1,2-diamines: synthesis and utility · discovered by sir alexander fleming in 1928 fleming, florey...

1,2-Diamines: Synthesis and Utility

Wei Li

MacMillan Group Meeting

November 6, 2013

1,2-diamines

X

Y

NH2

NH2


■ part 1: importance

■ part 2: synthetic methods ■ part 3: utilization

NH2

Pt

H2N

O

O O

O

Medicinal agents Ligands in catalysis

N NAr Ar

ArN NAr

R RHN

NHN N

HN

OH2N

ONH2

OHOH

Natural product

1,2-diamines

X

NHY

NH2

XY

X

NH3

Y

NH3

X

NH

Y

NH

HN

NH3

■ resolution

■ chiral auxiliaries

■ chiral ligands

■ natural product synthesis

■ medicinal use

X

NH2

Y

NH2

Importance of 1,2-Diamines in Chemical Fields

■ Penicillin

HNR

O NO

SH

CO2H

CH3

CH3

Penicillin: a group of antibiotics

Penicillum fungi

■

■

Discovered by Sir Alexander Fleming in 1928■

Fleming, Florey and Chain - Nobel Prize, 1945■

" When I woke up just after dawn on September 28, 1928,I certainly didn't plan to revolutionise all medicine bydiscovering the world's first antibiotic, or bateria killer,but I suppose that was exactly what I did"

- Sir Alexander Fleming

saved millions of people from baterial infection■


■ Medicinal agents

NH2

Pt

H2N

O

O O

O

Eloxatin: anticancer drug

S

NHHN

O

CO2H

Biotin: vitamin H

H2N

OCHEt2

OEt

O

AcHN

Tamiflu: antiviral drug

NH

diaminocylcohexane:

N

O

Cl

Cl

opioid receptor agonist


■ Ligands in catalysis

Grubbs metathesis catalyst Noyori hydrogenation catalyst

Maruoka organocatalyst

N N

RuPyCl

Cl

PyPh

PhPh

P

P

Ru

Cl

Cl

HN

NH

N N

O O tBu

tButBu

tBu

Mn

Cl

Jacobsen epoxidation catalyst

NHTf

NH2EtO2C

Ph Ph

Ph Ph


■ Structural motif in natural products

HN

NHN N

HN

OH2N

O

NH2

OH

OH

Sexitoxin

NH

N

N NH

O

Br

HO

O

agelastatin A

O

O

NH

HN

O

OH

HOHO

CO2H

O OH

balanol

N

N

N

O

H

H H

OH

OH

Me

MeO

OH

H

Me

Bioxalomycin α2


■ Structural motif in natural products

HN

NHN N

HN

OH2N

ONH2

OHOH

Saxitoxin

NHN

N NH

O

Br

HO

O

agelastatin A

O

O

NH

HN

O

OH

HOHO

CO2HO OH

balanol

NN

N

O

H

H H

O H

OHMe

MeOOH

H

Me

Bioxalomycin α2


■ total synthesis of pactamycin

O Me

HO HN

HN NH2O

NMe2

OMe

OH

Me

O

OHMe OH

pactamycin

Malinowski, J. T.; Sharpe, R. J.; Johnson, J. S. Science. 2013, 340, 180.




