9th Florida Heterocyclic and Synthetic ConferenceGainesville March 9 -12, 2008

New Routes to Versatile Heterocycles from Small Ring Compounds*

Armin de Meijere

Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany

e-mail: Armin.deMeijere@chemie.uni-goettingen.dehttp://www.adm.chemie.uni-goettingen.de

Workshop Siena 2008

* For recent reviews and publications see: A. de Meijere, A. F. Khlebnikov, S. I. Kozhushkov, R. R. Kostikov, P. R. Schreiner, A. Wittkopp, C.Rinderspacher, D. S. Yufit, J. A. K. Howard, Chem. Eur. J. 2002, 8, 828–842; A. de Meijere, S. I. Kozhushkov, A. I. Savchenko, J. Organomet. Chem. 2004, 689, 2033–2055.O. V. Larionov, A. de Meijere, Org. Lett. 2004, 6, 2153–2156.M. Limbach, S. Dalai, A. de Meijere, Adv. Synth. Catal. 2004, 346, 760–766.V. Belov, M. Brands, S. Raddatz, J. Krüger, S. Nikolskaya, A. de Meijere, Tetrahedron 2004, 60, 7579–7589.B. D. Zlatopolskiy, A. de Meijere, Chem. Eur. J. 2004, 10, 4718–4727.

A. de Meijere et al.[1] Adv. Synth. Catal. 2004, 346, 760. – [2] Org. Synth. 1990, 69, 148–153. – [3] Unpublished results. – [4] Eur. J. Org. Chem. 2007, 4479. – [5] Org. Synth. 2000, 78, 142. – [6] Eur. J. Org. Chem. 2001,3607. – [7] Synthesis 1993, 998. – [8] Eur. J. Org. Chem. 2003, 869.

Reactive Small Ring Building Blocks for Various Heterocycles

Krdia-340-a

CO2R

X

X = H[1], Cl,[1,2] Br,[2]

NHZ[3][5][4]

SE = 41.7 kcal/mol SE = 77.4 kcal/mol

SE = 74.6 kcal/mol

NO2

tBuO2C[8][7]

OBn

SE = ∼42 kcal/mol

[6]

Review:

Topics Curr. Chem.2000, 207, 89–147.

CO2H

NH2

NH3+Cl–

HO2C

tBuP

tBu

Co

NH

COOEt

PhPh

X

Y X, Y = CO2Et

R2O2C R1

ER

R

E

H

O

R

( )

OHO

RN

n

X

R

O

Ar

ER

N=CPh2

Bicyclopropylidene: A Highly Compact Multifunctional Building Block

Bcpdia-41

Bcpdia-13b

Versatile New Synthesis of Bicyclopropylideneand Methylenespiropentane

A. de Meijere, S. I. Kozhushkov, T. Späth, N. S. Zefirov J. Org. Chem. 1993, 58, 502–505.

A. de Meijere, S. I. Kozhushkov, T. Späth, Org. Synth. 2000, 78, 142–151.

A. de Meijere, S. I. Kozhuskov, D. Faber, V. Bagutskii, R. Boese, T. Haumann, R. Walsh, Eur. J. Org. Chem. 2001, 3607–3614.

Bcpdia-13b

R CO2Me2 EtMgBrTi(OiPr)4 HO

R

O. G. Kulinkovich et al. Synthesis 1991, 234.

CO2MeOH Br

2 EtMgBrTi(OiPr)4

Ph3P Br2Pyr., CH2Cl2

KOtBuDMSO

98% (crude) 78% 81%

90%

FVP350 °C

ERC

Domino Heck-Diels-Alder Reactions of Bicyclopropylidene with Aryl Iodides and Dienophiles

H. Nüske, S. Bräse, S. I. Kozhushkov, A. de Meijere, Chem. Eur. J. 2002, 8, 2350–2369. Pdc-053a

+ ArI +R1

R2

PPh3 (15 mol%)Pd(OAc)2 (5 mol%)

MeCN, Et4NCl, K2CO3

80 °C, 20 h

Ar R1

R2

ArPhPhPh

4-Tol4-Pyr4-Pyr CO2Me

HCO2MeCO2Me

HHR1 R2

CO2MeCO2tBuCO2MeCO2MeCO2tBuCO2Me

%100

8797998160

Ar

PdIAr

PdI

Ar

The Combinatorial Potential of the New Three-Component Reaction

H. Nüske, S. Bräse, S. I. Kozhushkov, A. de Meijere, Chem. Eur. J. 2002, 8, 2350–2369.

Pdc-089

I

XY Acc2

YAcc1

+ +PPh3, Bu4NClPd(OAc)2

K2CO3, MeCN80 °C, 2 d

X

Y Acc1

Y Acc2

CO2Me

MeO

CONHtBu

Cl Cl

NPh

O

O

N

Cl

NMeN

O

O

MeO

CO2Me

NO2

N

CO2Me

(92%) (53%) (23%)

(81%)(40%)(55%)

