The synthesis of piperidine nucleoside analogs - A comparison of several methods to access the introduction of nucleobases

Tetrahedron 67 (20 1 1 ) 1485e1500

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The synthesis of piperidine nucleoside analogsda comparison of several

methods to access the introduction of nucleobases

*

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Sona Kovackova, Martin Dracínsky, Dominik Rejman

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Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 18 August 2010

Received in revised form 15 November 2010

Accepted 9 December 2010

Available online 16 December 2010

This work deals with the synthesis of piperidine and hydroxypiperidine analogs of nucleosides. Starting

from commercially available 3-hydroxypiperidine, proline or 4-hydroxyproline, a series of piperidine

derivatives of both purine and pyrimidine nucleobases was prepared. Various methods of nucleobase

attachment were evaluated. The prepared compounds were tested for cytostatic, antibacterial, and an-

tiviral properties but no signiﬁcant activity was found.

Keywords:

Piperidine derivatives

Nucleoside analogs

Nucleobase

Proline

1. Introduction

compounds offer a site for the further modiﬁcation of the pyrroli-

dine nitrogen atom. Thus, we prepared a series of nucleoside

Azasugars (iminosugars) belong to a family of polyhydroxylated

alkaloids. Many azafuranose and azapyranose analogs are potent

a

phosphonate analogs.^20,21Phosphonate derivative 7 was found as

a potent inhibitor of thymidine phosphorylase from spontaneous

SD-rat lymphoma cells exhibiting IC₅₀of 11 nM.²²

- and b

-glycosidase inhibitors^1,2and also have antidiabetic, anti-

cancer, and antiviral properties.³N-Butyl-1-deoxynojirimycin 1

(ZavescaÔ) is used in Gaucher disease treatment. Another azasugar,

Miglitol 2, which is commercially available in the USA and Canada,

is used for the treatment of type II diabetes (GLYSETÔ). The

chemical and biological properties of iminosugars have been well

reviewed in past years.^4e7

The synthesis of piperidine nucleoside analog 8 where the

nucleobase is attached to the piperidine nitrogen atom was pub-

lished by Pedersen et al.²³Prukala²⁴reported the synthesis of the

piperidine derivative of cytosine 9, where the cyclic amine was in-

troduced through a methylene bridge at position 5 of the cytosine via

a Mannich-type reaction. N-methyl-D-ribopyranuronamide nucleo-

Sugar-modiﬁed nucleosides represent an important group of

antimetabolites that exhibit a variety of biological properties. First,

azasugar nucleoside analog 3 was reported by Reist et al.⁸The ring

nitrogen atom of this compound was acylated otherwise it would

undergo spontaneous hydrolysis. Owing to the instability of

iminonucleosides, most of the research has been focused on non-

glycosidic or aza-C-nucleosides.^9e15Aza-C-nucleosides 4 and 5

(D-immucillin-H and D-DADMe-immucillin-H) have been shown to

be potent inhibitors of human purine nucleoside phosphorylase

with K_ivalues of 56 and 16 pM, respectively.¹⁶These compounds

are now in clinical trials for the treatment of T- and B-cell cancers

and a variety of autoimmune diseases.¹⁷The synthesis of pyrroli-

dine nucleosides 6aec has been reported by our group.^18,19Such

sides 10aeb and 11aeb were synthesized and evaluated in antiviral

and cytotoxic assays, however, no activity was found.^25,26Piperidine

nucleoside 12 was prepared by Kim et al.,²⁷and it seemed that

oligonucleotides containing this modiﬁcation exhibited a strong

hybridization with RNA depending on the location and number of

substitutions. Also, the increase of hydrophobicity in these modiﬁed

oligonucleotides can be advantageous for cellular uptake.

Nucleobase attachment to the sugar-mimicking part represents

the key step in the synthesis of a variety of nucleoside analogs.

Sugar-modiﬁed nucleoside analogs, where the nucleobase is not

attached via a glycosidic bond, are usually prepared by (i) the nu-

cleophilic displacement of an activated hydroxyl with a nucleobase

under Mitsunobu conditions, (ii) the nucleophilic displacement of

mesyloxy, tosyloxy or halogen moieties with nucleobases, and (iii)

nucleobase assembly on primary amino derivatives.

Mitsunobu nucleosidation usually consists of the reaction of

a hydroxy compound with the nucleobase in the presence of tri-

phenylphosphine and diethyl or diisopropyl azodicarboxylate in

* Corresponding author. Tel.: þ420 220 183 381; fax: þ420 220 183 578; e-mail

address: rejman@uochb.cas.cz (D. Rejman).

doi:10.1016/j.tet.2010.12.029

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S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1486

THF.^28e30The nucleobases react as ambident nucleophiles, leading

to mixtures of N¹/O isomers for pyrimidines and N⁷/N⁹isomers for

purines. The other disadvantage of this method is the complex

reaction mixture rendering the isolation of the desired product

difﬁcult. Because of the low solubility of unprotected nucleobases

in THF, and the tendency to form unwanted isomers, various

modiﬁcations have been described. Concerning pyrimidines, the

use of 3-N-benzoyluracil^31,32and 4-N-benzoylcytosine^33,34has

been employed. 6-Chloropurine or 2-amino-6-chloropurine are

frequently used to obtain derivatives of adenine or guanine, res-

pectively.^35,36Michael and Strazewski³⁷used N⁶-bis-Boc-protected

adenine in a Mitsunobu reaction, during the synthesis of nepla-

nocin A and obtained the desired product at a 98% yield.

The nucleophilic displacement of mesyloxy, tosyloxy or halogen

groups with nucleobases is often used in the synthesis of nucleoside

analogs.^38e42The reaction is usually carried out in a polar aprotic

solvent (e.g., DMF, DMSO) in the presence of cesium carbonate or

sodium hydride as bases to generate the nucleobase anion. This

reaction is often accompanied by the formation of unwanted

regioisomers (mostly in a pyrimidine series) and a competing

elimination reaction, thereby decreasing the yield of the desired

product (Fig. 1).

2. Results and discussion

2.1. Optimization of the nucleosidation reaction and

synthesis of the racemic piperidin-3-yl derivatives of

nucleobases

Here, we report the synthesis of nucleoside analogs where the

ribose moiety is replaced with a piperidine ring. According to our

experiences with the synthesis of pyrrolidine nucleosides, the de-

velopment of suitable strategies for nucleobase attachment to the

protected piperidine ring has been the most challenging task. Thus,

N-protected 3-hydroxypiperidine was selected as a model starting

material, and various conditions for nucleobase attachment were

evaluated.

Synthesis started from the commercially available (RS)-3-

hydroxypiperidine (19). This compound was transformed into

N-Boc (tert-butyloxycarbonyl) derivative 20a (97%) and N-Tr (Trityl)

derivative 20b (30%), and these compounds were mesylated giving

21a (85%) and 21b (94%) (Scheme 1). Compounds 20a,b and 21a,b

were used for the Mitsunobu reaction and nucleophilic displace-

ment, respectively.

OH

OMs

i

ii

N

R

N

H

N

R

O

NH₂

N

H

N

19

OH

N

NH

O

20a R= Boc

20b R= Tr

21a R= Boc

21b R= Tr

HO

OH

HO

OH

H

N

HO

N

n-Bu

HO OH

4

HO OH

3

(i) Boc₂O-NaHCO₃, or TrCl-NaHCO₃(ii) MsCl, Py

1

OH

2

Scheme 1.

O

NH

H

O

N

O

P

OH

HN

Boc-derivative 20a and trityl derivative 20b were treated with

nucleobase under Mitsunobu conditions (Table 1). Reactions were

performed in dioxane at 100 ^ꢀC (according to Richichi²⁹) or THF at

0e5 ^ꢀC. It appeared that N-Boc-3-hydroxypiperidine 20a was not

a convenient substrate for Mitsunobu nucleosidation. In dioxane, it

rapidly decomposed at high temperatures, and a mixture of com-

pounds was obtained when treated with pyrimidine and purine

bases. Also, the reactions in THF at low temperatures did not afford

the expected pyrimidine or purine derivates of nucleobases. Only

products of elimination, the 2,3 and 3,4 unsaturated compounds,

were isolated at a yield of ∼50% (entries 1e6). By contrast, we were

able to isolate the 6-chloropurine and 6-chloro-2-aminopurine

derivatives in 25% and 27% yields, respectively, when using N-trityl

derivative 20b as a starting material (entries 9 and 11). However,

the reaction of 20b with pyrimidines did not afford any desired

product (entries 7 and 8). Similar results were obtained during the

synthesis of pyrrolidine nucleosides described previously.¹⁸

It is necessary to note that the order of the addition of reagents

and substrates might play an important role in the result of the

Mitsunobu reaction. We obtained the best results when DIAD was

ﬁrst added dropwise to the stirred triphenylphosphine in THF,

followed by the addition of 20a or 20b and nucleobase in THF. One

drawback of the Mitsunobu reaction is the poor solubility of

nucleobase in THF. Thus, to improve results, we attempted to use 6-

N-bis(Boc)adenine³⁷(entry 13). Unfortunately, no improvement

was observed (Scheme 2).

H

N

NH

O

HO

N

HO

N

HO

B

HO

T

HO

8

7

5

6a B= T

6b B= A

6c B= G

O

Ph

O

HN

N

NH₂

N

B

N

HO

N

O

N

B

OH

HO

10a B= A

10b B= T

HO

NH₂

N

OH

HO

11a B= A

9

12

11b B= T

Fig. 1. Derivatives of iminosugars.

The last often used method is called the nucleobase build-up

procedure. It consists of the reaction of primary amine with urea

derivatives 13ae14b^43e46or 4,6-dichloropyrimidines 16e18^47e50

(Fig. 2), forming an intermediate that undergoes a cyclization

reaction to afford appropriate pyrimidine or purine derivatives,

respectively. Recently, we described new reagents 15aeb for the

synthesis of N¹-substituted uracil and thymine, giving excellent

results with a variety of structurally diverse amines.⁵¹

O₂N

O

Cl

N

O

For the alkylation reactions of the purine and pyrimidine

nucleobases with 3-mesyloxy-N-protected piperidine, different

combinations of solvents (DMSO, DMF) and bases (NaH, Cs₂CO₃)

were investigated. Generally, nucleobases and bases were ﬁrst

allowed to react in DMSO (or DMF) at 120 ^ꢀC to form the appro-

priate salt. Then, 3-mesyloxypiperidine in DMSO (DMF) was added

dropwise into the reaction mixture.

R₂

Cl

N

O

N

H

O

N

H

R₂

R₁

13a R₁= H, R₂= NCO

16 R₁= H, R₂= NH₂

17 R₁= NH₂, R₂= NH₂

18 R₁= NH₂, R₂= H

13b R₁= CH₃, R₂= NCO

14a R₁= H, R₂= OCH₂CH₃

14b R₁= CH₃, R₂= OCH₂CH₃

15a R= H

15b R₁= CH₃

Fig. 2. Reagents for nucleobase construction.

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S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1487

X

B

N

Tr

N

R

N

R

N

R

N

R

20a R= Boc, X= OH

20b R= Tr, X= OH

21a R= Boc, X= OMs

21b R= Tr, X= OMs

25a R= Boc

26a R= Boc

24a B= adenine

25b R= Tr

26b R= Tr

22a R= Boc, B= thymine

22b R= Boc, B= 2-O-cytosine

22c R= Boc, B= cytosine

22d R= Boc, B= adenine

23a R= Tr, B= 6-chloropurine

24b B= thymine

24c B= 2-O-cytosine

23b R= Tr, B= 2-amino-6-chloropurine

23c R= Tr, B= adenine

23d R= Tr, B= 2-O-cytosine

23e R= Tr, B= thymine

Scheme 2.

Table 1

Optimization of the nucleosidation reaction

R

X

B^a

Reagents

T (^ꢀC)

22/23

24

25

26

Yield%

1

2

3

4

5

6

7

8

Boc

Tr

OH

T

THF, DIAD, PPh₃

Dioxane, DIAD, PPh₃

THF, DIAD, PPh₃

Dioxane, DIAD, PPh₃

THF, DIAD, PPh₃

Dioxane, DIAD, PPh₃

THF, DIAD, PPh₃

Dioxane, DIAD, PPh₃

THF, DIAD, PPh₃

Dioxane, DIAD, PPh₃

THF, DIAD, PPh₃

DMSO, Cs₂CO₃

DMSO, NaH

DMF, Cs₂CO₃

DMSO, NaH

DMF, Cs₂CO₃

DMSO, Cs₂CO₃

DMSO, NaH

DMSO, Cs₂CO₃

0e5

100

0e5

100

0e5

100

0e5

100

0e5

100

0e5

120

0

d

25^b(25þ26)

0^c

d

n.d.

Cl-Pu

Cl-G

Bz-A

T

Cl-Pu

Cl-G

Boc-Pu

T

0

d

33^b(25þ26)

n.d.

18

0^c

d

n.d.

22

0^c

d

0^c

d

0

d

0^c

d

n.d.

9

25^d(23a)

0^c

d

32 (25þ26)

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

d

n.d.

28

n.d.

n.d

n.d.

27^d(23b)

0^c

d

n.d

n.d.

23

n.d.

Tr

d

Boc

Tr

OH

0^c

d

OMs

16^d(22a)

0^c

d

15^d(22a)

0^e

d

C

d

18^d(22c)

16^d(22d)

18^d(22d)

0^c

d

A

U

A

Cl-G

C

T

A

T

d

n.d.

d

29 (25þ26)

d

18^d(24a)

n.d.

18^d(23c)

35^g(23cþ24a)

10^d(23b)

28^g(23dþ24c)

27^g(23eþ24b)

38^g(23cþ24a)

40^g(23eþ24b)

45^g(23cþ24a)

n.d.

DMF, Cs₂CO₃

DMSO, Cs₂CO₃

ECOENG212/DMF, Cs₂CO₃

[BMIM]PF₆/DMF, Cs₂CO₃

d^f

A

a

T¼thymine, Cl-Pu¼6-chloropurine, Cl-G¼2-amino-6-chloropurine, Boc-Pu¼6-N-bis-tert-butyloxycarbonyl purine, C¼cytosine, A¼adenine, U¼uracil.

b

c

d

e

f

Only products of elimination were isolated.

TLC, complicated mixture.

Isolated yield.

O-Derivatives (29%) was isolated.

Not isolated.

g

Isolated yield of the mixture of piperidine and pyrrolidine derivatives.

The alkylation of thymine with 21a in the presence of Cs₂CO₃

identiﬁed as the appropriate pyrrolidine derivatives 24a,b, the

result of piperidine ring contraction^52e54(entries 22e29). The ratio

between the formed piperidine and pyrrolidine derivative was 1:1

(adenine derivatives 23c/24a), 3:2 (thymine derivatives 23e/24b),

and 7:3 (2-O-cytosin derivatives 23d/24c). We assume that the

pyrrolidine derivatives 24aec were formed through the azir-

idinium intermediate (Scheme 3).

afforded a 16% yield of 22a in DMSO and 15% yield of 22a in DMF

(entries 14 and 16). When NaH was used as a base in DMSO only

a complex mixture of compounds was obtained (entry 15). The

alkylation of cytosine led to a 29% yield of O-derivative 22b when

NaH was used as a base (entry 17), whereas when Cs₂CO₃was used,

the desired N¹-derivative 22c was obtained in a 18% yield (entry

18). Adenine was alkylated in the presence of Cs₂CO₃giving a 16%

yield of 22d in DMF and 18% yield in DMSO (entries 19 and 20).

Uracil was attempted to react in DMSO using NaH as a base giving

a complex mixture of products (entry 21). In all cases, the products

of competing elimination reactions 25a and 26a were observed.

When treating N-trityl-3-mesyloxyderivative 21b under alkyl-

ation conditions, we observed the formation of another by-product

(besides the products of elimination 25b and 26b), which were

B

21b

23c 23e

or

24a 24b

or

N

Tr

B

Scheme 3.

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Ionic liquids have been reported as advantageous dipolar aprotic

The reaction of aminopiperidine 30 with 2-nitrophenyl 3-

ethoxyacryloylcarbamate (15a) and 2-nitrophenyl 3-ethoxy-2-

methylacryloylcarbamate (15b)⁵¹proceeded smoothly within

10 min at room temperature (rt; Scheme 6). Products 31a and

solvents ideal for alkylation reactions.^55,56To our best knowledge,

no article concerning nucleosidation in ionic liquids has been

published so far. We performed alkylation in ECOENG212/DMF and

[BMIM]PF₆/DMF (entries 27e29). Although the yield of the product

increased, the removal of the ionic liquid seemed to be complicated,

as well as the separation of the piperidine product from the pyr-

rolidine by-product.

X

H

N

H

N

B

O

ii

i

30

O

N

H

N

Boc

The ﬁnal nucleosides 27a,b and 28b were obtained after treat-

ment with TFA in DCM for thymine derivatives. Derivatives 23a,b

were treated with ammonia in ethanol and NaOH to obtain the

adenine 27c and guanine 27d derivatives, respectively (Scheme 4).

After treatment with TFA, the obtained free piperidine nucleosides

were deionized on a Dowex 50 in H^þform, and ﬁnally puriﬁed by

a preparative reversed phase HPLC.

32 B= uracil

31a X= H

31b X= CH₃

27a B= thymine

i. 15a or 15b, dioxane r.t.; ii. Dowex 50 H⁺, dioxane, 80 °C

Scheme 6.

B

i or ii or iii

i

22a-d

24a-b

23a-e

N

H

N

H

28a B= adenine

28b B= thymine

27a B= thymine

27b B= cytosine

27c B= adenine

27d B= guanine

i. 20% TFA/DCM; ii. 1. NH₃/EtOH, 2. 20% TFA/DCM; iii. 1. NaOH, dioxane/H₂O, 2. 20% TFA/DCM

Scheme 4.

Since neither Mitsunobu coupling nor direct alkylation afforded

satisfactory results, we were forced to look for another approach to

piperidine nucleoside synthesis. Thus nucleobase assembly on

primary amines was evaluated.

We prepared (R,S)-3-amino-1-N-tert-butyloxycarbonyl-piperi-

dine (30) in two steps starting from (R,S)-N-Boc-3-mesyloxy-

piperidine (21a). Mesyl derivative 21a was ﬁrst transformed into 3-

azido derivative 29 by reaction with sodium azide in DMF in a 95%

yield, which was then treated with H₂, Pd/C in ethanol to obtain

aminopiperidine 30 in a 90% yield (Scheme 5).

