Stereoselective synthesis of branched cyclopentitols by titanium(III)-promoted reductive cyclization of 4-oxiranylaldehydes and 4-oxiranyl ketones derived from hexoses

Article abstract of DOI:10.1055/s-2008-1067257

Titanocene chloride efficiently promotes the intramolecular reductive cross coupling of highly functionalized 4-oxiranyl-aldehydes and 4-oxiranyl ketones derived from readily available hexoses affording branched cyclopentitols with good stereoselectivity.

Full text of DOI:10.1055/s-2008-1067257

3160
SPECIAL TOPIC
Stereoselective Synthesis of Branched Cyclopentitols by Titanium(III)-
Promoted Reductive Cyclization of 4-Oxiranylaldehydes and 4-Oxiranyl
Ketones Derived from Hexoses
T
i(III)-Pro
o
mote
d
Redu
s
ctive Cyc
e
lization Luis Chiara,* Sofía Bobo, Esther Sesmilo
Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
Fax +34(91)5644853; E-mail: jl.chiara@iqog.csic.es
Received 19 May 2008
Abstract: Titanocene chloride efficiently promotes the intramolec-
ular reductive cross coupling of highly functionalized 4-oxiranyl-
aldehydes and 4-oxiranyl ketones derived from readily available
hexoses affording branched cyclopentitols with good stereoselec-
tivity.
Key words: carbohydrates, electron transfer, epoxides, radical re-
actions, titanium
Epoxides are a highly valuable and versatile group of
compounds widely used in organic synthesis due to their
varied reactivity and their straightforward preparation
from readily available alkene or carbonyl precursors, gen-
erally with high control over their relative and absolute
stereochemistry. The strained three-membered oxirane
ring is prone to ring-opening reactions with nucleophiles
and low-valent-metal reagents. Both types of ring-open-
Scheme 1 Disconnection of branched cyclic or acyclic 1,3-diols I
ing reaction complement each other in terms of polarity
and regioselectivity. Thus, while nucleophiles preferen-
tially attack the less substituted carbon of the oxirane ring,
single electron transfer from low-valent-metal reagents1
produce the most substituted b-metal oxide C-radical re-
gioselectively, which subsequently adds to electrophilic
radical acceptors.
based on the intra- or intermolecular reductive cross-coupling of epo-
xides with carbonyl compounds and possible mechanistic scenarios
for the C–C bond-forming reaction
involving the oxidative addition of a low-valent-metal re-
agent to the epoxide or the carbonyl group. Examples of
C–C bond-forming reactions following each of these
mechanistic pathways have been described in the litera-
ture,3 with the only exception of path d, which has no pre-
cedent.
Due to our longstanding interest in the exploration of new
strategies for the stereoselective synthesis of highly func-
tionalized cyclitols starting from readily available carbo-
hydrate precursors,2 we decided to explore the
disconnection strategy shown in Scheme 1 for the direct
preparation of branched cyclitols of structure I from 4-ox-
iranylcarbonyl substrates II. A number of possible mech-
anistic scenarios could be contemplated for the
cyclization step, each involving a different generic reac-
tive intermediate A–D. Purportedly, we could envisage
the C–C bond-forming step as proceeding through a radi-
cal (a, d) or a carbanionic pathway (b, c). In the first case,
the required radical intermediates A or D could originate
via single electron transfer (SET) reduction of the epoxide
or the carbonyl group, respectively. In the ionic alterna-
tive, generic carbanionic intermediates B or C could be
formed from II either by two sequential SET reductions
via radicals A and D or, directly, by a bielectronic process
Our group has recently described the first successful re-
ductive cross coupling of epoxides with aldehydes and
ketones4 promoted by samarium diiodide, for which we
proposed an epoxide-derived C-radical of type A as the
key reactive intermediate in the C–C bond-forming step.
The reaction took place intermolecularly and provided a
new access to C-glycosides from 1,2-anhydrohexoses in a
stereoselective way, which complemented other ap-
proaches previously described. With the intention of ex-
ploring an intramolecular version of this reaction that
could give access to polyoxygenated branched carbocy-
cles, we decided to synthesize appropriate substrates from
readily available hexoses.
Using D-glucose as the starting material, two epimeric 4-
oxiranylaldehydes and two epimeric 4-oxiranyl ketones
were prepared to study the reductive cyclization reaction.
Selective acetolysis5 of readily available tetrabenzylated
D-glucose 1 afforded the corresponding 1,6-di-O-acetyl
derivative 2 (Scheme 2). Treatment of 2 with an excess of
SYNTHESIS 2008, No. 19, pp 3160–3166
x
x.
x
x
.
2
0
0
8
Advanced online publication: 05.09.2008
DOI: 10.1055/s-2008-1067257; Art ID: C03408SS
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Ti(III)-Promoted Reductive Cyclization
3161
BnO
BnO
BnO
lithium aluminum hydride produced the sequential reduc-
tion of the ester groups and the sugar acetal to give 2,3,4-
tri-O-benzyl-D-glucitol (3). Regioselective acetylation of
the primary hydroxy groups of 3 under Yamamoto
conditions6 followed by in situ mesylation of the second-
ary hydroxy group gave 4 in good overall yield. Metha-
nolysis of the acetate esters under basic conditions
proceeded with concomitant intramolecular SN2 displace-
ment of the mesylate group at C5 to yield the 4-oxiranyl
alcohol 5 of L-ido configuration. Alternatively, treatment
of triol 3 under Mitsunobu conditions7 afforded the 4-ox-
iranyl alcohol 6 of D-gluco configuration diastereoselec-
tively, together with a minor amount of its epimer 5.
Swern oxidation of 5 and 6 gave the epimeric 4-oxiranyl-
aldehydes 7 and 8, respectively, in quantitative yield,
which were immediately used in the reductive cyclization
reaction.
+
–
O
OH
MePPh3 Br , n-BuLi
OH
OBn
BnO
BnO
THF, r.t.
76%
BnO
OBn
10
9
MCPBA, NaHCO3
CH2Cl2, r.t.
45%
(83% based on
recovered 10)
BnO
BnO
BnO
OH
O
DMP
O
BnO
O
CH2Cl2, r.t.
92%
BnO
OBn
BnO
OBn
12a,b (2:1)
11a,b (2:1)
Scheme 3
The epimeric 4-oxiranyl ketones 12a,b were prepared
from readily available 2,3,4,6-tetra-O-benzyl-D-glucose8
(9) as shown in Scheme 3. Wittig methylenation9 of 9 and
subsequent epoxidation of the resultant vinyl derivative
10 with m-chloroperbenzoic acid gave epoxide 11a,b as
an inseparable 2:1 mixture of diastereoisomers in moder-
ate yield. The epoxidation reaction was stopped before the
starting 10 was completely consumed to avoid the degra-
dation of the product observed with longer reaction times.
