Boron trifluoride-induced, new stereospecific rearrangements of chiral epoxy ethers. Ready access to enantiopure 4-(diarylmethyl)-1,3-dioxolanes and 4,5-disubstituted tetrahydrobenzo[c]oxepin-4-ols

Article abstract of DOI:10.1021/jo052208e

Upon treatment with BF₃ · Et₂O at low temperature, enantiopure benzyl-type ethers of arylglycidols with electron withdrawing substituents at the skeletal aryl group and electron donating substituents at the benzyl group undergo stere

Full text of DOI:10.1021/jo052208e

Boron Trifluoride-Induced, New Stereospecific Rearrangements of
Chiral Epoxy Ethers. Ready Access to Enantiopure
4-(Diarylmethyl)-1,3-dioxolanes and 4,5-Disubstituted
Tetrahydrobenzo[c]oxepin-4-ols
Gabriela Islas-Gonza´lez,† Jordi Benet-Buchholz,‡ Miguel A. Maestro,§ Antoni Riera,† and
Miquel A. Perica`s*,†,‡
Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain, Departament de Qu´ımica
Orga`nica and Parc Cient´ıfic de Barcelona, UniVersitat de Barcelona, 08028 Barcelona, Spain, and
Facultade de Ciencias, UniVersidade da Corun˜a, 15071 A Corun˜a, Spain
mapericas@iciq.es
ReceiVed October 23, 2005
Upon treatment with BF3‚Et2O at low temperature, enantiopure benzyl-type ethers of arylglycidols with
electron withdrawing substituents at the skeletal aryl group and electron donating substituents at the
benzyl group undergo stereospecific rearrangements of Friedel-Crafts type, leading to enantiopure
4-diarylmethyl-1,3-dioxolanes (2) or to enantiopure trans-4,5 disubstituted tetrahydrobenzo[c]oxepin-4-
ols (5). The course of the reactions is controlled by the substitution pattern at the benzyl ether: While
benzylic systems activated toward ipso substitution afford diarylmethanes 2 through a Friedel-Crafts
reaction followed by fragmentation, benzylic systems activated toward ortho attack lead to enantiopure
oxepinols 5 through a 7-endo-tet ring closure of Friedel-Crafts type.
Introduction
of 1,2-difunctional compounds of many different types, elec-
trophiles (Lewis acids) trigger a variety of rearrangements
ultimately leading to carbonyl compound through carbocation
or carbocation-like intermediates.3
Enantiomerically pure diarylmethane derivatives are important
chiral building blocks in medicinal chemistry due to the large
number of therapeutic agents that possess this structural motif.1
Despite its increasing demand, methods for their enantioselective
preparation are scarce, mostly relying on the catalytic arylation
of aldehydes.2
On the other hand, epoxides depict an extremely rich and
varied reactivity. While nucleophiles easily perform ring opening
of the epoxide ring, thus allowing the stereospecific preparation
(2) For recent work on preparation of enantiopure, heterosubstituted
diarylmethanes by enantioselective phenyl transfer to aldehydes, see: (a)
Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Muniz, K. Angew. Chem., Int.
Ed. 2000, 39, 3465-3467. (b) Bolm, C.; Rudolph, J. J. Am. Chem. Soc.
2002, 124, 14850-14851. (c) Fontes, M.; Verdaguer, X.; Sola`, L.; Perica`s,
M. A.; Riera, A. J. Org. Chem. 2004, 69, 2532-2543. (d) Ji, J.-X.; Wu, J.;
Au-Yeung, T. T.-L.; Yip, C.-W.; Haynes, R. K.; Chan, A. S. C. J. Org.
Chem. 2005, 70, 1093-1095. (e) Tomita, D.; Wada, R.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 4138-4139. For a successful
approach based on Ru-catalyzed hydrogenation, see: (f) Ohkuma, T.;
Koizumi, M.; Ikehira, H.; Yokozawa, T.; Noyori, R. Org. Lett. 2000, 2,
659-662. For de-racemization approaches, see: (g) Prat, L.; Mojovic, L.;
Levacher, V.; Dupas, G.; Que´guiner, G.; Bourguignon, J. Tetrahedron:
Asymmetry 1998, 9, 2509-2516. (h) Prat, L.; Dupas, G.; Duflos, J.;
Que´guiner, G.; Bourguignon, J.; Levacher, V. Tetrahedron Lett. 2001, 42,
4515-4518. For a conjugate addition approach, see: (i) Paras, N. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894-7895.
* To whom correspondence should be addressed at ICIQ.
† Universitat de Barcelona.
‡ Institute of Chemical Research of Catalonia.
§ Universidade da Corun˜a.
(1) See, for instance: (a) Silvestri, R.; Artico, M.; De Martino, G.; Ragno,
R.; Massa, S.; Loddo, R.; Murgioni, Ch.; Giulia, L. A.; La Colla, P.; Pani,
A. J. Med. Chem. 2002, 45, 1567-1576. (b) Chiral Drugs; Challener, C.
A., Ed.; Ashgate: Burlington, VT, 2001; p 278.
10.1021/jo052208e CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/12/2006
J. Org. Chem. 2006, 71, 1537-1544
1537

Islas-Gonza´lez et al.
SCHEME 2. Reaction Conditions for the Stereospecific
SCHEME 1. Ring Opening and Rearrangement of
Triphenylethylene Oxide
Rearrangement of 1a Leading to 2a
of phenylglycidol was employed as a substrate, the course of
the reaction was completely different, a nonfluorinated re-
arrangement product being obtained.
In the Lewis acid-mediated reactions of epoxides, if a
nucleophile (either external or internal) is present in the reaction
medium, attack on the carbocation intermediate can occur and
products similar to those resulting from purely nucleophilic
attack can arise, often with regiochemical reversal. This is
illustrated in Scheme 1 with examples from our laboratory.4
Among these Lewis acid-mediated nucleophilic additions to
epoxides, reactions where the nucleophile is an aromatic ring
are particularly interesting because of the nature of the resulting
systems. They represent a special type of Friedel-Crafts
reactions, suitable for the preparation of enantiopure compounds
whenever readily available enantiopure epoxides are employed
as reactants. Until now, most of examples in this reappraisal of
Friedel-Crafts chemistry refer to intermolecular processes,
where a variety of Lewis acids have been used to induce the
reactions.5
Over the past years, we have been involved in the develop-
ment of modular ligands for asymmetric catalysis from enan-
tiopure epoxy alcohols and epoxy ethers.6 While working on
the boron trifluoride-mediated synthesis of oxazolines6h from
benzyl-type ethers of phenylglycidol, we discovered that these
substrates can experience a regioselective and stereospecific
ring-opening hydrofluorination under very mild reaction condi-
tions.7 We also observed that, when the p-methoxybenzyl ether
We were intrigued by this behavior, and we have now studied
in detail this alternate pathway. We report in this paper how
enantiomerically pure benzyl-type ethers of arylglycidols con-
taining electron withdrawing groups on the skeletal aryl
substituent and properly placed electron donating groups on the
benzyl moiety experience stereospecific intramolecular Friedel-
Crafts reactions when treated with BF3‚Et2O at low temperature
to afford either enantiopure diarylmethanes (through an unprec-
edented ipso attack followed by fragmentation) or enantiopure
trans-4,5-disubstituted tetrahydrobenzo[c]oxepin-4-ols.
Results and Discussion
Our study of the boron trifluoride-mediated rearrangement
of benzyl ethers of arylglycidols began with epoxy ether 1a,
containing a strong electron withdrawing nitro group on the
skeletal phenyl group. We anticipated that the presence of this
group would decrease the rate of the potentially competitive
ring-opening hydrofluorination of the epoxide. According to our
expectations, when epoxy ether 1a was treated with this reagent
under very mild conditions (0.3 equiv of BF3‚OEt2, 0.1 M
CH2Cl2, -35 °C, 1 h), the reaction afforded the rearranged
compound 2a as the sole reaction product;8 however, conversion
of the starting material was incomplete (65%). Very gratifyingly,
a complete conversion of 1a into the enantiomerically pure
diarylmethane derivative 2a was recorded when the reaction
was carried out at 20 °C in the presence of 1 equiv of BF3‚
OEt2 (Scheme 2).
(3) For recent reviews on the chemistry of epoxides, see: (a) Pastor, I.
M.; Yus, M. Curr. Org. Chem. 2005, 9, 1-29. (b) Aziridines and Epoxides
in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, Germany,
2006.
(4) (a) Sola`, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Perica`s,
M. A.; Riera, A.; Alvarez-Larena, A.; Piniella, J.-F. J. Org. Chem. 1998,
63, 7078-7082. (b) Reddy, K. S.; Sola`, L.; Moyano, A.; Perica`s, M. A.;
Riera, A. J. Org. Chem. 1999, 64, 3969-3974. (c) Garc´ıa-Delgado, N.;
Fontes, M.; Perica`s, M. A.; Riera, A.; Verdaguer, X. Tetrahedron:
Asymmetry 2004, 15, 2085-2090.
