Synthesis of unnatural cyclitols via a combined enzymatic-palladium catalysis approach

Article abstract of DOI:10.1016/j.jorganchem.2008.01.006

The Suzuki-Miyaura cross-coupling reaction of a hydroxylated vinyl bromide obtained by a chemoenzymatic approach with a diverse range of potassium organotrifluoroborates has been accomplished catalyzed by Pd(PPh₃)₄ in satisfactory yields. A variety of functional groups are tolerated in the nucleophilic partner.

Full text of DOI:10.1016/j.jorganchem.2008.01.006

Available online at www.sciencedirect.com
Journal of Organometallic Chemistry 693 (2008) 1136–1142
www.elsevier.com/locate/jorganchem
Synthesis of unnatural cyclitols via a combined
enzymatic-palladium catalysis approach
a
a,
b,
*
*
Ana Bellomo , David Gonzalez , H e` lio A. Stefani
a
Departamento de Qu ı´ mica Org a´ nica, Facultad de Qu ı´ mica, UdelaR, General Flores 2124, C.C. 1157 Montevideo, Uruguay
b
Departamento de Farm a´ cia, Faculdade de Ci eˆ ncias Farmac eˆ uticas, Universidade de S a˜ o Paulo, S a˜ o Paulo, SP, Brazil
Received 12 October 2007; received in revised form 5 January 2008; accepted 5 January 2008
Available online 11 January 2008
Abstract
The Suzuki–Miyaura cross-coupling reaction of a hydroxylated vinyl bromide obtained by a chemoenzymatic approach with a diverse
range of potassium organotrifluoroborates has been accomplished catalyzed by Pd(PPh
groups are tolerated in the nucleophilic partner.
3 4
) in satisfactory yields. A variety of functional
Ó 2008 Elsevier B.V. All rights reserved.
Keywords: Suzuki–Miyaura cross-coupling reaction; Potassium organotrifluoroborate salts; Conduritol nucleus; Biocatalysis
1
. Introduction
products are on demand as potential leads for the pharma-
ceutical and agrochemical industries. Therefore, we have
embraced the search for a short strategy to generate fami-
lies of compounds containing several chiral centers and
tunable lipophilicity by the combination of the Suzuki–
Miyaura coupling and biotransformations demonstrating
the complementary nature of biocatalysis and organome-
tallic chemistry.
Although the development of organic chemistry in the
past century has been immense, there are still limitations
in the effectiveness of the traditional synthetic approach
to the manufacture of valuable molecules and natural
products. In addition, environmental concerns about the
traditional organic methodology has become a major
drawback for the further development of synthetic chemis-
try. Biotechnology, overcomes some of these issues but, at
the present state of knowledge, it cannot completely substi-
tute traditional organic methods. As a consequence, the
combination of the two methodologies in a single strategy
results in one of the most effective approaches for the effi-
cient preparation of relevant natural products and high
added-value molecules.
Boronic acids and boronate esters are the most com-
monly used nucleophiles in Suzuki cross-coupling reac-
tions. However, several groups have explored the use of
potassium organotrifluoroborate salts (RBF K) as an
3
alternative to these boron reagents in Suzuki coupling reac-
tions [1]. These salts are readily prepared by the addition of
an aqueous solution of inexpensive, widely available KHF2
to an ample variety of organoboron intermediates [2].
We made use of the power of enzymatic catalysis to
incorporate chirality into an aromatic ring and prepared
a conduritol nucleus by the well known toluene dioxygen-
ase oxidation of arenes [3] followed by chemical oxidation
and azidolysis.
There is a growing interest in the generation of diversity
by means of simple albeit efficient reactions. Enantiopure
compounds of medium complexity, that resemble natural
*
Corresponding authors. Tel.: +5982 929 01 06 (D. Gonzalez); fax: +55
The library of compounds to be synthesized will contain
an azide functionality which could be used to generate tri-
azoles by the well-known Huisgen procedure and it could
11 30913654 (H.A. Stefani).
E-mail addresses: davidg@fq.edu.uy (D. Gonzalez), hstefani@usp.br
(H.A. Stefani).
0
022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.01.006

A. Bellomo et al. / Journal of Organometallic Chemistry 693 (2008) 1136–1142
1137
also be reduced to an amino group so as to incorporate
amino acidic units in the conduritol moiety by amidation
reactions.
the best of our knowledge, this article describes the first
example where these diols are used as electrophilic partners
to be coupled with aryltrifluoroborates.
Our initial studies of this process focused on developing
the best set of reaction conditions for the palladium cata-
2
. Results and discussion
lyzed cross-coupling of RBF K with vinyl bromide (4).
