Synthesis and configurational assignment of chiral salicylic aldehydes: Novel building blocks for asymmetric catalysis

Article abstract of DOI:10.1002/1099-0690(200208)2002:16<2800::AID-EJOC2800>3.0.CO;2-4

We report the synthesis of three novel and chiral salicylic aldehyde building blocks 6-8, each in both enantiomerically pure forms. Two of these salicylic aldehydes were prepared from (+)-camphene and each bear a [2.2.1]bicycloheptyl substituent ortho to the salicylic hydroxy group. In the third case, the chiral element at the 6-position is a (1-phenylethyl) group. The synthetic sequences consisted of ortho-alkylation of para-cresol with either camphene or styrene and subsequent ortho-formylation of the product phenols, The chromatographic separation of enantiomers was accomplished through the diastereomeric imines obtained from condensation of the racemic salicylic aldehydes with (R)-phenylglycinol. Finally, the absolute configurations of two of the salicylic aldehydes were established by X-ray crystallography. For this purpose, the (1-phenylethyl)-substituted salicylic aldehyde was condensed with L-valinamide, and the relative configuration of the resulting Schiff base diastereomer 12 was determined. In the second case, the racemic intermediate phenol rac-15 was separated by HPLC on a chiral stationary phase, ortho-brominated, and analyzed by anomalous X-ray scattering. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200208)2002:16<2800::AID-EJOC2800>3.0.CO;2-4

FULL PAPER
Synthesis and Configurational Assignment of Chiral Salicylic Aldehydes: Novel
Building Blocks for Asymmetric Catalysis
Albrecht Berkessel,*[a] Matthias R. Vennemann,[a] and Johann Lex[a]
Dedicated to Professor Dr. Dr. h.c. Waldemar Adam on the occasion of his 65th birthday
Keywords: Aldehydes / Asymmetric catalysis / Chiral auxiliaries / Electrophilic substitution / Schiff bases
We report the synthesis of three novel and chiral salicylic
aldehyde building blocks 6−8, each in both enantiomerically
pure forms. Two of these salicylic aldehydes were prepared
from (+)-camphene and each bear a [2.2.1]bicycloheptyl sub-
nol. Finally, the absolute configurations of two of the salicylic
aldehydes were established by X-ray crystallography. For
this purpose, the (1-phenylethyl)-substituted salicylic alde-
hyde was condensed with L-valinamide, and the relative con-
stituent ortho to the salicylic hydroxy group. In the third case, figuration of the resulting Schiff base diastereomer 12 was
the chiral element at the 6-position is a (1-phenylethyl)
group. The synthetic sequences consisted of ortho-alkylation
of para-cresol with either camphene or styrene and sub-
determined. In the second case, the racemic intermediate
phenol rac-15 was separated by HPLC on a chiral stationary
phase, ortho-brominated, and analyzed by anomalous X-ray
sequent ortho-formylation of the product phenols. The chro- scattering.
matographic separation of enantiomers was accomplished
through the diastereomeric imines obtained from condensa- ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
tion of the racemic salicylic aldehydes with (R)-phenylglyci- 2002)
Introduction
Chiral Schiff bases play extremely important roles as li-
gands in metal-mediated asymmetric catalysis. The most
prominent examples are the manganese-salen complexes in-
troduced by Jacobsen and Katsuki for the asymmetric
epoxidation of olefins, or their use as ligands for chiral
Lewis acids, for the enantioselective opening of meso- or
racemic epoxides, for example.[1,2] In most cases the overall
chirality of the Schiff base complexes is due to chirality in
the diamine component, such as, for example, in the case For example, the ligand 3 was shown by Bolm et al. to
of the manganese complex 1.[3] Introduction of a second induce an enantiomeric excess of 70% in the V-catalyzed
element of chirality in the form of a chiral salicylic aldehyde oxidation of thioanisole (Scheme 1).[6] We reasoned that in
gives rise to diastereomeric ligands/complexes. The troduction of a chiral salicylic aldehyde moiety might also
‘‘matched’’ diastereomer of these materials should be ex- further increase the selectivity of the chiral catalyst in this
pected to afford even better enantioselection, whereas the case. As reported earlier, we synthesized the Schiff bases 4
‘‘mismatched’’ diastereomer should perform worse.[4] This and 5, and assessed their performance as ligands in V-cata-
concept of ‘‘matched/mismatched’’ salen-ligands has been lyzed asymmetric sulfoxidations.[7] As expected, the sulfox-
exploited in particular by Katsuki et al., as exemplified by ides were indeed obtained in higher enantiomeric purities
the ruthenium complex 2.[5]
(Scheme 1). The preparation of the axially chiral, binaph-
Simple 1:1 adducts of salicylic aldehydes and chiral, am- thyl-derived building block present in 4 was first reported
ino acid-derived 1,2-amino alcohols have found use in the by Katsuki et al.[8] Here we report the synthesis of the en-
vanadium-catalyzed asymmetric sulfoxidation of thioethers. antiomerically pure chiral salicylic aldehydes 6Ϫ8, as well
as their enantiomers ent-6Ϫ8, together with the configura-
[a]
Institut für Organische Chemie der Universität zu Köln,
tional assignments of 6/ent-6 and 7/ent-7. We are confident
that chiral salicylic aldehydes of this type will prove benefi-
cial for many other catalytic asymmetric transformations.
Greinstrasse 4, 50939 Köln, Germany
Fax: (internat.) ϩ49-(0)221/470Ϫ5102
E-mail: berkessel@uni-koeln.de
2800
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0816Ϫ2800 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 2800Ϫ2807

Synthesis and Configurational Assignment of Chiral Salicylic Aldehydes
FULL PAPER
For the assignment of configuration, the aldehyde 6 was
derivatized with -valinamide, affording the crystalline
imine 12 (Scheme 3). X-ray crystallography of 12 (Figure 1)
unambiguously established the S configuration in the sali-
cylic aldehyde 6.
Scheme 3
Scheme 1
Results
Figure 1. X-ray crystal structure of the imine 12
(1-Phenylethyl)-Substituted Salicylic Aldehydes 6/ent-6
Our synthesis of the aldehydes 6 and ent-6 began with the
known acid-catalyzed ortho-alkylation of para-cresol with
styrene (Scheme 2), affording the racemic phenol rac-9 in
good yield.[9] ortho-Formylation according to Casiraghi et
Isobornyl- and Camphenyl-Substituted Aldehydes 7, 8, ent-
7, and ent-8
The first step in our synthesis of the isobornyl- or cam-
al. provided the salicylic aldehyde rac-6.[10] For the separa- phenyl-substituted salicylic aldehydes 7, ent-7, 8, and ent-8
tion of enantiomers, rac-6 was treated with (R)-phenylglyci- was the acid-catalyzed addition of (ϩ)-camphene 14 to p-
nol 10.[11] The resulting diastereomeric imines 11a and 11b cresol 13 (Scheme 4).[12] With the well known camphenyl-
were separated by preparative HPLC on silica. Acid-cata- isobornyl rearrangement in mind, we expected to obtain the
lyzed hydrolysis of the imines 11a and 11b afforded the en- racemic (2-isobornyl)cresol rac-15.[13] However, chromato-
antiomerically pure aldehydes 6 and ent-6, respectively graphic workup of our reaction mixture revealed that two
(Scheme 2).
alkylated cresols had been produced in racemic form and
Scheme 2
Eur. J. Org. Chem. 2002, 2800Ϫ2807
2801

A. Berkessel, M. R. Vennemann, J. Lex
FULL PAPER
in a 1:1 ratio: namely rac-15 and rac-16 (Scheme 4). The This proved suitable for X-ray crystallography, including
structural assignments of the product phenols were based the determination of absolute configuration by anomalous
on X-ray crystal structures determined for rac-15 and rac- X-ray scattering (Figure 2). The configuration of the (Ϫ)-
16 (Figure 2).
enantiomer 15 was established as 1S, as shown in Scheme 4.