NH2

Pt

H2N

O

O O

O


N NAr Ar

ArN NAr

R RHN

NHN N

HN

OH2N

ONH2

OHOH

Natural product

1,2-diamines

X

NHY

NH2

XY

X

NH3

Y

NH3

X

NH

Y

NH

HN

NH3

■ resolution


■ chiral ligands


■ medicinal use

X

NH2

Y

NH2

Synthesis of 1,2-Diamines

X

NH2

Y

NH2

1,2-diamines

X

NR

Y

NH2

R2NH2

RN

X Y

+

+

or


X

NH2

Y

NH2

1,2-diamines

X

NRY

NH2

R2NH2

RN

X YX

O

NR2

NO2

NR

Y

X+

+

or or +


X

NH2

Y

NH2

1,2-diamines

X

NRY

NH2

X Y

NR

R2NH2

RN

X Y

NR

X

O

NR2

NO2

NR

Y

X+

+

or or +

+


X

NH2

Y

NH2

1,2-diamines

X

NRY

NH2

X

R2NH

Y

R2NH

X Y

NR

R2NH2

RN

X Y

NR

X

O

NR2

NO2

NR

Y

X+

+

or or +

+


■ aziridine openning by nitrogen nucleophiles

X

NH2

Y

NH2

1,2-diamines

R2NH

RN

X Y

■ N-aziridines protection is necessary

■ "unactivated" aziridines - protonation, or quarternarization,or activation by a Lewis acid

■ "activated" aziridines - Ts, Ns, Acyl, etc.■ regioselectivity

■ aziridine openning by nitrogen nucleophiles

TsN

tBuMe2SiO OR

KOtBuTHF, 0°C

87%tBuMe2SiO

NHTs

BnNO

O

tBuMe2SiONHTs

N3

tBuMe2SiON3

NHTs

OH

OH

NaN360%

27%

DMF, 50°C

R =NHBn

OR = H


■ nucleophile addition into α-amino imines

X

NH2

Y

NH2

1,2-diamines

■ chiral pool

■ chelation control feasible

■ non-chelation - Felkin-Anh model

■ syn or anti diamine

■ access to both syn and anti diamines

X

NR

Y

NH2

Bn2N

NBn

R

Bn2N

NHBn

R

R1R1Li/CeCl3

Bn2N

NBn

R

MLn

R1

Reetz, M. T.; Jaeger, R.; Drewlies, M.; Hubel, M. Angew. Chem. Int. Ed. 1991,30, 103.

Bn2N

NTs

R

Bn2N

NHTs

R

R1

R1MgX

NTsH

NBn2

H R

Nu


■ nitro-Mannich or aza-Henry

X

NH2

Y

NH2

1,2-diamines

■ diastereoselective example - Anderson

NO2

NR

YX

Noble, A.; Anderson, J. C. Chem. Rev. 2013,113, 2887.

R

NO2

1) nBuLi, THF, -78°C

2) PMBN=CHR1

3) AcOH, THF

-78°C to 0°C

R1R

NO2

NHPMB 60-95% yield

NO

HN

O

R

H

Ar

R NO

HN

O

R

HH

ArH R

Adam, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org. Chem. 1998, 63, 9932.favored


■ enantioselective syn nitro-Mannich reaction - Shibasaki

X

NH2

Y

NH3

1,2-diamines

Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007,129, 4900.

R

NBoc

R1 NO2

catalyst (2.5-10 mol%)R

R1

NH

NO2

Boc

THF, -40°C

62-99%>20:1 dr

83-98% e.e.

N N

O

O

O

O

Cu

Sm

OArAr = 4-tBuPh

catalyst

Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010,132, 4925.

R H

N

OtBu

ONO2H

R1

Cu

Sm R H

N

OtBu

ONO2R1

H

Cu

Sm

favored

Cu

SmArO

or

catalyst


■ enantioselective anti nitro-Mannich reaction - Wang

X

NH2

Y

NH2

1,2-diamines

Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue. Z.-Y.; Teng, H.-L. J. Am. Chem. Soc. 2008,130, 8606.

R

NBoc

R1 NO2

catalyst (2.5-10 mol%)

RR1

NH

NO2

Boc

THF, -40°C

85-99%

>93:7 dr

96-99% e.e.

catalyst

NMe2

NH

NH

S Ph

Ph

HNSO2

CF3

CF3

NO

HN

O

R

H

Ar

R NO

HN

O

R

HH

ArH R

favored


■ Mannich reaction of α-aminol carbonyl with imines

X

NH2

Y

NH3

1,2-diamines

■ recent examples - MaruokaArrayas. R. G.; Carretero, J. C. Chem. Soc. Rev. 2009,38, 1940.

