Cyclopropanes: A World of Wonders and Benefits New ... · 2R, CN, CH 2OR, CH 2Cl SiMe 3, CH 2SiMe...
Transcript of Cyclopropanes: A World of Wonders and Benefits New ... · 2R, CN, CH 2OR, CH 2Cl SiMe 3, CH 2SiMe...
Cyclopropanes: A World of Wonders and BenefitsNew Methodologies
Armin de Meijere
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen,Tammannstr. 2, 37077 Göttingen, Germany
e-mail: [email protected]://www.adm.chemie.uni-goettingen.de
Kassel, 8.05.2007
Organisch-Chemisches Institut, Universität Münster, 3. Juni 2009
1 Viktor Meyer (1876) doubts that they can exist at all.
2 August Freund (1882) and William Henry Perkin (1883–84) synthesize the first cyclopropanes.
3 Adolf von Baeyer (1885) rationalizes the enhanced reactivity of cyclopropaneson the basis of their inherent ring strain.
4 Since Ruzicka and Staudinger (1924) at the latest, every chemist knows that cyclopropanes exist in nature.
Small Rings
Small Rings
A. de Meijere et al. 1991–2005
Scientific curiosity, then and now
GDCh-Dia-1b
+NaOEt
Synthesis and ring opening: W. H. Perkin, Ber. dtsch. Chem. Ges. 1884, 17, 54–59.
"Strain theory": A. von Baeyer, Ber. dtsch. Chem. Ges. 1885, 18, 2269–2281.
EtOHBr
Br CO2Et
CO2Et CO2Et
CO2Et Br
CO2Et
CO2EtHBr
GDCh-Dia-2b
Old and New Natural Cyclopropane Derivates
CO2H
NH2
RCO2H
NH2
O
OH
OHIlludin SR = Me: norcoronamic acid
Inhibitors of the ethyleneforming enzyme
ACCPrecursor of the
phytohormone ethylene
N
O
H
NH
O2N
O
HNO
HNO
O HNO
HN
O ClNOH
NO2
ONH
NOO
Hormaomycin,a metabolite from
Streptomyces griseoflavuswith antimalerial activity
FR-900848, a fungicidal antibiotic
O
OH
OH
NHN
O
O
R = Et: coronamic acid a highly cytotoxicconstituent of Clitocybe illudens
N H
OU-106305
an inhibitor of the cholesteryl transfer protein
H2NCO2H
NH
OO
ONH
OBelactosin A, a potent proteasome inhibitor
Pyrethrin Ian insecticide
OO
O
RN H
N HN H
N HN H
N HOR'
OOOOOO
S. Abele, P. Seiler, D. Seebach, Helv. Chim. Acta 1999, 82, 1559.
S
N
CO2HO
N HR
O
NN
F
N
CO2HO
HN
F
N
F
F
CO2HO
N••
H2N
Trovafloxacin (PFIZER)a next generation
antiinfective
Ciprofloxacin (BAYER)a broad spectrum antiinfective
CIPROBAY ®
2.8 times more active thanAmpicillin (BEECHAM)
N. F. Osborne, J. Chem. Soc. Perkin Trans. I 1982, 1435.
To Model Nature or Even Surpass it
GDCh-Dia-3
[1] T. Liese, F. Seyed-Mahdavi, A. de Meijere, Org. Synth. 1990, 69, 148–153. [2] A. de Meijere, S. Teichmann, F. Seyed-Mahdavi, S. Kohlstruk, Liebigs Ann. 1996, 1989–2000.[3] A. de Meijere, S. I. Kozhushkov, T. Späth, Org. Synth. 2000, 78, 142–151. [4] A. de Meijere, S. I. Kozhuskov, D. Faber, V. Bagutskii, R. Boese, T. Haumann, R. Walsh, Eur. J. Org.
Chem. 2001, 3607–3614.For a review on strain energies in these compounds, see: A. de Meijere, S. I. Kozhushkov, A. F. Khlebnikov,
Top. Curr. Chem. 2000, 207, 89–147.
Reactive Small Ring Building Blocks for Various Applications
Krdia-340
CO2R
X
X = Cl,[1] F, OSiR3, SPh, N3,[2] NHZ
[3] [4]
SE = 41.7 kcal/mol SE = 77.4 kcal/mol SE = 74.6 kcal/mol
Methyl 2-Chloro-2-cyclopropylideneacetates from Tetrachlorocyclopropene and Alkenes
Review: A. de Meijere, S. I. Kozhushkov, L. P. Hadjiarapoglou, Topics Curr. Chem. 2000, 207, 149–227.
* Commercially available from Merck-Schuchardt** Preparation see: T. Liese, F. Jaekel, A. de Meijere, Org. Synth. 1990, 69, 144–147.
