Oxiranyl anion-mediated synthesis of highly enantiomerically enriched styrene oxide derivatives

Article abstract of DOI:10.1021/ol026212d

(Matrix presented) The stereospecific α-lithiation of optically active styrene oxides and the trapping reaction of the corresponding highly reactive intermediates with electrophiles to produce optically active styrene oxide derivatives are described. This methodology has been applied to the synthesis of an optically active oral antifungal agent of industrial interest.

Full text of DOI:10.1021/ol026212d

ORGANIC
LETTERS
2
002
Vol. 4, No. 14
445-2448
Oxiranyl Anion-Mediated Synthesis of
Highly Enantiomerically Enriched
Styrene Oxide Derivatives
2
Vito Capriati, Saverio Florio,* Renzo Luisi, and Antonio Salomone
C.N.R., Istituto di Chimica dei Composti OrganoMetallici-ICCOM,
Sezione di Bari, Dipartimento Farmaco-Chimico, UniVersit a` di Bari,
Via E.Orabona 4, I-70126 Bari, Italy
florio@farmchim.uniba.it
Received May 20, 2002
ABSTRACT
The stereospecific r-lithiation of optically active styrene oxides and the trapping reaction of the corresponding highly reactive intermediates
with electrophiles to produce optically active styrene oxide derivatives are described. This methodology has been applied to the synthesis of
an optically active oral antifungal agent of industrial interest.
5
The utility of optically active styrene oxide derivatives as
chiral building blocks for the synthesis of natural products
and biologically active compounds is well documented.
lation chemistry followed by stereospecific cyclodehydra-
6
7
tion. The successful use of the Mitsunobu reaction and of
the asymmetric reduction of substituted 2-sulfonyloxyac-
etophenone derivatives for the stereoselective synthesis of
1
8
Accordingly, efforts have been made for the development
of catalytic, stereoselective epoxidation methodologies of
styrene oxides have been also recently described.
2
To our knowledge, the oxiranyl anion-based methodology9
directed to the preparation of enantiomerically enriched
styrene oxide derivatives has not been investigated yet,
terminal olefins. The hydrolytic kinetic resolution of terminal
epoxides using chiral (salen)-Cr and (salen)-Co(III) com-
3
4
plexes and of epoxide hydrolases has also been developed.
10
Indirect routes are based mainly on asymmetric dihydroxy-
although some evidences reported by Eisch on racemic cis-
disubstituted â-phenylepoxysilanes and cis- and trans-
diphenyloxiranes and by our group on â-aryl-substituted
(1) For recent examples, see: (a) Hattori, K.; Nagano, M.; Kato, T.;
11
Nakanishi, I.; Imai, K.; Kinoshita, T.; Sakane, K. Bioorg. Med. Chem. Lett.
oxazolinyloxiranes have proved the configurational stability
1
995, 5, 2821-2824. (b) Di Fabio, R.; Pietra, C.; Thomas, R. J.; Ziviani,
L. Bioorg. Med. Chem. Lett. 1995, 5, 551-554. (c) Sher, P. M.; Mathur,
A.; Fisher, L. G.; Wu, G.; Skwish, S.; Michel, I. M.; Seiler, S. M.;
Dickinson, K. E. J. Bioorg. Med. Chem. Lett. 1997, 7, 1583-1588.
(5) For a review, see: Kolb, H. C.; Sharpless, K. B. Transition Met.
Org. Synth. 1998, 2, 219.
(6) (a) Jang, D. O.; Joo, Y. H.; Cho, D. H. Synth. Commun. 2000, 4489.
(b) For a review, see: Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K.
