The preparation of chiral salicylaldehydes based on Kagan's ether

Article abstract of DOI:10.1081/SCC-100106046

Two related routes to chiral salicylaldehydes which are derivatives of Kagan's ether have been developed. One route which is particularly simple begins with 2,6-diallylphenol. Facile conversion to a substituted benzofuran and assemblage of the basic framework of Kagan's ether is followed by an ozonolysis of the benzofuran ring to reveal the hydroxyaldehyde functionality characteristic of salicylaldehydes.

Full text of DOI:10.1081/SCC-100106046

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THE PREPARATION OF CHIRAL SALICYLALDEHYDES
BASED ON KAGAN'S ETHER
Michael Harmata a , Yanhong Wu a , Mehmet Kahraman a & Christopher J. Welch b
a Department of Chemistry , University of Missouri-Columbia , Columbia, Missouri,
65211, U.S.A.
b Merck and Co., Inc. , P.O. Box 2000 MS 80E 200, Rahway, NJ, 07065, U.S.A.
Published online: 20 Aug 2006.
To cite this article: Michael Harmata , Yanhong Wu , Mehmet Kahraman & Christopher J. Welch (2001) THE PREPARATION
OF CHIRAL SALICYLALDEHYDES BASED ON KAGAN'S ETHER, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:21, 3345-3359, DOI: 10.1081/SCC-100106046
To link to this article: http://dx.doi.org/10.1081/SCC-100106046
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SYNTHETIC COMMUNICATIONS, 31(21), 3345–3359 (2001)
THE PREPARATION OF
CHIRAL SALICYLALDEHYDES
BASED ON KAGAN’S ETHER
Michael Harmata,1, Yanhong Wu,1
*
y
Mehmet Kahraman,1 and Christopher J. Welch2,
1Department of Chemistry, University of
Missouri-Columbia, Columbia,
Missouri 65211
2Regis Technologies, Inc., 8210 Austin Avenue,
P.O. Box 519, Morton Grove, Illinois 60053
ABSTRACT
Two related routes to chiral salicylaldehydes which are
derivatives of Kagan’s ether have been developed. One route
which is particularly simple begins with 2,6-diallylphenol.
Facile conversion to a substituted benzofuran and assemblage
of the basicframework of Kagan’s ether is followed by an
ozonolysis of the benzofuran ring to reveal the hydroxyalde-
hyde functionality characteristic of salicylaldehydes.
*Corresponding author.
y Current address: Merck and Co., Inc., P.O. Box 2000 MS 80E 200, Rahway, NJ
07065.
3345
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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3346
HARMATA ET AL.
The development and application of chiral ligands which are Schiff
bases of salicylaldehydes is an important aspect of recent and current
research in the design of new catalytic, asymmetric processes.1 In general,
these ligands are prepared from a chiral amine or diamine component and
an achiral salicylaldehyde. Some attempts have been made, however, to use
chiral salicylaldehydes in the preparation of such ligands and some of these
serve well in certain catalytic processes.2 Overall, however, the amount of
attention which has been paid to the incorporation of chiral salicylaldehydes
into such ligands is limited and this represents an area of opportunity as new
ligands for known and new catalytic processes are explored.
As part of our effort to take advantage of this situation, we have begun
a program designed to explore the incorporation of chiral salicylaldehydes
into various ligands and study the potential of such ligands in various
catalytic processes. The first step in the process is the synthesis of chiral
salicylaldehydes. Motivated, at least in part, by out experience in the area,3
we have initially chosen to explore compounds which are derivatives of
Kagan’s ether. This paper describes the synthesis of two such compounds.
Our first approach was a rather straightforward one based on chem-
istry that was well-established. Anticipating formylation of a phenol as a
route to salicyclaldehyde synthesis, we targeted compound 1. Treatment of 2
with n-BuLi to effect metal-halogen exchange followed by alkylation with
2-benzyloxyphenylacetaldehyde afforded the alcohol 5 in 63% yield
(Scheme 1).3i Cyclic acetal formation to 6 could be effected with tosic acid
in rather low, but unoptimized, yield. Unfortunately, typical reaction con-
ditions to effect intramolecular Friedel–Crafts alkylation were not success-
ful. Treatment of 6 with SnCl4 in dichloromethane at ꢀ78ꢁC resulted in
decomposition and no apparent cyclization to 7. Treatment of 6 with
excess tosic acid in dichloromethane at room temperature resulted in the
elimination of water to form enol ether 8, though no attempts to further
investigate the compound or the process were made.
Rather than pursue a solution to the cyclization of 6 we chose to
modify the substrate by adding an additional electron-donating group
which should facilitate cyclization. The target thus became phenol 16
and its successful synthesis is shown in Scheme 2. O-Allylation of p-meth-
oxyphenol followed by a Claisen rearrangement afforded the phenol 11
in good yield.4 Protection of the hydroxy group and ozonolysis gave
the aldehyde 12 in 84% yield. Reaction of this aldehyde with organolithium
3 afforded alcohol 13 in 72% yield. Cyclic acetal formation and intramole-
cular Friedel–Crafts alkylation gave 15 in 85% yield. This could be depro-
tected by simple hydrogenolysis to afford 16. Interestingly, treatment of 13
with tosic acid in dichloromethane at room temperature gave only the
corresponding enol ether and no. 15, though we have been able to effect

