Stereoselective synthesis of conformationally constrained 2′-deoxy-4′-thia β-anomeric spirocyclic nucleosides featuring either hydroxyl configuration at C5′

Stereoselective Synthesis of Conformationally Constrained

2′-Deoxy-4′-thia â-Anomeric Spirocyclic Nucleosides Featuring

Either Hydroxyl Configuration at C5′

Shuzhi Dong and Leo A. Paquette*

Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210

paquette.1@osu.edu

Received October 29, 2004

An enantioselective approach to 2′-deoxy-4′-thia spirocyclic nucleosides featuring an R- or â-hydroxyl

substituent at C-5′ of the carbocyclic ring is detailed. The starting point is the mandelate acetal 8.

The overall strategy involves the stereocontrolled dihydroxylation of this dihydrothiophene,

subsequent generation of the keto acetonide 12 followed by its Meerwein-Ponndorf-Verley

reduction and â-elimination, protection of the resulting dihydroxy thiaglycal, electrophilic glyco-

sidation according to the Haraguchi protocol, reductive removal of the phenylseleno group, and

end-game global deprotection. Acquisition of the R- and â-5′-isomers is equally facile. Various 1D

and 2D NMR techniques are used for assigning configuration.

During the past four decades, 4′-thianucleosides have

emerged from the realm of heterocyclic curiosities to

become candidate compounds for clinical evaluation.

These mimics in which the furanose ring oxygen is

replaced by a sulfur atom have come under intense

preparative scrutiny.^1,2This effort has been fueled in

large part by the very promising antiviral³and anticancer

activities⁴of members of this class. The increased stabil-

ity of the glycosidic bond to nucleases⁵with resultant

decreases in the rate of metabolic degradation⁶has also

not gone unnoticed. The earliest access route designed

to reach 4′-thianucleosides involved Vorbru¨ggen-type

coupling of activated 4-thiapentafuranoses to silylated

nucleobases.⁷Early on, such classical glycosylations were

recognized to suffer from an inability to deliver predomi-

nantly the â-anomer. A notably weak aspect was the lack

of dependability even when neighboring C-2 acyloxy

participation was available.⁸For this reason, recourse

was in turn made to adaptation of the Pummerer

rearrangement.⁹However, this approach likewise suffers

from coproduction of significant amounts of the R-ano-

mer,¹⁰especially in the absence of suitable control ele-

ments.¹¹

These shortcomings in turn prompted the utilization

of 4-thiafuranoid glycals as glycosyl donors.^2r,12The

practicalities are such that reaction between a dihydro-

thiophene typified by 1 and a silylated nucleobase in the

presence of phenylselenenyl chloride affords the â-ano-

mer 2. Subsequent radical-mediated removal of the PhSe

substituent gives rise directly to 3.

More recently, the use of hypervalent iodine com-

pounds for coupling cyclic sulfides with silylated nucleo-

bases has been developed.^2s

Several years ago, we introduced the concept of spiro-

cyclic restriction in nucleosides.¹³Structural modification

in the manner exemplified by 4 allows for proper con-

(1) Review: Yokoyama, M. Synthesis 2000, 1637.

Published on Web 02/02/2005

1580

J. Org. Chem. 2005, 70, 1580-1596

Synthesis of 2′-Deoxy-4′-thia â-Anomeric Spirocyclic Nucleosides

formational biasing and for the purposeful distinction

between C5′-stereoisomers (a and b series).¹⁴Among the

synthetic issues that have since been addressed are those

of devising workable approaches to analogues bearing a

modified 2′-deoxyribose moiety such as 5.¹⁵As matters

progressed, a practical route to enantiomerically pure

spiro[4.4]nonanes 6 has been realized.¹⁶We have now

focused our attention on extending this investigation to

include the sulfur analogues 7a and 7b. Our prospects

for success were derived in part from methodology

developed earlier for incorporating sulfur at the apex

position of spirocyclic deoxy congeners.¹⁷

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Results and Discussion

Chemoselective Oxidation Profile. With the ready

availability of optically pure 8,¹⁷we undertook to explore

those features that would result in the selective oxidation

of its double bond and not its sulfur atom. The involve-

ment of 8 was founded on the expectation that the

significant steric shielding of the mandelate unit might

cleanly differentiate the R and â faces of the 2,5-

dihydrothiophene ring. For calibration purposes, 8 was

initially subjected to the action of sodium periodate

supported on silica gel¹⁸as well as the Davis oxaziridine

reagent.¹⁹In line with expectations,²⁰both sets of condi-

tions afforded exclusively one diastereomer of the unsat-

urated sulfoxide 9, further treatment of which with

m-chloroperbenzoic acid gave sulfone 10 (Scheme 1).

Other reagents such as peracetic acid²¹and manganese

dioxide²²are recognized for their capability to oxidize

sulfides to sulfoxides. All four reagents share the char-

acteristic of engaging very slowly, if at all, in the further

oxidation of sulfoxides to sulfones.

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3140.

In contrast, permanganate ion and osmium tetroxide

oxidize sulfoxides rapidly to sulfones, but react slowly

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Shewach, D. S.; Tiwari, K. N.; Secrist, J. A., III. Biochem. Pharmacol.

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J. Org. Chem, Vol. 70, No. 5, 2005 1581

Dong and Paquette

SCHEME 1

FIGURE 1. Global energy minimum of diol 11.

with sulfides. In fact, OsO₄has been reported to be totally

inert to reaction with sulfides.²³However, Kaldor²⁴and

Priebe²⁵have shown that in the presence of tertiary

amines, OsO₄efficiently oxidizes sulfides to sulfones, and

furthermore that catalytic quantities of OsO₄in the

presence of stoichiometric amounts of trialkylamine

N-oxides likewise accomplish this transformation. More

relevantly, Hauser used the above reagents to stereo-

specifically dihydroxylate an olefinic center in an acyclic

system that was guided by a sulfoxide group more remote

than homoallylic, and furnished diacetoxy sulfones as the

final products after acetylation.²⁶The use of these oxidant

combinations in the present context is consequently

precluded.

SCHEME 2

AD process, and 8 is no exception. Members of this

structural class tend to react slowly and to give rise to

low ee values.³⁰Ultimately, we found that the chiral

ligand (DHQD)₂PYR³¹was more suitable than (DHQD)₂-

PHAL, and that raising the potassium osmate level to

10 mol % with co-addition of 2 equiv of methanesulfo-

namide rectified the rate problem. An increase in the

reaction temperature from room temperature to 40 °C

as recommended by others³²resulted in decomposition

and is ill-advised. Under the optimized conditions, 11 was

isolated in 66% yield at 84% conversion.

It is well-known that many tertiary amines can dra-

matically accelerate catalytic osmium-promoted dihydro-

xylation by enhancing the rate of formation of osmate

esters.³²The possibility of utilizing DABCO presented

itself since our concern was not stereoselectivity but

chemoselectivity. Indeed, the use of DABCO furnished

11 in 53% yield at 77% conversion. Unfortunately,

hydrolysis of the mandelate acetal and oxidation at sulfur

were observed to be competing processes. Remarkably,

both problems were well resolved when the reaction

mixture was buffered with 3 equiv of sodium bicarbon-

ate.³³These conditions were accompanied by a cleaner,

faster reaction, and gave rise to 11 in 77% yield at 77%

conversion after overnight stirring (Scheme 2). The

stereochemical assignment to 11 was based on a NOESY

correlation between the benzylic proton and H-2, reflect-

ing an S-type (2-endo/3-exo) conformation (Figure 1). The

calculations were performed with Monte Carlo simula-

More recently, Sharpless²⁷and Sammakia²⁸described

the use of AD-mix reagents for the dihydroxylation of

olefins in the presence of sulfides, disulfides, and dithianes

with potassium ferricyanide serving as the co-oxidant.

These researchers also defined the scope of this trans-

formation and illustrated that prevailing steric and

electron-withdrawing factors resident in the substrates

determined the extent of sulfur over-oxidation. Although

a mechanistic rationale of these phenomena remains

elusive, synthetic applicability of the AD-mix process for

the present purposes demanded exploration.

The choice between AD-mix-R or AD-mix-â²⁹happens

not to be a critical one because only the R face of the

carbon-carbon double bond in 8 is approachable by these

sterically demanding reagents. Therefore, selection of the

mismatched ligand would only retard the reaction rate

and likely lower the yield. Our early experimental probes

showed the AD-mix-â yields to be favored over those

realized from the AD-mix-R reagent by a factor of 3:1.

Consequently, (DHQD)₂PHAL is of the proper chirality

to serve as a ligand of choice.

Cyclic cis-disubstituted olefins related to 8 are recog-

nized to be the most difficult type to be oxidized in the

(23) (a) Stork, G.; van Tamelen, E. E.; Friedman, L. J.; Burgstahler,

A. W. J. Am. Chem. Soc. 1953, 75, 394. (b) Djerasi, C.; Engle, R. R. J.

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Chem. 1975, 53, 1362. (e) Vedejs, E.; McClure, C. K. J. Am. Chem.

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1582 J. Org. Chem., Vol. 70, No. 5, 2005

Synthesis of 2′-Deoxy-4′-thia â-Anomeric Spirocyclic Nucleosides

SCHEME 3

SCHEME 4

tions (MacroModel version 5.0) of 5000 different confor-

mations in the MM3 force field.

To arrive at 12, the diol was heated in neat 2,2-

dimethoxypropane containing a catalytic quantity of

p-toluenesulfonic acid,³⁴and the resulting acetonide was

hydrolyzed with lithium hydroxide in THF and water.³⁵

The yield of 12 was 96% over two steps.

als.³⁹However, such R protons are only very weak acids,

and their removal requires a strong base. Often, organ-

olithium reagents are used in conjunction with additives

such as hexamethylphosphoramide,⁴⁰tetramethylethyl-

enediamine,⁴¹and DABCO.⁴²In the present case, 13 was

treated with tert-butyllithium (6 equiv) and HMPA

(12 equiv) in THF at -78 °C. These conditions gave rise

to diol 17 in 49% yield at 55% conversion (Scheme 4).

Recourse to other solvents (e.g., pentane) or alternative

ligands (e.g., TMEDA) proved notably less effective, as

did prior hydroxyl protection as the TBS ether. Although

17 is sufficiently stable to allow its purification by flash

chromatography, storage under nitrogen at -10 °C is

mandatory. This sensitive glycal decomposes rapidly in

the presence of methanol.

The instability of 17 was also apparent during at-

tempts at silylation. Treatment with tert-butyldimethyl-

silyl triflate and 2,6-lutidine at -78 °C⁴³led only to

decomposition. In the presence of the less reactive silyl

chloride, potassium hydride, and 18-crown-6,⁴⁴no reac-

tion was noted. Interesting results were recorded, how-

ever, when TBSCl was admixed with silver nitrate in the

presence of different base and solvent combinations.

Conditions of this type were originally reported by the

Ogilvie group for the selective synthesis of either 2′,5′-

or 3′,5′-disilylated purine and pyrimidine arabinonucleo-

sides.⁴⁵From among the combinations explored, the

addition of TBSCl to a THF solution of 17, AgNO₃, and

pyridine furnished 18 (56% at 62% conversion) after

overnight stirring. With a switch from pyridine to

Synthesis of the 4-Thiaglycal. The next interim goal

was considered to be a pair of suitably protected 4-thia-

glycals otherwise epimeric at C5. It was hoped that

conditions would be found to transform 12 into ap-

proximately equal amounts of the secondary carbinols.

In their study of the parent thiaspiro ketone, Dmitroff

and Fallis noted that methyllithium, methylmagnesium

bromide, and several hydride reagents exhibited a strong

preference for attack anti to the sulfur atom.³⁶More

balanced product distributions have been noted with zinc

borohydride³⁶and lithium aluminum hydride.¹⁷However,

exposure of 12 to either of these reagents resulted in

highly favored conversion to the syn carbinol 13 (25:1 for

Zn(BH₄)₂; 15:1 for LiAlH₄). When alternative recourse

was made to Meerwein-Ponndorf-Verley reduction,³⁷13

and 14 were concomitantly produced in 61% and 22%

yield, respectively (Scheme 3). This protocol was equally

successful on larger scale, providing that care was taken

to use saturated sodium potassium tartrate and sodium

hydroxide solutions in the workup. Treatment with the

more customary 1 N HCl solution³⁸caused destruction

of the acetonide unit.

The derived benzoate esters 15 and 16 were easily

distinguished on the basis of NOE studies. For example,

the syn nature of the three carbinol protons in 15 was

made evident by the correlations observed between H-5/

H-2 and H-5/H-3 as shown in A.

(34) Baumgartner, J.; Weber, H. Chirality 2001, 13 159.

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77, 509.

At this point, the conversion of 13 into a glycal in

preparation for eventual nucleoside formation was tar-

geted for attention. We were mindful that the presence

of a sulfide atom exerts an acidifying effect on its R

protons as a consequence of electron-withdrawing effects

and stabilization of the resulting carbanion by d orbit-

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J. Org. Chem, Vol. 70, No. 5, 2005 1583

Dong and Paquette

SCHEME 5

SCHEME 6

DABCO, all of 17 was consumed with generation of both

18 and the bis-silylated derivative 19 (Scheme 4). The

most reactive conditions proved to involve 1,2-dimethoxy-

ethane as the solvent and triethylamine as the base. In

this instance, the outcome after 3 h was to form all three

possible products, including the regioisomer 20 not

previously encountered. The two monoprotected spiro

thiaglycals were amenable to conversion to 19 simply by

extending the reaction time.

The necessary distinction between 18 and 20 was

achieved by application of 2D-NOESY spectroscopy. For

18, correlations were observed between the silyl methyl

protons and H-2, as well as between the silyl tert-butyl

protons and H-8â (see B). These characteristic patterns

are not seen in 20. Added confirmation was derived by

subjecting 18 to D₂O exchange. Its free OH peak,

observed as a broad doublet, exhibited a COSY correla-

tion with H-5 (³J_5,5-OH) 4.9 Hz), which disappeared

when shaken with D₂O. Simultaneously, the H-5 signal

became a pseudotriplet, thereby establishing the location

of the hydroxyl group.

Notwithstanding the success encountered above, the

bifunctional 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane

reagent (TIPDSCl₂)^2rproved to be superior. Despite the

apparently long distance between the two hydroxyl

groups in 17, protection occurs readily at both sites in

excellent yield (90%). The advantages offered by 21

(Scheme 5) are made apparent in the sequel. MM3

calculations establish that the belt generated upon

introduction of the bifunctional TIPDS protecting group

is structured across the â-surface of the spironucleoside

core.

ever, comprehensive analysis of the relatively less com-

plex spectrum of 25 permitted definition of its stereo-

chemistry. Two key NOESY correlations were observed

for H-1′/H-8′R and H-6/H-3′ (see C), thereby ruling out

the R-configuration. Since the generation of 22-24

proceeds via the same mechanistic pathway, these spiro

nucleosides should also be â-configured. Indeed, the

subsequent transformation products to be defined below

provide spectral evidence that confirms this conclusion.

Stereoselective Synthesis of Spirocyclic 2′-Deoxy-

4′-â-thianucleosides. With spirothiaglycals 19 and 21

in hand, their response to electrophilic glycosidation

chemistry was explored. The first demonstration that 19

would react in the manner envisioned came upon reaction

with phenylselenenyl chloride and persilylated thymine

in CH₃CN at 0 °C. The coupling was complete within 1 h

and gave 53% of 22 along with a minor diastereomer

(13%, Scheme 6). No difficulties were encountered in

substituting N-iodosuccinimide as the electrophile. In

fact, the distribution of 23 and the R-isomer was es-

sentially identical at 52:13. Improved stereoselectivity

was realized with 21 as the glycosidation substrate. More

specifically, the isolated yields of 24 and 25 reached 76%

and 70%, respectively.

