Regio- and stereochemical aspects in the synthesis of homoallylic alcohols from benzoins and their iodocyclisation to 2,3-diphenyltetrahydrofurans

Article abstract of DOI:10.1016/j.tet.2006.02.031

Indium mediated allylation, crotylation and cinnamylation of benzoins and its substituted derivatives in THF-H₂O (2/1) provide a range of homoallylic alcohols. In general, the benzoins undergo allylation and crotylation in a sluggish manner com

Full text of DOI:10.1016/j.tet.2006.02.031

Tetrahedron 62 (2006) 4018–4026
Regio- and stereochemical aspects in the synthesis of homoallylic
alcohols from benzoins and their iodocyclisation to
2
,3-diphenyltetrahydrofurans
Subodh Kumar, Pervinder Kaur, Anu Mittal and Palwinder Singh
* *
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
Received 3 October 2005; revised 25 January 2006; accepted 10 February 2006
Available online 7 March 2006
2
Abstract—Indium mediated allylation, crotylation and cinnamylation of benzoins and its substituted derivatives in THF–H O (2/1) provide
a range of homoallylic alcohols. In general, the benzoins undergo allylation and crotylation in a sluggish manner compared to those observed
earlier in the case of a-hydroxy aldehydes and are significantly affected by the electronic features of both the benzoin and indium
organometallic reagent. The reactions exhibit higher order of diastereoselectivities than those observed for a-hydroxy aldehydes. The
0
cinnamylation though proceeds in a highly diastereoselective manner but is restricted to only benzoin and 4,4 -dichlorobenzoin. The
homoallylic alcohols undergo I mediated intramolecular diastereoselective cyclization to provide 2,3-diphenyltetrahydrofuran derivatives.
2
The relative stereochemistries in tetrahydrofurans and homoallylic alcohols have been assigned by coupling constants, NOE experiments and
in one case by X-ray crystallography.
q 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
sterically less hindered face to provide syn homoallylic
alcohols. The presence of water does not inhibit the
operation of chelation control. The choice of the solvent,
different additives and pH of the reaction medium also affect
the diastereoselective outcome of the reaction. However,
due to poor reactivities of ketones compared to aldehydes
towards nucleophiles, these investigations have been
The allylation of carbonyl compounds with allyl organo-
metallic reagents constitutes a simple approach for the
synthesis of homoallylic alcohols, versatile synthons in
1
organic synthesis. The stability of indium metal in water,
ease in generation of allyl indium reagents under anhydrous
conditions and in situ generation under aqueous Barbier
type conditions; the lower basicity and thus the higher
stability of allylindium reagents in the presence of water
and other proton donor functionalities such as OH, COOH;
6
limited to allylation of hydroxycyclohexanones and
carbohydrates with only allyl bromide.
7
The present work is aimed to unravel the regio- and
diastereochemical aspects in allylation of benzoins—the
acyclic a-hydroxyketones with allyl and substituted allyl
the applicability even in the presence of NO , CN, ester
2
8
functional groups, have highlighted the superiority of allyl
2
indium reagents over conventional organometallic
bromides. The presence of two aryl rings at adjacent carbons
make them attractive synthons for a,b-diaryl heterocycles—
an essential structural feature in many bioactive molecules
3
reagents. The environment friendly reaction conditions
and the higher reactivities in these multi-component
reactions in aqueous media are added advantages of indium
mediated allylation reactions.
9
especially COX-2 inhibitors.
4
The findings show that benzoins, in general, undergo indium
mediated allylation and crotylation in a sluggish manner
than those observed earlier in the case of a-hydroxy
aldehydes. The presence of electron-withdrawing groups
on the aryl rings facilitates the allylation and the presence of
electron-donating groups retards the allyl transfer. The
cinnamylation proceeds in a highly diastereoselective
5
The pioneering investigations of Paquette et al. on the
stereochemical outcome of allylation of a-hydroxy alde-
hdyes, in general, show the participation of Cram’s
chelation model and allylic anions preferably add from the
Keywords: Benzoins; Indium; Homoallylic alcohols; Iodocyclisation;
Regioselective; Diphenyltetrahydrofurans.
0
manner (O98:2) with benzoin and 4,4 -dichlorobenzoin.
Homoallylic alcohols thus obtained undergo I mediated
diastereoselective intramolecular cyclizations to give
*
Corresponding authors. Tel.: C91 183 2258802; fax: C91 183 2258820
S.K.); (P.S.); e-mail: subodh_gndu@yahoo.co.in
2
(
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.031

S. Kumar et al. / Tetrahedron 62 (2006) 4018–4026
4019
0
2
,3-diaryltetrahydrofurans. The configurations of tetra-
4,4 -Dichlorobenzoin 1b undergoes allylation faster than
benzoin 1a and in the case of anisoin 1d and benzanisoin
1c, possessing electron-donating group (OMe) the allyla-
tion takes a longer time (Table 1, entry 1–4). The presence
of a strong electron-donating group [N(CH ) ] leads to
hydrofurans and homoallylic alcohols have been assigned
by NOE experiments and by X-ray crystallography in one
case.
3
2
complete inhibition of the allyl transfer even at elevated
temperature (50 8C). A comparison of reaction times
required for allylation of benzoins with those of
2
. Results and discussion
5
2.1. Diastereoselective allylation with allyl bromide:
generation of one new chiral center
a-hydroxyaldehydes shows that benzoins (4–14 h) take
more time for completion of the reaction than taken by
a-hydroxyaldehydes (2–4 h). These results are in agree-
ment with the known higher reactivities of aldehydes
compared to ketones towards nucleophilic addition
reactions. Interestingly, the lower reactivities of benzoins
towards indium mediated allylation than observed
for a-hydroxyaldehydes, results in high (O99:1)
diastereoselectivities.
A solution of 1a, allyl bromide 2 and indium metal
(
suspension) (1:1.5:1) in THF–H O (2/1) on stirring at
2
3
0G2 8C for 6–8 h, after usual work-up and chromato-
10
graphy provided (1R*,2S*)-3a (92%), mp 95 8C, (lit. mp
6–97 8C (Scheme 1). This procedure offers a convenient
alternative to similar allylation performed through tetra-
allyltin. In order to evaluate the contribution of electronic
features on the reactivity and diastereoselectivity of
allylation on benzoins, the substituted benzoin derivatives
9
1
0
In these reactions, the formation of syn products can be
visualized on the basis of classic Cram’s chelation model 4
(Scheme 2). The ability of the indium cation to lock
the hydroxy carbonyl substrates conformationally prior to
the nucleophilic attack is indicative that co-ordination to the
substrate indeed overcomes the solvation forces.
1
b–1e were subjected to indium mediated allylation under
Barbier type conditions. Benzoins 1b–1d on allylation gave
homoallylic alcohols 3b–3d with diastereoselectivities
O99:1 (Scheme 1, Table 1). N,N-Dimethylbenzoin 1e
did not undergo indium mediated allylation and even on
performing the reaction at 50 8C, the starting 1e (w50%)
was recovered.
L
L
In
O
O
Ph
Ph
O
O
L
R2
In
O
H
Ph
L
Br
Ph
H
+
4
OH
R1
2
1a-1e
In
Scheme 2.
THF : H O (2:1)
2
R1
2.2. Diastereoselective allylation with substituted allyl
bromides: generation of two new chiral centers
R2
The allylic anions generated from substituted allyl bromides
are unsymmetrical and the documented preferred carbon–
carbon bond formation in the case of aldehydes from the
more substituted carbon results in the generation of two new
OH
HO
3
a-3d
syn-
2
1
2
1
2
chiral centers. In the case of benzoins, it would lead to
For 1, 3 (a) R = R = H; (b) R = R = Cl;
formation of homoallylic alcohols with three chiral centers
resulting in possible formation of four diastereomers. In
order to evaluate the regio- and stereoselective aspects in
allylation of benzoins 1a–1d, indium mediated Barbier type
allylations with crotyl bromide, cinnamyl bromide and ethyl
1
2
1
2
(
c) R = OCH , R = H ; (d) R = R = OCH ;
3 3
1
2
(
e) R = N(CH ) , R = H
3
2
Scheme 1.
4-bromocrotonate were performed.
