A stereo- and regio-controlled synthesis of bromothiophenyl C-nucleosides. Tandem bromination-ribosylation via halogen dance process

Article abstract of DOI:10.1016/j.tetlet.2008.07.071

Metallation-ribosylation of 2-bromothiophene 1 when conducted at room temperature afforded the original glycosylated dibromothiophene 3b following a regiocontrolled halogen transfer-based halogen-dance process. Then, stereocontrolled reduction-cyclization of hemiacetals 3a-c allowed straightforward access to the halogenated thiophenyl-C-nucleosides 6a-c.

Full text of DOI:10.1016/j.tetlet.2008.07.071

Tetrahedron Letters 49 (2008) 6171–6174
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A stereo- and regio-controlled synthesis of bromothiophenyl C-nucleosides.
Tandem bromination-ribosylation via halogen dance process
Corinne Peyron a, Jean Michel Navarre a, Didier Dubreuil b, Pierre Vierling a, Rachid Benhida a,
*
a Laboratoire de Chimie des Molécules Bioactives et des Arômes UMR CNR-UNSA 6001, Institut de Chimie de Nice, Université de Nice-Sophia Antipolis,
Parc Valrose, 06108 Nice Cedex 2, France
b Université de Nantes, CEISAM, Chimie et Interdisciplinarité, Synthèse, Analyse, Modélisation, CNRS, UMR CNRS 6230, UFR des Sciences et des Techniques,
2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Metallation–ribosylation of 2-bromothiophene 1 when conducted at room temperature afforded the
original glycosylated dibromothiophene 3b following a regiocontrolled halogen transfer-based halo-
gen-dance process. Then, stereocontrolled reduction-cyclization of hemiacetals 3a–c allowed straightfor-
ward access to the halogenated thiophenyl-C-nucleosides 6a–c.
Received 25 June 2008
Revised 8 July 2008
Accepted 11 July 2008
Available online 16 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Halogen dance
Tandem process
Stereocontrolled synthesis
C-nucleosides
C-Nucleosides are important targets in modern organic chemis-
try due to their high potential value as bioactive molecules and
biochemical probes.1 Recently, several synthetic C-nucleosides
have been studied as building blocks in artificial DNA and RNA
for different biochemical applications.2 They have been found in
a lot of naturally occurring and synthetic products with potent
antiviral or antitumor activities. Among them, tiazofurin has
recently been approved as an orphan drug for treatment of chronic
myelogenous leukemia in accelerated phase or blast crisis.3 The
benzamide riboside is another tiazofurin analog with improved
biological properties.4 Therefore, stereospecific methods which
allow access to suitable precursors are of great interest.
In connection with our ongoing project aimed at using 2-bro-
mothiophene 1 as starting material for post-synthetic transforma-
tions and to prepare various probe-like C-nucleosides by their
incorporation into oligonucleotides,5 we envisioned the prepara-
tion of new brominated thiophene C-nucleosides as candidates to
advanced procursors.
of bromothiophenyl C-nucleosides with a total regio- and stereo-
control. The synthesis involves three key steps (Fig. 1): (1) regio-
controlled halogen dance/glygosylation tandem reaction, (2)
stereoselective hemiacetal reduction and (3) stereocontrolled
intramolecular cycloetherification leading to novel brominated
thiophenyl-C-nucleosides.
Thus, regioselective ortho-lithiation of 1, using LDA in THF at
ꢀ78 °C, followed by addition of the protected ribonolactone 2
Y
Y
X
OH
HO
O
O
S
HO
TBDPSO
S
(3)
(1)
O
X
HO
Y
OH
6a-c
4a-c
(2)
We have recently reported that metallation–alkylation of 2-bro-
Y
mothiophene conducted at low temperature led to the side
a-
alkylation, while, when conducted at room temperature the
formation of dibromothiophenes occured following an original
alkylation/halogen-dance tandem process.6 To further explore the
scope of this reaction, we report herein a straightforward synthesis
X
O
S
X
TBDPSO
OH
3a-c
S
2-bromo (1)
3-bromothiophene
O
O
* Corresponding author. Tel.: +33 (0)4 92 07 61 74; fax: +33 (0)4 92 07 61 51.