For the preparation of the enantiomerically pure salicylic
aldehydes 7 and ent-7 on larger scales, the separation of the
enantiomers of the intermediate phenol rac-15 by preparat-
ive HPLC on chiral phase with subsequent Casiraghi for-
mylation proved tedious, and so the synthetic sequence
summarized in Scheme 5 was elaborated. Firstly, the ra-
cemic phenol rac-15 was formylated to provide the racemic
aldehyde rac-7 (71%).[10] Treatment of this racemate with
(R)-phenylglycinol (10)[11] resulted in the formation of the
diastereomeric imines 18a and 18b. These could easily be
separated by preparative HPLC on silica. Finally, acid-cata-
lyzed hydrolysis of the separated imines 18a and 18b liber-
ated the enantiomerically pure salicylic aldehydes 7 and
ent-7.
Scheme 4
Scheme 5
Formylation of the separated enantiomeric phenols 15
and ent-15 (vide supra) enabled us to assign absolute con-
figurations to the salicylic aldehydes 7 and ent-7 obtained
by hydrolysis of the imines 18a and 18b (comparison of op-
tical rotation and HPLC coinjection on Chiralcel OJ). Con-
sequently, the relative and absolute configurations of the
diastereomeric imines 18a and 18b were also established.
The analogous chromatographic separation of the race-
mate rac-8 through the diastereomeric imines derived from
treatment with (R)-phenylglycinol (10)[11] proved not to be
viable. Nevertheless, both the racemate rac-16 and the indi-
vidual phenols 16 and ent-16 (from the small-scale separa-
tion of rac-16 on Chiralcel OJ) could be converted into the
corresponding salicylic aldehydes rac-8, 8, and ent-8, re-
spectively, by Casiraghi formylation.[10] No assignment of
absolute configuration was carried out for the separated
phenols 16/ent-16 or the aldehydes 8/ent-8. Consequently,
the configurations shown for the aldehyde 8 and for the
phenol 16 in Scheme 1 and Scheme 4 have been chosen ar-
bitrarily.
Figure 2. X-ray crystal structures of the phenols rac-15, rac-16, and
ent-17 (only one enantiomer shown for rac-15/16)
The racemic mixtures rac-15 and rac-16 were separated
into their pure enantiomers by preparative HPLC on
Chiralcel OJ. For the assignment of absolute configuration,
the dextrorotatory phenol ent-15 was treated with bromine,
Discussion
The acid-catalyzed alkylation of para-cresol with styrene
affording the crystalline ortho-bromophenol ent-17 (89%). proceeded with the expected Markovnikov regioselectivity
2802
Eur. J. Org. Chem. 2002, 2800Ϫ2807

Synthesis and Configurational Assignment of Chiral Salicylic Aldehydes
and thus provided access to the chiral skeleton of the sali-
FULL PAPER
Conclusion
cylic aldehydes 6 and ent-6. Clearly, the addition product
was formed as a racemic mixture (rac-9). The analogous
addition of (ϩ)-camphene requires more detailed comment.
It has been known for decades that the generation of the 2-
camphenyl cation and subsequent trapping with nucleo-
philes usually gives rise to products with a camphenyl- or
an isobornyl skeleton. Probably the most prominent ex-
ample is the rearrangement of camphenyl chloride 19 to
isobornyl chloride 20 (Scheme 6), studied as early as the
1920s by Meerwein et al.[13] Terpene rearrangements of this
type are usually accompanied by at least partial, and in
many cases complete, racemization.[14] For the 2-camphenyl
cation, the most prominent pathway for racemization is an
exo-2,3-methyl shift.[15] By our current mechanistic under-
standing, the bridged cation 21 accounts for the product
structures observed experimentally.[16] Firstly, attack of a
nucleophile at C-2 would give rise to exo-products incorp-
orating the unrearranged (2-camphenyl) skeleton, whereas
attack at C-1 would provide access to the isobornyl vari-
ants. Clearly, a reversible 1,2-hydrogen shift between posi-
tions 6 and 1 of the bridged cation 21 would result in race-
mization as well.[15] Finally, a 1,2-H-shift from C-6 to C-2
and subsequent attack of a nucleophile at C-6 could give
rise to an exo-(5-camphenyl) product. In our case, the prod-
ucts resulting from the attack of para-cresol on C-1 (i.e.,
rac-15) and on C-6 (i.e., rac-16) were formed in equal
amounts (Scheme 4, Scheme 6). However, the (2-cam-
phenyl)-cresol 22 that would result from attack at C-2 was
not observed as a product in our experiments. It may be
argued either that the attack of the nucleophile (para-cresol)
on the ‘‘tertiary position’’ of the cation 21 was disfavored
for steric reasons, or that the charge density at this ‘‘tertiary
position’’ was too low for efficient electrophilic attack on
the aromatic substrate.
In summary, we present the synthesis of three novel chiral
salicylic aldehydes, each in both enantiomeric forms (i.e., 6,
ent-6, 7, ent-7, 8, ent-8). These aldehydes have already
proven their potential in asymmetric catalysis, namely as
building blocks for ligands used in the asymmetric sulfoxid-
ation of prochiral thioethers.[7] It is to be expected that their
incorporation into other Schiff base catalysts, originally
based on chiral amines and achiral salicylic aldehydes,
should also result in improved enantioselectivities.
Experimental Section
General: All solvents and organic substances were purified by
1
standard methods. H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded at ambient temperature in deuterated chloro-
form (CDCl3). Melting points are corrected. Analytical thin layer
chromatography was performed on 0.25 mm POLYGRAM Sil G/
UV plates (MachereyϪNagel). Column chromatography was per-
formed on 230 Ϫ 400 mesh silica gel (MachereyϪNagel).
