D.A. Evans Ambiphilic Functional Groups-3: Hydrazone-Based Transformations Chem 206 http:/www.courses.fasharvardedu/-chem206/ Relevant Background Reading Hutchins, R O (1991). Reduction of C=X to CH2 by Wolff-Kishner and Other Hydrazone Methods". Comprehensive Organic Synthesis. Trost and Fleming Chemistry 206 Oxford, Pergamon Press. 8: 327 shapiro, R H (1976). Alkenes from Tosylhydrazones. Org. React (N.Y. )23 dvanced Organic Chemistry Addlington, R. M. and A. G. M. Barrett (1983). " Recent Applications of the Lecture Number 28 Shapiro Reaction. ACC. Chem. Res 16: 55 Chamberlin, and Bloom Lithioalkenes from arylsulphonyl-hydraz Ambiphilic Functional Groups-3 Org. React (N.Y. )39: 1 Hydrazone-Based Transformations Bergbreiter, and Momongan(1991). Hydrazone Anions" Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 2 Wolff-Kischner eduction Cume Question, November, 2000 Wharton Rearrangement Sorensen and coworkers recently reported the synthesis of (-)-hispidospermidin(Sorens I Eschenmoser-Tanabe Fragmentation ACS. 2000, 122, 9556). The Shapiro Reaction, along with meth a Reduction of Tosyl Hydrazones: The Alkene Walk Whitesell, was use in the construction of intermediate 3 from the indicated building blocks 1 Tosyl Hydrazone- Based Fragment Coupling The sh Bamford-Stevens reaction Reading Assignment for this Week: (-hispidospermidin Shapiro Reaction: Chamberlin, and Bloom. "Lithioalkenes from HCL,CH3CN,75% Intermediate n-BuLi(2.05equv) Intermediate arylsulphonyl-hydrazones. Org. Reactions 1990, 39: 1.(handout Wolff-Kishner Related Reactions: Hutchins, (1991).Reduction of C=X to MgBr2,78°c CH2 by Wolff-Kishner and Other Hydrazone Methods". Comprehensive Organic then add 2 Synthesis. Trost and Fleming. OXford, Pergamon Press. 8: 327. (in library) Matthew d shair Monda November 25. 2002
http://www.courses.fas.harvard.edu/~chem206/ 1 1 Me H O Me 2 O O Me Me Ph Me Me O Me Me MeO O Me Me Ph Me HO 3 Me HN R O Me H Me H H D. A. Evans Chem 206 Matthew D. Shair Monday, November 25, 2002 Reading Assignment for this Week: Ambiphilic Functional Groups–3: Hydrazone-Based Transformations Relevant Background Reading Chemistry 206 Advanced Organic Chemistry Lecture Number 28 Ambiphilic Functional Groups–3 Hydrazone-Based Transformations ■ Wolff-Kischner Reduction ■ Wharton Rearrangement ■ Eschenmoser-Tanabe Fragmentation ■ Reduction of Tosyl Hydrazones: "The Alkene Walk" ■ Tosyl Hydrazone-Based Fragment Coupling ■ The Shapiro Reaction ■ Bamford-Stevens Reaction Hutchins, R. O. (1991). "Reduction of C=X to CH2 by Wolff-Kishner and Other Hydrazone Methods". Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 8: 327. Shapiro, R. H. (1976). “Alkenes from Tosylhydrazones.” Org. React. (N.Y.) 23: 405. Addlington, R. M. and A. G. M. Barrett (1983). “Recent Applications of the Shapiro Reaction.” Acc. Chem. Res. 16: 55. Chamberlin, and Bloom (1990). “Lithioalkenes from arylsulphonyl-hydrazones.” Org. React. (N.Y.) 39: 1. Bergbreiter, and Momongan (1991). "Hydrazone Anions". Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 2: 503. Cume Question, November, 2000 Sorensen and coworkers recently reported the synthesis of (–)-hispidospermidin (Sorensen JACS. 2000, 122, 9556). The Shapiro Reaction, along with methodology developed by Whitesell, was use in the construction of intermediate 3 from the indicated building blocks 1 and 2 (eq 1). (eq 1) (–)-hispidospermidin 2,4,6-triisoproylbenzenesulfonyl hydrazine, HCl, CH3CN, 75% Intermediate A MgBr2 , -78 °C then add 2 55% Intermediate B Shapiro Reaction: Chamberlin, and Bloom. “Lithioalkenes from n-BuLi (2.05 equiv) arylsulphonyl-hydrazones.” Org. Reactions 1990, 39: 1. (handout) Wolff-Kishner & Related Reactions: Hutchins, (1991). "Reduction of C=X to CH2 by Wolff-Kishner and Other Hydrazone Methods". Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 8: 327. (in library)
D. A Evans, N. Finney Hydrazone Transformations- 1 Chem 206 Hydrazone Anions: A useful Reversed Polarity Equivalent R Me?N 1.03:2DMs A-C(+) A-C(+) R=H or alkyl nBu0cuN界rbu,N Lassaletta. J-M. et al. Tet Lett. 1992. 33 3691 J E. Baldwin, et al. JcS Chem. Comm. 1983. 1040 HcHO Wolff-Kishner Reduction Procedures Pr 1. n-BuLi NaoCH2 CH2O (HOCH2CH2)20 HoP 2. H/H2O reflux and then heat to210℃c larton D. H. R, Ives, D. A J, and Thomas B. R. J. chem. Soc. 1955. 2056. 1. n-BuLi.-78°c OCH3 For particulary hindered ketones: anhydrous hydrazine or formation of hydrazone under acid catalysis(hydrazine hydrazine dihydrochloride), then basi er these forcing conditions, saponification, epimerization, and methyl ether A-C avage can occur Mechanism R2C=N-NH R2C=N-NH R2C--NNH hydrolysis Me RnR→、一B9H J E. Baldwin. et al. JCS Chem. Comm. 1984. 1095 A-C(- RO-H
R2C N N H (RDS)* –N2 R2C H R2C H H tBu N N iPr H H A C(+) N N:– R H R O iPr HO Ph H THF R H N N:– R H i N Pr N tBu i N Pr N tBu LiO H Ph H PhCHO R H N N: R A C(–) tBu N N iPr H Me2N N CH2 A C(–) CH3CO2 Me Me Me O O R Me H H H R N R' O O CH2Cl2 Me H N NH tBu O Me OCH3 O OCH3 Me Me O O OCH3 Me Me N N H tBu O OCH3 Me Me N N tBu H H + , H2O A C(–) A C(+) R2C N NH2 R2C N NH A C(–) A C(–) OH OH RO–H RO–H Me2N N R NO2 R' H O R' NO2 R H H H Me R Me Me Me HO R2C N NH H RO A C(+) Hydrazone Transformations-1 Chem 206 Hydrazone Anions: A useful Reversed Polarity Equivalent ✔✔ (+) (–) (–) n-BuLi, 0°C 2. H+ /H2O 95% 1. n-BuLi J. E. Baldwin, et al. JCS Chem. Comm. 1983, 1040. 1. n-BuLi, -78°C J. E. Baldwin, et al. JCS Chem. Comm. 1984, 1095. 58% Lassaletta, J-M, et al.Tet. Lett. 1992, 33, 3691. (40-92%) R=alkyl or aryl R'=H or alkyl + 1. O3 ; 2. DMS For particulary hindered ketones: anhydrous hydrazine or formation of hydrazone under acid catalysis (hydrazine/hydrazine dihydrochloride), then basify. Under these forcing conditions, saponification, epimerization, and methyl ether cleavage can occur. Barton, D. H. R., Ives, D. A. J., and Thomas, B. R. J. Chem. Soc. 1955, 2056. N2H4, NaOCH2CH2OCH2CH2OH, (HOCH2CH2 )2O Wolff-Kishner Reduction Procedures reflux and then heat to 210°C + Mechanism D. A. Evans, N. Finney RT, ca. 24h hydrolysis
