Synthesis, Spectroscopy, Reactivity, Utility

Bent and Twisted Amides

Reviews:

Chem Rev 83, 549 (1983) H.K. Hall Jr., Ali El-Shekeil

Structure and Reactivity J.F. Liebman, A. Greenberg eds. CH 4 Twisted Bridgehead Bicyclic Lactams, A. Greenberg

J.K. Lynch Group Meeting 4/30/91

01-TitlePage 5/1/91 3:03 PM

X X

Justus Lieb.Ann.Chem. 437,1(1924) J.Bredt, H.Thouet, J.SchmitzACIEE 12, 464 (1973) G. Koebrich (review)

Bredt's Rule

(2)(1)

" in systems of the camphane and pinaneseries and related compounds (1) and (2),the branching points A and B of the carbon bridges (bridgeheads) cannot be involved ina carbon double bond."

B

A

B

A

-HBr -H2O

-H2O

-HBr

O

O

O O

O

OCOOH

COOH

Br

COOR

Br

COOR

COOR COOR

COOH

COOHO

O

O

02-Bredt'sRule-1 5/1/91 11:46 AM

Chem. Rev. 83, 549 (1983) H.K. Hall Jr., S. El-Skekeil

[3.2.1][3.2.1][2.2.2][2.2.1]

Detected by Trapping

Isolated Bridgehead Olefins

Bredt's Rule- Strained Bridgehead Olefins

[4.2.1][4.2.1][3.3.1]

03-Bredt'sRule-2 4/28/91 1:49 PM

Tet. 21, 2257, (1965) V.H. Pracejus, M. Kehlen, H. Kehlen, H. Matschiner

.HCl .HCl

SOCl2

60°C, 4h

IgnitedK2CO3

CHCl3

aq. K2CO3

C7H11ONCal N 11.20Found N 11.61

.HCl

Et3N

R1=R2=R3=HR1=R2=H, R3=CH3 Note: pka=5.33R1=H, R2=R3=CH3R1=R3=CH3, R2=HR1=R2=R3=CH3

J.Gen.Chem.USSR (Eng.Trans) 27, 83 (1957) L.N. Yakhontov, M.V. Rubsitov

Structure and Reactivity CH4, p140 A.Greenberg

Synthesis of Bridgehead Bicyclic Lactams

N

ONH

COOH COCl

NH

O

N

R3R3

R1

R2NH

COCl

04-Syn-His 5/1/91 11:56 AM

Et3N

ClCOOEt

2) NaOH 3) NaBH4

1) CH2=CHCOOEt

JOC 34, 183 (1969) M. Denzer, H. Ott

>90%

DCC, CH3CN

Synthesis-Active Ester

JOC 51, 2676 (1986) R. S. Brown, V. Somayaji

DCC, CH3CN

2) HCl 3) KOH

1) Ag2O, EtOH

N

O

CHN2

TOS

N

TOS

COOH

N O

X X

XX

N

H

OH

O

X

NO

NH

N

Cl

Ph Ph

Cl

HN

N

COOH N

NCl

Ph

O

05-Syn1-ActiveEster 4/27/91 9:22 AM

(5,6,7 membered lactams)

1.0 Bu2SnO

Toluene∆, 12hrs

77%

(∆, 2.5%)

Synthesis- DibutylTinOxide

JACS 105, 7130(1983) K. Steliou, M. PoupartHelv. 70, 1981(1987) R. Brehm, D. Ohnhauser, H.Gerlach

(CH2)n

NH2

(CH2)n

n=3,4,5

(CH2)n

+ Bu2SnO

Bu2SnO

-H2O

(CH2)n(CH2)n polyamide

NH

OHON

O

H2N (CH2)nCOOH

O

OSnR2

OH

O

SnR2

NH

O O

NH

Sn

R

R

OO

O

O

NH2

H2N

06-Syn2TinOxide 4/30/91 5:35 PM

Synthesis- Pd, Rh

JACS 108, 6431 (1986) R.M. Williams, B.H. Lee

C6H6, ∆, 1hr

Rh2(OAc)4

CH3CN

TsN3, 25°C 50%

JCS Chem Comm. 1696(1986) R. Grigg, et. al

R=H 88%R=Ph 55%

CH3CN, 30-80 °CEt4NCl, K2CO3

0.1 Pd(OAc)2, 0.2 PP3IN

O

R

N

R

O

N

O

Me

tBuO2C

H

O

H

OtBu

O O

Me

O

NHNH

O

Me

OO

OtBuCN2

07-Syn3Rh,Pd 4/27/91 10:50 AM

spiro pyrazolium ylide

+

40-50% overall

-EtOH, ∆

isolable60-70%

∆

[1,4]

>95%

1,4 elim.EtOH

X=CH2CH2

CH2OCH2

(CH2)3 (CH2)4

Synthesis- Spiro Pyrazolium Ylides

6Πelectrocy.