The issue of mechanism has been addressed by Hara-

guchi et al.^2rwho concluded that these face-selective

electrophilic additions are controlled by the silyl protect-

ing groups in use. For example, the TIPDS group was

thought to shield the R-face of the thiaglycal double bond

less than a 3-O-TBS substituent, thus giving rise to

preferential R-face attack by the electrophilic agent and

increased â/R-anomeric ratios. While this interpretation

is a useful conceptual advance, other studies have defined

that bulky substituents at the C-3 allylic centers are

1

The H NMR spectra of 22-24 are characterized by

extensive overlap of several characteristics signals. How-

(45) (a) Ogilvie, K. K.; McGee, D. P. C.; Boisvert, S. M.; Hakimelahi,

G. H.; Proba, Z. A. Can. J. Chem. 1983, 61, 1204. (b) Ogilvie, K. K.;

Hakimelahi, G. H.; Proba, Z. A.; McGee, D. P. C. Tetrhedron Lett. 1982,

23, 1997. (c) Hakimelahi, G. H.; Proba, Z. A.; Ogilvie, K. K. Tetrahedron

Lett. 1981, 22, 5243.

1584 J. Org. Chem., Vol. 70, No. 5, 2005

Synthesis of 2′-Deoxy-4′-thia â-Anomeric Spirocyclic Nucleosides

SCHEME 7

SCHEME 8

necessary for attaining considerable regio- and stereo-

selectivities in glycosidation chemistry.⁴⁶

Added insight into these issues is available from the

more extensively investigated field of non-sulfur glycal

chemistry. According to Castillon,⁴⁷the stereoselectivity

of organoselenium addition reactions cannot be accounted

for only in terms of the steric hindrance provided by the

substituents resident at C-3 and C-5. In the phenyl-

selenonium ion-forming transition state, the aryl group

is far removed from substituents on the glycal ring.⁴⁸

Furthermore, the initial addition process is reversible and

therefore thermodynamically controlled.⁴⁹The possibility

remains open that the relative stability of the selenonium

cations might be controlled by the steric bulk and/or

stereoelectronic stabilizing effect of the C-3/C-5 substit-

uents. In addition, the global conformational character-

istics of the glycal may lock the selenonium cation and

thereby predetermine the stereoselectivity of nucleophilic

attack by the nucleobase.

Studies involving removal of the heteroatom at C-2′

ensued. Unexpectedly, exposure of 22 to the action of tri-

n-butyltin hydride and triethylborane in benzene at room

temperature^2rafforded only the ring-opened product 26

(Scheme 7). This reaction pathway may be facilitated by

the formation of a boron-sulfur complex followed by

â-radical elimination with release of ring strain. The

complication was skirted to some extent by the reduction

of iodide 23 with Bu₃SnH and AIBN in toluene at 60 °C.⁵⁰

Although the desired compound was obtained, the extent

of conversion was low (25%). As a consequence of the

precedent,⁵⁰more elevated temperatures were expected

to lead to 26 and were therefore not examined. The

combination of relatively low stereoselectivity in the

glycosylation step and the poor efficiency of the ensuing

radical reduction caused the route involving 19 to be

abandoned. It was then found that the conversion of 24

into 28 proceeds quantitatively at -78 °C under a

continuous flow of oxygen. Ultimate arrival at 29 was

accomplished by routine treatment with TBAF. However,

purification of this nucleoside was less than straightfor-

ward. When eluted from silica gel with 10% methanol in

CH₂Cl₂, 29 was appreciably contaminated with tetra-n-

butylammonium salts. The R_fof these salts was greatly

curtailed with a solvent change to 5% methanol in ethyl

acetate, but tailing became an insurmountable problem.

After considerable experimentation, 20% ethanol in

toluene was found to be ideally suited to our purposes.

Introduction of Other Nucleobases. With the dem-

onstration of a successful synthetic strategy to reach 29,

attention was directed to the introduction of other

nucleobases. Three pyrimidine examples are grouped into

Scheme 8. The generation of 30 and 32, as well as their

conversion to 31 and 33, respectively, proceeded rather

(46) Collins, P. M.; Ferrier, R. J. Monosaccharides, Their Chemistry

and Their Roles in Natural Products; John Wiley & Sons: Chichester,

U.K., 1995; pp 319ff.

(47) Diaz, Y.; El-Laghdach, A.; Castillon, S. Tetrahedron 1997, 53,

10921.

(48) Wang, J.; Wurster, J. A.; Wilson, L. J.; Liotta, D. Tetrahedron

Lett. 1993, 34, 4881.

(49) Diaz, Y.; El-Laghdach, A.; Matheu, M. I.; Castillon, S. J. Org.

Chem. 1997, 62, 1501.

(50) Miller, J. A.; Pugh, A. W.; Ullah, G. M. Tetrahedron Lett. 2000,

41, 3265.

J. Org. Chem, Vol. 70, No. 5, 2005 1585

Dong and Paquette

SCHEME 9

smoothly. In contrast, treatment of 21 with persilylated

5-fluorouracil resulted in conversion to a 1:1 mixture of

anomers 34 and 35. Chromatographic separation proved

feasible, thereby allowing for the ultimate acquisition of

pure 36.

Spectroscopic definition of anomeric configuration in

these systems originated with 24 and its diastereomer.

For the â-anomer, strong NOESY interaction is seen

between H-3′ and H-6 (see D); in contrast, H-3′ of the

R-anomer correlates with H-1′ (see E). Another useful

of adenosine deaminase⁵⁴and purine nucleoside phos-

phorylase,⁵⁵the pursuit of analogues resistant to forming

inactive metabolites in this manner is of timely interest.

The spirocyclic architecture and carbon-sulfur glycosidic

bond under consideration here hold promise of offering

such resistance to nucleoside metabolizing enzymes. With

this goal in mind, 21 was brought separately into reaction

with N⁶-benzoyladenine and N²-acetylguanine along with

an equivalent of N,O-bis(trimethylsilyl)acetamide for

1 h prior to the addition of phenylselenenyl chloride.^2r

Three separable products were isolated in the adenine

example, and two were observed for the guanine base.

Interestingly and of great practical value, we found that

for the adenine example the two minor products iso-

merized to the major one in a few days after standing in

an NMR tube. Since the N-9-â isomers are recognized to

be thermodynamically advantaged,⁵⁶it follows that these

targeted isomers should be the major products. Conse-

quently, the reaction mixtures were incubated at 60 °C

overnight, and 37 was isolated in 89% yield (Scheme 9).

However, no significant isomerization was observed for

the guanine base, and the extent of silylation affected

the regiochemical outcome. Under the above conditions,

39 was isolated in 73% yield along with a small amount

of 38. When bis-silylated nucleobase was employed, 38

and 39 were isolated in 48% and 45% yield, respectively.

In agreement with the tentative assignments as â

isomers, the anomeric proton in 37-39 appeared as

doublets with a small coupling constant (J ) 2.2-2.6 Hz).

However, NOESY experiments failed to confirm the

stereochemical features beyond reasonable doubt. On the

diagnostic is the chemical shift of H-3′. This proton in D

appears at 4.72 ppm in CDCl₃, and is seen to be shifted

downfield due to the deshielding effect of the C-2 keto

group in the thymine moiety.^51,52In E, H-3′ exhibits a

chemical shift of 4.15 ppm. Comparable features are

apparent in 34 (4.54 ppm) and 35 (4.13 ppm).

Another empirical criterion based on anomeric proton

line shapes has been extended to 4′-thianucleosides.⁵³

Thus, the H-1′ of â-anomers often appear as an “apparent

triplet”, in contrast to the doublet of doublets nature of

H-1′ exhibited by their R counterparts. All four of the

pyrimidine 4′-thiaspironucleosides conform well to this

trend.

Last, it has been noted that the splitting patterns of

H-1′ in the 2′-deoxy-2′-phenylseleno derivatives doubly

protected with a 1,1,3,3-tetraisopropyldisiloxane-1,3-diyl

unit at the 3′- and 5′-hydroxyl groups also allow for the

assignment of anomeric configuration. For the â isomers,

either a slightly broadened singlet or a narrowly coupled

doublet (J < 3.2 Hz) is generally observed. On the other

hand, the R isomers feature a doublet with J values

larger than 9.8 Hz.

(51) (a) Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura,

S.; Sakata, S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1996, 61, 822.

(b) Yoshimura, Y.; Kitano, K.; Yamada, K.; Satoh, H.; Watanabe, M.;

Miura, S.; Sakata, S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1997, 62,

3140.

(52) (a) Okabe, M.; Sun, R.-C.; Tam, S. Y.-K.; Todaro, L. J.; Coffen,

D. L. J. Org. Chem. 1988, 53, 4780. (b) Brånalt, J.; Kvarnstro¨m, I.;

Classon, B.; Samuelsson, B. J. Org. Chem. 1996, 61, 3604.

(53) (a) Robins, M. J.; Robins, R. K. J. Am. Chem. Soc. 1963, 87,

4934. (b) Robins, M. J.; Wood, S. G.; Dalley, N. K.; Herdewijn, P.;

Balzarini, J.; De Clercq, E. J. Med. Chem. 1989, 32, 1763. (c) Ye, S.;

Rezende, M. M.; Deng, W.-P.; Herbert, B.; Daly, J. W.; Johnson, R. A.;

Kirk, K. L. J. Med. Chem. 2004, 47, 1207.

(54) Balzarini, J.; Kang, G.-J.; Dalal, M.; Herdewijn, P.; De Clercq,

E.; Broder, S.; Johns, D. B. Mol. Pharmacol. 1987, 32, 162.

(55) Johnson, M. A.; Ahluwalia, G.; Connelly, M. C.; Cooney, D. A.;

Broder, S.; Johns, D. G.; Fridland, A. J. Biol. Chem. 1988, 263, 15354.

(56) Paquette, L. A.; Kahane, A.; Seekamp, C. K. J. Org. Chem. 2004,

69, 5555.

In light of the discovery of the significant anti-HIV

activity of the purine nucleoside 2′,3′-dideoxyadenosine⁵⁴

and its known susceptibility to degradation by the action

1586 J. Org. Chem., Vol. 70, No. 5, 2005

Synthesis of 2′-Deoxy-4′-thia â-Anomeric Spirocyclic Nucleosides

SCHEME 10

other hand, assignment of the site of attachment of the

purine base (N-7 or N-9) could be confirmed by hetero-

nuclear long-range bond correlation (HMBC).^53cAs shown

involving H-1′ and H-2′R, and a comparable level of

significant interaction involving H-3′ and H-2′â.

3

in F and G, a J_C-Hinteraction is anticipated between

H-1′ and C-4 in the N-9 regioisomer, while the N-7

3

congeners should be distinguished by J_C-Hcoupling

between H-1′ and C-5.⁵⁷In actuality, the HMBC spec-

trum of 37 and 38 conformed to the expectations given

by F and G with no evidence for a correlation involving

H-1′ and C-5. Compound 39 was tentatively assigned as

the N-7 isomer without the expected H-1′/C-5 correlation

observed, and the regiochemistry was confirmed only

after the final product was obtained.

The â-configuration is not perturbed upon desilylation

with TBAF and subsequent treatment with methanolic

ammonia. UV spectral measurements have indicated that

red-shift absorptions are associated with nucleosides

where glycosylation has occurred at the 7-position of the

purine bases.⁵⁸Actually, 45 displays a UV maximum at

288 nm. In contrast, the UV maxima for 43 and 44 (λ_max

262 and 260 in CH₃OH, respectively) suggested the

possibility that the N⁹-substituted isomer was actually

in hand. However, analysis based on the ¹³C shifts of C-5

and C-8 in the nucleobase is considered to be a more

reliable indicator of regiochemistry.⁵⁹The Kjellberg-

Johansson analysis rests on the fact that C-5 in N-7

systems appears more than 5 ppm upfield from that in

With 37-39 in hand, the final steps to 43-45 were

traversed via well-established reactions (Scheme 10). For

instance, radical-mediated removal of the phenylseleno

groups^2rserved to deliver 40-42 in quantitative yield.

NOESY experiments involving these intermediates con-

vincingly established the anomeric configuration at C-1′

to be as in H-J as a consequence of a strong correlation

(57) This analysis was expected to be facilitated by the fact that

the ¹³C chemical shift of C-4 is more than 25 ppm downfield of C-5.

(58) Yoshimura, Y.; Watanabe, M.; Satoh, H.; Ashida, N.; Ijichi, K.;

Sakata, S.; Machida, H.; Matsuda, A. J. Med. Chem. 1997, 40, 2177.

(59) Kjellberg, J.; Johansson, N. G. Tetrahedron 1996, 42, 6541.

J. Org. Chem, Vol. 70, No. 5, 2005 1587

Dong and Paquette

TABLE 1. Comparison of ¹³C NMR Shifts (ppm) for

Adenosine, Guanosine, and 43-45 (DMSO-d₆Solution)

carbon

adenosine

43

guanosine

44

45

C-5

C-8

119.6

140.2

119.1

140.0

117.5

136.9

116.4

136.2

108.0

142.2

SCHEME 11

FIGURE 2. End products in the anti series.

SCHEME 12

N-9 isomers. For C-8, the reverse is true, with the signal

in N-7 derivatives being distinguished from that in N-9

isomers by being positioned further than 5 ppm down-

field. The data compiled in Table 1 for 43 and 44 are seen

to compare very closely with those of adenosine and

guanosine, respectively, thereby ruling out alternative

structural assignments. The N-7 feature of 45 was

confirmed by this comparison, with 9.5 ppm upfield for

C-5, and 5.3 ppm downfield for C-8.

Synthetic Studies in the Anti Series. To gain

broader implementation of the achievements recorded

above, we pressed on with transformations involving the

anti-configured congeners. Treatment of acetonide 14

with tert-butyllithium and HMPA supplied the 4-thi-

aglycal in 70% yield at 84% conversion (Scheme 11). This

compound exists as a solid and came qualitatively to be

regarded as less prone to degradation than the R-diol 17.

However, adoption of the identical procedure for its

protection as the TIPDS derivative gave only 41% of the

desired 47 along with 55% of an unidentified product

which proved unresponsive to glycosidation. A viable

alternative approach involving the use of silver triflate

and sym-collidine⁶⁰proved to be a key advance in ef-

ficiency (91%). These conditions were also suited to the

preparation of the highly strained DTBS congener 48.

For the purpose of assessing relative glycosidation

efficiencies, 47 and 48 were treated identically with

silylated thymine and uracil in the presence of phenyl-

selenenyl chloride (Scheme 12). Both protected diols

reacted readily at 0 °C to give 49-52. In the glycosidation

related to 51, both anomers were formed in a ratio of

14:1. The somewhat lower yields realized for the genera-

tion and reactions of 48 conspired to cause us to proceed

ahead with 47.

with an equivalent of BSA. A particularly noteworthy

finding associated with 54 is the high stereoselectivity

of its formation in good yield. This feature contrasts with

the poor anomeric distribution realized for the syn

counterpart when bis-O-TMS-5-fluorouracil was used

(1:1 ratio of 34 and 35).

Thereafter, removal of the phenylseleno groups and

unmasking of the hydroxyl substituents and nucleobases

were accomplished via routine operations to furnish the

six spirocyclic 4′-thianucleosides within the anti series

defined in Figure 2.

Overview. In conclusion, synthetic routes to enan-

tiopure spiroannulated 2′-deoxy-4′-â-thiathymidine, -uri-

dine, -5-fluorouridine, -cytidine, -adenosine, and -gua-

nosine have been developed in both the syn and anti

series. The synthetic pathway is initiated with an enan-

tiomerically pure mandelate ketal, chemo- and stereo-

selective oxidation of its double bond under modified AD

conditions, and â-elimination of the sulfide acetonide.

Electrophilic glycosidation reactions mediated by the

presence of phenylselenenyl chloride lead to incorporation

of the nucleobases. The presence of a siloxane belt across

the â-face of the glycal may facilitate installation of the

proper anomeric configuration and ultimate arrival at the

targeted 2′-deoxy-4′-thiaspironucleosides. Much has been

learned about the chemistry of spirocyclic sulfides in the

course of this investigation. We are currently developing

a program targeting RNA models having analogous

structural features. Results of this effort will be disclosed

Once the â-configurational assignment to 49 had been

confirmed by 2D NMR techniques, the four additional

nucleobases specified in Scheme 13 were incorporated

into this anti-4-thiaglycal. The mono-O-TMS-5-fluorou-

racil was generated in situ by treatment of 5-fluorouracil

(60) Ziegler, T.; Echkhardt, E.; Neumann, K.; Birault, V. Synthesis

1992, 1013.

