Chiral Allenes C Oac C Co2me Andrew M

y a C C z C

Orthogonal Bonding

Enantioselective Synthesis of

O Axial Chiral Allenes C OAc C CO2Me Andrew M. Harned Monday, May 1, 2006 OPh OAc 8 pm O O HO OH 147 Noyes O

NPh Pd(PPh3)4 D-camphorsulphonic R2 Ph NPh MsO CO (200 psi) R1 acid R2 C C 3 Ph Ph 1 THF, R OH H 3 Benzene, heat R CO2R HO NPh NPh Ph rt 5 examples 80-86% yield [α]5461 = +437º 95% ee 80-93% ee Axial Chiral Allenes: Useful Curiosities

1) The basics of Allenes and Axial Chirality

a) A brief history of allenes b) Spectroscopy c) Types of chiral allenes d) General axial chirality e) Natural products with axial chiral allenes f) Allenes as Pharmaceutical Agents

2) Methods of Synthesizing Axially Chiral Allenes a) Propargyl alcohol derivatives b) Elimination from allylic compounds c) Stiochiometric chiral reagents c) Kinetic resolution d) Catalytic methods

3) Conclusions

General Allene Reviews: (General reviews) Taylor, D. R. Chem. Rev. 1967, 67, 317-359. Pasto, D. J. Tetrahedron 1984, 40, 2805-2827. (Electrophilic additions to allenes) Smadja, W. Chem. Rev. 1983, 83, 263-320. (Synthesis with organometallics) Krause, N.; Hoffmann-Röder, A. Tetrahedron 2004, 60, 11671-11694. (Synthesis of allenic esters) Miesch, M. Synthesis 2004, 746-752. (Pd reactions of allenes) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Hkan, F. A. Chem. Rev. 2000, 100, 3067-3125. (Selective reactions with transition metals) Hashmi, A. S. K. Angew. Chem. Int. Ed. 2000, 39, 3590-3593. Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis; Wiley & Sons: New York, 1984. The Chemistry of the Allenes; Landor, S. R., Ed.; Academic Press: New York, 1982. The Chemistry of Ketenes, Allenes and Related Compounds; Patai, S., Ed.; The Chemistry of Functional Groups; Wiley & Sons: New York, 1980. Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004. Bruneau, C.; Renaud, J.-L. Allenes and cumulenes. In Comprehensive Organic Functional Group Transformations II; Katritzky, A. R., Taylor, R. J. K., Eds.; Elsevier: Oxford, 2005. A Brief History of Allenes

1874-1875: Jacobus H. van't Hoff predicts the correct structures of alenes and cumulenes as well as their axial chirality (La Chemie dans l'Espace, Bazendijk: Rotterdam, 1875).

1887: In an attempt to prove the nonexistence of these compounds, B. S. Burton and H. von Pechmann report the first synthesis of an allene (Ber. Dtsch. Chem. Ges. 1887, 20, 145-149). The paucity of analytical techniques make it very difficult to distinguish from the corresponding alkynes, and the structure is not proven (E. R. H. Jones, G. H. Mansfield, M. L. H. Whiting J. Chem. Soc. 1954, 3208-3212) for almost 70 years!

1924: First naturally occuring allene, pyrethrolone, characterized by H. Staudinger and L. Ruzicka (Helv. Chim. Acta 1924, 7, 177).

HO O

C Me Pyrethrolone Me

1935: First axially chiral allene synthesized by P. Maitland and W. H. Mills (Nature 1935, 135, 994; J. Chem. Soc. 1936, 987-998).

NPh D-camphorsulphonic acid Ph NPh Ph Ph C [α]5461 = +437º HO NPh Benzene, heat NPh Ph

1952?: First cyclic allenes synthesized by A. T. Blomquist, R. E. Burge, Jr. and A. C. Sucsy (J. Am. Chem. Soc. 1952, 74, 3636- 3642; J. Am. Chem. Soc. 1952, 74, 3643-47). Ring sizes above nine can be isolated. 1,2-Cyclooctadiene can be detected in small amounts at low temperatures. Ring sizes of seven or below cannot be isolated or detected. Their intermediacy has been determined through trapping/degradation studies. M. Regitz and coworkers have described a stable six membered cyclic allene, but is not a hydrocarbon (Angew. Chem. Int. Ed. 2000, 39, 1261-1263). Structure and Spectroscopy of Allenes

IR Spectroscopy: The diagnostic stretch can be found at 2000-1900 cm-1 (C=C=C asymm. stretch) and is usually strong. For comparison, alkynes are at 2260-2100 cm-1 and olefins are at 1690-1635 cm-1. Only other functional groups near this range are: diazo, cyanates, isocyanates, thiocyanates, isothiocyanates, and ketenes; but are typically at slightly higher wavenumbers.

1H NMR Spectroscopy: Typically in the same area as olefinic protons, but slightly upfield (~4.4 - 4.9 ppm).

13C NMR Spectroscopy: Cα and Cγ are more upfield than typical olefin (~73 - 120 ppm). Cβ is actually slightly more downfield than a ketone! (200-220 ppm)

a y

sp2 Cα Cβ Cγ

b z

O y a O N(i-Pr)2 C H C z TMS C C O

b PhHN O

Orthogonal Bonding Schultz-Fademrecht, C.; Wibbeling, B.; Fröhlich, R.; Hoppe, D. Org. Lett. 2001, 3, 1221-1224. Structure and Spectroscopy of Allenes

1H NMR Spectroscopy: Typically in the same area as olefinic protons, but slightly upfield (~4.4 - 4.9 ppm).

13C NMR Spectroscopy: Cα and Cγ are more upfield than typical olefin (~73 - 120 ppm). Cβ is actually slightly more downfield than a ketone! (200-220 ppm)

a y

sp2 Cα Cβ Cγ

b z

a O N(i-Pr)2 H y z TMS C O b PhHN O

Orthogonal Bonding Schultz-Fademrecht, C.; Wibbeling, B.; Fröhlich, R.; Hoppe, D. Org. Lett. 2001, 3, 1221-1224. Types of Chiral Allenes

Asymmetric allenes (no element of symmetry)

A B H H H H H A D A D D • • • • • A A A A H H B A B E D D D B B B D B (S) (R)

Dissymmetric allene (C2 proper axis of rotation)

A A H H • • A D B B D B A B (S) (S)

Chiral Allene Reviews: Rossi, R.; Diversi, P. Synthesis 1973, 25-36. Runge, W. Stereochemistry of Allenes. In The Chemistry of Allenes; Landor, S. R., Ed.; Academic Press: New York, 1982; 580-678. Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis; Wiley & Sons: New York, 1984, 1-8. Hoffmann- Röder, A.; Krause, N. Angew. Chem. Int. Ed. 2002, 41, 2933-2935. Ohno, H.; Nagaoka, Y.; Tomioka, K. Enantioselective synthesis of Allenes. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; 141-181. Types of Chiral Allenes

