P-Stereogenic Compounds
Brandon Rosen
Configurational Stability of P-Chiral Molecules
H
H
N
H
H
H
N
H
vs.
H
Asymmetric Hydrogenation
H
P
H
H
Ph
H
P
H
L* = Ph
15% ee
P
Me
Me
(69% ee)
132 kJ/mol
H
H
Ph * CO2H
Me
[Rh]/L*
Inversion Energy Barriers
A
H2
CO2H
H
Knowles, Chem. Commun. 1968, 1445.
24.2 kJ/mol
H
29 March 2014
H
A
H
CO2H
A = As 164 kJ/mol
NHAc
H2
* CO2H
NHAc
[Rh]/L*
OMe
P
L* = Me
Cy
85% ee
A = Sb 184 kJ/mol
A = Bi
Knowles, JCS Chem. Comm. 1972, 10.
264 kJ/mol
Schwerdtfegr, JACS 1992, 96, 6807
OMe
Additional Inversion Energy Barriers
Cy
P Me
Me
149 kJ/mol
Ph
P Me
Me
126 kJ/mol
H+
Ph
P
H
i-Pr
Ph
P
t-Bu
Me
Ph
Ph
Me
129 kJ/mol
137 kJ/mol
H
P+
Ph
H
i-Pr
P
Me
98 kJ/mol
Ph
Pi-Pr
Me
81 kJ/mol
i-Pr
P Ph
* CO2H
NHAc
[Rh]/L*
96% ee
P
P Ph OMe
Ph
[(R,R)-DiPAMP]
L* =
Knowles, JACS 1972, 97, 2567.
Monsanto Synthesis of L-DOPA
H+
Seconday phosphines can
racemize through acid-base
chemistry
P
H
Ph
O
MeO
AcHN
H
HO
CO2H
Ac2O; then H 2O
vanillin
Global market for L-DOPA is
estimated to be ca. 250
tons/year with a market volume
> $100 billion.
Early Investigations into P-Chiral Molecules
O
Meisenheimer, 1911:
P Me
Ph
Me
NHAc
H2
67 kJ/mol
Bi-Pr
B-
P Me
i-Pr
O
CO2H
S
P
Ph
n-Bu
Davies & Mann, 1944:
MeO
CO2H
NHAc
AcO
H2
[Rh]
(R,R)-DiPAMP
[substrate:catalyst ratio = 20,000:1]
HO
HO
CO2H
NH 2
H 3O+
MeO
AcO
CO2H
NHAc
L-DOPA
O
HO 2C
O
Meisenheimer, 1926:
P Ph
Ph
Me
Horner, 1961:
Ph
P Me
Me
Ph
McEwen, 1959:
Knowles, 1968:
Horner, 1968:
Ph
Ph
IP+
Me
Me
P
Me
In 2001, William S. Knowles
was awarded the Nobel Prize in
Chemistry for his "work on
chirally catysed hydrogenation
reactions".
"The inventive process is not clearly
understood, but one factor that
seems to be important is to have a
heavy infusion of naivety."
Me
1
P-Stereogenic Compounds
Brandon Rosen
Interconversions Between P-Chiral Molecules
Resolution of Racemic/Diastereomeric Mixtures
Phosphine Oxides and Phosphine Sulfides
O
P 2
1
R
R
R3
X2
H 2O
[inversion]
R1
29 March 2014
Chiral Auxiliaries for Resolution of Phosphine Oxides/Phosphonium Salts
mCPBA, TBHP,
P 3
R
R2
H 2O2, etc.
[retention]
O
P 3
1
R
R
R2
Ph
Me Me SO 3H
O
Me Me SO 3H
O
Br
(–)-CSA
P
R1 3R 2
R
HSiCl 3
Et 3N
[inversion]
O
P 3
1
R
R
R2
HSiCl 3
P
R1 2R 3
R
Me
NH 2
[retention]
Ph Ph
CO2H
O
CO2H
Horner, Tet. Lett. 1965, 17 , 1157
(–)-Taddol
Me
Ph
R1
P 3
R
R2
S
P
R1 2R 3
R
Si2Cl6
or Raney Ni
R1
CeCl 3
93% ee
OMe
P
Me
Cy
P 3
R
R2
P 3
R
R2
S
P 3
1
R
R
R2
N
While this method provides
products in good yields,
enantiopurity is destroyed.
