Voituriez Arnaud

A. B. Charette Group

04/04/2006

Enantioselective Additions of OrganolithiumsDerivatives to Carbonyls

Literature meeting

Content

Introduction

Classes of chiral reagents

General features in enantioselective additions of organolithiums to carbonyls

3-Aminopyrrolidine Lithium Amide: opening of a black box

The industrial synthesis of Efavirenz

Enantioselective Additions of Organolithiums to Carbonyls

Since it is known that organolithium reagents and ligands lithiated in situ form mixed anionic aggregates, the understanding of the nature of these aggregates provides a way to design chiral reagents…

Nucleophilic addition to carbonyl carbon using organometallic reagents(R2Zn, RMgX or RLi) is a central reaction in organic synthesis allowing the formation of C-C bonds.

When a chiral ligand is used, optically active alcohol is obtained:

R1ML* +

O

R2 R3

OH

R2 R1

* R3

Only few examples of asymmetric alkylation reactions using RLi reagenthave been reported.

Classes of Chiral Reagents

These structures share probably a common chelating pattern

Li cation in a five membered metallacycle

Tight experimental conditions (T<-100°C, solvent mixtures)

XLi

Y

RX,Y = O, N

*

AminoalcoholatesDiamines Lithium amides

N

N*

R*OLi R*RNLi

1.

2.

3.

Chiral Diamines and O-alkylated Ligands

NN

Nozaki, 6% (op)TL, 1968, 38, 4097.

O

N

O

N

O

N

O

N

N

N

Seebach, 33% (op)co-solvent: pent / tartrate

ACIEE, 1969, 8, 982.

Seebach, 52% (op)2 equiv. tartrate

HCA, 1979, 62, 1710.

N N

Cram, 95% (op)L*/n-BuLi/PhCHO: 5.0/4.4/1.2

59% (op)L*/n-BuLi/PhCHO: 3.6/3.4/1.2

JACS, 1981, 103, 4585.

ON

Whitesell, 17% (op)L*/n-BuLi/PhCHO:1.6/1.3/1.2

pentane, -78°CJOC, 1981, 46, 2798.

1.

O

HPh

OH

n-BuPh

L*

n-BuLi*

O

HPh

OH

n-BuPh

L*

n-BuLi*

Aminoalcoholates Ligands

NN

HO

Mukaiyama, 72% (op)L*/n-BuLi/PhCHO:4.05/6.75/1.0

benzene, -123°CChem. Lett., 1978, 219.

Mukaiyama, 95% (op)L*/n-BuLi/PhCHO: 4.05/6.75/1.0

MeOCH2OMe/Me2O, -123°CJACS, 1979, 101, 1455.

NN

MeO

Mukaiyama, 14% (op)L*/n-BuLi/PhCHO:4.05/6.75/1.0

Chem. Lett., 1978, 219.

Ph

HO N

Ph

Schön, Naef, 78% (ee)L*/n-BuLi/PhCHO: 1/2/1

82% (ee)L*/n-BuLi/PhCHO: 4/2/1

THF, -78°C.TA, 1999, 10, 169.

N N

HO OH

Colombo, 36% (op)L*/n-BuLi/PhCHO: 3/2/1

DMM, -78°C.T, 1982, 38, 2725.

N N

MeO OMe

Colombo, 15% (op)L*/n-BuLi/PhCHO: 3/2/1

hexane, -78°C.T, 1982, 38, 2725.

Ph

HO NMe2

Ph

Jackman, 75% (ee, GC)L*/n-BuLi/PhCHO: 0.3/0.15/0.1

THF, -78°C.T, 1994, 50, 6109.

Collum, 91% (ee, GC)L*/n-BuLi/PhCHO: 1.5/1/1

THF/pentane, -115°C.JACS, 2001, 123, 8039.

2.

Aminoalcoholates Ligands

Goldfuss, 80% (ee)Tol, -78°C.

X-rayChem. Eur. J., 2002, 8, 5211.Chem. Eur. J., 2004, 10, 5422.

OH

SiMe3

OMe

NOH

Collum, 78% (ee)THF, -78°C.

phenylacetylide additionJOC, 2001, 66, 6291.

OO O

O

O OLn

Li

Li Li

Aspinall, 67% (ee)L*/n-BuLi/PhCHO: 1/2/1

L*/n-BuLi/PhCHO: 1/1/1: 39% eeEt2O, -98°C.

Organomet., 1999, 18, 1366.

OH NBn2

Knollmüller, 32% (ee)L*/n-BuLi/PhCHO: 5.2/9.2/1

Et2O, -78°C.TA, 1999, 10, 3969.

2.

