Massachusetts Institute of TechnologyOrganic Chemistry 5.511

November 16, 2007Prof. Rick L. Danheiser

Unit 4

Stereocontrolled 1,2-Addition to Carbonyl Groups

General Methods for the Preparation of Organozinc Compounds

Oxidative Addition R-I

Zn, Me3SiClBrCH2CH2Br

THFor

LiNaph, ZnCl2

R-ZnI

Halogen-ZincExchange

Transmetalation

R-I2-5 equiv Et2Zncat CuI or CuCN R2Zn + EtI, Et2Zn (volatile)

RLi or RMgX + ZnBr2 or ZnCl2 R-ZnX

R-BEt2 + 2 equiv Et2Zn, rt (neat) R2Zn + Et3B (volatile)

Lecture 14

Substrate Control: 1,2-Induction by Molecular Framework

Substrate Control: 1,3-Induction by Molecular Framework

Reagent Control: Reduction of Ketones

Reagent Control: Organozinc and Related Addition Reactions

Addition of Alkyl, Aryl, Alkenyl, and Alkynyl Metal Compounds

Asymmetric Addition of Alkenylmetal Compounds to Aldehydes

Alkenylzinc Additions

Case Studies

(1) Synthesis of (R)-(-)-MusconeOppolzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993, 115, 1593

OMe

NHCOCl3

Ph HO2C

NHCOCl3

(2) Synthesis of Allylic Amines and Amino AcidsChen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 12,225

"To obtain the perfume from a musk deer, theanimal is killed and the gland completelyremoved and dried, either in the sun, on a hot stone, or by immersion in hot oil. It appearsin commerce as "musk in pod" (i.e. the glandsare entire) or as "musk in grain" (in which theperfume has been extracted from itsreceptacle). Since obtaining natural muskrequires killing the endangered animal, nearlyall muscone used in perfumery today issynthetic."

Moschus moschiferus

Leopold Ruzicka(1887-1976)

Nobel Prize 1939

Jamison Vinylation

J. D. Morrison ligand

Ar R1

O

HR2

Ni(COD)2 (10 mol%)(+)-NMDPP (20 mol%)

2 equiv Et3BOH

Ar

R1

R2

+

EtOAc-DMI

Frontier: Enantioselective NHK (Nozaki-Hiyama-Kishi) Reactions Y. Kishi et al. J. Am. Chem. Soc. 2004,126, 12248, Org. Lett. 2004, 6, 5031

Asymmetric Addition of Alkenylmetal Compounds to Aldehydes

Asymmetric Addition of Alkynylzinc Compounds to Aldehydes

Reviews:(1) "Asymmetric Alkynylzinc Additions to Aldehydes and Ketones" , Pu, L. Tetrahedron 2003, 59, 9873(2) "Acetylenes in Catalysis: Enantioselective Additions to Carbonyl Groups and Imines and Applications Beyond", Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2004, 4095

Erick M. Carreira

Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442Moslin, R. M.; Miller-Moslin, K. M.; Jamison, T. F. Chem. Commun. 2007, 4441Van Dyke, A. R.; Miller, K. M.; Jamison, T. F. Organic Syntheses 2007, 84, 111

Frontier: Asymmetric Vinylation of Ketones

modified Yoshioka ligand

P. J. Walsh J. Am. Chem. Soc. 2004,126, 6538 J. Org. Chem. 2005, 70, 448 J. Am. Chem. Soc. 2005,127, 8355

Asymmetric Addition of Alkynylzinc Compounds to Aldehydes

OSit-BuMe2

CHO

OSiR3

OH

OAc

OSiR3

OH

OAc

+

OAc1.2 equiv

1.1 equiv Zn(OTf)21.2 equiv Et3N

toluene, rt

OH

NMe2

HO NMe2

MePh

HO NMe2

MePh

80

96

9

20

4

91

1.2 equiv

E. M. Carreira et al. J. Am. Chem. Soc. 2001, 123, 9687, Org. Lett. 2001, 3, 3017Double Asymmetric Synthesis: Carreira Alkynylation

L. Pu et al. PNAS 2004, 101, 5417; J. A. Marshall et al. Org. Lett. 2003, 5, 3197 Also see J. A. Baldwin et al. Tetrahedron 2005, 61, 7219

Double Asymmetric Synthesis: Chan-Pu Alkynylation

OSit-BuMe2

CHO

OSiR3

OH

SiMe3 OSiR3

OH

SiMe3

+SiMe3

4 equiv

4 equiv Et2Zn4 equiv Ti(OiPr)4toluene-Et2O, rt

no ligand

(S)-BINOL

(R)-BINOL

Carreira method

45% 85 15

55% 45 55

60% 92 8

70%

69%

0.4 equiv

0.4 equiv

0%

Review: "Alkynylation of Chiral Aldehydes: Alkoxy-, Amino-, and Thio-Substituted Aldehydes", Guillarme, S.; Pie, K.; Banchet, A.; Liard, A.; Haudrechy, A. Chem. Rev. 2006, 106, 2355

M. Shibasaki et al.

Frontiers in Asymmetric Alkynylation

B. M. Trost et al. J. Am. Chem. Soc. 2006, 128, 8; Org. Lett. 2006, 8, 4461

J. Am. Chem. Soc. 2005, 127, 13,760Chem. Commun. 2007, 948

Takita, R.; Harada, S.; Ohshima, T.;Matsunaga, S.; Shibasaki, M.Organic Syntheses 2007, 85, 118

73-77%, 98% ee

83-89%, 99% ee

O

O

Me

OMe O O

NOHN

OOMe

O

O

Me

Me

Leucascandrolide A

H

H

H

Case Study

Fettes, A.; Carreira, E. M.J. Org. Chem. 2003, 68, 9274