postdoc-hélène lebel (advisor : prof. eric n. jacobsen)

1

KINETIC RESOLUTION OF 2,2-DISUBSTITUTED EPOXIDES KINETIC RESOLUTION OF 2,2-DISUBSTITUTED EPOXIDES APPLICATION TO THE TOTAL SYNTHESIS OF TAUROSPONGIN AAPPLICATION TO THE TOTAL SYNTHESIS OF TAUROSPONGIN A

Postdoc-Hélène Lebel(Advisor : Prof. Eric N. Jacobsen)

January 1998-June 1999

2

Isolation and Biological ActivitiesIsolation and Biological Activities

HO3S

HN

O OH O O

O O

Taurospongin A

13

Kobayashi and coworkers, J. Org. Chem. 1997, 62, 3831-3836.

•Isolated from Okinawan marine sponge Hippospongia sp.

•Inhibitory activity against DNA polymerase (IC50 = 7.0 µM) and HIV reverse transcriptase (IC50 = 6.5 µM).

•Weak inhibitory activity against c-erB-2 kinase (IC50 = 28 µg/mL).

•No cytotoxicity against murine lymphoma L1210 and human epidermoid carcinoma KB cells (IC50 > 10 µg/mL).

3

Proposed Synthetic ApproachProposed Synthetic Approach

HO3S

HN

O OH O O

O O 13

O OH O OPG

O

PGO

PGOO

3 7 9

3 7 9

3

Kinetic resolution of 2,2-disubstituted epoxides.

4

Kinetic Resolution of Epoxides by Asymmetric Ring OpeningKinetic Resolution of Epoxides by Asymmetric Ring Opening

RO

NuX RO

R

OXNu

Cat*

Max y. : 50% Max y. : 50%

RO

+ +

•50% waste of the material: starting material has to be inexpensive.

•Easy separation of epoxide and product.

•Possibility of high ee for the recovered substrate, even with moderately selective systems.

Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5-26.Robinson, D.; Bull, S. D. Tetrahedron: Asymmetry 2003, 14, 1407-1446.

5

Kinetic Resolution of Epoxides : Theoretical ConsiderationsKinetic Resolution of Epoxides : Theoretical Considerations

krel = ln[(1-c)(1-ee)]ln[(1-c)(1+ee)]

kf

ks=

Recovered Substrate Product

= ln[(1-c)(1+ee)]ln[(1-c)(1-ee)]

krelkf

ks=

6

Kinetic Resolution of Epoxides : Chromium and Cobalt CatalystsKinetic Resolution of Epoxides : Chromium and Cobalt Catalysts

RO

(±)N N

HH

O OM

t-Bu

t-But-Bu

t-Bu

(S,S)-1 : M = Cr(N3)(S,S)-2 : M = Co(OAc)

RO

(±)

(S,S)-1 (0.5-2.0%)

TMSN3 (0.5 equiv) R

OTMSN3

40-49% y.89-98%ee

krel = 44-280

H2O (0.5 equiv)

Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 7420-7421.

(S,S)-2 (0.5-2.0%)R

OR

OH+ OH krel = 50 - >400

44-46% y.98-99%ee

38-50% y.86-98%ee

Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936-938.

Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307-1315.

7

Crystal Structure of (S,S)-(Salen)CrNCrystal Structure of (S,S)-(Salen)CrN33 complex complex

Karl B. Hansen

8

Kinetic Resolution of 2,2-Disubstituted EpoxidesKinetic Resolution of 2,2-Disubstituted Epoxides

•Discrimination between a methyl and an alkyl group.

•Increase the global steric hindrance : deleterious for catalytic activity.

H

OMe

Me

OH

Me

OR

R

OMe

krel = >400

X X

9

Solvent Conversion

0.5 equiv

0.5 equiv

0.5 equiv

2.0 equiv

TBME---

---

0%

0%

0%

0%

OR ee (epoxide)

OBn

OBn

2.0 equiv

2.0 equiv

TBME

TBME

0%

0%

---

------

---

---

---

2.0 equiv TBME 0% ---

2.0 equiv TBME 0% ---

OBn 0.5 equiv CoOAc (1.0 equiv) TBME 50% (40 h)(OAc)

0%

Entry

1

2

3

4

5

6

7

8

9

H2O

THF

M

OTBS

OTBS

OTBS

OTBS

CoOAc

CoOAc

CoOAc

CoOAc

CoOAc

CoOC(CF3)

OTBS CoOC(CF3)

OH CoOC(CF3)

Hydrolytic Kinetic Resolution of 2,2-Disubstituted EpoxidesHydrolytic Kinetic Resolution of 2,2-Disubstituted Epoxides

ROO

H2O (x equiv) / solvent RO

ROH

OH+

(R,R)-(Salen)M (2 mol%)X

10

Kinetic Resolution of 2,2-Disubstituted EpoxidesKinetic Resolution of 2,2-Disubstituted EpoxidesR

OR'OH (x equiv) R

O

ROR

OH+

(R,R)-(Salen)M (2 mol%) X

PhOH (2.0 equiv)

