Ph OK The Memory of Chirality, Mediated OEt by · PDF fileThe Memory of Chirality, Mediated...

The Memory of Chirality, Mediatedby Rotational Restriction

Michael H. OberMay 27th, 2003

OKPh

MeO

EtO

EtO

OEt

OEt

OKMeO

Ph

OMR1

N

OR2

R3 R4

*

The Memory of Chirality

O

OMePh

OMeH

O

OMePh

HMeO

OMe

PhOMe

OM

B-M+

B-M+

O

OMePh

OMeMe

MeI

O

OMePh

OMeH

O

OMePh

OMeR*chiral

intermediateR+B-M+

Kawabata, T.; Fuji, K. Top. Stereochem. 2003, 23, p.175-205.

“Memory of chirality” signifies asymmetric transformation in which the chirality of theStarting materials is preserved in the configurationally labile intermediates (typicallyEnolates) during the transformation. Kawabata, T.; Fuji, K.

Memory of chirality can be defined as a phenomenon in which the chirality of a startingHaving a chiral sp3-carbon is preserved in the reaction product even though the reactionProceeds at the chiral carbon as a reaction center through reactive intermediates such asCarbanion, singlet monoradicals, biradicals, or carbenium ions. Matsumura, Y. et al

The Memory of Chirality – Ketone Alkylation

Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991, 113, 9694.

KH (2 equiv)EI (20 equiv)

18-crown-6 (2 equiv)THF, -78 oC -> -20 oC

OMeO

PhH

OEt

OEt

OR

PhMeO

OEt

OEt

OMeO

PhH

OEt

OEt

OR

PhMeO

OEt

OEt

OKMeO

Ph

OEt

OEt

1. KH 2. EI

Entry12a

3456

EIMe-IMe-IEt-I

PhCH2-BrCH2=CHCH2-BrCH2CH2COCH3

RMeMeEt

CH2PhCH2CH=CH2

CH2CH2COCH3

yield (%)485427313625

ee (%)667365674870

config.RRR---

a Toluene

The Memory of Chirality – α-alkylation

OKPh

MeO

EtO

EtO

OEt

OEt

OKMeO

Ph

Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991, 113, 9694.Kawabata, T.; Fuji, K. Top. Stereochem. 2003, 23, p.175-205.

DGrac = 22.6 kcal mol-1

t1/2 = 53m @ rt

KH (2 equiv)Ac2O (20 equiv)


93% ee

OAcMeO

Ph

OEt

OEt

OAcPh

OMe

OEt

OEt

+

25, 59% 6%

OMeO

PhH

27%, 93% ee

+

KH (2 equiv)MeI (20 equiv)


93% ee

OMe

PhMeO

48%, 66% ee

OAcPh

OMe

OEt

OEt

+

27, 27%, 43% ee

DGrac ~ 10 kcal mol-1

OEt

OEt

OMeO

PhH

OEt

OEt

OMeO

PhH

OEt

OEt

OEt

OEt

OMeO

PhH KH (2 equiv)

MeI (20 equiv)


OMe

PhMeO

OEt

OEt

OEt

OEt


Fuji, K. et al J. Am. Chem. Soc. 1994, 116, 10809.

PhCO2Me

NR2R1

PhCO2Me

Me NR1

R21. base, THF, -78 oC

2. MeI, -78 oC -> rt

R1

HMeMeMeMeMeMe

R2

CO2t-BuCH2PhCHOCOPh

CO2CH2PhCO2Ad

CO2t-Bu

ee of SM (%)96989496949496

baseLDALDA

LHMDSLDA

LHMDSLHMDSLHMDS

yield (%)57456650403830

ee (%)00012263536

PhCO2Et

NBocMe

PhCO2Et

Me NMe

Boc

1. base, THF, -78 oC

2. RX (10 equiv), -78 oC

base (equiv)KHMDS (1.2)

LDA (1.2)LTMP (1.0)LTMP (2.0)LTMP (4.0)LTMP (1.0)LTMP (1.0)

