The Chemistry of Larry E. Overman Application in Total ... · The Chemistry of Larry E. Overman Application in Total Synthesis Distinguished Professor of Chemistry University of California,

The Chemistry of Larry E. Overman Application in Total SynthesisDistinguished Professor of ChemistryUniversity of California, Irvine http://faculty.sites.uci.edu/overman/!

Topic Review!!

Bern, May, 1st 2014!

Julien Pomarole!

Index"

Ø  Introduction : !—  About Larry E. Overman!—  Overman Rearrangement!

Ø  Prins-Pinacol type reaction!

Ø  Iminium Chemistry!—  Biginelli condensation!—  Aza-Cope/Mannich rearrangement!

Ø  Formation of quaternary carbon-center!—  Heck-type Cyclization!—  Radical pathway!

Ø  Conclusion!

2

About Larry E. Overman"

Ø  B. A. from Earlham College, Richmond, IND (1965)!Ø  Ph.D from University of Wisconsin, Madison, WI

(1969)!Under the supervision of Pr Howard H. Whitlock Jr."

Ø  NIH postdoctoral fellowship, Columbia University, New York, NY (1969-1971),!with Pr Ronald Breslow"

Ø  Joined University of California, Irvine, CA (1971)!Ø  1971-1974: Assistant Professor"Ø  1974-1994: Full Professor"Ø  1994-currently: Distinguished Professor"!

!

3 http://faculty.sites.uci.edu/overman/!http://www.scienceblog.com/community/older/2003/C/2003436.html!http://pubs.acs.org/cen/awards/8106/8106awards.html!

•  Allylic imidate rearrangement: Mumm and Möller (1937)!!!•  Overman rearrangement (1974, allylic trichloroacetimidate rearrangement)!

Overman Rearrangement"

4 (1)  Mumm, O.; Möller, F. Ber. 1937, 11, 2214–2227.!(2)  Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597–599.!(3)  Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901–2910.!

m-xylene

reflux (140 °C)O NH

CCl3

O NH

CCl3

O NH

CCl3HgX2 cat.

or Pd(II) cat.

O NHCl3C

O NH

MX2

CCl3

O NH

MX2

CCl3

O N

MX2

CCl3

via

H

Overman Rearrangement"

5

OHN

CCl3

O∗∗

HN

CCl3COP-Cl (5 mol%)

DCMr.t, 18 hR R

OHN

CCl3

80%94% ee

OHN

CCl3

Ph83%

96% ee

OHN

CCl3

87%95% ee

NBn

Boc

OHN

CCl3

HO

84%80% ee

OHN

CCl3

73%95% ee

MeO

O

OHN

CCl3

80%94% ee

O

Overman, L. E.; Owen, C. E.; Pavan, M. M.; Richards, C. J. Org. Lett. 2003, 5, 1809–1812.!Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125, 12412–12413.!

Prins-Pinacol rearrangement Strategy Formation of high substituted tetrahydrofuran"

6

O

OHHO

O

OMe

O(–)-citreoviridin

O CHO

OHHO

(–)-citreoviral

O

HHO

H

O2CPr

H

AcO

asbestinin-1O

OH

HHO

H

H

H

C7H15CO2HO H

biarellin E

O

OH

HH

O

O

H

H

H

C7H15CO2

biarellin F

O RR

RRR

RR

R

•  First example : Mousset and co-worker (1969)!

•  Mechanism :!

•  Overman’s condition (1987):!

Prins-Pinacol rearrangement Strategy Prins-Pinacol reaction"

7 Martinet, P., Mousset, G., Colineau, M. Acad. Sci. C. 1969, 268, 1303-1306.!Hopkins, M. H., Overman, L. E. J. Am. Chem. Soc. 1987, 109, 4748 "Overman, L. E., Pennington, L. D. J. Org. Chem. 2003, 68, 7143!

