Spirocyclic restriction of nucleosides

Article abstract of DOI:10.1071/CH03267

The concept of spirocyclic restriction as applied broadly to the field of nucleoside mimics makes possible the generation of diastereomeric pairs configured with a syn- or anti-oriented hydroxyl substituent at C5′. The development of concise synthetic rou

Full text of DOI:10.1071/CH03267

Review
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 7–17
Spirocyclic Restriction of Nucleosides
Leo A. Paquette
Evans Chemical Laboratories, Ohio State University, Columbus, OH 43210, USA (e-mail: paquette.1@osu.edu).
The concept of spirocyclic restriction as applied broadly to the field of nucleoside mimics makes possible the gener-
ation of diastereomeric pairs configured with a syn- or anti-oriented hydroxyl substituent at C5ꢀ. The development
of concise synthetic routes to spiro-fused nucleosides bearing all possible natural bases and expectedly capable of
enforcing a conformation favourable for duplex formation on incorporation into oligomers represents a significant
new direction in the design of antisense molecules. The present overview describes the convenient approaches that
have been developed in this laboratory for accessing varied members of this class, including analogues that feature
sulfur and carbon at the apical position.
Manuscript received: 10 October 2003.
Final version: 1 November 2003.
Introduction
R2
R1
BB
R2
B
B
R1
O
O
The structural modification of nucleosides continues to repre-
sent a vibrant area of synthetic organic and bioorganic chem-
istry because select compounds of this class are amenable
to the treatment of those diseases where the normal and dis-
eased states differ with regard to the enzymes involved in
the processing of nucleic acids. Viral diseases are recog-
nized to often fit these criteria. Furthermore, the enzymes
involved appear to have strict conformational requirements
with respect to the geometry adopted by the furanose ring.[1]
These fascinating interdependencies have prompted several
research groups to undertake the preparation of modified
nucleosides that feature restrictions in conformational flexi-
bility in order to attain a more optimal level of puckering.[2]
Bicyclo[3.1.0]hexane-[3,4] and bicyclo[3.3.0]octane-based
carbocyclic mimics[5] have been examined as potentially
useful pseudosugars. For reasons to be detailed below, we
have independently pursued a comprehensive investigation of
4ꢀ-spirocyclic nucleosides that also include the thia and carba
series. The synthetic component of this major undertaking
is presently nearing completion and constitutes the basis of
this report.
1
2
R2
R2
B
B
B
R1
B
R1
O
O
OH
OH OH
3
4
a, R1ꢀ H, R2ꢀ OH
b, R1ꢀ OH, R2ꢀ H
Diagram 1.
the magnitude of these torsion angles. Such constraints hold
potential importance in modulation of the sugar–phosphate
DNA backbone, and ultimately the secondary structure of
DNA and base recognition.[6]
Extensive crystal structure data, most notably those for
DNA and RNA fragments, reveal the existence of consid-
erable void space (likely occupied by water molecules) in
the region below C4ꢀ of each nucleoside building block.[7]
The area being referred to is sufficiently voluminous to
accommodate more than the string of three methylene groups
under consideration in 1–4. Accordingly, there are no per-
tinent untoward concerns dealing with non-bonded steric
superimposition.
The spirocyclic substitution pattern also precludes the
possibility of free radical-induced degradation arising from
hydrogen atom abstraction at C4ꢀ. The advantages offered by
C4ꢀ alkylation in warding off this destructive pathway have
been responsible for the rapid rise in prominence of simpler
analogues of this type.[8]
Why 4ꢀ-Spiroalkylated Nucleosides?
One may justifiably raise questions regarding the impor-
tance underlying 4ꢀ-spiroalkylated nucleosides. In fact, there
are several quite relevant reasons why the unprecedented
structural features resident in 1–4 (Diagram 1) might hold
considerable potential. It will be recognized, for example, that
the torsion angle about the C4ꢀ C5ꢀ bond of the furanose ring
is necessarily fixed so that the key hydroxyl group at this site
is now oriented specifically anti (a series) or syn (b series)
to the furanose oxygen. Limitations are therefore placed on
In addition to these features, the spirocyclic array resident
in 1–4 provides an inherent atomic arrangement where some
© CSIRO 2004
10.1071/CH03267
0004-9425/04/010007

8
L. A. Paquette
O
(A)
(B)
(C)
Ph
H
HO
O
O
COH
1.
X
X
Li
2. Dowex-50X
Sc(OTf)3
CH2Cl2, CH3CN
∆
(ꢃ)-5
X ꢀ O, S
O
O
Fig. 1. The minimum-energy conformations of natural thymidine (A),
3a (B), and 3b (C).
Ph
Ph
O
O
O
O
ꢁ
X
X
conformational biasing operates, but not to the level of struc-
tural rigidification. Fully optimizedAmber calculations in the
gas phase have made evident a striking similarity between
the low-energy conformation adopted by natural thymidine
(A) and those adopted by the two 1-oxaspiro[4.4]nonane
isomers defined as B and C (Fig. 1).[9] The overlap of B
on A is truly remarkable (root mean square 0.007). For C,
the departure from direct superimposition is not as perfect
(RMS 0.058), but nevertheless very acceptable. Note that
this theoretical treatment projects the cyclopentyl hydroxyl
group pseudoequatorially in both stereoisomeric series. Of
additional interest is the topological change associated with
epimers B and C (γ = +sc and ap, respectively).