PhOH (2.0 equiv)0%

0%

---

---PhOH (2.0 equiv)

PhOH (2.0 equiv)

0%

0%

---

---

n-Pr

R'OH (x equiv) Conv. ee (epoxide)

OBn

OBn

OBn

AcOH (0.5 equiv)

AcOH (0.5 equiv) +EtN(i-Pr)2 (0.5 equiv)

0% ---

AcOH (0.5 equiv)

(R,R)-CoOAc (0.01 equiv)+ (R,R)-CrN3 (0.01 equiv)(S,S)-CoOAc (0.01 equiv)+ (R,R)-CrN3 (0.01 equiv)

0% ---

(R,R)-CoOAc (0.01 equiv)+ (R,R)-CrN3 (0.01 equiv)OBn

OBn

AcOH (0.5 equiv)

AcOH (0.5 equiv)

AcOH (0.5 equiv)

15% (40 h)

0%

---

20% (40 h)

0% ---

Entry

1

23

4

5

6

7

8

9

10

0% ---

OTBS

OTBS

CoOAc

CoOC(CF3)

OH

OH

CoOAc

CoOC(CF3)

R M

CoOAc

CrN3

CoOAc

11

TBSOO

TMSN3 (0.5 equiv) / TBME

TBSOO

TBSON3

OH

+(S,S)-(Salen)CrN3 (2 mol%) TBSO

OTMSN33 days

1 : 135-40% conv.

Kinetic Resolution of 2,2-Disubstituted Epoxides Kinetic Resolution of 2,2-Disubstituted Epoxides with Trimethylsilyl Azidewith Trimethylsilyl Azide

12

Proposed Catalytic Cycle for the (Salen)Cr(III) Catalyzed Proposed Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of Epoxides with TMSNAsymmetric Ring Opening of Epoxides with TMSN33

N3

Cr

O

Cr

RO

RN3

RN3

OH

RN3

OTMS

Hansen, K. B.; Leighton, J. L.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 10924-10925.

TMSN3

HN3

13

Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of 2,2-DisubstitutedRing Opening of 2,2-Disubstituted Epoxides with TMSNEpoxides with TMSN33

N3

Cr

O

Cr

RO

RN3

RN3

OH

R'

R'

R'

RN3

OTMSR'

TMSN3

HN3

X

14

Kinetic Resolution of 2,2-Disubstituted Epoxides with Kinetic Resolution of 2,2-Disubstituted Epoxides with Trimethylsilyl AzideTrimethylsilyl Azide

TBSOO

TMSN3 (0.5 equiv), ROH / TBME TBSOO

TBSON3

OH+

(S,S)-(Salen)CrN3 (2 mol%)

12 hours

Conversion

i-PrOH (1.0 equiv) 35%

45%

0%

i-PrOH (0.5 equiv)

MeOH (1.0 equiv)

ROH

15

Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of Epoxides with TMSNRing Opening of Epoxides with TMSN33 and 2-Propanol and 2-Propanol

N3

Cr

O

Cr

RO

RN3

RN3

OH

R'

R'

R'

RN3

OTMSR'

TMSN3 + i-PrOH

TMSN3

HN3

X

i-PrOTMS

16

Kinetic Resolution of 2,2-Disubstituted Epoxides Kinetic Resolution of 2,2-Disubstituted Epoxides with HNwith HN3 3 Catalyzed by a (Salen)Cr(III) ComplexCatalyzed by a (Salen)Cr(III) Complex

RO

TMSN3, i-PrOH / TBME RO(R,R)-(Salen)CrN3 (2 mol%)

Entry Epoxide Reagents (equiv) Yield ee

1

2

3

4

OTBSO

OBnO

OPh

O

O5

0.55

0.55

0.60

0.55

0.50

42%

44%

44%

42%

46%

99%

95%

97%

99%

98%

Lebel, H.; Jacobsen, E. N. Tetrahedron Lett. 1999, 40, 7303-7306.

17


R1

R2O

TMSN3, i-PrOH / TBME R1

R2O

(Salen)CrN3 (2 mol%)+

R1

R2HON3 +

R1

R2N3

OH

external internal

Entry Epoxide Conv. ee (epoxide)

1

2

3

50%

35%

≤5%

36%

25%

---

Regio (ext:int)

PhO

O

O

1.5 : 1

1 : 3

---

18


RO

TMSN3, i-PrOH / TBME RO(R,R)-(Salen)CrN3 (2 mol%)

Entry Epoxide Reagents (eq) Yield ee

1

2

3

4

EtO2CO

t-BuO2CO

PhO

O

0.65

0.55

0.50

0.50

37%

46%

45% conv.(1 : 6, ext:int)

50% conv.(<1 : 10, ext:int)

74%

85%

41%

10%

19


TMSN3, i-PrOH / TBME

(R,R)-(Salen)CrN3 (2 mol%)R

TMS

O

RTMS

O

Entry Reagents (equiv) Yield ee (epoxide)

1

2

3

0.50

0.50

0.70a


48%


16%

45%

80%

No Reaction is observed with epoxides substituted by terminal alkyne.

