哈佛大学：《高等有机化学》（英文版）Lecture 26 B Synthetic Applications of -Diazocarbonyl Compounds

Chemistry 206 Advanced Organic Chemistry Handout 26B Synthetic Applications of a-Diazocarbony Compounds An Evans group Afternoon Seminar Krista B. goodman January 15, 1999 Matthew d. shair Monday, November 18. 2002

Matthew D. Shair Monday, November 18, 2002 Chemistry 206 Advanced Organic Chemistry Handout 26B Synthetic Applications of -Diazocarbonyl Compounds An Evans Group Afternoon Seminar Krista B. Goodman January 15, 1999

Krista beaver Synthetic Applications of a-Diazocarbonyl Derivatives Chem 206 Synthetic Applications of a-Diazocarbonyl Compounds Synthesis of a-Diazocarbonyl Compounds An Evans Group Afternoon Seminal First synthesized by Curtius in 1883 by diazotization of a-amino acids Krista Beaver January 15, 1999 Arndt-Eistert synthesis(1927) 1.(CICO)2, DMF eading references 2. CH2N2 McKervey and Ye, Chem. Rev. 1994 1091 Dtsch. Chem Doyle, McKervey and Ye, Modern Methods for Organic Synthesis with 1 Diazo Compounds, Wiley, 1998 0c19861282 Diazocarbonyl Compounds. Structure and nomenclator see Danheiser JOC 1990 1960 azocarbonyl Diazonium Acyl Transfer insertion rearrangement Badet, JOC 1993 1641 solomys 26B-011111/017:59PM

Krista Beaver Synthetic Applications of α-Diazocarbonyl Derivatives Chem 206 Synthetic Applications of α-Diazocarbonyl Compounds An Evans Group Afternoon Seminar Krista Beaver January 15, 1999 Leading References: McKervey and Ye, Chem. Rev. 1994 1091 Doyle, McKervey and Ye, Modern Methods for Organic Synthesis with Diazo Compounds, Wiley, 1998 Diazocarbonyl Compounds: Structure and Nomenclature R' R O N N acid R' R O N N ∆, hv or M R' R O cyclopropanation insertion rearrangement ylide formation Diazocarbonyl Diazonium solvolysis rearrangement displacement Synthesis of α-Diazocarbonyl Compounds • First synthesized by Curtius in 1883 by diazotization of α-amino acids R OH O • Arndt-Eistert synthesis (1927) R O N2 1. (ClCO)2, DMF 2. CH2N2 • Diazo Transfer R O R' RSO2N3, base R O R' N2 • Acyl Transfer O O N N2 O O ROH O O R N2 Arndt and Eistert, Ber. Dtsch. Chem. Ges. 1927 60B 1122 Pettit, JOC 1986 1282 Regitz, ACIEE 1967 733 Badet, JOC 1993 1641 For temporary activation of carbonyl compounds prior to diazo transfer, see Danheiser, JOC 1990 1960 R=Me, Ts, etc. 26B-01 11/11/01 7:59 PM

Krista beaver Synthetic Applications of a-Diazocarbonyl Derivatives Chem 206 Some Reactions of a-Diazocarbonyl Compounds Acid Catalyzed Reactions of Diazo compounds H SiR3 R2R Common acids include BF3. 0Et2, HE mechanism of activation is unclear for both Lewis and protic acids: CNs SeR activation may occur by protonation on C or o Aco SeR Acid-Catalyzed Reactions TFA-20°c Mander. Chem. Comm. 1971 773 Having become familiar with the peculiarities of diazoketone chemistry while preparing [other Adapted from McKervey. Chem. Rev. 1994 1090 diazomethane. d cured to s trat we aght be able mo subst ute ae gap grs p for bromine Mander, JACS 1980 6626 26B-021220994:05PM