D. A. Evans, N. Finney Hydrazone Transformations-2 Chem 206 The Wharton Rearrangement 1. LAH Me W-K 2HH20 CHO CO2CH3 L H. Zalkow, NN. Girotra J.Org. Chem. 1964, 29, 1299 Elimination of (-Lea oups This example illustrates the 2 possible modes for the decomposition of A. BrcH2、Me BrcH2、Me H Kishner CHOH.△ Me a A-C(+) adical -B D.H. Gusyafson, W. F. Erman J. Org. Chem. 1965, 30, 1665 G. Stork et al. JACS 1977. 99. 7067 Some procedural improvements ca.40%,32pa KDA, Ko Bu, etc M Kupchan JACS 1967, 89, 6327 For stable hydrazones, strongly basic conditions favor the ionic pathway C Dupuy, J. L Luche Tetrahedron Lett. 1989, 44, 3437
Me Me O O CO2CH3 O O O Me O O Me O Me BrCH2 Me Me H N N H Br Me -B Me Me CHO –N2 –HBr BrCH2 Me NNH Me W-K –N2 Me Me CH2 O O Me O O Me H A C(–) Me Me Me Me Me OH Me Me Me Me Me O Me O Me Me Me Me O O N2H4 CH3OH, D R R R NNH R O O N Me Me Me Me H N H A C(+) NH2NH2 •H2O N2H4 Me Me Me Me OH :B OH H R R R R OH Me Me Me Me –N2 Me Me Me Me OH N NH OH Me Me Me Me A Hydrazone Transformations-2 Chem 206 L. H. Zalkow, N. N. Girotra J. Org. Chem. 1964, 29, 1299. 1. LAH 2. H+ /H2O 3. CrO3 Elimination of -Leaving Groups D. H. Gusyafson, W. F. Erman J. Org. Chem. 1965, 30, 1665. N2H4, H+ WolffKishner WolffKishner S. M. Kupchan JACS 1967, 89, 6327. ca. 40%, 3:2 b:a 76% Some procedural improvements: G. Stork et al. JACS 1977, 99, 7067. 20% For stable hydrazones, strongly basic conditions favor the ionic pathway. –N2, H• • This example illustrates the 2 possible modes for the decomposition of A. 30% The Wharton Rearrangement C. Dupuy, J. L. Luche Tetrahedron Lett. 1989, 44, 3437. KDA, KOtBu, etc. D. A. Evans, N. Finney radical pathway polar pathway
D. A. Evans, N Finney Hydrazone Transformations-3 Chem 206 Tosylhydrazones- Better Than Hydrazones R|clH NaOAC3H20 =NNHTs+ N一NH Tosylhydrazones are isolable, stable, and easily prepared The presence of the tosyl leaving group strongly biases the system towards polar reaction pathways under hydridic reducing conditions R Ts CHO NHTS LAH (XS) R-C-N一 C-N-NH THF,△ G W. Kabalka, et al. J. Org. Chem. 1975, 40, 1834 Another Interesting Leaving Group H/H2O Ph LAH OI L. Caglioti, M. Magi Tetrahedron 1963, 19, 1127 -stilbene Further refinements Very mild reduction with NaBH3CN under slightly acidic conditions(pH 4-5) No reduction in the absence of acid; carbonyl, nitro, nitrile FGs unaffected Aromatic, sterically hindered carbonyls very poor substrates A R. Chamberlin, et al. Tetrahedron Lett. 1991, 32, 1691 laBH3 CN, CH3 COz NHTS R.O. Hutchins et al. JA