E-mail address: benhida@unice.fr (R. Benhida).
Figure 1. Retrosynthetic pathway (1) regio-controlled glycosylation, (2) stereo-
controlled reduction, and (3) intramolecular ring closure and deprotection.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.071

6172
C. Peyron et al. / Tetrahedron Letters 49 (2008) 6171–6174
temperature afforded the 3,5-dibromo hemiacetal adduct 3b as
Br
3a
the sole product of the reaction (95% yield). The structures of 3a
and 3b were unambiguously confirmed by MS and NMR spectros-
copy.7 As expected, 3a results from a lithiation/glycosylation
sequence while 3b is produced following tandem halogen dance/
ribosylation process involving a cascade of bromide transfer.6 In
O
S
TBDPSO
OH
O
O
O
O
LDA/ THF/ -78˚C
then 2
96%
TBDPSO
O
O
A
O
1
Br
2
S
O
O
Br
O
S
LDA/ THF/ RT
then 2
O
4aS
95%
Br
H
O
OH
S
3a
OTBDPS
H
Br
Br
O
S
B
n+
TBDPSO
M
OH
n+
M
3b
O
O
O
O
O
O
O
4aR
O
H
Scheme 1. 1 (2.2 equiv), LDA (2.2 equiv), 2 (1 mmol).
S
OH
S
OTBDPS
Br
3a
H
afforded the hemiacetal product 3a in 96% yield (Scheme 1). Inter-
estingly, the same reaction sequences when performed at room
Br
C
n+
M
n+
M
O
Br
O
O
LDA/ THF/
O
4bS (X= Br)
4cS (X= H)
O
Br
Br
-78˚C, 0˚C or rt
O
O
then 2
S
OH
H
TBDPSO
S
Br
S
OH
OTBDPS
3b and 3c
+
X
90-97%
S
X
O
O
3c
H
H
Scheme 2. Bromine and sulfur atoms directed and stabilized metallation (no
halogen dance).
Scheme 3. Felkin-Ahn (A) and chelated model (B and C).
Table 1
Y
Y
OH
O
HO
O
OH O
Reduction
see table
S
TBDPSO
X
TBDPSO
S
X
O
O
3a-c
4a-c S or R
Entrya
Substrat
Reducing agent
T (°C)/ Time (h)
Yieldb (%)
S/R ratioc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3a X = Br, Y = H
3a
3a
3a
3a
3a
3a
3a
NaBH4
NaBH4
NaBH4
LiAlH4
DIBAL-H
rt/0.5
0/1
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4c
4c
4c
85
50/50
45/55
50/50
70/30
75/25
95/5
>98/2
30/70
5/95
50/50
0
80
79
90
90
85
82
92
87
86
0
ꢀ78/1
0/1
0/1
0/1
L
-Selectride
-Selectride
L
ꢀ78/1
0/1
3a
L-Selectride/ZnCl2
ꢀ78/1
0/0.5
ꢀ78 or rt/ 4
ꢀ78/1.5
0/0.5
3b X = Y = Br
3b
3b
3c X = H, Y = Br
3c
3c
NaBH4
L-Selectride
L-Selectride/ZnCl2
80
85
0
>98/2
50/50
0
NaBH4
L-Selectride
ꢀ78 or rt/4
L-Selectride/ ZnCl2
ꢀ78/1.5
86
>98/2
Conditions:
a
Reducing agent (1.5 equiv), THF. ZnCl2 (1 equiv).
Yield of pure isolated products.
b
c
S/R ratio based on 1H NMR and HPLC analysis.