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CHIRAL SALICYLALDEHYDES
3347
Scheme 1.
Friedel–Crafts alkylation under these conditions in other selected
systems.3b,d
The formylation of 16 turned out to be troublesome. The Reimer–
Tiemann method5 afforded only a 13% yield of 17, though this reaction
works with p-methoxyphenol to afford the corresponding salicylaldehyde in
65% yield (Scheme 3). We also tried methods involving formylation of
magnesium phenoxides and a tin-mediated approach.6 While these methods
produce the corresponding salicylaldehyde with p-methoxyphenol, they
failed to give 17 using 16 as a substrate. However, it should be noted that
these experiments were carried out with racemic 16, which possesses a low
solubility in the solvents (benzene or toluene) used in these reactions.
We eventually pursued a longer sequence for formylation as depicted
Scheme 4.2c Allylation of 16 and Claisen rearrangement gave phenol 19 in
80% yield. However, at this stage we found that rhodium catalyzed isomer-
ization was problematic, affording the desired compound 20 in only 32%

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3348
HARMATA ET AL.
Scheme 2.
yield along with the benzofuran 21 in 20% yield.7 Fortunately, a palladium
chloride catalyzed isomerization was successful and afforded 20 in 86%
yield.8 Ozonolysis then gave the aldehyde 17.
Enantiomerically-enriched 17 could be prepared as well. This simply
involved chromatographic resolution of 16 on a (3R, 4S) Whelk-O 1 column
Scheme 3.

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3349
Scheme 4.
(5% ethanol in hexane) followed by recrystallization from THF/hexane and
carrying the non-racemic material through the subsequent reaction steps.
This sequence undoubtedly could stand improvement. One approach
to that end involves ozonolysis of 2,6-diallylphenol followed by treatment
with polyphosphoric acid (Scheme 5). This afforded the benzofuran 23 in
55% yield. Reaction of this aldehyde with 3 gave the alcohol 24 in 64%
yield. Treatment of 24 with catalyticamounts of tosicacid from
ꢀ78ꢁC to
room temperature gave the Kagan’s ether derivative 25 in 86% yield. This
could be ozonized to give the salicylaldehyde 26 in 72% yield directly. We
initially anticipated the formation of the formate ester from the benzofuran
and are not certain as to the timing of the loss of this group.9 This sequence
should be generally applicable to the synthesis of salicyclaldehydes ulti-
mately derived from para-substituted phenols.
The ligand 27 was prepared from one of the enantiomers of 17 and
(R,R)-1,2-cyclohexanediamine. Preliminary results suggest that it is not
effective in the asymmetric epoxidation reaction, though more studies are
required. For example, using the manganese complex of 27 and a NaOCl
oxidant system, epoxidation of dihydronaphthalene gave product in only
20% ee while trans-stilbene afforded a low yield of racemic epoxide.10

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HARMATA ET AL.
Scheme 5.
In summary, we have developed two routes to chiral salicylaldehydes
which are derivatives of Kagan’s ether. Refining these methods, producing a
range of compounds and synthesizing and testing ligands is part of our
future work. Results will be reported in due course.
EXPERIMENTAL
All air and moisture sensitive reactions were carried out under an
atmosphere of nitrogen. All reactive liquid reagents were transfered by
syringe and were added into flask through a rubber septum. Methylene