The use of menthyl phosphinates as a method for the synthesis of optically active
phosphines was first reported in 1967: Mislow JACS 1967, 89, 4784 and JACS 1968, 90,
4842.
MeO
MgBr
BH 3
P(OMe) 3
MeO
P(OMe) 2
1. Si2Cl6
R1
P 3
R
R2
or H +, then B (for R = alkyl)
P
R1 2R 3
R
2. BH 3
Corey, JACS 1993, 115 , 11000
1. MeI
2. H 2O
3. SOCl2
OMe
R 3N or ROH
(-)-quinine
Resolution of Menthylphosphinates
0% ee
BH 3
(–)-Sp
OH
N
Imamoto, JACS 1990, 112 , 5245
R1
H
O
Phosphine-borane complexes are very stable and allow functionalization at phosphorus or
an attached methyl group, as well as stabilizing alkyl phosphines.
BH 3
N
N
(+)-cinchonine
LAH, NaBH 4
N
(–)-MenOH
N
Phosphine Boranes
O OMe
P
Me
Cy
H
Me
OH
S8
Ph Ph
Me
CO2H
(–)-ephedrine
2. LAH
OH
OH
O
OH Me
Me NH OH
1. MeOTf
O
Me
Me
Ph
O
(+)-DBTA
(+)-BrCSA
OH
O
O
P
Ph
P Ph OMe
[(R,R)-DiPAMP]
1. LDA
2. CuCl2
3. HSiCl 3, Bu 3N
MeO
MeO
O
P
Cl
Me
O
MeO
PhMgCl
P
Me
Ph
[inversion]
(–)-MenOH
pyridine
O
P
OMen
Me
(4:1 d.r.)
Many phosphine-borane complexes can be used directly as ligands in organometallic
reactions. See Jugé, JOMC, 2001, 624, 333.
2
P-Stereogenic Compounds
Brandon Rosen
29 March 2014
Resolution of Menthylphosphinates
O
MenO P
Ph
O
P Ph
OMen
O
P
Ph
LDBB
0 °C
O
P Ph
MeI
[retention]
O
Me P
Ph
O
P Ph
Me
[retention]
MeO
O
P O
TfO t-Bu
B(OH) 2
OMe
O
MeO
[Pd]/BI-DIME
Ph
MeO
P O
t-Bu
OMe
t-Bu
MeO
Extremely hindered
Suzuki couplings!
t-Bu
Imamoto, Tet. Lett. 1991, 32, 3375
O
Resolution of Menthylphosphinite Borane Complexes
[Pd]/L*
(HO) 2B
Menthylphosphinite borane complexes react analogously to menthylphosphinates. While
Grignard reagents are typically employed for functionalization of menthylphosphinates,
organolithiums are preferred for menthylphosphinite boranes.
Br
P(O)OEt 2
For reduction of the menthoyl group, LiNap or Li/NH 3 is preferred.
P(O)OEt 2
88%
90% ee
MeO
Me
P
t-Bu
OMe
L*
Other Methods Based on Menthol Derivatives
MePCl 2
OMe
1. t-BuMgCl
2. 1,3-dimethoxybenzene
BuLi
3. H 2O2
MeO
OMe
BuLi
Me
P
O
t-Bu
I2
MeO
1. BBr 3
2. K 2CO 3
O
O
P O
HO t-Bu
KOH
P O
O t-Bu
O
> 99% ee Me
O
menthyl chloroformate
O
[kilo-scale]
P
I
O
t-Bu
recrystalize
42%, > 99% de
Me
HO
P O
t-Bu
Me
O H O
O
3 steps
P H P
MeO t-Bu t-Bu OMe
3 steps
P O
HO t-Bu
BIBOPs
Tang, Org. Lett. 2010, 12 , 176.
