Asymmetric synthesis of 4′-quaternary 2′-deoxy-3′-epi- β-C-nucleosides

Article abstract of DOI:10.1055/s-2005-872658

An efficient diastereo- and enantioselective synthesis of 4′-quaternary 2′-deoxy-3′-epi-β-C-nucleosides is described employing the RAMP-hydrazone methodology to establish the first stereocentre. Further key steps include diastereoselective nucleophilic 1,

Full text of DOI:10.1055/s-2005-872658

LETTER
2391
Asymmetric Synthesis of 4¢-Quaternary 2¢-Deoxy-3¢-epi-b-C-Nucleosides
Synthesisof
Q
uate
i
rnar
y
e
e
pi-Nucleos
t
ide An
e
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 18 July 2005
We now wish to disclose our syntheses of the b-C-nucleo-
sides 8a and 8b, which were accomplished in 9 steps in
overall yields of 16% and 22%, respectively, starting from
2,2-dimethyl-1,3-dioxan-5-one (1)10 (Scheme 1). First of
all the RAMP-hydrazone a-alkylation methodology11
provided the tert-butyl ketoester 2 in a good yield of
57% over 3 steps and with excellent enantioselectivity (ee
≥ 99%).
Abstract: An efficient diastereo- and enantioselective synthesis of
4¢-quaternary 2¢-deoxy-3¢-epi-b-C-nucleosides is described em-
ploying the RAMP-hydrazone methodology to establish the first
stereocentre. Further key steps include diastereoselective nucleo-
philic 1,2-additions with Grignard and organocerium reagents.
Key words: asymmetric synthesis, nucleoside analogues, hydra-
zones, organocerium reagents, diastereoselective reduction
A wide range of substituents R1 were incorporated into 2
by employing various Grignard reagents, the tert-butyl-
ester functionality being a good directing group for the
formation of the second stereocentre.12 The diastereomer-
ic excesses ranged from good to excellent (de = 70–98%),
and the minor diastereoisomer could easily be separated
The synthesis of novel nucleoside analogues has attracted
increasing interest in recent years in order to study their
behaviour in oligonucleotides or their biological activi-
ty.1–9 A large number of nucleoside analogues have al-
ready been synthesised by several groups. Alongside
abundant modifications of the structure of nucleobases,1 a
wide variety of sugar analogues have also been devel-
oped, most of them severely altering the nucleoside
structure and leading to carbocyclic, acyclic, thio or aza
nucleosides.2 Nucleoside analogues with structures closer
to the natural building blocks have also been investigated.
For example, 4¢-quaternary nucleosides have been devel-
oped by Marx et al. and proved to lead to superior selec-
tivity compared to natural nucleosides when inserted into
oligonucleotides.3 Other groups have synthesised 4¢-qua-
ternary nucleosides in order to study their biological
activity4 or developed syntheses of 4¢-branched bicyclic
nucleoside analogues.5 Numerous investigations were
reported on C-nucleoside synthesis, using various ap-
proaches.6 For instance, in the studies of Kool7 and
Leumann,8 those nucleoside analogues were introduced
into oligonucleotides, which allowed them to study stack-
ing and shape-mimicking effects separately from hydro-
gen-bonding interactions occurring between natural
nucleobases.
