Rhodium Carbenes and C H functionalization

Transcription

1 odium Carbenes and C functionalization 2 2 δ - δ + S 3 a Me 2 C S 2 Ar lizabeth Goldstein Stoltz/eisman Lit Meeting December 15th, 2017

2 Seminar utline I. Introduction to Carbenes II. Mechanism of C insertion III. Intramolecular C insertion IV. Intermolecular C insertion V. C insertion in Synthesis VI. Further esources

3 Seminar utline I. Introduction to Carbenes II. Mechanism of C insertion III. Intramolecular C insertion IV. Intermolecular C insertion V. C insertion in Synthesis VI. Further esources

4 What is a Carbene? a neutral, divalent carbon atom with 2 unpaired electrons. Can exist in 2 electronic states: triplet or singlet. Triplet: Singlet: ground state of most carbenes can be thought of as diradicals partially filled p and sp 2 orbitals substituents on the carbene carbon can lead to a singlet ground state can be thought of as a zwitterion empty p orbital (+) and filled sp 2 hybrid orbital ( )

5 eactivity of Free Carbenes Free Carbenes undergo insertion reactions yielding a statistical mixture of products. 1 : 6 methylene must be classified as the most indiscriminate reagent known in organic chemistry von. Doering, JACS 1956, 78, hυ Me + C2 radical pair oss, JACS 1969, 91, 59 & 55.

6 Generation of Carbenes Δ, hυ, or M 2 M= Cu, Pd, hυ diazirine Base Slow C 3 C 3 C 2 + C 2 I 2 Zn/Cu Simmons-Smith eagent ZnI 2 carbenoid metal carbene

7 Generation of Metal Carbenes/Carbenoids M 2 ML n M= Cu, Pd, t 2 Copper Dust 2 t t Silberrad, J.Chem. Soc., Trans. 1906, 89, 179. Cu + 2 Δ oyori, TL 1966, 59

8 Generation of Metal Carbenes M 2 ML n M= Cu, Pd, First xample of 2 (Ac) catalyzed Diazo decomposition: 2 t 2 (Ac) 25 C t Teyssie, Tetrahedron Lett. 1973, The discovery by Teyssie and co-workers that odium (II) acetate, a binuclear rhodium compound with one available coordination site per metal center, is an exceptionally effective catalyst for a wide variety of catalytic transformations involving diazo compounds holds singular importance in the history of this developing methodology. Doyle, Acc. Chem. es. 1986, 19,

9 Why odium Carbenes Metal Carbenes are less reactive than free carbenes Lower reactivity allows for the possibility of controlling selectivity odium carbenes have become popular due to their selectivy and ease of catalyst modification Compounds are usually air-stable and are relatively easy to handle. The following catalyst classes were some of the first utilized: Ar Ar Ar P Ar X Ar 2 (Ac) carboxamidates phosphates Ar Teyssie TL 1973, 2233 Bernal, Bear Inorg. Chem. 1986, 25, 260 Doyle TL 1992, 33, 5983 & 5987 porphoryns Callot TL 1980, 21, (C) 16 2 (TFA) Doyle TL 1981, 22, 1783 Doyle Inorg. Chem. 198, 23, 368

10 asses of Carbenes Selectivity in C- insertion reactions can be tuned by electronics in the Carbene or Catalyst. Acceptor/Acceptor Acceptor Donor/Acceptor Donor/Donor Y ML n Z Y ML n Y ML n ML n increasing stability and selectivity increasing reactivity and electrophilicity More reactive carbenes can be difficult to use selectively. More stable carbenes can be difficult to form Most commonly used classes are acceptor and donor/acceptor acceptor carbenes are commonly used in intramolecular C- insertions donor/acceptor carbenes have been utilized in many asymmetric C- insertions

11 Seminar utline I. Introduction to Carbenes II. Mechanism of C insertion III. Intramolecular C insertion IV. Intermolecular C insertion V. C insertion in Synthesis VI. Further esources

12 Metal Carbenes Yates proposed that metal carbenes were transient electrophiles that could react with nucleophiles: 2 Cu Cu X X lectrophile Yates, JACS 1952, 7, Pirrung, JACS 1996, 118, δ - δ + Carbenoid Metal Carbene A stable carbene was isolated by Padwa: 2 (t-buc) Arduengo, Padwa, Snyder, JACS 2001, 123, 11318

