A Dash of proline to induce chirality Christian Perreault Literature Meeting February 6 th, 2006.

A Dash of proline to induce chirality

Christian Perreault

Literature MeetingFebruary 6th, 2006

Synthesis of (-)-Littoralisone

Enantioselective Organocatalytic α-Oxidation of aldehydes

OOO

OHOH

OHO

H

O

O

H

H

H

OH

O

H

David W. C. MacMillan et Al. J. Am. Chem. Soc. 2005, 127, 3696.

1,4 Selective Michaël addition induced by proline

Aldol reaction catalyzed by proline

• Nine-membered lactone in an heptacyclic framework

• Glycosidic unity : (β)-D-Glucose

• Elaborated optically active cyclobutane

• 14 stereocenters within a 24 carbon framework

(-)-Littoralisone

OOO

OHOH

OHO

H

O

O

H

H

H

OH

O

H

Challenge of the synthesis

Verbena littoralis

(1) Castro, O., Umana, E. Int. J. Crude Drug Res. 1990, 28, 175 (2) Ohizumi, Y.,et al J. Org. Chem. 2001, 66, 2165.

OHOO

OHOH

OHO

H

O

O

H

H OOO

OHOH

OHO

H

O

O

H

H

H

OH

O

H

(-)-Brasoside 1 (-)-Littoralisone 2

Origins

• Verbena littoralis grows in Costa Rica

• It is a shrub widely used in folk medecine as an effective antidiarrhetic.

• It has also been claimed as a remedy for typhoid fever, for relieving inflammations from insects bites and for cancer.

• First isolation and structure elucidation of Littoralisone in 2001

• This heptacyclic iridolactone glucoside shown activity on PC12D nerve cells.

(-)-Littoralisone retrosynthesis

Intramolecular organocatalysed 1,4-addition

Two steps approach carbohydrate synthesis

OOO

OHOH

OHO

H

O

O

H

H

H

OH

O

H

O

H

HOAc

OO

OH

OTMSO

O

BnO

OO

TMSO

OBn

OBnOBn

O

BnO

OOO

OBnOBn

OBnO

H

O

O

H

H

O

BnO

OOBn

O

OBn

(-)- citronellol

[2+2]

+

(-)-Littoralisone synthesis

OH

O

OMes

ONHPh

OMes

O

OMes

OMes

OH

CO2Me

(-)- citronellol

MesCl, DMAP,pyridine

CH2Cl223°C99%

O3, PPh3

CH2Cl2, MeOHpyridine-78°C96%

i) D-proline, PhN=ODMSO, 23°C

ii) (EtO)2P(O)CH2CO2MeDBU, LiCl, MeCN

-15°C

iii) MeOH, NH4Cl56%

One isomer

1 2

3 4

Enantioselective α-Oxidation of Aldehyde

Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029.

Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc. 1963, 85, 207.

R’= Alkyl-X, BzCl, Acrylonitrile

Stork identified the usefullness of a condensed secondary amine on a carbonyl, for α-alkylation on the molecule

Enantioselective α-Oxidation of Aldehyde

(1) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973, 38, 3239.(2) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 476.

(1) (2)

Enantioselective α-aminoxylation of Aldehyde

(1) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2002, 122, 2395. (2) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827.(3) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798.(4) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273. (Proposed transition state)(5) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395 (Proposed transition state)

(1)

(3)

(2)

(4-5)

Enantioselective α-amination of Aldehyde (1)

(1) List, B.; J. Am. Chem. Soc. 2002, 124, 5657. (2) Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 2103.

First direct catalytic asymmetric α-amination of aldehyde Good yield an ee Product is a useful precursor for 2-oxazolidinones and other α-amino and α-hydrazino acid derivatives

scheme 1

scheme 2(2)

Enantioselective α-aminoxylation of Aldehyde

Zhong, G. Angew. Chem. Int. Ed. 2003, 42, 4247. (June)MacMillan, D. W. C. et al. J. Am. Chem. Soc. 2003, 125, 10808. (July)Hayashi, Y.; Junichiro, Y.; Kazuhiro, H.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293 (August)

Broad scope of compatible functionnality (scheme 1)

Alternative for Aminohydroxylation and Dihydroxylation of terminal alkene (scheme 3)

scheme 1 scheme 2

scheme 3

Enantioselective α-aminoxylation of aldehyde + olefination in situ (1)