1588 J. Org. Chem., Vol. 70, No. 5, 2005

Synthesis of 2′-Deoxy-4′-thia â-Anomeric Spirocyclic Nucleosides

SCHEME 13

(br), 1796, 1323; ¹H NMR (500 MHz, CDCl₃) δ 7.46-7.40

(m, 5 H), 5.67 (s, 1 H), 4.58 (dd, J ) 10.0, 6.2 Hz, 1 H), 4.28

(d, J ) 3.6 Hz, 1 H), 3.00 (dd, J ) 11.0, 5.6 Hz, 1 H), 2.93

(dd, J ) 11.0, 7.1 Hz, 1 H), 2.86 (br s, 1 H), 2.67 (br s, 1 H),

2.59-2.54 (m, 1 H), 2.41-2.35 (m, 1 H), 2.31-2.25 (m, 1 H),

2.02-1.96 (m, 1 H), 1.93-1.80 (m, 2 H); ¹³C NMR (75 MHz,

CDCl₃) δ 170.9, 134.7, 129.2, 128.8 (2 C), 126.1 (2 C), 118.9,

77.9, 76.1, 75.4, 66.7, 34.1, 33.2, 32.4, 18.1; ES HRMS m/z

(M + Na⁺) calcd 345.0767, obsd 345.0772; [R]²²_D+28.0 (c 1.05,

acetone).

Acetonide 12. To a stirred solution of 11 (322 mg, 1 mmol)

in 2,2-dimethoxypropane (3 mL) was added p-toluenesulfonic

acid (2 mg). The reaction mixture was refluxed for 3 h,

potassium carbonate (5 mg) was introduced, and concentration

was effected to afford a dark oil.

shortly. Biological evaluation of the nucleosides reported

herein is presently under investigation.

Experimental Section

Sulfoxide 9. A slurry of 8 (50 mg, 0.17 mmol) and 10%

NaIO₄/SiO₂(0.21 mmol/g, 1.66 g, 0.34 mmol) in a 1:1 mixture

of CH₂Cl₂and hexanes (10 mL) was stirred vigorously for

24 h at rt. The reaction mixture was filtered, and the silica

was washed with 1% MeOH/Et₂O. The combined fractions

were concentrated and subjected to flash chromatography on

silica gel (2:1 EtOAc/hexanes) to afford 9 (40.2 mg, 76%) as a

white solid: mp 125-126 °C; IR (CHCl₃, cm^-1) 1802, 1242,

1042; ¹H NMR (300 MHz, CDCl₃) δ 7.43-7.35 (m, 5 H), 6.21-

6.18 (m, 1 H), 5.86-5.82 (m, 1 H), 5.33 (s, 1 H), 4.15-4.08

(m, 1 H), 3.48-3.41 (m, 1 H), 2.70-2.56 (m, 2 H), 2.39-2.32

(m, 1 H), 2.22-2.14 (m, 1 H), 2.10-2.01 (m, 2 H); ¹³C NMR

(75 MHz, CDCl₃) δ 170.1, 133.9, 130.4, 129.3, 129.2 (2 C),

128.9, 126.2 (2 C), 119.5, 88.4, 76.2, 59.0, 35.8, 25.0, 19.2; ES

The oily residue was placed under high vacuum for 30 min,

dissolved in a 2:1 mixture of THF/H₂O (15 mL), and treated

with LiOH‚H₂O (128 mg, 3 mmol). The heterogeneous solution

was vigorously stirred for 4 h and extracted with Et₂O

(3 × 10 mL). The combined organic extracts were washed with

brine, dried, and concentrated in vacuo to afford a yellow oil

that was subjected to flash chromatography on silica gel

(7% EtOAc/hexanes) to give 12 as a faint yellow oil (219 mg,

HRMS m/z (M + Na⁺) calcd 327.0661, obsd 327.0666; [R]²²

+248 (c 0.45, acetone).

D

Sulfone 10. To an ice-cold, stirred solution of 9 (35 mg, 0.12

mmol) in CH₂Cl₂(10 mL) was added a precooled solution of

m-CPBA (19.9 mg, 0.12 mmol) in CH₂Cl₂(5 mL). The reaction

mixture was stirred for 6 h at 0 °C, quenched with saturated

NaHCO₃solution (10 mL), dried, and concentrated in vacuo

to afford an oil that was subjected to flash chromatography

on silica gel (2:1 EtOAc/hexanes). Sulfone 10 was obtained as

a colorless oil (30 mg, 81%): IR (neat, cm^-1) 1807, 1320;

¹H NMR (300 MHz, CDCl₃) δ 7.43-7.36 (m, 5 H), 6.31-6.26

(m, 1 H), 6.15-6.11 (m, 1 H), 5.44 (s, 1 H), 3.95-3.88 (m, 1

H), 3.79-3.72 (m, 1 H), 2.77-2.72 (m, 1 H), 2.67-2.59 (m, 1

H), 2.36-2.26 (m, 1 H), 2.11-1.97 (m, 3 H); ¹³C NMR (75 MHz,

CDCl₃) δ 170.1, 134.2, 131.3, 129.2, 128.9 (2 C), 126.2 (2 C),

126.0, 118.2, 76.6, 75.7, 55.3, 35.3, 29.7, 29.1, 17.6; ES HRMS

1

96%): IR (neat, cm^-1) 1723, 1207, 1050; H NMR (300 MHz,

CDCl₃) δ 5.00 (t, J ) 4.3 Hz, 1 H), 4.49 (d, J ) 5.5 Hz, 1 H),

3.04 (dd, J ) 13.1, 4.3 Hz, 1 H), 2.82 (d, J ) 13.1 Hz, 1 H),

2.65 (dd, J ) 20.0, 8.7 Hz, 1 H), 2.22-1.84 (series of m, 5 H),

1.49 (s, 3 H), 1.30 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ 211.8,

110.9, 84.7, 84.6, 67.2, 36.6, 35.2, 31.8, 26.1, 24.5, 20.6; ES

HRMS m/z (M + Na⁺) calcd 251.0712, obsd 251.0718; [R]²²

+77.8 (c 1.67, acetone).

D

Meerwein-Ponndorf-Verley Reduction of 12. A solu-

tion of 12 (110 mg, 0.5 mmol) in dry isopropyl alcohol (2.5 mL)

was treated with aluminum isopropoxide (200 mg, 1.0 mmol),

refluxed for 17 h, and distilled slowly at atmospheric pressure

until 1.5 mL of distillate had collected. The distillation flask

was evaporated to dryness and the residue was dissolved with

dry ether (5 mL). The mixture was quenched with saturated

Rochelle’s salt solution (3 mL), stirred for 30 min, and treated

with 1 N NaOH (3 mL). After extraction of the aqueous phase

with ether, the combined organic solutions were washed with

water, dried, and concentrated in vacuo to afford an oil that

was subjected to flash chromatography on silica gel (20%

EtOAc/hexanes). In total, 91.9 mg of reduction product was

obtained as a colorless oil (83% overall yield), which included

m/z (M + Na⁺) calcd 343.0611, obsd 343.0608; [R]²⁰-124

D

(c 2.86, acetone).

Dihydroxylation of 8. To a mixture consisting of DABCO

(11.2 mg, 0.1 mmol), K₂OsO₂(OH)₄(36.8 mg, 0.1 mmol), K₃-

Fe(CN)₆(988 mg, 3 mmol), K₂CO₃(415 mg, 3 mmol), MeSO₂-

NH₂(190 mg, 2 mmol), NaHCO₃(252 mg, 3 mmol), and

10 mL of t-BuOH-H₂O (l: l, 5 mL of each) was added 8 (288

mg, 1 mmol). After vigorous overnight stirring at rt, Na₂SO₃

(1.5 g) was added and stirring was maintained for 60 min. The

workup followed the standard Sharpless procedure, except that

the combined organic layers were not washed with 2 N KOH

to remove MeSO₂NH₂, in consideration of the hydrolysis of the

mandelate protecting group. The crude product was purified

by flash chromatography on silica gel (1:2 EtOAc/hexanes) to

afford 11 as a white solid, mp 123-124 °C. The yield was 77%

with 23% starting material recovered: IR (CHCl₃, cm^-1) 3427

1

syn isomer 13 (61%) and anti isomer 14 (22%) (based on H

NMR analysis).

For 13: IR (neat, cm^-1) 3451 (br), 1372, 1209; ¹H NMR (300

MHz, CDCl₃) δ 4.89 (dt, J ) 5.1, 0.9 Hz, 1 H), 4.19 (d, J ) 5.5

Hz, 1 H), 3.59 (br s, 1 H), 2.94 (dd, J ) 13.0, 4.7 Hz, 1 H), 2.75

(d, J ) 13.0 Hz, 1 H), 2.22-2.16 (m, 1 H), 1.90-1.59 (series of

J. Org. Chem, Vol. 70, No. 5, 2005 1589

Dong and Paquette

m, 5 H), 1.51 (s, 3 H), 1.30 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃)

purified by flash chromatography on silica gel (5% EtOAc/

hexanes) to furnish 18 (56% yield at 62% conversion) as a

colorless oil.

δ 110.7, 86.6, 83.7, 74.3, 73.3, 36.7, 31.7, 29.3, 26.3, 24.7, 21.0;

ES HRMS m/z (M + Na⁺) calcd 253.0869, obsd 253.0877; [R]²⁰

+139 (c 1.68, acetone).

D

Method B. DABCO (31 mg, 0.28 mmol) was dissolved in

dry THF. Silver nitrate (20 mg, 0.12 mmol) was added and

the mixture was stirred for 5 min. TBSCl (21 mg, 0.14 mmol)

was introduced and, after an additional 5 min, 17 (8 mg, 0.047

mmol) was added and the reaction mixture was stirred at rt

overnight. The cloudy white reaction mixture was worked up

as above to give 18 (40%) and 19 (49%) after chromatography

on silica gel (1% to 5% EtOAc/hexanes).

Method C. This procedure is identical to that described in

method A except that DME replaced THF and triethylamine

replaced pyridine. After the addition of silver nitrate, the

reaction mixture soon turned into black. Quenching the

reaction after 3 h afforded three products: 19 (46%), 18 (25%),

and 20 (24%). When reaction was allowed to proceed overnight,

19 was the sole product (88%).

For 14: white solid; mp 77-79 °C; IR (neat, cm^-1) 3453 (br),

1372, 1209; ¹H NMR (300 MHz, CDCl₃) δ 4.93 (dt, J ) 5.5, 1.4

Hz, 1 H), 4.84 (d, J ) 5.8 Hz, 1 H), 4.10 (t, J ) 5.8 Hz, 1 H),

2.84 (d, J ) 12.7 Hz, 1 H), 2.35-2.25 (m, 2 H), 1.84-1.58

(series of m, 5 H), 1.52 (s, 3 H), 1.34 (s, 3 H); ¹³C NMR (75

MHz, CDCl₃) δ 110.7, 84.0, 80.9, 77.2, 69.1, 37.2, 34.0, 29.7,

26.3, 24.7, 20.4; ES HRMS m/z (M + Na⁺) calcd 253.0869, obsd

253.0880; [R]²⁰+177 (c 0.32, acetone).

D

Benzoylation of 13 and 14. Benzoyl chloride (0.51 mL,

4.4 mmol) was added dropwise to a stirred solution of 13 and

14 (both epimers, 252 mg, 1.1 mmol) and a catalytic amount

of DMAP in dry pyridine (5 mL) at 0 °C. The mixture was

stirred for 24 h at rt, treated with ice-cold saturated NaHCO₃

solution (5 mL), and extracted with CHCl₃(3 × 5 mL). The

chloroform extracts were washed with water (2 mL) and brine

(2 mL), and evaporated in vacuo to afford a syrup. The syrupy

residue was evacuated overnight to remove pyridine, and the

benzoates were separated and purified by chromatography on

silica gel (5% EtOAc/hexanes). The first to elute was 16

(88 mg, 24%), followed by 15 (275 mg, 75% yield), both as

colorless oils.

For 18: IR (neat, cm^-1) 3486, 1471, 1256; ¹H NMR (500

MHz, CDCl₃) δ 6.32 (d, J_1,2) 6.1 Hz, 1 H, H-1), 5.70 (dd, J_1,2

) 6.1 and J_2,3) 2.8 Hz, 1 H, H-2), 4.49 (d, J_2,3) 2.8 Hz, 1 H,

H-3), 3.82 (br d, J_5,5-OH) 4.9 Hz, 1 H, H-5), 2.42-2.37 (m, 1

H, H-8â), 2.29 (br d, J_5,5-OH) 4.9 Hz, 1 H, 5-OH), 2.07-1.99

(m, 2 H, H-6â, H-8R), 1.88-1.80 (m, 1 H, H-7R), 1.78-1.64

(m, 2 H, H-6R, H-7â), 0.94 (s, 9 H, t-Bu), 0.13 (s, 3 H, CH₃),

0.12 (s, 3 H, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ 128.2, 126.0,

80.6, 76.3, 75.6, 31.6, 28.6, 25.8 (3 C), 20.5, 18.2, -4.0, -4.8;

EI HRMS m/z (M⁺) calcd 286.1417, obsd 286.1419; [R]¹⁸_D+182

(c 0.43, CHCl₃).

For 15: IR (neat, cm^-1) 1715, 1274; ¹H NMR (300 MHz,

CDCl₃) δ 8.06-8.03 (m, 2 H), 7.59-7.53 (m, 1 H), 7.47-7.42

(m, 2 H), 5.22 (t, J ) 5.0 Hz, 1 H), 4.92 (dt, J ) 5.4, 1.3 Hz,

1 H), 4.39 (d, J ) 5.8 Hz, 1 H), 3.09 (dd, J ) 12.9, 5.0 Hz, 1

H), 2.76 (d, J ) 11.7 Hz, 1 H), 2.36-2.16 (m, 2 H), 2.04-1.77

(series of m, 4 H), 1.53 (s, 3 H), 1.33 (s, 3 H); ¹³C NMR

(75 MHz, CDCl₃) δ 166.4, 133.5, 130.7, 130.2 (2 C), 128.9

(2 C), 111.6, 87.2, 84.3, 78.7, 70.3, 37.9, 31.3, 30.6, 26.7, 25.2,

21.2; ES HRMS m/z (M + Na⁺) calcd 357.1131, obsd 357.1138;

For 19: IR (neat, cm^-1) 1463, 1257, 1066; ¹H NMR (300

MHz, CDCl₃) δ 6.28 (dd, J ) 6.2, 1.0 Hz, 1 H), 5.47 (dd, J )

6.2, 2.5 Hz, 1 H), 4.51 (br d, J ) 1.6 Hz, 1 H), 3.87 (pseudo-t,

J ) 4.7 Hz, 1 H), 2.42-2.33 (m, 1 H), 1.96-1.55 (series of m,

5 H), 0.86 (s, 9 H), 0.83 (s, 9 H), 0.08 (s, 6 H), 0.07 (s, 3 H),

0.06 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ 129.3, 123.6, 81.6,

78.1, 74.4, 32.8, 29.5, 25.8 (6 C), 20.6, 18.1, 14.1, -4.5 (2 C),

-4.8 (2 C); EI HRMS m/z (M⁺) calcd 400.2281, obsd 400.2288;

[R]²²+110 (c 2.39, acetone).

D

For 16: IR (neat, cm^-1) 1715, 1270; ¹H NMR (300 MHz,

CDCl₃) δ 8.03-8.00 (m, 2 H), 7.69-7.64 (m, 1 H), 7.59-7.43

(m, 2 H), 5.32 (dd, J ) 6.0, 2.2 Hz, 1 H), 4.93 (t, J ) 4.6 Hz,

1 H), 4.63 (d, J ) 5.6 Hz, 1 H), 3.17 (dd, J ) 13.2, 4.6 Hz,

1 H), 2.80 (d, J ) 13.2 Hz, 1 H), 2.53-2.37 (m, 2 H), 2.01-

1.70 (series of m, 4 H), 1.53 (s, 3 H), 1.29 (s, 3 H); ¹³C NMR

(75 MHz, CDCl₃) δ 165.9, 134.4, 130.5 (2 C), 130.2, 129.1

(2 C), 110.5, 84.6, 84.0, 81.4, 69.7, 37.6, 31.6, 31.5, 26.1, 24.7,

21.2; ES HRMS m/z (M + Na⁺) calcd 357.1131, obsd 357.1133;

[R]¹⁸+80.0 (c 0.97, CHCl₃).

