Synthesis and incorporation into oligodeoxynucleotides of carbocyclic exo-amino nucleosides

FEATURE ARTICLE

1011

Synthesis and Incorporation into Oligodeoxynucleotides of Carbocyclic

exo-Amino Nucleosides

C

arbocyclic exo-A

e

minoNucle

z

osides lem Yaren, Pascal Röthlisberger, Christian J. Leumann*

Department of Chemistry and Biochemistry, University of Bern, Freiestr. 3, 3012 Bern, Switzerland

Fax +41(31)6313422; E-mail: leumann@ioc.unibe.ch

Received 23 December 2011; revised 31 January 2012

(Figure 1). A natural representative of this class is clito-

cine, which was first isolated from the mushroom Clyto-

cybe inversa,¹³and later found to have potent cytostatic

activity against several leukemia cell lines via inhibition

Abstract: The preparation of a series of carbocyclic exo-amino nu-

cleosides from selected primary aromatic amines in both the C1¢ a-

and b-epimeric form as well as the corresponding building blocks

for DNA synthesis is described. These nucleosides were incorporat-

ed into oligodeoxynucleotides and their base-pairing properties of the enzyme adenosine kinase.^14,15Other examples of

such nucleosides include clitocine mimics,¹⁶as well as the

with natural bases and, in part, with themselves investigated. The

results obtained confirm that such nucleoside analogues engage in

products of oxidative DNA base lesion FapydG, FapydA,

specific interactions with natural nucleotides in DNA duplexes. In

and MeFapydG.¹⁷

addition they can form self-pairs that match or exceed the stability

exo-Amino nucleosides are relatively unstable due to their

hemiaminal bond to a primary aromatic amine. It is there-

fore a logic extension to replace in this group of analogues

the ribofuranose oxygen by a methylene group resulting in

stable carbocyclic exo-amino nucleosides (Figure 1). The

literature on the synthesis and biological profile of this

class of nucleoside analogues, however, is scarce.^18,19

of Watson–Crick base-pairs. Thus, carbocyclic exo-amino nucleo-

sides can be taken into consideration in the design of novel base-

pairs for the extension of the genetic alphabet, or for other applica-

tions in biotechnology.

1

Introduction

2

Synthetic Routes

2.1

Synthesis of Carbocyclic exo-Amino Nucleosides and

Building Blocks

2.2

3

4

Synthesis of Oligonucleotides

Pairing Properties of Oligonucleotides

Discussion and Conclusions

A)

OH

O

N

NH

Key words: nucleosides, oligonucleotides, nucleobases, molecular

recognition, medicinal chemistry

HO

carbocyclic

nucleosides

exo-amino

nucleosides

carbocyclic exo-

amino nucleosides

1

Introduction

B)

NH₂

Carbocyclic nucleosides are nucleoside analogues in

which the furanose ring oxygen has been replaced by a

methylene group (Figure 1). This replacement converts

the glycosidic bond into a chemically more stable C–N

bond, preventing it from hydrolytic cleavage and render-

ing the carbocyclic nucleosides metabolically more sta-

ble. Such nucleosides are of interest for a variety of

reasons. First and foremost, this class of compounds

shows interesting antitumor and antiviral properties. Ex-

amples of drugs being currently used in therapy include

Abacavir, Entecavir, Carbovir, (carbocyclic purine ana-

logues) and carba-BVdU, a pyrimidine analogue with anti

HSV-1 activity.^1–4In addition such nucleosides have been

investigated in the past in the context of antisense oligo-

nucleotides,^5–11or as constituents of aptamers.¹²

O

R =

O

β

NH

R

AN

DAN

O

NH₂

O

N

O

R =

α

NH

R

O

DAB

AP

CHR

Figure 1 (A) General chemical structures of carbocyclic-, exo-

amino-, and carbocyclic exo-amino nucleosides; (B) carbocyclic a-

and b-exo-amino nucleosides investigated in DNA base recognition

in this study.

A related class of nucleoside analogues are exocyclic ami-

no nucleosides in which the bases are attached to the ri-

bose sugar via a primary aromatic amino function

In a completely different context there is growing interest

in nucleoside analogues that could be used as additional

coding units for the expansion of the genetic alphabet.^20–24

For example, an additional replicable, transcribable, and

SYNTHESIS 2012, 44, 1011–1025

x

x.

x

x.

2

0

1

2

Advanced online publication: 02.03.2012

DOI: 10.1055/s-0031-1289737; Art ID: T117811SS

1012

O. Yaren et al.

FEATURE ARTICLE

translatable orthogonal base-pair would allow for the in- base surrogates using selected individuals from the library

troduction of unnatural amino acids into proteins and of amines used in the above-mentioned assay. These units

would, thus, greatly enhance the potential of protein engi- were incorporated into oligonucleotides and their pairing

neering. However, the structural space of DNA base ana- properties with the four natural DNA bases and with

logues that recognize each other specifically in a Watson– themselves explored by fluorescence and UV T_mmeasure-

Crick like manner is limited and design rules that are dif- ments.

ferent from classical hydrogen bonding complementari-

ties are largely elusive.

2

Synthetic Routes

In this context, we recently developed a combinatorial as-

say for the discovery of novel base surrogates out of a li-

brary of aromatic amines.²⁵The assay is based on the

reversible formation of hemiaminals of primary aromatic

amines with a chemically functional abasic site in the cen-

ter of a DNA duplex in a parallel fashion. Matches were

identified by fluorescence-based thermal melting experi-

ments. The resulting structures, after hemiaminal forma-

tion, are exo-amino nucleosides, which in many cases are

likely to be chemically unstable. Again, conferring stabil-

ity to such nucleosides can be achieved by replacing the

deoxyribofuranose by a carbocyclic sugar unit, resulting

in carbocyclic exo-aminonucleosides (Figure 1).

2.1

Synthesis of Carbocyclic exo-Amino Nucleo-

sides and Building Blocks

For the synthesis of the carbocyclic sugar we leaned on a

synthetic route developed by Biggadike and Meier.^26,27

Since we were in need of both the a- and b-nucleosides,

we decided to attach the aromatic amines via reductive

amination to the already known (3S,4R)-ketone 1

(Scheme 1).²⁸The aromatic amines chosen, namely

aniline (AN), naphthalene-1,5-diamine (DAN), benzene-

1,3-diamine (DAB), pyridin-3-amine (AP), and 6-amino-

flavone (CHR) have been selected from the previously

described combinatorial assay.²⁵

In this feature article we report on the synthesis of such

carbocyclic amino nucleosides with aromatic amines as

Biographical Sketches

Ozlem Yaren was born in Ulm in 2006. From 2007– novel DNA base pairs. Cur-

1982 in Izmir, Turkey. She 2011 she worked on her rently she is working as a

received her Bachelor’s de- Ph.D. at the University of post-doctoral fellow with

gree in chemistry at Koc Bern, Switzerland, under Prof. Steven Benner at the

University in 2004. After the guidance of Prof. Chris- Foundation for Applied Mo-

this she moved to Germany tian Leumann. Her Ph.D. lecular Evolution (FfAME)

where she earned her Mas- work was concerned with in Gainesville, Florida.

ter’s degree in Material Sci- the design of a combinatori-

ence at the University of al assay for the discovery of

Pascal Röthlisberger was University of Bern where he the supervision of Prof.

born in 1985 in Bern. After earned his B.Sc. degree in Christian Leumann and is

training as a chemistry tech- chemistry in 2010. He fin- just about to start a Ph.D. in

nician with Hoffmann La- ished his M.Sc. degree in the same group.

Roche in Basel in 2004, he chemistry earlier this year

gained admission to the with a Master’s thesis under

Christian J. Leumann was as a postdoctoral fellow to DNA-analogues for appli-

born in 1958. He obtained investigate catalytic anti- cations in nanotechnology,

his Ph.D. degree in 1986 bodies (Prof. Peter G. the design, synthesis and

from the Federal Institute of Schultz). In 1988 he re- characterization of novel

Technology

(ETH)

in turned to ETH Zürich to backbone modified nucleic

Zürich, Switzerland, for his start his independent career. acid analogues for oligonu-

work on biomimetic methy- Five years later he was ap- cleotide-based therapy, the

lation reactions on hexahy- pointed full professor at the development of novel tools

droporphyrin

derivatives University of Bern, Switzer- for DNA-based diagnostics,

(Prof. A. Eschenmoser). He land. His research interests and research on the biologi-

then moved to the Universi- are the synthesis and charac- cal properties of damaged

ty of Berkeley (1987–1988) terization of base-modified RNA.

Synthesis 2012, 44, 1011–1025

FEATURE ARTICLE

Carbocyclic exo-Amino Nucleosides

1013

TFA

The synthesis of the phosphoramidite building blocks

6a,b (Scheme 1) started with the carbocyclic ketone 1,

which was obtained from cyclopentadiene in four steps

and 16% overall yield. Reductive amination of aniline and

1 with sodium cyanoborohydride yielded 2 as a 1:1 mix-

ture of diastereomers in 50% yield that could not be re-

solved by standard chromatographic techniques. In fact, it

turned out that chromatographic separation was only pos-

sible on the level of the tritylated compounds 5a,b. This

emerged as a recurring feature and was also experienced

in the syntheses of the other carbocyclic exo-amino nucle-

osides. In view of the projected oligonucleotide synthesis,

we decided to protect the secondary amino function in 2

with trifluoroacetic anhydride, which gave 3 in excellent

yields. After Lewis acid promoted removal of the benzyl

groups to give 4 followed by standard tritylation to give 5,

the C1¢ epimers 5a,b could be isolated separately and the

respective configurations were assigned by ¹H,¹H-ROESY

spectroscopy (strong NOE effects between H1¢ and H3¢ in

5a and between H1¢ and H4¢ in 5b (see Supporting

Information). Both, 5a and 5b were then separately con-

verted into the phosphoramidite building blocks 6a and

6b.

NHR

HO

NH

BnO

(a)

NR

N

(c)

(d)

TFA

1

BnO

HO

7 R = H

9

(b)

8 R = TFA

TFA

NH

DMTO

N

TFA

+

HO

10α

10β

(e)

TFA

(e)

NH

DMTO

N

TFA

O

P

O

P

(i-Pr)₂N

OCH₂CH₂CN

(i-Pr)₂N

OCH₂CH₂CN

11α

11β

Scheme 2 Reagents and conditions: (a) 1. naphthalene-1,5-diamine,

AcOH, r.t., 2 h, 2. NaBH₃CN, r.t., 16 h, 37%, a/b (1:1); (b) TFAA,

Et₃N, CH₂Cl₂, 0 °C, 2 h, 98%; (c) 10% Pd/C, H₂, MeOH, r.t., 2 h,

BnO

HO

O

NR

N

(d)

(a)

(c)

TFA

97%; (d) DMT-Cl, pyridine, r.t.,

4

h, 43%; (e) (i-

Pr₂N)PCl(OCH₂CH₂CN), i-Pr₂NEt, THF, r.t., 2 h, 62% (11b), 88%

(11a).

BnO

HO

1

2 R = H

3 R = TFA

4

(b)

TFA

NH

NHR

HO

DMTO

BnO

DMTO

N

NR

TFA

(d)

(c)

+

(a)

TFA

1

HO

BnO

HO

5α

5β

(e)

12 R = H

14

(b)

(e)

13 R = TFA

DMTO

TFA

NH

TFA

NH

DMTO

O

P

O

P

N

+

TFA

OCH₂CH₂CN

(i-Pr)₂N

OCH₂CH₂CN

6α

6β

HO

15α

(e)

15β

Scheme 1 Reagents and conditions: (a) 1. aniline, AcOH, r.t., 2 h,

2. NaBH₃CN, r.t., 16 h, 50%, a/b (1:1); (b) TFAA, Et₃N, CH₂Cl₂, 0

°C, 2 h, 94%; (c) 1. 1 M BCl₃, CH₂Cl₂, –78 °C, 6 h, 2. MeOH, –20 °C

to r.t., 16 h, 86%; (d) DMT-Cl, pyridine, r.t., 4 h, 56%; (e) (i-

Pr₂N)PCl(OCH₂CH₂CN), i-Pr₂NEt, THF, r.t., 2 h, 48% (6b), 68%

(6a).

TFA

NH

(e)

NH

DMTO

N

TFA

O

P

O

P

(i-Pr)₂N

The synthesis of the naphthalene-1,5-diamine containing

building blocks 11a,b (Scheme 2) followed the same

lines. The reductive amination leading to 7 was slightly

less efficient, but yielded again a 1:1 ratio of C1¢ epimers.

Trifluoroacetic anhydride treatment to give 8 resulted, as

expected, in the protection of both amino functions. Inter-

(i-Pr)₂N

OCH₂CH₂CN

16β

OCH₂CH₂CN

16α

Scheme 3 Reagents and conditions: (a) 1. benzene-1,3-diamine,

AcOH, 2. NaBH₃CN, THF, r.t., 18 h, 38%, a/b (1:1); (b) TFAA, Et₃N,

CH₂Cl₂, 0 °C, 1 h, 94%; (c) 10% Pd/C, MeOH, H₂, r.t., 1.5 h, 100%; (d)

DMT-Cl, pyridine, r.t., 3.5 h, 40%; (e) (i-Pr₂N)PCl(OCH₂CH₂CN),

i-Pr₂NEt, THF, r.t., 0.5 h, 81% (16b), 77% (16a).

Synthesis 2012, 44, 1011–1025

1014

O. Yaren et al.

FEATURE ARTICLE

isomeric E/Z forms at the secondary amide function. This

additional isomerism was observed with most of the nu-

cleosides prepared in this study as best evidenced by the

³¹P NMR spectra of the corresponding phosphoramidites

that often displayed more than two signals (see Supporting

Information). However, only in the case of the tritylated

compound 10 could all four isomers be separate by chro-

matography. The appearance of rotamerism was of no

consequence for the synthesis of oligonucleotides as it

was only associated with the protecting groups that were

removed after oligonucleotide synthesis. For reasons of

simplified spectroscopic analysis, we isolated and contin-

ued the synthesis only with the major a- and b-isomers of

10. The assignment of configuration was again performed

N

BnO

(a)

HO

NR

N

(c)

(d)

TFA

1

BnO

HO

19

17 R = H

18 R = TFA

(b)

N

DMTO

N

+

TFA

HO

20α

(e)

20β

(e)

1

by H,¹H-ROESY-spectroscopy. Phosphitylation of 10a

N

and 10b to give 11a and 11b finally concluded this synthe-

sis.

DMTO

N

TFA

Likewise the syntheses of 16a,b, 21a,b, and 26a,b

(Schemes 3– 5) was achieved. In all cases the reductive

amination yielded roughly 1:1 mixtures of C1¢ epimers in

yields of 40–50%.

O

P

O

P

(i-Pr)₂N

OCH₂CH₂CN

(i-Pr)₂N

21β

21α

Scheme

4

Reagents and conditions: (a) 1. pyridin-3-amine,

Mg(ClO₄)₂, MeOH, AcOH, 2. NaBH₃CN, r.t., 18 h, 50%, a/b (1:1);

(b) TFAA, Et₃N, CH₂Cl₂, 0 °C, 1 h, 87%; (c) 10% Pd/C, MeOH, H₂,

r.t., 1.5 h, 98%; (d) DMT-Cl, pyridine, r.t., 3.5 h, 55%; (e) (i-

Pr₂N)PCl(OCH₂CH₂CN), i-Pr₂NEt, THF, r.t., 0.5 h, 86% (21b), 65%

(21a).