C. Peyron et al. / Tetrahedron Letters 49 (2008) 6171–6174
6173
Br
Br
O
S
b
O
O
a
S
4a-S
TBDPSO
HO
HO
62%
91%
O
O
O
HO
HO
OH
6aβ
5aβ
O
a
b
4a-R
TBDPSO
S
S
59%
Br
87%
Br
X
O
OH
Br
5aα
6aα
Br
X
O
O
4b-
S
S
(X= Br)
(X= H)
S
S
b
a
TBDPSO
HO
4c-
O
O
HO
OH
6bβ (X= Br)
6cβ (X= H)
95%
90%
5bβ (X= Br)
5cβ (X= H)
93%
65%
Scheme 4. Reagents and condition: (a) DEAD, PPh3, THF, 70 °C. (b) aq H2SO4, dioxane.
contrast to 2-bromothiophene, when 3-bromothiophene was sub-
jected to lithiation–glycosylation with ribonolactone, the halogen-
dance reaction did not occur and only the 5-ribosylated product 3c
was isolated.7 Moreover, as shown in Scheme 2, the temperature
had no effect on the regioselectivity of the reaction. In this case,
the 2-lithiated intermediate is highly stabilized by both ‘Br’ and
‘S’ atoms, thus hampering the halogen transfer.8
With hemiacetals 3a, 3b and 3c in hand, the synthesis of
bromothiophenyl-C-nucleosides was next investigated, following
ketone reduction and C40–C10 cycloetherification sequence. Thus,
treatment of 3a, 3b and 3c with NaBH4 gave good yield of the cor-
responding diols 4a, 4b and 4c, respectively (Table 1, entries 1–3,
10 and 13). No stereoselectivity was observed in this reaction even
at low temperatures for example, the diols were obtained as an
equimolar mixture of R/S diastereomers. When LiAlH4 or DIBAL-H
was used for the reduction of 3a, a low stereoselectivity was no-
ticed (R/S = 70/30, entries 4 and 5). Interestingly, reduction of 3a
pected results could also be ascribed to the bromine atom effect in
position 3 thus, allowing the hydride delivery from the less bulky
face (Scheme 3C).
The ring-closing step was then achieved using intramolecular
Mitsunobu reaction on diols 4aR, 4aS, 4bS and 4cS, to give the pro-
tected C-nucleosides 5aa, 5ab, 5bb and 5cb, respectively, in moder-
ate to high yields (Scheme 4). In all cases, selective C40–C10
cycloetherification was observed according to a more reactive ben-
zylic hydroxy at C10 versus C40. In line with this result, we found
that the dibromothiophene diol 4bS undergoes clean and high
yielding cyclization (95% yield) compared to the monobrominated
analogs 4aS, 4aR, and 4cS (59–65% yield). This is probably due to
the halogen withdrawing effect thus activating the benzylic hydro-
xy position for an easy intramolecular C40–C10 ring closure. Finally,
the stereochemistry of each cyclized product was determined on
the basis of 1H 2D NOESY experiments. Indeed, the b configuration
(5a–cb) was clearly evidenced by a NOE correlation between H10
and H40. In the same way, we observed for the other anomer
using
L
L-selectride (Felkin-Ahn model, Scheme 3A) or a couple of
-selectride/ZnCl2 (chelation control, Scheme 3B)9,10 provided high
(5a
a
) clear NOE correlations between H10–H30 and H10–H50 in
configuration.
yield and high diastereomeric ratio of the corresponding diols 4aR
and 4aS, respectively (entries 6–9).11 The stereochemistry of each
diol was unambiguously assigned by correlation with the stereo-
chemistry of their cyclized product taking into account an inver-
sion of the configuration at C10 stereocenter (vide infra).