Table 1. Diastereoselective allylation of benzoins 1a–1e
1
2
Entry
R
R
Product Time
h)
dr
Yield
(%)
Stirring of a solution of benzoin 1a with cinnamyl bromide
(5) in THF–H O (2/1) at 0 8C containing fine flakes of
(
2
C
indium gave a pale yellow liquid (85%), M m/z 330
1
2
3
4
5
H
Cl
OCH
OCH
H
Cl
H
OCH
H
3a
3b
3c
3d
3e
7–8
4–5
12–14
12–14
24
O99:1
O99:1
O99:1
O99:1
92
45
69
72
1
(Scheme 3). It’s H NMR spectrum shows a singlet at d 3.02
3
(PhCHOH), doublet at d 4.14 (PhCH) and multiplet at d
3
3
5
7
.11–5.17 (]CH ), dt at 6.15 (1H, ]CH) and multiplet at
2
N(CH
3
)
2
No reaction
.02–7.56 (15H, ArH). These spectral data along with the
C NMR spectrum assigns structure 6a for this compound.
1
3
The time required for allylation of benzoins 1a–1e is
considerably affected by the nature of the substituent on
the aryl ring and is by and large in parallel with the
electron-densities available on the carbonyl carbon.
Therefore, cinnamylation of 1a proceeds in a complete
regio- and diastereoselective manner and provides only the
g-addition product. The presence of only one set of signals
1
13
in the H and C NMR spectra of 6a indicates that only one

4020
S. Kumar et al. / Tetrahedron 62 (2006) 4018–4026
R2
R2
O
O
+
C H
6
5
Br
+
H3C
Br
OH
R1
OH
R1
5
a R1 = R = H;
b R1 = R = Cl
2
1
1
7
In
2
1
2
THF:H O (2:1)
1a R = R = H;
2
1
2
In
THF:H2O (2:1)
1
b R = R = Cl,
R1
1
2
1
d R = R = OCH
3
R2
R1
R1
2
OH
R2
R2
1
HO
3
5
C H
6
2
OH
3
2
OH
3
6
(a-b)
1
1
+
syn,syn-
yield
85%
HO
HO
H C
H C
3
d.r.
3
1
2
6
a R = R = H;
>98:2
>98:2
8
9
1
2
6
b R = R = Cl
88%
syn,anti-
syn,syn-
Scheme 3.
yield
78%
74%
71%
dr
1
2
For 8 and 9 (a) R = R = H
64:36
diastereomer is formed. On the basis of NOE experiments
on its iodocyclized tetrahydrofuran derivatives 14a and 15a,
it has been assigned as syn,syn-addition product-
1
2
(b) R = R = Cl
64:36
78:22
1
2
(c) R = R = OCH
3
(
1R*,2S*,3R*)-1,2,3-triphenylpent-4-ene-1,2-diol (6a). 1b
also underwent diastreoselective cinnamylation to provide
b. However, the electron rich benzoins 1c and 1d failed to
Scheme 4.
6
react with cinnamyl bromide under these conditions.
Table 2. Diastereoselective allylation of benzoins 1 with substituted allyl
bromides
In the case of crotyl bromide, the minimum steric
requirement inherited by the CH group provides a good
Entry
Allyl
bromide
Benzoin Time
(h)
Product
(syn,syn:syn,anti) (%)
Yield
3
opportunity to test the diastereoselectivity of the system
under investigation. The reaction of benzoin 1a with crotyl
1
2
3
4
5
5
5
7
7
7
1a
1b
1a
1b
1d
24
6a (98:2)
6b (98:2)
8aC9a (64:36)
8bC9b (64:36)
8cC9c (78:22)
85
88
78
71
74
bromide in THF–H O (2/1) at 0 8C gave a yellow liquid
2
4–5
3–4
1–2
5–6
1
78% yield) (Scheme 4). Its H NMR spectrum shows two
(
distinct signals each for CH , CH and ]CH protons in a
3
6
and could be assigned to CH attached to the sp hybridized
4:36 ratio. The two CH doublets appear at d 0.93 and 1.06
3
3
3
carbon. The absence of a signal due to the methyl group
between d 1.5–2.5 shows the non-formation of a-addition
product. Therefore, the crotylation too proceeds in a highly
regioselective manner to provide only the g-addition
products. Further, out of the possible four diastreomers
only two are formed. The two diastereomers could not be
separated but relative configurations at the chiral centers
have been assigned on the basis of NOE experiments on
their iodocyclized products 12a and 13a. The major
diastereomer has been assigned the configurations
The allylation reactions of 1a with cinnamyl and crotyl
bromide also proceed through Cram’s chelation model. The
reaction of benzoin 1a and 1b with cinnamyl bromide
proceed through transition state A resulting in the formation
of syn,syn-addition product in which the cinnamyl anion is
transferred to the carbonyl carbon from less hindered
p-face. However, crotylation of 1a, 1b and 1d preferentially
proceeds through transition state B, resulting in formation
of the syn,anti- as the major products (Scheme 5).
(
1R*,2S*,3R*)-8a and found to be syn,anti-addition product
H
and minor, which is a syn,syn-addition product has been
assigned configurations (1R*,2S*,3S*)-9a. Similarly, 1b
and 1d on crotylation gave 8bC9b and 8cC9c (Table 2).
Amongst these pairs of diastereomers 8a–8c and 9a–9c, the
methine vinylic proton (]CH) of syn,anti-addition products
Ph
Ph
OH
O
R = CH , Ph
Ph
R
L
L
3
In
Ph
O
HO
H
R
H
syn, syn-
A
8
appear downfield at d 6.07–6.12 in comparison with that
of the syn,syn-addition products 9 (d 5.78–5.92). These
results are in consonance with earlier reported downfield
appearance of methine vinylic proton in anti-addition
product compared to in syn-addition product. The
allylation of 1a–1d with ethyl 4-bromocrotonate failed
to occur even at elevated temperature (50 8C) and only
unreacted 1a–1d could be isolated.
R Ph
Ph
Ph
O
OH
H
L
L
R = CH3
In
1
1
Ph
HO
O
R
H
H
syn, anti-
B
Scheme 5.

S. Kumar et al. / Tetrahedron 62 (2006) 4018–4026
4021
1
2
The comparison of these results with crotylation of
-hydroxypropanal shows that whereas in the latter case
the mixture of syn,syn-, syn,anti- and anti,anti-addition
products is formed, the crotylations of benzoins provide
only syn,syn- and syn,anti-addition products.
the polarity of the solvent,
in order to improve
2
diastereoselectivities, the iodocyclisation was performed at
different temperatures using solvents with varied polarities.
It was observed that lowering the reaction temperature to
0 8C increased the overall yield to 90% and marginally
improved the diastereoselectivity from 80:20 to 86:14.
However, on performing iodocyclisation in CH Cl
5
d
2.3. Diastereoselective conversion of homoallylic
alcohols to 2,3-diphenyltetrahydrofurans 10–15
2
2
diastereoselectivity decreased and in toluene both yield
and diastereoselectivity was lowered (Table 3).
Stirring a mixture of 3a, I and NaHCO in dry CH CN for
2
3
3
7
2 h after usual work up gave a mixture of two
Table 3. Effect of solvent and temperature on iodocyclisation of 2a
1
diastereomers in the ratio 80:20 ( H NMR integration)
Scheme 6). The fast moving component (minor 8%) in its
S.no.
Solvent
Temperature (8C)
10:11
Yield (%)
(
1
1
2
3
4
CH CN
3
30
0
0
20:80
14:86
25:75
20:80
40
90
87
75
H NMR spectrum shows two 1H double doublets at d 2.48
and 2.78 (H-4), a doublet at d 3.63 (CH I), 1H singlet at d
CH
CH
3
CN
Cl
2
2
2
5.29 (H-2), 1H multiplet at d 4.57–4.72 (H-5) and 10H
multiplet at d 7.04–7.39. The assignment of the signals has
Toluene
0
been carried out on the basis of decoupling experiments and
H– C COSY spectrum. The relative configurations at C-2
Iodocyclisation of a 64:36 mixtures of 8a and 9a in CH CN
3
1
13
at 0 8C provides a 64:36 mixtures of two diastereomers
Scheme 7). The diastereomeric ratio has been calculated on
1
and C-3 carbons are predefined by H NMR and X-ray
structure of 3a, and relative configurations at C-2 and C-5
carbons could be assigned on the basis of NOE
experiments. The observation of positive NOE at H-4a
and H-5 on irradiating H-2 and NOE at H-2, H-5 on
irradiating H-4a indicates the presence of H-2, H-4a and
H-5 protons on the same side of tetrahydrofuran ring. On
the basis of these results the minor component has been
assigned the structure (2R*,3S*,5R*)-5-iodomethyl-2,3-
diphenyl-tetrahydro-furan-3-ol (10) (Fig. 1).
(
the basis of integration of 1H singlets due to H-2 protons of
two diastereomers at d 5.57 (major) and 5.94 (minor). The
formation of only two compounds indicates that 8a and 9a
underwent highly regio- and stereoselective iodocyclisation
to provide one product each, 12a and 13a, respectively.