2.2

Synthesis of Oligonucleotides

Oligonucleotides ON1–12 (Table 1) carrying a fluores-

cein (FAM) label at the 5¢-end or a dabcyl quencher at the

3¢-end were prepared on a Pharmacia Gene Assembler

plus DNA synthesizer in the DMT-off mode applying

classical solid phase phosphoramidite chemistry.²⁹

Changes applied to the standard synthesis cycle were an

1

estingly, the H NMR spectrum of 8 (and the following

compounds 9–11) indicated the presence of another set of

two minor a- and b-isomers (total of four) arising from

TFA

HO

BnO

R

N

(d)

N

(c)

(a)

1

O

HO

BnO

O

22 R = H

23 R = TFA

24

(b)

TFA

N

TFA

N

O

DMTO

+

O

HO

25α

25β

(e)

TFA

N

O

TFA

DMTO

N

O

P

O

P

OCH₂CH₂CN

(i-Pr)₂N

OCH₂CH₂CN

(i-Pr)₂N

26α

26β

Scheme 5 Reagents and conditions: (a) 1. 6-aminoflavone, AcOH, r.t., 2 h, 2. NaBH₃CN, r.t., 16 h, 38%, a/b (1:1); (b) TFAA, Et₃N, CH₂Cl₂,

0 °C, 2 h, 74%; (c) 10% Pd/C, H₂, MeOH, r.t., 2 h, 75%; (d) DMT-Cl, pyridine, r.t., 2 h, 80%; (e) (i-Pr₂N)PCl(OCH₂CH₂CN), i-Pr₂NEt, THF,

r.t., 1 h, 69% (26b), 63% (26a).

Synthesis 2012, 44, 1011–1025

FEATURE ARTICLE

Carbocyclic exo-Amino Nucleosides

1015

extended coupling time of 3.5 minutes for the phosphor-

amidites 6, 11, 16, 21, and 26 and the replacement of tet-

razole for (ethylthio)tetrazole as the activator.

3

Pairing Properties of Oligonucleotides

We performed T_mmeasurements to determine thermal du-

plex stabilities with complementary DNA containing all

four natural bases opposite the respective residue Y. The

natural oligodeoxynucleotides complementary to ON1–

10 were equipped with a 3¢-dabcyl label while those com-

plementary to ON11 and ON12 contained a 5¢-FAM la-

bel. Such duplexes contained a fluorescence quencher pair

at the end, which was necessary to follow denaturation by

fluorescence spectroscopy. The fluorescence measure-

ments (Supporting Information) were performed to com-

ply with the measurements of the previous assay.²⁵The

UV-measurements were carried out to validate the fluo-

rescence measurements. As expected, we found no signif-

icant differences between the T_m-values determined by the

two methods. Figure 2 summarizes the T_mdata obtained

from UV-melting curves (numerical values are given in

the Supporting Information).

Oligonucleotides were cleaved from the solid support and

deprotected by standard methods (33% aq NH₃, r.t. to 55

°C, 16–24 h). The crude oligonucleotides were purified by

either reversed phase or ion exchange HPLC. The struc-

tural integrity was controlled by ESI-mass spectrometry.

Sequences and analytical data of ON1–12 are given in

Table 1.

Table 1 Sequences and Mass Analytical Data of Oligodeoxy-

nucleotides Synthesized

Sequence of ON1–10 5¢-(6-FAM-GTCCTYGCTGAG)-3¢

Sequence of ON11,12 5¢-(CTCAGCYAGGAC-dabcyl)-3¢

Y =

Yield^a(%) MS m/z

Calcd

Found

4154.9

4154.8

4217.8

4170.0

4156.0

4298.6

4298.7

4201.2

ON1

ON2

ON3

ON4

ON5

ON6

ON7

ON8

ON9

ON10

ON11

ON12

a-AN

90

95

50

42

75

79

80

82

40

45

87

85

4154.3

4217.8

4168.8

4154.8

4298.6

4201.1

Interestingly ON1 gave no sigmoidal transitions in the

melting curves in the temperature interval applied (30–70

°C) irrespective of the complementary bases, suggesting

that a potential T_mwould be below 30 °C. The most dis-

criminating modification was a-DAB (ON5) which

showed T_mdifferences of up to 4 °C between the strongest

(G) and the weakest (C) complementary base. The least

discriminating entity was b-DAN (ON4) with a maximum

DT_mbetween all four natural bases of only 1 °C. The high-

est affinities were obtained with a-DAN (ON3) indicating

that the a-configured naphthalene-1,5-diamine displays

the most stabilizing interactions. Interestingly, there are

examples where the a-configured nucleotides show stron-

ger binding, as in the case of DAN, as well as also the op-

posite, reflected in the T_ms of AP. In all cases the T_ms were

lower than that of a classical matched duplex with a T–A

(T_m= 54 °C) or a C–G (T_m= 58 °C) instead of a Y–N

base-pair.

b-AN

a-DAN

b-DAN

a-DAB

b-DAB

a-AP

b-AP

a-CHR

b-CHR

a-CHR

b-CHR

^aRatio of OD^260nmbefore and after HPLC.

While the syntheses of oligonucleotides with building

blocks 6, 16, 21, and 26 was smooth, that with building

block 11 showed some complications. After standard

deprotection, the HPLC showed two major peaks in a ratio

of 2:3 that could be associated by mass spectrometry with

the expected oligonucleotide carrying one trifluoroacetyl

group, or one trifluoroacetyl and an acetyl group, respec-

tively. The acetyl group arises from the capping step dur-

ing synthesis, while the trifluoroacetyl group from

incomplete removal during deprotection. We reasoned

that this was the consequence of the relatively high nu-

cleophilicity of the naphthalene-1,5-diamine system,

where the two amino groups are in a vinylogous hydrazi-

noid arrangement. Indeed, treatment of the oligo-

nucleotide carrying only the trifluoroacetyl group with a

stronger base (1 M NaOH) for two hours lead to the fully

deprotected oligonucleotide.

Figure 2 Graphical representation of the T_mvalues (°C) from UV

melting curves (260 nm) of ON2A–ON8A with complementary de-

oxyoligonucleotides presenting each of the four natural bases oppo-

site the modification Y (duplex concd 0.6 mM in 3.5 mM MgCl₂, 50

mM KCl, 10 mM tris, pH 8.0).

Synthesis 2012, 44, 1011–1025

1016

O. Yaren et al.

FEATURE ARTICLE

ON9–12 were prepared to investigate not only comple- Despite several attempts to optimize this reaction the

mentary binding to the natural bases, but also self-pair for- yields of the reductive amination remained in the range

mation. The extended aromatic surface of the chromene 37–50%. The most prominent side reaction was the reduc-

system calls for interstrand stacking interactions as a du- tion of the ketone, indicating that either Schiff base forma-

plex stabilizing factor. While such interactions were tion or the reactivity of the immonium ion towards

known to occur with aromatic residues, such as biphenyls hydride reduction was yield determining.

and/or phenanthrenes, or other extended chromophores, ^30–32

The incorporation of the corresponding building blocks

it was unclear whether this may also occur in the series of

into oligonucleotides via phosphoramidite chemistry was

carbocyclic exo-amino nucleosides where the linkage

straightforward. The only problem encountered here was

that of incomplete removal of the trifluoroacetyl protect-

ing groups during deprotection as well as the introduction

between the aromatic residue and the sugar contains an

additional conformationally flexible single bond.

As can be seen from Figure 3, both epimeric forms have a of an acetyl group during the capping step in the case of

preference for an opposing cytosine base with the a- naphthalene-1,5-diamine. We hypothesized that this was

epimer showing generally slightly higher T_ms compared to due to the high nucleophilicity of the two amino groups

the b-epimer. Surprisingly, the thermal duplex stabilities that are in a vinylogous hydrazinoid arrangement. The

are in all cases as high as that of the control duplex with problem of acetylation can be easily prevented by either

either an T–A or a C–G base-pair. Thus, the chromene res- omitting the capping step or by replacing acetic anhydride

idue is significantly more stabilizing than each of the oth- as capping reagent by phenoxyacetic anhydride,³³or tri-

er aromatic amines. The most stable duplexes are formed fluoroacetic anhydride that are known to lead to more la-

when two CHR residues are placed against each other. In bile amides with aromatic amines that are cleavable under

this series a,a-CHR interactions are strongest, a,b- or normal oligonucleotide deprotection conditions.

b,a-CHR intermediate and b,b-CHR the weakest. All

In terms of molecular recognition in duplex structures we

these data are in agreement with the CHR residues engag-

find in general that the T_m-values observed here with the

ing in interstrand stacking interactions with either natural

bases or with themselves.

carbocyclic exo-amino nucleosides match well with those

observed previously in the parallel screen²⁵with the (non-

carbocyclic) exo-amino nucleosides. This validates the

methodology of the screen and suggests that there are no

significant differences in complementary base recognition

as a function of whether there is a CH₂group or an oxygen

atom in the five-membered ring. This complies well with

earlier findings on oligonucleotides containing carbocy-

clic nucleotides with natural bases, where also no major

deviations in T_ms were observed as compared to natural

nucleosides.⁵

From Figure 2 it becomes clear that both the a- and b-

epimeric nucleosides can discriminate between opposing

natural bases, which suggests the presence of some level

of molecular recognition. In some cases, such as with

DAN and DAB, the a-form leads to higher T_ms whereas in

others, for example, with AP, the b-epimer leads to higher

stabilization. From model considerations of a DNA du-

plex in the B-conformation it appears that a shift from b to

a is associated with a translational shift of the aromatic

residue within the plane of the DNA base-pairs. Thus,

changing from a to b does not interrupt the base stack, but

leads exclusively to a different location of the aromatic

residue within the base stack. We, therefore, hypothesize

that the differences in stability observed for a- and b-

epimers of AN, DAN, DAB, and AP are due to differen-

tial edge-to-edge interactions of the natural bases by hy-

drogen bonds and/or hydrophobic interactions.

Figure 3 Graphical representation of T_mvalues of ON11 and ON12

paired against natural complements with each of the four natural

bases opposite the CHR base or against ON9 and ON10 exhibiting a

CHR self-pair. Experimental conditions as for Figure 2.

4

Discussion and Conclusions

In this work we have achieved a synthetic access to a se-

ries of carbocyclic exo-amino nucleosides and corre-

sponding oligonucleotides. The synthesis relies on a

reductive amination procedure to connect the base surro-

gates with a carbocyclic sugar unit. This reductive amina-

tion leads in all cases to nearly 1:1 mixtures of C1¢

epimers. We rationalize this lack of selectivity with the

trans arrangement of the substituents at C3¢ and C4¢ of the

cyclopentanone unit, obstructing hydride attack of the situ

formed immonium ion from both sides in the same way.

The situation is somewhat different in the case of the

chromene residue CHR, where the aromatic surface is too

large to permit edge to edge interactions with natural

bases. In these cases we believe that recognition occurs by

interstrand stacking interactions. The differences between

a- and b-epimers is, thus, only a consequence of different

Synthesis 2012, 44, 1011–1025

FEATURE ARTICLE

Carbocyclic exo-Amino Nucleosides

1017

N-{(3S,4R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]cyclopen-

tyl}aniline (2)

Starting from 1 (1.8 g, 5.8 mmol); yield: 1.1 g (50%); TLC (hexane–

EtOAc, 3:1): R_f= 0.65.

¹H NMR (400 MHz, CDCl₃): d = 7.43–7.23 (m, 10 H, H_arom), 7.21–

7.08 (m, 2 H, H_aniline), 6.67 (tdt, J = 7.4, 4.1, 1.1 Hz, 1 H, H_aniline),

6.61–6.52 (m, 1 H, H_aniline), 6.52–6.42 (m, 1 H, H_aniline), 4.60–4.36

(m, 4 H, CH₂Ph), 4.10–3.86 (m, 2 H, H1¢, H3¢), 3.57–3.48 (m, 1 H,

H5¢), 3.48–3.40 (m, 0.5 H, H5¢), 3.37 (dd, J = 9.2, 6.8 Hz, 0.5 H,

H5¢), 2.59–2.31 (m, 1.5 H, H4¢, H6¢), 2.16 (qd, J = 13.1, 6.0 Hz, 1

H, H2¢), 2.06–1.96 (m, 0.5 H, H6¢), 1.91–1.78 (m, 1 H, H2¢), 1.71

(ddd, J = 13.5, 7.2, 6.4 Hz, 0.5 H, H6¢), 1.32 (td, J = 13.2, 6.8 Hz,

0.5 H, H6¢).

stacking geometries. It is remarkable that such CHR/nu-

cleobase pairs are as stable as a matched Watson–Crick

base-pair. Into this picture fits also the self-recognition of

CHR. We note that the T_ms of the self-pairs are higher by

up to 6 °C compared to those of duplexes with a C–G pair

instead. This is due to the higher hydrophobicity of the

aromatic units, avoiding hydration by self-assembly upon

duplex formation.

In conclusion we find that carbocyclic exo-amino nucleo-

sides show all the characteristics of exo-amino nucleo-

sides in DNA base recognition. Despite the structural

flexibility imposed by the additional bond between the ar-

omatic and the sugar unit these molecular entities engage

in specific interactions with natural nucleotides and can

lead to self-pairs that match or exceed the stability of Wat-

son–Crick base-pairs. These are necessary prerequisites

for applications as tools in biotechnology. In a completely

different context, such carbocyclic exo-amino nucleosides

may also be of interest in medicinal chemistry. Corre-

sponding testing for antiviral activity will be performed in

the near future.

¹³C NMR (101 MHz, CDCl₃): d = 147.64 (d, C_aniline), 138.41 (d,

q-C_Bn), 129.19 (s), 128.41 (d), 127.79 (s), 127.71–127.44 (m) (C_Bn,

C

_aniline), 117.01 (s, C_aniline), 113.29 (d, C_aniline), 81.89 (d, C3¢), 73.16

(d, CH₂Ph), 72.07 (d, C5¢), 71.10 (d, CH₂Ph), 52.78 (d, C1¢), 44.77

(d, C4¢), 39.02 (d, C2¢), 34.98 (d, C6¢).

HRMS (ESI+): m/z [M + H]⁺calcd for C₂₆H₃₀NO₂: 388.2271;

found: 388.2271.

N¹-{(3S,4R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]cyclopen-

tyl}naphthalene-1,5-diamine (7)

Starting from 1 (3 g, 9.7 mmol); yield: 1.62 g (37%); TLC (hexane–

EtOAc, 3:1): R_f= 0.29.

Reactions were carried out under argon. Solvents for reactions were

dried by filtration over activated alumina. Solvents for extractions

and chromatography were technical grade and distilled before use.

All other reagents were purchased from Fluka, Aldrich, Acros Or-

ganics, Hänseler, ABCR, and TCI and were of the highest quality

available. TLC was carried out using pre-coated silica gel plates

SIL-G-25 UV254 (Macherey-Nagel). Visualization was performed

under UV-light (254 nm or 350 nm) and by using the following

staining reagents; (a): Ce(SO₄)₂(10.5 g), phosphomolybdic acid (21

g), concd H₂SO₄(60 mL), and H₂O (900 mL), or (b): anisaldehyde

(10 mL), concd H₂SO₄(10 mL), AcOH (2 mL), and EtOH (180

mL). Flash chromatography (FC) was performed on Silica Gel 60

(mesh size: 40–63 mm) from Fluka or SiliCycle. DMT = 4,4¢-

dimethoxytrityl, TFA = trifluoroacetyl.

¹H NMR (400 MHz, CDCl₃): d = 7.40–7.27 (m, 11 H, H_arom

,

H_Naphth), 7.22–7.11 (m, 2 H, H_Naphth), 7.07–7.00 (m, 1 H, H_Naphth),

6.78–6.68 (m, 1 H, H_Naphth), 6.59 (dd, J = 20.6, 7.5 Hz, 1 H, H_Naphth),

4.63–4.45 (m, 4 H, CH₂Ph), 4.23–4.14 (m, 1 H, H1¢), 4.24–4.14 (m,

1 H, H3¢), 4.08–4.00 (m, 1 H, H3¢), 3.54 (d, J = 5.2 Hz, 1 H, H5¢),

3.50–3.31 (m, 1 H, H5¢), 2.64–2.51 (m, 1 H, H4¢, H6¢), 2.47–2.39

(m, 0.5 H, H4¢), 2.27–2.09 (m, 2 H, H2¢, H6¢), 1.99 (dt, J = 18.1, 6.4

Hz, 0.5 H, H2¢), 1.68 (ddd, J = 13.1, 9.5, 5.6 Hz, 0.5 H, H6¢), 1.52–

1.47 (m, 0.5 H, H6¢).

