A New System for Catalytic Asymmetric Epoxidation Using Iminium Salt Catalysts

Full text of DOI:10.1021/jo972289h

2
774
J . Org. Chem. 1998, 63, 2774-2777
A New System for Ca ta lytic Asym m etr ic
Sch em e 1
Ep oxid a tion Usin g Im in iu m Sa lt Ca ta lysts
Philip C. Bulman Page,*,† Gerasimos A. Rassias,†
‡
§
Donald Bethell, and Mark B. Schilling
Department of Chemistry, Loughborough University,
Loughborough, Leicestershire LE11 3TU, England,
Department of Chemistry, University of Liverpool,
Oxford Street, Liverpool L69 3BX, England, and
GlaxoWellcome Research & Development Ltd,
Gunnels Wood Road, Stevenage,
derived from a dihydroisiquinoline, are electrophilic
oxygen-transfer reagents, effective for sulfide and alkene
oxidation 8 in a novel iminium ion analogue of the nitrile-
9
mediated Payne epoxidation procedure. It was further
established that these oxidation reactions may be carried
Hertfordshire SG1 2NY, England
10
out catalytically using “Caroate” (Oxone) as oxidant. In
this remarkably simple process, addition of Oxone to an
iminium ion of the correct properties under the correct
pH conditions produces a highly reactive oxidative in-
Received December 18, 1997
Enantiomerically pure or optically enriched chiral
epoxides are widely used synthons of high versatility and
are now among the most important intermediates for
asymmetric carbon-carbon bond formation.1 As a result,
systems for asymmetric epoxidation remain of prime
importance in organic chemistry. The most successful,
even ubiquitous, techniques currently available include
the Sharpless procedure, limited to allylic alcohol epoxi-
termediate, presumed to be an oxaziridinium ion, which
is able to transfer oxygen to alkene substrates with
regeneration of the iminium species under the reaction
conditions, giving overall a catalytic process. A variety
of alkene structural types proved successful substrates.
More recently, Hanquet and Lusinchi have shown that
a related enantiomerically pure oxaziridinium salt 2,
prepared in five steps from norephedrine, may be used
to achieve catalytic asymmetric epoxidation of alkenes
2
dation, and the J acobsen procedure, most successful for
cyclic cis-alkene, particularly arylalkene, substrates.3
More recently, chiral dioxiranes effective for asymmetric
epoxidation have been reported, although the scope and
4
generality of these systems has yet to be established.
5
The oxaziridine reagents of Davis, and related proce-
dures, are highly successful for sulfur oxidation, but are
6
not widely applicable to epoxidation. A more general
process for the enantioselective epoxidation of simple
alkenes remains a tantalizing and unsolved problem.
Recent reports of the use of imine derivatives as epoxi-
dation catalysts prompt us to describe our own results
in this area (Scheme 1).
1
1
by Oxone, for example of trans-stilbene with 33% ee.
Aggarwal has since reported a C2 symmetric system
derived from BINAP which provides up to 71% ee, in the
epoxidation of 1-phenylcyclohexene, and 31% ee with
trans-stilbene as substrate.12 Very recently, Armstrong
has shown that even acyclic iminium slats can catalyze
epoxidation by Oxone.13
The existence of oxaziridinium salts as reactive inter-
mediates was first shown in 1976.7 It was not until
a
1
987, however, that Hanquet and Lusinchi reported the
We now show that iminium salts 3, also formally
derived from a dihydroisoquinoline and a primary amine,
but chiral at the exocyclic nitrogen substituent, may be
used to achieve catalytic asymmetric epoxidation of
alkenes by Oxone (Scheme 1). We have thus far achieved
ees of up to 73% and good yields in very clean reactions
carried out at 0 °C or at room temperature over ca. 45
min in the presence of as little as 0.3 mol % of catalyst.
generation of an oxaziridinium salt for only the second
time.7b They subsequently showed that such salts 1,
†
Loughborough University; pcbpage@lboro.ac.uk.
University of Liverpool.
GlaxoWellcome.
‡
§
(1) Sharpless, K. B. Aldrichimica Acta 1983, 16, 67. Gorzynski
Smith, J . Synthesis l984, 629; Behrens C. H.; Katsuki, T. Coord. Chem.
Rev. 1995, 140, 189.
(
2) Katsuki T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102, 5974.
Pfenninger, A. Synthesis 1986, 89.