B. Chem. ReV. 1994, 94, 2483. (c) Adiyaman, M.; Khanapure, S. P.; Hwang,
S. W.; Rokack, J. Tetrahedron Lett. 1995, 7367. (d) O’Donnell, C. J.; Burke,
S. D. J. Org. Chem. 1998, 63, 8614.
(2) (a) Collman, J. P.; Wang, Z.; Straumanis, A.; Quelquejeu, M.; Rose,
E. J. Am. Chem. Soc. 1999, 121, 460. (b) Palucki, M.; Popisil, P. J.; Zhang,
W.; Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116, 9333. (c) For a review,
see: Jacobsen, E. N.; Wu, M. H. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1
6
1
999; Vol. II, Chapter 18.2. (d) Warren, J. D.; Shi, Y. J. Org. Chem. 1999,
4, 7675-7677. (e) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3,
929.
(7) Weissman, S. A.; Rossen, K.; Reider, P. J. Org. Lett. 2001, 3, 2513.
(8) Cho, B. T.; Choi, O. K. Bull. Korean Chem. Soc. 2001, 22, 443-
444 and references therein.
(9) (a) Satoh, T. Chem. ReV. 1996, 96, 3303-3325. (b) Mori, Y. ReV.
Heteroatom Chem. 1997, 17, 183-211. (c) Hodgson, D. M.; Norsikian, S.
L. M. Org. Lett. 2001, 3, 461-463. (d) Yamauchi, Y.; Katagiri, T.;
Uneyama, K. Org. Lett. 2002, 4, 173-176.
(10) (a) Eisch, J. J.; Galle, J. E. J. Organomet. Chem. 1988, 341, 293-
313. (b) Eisch, J. J.; Galle, J. E. J. Org. Chem. 1990, 55, 4835-4840.
(11) Capriati, V.; Degennaro, L.; Favia, R.; Florio, S.; Luisi, R. Org.
Lett. 2002, 4 (9), 1551-1554.
(3) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1
997, 277, 936-938. (b) Brandes, B. D.; Jacobsen, E. N. Tetrahedron:
Asymmetry 1997, 8, 3927. (c) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N.
AdV. Synth. Catal. 2001, 343, 5-26. (d) Schaus, S. E.; Brandes, B. D.;
Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307-1315.
(4) For an application, see: Pedragosa-Moreau, S.; Morriseau, C.; Zylber,
J.; Archelas, A.; Baratti, J.; Furstoss, R. J. Org. Chem. 1996, 61, 7402.
1
0.1021/ol026212d CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/13/2002

of aryl-substituted lithiated oxiranes. Therefore, we felt
encouraged to study the lithiation of optically active (R)-
and (S)-styrene oxides and subsequent trapping reaction with
electrophiles. We considered that the use of such stereo-
chemically stable terminal oxiranyllithiums could open a
useful route to optically active more functionalized styrene
oxide derivatives that would be key building blocks, from a
synthetic standpoint, for asymmetric synthesis of “target”
molecules. Herein, we describe the successful use of this
oxiranyl anion methodology for the stereoselective synthesis
of styrene oxide derivatives. The typical procedure for the
generation of oxiranyllithiums starting from either (S)- or
Table 1. Reaction of Lithiated (R)- and (S)-1a with
Electrophiles
[R]26
a
1
a
electrophile
product (% yield)
er
D
(R)-3a (>95)b
(S)-3a (>95)
(R)-3b (>95)b
98/2c
98/2c
98/2c
98/2c
98/2c
-24
+27
-20
+17
-30
+29
-42
+42
-22
+20
d
R
CH3OD
CH3OD
CH3I
CH3I
CH3CH2I
CH3CH2I
b
d
e
S
R
S
R
S
R
S
R
S
b,f
(S)-3b (>95)
(R)-3c (>95) b
g
b,f
98/2c
(S)-3c (>95)
(R)-3d (65)
f,h
98/2i
CH2dC(CH3)CH2Cl
CH dC(CH )CH Cl
(S)-3d (65)f,h
(R)-3e (45)f,h,j
(S)-3e (40)f,h,j
98/2i
98/2k
98/2k
2
3
2
(R)-styrene oxide and reactions with electrophiles is il-
PhCH2Br
PhCH2Br
lustrated in Scheme 1.