Unfortunately, in contrast to 3a, reduction of derivatives 3b and
accordance with an
a
The last step consists on the cleavage of the isopropylidene and
TBDPS protecting groups. Thus, treatment of protected precursors
5aa, 5ab, 5bb, and 5cb, with aq H2SO4 in dioxane afforded good
yields (87–95%) of the corresponding free nucleosides 6a
a, 6ab,
6bb, and 6cb, respectively (87–95%) (Scheme 4).13
3c with
L
-selectride alone (entries 11 and 14) did not work even
In conclusion, we discovered a new halogenation/glycosylation
tandem reaction that allows access to bromothiophenyl C-nucleo-
sides from 2-bromothiophene. The process most probably involves
an original halogen transfer cascade in highly regiocontrolled and
ordered fashion. The reduction and ring-closing steps were effi-
ciently achieved with a full stereocontrol leading to C-nucleosides
with fixed anomeric configuration. The presence of bromine(s)
would provide useful post-synthetic transformations for the prep-
aration of original functionnalized thiophenyl C-nucleosides.
under forced conditions (excess of the reducing agent and high
temperature). In these cases, the hydride delivery from the bulky
L-selectride reagent was probably hampered by the bromine atom
in position 3 of the thiophene ring. Indeed, we expected that this
halogen in proximity of the ketone induced a conformation change
to minimize the electrostatic repulsion with the carbonyl group
which resulted in a twisted, non-planar thiophene–ketone confor-
mation. In this case both faces are protected from the bulky
selectride approach. Surprisingly, while the reduction of 3a with
-selectride/ZnCl2 gave the expected 4aR diol according to a chela-
L-
L
Acknowledgments
tion control model (Scheme 3B), the reduction of 3b and 3c under
the same conditions led to the opposite stereochemical out-
come:4bS and 4cS, respectively (entries 12 and 15).12 These unex-
The authors thank la région PACA and CNRS for financial
support and for a doctoral fellowship (BDI) to CP.

6174
C. Peyron et al. / Tetrahedron Letters 49 (2008) 6171–6174
0
0
3.23 (d, 1H, J = 7.6 Hz, OH), 3.72–3.95 (m, 2H, H5 ), 4.12–4.20 (m, 1H, H4 ), 4.20–
References and notes
0
0
4.30 (m, 1H, H3 ), 4.43 (dd, 1H, J = 2.1 and 6.3 Hz, H2 ), 5.30 (dd, 1H, J = 1.9 and
0
6.3 Hz, H1 ), 6.81 (d, 1H, J = 3.6 Hz, H4), 6.90 (d, 1H, J = 3.8 Hz, H3), 7.35–7.50 (m,
1. For recent reviews on the chemistry of C-glycoside analogues, see: (a) Wu,
Qinpei; Simons, C. Synthesis 2004, 1533; (b) Bililign, T.; Griffith, B. R.; Thorson, J.
S. Nat. Prod. Rep. 2005, 22, 742; (c) Lee, D. Y. W.; He, M. S. Curr. Top. Med. Chem.
2005, 5, 1333.
2. (a) Kool, E. T. Acc. Chem. Res. 2002, 35, 936; (b) Sismour, A. M.; Benner, S. A.
Nucleic Acids Res. 2005, 33, 5640; (c) Leconte, A. M.; Matsuda, S.; Hwang, G. T.;
Romesberg, F. E. Angew. Chem., Int. Ed. 2006, 45, 4326.
6H, Ph), 7.62–7.72 (m, 4H, Ph). 13C NMR (50 MHz, CDCl3) d 19.46 (C(CH3)3),
0
0
0
24.72 (CH3), 24.82 (CH3), 27.0 (C(CH3)3), 65.41 ðC5 Þ, 68.08 ðC1 Þ, 69.76 ðC3 Þ,
0
0
77.35 ðC4 Þ, 79.79 ðC2 Þ, 109.11 (C(CH3)2), 112.19 (C2), 124.88 (C4), 127.9 (CPh),
129.31 (C3), 130.04 (CPh), 132.96 (CPh), 135.66 (CPh), 147.59 (C5). (ESI+) m/z (rel
intensity): 613.5–615.6 (91, 100, MNa+). Diol 4aR: TLC (cyclohexane/AcOEt: 8/
2): Rf = 0.43. 1H NMR (200 MHz, CDCl3) d 1.04 ppm (s, 9H, tBu), 1.32 (s, 3H,
0
CH3), 1.37 (s, 3H, CH3), 2.94 (d, 1H, J = 4.8 Hz, OH), 3.60–3.85 (m, 4H, OH, H4
,
3. For a brief overview of the biological and clinical impact of Tiazofurin, see:
Grifantini, M. Curr. Opin. Invest. Drugs 2000, 1, 257.