13 lectronics of Carbenes Molecular rbital Diagram of Fischer Carbene Diagram of orbital overlap between odium complex and Carbene Donor/Acceptor carbenes are similar to Fischer carbenes. Donor/Acceptor carbenes display more σ electronic character on the carbene carbon, and more π electronic character on the metal center, resulting in more electrophilic character on the carbene carbon. Berry, Dalton Trans., 2012, 1, 700 Traditional Fischer carbenes are more stable due to the presence of a heteroatom that also lowers the electrophilicity

14 Metal Carbenes A more relevant metal carbene has been isolated and studied. This donor/acceptor type carbene has been investigated for physical and chemical properties. The isolated carbene can be utilized in stoichiometric C functionalization reactions in comparable yields first confirmation that a genuine rhodium carbene is formed under these reaction conditions (as proposed by Pirrung) xhibits similar aman vibrations to those previously observed for Fischer-type carbenes M spectroscopy reveals that the cabenoid carbon is highly deshielded. The -=C bonding framework has been shown to follow the 3-center orbital paradigm (i.e.the double bond character is distributed between the three centers (the two odiums and the carbene carbon) Berry, Dalton Trans., 2012, 1, 700. Berry, Davies Sciencexpress 2013

15 C functionalization C functionalization has become a very popular field of study recently Direct C functionalization can introduce complexity quickly C bonds are very prevalant in organic molecules Selectivity can therefore be a problem Directing groups can be utilized to improve selectivity Alternatively, sterics and electronics can be used to influence selectivity There are many different types of C functionalization C oxidations are common functionalization reactions metal carbene C functionalization proceeds through a different mechanism

16 Mechanism of C functionalization 2 C ML n Metal Carbene C- functionalization 1 2 C L n M L n M xidative Addition C- activation C X C C ML n X

17 Mechanism of C functionalization A B D X Y 2 L A B D 2 L X Y B A D Y X or Carbenoids empty p orbital interacts with the σ bond of the C bond A B D X Y 2 L bond formation may proceed as odium dissociates (top) r there may be a transfer of to odium followed by reductive elimination (bottom) Doyle, JACS 1993, 115, Taber, JACS 1996, 118, 57.

18 eactivity of odium Carbenes Insertion into bond: 2 t 2 (Ac) 25 C t Teyssie, Tetrahedron Lett. 1973, Insertion into bond: 2 C 2 2 (Ac) 80 C C 2 atcliffe, Tetrahedron Lett. 1980, 21, 31 Insertion into S bond: 2 C 2 Me BnS 2 (TPA) (2 mol%) chiral spiro phosphoric acid (2 mol%) c exane, 25 C, 5 min SBn C 2 Me up to 96% yield, 96% ee Zhu, Yu, Zhou Chem Sci. 201, 5,

19 eactivity of odium Carbenes Insertion into B bond: 2 2 (esp) 2 (1 mol%) B 3 C 2 t 1.2 equiv C % yield B 2 t Curran, JACS 2013, 135, Insertion into Si bond: 2 Si C 2 t Xu, JACS 2016, 138, [(C 2 ) 2 ] 2 (1.5 mol%) ligand (3.3 mol%) C 2 2, 23 C, 6 h 8% yield, 9% ee Si t Insertion into C bond: 2 (Ac) t t 2 Alonso, Tetrahedron 1989, 5, 69.

20 Seminar utline I. Introduction to Carbenes II. Mechanism of C insertion III. Intramolecular C insertion IV. Intermolecular C insertion V. C insertion in Synthesis VI. Further esources

21 Intramolecular C insertion C 2 Me 2 Ac C 2 Me 2 C 2 2, 23 C 8-68% yield = alkyl Competion xperiments to determine inherent selectivity: 1 C 2 Me 2 Ac 2 2 C 2 2, 23 C 1 2 C 2 Me 2 1 C 2 Me methine > methylene > methyl, potentially due to electron donating ability of alkyl groups. allylic and benzylic methylenes also disfavored due to their electron withdrawing characteristics insertion into aromatic rings occur readily appoport, J. rg. Chem. 1982, 7, Taber, JACS 1986, 108,

