villiger oxidation R= Me n-CsH REP Formal [5+2: 1 isomer 89, 3 steps Note: Intermolecular vanant failed to react Rumbo, A; Castedo, L; Mourino, A; Mascarenas, J. L.J. Org. Chem. 1993, 58, 5585 33A-053/14965:33PM
H H SiMe2(NMe2) HO Ph Si O Ph Ph Me2Si O Ph OH OH O CO2Me R O Si Ph Ph O O Si CO2Me H R Ph Ph O O Si CO2Me H R Ph Ph + H-SiMe2(NEt2) O O BzO OH 1 mol% Ni(acac)2 2 mol% DIBAl-H benzene, 50 °C 52% Z:E = 94:6 + Et2O, r.t. 10 h O O BzO O 1 isomer KF, H2O2 75%, 3 steps Silicon Connected to Diene: xylene SiMe2 Tamao, K; Kobayashi, K; Ito, Y. J. Am. Chem.Soc. 1989, 111, 6478. ClMe2Si Photochemical [2+2]: Crimmins, M. T.; Guise, L. E. Tet. Lett. 1994, 35, 1657. O O SiMe2 O + hν, >350 nm 70-80% BzO R = n-C5H11 R = Me R = Ph H 90 : 10 85 : 15 >95 : 5 O OH 170 °C O Note: Similar results were obtained with a four atom tether. Also, for the subsequent Tamao oxidation, protection of the ketone was necessary to prevent Baeyer-Villiger oxidation. BzO 1 isomer Formal [5+2]: KF m-CPBA OH Et3N 78%, 3 steps Rumbo, A.; Castedo, L.; Mourino, A.; Mascarenas, J. L. J. Org. Chem. 1993, 58, 5585. Note: Intermolecular variant failed to react. 33A-05 3/14/96 5:33 PM
Diels-Alder To Form 6-Atom Tether Ring MeLi 72%, 2 steps 190c KEH.o 5%, 2 steps R=Me or ph exception REMO CO2Et Note: Intermolecular variant gives xylene 1: 1 ratio with opposite Diels-Alder To Form 7-Atom Tether Ring Note: With silyl ether tether Toluene MeLi 25%, 2 steps shorter tether versions ratio not determined However 1 isomer 1 isomer Shea, K. J. Zandi, K S: Staab. A. J: Carr R. Tetrahedron Let. 1990, 31 5885 33A-063/149611:22PM
O Si R R Si O R R TMS OH OH OH O Si O R t-Bu t-Bu CO2Et R O O Si EtO2C O O Si EtO2C R t-Bu t-Bu O Si O R CO2Et t-Bu t-Bu O Si O R CO2Et t-Bu t-Bu exception: TMS 72%, 2 steps 75%, 2 steps Shea, K. J.; Zandi, K. S.; Staab, A. J.; Carr. R. Tetrahedron Lett. 1990, 31, 5885. O Si Me Me Si O Me Me OH O Si O CO2Me 190 °C R = Me or Ph cis:trans = 1:1 Ph Ph MeLi R = Me KF, H2O2 R = Ph Note: In general, yields are good and regioselectivity is absolute, but stereoselectivity is poor. O Si O Diels-Alder To Form 6-Atom Tether Ring: ‡ ‡ Ph Ph CO2Me H vs. xylene 160 °C >90% R = Me or H R = H R = Me 90 10 >99 <1 O Si O : : Gillard, J. W.; Fortin, R.; Grimm, E. L.; Maillard, M.; Tjepkema, M.; Bernstein, M. A.; Glasser, R. Tetrahedron Lett. 1991, 32, 1145. Ph Ph Toluene 190 °C MeLi O Si O ratio not determined 25%, 2 steps Note: With monosilyl ether tether, reaction is slow and poor yielding in comparison to shorter tether versions. Ph Ph CO2Me H 1 isomer However: Diels-Alder To Form 7-Atom Tether Ring: 175 °C 98% 175 °C 77% 1 isomer CO2Me Note: Intermolecular variant gives 1:1 ratio with opposite regiochemistry. Note: Yields are generally high and selectivities good for 5-member silyl acetal tethers. In the case of type II Diels-Alders, regioselectivity and stereoselectivity are absolute. 33A-06 3/14/96 11:22 PM