Krista Beaver Synthetic Applications of α-Diazocarbonyl Derivatives Chem 206 R R1 N2 O R R1 O X X R R1 O H X R R1 O H OR R R1 O R2 OR R R1 O H OTs R R1 O H OCOR2 R R1 O H O2P(OR2)2 R R1 O H SR R R1 O RS SR R R1 O R2 R3 R R1 O H SeR R R1 O R2 H R R1 O AcO SeR R R1 O CNS SeR R R1 O HO OH R R1 O H NR2R3 R R1 O H SiR3 R R1 O H BR2 R R1 O H OH R R1 O H PO(OR)2 Some Reactions of α−Diazocarbonyl Compounds Adapted from McKervey, Chem. Rev. 1994 1090 Acid Catalyzed Reactions of Diazo Compounds Review: Smith, Tet. 1981 2407 H3C CH3 O N N acid H3C CH3 O N N Diazocarbonyl Diazonium Common acids include BF3•OEt2, HBF4, TFA, etc. Mechanism of activation is unclear for both Lewis and protic acids; activation may occur by protonation on C or O Acid-Catalyzed Reactions OMe O N2 O -25°C, 2 min (82%) O TFA Gibberrellic Acid Mander, JACS 1980 6626 Cl3COCO OCOCCl3 HO O N2 TFA, -20°C (96%) O O "Having become familiar with the peculiarities of diazoketone chemistry while preparing [other compounds] (and, I might add, inured to handling uncomfortably large quantites of diazomethane), it occurred to us that we might be able to substitute a diazo group for bromine." Lewis Mander Mander, Chem. Comm. 1971 773 Tet., 1991 134 26B-02 12/20/99 4:05 PM

Krista beaver Synthetic Applications of a-Diazocarbonyl Derivatives Chem 206 More Acid Catalysis B-Ketoester synthesis Olefins as nucleophiles Roskamp, JOC 1989 3258 Yields are good when R is aliphatic: moderate when aromatic Smith's cyclopentenone annulation: Ring expansion N2 BF3 OE 2 Me COE ars ca Eto2 CCHN2 Smith.T19754225 Ghosh. Chem. Comm. 19881421 Aplysin Rearrangement Substitution: BF3OEt2 ROH, BF3. 0Et2 Mander. Aust. J. Chem. 1979 1975 Thiols also work well John and thomastl 1978 995 Polyene cyclizations Tetrahydrofuran Synthesis BnO- CCHN2 Smith. JACS 1981 2009 Diastereoselectivity increases with size of independent of Lewis acid or protecting group TL 1998 8195 26B-031220994:14PM

Krista Beaver Synthetic Applications of α-Diazocarbonyl Derivatives Chem 206 Smith, TL 1975 4225 Me Me O N2 BF3•OEt2 O Me Me (40 - 65%) O Me Me Lindlar's cat. (100%) Smith's cyclopentenone annulation: More Acid Catalysis Olefins as nucleophiles: Me O N2 Me O Me Me Cl HCl (100%) Mander Jasmone O R N2 O R O OBF3 N2 O O R BF3•OEt2 Mander, Aust. J. Chem. 1979 1975 N2 O Rearrangement: Polyene cyclizations: O Me Me O Me Me 46% 12% + Smith, JACS 1981 2009 BF3•OEt2 EtO H O N2 SnCl2 EtO O R' O Me O Me Me O Me O Me Me O CO2Et R H O BF3•OEt2 Roskamp, JOC 1989 3258 Ghosh, Chem. Comm. 1988 1421 + EtO2CCHN2 (81%) Me O Me Me Me Br Aplysin (50 - 90%) β-Ketoester synthesis: Ring expansion: Yields are good when R is aliphatic; moderate when aromatic TESO O R H BF3•OEt2 BnO2CCHN2 (53 - 87%) O R OH CO2Et Angle, TL 1998 3119 N S N2 O O O Me Me CO2CH2CCl3 H N S O O O Me Me CO2CH2CCl3 H John and ThomasTL 1978 995 ROH, BF3•OEt2 RO ">60%" Thiols also work well TL 1998 8195 Diastereoselectivity increases with size of R; independent of Lewis acid or protecting group diastereoselection 3:1 - 20:1 Substitution: Tetrahydrofuran Synthesis: 26B-03 12/20/99 4:14 PM

Krista beaver Synthetic Applications of a-Diazocarbonyl Derivatives Chem 206 Substitution reactions Base-nduced reactions Kapur and Fasel, TL 1985 3875 DA is the optimal base for lithiation Pellicciari JCS Perkins /1985 493 Synthesis of a-substituted chiral acids: Ester alkylation Displacement occurs with Ingold, Nature 1950 179 tention of stereochemistry Rapoport, JOC 1985 5223 other examples, see McKervey Reaction with boranes Seyferth, JOC 1971 1379 EtO2 CCHN2, then D2O ilbert. JOC 1982 1837 (97%,100%d) Hooz, JACS 1969 6195 OBB Mechanism? n-Buli. the (61%) Wojtkowski, JOC 1971 1790 26B-041220994:24PM

