Chemfiles Vol. 10, No. 4

Volume 10, Number 4 • 2010

Aldrich

Asymmetric Synthesis

Catalysis

Chemical Biology

Organometallics

Building Blocks

Synthetic Reagents

Stockroom Reagents

Labware Notes

Chemistry Services

Fe(S,S-PDP) - an electrophilic iron catalyst for site-selective C-H oxidation

74511 ChemFiles 10.4_home.indd 174511 ChemFiles 10.4_home.indd 1 10/28/2010 10:25:06 AM10/28/2010 10:25:06 AM

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3

Intro

du

ctio

n

Volume 10, Number 4

Sigma-Aldrich Corporation

6000 N. Teutonia Ave.Milwaukee, WI 53209, USA

Editorial Team

Haydn Boehm, Ph.D.

Wesley Smith

Dean Llanas

Sharbil J. Firsan, Ph.D.

Weimin Qian, Ph.D.

Production Team

Cynthia Skaggs

Carrie Spear

Chris Lein

Tom Beckermann

Christian Hagmann

Denise de Voogd

Chemistry Team

Daniel Weibel, Ph.D.

Josephine Nakhla, Ph.D.

Matthias Junkers, Ph.D.

Mark Redlich, Ph.D.

Troy Ryba, Ph.D.

Todd Halkoski

Paula Freemantle

Mike Willis

Aldrich ChemFiles Subscriptions

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website at: aldrich.com/chemfi les or contact your local Sigma-Aldrich

offi ce (see back cover).

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Aldrich Chemistry Products

Aldrich brand products are sold through Sigma-Aldrich, Inc.

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Aldrich ChemFiles (ISSN 1933–9658) is a publication of Aldrich Chemical

Co., Inc. Aldrich is a member of the Sigma-Aldrich Group. © 2010

Sigma-Aldrich Co.

AldrichIntroduction

Haydn Boehm, Ph. D.Global Marketing Manager: Chemical Synthesis

[email protected]

Dear Chemists

Firstly I would like to off er congratulations from all

of us here at Sigma-Aldrich to Prof. Richard Heck

of the University of Delaware in Newark, US, Prof.

Ei-ichi Negishi of Purdue University, US, and Prof.

Akira Suzuki of Hokkaido University in Japan, who were awarded the 2010

Nobel Prize for chemistry. These three pioneers of synthetic organic chemistry

were acknowledged for their eponymous palladium-catalyzed cross-coupling

reactions, which form new carbon-carbon bonds under mild conditions, and are

now indispensable to both research laboratories and industrial processes around

the world.

Indeed this news has proven very timely as Prof. Negishi was our second speaker

in the new Aldrich Chemistry Webinars series, and his ZACA Reaction Webinar

was broadcast live from the 5th Annual Negishi-Brown and CAOSS Lectures from

Purdue University on Tuesday, October 12, in partnership with the American

Chemical Society and C&EN Webinars. If you were unable to attend the webinar

then you can access it via aldrich.com/cheminars.

The cover molecule of our fourth edition of the new Aldrich ChemFiles is

Fe(S,S-PDP), which was originally reported by Prof. Christina White, and is now

available from Aldrich Chemistry as part of our chiral 2,2’-bipyrrolidines portfolio

(Asymmetric Synthesis). In Aldrich ChemFiles 10.4 we also introduce the latest

building blocks for chemical biology (Chemical Biology), PEMB for reductive

aminations (Synthetic Reagents), new gold catalysts (Catalysis), new organotins

and organozincs (Organometallic Reagents), and our new oxetane portfolio

(Building Blocks).

I hope that Aldrich ChemFiles 10.4 keeps you informed of the new Aldrich

Chemistry products that facilitate the latest research methodologies and trends,

and allows you to access key starting materials and reagents more effi ciently.

Thanks for reading,

Haydn Boehm, Ph. D.

Table of Contents

Asymmetric Synthesis ...............................................................................................................................4

Catalysis ................................................................................................................................................................6

Chemical Biology ....................................................................................................................................... 10

Organometallic Reagents .................................................................................................................... 12

Building Blocks ............................................................................................................................................ 14

Synthetic Reagents ................................................................................................................................... 16

Stockroom Reagents ............................................................................................................................... 18

Labware Notes .............................................................................................................................................. 20

Chemistry Services ................................................................................................................................... 22


4

Asy

mm

etr

ic S

ynth

esi

s

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com

On the basis of this set of selectivity rules the preferential oxidation

of the electron-rich and sterically unencumbered tertiary C–H

bond at C-10 of antimalarial tetracyclic compound (+)-artemisinin

(361593) was predicted. In addition to the site selectivity issue

posed in this substrate, a chemoselectivity challenge is present

in the form of a sensitive endoperoxide moiety known to be

prone to Fe(II)-mediated cleavage.3 (+)-10β-Hydroxyartemisinin

was generated in diastereomerically pure form as the major

product in 54% yield (after recycling of artemisinin). Interestingly,

(+)-artemisinin (361593) has previously been transformed

enzymatically with microbial cultures of Cunninghamella echinulata

to 10β-hydroxyartemisinin in 47% yield with substantially longer

reaction times and a 10-fold lower volume throughput.3 The ability

of the simple, small molecule iron catalyst Fe(S,S-PDP) (730459)

with broad substrate scope to achieve P-450-like tailoring enzyme

selectivities is remarkable.

O

O

CH3

O

O

HCH3

O

H

H3C

O

OO

O

HCH3

O

H

H3C

OHH3C

H2O2

54%(+)-artemisinin

730459

NN

NCCH3

NCCH3NN

Fe2

(SbF6 )2

Scheme 2: Selective aliphatic iron-catalyzed C–H oxidation

Recently, Prof. White reported the same bulky, electrophilic

iron catalyst is capable of site-selective oxidation of isolated,

unactivated secondary C–H bonds to aff ord mono-oxygenated

products in preparatively useful yields without the use of directing

or activating groups (Scheme 3).4

730459 (15 mol %)AcOH (1.5 eq)H2O2 (3.6 eq)

CH3CN, rt, 30 min

EWGCH3

H H

nEWG

CH3n

O

H H H H

H3CO

O

CH3

O

50%

H3CO

O

51%

CH3

OH3CO

O

CH3

O

54%CH3

H3CO

O

CH3

O

43%

CH3

Scheme 3: Selective iron-catalyzed methylene oxidation

In 2008, Prof. Lawrence Que developed an iron catalyst bearing

the optically active 6-Me2-BPBP ((R,R)-1,1’-bis(6-methyl-2-

pyridinylmethyl)-2,2’-bipyrrolidine) ligand (712337) for asymmetric

olefi n dihydroxylation.5 This complex is hitherto one of the most

eff ective reported to date achieving up to 97% enantiomeric

excess of the syn-diol product from cis-disubstituted olefi ns

(Scheme 4). These ee values are comparable to those obtained

with the osmium-based AD α or β mixes (392758 or 392766).

