Dipolar Cycloadditions You Love Them

Home , Azomethine ylide, Ylide

SO Ph Me 2 H O Me H N H O N R SO2 H H Ph O O Dipolar Cycloadditions You Love Them. You Hate Them. You Need Them. Mike Meyer

Stoltz Group Meeting, April 3rd, 2006

NO2 O O

N N O N O S O Rz N N Me R R N z e Me Re N O CO2Me H Et CO2Me A Guide for the Discussion of Dipolar Cycloadditions:

1. Types and Classification of 1,3 Dipoles Ph

2. Molecular Theory Behind 1,3-Dipolar Cycloadditions N

3. Types of Dipoles Good Sources: W(CO)5 a. Nitrones Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. Gothelf,K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863. b. Nitrile Oxides Padwa, A. Synthetic applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products John Wiley & Sons, 2002, p. 269-301. c. Carbonyl Ylides H d. Diazoalkanes O H OAc Me e. Azomethine ylides O g. Miscellaneous O N OTBS O

O Ph O CO2Me O N O O N N R O H H H O O Types and Classification of 1,3-Dipoles

Two Types of Dipoles: Classification of the Allyl Anion Type 1,3-Dipoles (1) Allyl anion N O C O Nitrones C C Carbonyl Ylide Y Y X Z X Z N O C N - Bent C N Azomethine Imines Carbonyl Imines - Y = N, O, S

N O (2) Propargyl/allenyl anion C C Azomethine Ylides C O Carbonyl Oxides

X Y Z X Y Z N O N N Azimines N N Nitrosimines - Linear - Y = Nitrogen N Azoxy Compounds O Nitrosoxides N O N O

N Nitro Compounds O Ozone O O O O

Classification of the Propargyl/Allenyl Anion Type 1,3-Dipoles

C N O Nitrile Oxides C N C Nitrile Ylides N N N Azides

C N N Nitrile Imines N N C Diazoalkanes N N O Nitrous Oxide Molecular Theory Behind 1,3-Dipolar Cycloadditions

Dipole Alkene Dipole Alkene Dipole Alkene

LUMO

Energy

HOMO

Type I Type II Type III

HOMOdipole—LUMOalkene HOMOdipole—LUMOalkene HOMOalkene—LUMOdipole

HOMOalkene—LUMOdipole

Types of azomethine ylides, nitrones, ozone, Dipoles azomethine imines, nitrile oxides nitrous oxide nitrile ylides Molecular Theory Behind 1,3-Dipolar Cycloadditions (cont'd)

What about Lewis acid activation?

Dipole Alkene Dipole Alkene

LUMO Alkene-LA Dipole-LA Energy

HOMO

Coordination of the LA to either the dipole or the alkene results in LUMO lowering, and a faster reaction rate. Another Consideration: Endo vs. Exo

R1 O 1 O 1 O N R N R N O OR2 OR2 R2O O O endo exo

2 diastereomers (racemic) Endo: H H Me 1 Me O 1 R O R1 R O N N N 2 H O Secondary 2 H O R O 2 R O H R O2C overlap is minimal H Me Me Me

Exo: H H O 1 O R1 R O R1 2 R2O C R O2C 2 N N Me Me N Me 2 Me H R O2C H H Me H A Usefull Dipole: Nitrones (a.k.a. Azomethine Oxides)

What is a nitrone? - E/Z mixtures of the nitrone can occur, resulting in mixtures R1 O of stereoisomers N O HN

2 OH 2 R - Cyclic nitrones avoid geometrical isomers, and generally give R better selectivity

nitrone species - Dipolar cycloadditions with nitrones can produce: isoxazolidines, nucleosides, lactams, quinolizidines, indolizidines, pyrrolizidines, Examples of cyclic nitrones: peptides, amino acids (alcohols), and more

RO OR O O OH O O O O O O N O N N O N O Bn N O O N O O O Ph Most common reaction with nitrones:

R1 O R1 N 4 R 2 N NHR1 OH R3 R - 1,3-DC with nitrones can create 2 * O R upto three stereogenic centers * * R2 * * * R4 3 4 R1 O R R R3 N isoxazolidine β-amino alcohols (acids) R2 Nitrones: In the Beginning

In the early 1970's, organic chemists began to use 1,3 DC to build complex intermediates and important building blocks in the realm of total synthesis.

