A chiral electrophilic selenium reagent to promote the kinetic resolution of racemic allylic alcohols

Article abstract of DOI:10.1021/ol048001+

(Chemical Equation Presented) The first example of a kinetic resolution process promoted by electrophilic selenium reagents is reported. Racemic allylic alcohols react with half equivalents of a selenenylating agent in methanol leading to the regiospecific formation of the corresponding addition products with a very high level of facial selectivity (from 95:5 to 98:2 dr). The unreacted alcohols can be recovered in an optically enriched form (from 90 to 94% ee).

Full text of DOI:10.1021/ol048001+

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4751-4753
A Chiral Electrophilic Selenium Reagent
To Promote the Kinetic Resolution of
Racemic Allylic Alcohols
Marcello Tiecco,* Lorenzo Testaferri, Claudio Santi, Cristina Tomassini,
Rosaria Bonini, Francesca Marini, Luana Bagnoli, and Andrea Temperini
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica,
UniVersita` di Perugia, Italy
tiecco@unipg.it
Received September 30, 2004
ABSTRACT
The first example of a kinetic resolution process promoted by electrophilic selenium reagents is reported. Racemic allylic alcohols react with
half equivalents of a selenenylating agent in methanol leading to the regiospecific formation of the corresponding addition products with a
very high level of facial selectivity (from 95:5 to 98:2 dr). The unreacted alcohols can be recovered in an optically enriched form (from 90 to
94% ee).
Chiral allylic alcohols have recently attracted great attention
due to their stereodirecting propensity in diasteroselective
reactions.1 They can be considered valuable substrates to
effect both synthetic2 and mechanistic investigations.3 The
most common way to prepare chiral allylic alcohols involves
asymmetric reductions,4 elimination of iodo ketal,5 and
enzymatic,6 as well as nonenzymatic,7 kinetic resolutions.
During the last 10 years, chiral nonracemic electrophilic
selenium reagents were successfully employed in a number
of enantioselectitive addition reactions with very high levels
of facial selectivity.8
We now report that by combining the stereocontrol of the
allylic hydroxy group with the facial selectivity of the chiral
nonracemic selenium reagent it is possible to effect the
kinetic resolution of racemic allylic alcohols. To the best of
our knowledge, this is the first example of a kinetic resolution
process promoted by an organoselenium reagent. This proc-
ess allows a very common class of organic substrates to be
obtained in an enantiomerically enriched form.
We have recently reported that the di-2-[methoxy-6-[(1S)-
1-methylthio]ethyl]phenyl] diselenide 1 is a suitable precursor
for the production of very efficient electrophilic reagents.
As indicated in Scheme 1, the treatment of the diselenide 1
with bromine gives the aryl selenenyl bromide 2. The triflate
3 can be prepared from 2 by reaction with AgOTf in
CH2Cl2 at 0 °C.9
(1) (a) Adam, W.; Alsters, P. L.; Neuman, R.; Saha-Moeller, C. R.;
Sloboda-Rozner, D.; Zhang, R. J. Org. Chem. 2003, 68, 1721. (b) Adam,
W.; Alsters, P. L.; Neuman, R.; Saha-Moeller, C. R.; Sloboda-Rozner, D.;
Zhang, R. Synlett 2002, 2011. (c) Adam, W.; Botke, N. J. Am. Chem. Soc.
2000, 122, 9846. (d) Charlette, A.; Lebel, H.; Gagnon, A. Tetrahedron 1999,
55, 8845.
(2) (a) Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237. (b) Gau,
A.; Lin, G.; Uang, B.; Liao, F.; Wang, S. J. Org. Chem. 1999, 64, 2194.
(3) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703.
(4) (a) Ohkuma, T.; Ikehira, H.; Ihariya, T.; Noyori, R. Synlett 1997,
467. (b) Yadav, J.; Reddy, B.; Reddy, K. Tetrahedron 2003, 59, 5333.
(5) Schneider, C.; Kazmaier, U. Synthesis 1998, 1314.
Scheme 1
(6) Kamal, A.; Sandbhor, M.; Shaik, A.; Sravanthi, V. Tetrahedron:
Asymmetry 2003, 14, 2839.
(7) (a) Vedejs, E.; MacKay, J. A. Org. Lett. 2001, 3, 535. (b) Ballemin-
Loponnaz, S.; Tweddwl, J.; Ruble, J. C.; Breitting, F. M.; Gregory, C. Chem.
Commun. 2000, 1009.
10.1021/ol048001+ CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/11/2004