Examples of Biologically Active Biaryls

PDC-187

NNHN N

OH3C

O

CO2H

CH3H3C

N

O

O

NCH3

H3C

NHON

H

HNN

O

O

CH3

N CH3

OH3C

O

CH3H3C

SCF3

X

N

R2

R1

Antihypertensive Drug Gram-positive and Gram-negative inhibitor

Histamine H3 Receptor Antagonist LFA-1/CAM-1 antagonist Non-steroidal Anti-inflammatory DrugAntiarthritic

O

Nitrone Cycloadditions to Methylenecyclopropane and Bicyclopropylidene

A. Brandi, A. Goti, S. Kozhushkov, A. de Meijere, J. Chem. Soc. Chem. Commun. 1994, 2185.C. Zorn, B. Anichini, A. Goti, A. Brandi, S. I. Kozhushkov, A. de Meijere, L. Citti, J. Org. Chem. 1999, 64, 7846–7855.

Bcp-006

R2 O–N+

R1

+ON

R2

R1

NR2

R1 O

Me O–N+

Ph+

ONMe

Ph

NMe

Ph O60 °CC6H6

110 °CC6H5Me

63%93%

N+ +O–

80%ON

76%N

O

Review: A. Brandi et al. Synlett 1993, 1.

69–86% 50–60%

65–90%+ regioisomer

35–10%

1,3-Dipolar Cycloadditions onto Bicyclopropylidene

B. Anichini, A. Goti, A. Brandi, S. I. Kozhushkov, A. de Meijere, Synlett 1997, 25–26.

Bcp-029

N

H OtBuO

tBuO

NO

xylenes120 °C, 10 h

tBuO

NO

xylenes120 °C, 10 h

OtBu

N

H OtBuO

OtBu

ON NO • • N

••

O

66% 61%

C. Zorn, B. Anichini, A. Goti, A. Brandi, S. I. Kozhushkov, A. de Meijere, L. Citti, J. Org. Chem. 1999, 64, 7846–7855. Krdia-358

Aza Analogues of Illudins and Ptaquiloside and Their DNA-Cleaving Activity

Krdia-358

N

tBuO

O–+ O N

H OtBu

N

H OtBuO

N

H OHO

N

O

N

O

N

O

MeOOMe

N

ONH

ON

O

N

OOH

N

OOH

OHN

OOH

HOH3C

CH3 OH

CH2RCH3

O

O

CH3

OH

CH3HO

Illudin S (R = OH)Illudin M (R = H)

CH3

+

C6H660 °C, 2 d

80%

C6H4Me2120 °C, 8 h

TFA,25 °C, 2 h

84%80%d. e. >95% [α]D25 +97.8

(c 0.50, MeOH)

++ – + ++

– ++

+ –

Aglycon of ptaquiloside

Krdia-440

1,3-Dipolar Cycloadditions of Nitrones to Methylenecyclopropanes and Possible Subsequent Transformations

For n = 0 see: F. M. Cordero, F. Pisaneschi, A. Goti, J. Ollivier, J. Salaün, A. Brandi, J. Am. Chem. Soc. 2000, 122, 8075–8076.

n = 0, 1

ON

R1

R2

n+ –

+R1

R2 NO

n = 0, 1

n

n

OR2N

R1

n = 0, 1

Δ, H+

NR2

OH

OR1

H

n = 1

Spirocyclopropanated β-Lactams from Nitrones and Bicyclopropylidene

Krdia-441

A. Zanobini, M. Gensini, J. Magull, S. I. Kozhushkov, A. de Meijere, A. Brandi, Eur. J. Org. Chem. 2004, 4158–4166.

ON

R1

R2+ –

R1

R2 NO

1OR2

N

R1C6H6, 20–60 °C

2–36 d71–100%

MeCN, TFA

70 °C, 0.5–12 h75–96%

PMB = p-methoxybenzyl

1abcdef

R1

CO2MePhCNCNPh2-Py

BnBnBnPMBMeMe

R2 2abcdef

%

1009594

1009371

3abcdef

%

787575949696

2 3

One-Pot Synthesis of Spirocyclopropanated β-Lactams –A New Three-Component Reaction

A. Zanobini, A. Brandi, A. de Meijere, Eur. J. Org. Chem. 2006, 1251–1255.

Krdia-444

+RNHOH • HCl

+CH2O (aq.)

NaOAc, EtOH100 °C (MW)

1 hN

R O

R

Bnp-MeOBn

CHPh2

%

685349

+

R1NHOH • HCl+

HOR2

O

O

NaOAc (2 equiv.)EtOH, 80 °C

(MW), 15–105 min NR1 O

EtOO

2 equiv. each

1 equiv.