Asymmetric allenes (no element of symmetry)

A B H H H H H A D A D D • • • • • A A A A H H B A B E D D D B B B D B (S) (R) Not covered Allene is not stereogenic

Dissymmetric allene (C2 proper axis of rotation)

A A H H • • A D B B D B A B (S) (S)

1 1 CO H 2 CH3 HO C H 4 3 2 4 3 H CH 3 • C4H9 CO2H C H CH CCW = (S) 4 9 3 C4H9 H 2 2 CCW = (S) R = M S = P

Predicting absolution configuration and magnitude of rotation (Lowe-Brewster Rule)

J. H. Brewster (Topics in Stereochemistry, 1967, 2, 1-72): Through mathematical models, the actual optical rotation of optically pure chiral allenes can be calculated. At one time this was a very common method to determine approximate optical purity (i.e. % ee). Not very amenable to more complicated systems, and has now been supplanted by GC, HPLC, and NMR methods.

G. Lowe (J. Chem. Soc., Chem. Commun., 1965, 411-413):

The absolute configuration can be assignned based on the sign (+ or -) of rotation. From this, you can then assign S or R.

A Most polarizable group A is placed at the top. If Y is more polarizable than X, the allene will X Y be dextrorotatory (+). If X is more polarizable than Y, the allene will be levorotatory (-).

B General Axial Chirality Determining configuration

1 1 CO2H CH3 4 3 HO2C H 4 3 • H CH3 C4H9 CO2H C4H9 CH3 C H H CCW = (S) 2 4 9 2 CCW = (S) R = M S = P

Predicting absolution configuration and magnitude of rotation (Lowe-Brewster Rule)

G. Lowe (J. Chem. Soc., Chem. Commun., 1965, 411-413):

The absolute configuration can be assignned based on the sign (+ or -) of rotation. From this, you can then assign S or R.

Ph CO2H Cl

H Ph HO2C Ph Me t-Bu

H H H (+)-S (-)-R (-)-S Allenes as Natural Products Not just curiosities anymore CO Me 2 H H Br O O H NH3 C C H nC8H17 C H C CO2 OH Br O H H HO H ~80% ee Et Isolaurallene "Grasshopper Ketone" Insect Pheromone

OH H HO O H H H O C C C H O H H OH Br HO Mimulaxanthin Okamurallene C

AcO OAc C H O OH H HN O C C O O C OAc O O O O H Isodihydrohistrionicotixin Acalycixeniolide E Nicotine acetylcholine receptor active Anti-angiogenic

About 150 Natural Allenes are known. Most are chiral but not necessarily enantiopure. Krause, N.; Hoffmann-Röder, A. Allenic Natural Products and Pharmaceuticals. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; 997-1039. Allenes as Pharmaceutical Agents Not just curiosities anymore

H CO2Na O CO2 C C CO2Me C NH3 OH OPh HO OH OH

Enprostil Vitamin B6-dependent OH OH Gastric acid inhibitor decarboxylase inhibitor (suicide substrate) Anti-thrombotic agent

O NH2 NH2 P(OEt)2 N C N N

O N N N

H C H C OH OH MeO H H (R)-Cytallene (R)-Adenallene Sterol biosynthesis inhibitor (AIDS-related pathogen) Inhibitors of HIV and Hepatitis B replication

Krause, N.; Hoffmann-Röder, A. Allenic Natural Products and Pharmaceuticals. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; 997-1039. Chirality Transfer from Propargylic Alcohols

A) Copper-Mediated Methods Alkylation Halogenation

B) Rearrangements

D) SN2' reactions

C) Palladium (0)-Mediated Methods

anti-elimination Nu R3 R3 Nu R1 Nu R1 R1 2 2 C R R R2 R3 LG LG

syn-elimination

3 1 R R 3 1 Z Nu R2 1 R R 3 R 2 R C R R2 O Nu OH Z Nu The Beginnings

3 R 4 1 3 R1 LiCuR 2 R R R2 C R2 R4 OAc

Rona, P.; Crabbé, P. J. Am. Chem. Soc. 1969, 91, 3289-3292.

anti-elimination

2 2 R R 2 Cu R 1 1 2 Red. R MCuR2 R Cu R Elim. R2 2 H R1 R1 H C C H H LG LG H H

Luche, J.-L.; Barreiro, E.; Dollat, J.-M.; Crabbé, P. Tetrahedron Lett. 1975, 4615. Dollat, J.-M.; Luche, J.-L.; Crabbé, P. J. Chem. Soc., Chem. Comm. 1977, 761-762.

Many studies with steriodal stystems. Complications due to racemization of product by dialkyl cuprates. Proparglyic Esters nonsteriodal, acyclic allenes

1 R R2CuBr MgBr LiBr R2 ⋅ ⋅ R1 H C [{RCuX}M] H LG H

R1 = Ph, t-Bu, octyl, Me 70-96% yield >98% anti-selectivity LG = OS(O)Me or OSO2Me

R2 R2 X R2 X 1 III R 2 2 [R CuX][MgX] 1 1 Cu R R Cu R Cu - LG R1 H H H C H LG H LG LG

- CuIX L Cu R

2 d R xz px R1 R1 C H C C H H H π π* σ* O Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726-3730.

Corey Tetrahedron Lett. 1984, 25, 3063-3066 Proparglyic Esters

CBr4 Cu CO2Me PPh , Pyr PO 3 3 CO2Me PO C 3 H THF 88% H 97% Br (R) 4 steps >94% ee 25 D-Mannitol TBDPSO [α] D -63.8° (c = 0.43, MeOH) 62% OH >97% ee

Cu CO2Me TsCl, Et N PO 3 3 H PO C CH Cl 2 2 OTs 96% CO2Me 99% H 3 (S) >94% ee 25 [α] D +65.0° (c = 0.34, MeOH)

TBDPSO TBAF HO CO2Me CO2Me Antifungal constituent from C 3 C 3 Sapium japonicum H H H THF H lit. [α] D -51.3° (c 0.94, CHCl ) 98% 12 3 [α]25D -53.4° (c = 0.31, CHCl3)

Gooding, O. W.; Beard, C. C.; Jackson, D. Y.; Wren, D. L.; Cooper, G. F. J. Org. Chem. 1991, 56, 1083-1088. Enantioenriched Propargyl Alcohols

CBr4, PPh3 O (R)-Alpine borane OH Pyr, THF, 20 °C Br

PO C H THF, 20 °C PO C H 63% PO C H 7 15 63% 7 15 7 15 OP = OSit-Bu2Ph 88% ee

LiBr, Cu2I2 H H N N Me MeMgBr Me C C C8H17O O THF, 0 °C PO S C7H15 80% C7H15 52% ee liquid crystalline properties

Zab, K.; Kruth, H.; Tschierske, C. J. Chem. Soc., Chem. Comm. 1996, 977-978.