(5) For stereoselective, intermolecular Friedel-Crafts type alkylations
involving epoxides, see: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 2004, 43, 550-556. (b) Bandini, M.; Melloni, A.;
Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199-1222.
(6) (a) Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Org.
Chem. 1997, 62, 4970-4982. (b) Vidal-Ferran, A.; Moyano, A.; Perica`s,
M. A.; Riera, A. Tetrahedron Lett. 1997, 38, 8773-8776. (c) Jimeno, C.;
Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron Lett.
1999, 40, 777-780. (d) Puigjaner, C., Vidal-Ferran, A.; Moyano, A.; Perica`s,
M. A.; Riera, A. J. Org. Chem. 1999, 64, 7902-7911. (e) Jimeno, C.;
Moyano, A.; Perica`s, M. A.; Riera, A. Synlett 2001, 1155-1157. (f) Fontes,
M.; Verdaguer, X.; Sola`, L.; Vidal-Ferran, A.; Reddy, K. S.; Riera, A.;
Perica`s, M. A. Org. Lett. 2002, 4, 2381-2383. (g) Pasto´, M.; Riera, A.;
Perica`s, M. A. Eur. J. Org. Chem. 2002, 2337-2341. (h) Perica`s, M. A.;
Puigjaner, C.; Riera, A.; Vidal-Ferran, A.; Go´mez, M.; Jime´nez, F.; Muller,
G.; Rocamora, M. Chem. Eur. J. 2002, 8, 2164-2178. (i) Jimeno, C.; Pasto´,
M.; Riera, A.; Perica`s, M. A. J. Org. Chem. 2003, 68, 3130-3138.
(7) Islas-Gonza´lez, G.; Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.;
Riera, A.; Perica`s, M. A. Tetrahedron Lett. 2004, 45, 6337-6341.
It is to be mentioned that the structural assignment of 2a posed
some initial challenge: Whereas 13C NMR experiments clearly
indicated the presence of two methylene and two nonaromatic
methine groups, two distinct singlets (one proton each) at 4.94
and 5.08 ppm, correlated with one single methylene carbon,
1
were present in the H NMR spectra. Since no situation with
2JHH ) 0 was easily anticipated for structures related to 1a,
more solid arguments for the structural assignment were sought
from X-ray crystallography. In this way, the structure and the
(8) For recent examples of BF3-induced rearrangements in epoxides,
see: (a) Jung, M. E.; Anderson, K. L. Tetrahedron Lett. 1997, 38, 2605-
2608. (b) Kita, Y.; Kitagaki, S.; Yoshida, Y.; Mihara, S.; Fang, D.-F.; Kondo,
M.; Okamoto, S.; Imai, R.; Akai, S.; Fujioka, H. J. Org. Chem. 1997, 62,
4991-4997. (c) Kita, Y.; Furukawa, A.; Futamura, J.; Higuchi, K.; Ueda,
K.; Fujioka, H. Tetrahedron Lett. 2000, 41, 2133-2136. (d) Kita, Y.;
Furukawa, A.; Futamura, J.; Higuchi, K.; Ueda, K.; Fujioka, H. Tetrahedron.
2001, 57, 815-825. (e) Kita, Y.; Furukawa, A.; Futamura, J.; Higuchi, K.;
Ueda, K.; Fujioka, H. J. Org. Chem. 2001, 66, 8779-8786. (f) Kita, Y.;
Futamura, J.; Ohba, Y.; Sawama, Y.; Ganesh, K. J.; Fujioka, H. J. Org.
Chem. 2003, 68, 5917-5924.
1538 J. Org. Chem., Vol. 71, No. 4, 2006

Chiral Epoxy Ether Stereospecific Rearrangement
SCHEME 3. Mechanistic Rationale for the Stereospecific
Formation of Diarylmethane 2a from 1a
FIGURE 1. Bis(sulfonamide) 3a, with an ORTEP plot (ellipsoids at
40% probability) of its crystal structure.
absolute configuration of 2a could be unambiguously assigned
on the basis of the X-ray analysis of the crystalline derivative
3a (Figure 1), obtained from dioxolane 2a9 through reduction
of the nitro group (H2, Pd/C) and tosylation.10
electron donating substituents on the aryl ring preferentially
rearrange to â-alkoxyaldehydes.7,12
On the other hand, if the mechanistic assumption in Scheme
3 is correct, substituents on the aryl moiety of the benzyl ether
that increase the electron density at the ipso carbon should also
increase the ease for the rearrangement, leading to diarylmethane
derivatives.
While several examples of Lewis acid-mediated ring opening
of epoxides with arenes (or Friedel-Crafts reactions with
epoxides, in an alternate view) are known,11 an intramolecular
stereospecific process like the one leading to 2a is unprec-
edented. A mechanistic rationale for this reaction is shown in
Scheme 3. As a key feature, ipso attack to the activated epoxide
by the benzyl ether moiety, followed by fragmentation, is the
vehicle for the stereospecific delivery of a phenyl group to a
benzylic position, ultimately leading to the formation of an
enantiopure diarylmethane derivative.
For the reasons given above, extension of this method to the
preparation of other enantiopure diarylmethanes was attempted
among epoxy ethers bearing electron withdrawing substituents
on the skeletal phenyl ring of the starting epoxide. In this
context, it is important to point out that phenylglycidyl ethers,
when submitted to the same reaction conditions, experience ring-
opening hydrofluorination,7 while arylglycidyl ethers with
Results obtained when submitting epoxy ethers fulfilling the
aforementioned structural criteria to BF3‚OEt2 under a variety
of experimental conditions have been summarized in Table 1.
Starting from enantiopure epoxy ethers 1a-f, prepared by
alkylation with the corresponding benzyl halides (see Experi-
mental Section) of epoxy alcohols prepared in enantiomerically
pure form by the Sharpless procedure,13 enantiopure 4-(diaryl-
methyl)-1,3-dioxolanes 2a-f are obtained in good yields as the
sole reaction products under very mild reaction conditions and,
generally, in short reaction times. In only one case (entry b),
the corresponding fluoro alcohol arising from ring opening of
the starting epoxide was also obtained in 25% yield.7
With respect to reactivity, the anticipated trend is observed:
electron withdrawing groups on the skeletal phenyl substituent
and electron donating groups on the benzyl substituent favor
the rearrangement leading to 2. It is to be noted, however, that
the formation of the dioxolane products responds to a combina-
tion of factors: availability of a low-energy path for the
intramolecular Friedel-Crafts reaction with the epoxide and
inhibition of alternative reactivities of the epoxide (ring opening
by fluoride, Lewis acid-mediated rearrangement) that would lead
to fluoro alcohol or carbonyl products. Probably as a combina-
tion of these two factors, the highest reactivity among the studied
substrates is depicted by 1d, which was completely converted
after 5 min at -78 °C in the presence of 0.33 equiv of BF3‚
OEt2. Much for the same reasons, while p-methoxy benzyl ethers
led to dioxolane products under mild conditions (entries c-g),
the o- and m-methoxy benzyl ethers of phenylglycidol yielded
mainly the corresponding fluoro alcohols.7
(9) For examples of 1,3-dioxolanes with nonequivalent, yet noncoupled
C-2 protons, see: (a) Gras, J. L.; Poncet, A. Bull. Soc. Chim. Fr. 1991,
128, 566. (b) McCombie, W. S.; Metz, A. W. Tetrahedron Lett. 1987, 28,
383. (c) Hojo, M.; Aihara, H.; Suginohara, Y.; Sakata, K.; Nakamura, S.;
Murakami, Ch.; Hosomi, A. J. Org. Chem. 1997, 62, 8610.
(10) (a) To a solution of 2a (0.012 g, 0.042 mmol) in AcOEt (1 mL)
and MeOH (0.100 mL), 10% Pd/C (0.020 g) was added, and the mixture
was stirred under H2 at room temperature for 3 h. The reaction mixture
was filtered through a short pad of Celite, the solvent was evaporated in
vacuo, and the resulting oil (0.011 g) was used for the next reaction without
purification. (b) To a solution of the hydrogenation product (0.008 g, 0.031
mmol) in anhydrous CH2Cl2 (0.50 mL) under N2 at room temperature
DMAP (0.003 g, 0.031 mmol), p-toluenesulfonyl chloride (0.009 g, 0.047
mmol) and Et3N (0.004 mL, 0.031 mmol) were added. After 3 h of stirring,
a saturated solution of NH4Cl (1 mL) was added. The aqueous solution
was extracted with CH2Cl2 (3 × 2 mL), and the combined organic extracts
were dried (Na2SO4) and concentrated in vacuo. The residual oil was purified
by column chromatography using hexane:EtOAc (80:20) as eluent to give
a sample of pure 3a [1H NMR (400 MHz, CDCl3) δ 2.45 (s, 6H), 3.54 (dd,
J ) 6.8, 8.4 Hz, 1H), 3.84 (dd, J ) 6.4, 8.4 Hz, 1H), 4.04 (d, J ) 9.2 Hz,
1H), 4.70 (m, 1H), 4.96 (s, 1H), 5.06 (s, 1H), 6.96 (d, J ) 8.4 Hz, 4H),
7.20-7.32 (m, 8H), 7.78 (d, J ) 8.4 Hz, 5H)]. A recrystallization from
dichloromethane afforded crystals suitable for X-ray diffraction.