31b were puriﬁed by ﬂash chromatography and then cyclized

by heating with a Dowex 50H^þin dioxane at 80 ^ꢀC, which also

caused Boc group removal. The ﬁnal puriﬁcation of free nu-

cleosides was performed using preparative HPLC. Both pyrimi-

dine derivatives were obtained in excellent overall yields: 78%

for the uracil derivative 32a and 70% for the thymine derivative

27a.

A purine nucleobase on the piperidine skeleton was con-

47

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structed according to Hrebabecky et al. The reaction of (R,S)-3-

amino-1-N-tert-butyloxycarbonylpiperidine (30) with 5-amino-

4,6-dichloropyrimidine (16) or 2,5-diamino-4,6-dichloropyrimidine

(17) afforded compounds 33a (70%) and 33b (56%), respectively

(Scheme 7), which upon reaction with neat diethoxymethyl ace-

tate⁵⁷provided 6-chloropurine derivatives 34a and 34b, res-

pectively. In the case of compound 33b, only 1.1 M equiv of

diethoxymethyl acetate were used and the reaction was carried

out in DMF. Otherwise, the formylation of the exocyclic 2-amino

group occurred. The ﬁnal treatment of 34a and 34b with am-

monia and 1 M NaOH, followed by Boc group removal with TFA,

afforded good yields of the desired adenine 27c (58%) and gua-

nine 27d (64%) derivatives, respectively.

N₃

i

NH₂

ii

21a

N

Boc

N

Boc

29

30

i. NaN_3,DMF; ii. H₂, Pd/C, EtOH

Scheme 5.

N

NH₂

Cl

H

N

Cl

N

B

iii

i

ii

N

30

N

Y

N

Boc

N

Boc

N

H

Y

27c B= adenine

27d B= guanine

34a Y= H

33a Y= H

33b X= NH₂

34b X= NH₂

(i) 17 or 16, Et₃N, n-butanol, 120 °C, pressure vessel; (ii) 1. diethoxymetylacetate, DMF, 100 °C;

(iii) 1. NaOH or NH₃; 2. 20 % TFA in DCM, R.T

Scheme 7.

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S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1489

2.2. Synthesis of enantiomeric piperidin-3-yl and (3R,5S)-3-

hydroxypiperidin-5-yl derivatives of nucleobases

derivatives 41a and 41b were transformed into 3-amino com-

pounds 43a and 43b in two steps via the 3-mesyloxy and 3-azido

derivatives 42a,b. The nucleophilic displacement of the mesyloxy

group for azido one proceeded as expected with the inversion of

conﬁguration. The reduction of azido compounds to the amino

derivatives proceeded smoothly in 86% (43a) and 72% (43b) by

hydrogenation under a Pd/C catalysis. The hydrogenation of the

dimethoxytrityl derivative 42b should be checked thoroughly be-

cause of the possibility of DMTr group removal. After observing the

complete azido group reduction, the reaction needed to be worked

up immediately.

Thymine and uracil nucleobases were constructed on amino

moieties of 43a and 43b using reagents 15a and 15b (Scheme 9).

The smooth reaction in dioxane within 15 min resulted in the for-

mation of 44aec, which were isolated in 80% (44a), 98% (44b), and

95% (44c) yields. The ureido intermediates 45aec were then

cyclized by heating with a Dowex 50 in H^þform in dioxane at 80 ^ꢀC

for 30 min. Under these conditions, both the Boc and DMTr groups

were removed, and the fully deprotected nucleosides 45aec were

obtained at 84% (45a, uracil derivative), 75% (45b, uracil derivative),

and 81% (46c, thymine derivative) yields.

Compounds 40a and 40b (hydroxy- and dihydroxypiperidine)

were prepared from the appropriate prolinols according to the

procedure published by Cossy et al.⁵⁸(Scheme 8). First, the prolines

36a and 36b were converted to methyl esters by reaction with

MeOH/SOCl₂, and these compounds were benzylated on nitrogen

atom to obtain 37a and 37b. The compound 37b was then treated

with TBDPSCl to protect the secondary hydroxy group (compound

37c). The ester functions of the proline derivatives 37aec were

easily reduced with LiAlH₄in the next step. However, the work-up

of the reaction mixture of 37c resulted in TBDPS group removal.

This observation is in contrast to published results.⁵⁸The authors

reported a 90% yield and observed no TBDPS group deprotection

during reaction work-up. The rearrangement of prolinol derivatives

38a and 38b to the corresponding piperidine compounds 39 was

performed by reaction with triﬂuoroacetic anhydride and trie-

thylamine in THF. The following saponiﬁcation led to hydroxy-

piperidine 39a (51%) and dihydroxypiperidine 39b (49%). Although

the ring expansion did not proceed completely, we were able to

separate the prolinol and piperidine derivatives using ﬂash chro-

matography on a silica gel, and thereby recover the starting

material.

Purine nucleobases were constructed on the amino derivative

43a (Scheme 10). The reaction of 43a with 4,6-dichloropyrimidines

16 or 17 was carried out in n-butanol at 120 ^ꢀC in a pressure vessel

Z

OH

O

iii

OH

i, ii

iv

N

H

N

Bn

N

Bn

O

N

Bn

36a Z=H

35a Z=H

37a Z=H

36b Z=OH

38a Z=H

35b Z=OH

37b Z=OH

36c Z=OTBDPS

38b Z=OH

v

Z

NH₂

Z

OH

Z

N₃

Z

OH

Z

OH

vii

ix

vi

viii

N

Boc

N

Boc

N

Boc

N

Boc

N

H

43a Z=H

41a Z=H

40a Z=H

39a Z=H

42a Z=H

43b Z=ODMTr

41b Z=ODMTr

40b Z=OH

39b Z=OH

42b Z=ODMTr

(i) 1. SOCl₂, MeOH; 2. BnBr, K₂CO₃; (ii)1. SOCl₂, MeOH; 2. BnBr, K₂CO₃; 3. TBDPSCl; (iii) LiAlH₄;

(iv) (CF₃CO)₂O, Et₃N; (v) H₂, Pd/C; (vi) Boc₂O, NaHCO₃; (vii) DMTrCl, py; (viii) 1. MsCl, DMAP; 2.

NaN₃, DMF; (ix) H₂, Pd/C

Scheme 8.

The tert-butyloxycarbonyl group was ﬁrst introduced onto 39a

for 3e4 days, providing products 46a and 46b in 68% and 72%

yields, respectively. The reaction of 46a and 46b with diethoxy-

methyl acetate provided 47a (68%, 6-chloropurine derivative) and

47b (72%, 2-amino-6-chloropurine derivative), respectively. Final

nucleosides were obtained, after NaOH (guanine derivative) or NH₃

(adenine derivative) treatment followed by the deprotection of the

tert-butoxycarbonyl group, in 65% (48a, adenine derivative) and

68% (48b, guanine derivative) yields.

and 39b followed by the partial dimethoxytritylation of 39b, which

afforded the monoprotected piperidine 41b in a 35% yield. The bis-

dimethoxytrityl derivative was also obtained, and we succeeded in

the regeneration of 40b by the treatment of the bis-DMTr derivative

with 1.5% TFA in DCM for 15 min at rt followed by neutralizing the

reaction mixture with a solid sodium hydrogencarbonate (the Boc

group was not cleaved under these conditions). The 3-hydroxy

X

H

N

H

N

Z

B

Z

O

i

ii

43a or 43b

O

N

H

N

Boc

44a Z= H, X= H

44b Z= ODMTr, X= H

44c Z= ODMTr, X= CH₃

45a Z= H, B= uracil

45b Z= OH, B= uracil

45c Z= OH, B= thymine

(i) 15a or 15b, dioxane, r.t.; (ii) DOWEX 50 H⁺, dioxane, 80 °C

Scheme 9.

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S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1490

N

NH₂

Cl

H

N

Cl

B

N

iii

i

ii

N

43a

N

Y

N

Boc

N

H

N

Boc

Y

46a Y= H

46b Y= NH₂

48a B= adenine

48b B= guanine

47a Y= H

47b Y= NH₂

(i) 17 or 16, Et₃N, n-butanol, 120 °C, pressure vessel; (ii) 1. diethoxymetylacetate, DMF, 100 °C;

(iii) 1. NaOH or NH₃2. 20 % TFA in DCM, R.T

Scheme 10.

3. Conformation of piperidine derivatives

The two signals are apparent at low temperatures. The signal in

the lower ﬁeld corresponds to the H-3 axial (triplet of triplets,

J_3,2ax¼J_3,4ax¼10.8, J_3,2eq¼J_3,4eq¼4.4). At higher temperatures the

signals are averaged and H-3 appears as triplet of triplets

(J_3,2a¼J_3,4a¼8.1, J_3,2b¼J_3,4b¼3.8).

Protected piperidine derivatives had broad signals in NMR

spectra at rt. This is not surprising in the case of Boc-protected

compounds because it is well known that the CeN bond in amides

has a partially double bond character, and free rotation around this

bond is slowed down. The slow interconversion of the CeN

rotamers causes the broadening of NMR signals and, therefore, we

usually measured the ¹H and ¹³C NMR spectra of these compounds

at elevated temperatures where the rotation around the CeN bond

is faster and sharp averaged signals can be observed. The broad-

ening of NMR signals of trityl-protected piperidines was, by con-

trast, surprising, and a more detailed study had to be carried out to

explain this behavior. When samples of compounds 21b, and 23b in

CDCl₃were heated to 323 K, the signals became narrower, and

when they were cooled to 240 K the spectra split into two sets of

signals with different integral intensities, corresponding to the pi-

peridine derivatives with the substituent in position 3 in the axial

or equatorial positions, respectively. Both forms had a chair con-

formation, and the axial/equatorial conformers were easily identi-

ﬁed from the ¹H coupling patterns. In the equatorial conformer, the

hydrogen in position 3 is axial and appears as a multiplet with big

coupling constants because of the axialeaxial interaction (10.8 Hz)

to the H4-axial and H2-axial. The broadening of the signals at rt is

caused by the slow interconversion between these two conformers

by ring inversion with simultaneous nitrogen inversion. From the

ratio between the two conformers of compound 21b at 240 K we

could calculate the free energy difference between them (0.36 kcal/

mol), which is very close to the 0.56 kcal/mol difference found

between the two conformers of the mesyloxycyclohexane de-

rivative.^59,60This supports the previous observation that the steric

demands of a nitrogen lone pair in piperidine is only slightly lower

than that of hydrogen in cyclohexane (Fig. 3).⁶¹

4. Conclusions

Various approaches for the introduction of nucleobases onto the

piperidine skeleton were investigated. The nucleobase assembly on

primary amine seemed to be the method of choice. Using this

method a series of racemic and enantiomeric piperidine analogs of

nucleosides was prepared. When comparing two synthetic ways for

(thymin-1-yl)piperidine 27a preparation, the strategy via nucleo-

base build-up provides 27a in a 49% overall yield (from 3-hydroxy-

piperidine, over six steps), whereas via alkylation 27a it was

isolated in a 10% overall yield (from 3-hydroxypiperidine, over four

steps). (Uracil-1-yl)piperidine 32 was prepared via nucleobase

build-up at a 54% overall yield (over six steps) starting from 3-

hydroxypiperidine. Attempts for the direct alkylation of 21a with

uracil failed, when only O-derivatives and products of elimination

were formed.

The prepared compounds 27aed, 28a,b, 32, 45aec, and 48a,b

offer further possibility for derivatization at the piperidine nitrogen

atom, thereby providing the chance to prepare other types of

structurally diverse compounds, e.g., phosphonate pyrrolidine nu-

cleotides, and consequently, enlarge the area of potentially bi-

ologically active compounds. This makes these compounds

interesting, although no signiﬁcant cytostatic (L1210, HL60, HeLa

S3, CCRF-CEM), antibacterial (Enterococcus faecalis CCM 4224,

Staphylococcus aureus CCM 4223, Escherichia coli CCM 3954, Pseu-

domonas aeruginosa CCM 3955 Bacillus subtilis, Streptococcus aga-

lactiae), and antiviral activities (HIV, HCV, RSV) of the prepared

compounds were observed.

5. Experimental

5.1. General

Unless stated otherwise, all used solvents were anhydrous. Re-

agents 15a,b were prepared according to Ref. ⁵¹. The ﬁnal products

were lyophilized from water, and dried over phosphorus pentoxide

at 50e70 ^ꢀC and 13 Pa. TLC was performed on a silica gel pre-coated

aluminium plates silica gel/TLC-cards, UV 254 (Fluka), and com-

pounds were detected by UV light (254 nm), by heating (the de-

tection of dimethoxytrityl group; orange color), by spraying with

a 1% ethanolic solution of ninhydrin to visualize amines and by

spraying with a 1% solution of 4-(4-nitrobenzyl)pyridine in ethanol

followed by heating and treating with gaseous ammonia (blue color

detection of alkylating agents e.g., mesyl derivatives). Preparative

column chromatography was carried out on a silica gel (40e60 mm;

Fluka), and elution was performed at the ﬂow rate of 40 ml/min.

Fig. 3. Temperature dependence of hydrogen H-3 signal of compound 21b.

Analytical RP HPLC was performed on an LC5000 Liquid

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S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1491

Chromatograph (INGOS-PIKRON, CR) using a Luna C18 (2) column

(4.6ꢁ150 mm) at a ﬂow rate of 1 ml/min by a gradient elution of

methanol in 0.1 M TEAB pH 7.5 (A¼0.1 M TEAB; B¼0.1 M TEAB in

50% aqueous methanol; C¼methanol). Preparative RP HPLC was

performed on an LC5000 Liquid Chromatograph (INGOS-PIKRON,

CR) using a Luna C18 (2) column (250ꢁ21.2 mm) at a ﬂow rate of

10 ml/min by a gradient elution of methanol in 0.1 M TEAB pH 7.5

(A¼0.1 M TEAB; B¼0.1 M TEAB in 50% aqueous methanol;

C¼methanol). All ﬁnal compounds were lyophilized from water.

Melting points were determined on a Stuart SMP model 3 and are

uncorrected. Optical rotation values were measured on a polarim-

eter AUTOPOL IV (Rudolph Research Analytical, USA) for the so-

dium D line at 20 ^ꢀC. Mass spectra were recorded on a ZAB-EQ (VG

Analytical) instrument, using FAB (ionization with Xe, accelerating

voltage 8 kV; glycerol and thioglycerol were used as matrices) and

on an LTQ Orbitrap XL (Thermo Fisher Scientiﬁc) using ESI ioniza-

tion. NMR spectra were measured on Bruker AVANCE 400 (¹H at

400 MHz, ¹³C at 100.6 MHz), Bruker AVANCE 500 (¹H at 500 MHz,

the mixture was ﬁltered, and the Dowex was subsequently washed

with dioxane (∼25 ml), ethanol (∼25 ml), water (∼25 ml), and

product was eluted with 2.5% NH₃in H₂O (∼100 ml). The ﬁnal pu-

riﬁcation was achieved with RP HPLC.

5.1.1. (RS)-1-N-tert-Butyloxycarbonyl-3-hydroxypiperidine (20a). 3-

Hydroxypiperidine (20.20 g, 0.2 mol) was dissolved in 1 L of H₂O/

EtOH (1:1, v/v). Then, NaHCO₃was added (100.80 g, 1.6 mol), stir-

ring at rt, followed by the addition of Boc₂O (52.30 g, 0.24 mol). The

reaction was completed in 4.5 h (TLC in 10% EtOH/CHCl₃, ninhydrin

detection). The mixture was ﬁltered and the ﬁltrate was evapo-

rated. The crude product was then puriﬁed by ﬂash chromatogra-

phy on a silica gel by a linear gradient of ethanol in CHCl₃(0/10%).

The product was obtained in a 97% (39.30 g, 0.195 mol) yield as

a colorless oil, which crystallized in the fridge (mp¼71.2e73.4 ^ꢀC).

n_max(KBr) 3468 (vs), 2981 (s), 2943 (s), 2864 (s), 1695 (vs), 1670

(vs), 1481 (s), 1472 (s), 1459 (s), 1450 (s), 1432 (vs), 1393 (vs), 1367

(vs), 1259 (vs), 1241 (vs), 1169 (vs), 1154 (vs), 1104 (m), 1073 (vs),

1024 (m), 1003 (w), 460 (w); d_H(CDCl₃, 400.1 MHz) 3.78e3.82 (2H,

m, J_gem12.9 Hz, H-2a), 3.68e3.73 (1H, m, H-3), 3.56e3.61 (1H, m,

H-6a), 2.98 (2H, dd, J_gem12.9 Hz, J_2b-37.9 Hz, H-2b), 2.99e3.06

(1H, m, H-6b), 1.89e1.93 (1H, m, H-4a), 1.72e1.77 (1H, m, H-5a),

1.38e1.54 (11H, m, (CH₃)₃, H-4b, H-5b); d_C(CDCl₃, 100.6 MHz) 155.1

(CO), 79.7 (C(CH₃)), 66.0 (C-3), 50.5 (C-2), 44.0 (C-6), 32.5 (C-4), 28.4

(CH₃), 22.5 (C-5); HRMS (FAB) C₁₀H₂₀NO₃(MþH)^þcalcd 202.1447,

found 202.1443.

¹³C at 125.7 MHz) and/or Bruker AVANCE 600 (¹H at 600.1 MHz, ¹³

at 150.9 MHz) spectrometers. Chemical shifts (in ppm, scale) were

C

d

referenced to TMS as the internal standard; coupling constants (J)

are given in hertz. The complete assignment of protons and carbons

was done by the analysis of correlated homonuclear 2D-COSY and

heteronuclear ¹He¹³C HSQC and ¹He¹³C HMBC spectra. Relative

conﬁguration was checked using the DPFGSE-NOE and 2D-ROESY

techniques. Nucleobase atom numbering was also used in the case

of linear intermediates.