R1

BntBuPMB

R2

EtEtMe

%

725378

A. Zanobini, M. Gensini, J. Magull, S. I. Kozhushkov, A. de Meijere, A. Brandi, Eur. J. Org. Chem. 2004, 4158–4166.

Krdia-443

Dipeptides from Spirocyclopropanated N-Acyl-β-lactams 4

NR3 NOtBu

OR1

H

O

H O

ONR1

R3 O(or 7)

DMF, 60 or 152 °C

tBuO2C NH2·HCl7·HCl (R4 = H) or

4b, 6

ONMeO2C

O

4a

DMF, 152 °C, 20 h

tBuO2C NH27

51%

O

N ON

OtBuO

HO

8

10–12

R4

R4

12–70 h

Starting Material4b66

R1

PhCNCN

PhOtBuOtBu

R3 R4

HHBn

%

6184

Product

101112

9·HCl (R4 = Bn), NEt3

81[a]

[a] Diasteromeric ratio 1:1.1

Krdia-522

Functionally Substituted 5-Azaspiro[2.3]hexanes by [2+2]Cycloadditions

OBn R

TsN+

A: MeCN, 80 °C

B: EtOAc, [Ag(fod)](10 mol%), 30 °C R

OBn

NTs

R

Php-MeOC6H4p-CF3C6H4t-BuPhCO2Et B

BAAAA

Cond. t [h]

4046

6613742 45

9480918297

Yield (%) cis/trans

51:124:118:129:1

135:135:1

Ph

OBn

NTs Ph

OBn

NTs

MeCN, 80 °C

quant.

(2.1 kcal/mol) cis/trans 50:1(0 kcal/mol)

+ NTs

PhOBnn. r.

A or B

I. Nakamura, T. Nemoto, A. de Meijere, Y. Yamamoto, Angew. Chem. Int. Ed. 2006, 45, 5176–5179.

A. de Meijere et al.[1] Adv. Synth. Catal. 2004, 346, 760. – [2] Org. Synth. 1990, 69, 148–153. – [3] Unpublished results. – [4] Eur. J. Org. Chem. 2007, 4479. – [5] Org. Synth. 2000, 78, 142. – [6] Eur. J. Org. Chem. 2001,3607. – [7] Synthesis 1993, 998. – [8] Eur. J. Org. Chem. 2003, 869.

Reactive Small Ring Building Blocks for Various Heterocycles

Krdia-340-a

CO2R

X

X = H[1], Cl,[1,2] Br,[2]

NHZ[3][5][4]

SE = 41.7 kcal/mol SE = 77.4 kcal/mol

SE = 74.6 kcal/mol

NO2

tBuO2C[8][7]

OBn

SE = ∼42 kcal/mol

[6]

Krdia-412

A: SOCl2, NCS, cat. conc. HCl, 1,2-DCE, 85 °C, 15 h; B: SOCl2, NBS, cat. conc. HBr, 1,2-DCE, 85 °C, 15 h.

Advanced Syntheses of Cyclopropylideneacetates – Versatile Multifunctional Building Blocks for Organic Synthesis

M. Limbach, S. Dalai, A. de Meijere, Adv. Synth. Catal. 2004, 346, 760–766.

OMe

O

MeO

MeOEtMgBr (2.5 equiv.),

Ti(OiPr)4 (0.2 equiv.),Et2O, 0 → 20 °C, 12 h

OHMeO

1) MsCl, Py, CH2Cl2, 20 °C, 15 h2) cat. conc. HCl, H2O2, THF/H2O

(2:1), 60 °C, 8 h

MeO

96% 74%

OMsHO

OBnOH, cat.pTsOH, toluene60 °C, 6 h

OMsBnO

O KOtBu, tBuOMe,0 → 20 °C, 18 h

97%H

O

BnO

1) A or B2) MeOH,

85 °C, 30 minOMsMeO

O

X

NEt3, CH2Cl2,0 °C, 4 h

XO

MeO

X = Cl: 99%X = Br: 98%

X = Cl: 75%X = Br: 71%

83%

Two Possibilities to Obtain Heterocycles from 2-Chloro-2-cyclo-propylideneacetates and a Bisnucleophile

A. de Meijere, I. D. Kuchuk, V. V. Sokolov, T. Labahn, K. Rauch, M. Es-Sayed, T. Krämer,Eur. J. Org. Chem. 2003, 985–997.

Krdia-346

CO2R

¯Y

HZ+

Y

Z¯

Y

RO2C ZO

Y

Cl Z

Cl Cl CO2R

A. de Meijere, S. Teichmann, D. Yu, J. Kopf, M. Oly, N. von Thienen, Tetrahedron 1989, 45, 2957–2968; Tetrahedron–Symposia–in–Print Number 38.

Various Spirocyclopropanated Heterocycles from 2-Chloro-2-cyclo-propylideneacetate and Bisnucleophiles

Krdia-347

N

SN

S

MeO2CH

HCl

OO

O

MeO2C

S

SMeO2C

N

O

MeO2CH

N

S

MeO2CH

OH

OH, KOH

SH

NH2

KOH, PTCH3NSH

ClKOH, PTC

H3NSH

ClK2CO3, PTC

HS SHKOH, PTC

Cl CO2MeOH

NH2, K2CO3

PTC = dibenzo-[18]-crown-[6]