Prins-Pinacol rearrangement Strategy (–)-citreoviral synthesis"

8

SiMe2Ph

Me

1. TaCl5, ZnBenzene/DME

2. 163. NaOH, H2O

OH

PhMe2Si

OTBDPS

2 steps OTMS

PhMe2Si

OTMS

20

TMSOTf (0.1 eq)DCM, –30 °C

PhMe2Si

O

O

OTBDPS41%

O

SiMe2PhO

OTBDPS47%

Hanaki, N.; Link, J. T.; MacMillan, D.; Overman, L. E. Org. Lett. 2000, 2, 223–226.!

O

OTBDPS16

MeO OMe

OTBDPS20

Prins-Pinacol rearrangement Strategy (–)-citreoviral synthesis"

9

PhMe2Si

O

O

OTBDPSO

SiMe2PhO

OTBDPS

SnCl4 (1.2 eq)

DCM, –78 °C89%

13 steps

O CHO

OHHO

(–)-citreoviral

Hanaki, N.; Link, J. T.; MacMillan, D.; Overman, L. E. Org. Lett. 2000, 2, 223–226.!

Prins-Pinacol rearrangement Strategy Biarellin E and F syntheses"

10 Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc. 2003, 125, 6650–6652.!

O

OH

HH

O

O

H

H

H

C7H15CO2

biarellin F

O

OH

HHO

H

H

H

C7H15CO2HO H

biarellin E

Prins-Pinacol rearrangement Strategy Biarellin E and F syntheses"

11 Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc. 2003, 125, 6650–6652.!

OO

H

H

8 steps

TIPSOOH

HO

TMS

H

TIPSOOH

HO

TMS

H

CHO

TBDPSO

1. p-TsOH•H2O, MgSO4DCM, –78 to –20 °C

2. SnCl4 (0.1 eq), DCM–78 °C to rt

(84%, 2 steps)

O

TBDPSO TMS

TIPSO H CHO

H H

H

18 Steps

O

OH

HHO

H

H

H

C7H15CO2HO H

biarellin E

Dess-Martin Periodinate

DCM, rt79%

O

OH

HH

O

O

H

H

H

C7H15CO2

biarellin F

Prins-Pinacol rearrangment Strategy (+)-Sieboldine A synthesis"

12 Canham, S. M.; France, D. J.; Overman, L. E. J. Org. Chem. 2013, 78, 9–34.!

O

O

N OHO

(+)-sieboldine AOR"O

OR'OR

Prins-pinacolrearrangement OTMS

OR'OR"

Me

R3OOR2

Prins-Pinacol type Reaction(+)-Sieboldine A synthesis"

13

OTBDPSO

OPhOMe

19

OH

OMe

OPh

OTBDPS

17

+TMSO

OMe

OPh

OTBDPS18

+

OTMS

OPhOTBDPS

MeO

OMe

conditions

Canham, S. M.; France, D. J.; Overman, L. E. J. Org. Chem. 2013, 78, 9–34.!

OTMS

OPhOTBDPS

MeOOMe

M-X (L.A.)

–MOMe

TMSO

OTBDPS

OMe

A

X

OPh



OH

OMe

OPh

OTBDPS

17

– TMSX

TMSO

OMe

OPh

OTBDPS18

– HX

Prins

TMSO

OTBDPS

H

OPhX

B

OTBDPSO

OPhOMe

19

Pinacolrearrangement



OSiR3

OPhOTBDPS

MeOOMe

OTBDPSO

OPhOMe

19

conditions

O

O9 steps

51%OTES

OPhOTBDPS

Pinacol-terminated 1,6-enyne cyclization(+)-Sieboldine A synthesis"

16 Canham, S. M.; France, D. J.; Overman, L. E. J. Org. Chem. 2013, 78, 9–34.!Canham, S. M.; France, D. J.; Overman, L. E. J. Am. Chem. Soc. 2010, 132, 7876–7877.!