3
We first exposed bromobenzene (1) to a culture of the
For this purpose we used an electron-neutral organotrifluo-
roborate (phenyltrifluoroborate) as the test case.
mutant strain Pseudomonas putida 39/D in order to gener-
ate a cis-cyclohexadiene diol with very high regio- and
enantioselectivity. The resulting bromodiene diol (2) has
been extensively exploited by Hudlicky [4], Banwell [5],
and others [6] to synthesize a varied array of natural and
unnatural compounds in step-economic sequences.
The results showed that the choice of the catalyst and sol-
vent was crucial. Palladium (II) and (0) species were
employed in the cross-coupling reaction and the best results
were reached with the Pd(0) catalyst (Table 1). The use of
PdCl (dppf)CH Cl in THF or DMF as well as the ligand
2
2
2
We have previously used this reaction for the prepara-
tion of inositols [7], aminoconduritols [8] and sulfur con-
taining cyclitol analogs [9] introducing the required
functionality in the cyclohexadiene nucleus in a stereospe-
cific fashion by standard chemical means. One of the best
procedures to do this is the epoxidation of a protected
derivative to furnish oxirane (3) with complete regio- and
stereospecifity [10]. Furthermore, alternative strategies to
achieve these functionalizations involve a palladium-cata-
lyzed trans-diacetoxylation of a protected 3,5-cyclohexadi-
ene-1,2-diol [11]. The resulting epoxide 3 is subjected to an
azidolysis reaction rendering hydroxyazide (4) which was
envisioned to be a very useful intermediate because it can
be further functionalized [12] and the vinyl bromide moiety
can operate as partner in a palladium-catalyzed Suzuki
cross-coupling reaction.
system Pd(OAc) /DPE phos in MeOH did not render the
desired product (Table 1, entries 1, 2 and 4). However,
2
PdCl (dppf)CH Cl in THF–H O and Pd(OAc) /2-(di-t-
2
2
2
2
2
butylphosphino)biphenyl in MeOH did show product for-
mation although in modest yields (Table 1, entries 3 and
5). The more reactive Pd(PPh ) in toluene–H O proved to
3
4
2
be the superior choice so it was selected as the palladium
source for the following experiments (Table 1, entries 6–9).
Table 1
Catalyst and solvent optimization of the cross-coupling reaction of
potassium phenyltrifluoroborate with hydroxyazide (4)
Entry Pd source
mol%)
Ligand
(mol%)
Solvent
Yield
(%)
(
1
2
3
PdCl (dppf)CH
10)
2
2
Cl
2
None
THF
(
PdCl (dppf)CH Cl None
2
2
2
DMF
The efficiency and advantages of the organotrifluorobo-
rates in a variety of cross-coupling reactions have been
already established [13] so we sought to extend their utility
to systems not previously studied. Herein, we report the
palladium-catalyzed Suzuki cross-coupling reactions car-
(10)
PdCl
2
(dppf)CH
2
Cl
2
None
THF–H
2
O
45
35
(
10)
4
5
Pd(OAc)
Pd(OAc)
2
(3)
(3)
DPE phos (6.5)
2-(di-t-butilfosfino)- MeOH
MeOH
2
bifenilo (6.5)
a
ried out between the required RBF K and vinyl bromide
6
7
8
9
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
3
)
4
4
4
4
(2)
(4)
(6)
(10)
None
None
None
None
Toluene–H
Toluene–H
Toluene–H
Toluene–H
2
2
2
2
O
O
O
O
70
70
64
65
3
b
)
)
)
(
4) to produce trisubstituted olefines of type 5 (Scheme 1).
Molander and co-workers have described several proce-
dures for the coupling of RBF K with a range of electro-
3
Reaction conditions: vinyl bromide (4) (1 mmol), PhBF
Cs CO (3 equiv.). Entries 1–3: reflux; entries 4–5: rt to reflux; entries 6–9:
0a °C.
3
K (1.2 equiv.),
philes and have shown the vast scope of these reagents
and simplified the coupling protocols [14]. However, there
are only few reports in the literature referring to the use of
cis-cyclohexadiene diols in Suzuki couplings [6b,15] and to
2
3
9
Product 5a/starting material 4: 1/1 (NMR conversion).
Product 5a/starting material 4: 7/3 (NMR conversion).
b
Scheme 1. Chemoenzymatic preparation of the azidoconduritol derivative 4 and olefines 5.

1138
A. Bellomo et al. / Journal of Organometallic Chemistry 693 (2008) 1136–1142
Among the tested solvents, toluene–H O was far the
Table 3
2
Coupling of functionalized potassium trifluoroborates with hydroxyazide
most effective system. The critical role of water has been
previously noted [16]. In fact, water facilitates the solubili-
zation of the components of the coupling reaction. It is a
well documented fact that solubilization is accomplished
at the expense of promoting the protiodeborination of
the potassium salt [17], thus a delicate balance must be
reached. We found that the reaction of potassium phenyl-
trifluoroborate with 4 and Pd(PPh ) in a 1/3.5 water/tolu-
(4)
Br
Ar
Pd(PPh3)4
Cs2CO3
O
O
O
O
ArBF3K
N3
toluene-H2O
N3
90°C
OH
OH
4
5a-5i
3
4
ene mixture provided the cross-coupled product in very
good yield.