These results demonstrate for the fi rst time that a synthetic

nonheme iron catalyst can approach the high enantioselectivity

found in syn-dihydroxylating enzymatic systems.

Asymmetric SynthesisDaniel Weibel, Ph.D. European Market Segment Manager, Chemistry

[email protected]

Chiral 2,2’-Bipyrrolidines

C2-symmetrical, chiral 2,2’-bipyrrolidines

have recently emerged as interesting

structural chiral motifs in a number of

ligands for asymmetric transformations

(Figure 1). When the two nitrogen atoms function either in a

bidentate chelate ligand or are covalently bonded to another

atom, the two pyrrolidines adopted a stair-like structure, which

creates a highly asymmetric environment.

Figure 1. Commercially available chiral 2,2’-bipyrrolidines.

Prof. Denmark has exploited this feature in the development of a

highly selective catalyst for asymmetric allylations.1 The addition of

allylic trichlorosilanes to unsaturated aldehydes can be catalyzed

by chiral bisphosphoramide derived from 2,2’-bipyrrolidine (for the

corresponding chiral bisphosphoramide catalyst derived from

N,N′-dimethyl-1,1′-binaphthyldiamine, (715549) to give homo-

allylic alcohols with excellent diastereo- and enantioselectivities

(Scheme 1).

NP

N

HH O

N(CH2)5

NP

N

N HH

O

CH3 CH3

R1

R2

SiCl3

R

O

H R

OH

CH2R1 R2

+

1. (5-10 mol %)Hunig's base, -78°C

2. NaHCO3, KF

R

OH

CH2 R

OH

CH2

CH3

R

OH

CH2

CH3

R

OH

CH2H3C CH3

84-92%80-88% ee

57-83%anti/syn: 99/181-86% ee (anti)

54-91%anti/syn: >95/588-95% ee (syn)

70-89%88-96% ee

Scheme 1: Highly selective asymmetric allylic allylations using a bisphos-

phoramide organocatalyst

In 2007, Prof. Christina White reported on an iron-based small

molecule catalyst Fe(S,S-PDP) (730459) bearing the (S,S)-1,1’-bis(2-

pyridinylmethyl)-2,2’-bipyrrolidine (712361) moiety as chelating

ligand that uses hydrogen peroxide to oxidize a broad range of

substrates.1 Predictable selectivity is achieved solely on the basis

of the electronic and steric properties of the C–H bonds, without

the need for directing groups. This type of general and predictable

reactivity stands to enable aliphatic C–H oxidation as a method for

streamlining complex molecule synthesis (Scheme 2).

NH

NH

H H

HO2CCO2H

OH

OH

NH

NH

H H

HO2CCO2H

OH

OH

NH

NH

H H

HO2C CO2H1.5•

688622 688746 712116


5Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

R'R

H3C∗∗ ∗∗ CH3

OH

OH

2 mol %35% H2O2 (10 eq)

CH3CN, rt, 20 min

NN

OTfCH3

OTfNN CH3

Fe2

H3C ∗∗ ∗∗ CH3

OH

OH

96% ee97% ee

H3C∗∗

78% ee

OHOH H3C ∗∗ ∗∗

O

O CH3

OH

OH

76% ee

∗∗ ∗∗

OH

R'OH

R'

HH

Scheme 4: Iron-catalyzed asymmetric olefi n cis-dihydroxylation

References (1) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488. (2) Chen, M.

S.; White, M. C. Science 2007, 318, 783. (3) Zhan, J.; Guo, H.; Dai, J.; Zhang, Y.; Guo, D.

Tetrahedron Lett. 2002, 43, 4519. (4) Chen, M. S.; White, M. C. Science 2010, 327, 566.

(5) Suzuki, K.; Oldenburg, P. D.; Que, L, Jr. Angew. Chem. Int. Ed. 2008, 47, 1887.

Asym

me

tric Syn

the

sis

NH

NH

H H

HO2CCO2H

OH

OH

688622

NH

NH

H H

HO2CCO2H

OH

OH

NH

NH

H H

HO2C CO2H1.5•

688746 712116

NN

NCCH3

NCCH3NN

Fe2

(SbF6 )2HH

730459

N N

H H

N N

• 4HCl

N N

H H

N N

• 4HCl

712353 712361

N N

H H

N N

• 4HClCH3 H3C

712337

N N

H H

N N

• 4HClCH3 H3C

712345

Chiral 2,2’-Bipyrrolidines

For a complete list of bipyrrolidines available from Aldrich

Chemistry, please visit aldrich.com/bipyrrolidines

Let DiscoveryCPR Put High Throughput Back in Your Operation!

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6 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com

Ca

taly

sis

CatalysisJosephine Nakhla, Ph.D.Market Segment ManagerOrganometallics & Catalysis

[email protected]

Alkyne Hydration

The hydration of alkynes has been

extensively studied for more than

100 years. This reaction allows access

to various carbonyl derivatives from alkyne precursors. Nolan

and coworkers reported alkyne hydration using a gold catalyst.

Nolan, a pioneer in the use of N-heterocyclic carbenes (NHCs)

as ligands in various catalytic transformations with diff erent

metals, developed conditions employing a gold-NHC complex

and silver hexafl uoroantimonate for the hydration of alkynes

(Scheme 1). It is important to note that an acid is not needed for

this transformation and the reaction was feasible at low catalyst

loadings (10 ppm).

R1 R2

N N

AuCl

(0.01 mol %)AgSbF6

1,4-Dioxane/H2O (2:1)120 °C, 18 h

R1 R2O

O

H3CO

OF

O

O

O O

88% 97% 72%

76% 95%

Scheme 1: Hydration of alkynes using gold-NHC complex

Reference (1) Marion, N.; Ramón, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448.

Intramolecular Cycloaddition of 1,3-Enynes

with Alkenes

Echavarren and co-workers employed a crystalline gold complex

containing either the o-biphenyl phosphine ligand JohnPhos,

or a bulky aryl ether phosphine under mild conditions to eff ect

the [4+2] cycloaddition of 1,3-enynes with olefi ns. A family of bi-

and tricyclic scaff olds were prepared in good yields (Scheme 2).

Both electron-withdrawing and electron-donating groups were

tolerated on the aryl moiety.

R2R1

P SbF6

(2 mol %)

CH2Cl2, rtH

R2R1

R3

R3H3CO2CH3CO2C

H3CO2CH3CO2C

H CH3

R3H3CO2CH3CO2C

HCN

H3CO2CH3CO2C

HNO2

H3CO2CH3CO2C

78%

74%

Ph H

58%

O P AuCl

3

RR

(5 mol %)AgSbF6 (5 mol %)

CH2Cl2, rt

RR

PhO2SPhO2S

94%

OHO

56%

Au NCCH3

+

Scheme 2: Intramolecular cycloaddition of 1,3-enynes with alkenes

Reference (1) Nieto-Oberhuber, C.; Pèrez-Galán, P.; Herrero-Gómez, E.; Lauterbach,

T.; Rodriguez, C.; López, S.; Bour, C.; Rosellón, A.; Cárdenas, D. J.; Echavarren, A. M. J.

