Aminoalcohols V [1]: A method for the synthesis of enantiomerically pure ring-chlorinated epinephrines and norepinephrines

Article abstract of DOI:10.1007/PL00010225

The synthesis of enantiomerically pure 5-and 6-chloroepinephrine hydrochloride, resp., as well as 6-chloronorepinephrine hydrochloride is described starting from ring chlorinated O-benzylated dihydroxybenzaldehyde cyanohydrins, which are O-protected using

Full text of DOI:10.1007/PL00010225

Monatshefte fuÈr Chemie 130, 451±470 (1999)
Aminoalcohols V [1]: A Method
for the Synthesis of Enantiomerically
Pure Ring-Chlorinated Epinephrines
and Norepinephrinesa
1
1
1
Max KnollmuÈller1;Ã, Peter Gartner , Josef Pernerstorfer , Peter Pojarliev ,
È
and Hartmut B. Stegmann2
1
Institute of Organic Chemistry, Vienna University of Technology, A-1060 Vienna, Austria
2
Institute of Organic Chemistry, University of TuÈbingen, D-72076 TuÈbingen, Germany
Summary. The synthesis of enantiomerically pure 5- and 6-chloroepinephrine hydrochloride, resp.,
as well as 6-chloronorepinephrine hydrochloride is described starting from ring chlorinated
O-benzylated dihydroxybenzaldehyde cyanohydrins, which are O-protected using an enantiomeri-
cally pure acetal-type protecting group (MBE). After lithium aluminum hydride reduction, followed
± if necessary ± by N-protection and methylation, removal of the chiral auxiliar and deprotection by
hydrogenation furnished the target compounds with enantiomeric purities above 96% ee in high
chemical yield, if well de®ned reaction conditions during the hydrogenation process were closely
observed.
Keywords. Chloroepinephrine; Chloronorepinephrine; Enantiomeric purity; Hydrogenation.
Aminoalkohole, 5. Mitt. [1]: Ein Verfahren zur Synthese von enantiomerenreinen
kernchlorierten Epinephrinen und Norepinephrinen
Zusammenfassung. Die Herstellung von enantiomerenreinem 5- und 6-Chlorepinephrin-hydro-
chlorid bzw. von 6-Chlornorepinephrin-hydrochlorid wird beschrieben. Ausgehend von chlorsub-
stituierten mit O-Benzyl geschuÈtzten Dihydroxybenzaldehydcyanhydrinen, die mit einer
enantiomerenreinen acetalischen Schutzgruppe (MBE) am Cyanhydrinsauerstoff derivatisiert sind,
È
È
erhalt man nach LAH-Reduktion und, falls notwendig, N-Schutzung und Methylierung die O- und
N-geschuÈtzen Chlorepinephrine bzw. Chlornorepinephrine. Nach Spaltung des MBE-Acetals und
hydrogenolytischer Entfernung der Benzyl- bzw. Benzyloxycarbonylgruppe werden die Zielverbin-
dungen in guter chemischer Ausbeute mit Enantiomerenreinheiten uÈber 96% ee erhalten, wenn
È È
bestimmte Reaktionsparameter wahrend der Hydrierung prazise eingehalten werden.
Introduction
Besides their pharmacological activity towards adrenergic receptors [2], catecho-
lamines are readily oxidized by molecular oxygen at physiological pH and
Dedicated to Professor Dr. Gottfried Heinisch on the occasion of his 60th birthday
a
Ã
Corresponding author