(RS)-4-Methyl-2-(1-phenylethyl)phenol (rac-9): A solution of styr-
ene (52.0 g, 500 mmol, 1.00 equiv.) in toluene (400 mL) was added
dropwise over 2 h, at 100 °C under nitrogen, to a mixture of p-
cresol (108 g, 1.00 mol, 2.00 equiv.) and conc. sulfuric acid (10.0 g,
100 mmol, 0.20 equiv.). The mixture was heated under reflux for
5 h and allowed to cool to room temperature. Water (400 mL) was
added, and the mixture was extracted with diethyl ether. The or-
ganic layer was dried over sodium sulfate, and the solvent was evap-
orated under reduced pressure to provide the desired product
(75.4 g, 355 mol, 71%) as a colorless oil after distillation (130 °C,
0.70 mbar). Rf ϭ 0.30 (silica gel, toluene). 1H NMR (300 MHz,
CDCl3, room temp.): δ ϭ 1.69 (d, J ϭ 7.2 Hz, 3 H), 2.36 (s, 3 H),
4.42 (q, J ϭ 7.2 Hz, 1 H), 4.62 (s, br.), 1 H), 6.69 (d, J ϭ 8.1 Hz,
1 H), 6.98 (dd, J ϭ 8.1, J ϭ 2.2, 1 H), 7.12 (d, J ϭ 2.2 Hz, 1 H),
7.23Ϫ7.41 (m, 5 H) ppm. 13C{1H} NMR (75 Hz, CDCl3, room
temp.): δ ϭ 20.9, 21.1, 38.8, 116.0, 126.5, 127.6, 128.0, 128.6, 130.1,
131.9, 145.6, 151.1 ppm. IR (film): ν˜ ϭ 3535 cmϪ1, 3026, 2967,
2930, 2874, 1601, 1506, 1496, 1256, 1195, 811, 700. C15H16O
(212.29): calcd. C 84.86, H 7.60; found C 84.83, H 7.47.
(RS)-2-Hydroxy-5-methyl-3-(1-phenylethyl)benzaldehyde (rac-6):
Tin() chloride (547 mg, 2.10 mmol, 0.10 equiv.) and paraformal-
dehyde (1.46 g, 48.6 mmol, 2.20 equiv.) were added in small por-
tions at room temperature to a solution of the phenol rac-9 (4.46 g,
21.1 mmol, 1.00 equiv.) and tri-n-butylamine (1.56 g, 8.40 mmol,
0.40 equiv.) in toluene (40 mL). The mixture was heated under re-
flux for 8 h. After cooling to room temperature, the reaction mix-
ture was poured onto 100 g ice and acidified to pH 2 with 2 
hydrochloric acid. The aqueous layer was extracted with diethyl
ether (3 ϫ 50 mL). The extract was dried over sodium sulfate and
the solvent was removed under reduced pressure. Purification of
the crude product by chromatography (silica gel, dichloromethane)
afforded 3.80 g (15.8 mmol, 75%) of the aldehyde rac-6 as pale yel-
low crystals. Rf ϭ 0.55 (silica gel, toluene); m.p. 53 °C (methanol).
1H NMR (300 MHz, CDCl3, room temp.): δ ϭ 1.62 (d, J ϭ 7.3 Hz,
3 H), 2.30 (s, 3 H), 4.61 (q, J ϭ 7.2 Hz, 1 H), 7.15Ϫ7.32 (m, 7 H),
9.82 (s, 1 H), 11.19 (s, 1 H) ppm. 13C{1H} NMR (75 Hz, CDCl3,
room temp.): δ ϭ 20.6, 36.7, 120.1, 126.1, 127.7, 128.4, 128.7,
131.5, 134.9, 136.2, 145.3, 157.1. 196.7 ppm. IR (KBr pellet, cmϪ1
)
Scheme 6
3500Ϫ3100, 3085, 3060, 3026, 2968, 2932, 2840, 1654, 1618, 1602,
Eur. J. Org. Chem. 2002, 2800Ϫ2807
2803

A. Berkessel, M. R. Vennemann, J. Lex
1495, 1259, 1236, 699. C16H16O2 (240.30): calcd. C 79.96, H 6.72; The enantiomeric purities of the salicylic aldehydes 6 and ent-6
FULL PAPER
found C 79.81, H 6.82.
were established by analytical HPLC (Chiralcel OD-H; n-hexane/
2-propanol, 200:1, 1 mL/min).
[R-(R*,S*)]- and [R-(R*,R*)]-β-{[[2-Hydroxy-5-methyl-3-(1-phen-
ylethyl)phenyl]methylene]amino}phenylethanol (11a and 11b): The
aldehyde rac-6 (1.79 g, 7.45 mmol) and (R)-phenylglycinol 10
(1.02 g, 7.45 mmol) were dissolved in toluene (25 mL) under nitro-
(R)-2-Hydroxy-5-methyl-3-(1-phenylethyl)benzaldehyde
Analogously to the preparation of 6, the imine 11b (1.55 g,
(ent-6):
4.32 mmol) was hydrolyzed to provide the enantiomerically pure
aldehyde ent-6 (985 mg, 4.10 mmol, 98%). m.p. 29Ϫ30 °C. [α]D20
ϭ
˚
gen, and molecular sieves (5 A, 6.00 g) were added. The mixture
65.2, [α]578 ϭ Ϫ176.8, [α]546 ϭ Ϫ212.6, [α]436 ϭ Ϫ573.3 (c ϭ 0.90,
chloroform). C16H16O2 (240.30): calcd. C 79.96, H 6.72; found C
79.73, H 6.52.
was heated under reflux for 5 h. The molecular sieves were removed
by filtration and washed with toluene. The organic phases were
collected, and the solvent was removed under reduced pressure.
Purification of the crude product by chromatography (silica gel,
dichloromethane, 2-propanol; 50:1) afforded a mixture of the
diastereomers 11a and 11b (2.62 g, 7.29 mmol, 98%). The
diastereomers 11a and 11b were separated by preparative HPLC
(LiChrosorb Si-60; dichloromethane/2-propanol, 600:1, 80 mL/
min). Separation of 2.50 g (6.95 mmol) of the mixture afforded the
imines 11a (1.18 g, 3.29 mmol, 47%, Ͼ98% de) and 11b (1.04 g,
2.89 mmol, 42%, Ͼ98% de) as yellow oils.
[S-[R,R-(E)]]-2-{[[2-Hydroxy-5-methyl-3-(1-phenyethyl)phenyl]-
methylene]amino}-3-methylbutaneamide (12): The salicylic aldehyde
6 (195 mg, 811 µmol) was added at room temperature to a solution
of -valinamide hydrochloride (123 mg, 811 µmol) and potassium
hydroxide (45.5 mg, 811 µmol) in methanol (15 mL). Molecular
˚
sieves (4 A, 8 mg) were added and the mixture was shaken at room
temperature for 12 h. After filtration, the solvent was removed un-
der reduced pressure. The residue was taken up in chloroform (20
mL). The mixture was filtered and the solvent was removed under
reduced pressure, affording the crude imine 12 (270 mg, 798 µmol,
98%) as a yellow solid. An analytical sample was recrystallized
from chloroform/n-hexane. Rf ϭ 0.74 (silica gel, ethyl acetate); m.p.
The diastereomeric purities of the imines 11a and 11b were estab-
lished by analytical HPLC (LiChrosorb Si-60; dichloromethane/
2-propanol, 100:1, 1 mL/min).