O
O
OtBu
a
O
O
O
O
O
57%
(over 3 steps)
H3C CH3
H3C CH3
ee ≥99%
2
1
b
66–98%
R1 OH
R1
O
OtBu
O
O
c
HO
O
O
99%
HO
H3C CH3
4a–e
3a–e
de, ee ≥99%
R1 = Me, Et, All, Ph, p-F-Ph
d
81–99%
H3C OH
R1
O
R2
O
e
TBSO
82–99%
OTBS OTBS O
R1 = Me
R
TBSO
5a–e
Concerning the synthetic aspect, 4¢-quaternary 2¢-deoxy-
3¢-epi-b-C-nucleosides 8 are challenging target molecules
for asymmetric synthesis, since they require the formation
of three stereocentres, one of them quaternary, in a five-
membered ring. We were interested in synthesising these
nucleoside analogues as they combine a variety of modi-
fications, which could be of great biological interest. For
example, 3¢- or 4¢-epimers of deoxynucleosides are
expected to have a local influence on double helix con-
formation when inserted into DNA (base-flipping).9
2 = Ph, Naph
6a,b
f
70–92%
H3C
HO
H3C
O
O
R2
R2
g
HO
TBSO
TBSO
60–65%
8a,b
7a,b
de, ee ≥99%
Scheme 1 Reagents and conditions: (a) 1. RAMP, benzene, reflux;
2. t-BuLi, THF, –78 °C, then tert-butylbromoacetate, –100 °C; 3. O3,
CH2Cl2, –78 °C; (b) R1MgBr, THF, –78 °C or –100 °C; (c) 3 N HCl,
MeOH, r.t.; (d) TBSOTf, pyridine, THF, 0 °C; (e) CeCl3, R2Li, THF,
–110 °C to –99 °C; (f) Me4NHB(OAc)3, MeCN, AcOH, –30 °C;
(g) TFA–CHCl3 (4:1), CHCl3, 0 °C.
SYNLETT 2005, No. 15, pp 2391–2393
Advanced online publication: 05.08.2005
DOI: 10.1055/s-2005-872658; Art ID: G22705ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.0
9
.2
0
0
5

2392
D. Enders et al.
LETTER
by column chromatography giving access to diastereo- Table 2 C-Nucleoside Formation from Lactone 5a
and enantiomerically pure alcohols 3a–e in good to excel-
R2
Yield of 6 Yield of 7 Yield of 8 ee of 8
lent yields (de, ee ≥ 99%). Subsequent cyclisation13 with
methanolic hydrochloric acid led to lactones 4a–e with
excellent yields in all cases, followed by transformation to
the corresponding TBS ethers 5a–e in very good to excel-
lent yields (Table 1).
For the TBS protection14 of the secondary alcohol neigh-
bouring a quaternary centre, the use of TBSOTf was nec-
essary, as reaction with TBSCl led to the mono-protected
product only, even when the reaction mixture was ex-
posed to harsh conditions (reflux in pyridine). The choice
of base was also crucial for the outcome of the reaction.
Thus, the use of commonly employed 2,6-lutidine led to
elimination, which could be suppressed by using 2,6-di-
tert-butyl pyridine as reported by Chamberlin et al.15 Fur-
ther investigations showed that the far less expensive
pyridine was sufficient to obtain the desired products.
(%)
(%)
(%)
(%)a
≥ 99
≥ 99
a
Ph
82
70
65
b
Naph
99
92
60
a Determined by CSP-GC (Chirasil-dex) / HPLC (DAICELAD.M).
≥ 99%).19 The reaction proceeded smoothly to give pro-
tected b-C-nucleosides 7a,b in good to excellent yields
(Table 2). Investigations with other reducing agents have
not resulted in a-nucleosides so far. The relative b-con-
figuration was confirmed by NOE experiments on 7a.
In the final deprotection step20 a screening of typical de-
silylating agents indicated the sensitivity of the stereocen-
tres. Among the tested reagents only trifluoroacetic acid
in chloroform resulted in complete conversion and, more
importantly, retention of all stereocentres leading to the
desired products 8a,b in good yields and excellent diaste-
reomeric and enantiomeric excesses (de, ee ≥ 99%).21
Table 1 Preparation of the Doubly TBS-Protected Lactones 5a–e
R1
Yield of 3 de,a,b eec of 3 Yield of 5
(%)
86
66
88
98
66
(%)
(% over 2 steps)
In conclusion, we have developed a highly diastereo- and
enantioselective route to 4¢-quaternary 2¢-deoxy-3¢-epi-b-
C-nucleosides, where the substituents at the 4¢-position
can vary from alkyl and allyl to aromatic. The syntheses
of two derivatives (8a,b) were completed over nine steps
in overall yields of 16% and 22%, respectively. We now
envisage to apply the SAMP auxiliary to this method in
order to synthesise 4¢-quaternary 2¢-deoxy-4¢-epi-a-C-nu-
cleosides.
a
b
c
Me
≥ 99, ≥ 99
≥ 99, ≥ 99
≥ 99, ≥ 99
≥ 99, ≥ 99
≥ 99, ≥ 99
85
98
89
80
86
Et
Ph
d
e
p-F–Ph
All
a Determined by GC (CP-Sil-8).
b After column chromatography.
c Determined by CSP-GC (Chirasil-dex, Chirasil L-Val).
