Practical synthesis of 1′-substituted Tubercidin C-nucleoside analogs

Article abstract of DOI:10.1016/j.tetlet.2011.11.055

Several 1′-substituted analogs of Tubercidin C-nucleosides were prepared using a highly convergent synthesis. Good to high diastereoselectivity was achieved using a variety of nucleophiles targeting the 1′-position. The source for this stereoselectivity i

Full text of DOI:10.1016/j.tetlet.2011.11.055

Tetrahedron Letters 53 (2012) 484–486
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Practical synthesis of 10-substituted Tubercidin C-nucleoside analogs
⇑
Sammy E. Metobo , Jie Xu, Oliver L. Saunders, Thomas Butler, Evangelos Aktoudianakis, Aesop Cho,
⇑
Choung U. Kim
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA
a r t i c l e i n f o
a b s t r a c t
Several 10-substituted analogs of Tubercidin C-nucleosides were prepared using a highly convergent
synthesis. Good to high diastereoselectivity was achieved using a variety of nucleophiles targeting the
10-position. The source for this stereoselectivity is herein proposed. It is thought to be attributed to a tem-
perature-dependent chelation of the incoming nucleophile to either the 20- or 30-benzyloxy ether of the
ribose core.
Article history:
Received 12 October 2011
Accepted 11 November 2011
Available online 18 November 2011
Keywords:
Tubercidin
Ó 2011 Elsevier Ltd. All rights reserved.
C-nucleosides
Stereoselective
Chelation
Introduction
synthesis, not only suffers from a low yield, but also does not allow
for an efficient access to various 10-substitutions, a position that we
There are many C-nucleosides that exhibit antibacterial, antivi-
ral, and antitumor properties, however only a few have been inves-
tigated for drug discovery.1 Perhaps, this has been due to a lack of
practical, stereo-controlled syntheses of C-nucleosides that take
advantage of the convergent coupling similar to those available
in the synthesis of N-nucleosides.2
Tubercidin 1 (7-deazaadenosine, Fig. 1) is an adenosine mimic
that is highly cytotoxic, capable of interfering with numerous bio-
logical processes.3 Compound 2, the C-nucleoside analog of Tub-
ercidin, has previously been synthesized by Klein and co-workers
albeit in low yield.4 It has a nearly equipotent cytotoxicity com-
pared to 1. Klein’s approach entailed the coupling of the ribose lac-
tol with pyrrolemagnesium bromide as a synthon that was used to
eventually access 7,9-dideaza-4-aza-adenosine. However, this
have become interested in for biological evaluation.5
Chemistry
In recent years there has been an extensive variety of syntheses
of compounds modeled on C-nucleosides.6 Three approaches have
been primarily used for the synthesis of C-nucleosides: (i) con-
struction of the heterocycle on the preformed carbohydrate,7 (ii)
construction of a sugar moiety onto a preformed heterocycle unit,8
and (iii) direct coupling of a preformed sugar moiety onto a pre-
formed heterocyclic unit.9
We were particularly attracted to the last method as it was a
convergent and synthetically practical strategy that we envisioned
would allow access to 10-substituted nucleosides. High
b
NH2
N
NH2
N
NH2
N
HO
N
N
HO
N
HO
O
O
O
N
N
N
R
HO OH
HO OH
HO OH
R = CN, Me, allyl
Figure 1. Tubercidin 1, Tubercidin-C-nucleoside 2 and 10-substituted C-nucleoside analogs.
1
2
HL-60 (ID50) = 0.82 nM
HL-60 (ID50) = 0.64 nM
⇑
Corresponding authors.
