BoroalkylGroupMigraonProvidesaVersaleEntryintoαAminoboroni ...ccc.chem.pitt.edu/wipf/Current...
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Boroalkyl Group Migra/on Provides a Versa/le Entry into αAminoboronic Acid Deriva/ves Zhi He, Adam Zadilk, Jeffrey D. St. Denis, Naila Assem and Andrei K. Yudin JACS, 2012, 134, 9926 Jaideep Saha Wipf Group Current Literature December 1, 2012 1 Jaideep Saha @ Wipf Group Page 1 of 16 1/12/2013
Transcript of BoroalkylGroupMigraonProvidesaVersaleEntryintoαAminoboroni ...ccc.chem.pitt.edu/wipf/Current...
Boroalkyl Group Migra/on Provides a Versa/le Entry into α-‐Aminoboronic Acid Deriva/ves
Zhi He, Adam Zadilk, Jeffrey D. St. Denis, Naila Assem and Andrei K. Yudin
JACS, 2012, 134, 9926
Jaideep Saha Wipf Group Current Literature
December 1, 2012
1
Jaideep Saha @ Wipf Group Page 1 of 16 1/12/2013
XR
X = Br, I 1. R''M
2. B(OR')3
B(OR')2R H2O, H+
B(OH')2R
HR
X = Br, I
DG
Directed ortho metallation
SiR3R BBr3 BBr2
R H2O, H+B(OH')2
R
XR
X = Br, I or H
(OR')2B B(OR')2HB(OR')2
Pd or TMB(OR')2
R H2O, H+B(OH')2
R
(OR')2B B(OR')2(eg B2pin2)
X
R Y
electrophilic centerTM
X
R [B]Y
RR2BH
(hydroboration)R BR2
R1 BOR'
OR'BOR'
OR'
Cl
R1
R2MLiCHCl2 BOR'
OR'
R2
R1
Matteson homologation
Installa/on of Boron func/onality
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-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐
R BOH
OH BO OO O
NMe
R
sp2 sp3
N
HO2C CO2H
Me
MIDA
MIDA: N-‐methyliminodiaceNc acid
R BOH
OH Dean-Stark RBO OO O
NMe
R BBr
Br
MIDA
MIDAR
BO OO O
NMe
RMgXB(OMe)3
R B(OMe)3MgBr
BO OO O
NMe
RMIDA
Suzuki-‐Miyaura cross coupling reacNon of boronic acids is a very frequently uNlized reacNon In organic chemistry.
Many boronic acids are unstable and SuscepNble for decomposiNon.
JACS, 2008, 130, 466
MIDA boronates
PreparaNon:
MIDA boronates are chemically compaNble To a wide range of reagents, thus allowing GeneraNon of complex boronic acid surrogates
Burke group, UIUC
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BO O
O O
NMe
MgBrB(OMe)3
THF-78 oC
B(OMe)3
MgBr
N
HO2C CO2H
Me
DMSO120 -160 oC 45 g0.5 mol
51%
Br
PdCl2(PPh3)2DMF, Et3N
R BO O
O O
NMe
R
Br
O2N
Pd(OAc)2/ SPhosK3PO4Dioxane-H2O, 60 oC33-95 % R
NO2
86%
B
Br
OH
OH
N
HO2C CO2H
Me
PhMe-DMSODean-Stark Br
BO O
O O
NMe B
R
OH
OH
Pd(OAc)2 /
Ph
PCy2K3PO4
BO O
O O
NMe
RR = Me (67%)
-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐
Prepara/on and reac/ons
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PCy2MeO OMe
A
N
HO2C CO2H
Me
Br BBr2
2,6-lutidine, DMSO60%
BO O
O O
NMe
Br
BB1
PhB(OH)2
Pd(OAc)2 / KF
92%B
O OO O
NMe
Ph
SnBu3
Pd2dba3, Fur3P91%
BO O
O O
NMe
O
MeO
Pd(OAc)2, PPh3, Et3N90%
BO O
O O
NMe
O
MeO
PdCl2(CH3CN)2
A
A, KOAc
OB
O
2
71%
BO O
O O
NMe
OBO
ZnClBu3Sn
Pd(OAc)2, A66%
BO O
O O
NMe
Bu3Sn
Boronic acid surrogates
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BO O
O O
NMe
OBO
ICl
PdCl2dppf, K3PO4
54%
BO O
O O
NMe
Cl
BO O
O O
NMe
Bu3Sn
ICl
Pd2dba3, As3P72%
BO O
O O
NMe
ClMe
B(OH)22
A
Pd(OAc)2, Cs2CO364%
BO O
O O
NMe
Me2
Cl
OAcMe
Me
Me
TESOB
OOOO
NMe
Me+
Pd(OAc)2, 1 N aq. NaOH
PCy2iPrO OiPr
THF
48%
OAc
Me
Me
TESOMe
Itera/ve cross coupling reac/ons: applica/on in total synthesis
6
OMe
Me
Me
HO O OH OH
OH
OH OH O
OH OH
CO2H
O
HONH2
Me
OHamphotericin B
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TMS1. BBr3
2.