a
b
c 0.5-1.4, CHCl3 (see the Supporting Information for details). Yield
1
calculated by weighing the crude reaction product and H NMR analysis;
no starting material or other byproducts could be observed. Enantiomeric
ratio by GC analysis on a chiraldex B-DM capillary column. See ref 12.
c
Scheme 1a
d
e
f
g
Lit. -20.1 (c 1.02, CHCl3), see ref 12. Presumed configuration. Lit.
i
-
25.2 (c 0.64, CHCl3), see ref 2d. h Isolated yields. Enantiomeric ratio
j
by HPLC employing a Daicel Chiralcel OD-H column. Diphenylethane
also formed as byproduct. k Enantiomeric ratio by H NMR analysis in the
presence of a chiral solvating agent (see the Supporting Information for
details).
1
the ligand gave the best results, affording the product almost
quantitatively.
The presence of TMEDA was unavoidable, as lithiation
of racemic styrene oxide in the absence of this ligand
produced a mixture of products that originated from the
s-BuLi-promoted degradation reaction of lithiated styrene
a
Key: (i) s-BuLi/TMEDA, THF, -98 °C, 10 min; (ii) electro-
phile.
1
4
oxide: 3-methyl-2-phenyl-pent-1-ene 4, trans-3-methyl-
1
4
1
2
-phenyl-pent-1-ene 5, and diastereomeric 2,3-diphenyl-
1
5
-buten-1,4-diols 6 which were isolated and characterized
Treatment of a precooled mixture (-98 °C) of styrene
oxide (R)-1a (1 equiv) and TMEDA (3 equiv) with s-BuLi
1.2 equiv) in THF for 10 min led to regioselective generation
of oxiranyllithium (R)-2a, which was subsequently allowed
to react with a series of electrophiles to give stereospecifically
the corresponding R,R-disubstituted epoxides (R)-3a-e in
good to excellent yields and very high enantiomeric ratios
(
Figure 1). It is also worth pointing out that under these
optimized conditions the anion proved to be stable, at -98
(
1
6
°
C, for only 30 min.
(er 98/2 in all cases) (Table 1).
The optical activity of 3a-e was measured; 3a showed
12
the same optical rotation of the starting material, while that
2
d,12
of 3b,c matched quite well the values of the literature.
This fact proves that the reactions proceed without epimer-
ization at the stereogenic center. The R configuration to
compounds 3d,e was presumed and assigned by analogy.
The combination of base, ligand, and solvent was exam-
ined to optimize the yield of 3a-e. The use of s-BuLi (n-
BuLi and LDA were ineffective) as the base (1.2 equiv) and
Figure 1.
Lithiated styrene oxide (R)-2a also reacted smoothly with
ketones (acetone and cyclopentanone) to give products 3f,g
in good yields (Scheme 2 and Table 2). The reaction of (R)-
2a with aldehydes (benzaldehyde and p-chlorobenzaldehyde)
led to good yields of products 3h-k, although with poor
1
3
a donor solvent such as THF and of TMEDA (3 equiv) as
(
12) It is interesting to observe that while the [R]20D reported for the
diastereoselection at the newly created stereogenic center
commercial samples (Aldrich) of (R)- and (S)-styrene oxides, measured neat,
are +33 and -33, respectively, those measured by us in CHCl3 solution
17,18
(anti/syn ratio ) 66/34).
Diastereomers could be nicely
2
6
are opposite as signs for both. (R)-styrene oxide: [R] D ) -23 (c 0.8,
2
8
CHCl3); (S)-styrene oxide: [R] D ) +23 (c 0.7, CHCl3). A solvent-
dependent optical rotation sign has been also recently ascertained in the
case of R-methylstyrene oxide (see: Archelas, A.; Furstoss, R. J. Org. Chem.
(14) Doris, E.; Dechoux, L.; Mioskowski, C. Tetrahedron Lett. 1994,
35, 7943.
(15) Spectral data matched very well those reported in the literature:
Toda, F.; Takeira, Y.; Kataoka, Y.; Mori, K.; Sato, T.; Segawa, M. J. Chem.
Soc., Chem. Commun. 1984, 1234-1235.