E-mail addresses: smetobo@gilead.com (S.E. Metobo), choung.kim@gilead.com (C.U. Kim).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.055

S. E. Metobo et al. / Tetrahedron Letters 53 (2012) 484–486
485
Table 1
NH2
N
Diastereoselective substitutions of hemiacetal 5 with various nucleophiles
NH2
N
BnO
O
O
N
BnO
Nucleophile
R
Lewis acid Temp (°C) Time (h) Yield (%)
a
/b
(a)
O
N
+
Triethylsilane
TMSCN
H
CN
BF3ꢁOEt2
TMSOTf
TMSOTf
BF3ꢁOEt2
0
0
ꢀ78
ꢀ78
ꢀ78
0
1
2
3
3
2
3
2
82
76
65
58
55
45
75
5/95
OH
N
BnO OBn
N
43/57
15/85
11/89
13/87
Br
BnO OBn
4
3
5
AllylTMS
AlMe3
AllylTMS
Allyl BF3ꢁOEt2
NH2
NH2
N
Me
BF3ꢁOEt2
Allyl BF3ꢁOEt2
0
26/74
(c)
N
(b)
N
N
O
O
HO
N
N
H
BnO
BnO
H
OBn
OH
HO
yield. Nitrile 6b was also synthesized using trimethylsilyl trifluoro-
methanesulfonate as a Lewis acid without any significant erosion
of selectivity or yield. Allyl 6c, was obtained using allyltrimethylsi-
lane in the presence of boron trifluoride etherate. When the reac-
6a
7
Scheme 1. Reagents and conditions: (a) Method A: (i) compound 3, n-BuLi
(3.3 equiv), THF, ꢀ78 °C (ii) add 4; 3 h, 38% yield. Method B: (i) 3, 1,1,4,4-
tetramethyl-1,4-dichlorodisilylethylene (1.2 equiv), NaH (2.2 equiv, 60% mineral
oil), n-BuLi (3.3 equiv), THF, ꢀ78 °C (ii) add 4; 1 h, 60% yield. (b) BF3ꢁOEt2 (3 equiv),
tion was carried out at 0 °C, a ratio of 74:26 b:
At -78 °C, the ratio improved modestly to 87:13 b:
a
a
in a 76% yield.
in a 70% yield.
triethylsilane (4 equiv), CH2Cl2, 0 °C, 2 h. ratio of anomers 95:5 (b:
BCl3, CH2Cl2, ꢀ78 °C, 2 h, 78% yield.
a) yield 82%. (c)
When the reaction was carried out at 0 °C, the 10-Me analog 6d
was obtained using trimethyl aluminum and boron trifluoride
etherate in a 45% yield approximately a 1:1 mixture of the two
anomers. However, when the reaction temperature was lowered
to less than 5% conversion to product was observed.
stereoselectivity has been achieved by the anomeric reduction of
the hemiacetal intermediates prepared by coupling of aryl lithium
reactants to protected ribonolactones.10 Further, this synthetic ap-
proach allowed for practical iterations of either the heterobase or
furanose moieties.
Discussion
Our approach began with lithiating a fully elaborated bromo
heterocycle 3 (Scheme 1).11 Though compound 3 possess an acidic
amino group and is sparingly soluble in THF, the addition of n-bu-
tyl lithium at ꢀ78 °C, afforded the lithio species, which was reacted
with the tribenzyl lactone 4.12 This generated hemiacetal 5 as an
inconsequential 3:1 anomeric mixture in a 38% yield. The absolute
stereochemistry was not determined. Our yield was improved to
60% when the 6-amino group of 3 was transiently protected as
its stabase adduct.13,14 The resulting hemiacetal 5 was then sub-
jected to anomeric reduction using triethylsilane and boron tri-
fluoride etherate to furnish 6a.15 The reaction was carried out at
There is a considerable volume of work in the literature in-
tended to explain and predict the stereochemical outcome of
nucleophilic substitutions to various ribono-oxocarbenium ions.18
Reissig and Schmitt proposed a Felkin–Ahn model for the selectiv-
ity seen in c
-lactols.19 More recently, Guindon has proposed a SN2
‘exploded model’ that puts forth evidence that substituents at C-2
are more likely to influence the stereochemical outcome of nucle-
ophilic addition to the C-1 than substituent’s at C-3.20 Woerpel has
provided empirical evidence to support the ‘inside-attack’ model.
Specifically it is proposed addition takes place toward the concave
face of the envelope conformation of the transition state oxocarbe-
nium ion.21
In our work, it is clear there is a temperature effect influencing
the stereoisomeric ratio when 5 is subjected to certain nucleo-
philes. To explain this, a mechanism for the stereoselective ano-
meric reduction is postulated below (Scheme 3).
0 °C to yield a 95:5 ratio of b:a
anomers (determined by 1H NMR
and NOESY spectroscopy). The benzyl protecting groups were then
globally removed using boron trichloride to provide the corre-
sponding nucleoside 7 in a 40% yield over three steps.