Me

a 5 mol% of (R,R)-(Salen)CrN3 was used.

R

20

Kinetic Resolution of 2,2-Disubstituted Epoxides: Formation of Azido Alcohols

O

TMSN3 (0.5 equiv), i-PrOH (0.5 equiv)

(R,R)-(Salen)CrN3 (2 mol%) / TBME

BnOO

BnO49% y. 88% ee

HO

BnON3

N3

BnOOH

+

46% y. 93% ee 4% y. 20% ee

Two reaction pathways:

-Highly selective terminal attack-Poorly selective internal attack

Variation of the ratio of regioisomers with conversion

21

Proposed Cooperative MechanismProposed Cooperative Mechanism

•No reaction background in absence of catalyst.•Catalyst concentration did not affect the regioselectivity.•No erosion of the enantiomeric excess

Rate = kobs[catalyst]2[epoxide]-1[HN3]0

N3

Cr

O

N3

Cr+ N3

O CrCr

N3

Selective Pathway: bimetallic

Unselective Pathway: monometallic (????)

O

N3

Cr+ N3

O Cr N3

TerminalAttack

InternalAttack

Me

R

R Me

R Me

MeR

In the case of the desymmetrisation of meso epoxides:

HN3

22


OR

HOR N3

N3

R OH

OR

OHR N3

N3

R OH

kterm

kterm

kint

kint

kterm S >>>> kint S > kterm R ~ kint R

R

S

23


TMSN3, i-PrOH / TBME

(R,R)-(Salen)CrN3 (2 mol%)

RO

R

HON3

Entry Azido Alcohol Reagents (equiv) Yield ee

1

2

3

4

5

0.50

0.50

0.50

0.50

0.50

46%

47%

45%

44%

40%

93%

90%

92%

95%

99%

HO

BnON3

HO

TBSON3

HO

PhN3

HON3

HON3

24

Kinetic Resolution of 2,2-Disubstituted Epoxides Kinetic Resolution of 2,2-Disubstituted Epoxides with Chromium Catalyst and TMSNwith Chromium Catalyst and TMSN33

TBSOO

TMSN3 (0.65 equiv)i-PrOH (0.65 equiv) / TBME TBSO

O(S,S)-(Salen)CrN3 (2 mol%)0 °C, 12 hours

37% yield (5.5 g)97% ee, krel = 14

(15 g, 69 mmol)

TBSOO

Absolute Stereochemistry

1. TBAF / THF2. NaH, BnBr / THF, DMF

BnOO

[α]D = +7.89 (c 3.40, CHCl3)

Lit: [α]D = +9.60 (c 2.95, CHCl3)

G ill, M.; Sm rdel, A. F. Tetrαhedron: Asym m etry 1990, 1, 453-464.

25

Retrosynthetic AnalysisRetrosynthetic Analysis

HO3S

HN

O OH O O

O O 13

O OH O OPG

O

PGO

3 7 9

3 7 9

OPG

PGO 3

O OPG

7 9

OPG

PGO 3

O OH

9ROPGOO

3

26

Synthesis of PrecursorsSynthesis of Precursors

TBSOO

H , BuLi (1.5 equiv)BF3•OEt2 (1.5 equiv) / THF

-78 °C to rt 81% y.

TBSO

OH

TBSO

OTES

TESOTf2,6-lutidine

CH2Cl2

97% y.

MeO

OO

1. (R)-BINAP-Ru(II)H2 (100 atm) / MeOH

2. TBSCl, Imidazole

MeO

OTBSO84% y. (2 steps)99% ee

Noyori and coworkers JACS 1988, 110, 629-631; Tet. Lett. 1991, 32, 4163-4166.

CH2Cl2

27

Synthesis of Ketone by Alkylation of anSynthesis of Ketone by Alkylation of an in-situ Generated Weinreb Amidein-situ Generated Weinreb Amide

R OMe

ClMgO N(OMe)Me

R N(OMe)Me

O

R Ph

O

-MeOMgClOMeClMg

O N

PhR

Me

Me(MeO)NMgCl

RCO2Me

PhMgCl

NH

OOMeMe

H

HHO

H

Me 1. Me(MeO)NH•HCl (1.25 equiv) / THF

2. PhMgCl (8 equiv) / THF, -5 °C

NH

OPhMe

H

HHO

H

Me

Williams and coworkers Tet. Lett. 1995, 36, 5461-5464.

87% yield

28

Synthesis of Propargylic KetoneSynthesis of Propargylic Ketone

TBSO

OTES

MeO

OTBSO

N

OTBSO

Me

MeOTBSO

OTES Li

t-BuLi / THF-78 °C

Me(MeO)NH2Cl, i-PrMgClTHF, int. temp. < -10 °C

TBSO

OTES

O OTBS72% y.