Am. Chem. Soc. 2008, 130, 269.

Propargyl Claisen RearrangementToste and coworkers reported the use of the gold catalyst

[(Ph3PAu)3O]BF4 for the rapid two-step, one-pot sequence of a

Claisen rearrangement of a propargyl vinyl ether followed by a

reduction of the resulting aldehyde functionality to provide a

variety of homoallenic alcohols. The reactions are generally high

yielding and the robust catalyst system is able to induce almost

complete chirality transfer (in most cases, ee’s were >90%). Low

catalyst loadings (1 mol %) and substitution at the alkyne is well

tolerated generating the desired allenes in high yields (Scheme 3).

Reference (1) Sherry, B. S.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.

R3R1 O

Au Au

O

Au

Ph3P PPh3

BF4

•R1 R3

OH(1 mol %)CH2Cl2, rt;

NaBH4, MeOH, rt

•H

OH

•

OH

•

OH

78%

PivO

81%

F3C

86%

PPh3

Scheme 3: Preparation of homoallenic alcohols via Claisen rearrangement/

reduction sequence



Gold Catalysts from Sigma-Aldrich

Ca

talysis

SbF6-

Pt-Bu t-Bu

Au N C CH3

697575

P

AuCl

254037

P AuCl

715050

P

AuCl

t-But-Bu

679771

CH3

PCH3

H3C AuCl

404217

P

AuCl

CH3H3C

H3C

288225

SH3C

H3CAuCl

420727

N N

AuCl

i-Pr

i-Pr

i-Pr

i-Pr

696277

i-Pr

Pi-Pr AuCl

i-Pr

687510

PCH3

AuCl

702749

NAu

P

SSOO

O OCF3F3C

1/2 CH3C6H5

677922

O

Au AuAu

PPh3Ph3P

PPh3 BF4−

665142

NaAuCl4 • 2H2O

298174

AuBr3

398470

AuCl

481130

AuCl3

334049

NAuCl3•

677876

Silver Salt Additives

For a complete list of Gold Catalysts available from Aldrich Chemistry, please visit aldrich.com/gold

Ag N

S

S

O

O

CF3

OO

CF3

668001

SO

OOAg

H3C

AgSbF6

176427 227730

AgBF4

208361

AgPF6 SO

OF3C OAg

227722 176435


Aldrich® Chemistry WebinarsZirconium-catalyzed Asymmetric Carboalumination of Alkenes (ZACA Reaction)Your speaker for this Aldrich

sponsored webinar is:

Ei-ichi Negishi, Ph.D.

H. C. Brown Distinguished

Professor of Chemistry

Purdue University

Co-Winner of 2010

Nobel Prize in Chemistry

To watch a recording of this webinar, please visit

aldrich.com/ ZACAwebinar

Overview: Many, if not the majority, of the organic compounds that are of interest and

importance to mankind are chiral or optically active. Until recently, the major route to

such chiral compounds and biocatalysts was the biosynthesis performed by nature,

which employed enzymes as synthetic tools. Slowly but surely, other methods have

emerged and their signifi cance was predicted to increase signifi cantly during the 21st

century, when W. Knowles, R. Noyori, and K. B. Sharpless were awarded the 2001 Nobel

Prize for their pioneering research using non-biological asymmetric methods for C–H

and C–O bond formation.

What about the all-important C–C bond formation for asymmetric organic skeleton

formation? This webinar introduces the discovery, development and application

of the ZACA reaction, and showcases how its effi cient, selective, potentially green

and economical syntheses of biologically and medicinally important chiral organic

compounds can benefi t mankind.

To view previous and future webinars, please visit aldrich.com/cheminars

Hosted by:

i) R23Al, Cat. (-)-(NMI)2ZrCl2

ii) O2R1 R1

R2

OH

(-)-(NMI)2ZrCl2=2ZrCl2

R2 = Me, 68–92% yield, 70–90% eeR2 = Et, 56–90% yield, 85–95% eeR2 = Higher primary alkyl groups,

74–85% yield, 90–95% ee

©2010 Sigma-Aldrich Co. All rights reserved. Sigma-Aldrich and Aldrich are trademarks belonging to Sigma-Aldrich Co. and its affiliate Sigma-Aldrich Biotechnology, L.P.

Areas covered in the webinar:

Discovery and development of the ZACA • reaction

Its application to effi cient and selective • synthesis of chiral natural products

Synthesis of vitamins (E, K, etc.) and other • compounds of dietary and medicinal interest

Who should attend:

Organic Chemists • Medicinal Chemists• Anyone involved in research in academic or • corporate labs


Renewable and Alternative Energy Web Portal

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Selected Applications of Metal-Organic Frameworks in Sustainable Energy Technologies

TM

Vol. 4, No. 4

72680_MM4-4_US_r7.indd 172680_MM4-4_US_r7.indd 1

12/3/2009 2:44:33 PM


10

Ch

em

ica

l Bio

log

y

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com

[email protected]

New Building Blocks for

Chemical Biology

Modern automated synthesis protocols

allow the fast and effi cient production of

biopolymers like peptides and even proteins, or oligonucleotides.

In recent years, even the automated synthesis of complex

carbohydrates has been described.1 Automated synthesis

procedures build the bridge to Chemical Biology. It does not

require a fully trained chemist to perform automated synthesis.

Even groups with a primary focus on biology research can utilize

synthesizers to produce primers, test molecules, probes, etc.,

quickly and effi ciently. On the other hand, chemistry benefi ts

equally from automated procedures. Synthesis challenges that

used to take weeks or months can today be completed in a matter

of hours or a few days accelerating research tremendously. Fast

and effi cient synthesis is only possible if all necessary tools are

readily available. Sigma-Aldrich is proud to off er a leading choice of

tools and building blocks for advancing science in the "omics" era

(genomics, proteomics, glycomics, metabolomics – to name just

a few). This issue of Aldrich ChemFiles highlights some examples of

recent additions to our portfolio.

Beta Amino Acids

Although they are less abundant than their α-analogues,

β-amino acids occur in nature both in free form and bound to

peptides. Oligomers composed exclusively of β-amino acids

(so-called β-peptides) might be the most thoroughly investigated

peptidomimetics. Besides being remarkably stable to metabolism,

exhibiting slow microbial degradation, and inherently stable to

proteases and peptidases, they fold into well-ordered secondary

structures consisting of helices, turns, and sheets. In this respect,

the most intriguing eff ects have been observed when β2-amino

acids are present in the β-peptide backbone.2 A whole new

“world” has emerged from the design of fascinating new peptidic

macromolecules from β- and γ-homologated proteinogenic amino

acids and other components. Sigma-Aldrich has a history as a

leading supplier of β3-amino acids. Now, the portfolio of β2-amino

acids is signifi cantly increased with members that had not yet been

available commercially.