Krdia-277
Cl
ClCl
Cl
150–180 °C
ClCl
ClCl
Rm = H, alkyl, aryl, alkenyl, COR, CO2R, CN, CH2OR, CH2Cl SiMe3, CH2SiMe3, CH2OSiMe2But, OAc
R1
R4 R3
R2
60–80%(21–95%)
Cl
CO2MeR3
R4
R1
R2 ClCl
ClCl
1) NaOMe, MeOH110 °C, 1–3 d
2) H3O
up to 85%
Rn m
ClCl
ClCl CO2Me
Cl
* **Cl
ClCl
Cl
C2H4 (20 bar)C2Cl4, K2CO3
170 °C, 17 h
+
••
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 min
OMsMeO
O
X
NEt3, CH2Cl2,0 °C, 4 h
XO
MeO
X = Cl: 99%X = Br: 98%
X = Cl: 75%X = Br: 71%
83%
CO2MeOH Br
2 EtMgBrTi(OiPr)4
Ph3P Br2
Pyr., CH2Cl2
KOtBuDMSO
98% (crude) 78% 81%
90%
FVP350 °C
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.
ERC
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
Review:
Topics Curr. Chem.2000, 207, 89–147.
Bicyclopropylidene: A Highly Compact Multifunctional Building Block
Bcpdia-41
+ 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
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
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
YAcc1
YAcc2
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
A. de Meijere, H. Nüske, M. Es-Sayed, T. Labahn, M. Schroen, S. Bräse, Angew. Chem. Int. Ed. 1999, 38, 3669–3672.
Combination of Cross-Coupling, Diels-Alder Reactionand Cross-Coupling with a Combinatorial Potential
I
NN
N
N
NN
N
N
Et4NClPd(OAc)2, PPh3
CO2Me
MeOH, (H2 for cPent), 2–12 hTFA, Pd(OAc)2 or Pd/C
= Merrifield resin
K2CO3, DMF80 °C, 2 d
CO2Me
CO2Me
R
Nor
3-cyclopentenylcyclopentyl(E)-2-pyridylethen-2-yl
786755
R %
Pdc-092
I,
HE E
43%
I,
E E E
E
35 °C
60%
E E
70 °C
49%
87%
PdI
PdI
A
A
E
E
70 °C
A : Pd(OAc)2, PPh3, NEt3, DMF, 80 °C, 4 h.
E
E
H. Nüske, S. Bräse, S. I. Kozhushkov, M. Noltemeyer, M. Es-Sayed, A. de Meijere, Chem. Eur. J. 2002, 8, 2350–2369.
An Inter-Intermolecular Domino of Heck and Diels-Alder Reactions
Pdc-052
PDC-056
Pd(0)-Catalyzed [3+2] Cycloadditions with Alkenes
MeO2C CO2Me
CO2Me
CO2Me
130 °C, 2 h54%
Pd(dba)2
P(iPr)2(tBu)
CO2Me
PhCO2Me
110 °C, 3 h58%
110 °C, 3 h81%
MeMeO2C Me CO2Me
MeO2C Ph Ph
+
+
+
74% 26%
90% 10%
89% 11%
P. Binger, P. Wedemann, S. I. Kozhushkov, A. de Meijere, Eur. J. Org. Chem. 1998, 113–119.
A New Sequence for the Generation of Five-Seven-Ring Combinations
A: Pd(dba)2, P(iPr)2(tBu), toluene, 110 °C, 3 h. – B: 2-Butyne, [RhCl(PPh3)3], AgOTf, toluene, 110 °C, 3 h.
P. Binger, P. Wedemann, S. I. Kozhushkov, A. de Meijere, Eur. J. Org. Chem. 1998, 113–119.
PDC-059
E EE E
E
E+
A
83%
B
51%
E = CO2Et
An Unexpected [2+3+2]Cocyclization of Bicyclopropylidene with an 1,6-Enyne
PDC-200plt
EE
EE
E
E
Ni(cod)2 (10 mol%)PPh3 (20 mol%)
toluene, r. t.+
E = CO2Et
83%
not found
L. Zhao, A. de Meijere, Adv. Synth. Catal. 2006, 348, 2484–2492.
PDC-201plt
[2+3+2] Cocyclizations of Bicyclopropylidene with Terminal Alkynes
L. Zhao, A. de Meijere, Adv. Synth. Catal. 2006, 348, 2484–2492.
2 ×
PPh3Ni
PPh3 PPh3NiPPh3
R
PPh3Ni
PPh3R
PPh3
Ni PPh3R
Ni(cod)2PPh3
toluener. t.