6
7
LiOH,
THF, H2O
LiOH,
THF, H2O
(ꢁ)-5
(ꢂ)-5
Scheme 1. Acetalization with (R)-(–)-mandelic acid.
O
HO
H
HO
H
Al(OPri)3
PriOH
L-Selectride
O
O
O
THF, ꢂ78ºC
8
(ꢁ)-5
9
O
HO
H
H
HO
LiAlH4
S
S
S
ꢁ
ether, 20ºC
Preliminary Studies
(ꢁ)-6
10
(2:3)
11
Several years ago, we reported the first examples of oxo-
nium ion-initiated pinacolic ring expansion.[10–12] Subse-
quently, parallel studies revealed that thionium ions react
in a parallel manner.[13] When 5-lithiated 2,3-dihydrofuran
and 2,3-dihydrothiophene are reacted initially with cyclo-
butanone, the door is opened to a two-step entry to possible
oxygen- and sulfur-containing spirocyclic precursors to 1–4
as reflected in the generation of 5. The discovery that these
ketones are particularly well suited to resolution via acetaliza-
tion with (R)-(–)-mandelic acid under catalysis by scandium
triflate[14,15] was deemed to be particularly advantageous to
our goals (Scheme 1). Following the alkaline hydrolysis of 6,
it was discovered that the resulting (+)-5 (X = O) could be
reduced to 8 or 9 with essentially complete diastereoselec-
tivity (Scheme 2).[14] The reduction of (+)-5 (X = S) of 98%
e.e. with lithium aluminium hydride in ether at 20◦C was
observed by us to proceed in a significantly less stereoselec-
tive fashion than previously reported.[16] The observed 2 : 3
partitioning of 10 and 11 was in fact welcomed by us since
both diastereomeric series were accessed simultaneously,
and 10 and 11 differ sufficiently in polarity to make their
chromatographic separation routine.[15]
Scheme 2. Reduction stereoselectivities of spiroketones.
+
Br
O
NBS,
O
HO
O
Br
O
O
H
O
O
i
Pr OH,
ꢂ78ºC → rt
(96%)
12
13
(ꢃ)-14
1. reduction;
protection
1. resolution
2. PCC, CrO3
2. xylene, ∆
O
3. DBU,
3,5-DMP
toluene, ∆
4Å MS, ꢂ20ºC
(ꢂ)-15
H
RO
RO
H
O
O
O
or
O
16
17
Scheme 3. Bromonium ion-mediated route to epimeric unsaturated
lactones. NBS = N-bromosuccinimide, DBU = 1,8-diazabicyclo
[5.4.0]undec-7-ene, PCC = pyridium chlorochromate, DMP =
dimethylpyrazole.
Leo Paquette received his B.Sc. degree in chemistry magna cum laude from Holy Cross College in 1956 and his Ph.D. from
MIT in 1959. After serving as a medicinal chemist at Upjohn (1959–1963), he joined the faculty at Ohio State University
and was promoted to Professor in 1969. Subsequently, he held the Kimberly Professorship in chemistry (1981–1987) and now
is a Distinguished University Professor there (1987–). He has held numerous Fellowships (Alfred P. Sloan Foundation 1965,
Guggenheim 1976–1977, Senior Humboldt 1989) and an Awardee of the Japanese Society for the Promotion of Science (1992).
On several occasions he has been honored by the American Chemical Society (Morley Medalist 1971, Columbus Section Award
1979, Award for Creative Work in Synthetic Organic Chemistry 1984, Arthur C. Cope Award 1987, Ernest Guenther Award
1992). He has also been the recipient of many international awards including, most recently, the Centenary Lectureship of the
Royal Society of Chemistry and the S. T. Li Prize for Science and Technology. His current research interests focus on the total
synthesis of natural and unnatural products, the development of synthetic methodology and catalytic asymmetric methods, and
organometallic chemistry.

Spirocyclic Restriction of Nucleosides
9
TBSO
TBSO
1. LHMDS,
PhSSO2Ph
TBSO
TBSO
H
H
H
RuCl3
NaIO4
O
O
O
O
O
O
O
2. EtMgBr,
+
SPh
H3O
18
19
20
H
TBSO
H
1. [O]
O
O
2. CaCO3,
CCl4, ∆
21
3. Ph3P
22
Scheme 4. Preferred route involving initial ruthenium-promoted oxidation to the lactone
level. LHMDS = lithium hexamethyldisilazide, TBS = tert-butyl dimethylsilyl.
O
More Advanced Functionalization
Ph
Se
OH
SePh
S
ꢁ
S
PhSeCl
O
Pr OH
(70%)
The need for introducing higher levels of unsaturation into
these spirocyclic intermediates was initially approached from
two directions in both the oxygen and sulfur series. The
first route entailed initiation of the rearrangement of 12
with NBS in isopropyl alcohol containing 10 equivalents of
propylene oxide at −78◦C to deter any acid buildup. The
high degree of diastereoselectivity that leads to 14 can be
rationalized in terms of the generation of bromonium ion
13. Subsequent anti migration of the methylene unit with
avoidance of unfavourable steric interactions leads to forma-
tion of the syn product (Scheme 3).[14] The resolution of 14
via transient coupling to Johnson’s (S)-(+)-sulfoximine, E2
elimination in the presence of DBU to give (–)-15, and regio-
selective oxidation of a protected form of the derived alcohols
resulted in controlled formation of either 16 or 17, both in
enantiomerically pure form.[14]
H O
S
i
(ꢃ)-23
24
(ꢃ)-25
O
Ph
1.