Entry
1
ArBF
3
K
Time (h)
2.0
Isolated yield 5: (%)
(homocoupling)
The use of Pd(PPh ) in 3.5/1 toluene–H O mixture was
3
4
2
5a: 64 (10)
5b: 71 (8)
5c: 70 (7)
3
BF K
employed to study the effect of catalyst loading (Table 1,
entries 6–9). The best result was achieved when 6 mol%
of catalyst was used (Table 1, entry 8). Simply rising the
mol percentage of catalyst from 2% to 6% resulted in the
complete conversion of 4–5a in 64% yield along with only
2
3
2.0
1.7
BF K
3
H3CO
1
0% of the homocoupling side product. When 4 mol% of
catalyst was employed, results comparable to 2 mol% were
obtained. With catalyst loading above the optimum (Table
3
BF K
1
, entry 9) the starting material was still used up, but the
percentage of homocoupled product was found to be
5%. This illustrates the best amount of catalyst needed
3
H C
1
4
5
6
7
8
9
8.0
4.5
6.5
3.0
9.0
5.5
5d: 60 (20) prod./s.m.: 3/2
BF
3
K
for the reaction to be efficient.
Next, we turned our attention to the study of the influ-
ence of other parameters such as nature of the base and
reaction temperature. The cross-coupling reactions in all
studied reaction cases were performed in the presence of
CH
3
5e: 62 (30)
3
BF K
3
equiv. of base [18]. Several inorganic bases were surveyed.
F
Na CO did not render the desired product at any temper-
2
3
ature (Table 2, entries 1 and 2) and K CO showed little
cross-coupling product formation (Table 2, entry 3).
2
3
5f: 57 (23)
3
BF K
Cs CO afforded the best result working at 90 °C while
F3C
2
3
lower reaction temperatures were ineffective or inefficient.
Careful analysis of the reaction data revealed that the
best conditions for the coupling were the use of vinyl bro-
mide 4 (1 mmol), RBF K (1.2 equiv.), Pd(PPh ) (6 mol%)
5g: 45 (21)
3
BF K
3
3 4
OHC
HOOC
and Cs CO (3.0 equiv.) diluted in toluene/H O (3.5/1),
2
3
2
under heating at 90 °C.
Recovered s.m.: 40 (20)
3
BF K
To probe the scope of these optimized conditions we
extended the coupling reaction to other representative
potassium organotrifluoroborates and the results obtained
are summarized in Table 3.
5h: 50 (14)
3
BF K
S
Table 2
Activator and temperature optimization in the cross-coupling reaction of
potassium phenyltrifluoroborate with hydroxyazide (4)
a
1
0
1
10.0
24.0
5i: 43 (20) prod./s.m.: 2/1
3
BF K
S
Entry
Base
T (°C)
Yield (%)
1
2
3
4
5
6
7
aq. Na
aq. Na
2
CO
CO
3
50
70
50
Reflux
rt
1
Recovered s.m.: 85
2
3
3
BF K
K
K
2
CO
CO
3
35
Decomposition
Recovered s.m.
45
64
N
2
3
Cs
2
Cs
2
Cs
2
CO
3
CO
CO
3
50
90
Reaction conditions: vinyl bromide (4) (1 mmol), RBF
Pd(PPh (6 mol%) (unless otherwise noted), Cs CO (3 equiv.), toluene/
O (3.5/1), 90 °C.
3
K (1.2 equiv.),
3
)
4
2
3
3
H
2
a
3
Reaction conditions: vinyl bromide (4) (1 mmol), PhBF K (1.2 equiv.),
Results obtained using 10 mol% of the catalyst.
Pd(PPh (6 mol%), toluene/H O (3.5/1).
3
)
4
2

A. Bellomo et al. / Journal of Organometallic Chemistry 693 (2008) 1136–1142
1139
The reaction proceeded with satisfactory yields in most
4. Experimental
cases and it was tolerant to a variety of functional groups.
Compatibility was demonstrated with fluoro, ether and
aldehyde groups. Coupling reactions with electron-rich
potassium aryltrifluoroborates proceeded in very good
yields. Potassium 4-methylphenyltrifluoroborate was the
best substrate, with the product 5c obtained in 70% isolated
yield in less than 2 h (Table 3, entry 3).
Even electron-withdrawing substituted aryltrifluorobo-
rate salts afforded the corresponding products (Table 3,
entries 5–7). As outlined in entry 7, the presence of an alde-
hyde group did not preclude the cross-coupling reaction.