As already mentioned, the reactions leading to dioxolanes
2a-f are in general very clean. For instance, when the
(11) (a) Taylor, K. S.; Hockerman, H. G.; Karrick, L. G.; Lyle, B. S.;
Schramm, B. S. J. Org. Chem. 1983, 48, 2449-2452. (b) Tanis, P. S.;
Raggon, W. J. J. Org. Chem. 1987, 52, 819-827. (c) Broka, A. C.; Chan,
S.; Peterson, B. J. Org. Chem. 1988, 53, 1584-1586. (d) Taylor, K. S.;
May, A. S.; Stansby, S. E. J. Org. Chem. 1996, 61, 2075-2080. (e) For an
intermolecular process leading to a racemic diarylmethane, see: Taylor,
K. S.; Clark, L. D.; Heinz, L. K.; Schramm, B. S.; Westermann, D. C.;
Barnell, K. K. J. Org. Chem. 1983, 48, 592-596.
(12) For a recent account on the rearrangement of silyl ethers of glycidols
to â-alkoxyaldehydes catalyzed by a Cr(III) porphyrin complex, see: Suda,
K.; Kikkawa, T.; Nakajima, S.; Takanami, T. J. Am. Chem. Soc. 2004, 126,
9554-9555.
(13) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. (b) Katsuki,
T.; Mart´ın, V. S. Org. React. 1996, 48, 1-299.
J. Org. Chem, Vol. 71, No. 4, 2006 1539

Islas-Gonza´lez et al.
TABLE 1. Stereospecific Rearrangement of Epoxy Ethers 1a-f Leading to Diarylmethanes 2a-f
entry
R
R′
Ph
ee 1 (%)
T (°C)
t (min)
BF3‚OEt2 (equiv)
yield (%)
ee 2 (%)
a
b
c
d
e
f
NO2
CF3
CF3
H
NO2
Cl
95
96
96
99
95
80
rt
rt
30
180
30
5
30
5
1.0
0.5
1.0
0.5d
2.0
0.3
60
60a
60
59
28
44
98
96
97
>99
98
Ph
PMP
PMP
PMP
PMP
-35b
-35c
rt
-20
85
a The corresponding fluoro alcohol arising from the ring opening was also obtained in this case (25% yield). b When the reaction was performed at 0 °C
(1 h), the yield was 40%. c At -50 °C (5 min reaction), the yield was 46%; at -78 °C (0.3 equiv of BF3‚OEt2, 5 min reaction), the yield was 44%. d With
1 equiv of BF3‚OEt2 under the same reaction conditions, the yield was 48%.
SCHEME 4. Reaction Conditions for the Stereospecific
Rearrangement of 4a Leading to 5a
FIGURE 2. Tetrahydrobenzoxepinol 5a, with an ORTEP plot (el-
lipsoids at 50% probability) of its crystal structure.
SCHEME 5. Mechanistic Rationale for the Formation of
Tetrahydrobenzoxepinol 5a from 4a
rearrangement of 1c was studied by NMR in CD2Cl2 at -30
°C, it was observed that the conversion of the starting material
was complete after 30 min and that 2c was the sole product
arising from the reaction. Despite that, the reaction yield was
limited to ca. 60%, as for other examples in Table 1. The
possibility that this limit in yield could arise from product
association with BF3 leading to decomposition during hydrolysis
led us to explore the use of a less oxophilic Lewis acid, such as
InBr3, which has been shown to promote Friedel-Crafts
reactions of epoxides.14 However, when this reagent was used
with 1d (1 equiv, 0 °C, 15 min), a mixture of 2d and the two
regioisomeric fluoro alcohols arising from the ring opening of
the epoxide was obtained.
Very interestingly, the course of the electrophilic attack of
the epoxide on the benzyl ether moiety can be fine-tuned by
manipulation of the electronic properties of the benzyl group.
We reasoned that, if a 3,5-dimethoxybenzyl substituent was used
as protecting group in the starting epoxy ether, the nucleophilic
reactivity of the aromatic system would shift from the ipso to
the ortho/ortho′ positions and that the double activation at these
sites would overcome the tendency of the simple m-methoxy-
benzyl ether (see above) to preferentially undergo ring-opening
hydrofluorination. In agreement with these expectations, when
epoxy ether 4a (R ) H, >99% ee) was treated with BF3‚OEt2
in dichloromethane at -78 °C (Scheme 4), a fast reaction took
place and the enantiomerically pure tetrahydrobenzoxepinol 5a
(>99% ee) could be isolated in 80% yield.
Benzo[c]oxepin 5a could be crystallized, and X-ray analysis
allowed its stereochemical assignment (Figure 2). A mechanistic
rationale for this rearrangement is provided in Scheme 5. As in
the reaction leading to diarylmethanes (Scheme 2), the aryl
group in the benzyl moiety behaves as a nucleophile toward
the R-aryl carbon of the epoxide, which suffers a stereospecific
SN2 type ring opening. In this case, however, the presence of a
(14) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A. J. Org.
Chem. 2002, 67, 5386-5389.
1540 J. Org. Chem., Vol. 71, No. 4, 2006

Chiral Epoxy Ether Stereospecific Rearrangement
TABLE 2. Stereospecific Rearrangement of Epoxy Ethers 4a-d
Leading to Tetrahydrobenzoxepinols 5a-d
Conclusions
In summary, the BF3‚OEt2-promoted rearrangements de-
scribed here provide useful and stereospecific methods for the
synthesis of enantiopure diarylmethane derivatives (4-(diaryl-
methyl)-1,3-dioxolanes and tetrahydrobenzoxepinols) from readily
available, enantiopure O-benzyl-protected epoxy alcohols. Very
interestingly, the regiochemical course of the underlying
Friedel-Crafts process can be easily controlled by shifting the
nucleophilic reactivity in the benzyl moiety of the substrate from
the ipso to the ortho/ortho′ positions.
entry
R
ee 4 (%)
yield (%)
ee 5 (%)
a
b
c
d
H
CF3
Cl
>99
96
80
80
>99
96
80
14 (54)a
60 (75)a
60
Ph
78
80
a Reactions did not proceed to completion. Yield according to conversion
is given in parentheses.
hydrogen atom as a substituent on the nucleophilic aromatic
carbon allows the process to be completed as an intramolecular
Friedel-Crafts reaction.