48%

43%42% 40%

PTC

42%

PTC46%

Run in two-phase solventSystem CH2Cl2/H2O

M. W. Nötzel, M. Tamm, T. Labahn, M. Noltemeyer, M. Es-Sayed, A. de Meijere, J. Org. Chem. 2000, 65, 3850–3852.

2-Chlorocyclopropylideneacetate Reacting with Aroylamides

Krdia-067a

CO2Me

Cl+ H2N Ar

ODMF, –10 → 20 °C1 eq NaH

24 h O

CO2Me

N Ar NPh

CO2MeOH

H O2) 5 M NaOH, PhCOCl1) 1 N HCl, 100 °C

Ar = Ph, 66%

Ar

PhC6H4-2-OMeC6H4-4-BrC6H4-4-CNC6H4-2-ClC6H4-2-IC6H4-3-FC6H4-2-NO2

%

5069786679747638

A Taxol® Analog with a Cyclopropanated Side Chain I

Keys: a. DCC, 4-PP, toluene, RT, 24 h, 85%; b. HF-pyridine, THF, 0 °C to RT, 24 h, 90%; c. 0.1 N HCl, 1,4-dioxane (1:1), 50 °C, 1 h, 85%; d. 0.1 N NaHCO3, 1,4-dioxane (1:1), RT, 6 h, 80%.C. Liu, M. Tamm, M. W. Nötzel, A. de Meijere, J. K. Schilling, D. G. I. Kingston, Tetrahedron Lett. 2003, 44, 2049–2052.

OHOHO

HOAc

OTESOAcO

O

PhO

O

N

Ph OH

O+

OHO OAc

OTESOAcO

OO

PhO

NO

Ph

OO

HO OAc

OAcO

OO

PhO

ONHPh

O

OH

YX

OHO OAc

OTESOAcO

OO

PhO

NO

Ph

OO

HO OAc

OAcO

OO

PhO

ONHPh

O

OH

YX

a

6a-16a-2 X = H, Y = OH

X = OH, Y = H

b, c, d

b, c, d

+

6b-16b-2

X = OH, Y = HX = H, Y = OH

Krdia-394

M. W. Nötzel, T. Labahn, M. Es-Sayed, A. de Meijere, Eur. J. Org. Chem. 2001, 3025–3030.

Thiazoline-4-carboxylates and Cysteine Derivatives Incorporating Cyclopropyl Groups

Krdia-342

CO2Me

ClR1 +

R2 NH2

S S

N

R2

CO2Me

NaHCO3, MeCN80 °C, 2−5 h

SR2 NH

CO2MeCl

R1 R1

37–92%20 examples

R1

HHHHHMeMeEt

(CH2)2OBn

R2

PhMe4-Br-Ph4-MeOC6H4NMe2PhMeMeMe

Yield (%)

867385534951527877

D. R.

—————

1.2 : 11.9 : 1

1.7 : 1 : 11.1 : 1

S

N

Me

CO2Me

NH

SH

MeO2C

OSH

CO2HNH3Cl

3 N HClΔ, 3 h

H2OΔ, 5 h

89%93%

Cyclobutene-Annelated Pyrimidinones from 2-Chloro-2-cyclopropylideneacetates and Amidines

M. W. Nötzel, T. Labahn, K. Rauch, A. de Meijere, Org. Lett. 2002, 4, 839–841. Krdia-343

+HN NH2

R

N

NH

REt3N, dioxane25 °C, 2 d

CO2Me

N

CO2Me

N

R

CO2Me

N R

NH2

Cl NH2

R

–MeOH

O

NH2N

NH2R

CO2MeCl

CO2Me

Cl

Cl

R

HPhp-Me-PhNMe2NH2

Yield (%)

57847959–[a]

a Decomposition

Cyclobutene-Annelated Pyrimidinones as Heteroanalogues of Benzocyclobutenes

M. W. Nötzel, T. Labahn, K. Rauch, A. de Meijere, Org. Lett. 2002, 4, 839–841.

Krdia-344

R2 R3

R4R1

+170 °C,

8 hNH

N Ph

O

NH

N Ph

O

R3

R2

R4

R1NH

N Ph

O

R4

R1

R3

R2

+

R1

CO2MeCNCO2MeCO2MeCO2Me

R2

HHH

CO2MeH

R3

HH

CO2MeHPh

R4

HHHHH

Yield (%)78478473[a]

82[b]

Ratio2.4:1

2:1——2:1

[a] Mixture of cis- and trans-dicarboxylate in the ratio of 4.8:1. –[b] Pure trans-isomer.

N

NH

Ph

O

Krdia-511aS. Dalai, V. N. Belov, S. Nizamov, K. Rauch, D. Finsinger, A. de Meijere, Eur. J. Org. Chem. 2006, 2753–2765.