Similarly, iodocyclisation of mixture of 8bC9b in CH CN
3
at 0 8C gave 12b and 13b in 1:1 ratio (Scheme 7). In case of
12a–12b, JH4,H5Z9.3 Hz and in 13a–13b JH4,H5Z4.5 Hz
show that H-4 and H-5 are placed trans to each other in 12
and cis to each other in 13. The relative stereochemistries at
C-2, C-4 and C-5 carbons in 12a–12b and 13a–13b have
been assigned on the basis of coupling constants, NOE
experiments and by X-ray structure in the case of 12b.
Ha
HO
Ph
H
Ha
HO
Ph
H
Ph
OH
3
3
Ph
I2, NaHCO3
Hb
Hb
H
4
5
4
+
I
I
CH CN
2 O 5
2 O
HO
3
Ph
Ph
H
3
a
1
0
11
R1
R1
(2R*, 3S *, 5R*)-
(2R*, 3S *, 5S *)-
2
2
R
R
Scheme 6.
OH
OH
+
HO
HO
(
δ 2.45)
H C
3
H C
3
(
δ 2.78)
Ha
Ha
Ph
HO
8a,8b
Syn, Anti-
9a,9b
Syn, Syn-
Ph
Hb (δ 2.62)
Hb (δ 2.48)
HO
δ 5.29) H
4
4
H
2
I2, NaHCO
(
2
(δ 4.57-4.72)
H
3
o
I
I
O
CH CN, 0 C
Ph
O
Ph
H
3
R1
1
R
1
0
11
Figure 1. The relative stereochemistries in 10 and 11 from NOE
experiments.
H
CH3
HO
H
CH
H
HO
H
3
+ H
2
H
2
I
I
5
O
O 5
The slow moving component (major diastereomer, 32%) in
its H NMR spectrum shows two 1H double doublets at d
1
2
3
4
.45 and 2.62 (CH -4) and two double doublets at d 3.51 and
2
.61 (CH I), 1H singlet at d 5.53 (H-2) and multiplet at d
2
.55–4.60 (H-5) along with aromatic protons. The presence
2
2
R
12a, 12b
R
13a,13b
Yield
d. r.
1
2
For 12 and 13 (a) R , R = H 68% / 5%
64:36
of NOE at H-4a and its absence at H-5 on irradiating H-2
assigns the structure (2R*,3S*,5S*)-5-iodomethyl-2,3-
diphenyl-tetrahydro-furan-3-ol (11) to this isomer. There-
fore, 3a undergoes regioselective iodocyclisation to provide
only tetrahydrofuran derivatives. However, the cyclization
proceeds with moderate diastereselectivity to provide two
diastereomers in 80:20 ratio. Since, diastereoselectivities in
iodocyclisations of 3a are affected by the temperature and
1
2
(
b) R , R = Cl 40% / 30 % 50:50
Scheme 7.
The X-ray crystal structure of 12b (Fig. 2) shows that CH2I,
C(5) Ph and C(12) H are placed on one face of the five
member ring whereas C(12) Ph, OH and CH are on the
3
other face of the five member ring. As a result the protons at

4022
S. Kumar et al. / Tetrahedron 62 (2006) 4018–4026
Ph
Ph
HO
H
H
H
Ph
Ph
H
H
14.2%
(δ 3.61)
(
δ 6.11)
HO
δ 5.87) H
5.3%
(
O
I
Ph
I
H (δ 3.19)
Ph
O
CH2
H
(
(δ 3.82)
9.2%
δ 3.51)
3.65%
15a
1
4a
Figure 3. The relative stereochemistries in 14a and 15a from NOE
experiments.
are on same face and H-4 and H-5 are on the other
face of tetrahydrofuran ring and assign structure
(2R*,3S*,4S*,5S*)-14a to the major component.
In the case of minor diastereomer, irradiation of H-5 (dt, d
.87) shows 3.65% NOE enhancement of H-2 and
irradiation of CH I (d, d 3.82) shows 5.34% NOE
4
2
Figure 2. The ORTEP view (50% ellipsoid) of 12b.
enhancement of CH-4 (d 3.61). Therefore, H-5 and H-2
are on same face of the furan ring and CH I and H-4 are on
2
C(2) and C(3) carbons are placed trans to each other. C(12)–
O(2)–C(2)–C(3) atoms of the tetrahydrofuran ring are by
and large in the same plane and C(5) carbon bearing phenyl
and hydroxyl groups moves out of plane making the five
member ring as an envelope type structure. All atoms of Cl-
Ph rings are in one plane. Cl-Phenyl at the C(5) carbon is
almost perpendicular to the plane of five member ring.
The results of NOE experiments on 12b are consistent with
the X-ray structure.
the other face of the furan ring (Fig. 3). These spectral data
assign structure (2R*,3S*,4S*,5R*)-15a to the minor
component. Similarly, 6b on iodocylisation gave non-
separable mixture of 14b and 15b.
3. Conclusion
The benzoins in indium mediated allylation reactions follow
Cram’s chelation model to provide mainly or only syn-
addition products. The reactions are more sluggish than for
a-hydroxy aldehdyes but exhibit higher regio- and
diastereoselectivity and are significantly affected by the
electron-densities available on the ketone carbon and the
reactivity of the allylic anion. The more reactive allylic and
crotyl anions add on the benzoins 1a–1d, but cinnamyl
anion adds on electron-deficient benzoins 1a and 1b only
and least reactive ethyl crotonate anion fails to react with all
the benzoins. The diastereoselectivities in iodine mediated
intramolecular cyclizations are significantly affected by the
substituent at C-3 of the homoallylic alcohols. Also the
presence or absence of a substituent at C-4 carbon do not
affect the preffered relative stereochemistries at C-2 and C-5
carbons and in the case of the only or the major iodocyclized
Iodocyclisation of 6a gave a 70:30 mixture of two
diastereomers 14a and 15a (Scheme 8). H NMR of this
1
mixture shows distinct signals for all the protons except aryl
protons. The assignment of the signals to specific protons
has been made on the basis of 1H decoupling experiments.
In the minor component, decoupling of 1H dt at d 4.87
converts doublets at d 3.82 and 3.61 into singlets. In the
major component, decoupling of H-5 (ddd at d 5.46)
converts H-4 doublet (d 3.64) into singlet and two double
doublets due to CH I (d 3.19 and 3.51) into two doublets.
2
The assignment of relative stereochemisteries at various
carbons is made on the basis of NOE experiments. In major
diastereomer, irradiation of H-5 (ddd at d 5.46) shows
14.2% NOE enhancement of H-4 (d 3.64) and irradiation
of H-2 singlet (d 6.11) shows 9.2% NOE enhancement of
tetrahydrofuran derivatives C2-Ph and C-5 CH I are placed
2
on the opposite face.
1
H of CH I (d 3.51) (Fig. 3). Therefore, H-2 and CH I
2
2
R1
R1
1
R
R2
4. Experimental
Ph
H
H
Ph
H
HO
H
I2, NaHCO3
HO
H
+
H
OH
I
I
4
.1. General details
CH CN, 0 °C
O
O
3
HO
C H
1
Melting points were determined in capillaries. H and
13
C
NMR spectra were run on JEOL 300 and 75 MHz NMR,
6
5
R2
4a / 14b
R2
6a / 6b
1
15a / 15b
respectively, using CDCl as solvent. Chemical shifts are
3
given in ppm with TMS as an internal reference. J values are
given in Hertz. Chromatography was performed with silica
yield
80%
75%
d. r.
1
2
For 14 and 15 (a) R = R = H
70:30
53:47
1
00–200 mesh and the reactions were monitored by thin-
1
2
(
b) R = R = Cl
layer chromatography (TLC) with silica plates coated with
silica gel HF-254.
Scheme 8.

S. Kumar et al. / Tetrahedron 62 (2006) 4018–4026
4023
4
.2. General procedure
2.68 (dd, J Z14 Hz, J Z8.7 Hz, 1H, 1H of CH ), 2.85 (dd,
1 2 2
J Z14 Hz, J Z5.4 Hz, 1H, 1H of CH ), 3.73 (s, 3H,
1
2
2
Procedure A. Barbier type conditions: the carbonyl
compound 1 (5 mmol), allyl bromide (7.5 mmol), indium
OCH ), 3.75 (s, 3H, OCH ), 4.74 (s, 1H, CH), 5.07–5.18 (m,
2H, ]CH ), 5.52–5.63 (m, 1H, CH), 6.67 (d, JZ9 Hz, 2H,
3 3
2
metal (5 mmol) were taken in THF–H O (2/1) mixture
2
(10 mL) and the reaction mixture was stirred at 30C2 8C till
the indium metal dissolved. The turbid reaction mixture was
ArH), 6.72 (d, JZ9 Hz, 2H, ArH), 6.91 (d, JZ9 Hz, 2H,
ArH), 7.03 (d, JZ9 Hz, 2H, ArH); the decoupling of 2H
doublet at d 6.91 converts doublet at d 6.67 into singlet and
decoupling of doublet at d 7.03 converts doublet at d 6.72
into singlet. This indicates that two doublets at d 7.03 and
6.72 and two doublets at d 6.67 and 6.91 are due to protons
treated with 4 N HCl and was extracted with CHCl (3!