5.1.2. (RS)-3-Hydroxy-1-N-tritylpiperidine (20b). 3-Hydroxypiper-

idine (18.16 g, 0.18 mol) and NaHCO₃(76.00 g, 0.9 mol) were sus-

pended in 1 L of H₂O/dioxane (1:1, v/v). Tritylchloride (60 g,

0.22 mol) in 500 ml of dioxane was added to this stirred mixture at

rt. After 2 h, the mixture was ﬁltered and the ﬁltrate was evapo-

rated under reduced pressure. The crude product was puriﬁed by

ﬂash chromatography on a silica gel by a linear gradient of ethyl

acetate in toluene (0/100%). The product was obtained as a light

yellow amorphous solid in a 30% yield (20.00 g, 58 mmol).

n_max(KBr) 3571 (w), 3493 (w), 3470 (w), 3082 (w), 3054 (w), 3029

(w), 3019 (w), 2999 (w),1595 (w),1580 (w),1489 (m),1447 (m),1447

(m), 1284 (w), 1213 (m), 1157 (w), 1088 (w), 1078 (w), 1072 (w), 1066

(w), 1033 (w), 1001 (w), 934 (w), 908 (w), 846 (vw), 761 (m), 750 (s),

710 (vs), 701 (s), 631 (m), 544 (vw); d_H(DMSO, 499.8 MHz, 80 ^ꢀC)

7.39e7.42 (6H, m, H_oeTr), 7.26e7.30 (6H, m, H_meTr), 7.16 (3H, m,

H_peTr), 3.76e7.79 (1H, m, H-3), 2.88e3.00 (1H, m, H-2b), 2.70 (1H, m,

H-6b), 1.83 (1H, m, H-4b), 1.62e1.70 (2H, m, H-5), 1.37 (1H, m, H-6a),

1.27 (1H, m, H-2a), 0.95 (1H, m, H-4a); d_C(DMSO, 125.7 MHz, 80 ^ꢀC)

143.1 (C-1⁰), 129.3 (C-2⁰), 127.9 (C-3⁰), 126.3 (C-4⁰), 77.3 (CePh₃), 67.1

(C-3), 56.7 (C-2), 48.7 (C-6), 34.3 (C-4), 23.8 (C-5); HRMS (FAB)

C₂₄H₂₆NO (MþH)^þcalcd 344.201440, found 344.202339.

O

6

3

1

X

5

4

2

N

O

H

R

General method A: DIAD (3 mmol) was slowly added to the

solution of N-protected-3-hydroxypiperidine (1 mmol), PPh₃

(3 mmol), and nucleobase (1 mmol) in 15 ml of reﬂuxing dioxane.

This mixture was stirred at 100 ^ꢀC for 1 h and then concentrated

under reduced pressure and puriﬁed by ﬂash chromatography on

a silica gel.

General method B: Triphenylphosphine (3.0 mmol) was added to

the stirred mixture of DIAD (3.0 mmol) in dry THF at 0 ^ꢀC. After

30 min, nucleobase (1.0 mmol) and N-protected-3-hydroxypiper-

idine in THF was added dropwise to the solution of DIAD and tri-

phenylphosphine. The product was puriﬁed by ﬂash chromatography

on a silica gel.

General method C: Nucleobase (1.5 mmol) and base (1.5 mmol)

were heated at 100 ^ꢀC in dry DMF/DMSO (15 ml). Mesyl derivative

(1 mmol) dissolved in dry DMF/DMSO (10 ml) was then added

dropwise and the mixture was heated at 120 ^ꢀC for 3 h. The solvent

was evaporated and product puriﬁed on a silica gel using ﬂash

chromatography.

General method D: N-Boc/N-trityl derivative (1.0 mmol) was

treated overnight with 20% TFA in DCM (30 ml). The mixture was

extracted with water and then the aqueous phase was applied to

a column of the Dowex 50 in H^þform (20 ml). The column was

washed with 50% aqueous ethanol (∼200 ml) and the product

was eluted with 2.5% NH₃in H₂O (∼100 ml). Final puriﬁcation was

performed on preparative RP HPLC.

5.1.3. (RS)-1-N-tert-Butyloxycarbonyl-3-mesyloxypiperidine (21a).

Hydroxypiperidine 20a (20.10 g, 0.1 mol) and DMAP (61.08 g,

0.5 mol) were co-evaporated with anhydrous dichloromethane

(DCM) and suspended in 1 L DCM. The mixture was cooled to 0 ^ꢀC

and mesyl chloride (38 ml, 0.5 mol) was added dropwise under

cooling and vigorous stirring. After 2 h TLC (10% EtOH/CHCl₃,

ninhydrin detection) showed the complete consumption of the

starting material. Water (20 ml) was added to the mixture and

stirring continued for an additional 10 min. The mixture was

extracted with saturated NaHCO₃(3ꢁ), and the combined organic

phases were dried over anhydrous Na₂SO₄. Sodium sulfate was

ﬁltered off and the ﬁltrate was evaporated. The product was puri-

ﬁed by ﬂash chromatography on a silica gel using a linear of gra-

dient ethyl acetate in toluene. The product was obtained as a white

amorphous solid in a 85% yield (23.90 g, 85.5 mmol).

General method E: Compounds 15a (1.1 mmol) or 15b (1.3 mmol)

was added to the solution of amine (1 mmol) in dioxane (10 ml/

mmol). The reaction mixture was stirred at rt for 30 min. The solvent

was then evaporated and the product was puriﬁed on a silica gel.

General method F: Dowex 50 in H^þform (2 g/mmol) was added

to the solution of urea derivatives (1 mmol) in dioxane (10 ml/

mmol). The reaction mixture was heated to 90 ^ꢀC for 30 min. Then

n_max(KBr) 1693 (vs), 1463 (s), 1428 (s), 1245 (s), 1391 (m), 1365

(s), 1351 (vs), 1179 (vs), 976 (s), 938 (s), 929 (s), 904 (s), 543 (s), 524

ꢀ

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S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1492

(s); d_H(DMSO, 499.8 MHz, 50 ^ꢀC) 4.70 (1H, m, H-3), 3.60e3.64 (2H,

m, H-2), 3.42 (1H, ddd, J_gem13.4 Hz, J_6b-57.2 and 3.9 Hz, H-6b), 3.34

(1H, ddd, J_gem13.4 Hz, J_6a-57.6 and 3.8 Hz, H-6a), 3.03 (3H, s,

CH₃SO₂), 1.97 (1H, m, H-4b), 1.89 (1H, m, H-4a), 1.82 (1H, m, H-5b),

1.54 (1H, m, H-5a), 1.46 (9H, s, (C(CH₃)₃)); d_C(CDCl₃, 125.7 MHz,

50 ^ꢀC) 154.7 (COO), 80.1 (C(CH₃)₃), 75.3 (C-3), 47.9 (C-2), 43.5 (C-6),

38.8 (SO₂CH₃), 30.5 (C-4), 28.3 (C(CH₃)₃), 21.7 (C-5); HRMS (FAB)

C₁₁H₂₂NO₅S (MþH)^þcalcd 280.1212, found 280.1223.

m, H-6a), 1.77e1.82 (2H, br s, H-4a, H-4b), 1.68 (1H, m, H-5b),

1.10e1.46 (10H, m, H-5a, CH₃); d_c(DMSO, 150.9 MHz) 165.8 (C-4⁰),

162.0 (C-2⁰), 154.2 (C]O), 152.2 (C-6⁰), 99.7 (C-5⁰), 78.6 (C(CH₃)₃),

70.1 (C-3), 46.5 (C-2), 43.1 (C-6), 28.7 (C-4), 28.0 (CH₃), 20.7 (C-5);

HRMS (ESI) C₁₄H₂₃O₃N₄(MþH)^þcalcd 295.1765, found 295.1765.

5.1.7. (RS)-1-N-tert-Butyloxycarbonyl-3-(cytosin-1-yl)piperidine

(22c). Nucleoside derivative 22c was prepared from mesyl derivative

21a (500 mg, 1.79 mmol), cytosine (297 mg, 2.68 mmol), and Cs₂CO₃

(873 mg, 2.68 mmol) in DMSO according to general procedure C in

a 18% yield (94 mg, 0.322 mmol) as a white amorphous solid.

n_max(CHCl₃) 3392 (vs), 3212 (s), 2980 (m), 2954 (m), 2934 (m),

2865 (m), 1673 (vs),1656 (vs), 1602 (s), 1532 (m), 1500 (s), 1480 (m),

1455 (m),1429 (m),1410 (m),1394 (m),1369 (m),1349 (m),1271 (s),

1247 (s), 1155 (m), 860 (w); d_H(DMSO, 499.8 MHz, 80 ^ꢀC) 7.59 (1H,

5.1.4. (RS)-3-Mesyloxy-1-N-tritylpiperidine (21b). Piperidine de-

rivative 20b (16.61 g, 48 mmol) and DMAP (29.32 g, 0.241 mmol)

were co-evaporated with anhydrous DCM and suspended in 1 L

DCM. The mixture was cooled to 0 ^ꢀC and mesyl chloride (18.5 ml,

0.241 mmol) was added dropwise under cooling and vigorous

stirring. After 2 h TLC showed the complete consumption of the

starting material. Water (20 ml) was added to the mixture a stirring

continued for 10 min. The mixture was extracted with saturated

NaHCO₃(3ꢁ), and the combined organic phases were dried over

Na₂SO₄. Sodium sulfate was ﬁltered and the ﬁltrate was evaporated.

The product was puriﬁed by ﬂash chromatography on a silica gel

using a linear gradient of ethyl acetate in toluene. The product was

obtained as a light yellow foam in a 94% yield (18.90 g, 43.6 mmol).

n_max(KBr) 3082 (m), 3066 (m), 3029 (m), 3019 (m), 2990 (m),

2946 (m), 2921 (m), 2850 (m), 1596 (m), 1583 (w),1488 (s), 1448 (s),

1419 (w), 1352 (vs), 1330(s), 1316 (m), 1213 (m), 1173 (vs), 1159 (s),

1115 (m), 1086 (w), 1033 (m), 1003 (m), 982 (vs), 951 (vs), 938 (s),

909 (s), 840 (m), 775 (m), 762 (s), 744 (s), 708 (vs), 698 (vs), 641 (m),

629 (m), 539 (s), 523 (s); d_H(DMSO, 499.8 MHz, 50 ^ꢀC) 7.46 (6H, m,

H_oeTr), 7.25 (6H, m, H_meTr), 7.14 (3H, m, H_peTr), 4.92 (1H, m, H-3),

2.94 (3H, m, CH₃SO₂), 2.90 (1H, br s, H-2a), 2.50 (1H, br s, H-6a), 2.1

(1H, br s, H-5a), 1.69e2.04 (4H, m, H-2b, H-6b, H-5b, H-5a), 1.56

(1H, m, H-4b); d_C(CDCl₃, 125.7 MHz, 50 ^ꢀC) 142.3 (CeTr), 129.2

(CH_oeTr), 127.6 (CH_meTr), 126.2 (CH_peTr), 78.2 (C-3), 77.3 (C(Ph)₃),

53.4 (C-2), 48.2 (C-6), 38.6 (CH₃eMs), 31.3 (C-4), 23.1 (C-5); HRMS

(FAB) C₂₅H₂₈NO₃S (MþH)^þcalcd 422.1790, found 422.1768.

0

d, J_{6 -5}7.4 Hz, H-6 ), 6.84 (2H, br s, NH₂), 5.72 m (1H, d, J_{5 -6}7.4 Hz,

H-5⁰), 4.32 (1H, m, H-3), 3.86e3.92 (2H, m, H-2b, H-6b), 2.89 (1H,

m, H-2a), 2.73 (1H, m, H-6a), 1.73e1.82 (3H, m, H-4a, H-4b, H-5b),

1.46 (1H, m, H-5a), 1.41 (9H, s, H-3, (CH₃)₃); d_c(DMSO, 125.7 MHz,

80 ^ꢀC) 165.1 (C-4⁰), 155.2 (C-2⁰), 153.8 (C]O), 142.0 (C-6⁰), 93.4 (C-

5⁰), 78.9 (C(CH₃)₃), 51.4 (C-3), 47.0 (C-2), 43.1 (C-6), 28.3 (C-4), 27.9

(CH₃), 24.17 (C-5); HRMS (ESI) C₁₂H₂₂O₃N₄Na (MþNa)^þcalcd

317.1584, found 317.1584.

5.1.8. (RS)-3-(Adenin-9-yl)-1-N-tert-butyloxycarbonylpiperidine

(22d). Nucleoside derivative 22d was prepared from mesyl de-

rivative 21a (500 mg, 1.79 mmol), adenine (362 mg, 2.68 mmol),

and Cs₂CO₃(873 mg, 2.68 mmol) in DMSO according to general

procedure C in a 18% yield (102 mg, 0.322 mmol) as a white

amorphous solid.

n_max(CHCl₃) 3526 (w), 3414 (w), 2981 (m), 2957 (m), 2930 (m),

2866 (w),1688 (s),1630 (vs),1587 (m),1575 (w),1507 (w),1471 (m),

1456 (m), 1425 (m), 1416 (m), 1394 (m), 1368 (m), 1346 (w), 1328

(w), 1300 (w), 1268 (m), 1245 (s), 1162 (m), 1151 (m), 860 (w), 649

(w); d_H(DMSO, 499.8 MHz) 8.21 (1H, s, H-8⁰), 8.14 (1H, s, H-2⁰), 7.23

(2H, br s, NH₂), 4.39 (1H, m, H-3), 4.10 (1H, vbr s, H-2a), 3.89 (1H, br

m, H-6a), 2.94 (1H, vbr s, H-2b), 2.20 (1H, m, H-4a), 2.07 (1H, m, H-

4b), 1.77 (1H, m, H-5a), 1.53 (1H, m, H-5b), 1.36 (9H, s, (CH₃)₃); d_C

(DMSO,125.7 MHz) 156.2 (C-6⁰),153.9 (C]O),152.5 (C-2⁰),149.4 (C-

4⁰), 139.1 (C-8⁰), 119.0 (C-5⁰), 79.3 (C(CH₃)₃), 50.7 (C-3), 47.7 (C-2),

43.5 (C-6), 29.2 (C-4), 28.1 (C(CH₃)₃), 23.9 (C-5); HRMS (ESI)

C₁₅H₂₃O₂N₆(MþH)^þcalcd 319.1877, found 319.1877.

5.1.5. (RS)-1-N-tert-Butyloxycarbonyl-3-(thymin-1-yl)piperidine

(22a). Thymine derivative 22a was prepared from mesyl derivative

21a (500 mg, 1.79 mmol), thymine (339 mg, 2.68 mmol), and

Cs₂CO₃(873 mg, 2.68 mmol) in DMSO, according to general pro-

cedure C in a 16% yield (88 mg, 0.284 mmol) as a white foam.

n_max(KBr) 3167 (w), 2979 (w), 1701 (s), 1684 (vs), 1651 (m), 1519

(vw), 1470 (w), 1430 (m), 1422 (m), 1391 (w), 1366 (w), 1313 (w),

1274 (m), 1259 (w), 1244 (m), 1155 (m), 862 (w), 758 (w), 466 (vw);

d_H(DMSO, 499.8 MHz) 11.24 (1H, s, NH-3⁰), 7.57 (1H, s, H-6⁰), 4.18

(1H, m, H-3), 3.85 (2H, m, H-2a, H-6a), 2.90 (1H, br s, H-2b), 2.66

(1H, m, H-6b), 1.75 (6H, m, H-4a, H-4b, H-5a, CH₃), 1.40 (1H, m, H-

5b), 1.36 (9H, s, (CH₃)₃); d_c(DMSO, 125.7 MHz) 163.8 (C-4⁰), 154.0

(C]O),150.9 (C-2⁰),137.7 (C-6⁰),109.1 (C-5⁰), 79.2 (C(CH₃)₃), 50.9 (C-

3), 46.5 (C-2), 43.2 (C-6), 28.2 (C-4), 28.1 (C(CH₃)₃), 24.5 (C-5), 12.2

(CH₃); HRMS (ESI) C₁₅H₂₄O₄N₃(MþH)^þcalcd 310.1761, found

310.1760.

5.1.9. (RS)-3-(6-Chloropurin-9-yl)-1-N-tritylpiperidine (23a). 6-Chlo-

ropurine derivative 23a was prepared from hydroxy derivative 20b

(343 mg, 1 mmol), 6-chloropurine (154 mg, 1 mmol), DIAD (0.59 ml,

3 mmol), and PPh₃(786 mg, 3 mmol) according to general procedure

B (THF) in a 25% yield (84 mg, 0.25 mmol) as a light yellow foam.

n_max(KBr) 3285 (s), 3251 (s), 3085 (vw), 3056 (w), 3033 (m),

1738 (vs), 1691 (vs), 1591 (m), 1558 (m), 1526 (s), 1490 (m), 1448

(m), 1438 (w), 1336 (m), 1314 (m), 1219 (m), 1146 (m), 1086 (w),

1035 (m), 1004 (w), 936 (w), 902 (w), 793 (w), 763 (m), 747 (m), 710

(m), 700 (w), 649 (w), 636 (m); d_H(CDCl₃, 499.9 MHz, 320 K) 8.70

(1H, s, H-2⁰), 8.09 (1H, br s, H-8⁰), 7.12e7.48 (15H, m, CeHeTr), 5.09

(1H, m, H-3); 3.40 (1H, m, H-2_eq); 3.06 (1H, m, H-6_eq); 2.26 (1H, m,

H-4_eq); 2.05 (1H, m, H-5_ax); 1.94 (1H, m, H-5_eq); 1.57e1.88 (3H, m,

H-2_ax, H-4_ax, H-6_ax); d_C(CDCl₃, 125.7 MHz, 320 K) 152.3 (C-4⁰), 151.9

(C-2⁰), 151.0 (C-6⁰), 145.6 (C-8⁰), 144.6 (Cetrityl), 131.6 (C-5⁰), 129.0

(C_oetrityl), 127.6 (C_metrityl), 126.3 (C_petrityl), 77.4 (CePh₃), 54.2

(C-2), 53.2 (C-3), 48.4 (C-6), 30.4 (C-4), 24.6 (C-5); HRMS (ESI)

C₂₉H₂₇N₅Cl (MþH)^þcalcd 480.1950, found 480.1950.

5.1.6. (RS)-1-N-tert-Butyloxycarbonyl-3-(cytosin-2-O-yl)piperidine

(22b). Cytosine O-derivative 22c was prepared from mesyl de-

rivative 21a (500 mg, 1.79 mmol), cytosine (297 mg, 2.68 mmol),

and Cs₂CO₃(873 mg, 2.68 mmol) in DMSO, according to general

procedure C in a 29% yield (150 mg, 0.519 mmol) as a white

amorphous solid.

n_max(KBr) 3390 (m), 3330 (m), 3244 (w, sh), 3180 (m, br), 3005

(w), 2971 (m), 1678 (s), 1644 (s), 1592 (s), 1559 (s),1479 (m), 1462

(m), 1428 (s), 1407 (vs), 1365 (s), 1340 (m), 1280 (m), 1256 (m), 1241

(m), 1173 (m), 1146 (s), 1094 (m), 1075 (w), 859 (w), 811 (w), 769

5.1.10. (RS)-3-(2-Amino-6-chloropurin-9-yl)-1-N-tritylpiperidine

(23b). 2-Amino-6-chloropurine derivative 23b was prepared from

hydroxy derivative 20b (343 mg, 1.0 mmol), 6-chloro-2-amino-

purine (169 mg, 1.0 mmol), DIAD (0.59 ml, 3 mmol), and PPh₃

(w); d_H(DMSO, 600.1 MHz) 7.86 (1H, d, J_{6 -5}6.2 Hz, H-6⁰), 7.46 (2H,

0

br s, NH₂), 6.14 (1H, d, J_{5 -6}6.2 Hz, H-5⁰), 4.85 (1H, br s, H-3), 3.95

0

(1H, br s, H-2b), 3.63 (1H, br s, H-6b), 3.25 (1H, m, H-2a), 3.00 (1H,

ꢀ

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S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1493

(786 mg, 3 mmol) according to general procedure B (in THF) in

a 27% yield (95 mg, 0.27 mmol) as a light yellow foam.