The kinetic resolution of racemic allylic derivatives could
be obtained by effecting the methoxyselenenylation of the
double bond using the electrophilic aryl selenenyl triflate 3
(Scheme 2).
cyclic allylic alcohol 4h, all the reactions proceeded with
complete regioselectivity. The Markovnicov addition prod-
ucts 5a-f were obtained in the cases of the trans-disubsti-
tuted olefins 4a-f, and the anti Markownicov adduct 5g was
formed in the case of the monosubstituted olefin 4g.
The kinetic resolution process seems to be more efficient
when the aryl-substituted olefins 4a-e were employed. In
these cases, in fact, two diasteroisomeric addition products
5a-e were obtained in good chemical yields and with very
high diasteroisomeric ratios (from 95:5 to 98:2). Moreover,
the enantiomeric excess of the recovered allylic alcohols was
similarly very good (from 90 to 94% ee). Only in the case
of the cyclic allylic alcohol 4h did the reaction afford a
complex mixture of isomers, which could not be separated,
and the unreacted alcohol showed a moderate enantiomeric
excess. The diasteroisomeric ratios, as well as the enantio-
meric excesses, were determined by NMR and in some cases
confirmed by GC-MS. In no case could the two diastereo-
isomeric addition products 5 be separated (Scheme 3).
Scheme 2
Preliminary experiments were carried out starting from the
alcohol 4a.
Two equivalents of the racemic allylic alcohol rac-4a
reacted with 1 equiv of the selenenylating reagent 3 in a
10:1 mixture of CH2Cl2/MeOH at -30 °C afforded the
addition product 5a in a diasteroisomeric ratio of 98:2. A
complete regioselectivity associated with a good facial
selectivity (Table 1) was observed. The unreacted alcohol
Scheme 3
Table 1. Preliminary Kinetic Resolution Results
reaction
time (h)
addition products
yield (%) (dr, %)
resolved products
yield (%) (ee, %)
racemate
The absolute configurations of the recovered alcohols (S)-
4a-d and (R)-4g were assigned by comparison of the sign
of the optical rotations with those reported in the literature.6,10
By analogy with the alcohols (S)-4a-d, the S configuration
was also assigned to 4e and 4f.
rac-4a
rac-6
rac-7
3
48
20
5, 46 (98:2)
8, 40 (91:9)
9, 45 (97:3)
(S)-4a, 45 (92)
(S)-6, 40 (82)
(S)-7, 40 (64)
The selenium addition derivative 5a was deselenenylated
by treatment with Ph3SnH and AIBN in refluxing benzene
and afforded the (2R,4S)-4-methoxy-4-phenylbutan-2-ol 10
in 90% yield11 (Scheme 4). Since the methoxyselenenylation
(S)-4a could be obtained in an enantiomerically enriched
form (92% ee) by column chromatography.
As reported in Scheme 2 and Table 1, the same procedure
was also applied to the allylic ethers rac-6 and rac-7. The
best facial selectivity was obtained in the presence of the
unprotected hydroxy group. These reaction conditions were
therefore employed to effect the kinetic resolutions of a
number of other allylic alcohols.
Scheme 4
The results of these experiments are summarized in Table
2. It can be observed that, with only the exception of the
Table 2. Kinetic Resolution of Allylic Alcohols
reaction is a stereospecific anti addition process, compound
5a should have the 2R,3S,4R configuration. The same con-
figuration can be assigned by analogy to the adducts 5b-f.
adducts 5
resolved 4
racemate 4
R′
yield
(%)
yield
ee (%)
R
dr
(%) (S value)
a
b
c
d
e
f
Ph-
Me-
Me-
Me-
Me-
46
43
36
40
47
35
35
35
98:2
96:4
96:4
95:5
97:3
85:15
60:40
45
43
35
42
48
92 (0.83)
92 (0.79)
94 (0.66)
90 (0.76)
94 (0.90)
4-Br-C6H4
4-Cl-C6H4
4-Me-C6H4
(8) (a) Tiecco, M. In Topics in Current Chemistry: Organoselenium
Chemistry: Modern DeVelopments in Organic Synthesis; Wirth, T., Ed.;
Electrophilic Selenium, Selenocyclizations; Springer-Verlag: Heidelberg,
2000; p 7. (b) Organoselenium ChemistrysA Practical Approach; Back,
T. G., Ed.; Oxford: New York, 2000. (c) Wirth, T. Angew. Chem., Int. Ed.
2000, 39, 3742. (d) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.;
Marini, F.; Bagnoli, L.; Temperini, A. Angew. Chem., Int. Ed. 2003, 42,
3131.
2-Br-5-MeO-C6H3 Me-
Me-
H-
-(CH2)3-
Me-
n-Bu-
25a 60a (0.30)
g
h
20
20 (0.08)
20 (0.06)
mix isomers 15
a Not isolated. Yield and ee calculated by GC-MS.
(9) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.;. Marini, F.;
Bagnoli, L.; Temperini, A. Chem. Eur. J. 2002, 8, 1118.
4752
Org. Lett., Vol. 6, No. 25, 2004