Experimental Section
When epoxy ethers 4b-d were submitted to the same reaction
conditions, aryl-substituted tetrahydrobenzoxepinols 5b-d were
formed stereospecifically, the enantiomeric purity of the starting
materials being conserved in all cases in the cyclization products
(Table 2). To get some insight into the factors controlling the
reactivity of epoxy ethers 4 in this process, all reactions were
performed under the same reaction conditions (-78 °C in
dichloromethane, 15 min). It could be seen in this way that
substrates with a more electron-rich skeletal aryl substituent (4a
and 4d) are those undergoing the fastest Friedel-Crafts cy-
clization. Even the substrates containing an electronically poor
aryl substituent (4b and 4c) react to a considerable extent under
these very mild conditions, and, more importantly, they experi-
ence exclusively Friedel-Crafts cyclization vs ring-opening
hydrofluorination. The nucleophilic power of the 3,5-dimeth-
oxybenzyl is an important factor in reactivity control since, as
mentioned above, the m-methoxybenzyl ether of the same
substrate leads to the corresponding fluorhydrin when submitted
to the same treatment.7
The very low temperature at which BF3‚OEt2 is able to induce
the considered process in truly remarkable. In this sense, it is
interesting to compare our results with those recently reported
by He15 on the formally related intramolecular cyclialkylation
of aryl ethers of epoxy alcohols leading to 3-chromanols. This
process, mediated by the AuCl3/3AgOTf system, requires to
proceed temperatures of 50 °C or higher and has been reported
to fail when BF3‚OEt2 is employed as the catalyst.16
(2S,3S)-3-(4-Nitrophenyl)-2-(benzyloxymethyl)oxirane (1a). A
solution of (2S,3S)-2,3-epoxy-3-(4′-nitrophenyl)propan-1-ol (0.2 g,
1.025 mmol) in dimethylformamide (DMF, 2 mL) was added via
cannula to a suspension of sodium hydride (0.045 g, 1.13 mmol)
in DMF (2 mL) at -20 °C under N2. The mixture was stirred for
20 min, and benzyl bromide (0.121 mL, 1.025 mmol) was added
via syringe. After 5 h of stirring at -20 °C, MeOH (1 mL) and
brine (2 mL) were added, and the solution was extracted with ether
(3 × 5 mL). The combined organic extracts were dried and
concentrated in vacuo, and the residual oil was purified by column
chromatography using hexane:EtOAc (80:20/60:40) as the eluent
20
to give 0.20 g (68%) of 1a as an oil: [R]D ) -24.0 (c ) 0.485
1
in CHCl3); IR (CHCl3) 3033, 2861, 1605, 1522, 1348 cm-1; H
NMR (400 MHz, CDCl3) δ 3.19 (m, 1H), 3.65 (dd, J ) 4.8, 11.6
Hz, 1H), 3.82 (dd, J ) 3.2, 11.6 Hz, 1H), 3.92 (d, J ) 2.0 Hz,
1H), 4.62 (s, 2H), 7.32 (m, 1H), 7.36 (d, J ) 4.4 Hz, 4H), 7.43 (d,
J ) 8.4 Hz, 2H), 8.20 (d, J ) 8.8 Hz, 2H); 13C NMR (100 MHz)
δ 55.1, 62.1, 69.4, 73.8, 124.0, 126.7, 128.1, 128.2, 128.8, 137.8,
144.8, 148.1; MS (CI, NH3) m/z: 303 [M + NH4]+. HRMS (CI).
Calcd for [M + H]+: 286.1079. Found: 286.1087.
(2S,3S)-3-(4-(Trifluoromethyl)phenyl)-2-(benzyloxymethyl)-
oxirane (1b). A solution of (2S,3S)-2,3-epoxy-3-(4-(trifluorometh-
yl)phenyl)propan-1-ol (0.22 g, 1.01 mmol) in DMF (5 mL) was
added via cannula to a suspension of sodium hydride (0.044 g, 1.11
mmol) in DMF (5 mL) at -20 °C under N2. The mixture was stirred
for 20 min, and benzyl bromide (0.132 mL, 1.11 mmol) was added
to the mixture. After 4 h of stirring at -20 °C, the reaction mixture
was treated as described for 1a. The residual oil was purified by
column chromatography using hexane:ether (47:3/ 45:5) as eluent
to give 0.258 g (83%) of 1b as a white solid: mp ) 58-60 °C;
[R]D20 ) -24.0 (c ) 0.96 in CHCl3); IR (CHCl3) 3441, 2858, 1622,
Although some examples of Friedel-Crafts type cyclization
of epoxides leading to seven-membered rings are known,17 the
totally regioselective and stereospecific formation of tetra-
hydrobenzoxepinols 5 is unprecedented. Since oxygenated
seven-membered rings are appealing from the pharmacological
perspective18 and, despite considerable synthetic effort,19 meth-
ods for their enantioselective synthesis have remained practically
unexplored, the stereospecific Friedel-Crafts cyclization of
enantiopure epoxyethers 4 leading to 5 offers a considerable
interest.
1
1323, 1116 cm-1; H NMR (400 MHz, CDCl3) δ 3.21 (m, 1H),
3.68 (dd, J ) 5.2, 11.6 Hz, 1H), 3.84 (d, J ) 3.2 Hz, 1H), 3.87 (m,
1H), 2H), 7.31 (m, 3H), 7.37 (m, 4H), 7.59 (d, J ) 8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 55.1, 61.5, 64.4, 73.5, 125.4 (q, J
) 3.8 Hz), 125.9, 127.8 (d, J ) 9.0 Hz), 128.5, 137.7, 141.1; 19F
NMR (376 MHz, CDCl3) δ -63.0 (s, CF3); MS (CI, CH4) m/z:
309 [M + H]+. Anal. Calcd for C17H15F3O2 : C, 66.23; H, 4.90.
Found: C, 66.21; H, 5.07.
(2S,3S)-3-(4-(Trifluoromethyl)phenyl)-2-((4-methoxy)benzyl-
oxymethyl)oxirane (1c). A solution of (2S,3S)-2,3-epoxy-3-(4-
(trifluoromethyl)phenyl)propan-1-ol (0.20 g, 0.917 mmol) in DMF
(5 mL) was added via cannula to a suspension of sodium hydride
(0.04 g, 1.01 mmol) in DMF (5 mL) at -20 °C under N2. The
mixture was stirred for 20 min, and 4-methoxybenzyl chloride
(0.136 mL, 1.01 mmol) was added to the mixture. After 3 h of
stirring at 0 °C, the reaction mixture was treated as described for
1a. The residual oil was purified by column chromatography using
hexane:ether (48:2) as eluent to give 0.22 g (71%) of 1c as a white
solid: mp ) 47 °C; [R]D20 ) -26.0 (c ) 1.2 in CHCl3); IR (CHCl3)
2897, 1612, 1330, 1119, 839 cm-1; 1H NMR (400 MHz, CDCl3) δ
3.81 (m, 1H), 3.63 (dd, J ) 5.2, 11.6 Hz, 1H), 3.80 (d, J ) 2.8 Hz,
1H), 3.81 (s, 3H), 3.83 (dd, J ) 2.0, 6.6 Hz, 1H), 4.55 (d, J ) 3.2
Hz, 2H), 6.88 (d, J ) 8.4 Hz, 2H), 7.28 (d, J ) 8.4 Hz, 2H), 7.37
(15) Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 5964-5965.
(16) A Friedel-Crafts type mechanism was discarded for this process
on the basis of the inefficiency of Lewis acids to catalyze it.
(17) (a) Molander, G. A.; Andrews, S. W. J. Org. Chem. 1989, 54, 3114-
3120. (b) Nogumo, S.; Miyoshe, I.; Akita, H.; Kawahara, N. Tetrahedron
Lett. 2002, 43, 2223-2226. (c) For a review, see: Marson, C. A.
Tetrahedron 2000, 56, 8779-8794.
(18) (a) Maier, A. C.; Wu¨nsch, B. Eur. J. Org. Chem. 2003, 714-720.
(b) Wolin, R.; Connolly, M.; Kelly, J.; Weinstein, J.; Rosenblum, S.; Afonso,
A.; James, L.; Kirschmeier P.; Bishop, R. W. Bioorg. Med. Chem. Lett.
1998, 8, 2521-2526. (c) Ohshima, E.; Otaki, S.; Sato, H.; Kumazawa, T.;
Obase, H.; Ishii, A.; Ishii, H.; Ohmori, K.; Hirayama, N. J. Med. Chem.
1992, 35, 2074-2084.
(19) (a) O’Shea, F. D.; Sharp, T. J. J. Chem. Soc., Perkin Trans. 1 1997,
3025-3034. (b) Chattopadhyay, K. S.; Maity, S.; Panja, S. Tetrahedron
Lett. 2002, 43, 7781-7783.
J. Org. Chem, Vol. 71, No. 4, 2006 1541

Islas-Gonza´lez et al.
(d, J ) 8.0 Hz, 2H), 7.59 (d, J ) 8.0 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 55.2, 55.3, 61.5, 69.1, 73.19, 113.9, 125.4 (c, J )
3.8 Hz), 125.9 (d, J ) 2.6 Hz), 129.5, 129.8, 130.4 (d, J ) 32.7
Hz), 141.2, 159.4 (d, J ) 1.3 Hz); 19F NMR (376 MHz, CDCl3) δ
-63.0 (s, CF3); MS (CI, CH4) m/z: 339 [M + H]+. Anal. Calcd
for C18H17F3O3 : C, 63.90; H, 5.06. Found: C, 64.06; H, 4.99.
(2S,3S)-3-Phenyl-2-((4-methoxy)benzyloxymethyl)oxirane (1d).
