journal years in review: organic letters 2001, volume 3 · 1 ruben eckermann gaich-group seminar...

1

Ruben Eckermann Gaich-Group Seminar

April 23rd, 2015

Journal Years in Review: Organic Letters 2001, Volume 3

Gaich-‐Group Seminar Ruben Eckermann Statistics

2

OL 2001 facts: -  4325 pages -  2188 published articles -  117 articles with title „Total Synthesis“

Most profilic authors: -  Daniel H. Rich (14) -  Amos B. Smith (14) -  Elias J. Corey (13) -  Luis Castedo (13) -  Raymond L. Funk (12) -  Paul J. Reider (12)

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Gaich-‐Group Seminar Ruben Eckermann

3

Statistics

Most cited papers (general): -  Dissected Nucleus-Independent Chemical Shift Analysis of n-Aromaticity

and Antiaromaticity (Paul von Ragué Schleyer); 2465 - 2468 citings: 519

-  Efficient proline-catalyzed Michael addiditons of unmodified ketones to

nitro olefins (Benjamin List); 2423 - 2425 citings: 488

-  Air-Stable Trialkylphosphonium Salts: Simple, Practical, and Versatile

Replacement for Air-Sensitive Trialkylphosphines (Gregory C. Fu); 4295 - 4298

citings: 482

Scifinder


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Most cited papers (total synthesis): -  Total Synthesis of the Mirotubule-Stabilizing Agent (-)-Laulimalide (Ian Paterson); 3149 - 3152

citings: 90

-  First Total Synthesis of Martinellic Acid (Dawei Ma) 2189 - 2191

citings: 87 -  Total Synthesis of (-)-Salicylihalamide A (Barry B. Snider) 1817 - 1820

citings: 86

Statistics

Scifinder

Gaich-‐Group Seminar Ruben Eckermann Isolations

5

OAcOH

H

Me OHOH

OH

AcO

Me

Artisane (1)

MeN

NH

O

O

NLycoposerramine A (2)

MeMe

Me

Me

AcOPasslerin A (3)

HO2C

OO

OO

O OO

Phomoidride D (4)

O

Me

Me

OAcAcO H

CO2Me

OH

O

Salvionorin C (5)

No. 24, 3935 - 3937 No. 10, 1443 - 1445

No. 10, 1415 - 1417

No. 26, 4165 - 4167

No. 26, 4243 - 4245


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Total Synthesis

Total syntheses in

detail

Gaich-‐Group Seminar Ruben Eckermann Total Synthesis

7

Steven M. Weinreb, 3507 - 3510 Robert B. Grossman, 4027 - 4030 William J. Kerr, 2945 - 2948

Kunio Ogasawara, 291 - 293

Raymond L. Funk, 3923 - 3925

Barry B. Snider, 4217 - 4220

HN

H

HO

H

C6H13

Lepardiformine (6)

Me

OO

Me

O

O

(±) - Sacacarin (7)

Me

Me MeH

Me

(±) - α-Cedrene (8)

MeMe

Me

Me O

(+) - Aminocenone (10)

HON Me

MeAphanorphine (11)

Lennoxamine (12)

Me

Me MeH

(±) - β-Cedrene (9)

NH

HO

O NHN

HN

HN

HN

NH

(±) - Martinellic Acid (13)

NO

MeO

MeO

O

O

Gaich-‐Group Seminar Ruben Eckermann Lepadiformine

8

Pu Sun, Cuixiang Sun, Steven M. Weinreb, No. 22, 3507 - 3510

Key features: -  Spirocyclization of allylsilane/N-acyliminium

ion -  Radical-based α-oxidation of an amide -  N-acyliminium ion additions

HN

H

HO

H

C6H13

Si MgBr

Grignard

Grignard

C6H13MgBr

NMe

I

SiMe3

Alkylation

Allylsilaneaddition

CO - Insertion


9

Lepadiformine

NMe

1) LDA, -78°C to rt

I

SiMe3

2) NEt3

NO2

Cl

O

3) TFA, CH2Cl2

57%

14

NO

O2N

15

4) NaBH4, Cu(acac)2 EtOH5) NaNO2, HCl, CuCl MeOH, 0°C to rt

77%N

Ph

O

16

MeO

6) CuBr2*SMe2, BF3*OEt2 Et2O, -78°C to rt

Si MgBr

7) H2O2, NaHCO3 MeOH, THF, Δ

83%

N

Ph

O

17

HO

H

8) Rh(CO)2acac, CO/H2 P(OPh)3, THF, 60°C9) HCl, MeOH, (MeO)3CH10) LiOH, EtOH/H2O, Δ