Mild oxidation of 11a,b with the Dess–Martin periodi-
nane yielded the 4-oxiranyl ketones 12a,b as an insepara-
ble mixture of diastereoisomers.
With our two pairs of epimeric 4-oxiranylcarbonyl sub-
strates at hand, we were ready to investigate the reductive
cyclization reaction. Based on our previous results for the
intermolecular reductive coupling of epoxides with carbo-
nyl compounds,4 we first tried to carry out the correspond-
ing intramolecular counterpart under similar reaction
conditions, using samarium diiodide as the reducing
agent.10 However, complex reaction mixtures were ob-
tained for all substrates assayed, containing intermolecu-
lar pinacol coupling products and iodohydrins,10 but none
of the expected reductive cyclization products. We next
AcO
BnO
AcOH, Ac2O, H2SO4
O
O
(6:1:0.05)
BnBr, KOH
D-glucose
BnO
BnO
OAc
OBn
BnO
BnO
OBn
OBn
DMSO, r.t.
64%
r.t., 3 h
69%
1
2
LiAlH4, THF, 0 °C, 2 h
92%
O
AcO
BnO
HO
1) MeCOCl, DIPEA
CH2Cl2, –78 °C
OMs
OH
K2CO3
OH
OBn
BnO
BnO
OAc
OH
BnO
BnO
MeOH/CH2Cl2
78%
2) MeSO2Cl, –50 °C
BnO
OBn
OBn
78%
5
4
3
(one-pot, 2 steps)
(COCl)2, DMSO, Et3N
THF, –65 °C
PPh3, DIAD
PhMe, 110 °C, 4
h
quant.
O
O
O
(COCl)2, DMSO, Et3N
BnO
BnO
BnO
BnO
O
O
OH
OBn
BnO
BnO
+
5
THF, –65 °C
96%
OBn
OBn
6%
7
8
6
56%
Scheme 2
Synthesis 2008, No. 19, 3160–3166 © Thieme Stuttgart · New York

3162
J. L. Chiara et al.
SPECIAL TOPIC
tried titanocene chloride (Cp2TiCl)3a,11–13 as reducing
agent, which gave poor results in our previous intermolec-
ular coupling reactions.4 Thus, addition of a 0.04 M solu-
tion of epoxyaldehydes 7 or 8 in tetrahydrofuran to
titanocene chloride, prepared in situ by reduction of ti-
tanocene dichloride with zinc dust, resulted in the forma-
tion of a mixture of tri- and dibenzylated cyclopentitols 13
and 14, respectively, in approximately the same ratio and
yield independent of the starting epoxyaldehyde used
(Scheme 4). Both products were fully characterized after
acetylation of the hydroxy groups. Compound 13 and its
debenzylated analogue 14 were transformed into a single
pentaacetylated derivative in quantitative yield after cata-
lytic hydrogenolysis of the benzyl groups and peracetyla-
tion showing that they shared the same stereochemistry.
OBn
OH
OBn
OH
Cp2TiCl2, Zn BnO
THF, r.t.
BnO
OH
OH
12a,b
+
BnO
OBn
BnO
OBn
15
16
30%
15%
OH
OH
BnO
BnO
BnO
BnO
BnO
O
Cl
O
+
+
Me
OBn
BnO
OBn
17
8%
18
12%
+ others
Scheme 5
OH
BnO
OH
Cp2TiCl2, Zn
THF, r.t.
w
7 or 8
OAc
H2C H5
BnO
13 (R = Bn) 14 (R = H)
OR
m
3JH1,H2 = J1,5 = 5.6 Hz
3JH4,H5 = 7.1 Hz
H4
BnO
H1
OAc
H2
OBn
(from 7)
(from 8)
41%
40%
10%
13%
BnO
13
s
m
H3
Scheme 4
w
w
BnO
HO CH2
OBn
The cyclization of the epimeric mixture of epoxy ketones
12a,b with titanocene dichloride and zinc under the same
conditions gave a separable mixture of diastereoisomeric
cyclopentitols in moderate yield, together with a series of
minor products from which we could only isolate and
characterize chlorohydrin 17 (as a cyclic hemiacetal) and
its isomeric dehalogenated analogue 18 (Scheme 5). The
formation of chlorohydrins in reactions promoted by ti-
tanocene chloride has been described before.13 Replacing
zinc by other metals, such as manganese or samarium, in
the reduction of titanocene dichloride did not affect the
yields or the stereoselectivity of the reductive cyclization
reaction significantly.
m
m
w
H2C OH
H4
BnO
CH2OH
H1
H4
BnO
BnO
CH2OH
H1
BnO
H2
OBn
H2
OBn
m
H3
H3
s
3JH1,H2 = 8.5 Hz
3JH1,H2 = 1.2 Hz
15
16
Figure 1 Selected H–1H correlations (s: strong; m: medium; w:
weak) observed in the 2D NOESY spectra of the carbocyclic products
obtained in this work and three-bond 1H–1H coupling constants invol-
ving the ring protons at the newly generated stereocenters.
1
titanoxide C-radical III and IV resulting from the regiose-
lective single electron transfer opening of the oxiranyl
ring (Figure 2).14 As formerly proposed by RajanBabu
and Nugent for the related reductive cyclization of hex-
ose-derived epoxyalkenes,13 the stereoselectivity of our
cyclization reactions can be explained assuming a chair-
like transition state where the b-titanoxy C-radical, the ti-
tanium-coordinated carbonyl group,14b and most other
substituents are equatorially disposed (transition states
geometrically close to the conformers of intermediates III
and IV shown in Figure 2). The chelated titanium dialkox-
ide V can account for the formation of the minor debenzy-
lated product 14 in the cyclization of 7/8, via nucleophilic
cleavage of the activated benzyl ether by the excess chlo-
ride ion present in the reaction medium.
The stereochemistry of the carbocyclic products 13, 15,
and 16 was deduced from a detailed analysis of their 1H–
1H 2D-NOESY spectra. The observed NOESY correla-
tions with diagnostic value are schematically represented
in Figure 1. The corresponding JH,H coupling constants
involving the ring protons at the new stereocenters
3
(Figure 1) were not diagnostic, except for the case of com-
3
pound 16, for which the low value observed for JH1,H2
confirmed the trans stereochemistry assigned for these
protons from the NOESY data. In all cyclizations, the ma-
jor or exclusive cyclitol diastereoisomer presents a trans
relationship between the hydroxymethyl group derived
from the epoxide and the vicinal alkoxide substituent, in-
dependently of the starting epoxide epimer used.