(16) A computational and NMR investigation on the lithiated styrene
oxide is underway and will be reported in due course.
1
999, 64, 6112-6114) and of other styrene oxide derivatives (see: Imanishi,
H.; Katsuki, T. Tetrahedron Lett. 1997, 38, 251-254).
13) Quantity of TMEDA less than 1 equiv led to the recovery of starting
material and to minor yields of products.
(
2446
Org. Lett., Vol. 4, No. 14, 2002

1
careful inspection of their H NMR spectra. Use was made
1
9
of the observation that for such diastereomeric epoxy
alcohols the carbinol proton of the syn isomer absorbs at
lower field than the corresponding proton of the anti isomer
Scheme 2
(δ 5.05 vs 5.02 for 3i and 3h; 5.04 vs 4.99 for 3k and 3j,
respectively). The relative configuration of 3i was also
2
0
confirmed by crystallographic X-ray analysis. In the case
of (1S,2R)-3h, its relative and absolute configuration was
1
9
unambiguously ascertained by LiAlH
4
reduction and com-
2
6
parison of the optical activity ([R]
D
) -27, c 0.82 THF)
and spectroscopic data ( H NMR) of the resulting diol 7
1
(Scheme 3) with the literature data of its enantiomer (R,R)-8
Scheme 3
separated by preparative HPLC (see the Supporting Informa-
tion) and analyzed via chiral GC or chiral HPLC (er ) 98/
2, see the Supporting Information) (Scheme 2 and Table 2).
Table 2. Reaction of Lithiated (R)- and (S)-1a with Ketones
and Aldehydes
1
a
electrophile
product (% yield)
er
[R]26 a
D
b,c
98/2d
R
(CH3)2CO
(CH3)2CO
cyclopentanone
cyclopentanone
PhCHO
(R)-3f (>95)
(S)-3f (>95)
(R)-3g (70)
-49
+50
-56
+52
-44
-45
+41
+45
-80
-39
+87
+42
b,c
98/2d
S
R
S
R
([R]26 ) +34, c 1.01, THF).21 Therefore, we presume that
c,e
98/2d
D
2
2
(S)-3g (65)c,e
98/2d
(80%)e-g 98/2d
98/2d
7 should have the S,S configuration. The absolute config-
uration to diastereomeric epoxy alcohols 3i and 3j,k was
assigned by analogy.
(1S,2R)-3h
(
1R,2R)-3i
(1R,2S)-3h
1S,2S)-3i
(1S,2R)-3j
1R,2R)-3k
(1R,2S)-3j
1S,2S)-3k
S
R
S
PhCHO
(80%)e,f,h 98/2d
98/2d
In a similar way, lithiation of (S)-1a (Scheme 1) and
reactions of the resulting R-lithiated styrene oxide (S)-2a with
the same electrophiles stereospecifically furnished good
yields of products (S)-3a-e (Table 1) and 3f-k (Scheme 2
and Table 2), S configured at the R-carbon.
(
p-ClC6H4CHO
p-ClC6H4CHO
(82%)e-g 98/2i
(
98/2i
(80%)e,f,h 98/2i
98/2i
(
The ring opening of 3h, presumed to be (1R,2S), by
a
b
c 0.6-1.0, CHCl3 (see the Supporting Information for details). Yield
1
LiAlH
activity ([R]
4
gave the (R,R)-diol 8 (Scheme 3), whose optical
calculated by weighing the crude reaction product and H NMR analysis;
no starting material or other byproducts could be observed. Presumed
configuration. Enantiomeric ratio by GC analysis on a chiraldex B-DM
c
26
D
) +32, c 0.80, THF) matched very well the
d
e
f
literature value reported above. A short, highly efficient
or Supelco â-DEX 120 capillary column. Isolated yields. Overall yields
in both diastereoisomers; dr 1S,2R/1R,2R (or 1R,2S/1S,2S) ) 66/34,
synthesis of an industrial relevant triazole antifungal agent
g
separated by preparative HPLC. Relative and absolute configuration
23
such as 13 (Scheme 4) illustrates the value of our
h
ascertained as described. Relative and absolute configuration assigned by
analogy and ascertained in the case of (1R,2S)-3h. Enantiomeric ratio by
HPLC employing a Daicel Chiralcel OD-H column.
i
methodology starting from optically active (S)-4-chloro-
styrene oxide 10 (Scheme 4).
