From intriguing reactivity of 2-bromothiophene to the first synthesis of C1′-disubstituted C-nucleosides

Article abstract of DOI:10.1055/s-0028-1087537

A two-step approach to a family of C1′-disubstituted C-nucleosides is described. It relies on a double aryl condensation on ribonolactone 1 to give the desired disubstituted diols 2c, 6c and 7c. The cycloetherification of these diols followed by protectin

Full text of DOI:10.1055/s-0028-1087537

472
LETTER
From Intriguing Reactivity of 2-Bromothiophene to the First Synthesis of
C1¢-Disubstituted C-Nucleosides
F
irst Synthesis of
o
C1
¢
-Disubs
r
C
i
-Nucle
o
n
sides ne Peyron, Rachid Benhida*
Laboratoire de Chimie des Molécules Bioactives et des Arômes, UMR 6001 CNRS, Institut de Chimie de Nice, Université de Nice-Sophia
Antipolis, 28 Avenue de Valrose, 06108 Nice Cedex 2, France
Fax +33(4)92076151; E-mail: benhida@unice.fr
Received 24 October 2008
electron-rich aromatics and the ribonolactone 1 followed
Abstract: A two-step approach to a family of C1¢-disubstituted
by an efficient intramolecular cycloetherification.
C-nucleosides is described. It relies on a double aryl condensation
on ribonolactone 1 to give the desired disubstituted diols 2c, 6c and
7c. The cycloetherification of these diols followed by protecting
group cleavage gave high yields of C-nucleosides 2d, 6d and 7d, re-
spectively, featuring two hydrophobic aryl groups as nucleobase
surrogates.
We have recently reported that metallation–ribosylation
of 2-bromothiophene conducted at low temperature led to
the hemiacetal 2ah (C5-glycosylation) while, when con-
ducted at room temperature the formation of glycosylated
dibromothiophene 3ah occurred following an original
ribosylation–halogen-dance tandem process (Scheme 1).8
Key words: C-nucleosides, double aryl–aldol condensation, cyclo-
etherification
NH2
N
C-Nucleosides are well-known nucleoside analogues that
contain a stable carbon–carbon linkage between the fura-
nose ring and the heterocyclic base instead of the hydro-
lyzable carbon–nitrogen bond in the classical N-
nucleosides. They have been found in natural as well as in
synthetic analogues with interesting biological activity.
Among them, tiazofurin, pyrazofurin, formycin and
showdomycin were reported as potent antitumor or antibi-
otic compounds.1 Thus, tiazofurin has been recently ap-
proved as an orphan drug for treatment of chronic
myelogenous leukemia in accelerated phase or blast cri-
sis.2 Pseudouridine is the most abundant natural C-nucleo-
side mainly found in ribosomal and transfer RNAs and
has instigated intense studies.3 Another attractive feature
of C-nucleosides arises from their high potential use as
building blocks in modern nucleic acid chemistry by their
incorporation into artificial DNAs and RNAs.4 Therefore,
a large number of synthetic strategies to C-nucleosides
have recently been explored.5 However, less attention has
been focused on their C1¢-disubstituted analogues and the
reported works only concerned the synthesis of C1¢-
branched N-nucleoside analogues of the antitumor antibi-
otic angustmycin (Figure 1).6 Therefore, a direct and prac-
tical method which allows access to C1¢-disubstituted C-
nucleosides are of great interest since, in our knowledge,
such analogues were not reported in literature.