-10 °C to 60 °C

TBSO

OTES24%

1.0 equiv 1.0 equiv

29

Diastereoselective Reduction of Diastereoselective Reduction of -Alkoxy Ketone-Alkoxy Ketone

O OPG

R

OH OPG

R

OOPG

M

H

"H" from the bottom face

Via:

Key issues:

•Need to differentiate both alcohols.

•Few examples with only modest stereoselectivities for 1,3-induction with chelating protecting group.

Alternative solution:

•Use chiral catalyst capable of overriding any inherent substrate bias.

30

Asymmetric Transfer Hydrogenation of Asymmetric Transfer Hydrogenation of α,α,-Acetylenic Ketones-Acetylenic Ketones

R1R2

O

R1R2

OH

NH

RuNPh

Ph

Ts

0.5 mol%

Noyori and coworkers J. Am. Chem. Soc. 1997, 119, 8738-8739.

85-99% y.95-99% ee

NH

RuNPh

Ph

Ts

NH2

NHPh

Ph

Ts

+ [RuCl2(h6-p-cym ene)]2

i-PrOH

31

Asymmetric Transfer Hydrogenation of Asymmetric Transfer Hydrogenation of α,α,-Acetylenic Ketones-Acetylenic Ketones

OTES

O OTBS

TBSO

OTES

OH OTBS

TBSO

OTES

O OTBS

TBSO

OTES

OH OTBS

NH

RuNPh

Ph

Ts

2 mol%

87% yield≥20:1 dr

Both diastereoisomers areseparable by flash chromatography.

NH

RuNPh

Ph

Ts

94% yield≥20:1 dr

TBSOi-PrOH

i-PrOH

32

Synthesis of the Saturated DiolSynthesis of the Saturated Diol

TBSO

OTES OAc OTBS

TBSO

OTES

OH OTBS

1. Pd(OH)2, Et3N / EtOAc, H2

2. Ac2O, DMAP / Pyridine

HO

OH OAc OTBS

TBAF, HOAcTHF

92% y. (2 steps)

86% y.

33

Taurine Coupling : First AttemptTaurine Coupling : First Attempt

HO

OH OAc OTBS

HO

OH OAc OTBSO

HN

OH OAc OHOHO3S

HN

OH OH OAcOHO3S

+

1. EtO2CCl, Et3N / THF

2.

Et3N / H2O, MeCN

Tempo, Aliquat 336, KBr, NaOCl H2O, CH2Cl2

78% y.

HO3SNH2

34

Synthesis of Unsaturated Fatty Acid ChainSynthesis of Unsaturated Fatty Acid Chain

MeO2CHO2C

Br OTBS+

1. n-BuLi / THF, HMPA, -45 °C

2. p-TsOH (cat) / MeOH, reflux

OH

78% yield

MeO2C

CHO

PDC / CH2Cl2Celite, MS 4A

74% yield

1. (PhO)3P, I2

2. Ph3P / CH3CN, reflux

87% yield (2 steps)

IPh3P (CH2)15CH3HO (CH2)15CH3

O 13

HO

35

Synthesis of Unsaturated Fatty Acid ChainSynthesis of Unsaturated Fatty Acid Chain

MeO2CH

O

IPh3P (CH2)15CH3 +

(2.0 equiv)NaHMDS (1.8 equiv) / THF

-20 °C to rt

O 13

MeO

72% yield (1 isomer, NMR)

O 13

HO

LiOH 1N / MeOH, THF83% yield

34% overall yield, 5 steps

36

Esterification with the Unsaturated Fatty Acid ChainEsterification with the Unsaturated Fatty Acid Chain

HO

OH OAc OTBS

1. Tempo, Aliquat 336, KBr, NaOClH2O, CH2Cl2

2. Allyl bromide, i-Pr2NEt / CH2Cl2

81% yield (2 steps)

O

OH OAc OTBSO

1. HF•Pyr / Pyr, THF

2. DIC, i-Pr2NEt, DMAP HO

O 13

O

O OH O O

O O 13

75% yield (2 steps)

CH2Cl2

37

Completion of the SynthesisCompletion of the Synthesis

O

O OH O O

O O

Taurospongin A

13

HO3S

HN

O OH O O

O O 13

1. Pd(PPh3)4, pyrrolidine / CH2Cl22. EtO2CCl, Et3N / THF

3.

Et3N / MeCN, H2O (1:1)

68% yield (3 steps)

HO3SNH2

MeO3S

HN

O OH O O

O O 13

CH2N2

[α]D = -3.0° (c 0.53, CHCl3)Lit: [α]D = -1.4° (c 0.78, CHCl3)

Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624.