OTES

OPhOTBDPS OTBDPSO

OPhconditions

72

+

OH

OPh

TBDPSO

73


18 Canham, S. M.; France, D. J.; Overman, L. E. J. Am. Chem. Soc. 2010, 132, 7876–7877.!

OTES

OPhOTBDPS

[Au]+

TESO

OPh

TBDPSO

[Au]+

J

O

OPh

TBDPSO

Et3Si

1,6-EnyneCyclization

[Au]

K

OH

OPh

TBDPSO

73

[3,3]

Heterocyclization

O

OPh

TBDPSOL

[Au]Et3Si 1

1'

3

3'

OTBDPSO

OPh

72

Pinacol

Shift



OTBDPSO

OPh

72

10 Steps

10%

O

O

N OHO

(+)-sieboldine A

Iminium Chemistry Nucleophile-promoted iminium ion-alkyne cycliztn"

20

N

H OH

OHN

OH

OH

(+)-pumilotoxin A (+)-Allopumiliotoxin 339A

OHOH

H

Overman, L. E.; Robinson, L. A. J. Am. Chem. Soc 1992, 114, 368–369.!Caderas, C.; Lett, R.; Overman, L. E. J. Am. Chem. Soc 1996, 118, 9073–9082.!

N

R

OHOH

H

NH

R

HO

O

(CH2O)nX–

H+

X


21 Overman, L. E.; Robinson, L. A. J. Am. Chem. Soc 1992, 114, 368–369.!

HO10 Steps

19% OO

ON

OBnH

TsOH (3 eq)NaI (10 eq)

(CH2O)n (5 eq)

H2O/Aceton (10:1)100 °C, 2h81%

NOH

OH

OHOBn

H

I

1. n-BuLi (excess)THF, –78 °C to 23 °Cthen MeOH, 81%

2. Li (excess)liquid NH3, –78 °C3 min, 76%

NOH

OH

(+)-Allopumiliotoxin 339A

OHOH

H


22 Overman, L. E.; Robinson, L. A. J. Am. Chem. Soc 1992, 114, 368–369.!

OO

ON

OBnHH+

H2O OHOH

OHNH

OBnH

H+(CH2O)n

N

OBnH

R

OH

I– NOH

OH

OHOBn

H

I

3 Steps

51%OHOBn

O

Et O LDA, TBDMSClTHF/HMPA, –78 °C to 23 °C

then MeOH/HCl90% (7:1 dr)

MeO2C

OBn


23 Caderas, C.; Lett, R.; Overman, L. E. J. Am. Chem. Soc 1996, 118, 9073–9082.!

NH

OHH

OBnNaI

(CH2O)n, CSA

H2O, 100 °C60%

NOBn

OHH

I

1. n-BuLi (excess)THF, –78 °C to 23 °Cthen MeOH, 92%

2. Li (excess)liquid NH3, –78 °C3 min, 85%

N

H OH

OH

(+)-pumilotoxin A

7 Steps

54%

Iminium Chemistry Biginelli condensation"

24

NH

N

NH

HH

O

O

NH

N

NH

HH

C7H15Batzelladine F

NH

N

N

O

O

O

N NH2

OH

NH214

OH

H

O

(–)-Crambidine

McDonald, A. I.; Overman, L. E. J. Org. Chem. 1999, 64, 1520–1528.!Cohen, F.; Overman, L. E. J. Am. Chem. Soc. 2001, 123, 10782–10783.!Overman, L. E.; Rhee, Y. H. J. Am. Chem. Soc. 2005, 127, 15652–15658.!

NH

N

NH

NH

N

NH

O

OHN

NH2

H2NH H

(CH2)8CH3

Batzelladine D


25

SNH

NH2 OH

R2

H

EtO

O

R

O O

R2 H2N NH

OMe

N

NH

OMe

O

EtO

R

R2

H+ cat.

SNH

H2NR2

OH

SNH

NR2

HP.T.

– H2O

O

R

OH

OEt

S

N NH

R2

OR

O

OEtH

N

HNS R2

OEt

O

RHO

6-exo-trigN

HNS R2

OEt

O

ROHH

H+

N

HNS R2

OEt

O

R

– H2ON

HNS R2

OEt

O

R

– H+

•  Disocvery by Pietro Biginelli in 1891:!