1
160 °C (chloroform/n-hexane). H NMR (300 MHz, CDCl3, room
Imine 11a: Rf ϭ 0.25 (silica gel, dichloromethane). 1H NMR
(300 MHz, CDCl3, room temp.): δ ϭ 1.61 (d, J ϭ 7.2 Hz, 3 H),
1.83 (s, br.), 1 H), 2.26 (s, 3 H), 3.88 (ψd, J ϭ 6.6 Hz, 2 H), 4.43
(ψt, J ϭ 6.6 Hz, 1 H), 4.66 (q, J ϭ 7.2 Hz, 1 H), 6.94 (d, J ϭ
1.1 Hz, 1 H), 7.07 (d, J ϭ 1.1 Hz, 1 H), 7.15Ϫ7.41 (m, 10 H), 8.42
(s, 1 H), 13.27 (s, br.), 1 H) ppm. 13C{1H} NMR (75 Hz, CDCl3,
room temp.): δ ϭ 20.5, 20.9, 36.9, 67.6, 75.9, 118.0, 125.8, 127.1,
127.5, 127.7, 127.8, 128.2, 128.8, 129.8, 131.8, 133.9, 139.4, 146.1.
156.2, 166.6 ppm. IR (KBr pellet): ν˜ ϭ 3574 cmϪ1, 3412, 3083,
3060, 3026, 2965, 2930, 2872, 1630, 1600, 1493, 1461, 1451, 1262,
1238, 699. HRMS m/z ϭ 359.1880 (60.9%, C24H25NO2ϩ: [Mϩ],
|∆mu ϭ 0.5|).
temp.): δ ϭ 0.94 (d, J ϭ 7.0 Hz, 3 H), 1.02 (d, J ϭ 7.0 Hz, 3 H),
1.61 (d, J ϭ 7.0 Hz, 3 H), 2.28 (s, 3 H), 2.35Ϫ2.53 (m, 1 H), 3.67
(d, J ϭ 4.0 Hz, 1 H), 4.64 (q, J ϭ 7.0 Hz, 1 H), 5.47 (s, br.), 1 H),
6.01 (s, br.), 1 H), 6.95Ϫ7.40 (m, 7 H), 8.26 (s, 1 H), 12.54 (s, br.),
1 H) ppm. 13C{1H} NMR (75 Hz, CDCl3, room temp.): δ ϭ 17.3,
19.6, 20.5, 21.0, 32.1, 36.8, 79.5, 117.6, 125.9, 127.7, 128.0, 128.3,
130.2, 132.4, 134.0, 145.8, 155.8, 168.1, 173.6 ppm. IR (KBr pellet):
ν˜ ϭ 3471 cmϪ1, 3230, 3100, 2963, 2870, 1694, 1662, 1628, 1591,
1458, 1368, 705. C21H26N2O2 (338.44): calcd. C 74.53, H 7.74, N
8.28; found C 74.25, H 7.73, N 8.13.
(1S-exo)- and (1R-exo)-4-Methyl-2-(1,7,7-trimethylbicyclo[2.2.1]-
hept-2-yl)phenol (rac-15) and [1S-(2exo,6exo)]- and [1R--
(2exo,6exo)]-4-Methyl-2-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)-
phenol (rac-16): (ϩ)-Camphene (14, 10.4 g, 76.5 mmol, 1.00 equiv.)
was added dropwise under nitrogen, over a period of 4 h, to a re-
fluxing solution of p-cresol (13, 16.5 g, 153 mmol, 2.00 equiv.) and
conc. sulfuric acid (1.50 g, 15.3 mmol, 0.20 equiv.) in toluene (25
mL). The mixture was heated under reflux for an additional 6 h.
After the mixture had cooled to room temperature, water (100 mL)
was added. The organic layer was extracted with diethyl ether (4 ϫ
100 mL). The extract was dried over sodium sulfate and the solvent
was removed under reduced pressure. After chromatography (silica
gel, toluene) of the crude product, followed by kugelrohr distilla-
tion (170 °C, 0.40 mbar), a mixture of the isomers rac-15 and rac-
16 (10.3 g, 42.2 mmol, 55%) was obtained (HPLC: rac-15/rac-16 ϭ
1.0:1.0). Separation of 8.50 g (34.8 mmol) of this mixture by pre-
parative HPLC (LiChrosorb Si-60, dichloromethane/2-propanol,
500:1, 80 mL/min) afforded rac-15 (4.20 g, 17.2 mmol, 49%) and
rac-16 (3.43 g, 14.5 mmol, 40%) as colorless oils, both of which
crystallized after several days. Both racemic mixtures rac-15 and
rac-16 were separated by preparative chiral HPLC (Chiralcel OJ,
heptane/2-propanol, 80:20). The separation of 2.20 g (9.00 mmol)
of rac-15 afforded 15 (1.01 g, 4.13 mmol, 46%, Ͼ99.5% ee) and ent-
15 (950 mg, 3.89 mmol, 43%, Ͼ99.5% ee). The separation of 2.12 g
(8.69 mmol) of rac-16 afforded 16 (820 mg, 3.36 mmol, 39%, 99%
ee) and ent-16 (790 mg, 3.23 mmol, 37%, Ͼ99% ee).
Imine 11b: Rf ϭ 0.23 (silica gel, dichloromethane). 1H NMR
(300 MHz, CDCl3, room temp.): δ ϭ 1.63 (d, J ϭ 7.3 Hz, 3 H),
1.71 (s, br.), 1 H), 2.24 (s, 3 H), 3.90 (ψd, J ϭ 6.6 Hz, 2 H), 4.44
(ψt, J ϭ 6.6 Hz, 1 H), 4.67 (q, J ϭ 7.3 Hz, 1 H), 6.94 (d, J ϭ
1.1 Hz, 1 H), 6.99 (d, J ϭ 1.1 Hz, 1 H), 7.15Ϫ7.21 (m, 1 H),
7.27Ϫ7.33 (m, 5 H), 7.36Ϫ7.41 (m, 4 H), 8.44 (s, 1 H), 13.26 (s,
br.), 1 H) ppm. 13C{1H} NMR (75 Hz, CDCl3, room temp.): δ ϭ
20.5, 20.7, 36.8, 67.7, 75.7, 118.0, 125.8, 127.2, 127.5, 127.7, 127.8,
128.2, 128.8,.129.8, 132.1, 134.1, 139.3, 145.8. 156.1, 166.7 ppm.
IR (KBr pellet): ν˜ ϭ 3584 cmϪ1, 3462, 3083, 3060, 3026, 2965,
2928, 2872, 1628, 1600, 1493, 1456, 1452, 1262, 1238, 699. HRMS
m/z ϭ 359.1879 (69.4%, Mϩ, C24H25NO2ϩ:[Mϩ], |∆mu ϭ 0.6|).