To effect a complete resolution process and to obtain the
enantiomeric allylic alcohols also, the arylseleno and the
methoxy groups must be eliminated from the addition prod-
ucts 5. This elimination process was carried out in the cases
of compounds 5a and 5c. The treatment of these compounds
with a catalytic amount of CF3SO3H in the presence of 2
equiv of styrene afforded the corresponding (R)-allylic
alcohols 4a and 4c in good yields and with an enantiomeric
excess identical to the diasteroisomeric excess of the starting
compounds (Scheme 5). The methoxyselenenylation product
Figure 1. Stereocontrolling property of the hydroxy group.
and ethers, provides a very high regio- and stereoselectivity
in the formation of the seleniranium intermediate.12 In the
case of the cyclic alkenol this participation is probably for-
bidden and this can explain the formation of a mixture of
isomers.
Scheme 5
In summary, we have described here a new method to
effect the kinetic resolution of allylic alcohols using a meth-
oxyselenenylation reaction promoted by an electrophilic
chiral non racemic selenium reagent. The procedure has been
optimized in order to obtain both enantiomers in an high
enantiomerically enriched form and in very good chemical
yields.
of styrene 11 was also obtained. This reaction can also be
effected in the absence of styrene. In this case the desele-
nenylation process is slower, but it presents the considerable
advantage that the arylseleno moiety is almost completely
recovered as the diselenide 1.
The syn relationship between the hydroxy and the arylse-
leneno groups in compounds 5 and the anti Markovnicov
orientation observed in the methoxyselenenylation of the
monosubstituted olefin 4g is probably due to a stabilizing
interaction between the allylic oxygen and the selenium atom
(Figure 1). This interaction, as already observed in other
selenium electrophilic addition reactions to allylic alcohols
Acknowledgment. Financial support from MIUR, Na-
tional Project “Stereoselezione in Sintesi Organica. Metod-
ologie ed Applicazioni”, FIRB Project 2001, Consorzio
CIMPIS, and the University of Perugia “Progetti di Ateneo”
is gratefully acknowledged.
Supporting Information Available: Physical and spectral
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL048001+
(11) Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307.
(12) (a) Back, T. G. In Organoselenium Chemistry; Liotta, D., Ed.;
Electrophilic Selenium Reactions; Wiley: New York, 1987; p 1. (b) Aprile,
C.; Gruttadauria, M.; Amato, M. E.; D’anna, F.; Lo Meo, P.; Riela, S.;
Noto, R. Tetrahedron 2003, 59, 2241. (c) Cooper, M. A.; Ward, D.
Tetrahedron 2004, 60, 7963.
(10) (a) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am.
Chem. Soc. 1988, 110, 1539. (b) Lee, D.; Huh, E. A.; Kim, M.-J.; Jung, H.
M.; Koh, J. H.; Park, J. Org. Lett. 2000, 15, 2377. (c) Hideaki, R. Agric.
Biol. Chem. 1987, 51, 3369.
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