O OH a) BuLi, 2.5 mol% [(p-cymene)RuCl2]2 THF, -78 °C (S,S)-TsDPEN, KOH, i-PrOH b) MsCl C 75% c) MeCuCNMgBr Ph Ph Ph 71% Me >95% ee >95% ee

Buisine, O.; Aubert, C.; Malacria, M. Synthesis 2000, 985-989. Enantioenriched Propargyl Alcohols

CBr4, PPh3 O (R)-Alpine borane OH Pyr, THF, 20 °C Br

PO C H THF, 20 °C PO C H 63% PO C H 7 15 63% 7 15 7 15 OP = OSit-Bu2Ph 88% ee

LiBr, Cu2I2 H H N N Me MeMgBr Me C C C8H17O O THF, 0 °C PO S C7H15 80% C7H15 52% ee liquid crystalline properties

Zab, K.; Kruth, H.; Tschierske, C. J. Chem. Soc., Chem. Comm. 1996, 977-978.

CpCo BuLi, Ph2P(O)Cl C THF, -78 to 50 °C C CpCo(CO)2 H Ph 78% Ph THF, Δ, hν Ph Me Me quant. Ph P Me PPh2 2 O O >95% ee

Buisine, O.; Aubert, C.; Malacria, M. Synthesis 2000, 985-989. Enantioenriched Propargyl Alcohols

O OH MsCl OMs (S)-BINAL-H TEA

H17C8 91% C8H17 DCM, 0 ºC C8H17 95% 95% ee

H17C8 H17C8 H Cp2ZrCl2, BuLi H TMS MgCl C CO, 20 psi O LiBr, CuBr, THF THF -60 ºC to rt -78 ºC to rt to 0 ºC 95% TMS 39% TMS 85% ee Brummond, K. M.; Kerekes, A. D.; Wan, H. J. Org. Chem. 2002, 67, 5156-5163.

1) Ph Me

HO NMe2 N CuCNLi Zn(OTf) OMs 1) Ph Ph 2 H CHO PhMe, 23 ºC Boc 82% C + 2) MsCl, TEA 2) TMSOTf CH2Cl2, -40 ºC Ph CH2Cl2, -40 ºC MeHN 80% 99% ee 99% 83% ee

Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855-3858. Enantioenriched Cyclic Allenes

OAc Lipase OAc OH (Mucor miehei) + Phosphate Buffer n n n A, n = 1 B, n = 2 (S)-A-OAc (R)-A-OH 40% (64% ee) 43% (91% ee)

(S)-B-OAc (R)-B-OH 50% (60% ee) 20% (90% ee)

OAc OAc

RMgX C RMgX C CuBr, LiBr R CuBr, LiBr R THF, -70 ºC THF, -70 ºC (91% ee) (+) (60% ee) (-) (60% ee) R = Bu, i-Pr, t-Bu R = Bu, i-Pr, t-Bu

% ee determined for R = Bu, t-Bu by GC, Enantioseparation not achieved for others

Zelder, C.; Krause, N. Eur. J. Org. Chem. 2004, 3968-3971. Silyl Cuprates

1a) HCCMgBr, DCM OBn OBn -78 to 0 °C, 89% 1) (Me2PhSi)2Cu(CN)Li2 b) Separate 2:1 dr THF, -96 °C, 84% OHC OTBS OTBS 2) Ac2O, TEA, DMAP AcO H 2) DIBALH, PhMe DCM, 98% -78 to 0 °C, 78% CN CN or OBn DEAD, PPh3, HOAc Pyr, THF Me2PhSi -45 °C to rt, 86% C OTBS H H CHO

O Br

N O PPh3 OBn H SiPhMe2 Br mesitylene H 2) TBAF, THF, 0 °C 50 °C then reflux 63% overall Ar C H N OTBS N OBn H

OTBS O O

O OMe

O OH Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 2050-2051. N H For an alternative approach to allenyl silanes, see: Guintchin, B. K.; (-)-coccinine Bienz, S. Organometallics 2004, 23, 4944-4951. Propargylic Silanes

TMS Me OMs HSiCl , CuCl Me 3 C 55-92% yield + R TMS Me H 89:11 to 98:2 R >95% chirality transfer H DIEA, RCHO DMF OH TMS OH

TMS OMs Me H Me "CuSiCl3" C Me CuX H H XCu TMS SiCl TMS 3 SiCl3

reductive Me H TMS elimination Me C SiCl3 - CuCl H TMS Cl3Si RCHO RCHO

Me H TMS Me Me TMS Me C SiCl3 H R C Cl3Si H TMS R O H O TMS OH OH R R H

This Work: Marshall, J. A.; Adams, N. D. J. Org. Chem. 1997, 62, 8976-8977. For similar chemistry with stannanes, see: Marshall, J. A.; Yu, R. H.; Perkins, J. F. J. Org. Chem. 1995, 60, 5550-5555. SN2' reaction H

CO2Me OH DIBAL-H C

O CH2Cl2 0 ºC HO HO 80% OH O enantiomerically pure H O O

Furuichi, N.; Hara, H.; Osaki, T.; Mori, H.; Katsumura, S. C Angew. Chem. Int. Ed. 2002, 41, 1023-1026. OH HO peridinine OH

Bn O N N Al N O H Tf Me Tf O OBn C9H19MgBr H C9H19 + 10 mol % CuBr (10 mol%) C O Me THF Me OBn Br Et 94% ee -78 ºC CO2H 91:9 dr BnO Me 1) AgNO3 (-)-malyngolide C9H19 2) H , Pd/C antibiotic Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122, 10470-10471. 2 O O OH 94% ee Halogenations

Syn-halogenation 48% aq HBr CuBr, NH4Br t -Bu L t -Bu Cu powder Me Syn t -Bu Me Cu L H H C 1 H O Br HO "HCuCl2" 2 Br Me No 2H-exchange at C-1 in D O/DBr, Original proposed mechanism 2 or in H2O/HBr with 1-d alcohol

Landor, S. R.; Demetriou, B.; Evans, R. J.; Grzeskowiak, R.; Davey, P. J. Chem. Soc., Perkin Trans. 2 1972, 1995-1998. Halogenations

Syn-halogenation 48% aq HBr t -Bu CuBr, NH4Br Me t -Bu Cu powder Syn t -Bu Me H H H C 1 Br HO "HCuCl2" HO Cu Br Me

Br 2 No H-exchange at C-1 in D2O/DBr, or in H2O/HBr with 1-d alcohol

Landor, S. R.; Demetriou, B.; Evans, R. J.; Grzeskowiak, R.; Davey, P. J. Chem. Soc., Perkin Trans. 2 1972, 1995-1998.