22 Intramolecular C insertion C 2 Me 2 Ac C 2 Me 2 C 2 2, 23 C 8-68% yield = alkyl igh selectivity for 5-membered ring formation can be explained by a highly ordered transition state: Me C 2 2 L chiral ester: = diastereoselective reaction: >8.1 dr 55 62% yield Alkyl Chain Substituents can lead to >95% diastereoselectivity The ydrogen in the ring is the one that is transfered The alkyl group is equatorial diastereoselectivity can be achieved by destabilizing one of the chair-like transition states. This can be done by using a chiral ester (see above) or substitution on the alkyl chain. appoport, J. rg. Chem. 1982, 7, Taber, JACS 1983, 105,

23 Intramolecular C insertion electron-withdrawing groups inhibit adjacent C bonds. 2 Ac 2 C 2 Me C 2 2, 23 C C 2 Me ( ) n C 2 Me n=0 no reaction n=1 no reaction n=2 6% yield ( ) n C 2 Me 8-68% yield = alkyl Stork, Tetrahedron Lett. 1988, 29, Alkoxy groups activate C bonds. 2 2 Ac Bn Bn Bn 30% yield not observed Spero, Tetrahedron 1991, 7, 1765.

24 Seminar utline I. Introduction to Carbenes II. Mechanism of C insertion III. Intramolecular C insertion IV. Intermolecular C insertion V. C insertion in Synthesis VI. Further esources

25 Intermolecular C insertion C 2 t C 2 t (II) catalyst A B t 2 C 2 t catalyst ratio (A:B:C:D) 2 (Ac) 1:8:90:1 2 (9-trp) 18:18:27:37 2 (TFA) 5:25:66: C C 2 t D Teyssie, Bull. Soc. Chim. Belg. 198, 93, 95 Intermolecular C insertions of carbenes and metal carbenoids have the reputation of being unselective, resulting usually in mixtures of products and are, therefore, considered of no synthetic significance. In addition to their lack of selectivity, the intermolecular carbenoid insertions suffer from competing secondary reactions, such as formation of formal carbene dimers. Müller, Tetrahedron 2000, 56,

26 Intermolecular C insertion MeC 2 (S-DSP) CMe S 2 Ar Me 2 C 2 cyclohexane 51% yield, 3% ee Me 2 C Ar=p (C )C 6 2 (S-DSP) 2 (S-DSP) Me 2 C 2 cyclohexane 50% yield, 83% ee Me 2 C 2 (S-DSP) cyclohexane, C Me 2 C 2 ( ) n 53 96% yield, 67 93% ee n=1,2,3 =,, Me Me 2 C ( ) n Davies, JACS 1997, 119, It was later shown that the enantioselectivity could be improved to 88 96% by performing the reaction at 10*C, with no appreciable loss in yield. Davies, JACS 2000, 122,

27 Intermolecular C insertion arly site selectivity was achieved by using heteroatom directing groups: S 2 Ar Ar=p (C )C 6 2 (S-DSP) Boc Ar 2 C 2 Me 1. 2 (S DSP) hexane, 50 C 2. TFA C 2 Me Ar up to 72% yield up to 9% ee up to 9% de Davies, JACS 1999, 121, TBS Ar 2 C 2 Me 2 (S DSP) hexane, 23 C up to 72% yield up to 92% ee up to 98% de Me 2 C Ar TBS Davies, rg. Lett. 1999, 1,

28 Intermolecular C insertion C insertion can act as a formal aldol reaction leading to syn aldol products 2 Si( 1 ) C 2 Me 2 (-DSP) (1 mol%) 2,2-dimethylbutane, 23 C 1 =thyl, n-propyl, n-butyl 2 = 1 -C 2 Me 2 C 2 Si( 1 ) 3 S 2 Ar Ar=p (C )C 6 2 (-DSP) 52 70% yield, >90% de, 92 95% ee 2 (-DSP) (1 mol%) 2 C 2 Me t Si t 2,2-dimethylbutane, 23 C =Me, 51 52% yield, >90% de, 93 9% ee Me 2 C Si t 2 (-DSP) (1 mol%) 2 C 2 Me Si(t) 2,2-dimethylbutane, 23 C 32% yield, 97% ee, 80% de Me 2 C 2 Si(t) 3 Davies, rg. Lett. 2000, 2,

29 Intermolecular C insertion C insertion can also act as a formal claisen reaction p- 2 2 (S-DSP) C 2 Me C 2 Me S 2 Ar Ar=p (C )C 6 2 (S-DSP) yield de ee Ar TMS TBDPS p- 2 C 2 Me 2 (S-DSP) 23 C 1 2 C 2 Me p 1 2 yield dr ee (major) ee (minor) Me Me 67 75: t 56 56: : Davies, rg. Lett. 2001, 3,