The fact that the epimeric 4-oxiranylaldehydes 7 and 8
gave identical outcomes in the reductive cyclization reac-
tion clearly confirmed that both cyclizations proceed
through a common reactive intermediate, the purported b-
In conclusion, we have shown that the reductive cross
coupling of epoxides with carbonyl groups promoted by
titanocene chloride can be successfully applied to the ste-
Synthesis 2008, No. 19, 3160–3166 © Thieme Stuttgart · New York

SPECIAL TOPIC
Ti(III)-Promoted Reductive Cyclization
2,3,4-Tri-O-benzyl-D-glucitol (3)
3163
Bn
Bn
TiIII
OTiIV
TiIII
To a soln of 2 (640 mg, 1.20 mmol) in THF (10 mL) at 0 °C was
added 1.0 M LiAlH4 in THF (2.37 mL, 2.37 mmol). The mixture
was stirred at 0 °C for 2 h, EtOAc (10 mL) was added, and the mix-
ture was stirred at r.t. for 30 min. The crude mixture was washed
with 2% aq HCl, the phases were separated, and the aqueous phase
was extracted with EtOAc (2 × 15 mL). The combined organic
phases were washed with sat. aq NaHCO3 (25 mL) and brine (25
mL), dried (anhyd Na2SO4), filtered, and concentrated at reduced
pressure. The residue was purified by flash chromatography (hex-
ane–EtOAc, 1:3) to afford 3 (500 mg, 92%) as a colorless oil.
O
O
O
O
OTiIV
O
Bn
Bn
BnO
O
OBn
BnO
III
IV
Bn
O
OTiIV
O
Bn
V
O
TiIV
Cl
O
Ph
1H NMR (300 MHz, CDCl3): d = 7.39–7.28 (m, 15 H), 4.67–4.60
(m, 6 H, 3 CH2Ph), 3.91–3.60 (m, 8 H), 3.45 (d, J = 3.8 Hz, 1 H),
2.29–2.20 (m, 2 H).
Figure 2
13C NMR (75 MHz, CDCl3): d = 137.9 (0), 137.6 (0), 137.5 (0),
129.5–127.9 (15 C, +), 79.3 (+), 79.2 (+), 77.0 (–), 74.2 (–), 73.7
(–), 73.2 (+), 71.7 (+), 63.6 (–), 61.8 (–).
reoselective preparation of highly functionalized
branched cyclitols from readily available hexose precur-
sors. Our stereochemical results using epimeric 4-oxira-
nylaldehydes are in agreement with the mechanism
proposed3a,14 for this reductive coupling reactions involv-
ing a b-titanoxy C-radical intermediate.
1,6-Di-O-acetyl-2,3,4-tri-O-benzyl-5-O-mesyl-D-glucitol (4)
To a soln of 3 (350 mg, 0.77 mmol) and DIPEA (0.81 mL, 4.64
mmol) in CH2Cl2 (7.5 mL) at –78 °C was added dropwise AcCl
(132.36 mL, 1.93 mmol). The mixture was stirred at –78 °C for 1.5
h and the temperature was raised to –50 °C and MsCl (89.70 mL,
1.16 mmol) was added. The mixture was stirred at –50 °C for 10
min and the temperature was allowed to reach 0 °C and stirred for
30 min. H2O (10 mL) was added, the phases were separated and the
aqueous phase was extracted with CH2Cl2 (3 × 15 mL). The com-
bined organic phases were washed with aq 2% HCl (50 mL), sat. aq
NaHCO3 (50 mL), and brine (50 mL), dried (anhyd Na2SO4), fil-
tered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane–EtOAc, 5:2) to afford 4
(375 mg, 78%) as a colorless oil.
Air- and/or moisture-sensitive reactions were carried out in anhyd
solvents under an atmosphere of argon in oven-dried glassware. All
anhyd solvents were distilled prior to use: THF and toluene from
Na/benzophenone and CH2Cl2, DMF, and MeCN from CaH2. Com-
mercial reagents were used without purification. Column chroma-
tography was carried out by using Merck silica gel 60 (230–400
mesh). Optical rotations were determined on a Perkin Elmer 241-
MC polarimeter. Specific optical rotations [a]D are given in
1
10–1 × deg × cm2 × g–1. H and 13C NMR spectra were recorded at
20–25 °C on Bruker AMX-300, Varian Inova 300, Varian Inova
400, or Varian Mercury 400 spectrometers; residual protons in the
NMR solvent (CHCl3 d = 7.26; CH2Cl2 d = 5.30) were used as the
reference, assignment was based on DQ-COSY. The multiplicity of
13C NMR signals was assigned with the help of DEPT spectra and
are indicated as follows: (+) CH3 or CH carbon; (–) CH2 carbon; (0)
quaternary carbon. Assignments of 13C NMR signals are based on
HSQC and HMBC spectra.
[a]D22 +22.3 (c 1.15, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.35–7.25 (m, 15 H), 5.06 (dt,
J = 2.6, 8.4 Hz, 1 H, H5), 6.65–4.57 (m, 6 H, 3 CH2Ph), 4.48 (dd,
J = 2.4, 12.6 Hz, 1 H, H6), 4.37 (dd, J = 3.9, 11.9 Hz, 1 H, H1), 4.27
(dd, J = 8.4, 12.6 Hz, 1 H, H6¢), 4.21 (dd, J = 6.5, 11.9 Hz, 1 H,
H1¢), 4.06 (dd, J = 6.1, 2.6 Hz, 1 H, H4), 3.86 (ddd, J = 3.9, 5.0, 6.5
Hz, 1 H, H2), 3.69 (dd, J = 6.1, 5.0 Hz, 1 H, H3), 2.88 (s, 3 H,
SO2CH3), 2.01 (s, 3 H, Ac), 2.00 (s, 3 H, Ac).
13C NMR (75 MHz, CDCl3): d = 170.7 (0), 170.4 (0), 137.6 (0),
137.5 (0), 137.4 (0), 128.5–127.9 (15 C, +), 81.1 (+), 79.6 (+), 78.3
(+), 76.5 (+), 74.9 (–), 74.6 (–), 73.1 (–), 63.4 (–), 62.9 (–), 38.3 (+),
20.9 (+), 20.7 (+).
1,6-Di-O-acetyl-2,3,4-tri-O-benzyl-D-glucose (2)
Benzyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside8 (1, 7.0 g, 11.09
mmol) was dissolved in AcOH–Ac2O–H2SO4 (6:1:0.05, 280 mL).