0
0
0
H
5 ), 4.01–4.17 (m, 1H, H3 ), 4.24 (dd, 1H, J = 3.2 and 7.4 Hz, H2 ), 5.07 (dd, 1H,
0
J = 2.7 and 8.7 Hz, H1 ), 6.81 (dd, 1H, J = 1.0 and 3.8 Hz, H4), 6.91 (d, 1H,
4. Novotny, L.; Rauko, P.; Yalowitz, J. A.; Szekeres, T. Curr. Med. Chem. 2002, 9, 773.
5. (a) Guianvarc’h, D.; Fourrey, J.-L.; Sun, J.-S.; Maurisse, R.; Benhida, R. . Bioorg.
Med. Chem. 2003, 11, 2751; (b) Guianvarc’h, D.; Fourrey, J.-L.; Maurisse, R.; Sun,
J.-S. ; Benhida, R. Org. Lett. 2002, 4, 4209; (c) Guianvarc’h, D.; Fourrey, J.-L.; Tran
Huu Dau, M.-E.; Guérineau, V.; Benhida, R. J. Org. Chem. 2002, 67, 3724; For
post-synthetic transformation of halogenated C-nucleosides see: (d) Spadafora,
M.; Mehiri, M.; Burger, A.; Benhida, R. Tetrahedron Lett. 2008, 49, 3967; (e)
Stefko, M.; Pohl, R.; Kepetárová, B.; Hocek, M. Eur. J. Org. Chem. 2008, 1689; (f)
Barta, J.; Pohl, R.; Kepetárová, B.; Ernsting, N. P.; Hocek, M. J. Org. Chem. 2008,
72, 6797; (g) Joubert, N.; Pohl, R.; Klepetárová; Hocek, M. J. Org. Chem. 2007, 72,
6797.
J = 3.8 Hz, H3), 7.35–7.45 (m, 6H, Ph), 7.58–7.70 (m, 4H, Ph). 13C NMR (50 MHz,
0
CDCl3) d 19.46 (C(CH3)3), 24.72 (CH3), 24.82 (CH3), 27.0 (C(CH3)3), 65.41 ðC5 Þ,
0
0
0
0
68.08 ðC1 Þ, 69.76 ðC3 Þ, 77.35 ðC4 Þ, 79.79 ðC2 Þ, 109.11 (C(CH3)2), 112.19 (C2),
124.88 (C4), 127.9 (CPh), 129.31 (C3), 130.04 (CPh), 132.96 (CPh), 135.66 (CPh),
147.59 (C5). (ESI+) m/z: (rel intensity): 613.5– 615.5 (93, 100, MNa+).
12. Diol 4bS: TLC (cyclohexane/AcOEt: 8/2): Rf = 0.58. 1H NMR (200 MHz, CDCl3) d
1.08 (s, 9H, tBu), 1.35 (s, 3H, CH3), 1.53 (s, 3H, CH3), 2.89 (d, 1H, J = 5.3 Hz, OH),
0
0
3.16 (d, 1H, J = 6.3 Hz, OH), 3.75–3.96 (m, 2H, H5 ), 4.21–4.28 (m, 2H, H3 and
0 0 0
4 ), 4.34–4.42 (m, 1H, H2 ), 5.46 (dd, 1H, J = 1.3 and 6.2 Hz, H1 ), 6.89 (s, 1H,
H
H3), 7.33–7.48 (m, 6H, Ph), 7.62–7.72 (m, 4H, Ph). 13C NMR (50 MHz, CDCl3) d
0
19.34 (C(CH3)3), 24.84 (CH3), 26.66 (CH3), 26.88 (C(CH3)3), 65.18 ðC5 Þ, 67.92–
6. Peyron, C.; Navarre, J.-M.; Van Craynest, N.; Benhida, R. Tetrahedron Lett. 2005,
46, 3315.
