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

DIPAMP

MeO CO2H

NHAcAcO

MeO CO2H

[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

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

Knowles, W. S. Acc. Chem. Res. 1983, 16, 106—112.

Ligands in Asymmetric Catalysis

TangPhos

tBu Me

QuinoxP

P PRMe

MeO-BIBOP

MeO-BOPMiniphos

MeMeMe

TrichickenfootPhos

MeMeMe

DuPhos

DuanPhos

DIPAMP

Tenofovir Alafenamide

MeHO F

Sofosbuvir

EtHO OH

Remdesivir

Anti-Virals with Chiral Phosphorus

Nucleotide Triphosphate

Nucleobase

Nucleoside Nucleotide

Kinase

Pradere, U.; Garnier-Amblard, E. C.; Coats, S. J.; Amblard, F.; Schinazi, R. F. Chem Rev. 2014, 114, 9154—9218.

Nucleotide Prodrugs

Free Nucleotide

no or low cell penetration

EtHO OH

ProTide efficient cell penetration

ORHNOR

in vivo deprotection Kinase

EtHO OH

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

PP P P

λ5-σ5 λ5-σ4 λ3-σ3 λ3-σ2 λ5-σ3

Rphosphine

Rphosphinite

ORphosphonite

ORphosphite

Rphosphine(amin)

ORphosphon-amidite

PNR2RO

ORphosphor-amidite

NR2phosphine(diamin)

PNR2RO

NR2phosphoro-diamidite

PNR2R2N NR2

phosphine(triamin)

PNR2R2N NR2

phosphoramide

NR2phosphonamide

PNR2RO

NR2phosphoro-diamidate

Rphosphinamide

NR2phosphon-amidate

PNR2RO

ORphosphor-amidate

Rphosphine

Rphosphinate

ORphosphonate

ORphosphate

Coordination Chemistry

Nomeclature

Discovery of Chiral Phosphorus

PhPCl2

i) MeOH, Pyridineii) MeI

iii) PCl5iv) (—)-menthol Ph

mixture of diastereomers

crystallization

BrMgMe

inversion of configuration Me

(S)P (R)P

(S)P (R)

inversion of configuration

PMe Me

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.

R N RR

Inversion barrier ~ 5 kcal/mol

R P RR

Inversion barrier not known

HSiCl3

Walsh Correlation Diagram for Planar vs Pyramidal XH3

Gilheany, D. G. Chem Rev. 1994, 94, 1339—1374.

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.

δE E ∝ 1/δE

Amine vs Phosphine Inversion

~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

ΔG‡130= 32.1 kcal/molΔG‡

130= 35.6 kcal/mol

R P RR

ΔG‡25= 16 kcal/mol

P MePh

ΔG‡110= 19.4 kcal/mol

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

The Jugé-Stephan Method: Ephedrine-Borane Complexes

Jugé, S. Phosphorus, Sulfur, and Silicon 2008, 183, 233—248.

R1PNMe2

NMe2 MePh

R1P ON

+Δ, PhMe

then BH3•THF

95:5 d.r.

R1P ON

BH3Li R2 NHO

Ph NHMe

H3B R1

BH3H2O

—LiOH

BH3MeOH/H+

inversionP R2R1

BH3 Li R3

inversionP

R2 R1R3

R2 R1R3retention

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.

t-Bu OMe

MeO OMe

OMeMeOMe

Not accessible via the Jugé-Stephan method

• Cu-catalyzed propargylation • Rh-catalyzed hydrogenation •• Pd-catalyzed Suzuki coupling & Miyaura borylation •

PhN-Me-imidazole

CH2Cl285% yield, >99:1 d.r.BI Auxiliary

NHMeTs

PhR1 R2

58 — 91% yield62 — 91% yield

90 — 99% ee

PCl2OMeMeO

i) BI Auxiliary, CH2Cl2/Pyridine

ii) H2O2

85% yield>99.5:0.5 d.r.

NHTsMe

t-BuOMe

t-BuLi

THF—40 ºC

THF, rt

OMeMeOMe

96% yield 63% yield98.3:1.7 e.r.

The PSI Reagent: Chiral Phosphorothioate Synthesis

O Base

Phosphorothioate• Improved cellular uptake

• Increased stability to nucleases

SPHSSC6F5

Et3N •

(—)-limonene oxide

Phosphorus-Sulfur Incorporation (PSI Reagent, ψ)

O Base

DBU, MeCN

OHS OP

Knouse, K. W.; deGruyter, J. N. et al. Science 2018, 361, 1234—1238.