A solution of (2S,3S)-2,3-epoxy-3-phenylpropan-1-ol (0.51 g, 3.4
mmol) in DMF (5 mL) was added via cannula to a suspension of
sodium hydride (0.149 g, 3.74 mmol) in DMF (5 mL) at -20 °C
under N2. The mixture was stirred for 20 min, and 4-methoxybenzyl
chloride (0.505 mL, 3.74 mmol) was added to the mixture. After 3
h of stirring at -20 °C and 2 h at 0 °C, the reaction mixture was
treated as described for 1a. The residual oil was purified by column
chromatography using hexane:ether (48:2/45:5) as eluent to give
0.78 g (85%) of 1d as an oil: [R]D20 ) -35.0 (c ) 1.1 in CHCl3);
IR (CHCl3) 2997, 2934, 2836, 1612, 1585, 1513, 1248, 1174, 820
cm-1; 1H NMR (400 MHz, CDCl3) δ 3.20 (m, 1H), 3.60 (dd, J )
5.2, 11.6 Hz, 1H), 3.79 (dd, J ) 2, 13 Hz, 1H), 3.81 (s, 3H), 3.83
(d, J ) 2.8 Hz, 1H), 4.56 (d, J ) 4.4 Hz, 2H), 6.89 (d, J ) 8.8 Hz,
2H), 7.25-7.34 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 55.2,
55.9, 61.2, 69.5, 73.0, 113.8, 125.7, 128.2, 128.4, 129.4, 129.9,
136.9, 159.3; MS (CI, CH4) m/z: 271 [M + H]+. HRMS (CI).
Calcd for [M + H]+: 271.1334. Found: 271.1336.
combined organic extracts were dried and concentrated in vacuo,
and the crude product was purified by column chromatography
using hexane:ether:toluene (70:20:10) as the eluent to give 2a (0.030
20
g, 60%) as a white solid: mp 83-85 °C; [R]D ) +8.3 (c ) 1.0
1
in CHCl3); IR (CHCl3) 2860, 1596, 1518, 1349, 1088 cm-1; H
NMR (400 MHz, CDCl3) δ ) 3.61 (dd, J ) 6, 8.6 Hz, 1H), 3.89
(dd, J ) 6, 8.6 Hz, 1H), 4.15 (d, J ) 9,6 Hz, 1H), 4.78 (m, 1H;
CH), 4.94 (s, 1H), 5.08 (s, 1H), 7.23-7.38 (m, 5H), 7.52 (d, J )
8.8 Hz, 2H), 8.16 (d, J ) 8.8 Hz, 2H); 13C NMR (100 MHz) δ
54.9, 69.2, 77.9, 95.9, 124.0, 127.9, 128.4, 129.4, 129.6, 139.9,
149.6; MS (EI) m/z (%): 285 [M]+, 213 [M - C3H5O2]+. Anal.
Calcd for C16H15NO4: C, 67.36; H, 5.30; N, 4.91. Found: C, 67.28;
H, 5.39; N, 4.86. ee ) 98% (HPLC: Chiralcel AD, 10% 2-propanol
in hexane, 0.5 mL/min, (S,S) isomer 32.06 min, (R,R) isomer 37.05
min).
(4R)-[Phenyl-(R)-(4-(trifluoromethyl)phenyl)methyl]-1,3-di-
oxolane (2b). A solution of enantiomerically pure (96% ee) (2S,3S)-
1b (0.051 g, 0.165 mmol) in anhydrous. CH2Cl2 (1.65 mL) and
BF3.Et2O (0.01 mL, 0.082 mmol) under N2 was stirred for 3 h at
room temperature. The reaction mixture was treated as described
for 2a, and the crude product was purified by column chromatog-
raphy using hexane:EtOAc (80:20) as the eluent to give the 2b
20
(0.030 g, 60%): [R]D ) -2.0 (c ) 1.4 in CHCl3); IR (CHCl3)
1
2860, 1596, 1518, 1349, 1088, 704 cm-1; H NMR (400 MHz,
CDCl3) δ 3.59 (dd, J ) 6.4, 8.6 Hz, 1H), 3.89 (dd, J ) 6.4, 8.4
Hz, 1H), 4.07 (d, J ) 12 Hz, 1H), 4.74-4.80 (m, 1H), 4.95 (s,
1H), 5.08 (s, 1H), 7.22-7.34 (m, 5H), 7.47 (d, J ) 8.4 Hz, 2H),
7.56 (d, J ) 8.4 Hz, 2H); 13C NMR (100 MHz) δ 54.6, 69.0, 77.8,
95.6, 122.8, 125.4 (q, J ) 3.8 Hz), 127.4, 128.2, 128.7, 129.0, 140.3,
145.8; 19F NMR (376 MHz, CDCl3) δ -63.0 (s, CF3); MS (CI,
NH3) m/z: 326 [M + NH4]+. HRMS (CI). Calcd for [M]+:
309.1102. Found: 309.1109. ee ) 96% (HPLC: Chiralcel ODH,
2% 2-propanol in hexane, 0.5 mL/min, (S,S) isomer 15.91 min,
(R,R) isomer 17.40 min).
(2S,3S)- 3-(4′-Nitrophenyl)-2-((4-methoxy)benzyloxymethyl)-
oxirane (1e). A solution of (2S,3S)-2,3-epoxy-3-(4′-nitrophenyl)-
propan-1-ol (0.146 g, 0.748 mmol) in DMF (2 mL) was added via
cannula to a suspension of sodium hydride (0.033 g, 0.823 mmol)
in DMF (5 mL) at -20 °C under N2. The mixture was stirred for
20 min, and 4-methoxybenzyl chloride (0.111 mL, 0.823 mmol)
was added to the mixture via syringe. After 5 h of stirring at -20
°C, the reaction mixture was treated as described for 1a. The
residual oil was purified by column chromatography using hexane:
EtOAc:Tol (70:20:10) as the eluent to give 0.115 g (49%) of 1e as
20
an oil: [R]D ) -31.6 (c ) 1.0 in CHCl3); IR (CHCl3) 3417,
(4R)-[(4-Methoxyphenyl)-(R)-(4-(trifluoromethyl)phenyl)-
methyl]-1,3-dioxolane (2c). A solution of enantiomerically pure
(96% ee) (2S,3S)-1c (0.030 g, 0.088 mmol) in anhydrous CH2Cl2
(0.9 mL) and BF3‚Et2O (0.011 mL, 0.088 mmol) under N2 was
stirred for 30 min at -35 °C. The reaction mixture was treated as
described for 2a, and the crude product was purified by column
chromatography using hexane:EtOAc (9:1) as the eluent to give
2c (0.018 g, 60%) as a liquid: [R]D20 ) -4.2 (c ) 0.96 in CHCl3);
1
2935, 2837, 1611, 1514, 1248, 818 cm-1; H NMR (400 MHz,
CDCl3) δ 3.19 (m, 1H), 3.66 (dd, J ) 4.8, 12.0 Hz, 1H), 3.80 (s,
3H), 3.83 (d, J ) 3.2 Hz, 1H), 3.90 (d, J ) 2.0 Hz, 1H), 4.55 (d,
J ) 1.6 Hz, 2H), 6.89 (d, J ) 8.8 Hz, 2H), 7.28 (d, J ) 8.4 Hz,
2H), 7.42 (d, J ) 8.8 Hz, 2H) 8.18 (d, J ) 8.8 Hz, 2H); 13C NMR
(100 MHz) δ 54.8, 55.2, 61.9, 68.8, 73.2, 113.9, 123.7, 126.4, 129.5,
129.6, 144.6, 147.8, 159.4; MS (CI, CH4) m/z: 356 [M + C3H5]+,
344 [M + C2H5]+, 316 [M + H]+, 121. HRMS (CI). Calcd for
[M]+: 315.1107. Found: 315.1105.
(2S,3S)-3-(4-Chlorophenyl)-2-((4-methoxy)benzyloxymethyl)-
oxirane (1f). A solution of (2S,3S)-2,3-epoxy-3-(chlorophenyl)-
propan-1-ol (0.304 g, 1.65 mmol) in DMF (5 mL) was added via
cannula to a suspension of sodium hydride (0.072 g, 1.82 mmol)
in DMF (5 mL) at -20 °C under N2. The mixture was stirred for
20 min, and 4-methoxybenzyl chloride (0.245 mL, 1.82 mmol) was
added to the mixture. After 5 h of stirring at -20 °C, the reaction
mixture was treated as described for 1a. The residual oil was
purified by column chromatography using hexane:ether (96:4) as
eluent to give 0.32 g (64%) of 1f as a white solid: mp ) 58 °C;
[R]D20 ) -28.6 (c ) 1.0 in CHCl3); IR (CHCl3) 2907, 2836, 1612,
1513, 1247, 1089, 821 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.17
(m, 1H), 3.60 (dd, J ) 5.6, 11.4 Hz, 1H), 3.75 (d, J ) 2.0 Hz,
1H), 3.79 (dd, J ) 3.2, 11.6 Hz, 1H), 3.80 (s, 3H), 4.54 (d, J ) 4.0
Hz, 2H), 6.88 (d, J ) 8.8 Hz, 2H), 7.18 (d, J ) 8.4 Hz, 2H), 7.29
(t, J ) 8.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 55.3, 61.3,
69.3, 73.1, 113.8, 127.0, 128.7, 129.4, 129.8, 134.0, 135.5, 159.4;
MS (CI, CH4) m/z 305 [M + H]+. Anal. Calcd for C17H17ClO3 :
C, 67.00; H, 5.62. Found: C, 67.28; H, 5.44.