Chemical BiologyMatthias Junkers, Ph.D.Product Manager

Proline Analogs

Proline is a non-polar, natural amino acid that forms a tertiary

amide when incorporated into peptides. Thus, it is the only

proteinogenic amino acid that does not act as a hydrogen bond

donor in a peptide chain. Proline is known as a classical breaker

of both the α-helical and β-sheet secondary structures in proteins

and peptides, and it plays a crucial role in protein folding. Synthetic

proline derivatives, mimetics and analogs off er further options to

tune the biological, pharmaceutical, or physicochemical properties

of peptides and proteins.

In recent years proline derivatives and analogs have also found

increasing popularity as organocatalysts in asymmetric synthesis.4

Unsaturated Amino Acids

Recent developments in Chemical Biology research have increased

the demand of amino acid building blocks with unsaturated side

chains. Alkyne moieties can be used in bioorthogonal synthesis

strategies to form hybrid structures, introduce chemical probes into

biomolecules, or link large fragments with each other. The most

prominent technique relies on the Huisgen dipolar cycloaddition

reaction between an azide and an alkyne.

Olefi n moieties open amino acids and peptides to metathesis

reactions and a full range of other bioorthogonal synthesis routes.

Olefi n metathesis is a key to the production of hydrocarbon

stapled peptides.5 Stapled peptides are currently in discussion as

a new class of superpotent drugs or magical bullets promising

to make peptide α-helices more potent and cell permeable by

locking them in the most active conformation.6

References: (1) Timmer, M.S.M.; Adibekian, A.; Seeberger, P.H. Angew. Chem. Int. Ed.

2005, 44, 7605. (2) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206. (2) Seebach, D.;

Beck, A.K.; Bierbaum, D.J. Chem. Biodiv. 2004, 1, 1111. (4) (a) Vignola, N.; List, B. J. Am.

Chem. Soc. 2003, 125, 450. (b) Dalko, P.I.; Moisan, L.; Angew. Chem. Int. Ed. 2004, 43,

5138. (5) Walensky, L.D. et al. Science 2004, 305, 1466. (6) Kritzer, A.K. Nature Chemi-

cal Biology 2010, 6, 566.

NOH

O

Boc

CH

N OH

OHC

BocN OH

O

Boc

H2C

711985 711977 717045

NH

OCH3

O

N OH

O

Boc

F

712884 717010



Ch

em

ical B

iolo

gy

New Amino Acid Building Blocks Monosaccharides

For a complete list of building blocks available from Aldrich

Chemistry, please visit aldrich.com/chemprod

OH

O

H3C

NH2

CH3

• HClOH

O

H3C

NH2

CH3

• HClOH

O

H2N

OH

714135 714143 714119

OH

O

H2N

OH

HN

BocOH

O NH

BocOH

O

714127 713821 713856

HN

BocOH

O NBoc

O

O

CH3

NH

BocOH

O

713848 713724 713813

NH

OH

O

BocNH

OH

O

BocO

O

NHBoc

713864 713872 713473

NH OH

OBoc

O

OCH3H2N

• HCl

O

OH2N

CH3H3C

• HCl

670243 726273 726354

H2N OH

O

HNBoc

HCOH

O

HNBoc

OH

O

HNBoc

HC

726230 712221 714240

OH

O

HNBoc

HCOH

ONH2

HC• HCl

714232 711926

H2N NH2

OHHO OH

• 2HBr

N3 N3

O

O

O CH3

O

H3C

O

O

CH3 O

O

HO

HO

714216 714224 725978

O

O

OO

OH

OCH3

H3C

H3C

H3C

O

O

OO

N3

OCH3

H3C

H3C

H3C O O

OH

OHH

OH

712167 712736 725862

O

OBn

OBn

OH

OBn OCH3

O N3

CNOAc

OAcAcO

OAc

O

OH

OHHO

N3

OH

712140 712817 712752



Org

an

om

eta

llics

OrganometallicsJosephine Nakhla, Ph.D.Market Segment ManagerOrganometallics & Catalysis

[email protected]

Suzuki CouplingThe cross-coupling of organoborons with

organic electrophiles in the presence of

a palladium catalyst (Scheme 1), is one

of the most widely utilized methods for C –C bond formation in

transition metal chemistry. Organoboron reagents are readily

prepared or are commercially available, relatively non-toxic, and do

not react with common functional groups. Several new product

additions to our boron portfolio are highlighted below.

R1 X R2 BY2+ PdLn

R1 R2

R1 = aryl, heteroaryl, alkenylR2 = aryl, heteroaryl, alkenyl, alkylX = Cl, Br, I, OTf

BYn = Y=(OH)2, F3K,

+ BY2X

BO

BO

N

OOO

H3C

or

(MIDA)

Scheme 1: The Suzuki reaction

Reference: Wolfe, J. P.; Nakhla, J. S. The Suzuki Reaction. Name Reactions for

Homologations. John Wiley & Sons, Inc. (2009), (Pt. 1), 163–184.

New Boronic Acids and Boronate Esters

Stille CouplingThe cross-coupling of organotins with organic electrophiles in the

presence of a transition-metal catalyst (Scheme 2), remains one

of the most viable methods for the formation of C–C bonds in

organic chemistry, particularly with heterocyclic nucleophiles. The

Stille reaction, like other commonly used cross-couplings, has been

employed in methodology development, countless elegant natural

product syntheses, and in materials science.

R1 X R2 Sn(alkyl)3+M(0)

R1 R2

R1 = aryl, heteroaryl, alkenyl, acyl, benzyl, alkylR2 = aryl, heteroaryl, alkenyl, alkynyl, allyl, benzyl, alkylX = Cl, Br, I, OTf

X Sn(alkyl)3+

Scheme 2: The Stille reaction

Reference: Mascitti, Vincent. Stille coupling. Name Reactions for Homologations.

John Wiley & Sons, Inc. (2009), (Pt. 1), 133–162.