Access to 5,8-Dideaza-5,6,7,8-tetrahydrofolic Acid Analogues

OO

R

N

N

NH

N NH2

O

NH

N NH2

O

R

NNH

O OH

HN

O OH

R = H

O

N

NH

R

O

N

NH

R

PhO2S175 °C, 12 h

SO2PhHN(SiMe3)2R = Ph

N

N

Ph

OSiMe3

PhO2S

N

NH

Ph

PhO2SR1

O

N

NH

Ph

OR1

1) nBuLi, THF–78 °C

2) MeI or EtBr

1) KOtBu25 °C, 2 h

2) H2, Pd/CMeOH

R = Ph, 4-ClC6H42-Br-C6H4, 2-FC6H44-BnOC6H4, 2-Ph-C6H4, SMe

56–84%

99%

R1 = Me: 83%R1 = Et: 86% R1 = Et: 90%

R1 = Me: 92%O

NH

N NR2

PhO2S

NH2•HCl

R

HN

1) Et3N, dioxane25 °C, 2 d

CO2Me

Cl+

2) SO2Ph175 °C, 15 h O

N

NH

R

PhO2S

R = Ph: 43%R = 2-F-C6H4: 46%

O

NH

N NuH,180 °C, 12–15 h

O

NH

NSMe Nu

PhO2S PhO2S63–93%O

NH

N Nu

2) Pd/C, H2MeOH, 15 h

1) KOtBu, THF25 °C, 15 h

83–96%

Nu = NMe2,

NHBn,

Im-H,

ON

NMeN

NBnN

Nu = ON , NMeN

NHN

S. Dalai, V. N. Belov, S. Nizamov, K. Rauch, D. Finsinger, A. de Meijere, Eur. J. Org. Chem. 2006, 2753–2765.

Access to 5,8-Dideaza-5,6,7,8-tetrahydrofolic Acid Analogues

Krdia-512

Yet, Iminoimidazolinecarboxylates from N’,N’’,N’’’-Triarylguanidines

M. Nötzel, D. Frank, A. de Meijere, unpubl. resultsNötzel1

+

NaH,MeCN

0 → 25 °C,12 h

R1

N

MeO2CR1

N

NMeO2CR1

MeO2C Cl

NR2

HNR2

N

MeO2C Cl

NR2

HNR2

N

R2R2NH

NH

NR2

R2

R2

NR2

R2

R2

R2

NR2

NR2

MeO2C Cl

R1

NaO

OMe

R1

R1

Cl

OMeNaO

R1

NHR2R2N

(E) enolate

HA

NR2

NR2

HNR2

NR2

Cl

R1

HMeEtiPrH

R2

PhPhPhPh4-BrC6H4

%8383759550

Solving the Selectivity Problem

M. Limbach, V. Korotkov, A. de Meijere, unpubl. results Krdia-355

ClO

NHBocN

Conditions

N

N O

H

+N O

NHCl

O

O

MeO

O

MeO

ClO

MeO

1) H2N(CH2)3OBn, THF,0 → 25 °C, 8 h

2) Boc-Gly-OH, DCC, Py,THF, 0 → 25 °C, 12 h

88%

OBn

OBnOBn

3

33

Conditions

1) TFA, CH2Cl22) aqu. K2CO3, CH2Cl2

29 66

1) KOH, MeOH, 20 °C, 15 h2) conc. HCl, 20 °C, 2 h3) MeOH, NH3, 0 → 25 °C, 6 h4) MeOH, conc. H2SO4, 15 h 93

1) HCl, MeOH2) MeOH, NH3, 60 °C

89

% %

—

—

Versatile Access to Spirocyclopropanated Piperazinones

Krdia-431Krdia-431M. Limbach, V. Korotkov, A. de Meijere, unpubl. results

H2NR3, NEt3,MeOH, temp., time

ClO

MeO

R1

OBrN

O

MeO

R1

N O

R3N

R2

R2

1) H2NR1, THF, 0 → 20 °C2) BrCHR2COCl, aq. NaHCO3,

1,2-C2H4Cl2, 20 °CCl

O

MeO

62–99%21 examples

ClO

MeO

R1

OBrN

R2

O

MeO

R1

N O

R3N R2Cl

O

MeO

R1

O

NR2

NH

– R3

R1

p-CH2C6H4-Cl

p-CH2C6H4-OCF3

p-CH2C6H4-Cl

H

C6H5

H

87

62

99

R2 Yield (%)R3

p-CH2C6H4-Cl

p-CH2C6H4-Cl H

H

o-CH2C6H4-CF3

p-C6H4-OMe

(CH2)2-(3-indolyl)

p-CH2C6H4-NO2

CH(CH3)2

Temp. [°C ]

20

50

40

20

20

Time [h]

72

12

16

48

72

84

90

The Patent Literature Lists 191 Pharmacologically RelevantCompounds with Cyclopropylamine Moieties

Krdia-163

NN

F

N

CO2HO

N

F

N

F

F

CO2HO

Trovafloxacin (PFIZER)Ciprofloxacin (BAYER)CIPROBAY ®

Three examples are broad-spectrum antibiotics:

N••

H2NH

TROVAN ®

F

N

CO2HO

MeONN

H

Moxifloxacin (BAYER)AVALOX ®

Simple Access to 6-Amino-3-azabicyclo[3.1.0]hexane – A Bicyclic DiamineScaffold for Combinatorial Synthesis of Lead Compounds

A. de Meijere et al. Chem. Eur. J. 2002, 8, 3789–3801.

Krdia-166

+ MeTi(OiPr)3 (iPrO)2Ti

H NBn2

O

2.5MgBr

NBn

(iPrO)2Ti N Bn

•Bn2N N Bn•

H2, Pd C•H2N NH•

up to 87%

CH4

Ti(OiPr)4 + MeMgCl

NBoc•

H2N NBoc•

≥65% overall

By the same route

quant.