452
M. KnollmuÈller et al.
temperature [3, 4]. In vivo, this oxidation pathway is frequently considered as a
triggering mechanism for some neuropathologies [3, 5±8]. Moreover, 6-hydroxy-
dopamine, a hydroxylated catecholamine, and related compounds which are
oxidized with outstanding ease, exert a pronounced selective neurotoxicity [9±11].
Therefore, it was suggested to apply 6-hydroxy-dopamine for chemical surgery by
free-radical cell killing [12], particularly in the treatment of neuroblastoma, in
combination with ascorbate which was shown to enhance the neurotoxic effect
[13, 14]. Possible mechanisms of its toxicity include production of highly reactive
oxygen species such as superoxide, hydrogen peroxide, and hydroxyl radicals and/
or the interaction of one or more of the oxidation products (e.g. quinones) with
thiol groups of several intraneuronal proteins or peptides like GSH.
Just recently it was found that autoxidation of catecholamines can be inhibited
by ascorbate if no quinoid products from oxidative transformation of catechola-
mines are present, whereas 6-hydroxy-dopamine is unconditionally oxidized and
ascorbate even accelerates this reaction [15]. Being interested in the autoxidation
as well as the cytotoxic behavior of enantiomerically pure ring-chlorinated
epinephrines and norepinephrines both alone and in the presence of ascorbate, we
were looking for a method to synthesize these compounds.
Results and Discussion
So far, racemic chloronorepinephrines and N-substituted ring-chlorinated
analogues have been synthesized from suitably substituted benzaldehydes
either via ring opening of styrene oxides [16] or via lithium aluminum hydride
reduction of cyanohydrin trimethylsilylethers [17]. Considering the fact that
enantiomerically pure ¯uoronorepinephrines obtained by racemate resolution using
a chiral HPLC column racemized very easily even under weakly acidic conditions
[18], we considered that our previously described method [19, 20] for the
synthesis of enantiomerically pure pharmacologically active ꢀ-aminoalcohols was
well suited, because it allows to monitor the stereogenic integrity until the very last
step and gives information about the absolute con®guration of the secondary
alcohol.
Thus, O-benzyl protected aldehydes 1a,b [16] afforded hydroxynitriles 2a,b
upon reaction with acetonecyanohydrin under basic catalysis. These were O-
protected with lactol anhydride (MBE)2O) to give the diastereomeric acetals 3a,b/
4a,b. Their chromatographic separation being dif®cult, the mixture of diaster-
eomers was then reduced with lithium aluminum hydride to give the O-protected
aminoalcohols 5a,b/6a,b which could be separated much easier.
In a second approach, we tried to obtain these O-protected ꢀ-aminoalcohols
with the phenolic hydroxyl groups unprotected. This time cyanohydrin 2c was
obtained from aldehyde 1c by consecutive reaction with sodium metabisul®te and
potassium cyanide [21]. Acetal formation with (MBE)2O yielded cleanly the
diastereomeric O-protected cyanohydrins 3c/4c; however, we were not able to
reduce 3c/4c with lithium aluminum hydride. Anyway, since the route via the
benzyl-protected cyanohydrins offered a further advantage, because the H2O
solubility was signi®cantly reduced compared to the unprotected compounds and
therefore handling was easier, we did not pursue this synthetic pathway.

EPC Synthesis of Epinephrines and Norepinephrines
453
Scheme 1. Synthesis of enantiomerically pure 5- and 6-chloroepinephrine 12a,b and ent-12a,b
(although the compounds are called 5- and 6-chloroepinephrine from the point of view of systematic
nomenclature, the chloro substituents are located in positions 3 and 2, resp.)
In contrast to earlier observations it proved best to use a 1:1 molar ratio of
lithium aluminum hydride to nitrile [19] and to add the reducing agent to the
cyanohydrin [22]. An excess of reducing agent as well as a long reaction time gave
signi®cantly lower yields. However, the reduction of 3b/4b afforded a small
amount of an unexpected by-product 13 which was shown to furnish substituted

454
M. KnollmuÈller et al.
Scheme 2. By-products of the synthesis of 5- and 6-chloroepinephrine 12a,b and ent-12a,b
benzoic acid 14 by acidic degradation in methanol (Scheme 2). The oxidation of
intermediates from lithium aluminum hydride reduction is not unprecedented [22]
and may be facilitated in this case by the capto-dative effect [23].
The assignment of con®guration for the O-protected cyanohydrins 3a±c/4a±c
and aminoalcohols 5a,b/6a,b was elaborated based on characteristic shift
differences in their H NMR spectra [24±28]. The diastereomeric purity, which
1
1
was calculated from the integrals of the H NMR spectra, was >98% de for 5a,b
and 6a,b after chromatographic separation.
N-Protection with benzyl chloroformate (Z-Cl) afforded 7a,b and 8a,b which
on subsequent reaction with lithium diisopropylamide and methyl iodide gave
protected epinephrines 9a,b and 10a,b in good yields. In one instance we tried to
replace lithium diisopropylamide with sodium hydride, but alkylation with methyl
iodide in DMF gave only poor yields of 9b. Whereas 9b and 10a were obtained in
nearly quantitative yield, the conversion to 9a and 10b was only about 70% even if
a large excess of methyliodide was used. This must be attributed to a steric
hindrance more pronounced in 9a and 10b than in 10a and 9b.
An indication that steric interactions might be responsible for this effect may be taken from the
fact that all these compounds show a double set of speci®c NMR signals, e.g. aromatic protons,
benzylic protons, and NCH3 signals in the 1H NMR and C-2, C-6, OCH, OCH2, and NCH3
resonances in the 13C NMR spectra. The double set of signals collapses to only one set at about
85ꢀ C. This shows that it is caused by a restricted rotation around a bond, but even from model
studies it is not possible to decide conclusively which bond causes this atropisomerism. It might be
caused by the E/Z-isomerism of the carbamate part [29], but in this case this type of isomerism
should be observed at the next step of the synthesis as well, which is not the case. Most probably,
rotation around several bonds is restricted as a result of the very rigid structure of the acetal part due
to n-ꢁÃ-interactions [24, 25] as well as to the carbamate whose C±N-bond is known to possess partial
double bond character [29].
The hydrogen chloride catalyzed reaction of 9a,b and 10a,b with methanol then
afforded-under concomitant formation of methyl acetal (MBEOCH3), which could
be recycled to the anhydrolactol ((MBE)2O) [30] ± the benzyl- and Z-protected
chloroepinephrines 11a,b and ent-11a,b without any observable formation of the
other enantiomer. In the case of 9a, the chromatographic puri®cation of which was
very tedious, the obtained mixture with 7a was used and puri®cation was
performed very easily by crystallization of 11a. Although it was quite disap-
pointing that we had to remove our probe for stereochemical integrity already at
this stage, it was the only way to go, because several attempts to remove the
benzyl- and Z-group by hydrogenation ®rst had failed, probably due to the bulky
MBE-group.