38

STEREOSELECTIVE CYCLOPROPANATION OF ALLYLIC ALCOHOLS: STEREOSELECTIVE CYCLOPROPANATION OF ALLYLIC ALCOHOLS: APPLICATION TO THE TOTAL SYNTHESIS OF (+)-U-106305APPLICATION TO THE TOTAL SYNTHESIS OF (+)-U-106305

Ph.D. Thesis-Hélène Lebel(Advisor : Prof. André B. Charette)

May 1993-December 1997

39

OTi

O

OO

i-PrO Oi-Pr

PhPh Ph

Ph 1995

(ChristianBrochu)

Stereoselective Cyclopropanations: An OverviewStereoselective Cyclopropanations: An OverviewRelative Stereocontrol

Absolute Stereocontrol

"CH2"R2 R4

R1

R3 R3

R1

R4R2

OH OH

•Cyclic Substrates : Weinstein, Dauben, Denmark - Sylvie Prescott

•Acyclic Substrates : Pereyre, Molander - Hélène Lebel

"CH2"R2 OH

R1

R3 R3

R1

OHR2

•Chiral Auxiliary •Chiral Stoichiometric Ligand •Chiral Catalyst

1991(B. Côté, J.F. Marcoux, N. Turcotte)

OBnO

BnOBnO

OHO

R1

R2

R3

OB

O

Bu

CONMe2Me2NOC

1994

(Hélène Juteau)

40

Stereoselective Cyclopropanations Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcoholsof Acyclic Chiral Allylic Alcohols

Anti Syn

"CH2" "CH2"R4R2

R1

R3

OH

R4R2

R1

R3

OH

R4R2

R1

R3

OH

41

Stereoselective Cyclopropanations of Acyclic Chiral Allylic Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols : Literature Precedent (1994)Alcohols : Literature Precedent (1994)

OH OH

M. Pereyre J. Chem. Research. Synop. 1978, 179.

Zn-Cu, CH2I2Et2O, Reflux

RatioSyn/Anti

E = 57 : 43

Z = >99 : 1

"CH2" = IZnCH2I / Et2O

Ph R

OH

Ph R

OH

G. Molander J. Org. Chem. 1989, 54, 3525-3532. M. Lautens J. Org. Chem. 1992, 57, 798-800.

Sm(Hg), CH2I2THF, -78 °C to rt

"CH2" ISmCH2I / THF

R = Bu, 1 : 1.4R = Me, 1 : 6

=

R = i-Pr, 200 : 1

Me

N

N

MeO

OMeOH

Me

N

N

MeO

OMeOH

Schöllkopf et al. Liebigs Ann. Chem. 1991, 857 and Tetrahedron 1988, 44, 5293.

Et2Zn (2.5 equiv), CH2I2 (2.5 equiv)

Hexanes>98% de

"CH2" EtZnCH2I / Hexanes=

42

Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Zinc ReagentsZinc Reagents

Intramolecular Hydrogen Bonding : Separation of both diastereomers by TLC

H. Mollendal Acta Chem. Scand. 1992, 46, 861. L. Joris J. Am. Chem. Soc. 1968, 90, 327.

Me Me

O

-polar (H-Bond)

H

Me Me

OH

+polar (no H-Bond)

Ph Me

OH

Ph Me

OHEt2Zn, CH2I2

CH2Cl2, 0 °C to rt

RatioSyn / AntiConversion

75% 6.6 : 1

3.2 : 1>98%

2.3 : 1

85%

Zinc reagent

2 1

5 5

10 5

2 4

5 10

EtZnCH2I + Et2Zn

95%

>98% 7.0 : 1

6.6 : 1

Et2Zn CH2I2

EtZnCH2I

EtZnCH2I

Zn(CH2I)2

Zn(CH2I)2

43

Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Determination of the Relative StereochemistryDetermination of the Relative Stereochemistry

Ph O

OMeH

NO2Ph

Op-NO2Bz

44

R1 R2

OH

R1 R2

OHEtZnCH2I (5 equiv)

CH2Cl2, -10 °C to rt

Stereoselective Cyclopropanations with Zinc Reagents :Stereoselective Cyclopropanations with Zinc Reagents :E-Disubstituted Chiral Allylic AlcoholsE-Disubstituted Chiral Allylic Alcohols

Allylic alcoholRatio

Syn / AntiYield

86% 7 : 1

87%

130 : 1

110 : 1

75% 6 : 1

97%

Ph Me

OH

Me Me

OH

Ph Et

OH

n-Pr Et

OH

Allylic alcoholRatio

Syn / AntiYield

98% 150 : 1

>200 : 1

97% >200 : 1

84%

Ph Bu

OH

Ph i-Pr

OH

Ph t-Bu

OH

45

R1 R4

OH

R1 R4

OHEtZnCH2I (5 equiv)


R2

R3

R2

R3

Stereoselective Cyclopropanations with Zinc Reagents :Stereoselective Cyclopropanations with Zinc Reagents :E-Disubstituted and Z-Trisubstituted Chiral Allylic AlcoholsE-Disubstituted and Z-Trisubstituted Chiral Allylic Alcohols

Charette, A. B., Lebel, H. J. Org. Chem. 1995, 60, 2966-67

OH

Me

Ph

Ph Et

OH

Me

Ph Me

OH

Me

96%

>200 : 1

>200 : 1

98%

Allylic alcohol

95%

YieldRatio

Syn / Anti

33 : 1

95% >200 : 1

Allylic alcohol YieldRatio

Syn / Anti

OH

Et

Ph

46

Stereoselective Cyclopropanations of Chiral Allylic AlcoholsStereoselective Cyclopropanations of Chiral Allylic Alcohols