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(Sonderforschungsbereich 380) and the Fonds der Chemischen
Industrie. We thank the companies Bayer AG, BASF AG, Wacker
Chemie and Degussa AG for the donation of chemicals.
Subsequently, nucleophilic 1,2-addition of organocerium
reagents16 on the TBS-protected lactone 5a was per-
formed.17 The cyclic hemi-acetals formed during the
course of this reaction opened to give the g-hydroxy-
ketones 6a,b in good yields. The reaction temperature
proved to be very important for the reproducibility of this
addition. On the one hand the temperature had to be kept
below –105 °C to prevent a second addition to the new
keto functionality, on the other hand the ring-opening
seemed to only occur at temperatures above –105 °C. At
lower temperature only a complex mixture of elimination
products along with the desired product was found. For
these reasons, our strategy was to perform the reaction at
temperatures below –105 °C in order to avoid double ad-
dition and then allow the mixture to warm up to –99 °C
right before quenching. This led to the satisfying results
shown in Table 2.
References
(1) Vorbrüggen, H.; Ruh-Pohlenz, C. Org. React. 1999, 55, 1.
(2) (a) For an overview see: Perspectives in Nucleoside and
Nucleic Acid Chemistry; Kisakürek, M. V.; Rosemeyer, H.,
Eds.; VHCA: Zürich, 2000. (b) For a review on aza
nucleosides see: Yokoyama, M.; Momotake, A. Synthesis
1999, 1541. (c) For a review on thio nucleosides see:
Yokoyama, M. Synthesis 2000, 1637.
(3) Summerer, D.; Marx, A. Angew. Chem. Int. Ed. 2001, 40,
3693; Angew. Chem. 2001, 113, 3806.
(4) (a) Nomura, M.; Shuto, S.; Tanaka, M.; Sasaki, T.; Mori, S.;
Shigeta, S.; Matsuda, A. J. Med. Chem. 1999, 42, 2901.
(b) Shuto, S.; Kanazaki, M.; Ichikawa, S.; Minakawa, N.;
Matsuda, A. J. Org. Chem. 1998, 63, 746. (c) Waga, T.;
Ohuri, H.; Meguro, H. Nucleosides Nucleotides 1996, 15,
287. (d) O-Yang, C.; Wu, H. Y.; Fraser-Smith, E. B.;
Walker, K. A. M. Tetrahedron Lett. 1992, 33, 37. (e) O-
Yang, C.; Kurz, W.; Eugui, E. M.; McRoberts, M. J.;
Verheyden, J. P. H.; Kurz, L. J.; Walker, K. A. M.
Tetrahedron Lett. 1992, 33, 41. (f) Rangam, G.; Rudinger,
N. Z.; Müller, H. M.; Marx, A. Synthesis 2005, 1467.
Reduction was then performed according to Evans et al.
with tetramethyl ammonium triacetoxy borohydride,18
which to our surprise not only led to the cyclised products
7a,b but also showed complete diastereoselectivity to-
wards the b-configuration of the C-nucleoside formed (de
Synlett 2005, No. 15, 2391–2393 © Thieme Stuttgart · New York

LETTER
Synthesis of Quaternary epi-Nucleoside Analogues
2393
(5) (a) Obika, S.; Osaki, T.; Sekiguchi, M.; Somjing, R.; Harada,
Y.; Imanishi, T. Tetrahedron Lett. 2004, 45, 4801.
(b) Montembault, M.; Bougougnon, N.; Lebreton, J.