- Huisgen was the first chemist to successfully prove that 1,3 DC occur through a concerted mechanism.

Some examples involving nitrones:

Me H Ph Me Me N H Bn Me Bn H N H N O Ph N vs. N O H O Ph N Ph Me N O H N Ph O Me Me Me O H H H O O H Ph

disfavored favored White, J. D., et. al.; Tetrahedron, 1989, 45, 6631.

O O O O 3 simple PMBO O PMBO O O O H Δ Δ H steps H HO

EtO2C N N N N O O PMBO O 74% yield Cordero, F.M., et. al.; Org Lett. 2000, 2, 2475. Nitrones: Getting More Complicated

Thermal transannular cycloaddition: H H HOHN O O MeO C O 1. K2CO3, 2 p-TsOH PhMe, Δ N MeOH, 88% HO HN O O N O O O MeOH, H2O, Δ 2. SmI2, rt, 64% HO O H 70% yield 64 % yield H H

White, J. D., et. al.; Org. Lett. 2001, 3, 413.

A three component coupling: R3 CO R 1 3 10 mol % Yb(OTf) 2 R O R 3 O R1 N O 4 Å MS N CO2R 21 examples 1 R NHOH 2 66-96% yield 2 PhMe, rt, 30 min. R R H R2 RO2C CO2R R1 = aryl, benzyl tetrahydro-1,2-oxazines R2 = alkyl, alkenyl, aryl, heteroaryl R3 =alkyl, alkenyl, phenyl, heteroaryl I

1. 10 mol % Yb(OTf)3 20 mol % Pd(PPh3)4 I O 4 Å MS, PhMe, rt, 30 min O TEA, CH3CN, 80 °C N O CO Me 2. 42-71 % yield overall N 2 NHOH R H CO2R R CO Me 5 examples 2 MeO2C CO2Me R CO2R FR900482 analogs Young, I. S.; Kerr, M. A. Org. Lett. 2003, 6, 139. antitumor, antibiotic For a cat. enantiosel. 1,3-DC using a heterochiral Yb catalyst, see: Kobayashi, JACS, 1998, 120, 5840. Examples of Asymmetric 1,3-Dipolar Cycloadditions using Nitrones SbF Chiral Metal Complex: 6 H (C F ) P 6 5 2 M O O M = Fe, Ru P(C6F5)2 Ph O M = Fe for the following table Ph entry nitrone enal yield (%) product ee (%)

Me CHO H 1 92 CHO 96 N N Me O O Me CHO H 2 71 CHO >96 N N Me O O CHO CHO H 3 75 75 Me N N O O Me CHO H 4 71 94 N CHO O N Me O Kündig, E. P., et. al.; J. Am. Chem. Soc. 2002, 124, 4968. For a similar system using a Co(salen)* complex, see: Yamada, T., et. al.; Org Lett. 2002, 4, 2457. For a similar system using a bis-TiL2* complex, see: Maruoka, K., et. al.; J. Am. Chem. Soc. 2005, 127, 11926. The One and Only, Enantioselective Organocatalytic 1,3-Dipolar Cycloaddition using Nitrones

Z Z Z N N O N O O R 20 mol% cat. R R1 R R1 CH3NO2-H2O, -20 °C 3-5 d CHO CHO R1 O endo exo

1 Catalyst: entry Z R R endo:exo yield % ee (endo) O Me 1 Bn Ph Me 94:6 98 94 N Ph Me 2 Allyl Ph Me 93:7 73 98 N Me H HClO4 3 Me Ph Me 95:5 66 99

