Asymmetric Synthesis of Phosphorous Stereocenters · 2020. 10. 8. · i-Pr Me iii) PCl 5 iv)...
Transcript of Asymmetric Synthesis of Phosphorous Stereocenters · 2020. 10. 8. · i-Pr Me iii) PCl 5 iv)...
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Jake GanleyDepartment of Chemistry
Princeton University
Asymmetric Synthesis of Phosphorous Stereocenters Fundamentals and Applications
Group MeetingMay 20, 2020
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Early Utility of Chiral Phosphorus Compounds
P P
OMe
OMe
DIPAMP
AcO
MeO CO2H
NHAcAcO
MeO CO2H
NHAcH
[Rh((R,R)-DiPAMP)COD]BF4H2+
95% ee
Ph3P Rh PPh3Cl
PPh3 MeP
(R)3*P Rh P*(R)3Cl
P*(R)3
William KnowlesPride of Taunton, MA
Wilkinson’s Catalyst Horner & Mislow’s Chiral Phosphines
Asymmetric Hydrogenation Catalyst?
CO2H H2+[RhCl(L*)3]BF4 CO2H
MeH
15% ee
“This modest result was of course of no preparative value…While groping in this area, another development appeared…that a fairly massive dose of L-DOPA was useful in treatinng Parkinson’s disease.”
—William Knowles, Nobel Lecture, Dec 8, 2001
Me
Knowles, W. S. Acc. Chem. Res. 1983, 16, 106—112.
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Ligands in Asymmetric Catalysis
P
PH
H
TangPhos
N
N P
P
tBu Me
tBuMe
QuinoxP
P
OP
O
OMe
OMe
P PRMe
MeR
MeO-BIBOP
P
O
OMe
PtBu
tBu
MeO-BOPMiniphos
MeMeMe
MeMe
Me
MeMe
Me
MeMeMe
MeMeMe
P PMe
TrichickenfootPhos
MeMe
Me
Me
MeMe
MeMeMe
P
P
R
R
RR
DuPhos
P
PtBu
tBu
H
H
DuanPhos
P P
OMe
OMe
DIPAMP
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OPOO
HN
Me
O
O
Me
Me
Me
N
N
N
N
H2N
Tenofovir Alafenamide
OOPOO
HN
Me
O
O
Me
MeHO F
N
Sofosbuvir
Me
NH
O
O
OOPOO
HN
Me
O
O
Et
EtHO OH
CN
NN
N
NH2
Remdesivir
Anti-Virals with Chiral Phosphorus
Nucleotide Triphosphate
OO
HO OH
CN
NN
N
NH2
Nucleobase
Sugar
PO
O
O
PO
O
O
PO
O
O
OHO
HO OH
CN
NN
N
NH2
OO
HO OH
CN
NN
N
NH2
PO
O
O
Nucleoside Nucleotide
Kinase
Slow
Pradere, U.; Garnier-Amblard, E. C.; Coats, S. J.; Amblard, F.; Schinazi, R. F. Chem Rev. 2014, 114, 9154—9218.
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Nucleotide Prodrugs
OO
HO OH
CN
NN
N
NH2
PO
O
O
Free Nucleotide
no or low cell penetration
OOPOO
HN
Me
O
O
Et
EtHO OH
CN
NN
N
NH2
ProTide efficient cell penetration
OP
ORHNOR
Nu
OP
OOO
NuOP
OOO
NuPO
OPO
OO
in vivo deprotection Kinase
OOPOO
HN
Me
O
O
Et
EtHO OH
CN
NN
N
NH2
Stereochemistry at Phosphorus Impacts:• Potency • Toxicity • Rate of Metabolism •
Pradere, U.; Garnier-Amblard, E. C.; Coats, S. J.; Amblard, F.; Schinazi, R. F. Chem Rev. 2014, 114, 9154—9218.