Ar
Ar
N
CH2OH
O
O
HO
HO
HO
OH
HO
OH
angustmycin
C1'-disubstituted C-nucleosides
Figure 1 Structure of angustmycin and the targeted C1¢-disubstitu-
ted C-nucleosides
Intrigued by this chemical reactivity of 2-bromothiophene
we carefully analyzed, in this work, the first aryl–aldol
condensation step and the structure of the resulting prod-
ucts. The 1H and 13C NMR of 3ah were clearly assigned to
the hemiacetal form (a/b anomers, Scheme 1). In contrast,
the 1H and 13C NMR of 2ah revealed the presence of two
stable species, e.g., the hemiacetal 2ah (a/b) and the hy-
droxyketone opened form 2ak (Scheme 1).9 We clearly
observed that the hydroxyketone form appeared with 2-
bromothiophene (2ah vs. 2ak) and disappeared in the case
of dibromothiophene (3ah vs. 3ak). This difference be-
tween 2ah and 3ah was reasonably attributed to the effect
of the bromine atom in position 3. Therefore, in the case
of compound 3ah we hypothesized that the a/b equilibri-
um is very rapid and takes place following ring-opening/
ring-closing process that involves the unstable hydroxy-
ketone intermediate 3ak (equilibrium in favor of the hemi-
acetal). This was clearly attested by the observed change
of the a/b ratio of 3ah depending on the reaction time and
concentration (1H NMR). Interestingly, in the second case
with 2-bromothiophene, the hydroxyketone intermediate
2ak seems to be very stable. Moreover, the presence of sta-
ble 2ak was unambiguously attested by simply prolonging
the reaction time of the condensation reaction since, after
36 hours, the disubstituted product 2b resulting from a
second aryl addition on 2ak was isolated in 45% yield.10 In
contrast, the hemiacetal 3ah remains unchanged even after
As a continuation of our interest in the synthesis of new
nucleoside analogues,7 we report herein a direct strategy
to new C-nucleosides bearing two aryl groups at the ano-
meric position (Figure 1). The synthesis involved two key
operations: a double aryl–aldol condensation between
SYNLETT 2009, No. 3, pp 0472–0476
x
x.
x
x.
2
0
0
9
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087537; Art ID: G35408ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
First Synthesis of C1¢-Disubstituted C-Nucleosides
473
ΔδH = 0 ppm
H
H
δ = 113 ppm
O
Br
S
TBDPSO
OH
O
O
(α/β mixture)
Br
2ah
108 ppm
O
O
O
LDA, THF, r.t.
LDA, THF, –78 °C
Br
+
S
TBDPSO
TBDPSO
ΔδH = 0.7 ppm
OH
2-bromothiophene
(2.5 equiv), 1.5 h
2-bromothiophene
(2.5 equiv), 15 min
O
O
O
O
190 ppm
OH
H
O
92%
96%
H
3ah
(α/β)
1
TBDPSO
LDA, THF, –78 °C
S
Br
3ah (α)
2-bromothiophene 45%
(2.5 equiv), 36 h
O
O
2ak
Br
stable hydroxyketone
(isolated)
S
H
OH HO
Br
O
O
TBDPSO
TBDPSO
S
O
O
S
Br
O
Br
O
2b
3ak
3ah (β)
Scheme 1 Reactivity of 2-bromothiophene towards the ribonolactone 1 (h = hemiacetal and k = hydroxyketone)
a long reaction time. Interestingly, successive silica gel conditions (Scheme 2). We observed that bromobenzene,
chromatography successfully gave the pure 2ah and 2ak thiazole and imidazole (electron-deficient aromatics) af-
and their expected structures were clearly evidenced by forded the corresponding hemiacetals (a/b mixture) 4ah,
NMR (Scheme 1).9
5ah and 6ah, respectively,12 while anisole and benzofuran
gave the hemiacetals 7ah, 8ah and the hydroxyketones 7ak,
8ak, respectively, as pure isolated products.13 Moreover,
as observed in the case of 2-bromothiophene, a prolonged
reaction time led to the disubstituted products 7b and 8b
(Scheme 2). These results clearly attested for the postulat-
ed hypothesis e.g. the electronic effect of the aryl group at
C1¢ on the stability of the resulting hemiacetals vs. hy-
droxyketone forms.
For example, the 1H NMR of 2ah exhibited a single broad
signal at d = 7.20 ppm for H-3 and H-4 (d = 7.20, s, 2 H,
H-3 and H-4) while these protons appeared as two sepa-
rated doublets at d = 7.12 and 7.82 ppm for 2ak, respec-
tively, with a coupling constant of 4 Hz.11 In the same
way, the 13C NMR showed the C1¢ at d = 113 ppm for 2ah
and the C=O at d = 190 ppm for 2ak.