1
IR (CHCl3) 2937, 2840, 1618, 1513, 1327, 1123, 828 cm-1; H
NMR (400 MHz, CDCl3) δ 3.59 (dd, J ) 6.8, 8.4 Hz, 1H), 3.77
(s, 3H), 3.89 (dd, J ) 6.4, 8.4 Hz, 1H), 4.02 (d, J ) 9.6 Hz, 1H),
4.68-4.75 (m, 1H), 4.94 (s, 1H), 5.07 (s, 1H), 6.84 (d, J ) 8.8
Hz, 2H), 7.14 (d, J ) 8.8 Hz, 2H), 7.46 (d, J ) 8.4 Hz, 2H), 7.56
(d, J ) 8.4 Hz, 2H); 13C NMR (100 MHz) δ 53.8, 55.2, 69.1, 77.9,
95.6, 114.4, 125.4 (q, J ) 3.8 Hz), 128.6, 129.2, 132.4, 146.2, 158.8;
19F NMR (376 MHz, CDCl3) δ -62.90 (s, CF3); MS (CI, CH4)
m/z 339 [M + H]+. HRMS (CI). Calcd for [M]+: 338.1129.
Found: 338.1131. ee ) 97% (HPLC: Chiralcel OD-H, 5%
2-propanol in hexane, 0.5 mL/min, (S,S) isomer 15.52 min, (R,R)
isomer 17.97 min).
(4R)-[(4-Methoxyphenyl)-(R)-(4-phenyl)methyl]-1,3-dioxo-
lane (2d). A solution of enantiomerically pure (99% ee) (2S,3S)-
1d (0.022 g, 0.081 mmol) in anhydrous CH2Cl2 (0.8 mL) and BF3.‚
Et2O (0.005 mL, 0.04 mmol) under N2 was stirred for 5 min at
-35 °C. The reaction mixture was treated as described for 2a, and
the crude was purified by column chromatography using hexane:
EtOAc (9:1) as the eluent to give 2d (0.018 g, 59%) as a white
20
solid: mp ) 113 °C; [R]D ) -7.0 (c ) 0.98 in CHCl3); IR
(CHCl3) 2954, 2901, 2851, 1610, 1513, 1255, 1081, 940 cm-1; 1H
NMR (400 MHz, CDCl3) δ 3.57 (dd, J ) 6.8, 8.4 Hz, 1H), 3.77
(s, 3H), 3.88 (dd, J ) 6.4, 8.2 Hz, 1H), 3.97 (d, J ) 9.6 Hz, 1H),
4.73 (m, 1H), 4.94 (s, 1H), 5.06 (s, 1H), 6.81 (dd, J ) 2.0, 6.6 Hz,
2H), 7.16 (dd, J ) 2.0, 6.6 Hz, 2H), 7.20-7.35 (m, 5H); 13C NMR
(100 MHz) δ 53.8, 55.2, 69.1, 78.2, 95.5, 114.2, 126.6, 128.2, 128.5,
129.1, 133.4, 142.1, 158.5; MS (CI, CH4) m/z 271 [M + H]+. Anal.
(4R)-[(R)-(4-Nitrophenyl)phenylmethyl]-1,3-dioxolane (2a). A
solution of enantiomerically pure (95% ee) (2S,3S)-1a (0.05 g, 0.175
mmol) in anhydrous CH2Cl2 (1.7 mL) and BF3.Et2O (0.022 mL,
0.175 mmol) under N2 was stirred for 30 min at room temperature.
The reaction mixture was treated with a saturated NaHCO3 solution;
the aqueous solution was extracted with CH2Cl2 (3 × 3 mL). The
1542 J. Org. Chem., Vol. 71, No. 4, 2006

Chiral Epoxy Ether Stereospecific Rearrangement
20
Calcd for C17H18O3 : C, 75.53; H, 6.71. Found: C, 75.75; H, 6.35.
ee ) >99% (HPLC: Chiralcel OD, 5% 2-propanol in hexane, 0.5
mL/min, (S,S) isomer 18.94 min, (R,R) isomer 20.30 min).
(4R)-[(R)-(4-Nitrophenyl)(4-methoxyphenyl)methyl]-1,3-dioxo-
lane (2e). A solution of enantiomerically pure (95% ee) (2S,3S)-
1e (0.050 g, 0.16 mmol) in anhydrous CH2Cl2 (1.6 mL) and
BF3.Et2O (0.03 mL, 0.32 mmol) under N2 was stirred for 30 min
at room temperature. The reaction mixture was treated as described
for 2a, and the crude product was purified by column chromatog-
raphy using hexane:EtOAc (47:3) as the eluent to give 2e (0.014
as an oil: [R]D ) -19.0 (c ) 0.6 in CHCl3); IR (CHCl3) 2940,
2841, 1598, 1326, 1206, 1067, 838 cm-1; H NMR (400 MHz,
1
CDCl3) δ 3.21 (m, 1H), 3.66 (dd, J ) 5.2, 11.6 Hz, 1H), 3.79 (s,
6H), 3.83 (d, J ) 3.2 Hz, 1H), 3.85 (d, J ) 2.8 Hz, 1H), 4.56 (d,
J ) 4.0 Hz, 2H), 6.40 (t, J ) 2.0 Hz, 1H), 6.52 (d, J ) 2.4 Hz,
2H), 7.38 (d, J ) 8.0 Hz, 2H), 7.59 (d, J ) 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 55.2, 55.3, 61.5, 69.5, 73.4, 99.8, 105.5, 125.5
(q, J ) 3.8 Hz), 125.9, 140.1, 141.1, 161.0; 19F NMR (376 MHz,
CDCl3) δ -63.0 (s, CF3); MS (CI, NH3) m/z 386 [M + NH4]+,
369 [M + H]+. HRMS (CI). Calcd for (M)+: 368.1235. Found:
368.1225.
20
g, 28%) as a liquid: [R]D ) + 3.0 (c ) 0.32 in CHCl3); IR
(CHCl3) 2934, 2838, 1607, 1514, 1348, 1251, 1088 cm-1; 1H NMR
(400 MHz, CDCl3) δ 3.60 (dd, J ) 6.4, 8.4 Hz, 1H), 3.78 (s, 3H),
3.89 (dd, J ) 6.4, 8.4 Hz, 1H), 4.06 (d, J ) 9,6 Hz, 1H), 4.72 (m,
1H), 4.94 (s, 1H), 5.08 (s, 1H), 6.85 (d, J ) 8.4 Hz, 2H), 7.13 (d,
J ) 8.4 Hz, 2H), 7.50 (d, J ) 8.4 Hz, 2H), 8.16 (d, J ) 8.4 Hz,
2H); 13C NMR (100 MHz) δ 53.8, 55.3, 69.0, 77.8, 95.7, 114.6,
123.7, 129.2, 129.2, 131.7, 146.6, 149.8, 159.0; MS (CI, NH3)
m/z: 333 [M + NH4]+, 242 (100). HRMS (CI). Calcd for [M +
H]+: 316.1184. Found: 316.1179. ee ) 98.0% (HPLC: Chiralcel
OD, 5% 2-propanol in hexane, 0.5 mL/min, (S,S) isomer 40.91 min,
(R,R) isomer 44.14 min).
(2S,3S)-3-(4-Chlorophenyl)-2-((3,5-dimethoxy)benzyloxy-
methyl)oxirane (4c). A solution of (2S,3S)-2,3-epoxy-3-(chloro-
phenyl)propan-1-ol (0.201 g, 1.09 mmol) in DMF (5 mL) was added
via cannula to a suspension of sodium hydride (0.046 g, 1.15 mmol)
in DMF (5 mL) at -20 °C under N2. The mixture was stirred for
20 min, and 3,5-dimethoxybenzyl bromide (0.28 g, 1.15 mmol) in
DMF (3 mL) was added via cannula to the mixture. After 6 h of
stirring at -20 °C, the reaction mixture was treated as described
for 1a. The residual oil was purified by column chromatography
20
using hexane:ether (48:2) to give 4c (0.25 g, 68%) as an oil: [R]D
) -26.0 (c ) 1.25 in CHCl3); IR (CHCl3) 2939, 2838, 1598, 1458,
1
1205, 1157, 829 cm-1; H NMR (400 MHz, CDCl3) δ 3.19 (m,
(4R)-[(4-Methoxyphenyl)-(R)-(4-chlorophenyl)methyl]-1,3-di-
oxolane (2f). A solution of enantiomerically enriched (80% ee)
(2S,3S)-1f (0.080 g, 0.263 mmol) in anhydrous CH2Cl2 (2.6 mL)
and BF3‚Et2O (0.01 mL, 0.079 mmol) under N2 was stirred for 5
min at -20 °C. The reaction mixture was treated as described for
2a, and the crude product was purified by column chromatography
using hexane:ether (47:3) as the eluent to give 2f (0.035 g, 44%)
1H), 3.62 (dd, J ) 4.8, 11.4 Hz, 1H), 3.76 (d, J ) 1.6 Hz, 1H),
3.79 (s, 6H), 3.82 (dd, J ) 3.2, 11.6 Hz, 1H), 4.55 (d, J ) 4.8 Hz,
2H), 6.39 (t, J ) 2.4 Hz, 1H), 6.52 (d, J ) 2.4 Hz, 2H), 7.19 (d,
J ) 8.4 Hz, 2H), 7.30 (d, J ) 8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 55.3, 55.3, 61.2, 69.6, 73.4, 99.8, 105.4, 127.0, 128.7,
134.0, 135.4, 140.1, 160.9; MS (CI, NH3) m/z 352 [M + NH4]+,
335 [M + H]+. HRMS (CI). Calcd for (M + H)+: 335.1050.