X

O

NR2

NR

Y

O

NHZ

R

NBoc

1. amine catalyst

2. NaBH4

OH

NHZ

R

NH Boc

OH

NHZ

R

NH Boc

NH

NHTf

(S)-1L-proline : syn major, > 98% ee (S)-1 : anti major, > 97% ee

syn anti

Kano, T.; Sakamoto, R.; Akakura, M.; Maruoka, K. J. Am. Chem. Soc. 2012, 134, 7516.

■ NR2 is oftenPh

N

Ph■ Syn-diastereoselectivity■ both syn and anti can be obtained

Z= Cbz

■ enantioselective processes - well precedented


■ stereoselectivity rationale

X

NH2

Y

NH3

1,2-diamines


N

R

Boc H N

NH

OO

Z

N

R

Boc H NO

O

NHZ

O

NHZ

R

NH Boc

syn

O

NHZ

R

NH Boc

anti

N

R

Boc N

NHZ

NH

Tf

N

R

Boc NN

HTf

NHZ

fast slow

slow fast


■ Mannich reaction glycine ester Schiff bases with imines - Lambert

X

NH2

Y

NH3

1,2-diamines

R

NBoc

10 mol% 1

NHBoc

N

CO2R

1

63-99% yieldsyn

Bandar, J. S.; Lambert, T. H. J. Am. Chem. Soc. 2013, 135, 11799.

N CO2RPh

Ph 4Å mol sievesPhMe, rt

R

Ph

Ph N

Cy2N NCy2

Bn

OH

■ gram scale

■ alkyl and aryl imines >91:9 dr38-97% ee



X

NH2

Y

NH3

1,2-diamines

■ Stereochemical rationale

R

NBoc

10 mol% 1

NHBoc

N

CO2R

1

63-99% yieldsyn


N CO2RPh


R

Ph

Ph N

Cy2N NCy2

Bn

OH

■ gram scale


N

Cy2N NCy

H

Bn

OH

H

O

OR

N

Ph

PhPhH

NtBuO

O

H



X

NH2

Y

NH3

1,2-diamines

■ Stereochemical rationale

R

NBoc

10 mol% 1

NHBoc

N

CO2R

1

63-99% yieldsyn


N CO2RPh


R

Ph

Ph N

Cy2N NCy2

Bn

OH

■ gram scale


N

Cy2N NCy

H

Bn

OH

H

O

OR

N

Ph

PhPhH

NtBuO

O

HO

OR

N

Ph

PhPhH

NtBuO

O

H

ON

HBn

H

NCy2

NCy

H


■ transition metal catalyzed 1,2-diamination of alkenes

X

NH2

Y

NH2

1,2-diamines

■ early examples - Li

Cardona, F.; Goti, A. Nature Chemistry. 2009, 1, 269.

Li, G.; Wie, H.-X.; Kim, S. H.; Carducci, M. D. Angew. Chem. Int. Ed. 2001, 40, 4277.

PhCOR

TsNCl2

MeCN

+

condition a:[(C3F7CO2)2Rh]2 (2 mol%)

PPh3 (4 mol%), 4Å MSCH3CN, rt NN

CH2Cl2

Ts

Ph CORcondition b:

CH3CN, rt, 4Å MS

condition a: 66%, 26:1 d.r.condition b: 60%, 95:1 d.r.

Chen, D.; Timmons, C.; Wei, H.-X.; Li, G. J. Org. Chem. 2003, 68, 5742.

X

R2NH

Y

R2NH■ stoichimetric examples with Osmium (VIII)

■ relatively young field for catalytic processes

■ alkene stereochemistry - product

■ enantioselective processes are known

Muñiz, K. New J. Chem. 2005, 29, 1371.

N

Cl Ts

Ph COPh


■ metal-catalyzed intramolecular 1,2-diamination

X

NH2

Y

NH2

1,2-diamines

Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2005, 127, 14586.