JOC 50, 909 (1985) J. Chuche et. al.

X N NH2

EtO CO2Et

CO2EtCO2Et

CO2EtHNNX

NXHN CO2Et

CO2Et

N+-N

X

CO2Et

O

CO2Et

NX

N O

N CO2Et

C

O

N

X

08-Syn4SriroYlides 4/30/91 9:19 AM

1695 cm-1

1716 cm-1

1641 cm-1

1750 cm-1

1791 cm-1

1745-60 cm-1

1795 cm-1

1730 cm-1

1750 cm-1

1755 cm-1

1705 cm-1

Spectroscopy-IR

O

N O

O

CH3

N

CH3

O

O O

N

RN

O

Me

tBuO2C

H

O

H

N NO

O

NH

09-IR 5/1/91 11:49 AM

JCS Chem Comm 814 (1981) G.L. Buchanon

185.7 ppm169 ppm 210 ppm

188 ppm192 ppm213 ppm

Spectroscopy- NMR

9 8

6

41H

13C

W coupling Heq-Heq C's 6,8,9

none to C-4

N OO

CH3

N

CH3

O

N NOO

O

ON

Ph

N

O

Hax

Heq

Hax

Heq

Heq

10-NMR 4/30/91 9:26 AM

Haemanthidine

MnO2

CHCl3

NaBH4

MeOH

"facile"

aq. AcOH 100%

NaBH4Pt, AcOH

JOC 34, 183 (1969) M. Denzer, H. Ott

JACS 80, 2590 (1958) S.Uyeo, H.M. Fales, R.J. Highet, W.C. Wildman

Reactivity-Reduction

N

O

O

OH

OCH3

OHOCH3

O

NO

O

OH

N

N

Ph

O

Cl

ClN

HO

Ph

NH

NH

NH

Cl

O

Ph

Ph

O

Cl

NH

N

Me

11-React.-NaBH4 4/30/91 5:48 PM

HClCH3I

2) H2O

1) PhLi

R= OH, MeO, HNNH2

NHOH, morpholineRH

3) Quaternization reactions that leave the bicyclic ring intact occur with HCl and CH3I

2) Nucleophilic reagents, aprotic media break the N-C(CH3)2 bond

1) Protic nucleophilic reagents break the lactam linkage

Reactivity-General

Cl-I-

N OMe

Me

N+Me

MeO

COOR

Me

Me

Me

Me NH

NMe

MeO

N OMe

Me

NH

OMe

Me

Me

Me

CN

Me

Me

OH

Me

MeON

H

N+ OMe

Me

Me H

CNHO

12-React-Gen 4/29/91 6:33 PM

Twist and Tilt Deformations

Twist Angle Φ

Tilt Angle Θ

JOC 51, 2676 (1986) V. Somayaji, R.S. Brown

Θ

Φ

NY

Z

X

Y

X

Z

N

C3O

C4C1

N

N

C4C3

O C1

C4

O

C3C1

C1

O C3

C4

13-Twist/Tilt 4/30/91 9:30 AM

Reactivity-Twist vs Tilt

kOH M-1s-1kOH M

-1s-1

JOC 52, 805 (1987) H.S. Tilk, R.S. Brown

6.0 X 10-6kOH M-1s-1

0.271.12.816.9

kOH M-1s-1X

OCH3HBrNO2

Twist Angle Φ 0+- 10°Tilt Angle Θ 34°

JOC 15, 2676 (1986) V. Somayaji, R.S. Brown

7.55 X 10-66.0 X 102.62 X 102

kOH M-1s-1

X-rayTwist Angle Φ= 30-35°Tilt Angle Θ= 15-20°

MModTwist Angle Φ ~ 90°Tilt Angle Θ∼15-20°

N O

N

NO

NH

O

O

X

N

Me

Me

O

14-HydrolBBL 4/30/91 5:51 PM

JOC 51, 4866 (1986) V. Somayaji, K.I. Skorey, R.S. Brown, R.G. BallJOC 51, 4866 (1986) V. Somayaji, K.I. Skorey, R.S. Brown, R.G. Ball

15-JKLSer1 4/30/91 2:27 PM

JOC 51, 4866 (1986) V. Somayaji K.I. Skorey, R.S. Brown, R.G. Ball

Acylation of β-Amino Alcohols Model for Serine Protease

++

R=H, R'= CH2OHR=H, R'= CH3R=CH3, R'=CH2OHR= R'=CH3

R=CH3+ I-

R= :

N

O

(CH3)2NOH

R

N

N R'

R

16-JKLSer2 4/30/91 3:16 PM

R=CH3+ I-

R= :R=H, R'= CH2OHR=H, R'= CH3R=CH3, R'=CH2OHR= R'=CH3

+ +

Acylation of β-Amino Alcohols

JOC 51, 4866 (1986) V. Somayaji K.I. Skorey, R.S. Brown, R.G. Ball

H3C O

ONO2

(CH3)2NOH

R

N

N R'