However, the yield of product was lower than 50% in this
All solvents were purified prior to use. Melting points
were determined on a B u¨ chi B-545 apparatus and are uncor-
rected. Optical rotations were measured at 589 nm on a Per-
kin–Elmer 343 automatic polarimeter using a 1 mL cell
(concentration c given in g/100 mL). Infrared spectra (IR)
were recorded on a Varian 1000 FT-IR spectrometer and
peaks are reported in reciprocal cm along with relative sig-
nal intensities and characteristics: s (strong); m (medium);
w (with). Low-resolution mass spectra were performed on
a Bruker Daltonics model Esquire HCT (ESI-MS, ion trap)
and on a Shimadzu GCMS-QP5050A and molecular ion
peaks are listed with relative abundances. High-resolution
mass spectra were performed on a Bruker Daltonics model
TOFLC (ESI + mode). Nuclear magnetic resonance spectra
were recorded on Bruker Avance DPX-300 instrument with
tetramethylsilane as internal standard and chloroform-d as
solvent. Chemical shifts (d) are recorded in ppm and cou-
pling constants (J) are reported in Hertz. Retention factors
case (Table 3, entry 9). Less reactive RBF K (Table 3,
3
entry 8) led to recovery of the vinyl bromide starting mate-
rial and the sterically encumbered ortho-methylsubstituted
substrate (Table 3, entry 4) reacted slowly, with only partial
conversion to 5d. This compound exhibited very similar
chromatographic behaviour with the starting vinyl bro-
mide 4 and therefore could not be isolated in its pure state.
This result showed that the reaction is very sensitive to hin-
dered substrates as it is documented for some Suzuki–
Miyaura cross-couplings [19]. Potassium 4-methoxyphenyl-
trifluoroborate and potassium 4-fluorophenyltrifluorobo-
rate were tested as substrates that bear substituents with
p-releasing but inductively electron-withdrawing character-
istics. The results obtained in these cases indicated that the
reactions provided the desired products 5b and 5e in good
yields and just after a few hours of reaction (Table 3,
entries 2 and 5).
Continuing with our investigation, we explored the reac-
tion of bromide 4 with heteroaryltrifluoroborates. Although
potassium 3-thiophenetrifluoroborate could be used with
success, the cross-coupling of a 3-pyridyl nucleophile ren-
dered only recovered starting material (Table 3, entry 11)
and all the attempts to couple potassium 2-thiophenetriflu-
oroborate with 4 rendered the desired product along with
the starting vinyl bromide which could not be separated
from the product (Table 3, entry 10). Increasing the catalyst
loading from 6 to 10 mol% had no effect in reaching total
conversion suggesting that for this demanding substrate
more forcing conditions are required.
(R ) are reported for analytical thin layer chromatography
f
performed on aluminium plates treated with F-254 indica-
tor. Visualization was accomplished with the aid of UV light
and/or vanillin–H SO –MeOH as the detecting agent. Flash
2
4
column chromatography were carried out using silica gel
(Kieselgel 60, EM Reagents, 230–400 mesh).
Potassium organotrifluoroborate salts (4-fluorophenyl,
4-(trifluoromethyl)phenyl, 4-formylphenyl, 4-carboxy-
phenyl, and 3-thiophene) were obtained from commercial
sources while other derivatives (phenyl, 4-methylphenyl,
2-methylphenyl, 4-methoxyphenyl, 2-thiophene, and 3-pyr-
idine) were prepared according to the literature procedures
[20]. Pd(PPh3)4 was prepared following the procedure
described in the literature [21].
4.1. General procedure for Suzuki–Miyaura cross-coupling
reactions of vinyl bromide (4) and potassium
organotrifluoroborates
Cs CO (0.750 mmol, 3.0 equiv.), Pd(PPh3)4 (0.015
2
3
mmol, 6%), potassium organotrifluoroborate (0.275 mmol,
1.1 equiv.) and vinyl bromide (4) (0.25 mmol, 1.0 equiv.)
were added to a flame-dried two-necked flask equipped with
3
. Conclusion and outlook
a condenser. The system was purged with N for 2 min. The
2
solvents (0.75 mL of toluene and 0.2 mL of H O) were
2
In summary, palladium-catalyzed cross-coupling reac-
added and the mixture was put in an oil bath previously
set at 90 °C.