Krista Beaver Synthetic Applications of α-Diazocarbonyl Derivatives Chem 206 Substitution Reactions N S H2N O O O Me Me COOH H NaNO2, Br2 N S O O O Me Me COOH H Br Br Kapur and Fasel, TL 1985 3875 Synthesis of α-substituted chiral acids: Me COOH H2N H Me N2 H O OH O Me H O Nu￾Me COOH Nu H Ingold, Nature 1950 179 (90%) Nu = Br, Cl, F Displacement occurs with retention of stereochemistry For other examples, see McKervey, Chem. Rev. 1994 1091 Deamination: N S O O O Me Me COOH H Mg Reaction with Boranes BH3 B 3 EtO2CCHN2, then D2O CO2Et D H (97%, 100% d1) O N2 Bu3B OBBu2 Bu n-BuLi, then MeI O Bu Me Hooz, JACS 1969 6195 Wojtkowski, JOC 1971 1790 (61%) Base-Induced Reactions R Li O N2 R O N2 R2 OH R1 R1 R2 O Pellicciari, JCS Perkins I 1985 493 Rapoport, JOC 1985 5223 N2 Li CO2Et CO2Et N2 O + O O O CO2Et O Rh2(OAc)4 100% + Aldol-type reactions: Ester alkylation: Gilbert-Seyferth Reagent: N2 (MeO)2OP H R1 R2 O KOt-Bu R1 R2 + Seyferth, JOC 1971 1379 Gilbert, JOC 1982 1837 LDA is the optimal base for lithiation HO N2 O MeO O CF3COOH O Mechanism? 26B-04 12/20/99 4:24 PM

Krista beaver Synthetic Applications of a-Diazocarbonyl Derivatives Chem 206 Carbenoid Reactions. The Catalysts Ligand Effects: Selectivity Review Padwa. ACIEE 1994 1797 Methine versus methyl Decomposition can be catalyzed by HaVOC Heat or light Transition metals, including Cu", rh", Mn", Fe, C o", NIO, Ni, Zn, Mo",Rul"/, d Most common catalysts Rh2(oAC)4 90:10 Copper(): CuoTf, Cu(oTf)2, CuSO4, CuX, Cu(acac)2 Cyclopropanation versus C-H Insertion: Rh2(acam)4 100:0 Rhodium(): Much milder catalyst than Cu(introduced in 1973 by Tessie) Structures generally contain bridging lgands and contain a Rh-Rh single bond Reaction pathways are highly sensitive to steric and electronic effects Rhodium Carboxylate Ac)4, Rh2(tfa)4, Rh2(oct). Rhodium Carboxamidates:Rhz(acm)4. Rh2(cap)4 Padwa and Doyle, JACS 1993 8669 Rh2(OAC)444.56 Rh2(cF3CF2CF2 CONH)4 Rh2pt)40100 Rh2(cap)4 100:0 re Competition E nents Transition Metal Catalyzed Diazo Decomposition Dipolar Cycloaddition versus C-H insertion Rh(ll) MLn B Padwa and Moody, Tet. 1993 5109 Rh2(ptb)40100 Rh2( cap)4 100:0 These results imply that the metal is involved in the transition state Doyle, Chem. Rev. 1986 919 Reaction pathways can be controlled by tuning the ligands on the metal 26B-051220994:33PM