H
COH ,
O
O
S
HO
S
MCPBA, py
Sc(OTf)3
CH2Cl2, ꢂ78ºC
CH2Cl2, CH3CN
(94%)
(91%)
(ꢃ)-26
(ꢂ)-26
2. LiOH, THF,
H2O (73%)
Scheme 5. Pathway to laevorotatory dehydro thia ketone 26.
MCPBA = m-chloroperbenzoic acid, THF = tetrahydrofuran.
1. Ac2O,
NaOAc
TBSO
H
TBSO
H
O
S
10% NaIO4/SiO2,
S
A more efficient pathway took advantage of the ease with
which 18 (and its 5ꢀ-epimer) undergoes direct ruthenium
tetraoxideoxidationtogeneratelactone19(Scheme 4). Ensu-
ing two-step phenylsulfenylation[17] and sulfoxide elimina-
tion results in ready conversion into 21 (or 22) in convenient
fashion.[14,18]
CH2Cl2, hexanes
(95%)
2. (TsOH),
4Å MS,
C6H6, ∆
27
28 (4 : 1)
H
TBSO
TBSO
H
H
S
S
ꢁ
OAc
An effective means for arriving at desirable inter-
mediates in the thia series consists of phenylselenenyl
chloride-initiated ring expansion/rearrangement of alcohol
23 (Scheme 5).[15] As in the preparation of ( )-14, it is imper-
ative that propyleneoxidebepresentasanacid scavenger.The
conversion into 26, best effected by chemoselective oxidation
at selenium, was accomplished most effectively under basic
conditions at high dilution.[19] This spiro ketone was resolved
byacetalizationwith(R)-mandelicacid, purifiedbyfractional
crystallization, and subjected to alkaline saponification.
Formation of the TBS ethers of 10 and 11 provides sub-
strates ideally suited to examination of the sulfoxidation reac-
tion. As a direct consequence of inherent steric shielding,
both 27 and 31 were found to be unreactive to an excess of
MCPBA.[15] In remarkable contrast, alternative recourse to
sodium periodate supported on silica gel[20,21] proved notably
effective in oxidizing both tetrahydrothiophenes to 28 and
32 at the 10% level of loading (Scheme 6). Longer reaction
times were required for the α-siloxy series. This kinetic retar-
dation was accompanied by an increase in stereoselectivity
from 4 : 1 to 9 : 1. The use of ammonium molybdate[22]
(ꢁ)-29
(34%)
(ꢁ)-30
(31%)
1. Ac2O,
H
TBSO
TBSO
H
O
S
10% NaIO4/SiO2,
NaOAc
S
CH2Cl2, hexanes
(90%)
2. (TsOH),
4Å MS,
31
32 (9 : 1)
C6H6, ∆
H
TBSO
H
TBSO
H
S
S
ꢁ
OAc
(ꢁ)-33
(30%)
(ꢂ)-34
(28%)
Scheme 6. Pummerer approach to thionucleoside functionalization.
provided yet another convenient way to generate 28 and 32
without evidence of sulfone formation. With this reagent,
diastereomer ratios did not exceed 3 : 2.
Pummerer reactions carried out on 28 and 32 in hot acetic
anhydride containing sodium acetate[23] gave rise to complex

10
L. A. Paquette
MOMO
MOMO
H
H
reaction mixtures, which when heated with p-toluenesulfonic
acid in benzene containing 4 Å molecular sieves[24] con-
verged to the elimination products 29 and 33 alongside
acetates 30 and 34. Each of the four thiospirans was formed
in approximately 30% yield.The stereochemical assignments
to 30 and 34 rest on the results of nuclear Overhauser effect
measurements.[15]
1. Dibal-H
O
O
O
2. Ac2O, Et3N
(91%)
OAc
17
35
Cl
N
Cl
N
N
MOMO
H
O
N
N
H
N
MOMO
H
N
N
N
N
ꢁ
O
Pd2dba3 ⋅ CHCl3,
Ph3P, Et3N, THF
(50%)
N
N
Accessing Prototype Furanoside Mimics
36
Cl
(1 : 5)
37
In our view, the developments defined above set a very solid
foundation for arrival at nucleoside mimics endowed with
oxygen or sulfur as the central heteroatom. The one remain-
ing concern involved the possible inhibitory steric effect
induced by the protected 5ꢀ-hydroxyl on proper installation
of the nucleosidic bond. In an effort to gain an appreciation
of operational factors, lactone 17 was reduced to its lactol
and O-acylated to give 35 (Scheme 7). The stereodisposition
of the acetate functionality in 35 could not be ascertained
spectroscopically. We reasoned that if hydride delivery to 17
had occurred predominantly anti to the MOM group, then
conversion to a π-allylpalladium species and subsequent cou-
pling to a heterocycle should be met with overall retention.[25]
In the present example, coupling of 35 to 6-chloropurine
in the presence of Pd2(dba)3 · CHCl3, triphenylphosphine,
and triethylamine brought about smooth conversion into a
1 : 5 mixture of 36 and 37. When O-methylthymine was
involved, a 1 : 5 mixture of spironucleosides was again pro-
duced, and the major anomer was confirmed to be 39 by X-ray
crystallography.[26]
35
OMe
MOMO
CH3
N
H
O
OMe
H3C
H
N
O
N
H
N
O
MOMO
ꢁ
N
O
O
(π-allyl PdCl)2
Ph3P, Cs2CO3, THF
(50%)
N
H3C
39
OMe
38
(1 : 5)
Scheme 7. Synthesis of the first syn-dideoxy nucleoside. MOM =
methoxymethyl, dba = dibenzylideneacetone, Dibal-H = diisobutyl
aluminium hydride.