30 C insertion can also act as a formal michael reaction Intermolecular C insertion S 2 Ar TIPS Ar 2 C 2 Me 2 (S-DSP) Ar= p, TIPS C 2 Me Ar=p (C )C 6 2 (S-DSP) 90% yield, 2:1 dr, >90% ee Ar Si 3 Ar 2 C 2 Me 2 (S-DSP) 30 C Si 3 C 2 Me p =TIPS, TBDPS 65 66% yield, >90% de, 71 8% ee TIPS p- 2 C 2 Me 2 (S-DSP) 0 C TIPS C 2 Me 81% yield, 81:19 dr, 89% ee p- Davies, JACS 2001, 123,

31 Intermolecular C insertion Increasing eactivity due to electronics S 2 Ar Ar=p (C )C 6 2 (-DSP) Increasing reactivity due to sterics elatives rates with 2 (-DSP) Boc 26,000 2, increasing rate of reactivity Davies, Chem. Soc. ev., 2011, 0,

32 1 Me Me Me Me 2 (2 equiv) Me 2 C Me 2 C Me 2 C C 2 Me TBS TBS TBS 2 TBS Me Intermolecular Insertion 2 (-PTTL) Me 2 C Me 2 C Me 2 C DMB, 50 C TBS 76% yield, >97:3 d.r., 93% ee 58% yield, >97:3 d.r., 95% ee 86% yield, >97:3 d.r., 98% ee Me CF 3 Me Me Me TBS 92% yield, >97:3 d.r., 97% ee TBS Me Me Me Me Me 2 C 1 Me 2 C Me 2 C TBS Me 2 C TBS TBS 2 TBS 86% yield, >97:3 d.r., 96% ee 86% yield, >97:3 d.r., 97% ee Me Me 2 C Me Me 2 C 2 (-PTTL) TBS 7% yield, >97:3 d.r., 97% ee 77% yield, >97:3 d.r., 97% ee 92% yield, 9:6 d.r., 99% ee 77% yield, >97:3 d.r., 98% ee 76% yield, >97:3 d.r., 96% ee Davies, Yu JACS 2013, 135, TBS Me

33 Intermolecular Insertion Me 2 C conc., t 2 Me 2 C 2 1 TBS 1- =Me, Me, CF 3,, 0 C to 23 C 78 89% yield 1 Me 2 C Pd(Ac) 2, Li 2 C 3, I(Ac) 2 C 2 Me C 6 F 6, 100 C, 2 h 39 63% yield >13:1 r.r % ee 1 Davies, Yu, JACS 2013, 135,

34 Intermolecular C insertion The ester motif can be very important for selectivity and reactivity: C 2 C 2 t 2 2 (-BPCP) C 2 2, reflux A 2 (-BPCP) A:B yield ee Me 5: C 2 C3 13: C 2 B C 2 C 2 2 F 2 (-BPCP) C 2 2, reflux F yield ee Me 15 n.d. C 2 C Davies, JACS 201, 136,

35 Intermolecular C insertion 2 1 C 2 C 2 C 3 2 (-BPCP) (1 mol%) C 2 C 2 C C 2 2, reflux 2 (1.2 equiv) (p-) C 2 C 2 C 3 (p-) C 2 C 2 C 3 (p-) C 2 C 2 C 3 (p-) 2 (-BPCP) C 2 C 2 C 3 Ad 83% yield 91% ee 80% yield 9% ee 70% yield 93% ee 62% yield 89% ee (p-) C 2 C 2 C 3 83% yield 92% ee Piv (p-) C 2 C 2 C 3 58% yield 93% ee TBDMS (p-) C 2 C 2 C 3 77% yield 97% ee (p-) C 2 C 2 C 3 62% yield 89% ee Davies, JACS 201, 136,

36 Intermolecular C insertion 2 1 C 2 C 2 C 3 2 (-BPCP) (1 mol%) C 2 C 2 C C 2 2, reflux 2 (1.2 equiv) 2 (-BPCP) (p-) C 2 C 2 C 3 C 2 C 2 C 3 F 3 C C 2 C 2 C 3 F C 2 C 2 C 3 7% yield 88% ee 61% yield 99% ee 80% yield 98% ee 7% yield 82% ee C 2 C 2 C 3 C 2 C 2 C 3 C 2 C 2 C 3 C 2 C 2 C 3 S 1% yield 9% ee 57% yield 96% ee 6% yield 82% ee 3% yield 75% ee Davies, JACS 201, 136,