Krista Beaver Synthetic Applications of α-Diazocarbonyl Derivatives Chem 206 O O Carbenoid Reactions: The Catalysts Rh Rh O O O O O O Me Me Me Me L L Rhodium Acetate Decomposition can be catalyzed by: Heat or light Transition metals, including CuII, RhII, MnII, FeII, CoII, Ni0, NiII, ZnII, MoII, RuII, RuIII, PdIII Most common catalysts: Copper (I): Rhodium (II): Rhodium Carboxylates: Rhodium Carboxamidates: CuOTf, Cu(OTf)2, CuSO4, CuX, Cu(acac)2 Much milder catalyst than Cu (introduced in 1973 by Tessié) Structures generally contain bridging ligands and contain a Rh-Rh single bond Rh2(OAc)4, Rh2(tfa)4, Rh2(oct)4, Rh2(tpa)4, Rh2(pfb)4 Rh2(acm)4, Rh2(cap)4, Rh2(CF3CF2CF2CONH)4 Reaction pathways are highly sensitive to steric and electronic effects Review: Padwa, ACIEE 1994 1797 LnM CR2 N2 MLn B LnM CR2 B S: N2 R2C N2 Transition Metal Catalyzed Diazo Decomposition LnM SCR2 Doyle, Chem. Rev. 1986 919 Ligand Effects: Selectivity O N2 O O O O O Rh2(OAc)4 90:10 Rh2(pfb)4 38:61 Rh2(acam)4 100:0 H3C N2 CH3 O CH3 H3C O H3C CH3 O Rh2(OAc)4 44:56 Rh2(pfb)4 0:100 Rh2(cap)4 100:0 + + Rh(II) Rh(II) Doyle, JACS 1993 958 Padwa and Doyle, JACS 1993 8669 Methine versus methyl: Cyclopropanation versus C-H Insertion: H3C O H3COC H3COC Dipolar Cycloaddition versus C-H insertion: H CH3 N2 O O Rh(II) E E O O Ar CH3 E E O O CH3 + Rh2(OAc)4 75:25 Rh2(pfb)4 0:100 Rh2(cap)4 100:0 Padwa and Moody, Tet. 1993 5109 More Competition Experiments These results imply that the metal is involved in the transition state Reaction pathways can be controlled by tuning the ligands on the metal Conclusions: 26B-05 12/20/99 4:33 PM

Krista beaver Synthetic Applications of a-Diazocarbonyl Derivatives Chem 206 Generalizations: Sigma bond insertion Tandem O-H Insertion/Claisen Rearrangement PhH,△,20 66%) 95%ee eviews O-H Insertion: Moody Tet. 1995 10811 C-H Insertion: Sulikowski Tet. Asymm. 1998 3145 When x is a heteroatom insertion is facile When x is carbon: Only intramolecular processes are generally useful 5-membered ring formation is favored in general Z-Eno Transition State Wood. JACS Order of selectivity: methine methylene methyl Wood. JAC O-H Insertion Reactions CO Me COOH PhH△18hs|Ho COmE OH R 2(OAc)4 COM COOH OMEM OMEM B-Enol transition state Ganem. JACS 1982 6787 Merck Thienamycin Process TMSO TMSo人CO2Et Rh2(oct)4 Me" PhH80°c Rh2(oAc)a, then Na (75%, 2 steps) H the most complex alkoxyphosphonate yet described Fuchs,7L19947163 26B-061220994:39PM

Krista Beaver Synthetic Applications of α-Diazocarbonyl Derivatives Chem 206 Generalizations: Sigma Bond Insertion Only intramolecular processes are generally useful • When X is a heteroatom, insertion is facile Order of selectivity: methine > methylene > methyl 5 - membered ring formation is favored in general • When X is carbon: R N2 OEt O X-H catalyst R OEt O X H Reviews O-H Insertion: Moody Tet. 1995 10811 C-H Insertion: Sulikowski Tet. Asymm. 1998 3145 O-H Insertion Reactions CO2Me OH OMEM MeO2C CO2Me N2 Rh2(OAc)4 CO2Me O OMEM CO2Me CO2Me COOH O OH COOH Ganem, JACS 1982 6787 Chorismic Acid O AcO Me H OH TMSO H H O Me O AcO Me H TMSO H H O Me EtO2C PO(OEt)2 N2 Rh2(OAc)4, then NaH (75%, 2 steps) Fuchs, TL 1994 7163 (75%) CO2Et "the most complex alkoxyphosphonate yet described" Tandem O-H Insertion/Claisen Rearrangement Me OMe O N2 O Me OH + Me OCH3 HO O O Me Wood, JACS 1997 9641 98% ee 95% ee Rh2(OAc)4 O O H Me CO2Me Me [3,3] O O H Me CO2Me Me slow fast (66%) Wood, JACS 1999, in press Me OCH3 HO O O Me Me OMe O O O Me PhH, ∆, 20 min O Me HO CO2Me Me PhH, ∆, 18 hrs Z-Enol Transition State E-Enol Transition State 47% ee (75%) The opposite enantiomer is observed! Merck Thienamycin Process NH H Me OH H N2 O O O NO2 O Rh2(oct)4 N H Me OH H O OH CO2p-NB PhH, 80 °C 100% N H OH H O S CO2 NH3 Salzmann, JACS 1980 6161 Thienamycin 26B-06 12/20/99 4:39 PM