TBSO
TBSO
H
H
1. Dibal-H
O
O
OAc
O
2. Ac2O, py
(DMAP)
(94%)
SPh
SPh
20
40
OTMS
R
N
TMSO
N
SnCl4, CH2Cl2,
The implications that were drawn in the light of these
findings were that spirocyclic system 35 undergoes these
palladium-catalyzed reactions productively and that the
DIBAL-H reduction/O-acetylation sequence delivers pre-
dominantly the α-acetate. The need for a directing group
was obvious. To this end, recourse was made to the read-
ily available α-phenylthio lactone 20, submission of which to
the same two-step protocol afforded an anomeric mixture of
40 (Scheme 8).[18] The expectation was that SnCl4-promoted
coupling reactions between 40 and persilylated uracil or
thymine[27,28] would foster the intervention of an episulfo-
nium ion intermediate[29] and/or complexation of the tin salt
at the sulfur atom[30] and eventuate in selective formation
of the desired 1,2-trans glycosyl bond.[31–34] While 41a was
formed as a 9 : 1 mixture rich in the β-anomer, the somewhat
more bulky thymine reagent gave rise uniquely to 41b in line
with customary steric effects.
ꢂ78ºC → ꢁ20ºC
(61; 59%)
O
O
N
Ph
R
H
1.
PhSO2N
R
NH
NH
O
O
TBSO
TBSO
N
O
H
2. xylene,
py, ∆
(94; 88%)
O
O
SPh
42a, RꢀH
b, RꢀCH3
41a, RꢀH (9:1)
b, RꢀCH3 (>97:3)
1. H2, Pd/C, 1 atm
(90; 100%)
18[crown]-6
KF, THF
(57; 97%)
2. 18[crown]-6,
KF, THF
(83; 83%)
O
O
R
R
NH
NH
HO
HO
H
H
N
O
N
O
O
O
Following arrival at 41a and 41b, two avenues were
pursued to remove the phenylthio substituent. The oxida-
tive option involved conversion into the sulfoxide with the
Davis oxaziridine reagent[35] and subsequent thermal extru-
sion of phenylsulfenic acid in the presence of pyridine. The
unprotected didehydrodideoxy nucleosides 43a and 43b were
generated without evidence of epimerization by reaction with
potassium fluoride in THF.[18] As indicated in Scheme 8,
saturation of the dihydrofuran double bond in these sys-
tems was performed most efficaciously while the TBS group
remained installed.
43a, RꢀH
b, RꢀCH3
44a, RꢀH
b, RꢀCH3
Scheme 8. Nucleoside formation involving 40. DMAP =
4-dimethylaminopyridine.
The parallel conversion of 45 to 47 and 48 proved ini-
tially to be problematic, as reflected in the low yields (<25%)
incurred during introduction of the nucleobases (Scheme 9).
It was soon discovered that 45 is prone to a fragmentation

Spirocyclic Restriction of Nucleosides
11
OTMS
O
N
R
R
H
N
NH
TBSO
O
H
HO
1. PhSO2N
Ph
TMSO
N
O
O
O
OAc
2. xylene, py, ∆
SnCl4, CH3CN
ꢂ78ºC → ꢁ20ºC
SPh
SPh
45
46a, R ꢀ H (56%)
b, R ꢀ CH3 (69%)
O
O
N
R
R
H
NH
NH
HO
HO
10% Pd/C,
H
N
O
O
O
O
EtOH,
50 psi H2
47a, R ꢀ H (85%)
b, R ꢀ CH3 (78%)
48a, R ꢀ H (89%)
b, R ꢀ CH3 (91%)
Scheme 9. Nucleoside formation involving 45.
TBSO
H
TBSO
H
H
TBSO
OTBS
Dibal-H
O
O
X
O
O
O
SnCl4
CH2Cl2, ꢂ78ºC
45
53, X ꢀ OH
54, X ꢀ Cl
(52%)
PPh3, CCl4
THF, 50ºC
H
52
S
SPh
Ph
SnCl3OAc
Cl
N
49
50
N
N
N
TBSO
H
Cl
O
O
O
H2O
N
N
N
Na
TBSO
ꢁ
H
N
N
N
H
H
N
DMF/THF
0ºC → ꢁ20ºC
O
N
SPh
100ºC
51
12h
(1:1)
Cl
55 (17%)
56 (12%)
NH3, MeOH
sealed tube
90ºC, 8h
(82%)
Scheme 10. Ring cleavage of 45.
reaction not operative in 40. Evidently, the stereoelectronic
features resident in 45 are conducive to operation of an E2
elimination (Scheme 10). Once this irreversible step operates,
the resulting silyl enol ether functionality in 50 becomes sub-
ject to hydrolysis during the aqueous workup with liberation
of the cyclopentanone carbonyl group in 51.