From these results we expected that the additional bro-
mine atom in 3ah acts as an electron-withdrawing substit-
uent and thus, the observed difference in the hemiacetal
vs. ketone equilibrium is probably due to the electronic
nature of the aromatic ring. Since, with 3ah (dibromo-
thiophene) only the hemiacetal form predominates while
in the case of 2a both hemiacetal and hydroxyketone are
present with, the hydroxyketone 2ak available for a sec-
ond arylation to afford 2b. Therefore, to inspect the con-
tribution of this electronic effect we performed additional
experiments with electron-deficient (bromobenzene, thia-
zole and imidazole) and electron-rich (anisole and benzo-
furan) aromatics. Thus, these aromatic systems were
condensed with ribonolactone 1 under the same reaction
With diols 2b (2-bromothiophene), 7b (anisole) and 8b
(benzofuran) in hand, the synthesis of C1¢-disubstituted
C-nucleosides 2d, 7d and 8d was next investigated fol-
lowing C4¢–C1¢ cycloetherification and protecting group
cleavage sequence (Scheme 3). Thus, treatment of 2b, 7b
and 8b under Mitsunobu conditions gave high yields of
the corresponding protected C-nucleosides 2c, 7c and 8c,
respectively (Scheme 3).14 As expected, the cyclization
was found to be fast and high yielding (87–95%). This re-
sult is probably due to the effect of the two aryl groups at
C1¢ which induced selective activation of the benzylic
hydroxy position for an easy intramolecular C4¢-C1¢ ring
closure. The last step consists of the cleavage of the iso-
Synlett 2009, No. 3, 472–476 © Thieme Stuttgart · New York

474
C. Peyron, R. Benhida
LETTER
O
electron-deficient aryls
N
S
N
N
O
O
O
O
N
S
Br
aryl (2.5 equiv)
TBDPSO
TBDPSO
TBDPSO
1
OH
OH
OH
base, THF, –78 °C
76–95%
O
O
O
O
O
O
aryl = 1,3-dibromobenzene, thiazole,
sulfamoyl-imidazole
base = LDA or nBuLi
4ah (α/β)
5ah (α/β)
6ah (α/β)
95%
76%
83%
electron-rich aryls
OH HO
Ar
Ar
OH
O
4-bromoanisole or
Ar
O
benzofuran (2.5 equiv)
36 h
42–45%
Ar
TBDPSO
+
1
TBDPSO
TBDPSO
OH
n-BuLi, THF, –78 °C
80–85%
O
O
O
O
O
O
7ah (Ar = 4-methoxyphenyl)
8ah (Ar = 2-benzofuryl)
7ak (Ar = 4-methoxyphenyl)
8ak (Ar = 2-benzofuryl)
7b (Ar = 4-methoxyphenyl)
8b (Ar = 2-benzofuryl)
(α/β)
(isolated)
Scheme 2 Reactivity of electron-deficient and electron-rich aromatics. Lithiation was performed with LDA in the case of sulfamoylimidazole
and thiazole, and with n-BuLi in the case of 1,3-dibromobenzene, 4-bromoanisole (halogen–metal exchange) and benzofuran.
OH HO
Ar
Ph3P, DEAD, THF
reflux, 30 min
Ar
Ar
Ar
Ar
O
O
aq H2SO4, dioxane
76–84%
HO
TBDPSO
87–95%
TBDPSO
Ar
O
O
HO
OH
O
O
2b, 7b, 8b
2c, 7c, 8c
2d, 7d, 8d
OMe
,
Ar
=
,
Br
S
O
8
2
7
Scheme 3 Synthesis of C1¢-disubstituted C-nucleosides
propylidene and TBDPS protecting groups. Treatment of tuted C-nucleosides as well as the evaluation of their
protected precursors 2c, 7c and 8c with aqueous H2SO4 in antiviral activity are under way in our laboratory.
dioxane afforded good yields (76–84%) of the corre-
sponding free nucleosides 2d, 7d and 8d, respectively,
Acknowledgment
(Scheme 3).15 It is noteworthy that such analogues repre-
The authors thank the UNSA, the le Conseil Régional PACA and
the CNRS for financial support and for a doctoral fellowship (BDI)
to C.P.
sent a new family of C-nucleosides featuring two aryl or
heteroaryl groups at C1¢as nucleobase analogues. In our
knowledge, this type of structure is unprecedented in the
literature.