80% NH

18

HO

HOMe

OMe11) NaH, BnBr, THF -8°C to rt12) pTsOH, ac/H2O, Δ

13) HCl, MeOH, KCN ac/H2O

75%

14) BF3*OEt2, C6H13MgBr THF, -20°C to rt15) Na, NH3, -78°C, THF

67%HN

H

BnO

H

CN

19

HN

H

HO

H

C6H13

Lepardiformine (6)

Gaich-‐Group Seminar Ruben Eckermann (±) - Sacacarin

10

Ravindra M. Rasne, Robert B. Grossman, No. 25, 4027 - 4030

Key features: -  Selective mono – alkylation of malonates -  Double annulation strategy

Me

OO O

O

Br BrMe

PPh3O

CO2Et

EtO2C

CN

CN

Me3Si

O

MeLi - additionWittig

Substitution

Substitution Michael addition

Dieckmann

1

1

2

2 3

3

a

a

b

b

c

c d

d


11

(±) - Sacacarin

Br BrMe

1) NaH, DMF

CN

CN

2) NaH, DMF

CO2Et

EtO2C

50%

MeEtO2CEtO2C NC CN

2021

3) O3, CH2Cl2 then [TsOH], EtOH reflux

86%

MeEtO2CEtO2C

22

CN

CN

SiMe3O

4) 15 mol% KF*2H2O tBuOH, rt

66%

Me

EtO2C NC

CN

O

EtO2C Me

23

5) EtOH, HCl then HCl aq., DME6) NaOEt, EtOH reflux

then [TsOH], EtOHPhH/H2O, reflux

89%

Me

EtO2C NCOEt

EtO2C

O

24

7) MeLi, -78°C, THF then TMSCl then LiAlH4, 0°C

then H2O, filtratethen HCl aq., reflux

62%

Me

O

Me

O

HO

25O

8) NMO, TPAP, CH2Cl29) DMPU, Z/E = 4:1

10) [TsOH], PhH/H2O

then H2, Lindlar cat.EtOHthen 1 M HCl, THF

49%

PPh3O

HOOH

Me

O

Me

O

O

(±) - Sacacarin (26)O


12

(±) - Sacacarin

Me

O

Me

O

O

(±) - Sacacarin (reported)O

11) [TsOH], PhH/H2O

HOOH

then LiAlH4, THFthen NMO, TPAP, CH2Cl2then 1 N HCl, THF

MeMe

O

O

HOHO

Me

O

Me

O

O

(±) - Sacacarin (reported)O

Me

O

Me

O

O

(±) - Sacacarin (actual)

+

O

49% 19%

Gaich-‐Group Seminar Ruben Eckermann Cedrone

13

Peter L. Pauson, Angus J. Morrison, Mark McLaughlin, William J. Kerr, No. 19, 2945 - 2948

Key features: -  Pauson Khand reaction

Me

Me MeH

Me

(±) - α-Cedrene (8)

Me

Me MeH

(±) - β-Cedrene (9)

+

Me

Me MeH

O

Cedrone (27)

O

O

O

OEt

OTMS

PPh3

Me

OP OMe

O

OMeN2

Co2(CO)8

Wittig

Pauson Khand

1

1

2

23

34

45

56

6

1,4 - addition

Ohira Bestmann


14

Cedrone

O

O

O

1) TMSOTf, NEt3, -5°C2) Pd(OAc)2, diallyl carbonate MeCN, 81°C

3) Yb(OTf)3*3H2O

64%

OEt

OTMS

OO

OMeEtO2C

Me28 29

4) Ph3PEtBr, nBuLi, 0°C5) LiAlH4, 0°C6) DMP

7) Ohira Bestmann8) Co2(CO)8

O

OMe

Me30

Me

Co2(CO)6

71%

9) 4.3 eq BuSMe DCE, 83°C

95%

Me

Me Me

OO

O

Me

Me Me

OO

O

+

cis/trans = 2:1

31

32

10) H2, Pd/C11) LiAlH4, 0°C

12) BuLi, CS2, MeI13) Bu3SnH, AIBN PhH, 80°C

70%

Me

Me Me

O

O

H

33

14) 8 mol% CBr4/PPh3 ac

99%

Me

Me MeH

Cedrone (27)