Krista beaver Synthetic Applications of a-Diazocarbonyl Derivatives Chem 206 C-H Insertion. Reactions Generalizations: Cyclopropanation o CO-Me Reviews: Davies. Ald. Acta. 1997 107 Corey, JACS 1965 2518 For subsequent reactions: Calter, Evening Seminar 1992 Electron rich olefins work best Both concerted asynchronous and stepwise mechanisms have been propo Cyclopropanes can participate in tandem reactions (59%) Cyclopropanation Followed by rearrangement Wenkert JOC 1982 3243 OAc Et2AICI N2 (88%) (87%) COmE Rh2(oAc)4 Davies,Joc19924309;T1992 HcO Diastereoselection >99: 1 dams, JACS 1994 3296 97%ee Doyle, JACS 1994 4507 TBSO For a review of catalytic enantioselective carbene reactions, se Doyle, Chem. Rev. 1998 911 Corey, JACS 1985 5574 26B-071220/99446PM

Krista Beaver Synthetic Applications of α-Diazocarbonyl Derivatives Chem 206 C-H Insertion: Reactions Ph N N2 O S CO2Me Me Me N Ph S H H O CO2Me Me Me hv Me AcO Me H H N2 O OAc Me Me Me H H AcO Me OAc Rh2(OAc)4 O Corey, JACS 1965 2518 Wenkert, JOC 1982 3243 (59%) Rh2(OAc)4 AcO H3CO O N2 AcO H3CO AcO H3CO O O + (65%) Diastereoselection > 99:1 Adams, JACS 1994 3296 BnO O N2 O BnO Rh2(5R-MEPY)4 O O BnOH2C OBn 97% ee O O BnOH2C OBn 50% ee Diastereoselection 93:7 Doyle, JACS 1994 4507 + For a review of catalytic enantioselective carbene reactions, see: Doyle, Chem. Rev. 1998 911 Generalizations: Cyclopropanation R N2 OEt O catalyst R OEt O R2 R1 R1 R2 + Electron rich olefins work best Both concerted asynchronous and stepwise mechanisms have been proposed Cyclopropanes can participate in tandem reactions Reviews: Davies, Ald. Acta. 1997 107 Davies, Tet. 1993 5203 For subsequent reactions: Calter, Evening Seminar 1992 Cyclopropanation Followed by Rearrangement Rh2(oct)4 MeO2C N2 OEt H CO2Me OEt EtO CO2Me Davies, JOC 1992 4309; TL 1992 453 TBSO Me O O TBSO O Me O H TBSO O Me O H Et2AlCl (80%) TBSO O Me O O O OH Me HO H CO2Me Antheridic Acid Corey, JACS 1985 5574 Cu(TBS)2 (84%) (87%) Et2AlCl (88%) N2 26B-07 12/20/99 4:46 PM

Krista beaver Synthetic Applications of a-Diazocarbonyl Derivatives Chem 206 More cyclopropanation Reaction with Aromatic Rings COMe (79%) COzMe Rh( TBSP Buchner, Debigs Ann Chem. 1893 214 Davies,T19948939 Initial experiments gave poor selectivity, but transition metals help OEt (35%) C-0 DMB Wood. JACS 1997 9461 Tessie. Chem. Comm 1980 765 Joc1981873 Buchner Reaction: Confertin Synthesis Rh2( S-TBSP)4 Rh2(mandelate)4 94%ee CO2 Me vies,TL19937243 KMnO4, NalO Kervey, Chem. Comm. 1988 1028 JCS Perkins /1991 2565 cO,Me LiCuCnAr2 COMe Confertin Corey,L19945373 26B-081220994:59PM

