Vanadium-Catalyzed Selenide Oxidationwith in situ [2,3] Sigmatropic Rearrangement: Scope and

Asymmetric Applications

Campbell Bourland

February 6, 2002

R' SeR

R'

SeRO

R'

OH

R"

R"R" VO(acac)2,TBHP

CH2Cl2, mol. sieves

-50°C; PBu3

1

List of Abbreviations

e.e.

d.e.

TBHP

CHP

m-CPBA

acac

TBAF

SOS

ASOS

enantiomeric excess (% major enantiomer - % minor enantiomer)

diastereomeric excess (% major diastereomer - % minor diastereomer)

tert-butyl hydroperoxide

cumene hydroperoxide

meta-chloroperbenzoic acid

acetyl acetonate

tetrabutyl ammoniumfluoride

selenide oxidation with in situ [2,3] sigmatropic rearrangement

asymmetric selenide oxidation in situ [2,3] sigmatropic rearrangement2

Importance of Allylic Alcohols

Rapamycinprostaglandins

H

H

HO

HO HO H

OH

O

O

O

Me

Me

Me

O

OH

OMe Me Me

OMeHOH

Me

O

N

O

O

OH

OMe

OH

H

Me

3

Allylic Alcohols Useful as Precursors in Synthesis

Henbest and Wilson’s Asymmetric Epoxdiation:

Corey’s Asymmetric Epoxidation:

OHO

H

OCH3

Me

MeMe

OVO(acac)2

TBHP

OHO

H

OCH3

Me

MeMe

O

O

>20:1

Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1959, 1958.Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107, 256.

OH

m-CPBA

OH

O

10:1

4

Application of Selenides to Synthesis

Selenoxide Syn-Elmination to form alkene:

The SOS reaction:

RSe [O]

R'

H

RSe

R'

HOR'

RSe

[O]R"

RSe

R"O OH

R"

SeO

R"

R

Se-O

cleavage

5

Traditional Methods for Selenide Oxidation

Wirth, T. Tetrahedron 1999, 55, 1.

SePh

H2O2, 0-25°C

THF-MeOH, 71%

OH

Ph SePhm-CPBA, 25°C

MeOH, 90%

Ph

OH

6

Selenoxide vs. Sulfoxide

Se

R

S

RO

R OS

R OSe

O

7Reich, H. J. et. al. J. Am. Chem. Soc. 1983, 105, 2503.

Standard Protocol for Synthesis of the Allylic Selenides

R H

O

R OMe

OR'

R"R

R'

R"

DIBAL-H

o-nitrophenyl selenocyanatePBu3, THF

OH

R

R'

R"Se

NO2

Ph3P=CHCO2Me, CH2Cl2or

KHMDS, 18-crown-6, (CF3CH2O)2POCH2CO2Me

CH2Cl2

70-90%

90-99%

< 95%

8

Development of Vanadium-Catalyzed SOS Reaction

R SeNO2R'

RR'

SeO

NO2

RR'

OSe

NO2

RR'

OH PBu3

VO(acac)2, CHP, CH2Cl2

4 Å mol. sieves-10°C, 30 min

9

Utility of the Vanadium-Catazlyed SOS Reaction on (E)-Substrates

Carter, R. G.; Bourland, T. C. J. Chem. Soc. Chemm. Commun. 2000, 2031.

( )4 H

H

H

H

MeO

YieldR R''Entry

a

b

c

d

85%

75%

84%

80%

R'

H

H

H

H

R SeR''

R'

NO2

RR''

R' OHVO(acac)2, CHP

CH2Cl2, mol sieves,-10°C

10

Utility of the Vanadium-Catazlyed SOS Reaction on Tri-Substituted and (Z) Substrates

CH3

YieldR R''Entry

a 70%

b

R'

H

( )4

c H

H

H

H 63%

86%

R SeR''

R'

NO2

RR''

R' OHVO(acac)2, CHP

CH2Cl2, mol sieves,-10°C

11

Effects of a Stereocenter on SOS Reaction

SePh

VO(acac)2, CHP, CH 2Cl2

4 Å mol. sieves -10 °C, 60%

PhOH

1.1:1 d.r.