(S)-2-Hydroxy-5-methyl-3-(1-phenylethyl)benzaldehyde (6): Hydro-
chloric acid (5 mL, 10%) was added to a solution of the imine 11a
(3.05 g, 8.49 mmol) in methanol (15 mL). The mixture was heated
under reflux for 1 h, and the solvent was removed under reduced
pressure. The residue was diluted with 20 mL of water and ex-
tracted with dichloromethane (5 ϫ 30 mL). The organic layer was
dried over sodium sulfate, and the solvent was removed under re-
duced pressure. After chromatography (silica gel, dichloromethane)
of the crude product, followed by kugelrohr distillation (155 °C,
0.23 mbar), the enantiomerically pure aldehyde
6 (1.98 g,
8.24 mmol, 97%) was obtained as a colorless solid. m.p. 30 °C.
[α]2D0 ϭ ϩ167.1, [α]578 ϭ ϩ178.2, [α]546 ϭ ϩ214.8, [α]436 ϭ ϩ579.1
(c ϭ 0.93, chloroform). C16H16O2 (240.30): calcd. C 79.96, H 6.72; Racemate rac-15: Rf ϭ 0.45 (silica gel, toluene); m.p. 63 °C. 1H
found C 80.21, H 6.68.
NMR (300 MHz, CDCl3, room temp.): δ ϭ 0.80 (s, 3 H), 0.85 (s,
2804
Eur. J. Org. Chem. 2002, 2800Ϫ2807

Synthesis and Configurational Assignment of Chiral Salicylic Aldehydes
FULL PAPER
3 H), 0.91 (s, 3 H), 1.31Ϫ1.49 (m, 2 H), 1.56Ϫ1.69 (m, 2 H),
[α]2D0 ϭ ϩ8.6 (c ϭ 1.00, chloroform). C17H23OBr (323.27): calcd. C
1.83Ϫ1.92 (m, 2 H), 2.18Ϫ2.36 (m, 1 H), 2.37 (s, 3 H), 3.10 (ψt, 63.16, H 7.17; found C 62.89, H 7.06.
J ϭ 8.8 Hz, 1 H), 4.56 (s, 1 H), 6.66 (d, J ϭ 8.0 Hz, 1 H), 6.86 (dd,
(1RS-exo)-2-Hydroxy-5-methyl-3-(1,7,7-trimethylbicyclo[2.2.1]hept-
J ϭ 8.0, J ϭ 1.2, 1 H), 7.11 (d, J ϭ 1.2 Hz, 1 H) ppm. 13C{1H}
NMR (75 Hz, CDCl3, room temp.): δ ϭ 12.3, 20.3, 21.0, 21.5, 27.6,
33.9, 40.0, 45.5, 45.6, 48.1, 49.8, 114.8, 126.8, 128.9, 129.2, 129.3,
152.5 ppm. IR (KBr pellet): ν˜ ϭ 3314 cmϪ1, 3020, 2952, 2931,
2875, 1609, 1506, 1491, 1246, 1201, 808. C17H24O (244.37): calcd.
C 83.55, H 9.90; found C 83.38, H 9.91.
2-yl)benzaldehyde (rac-7): Tin()chloride (96.5 µL, 820 µmol,
0.10 equiv.) and paraformaldehyde (491 mg, 16.4 mmol,
2.00 equiv.) were added in small portions at room temperature to
a solution of the phenol rac-15 (2.00 g, 8.18 mmol, 1.00 equiv.) and
tri-n-butylamine (778 µL, 3.27 mmol, 0.40 equiv.) in toluene (12
mL). The mixture was heated under reflux under nitrogen for 10 h.
After cooling to room temperature, the solution was added to 200
mL of water and acidified to pH 2 with hydrochloric acid (10%).
The aqueous layer was extracted with toluene (3 ϫ 100 mL). The
extract was dried over sodium sulfate and the solvent was removed
under reduced pressure. Purification of the crude product by chro-
matography (silica gel, toluene) afforded the desired aldehyde rac-
7 (1.59 g, 5.83 mmol, 71%) as colorless crystals. Rf ϭ 0.65 (silica
gel, toluene); m.p. 103 °C (methanol). 1H NMR (300 MHz, CDCl3,
room temp.): δ ϭ 0.74 (s, 3 H), 0.82 (s, 3 H), 0.85 (s, 3 H),
1.29Ϫ1.43 (m, 1 H), 1.47Ϫ1.66 (m, 3 H), 1.79Ϫ1.92 (m, 2 H),
2.08Ϫ2.20 (m, 1 H), 2.33 (s, 3 H), 3.31 (ψt, J ϭ 9.0 Hz, 1 H), 7.15
(d, J ϭ 1.2 Hz, 1 H), 7.37 (d, J ϭ 1.2 Hz, 1 H), 9.83 (s, 1 H), 11.36
(s, 1 H) ppm. 13C{1H} NMR (75 Hz, CDCl3, room temp.): δ ϭ
12.2, 20.3, 20.7, 21.4, 27.4, 33.8, 39.6, 44.2, 45.7, 48.1, 50.0, 119.7,
127.8, 130.7, 132.6, 136.6, 159.2, 196.8 ppm. IR (KBr pellet): ν˜ ϭ
Enantiomer 15: M.p. 43 °C. [α]2D0 ϭ 59.9, [α]578 ϭ Ϫ62.6, [α]546
ϭ
Ϫ71.7, [α]436 ϭ Ϫ122.8 (c ϭ 0.45, chloroform). C17H24O (244.37):
calcd. C 83.55, H 9.90; found C 83.25, H 9.89.
The enantiomeric purities of the phenols 15 and ent-15 were estab-
lished by analytical HPLC (Chiralcel OJ; n-heptane/2-propanol,
80:20, 0.8 mL/min; or Chiralcel OD-H; n-hexane/2-propanol, 99:1,
1 mL/min).
Enantiomer ent-15: M.p. 43 °C. [α]2D0 ϭ ϩ60.5, [α]578 ϭ ϩ63.2,
[α]546 ϭ ϩ72.3, [α]436 ϭ ϩ123.7 (c ϭ 0.62, chloroform). C17H24O
(244.37): calcd. C 83.55, H 9.90; found C 83.26, H 10.04.
Racemate rac-16: Rf ϭ 0.42 (silica gel, toluene); m.p. 40 °C. 1H
NMR (300 MHz, CDCl3, room temp.): δ ϭ 0.93Ϫ0.97 (m, 6 H),
1.04 (s, 3 H), 1.32Ϫ1.43 (m, 3 H), 1.71Ϫ1.76 (m, 1 H), 1.77Ϫ1.83
(m, 1 H), 1.96Ϫ1.99 (m, 1 H), 2.21-2-32 (m, 1 H), 2.26 (s, 3 H),
2.79Ϫ2.87 (m, 1 H), 4.54 (s, 1 H), 6.67 (d, J ϭ 8.0 Hz, 1 H), 6.84
(dd, J ϭ 8.0, J ϭ 2.1, 1 H), 6.96 (d, J ϭ 2.1 Hz, 1 H) ppm. 13C{1H}
NMR (75 Hz, CDCl3, room temp.): δ ϭ 16.3, 20.8, 24.8, 27.7, 32.5,
33.5, 39.6, 40.6, 48.9, 49.8, 50.8, 115.0, 126.4, 126.8, 129.5, 132.7,
151.1 ppm. IR (KBr pellet): ν˜ ϭ 3288 cmϪ1, 3027, 2960, 2930,
2889, 2866, 1610, 1508, 1491, 1254, 1205, 807. C17H24O (244.37):
calcd. C 83.55, H 9.90; found C 83.34, H 9.66.