!!•  Mechanism :!

Biginelli, P. Ber. 1891, 24, 2962–2967.!Kappe, C. O. J. Org. Chem. 1997, 62, 7201–7204.!Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem. 1998, 63, 3454–3457.!


26

NH

N OHH

NH2

5

O

AllylO

O OTBDMS

6

NH

N

NH

HH

O

O

NH

N

NH

HH

C7H15Batzelladine F

NH

N

NH

HHO

OO

15

N

H2N NH2

HO C7H15

OHH

4

Cohen, F.; Overman, L. E. J. Am. Chem. Soc. 2001, 123, 10782–10783.!


27

OH O

OMe

5 Steps

58%

NH2 NH2

OMe

OMe

NCbz

MeS OMe

DCM85% OMe

OMeNHHN

NCbz

H210% Pd/C

AcOH, MeOH98% OMe

OMeNHHN

NH 6morpholine

AcOH, Na2SO4

CF3CH3OH, 60 °C82%

NH

N

NH

HHOTBDMS

O

AllylO

O OTBDMS

6

4 Steps

54 % NH

N

NH

HHO

OO

15

BF4-



28

NH

N

NH

HHO

OO

15

4 morpholine, AcOH

Na2SO4, CF3CH2OH, 60 °C59%

BF4-

NH

N

NH

HH

O

O

NH

N

NH2

HOH

C7H15

4 Steps

14%

NH

N

NH

HH

O

O

NH

N

NH

HH

C7H15Batzelladine F


N

H2N NH2

HO C7H15

OHH

4


29 Kappe, C. O. J. Org. Chem. 1997, 62, 7201–7204.!McDonald, A. I.; Overman, L. E. J. Org. Chem. 1999, 64, 1520–1528.!

Iminium Chemistry Aza-Cope/Mannich rearrangement"

30

Aza-Cope rearrangement :!

Jacobsen, E. J.; Levin, J.; Overman, L. E. J. Am. Chem. Soc 1988, 110, 4329–4336.!


31 Knight, S. D.; Overman, L. E. J. Am. Chem. Soc 1995, 117, 5776–5788.!

7 Steps

46%

N

HO

OtBu

N NMe

MeN O

H

H+(CH2O)nNa2SO4

MeCN, 80 °C98%

O

N

OtBu

N

NMeMeN

O



Me3Sn

OTIPS

OtBu

N

MeN

MeN

OI

Pd2dba3 (2.5 mol%Ph3As (22 mol%)

CO (50 psi), LiClNMP, 70 °C

80%N

MeN

MeN

O

TIPSO

OtBu

6 Steps

24%

N

N

O OH

H

H

(–)-strchnine[a]D25 = –139 (c =1.0, CHCl3)




34

NHBocO

HO

1. CDI, HN(OMe)Me•HClDCM, rt, 94%

2. Me2C=CHMgBr, CeCl3THF, –78 °C, 94%

HNBoc

O 68 (0.2 mol%)H2

i-PrOH, rt HNBoc

HO

91% ee

Martin, C. L.; Overman, L. E.; Rohde, J. M. J. Am. Chem. Soc. 2010, 132, 4894–4906.!

NBoc

AcO

AcO

6 Steps

28%

2 Steps

73%


35 Madin, A.; O'Donnell, C. J.; Oh, T.; Old, D. W. Angew. Chem. Int. Ed. 1999, 38, 2934–2936.!


36

104 Steps

45%

[Pd2dba3]•CHCl3 cat.Ag3PO4, Et3N

THF, reflux70%

10 steps

23%

Madin, A.; O'Donnell, C. J.; Oh, T.; Old, D. W. Angew. Chem. Int. Ed. 1999, 38, 2934–2936.!