The reaction mixture was stirred for the appropriate
time indicated in Table 3. Once the reaction was completed,
tions of a range of potassium organotrifluoroborates with
vinyl bromide (4) have been efficiently achieved, using
low catalyst loadings. More importantly, the coupling
turned out to be general with respect to a diverse array
of functionality although in the case of very unreactive
compounds we were not able to establish the best condi-
tions that would led to total conversion of the starting
materials in the desired products. We are currently working
in improving the yield of this reaction and in the further
functionalization of the conduritol moiety to attain a diver-
sity oriented collection of cyclitol conjugates.
it was diluted with hexanes and MgSO was added. The
4
organic layer was removed and the remaining MgSO paste
4
was triturated two times with hexanes and thrice with ethyl
acetate. The combined organic extracts were placed directly
into a plug of silica gel to remove the catalyst, thus yielding
the crude product. Further purification was accomplished
via column chromatography using a gradient of hexanes/
ethyl acetate (85/15, 80/20, and 70/30).

1140
A. Bellomo et al. / Journal of Organometallic Chemistry 693 (2008) 1136–1142
4
(
.1.1. (1R,2S,5R,6R)-2-azido-5,6-O-
isopropylidenedioxy)-4-(phenyl)cyclohex-3-ene-1-ol (5a)
(CH ), 26.07 (CH ), 21.18 (CH (arom.)). IR (neat): 3452
3 3 3
(O–H, w), 2921 (C–H (CH ), m), 2092 (N , s), 1256 (s),
3 3
24
White crystalline solid. M.p.: 123–124 °C. ½aꢀ + 9.78 (c
1208 (C–N, m), 1059 (C–O–C, s), 875 (C–H, s), 804
D
1
+
+
0
.755, CH Cl ). H NMR (CDCl , 300 MHz) 7.55 (d,
(C@C, s). GC–MS: 287 (M ꢁCH , 13), 273 (M ꢁN , 6),
2
2
3
3
+ +
2
Jo–m = 7.02, 2 H, Ho), 7.34 (m, 3H, Hm and Hp), 6.07 (d,
J3–2 = 1.29, 1H, H3), 5.04 (d, J5–6 = 5.97, 1H, H5), 4.20
144 (PhCH + 2H O + CH , 100), 105 (PhCH + CH ,
2 2 3 2 3
17), 91 (PhCH2 , 25), 77 (Ph, 17), 58 (C H O, 26), 43
+
3
6
(
9
dd, J6–5 = 6.18, J6–1 = 9.06, 1H, H6), 4.07 (bd, J2–1
=
(N + CH , 56). TLC: R 0.47 (hexane/EtOAc, 70/30).
2 3 f
HRMS: m/z calc. for (C H N O Na) : 324.1319. Found:
16 19 3 3
324.1318%.
+
.06, 1H, H2), 3.80 (t, J1–2 = 9.03, J1–6 = 9.12, 1H, H1),
.91 (bs, 1H, OH), 1.54 (s, 3H, CH ), 1.48 (s, 3H, CH ).
2
3
3
1
3
C NMR (CDCl , 75 MHz) 136.97 (C4), 135.82 (C
3
arom.–C4), 128.67 (di, C (Hm)), 128.57 (C (Hp)), 126.15
di, C (Ho)), 125.38 (C (H3)), 110.75 (C isopropylidene),
8.18 (C (H6)), 73.42 (C (H5)), 73.37 (C (H1)), 62.27 (C
H2)), 28.46 (CH ), 26.07 (CH ). IR (neat): 3441 (O–H,
4.1.4. (1R,2S,5R,6R)-2-azido-5,6-O-
(isopropylidenedioxy)-4-(2-(methyl)phenyl)cyclohex-3-
(
7
(
ene-1-ol (5d)
1
H NMR (CDCl , 300 MHz) 7.26–7.17 (m, 4 H, Ph),
3
3
3
w), 2091 (N , s), 1255 (s), 1208 (C–N, m), 1061 (C–O–C,
6.11 (bs, 1H, H3), 4.79 (d, J5–6 = 6.21, 1H, H5), 4.18 (dd,
J6–5 = 6.96, J6–1 = 9.48, 1H, H6), 3.91 (d, J2–1 = 8.34,
1H, H2), 3.77 (t, J1–2 = 9.03, J1–6 = 9.50, 1H, H1), 2.88
3
s), 875 (C–H, s), 810 (C@C, s). GC–MS: 201
+
+
(
1
M ꢁC H O–N , 22), 172 (43), 130 (M ꢁPh–2H O–N ,
3
6
2
2
3
00), 77 (Ph, 19), 58 (C H O, 10). TLC: R 0.48 (hexane/
EtOAc, 70/30). HRMS: m/z calc. for (C H N O Na) :
(bs, 1H, OH), 2.31 (s, 3H, CH (arom.)), 1.56 (s, 3H,
3
6
f
3
+
13
CH ), 1.43 (s, 3H, CH ). C NMR (CDCl , 75 MHz)