Outline

Reactions of Planar, Prochiral Phosphorus

Möller, T.; Sárosi, M. B.; Hey-Hawkins, E. Chem. Eur. J. 2012, 18, 16604—166607.

Planar Carbon• Nu—/E+ addition• Hydrogenation• Group transfer• Cycloaddition• More…

X = CR2, O, NR

• Nu—/E+ addition• Hydrogenation• Group transfer• Cycloaddition• Less…

i-Pr(OC)5W

W(CO)5

H2, [RhL2*]PF6

L = chiraphos, DIPAMP, DIOPracemic

i-Pr(OC)5W

W(CO)5

i-PrH2, [RhL2]PF6

L = diphos

i-PrMei-Pr

Me 95:5 d.r.

MeMe O

Δ, [1,5]

OO OR*

then S8P

Endo Exo

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

MeOH, —5 ºC

Me PArHNt-Bu

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

Enantioselective Deprotonation

s-BuLi (1.1 equiv)(—)-Sparteine (1.1 equiv)

Et2O, —78 ºC

Cu(OPiv)2

Ph PMe

P MePh

PhPhOH

(—)-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

88% yield, 79% ee

72% yield, 98% ee79:21 (S,S):Meso

t-BuPMe

i) n-BuLi (1.1 equiv)(—)-Sparteine (5 mol%)

PhMe, —78 ºC

ii) PhMe2SiCl

t-BuPMe

SSiMe2Ph

88% yield, 85:15 e.r.

• Ligated base more reactive than BuLi w/o ligand (54%. w/o Sparteine)

t-BuPMe

BuLi•(—)-sp

t-BuPMe

•(—)-sp

Catalytic Sparteine

• CuAAC • [2+2+2] • • Hydroetherification •

• Arylation • Annulation • • Borylation • Amidation •

• Acylation • Allylic Alkylation • • Hydroetherification •

• Metathesis •

• 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

Arene Phenol

Alcohol Alkene

Outline

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.

kS (fast)ProdS

kR (slow)ProdR

ΔG‡S

ΔG‡R

ΔΔG‡

SubS SubR

ProdS ProdR

racemic(2 equiv)

Cu(OTf)2/PhPyBox

Pd2(dba)3/Xiaophos

Ni(COD)2/BDPP

KR of Secondary Phosphine Oxides

Dynamic Kinetic Resolution

kS (fast)ProdS

kR (slow)ProdR

ΔΔG‡

ProdS ProdR

SubSCat*

SubRCat*

ΔG‡S

ΔG‡R

kS (fast)ProdS

kR (slow)ProdR

ProdS ProdR

SubSCat*

SubRCat*

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

94% ee to 0% ee88% recovery

25 mol%

MeCN, rt, 30 minPh

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.

EtNEt2

racemic

MeCl 58.3 kcal/mol

PMeMeCl

Cl58.3 kcal/mol

P PMeMe

Cl MeMe

29.4 kcal/mol

P HMeMe

Cl10.4 kcal/mol

Transition State Energies*:

Calculated Intermediates:

*B3LYP/6-311++G(2d,p)//B3LYP/6-31+G(2d)

—2.7

P HMeMe

—1.2

Me PMe Cl

ClHMe P

Me PMe Cl

HMe PMe Cl

Me PMe Cl

ClHMe P

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.

racemic

(COCl)2

OHi-PrMe

Arbusov

—R*Cl (slow)

retention

inversion

Allylic Alkylation of Phosphinic Acids

Rajendran, K. V.; Nikitin, K. V.; Gilheany, D. G. J. Am. Chem. Soc. 2015, 137, 9375—9381.

2.5 mol% Pd2(dba)3•CH3Cl6 mol% ligand

1 equiv Cs2CO3

THF, rt, 30—95 minPRO

racemicracemic

PPh2 Ph2P

ligand

racemic

fastest

slowest

96% yield, 7:1 d.r.97% ee

82% yield, 1.5:1d.r.91% ee

83% yield, 26:1 d.r.98% ee

73% yield20% ee

Substrate Scope Kinetic Selectivity

DKR vs DyKAT

SubSkS (fast)

SubRkR (slow)

Dynamic Kinetic ResolutionSubS

kS (fast)ProdS

SubRkR (slow)

kSCat* (fast)

kRCat* (slow)

kSCat*

kRCat*

Cat*Sub

Cat*SubSkS’’Cat* (fast)

Cat*SubR

kR’’Cat* (slow)ProdR

kSCat*

kRCat*

• 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

Metal-Catalyzed Phosphination via DyKAT

Glueck, D. S. Synlett 2007, 17, 2627—2634.