Matters were significantly upgraded when the glycosyla-
tion step was performed instead in acetonitrile. This solvent
switch was met with unexpected loss of the TBS protect-
ing group to give 46 directly. The advantages offered by this
eventuality were further reinforced by the finding that ther-
mal elimination of the derived sulfoxides gave rise to 47 and
ultimately 48 in an efficient manner.
NH2
NH2
N
N
N
N
N
TBAF, THF
(83%)
TBSO
H
H
HO
N
N
N
O
O
57
58
NH2
N
N
N
5 steps
HO
H
(ꢂ)-19
N
O
59
A creditworthy attribute of the global research plan is
its potential for the introduction of purine bases into target
nucleosides. This is notable because, with very few excep-
tions, standard approaches to C4ꢀ-substituted nucleosides all
derive from the Cannizzaro reaction of a thymidine-based
5ꢀ-aldehyde followed by reoxidation under somewhat forcing
conditions.The vigorous nature of the chemistry employed in
this sequence, using existing nucleosides as starting materi-
als, restricts it to the more robust bases. The end result is that
it is very unusual to see 4ꢀ-substituted systems with anything
other than thymine as base. The strategy that we have used
for the synthesis of purine mimics has involved the SN2-type
displacement of halide ion from chlorides such as 54 with
the sodium salt of 6-chloropurine.[35–38] The highly reactive
Scheme 11. Elaboration of adenine analogues. TBAF = tetrabutyl
ammonium fluoride.
electrophile 54 was prepared in a non-stereoselective man-
ner from 52 by sequential Dibal-H reduction and exposure to
triphenylphosphine and carbon tetrachloride (Scheme 11).
The involvement of 54 in glycosylation proceeded with
the formation of 55 and 56 in comparable amounts. The
generation of an epimeric mixture at this point was not an
element of concern since thermal activation of 56 at 100◦C
induced its epimerization to the desired 55. Substitutive ami-
nation followed by routine desilylation afforded 58. When

12
L. A. Paquette
recourse was made to laevorotatory lactone 19, conversion
into 59 was realised uneventfully by way of the identical
five-step sequence.[39]
instance, the coupling to triacetate 65 with persilylated uracil
afforded 66 as the sole nucleosidic product. Its twofold depro-
tection proceeded with excellent chemoselectivity to make
67 available.[26] The single-phase sodium-salt glycosylation
protocol was used to generate 68. In this instance, dihydrox-
ylation was most satisfactorily implemented by reaction with
ruthenium tetraoxide in a two-phase solvent system consist-
ing of ethyl acetate, acetonitrile, and water.[40] The rapidity
of this important step (complete within 5 min), its stereo-
selectivity, anditsoverallefficiency(60%)arenoteworthy.[39]
Generation of the spiro guanosine 70 was achieved by reac-
tion with 2-mercaptoethanol under basic conditions.[41–43]
An equally rewarding thrust involved the osmium
tetraoxide-catalyzed dihydroxylation of unsaturated spiro
lactones in the presence of NMO. An early series of exper-
iments involved the methoxymethyl derivative 17, where
introduction of the two hydroxyl groups occurred in a highly
diastereoselective manner as in 60 (Scheme 12).[26] The ensu-
ing one-pot reaction involved reduction with Dibal-H and
direct acetylation. Triacetate 61 so generated made possible
the implementation of the Vorbrüggen process. Specific use
of bis-O-silylated thymine and trimethylsilyl triflate gave rise
to 63 from which 64 was generated by routine deacetylation.
The reaction pathway developed for the conversion of 17
into 64 is not limited to the 5ꢀα series, but appears to be
generally applicable to the related β-epimer. Two represen-
tative examples are illustrated in Scheme 13. In the first
The Quest for 2ꢀ-Deoxy Spironucleosides
Since DNA is, like RNA, involved in a wide array of bio-
logical functions, 2ꢀ-deoxy congeners of the spirocyclic type
loom as interesting targets for deliberate incorporation in a
site-specific manner into nucleotide strands. This component
of our research undertaking has more recently been accorded
preliminary attention. Our expectation is that these new mim-
ics will hopefully hold interest as useful medicinal agents in
their own right in addition to imparting valuable therapeutic
properties when incorporated into oligomers.
MOMO
OsO4,
NMO,
H
1. Dibal-H
O
17
O
THF, py
(93%)
2. Ac2O, py
(61%)
OH OH
60
OTMS
O
The ready availability of unsaturated lactones generically
represented as 16 and 17 and the feasibility of dihydroxy-
lating the conjugated double bond in a relatively efficient
manner led to the selection of intermediates such as 71 and 73
as appropriate precursors to the key 2ꢀ-deoxy building blocks
(Scheme 14).[44,45] The highly polar character and elevated
water solubility of these substances prompted consideration
of their direct exposure to samarium iodide.The use of HMPA
as solvent resulted in reductive cleavage of the C2ꢀ hydroxyl
with generation of 72 and 74, respectively.[46] Dihydroxy lac-
tone 71 reacts more sluggishly than does 73 and requires a
considerably greater period of time to proceed to completion.