References and Notes
In summary, we have reported the first synthesis of new
C-nucleosides bearing two aryl or heteroaryl groups at
C1¢. The methodology is highly attractive since it was
efficiently achieved in two key steps using a double aryl–
aldol condensation and C4¢-C1¢ ring closure. This finding
was based on the observed electronic effect of the aryl
system on the equilibrium rate and the stability of the con-
densation products (hemiacetals vs. hydroxyketone
forms). The contribution of other factors to this stability
such as p-stacking and H-bonding will also be studied.
Finally, the application of our methodology to the stereo-
selective synthesis of functionalized C1¢-hetero-disubsti-
(1) For pyrazofurin and formycin, see: (a) Shaban, M. A. E.;
Nasr, A. Z. In Advances in Heterocyclic Chemistry, Vol. 68;
Katritzky, A. R., Ed.; Academic Press: San Diego, 1997,
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Heterocyclic Chemistry, Vol. 70; Katritzky, A. R., Ed.;
Academic Press: San Diego, 1998, 230. (c) For
showdomycin, see: Nishimura, H.; Mayama, M.; Komatsu,
Y.; Kato, H.; Shimsoka, N.; Tanaka, Y. J. Antibiot., Ser. A
1964, 17, 148. (d) Rabinovitz, M.; Uehara, Y.; Vistica, D. T.
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H. B. J. Org. Chem. 1986, 51, 495.
(2) Grifantini, M. Curr. Opin. Invest. Drugs 2000, 1, 257.
Synlett 2009, No. 3, 472–476 © Thieme Stuttgart · New York

LETTER
First Synthesis of C1¢-Disubstituted C-Nucleosides
475
(3) (a) For recent articles, see: For a review, see: Maden,
B. E. H. Nature (London) 1997, 389, 129. (b)Chang, Y.-C.;
Herath, J.; Wang, T. H.-H.; Chow, C. S. Bioorg. Med. Chem.
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Chem. Biol. 2006, 13, 1125.
(10) 2b: 1H NMR (200 MHz, CDCl3 + CD3OD): d = 0.95 (s, 9 H,
Met-Bu), 1.24 (s, 3 H, Me), 1.36 (s, 3 H, Me), 3.26–3.39 (m,
2 H, H5¢), 3.62 (d, 1 H, J = 4.0 Hz, H4¢), 4.26 (dd, 1 H, J = 6.8,
9.8 Hz, H3¢), 4.65 (d, 1 H, J = 6.8 Hz, H2¢), 6.68 (d, 1 H, J =
3.9 Hz, H4), 6.76 (d, 1 H, J = 3.9 Hz, H3), 6.84 (d, 1 H, J =
3.8 Hz, H3), 7.05 (d, 1 H, J = 3.9 Hz, H4), 7.27–7.36 (m, 6 H,
Ph), 7.45–7.62 (m, 4 H, Ph). 13C NMR (50 MHz, CDCl3 +
CD3OD): d = 19.65 (CMe3), 24.14 (Me), 26.54 (Me), 27.14
(Me, t-Bu), 65.68 (C4¢), 69.58 (C5¢), 76.09 (C3¢), 77.63 (C1¢),
83.83 (C2¢), 109.32 (CMe2), 112.38–113.32 (C2), 125.54–
125.60 (C4), 128.13–128.22 (CPh), 129.25–129.63 (C3),
130.24–130.29 (CPh), 135.91 (CPh), 148.09–152.36 (C5). MS
(ESI+): m/z = 773.2, 775.1, 777.1 (49, 100, 60) [M + Na]+.
(11) The variation of Dd values (thiophene protons H3 and H4):
Dd = 0 for 2ah and 0.7 for 2aK could be explained by the
possible anisotropy of the TBDPS group (aryl-TBDPS
p-stacking).
(4) (a) Kool, E. T. Acc. Chem. Res. 2002, 35, 936. (b) Haberli,
A.; Leumann, C. J. Org. Lett. 2002, 4, 3275.