Found: 335.1047.
20
as an oil: [R]D ) -2.0 (c ) 0.5 in CHCl3); IR (CHCl3) 2934,
2837, 1512, 1252, 1090, 807 cm-1; 1H NMR (400 MHz, CDCl3) δ
3.56 (dd, J ) 6.4, 8.4 Hz, 1H), 3.77 (s, 3H), 3.87 (dd, J ) 6.4, 8.4
Hz, 1H), 3.94 (d, J ) 9.6 Hz, 1H), 4.66 (m, 1H), 4.93 (s, 1H),
5.05 (s, 1H), 6.83 (d, J ) 8.8 Hz, 2H), 7.12 (d, J ) 8.8 Hz, 2H),
7.27 (s, 4H); 13C NMR (100 MHz) δ 53.2, 55.2, 69.0, 78.1, 95.6,
114.3, 128.6, 129.1, 129.6, 132.4, 132.9, 140.7, 158.6; MS (CI,
NH3) m/z 322 [M + NH4]+, 231 (100%). HRMS (CI). Calcd for
[M]+: 304.0866. Found: 304.0866. ee ) 85% (HPLC: Chiralcel
ODH, 5% 2-propanol in hexane, flux 0.5 mL/min, (S,S) isomer
16.71 min, (R,R) isomer 18.17 min).
(2S,3S)-3-Biphenyl-2-((3,5-dimethoxy)benzyloxymethyl)oxi-
rane (4d). A solution of (2S,3S)-2,3-epoxy-3-(biphenyl)propan-1-
ol (0.238 g, 1.05 mmol) in DMF (5 mL) was added via cannula to
a suspension of sodium hydride (0.044 g, 1.10 mmol) in DMF (5
mL) at -20 °C under N2. The mixture was stirred for 20 min, and
3,5-dimethoxybenzyl bromide (0.27 g, 1.10 mmol) in DMF (3 mL)
was added via cannula to the mixture. After 5 h of stirring at -20
°C, the reaction mixture was treated as described for 1a. The
residual oil was purified by column chromatography using hexane:
ether (48:2) to give 4d (0.24 g, 61%) as an oil: [R]D20 ) -24.5 (c
) 1.0 in CHCl3); IR (CHCl3) 2938, 2838, 1598, 1458, 1205, 1156,
836 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.29 (m, 1H), 3.64 (dd,
J ) 5.2, 11.4 Hz, 1H), 3.79 (s, 6H), 3.83 (d, J ) 2.0 Hz, 1H), 3.86
(dd, J ) 2.8, 11.4 Hz, 1H), 4.57 (d, J ) 4.8 Hz, 2H), 6.40 (t, J )
2.4 Hz, 1H), 6.54 (d, J ) 2.0 Hz, 2H), 7.35 (t, J ) 7.4 Hz, 3H),
7.43 (t, J ) 8.0 Hz, 2H), 7.56 (d, J ) 6.8 Hz, 4H); 13C NMR (100
MHz, CDCl3) δ 55.3, 55.7, 61.2, 69.9, 73.3, 99.8, 105.4, 126.2,
127.0, 127.2, 127.4, 128.8, 135.9, 140.3, 140.6, 141.3, 160.9; MS
(CI, NH3) m/z 394 [M + NH4]+, 377 [M + H]+, 359. HRMS (CI).
Calcd for [M + H]+: 377.1752. Found: 377.1746.
(2S,3S)-3-Phenyl-2-((3,5-dimethoxy)benzyloxymethyl)oxi-
rane (4a). A solution of (2S,3S)-2,3-epoxy-3-phenylpropan-1-ol (1.5
g, 10 mmol) in DMF (5 mL) was added via cannula to a suspension
of sodium hydride (0.42 g, 10.5 mmol) in DMF (20 mL) at -20
°C under N2. The mixture was stirred for 20 min, and 3,5-
dimethoxybenzyl bromide (2.55 g, 10.5 mmol) in DMF (10 mL)
was added via cannula to the mixture. After 3 h of stirring at -20
°C and 4 h of stirring at 0 °C, the reaction mixture was treated as
described for 1a. The residual oil was purified by column
chromatography using hexane:ether (96:4) as eluent to give 4a (1.5
g, 50%): [R]D20 ) -27.0 (c ) 0.98 in CHCl3); IR (CHCl3) 2999,
2939, 2839, 1598, 1462, 835, 698 cm-1 1H NMR (400 MHz,
;
(4R,5S)-1,3,4,5-Tetrahydro-6,8-dimethoxy-5-phenylbenz[c]-
oxepin-4-ol (5a). A solution of enantiomerically pure (ee > 99%)
(2S,3S)-4a (0.104 g, 0.346 mmol) in anhydrous CH2Cl2 (3.5 mL)
and BF3‚Et2O (0.013 mL, 0.104 mmol) under N2 was stirred for
15 min at -78 °C. The reaction mixture was treated as described
for 2a, and the crude product was purified by column chromatog-
raphy using hexane:AcOEt (9:1/8:2) as the eluent to give 5a (0.088
CDCl3) δ 3.25 (m, 1H), 3.61 (dd, J ) 5.2, 11.6 Hz, 1H), 3.78 (s,
6H), 3.85 (dd, J ) 2.8, 11.6 Hz, 1H), 4.56 (d, J ) 5.2 Hz, 1H),
6.39 (t, J ) 2.4 Hz, 1H), 6.53 (d, J ) 2.4 Hz, 2H), 7.25-7.36 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 55.3, 55.9, 61.1, 69.9, 73.3,
99.8, 105.4, 125.7, 128.2, 128.5, 136.8, 140.2, 160.9; MS (CI, NH3)
m/z 318 [M + NH4]+, 301 [M]+. HRMS (CI). Calcd for (M)+:
300.1362. Found: 300.1359.
(2S,3S)-3-(4-(Trifluoromethyl)phenyl)-2-((3,5-dimethoxy)ben-
zyloxymethyl)oxirane (4b). A solution of (2S,3S)-2,3-epoxy-3-(4-
(trifluoromethyl)phenyl)propan1-ol (0.23 g, 1.09 mmol) in DMF
(5 mL) was added via cannula to a suspension of sodium hydride
(0.046 g, 1.15 mmol) in DMF (5 mL) at -20 °C under N2. The
mixture was stirred for 20 min, and 3,5-dimethoxybenzyl bromide
(0.28 g, 1.15 mmol) in DMF (3 mL) was added via cannula to the
mixture. After 6 h of stirring at -20 °C, the reaction mixture was
treated as described for 1a. The residual oil was purified by column
chromatography using hexane:ether (48:2) to give 4b (0.319 g, 79%)
20
g, 80%) as a white solid: mp113-114 °C; [R]D ) -29.6 (c )
1.0 in CHCl3); IR (CHCl3) 3440, 2940, 2839, 1606, 1492, 1153
1
cm-1; H NMR (400 MHz, CDCl3) δ 2.44 (d, J ) 10.4 Hz, 1H),
3.65 (d, J ) 12.8 Hz,), 3.72 (s, 3H), 3.77 (d, J ) 2.4 Hz), 3.84 (s,
3H), 3.95 (dd, J ) 3.2, 12.6 Hz), 4.39 (m, 1H), 4.51 (d, J ) 13.6
Hz, 2H), 5.37 (d, J ) 6.0 Hz, 1H), 6.40 (d, J ) 2.4 Hz, 1H), 6.49
(d, J ) 2.4 Hz, 1H), 7.0 (dd, J ) 1.6, 8.2 Hz, 2H), 7.17 (t, J ) 7.2
Hz, 1H), 7.26 (m, 2H); 13C NMR (100 MHz) δ 46.1, 55.3, 56.0,
71.5, 73.2, 75.9, 98.2, 106.1, 117.4, 126.1, 127.6, 128.5, 139.9,
142.2, 159.5, 160.5; MS (CI, CH4) m/z 318 [M + NH4]+; 301 [M
+ H]+, 283 [M + H - H2O]+. HRMS (CI). Calcd for [M + H]+:
J. Org. Chem, Vol. 71, No. 4, 2006 1543

Islas-Gonza´lez et al.