37 Intermolecular C insertion 2 C 2 C 2 C 3 (2 equiv) 2 (-BPCP) (1 mol%) C 2 C 2 C 3 C 2 2, reflux 2 (-BPCP) C 2 CC 3 C 2 Me C 2 CC 3 TBS C 2 CC 3 C 2 t 80% yield 92% ee 8% yield 58% ee 35% yield 97% ee C 2 CC 3 C 2 CC 3 C 2 CC 3 C 2 t C 2 Me 80% yield 95% ee Davies, JACS 2016, 138, % yield 97% ee 28% yield 99% ee

38 Intermolecular C insertion 2 C 2 C 2 C 3 (2 equiv) 2 (-BPCP) (1 mol%) C 2 2, reflux C 2 C 2 C 3 2 (-BPCP) C 2 CC 3 C 2 Me C 2 CC 3 C 2 Me C 2 CC 3 C 2 t C 2 CC 3 C 2 t TBS Me F 3 C 50% yield 93% ee 88% yield 98% ee 7% yield 95% ee 67% yield 98% ee C 2 CC 3 C 2 t C 2 CC 3 C 2 Me C 2 CC 3 C 2 Me C 2 CC 3 C 2 Me F 3 C Me Me Me 2 C Me 70% yield 99% ee 82% yield 99% ee 78% yield >99% ee 60% yield 89% ee Davies, JACS 2016, 138,

39 Intermolecular C insertion 2 C 2 C 2 C 3 (2 equiv) 2 (-BPCP) (1 mol%) C 2 2, reflux C 2 C 2 C 3 2 (-BPCP) C 2 CC 3 C 2 Me C 2 CC 3 C 2 Me C 2 CC 3 Me Me F 3 C C 2 t 87% yield 88% ee 8% yield 92% ee 81% yield 96% ee C 2 CC 3 C 2 CC 3 C 2 CC 3 F 3 C F 3 C C 2 Me F 3 C C 2 t 89% yield 98% ee 86% yield 97% ee 77% yield 97% ee Davies, JACS 2016, 138,

40 Intermolecular C insertion catalyst C =C 2 C 2 C 3 2 [-3,5-di(p-tBuC 6 )TPCP] (p-cf 3 ) (p-t-bu) (p-) (p-) 15:1 r.r. 1:1 d.r. 97% ee 91% yield 22:1 r.r. 2:1 d.r. >99% ee 91% yield 28:1 r.r. 55:1 d.r. 91% ee 87% yield 25:1 r.r. 20:1 d.r. 99% ee 99% yield (p-) (p-) (p-) (p-) F 27:1 r.r. 9:1 d.r. 91% ee 82% yield 18:1 r.r. 9:1 d.r. 97% ee 86% yield 18:1 r.r. 9:1 d.r. 93% ee 8% yield 18:1 r.r. 9:1 d.r. 92% ee 89% yield Davies, Musaev ature 2016, 533,

41 Intermolecular C insertion catalyst C =C 2 C 2 C 3 2 [-3,5-di(p-tBuC 6 )TPCP] (p-) (p-) TMS (p-) (p-) TMS t-bu 9:1 r.r. 9:1 d.r. 95% ee 65% yield 3:1 r.r. :1 d.r. >99% ee 0% yield 20:1 r.r. 9:1 d.r. 90% ee 85% yield 21:1 r.r. 7:1 d.r. 92% ee 83% yield (p-) t-bu Me 2 C (p-) F 3 C 2 C 2 C (p-) 3 C 2 C 2 C (p-) 16:1 r.r. 9:1 d.r. 91% ee 8% yield 18:1 r.r. 8:1 d.r. 92% ee 89% yield 30:1 r.r. 15:1 d.r. 99% ee 91% yield 19:1 r.r. 21:1 d.r. 98% ee 90% yield Davies, Musaev ature 2016, 533,