(c) Guianvarc’h, D.; Fourrey, J.-L.; Maurisse, R.; Sun, J.-S.;
Benhida, R. Org. Lett. 2002, 4, 4209. (d) Guianvarc’h, D.;
Fourrey, J.-L.; Sun, J.-S.; Maurisse, R.; Benhida, R. Bioorg.
Med. Chem. 2003, 11, 2751. (e) Leconte, A. M.; Matsuda,
S.; Hwang, G. T.; Romesberg, F. E. Angew. Chem. Int. Ed.
2006, 45, 4326.
(5) For recent reviews on the chemistry of C-glycoside
analogues, see: (a) Wu, Q.; Simons, C. Synthesis 2004,
1533. (b) Lee, D. Y. W.; He, M. S. Curr. Top. Med. Chem.
2005, 5, 1333. (c) For recent articles, see: Wellington,
K. W.; Benner, S. A. Nucleosides, Nucleotides Nucleic Acids
2005, 1309. (d) Guianvarc’h, D.; Fourrey, J.-L.;
(12) 4ah: 1H NMR (200 MHz, CDCl3): d = 1.07–1.12 (2 × s, 9 H,
Met-Bu), 1.25 (s, 3 H, Me), 1.38 (s, 3 H, Me), 3.75 (dd, 1 H,
J = 3.1, 11.2 Hz, H5¢), 3.95 (dd, 1 H, J = 3.0, 11.5 Hz, H5¢),
4.42–4.47 (m, 1 H, H4¢), 4.66 (d, 1 H, J = 5.7 Hz, H2¢), 4.87–
4.95 (m, 2 H, H3¢, OH), 7.24–7.26 (m, 1 H, Ar), 7.37–7.71
(m, 13 H, Ph, Ar). 13C NMR (50 MHz, CDCl3): d = 19.20
(CMe3), 24.87 (Me), 26.37 (Me), 26.92 (CMe3), 65.62 (C5¢),
82.04 (C3¢), 86.40 (C4¢), 88.36 (C2¢), 106.60 (C1¢), 112.87
(CMe2), 121.82 (C3), 124.59 (CHAr), 127.84 (CPh), 129.15
(CHAr), 129.82 (CHAr), 130.19 (CPh), 130.39 (CHAr), 131.22
(CPh), 135.62–135.81 (CPh), 141.37 (C1). MS (ESI+): m/z =
604.6–606.5 (95, 100) [M + Na],+ 620.5–622.5 (95, 100) [M
+ K]+.
Tran Huu Dau, M.-E.; Guérineau, V.; Benhida, R. J. Org.
Chem. 2002, 67, 3724. (e) Urban, M.; Pohl, R.; Klepetarova,
B.; Hocek, M. J. Org. Chem. 2006, 71, 7322. (f) Joubert,
N.; Pohl, R.; Klepetarova, B.; Hocek, M. J. Org. Chem.
2007, 72, 6797.
(6) (a) Kodama, T.; Shuto, S.; Ichikawa, S.; Matsuda, A. J. Org.
Chem. 2002, 67, 7706. (b) Haraguchi, K.; Kubota, Y.;
Tanaka, H. J. Org. Chem. 2004, 69, 1831. (c) Ogamino, J.;
Mizunuma, H.; Kumamoto, H.; Takeda, S.; Haraguchi, K.;
Nakamura, K. T.; Sugiyama, H.; Tanaka, H. J. Org. Chem.
2005, 70, 1684.
(7) (a) Guianvarc’h, D.; Benhida, R.; Fourrey, J.-L.; Maurisse,
R.; Sun, J.-S. Chem. Commun. 2001, 1814. (b) Peyron, C.;
Benhida, R.; Bories, C.; Loiseau, P. Bioorg. Chem. 2005, 33,
439. (c) Spadafora, M.; Burger, A.; Benhida, R. Synlett
2008, 1225. (d) Spadafora, M.; Mehiri, M.; Burger, A.;
Benhida, R. Tetrahedron Lett. 2008, 49, 3967.