301.1439. Found: 301.1435. ee > 99% (HPLC: Chiralcel OD-R,
30% H2O in methanol, 0.5 mL/min, (4R,5S) isomer 37.30 min,
(4S,5R) isomer 44.48 min).
Chiralcel OD, 5% ethanol: 95% hexane: 2% TFA, 0.5 mL/min,
(4R,5S) isomer 35.04 min, (4S,5R) isomer 53.33 min).
(4R,5S)-5-(4-Biphenyl)-1,3,4,5-tetrahydro-6,8-dimethoxy-
benzo[c]oxepin-4-ol (5d). A solution of enantiomerically enriched
(ee 78%) (2S,3S)-4d (0.05 g, 0.133 mmol) in anhydrous CH2Cl2
(1.3 mL) and BF3‚Et2O (0.005 mL, 0.040 mmol) under N2 was
stirred for 15 min at -78 °C. The reaction mixture was treated as
described for 2a, and the crude product was purified by column
(4R,5S)-5-[4-(Trifluoromethyl)phenyl]-1,3,4,5-tetrahydro-6,8-
dimethoxybenz[c]oxepin-4-ol (5b). A solution of enantiomerically
pure (ee 96%) (2S,3S)-4b (0.050 g, 0.136 mmol) in anhydrous
CH2Cl2 (1.4 mL) and BF3‚Et2O (0.005 mL, 0.040 mmol) under N2
was stirred for 15 min at -78 °C. The reaction mixture was treated
as described for 2a, and the crude product was purified by column
chromatography using hexane:AcOEt (9:1/8:2) as the eluent to give
5b (0.007 g, 14%) as an oil: [R]D20 ) +19.0 (c ) 0.1 in CHCl3);
chromatography using hexane:AcOEt (9:1/8:2) as the eluent to give
20
5d (0.030 g, 60%) as a white solid: mp ) 163-164 °C; [R]D
)
-18.0 (c ) 0.4 in CHCl3); IR (CHCl3) 3446, 2937, 1606, 1487,
1
1
IR (CHCl3) 3446, 2942, 2842, 1607, 1326, 1116, 837 cm-1; H
1201, 1153, 836 cm-1; H NMR (400 MHz, CDCl3) δ 2.40 (d, J
NMR (400 MHz, CDCl3) δ 2.40 (d, J ) 10.8 Hz, 1H), 3.60 (d, J
) 12.8 Hz, 1 H), 3.74 (s, 3H), 3.85 (s, 3H), 3.97 (dd, J ) 2.8, 12.4
Hz, 1 H), 4.41 (d, J ) 14.0 Hz, 1H), 4.43 (m, 1H), 4.59 (d, J )
14.0 Hz, 1H), 5.40 (d, J ) 6.0 Hz, 1H), 6.42 (d, J ) 2.4 Hz, 1H),
6.50 (d, J ) 2.8 Hz, 1H), 7.13 (d, J ) 8.4 Hz, 2H), 7.52 (d, J )
8.0 Hz, 2H); 13C NMR (100 MHz) δ 46.2, 55.3, 56.0, 71.5, 73.2,
75.9, 98.3, 106.2, 116.5, 125.6 (t, J ) 3.8 Hz), 128.1, 142.1, 144.3,
159.9, 160.5; 19F NMR (376 MHz) δ -62.9; MS (CI, NH3) m/z
386 (M + NH4)+, 369 (M + H)+, 350. Anal. Calcd for
C19H19F3O4: C, 61.95; H, 5.20. Found: C, 61.88; H, 5.33. ee 96%
(HPLC: Chiralcel OD, 5% ethanol: 95% hexane: 2% TFA, 0.5
mL/min, (4R,5S) isomer 36.43 min, (4S,5R) isomer 56.29 min).
(4R,5S)-5-(4-Chlorophenyl)-1,3,4,5-tetrahydro-6,8-dimethoxy-
benzo[c]oxepin-4-ol (5c). A solution of enantiomerically enriched
(ee 80%) (2S,3S)-4c (0.050 g, 0.149 mmol) in anhydrous CH2Cl2
(1.5 mL) and BF3‚Et2O (0.006 mL, 0.045 mmol) under N2 was
stirred for 15 min at -78 °C. The reaction mixture was treated as
described for 2a, and the crude product was purified by column
) 11.2 Hz, 1H), 3.73 (d, J ) 12.4 Hz, 0.5 H), 3.73 (s, 3H), 3.86
(s, 3H), 3.99 (dd, J ) 2.8, 12.4 Hz, 1H), 4.43 (m, 1H), 4.55 (d, J
) 9.2 Hz, 2H), 5.42 (d, J ) 6.0 Hz, 1H), 6.43 (d, J ) 2.4 Hz, 1H),
6.52 (d, J ) 2.8 Hz, 1H), 7.08 (d, J ) 8.0 Hz, 2H), 7.32 (t, J ) 7.6
Hz, 1H), 7.42 (t, J ) 8.0 Hz, 2H), 7.49 (d, J ) 8.4 Hz, 2H), 7.55
(dd, J ) 1.6, 8.4 Hz, 2H); 13C NMR (100 MHz) δ 45.9, 55.4, 56.1,
71.6, 73.3, 76.0, 98.3, 106.2, 117.4, 126.9, 127.2, 127.3, 128.1,
128.8, 139.0, 139.1, 140.7, 142.3, 159.6, 160.6; MS (CI, NH3) m/z
394 (M + NH4)+, 377 (M + H)+, 359 (M - H2O)+. Anal. Calcd
for C24H24O4: C, 76.57; H, 6.43. Found: C, 76.23; H, 6.46. ee
80% (HPLC: Chiralcel OD, 5% ethanol: 95% hexane: 2% TFA,
0.5 mL/min, (4R,5S) isomer 44.91 min, (4S,5R) isomer 57.59 min).
Acknowledgment. We thank DGI-MCYT (Grant BQU2002-
02459), DURSI (Grant 2001SGR50), Fundacio´n Ramon Areces,
Parc Cient´ıfic de Barcelona, and ICIQ Foundation for financial
support. G.I.-G. thanks PCB for a contract. We are indebted to
Dr. Ciril Jimeno for discussions and assistance in manuscript
preparation.
chromatography using hexane:AcOEt (9:1/8:2) as the eluent to give
20
5c (0.030 g, 60%) as a white solid: mp ) 129-130 °C; [R]D
)
Supporting Information Available: 13C NMR spectra of 1a,d,e,
2b,c,e,f, 4a-d, and 5a-d, X-ray crystal structure of 3a and 5a
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org. Crystallographic data corresponding to the struc-
tural analysis of 3a and 5a have been deposited with the Cambridge
Crystallographic Data Centre, CCDC Nos. 259178 and 259179.
These data can be obtained online (http://www.ccdc.cam.ac.uk) free
of charge (or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, U.K.; fax: (+44) 1223-
336-033; e-mail: deposit@ccdc.cam.ac.uk).
+12.6 (c ) 0.5 in CHCl3); IR (CHCl3) 3446, 2939, 2838, 1606,
1490, 1153, 836 cm-1; H NMR (400 MHz, CDCl3) δ 2.35 (d, J
1
) 10.8 Hz, 1H), 3.63 (d, J ) 12.8 Hz, 1 H), 3.74 (s, 3H), 3.85 (s,
3H), 3.96 (dd, J ) 3.2, 12.4 Hz, 1H), 4.34 (m, 1H), 4.43 (d, J )
13.6 Hz, 1H), 4.57 (d, J ) 13.6 Hz, 1H), 5.31 (d, J ) 5.6 Hz, 1H),
6.41 (d, J ) 2.4 Hz, 1H), 6.49 (d, J ) 2.4 Hz, 1H), 6.94 (d, J )
8.8 Hz, 2H), 7.24 (d, J ) 8.4 Hz, 2H); 13C NMR (100 MHz) δ
45.7, 55.3, 56.0, 71.5, 73.2, 75.9, 98.3, 106.1, 116.9, 128.7, 129.1,
132.0, 138.5, 142.1, 159.7, 160.5; MS (CI, NH3) m/z 352 (M +
NH4)+, 335 (M)+, 317 (M - H2O)+. Anal. Calcd for C18H19ClO4:
C, 64.57; H, 5.72. Found: C, 64.31; H, 5.74. ee 80% (HPLC:
JO052208E
1544 J. Org. Chem., Vol. 71, No. 4, 2006