(
19) Adam, W.; Braun, M.; Griesbeck, A.; Lucchini, V.; Staab, E.; Will,
B. J. Am. Chem. Soc. 1989, 111, 203-212.
20) Crystallographic data for compound (1R,2R)-3i have been deposited
at the Cambridge Crystallographic Data Centre (deposition no. CCDC-
86824). Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. [fax: (int.) +44-
1223/336-033; E-mail: deposit@ccdc.cam.ac.uk]. ORTEP view and CIF
file for compound (1R, 2R)-3i have been also reported as Supporting
Information.
Preliminary indications about the diastereomers’ relative
configurations (syn or anti, see Scheme 2) came from a
(
1
(17) The convention employed for describing syn and anti diastereomers
is as follows: if the main chain is written in an extended (zigzag)
conformation, the diastereomer that has the oxiranyl ring and the hydroxy
group both projecting either forward (bold bonds) or away from the viewer
(
dashed bonds) is called syn.
(21) Rosini, C.; Scamuzzi, S.; Focati, M. P.; Salvadori, P. J. Org. Chem.
1995, 60, 8289-8293. Spectroscopic data of racemic (1R*,2S*)-1,2-
diphenylpropane-1,2-diol were reported (Bach, T.; Kather, K. J. Org. Chem.
1996, 61, 3900-3901) and were also compared with those obtained by the
ring opening of a sample of racemic (1R*,2R*)-3i, which gave the
(1R*,2S*)-diol.
(22) The configuration at the tertiary benzylic carbon becomes S as the
priority of the groups around this stereogenic centre is inverted in the opened
product.
(18) The anti stereoselection observed conforms to the empirical steric
model for the prediction of the stereochemical outcome of reactions of chiral
anions with aldehydes in the absence of chelation control, proposed by
Bassindale and Taylor (Bassindale, A. R.; Ellis, R. J.; Lau, J. C.-Y.; Taylor,
P. G. J. Chem. Soc., Chem. Commun. 1986, 98-100) and that has been
also applied by Molander to explain the relative stereochemistry of the major
diastereoisomer formed by oxiranyl anions addition to carbonyl compounds
(
Molander, G. A.; Mautner, K. J. Org. Chem. 1989, 54, 4042-4050).
Probably, small energy differences between the two diastereomeric transition
states could explain, also in our case, the low diastereoselectivity observed
in the case of epoxy alcohols 3h-k.
(23) (a) Takahashi, K.; Ogata, M. J. Org. Chem. 1987, 52, 1877-1880.
(b) Ogata, M.; Matsumoto, H.; Tawara, K.; Ishiguro, T.; Hatta, T. (Shionogi
and Co., Ltd., Japan) Eur. Pat. Appl. EP 117578 A2 19840905, 1984.
Org. Lett., Vol. 4, No. 14, 2002
2447

Swern oxidation27 of 12 furnished quantitatively the target
28
Scheme 4a
hydroxy ketone (S)-13, which is a known antifungal agent.
Further synthetic applications are now in progress.
In conclusion, we proved in this paper that optically pure
styrene oxides can be successfully deprotonated and trapped
stereospecifically (retention of configuration) to produce
enantiomerically enriched substituted styrene oxide deriva-
tives. This methodology, coupled with Jacobsen’s HKR of
terminal aryl epoxides, has been advantageously applied to
the synthesis of a known oral antifungal agent.