Cl Syn or Anti-halogenation? H C HCuCl Ph 2 H ~4% ee H H H HCuI2 Ph C anti Ph I syn HO ~6% ee optically Br HCuBr2 H pure C Ph H ~22% ee Authors conclude syn-elimination is not general for HCuX2. Substituting for sulfinate ester gave better anti selectivity for X = Cl (24% ee) and X = Br (52% ee). X = I also gave anti, but low selectivity (~6% ee). Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1984, 49, 1649-1650. Halogenations

Anti-halogenation

H SOCl H Cl Ph 2 Ph Bu4NCuCl2 H C Ph Et2O Acetone H HO Cl 62% 0 ºC to rt 25 81% ee 67% 18% ee [α] D -94º (c 0.9, CHCl3) Muscio, O. J.; Jun, Y. M.; Philip, Jr., J. B. Tetrahedron Lett. 1978, 2379-2382.

a) BuLi, THF c) cuprate Ph H X H -70 ºC Ph -70 to 20 ºC Ph C H HO b) MsCl MsO H

20 50% ee [α] D deg (c 2, EtOH) cuprate equiv. X = Cl X = Br X = I Elsevier, C. J.; Meijer, J.; Tadema, G.; Stehouwer, P. M.; Bos, H. J. T.; LiCuX 1.2 530 920 1220 Vermeer, P. J. Org. Chem. 1982, 47, 2194-2196. 2 LiCu2X3 0.6 600 1040 1350 LiCu2X3 1.2 610 1235 1550 Halogenations OTs H 1) TMSCCLi CuBr HMPA, THF, -78 ºC LiBr O O C Br 2) TsCl, TEA, DMAP NBoc TMS THF NBoc 60 ºC CHO DCM, 0 ºC to rt TMS 88% 70% O NBoc OTs H 1) TMSCCLi CuBr HMPA, THF, -78 ºC LiBr O C O TMS 2) TsCl, TEA, DMAP NBoc TMS THF NBoc DCM, 0 ºC to rt 60 ºC Br 89% 75% D'Aniello, F.; Schoenfelder, A.; Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 9631-9636.

H O H 1) t-BuOOH (+)-tartrate, 94% 1) LDA, THF, 87%

O 2) PPh3, NCS O 2) ArSO2Cl, 96% TESO H ArO2SO 84% Cl Et HO >98:2 dr H H O H O H H H LiCuBr2 1) PPTS, MeOH O O 67% TESO H C 2) CBr4, oct3P Br H C Et 58% Et Br H Br H (-)-isolaurallene Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001, 123, 1533-1534 Rearrangements

SOBr 2 t-Bu propylene t-Bu Me t-Bu oxide Me H Me Br O C + Me S t-Bu OH Et2O, 0 ºC Br Br 94% ee O 52% yield, 90:10

Coery, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3055-3058. Initial studies: Evans, R. J. D.; Landor, S. R.; Smith, R. T. J. Chem. Soc. 1963, 1506-1511. Evans, R. J. D.; Landor, S. R. J. Chem. Soc. 1965, 2553-2559.

Ortho Claisen rearrangement EtO Me H O OH EtC(OEt) 3 H O Me t-Bu EtO EtCO2H t-Bu t-Bu H 98% ee E E' H C t-Bu EtO2C H Me EtO H Me C O H B t-Bu EtO C H 2 O Me EtO A t-Bu Me t-Bu Z' Z A:B = 9:1 complete chirality transfer rapid equilibrium, E reacts faster

Henderson, M. A.; Heathcock, C. H. J. Org. Chem. 1988, 53, 4736-4745. Rearrangements

TMS CHO Sn(OTf)2 O OTMS O + L* (cat) 1) deprotection TMSO EtS EtS C 2) MeC(OEt) CO2Et 3 Me Me TMS EtCO2H TMS EtS Me 86% 92% ee 92% ee

Mukaiyama, T.; Furuya, M.; Ohtsubo, A.; Kobayashi, S. Chem. Lett. 1991, 989-992.

TBSO O CO2Et CO2Me MeC(OEt)3 C H H OH C OPh HCO2H H OPh 70% H THPO OTHP 1 isomer HO OH enprostil

1) CBr4, PPh3 CO2Me C 2) CO2Me H Cu H 78% 1 isomer

Cooper, G. F.; Wren, D. L.; Jackson, D. Y.; Beard, C. C.; Galeazzi, E.; Van Horn, A. R.; Li, T. T. J. Org. Chem. 1993, 58, 4280-4286. Rearrangements

H OH H MeC(OEt) 3 (CH2)6CH3 (CH2)6CH3 EtO2C C N H+ RO Me OTIPS OTIPS 71% H Me 5

Ha, J. D.; Lee, D.; Cha, J. K. J. Org. Chem. 1997, 62, 4550-4551. clavepictine A, R = Ac Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012-10020. clavepictine B, R = H

[2,3]-Wittig Rearrangement OH C H 1) LDA AgNO 7 15 MeO2C 3 * Me C 2) CH2N2 H MeO2C Me 80% C7H15 O HO C 2 dr 93:7 O complete transfer of chirality O C7H15 MeO M Me Favored 1) CH N O H 2 2 One diastereomer Me H 2) LDA, Cp2ZrCl2 Me THF, -78 ºC, 57% H O H Me Marshall, J. A.; Robinson, E. D.; Zapata, A. J. Org. Chem. 1989, 54, 5854-5855. O M Me Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1990, 55, 2995-2996. MeO Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1990, 56, 4913-4918. Rearrangements

HN SO2Ar N OH N H N - N H NBSH - HSO2Ar 2 R1 2 2 2 C R R R H PPh3, DEAD 23 ºC R2 R1 R1 R1 71-91% -15 ºC complete transfer of chirality Meyers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492-4493. For a synthetic application of this, see: Shepard, M. S.Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 2597-2605.

