Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

328 Fluorine in Medicinal Chemistry and Chemical Biology

Figure 12.10 Photocleavage of supercoiled φ X174 plasmid DNA by cyclopropane deriva-

tives (S,S) - and (R,R) - 18 . The (R,R) - isomer may bind with DNA more easily than the (S,S) -

isomer via intercalative or groove binding. Reaction buffer: 25 mM sodium phosphate pH 7.0

(20% DMSO). Concentrations of photocleavers are 100 m M (1.2 equivalents of DNA in base

pairs) for (S,S) - 18 and 85.5 µ M (0.667 equivalents of DNA in base pairs) for (R,R) - 18 . Samples

were irradiated at 25 ° C for 40 min at a distance of 4 cm using a xenon lamp with a polystyrene

ﬁ lter (365 nm) Electrophoresis was run using 0.8% agarose gel with TAE buffer at 100 V for

40 min. The gel was stained with EtBr and visualized by UV - B lamp (transilluminator).

or minor - groove binding of the anthracene moiety to certain DNA sequence (see Figure

12.11 ) [22b] .

On the basis of these results, we set out to synthesize a molecular tool for designing

novel DNA - markers. Thus, tetrakis( gem - diﬂ uorocyclopropane) 59 was prepared through

homometathesis reaction of ( S,R,R,S ) - 58 using the Grubbs type II catalyst [37] . Oleﬁ n

59 was reacted with ethyl diazoacetate in the presence of Cu(OAc)

2

as catalyst in CH

2

Cl

2

at 40 ° C to give pentakis(cyclopropane) 60 . Hydrolysis and the subsequent esteriﬁ cation

with pyrenylmethanol using EDC in the presence of DMAP afforded pyrenyl ester 61 as

a mixture of diastereomers [22a] (see Scheme 12.5 ). Separation of diastereomers,

derivatization, and evaluation of the activity of each isomer as sequence - speciﬁ c DNA -

marker is actively underway in our laboratory.

12.6 Conclusions and Outlook

Introduction of two ﬂ uorine atoms to a cyclopropane ring can alter its chemical reactivity

and biological activity due to the strong electron - withdrawing nature of ﬂ uorine, and this

can make it possible to create new molecules that exhibit unique biological activities or

functions. As described above, numerous studies have been performed by focusing on

preparing diﬂ uoro - mimics of biologically active cyclopropane - containing compounds.

However, we found that rather simple 9 - anthracenecarboxylic acid esters or amides of

gem-Diﬂ uorocyclopropanes as Key Building Blocks for Novel Biologically Active Molecules 329

Figure 12.11 Working hypothesis for the origin of difference in DNA - cleaving activities

between ( S,S ) - 18 and ( R,R ) - 18 . The ( R,R ) - isomer may bind to DNA more tightly than the

( S,S ) - isomer via intercalation or minor - groove binding. See color Plate 12.11.

Scheme 12.5 Synthesis of a novel molecule 61 as a key building block for potential sequence -

speciﬁ c markers of DNA.

330 Fluorine in Medicinal Chemistry and Chemical Biology

gem - diﬂ uorocyclopropanes possess considerable DNA - cleaving activity that is switched

on by photoirradiation. This ﬁ nding suggests that gem - diﬂ uorocyclopropane -

containing compounds may exhibit singular biological activities and that the gem -

diﬂ uorocyclopropane structure may serve as a useful building block for a variety of

unique functional molecules.

Acknowledgments

I am grateful to Dr. Keiko Ninomiya of Kyoto University for performing the DNA -

cleavage assays for our anthracene – gem - diﬂ uorcyclopropane hybrids. I am also grateful

to Professor Masahiko Sisido of Okayama University for helpful discussions throughout

this work. I gratefully acknowledges my students, in particular, Dr. Koichi Ishida

(Mitsukura) who is now an Assistant Professor at the Gifu University, Miss Nanane

Ishida, Mr. Kuhihiko Tanimoto, and Mr. Manabu Kanbara, for their contributions to this

work.

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37.

13

Fluorous Mixture Synthesis ( FMS ) of

Drug - like Molecules and Enantiomers,

Stereoisomers, and Analogues of

Natural Products

Wei Zhang

13.1 Introduction

13.1.1 Natural Products and Synthetic Drug - like Compounds

Mother nature is a good resource for new molecules; over 10 000 natural products are

isolated each year [1] . Historically, natural products have provided a good number of leads

for the development of new drugs [2] . However, since natural products are commonly

screened as an extraction mixture, deconvolution of an active component and structural

characterization are difﬁ cult tasks. In addition, isolation of natural products has a long

cycle time and is considered expensive [3] . These limitations have prompted efforts to

synthesize natural product analogues and natural - product - like compounds for biological

screening and quantitative structure – activity relationship (QSAR) studies.