3600Ϫ3300 cmϪ1, 3000, 2950, 2877, 2844, 1653, 1617, 1600, 1476,
1259, 1243, 746. HRMS m/z ϭ 272.1774 (1.9%, Mϩ, C18H24O2
[Mϩ], |∆mu ϭ 0.3|).
:
ϩ
[1S-[2exo(S*)]]- and [1R-[2exo(R*)]-β-{[[2-Hydroxy-5-methyl-3-
(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)phenyl]methylene]amino}-
phenylethanol (18a and 18b): A solution of the aldehyde rac-7
(272 mg, 1.00 mmol, 1.00 equiv.) and (R)-phenylglycinol 10
(151 mg, 1.10 mmol, 1.10 equiv.) in methanol (10 mL) was stirred
for 3 days at room temperature. The solvent was removed under
reduced pressure. The crude product was purified by chromato-
graphy (silica gel, dichloromethane, 2-propanol; 100:1). The re-
sulting mixture of diastereomers 18a and 18b was separated by pre-
parative HPLC (LiChrosorb Si-60; dichloromethane, 2-propanol,
600:1, 80 mL/min) to provide the imines 18a (148 mg, 378 µmol,
38%, Ͼ99% de) and 18b (165 mg, 421 µmol, 42%, Ͼ99% de) as yel-
low solids.
Enantiomer 16: [α]D20 ϭ 42.9, [α]578 ϭ Ϫ45.2, [α]546 ϭ Ϫ51.5,
[α]436 ϭ Ϫ88.8 (c ϭ 0.72, chloroform). C17H24O (244.37): calcd. C
83.55, H 9.90; found C 83.31, H 9.87.
The enantiomeric purities of the phenols 16 and ent-16 were estab-
lished by analytical HPLC (Chiralcel OJ; n-heptane/2-propanol,
80:20, 0.8 mL/min; or Chiralcel OD-H; n-hexane/2-propanol, 99:1,
1 mL/min).
Compound 18a: Rf ϭ 0.33 (silica gel, dichloromethane); m.p. 58Ϫ59
°C. H NMR (300 MHz, CDCl3, room temp.): δ ϭ 0.81 (s, 3 H),
Enantiomer ent-16: [α]2D0 ϭ ϩ42.3, [α]578 ϭ ϩ44.5, [α]546 ϭ ϩ50.9,
[α]436 ϭ ϩ87.8 (c ϭ 0.65, chloroform). C17H24O (244.37): calcd. C
83.55, H 9.90; found C 83.42, H 9.92.
1
0.84 (s, 3 H), 0.91 (s, 3 H), 1.31Ϫ1.41 (m, 1 H), 1.53Ϫ1.64 (m, 3
H), 1.80Ϫ1.85 (m, 3 H), 2.05Ϫ2.18 (m, 1 H), 2.27 (s, 3 H), 3.35
(ψt, J ϭ 9.0 Hz, 1 H), 3.84Ϫ3.98 (m, 2 H), 4.46 (dd, J ϭ 7.7, J ϭ
5.4, 1 H), 6.88 (d, J ϭ 1.1 Hz, 1 H), 7.18 (d, J ϭ 1.1 Hz, 1 H),
2.27Ϫ7.40 (m, 5 H), 8.42 (s, 1 H), 13.41 (s, br.), 1 H) ppm. 13C{1H}
NMR (75 Hz, CDCl3, room temp.): δ ϭ 12.3, 20.3, 20.6, 21.2, 27.3,
34.0, 39.6, 44.3, 45.5, 47.8, 49.7, 67.6,.75.5, 117.3, 126.4, 127.0,
127.6, 128.6, 129.0, 131.5, 132.2, 139.3, 157.9, 166.8 ppm. IR (KBr
pellet): ν˜ ϭ 3422 cmϪ1, 2052, 3025, 2950, 2875, 1628, 1598, 1491,
(1S-exo)-1-Bromo-5-methyl-3-(1,7,7-trimethylbicyclo[2.2.1]hept-2-
yl)phenol (ent-17): A solution of bromine (65.4 mg, 409 mmol) in
tetrachloromethane (1 mL) was added dropwise at 0 °C to a solu-
tion of ent-15 (100 mg, 409 mmol) in tetrachloromethane (1 mL).
After final decoloration, the mixture was washed with 2 mL of a
saturated solution of sodium thiosulfate and with 2 mL of water.
The organic layer was dried with sodium sulfate and the solvent
was removed under reduced pressure to afford ent-17 (117 mg,
362 mmol, 89%) as colorless crystals. For analytic purposes, a
sample of ent-17 was sublimed (75 °C, 0.1 mbar). Rf ϭ 0.75 (silica
gel, toluene); m.p. 95 °C. 1H NMR (300 MHz, CDCl3, room
temp.): δ ϭ 0.77 (s, 3 H), 0.84 (s, 3 H), 0.87 (s, 3 H), 1.22Ϫ1.40
(m, 2 H), 1.41Ϫ1.68 (m, 2 H), 1.76Ϫ1.92 (m, 2 H), 2.07Ϫ2.20 (m,
1454, 1258, 700. HRMS m/z
ϭ
391.2476 (100.0%, Mϩ,
C26H33NO2ϩ:[Mϩ], |∆mu ϭ 3.6|).
The diastereomeric purities of the imines 18a and 18b were estab-
lished by analytical HPLC (LiChrosorb Si-60; dichloromethane/
2-propanol, 200:1, 1 mL/min).
1 H), 2.25 (s, 3 H), 3.25 (t, J ϭ 9.1 Hz, 1 H), 5.46 (s, 1 H), 7.04 (s, Compound 18b: Rf ϭ 0.33 (silica gel, dichloromethane); m.p. 59 °C.