R R
R
tBuMe3SiCpr(Me)CprPhnBuHOEtCO2MeCH2OH 25
85777656592879293
Product (%)
PDC-199
Yet another [2+2+2]Cocyclization of Bicyclopropylidene and Internal Alkynes
R
R
+Ni(cod)2, PPh3
C6H6, r. t.
R
RNiL2
CH2OMePhCprR %
362573
L. Zhao, D. Frank, A. de Meijere 2006
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%
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
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
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-067
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%
O
CO2Me
N
E
+
O
MeO2C
N
N
O
CO2Me
E,Pd(OAc)2,
NEt3, PPh3DMF, 80 °C, 24 h
Ar =C6H4-2-IAr
PhC6H4-2-OMeC6H4-4-BrC6H4-4-CNC6H4-2-ClC6H4-2-IC6H4-3-FC6H4-2-NO2
%
5069786679747638
25%
56%
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
N H
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
Ti(OiPr)4MgBr
R3
(iPrO)2Ti
R3
R3
(iPrO)2Ti
R3
R3
OR2
O
R1
MgBrR3
2
O(iPrO)2Ti
R1OR2
R3MgBr
R3
R3
R1 O(iPrO)2Ti
R3
R3
R1 OMgBr
2 iPrOMgBr
R3
R1 OH
H2O+
NR2 2
O
R1
MgBrR3
NR2 2
R1R3
R1
O
R3
(iPrO)2Ti
R3
Ti(OiPr)4,
?
Mechanistic Considerations of the Titanium-Mediated Cyclopropanation of Esters
The originalKulinkovich protocol:[*]
[*] O. G. Kulinkovich, S. V. Sviridov,D. A. Vasilevski, Synthesis 1991, 234.
Our adaption:[**]
[**] V. Chaplinski, A. de Meijere,Angew. Chem. Int. Ed. Engl. 1996, 35, 413–414.
Krdia-214n
NR2 2
O
R3MgBr
+Ti(OiPr)4
R3
R1
NR2 2
O(iPrO)2Ti
R3
R1
NR2 2
(iPrO)2Ti
R3
2 THF, –78
[(iPrO)2Ti=O]n
R3
(iPrO)2Ti
R3
NR2 2R1O
R1
NMe256%
NBn251%
ON
74%
N(iPr)276%
N(tBu)2
20%NBn2
69%
→ 20 °C
–
+–
A Versatile Synthesis of Cyclopropylamines
V. Chaplinski, A. de Meijere, Angew. Chem. Int. Ed. Engl. 1996, 35, 413–414. See also: Chem. & Engineering News "Science Concentrates" 19. Feb. 1996.
Krdia-057e
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 ®
The Patent Literature Lists 191 Pharmacologically RelevantCompounds with Cyclopropylamine Moieties
Krdia-163
R1 NR2 2
O
R3MgBr
+
MeTi(OiPr)3
R3
R1
NR2 2(iPrO)2Ti
R3
THF
CH4
R1 R2 R3 %
51 (38)a
86
Me
VinBn
BnEt
H
a Yield with Ti(OiPr)4r. t.
NBn2NBn2 NBn2
2c2b 2d
cdef
H
H
Bn
Bn
Me
H
89
95
E/Z
1.1:16.5:1
1 2 ba
Et Bn H 7077HBnMe
V. Chaplinski, A. de Meijere, Angew. Chem. Int. Ed. Engl. 1996, 35, 413–414.
Modified Reagent and Conditions for the Cyclopropanation of Dialkylamides
Krdia-070
NBn2R
O1.2 eq MeTi(OiPr)3
2.0 eq EtMgBr
r. t. NBn2R
H NBn2O
NBn2 NBn2
NBn2
O
NBn2
NBn2
O
NBn2
NBn2
O
H
NBn2
O
NBn2
NBn2
O
NBn2
NBn2
O
NBn2
Amide Cyclopropylamine Yield (%)
>95
77
70
62
44
25
52
Harald Winsel, Markus Kordes 1997–98
Influence of the Substituent on the Carbonyl Group I
Krdia-206
NBn2R
O1.2 eq MeTi(OiPr)3
2.0 eq EtMgBr
r. t. NBn2R
H NBn2
NBn2
NBn2
NBn2
NBn2
NBn2
Cyclopropylamine Yield (%)
>95
77
70
62
44
25
Cyclopropylamine Yield (%)
47
63
<10
49
48
38
NBn2Cl
NBn2Ph
NBn2BnO
NBn2Cl
NBn2Ph
NBn2BnO
NBn2
+
3 : 1
Influence of the Substituent on the Carbonyl Group
Harald Winsel, Markus Kordes 1997–98 Krdia-206a
Grignard Reagent Cyclopropylamine Yield (%)
79
81
86
DiastereomericRatio
MgBr
MgBr
MgBr
MgBr
1 : 6.0
1 : 1.6
NMe2(MeO)2PO
NMe2(MeO)2POO 1.2 eq MeTi(OiPr)3
r. t.