For a complete list of boron reagents available from Aldrich

Chemistry, please visit aldrich.com/boron

706256 706221 686816

666556

NH

N

BHO

OH

N

N

NH2

BHO

OH

N

BOH

BrOH

NBr

BOH

OH

N

BOH

OH

OH3C SCH3

O

BHO

OH

718815 701939

720828 715409 709379

NH

N

BHO

OH NH

NBOH

HO • HCl

NH

N

BHO OH

• HCl

720798

NN

BHO

OH CH3 N

BOH

OH

NH

Boc

BOH

OHBr

OHO

717681 718785

OHO

O2N BOH

OH

721042

O

OH

O

BHO

OH

BOH

OH

O2N

717622 720771

BOO

NH

H3C

H3C CH3

CH3

CH3

CH3H3CH3C

N NO

NBO

O

CH3H3C

H3C

H3C

716251 716227

NH

NNB

O

O

CH3H3C

H3CH3C

715557

N

OB

OCH3

H3CH3C

CH3

CN

ClN N

NBO

O

CH3H3C

H3CH3C

718920 715476

NS

NBO

O

CH3H3C

H3CH3C

715565

NN

O

BO

OH3C

H3C

NN

O

BO

O

H3C

H3C

H3CCH3

724270 718823

BOO

H3CH3C

H3C

CH3

NN

H3C CH3

716243

BO

O

718491

New Boronic Acids and Boronate Esters—

cont'd



Org

an

om

eta

llics

Negishi Coupling

The cross-coupling of organozincs with organic electrophiles in

the presence of a transition-metal catalyst (Scheme 3), is widely

utilized due to the mild, yet reactive nature of organozinc halides.

R1 X1 R2 Zn X2+NiLn or PdLn

R1 R2

R1 = aryl, alkenyl, acylR2 = aryl, heteroaryl, alkenyl, allyl, benzyl, homoallyl, homopropargylX1 = Cl, Br, I, OTfX2 = Cl, Br, I

+ ZnX1X2

Scheme 3: The Negishi reaction

Reference: Yet, Larry. Negishi Cross-Coupling Reaction. Name Reactions for

Homologations. John Wiley & Sons, Inc. (2009), (Pt. 1), 70–99.

Pd

Cl

Pd

Cl Pd

CH3

SiCH3

CH3H3C

SiCH3

H3C

CH2

CH3

PdCl

PdCl H2C

CH3

720526 719986 700045

Pd

CH2

721689

FePh PhPhPh

Ph

Pt-Bu

t-Bu

PCy2

O

O

P(t-bu)3

675784

Hartwig

675709

Guram

570958

Fu

Pt-Bu2

638439

Buchwald

N N

H3CCH3

CH3H3C

H3CCH3

CH3H3C Pd

Cl

709042

Nolan

Pd(OAc)2 Pd2(dba)3

520764 328774

Pd(PPh3)4

216666

ZnBrCH3H3C

ZnBr N ZnBr

680982 680966 499382

F

F

ZnBr

N

O

ZnIZnI

710261 710296 630411

ZnBr ZnBrO

OZnBr

710318 710326 710288

SBr

ZnBrSH3C

ZnBr

714356 710237

Organozincs

For a complete list of organotin reagents available from

Aldrich Chemistry, please visit aldrich.com/organotin

Organotin Reagents from Aldrich

717703 683930 719366

678333

SBu3Sn SnBu3

SBu3Sn N

H3C

Bu3Sn

NBu3Sn N

Bu3Sn

N

N

Cl Cl

Bu3Sn

698598 718807

719730

N

NBu3Sn

706868 707031

706981 707813

N

NBu3Sn

Cl

N

N

OCH3Bu3Sn

ONBu3Sn

OCH2CH3

O

NN

CH3

Bu3Sn

N

N

CH3

Bu3Sn

O

N

Bu3Sn

717630

638617 642541

S

N

Bu3Sn

S

NSnBu3

Br

NCH3

Bu3SnN

N

CH3

Bu3Sn

N

N

CH3

Bu3Sn

706965

675679 719501 718793

For a complete list of organozinc reagents available from

Aldrich Chemistry, please visit aldrich.com/zinc

Common Catalysts Employed for

Cross-Coupling

New Palladium Catalysts from

Aldrich Chemistry

Common Ligand or Catalyst Families

For a complete list of catalysts available from Aldrich

Chemistry, please visit aldrich.com/catalysis



Bu

ildin

g B

lock

s

[email protected]

Building BlocksMark Redlich, Ph.D.Product Manager

Oxetanes

Oxetanes are the closest homologs to

epoxides, but historically have received far

less attention than their three-membered-

ringed brethren. However, oxetanes have received increasing

exposure as attractive modules for drug discovery, largely due

to a recent series of reports from Rogers-Evans, Carreira, and

coworkers. They have demonstrated the improved physico- and

biochemical properties of a molecular scaff old when an oxetane

unit replaces a gem-dimethyl unit1 and also reported an oxetane

ring can function as a surrogate for a carbonyl group.1b,2 More

recently, they have demonstrated the use of 1,6-substituted

azaspiro[3.3]heptanes containing an oxetane ring as alternatives to

unstable 1,3-heteroatom substituted cyclohexanes.3 In most cases,

3-oxetanone, 731536, was the principal building block employed

by the authors to install the oxetane unit (Scheme 1).

O

O

731536

O

NO2

O

OEt

O

O

H

O

O

CH3

O

O

CN

O

POEt

OOEt

O

SO2Ph

O

OCl

Scheme 1: Oxetane Derivatives Synthesized from 3-Oxetanone

The presence of the oxetane moiety in drug-like and biologically

active molecules is nothing new to synthetic and medicinal

chemists. Perhaps the best-known examples of oxetane-containing

drugs are the natural product paclitaxel (Taxol®) and its synthetic

analog docetaxel (Figure 1). Joëlle Dubois and coworkers studied

the eff ect of the deletion of the oxetane ring in analogs of

docetaxel and found the analogs to be less active than docetaxel

in biological assays.4 Merrilactone A (Figure 2) shows promise as

a nonpeptidal neurotropic agent, 5 and the β-amino acid oxetin

(Figure 3) has demonstrated both herbicidal and antibiotic

activity.6

OHOAc

OHO

OHOBz

O

O

OHPh

R2HNR1O

Paclitaxel: R1 = Ac, R2 = BzDocetaxel: R1 = H, R2 = Boc

Figure 1: Paclitaxel (Taxol®) and Docetaxel

OO

O

O

O

HO

Figure 2: Merrilactone A

HN

O

NH

N

NH

NH2Br

Br

Figure 3: β-Amino Acid Oxetin

We are pleased to now off er a wide selection of new oxetane

building blocks for a variety of applications in synthetic and

medicinal chemistry.

New Oxetanes

For a complete list of oxetanes available from Aldrich

Chemistry, please visit aldrich.com/oxetane

O

O

O

OH

O

I

731536 733296 731560

O

CN

O

H2NO

OH

O

HN

731579 733091 731544

O

NH

O

NH

731587 731609



Bu

ildin

g B

locks

Halogenated Pyridines

Pyridines continue to be extremely popular building blocks for

synthetic chemists across a number of disciplines. The pyridine

moiety is found in a wide range of synthetic targets with

applications in catalysis, drug design, molecular recognition,

and natural product synthesis. Halogenated pyridines in

particular are attractive building blocks for various cross-coupling

methodologies. Sigma-Aldrich is pleased to off er these useful

halogenated pyridines for your research.