(1) Zhong, G.; Yongping, Y. Org. Lett. 2004, 6, 1638. (2) Momiyama, N,; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038

Eliminate problems of purification Acceptable yield (for 2 steps) and good ee’s Good method to create an allylic alcohol

O

OMes

ONHPh

OMes

OH

CO2Me



-15°C

iii) MeOH, NH4Cl56%

One isomer

3 4

scheme 1 (1)

scheme 2 (2)

Donna Blackmond’s et al observation

(1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, 3317.(2) Nielsen, L. P. C. N.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360.(3) Singh, U. K.; Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14104

Rate is a lot faster (10min.) compared to other proline catalyzed reaction ex: Aldol reaction between acetone and isobutyraldehyde required 48h at 30mol%

(1)

(2-3)

Rate of the reaction accelerate over time process Experiment suggest an autocatalytic or autoinductive reactions!

Experiment suggest that the reaction is mediated by a proline-product adduct

Donna Blackmond’s et al observation

(1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, 3317.

Enantiomeric excess was higher than that expected for a linear relationship Clue to establish a model for the evolution of homochirality through precursor of low optical activity (Rate acceleration + ee’s improvement in time)

(1)

Finding the active specie (1)

(1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, 3317.(2) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2353(first explanation for non-linear product enantioselectivity)

This scheme showes a general mechanism for a product-induced reaction in which both rate and selectivity improve over time for the case in which one enantiomer is present in excess concentration relative to the other.

First proposition for the improved catalyst: α-effect and bronsted acid

(1)

(1) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 11770.

Rate enhancement is independent of the enantiomer of 3 and the proline utilized No erosion of ee and final configuration dictated by the proline stereochemistry

Utilization of specie 6 improves efficiency (reaction rate) of other proline catalyzed transformations such as aldol and aminoxylation reaction.

Finding the active specie

This reaction presents same nonlinear effect than for the aminoxylation

(1) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 11770.

(1)Finding the active specie

(1) Iwamura, H.; Wells, D. H.; Mathew, S. P.; Klussmann, M.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 16312.

Reaction 2b

a) 10mol% of 5bb) 10mol% of 5cc) 20mol% of 4L

a) and b) presents the same kinetics properties: active specie cannot be 5b or 5c but help the formation of the super catalyst

a) and b) as well as c), show an acceleration proportionnal to the product concentration: acceleration is not due to a solvatation of proline in time

Finding the active specie (1)

three-point hydrogen bonding help to increased the active specie concentration into the cycle In aldol reaction, the two-point hydrogen bonding inhibited the formation of a more active species Transition state (in this proposition) is similar to the first proposed by List and Houk

(1) Blackmond, D. G. et al J. Am. Chem. Soc. 2004, 126, 16312.

Blackmond theory

DFT calculation using B3LYP/6-31G

H

O

O

H

OO

NH

H

O

OH

O

OH


OH

O

OMes

ONHPh

OMes

O

OMes

OMes

OH

CO2Me

(-)- citronellol

MesCl, DMAP,pyridine

CH2Cl223°C99%

O3, PPh3

CH2Cl2, MeOHpyridine-78°C96%



-15°C

iii) MeOH, NH4Cl56%

One isomer

1 2

3 4


OMes

OTBDPS

CO2Me

O

OTBDPS

O

TBDPSClimidazole

DMAP, DMF23°C97%

1) DIBAL, Et2O-78°C96%

2) DMP, CH2Cl223°C

5 6OMes

OH

CO2Me

4

H

H

O

OTBDPSO

O

H

HOAc

TBDPSO

i) L-Proline, DMSO40°C

7 8

ii) Ac2O, pyridineDMAP

0°C83% (2 étapes)

Anomeric effect

O

H

HOAc

OO

11

O

OAc

H

H

VS

2 anomeric effects

1 anomeric effectO

H

HOAc

OO

O

OAc

H

H

O

OTBDPS

O

T (°C)

PhNHMe

CHCl3

CHCl3

CHCl3

DMSO

DMSO

DMSO

O

H

HOH

TBDPSO

A

H

TBDPSO HO

O

B

A:B

30 mol% catalyst

6

entrie catalyst solvent time (h) Combined Yield (%)