Ph PhOH

1.2:1 d.r.Se

O2N

O2N

VO(acac)2, CHP, CH 2Cl2

4 Å mol. sieves -10 °C, 71%

12

Conclusion from Racemic SOS Reaction

• Conditions optimized for racemic series of Vanadium-catalyzed SOS reaction.

• System works on a wide variety of substrates.

• Good yields, short reaction times.

• Stereocenter does not effect SOS reaction.

13

Fujita’s Asymmetric Oxidation of Sulfides with Salen-VO(acac)2

Nokijima, K.; Kojima, M.; Fujita, J. Chem. Lett. 1986, 1433.

N N

OH HO

X X

1 X = OMe2 X = OEt3 X = t-Bu

SCH3

VO(acac)2, 1 - 3

CHP, -20°C, CH2Cl2, 2h SCH3

O

up to 41% e.e.

96%

14

Bolm’s Ligand-Based for Asymmetric Oxidation of Sulfides

Bolm, C.; Bienwald, F. Angew. Chem. Int. Ed. Engl. 1995, 34, 2640.

S

SPh

VO(acac)2 (1 mol %), ligand

H2O2, CH2Cl2, r.t. 16h, 84%

S

SPh

O

t-Bu

OHt-Bu

N

HO

85% e.e.

ligand

15

Two Chiral Events Occurring in SOS Reaction

RSe

[O]R"

RSe

R"O

OH

R"

SeO

R"

RSe-O

cleavageRSe

R"O

Oxidation of selenide to chiral selenoxide:

Rearrangement of chiral selenoxide to alcohol:

16

Endo vs. Exo Pathways

• Endo pathway appears to be favored by calculations and experimental results

Reich, H. J. et. al. J. Am. Chem. Soc. 1983, 105, 2503.

SeR

R'Ar

O

H

H

exoHO

R

R'

H

H

SeR'

R

H

HO

Ar

endo

R

R'H

HOH

17

Davis’ Oxidation of Selenides

oxaziridine

Davis, F. A.; Reddy, T. R. J. Org. Chem. 1992, 57, 2599.

ClCl

O

N SO2Ph

0°C

oxaziridine

90-95% e.e.

Se SeO

(S)

18

Davis’ Work in SOS Reaction

• Chiral induction from selenoxide to selenenate only 70-80% efficient.

• (Z)-Olefin geometry gives higher selectivity.

• Stereochemical outcome consistent with an endo transition state.

Davis, F. A.; Reddy, T. R. J. Org. Chem. 1992, 57, 2599.

Cl

ClN

OSO2

oxaziridine

Se

R1

Oxaziridine, CDCl3, -60°C, Ph

OHR2

R1 = H, R2 = Ph 54% (40% e.e.) R

R1 = Ph, R2 = H 46% (60% e.e.) S

19

Vanadium-Catalyzed ASOS Reaction: Ligand-BasedApproach

20

SeNO2

VO(acac)2, CHPligand

CH2Cl2, 4 Å mol. sieves-30°C

ArN OH

t-Bu PhPh

N NAr Ar

t-Bu

t-Bu

OHAr =

OH

< 2% e.e.< 2% e.e.

Selected Examples of Ligand-Based ASOS Reaction

21

SeNO2

VO(acac)2, CHPligand

CH2Cl2, 4 Å mol. sieves-30°C

ArN OH

RR'R

N NAr Ar

t-Bu

t-Bu

OHAr =

OH

10% e.e.< 2% e.e.

R = t-Bu, R' = HR = Ph, R' = HR = i-Pr, R' = HR = CH3, R' = PhR = Ph, R' = H

R'

R = R' = PhR = R' = -(CH2)4

N OHAr

Problems with Ligand-Based System

L* = Chiral Schiff base ligandLB* = Chiral Auxiliary containing a Lewis Base

Se

R

VO(acac)2, CHP Chiral ligand

CH2Cl2, 4 Å mol. sieves

NO2R

OHR

VO

O

t-Bu

O

L*n

H

SeAr

R'

R'

R'

Se

R

VO(acac)2, CHP

CH2Cl2, 4 Å mol. sieves

LB*R

OH

Se

LB*

R

VO O

O

t-Bu

R' R'

R'

Ln

22

Auxiliary-Based System Used to Understand Ligand-Based Systems

Auxiliary Approach:

Ligand Approach:

N O

Bn

O

R

OR''

R'

R'

R''

O

N O

O

RBn

EtAlCl2

98 % d.e.