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Outline
1. Historical Background and Chemistry of Phosphorus
2. Chiral Auxiliaries
3. Facial Differentiation
4. Topos Differentiation
5. Enantiomer Differentiation
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Phosphorus Coordination Chemistry & Nomenclature
P
X
PP P P
X
X
λ5-σ5 λ5-σ4 λ3-σ3 λ3-σ2 λ5-σ3
PRR
Rphosphine
PORR
Rphosphinite
PORR
ORphosphonite
PORRO
ORphosphite
PNR2R
Rphosphine(amin)
PNR2R
ORphosphon-amidite
PNR2RO
ORphosphor-amidite
PNR2R
NR2phosphine(diamin)
PNR2RO
NR2phosphoro-diamidite
PNR2R2N NR2
phosphine(triamin)
PNR2R2N NR2
phosphoramide
PNR2R
NR2phosphonamide
PNR2RO
NR2phosphoro-diamidate
PNR2R
Rphosphinamide
PNR2R
NR2phosphon-amidate
PNR2RO
ORphosphor-amidate
PRR
Rphosphine
oxide
PORR
Rphosphinate
PORR
ORphosphonate
PORRO
ORphosphate
O
O
O
O
O
O
O O
O
O
Coordination Chemistry
Nomeclature
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Discovery of Chiral Phosphorus
PhPCl2
i) MeOH, Pyridineii) MeI
PhPMe
O
Oi-Pr
Me
iii) PCl5iv) (—)-menthol Ph
PMe
O
Oi-Pr
Me
MeP
Ph
O
Oi-Pr
Me
mixture of diastereomers
crystallization
PhP
Me
O
Oi-Pr
Me
BrMgMe
inversion of configuration Me
PPh
O
Me
(S)P (R)P
(S)P (R)
inversion of configuration
PMe Me
(R)
ΔG‡130 = 32.1 kcal/mol
Korpium, O.; Lewis, R. A.; Chickos, J.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4842—4846.Baechler, R. D.; Mislow, K. J. Am. Chem. Soc. 1969, 92, 3090—3093.
NRR
R N RR
R
NRR
R
Inversion barrier ~ 5 kcal/mol
PRR
R P RR
R
PRR
R
Inversion barrier not known
HSiCl3
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Walsh Correlation Diagram for Planar vs Pyramidal XH3
Gilheany, D. G. Chem Rev. 1994, 94, 1339—1374.
E
δE E ∝ 1/δE
Planar XH3 Pyramidal XH3
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δEN δEP
• Smaller HOMO-LUMO gap (δE) for phosphine results in greater stabilization energy (E) for pyramidal form
Walsh Correlation Diagram for Planar vs Pyramidal XH3
Gilheany, D. G. Chem Rev. 1994, 94, 1339—1374.
E
δE E ∝ 1/δE
Amine vs Phosphine Inversion
NRR
R PRR
R
~5-6 kcal/mol ~30-35 kcal/mol
Why is the inversion barrier so much higher for phosphine?
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Substituent Effects on Phosphine Inversion
PPh Me
PPh Me
ΔG‡130= 32.1 kcal/molΔG‡
130= 35.6 kcal/mol
PRR
R P RR
R
PRR
R
ΔG‡25= 16 kcal/mol
P MePh
MeMe
PPh
i-Pr
ΔG‡110= 19.4 kcal/mol
O
vs
Rauk, A.; Allen, L. C.; Mislow, K. Angew. Che. Int. Ed. 1970, 9, 400—414.Baechler, R. D.; Mislow, K. J. Am. Chem. Soc. 1971, 93, 773—774.
Egan, W.; Mislow, K. J. Am. Chem. Soc. 1971, 93, 1805—1806.