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CHIRAL SALICYLALDEHYDES
3351
chloride was freshly distilled from CaH2 prior to use. Tetrahydrofuran was
freshly distilled from sodium and benzophenone ketyl prior to use.
Methanol was distilled over magnesium methoxide prior to use. Acetone
was dried over K2CO3 prior to distill with KMnO4.
1
Both H and 13C NMR spectra were obtained on a Bruker ARX 250
or Bruker ARX 300 spectrometer. All NMR spectra were obtained as a
solution in CDCl3 with TMS as internal standard or as a solution in
DMSO. 1H NMR chemical shifts were reported in ppm referenced to
TMS (0 ppm) or the central peak of DMSO (2.49 ppm). Multiplicities
of signals in the 1H NMR spectra were reported as follows; s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet),
1
etc. The H NMR spectra of diastereomeric mixtures were reported as fol-
lows. The resonances for individual diastereomers were reported when poss-
ible. For resonances that didn’t overlap, integrations were recorded as the
number of hydrogens corresponding to individual diastereomers. For reso-
nances that overlapped, integrations were recorded as the number of hydro-
gens corresponding to two diastereomers. For example, if a one to one
diastereomeric mixture had resonances corresponding to one proton of
each diastereomer that didn’t overlap, each was integrated as one hydrogen.
If the resonances overlapped, then the signal was integrated as two hydro-
gens. 13C NMR chemical shifts were reported in ppm referenced to the
central peak of CHCl3 (77.0 ppm) or DMSO (39.5 ppm).
Infrared spectra were obtained on a Nicolet 200XB-FTIR spectro-
meter either as a neat liquid, film using chloroform as solvent with NaCl
cells or in KBr pellets. Intensities were reported as s (strong 67–100%), m
(medium 34–66%) and w (weak 0–33%).
Melting points were obtained on a Fisher–Johns Hot Stage melting
point apparatus and were uncorrected. Combustion analyses were per-
formed by MHW laboratories, Phoenix, AZ.
Analytical Thin Layer Chromatography (TLC) was performed on
Merck silica gel plates (Merck Kieselgel 60, 0.25 mm thickness) with F254
indicator. Compounds were visualized under UV lamp or by developing in
iodine, vanillin or phosphomolybdicacid followed by heating on a hot plate
at 250–300ꢁC. Flash chromatography was performed on 230–400 mesh silica
gel (Merck Kieselgel 60) with technical grade solvents that were distilled
prior to use.
2-Methoxy-4-phenylmethoxyphenylacetaldehyde (12). Ozone was
bubbled into a solution of compound 11 (0.43 g, 1.7 mmol, 1.0 equiv.) in
dry methylene chloride (10 mL) at 0ꢁC for 30 min. The reaction was mon-
itored by TLC. Ozone was removed and nitrogen was blown above the
solution for 10 min. Triphenylphosphine (0.60 g, 2.3 mmol, 1.3 equiv.) was
added slowly into the solution. The color of the solution turned to yellow.

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3352
HARMATA ET AL.
The mixture was allowed to stir at 0ꢁC for 15 min, then at r. t. for 2 h. The
solvent was removed on a rotatory evaporator. Purification of the residue by
flash chromatography (hexanes/EtOAc 5 : 1) afford the aldehyde as colorless
1
oil (0.31 g, 84%). H NMR (CDCl3, 250 MHz) d 9.67 (t, J ¼ 2.1 Hz, 1H),
7.36–7.28 (m, 5H), 6.89–6.71 (m, 3H), 4.99 (s, 2H), 3.72 (s, 3H), 3.63 (d,
J ¼ 2.1 Hz, 2H); 13C NMR (CDCl3, 62.5 MHz) d 199.6, 153.8, 150.8, 136.9,
128.5, 127.8, 127.2, 122.6, 117.3, 113.2, 113.0, 111.8, 70.7, 55.5, 45.5; IR
(neat) 2940 (w), 2914 (w), 2848 (w), 2743 (w), 1729 (s), 1512 (s), 1223 (s),
1052 (m) cmꢀ1; Anal. Calcd for C16H16O3: C, 74.98: H, 6.29. Found: C,
74.80; H, 6.40.
2-(2,2-Dimethoxyethyl)-a-(2-phenylmethoxy-5-methoxyphenylmethyl)-
benzenemethanol (13). To a solution of bromoacetal 2 (0.47 g, 1.9 mmol,
1.0 equiv.) in dry THF (5 mL) at ꢀ78ꢁC, n-BuLi (2.48 M in hexane,
0.85 mL, 2.1 Â 10ꢀ3 mol, 1.1 equiv.) was added slowly. The mixture was
allowed to stir at ꢀ78ꢁC for 45 min. A solution of aldehyde 12 in a small
amount of THF (0.54 g, 2.1 mmol, 1.1 equiv.) was added slowly. The result-
ing mixture was allowed to stir at ꢀ78ꢁC for 1 h, then at r. t. for 1 h. The
mixture was quenched with water (10 mL) and diluted with EtOAc (10 mL).
The layers were separated, and the aqueous layer was extracted with EtOAc
(2 Â 10 mL). The combined organic layers were washed with brine
(2 Â 30 mL), dried over Na2SO4, filtered and concentrated. Purification of
the residue by flash chromatography (hexanes/EtOAc 5 : 1, 2 : 1) afforded
pure alcohol as a colorless oil (0.58 g, 72%). 1H NMR (CDCl3, 250 MHz) d
7.53–7.16 (m, 9H), 6.85–6.67 (m, 3H), 5.29 (m, 1H), 5.06 (s, 2H), 4.41 (t,
J ¼ 5.4 Hz, 1H), 3.71 (s, 3H), 3.26 (s, 3H), 3.23 (s, 3H), 3.00 (m, 5H); 13C
NMR (CDCl3, 62.5 MHz) d 154.0, 150.7, 142.8, 137.4, 134.0, 130.5, 128.6,
128.5, 127.8, 127.2, 127.2, 126.9, 126.2, 117.5, 113.1, 112.1, 105.8, 70.8, 70.3,
55.6, 54.1, 53.4, 39.4, 35.9. IR (neat) 3447 (br), 2947 (m), 2835 (m), 1506 (s),
1460 (s), 1229 (s), 1117 (s), 1052 (s) cmꢀ1; Anal. Calcd for C26H30O5: C,
73.91: H, 7.16. Found: C, 73.88; H, 7.21.
3,4-Dihydro-3-methoxy-1-(2-phenylmethoxy-5-methoxyphenylmethyl)-
1H-2-benzopyran (14). To a solution of alcohol 13 (0.60 g, 1.4 mmol, 1.0
equiv.) in 10 mL CH2Cl2 at ꢀ78ꢁC, pTsOH-H2O (24 mg, 0.13 mmol,
0.09 equiv.) was added. The resulting mixture was allowed to stir at
ꢀ78ꢁC for 5 min, and then was warmed to r. t. for 20 min. The reaction
was quenched with dry K2CO3 (0.19 g, 1.4 Â 10.3 mol, 1.0 equiv.) The mix-
ture was allowed to stir at r. t. for 5 min, filtered and concentrated on a
rotatory evaporator. Purification of the residue by flash chromatography
(hexanes/EtOAc5 : 1, 1% TEA) afforded the intermediate 14 as colorless oil
(0.53 g, 96%). 1H NMR (CDCl3, 250 MHz) d 7.46–7.28 (m, 10H), 7.19–7.05
(m, 8H), 6.99–6.70 (m, 6H), 5.17–5.00 (m, 3H), 5.05 (s, 2H), 5.04 (s, 2H),
4.66 (dd, J ¼ 4.2, 7.4 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.58–3.41 (m, 2H),