2 steps

N N 4.28 Å

krdia-485a

Convenient Access to 2-Arylpyrroles from 2-Lithio-N,N-dibenzylcyclopropylamine and Nitriles

C. Tanguy, P. Bertus, J. Szymoniak, O. V. Larionov, A. de Meijere, Synlett 2006, 2339–2341.

Bn2N

SnBu3

1) nBuLi, THF–30 °C, 1–2 h

2) RCN3) H2O or AcOH Bn2N

NLi

R H2O orAcOH

Bn2N R+ HN

–

NLiNH

H2O orAcOH

NH

RBn2NN RHO

– Bn2NH

AcOH

HNRO

– H2ORCN

PhCN4-ClC6H4CN2-FC6H4CN1-NaphthCN2-NaphthCN2-PyrCN1-AdCN

R in product

Ph4-ClC6H42-FC6H41-Naphth2-Naphth2-Pyr1-Ad

%

80607668785566

NH

R

Bn2N H

O

SnBu3

+

MeTi(OiPr)3cHexMgBr

90%

Formal Cycloaddition of Acceptor-Substituted Methyl Isocyanides (1) to Cyclopropylpropiolates

Krdia-478O. V. Larionov, A. de Meijere, Angew. Chem. 2005, 114, 5809–5813; Angew. Chem. Int. Ed. 2005, 44, 5664–5667.

R1NC

CO2R2

reagent orcatalyst

cond.+N

CO2R2

HR1

N

NCO2Me

MeO2CPhN

:C

O

1 2-R2 3 5

R1 in

4

1 and 3

CO2MeCO2MeCO2MeSO2Tol

PhPh

CO2MeCO2Me

R2 in2-R2

MeMeMeMeMetBuMeMe

Reagent orCatal. (equiv.)

DBU (1.0)Cu0 (0.1)

KOtBu (1.1)KOtBu (1.1)KOtBu (1.1)

CsOtBu (1.1)CuSPh (0.05)

Cu0 (0.05)

Solvent

THFDMFTHFTHFTHFTHFDMFDMF

Time[h]

2462222

1216

Temp.[°C]

7070202020208570

Product

3a-Me3a-Me3a-Me

3c-Me/53a-Me

3c-tBu/53a-Me3a-Me

Yield (%)(Ratio)

17519693

96 (5:95)91 (96:4)

9392

• •

2,3,4-Trisubstituted Pyrroles by Formal Cycloaddition of Acceptor-Substituted Methyl Isocyanides

Krdia-479O. V. Larionov, A. de Meijere, Angew. Chem. 2005, 114, 5809–5813; Angew. Chem. Int. Ed. 2005, 44, 5664–5667.

R1NC

R3

R4+

N

R4

HR1

R3

R3

cPrcPrMecPr

MeOCH2CF3

Ph

R4

CO2tBuCO2tBuCO2tBuCO2tBu

P(O)(OEt)2CO2Et

CO2Me

CO2Et

CO2Me

Yield (%)(base)[a]

R1

(cat., mol%)[b]

CO2MeSO2TolCO2tBu

CNCO2MeSO2Tol

CO2tBu

CO2tBu

CO2Me

97 (KOtBu)93 (KOtBu)76 (KOtBu)83 (KHMDS)53 (KOtBu)76 (KHMDS)

45 (KOtBu)

—

87 (KOtBu)

94 (CuSPh, 5)91 (CuSPh, 5)83 (ns Cu0, 5)

—47 (ns Cu0, 5)

—

—

78 (ns Cu0, 5)

91 (CuSPh, 5)

CO2Me

O N

[a] Method A: Addition of base (1.2 equiv.), 1 h, then 1 h at 20 °C, THF.[b] Method B: Cu catalyst (ns Cu0 stands for preactivated nanosize copper powder), DMF, 85 °C, 12 h.

• •

The Absolute Configuration of Hormaomycin

B. D. Zlatopolskiy, K. Loscha, S. I. Kozhushkov, P. Alvermann, S. V. Nikolaev, A. Zeeck, A. de Meijere, Chem. Eur. J. 2004, 10, 4708–4717.

Krdia-356

NH HN

O2N

NH HN

NO2

HN

ClN

HO

HNN

O OO

O

O

OO

O

O

A Productive Synthesis of Enantiomerically Pure 3-(2'-Nitrocyclopropyl)alanine

O. V. Larionov, T. F. Savel'eva, K. A. Kochetkov, N. S. Ikonnokov, S. I. Kozhushkov, D. S. Yufit, J. A. K. Howard, V. N.Khrustalev, Y. N. Belokon, A. de Meijere, Eur. J. Org. Chem. 2003, 869–877.

Krdia-393

(S)-7

1) rac-4 (1.05 equiv.)NaH (1.2 equiv.)