3
2
5 mL). The organic phase was dried over Na SO . The
2 4
solvent was distilled off and the residue was column
chromatographed (silica gel, 60–120 mesh) to isolate pure
homoallylic alcohol. The reactions of 1 with cinnamyl and
crotyl bromides were performed at 0 8C.
1
3
of the same ring. C NMR (normal/DEPT-135) (CDCl ): d
3
42.4 (CH ), 55.0 (OCH ), 55.4 (OCH ), 78.1 (C), 80.1 (CH),
3
2
3
112.7 (CH), 112.8 (CH), 119.5 (CH ), 127.8 (CH), 128.9
2
(
CH), 131.5 (C), 133.4 (CH), 133.5 (C), 158.3 (C), 158.9
K1
4.2.1. (1R*,2S*)-1,2-Diphenyl-pent-4-ene-1,2-diol (3a).
Procedure A. 1.17 g, 92%, white solid, mp 95 8C (CHCl );
(C); IR nmax (KBr): 3369 (OH), 3404 (OH) cm . (Found C
72.30%, H 6.98% C19 requires C 72.59%, H 7.05%).
H O
22 4
3
C
C
1
M m/z 237 (M KOH); H NMR (CDCl ): d 2.58 (s, 1H,
3
OH, exchanges with D O), 2.59 (s, 1H, exchanges with
4.2.5. (1R*,2S*,3R*)-1,2,3-Triphenyl-pent-4-ene-1,2-diol
(6a). 1.40 g, 85%, pale yellow liquid, FAB mass M m/z
2
C
D O, OH), 2.77 (dd, J Z14.1 Hz, J Z8.7 Hz, 1H, 1H of
2
1
2
C
330 (M ); H NMR (CDCl ): d 3.02 (br s, 2H, 2!OH,
1
CH ), 2.93 (dd, J Z14.1 Hz, J Z5.7 Hz, 1H, 1H of CH ),
2
1
2
2
3
4
.80 (s, 1H, CH), 5.06–5.26 (m, 2H, ]CH ), 5.50–5.63 (m,
exchanges with D O), 4.14 (d, JZ8.7 Hz, 1H, CHPh), 5.11–
2
2
1
H, ]CH), 6.96–7.23 (m, 10H, ArH); C NMR (normal/
3
1
DEPT-135) (CDCl ): d 42.4 (CH ), 78.3 (C), 80.4 (CH),
5.17 (m, 2H, ]CH ), 5.22 (s, 1H, CHOH), 6.15 (dt, J Z
2
1
18 Hz, J Z9 Hz, 1H, ]CH), 7.02–7.56 (m, 15H, ArH). The
3
2
2
1
19.8 (CH ), 126.5 (CH), 126.9 (CH), 127.4 (CH), 127.6
2
decoupling of dt at d 6.15 converts doublet at d 4.14 into
1
3
(CH), 127.7 (CH), 133.2 (CH), 139.2 (C), 141.4 (C); IR nmax
(KBr): 3469 (OH), 3552 (OH) cm . (Found C 80.1%, H
singlet and multiplet at d 5.10–5.16 into broad singlet.
NMR (normal/DEPT-135) (CDCl ): d 58.2 (CH), 76.9
C
K1
3
6
.9% C H O requires C 80.28%, H 7.13%).
1
(CH), 80.8 (C), 117.9 (CH ), 126.9 (CH), 127.1 (CH), 127.4
2
7
18
2
(CH), 127.5 (CH), 128.4 (CH), 128.6 (CH), 130.0 (CH),
130.3 (CH), 138.2 (CH), 139.6 (C), 139.9 (C), 140.8 (C); IR
4
1
.2.2. (1R*,2S*)-1,2-Bis(4-chloro-phenyl)-pent-4-ene-
,2-diol (3b). 726 mg, 45%, white solid, mp 92 8C, FAB
K1
n
max (CHCl
82.75%, H 6.23% C23H O
22 2
): 3446 (OH), 3523 (OH) cm . (Found C
3
C
C
1
mass M m/z 323, 325, 327 (100:69:1) (M ); H NMR
(
requires C 83.60%, H 6.71%).
CDCl ): d 2.61 (br s, 2H, 2!OH), 2.71 (dd, J Z14 Hz,
3
1
J Z8.7 Hz, 1H, 1H of CH ), 2.87 (dd, J Z14 Hz, J Z
4.2.6. (1R*,2S*,3R*)-1,2-Bis(4-chloro-phenyl)-3-phenyl–
pent-4-ene-1,2-diol (6b). 1.76 g, 88%, white solid, mp
2
2
1
2
5
.4 Hz, 1H, 1H of CH ), 4.72 (s, 1H, CH), 5.12–5.21 (m,
2
C
C
2
ArH); C NMR (normal/DEPT-135) (CDCl ): d 42.5
H, ]CH ), 5.49–5.59 (m, 1H, CH), 6.92–7.26 (m, 8H,
72 8C (CHCl ); FAB mass M m/z 399 (M ), 401, 403
3
1
2
1
3
C
3
(100:69:1) (M ); H NMR (CDCl ): d 3.01 (br s, 1H, OH,
3
(
CH ), 77.9 (C), 79.6 (CH), 120.4 (CH ), 127.7 (CH),
2
exchanges with D O), 4.10 (d, JZ9.3 Hz, 1H, CHPh), 5.13–
2
2
1
1
27.9 (CH), 129.1 (CH), 131.5 (CH), 132.5 (CH), 133.0 (C),
33.5 (C), 137.6 (C) 139.8 (C); IR n (KBr): 3348 (OH),
5.18 (m, 3H, ]CH , CHOH), 5.85 (br s, 1H, exchanges
with D O), 6.10 (ddd, J Z13.8 Hz, J Z9 Hz, J Z6.3 Hz,
2
max
2
1
2
3
K1
13
1H, ]CH), 6.97–7.41 (m, 13H, ArH); C NMR (normal/
3421 (OH) cm . (Found C 63.0%, H 4.7% C H O Cl
2
requires C 63.17%, H 4.99%).
1
7
16
2
DEPT-135) (CDCl ): d 58.3 (CH), 75.4 (CH), 76.1 (CH),
3
80.4 (C), 118.5 (CH ), 127.2 (CH), 130.4 (CH), 131.2 (CH),
134.7 (C), 137.5 (CH), 138.2 (C), 138.9 (C), 139.2 (C),
2
4.2.3. (1R*,2S*)-1-(4-Methoxy-phenyl)-2-phenyl-pent-4-
ene-1,2-diol (3c). Procedure A. 979 mg, 69%, light yellow
K1
140.7 (C); IR nmax (KBr): 3421 (OH), 3434 (OH) cm
(Found C 68.9%, H 4.9% C H O Cl requires C 69.18%,
.
C
C
liquid, FAB mass M m/z 284 (M ); H NMR (CDCl ): d
1
3
23 20
2
2
2
.53 (br s, 1H, OH, exchanges with D O), 2.57 (br s, 1H,
2
H 5.05%).