0
0
0
0
69.75–76.22 ðC1 ; C3 and C4 Þ, 78.59 ðC2 Þ, 106.38 (C(CH3)2), 109.20 (C4), 112.60
(C2), 127.85–127.90 (CPh), 130.1 (C3), 131.4–131.8 (CPh), 131.39–32.77 (CPh),
135.54–135.58 (CPh), 142.19 (C5). (ESI+) m/z (rel intensity): 691.1–693.1–695.0
(93, 100, 47, MNa+). Diol 4cS: TLC (cyclohexane/AcOEt: 8/2): Rf = 0.56. 1H NMR
(200 MHz, CDCl3) d 1.08 (s, 9H, tBu), 1.35 (s, 3H, CH3), 1.52 (s, 3H, CH3), 2.86 (d,
7. Hemiacetal 3a: TLC (cyclohexane/AcOEt: 8/2): Rf = 0.63. 1H NMR (CD3OD,
200 MHz) d ppm 1.04–1.08 (2s, 9H, tBu), 1.24 (s, 3H, CH3), 1.42 (s, 3H, CH3),
0
0
0
3.71–3.94 (m, 2H, H5 ), 4.17–4.27 (m, 1H, H4 ), 4.47 (d, 1H, J = 5.7 Hz, H3 ), 4.84
0
(d, 1H, J = 3.9 Hz, H2 ), 6.83 (d, 1H, J = 3.9 Hz, H3 thiophene), 6.92 (d, 1H,
0
1H, J = 5.4 Hz, OH), 3.17 (d, 1H, J = 6.4 Hz, OH), 3.78–3.98 (m, 2H, H5 ), 4.22–
4.28 (m, 2H, H3 and H4 ), 4.40–4.46 (m, 1H, H2 ), 5.52 (dd, 1H, J = 1.6 and
J = 3.8 Hz, H4 thiophene), 7.35–7.46 (m, 6H, Ph), 7.64–7.72 (m, 4H, Ph). 13C NMR
(CD3OD, 50 MHz) d ppm 19.79 (C(CH3)3), 24.44 (CH3), 26.26 (CH3), 26.51
0
0
0
0
6.3 Hz, H1 ), 6.93 (d, 1H, J = 5.3 Hz, H4), 7.26 (d, 1H, J = 5.3 Hz, H5), 7.35–7.45
0
0
0
0
0
0
(C(CH3)3), 66.35 ðC5 Þ, 84.63 ðC2 Þ, 87.19 (C4 or C3 ), 88.07 ðC3 or C4 Þ, 106.85
(m, 6H, Ph), 7.63–7.70 (m, 4H, Ph). 13C NMR(50 MHz, CDCl3) d 19.45 (C(CH3)3),
0
(C(CH3)2), 113.40 ðC1 Þ, 113.80 (C2), 126.15 (C4), 127.60 (CPh), 127.93 (CPh),
0
0
0
24.98 (CH3), 26.98 (C(CH3)3), 31.08 (CH3), 65.34 ðC5 Þ, 67.60 ðC1 Þ, 69.82 ðC4 Þ,
129.28 (C3), 130.05 (CPh), 133.41 (CPh), 134.95 (CPh), 135.71 (CPh), 145.66 (C5).
MS (ESIꢀ) m/z (rel intensity): 587.0–589.0 (100, 69, MHꢀ). MS (ESI+): 610,8–
612,8 [100, 83, (MNa)+]. Anal. Calcd for C28H33BrO5SSi: C, 57.04; H, 5.64. Found:
C, 57.29; H, 5.87. Hemiacetal 3b TLC (cyclohexane/AcOEt: 8/2): Rf = 0.70. 1H
NMR (200 MHz, CD3OD) d 1.07 (2s, 9H, tBu), 1.27 (s, 3H, CH3), 1.32 (s, 3H, CH3),
0
0
77.36 ðC3 Þ, 79.05 ðC2 Þ, 107.59 (C(CH3)2), 109.15 (C3), 125.60 (C5), 127.9 (CPh),
129.57 (C4), 130.08 (CPh), 132.9 (CPh), 135.7 (CPh), 140.38 (C2). (ESI+) m/z (rel
intensity): 613.2–615.1 (93, 100, MNa+).