Quaternary Carbon-center formationHeck-type cyclization"

37 Overman, L. E.; Poon, D. J. Angew. Chem. Int. Ed. 1997, 36, 518–521.!


38

N

NNH

NH

Me

Me

(+)-calycanthine

NI Bn

O

N

O

OO

Bn ICO2Me

MeO2C

N

N

NH

NH

Me

Me

(+)-calycanthine

Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem. Soc 1999, 121, 7702–7703.!


39

CO2MeMeO2C

NI Bn

O

N

O

OO

Bn I6 Steps

15%

(Ph3P)2PdCl2 (10 mol%)Et3N, DMA

100 °C90%

NN

O Bn

O

Bn

OO

8 Steps

36%N

NNH

NH

Me

Me

(+)-calycanthine

N

N

NH

NH

Me

Me

(+)-calycanthine

Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem. Soc 1999, 121, 7702–7703.!

OTIPS

H

I

O

O

Pd(OAc)2 (30 mol%)PPh3 (60 mol%)

AgCO3

THF, refluxthen TBAF, THF, 23 °C

90% OH

O

OH


40

O

OTIPSO

O7 steps

44%

O

OTBDMS

1. LDA, 20% HMPA-THF, –78 °C2. TMSCl, –78 °C to 0 °C

3. HCl–H2O74%

O

OTIPS

HO

O

4 Steps

80%

Fox, M. E.; Li, C.; Marino, J. P. J. Am. Chem. Soc 1999, 121, 5467–5480.!

OBz

H

O

HHO2CHO

(–)-scopadulcic acid A

15 Steps

14%

OBz

H

O

HHO2CHO



41 Fox, M. E.; Li, C.; Marino, J. P. J. Am. Chem. Soc 1999, 121, 5467–5480.!

Quaternary Carbon-center formationHeck-Iminium Ion Cyclization"

42 Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127, 10186–10187.!

PPhPh

N

O

Pfaltz ligand

NH2

OTIPS

1. p-TsOH cat.Benzene, 50 °C, 95%

2. ClCO2Me, NaHMDSTHF, –78 °C, 56%

ON

O ON

MeO2C

OTIPS

1. Comin's reagent, NaHMDS,THF, –78 °C, 82%

2. 13, PdCl2(dppf)•DCM, THF, rtthen H2O2, 0 °C, 72%3. CsF, Cs2CO3, Comin's reagentDMF, rt, 95%

NMeO2C

OTf

NHBocPd(OAc)2 cat.

Pfaltz ligand cat.PMP, toluene, 170 °C

then CF3CO2HDCM, 0°C75%

NCO2Me

NBoc

99% ee

N N

Cl

OTf

OTfComin's reagent

B NHBoc

13

NH

N

HO

minfiensine


43

NMeO2C

OTf

NHBocHeck-type

cyclizationNCO2Me

BocHN

H+

NCO2Me

BocHN

NCO2MeNHBoc

– H+

NCO2Me

NBoc

Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127, 10186–10187.!

NH

N

HO

minfiensine

Pd(OAc)2 cat.K2CO3, Bu4Cl, NaO2CH

DMF, 80 °C80%

NCO2Me

N

TESO


44 Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127, 10186–10187.!

NCO2MeNBoc

5 steps

68% NCO2Me

N

TESO

I

8 Steps

30% NH

N

HO

minfiensine

NH

N

HO

minfiensine

Quaternary Carbon-center formationTertiary Radical pathway"

45 Schnermann, M. J.; Overman, L. E. Angew. Chem.Int. Ed. 2012, 51, 9576–9580.!

OMe

Me

Me

19(+)-fenchone

12 Steps

8%

H

Me MeH

Me

27

O

O

NPhth

H

Me MeH

Me

27

O

O

NPhth+

O

Cl

MeO2C

TBSO

28(1.5 eq)

29 (1.5 eq)[Ru(bpy)3](BF4)2 (0.01 eq)

DCMBlue LEDS, 2.5 h, rt

(61%)

H

MeH

Me

H Cl

MeO

MeO2CTBSO

H

30single

diastereoisomere

H

MeH

Me

Me

Aplyviolene

O

O

OAcO


46 Schnermann, M. J.; Overman, L. E. Angew. Chem.Int. Ed. 2012, 51, 9576–9580.!

H

MeH

Me

Me

Aplyviolene

O

O

OAcO

H

MeH

Me

H Cl

MeO

MeO2CTBSO

H

30single

diastereoisomere

OHR1

R2R3

Et3NDMAP cat.