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CHIRAL SALICYLALDEHYDES
3353
3.43 (s, 3H), 3.26 (s, 3H), 3.12–2.71 (m, 6H); 13C NMR (CDCl3, 62.5 MHz)
d 153.6, 153.5, 151.1, 151.0, 137.8, 137.6, 132.5, 131.3, 129.2, 129.0, 128.7,
128.5, 127.8, 127.8, 127.4, 127.3, 126.8, 126.6, 126.2, 126.0, 124.6, 124.4,
117.6, 117.5, 112.7, 112.7, 112.2, 111.8, 99.9, 96.8, 75.8, 70.8, 70.3, 55.8,
55.7, 55.0, 37.2, 36.8, 34.9, 34.0; IR (neat) 3079 (m), 3033 (m), 3000 (m),
2940 (s), 2914 (s), 2835 (s), 1598 (m), 1512 (s), 1473 (s), 1453 (s), 1440 (s),
1387 (s), 1296 (s), 1223 (s), 1137 (s), 1058 (s), 755 (s) cmꢀ1; Anal. Calcd for
C25H26O4: C, 76.90; H, 6.71. Found: C, 76.77; H, 6.63.
5,6,11,12-Tetrahydro-4-methoxy-1-phenylmethoxy-5,11-epoxydibenzo
[a,e]cyclooctene (15). Tin tetrachloride (0.090 mL, 0.77 mmol, 1.5 equiv.) was
added to dry CH2Cl2 (3 mL) at ꢀ78ꢁC under a nitrogen atmosphere. The
resulting solution was allowed to stir at ꢀ78ꢁC for 5 min. Acetal 14 (0.20 g,
0.51 mmol, 1.0 equiv.) in dry CH2Cl2 (2 mL) was added slowly via the syr-
inge into the solution at ꢀ78ꢁC. The color of the solution turned dark green.
After 15 min, the reaction was quenched with H2O (5 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (2 Â 5 mL). The
combined organic layers were washed with brine (2 Â 15 mL), dried over
Na2SO4 and concentrated on a rotatory evaporator. Purification of the
residue by flash chromatography (hexanes/EtOAc 5 : 1) afforded the product
as white solid (0.16 g, 89%). m.p 118–120ꢁC; H NMR (CDCl3, 250 MHz)
1
d 7.37–7.29 (m, 5H), 7.10–6.97 (m, 4H), 6.60 (d, J ¼ 8.8 Hz, d, J ¼ 8.8 Hz,
2H), 5.41 (d, J ¼ 6.3 Hz, 1H), 5.30 (d, J ¼ 6.3 Hz, 1H), 4.92 (d, J ¼ 11.8 Hz, d,
J ¼ 11.8 Hz, 2H), 3.78 (s, 3H), 3.42 (dd, J ¼ 6.4, 16.6 Hz, 1H), 3.26 (dd,
J ¼ 6.4, 17.1 Hz, 1H), 2.90 (d, J ¼ 17.1 Hz, 1H), 2.91 (d, J ¼ 16.6 Hz, 1H);
13C NMR (CDCl3, 62.5 MHz) d 150.3, 149.4, 137.9, 137.5, 132.5, 129.0,
128.4, 127.7, 127.4, 127.1, 126.60, 125.7, 125.4, 122.4, 109.5, 107.1, 70.2,
68.9, 65.7, 55.4, 33.2, 31.0; IR (KBr) 2940 (m), 1486 (s), 1262 (s), 1078
(s) cmꢀ1; Anal. Calcd for C24H22O3: C, 80.42; H, 6.19. Found: C, 80.43;
H, 6.30.
5,6,11,12-Tetrahydro-4-methoxy-5,11,-epoxydibenzo[a,e]cycloocten-1-ol
(16). In a hydrogenation bottle compound 15 (0.14 g, 3.9 Â 10ꢀ4 mol, 1.0
equiv.) was placed along with EtOH (20 mL) and MeOH (20 mL), followed
by addition of 10% Pd/C (0.043 g, 4.1 Â 10ꢀ5 mol, 0.1 equiv.). The reaction
mixture was placed on hydrogenation apparatus. The hydrogenation bottle
was allowed to shake for 24 h under 40 psi of H2. The mixture was filtered
through celite and rinsed with EtOAc. The solvent was removed on a rota-
tory evaporator. Purification of the residue by flash chromatography (hex-
anes/EtOAc2 : 1) afforded the ocmpound as white solid (97 mg, 93%).
Recrystallization from hexane/THF gave 16 as a white crystalline solid.
m.p 199–200ꢁC; H NMR (DMSO, 250 MHz) d 8.58–6.97 (m, 4H), 6.58
1
(d, J ¼ 8.8 Hz, d, J ¼ 8.8 Hz, 2H), 5.24 (d, J ¼ 6.2 Hz, 1H), 5.23 (d,
J ¼ 6.1 Hz, 1H), 3.29 (dd, J ¼ 6.3, 16.5 Hz, 1H), 3.03 (dd, J ¼ 6.3, 17.0 Hz,

