Stereocontrolled approach to δ- and γ-lactones and 1,3-diols. The role of X- ion in the selenolactonization

Article abstract of DOI:10.1016/S0040-4039(02)00093-X

Two complementary approaches have been realized for the stereoselective synthesis of 4,6-disubstituted δ-lactones and 1,3-anti and syn diols. In the 6-endo selenolactonization the role of the X^- ion on the stereoselectivity is shown. Moreover,

Full text of DOI:10.1016/S0040-4039(02)00093-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1669–1672
Stereocontrolled approach to d- and g-lactones and 1,3-diols.
The role of X− ion in the selenolactonization
Michelangelo Gruttadauria,* Carmela Aprile and Renato Noto
Dipartimento di Chimica Organica ‘E. Paterno`’, Universita` di Palermo, Viale delle Scienze, Parco d’Orleans II, 90128 Palermo,
Italy
Received 21 December 2001; revised 9 January 2002; accepted 11 January 2002
Abstract—Two complementary approaches have been realized for the stereoselective synthesis of 4,6-disubstituted d-lactones and
1,3-anti and syn diols. In the 6-endo selenolactonization the role of the X− ion on the stereoselectivity is shown. Moreover, the
highly stereoselective transformation of the 6-endo d-lactone to the 5-exo g-lactone is reported. © 2002 Elsevier Science Ltd. All
rights reserved.
OH
Lactones are not only found in the structures of many
natural products, but they also constitute very useful
synthetic intermediates, especially for the stereoselective
synthesis of complex molecules. Halolactonization and
selenolactonization are probably the most employed
methods. In recent years we have been interested in the
stereoselective synthesis of oxygenated heterocycles via
the intermediate formation of a seleniranium ion.1–5
1: R=Et
2: R=H
O
OR Ph
O
2
a or b
=
/
=
/
H
OH
O
SePh
SePh
O
SePh
Ph
O
O
6 Ph 5
OH
3
4
Here we report preliminary observations on the stereo-
controlled synthesis of d- and g-lactones and 1,3-anti
and syn diols. We used as model compounds for our
study b-hydroxy ester 1 and b-hydroxy acid 2 that were
readily prepared from cinnamaldehyde.
OH
O
SePh
O
Ph
O
O
Ph
5
6
Scheme 1. Reagents and conditions: (a) PhSeX, K2CO3,
CH2Cl2, −78°C; (b) PhSeX, TBAX, K2CO3, CH2Cl2, −78°C.
Hydroxy acid 2 was allowed to react with PhSeCl (1
equiv.) and potassium carbonate (3 equiv.) at −78°C in
dichloromethane to give compounds 5 and 6 (Scheme
1).6 We were disappointed to find poor results from this
However, it should be noted that when using one or
two equivalents of PhSeBr higher diastereoselectivity
was found compared with PhSeCl. In order to under-
stand the role of the X− counter ion we then realized
the reaction using one equivalent of PhSeCl and one
equivalent of TBAX (X=ClO4, Cl, Br). With TBAClO4
and TBACl (entries 4 and 5) the yield was poor, but
interestingly, the diastereoselectivity was the same as
observed when using two equivalents of PhSeCl (entry
2). With TBABr (entry 6) the yield was very low, but a
further increase in diastereoselectivity was obtained. In
this case the diastereoselectivity was similar to that
obtained with PhSeBr. Good diastereoselectivity was
also found using two equivalents of PhSeCl and one
equivalent of TBAClO4, TBACl or TBABr (entries
1
reaction. Indeed very low selectivity (determined by H
NMR) was found (Table 1, entry 1). However, increas-
ing the amount of PhSeCl we found interesting results.
The diastereoselectivity meaningfully increased when
we used two equivalent of PhSeCl (entry 2). A further
increase was observed with three equivalents of PhSeCl
(entry 3). Obviously, it is not usual to find higher
diastereoselectivities when the equivalent amount of
reactant is increased. For example, increasing the
amount of PhSeBr did not give a significantly different
diastereoselectivity (entries 13–15).
Keywords: selenium; cyclization.