Following silylation of the OH functionality in 74, conver-
sion into the anomeric acetates 75 proved uneventful. These
accomplishments allowed for the ultimate incorporation of
uracil as in 76. Although the efficiency of this Vorbrüggen
CH3
H3C
MOMO
H
N
NH
O
RO
H
TMSO
N
OAc
N
O
O
TMSOTf
THF
(76%)
AcO OAc
AcO OAc
61
62, RꢀMOM
63, RꢀH
O
H3C
NH
K2CO3
HO
H
N
O
MeOH
(95%)
O
HO OH
64
Scheme 12. Synthesis of the first fully substituted spironucleoside.
NMO = N-methylmorpholine-N-oxide.
O
N
O
N
OTMS
N
NH
NH
PMBO
PMBO
H
HO
H
H
1. DDQ, H2O,
CH2Cl2 (91%)
O
O
N
OTMS
O
O
O
OAc
2. K2CO3,
MeOH (99%)
TMSOTf,
CH2Cl2
(54%)
AcO OAc
AcO OAc
HO OH
65
66
67
Cl
Cl
N
O
N
N
N
N
N
1. HOCH2CH2SH,
NaOMe
NH
NH2
TBSO
TBSO
H
H
HO
H
RuCl3, NaIO4,
N
N
N
O
N
O
NH2
N
NH2
O
MeOH, ∆
2. KF, 18[crown]-6
(37%)
CH3CN, EtOAc
(60%)
HO OH
HO OH
68
69
70
Scheme 13. Generation of uridine and guanosine prototypes. PMB = p-nitrobenzoate, DDQ = 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone.

Spirocyclic Restriction of Nucleosides
13
TBSO
H
Ph
O
Ph
O
TBSO
K2OsO2(OH)4,
DABCO,
CH3SO2NH2,
H
O
O
SmI2
O
1. Me2C(OMe)2,
TsOH (96%)
O
O
O
O
O
HMPA
(74%)
S
S
HO OH
OH
K3Fe(CN)6,
NaHCO3,
K2CO3
2. LiOH, H2O,
THF (100%)
71
72
OH
HO
TBSO
TBSO
H
(100%)
H
1. TBSOTf, 2,6-lutidine
2. Dibal-H, ꢂ78ºC
77
78
SmI2
O
O
O
HO
H
O
1. ButLi,
HMPA, THF
O
O
HMPA
(90%)
3. Ac2O, py
(54%)
S
S
Al(OPri)3
OH
HO OH
PriOH, ∆
(61% α; 22% β)
ꢂ78ºC (89%)
2. TBSCl, Et3N
AgNO3, DME
(88%)
74
73
O
O
O
O
OTMS
NH
79
80
N
TBSO
1.
H
O
HO
H
OTMS
O
N
O
N
OTMS
H3C
O
OAc
N
H3C
NH
SnCl4, CH2Cl2
ꢂ78ºC → ꢁ20ºC
2. TBAF, THF (8%)
OTBS
TBSO
OH
N
OTMS
H
TBSO
H
O
N
PhSeCl
75
S
76
S
CH3CN, 0ºC
(66%)
OTBS
Scheme 14. Realization of a synthetic approach to 2ꢀ-deoxy spiro-
nucleosides. HMPA = hexamethyl phosphoramide.
TBSO
SePh
81
82
OTMS
H3C
N
reaction sequence is presently low, albeit in line with existing
precedent,[28c] improvements continue to be sought.[44,45]
N
OTMS
NIS, CH3CN, 0ºC
(65%)
More Advances in the Spirothianucleoside Sector
O
O
Concurrently, we have addressed an expeditious means for
the generation of 2ꢀ-deoxy thiaspironucleosides. As a direct
consequence of the divergent chemical reactivity of tetra-
hydrofuran and tetrahydrothiophene ring systems, the devel-
opment of an entirely different approach was needed. The
most attractive pathway to surface at this time is summarized
in Scheme 15.[47] The enantiomerically pure mandelic acid
acetal was initially prepared from 26 as outlined previously. It
proved particularly advantageous to preserve the acetal func-
tionality during the course of the ensuing dihydroxylation.
Theconversionof 77 into78waseffectedinquantitativeyield
in the presence of potassium osmate and DABCO without
evidence of competing oxidation at sulfur.[48] Also encour-
aging, acetonide formation and saponification proceeded in
96% overall yield to give 79. We next explored the stereo-
chemical course of various reductions of the carbonyl group
in this ketone and settled on the use of Meerwein–Ponndorf–
Verley conditions. α-Alcohol 80 was isolated in 61% yield
along with 22% of the β-isomer.This reduction gave the most
equitable distribution of the two key epimeric intermediates.
Introduction of a 1ꢀ,2ꢀ-double bond was achieved by treating
80 with tert-butyllithium in THF containing HMPA.[49] Sub-
sequent silylation resulted in masking of the two hydroxyl
groups in a manner identical to that in 81. This compound
was then examined for its ability to react in the desired way
with either phenylselenenyl chloride or N-iodosuccinimide
in the presence of persilylated thymine.[50] Both reactions
proved to be remarkably successful, giving rise to 82 and 83
as single diastereomers.The indicated stereochemical assign-
ments are based on the results of NOESY experiments. To
complete the conversion into 84, we selected radical condi-
tionsforthechemoselectivereductivecleavage.Thenine-step
conversion of 77 into this enantiopure spirothianucleoside
H3C
H
H3C
NH
NH
1. Bu3SnH,
AIBN
TBSO
HO
H
O
N
O
N
S
S
C6H6, ∆
2. TBAF, THF
(55%)
I
TBSO
OH
83
84
Scheme 15. An effective route to 2ꢀ-deoxy spirothianucleosides.
