Cyclopropanes: A World of Wonders and Benefits New ... · 2R, CN, CH 2OR, CH 2Cl SiMe 3, CH 2SiMe...

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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: Armin.deMeijere@chemie.uni-goettingen.dehttp://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

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

CO2EtHBr

GDCh-Dia-2b

Old and New Natural Cyclopropane Derivates

OHIlludin SR = Me: norcoronamic acid

Inhibitors of the ethyleneforming enzyme

ACCPrecursor of the

phytohormone ethylene

O ClNOH

Hormaomycin,a metabolite from

Streptomyces griseoflavuswith antimalerial activity

FR-900848, a fungicidal antibiotic

R = Et: coronamic acid a highly cytotoxicconstituent of Clitocybe illudens

OU-106305

an inhibitor of the cholesteryl transfer protein

H2NCO2H

OBelactosin A, a potent proteasome inhibitor

Pyrethrin Ian insecticide

N HN H

N HOR'

OOOOOO

S. Abele, P. Seiler, D. Seebach, Helv. Chim. Acta 1999, 82, 1559.

N••

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

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

150–180 °C

Rm = H, alkyl, aryl, alkenyl, COR, CO2R, CN, CH2OR, CH2Cl SiMe3, CH2SiMe3, CH2OSiMe2But, OAc

60–80%(21–95%)

CO2MeR3

R2 ClCl

1) NaOMe, MeOH110 °C, 1–3 d

2) H3O

up to 85%

ClCl CO2Me

* **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.

MeOEtMgBr (2.5 equiv.),

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

1) MsCl, Py, CH2Cl2, 20 °C, 15 h2) cat. conc. HCl, H2O2, THF/H2O (2:1), 60 °C, 8 h

96% 74%

OBnOH, cat.pTsOH, toluene60 °C, 6 h

OMsBnO

O KOtBu, tBuOMe,0 → 20 °C, 18 h

1) A or B2) MeOH, 85 °C, 30 min

OMsMeO

NEt3, CH2Cl2,0 °C, 4 h

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

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

CO2MeOH Br

2 EtMgBrTi(OiPr)4

Ph3P Br2

Pyr., CH2Cl2

KOtBuDMSO

98% (crude) 78% 81%

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

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

NH3+Cl–

Y X, Y = CO2Et

R2O2C R1

N=CPh2

Review:

Topics Curr. Chem.2000, 207, 89–147.

Bicyclopropylidene: A Highly Compact Multifunctional Building Block

Bcpdia-41

+ ArI +R1

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

MeCN, Et4NCl, K2CO3 80 °C, 20 h

ArPhPhPh

4-Tol4-Pyr4-Pyr CO2Me

HCO2MeCO2Me

HHR1 R2

CO2MeCO2tBuCO2MeCO2MeCO2tBuCO2Me

8797998160

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

+ +PPh3, Bu4NClPd(OAc)2

K2CO3, MeCN80 °C, 2 d

CONHtBu

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

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

Examples of Biologically Active Biaryls

PDC-187

NNHN N

CH3H3C

NHON H

CH3H3C

Antihypertensive Drug Gram-positive and Gram-negative inhibitor

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

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

Et4NClPd(OAc)2, PPh3

MeOH, (H2 for cPent), 2–12 hTFA, Pd(OAc)2 or Pd/C

= Merrifield resin

K2CO3, DMF80 °C, 2 d

3-cyclopentenylcyclopentyl(E)-2-pyridylethen-2-yl

786755

Pdc-092

35 °C

70 °C

A : Pd(OAc)2, PPh3, NEt3, DMF, 80 °C, 4 h.

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

130 °C, 2 h54%

Pd(dba)2

P(iPr)2(tBu)

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 = CO2Et

An Unexpected [2+3+2]Cocyclization of Bicyclopropylidene with an 1,6-Enyne

PDC-200plt

Ni(cod)2 (10 mol%)PPh3 (20 mol%)

toluene, r. t.+

E = CO2Et

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.

PPh3Ni

PPh3 PPh3NiPPh3

PPh3Ni

Ni PPh3R

Ni(cod)2PPh3

toluener. t.

tBuMe3SiCpr(Me)CprPhnBuHOEtCO2MeCH2OH 25

85777656592879293

Product (%)

PDC-199

Yet another [2+2+2]Cocyclization of Bicyclopropylidene and Internal Alkynes

+Ni(cod)2, PPh3

C6H6, r. t.

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+

Me O–N+

Ph O60 °CC6H6

110 °CC6H5Me

63%93%

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

H OtBuO

xylenes120 °C, 10 h

H OtBuO

ON NO • • N

••

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

n+ –

n = 0, 1

Δ, H+

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.

R2+ –

R1C6H6, 20–60 °C

2–36 d71–100%

MeCN, TFA

70 °C, 0.5–12 h75–96%

PMB = p-methoxybenzyl

1abcdef

CO2MePhCNCNPh2-Py

BnBnBnPMBMeMe

R2 2abcdef

1009594

1009371

3abcdef

787575949696

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)

Bnp-MeOBn

685349

R1NHOH • HCl+

NaOAc (2 equiv.)EtOH, 80 °C

(MW), 15–105 min NR1 O

2 equiv. each

1 equiv.