OH H ClP(OEt)2 TEA HO2C PO H O O C 3 2 P(O)(OEt)2 N DCM N NH2 -10 ºC to rt H Boc Boc AP5 NMDA antagonist

Muller, M.; Mann, A.; Taddei, M. Tetrahedron Lett. 1993, 34, 3289-3290. Palladium Catalysis transmetallation

Ph PdXL2 H PdL 2.5-3.2 mol% C PhZnCl H 2 Ph C Pd(PPh3)4 H Ph H PhZnCl H Ph

X THF/Et2O -50 to 25 ºC L2XPd Ph 28% ee H H C X = OAc, OTFA, Ph OS(O)Me Ph H 82:18 anti/syn (Determined by Elsevier, C. J.; Stehouwer, P. M.; Westmijze, H.; Vermeer, P. J. Am. Chem. Soc. 1983, 48, 1103-1105. correlation of rotations)

CuI, ZnCl2 i-Pr2NH, Pd(PPh3)4 cat. Pd(PPh ) Bu OCO Et 3 4 Bu H Ph 2 PhZnBr H C Bu C Me H Me THF Me THF Ph 85% ee 93% ee 83% ee Ph Substituting Ph at alkyne terminus resulting in lower stereoselectivity

Dixneuf, P. H.; Guyot, T.; Ness, M. D.; Roberts, S. M. J. Chem. Soc., Chem. Comm. 1997, 2083-2084. Palladium Catalysis transmetallation

10 mol% H conditions X Pd(PPh ) H Ph B(OH)2 3 4 Ph C + C H Ph dioxane H X = OH H 100 ºC 10% ee 92% ee 10 min 92% ee 76% X = OCO2Me Yoshida, M.; Gotou, T.; Ihara, M. Tetrahedron Lett. 2004, 45, 5573-5575.

Ph 10 mol% O B(OH) Pd(PPh3)4 + 2 OH Ph 2:1 dioxane/H2O C 80 ºC, 1-3 h 92% ee 92% 92% ee

Yoshida, M.; Ueda, H.; Ihara, M. Tetrahedron Lett. 2005, 46, 6705-6708.

H X H R conditions Pd(DPEphos)Cl2 R C + Ph3In C H R H Ph H THF, rt, 8h Ph X = OBz 70% >95% ee R = Me 100% ee 84-86% ee X = OAc, OBz R = Ph Riveiros, R.; Rodriguez, D.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 2006, 8, 1403-1406. Palladium Catalysis Carbonylation

1 mol% Pd (dba) ⋅CHCl O 2 3 3 1 8 mol% PPh 1 R 3 1 4 3 R R R R O CO (1-30 atm) R3 C R3 C R2 C O R2 O R2 1 L Pd O R R4OH, 20-100 ºC 2 PdL R3 OR4 2 OR4 R2 1-44 h R4O (±) (±) 44-99% yield Tsuji, J.; Sugiura, T.; Minami, I. Tetrahedron Lett. 1986, 27, 731-734.

5 mol% Pd (dba) 2 3 MOMO 20 mol% PPh3 MeO CO OMOM CO (1 atm) 2 H 3 C 3 C H C H 2:1 PhH/MeOH 6 13 CO Me 6 13 50-60 ºC, 4.5 h 2 70% ee 70% yield <5% ee

Possible racemization by PPh3

Marshall, J. A.; Wolf, M. A. J. Org. Chem. 1996, 61, 3238-3239. Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997, 62, 367-371. Palladium Catalysis Carbonylation

Pd(PPh ) 2 3 4 2 I R MsO CO (200 psi) 1 R IBr 2 R R C 3 H 1 THF, R OH 3 CH2Cl2 1 R CO2R R O rt -78 ºC O 5 examples 80-86% yield 1 h 95% ee 80-93% ee 89-97% yield 80-93% ee

Marshall, J. A.; Wolf, M. A. J. Org. Chem. 1996, 61, 3238-3239. Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997, 62, 367-371. Pd-catalyzed formation of butenolides from allenic acids with high chirality transfer: Ma, S.; Shi, Z. J. Chem. Soc., Chem. Commun. 2002, 540-541. Palladium Catalysis Carbonylation

OH 14 steps BuLi O O O THF- pentane HO $$ -78 ºC 88%

MsCl Pd(PPh3)4 Et N CO (1 atm) 3 O O R = OCH2CH2TMS CH Cl TMSCH CH OH 2 2 2 2 H C -78 ºC MsO THF 75% (2 steps) CO2R 1 diastereomer

1) TBAF, THF 93% PPh3 O O CH CN 2) AgNO 3 H C 3 55 ºC Acetone, 68% O 92 h CO R 2 O 85:15 (-)-kallolide B Marshall, J. A.; Wallace, E. M.; Coan, P. S. J. Org. Chem. 1995, 60, 796-797. (unnatural) Marshall, J. A.; Bartley, G. S.; Wallace, E. M. J. Org. Chem. 1996, 61, 5729-5735. Palladium Catalysis

R R 5 mol% Pd(OAc)2 H reductive H H H 7.5 mol% dppe insertion C elimination H O O R C PdL THF PdL2 2 R S S SO2Tol TolO2S O Tol O Tol 87% ee R = Me, Pentyl

Hiroi, K.; Kato, F. Tetrahedron 2001, 57, 1543-1550.

2 mol% Pd(acac)2

SiMe2Ph NC O SiPh Ph Si C H 2 SiMe Ph 2 6 13 8 mol% then BuLi H 2 O C Me SiMe2Ph Toluene, reflux THF, -78 ºC Me C6H13 Me C6H13 86% 97% ee CHO OH C6H13 76% yield 95:5 syn:anti TiCl 93% ee 4 Me

Suginome, M.; Matsumoto, A.; Ito, Y. J. Org. Chem. 1996, 61, 4884-4885. Allenylmetal Compounds

1.5 equiv Ti(Oi-Pr)4 TMS TMS 3 equiv i-PrMgCl 2 2 (i-PrO)2XTi 2 R R Et2O, -50 to -40 ºC R PhCHO 1 R1 C R R1 A TMS X Ph OH X = OCO Et or OPO(OEt) 2 2 72-87% yield

A Ti(Oi-Pr) R2 2 Ti(Oi-Pr) 1 Ti(Oi-Pr)4 2 R + Ti(Oi-Pr)2 TMS 2 i-PrMgCl X

TMS 1 2 R2 R R 1 R1 PhCHO R Ti(Oi-Pr)2 C X Ti(Oi-Pr)2 2 TMS Ph OH R TMS

Okamoto, S.; An, D. K.; Sato, F. Tetrahedron Lett. 1998, 39, 4551-4554. (Mechanism) Nakagawa, T.; Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36, 3207-3210. Allenylmetal Compounds %ee / Config. TMS TMS Bu TMS Bu Bu H 49 / (1R,2S) H C 2 H 49 / (1S,2S) 97% ee (i-PrO)2XTi OCO2Et Ph 1 OH