N O

O

R

O

Cu(OTf)2, (2-10 mol %),

O N O

OH

RH

94 % e.e.O

N

O

Nt-Bu t-Bu

Evans, D. A.; et. al. J. Am. Chem. Soc. 1999, 121, 686. 23

Williams Use of Auxiliary for Asymmetric Oxidation of Sulfides

S N

O

Me R

R'

S N

O

Me RO

R'

See Table

THBP, CH2Cl2-20°C

Entry R R’ Metal Time d.e.

a i-Pr H VO(acac)2 24 h 70%

b CH2OH Ph VO(acac)2 3 h 74%

c CH2OH Ph Ti(Oi-Pr)4 4 h 94%

Williams, J. M. J.; et. al. J. Chem. Soc. Perkin Trans. 1 1996, 331. 24

Examples of Auxiliaries Utilized in ASOS Reactions

R' SeR m-CPBA

R"

R" OH

R'

OHN

OMe

Me

H

NMe2

Fe

Ts

68% (32% d.e.) 81% (66% d.e.)60% (89% d.e.) 88% (66% d.e.)

R =

R' = PhR" = H

R' = PhR" = H

R' = PhR" = H

CH2CH2CH CMe2R' = R " = Me

Reich, H. J.; Yelm, K. E. J.

Org. Chem. 1991, 56, 5672

Fujita, K.; et. al. Synlett 1998,

987.

Uemura, S.; et. al.

J. Org. Chem. 1995,

60, 4114.

Koizumi, N.; et. al.

Tetrahedron1997, 53,

12115 25

(t-BuOCl instead of m-CPBA)

Synthesis of Monodentate Auxiliaries Applied to Vanadium-Catalyzed ASOS Reaction

Br

Br

N

O

H

O

N

OHH2N

R1

OH

R1

SOCl2, CH2Cl2

R1

Se

O

N R1

Ph

Br

COCl

Et3N, CH2Cl2, 0°C to r.t.

t-BuLi, THF, 78°C;Se powder then

Cinnamyl bromide

50-74%

50-74%

61-73% 26

ASOS Reaction with Mondentate Auxiliaries

VO(acac)2, TBHPCH2Cl2, mol. sieves, -50°C;

PBu3

SeO

Ar

Ph

O

N

Se Ph

O

N

SeV(O)Ln

OOt-Bu

H

OH

Ph

R

R

H

endo

27

Results From Monodentate ASOS Reaction

Entry R R' Yield d.e.

1 Bn H 78% 10% (R)

2 H i-Pr 56% 22% (S)

3 t-Bu H 52% 40% (R)

VO(acac)2, TBHPCH2Cl2, mol. sieves, -50°C;

PBu3

O

NR'

Se Ph

OHR

1

4

69

28

Camphor Based Monodentate Oxazoles

ON

exo

Se

Ph

OH

6% d.e.

OH

14% d.e.endo

NO

Se Ph

VO(acac)2, TBHPmol. sieves, CH2Cl2, -35°C;

PBu3, 50%

VO(acac)2, TBHPmol. sieves, CH2Cl2, -40°C;

PBu3, 57%

29

Monodentate Auxillary with m-CPBA

O

N

Se Ph m-CPBA, CH2Cl2mol. sieves, -50°C;

PBu3, 41%

OH

Only 4% d.e.

O

N

Se Ph VO(acac)2, TBHPCH2Cl2, mol. sieves, -50°C;

PBu3, 52%

OH

40% d.e.

30

Williams Use of Auxiliary for Asymmetric Oxidation of Sulfides

S N

O

Me R

R'

S N

O

Me RO

R'

See Table

THBP, CH2Cl2-20°C

Entry R R’ Metal Time d.e.

a i-Pr H VO(acac)2 24 h 70%

b CH2OH Ph VO(acac)2 3 h 74%

c CH2OH Ph Ti(Oi-Pr)4 4 h 94%

Williams, J. M. J.; et. al. J. Chem. Soc. Perkin Trans. 1 1996, 331. 31

Synthesis of Bidentate Auxiliary System

Se

O

NOSiR3

Ph

TBAF, THF, AcOH

Se

O

NOH

Ph

t-BuLi, THF, -78°C;Se powder then

Cinnamyl bromide, 70-72%

Br

O

NOSiR3

76-94%

32

ASOS Reaction with Bidentate Auxiliary

Se

O

N

PhVO(acac)2, TBHP,

CH2Cl2, mol. sieves, -50°C;