TsNHNH2 LAH (xs) THF, D THF, D CHO N NHTs H N N Ts H CH3 H N NHTs H N N – H R C R NNHTs Me H – Me N N Ph Ph OR B RO NH Ts C N H R R OAc O BH O R–H R C R H N NH Ph Ph N N R Me Me R C R H N B NH Ts RO OR –N2 C H H R R NaOAc•3H2O Ph Ph N N R Me Me N N R Hydrazone Transformations-3 Chem 206 – – L. Caglioti, M. Magi Tetrahedron 1963, 19, 1127. –Ts– H + /H2O Tosylhydrazones – Better Than Hydrazones Tosylhydrazones are isolable, stable, and easily prepared. The presence of the tosyl leaving group strongly biases the system towards polar reaction pathways under hydridic reducing conditions. Further Refinements Very mild reduction with NaBH3CN under slightly acidic conditions (pH 4-5). No reduction in the absence of acid; carbonyl, nitro, nitrile FGs unaffected. Aromatic, sterically hindered carbonyls very poor substrates. NaBH3CN, CH3CO2H 94% R. O. Hutchins, et al. JACS 1973, 95, 3662. 59% G. W. Kabalka, et al. J. Org. Chem. 1975, 40, 1834. – + -stilbene LAH A. R. Chamberlin, et al. Tetrahedron Lett. 1991, 32, 1691. Another Interesting Leaving Group D. A. Evans, N. Finney
D. A. Evans Hydrazone Transformations-4 Chem 206 The Eschenmoser-Tanabe Fragmentation Tosylhydrazone Reductions: The Alkene Walk TsNHNH2, ACOH N NNHTS base H C. Djerassi, et al. JACS 1976, 98, 2275 A Eschenmoser. et al. Helv. Chem. Acta 1967. 50. 708. This has been developed into a reliable reduction N A Eschenmoser, et al. Hel. Chem. Acta 1967. 50. 2108 16 cases reported: Hutchins, et al. JOC 1975, 40, 92
N N H NaBD3CN Me TsNHN N N H H Ts NaBH3CN N N H Ts H H - + CH3 O O O H N N Ts CH3 O O CH3 Ph N NH2 O Ph N N H CH3 –N2 CH3 N O N Ph H N O CH3 N H Ts H CH3 O Ph CH2 H3C CHO D O S O Ar Me NNHTs Me Me Me Me O Me O Me Me H D Me H Me Me Me Me Hydrazone Transformations-4 Chem 206 + + + 94% HOAc Et2O, 0°C A. Eschenmoser, et al. Helv. Chem. Acta 1967, 50, 708. TsNHNH2, AcOH + The Eschenmoser–Tanabe Fragmentation CH2Cl2, RT A. Eschenmoser, et al. Helv. Chem. Acta 1967, 50, 2108. : + 68% D. A. Evans Tosylhydrazone Reductions: The Alkene Walk C. Djerassi, et al. JACS 1976, 98, 2275. 16 cases reported: Hutchins, et al. JOC 1975, 40, 923 84% 81% This has been developed into a reliable reduction base
D. A. Evans, N. Finney Hydrazone Transformations-5 Chem 206 Alkene Walk: Syntheses Sulfonylhydrazone Reductions: Alcohol Deoxygenation Eto2 CN=NCO2Et RCH2-OH Me 1. NH2NHTS, THF, 25C Ph30℃0RC4 3. NaOAC3H20 RCH2-N=N-H Mitsunobo Reaction) -HSO2Ts Compactin Wendler N. L. et al. Tet. Lett. 1982. 23. 5501 Meo MeO The stereochemical course of the hydrazone reduction may be The intervention of radicals has been implicated (again) stereospecifically transferred via the 1, 3-rearrangement DAEL 1. NH NHTS, THF, 25"C( 2 CB 3. NaOAC3H20 Maryanoff, B E, et al. Tet. Lett. 1992, 33, 5009. 10 cases reported: A Myers, et al. JACS 1997, 119, 8572
O H H MeO AcO Me O CO2Et N H H MeO AcO Me H N Ts H –HSO2Ts –OAc [H] AcO MeO H H Me H CO2Et H N H H MeO AcO Me N H RCH2 OH NO2 SO2–NHNH2 OH OH OMe MeO Bu OH Me N O OH EtO2CN NCO2Et Ph3P, –30 °C ● RCH2 H RCH2 N S O O Ar NH2 Bu H Me N O Me OMe MeO RCH2 RCH2 N N–H In● ● Me S O O– Ar Hydrazone Transformations-5 Chem 206 Sulfonylhydrazone Reductions: Alcohol Deoxygenation ~0 °C 80% 86% 86% The intervention of radicals has been implicated (again): 10 cases reported: A. Myers, et al. JACS 1997, 119, 8572. D. A. Evans, N. Finney Compactin, Wendler, N. L., et al. Tet. Lett. 1982, 23, 5501. 