* Corresponding author. Tel.: +39091596919; fax: +39091596825;
e-mail: mgrutt@unipa.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00093-X

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M. Gruttadauria et al. / Tetrahedron Letters 43 (2002) 1669–1672
Table 1. Yields and selectivities for the 6-endo cyclization
Entry
PhSeCl (equiv.)
TBAClO4 (equiv.)
TBACl (equiv.)
TBABr (equiv.)
Yield (%)a
5/6
1
2
3
4
5
6
1
2
3
1
1
1
1
1
1
2
2
2
–
–
–
1
–
–
1
–
–
1
–
–
–
–
–
–
1
–
–
1
1
–
1
–
–
–
–
–
–
1
–
–
–
–
–
1
40b
69b
97b
25c
10c
8c
57/43
76/24
89/11
78/22
75/25
90/10
89/11
76/24
77/23
88/12
88/12
90/10
7d
8e
9f
10
11
12
59c
13c
7c
60c
43c
42c
PhSeBr
13
14
15
16
17
18
19d
1
2
3
1
1
1
1
–
–
–
1
–
–
1
–
–
–
–
1
–
–
–
–
–
–
–
1
–
48b
94b
90b
48c
10c
7c
89/11
93/7
92/8
94/6
87/13
89/11
95/5
49c
a Reaction time 1 h; in all the reactions reported the remaining products were starting material and (PhSe)2.
b Isolated yield.
c Determined by 1H NMR.
d PhSeX and TBAX added to a solution of compound 2.
e Reaction time: 30 min.
f Reaction time: 15 min.
10–12). In particular, using PhSeCl (2 equiv.) and
TBACl (1 equiv.) we found the same diastereoselectiv-
ity obtained using 3 equiv. of PhSeCl (entries 3 and 11).
Again high diastereoselectivities were found with
PhSeBr and TBAX (entries 16–18). The reactions per-
formed with TBAX were usually realized by adding the
PhSeX solution to a mixture of compound 2 and
TBAX. When we added to the solution of compound 2
a solution of PhSeCl and TBAClO4 we found, respec-
tively, better yield and diastereoselectivity (entries 4 and
7). No change was observed when we used PhSeBr
pre-mixed with TBAClO4 (entries 16 and 19). Finally,
the reaction with PhSeCl and TBACl was stopped at
different times, but yield and stereoselectivity did not
change (entries 5, 8 and 9). These data indicate that the
reaction carried out with PhSeCl with or without
TBAX showed selectivities ranging from 57 to 90%.
Reactions carried out with PhSeBr with or without
TBAX showed higher selectivities (87–95%). When the
reaction was realized with only one equivalent of
PhSeX with or without TBAX, the yield was poor.
When the reaction was carried out with two or three
equivalents of PhSeX both yield and stereoselectivity
were high.
a lower energy transition state, then explaining the
preference for the d-lactone having the OH group
axially disposed. These factors, however, are not suffi-
cient to explain the observed diastereoselectivity with
the increasing amount of X− counter ion. It is known
that the counter ion of the selenium electrophile plays
an important but still not well understood role in the
addition reactions.13 Both seleniranium ions, generated
by the attack of the PhSe+ species on both sides of the
CꢀC double bond, have the stabilizing interaction
between the positive selenium atom and the allylic
oxygen atom. It should be noted that in seleniranium
ion 7 the unfavourable nonbonding interaction between
the CH2COO− group and the hydrogen atom should
lead to a higher energy for this seleniranium ion com-
pared with the seleniranium 8 where this interaction is
absent (Scheme 2). Seleniranium 7, depicted in Scheme
2, shows that it is possible to maintain the Se–O
interaction during the cyclization process (see 9),
whereas in seleniranium 8, when the COO− group
reaches C6, the Se–O interaction is lost (see 10).
Seleniranium 8 is more stable and the activation energy
for its cyclization is higher, while seleniranium ion 7 is
less stable with a lower transition state energy for the
cyclization process. Then, seleniranium ion 8 lives suffi-
ciently to undergo the intermolecular attack of the Cl−
The major diastereoisomer could come via transition
state 3 that displays the intramolecular hydrogen bond
and also a stabilizing Se···O interaction, absents in the
transition state 4 leading to the minor diastereoisomer.