¹³C NMR (101 MHz, CDCl₃): d = 143.27 (s, C_Naphth), 143.09–

142.20 (m, C_Naphth), 139.14–138.12 (m, q-C_Bn), 129.03–127.07 (m,

C_Bn, C_Naphth), 125.62 (d, C_Naphth), 124.88 (d, C_Naphth), 124.46–123.60

(m, C_Naphth), 110.96 (d, C_Naphth), 110.02–108.59 (m, C_Naphth), 104.89

(d, C_Naphth), 82.35 (d, C3¢), 73.14 (d, CH₂Ph), 72.04 (d, C5¢), 71.21

(d, CH₂Ph), 53.04 (d, C1¢), 44.79 (d, C4¢), 38.87 (d, C2¢), 35.54–

33.68 (d, C6¢).

NMR spectra were recorded on a Bruker AC-300, Bruker DRX-

1

400, or Bruker DRX-500 spectrometer. H NMR spectra were re-

corded at 300 MHz or 400 MHz relative to undeuterated residual

solvent [d = 7.26 (CDCl₃), d = 3.31 (CD₃OD), d = 2.50 (DMSO-d₆),

and d = 2.05 (acetone-d₆)]. ¹³C NMR spectra were recorded at 75

MHz or 101 MHz relative to undeuterated residual solvent [d =

77.16 (CDCl₃), d = 49.00 (CD₃OD), d = 29.84 and 206.26 (acetone-

d₆), and d = 39.52 (DMSO-d₆)]. Signal assignments were based on

DEPT or APT experiments, or on ¹H/¹H and ¹H/¹³C correlation ex-

periments (COSY/HSQC). ¹H/¹H-ROESY experiments were re-

corded at 400 MHz. ³¹P NMR spectra at 162 MHz relative to 85%

H₃PO₄as the external standard. ¹⁹F NMR spectra were recorded at

376 MHz. ESI-MS were recorded either on a Fisons Instrument VG

Platform (low resolution) or on an Applied Biosystems, Sciex

QSTAR Pulsar (high resolution).

HRMS (ESI+): m/z [M + H]⁺calcd for C₃₀H₃₃N₂O₂: 453.2537;

found: 453.2539.

N¹-{(3S,4R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]cyclopen-

tyl}benzene-1,3-diamine (12)

Starting from 1 (1 g, 3.2 mmol); yield: 460 mg (36%); TLC (hex-

ane–EtOAc, 1:1): R_f= 0.35.

¹H NMR (400MHz, CDCl₃): d = 7.39–7.22 (m, 10 H, H_arom), 7.69

(q, J = 7.9 Hz, 1 H, H_phenylene), 6.06–5.97 (m, 1.5 H, H_phenylene), 5.95–

5.86 (m, 1 H, H_phenylene), 5.75 (t, J = 2.1 Hz, 0.5 H, H_phenylene), 4.56–

4.37 (m, 5 H, CH₂Ph, H5¢), 4.01–3.83 (m, 2 H, H1¢, H3¢), 3.52–3.31

(m, 1 H, C5¢), 2.57–2.30 (m, 1.5 H, H4¢, H6¢), 2.20–2.06 (m, 1 H,

H2¢), 2.04–1.95 (m, 0.5 H, H6¢), 1.89–1.78 (m, 1 H, H2¢), 1.74–1.61

(m, 0.5 H, H6¢), 1.37–1.28 (m, 0.5 H, H6¢).

¹³C NMR (101 MHz, CDCl₃): d = 148.96 (d, C_phenylene), 147.57 (s,

q-C_Bn), 130.15 (d, C_phenylene), 128.55 (d), 128.01 (s), 127.77 (d),

127.70–127.58 (m) (C_Bn), 104.92–104.25 (m, C_phenylene), 100.27–

99.76 (m, C_phenylene), 82.01 (d, C3¢), 73.30 (d, CH₂Ph), 72.24 (d,

C5¢), 71.23 (d, CH₂Ph), 52.87 (d, C1¢), 44.88 (d, C4¢), 39.20 (d,

C2¢), 35.20 (d, C6¢).

Reductive Aminations; General Procedure

To a soln of 1²⁸(3–10 mmol) in THF (10 mL/mmol) was added gla-

cial AcOH (2 equiv) and amine (2 equiv) at r.t. and the resulting

mixture was stirred for 2 h. To this mixture, NaBH₃CN (2 equiv)

was added and the mixture was stirred for a further 16 h. The result-

ing mixture was washed with sat. NaHCO₃and brine, and the aque-

ous layer was extracted with Et₂O. After evaporation of the

solvents, the crude residue was purified by flash chromatography

(hexane–EtOAc, 3:1) to yield the desired product 2, 7, 12, or 22,

each as a 1:1 mixture of a/b-epimers as a colorless oil.

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₂₆H₃₁N₂O₃: 403.2380;

found: 403.2380.

Synthesis 2012, 44, 1011–1025

1018

O. Yaren et al.

FEATURE ARTICLE

(3S,4R)-6-{3-(Benzyloxy)-4-[(benzyloxy)methyl]cyclopentyl-

amino}-2-phenyl-4H-chromen-4-one (22)

Starting from 1 (1.56 g, 5 mmol); yield: 1.00 g (38%); TLC (hex-

ane–EtOAc, 2:1): R_f= 0.27.

¹H NMR (400 MHz, CDCl₃): d = 8.01–7.76 (m, 2 H, H_chrom), 7.57–

7.44 (m, 3 H, H_chrom), 7.43–7.30 (m, 11 H, H_arom), 7.24 (dd, J = 14.5,

2.9 Hz, 1 H, H_chrom), 6.92–6.74 (m, 1 H, H_chrom), 6.57 (dd, J = 9.0,

2.9 Hz, 1 H, H_chrom), 4.59–4.44 (m, 4 H, CH₂Ph), 4.42–4.27 (m, 1 H,

NH), 4.04 (dtd, J = 11.0, 6.2, 3.7 Hz, 2 H, H1¢, H3¢), 3.62–3.31 (m,

2 H, H5¢), 2.61–2.46 (m, 1 H, H4¢), 2.48–2.25 (m, 1 H, H6¢), 2.23–

2.03 (m, 1 H, H2¢), 2.03–1.83 (m, 1 H, H2¢), 1.55–1.35 (m, 1 H,

H6¢).

H3¢), 3.59–3.48 (m, 1 H, H5¢), 3.41 (qt, J = 18.8, 9.2 Hz, 1 H, H5¢),

2.57–2.43 (m, 1 H, H2¢, H4¢), 2.34 (dtd, J = 15.7, 10.7, 6.4 Hz, 1 H,

H6¢, H4¢), 2.26–2.12 (m, 0.5 H, H2¢), 2.06–1.91 (m, 0.5 H, H6¢),

1.93–1.77 (m, 0.5 H, H6¢), 1.73–1.53 (m, 1 H, H2¢), 1.50–1.32 (m,

0.5 H, H6¢).

¹³C NMR (101 MHz, CDCl₃): d = 156.91 (dd, CF₃C=O), 138.42

(dd, C_aniline), 135.63 (s, q-C_Bn), 134.88 (s, q-C_Bn), 130.43 (d), 129.44

(d), 129.02 (d), 128.41 (dd), 127.79–127.37 (m) (C_Bn, C_aniline, CF₃),

79.65 (d, C3¢), 73.13 (t, CH₂Ph), 72.08–71.50 (m C5¢), 70.85 (s,

CH₂Ph), 57.48 (s, C1¢), 55.29 (s, C1¢), 44.28 (s), 43.37 (s) C4¢, 36.39

(s), 35.07 (s) C2¢, 31.18 (s), 30.46 (s) C6¢.

¹⁹F NMR (376 MHz, CDCl₃): d = –67.22 (d, N-TFA).

HRMS (ESI+): m/z [M + H]⁺calcd for C₂₈H₂₉F₃NO₃: 484.2093;

¹³C NMR (101 MHz, CDCl₃): d = 178.61 (d), 162.62 (d), 149.30

(d), 145.25 (d) (C_chrom), 139.17–137.65 (m, q-C_Bn), 131.74 (d,

found: 484.2094.

C_chrom), 130.71–127.23 (m, C_Bn, C_chrom), 126.16 (s), 124.85 (s),

121.87 (d), 118.92 (d), 106.64 (s), 104.00 (d) (C_chrom), 81.54 (d,

C3¢), 73.80 (d, CH₂Ph), 72.05 (d, C5¢), 71.23 (t, CH₂Ph), 53.12 (d,

C1¢), 44.76 (d, C4¢), 38.73 (d, C2¢), 34.75 (d, C6¢).

HRMS (ESI+): m/z [M + H]⁺calcd for C₃₅H₃₄NO₄: 532.2482;

(3S,4R)-N-{3-(Benzyloxy)-4-[(benzyloxy)methyl]cyclopentyl}-

2,2,2-trifluoro-N-[5-(2,2,2-trifluoroacetylamino)naphthalen-1-

yl]acetamide (8)

Starting from 7 (1.62 g, 3.6 mmol); yield: 2.3 g (98%); TLC (hex-

ane–EtOAc, 3:1): R_f= 0.48.

found: 532.2483.

¹H NMR (400 MHz, CDCl₃): d = 8.43 (s, 1 H, NH-TFA), 7.96–7.85

(m, 2 H, H_Naphth), 7.78 (ddd, J = 10.9, 8.5, 3.1 Hz, 1 H, H_Naphth),

7.64–7.48 (m, 2 H, H_Naphth), 7.45–7.19 (m, 10 H, H_Bn), 7.16–7.07

(m, 1 H, H_Naphth), 5.11–4.81 (m, 1 H, H1¢), 4.59–4.22 (m, 4 H,

CH₂Ph), 3.89–3.61 (m, 1 H, H3¢), 3.49–3.19 (m, 2 H, H5¢), 2.74–

2.50 (m, 0.5 H, H2¢), 2.43–2.23 (m, 1 H, H4¢), 2.21–2.04 (m, 1 H,

H2¢, H6¢), 1.98–1.73 (m, 1 H, H2¢), 1.66–1.49 (m, 0.5 H, H6¢), 1.44–

1.29 (m, 0.5 H, H6¢), 1.23–1.10 (m, 0.5 H, H6¢).

¹³C NMR (101 MHz, CDCl₃): d = 158.30–157.16 (m, CF₃C=O),

156.37–155.30 (m, CF₃C=O), 138.58–138.02 (m, q-C_Naphth),

134.54–132.45 (m, q-C_Bn), 130.14–126.88 (m, C_Bn, C_Naphth),

126.35–125.96 (m, CF₃), 122.92 (ddd, C_Naphth), 79.67 (dd, C3¢),

74.02–72.40 (m, CH₂Ph), 72.51–71.31 (m, CH₂Ph), 70.89 (d, C5¢),

59.95–59.50 (m, C1¢), 57.53 (d, C1¢), 44.80–43.11 (m, C4¢, 37.44–

34.46 (m, C2¢), 32.00–29.72 (m, C6¢).

N-{(3S,4R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]cyclopen-

tyl)pyridin-3-amine (17)

To a soln of 1 (0.1 g, 0.32 mmol, 1 equiv) in anhyd MeOH (1 mL)

was added pyridine-3-amine (60 mg, 0.64 mmol, 2 equiv), AcOH

(20 mL, 0.32 mmol, 1 equiv), and Mg(ClO₄)₂(4 mg, 0.016 mmol,

0.05 equiv) at r.t. and the mixture was stirred for 2 h. Then

NaBH₃CN (24 mg, 0.38 mmol, 1.2 equiv) was added and the mix-

ture stirred for a further 18 h at r.t. The mixture was then quenched

with sat. NaHCO₃(8 mL), and extracted with EtOAc (3 × 10 mL).

The organic layers were combined, dried (Na₂SO₄), and concentrat-

ed under vacuum. The crude product was purified by flash chroma-

tography (hexane–EtOAc, 2:1 to 1:1) to yield 17 (61 mg, 50%) as a

colorless oil; ratio a/b 1:1; R_f= 0.35 (hexane–EtOAc, 1:2).

¹H NMR (400 MHz, CDCl₃): d = 8.04–7.78 (m, 2 H, H_Py), 7.46–

7.26 (m, 10 H, H_Bn), 7.13–6.99 (m, 1 H, H_Py), 6.87–6.65 (m, 1 H,

H_Py), 4.65–4.44 (m, 4 H, CH₂Ph), 4.10–3.92 (m, 2 H, H1¢, H3¢),

3.62–3.34 (m, 2 H, H5¢), 2.60–2.52 (m, 0.5 H, H4¢), 2.52–2.37 (m,

1 H, H4¢, H6¢), 2.14 (m, 1 H, H2¢), 2.09–1.98 (m, 0.5 H, H6¢), 1.97–

1.84 (m, 1 H, H2¢), 1.72 (m, 0.5 H, H6¢), 1.48–1.36 (m, 0.5 H, H6¢).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.90 to –68.73 (m, N-TFA),

–74.84 to –75.79 (m, NH-TFA).

HRMS (ESI+): m/z [M + H]⁺calcd for C₃₄H₃₁F₆N₂O₄: 645.2183;

found: 645.2195.

¹³C NMR (101 MHz, CDCl₃): d = 143.65–143.63 (d, C_Py), 139.01–

137.89 (m, C_Py), 136.65 (d, C_Py), 129.09–127.39 (m, C_Bn), 123.76

(d, C_Py), 119.03 (d, C_Py), 82.07 (d, C3¢), 73.40 (d, CH₂Ph), 72.10 (d,

C5¢), 71.30 (d, CH₂Ph), 52.81 (d, C1¢), 44.86 (d, C4¢), 38.94 (d,

C2¢), 34.88 (d, C6¢).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₂₅H₂₉N₂O₂: 389.2224;

found: 389.2224.

N-{(3S,4R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]cyclopentyl}-

2,2,2-trifluoro-N-[3-(2,2,2-trifluoroacetamido)phenyl]acet-

amide (13)

Starting from 12 (0.96 g, 2.4 mmol); yield: 1.36 g (94%); TLC (hex-

ane–EtOAc, 3:1): R_f= 0.46.

¹H NMR (400 MHz, CDCl₃): d = 7.93 (d, J = 14.6 Hz, 1 H, NH-

TFA), 7.65–7.38 (m, 3 H, H_phenylene), 7.37–7.14 (m, 10 H, H_arom),

7.04 (t, J = 7.0 Hz, 1 H, H_phenylene), 5.04 (s, 0.5 H, C1¢), 4.90 (s, 0.5

H, H1¢), 4.55–4.32 (m, 4 H, CH₂Ph), 3.80 (dd, J = 12.4, 6.9 Hz, 0.5

H, H3¢), 3.72 (s, 0.5 H, H3¢), 3.46–3.19 (m, 2 H, H5¢), 2.38 (dd,

J = 15.8, 10.1 Hz, 1 H, H4¢, H2¢), 2.21 (s, 1 H, H4¢, H6¢), 2.07 (d,

J = 18.4 Hz, 0.5 H, H2¢), 1.86 (s, 0.5 H, H6¢), 1.74 (d, J = 17.4 Hz,

0.5 H, H6¢), 1.74 (d, J = 17.4 Hz, 1 H, H2¢), 1.55 (d, J = 12.0 Hz, 0.5

H, H6¢).