Li, OPRD 2013, 17 , 1061.
3 steps
O
MeO
P t-Bu
OMe
O
P
MeO t-Bu
P(t-Bu)2
POPs
Tang, Org. Lett. 2010, 12 , 1104.
i-Pr
i-Pr
Me
Cl
PhMePNa
i-Pr
Me
P
Ph
• converted to phosphine
oxide, separated, and
reduced
Me
Me
P
Ph
Me
First P- and C-chiral
phosphine ligand; gives
14-71%
ee
in
Rhcatalyzed hydrogenations.
Mosher, Tet. Lett. 1977, 29, 2487.
Resolution with Cyclometallated
Pd Complexes
RR
R1 R R
N
N
Cl
Pd
Pd
Cl
R1 R R
N Cl
Pd
R2
P R3
R4
R1
PR 2R 3R 4
Examples of P-stereogenic phosphines resolved
in this manner:
Me
Me Me Me Me
P
Ph
Ph
Ph
Me
P
P
P
Ph
Ph
Ph
BIPNOR
Ph 2P
P
Ph
P
Ph
P
Ph
P
Ph
R1 R R
N Cl
Pd
R2
P R3
R4
1. separate
2. dppe
P 2
P
R R4 3R2
R3
R
Otsuka, JACS 1971, 93, 4301.
R4
PPh 2
BI-DIME
Tang, ACIE 2010, 49, 5879.
3
P-Stereogenic Compounds
Brandon Rosen
29 March 2014
Dynamic Resolution of Secondary Phosphine Boranes
BH 3
1. n-BuLi, Et 2O
BH 3
1. t-BuMgCl
PhPCl 2
2. o-AnCH2Cl
2. LAH
3. BH 3•DMS
Ph
P
H
t-Bu
BH 3
BH 3
0% ee
P
t-Bu
1. n-BuLi, Et 2O
(-)-sparteine
2. o-AnCH2Cl
• Metallation and quench occur
rapidly at - 78°C, but equilibration
at room temp is required;
equilibration at 0 °C results in
product
with
35%
ee
Ph
N
OMe
Ph
Me Me
t-Bu
Ph
P
N
BH 3
Fe
O
Binol
Bn
N
P
NEt 2
OH
Ph
N
Ph
t-Bu
P
BH 3
> 99% ee
Bn
• Useful for Pd-catalyzed
allylic amination
N
Me
Helmchen, Tetrahedron 1996, 52, 7547.
Ph
BH3
N Me
Ph
BH 3
R P
HO N Me
RLi
Me
Ph
Br
[Pd]/L*
O
Ph
N
Me
Me
BH 3
H +, MeOH
- ephedrine
Me
Ph
BH 3
R'Li
P
OMe
R
Ph
P
R
R'
• Modular nature of this route allows synthesis of enantiomers with ease
Jugé, Tet. Lett. 1970, 31, 6357.
BH 3
HCl
- ephedrine
Ph
Me
P
Cl
R
• More reactive chlorophosphine can also
be prepared, but racemization is a bigger
problem.
Me
Preparation of P-Stereogenic AMPP Ligands:
Ph
BH 3
R P
LiO N Me
Ph
Ph
Me
Ph 2P
Ph R' R Ph
H 3B P
P BH 3
O
N Me
BH 3
P
Cl
R'
Ph
O
Ph
Me
PPh 2
N Me
Me
(–)-EPHOS
Boehringer Ingelheim Modification
(R, R P ): R = Ph, R1 = t-Bu
(R, SP ): R = t-Bu, R1 = Ph
Me
Br
R
Jugé, Tetrahedron: Asym. 1999, 10 , 4729.
NMe 2
P R1
R
3. BH 3•THF
4. CF 3SO 3H; KOH
N
2. ClPArAr2
Jugé, Tetrahedron: Asym. 2000, 11 , 3939.