3) Chang, S. B.; Galvin, J . M.; J acobsen, E. N. J . Am.. Chem.. Soc.
994, 116, 6937.
4) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J .-H.;
(
(8) Hanquet, G.; Lusinchi, X.; Milliet, P. Tetrahedron Lett. 1988,
29, 3941.
1
(
(9) Payne, G. B.; Deming, P. H.; Williams, P. H. J . Org. Chem. 1961,
26, 659. Payne, G. B. Tetrahedron 1962, 18, 763. Bach, R. D.; Knight,
J . W. Org. Synth. 1981, 60, 63. Gagnieu, C. H.; Grouiller, A. V. J . Chem.
Soc., Perkin Trans. 1 1982, 1009. Arias, L. A.; Adkins, S.; Nagel, J .;
Bach, R. D. J . Org. Chem. 1983, 48, 888. Page, P. C. B.; Graham, A.
E.; Bethell, D.; Park, B. K. Synth. Commun. 1993, 1507.
(10) Hanquet, G.; Lusinchi, X.; Milliet, P. C. R. Acad. Sci. Paris
1991, 313, S11, 625. Lusinchi, X.; Hanquet, G. Tetrahedron 1997, 53,
13727.
Cheung, K.-K. J . Am. Chem. Soc. 1996, 118, 491. Tu, Y.; Wang, Z.-X.;
Shi, Y. J . Am. Chem. Soc. 1996, 118, 9806. Yang, D.; Wang, X. C.;
Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J . Am. Chem. Soc. 1996, 118,
1
2
1311. Wang, Z.-X.; Tu, Y.; Frohn, M.; Shi, Y. J . Org. Chem. 1997, 62,
328.
(
5) Davis, F. A.; Reddy, R. T.; Han, W.; Reddy, R. E. Pure Appl.
Chem. 1993, 65, 633.
6) Page, P. C. B.; Heer, J . P.; Bethell, D.; Collington, E. W.;
(
Andrews, D. M. Tetrahedron: Asymmetry 1995, 6, 2911. Page, P. C.
B.; Heer, J . P.; Bethell, D.; Collington, E. W.; Andrews, D. M. Synlett
(11) Boh e´ , L.; Hanquet, G.; Lusinchi, M.; Lusinchi, X. Tetrahedron
Lett. 1993, 34, 7271.
(12) Aggarwal, V. K.; Wang, M. F. J . Chem. Soc., Chem. Commun.
1996, 191.
(13) Armstrong, A.; Ahmed, G.; Garnett, I.; Goacolou, K. Synlett
1997, 1075.
1
995, 773.
7) (a) Milliet, P.; Picot, A.; Lusinchi, X. Tetrahedron Lett., 1976,
573. Ibid. 1577. (b) Hanquet, G.; Lusinchi, X.; Milliet, P. Tetrahedron
(
1
Lett. 1987, 28, 6061.
S0022-3263(97)02289-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/25/1998

Notes
J . Org. Chem., Vol. 63, No. 8, 1998 2775
Sch em e 2
The iminium salts used have the advantages that they
are extremely easy to prepare on any scale (Scheme 2)
and that the structural variation available is large
because the chirality is resident in the amine component.
Treatment of isochroman with bromine in carbon tetra-
chloride under reflux for 1 h followed by exposure to
concentrated hydrobromic acid provides 2-(2-bromoethyl)-
benzaldehyde.14 Primary amines condense smoothly and
rapidly with this material at 0 °C to furnish the corre-
sponding dihydroisoquinolinium bromides. These or-
ganic salts are oils, and the consequent difficulties
encountered on attempted purification by conventional
methods dictated a change of counterion. Addition of
sodium tetraphenylborate to the condensation reaction
mixture induces formation of the corresponding tetraphe-
nylborate salts, which are precipitated in remarkably
clean form from the reaction mixture as crystalline solids.
Overall yields of catalyst are generally between 30 and
forms, as both enantiomers of the parent amine are
commercially available. Although selectivities do not
generally vary greatly with temperature, the optimum
for reaction rate appears to be ca. 0 °C. A selection of
the results obtained at this temperature is shown in
Table 1.
6
5%, limited in part as a consequence of a side reaction,
elimination of hydrogen bromide from the bromoethyl
moiety of the precursor. No chromatography is necessary
at any point in this sequence.