Similar intramolecular hydrogen bonds have been
claimed in the 6-exo iodolactonozation.7 Moreover, it
has been reported that selenium can interact with
nearby heteroatoms.8–12 These two factors could lead to
or Br− or ClO4 species at the positively charged sele-
−
nium atom. As a matter of fact, in increasing the
amount of X− we increased the selectivity since selenira-
nium 8 is preferentially destroyed to again give starting
material and PhSeX.14 The increasing amount of

M. Gruttadauria et al. / Tetrahedron Letters 43 (2002) 1669–1672
1671
the PhSe group in d-lactones and the exocyclic position
of the PhSe group in g-lactones allows alignment of
selenium, carbon and oxygen atoms at the required
180°.
The intermediate seleniranium ions 9 and 10 then
cyclized to give the thermodynamically more stable
g-lactone 20 with excellent stereoselectivity. The cycliza-
tion realized under kinetic conditions afforded exclu-
sively the d-lactones because the phenyl group can
support the partial positive charge at C6 allowing the
rupture of C6ꢁSe bond, whereas the allylic OH group
disfavours the attack at C5.1
In conclusion, two complementary approaches have
been realized for the stereoselective synthesis of 4,6-di-
substituted d-lactones. The first approach is based on
Scheme 2.
PhSeX gave, as expected, higher yield; the increasing
amount of X− gave lower yield since it destroys the
intermediate seleniranium ions.15 Moreover, the sele-
nium cation being a soft electrophile reacts better with
intramolecular
selenolactonization.
The
second
approach is based on the intermolecular hydroxysele-
nenylation followed by cyclization. In the former case,
electronic effects, such as Se···O interaction and
intramolecular hydrogen bond, as well as the nature
and concentration of X− species are important factors
for the stereoselective outcome of these reactions. To
the best of our knowledge the effect of the concentra-
tion and the nature of X− ions on the stereoselectivity
of cyclizations induced by PhSeX is shown for the first
time. In the latter case the first example of direct
Br− than with Cl− or ClO4 . The best conditions, from
−
a synthetic point of view, were with two equivalents of
PhSeBr.
In order to synthesize the 4,6-diequatorial d-lactone,
b-hydroxy ester 1 was allowed to react with PhSeCl16 in
acetonitrile/water for
a
few minutes.17 We were
delighted to find a very interesting result. The 1,3-anti
diol 12 was obtained in 80% yield and in excellent
diastereomeric ratio (95/5). The reaction proceeds
through the more stable seleniranium ion 11, which
undergoes the attack by a molecule of water to give 12.
When the reaction was quenched after 30 min the yield
was lower (65%) with almost the same selectivity. The
lower yield can be ascribed to the acid conditions
realized during the reaction. Indeed, it is well known
that hydroxy selenides react under these conditions.4,5
The stereochemistry was not confirmed at this stage,
but when d-lactone 14 was obtained. Also, the
diastereomeric ratio was better confirmed by the 1H
NMR spectrum of 13 obtained after removal of the
PhSe group (95% yield). Finally, cyclization of 13 in
refluxing toluene gave the d-lactone 14 in 70% yield
(Scheme 3).
Scheme 3. Reagents and conditions: (a) PhSeCl, CH3CN/H2O,
rt, 80%; (b) Bu3SnH, AIBN, C6H6, reflux, 95%; (c) cat. PPTS,
toluene, reflux, 70%; (d) LiAlH4, Et2O, rt, 80%.