SiocPhox
1. BuLi
2. ClP(Ph)(tBu)
Me
O
P
Ph
Hou & Dai, JACS 2001, 123 , 7471.
O
Ar2
P-Stereogenic Compounds Derived From Heterocycles
Ph
BH 3
R P
HO N Me
O
Ph
Ar
O
Jugé's Method
OMe
O
NMe 2
Br
R
P
+ diastereomer
Other Chiral Backbones
(N 2Et) 2P
N
Livinghouse, JACS 1997, 120 , 5116.
• Generally limited to P(BH 3)(Ph)(tBu)
N
F
R
95% ee
P
t-Bu
1.Mg 0
O
BH 3
P
O
Me Ph P
Ph
t-Bu
t-Bu
• Use of THF results in completely
93% ee
> 82% ee
unselective
quench
Fe
LiPArAr 2
O
(R, R P ): 89% ee
(R, SP ): 34% ee
Me
Cl
N
H
OH
(6 steps)
Ts
PhP(O)Cl 2
Me
Cl
Me-imidazole
98:2 dr
[100 gram scale]
Me
RMgBr
Cl
N
Ts
H
N
O
P O
or RLi
O
R P
Ph
O
[P–N bond cleavage!] Ph
Ts
Buchwald, Org. Lett. 2002, 4, 999.
4
P-Stereogenic Compounds
Brandon Rosen
Me
Cl
N
H
Ts
O
R P
Ph O
MeO
O
P
R'
R
Ph
R'MgBr
or R'Li
O
P
t-Bu
Ph
MeO
MeO
O
P
OMe Ph
29 March 2014
Deprotonation of Dimethylphosphine Derivatives
BH 3
Ph
s-BuLi
P
Me
Me
BH 3
benzophenone
(–)-sp
Ph
P
Me
OH
Ph
Ph
• Corresponding phosphine
sulfide
gives
analogous
product in comparable ee with
n-BuLi/(–)-sp complex.
79% ee
Evans, JACS 1995, 117 , 9075.
Han, JACS 2013, 135 , 2474.
• Phosphines prepared using Jugé's method and its variations are generally limited to
Ph-substituted phosphines; trialkylphosphines are inaccessible.
Functionalization of Phosphines Prepared Using Jugé's Method
BH 3
BH 3
BH 3
s-BuLi
P
R
Me
Ph
Li
DMF
O
H
R
BH 3
P
R
Ph
P
R
Ph
BH 3
R
P
Ph
s-BuLi
(–)-sp
99% ee
BH 3
s-BuLi, (–)-sp
P
Me
Me
O2
71–93% ee
BH 3
R
P
Me
BH 3
-HCHO
OH
cat. RuCl 3
R
P
H
Me
Imamoto, JOC 2000, 65, 4185.
P
R
Ph
BisP* ligands: R = t-Bu, Et 3C, 1-adamantyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl.
BH 3
1. s-BuLi, (–)-sp
P
Me 2. CuCl2
R
Me
BH 3
BH 3
P
R
Me
BH 3
P
R
Me
1. TfOH
R
2. K 2CO 3
P
Me
P
R
Me
MiniPHOS ligands: R = t-Bu, i-Pr, cyclohexyl, Ph.
P
R
Si
Ph
R' R'
O
Li
P
Ph
Me
S
P
Ph
Me
-CO2
BH 3
EtI
O
P
Ph
Me
1. s-BuLi, (–)-sp
2. RPCl 2
P
Me 3. MeMgBr
R
Me
4. BH 3•THF
P-Stereogenic Compounds By Enantioselective Deprotonation
O
P
Me
Ph
Me
ArCH2Cl
BH 3
Cl2SiR'2
BH 3
P
H
Ph
Me
2. recrystallize
3. Li-napthalenide
BH 3
n-BuLi
Livinghouse, JOC 2001, 66, 1514.