CH_aH_bO), 3.72 (1H, m, H-2), 3.28 (1H, ddd, J_gem12.4 Hz, J_5a,38.5 ,

6.4 Hz, H-5a), 2.97 (1H, ddd, J_gem12.4 Hz, J_5b,48.5 , 5.0 Hz, H-5b),

1.50 (1H, m, H-3a), 1.45 (1H, m, H-4a), 0.75 (2H, m, H-3b, H-4b); d_C

(CDCl₃, 125.7 MHz, 320 K) 165.1 (C-2⁰), 164.7 (C-4⁰), 157.0 (C-6⁰),

145.2 (C_ietrityl), 129.4 (C_oetrityl), 127.3 (C_metrityl), 125.8 (C_petri-

tyl), 99.0 (C-5⁰), 77.58 (CePh₃), 68.8 (CH₂O), 59.1 (C-2), 49.8 (C-5),

27.7 (C-3), 23.7 (C-4); HRMS (ESI) C₂₈H₂₉N₄O (MþH)^þcalcd

437.2335, found 437.2339.

n_max(KBr) 3492 (vs), 3440 (vs), 3082 (vw), 3056 (w), 3030

(vw), 3020 (vw), 2939 (w), 2862 (vw), 1611 (vs), 1563 (s), 1506 (m),

1490(m), 1457 (m), 1449 (m), 1440 (w), 1403 (w), 1287 (w), 1213

(m), 1185 (w), 1112 (vw), 1086 (w), 1032 (w), 1003 (w), 937 (vw),

910 (m), 848 (vw), 786 (w), 776 (w), 745 (m), 710 (s), 699 (m), 639

(m), 632 (m); d_H(CDCl₃, 499.9 MHz, 320 K) 7.67 (1H, s, H-8⁰),

7.02e7.47 (15H, m, CeHeTr), 5.52 (2H, br s, NH₂), 4.85 (1H, m, H-

3), 3.56 (1H, dm, J_gem10.5 Hz, H-2_eq), 3.23 (1H, dm, J_gem11.4 Hz, H-

6_eq), 2.24 (1H, dm, J_gem11.3 Hz, H-4_eq), 2.04 (1H, m, H-5_ax), 1.86

(1H, dm, J_gem12.8 Hz, H-5_eq), 1.62 (1H, qd, J_gem¼J_4ax-3¼J_4ax-5ax

11.3 Hz, H-4_ax), 1.51 (1H, t, J_2ax-3¼J_gem10.7 Hz, H-2_ax), 1.42 (1H, t,

J_6ax-5ax¼J_gem12.0 Hz, H-6_ax); d_C(CDCl₃, 125.7 MHz, 320 K) 158.93

(C-2⁰), 153.73 (C-4⁰), 151.23 (C-6⁰), 144.85 (Cetrityl), 142.05 (C-8⁰),

129.15 (C_oetrityl), 127.58 (C_metrityl), 126.23 (C_petrityl), 125.48 (C-

5⁰), 77.45 (CePh₃), 53.92 (C-2), 52.68 (C-3), 48.46 (C-6), 30.16 (C-

4), 24.66 (C-5); HRMS (ESI) C₂₉H₂₈N₆Cl (MþH)^þcalcd 495.2058,

found 495.2058.

5.1.13. (RS)-3-(Thymin-1-yl)-1-N-tritylpiperidine (23e) and 2-(thy-

min-1-yl)methyl-1-N-tritylpyrrolidine (24b). Thymine derivatives

23e and 24b were prepared from mesyl derivative 21b (753 mg,

1.79 mmol), thymine (339 mg, 2.68 mmol), and Cs₂CO₃(873 mg,

2.68 mmol) in DMSO according to general procedure C in a 27% yield

(217 mg, 0.482 mmol) as a white foam (mixture of 23e and 24b).

NMR data for 23e: d_H(CDCl₃, 499.9 MHz, 320 K) 9.60 (1H, br s,

N3⁰-H), 7.46 (6H, m, H_oeTr), 7.25 (6H, m, H_meTr) 7.12 (3H, m,

H_peTr), 6.83 (1H, br s, H-6⁰), 4.98 (1H, m, H-3), 3.28 (1H, m, H-2_eq),

3.11 (1H, m, H-6_eq),1.95 (1H, m, H-5_ax),1.94 (1H, m, H-4_eq), 1.79 (3H,

d, ⁴J 1.0 Hz, CH₃), 1.76 (1H, m, H-5_eq), 1.44 (1H, m, H-2_ax), 1.39 (1H,

m, H-6_ax), 1.30 (1H, m, H-4_ax); d_C(CDCl₃, 125.7 MHz, 320 K) 163.6

(C-4⁰), 150.9 (C-2⁰), 144.8 (C_ietrityl), 136.2 (C-6⁰), 129.0 (C_oetrityl),

127.5 (C_metrityl), 126.0 (C_petrityl), 110.1 (C-5⁰), 77.3 (CePh₃), 53.1

(C-2), 52.5 (C-3), 48.2 (C-6), 29.4 (C-4), 24.6 (C-5), 12.2 (CH₃).

NMR data for 24b: d_H(CDCl₃, 499.9 MHz, 320 K) 9.60 (1H, br s,

N3⁰-H), 7.52 (6H, m, H_oeTr), 7.21 (6H, m, H_meTr) 7.14 (3H, m,

5.1.11. (RS)-3-(Adenin-9-yl)-1-N-tritylpiperidine (23c) and 2-(ad-

enin-9-yl)methyl-1-N-tritylpyrrolidine (24a). Adenine derivatives

23c and 24a were prepared from 21b (753 mg, 1.79 mmol), adenine

(362 mg, 2.68 mmol), and Cs₂CO₃(873 mg, 2.68 mmol) in DMF

(25 ml) according to general procedure C in a 35% yield (410 mg,

0.895 mmol) as a light yellow foam (mixture of 23a and 24a).

NMR data for 23c: d_H(CDCl₃, 499.9 MHz, 320 K): 8.34 (1H, br s,

H-2⁰), 7.77 (1H, br s, H-8⁰), 7.44 (6H, m, H_oeTr), 7.22 (6H, m, H_meTr),

7.14 (3H, m, H_peTr), 5.61 (2H, br s, NH₂), 5.00 (1H, m, H-3), 3.34 (1H,

br m, H-2_eq), 3.05 (1H, br m, H-6_eq), 2.24 (1H, br m, H-4_eq), 2.03 (1H,

br m, H-5_ax), 1.91 (1H, br m, H-5_eq), 1.64e1.87 (3H, br m, H-2_ax, H-

4_ax, H-6_ax); d_C(CDCl₃, 125.7 MHz, 320 K) 155.3 (C-6⁰), 152.8 (C-2⁰),

150.1 (C-4⁰), 144.9 (C_ietrityl), 141.0 (C-8⁰), 129.1 (C_oetrityl), 127.6

(C_metrityl), 126.2 (C_petrityl), 119.7 (C-5⁰), 77.4 (CePh₃), 54.3 (C-2),

52.3 (C-3), 48.5 (C-6), 30.7 (C-4), 24.7 (C-5).

NMR data for 24a: d_H(CDCl₃, 499.9 MHz, 320 K) 8.32 (1H, br s, H-

2⁰), 7.73 (1H, br s, H-8⁰), 7.52 (6H, m, H_oeTr), 7.22 (6H, m, H_meTr),

7.16 (3H, m, H_peTr), 5.62 (2H, br s, NH₂), 4.29 (1H, dd, J_gem13.9 Hz,

J_vic5.4 Hz, CH_aH_bN), 4.26 (1H, dd, J_gem13.9 Hz, J_vic7.0 Hz, CH_aH_bN),

3.78 (1H, m, H-2), 3.18 (1H, ddd, J_gem12.5 Hz, J_5a,38.5, 6.9 Hz, H-5a),

2.97 (1H, ddd, J_gem12.5 Hz, J_5b,48.7 , 5.1 Hz, H-5b), 1.36 (1H, m, H-

4a), 1.26 (1H, m, H-3a), 0.84 (1H, m, H-3b), 0.73 (1H, m, H-4b); d_C

(CDCl₃, 125.7 MHz, 320 K) 155.3 (C-6⁰), 153.0 (C-2⁰), 150.7 (C-4⁰),

144.9 (C_ietrityl), 141.0 (C-8⁰), 129.6 (C_oetrityl), 127.6 (C_metrityl),

126.3 (C_petrityl), 119.4 (C-5⁰), 77.9 (CePh₃), 61.4 (C-2), 50.0 (C-5),

48.2 (CH₂N), 28.7 (C-3), 23.7 (C-4); HRMS (ESI) C₂₉H₂₉N₆(MþH)^þ

calcd 461.2448, found 461.2449.

4

H_peTr), 6.73 (1H, q, J 1.1 Hz, H-6⁰), 3.93 (1H, dd, J_gem13.5 Hz, J_vic

8.2 Hz, CH_aH_bN), 3.64 (1H, dd, J_gem13.5 Hz, J_vic8.8 Hz, CH_aH_bN), 3.66

(1H, m, H-2), 3.26 (1H, ddd, J_gem12.5 Hz, J_5a,38.8 , 5.8 Hz, H-5a), 2.97

(1H, ddd, J_gem12.5 Hz, J_5b,48.3 , 5.8 Hz, H-5b), 1.87 (3H, d, ⁴J 1.1 Hz,

CH₃), 1.50 (1H, m, H-3a), 1.26 (1H, m, H-4a), 0.82 (2H, m, H-3b, H-

4b); d_C(CDCl₃, 125.7 MHz, 320 K) 164.2 (C-4⁰), 151.3 (C-2⁰), 144.8

(C_ietrityl), 140.7 (C-6⁰), 129.4 (C_oetrityl), 127.5 (C_metrityl), 126.2

(C_petrityl), 110.3 (C-5⁰), 77.5 (CePh₃), 60.3 (C-2), 51.0 (CH₂N), 49.5

(C-5), 27.9 (C-3), 23.7 (C-4), 12.0 (CH₃); HRMS (ESI) C₂₉H₂₈O₂N₃Na

(MþNa)^þcalcd 474.2152, found 474.2150.

5.1.14. 1-N-tert-Butyloxycarbonyl-1,2,3,6-tetrahydropyridine

(25a). Tetrahydropyridine derivative 25a was prepared from mesyl

derivative 21a (500 mg, 1.79 mmol), thymine (339 mg, 2.68 mmol),

and Cs₂CO₃(873 mg, 2.68 mmol) in DMSO according to general pro-

cedure C in a 23% yield (75 mg, 0.009 mmol) as a white amorphous

solid.

n_max(KBr) 3072 (vw), 3039 (w), 2981 (s), 2930 (s), 2845 (m),

1686 (vs), 1654 (s), 1477 (m), 1467 (m), 1451 (s), 1425 (vs), 1391 (s),

1367 (s),1340 (m),1285 (s),1250 (s),1244 (s),1171 (vs),1150 (s), 859

(w), 701 (w); d_H(CDCl₃, 500.0 MHz) 5.82 (1H, m, H-4), 5.64 (1H, m,

H-3), 3.87 (2H, m, H-2), 3.48 (2H, br t, H-6), 2.13 (2H, m, H-5), 1.47

(9H, s, (CH₃)₃); d_C(CDCl₃, 125.7 MHz) 154.9 (C]O), 125.1 (C-4),

124.3 (C-3), 79.3 (Ce(CH₃)₃), 43.3 (br s, C-2), 40.8 and 39.3 (C-6),

5.1.12. (RS)-3-(Cytosin-2-O-yl)-1-N-tritylpiperidine (23d) and 2-(cyto-

sin-2-O-yl)methyl-1-N-tritylpyrrolidine (24c). Cytosine derivatives

23d and 24c were prepared from mesyl derivative 21b (753 mg,

1.79 mmol), cytosine (297 mg, 2.68 mmol), and Cs₂CO₃(873 mg,

2.68 mmol) in DMSO according to general procedure C in a 28% yield

(218 mg, 0.501 mmol) as a white foam (mixture of 23d and 24c).

28.4 (CH₃), 25.0 (C-5); HRMS (FAB) C₂₄H₂₃

326.1909, found 326.1901.

N

(MþH)^þcalcd

5.1.15. 1-N-Trityl-1,2,3,6-tetrahydropyridine (25b). Tetrahydropyridine

derivative 25a was prepared from hydroxy derivative 20b (343 mg,

1 mmol), 6-chloropurine (154 mg, 1 mmol), DIAD (0.59 ml, 3 mmol),

and PPh₃(786 mg, 3 mmol) according to general procedure B (THF) in

a 32% yield (104 mg, 0.32 mmol) as a light yellow foam.

n_max(KBr) 3082 (w), 3056 (w), 3028 (w),1655 (w),1596 (w), 1488

(m), 1466 (w), 1448 (m), 1439 (w), 1319 (w), 1213 (w), 1177 (w), 1159

(vw),1082 (w),1033 (w), 999 (w), 936 (w), 902 (w), 843 (w), 773 (w),

751 (m), 744 (s), 710 (vs), 699 (m), 642 (w), 629 (s); d_H(CDCl₃,

600.1 MHz) 7.49 (6H, m, H_oeTr), 7.22 (6H, m, H_meTr) 7.11 (3H, m,

H_peTr), 5.68 (1H, m, H-4), 5.62 (1H, m, H-3), 2.83 (2H, m, H-2), 2.34

(2H, br s, H-6), 2.23 (2H, br s, H-5); d_C(CDCl₃, 150.9 MHz) 142.6

(Cetrityl), 129.2 (C_oetrityl), 127.3 (C_metrityl), 126.5 (C-3), 125.8

0

NMR data for 23d: d_H(CDCl₃, 499.9 MHz, 320 K) 7.89 (1H, d, J_{6 ,5}

5.7 Hz, H-6⁰), 7.48 (6H, m, H_oeTr), 7.20 (6H, m, H_meTr), 7.08 (3H, m,

0

H_peTr), 5.93 (1H, d, J_{5 ,6}5.7 Hz, H-5 ), 5.22 (1H, m, H-3), 5.04 (1H, br

s, NH₂), 3.28 (1H, br m, H-2_eq), 2.90 (1H, br m, H-6_eq),1.50e2.10 (6H,

br m, H-2_ax, H-5, H-4, H-6_ax); d_C(CDCl₃, 125.7 MHz, 320 K) 164.8 (C-

2⁰), 164.6 (C-4⁰), 157.1 (C-6⁰), 145.2 (C_ietrityl), 129.1 (C_oetrityl), 127.1

(C_metrityl), 125.7 (C_petrityl), 98.9 (C-5⁰), 77.1 (CePh₃), 72.2 (C-2),

52.4 (C-3), 48.5 (C-6), 30.1 (C-4), 23.4 (C-5).

0

NMR data for 24c: d_H(CDCl₃, 499.9 MHz, 320 K) 7.90 (1H, d, J_{6 ,5}

5.7 Hz, H-6⁰), 7.60 (6H, m, H_oeTr), 7.₀20 (6H, m, H_meTr), 7.10 (3H, m,

0

H_peTr), 5.94 (1H, d, J_{5 ,6}5.7 Hz, H-5 ), 5.01 (1H, br s, NH₂), 4.57(1H,

dd, J_gem10.1 Hz, J_vic4.3 Hz, CH_aH_bO), 3.16 (1H, t, J_gem¼J_vic10.1 Hz,

ꢀ

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S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1494

(C_petrityl),124.9 (C-4), 77.0 (CePh₃), 47.0 (C-2), 45.5 (C-6), 27.2 (C-5);

HRMS (FAB) C₂₄H₂₃N (MþH)^þcalcd 326.1909, found 326.1901.

1050 (s), 782 (w); d_H(DMSO, 500.0 MHz) 10.4 (1H, vbr s, NH), 7.82

(1H, br s, H-8⁰), 6.46 (2H, br s, NH₂), 4.18 (1H, m, H-3), 3.10 (1H, dm,

J_gem11.8 Hz, H-2b), 2.90 (1H, dm, J_gem12.2 Hz, H-6b), 2.83 (1H, dd,

J_gem11.8 Hz, J_2a-39.9 Hz, H-2a), 2.52 (1H, td, J_gem¼J_6a-5a11.9 Hz, J_6a-5b

2.8 Hz, H-6a), 1.98 (1H, m, H-4b), 1.89 (1H, m, H-4a), 1.72 (1H, dm,

J_gem13.4 Hz, H-5b), 1.50 (1H, m, H-5a); d_C(DMSO, 125.7 MHz) 157.0

(C-6⁰), 153.5 (C-2⁰), 150.9 (C-4⁰), 135.5 (C-8⁰), 116.6 (C-5⁰), 51.1 (C-3),

50.7 (C-2), 45.2 (C-6), 30.6 (C-4), 25.3 (C-5); HRMS (ESI) C₁₀H₁₅ON₆

(MþH)^þcalcd 235.1302, found 235.1302.