D

For 20: IR (neat, cm^-1) 3389, 1457, 1260; ¹H NMR (300

MHz, CDCl₃) δ 6.41 (d, J ) 6.1 Hz, 1 H), 5.69 (dd, J ) 6.1, 2.9

Hz, 1 H), 4.22 (br s, 1 H), 3.87 (dd, J ) 5.5, 3.9 Hz, 1 H), 2.38-

2.27 (m, 1 H), 2.04-1.56 (series of m, 5 H), 0.87 (s, 9 H), 0.07

(s, 3 H), 0.04 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ 132.3, 123.2,

84.9, 77.2, 74.6, 32.6, 28.6, 25.8 (3 C), 20.6, 18.3, -4.6, -4.9;

EI HRMS m/z (M⁺) calcd 286.1417, obsd 286.1419; [R]¹⁸_D+6.4

(c 0.22, CHCl₃).

[R]²⁰+9.3 (c 0.91, acetone).

D

â-Elimination of 13. To a solution of 13 (49.4 mg, 0.21

mmol) and freshly distilled HMPA (0.45 mL, 2.52 mmol) in

dry THF (3 mL) was added t-BuLi (0.89 mL, 1.4 M in pentane,

1.26 mmol) at -78 °C. An orange color was immediately

observed. After being stirred at this temperature for 4 h, the

reaction mixture was gradually warmed to 0 °C and main-

tained at this temperature for 3 h. Ether (2 mL) was added

followed by saturated aqueous NH₄Cl (1 mL) and water (1 mL).

The aqueous layer was extracted with ether (4 × 2 mL) and

the combined organic extracts were washed with brine (2 mL),

dried (Na₂SO₄) and concentrated in vacuo. The residue was

subjected to flash chromatography on silica gel (20% EtOAc/

hexanes) to give 17 as a white solid (17 mg, 49% yield at 55%

conversion): mp 77-79 °C; IR (CHCl₃, cm^-1) 3332 (br), 1300,

1022; ¹H NMR (300 MHz, d₆-benzene) δ 5.80 (d, J ) 6.1 Hz, 1

H), 5.39 (dd, J ) 6.1, 2.9 Hz, 1 H), 3.91 (d, J ) 2.9 Hz, 1 H),

3.57 (br s, 1 H), 2.30-1.40 (series of m, 6 H); ¹³C NMR

(75 MHz, d₆-benzene) δ 128.3, 127.7, 79.9, 75.7, 45.4, 31.5, 28.2,

TIPDS Protection of Glycal 17. The process described

in method A was adapted. Starting from 17 (50 mg, 0.29

mmol), TIPDSCl₂(0.11 mL, 0.35 mmol), AgNO₃(124 mg, 0.73

mmol), and pyridine (0.12 mL, 1.45 mmol), the usual workup

and flash chromatography on silica gel (1% EtOAc/hexanes)

afforded 21 (108 mg, 90%) as a white solid: mp 81-82 °C; IR

1

(CHCl₃, cm^-1) 1465, 1216, 1091; H NMR (300 MHz, CDCl₃)

δ 6.17-6.14 (m, 1 H), 5.76 (dd, J ) 6.2, 1.7 Hz, 1 H), 5.12 (br

s, 1 H), 3.99 (dd, J ) 11.1, 7.3 Hz, 1 H), 2.09-1.57 (series of

m, 6 H), 1.11-0.83 (m, 28 H); ¹³C NMR (75 MHz, CDCl₃)

δ 126.6, 123.7, 77.2, 76.1, 71.5, 29.8, 26.9, 17.5 (4 C), 17.3, 17.2,

16.8, 14.5 (4 C), 13.7, 12.9; EI HRMS m/z (M⁺) calcd 414.2075,

obsd 414.2129; [R]¹⁸-8.7 (c 0.82, CHCl₃).

D

Glycosidation Reactions of 19. Method A: PhSeCl as

Electrophile. To a stirred CH₃CN solution (1.0 mL) of 19

(10 mg, 0.025 mmol) and bis-O-trimethylsilylthymine (10.8 mg,

0.038 mmol) was added a CH₃CN solution (0.5 mL) of PhSeCl

(7.7 mg, 0.038 mmol) at 0 °C under N₂. After 1 h, the reaction

mixture was partitioned between CHCl₃and saturated NaH-

CO₃solution. Silica gel chromatography (15% EtOAc/hexanes)

of the organic layer gave 22 (53%) as a white foam, as well as

a minor isomer (13%, inseparable, based on ¹H NMR analysis,

11.3 mg total, 66% overall yield): IR (CHCl₃, cm^-1) 1681, 1463,

1253; ¹H NMR (500 MHz, CDCl₃) δ 8.14 (s, 1 H), 7.52 (d, J )

7.3 Hz, 2 H), 7.53-7.26 (m, 2 H), 7.20-7.17 (m, 2 H), 6.78

(d, J ) 10.7 Hz, 1 H), 4.35 (d, J ) 2.9 Hz, 1 H), 4.16-4.06

21.2; EI HRMS m/z (M⁺) calcd 172.0553, obsd 172.0542; [R]²²

+351 (c 1.01, CHCl₃).

D

Silylation of Glycal 17. Method A. Glycal 17 (8 mg, 0.047

mmol) was dissolved in THF and pyridine (19 µL, 0.24 mmol)

was added. Silver nitrate (20 mg, 0.12 mmol) was introduced

and stirring was maintained for 1 h at rt prior to the addition

of TBSCl (18 mg, 0.12 mmol). The next morning, the cloudy

white reaction mixture was filtered into a saturated NaHCO₃

aqueous solution. The product was extracted into CH₂Cl₂and

1590 J. Org. Chem., Vol. 70, No. 5, 2005

Synthesis of 2′-Deoxy-4′-thia â-Anomeric Spirocyclic Nucleosides

(m, 1 H), 3.91 (dd, J ) 10.7, 2.9 Hz, 1 H), 2.12-1.95 (m, 3 H),

1.69-1.53 (series of m, 6 H), 1.05 (s, 9 H), 0.97 (s, 9 H), 0.35

(s, 3 H), 0.19 (s, 3 H), 0.16 (s, 3 H), 0.12 (s, 3 H); ¹³C NMR (75

MHz, CDCl₃) δ 163.0, 150.7, 135.7, 135.2, 129.1 (2 C), 128.2

(2 C), 127.6, 110.7, 82.7, 79.0, 72.9, 63.7, 56.1, 34.4, 31.6, 26.3

(3 C), 26.2 (3 C), 18.6, 18.4, 18.3, 12.2, -2.9, -3.0, -3.8, -4.3;

HRMS m/z (M + Na⁺) calcd 689.1368, obsd 689.1429; [R]¹⁸

+1.7 (c 0.47, CHCl₃).

D

Ring-Opened Product 26. To a stirred benzene solution

(2 mL) of 22 (7.8 mg, 0.011 mmol) were added Bu₃SnH

(9.2 µL, 0.033 mmol) and Et₃B (1 M THF solution, 11.4 µL,

0.011 mmol), and the reaction mixture was stirred at rt with

O₂injected via syringe at intervals. After 2 h, the reaction

mixture was evaporated and the residue was purified by flash

chromatography on silica gel to give 26 as a yellow oil

(3.0 mg, 50% at 50% conversion): IR (neat, cm^-1) 1650, 1463,

1254; ¹H NMR (400 MHz, CDCl₃) δ 8.14 (br s, 1 H), 7.28 (d, J

) 1.1 Hz, 1 H), 7.08 (dd, J ) 14.6, 0.7 Hz, 1 H), 5.71 (dd, J )

14.6, 8.0 Hz, 1 H), 4.19 (t, J ) 7.5 Hz, 1 H), 4.12 (d, J ) 8.2

Hz, 1 H), 2.03-1.85 (series of m, 5 H), 1.68-1.54 (m, 2 H),

1.35-1.26 (m, 2 H), 0.91 (s, 9 H), 0.89 (s, 9 H), 0.11-0.05

(m, 12 H); ¹³C NMR (75 MHz, CDCl₃) δ 135.3, 125.8, 119.0,

112.0, 101.5, 98.6, 75.9, 75.1, 63.6, 32.5, 32.4, 25.9 (6 C), 19.1

(3 C), 12.5, -3.1, -3.5, -4.6, -4.7; ES HRMS m/z (M + Na⁺)

ES HRMS m/z (M + Na⁺) calcd 705.2087, obsd 705.2117; [R]¹⁸

D

+32.5 (c 0.93, CHCl₃).

Method B: Using NIS as Electrophile. The reaction was

carried out as described above except for the substitution of

NIS (8.4 mg, 0.038 mmol) as the electrophile. The usual

workup and silica gel chromatography (10% EtOAc/hexanes)

gave 23 (52%) as a pale oil and a minor isomer (13%, based

on ¹H NMR analysis, 10.5 mg total, 65% overall yield): IR

1

(CHCl₃, cm^-1) 1682, 1471, 1253; H NMR (500 MHz, CDCl₃)

δ 8.27 (s, 1 H), 7.70 (d, J ) 1.2 Hz, 1 H), 6.56 (d, J ) 10.7 Hz,

1 H), 4.77 (dd, J ) 10.7, 2.7 Hz, 1 H), 4.05-4.02 (m, 2 H),

2.09-1.97 (series of m, 6 H), 1.69-1.64 (m, 3 H), 1.04 (s, 9 H),

1.00 (s, 9 H), 0.36 (s, 3 H), 0.21 (s, 3 H), 0.20 (s, 3 H), 0.17

(s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ 163.2, 150.5, 135.7, 111.8,

82.0, 78.8, 72.3, 62.9, 34.6, 32.5, 31.0, 26.3 (3 C), 26.1 (3 C),

18.5, 18.3, 18.2, 12.5, -2.4, -2.8, -4.1, -4.3; ES HRMS m/z

(M + Na⁺) calcd 675.1575, obsd 675.1570; [R]¹⁸_D+37.9 (c 0.97,

CHCl₃).

calcd 549.2609, obsd 549.2616; [R]¹⁸+26.2 (c 0.21, CHCl₃).

D

Radical Reduction of 23. Iodonucleoside 23 (4.9 mg,

0.0075 mmol) and AIBN (0.4 mg, 0.0026 mmol) were dissolved

in dry toluene (0.5 mL) and this solution was added slowly to

a solution of Bu₃SnH (6.1 µL, 0.023 mmol) in dry toluene

(1.5 mL) being stirred under argon at 45 °C. The temperature

was gradually raised to 60 °C and stirring was maintained

for 6 h. After being cooled to rt, the reaction mixture was

diluted with a saturated solution of NH₄Cl (2 mL) and

extracted with ethyl acetate (3 × 2 mL). The combined organic

phases were washed with brine, dried, and freed of solvents.

The residue was purified by flash chromatography on silica

gel (1:4 EtOAc/hexanes) to give 27 as a white foam (0.9 mg,

22% at 25% conversion): IR (CHCl₃, cm^-1) 1682, 1470, 1257;

¹H NMR (400 MHz, CDCl₃) δ 8.00 (br s, 1 H), 7.92 (s, 1 H),

6.35 (t, J ) 7.0 Hz, 1 H), 4.12 (t, J ) 4.3 Hz, 1 H), 4.00 (t, J )

7.1 Hz, 1 H), 2.33-2.31 (m, 2 H), 2.21-2.04 (series of m, 4 H),

1.94-1.90 (m, 5 H), 0.93 (s, 9 H), 0.91 (s, 9 H), 0.12-0.07

(m, 12 H); ¹³C NMR (75 MHz, CDCl₃) δ 163.5, 150.5, 137.2,

110.7, 84.7, 77.8, 77.3, 59.2, 43.8, 32.7, 32.6, 26.0 (3 C), 25.7

(3 C), 18.8, 18.3, 18.0, 12.6, -4.0, -4.3 (2 C), -4.9; ES HRMS

Glycosidation Reactions of 21. Method A: PhSeCl as

Electrophile. The reaction was carried out according to the

procedure described for the preparation of 22 starting with

21 (11.3 mg, 0.027 mmol), bis-O-trimethylsilylthymine (11.1

mg, 0.041 mmol), and PhSeCl (7.8 mg, 0.041 mmol). The usual

workup and silica gel chromatography (20% EtOAc/hexanes)

gave 24 as a white foam (14.4 mg, 76%) and a minor isomer

(0.8 mg, 4%).

1

For 24: IR (CHCl₃, cm^-1) 1690, 1464, 1134; H NMR (500

MHz, CDCl₃) δ 7.82 (s, 1 H), 7.64 (d, J ) 6.8 Hz, 2 H), 7.31-

7.25 (m, 3 H), 7.21 (d, J ) 0.8 Hz, 1 H), 6.45 (d, J ) 3.2 Hz, 1

H), 4.78 (d, J ) 8.3 Hz, 1 H), 4.12-4.07 (m, 2 H), 2.16-2.11

(m, 2 H), 2.06-1.95 (m, 2 H), 1.88 (s, 3 H), 1.86-1.78 (m, 1

H), 1.68-1.56 (m, 1 H), 1.19-1.09 (m, 28 H); ¹³C NMR (75

MHz, CDCl₃) δ 163.4, 149.5, 136.3, 135.8, 129.2 (2 C), 128.3

(2 C), 128.1, 111.9, 72.9, 72.8, 71.3, 65.3, 53.5, 29.9, 29.5, 17.6

(2 C), 17.21 (3 C), 17.19, 17.12 (2 C), 17.09, 13.7, 13.6, 12.9,

12.7, 12.6; ES HRMS m/z (M + Na⁺) calcd 719.1880, obsd

m/z (M + Na⁺) calcd 549.2609, obsd 549.2616; [R]¹⁹+19.8

D

(c 0.64, CHCl₃).

Radical Reduction of 24. A stirred toluene solution (4 mL)

of 24 (30 mg, 0.043 mmol) was treated with Bu₃SnH (35 µL,

0.13 mmol) and Et₃B (1 M THF solution, 43 µL, 0.043 mmol)

at -78 °C, and the reaction mixture was provided with a

continuous O₂flow. After 1 h, the solvents were evaporated

and the residue was purified by flash chromatography on silica

gel (20% EtOAc/hexanes) to give 28 (24 mg, quantitative) as

719.1924; [R]¹⁸+39.3 (c 0.30, CHCl₃).

D

For the minor isomer: IR (CHCl₃, cm^-1) 1689, 1465, 1140;

¹H NMR (300 MHz, CDCl₃) δ 7.82 (br s, 1 H), 7.54-7.51 (m, 2

H), 7.26-7.14 (m, 3 H), 6.86 (d, J ) 1.1 Hz, 1 H), 6.24 (d, J )

9.9 Hz, 1 H), 4.16-4.05 (m, 2 H), 3.92 (dd, J ) 11.8, 9.9 Hz, 1

H), 2.28-2.25 (m, 1 H), 2.05-1.83 (series of m, 4 H), 1.74 (d,

1

a colorless oil: UV (MeOH) λ_max272 nm (ꢀ 24 800); H NMR

J ) 1.1 Hz, 3 H), 1.55-1.48 (m, 1 H), 1.17-1.00 (m, 28 H); ¹³

C

(300 MHz, CDCl₃) δ 8.26 (br s, 1 H), 7.69 (d, J ) 1.1 Hz, 1 H),

6.17 (dd, J ) 9.4, 1.2 Hz, 1 H), 4.44 (dd, J ) 12.6, 6.6 Hz,

1 H), 4.02 (dd, J ) 11.5, 7.3 Hz, 1 H), 2.45 (dd, J ) 12.6, 9.4

Hz, 1 H), 2.12 (ddd, J ) 12.6, 6.6, 1.2 Hz, 1 H), 1.96-1.90

(series of m, 5 H), 1.74-1.58 (m, 3 H), 1.37-1.29 (m, 1 H),

1.20-0.98 (m, 28 H); ¹³C NMR (75 MHz, CDCl₃) δ 163.1, 150.6,

136.5, 111.5, 72.1, 71.2, 70.7, 54.8, 39.0, 30.1, 28.7, 17.7 (2 C),

17.5, 17.33, 17.25 (2 C), 17.22, 17.16, 17.09, 16.7, 13.6, 12.9,

12.7, 12.4; ES HRMS m/z (M + Na⁺) calcd 563.2402, obsd

NMR (75 MHz, CDCl₃) δ 162.4, 150.0, 135.7, 134.6, 129.1

(2 C), 128.0 (2 C), 127.3, 111.7, 72.9, 71.8, 67.8, 61.6, 50.8, 29.8,

28.5, 17.7, 17.6, 17.5 (2 C), 17.4, 17.3, 17.2, 17.10, 17.06, 16.4,

14.6, 13.6, 13.1, 12.7; ES HRMS m/z (M + Na⁺) calcd 719.1880,

obsd 719.1889; [R]²²-26.1 (c 0.87, CHCl₃).