OH, exchanges with D O), 2.71 (dd, J Z14 Hz, J Z
2
1
2
8
1
5
8
.7 Hz, 1H, 1H of CH ), 2.90 (dd, J Z14 Hz, J Z5.4 Hz,
4.2.7. (1R*,2S*,3R*)-3-Methyl-1,2-diphenyl-pent-4-ene-
1,2 diol (8a)D(1R*,2S*,3S*)-3-methyl-1,2-diphenyl-
pent-4-ene-1,2 diol (9a). 998 mg, 78%, pale yellow liquid,
2
1
2
H, 1H of CH ), 3.77 (s, 3H, OCH ), 4.81 (s, 1H, CH), 5.08–
.19 (m, 2H, ]CH ), 5.51–5.63 (m, 1H, CH), 6.74 (d, JZ
2
3
2
1
.7 Hz, 2H, ArH), 6.99–7.21 (m, 7H, ArH); C NMR
3
C
C
1
FAB mass M m/z 268 (M ); H NMR (CDCl ): d 0.90 (d,
3
(
7
1
normal/DEPT-135) (CDCl ): d 42.3 (CH ), 55.1 (CH ),
3
8.1 (C), 80.5 (CH), 112.9 (CH), 119.7 (CH ), 127.4 (CH),
2
27.6 (CH), 127.8 (CH), 127.9 (CH), 127.9 (CH), 128.4
JZ6.6 Hz, 3H, CH3-major), 1.02 (d, JZ6.9 Hz, 3H, CH3-
), 1.25 (br s, 2H, 2!OH, exchanges with D O), 2.92–
2.99 (m, 1H, CHmajor), 3.02–3.09 (m, 1H, CHminor), 5.12–
2
3
minor
2
(
1
CH), 130.1 (CH), 132.3 (CH), 133.2 (CH), 133.3 (CH),
33.4 (C), 139.3 (C), 158.4 (C); IR n (CHCl ): 3390
5.34 (m, 3H, 2H of ]CH , 1H of CHOH), 5.86 (ddd, J Z
2
1
max
3
18.3 Hz, J Z9.9 Hz, J Z7.8 Hz, 1H, ]CHminor), 6.13
2 3
K1
OH), 3430 (OH) cm . (Found C 76.5%, H 6.90%
(
C H O requires C 76.03%, H 7.09%).
(ddd, J Z19.2 Hz, J Z9.0 Hz, J Z8.1 Hz,1H, ]CHmajor),
1 2 3
1
8 20 3
6.98–7.19 (m, 10H, ArH); decoupling of doublet at d 0.90
due to CH3-major converts multiplet at d 2.92–2.99 into
doublet while decoupling of d at d 1.06 converts multiplet at
4
1
.2.4. (1R*,2S*)-1,2-Bis(4-methoxy-phenyl)-pent-4-ene-
,2-diol (3d). 1.13 g, 72%, white solid, mp 90 8C
1
3
3.02–3.09 into doublet; C NMR (normal/DEPT-135)
(CDCl ): d 14.2 (CH3-minor), 16.2 (CH3-major), 44.6 (CH-
minor), 45.2 (CHmajor), 76.6 (CH), 77.9 (CH), 80.6 (C-minor),
C
C
1
(
(
CHCl ); FAB mass M m/z 314 (M ); H NMR
3
3
CDCl ): d 2.59 (br s, 2H, 2!OH, exchanges with D O),
3
2

4024
S. Kumar et al. / Tetrahedron 62 (2006) 4018–4026
8
0.8 (C-major), 116.4 (CH2-minor), 116.8 (CH2-major), 126.6
CH), 126.7 (C), 126.8 (CH), 127.1 (CH), 127.2 (CH), 127.4
stirring was continued for 24–72 h at 0 8C in dark (TLC
monitoring). The reaction mixture was diluted with water
and extracted with CHCl . The organic layer was washed
3
with saturated aqueous sodium thiosulphate to remove
excess of iodine. The organic layer was dried over
anhydrous sodium sulphate and was distilled off. The
residue was column chromatographed (silica gel 100–200)
to isolate substituted tetrahydrofuran derivatives.
(
(
(
(
CH), 127.5 (C), 127.5 (CH), 127.6 (CH), 127.8 (CH), 127.9
CH), 140.3 (CH), 141.1 (CH); IR nmax (CHCl ): 3479
3
K1
OH), 3492 (OH) cm . (Found C 80.27%, H 7.12%
C H O requires C 80.56%, H 7.51%).
18 20 2
4.2.8. (1R*,2S*,3R*)-1,2-Bis(4-chloro-phenyl-3-methyl-
pent-4-ene-1,2-diol (8b)D(1R*,2S*,3S*)-3-methyl-1,2-
bis(4-chloro-phenyl)-pent-4-ene-1,2-diol (9b). 1.19 g,
7
3
6
1
4.3.1. (2R*,3S*,5R*)-2,3-Diphenyl-3-hydroxy-5-iodo-
methyl tetrahydrofuran (10). Procedure B. Higher Rf
component: 91 mg, 8%; white solid, mp 98 8C (CHCl );
C
1%, light yellow liquid, FAB mass M m/z 337, 339,
C
1
41 (100:69:1) (M ); H NMR (CDCl ): d 0.86 (d, JZ
3
3
C
1
.9 Hz, 3H, CH3-minor), 0.97 (d, JZ6.9 Hz, 3H, CH3-major),
FAB mass M m/z 380; H NMR (CDCl ): d 1.92 (br s, 1H,
3
.93 (br s, 1H, exchanges with D O), 2.39–2.41 (m, 1H,
exchanges with D O), 2.48 (dd, J Z14.1 Hz, J Z3.9 Hz, 4-
2
2
1
2
CHminor), 2.52–2.58 (m, 1H, CHmajor), 4.61 (d, JZ7.5 Hz,
H ), 2.78 (dd, J Z14.8 Hz, J Z9 Hz, 4-H ), 3.63 (d, JZ
b 1 2 a
1
1
H, CHPh), 5.02–5.09 (m, 2H, ]CH ), 5.78 (ddd, J Z
6.6 Hz, 2H, 5-CH I), 4.57–4.72 (m, 1H, 5-H), 5.29 (s, 1H, 2-
2
2
1
1
3
H), 7.04–7.39 (m, 10H, ArH); C NMR (normal/DEPT-
7.4 Hz, J Z10.2 Hz, J Z7.8 Hz, 1H, ]CHmajor), 6.05
2
3
(
ddd, J Z17.1 Hz, J Z10.2 Hz, J Z9 Hz, 1H, ]CHminor),
135) (CDCl ): d 10.7 (CH I), 48.4 (CH -4), 77.9 (CH-5),
3
1
2
3
2
2
7
.22–7.32 (m, 6H, ArH), 7.49 (d, JZ8.7 Hz, 1H, ArH), 7.92
82.2 (C-3), 90.8 (CH-2), 125.2 (CH), 126.5 (CH), 127.2
(CH), 128.2 (CH), 128.2 (CH), 134.7 (C), 141.9 (C). NOE
experiments: irradiation of singlet at d 5.29 (2-H) shows
positive NOE with signals at d 4.57–4.72 (5-H), 2.79 (4-Ha)
and 7.05, 7.39 (ArH) and irradiation of multiplet at d 4.57–
4.72 (5-H) shows positive NOE with dd at d 2.79 and
doublet at d 3.63 shows positive NOE with dd at d 2.48; IR
1
3
(
(
(
(
d, JZ8.7 Hz, 1H, ArH); C NMR (normal/DEPT-135)
CDCl ): (major component) d 13.8 (CH3-major), 44.6
CHmajor), 76.5 (CH), 77.2 (C), 115.9 (CH2-major), 127.8
CHmajor), 128.5 (CHmajor), 131.3 (CH major), 132.9 (CH
3
major), 132.3 (CH), 139.9 (CH major), 140.2 (Cmajor), 141.8
Cmajor), 192.4 (Cmajor). Some signals for minor component
are at d 14.1 (CH3-minor), 46.4 (CH minor), 117.3 (CH2-minor),
28.4 (CH minor), 140.2 (CH minor); IR nmax (CHCl ): 3446
(
K1
nmax (KBr): 3421 (OH) cm . (Found C 53.4%, H 4.2%
C H IO requires C 53.70%, H 4.51%).
1
3
17 17
2
K1
(OH) cm . (Found C 63.90%, H 5.00% C H Cl O
18 18 2 2
requires C 64.11%, H 5.38%).