O

Gaich-‐Group Seminar Ruben Eckermann (+) - Arnicenone

15

Yosuke Iura, Tsutomu Sugahara, Kunio Ogasawara, No. 2, 291 - 293

O

O

OH1

1

2

2

334 4

55

6 6

NMe2

MeO OMe Br

Me2CuLi

MeI

MeMgI

Co2(CO)8Pauson Khand

a

ab

b

c

c

Alkylation

EschenmoserClaisen

Key features: -  Pauson Khand reaction -  Eschenmoser Claisen rearrangement -  Chirality transfer via DA / retro-DA


16

(+) - Arnicenone

16) tBuOK, MeI HMPA/THF, -25°C

17) MeMgI, CuBr*SMe2

60%

41

OBn

Me

MeO

Me

18) H2, Pd/C19) N - PhS-succinimide PBu320) mCPBA, -78°C

21) CaCO3, Ph2O reflux22) [pTsOH], CH2Cl2 reflux

38%

MeMe

MeMe

O

(+) - Aminocenone (10)

O

OH

1) DIBAL-H2) NBS, CH2Cl2 0°C

99%

34

OOH

35

Br

3) Ph2O, reflux

4) LDA, THF -78°C

65%

NMe2

MeO OMe

Br O

36

BrCONMe2

5) Co2(CO)8, CH2Cl2

then CH2Cl2/DMSOreflux

66%O

CONMe2Br

O

37

6) Me2CuLi, THF, -20°C7) (CH2OH)2, [pTsOH]

8) LiBH(Et)3, THF9) NaH, BnBr, THF

74%

Br

O

38

OO

OBn

Me

10) Zn, AcOH/EtOH reflux11) NaHCO3, Ph2O reflux

12) NH2NH2*H2O, K2CO3 TEG, 250°C

72%

39

OBn

MeHO

H13) ArCO2H, PPh3 DIAD, CH2Cl214) aq. NaOH, MeOH

15) MnO2, CH2Cl257%

40

OBn

Me

HO

Gaich-‐Group Seminar Ruben Eckermann (±) - Lennoxamine

17

James R. Fuchs, Raymond L. Funk, No. 24, 3923 - 3925

NO

MeO

MeO

MeO

MeO

OCl

Br

O

O

O

O

O

NH2

O

O

Acylation

Enamineformation

Radicalcyclization

Electrophilicaromaticsubstituion

Key features: -  Masked acrolein-unit -  Electrophilic aromatic substitution


18

(±) - Lennoxamine

NH2

O

O

1) PhMe, MS

O

O

O

2) DIPEA, rt

62%

OMeOMeO

Cl

Br

NO

MeO

MeO

O

O

O

OBr

4243

3) BF3*OEt2, MeCN

61% NO

MeO

MeO

O

O

Br O

44

4) NaO2Cl, 0°C5) Pb(OAc)4, DMF Cu(OAc)2, 105°C

6) Bu3SnH, AIBN PhH, reflux

30%

Lennoxamine (12)

NO

MeO

MeO

O

O

Gaich-‐Group Seminar Ruben Eckermann (±) - Aphanorphine

19

James R. Fuchs, Raymond L. Funk, No. 24, 3923 - 3925

Key features: -  Masked acrolein-unit -  Electrophilic aromatic substitution

HON Me

MeMeO O

Cl

Me

O

O

NMe

Electrophilicaromaticsubstitution

Enamideformation

Alkylation


20

(±) - Aphanorphine

MeO O

Cl

Me

1) Lutitidine, PhMe

O

O

NMe68%

MeO O

NMe

Me

OO

2) 2 eq MeAlCl2 CHCl3, rt

3) NaBH4, MeOH63%

MeONMe

Me O

OH

45 46 47

4) MsCl, NEt35) tBuOK, THF, reflux

6) LiAlH4, THF, reflux7) BBr3, CH2Cl2, rt

46%

HON Me

MeAphanorphine (11)