R

17-JKLSer3 4/30/91 3:13 PM

Science 863 (1990) M.K. Rosen, R.F Standert, A. Galat, M. Nakatsuka, S.L. Schreiber Science 863 (1990) M.K. Rosen, R.F Standert, A. Galat, M. Nakatsuka, S.L. Schreiber

Mechanism of Rotomase Enzymes

18-JKLFK1 4/30/91 1:49 PM

Biochemistry 3813 (1990) R.K. Harrison, R.L. SteinJOC 4984 (1990) M.W. Albers, C.T. Walsh, S.L. SchreiberBiochemistry 3813 (1990) R.K. Harrison, R.L. SteinJOC 4984 (1990) M.W. Albers, C.T. Walsh, S.L. Schreiber

Rotomase Inhibitors- Leucine Twisted Amide Mimics

19-JKLFK2 4/30/91 2:03 PM

Science 251, 283 (1991) S. L. SchreiberScience 251, 283 (1991) S. L. Schreiber

Rotomase Inhibitors

20-JKLFK3 4/30/91 2:13 PM

Rotational Barriers, Amide and Ester Resonance

∆G-exp

∆G-exp

∆G-exp

∆G-exp

∆G-calc

∆G-calc

∆G-calc

∆G-calc

3.900 Kcal/mole

4.61 Kcal/mole

4.750 Kcal/mole

5.59 Kcal/mole

3.850 Kcal/mole

1.19 Kcal/mole

1.15 Kcal/mole

8.51 Kcal/mole

8.63 Kcal/mole

K.B. Wiberg, K.E. Laidig JACS 109, 5935 (1987)

OH

O

H

O

O

H

H

O

OCH3

H

O

CH3

O

H

OCH3

O

H3C H3C

O

O

CH3

H

O

O

H H

H

H

HHO

O

H

21-Wiberg1 4/30/91 10:38 AM

K.B. Wiberg, K.E. Laidig JACS 109, 5935 (1987)

2.3 Kcal/mole∆G-calc

Rotational Barrier

Exp 18-19 Kcal/moleCalc 15.3 Kcal/mole

"calculated satisfactorally"

Calc. RC-O Å

1.233

1.400

1.188

1.193

model for 50%charge transfer

C-O single bond

no resonance

indicative of a normal C=Odouble bond, little evidenceof loss of double bond character

Amide Resonance?

H

O

N NH

H

H H

H NH

H

O

H

O

H3C O-

O

H3CO

CH3

H3CH

O

H N

O

H

H

O

N

H

HH

H N+H

H

O-

22-Wiberg2 4/30/91 11:09 AM

DE Kcal/mole (calc)

µ(D)

rC=OrC-NrC-HrN-H

4.095(3.85exp)

0.0

1.19271.34891.09100.99570.9923

15.34

1.573

1.18321.42731.08761.0055

17.60

4.080

1.17891.42301.09431.0046

Calculated energies,dipolemoment and bond lenghts

C-N bond length decreases 0.08Å suggests some double bond characterBut, C-O bond length increases by only 0.01Å suggesting C=Orelatively unaffected by rotation

planar B

Calculated Electron Populations (units-electrons)

planar

A

B

N 8.476 C 4.020 O 9.392

N 8.222

N 8.209

C 4.242

C 4.226

O 9.343

O 9.318

Amide Resonance?

A

∆ -0.254

∆ -0.267

∆ +0.222

∆ +0.206

∆ -0.049

∆ -0.074

O

N

H

HH N

HH

O

H H

O

N

HH

23-Wiberg3 4/30/91 6:03 PM

Twist

Tilt

90

15-20

31

25

60260

36

16.4

17

16

10

5.52 X 10_4kOH

M-1s-1

solution high energy barrier to formation - solvent interactions on TS and products - must be due to structural changes for rehybridization at N. Twist amides don't have to rehybridize and therefore have a faster rate of hydrolysis (destabilized GS).

gas phase"barrierless"by calculation

-OH

JACS 112, 6383 (1990) R.S. Brown et.al.

Twisted Amides- Support for No Amide Resonance

N

OO

N N

O O

H NH2

O

H NH2

OHO-

N

24-BrownNoRes 4/30/91 4:07 PM

JACS 113, 2865 (1991) Charles L. Perrin

Atomic Size Dependence of Bader Electron Populations:Significance for Questions of Resonance Stabilization

" At this time we decline to judge whether resonance is important for carboxylates and related species. Our results do not justifyany conclusions except the one that some previous objections to resonance are unfounded."

Bader electron populations (used by Wiberg) exaggerate electron density at electronegative atoms.The resulting atomic charges are judged to be unreliable, especially as evidence against resonance in carboxylate anions and related species.

25-Perrin 4/30/91 4:22 PM