42 Intermolecular C insertion Computational studies were conducted to determine the origin behind the high selectivity observed: 2 [-3,5-di(p-tBuC 6 )TPCP] By X ray crystallography, the catalyst was determined to be D 2 symmetrical, i.e. both faces of the catalyst are the same. the ligand adopts an α,β,α,β ligand geometry computationally, the α,α,α,α ligand geometry was shown to be disfavored by 5 kcal/mol primary C bonds are not electronically activated enough for C insertion A bulky catalyst allows for selective insertion into the most accesible secondary C bond. Davies, Musaev ature 2016, 533,

43 1 2 2 Intermolecular C insertion 2 (S-TCPTAD) (1 mol%) C 2 2, 39 C Ar =C 2 C 2 CF 3 2 (S-TCPTAD) (p-) (p-) (p-) >98:2 r.r. 81% ee 86% yield 39 C 87:13 r.r. 77% ee 76% yield 0 C 96: r.r. 87% ee 65% yield 39 C 92:8 r.r. 82% ee 73% yield 0 C 98:2 r.r. 92% ee 6% yield (p-) (p-) (p-) (p-) >98:2 r.r. 83% ee 93% yield 11:89 r.r. 81% ee 9% yield >98:2 r.r. 86% ee 66% yield >98:2 r.r. 78% ee 87% yield Davies, Musaev ature 2017, 551,

44 1 2 2 Intermolecular C insertion 2 (S-TCPTAD) (1 mol%) C 2 2, 39 C =C 2 C 2 CF 3 Ar 2 (S-TCPTAD) (p-) >98:2 r.r. 8% ee 70% yield >98:2 r.r. 77% ee 90% yield (p-) 39 C 88:12 r.r. 76% ee 73% yield (p-) 0 C 91:9 r.r. 9% ee 66% yield >96: r.r. 68% ee 60% yield 98:2 r.r. 75% ee 81% yield Davies, Musaev ature 2017, 551, CF 3 >98:2 r.r. 7% ee 89% yield Me >98:2 r.r. 63% ee 9% yield

45 Intermolecular C insertion The rhodium carbene inserts selectively into the most accesible tertiary C bond: 2 (p-) C 2 C 2 CF 3 (p-) 2 (TCPTAD) C 2 C 2 CF 3 39 C >98:2 r.r. 11:1 d.r. 78% yield 2 (S-TCPTAD) (p-) 2 (p-) C 2 C 2 CF 3 C 2 C 2 CF 3 Ac 2 (TCPTAD) Ac 39 C >98:2 r.r. 11:1 d.r. 6% yield Davies, Musaev ature 2017, 551,

46 Intermolecular C insertion Computational Studies were undertaken to determine how the site selectivity arises: less sterically demanding catalyst leads to favored tertiary bond insertion tertiary bond insertion is most favored electronically X ray crystallography and computational studies show the catalyst adopts a slightly distorted C symmetric structure The steric enviornment is different on either side of the catalyst. 2 (S-TCPTAD) The rhodium face with the phtalimido groups is more accesible than the face with the adamantyl groups. a π-stacking interaction between the carbene and rhodium leads to a preferential attack at the e face of the carbene. The approach of the substrate leads to the selectivity for the most accesible tertiary C bond Davies, Musaev ature 2017, 551,

47 Seminar utline I. Introduction to Carbenes II. Mechanism of C insertion III. Intramolecular C insertion IV. Intermolecular C insertion V. C insertion in Synthesis VI. Further esources

48 Synthesis of italin threo-methylphenidate (marketed as italin, etc.) is used to treat ADD and narcolepsy. A is the active component as the 2 enantiomer S 2 Ar Ar=p (C )C 6 2 (S-DSP) Boc 2 C 2 Me 1. catalyst C 2 Me C 2 Me TFA A B cat eq. 1 DSP DSP 0.25 bidsp 0.25 yield A:B ee (A) 9 3:57 3 (2S) 86 50:50 25 (2S) 73 71:29 86 (2) Ar 2 S S 2 Ar 2 Ar=p (C )C 6 Davies, JACS 1999, 121, (S-biDSP)

49 Formal Synthesis of (+) Sertraline (+) Sertraline (Zoloft) is an antidepressant of the SSI class. Introduced by Pfizer in 1991, and still in use today. S 2 Ar Ar=p (C )C 6 2 (S-DSP) Me 2 C 2 2 (S-DSP) 1. DDQ, C 2 Me 2. 2, Pd/C 52% yield, 96% ee over 3 steps Me 1. 6 Me 2. S 3 79% yield, 96% ee Davies, rg. Lett. 1999, 1, (+) Sertraline