EPC Synthesis of Epinephrines and Norepinephrines
455
Eventually, the remaining protecting groups in 11a,b and ent-11a,b were
removed by hydrogenation in the presence of less than one equivalent of hydrogen
chloride to yield enantiomerically pure ring-chlorinated epinephrines 12a,b and
ent-12a,b. Although the reaction took place quite easily this time, it was essential
to observe several reaction parameters very carefully. Thus, if the amount of added
acid or the temperature, even only during work-up, was too high or the
hydrogenation was not immediately stopped after being completed ± the time
for this in fact depends strongly on the quality of the palladium catalyst ±,
considerable amounts of methyl ether 15a,b (Scheme 2) were formed, in some
cases being the sole product [31]. Quite luckily, the formation of 15a,b occurs only
after the benzyl- and Z-groups have been completely removed, but happens very
1
fast thereafter. This was determined by H NMR analysis of samples taken after
de®ned reaction times. On the other hand, if not enough hydrochloric acid or only
acetic acid was present during the hydrogenation process, the aryl-chlorine bond
was reductively cleaved [32] giving rise to epinephrines in nearly quantitative
yield. When methanol was replaced by isopropanol as solvent, similar results were
obtained, and the isopropyl ether was formed as a by-product. In THF the
protecting groups were removed slowly, and thus concomitant dehalogenation took
place yielding epinephrine in nearly quantitative yield. With this procedure,
enantiomerically pure 6-chloronorepinephrine 17 and ent-17, resp., could be
obtained in a very similar way from 5a and 6a following the route outlined in
Scheme 3.
Finally, we established the enantiomeric purity of our target compounds. Since
the free aminoalcohols 12a,b and ent-12a,b, the triacetylated [33] derivatives 18b,c
and ent-18b,c, and the triphenylsulfonyl substituted [34] compounds 18a and ent-
18a could not be separated by HPLC on substituted cellulose as stationary phase,
1
and H NMR spectra using enantiomerically pure shift reagents or mandelic acid
[35] as chiral probes did not give any information on the enantiomeric excess, we
decided to apply our own method established earlier [19]. Thus, acetyl or
triphenylsulfonyl substituted derivatives of chloroepinephrine 18a,b and ent±18a,b
were reacted with an excess of anhydrolactol ((MBE)2O) under acidic catalysis to
Scheme 3. Synthesis of enantiomerically pure 6-chloronorepinephrine 17 and ent-17

456
M. KnollmuÈller et al.
Scheme 4. Derivatization of 5- and 6-chloroepinephrine 12a,b and ent-12a,b to determine the
enantiomeric excess
give diastereomeric acetals 19a,b and 20a,b (Scheme 4). From these, the
enantiomeric purity of the aminoalcohols could be simply determined by 1H NMR
or better by HPLC. With the chloronorepinephrines 17 and ent-17 the same
sequence was performed, but only on an analytical scale. All target compounds
showed a stereochemical purity above 96% ee.
Experimental
All reactions were carried out under a nitrogen atmosphere in dry, freshly distilled solvents under
anhydrous conditions unless otherwise stated. Tetrahydrofuran (THF) and diethyl ether (Et2O) were
distilled from sodium/benzophenone. All other reagents were purchased in standard commercial
quality unless otherwise stated. Reactions were monitored by TLC on 0.25 mm E. Merck silica gel
plates (60F-254) using UV light as visualizing agent and 5% ethanolic phosphomolybdic acid
solution and heat as developing agents. For vaccum ¯ash chromatography (VFC) and column
chromatography (CC), the amount of E. Merck silica gel 60 (0.2±0.5 mm mesh size) and the eluent
are given. Melting points were recorded according to Ko¯er and are uncorrected. Microanalyses
were performed at the Institute of Physical Chemistry, University of Vienna; their results agreed
satisfactorily with the calculated values. NMR spectra were recorded on a Bruker AC 200 instrument
and calibrated using the solvent as secondary internal standard. Optical rotations were recorded on a
Perkin Elmer 241 polarimeter. HPLC separations were performed on a Shimadzu system (LC-8A
pump and SPD-6AV detector) using a silica gel Si60 column and 1% 2-propanol in n-hexane as
eluent. UV light (250 nm) was used for detection. The signals were recorded and integrated with a
DP 700 from Carlo Erba.
2-Chloro-4,5-di(phenylmethoxy)benzaldehyde (1a) [16, 36, 37], 3-chloro-4,5-di(phenylmethoxy)-
benzaldehyde (1b) [16, 37, 38], and 3-chloro-4,5-dihydroxybenzaldehyde (1c) [16, 37, 38] were
prepared according to the literature.