Conjugation/HyperconjugationFactors that favor rehydrization (π delocalization of lone pair)
flatten the pyramid and lower the barrier to inversion
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Outline
1. Historical Background and Chemistry of Phosphorus
2. Chiral Auxiliaries
3. Facial Differentiation
4. Topos Differentiation
5. Enantiomer Differentiation
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The Jugé-Stephan Method: Ephedrine-Borane Complexes
Jugé, S. Phosphorus, Sulfur, and Silicon 2008, 183, 233—248.
R1PNMe2
NMe2 MePh
OH
NHMe
R1P ON
Me
Ph
Me
BH3
+Δ, PhMe
then BH3•THF
95:5 d.r.
R1P ON
Me
Ph
Me
BH3Li R2 NHO
P
Ph NHMe
BH3R1
LiR2
NHOP
Ph NHMe
BH3R1
LiR2
NHOP
Ph NHMe
H3B R1
LiR2
PR2R1
NMe
PhMe
OH
BH3H2O
—LiOH
PR2R1
NMe
PhMe
OH
BH3MeOH/H+
inversionP R2R1
MeO
BH3 Li R3
inversionP
R2 R1R3
BH3P
R2 R1R3retention
DABCO
Ephedrine
• Methanolysis necessary due to innertness of P—N bond to organometallic carbon nucleophiles Limitation: bulky nucleophiles either don’t
work or require forcing conditions that result in degradation in stereochemical fidelity
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The BI Auxiliary: Second Generation Amino-Alcohol
Han, Z. S. et al. J. Am. Chem. Soc. 2013, 135, 2474—2477.
P
OP
O
t-Bu
t-Bu OMe
OMe
P
O
t-Bu OMe
Pt-Bu
t-BuP
O
t-Bu
R
MeO OMe
OP Me
OMeMeOMe
MeMe
Not accessible via the Jugé-Stephan method
• Cu-catalyzed propargylation • Rh-catalyzed hydrogenation •• Pd-catalyzed Suzuki coupling & Miyaura borylation •
Cl
OH
NH
MeTs
PCl
Cl
O
Cl
O
N
MeTs
PO
PhN-Me-imidazole
CH2Cl285% yield, >99:1 d.r.BI Auxiliary
Cl
O
NHMeTs
PO
PhR1
R1 M
THF
R2 M
THFPO
PhR1 R2
58 — 91% yield62 — 91% yield
90 — 99% ee
PCl2OMeMeO
i) BI Auxiliary, CH2Cl2/Pyridine
ii) H2O2
Cl
O
N
MeTs
PO
85% yield>99.5:0.5 d.r.
MeO
OMe
Cl
O
NHTsMe
PO
t-BuOMe
MeO
t-BuLi
THF—40 ºC
MeLi
THF, rt
OP Me
OMeMeOMe
MeMe
96% yield 63% yield98.3:1.7 e.r.
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The PSI Reagent: Chiral Phosphorothioate Synthesis
O Base
RO
OPO
OHS
O
Base
RO
Phosphorothioate• Improved cellular uptake
• Increased stability to nucleases
MeO
Me
SPHSSC6F5
SC6F5
Et3N •
(—)-limonene oxide
Me
SP
O
Me
HS
SC6F5
Phosphorus-Sulfur Incorporation (PSI Reagent, ψ)
O Base
RO
HOMe
SP
O
Me
HS
O
ORO
Base
Me
SP
O
Me
HS
O
ORO
Base
O Base
HO
RO
DBU, MeCN
T
G
T
C
AC
T
T
T C
AT
AA
C
TGG
5’
3’
OPO
OHS
OPO
OHS OP
O
OHOvs
Knouse, K. W.; deGruyter, J. N. et al. Science 2018, 361, 1234—1238.
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Outline
1. Historical Background and Chemistry of Phosphorus
2. Chiral Auxiliaries
3. Facial Differentiation
4. Topos Differentiation
5. Enantiomer Differentiation
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Reactions of Planar, Prochiral Phosphorus
Möller, T.; Sárosi, M. B.; Hey-Hawkins, E. Chem. Eur. J. 2012, 18, 16604—166607.