Cu(II)
P
R
Ph
BH 3
1. PivCl
KOH
NR''
R'
OH
Ph
Ph
79% ee
P
R
Ph
R'
ClSiR' 3
P
Ph
Me
BH 3
R''HN
P
R
Ph
R' 3Si
BH 3
BH 3 BH 3
P
R
Me
P
R
Me
1. TfOH
R
2. KOH
P
Me
P
R
Me
Imamoto, PNAS 2003, 101 , 5385.
Trichickenfootphos
Me
14% ee
Raston & White, J. Chem. Soc. Dalton Trans. 1989, 105.
BH 3
t-Bu
1. s-BuLi
2. ClP(t-Bu)2
P
Me 3. BH 3•DMS
Me
4. chiral HPLC
5. DABCO
P
P
t-Bu
t-Bu
Me t-Bu
Me
Me
NH 2
CO2H
Lyrica (preglabin)
+ enantiomer
Hoge, JACS 2004, 126 , 5966.
5
P-Stereogenic Compounds
Brandon Rosen
Optically Active Oligophosphines or: Just Because We Can
BH 3
P
t-Bu
Me
BH 3
BH 3
1. s-BuLi, (–)-sp
t-Bu
P
t-Bu P
Me
P
t-Bu 2. CuCl2
Me
BH 3
P
t-Bu
BH 3
Me
P t-Bu
BH 3
26%
+ 14% hexaphosphine
BH 3
t-Bu P
Me
BH 3
t-Bu
P
P
t-Bu
BH 3
Me
P t-Bu
1. s-BuLi, (–)-sp
29% octaphosphine
+ 9% dodecaphosphine
2. CuCl2
BH 3
29 March 2014
"Although the desymmetrisation of tert-butyldimethylphosphine borane and the
analogous sulfide has been widely used, the application of the same chemistry to other
substrates, especially cyclic phosphines, is still relatively undeveloped and further
advances are likely to appear."
• Because this method relies almost entirely on (–)-sparteine, the use of other (+)sparteine variants or other chirality inducers merits exploration.
Miscellaneous Reactions Employing P-Stereogenic Ligands
Hydrovinylation
Me
Me
[Ni]/L*
R
Chujo, Chem. Asian J. 2007, 2, 1166.
93% ee
L* =
Me
R
Deprotonation of Cyclic Phosphine Derivatives
t-Bu
1. s-BuLi, (–)-sp
P
BH 3 2. CuCl2
t-Bu
P
BH 3
HBF 4
P
t-Bu
BH 3
P
P
t-Bu t-Bu
DiSquareP*
[very air sensitive]
HH
1. s-BuLi, (–)-sp
t-Bu
S 2. CuCl2
t-Bu
P
S t-Bu
Si2Cl6
P
S
1. s-BuLi, (–)-sp
P
t-Bu BH 3 2. CO2
HH
P CO2H
t-Bu BH 3
79%
trans/cis = 7.4
76% ee (trans)
P CO2H
t-Bu BH 3
25% overall
97% ee (trans)
MeO 2C
CO2Me
Ph
92% ee
Ph
Ph
O
H OTMS
O
OTBS
H
Me H
L* =
Fe
Me
P
Me
Ph
Me t-Bu
N P
L* =
N P
t-Bu Me
[Ni]/L*
3:1 d.r.
Me
O
H OTMS
(–)-terpestacin
Me H
OH
R
Me
Rh-Catalyzed Conjugate Additions
Kobayashi, Tet. Lett. 2001, 42, 7303.
O
"This is an interesting result because up to now the six-membered phosphorinane ring
has been rarely present in ligands for enantioselective catalysis, especially compared to
the very common five-membered phospholane counterpart. Therefore, further
developments in this area should be seen in the near future."
Ph
N
P Me
Reductive Alkyne-Aldehyde Coupling
P
P
t-Bu
t-Bu
TangPhos
[very air sensitive]
[up to 10000 turnovers]
Zhang, ACIE 2002, 41, 1612.
recrystallization
[Pd]/L*
OAc
Ph
Me
Me
Me
Allylic Substitution
Imamoto, Synthesis 2004, 1353.