Tetrahedron Lett. 2002, 43, 8091. (c) Obika, S.; Morio, K.-
i.; Nanbu, D.; Hari, Y.; Itoh, H.; Imanishi, T. Tetrahedron
2002, 58, 3039. (d) Singh, S. K.; Kumar, R.; Wengel, J. J.
Org. Chem. 1998, 63, 6078.
(6) For a review see: Wu, Q.; Simons, C. Synthesis 2004, 1533.
(7) For a review see: Kool, E. F. Annu. Rev. Biochem. 2002, 71,
191.
(8) Brotschi, C.; Häberli, A.; Leumann, C. J. Angew. Chem. Int.
Ed. 2001, 40, 3012; Angew. Chem. 2001, 113, 3101.
(9) For reviews see: (a) Roberts, R. J.; Cheng, X. Annu. Rev.
Biochem. 1998, 67, 181. (b) Cheng, X.; Roberts, R. J.
Nucleic Acids Res. 2001, 29, 3784. (c) Huang, N.;
MacKerell, A. D. Philos. Trans. R. Soc. London, Ser. A
2004, 362, 1439.
(10) For a recent review see: Enders, D.; Voith, M.; Lenzen, A.
Angew. Chem. Int. Ed. 2005, 44, 1304; Angew. Chem. 2005,
117, 1330.
under these conditions for an additional hour. After cooling
down to r.t. the flask was filled with argon and abs. THF (4
mL/mmol of CeCl3) was added. The suspension was stirred
for at least 1 h and then placed in an ultrasound bath for an
extra hour. The mixture was then cooled down to –78 °C and
the lithium reagent was added dropwise. After 2 h stirring at
low temperature a bright yellow colour indicated the
formation of the active cerium reagent. The mixture was
then cooled down to –105 °C and lactone 5a was added in
abs. THF (5 mL/mmol), carefully keeping the temperature
below –100 °C. After 30 min, the reaction mixture was
allowed to warm up to –99 °C and quenched with H2O (10
mL/mmol). Extraction with CH2Cl2 (100 mL/mmol)
followed by treatment with brine and drying over MgSO4
provided the desired products 6a,b, which could be purified
by column chromatography (silica gel, Et2O–n-pentane).
(18) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(19) Typical Procedure for the Reduction According to
Evans.
(11) For a review see: Enders, D.; Job, A.; Janeck, C. F.; Bettray,
W.; Peters, R. Tetrahedron 2002, 58, 2253.
A suspension of Me4NHB(OAc)3 (3.0 equiv) in abs. MeCN
(5 mL/mmol) was treated with abs. AcOH (5 mL/mmol)
under an argon atmosphere. The resulting solution was
cooled down to –30 °C and added to a solution of the
hydroxyketone 6a,b in abs. MeCN (2.5 mL/mmol). The
reaction was left standing overnight at –26 °C. Quenching
the reaction with a solution of 10% Na/K-tartrate in H2O (10
mL/mmol) led to a precipitate, which was dissolved by
addition of a sat. aq solution of Na2CO3. The aqueous phase
was extracted with Et2O (100 mL/mmol) and the combined
organic layers were washed with brine and dried over
MgSO4. The cyclised products 7a,b were purified by column
chromatography (silica gel, Et2O–n-pentane).
(12) Typical Procedure for the Grignard Reaction.
In a dried Schlenk flask, equipped with a magnetic stirrer,
the ketone 2 was dissolved in abs. THF (10 mL/mmol) under
an argon atmosphere. The solution was cooled to –78 °C or
–100 °C, respectively, depending on the Grignard reagent
employed, which was then slowly added (2.0 equiv). The
mixture was allowed to stir while maintaining the
temperature constant for 4 h. The reaction was then stopped
by addition of sat. aq solution of NH4Cl (5 mL/mmol). After
warming up to r.t. the precipitate was dissolved by dilution
with H2O. The aqueous phase was extracted with Et2O (50
mL/mmol) and the combined organic layers were washed
with brine and dried over MgSO4. Column chromatography
(silica gel, Et2O–n-pentane) gave the corresponding alcohols
3a–e as colourless crystals.