1. NH2NHTs, THF, 25°C Alkene Walk: Syntheses 1. NH2NHTs, THF, 25°C 2. CB 3. NaOAc•3H2O (60%) Topiramate, Maryanoff, B. E., et al. Tet. Lett. 1992, 33, 5009. The stereochemical course of the hydrazone reduction may be stereospecifically transferred via the 1, 3-rearrangement (Mitsunobo Reaction) Org Rxns Volume 29 2. Catecholborane 3. NaOAc•3H2O
D. A Evans, N. Finney Hydrazone Transformations-5 Chem 206 Tosylhydrazone-Based Fragment Coupling Stereoselective Construction of trisubstituted olefins AG. Myers, P.J. Kukkola JACS, 1990, 112, 8208. 2)Et3N, TBSOTf I TBS R-U LiN RR CF3CH2OH R /p g O CHo 4) AcOH, F3CCH20 TBS=t-BuMe SH -78→t Ratio Z: E Yield The monoalkyl azene a decomposes via a radical pathway A.G. Myers etal. JACS, A Complex Application: ASmith etal. JACS 1999, 121, 7423 TBS Meo OMet-BuLi(1.8 eq. ether,-78°c OMe as above) 82%,>201c3
R H N N TBS Ts R H O R' Li R R' LiN N TBS Ts R R' R R' N NH O CHO O O O O Me Me Me Me R' Li AcOH CF3CH2OH A RO Ph Me Me RO Me N NHSO2AR H Ph Me LI H Et Li H Me Li Me H Me CHO Me H Me H Et Li H Me CHO Me H Me Me Li Me H Bu Bu HO OH HO OH Me Me MeO OMe MeO OMe Me RO Bu Bu Me Me I MeO OMe Bu MeO OMe Me RO N Bu N TBS Ts O O O O O Me Me Me Me N N SO2Ar TBS Me Li Me H RLi Me Me H Me H Et CH3 O O O O O Me Me Me Me H Me Et Me Me H Me H Me Et O O O O O Me Me Me Me H Et Me O O O O O Me Me Me Me N Me Me H N H D. A. Evans, N. Finney Hydrazone Transformations-5 Chem 206 Tosylhydrazone-Based Fragment Coupling TBS = t-BuMe2Si– –78 °C –78 ® rt The monoalkyl azene A decomposes via a radical pathway 95% 16 cases reported: A. G. Myers etal. JACS, 1998, 120, 8891. 50:50 79% 20:1 90%, ca. 2:1 (as above) (E) Cylindrocyclophane-F t-BuLi (1.8 eq.) ether, -78 °C (73%) A Complex Application: A. Smith etal. JACS 1999, 121, 7423 A. G. Myers, P. J. Kukkola JACS, 1990, 112, 8208
D A. Evans The Shapiro Reaction -1 Chem 206 Deprotonation of the monoanion occurs predominantly at the kinetically more acidic site giving after elimination the less substituted alkene produc N2 BuLi 2. Quench TrisH、 TMEDAhexane General reviews. Trost, Ed, Comprehensive Organic Synthesis 1992, Vol 6, Chapters 4.3 92, Vol 6, Chapters 4.6. (E(z)=4:1 Shapiro, Organic Reactions 1976, Vol 23, pp 405-507 Mechanism In THF solution regiochemical ratios generally reflect the starting SOaR hydrazone geometries Bond J. Org. Chem. 1978. 43, 154 bUli bUli H 1. TSNHNH2 Grieco J. Org. Chem. 1977. 42, 1717 NR- Side Reaction Li bUlI. THF NHTS propylsulfony! (Trisyl) group is use (Roberts Tet. Let. 1981, 22, 4895 Trisyl Nemoto et al JCS. Perkin Trans. 1 1985. 927. 1. TSNHNH2 O 1.TsNHNH Regiochemistry 2. MeLi, Et0 1. TSNHNH2 via trianion 98% (2%) 2. MeLi, Et,O 1. TsNHNH2 2. LDA (5%