DABCO = 1,4-diazabicyclo[2.2.2]octane, AIBN = azobis(isobutyro-
nitrile).
is illustrative of a convenient means for assembling these
attractive compounds.
Carbaspironucleosides Having Natural C1ꢀ Absolute
Configuration
Theexplosiveinterestincarbocyclicnucleosideswitnessedin
the past decade is a likely reflection of the potent antiviral and
antitumour properties of select members of this class[51–53]
and their improved metabolic stability as a consequence of
the absence of a glycosyl linkage.[54] Retrosynthetic con-
sideration of the spiro equivalents 88 and 89 led us back
to readily available ( )-spiro[4.4]nonane-1,6-dione,[55] the
reduction of which with LiBut(Bui)2AlH has previously been
shown to deliver the racemic cis,cis-diol[57] (Scheme 16).The
last compound has been effectively resolved with generation
of (–)-85 and (+)-85 via ketalization with (1R)-(+)-
camphor.[56] According to our strategy, the laevorotatory
enantiomer was to serve as a practical precursor to 88 in light
of the absolute configurational features held in common by
this pair of compounds. Our ready procurement of 89 on
the other hand was to rest on the suitable monoprotection of

14
L. A. Paquette
TBSO
TBSO
H
HO
HO
H
H
B
OH
RO
disiamylborane;
HO
H
POCl3
H
H
OH
H2O2, OH–
(70%)
py
(56%)
OH
(ꢁ)-90
(ꢁ)-91
(ꢂ)-85
86
88
TBSO
TBSO
H
H
HO
RO
H
H
B
H
OH
H
H
OH
H
ꢁ
OH
OH
(ꢁ)-99
(ꢁ)-100
(ꢁ)-85
87
89
1. Ph3P, DIAD,
PhCOOH (86%)
Scheme 16. Retrosynthetic construction of the epimeric spiro-
carbanucleosides reflecting the ‘merger of chirality’ concept.
2. NaOH, aq. MeOH
(71%)
O
N
NH2
TBSO
1. 95 or 96
H
H
TBSO
H
TBSO
POCl3
OH
CH3
CrO3
HN
N
H
O
DIAD, Ph3P,
THF or dioxane
(52%; 43%)
O
py
(56%)
3,5-DMP
(53%)
H
HO
HO
O
ꢁ
N
(ꢂ)-90
(ꢂ)-91
(ꢁ)-92
2. TBAF, THF
(80%; 79%)
3. NH3, MeOH
(90%; 95%)
(ꢁ)-101
(ꢁ)-102
TBSO
H
H
TBSO
OH
H
H
NaBH4
ꢁ
CeCl3
(99%)
Scheme 18. The conversion of (+)-90 into spirocarbanucleosides
OH
properly configured at C1ꢀ.
(ꢂ)-93
(ꢁ)-94
1. Ph3P, DIAD,
PhCOOH (90%)
1. H2, 10% Pd-C (72%)
of (+)-91 was properly directed by involving the steri-
cally demanding disiamylborane reagent. The distribution of
isolated 99 and 100 was 19 and 51%. For the purpose of max-
imizing the available amount of 100, the Mitsunobu reaction
was successfully applied once again. At this point, practical
crossover to the diastereomeric manifold was realised and the
acquisition of 101 and 102 was accomplished in the manner
developed earlier.
This conversion of the enantiomers of 90 by differ-
ent synthetic pathways into epimeric dideoxy spirocytidines
and spirothymidines having natural absolute stereochemistry
at C1ꢀ constitutes an unprecedented ‘merger-of-chirality’
principle of potentially bioactive application.
O
NHBz
2. NaOH, aq MeOH
(90%)
Bz
CH3
2.
O
N
N
or
O
N
H
N
H
NH2
O
95
96
CH3
N
DIAD, Ph3P,
THF or dioxane
(30%; 30%)
HN
H
HO
HO
H
O
N
O
N
ꢁ
3. NH3, MeOH
(89%; 74%)
(ꢂ)-97
(ꢂ)-98
4. TBAF, THF
(74%; 75%)
Scheme 17. Exemplary spirocarbanucleoside construction. DIAD =
diisopropyl azodicarboxylate.
Another spirocarbanucleoside theme developed more
recently in this laboratory involves the conversion of spiro-
cyclic enones such as (+)-92 into 2ꢀ-deoxy nucleosides as
exemplified by the adenosine derivative 108[65] (Scheme 19).
The successful pathway relies on the susceptibility of 92 and
structural analogues thereof to undergo base-promoted con-
version to the respective epoxy ketones, whose reduction with
samarium iodide inTHF[66] furnishes the β-hydroxycarbonyl
product resulting from cleavage of the α-C O bond. In the
specific case of 92, the conversion into 103 was highly stereo-
selective, thus allowing for clear definition of the configura-
tion of C3ꢀ in 104. The Dibal-H reduction of 104 gave rise to
a chromatographically separable mixture of 105 and 106 in a
1 : 3.5 ratio. Standard conditions for the Mitsunobu reaction
allow for total conversion of 105 into 106 and full use of the
material supply. The mesylation of 106 to give 107 followed
by SN2 displacement with the sodium salt of adenine[67] and
desilylation affords in good yield the adenosine analogue 108.