D

Method B: NIS as Electrophile. The reaction was carried

out according to the procedure described for the preparation

of 23 starting with 21 (12.8 mg, 0.031 mmol), bis-O-trimethyl-

silylthymine (12.5 mg, 0.047 mmol), and NIS (10.4 mg, 0.047

mmol). The usual workup and silica gel chromatography (15%

EtOAc/hexanes) gave 25 as a white solid (14.4 mg, 70%, along

with 12% minor isomer, 2.5 mg): mp 164-166 °C; IR (CHCl₃,

cm^-1) 1712, 1464, 1388; ¹H NMR (500 MHz, CDCl₃) δ 8.26

563.2412; [R]²²-62.3 (c 0.65, CH₃OH).

D

Completion of Spiro-2′-deoxy-4′-thiathymidine Ana-

logue Synthesis. A stirred THF solution (2 mL) of 28 (20 mg,

0.037 mmol) was treated with tetrabutylammonium fluoride

(1 M THF solution, 81 µL, 0.081 mmol) under Ar at 0 °C. After

2 h, the reaction mixture was evaporated and the residue was

chromatographed on silica gel (20% EtOH/toluene) to afford

29 (10 mg, 90%) as a white solid: mp 104-105 °C; UV (MeOH)

λ_max272 nm (ꢀ 8900); ¹H NMR (300 MHz, CD₃OD) δ 8.40

(d, J ) 1.1 Hz, 1 H), 6.46 (t, J ) 7.6 Hz, 1 H), 4.14 (t, J ) 3.7

Hz, 1 H), 4.01 (t, J ) 7.3 Hz, 1 H), 2.37 (dd, J ) 7.6, 3.9 Hz,

2 H), 2.25-2.15 (m, 1 H), 2.08-2.00 (m, 1 H), 1.96-1.87 (series

of m, 4 H), 1.68-1.58 (m, 3 H); ¹³C NMR (75 MHz, CD₃OD)

δ 168.9, 155.3, 142.6, 114.2, 81.8, 80.8, 77.8, 64.3, 46.5, 36.1,

(s, 1H, NH), 7.56 (d, J_6,CH3) 1.1 Hz, 1 H, H-6), 6.60 (d, J_1′,2′

)

2.8 Hz, 1 H, H-1′), 4.56 (dd, J_2′,3′) 7.4 and J_1′,2′) 2.8 Hz, 1 H,

H-2′), 4.06 (dd, J_5′,6′R) 11.7 and J_5′,6′â) 7.2 Hz, 1 H, H-5′),

3.94 (d, J_2′,3′) 7.4 Hz, 1 H, H-3′), 2.39-2.34 (m, 1 H, H-8′R),

2.17-2.11 (m, 1 H, H-8′â), 2.05-1.91(m, 5 H, CH₃, H-6′â,

H-7′R), 1.83-1.77 (m, 1 H, H-7′â), 1.61-1.52 (m, 1 H, H-6′R),

1.23-1.07 (m, 28 H, TIPDS); ¹³C NMR (75 MHz, CDCl₃)

δ 149.9 (2 C), 135.8, 112.3, 101.4, 73.2, 72.0, 71.4, 65.7, 45.1,

33.0, 29.8, 29.1, 17.5, 17.2 (4 C), 13.6 (4 C), 12.7 (4 C); ES

J. Org. Chem, Vol. 70, No. 5, 2005 1591

Dong and Paquette

35.9, 22.5, 15.1; ES HRMS m/z (M + Na⁺) calcd 321.0879, obsd

a white solid: 223 °C dec; UV (MeOH) λ_max278 nm (ꢀ 9500);

¹H NMR (300 MHz, CD₃OD) δ 8.55 (d, J ) 7.4 Hz, 1 H), 6.45

(t, J ) 6.9 Hz, 1 H), 5.92 (d, J ) 7.3 Hz, 1 H), 4.12 (t, J ) 4.1

Hz, 1 H), 3.98 (t, J ) 7.2 Hz, 1 H), 2.41-2.16 (m, 3 H), 2.05-

1.99 (m, 1 H), 1.95-1.86 (m, 1 H), 1.67-1.57 (m, 3 H); ¹³C NMR

(75 MHz, CD₃OD) δ 169.8, 161.3, 147.4, 98.7, 81.3, 80.5, 77.4,

65.3, 46.9, 35.9 (2 C), 22.5; ES HRMS m/z (M + Na⁺) calcd

321.0874; [R]¹⁹-9.4 (c 2.25, CH₃OH).

D

2′-Phenylseleno-4′-thiauridine Analogue 30. The reac-

tion was carried out according to the procedure described for

the preparation of 22 starting from 21 (100 mg, 0.24 mmol),

bis-O-trimethylsilyluracil (93 mg, 0.36 mmol), and PhSeCl

(70 mg, 0.36 mmol). The usual workup followed by silica gel

chromatography (20% EtOAc/hexanes) of the crude product

gave 30 as a white solid (123 mg, 75%): mp 74-75 °C; UV

306.0883, obsd 306.0898; [R]¹⁹-12.1 (c 0.90, CH₃OH).

D

2′-Phenylseleno-4′-thia-5-fluorouridine Analogues 34

and 35. The reaction was carried out according to the

procedure described for the preparation of 22 starting from

21 (100 mg, 0.24 mmol), bis-O-trimethylsilyl-5-fluoro-uracil

(100 mg, 0.36 mmol), and PhSeCl (70 mg, 0.36 mmol). The

usual workup and silica gel chromatography (10% EtOAc/

hexanes) gave â isomer 34 (70 mg, 41%) and R isomer 35

(68 mg, 70%), both as white foams.

1

(MeOH) λ_max268 nm (ꢀ 12 800); H NMR (300 MHz, CDCl₃)

δ 8.08 (br s, 1 H), 7.77 (d, J ) 8.1 Hz, 1 H), 7.66-7.63 (m, 2

H), 7.29-7.21 (m, 3 H), 6.32 (d, J ) 2.6 Hz, 1 H), 5.62 (dd, J

) 8.1, 2.3 Hz, 1 H), 4.55 (d, J ) 7.3 Hz, 1 H), 4.01, (dd, J )

11.8, 6.9 Hz, 1 H), 3.91 (dd, J ) 7.3, 2.6 Hz, 1 H), 2.15-2.10

(m, 2 H), 1.96-1.88 (m, 2 H), 1.82-1.68 (m, 1 H), 1.59-1.51

(m, 1 H), 1.13-0.88 (m, 28 H); ¹³C NMR (75 MHz, CDCl₃) δ

162.5, 149.4, 141.0, 135.9, 129.2 (2 C), 128.42 (2 C), 128.36,

102.4, 72.9, 72.2, 70.6, 65.9, 54.8, 30.4, 29.2, 17.33, 17.29

(2 C), 17.20 (2 C), 17.15, 17.11, 17.03, 16.97, 13.6, 13.5, 13.3,

12.8; ES HRMS m/z (M + Na⁺) calcd 705.1723, obsd 705.1759;

1

For 34: UV (MeOH) λ_max274 nm (ꢀ 10 600); H NMR (300

MHz, CDCl₃) δ 9.36 (br d, J ) 3.7 Hz, 1 H), 7.83 (d, J ) 6.1

Hz, 1 H), 7.67-7.64 (m, 2 H), 7.26-7.21 (m, 3 H), 6.35 (s, 1

H), 4.54 (d, J ) 7.5 Hz, 1 H), 4.07 (dd, J ) 11.6, 7.0 Hz, 1 H),

3.89 (dd, J ) 7.5, 2.5 Hz, 1 H), 2.15-2.04 (m, 2 H), 1.97-1.91

(m, 2 H), 1.82-1.72 (m, 1 H), 1.58-1.51 (m, 1 H), 1.15-0.90

(m, 28 H); ¹³C NMR (75 MHz, CDCl₃) δ 156.5 (d, J ) 26.6 Hz,

1 C), 148.4, 140.1 (d, J ) 239.0 Hz, 1 C), 136.0 (2 C), 129.2

(2 C), 128.5, 128.3, 125.0 (d, J ) 34.1 Hz, 1 C), 72.8, 72.3, 71.0,

66.2, 54.8, 30.3, 29.3, 17.36, 17.27 (2 C), 17.20, 17.16 (2 C),

17.12, 17.09, 16.98, 13.59, 13.25 (2 C), 12.77; ES HRMS m/z

(M + Na⁺) calcd 723.1629, obsd 723.1628; [R]²⁴_D+69.1 (c 1.17,

CH₃OH).

[R]²²+65.3 (c 1.03, CH₃OH).

D

2′-Deoxy-4′-thiauridine Analogue 31. Removal of the

phenylseleno group followed the procedure for preparing 28

starting from 30 (86 mg, 0.13 mmol), Bu₃SnH (0.10 mL, 0.39

mmol) and Et₃B (1 M THF solution, 0.13 mL, 0.13 mmol) in

toluene (12 mL). After purification of the crude product by flash

chromatography on silica gel (20% EtOAc/hexanes), the result-

ant 2′-deoxy derivative was desilylated according to the

procedure for preparing 29 by treatment with TBAF (1 M THF

solution, 0.28 mL, 0.28 mmol) in THF (3 mL). Finally,

chromatography on silica gel (20% EtOH/toluene) furnished

31 (32.5 mg, 91%) as a white solid: mp 166-167 °C; UV

1

For 35: UV (MeOH) λ_max274 nm (ꢀ 10000); H NMR (300

MHz, CDCl₃) δ 8.91 (br s, 1 H), 7.55-7.52 (m, 2 H), 7.28-7.17

(m, 4 H), 6.28 (dd, J ) 9.8, 1.5 Hz, 1 H), 4.15-4.05 (m, 2 H),

3.82 (dd, J ) 11.7, 9.8 Hz, 1 H), 2.30-2.26 (m, 1 H), 1.99-

1.73 (series of m, 4 H), 1.54-1.47 (m, 1 H), 1.17-0.97 (m, 28

H); ¹³C NMR (75 MHz, CDCl₃) δ 156.0 (d, J ) 26.8 Hz, 1 C),

148.8, 140.4 (d, J ) 238.8 Hz, 1 C), 134.49, 134.42, 129.29,

129.25, 128.2, 127.1, 124.1 (d, J ) 33.1 Hz, 1 C), 72.8, 71.8,

68.0, 62.1, 51.0, 30.9, 29.8, 17.7, 17.48, 17.44, 17.33, 17.23,

17.11, 17.06, 16.98, 16.3, 14.6, 13.5, 13.1, 12.7; ES HRMS m/z

(M + Na⁺) calcd 723.1629, obsd 723.1626; [R]²⁴_D-23.2 (c 1.30,

CH₃OH).

1

(MeOH) λ_max266 nm (ꢀ 7500) and 236 nm (ꢀ 2300); H NMR

(300 MHz, CD₃OD) δ 8.56 (d, J ) 8.1 Hz, 1 H), 6.44 (t, J ) 7.4

Hz, 1 H), 5.71 (d, J ) 8.1 Hz, 1 H), 4.13 (t, J ) 3.7 Hz, 1 H),

3.99 (t, J ) 7.2 Hz, 1 H), 2.39-2.34 (m, 2 H), 2.25-2.15 (m, 1

H), 2.04-1.87 (m, 2 H), 1.65-1.52 (m, 3 H); ¹³C NMR (75 MHz,

CD₃OD) δ 168.7, 155.1, 146.9, 105.2, 81.8, 80.7, 77.9, 64.6, 46.5,

36.0, 35.9, 22.4; ES HRMS m/z (M + Na⁺) calcd 307.0723, obsd

307.0729; [R]¹⁹-5.4 (c 1.68, CH₃OH).

D

2′-Phenylseleno-4′-thiacytidine Analogue 32. The reac-

tion was carried out according to the procedure described for

the preparation of 22 starting from 21 (100 mg, 0.24 mmol),

1-O-trimethylsilyl-N⁴-acetylcytosine (82 mg, 0.36 mmol), and

PhSeCl (70 mg, 0.36 mmol). The usual workup followed by

silica gel chromatography (50% EtOAc/hexanes) of the crude

product gave 32 as a white foam (92 mg, 53%): UV (MeOH)

2′-Deoxy-4′-thia-5-fluorouridine Analogue 36. Removal

of the phenylseleno group followed the procedure for preparing

28 starting from 34 (70 mg, 0.10 mmol), Bu₃SnH (0.08 mL,

0.30 mmol) and Et₃B (1 M THF solution, 0.10 mL, 0.10 mmol)

in toluene (10 mL). After purification by flash chromatography

on silica gel (20% EtOAc/hexanes) the resultant 2′-deoxy

derivative was desilylated according to the procedure for

preparing 29 by treatment with TBAF (1 M THF solution,

0.24 mL, 0.24 mmol) in THF (3 mL). Finally, the reaction

mixture was chromatographed on silica gel (15% EtOH/

toluene) to afford 36 (28 mg, 94%) as a colorless syrup: UV

(MeOH) λ_max274 nm (ꢀ 7100); ¹H NMR (300 MHz, CD₃OD)

δ 8.85 (d, J ) 7.3 Hz, 1 H), 6.44 (dt, J ) 7.5, 1.5 Hz, 1 H), 4.13

(t, J ) 3.6 Hz, 1 H), 4.01 (t, J ) 7.5 Hz, 1 H), 2.40-2.32 (m, 2

H), 2.25-2.14 (m, 1 H), 2.04-1.87 (m, 2 H), 1.68-1.57 (m, 3

H); ¹³C NMR (75 MHz, CD₃OD) δ 161.9 (d, J ) 26.6 Hz, 1 C),

153.8, 144.0 (d, J ) 231.2 Hz, 1 C), 130.7 (d, J ) 35.1 Hz,

1 C), 82.1, 80.7, 77.9, 65.2, 46.5, 36.1, 35.9, 22.4; ES HRMS

1

λ_max302 (ꢀ 6600) and 250 nm (ꢀ 14 100); H NMR (300 MHz,

CDCl₃) δ 10.58 (br s, 1 H), 8.44 (d, J ) 7.5 Hz, 1 H), 7.71-

7.68 (m, 2 H), 7.34 (d, J ) 7.5 Hz, 1 H), 7.23-7.16 (m, 3 H),

6.32 (s, 1 H), 4.41 (d, J ) 6.2 Hz, 1 H), 3.98 (dd, J ) 11.5, 7.1

Hz, 1 H), 3.84 (d, J ) 6.2 Hz, 1 H), 2.21-2.09 (series of m, 5

H), 1.93-1.86 (m, 2 H), 1.80-1.74 (m, 1 H), 1.62-1.52 (m, 1

H), 1.19-0.77 (m, 28 H); ¹³C NMR (75 MHz, CDCl₃) δ 171.6,

162.9, 154.9, 146.2, 135.8 (2 C), 129.5, 129.0 (2 C), 128.2, 96.6,

73.0, 71.6, 70.1, 67.7, 56.0, 31.2, 29.0, 24.8, 17.44, 17.35, 17.29,

17.18 (2 C), 17.14, 17.10, 16.9, 16.8, 13.8, 13.6, 13.3, 12.7; ES

HRMS m/z (M + Na⁺) calcd 746.1989, obsd 746.1990; [R]²²

+20.1 (c 0.72, CH₃OH).