¹³C NMR (101 MHz, CDCl₃): d = 138.35 (m, C_phenylene), 129.97 (s,

C_phenylene), 128.68–127.76 (m, C_Bn, CF₃, C_phenylene), 122.62 (s),

122.37 (s), 121.34 (s) (C_phenylene), 79.76 (s, C3¢), 73.37 (s), 73.07 (s)

(CH₂Ph), 71.80 (d, J = 11.5 Hz, C5¢), 70.99 (s, CH₂Ph), 58.30–

57.22 (m, C1¢), 56.01–55.09 (m, C1¢), 44.36 (s, C4¢), 43.56 (s, C4¢),

36.55 (s), 35.20 (s) (C2¢), 31.26 (s), 30.67 (s) (C6¢).

Trifluoroacetylation; General Procedure

To a soln of benzylated carbocyclic nucleosides 2, 7, 12, 17, or 22

(1–3 mmol) in CH₂Cl₂(30 mL/mmol) at 0 °C was added Et₃N (2

equiv) and TFAA (2 equiv); the mixture was stirred at this temper-

ature for 2 h. After completion of the reaction (TLC monitoring),

the mixture was quenched with H₂O. The organic layer was washed

with brine and then evaporated under reduced pressure. The result-

ing residue was purified FC (hexane–EtOAc, 3:1) to yield com-

pound 3, 8, 13, 18, or 23 as a a/b 1:1 mixture as a yellowish foam.

(3S,4R)-N-{3-(Benzyloxy)-4-[(benzyloxy)methyl]cyclopentyl}-

2,2,2-trifluoro-N-phenylacetamide (3)

Starting from 2 (1 g, 2.6 mmol); yield: 1.17 g (94%); TLC (hexane–

EtOAc, 4:1): R_f= 0.56.

¹⁹F NMR (376 MHz, CDCl₃): d = –67.30 (d, N-TFA), –75.65 (d,

NH-TFA).

¹H NMR (400 MHz, CDCl₃): d = 7.60–7.21 (m, 15 H, H_arom

_aniline), 5.27–5.20 (m, 0.5 H, H1¢), 5.10–4.90 (m, 0.5 H, H1¢), 4.66–

,

H

4.48 (m, 4 H, CH₂Ph), 3.92 (dt, 0.5 H, H3¢), 3.87–3.74 (m, 0.5 H,

Synthesis 2012, 44, 1011–1025

FEATURE ARTICLE

Carbocyclic exo-Amino Nucleosides

1019

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₃₀H₂₉F₆N₂O₄: 595.2026;

found: 595.2026.

1.86–1.49 (m, 2.5 H, H4¢, H2¢, H6¢), 1.39–1.08 (m, 1 H, H6¢), 0.95–

0.67 (m, 0.5 H, H6¢).

¹³C NMR (101 MHz, DMSO-d₆): d = 157.20–155.09 (m, CF₃C=O),

136.04–134.00 (m, C_Naphth), 133.25–131.66 (m, C_Naphth, CF₃),

125.14 (d, C_Naphth), 71.43–69.61 (m, C3¢), 62.12 (s, C5¢), 58.13–

55.56 (m, C1¢), 49.36–45.20 (m, C4¢), 38.33–36.51 (m, C2¢), 32.13–

28.65 (m, C6¢).

¹⁹F NMR (376 MHz, DMSO-d₆): d = –67.25 to –67.52 (m, N-TFA),

–73.37 (d, NH-TFA).

N-{(3S,4R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]cyclopentyl}-

2,2,2-trifluoro-N-(pyridin-3-yl)acetamide (18)

Starting from 17 (0.49 g, 1.3 mmol); yield: 0.53 g (87%); TLC (hex-

ane–EtOAc, 2:1): R_f= 0.42.

¹H NMR (400 MHz, CDCl₃): d = 8.67 (t, J = 3.9 Hz, 1 H, H_Py), 8.45

(s, 1 H, H_Py), 7.67–7.08 (m, 12 H, H_Bn, H_Py), 5.17–5.01 (m, 0.5 H,

H1¢), 4.94 (m, 0.5 H, H1¢), 4.43 (m, 4 H, CH₂Ph), 3.81 (s, 0.5 H,

H3¢), 3.70 (s, 0.5 H, H3¢), 3.42–3.20 (m, 2 H, H5¢), 2.43–2.30 (m,

0.5 H, H4¢), 2.29–2.13 (m, 1 H, H4¢, H6¢), 2.07 (d, J = 18.6 Hz, 1 H,

H2¢), 1.88 (m, 0.5 H, H6¢), 1.67 (m, 0.5 H, H6¢), 1.42 (m, 1 H, H2¢),

1.29–1.14 (m, 0.5 H, H6¢).

¹³C NMR (101 MHz, CDCl₃): d = 156.59 (m, CF₃C=O), 150.91 (d,

C_Py), 139.62–136.43 (d, C_Py), 132.16 (d, CF₃), 129.29–126.78 (m,

C_Bn), 123.70 (d, C_Py), 79.56 (s, C3¢), 73.23 (d, CH₂Ph), 71.65 (d,

C5¢), 71.05 (s, CH₂Ph), 57.71 (s, C1¢), 55.68 (s, C1¢), 44.29 (s, C4¢),

43.51 (s, C4¢), 36.55 (d, C2¢), 35.31 (s, C2¢), 30.42 (m, C6¢).

HRMS (ESI+): m/z [M + Na]⁺calcd for C₂₀H₁₈F₆N₂NaO₄:

488.1063; found: 488.1070.

2,2,2-Trifluoro-N-[(3S,4R)-3-hydroxy-4-(hydroxymethyl)cyclo-

pentyl]-N-[3-(2,2,2-trifluoroacetamido)phenyl]acetamide (14)

Starting from 13 (0.46 g, 0.77 mmol); yield: 0.32 g (100%); TLC

(5% MeOH–CH₂Cl₂): R_f= 0.14.

¹H NMR (400 MHz, DMSO-d₆): d = 11.44 (s, 1 H, NH-TFA), 7.80

(t, J = 8.9 Hz, 1 H, H_phenylene), 7.62 (d, J = 12.0 Hz, 1 H, H_phenylene),

7.53 (q, J = 8.2 Hz, 1 H, H_phenylene), 7.22 (d, J = 7.7 Hz, 1 H,

H_phenylene), 4.94 (d, J = 5.8 Hz, 0.5 H, H1¢), 4.63 (s, 1.5 H, OH), 4.51

(d, J = 6.3 Hz, 0.5 H, H1¢), 4.45 (s, 0.5 H, OH), 3.70 (s, 1 H, H3¢),

3.40 (dd, J = 9.8, 5.0 Hz, 0.5 H, H4¢), 3.30–3.15 (m, 2 H, H5¢), 2.10

(d, J = 5.9 Hz, 0.5 H, H6¢), 2.02 (d, J = 7.0 Hz, 0.5 H, H2¢), 1.79–

1.37 (m, 2.5 H, H6¢, H2¢), 1.34–1.18 (m, 0.5 H, H2¢), 1.12–0.94 (m,

0.5 H, H6¢).

¹³C NMR (101 MHz, DMSO-d₆): d = 156.52–151.33 (m, CF₃C=O),

136.82–134.97 (m, C_phenylene, CF₃), 129.50 (s), 127.50 (s), 122.25

(s), 121.76 (s) (C_phenylene), 70.59 (s, C3¢), 62.32 (d, C5¢), 55.79–54.65

(m, C1¢), 47.92–47.07 (m, C4¢), 37.72 (s, C2¢), 30.38–29.16 (m,

C6¢).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.08 to –67.67 (m, N-TFA).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₂₇H₂₈F₃N₂O₃: 485.2047;

found: 485.2047.

N-{(3S,4R)-3-(Benzyloxy)-4-[(benzyloxy)methyl]cyclopentyl}-

2,2,2-trifluoro-N-(4-oxo-2-phenyl-4H-chromen-6-yl)acetamide

(23)

Starting from 22 (1.03 g, 1.6 mmol); yield: 0.90 g (74%); TLC (hex-

ane–EtOAc, 2:1): R_f= 0.55.

¹H NMR (400 MHz, CDCl₃): d = 8.10–7.86 (m, 3 H, H_chrom), 7.65–

7.40 (m, 5 H, H_arom, H_chrom), 7.39–7.27 (m, 6 H, H_arom, H_chrom), 7.25–

7.07 (m, 4 H, H_arom, H_chrom), 6.86 (d, J = 7.5 Hz, 1 H, H_chrom), 5.23–

4.87 (m, 1 H, H1¢), 4.56–4.35 (m, 4 H, CH₂Ph), 3.85–3.66 (m, 1 H,

H3¢), 3.45–3.28 (m, 2 H, H5¢), 2.46–2.32 (m, 1 H, H4¢), 2.31–2.06

(m, 2 H, H2¢, H6¢), 2.00–1.67 (m, 1 H, H6¢), 1.57–1.42 (m, 1 H,

H2¢).

¹⁹F NMR (376 MHz, DMSO-d₆): d = –66.36 (d, J = 8.0 Hz, N-

TFA), –73.96 (d, J = 12.7 Hz, NH-TFA).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₁₆H₁₇F₆N₂O₄: 415.1087;

found: 415.1087.

¹³C NMR (101 MHz, CDCl₃): d = 176.21 (s), 163.95 (s) (C_chrom),

156.47 (d, CF₃C=O), 138.26 (s, C_chrom), 136.74–134.60 (m, q-C_Bn),

131.68 (d), 130.25–125.55 (m), 125.03–122.90 (m), 119.25 (s),

2,2,2-Trifluoro-N-[(3S,4R)-3-hydroxy-4-(hydroxymethyl)cyclo-

pentyl]-N-(pyridin-3-yl)acetamide (19)

Starting from 18 (642 mg, 1.32 mmol); yield: 395 mg (98%); TLC

(5% MeOH–CH₂Cl₂): R_f= 0.27.

118.03–117.00 (m), 115.38–113.84 (m), 107.71 (s), (C_Bn, C_chrom

,

CF₃), 79.72 (m, C3¢), 72.92 (s, CH₂Ph), 71.51 (s, C5¢), 57.94 (d,

C1¢), 44.18 (d, C4¢), 34.69 (d, C2¢), 30.85 (d, C6¢).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.19 (d, N-TFA).

HRMS (ESI+): m/z [M + Na]⁺calcd for C₃₇H₃₂F₃NNaO₅: 651.2125;

¹H NMR (400 MHz, CD₃OD): d = 8.66 (t, J = 5.3 Hz, 1 H, H_Py),

8.53 (d, J = 9.8 Hz, 1 H, H_Py), 7.86 (t, J = 9.5 Hz, 1 H, H_Py), 7.59

(dd, J = 12.4, 7.2 Hz, 1 H, H_Py), 5.10 (t, J = 7.5 Hz, 0.5 H, H1¢), 4.83

(m, 0.5 H, H1¢), 3.89 (dd, J = 11.5, 5.6 Hz, 1 H, H3¢), 3.58–3.44 (m,

2 H, H5¢), 2.37–2.28 (m, 0.5 H, H2¢), 2.20 (dd, J = 12.8, 6.7 Hz, 0.5

H, H6¢), 1.96 (m, 1.5 H, H2¢, H4¢, H6¢), 1.86–1.71 (m, 1 H, H2¢,

H4¢), 1.69–1.55 (m, 0.5 H, H6¢), 1.42 (m, 0.5 H, H2¢), 1.21 (m, 0.5

H, H6¢).

¹³C NMR (101 MHz, CD₃OD): d = 157.27 (CF₃C=O), 151.80 (s,

C_Py), 151.18 (s, C_Py), 140.36 (s, C_Py), 134.39 (s, CF₃), 125.53 (s,

C_Py), 73.00 (d, C3¢), 64.14 (d, C5¢), 58.66 (s, C1¢), 57.17 (s, C1¢),

49.82 (s, C4¢), 48.58 (s, C4¢), 39.79 (s, C2¢), 38.91 (s, C2¢), 32.24 (s,

C6¢), 31.28 (s, C6¢).

found: 651.2123.

Debenzylation; General Procedure

To a soln of TFA-protected nucleosides 8, 13, 18, or 23 (1–3 mmol)

in MeOH (5 mL/mmol) was added 10% Pd/C (0.11 equiv) at r.t. and

the mixture was hydrogenated at atmospheric pressure. When the

reaction was complete (TLC monitoring), Pd/C was filtered off.

MeOH was evaporated and the resulting residue was purified by FC

(5% MeOH–CH₂Cl₂) to yield 9, 14, 19, or 24 as a/b 1:1 mixtures as

slightly yellow foam.

¹⁹F NMR (376 MHz, CD₃OD): d = –64.90 (s, N-TFA).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₁₃H₁₆F₃N₂O₃: 305.1108;

found: 305.1108.

2,2,2-Trifluoro-N-(5-{(3S,4R)-[3-hydroxy-4-(hydroxymeth-

yl)cyclopentyl](2,2,2-trifluoroacetyl)amino}naphthalen-1-

yl)acetamide (9)

Starting from 8 (2.30 g, 3.6 mmol); yield: 1.60 g (97%); TLC (5%

MeOH–CH₂Cl₂): R_f= 0.22.

¹H NMR (400 MHz, DMSO-d₆): d = 8.10 (t, J = 13.2 Hz, 1 H,

H_Naphth), 7.89–7.52 (m, 5 H, H_Naphth), 5.04–4.82 (m, 0.5 H, H1¢),

4.79–4.64 (m, 0.5 H, H1¢), 3.78–3.56 (m, 1 H, H3¢), 3.44–3.20 (m,

2 H, H5¢), 2.42–2.25 (m, 0.5 H, H2¢), 2.14–1.93 (m, 0.5 H, H2¢),

2,2,2-Trifluoro-N-[(3S,4R)-3-hydroxy-4-(hydroxymethyl)cyclo-

pentyl]-N-(4-oxo-2-phenyl-4H-chromen-6-yl)acetamide (24)

Starting from 23 (900 mg, 1.4 mmol); yield: 470 mg (75%); TLC

(5% MeOH–CH₂Cl₂): R_f= 0.31.

¹H NMR (400 MHz, acetone-d₆): d = 8.22–8.08 (m, 2 H), 8.04 (d,

J = 11.9 Hz, 1 H), 7.98–7.78 (m, 2 H), 7.69–7.56 (m, 3 H), 6.94 (d,

J = 2.9 Hz, 1 H) (H_chrom), 5.22–4.83 (m, 1 H, H1¢), 3.93 (dd,

Synthesis 2012, 44, 1011–1025

1020

O. Yaren et al.

FEATURE ARTICLE

J = 40.5, 23.2 Hz, 1 H, H3¢), 3.62–3.50 (m, 1 H, H5¢), 3.40 (d,

J = 5.7 Hz, 1 H, H5¢), 2.34–2.15 (m, 1 H, H6¢), 1.98 (dd, J = 21.5,

5.2 Hz, 1 H, H4¢), 1.91–1.80 (m, 1 H, H2¢), 1.76–1.42 (m, 1 H, H2¢),

1.39–1.19 (m, 1 H, H6¢).

¹³C NMR (101 MHz, acetone-d₆): d = 178.14–177.12 (m, C_chrom),

165.41–163.87 (m, C_chrom), 157.63–156.10 (m, CF₃C=O), 138.41–

136.62 (m, C_chrom), 130.06 (m, C_chrom), 120.98–119.44 (m, C_chrom),

118.67–116.79 (m, CF₃, C_chrom), 108.05 (s, C_chrom), 71.82 (d, C3¢),

64.56 (d, C5¢), 57.58 (d, C1¢), 50.57 (d, C4¢), 38.84 (d, C2¢), 31.92

(d, C6¢).