13. Compound 5bb: TLC (cyclohexane/AcOEt: 8/2): Rf = 0.62. 1H NMR (500 MHz,
CDCl3) d 1.07 (s, 9H, tBu), 1.33 (s, 3H, CH3), 1.54 (s, 3H, CH3), 3.90 (dd, 1H, J = 4.9
0
0
0
0
3.80 (m, 2H, H5 ), 4.23 (m, 1H, H4 ), 4.85 (m, 1H, H3 ), 4.90 (br s, 1H, H2 ), 6.95 (s,
0
0
and 10.5 Hz, H5 ), 3.94 (dd, 1H, J = 3.3 and 10.3 Hz, H5 ), 4.30 (d, 1H, J = 6.5 Hz,
1H, H thiophene), 7.42 (m, 6H, Ph), 7.67 (m, 4H, Ph). 13C NMR (50 MHz,
0
0
0
H
3 ), 4.36 (m, 1H, H4 ), 4.70 (d, 1H, J = 5.1 Hz, H2 ), 5.49 (dd, 1H, J = 1.2 and
0
CD3OD)d 20.04 (C tBu), 25.37 (CH3), 26.91 (CH3), 27.36 (CH3 tBu), 66.25 ðC5 Þ,
5.1 Hz, H1 ), 7.03 (s, 1H, H3), 7.41–7.48 (m, 6H, Ph), 7.74–7.79 (m, 4H, Ph). 13C
0
0
0
0
0
84.82 ðC3 Þ, 86.95 ðC4 Þ, 87.30 ðC2 Þ, 107.13 (Cisop), 108.08 ðC1 Þ, 112.88 (CBr–S),
113.87 (CBr–C–S), 128.91 (CPh), 131.04 (CPh), 134.44 (CH), 134.52 (CPh), 136.71
(CPh), 141.78 (C–S). MS (ESI+) m/z (rel intensity): 688.7–690.7–692.7 (47, 100,
50, MNa+), 704.6–706.6–708.6 (36, 100, 64, MK+). Hemiacetal 3c 1H NMR
(200 MHz, CD3OD) d ppm 1.08 (s, 9H, tBu), 1.27 (s, 3H, CH3), 1.29 (s, 3H, CH3),
NMR (125 MHz, CDCl3) d 19.46 (C(CH3)3), 24.97 (CH3), 26.78 (CH3), 27.00
0
0
0
0
0
(C(CH3)3), 65.30 ðC5 Þ, 68.04 ðC1 Þ, 69.86 ðC2 Þ, 76.33 ðC3 Þ, 78.70 ðC4 Þ, 106.49
(C4), 109.31 (C(CH3)2), 112.72 (C2), 128.02 (CPh), 130.09 (CPh), 131.50 (C3),
132.89 (CPh), 135.67 (CPh), 142.31 (C5). MS (ESI+) m/z (rel intensity): 673.4–
675.7–677.5 (51, 100, 51, MNa+). Compound 6bb: TLC (CH2Cl2/MeOH: 8/2):
0
0
0
0
3.71–3.96 (m, 2H, H5 ), 4.18–4.29 (m, 1H, H4 ), 4.90 (br s, H2 and H3 ), 6.92 (d,
1H, J = 5.3 Hz, H5 or H4), 7.27 (d, 1H, J = 5.3 Hz, H4 or H5), 7.36–7.46 (m, 6H, Ph),
7.64–7.72 (m, 4H, Ph). 13C NMR (50 MHz, CD3OD) d ppm 20.45 (C(CH3)3), 25.88
Rf = 0.33. 1H NMR (200 MHz, CD3OD) d 3.07 (m, 2H, H5 ), 3.95–4.58 (m, 2H,
0
0
0
0
0
H3 and H4 ), 4.42–4.49 (m, 1H, H2 ), 5.32 (d, 1H, J = 3.6 Hz, H1 ), 6.95 (s, 1H,