D

m/z (M + Na⁺) calcd 325.0629, obsd 325.0631; [R]¹⁹+3.6

D

2′-Deoxy-4′-thiacytidine Analogue 33. Removal of the

phenylseleno group followed the procedure for preparing 28

starting from 32 (92 mg, 0.13 mmol), Bu₃SnH (0.11 mL, 0.39

mmol) and Et₃B (1 M THF solution, 0.13 mL, 0.13 mmol) in

toluene (13 mL). After purification by flash chromatography

on silica gel (50% EtOAc/hexanes), the resultant 2′-deoxy

derivative was desilylated according to the procedure for

preparing 29 by treatment with TBAF (1 M THF solution, 0.27

mL, 0.27 mmol) in THF (3 mL). The reaction mixture was

stirred for 3 h, evaporated to dryness, and placed under high

vacuum for 30 min. Methanolic ammonia (5 mL) was added,

and the mixture was kept at rt for 5 h prior to chromatography

on silica gel (30% EtOH/toluene) to afford 33 (35 mg, 97%) as

(c 1.12, CH₃OH).

Adenosine Analogue 37. The reaction was carried out

according to the procedure described for the preparation of 22

starting from 21 (100 mg, 0.24 mmol), monosilylated

N⁶-benzoyladenine, which was prepared from addition of BSA

(89 µL, 0.36 mmol) to N⁶-benzoyladenine (87 mg, 0.36 mmol)

and stirring for 1 h, and PhSeCl (70 mg, 0.36 mmol). The

reaction mixture was kept at 0 °C for 1 h, then incubated at

60 °C overnight. The usual workup and silica gel chromatog-

raphy (20-40% EtOAc/hexanes) gave 37 as a colorless syrup

(173 mg, 89%): UV (MeOH) λ_max266 nm (ꢀ 18 500) and 226

1

nm (ꢀ 35 600); H NMR (500 MHz, CDCl₃) δ 9.06 (br s, 1 H),

1592 J. Org. Chem., Vol. 70, No. 5, 2005

Synthesis of 2′-Deoxy-4′-thia â-Anomeric Spirocyclic Nucleosides

8.63 (s, 1 H), 8.02 (d, J ) 4.4 Hz, 2 H), 7.79 (s, 1 H), 7.62-7.59

(m, 1 H), 7.54-7.51 (m, 4 H), 7.22-7.19 (m, 1 H), 7.13-7.10

(m, 2 H), 6.39 (d, J ) 2.6 Hz, 1 H), 5.22 (d, J ) 7.7 Hz, 1 H),

4.60 (dd, J ) 7.7, 2.6 Hz, 1 H), 4.12 (dd, J ) 11.7, 7.3 Hz, 1

H), 2.28-2.18 (m, 2 H), 2.07-1.93 (m, 2 H), 1.86-1.74 (m, 1

H), 1.62-1.52 (m, 1 H), 1.20-0.91 (m, 28 H); ¹³C NMR (75

MHz, CDCl₃) δ 164.8, 152.3, 151.1, 149.4, 141.8, 135.7 (2 C),

133.6, 132.7, 129.2 (2 C), 128.8 (2 C), 128.4, 127.9 (2 C), 127.8,

123.3, 72.9, 72.8, 71.7, 63.6, 52.9, 30.3, 29.5, 17.4, 17.30, 17.25

(3 C), 17.20 (2 C), 17.15, 17.06, 13.5 (2 C), 13.0, 12.8; ES HRMS

mp 261-263 °C; UV (MeOH) λ_max286 (ꢀ 16 500) and 264 nm

(ꢀ 22 900); ¹H NMR (300 MHz, CDCl₃) δ 12.16 (br s, 1 H), 9.61

(br s, 1 H), 8.19 (s, 1 H), 5.84 (d, J ) 7.8 Hz, 1 H), 4.49 (dd, J

) 12.5, 5.7 Hz, 1 H), 4.03 (dd, J ) 11.5, 7.3 Hz, 1 H), 2.58-

2.49 (m, 1 H), 2.37-2.27 (m, 4 H), 2.01-1.53 (series of m,

6 H), 1.12-0.85 (m, 28 H); ¹³C NMR (75 MHz, CD₃OD) δ 172.0,

155.9, 148.2, 147.4, 137.8, 121.4, 72.0, 70.5, 70.0, 53.0, 40.0,

30.1, 28.8, 24.5, 17.5, 17.4, 17.3, 17.2, 17.17, 17.14, 17.09, 17.06,

16.7, 13.6, 13.5, 13.2, 12.6; ES HRMS m/z (M + Na⁺) calcd

630.2572, obsd 630.2555; [R]¹⁹-32.5 (c 0.08, CH₃OH).

D

m/z (M + Na⁺) calcd 832.2258, obsd 832.2269; [R]¹⁹+16.6

D

Tin Hydride Reduction of Guanosine Analogue 39.

Removal of the phenylseleno group followed the procedure for

preparing 28 starting from 39 (37 mg, 0.048 mmol), Bu₃SnH

(39 µL, 0.14 mmol) and Et₃B (1 M THF solution, 48 µL, 0.048

mmol) in toluene (5 mL). After purification by flash chroma-

tography on silica gel (75% EtOAc/hexanes), 42 was obtained

as a colorless syrup (27 mg, quant): UV (MeOH) λ_max268

(ꢀ 12 200) and 224 nm (ꢀ 21 600); ¹H NMR (500 MHz, CDCl₃)

δ 12.36 (br s, 1H), 10.94 (br s, 1 H), 8.56 (s, 1 H), 6.39 (d, J )

7.2 Hz, 1 H), 4.37 (dd, J ) 12.7, 5.3 Hz, 1 H), 4.06 (dd, J )

11.6, 7.2 Hz, 1 H), 2.67-2.62 (m, 1 H), 2.40-2.36 (m, 4 H),

2.07-1.58 (series of m, 6 H), 1.33-0.88 (m, 28 H); ¹³C NMR

(75 MHz, CD₃OD) δ 173.4, 157.3, 153.2, 148.4, 142.4, 112.1,

72.0, 69.7, 69.6, 56.8, 41.2, 30.0, 28.9, 24.6, 17.44, 17.40, 17.30,

17.25, 17.19, 17.11, 17.02, 16.99, 16.65, 13.6, 13.5, 13.3, 12.5;

(c 0.99, CH₃OH).

Guanosine Analogues 38 and 39. The reaction was

carried out according to the procedure described for the

preparation of 22 starting from 21 (93 mg, 0.22 mmol), bis-

silylated N²-acetylguanine, which was prepared from addition

of BSA (0.18 mL, 0.36 mmol) to N²-acetylguanine (70 mg, 0.36

mmol) and stirring for 1 h, and PhSeCl (70 mg, 0.36 mmol).

The reaction mixture was kept at 0 °C for 1 h, then raised to

rt overnight. The usual workup and silica gel chromatography

(50% EtOAc/hexanes to 10% CH₃OH/EtOAc) gave 38 (82 mg,

48%) and 39 (77 mg, 45%).

For 38: colorless syrup; UV (MeOH) λ_max268 (ꢀ 22 400); ¹H

NMR (300 MHz, CDCl₃) δ 11.85 (br s, 1 H), 8.13 (br s, 1 H),

8.00 (s, 1 H), 7.55-7.52 (m, 2 H), 7.23-7.14 (m, 3 H), 6.06

(d, J ) 2.2 Hz, 1 H), 4.76 (d, J ) 7.1 Hz, 1 H), 4.16 (dd, J )

7.1, 2.2 Hz, 1 H), 4.04 (dd, J ) 11.7, 7.1 Hz, 1 H), 2.28 (s, 3 H),

2.18-1.53 (series of m, 6 H), 1.21-0.90 (m, 28 H); ¹³C NMR

(75 MHz, CDCl₃) δ 171.0, 155.6, 146.5 (2 C), 137.8, 135.7,

130.9, 128.9 (2 C), 127.7 (2 C), 121.4, 72.8, 72.1, 70.5, 62.9,

55.3, 30.3, 29.4, 24.5, 17.39, 17.37, 17.28, 17.20, 17.15, 17.11,

17.04, 16.99, 13.6, 13.5, 13.2, 12.7; ES HRMS m/z (M + Na⁺)

ES HRMS m/z (M + Na⁺) calcd 630.2572, obsd 630.2598; [R]¹⁹

+62.1 (c 0.34, CH₃OH).

D

Adenosine Analogue 43. A 126 mg (0.19 mmol) sample

of 40 was desilylated according to the procedure described for

the preparation of 29 by treatment with TBAF (1 M THF

solution, 0.42 mL, 0.42 mmol) in THF (4 mL). The reaction

mixture was stirred for 4 h, evaporated to dryness, and placed

under high vacuum for 30 min. Methanolic ammonia (9 mL)

was added to the residue, and the mixture was kept at rt

overnight prior to chromatography on silica gel (20% EtOH/

toluene) to afford 43 (57 mg, 97%) as a white solid: mp 214

°C dec; UV (MeOH) λ_max262 nm (ꢀ 12 900); ¹H NMR (400 MHz,

DMSO-d₆) δ 8.53 (s, 1 H), 8.13 (s, 1 H), 7.26 (s, 2 H), 6.25 (t,

J ) 6.8 Hz, 1 H), 5.31 (d, J ) 4.8 Hz, 1 H), 5.29 (d, J ) 5.6 Hz,

1 H), 4.13 (br dd, J ) 8.6, 4.2 Hz, 1 H), 3.93 (dd, J ) 12.4, 6.8

Hz, 1 H), 2.63-2.57 (m, 1 H), 2.46-2.40 (m, 1 H), 2.21-2.14

(m, 1 H), 1.96-1.93 (m, 1 H), 1.79-1.71 (m, 1 H), 1.57-1.43

(m, 3 H); ¹³C NMR (75 MHz, DMSO-d₆) δ 156.2, 152.4, 149.2,

140.0, 119.1, 76.2, 75.9, 74.1, 57.8, 43.7, 32.6, 31.9, 19.3; ES

calcd 786.2050, obsd 786.2063; [R]¹⁹+96.8 (c 0.80, CH₃OH).

D

For 39: white solid, mp 230-231 °C dec; UV (MeOH) λ_max

270 (ꢀ 19 300) and 220 nm (ꢀ 32 300); ¹H NMR (500 MHz,

CDCl₃) δ 12.19 (br s, 1 H), 11.19 (br s, 1 H), 8.07 (s, 1 H), 7.62-

7.60 (m, 2 H), 7.19-7.12 (m, 3 H), 6.71 (d, J ) 2.5 Hz, 1 H),

4.92 (d, J ) 7.1 Hz, 1 H), 4.24 (dd, J ) 7.1, 2.5 Hz, 1 H), 4.08

(dd, J ) 11.7, 7.2 Hz, 1 H), 2.38 (s, 3 H), 2.23-2.20 (m, 2 H),

1.99-1.91 (m, 2 H), 1.81-1.73 (m, 1 H), 1.62-1.54 (m, 1 H),

1.19-0.91 (m, 28 H); ¹³C NMR (75 MHz, CDCl₃) δ 173.2, 156.6,

152.4, 148.2, 142.2, 135.8 (2 C), 129.0 (2 C), 128.6, 128.1, 111.7,

73.0, 72.1, 70.6, 65.8, 55.4, 30.3, 29.3, 24.6, 17.38, 17.31 (2 C),

17.25 (2 C), 17.19, 17.15, 17.0, 16.9, 13.6, 13.4, 13.3, 12.8; ES

HRMS m/z (M + Na⁺) calcd 330.0995, obsd 330.1002; [R]¹⁹

-18.1 (c 0.16, CH₃OH).

HRMS m/z (M + Na⁺) calcd 786.2050, obsd 786.2022; [R]¹⁹

+258 (c 0.06, CH₃OH).

D

Guanosine Analogue 44. A 51 mg (0.084 mmol) sample

of 41 was desilylated according to the procedure described for

the preparation of 29 by treatment with TBAF (1 M THF

solution, 0.24 mL, 0.24 mmol) in THF (3 mL). The reaction

mixture was stirred for 4 h, evaporated to dryness, and placed

under high vacuum for 30 min. Methanolic ammonia (7 mL)

was added to the residue, and the mixture was kept at rt

overnight prior to chromatography on silica gel (30% EtOH/

toluene) to afford 44 (26 mg, 96%) as a white solid: mp 245-

247 °C; UV (MeOH) λ_max260 nm (ꢀ 7300); ¹H NMR (400 MHz,

DMSO-d₆) δ 10.72 (br s, 1 H), 8.16 (s, 1 H), 6.57 (br s, 2 H),

6.00 (t, J ) 6.8 Hz, 1 H), 5.31 (br s, 1 H), 5.16 (d, J ) 5.2 Hz,

1 H), 4.10 (br s, 1 H), 3.91 (d, J ) 5.2 Hz, 1 H), 2.48-2.45

(m, 1 H), 2.38-2.32 (m, 1 H), 2.18-2.11 (m, 1 H), 1.93-1.88

(m, 1 H), 1.78-1.72 (m, 1 H), 1.54-1.50 (m, 3 H); ¹³C NMR

(75 MHz, DMSO-d₆) δ 156.8, 153.8, 150.9, 136.2, 116.4, 76.0,

75.8, 73.7, 56.8, 43.9, 32.4, 31.9, 19.0; ES HRMS m/z (M +

Tin Hydride Reduction of Adenosine Analogue 37.

Removal of the phenylseleno group followed the procedure for

preparing 28 starting from 37 (46 mg, 0.057 mmol), Bu₃SnH

(46 µL, 0.17 mmol) and Et₃B (1 M THF solution, 57 µL, 0.057

mmol) in toluene (6 mL). After purification by flash chroma-

tography on silica gel (50% EtOAc/hexanes), 40 was obtained

as a colorless syrup (37 mg, quant): UV (MeOH) λ_max282

(ꢀ 20 200) and 234 nm (ꢀ 14 300); ¹H NMR (500 MHz, CDCl₃)

δ 9.15 (br s, 1 H), 8.81 (s, 1 H), 8.51 (s, 1 H), 8.06 (d, J ) 7.4

Hz, 2 H), 7.63 (t, J ) 7.4 Hz, 1 H), 7.55 (d, J ) 7.4 Hz, 1 H),

6.24 (d, J ) 8.2 Hz, 1 H), 4.71 (dd, J ) 12.4, 6.1 Hz, 1 H), 4.11

(dd, J ) 11.6, 7.3 Hz, 1 H), 2.68-2.60 (m, 1 H), 2.53-2.48

(m, 1 H), 2.11-1.59 (series of m, 6 H), 1.18-0.93 (m, 28 H);

¹³C NMR (75 MHz, CDCl₃) δ 164.7, 152.5, 151.6, 149.5, 142.0,

133.6, 132.8, 128.8 (2 C), 127.9 (2 C), 123.5, 72.0, 70.9, 70.4,

53.3, 39.6, 30.2, 28.8, 17.52, 17.49, 17.33, 17.25 (2 C), 17.21,

17.1 (2 C), 16.7, 13.6, 13.5, 13.1, 12.6; ES HRMS m/z (M +

Na⁺) calcd 676.2779, obsd 676.2762; [R]¹⁹_D-50.2 (c 0.60, CH₃-

OH).

Na⁺) calcd 346.0944, obsd 346.0951; [R]²⁰-3.1 (c 0.13, CH₃-

D

OH).

Tin Hydride Reduction of Guanosine Analogue 38.

Removal of the phenylseleno group followed the procedure for

preparing 28 starting from 38 (82 mg, 0.11 mmol), Bu₃SnH

(0.10 mL, 0.37 mmol) and Et₃B (1 M THF solution, 0.12 mL,

0.12 mmol) in toluene (12 mL). After purification by flash

chromatography on silica gel (75% EtOAc/hexanes to 10% CH₃-

OH/EtOAc), 41 was obtained as a white solid (65 mg, quant):

Guanosine Analogue 45. A 18 mg (0.030 mmol) sample

of 42 was desilylated according to the procedure described for

the preparation of 29 by treatment with TBAF (1 M THF

solution, 0.07 mL, 0.07 mmol) in THF (1 mL). The reaction

mixture was stirred for 4 h, evaporated to dryness, and placed

under high vacuum for 30 min. Methanolic ammonia (2 mL)

was added to the residue, and the mixture was kept at rt

J. Org. Chem, Vol. 70, No. 5, 2005 1593

Dong and Paquette

overnight prior to chromatography on silica gel (230% EtOH/

toluene) to afford 45 (18 mg, 72%) as a white solid: mp 246-

247 °C; UV (MeOH) λ_max288 nm (ꢀ 5400) and 252 nm (ꢀ 5100);

¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (br s, 1 H), 8.51 (s, 1

H), 6.35 (t, J ) 6.2 Hz, 1 H), 6.28 (br s, 2 H), 5.31 (br s, 1 H),

5.13 (d, J ) 4.6 Hz, 1 H), 4.06 (br s, 1 H), 3.89 (d, J ) 4.6 Hz,

1 H), 2.48-2.37 (m, 2 H), 2.18-2.11 (m, 1 H), 1.94-1.88 (m, 1

H), 1.76-1.69 (m, 1 H), 1.63-1.41 (m, 3 H); ¹³C NMR (75 MHz,

DMSO-d₆) δ 160.1, 154.7, 152.9, 142.2, 108.0, 75.5, 75.0, 73.2,

59.8, 44.6, 32.3, 31.7, 19.1; ES HRMS m/z (M + Na⁺) calcd

Glycosidation of 47 To Form 50. The reaction was carried

out according to the procedure described for the preparation

of 22 starting from 47 (80 mg, 0.19 mmol), bis-O-trimethyl-

silyluracil (78 mg, 0.29 mmol), and PhSeCl (56 mg, 0.29 mmol).