1

2

3

4

5

6

+

L-proline 23 12 61 3:1

L-proline 23 48 54 1:19

23 48 87

conditions

1:19

L-proline 40 48 91 10:1

(±)-proline

D-proline

40

40

48

48

86

83

2:1

1:2

O

H

HOH

TBDPSO

A

Only AD-Proline

DMSO48h, 40oC

Organocatalyzed Michael addition

Kinetic control

O

OTBDPS

O

NR2

OTBDPS

O O

H

HOH

TBDPSO

A

H

TBDPSO HO

O

B

1) Enamine / Enone

6

proline +

O

OTBDPS

O

OH

OTBDPS

NR2 O

H

HOH

TBDPSO

A

H

TBDPSO HO

O

B

+

2) Enol/ Eniminium

6

proline

• 2 plausible reactive species


• 3 parameter to look at:

1) enol / enamine geometry: trans favored

Me

OR

X

NCO2H

Me

OR

X

OH

N

CO2H

Me

OR

Me

OR

XOH

X


2) enol / enamine reactive face

a) Allylic strain

b) Proline’s asymmetric induction / hydrogen bonding

In DMSO,Hydrogen bonding activation is questionable!

Me

OR

ON

CO2H

Me

OR

ON

CO2H

Favored

Me

OR

ON

Me

OR

ON

CO2H

Favored

OO

H

Me

OR

OMe

OR

OX

X

A1,3min

A1,3max


c) Relative orientation of nucleophile / electrophile

3) enone / eniminium reactive face

a) Allylic strain

Me

OR

XX Me

OR

X

X

Favored

Me

OR

XXMe

ORX

X

Favored

A1,3minA1,3max


b) Proline asymmetric induction

c) nucleophile / electrophile relative orientation

Me

OR

XX

Me

ORX

Favored

X

Me

OR

NX

HO2C

Me

OR

NX

HO2C

Favored


O

OTBDPS

O O

H

HOH

TBDPSO

A

H

TBDPSO HO

O

B6

+

10:1

O

OTBDPS

O O

H

HOH

TBDPSO

A

H

TBDPSO HO

O

B6

+

1:2

L-proline

DMSO

DMSO

D-proline

O

OTBDPS

O

NR2

OTBDPS

O O

H

HOH

TBDPSO

A

H

TBDPSO HO

O

B

1) Enamine / Enone

6

L-proline +

10:1


Me

OR

ON

CO2H

Me

OR

O

N

CO2H

Me

RO

ON

HO2C

Me

RO

N

HO2C

O

A1,3min

A1,3min

A1,3max

A1,3max

A1,3max A1,3min

A1,3minA1,3max

Majo

Mino

Majo

Mino

O

OTBDPS

O

NR2

OTBDPS

O O

H

HOH

TBDPSO

A

H

TBDPSO HO

O

B

1) Enamine / Enone

6

L-proline +

10:1


Me

OR

ON

Me

OR

O

N

Me

RO

ON

Me

RO

N

O

A1,3min

A1,3min

A1,3max

A1,3max

A1,3max A1,3min

A1,3minA1,3max

Mino

Majo

Mino

Majo

CO2H

HO2C

CO2H

HO2C

O

OTBDPS

O

NR2

OTBDPS

O O

H

HOH

TBDPSO

A

H

TBDPSO HO

O

B

1) Enamine / Enone

6

D-proline +

1:2


Me

OR

N

HO2C

OH

Me

OR

N CO2H

OH

Me

RO

NOH

Me

RO

OH

N

HO2C

CO2HA1,3min

A1,3min

A1,3min

A1,3minA1,3max

A1,3max

A1,3max

A1,3max

Majo

Mino

Majo

Mino

O

OTBDPS

O

OH

OTBDPS

NR2

O

H

HOH

TBDPSO

A

H

TBDPSO HO

O

B

+

2) Enol / Eniminium

6

L-proline

10:1


Me

OR

N

HO2C

OH

Me

OR

N CO2H

OH

Me

RO

NOHCO2H

Me

RO

OH

N

HO2C

A1,3min

A1,3min

A1,3min

A1,3minA1,3max

A1,3max

A1,3max

A1,3max

Mino

Majo

Mino

Majo

O

OTBDPS

O

OH

OTBDPS

NR2

O

H

HOH

TBDPSO

A

H

TBDPSO HO

O

B

+

2) Enol / Eniminium

6

D-proline

1:2


• The two combinations implying proline can be operative to explain stereochemistry observed

• Hydrogen bonding to explain diastereoselectivity is questionnable

• Others kinetic datas necessary to identified the reactive specie:

Which active specie you think it is involved? Any other ideas?