O

HPh

OH

n-BuPh

L*

n-BuLi*

Lithium Amides Ligands

NBn

HN CHPh2

Duhamel, Maddaluno, 73%L*/n-BuLi/PhCHO: 1.5/2.5/1

THF, -78°C.TA, 1997, 8, 1519.

NH

Ph Ph

OMe

Hogeveen, Eleveld, 90% (op)L*/n-BuLi/PhCHO: 4.0/6.7/1.0

DMM/DEE, -116°CTL, 1984, 25, 5187.

Davidsson, 72% (ee, GC)L*/n-BuLi/PhCHO: 1/0.45/0.25

DMM/DEE, -116°CChem. Eur. J. 1999, 5, 2348.

NH

Ph Ph

OMe

Davidsson, 75% (ee)L*/n-BuLi/PhCHO: 1/0.45/0.25

Et2O, -116°C.N-Me, 2% ee

Chem. Eur. J. 1999, 5, 2348.

NH

Ph

OMe

Davidsson, 82% (ee)L*/n-BuLi/PhCHO: 1/0.45/0.25

DME, -116°C.DMM/DME, 91% (ee)up to 98.5 %ee with aliphatic aldehydes

Chem. Eur. J. 1999, 5, 2348.TA 1999, 10, 527.

3.

O

HPh

OH

n-BuPh

L*

n-BuLi*

Better Understanding of the System…

McGarrity1 : « Rapid injection NMR » : n-BuLi additions to PhCHO at –85°C

Dimeric n-BuLi was found to be 10 times more reactive than the tetrameric species.

Reactivity of Li4(n-Bu)2(OBu)2 = Reactivity of (n-BuLi)2

Why the addition of the « chiral L*n-BuLi » instead of the n-BuLi ?

1 JACS 1985, 107, 1810.

n-BuLi + Toluene-d8

THF-d8 Tetrameric n-BuLi + Dimeric n-BuLi(1/6 after 22 s)

Better Understanding of the System…

1 See, for example enolate alkylations JACS 1999, 121, 6213.

Effect of ligand and solvent ?

Coordinating solvents (THF) and/or ligands (TMEDA) de-aggregateorganolithiums and hence give rise to higher reactivities than the oligomers1

Is a catalytic procedure possible?

Because of high reactivity of non-modified organolithiums towards aldehydes,catalytic procedures seem to be hardly possible…

Temperature ?

A maximum of –78°C is necessary…

Better Understanding of the System…

Optimized conditions:

Ethereal solvents, low temperatures, protic ligands

Central role of mixed chiral organolithium aggregates in nucleophilic alkylation

Subject of intensive research…

R2R1X H

X = N, O

R2R1X Li R2R1X Li

Li R3

R4CHOOLi

R4 R3*

R3-Li

R3-H

R3 = n-Bu, Me,...

XR1R2X-Li

R3-Li

Mixed Complex: Li-1 / n-Bu[6Li]

Hilmersson and Davidsson Chem. Eur. J. 1999, 5, 1348.

Mixed Complex: Li-Amide / n-Bu[6Li]

Hilmersson T 2002, 58, 4717.

The mixed lithium amide/n-BuLi B aggregate alkylates faster than the pure n-BuLi oligomers A

A B

Bu Li

Li Bu

Li Bu

LiBu

(n-BuLi)4

O

NPhLi

Li

Me

N

O

Ph

Me

O

NPhLi

Li

Me

n-Bu

(Li-Amide)2Li-Amide/n-BuLi

+ 2 4

n-Bu

HLiO

O H

3-Aminopyrrolidine Lithium Amide

Tetrahedron: Asymmetry 1997, 8, 1519-1523.

J. Am. Chem. Soc. 1997, 119, 10042-10048.

J. Org. Chem. 1998, 63, 8266-8275.

J. Am. Chem. Soc. 2002, 124, 15267-15279.

Pierre Duhamel, Jacques Maddaluno et al.

J. Organomet. Chem. 1997, 549, 81-88.J. Org. Chem. 2000, 65, 8899-8907.

DFT studies, with C. Fressigné, C. Giessner-Prettreand B. Silvi:

J. Org. Chem. 2001, 66, 6476-6479.

Tetrahedron 2002, 58, 4707-4716.

J. Org. Chem. 2003, 68, 1290-1294.

Organometallics 2003, 22, 4090-4097.

J. Org. Chem. 2005, 70, 7816-7828.

Tetrahedron 2005, 61, 3325-3334.

3-AP

N

HN

CH2R

R1

R2

Enantioselective addition to aldehydesNMR studies

Pure Appl. Chem. 2006, 78, 321-331.