The mixture was stirred at r.t. for 3 h and then diluted with CH2Cl2
(150 mL) and poured into H2O–ice (250 mL). The mixture was
carefully neutralized with NaHCO3, the phases were separated, and
the aqueous phase was extracted with CH2Cl2 (3 × 100 mL). The
combined organic phases were washed with brine (400 mL), dried
(anhyd Na2SO4), filtered, and concentrated at reduced pressure. The
residue was purified by flash chromatography (hexane–EtOAc, 3:1)
to afford 2 (4.1 g, 69%) as a colorless oil; mixture of anomers
(a/b 17:3).
5,6-Anhydro-2,3,4-tri-O-benzyl-l-iditol (5)
To a soln of 4 (410 mg, 0.68 mmol) in CH2Cl2–MeOH (1:1, 9 mL)
at 0 °C, was added a suspension of K2CO3 (165 mg, 1.20 mmol) in
MeOH (7 mL). The mixture was stirred at 0 °C for 4 h, H2O (20 mL)
was added and the mixture was extracted with CH2Cl2 (3 × 20 mL).
The combined organic phases were washed with brine (40 mL),
dried (anhyd Na2SO4), filtered, and concentrated at reduced pres-
sure. The residue was purified by flash chromatography (hexane–
EtOAc, 1:1) to afford 6 (230 mg, 78%) as a colorless oil.
1H NMR (300 MHz, CDCl3): d = a/b mixture: 7.34–7.26 (m, 15 H),
6.31 (d, J = 3.4 Hz, 1 H, H1a), 5.61 (d, J = 8.1 Hz, 1 H, H1b), 5.00–
4.54 (m, 6 H, CH2Ph), 4.28 (dd, J = 3.6, 12.3 Hz, 1 H, H6), 4.22 (dd,
J = 2.2, 12.3 Hz, 1 H, H6¢), 3.97 (t, J = 9.2 Hz, 1 H, H4), 3.92 (ddd,
J = 2.2, 3.6, 9.2 Hz, 1 H, H5), 3.66 (dd, J = 3.4, 9.7 Hz, 1 H, H2),
3.56 (dd, J = 9.3, 9.7 Hz, 1 H, H3), 2.15 (s, 3 H, Ac), 2.02 (s, 3 H,
Ac).
13C NMR (75 MHz, CDCl3): d = a-anomer: 170.4 (0), 169.0 (0),
138.4 (0), 137.6 (0), 137.4 (0), 128.3–127.5 (15 C, +), 90.5 (+), 81.5
(+), 78.8 (+), 77.6 (–), 73.0 (2 C, –), 71.0 (+), 62.6 (–), 20.8 (+), 20.5
(+); b-anomer, key signals: 95.4 (+), 81.9 (+), 79.9 (+), 77.4 (+),
74.8 (–), 72.8 (–), 69.2 (–), 68.8 (+), 62.9 (–).
[a]D22 –20.9 (c 0.42, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.35–7.25 (m, 15 H), 4.84–4.57
(m, 6 H, 3 CH2Ph), 3.86–3.80 (m, 1 H), 3.71 (ddd, J = 3.3, 6.2, 9.3
Hz, 1 H), 3.54–3.45 (m, 1 H), 3.25–3.14 (m, 2 H), 2.91 (d, J = 4.4
Hz, 1 H, OH), 2.49 (t, J = 4.3 Hz, 1 H), 2.39 (dd, J = 2.3, 4.8 Hz, 1
H), 2.09 (t, J = 6.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 138.9 (0), 138.5 (0), 138.3 (0),
129.3–128.5 (15 C, +), 80.4 (+), 80.3 (+), 78.3 (+), 75.2 (–), 73.7
(–), 72.7 (–), 61.9 (–), 53.8 (+), 43.4 (–).
Synthesis 2008, No. 19, 3160–3166 © Thieme Stuttgart · New York

3164
J. L. Chiara et al.
SPECIAL TOPIC
5,6-Anhydro-2,3,4-tri-O-benzyl-D-glucitol (6)
(2x)-1,2-Anhydro-3,4,5,7-tetra-O-benzyl-D-gluco-heptitols
To a soln of 3 (378 mg, 0.83 mmol) and Ph3P (329 mg, 1.25 mmol)
in toluene (10 mL) at 110 °C was added dropwise DIAD (200 mL,
1.00 mmol). The mixture was stirred at 110 °C for 4 h and then
cooled to r.t. and diluted with Et2O (20 mL). The mixture was
washed with sat. aq NaHCO3 (20 mL) and brine (20 mL), dried (an-
hyd Na2SO4), filtered, and concentrated at reduced pressure. The
residue was purified by flash chromatography (CH2Cl2–EtOAc,
15:1) to afford 6 (204 mg, 56%) and 5 (20 mg, 6%), as colorless oils.
11a,b
To a suspension of m-CPBA (287 mg, 1.66 mmol) and NaHCO3
(140 mg, 1.66 mmol) in CH2Cl2 (9 mL) at r.t. was added a soln of
10 (448 mg, 0.832 mmol) in CH2Cl2 (5 mL). The mixture was
stirred at r.t. for 12 h, 10% aq Na2S2O3 (10 mL) was added, and the
mixture was stirred for 10 min. The phases were separated and the
aqueous phase was extracted with CH2Cl2 (2 × 15 mL). The com-
bined organic phases were washed with brine (20 mL), dried (anhyd
Na2SO4), filtered, and concentrated at reduced pressure. The residue
was purified by flash chromatography (hexane–EtOAc, 4:1) to af-
ford 11 (207 mg, 45%) as a colorless oil (2:1 mixture of diastereo-
isomers) and recovered 10 (205 mg, 46%).
[a]D22 +4.8 (c 0.6, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.35–7.26 (m, 15 H), 4.54–4.08
(m, 6 H, 3 CH2Ph), 3.81–367 (m, 3 H), 3.53–3.48 (m, 2 H), 3.14 (td,
J = 0.9, 2.7 Hz, 1 H), 2.78 (dd, J = 3.9, 5.4 Hz, 1 H), 2.74 (dd,
J = 2.8, 5.4 Hz, 1 H), 2.07 (t, J = 6.4 Hz, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 138.2 (0), 138.0 (0), 137.7 (0),
128.4–127.7 (15 C, +), 79.5 (+), 79.4 (+), 77.2 (+), 74.8 (–), 73.0
(–), 62.2 (–), 61.5 (–), 51.0 (+), 47.4 (–).