XR1
R2
Planar Carbon• Nu—/E+ addition• Hydrogenation• Group transfer• Cycloaddition• More…
X = CR2, O, NR
X PR1
R2 R3
• Nu—/E+ addition• Hydrogenation• Group transfer• Cycloaddition• Less…
PPh H
i-Pr(OC)5W
W(CO)5
PPh
Hi-Pr
H2, [RhL2*]PF6
L = chiraphos, DIPAMP, DIOPracemic
PH
i-Pr(OC)5W
W(CO)5
PH
i-PrH2, [RhL2]PF6
L = diphos
i-PrMei-Pr
Me 95:5 d.r.
PH
Me Me
P
Me Me
PO
MeMe O
OR*
H
H
Δ, [1,5]
S
OO OR*
then S8P
OO
OR*
P
OO
OR*
Endo Exo
i-Pr
MeR* = 87% yield, 98:2 d.r.
93:7 endo/exo
de Vaumas, R.;Marinetti, A.; Ricard, L.; Mathey, F. J. Am. Chem. Soc. 1992, 114, 261—266.
PNt-Bu
Ar
MeOH, —5 ºC
NMe2
i-Pr
Me PArHNt-Bu
OMe
55% ee
X = C, N
Planar Phosphorus
Ar = 2,4,6-(t-Bu)-Ph
Mikolajczyk, M. et al. Phosphorus and Sulfur 1988, 36, 267—270.
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Outline
1. Historical Background and Chemistry of Phosphorus
2. Chiral Auxiliaries
3. Facial Differentiation
4. Topos Differentiation
5. Enantiomer Differentiation
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Enantioselective Deprotonation
N N
BuLi
PhPMe
Me
S
s-BuLi (1.1 equiv)(—)-Sparteine (1.1 equiv)
Et2O, —78 ºC
Cu(OPiv)2
PhPMe
Ph PMe
P MePh
PhPMe
Me
BH3
or
O
PhPhOH
PhPh
(—)-Sparteine/BuLi Complex
Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995, 117, 9075—9076. Gammon, J. J.; Canipa, S. J.; O’Brien, P.; Kelly, B.; Taylor, S. Chem. Comm. 2008, 3750—3752.
BH3
BH3 BH3
88% yield, 79% ee
72% yield, 98% ee79:21 (S,S):Meso
t-BuPMe
Me
i) n-BuLi (1.1 equiv)(—)-Sparteine (5 mol%)
PhMe, —78 ºC
ii) PhMe2SiCl
S
t-BuPMe
SSiMe2Ph
88% yield, 85:15 e.r.
• Ligated base more reactive than BuLi w/o ligand (54%. w/o Sparteine)
t-BuPMe
Me
S
t-BuPMe
SLi
BuLi•(—)-sp
BuLi
t-BuPMe
SLi
•(—)-sp
Catalytic Sparteine
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RPX
RPX
RPX
• CuAAC • [2+2+2] • • Hydroetherification •
• Arylation • Annulation • • Borylation • Amidation •
HO
HO
• Acylation • Allylic Alkylation • • Hydroetherification •
• Metathesis •
RPX
OH
OH
• Acylation •
Catalytic Desymmetrization
Harvey, J. S.; Gouverneur, V. Chem Comm. 2010, 46, 7477—7485. Chrzanowski, J.; Krasowska, D.; Drabowicz, J. Heteroatom Chem. 2018, 29, e21476.
Diesel, J.; Cramer, N. ACS Catal. 2019, 9, 9164—9177.
Alkyne
RPX
H
H
Arene Phenol
Alcohol Alkene
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Outline
1. Historical Background and Chemistry of Phosphorus
2. Chiral Auxiliaries
3. Facial Differentiation
4. Topos Differentiation
5. Enantiomer Differentiation
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Kinetic Resolution
Beaud, R.; Phipps, R. J.; Gaunt, M. J. J. Am. Chem. Soc. 2016, 138, 13183—13186.Dai, Q.; Li, W.; Li, Z.; Zhang, J. J. Am. Chem. Soc. 2019, 141, 20556—20564.