Gaich-‐Group Seminar Ruben Eckermann (±) – Martinellic Acid

21

Sean M. O‘Hare, Yong Ahn, Barry B. Snider, No. 26, 4217 - 4220

NH

HO

O NHN

HN

HN

HN

NH

Br

NH2

OH

O

OO

O1

1

2

2

3

3

4

4

5

5

6

6

BnHNCO2H

a

ab

b

CO

H2N

H2N

CNBr

CNBr

1,3 - dipolar CA

1,4 - addition

Guanidinesynthesis

Guanidinesynthesis

Key features: -  Vinyl – pyrrolidinone synthesis -  Azomethine ylide 1,3 – dipolar CA -  Guanidine synthesis


22

(±) – Martinellic Acid

Br

NH2

OH

1) PhMe, reflux

2) MnO2, CH2Cl287%

O

OO

O

Br

N

O

O48 49

3) PhMe, refluxBnHN

CO2H

4) LiBH4, MeOH THF, reflux

52%

NH

BrBnN

50

5) 10 eq AcCl 20 eq NEt3, CH2Cl2

6) Pd(OAc)2, PPh3 NaOAc, CO MeOH, 130°C

57%

NH

MeO2CBnN

51OH OH

7) TFAA, par, CH2Cl28) MsCl, pyr, CH2Cl2 then NaN3, DMF

9) NaOMe, CH2Cl210) Pd(OH)2, H2 MeOH/HCl

69%

NH

MeO2CHN

52

NH2

11) CNBr, 0°C NaHCO3, MeOH12) (CF3)2CHOH, 120°C

H2N13) 0.15 M NaOH MeOH, reflux

62%

NH

HO

O NHN

HN

HN

HN

NH

(±) - Martinellic Acid (13)


23

Total Synthesis

Core structures &

Key steps

Gaich-‐Group Seminar Ruben Eckermann 5-7-6-3 Tigliane ring system

24

Meghan A. Flynn, Sarah E. Reisman, Timo V. Ovaska, No. 1, 115 - 117

OHMe

Me Me

MeMe

Me

(+) - 3-carene (53) 54

10 mol% MeLiPh2O, 185°C, 1h

76%

OH

H

MeMe

Me

55

tandem 5-exo-dig cyclization / Claisen rearrangement

HO

H

MeMe

Me

Phorbol (56)

HO OH

OH

H

OH

O

Gaich-‐Group Seminar Ruben Eckermann Cyathane Diterpenes

25

Francis Gosselin, Michael A. Brodney, F. Christopher Bi, Paul A. Wender, No. 13, 2105 - 2108

(S) - (-) - Limonene (57)

OH

MeO

Me

58

5 mol% [Rh(CO)2Cl]2DCE, 80°C, 3.5h

90%

O

Me

HO

Me

H

59

Intramolecular [5+2] - cycloaddition Me

(+) - Allocyathin B2 (60)CHO

MeOH

Gaich-‐Group Seminar Ruben Eckermann Pinnaic acid core

26

Alexandre F. T. Yokochi, Eric A. Korf, Paul R. Blakemore, James D. White, No. 3, 413 - 415

HN

H

H

Pinnaic Acid (64)

HO2C

Me

OHClHO

Nitrone formation Dipolar [3+2] cycloaddition

O

OO

O

N3

1) PPh3, THF, Δ pMeOC6H4CHO2) mCPBA, CH2Cl2 -78°C to rt

3) pTsOH*H2O, Δ MeOH/H2O (5:1)

55%

N+-OO

6162

PhMe, reflux

64%N

OO

O H

H H

63

O

Gaich-‐Group Seminar Ruben Eckermann FR901483 core

27

Jun-Ho Maeng, Raymond L. Funk, No. 8, 1125 - 1128

O O

N

Me Me

OOMe

OMe

OTIPS1) 2eq

benzonitrile120 °C, 16h

64%

TIPSO

N

OO

OMeMeO 2) KOtBu (EtOAc/THF)3) TFA, H2O (1:1)

79% N

O

HO

O

65 66 67

Acrolein synthone for Diels Alder Two sequential Aldol caclizations

N

FR901483 (68)