For a complete list of halogenated pyridines available from

Aldrich Chemistry, please visit aldrich.com/hal-pyr

N

I

N

Br

F N

Br

NH2

722170 722421 720224

N

Br

SHN Cl

OH

N

F3C Cl

720895 714445 714488

N

Cl F

FN

Cl

Cl

I

N

I

Cl

I

720208 730564 724084

N

Br

OCH3

Br

N

CH3

Cl

I

N

BrBr

H

O

722731 724092 707325

N

Cl

Cl

O OH

N

NH2

Cl

Br

N

NH2

Cl

I

724076 720909 720372

N Cl

FOH

O

N CH3

BrOH

O

697338 717576

N OCH3

BrOH

O

725250

Other New Building Blocks

For a complete list of building blocks available from Aldrich

Chemistry, please visit aldrich.com/bb

References: (1) (a) Wuitschik, G. et al. Angew. Chem., Int. Ed. 2006, 45, 7736. (b)

Wuitschik, G. et al. J. Med. Chem. 2010, 53, 3227. (2) Wuitschik, G. et al. Angew.

Chem., Int. Ed. 2008, 47, 4512. (3) Burkhard, J. A. et al. Org. Lett. 2010, 12, 1944.

(4) Deka, V. et al. Org. Lett. 2003, 5, 5031. (5) (a) Birman, V. B.; Danishefsky, S. J. J. Am.

Chem. Soc. 2002, 124, 2080. (b) Huang, J.-M. et al. Tetrahderon Lett. 2000, 41, 6111.

(c) Huang, J.-M. et al. Tetrahderon 2001, 57, 4691. (6) Omura, S. et al. J. Antibiot.

1984, 37, 1324.

C CH2 H2C C O

O

HC NH2

715018 714992 715190

HCOH

CH3

CH3 NH2• HCl SiH3C

CH3

CH3

NH2

723800 720356 686360

NH2

NH2

NH2

OCH3

CH3

NH2

OCH3

H3C

721492 721484 724688

NH2

CH3

H3CONH

N

NH2NH2

HNBoc

724661 718084 709662

HNCH3

ONH2N

BrN

S NH

Boc

727547 708399 723649

N

S NH2

H3C

O

HONH

H3CO

F3C

722375 723789

NH

CH3

HO

716529

NN

CH3

Br

N

NH

OSiH3CCH3

CH3N

N

Br

717215 723770 721050

NH

H3CO

724378



Syn

the

tic

Re

ag

en

ts

Carbonyl AmineYield (%)

neatYield (%)

MeOH

PhNH2

OPhNH2

CHO

CHOPr2NH

H3C C3H7

O

PhNH2

C4H9 CHO PhNH2

CHOBnNH2

a Isolated as the dialkylammonium acetateb No reductive ammination product, benzyl alcohol generatedc Percent conversion in 1 h

OBnNH2

H3C C3H7

O

BnNH2

BnNH2

O

CH3

72 80

87a 92a

0b 96

92 94

92 93

83a 70a

74 94

84 83

62c 70

Product

NH

Ph

NH

Bn

C4H9

HN

Ph

NPr

HN

Ph

HN

Bn

H3C C3H7

HNPh

H3C C3H7

HNBn

HN

CH3

Bn

Selected Examples

Pr

Scheme 2: Selected reductive amination examples run in

methanol and neat.

[email protected]

5-Ethyl-2-methylpyridine

borane (PEMB): A New

Reagent for Reductive

Aminations

NH3C

CH3

5-Ethyl-2-methylpyridine borane (PEMB) 725080

BH3

PEMB

.

Figure 1: Structure of the new reductive amination reagent, PEMB (725080).

The reaction of a primary amine with an aldehyde or ketone in the

presence of an appropriate hydride source provides quick access

to an array of secondary amines. Critical to the success of this

transformation is the nature of the reducing agent. Highly reactive

hydrides will be intolerant not only with the weak Brönsted acid

catalysts commonly employed but also with water generated upon

iminium ion formation.

R H

O

R R

O

R H

HN

R R

HN

R

R

Useful Applications of PEMB

R H

NR

1. PEMB

NH2,R rt

AcOH

NH2,R

AcOH

R R

NR

50 o C

2. workup

1. PEMB

2. workup

Scheme 1: Representative transformation conditions for reduction

amination with PEMB.

5-Ethyl-2-methylpyridine (PEMB) exhibits enhanced shelf stability

relative to other amine-boranes for reductive aminations

(Scheme 1). Studies have shown solvolysis is slow (less than 7%

daily) in water/THF or methanol solutions.

Reductive aminations with PEMB can be run in methanol. However,

solvent can be eliminated completely and the reactions can be run

neat, often with better yield than when run in solution (Scheme 2).

Unlike some other hydride reducing agents, two of the three

borane hydrides are utilized and usually an excess of reagent is not

required.

Synthetic ReagentsTroy Ryba, Ph.D.Product Manager

References: Burkhardt, E. R.; Coleridge, B. M. Tetrahedron Lett. 2008, 49, 5152–5155.



Syn

the

tic Re

ag

en

ts

Amine Boranes

For a complete list of Amine Boranes available from Aldrich Chemistry, please visit aldrich.com/amineboranes

NH3C

BH3

654213

N

BH3

PhNEt2

BH3

179752 179043

N

O

BH3

CH3

262323

Me2NH

BH3

i-Pr2NEt

BH3

180238 253111

t-BuNH2

BH3

197939

N

O

BH3

H

180203

Et3N

BH3

178977

Me3N

BH3

178985

H3N

BH3

287717

Materials ScienceMaterials Science

Metal-Organic Frameworks (MOFs) are porous coordination

networks with record-setting surface areas. MOFs are built from

metal ion clusters connected by organic linker molecules or struts.

They are designed for specifi c applications requiring high surface

area materials.

Aldrich Materials Science is uniquely positioned to assist you in

constructing your own MOF. Please review our current off ering

of organic linkers, high-purity metal salts, and solvents, or request

custom-designed materials to meet your research needs.