H4). 13C NMR (50 MHz, CD3OD)d 58.77 ðC5 Þ, 75.98–77.01–78.82–79.43
0
0
0
0
(CH3), 27.33 (CH3), 27.78 (C(CH3)3), 66.82 ðC5 Þ, 85.33 ðC3 Þ, 87.48 ðC4 Þ, 87.58
+
0
0
0
0
ðC1 ; C2 ; C3 and C4 Þ, 107.88 (C3), 114.23 (C5), 126.78 (C4). MS (ESI ) m/z (rel
intensity): 394.5–396.8–398.4 [51, 100, 50, (MNa)+]. Anal. Calcd for
C9H10Br2O4S: C, 28.90; H, 2.69. Found: C, 29.11; H, 2.54. Compound 6cb: TLC
(MeOH/H2O: 8/2): Rf = 0.6. 1H NMR (200 MHz, CDCl3+ CD3OD) d 3.74 (dd, 1H,
0
0
0
ðC2 Þ, 107.75 (C1 or C3), 109.18 (C(CH3)2), 114.17 (C3 or C1 ), 126.73 (C5), 128.98
(C4), 129.31 (CPh), 131.43 (CPh), 132.59 (C2), 134.99 (CPh), 137.13 (CPh). (ESI+) m/
z (rel intensity): 611.3–613.3 (91, 100, MNa+). Anal. Calcd for C28H33BrO5SSi: C,
57.04; H, 5.64. Found: C, 57.17; H, 5.73.
0
0
J = 4.3 and 12.1 Hz, H5 ), 3.86 (dd, 1H, J = 3.5 and 12.1 Hz, H5 ), 3.93–4.03 (m,
8. For the use of a bromine atom as ortho-directing group, see: (a) Lulinski, S.;
Serwatowski, J. J. Org. Chem. 2003, 68, 5384; (b) Lulinski, S.; Serwatowski, J. J.
Org. Chem. 2003, 68, 9384; (c) Gohier, F.; Mortier, J. J. Org. Chem. 2003, 68, 2030.
9. Navarre, J.-M.; Guianvarc’h, D.; Farese Di Giorgio, A.; Condom, R.; Benhida, R.
Tetrahedron Lett. 2003, 44, 2199.
10. Hanessian, S.; Machaalani, R. . Tetrahedron Lett. 2003, 44, 8321.
11. Diol 4aS: TLC (cyclohexane/AcOEt: 8/2): Rf = 0.52. 1H NMR (200 MHz, CDCl3) d
1.07 (s, 9H, tBu), 1.36 (s, 3H, CH3), 1.46 (s, 3H, CH3), 2.88 (d, 1H, J = 5.5 Hz, OH),
0
0
0
0
1H, H4 ), 4.05–4.18 (m, 2H, H2 and H3 ), 5.15 (d, 1H, J = 4.4 Hz, H1 ), 6.93 (d, 1H,
J = 5.3 Hz, H4), 7.24 (d, 1H, J = 5.3 Hz, H5). 13C NMR (50 MHz, CDCl3 + CD3OD) d
0
0
0
0
0
62.49 ðC5 Þ, 71.05 ðC3 Þ, 77.37 ðC2 Þ, 80.83 ðC1 Þ, 84.04 ðC4 Þ, 125.36 (C5), 130.51
(C4), 138.00 (C2). MS (ESI+) m/z (rel intensity): 316.7–318.7 [100, 98 (MNa)+].
Anal. Calcd for C9H11BrO4S: C, 36.62; H, 3.76. Found: C, 36.76; H, 3.83.