50 Synthesis of ()-( )-olipram ()-( )-olipram is a potent and selective phosphodiesterase type IV inhibitor. Used as a prototype molecule for drug discovery, though not used itself due to side effects and a need for high dosages. 6 steps Me 2 C 2 Me Me 2 (S-BPTTL) C 38% yield 2 Me 2 (S-BPTTL) Me 2 C steps Me 7% yield, 88% ee 2% yield ()-( )-olipram anefeld, Synlett 1999, 11,

51 Synthesis of (+)-Conocarpan (+) Conocarpan is a natural product with various biological activities TIPS 3 steps C 2 Me 2 2 (S-PTTA) C 2 Me 51% yield TIPS TIPS 2 (S-PTTA) Å MS 6 steps a 2 C 3 8% yield, 97:3 d.r., 8% e.e. Me 2 C 50% yield 71% yield ashimoto, J. rg. Chem. 2009, 7, ( ) epi-conocarpan (+) conocarpan

52 Synthesis of ( )-Indoxamycin Core Indoxamycins A Indoxamycin F C 2 C 2 2 (-PTAD) 2 C 2 Me C 2 Me 2 (-PTAD) C 2 Me Pd(Ac) 2 Ac-Gly- Ag 2 C 3 C 2 Me 55% yield, >20:1 d.r. C 2 Me 50% yield >20:1 d.r. C 2 Me Davies, Sorensen, ACI 2016, 55,

53 Synthesis of Dictyodendrins A and F A formal synthesis of Dictyodendrin A and a synthesis of Dictyodendrin F was reported utilizing a sequential C functionalization strategy. Collaboration between Davies and Itami Groups. Me I Me (C)(P[C(CF 3 ) 2 ] 3 ) 2 Me 52% yield Me Me 2 (S-TCPTAD) S 3 a Me 2 C 2 Me Me 2 C C 2 Me 7 steps Me 2 C 2 (S-TCPTAD) ;BS 70% yield Me Me 12% yield Me Dictyodendrin A Davies, Itami, JACS 2015, 137, 6 67.

54 Synthesis of Dictyodendrins A and F A formal synthesis of Dictyodendrin A and a synthesis of Dictyodendrin F was reported utilizing a sequential C functionalization strategy. Collaboration between Davies and Itami Groups. I Me Me Me (C)(P[C(CF 3 ) 2 ] 3 ) 2 52% yield Me 2 (S-TCPTAD) Me Me 2 C 2 Me Me 2 C C 2 Me 5 steps 2 (S-TCPTAD) ;BS 70% yield Me Me 3% yield Davies, Itami, JACS 2015, 137, Me Dictyodendrin F

55 Conclusions Carbene chemistry has come a long way in recent years C functionalization reactions are simplifying disconnections Discovery of odium carbenes resulted in the development of selective C functionalization reactions The electronics of the carbene carbon center and the odium catalyst serve key roles Site selectivity was first discovered by exploiting heteroatom effects More recently, tuning of the catalyst has resulted in selective insertions into unactivated C bonds C insertion reactions have been utilized in various synthetic efforts A more thorough understanding of the mechanism and electronics of the system will help drive the field further While a lot of progress has been made, many questions remain unanswered Selectivity is still a problem in many cases for this chemistry, especially in more complex systems

56 Seminar utline I. Introduction to Carbenes II. Mechanism of C insertion III. Intramolecular C insertion IV. Intermolecular C insertion V. C insertion in Synthesis VI. Further esources

57 Additional esources ther lit meetings: Uttam Tambar, Stoltz/eisman group, 200 (on the Stoltz Group Website) ian go Laforteza, 2010, Princeton, Macmillan Group Lit seminars (online) Books: Doyle, 2013, Contemporary Carbene Chemistry (specifically Chapter 12 on odium Carbenes by Davies) Doyle, 1998 Modern Catalytic Methods for rganic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides eviews: Machado, Beilstein J. rg. Chem. 2016, 12, You SC Adv., 201,, Maguire, McKervey Beilstein J. rg. Chem. 2016, 12, Davies Chem. Soc. ev., 2011, 0, Doyle Chem. ev. 2010, 110, Davies Chem. ev. 2003, 103, Doyle Chem ev. 1986, 86, 919.