N

NH2

CH2R

N

N

CH2R

O

R2R1

R1

R2

NH

NHOOC

OH

1. -CO2

2. ClCOR

OH

COR

N

HN

CH2R

R1

R2

1. ClSO2Me

2. H2NCHR1R23. LiAlH4

LiAlH4

3-Aminopyrrolidine Lithium Amide

N

HN

CH2R

Ph

Ph

O

H

OH

n-Bu3-AP/n-BuLi/RCHO

1.5/2.5/1THF, -78°C 70%, 73%ee

Why are the (R1,R2) groups important?

Enantioselective addition:

Synthesis:

TA 1997, 8, 1519.

3-Aminopyrrolidine Lithium Amide

N

Ph

HNPh

R

N

Ph

LiNPh

NN

LiPh

Ph

Ph

NN

LiPh RPh

Li

R = H, Ph

n-BuLi

1 éq.

n-BuLi

1 éq.

R = H, Ph

3

n

o-TolCHO R = H: 49% ee R = Ph: 73% ee

Norbornyl-like bridged structureExtremely simple spectra

Dimeric lithium amide

The amides A and B adopt drastically different structures in solution:

JACS 1997, 119, 10042.

A

B

N

HNPh

Ph6

5 2

7

N

HNPh

Ph6

5 2

7

Ph

H7 H6

H2

H2’, H5’

H7H6 H2 H2’

H2 H5

H5’

H5

N

NLi

Ph

LiN

N

Ph

Ph

Ph

NN

LiPh

LiPh

NN

LiPh

LiPhPh

5

6

NN

LiPh

Ph

Ph2

7

(-40°C)

(25°C)

(-40°C)

(-70°C)

(-70°C)

(-70°C)

Proposed Models for Tolualdehyde Docking

OH

n-Bu

1. Coordination between the metal cation and the carbonyl oxygen

2. Transfer to the butyl anion onto the carbonyl

3-Aminopyrrolidines Li-Amides as Chiral Ligands for RLi Derivatives

Presence of a Second Asymmetric Center on the 3-AP

JOC 1998, 63, 8266.

JACS 2002, 124, 15267.

n-Buo-Tol

n-Buo-Tol

OH

OH

45%, 80%ee

66%, 74%ee

o-Tol

O

THF, -78°C

o-Tol

O

THF, -78°C

R

S

N

HNPh

RMe

H

N

HNMe

SPh

H

THF, -78°C

THF, -78°C

n-BuLi

n-BuLi NN

LiMe

H

Li

n-Pr

exo

PhMe

NN

LiMe Li

H

PhMe

n-Prendo

R

S

Presence of a Second Asymmetric Center on the 3-AP

Presence of a Second Asymmetric Center on the 3-AP

6Li spectrum of [6Li]-3cIn THF-d8 at –78°C

6Li spectrum of [15N,6Li]-3c

15N spectrum of [15N,6Li]-3c

Quintet : Two 6Li (I=1); 1J = 8.0 HzEmpirical rule: 1J (13C/6Li) = 17/n

13C spectrum of [6Li]-3c

Doublet : One 15N (I=1/2); 1J = 1.3 Hz

A Useless Chiral Center?

Diamine Yield (%) ee (%) Conf.

3rac, 8S 56 65 S3S, 8S 66 74 S

3rac, 8R 62 79 R3S, 8R 42 80 R

(3S,8S) and (3R,8S) 3-AP Lithium amide leading to(S)-1-phenylethanol

Theoretical Consideration

Crucial piece of information, not available from spectroscopy: The approach and docking of the aldehyde on the mixed aggregates

. Oxygen-Lithium coordination

. Tendency for the nucleophile to follow a Burgi-Dunitz type trajectory

JOC 2000, 65, 8899.

Solvent Effect on the Mixed Aggregates

6Li spectra of 3bT 2005, 61, 3325.

Progressive addition of THF-d8 in DEE-d10

1

2

Aldehyde Docking

N Li

NLi

Me

MeH

MePh

S

O

H ArN Li

N Li

Me

MeH

MePh

S

O

H

ArAr

MeHOH (R)

S S

Aldehyde Docking

Fressigné, C.; Giessner-Prettre, C. in progress

NLi

N

Li

Me

Me

H

Me

Ph

S O

HAr

N Li

N

Li

Me

Me

H

Me

Ph

S O H

Ar

H

MeArOH (S)

S S

NN

LiMe

H

Li

Me

Ph

N

HNPh

RN

N

HNPh

Ph

Ph

NN

N

Li

H

Li

Me

Ph

PhPh

NN

LiMeH

Li

Me

Ph

N

HNPh

R

Me

NN

Li

Li

Me

Ph

N

HNPh

R

Me

NMe2

N

Structure Effects

80 % ee (R)Rate = 1

80 % ee (R)Rate = 1

46 % ee (R)Rate = 0.3

71% ee (R)Rate > 1

Enantioselective Hydroxyvinylation with Lithioethenes

Synlett 2005, 10, 1555.