Note: The shown table is abbreviated. 4 Bn C6H4Cl-4 Me 92:8 78 95

5 Bn Cy Me 99:1 70 99 Overall: 15 examples 70-98% yield C H Cl-4 90-99% ee 6 Bn 6 4 H 80:20 80 91

Jen, W. S.; Weinger, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. Synthetic Applications of Nitrones Toward Natural Product Syntheses

Gribble:

O N H H H N 1. 6% Na(Hg), Na2HPO4 N PhCH 0 °C, 40 min, 91% 3 O N H H H H Δ, 5 h N 2. Zn, AcOH/H2O, 50 °C N H 1.5 h, 96% PhO2S PhO S H 2 3. TFA, Δ, 12 h, 77% (—)-hobartine Gribble, G. W.; Barden, T. C. J. Org. Chem. 1985, 50, 5902.

Petrini (not a 1,3-DC):

MOMO OMOM MOMO OMOM PMBMgBr MOMO OMOM HO OH 30% H2O2 MgBr2 (1 equiv) 1. RaNi, H2

PMB + PMB N cat. SeO2 N CH2Cl2 N 2. H3O N H H O OH (—)-anisomycin A 64% yield from A 12% yield from L-tartaric acid Ballini, R.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1992, 57, 1316. A Guide for the Discussion of Dipolar Cycloadditions:

1. Types and Classification of 1,3 Dipoles Ph

2. Molecular Theory Behind 1,3-Dipolar Cycloadditions N

3. Types of Dipoles: W(CO)5 a. Nitrones

b. Nitrile Oxides

c. Carbonyl Ylides H O H OAc Me d. Diazoalkanes O e. Azomethine ylides N O O g. Miscellaneous OTBS O

O Ph O CO2Me O N O O N N R O H H H O O Nitrile Oxides: Powerfull Dipoles in 1,3-Dipolar Cycloadditions

What is a nitrile oxide, and how is it made?

NO2 O Bn MeO N R N alkyl nitro moiety Me H O PhNCO, "Mukaiyama method" OMe O DCC N cat. base T., Mukaiyama; T., Hoshino J. Am. Chem. Soc. 1960, 82, 5339. N M. J., Kurth, et. al.; J. Org. Chem. 2000, 65, 499. Me A. P., Kozikowski; H., Ishida J. Am. Chem. Soc. 1980, 102, 4265. O A. K., Parhi; R. W. Franck Org. Lett. 2004, 6, 3063 O O N HO HO Tf2O, TEA TEA N NCS/NaOCl/Cl2 N OTBDPS R N -40 °C to 0 °C - HCl H R R Cl R O-silylated hydroxamates nitrile oxide hydroximinoyl chloride oxime

E. M., Carreira, et. al.; Org. Lett. 2000, 2, 539. J. W., Bode; E. M. Carreira J. Am. Chem. Soc. 2001, 123, 3611. M. J., Kurth, et. al.; Tet. Lett. 1999, 40, 3535. Relative Reactivity of Dipolarophiles with Nitrile Oxides

A relative reactivity guide for achiral dipolarophiles:

EWG = CO2Me X = O, Si X = OR, SI, EWG, Halogen EWG n = 1, 2 EWG EWG > EWG > X > ≈ Ph ≈ EWG > > ≈ EWG X n Ph

8 6 2-5 1 0.4-0.7 0.01-0.30

Regioselctivity with nitrile oxides: O N MeO R1 R O N Base HON MeO R1 R R O Cl 1 O When R = H: R1 O OMe R Yield (%) A:B A B 2,6-Cl2C6H3 93 93:7 1 CO2Et 94 >99:1 When R ≠ H, the selectivity breaks down to give unpredictable mixtures.