Ph 1 OH TMS (i-PrO) XTi Bu 2 Bu H C 2 94 / (1S,2R) H Bu 94 / (1R,2R) TMS 97% ee OPO(OEt) H 2 TMS

TMS TMS TMS R C Me Me Me 85 / (2S) (i-PrO)2XTi 2 87% ee OCO Et 2 Ph 1 OH

TMS (i-PrO) XTi 1 2 R Ph OH Me C Me 2 8.3 / (2R) 87% ee TMS OPO(OEt)2 Me TMS

Okamoto, S.; An, D. K.; Sato, F. Tetrahedron Lett. 1998, 39, 4551-4554. (Mechanism) Nakagawa, T.; Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36, 3207-3210. Allenylmetal Compounds

Oi-Pr Oi-Pr i-PrO Ti anti (i-PrO) XTi i-PrO Ti anti (i-PrO) XTi Bu 2 Bu 2 Bu C C H H Me H TMS TMS TMS TMS O (OEt)2 O (OEt)2 P P 2º phosphate 3º phosphate O (high selectivity) O (low selectivity)

TMS syn TMS i-PrO Me R Ti C Me i-PrO O (i-PrO) XTi O 2

OEt 2º or 3º carbonate (moderate selectivity)

CO Et 1.5 equiv Ti(Oi-Pr)4 2 2 TMS 3 equiv i-PrMgCl R2 TMS R R1 Et O, -50 to -40 ºC CO Et 2 2 CO Et H 2 95 or 98% ee 1 OPO(OEt)2 R CO2Et > 97:3 anti:syn Song, Y.; Okamoto, S.; Sato, F. Org. Lett. 2001, 3, 3543-3545. > 88 to 96% ee

For reviews of the synthesis and reactivity of allenylmetal compounds, see: Marshall, J. A. Chem. Rev. 1996, 96, 31-47. Marshall, J. A. Chem. Rev. 2000, 100, 3163-3185. Marshall, J. A.; Gung, B. W.; Grachan, M. L. Synthesis and reactions of allenylmetal compounds. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; 493-592. Allylic Elimination (β-elimination)

A) Chirality transfer from allylic position

LG X LG R1 Z "Activator" Z H R3 R3 C R3 X R2 R1 R2 R1 R2

B) Chiral leaving groups

O H HR HS R 4 R1 Y oxidation Y H - HOYR 4 3 4 S H R R R 3 C R R3 R2 R1 R2 R1 R2

Y = S, Se Allylic Elimination (β-elimination) Chirality at allylic position

OH Bu3SnH OH O CBS AIBN Swern reduction Me Me C H Me C H neat 6 13 6 13 C6H13 90 ºC SnBu3 SnBu3

OH MsCl H TEA H Me C H C 6 13 CH Cl Me 2 2 C6H13 SnBu3 0 ºC to rt 94% ee 51% ee anti elimination Konoike, T.; Araki, Y. Tetrahedron Lett. 1992, 33, 5093-5096. Allylic Elimination (β-elimination) Chirality at allylic position

OH Bu3SnH OH O CBS AIBN Swern reduction Me Me C H Me C H neat 6 13 6 13 C6H13 90 ºC SnBu3 SnBu3

OH Ac O OAc 2 H DMAP TBAF H C Me C6H13 Me C6H13 81% Me C6H13 SnBu3 SnBu3 94±2% ee 94% ee anti elimination F Konoike, T.; Araki, Y. Tetrahedron Lett. 1992, 33, 5093-5096.

O 6 equiv R H i-PrMgCl H Tol S C 1) OHC 51% OAc CO Me -78 ºC C8H17 O 2 10 min CO2Me LDA, THF, -78 ºC 95% 81% ee 31% (78% brsm) C8H17 Tol S

2) Ac2O O (R) C H 8 17 R 6 equiv CO2Me i-PrMgCl H Tol S OAc C 44% H -78 ºC C H 10 min 8 17 Satoh, T.; Hanaki, N.; Kuramochi, Y.; Inoue, Y.; C H Hosoya, K.; Sakai, K. Tetrahedron 2002, 58, 2533-2549. 8 17 91% 84% ee Allylic Elimination (β-elimination) Chirality at allylic position

1) Ph N Ph O O Li Ph Ph PPh2 R1 R1 TMSCl, THF, -78 ºC R1 NaH P R2 PPh2 O C R1 2) H O DMF O H 2 R2 OH H 3) TBAF, THF 60 ºC R2

R1=Ph, R2=t-Bu, 87%, 28% ee R1=Ph, R2=t-Bu, 89%, ~12% ee R1=t-Bu, R2=t-Bu, 58%, 51% ee R1=t-Bu, R2=t-Bu, 74%, ~23% ee

This work: Fox, D. J.; Medlock, J. A.; Vosser, R.; Warren, S. J. Chem. Soc., Perkin Trans. 1 2001, 2240-2249. For related achiral systems, see: Nagaoka, Y.; Tomioka, K. J. Org. Chem. 1998, 63, 6428-6429. Inoue, H.; Tsubouchi, H.; Nagaoka, Y.; Tomioka, K. Tetrahedron 2002, 58, 83-90. Allylic Elimination (β-elimination) Chiral leaving groups

SAE Et3N or or Davis O nC H R Ts KOtBu R Ts Epoxidation - ArSeOH 7 15 H nC7H15 SeAr C ArSe H ArSe H Ts H Ts 45 examples Not isolated 9-100% yield Can racemize with H2O 1-42% ee

Komatsu, N.; Murakami, T.; Nishibayashi, Y.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 3697-3702. Allylic Elimination (β-elimination) Chiral leaving groups

SAE Et3N or or Davis O nC H R Ts KOtBu R Ts Epoxidation - ArSeOH 7 15 H nC7H15 SeAr C ArSe H ArSe H Ts H Ts 45 examples Not isolated 9-100% yield Can racemize with H2O 1-42% ee

Komatsu, N.; Murakami, T.; Nishibayashi, Y.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 3697-3702.