Zn(CH2I)2 IZnCH2I ZnI2

Zn(CH2I)2

EtZnCH2I

Et2Zn

Zn(CH2I)2 Et2Zn

IZnCH2I

EtZnI

2 EtZnCH2I

IZnCH2I ZnI2

IZnCH2I2

LewisAcid

Sterichindrance EtZnCH2I EtZnI

Diastereoselectivity = 1 : 1



47


Et2ZnCH2I2

EtH

Ph

H

OZnEtCH3

ZnICH2Et

Ph

H

OZnEtCH3

Ph

H

OHCH3

H H H

Et2Zn

+

EtZnCH2I

Ph

H H

OZnEtCH3

ZnIEt

Syn

48


Et2ZnCH2I2

Ph

CH3

HOZnEt

Ph

CH3

HOH

H H

Et2Zn

+

EtZnCH2IPh

H

OZnEtH

CH3

ZnEt

ICH2

EtH

Ph

H

OZnEtH

CH3

ZnEt

I

Anti

49

R1 R4

OBn

R1 R4

OBnEtZnCH2I (5 equiv)


R2

R3

R2

R3

+ R1 R4

OBnR2

R3Syn Anti

Stereoselective Cyclopropanations of Chiral Allylic EthersStereoselective Cyclopropanations of Chiral Allylic Ethers

Allylic etherRatio

Syn / AntiYield

94% 1 : 9 88%

1 : 2

1 : 2

98% 1 : 7

97%

Ph Me

OBn

Ph Me

OBn

Ph Et

OBn

n-Pr Et

OBn

Allylic etherRatio

Syn / AntiYield

15 : 1

82% 19 : 1

85%

Ph i-Pr

OBn

Me

OBnPh

50


R1 R4

OMe

R1 R4

OMeEtZnCH2I (5 equiv)


R2

R3

R2

R3

+ R1 R4

OMeR2

R3Syn Anti

Allylic etherRatio

Syn / AntiYield

95% 1 : 2

3 : 193%

Ph Me

OMe

Ph Et

OMe

17 : 1

94% >20 : 1

80%

Ph i-Pr

OMe

Me

OMePh

51


Ph

OBn

CH3

HH

EtZnCH2I

Ph HCH3

OBnZn

Et

ICH2

Ph

OBn

CH3

HH

Anti

52

Stereoselective Cyclopropanations Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcoholsof Acyclic Chiral Allylic Alcohols

Anti Syn

"CH2" "CH2"R4R2

R1

R3

OH

R4R2

R1

R3

OH

R4R2

R1

R3

OH

Chiral Ligand ????

53

R2

R1

R3OH R2

R1

R3OH

OB

O

Me2NOC CONMe2

Bu

2 equiv Zn(CH2I)2 or Zn(CH2I)2•DME

1.1 equiv

Enantioselective Cyclopropanations of Allylic Alcohols : Enantioselective Cyclopropanations of Allylic Alcohols : Chiral DioxaborolaneChiral Dioxaborolane

Ph OHOH

Bu3Sn OHBu3Sn OH

95% yield94% ee

BnO

93% yield91% ee

I OHI OH

88% yield90% ee

73% yield90% ee

83% yield90% ee71% yield

83% ee

OH

85% yield94% ee

OH

OTIPS85% yield88% ee

Ph OH

96% yield85% ee

Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651. Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995, 60, 1081. Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120, 11943.

54

Me

OH

Ph Me

OH

Ph Me

OH

Ph

+

Me

OH

Ph

+

MePh Me

OH

Ph+

320 : 48

520 : 1

anti-(S)

anti-(R)

syn-(S)

syn-(R)

OB

O

Me2NOC CONMe2

Bu

OH

(S)

(R)

Zn(CH2I)2

Enantioselective Cyclopropanations of Chiral Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral DioxaborolaneAllylic Alcohols : Chiral Dioxaborolane

No possibility for kinetic resolution : both enantiomers react at the same rate

55

R1 R3

OH

R1 R3

OH

CH2Cl2, -10 °C

Zn(CH2I)2, 2.2 equiv., Ligand, 1.2 equiv.

R2 R2


Allylic alcohols Ratio Syn / AntiYield

98%74% (80%)

<1 : 200 1 : 12

Ph Me

OH

Ph Me

OH

Ph Et

OH

n-Pr Et

OH

Chiral Ligand

R,RS,S

R,RS,S

R,RS,S

R,RS,S

Me

92%57% (60%)

<1 : 200 1 : 20

83%54% (59%)

1 : 281 : 12

84%54% (59%)

1 : 321 : 12

56


R1 R3

OH

R1 R3

OH

CH2Cl2, -10 °C

Zn(CH2I)2, 2.2 equiv., Ligand, 1.2 equiv.R2 R2

Allylic Alcohol Ratio Syn / AntiYield

Ph i-Pr

OH

Et

OH

Chiral Ligand

R,RS,S

R,RS,S

40% (63%)16% (37%)

1 : 1.81.6 : 1

30%20%

>20 : 1>20 : 1

Ph

Charette, A. B.; Lebel, H.; Gagnon, A. Tetrahedron 1999, 55, 8845-8856.