RXMeIMeIMeIMeIMeI

CH2=CHCH2BrMOMCl

yield (%)79574042361524

ee (%)20 (R)22 (S)82 (S)73 (S)66 (S)88 -69 -

OMR1

N

OR2

R3 R4

chiral C-N axis

*

R1

N

OR2

R3 R4

* M

chiral nitrogen

N OOR2R1

MR4R3

chiral plane

NOO

OEt

Ot-Bu

Ph

MeOCH2

NOO

OEt

Ot-Bu

Ph

CH2OMeK


Fuji, K. et al. Angew. Chem. Int. Ed. 2000, 39, 2155.Kawabata, T.; Fuji, K. Top. Stereochem. 2003, 23, p.175-205.

PhCO2Et

Me NBoc

MOM1. KHMDS, THF, -78 oC

2. MeI, -78 oC -> rt

PhCO2Et

NMOMBoc

conditions-78 oC, 30m-78 oC, 24h

-78 oC, 30m -> -40 oC, 30m-78 oC, 30m -> 0 oC, 30m

yield (%)96848858

ee (%)813650

CO2Et

NMOMBoc

PhCO2Et

Me NBoc


2. MeI, -78 oC -> rt

PhCO2Et

NMOMBoc

rac (S), >99% ee

+

CO2Et

Me NBoc

MOM+

rac 79% yield

(S) 79% yield74% ee

MOMMOM

Ph OTBS

OEt

NMOMBoc

Ph OTBS

OEt

NMOMBoc

1. KHMDS, THF, -78 oC

2. MeI, -78 oC -> rt

PhCO2Et

NMOMBoc

Ph OEt

OTBS

NMOMBoc

+

57% 27%DGrac = 16.8 kcal mol-1t1/2 ~ 4d @ -78 oC


Ph OK

OEt

NBocBoc

PhCO2Et

NBocBoc

PhCO2Me

Me NBoc


(S), >99% ee rac

2. MeI, -78 oC -> rt

PhN

O

O

HBoc

(S), >99% ee

1. KHMDS, THF, -78 oC 2. MeI, -78 oC -> rtPh

NO

OK

Boc

PhN

O

O

MeBoc

rac

Kawabata, T.; Fuji, K. Top. Stereochem. 2003, 23, p.175-205.

Diastereoisomeric Atropisomers

Bowles, P.; Clayden, J.; Tomkinson, M. Tetrahedron Lett. 1995, 36, 9219.

R3 R4

O NR2

R1

Me

O NMe

MeO N

Et

EtO N

i-Pr

i-Pr

DGrac 64 kJ mol-1t1/2 ~ 0.01s @ rt

DGrac 75 kJ mol-1t1/2 ~ 2s @ rt

DGrac 100.9 kJ mol-1t1/2 ~ 6h @ rt

1. s-BuLiTHF, -78 oC

2. R3X

DGrac >95 kJ mol-1t1/2 > 1h @ rt

R1= R2 = Et or i-PrR3 = Me or Me3Si

O N

R3

O NR2

R1 R1

R2

Stereoselective Additions of Atropisomers

Bowles, P.; Clayden, J.; Tomkinson, M. Tetrahedron Lett. 1995, 36, 9219.


2. R2CHO, -78 oC3. NH4Cl, -20 oC

O NR1

R1

O NR1

R1

OH

R2

O NR1

R1

OH

R2

+

anti syn

R2=MeEt

n-C5H11i-PrPh

R1 = Et

yield (%)6776858585

anti : syn23 : 7722 : 7823 : 7730 : 7049 : 51

R1 = i-Pr

yield (%)9279759189

anti : syn15 : 8510 : 9018 : 8223 : 7728 : 72

Stereoselective Additions to Atropisomers

R2MMeLiBuLiPhLi

MeMgBrAllylMgBrBuMgClPhMgBr

R1 = Et

yield (%)94565291977281

anti : syn70:3085:1519:8125:7542:5815:8514:86

R1 = i-Pr

yield (%)90839566945771

anti : syn80 : 2085 : 1534 : 6623 : 7739 : 6115 : 853 : 97

Clayden, J.; Westlund, N.; Wilson, F.X. Tetrahedron Lett. 1996, 37, 5577.