Positioned away from sidechain of Fc*

(FcSe) R 2 H NaBH R 4 R CO2Et mCPBA H CO Et EtOH Se CO2Et 2 Fc* CH2Cl2 Se 4Å MS O R = Me, Et, Pr Fc* -78 to -20 ºC Not isolated Me H Me N - HOSeFc* H 2 C R CO2Et (FcSe)2 = Fe Se Se Fe 38-59% yield 75-89% ee NMe2 Hishibayashi, Y.; Singh, J. D.; Fukuzawa, S.; Uemura, S. J. Org. Chem. 1995, 60, 4114-4120. Me (S,R) Allylic Elimination (β-elimination) Equilibration of allylic metal center

then, Bu Zn, 2 MgBr O Bu Cu 2 2 BuCu⋅MgBr2 0 to 5 ºC H S H S O THF then, I Tol -70 to 20 ºC Tol Bu I

Bu Bu Bu ZnBu Bu ZnBu syn Bu Bu C H H S O H S O H Tol Tol 75% yield 3 65% ee "Racemic" sp Thermodynmic organometallic equilibration; "Enantioenriched" sp3 organometallic

Varghese, J. P.; Zouev, I.; Aufauvre, L.; Knochel, P.; Marek, I. Eur. J. Org. Chem. 2002, 4151-4158. Stoichiometric Chiral Reagents and Auxilliaries

A) Asymmetric Deprotonation-Protonation

B* H HR HS B* R R2 HS 1 HS C R 1 R1 R E R2 R2

B) Asymmetric Horner-Wadsworth-Emmons

O O O P O H (*RO)2 OR R2 C Nu C Nu C R1 CO2R 2 2 R1 R R1 R Asymmetric Deprotonation

H H BuLi Ti(Oi-Pr)3 R S N N (-)-sparteine TiCl(Oi-Pr)3 CbO O Li CbO pentane R1 INVERSION! R1 -78 ºC N O R1 = TMS, t-Bu R1

Precipitates from reaction Equilibrates in THF

Ti(Oi-Pr) 3 R1 AcOH OCb TMS: 86% yield, 88% ee C t-Bu: 80% yield, 84% ee CbO H H R1

H R1 2 R1 OCb R CHO OCb C 73-86% yield TiX 2 H H 3 R 93->95% ee O OH R2 1 diastereomer

This Work: Schultz-Fademrecht, C.; Wibbeling, B.; Fröhlich, R.; Hoppe, D. Org. Lett. 2001, 3, 1221-1224. For inversion in Li-Ti exchange with allyl species, see: Paulsen, H.; Graeve, C.; Hoppe, D. Synthesis, 1996, 141-144. Asymmetric Deprotonation

O BuLi (2 equiv) Li O H H R THF, -78 ºC, 2 h t-BuOH O C O O O H R R H O R = Me, 55%, 20/1 dr R = t-Bu, 65%, 3/1 dr

O Me N O H H Ph BuLi O δ O O O t-Bu O THF O Li OH OH -78 ºC t-Bu C 30 min HCl δ H C (CF3)2CHOH Me CF CH OH H Ph Me H 3 2 Ph t-Bu

O O t-Bu H H + OH OH O H t-Bu Ph Me Ph Me

This Work: Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem. Soc. 2002, 124, 10091-10100. For examples with a fructose-derived auxilliary, see: Hausherr, A.; Orschel, B.; Scherer, S.; Reissig, H.-U. Synthesis 2001, 1377-1385. Asymmetric Protonation

5 mol% Pd(PPh3)4 1) (R)-BINOL-Ti SmI (2 equiv) OPO(OEt) 2 O CH2Cl2, 95% 2 t-BuOH (1.1 equiv) + 2) BuLi THF H C CO2Me (EtO)2POCl 53% CO2Me CO2Me 94% Racemic! Pd0

R2 PdII R2 R1 H C R2 C H R1 PdII R1 PdII 2 SmII

Pd0

R2 SmIII R2 R1 H C R2 C H R1 SmIII R1 SmIII

R*OH R*OH

R2 R2 R1 H C C H R1 H H

Mikami, K.; Yoshida, A. Angew. Chem. Int. Ed. 1997, 36, 858-860. Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889-898. Asymmetric Protonation

5 mol% Pd(PPh3)4 1) (R)-BINOL-Ti SmI (2 equiv) OPO(OEt) 2 O CH2Cl2, 95% 2 t-BuOH (1.1 equiv) + 2) BuLi THF H C CO2Me (EtO)2POCl 53% CO2Me CO2Me 94% Racemic!

5 mol% Pd(PPh ) H OPO(OEt)2 3 4 O SmI2 (2 equiv) + C CO2Me THF O OH CO Me 68% 2 H 1.1 equiv racemic >95% ee

R' R' H H Ph Ph O O O O Sm H Sm H with R' R' HO OH

H R R H 71% yield 86% ee E E

Mikami, K.; Yoshida, A. Angew. Chem. Int. Ed. 1997, 36, 858-860. Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889-898. Asymmetric HWE

1 BuLi KHMDS R ZnCl R1 R1 2 A H CO2BHT C O C 2 CO Me R THF R2 THF R2 2 -78 ºC -78 ºC to rt 60-94% yield 4-84% ee

1 LDA LDA R ZnCl R1 R1 2 A H CO2Ph C O C 2 CO Me R THF R2 THF R2 2 -78 ºC -78 ºC to rt 21-71% yield 32-89% ee O si face Me C

Me 2+ Zn L O O O S P O O O O OMe P O OMe Me Me A re face blocked by Me

This work: Tanaka, K.; Otsubo, K.; Fuji, K. Tetrahedron Lett. 1996, 37, 3735-3738. Yamazaki, J.; Watanabe, T.; Tanaka, K. Tetrahedron: Asymmetry 2001, 12, 669-675. For examples of Wittig-type olefinations of ketenes, see: Lang, R. W.; Hansen, H. J. Helv. Chim. Acta 1980, 63, 438-55. Tanaka, K.; Otsubo, K.; Fuji, K. Synlett 1995, 933-934. Tanaka, K.; Otsubo, K.; Fuji, K. Tetrahedron Lett. 1995, 36, 9513-9514. Chiral Catalysis and Kinetic resolution Kinetic Resolution

Sharpless Asymmetric H OH Epoxidation OH C C7H15 C H C7H15 H run to ~60% conversion H 40% ee

Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodard, S. S. Pure Appl. Chem. 1983, 55, 589-604.

R H 2 mol% cat R H PhIO C C CH2Cl2 H R -40 ºC H R 61-98% ee Noguchi, Y.; Takiyama, H.; Katsuki, T. Synlett 1998, 543-545 Me Me 57-83% conversion

Me Me

N N Mn+ O O Ph Ph Kinetic Resolution H

R C R HAr NAr 1.8 equiv R N H H H H C H Zr C + Zr C R R C6H6 H R R (R) R (S) (S,S) 50-61% conv (S,S,R) >95% recovery 78-98% ee 85-93% ee

C HAr H NAr 1 equiv N Zr Zr

100% conv. Ar N H (S,S) (S,S,R) Zr R 1 diastereomer! R C

C H Thought to involve stepwise mechanism; therefore highly Only favored stereoselective, not stereospecific approach 84% ee 93% yield C H (S) H

Sweeney, Z. K.; Salsman, J. L.; Anderson, R. A.; Bergman, R. G. Angew. Chem. Int. Ed. 2000, 39, 2339-2343. Kinetic Resolution deracemization

RO2C H 1 mol% Et N RO2C 3 CO2R C C H H CO R pentane H 2 -20 ºC R = (-)-L-menthyl 2 days (R) crystallizes 5:4 dr 90% yield >98% de

Node, M.; Nishide, K.; Fujiwara, T.; Ichihashi, S. J. Chem. Soc., Chem. Commun.1998, 2363-2364.