silyl Acetal 7-Atom Tether Ring eader. J. C. Tetrahedron Lett. 19 170°c COMe CO,Me Note: Intermolecular variant gives a mixture of 4 diastereomers Craig, D. Reader, J C. Tetrahedron Lett. 1992, 33, 6165 Type ll Diels-Alder To Form 8-Atom Tether Ring H 5-200 H 1 isomer Longer Tether Pn however COMe hea, K. J: Staab A J. Zandi, K. S. Tetrahedron Lett. 1991. 32, 2715. 33A-073/149611:27PM
O O Si Me Ph Ph CO2Me R O O Si H H R CO2Me Me Ph Ph O O Si Me Ph Ph CO2Me Me O O Si H H Me CO2Me Me Ph Ph Me Me O O Si H H Me CO2Me Me Ph Ph Me Si O R2 R1 O Me Me Si O O R1 R2 Me Me O Si O O O Ph Ph O Si O O O Ph Ph Me CO2Me H CO2Me O Si O O O Ph Ph 160 - 170 °C R = H 64% R = Me 100% 1 isomer Silyl Acetal 7-Atom Tether Ring: H O Si O O O 170 °C 94% Craig, D.; Reader, J. C. Tetrahedron Lett. 1992, 33, 6165. Craig, D.; Reader, J. C. Tetrahedron Lett. 1990, 31, 6585. Craig, D.; Reader, J. C. Tetrahedron Lett. 1992, 33, 4073. 1:1 mixture of diastereomers Note: Intermolecular variant gives a mixture of 4 diastereomers. 1 : 1 Ph Ph 1 isomer 115 - 200 °C Me + R1 R2 Yield H O Si O H Me H H Me CN H H Me Ph Me Pr Longer Tethers: 98% 88% 78% 93% 65% 53% Ph Ph 1 isomer 80 °C 90% Me Shea, K. J.; Staab, A. J.; Zandi, K. S. Tetrahedron Lett. 1991, 32, 2715. O O Type II Diels-Alder To Form 8-Atom Tether Ring: however: + 70 : 30 33A-07 3/14/96 11:27 PM
Radical Cyclizations to Form 1,3-Diols 1)AC O, KF 0%, 3 steps KF, H2O2 85%, 3 steps Note: The rate of 5-exo trig- cyclization radical from 5-exo lization precludes the formation of the 6-er 1)n-Bu3SnH, AIBN R=Ph Nishiyama, H. Kitajima. T: Matsumoto, K ; Itoh, K.J. Org. Chem. 1984, 49, 2298 Transition States Other Examples 1 1)n-Bu3SnH, AIBN 33A-083/149611:36PM
Ph OH Ph O Si Br Me Me Si O Ph Me Me Ph OAc OH Ph OH OH R O Si Me Me Br R Me OH OH R Me OH OH R OH OH Transition States: O R Si Me Me R1 R2 1) Ac2O, KF 2) H2O2 O Si Me R Me R2 R1 BrCH2SiMe2Cl Me Ph O Si Br Me Me Me O KF, H2O2 Si Br Me Me Note: The rate of 5-exo trig-cyclization is markedly slower when the radical is α to silicon. Thus, 6-endo becomes a competing pathway. In the case of phenyl substitution, the stabilized benzylic radical formed from 5-exo cyclization precludes the formation of the 6-endo product. 1) n-Bu3SnH, AIBN 2) KF, H2O2 80%, 3 steps 85%, 3 steps + Ph n-Bu3SnH AIBN + R = Me R = i-Pr R = t-Bu R = vinyl R = Ph Me Ph 66% 74% 66% 52% 48% 14% - - 9% 4% OH OH 15% 16% 26% 24% 36% Nishiyama, H.; Kitajima, T.; Matsumoto, K.; Itoh, K. J. Org. Chem. 1984, 49, 2298. Me Ph Radical Cyclizations to Form 1,3-Diols: . OH OH . vs. A1,3 strain Me Ph Other Examples: 1) n-Bu3SnH, AIBN 2) KF, H2O2 85%, 2 steps OH OH 1) n-Bu3SnH, AIBN 2) KF, H2O2 94%, 2 steps 1 isomer + 5 : 1 33A-08 3/14/96 11:36 PM