1 H), 7.09 (s, 1 H) ppm. 13C{1H} NMR (75 Hz, CDCl3, room 1H NMR (300 MHz, CDCl3, room temp.): δ ϭ 0.77 (s, 3 H), 0.83
temp.): δ ϭ 12.2, 20.3, 20.7, 21.4, 27.4, 34.0, 39.6, 45.6, 46.0, 48.0,
50.1, 110.1, 128.5, 128.9, 129.9, 131.4, 148.9 ppm. IR (KBr): ν˜ ϭ
(s, 3 H), 0.89 (s, 3 H), 1.31Ϫ1.42 (m, 1 H), 1.51Ϫ1.65 (m, 3 H),
1.80Ϫ1.84 (m, 3 H), 2.07Ϫ2.17 (m, 1 H), 2.27 (s, 3 H), 3.33 (ψt,
3511 cmϪ1, 3022, 2948, 2876, 1472, 1465, 1235, 1190, 844, 767. J ϭ 9.0 Hz, 1 H), 3.87 (ψd, J ϭ 6.6 Hz, 2 H), 4.46 (ψt, J ϭ 6.6 Hz,
Eur. J. Org. Chem. 2002, 2800Ϫ2807
2805

A. Berkessel, M. R. Vennemann, J. Lex
FULL PAPER
1 H), 6.89 (d, J ϭ 1.1 Hz, 1 H), 7.18 (d, J ϭ 1.1 Hz, 1 H),
300 mg, 1.23 mmol) was formylated to afford the enantiomerically
2.25Ϫ7.43 (m, 5 H), 8.42 (s, 1 H), 13.36 (s, br.), 1 H) ppm. 13C{1H} pure aldehyde 7 (50.0 mg, 184 µmol, 15%). [α]2D0 ϭ ϩ35.3, [α]578
ϭ
NMR (75 Hz, CDCl3, room temp.): δ ϭ 12.2, 20.3, 20.6, 21.2, 27.3, ϩ38.4, [α]546 ϭ ϩ52.3, [α]436 ϭ ϩ232.1 (c ϭ 0.52, chloroform).
34.0, 39.6, 44.4, 45.5, 47.8, 49.7, 67.6, 75.6, 117.3, 126.4, 126.9,
127.6, 128.6, 128.9, 131.5, 132.1, 139.3, 157.9, 166.7 ppm. IR (KBr
pellet): ν˜ ϭ 3408 cmϪ1, 3052, 3026, 2951, 2875, 1629, 1598, 1491,
C18H24O2 (272.38): calcd. C 79.37, H 8.88; found C 79.31, H 8.84.
(1R-exo)-2-Hydroxy-5-methyl-3-(1,7,7-trimethylbicyclo[2.2.1]-hept-
2-yl)benzaldehyde (ent-7): Analogously to the preparation of the
aldehyde rac-7 from the phenol rac-15 (vide supra), phenol ent-15
(98.6% ee, 226 mg, 925 µmol) was formylated to afford the enanti-
1454, 1259, 700. HRMS m/z
ϭ
391.2519 (100.0%, Mϩ,
C26H33NO2ϩ: [Mϩ], |∆mu ϭ 0.8|).
omerically pure aldehyde ent-7 (104 mg, 382 µmol, 41%). [α]D20
ϭ
(1S-exo)-2-Hydroxy-5-methyl-3-(1,7,7-trimethylbicyclo[2.2.1]hept-2-
yl)benzaldehyde (7): Hydrochloric acid (2 mL, 32%) was added to
a solution of the imine 18a (148 mg, 378 µmol) in ethanol (3 mL).
The mixture was stirred overnight. The solvent was removed under
reduced pressure, and the residue was partitioned between 10 mL
water and 75 mL of dichloromethane. The organic layer was dried
over sodium sulfate, and the solvent was removed under reduced
pressure. Chromatography (silica gel, dichloromethane) of the
crude product afforded the enantiomerically pure aldehyde 7
(80.0 mg, 294 µmol, 78%) as a colorless solid. m.p. 109 °C (meth-
34.9, [α]578 ϭ Ϫ37.8, [α]546 ϭ Ϫ51.1, [α]436 ϭ Ϫ227.1 (c ϭ 0.50,
chloroform). C18H24O2 (272.38): calcd. C 79.37, H 8.88; found C
79.37, H 8.84.
[1RS-(2exo,6exo)]-2-Hydroxy-5-methyl-3-(5,5,6-trimethylbicyclo-
[2.2.1]hept-2-yl)benzaldehyde (rac-8): Analogously to the prepara-
tion of salicylic aldehyde rac-7 from the phenol rac-15 (vide supra),
the phenol rac-16 (2.00 g, 8.18 mmol) was formylated to afford the
aldehyde rac-8 (1.85 g, 6.79 mmol, 83%). Rf ϭ 0.64 (silica gel, tolu-
ene). 1H NMR (300 MHz, CDCl3, room temp.): δ ϭ 0.88Ϫ0.94
(m, 6 H), 1.07 (s, 3 H), 1.25Ϫ1.44 (m, 3 H), 1.72Ϫ1.77 (m, 1 H),
1.77Ϫ1.82 (m, 1 H), 1.90Ϫ1.95 (m, 1 H), 2.24Ϫ2.32 (m, 1 H), 2.32
(s, 3 H), 3.00Ϫ3.08 (m, 1 H), 7.14 (d, J ϭ 1.2 Hz, 1 H), 7.24 (d,
J ϭ 1.2 Hz, 1 H), 9.82 (s, 1 H), 11.22 (s, 1 H) ppm. 13C{1H} NMR
(75 MHz, CDCl3, room temp.): δ ϭ 16.3, 20.6, 24.8, 27.6, 32.6,
33.6, 39.6, 39.9, 48.8, 49.8, 50.8, 119.0, 128.2, 130.2, 134.2, 135.9,
157.8, 196.8 ppm. IR (NaCl, film): ν˜ ϭ 3600Ϫ3100 cmϪ1 (br.),
3010, 2950, 2873, 2840, 1650, 1618, 1604, 1451, 1262, 1249, 731.
anol). [α]2D0 ϭ ϩ42.7, [α]578 ϭ ϩ46.7, [α]546 ϭ ϩ62.8, [α]436
ϭ
ϩ281.7 (c ϭ 0.30, chloroform). C18H24O2 (272.38): calcd. C 79.37,
H 8.88; found C 79.08, H 8.95.
The enantiomeric purities of the salicylic aldehydes 7 and ent-7
were established by analytical HPLC (Chiralcel OD-H; n-hexane/
2-propanol, 200:1, 0.25 mL/min).
(1R-exo)-2-Hydroxy-5-methyl-3-(1,7,7-trimethylbicyclo[2.2.1]hept-
2-yl)benzaldehyde (ent-7): As in the preparation of 7, imine 18b
(165 mg, 421 µmol) was hydrolyzed to provide the enantiomerically
pure aldehyde ent-7 (100 mg, 367 µmol, 87%). m.p. 108Ϫ109 °C
[1S-(2exo,6exo)]-2-Hydroxy-5-methyl-3-(5,5,6-trimethylbicyclo-
[2.2.1]hept-2-yl)benzaldehyde (8): Analogously to the preparation of
salicylic aldehyde rac-7 from the phenol rac-15 (vide supra), the
phenol 16 (300 mg, 1.23 mmol) was formylated to afford the alde-
hyde 8 (50.0 mg, 184 µmol, 15%). [α]589 ϭ ϩ35.3, [α]578 ϭ ϩ38.4,
[α]546 ϭ ϩ52.3, [α]436 ϭ ϩ232.1 (c ϭ 0.52, chloroform). C18H24O2
(272.38): calcd. C 79.37, H 8.88; found C 79.31, H 8.84.
(methanol). [α]D20 ϭ 42.3, [α]578 ϭ Ϫ46.2, [α]546 ϭ Ϫ62.2, [α]436
ϭ
Ϫ279.9 (c ϭ 0.07, chloroform). C18H24O2 (272.38): calcd. C 79.37,
H 8.88; found C 79.36, H 8.69.