1
5
17
3
3
3
3
3
3
10.1162. Found: 310.1160%.
137.70 (C arom.–CH ), 135.65 (C4 and C arom.–C4),
3
130.82 (C (H3)), 130.42, 128.47, 125.1 (Ph), 111.22 (C iso-
4.1.2. (1R,2S,5R,6R)-2-azido-5,6-O-(isopropylidene-
dioxy)-4-(4-(methoxy)phenyl)cyclohex-3-ene-1-ol (5b)
propylidene), 77.85 (C (H6)), 73.61 (C (H5)), 72.83 (C
(H1)), 62.16 (C (H2)), 28.11 (CH ), 25.86 (CH ), 20.09
3
3
24
+
White crystalline solid. M.p.: 147–149 °C. ½aꢀ + 11.96
(CH (arom.)). ESI-MS: 324 ((M+Na) , 100), 259
D
3
+
1
(
c 0.605, CH Cl ). H NMR (CDCl , 300 MHz ) 7.50 (d,
(M ꢁCH –N , 18), 201 (259.0–C H O, 46), 183 (201–
2
2
3
3
2
3
6
Jm–o = 8.28, 2H, HmOCH3), 6.90 (d, Jo–m = 8.31, 2H,
HoOCH3), 5.98 (bs, 1H, H3), 5.02 (d, J5–6 = 5.52, 1H, H5),
H O, 23). This compound had identical chromatographic
2
properties with the starting material and could no be iso-
lated in the pure state.
4
8
3
.19 (t, J6–5 = 6.69, J6–1 = 8.19, 1H, H6), 4.07 (bd, J2–1
=
.82, 1H, H2), 3.82 (bs, 4 H, H1 and CH (OCH arom.)),
3
3
1
3
.05 (bs, 1H, OH), 1.55 (s, 3H, CH ), 1.49 (s, 3H, CH ).
C
4.1.5. (1R,2S,5R,6R)-2-azido-5,6-O-(isopropylidene-
dioxy)-4-(4-(fluoro)phenyl)cyclohex-3-ene-1-ol (5e)
3
3
NMR (CDCl , 75 MHz) 159.88 (C arom.–OCH ), 135.08
3
3
2
4
(
1
C4), 129.45 (C arom.–C4), 127.40 (di, C ðHm
Þ),
White solid. M.p.: 99–102 °C. ½aꢀ + 11.10 (c 0.45,
OCH3
D
1
23.35 (C (H3)), 114.04 (di, C ðHo
Þ), 110.92 (C isopro-
CH Cl ). H NMR (CDCl , 300 MHz) 7.53 (m, 2H,
OCH3
2
2
3
pylidene), 78.21 (C (H6)), 73.44 (di, C (H1) and C (H5)),
2.25 (C (H2)), 55.32 (C (OCH )), 28.10 (CH ), 26.07
Hm ), 7.04 (m, 2H, Ho ), 5.99 (bs, 1H, H3), 4.98 (d,
F F
6
J5–6 = 5.46, 1H, H5), 4.19 (dd, J6–5 = 6.00, J6–1 = 8.94,
1H, H6), 4.07 (bd, J2–1 = 8.37, 1H, H2), 3.78 (bt, J1–2
8.25, J1–6 = 8.58, 1H, H1), 2.89 (bs, 1H, OH), 1.53 (s,
3
3
(
CH ). IR (neat): 3460 (O–H, w), 2091 (N , s), 1250 (s),
=
3
3
1
193 (C–N, m), 1058 (C–O–C, s), 875 (C–H, s), 817
+
13
(
C@C, s). GC–MS: 216 (M ꢁC H O–N , 8), 109
3H, CH ), 1.47 (s, 3H, CH ).
C NMR (CDCl3,
3
6
3
3
3
+
(
M ꢁC H O–N –OCH Ph, 6), 96 (Ph+H O, 10), 77 (Ph,
75 MHz) 162.90 (d, JCF = 247, C arom.–F), 134.90 (C4),
3
6
3
3
2
3
9
), 58 (C H O, 20), 43 (N + CH , 100). TLC: R 0.46 (hex-
133.17 (C arom.–C4), 127.98 (d, di, J = 8, C (Hm )),
3
6
2
3
f
CF
F
2
ane/EtOAc,
70/30).
HRMS:
m/z
calc.
for
125.31 (C (H3)), 115.91(d, di, J = 21, C (Ho )), 110.82
CF F
+
(
C H N O Na) : 340.1268. Found: 340.1266%.
(C isopropylidene), 78.15 (C (H6)), 73.43 (di, C (H1) and
C (H5)), 62.17 (C (H2)), 28.43 (CH ), 26.07 (CH ). IR
1
6
19
3
4
3
3
4.1.3. (1R,2S,5R,6R)-2-azido-5,6-O-(isopropylidene-
dioxy)-4-(4-(methyl)phenyl)cyclohex-3-ene-1-ol (5c)
(neat): 3465 (O–H, w), 2096 (N , s), 1229 (C–F, m), 1207
3
(C–N, m), 1062 (C–O–C, s), 979 (C–H, s), 875 (C@C, s).
