The Chemistry of Larry E. Overman Application in Total ... · • Allylic imidate rearrangement: Mumm and Möller (1937)!!! • Overman rearrangement (1974, allylic trichloroacetimidate

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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Documents

The Chemistry of Larry E. Overman Application in Total ... · • Allylic imidate rearrangement: Mumm and Möller (1937)!!! • Overman rearrangement (1974, allylic trichloroacetimidate