Besides natural products, synthetic small molecules are another source of drug can-

didates. Drug - like synthetic molecules usually have privileged structures such as indole,

benzopyran, and benzodiazepinone rings [4] . Compared with natural products, drug - like

synthetic small compounds tend to have more aromatic rings, planar molecular structures,

and few stereogenic centers. They usually have appropriate size and hydrogen - bonding

capacity to bind in the active - site pockets of biological targets. Chemical stability and

Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima

336 Fluorine in Medicinal Chemistry and Chemical Biology

physical properties such as solubility and log P are always considered in the design of

synthetic compounds. The drug - likeness of synthetic compounds can be estimated by the

“ Lipinski rule - of - ﬁ ve. ” [5] .

Natural product analogues and drug - like compounds are commonly prepared by solu-

tion - phase synthesis. Solution - phase chemistry has favorable reaction kinetics and is easy

for intermediate analysis. However, compounds are produced “ one at a time, ” followed

by a tedious puriﬁ cation process such as chromatography. This is not productive in the

preparation of compound libraries for QSAR studies. The advance of solid - phase synthesis

and solid - supported solution - phase synthesis has signiﬁ cantly increased the throughput of

compound puriﬁ cation processes. Nevertheless, disadvantages such as unfavorable hetero-

geneous reaction kinetics and difﬁ culty in monitoring the reaction process have limited

the capacity of solid - phase synthetic technology to access many natural product analogues

and complex drug - like molecules [6] . The recent development of ﬂ uorous technologies

has provided a solution - phase approach for the synthesis of complicated molecules and

their analogues.

13.1.2 The Concept of Fluorous Mixture Synthesis

Fluorous chemistry integrates the characteristics of solution - phase reactions and the phase

tag strategy developed for solid - phase chemistry [7 – 15] . Perﬂ uoroalkyl chains instead of

polymer beads are used as the phase tags to facilitate the separation process. In 2001 the

Curran group ﬁ rst reported the concept of ﬂ uorous mixture synthesis (FMS) for solution -

phase library synthesis [16] . FMS is able to produce individual pure compounds without

the effort of deconvolution. It adapts literature procedures to synthesize complex natural

products, their enantiomers and diastereomers. FMS can also be used for the development

of new synthetic protocols and to make novel drug - like molecules [17, 18] .

Fluorous mixture synthesis consists of the following general steps (see Scheme

13.1 ).

1. Individually attach a set of substrates to a corresponding set of homologous ﬂ uorous

tags with increasing ﬂ uorine content.

2. Mix the tagged substrates in one pot.

3. Conduct multistep mixture synthesis in one - pot or in split - parallel fashion.

4. Separate the mixtures (demixing) of tagged products by high - performance chromato-

graphy (HPLC) on a ﬂ uorous stationary phase (F - HPLC).

5. Detag to release ﬁ nal products.

The efﬁ ciency of FMS is directly proportional to the number of components mixed (step

2), the length of mixture synthesis (step 3), and the number of splits (step 3).

A ﬂ uorous stationary phase such as Fluoro Flash

®

, Si(Me)

2

CH

2

CH

2

C

8

F

17

is hydropho-

bic and lipophobic, but has strong afﬁ nity for ﬂ uorous compounds [19] . F - HPLC has the

capability to separate mixtures of ﬂ uorous compounds according to their ﬂ uorine content

[20 – 24] . A molecule with a long perﬂ uoroalkyl (R

f

) chain gives a longer retention time.

A typical mobile phase for ﬂ uorous F - HPLC is a gradient of MeOH – H

2

O with MeOH

increasing up to 100%, which is similar to that in reversed - phase HPLC. Other solvents

FMS of Drug-like Molecules and Enantiomers, Stereoisomers 337

such as MeCN or THF can be used to replace MeOH for gradient elution. An F - HPLC

trace shown in Figure 13.1 demonstrates a semipreparative - scale ( ∼ 5 mg) separation

of a mixture of seven ﬂ uorous - tagged mappicine analogues bearing different R

1

and R

f

groups [25] .

13.1.3 Quasi - racemic FMS

Enantiopure or enantioenriched compounds can be obtained by asymmetric synthesis or

by separation of a racemic reaction mixture. Quasi - racemic FMS provides a new approach

to enantiomeric compounds (see Scheme 13.2 ) [26, 27] . Quasi - racemic synthesis starts

with two individual R - and S - enantiomers attached to two different ﬂ uorous tags. After

steps of mixture synthesis followed by F - HPLC demixing and detagging, two individual

products as enantiomers are obtained (see Sections 13.2.1 and 13.2.2 ). The separation and

identiﬁ cation of the ﬁ nal quasi - enantiomers are ensured by the phase - tag - based F - HPLC.

In a more complicated quasi - racemic FMS, additional enantiomerically pure building

blocks and ﬂ uorous tags can be used to generate more chiral centers and more than two

products as stereoisomers (see Sections 13.2.3 to 13.2.8 ).

13.1.4 Tags for FMS

Each ﬂ uorous tag (also called protecting group or linker) has two attachment points. One

is permanently bound to a perﬂ uoroalkyl (R

f

) chain and the other is temporarily attached

to a reaction substrate so that it can be cleaved to release the product from the support at

Scheme 13.1 Schematic diagram of FMS.

Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

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