24
+
White crystalline solid. M.p.: 1119–121 °C. ½aꢀ + 9.66
GC–MS: 207 (M ꢁPhF, 10), 77 (Ph, 3), 58 (C H O, 35),
D
3
6
1
(
c 0.595, CH Cl ). H NMR (CDCl , 300 MHz) 7.43 (d,
43 (N + CH , 100). TLC: R 0.44 (hexane/EtOAc, 70/
2 3 f
30). HRMS: m/z calc. for (C H FN O Na) : 328.1068.
15 16 3 3
2
2
3
+
Jm–o = 8.13, 2H, HmCH3), 7.16 (d, Jo–m = 8.01, 2H, HoCH3),
6
4
9
2
.01 (d, J3–2 = 1.80, 1H, H3), 5.02 (d, J5–6 = 5.94, 1H, H5),
Found: 328.1066%.
.17 (dd, J6–5 = 6.09, J6–1 = 9.12, 1H, H6), 4.05 (d, J2–1
=
.03, 1H, H2), 3.77 (t, J1–2 = 9.09, J1–6 = 9.09, 1H, H1),
4.1.6. (1R,2S,5R,6R)-2-azido-5,6-O-
(isopropylidenedioxy)-4-(4-
(trifluoromethyl)phenyl)cyclohex-3-ene-1-ol (5f)
.79 (bs, 1H, OH), 2.34 (s, 3H, CH (arom.)), 1.52 (s, 3H,
3
1
3
CH ), 1.46 (s, 3H, CH ). C NMR (CDCl , 75 MHz)
3
3
3
2
D
4
1
38.53 (C arom.–CH ), 135.69 (C4), 134.11 (C arom.–
Brownish crystalline solid. M.p.: 118–119 °C. ½aꢀ
+
3
1
C4), 129.38 (C ðHo Þ), 126.00 (di, C ðHm Þ), 124.34
12.7 (c 0.56, CH Cl ). H NMR (CDCl , 300 MHz) 7.64
(m, 4 H, HoCF3 and HmCF3), 6.13 (bs, 1H, H3), 5.02 (d,
J5–6 = 6.00, 1H, H5), 4.23 (dd, J6–5 = 6.27, J6–1 = 9.03,
CH3
CH3
2
2
3
(
7
C (H3)), 110.69 (C isopropylidene), 78.15 (C (H6)),
3.46 (C (H5)), 73.38 (C (H1)), 62.30 (C (H2)), 28.46

A. Bellomo et al. / Journal of Organometallic Chemistry 693 (2008) 1136–1142
1141
+
1
9
3
H, H6), 4.11 (bd, J2–1 = 8.97, 1H, H2), 3.81 (t, J1–2
=
193 (M ꢁC H O–N , 22), 136 (C H S + CH , 34), 43
3
6
3
4
4
3
.09, J1–6 = 9.12, 1H, H1), 2.80 (bs, 1H, OH), 1.54 (s,
(N + CH , 100). TLC: R 0.53 (hexane/EtOAc, 70/30).
HRMS: m/z calc. for (C H N O SNa) : 316.0726.
13 15 3 3
2
3
f
1
3
+
H, CH ), 1.48 (s, 3H, CH ).
C NMR (CDCl3,
3
3
7
5 MHz) 140.50 (C4), 135.01 (C arom.–C4), 130.47 (d,
Found: 316.0729%.