5.1.16. 1-N-tert-Butyloxycarbonyl-1,2,3,4-tetrahydropyridine

(26a). Tetrahydropyridine derivative 26a was prepared from mesyl

derivative 21a (500 mg, 1.79 mmol), thymine (339 mg, 2.68 mmol),

and Cs₂CO₃(873 mg, 2.68 mmol) in DMSO according to general

procedure C in a 28% yield (92 mg, 0.28 mmol) as a white amor-

phous solid. All spectral data recorded were in accordance with the

literature data.⁶²

5.1.21. 2-(Adenin-9-yl)methylpyrrolidine (28a). Pyrrolidine nucleo-

side 28a was prepared according to general method D from mixture

of adenine derivatives 24a and 23c (159 mg, 0.500 mmol) in a 40%

yield (47 mg, 0.216 mmol) as a white amorphous solid.

n_max(KBr) 3445 (vs), 3279 (s), 3121 (m), 3118 (m), 2975 (m),

2955 (m), 2944 (m), 2870 (m), 2842 (w), 1668 (s), 1641 (s),1600 (s),

1573 (m), 1517 (w), 1484 (m), 1428 (m), 1420 (m), 1345 (m), 1299 (s),

1210 (w), 990 (w), 796 (w), 728 (w), 642 (w); d_H(DMSO, 600.1 MHz)

8.12 (1H, s, H-2⁰), 8.11 (1H, s, H-8⁰), 7.20 (2H, br s, NH₂), 4.05 (1H, dd,

J_gem13.7 Hz, J_CH2eH25.6 Hz, (CH₂)aeN), 3.97 (1H, dd, J_gem13.7 Hz,

5.1.17. (RS)-3-(Thymin-1-yl)piperidine (27a). Nucleoside 27a was

prepared according to general method F from ureido derivative 31b

(355 mg, 1 mmol) in a 80% yield (167 mg, 0.8 mmol) as a white

amorphous solid.

n_max(KBr) 3424 (m), 3301 (w), 3194 (w), 3059 (w),1687 (vs),1468

(m), 1445 (m), 1389 (w), 1337 (w), 1260 (m), 1116 (w), 1101 (w), 888

0

(w), 811 (w), 765 (w); d_H(DMSO, 600.1 MHz) 7.63 (1H,q, J_{6 -CH3}

1.2 Hz, H-6⁰), 4.26 (1H, m, H-3), 2.82 (2H, m, H-2b, H-6b), 2.60 (1H, t,

0

J_gem¼J_2a-310.2 Hz, H-2a), 2.38 (1H, m, H-6a),1.76 (3H, d, J_CH3-61.2 Hz,

CH₃), 1.65e1.76 (3H, m, H-4a, H-4b, H-5b), 1.45 (1H, m, H-5a); d_C

(DMSO,150.9 MHz) 163.9 (C-4⁰), 151.1 (C-2⁰),138.1 (C-6⁰),108.8 (C-5⁰),

52.2 (C-3), 49.9 (C-2), 45.3 (C-6), 29.3 (C-4), 26.5 (C-5), 12.3 (CH₃);

HRMS (ESI) C₁₀H₁₆O₂N₃(MþH)^þcalcd 210.1237, found 210.1238.

J_CH2eH27.4 Hz, (CH₂)beN), 2.74 (2H, t, J_H6-H56.7 Hz, H-5), 3.45 (1H,

m, H-2), 1.70 (1H, m, H-3b), 1.61 (1H, m, H-4b), 1.54 (1H, m, H-4a),

1.34 (1H, m, H-3a); d_C(DMSO, 150.9 MHz) 156.1 (C-6⁰), 152.4 (C-2⁰),

149.8 (C-4⁰), 141.5 (C-8⁰), 118.7 (C-5⁰), 57.4 (C-2), 48.0 (CH₂N), 46.1

(C-6), 29.1 (C-3), 25.5 (C-4); HRMS (ESI) C₁₀H₁₅N₆(MþH)^þcalcd

219.1353, found 219.1352.

5.1.18. (RS)-3-(Cytosin-1-yl)piperidine (27b). Nucleoside 27b was

prepared according to general method D from cytosine derivative

22c (294 mg,1 mmol) in a 87% yield (168 mg, 0.87 mmol) as a white

amorphous solid.

5.1.22. 2-(Thymin-1-yl)methylpyrrolidine (28b). Pyrrolidine nucle-

oside 28b was prepared according to general method D from thy-

mine derivative 24b (254 mg, 0.500 mmol) in a 38% yield (39 mg,

0.183 mmol) as a white amorphous solid.

n_max(KBr) 3420 (s), 3197 (m), 2947 (w), 2864 (vw), 1646 (vs),

1612 (s), 1574 (m), 1525 (m), 1489 (s), 1455 (m), 1399 (m), 1375 (m),

1331 (w), 1282 (m), 786 (m); d_H(DMSO, 500.0 MHz) 7.66 (1H, bd,

n_max(KBr) 3173 (w), 3058 (w),1688 (vs),1471 (w),1454 (w),1438

(w), 1387 (w), 1348 (w), 1265 (w), 1201 (m), 1176 (m), 1130 (m); d_H

J_{6 -5}6.8 Hz, H-6⁰), 7.04 (1H, br s) and 7.14, (1H, br s, NH₂), 5.70 (1H,

0

bd, J_{5 -6}7.2 Hz, H-5 ), 4.57 (1H, m, H-3), 3.03e3.13 (2H, m, H-2b, H-

6b), 2.85 (1H, m, H-2a), 2.62 (1H, m, H-6a), 1.74e1.85 (3H, m, H-4a,

H-4b, H-5b), 1.52 (1H, m, H-5a); d_C(DMSO, 125.7 MHz) 165.3 (C-4⁰),

155.5 (C-2⁰), 142.5 (C-6⁰), 94.0 (C-5⁰), 50.6 (C-3), 47.3 (C-2), 43.8 (C-

6), 28.1 (C-4), 23.5 (C-5); HRMS (ESI) C₉H₁₅ON₄(MþH)^þcalcd

195.1240, found 195.1240.

(DMSO) 7.47 (1H, q, J_{6 -CH3}1.2 Hz, H-6⁰), 3.66 (1H, dd, J_gem13.3 Hz,

J_CH2-24.8 Hz, (CH₂)beN), 3.34 (1H, dd, J_gem13.3 Hz, J_CH2-28.4 Hz,

(CH₂)aeN), 3.26 (1H, m, H-2), 2.75 (2H, t, J_5-46.8 Hz, H-5), 1.73 (3H,

0

d, J_CH3-61.2 Hz, CH₃), 1.62e1.75 (2H, m, H-4b, H-3b), 1.56 (1H, m, H-

4a), 1.28 (1H, m, H-3a); d_C(DMSO) 164.6 (C-4⁰), 151.3 (C-2⁰), 142.7

(C-6⁰), 107.6 (C-5⁰), 56.8 (C-2), 52.0 (CH₂N), 45.9 (C-5), 28.98 (C-3),

25.5 (C-4), 12.2 (CH₃); HRMS (ESI) C₁₀H₁₆O₂N₃(MþH)^þcalcd

210.1237, found 210.1237.

5.1.19. (RS)-3-(Adenin-9-yl)piperidine (27c). Nucleoside 27c was

prepared according to general method D from adenine derivative

22d (318 mg,1 mmol) in a 72% yield (156 mg, 0.72 mmol) as a white

amorphous solid.

5.1.23. (RS)-3-Azido-1-N-tert-butyloxycarbonylpiperidine (29). Mesyl

derivative 21a (5.00 g, 17.9 mmol) and sodium azide (4.60 g,

71.6 mmol) were suspended in anhydrous DMF (50 ml) and heated

to 100 ^ꢀC. The reaction ﬁnished in 2 h. The DMF was evaporated,

and the crude product dissolved in chloroform and extracted with

saturated NaHCO₃. The organic phases were combined and dried

over sodium sulfate. Na₂SO₄was ﬁltered and the product was

puriﬁed by ﬂash chromatography using a linear gradient of ethyl

acetate in toluene. The product was obtained in a 87% yield (3.53 g,

15.6 mmol) as a light yellow oil.

n_max(KBr) 2981 (s), 2949 (s), 2935 (s), 2863 (m), 2101 (vs), 1687

(vs), 1477 (s), 1467 (s), 1425 (vs), 1393 (s), 1368 (vs), 1345 (m), 1243

(vs), 1173 (vs), 1152 (vs), 556 (w); d_H(CDCl₃, 400.1 MHz) 3.80 (1H, br

m, H-2a), 3.58 (1H, br s, H-6a), 3.47 (1H, m, H-3), 3.15 (2H, br m, H-

2b, H-6b), 1.97 (1H, br s, H-4b), 1.76 (1H, br m, H-5a), 1.42e1.64 (2H,

m, H-5b, H-4b), 1.46 (9H, s, (CH₃)₃); d_C(CDCl₃, 100.6 MHz) 154.6

(CO), 80.0 (C(CH₃)), 56.4 (br s, C-3), 47.8 (C-2), 43.7 (br s, C-6), 29.9

(C-4), 28.3 (CH₃), 22.6 (C-5); HRMS (ESI) C₁₀H₁₈O₂N₄Na (MþNa)^þ

calcd 249.1322, found 249.1322.

n_max(KBr) 3504 (m), 3395 (m), 3313 (s), 3298 (s), 3260 (s), 3137

(s), 1657 (vs), 1642 (vs), 1634 (vs), 1598 (vs), 1571 (s), 1474 (s), 1449

(m), 1413 (m), 1327 (m), 1302 (m), 1205 (m), 1112 (m), 884 (w), 820

(w), 798 (m), 721 (m), 647 (m); d_H(DMSO, 600.1 MHz) 8.27 (1H, s,

H-8⁰), 8.13 (1H, s, H-2⁰), 7.22 (2H, br s, NH₂), 4.38 (1H, m, H-3), 3.10

(1H, dd, J_gem11.6 Hz, J_2b-34.3 Hz, H-2b), 2.89 (2H, m, H-2a, H-6b),

2.51 (1H, ddd, J_gem12.0 Hz, J_6a-5a11.8 Hz, J_6a-5b2.8 Hz, H-6a), 2.04

(2H, m, H-4), 1.70 (1H, m, H-5b), 1.53 (1H, m, H-5a); d_C(DMSO,

150.9 MHz) 156.2 (C-6⁰), 152.4 (C-2⁰), 149.4 (C-4⁰), 139.3 (C-8⁰), 119.0

(C-5⁰), 52.1 (C-3), 51.2 (C-2), 45.5 (C-6), 30.6 (C-4), 25.9 (C-5); HRMS

(ESI) C₁₀H₁₅N₆(MþH)^þcalcd 219.1353, found 219.1353.

5.1.20. (RS)-3-(Guanin-9-yl)piperidine (27d). Nucleoside 34b (500

mg, 1.42 mmol) was treated with 1 M NaOH in 30% aqueous dioxane

for 2 days. The reaction was treated with a Dowex 50 in trimethyl-

ammonium form. The Dowex was ﬁltered and the ﬁltrate evaporated

to give a crude guanine derivative, which was then treated according

to general procedure D and ﬁnally puriﬁed by reversed phase HPLC.

The product was obtained in a 64% yield (203 mg, 0.87 mmol) as

a white amorphous solid.

5.1.24. (RS)-3-Amino-1-N-tert-butyloxycarbonylpiperidine (30).

Azido derivative 29 (3.53 g) and Pd/C catalyst (150 mg) were

suspended in ethanol (150 ml). The mixture was hydrogenated at rt

under atmospheric pressure for 12 h (TLC controlled, 50% ethyl

n_max(KBr) 3413 (vs), 2974 (s), 2931 (m), 1687 (m), 1627 (m), 1577

(w), 1533 (w), 1475 (w), 1456 (w), 1450 (w), 1377 (w), 1089 (m),

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0 0

J_gem12.5 Hz, H-6_eq), 2.58 (1H, dd, J_gem11.6 Hz, J_{2 ax-3}10.6 Hz, H-2_ax),

acetate/toluene, ninhydrin detection). The mixture was ﬁltered

through a layer of Celite for catalyst removal. The solvent was

evaporated and the product was dried on an oil pump. The product

was obtained in a 90% yield (2.82 g, 14 mmol) as a colorless liquid.

n_max(CHCl₃) 3376 (w), 3316 (vw), 2981 (s), 2940 (s), 2861 (s),

1682 (vs), 1477 (s), 1467 (s), 1452 (s), 1427 (vs), 1393 (s), 1367 (vs),

1268 (vs), 1243 (vs), 1172 (vs), 1157 (vs), 860 (s), 464 (w); d_H(CDCl₃,

400.1 MHz) 3.93 (1H, br s, H-2a), 3.82 (1H, br d, J_gem13.0 Hz, H-6a),

2.81 (1H, ddd, J_gem13.2 Hz, J_6b-5a3.3 Hz, J_6b-5a10.9 Hz, H-6b), 2.77

(1H, m, H-3), 2.58 (1H, br s, H-2b), 1.91 (1H, m, H-4a), 1.68 (1H, dm,

J_gem13.6 Hz, H-5a), 1.48 (1H, m, H-5b), 1.45 (9H, s, (CH₃)₃), 1.22 (1H,

m, H-4b); d_C(CDCl₃,100.6 MHz) 154.8 (CO), 79.4 (C(CH₃)), 52.3 (br s,

C-2), 47.6 (C-3), 43.9 (br s, C-6), 33.9 (br s, C-4), 28.4 (CH₃), 23.6 (C-

5); HRMS (ESI) C₁₀H₂₁O₂N₂(MþH)^þcalcd 201.1598, found 201.1597.

0

2.38 (1H, td, J_gem¼J_{6 ax-5 ax}12.1 Hz, J_{6 ax-5 eq}2.7 Hz, H-6_ax), 1.64e1.80

(3H, m, H-4, H-5_eq), 1.45 (1H, m, H-5_ax); d_C(DMSO, 125.7 MHz)

163.3 (C-4⁰), 151.1 (C-2⁰), 142.5 (C-6⁰), 101.0 (C-5⁰), 52.4 (C-3), 49.9

(C-2), 45.30 (C-6), 29.3 (C-4), 26.3 (C-5); HRMS (ESI) C₉H₁₄O₂N₃

(MþH)^þcalcd 196.1081, found 196.1078.

5.1.28. (RS)-3-[(5-Amino-6-chloropyrimidin-4-yl)amino]-1-N-tert-

butyloxycarbonylpiperidine (33a). Amino derivative 30 (366 mg,

1.82 mmol), 5-amino-4,6-dichloropyrimidine 16 (600 mg, 3.65

mmol), and triethylamine (1.09 ml, 7.86 mmol) were suspended in

ethanol (20 ml) and heated to 110 ^ꢀC in a pressure vessel over 48 h.

After the reaction was completed, the solvent was evaporated and

residue chromatographed on a silica gel using a linear gradient of

ethyl acetate in toluene. The product was obtained in a 70% yield

(375 mg, 1.27 mmol) as a dark orange foam.

n_max(KBr) 3468 (m), 3366 (s), 3330 (m), 3259 (w), 2983 (w),

2916 (w),1692 (m),1646 (vs),1579 (vs),1561 (s),1494 (w),1477 (m),

1439 (s), 1416 (s), 1390 (m), 1367 (m), 1170 (s), 1158 (s), 1104 (m),

923 (m), 769 (m), 461 (w); d_H(DMSO, 499.8 MHz, 80 ^ꢀC) 7.75(1H, s,

H-2⁰), 6.32 (1H, br d, J_NH-36.4 Hz, NH), 4.88 (2H, br s, NH₂), 3.97 (1H,

m, H-3), 3.89 (1H, m, H-2_eq), 3.63 (1H, m, H-6_eq), 2.92e3.03 (2H, m,

H-2_ax, H-6_ax), 1.99 (1H, m, H-4_eq), 1.79 (1H, m, H-5_eq), 1.54 (1H, m,

H-4_ax), 1.45 (1H, m, H-5_ax), 1.36 (9H, s, (CH₃)₃); d_C(DMSO,

125.7 MHz, 80 ^ꢀC) 153.9 (COO), 151.4 (C-4⁰), 145.4 (C-2⁰), 137.5 (C-

6⁰), 123.4 (C-5⁰), 78.4 (C(CH₃)₃), 47.6 (C-2), 46.9 (C-3), 43.4 (C-6),

29.5 (C-4), 27.8 (C(CH₃)₃), 22.9 (C-5); HRMS (ESI) C₁₄H₂₃O₂N₅Cl

(MþH)^þcalcd 328.1535, found 328.1536.

5.1.25. 1-((RS)-1-N-tert-butyloxycarbonylpiperidin-3-yl)-3-((E)-3-

ethoxyacryloyl)urea (31a). Urea derivative 31a was prepared accor-

ding to general method E using reagent 15a (753 mg, 2.69 mmol)

fromaminoderivative30(490 mg, 2.45 mmol)ina87%yield(740 mg,

2.17 mmol) as a light yellow foam.

n_max(KBr) 3384 (w), 3233 (m), 3128 (m), 3096 (m), 2980 (s),

1708 (vs), 1690 (vs), 1677 (vs), 1632 (s), 1610 (s), 1553 (vs), 1498 (s),

1475 (s), 1465 (m), 1394 (m), 1381 (m), 1365 (s), 1242 (s), 1165 (vs),

1150 (vs), 970 (w); d_H(CDCl₃, 500.0 MHz) 9.66 (1H, br s, H-3), 8.61

0

(1H, bd, J_1e37.7 Hz, H-1), 7.63 (1H, d, J_6-512.3 Hz, H-6), 5.37 (1H, d,

J_5-612.2 Hz, H-5), 3.97 (2H, q, J_CH2eCH37.1 Hz, OCH₂CH₃), 3.71e3.87

(2H, m, H-2⁰b, and H-3⁰), 3.56 (1H, ddd, J_gem13.2 Hz, J_{6 b-5 b}3.4 Hz,

0

J_{6 b-5 a}6.4 Hz, H-6⁰b), 3.14e3.24 (2H, m, H-2⁰a, H-6⁰a), 1.94 (1H, m,

H-4⁰b), 1.71 (1H, m, H-5⁰b), 1.51e1.60 (2H, m, H-4⁰a, H-5⁰a), 1.44 (9H,

br s, (CH₃)₃), 1.35 (3H, t, J_CH3eCH27.1 Hz, OCH₂CH₃); d_C(CDCl₃,

125.7 MHz) 168.2 (C-4), 162.6 (C-6), 154.7 and 154.7 (Boc-C]O),

154.5 (C-2), 97.9 (C-5), 79.6 (C(CH₃)₃), 67.4 (OCH₂CH₃), 48.2 (C-2⁰),

45.7 (C-3⁰), 43.4 (C-6⁰), 30.2 (C-4⁰), 28.3 (Boc-CH₃), 22.9 (C-5⁰), 14.4

(OCH₂CH₃); HRMS (ESI) C₁₆H₂₈O₅N₃(MþH)^þcalcd 342.2023, found

342.2017.