2. Me2NCHO3. NH4Cl

O N

CHO

O NR1

R1 R1

R1

R1 = Et, 78%R1 = i-Pr, 82%

R2M

THF, -78 oC

O NR1

R1

OH

R2

O NR1

R1

OH

R2

+

anti syn

Resolution of Atropisomers

Clayden, J.; Lai, L.W. Angew. Chem. Int. Ed. 1999, 38, 2556.

Resolution of Atropisomers Redux

Clayden, J.; Mitjans, D.; Youssef, L.H. J. Am. Chem. Soc. 2002, 124, 5266.

s-BuLi

THF, -78 oC

O NR1

R1

R2

R3

-78 oC -> 0 oCNH4Cl

O N

R2

R3

S

R1

R1

anti-3

syn-3

O NR1

R1

R2

R3

Li

O

O N

R2

R3

S

R1

R1

O

O NR1

R1

R2

R3

Li

t-BuLi

THF, -78 oC5m

E+O NR1

R1

R2

R3

E

1 2

24

*

OSO

Resolution of Atropisomers Redux


1. m-CPBACHCl2, -15 oC

2. 0 oC, 2h

O Ni-Pr

i-Pr

SPh

O N

S

i-Pri-Pr

anti syn

PhPh

O N

S

i-Pri-Pr

OPh

+

75 25

O N

S

i-Pri-Pr

anti syn

PhPh

O N

S

i-Pri-Pr

OPh

+

95 5

H2O, rt

1. m-CPBACHCl2, -15 oC

2. H2O, rt

O Ni-Pr

i-Pr

SR

O N

S

i-Pri-Pr

anti syn

PhR

O N

S

i-Pri-Pr

OR

+

RPh

t-BuMe

anti : syn>98 : 2>98 : 2>95 : 5

yield (%)787474

Application with a Memory of Chirality


anti-B

O N

R2

R3

S

R1

R1

O

O NR1

R1

R2

R3

Br

O NR1

R1

R2

R3

Li

t-BuLiTHF, -78 oC, 10m

t-BuLiTHF, -78 oC, 10m

t-BuCHO

O N

R2

R3

i-Pri-PrOH

O N

R2

R3

i-Pri-PrOH

anti-C

syn-C

O N

R2

R3

i-Pri-Pr

O

OR2

R3MeSO3H

MeOH, D5m

benzobenzobenzo

R2

MeOH

R3

HH

D

yield (%)9189908977

ee (%)9487--0

yield (%)90-

9494-

ee (%)84-

>9978-

A SMABAAA

R1

aabba

a = i-Pr NOb =

Anionic Dearomatization

Ahmed, A.; Clayden, J.; Rowley, M. Chem. Comm. 1998, 297.

t-BuLi

THF, -78 oC2h

O Nt-Bu

PhO N

t-BuPh

Li

1. HMPA (6 equiv) -78 oC, 16h2. NH4Cl

MeI, -78 oCO N

t-BuPh

Li+

O Nt-Bu

Ph

Me

O Nt-Bu

Ph

Me+

56% 28%

NH

HPh

O t-Bu

82%

1. t-BuLi THF, -78 oC, 2h 2. HMPA (6 equiv) -78, 16h3. RX

O Nt-Bu

PhN

R

HPh

O t-BuN

R

HPh

O t-Bu

+

a b

RX =MeI

n-BuBrBnBr

yield (%)928172

ratio a : b3 : 15 : 1

a only

Mechanism of the Anionic Dearomatization

Ahmed, A.; Clayden, J.; Rowley, M.. Tetrahedron Lett. 1998, 39, 6103.