2
JCF = 33, C arom.–CF ), 127.58 (C (H3)), 126.58 (di,
3
3
C ðHmCF3 )), 125.62 (d, di J = 4, C (HoCF3 )), 124.21 (q,
CF
4.1.9. (1R,2S,5R,6R)-2-azido-5,6-O-
0
J
= 272, CF ), 110.98 (C isopropylidene), 78.07 (C
(isopropylidenedioxy)-4-(thiophen-2 -yl)cyclohex-3-ene-1-
ol (5i)
CF
3
(
H6)), 73.41 (C (H5)), 73.22 (C (H1)), 62.04 (C (H2)),
1
0
0
2
2
8.37 (CH ), 26.06 (CH ). IR (neat): 3425 (O–H, w),
124 (N , s), 1251 (C–F (CF ), m), 1218 (C–N, m), 1068
H NMR (CDCl , 300 MHz) 7.24 (m, 2H, H3 and H4 ),
3
3
3
0
7.00 (bs, 1H, H5 ), 6.02 (bs, 1H, H3), 4.97 (d, J = 5.88,
3
3
5–6
(
C–O–C, s), 876 (C–H, s), 820 (C@C, s). GC–MS: 229
1H, H5), 4.16 (dd, J6–5 = 6.30, J6–1 = 9.09, 1H, H6), 4.07
(d, J2–1 = 8.91, 1H, H2), 3.76 (t, J1–2 = 9.15, J1–6 = 9.57,
+
+
(
(
M ꢁCF – C H O, 31), 209 (M ꢁPhCF , 12), 145
3
3
6
3
+
PhCF , 10), 101 (CF + H O + CH , 46), 69 (CF , 17),
1H, H1), 2.78 (bs, 1H, OH), 1.55 (s, 3H, CH ), 1.49 (s,
3
3
2
3
3
3
1
3
4
3
3 (N + CH , 100). TLC: R 0.32 (hexane/EtOAc, 70/
3H, CH3). C NMR (CDCl , 75 MHz) 140.96 (C4),
130.81 (C heteroarom.–C4), 130.51 (C (H2 )), 127.68 (C
(H5 )), 125.89 and 125.81 (C (H3 and H4 )), 123.42 (C
H3)), 110.92 (C isopropylidene), 78.06 (C (H6)), 73.67
(C (H5)), 73.53 (C (H1)), 62.16 (C (H2)), 28.42 (CH ),
2
3
f
3
+
0
0
0). HRMS: m/z calc. for (C H F N O Na) : 378.1036.
1
6
16
3
3
3
0
0
Found: 378.1034%.
(
4
(
.1.7. (3S,4R,5R,6R)-4-(3-azido-4-hydroxy-5,6-O-
isopropylidenedioxy)cyclohex-1-enyl)benzaldehyde (5g)
3
+
+
26.09 (CH ). ESI-MS: 316 ((M+Na) , 44), 251 (M ꢁN ,
3
3
25
Yellow solid. M.p.: 104–106 °C. ½aꢀ + 22.08 (c 0.36,
100), 193 (251–C H O, 89). This compound had identical
3 6
D
1
CH Cl ). H NMR (CDCl , 300 MHz) 10.02 (s, 1H,
CHO), 7.89 (d, 2H, Jo–m = 8.13, HoCHO), 7.72 (d, 2H,
Jm–o = 8.19, HmCHO), 6.20 (s, 1H, H3), 5.05 (d, J5–6
chromatographic properties with the starting material
and could no be isolated in the pure state.
2
2
3
=
6
4
9
1
.03, 1H, H5), 4.24 (dd, J6–5 = 6.39, J6–1 = 8.91, 1H, H6),
.12 (d, J2–1 = 10.20, 1H, H2), 3.82 (t, J1–2 = 9.06, J1–6
.09, 1H, H1), 2.84 (bs, 1H, OH), 1.55 (s, 3H, CH ),
Acknowledgements
=
3
The following organizations contributed to support this
work: CNPq and FAPESP for financial support. A.B. is
grateful to PEDECIBA and DINACYT for a Doctoral
Fellowship. MestreNova generously granted a license for
the use of its NMR processing software.
1
3
.49 (s, 3H, CH3). C NMR (CDCl , 75 MHz) 191.67
3
(CHO), 142.84 (C4), 136.06 (C arom.–C4), 135.12
(C–CHO arom.), 130.04 (di, C ðHoCHOÞ), 128.27 (C
(H3)), 126.84 (di, C (HmCHO)), 110.99 (C isopropylidene),
7
8.07 (C (H6)), 73.36 (C (H5)), 73.14 (C (H1)), 62.11 (C
(
H2)), 28.38 (CH ), 26.09 (CH ). IR (neat): 3461 (O–H,
3
3
Appendix A. Supplementary material
w), 2989 and 2923 (C–H (CHO)), 2095 (N , s), 1698
3
(
(
4
C@O, s), 1258 (s), 1213 (C–N, m), 1060 (C–O–C, s), 877
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.jorganchem.
+
C–H, s), 811 (C@C, s). GC–MS: 282 (M ꢁCH – H O,
3
2
+
+
), 210 (M ꢁPhCHO, 5), 182 (M ꢁC H O–Ph, 3), 105
3
6
2008.01.006.
+
(
(
PhCO , 4), 85 (C H O + N , 34), 77 (Ph, 4), 58
3 6 2
+
C H O, 100), 51 (C H , 4), 43 (N + CH , 77). TLC:
3
6
4
3
2
3
R 0.28 (hexane/EtOAc, 70/30). HRMS: m/z calc. for
f
References
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(
C H N O Na) : 338.1111. Found: 338.111%.
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2
2
3
0
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7
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(
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3
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0
0
1
1
1
38.61(C4), 131.11 (C heteroarom.–C4), 126.09 (C (H4 )),
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(
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3
(
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3 3
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207 (C–N, m), 1056 (C–O–C, s), 866 (C–H, s), 777
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