Epimer 5b

¹H NMR (400 MHz, CDCl₃): d = 7.47–7.33 (m, 4 H, H_DMT), 7.33–

7.23 (m, 5 H, H_DMT, H_aniline), 7.22–7.10 (m, 5 H, H_DMT), 6.86–6.74

(m, 4 H, H_DMT), 5.12–4.95 (m, 1 H, H1¢), 3.92–3.83 (m, 1 H, H3¢),

3.78 (d, J = 3.4 Hz, 6 H, OMe), 3.19 (ddd, J = 13.8, 9.0, 5.0 Hz, 1

H, H5¢), 2.91 (dd, J = 8.9, 7.3 Hz, 1 H, H5¢), 2.13 (s, OH-C3¢), 2.09

(dd, J = 9.0, 4.1 Hz, 1 H, H6¢), 2.07–2.03 (m, 1 H, H4¢), 1.95 (ddd,

J = 11.7, 7.7, 3.9 Hz, 1 H, H2¢), 1.81 (dt, J = 13.7, 8.2 Hz, 1 H, H2¢),

1.24 (t, J = 4.9 Hz, 1 H, H6¢).

¹³C NMR (101 MHz, CDCl₃): d = 158.41 (d, CF₃C=O, C_DMT),

144.76 (d, C_DMT), 136.13–135.66 (m, C_DMT), 130.36–130.11 (m,

¹⁹F NMR (376 MHz, CD₃OD): d = –67.80 (d, N-TFA).

HRMS (ESI+): m/z [M + H]⁺calcd for C₂₃H₂₁F₃NO₅: 448.1366;

C

_DMT, C_aniline), 129.94 (t, C_aniline), 129.64–128.79 (m, C_DMT),

128.29–127.53 (m, C_DMT), 126.71 (d, CF₃), 117.94–117.43 (m,

_aniline), 114.28 (s, C_aniline), 113.29–113.01 (m, C_DMT), 86.15 (s,

found: 448.1347.

C

C_DMT), 74.40 (d, C3¢), 65.34 (d, C5¢), 56.79 (d, C1¢), 55.09 (d,

2,2,2-Trifluoro-N-[(3S,4R)-3-hydroxy-4-(hydroxymethyl)cyclo-

pentyl]-N-phenylacetamide (4)

OMe), 46.83 (d, C4¢), 37.39 (d, C2¢), 31.40 (d, C6¢).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.40 (s, N-TFA).

A 1 M soln of BCl₃in CH₂Cl₂(33 mL) was slowly added to a soln

of 3 (1.165 g, 2.4 mmol) in CH₂Cl₂(140 mL) at –78 °C. The mixture

was stirred for 6 h at –78 °C. The mixture was allowed to warm to

–20 °C and MeOH (62 mL) was added slowly and the mixture

stirred at r.t. for a further 16 h. The solvents were removed under re-

duced pressure and the residue was concentrated several times with

MeOH. The crude product was purified by flash chromatography

(5% to 10% MeOH–CH₂Cl₂) to yield nucleoside 4 (628 mg, 86%)

as a colorless oil; ratio a/b 1:1; TLC (5% MeOH–CH₂Cl₂):

R_f= 0.35.

¹H NMR (400 MHz, CD₃OD): d = 7.57–7.44 (m, 3 H, H_aniline), 7.31

(d, J = 7.0 Hz, 2 H, H_aniline), 5.07 (tt, J = 10.4, 7.4 Hz, 0.5 H, H1¢),

4.81 (ddd, J = 15.3, 9.1, 5.6 Hz, 0.5 H, H1¢), 3.88 (tt, J = 7.4, 5.1 Hz,

1 H, H3¢), 3.65–3.56 (m, 0.5 H, H5¢), 3.53–3.47 (m, 0.5 H, H5¢),

3.45–3.34 (m, 1 H, H5¢), 2.34–2.26 (m, 0.5 H, H2¢), 2.26–2.15 (m,

0.5 H, H6¢), 2.05–1.99 (m, 0.5 H, H4¢), 1.98–1.90 (m, 1 H, H2¢,

H6¢), 1.87–1.80 (m, 1 H, H6¢, H4¢), 1.67 (ddd, J = 13.3, 10.3, 7.0

Hz, 0.5 H, H2¢), 1.48 (td, J = 11.6, 9.2 Hz, 0.5 H, H2¢), 1.26 (dt,

J = 12.4, 10.2 Hz, 0.5 H, H6¢).

Epimer 5a

¹H NMR (400 MHz, CDCl₃): d = 7.50–7.34 (m, 5 H, H_DMT), 7.34–

7.26 (m, 5 H, H_DMT, H_aniline), 7.24–7.13 (m, 4 H, H_DMT), 6.87–6.78

(m, 4 H, H_DMT), 4.78–4.64 (m, 1 H, H1¢), 3.98–3.89 (m, 1 H, H3¢),

3.80 (s, 6 H, OMe), 3.22 (dd, J = 9.0, 5.3 Hz, 1 H, H5¢), 2.95 (dd,

J = 16.0, 7.2 Hz, 1 H, H5¢), 2.70 (s, 1 H, OH-C3¢), 2.32–2.20 (m, 1

H, H2¢), 2.11–1.99 (m, 1 H, H4¢), 1.87 (ddd, J = 13.5, 10.2, 8.1 Hz,

1 H, H6¢), 1.70 (ddd, J = 12.6, 8.5, 6.3 Hz, 1 H, H6¢), 1.61 (dd,

J = 10.2, 8.5 Hz, 1 H, H2¢).

¹³C NMR (101 MHz, CDCl₃): d = 158.49 (d, CF₃C=O, C_DMT),

144.65 (s, C_DMT), 135.73 (d, C_DMT), 129.92 (t, C_aniline), 129.64–

129.05 (m, C_DMT), 128.21–127.51 (m, C_DMT), 126.82 (s, CF₃),

117.43–116.96 (m, C_aniline), 114.97–114.73 (m, C_aniline), 113.48–

112.88 (m, C_DMT), 86.17 (s, C_DMT), 75.20 (s, C3¢), 65.83 (s, C5¢),

56.00 (s, C1¢), 55.16 (d, OMe), 45.53 (d, C4¢), 37.95 (s, C2¢), 29.75

(d, C6¢).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.42 (s, N-TFA).

¹³C NMR (101 MHz, CD₃OD): d = 156.95 (dd, CF₃C=O), 138.67–

136.02 (m, C_aniline), 132.44–129.27 (m, C_aniline, CF₃), 120.22–115.77

(m, C_aniline), 73.91–72.37 (m, C3¢), 64.43 (d), 64.23 (d) C5¢, 58.48

(s), 56.84 (s) C1¢, 49.92 (s), 48.33 (s) C4¢, 39.74 (s), 38.83 (s) C2¢,

32.36 (s), 31.22 (s) C6¢.

¹⁹F NMR (376 MHz, CD₃OD): d = –68.80 (s, N-TFA).

HRMS (ESI+): m/z [M + H]⁺calcd for C₁₄H₁₆F₃NO₃: 304.1155;

HRMS (ESI+): m/z [M + Na]⁺calcd for C₃₅H₃₄F₃NNaO₅: 629.2281;

found: 629.2295.

N-[(3R,4S)-3-{[Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-hydroxycyclopentyl]-2,2,2-trifluoro-N-[5-(2,2,2-trifluoro-

acetylamino)naphthalen-1-yl]acetamide (10)

Starting from 9 (1.6 g, 0.34 mmol); total yield of 10a and 10b: 1.11

g (43%); ratio a/b 1:1; the minor rotamers of 10a and 10b were not

isolated; TLC (1% MeOH–CH₂Cl₂): R_f(10a) = 0.41, R_f(10b) =

0.31.

found: 304.1161.

DMT Protection; General Procedure

To a soln of the debenzylated carbocyclic nucleosides 4, 9, 14, 19,

or 24 (1–3 mmol) in pyridine (8 mL/mmol) at r.t. was added DMT-

Cl (1.3 equiv) in portions over 30 min. The resulting orange mixture

was stirred at r.t. for 3–4 h. Pyridine was co-evaporated with toluene

under reduced pressure. The residue was diluted with CH₂Cl₂and

washed with brine and the organic phase was dried (Na₂SO₄). After

evaporation of the solvent, the crude product was purified by flash

chromatography (0.2 to 1% MeOH–CH₂Cl₂or 2 to 30% hexane–

EtOAc) to yield both epimers a and b of 5, 10, 15, 20, or 25 in equal

amounts as a colorless foam. The respective configurations were as-

signed by ¹H/¹H-ROESY or NOE difference spectroscopy based on

H1¢H3¢ vs H1¢–H4¢ interactions for a- and b-epimers, respectively.

Epimer 10b

¹H NMR (400 MHz, CDCl₃): d = 8.50 (d, J = 17.0 Hz, 1 H, NH-

TFA), 7.90 (dd, J = 19.9, 8.0 Hz, 2 H, H_Naphth), 7.78 (d, J = 8.5 Hz,

1 H, H_Naphth), 7.64–7.58 (m, 1 H, H_Naphth), 7.51 (dd, J = 8.5, 7.4 Hz,

1 H, H_Naphth), 7.34–7.27 (m, 4 H, H_Naphth, H_DMT), 7.24–7.14 (m, 6 H,

H_DMT), 6.81–6.74 (m, 4 H, H_DMT), 5.11–4.94 (m, 1 H, H1¢), 4.02–

3.88 (m, 1 H, H3¢), 3.84–3.75 (m, 6 H, OMe), 3.26–3.15 (m, 1 H,

H5¢), 3.00–2.87 (m, 1 H, H5¢), 2.46–2.30 (m, 1 H, H6¢), 2.14–2.07

(m, 1 H, H4¢), 1.86–1.76 (m, 1 H, H2¢), 1.60–1.42 (m, 2 H, H2¢,

H6¢).

¹³C NMR (101 MHz, CDCl₃): d = 158.43 (d, CF₃C=O, C_DMT),

144.65 (s, C_DMT), 135.99 (d, C_DMT), 133.37 (d, C_Naphth), 129.93 (d,

C_DMT), 129.28–125.31 (m, C_DMT, C_Naphth, CF₃), 124.57–121.97 (m,

N-[(3R,4S)-3-{[Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-hydroxycyclopentyl]-2,2,2-trifluoro-N-phenylacetamide

(5)

Starting from 4 (628 mg, 2.1 mmol); total yield of 5a and 5b: 700

mg (56%); ratio a/b 1:1; TLC (CH₂Cl₂containing 0.5% MeOH):

R_f(5a) = 0.28, R_f(5b) = 0.13.

C

_Naphth), 113.18 (s, C_DMT), 86.22 (s, C_DMT), 74.42 (s, C3¢), 65.26 (s,

C5¢), 59.04 (s, C1¢), 55.30 (d, OMe), 46.79 (s, C4¢), 36.99 (s, C2¢),

31.91 (s, C6¢).

¹⁹F NMR (376 MHz, CDCl₃): d = –68.28 to –68.52 (m, N-TFA),

–75.05 to –75.43 (m, NH-TFA).

Synthesis 2012, 44, 1011–1025

FEATURE ARTICLE

Carbocyclic exo-Amino Nucleosides

1021

HRMS (ESI+): m/z [M + Na]⁺calcd for C₄₁H₃₆F₆N₂NaO₆:

790.2370; found: 790.2382.

¹⁹F NMR (376 MHz, CDCl₃): d = –67.33 (s, N-TFA), –75.62 (s,

NH-TFA).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₃₇H₃₅F₆N₂O₆: 717.2394;

found: 716.2312.

Epimer 10a

¹H NMR (400 MHz, CDCl₃): d = 8.74 (d, J = 13.4 Hz, 1 H, NH-

TFA), 7.95 (t, J = 8.0 Hz, 1 H, H_Naphth), 7.88 (t, J = 7.4 Hz, 1 H,

N-[(3R,4S)-3-{Bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-

4-hydroxycyclopentyl]-2,2,2-trifluoro-N-(pyridin-3-yl)acet-

amide (20)

Starting from 19 (390 mg, 1.3 mmol); yield: 20a (224 mg, 28%) and

20b (221 mg, 27%); TLC (hexane–EtOAc, 2:1): R_f(20a) = 0.34,

R_f(20b) = 0.19.

H

_Naphth), 7.75 (t, J = 6.5 Hz, 1 H, H_Naphth), 7.66–7.58 (m, 2 H,

_Naphth), 7.43 (dd, J = 10.7, 3.3 Hz, 1 H, H_Naphth), 7.41–7.33 (m, 2 H,

H_DMT), 7.33–7.27 (m, 5 H, H_DMT), 7.23–7.17 (m, 2 H, H_DMT), 6.86–

6.80 (m, 4 H, H_DMT), 4.67–4.48 (m, 1 H, H1¢), 3.92 (dt, J = 14.4, 8.0

Hz, 1 H, H3¢), 3.83–3.78 (m, 6 H, OMe), 3.35–3.23 (m, 1 H, H5¢),

3.05–2.96 (m, 1 H, H5¢), 2.94–2.80 (m, 1 H, OH-C3¢), 2.30–2.17

(m, 2 H, H4¢, H6¢), 2.19–2.10 (m, 1 H, H2¢), 2.00–1.86 (m, 1 H,

H6¢), 1.57–1.41 (m, 1 H, H2¢).

¹³C NMR (101 MHz, CDCl₃): d = 159.09–158.19 (m, C_DMT),

158.01–155.53 (m, CF₃C=O), 144.60 (s, C_DMT), 135.87 (d, C_DMT),

134.93 (s, C_Naphth), 132.22 (s, C_Naphth), 130.66–126.04 (m, C_DMT

Epimer 20b

¹H NMR (400 MHz, CDCl₃): d = 8.61 (dd, J = 4.8, 1.5 Hz, 1 H,

H_Py), 8.37 (s, 1 H, H_Py), 7.43 (d, J = 8.1 Hz, 1 H, H_Py), 7.38–7.04 (m,

11 H, H_DMT, H_Py), 6.77–6.63 (m, 4 H, H_DMT), 4.68 (s, 1 H, H1¢),

3.91–3.76 (m, 1 H, H3¢), 3.69 (s, 6 H, OMe), 3.13 (s, 1 H, H5¢), 2.87

(m, 1 H, H5¢), 2.49 (d, J = 15.4 Hz, 1 H, H4¢), 2.27–2.09 (m, 1 H,

H6¢), 1.99–1.85 (m, 1 H, H2¢, 1.77–1.54 (m, 1 H, H2¢), 1.45 (m, 1

H, H6¢).

,

C_Naphth, CF₃), 124.09–122.13 (m, C_Naphth), 113.19 (s, C_DMT), 86.49

(s, C_DMT), 75.39 (s, C3¢), 65.85 (s, C5¢), 58.97 (s, C1¢), 55.24 (d,

OMe), 45.80 (s, C4¢), 37.33 (s, C2¢), 30.99 (s, C6¢).

¹⁹F NMR (376 MHz, CDCl₃): d = –68.46 (d, N-TFA), –75.07 to

¹³C NMR (101 MHz, CDCl₃): d = 158.71 (s, CF₃C=O, C_DMT),

150.76 (s, C_Py), 144.77 (s, C_DMT), 139.71–135.91 (d, C_DMT, C_Py),

130.10 (d, C_DMT), 128.12–125.76 (m, C_DMT, CF₃), 123.89 (s, C_Py),

113.37 (s, C_DMT), 86.15 (d, C_DMT), 75.17 (s, C3¢), 65.96 (s, C5¢),

56.69 (s, C1¢), 55.37 (s, OMe), 45.78 (s, C4¢), 38.21 (s, C2¢), 29.9

(s, C6¢.

¹⁹F NMR (376 MHz, CDCl₃): d = –67.34 (s, N-TFA).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₃₄H₃₄F₃N₂O₅: 607.2414;

–75.42 (m, NH-TFA).

HRMS (ESI+): m/z [M + Na]⁺calcd for C₄₁H₃₆F₆N₂NaO₆:

790.2370; found: 790.2382.

N-[(3R,4S)-3-{[Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-hydroxycyclopentyl]-2,2,2-trifluoro-N-[3-(2,2,2-trifluoro-

acetamido)phenyl]acetamide (15)

Starting from 14 (320 mg, 0.70 mmol); yield: 15a (101 mg, 18%)

and 15b (124 mg, 22%); TLC (hexane–EtOAc, 2:1): R_f(15a) =

0.15, R_f(15b) = 0.13.

found: 607.2414.