Liu, X.-T.; Zhang, Y.-Q.; Han, X.-Y.; Sun, S.-P.; Zhang, Q.-W. J. Am. Chem. Soc. 2019, 138, 16584—16589.
SubS
CatR
kS (fast)ProdS
SubR
CatR
kR (slow)ProdR
ΔG‡S
ΔG‡R
ΔΔG‡
SubS SubR
ProdS ProdR
PhPR
H
O
PhPR
OPh
PhPR
O
Br
racemic(2 equiv)
ArI
Ar
BF4
Ph
OAc
R
PhPR
O
R
Cu(OTf)2/PhPyBox
Pd2(dba)3/Xiaophos
Ni(COD)2/BDPP
KR of Secondary Phosphine Oxides
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Dynamic Kinetic Resolution
SubS
Cat*
kS (fast)ProdS
SubR
Cat*
kR (slow)ProdR
ΔΔG‡
krac
ProdS ProdR
SubSCat*
SubRCat*
ΔG‡S
ΔG‡R
SubS
Cat*
kS (fast)ProdS
SubR
Cat*
kR (slow)ProdR
Int
kSI
kRI
ProdS ProdR
SubSCat*
SubRCat*
Int
ΔΔG‡
ΔG‡S
ΔG‡R
Achiral Transition State
Achiral Intermediate
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Catalyzing Pyraidal Inversion
E = 41.2 kcal/molE =16.9 kcal/mol
Po-TolPh
MePo-Tol Ph
Me Po-TolPh
MePo-Tol Ph
Me
PhP
Me
94% ee to 0% ee88% recovery
PhP
Me
88% ee to 12% ee86% recovery
PMe
95% ee to 36% ee73% recovery
Me
PhP
MeAr
25 mol%
MeCN, rt, 30 minPh
PMe
Ar
N
Me
Me
Me
PF6
Me
Me Me
OMe
Reichl, K. D.; Ess, D. H.; Radosevich, A. T. J. Am. Chem. Soc. 2013, 135, 9354—9357.
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Configurational Stability of Chlorophosphines
Hubel, S.; Bertrand, C.; Darcel, C.; Bauduin, C.; Jugé, S. Inorg. Chem. 2003, 42, 420—427.
PhPEt
ClPhP
EtNEt2
HClPh
PEt
Cl
EtP
PhCl
EtP
PhCl
racemic
MeP
MeCl 58.3 kcal/mol
PMeMe
PMeMeCl
Cl58.3 kcal/mol
P PMeMe
Cl
Cl MeMe
29.4 kcal/mol
P HMeMe
Cl
Cl10.4 kcal/mol
Transition State Energies*:
Calculated Intermediates:
*B3LYP/6-311++G(2d,p)//B3LYP/6-31+G(2d)
+10.4
—2.7
0.0
P HMeMe
Cl
Cl
—1.2
Me PMe Cl
ClHMe P
Me Cl
ClH
Me PMe Cl
Cl
HMe PMe Cl
Cl
H
Me PMe Cl
ClHMe P
Me Cl
ClH
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Dynamic Kinetic Resolution of Chlorophosphonium Salts
Rajendran, K. V.; Nikitin, K. V.; Gilheany, D. G. J. Am. Chem. Soc. 2015, 137, 9375—9381.Jennnings, E. V.; Nikitin, K. V.; Ortin, Y.; Gilheany, D. G. J. Am. Chem. Soc. 2014, 136, 16217—16226.
Rajendran, K. V.; Gilheany, D. G. Chem. Comm. 2012, 48, 10040—10042.