0

5.1.29. (RS)-1-N-tert-Butyloxycarbonyl-3-[(2,5-diamino-6-chloro-

pyrimidin-4-yl)amino]piperidine (33b). Amino derivative 30 (1.05 g,

5.24 mmol), 2,5-diamino-4,6-dichloropyrimidine 17 (1.03 g, 5.76

mmol), and triethylamine (3.1 ml, 22.53 mmol) were suspended in

n-butanol (55 ml) and heated to 140 ^ꢀC in a pressure vessel over

48 h. After the reaction was completed, the solvent was evaporated

and the residue chromatographed on a silica gel using a linear gra-

dient of ethyl acetate in toluene. The product was obtained in a 56%

yield (1.00 g, 2.92 mmol) as a dark orange foam.

n_max(KBr) 3493 (s), 3405 (s), 3213 (m), 2975 (m), 2934 (m), 2858

(w), 1688 (s), 1617 (s), 1571 (vs), 1502 (m), 1467 (s), 1430 (s), 1442 (s),

1392 (m), 1366 (m), 1308 (w), 1265 (m), 1242 (m), 1174 (m), 1153 (s),

860 (w), 773 (w); d_H(DMSO, 499.8 MHz, 80 ^ꢀC) 6.06 (1H, br d, J_NH-3

7.4 Hz, NH), 3.92 (1H, m, H-3), 5.35 (2H, br s, NH₂), 3.82 (1H, m,

H-2_eq), 3.77 (2H, br s, NH₂), 3.63 (1H, m, H-6_eq), 2.94e3.01 (2H, m,

H-2_ax, H-6_ax), 1.94 (1H, m, H-4_eq), 1.75 (1H, m, H-5_eq), 1.51 (1H, m, H-

4_ax), 1.42 (1H, m, H-5_ax), 1.38 (9H, s, (CH₃)₃); d_C(DMSO, 125.7 MHz,

80 ^ꢀC) 78.4 (C(CH₃)₃), 47.7 (C-2), 46.2 (C-3), 43.2 (C-6), 29.6 (C-4),

27.8 (C(CH₃)₃), 22.9 (C-5); HRMS (ESI) C₁₄H₂₄O₂N₆Cl (MþH)^þcalcd

343.1644, found 343.1645.

5.1.26. 1-((RS)-1-N-tert-Butyloxycarbonylpiperidin-3-yl)-3-((E)-3-

ethoxy-2-methylacryloyl)urea (31b). Urea derivative 31b was pre-

pared according to general method E using reagent 15b (760 mg,

2.58 mmol) from amino derivative 30 (470 mg, 2.34 mmol) in

a 82% yield (751 mg, 2.11 mmol) as a light yellow foam.

n_max(KBr) 3288 (s), 2981 (s), 2938 (m), 2867 (m), 1764 (s), 1751

(s), 1691 (vs), 1677 (vs), 1652 (vs), 1620 (m), 1546 (s), 1527 (s), 1479

(s), 1468 (s), 1448 (s), 1424 (s), 1392 (s), 1367 (s), 1305 (s), 1268 (s),

1243 (s), 1211 (vs), 1175 (s), 1148 (vs), 1108 (s), 1096 (m), 861 (w),

765 (m), 656 (w); d_H(CDCl₃, 500.0 MHz) 8.87 (1H, br m, NH-1),

8.04e8.33 (1H, br m, NH-3), 7.41 (1H, s, H-6), 4.06 (2H, m,

OCH₂CH₃), 3.83 (1H, br s, H-3⁰), 3.71e3.87 (2H, m, H-2⁰b, and H-3⁰),

3.56 (1H, ddd, J_gem13.2 Hz, J_{6 b,5}3.4 Hz and 6.4 Hz, H-6⁰b),

3.14e3.24 (2H, m, H-2⁰a, and H-6⁰a),1.94 (1H, m, H-4⁰b),1.71 (1H, m,

H-5⁰b), 1.51e1.60 (2H, m, H-4⁰a, H-5⁰a), 1.44 (9H, s, (CH₃)₃), 1.35 (3H,

t, J_CH3eCH27.1 Hz, OCH₂CH₃); d_C(CDCl₃, 125.7 MHz) 169.8 and 169.8

(C-4), 157.4 and 157.4 (C-6), 154.7 (Boc-C]O), 153.7 and 153.6 (C-2),

107.3 (C-5), 79.6 (C(CH₃)₃), 70.1 (OCH₂CH₃), 48.7 (C-2⁰), 45.7 (C-3⁰),

43.2 (C-6⁰), 28.3 (Boc-CH₃), 22.8 (C-5⁰), 15.3 (OCH₂CH₃), 8.7 (CH₃);

HRMS (ESI) C₁₇H₂₉O₅N₃Na (MþH)^þcalcd 378.1999, found 378.1999.

0

5.1.30. (RS)-1-N-tert-Butyloxycarbonyl-3-(6-chloropurin-9-yl)piper-

idine (34a). Pyrimidine derivative 33a (370 mg, 1.12 mmol) and

diethoxymethyl acetate (10 ml, 61.22 mmol) were stirred at rt for

8 h and then heated to 120 ^ꢀC for the next 24 h. After the reaction

was completed, the solvent was evaporated and residue chroma-

tographed on a silica gel using a linear gradient of 10% EtOH/CHCl₃

in CHCl₃. The product was obtained in a 91% yield (345 mg,

1.022 mmol) as a light yellow foam.

n_max(CHCl₃) 3122 (vw), 3067 (vw), 2983 (m), 2953 (m), 2933

(m), 2866 (m),1689 (vs),1591 (vs),1562 (s),1511 (w),1487 (m),1477

(m), 1468 (m), 1455 (m), 1443 (s), 1426 (s), 1406 (s), 1395 (s), 1368

(s), 1339 (s), 1259 (s), 1244 (s), 1194 (s), 1172 (s), 1150 (vs), 938 (m),

861 (m), 647 (w), 637 (m); d_H(DMSO, 499.8 MHz, 100 ^ꢀC) 8.74 (1H,

s, H-2⁰), 8.65 (1H, s, H-8⁰), 4.62 (1H, t, J_3-2b¼J_3-4a9.7 Hz, J_3-2a¼J_3-4

4.3 Hz, H-3), 4.17 (1H, ddt, J_gem12.9 Hz, J_2a-34.3 Hz, J_2a-4b¼J_2a-6a

1.4 Hz, H-2a), 3.52 (1H, dd, J_gem12.9 Hz, J_2b-39.7 Hz, H-2b), 3.06 (1H,

5.1.27. (RS)-3-(Uracil-1-yl)piperidine (32). Nucleoside 32 was pre-

pared according to general method F from urea derivative 31a

(730 mg, 2.14 mmol) in a 89% yield (371 mg, 1.9 mmol) as a white

amorphous solid.

n_max(CHCl₃) 3392 (m), 3173 (m), 2949 (s), 2862 (m), 2823 (m),

1755 (m), 1685 (vs), 1627 (m), 1462 (s), 1446 (s), 1439 (s), 1384 (s),

1360 (m), 1338 (m), 1259 (s); d_H(DMSO, 499.9 MHz) 11.20 (1H, br s,

NH), 7.78 (1H, d, J_{6 -5}8.0 Hz, H-6⁰), 5.53 (1H, d, J_{5 -6}8.0 Hz, H-5⁰),

4.26 (1H, m, H-3), 2.87 (1H, dm, J_gem11.7 Hz, H-2_eq), 2.80 (1H, dm,

0

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S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1496

ddd, J_gem13.3 Hz, J_6b-5b10.07 Hz, H-6b), 2.31 (1H, dddd, J_gem13.3 Hz,

J_4a-5b11.2 Hz, J_4a-39.7 Hz, J_4a-5a4.3 Hz, H-4a), 2.22 (1H, br m, J_gem

13.1 Hz, J_4b-5a4.8 Hz, J_4b-34.3 Hz, J_4b-5b3.7 Hz, H-4b), 1.87 (1H, m,

J_gem13.9 Hz, J_5b-4b4.8 Hz, J_5a-4a¼J_5a-6a4.3 Hz, J_5a-6b3.3 Hz, H-5a),

1.63 (1H, m, J_gem13.9 Hz, J_5b-4a11.2 Hz, J_5b-6b10.7 Hz, J_5b-6a4.3 Hz,

J_5b-4a3.7 Hz, H-5b), 1.41 (9H, s, (CH₃)₃); d_C(DMSO, 125.7 MHz,

100 ^ꢀC) 153.6 (CO), 151.5 (C-4⁰), 150.8 (C-2⁰), 149.1 (C-6⁰), 145.1

(C-8⁰), 130.9 (C-5⁰), 79.0 (C(CH₃)₃), 51.5 (C-3), 47.0 (C-2), 43.1 (C-6),

28.5 (C-4), 27.7 (C(CH₃)₃), 23.2 (C-5); HRMS (ESI) C₁₅H₂₁O₂N₅Cl

(MþH)^þcalcd 338.1378, found 338.1378.

using a linear gradient of EtOH in CHCl₃. The product was obtained

in a 85% yield (20 g, 0.104 mol) as a light yellow liquid. All spectral

data recorded were in accordance with the literature data.⁵⁸

5.1.35. (2S,4R)-(1-N-Benzyl-4-hydroxypyrrolidin-2-yl)methanol

(37b). A solution of pyrrolidine derivative 36b (21.00 g, 0.085 mol)

in THF (120 ml) was added dropwise to a suspension of LiAlH₄

(12.93 g, 0.34 mmol) in THF (300 ml). The mixture was stirred until

the complete consumption of the product (∼16 h). Water was care-

fully added at 0 ^ꢀC (CAUTION! gas evolving), and the mixture

was then ﬁltered. Product 37b was puriﬁed by ﬂash chromatography

on a silica gel using a linear gradient of EtOH in CHCl₃. The product

was obtained in a 77% yield (13.50 g, 0.065 mmol) as an orange

liquid. All spectral data recorded were in accordance with the liter-

ature data.⁵⁸

5.1.31. (RS)-3-(2-Amino-6-chloropurin-9-yl)-1-N-tert-butyloxy-

carbonylpiperidine (34b). Pyrimidine derivative 33b (370 mg,

1.12 mmol) and diethoxymethyl acetate (0.164 ml, 1.232) in DMF

(20 ml) were stirred at rt for 6 h and then heated to 120 ^ꢀC for the

next 24 h. After the reaction was completed, the solvent was

evaporated and the residue chromatographed on a silica gel using

a linear gradient of 10% EtOH/CHCl₃in CHCl₃. The product was

obtained in a 50% yield (190 mg, 0.562 mmol) as a light orange oil.

n_max(KBr) 3500 (s), 3330 (m), 3215 (m), 2976 (w),1690 (s), 1612

(vs), 1563 (s), 1512 (m), 1466 (m), 1425 (m), 1406 (s), 1391 (m), 1367

(m), 1312 (w), 1244 (m), 1213 (w), 1173 (m), 1155 (m), 786 (w), 642

(w); d_H(DMSO, 500.0 MHz, 50 ^ꢀC) 7.87 (1H, s, H-8⁰), 5.01 (2H, vbr s,

NH₂), 4.40 (1H, m, H-3), 4.19 (1H, m, J_gem13.3 Hz, H-2_eq), 3.90 (1H,

bdt, J_gem13.5 Hz, J_6eq-54.3 Hz, H-6_eq), 3.44 (1H, dd, J_gem13.2 Hz, J_2ax-

₃9.3 Hz, H-2_ax), 3.09 (1H, ddd, J_gem13.4 Hz, J_6ax-5ax10.4 Hz, J_6ax-5eq

3.3 Hz, H-6_ax), 2.14e2.22 (2H, m, H-4), 1.81 (1H, m, H-5b), 1.67 (1H,

m, H-5a), 1.47 (9H, s, (CH₃)₃); d_C(DMSO, 125.7 MHz, 50 ^ꢀC) 158.8 (C-

2⁰), 154.5 (CO), 153.5 (C-4⁰), 151.5 (C-6⁰), 140.4 (C-8⁰), 125.4 (C-5⁰),

80.5 (C(CH₃)₃), 51.6 (C-3), 47.7 (C-2), 43.7 (C-6), 29.8 (C-4), 28.4 (C

(CH₃)₃), 23.7 (C-5); HRMS (ESI) C₁₅H₂₂O₂N₆Cl (MþH)^þcalcd

353.1487, found 353.1489.

5.1.36. (S)-1-N-Benzyl-3-hydroxypiperidine (38a). Triﬂuoroacetic

anhydride (5.7 ml, 41.05 mmol) was added dropwise to a solution of

pyrrolidine derivative 37a (17.00 g, 88.8 mmol) in THF (900 ml), and

then cooled to ꢂ78 ^ꢀC. After 1 h, Et₃N (50 ml, 355 mmol) was added

dropwise at ꢂ78 ^ꢀC. The reaction mixture was stirred for 20 min at

0 ^ꢀC and then heated at reﬂux for 60 h. After the addition of an

aqueous 2.5 M NaOH solution (210 ml), the mixture was stirred for

2 h at rt and then extracted with ethyl acetate, dried with MgSO₄,

and evaporated to dryness in a vacuum. The product was obtained

by puriﬁcation on a silica gel using a linear gradient of 10% EtOH/

CHCl₃in CHCl₃in a 51% yield (8.95 g, 45.2 mmol) as a colorless oil.

All spectral data recorded were in accordance with the literature

data.⁵⁸

5.1.37. (3R,5R)-1-N-Benzyl-3,5-dihydroxy-piperidine (38b). Triﬂuoro-

aceticanhydride (5.7 ml, 41.05 mmol) was added dropwise to a so-

lution of pyrrolidine derivative 37b (7.70 g, 37.3 mmol) in THF

(300 ml), and then cooled to 0 ^ꢀC. After 1 h, Et₃N (23.08 ml,

166 mmol) was added dropwise at ꢂ78 ^ꢀC. The reaction mixture was

stirred for 20 min at 0 ^ꢀC and then heated at reﬂux for 60 h. After the

addition of an aqueous 2.5 M NaOH solution (210 ml), the mixture

was stirred for 2 h at rt and then extracted with ethyl acetate, dried

with MgSO₄, and evaporated to dryness in a vacuum. The product

was obtained by puriﬁcation on a silica gel using a linear gradient of

10% EtOH/CHCl₃in CHCl₃in a 49% yield (3.70 g, 18.22 mmol) as

a colorless oil. All spectral data recorded were in accordance with the

literature data.⁵⁸

5.1.32. (S)-1-N-Benzyl-2-methoxycarbonylpyrrolidine (36a). Thionyl

chloride (20 ml, 0.275 mol) was added dropwise to a stirred sus-

pension of (R)-proline (35a) (26.20 g, 0.228 mol) in MeOH (900 ml)

at 0 ^ꢀC. After the consumption of the starting material, methanol was

evaporated under reduced pressure. The resulting solid was sus-

pended in DCM (500 ml), and Et₃N (127 ml, 0.915 mol) and BnBr

(33 ml, 0.275 mol) were added. The mixture was reﬂuxed for 10 h.

The solvent was evaporated and the product puriﬁed by ﬂash

chromatography on a silica gel using a linear gradient of EtOH in

CHCl₃. The product was obtained as a light yellow oil in a 75% yield

(34.00 g, 0.159 mol). All spectral data recorded were in accordance

with the literature data.⁵⁸

5.1.38. (R)-3-Hydroxypiperidine (39a)^63e65. Hydroxypiperidine 38a

(7.25 g, 38.42 mmol) was hydrogenated in ethanol (200 ml) at an

atmospheric pressure using Pd/C (150 mg) as a catalyst. After the

reaction was ﬁnished, the mixture was ﬁltered through Celite and

the ﬁltrate was evaporated. Product 39a was obtained in a 90% yield

(3.50 g, 34.6 mmol) as a light yellow oil.

5.1.33. (2S,4R)-1-N-Benzyl-4-hydroxy-2-methoxycarbonylpyrroli-

dine (36b). Thionyl chloride (20 ml, 0.275 mol) was added drop-

wise to a stirred suspension of (2R,4R)-4-hydroxyproline (35b)

(30.00 g, 0.228 mol) in MeOH (900 ml) at 0 ^ꢀC. After the con-

sumption of the starting material, methanol was evaporated under

reduced pressure. The resulting solid was suspended in DCM

(500 ml), and Et₃N (127 ml, 0.915 mol) and BnBr (33 ml, 0.275 mol)

were added. The mixture was reﬂuxed for 10 h. The solvent was

evaporated and the product puriﬁed by ﬂash chromatography us-

ing a linear gradient of EtOH in CHCl₃. The product was obtained as

a light yellow oil in a 70% yield (37.00 g, 0.160 mol). All spectral data

recorded were in accordance with the literature data.⁵⁸

All NMR data of compound 39a were in accordance with the

NMR data published for its enantiomer, (S)-3-hydroxypiperidine.⁶⁶

[

a

]

²⁰þ11.9 (c 0.345, EtOH); n_max(KBr) 3409 (vs), 3301 (vs), 3112

D

(s), 2967 (s), 2935 (vs), 2899 (s), 2856 (s), 2825 (s), 1632 (m), 1554

(m), 1470 (m), 1443 (s), 1379 (w), 1360 (w), 1344 (w), 1329 (m);

HRMS (ESI) C₅H₁₂ON (MþH)^þcalcd 102.0913, found 102.0912.

5.1.39. (3R,5R)-Dihydroxypiperidine (39b)^67,68. Dihydroxypiperidine

38b (2.93 g, 5.38 mmol) was hydrogenated in ethanol (70 ml) at an

atmospheric pressure using Pd/C (100 mg) as a catalyst. After the

reaction was ﬁnished, the mixture was ﬁltered through Celite and

the ﬁltrate was evaporated. Product 39b was obtained in a 79% yield

(2.20 g, 4.24 mmol) as a colorless oil.

5.1.34. (S)-(1-N-Benzyl-pyrrolidin-2-yl)methanol (37a). A solution

of pyrrolidine derivative 36a (26.84 g, 0.122 mol) in THF (150 ml)

was added dropwise to a suspension of LiAlH₄(18.58 g, 0.489 mol)

in THF (400 ml). The mixture was stirred until the complete con-

sumption of the product (∼16 h). Water was carefully added at 0 ^ꢀC

(CAUTION! gas evolving), and the mixture was then ﬁltered.