Major Isomer 11a
1H NMR (300 MHz, CDCl3): d = 7.37–7.21 (m, 20 H), 4.83–4.44
(m, 8 H, 4 CH2Ph), 4.00–3.96 (m, 1 H, H7), 3.88–3.84 (m, 2 H, H8,
H8¢), 3.67–3.57 (m, 3 H, H4, H5, H6), 3.12 (ddd, J = 2.9, 3.5, 5.4
Hz, 1 H, H3), 2.83 (d, J = 5.0 Hz, 1 H, OH), 2.68–2.72 (m, 2 H, H1,
H2).
5,6-Anhydro-2,3,4-tri-O-benzyl-L-idose (7); Typical Procedure
To a soln of (COCl)2 (50 mL, 0.57 mmol) in CH2Cl2 (1.5 mL) at
–65 °C was added a soln of DMSO (122 mL, 1.71 mmol) in CH2Cl2
(1.0 mL). The mixture was stirred at –65 °C for 15 min and a soln
of 5 (169 mg, 0.39 mmol) in CH2Cl2 (1.5 mL) was added dropwise.
The mixture was stirred at –65 °C for 30 min, Et3N (275 mL, 1.95
mmol) was added dropwise and the stirring was continued at –65 °C
to r.t. for 1 h. The mixture was diluted with CH2Cl2 (10 mL), sat. aq
NaHCO3 (20 mL) was added, the phases were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic phases were washed with brine (20 mL), dried (anhyd
Na2SO4), filtered, and concentrated at reduced pressure. The residue
was purified by flash chromatography (hexane–EtOAc, 1:1) to af-
ford 7 (171 mg, 100%) as a colorless oil. Compound 7 was used im-
mediately for the reductive cyclization reaction.
13C NMR (75 MHz, CDCl3): d = 138.3 (0), 138.1 (0), 138.0 (0),
128.4–127.4 (20 C, +), 79.7 (–), 79.6 (–), 77.8 (–), 77.7 (–), 74.6 (+),
73.6 (+), 73.4 (+), 71.1 (+), 70.9 (–), 51.3 (+), 46.1 (–).
Minor Isomer 11b
1H NMR (300 MHz, CDCl3) (selected signals): d = 3.29 (dd,
J = 4.0, 7.0 Hz, 1 H, H4), 3.16 (m, 1 H, H3), 2.45 (t, J = 4.6 Hz, 1
H, H2), 2.27 (dd, J = 2.7, 4.8 Hz, 1 H, H1).
13C NMR (75 MHz, CDCl3): d = 138.3 (0), 138.1 (0), 138.0 (0),
128.4–127.4 (20 C, +), 79.9 (–), 78.2 (–), 77.8 (–), 77.7 (–), 74.0 (+),
73.7 (+), 73.4 (+), 72.3 (+), 70.7 (–), 53.3 (+), 43.1 (–).
6,7-Anhydro-1,3,4,5-tetra-O-benzyl-L-xylo-hept-2-uloses 12a,b
To a suspension of Dess–Martin periodinane (183 mg, 0.43 mmol)
in CH2Cl2 (3.5 mL) was added a soln of 11 (80 mg, 0.14 mmol) in
CH2Cl2 (1.0 mL) at r.t. and the mixture was stirred for 30 min. Et2O
(20 mL) and 10% aq Na2S2O3 soln (10 mL) were added and the mix-
ture was stirred for 10 min. The phases were separated and the aque-
ous phase was extracted with Et2O (2 × 10 mL). The combined
organic phases were washed with sat. aq NaHCO3 (15 mL), brine
(15 mL), dried (anhyd Na2SO4), filtered, and concentrated under re-
duced pressure. The residue was purified by flash chromatography
(hexane–EtOAc, 4:1) to afford 12 (73 mg, 92%) as a colorless oil;
2:1 mixture of diastereoisomers.
5,6-Anhydro-2,3,4-tri-O-benzyl-D-glucose (8)
Following the typical procedure for 7, compound 6 (105 mg, 0.24
mmol) afforded 8 (100 mg, 96%) as a colorless oil after flash chro-
matography (hexane–EtOAc, 1:1). Compound 8 was used immedi-
ately for the reductive cyclization reaction.
3,4,5,7-Tetra-O-benzyl-1,2-dideoxy-D-gluco-hept-1-enitol (10)
To a suspension of Ph3MePBr (7.93 g, 22.20 mmol) in THF (48 mL)
at –20 °C, was added dropwise 1.6 M BuLi in hexane (13.9 mL).
The mixture was stirred at –20 °C for 15 min, at r.t. for 1 h, and then
cooled again to –20 °C. To this was added dropwise a soln of 9 (3.00
g, 5.55 mmol) in THF (16 mL). The mixture was stirred at –20 °C
for 15 min and at r.t. for 6 h, acetone was added (25 mL), and the
mixture was stirred at r.t. for 30 min. Et2O (100 mL) was added and
the precipitate of Ph3PO was removed by filtration through Celite.
The filter was rinsed with Et2O and the combined filtrate and wash-
ings were washed with aq sat. NaHCO3 (50 mL), brine (50 mL),
dried (anhyd Na2SO4), filtered, and concentrated at reduced pres-
sure. The residue was purified by flash chromatography (hexane–
EtOAc, 4:1) to afford 10 (2.28 g, 76%) as a colorless oil.
Major Isomer 12a
1H NMR (300 MHz, CDCl3) (selected signals): d = 3.66 (t, J = 5.3
Hz, 1 H, H4), 3.16 (ddd, J = 2.4, 3.5, 5.7 Hz, 1 H, H3), 2.76 (dd,
J = 3.8, 5.3 Hz, 1 H, H2), 2.70 (dd, J = 2.3, 5.3 Hz, 1 H, H1).
13C NMR (75 MHz, CDCl3): d = 206.7 (0), 137.9 (0), 137.4 (0),
137.1 (0), 128.3–127.7 (20 C, +), 81.6 (+), 80.6 (+), 577.4 (+), 74.6
(CH2Ph), 74.2 (CH2Ph), 74.1 (CH2Ph), 73.5 (CH2Ph), 73.1 (–), 50.7
(+), 45.8 (–).
Minor Isomer 12b
[a]D22 +24.5 (c 0.8, CHCl3).
1H NMR (300 MHz, CDCl3) (selected signals): d = 3.42 (dd,
J = 4.8, 6.8 Hz, 1 H, H2), 3.26 (ddd, J = 2.6, 4.1, 6.8 Hz, 1 H, H3),
2.66 (t, J = 4.5 Hz, 1 H, H4), 2.50 (dd, J = 2.6, 4.8 Hz, 1 H, H1).