OP
AlkAr
Ph
racemic
PAlk
ArPh
ClCl
PAlk
ArPh
Cl Cl
(COCl)2
fast
slow
PAlk
ArPh
OR*Cl
PAlk
ArPh
OR*Cl
OHi-PrMe
OHi-PrMe
PAlk
ArPh
PAlk
ArPh
O
PAlk
ArPh
O
PAlk
ArPh
BH3
Arbusov
—R*Cl (slow)
—OH
LAH
NaBH4
retention
inversion
inversion
inversion
major
minor
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Allylic Alkylation of Phosphinic Acids
Rajendran, K. V.; Nikitin, K. V.; Gilheany, D. G. J. Am. Chem. Soc. 2015, 137, 9375—9381.
PROH
OBr
2.5 mol% Pd2(dba)3•CH3Cl6 mol% ligand
1 equiv Cs2CO3
THF, rt, 30—95 minPRO
O
+
racemicracemic
NH
HN
O O
PPh2 Ph2P
ligand
PROH
O
racemic
Br
racemic
PRO
O
PdL*
Base
PdL*
PRO
O
PRO
O
PRO
O
PRO
O
fastest
fast
slow
slowest
PMe
O
O
96% yield, 7:1 d.r.97% ee
Pt-Bu
O
O
82% yield, 1.5:1d.r.91% ee
Pt-Bu
O
O
83% yield, 26:1 d.r.98% ee
Pt-Bu
O
O
73% yield20% ee
Ph
Me
Me
Substrate Scope Kinetic Selectivity
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DKR vs DyKAT
SubSkS (fast)
ProdS
SubRkR (slow)
ProdR
Int
kSI
kRI
Dynamic Kinetic ResolutionSubS
kS (fast)ProdS
SubRkR (slow)
ProdR
krac
SubS
kSCat* (fast)
ProdS
SubR
kRCat* (slow)
ProdR
kSCat*
kRCat*
Cat*Sub
Cat*SubSkS’’Cat* (fast)
ProdS
Cat*SubR
Cat*
kR’’Cat* (slow)ProdR
Cat*
Cat*
SubS
SubR
kSCat*
kRCat*
Cat*
• Racemization of substrate occurs via an achiral intermediate or transition state
• Resolving agent can be a chiral catalyst or reagent
Dynamic Asymmetric Transformation (#1)
• Single catalyst-substrate is formed from both enantiomers, followed by diastereomeric reaction pathways
• Selectivity determined by relative rates of product formation
• Selectivity determined by relative reaction rates of product forming steps
Dynamic Asymmetric Transformation (#2)
• Catalyst binds substrate to form two diastereomeric pairs
• Selectivity is determined by relative concentrations of Cat*Sub adducts & rates of product formation (kR’’Cat*/kS’’Cat*)
• Epimerization of substrate occurs on the chiral catalyst
krac
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kS
M(L*)
kR
base
base
M(L*)
kRS
Metal-Catalyzed Phosphination via DyKAT
Glueck, D. S. Synlett 2007, 17, 2627—2634.
HPR1R2
HPR1
R2
(*L)MPR1R2
M(L*)PR1
R2
EPR1R2
EPR1
R2
kSR
Electrophile
Electrophile
Curtin-Hammmett Kinetics
If P-inversion is much faster than P—C bond formation (kRS/kSR >> kR/kS)
then product ratio:
SS
R R
[S][R]
= KeqkSkR
HPR1
R2
EWG
X
Ar X
PR1
R2
PR1
R2
PR1
R2
EWG
Ar
racemic
Hydrophosphination
Phosphine Arylation
Phosphine Alkylation
M(L*)
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MR
P RR
MR
RP M R
R
Phosphine Phosphido Phosphenium
• Lone pair coordinated to metal• Psuedotetrahedral
• Lone pair localized on P• Pyramidal about P
• Long M—P bond length
• Multiple M—P bond (dπ—pπ)• Planar about P
• Short M—P bond length
Metal-Assisted Pyramidal Inversion
Glueck, D. S. Synlett 2007, 17, 2627—2634.Rogers, J. R.; Wagner, T. P. S.; Marynick, D. S. Inorg. Chem. 1994, 33, 3104—3110.