Pd(OAc)2 (5-25 mol%)PhI(OAc)2 (2.2 equiv.)

CH2Cl2, rt

NH NH

TsO

NN

n n

n = 1,2,3

O

Ts

Pd(II)

NH

N

OTs

Pd(II)Ln

NPd(II)Ln

NTs

O

NPd(IV)Ln

NTs

O

N NTs

O

Pd(IV)Ln

178-95%

PhI(OAc)2

Syn - aminopalladation

Amidedissociation

2 1 OAc+


■ syn-aminopalladation mis-assignment

X

NH2

Y

NH2

1,2-diamines



CH2Cl2, rt

NH NH

TsO

NN

n n

n = 1,2,3

O

Ts

278-95%

1

Muñiz, K.; Hövelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763.

NH NH

TsO

D

NN

O

Ts

DH

H

NN

O

Ts

HD

H

NH NH

TsO

D

Jtrans = 8.6 Hz

Jcis = 8.8 Hz Jtrans = 4.4 Hz

2005:

2008:


■ syn-aminopalladation mis-assignment

X

NH2

Y

NH2

1,2-diamines



CH2Cl2, rt

NH NH

TsO

NN

n n

n = 1,2,3

O

Ts

278-95%

1

Muñiz, K.; Hövelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763.

NH NH

TsO

D

NN

O

Ts

DH

H

NN

O

Ts

HD

H

NH NH

TsO

D

Jtrans = 8.6 Hz

Jcis = 8.8 Hz Jtrans = 4.4 Hz

2005:

2008:

TsN

NTs

89%

NNCO2R1

NCO2R1

RR

70-99%

NN

O

Ts

CO2Et

92% (1.3:1 dr)

NNCO2Me

SRR

99%

OO


■ metal catalyzed intermolecular 1,2-diamination of alkenes

X

NH2

Y

NH2

1,2-diamines

■ diaziridinone as source of diamineBar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2005, 127, 7308.

(MeCN)2PdCl2 (5 mol%)

R1RHN NHR

O

60-99%>95% alkene regioselectivity

Benzoquinone (1 equiv.)+

Pd(PPh3)4 (10 mol%)R1

O

46-95%>95% dr

+N NR2

R3

NN

R1 R2

O

R3

Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 763.

>95% alkene regioselectivity

■ dienes required as substrates■ least substituted alkene

■ no external oxidant necessary■ highly stereospecific■ more substituted alkenes

NRRN

O

R1


■ metal catalyzed intermolecular 1,2-diamination of alkenes

X

NH2

Y

NH2

1,2-diamines

■ proposed mechanism


O

46-95%>95% dr

+N NR2

R3

NN

R1 R2

O

R3


>95% alkene regioselectivity■ no external oxidant necessary■ highly stereospecific■ more substituted alkenes

Pd(0)

O

RN NR

RNPdLn

NR

O

RNPd

NR

O

R1

R1

RN

O

NRPdII

II

II

prdt


■ 1,2-diamination of alkenes

X

NH2

Y

NH2

1,2-diamines


O

55-93%+

N N

RNN

O


R1

R

RNPdLn

NR

O

II

Pd(0)

Pd(0)

RNPd

NR

O

R1II

R

R1

RN

O

NRPdII

R

NRRN

O

R1

R

O

RN NR

RNPdLn

NR

O

II R1

R

RNPd

NR

O

R1 II

R

H

HRHN

PdNR

O

R1 II

R

R1

R

RHN NHR

O+


■ enantioselective 1,2-diamination of alkenes

X

NH2

Y

NH2

1,2-diamines

■ enantioselective allylic and homoallylic diamination of terminal olefins

Pd2(dba)3 (5 mol%)R1

O

60-95%91-95% e.e.

+N N

NN

R1

O


L1 (22 mol%)

O

OP NL1 =

Pd2(dba)3 (5 mol%)R1

O

50-85%89-94% e.e.