Acknowledgment. This work was carried out under the
framework of the National Project “Stereoselezione in Sintesi
Organica, Metodologie ed Applicazioni” supported by the
Ministero dell’Istruzione, dell’Universit a` e della Ricerca
(
(
MIUR, Rome) and by the University of Bari and CNR
Rome). We are also grateful to Prof. Marcel Pierrot of the
Centre Scientifique Saint-Jerome, Marseille, France, for
performing X-ray analysis on compound (1R,2R)-3i.
a
Key: (i) CF
3
COCH
salen)Co ‚OAc, H O (0.55 equiv), 0 °C, 38% yield, er 99/1; (iii)
CHO; 80%
3 2 2
/H O , quantitative yield; (ii) (S,S)-
III
(
2
6 4
s-BuLi/TMEDA, THF, -98 °C, 10 min; (iv) p-ClC H
yield, anti/syn 2/1; (v) H ; (vi) NaH/1,2,4-triazole, DMF, 70 °C, 3
h, 78% yield; (vii) Swern oxidation (quantitative).
+
Supporting Information Available: Full experimental
1
13
details and characterization data ( H and C NMR, physical
data) for compounds 3a-k, for syn and anti epoxy alcohols
1
1. ORTEP view (Figure S1) and CIF file for compound
(
1R,2R)-3i. This material is available free of charge via the
(
S)-10 was easily synthesized (er 99/1, by chiral GC)24
by epoxidation of the corresponding commercially available
olefin 9 using H as oxidant and CF COCH as the catalyst
quantitative yield) followed by a hydrolytic kinetic
Internet at http://pubs.acs.org.
O
2 2
3
3
OL026212D
2
5
(
3d
III
resolution (HKR) catalyzed by the chiral (S,S)-(salen)Co
(26) Syn and anti diastereomeric epoxy alcohols 11 could be separated
by preparative HPLC and spectroscopically characterized. Both resulted to
be optically pure (er 99/1, by chiral HPLC) so testifying once more the
configurational stability (S) of the corresponding R-lithiated p-chloro-
substituted oxiranyllithium. The configuration to the carbinol carbon was
assigned by analogy to the other epoxy alcohols.
complex‚OAc (38% isolated yield). Subsequent lithiation
with s-BuLi/TMEDA in THF in the usual way and reaction
with p-chlorobenzaldehyde afforded a mixture of diastere-
omeric epoxy alcohols 11 (80% isolated yield; anti/syn 2/1)
that was afterward reacted with 1,2,4-triazole/NaH in DMF
26
(
27) Lindstrom, U. M.; Somfai, P. Synthesis 1998, 109-117.
23a
(28) Mp: 118-120 °C (Et2O) (lit. mp 161-163 °C (Et2O), lit. (()-
3 (Ogata, M.; Matsumoto, H.; Takahashi, K.; Shimizu, S.; Kida, S.;
1
at 70 °C for 3 h leading to diol 12 (78% isolated yield).
Murabayashi, A.; Shiro, M.; Tawara, K. J. Med. Chem. 1987, 30, 1064-
1
26
068) mp 102-104 °C (AcOEt/iPr2O)). [R] D ) +113.5 (c 1.6, CHCl3)
2
6
4
20
23a 23
(
24) [R] D ) +27 (c 1, CHCl3) (lit. [R] D ) +19.3 (c 1.16, CHCl3,
(lit. [R] D ) +117.3 (c 1.0, CHCl3)). The synthesis of (S)-(+)-3-(4-
chlorophenyl)-2-phenyl-3-oxo-1-(1H-1,2,4-triazol-1-yl)propan-2-ol starting
from (S)-styrene oxide gave a product (overall yield 62%) with ee 98/2 by
chiral HPLC (OB-H, hexane/iPrOH 95/5, flow rate 0.7 mL/min, tRminor )
28.44 min, tRmajor ) 45.8 min), [R]26D ) +203 (c 0.65, CHCl3).
ee > 98%)). It is worth pointing out that Jacobsen (ref 3d) has reported an
24
optical activity ([R] D ) -23.8, c 3.41 CHCl3, ee > 99%) of the enantiomer
(
R)-10.
(25) Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807-8810.
2448
Org. Lett., Vol. 4, No. 14, 2002