THF, 23 °C90%-quant.

O

ClO

N

O

O

Quaternary Carbon-center formationRadical Pathway"

47

O

R3

R1R2

O

O

ON

O

O

Ru(Bpy)3](PF6)2 (1.5 mol%)i-Pr2NEt•HBF4 (1 eq)

Hantzch ester (1.5 eq)Methyl vinyl ketone (1 eq)

THF/DCM, rtblue LEDs

R3

R1R2

O

O

OO

43%O

OO

OPhth

Ru(Bpy)3](PF6)2 (1.5 mol%)i-Pr2NEt•HBF4 (1 eq)

Hantzch ester (1.5 eq)Methyl vinyl ketone (1 eq)

THF/DCM, rtblue LEDs

O

82%

H

H

O

82%

O

22%

O

65%

O

O

Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. J. Am. Chem. Soc. 2013, 135, 15342–15345.!


48 Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. J. Am. Chem. Soc. 2013, 135, 15342–15345.!

H

H

O

OMe

N

O

O

[RuI(bpy)3]+ [RuII(bpy)3]2+

*[RuII(bpy)3]2+NR3

[NR3]•+hυ

H

H

Me

H

H

MeOMe

O

NH

CO2EtH

Me

EtO2C

Me

H

NH

CO2Et

Me

EtO2C

Me

H

H

H

O

OMe

N

O

O

O

OMe

H

H

MeOMe

O

N

MeO2C CO2Me


49

Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda, M. J. Am. Chem. Soc. 1991, 113, 9401–9402.!Andrews, R. S.; Becker, J. J.; Gagné, M. R. Angew. Chem. Int. Ed. 2010, 49, 7274–7276.!Andrews, R. S.; Becker, J. J.; Gagné, M. R. Org. Lett. 2011, 13, 2406–2409.!Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. J. Am. Chem. Soc. 2013, 135, 15342–15345.!

Conclusion"

Ø  Differents strategies with highly stereo-control:!—  Prins-Pinacol rearrangement.!—  Aza-Cope/Mannich rearrangement.!—  Biginelli condensation!—  Heck-type cyclization!

Ø  Amazing variety of natural product were synthetized in his lab.!!!

50 http://faculty.sites.uci.edu/overman/!

O

O

N OHO

(+)-sieboldine ANH

N

HO

minfiensine

NH

N

NH

HH

O

O

NH

N

NH

HH

C7H15Batzelladine F

H

MeH

Me

Me

Aplyviolene

O

O

OAcOO

OH

HH

O

O

H

H

H

C7H15CO2

biarellin F

N

N

NH

NH

Me

Me

(+)-calycanthineOBz

H

O

HHO2CHO


Conclusion on Larry E. Overman"

!Ø  Overman’s Lab has completed synthesis of more of 80 complex natural

products and close to of 364 publication in major journal.!!Ø  2003 : ACS Arthur C. Cope Award!!

—  "I hated chemistry in high school.” (Overman, 2003)!!—  “I had absolutely no interest in chemistry until I was inspired by a great teacher

in college. What ultimately intrigued me was not only the idea of studying the natural world but also creating things that didn't exist before.” (Overman, 2003)!

51 http://faculty.sites.uci.edu/overman/!http://www.scienceblog.com/community/older/2003/C/2003436.html!http://pubs.acs.org/cen/awards/8106/8106awards.html!

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The Chemistry of Larry E. Overman Application in Total ... · The Chemistry of Larry E. Overman Application in Total Synthesis Distinguished Professor of Chemistry University of California,