OPO

HOHO

OH

MeO

NH


28

Total Synthesis

Methodologies

Gaich-‐Group Seminar Ruben Eckermann Semipinacol rearrangements

29

Michael D. B. Fenster, Brian O. Patrick, Gregory R. Dake, No. 13, 2109 - 2112

NTs

TBSOOH

CSA, CHCl345°C, 13h

81% NTs

OTBSO

NTs

OTBSO+

2.8 : 169 70 71

NTs

TBSOOTMS

1) DMDO2) TiCl4, -78°C CH2Cl2, 0.5h

94% NTs

OTBSOOH

72 73

Gaich-‐Group Seminar Ruben Eckermann Homologated Allylic alcohols

30

Elizabeth Kinchin, Andrew Cridland, Lilian Alcaraz, No. 25, 4051 - 4053

O44

S

THF, -10°C to rt88%

44HO

74 75

BocN

O S


BocNOH

76 77

O

O

O S


O

O

OH

78 79

OTBS

O

S


OTBSOH

80 81

Gaich-‐Group Seminar Ruben Eckermann Vinylogous Mukaiyama Aldol

31

Jorma Hassfeld, Mathias Christmann, Markus Kalesse, No. 22, 3561 - 3564

O

HCO2Me

OH

Me

OMe

OTBS

B(C6H5)3, Et2OiPrOH, -78°C

84%82 83

H

O

Me

OTBS

Me

OTBSMeO2C

OH

Me

OMe

OTBS


67%84 85

H

O

Me Me

OO

OMe

OTBS


50% Me Me

OO

MeO2C

Me

OH

86 87

Gaich-‐Group Seminar Ruben Eckermann LA – catalyzed [4 + 3] - cyclizations

32

Ronald A. Aungst, Raymond L. Funk, No. 22, 3553 - 3555

O O

OTBSBu

PhMe110 °C, 3h

99%H

O

BuOTBS Me

EtAlCl2, CH2Cl2-78°C, 12h

O

TBSOBu

Me

88 89 9050%

endo / exo = 3:97

O O

OTBSBu

PhMe110 °C, 3h

99%H

O

BuOTBS

88 89


76%

O O

TBSOBu

91

O

endo / exo = 77:23

O O

OTBS


74%

O

TBSO

endo / exo = 79:2192 93

Gaich-‐Group Seminar Ruben Eckermann trans - Hydroisoquinolones

33

Asayuki Kamatani, Larry E. Overman, No. 8, 1229 - 1232

CbzHN

OTIPS (CH2O)nCs2CO3, THF

CbzN

OTIPS

HOCbzN

OH

H

MsCl, NEt3CH2Cl2

67%

98 99 100

CbzHN


CbzN

OTIPS

HOCbzN

OH

H

MsCl, NEt3CH2Cl2

76%

95 96 97

CbzHN


CbzN

OTIPS

HO

MsCl, NEt3CH2Cl2

76% CbzN

OH

H92 93 94

Gaich-‐Group Seminar Ruben Eckermann Allenes by (-) – Sparteine mediated lithiation

34

Carsten Schulz-Fademrecht, Birgit Wibbeling, Roland Fröhlich, Dieter Hoppe, No. 8, 1221 - 1224

OMe3Si

H H

N

O nBuLi, (-)-sparteinepentane, -78°C, 4h

OMe3Si

H Li

N

O

NNClTi(OiPr)3, -78°C10 min

OMe3Si

(PrOi)3Ti H

N

O

O

-78°C, 2hH

OCb

Me3Si

OH

101

102

103

10476%, >95% ee

Gaich-‐Group Seminar Ruben Eckermann Substituted Azulenes

35

John L. Kane, Kevin M. Shea, Aimee L. Crombie, Rick L. Danheiser, No. 7, 1081 - 1084

Br

ON2

0.5 mol% Rh2(OCOtBu)4CH2Cl2, rt, 45min

then Ac2O, DMAP, rt5min

72%

OAc

105 106

Br

ON2

1 mol% Rh2(OCOtBu)4, Et2Ort, 45min

then PhNTf2, DMAP, rt5min

42%OTf

5 mol% Pd(OAc)2, BEt3(o-biphenyl)PCy2, KFTHF, reflux, 20min

107 108 109

Gaich-‐Group Seminar Ruben Eckermann Q & A

36

Questions &

Answers

journal years in review: organic letters 2001, volume 3 · 1 ruben eckermann gaich-group seminar...

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