57


OB

O

CONMe2Me2NOC

Bu O PhZn

CH2I

HO Ph

Me AntiH

HO Ph

H SynMe

58

U-106305(or any of other 63 isomers)

NH

O

Novel cholesteryl ester transfer protein inhibitor

Kuo and coworkers, J. Am. Chem. Soc. 1995, 117, 10629-10634. (Upjohn)Isolation:

Biological Activity:

Structure and Biological Activity of U-106305Structure and Biological Activity of U-106305

High Density Lipoproteines(HDL)

Cholesterol

Cholesteryl ester transfer protein

Very Low and Low Density Lipoproteines

(VLDL and LDL)Cholesterol

•Decrease the concentration of cholesterol in HDL: increase of coronary risk.•Animals deficient in plasma cholesteryl ester transfer activity are resistant to atherosclerosis.•Human with a genetic deficiency of CETP have an apparent resistance to atherosclerosis.

P. Barter and K.-A. Rye Clinical and Experimental Pharmacology and Physiology 1994, 21, 663-672.

59

MeHN

O

RO Me

ROOH

Retrosynthetic Analysis of U-106305Retrosynthetic Analysis of U-106305

60

Retrosynthetic Analysis of U-106305Retrosynthetic Analysis of U-106305

HOOH

HOOH

HOOH

HOOH

HOOH

61

Synthesis of theTricyclopropyldimethanolSynthesis of theTricyclopropyldimethanol

HOOBn

OB

O

Bu

Me2NOC CONMe2

HOOBn

HOOHZn(CH2I)2•DME (2.0)

CH2Cl2, 0-25 °C

OHHO

H2, Pd/C

1. PDC, CH2Cl2

2. (MeO)2P(O)CHCOOEt

(1.1)

quant. (ca. 91% ee)quant.

3. DIBAL-H, CH2Cl2, 99%

THF, 49% (EE/EZ: 7/1)

EtOH

OB

O

Bu

Me2NOC CONMe2

CH2Cl2, 0-25 °C

(2.2)

90%, ≥ 10 : 1

OHHO

Zn(CH2I)2•DME, (4.4)

62

Synthesis of the PentaclopropyldimethanolSynthesis of the Pentaclopropyldimethanol

OHHO

HOH2CCH2OH

HOH2CCH2OH

11 étapes (14% rend. global)≥ 10 : 1

1. PDC, CH2Cl22. (MeO)2P(O)CHCOOEt

3. DIBAL-H, CH2Cl2, 99%THF, 41% (EE/EZ: 5/1)

OB

O

Bu

Me2NOC CONMe2

CH2Cl2, 0-25 °C

(2.2)

90%, ≥ 10 : 1

Zn(CH2I)2•DME, (4.4)

63

Asymmetric Double CyclopropanationsAsymmetric Double Cyclopropanations

95%

85.74%

9%

0.24%

77.4

8.14

0.21

8.14

0.42

0.42

0.02

0.21

0.02

0.0006

0.00003

0.0012

0.01

0.0012

0.02

0.02

0.42

0.01

0.42

4.07

0.48 5

4.51

0.01

64

RO Me

ROH

O

MeX

X = S, P, Si

RO CH2OH

Olefination

RO Me

Chemoselective Cyclopropanation+ Deoxygenation

Approach to 1,2-DicyclopropylalkenesApproach to 1,2-Dicyclopropylalkenes

65

Approach to Approach to 1,2-Dicyclopropylalkenes1,2-Dicyclopropylalkenes

TIPSOH

O

HOOH

1. TIPSCl, NaH2. PDC, CH2Cl2

50%

TIPSO CH2OH

TIPSO CH2OH

1. NaHMDS / THF -78 °C(ETO)2(O)P CO2Et

2. DIBAL-H / CH2Cl248%

Zn(CH2I)2•DME (3.0 equiv)CH2Cl2, -10 °C

OB

O

Me2NOC

Bu

CONMe2

(1.2 equiv)

81%, >20 : 1 de; 9 : 1 (mono : bis)

R

Deoxygenation

X

NSPh

O

O

1. Bu3P, C6H6

2. Raney Ni, EtOH, -40 °C

,

Barrett Deoxygenation

~40%

66


RO

RO

MeX+

OlefinationX = S, P, Si

H

O

•Ratio E : Z

•Possible decomposition or racemization of the cyclopropylmethyl carbanion

MeX MeXXMe

67


RO

RO

Me OH

H

O

2.S

NSNa

Me SO2BT

Me+ S

M

S

N

S. Julia Olefination

O O

1. MsCl, Et3N

3. MCPBA, 0-25 °C

Base

S. Julia T.L. 1991,1175; BSCF 1993, 336 et 856. P. Kocienski Synthesis 1996, 285 et 652.

68


1 : 1

TIPSOH

O

SO O

TIPSO

TIPSOS

N++

NaHMDS / THF

-60 ou -78 °C

25 °C

Solvant (M) Ratio (E : Z)

DMF (0.005 M) 3.8 : 1

Temp.