Product 37a was puriﬁed by ﬂash chromatography on a silica gel

[

a

]

²⁰þ49.4 (c 0.245, EtOH); n_max(KBr) 3410 (vs), 3354 (vs), 3313

D

(s), 3268 (vs), 3076 (s), 2941 (s), 2926 (vs), 2900 (s), 2854 (s), 2761

(s), 2707 (s), 2598 (m), 1632 (w), 1558 (w), 1477 (m), 1455 (m), 1443

ꢀ

ꢁ

S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1497

(s), 1431 (s), 1418 (m), 1066 (s), 1008 (s), 995 (m), 867 (s); d_H(DMSO,

500.0 MHz) 3.74 (2H, br s, OH), 3.68 (2H, m, H-3, H-5), 2.33 (2H, m)

and 2.62 (2H, m, H-2, H-6), 1.57 (2H, br t, J_4-35.5 Hz, H-4);

d_C(DMSO, 125.7 MHz) 64.48 (C-3, C-5), 52.64 (C-2, C-6), 41.04

(C-4); HRMS (ESI) C₅H₁₂O₂N (MþH)^þcalcd 118.0863, found

118.0861.

(C(CH₃)₃), 66.4 (C-5), 64.4 (C-3), 55.1 (OCH₃), 49.7 (C-6, C-2), 38.7

(C-4), 28.4 (C(CH₃)₃); HRMS (ESI) C₃₁H₃₇O₆NNa (MþNa)^þcalcd

542.2513, found 542.2511.

5.1.43. (S)-3-Azido-1-N-tert-butyloxycarbonylpiperidine (42a). Mesyl

derivative 41a (9.20 g, 32.9 mmol) and sodium azide (8.56 g,

131.7 mmol) were heated to 90 ^ꢀC in DMF (200 ml) for 12 h. The

solvent was then evaporated and the product was obtained in a 91%

yield (6.77 g, 29.9 mmol) as a light yellow liquid after puriﬁcation on

a silica gel using a linear gradient of ethyl acetate in toluene.

¹H NMR, ¹³C NMR, and IR spectra were identical to those of 29.

HRMS (ESI) C₁₀H₁₈O₂N₄Na (MþNa)^þcalcd 249.1322, found

5.1.40. (3R,5R)-1-N-tert-Butyloxycarbonyl-3,5-dihydroxypiperidine

(40b). Boc₂O (4.58 g, 21.02 mmol) was added to a stirred suspen-

sion of dihydroxypiperidine 39b (2.00 g, 17.52 mmol) and NaHCO₃

(7.35 g, 87.60 mmol) in 200 ml ethanol/water (1:1, v/v). After 2 h

TLC (ethyl acetate/acetone/ethanol/water¼4:1:1:1, v/v) showed

the total consumption of the starting material. The mixture was

then ﬁltered through Celite and the product puriﬁed by ﬂash

chromatography on a silica gel using a linear gradient of (ethyl

acetate/acetone/ethanol/water¼4:1:1:1, v/v) in ethyl acetate.

Product 40b was obtained in a 92% yield (3.50 g, 16.10 mmol) as an

249.1320; [

a]

²⁰þ19.3 (c 0.302, EtOH).

D

5.1.44. (3S,5R)-3-Azido-1-N-tert-butyloxycarbonyl-5-dimethoxy-

trityloxypiperidine (42b). Hydroxypiperidine derivative 41b (3.00 g,

5.7 mmol) and DMAP (1.05 g, 8.6 mmol) were dissolved in DCM

(100 ml). Mesyl chloride (1.6 ml, 8.6 mmol) was added dropwise to

DCM (50 ml). The reaction was completed within 1 h (TLC con-

trolled, 20% ethyl acetate/toluene). The mixture was cooled to 0 ^ꢀC

and the reaction was quenched with water (10 ml). The mixture

was then washed with H₂O (150 ml) and the organic phase was

evaporated. The crude product (4.00 g) was used in the next step

without further characterization.

Crude (3R,5R)-N-tert-butyloxycarbonyl-5-dimethoxytrityloxy-3-

mesyloxypiperidine (4.00 g) and sodium azide (1.40 g, 23.08 mmol)

were heated to 90 ^ꢀC in DMF (100 ml) for 12 h. The solvent was then

evaporated and the product was obtained in a 93% yield (2.93 g,

5.37 mmol, over two steps) as a colorless oil after puriﬁcation on

a silica gel using a linear gradient of ethyl acetate in toluene.

orange oil.

20

[a]

ꢂ3.2 (c 0.215, EtOH); n_max(KBr) 3495 (s), 3273 (m), 2976

D

(m), 2930 (m), 1684 (vs), 1477 (m), 1462 (m), 1456 (m), 1439 (m),

1428 (s), 1414 (m), 1393 (m), 1368(m), 1335 (w), 1304 (w), 1245 (m),

1235 (s), 1169 (s), 1151 (s), 1061 (m), 984 (w), 465 (w); d_H(DMSO,

499.8 MHz, 120 ^ꢀC) 4.21 (2H, br s, OH), 3.83 (2H, m, H-3, H-5),

3.38 (2H, dd, J_gem13.0 Hz, J_2b-33.5 Hz, H-2b, H-6b), 3.10 (2H, J_gem

13.0 Hz, J_2a-36.5 Hz, H-2a, H-6a), 1.65 (2H, t, J_4-35.5 Hz, H-4),

1.42 (9H, s, (CH₃)₃); d_C(DMSO, 125.7 MHz, 120 ^ꢀC) 154.4 (CO),

77.9 (C(CH₃)₃), 62.6 (C-3, C-5), 49.6 (C-2, C-6), 40.0 (C-4), 27.8

(CH₃); HRMS (ESI) C₁₀H₁₉O₄Na (MþNa)^þcalcd 240.1206, found

240.1206.

5.1.41. (R)-1-N-tert-Butyloxycarbonyl-3-hydroxypiperidine

(41a). Hydroxypiperidine 39a (3.72 g, 36.8 mmol) was dissolved

in a mixture of H₂O/EtOH (250 ml, 1:1, v/v). Then, NaHCO₃(15.40 g,

183.5 mmol) was added, followed by the addition of Boc₂O (9.63 g,

44.1 mmol). After the reaction was completed, the mixture was

ﬁltered and the ﬁltrate was evaporated. The crude product was

then puriﬁed by ﬂash chromatography on a silica gel using a linear

gradient of 10% EtOH/CHCl₃in CHCl₃. Product 41a was obtained in

a 97% yield (6.70 g, 33.51 mmol) as a colorless oil.

[

a

]

²⁰ꢂ10.0 (c 0.169, EtOH); n_max(KBr) 2974 (m), 2837 (m), 2098

D

(s), 1697 (s), 1464 (m), 1446 (m), 1418 (m), 1366 (m), 1251 (vs), 1034

(m); d_H(CDCl₃, 499.8 MHz, 50 ^ꢀC) 7.47 (2H, m, H-2⁰⁰), 7.35e7.39 (4H,

m, H-2⁰), 7.28 (2H, m, H-3⁰⁰), 7.21 (1H, m, H-4⁰⁰), 6.80e6.85 (4H, m,

H-3⁰), 4.04 (1H, br m, H-2_eq), 3.88 (1H, dd, J_gem12.9 Hz, J_6eq-34.7 Hz,

H-6_eq), 3.78 (6H, s, OCH₃), 3.45 (1H, tt, J_5-6ax¼J_5-4ax10.0 Hz, J_5-

¼J_5-4eq4.5 Hz, H-5), 3.03 (1H, tt, J_3-4ax¼J_3-2ax10.9 Hz, J_3-4eq¼J_3-2eq

6eq

4.5 Hz, H-3), 2.62 (1H, dd, J_gem12.9 Hz, J_6ax-510.0 Hz, H-6_ax), 2.45

(1H, br t, J_gem¼J_2ax-311.7 Hz, H-2_ax),1.50 (1H, m, H-4_eq),1.38 (9H, s, C

(CH₃)₃), 1.27 (1H, ddd, J_gem12.5 Hz, J_4ax-511.4 Hz, J_4ax-310.2 Hz, H-

4_ax); d_C(CDCl₃, 125.7 MHz, 50 ^ꢀC) 158.8 and 158.8 (C-4⁰), 154.2

(COO), 145.6 (C-1⁰⁰), 136.6 and 136.7 (C-1⁰), 130.2 and 130.2 (C-2⁰),

128.3 (C-2⁰⁰), 127.8 (C-3⁰⁰), 126.9 (C-4⁰⁰), 113.2 and 113.2 (C-3⁰), 86.7

(5-OeC), 80.1 (C(CH₃)₃), 67.2 (C-5), 55.2 (OCH₃), 54.9 (C-3), 49.1 (C-

6), 47.3 (C-2), 37.6 (C-4), 28.3 (C(CH₃)₃); HRMS (ESI) C₃₁H₃₆O₅N₄Na

(MþNa)^þcalcd 567.2578, found 567.2578.

¹H NMR, ¹³C NMR, and IR spectra were identical to those of

20a. HRMS (ESI) C₁₀H₁₉O₃NNa (MþNa)^þcalcd 224.12571, found

20

224.12563; [

a

]

þ16.6 (c 0.717, EtOH).

D

5.1.42. (3R,5R)-5-Dimethoxytrityloxy-1-N-tert-butyloxycarbonyl-3-

hydroxypiperidine (41b). A solution of dimethoxytritylchloride

(5.45 g, 16.1 mmol) in anhydrous pyridine (50 ml) was added

dropwise to a stirred mixture of 40b (3.5 g, 16.1 mmol) in pyridine

(150 ml) under an argon atmosphere. After 7 h the reaction was

quenched with water (10 ml) and evaporated. Product 41b was

obtained in a 36% (3.00 g, 5.7 mmol) yield as a light yellow foam

after puriﬁcation on a silica gel using a linear gradient of ethyl ac-

etate in toluene.

5.1.45. (S)-3-Amino-1-N-tert-butyloxycarbonylpiperidine

(43a).

Azido derivative 42a (6.77 g, 29.9 mmol) and Pd/C catalyst (150 mg)

were hydrogenated in ethanol (200 ml) at an atmospheric pressure

overnight. The catalyst was ﬁltered through Celite and the solvent

was evaporated. Product 43a was obtained in a 90% yield (5.39 g,

26.9 mmol) as a colorless liquid without further puriﬁcation.

¹H NMR, ¹³C NMR, and IR spectra were identical to those of 30.

HRMS (ESI) C₁₀H₂₁O₂N₂(MþH)^þcalcd 201.1598, found 201.1597;

[

a]

²⁰ꢂ8.0 (c 0.387, EtOH); n_max(KBr) 3436 (m), 3057 (w), 3035

D

(vw), 3001 (w), 2974 (m), 2837 (w), 1691 (s), 1671 (s), 1608 (m),

1582 (w), 1509 (vs), 1492 (m), 1477 (m), 1463 (m), 1445 (m), 1392

(w), 1366 (m), 1301 (m), 1251 (vs), 1117 (w), 1064 (m), 1035 (s), 1011

(w), 1001 (vw), 945 (w), 913 (vw), 867 (w), 827 (w), 791 (w), 766

(w), 754 (w), 727 (w), 634 (vw); d_H(CDCl₃, 499.8 MHz, 50 ^ꢀC) 7.49

(2H, m, H-2⁰⁰), 7.36e7.41 (4H, m, H-2⁰), 7.19e7.28 (3H, m, H-3⁰⁰,

H-4⁰⁰), 6.79e6.83 (4H, m, H-3⁰), 3.95 (1H, br s, H-3), 3.86 (1H, m, H-

5), 3.78 (6H, s, OCH₃), 3.75 (1H, m, H-2b), 3.61 (1H, m, H-6b), 3.09

(1H, br d, J_gem13.5 Hz, H-6a), 2.96 (1H, dd, J_gem13.0 Hz, J_2a-37.6 Hz,

H-2a), 1.47 (9H, s (CH₃)₃), 1.01e1.13 (2H, m, H-4); d_C(CDCl₃,

125.7 MHz, 50 ^ꢀC) 158.5 and 158.5 (C-4⁰), 145.7 (C-1⁰⁰), 136.7 and

136.9 (C-1⁰), 130.2 and 130.3 (C-2⁰), 128.2 and 128.3 (C-2⁰⁰), 127.7

(C-3⁰⁰), 126.7 (C-4⁰⁰), 113.0 and 113.0 (C-3⁰), 86.3 (3-OeC), 79.8

[a

]

²⁰þ26.0 (c 0.308, EtOH).

D

5.1.46. (3S,5R)-3-Amino-1-N-tert-butyloxycarbonyl-5-dimethoxy-

trityloxypiperidine (43b). Azido derivative 42b (2.93 g, 5.37 mmol)

and Pd/C catalyst (100 mg) were hydrogenated in ethanol (100 ml)

at an atmospheric pressure overnight. The catalyst was ﬁltered

through Celite and the solvent was evaporated. The product was

obtained in a 79% yield (2.20 g, 4.24 mmol) as a white foam without

further puriﬁcation.

20

[

a

]

þ7.3 (c 0.328, EtOH); n_max(CHCl₃) 3379 (vw), 3311 (vw),

D

3088 (vw), 3060 (vw), 2979 (m), 2960 (w), 2935 (m), 2859 (w),

ꢀ

ꢁ

S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1498

2840 (w), 1683 (s), 1608 (m), 1583 (w), 1509 (vs), 1494 (w), 1478

(w), 1464 (m), 1457 (m), 1444 (m), 1425 (m), 1393 (w), 1367 (m),

1301 (m), 1253 (vs), 1176 (s), 1153 (m), 1117 (w), 1080 (w), 1036 (s),

1012 (w), 950 (vw), 912 (w), 861 (w), 831 (m), 709 (w), 702 (w),

640 (w), 615 (vw), 599 (w), 584 (w); d_H(CDCl₃, 499.8 MHz, 80 ^ꢀC)

7.42 (2H, m, H-2⁰⁰), 7.28e7.32 (6H, m, H-2⁰, H-3⁰⁰), 7.23 (1H, m,

H-4⁰⁰), 6.88 (4H, m, H-3⁰), 3.76 (6H, s, OCH₃), 3.70 (1H, m, H-2_eq),

3.56 (1H, dm, J_gem12.7 Hz, H-6_eq), 3.34 (1H, m, H-5), 2.56 (1H, dd,

J_gem12.7 Hz, J_6ax-59.5 Hz, H-6_ax), 2.28e2.31 (1H, m, H-3, H-2_ax),

1.55 (1H, m, H-4_eq), 1.32 (9H, s, C(CH₃)₃), 1.10 (1H, m, H-4_ax); d_C

(CDCl₃, 125.7 MHz, 80 ^ꢀC) 158.1 (C-4⁰), 153.5 (COO), 145.6 (C-1⁰⁰),

136.4 (C-1⁰), 129.6 and 129.6 (C-2⁰), 127.7 (C-2⁰⁰), 127.3 (C-3⁰⁰),

126.4 (C-4⁰⁰), 113.0 (C-3⁰), 85.7 (5-OeC), 78.3 (C(CH₃)₃), 67.53 (C-

5), 54.9 (OCH₃), 51.2 (C-2), 48.5 (C-6), 46.3 (C-3), 41.4 (C-4), 27.8

(C(CH₃)₃); HRMS (ESI) C₃₁H₃₈O₅N₂Na (MþNa)^þcalcd 541.2673,

found 541.2673.

(w), 1060 (w), 1035 (m), 1010 (w), 934 (vw), 912 (w), 755 (w), 701

(w), 600 (w), 585 (w), 529 (vw); d_H(CDCl₃, 499.8 MHz, 50 ^ꢀC) 8.65

(1H, d, J_1-57.9 Hz, H-1), 7.54 (1H, br s, H-3), 7.49 (2H, m, H-2⁰⁰⁰),

0

7.37e7.40 (4H, m, H-2⁰⁰), 7.27 (1H, br s, H-6), 7.24 (2H, m, H-3⁰⁰⁰), 7.18

(1H, m, H-4⁰⁰⁰), 6.79e6.83 (4H, m, H-3⁰⁰), 4.03 (2H, q, J_CH2eCH37.1 Hz,

OCH₂CH₃), 3.82 (1H, br s, H-6⁰b), 3.78 (6H, s, OCH₃), 3.48e3.62 (3H,

m, H-2⁰b, H-3⁰, H-5⁰), 2.74e3.02 (2H, m, H-2⁰a, H-6⁰a), 1.74 (3H, d,

J

_CH3-61.2 Hz, 5-CH₃), 1.65 (1H, br m, H-4⁰b),1.41 (9H, s, C(CH₃)₃),1.31

(3H, t, J_CH3eCH27.1 Hz, OCH₂CH₃), 1.24 (1H, m, H-4⁰a); d_C(CDCl₃,

125.7 MHz, 50 ^ꢀC) 168.6 (C-4), 158.6 (C-4⁰⁰), 157.2 (C-6), 154.5 (C-2),

154.0 (COO), 145.8 (C-1⁰⁰⁰), 136.8 and 136.9 (C-1⁰⁰), 130.4 (C-2⁰⁰),

128.5 (C-2⁰⁰⁰), 127.6 (C-3⁰⁰⁰), 126.7 (C-4⁰⁰⁰), 113.1 and 113.2 (C-3⁰⁰),

106.5 (C-5), 86.8 (3⁰-OeC), 79.6 (C(CH₃)₃), 70.2 (OCH₂CH₃), 67.2 (C-

3⁰), 55.1 (OCH₃), 49.2 (C-2⁰), 48.1 (C-6⁰), 44.9 (C-5⁰), 37.5 (C-4⁰), 28.3

(C(CH₃)₃), 15.3 (CH₂CH₃), 8.8 (5-CH₃); HRMS (ESI) C₃₇H₄₅O₈N₃Na

(MþNa)^þcalcd 682.3099, found 682.3102.

5.1.47. 1-((S)-1-N-tert-Butyloxycarbonylpiperidin-3-yl)-3-((E)-3-

ethoxyacryloyl)urea (44a). Urea derivative 44a was prepared

according to general method E from amino derivative 43a (300 mg,

1.5 mmol) and reagent 15a (420 mg, 1.5 mmol) in a 80% yield

(410 mg, 1.2 mmol) as a light yellow foam.

5.1.50. (S)-3-(Uracil-1-yl)piperidine (45a). Nucleoside 45a was

prepared according to general method F from 44a (410 mg,1.2 mmol)

in a 84% yield (196 mg, 1.0 mmol) as a white amorphous solid.

¹H NMR, ¹³C NMR, and IR spectra were identical to those of 32.

HRMS (ESI) C₉H₁₄O₂N₃(MþH)^þcalcd 196.1081, found 196.1081;

¹H NMR, ¹³C NMR, and IR spectra were identical to those of 31a.

HRMS (ESI) C₁₆H₂₈O₅N₃(MþH)^þcalcd 342.2023, found 342.2024;

[a

]

²⁰ꢂ52.5 (c 0.257, EtOH).

D

[

a]

²⁰þ34.7 (c 0.305, EtOH).