Aldrich MOF Constructor

Organic Linker Molecules for Metal-Organic Frameworks

For a complete list of organic linker molecules for MOFs, please visit aldrich.com/mofl inkers

HO

HO

O

O

OH

OH

O

O

OH

OH

O

O

HO

HO

O

O

OH

OHHO

OO

O

OHHO

H2N

NH2

O

O

OHHO

O

O

OHHO

HO

OH

O

O

OHHO

O

O

716499 716502 714747 717312 523763 382132 185361

O

O

O

OH OH

OH

NH

N N

NH

CH3

R

R R

R = *O

OH

N

N

N

HN

NH

NH

O

OH

O

HO OH

O

O

OH

O

OH

O

HO

O

HO

OHO

O

HO

O

OH

482749 I202 M50850 706884 719250 715298 686859

An Easy Way to Design your Own MOF

High-Purity Metal Salts for Synthesis of Metal-Organic Frameworks

For a complete list of metal salts and other related materials, please visit aldrich.com/ceramics

Zn(NO3)2 • xH2O Mg(NO3)2 • 6H2O Cu(NO3)2 • 2.5 H2O Al(NO3)3 • 9H2O

230006 203696 467855 229415

Ni(NO3)2 • 6H2O Cu(NO3)2 • xH2O Co(NO3)2 • 6H2O

203874 229636 203106



Sto

ckro

om

Re

ag

en

ts

By always listening, Sigma-Aldrich delivers.

Monthly Savings from Sigma-Aldrich

Easy-to-fi nd site off ers monthly savings

on Chemistry, Life Science, Analytical and

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For specifi c country discounts, visit us at sigma-aldrich.com

Stockroom ReagentsTodd HalkoskiMarket Segment ManagerSolvents

[email protected]

Sigma-Aldrich is a leading

global supplier and

manufacturer of high

quality, stockroom and

essential research products.

We specialize in providing the most comprehensive product

range and widest selection of purity grades to fulfi ll your particular

application needs.

Solvents• As a leading supplier of high-purity, research grade solvents, we

have the solvent to meet your exact needs

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levels down to ppb and ppt.

Routine Organic and Inorganic Reagents• Adsorbents, Filter Aids and Drying Agents•

You will also fi nd several programs that off er unique solutions to

help control your costs. One may be right for you!

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benefi t, their members receive savings on a wide range of Sigma-

Aldrich Chemistry products.

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Get your new lab set up in an easy and economical way.

Your lab is eligible for the program if:

You are starting a new lab• You are moving to a new location• You have received your fi rst research grant•

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The Sigma-Aldrich Pressure-Temperature Nomograph allows you

to quickly and easily

estimate boiling points

at various pressures.

Interactive controls

simplify calculations to

improve the efficiency

of your distillation or

evaporation process.

Pressure Conversion Tab: Use the built-in Pressure Conversion

Calculator to convert among five units of pressure using either

numeric values or scientific notation.

Temperature Conversion Tab: Quickly calculate temperature

conversions without leaving the Nomograph.

Printable: Need a hard copy to take with you? Simply right-click

and select 'print'.

sigma-aldrich.com/nomograph


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Lab

wa

re N

ote

s

Labware NotesPaula FreemantleProduct Manager

[email protected]

Distillation Adapter for

On-The-Fly Sampling

Distillation is the most widely used bulk

separation method used in the laboratory

as well as industry. Beyond purifi cation, it is widely used to

characterize complex fl uids (such as fuels) through measurement

of the distillation curve, a plot of the boiling temperature against

volume distilled. A common theme in both of these applications is

the desire to understand the composition. In purifi cation, the goal

is to monitor the distillation progress, and in fl uid characterization,

one seeks to relate the composition to the temperature data.

The distillate sampling adapter (Figure 1) installed following

a condenser or distillation column, can provide this important

capability without the need for cumbersome, expensive and

often unreliable fraction collectors.1–3 The fl ow of the distillate

is focused to drop into a 0.05 mL “hammock” that is positioned

directly below the fl ow path. The sampling port, equipped with

a vacuum tight valve, allows access to the hammock with a

standard chromatographic syringe, through a septum. To sample

the distillate, one simply positions the chromatographic syringe,

preferably equipped with a blunt tipped needle, in the well of

the hammock. It is a simple matter to withdraw samples as the

distillation progresses. The sample can then be directly injected

into the gas chromatograph or spectrometer, or injected into an

autosampler vial for analysis later. Indeed, any analytical technique

that is applicable for liquid samples ranging in volume from

1 to 50 microliters can be used to characterize the distillate.

This adapter has been used for many complex fl uid analyses,

including gasolines, diesel fuels, rocket kerosenes, jet fuels,

crude oils, transformer fl uids, waste oils and arson accelerants.

Some of the analytical techniques applied to distillate fraction

analysis include gas chromatography (with mass selective, fl ame

ionization and chemiluminescence detection), FTIR spectroscopy,

Karl Fischer coulombic titrimetry and refractometry. The ability

to couple quantitative analysis with the distillation opens the

door to thermochemical determinations such as the enthalpy of

combustion of fuels, as a function of distillate cut. The adapter has

also been used to measure corrosivity of crude oil fractions, with a

copper coupon test performed at various distillate cuts.

Figure 1: Distillate sampling adapter.

For a complete list of adapters available from Aldrich

Chemistry, please visit aldrich.com/labware

Aldrich GC sampling adapter, with vacuum connection

and PTFE valve

Joint size Cat. No.

14/20 Z56989524/40 Z56990929/32 Z569917Replacement valve septa 33310-USeptum inserter for valve 33311

References: (1) Bruno, T. J., Ott, L.S., Lovestead, T.M., Huber, M.L., The composi-

tion explicit distillation curve technique: relating chemical analysis and physical

properties of complex fl uids. J. Chromatogr. 2010, A1217, 2703–2715. (2) Bruno,

T. J., Ott, L.S., Lovestead, T.M., Huber, M.L., Relating complex fl uid composition and

thermophysical properties with the advanced distillation curve approach. Chemi-

cal Eng. Tech. 2010, 33, (3), 363–376. (3) Bruno, T. J., Ott, L.S., Smith, B.L., Lovestead,

T.M., Complex fl uid analysis with the advanced distillation curve approach. Anal.

Chem. 2010, 82, 777–783.



Lab

wa

re N

ote

s

Hamilton® Syringe, 700 SeriesThis syringe is a good choice for use with the sampling adapter.

volume 10 μL, needle size 22s ga (blunt tip)

Cat. No. 58380-U

Aldrich Distillation Glassware

Apparatus• Condensers• Distilling columns and packings• Heads• Traps• Glassware kits•

For a complete list of distillation products available from

Aldrich Chemistry, please visit aldrich.com/labware

News and Innovation

New Aldrich Condenser Design Eliminates Puddling on EquipmentCondensate cup catches water that forms on

the outer surface of the condenser during

use and eliminates puddling on reactor and

equipment. Tubing connects to cup's hose barb

to drain away water automatically.