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3354
HARMATA ET AL.
1H), 2.79 (d, J ¼ 16.6 Hz, 1H), 2.68 (d, J ¼ 17.1 Hz, 1H); 13C NMR (DMSO,
62.5 MHz) d 148.3, 147.6, 138.0, 132.1, 128.7, 126.6, 126.3, 125.7, 125.4,
119.6, 112.3, 108.2, 67.8, 64.8, 55.5, 33.1, 30.8; IR (KBr) 3329 (m), 2947
(w), 2908 (w), 2835 (w), 1499 (s), 1269 (s), 1071 (s) cmꢀ1; Anal. Calcd for
C17H16O3: C, 76.10; H, 6.01. Found: C, 75.92; H, 5.93.
5,6,11,12-Tetrahydro-4-methoxy-1-(2-propenyloxy)-5,11-epoxydibenzo
[a,e]cyclooctene (18). To a solution of compound 16 (0.11 g, 0.41 mmol,
1.0 equiv.) in dry acetone (7 mL), allyl bromide (0.071 mL, 0.82 mmol, 2.0
equiv.) and anhydrous potassium carbonate (0.17 g, 1.2 mmol, 3.0 equiv.)
were added. The resulting mixture was refluxed under nitrogen atmosphere
for 12 h. The mixture was poured into water (8 mL) and extracted with ether
(2 Â 8 mL). The combined organic layers were washed with saturated
NaHCO3 (15 mL), brine (2 Â 15 mL), dried over Na2SO4. Filtration and
solvent removal afforded a white solid (0.12 g, 92%). m.p 102–104ꢁC;
1H NMR (CDCl3, 250 MHz) d 7.10–6.97 (m, 4H), 6.57 (s, 2H), 6.07–5.92
(m, 1H), 5.41–5.19 (m, 4H), 4.46–4.33 (m, 2H), 3.79 (s, 3H), 3.42 (dd,
J ¼ 6.4, 16.6 Hz, 1H), 3.23 (dd, J ¼ 6.4, 17.1 Hz, 1H); 2.91 (d, J ¼ 16.6 Hz,
1H), 2.86 (d, J ¼ 17.1 Hz, 1H); 13C NMR (CDCl3, 62.5 MHz) d 150.2, 149.3,
137.9, 133.7, 132.5, 129.0, 127.3, 126.6, 125.6, 125.4, 122.3, 116.9, 109.4,
107.1, 69.1, 68.9, 65.7, 55.4, 33.3, 30.9; IR (KBr) 3085 (w), 3026 (w), 2934
(w), 2842 (w), 1657 (w), 1611 (w), 1486 (s), 1460 (m), 1335 (w), 1275 (s),
1078 (s) cmꢀ1; Anal. Calcd for C20H20O3: C, 77.90; H, 6.54, Found:
C, 77.77; H, 6.72.
5,6,11,12-Tetrahydro-4-methoxy-2-(2-propenyl)-5,11-epoxydibenzo[a,e]
cycloocten-1-ol (19). A solution of compound 18 (54 mg, 0.17 mmol)
in N,N-dimethylaniline (3 mL) was heated under reflux for 2 h. The mixture
was diluted with EtOAc(8 mL) and washed with 10% HCl (8 mL) to remove
the N,N-dimethylaniline. The organiclayer was washed with bring
(2 Â 8 mL), dried over Na2SO4, and concentrated on a rotatory evaporator.
Purification of the residue by flash chromatography on silica gel (hexanes/
EtOAc5 : 1) afforded the produtc as white solid (47 mg, 87%). mp
144–145ꢁC; H NMR (CDCl3, 250 MHz) d 7.35 (s, 1H), 7.13–6.96 (m, 4H),
1
6.41 (s, 1H), 5.99–5.83 (m, 1H), 5.39 (d, 6.2 Hz, 1H), 5.30 (d, 6.3 Hz, 1H),
5.16–5.08 (m, 2H), 3.77 (s, 3H), 3.40 (dd, J ¼ 6.3, 16.6 Hz, 1H), 3.28 (d,
J ¼ 6.4 Hz, 2H), 3.21 (dd, J ¼ 6.4, 16.6 Hz, 1H), 2.89 (d, J ¼ 16.6 Hz, 1H),
2.75 (d, J ¼ 16.5 Hz, 1H); 13C NMR (CDCl3, 62.5 MHz) d 148.6, 145.0,
137.2, 135.8, 132.0, 128.6, 127.8, 126.2, 125.2, 124.8, 122.3 ,120.0, 116.2,
108.7, 68.3, 65.2, 54.9, 35.3, 32.8, 30.2; IR (film) 3414 (br), 3085 (w), 3013 (w),
2940 (w), 2901 (w), 2848 (w), 1651 (w), 1618 (w), 1490 (m), 1473 (m), 1433
(m), 1348 (m), 1262 (m), 1223 (m), 1078 (s), 762 (s) cmꢀ1; Anal. Calcd for
C20H20O3: C, 77.90; H, 6.54. Found: C, 77.72; H, 6.34.