-60 °C

DMF (0.05 M) 3.5 : 1-60 °C

DME (0.05 M) -60 °C 2.4 : 1

Diglyme (0.05 M) -65 °C 1.8 : 1

THF (0.05 M) -78 °C 1.1 : 1

TMEDA (0.05 M) -40 °C 1 : 2.5

Dioxane (0.05 M) 1 : 4.0

Et2O (0.05 M)

CH2Cl2 (0.05 M)

Toluène (0.05 M)

-78 °C

-78 °C

-78 °C

1 : 7.7

1 : 9.8

1 : 10

69

O M

OSR2

H

H

R1

O

NS

R1 H

O

R2 S

M

O OS

N

Non-Coordinating Solvent:Closed Transition State

OMSO2BTR2

H

H

R1H

SO2MR2

H

R1

BTO

R1

H H

R2

Coordinating Solvent:Opened Transition State

S

NM

O SO

LL

R2 H

R1H

O

HR2 H

SO2BT

OM

R1H

R2 H

SO2M

OBT

R1

R2

HR1

H

Solvent Effect in the S. Julia OlefinationSolvent Effect in the S. Julia Olefination

70

TIPSO

HO

Me

H

O S

1. NaHMDS, THF DMF (0.005 M), -60 °C2. Bu4NF / THF

4.4 : 1

(E:Z)

S

N

O O

+

92%

1. PDC, CH2Cl2, 87%

HN

O

HN

OP(O)(OEt)2

(+)-U-106305

NaH, DME 80%

Synthetic: [α]D = +297°Nαturαl: [α]D = -270°

2.

Completion of the Synthesis of (+)-U-106305Completion of the Synthesis of (+)-U-106305

Charette, A. B.; Lebel, H.J. Am. Chem. Soc. 1996, 118, 10327-10328.

71

Ph OH

OHBnO

84%>20 : 1 chemo21 : 1 enantio

OHTIPSO

85%8 : 1 chemo

>20 : 1 enantio

78% rdt8 : 1 chemo

>20 : 1 enantio

OH OHLigand, 1.2 equiv / CH2Cl2Zn(CH2I)2•DME (2-3 equiv)

R R

Chemoselective Cyclopropanation of DienolChemoselective Cyclopropanation of Dienol

Charette, A. B.; Juteau, H.; Lebel, H.; Deschenes, D. Tetrahedron Lett. 1996, 37, 7925-7928.

72

Double Cyclopropanation of Dienes : Double Cyclopropanation of Dienes : Stereochemical Outcome ?Stereochemical Outcome ?

OHR

OH

Chiral Ligand / CH2Cl2

R

OHR

Stereochemistry???

Zn(CH2I)2

Zn(CH2I)2

73

Double Cyclopropanation of DienesDouble Cyclopropanation of Dienes

OHCH2Cl2, -10 °C

OHBnO BnO

EtZnCH2I (5 éq)

ICH2ZnCH2I (5 éq)

>95%7 : 1

RZnCH2I

OH OHBnO BnOx xLigand, 1.2 éq

CH2Cl2, -10°C

Zn(CH2I)2•DME

OHBnO

Zn(CH2I)2•DME (8 éq)90%, 7 : 1

OHBnO

Zn(CH2I)2•DME (6 éq)93%, 7 : 1

3

74

HOOH

HOOH

HOOH

TIPSOOH

TIPSO CO2Et

EtO2CCO2Et

1. PDC, CH2Cl22. (EtO)2P(O)CH2CH=CHCO2Et

T1/2 (C6D6) = 1 h

1. TBAF, THF2. PDC, CH2Cl23. (EtO)2P(O)CH2CH=CHCOOEt NaHMDS / THF, -78 °C

DIBALH / CH2Cl2-78 °C

55%

46%

53%

NaHMDS / THF, -78 °C

HOH2CCH2OH

AsymmetricAsymmetricTetracyclopropanationTetracyclopropanation

75

EtO2CCO2Et 25 °C

180 °C

T1/2 (C6D6) = 1 heureEtO2C CO2Et

H H

25 °C 160 °C

Cope Divinylcyclopropane RearrangementCope Divinylcyclopropane Rearrangement

76

Asymmetric TetracyclopropanationAsymmetric Tetracyclopropanation

HOH2CCH2OH

HOOH

HOOH

CH2Cl2, -10 °C

+

90%

Zn(CH2I)2•DME(6 + 3 + 3 equiv)

OB

O

CONMe2Me2NOC

Bu

2.4 éq

6

1

postdoc-hélène lebel (advisor : prof. eric n. jacobsen)

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