Me

OR

N

HO2C

OH

A1,3min

A1,3min

Enol / Eniminium

Me

OR

ON

CO2HA1,3min

A1,3min

Enamine / Enone



POCl3

O

H

HOAc

TBDPSO CHO

O

H

HOAc

OO

O

H

HOAc

TBDPSO CO2H

DMF-20°C à 23°C

73%

NaClO2, NaH2PO4

t-BuOH, 2-methylbutène23°C93%

1) HF-pyridine,THF23°C

2) DCC, CH2Cl223°C82%

9

10

O

H

HOAc

TBDPSO

8

11


α:β = 8:1

H

OBn

O

H

OBn

O

HOBn

O

OBn

OHD-proline

Dioxane4:1 dr

98% ee78%

12

BnO

O

O

OHDMP

BnO

O

O

OCH2Cl223°C95%

TMSCl, Et3N

CH3CN23°C82%

13 14

BnO

O

O

OTMS

HOBn

O

OBn

OH

OH

OO

OH

OBn

OBn

O

BnOMgBr2-OEtToluene-20°C

10:1 dr65%

12

1615

TMSO

OZ

HOY

O

OY

OH

OTMS

OZ

OH

OY

OH

OY

O

YO

OH

YO

OZ

OH

Acide de Lewis

H

O

OY

D-Proline

OY

HO2C H

O

OY

H

O

OYOY

OH

Glycosidic part done by a MacMillan methodology

Alan B. Northrup, David W. C. MacMillan, Sciences. 2004, 305, 1752.

1) Enantioselective organocatalyzed dimerisation of aldehydes

2) Mukaiyama aldol + Cyclisation

1) Enantioselective organocatalyzed dimerisation of aldehydes

• α-hydroxyaldehyde must readily participate as both a nucleophilic and electrophilic coupling partner

• product must be inert to enolization and or carbonyl addition

Alan B. Northrup, David W. C. MacMillan, Sciences. 2004, 305, 1752.David W. C. MacMillan et Al. J. Am. Chem. Soc. 2003, 125, 10808.Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152

Carbohydrate synthesis in two steps via 2 selective aldol reactions

H

OR

O

H

OR

O

O H N

O

O

RORO

HOR

O

OR

OH

OH O

RORO

D-proline

98% ee4:1

78%

2) Mukaiyama aldol + cyclisation catalysed by a lewis acid



TMSO

OZ

HOY

O

OY

OH

OTMS

OZ

OH

OY

OH

OY

O

YO

OH

YO

OZ

OH

Acide de Lewis

OO

OH

OBn

OBn

O

BnO OH

OO

TMSO

OBn

OBn

OBn

O

BnO

OO

OBn

OBn

OBn

O

BnO OH

OO

OBn

OBn

OBn

O

BnO

BnO

TMSCl, Et3NPd/Al2O3, HCO2NH4

MeOH23°C68%

BnBr, Ag2O

CH2Cl223°C

PhH80°C91%

16 17

18 19


α:β = 8:1

α:β = 12:1 β only


O

H

HOAc

OO

OO

TMSO

OBn

OBn

OBn

O

BnO

OO

OHOH

OOHO

H

O

O

H

H

H

OH

O

H

TMSOTf (0.3 equiv.)

OOO

OBnOBn

OBnO

H

O

O

H

H

O

OBn

+CH3CN-30°C74%

1) hu (350 nm)PhH23°C

2) 50 mol% Pd/C, H2EtOAc23°C

84% (2 steps)

(-)-Littoralisone

11 19 20

• Efficient and convergent synthesis

• 13 steps for the longest sequence

• 13% overall yield (average of 85% per step)

• 13 stereocenters installed, 14th from chiral pool

• 6 steps of protection / deprotection

Conclusion

A Dash of proline to induce chirality Christian Perreault Literature Meeting February 6 th, 2006.

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Transcript of A Dash of proline to induce chirality Christian Perreault Literature Meeting February 6 th, 2006.