Very hindered amines give inferior conversions, typi-
cally of the order of 25-30%, presumably due to an
increased tendency to act as bases rather than nucleo-
philes, as evidenced by the increased proportion of
The effectiveness and selectivity of the process is no
doubt governed by a number of factors, including the
structures of the catalyst and substrate, the concentra-
tion, the catalyst loading, the solvent used, and the
temperature. The structural features of the catalyst
which determine the pattern of enantioselectivity in our
system however remain unclear; both bornyl 3h and
menthyl 3d systems gave disappointing ees, despite the
popularity and selectivity of enantioselective catalysts
and chiral auxiliaries based upon these terpenes. The
process is more selective than the Hanquet system
presumably because the center of asymmetry is nearer
to the reacting center, although the myrtanyl derivative
2
-vinylbenzaldehyde and derived imine observed. Nev-
ertheless, the small quantities required to catalyze the
epoxidation reaction and the lack of any necessary
purification more than compensate for reduced yields and
the cost of some of the chiral amines screened. Typically,
for the epoxidation of 1-phenyl 1-cyclohexene on a 420
mg scale, less than 8 mg of most catalysts were used for
ca. 70% isolated yields of epoxide within a 1 h reaction
time. The fact that quantitative conversions can be
accomplished within 1 h using only 0.3 mol % of the
catalyst is unprecedented for iminium salts involved in
such a reaction. Overall, the synthesis of the catalyst
and the asymmetric oxidation together takes no longer
than 6 h.
3
f, which has its asymmetric centers relatively remote
from the reaction site, is more selective than the isobornyl
system 3i. It is clear from the cases examined that
increased steric hindrance near the reaction site is
important, but is evidently not the only factor which
governs enantioselectivity. For example, the fenchyl
derivative 3g, which is the most sterically demanding,
gave the best enantioselectivity in acetonitrile-water (1:
Typical oxidation conditions, with Oxone (2 equiv) as
oxidant, acetonitrile-water (1:2 or 1:1) as solvent, sodium
carbonate (4 equiv) as base, and 0.3-5 mol % of dihy-
droisoquinolinium salt, were used to investigate the
catalytic asymmetric epoxidation of 1-phenylcyclohexene
2
), albeit at the expense of the rate of the process. The
N-isopinocampheyl salt 3e, however, which has consider-
ably less steric requirements, is almost as selective, but
is significantly more selective than the bornyl, menthyl,
and steroidal systems 3h , 3d , and 3j, which are all of
similar or higher steric demand. Furthermore, the rate
of conversion is similar for these four systems. While it
is as yet difficult to draw firm conclusions about the
effects of alkene structure upon enantioselectivity, our
results so far appear to suggest that the system is most
effective with disubstituted substrates, thus neatly comple-
menting currently available procedures, which commonly
4
. One of the more selective catalysts, the N-isopinocam-
pheyl 3e derivative, was also used in the catalytic
asymmetric epoxidation of a range of alkenes 5-7, giving
up to 73% ee for trans-stilbene as substrate. Complete
retention of double bond stereochemistry is observed.
This catalyst is readily accessible in both enantiomeric
(14) Rieche, A.; Schmitz, A. Chem. Ber. 1956, 89, 1257.

2
776 J . Org. Chem., Vol. 63, No. 8, 1998
Notes
Ta ble 1. Ca ta lytic Asym m etr ic Ep oxid a tion
Hz), 10.14 (1 H, s); δ
C
(250 MHz) 33.17, 36.70, 128.10, 132.51,
1
34.14, 134.33, 134.88, 140.95, 193.33.
Typ ica l P r oced u r e for th e Syn th esis of Tetr a h yd r oiso-
qu in olin iu m Sa lts. A flask containing neat bromoaldehyde
1.1 equiv, or 1.6 equiv if crude) is cooled by means of an ice
bath. The appropriate amine (1.0 equiv) is dissolved in ethanol
15 mL/g of amine) and the solution added dropwise with
catalyst
major
catalyst alkene loading/mol % yield/% ee/%§ enantiomer
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
e
e
e
e
e
f
4
4
4
4
4
4
5
6
6
7
4
4
4
4
4
5
5
1
0.5
0.5
5
5
5
54
70
39
63
68
68
73
75
78
72
66
45
60
58
47
0
0
(+)-(R,R)
(+)-(R,R)
(-)-(S,S)
(+)-(R,R)
(+)-(R,R)
(+)-(R,R)
(-)
(+)-(R,R)
(+)-(R,R)
(+)-(R,R)
(-)-(S,S)
(+)-(R,R)
(+)-(R,R)
(+)-(R,R)
(-)-(S,S)
(
25
19
27
40
63
68
73
15
12
32
18
8
(
vigorous stirring to the cooled bromoaldehyde. After the addition
is complete, stirring is continued for 1 h; then the cooling bath
is removed, and the reaction mixture is stirred for a further 1 h
while attaining ambient temperature (Somewhat increased
yields are obtained if the reaction mixture is left to stand
overnight, particularly with hindered amines). Sodium tet-
raphenyl borate (1 equiv) is added to the reaction mixture in
acetonitrile solution (precipitation of sodium bromide may occur).