Epimer 20a

¹H NMR (400 MHz, CDCl₃): d = 8.56 (d, J = 3.6 Hz, 1 H, H_Py), 8.31

(s, 1 H, H_Py), 7.37 (s, 1 H, H_Py), 7.29–7.06 (m, 11 H, H_DMT, H_Py),

6.71 (t, J = 5.8 Hz, 4 H, H_DMT), 4.99 (s, 1 H, H1¢), 3.79 (d, J = 3.1

Hz, 1 H, H3¢), 3.69 (s, 6 H, OMe), 3.10 (s, 1 H, H5¢), 2.81 (s, 1 H,

H5¢), 2.11–2.00 (m, 2 H, H4¢, H6¢), 1.96–1.86 (m, 1 H, H2¢), 1.64

(s, 1 H, H2¢), 1.07 (q, J = 14.0 Hz, 1 H, H6¢).

Epimer 15b

¹H NMR (400 MHz, CDCl₃): d = 8.29 (d, J = 67.2 Hz, 1 H, NH-

TFA), 7.72–7.00 (m, 13 H, H_DMT, H_phenylene), 6.88–6.71 (m, 4 H,

H_DMT), 5.09–4.92 (m, 1 H, H1¢), 3.94 (d, J = 14.1 Hz, 1 H, H3¢),

3.78 (s, 7 H, OMe), 3.20 (dd, J = 9.2, 4.5 Hz, 1 H, H5¢), 2.94 (t,

J = 7.9 Hz, 1 H, H5¢), 2.26 (s, 1 H, OH-C3¢), 2.09 (d, J = 4.2 Hz, 2

H, H4¢), 1.96 (d, J = 7.9 Hz, 1 H, H6¢), 1.80 (dt, J = 13.7, 8.3 Hz, 1

H, H2¢), 1.68 (s, 1 H, H2¢), 1.28–1.16 (m, 1 H, H6¢).

¹³C NMR (101 MHz, CDCl₃): d = 158.76 (s, CF₃C=O, C_DMT),

151.14 (s, C_Py), 150.75 (s, C_Py), 144.95 (s, C_DMT), 137.86 (s, C_Py),

136.04–128.17 (m, C_DMT), 127.09 (s, CF₃), 123.88 (s, C_Py), 113.40

(s, C_DMT), 86.55 (s, C_DMT), 74.53 (s, C3¢), 65.49 (s, C5¢), 57.16 (s,

C1¢), 55.47 (s, OMe), 47.01 (s, C4¢), 37.62 (s, C2¢), 31.57 (s, C6¢).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.36 (s, N-TFA).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₃₄H₃₄F₃N₂O₅: 607.2414;

¹³C NMR (101 MHz, CDCl₃): d = 158.71–155.41 (m, CF₃C=O,

C_DMT), 145.00 (s, C_DMT), 136.92 (m, C_phenylene), 135.93–135.14 (m),

130.21 (d, C_DMT), 130.17 (m, C_phenylene), 128.15–127.05 (s, C_DMT

,

CF₃), 122.39 (s), 121.46 (s) (C_phenylene), 113.38 (s, C_DMT), 86.51 (s,

C

_DMT), 74.51 (s, C3¢), 65.63 (s, C5¢), 60.69 (s), 57.37 (s, C1¢), 55.47

(s, OMe), 47.04 (s, C4¢), 37.71 (s, C2¢), 31.74 (s, C6¢).

found: 607.2414.

¹⁹F NMR (376 MHz, CDCl₃): d = –65.15 to –67.72 (m, N-TFA),

N-[(3R,4S)-3-{[Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-hydroxycyclopentyl}-2,2,2-trifluoro-N-(4-oxo-2-phenyl-

4H-chromen-6-yl)acetamide (25)

Starting from 24 (470 mg, 1.05 mmol); total yield of 25a and 25b:

623 mg (80%); ratio a/b 1:1; TLC (0.5% MeOH–CH₂Cl₂): R_f(25a) =

0.15, R_f(25b) = 0.11.

–74.57 to –76.27 (m, NH-TFA).

HRMS (ESI⁺): m/z [M + Na]⁺calcd for C₃₇H₃₄F₆N₂NaO₆: 739.2219;

found: 739.2219.

Epimer 15a

¹H NMR (400 MHz, CDCl₃): d = 8.11 (d, J = 19.3 Hz, 1 H, NH-

TFA), 7.61–6.90 (m, 13 H, H_DMT, H_phenylene), 6.73 (d, J = 8.8 Hz, 4

H, H_DMT), 4.71–4.52 (m, 1 H, H1¢), 3.91–3.79 (m, 1 H, H3¢), 3.71

(d, J = 3.8 Hz, 6 H, OMe), 3.15 (s, 1 H, H5¢), 2.88 (t, J = 8.7 Hz, 1

H, H5¢), 2.70–2.58 (m, 1 H, OH-C3¢), 2.26–2.07 (m, 1 H, H2¢), 1.98

(d, J = 14.3 Hz, 1 H, H4¢), 1.79 (d, J = 6.9 Hz, 1 H, H6¢), 1.63 (ddd,

J = 13.8, 8.9, 6.9 Hz, 1 H, H6¢), 1.55–1.42 (m, 1 H, H2¢).

Epimer 25b

¹H NMR (400 MHz, CDCl₃): d = 8.05–7.95 (m, 3 H, H_chrom), 7.76–

7.43 (m, 6 H, H_chrom, H_DMT), 7.32–7.13 (m, 8 H, H_chrom, H_DMT), 6.89–

6.78 (m, 5 H, H_DMT, H_chrom), 5.21 (dd, J = 16.9, 7.9 Hz, 1 H, H1¢),

4.03 (t, J = 21.9 Hz, 1 H, H3¢), 3.80 (s, 6 H, OMe), 3.41–3.14 (m, 1

H, H5¢), 2.98 (dt, J = 55.9, 7.2 Hz, 1 H, H5¢), 2.26–2.13 (m, 2 H,

H6¢, H4¢), 2.13–2.00 (m, 1 H, H2¢), 1.98–1.77 (m, 1 H, H2¢), 1.44–

1.26 (m, 1 H, H6¢).

¹³C NMR (101 MHz, CDCl₃): d = 158.69–155.12 (m, CF₃C=O,

C_DMT), 144.81 (s, C_DMT), 137.12 (m, C_phenylene), 135.95 (d, C_DMT),

130.12 (d, C_DMT), 129.28 (s, C_phenylene), 128.11–127.04 (m, C_DMT

,

¹³C NMR (101 MHz, CDCl₃): d = 176.76 (s, C_chrom), 164.37 (s,

CF₃, C_phenylene), 122.18 (s), 121.38 (s) (C_phenylene), 113.36 (s, C_DMT),

86.64 (s, C_DMT), 75.43 (s, C3¢), 65.98 (s, C5¢), 55.93 (s, C1¢), 55.37

(s, OMe), 45.80 (s, C4¢), 38.29 (s, C2¢), 30.08 (s, C6¢).

C_chrom), 158.44 (s, CF₃C=O), 155.97 (s, C_DMT), 144.76 (s, C_DMT),

137.40–118.48 (m, C_DMT, C_chrom, CF₃), 113.09 (s, C_DMT), 107.65 (s,

Synthesis 2012, 44, 1011–1025

1022

O. Yaren et al.

FEATURE ARTICLE

¹⁹F NMR (376 MHz, CDCl₃): d = –67.34 (d, N-TFA).

HRMS (ESI+): m/z [M + Na]⁺calcd for C₄₄H₅₁F₃N₃NaO₆P:

829.3360; found: 829.3375.

C_chrom), 86.32 (s, C_DMT), 74.36 (s, C3¢), 65.11 (s, C5¢), 56.84 (s, C1¢),

55.19 (d, OMe), 46.79 (s, C4¢), 37.73 (s, C2¢), 31.50 (s, C6¢).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.14 (s, N-TFA).

HRMS (ESI+): m/z [M + Na]⁺calcd for C₄₄H₃₈F₃NNaO₇: 773.2493;

found: 773.2508.

(1S,2R,4S)-2-{[(Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-(2,2,2-trifluoro-N-phenylacetamido)cyclopentyl 2-Cyano-

ethyl Diisopropylphosphoramidite (6a)

Starting from 5a (76 mg, 0.13 mmol); yield: 70 mg (68%); TLC

(hexane–EtOAc, 2:1): R_f= 0.68.

Epimer 25a

¹H NMR (400 MHz, CDCl₃): d = 8.07 (d, J = 2.3 Hz, 1 H, H_chrom),

8.00–7.90 (m, 2 H, H_chrom), 7.68 (d, J = 8.8 Hz, 1 H, H_chrom), 7.60–

7.37 (m, 5 H, H_DMT, H_chrom), 7.33–7.11 (m, 8 H, H_DMT, H_chrom), 6.85

(dd, J = 16.1, 11.5 Hz, 5 H, H_DMT, H_chrom), 4.87–4.68 (m, 1 H, H1¢),

3.97 (s, 1 H, H3¢), 3.80 (s, 6 H, OMe), 3.34–3.17 (m, 1 H, H5¢), 2.99

(dt, J = 17.3, 8.8 Hz, 1 H, H5¢), 2.45–2.20 (m, 1 H, H2¢), 2.08 (dd,

J = 10.7, 5.7 Hz, 1 H, H4¢), 1.99–1.86 (m, 1 H, H6¢), 1.86–1.73 (m,

1 H, H6¢), 1.70–1.56 (m, 1 H, H2¢).

¹H NMR (400 MHz, CDCl₃): d = 7.53–7.40 (m, 4 H, H_DMT), 7.38–

7.30 (m, 5 H, H_DMT, H_aniline), 7.27–7.16 (m, 5 H, H_DMT, H_aniline),

6.91–6.81 (m, 4 H, H_DMT), 5.01–4.83 (m, 1 H, H1¢), 4.19–3.98 (m,

1 H, H3¢), 3.82 (d, J = 2.6 Hz, 6 H, OMe), 3.77–3.60 (m, 1 H,

POCH₂), 3.57–3.41 (m, 3 H, Me₂CH, POCH₂), 3.23–3.13 (m, 1 H,

H5¢), 3.11–2.94 (m, 1 H, H5¢), 2.60–2.53 (m, 1 H, CH₂CN), 2.47–

2.38 (m, 1 H, CH₂CN), 2.36–2.26 (m, 1 H, H2¢), 2.21–2.07 (m, 1 H,

H4¢), 2.05–1.94 (m, 1 H, H6¢), 1.94–1.81 (m, 1 H, H6¢), 1.62–1.48

(m, 1 H, H2¢), 1.09 (ddt, J = 29.4, 24.9, 6.3 Hz, 12 H, Me₂CH).

¹³C NMR (101 MHz, CDCl₃): d = 158.43 (d, C_DMT), 156.89 (d,

CF₃C=O), 144.99 (d, C_DMT), 136.35–136.02 (m, C_DMT), 135.21 (d,

C_aniline), 130.56 (d), 130.27–130.08 (m), 129.43 (d), 129.08 (d),

128.25 (d), 127.77 (s) (C_DMT, C_aniline), 126.71 (d, CF₃), 120.79–

120.65 (m, C_aniline), 117.65 (d, CN), 114.90 (s, C_aniline), 113.41–

112.94 (m, C_DMT), 85.94 (s, C_DMT), 74.92 (s, C3¢, 73.78 (s, C3¢,

63.84 (d, s, C5¢, 58.18 (dd, POCH₂), 55.62 (s, C1¢), 55.21 (d, OMe),

45.36 (dd, C4¢), 43.05 (d, Me₂CH), 37.89 (s, C2¢), 30.38 (d, C6¢),

24.50 (ddd, Me₂CH), 20.22 (dd, CH₂CN).

¹³C NMR (101 MHz, CDCl₃): d = 177.73 (s, C_chrom), 164.48 (s,

C_chrom), 158.55 (s, CF₃C=O), 155.45 (s, C_DMT), 145.54–143.75 (m,

C_DMT, C_chrom), 137.00–123.50 (m, C_DMT, C_chrom, CF₃), 119.45 (s,

_chrom), 113.22 (s, C_DMT), 107.73 (s, C_chrom), 86.67 (s, C_DMT), 75.29

C

(s, C3¢), 65.94 (s, C5¢), 55.61 (s, C1¢), 55.22 (s, OMe), 45.44 (s,

C4¢), 37.73 (s, C2¢), 29.66 (s, C6¢).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.18 (s, N-TFA).

HRMS (ESI+): m/z [M + Na]⁺calcd for C₄₄H₃₈F₃NNaO₇: 773.2493;

found: 773.2508.

Phosphoramidites; General Procedure

To a soln of H_DMT-protected nucleosides 5a, 5b, 10a, 10b, 15a, 15b,

20a, 20b, 25a, or 25b (0.1–0.5 mmol) in THF (2.5 mL/mmol) was

added i-Pr₂NEt (3 equiv) and (2-cyanoethoxy)chloro(diisopropyl-

amino)phosphine (1.2 equiv) at r.t. The resulting mixture was

stirred for 0.5–1 h at r.t. When reaction was complete (TLC moni-

toring), the mixture was diluted with EtOAc, washed with sat.

NaHCO₃, and the aqueous layers extracted with CH₂Cl₂. The com-

bined organic layers were dried (Na₂SO₄) and the solvent was evap-

orated under reduced pressure. The crude product was purified by

FC (hexane–EtOAc, 2:1) to yield 6a, 6b, 11a, 11b, 16a, 16b, 21a,

21b, 26a, or 26b as a colorless foam.

³¹P NMR (162 MHz, CDCl₃): d = 148.33 (s), 147.91 (s).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.30 (d, N-TFA).

HRMS (ESI+): m/z [M + Na]⁺calcd for C₄₄H₅₁F₃N₃NaO₆P:

829.3360; found: 829.3375.

(1S,2R,4R)-2-{[(Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-{2,2,2-trifluoro-N-[5-(2,2,2-trifluoroacetamido)naph-

thalen-1-yl]acetamido}cyclopentyl 2-Cyanoethyl Diisopropyl-

phosphoramidite (11b)

Starting from 10b (218 mg, 0.28 mmol); yield: 168 mg (62%); TLC

(hexane–EtOAc, 2:1): R_f= 0.52.

(1S,2R,4R)-2-{[(Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-(2,2,2-trifluoro-N-phenylacetamido)cyclopentyl 2-Cyano-

ethyl Diisopropylphosphoramidite (6b)

Starting from 5b (344 mg, 0.57 mmol); yield: 220 mg (48%); TLC

(hexane–EtOAc, 2:1): R_f= 0.7.

¹H NMR (400 MHz, CDCl₃): d = 7.51–7.36 (m, 4 H, H_DMT), 7.36–

7.20 (m, 10 H, H_DMT, H_aniline), 6.84–6.75 (m, 4 H, H_DMT), 5.21–5.09

(m, 1 H, H1¢), 4.11–3.98 (m, 1 H, H3¢), 3.85–3.79 (m, 6 H, OMe),

3.79–3.71 (m, 1 H, POCH₂), 3.65–3.48 (m, 3 H, Me₂CH, POCH₂),

3.10–2.91 (m, 2 H, H5¢), 2.66–2.58 (m, 1 H, CH₂CN), 2.47–2.38

(m, 1 H, CH₂CN), 2.27 (dd, J = 20.1, 6.6 Hz, 2 H, H4¢, H6¢), 2.17–

1.97 (m, 1 H, H2¢), 1.71–1.58 (m, 1 H, H2¢), 1.51–1.31 (m, 1 H,

H6¢), 1.22–1.03 (m, 12 H, Me₂CH).