TiClPMe2
Calculated Inversion Barrier: 2.6 kcal/mol
Early Transition Metalsstabilize planar form through
metal—ligand π bonding
FeCPMe2C
O
O
Middle/Late Transition Metalsinductively destabilize pyramidal
ground state
Calculated Inversion Barrier: 20.5 kcal/mol
P
PPt
Me Me
Me MeX
PMe(TRIP)
Inversion Barrier: 10—13 kcal/mol
Platinum(DuPhos)Phosphido
P
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Asymmmetric Hydrophosphination of Alkenes
Glueck, D. S. Synlett 2007, 17, 2627—2634.Kovacik, I.; Wicht, D.; Grewal, N. S.; Glueck, D. S. Organometallics 2000, 19, 950—953.
Huang, Y.; Pullarkat, S. A.; Li, Y.; Leung, P.-H. Inorg. Chem. 2012, 51, 2533—2540.
HPPh CO2t-Bu
PPh
t-BuO2C5 mol% Pt[(R,R)-MeDuPhos](trans-stilbene)
THF, rt+
17% ee
i-Pr
i-Pr i-Pr
i-Pr
i-Pri-Pr
HPPh
Me
10 mol% catalyst1 equiv Et3N
THF, —80 ºC+
O
Ar
Ar Ar
O
Ar
PPh
Me PdP
Me PhPh
NCMe
NCMe
ClO4
1.2 equivcatalyst
O
Ph
PPh
Me
MeO
99% yield, 91:9 d.r.82% ee
O
Ph
PPh
Me
Cl
98% yield, 87:13d.r.62% ee
O
Ph
PPh
Me
O2N
95% yield, 82:18 d.r.42% ee
Ph
OPPh
Me
97% yield, 78:22 d.r.61% ee
Br
Ph
OPPh
Me
96% yield, 87:13d.r.72% ee
F
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Asymmmetric Arylation & Alkylation of Phosphines
Glueck, D. S. Synlett 2007, 17, 2627—2634.Moncarz, J. R.; Laritcheva, N. F.; Glueck, D. S. J. Am. Chem. Soc. 2002, 124, 13356—13357.
Scriban, C.; Glueck, D. S. J. Am. Chem. Soc. 2006, 128, 2788—2789.
PH
Me
i-Pr
i-Pri-Pr
5 mol% Pd[(R,R)-MeDuPhos](Ph)(I)1 equiv PhI
NaOSiMe3PhMe, 4 ºC
PPh
Me
i-Pr
i-Pri-Pr
84% yield, 78% ee
kS1.4 x 10—4 s—1
kR4.7 x 10—4 s—1
kSR
*LPdPArMe
PdL*P
ArMe
PhPArMe
PhP
ArMe
kRS
Red. Elim.
Red. Elim.
Sprod (major)
RprodSint
Rint (major)
≈ 102 s—1
PH
Me
Ph
PhPh
5 mol% Pd[(R,R)-MeDuPhos](Ph)(Cl)1 equiv BnBr
NaOSiMe3PhMe, 4 ºC
PBn
Me
Ph
PhPh
86% yield, 81% ee
Pd-Catalyzed Arylation
Pt-Catalyzed Alkylation
• Major intermediate gave major product
• Minor intermediate undergoes reductive elimination three times faster
• Key challenge: finding a catalyst where the major intermediate undergoes faster
reductive elimination
Basis for Selectivity
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Asymmmetric Arylation & Alkylation of Phosphines (cont)
Chan, V. S.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 15122—15123.Chan, V. S.; Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 2786—2787.
Huang, Y.; Li, Y.; Leung, P.-H.; Hayashi, T. J. Am. Chem. Soc. 2014, 136, 4865—4868.