1H NMR (300 MHz, CDCl3): d = 7.38–7.22 (m, 20 H), 5.85 (ddd,
J = 7.6, 10.5, 17.2 Hz, 1 H, H2), 5.30 (dd, J = 0.7, 10.5 Hz, 1 H,
H1), 5.26 (ddd, J = 0.7, 2.0, 17.2 Hz, 1 H, H1¢), 4.83–4.40 (m, 8 H,
4 CH2Ph), 4.20 (dd, J = 6.0, 7.5 Hz, 1 H, H3), 4.04 (dt, J = 5.4, 10.4
Hz, 1 H, H6), 3.76 (m, 2 H, H4, H5), 3.62 (d, J = 1.3 Hz, 1 H, H7),
3.61 (d, J = 2.7 Hz, 1 H, H7¢), 2.85 (d, J = 5.5 Hz, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 206.6 (0), 137.8 (0), 137.2 (0),
136.9 (0), 128.3–127.7 (20 C, +), 81.7 (+), 79.9 (+), 79.5 (+), 73.6
(–), 73.5 (–), 73.1 (–), 72.4 (–), 72.2 (–), 52.3 (+), 43.1 (–).
13C NMR (75 MHz, CDCl3): d = 138.5 (0), 138.4 (0), 138.3 (0),
138.1 (0), 135.4 (+), 129.3–127.5 (20 C, +), 118.9 (–), 81.5 (+), 81.3
(+), 78.5 (+), 74.7 (–), 73.3 (–), 73.2 (–), 71.3 (–), 70.7 (–), 70.4 (+).
Synthesis 2008, No. 19, 3160–3166 © Thieme Stuttgart · New York

SPECIAL TOPIC
Ti(III)-Promoted Reductive Cyclization
3165
(1S,2S,3S,4R,5S)-2,3,4-Tris(benzyloxy)-5-(hydroxymethyl)cy-
clopentanol (13) and (1S,2S,3R,4R,5S)-3,4-Bis(benzyloxy)-5-
(hydroxymethyl)cyclopentane-1,2-diol (14); Typical Procedure
A dark green soln of Cp2TiCl was prepared by stirring Cp2TiCl2
(105 mg, 0.42 mmol) with Zn dust (85 mg, 1.30 mmol) in THF (2
mL) at r.t. for 2 h. To this soln was added dropwise a soln of 7 (60
mg, 0.14 mmol) in THF (3.5 mL) at r.t. and the mixture was stirred
for 5 h. The reaction was quenched by addition of 10% aq H2SO4 (5
mL), the mixture was vigorously stirred for 10 min, CH2Cl2 (15 mL)
was added, and the phases were separated. The aqueous phase was
extracted with CH2Cl2 (2 × 10 mL). The combined organic phases
were washed with aq sat. NaHCO3 (10 mL) and brine (10 mL), dried
(anhyd Na2SO4), filtered, and concentrated at reduced pressure. The
residue was purified by flash chromatography (hexane–EtOAc, 1:1)
to afford 13 (25 mg, 41%) and 14 (5 mg, 10%) as colorless oils.
Compounds 13 and 14 were characterized as their corresponding di-
and triacetates, respectively, after acetylation with Ac2O in pyri-
dine.
H1¢, H 1¢¢), 3.67 (d, J = 9.4 Hz, 1 H, H6), 3.49 (d, J = 9.4 Hz, 1 H,
H6¢), 3.12 (s, 1 H, OH), 2.37 (t, J = 5.5 Hz, 1 H, OH), 2.32 (dt,
J = 4.9, 8.5 Hz, 1 H, H1).
13C NMR (75 MHz, C6D6): d = 138.3 (0), 138.1 (0), 138.0 (0), 137.5
(0), 128.3–127.5 (20 C, +), 87.7 (C4), 86.8 (C3, +), 82.7 (C2, +),
80.6 (C5, 0), 73.8 (C6, –), 73.0 (CH2Ph, –), 72.6 (CH2Ph, –), 72.6
(CH2Ph, –), 72.2 (CH2Ph, –), 60.5 (C1¢, –), 49.8 (C1, +).
(1S,2S,3R,4S,5S)-2,3,4-Tris(benzyloxy)-1-(benzyloxymethyl)-5-
(hydroxymethyl)cyclopentanol (16)
[a]D22 +8.82 (c 0.6, CHCl3).
1H NMR (400 MHz, C6D6): d = 7.33–7.02 (m, 20 H), 4.69–4.50 (m,
6 H, 3 CH2Ph), 4. 36 (t, J = 6.1 Hz, 1 H, H3), 4.17 (dd, J = 5.8, 1.2
Hz, 1 H, H2), 4.13–4.09 (m, 2 H, CH2Ph), 3.95 (d, J = 6.3 Hz, 1 H,
H4), 3.84–3.67 (m, 2 H, H1¢, H1¢¢), 3.43 (d, J = 10.0 Hz, 1 H, H6),
3.32 (d, J = 10.0 Hz, 1 H, H 6¢), 2.78 (s, 1 H, OH), 2.62 (br s, 1 H,
OH), 2.39 (m, 1 H, H1).
13C NMR (75 MHz, C6D6): d = 139.4 (0), 139.2 (0), 138.7 (0), 137.8
(0), 128.7–127.5 (20 C, +), 88.3 (C4, +), 82.9 (C3, +), 82.5 (C2, +),
78.0 (C5, 0), 73.8 (C6, –), 73.2 (CH2Ph, –), 72.5 (CH2Ph, –), 72.2
(CH2Ph, –), 72.1 (CH2Ph, –), 60.6 (C1¢, –), 53.9 (C1, +).
(1S,2R,3S,4R,5R)-1-Acetoxy-5-(acetoxymethyl)-2,3,4-tris(ben-
zyloxy)cyclopentane (13-Ac2)
[a]D22 +12.4 (c 0.12, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.36–7.26 (m, 15 H), 4.99 (t,
J = 5.6 Hz, 1 H, H1), 4.92–4.45 (m, 6 H, 3 CH2Ph), 4.12 (dd,
J = 1.0, 4.6 Hz, 2 H, H6, H6¢), 4.11 (t, J = 5.9 Hz, 1 H, H3), 3.99 (t,
J = 5.6 Hz, 1 H, H 2), 3.67 (dd, J = 5.6, 7.1 Hz, 1 H, H4), 2.41 (m,
1 H, H5), 2.09 (s, 3 H, Ac), 1.98 (s, 3 H, Ac).
13C NMR (75 MHz, CDCl3): d = 170.0 (0), 169.9 (0), 138.9 (0),
138.8 (0), 138.7 (0), 129.3–127.5 (15 C, +), 87.2 (C3, +), 81.7 (C4,
+), 81.0 (C2, +), 72.5 (C3-CH2Ph, –), 72.4 (C2-CH2Ph, –), 72.1
(C4-CH2Ph, –), 72.0 (C1, +), 62.8 (C6, –), 46.9 (C5, +), 20.5
(CH3CO, +) 20.2 (CH3CO, +).