(13) 7ah: 1H NMR (200 MHz, CDCl3): d = 1.08–1.12 (2 × s, 9 H,
Met-Bu), 1.26 (s, 3 H, Me), 1.40 (s, 3 H, Me), 3.71–4.01 (m,
5 H, H5¢, OMe), 4.38–4.52 (m, 2 H, H4¢, OH), 4.63 (d, 1 H,
J = 5.7 Hz, H2¢), 4.92 (dd, 1 H, J = 1.5, 5.7 Hz, H3¢), 6.89 (d,
2 H, J = 8.9 Hz, H3), 7.36–7.44 (m, 6 H, Ph), 7.54 (d, 2 H,
J = 8.8 Hz, H2), 7.65–7.75 (m, 4 H, Ph). 13C NMR (50 MHz,
CDCl3): d = 19.39–19.49 (CMe3), 25.14–25.20 (Me), 26.71–
26.82 (Me), 27.04–27.11 (CMe3), 55.38 (OMe), 65.88 (C5¢),
82.23–82.33 (C3¢), 86.43–86.54 (C4¢), 88.25 (C2¢), 107.30
(C1¢), 112.84 (CMe2), 113.12 (C3), 128.08–128.13 (CPh),
128.44 (C2), 130.19–130.35 (CPh), 131.60 (C1), 132.22–
132.32 (CPh), 135.78–135.95 (CPh), 159.70 (C4). MS (ESI+):
m/z = 557.2 [M + Na]+.
(8) Peyron, C.; Navarre, J. M.; Dubreuil, D.; Vierling, P.;
Benhida, R. Tetrahedron Lett. 2008, 49, 6171.
(9) 2ah: 1H NMR (200 MHz, CDCl3): d = 1.07–1.11 (2 × s, 9 H,
Met-Bu), 1.30 (s, 3 H, Me), 1.48 (s, 3 H, Me), 3.72 (dd, 1 H,
J = 3.6, 11.2 Hz, H5¢), 3.90 (dd, 1 H, J = 3.5, 11.3 Hz, H5¢),
4.36 (t, 1 H, J = 2.5 Hz, H4¢), 4.62 (d, 1 H, J = 5.7 Hz, H3¢),
4.75 (s, 1 H, OH), 4.89 (dd, 1 H, J = 1.4, 5.6 Hz, H2¢), 6.96
(s, 2 H, H3, H4), 7.37–7.46 (m, 6 H, Ph), 7.57–7.72 (m, 4 H,
Ph). 13C NMR (50 MHz, CD3OD): d = 19.79 (CMe3), 24.44
(Me), 26.26 (Me), 26.51 (CMe3), 66.35 (C5¢), 84.63 (C2¢),
87.19 (C4¢ or C3¢), 88.07 (C3¢ or C4¢), 106.85 (CMe2), 113.40
(C1¢), 113.80 (C2), 126.15 (C4), 127.60 (CPh), 127.93 (CPh),
129.28 (C3), 130.05 (CPh), 133.41 (CPh), 134.95 (CPh), 135.71
(CPh), 145.66 (C5). MS (ESI+): m/z = 610.8–612.8 (100, 83)
[M + Na]+. MS (ESI–): m/z = 587.0–589.0 (100, 69) [M – H]–
. Anal. Calcd for C28H33BrO5SSi: C, 57.04; H, 5.64. Found:
C, 57.29; H, 5.87.
7ak: 1H NMR (200 MHz, CDCl3): d = 1.06 (s, 9 H, Met-Bu),
1.12 (s, 3 H, Me), 1.31 (s, 3 H, Me), 3.73–3.81 (m, 2 H, H5¢),
3.87 (s, 3 H, OMe), 4.40–4.52 (m, 2 H, H4¢, OH), 4.72–4.82
(m, 1 H, H2¢), 5.23 (d, 1 H, J = 5.5 Hz, H3¢), 6.98 (d, 2 H, J =
7.1 Hz, H3), 7.33–7.44 (m, 6 H, Ph), 7.62–7.75 (m, 4 H, Ph),
8.13 (d, 2 H, J = 8.1 Hz, H2). 13C NMR (50 MHz, CDCl3):
d = 19.21 (CMe3), 26.18 (Me), 26.79 (CMe3), 27.25 (Me),
55.06–55.44 (OMe), 64.77 (C5¢), 68.89 (C2¢), 72.73 (C3¢),
79.35 (C4¢), 111.04 (CMe2), 113.66 (C3), 127.71–127.74
(CPh), 129.77 (C2), 131.44–131.94 (CPh), 135.46–135.58
(CPh), 163.79 (C4), 195.70 (C1¢). MS (ESI+): m/z = 557.6
[M + Na]+. Similar variation of Dd was observed (H2 and H3
protons, 7ah vs. 7aK): Dd = 0.65 for 7ah and 1.15 for 7ak.