After 5 min, the solvents are removed in a rotary evaporator,
and the solid or viscous oil obtained is macerated in hot ethanol,
causing the organic salt to precipitate. The salt is isolated by
suction filtration, washed with ethanol/water (1:1) to remove
sodium bromide, with ethanol to remove water, and finally with
diethyl ether. The product thus obtained is of high purity and
may be recrystallized from ethanol/acetonitrile (90-95/10-5) if
required (crystallinity depends on parent amine).
b
b
b
b
b
‡
10
5
0.5
0.5
0.5
0.5
0.5
g
h
i
j
14
a
Determined by HPLC (Chiralcel OJ ) and/or 1H NMR spec-
b
troscopy in the presence of Eu((-)-hfc)3. Acetonitrile-water 1:1
c
used as solvent. Recrystallized to 95% ee in one recrystallization.
exhibit highest enantioselectivities in epoxidation of
trisubstituted alkenes.
(S)-(-)-r-Meth ylben zyla m in e d er iva tive: 42% yield, mp
2
0
1
1
2
68-169 °C. [R]
D
-9.42°, c ) 1.57, (CH
(400 MHz, CD
.99 (2 H, t, J 7.63 Hz), 3.65-3.71 (2 H, m), 5.24 (1 H, q, J 6.81
3
CN); νmax (Nujol) 1647,
605, 1572 cm 1; δ
-
CN) 1.82 (3 H, d, J 6.90 Hz),
H
3
Con clu sion
Hz), 6.82 (4 H, t, J 7.22 Hz), 6.97 (8 H, t, J 7.43 Hz), 7.25-7.29
8 H, m), 7.37 (1 H, d, J 7.62 Hz), 7.45 (5 H, m), 7.54 (1 H, t, J
7.61 Hz), 7.75 (1 H, t, J 7.59 Hz), 7.83 (1 H, d, J 7.59 Hz), 8.97
1 H, s); δ (400 MHz, CD CN) 17.61, 24.57, 46.96, 68.86, 117.00,
21.44, 124.34, 125.30, 127.22, 127.96, 128.10, 129.05, 129.29,
30.83, 133.77, 135.37, 136.73, 138.01, 164.57.
(
We have developed a new catalytic procedure for
asymmetric epoxidation, applicable to unfunctionalized
alkene substrates. We would emphasize the extreme
simplicity of the procedure described, the ease of prepa-
ration of a wide range of catalysts without need for
chromatography, the absence of any sensitive materials,
and the retention of double bond stereochemistry. The
procedure requires no close monitoring, and provides
remarkably clean reactions in an inexpensive, simple,
and rapid process using minimal quantities of catalyst.
Further development by modification of catalyst struc-
ture and extension to functionalized alkene substrates
is in progress.
(
1
1
C
3
(
R)-(+)-Cycloh exyleth yla m in e d er iva tive: 58% yield, mp
20
1
1
78-180 °C. [R]
D
+22.53°, c ) 1.26 (CH
3
CN); νmax (Nujol) 1641,
603, 1573 cm-1; δ
H
(400 MHz, CD CN) 1.00-1.04 (1 H, m),
3
1.18-1.27 (3 H, m), 1.44 (3 H, d, J 2.71 Hz), 1.60-1.79 (6 H,
m), 1.92-1.94 (1 H, m), 3.16 (2 H, t, J 7.88 Hz), 3.83-3.87 (3 H,
m), 6.83 (4 H, t, J 7.2 Hz), 6.98 (8 H, t, J 7.42 Hz), 7.25-7.29 (8
H, m), 7.44 (1 H, d, J 7.62 Hz), 7.51 (1 H, t, J 7.64 Hz), 7.74-
.79 (2 H, m), 8.67 (1 H, s); δ (400 MHz) 14.71, 24.41, 24.96,
C
5.17, 25.24, 27.89, 29.33, 39.55, 45.24, 45.41, 72.60, 117.00,
21.48, 124.21, 125.33, 128.00, 128.12, 133.48, 135.44, 136.96,
7
2
1
137.93, 165.15.