1,3,4,5-Tetra-O-benzyl-7-chloro-7-deoxy-a-L-gluco-hept-2-ulo-
pyranose (17)
1H NMR (400 MHz, CHCl3): d = 7.35–7.17 (m, 20 H), 4.95–4.58
(m, 8 H, 4 CH2Ph), 4.11 (dt, J = 3.2, 9.9 Hz, 1 H, H1), 4.07 (t,
J = 9.3 Hz, 1 H, H3), 3.79 (d, J = 3.3 Hz, 2 H, H1¢, H1¢¢), 3.67 (t,
J = 9.5 Hz, 1 H, H 2), 3.52 (d, J = 9.5 Hz, 1 H, H4), 3.49 (s, 1 H,
OH), 3.48 (d, J = 10.6 Hz, 1 H, H6), 3.40 (d, J = 10.4 Hz, 1 H, H6¢).
13C NMR (75 MHz, CDCl3): d = 138.4 (0), 138.0 (0), 137.9 (0),
137.8 (0), 128.4–127.7 (20 C, +), 97.9 (C5, 0), 83.2 (C3, +), 79.3
(C4, +), 78.7 (C2, +), 75.6 (C3-CH2Ph), 75.4 (C4-CH2Ph), 75.2
(C2-CH2Ph), 73.8 (C6-CH2Ph), 71.7 (C6, –), 70.9 (C1, +), 44.8
(C1¢, –).
(1S,2R,3S,4R,5R)-1,2-Diacetoxy-5-(acetoxymethyl)-3,4-bis(ben-
zyloxy)cyclopentane (14-Ac3)
[a]D22 –0.75 (c 0.8, CHCl3).
MS (ESI+): m/z = 611.2 [M + Na]+, 606.2 [M + NH4]+.
1H NMR (300 MHz, CDCl3): d = 7.45–7.17 (m, 10 H), 5.21 (t,
J = 5.0 Hz, 1 H, H2), 5.07 (dd, J = 5.2, 8.7 Hz, 1 H, H 1), 4.73–4.49
(m, 4 H, 2 CH2Ph), 4.16 (d, J = 4.4 Hz, 2 H, H6, H6¢), 3.99 (t,
J = 4.1 Hz, 1 H, H3), 3.74 (dd, J = 4.4, 8.1 Hz, 1 H, H4), 2.48 (dt,
J = 4.4, 8.3, 12.6 Hz, 1 H, H5), 2.08 (s, 3 H, Ac), 2.04 (s, 3 H, Ac),
2.00 (s, 3 H, Ac).
13C NMR (75 MHz, CDCl3): d = 170.7 (0), 169.9 (2 C, 0), 137.8 (0),
137.6 (0), 129.4–127.7 (10C, +), 85.9 (C3, +), 81.3 (C4, +), 74.1
(C2, +), 72.3 (2 C, 2 CH2Ph), 70.6 (C1, +), 61.6 (C6, –), 45.8 (C5,
+), 20.7 (2 C, 2CH3CO, +), 20.6 (CH3CO, +).
1,3,4,5-Tetra-O-benzyl-7-deoxy-b-D-ido-hept-2-ulopyranose
(18)
1H NMR (500 MHz, CHCl3): d = 7.45–7.11 (m, 20 H), 4.73–4.24
(m, 8 H, 4 CH2Ph), 4.33 (d, J = 3.1 Hz, 1 H, H4), 4.07 (m, 1 H, H1),
3.99 (dd, J = 1.6, 10.2 Hz, 1 H, H6), 3.89 (dd, J = 1.8, 3.1 Hz, 1 H,
H3), 3.61 (dd, J = 1.8, 7.5 Hz, 1 H, H2), 3.09 (d, J = 10.2 Hz, 1 H,
H6¢), 3.00 (d, J = 1.6 Hz, 1 H, OH), 1.23 (d, J = 6.4 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 139.0 (0), 137.8 (0), 137.8 (0),
137.7 (0), 128.7–127.1 (20 C, +), 95.1 (C5, 0), 79.7 (CH2Ph, –),
79.6 (C2, +), 73.9 (CH2Ph, –), 73.2 (CH2Ph, –), 72.7 (C3, +), 72.1
(C4, +), 72.0 (CH2Ph, –), 70.7 (C6, –), 66.5 (C1, +), 20.6 (CH3, +).
Reductive Cyclization of 4-Oxiranylaldehyde 8
Following the typical procedure from 7, compound 8 (100 mg, 0.23
mmol) was cyclized with Cp2TiCl to afford 13 (48 mg, 40%) and 14
(14 mg, 13%).
MS (ESI+): m/z = 577.1 [M + Na]+, 555.2 [M + 1]+.
Acknowledgment
Reductive Cyclization of 4-Oxiranyl Ketones 12a,b
Following the typical procedure from 7, the mixture of diastereo-
isomeric 4-oxiranyl ketones 12a,b (100 mg, 0.18 mmol) was cy-
clized to yield 15 (30 mg, 30%), 16 (15 mg, 15%), 17 (8 mg, 8%),
and 18 (12 mg, 12%), as colorless oils after column chromatogra-
phy (hexane–EtOAc, 2:1).
We thank MEC for financial support (projects BQU2003-03550-
C03-02 and CTQ2006-15515-C02-02/BQU) and Comunidad de
Madrid (predoctoral fellowship to E.S.).
References
(1R,2S,3R,4S,5S)-2,3,4-Tris(benzyloxy)-1-(benzyloxymethyl)-5-
(hydroxymethyl)cyclopentanol (15)
(1) For recent reviews on epoxide opening by single electron
transfer, see: (a) Gansauer, A.; Justicia, J.; Fan, C. A.;
Worgull, D.; Piestert, F. Top. Curr. Chem. 2007, 279, 25.
(b) Daasbjert, K.; Svith, H.; Grimme, S.; Gerenkam, M.;
Muck-Lichtenfeld, C.; Gansauer, A.; Barchuk, A. Top. Curr.
Chem. 2006, 263, 39.
[a]D22 –5.83 (c 0.7, CHCl3).
1H NMR (400 MHz, C6D6): d = 7.34–7.05 (m, 20 H), 4.68–4.51 (m,
8 H, 4 CH2Ph), 4.27 (dd, J = 5.8, 8.5 Hz, 1 H, H2), 4.06 (t, J = 5.5
Hz, 1 H, H3), 3.93 (d, J = 5.2 Hz, 1 H, H4), 3.85 (t, J = 5.3 Hz, 2 H,
Synthesis 2008, No. 19, 3160–3166 © Thieme Stuttgart · New York

3166
J. L. Chiara et al.
SPECIAL TOPIC
(2) (a) Chiara, J. L.; Garcia, A.; Sesmilo, E.; Vacas, T. Org. Lett.