¹H NMR (400 MHz, CDCl₃): d = 8.56 (s, 1 H, NH-TFA), 7.99–7.75

(m, 3 H, H_Naphth), 7.71–7.57 (m, 1 H, H_Naphth), 7.52–7.43 (m, 1 H,

H_Naphth), 7.37–7.27 (m, 3 H, H_Naphth, H_DMT), 7.25–7.10 (m, 7 H, H_D-

_MT), 6.81–6.66 (m, 4 H, H_DMT), 5.18 (dq, J = 15.6, 7.8 Hz, 1 H, H1¢),

4.01 (ddd, J = 18.3, 5.2, 2.7 Hz, 1 H, H3¢), 3.84–3.78 (m, 6 H,

OMe), 3.71–3.63 (m, 1 H, POCH₂), 3.61–3.46 (m, 3 H, Me₂CH,

POCH₂), 3.05–2.96 (m, 1 H, H5¢), 2.95–2.84 (m, 1 H, H5¢), 2.57–

2.47 (m, 2 H, C6¢, CH₂CN), 2.44–2.35 (m, 1 H, CH₂CN), 2.31 (dd,

J = 14.7, 10.2 Hz, 1 H, H4¢), 1.99–1.80 (m, 1 H, H2¢), 1.53 (ddd,

J = 21.6, 18.6, 9.6 Hz, 1 H, H6¢), 1.38–1.23 (m, 1 H, H2¢), 1.15–

1.01 (m, 12 H, Me₂CH).

¹³C NMR (101 MHz, CDCl₃): d = 158.29 (d, CF₃C=O, C_DMT),

144.72 (s, C_DMT), 136.94–135.50 (m, C_DMT), 133.11 (d, C_Naphth),

130.83–125.86 (m, C_DMT, C_Naphth, CF₃), 123.14 (dd, C_Naphth), 117.51

(s, CN), 113.03 (t, C_DMT), 85.80 (s, C_DMT), 74.91 (dd, C3¢), 63.82 (d,

C5¢), 58.64 (d, POCH₂), 58.14 (d, C1¢), 55.31 (t, OMe), 45.82 (s,

C4¢), 43.12 (d, Me₂CH), 36.66 (s, C2¢), 31.78 (s, C6¢), 24.78–24.19

(m, Me₂CH), 20.23 (dd, CH₂CN).

¹³C NMR (101 MHz, CDCl₃): d = 158.38 (d, C_DMT), 156.89 (d,

CF₃C=O), 144.99 (s, C_DMT), 136.63–136.08 (m, C_DMT), 135.36 (d,

C_aniline), 130.33 (t), 130.05 (d), 129.36 (d), 129.01 (t), 128.12 (d),

127.74 (d) (C_DMT, C_aniline), 126.65 (d, CF₃), 121.23–120.35 (m,

C_aniline), 117.64 (d, CN), 114.90 (s, C_aniline), 113.53–112.48 (m,

C_DMT), 85.76 (s, C_DMT), 74.62 (dd, C3¢), 63.79 (d, C5¢), 58.18 (dd,

³¹P NMR (162 MHz, CDCl₃): d = 147.66 (s), 147.58 (s).

¹⁹F NMR (376 MHz, CDCl₃): d = –68.34 (d, N-TFA), –75.21 to

–75.34 (m, NH-TFA).

POCH₂), 56.82 (s, C1¢), 55.20 (d, OMe), 46.23 (dd, C4¢), 43.14 (dd,

Me₂CH), 37.62–36.98 (m, C2¢), 31.33 (d, C6¢), 24.93–24.05 (m,

Me₂CH), 20.27 (dd, CH₂CN).

³¹P NMR (162 MHz, CDCl₃): d = 147.83 (s), 147.31 (s).

HRMS (ESI+): m/z [M + Na]⁺calcd for C₅₀H₅₃F₆N₄NaO₇P:

990.3401; found: 990.3411.

Synthesis 2012, 44, 1011–1025

FEATURE ARTICLE

Carbocyclic exo-Amino Nucleosides

1023

(1S,2R,4S)-2-{[(Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-{2,2,2-trifluoro-N-[5-(2,2,2-trifluoroacetamido)naph-

thalen-1-yl]acetamido}cyclopentyl 2-Cyanoethyl

Diisopropylphosphoramidite (11a)

Starting from 10a (284 mg, 0.37 mmol); yield: 315 mg (88%); TLC

(hexane–EtOAc, 2:1): R_f= 0.6.

H, C_DMT), 5.01–4.73 (m, 1 H, H1¢), 4.19–4.07 (m, 1 H, H3¢), 3.79 (s,

6 H, OMe), 3.66–3.36 (m, 4 H, Me₂CH, POCH₂), 3.19–2.94 (m, 2

H, H5¢), 2.71–2.56 (m, 1 H, CH₂CN), 2.45–2.34 (m, 1 H, CH₂CN),

2.34 (s, 1 H, H2¢), 2.14–1.95 (m, 1 H, H4¢), 1.89–1.85 (m, 1 H, H6¢),

1.85–1.70 (m, 0.5 H, H6¢), 1.64–1.50 (s, 1 H, H2¢, 1.25–1.14 (s, 0.5

H, H6¢), 1.05–0.84 (m, 12 H, Me₂CH).

¹H NMR (400 MHz, CDCl₃): d = 8.80 (s, 1 H, NH-TFA), 7.97 (dd,

J = 8.5, 6.2 Hz, 1 H, H_Naphth), 7.89–7.76 (m, 2 H, H_Naphth), 7.64–7.54

(m, 2 H, H_Naphth), 7.51–7.37 (m, 4 H, H_Naphth, H_DMT), 7.32–7.14 (m,

6 H, H_DMT), 6.92–6.79 (m, 4 H, H_DMT), 4.99–4.82 (m, 1 H, H1¢),

4.09–3.92 (m, 1 H, H3¢), 3.84–3.75 (m, 6 H, OMe), 3.52–3.33 (m,

4 H, Me₂CH, POCH₂), 3.11 (dddd, J = 26.6, 15.3, 8.9, 5.5 Hz, 2 H,

H5¢), 2.38–2.24 (m, 4 H, CH₂CN, H6¢, H4¢), 2.20–2.06 (m, 2 H, H2¢,

H6¢), 1.39–1.22 (m, 1 H, H2¢), 1.07–0.75 (m, 12 H, Me₂CH).

¹³C NMR (101 MHz, CDCl₃): d = 158.59–155.12 (d, CF₃C=O,

C_DMT), 145.06 (s, C_DMT), 136.06 (d, q-C_phenylene), 130.31–126.89 (m,

C_DMT, C_phenylene, CF₃), 123.10–120.24 (m, C_phenylene), 113.22 (s,

C_DMT), 86.81–85.66 (m, C_DMT), 75.88 (s, C3¢, 63.46 (d, C5¢, 58.35–

57.28 (d, POCH₂), 55.36 (d, OMe), 45.61 (d, C4¢, 43.19 (d,

Me₂CH), 39.59 (s, C2¢), 30.18 (s, C6¢), 24.69–24.14 (m, Me₂CH),

21.19 (s, CH₂CN).

³¹P NMR (162 MHz, CDCl₃): d = 153.34–139.04 (m).

¹³C NMR (101 MHz, CDCl₃): d = 158.44 (s, C_DMT), 157.96–154.82

(m, CF₃C=O), 144.98 (d, C_DMT), 137.06–135.74 (m, C_DMT), 134.36–

132.38 (m, C_Naphth), 130.73–125.51 (m, C_DMT, C_Naphth, CF₃), 124.35–

122.15 (m, C_Naphth), 118.46–116.98 (m, CN), 113.11 (s, C_DMT),

86.01 (d, C_DMT), 73.69 (d, C3¢), 63.76 (d, C5¢), 58.59–58.05 (m,

POCH₂), 57.84–57.17 (m, C1¢), 55.23 (d, OMe), 45.51–45.09 (m,

C4¢), 42.96 (t, Me₂CH), 36.84 (d, C2¢), 31.58 (d, C6¢), 24.82–23.96

(m, Me₂CH), 20.04 (dd, CH₂CN).

³¹P NMR (162 MHz, CDCl₃): d = 148.11 (s), 147.95 (s).

¹⁹F NMR (376 MHz, CDCl₃): d = –66.10 to –69.92 (m, N-TFA),

–75.07 to –76.89 (m, NH-TFA).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.29 (m, N-TFA), –75.66 (s,

NH-TFA).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₄₆H₅₂F₆N₄O₇P: 917.3472;

found: 917.3472.

(1S,2R,4R)-2-{[(Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-[2,2,2-trifluoro-N-(pyridin-3-yl)acetamido]cyclopentyl 2-

Cyanoethyl Diisopropylphosphoramidite (21b)

Starting from 20b (108 mg, 0.18 mmol); yield: 124 mg (86%); TLC

(hexane–EtOAc, 1:1): R_f= 0.65.

¹H NMR (400 MHz, CDCl₃): d = 8.70 (dd, J = 4.7, 1.3 Hz, 1 H,

H_Py), 8.49 (s, 1 H, H_Py), 7.55 (s, 1 H, H_Py), 7.49–7.38 (m, 3 H, H_DMT),

7.36–7.26 (m, 6 H, H_DMT), 7.25–7.14 (m, 1 H, H_Py), 6.87–6.75 (m,

4 H, H_DMT), 4.95 (dd, J = 17.9, 8.3 Hz, 1 H, H1¢), 4.12 (q, J = 7.1

Hz, 1 H, H3¢), 3.79 (d, J = 2.3 Hz, 6 H, OMe), 3.77–3.57 (m, 1 H,

POCH₂), 3.56–3.37 (m, 3 H, Me₂CH, POCH₂), 3.14–2.96 (m, 2 H,

H5¢), 2.56 (t, J = 6.3 Hz, 1 H, CH₂CN), 2.39 (t, J = 6.4 Hz, 1 H,

CH₂CN), 2.37–2.28 (m, 1 H, H2¢), 2.11 (dd, J = 10.0, 5.1 Hz, 1 H,

H4¢), 2.03–1.82 (m, 1 H, H6¢), 1.80–1.67 (m, 1 H, H6¢), 1.48 (d,

J = 7.6 Hz, 1 H, H2¢), 1.19–0.88 (m, 12 H, Me₂CH).

HRMS (ESI+): m/z [M + Na]⁺calcd for C₅₀H₅₃F₆N₄NaO₇P:

990.3401; found: 990.3411.

(1S,2R,4R)-2-{[(Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-{2,2,2-trifluoro-N-[3-(2,2,2-trifluoroacetamido)phe-

nyl]acetamido}cyclopentyl 2-Cyanoethyl Diisopropyl-

phosphoramidite (16b)

Starting from 15b (124 mg, 0.16 mmol); yield: 120 mg (81%); TLC

(hexane–EtOAc, 2:1): R_f= 0.4.

¹H NMR (400 MHz, CDCl₃): d = 8.98–8.03 (m, 1.5 H, NH-TFA,

¹³C NMR (101 MHz, CDCl₃): d = 158.60 (d, CF₃C=O, C_DMT),

151.32 (s, C_Py), 150.66 (d, C_Py), 145.03 (s, C_DMT), 138.13 (s, C_Py),

136.23 (d, C_DMT), 132.12–127.41 (m, C_DMT, CF₃), 126.89 (d, J = 4.0

Hz), 123.77 (s, C_Py), 117.64 (s, CN), 113.22 (s, C_DMT), 86.16 (s,

H_phenylene), 7.87–6.98 (m, 12.5 H, H_DMT, H_phenylene), 6.90–6.66 (m, 4

H, H_DMT), 5.01 (d, J = 87.9 Hz, 1 H, H1¢), 4.12–3.95 (m, 1 H, H3¢),

3.86–3.71 (m, 6 H, OMe), 3.64–3.38 (m, 4 H, Me₂CH, POCH₂),

2.99 (dt, J = 14.6, 8.9 Hz, 2 H, H5¢), 2.75–2.56 (m, 1 H, CH₂CN),

2.54–2.33 (m, 1 H, CH₂CN), 2.31–2.11 (m, 2 H, H4¢, H6¢), 1.87 (m,

0.5 H, H2¢), 1.61 (s, 1.5 H, H2¢), 1.33–1.19 (m, 1 H, H6¢), 1.19–0.97

(m, 12 H, Me₂CH).

¹³C NMR (101 MHz, CDCl₃): d = 172.36 –158.51 (s, CF₃C=O,

C_DMT), 145.17 (s, C_DMT), 136.27 (m, C_phenylene), 130.03 (m), 128.21

(m), 127.78–127.48 (m), 126.80 (s) (C_DMT, CF₃), 122.07–120.91

(m, C_phenylene), 74.86 (s, C3¢), 64.46–62.73 (m, C5¢), 58.53–56.08

(m, OMe, POCH₂), 55.35 (m, C1¢), 46.48 (s, C4¢), 43.29 (m,

Me₂CH), 37.71 (s, C2¢), 31.59–28.84 (m, C6¢), 25.75–23.77 (m,

Me₂CH), 21.19 (s, CH₂CN).

C

_DMT), 73.68 (s, C3¢), 63.59 (s, C5¢), 58.49 (d, POCH₂), 55.59 (s,

C1¢), 55.26 (s, OMe), 45.55 (s, C4¢), 43.19 (d, Me₂CH), 38.01 (s,

C2¢), 30.20 (d, C6¢), 24.67 (m, Me₂CH), 20.69–20.28 (m, CH₂CN).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.28 (d, N-TFA).

³¹P NMR (162 MHz, CDCl₃): d = 150.98–145.97 (m).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₄₃H₅₁F₃N₄O₆P: 807.3493,

found: 807.3493.

(1S,2R,4S)-2-{[(Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-[2,2,2-trifluoro-N-(pyridin-3-yl)acetamido]cyclopentyl

2-Cyanoethyl Diisopropylphosphoramidite (21a)

Starting from 20a (110 mg, 0.18 mmol); yield: 95 mg (65%); TLC

(hexane–EtOAc, 1:1): R_f= 0.67.

¹H NMR (400 MHz, CDCl₃): d = 8.59 (s, 1 H, H_Py), 8.38 (s, 1 H,

H_Py), 7.42 (d, J = 8.1 Hz, 1 H, H_Py), 7.35–7.02 (m, 10 H, H_DMT, H_Py),

6.71 (dd, J = 8.8, 6.5 Hz, 4 H, H_DMT), 5.07 (s, 1 H, H1¢), 4.10–3.87

(m, 1 H, H3¢), 3.79–3.61 (m, 7 H, OMe, POCH₂), 3.49 (m, 3 H,

POCH₂, Me₂CH), 2.89 (m, 2 H, H5¢), 2.53 (t, J = 6.3 Hz, 1 H,

CH₂CN), 2.33 (t, J = 6.4 Hz, 1 H, CH₂CN), 2.20 (m, 2 H, H4¢, H6¢),

2.05–1.96 (m, 1 H, H2¢), 1.59–1.41 (m, 1 H, H2¢), 1.21 (m, 1 H,

H6¢), 1.12–0.74 (m, 12 H, Me₂CH).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.30 (s, N-TFA), –75.14 (s,

NH-TFA).

³¹P NMR (162 MHz, CDCl₃): d = 150.10–143.17 (m).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₄₆H₅₂F₆N₄O₇P: 917.3472;

found: 917.3472.

(1S,2R,4S)-2-{[(Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-{2,2,2-trifluoro-N-[3-(2,2,2-trifluoroacetamido)phe-

nyl]acetamido}cyclopentyl 2-Cyanoethyl Diisopropyl-

phosphoramidite(16a)

Starting from 15a (100 mg, 0.14 mmol); yield: 98 mg (77%); TLC

(hexane–EtOAc, 2:1): R_f= 0.38.