(
+)-Isobor n yla m in e d er iva tive: 17% yield, mp 196-197
20
°
1
1
(
(
C. [R]
D
-
+6.88°, c ) 1.22 (CH
3
CN); νmax (Nujol) 1649, 1601,
Exp er im en ta l Section
1
572 cm ; δ (CD CN, 400 MHz) 0.84 (3 H, s), 0.89 (3 H, s),
H 3
.12 (3 H, s), 1.25-1.31 (1 H, m), 1.36-1.40 (1 H, m), 1.67-1.72
2
-(2-Br om oeth yl)ben za ld eh yd e. Bromine (60 g, 0.37 mol)
1 H, m), 1.85-1.91 (2 H, m), 1.97 (1 H, t, 4.34 Hz), 2.39-2.48
is added through a reflux condenser over a period of 5 min with
stirring to an ice cooled solution of isochroman (50 g, 0.37 mol)
in carbon tetrachloride (200 mL). After the vigorous reaction
subsides, (ca. 5 min), the cooling bath is removed and the dark
brown solution heated under reflux until the reaction mixture
becomes pale yellow (indicative of complete consumption of
bromine; ca. 1 h). The solution is then allowed to reach ambient
temperature, and the solvent is removed under reduced pres-
sure. To the yellow oil obtained (1-bromoisochroman), 75 mL
of 48% aqueous hydrobromic acid is added and the reaction
mixture is brought to reflux (dark green-blue). After ap-
proximately 10-15 min the solution is allowed to cool and
extracted with diethyl ether (4 × 50 mL) (Care: The solution
must be at room temperature or below prior to extraction with
ether; first ether extract may be the lower layer as it is very
concentrated with organic material). The organic extracts are
washed with water (2 × 30 mL) and then with dilute sodium
bicarbonate solution and dried over magnesium sulfate. Evapo-
ration of the solvent under reduced pressure furnishes 67.5 g
1 H, m), 3.06-3.14 (2 H, m), 3.81-3.87 (1 H, m), 3.89-3.95 (2
H, m), 6.82 (4 H, t, J 7.17 Hz), 6.98 (8 H, t, J 7.44 Hz), 7.25-
7
7
(
.29 (8 H, m) 7.41 (1 H, d, J 7.56 Hz), 7.50 (1 H, t, J 7.60 Hz),
.75 (1 H, t, J 7.62 Hz), 7.81 (1 H, d, J 7.59 Hz), 8.81 (1 H, s); δ
CN, 400 MHz) 11.92, 19.09, 19.92, 24.52, 25.84, 33.19, 36.95,
C
CD
3
4
1
4.39, 47.99, 50.92, 52.00, 77.91, 116.99, 121.44, 124.64, 125.31,
27.89, 128.07, 133.71, 135.38, 135.45, 137.91, 164.20.
(
-)-Bor n yla m in e d er iva tive: 26% yield, mp 198-200 °C.
D
2
0
[
R]
-33.20°, c ) 1.53 (CH
3
CN); νmax (Nujol) 1645, 1600, 1575
cm-1; δ
(CD CN, 400 MHz) 0.96 (3 H, s), 0.98 (3 H, s), 1.00 (3
H
3
H, s), 1.22-1.28 (1 H, m), 1.47-1.51 (2 H, m), 1.65-1.70 (1 H,
m), 1.85-1.91 (2 H, m), 2.29-2.36 (1 H, m), 3.11 (2 H, t, 7.84
Hz), 3.81-3.88 (2 H, m), 4.24-4.27 (1 H, m), 6.82 (4 H, t, J 7.24
Hz), 6.97 (8 H, t, J 7.66 Hz), 7.25-7.28 (8 H, m) 7.44 (1 H, d, J
7
.60 Hz), 7.51 (1 H, t, J 7.63 Hz), 7.75 (1 H, t, J 7.59 Hz), 7.85
(1 H, d, J 7.68 Hz), 8.67 (1 H, s); δ (CD CN, 400 MHz) 13.03,
C
3
1
7
1
7.35, 18.63, 24.59, 26.32, 26.63, 31.24, 43.85, 50.11, 51.54, 51.63,
6.34, 116.99, 121.44, 124.63, 125.31, 127.90, 128.05, 133.71,
35.38, 137.19, 137.87, 164.71.