The usual workup and silica gel chromatography (20% EtOAc/

hexanes) gave 50 as a colorless syrup (105 mg, 80%): UV

1

(MeOH) λ_max266 nm (ꢀ 25 600); H NMR (300 MHz, CDCl₃)

δ 8.80 (br s, 1 H), 7.72-7.69 (m, 2 H), 7.65 (d, J ) 8.1 Hz, 1

H), 7.33-7.26 (m, 3 H), 5.87 (d, J ) 1.7 Hz, 1 H), 5.60 (dd, J

) 8.1, 2.0 Hz, 1 H), 4.86 (d, J ) 6.2 Hz, 1 H), 4.46 (br s, 1 H),

4.14 (dd, J ) 6.2, 1.7 Hz, 1 H), 2.78-2.70 (m, 1 H), 2.19-2.14

(m, 1 H), 1.96-1.67 (series of m, 4 H), 1.14-0.82 (m, 28 H);

¹³C NMR (75 MHz, CDCl₃) δ 162.9, 149.6, 141.1, 136.3 (2 C),

129.2 (2 C), 128.5, 128.1, 101.5, 83.6, 74.4, 69.1, 67.1, 59.2,

34.4, 32.2, 20.4, 17.7, 17.6, 17.5, 17.3, 17.1 (2 C), 17.0, 13.6,

13.4, 13.3, 13.0; ES HRMS m/z (M + Na⁺) calcd 705.1723, obsd

346.0944, obsd 346.0955; [R]¹⁸+42.0 (c 0.10, CH₃OH).

D

â-Elimination of 14. The reaction was carried out accord-

ing to the procedure described for the preparation of 17

starting from 14 (434 mg, 1.89 mmol), HMPA (3.94 mL, 22.7

mmol) and t-BuLi (1.4 M in pentane, 8.0 mL, 11.3 mmol).

Comparable workup followed by silica gel chromatography

(20% EtOAc/hexanes) afforded 46 as a white solid (226 mg,

705.1743; [R]¹⁹+23.1 (c 0.59, CH₃OH).

D

Glycosidation of 48 To Form 51. The reaction was carried

out according to the procedure described for the preparation

of 22 starting from 48 (20 mg, 0.06 mmol), thymine (12 mg,

0.09 mmol), BSA (50 µL, 0.19 mmol) and PhSeCl (27 mg, 0.13

mmol). The usual workup and silica gel chromatography (20%

EtOAc/hexanes) gave 51 (24 mg, 63%) consisting of an ano-

meric ratio of 14:1.

70% yield at 84% conversion): mp 97-98 °C; IR (CHCl₃, cm^-1

)

3270 (br), 1453, 1307; ¹H NMR (300 MHz, CDCl₃) δ 6.41 (d, J

) 6.1 Hz, 1 H), 5.81 (dd, J ) 6.1, 2.9 Hz, 1 H), 4.93 (d, J ) 2.9

Hz, 1 H), 4.06 (dd, J ) 5.7, 2.7 Hz, 1 H), 2.51-2.43 (m, 1 H),

2.29-2.17 (m, 1 H), 2.01-1.59 (series of m, 4 H); ¹³C NMR (75

MHz, CDCl₃) δ 130.1, 125.0, 80.8, 78.1, 73.6, 33.5, 28.9, 21.0;

EI HRMS m/z (M⁺) calcd 172.0553, obsd 172.0542; [R]²⁰_D+217

(c 1.06, CHCl₃).

For â-isomer 51: white solid, mp 106-107 °C; UV (MeOH)

λ_max274 nm (ꢀ 11 600); ¹H NMR (300 MHz, CDCl₃) δ 8.11

(br s, 1 H), 7.65-7.62 (m, 2 H), 7.33-7.21 (m, 3 H), 6.89 (d, J

) 1.1 Hz, 1 H), 6.15 (d, J ) 3.4 Hz, 1 H), 5.34 (d, J ) 8.0 Hz,

1 H), 4.63 (d, J ) 3.6 Hz, 1 H), 4.26 (dd, J ) 8.0, 3.4 Hz, 1 H),

2.88-2.80 (m, 1 H), 2.07-1.94 (m, 3 H), 1.89-1.83 (series of

m, 4 H), 1.76-1.68 (m, 1 H), 1.16 (s, 9 H), 1.08 (s, 9 H); ¹³C

NMR (75 MHz, CDCl₃) δ 162.9, 149.2, 136.9, 135.1, 129.3

(2 C), 129.2 (2 C), 128.6, 111.6, 84.9, 77.2, 67.3, 67.1, 52.4, 34.3,

31.5, 28.8 (3 C), 27.4 (3 C), 23.4, 21.5, 20.7, 12.6; ES HRMS

TIPDS Protection of 46. TIPDSCl₂(0.70 mL, 2.2 mmol)

was added at rt to a stirred suspension of 46 (189 mg, 1.1

mmol), AgOTf (1.4 g, 5.5 mmol) and 2,4,6-collidine (0.58 mL,

4.4) in DMF (20 mL), and stirring was continued for 3 h. The

yellowish pink reaction mixture was poured into H₂O and

extracted with CH₂Cl₂. The combined organic layers were

washed with aq. NaHCO₃, dried, filtered and concentrated.

The residue was chromatographed on silica gel (1% EtOAc/

hexanes) to give 47 (411 mg, 91%) as a colorless oil; IR (CHCl₃,

cm^-1) 1464, 1087, 1023; ¹H NMR (300 MHz, CDCl₃) δ 6.11 (dd,

J ) 5.8, 2.1 Hz, 1 H), 5.52-5.44 (m, 2 H), 4.57 (br s, 1 H),

2.66-2.59 (m, 1 H), 2.04-1.68 (series of m, 5 H), 1.16-0.85

(m, 28 H); ¹³C NMR (75 MHz, CDCl₃) δ 127.5, 123.3, 81.5, 80.0,

74.4, 34.6, 29.2, 19.3, 17.8, 17.7, 17.6, 17.5, 17.36, 17.3, 17.2,

17.0, 14.4, 13.6, 13.4, 12.8; ES HRMS m/z (M + Na⁺) calcd

m/z (M + Na⁺) calcd 617.1379, obsd 617.1352; [R]²¹+3.0

D

(c 1.50, CH₃OH).

For the R-isomer: yellow foam; IR (CHCl₃, cm^-1) 3392, 3190,

1682, 1476; ¹H NMR (300 MHz, CDCl₃) δ 8.89 (br s, 1 H), 7.65-

7.62 (m, 2 H), 7.32-7.17 (m, 3 H), 6.97 (d, J ) 1.1 Hz, 1 H),

6.34 (d, J ) 10.2 Hz, 1 H), 4.58 (d, J ) 11.6 Hz, 1 H), 4.49

(d, J ) 3.3 Hz, 1 H), 3.63 (dd, J ) 11.6, 10.2 Hz, 1 H), 2.88-

2.79 (m, 1 H), 2.04-1.62 (series of m, 8 H), 1.18 (s, 9 H), 1.08

(s, 9 H); ¹³C NMR (75 MHz, CDCl₃) δ 163.0, 150.6, 135.7, 135.4,

129.3 (2 C), 129.0 (2 C), 126.6, 112.3, 84.9, 77.8, 63.7, 60.7,

50.7, 34.6, 32.6, 28.9 (3 C), 27.3 (3 C), 23.3, 20.7, 20.4, 12.8;

437.1972, obsd 437.2003; [R]¹⁹+13.3 (c 1.47, CHCl₃).

D

DTBS Protection of 46. The reaction was carried out

according to the procedure described for the preparation of 47

starting from 46 (37 mg, 0.22 mmol), DTBSCl₂(0.09 mL, 0.44

mmol), AgOTf (276 mg, 1.1 mmol) and 2,4,6-collidine (0.11 mL,

0.88 mmol) in DMF (4 mL). The same workup and flash

chromatography on silica gel (1% EtOAc/hexanes) afforded 48

(48.5 mg, 77%) as a colorless oil: IR (CHCl₃, cm^-1) 1641, 1476,

ES HRMS m/z (M + Na⁺) calcd 617.1379, obsd 617.1391; [R]¹⁹

+20.1 (c 1.99, CHCl₃).

D

Glycosidation of 48 To Form 52. The reaction was carried

out according to the procedure described for the preparation

of 22 starting from 48 (35.5 mg, 0.11 mmol), bis-O-trimethyl-

silyluracil (44 mg, 0.17 mmol), and PhSeCl (33 mg, 0.17 mmol).

The usual workup and silica gel chromatography (25% EtOAc/

hexanes) gave 52 as a yellow foam (47 mg, 71%): UV (MeOH)

λ_max268 nm (ꢀ 8400); ¹H NMR (300 MHz, CDCl₃) δ 9.07 (br s,

1 H), 7.64-7.61 (m, 2 H), 7.26-7.21 (m, 4 H), 6.25 (d, J ) 3.4

Hz, 1 H), 5.68 (d, J ) 8.0 Hz, 1 H), 5.29 (d, J ) 7.9 Hz, 1 H),

4.61 (d, J ) 3.4 Hz, 1 H), 4.21 (dd, J ) 7.9, 3.4 Hz, 1 H), 2.88-

2.80 (m, 1 H), 2.07-1.67 (series of m, 5 H), 1.14 (s, 9 H), 1.08

(s, 9 H); ¹³C NMR (75 MHz, CDCl₃) δ 162.7, 149.3, 141.1, 135.0

(2 C), 129.3 (2 C), 128.5, 128.2, 103.3, 84.8, 77.2, 67.3, 66.8,

52.7, 34.3, 31.5, 28.8 (3 C), 27.4 (3 C), 23.4, 21.4, 20.7; ES

1

1120; H NMR (300 MHz, CDCl₃) δ 6.17 (dd, J ) 6.1, 3.2 Hz,

1 H), 5.92 (dd, J ) 6.1, 1.8 Hz, 1 H), 5.46-5.44 (m, 1 H), 4.80

(d, J ) 3.5 Hz, 1 H), 2.79-2.70 (m, 1 H), 1.89-1.74 (series of

m, 5 H), 1.12 (s, 9 H), 1.05 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃)

δ 128.0, 123.4, 82.7, 82.0, 72.0, 34.7, 29.1 (3 C), 28.7, 27.4

(3 C), 23.1, 20.4, 20.1; EI HRMS m/z (M⁺) calcd 312.1574, obsd

312.1595; [R]¹⁹-13.5 (c 0.80, CHCl₃).

D

Glycosidation of 47 To Form 49. The reaction was carried

out according to the procedure described for the preparation

of 22 starting from 47 (64 mg, 0.15 mmol), bis-O-trimethyl-

silylthymine (62 mg, 0.23 mmol), and PhSeCl (44.8 mg, 0.23

mmol). The usual workup and silica gel chromatography

(20% EtOAc/hexanes) gave 49 as a white foam (80 mg, 75%):

UV (MeOH) λ_max274 nm (ꢀ 12 100); ¹H NMR (300 MHz, CDCl₃)

δ 8.31 (br s, 1 H), 7.71-7.68 (m, 2 H), 7.35-7.25 (m, 4 H),

5.86 (d, J ) 2.0 Hz, 1 H), 4.88 (d, J ) 6.3 Hz, 1 H), 4.46 (br s,

1 H), 4.14 (dd, J ) 6.3, 2.0 Hz, 1 H), 2.76-2.68 (m, 1 H), 2.21-

2.17 (m, 1 H), 2.01-1.70 (series of m, 7 H), 1.17-0.88 (m, 28

H); ¹³C NMR (75 MHz, CDCl₃) δ 163.2, 149.6, 136.7, 129.2

(2 C), 128.5 (2 C), 128.2, 110.2, 83.7, 74.6, 69.5, 66.6, 59.5, 34.4,

31.8, 20.3, 17.64, 17.59, 17.51, 17.3, 17.2, 17.1, 17.0, 16.7, 13.4,

13.13, 13.06, 12.5; ES HRMS m/z (M + Na⁺) calcd 719.1880,

HRMS m/z (M + Na⁺) calcd 603.1222, obsd 603.1227; [R]¹⁹

+28.5 (c 2.57, CH₃OH).

D

Protected Spironucleoside 53. The reaction was carried

out according to the procedure described for the preparation

of 22 starting from 47 (80 mg, 0.19 mmol), 1-O-trimethylsilyl-

N⁴-acetylcytosine (66 mg, 0.29 mmol), and PhSeCl (56 mg, 0.29

mmol). The usual workup and silica gel chromatography (50%

EtOAc/hexanes) gave 53 as a white solid (60 mg, 43%): mp

224-226 °C; UV (MeOH) λ_max284 (ꢀ 8700) and 248 nm

(ꢀ 13 400); ¹H NMR (300 MHz, CDCl₃) δ 10.07 (br s, 1 H), 8.10

(d, J ) 7.5 Hz, 1 H), 7.79-7.74 (m, 2 H), 7.34 (d, J ) 7.5 Hz,

obsd 719.1859; [R]¹⁹+8.9 (c 1.24, CH₃OH).

D

1594 J. Org. Chem., Vol. 70, No. 5, 2005

Synthesis of 2′-Deoxy-4′-thia â-Anomeric Spirocyclic Nucleosides

1 H), 7.31-7.21 (m, 3 H), 5.89 (d, J ) 1.2 Hz, 1 H), 4.81 (d, J

) 5.6 Hz, 1 H), 4.50 (br s, 1 H), 4.16 (dd, J ) 5.6, 1.2 Hz, 1 H),

2.81-2.73 (m, 1 H), 2.23-2.16 (m, 4 H), 2.01-1.70 (series of

m, 4 H), 1.13-0.71 (m, 28 H); ¹³C NMR (75 MHz, CDCl₃)

δ 171.0, 162.8, 154.8, 145.8, 136.1 (2 C), 129.1 (2 C), 129.0,

128.3, 96.0, 84.0, 74.1, 69.2, 69.0, 59.7, 34.3, 32.5, 24.9, 20.4,

17.7, 17.6, 17.5, 17.3, 17.2, 17.02 (2 C), 16.96, 13.5, 13.3, 13.2,

13.0; ES HRMS m/z (M + Na⁺) calcd 746.1989, obsd 746.2003;

by treatment with TBAF (1 M THF solution, 0.32 mL, 0.32

mmol) in THF (3 mL). The residue was chromatographed on

silica gel (10% EtOH/toluene) to afford 57 (44 mg, quant) as a

white solid: mp 205-206 °C; UV (MeOH) λ_max272 nm (ꢀ 7200);

¹H NMR (300 MHz, CD₃OD) δ 7.91 (d, J ) 1.1 Hz, 1 H), 6.52

(t, J ) 7.9 Hz, 1 H), 4.52 (t, J ) 3.2 Hz, 1 H), 4.22 (dd, J ) 5.8,

4.5 Hz, 1 H), 2.42-2.32 (series of m, 3 H), 2.20-2.07 (m, 1 H),

1.92-1.56 (series of m, 7 H); ¹³C NMR (75 MHz, CD₃OD)

δ 168.2, 155.2, 141.3, 114.7, 84.5, 78.0, 76.4, 64.8, 46.9, 35.9,

35.6, 23.6, 15.1; ES HRMS m/z (M + Na⁺) calcd 321.0879, obsd

[R]¹⁹-28.7 (c 1.04, CH₃OH).