Mechanism of Dearomatization

Clayden, J. et al Angew. Chem. Int. Ed, 2002, 41, 1049.

Selectivity of Dearomatization

Clayden, J.; Bragg, R.A. Tetrahedron Lett. 1999, 40, 8323.

O N PhN

H

HPh

O

Me

Me

Ph

Me

MePh1. t-BuLi, THF, -78 oC, 2h

2. DMPU (6 equiv), -78 oC, 16h

3. MeOH

(-) (+)49%

O N Ph

Me

Ph

(-)

O N Ph

Me

PhMe

NH

HPh

OMe

MePh

(rac)

1. t-BuLi, THF, -78 oC

2. MeI

1. t-BuLi, THF, -78 oC, 2h2. DMPU (6 equiv), -78 oC, 16h

3. MeOH80% 44%

Selectivity of the Anionic Dearomatization

Clayden, J.; Bragg, R.A. Tetrahedron Lett. 1999, 40, 8327.

Stability of the Li Intermediates

Bragg, R.A.; Clayden, J.; Menet, C.J. Tetrahedron Lett., 2002, 43, 1955.

Stability of the Li Intermediates

Bragg, R.A.; Clayden, J.; Menet, C.J. Tetrahedron Lett., 2002, 43, 1955.7,9,11 R = p-MeOC6H4, Ar = Ph8,10,12 R = t-BuO, Ar = p-MeOC6H4

Enantioselective Anionic Dearomatization

Clayden, J.; Menet, C.J.; Mansfield, D.J. Chem. Comm. 2002, 38.

Synthesis of (-)-Kainic Acid

H2N Ph

p-MeOC6H4COCl

Et3N, CH2Cl287%

NH

Ph

O

MeO

N Ph

O

MeO

NaH, BnBr

DMF87%

N Ph

O

MeO

1, LiCl

THF Li

NMeO

H

OLi

Ph

-78 -> 0 oC

1. NH4Cl,H2O2. HCl, H2O

88%, 81%ee(52%, 99%ee)rcyst

NO

H

O

Ph

HMe2CuLiMe3SiCl

NMe3SiO

H

O

Ph

HH3C

CF3CO2H

100%, 99%ee(2 steps)

NHO

H

OHH3C

Ph NLi

1

Clayden, J. et al Tetrahedron, 2002, 58, 4727.

Synthesis of (-)-Kainic Acid

NHO

H

OHH3C

NBocO

H

OHH3CBoc2O

Et3N, DMAP

90%

1. 12% RuCl3 NaIO4 (17 equiv) H2O, MeCN, EtOAc 2. CH2N2

57%

NBocO

H CO2Me

OHH3C

70% m-CPBA

CH2Cl288%

NBoc

H CO2Me

OH

O

CH3

O

NBoc

H CO2Me

OH

MeO2C

OH

H3C

NaOMeMeOH

-78 oC99%

NBoc

CO2MeMeO2C

NSePh

O

O

1.

Bu3P, 20 oC

2. H2O2, py, -40 oC

99%

NBoc

CO2MeMeO2C

O

NH

CO2HMeO2C

1. DiBAL, -78 oC

2. Et3SiH, BF3 OEt244%

1. LiOH, H2O2. CF3CO2H

3. Dowex-5080%

(-)-kainic acid

Clayden, J. et al Tetrahedron, 2002, 58, 4727.

Conclusions

The application of the “memory of chriality” concepts are powerful yet still underdeveloped, due to the lack of examples which fall within the field.

The applications, although limited, are found within a wide breadth of chemistries.

The combination of “chiral memory” and “hindered atropisomers” provide for a novelmethod for the retention of chirality lost at a center

OKPh

MeO

EtO

EtO

OEt

OEt

OKMeO

Ph

OMR1

N

OR2

R3 R4

*

Clayden, J.; Tchabanenko. Chem. Comm. 2000, 317.

Ph OK The Memory of Chirality, Mediated OEt by · PDF fileThe Memory of Chirality, Mediated...

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