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)...
Jake GanleyDepartment of Chemistry
Princeton University
Asymmetric Synthesis of Phosphorous Stereocenters Fundamentals and Applications
Group MeetingMay 20, 2020
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.
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
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.
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.
Outline
1. Historical Background and Chemistry of Phosphorus
2. Chiral Auxiliaries
3. Facial Differentiation
4. Topos Differentiation
5. Enantiomer Differentiation
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
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
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
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?
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
Outline
1. Historical Background and Chemistry of Phosphorus
2. Chiral Auxiliaries
3. Facial Differentiation
4. Topos Differentiation
5. Enantiomer Differentiation
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
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.
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.
Outline
1. Historical Background and Chemistry of Phosphorus
2. Chiral Auxiliaries
3. Facial Differentiation
4. Topos Differentiation
5. Enantiomer Differentiation
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.
Outline
1. Historical Background and Chemistry of Phosphorus
2. Chiral Auxiliaries
3. Facial Differentiation
4. Topos Differentiation
5. Enantiomer Differentiation
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
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
Outline
1. Historical Background and Chemistry of Phosphorus
2. Chiral Auxiliaries
3. Facial Differentiation
4. Topos Differentiation
5. Enantiomer Differentiation
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
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
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.
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
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
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
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
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*)
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
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
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
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
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
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)
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