D

Protected Spironucleoside 54. The reaction was carried

out according to the procedure described for the preparation

of 22 starting from 47 (80 mg, 0.19 mmol), 5-fluorouracil

(47 mg, 0.29 mmol), BSA (71 µL, 0.29 mmol) and PhSeCl (56

mg, 0.29 mmol). The usual workup and silica gel chromatog-

raphy (15% EtOAc/hexanes) gave 54 (114 mg, 82%) as a white

foam: UV (MeOH) λ_max274 nm (ꢀ 12 400); ¹H NMR (300 MHz,

CDCl₃) δ 9.04 (br s, 1 H), 7.81 (d, J ) 6.3 Hz, 1 H), 7.74-7.69

(m, 2 H), 7.34-7.25 (m, 3 H), 5.86 (d, J ) 2.0 Hz, 1 H), 4.83

(d, J ) 6.2 Hz, 1 H), 4.48 (br s, 1 H), 4.11 (dd, J ) 6.2, 2.0 Hz,

1 H), 2.80-2.71 (m, 1 H), 2.20-2.14 (m, 1 H), 2.01-1.72 (series

of m, 4 H), 1.17-0.83 (m, 28 H); ¹³C NMR (75 MHz, CDCl₃)

δ 156.5 (d, J ) 26.7 Hz, 1 C), 148.3 139.6 (d, J ) 236.8 Hz, 1

C), 136.4 (2 C), 129.2 (2 C), 128.6, 127.9, 125.3 (d, J ) 34.1

Hz, 1 C), 83.6, 74.3, 69.2, 67.3, 59.2, 34.4, 32.1, 20.4, 17.6, 17.5,

17.4, 17.3, 17.2 (2 C), 17.1, 17.0, 13.6, 13.5, 13.4, 13.1; ES

321.0876; [R]¹⁹-58.3 (c 0.12, CH₃OH).

D

2′-Deoxy-4′-thiauridine Analogue 58. The phenylseleno

group in 50 was removed according to the procedure described

for the preparation of 28 starting from 50 (109 mg, 0.16 mmol),

Bu₃SnH (0.13 mL, 0.48 mmol), and Et₃B (1 M THF solution,

0.16 mL, 0.16 mmol) in toluene (16 mL). After purification by

flash chromatography on silica gel (20% EtOAc/hexanes), the

resultant 2′-deoxy derivative was desilylated according to the

procedure described for the preparation of 29 by treatment

with TBAF (1 M THF solution, 0.39 mL, 0.39 mmol) in THF

(4 mL). The residue was chromatographed on silica gel (10%

EtOH/toluene) to afford 58 (44 mg, 98%) as a white solid: mp

203-204 °C; UV (MeOH) λ_max266 nm (ꢀ 6700); ¹H NMR (300

MHz, CD₃OD) δ 8.11 (d, J ) 8.1 Hz, 1 H), 6.52 (t, J ) 8.9 Hz,

1 H), 5.76 (d, J ) 8.1 Hz, 1 H), 4.53 (t, J ) 3.3 Hz, 1 H), 4.21

(dd, J ) 5.7, 4.1 Hz, 1 H), 2.44-2.31 (m, 3 H), 2.20-2.09

(m, 1 H), 1.86-1.57 (m, 4 H); ¹³C NMR (75 MHz, CD₃OD)

δ 168.5, 155.1, 145.9, 105.7, 84.4, 78.2, 76.8, 65.1, 47.0, 36.0,

35.6, 23.8; ES HRMS m/z (M + Na⁺) calcd 307.0723, obsd

HRMS m/z (M + Na⁺) calcd 723.1629, obsd 723.1642; [R]¹⁹

+34.1 (c 0.61, CH₃OH).

D

Adenosine Analogue 55. The reaction was carried out

according to the procedure described for the preparation of 37

starting from 47 (40 mg, 0.10 mmol), N⁶-benzoyladenine

(35 mg, 0.15 mmol), BSA (36 µL, 0.15 mmol) and PhSeCl

(28 mg, 0.15 mmol). The usual workup and silica gel chroma-

tography (20-40% EtOAc/hexanes) gave 55 as a colorless

307.0719; [R]¹⁹-50.8 (c 0.12, CH₃OH).

D

2′-Deoxy-4′-thia-5-fluorouridine Analogue 59. The phe-

nylseleno group in 54 was removed according to the procedure

described for the preparation of 28 starting from 54 (116 mg,

0.17 mmol), Bu₃SnH (0.13 mL, 0.51 mmol) and Et₃B (1 M THF

solution, 0.17 mL, 0.17 mmol) in toluene (17 mL). After

purification by flash chromatography on silica gel (15% EtOAc/

hexanes), the resultant 2′-deoxy derivative was desilylated

according to the procedure described for the preparation of 29

by treatment with TBAF (1 M THF solution, 0.38 mL, 0.38

mmol) in THF (4 mL). The residue was chromatographed on

silica gel (10% EtOH/toluene) to afford 59 (50 mg, quant) as a

white solid: mp 183-184 °C; UV (MeOH) λ_max274 nm (ꢀ 5700);

¹H NMR (300 MHz, CD₃OD) δ 8.30 (d, J ) 6.8 Hz, 1 H), 6.48

(dt, J ) 7.6, 1.6 Hz, 1 H), 4.50 (t, J ) 3.4 Hz, 1 H), 4.21 (t, J

) 5.5 Hz, 1 H), 2.48-2.33 (m, 3 H), 2.20-2.08 (m, 1 H), 1.84-

1.58 (m, 4 H); ¹³C NMR (75 MHz, CD₃OD) δ 161.9 (d, J ) 26.1

Hz, 1 C), 153.8, 144.2 (d, J ) 232.7 Hz, 1 C), 129.6 (d, J )

35.0 Hz, 1 C), 84.4, 77.9, 76.2, 65.6, 47.1, 35.8, 35.4, 23.5; ES

1

syrup (53 mg, 68%): UV (MeOH) λ_max282 nm (ꢀ 21 000); H

NMR (300 MHz, CDCl₃) δ 9.08 (br s, 1 H), 8.67 (s, 1 H), 8.00

(d, J ) 7.3 Hz, 2 H), 7.64-7.57 (m, 3 H), 7.53-7.48 (m, 3 H),

7.35-7.24 (m, 3 H), 5.86 (d, J ) 0.9 Hz, 1 H), 5.81 (d, J ) 6.4

Hz, 1 H), 4.65 (dd, J ) 6.4, 0.9 Hz, 1 H), 4.61 (br s, 1 H), 2.82-

2.74 (m, 1 H), 2.30-2.23 (m, 1 H), 2.04-1.66 (series of m,

4 H), 1.20-0.87 (m, 28 H); ¹³C NMR (75 MHz, CDCl₃) δ 164.5,

152.2, 150.7, 149.6, 142.1, 135.6 (2 C), 133.6, 132.8, 129.5

(2 C), 128.9 (2 C), 128.6, 128.5, 127.8 (2 C), 124.0, 83.4, 75.5,

70.8, 63.2, 58.9, 34.3 (2 C), 31.7, 20.3, 17.69, 17.64, 17.41, 17.33,

17.23, 17.20, 17.07, 13.40, 13.37, 13.09, 12.77; ES HRMS m/z

(M + Na⁺) calcd 832.2258, obsd 832.2236; [R]²⁰_D-66.4 (c 1.37,

CH₃OH).

Guanosine Analogue 56. The reaction was carried out

according to the procedure described for the preparation of 38

starting from 47 (80 mg, 0.19 mmol), N²-acetylguanine (56 mg,

0.29 mmol), BSA (71 µL, 0.29 mmol), and PhSeCl (56 mg, 0.29

mmol). The usual workup and silica gel chromatography (50%

EtOAc/hexanes to 10% CH₃OH/EtOAc) gave 56 as a colorless

syrup (61 mg, 42%) along with a minor product (27 mg, 18%):

UV (MeOH) λ_max264 (ꢀ 14 700) and 224 nm (ꢀ 25 400); ¹H NMR

(300 MHz, CDCl₃) δ 11.77 (br s, 1 H), 7.98 (s, 1 H), 7.77 (s, 1

H), 7.73-7.69 (m, 2 H), 7.40-7.30 (m, 3 H), 5.76 (s, 1 H), 4.89

(d, J ) 5.8 Hz, 1 H), 4.50 (br s, 1 H), 4.18 (d, J ) 5.8 Hz, 1 H),

2.74-2.70 (m, 1 H), 2.32-2.28 (m, 4 H), 2.13-1.72 (series of

m, 4 H), 1.25-0.83 (m, 28 H); ¹³C NMR (75 MHz, CDCl₃)

δ 170.9, 155.4, 146.5 (2 C), 137.5, 137.0, 129.6, 129.0 (2 C),

127.6 (2 C), 121.9, 84.1, 74.1, 68.8, 62.6, 60.7, 34.4, 29.7, 24.4,

20.4, 17.8, 17.6, 17.54, 17.46, 17.3, 17.2, 17.1, 17.0, 13.5, 13.3,

13.1, 13.0; ES HRMS m/z (M + Na⁺) calcd 786.2050, obsd

HRMS m/z (M + Na⁺) calcd 325.0629, obsd 325.0632; [R]¹⁹

-50.0 (c 0.12, CH₃OH).

D

2′-Deoxy-4′-thiacytidine Analogue 60. The phenylseleno

group in 53 was removed according to the procedure described

for the preparation of 28 starting from 53 (64.5 mg, 0.09

mmol), Bu₃SnH (0.07 mL, 0.27 mmol) and Et₃B (1 M THF

solution, 0.09 mL, 0.09 mmol) in toluene (9 mL). After

purification by flash chromatography on silica gel (50% EtOAc/

hexanes), the resultant 2′-deoxy derivative was desilylated

according to the procedure described for the preparation of 29

by treatment with TBAF (1 M THF solution, 0.21 mL, 0.21

mmol) in THF (2.5 mL). The reaction mixture was stirred for

1 day, evaporated to dryness, and placed under high vacuum

for 30 min. Methanolic ammonia (4 mL) was added to the

residue, and the mixture was kept at rt overnight prior to

chromatography on silica gel (30% EtOH/toluene) to afford 60

(24 mg, 96%) as a colorless syrup. UV (MeOH) λ_max278 nm (ꢀ

786.2016; [R]¹⁹-9.1 (c 1.56, CH₃OH).

D

2′-Deoxy-4′-thiathymidine Analogue 57. The phenyl-

seleno group in 49 was removed according to the procedure

described for the preparation of 28 starting from 49 (102 mg,

0.15 mmol), Bu₃SnH (0.12 mL, 0.45 mmol) and Et₃B (1 M THF

solution, 0.15 mL, 0.15 mmol) in toluene (15 mL). After

purification by flash chromatography on silica gel (20% EtOAc/

hexanes), the resultant 2′-deoxy derivative was desilylated

according to the procedure described for the preparation of 29

1

5500); H NMR (300 MHz, CD₃OD) δ 8.14 (d, J ) 7.3 Hz, 1

H), 6.56 (t, J ) 7.5 Hz, 1 H), 5.97 (d, J ) 6.6 Hz, 1 H), 4.54 (br

s, 1 H), 4.20 (t, J ) 4.6 Hz, 1 H), 2.49-2.09 (series of m, 4 H),

1.89-1.58 (series of m, 4 H); ¹³C NMR (75 MHz, CD₃OD)

δ 169.8, 161.3, 146.3, 99.3, 84.4, 78.3, 76.4, 65.9, 47.4, 36.0,

35.7, 23.9; ES HRMS m/z (M + Na⁺) calcd 306.0883, obsd

306.0869; [R]¹⁹-59.5 (c 0.21, CH₃OH).

D

J. Org. Chem, Vol. 70, No. 5, 2005 1595

Dong and Paquette

2′-Deoxy-4′-thiaadenosine Analogue 61. The phenyl-

seleno group in 55 was removed according to the procedure

described for the preparation of 28 starting from 55 (141 mg,

0.17 mmol), Bu₃SnH (0.14 mL, 0.51 mmol) and Et₃B (1 M THF

solution, 0.17 mL, 0.17 mmol) in toluene (17 mL). After

purification by flash chromatography on silica gel (20% EtOAc/

hexanes), the resultant 2′-deoxy derivative was desilylated

according to the procedure described for the preparation of 29

by treatment with TBAF (1 M THF solution, 0.38 mL, 0.38

mmol) in THF (4 mL). The reaction mixture was stirred for

4 h, evaporated to dryness, and placed under high vacuum

for 30 min. Methanolic ammonia (9 mL) was added to the

residue, and the mixture was kept at rt overnight prior to

chromatography on silica gel (20% EtOH/toluene) to afford 61

(53 mg, 98%) as a white solid: mp 202-203 °C; UV (MeOH)

λ_max262 nm (ꢀ 12 700); ¹H NMR (300 MHz, CD₃OD) δ 8.39

(s, 1 H), 8.19 (s, 1 H), 6.42 (t, J ) 7.5 Hz, 1 H), 4.63 (br t, J )

3.2 Hz, 1 H), 4.41 (t, J ) 5.4 Hz, 1 H), 3.00-2.93 (m, 1 H),

2.69-2.61 (m, 1 H), 2.46-2.36 (m, 1 H), 2.17-2.10 (m, 1 H),

1.90-1.60 (series of m, 6 H); ¹³C NMR (75 MHz, CD₃OD)

δ 157.4, 153.4, 150.2, 141.7, 120.8, 82.1, 75.8, 74.0, 61.5, 45.0,

33.1, 32.8, 21.1; ES HRMS m/z (M + Na⁺) calcd 330.0995, obsd

solution, 43 µL, 0.043 mmol) in toluene (5 mL). After purifica-

tion by flash chromatography on silica gel (50% EtOAc/

hexanes) the resultant 2′-deoxy derivative was desilylated

according to the procedure described for the preparation of 29

by treatment with TBAF (1 M THF solution, 0.1 mL, 0.1 mmol)

in THF (1 mL). The reaction mixture was stirred for 4 h,

evaporated to dryness, and placed under high vacuum for

30 min. Methanolic ammonia (2 mL) was added to the residue,

and the mixture was kept at rt overnight prior to chromatog-

raphy on silica gel (30% EtOH/toluene) to afford 62 (12.5 mg,

91%) as a white solid, mp 220-222 °C; UV (MeOH) λ_max260

nm (ꢀ 8500); ¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (br s,

1 H), 8.01 (s, 1 H), 6.61 (br s, 2 H), 6.14 (dd, J ) 9.4, 6.2 Hz,

1 H), 5.43 (br s, 1 H), 5.16 (br s, 1 H), 4.51 (s, 1 H), 4.20

(s, 1 H), 2.70-2.63 (m, 1 H), 2.41-2.23 (m, 2 H), 1.97-1.91

(m, 1 H), 1.75-1.20 (series of m, 4 H); ¹³C NMR (75 MHz,

DMSO-d₆) δ 156.7, 153.7, 151.0, 135.5, 113.0, 79.5, 73.8, 73.6.,

58.2, 43.7, 32.4, 32.2, 20.4; ES HRMS m/z (M + Na⁺) calcd

346.0944, obsd 346.0942; [R]²²-15.6 (c 0.09, CH₃OH).

D

1

Supporting Information Available: High-field H and

330.0991; [R]¹⁹-77.8 (c 0.18, CH₃OH).

¹³C NMR spectra for all compounds described herein. This

material is available free of charge via the Internet at

http://pubs.acs.org.

D

2′-Deoxy-4′-thiaguanosine Analogue 62. The phenyl-

seleno group in 56 was removed according to the procedure

described for the preparation of 28 starting from 56 (33 mg,

0.043 mmol), Bu₃SnH (35 µL, 0.13 mmol) and Et₃B (1 M THF

JO048071U

1596 J. Org. Chem., Vol. 70, No. 5, 2005

Article Doi

Stereoselective synthesis of conformationally constrained 2′-deoxy-4′-thia β-anomeric spirocyclic nucleosides featuring either hydroxyl configuration at C5′

DOI: 10.1021/jo048071u

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Article abstract of DOI:10.1021/jo048071u

Full text of DOI:10.1021/jo048071u

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