(14) 2c: 1H NMR (200 MHz, CDCl3): d = 1.05 (s, 9 H, Met-Bu),
1.29 (s, 3 H, Me), 1.39 (s, 3 H, Me), 3.70–4.12 (m, 3 H, H4¢,
H5¢), 4.76 (dd, 1 H, J = 2.9, 5.9 Hz, H3¢), 5.01 (d, 1 H, J = 5.8
Hz, H2¢), 6.41 (d, 1 H, J = 3.8 Hz, H4), 6.83 (d, 1 H, J = 3.9
Hz, H3), 6.87 (d, 1 H, J = 3.9 Hz, H3), 6.98 (d, 1 H, J = 3.8
Hz, H4), 7.32–7.45 (m, 6 H, Ph), 7.65–7.78 (m, 4 H, Ph).
13C NMR (50 MHz, CDCl3): d = 19.38 (CMe3), 24.68 (Me),
25.77 (Me), 26.94 (CMe3), 61.83 (C5¢), 77.36, 78.88, 80.43,
81.37 (C4¢, C3¢, C1¢, C2¢), 112.38–113.32 (C2), 113.36 (CMe2),
126.13–126.27 (C4), 127.74–127.81 (CPh), 128.83–129.79
(C3), 133.51 (CPhl), 135.8–135.89 (CPh), 145.13–147.38 (C5).
2ak: 1H NMR (200 MHz, CDCl3): d = 1.05 (s, 9 H, Met-Bu),
1.34 (s, 3 H, Me), 1.44 (s, 3 H, Me), 2.81 (d, 1 H, J = 4.8 Hz,
OH), 3.72–3.92 (m, 3 H, H4¢, H5¢), 4.59 (t, 1 H, J = 6.1 Hz,
H3¢), 4.98 (d, 1 H, J = 5.5 Hz, H2¢), 7.12 (d, 1 H, J = 4.0 Hz,
H4), 7.33–7.44 (m, 6 H, Ph), 7.62–7.70 (m, 4 H, Ph), 7.82 (d,
1 H, J = 4.1 Hz, H3). 13C NMR (50 MHz, CDCl3): d = 19.41
(CMe3), 26.25 (Me), 26.96 (CMe3), 27.27 (Me), 64.79 (C5¢),
72.81 (C4¢), 77.41 (C3¢), 80.72 (C2¢), 111.67 (CMe2), 124.47
(C2), 127.90 (CPh), 129.94 (CPh), 131.39 (C4), 133.10 (CPh),
135.23 (C3), 135.70 (CPh), 145.66 (C5), 190.18 (C1¢). MS
(ESI+): m/z = 611.1–613.1 (93, 100) [M + Na]+. Anal. Calcd
for C28H33BrO5SSi: C, 57.04; H, 5.64. Found: C, 57.17; H,
5.73.
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C. Peyron, R. Benhida
LETTER
MS (ESI+): m/z = 755.0, 757.0, 759.0 (51, 100, 60) [M +
Na]+.
7.9 Hz, H5¢), 3.82–3.96 (m, 2 H, H3¢, H4¢), 4.49 (d, 1 H, J =
2.8 Hz, H2¢), 6.54 (d, 1 H, J = 3.9 Hz, HTh), 6.87 (d, 1 H, J =
3.9 Hz, HTh), 7.01–7.08 (m, 2 H, HTh). 13C NMR (50 MHz,
CDCl3 + CD3OD): d = 62.47 (C5¢), 71.33 (C3¢), 80.42 (C4¢),
82.65 (C2¢), 88.64 (C1¢), 112.09–112.18 (C2), 125.67–126.22
(C4), 128.26–129.30 (C3), 140.58–141.82 (C5). MS (ESI+):
m/z = 476.5, 478.5, 480.5 (49, 100, 54) [M + Na]+. Anal.