4.3.2. (2R*,3S*,5S*)-2,3-Diphenyl-5-iodo methyltetra-
hydro-furan-3-ol (11). Procedure B. Lower R component:
f
C
C
1
4.2.9. (1R*,2S*,3R*)-1,2-Bis(4-methoxy-phenyl)-3-
methyl-pent-4-ene-1,2 diol (8c)D(1R*,2S*,3S*)-3-
365 mg, 32%; pale yellow liquid; M m/z 380 (M ); H
NMR (CDCl ): d 1.79 (br s, 1H, exchanges with D O), 2.45
3
2
methyl-1,2-bis(4-methoxy-phenyl)-pent-4-ene-1,2 diol
(
(dd, J Z12.9 Hz, J Z9.3 Hz, 4-H ), 2.62 (dd, J Z10.2 Hz,
J Z6.0 Hz, H-4 ), 3.49 (dd, J Z10.2 Hz, J Z3.3 Hz, 1H
2 b 1 2
1 2 a 1
C
9c). 1.21 g, 74%, light yellow liquid, FAB mass M m/z
C
1
3
28 (M ); H NMR (CDCl ): d 0.89 (d, JZ6.9 Hz, 3H,
of CH I), 3.60 (dd, J Z10.2 Hz, J Z6.0 Hz, 1H of CH I),
3
2 1 2 2
CH3-major), 1.01 (d, JZ6.6 Hz, 3H, CH3-minor), 1.25 (br s,
H, 2!OH, exchanges with D O), 2.83–2.86 (m, 1H,
CHmajor), 2.90–2.95 (m, 1H, CHminor), 3.73 (s, 3H, OCH3),
4.50–4.59 (m, 1H, H-5), 5.51 (s, 1H, H-2), 6.98–7.45 (m,
10H, ArH); C NMR (normal/DEPT-135) (CDCl ): d 12.4
1
3
2
2
3
(CH I), 49.4 (CH K4), 77.1 (CH-5), 83.4 (C-3), 89.9
2
2
3
5
]
.76 (s, 3H, OCH ), 5.19–5.29 (m, 3H, ]CH , CHOH),
3
(CH-2), 125.3 (CH), 126.6 (CH), 127.4 (CH), 128.3 (CH),
128.4 (CH), 135.1 (C), 141.2 (C). NOE experiments:
irradiation of singlet at d 5.51 (2-H) shows NOE for signals
2
.82 (ddd, J Z17.4 Hz, J Z13.4 Hz, J Z10.5 Hz, 1H,
1 2 3
CHminor), 6.11 (ddd, J Z17.1 Hz, J Z10.2 Hz, J Z
1 2 3
9
(
Hz, 1H, ]CH
), 6.64–6.74 (m, 4H, ArH), 6.96–7.08
m, 4H, ArH); C NMR (normal/DEPT-135) (CDCl ): d
at d 2.45 (4-H ) and Ph (d 7.04, 7.45) but does not show
a
NOE for H-5 (d 4.50–4.59). The dd at d 2.62 (H ) shows
b
major
3
1
3
1
4.2 (CH3-minor), 16.2 (CH3-major), 44.5 (CHminor), 44.8
positive NOE with signal at H-5 (d 4.50–4.59); IR n
(CHCl ): 3546 (OH) cm . (Found C 53.4%, H 4.2%
max
K1
(
(
CHmajor), 55.0 (OCH3-minor), 55.1 (OCH3-major), 76.1
CHminor), 77.4 (CHmajor), 80.4 (Cminor), 80.6 (Cmajor),
3
C H IO requires C 53.70%, H 4.51%).
17
17
2
1
12.4 (CHminor), 112.5 (CHmajor), 112.8 (CHmajor), 113.0
(
(
(
CHminor), 116.2 (CH2-minor), 116.6 (CH2-major), 127.9
CHminor), 128.1 (CHmajor), 129.1 (CHmajor), 129.2
CHminor), 131.8 (Cmajor), 132.4 (Cminor), 132.4 (Cminor),
4.3.3. (2R*,3S*,4R*,5S*)-2,3-Diphenyl-4-methyl-5-iodo-
methyl tetrahydro-furan-3-ol (12a). Procedure B. 804 mg,
C
68%, white solid, mp 98 8C (CHCl ); FAB mass M m/z
3
C
1
1
(
32.5 (CHmajor), 140.5 (CHminor), 140.1 (CHmajor), 158.1
Cminor), 158.2 (Cmajor), 158.8 (Cmajor). Signals for major
394 (M ); H NMR (CDCl ): d 0.91 (d, JZ6.9 Hz, 3H,
3
CH ), 1.61 (br s, 1H, exchanges with D O), 2.68 (dq, J Z
3
2
1
1
13
and minor compounds are assigned on the basis of H– C
HETCOR experiment); IR n (CHCl ): 3395 (OH), 3440
9.3 Hz, J Z6.6 Hz, 1H, CH), 3.48 (dd, J Z10.8 Hz, J Z
2 1 2
max
3
3.3 Hz, 1H, 1H of CH I), 3.76 (dd, J Z10.8 Hz, J Z
2
1
2
K1
OH) cm . (Found C 72.85%, H 7.11% C H O requires
(
C 73.15%, H 7.37%).
3.9 Hz, 1H, 1H of CH I), 3.90 (dt, J Z9.3 Hz, J Z3.6 Hz,
2
0
24
2
2 1 2
1H, CH-5), 5.56 (s, 1H, CH-2), 7.02–7.30 (m, 2H, ArH),
.32–7.47 (m, 8H, ArH); decoupling of dq at d 2.68 converts
doublet at d 0.91 due to CH into singlet while decoupling of
7
4
.3. Iodine mediated cyclization of homoallylic alcohols
3
double doublet at d 3.48 converts double doublet at d 3.76
1
3
Procedure B. Sodium hydrogen carbonate (9 mmol) was
added to an ice cold solution of homoallylic alcohol
into doublet and dt at d 3.90 into double doublet; C NMR
(normal/DEPT-135) (CDCl ): d 8.7 (CH ), 12.3 (CH ), 52.5
3
3
2
(3 mmol) in dry acetonitrile and resulting suspension was
stirred for 15 min at 0 8C. Iodine (9 mmol) was added and
(CH), 82.1 (CH), 83.9 (C), 89.5 (CH), 125.6 (CH), 126.6
(CH), 127.4 (CH), 128.3 (CH), 128.3 (CH), 128.4 (CH),

S. Kumar et al. / Tetrahedron 62 (2006) 4018–4026
4025
1
35.4 (C), 140.7 (C). NOE experiments: the irradiation of
H-4 dq at d 2.68 shows NOE with H-2 (7.06%) and CH2I
3.77, 2.77%). Irradiation of H-5 (d 3.88–3.93) shows NOE
with CH (10.6%) (d, d 0.92) and irradiation 1H of CH I at d
Procedure B. 70 mg, 5%; pale yellow liquid; FAB mass
M
3H, CH ), 1.64 (br s, 1H, OH exchanges with D O), 2.49
3 2
C
C
1
m/z 463 (M ); H NMR (CDCl ): d 0.79 (d, JZ7.5 Hz,
3
(
(dq, J Z7.5 Hz, J Z4.5 Hz, 1H, CH-4), 3.13 (t, JZ9.3 Hz,
3
2
1
2
3
CH I proton at d 3.48 shows 2.8% NOE with H-2 proton at d
5
.76 shows 16.1% NOE with H-2 and irradiation of other
1H, 1H of CH I), 3.42 (dd, J Z9.9 Hz, J Z6.3 Hz, 1H, 1H
2 1 2
of CH I), 5.07 (ddd, J Z9.0 Hz, J Z5.4 Hz, J Z4.5 Hz,
2
2
1
2
3
K1
.56; IR nmax (KBr): 3550 (OH) cm . (Found C 54.6%, H
1H, CH-5), 5.81 (s, 1H, CH), 7.03–7.50 (m, 10H, ArH);
decoupling of dq at d 2.49 converts doublet at d 0.79 due to
CH3 into singlet and ddd at d 5.07 into a dd, while
decoupling of ddd at d 5.07 converts dd at d 3.42 and triplet
4
.6% C H IO requires C 54.84%, H 4.86%).
1
8
19
2
4.3.4. (2R*,3S*,4S*,5S*)-2,3-Diphenyl-4-methyl-5-iodo-
methyl tetrahydro-furan-3-ol (13a). Procedure B.
1
3
C
at d 3.13 into two doublets and dq at d 2.49 into quartet;
NMR (normal/DEPT-135) (CDCl ): d 3.4 (CH ), 10.2
(CH ), 48.7 (CH), 82.5 (CH), 83.3 (CH), 86.0 (C), 128.3
C
90 mg, 5%; pale yellow liquid; FAB mass M m/z 394
5
(
3
2
C
1
M ); H NMR (CDCl ): d 0.78 (d, JZ7.5 Hz, 3H, CH ),
3
3
3
1
7
.64 (br s, 1H, OH exchanges with D O), 2.52 (dq, J Z
(CH), 128.4 (CH), 128.6 (CH), 128.7 (CH), 133.9 (C), 134.1
(C), 135.1 (C), 138.8 (C). NOE experiments: the irradiation
2
1
.5 Hz, J Z4.5 Hz, 1H, CH-4), 3.15 (t, JZ9.3 Hz, 1H, 1H
2
of CH I), 3.44 (dd, J Z9.3 Hz, J Z6.3 Hz, 1H, 1H of
of CH
(s, d 5.81) and 3.36% enhancement of 1H of CH
The irradiation of H-4 (ddd, d 2.49) shows 13.06% NOE
enhancement of H-5 (ddd, d 5.07); IR nmax (CHCl ): 3436
I O
2
3
(d, d 0.79) shows 3.62% NOE enhancement of H-2
2
1
2
CH I), 5.10 (ddd, J Z9.0 Hz, J Z6.0 Hz, J Z4.5 Hz, 1H,
I (t, d 3.13).