(+)-85, subsequent conversion into 87 presumably via the
cyclopentene, and ultimately deployment of an SN2 reaction
to invert configuration.
Consistent with the non-bonded steric compression
present in 90, its dehydration proved to be problematic. Ulti-
mately, phosphorous oxychloride was found to be capable of
generating 91 in satisfactory yield[57] (Scheme 17). Expect-
edly, the major competing process was Wagner–Meerwein
rearrangement. Sequential oxidation with the chromium
trioxide–3,5-dimethylpyrazole complex[58,59] and reduction
accordingtoLuche[60] produced 93and 94ina1 : 1diastereo-
meric ratio. Following their ready chromatographic separa-
tion, 93 could be individually transformed into 94, thereby
allowing for the acquisition of appreciable amounts of the
latter.This accomplished, 94 was subjected to catalytic hydro-
genation and cleanly converted into both 97 and 98 by
means of established processes.[61–64] The selectivity of the
individual reactions was rewardingly high.
Future Prospects
The next phase of this investigation called again for
the dehydration of 90, although now in the form of the
(+)-enantiomer[58] (Scheme 18).The regiodirected hydration
For antisensechemotherapytobesuccessful, thenewlydevel-
oped spirocyclic nucleotides will need to be resistant to

Spirocyclic Restriction of Nucleosides
15
TBSO
H
(a)
TBSO
1. SmI2, THF
(60%)
H
H2O2,
NaOH
O
(ꢁ)-92
O
2. TBSOTf,
2,6-lutidine
(99%)
MeOH
(78%)
O
OTBS
(ꢂ)-103
(ꢂ)-104
TBSO
H
CH3SO2Cl,
Et3N
TBSO
H
OH
Dibal-H
ꢁ
THF, ꢂ78ºC
(99%)
CH2Cl2, 0ºC
(81%)
OH
OTBS
TBSO
(ꢁ)-105
(ꢂ)-106
(1:3.5)
1. Ph3P, DIAD,
PhCOOH, THF (86%)
2. NaOMe, MeOH
(80%)
NH2
N
N
TBSO
H
1. adenine, NaH,
DMF (60%)
(b)
HO
H
N
N
2. TBAF, THF
(70%)
OSO2CH3
TBSO
OH
(ꢁ)-107
(ꢂ)-108
Scheme 19. Acquisition of a deoxy spirocarbanucleoside.
5ꢄ-gctactacgtgcg-3ꢄ
(site of spirocyclic nucleoside insertion)
Diagram 2.
Fig. 2. Computed changes in the duplex structure of a 13-mer duplex
as a central thymidine is exchanged for 3a (B =Th) and 3b (B =Th)
(Amber program, Na+ ions not shown for clarity).
nuclease activity and be capable of modulating viral gene
expression.[68] As discussed at the outset, 1–4 may be resis-
tant to enzymatic transformations and have improved bio-
availability. However, will nucleosides incorporating these
building blocks provide duplexes with complementary
nucleic acids that are stable? Molecular modelling stud-
ies have provided the exciting prospect that spirocyclo-
DNA/RNAhybridsarequitecapableofrealizingbase-pairing
interactions closely comparable to natural nucleic acids.
Of course, confirmation of these predictions must await the
actual determination of their properties, most particularly
thermal denaturation.
reorganization) should materialize despite the obvious dis-
parity in backbone and furanose ring torsional angles. The
possibility of arresting DNA synthesis without sequentially
altering the hydrogen-bonding geometry of template bases
has been reported.[69]
An increasing variety of gene products are being dis-
covered that are regulated by antisense RNA molecules
expressed intracellularly.[70,71] It is hoped that the spiro-
cyclic restriction approach outlined herein will ultimately
prove feasible for therapeutic applications in the context
of gene therapy. Increasing RNA binding affinity to syn-
thetic oligonucleotides does not alone lead to biological
efficacy. These compounds must also penetrate cells and
reach cytoplasm where they must bind effectively to m-RNA
and particularly the crucial initiation codon region.[72] The
conservative spirocyclic modifications proposed here are apt
to possess improved properties such as suitably enhanced
lipophilicity, resistance to alkaline hydrolysis, as well as sta-
bility toward nuclease degradation. We end by quoting Piet
Herdewijn:[2b] ‘… the design and synthesis of conformation-
ally restricted oligonucleotides remains challenging research
with great potential for future drug development in all fields
of oligomeric structures.’
These results of molecular modelling studies are illus-
trated here for 13-mer systems having the base sequence
depicted in Diagram 2.
The computations made provision for the inclusion of
sodium ions, which were subsequently deleted from Fig. 2
for purposes of clarity. For this model-building exercise, a
centrally located thymidine unit was replaced by 3b (B =Th)
as well as by 3a (B =Th). The fidelity of the base-pairing in
all three systems is remarkably good. The magnified regions
are intended to provide improved visualization of the central
core of these oligonucleotides. In light of these indicators,
the anticipated reduction in the entropy term upon duplex
formation with both 3a and 3b (a consequence of structural

16
L. A. Paquette
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