DMF/MeCN (1:2)–50→0 °C, 40–50 min

2) 60% aq. AcOH

6aO

NNi

N

N

O

O

H

NO2

6bO

NNi

N

N

O

O

H

NO2

+

Precipitate 44% (ratio 6a/6b = 85:15)From the mother liquor 41% (ratio 6a/6b = 25:75)

(S)-5O

NNi

N

N

O

OH

H

CH3NO2

Br

CO2tBuBr

+ OH1

2

CO2tBu

rac-3

NO2 NO2

I

rac-4

NO2K2CO3, DMSO35 °C, 24 h

addition of 1during 15 h, then

25 °C, 30 h59%

inverseaddition of

LiAlH4

Et2O–10 °C, 3 h

98%

I2, PPh3, Im-H

Et2O/MeCN(1.5:1)

93%

1) 6 N aq. HCl, MeOHreflux 7 min

2) DOWEXMonosphere 650Cin H+ form

6a

PhO

N

O

NHBn

HNO2H2N

CO2H(2S,1'R,2'S)-NCP

+Cl–

(S)-5recycle

+

Ring Closure of the Acyclic Precursor to the Hexapeptolide II

B. D. Zlatopolskiy, A. de Meijere, Chem. Eur. J. 2004, 10, 4718–4727.

Krdia-357b

DIEA = (iPr)2EtNHATU = N,N,N',N'-Tetramethyl-o-(7-azabenzotriazol-1-yl)-

uroniumhexafluorophosphate

NH HN

O2N

NH HN

NHMeZNOO

O

NH HN

O2N

NH HN

NHMeZO

1) 2 N HCl/EtOAc, RT, 45 min2) HATU, DIEA, collidine,

CH2Cl2, 0.10 mM,0 → 20 °C, 16 h

57%(after HPLC purification)MOMO

O

OO

O

O

O

O

O

O

O

NBoc

Boc(MeZ-6-peptide-OMOM) MeZ-cyclo-6-peptide

Completing the Target: Hormaomycin

Krdia-391

B. D. Zlatopolskiy, A. de Meijere, Chem. Eur. J. 2004, 10, 4718–4727.

NH HN

O2N

NH HN

NO2

HN

ClNRO

HNN

OOO

O

O

OO

O

ONH HN

O2N

NH HN

HNMeZN

OOO

OO

O

O

1) TFA/anisole, RT, 2 h2) Teoc-(2S)-(3-Ncp)AlaOH

HATU, HOAt, DIEA, collidineCH2Cl2, RT, 6 h

3) TFA, RT, 1 h4) (MOM)ChpaOH

HATU, HOAt, DIEA, collidineCH2Cl2, RT, 3.5 h

70%

(MOM)Chpa-(2S)-(3-Ncp)Ala-cyclo-6-peptide

MeZ-cyclo-6-peptide

R = MOM:

R = H: Hormaomycin

MgBr2•Et2O, EtSHCH2Cl2, RT, 3.5 h

73%

DIEA = (iPr)2EtNHOAt = 7-aza-1-hydroxybenzotriazoleHATU = N,N,N',N'-Tetramethyl-o-(7-azabenzotriazol-1-yl)-

uroniumhexafluorophosphate

U. M. Reinscheid, B. D. Zlatopolski, A. Zeeck, C. Griesinger, A. de Meijere, Chem. Eur. J. 2005, 11, 2929–2945.

The Structure of Hormaomycin in Solution

Krdia-356b

Krdia-450

U. M. Reinscheid, B. D. Zlatopolskiy, A. Zeeck, C. Griesinger, A. de Meijere, Chem. Eur. J. 2005, 11, 2929–2945.

Hormaomycin 1 and its aza-analogues 2a–c and epi-2a

NH HN

O2N

N N

HN

ClNHO

HN

Y

N

OOX

O

O

OO

O

O

X Y O MeNH

NH NMe NH

Me

12a

epi-2a2b2c

NO2

(β-Me)Phe I

(3-Ncp)Ala I

(β-Me)Phe II

Ile

(4-Pe)Pro

(3-Ncp)Ala II

Chpca

MeMe

RR

R

HHR

S

RR

R

S

S S

SR

S R

R

H

(R)-a-Ile instead of Ile

Hormaomycin Analogues with Fluoromethyl-Substituted Cyclopropylalanines

NH HN

FnH3–nC

N N

HN

ClN

HO

HNN

OO

OO

O

O

O

O

O

n

CFnH3–n

(β-Me)Phe I

(3-Fmcp)Ala I

(β-Me)Phe II

Ile

(4-Pe)Pro

(3-Fmcp)Ala II

Chpca

RS

R

HHR

S

RR

R

S

S S

SR

S S

R

Yield (%)

Overall yield after 16 stepsfrom Fmoc-Ile-OH

a-Thr2

17

3

15

V. Raev, A. de Meijere, unpubl. resultsKrdia-519

Natural and Nonnatural Members of the Belactosin Family of Proteasome Inhibitors

Krdia-413

H2NCO2H

NH

OO

ONH

O

Belactosin A

H2NNH

O CO2HNH O O

O

Belactosin C

H2NNH

O CO2H

NH

O

O

O

homo-Belactosin C

New Treatment Options Against Cancer, Inflammatory, and Autoimmune Diseases

Krdia-418

Synthesis of the Belactosin A Dipeptide Component

O. V. Larionov, A. de Meijere, Org. Lett. 2004, 6, 2153–2156.

H2N NO2

CO2H

H2N NH2

CO2H

H2, Pd/C, MeOH

98%

Eur. J. Org. Chem. 2003, 869. Mendeleev Comm. 2003, 199.