Calcd for C13H12Br2O4S2: C, 34.23; H, 2.65. Found: C,
34.48; H, 2.41.
7b: 1H NMR (200 MHz, CDCl3): d = 0.99 (s, 9 H, Met-Bu),
1.27 (s, 3 H, Me), 1.31 (s, 3 H, Me), 3.61–3.77 (m, 9 H, H4¢,
H5¢, OMe), 4.24 (dd, 1 H, J = 5.7, 9.2 Hz, H3¢), 5.04 (d, 1 H,
J = 5.7 Hz, H2¢), 6.76–6.97 (m, 4 H, H3), 7.32–7.68 (m, 14 H,
Ph, H2). 13C NMR (50 MHz, CDCl3): d = 19.31 (CMe3),
24.76 (Me), 26.88 (CMe3), 27.46 (Me), 55.20–55.23 (OMe),
65.09 (C5¢), 69.01 (C3¢, C4¢), 77.11 (C1¢), 83.05 (C2¢), 107.98
(CMe2), 113.06–113.50 (C3), 127.00–127.54 (C2), 127.82–
127.87 (CPh), 129.89–129.95 (CPh), 135.59–135.77 (CPh),
137.77 (C1), 158.28 (C4). MS (ESI+): m/z = 666.3 [M + Na]+.
7c: 1H NMR (200 MHz, CDCl3): δ = 1.04 (s, 9 H, Met-Bu),
1.21 (s, 3 H, Me), 1.36 (s, 3 H, Me), 3.44 (dd, 1 H, J = 6.4,
10.6 Hz, H5’), 3.64 (dd, 1 H, J = 5.1, 10.6 Hz, H5’), 3.78 (s, 6
H, OMe), 4.46-4.54 (m, 1 H, H4’), 4.84 (dd, 1 H, J = 2.5, 6.2
Hz, H3’), 5.29 (d, 1 H, J = 6.2 Hz, H2’), 6.80 (2d, 4 H, J = 8.9
Hz, H3), 7.28–7.44 (m, 10 H, Ph, H2), 7.58–7.69 (m, 4 H,
Ph).
7d: mp 90–92 °C. 1H NMR (200 MHz, CD3OD): d = 3.57
(dd, 1 H, J = 1.2, 12.6 Hz, H5¢), 3.67–3.85 (m, 8 H, H3¢, H4¢,
2 × OMe), 3.95 (dd, 1 H, J = 1.9, 12.6 Hz, H5¢), 4.66–4.71
(m, 1 H, H2¢), 6.77 (d, 2 H, J = 8.9 Hz, H3), 6.89 (d, 2 H, J =
8.9 Hz, H2), 7.24–7.37 (m, 4 H, H2, H3). 13C NMR (50 MHz,
CD3OD): d = 55.61–55.69 (Me), 67.69 (C3¢), 67.79 (C5¢),
71.35 (C4¢), 78.34 (C2¢), 84.67 (C1¢), 113.83–113.99 (C3),
114.39–115.06 (C3), 127.96–128.09 (C2), 129.08–129.31
(C2), 136.43–138.91 (C1), 159.45–160.21 (C4). MS (ESI+):
m/z = 385.3 [M + K]+. MS (ESI–): m/z = 381.8 [M + Cl]–.
Anal. Calcd for C19H22O6: C, 65.88; H, 6.40. Found: C,
66.03; H, 6.29.
(15) 2d: mp 181–182 °C. 1H NMR (200 MHz, CDCl3 + CD3OD):
d = 3.47 (dd, 1 H, J = 2.8, 9.6 Hz, H5¢), 3.69 (dd, 1 H, J = 2.7,
Synlett 2009, No. 3, 472–476 © Thieme Stuttgart · New York

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