(65% yield) of crude 2-(2-bromoethyl)benzaldehyde as an orange
oil approximately 85-90% pure. Analytically pure samples may
be obtained by vacuum distillation; chromatography is not
recommended. The crude material, which does not decompose
when stored in a flask in the presence of light and air (do not
store under nitrogen), was used for subsequent reactions. νmax
(+)-F en ch yla m in e d er iva tive: 61% yield, mp 153-155 °C.
[R]2
0
D
1
3
+12.53°, c ) 1.50 (CH CN); νmax (Nujol) 1649, 1605, 1577
-
H 3
cm ; δ (CD CN, 400 MHz) 1.04 (3 H, s), 1.29 (6 H, s), 1.40-
1.93 (7 H, m), 3.15 (2 H, t, 8.07 Hz), 3.89-3.92 (2 H, m), 3.65 (1
H, s), 6.83 (4 H, t, J 7.15 Hz), 6.98 (8 H, t, J 7.45 Hz), 7.25-7.29
(8 H, m) 7.43 (1 H, d, J 7.56 Hz), 7.52 (1 H, t, J 7.62 Hz), 7.76
-
1
(
neat) 2742, 1697, 1600, 1575, 1260, 1193, 755 cm ; δ
MHz, CD CN) 3.54-3.63 (4 H, m), 7.33 (1 H, d, J 7.96 Hz), 7.48
1 H, t, J 7.50 Hz), 7.54 (1 H, t, J 7.94 Hz), 7.80 (1 H, d, J 7.56
H
(400
3
(1 H, t, J 7.62 Hz), 7.91 (1 H, d, J 7.57 Hz), 8.75 (1 H, s); δ
C
(
(CD CN, 250 MHz), 24.18, 26.00, 30.04, 30.64, 32.22, 36.44,
3

Notes
J . Org. Chem., Vol. 63, No. 8, 1998 2777
4
1
6.26, 49.95, 53.77, 54.99, 56.95, 89.18, 122.70, 127.20, 130.06,
31.03, 133.63, 133.80, 139.73, 141.57, 142.79, 143.68, 170.64.
Typ ica l Ep oxid a tion P r oced u r e. Sodium carbonate (4
equiv) in water (8 mL/g) is added in one portion to an ice-cooled
flask containing Oxone (2 equiv), and the effervescence mani-
fested is allowed to subside (3 min). The tetrahydroisoquino-
linium salt (5 or 10 mol %) is dissolved in the same volume of
acetonitrile as that of water used and added to the reaction
mixture. The alkene is dissolved in the same volume of
acetonitrile and added to the reaction mixture in one portion.
For alkenes that exist in the solid state and are insoluble in
acetonitrile, addition should be carried out using the solid, but
the appropriate volume of acetonitrile should also be added. The
reaction mixture (a suspension) is stirred for 1 h (2 h for more
substituted alkenes) and then transferred to a separating funnel
where the acetonitrile layer is collected. The aqueous phase is
diluted with water and extracted thoroughly with diethyl ether
(or dichloromethane). The combined organic extracts are washed
with brine and dried over sodium sulfate. Evaporation of the
solvents gives a brown oil from which the epoxide is obtained
by chromatography on silica gel, using 5 or 10% ethyl acetate
in light petroleum ether as eluent.
(
-)-Isop in oca m p h eyla m in e d er iva tive: 70% yield, mp
20
2
1
38-240 °C. [R]
D
-24.70°, c ) 1.36 (CH
3
CN); νmax (Nujol) 1639,
600, 1574 cm 1; δ
-
H
(CD CN, 400 MHz) 1.12 (3 H, s), 1.18 (3 H,
3
d, J 7.02 Hz), 1.33 (3 H, s), 1.95-2.00 (3 H, m), 2.12-2.15 (2 H,
m), 2.42-2.60 (2 H, m), 3.24 (2 H, t, J 7.60 Hz), 4.08 (2 H, t, J
7
7
.65 Hz), 4.54 (1 H, m), 6.86 (4 H, t, J 7.20 Hz), 7.01 (8 H, t, J
.43 Hz), 7.28-7.32 (8 H, m) 7.49 (1 H, d, J 7.50 Hz), 7.56 (1 H,
C 3
t, J 7.58 Hz), 7.80-7.84 (2 H, m), 9.09 (1 H, s); δ (CD CN, 400
MHz) 18.71, 22.15, 25.00, 26.95, 31.38, 33.06, 38.72, 39.66, 40.76,
4
1
6.73, 44.62, 89.18, 117.03, 121.46, 124.71, 125.32, 127.93,
28.12, 133.42, 135.49, 136.96, 137.89, 166.44.