The diastereomeric structure 15 was obtained after
removal of the PhSe group in compound 5. Reduction
of compound 15 gave the triol 16. The mixture of
d-lactones 5 and 6 were isolated by washing the crude
reaction with light petroleum in order to remove
diphenyldiselenide. When the reaction mixture was
purified by chromatography we obtained a mixture of
d-lactones 5 and 6 and g-lactone 20. Then the mixture
of d-lactones 5 and 6 was stirred in dichloromethane
with silica gel and eluted to give a quantitative yield
(98%) of 4,5-trans-g-lactone 20 with excellent dias-
teromeric ratio (20/19 >95:5) (Scheme 4). The acid
conditions realized with silica gel caused the protona-
tion of d-lactones and the intramolecular Se attack at
C6 to afford ring opening. This rearrangement can be
ascribed to the fact that these reactions proceed via a
loose SN2 transition state. The equatorial position of
5
6
a
a
OH
OH
HO
SePh
SePh
SePh
SePh
Ph
O
Ph
O
HO
O
Ph
16
17
OH
O
OH
O
H
OH
Ph
Ph
9
10
-H
OH
OH
-H
Ph
O
O
O
O
SePh
SePh
19
20
Scheme 4. Reagents and conditions: (a) SiO2, CH2Cl2, rt, 98%.

1672
M. Gruttadauria et al. / Tetrahedron Letters 43 (2002) 1669–1672
formation of 1,3-anti diol synthesis with high
diastereoselectivity is reported. The 1,3-syn diol can be
prepared by reduction of the corresponding d-lactone.
At present this approach is under development in our
laboratory in order to understand the scope and limita-
tions of both the stereoselective synthesis of lactones
and 1,3-anti and syn diols.
6. 1H NMR (250 MHz, DMSO-d6) data for compounds 5
and 6 (mixture) l: 2.59 (1H, H-3, 6 overlapped with
DMSO-d6 and the following signal), 2.68 (dd, J=17.6
and 2.6 Hz, 1H, H-3, 5), 3.04 (dd, J=15.7 and 4.3 Hz,
1H, H-3, 6), 3.24 (dd, J=17.6 and 3.5 Hz, 1H, H-3, 5),
3.52 (dd, J=11.3 and 4.3 Hz, 1H, H-5, 6), 3.91 (d,
J=11.3 Hz, 1H, H-5, 5), 4.33–4.42 (m, 1H, H-4, 6),
4.43–4.47 (m, 1H, H-4, 5), 5.40 (d, J=11.3 Hz, 1H, H-6,
6), 5.66 (d, J=11.3 Hz, 1H, H-6, 5), 5.82 (d, J=3.9 Hz,
1H, OH, 6), 6.08 (d, J=3.8 Hz, 1H, OH, 5), 7.04–7.45
(m, 10H, Ar-H, 5+6).
Acknowledgements
7. Bedford, S. B.; Fenton, G.; Knight, D. W.; Shaw, D. E.
J. Chem. Soc., Perkin Trans. 1 1996, 1505.
8. Spichty, M.; Fragale, G.; Wirth, T. J. Am. Chem. Soc.
2000, 122, 10914.
9. Wang, X.; Houk, K. N.; Spichty, M.; Wirth, T. J. Am.
Chem. Soc. 1999, 121, 8567.
10. Wirth, T. Tetrahedron 1999, 55, 1.
Financial support from the University of Palermo
(funds for selected research topics) and Italian MURST
within the National Research Project ‘Non-aromatic
heterocycles in stereocontrolled processes’ is gratefully
acknowledged.
11. Fujita, K.; Murata, K.; Iwaoka, M.; Tomoda, S. Tetra-
hedron 1997, 53, 2029.
12. Tiecco, M.; Testaferri, L.; Bagnoli, L.; Marini, F.; Tem-
perini, A.; Tomassini, C.; Santi, C. Tetrahedron Lett.
2000, 41, 3241.
References
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13. Usually for highest yields selenenyltriflates are used:
Wirth, T. Tetrahedron 1999, 55, 1.
14. After aqueous work-up PhSeSePh was isolated.
15. The yields are referred to a reaction time of 1 h.
16. The reaction carried out with PhSeBr gave 12 in 67%
yield (95/5 ratio; 92% conversion).
17. Similar methoxyselenenylation has been reported: Kim,
K. S.; Park, H. B.; Kim, J. Y.; Ahn, Y. H.; Jeong, I. H.
Tetrahedron Lett. 1996, 37, 1249.
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