(20) Typical Procedure for the Deprotection.
To the TBS ethers 7a,b in CHCl3 at 0 °C was slowly added
a 4:1 mixture of TFA and CHCl3. The reaction progress was
monitored by TLC. When the reaction was completed the
solvent was evaporated under reduced pressure. Traces of
TFA were removed by repeated co-evaporation with MeOH.
Column chromatography with Et2O on silica gel gave rise to
the free b-nucleosides 8a,b.
(13) Typical Procedure for the Cyclisation.
The products 3a–e were dissolved in MeOH (3 mL/mmol)
and treated with 3 N methanolic HCl (3 mL/mmol, prepared
by mixing one part of aq HCl (12 N) with four parts of
MeOH). The reaction was stirred at r.t. until TLC control
indicated complete conversion of the starting material. All
solvents were evaporated under reduced pressure and the
product 4a–e was recrystallised from THF–n-pentane.
(14) Typical Procedure for the TBS-Protection.
To a solution of the diols 4a–e in abs. THF (10 mL/mmol)
was added pyridine (6.0 equiv), and the mixture was cooled
to 0 °C. Slow addition of TBSOTf (3.0 equiv), followed by
4 h of stirring, gave rise to the product. The reaction was
quenched with H2O (5 mL/mmol), extracted with Et2O (50
mL/mmol), washed with brine and dried over MgSO4. The
products 5a–e were then purified by column
(21) (2R,3R,5R)-2-(Hydroxymethyl)-2-methyl-5-(1-
naphthyl)tetrahydrofuran-3-ol (8b): mp 118 °C. IR
(KBr): n = 3517, 3325, 3047, 2962, 2913, 2862, 1597, 1508,
1435, 1373, 1340, 1283, 1220, 1101, 1055, 1016, 939, 913,
860, 778, 642, 560, 490 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.57 (s, 3 H, CH3), 2.09 (ddd, 1 H, J = 12.9, 9.3, 6.6 Hz,
ArCHCHH), 2.42 (t, 1 H, J = 6.2 Hz, CH2OH), 2.98 (d, 1 H,
J = 14.5 Hz, CHOH), 3.02 (ddd, 1 H, J = 12.9, 6.6, 6.3 Hz,
ArCHCHH), 3.87 (d, 2 H, J = 6.2 Hz, CH2OH), 4.36 (dd, 1
H, J = 14.5, 6.6 Hz, CHOH), 5.67 (dd, 1 H, J = 9.3, 6.3 Hz,
ArCH), 7.45–7.99 (m, 7 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): d = 22.01, 43.67, 66.92, 73.34, 79.74, 83.58,
121.72, 123.06, 125.37, 125.42, 125.90, 127.91, 128.64,
130.46, 133.46, 137.06 ppm. MS (EI): m/z (%) = 115 (5),
127 (9), 128 (25), 129 (9), 141 (19), 142 (9), 152 (11), 153
(24), 154 (18), 155 (31), 156 (9), 165 (12), 166 (10), 167
(24), 170 (9), 183 (5), 184 (5), 209 (75), 210 (11), 227 (52),
228 (8), 258 (100), 259 (17). [a]D25 +26.3 (c 0.99, CHCl3).
Anal. Calcd for C12H16O3: C, 74.39; H, 7.02. Found: C,
74.36; H, 7.19.
chromatography (silica gel, Et2O–n-pentane).
(15) Chamberlin, A. R.; Dezube, M.; Reich, S. H.; Sall, D. J. J.
Am. Chem. Soc. 1989, 111, 6247.
(16) Imamoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.;
Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904.
(17) Typical Procedure for the 1,2-Addition.
First, CeCl3·7H2O (2.0 equiv), placed in a Schlenk flask, was
dried without stirring at 130 °C in vacuo (approx. 0.05
mbar) for 1 h. It was subsequently ground up by stirring
Synlett 2005, No. 15, 2391–2393 © Thieme Stuttgart · New York