C6H5 99 >99:1 COMe 97 >99:1 Br 89 95:1 COPh 76 >99:1 A., Padwa Synthetic applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products John Wiley & Sons, 2002, p. 377- 2,4,6-Me C H 99 95:5 3 6 2 380. Synthetic Examples of Nitrile Oxides in 1,3-DC reaction: In the 1980's

In the Beginning, it was Kozokowski:

AcO O N OAc HO HN NO2 O AcO H PhNCO N cat. TEA H (1) H 24 hrs NH NH NH NH Isoxazoline Chanoclavine I 70-90% yield

A. P., Kozikowski; H., Ishida J. Am. Chem. Soc. 1980, 102, 4265.

THPO O N Me NO2 OTHP O THPO Me N O N PhNCO H H cat. TEA (2) H H NH NH NH dr = 1:1 NH (+)-paspaclavine

A. P., Kozikowski; Y. Y. Chen J. Org. Chem. 1981, 46, 5250. 1,3-Dipolar Cycloadditions using Nitrile Oxides in the 1980's (cont'd)

More Kozikowski:

H O O E PhNCO E O cat. TEA E NO2 PhH, reflux N N H O H O O 58% yield O H H O E = CO2Me

O CO2Me L-selectride H THF, -78 °C H 72% yield O O H N

O O E PhNCO E H cat. TEA NO2 H N PhH, reflux O H 65% yield H H O O

A. P. Kozikowski, et. al.; J. Am. Chem. Soc. 1984, 106, 1845. 1,3-Dipolar Cycloadditions using Nitrile Oxides moves into the 1990's

Curran(1987): p-phenol O O2N N O O OH O 1. p-ClC6H4NCO H H H TEA, 110 °C 4 steps 8 steps OEt O 2. mCPBA PhS O O 3. NaOH, 80 °C O O Me2OC OEt MeO2C H H H 54% yield over OEt TBSO OEt HO OEt 3 steps Specionin D. P., Curran, et. al; J. Am. Chem. Soc. 1987, 109, 5280.

Kurth:

NO O 2 N Ph Ph p-Ph(NCO)2 N O p-Ph(NCO)2 H NO2 3 steps Ph O cat. TEA cat. TEA Ph O O O N N PhH O O PhH H O O 88% yield 65% yield dr = 9:1 (syn:anti ) H Ph H Ph

M. J., Kurth, et. al; J. Org. Chem. 2000, 65, 499. 1,3-Dipolar Cycloadditions using Nitrile Oxides in the New Millennium

Dr. Mitomycin (Fukuyama):

CO2Et EtO2C O N OCONH2 MeO NOH MeO OMe H OH O NaOCl O multiple steps

CH Cl , 0 °C O 2 2 O O NH Me N Me N Me N p-Ns p-Ns FR-900482 analogue T., Fukuyama, et. al.; Org. Lett. 2001, 3, 2575. Carreira:

OTIPS OH O N O N O OTIPS NOC (EtO)2P (EtO)2P (CH2)3 H OH Me 94% yield Me Me OH

OH O N O R O N O (EtO) P N NOC 2 Me (EtO)2P H Me OH 79% yield OH Me OH S Me Me O Me O OH O J. W., Bode; E. M., Carreira J. Am. Chem. Soc. 2001, 123, 3611. Epothilone A (R = H), B (R = Me) A Guide for the Discussion of Dipolar Cycloadditions:

1. Types and Classification of 1,3 Dipoles Ph

2. Molecular Theory Behind 1,3-Dipolar Cycloadditions N

3. Types of Dipoles: W(CO)5 a. Nitrones

b. Nitrile Oxides

c. Carbonyl Ylides H O H OAc Me d. Diazoalkanes O e. Azomethine ylides N O O g. Miscellaneous OTBS O

O Ph O CO2Me O N O O N N R O H H H O O Carbonyl Ylides: How to Make the Dipole

3 types of carbonyl ylides:

(1) Unstablized ylides (2) Stablized ylides (3) Oxidopyrylium ion

R O O R O R' O R' R R O

Generation of the ylides: The most common method to generate a carbonyl ylide is from a metallocarbenoid: Ph CsF Ph Ph Ph Rh (OAc) TMS O Cl MeCN O O 2 4 O