We surmised that compound 5 could serve as an interme-
diate for the synthesis of various 10-substituted nucleosides
(Scheme 2).16
The stereochemical outcome upon the addition of various
nucleophiles to 5 was explored. Nitrile 6b was obtained using tri-
methylsilyl cyanide in the presence of boron trifluoride etherate.
Unlike the results obtained from the anomeric reductions with
triethylsilane, when the reaction was carried out at 0 °C, no stere-
oselectivity was observed (Table 1). When the reaction was run
In the case of 6a, at 0 °C, the chelation of silicon to either a 20- or
30-benzyl ether oxygen electron lone pair results in delivery of the
hydride anion from a favored face to furnish only the b anomer
almost exclusively. For 6b, at 0 °C, this proposed chelation is
compromised, as evidenced by the loss of selectivity. At ꢀ78 °C,
chelation of the silicon atom of the trimethylsilyl cyanide to the
benzyloxy group is effective and the result is that the cyanation
occurs stereoselectively (Fig. 2).This coordination results in the
at -78 °C, the anomeric stereoselectivity was 89:11 b:
a
in a 64%
delivery of the cyanide from the a-face preferentially.
It should be noted that there is no evidence as to which of the
20- or 30-benzyl ethers are responsible for the observed stereoselec-
tivity. Woerpel and co-workers has reported that the 30-benzyloxy
group plays a bigger role in determining the stereochemical out-
come of substitution at the 10-position, though he also found that
20-benzyl ethers also contribute.22
NH2
N
NH2
N
(a)
N
BnO
N
BnO
O
O
N
N
R
OH
BnO OBn
Methyl addition to the 10-position failed to proceed stereoselec-
6b R = CN
6c R = allyl
6d R = Me
OBn
BnO
tively yielding a 1:1 b:a anomeric mixture. This might be due to
6b-d
5
weak chelation of aluminum to the 20- or 30-benzyl ether oxygen
at 0 °C. At temperatures that gave good selectivity for the addition
of cyano and allyl moieties (ꢀ78 °C), there was no appreciable
product formed with trimethylaluminum. Carrying out the reac-
tion at 0 °C in order to effect conversion resulted in a complete loss
of stereoselectivity.
Scheme 2. Reagents and conditions: 6b: TMSCN (4 equiv), TMSOTf (3 equiv),
CH2Cl2, 0 °C. ratio of anomers 57:43 (b: ), 76%. At ꢀ78 °C, 5 h, 89:11 (b: ), 65%.
TMSCN (4 equiv), BF3ꢁOEt2 (3 equiv), CH2Cl2, ꢀ78 °C, 5 h, 85:15 (b: ), 58 %. 6c:
allyltrimethylsilane (3 equiv), BF3ꢁOEt2 (3 equiv), CH2Cl2, 0 °C 74:26 (b: ), 76%. At
ꢀ78 °C, 87:13 (b: ), 70 %. 6d: AlMe3 (5 equiv), BF3ꢁOEt2 (4 equiv), CH2Cl2, 0 °C, 12 h,
45% 52:48 (b: ).
a
a
a
a
a
a

486
S. E. Metobo et al. / Tetrahedron Letters 53 (2012) 484–486
NH2
N
NH2
NH2
N
N
BF3.OEt2
TES
BnO
N
BnO
O
O
N
N
O
N
N
N
H
OH
BnO
H
Si
0 o
C
O
BnO OBn
BnO OBn
BnO
Bn
6a
5
Scheme 3. Proposed mechanism for stereoselective dehydroxylation of 5.
5. Manuscript describing biological properties of these and related compounds is
being prepared and will be reported shortly.
6. Adamo, M. F. A.; Adlington, R. M.; Baldwin, J. E.; Day, A. L. Tetrahedron 2004, 60,
841.
7. (a) Adlington, R. A.; Baldwin, J. E.; Pritchard, G. J.; Spencer, K. C. Tetrahedron Lett.
2000, 41, 575; (b) Biocryst Pharmaceuticals WO 2008/089105 A2.; (c) Butora,
G.; Olsen, D. B.; Carroll, S. S.; McMassters, D. R.; Schmitt, C.; Leone, J. F.;
Stahlhut, M.; Burlein, C.; MacCoss, M. Bioorg. Med. Chem. 2007, 15, 5219.
8. Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B. J. Org. Chem. 1998, 63, 984.
9. Clazada, E.; Clarke, C. A.; Roussin-Bouchard, C.; Wightman, R. H. J. Chem., Soc.,
Perkin Trans. 1 1995, 517.
NH2
N
O
N
BnO
BnO
N
O
R
Si
Bn
R = CN, allyl
10. Piccirilli, J. A.; Krauch, T.; Macpherson, L. J.; Benner, S. A. Helv. Chim. Acta 1991,
397.
11. Bayer US patent WO2006-US46081.
12. Alessandrini, L.; Casati, S.; Ciuffreda, P.; Ottria, R.; Santaniello, E. J. Carb. Chem.
2008, 27, 332.
Figure 2. Proposed transition states for cyanation and allyation at ꢀ78 °C. O–Si
coordination preferentially delivers nucleophile from
a phase.
13. (a) Djuric, S.; Venit, J.; Magnus, P. Tetrahedron Lett. 1981, 22, 1787; (b)
Hildbrand, S.; Blaser, A.; Parel, S. P.; Leumann, C. J. J. Am. Chem. Soc. 1997, 119,
5499–5511.
Conclusion
14. Spectral data for compound 5: 7-Bromo-pyrrolo[2,1-f]triazine-4-ylamine
3
A practical and convergent synthetic approach to 10-substituted
C-nucleoside analogs is described. The hemiacetal obtained from
the coupling of the bromo heterocycle 3 and ribonolactone 4, is a
versatile intermediate en route to this novel class of nucleosides.
In the case of some nucleophiles, addition to the 10-position, re-
sulted in good stereoselectivity at reduced temperature. This pro-
tocol appears to be general and should allow for the facile access
to various C-nucleosides.
(2.78 gm, 1.1 equiv 13.2 mmol, prepared according to WO2007056170) was
suspended in anhydrous THF (70 mL). Under inert atmosphere, 1,1,4,4-
tetramethyl-1,4-dichlorodisilyethylene (2.83 gm, 1,1 equiv, 13.2 mmol) was
added along with sodium hydride (1.05 gm, 26.3 mmol, 2.2 equiv) was added
and the mixture was stirred for 20 min at room temperature. The reaction was
then cooled to ꢀ78 °C before n-BuLi (27.4 mL, 43.89 mmol, 1.6 M in Hexanes)
slowly over 5 min. The reaction was allowed to stir for a further 15 min before
lactone 4 (dissolved in 3 mL was added dropwise). When the reaction was
complete by LCMS, the reaction was quenched with acetic acid. The reaction
was concentrated in vacuo before being diluted in EtOAc and washing with
water, saturated NH4Cl and brine. The organic layers were dried over MgSO4,
filtered and concentrated in vacuo. The material was purified by silica
Biological evaluation for this new class of nucleosides will be re-
ported shortly.
chromatography (0–50% EtOAc/Hexanes) provided
a 3:1 mixture of 5
anomers. 4.38 gm (y. 60%) of a white solid was obtained.
1H NMR (400 MHz) (CD3)2CO 8.00 (s, 1H), 7.30–7.47 (m, 15H), 7.20 (d, 8.4 Hz,
1H), 6.87 (d, 8.4 Hz, 1H), 5.40 (d, 8.2 Hz, 1H), 4.65–4.4.0 (m, 3 H), 3.65 (dd, 8.8,
4.3.2, 1 H), 3.55 (dd, 8.8, 4.3.2, 1 H) LC–MS (m/z 553.01, M+H+).
15. Matulic-Adamic, J.; Beigelman, L. Tetrahedron Lett. 1997, 38, 1669–1672.
16. Experimental procedures for the syntheses of these or related compounds are
available in WO2009132135A1.
Acknowledgments
The authors would like to thank Michael O. Clarke and Lee
Chong for their help in the preparation of this manuscript.
18. Shenoy, S. R.; Smith, D. M.; Woerpel, K. A. J. Am. Chem. Soc. 2006, 128(26), 8671.
19. Reissig, H.-U.; Schmitt, A. Synlett 1990, 40.
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