(
-)-Men th yla m in e d er iva tive: 38% yield, mp 166-168 °C.
D
2
0
[
R]
-28.10°, c ) 1.71 (CH
3
CN); νmax (Nujol) 1643, 1605, 1576
cm-1; δ
H
(CD CN, 400 MHz) 0.79 (3 H, d, J 6.90 Hz), 0.94 (3 H,
3
d, J 6.81 Hz), 0.96 (3 H, d, J 6.51 Hz), 1.21-1.25 (1 H, m), 1.45-
1
2
.49 (1 H, m), 1.51-1.68 (2 H, m), 1.70-1.82 (3 H, m), 1.84-
.00 (2 H, m), 3.13 (2 H, t, J 7.94 Hz), 3.83-3.89 (3 H, m), 6.81
(
4 H, t, J 7.14 Hz), 6.98 (8 H, t, J 7.41 Hz), 7.25-7.28 (8 H, m)
1
-P h en yl-1-cycloh exen e oxid e: 68% yield; νmax (neat)
7
.42 (1 H, d, J 7.13 Hz), 7.50 (1 H, t, J 7.27 Hz), 7.74-7.77 (2 H,
m), 8.74 (1 H, s); δ (CD CN, 400 MHz) 14.30, 19.87, 20.81, 22.33,
4.56, 26.01, 31.23, 32.93, 72.97, 117.00, 121.47, 124.47, 125.31,
27.99, 128.13, 133.50, 135.44, 137.09, 138.06, 165.76.
-)-Myr ta n yla m in e d er iva tive: 75% yield, mp 173-174
3
9
(
084, 1602, 1495, 1446, 1359, 1249, 1173, 1132, 1079, 1030, 993,
C
3
-
1
H 3
74 cm ; δ (CDCl , 250 MHz) 1.22-1.35 (1 H, m), 1.53-1.64
2
1
3 H m), 1.99-2.06 (2 H, m) 2.16-2.18 (1 H, m), 2.26-2.32 (1
H, m), 3.10 (1 H, t, J 2.04 Hz), 7.28-7.44 (5 H, m); δ
C
(CDCl ,
3
(
2
0
250 MHz) 19.78, 20.09, 24.69, 28.15, 60.13, 61.84, 125.26, 127.12,
128.20, 142.80.
°
C. [R]
D
-
-10.66°, c ) 1.80 (CH
H 3
3
CN); νmax (Nujol) 1651, 1604,
1
1
1
2
6
574 cm ; δ (CD CN, 400 MHz) 1.13 (3 H, s), 1.28 (3 H, s),
1
-P h en yl-3,4-d ih yd r on a p h th a len e oxid e: 72% yield, mp
.57-1.58 (1 H, m), 1.94-2.05 (6 H, m), 2.47-2.49 (1 H, m),
.65-2.67 (1 H, m), 3.13 (2 H, t, J 7.89 Hz), 3.83-3.86 (4 H, m),
.87 (4 H, t, J 7.16 Hz), 7.02 (8 H, t, J 7.39 Hz), 7.29-7.33 (8 H,
1
9
2
04-106 °C. νmax (Nujol) 1602, 1486, 1307, 1155, 1074, 1042,
-
1
53 cm ; δ
H 3
(CDCl , 250 MHz) 2.1 (1 H, td, J 13.69, 5.76 Hz),
.49-2.60 (1 H m), 2.77 (1 H, dd, J 15.53, 5.63 Hz) 2.98-3.06 (1
m) 7.46 (1 H, d, J 7.27 Hz), 7.54 (1 H, t, J 7.33 Hz), 7.77-7.80
2 H, m), 8.68 (1 H, s); δ (CD CN, 400 MHz) 18.23, 22.05, 24.31,
4.95, 26.60, 32.25, 37.70, 37.91, 40.59, 42.89, 47.97, 65.62,
H, m), 3.71 (1 H, d, J 3.08 Hz), 7.11-7.31 (4 H, m), 7.45-7.61
5 H, m); δ (CDCl , 250 MHz) 22.14, 25.43, 60.89, 62.98, 125.95,
27.68, 127.87, 128.07, 128.18, 128.58, 129.82, 134.99, 137.45,
(
C
3
(
C
3
2
1
1
1
1
16.98, 121.46, 124.14, 125.32, 128.03, 128.05, 133.30, 135.76,
36.49, 137.90, 165.77.