+N N

NN

R1

O

L2 (22 mol%)

O

OP NL2 =

Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688.




NH2

Pt

H2N

O

O O

O


N NAr Ar

ArN NAr

R RHN

NHN N

HN

OH2N

ONH2

OHOH

Natural product

1,2-diamines

X

NHY

NH2

XY

X

NH3

Y

NH3

X

NH

Y

NH

HN

NH3

■ resolution


■ chiral ligands


■ medicinal use

X

NH2

Y

NH2

Utilization of 1,2-Diamines

■ resolution of racemates

Alexakis, A.; Mangeney, P.; Marek, I.; Rose-Munch, F.; Rose, E.; Semra, A.; Robert, F. J. Am. Chem. Soc. 1992, 114, 8288.

R CHO

racemic

R

NMe

MeN

Ph

Ph

R* CHO

chiral

1) separation

2) hydrolysis


■ resolution of racemates


Lucet, D.; Gall, T. L.; Mioskowski, C. J. Angew. Chem. Int. Ed. 1998, 37, 2580.

NHN

O

Me

Ph

Alexakis, A.; Mangeney, P.; Marek, I.; Rose-Munch, F.; Rose, E.; Semra, A.; Robert, F. J. Am. Chem. Soc. 1992, 114, 8288.

R CHO

racemic

RNMe

MeN Ph

Ph

R* CHO

chiral

1) separation

2) hydrolysis

MeN

BBr

NSO2

SO2

CF3

F3C

CF3

CF3

Ph Ph NHR

NHR


■ chiral ligands


Ph

NSO2CF3

Al

SO2CF3N

Ph

R

Ph

NSO2CF3

Ru

SO2CF3N

Ph

Br

NSO2R

Ti(OiPr)2

SO2RN

■ Lewis acid derivatives


■ chiral ligands


Ph

NSO2CF3

Al

SO2CF3N

Ph

R

Ph

NSO2CF3

Ru

SO2CF3N

Ph

Br

NSO2R

Ti(OiPr)2

SO2RN


■ salen-type ligands from 1,2 diamines and aromatic aldehydes

N N

OH HO


■ chiral ligands


Ph

NSO2CF3

Al

SO2CF3N

Ph

R

Ph

NSO2CF3

Ru

SO2CF3N

Ph

Br

NSO2R

Ti(OiPr)2

SO2RN


■ salen-type ligands from 1,2 diamines and aromatic aldehydes

N N

OH HO

■ N-heterocyclic carbene ligands

N N

Ph Ph

ArAr

X

■ Miscellaneous

NMe

NR2

1,2-Diamines in Synthesis

■ formal synthesis of (-)-Agelastatin A


NH

N

N NH

O

Br

HO

O

O

NHZ

NBoc

+

30 mol%

L-proline

Ph

O

NHZ

NH Boc

Ph

69%

6.4:1 dr, 98% ee

Br

NiCl2, CrCl2

DMSOCH3CN

OH

NHZ

NH Boc

Ph

73%

1) TFA, CH2Cl2

2) 1, EDCl, HOBt

DMAP, CH2Cl2

HN

Br

Br

HO2C

1

OH

NHZ

HN

Ph

67% over 2 steps

OHN

Br

Br

Hoveyda-Grubbscatalyst

HN NH

O

Br

toluene

OH

NH

Z

Br

78%

1,2-Diamines in Synthesis

■ formal synthesis of (-)-Agelastatin A


NH

N

N NH

O

Br

HO

O

IBX

DMSOHN NH

O

Br

OH

NH

Z

Br

HN NH

O

Br

O

NH

Z

Br

iPr2NEt

N NH

O

Br

O

NH

Z

Br

81%

3 steps

NH

N

N NH

O

Br

HO

O

(-)-agelastatin A

1,2-diamines: synthesis and utility · discovered by sir alexander fleming in 1928 fleming, florey...

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