nBuLi nBuLi nBuLi R R’ N NHTs R R’ BuLi Me O Me Me Me Me Me O Me Me O Me H Me Me H O O N NHTs N N Li SO2Ar N N Li Li MeO NNHTs Me H Me C5H11 N TrisHN O O Me Me Me CO2Et O S O O NR H Li S NR O O Me Me Me SO2 Me Me Me N N Li SO2Ar Li THF BuLi EtO2C Me Me Me O O Me Me O H Me Me H Me O C5H11 Li Li C5H11 H Me MeO CO2Et Me Me C5H11 Li General Reviews: Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapters 4.3 . Shapiro, Organic Reactions 1976, Vol 23, pp 405-507. Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapters 4.6. the Triisopropylsulfonyl (Trisyl) group is used (Roberts Tet. Let. 1981, 22, 4895). Trisyl = (95 %) (5 %) 1. TsNHNH2 2. LDA via trianion via dianion 2. LDA 1. TsNHNH2 2. K2CO3 , D 1. TsNHNH2 Bond J. Org. Chem. 1978, 43, 154. In THF solution regiochemical ratios generally reflect the starting hydrazone geometries Grieco J. Org. Chem. 1977, 42, 1717. Nemoto et. al. JCS, Perkin Trans. 1 1985, 927. 80 % nBuLi, THF 65 % 2. LDA 1. TsNHNH2 Deprotonation of the monoanion occurs predominantly at the kinetically more acidic site giving after elimination the less substituted alkene product. (100 %) 1. TsNHNH2 2. MeLi, Et2O (98 %) (2 %) + 2. MeLi, Et2O 1. TsNHNH2 Regiochemistry –TsLi Mechanism: + N2 2. Quench 1. Strong Base D. A. Evans The Shapiro Reaction-1 Chem 206 (E):(Z) = 4:1 TMEDA/hexane + 4 : 1 Side Reaction
D.A. Evans The Shapiro Reaction-2 Chem 206 Trapping of the intermediate alkenyllithium Ts R -STBS N CO2H =12:1 Me2NCHO 81% SiMe3 "Me3SiCI >20:1(E):2) Applications Myers, J. Am. Chem. Soc. 1990, 112, 8208 c6H13 NHTris 1. TSNHNH2, TSOH TMEDA/hexane 2. nBuLi TMEDa o 82% Bloom Tet lett 1984. 25. 4901 van Tamelen J. Am. chem. soc. 1983. 105. 142 Carbonyl Transposition 1. 2.1 equiv. nBuLi NNHTris BuLi TMEDATHF 2 eq HgCl2 2. Messe 3. 1 3quiv BuLi SMe Nakai Chem Lett. 1980. 1099 75% Shapiro alternatives Me COmE COmE COmE 2.7 eq LDA 0°cTHF styrene OH Me (Juvabione)Evans J. Am. Chem. Soc. 1980, 102, 774 loroxanthin Bautikofer Helv Chim. Acta. 1983. 66. 1148
N Cl NHTris C6H13 R’ OH R SiMe3 C6H13 R’ R O Me3SiCl RCH2Br Li Cl Br+ C6H13 Li CH2R C6H13 C6H13 Br CO2 Me2NCHO C6H13 CO2H CHO C6H13 N N Me Ph H TBS Ts O O Me Me H H O O O O O O N N(TBS)Ts Li H Me Et N H H N Ts TBS Ph C4H9 Me Me Me Me NNHTris Me HO Me Me Me HO Me Me Me Me Me Me OH Me OH HO Me Me Me Me Me Me Me Me Me NNHTs Me SMe Me O Me OMe O CO2Me H H2N N Ph H CO2Me N Me OMe N Ph H CO2Me Me OMe BuLi -N2 RCHO H H Me Me O O N N Me Ph C4H9 H H O O O O O Et Me H HO Li Me Me Me C4H9 Ph Me Myers, J. Am. Chem. Soc. 1990, 112, 8208 >20:1 (E):(Z) 81 % + 2. HOAc (E):(Z) = 12:1 -"TsTBS" 1. nBuLi Aphidicolin van Tamelen J. Am. Chem. Soc. 1983, 105, 142. 82 % 2. nBuLi, TMEDA 1. TsNHNH2 , TsOH Applications D. A. Evans The Shapiro Reaction-2 Chem 206 Trapping of the intermediate alkenyllithium TMEDA/hexane 75 % loroxanthin Baütikofer Helv. Chim. Acta. 1983, 66, 1148 BusLi TMEDA/hexane -78°C 0°C 82 % Bloom Tet Lett. 1984, 25, 4901 Carbonyl Transposition 1. 2.1 equiv. nBuLi 2. MeSSMe TMEDA/THF 2 eq. HgCl2 82 % Nakai Chem. Lett. 1980, 1099 Shapiro alternatives 2.7 eq. LDA 0°C THF - styrene (Juvabione) Evans J. Am. Chem. Soc. 1980, 102, 774 3. 1 3quiv BuLi warm