38.82.
tr a n s-Stilben e oxid e: 76% yield, mp 66-67 °C.
ν
max
(
+)-(2S,3S)-3-Am in o-2-ph en ylpiper idin e der ivative: 39%
-1
(
(
(
Nujol) 1601, 1492, 1284, 1176, 1157, 1094, 1072, 1025 cm ; δ
H
2
0
yield, mp 172-174 °C (dec). [R]
D
+141.62°, c ) 1.11 (CH
3
CN);
CDCl
CDCl
3
, 400 MHz) 3.84 (2 H, s), and 7.28-7.37 (10 H m); δ
, 400 MHz) 63.28, 125.98, 128.62, 129.31, 137.60.
C
-1
ν
max (Nujol) 3320, 1634, 1603, 1576 cm ; δ (CD CN, 400 MHz)
H 3
3
1
.91-1.98 (1 H, s), 2.24-2.33 (4 H, s), 2.47 (1 H, br), 2.66-2.70
tr a n s-(r-Meth yl)stilben e oxid e: 75% yield; νmax (neat)
(
(
1 H, m), 2.88-2.97 (2 H, m), 3.24 (1 H, m), 3.39 (1 H, m), 4.10
3
061, 1602, 1495, 1449, 1381, 1279, 1157, 1118, 1065, 1027, 980
1 H, m), 4.22 (1 H, m), 4.37 (1 H, m), 6.88 (4 H, t, J 7.01 Hz),
-1
cm ; δ
H
(CDCl
3
, 400 MHz) 1.46 (3 H, s), 3.96 (1 H, s), 7.30-
(CDCl , 400 MHz) 17.14, 63.48, 67.52, 125.57,
7
.02 (8 H, t, J 7.20 Hz), 7.26-7.36 (12 H, m) 7.40-7.42 (2 H,
7
1
.46 (10 H m); δ
C
3
m), 7.49 (1 H, t, J 7.24 Hz), 7.72-7.79 (2 H, m), 9.86 (1 H, s); δ
C
26.92, 127.70, 127.93, 128.60, 129.21, 136.36, 142.75.
3
(CD CN, 400 MHz) 20.28, 26.06, 28.95, 47.37, 52.94, 63.18, 69.75,
1
1
18.66, 123.17, 125.68, 126.96, 127.41, 129.38, 129.62, 129.73,
30.33, 135.31, 137.16, 137.90, 139.44, 140.67, 169.06.
Ack n ow led gm en t. This investigation has enjoyed
the support of the Engineering & Physical Science
Research Council, Loughborough University, and Glaxo
Wellcome Research & Development.
Ster oid a l a m in e d er iva tive: 11% yield, mp 125-127 °C.
2
0
[
1
1
R]
D
3
-1.2° c ) 1.33 (CH CN); νmax (Nujol) 3420, 1644, 1605,
-
1
578 cm ; δ
H 3
(CD CN, 400 MHz) 0.74 (3 H, s), 0.79 (3 H, s),
.11-1.93 (22 H, m), 2.44 (1 H, m), 3.13 (2 H, m), 3.87-3.92 (4
Su p p or tin g In for m a tion Ava ila ble: A4 photocopies of
H, m), 6.82 (4 H, t, J 7.17 Hz), 6.98 (8 H, t, J 7.42 Hz), 7.25-
13
13
C and DEPT C NMR spectra of products; full experimental
7
7
1
3
1
1
.29 (8 H, m) 7.47 (1 H, d, J 7.32 Hz), 7.51 (1 H, t, J 7.35 Hz),
.76-7.79 (2 H, m), 8.78 (1 H, s); δ (CD CN, 400 MHz) 10.92,
detail (14 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
C
3
1.24, 20.07, 22.75, 24.13, 24.87, 28.10, 28.55, 32.02, 32.64, 35.37,
5.59, 35.84, 36.68, 38.82, 46.15, 51.34, 52.88, 53.92, 65.27, 79.72,
17.21, 121.68, 124.68, 125.46, 128.18, 128.34, 133.82, 135.64,
37.37, 138.10, 164.43.
J O972289H