OR O RO2C + Et3N - Et3N RO2C CO2R H C RO2C H C H CO2R H - Et3N + Et3N H (R) H NEt3 (S)

Boc N Boc H RO2C N Cl CO2R AlCl H H C 3 N H CO2R H CH Cl H CO2R N + 2 2 C -78 ºC H CO R H N Boc 2 CO2R (-)-epibatidine Kinetic Resolution deracemization

RO2C H 1 mol% Et N RO2C 3 CO2R C C H H CO R pentane H 2 -20 ºC R = (-)-L-menthyl 2 days (R) crystallizes 5:4 dr 90% yield >98% de

Node, M.; Nishide, K.; Fujiwara, T.; Ichihashi, S. J. Chem. Soc., Chem. Commun.1998, 2363-2364.

i-PrO C H i-PrO C 2 (+)-Eu(hfc)3 2 H C C CDCl CO2i-Pr H CO2i-Pr 3 H 9 days 20 ºC (S) >95% ee

Naruse, Y.; Watanabe, H.; Ishiyama, Y.; Yoshida, T. J. Org. Chem. 1997, 62, 3862-3866 Chiral Catalysis The Beginning

BuLi cat Pd(R,R-DIOP) t-Bu H t-Bu H t-Bu MX PhI H C C C Ph H H THF H M -60 ºC to rt H -60 ºC (±) up to 25% ee MX = ZnCl, MgCl, CuBr/LiBr changing MX altered sense of induction

t-Bu -M+ t-Bu H H "fast" reacting C C enantiomer M H H t-Bu H

t-Bu Warning!-M+ t-Bu t-Bu M H "slow" reacting C C enantiomer SpeculationH H byH AMHH

t-Bu H C H M t-Bu t-Bu L Pd0 I H -L Pd0 H 2 C 2 C PhI L2Pd PdL Ph Ph H 2 H Ph MI de Graaf, W.; Boersma, J.; van Koten, G.; Elsevier, C. J. J. Organometallic Chem. 1989, 378, 115-124. Chiral Catalysis

10 mol% CO2Et Pd[(R)-BINAP]2 R2 1 EtO2C CO2Et EtO2C CO2Et dba (2 equiv to Pd) H R + or C CO2Et R1 Br Me NHAc CsOt-Bu H CH2Cl2, 20 ºC 34-75% yield 54-89% ee Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 2089-2090. Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Org. Chem. 2005, 70, 5764-5767.

2 2 Pd0(BINAP) Br R1 R1 R1 R1 Pd Pd Pd Br P P (2R) P P 34:66 dr (2S) P P by NMR

Nu Nu The presence of dba does not affect the ratio of H H 2R to 2S, but accelerates the H Nu interconversion 12-25 times. C C Nu H R1 R1 major minor Chiral Catalysis

CO2Et NHAc CO2Et OMe TiCl CO2Et NHAc 4 H + C CO2Et OMe TMS CH2Cl2 H -78 ºC t-Bu 90% yield 87% ee H 85% ee MeO (S) Ogasawara, M.; Ueyama, K.; Nagano, T.; Mizuhata, Y.; Hayashi, T. Org. Lett. 2003, 5, 217-219. t-Bu H C R H H t-Bu TMS O H Me C R (S) (R) H H Me TMS O O Me H R Favored C H H TMS t-Bu Disfavored Chiral Catalysis

1 mol% Pd (dba) CHCl 2 3⋅ 3 CO R2 4 mol% 2 1 3 R OPO(OEt)2 2 2 (R)-MeOBIPHEP R R O2C CO2R H C CO R2 C + 1 2 BSA, THF, rt R H H R3 H (±) 72-90% yield 69-90% ee Imada, Y.; Ueno, K.; Kutsuwa, K.; Murahashi, S.-I. Chem. Lett. 2002, 5, 140-141. Chiral Catalysis

PdCl(Allyl)2/L (1 mol% Pd) H MeMgBr H R R R + HSiCl3 C C (neat) 20 ºC Cl3Si Me Et2O TMS Me 37-90% yield 68-90% ee

R R R H R + Cl Si Pd H Me C Cl3Si Pd H 3 Pd Cl Si Cl Si L 3 Me L L 3

Me Fe

H R OH R OH R PhCHO MeO P C + Ph Ph Ph Fe Cl3Si Me DMF OMe Me Me 1:1 to 4:1 Me 100% chirality transfer (S)-(R)-bisPPFOMe

Han, J. W.; Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 12915-12916. For hydrosilylation of butadiynes with low selectivity, see: Tillack, A., Koy, C.; Michalix, D.; Fischer, C. J. Organometallic Chem. 2000, 603, 116-121. For hydroboration of ene-ynes with low selectivity, see: Matsumoto, Y.; Naito, M.; Uozumi, Y.; Hayashi, T. J. Chem. Soc., Chem. Commun. 1993, 1468-1469. Chiral Catalysis

OTMS O [RhCl(C4H4)2]2/L* (3 or 10 mol% Rh) ArTi(Oi-Pr)4Li TMSCl 61->99% yield 26-93% ee n n THF, 20 ºC C (configuration not reported) 30 min * Ar R R

[Rh]-Ar TMSCl ArTi(Oi-Pr)4Li

O O [Rh]

[Rh] isomerization C Ar determines * O stereochemistry R Ar R O PPh2 L* = O PPh2

O (R)-segphos Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6, 305-307. Conclusions Presented a flavor of the methods known to construct axial chiral allenes in an enantioselective manner, as well as a few reactions these products are useful for.

Many reliable methods for chirality transfer from pre-generated stereocenters with stiochiometric reagents.

There is still a deficiency in catalytic asymmetric methods. The selectivities of these processes are not as reliable, and scope has yet to be defined.

Allenes are not just theoretical curiosities and can be useful synthons for asymmetric synthesis as well as potentially useful final targets for biologically relavant molecules.

Prof. Kay Brummond Prof. James Marshall Prof. Tamio Hayashi University of Pittsburgh University of Virginia Kyoto University