A., Hosomi, et. al.; J. Org. Chem. 1997, 62, 8610. N2 O O OMe OMe A., Padwa, et. al.; J. Am. Chem. Soc. 1990, 112, 3100. N Δ -N2 O O Ph C6H4Cl Rh (OAc) Ph C6H4Cl N CHCl3 2 4

N2 CN O Ph O CN P. K. Sharma; J., Warkentin Tetrahedron Lett. 1995, 36, 7637. Ph H O M., Hamaguchi, et. al.; Tetrahedron Lett. 2000, 41,1457. Me Me Me O Me 254 nm For a plethora of examples using metallocarbenoids to generate Ph Ph Ph Ph carbonyl ylides, see: A., Padwa Synthetic applications of 1,3-Dipolar hν Cycloaddition Chemistry Toward Heterocycles and Natural Products John Wiley & Sons, 2002, p. 269-301. G. W., Griffin, et. al.; Tetrahedron 1981, 37, 3345. Enantioselective Catalyzed 1,3-Dipolar Cycloaddtions using Carbonyl Ylides Hashimoto:

1 1 MeO2C CO2Me MeO2C CO2Me entry R temp (°C) yield (%) % ee R O N2 1 1 C H 0 77 90 R O 6 5 Rh2L4* (1 mol %) 2 C6H5 -23 54 92 O CF3C6H5 0.08 M, 5 min

3 4-MeC6H4 0 67 92 O O 4 4-MeOC6H4 0 65 90 i-Pr 5 4-ClC6H4 0 78 87 H N L* = Note: The full table conatins 11 examples with 68-92 % ee O O O Rh Rh S.-i., Hashimoto, et. al.; J. Am. Chem. Soc. 1999, 121, 1417.

Suga: O OMe OMe entry temp (°C) yield (%) endo:exo % ee OMe Rh(OAc)2 O O 1 -10 96 88:12 91 CHN 2 -10 82 85:15 82 2 3 -10 53 91:9 89 O O O 4 -10 97 82:18 93 OMe OMe 5 -25 84 73:27 86 (S,S)-Pybox O O M(OTf) 6 -25 77 67:37 83 3 O O

7 -10 84 12:88 45 (exo) O OCH2Ar OCH2Ar OCH2Ar H O O endo exo H., Suga, et. al; J. Am. Chem. Soc. 2002, 124, 14836. Recent Examples of Carbonyl Ylides used in Natural Product Syntheses

Boger:

O O O

N N 1. - N2 N [4 + 2] 2. [3 + 2] N N O O RZ O RZ N N N N 60-88% yield N RZ RE RE RE Me CO2Me Me 11 examples Me H CO2Me CO2Me Core of vinoline D. L., Boger; et. al.; J. Am. Chem. Soc. 2002, 124, 11292. Padwa: O Cl CN H O O Me Me RhII RhII H O O H O Cl CN Me H OH H N2 O Me O HO 74 % yield 68 % yield CH2R Me dr = 4:1 (exo) dr = 3:1 O Illudin M (R = H) A illudin core and ptaquilosin core B Illudin S (R = OH) A., Padwa, et. al.; J. Am. Chem. Soc. 1994, 116, 2667. Synthetic Examples of 1,3-Dipolar Cycloadditions Using Oxidopyrylium Ylide

Wender: HO OH H AcO O O H OAc TBSO DBU Me OAc Me Me H H H CH2Cl2, rt O H O O OH AcO H O Me OH OTBS OTBS OH O phorbol K. C., Nicolaou; S. A., Snyder Classics in Total Synthesis II Wiley-VCH, 2003, Ch. 6.