5.1.51. (3S,5R)-5-Hydroxy-3-(uracil-1-yl)piperidine (45b). Urea de-

rivative 44b (440 mg, 0.653 mmol) was treated with a Dowex H^þ

(20 ml) in dioxane (50 ml) at 90 ^ꢀC. After 30 min, the mixture was

ﬁltered and washed with ethanol (30 ml) and water (30 ml). The

product was eluted with 2.5% NH₃in H₂O (∼50 ml) and further

puriﬁed by reversed phase HPLC. The product was obtained as

a white amorphous solid in a 75% yield (100 mg, 0.47 mmol).

D

5.1.48. 1-((3S,5R)-3-Amino-1-N-tert-butyloxycarbonyl-5-dimethoxy-

trityloxypiperidin-3-yl)-3-((E)-3-ethoxyacryloyl)urea (44b). Amino

derivative 43b (350 mg, 0.67 mmol) and reagent 15a (189 mg,

0.67 mmol) were dissolved in anhydrous dioxane (30 ml). The re-

action proceeded in 10 min. The crude product was puriﬁed on

a silica gel using a linear gradient of ethyl acetate in toluene.

Product 44b was obtained in a 98% yield (440 mg, 0.653 mmol) as

a light yellow foam.

[

a

]

²⁰ꢂ28.3 (c 0.130, EtOH); n_max(KBr) 3462 (vs), 3404 (m), 3286

D

(w), 2662 (w), 1696 (vs), 1656 (vs), 1640 (m), 1444 (m), 1429 (w),

1385 (m), 1276 (m), 1101 (w), 875 (w), 801 (w), 769 (w); d_H(DMSO,

499.9 MHz) 11.25 (1H, NH), 7.73 (1H, d, J_6-58.0 Hz, H-6), 5.52 (1H, d,

[

a

]

²⁰ꢂ24.2 (c 0.268, EtOH); n_max(KBr) 3237 (w), 3089 (w), 2977

D

J_5-68.0 Hz, H-5), 4.91 (1H, d, J_OH-54.2 Hz, HO), 4.28 (1H, m, H-3⁰),

0

(m), 2837 (w), 1693 (vs), 1680 (vs), 1655 (m), 1629 (m), 1609 (s), 1578

(w), 1543 (s), 1509 (vs), 1475 (m), 1463 (m), 1446 (m), 1422 (m), 1394

(w),1378 (w),1366 (m),1302 (m),1250 (vs), 1224 (m),1175 (vs), 1152

(s), 1080 (w), 1060 (w), 1034 (m), 1011 (w), 934 (vw), 912 (vw), 830

(m), 702 (w), 585 (w), 528 (vw); d_H(CDCl₃, 499.8 MHz, 50 ^ꢀC) 9.03

3.46 (1H, m, H-5⁰), 2.88 (1H, ddm, J_gem11.8 Hz, J_{6 eq,5}4.4 Hz, H-6 _eq),

0

2.78 (1H, ddm, J_gem11.8 Hz, J_{2 eq,3}4.1 Hz, H-2 _eq), 2.42 (1H, t,

0

J_gem¼J_{2 ax,3}11.4 Hz, H-2 _ax), 2.12 (1H, dd, J_gem12.1 Hz, J_{6 ax,5}10.2 Hz,

H-6⁰_ax), 1.95 (1H, dm, J_gem11.1 Hz, H-4⁰_eq), 1.58 (1H, m, H-4⁰_ax); d_C

(DMSO, 125.7 MHz) 163.3 (C-4), 151.1 (C-2), 142.4 (C-6), 101.2 (C-5),

67.1 (C-5⁰), 52.8 (C-6⁰), 51.6 (C-3⁰), 48.7 (C-2⁰), 38.7 (C-4⁰); HRMS

(ESI) C₉H₁₄O₃N₃(MþH)^þcalcd 212.1030, found 212.1030.

0

(1H, br s, H-3), 8.60 (1H, d, J_1-57.7 Hz, H-1), 7.52 (1H, d, J_6-512.2 Hz, H-

6), 7.48 (2H, m, H-2⁰⁰⁰), 7.36e7.40 (4H, m, H-2⁰⁰), 7.25 (2H, m, H-3⁰⁰⁰),

7.18 (1H, m, H-4⁰⁰⁰), 6.79e6.82 (4H, m, H-3⁰⁰), 5.26 (1H, d, J_5-612.2 Hz,

H-5), 3.89e3.94 (2H, m, OCH₂CH₃), 3.77 (1H, m, H-6⁰b), 3.77 (6H, s,

OCH₃), 3.49e3.59 (3H, m, H-2⁰b, H-3⁰, H-5⁰), 2.72e3.00 (2H, m, H-2⁰a,

H-6⁰a),1.40 (9H, s, C(CH₃)₃),1.63 (1H, br m, H-4⁰b),1.30 (3H, t, J_CH3eCH2

7.1 Hz, OCH₂CH₃), 1.27 (1H, m, H-4⁰a); d_C(CDCl₃, 125.7 MHz, 50 ^ꢀC)

167.6 (C-4), 162.7 (C-6), 158.6 (C-4⁰), 154.3 and 154.5 (COO and C-2),

145.7 (C-1⁰⁰⁰), 136.8 and 136.8 (C-1⁰⁰), 130.3 (C-2⁰⁰), 128.4 (C-2⁰⁰⁰), 127.6

(C-3⁰⁰⁰), 126.7 (C-4⁰⁰⁰),113.1 and 113.1 (C-3⁰⁰), 98.0 (C-5), 86.8 (3⁰-OeC),

79.6 (C(CH₃)₃), 67.5 (OCH₂CH₃), 67.2 (C-3⁰), 55.1 (OCH₃), 49.3 (C-2⁰),

47.9 (C-6⁰), 44.9 (C-5⁰), 37.4 (C-4⁰), 28.3 (C(CH₃)₃), 14.4 (CH₂CH₃);

HRMS (ESI) C₃₈H₄₇O₈N₃Na (MþNa)^þcalcd 696.3255, found 696.3258.

5.1.52. (3S,5R)-5-Hydroxy-3-(thymin-1-yl)piperidine (45c). Urea de-

rivative 44c (430 mg, 0.626 mmol) was treated with a Dowex H^þ

(20 ml) in dioxane (50 ml) at 90 ^ꢀC. After 30 min, the reaction mixture

was ﬁltered and the Dowex was washed with ethanol (30 ml) and

water (30 ml). The product was eluted with 2.5% NH₃in H₂O (∼50 ml)

and further puriﬁed by reversed phase HPLC. The product was

obtained as a white amorphous solid in a 81% yield (110 mg,

0.48 mmol).

[

a

]

²⁰ꢂ66.1 (c 0.233, EtOH); n_max(KBr) 3505 (w), 3470 (w), 3288

D

(w), 3145 (w), 3021 (w), 1682 (vs), 1657 (vs), 1639 (m), 1470 (m),

1429 (w), 1391 (w), 1374 (w), 1301 (w), 1277 (w), 1268 (w), 1118 (w),

1086 (w), 1065 (w), 1059 (w), 886 (w) 820 (w), 768 (w), 759 (w); d_H

(DMSO, 499.9 MHz) 11.21 (1H, br s, NH), 7.61 (1H, q, J_6-CH31.2 Hz, H-

6), 4.89 (1H, br s, OH), 4.28 (1H, m, H-3⁰), 3.46 (1H, m, H-5⁰), 2.76

5.1.49. 1-((3S,5R)-3-Amino-1-N-tert-butyloxycarbonyl-5-dimethoxy-

trityloxypiperidin-3-yl)-3-((E)-3-ethoxy-2-methylacryloyl)urea

(44c). Amino derivative 43b (350 mg, 0.67 mmol) and reagent 15b

(258 mg, 0.87 mmol) were dissolved in anhydrous dioxane (30 ml).

The reaction proceeded in 30 min. The crude product was puriﬁed

on a silica gel using a linear gradient of ethyl acetate in toluene.

Product 44c was obtained in a 95% yield (430 mg, 0.626 mmol) as

a light yellow foam.

0

(1H, ddd, J_gem11.7 Hz, J_{6 eq-5}4.6 Hz, J_{6 eq-4 eq}1.5 Hz, H-6₀_eq), 2.76

0

(1H, ddd, J_gem11.7 Hz, J_{2 eq-3}4.5 Hz, J_{2 eq-4 eq}1.6 Hz, H-2 _eq), 2.44

0

(1H, t, J_gem¼J_{2 ax-3}11.5 Hz, H-2 _ax), 2.12 (1H, dd, J_gem12.1 Hz, J_{6 ax-5}

10.2 Hz, H-6⁰_ax), 1.94 (1H, dm, J_gem11.2, H-4⁰_eq), 1.76 (3H, d, J_CH3-6

1.2 Hz, CH₃), 1.61 (1H, m, H-4⁰_ax); d_C(DMSO,125.7 MHz) 163.9 (C-4),

151.0 (C-2), 138.0 (C-6), 108.9 (C-5), 67.1 (C-5⁰), 52.8 (C-6⁰), 51.2 (C-

3⁰), 48.7 (C-2⁰), 38.8 (C-4⁰), 12.2 (CH₃); HRMS (ESI) C₁₀H₁₆O₃N₃

(MþH)^þcalcd 226.1186, found 226.1186.

[

a

]

²⁰ꢂ18.8 (c 0.069, EtOH); n_max(KBr) 3360 (w), 3259 (w), 2977

D

(m), 2836 (w), 1697 (vs), 1677 (vs), 1650 (m), 1620 (m), 1609 (m),

1542 (m), 1475 (m), 1463 (m), 1446 (m), 1421 (m), 1392 (w), 1379

(w), 1366 (m), 1301 (m), 1251 (s), 1210 (s), 1177 (s), 1151 (s), 1081

ꢀ

ꢁ

S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1499

5.1.53. (S)-1-N-tert-Butyloxycarbonyl-3-[(5-amino-6-chloropyr-

imidin-4-yl)amine]piperidine (46a). Amino derivative 43a (200 mg,

1.0 mmol), 5-amino-4,6-dichloropyrimidine 16 (179 mg, 1.1 mmol),

and triethylamine (0.59 ml, 4.3 mmol) were suspended in ethanol

(40 ml) and heated to 110 ^ꢀC in a pressure vessel over 48 h. After

the reaction was completed (TLC controlled 50% ethyl acetate/tolu-

ene), all the solvent was evaporated and the residue was chromato-

graphed on a silica gel using a linear gradient of ethyl acetate in

toluene. Product was obtained in 72% yield (235 mg, 0.72 mmol) as

a dark orange foam.

The product was isolated in a 68% yield (216 mg, 0.92 mmol) as

a white amorphous solid.

¹H NMR, ¹³C NMR, and IR spectra were identical to those of 27d.

HRMS (ESI) C₁₀H₁₅ON₆(MþH)^þcalcd 235.1302, found 235.1301;

[a

]

²⁰ꢂ22.9 (c 0.240, EtOH).

D

Acknowledgements

Support by grants #2B06065 (Ministry of Education, Youth and

Sports of the Czech Republic), #NR/9138e3 (Ministry of Health of

the Czech Republic), and ChemGen LC06077 (Ministry of Education,

Youth and Sports of the Czech Republic) under research project

Z40550506 is gratefully acknowledged. The authors are indebted to

the staff of the Department of Organic Analysis for the measure-

ments of HRMS. The authors are indebted to Dr. Ivan Votruba (IOCB,

Czech Academy of Sciences, Prague) for the examination of cyto-

¹H NMR, ¹³C NMR, and IR spectra were identical to those of 33a.

HRMS (ESI) C₁₄H₂₃O₂N₅Cl (MþH)^þcalcd 328.1535, found 328.1536;

20

[

a]

þ3.4 (c 0.355, EtOH).

D

5.1.54. (S)-1-N-tert-Butyloxycarbonyl-3-[(2,5-diamino-6-chloropyr-

imidin-4-yl)amino]piperidine (46b). Amino derivative 43a (1.05 g,

5.24 mmol), 2,5-diamino-4,6-dichloropyrimidine 17 (1.03 g, 5.76

mmol), and triethylamine (3.1 ml, 22.53 mmol) were suspended in

n-butanol (80 ml) and heated to 140 ^ꢀC in a pressure vessel over

48 h. After the reaction was completed, the solvent was evaporated

and the residue chromatographed on a silica gel using a linear

gradient of ethyl acetate in toluene. The product was obtained in

a 54% yield (969 mg, 2.82 mmol) as a light orange foam.

ꢁꢀ

static activity, Milan Kolar (Trios, s.r.o) for testing antibacterial

ꢁ

activity and Libor Krasny (IMG, Czech Academy of Sciences, Prague)

for testing bacterial RNA polymerase inhibition activity.

Supplementary data

Supplementary data associated with this article can be found in

the online version, at doi:10.1016/j.tet.2010.12.029. These data

include MOL ﬁles and InChiKeys of the most important compounds

described in this article.

¹H NMR, ¹³C NMR, and IR spectra were identical to those of 33b.

HRMS (ESI) C₁₄H₂₄O₂N₆Cl (MþH)^þcalcd 343.1644, found 343.1645;

20

[

a]

ꢂ31.1 (c 0.106, EtOH).

D

5.1.55. (S)-1-N-tert-Butyloxycarbonyl-3-(6-chloropurin-9-yl)piperidine

(47a). Pyrimidine derivative 46a (370 mg, 1.12 mmol) and diethoxy-

methyl acetate (0.185 ml, 1.12 mmol) in DMF (25 ml) were stirred at rt

for 8 h and then heated to 120 ^ꢀC for the next 24 h. The solvent was

evaporated and the residue was chromatographed on a silica gel using

a linear gradient of 10% EtOH/CHCl₃in CHCl₃. The product was

obtained as a light orange foam in a 68% yield (258 mg, 0.764 mmol).

¹H NMR, ¹³C NMR, HR-ESI, and IR spectra were identical to those

References and notes

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5. Davis, B. G. Tetrahedron: Asymmetry 2009, 20, 652e671.

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of 34a. [

a]

²⁰þ15.3 (c 0.170, EtOH).

D

8. Reist, E. J.; Gueffroy, D. E.; Blackford, R. W.; Goodman, L. J. Org. Chem. 1966, 31,

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2067e2071.

5.1.56. (S)-1-N-tert-Butyloxycarbonyl-3-(2-amino-6-chloropurin-9-

yl)piperidine (47b). Pyrimidine derivative 46b (680 mg, 1.98 mmol)

and diethoxymethyl acetate (0.324 ml,1.98 mmol) were stirred in DMF

(40 ml) at rt and then heated to 120 ^ꢀC for the next 24 h. The solvent

was evaporated and the residue was chromatographed on a silica gel

using a linear gradient of ethyl acetate in toluene. The product was

obtained as a light yellow foam in a 72% yield (502 mg, 1.42 mmol).

¹H NMR, ¹³C NMR, and IR spectra were identical to those of 47b.

12. Filichev, V. V.; Pedersen, E. B. Tetrahedron 2001, 57, 9163e9168.

13. Haberli, A.; Leumann, C. J. Org. Lett. 2001, 3, 489e492.

14. Schramm, V. L.; Tyler, P. C. Curr. Top. Med. Chem. 2003, 3, 525e540.

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16. Lewandowicz, A.; Ringia, E. A. T.; Ting, L.; Kim, K.; Tyler, P. C.; Evans, G. B.; Zub-

kova, O. V.; Mee, S.; Painter, G. F.; Lenz, D. H.; Furneaux, R. H.; Schramm, V. L.

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HRMS (ESI) C₁₅H₂₂O₂N₆Cl (MþH)^þcalcd 353.1487, found 353.1489;

20

[

a]

ꢂ20.8 (c 0.139, EtOH).

D

€

17. Clinch, K.; Evans, G. B.; Frolich, R. F. G.; Furneaux, R. H.; Kelly, P. M.; Legentil, L.;

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2009, 52, 1126e1143.

5.1.57. (S)-3-(Adenin-9-yl)piperidine (48a). Nucleoside 48a was

prepared from 47a (258 mg, 0.76 mmol) and aqueous NH₃. The

reaction progress was controlled by RP HPLC. When the reaction

was ﬁnished, the solvent was evaporated and the compound

treated according to general procedure D. After the reaction was

completed, the product was puriﬁed by preparative RP HPLC to give

48a in a 65% yield (107 mg, 0.49 mmol) as a white amorphous solid.

¹H NMR, ¹³C NMR, and IR spectra were identical to those of 27c.

ꢀ

18. Kocalka, P.; Pohl, R.; Rejman, D.; Rosenberg, I. Tetrahedron 2006, 62, 5763e5774.

ꢀ

19. Rejman, D.; Kocalka, P.; Budesínsky, M.; Rosenberg, I. Tetrahedron 2007, 63,

1243e1253.

ꢀ

ꢁ

20. Rejman, D.; Pohl, R.; Kocalka, P.; Masojídkova, M.; Rosenberg, I. Tetrahedron

2009, 65, 3673e3681.

ꢀ

ꢀꢀ

ꢁ

21. Vanek, V.; Budesínsky, M.; Rinnova, M.; Rosenberg, I. Tetrahedron 2009, 65,

862e876.

ꢀ

ꢁ

ꢀ

ꢁ

ꢀ

ꢁ

ꢀ

ꢁ

22. Kocalka, P.; Rejman, D.; Vanek, V.; Rinnova, M.; Tomeckova, I.; Kralíkova, S;

ꢁ

ꢀꢀ

ꢁ

Petrova, M.; Pav, O.; Pohl, R.; Budesínsky, M.; Liboska, R.; Tocík, Z.; Votruba, I.;

Rosenberg, I. Bioorg. Med. Chem. Lett. 2009, 20, 861e865.

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Med. Chem. 2005, 13, 973e983.

HRMS (ESI) C₁₀H₁₅N₆(MþH)^þcalcd 219.1353, found 219.1353;

20

[

a]

ꢂ6.4 (c 0.283, EtOH).

D

5.1.58. (S)-3-(Guanin-9-yl)piperidine (48b). Guanine derivative 47b

(502 mg, 1.42 mmol) was treated with 1 M NaOH in 30% dioxane/

water (50 ml) for 2 days. After this time, the reaction was treated

with a Dowex 50 in trimethylammonium form (100 ml) for 5 min.

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give a crude guanine derivative, which was then treated according

to general procedure D and ﬁnally puriﬁed by reversed phase HPLC.

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ꢀ

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S. Kovackova et al. / Tetrahedron 67 (2011) 1485e1500

1500

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The synthesis of piperidine nucleoside analogs - A comparison of several methods to access the introduction of nucleobases

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