PBu3

OH

OR

R Yield d.e. (configuration)

TIPS 52% < 2 %

H 63% 60 % (S)

33

Methylated Serine-based Auxillary ASOS Reaction

Se

O

N

Ph

NaH, MeI,0°C82%

R = HR = OMe

OH

< 5% d.e.

OR

VO(acac)2, TBHP,CH2Cl2, mol. sieves, -50°C;

PBu3, 50%

34

Bidentate Auxillary ASOS Reaction with Different Metal Catalysts

Se

O

N

Ph See Table, TBHP,

CH2Cl2, mol. sieves;PBu3

OH

OH

Entry Metal Temp Yield d.e.

a

b

c

d

e

f

g

Ti(Oi-Pr)4 (10 mol %)

Ti(Oi-Pr)4 (100 mol %)

MoO2(acac)2 (10 mol%)

Zr(acac)2 (10 mol %)

Mn(acac)2 (10 mol %)

m-CPBA (100 mol %)

VO(acac)2 (10 mol %)

-50 to -25°C

-50°C

-50°C

-50°C

-50°C

-50°C

-50°C

47%

60%

58%

35%

19%

63%

63%

30%

30%

25%

35%

34%

26%

60%35

Threonine-Based Auxillary ASOS Reaction

Se Ph

O

N

X

HVO(acac)2, TBHP,

CH2Cl2, mol. sieves,

-50°C; PBu3

OH

Y

X Y Yield d.e. (configuration)

OTIPS H 69% 15% (R)

OH H 74% 50% (S)

H OH 74% 66% (S)

36

Synthesis of Epimeric Selenides

BrHN

OOMe

O

OH

1) DAST, K2CO3, CH2Cl2, -78°C, 91%

2) i-PrMgCl, THF,-78°C, 49%

Br

O

N O

NaBH4, MeOH, r.t.

Br

O

N OH

Br

O

N OHH H

58% 42%

37

Synthesis of Iso-Propyl Selenides

Br

O

NHH

OTBS

Se

O

NHH

OTBS

Ph

Se

O

NHH

OH

Ph

TBAF, AcOHCH2Cl2, r.t.

t-BuLi, THF, 78°C;Se powder then

Cinnamyl bromide

Br

O

NHH

OH TBSOTf, 2,6-lutidine,CH2Cl2, 0°C

62%

75%

60%

38

ASOS Reaction with Iso-propyl Selenides

Se

O

NYH

X

Ph

VO(acac)2, CH2Cl2,mol. sieves, TBHP,

-50°C; PBu3

OH

X Y Yield d.e. (configuration)

OH H 61% 62% (R)

H OH 71% 70% (R)

39

Possible Explanation of Stereochemistry

40

SeH

O

N

Se Ph

SeN

OH

O

VO

O

t-Bu

O

MeH

OH

MeH

Ph

OH SeOO

N

H

OVO

Ln

Ph

H

endo

Me

H

SOO

N

H

OVO

Ln

exo

Me

H

Ph

H

Ph

OH

R

Ln

Ph

Conclusion

Racemic SOS reaction:• Developed the first catalytic, metal-based method.

• Requires only 10 mol% VO(acac)2 and applicable to a wide range of substrates.

Vanadium-catalyzed, Auxiliary-Based ASOS reaction:•Achieved up to 70% diastereomeric excess (d.e.) with an oxazole-based auxiliary.

• Laid the foundation for the development of a ligand- based ASOS reaction system.

41

Acknowledgements

Committee Members

Dr. Rich CarterDr. Mitch AveryDr. Dan Mattern

Lab Group

Wei ZhangDavid WeldonMelissa Gronemeyer

Chrissy CastrichiniDr. and Mrs. Walter BourlandRachel GravesThe Graves ClanStacy JonesQun ZhuG-Flo and Big SergeDr. Ismail AhmedDr. Linda SpargoThe University of Mississippi

42