Z568945 overall H 60 mm, Joint: ST/NS 14/20








For a complete list of condensing products available from

Aldrich Chemistry, please visit aldrich.com/labware



Ch

em

istr

y S

erv

ice

s

For a complete list of 3DPL or other cheminformatics available

from Aldrich Chemistry, please visit chemnavigator.com/cnc/products/3DPL.asp

Chemistry ServicesMike WillisMarket Segment Manager [email protected]

ChemNavigator® 3DPL™

(3-Dimensional Protein-Ligand Search)

3DPL Provides fast identification of targeted molecules3DPL off ers a rapid approach for selecting a population of

targeted molecules from starting sets of millions of small molecule

structures. 3DPL technology uses a protein structure and large

databases of small molecule structures to perform rapid, fl exible

virtual screening against all likely binding sites on the protein

surface. 3DPL is used to identify highly targeted sets of small

molecule structures likely to bind the protein surface. Discovery

companies can assay sets of hundreds to low thousands of

high value structures and avoid screening larger sets of tens of

thousands of diverse compounds.

3DPL is designed to allow drug discovery companies to identify

a target-focused set of chemistry and move to bioassay and lead

identifi cation as quickly and effi ciently as possible. 3DPL has several

major advantages that allow for rapid identifi cation of potential

active molecules:

Advantages of 3DPL Searching

Knowledge of active site not required:• 3DPL includes technology

for automated identifi cation of all sites on the protein surface of

appropriate size for binding with a therapeutic molecule. This

Convex Hull technology identifi es all potential binding sites that

can be used in fl exible screening, and it eliminates the need for an

identifi ed binding site as input for the screening experiment.

Entire protein surface may be considered: • Each small molecule

is compared against all potential binding sites on the 3D protein

surface to look for potential binding interactions. This approach

off ers the opportunity to identify ligands that would have been

overlooked by virtual screening technologies that focus on only

one or more pre-defi ned active sites on the protein surface.

Automatic conformational analysis: • Each small molecule ligand

is fl exed, in an energetically directed approach, and re-oriented

thousands of times in the search for potential matches between

the ligand and the protein surface.

Speed enables• in silico screening of millions of small molecules: 3DPL employs a unique and patented derivative fi eld grid to direct

small molecules to favorable binding conformations. The use of

these grids signifi cantly reduces computational time. Running

on a single 1.4 GHz server, 3DPL is able to evaluate over 8 million

chemical structures for binding across the entire protein surface in

less than 4 days—a 600-fold increase over the fastest technology

available today. Much larger structure sets can be run, which

eliminates the need to fi lter out large numbers of potentially

valuable samples before the virtual screening experiment.

3D Version of on-line iResearch™ Library included: • iResearch

Subscribers may now access a special on-line version of the

iResearch Library that is confi gured to use with 3DPL.

This provides access to over 20 million 3D ligands for use

in virtual screening.

Input to the system is a 3D protein model and a set of 3D small

molecule structures; output is a selection of scored small molecule

structures that have been calculated to show binding affi nity

for the protein surface. 3DPL can be used with ChemNavigator's

iResearch Library of over million unique structures to provide access

to the greatest diversity of commercially available small molecule

compounds.


The Next Generation of Labeled SynthonsFor Improved Site-Specifi c and Stereospecifi c Syntheses

Dr. Rodolfo Martinez and his group

at Highlands Stable Isotopes have

developed a novel set of patented

stable isotope synthetic reagents.

These exclusive reagents facilitate

the production of site-specific and

stereospecific labeled compounds.

They also help improve the speed

and quality of the synthesis of

labeled materials. These versatile

reagents include the following

categories:

Protected methyl addition • reagents

α• -Keto amide, acid, and ester

precursors

Olefi nation reagents•

Phenyl vinyl compounds•

Thioethers and dithioethers•

Phthalimides and succinimides•

To view the Next Generation of

Labeled Synthons offered by

ISOTEC® Stable Isotopes, visit

sigma-aldrich.com/sinext

For additional information,

please email the Stable Isotope

Technical Service Group at

[email protected]

Reference: Martinez, R. A.; Alvarez, M.

A.; Velarde, S. P.; Silks, L. A. P.; Stotter, P. L.;

Schmidt, J. G.; Unkefer, C. J. Large-Scale

Preparation of [13C]-Methyl Phenyl Sulfi de

from [13C]Methanol by a One-Step Process.

Org. Process Res. Dev. 2002, 6, 851.

S13CH3

N

13C

O

OBnPhS

13C

O

OBn H13C

13C

O

OR

13CH

X

R

S13CH

O

13CH2

n = 0-2

S

H13C

O

13CH

n = 0-2

H213C OH

S13CH2

On = 0-2

Br

13CH2

13C

O

H13C

13C

O

OR

13CH13C

H

O

H13C

13C13C

13CHW

X Y

Z

X = O,S,NR2,SiR3

W,X,Y,Z = H,O,S,NR2,SiR3

[13C]Methyl phenyl sulfide716081

H C3

CH3

Some of the most versatile compounds in the collection include the methyl addition

reagents of which methyl-13C phenyl sulfide (716081) is a notable example. Methyl

phenyl sulfide has a rich chemistry and, if prepared with carbon and deuterium

labels in the methyl group, is a versatile labeling precursor easily converted into a

nucleophilic or an electrophilic synthon.

Labeled methyl phenyl sulfide can be oxidized, adjusting the pKa and allowing for

subsequent modifications. A Raney® Ni mediated desulfurization can be used to

remove the sulfur, leaving a labeled methylene group. Alternatively, a 13C-labeled

aldehyde, carboxylic acid, or carboxylic ester can be prepared directly.

Ph

S13CH3

sec -BuLiSO2Cl2

or NCSPh

S13CH2

Cl

Ph

S13CH2

Li

H13C

13C

OR

O

13CH

O

1. PhSO13CH2LiH13C

13C

OR

O

13CH13C

PhS

HH

1. TFAAH13C

13C

OR

O

13CH13C

O

O LDA

R'x

H13C

13C

OR

O

13CH13C

PhS

R’H

O

Raney® Ni

H13C

13C

OR

O

13CH

H213C

R’

2. H2O

HH3C

Raney is a registered trademark of W.R. Grace and Co.

sigma-aldrich.com


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Safety-related Information sigma-aldrich.com/safetycenter

©2010 Sigma-Aldrich Co. All rights reserved. SIGMA, SAFC, SIGMA-ALDRICH, ALDRICH, FLUKA, and SUPELCO are trademarks belonging to Sigma-Aldrich Co. and its affiliate Sigma-Aldrich

Biotechnology, L.P. Sigma brand products are sold through Sigma-Aldrich, Inc. Sigma-Aldrich, Inc. warrants that its products conform to the information contained in this and other Sigma-Aldrich

publications. Purchaser must determine the suitability of the product(s) for their particular use. Additional terms and conditions may apply. Please see reverse side of the invoice or packing slip.

iResearch Library and 3DPL are trademarks of ChemNavigator, Hamilton is a registered trademark of Hamilton Co. and ChemNavigator, TraceSELECT, ISOTEC and Supply Rewards are registered

trademarks of Sigma-Aldrich Biotechnology LP and Sigma-Aldrich Co.

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