The Bingo Question:

What is the particularity of this molecule?

TsN

The Industrial Synthesis of Efavirenz

N

O

HO

F3CCl

Efavirenz (Merck)

Anti-AIDS drug, a non-nucleoside reverse transcriptase inhibitorfor a variety of HIV-1 mutant strains.

Used worldwide for the treatment of AIDS.

Enantioselective lithium acetylide addition yielding an efavirenz precursor

Nice illustration of interplay between asymmetric synthesis, NMR studies,X-ray structures and computational chemistry.

Grabowski, E. J. J. Chirality 2005, 17, 249.

The Story Begins with L-738,372.

N

N

PGO

Cl

N

NH

PGO

Cl

H

Quininen-BuLi

THF / -25°C

PG =84% Yield97% ee

1.8 Kg scale

Huffman JOC 1995, 60, 1590.

L-738,372

N

NH

HO

Cl

Enantioselective acetylide addition to an imine:

PG = smaller group: lower eeT = -40°C or 0°C: lower ee

At this point, the medicinal chemists were asked to focus their attention on what became efavirenz…

Optimization of the Key Step

The amine is quite acidic, so they decided to protect it:

Ephedrine alkoxides are the best chiral amino alcohols.

Thompson TL 1995, 49, 8937.

The Effect of the Temperature

This is known that the Li-aggregates change with temperature, but is there anyvariations on the ee?

Subsequent experiments showed that the reaction exhibits a nonlinear effect:

50% ee chiral alkoxide yields 77% ee of product, suggesting chiral mixed aggregate…

(30 min)

Necessity of « aging » the alkynylation mixture at 0°C. This « aging » effect implicates an unusually slow aggregate exchange

NMR Studies to Define the Nature of the Aggregation States

Cubic tetramer during the high-Temperature equilibration.

Ratio Ephedrine-Li / Acetylide-Li: 1 / 1

Thompson, Collum JACS 1998, 120, 2028.

Proposed Mechanism

This simple model predicts the observed enantioselectivity for the reaction.

Importance of the Stoichiometry

To complete the reaction, 2 moles of acetylide and 2 moles of ephedrine are needed!

1 2 2

At 1/1/1 ratio, alkynylation proceed rapidly, but only up to 50% conversion at -78°C.When warmed to 0°C, 90% conversion in 5 h, with 70% ee in the last 40% conversion!

So, what is the rather unreactive species formed after 50% conversion?

Infrared spectroscopic studies:Further addition on ketone at –78°C : IR detects CO and NH bands of ketoneNo C-H signal of protonated acetylene

After 50 % conversion: Substrate coexists with rather unreactive species, which does not alkynylate the CO or deprotonate the NH of the substrate!

3:1 alkoxide-acetylide aggregate

Unreactive

After 50% conversion, the product alkoxide is now present in the new

cubic tetramer that is formed.

Importance of the Stoichiometry

Reactive 2/2 aggregateReactive Reactive 3/1 aggregate (X-ray)

UnreactiveSemiempirical (MNDO) computational method

What is the Structure of the Tetramer After the Addition?

Tetramer that has nosymmetry

With 15N-ephedrine two 6Li of the product became doubletWith 15N-ketone, no change in the product spectrum. Xu, Collum JACS 2000, 122, 11212.

Proposed Reaction Pathways

Xu, Collum JACS 2000, 122, 11212.

The Manufacturing Process

4 steps, 76 % overall

Pierce JOC 1998, 63, 8536.

The Manufacturing Process : the Key Step

60 min

The chiral additive is easily recycled from the aqueous layer by basification with NaOH and Toluene extraction (>99% purity, 98% yield)

The Manufacturing Process : Completion of the Synthesis

AcOH, recristalisationTol / Heptane

7 steps, 76 % overall from chloroanilineOver 50 000 Kg have been prepared.

Enantioselective Ketone Alkynylation Reaction Mediated by Chiral Zinc Aminoalkoxides:

Direct Enantioselective Alkynylation of the Unprotected Ketoaniline

Tan ACIEE 1999, 38, 711.

Conclusion

The enantioselective addition of organolithium derivatives to carbonyls isone of the fundamental reactions in organic chemistry

The in-depth study of the chiral entity involved in an enantioselective reactioncan provide essential information regarding the exact mechanism of

asymmetry tranfer, and opening little by little « the black box ».

We have always to keep in mind that one day our ligands can be used in a 50 000 Kg scale

(mine too, if it is possible...)…