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3355
(E)-5,6,11,12-Tetrahydro-4-Methoxy-2-(1-propenyl)-5,11-epoxydibenzo
[a,e]cycloocten-1-ol (20). A solution of CH2Cl2 (5 mL) containing compound
19 (35 mg, 52 mmol, 0.11 mmol) and PdCl2(CH3CN)2 (1.5 mg,
5.8 Â 10ꢀ3 mmol) was heated under reflux for 4 h. The solution turned
deep red. After the solution cooled down, the mixture was filtered through
celite and concentrated on a rotatory evaporator. Purification of the residue
by flash chromatography on silica gel (hexanes/EtOAc 4 : 1) afforded the
product as white solid (30 mg, 86%). mp 190–192ꢁC; H NMR (CDCl3,
1
300 MHz) d 7.35–6.98 (m, 4H), 6.57 (s, 1H), 6.44 (dd, J ¼ 15.8, 1.6 Hz,
1H), 6.12–6.00 (m, 1H), 5.38 (d, J ¼ 6.2 Hz, 1H), 5.32 (d, J ¼ 6.2 Hz, 1H),
4.54 (s, 1H), 3.80 (s, 1H), 3.41 (dd, J ¼ 6.3, 16.6 Hz, 1H), 3.22 (dd, J ¼ 6.4,
16.4 Hz, 1H); 2.90 (d, J ¼ 16.6 Hz, 1H), 2.75 (d, J ¼ 16.1 Hz, 1H), 1.87
(dd, J ¼ 6.6, 1.6 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 149.0, 143.8,
137.5, 132.4, 128.3, 128.2, 126.5, 125.9, 125.6, 125.5, 125.2, 122.6, 120.07,
105.8, 68.7, 65.7, 55.3, 33.2, 30.7, 18.7; IR (KBr) 3289 (br), 3033 (w), 2993 (w),
2940 (w), 2901 (w), 2835 (w), 1618 (w), 1466 (m), 1321 (m), 1229 (s),
1078 (s) cmꢀ1; Anal. Calcd for C20H20O3: C, 77.90; H, 6.54. Found: C,
77.74; H, 6.45.
5,6,11,12-Tetrahydro-1-hydroxy-4-methoxy-5,11,-epoxydibenzo[a,e]cycl
ooctene-2-carboxaldehyde (17). Ozone was bubbled into a solution of
compound 20 (25 mg, 0.081 mmol, 1.0 equiv.) in CH2Cl2 (5 mL) at ꢀ78ꢁC
for 5 min. The reaction was monitored by TLC. Ozone was removed and
nitrogen was blown above the solution for 10 min. Tripenhylphosphine
(27 mg, 0.103 mmol, 1.27 equiv.) was added into the solution at ꢀ78ꢁC
The resulting mixture was allowed to stir at ꢀ78ꢁC for 15 min, then at
room temperature for 1 h. The solution turned orange. The solvent was
removed on a rotatory evaporator. Purification of the residue by flash chro-
matography (hexanes/EtOAc4:1) afforded the aldehyde as yellow solid
which was recrystallized from CH2Cl2 to give yellow needles (18 mg,
64%), m.p 161–162ꢁC; H NMR (CDCl3, 250 MHz) d 10.97 (s, 1H), 9.74
1
(s, 1H), 7.15–6.97 (m, 4H), 6.74 (s, 1H), 5.42 (d, J ¼ 6.6 Hz, 1H), 5.35 (d,
J ¼ 6.3 Hz, 1H), 3.85 (s, 3H), 3.46 (dd, J ¼ 6.6, 16.7 Hz, 1H), 2.88 (d,
J ¼ 17.1 Hz, 1H); 13C NMR (CDCl3, 62.5 MHz) d 195.7, 154.4, 148.4,
137.2, 137.0, 131.8, 128.9, 126.9, 126.1, 125.4, 122.6, 117.6, 109.2, 68.6,
66.0, 55.6, 32.9, 30.1; IR (KBr) 3450 (br), 2954 (w), 2908 (w), 2842 (w),
1651 (s), 1479 (s), 1335 (s), 1078 (s) cmꢀ1; Anal. Calcd for C18H16O4: C,
72.96; H, 5.44. Found: C, 73.02; H, 5.54.
7-Benzofuranylacetaldehyde (23). A 250 mL flask equipped with a mag-
neticstir bar was charged with 22 (1.0 g) and dry CH2Cl2 (57 mL) to give a
ca. 0.1 M solution. After cooling to 0ꢁC in an ice bath, ozone was bubbled
through the solution until TLC indicated that no starting material remained
(ca. 30 min.). Oxygen was then bubbled through the solution for a few