(1S-exo)-2-Hydroxy-5-methyl-3-(1,7,7-trimethylbicyclo[2.2.1]hept-2-
yl)benzaldehyde (7): Analogously to the preparation of the aldehyde
rac-7 from the phenol rac-15 (vide supra), phenol 15 (99.0%ee,
[1R-(2exo,6exo)]-2-Hydroxy-5-methyl-3-(5,5,6-trimethyl-
bicyclo[2.2.1]hept-2-yl)benzaldehyde (ent-8): Analogously to the pre-
Table 1. Experimental parameters of the X-ray structural analyses of rac-15, rac-16, 12, and ent-17.
Entry
rac-15
rac-16
12
ent-17
Formula
Mr
C17H24O
244.36
C17H24O
244.36
C21H26N2O2
338.44
0.20 ϫ 0.15 ϫ 0.15
Monoclinic
P21
8.288(1)
7.943(1)
14.798(1)
90
95.90(1)
90
969.0(2)
1.160
C17H23OBr
323.26
0.15 ϫ 0.15 ϫ 0.15
Orthorhombic
P212121
7.908(1)
13.881(1)
14.128(1)
90
90
90
1550.8(3)
1.385
4
Crystal dimensions [mm]
Crystal system
Space group
0.25 ϫ 0.10 ϫ 0.10
Triclinic
0.15 ϫ 0.10 ϫ 0.10
Triclinic
¯
¯
P1
P1
˚
a [A]
11.216(1)
11.291(1)
14.435(1)
111.27(1)
94.82(1)
115.96(1)
1465.9(2)
1.107
9.454(1)
12.036(1)
14.537(1)
106.56(1)
106.88(1)
94.45(1)
1493.9(5)
1.087
˚
b [A]
˚
c [A]
α [°]
β [°]
γ [°]
3
˚
V [A ]
ρcalcd. [gcmϪ3
Z
]
4
4
2
Radiation
Scan mode
2 Θmax [°]
Mo-Kα
ϕ/ω
Mo-Kα
ϕ/ω
Mo-Kα
ϕ/ω
Mo-Kα
ϕ/ω
54
54
54
54
Unique reflections
6391
6491
4038
3323
Observed reflections [I Ͼ 2σ(I)]
4424
2772
3320
2686
R (F)
0.0574
0.1360
0.185
0.1220
0.2872
0.304
0.0429
0.1015
0.138
0.0342
0.0746
0.182
Rw(F2)
ρfin. (max) [e·A
Ϫ3
˚
]
CCDC deposition no.
185866
185867
185868
185869
2806
Eur. J. Org. Chem. 2002, 2800Ϫ2807

Synthesis and Configurational Assignment of Chiral Salicylic Aldehydes
FULL PAPER
[1b]
Springer: Berlin, 1999; p. 649Ϫ677.
E. N. Jacobsen, M. H.
paration of salicylic aldehyde rac-7 from the phenol rac-15 (vide
supra), the phenol ent-16 (226 mg, 925 µmol) was formylated to
afford the aldehyde ent-8 (104 mg, 382 µmol, 41%). [α]589 ϭ Ϫ34.9,
Wu, in Comprehensive Asymmetric Catalysis; E. N. Jacobsen;
A. Pfaltz, H. Yamamoto, Eds.; Springer: Berlin, 1999; p.
1309Ϫ1326.
E. N. Jacobsen, Acc. Chem. Res. 2000, 33, 421Ϫ431.
J. F. Larrow, E. N. Jacobsen, J. Org. Chem. 1994, 59,
1939Ϫ1942.
[α]578 ϭ Ϫ37.8, [α]546 ϭ Ϫ51.1, [α]436 ϭ Ϫ227.1 (c ϭ 0.50, chloro-
[2]
form). C18H24O2 (272.38): calcd. C 79.37, H 8.88; found C 79.31,
[3]
H 8.84.
[4]
S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem.
1985, 97, 1Ϫ31; Angew. Chem. Int. Ed. Engl. 1985, 24, 1Ϫ30.
[5a] T. Takeda, R. Irie, T. Katsuki, Synlett 1999, 1157Ϫ1159. [5b]
Y. N. Ito, T. Katsuki, Bull. Chem. Soc. Jpn. 1999, 72, 603Ϫ619.
C. Bolm, F. Bienewald, Angew. Chem. 1995, 107, 2883Ϫ2885;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2640Ϫ2642.
A. H. Vetter, A. Berkessel, Tetrahedron Lett. 1998, 39,
1741Ϫ1744.
H. Sasaki, R. Irie, T. Katsuki, Synlett 1993, 300Ϫ302.
Ng. Ph. Bun-Hoi, H. Le Bihan, F. Binon, J. Org. Chem. 1952,
17, 243Ϫ248.
G. Casiraghi, G. Casnati, G. Puglia, G. Sartori, G. Terenghi, J.
Chem. Soc., Perkin Trans. 1 1980, 1862Ϫ1865.
M. Miller, L. S. Hegedus, J. Org. Chem. 1993, 58, 6779Ϫ6785.
L. J. Kitchen, J. Am. Chem. Soc. 1948, 70, 3608Ϫ3610.
H. Meerwein, K. van Emster, Ber. Dtsch. Chem. Ges. 1922,
55, 2500Ϫ2528.
X-ray Structure Determination of rac-15, rac-16, 12, and ent-17:
Crystals suitable for X-ray structural analyses were obtained in the
following ways: rac-15, rac-16: crystallization of the purified mat-
erials (oils) without added solvent. 12: crystallization from n-hex-
ane/chloroform; ent-17: sublimation at 75 °C, 0.1 mbar.
[5]
[6]
[7]
CCDC-numbers in Table 1 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB2 1EZ, UK; Fax: (internat.) ϩ44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
[8]
[9]
[10]
[11]
[12]
[13]
Acknowledgments
[14]
H. Meerwein, F. Montfort, Justus Liebigs Ann. Chem. 1924,
This work was supported by the Fonds der Chemischen Industrie
and in part by the Deutsche Forschungsgemeinschaft (Sonderfor-
schungsbereich 247 and Graduiertenkolleg ‘‘Selectivity in Organic
and Metal-Organic Synthesis and Catalysis’’). The authors thank
Dr. A. H. Vetter for synthetic support.
435, 207Ϫ218.
[15] [15a]
R. Haseltine, E. Huang, K. Ranganayakulu, T. S. Sor-
ensen, Can. J. Chem. 1975, 53, 1056Ϫ1066. [15b] T. S. Sorensen,
Acc. Chem. Res. 1976, 9, 257Ϫ265.
P. Brunelle, T. S. Sorensen, C. Taeschler, J. Org. Chem. 2001,
66, 7294Ϫ7302.
[16]
[1] [1a]
E. N. Jacobsen, M. H. Wu, in Comprehensive Asymmetric
Received March 4, 2002
Catalysis; E. N. Jacobsen; A. Pfaltz, H. Yamamoto, Eds.;
[O02114]
Eur. J. Org. Chem. 2002, 2800Ϫ2807
2807