N
HO2C CO2H
Me
BO O
O O
NR
Ph-B(OH)2
S SO O
Ph PhPd(OAc)2
BO O
O O
NR
Ph
mCPBA74%
BO O
O O
NMe
OB
O OO O
NMe
PhO
mCPBA
94%
d. r. >20:1
R = Me
N
HO2C CO2H
R =or
chiral oxiliary
Controlling diastreoselec/vity using chiral MIDA boronate
JACS, 2011, 133, 13774 7
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BO O
O O
NMe
PhO
TMSN3BF3.Et2O
DCM-30 oC
BO O
O O
NMe
Ph
N3
OH
+ BO
O
O
O
NMe
OPhH
(10%)Optimization
(98%)
OM
R1 R2
amphoteric C-enolate(disfavored)
Nu-E+ O
R1 R2
E+ M E+
ambident-O-enolate(favored)
Amphoteric α-‐boryl aldehyde
JACS, 2011, 133, 13770 Yudin Group
BOR
RNH OR
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[B]OR
H
[B]OPh
OH[B]
OPhH
Br
[B]NPh
HSO
tBu 85%NPhH
SO
tBu +
[B]
15:85
77%
73%
[B]
PhOH
97%
[B]
Ph CO2Et
Me
72%
[B]
PhNBn2
85%
[B]
ROSiR3
55-81%41%
[B]
R OTf
NaClO2, NaH2PO4, CyH, t-BuOH-H2O
Versa/lity of α-‐boryl aldehyde intermediate
JACS, 2011, 133, 13770 9
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BO OO O
NMe
O
Ph
BO OO O
NMe
PhO
BF3.Et2O BO
O
O
O
NMe
OPhH
Mechanism: Deuterium labeling experiment
JACS, 2011, 133, 13770 10
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Title Paper: Boroalkyl group migra/on-‐versa/le entry into α-‐aminoboronic acids
Why α-‐aminoboronic acids are important ?
Boron-‐containing therapeuNcs-‐
N
NO
NH O
HN B
OH
OH
VelcadeR
Proteasome Inhibitor
HO2C B
NH2. HClOH
OHArginase inhibitor
S
NN
O
HN
BHO OH
H2N
O
COOH
Lactamase Inhibitors
H2NO
NH O
HN
O
NH
COOHO
N
O
HN B
F
H
HCV NS3 inhibitor
H2N
NH
BOH
OHO
N
OR
Thrombin inhibitor
-----------------------------------
Chem. Soc. Rev. 2011, 40, 4279 11
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BO
O
O
O
NMe
OROH
BO
O
O
O
NMe
NRO
PO
PhO N3OPh
Et3NMeCN, 50 oC
Me
F
Ph
Ph
71%
57%
62%
91%
84%
86%
71%
73%
1.
2.
3.
4.
5.
6.
7.
8.
R
O
N NN
R-N=C=O
Title Paper: Boroalkyl group migra/on-‐versa/le entry into α-‐aminoboronic acids
Cur1us rearrangement
JACS, 2012, 134, 9926 12
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BO
O
O
O
N
OROH
Me PO
PhO N3OPh
Et3N
MeCN, 50 oC
R = Ph (d. r. > 95:5)R = CH2CH2Ph (d. r. > 95:5)
BO
O
O
O
N
R
Me
NO
R = Ph (d. r. > 85:5)R = CH2CH2Ph (d. r. > 95:5)
Streochemical Inves/ga/on of the migra/on
JACS, 2012, 134, 9926 13
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BO
O
O
O
NMe
NH
Ph
O
NHEt
(93%)
BO
O
O
O
NMe
NH
Ph
O
NH
iPr
(95%)
BO
O
O
O
NMe
NH
O
NH
tBu
(87%)
PhBO
O
O
O
NMe
NH
O
NHPh
(30%)Ph
BO
O
O
O
NMe
NH
O
N Et
(77%)
PhEt
Different transforma/ons of the α-‐borylisocyanate
BO
O
O
O
NMe
Ph NO
3 M HCl (aq.)MeCNquant.
B(OH)2
Ph NH3Cl Free amino boronic acid
BO
O
O
O
NMe
NRO
HNR''R'
THF, rt BO
O
O
O
NMe
NH
R
O
NR''
R'
α-‐boryl ureas
BO
O
O
O
NMe
NRO CuCl, DMF
BO
O
O
O
NMe
NH
R
O
O R'
R'OH
Ph
(80%)
(67%)
(60%)
(90%)
α-‐boryl carbamates
JACS, 2012, 134, 9926 14
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BO
O
O
O
NMe
NH
O
NH
tBuPh
1 M NaOH (aq.)THF
(90%)
BOHHO
NH
O
NH
tBuPh
BO
O
O
O
NMe
NH
Ph
O
O
Pd(PPh3)4DMBA
DCM/ MeOHB
O
O
O
O
NMe
NH2Ph(50%)
NHCbzO
HO
PyBOP, DIPEA(80%)
BO
O
O
O
NMe
NH
Ph NHCbzO
(d.r. 1:1, separable)
BO
O
O
O
NMe
OPhH
HO5 % Pd(PPh3)4
Et3B, Et3NB
O
O
O
O
NMe
OPhH
NaClO2, NaH2PO4 BO
O
O
O
NMe
OPhOH
DPPA, Et3N
MeCN(70%)
BO
O
O
O
NMe
Ph NO
6 M HCl, MeCN
(quant)
BOHHO
Ph NH3Cl
EtNH2
(85%)
BO
O
O
O
NMe
Ph NH
O
NH
Et
α-‐ureidoboronic acid
Boro-‐dipep1de
Quaternary boronic acid
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Summary and Outlook
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Ø An unprecedented boron-‐containing alkyl group migraNon is demonstrated. Ø Boryl isocyanate described in the literature is used with nitrogen and oxygen nucleophiles; therefore offers potenNal for generaNon of diverse library of boronic acid surrogates. Ø This method provides an alternaNve and versaNle method for the generaNon of α-‐aminoboronic acids and corresponding pepNdes which showed promise as drug candidates. Ø Screening of other nucleophiles that are compaNble to MIDA boronate Ø Other reacNons involving isocyanate, such as Diels-‐alder type reacNons.
Jaideep Saha @ Wipf Group Page 16 of 16 1/12/2013
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