Krista Beaver Synthetic Applications of α-Diazocarbonyl Derivatives Chem 206 H Davies, TL 1994 8939 More Cyclopropanation N H N H N O O DMB N2 Rh2(OAc)4 pinacolone 120°C N H N H N O O DMB N H N H N O DMB Wood, JACS 1997 9461 Rh2(TBSP)4 Ph CO2Me N2 Me Ph CO2Me 90% ee Staurosporine + (62%) Me CO2Me Ph Me (79%) Corey, TL 1994 5373 Ph OMe N2 O Rh2(S-TBSP)4 94% ee 1. KMnO4, NaIO4 2. Me2SO4, K2CO3, acetone Li2CuCnAr2 CO2Me CO2Me Cl Cl 1. 6N HCl, ∆ 2. ClSO3H Cl Cl O + Davies, TL 1993 7243 (79%) (97%, two steps) (84%) (82%) H CO2Me Ph Ph H CO2Me CO2Me Ph Reaction with Aromatic Rings • Discovered by Büchner (1893) N2 OEt O E E Büchner, Liebigs Ann. Chem. 1893 214 Doering, JACS 1956 5448 • Initial experiments gave poor selectivity, but transition metals help... OCH3 N2 OEt O ∆ E H3CO + 6 other products N2 OEt O E H3CO Rh (II) + E OCH3 + Tessié, Chem. Comm. 1980 765 (35%) (73%) JOC 1981 873 hv Büchner Reaction: Confertin Synthesis AcO Me N O 2 Me Me AcO Me O Rh2(mandalate)4 Me O Me OTBS H Me Me O H O H H Me Confertin McKervey, Chem. Comm. 1988 1028 JCS Perkins I 1991 2565 26B-08 12/20/99 4:59 PM

Krista beaver Synthetic Applications of a-Diazocarbonyl Derivatives Chem 206 Dipolar Cycloadditions: Carbonyl Ylides Ylide formation TMSO Reviews: Padwa. Chem. Rev. 1991 263 Merck,T19949185 Zaragozic Acid Skeleton Padwa. Chem. Rev. 1996 223 Barnes, Evening Seminar, March 16, 1993 is generally s, o or N and can be NRh2(OAc)4 Hides often undergo sigmatropic rearrangements or cycloadditions Et [2, sig Dauben JOC 1993 7635 人人 Rh2(oAc)4 Moc Kido and Kato, JCS Perkins 1 1992 229 Acorenone B Padwa. JOC 1995 2704 Stevens Rearrangement ([1, 2]alkyl shift Rh2(oAc)4 West, JACS 1993 1177 Vindoline skeleton Padwa. JOC 1995 6258 26B-091220995:14PM

Krista Beaver Synthetic Applications of α-Diazocarbonyl Derivatives Chem 206 Ylide Formation R N2 OEt O R2X catalyst R X OEt O R R X is generally S, O or N and can be sp2 or sp3 hybridized Ylides often undergo sigmatropic rearrangements or cycloadditions Reviews: Barnes, Evening Seminar, March 16, 1993 Padwa, Chem. Rev. 1991 263 Padwa, Chem. Rev. 1996 223 [2,3]-Sigmatropic rearrangement: Stevens Rearrangement ([1,2] alkyl shift): R2 N N2 R1 O Rh2(OAc)4 N O R1 R2 N O R2 R1 West, JACS 1993 1177 OMe SPh O N2 O S Ph O E SPh E O Rh2(OAc)4 Acorenone B Kido and Kato, JCS Perkins 1 1992 229 H H Dipolar Cycloadditions: Carbonyl Ylides O CO2Et N2 O H H H OAc Me Me H H O O CO2Et H AcO Me Me H H O CO2Et O Me Me AcO H Dauben, JOC 1993 7635 O R O MeO2C N2 TMSO Rh2(OAc)4 O R O MeO2C TMSO O R O MeO2C Merck, TL 1994 9185 TMSO (66%) Tigilane Skeleton Zaragozic Acid Skeleton Rh2(OAc)4 (86%) N N O OMe Me O N2 O Bz N Bz O N MeO2C O Me N Bz N O MeO2C O Me H H Rh2(pfb)4 N N O Et Me CO2Me O N N O Et Me CO2Me O O N O O CO2Me N2 Et N Me Rh2(OAc)4 (95%) Padwa, JOC 1995 6258 Padwa, JOC 1995 2704 Lysergic Acid Skeleton Vindoline Skeleton (93%) 26B-09 12/20/99 5:14 PM