1,2-Diamines: Synthesis and Utility · Discovered by Sir Alexander Fleming in 1928 Fleming, Florey...
Transcript of 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
1,2-Diamines: Synthesis and Utility
■ 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■
Importance of 1,2-Diamines in Chemical Fields
■ 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
Importance of 1,2-Diamines in Chemical Fields
■ 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
Importance of 1,2-Diamines in Chemical Fields
■ 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
Importance of 1,2-Diamines in Chemical Fields
■ 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
Importance of 1,2-Diamines in Chemical Fields
■ 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.
1,2-Diamines: Synthesis and Utility
■ 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
Synthesis of 1,2-Diamines
X
NH2
Y
NH2
1,2-diamines
X
NR
Y
NH2
R2NH2
RN
X Y
+
+
or
Synthesis of 1,2-Diamines
X
NH2
Y
NH2
1,2-diamines
X
NRY
NH2
R2NH2
RN
X YX
O
NR2
NO2
NR
Y
X+
+
or or +
Synthesis of 1,2-Diamines
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 +
+
Synthesis of 1,2-Diamines
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 +
+
Synthesis of 1,2-Diamines
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 +
+
Synthesis of 1,2-Diamines
■ 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
Synthesis of 1,2-Diamines
■ 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
Synthesis of 1,2-Diamines
■ 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
Synthesis of 1,2-Diamines
■ 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
Synthesis of 1,2-Diamines
■ 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
Synthesis of 1,2-Diamines
■ 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
Synthesis of 1,2-Diamines
■ stereoselectivity rationale
X
NH2
Y
NH3
1,2-diamines
Kano, T.; Sakamoto, R.; Akakura, M.; Maruoka, K. J. Am. Chem. Soc. 2012, 134, 7516.
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
Synthesis of 1,2-Diamines
■ 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
Synthesis of 1,2-Diamines
■ Mannich reaction glycine ester Schiff bases with imines - Lambert
X
NH2
Y
NH3
1,2-diamines
■ Stereochemical rationale
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
N
Cy2N NCy
H
Bn
OH
H
O
OR
N
Ph
PhPhH
NtBuO
O
H
Synthesis of 1,2-Diamines
■ Mannich reaction glycine ester Schiff bases with imines - Lambert
X
NH2
Y
NH3
1,2-diamines
■ Stereochemical rationale
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
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
Synthesis of 1,2-Diamines
■ 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
Synthesis of 1,2-Diamines
■ 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+
Synthesis of 1,2-Diamines
■ syn-aminopalladation mis-assignment
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
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:
Synthesis of 1,2-Diamines
■ syn-aminopalladation mis-assignment
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
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
Synthesis of 1,2-Diamines
■ 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
Synthesis of 1,2-Diamines
■ metal catalyzed intermolecular 1,2-diamination of alkenes
X
NH2
Y
NH2
1,2-diamines
■ proposed mechanism
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■ 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
Synthesis of 1,2-Diamines
■ 1,2-diamination of alkenes
X
NH2
Y
NH2
1,2-diamines
Pd(PPh3)4 (5 mol%)R1
O
55-93%+
N N
RNN
O
Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 763.
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+
Synthesis of 1,2-Diamines
■ 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
Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 8590.
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.
1,2-Diamines: Synthesis and Utility
■ 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
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
Utilization of 1,2-Diamines
■ resolution of racemates
■ chiral auxiliaries
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
Utilization of 1,2-Diamines
■ chiral ligands
Lucet, D.; Gall, T. L.; Mioskowski, C. J. Angew. Chem. Int. Ed. 1998, 37, 2580.
Ph
NSO2CF3
Al
SO2CF3N
Ph
R
Ph
NSO2CF3
Ru
SO2CF3N
Ph
Br
NSO2R
Ti(OiPr)2
SO2RN
■ Lewis acid derivatives
Utilization of 1,2-Diamines
■ chiral ligands
Lucet, D.; Gall, T. L.; Mioskowski, C. J. Angew. Chem. Int. Ed. 1998, 37, 2580.
Ph
NSO2CF3
Al
SO2CF3N
Ph
R
Ph
NSO2CF3
Ru
SO2CF3N
Ph
Br
NSO2R
Ti(OiPr)2
SO2RN
■ Lewis acid derivatives
■ salen-type ligands from 1,2 diamines and aromatic aldehydes
N N
OH HO
Utilization of 1,2-Diamines
■ chiral ligands
Lucet, D.; Gall, T. L.; Mioskowski, C. J. Angew. Chem. Int. Ed. 1998, 37, 2580.
Ph
NSO2CF3
Al
SO2CF3N
Ph
R
Ph
NSO2CF3
Ru
SO2CF3N
Ph
Br
NSO2R
Ti(OiPr)2
SO2RN
■ Lewis acid derivatives
■ 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
Kano, T.; Sakamoto, R.; Akakura, M.; Maruoka, K. J. Am. Chem. Soc. 2012, 134, 7516.
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
Kano, T.; Sakamoto, R.; Akakura, M.; Maruoka, K. J. Am. Chem. Soc. 2012, 134, 7516.
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