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