HPR1R2

(*L)MPR1R2

M(L*)PR1

EPR1R2

Electrophile

Curtin-Hammmett Kinetics

If P-inversion is much faster than P—C bond formation (kRS/kSR >> kR/kS)

then product ratio:

[S][R]

= KeqkSkR

racemic

Hydrophosphination

Phosphine Arylation

Phosphine Alkylation

RP M 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

Middle/Late Transition Metalsinductively destabilize pyramidal

ground state

Calculated Inversion Barrier: 20.5 kcal/mol

Me MeX

PMe(TRIP)

Inversion Barrier: 10—13 kcal/mol

Platinum(DuPhos)Phosphido

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

t-BuO2C5 mol% Pt[(R,R)-MeDuPhos](trans-stilbene)

THF, rt+

17% ee

i-Pr i-Pr

i-Pri-Pr

10 mol% catalyst1 equiv Et3N

THF, —80 ºC+

Me PdP

Me PhPh

1.2 equivcatalyst

99% yield, 91:9 d.r.82% ee

98% yield, 87:13d.r.62% ee

95% yield, 82:18 d.r.42% ee

97% yield, 78:22 d.r.61% ee

96% yield, 87:13d.r.72% ee

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.

i-Pri-Pr

5 mol% Pd[(R,R)-MeDuPhos](Ph)(I)1 equiv PhI

NaOSiMe3PhMe, 4 ºC

i-Pri-Pr

84% yield, 78% ee

kS1.4 x 10—4 s—1

kR4.7 x 10—4 s—1

*LPdPArMe

PhPArMe

Red. Elim.

Sprod (major)

RprodSint

Rint (major)

≈ 102 s—1

5 mol% Pd[(R,R)-MeDuPhos](Ph)(Cl)1 equiv BnBr

NaOSiMe3PhMe, 4 ºC

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.

Si(i-Pr)3

N(i-Pr)2

O N(i-Pr)2

5 mol% ((R,R)-Et-FerroTANE)PdCl2

DMPU, 60 ºCthen BH3•THF

53% yield, 98% ee

Pd-Catalyzed Arylation

10 mol% [(R)-i-Pr-PHOX)Ru(H)]BPh4

NaOt-amyl, THF, —30 ºCthen BH3•THF

85% yield, 85% ee

Ru-Catalyzed Arylation

PhPMes

5 mol% catalyst

Et3N, CHCl3, —45 ºCthen S8

96% yield, 98% ee

Pd-Catalyzed Oxidation

Me PhPh

catalyst

Assembly of ProTide via DyKAT

DiRocco, D. A. et al. Science 2017, 356, 426—430.

Uprifosbivir

kRS kSR

Mei-PrO

epi-Uprifosbivir

cat*PO

Mei-PrO

cat*PO

Mei-PrO

Catalyst Development for ProTide DyKAT

DiRocco, D. A. et al. Science 2017, 356, 426—430.

OHO PO

Mei-PrO

catalyst

1.2–1.5 equiv 2,6-lutidinesolvent, —10 ºC

entry mol% cat 5’:3’ % yield P(R):P(S)

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

cat A(1st order)

cat B(2nd order)

NNcat C

(1st order)catD

(1st order)

Conclusions & Future Outlook

Synthesis Structure Functionality

Asymmetric Catalysis

COVID-19 Treatment?Organocatalytic DyKAT

Phosphorus-Sulfur Incorporation (PSI Reagent, ψ)

(—)-Menthol Chiral Pool

NucleosidePO

Mei-PrO

O Base

Phosphoramidate

Phosphorothioate

PMeOMe

Phosphine

(R)3*P Rh P*(R)3Cl

P*(R)3

Spinal Muscular Atrophy Treatment

Mei-PrO

Asymmetric Synthesis of Phosphorous Stereocenters · 2020. 10. 8. · i-Pr Me iii) PCl 5 iv)...

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