Boc2O, Na2CO36 N aq. KOH

BocHN NO2

CO2H

Zn, AcOHr. t., 3 h

BocHN NH2

CO2H

1) Fmoc-OSu2) Cbz-Cl, DMAP, DIEA

61% over 3 steps

BocHN NHFmoc

CO2Bn

1) TFA, Pr3SiH2) Cbz-Ala-OH

EDC, HOAt

3) Et2NH75% over 3 steps

CbzHNCO2Bn

NH

O

NH2

Final Assembly of the Belactosins

Krdia-417

O. V. Larionov, A. de Meijere, Org. Lett. 2004, 6, 2153–2156.

H2NCO2H

NH

OO

ONH

O

Belactosin A

CbzHNCO2Bn

NH

O

NH2

CbzHNCO2Bn

NH

OO

ONH

OHO

SPh

OOH

O

+

EDC, AtOH,TMP

H2, Pd/C

52% (2 steps)

Overall yield: 32% over 14 steps

Krdie-523

S. Redlich, A. de Meijere, unpublished results.

Percyclopropylated Heterocycles for Fun?

1) nBuLi, THF–78 °C

2) Br(CH2)3Cl

78%

Cl( )3 LDA, THF

–78 °C → r. t.

15 h

86%

HgO (2 mol%)H2SO4 (5 mol%)

H2O/Me2CO (1:2)100 °C, 16 h

96%

O

1) LDA, THF–78 °C → r. t., 1 h

2) CuCl2, –78 °C→ r. t., 16 h

88%O

H2NR, HCl (cat.)or

NH4OAcEtOH/CHCl365 °C, 24 h

NR

R

BncPrH 43

4837

%

O S

H2SO4 (cat.)toluene, 65 °C

P4S10CCl470 °C, 3 d

41%36%

Krdia-484

syn-Octacyclopropyltricyclo[4.2.0.02,5]octa-3,7-diene for Fun

A. de Meijere, S. Redlich, D. Frank et al. Angew. Chem. Int. Ed. 2007, 46, 4574 - 4576 2006.

1) Cp2ZrCl2 (0.5 equiv.),n-BuLi (1.0 equiv.),THF, –78 °C → r.t., 1 h

ZrCp2

ZrCp2

II

CuI

X

67%

2) I2 (1.0 equiv.),–78 °C → r.t, 1 h

3) CuCl (1.0 equiv.),r.t., 1 h

Krdia-483

Real Fun and Energy – Octacyclopropylcubane

Dedicated to Professor Philip E. Eaton on the occasion of his 70th birthday

For reviews on cubane and its derivatives see:1) P. E. Eaton, Angew. Chem. 1992, 104, 1447–1462.2) G. W. Griffin, A. P. Marchand, Chem. Rev. 1989, 89, 997–1010.

Dec. >250 °CStable towards AgBF4, [Rh(COD)Cl]2E1/2 (SCE) = 2.15 V (irrev.)For comparison cubane E1/2 (SCE) = 1.73 V

pentane, 20 °Chν

48%

Strain energy:390 kcal/mol

A. de Meijere, S. Redlich, D. Frank, J. Magull, A. Hofmeister, H. Menzel, B. König, J. Svoboda,Angew. Chem. Int. Ed. 2007, 46, 4574 - 4576.

CEN_2006Chemical & Engineering News / January 9, 2006

Coworkers

Collaborations

Financial SupportGeorg-August-Universität Göttingen Konrad-Adenauer-Stiftung(State of Niedersachsen) Studienstiftung des Deutschen VolkesDeutsche Forschungsgemeinschaft Hermann-Schlosser-StiftungFonds der Chemischen Industrie Alexander-von-Humboldt StiftungBayerCropScience Deutscher Akademischer Austauschdienst

Bicyclopropylidenes andTriangulanes

Thomas Späth Rene Scheurich Sergei I. KozhushkovStefan Bräse Lars Arve Ingo Emme Heiko SchillHanno Nüske Baris Yucel Stefan Redlich Daniel Frank

Natural Products and Analogues

Markus KordesBoris D. ZlatopolskiyOleg V. LarionovSergei I. Kozhushkov

Coworker_II

Prof. Peter R. Schreiner, GießenComputations

Prof. Axel Zeeck, Göttingen Prof. Jörg Magull, GöttingenDr. Mazen Es-Sayed, BAYER AGProf. George Sheldrick, GöttingenProf. Stefan Bräse, KarlsruheDr. Kazutoshi Miyazawa, Chisso Corp.Dr. Dimitri S. Yufit, Durham Dr. Uwe ReinscheidProf. Alexander F. KhlebnikovProf. Roland Boese, Essen Prof. Christian Griesinger, GöttingenProf. Rafael R. Kostikov X-ray Crystal Structures Chemistry

Small Ring Architectures

Altes_Institut

Institut