2
2
1
2
3
CH-5), 5.93 (s, 1H, CH), 7.02–7.30 (m, 2H, ArH), 7.32–7.47
(m, 8H, ArH); decoupling of dq at d 2.52 converts doublet at
d 0.78 due to CH into singlet while decoupling of triplet at
3
K1
(OH) cm . (Found C 47.05%, H 3.26% C18
requires C 46.68%, H 3.70%).
H
17Cl
3
2
d 3.15 converts dd at d 3.44 into doublet and ddd at d 5.10
into dd. Decoupling of ddd at d 5.10 converts dd (d 3.44) and
triplet (3.15) into doublets and dq at d 2.52 into a quartet;
4.3.7. (2R*,3S*,4S*,5S*)-2,3,4-Triphenyl-5-iodomethyl
tetrahydro-furan-3-ol (14a) (2R*,3S*,4S*,5R*)-2,3,4-tri-
phenyl-5-iodomethyltetrahydro-furan-3-ol (15a). Pro-
1
3
C NMR (normal/DEPT-135) (CDCl ): d 3.8 (CH ), 10.2
3
2
(
(
1
CH ), 48.7 (CH), 82.3 (CH), 83.8 (CH), 86.3 (C), 126.9
3
CH), 127.2 (CH), 127.7 (CH), 128.1 (CH), 128.2 (CH),
28.4 (CH), 136.8 (C), 140.5 (C). NOE experiments: the
C
cedure B. 1.1 g, (81%), transparent liquid, FAB mass M
m/z 456 (M ); H NMR (CDCl ): (major) (14a): d 1.79 (br
C
1
3
irradiation of CH3 (d, d 0.78) shows 2.6% NOE
enhancement of H-2 (s, d 5.93) and 2.1% enhancement of
s, 1H, OH exchanges with D O), 3.19 (dd, J Z9.6 Hz, J Z
2
1
2
8 Hz, 1H, 1H of CH I), 3.51 (dd, J Z9.6 Hz, J Z6.9 Hz,
2
1
2
1
H of CH I (t, d 3.15). The irradiation of H-4 (dq, d 2.52)
2
1H, 1H of CH I), 3.64 (d, JZ4.5 Hz, 1H, H-4), 5.46 (ddd,
2
shows 11% NOE enhancement of H-5 (ddd, d 5.10).
Irradiation of H-2 singlet at d 5.93 shows 2.5% NOE
J Z7.2 Hz, J Z6.9 Hz, J Z4.5 Hz, 1H, H-5), 6.11 (s, 1H,
1
2
3
CH-2), 6.95–7.26 (m, 15H, ArH (majorCminor)). Compound
15a (minor): d 1.84 (br s, 1H, OH exchanges with D O),
enhancement of 1H of CH I (dd, d 3.44); IR n
(CHCl3):
495 (OH) cm . (Found C 54.34%, H 4.70% C H IO
2
max
2
K1
3
requires C 54.84%, H 4.86%).
3.61 (d, JZ3.9 Hz, 1H, H-4), 3.82 (d, J Z6.6 Hz, 2H,
1
8
19
2
1
CH I), 4.87 (dt, J Z6.6 Hz, J Z3.9 Hz, 1H, H-5), 5.87 (s,
2
1
2
1H, CH-2). Decoupling of dt at d 4.87 due to minor
4.3.5. (2R*,3S*,4R*,5S*)-2,3-Bis(4-chlorophenyl)-4-
methyl-5-iodomethyltetrahydrofuran-3-ol (12b). Pro-
component converts doublet at d 3.82 and 3.61 into singlet.
Decoupling of 1H ddd at d 5.46 (H-5 major diastereomer)
converts H-4 doublet (d 3.64) into singlet and two dds of
cedure B. 930 mg, 68%, white solid, mp 120 8C (CHCl );
3
C
C
1
FAB mass M m/z 463 (M ); H NMR (CDCl ): d 0.90 (d,
13
CH
(normal/DEPT-135) (CDCl
(CH ), 63.2 (CH), 83.1 (CH), 85.2 (CH), 86.3 (C), 126.4
K139.8 (CH). Compound 15a (minor) d 10.5 (CH ), 63.7
(CH), 84.3 (CH), 86.6 (CH), 86.8 (C). C NMR signals
I (d 3.19 and 3.51) into two doublets; C NMR
3
2
JZ6.9 Hz, 3H, CH ), 1.49 (br s, 1H, exchanges with D O),
): (compound 14a major) d 4.2
3
3
2
2
1
1
.63 (dq, J Z9 Hz, J Z6.9, 1H, CH-4), 3.47 (dd, J Z
2
1
2
1
0.8 Hz, J Z3.3 Hz, 1H, 1H of CH I), 3.75 (dd, J Z
2
2
2
1
1
3
0.8 Hz, J Z3.6 Hz, 1H, 1H of CH I), 3.86 (dt, J Z9.3 Hz,
2
2
1
1
13
J2Z3.6 Hz, 1H, CH-5), 5.46 (s, 1H, CH-2), 6.94–6.98 (m,
H, ArH), 7.20–7.26 (m, 2H, ArH), 7.32–7.38 (m, 8H,
ArH); decoupling of dq at d 2.63 converts doublet at d 0.90
have been assigned on the basis of H– C HETCOR
experiment. NOE experiments: in major diastereomer,
irradiation of H-5 (ddd, d 5.46) shows NOE with H-4
(14.2%, d 3.63) and irradiation of H-2 (s, d 6.11) shows
2
due to CH into singlet and double triplet at d 3.86 into
3
singlet while decoupling of dd at d 3.47 converts double
doublet at d 3.75 into doublet and dt at d 3.86 into triplet;
C NMR (normal/DEPT-135) (CDCl ): d 8.6 (CH ), 12.0
NOE with 1H of CH
irradiation of H-5 (dt, d 4.87) shows NOE with H-2 (4.76%,
d 5.87) and irradiation of CH I (d, d 3.82) shows NOE with
CH-4 (5.34%, d 3.61). IRmajor max (CHCl ): 3535
2
I (9.17%, d 3.51). In minor isomer,
1
3
3
3
2
(
(
CH ), 52.3 (CH), 81.9 (CH), 83.6 (C), 88.8 (CH), 127.0
2
CH), 127.9 (CH), 128.5 (CH), 128.7 (CH), 133.5 (CH),
n
3
K1
(OH) cm . (Found C 59.89%, H 4.92% C23
requires C 60.54%, H 4.64%).
H21IO
2
133.7 (CH), 134.2 (C), 138.9 (C). NOE experiments: the
irradiation of H-2 singlet at d 5.46 shows 6.03% NOE with
H-4 (d 2.63); irradiation of CH doublet at d 0.90 shows
3
4.3.8. (2R*,3S*,4S*,5S*)-2,3-Bis(4-chloro-phenyl)-5-iodo
methyl-4-phenyl-tetrahydro-furan-3-ol (14b) (2R*,
3S*,4S*,5R*)-2,3,4-triphenyl-5-iodomethyltetrahydro-
furan-3-ol (15b). Procedure B. 1.05 g, (81%), transparent
2
proton at d 3.47 shows 4% NOE with H-4; IR n
.5% NOE with H-5 (d 3.86) and irradiation of one of CH2I
(KBr):
3.20%
max
K1
3
C H Cl IO requires C 46.68%, H 3.70%).
529 (OH) cm
.
(Found
C
47.00%,
H
C
C
1
1
8
17
2
2
liquid, FAB mass M m/z 525 (M ); H NMR (CDCl ):
3
(major) (14b): d 1.72 (br s, 1H, OH exchanges with D O),
2
4.3.6. (2R*,3S*,4S*,5S*)-2,3-Bis(4-chlorophenyl)-4-
methyl-5-iodomethyltetrahydro-furan-3-ol (13b).
3.18 (dd, J Z9.9 Hz, J Z8.4 Hz, 1H, 1H of CH I), 3.49
1 2 2
(dd, J Z9.6 Hz, J Z7.2 Hz, 1H, 1H of CH I), 3.60 (t, JZ
1
2
2

4026
S. Kumar et al. / Tetrahedron 62 (2006) 4018–4026
3
.9 Hz, 1H, H-4), 5.42 (ddd, J Z8.1 Hz, J Z6.6 Hz, J Z
.5 Hz, 1H, H-5), 5.97 (s, 1H, CH-2), 7.02 (m, 13H, ArH
Jayan, C. N.; Pallai, B. S. Tetrahedron 2004, 60, 1959–1982.