PhPMe
Si(i-Pr)3
I
N(i-Pr)2
O
PhPMe
O N(i-Pr)2
5 mol% ((R,R)-Et-FerroTANE)PdCl2
DMPU, 60 ºCthen BH3•THF
BH3
+
53% yield, 98% ee
Pd-Catalyzed Arylation
PhPMe
HPh
PMe
10 mol% [(R)-i-Pr-PHOX)Ru(H)]BPh4
NaOt-amyl, THF, —30 ºCthen BH3•THF
BH3+
85% yield, 85% ee
Ru-Catalyzed Arylation
ClOMe
MeO
PhPMes
HPh
PMes
O
5 mol% catalyst
Et3N, CHCl3, —45 ºCthen S8
+
96% yield, 98% ee
Pd-Catalyzed Oxidation
OHS
O
OPh
Ph
Ph
Ph
PdP
Me PhPh
NCMe
NCMe
ClO4
catalyst
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Assembly of ProTide via DyKAT
DiRocco, D. A. et al. Science 2017, 356, 426—430.
O
HO Cl
N
Uprifosbivir
Me
HNO
O
kS
cat*
kR
cat*
kRS kSR
O
O
HO Cl
N
Me
HNO
OHO
PO
OPhNH
Mei-PrO
O
O
HO Cl
N
Me
HNO
OOPO
OPhNH
Mei-PrO
O
epi-Uprifosbivir
cat*PO
OPhNH
Mei-PrO
O
cat*PO
OPhNH
Mei-PrO
O
pro-R
pro-S
ClPO
OPhNH
Mei-PrO
O
ClPO
OPhNH
Mei-PrO
O
O
HO Cl
N
Me
HNO
OHO
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Catalyst Development for ProTide DyKAT
DiRocco, D. A. et al. Science 2017, 356, 426—430.
O
HO Cl
N
Me
HNO
OOO
HO Cl
N
Me
HNO
OHO PO
OPhNH
Mei-PrO
OClP
O
OPhNH
Mei-PrO
O
catalyst
1.2–1.5 equiv 2,6-lutidinesolvent, —10 ºC
+
entry mol% cat 5’:3’ % yield P(R):P(S)
none
solvent
1 CH2Cl2 ND 3 55:4520 mol% NMI2 CH2Cl2 96:4 49 52:4820 mol% cat A3 CH2Cl2 94:6 60 79:2120 mol% cat B4 CH2Cl2 98:2 62 89:11
20 mol% cat B5 1,3-dioxalane 98.3:1.7 81.6 92:8
2 mol% cat C6 1,3-dioxalane 99.1:0.9 86.0 98:2
2 mol% cat D7 1,3-dioxalane 98.8:1.2 92.1 99:1
NN
O
O
NH
t-Bu
NMI
cat A(1st order)
cat B(2nd order)
NN
OTBS
NN Me
NN
O
O
NH N
HO
O
NN N
N
O
O
NH N
HO
O
NNcat C
(1st order)catD
(1st order)
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Conclusions & Future Outlook
Synthesis Structure Functionality
Asymmetric Catalysis
COVID-19 Treatment?Organocatalytic DyKAT
NH
O
O
NN
O
O
NN
NH X
Me
SP
O
Me
HS
SC6F5
Phosphorus-Sulfur Incorporation (PSI Reagent, ψ)
PhP
Me
O
Oi-Pr
Me
(—)-Menthol Chiral Pool
NucleosidePO
ONH
Mei-PrO
O Ph
O Base
RO
OPO
OHS
O
Base
RO
Phosphoramidate
Phosphorothioate
PMeOMe
Phosphine
(R)3*P Rh P*(R)3Cl
P*(R)3
Spinal Muscular Atrophy Treatment
T
G
T
C
AC
T
T
T C
AT
AA
C
TGG
5’
3’
OPO
ONH
Mei-PrO
O Ph
O
HO OH
CN
NN
N
NH2