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3356
HARMATA ET AL.
minutes then dimethyl sulfide (2 equiv.) was added and the solution stirred
for 2 h at room temperature. The solution was diluted with ether and was
with water and brine and dried over Na2SO4 and the solvent was removed.
The crude product was dissolved in 124 mL of dry benzene to give a ca.
0.05 M solution. Polyphosphoricacid (1 g) was added and the solution was
refluxed for 25–30 min. The solution was cooled, washed with water and
bringe and the organiclayer dried over Na SO4. The solvent was removed
2
and the cruded product quickly purified by flash chromatography (hexanes/
EtOAc, 6 : 1) to afford 0.5 g (55%) of 23 as an oil. 1H NMR (CDCl3,
250 MHz) d 9.80 (t, J ¼ 2.2 Hz, 1H), 7.61 (d, J ¼ 2.2 Hz, 1H), 7.54 (dd,
J ¼ 1.2, 7.7 Hz, 1H), 7.21 (t, J ¼ 7.6 Hz, 1H), 7.10 (d(br), J ¼ 7.3 Hz, 1H),
6.77 (d, J ¼ 2.2 Hz, 1H), 3.94 (d, J ¼ 2.2 Hz, 2H); 13C NMR (CDCl3,
62.5 MHz) d 198.4, 153.6, 145.0, 127.5, 125.4, 123.1, 120.6, 115.9, 106.9,
44.6; Anal. Calcd for C10H8O2: C, 74.99; H, 5.03;. Found: C, 74.72; H, 4.92.
a-[2-(2,2-Dimethoxyethyl)phenyl]-7-benzofuranethanol (24). Bromide 2
(0.458 g) was added to a 25 mL oven dried flask equipped with a stir bar, N2
balloon, and a septum. THF (18 mL) was added to give a ca. 0.1 M solution.
The flask was cooled to ꢀ78ꢁC in a dry ice/isopropanol bath. After 10 min.,
n-BuLi (0.008 mL), 2.4 M, 1.1 eq.) was added via syringe over 5–10 min.
After 10 min, compound 23 dissolved in a small amount of was added.
The reaction mixture was allowed to stir for 1 h at ꢀ78ꢁC and for 2 h at
room temperature. The reaction was quenced with water and diluted with
EtOAc. The layers were separated and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with water and brine and
dried over Na2SO4. Flash chromatographic purification hexanes/EtOAc,
1
4 : 1) gave an oil (0.39 g, 64%). H NMR (CDCl3, 250 MHz) d 7.64–7.61
(m, 2H), 7.52–7.45 (m, 1H), 7.33–7.13 (m, 5H), 6.77 (dd, J ¼ 0.5, 2.2 Hz,
1H), 5.47–5.41 (m, 1H), 4.49 (t, J ¼ 5.6 Hz, 1H), 3.44–3.33 (m, 5H), 3.28 (s,
3H), 3.13 (dd, J ¼ 6.3, 14 Hz, 1H), 2.96 (dd, J ¼ 4.9, 14 Hz, 1H), 2.74 (d,
J ¼ 2.5 Hz, 1H); 13C NMR (CDCl3, 62.5 MHz) d 153.9, 144.6, 142.5, 134.1,
130.6, 127.4, 127.2, 127.0, 126.0, 125.5, 123.0, 122.6, 119.6, 106.8, 105.9,
69.9, 54.3, 53.4, 38.6, 36.0; Anal. Calcd for C20H22O4: C, 73.60; H, 6.79;
Found: C, 73.86; H, 6.52.
Compound 25. A 25 mL flame-dried flask equipped with a stir bar,
septum and N2 balloon was charged with compound 24 (0.44 g) and
26 mL of CH2Cl2. The flask was cooled to ꢀ78ꢁC. p-Toluene sulfonicacid
hydrate (23 mg) was added. The solution was stirred at ꢀ78ꢁC for several
minutes and then the cold bath was removed. The solution was stirred for
12 h. Approximately 1 g of anhydrous K2CO3 was added and the mixture
was stirred for 15 min. The mixture was filtered and the solvent removed.
Flash chromatographic purification afforded 25 in 86% yield. 1H NMR
(CDCl3, 250 MHz) d 7.49 (d, J ¼ 2.2 Hz, 1H), 7.35 (d, J ¼ 8 Hz, 1H),