MgBr2.0 eq R
R
NMe2(MeO)2PO
NMe2(MeO)2PO
NMe2(MeO)2PO
NMe2(MeO)2PO 82 1 : 1.4
R
H
Me
Vin
Ph
Versatility of the Method
H. Winsel, V. Gazizova, O. Kulinkovich, V. Pavlov, A. de Meijere, Synlett 1999, 1999–2003.Krdia-211
Reductive Cyclopropanation of Lactames
Krdia-273
O
N N + MeNHOH
EtEtMeTi(OiPr)4 (1 equiv.)EtMgBr (1.1 equiv.)
THF, 24 h
O
NBn
NBn
BnNH
OHEt
Et+
Ti(OiPr)4 (1 equiv.)EtMgBr (2 equiv.)
THF, r. t., 24 h
A. de Meijere et al. Synlett, 1997, 111–114.
O
N
Ph O
O
N
Ph
N NO
as above
EtMgBr,Ti(OiPr)4
THF, r. t., 15 h
52%
Cotinin
28% 56%
47% 3%
77%
N N
B. Stecker, M. Es-Sayed, A. de Meijere 2000
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-166a
NPG + +NBn2
HO MeTi(OiPr)3
THF
Et2OTi(OiPr)4 + MeMgCl
(3 Ti(OiPr)4 + TiCl4) + MeLi
cHexMgBr (2.5 equiv.)THF/Et2O0 → –5 °C, 50 minreflux, 15 minor r. t. 8 h
•NBn2N
•PG
•NH2N
•Boc
•NH2HN
•
•NBn2HN
•
N N 4.28 Å(X-ray)
93% (cryst.)
98%
98%
PG = Bn:PG = Boc: 90%
87% CF3CO2H, r. t.polym. base
PG = Boc
PG = Boc
PG = Bn
H2, Pd/C (1.7 mol%)MeOH, HOAc (5%)
H2, Pd/C (3 mol%)MeOH
Krdia-166b
A. de Meijere et al. Chem. Eur. J. 2002, 8, 3789–3801.
A Simple Access to exo-6-Amino-3-azabicyclo[3.1.0]hexane – The Mechanism
+ MeTi(OiPr)3 Ti(OiPr)2MgBr
NPG
Ti(OiPr)2NPG •NR2NPG
•
CH4
NR2
HO
up to 90%PG = Bn, Boc
N
HO
OtBu
O
Boc
1) PPh3, DIAD, MeI
2) DBU, C7H8, 85 °C, 8 h NOtBu
O
Boc
H NBn2
O
N
••
NBn2
Boc
MeTi(OiPr)3c-C6H11MgBrTHF, 17 h
OtBu
O
••O
N
R3O
N H
HNR1
ON H
HNO
R2
HN
THF, 0 °C → RT, 17 h
69% 49–51%+regioisomer
Easy Access to 3,4-(Aminohomo)proline as a BuildingBlock for New Hair-Pin Peptidomimetics
Farina Brackmann, Armin de Meijere 2003–05
N N4.25 Å
Krdia-398
Coworkers
Collaborations
Financial SupportGeorg-August-Universität Göttingen Studienstiftung des Deutschen Volkes(State of Niedersachsen) Alexander-von-Humboldt StiftungVolkswagen-Stiftung Deutscher Akademischer AustauschdienstDeutsche Forschungsgemeinschaft European UnionFonds der Chemischen Industrie
Bicyclopropylidenes andTriangulanes
Thomas Späth Baris YucelStefan Bräse Rafael R. KostikovHanno Nüske Alexander F. KhlebnikovRene Scheurich Sergei I. KozhushkovLars Arve
Pentacyclopropyl-cyclopentadiene
Ingo EmmeStefan Redlich
Vladimir Chaplinski Andrei SavchenkoAlexandre Kourdjoukov Björn SteckerSergei Sviridov Stefan WiedemannMarkus Kordes Christian StratmannCraig M. Williams Oleg LarionovHarald Winsel Boris Zlatopolski
CyclopropylaminesAnd More
Chemistry Computations X-ray Crystal StructuresMazen Es-Sayed, BAYER AG Peter R. Schreiner, Gießen Roland Boese, Essen Hans-Ulrich Siehl, Ulm Dimitri S. Yufit, DurhamIlan Marek, Haifa George Sheldrick, GöttingenAxel Zeeck, Göttingen Jörg Magull, GöttingenStefan Bräse, KarlsruheKazutoshi Miyazawa, Chisso Corp.
Coworker