BntBuPMB

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

R3 O(or 7)

DMF, 60 or 152 °C

tBuO2C NH2·HCl7·HCl (R4 = H) or

ONMeO2C

DMF, 152 °C, 20 h

tBuO2C NH27

10–12

12–70 h

Starting Material4b66

PhCNCN

PhOtBuOtBu

Product

101112

9·HCl (R4 = Bn), NEt3

[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

RO2C ZO

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

Cl+ H2N Ar

ODMF, –10 → 20 °C1 eq NaH

24 h O

N Ar NPh

CO2MeOH

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

Ar = Ph, 66%

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

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

ClR1 +

R2 NH2

NaHCO3, MeCN80 °C, 2−5 h

SR2 NH

CO2MeCl

37–92%20 examples

HHHHHMeMeEt

(CH2)2OBn

PhMe4-Br-Ph4-MeOC6H4NMe2PhMeMeMe

Yield (%)

867385534951527877

—————

1.2 : 11.9 : 1

1.7 : 1 : 11.1 : 1

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

REt3N, dioxane25 °C, 2 d

Cl NH2

–MeOH

CO2MeCl

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

+170 °C,

CO2MeCNCO2MeCO2MeCO2Me

CO2MeH

CO2MeHPh

Yield (%)78478473[a]

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.

Ti(OiPr)4MgBr

(iPrO)2Ti

MgBrR3

O(iPrO)2Ti

R3MgBr

R1 O(iPrO)2Ti

R1 OMgBr

2 iPrOMgBr

MgBrR3

(iPrO)2Ti

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

R3MgBr

+Ti(OiPr)4

O(iPrO)2Ti

(iPrO)2Ti

2 THF, –78

[(iPrO)2Ti=O]n

(iPrO)2Ti

NR2 2R1O

NMe256%

NBn251%

N(iPr)276%

N(tBu)2

20%NBn2

→ 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

Trovafloxacin (PFIZER)Ciprofloxacin (BAYER)CIPROBAY ®

Three examples are broad-spectrum antibiotics:

N••

TROVAN ®

Moxifloxacin (BAYER)AVALOX ®

The Patent Literature Lists 191 Pharmacologically RelevantCompounds with Cyclopropylamine Moieties

Krdia-163

R1 NR2 2

R3MgBr

MeTi(OiPr)3

NR2 2(iPrO)2Ti

R1 R2 R3 %

51 (38)a

a Yield with Ti(OiPr)4r. t.

NBn2NBn2 NBn2

2c2b 2d

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

O1.2 eq MeTi(OiPr)3

2.0 eq EtMgBr

r. t. NBn2R

H NBn2O

NBn2 NBn2

Amide Cyclopropylamine Yield (%)

Harald Winsel, Markus Kordes 1997–98

Influence of the Substituent on the Carbonyl Group I

Krdia-206

O1.2 eq MeTi(OiPr)3

2.0 eq EtMgBr

r. t. NBn2R

H NBn2

Cyclopropylamine Yield (%)

NBn2Cl

NBn2Ph

NBn2BnO

NBn2Cl

NBn2Ph

NBn2BnO

Influence of the Substituent on the Carbonyl Group

Harald Winsel, Markus Kordes 1997–98 Krdia-206a

Grignard Reagent Cyclopropylamine Yield (%)

DiastereomericRatio

1 : 6.0

1 : 1.6

NMe2(MeO)2PO

NMe2(MeO)2POO 1.2 eq MeTi(OiPr)3

MgBr2.0 eq R

NMe2(MeO)2PO

NMe2(MeO)2PO 82 1 : 1.4

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

N N + MeNHOH

EtEtMeTi(OiPr)4 (1 equiv.)EtMgBr (1.1 equiv.)

THF, 24 h

Ti(OiPr)4 (1 equiv.)EtMgBr (2 equiv.)

THF, r. t., 24 h

A. de Meijere et al. Synlett, 1997, 111–114.

as above

EtMgBr,Ti(OiPr)4

THF, r. t., 15 h

Cotinin

28% 56%

47% 3%

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

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

•NH2N

•Boc

•NH2HN

•NBn2HN

N N 4.28 Å(X-ray)

93% (cryst.)

PG = Bn:PG = Boc: 90%

87% CF3CO2H, r. t.polym. base

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

Ti(OiPr)2NPG •NR2NPG

up to 90%PG = Bn, Boc

1) PPh3, DIAD, MeI

2) DBU, C7H8, 85 °C, 8 h NOtBu

H NBn2

••

MeTi(OiPr)3c-C6H11MgBrTHF, 17 h

••O

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

Cyclopropanes: A World of Wonders and Benefits New ... · 2R, CN, CH 2OR, CH 2Cl SiMe 3, CH 2SiMe...

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