Cyclic Allylic Alcohols KF, H2O2 5%, 2 steps Note: In all cases a single isomer is obta has been employed in the synthesis of branched sugars. 60%, 2 steps Ho 1)n-BuaSnH, AIBN 2)KOM-Bu, DMSO Stork. G. Sofia M. JJ. Am. Chem. Soc. 1986. 108 6826 Introduction of Angular Functionalit )n-Bu3SnH, AIBN 3 Stork, G: Mah, R. Tetrahedron Lett, 1989, 30, 3609 1)n-BujSnH, AIBN (100%) n-Bu3SnH 2)KF,H2O2(455 AIBN (100% 1)n-BU3SnH, AIBN n-Bu SnH, AIBN KF, H2O2 "Poor Yield 33A-093/14965:42PM Lejeune, J; Lallemand, J. Y. Tetrahedron Lett. 1992, 33, 2977
O O Me Si Br Si Me Me Me HO OH O O Me Si Br Si Me Me Me HO OH Me Ot-Bu H Me Ot-Bu Me Ot-Bu H HO Me Me Ot-Bu H Me Me Me Me Me O Si Br Me Me Me Me Me Me Me HO Me H Me O Si Br Me Me Me HO Me H 1) n-Bu3SnH, AIBN 2) KF, H2O2 65%, 2 steps O Br Si Me Me OH OH H HO HO H H O Br Si Me Me H OH H HO H O Br Si Me Me H OTMS H O Br Si Me Me H OH O O HO H O Br Si Me Me O H O O H O 1) n-Bu3SnH, AIBN 2) KOt-Bu, DMSO 75%, 2 steps Cyclic Allylic Alcohols: Si Me Me H O Si Me Me n-Bu3SnH AIBN KF, H2O2 75%, 2 steps n-Bu3SnH AIBN KF, H2O2 88%, 2 steps KOt-Bu, DMSO 60%, 2 steps 1) n-Bu3SnH, AIBN 2) KOt-Bu, DMSO 80%, 2 steps H Note: In all cases a single isomer is obtained, resulting exclusively from 5-exo cyclization. This methodology has been employed in the synthesis of branched sugars. O Si CH3 CH3 Stork, G.; Sofia, M. J. J. Am. Chem. Soc. 1986, 108, 6826. 1) n-Bu3SnH, AIBN 2) KF, H2O2 91%, 2 steps 3.7 : 1 + n-Bu3SnH AIBN (100%) 1) n-Bu3SnH, AIBN (100%) 2) KF, H2O2 (45%) H H H O Si CH3 H3C n-Bu3SnH, AIBN "Poor Yield" 3 : 2 + Stork, G.; Mah, R. Tetrahedron Lett., 1989, 30, 3609. ‡ . Introduction of Angular Functionality: . ‡ Lejeune, J.; Lallemand, J. Y. Tetrahedron Lett. 1992, 33, 2977. 33A-09 3/14/96 5:42 PM
Selective Hydrovinylation/Hydroacylation KOt-Bu DMSOMH o 62%, steps 62%, 2 steps KF, H2O2 nCeR E:z=1:9 50%.2 steps Tamao, K; Maeda, K. Yamaguchi, T. Ito, Y.J. Am. Chem. Soc. 1989, 111, 4984 Dig-Cyclizations AIBN 65%, 2 step 1)Ph3 SnH, AIBN Joumet, M. Malacria, M. J. Org. Chem. 1992, 57, 3085 33A-103/11966:00PM
Me Me O Me Si Br Me Me Me O Si Me Me Me Me Me OH Me Me Me OH Me Me TMS Me OH Me Me O Me OH Me Me Br Me Me O Me Si Br Me Me Me O Si Me Me Me Me n-C6H13 n-C6H13 Me OH Me Me O n-C6H13 Me OH Me Me n-C6H13 O R Si Me Me H H H O Si Me Me H H H R n-Bu3SnH AIBN MeLi 52%, 2 steps KF, H2O2 KOt-Bu, DMSO/H2O 62%, 2steps 30%, 2 steps 62%, 2 steps NBS, DMF Selective Hydrovinylation/Hydroacylation: KOt-Bu DMSO/H2O 33%, 2 steps KF, H2O2 50%, 2 steps n-Bu3SnH AIBN Tamao, K.; Maeda, K.; Yamaguchi, T.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 4984. . E:Z = 1:9 E Only . 1 isomer Dig-Cyclizations: O Me Me Si Br Me Me Si O Me Me Me Me HO Me Me HO O Me Si Br Me Me Si O Me Me Me HO Me HO O Me Me Si Br Me Me Si O Me Me Me Me HO Me Me TMS OTHP OTHP OTHP C4H9 C4H9 C4H9 O Ph Me Me Si Br Me Me HO HO Ph O TMS Me Me E:Z = 95:5 Ph3SnH AIBN Ph3SnH AIBN Si Br Me Me Ph3SnH AIBN MeLi 60%, 2 steps KF, H2O2 65%, 2 steps E Only KF, H2O2 70%, 2 steps 1) Ph3SnH, AIBN 2) KF, H2O2 85%, 2 steps HO HO TMS E:Z = 25:75 E Only 1) Ph3SnH, AIBN 2) KF, H2O2 84%, 2 steps E:Z = 35:65 Journet, M.; Malacria, M. J. Org. Chem. 1992, 57, 3085. 33A-10 3/11/96 6:00 PM