P
Me P
N
Ph
Me
PhB(OH) 2
[Rh]/L*
> 99% ee
O
t-Bu P
L* =
Ph
P
t-Bu
Ph
Ph
6
P-Stereogenic Compounds
Brandon Rosen
Some Commercially Available P-Stereogenic Ligands
Me t-Bu
N P
Me t-Bu
N P
N P
t-Bu Me
N P
t-Bu Me
(R,R)-QunioxP*
866081-62-1
$95/100 mg
t-Bu
(S,S)-QunioxP*
1107608-80-9
$95/100 mg
P
t-Bu Me
(R,R)-BenzP*
919778-41-9
$75/50 mg
Fe
P
P
t-Bu t-Bu
(R,R,S,S)-DuanPhos
528814-26-8
$110/100 mg
P Fc*
Ph
ChenPhos
1036373-39-3
$62/100 mg
P Ph OMe
(-)-DIPAMP
55739-58-7
$221/250 mg
P
t-Bu
P
Ph
P Ph OMe
(+)-DIPAMP
97858-62-3
$153/250 mg
H P t-Bu
HH
H H
Some Medicinally Relevant P-Stereogenic Compounds
OMe
P
Ph
Me
P
Cy2P
OMe
P
t-Bu
29 March 2014
Me O
P
i-PrO
O
N
OPh
H
O
H
N
O
O
O
N
HO F
Me
Sovaldi (sofosbuvir)
Marketed by Gilead for
HCV infection
• Original route gave P-diastereomeric
mixture; separation of isomers by HPLC
revealed that SP isomer had 10-fold better
activity
H
O N
Me O
P
O N
i-PrO
Cl HO
N
O H OPh
Me
used immediately
HO F
after preparation
Me
i-PrO
O
Sofia, J. Med. Chem. 2010, 53, 7202.
(S,S,R,R)-TangPhos
470480-32-1
$115/100 mg
O
Fe P H
Ph
Me
(S)-Binapine
470480-32-1
$115/100 mg
F
Me O
P
i-PrO
Cl
N
OPh
H
O
F
C6F 5OH
i-PrO
Et 3N
Sofosbuvir
JoSPOphos
1221746-66-2
$80/100 mg
Me 2N
OEt
O
HO
N
GA (Tabun)
Discovered 1936
12k tons prepared
between 1942-45
O
O
P
Me
N OMe
H SMe
Acephate
1800 - 2000 tons
used annually
GB (Sarin)
O
P
H 2N OMe
SMe
Methamidophos
Me
SMe
O
P
i-PrHN O
Me
OEt
Fenamiphos
F
H
N
F
O
F
Me O
P
i-PrO
O
N
O H OPh
N
Me
F
F
F
Ross, J. Org. Chem. 2011, 76, 8311.
O
P
S OEt
Me
(i-Pr)2N
Me
VR
15557 tons produced
recrystallize
F
O
HO F
Et 2N
F
Me O
P
O
N
OPh
H
O
t-BuMgCl
O
P
S O
Me
Cl
OPh
t-Bu P H
(t-Bu)2P
O
P
Me
Oi-Pr
F
O
P
Cl
NH 2
Some (Very Dangerous) P-Stereogenic Compounds
O
P
O
Me O
P
HO
O
N
H
OPh
O
enzymatic ester
Sofosbuvir
hydrolysis
VX
H
N
O
O
HO F
O
N
HO
Me
O
PH O
P P
P
-O
O
O O
O- O- O-
H
N
O
O
O
N
[fast]
HO F
Me
-O
O
P
O
O-
HO F
O
N
Me
[slow]
H
N
O
O
O
HO F
[fast]
N t-Bu
O
P
N
i-PrO O
OEt
Tebupirimifos
H
N
O
O
N
Me
7