ORDER
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CHIRAL SALICYLALDEHYDES
3357
7.12–7.01 (m, 3H), 6.96 (d, J ¼ 7.8 Hz, 2H), 6.63 (d, J ¼ 2.1 Hz, 1H), 5.40 (d,
J ¼ 6.1 Hz, 2H), 3.59 (dd, J ¼ 6.1, 16.5 Hz, 1H), 3.58 (dd, J ¼ 6.0, 16.2 Hz,
1H), 3.12 (d, J ¼ 16.5 Hz, 1H), 2.81 (d, J ¼ 16.2 Hz, 1H); 13C NMR (CDCl3,
62.5 MHz) d 153.1, 144.5, 137.7, 133.8, 131.5, 129.1, 126.9, 126.0, 125.4,
125.2, 120.0, 118.6, 115.9, 106.7, 69.3, 68.7, 36.0, 30.5; Anal. Calcd for
C18H14O2: C, 82.42, 5.38; Found: C, 82.65; H, 5.30.
5,6,11,12-Tetrahydro-1-hydroxy-5,11-epoxydibenzo[a,e]cyclooctene-2-
carboxaldehyde (26). A 50 mL oven dried flask equipped with a stir bar was
charged with compound 25 (0.3 g) and 11 mL of dry CH2Cl2. The solution
was cooled to ꢀ78ꢁC in a dry ice/isopropanol bath. Ozone was bubbled
through the solution for about 15 min and when the solution turned blue,
TLC indicated the reaction was complete. Oxygen was bubbled through the
solution for an additional hour and the 2 equivalents of dimethyl sulfide
were added and the solution was allowed to come to room temperature over
3 h. The solvent was removed and the crude product purified by flash chro-
matography (hexanes/EtOAc, 4:1). 1H NMR (CDCl3, 250 MHz) d 11.29
(s, 1H), 9.76 (s, 1H), 7.33 (d, J ¼ 8.0 Hz, 1H), 7.19–7.07 (m, 3H),
7.01–6.96 (m, 1H), 6.78 (d, J ¼ 8.0 Hz, 1H), 5.38 (d, J ¼ 6.2 Hz, 1H), 5.27
(d, J ¼ 6.3 Hz, 1H), 3.58 (dd, J ¼ 6.4, 16.4 Hz, 1H), 3.27 (dd, J ¼ 6.2, 17.0 Hz,
1H), 2.91 (d, J ¼ 17.0 Hz, 1H), 2.80 (d, J ¼ 16.3 Hz, 1H); 13C NMR (CDCl3,
62.5 MHz) d 196.0, 159.8, 147.4, 137.5, 130.9, 130.7, 128.8, 127.0, 126.3,
125.5, 121.1, 118.6, 116.7, 69.5, 69.0, 35.3, 30.1; HRMS Calcd for
C17H14O3þH: 267.1021. Found: 267.1021.
ACKNOWLEDGMENTS
This work was supported by University of Missouri Research Board
to whom we are grateful. We thank the National Science Foundation for
partial support of the NMR (PCM-8115599) facility at the University of
Missouri-Columbia and for partial funding for the purchase of a
500 MHz spectrometer (CHE-89-08304) and an X-ray diffractometer
(CHE-90-11804). We acknowledge the services of the Nebraska Center for
Mass Spectrometry. Thanks to Dr. Neville Pavri for his assistance.
REFERENCES
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HARMATA ET AL.
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Hayashida, N.; Harayama, T. Chem. Pharm. Bull. 1993, 41, 1166.

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3359
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Received in the USA December 13, 2000

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