2006, 8, 3935. (b) Chiara, J. L.; Storch de Gracia, I.; Garcia,
A.; Bastida, A.; Bobo, S.; Martin-Ortega, M. D.
(4) Chiara, J. L.; Sesmilo, E. Angew. Chem. Int. Ed. 2002, 41,
3242.
(5) Ning, J.; Kong, F. Tetrahedron Lett. 1999, 40, 1357.
(6) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem.
1993, 58, 3791.
ChemBioChem 2005, 6, 186. (c) Chiara, J. L.; Garcia, A.;
Cristobal-Lumbroso, G. J. Org. Chem. 2005, 70, 4142.
(d) Chiara, J. L.; Garcia, A. Synlett 2005, 2607. (e) Chiara,
J. L.; Storch de Gracia, I.; Bastida, A. Chem. Commun.
2003, 1874. (f) Storch de Gracia, I.; Bobo, S.; Martin-
Ortega, M. D.; Chiara, J. L. Org. Lett. 1999, 1, 1705.
(g) Bobo, S.; Storch de Gracia, I.; Chiara, J. L. Synlett 1999,
1551. (h) Storch de Gracia, I.; Dietrich, H.; Bobo, S.;
Chiara, J. L. J. Org. Chem. 1998, 63, 5883. (i) Chiara, J. L.
In Carbohydrate Mimics: Concepts and Methods; Chapleur,
Y., Ed.; Wiley-VCH: New York, 1998, Chap. 7, 123–156;
and references cited therein.
(7) Robinson, P. L.; Barry, C. N.; Bass, S. W.; Jarvis, S. E.;
Evans, S. A. J. Org. Chem. 1983, 48, 5396.
(8) Decoster, E.; Lacombe, J. M.; Strebler, J. L.; Ferrari, B.;
Pavia, A. A. J. Carbohydr. Chem. 1983, 2, 329.
(9) Lancelin, J.-M.; Pougny, J.-R.; Sinaÿ, P. Carbohydr. Res.
1985, 136, 369.
(10) A failed intramolecular reductive coupling reaction of an
epoxide with an alkene in the presence of SmI2 has been
described. Epoxide deoxygenation and iodide opening of the
epoxide to yield the corresponding iodohydrin were the only
reactions observed under these conditions: Gansauer, A.;
Rinker, B. Tetrahedron 2002, 58, 7017.
(11) For a seminal work on C–C bond-forming radical reactions
of epoxides promoted by Cp2TiCl, see: Rajanbabu, T. V.;
Nugent, W. A. J. Am. Chem. Soc. 1989, 111, 4525.
(12) For recent reviews on radical reactions of epoxides
promoted by Cp2TiCl, see: (a) Gansauer, A.; Narayan, S.
Adv. Synth. Catal. 2002, 344, 465. (b) Gansauer, A.;
Lauterbach, T.; Narayan, S. Angew. Chem. Int. Ed. 2003, 42,
5556. (c) Cuerva, J. M.; Justicia, J.; Oller-López, J. L.; Oltra,
J. E. Top. Curr. Chem. 2006, 264, 63. (d) Barrero, A. F.;
del Moral, J. F. Q.; Sanchez, E. M.; Arteaga, J. F. Eur. J.
Org. Chem. 2006, 1627.
(3) For examples of C–C bond-forming reactions of epoxides
with carbonyl groups, see the following. Via radical
intermediate A using Cp2TiCl: (a) Fernandez-Mateos, A.;
Martin de la Nava, E.; Coca, G. P.; Silvo, A. R.; Gonzalez,
R. R. Org. Lett. 1999, 1, 607. Using SmI2: (b) see ref. 4. Via
dianionic intermediate B, using Li/arene reagents:
(c) Barluenga, J.; Fernandez-Simon, J. L.; Concellon, J. M.;
Yus, M. J. Chem. Soc., Perkin Trans. 1 1988, 3339.
(d) Cohen, T.; Jeong, I. H.; Mudryk, B.; Bhupathy, M.;
Awad, M. M. A. J. Org. Chem. 1990, 55, 1528. (e) Bachki,
A.; Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 1996, 7,
2997. (f) Soler, T.; Bachki, A.; Falvello, L. R.; Foubelo, F.;
Yus, M. Tetrahedron: Asymmetry 2000, 11, 493. Viaallylic
isomer analogues of dianionic intermediate B, using CrCl2–
LiI: (g) Fujimura, O.; Takai, K.; Utimoto, K. J. Org. Chem.
1990, 55, 1705. Using SnCl2–LiI: (h) Masuyama, Y.;
Nakata, J.; Kurusu, Y. J. Chem. Soc., Perkin Trans. 1 1991,
2598. Via dianionic intermediate C, using Li/arene
reagents: (i) Walborsky, H. M.; Murari, M. P. Can. J. Chem.
1984, 62, 2464. Using Yb–HMPA: (j) Hou, Z. M.;
Takamine, K.; Aoki, O.; Shiraishi, H.; Fujiwara, Y.;
Taniguchi, H. J. Chem. Soc., Chem. Commun. 1988, 668.
(k) Hou, Z. M.; Takamine, K.; Aoki, O.; Shiraishi, H.;
Fujiwara, Y.; Taniguchi, H. J. Org. Chem. 1988, 53, 6077.
(l) Takaki, K.; Tanaka, S.; Beppu, F.; Tsubaki, Y.; Fujiwara,
Y. Chem. Lett. 1990, 1427.
(13) Rajanbabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994,
116, 986.
(14) For recent mechanistic studies on SET opening reactions of
epoxides promoted by Cp2TiCl, see: (a) Gansauer, A.;
Barchuk, A.; Keller, F.; Schmitt, M.; Grimme, S.;
Gerenkamp, M.; Muck-Lichtenfeld, C.; Daasbjerg, K.;
Svith, H. J. Am. Chem. Soc. 2007, 129, 1359.
(b) Fernandez-Mateos, A.; Teijon, P. H.; Buron, L. M.;
Clemente, R. R.; Gonzalez, R. R. J. Org. Chem. 2007, 72,
9973. (c) Daasbjerg, K.; Svith, H.; Grimme, S.; Gerenkamp,
M.; Muck-Lichtenfeld, C.; Gansauer, A.; Barchuk, A.;
Keller, F. Angew. Chem. Int. Ed. 2006, 45, 2041.
Synthesis 2008, No. 19, 3160–3166 © Thieme Stuttgart · New York