Magnus: Me Me Me Me Me Me

TFA, CH2Cl2, rt O O O 82% yield HO O O O cyathin core

P., Magnus; L., Shen Tetrahedron, 1999, 55, 3553. A Guide for the Discussion of Dipolar Cycloadditions:

1. Types and Classification of 1,3 Dipoles Ph

2. Molecular Theory Behind 1,3-Dipolar Cycloadditions N

3. Types of Dipoles: W(CO)5 a. Nitrones

b. Nitrile Oxides

c. Carbonyl Ylides H O H OAc Me d. Diazoalkanes O N e. Azomethine ylides O O g. Miscellaneous OTBS O

O Ph O CO2Me O N O O N N R O H H H O O Using TMSCHN2 in 1,3-Dipolar Cycloadditions Carreira:

(1) Methodology

1 1 1 O R O TFA R O 1. NaCNBH R O R2 R2 3 R2 TMSCHN2 CH2Cl2 MeCN R1 TMS N Xc Xc OMe n-Hex:PhMe (1:1) 2. Mg(OMe) R2 O S N N N NH 2 HN NH 2 MeOH 65-78% yield

dr = 9-9.5:1 pyrazolidines Carreira, E. M., et. al.; J. Am. Chem. Soc. 1997, 119, 8379. (2) Total Synthesis

O O O TMSCHN Me 2 5 M NaOH HO OH N then acid workup N 150 °C, 5h O Me NH2 Me O2S N NH O2S 65% yield 68% yield Cα-methyl aspartic acid dr = 94:6 H., Sasaki; E. M., Carreira Synthesis 2000, 1, 135. Me Me Me HN N H N NH2 Xc H Me H O O O R OH N N OBn Me ent-stellettamide A Azomethine Ylides: How they are generated

1 2 R CHO RNHCH2R aldehydes

R R R N R1 N R2 R1 N R2 R1 R2 azomethine ylide aziridines imines

R N 2 3 1 3 R COR R O R

For a general review of azomethine ylides, see: I., Coldham; R., Hufton Chem. Rev. 2005, 105, 2765. Azomethine Ylides: A quick look at FMO

+3 +2 LUMO +1.4 +1 0 Z = electron deficient

HOMO -6.9 C = conjugated -8 R = alkyl -9 -9 X = electron rich -10.9 H N Z C R X

Dipole Dipolarophiles

Intramolecular Tethers:

R R R N N N Type I

N N N Type II

I., Coldham; R., Hufton Chem. Rev. 2005, 105, 2765. Azomethine Ylides Generated From Aldehydes

Kanemasa:

O O O H Ph MeHN CO Me Ph 2 Ph CO2Me CHO PhMe, Δ, 10 h N N CO2Me H Me Me 95% yield single diastereomer

S., Kanemasa; K., Doi; E., Wada Bull. Chem. Soc. Jpn. 1990, 63, 2866.

Harwood:

CHO H Ph O Ph N H N PhH, Δ O Ph N O O H H H O O

61% yield single diastereomer

L. M., Harwood; L. C., Kitchen Tetrahedron Lett. 1993, 34, 6603. Azomethine Ylides Generated From Imines

Parsons: CO2Et CO2Et H Ph TEA, MeCN N TIPSO TIPSO NH H3CO N Ph 9 9 H O O 36% yield O single diastereomer NH Cl

roseophilin P. J., Parsons, et. al.; Synlett. 2003, 1856.

Livinghouse:

MeO MeO —OTf MeO TfO TMS N N TMS CsF N MeO MeO MeO DME, 65 °C O O O 70% yield H single diastereomer erythrinane skeleton

T., Livinghouse, et. al.; J. Org. Chem. 1996, 51, 1159. Azomethine Ylides Generated From Aziridines Ar Ar Huisgen: N N

EtO2C CO2Et EtO2C CO2Et 1 2 hν Disrotatory 110 °C 110 °C Conrotatory Conrotatory

Ar Ar Ar Ar

N CO2Et EtO2C N N EtO2C N CO2Et

EtO2C CO2Et EtO2C CO2Et S S U W trans-1 cis-2

EtO2C CO2Et

Ar = p-MeOC6H4

EtO2C CO2Et EtO2C CO2Et

EtO2C N CO2Et EtO2C N CO2Et Ar Ar R., Huisgen, et. al.; J. Am. Chem. Soc. 1967, 89, 1753. R., Huisgen, et. al.; Tetrahedron Lett. 1966, 397. A Guide for the Discussion of Dipolar Cycloadditions:

1. Types and Classification of 1,3 Dipoles Ph

2. Molecular Theory Behind 1,3-Dipolar Cycloadditions N

3. Types of Dipoles: W(CO)5 a. Nitrones

b. Nitrile Oxides

c. Carbonyl Ylides H O H OAc Me d. Diazoalkanes O N e. Azomethine ylides O O g. Miscellaneous OTBS O

O Ph O CO2Me O N O O N N R O H H H O O Various Dipoles and Dipolarophiles in Dipolar Cycloadditions

Finney: OAc OAc OAc OAc R NaH, Nu-H O O N O O Nu RN3, CH(OEt)3 hν, (CH3)2CO cat. Sc(OTf)3 N NR AcO reflux, 24-36 h AcO N 10-12 h AcO THF, 3-4 h AcO NHR OAc OAc OAc OAc

R. S., Dahl; N. S., Finney J. Am. Chem. Soc. 2003, 126, 8356.

Nair (1,4-Dipolar Cycloaddition):

N CO2Me NTs H CO2Me DME, rt, 3 h N Ts CO2Me 7 examples, 43-92% yields N CO Me 5-10:1 dr 2 R R NTs

N CO2Me Ar 1,4-Dipolar Cycloaddition

CO2Me

V., Nair, et. al.; Org. Lett. 2002, 4, 3575. N Various Dipoles Used to Access N Complex Alkaloid Core Structures O isoschizizygane core

Padwa:

o-NO2C6H4 o-NO C H o-NO C H S 2 6 4 2 6 4 H5C2 O Δ S NH O C C C O O o-NO2C6H4 N O N O S C2H5 C2H5 N O C2H5 66% yield single diastereomer

o-NH2C6H4

+ 1. H2, (Pd/C) H HOAc N N N O N 2. LAH C2H5 N H C2H5 H C2H5

1 : 6

A., Padwa, et. al.; Org. Lett. 2005, 7, 2925. Dipoles Generated by Catalytic Methods Using Various Metals

Iwasawa:

Ph Ph OTIPS Ph OTIPS 10 mol % W(CO) O-i-Pr N 6 O-i-Pr Et3N N N H Et3N, MS4Å, hν PhMe, rt

W(CO)5 W(CO)5

OTIPS Ph Ph O O-i-Pr Et N-H H O 3 3 100 mol % = 84% N N 10 mol % = 71%

W(CO)5 W(CO)5 N., Iwasawa, et. al.; Org. Lett. 2006, 8, 895. Oh: O Me Me Me O 3 mol % AuBr3 O CO Et 1,2-DCE, rt, 8 h 2 CO2Et CO2Et CO Et CO2Et AuBr3 2 EtO2C 80% yield

C. H., Oh, et. al.; Org. Lett. 2005, 7, 5289. One Old Friend, and One Friendly Molecule

Maruoka, Taichi Kano:

O Ti(OiPr)4 Br N NH 4 steps 10 mol % BINOL Me N NH OEt CHO EtO2C O N CH2Cl2, -40 °C CHO HO C N 2 H N 42% yield, 88% ee Manzacidin A

T., Kano, T., Hashimoto, K., Maruoka J. Am. Chem. Soc. 2006, 128, 2174.

Pandey:

O O O OH H AgF O TMS O OH R N R N R CH CN 3 O N H O N H TMS 56% yield Pancracine

R = CH2CH2OBz "Overman Talk" G., Pandey, et. al; Org. Lett. 2005, 3713. Some Conclusions

- 1,3 DC are extremely powerful reactions that can generate multiple chiral centers, various heterocyclic or carbocyclic ring sizes, as well as a wide array of final products.

- There are many different dipoles, and there are various ways to make the more popular dipoles.

- Asymmetric 1,3 DC have good ee's, however lack a wide substrate scope for specific dipoles. This area is still underexplored and will continue to draw interest.

THE END