¹³C NMR (101 MHz, CDCl₃): d = 158.55 (d, CF₃C=O, C_DMT),

151.19 (s, C_Py), 150.64 (s, C_Py), 145.04 (s, C_DMT), 137.87 (s, C_Py),

136.13 (s), 132.32 (s), 130.15 (d, J = 7.2 Hz), 129.64–127.37 (m),

126.84 (d, J = 4.5 Hz), 123.71 (s, C_Py), 117.66 (s, CN), 113.18 (s,

¹H NMR (400 MHz, CDCl₃): d = 9.03–7.61 (m, 1.5 H, NH-TFA,

H_phenylene), 7.59–6.99 (m, 12.5 H, C_DMT, H_phenylene), 6.86–6.74 (m, 4

Synthesis 2012, 44, 1011–1025

1024

O. Yaren et al.

FEATURE ARTICLE

C_DMT), 85.99 (s, C_DMT), 74.52 (s, C3¢ 63.88 (d, C5¢), 58.22 (d,

POCH₂), 57.07 (s, C1¢), 55.24 (d, OMe), 46.28 (d, C4¢), 43.29 (dd,

Me₂CH), 38.47–36.56 (m, C2¢), 32.84–29.12 (m, C6¢), 25.66–23.24

(m, Me₂CH), 21.07–18.80 (m, CH₂CN).

HRMS (ESI+): m/z [M + H]⁺calcd for C₅₃H₅₆F₃N₃O₈P: 950.3752;

found: 950.3745.

Oligonucleotide Synthesis

All oligonucleotides were synthesized on a Pharmacia LKB Gene

Assembler Special DNA synthesizer on a 1.3-mmol scale using con-

ventional cyanoethyl phosphoramidite chemistry. Protected natural

nucleoside phosphoramidites, solid supports and the 3¢-dabcyl CPG

were from Glen Research. 6-FAM phosphoramidite was from Nu-

cleic Resources LLC. The concentration of the solns of the natural

phosphoramidites was 0.1 M and that of 6-FAM phosphoramidite

0.15 M in MeCN. A soln of 0.25 M 5-(ethylthio)-1H-tetrazole in

MeCN was used as activator. All other solns and reagents were pre-

pared according to the manufacturer’s protocol. After synthesis

(trityl-off mode), oligonucleotides were cleaved from the solid sup-

port and deprotected with 33% aq NH₃for 1 h at r.t. followed by 16

h at 55 °C.

¹⁹F NMR (376 MHz, CDCl₃): d = –67.35 (s, N-TFA).

³¹P NMR (162 MHz, CDCl₃): d = 149.50–145.10 (m).

HRMS (ESI⁺): m/z [M + H] calcd for C₄₃H₅₁F₃N₄O₆P: 807.3493;

found: 807.3493.

(1S,2R,4R)-2-{[(Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-[2,2,2-trifluoro-N-(4-oxo-2-phenyl-4H-chromen-6-yl)acet-

amido]cyclopentyl 2-Cyanoethyl Diisopropylphosphoramidite

(26b)

Starting from 25b (150 mg, 0.20 mmol); yield: 138 mg (69%); TLC

(hexane–EtOAc, 2:1): R_f= 0.35.

¹H NMR (400 MHz, CDCl₃): d = 8.16–7.94 (m, 3 H, H_chrom), 7.74–

7.45 (m, 5 H, H_DMT, H_chrom), 7.31–7.08 (m, 9 H, H_DMT, H_chrom), 6.97–

6.72 (m, 5 H, H_DMT, H_chrom), 5.31 (d, J = 46.7 Hz, 1 H, H1¢), 4.25-

4.11 (m, 1 H, H3¢), 3.85–3.73 (m, 7 H, OMe, POCH₂), 3.66 (dd,

J = 25.5, 18.6 Hz, 3 H, Me₂CH, POCH₂), 3.01 (ddd, J = 48.2, 39.0,

14.6 Hz, 2 H, H5¢), 2.71 (dd, J = 11.9, 5.8 Hz, 1 H, CH₂CN), 2.48

(dd, J = 12.2, 5.7 Hz, 1 H, CH₂CN), 2.43–2.14 (m, 3 H, H4¢, H6¢,

H2¢), 1.81–1.66 (m, 1 H, H2¢), 1.53–1.35 (m, 1 H, H6¢), 1.40–1.14

(m, 12 H, Me₂CH).

¹³C NMR (101 MHz, CDCl₃): d = 182.24 (d, C_chrom), 164.57 (d,

C_chrom), 159.04–157.56 (m, CF₃C=O, C_DMT), 145.57 (d, C_DMT),

137.00–135.46 (m, C_DMT, C_chrom), 130.17 (s), 129.21 (s), 129.73–

126.38 (m), 127.84 (s), 126.48 (s) (C_DMT, C_chrom, CF₃), 113.15 (s,

Purification and Analytical Characterization of Oligo-

nucleotides

Crude oligonucleotides were purified either by reversed phase (RP)

or by ion exchange chromatography using a linear gradient of buffer

B in buffer A.

A: RP-HPLC: column; SOURCE 15RPC ST 4.6/100 (Amersham

Pharmacia Biotech); buffer A: 0.1 M triethylammonium acetate

(TEAA) pH 7.0 in H₂O, buffer B: 0.1 M TEAA (pH 7.0) in MeCN–

H₂O 4:1.

B: Anion exchange HPLC: column; Dionex (DNAPac PA200);

buffer A: 25 mM Tris HCl in H₂O, pH 8.0; buffer B: 25 mM Tris

HCl + 1.25 M NaCl in H₂O, pH 8.0.

C_DMT), 108.37 (d, C_chrom), 87.08 (d, C_DMT), 74.06 (d, C3¢), 63.85 (d,

C5¢, 58.21 (dd, POCH₂), 57.39 (s, C1¢), 55.04 (d, OMe), 45.77 (dd,

C4¢), 43.89 (d, Me₂CH), 37.32 (s, C2¢), 30.86 (d, C6¢), 25.23 (ddd,

Me₂CH), 20.18 (dd, CH₂CN).

³¹P NMR (162 MHz, CDCl₃): d = 147.32 (s), 147.43 (s).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.15 (d, N-TFA).

Sep-Pak C₁₈(Waters) columns were used for desalting. The column

was first washed with MeCN (5 mL) and then conditioned with 0.1

M TEAA buffer (pH 7, 10 mL). Oligonucleotides were loaded as a

0.3 M TEAA soln. The column was washed with 0.1 M TEAA buff-

er (pH 7, 10 mL) and milli-Q-water (5 mL). Oligonucleotides were

then eluted with MeOH–H₂O (3:2, 3–4 mL). Collected fractions

were concentrated in a Speed-Vac SC 110 (Savant) and quantified

by UV/Vis spectroscopy at 260 nm (Nanodrop ND-1000). The mo-

lecular weight of the purified oligonucleotides was confirmed by

ESI–mass spectrometry (Table 1).

HRMS (ESI+): m/z [M + H]⁺calcd for C₅₃H₅₆F₃N₃O₈P: 950.3752;

found: 950.3746.

(1S,2R,4S)-2-{[(Bis(4-methoxyphenyl)(phenyl)methoxy]meth-

yl}-4-[2,2,2-trifluoro-N-(4-oxo-2-phenyl-4H-chromen-6-yl)acet-

amido]cyclopentyl 2-Cyanoethyl Diisopropylphosphoramidite

(26a)

Starting from 25a (143 mg, 0.19 mmol); yield: 125 mg (63%); TLC

(hexane–EtOAc, 2:1): R_f= 0.33.

UV Melting Curves

Thermal denaturation experiments were carried out on a Varian

Cary 3E UV/Vis spectrophotometer. Absorbances were monitored

at 260 nm and the heating rate was set to 0.5 °C/min. A cooling–

heating–cooling cycle in the temperature range of 70–30 °C was ap-

plied. Measurements were performed in duplicate. The first deriva-

tives of the melting curves, were calculated directly by the program

WinUV 3.0. To avoid evaporation of the soln upon heating, a layer

of dimethylpolysiloxane was added on top of the sample soln in the

cell.

¹H NMR (400 MHz, CDCl₃): d = 8.14–7.88 (m, 3 H, H_chrom), 7.70–

7.34 (m, 7 H, H_DMT, H_chrom), 7.29 (t, J = 9.6 Hz, 6 H, H_DMT, H_chrom),

7.20 (dt, J = 12.3, 6.1 Hz, 1 H, H_chrom), 6.91–6.74 (m, 5 H, H_DMT

,

H_chrom), 4.95 (d, J = 8.4 Hz, 1 H, H1¢), 4.10–3.98 (m, 1 H, H3¢), 3.79

(d, J = 1.8 Hz, 6 H, OMe), 3.73–3.57 (m, 1 H, POCH₂), 3.54–3.31

(m, 3 H, Me₂CH, POCH₂), 3.15–3.10 (m, 1 H, H5¢), 3.07–2.94 (m,

1 H, H5¢), 2.62–2.50 (m, 1 H, CH₂CN,), 2.46–2.22 (m, 2 H, CH₂CN,

H2¢), 2.17–2.08 (m, 1 H, H4¢), 1.97 (t, J = 16.6 Hz, 1 H, H6¢), 1.93–

1.76 (m, 1 H, H6¢), 1.62 (d, J = 30.0 Hz, 1 H, H2¢), 1.17–0.89 (m,

12 H, Me₂CH).

Supporting Information for this article is available online at

http://www.thieme-connect.com/ejournals/toc/synthesis.

¹³C NMR (101 MHz, CDCl₃): d = 182.20 (d, C_chrom), 164.51 (d,

C_chrom), 159.04–157.50 (m, CF₃C=O, C_DMT), 145.54 (d, C_DMT),

137.00–135.46 (m, C_DMT, C_chrom), 130.17 (s), 129.21 (s), 129.73–

126.32 (m), 127.80 (s), 126.41 (s) (C_DMT, C_chrom, CF₃), 113.08 (s,

C_DMT), 108.37 (d, C_chrom), 88.38 (d, C_DMT), 74.08 (d, C3¢), 63.84 (d,

C5¢, 58.19 (dd, POCH₂), 55.40 (s, C1¢), 54.82 (d, OMe), 45.16 (dd,

C4¢), 43.15 (d, Me₂CH), 37.50 (s, C2¢), 30.99 (d, C6¢), 25.34 (ddd,

Me₂CH), 20.18 (dd, CH₂CN).

Acknowledgment

The authors gratefully acknowledge financial support by the Swiss

National Science Foundation (grant No. 200020-130373).

References

(1) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.;

StClair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.;

³¹P NMR (162 MHz, CDCl₃): d = 148.37 (s), 148.12 (s).

¹⁹F NMR (376 MHz, CDCl₃): d = –67.12 (d, N-TFA).

Synthesis 2012, 44, 1011–1025

FEATURE ARTICLE

Reardon, J. E.; Dornsife, R. E.; Averett, D. R.; Krenitsky, T.

A. Antimicrob. Agents Chemother. 1997, 41, 1082.

(2) Helguera, A. M.; Rodríguez-Borges, J. E.; Caamaño, O.;

García-Mera, X.; González, M. P.; Cordeiro, M. N. D. S.

Mol. Inf. 2010, 29, 213.

(3) Hergueta, A. R.; Fernandez, F.; Lopez, C.; Balzarini, J.;

De Clercq, E. Chem. Pharm. Bull. 2001, 49, 1174.

(4) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192.

(5) Sagi, J.; Szemzö, A.; Szécsi, J.; Ötvös, L. Nucleic Acids Res.

1990, 18, 2133.

Carbocyclic exo-Amino Nucleosides

1025

(17) Greenberg, M. M. Acc. Chem. Res. 2012, 45, DOI: 10.1021/

ar2002182.

(18) Agrofoglio, L.; Condom, R.; Guedj, R.; Challand, S. R.;

Selway, J. Nucleosides Nucleotides 1994, 13, 1147.

(19) Agrofoglio, L.; Condom, R.; Guedj, R.; Challand, R.;

Selway, J. Tetrahedron Lett. 1993, 34, 6271.

(20) Wojciechowski, F.; Leumann, C. J. Chem. Soc. Rev. 2011,

40, 5669.

(21) Seo, Y. J.; Malyshev, D. A.; Lavergne, T.; Ordoukhanian, P.;

Romesberg, F. E. J. Am. Chem. Soc. 2011, 133, 19878.

(22) Seo, Y. J.; Hwang, G. T.; Ordoukhanian, P.; Romesberg, F.

E. J. Am. Chem. Soc. 2009, 131, 3246.

(6) Freier, S. M.; Altmann, K. H. Nucleic Acids Res. 1997, 25,

4429.

(7) Altmann, K. H.; B’Vierre, M. O.; De Mesmaeker, A.;

Moser, H. E. Bioorg. Med. Chem. Lett. 1995, 5, 431.

(8) Altmann, K. H.; Kesselring, R.; Francotte, E.; Rihs, G.

Tetrahedron Lett. 1994, 35, 2331.

(9) Altmann, K. H.; Kesselring, R. Synlett 1994, 853.

(10) Altmann, K. H.; Imwinkelried, R.; Kesselring, R.; Rihs, G.

Tetrahedron Lett. 1994, 35, 7625.

(11) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.;

Wang, J.; Wagner, R. W.; Matteucci, M. D. J. Med. Chem.

1996, 39, 3739.

(12) Saneyoshi, H.; Mazzini, S.; Aviñó, A.; Portella, G.;

González, C.; Orozco, M.; Marquez, V. E.; Eritja, R. Nucleic

Acids Res. 2009, 37, 5589.

(23) Kool, E. T.; Sintim, H. O. Chem. Commun. 2006, 3665.

(24) Hirao, I.; Kimoto, M.; Mitsui, T.; Fujiwara, T.; Kawai, R.;

Sato, A.; Harada, Y.; Yokoyama, S. Nat. Meth. 2006, 3, 729.

(25) Yaren, O.; Mosimann, M.; Leumann, C. J. Angew. Chem.

Int. Ed. 2011, 50, 1935.

(26) Biggadike, K.; Borthwick, A. D.; Evans, D.; Exall, A. M.;

Kirk, B. E.; Roberts, S. M.; Stephenson, L.; Youds, P.

J. Chem. Soc., Perkin Trans. 1 1988, 549.

(27) Ludek, O. R.; Meier, C. Synthesis 2003, 2101.

(28) Huang, H.; Greenberg, M. M. J. Org. Chem. 2008, 73, 2695.

(29) Oligonucleotides and Analogues - A Practical Approach;

Oxford University Press: Oxford, 1991.

(30) Brotschi, C.; Mathis, G.; Leumann, C. J. Chem. Eur. J. 2005,

(13) Kubo, I.; Kim, M.; Wood, W. F.; Naoki, H. Tetrahedron

Lett. 1986, 27, 4277.

(14) Moss, R. J.; Petrie, C. R.; Meyer, R. B.; Nord, L. D.; Willis,

R. C.; Smith, R. A.; Larson, S. B.; Kini, G. D.; Robins, R. K.

J. Med. Chem. 1988, 31, 786.

(15) Fortin, H.; Tomasi, S.; Delcros, J.-G.; Bansard, J.-Y.;

Boustie, J. ChemMedChem 2006, 1, 189.

11, 1911.

(31) Grigorenko, N. A.; Leumann, C. J. Chem. Eur. J. 2009, 15,

639.

(32) Matsuda, S.; Fillo, J. D.; Henry, A. A.; Rai, P.; Wilkens, S.

J.; Dwyer, T. J.; Geierstanger, B. H.; Wemmer, D. E.;

Schultz, P. G.; Spraggon, G.; Romesberg, F. E. J. Am. Chem.

Soc. 2007, 129, 10466.

(16) Varaprasad, C. V.; Habib, Q.; Li, D. Y.; Huang, J. F.; Abt, J.

W.; Rong, F.; Hong, Z.; An, H. Y. Tetrahedron 2003, 59,

2297.

(33) Hildbrand, S.; Blaser, A.; Parel, S. P.; Leumann, C. J. J. Am.

Chem. Soc. 1997, 119, 5499.

Synthesis 2012, 44, 1011–1025

Article Doi

Synthesis and incorporation into oligodeoxynucleotides of carbocyclic exo-amino nucleosides

DOI: 10.1055/s-0031-1289737

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Article abstract of DOI:10.1055/s-0031-1289737

Full text of DOI:10.1055/s-0031-1289737

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