D.A. Evans The Shapiro Reaction-Applications Chem 206 A Recent Aplication of the Shapiro Reaction Part B(7 points). Provide a mechanism for the transformation of intermediate B to the illustrated Cume Question, November, 2000 product 3. Use 3-dimensional represent illustrate the stereochemical asp din (Sorensen JACS 000, 122, 9556). The Shapiro Reaction, along with methodology developed by Whitesell, was use in the construction of intermediate 3 from the indicated building blocks l and 2 (eq 1) ck(S)face d C=O Me HCL,CH_CN, 75% Intermediate n-BuLi(2.05 equiv) Intermediate Me 3 Mattox-Kendall Dehydroh ation(Paquette, Reagents, Vol 5, p 3509) (eq 1) H2N-NHCO2Et Part A (8 points). Provide a mechanism for the Shapiro Reaction of I to intermediate B in the space below. Feel free to use a simplified analog of l such as 2. 2-dimethylcyclopentanone to answer this -Ar Problem: The syn relationship between Br and H renders the direct dehydrohalogenation with base BuLi(2.05 equi) unfavorable(relative to other potential reactions Solution; proceed via the hydrazone H2 AOAc. heat Eto2CH EtO2C0H BrO Eto2C
Me H O Br Me N NH EtO2C Me O Me N N EtO2C H Br H Me N N EtO2C H H Me N NH EtO2C 1 1 Me H O Me Me Me O H2N N SO2Ar H Me Me N N SO2Ar H Me Me Li 2 O O Me Me Ph Me Me O N N Me Me N N S Li Li Ar O O Me Me MeO O Me Me Ph Me HO Me Me N N Li 3 Me HN R O Me H Me H H S Ar O O Me Me Li Me H Br H O H2N–NHCO2Et Me Me MgBr Br H3O + Me Me MeO O Me Me Ph Me HO 2 O O Me Me Ph Me O Me Mg X X 3 D. A. Evans The Shapiro Reaction-Applications Chem 206 A Recent Aplication of the Shapiro Reaction Cume Question, November, 2000 Sorensen and coworkers recently reported the synthesis of (–)-hispidospermidin (Sorensen JACS. 2000, 122, 9556). The Shapiro Reaction, along with methodology developed by Whitesell, was use in the construction of intermediate 3 from the indicated building blocks 1 and 2 (eq 1). (eq 1) (–)-hispidospermidin 2,4,6-triisoproylbenzenesulfonyl hydrazine, HCl, CH3CN, 75% Intermediate A MgBr2 , -78 °C then add 2 55% Intermediate B n-BuLi (2.05 equiv) n-BuLi (2.05 equiv) Part A (8 points). Provide a mechanism for the Shapiro Reaction of 1 to intermediate B in the space below. Feel free to use a simplified analog of 1 such as 2,2-dimethylcyclopentanone to answer this question. Part B (7 points). Provide a mechanism for the transformation of intermediate B to the illustrated product 3. Use 3-dimensional representations to illustrate the stereochemical aspects of this individual step. MgBr2 , -78 °C then add 2 Front (Re) face of C=O blocked by Aryl moiety Back(Si) face of C=O attacked by Nu (eq 1) Mattox-Kendall Dehydrohalogenation (Paquette, Reagents, Vol 5, p 3509) AOAc, heat Problem: The syn relationship between Br and H renders the direct dehydrohalogenation with base unfavorable (relative to other potential reactions. Solution; proceed via the hydrazone. AOAc, heat tautomerization