(g) Chauhan, K. K.; Frost, C. G. J. Chem. Soc., Perkin Trans. 1
2000, 3015–3019. (h) Fringuelli, F.; Piermatti, O.; Pizzo, F.;
Vaccaro, L. Curr. Org. Chem. 2003, 7, 1661–1689. (i) Kumar,
S.; Kaur, P.; Kumar, V. Curr. Org. Chem. 2005, 9, 1205–1235.
3. (a) Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media;
Wiley: New York, 1997. (b) Li, C. J. Chem. Rev. 1993, 93,
2023–2035. (c) Lubineau, A.; Auge, J.; Queneau, Y. In
Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie:
Glasgow, 1998. (d) Paquette, L. A.; Lobben, P. C. J. Am.
Chem. Soc. 1996, 118, 1917–1930. (e) Li, C. J.; Zhang, W. C.
J. Am. Chem. Soc. 1998, 120, 9102–9103. (f) Wada, M.;
Fukuma, T.; Morioka, M.; Takahashi, T.; Miyoshi, N.
Tetrahedron Lett. 1997, 38, 8045–8048.
1
2
3
4
(majorCminor)). Compound 15 (minor): d 1.72 (br s, 1H, OH
exchanges with D O), 3.49 (t, JZ3.9 Hz, 1H, H-4), 3.77 (d,
2
JZ6.6 Hz, 2H,CH I), 4.84 (ddd, J Z6.6 Hz, J Z6.6 Hz,
2
1
2
J3Z3.3 Hz, 1H, H-5), 5.73 (s, 1H, CH-2). In minor
component, decoupling of ddd at d 4.84 converts doublet
at d 3.77 into singlet and triplet at d 3.59 into distorted
triplet. While decoupling of 1H ddd at d 5.42 (H-5 major
diastereomer) converts triplet at d 3.59 (H-4) into singlet
and two dds at d 3.175 and 3.49 (CH I) into two doublets;
2
1
3
C NMR (normal/DEPT-135) (CDCl ): (compound 14
3
major) d 3.6 (CH ), 63.0 (CH), 83.3 (CH), 84.9 (CH), 86.1
2
(C), 127.3–138.2 (CH, C)majorCminor (compound 15b minor)
d 10.0 (CH ), 63.6 (CH), 84.3 (CH), 86.0 (CH), 86.5 (C). In
2
4. (a) Pirrung, M. C.; Sarma, K. D. J. Am. Chem. Soc. 2004, 126,
major diastereomer, irradiation of H-5 (ddd, d 5.42) shows
14% NOE enhancement of H-4 (d 3.59) and irradiation of
H-2 (s, d 5.97) shows 3.86% NOE enhancement with 1H of
4
3
44–445. (b) Kumar, S.; Kaur, P. Tetrahedron Lett. 2004, 45,
413–3416.
5
. (a) Paquette, L. A.; Mitzel, T. M. J. Am. Chem. Soc. 1996, 118,
931–1937. (b) Paquette, L. A.; Mitzel, T. M. Tetrahedron
CH I (d 3.49). In minor diastereomer, irradiation of H-5
2
1
(
irradiation of CH I doublet (d 3.77) shows 5.17% NOE
ddd) shows 2.31% NOE enhancement of H-2 (d 5.73) and
Lett. 1995, 36, 6863–6866. (c) Paquette, L. A.; Bennett, G. D.;
Isaac, M. B.; Chhatriwala, A. J. Org. Chem. 1998, 63,
2
enhancement of CH-4 (d 3.59). IR
(OH) cm . (Found C 53.01%, H 3.98% C H Cl IO
23 19 2 2
requires C 52.60%, H 3.65%).
nmax (CHCl ): 3544
3
major
1
836–1845. (d) Paquette, L. A.; Mitzel, T. M. J. Org. Chem.
996, 61, 8799–8804. (e) Paquette, L. A.; Mitzel, T. M.; Isaac,
K1
1
M. B.; Crasto, C. F.; Schomer, W. W. J. Org. Chem. 1997, 62,
293–4301.
. (a) Paquette, L. A.; Lobben, P. C. J. Org. Chem. 1998, 63,
4
4
.4. X-ray crystal data collection for 12b
6
7
5
604–5616. (b) Lobben, P. C.; Paquette, L. A. J. Org. Chem.
998, 63, 6990–6998. (c) Paquette, L. A.; Lobben, P. C. J. Am.
Chem. Soc. 1996, 118, 1917–1930.
X-ray crystal data was measured by using q–2q scan mode.
The structures were solved by using direct method SHELX-
1
9
7. CCDC 284604, molecular formulae C H IO ; triclinic
18 17 2
. (a) Loh, T.; Ho, D. S.; Chua, G.; Sim, K. Synlett 1997,
5
˚
˚
space group P-1, aZ9.0434 A, bZ10.3870 A, cZ
1
VZ930.33(10) A , ZZ2, D Z1.653 mg/m , q range for
63–564. (b) Carda, M.; Castillo, E.; Rodriguez, S.; Murga, J.;
˚
1.0240 A, aZ78.543(4)8, bZ84.009(5)8, gZ66.497(6)8,
3 3
Marco, J. A. Tetrahedron: Asymmetry 1998, 9, 1117–1120.
. Preliminary communication. Kumar, S.; Kaur, P.; Singh, P.;
Chimnni, S. S. Synlett 2001, 1431–1433.
˚
c
8
9
data collection 1.89–24.978. The structure solution is based
on 3453 reflections, which converged to RZ0.0150.
Refinement method: full-matrix least squares on F2,
goodness of fitZ1.058.
. (a) Garg, R.; Kurup, A.; Mekapati, S. B.; Hansch, C. Chem.
Rev. 2003, 103, 703–731. (b) Prasit, P.; Wang, Z.; Brideau, C.;
Chan, C. C.; Charleson, S.; Cromlish, W.; Ethier, D.; Evans,
J. F.; Ford-Hutchinson, A. W.; Gauthier, J. Y.; Gordon, R.;
Guay, J.; Gresser, M.; Kargman, S.; Kennedy, B.; Leblanc, Y.;
Leger, S.; Mancini, J.; O’Neill, G. P.; Ouellet, M.; Percival,
M. D.; Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.;
Therien, M.; Vickers, P.; Wong, E.; Xu, L.-J.; Young, R. N.;
Zamboni, R.; Boyce, S.; Rupniak, N.; Forrest, M.; Visco, D.;
Patrick, D. Bioorg. Med. Chem. Lett. 1999, 9, 1773–1778. (c)
Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.;
Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.;
Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. J. Med.
Chem. 2000, 43, 775–777. (d) Penning, T. D.; Talley, J. J.;
Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.;
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.;
Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.;
Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347–1365.
Acknowledgements
We thank CSIR [01(1795)/02/EMR-II] for financial
assistance and SRF to Anu.; DST, New Delhi for the FIST
programme; CDRI Lucknow for FAB Mass spectra and
elemental analysis and IIT, Bombay for X-ray structure.
References and notes
1
. (a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207–2293.
b) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem.
(
Soc. 1996, 118, 9606–9614. (c) Felpin, F. X.; Girard, S.;
Vo-Thanh, G.; Robins, R. J.; Villieras, J.; Lebreton, J. J. Org.
Chem. 2001, 66, 6305–6312. (d) Loh, T. P.; Hu, Q. Y.; Ma,
L. T. J. Am. Chem. Soc. 2001, 123, 2450–2451. (e) Adam, W.;
Saha-Moller, C. R.; Schmid, K. S. J. Org. Chem. 2001, 66,
1
0. Yasuda, M.; Fujibayashi, T.; Baba, A. J. Org. Chem. 1998, 63,
6401–6404.
7
365–7371.
. For reviews see: (a) Cintas, P. Synlett 1995, 1087–1096.
b) Li, C. J. Tetrahedron 1996, 52, 5643–5668. (c) Li, C. J.;
2
11. (a) Paquette, L. A.; Rothhaar, R. R. J. Org. Chem. 1999, 64,
217–224. (b) Kaur, P.; Singh, P.; Kumar, S. Tetrahedron 2005,
61, 8231–8234.
(
Chan, T. H. Tetrahedron 1999, 55, 11149–11176. (d) Ranu,
B. C. Eur. J. Org. Chem. 2000, 13, 2347–2356. (e) Podlech, J.;
Maier, T. C. Synthesis 2003, 633–655. (f) Nair, V.; Ros, S.;
12. Labelle, M.; Morton, H. E.; Guindon, Y.; Springer, J. P. J. Am.
Chem. Soc. 1998, 110, 4533–4540.