EPC Synthesis of Epinephrines and Norepinephrines
457
(rac)-2-Chloro-ꢂ-hydroxy-4,5-di(phenylmethoxy)-benzeneacetonitrile (2a; C22H18ClNO3)
A catalytic amount of K2CO3 was added to a solution of 32.2 g (91.26 mmol) of 1a in 1200 ml of
ethanol at 50ꢀC. After 5 min, 25.2 ml (277 mmol) and 10 minutes later additional 35 ml (384 mmol)
of acetone cyanohydrin were added. The reaction was stopped by addition of 10 ml of 2 M HCl
(pH ˆ 4±5), and the solution was ®ltered and concentrated under diminished pressure. The residue
was taken up with 150 ml of toluene and washed three times with H2O. The toluene layer was dried
over Na2SO4, ®ltered, and the solvent was evaporated. The residue was crystallized from Et2O/
1
petroleum ether (PE) to give 29.8 g (content of 2a: 84% from H NMR, remaining material: 1a) of
crude 2a.
1
Yellowish crystals; H NMR (CDCl3, ꢃ, 200 MHz): 7.5±7.3 (m, 10H, ph0, ph00-H), 7.3, 6.97 (2s,
2H, 3, 6(ph)-H), 5.76 (s, 1H, CHCN), 5.2±5.1 (2s, 4H, 2 CH2O), 2.8 (bs, 1H, OH) ppm; 13C NMR
(CDCl3, ꢃ, 50 MHz): 150.0, 147.0 (2s, C(ph)-4,5), 136.2, 135.9 (2s, C(ph0, ph00)-1), 128.6±127.1
(10d, C(ph0, ph00)-2,3,4,5,6), 125.2, 124.4 (2s, C(ph)-1,2), 118.2 (s, CN), 115.5, 113.9 (2d,
C(ph)-3,6), 71.5, 71.3 (2t, 2 OCH2), 60.3 (d, CHOH) ppm.
(rac)-3-Chloro-ꢂ-hydroxy-4,5-di(phenylmethoxy)-benzenecetonitrile (2b; C22H18ClNO3)
2b was prepared from 50.3 g (143 mmol) of 1b and 121.7 g (1.43 mol) of acetone cyanohydrin in the
1
same manner as described for 2a to give 48.32 g (content of 2b: 94% from H NMR, remaining
material: 1b) of crude 2b.
Pale yellow crystals; 1H NMR (CDCl3, ꢃ, 200 MHz): 7.50±7.23 (m, 10H, ph0, ph00-H), 7.11, 7.04
(2d, J ˆ 2.04 Hz, 2H, 2,6(ph)-H), 5.39 (s, 1H, CHCN), 5.12, 5.05 (2s, 4H, 2CH2O), 2.97 (s, 1H,
OH) ppm; 13C NMR (DMSO-d6, ꢃ, 50 MHz): 153.2, 145.0 (2s, C(ph)-4,5), 136.2, 135.7, 132.0
(3s, C(ph, ph0, ph00)-1), 129.2 (s, C(ph)-3), 128.8, 128.7, 128.4, 128.4, 127.6 (5d, C(ph0, ph00)-2, 3, 4,
5, 6), 120.3 (d, C(ph)-2), 118.3 (s, CN), 110.5 (d, C(ph)-6), 75.3, 71.2 (2t, 2 CH2O), 62.6
(d, CHOH) ppm.
(rac)-3-Chloro-ꢂ,4,5-trihydroxybenzeneacetonitrile (2c; C8H6ClNO3)
A solution of 6.60 g (38.80 mmol) Na2S2O5 in 20 ml of H2O was added to 3.00 g (17.40 mmol) of 1c
and stirred at 50ꢀC until the solution became clear. The mixture was cooled to room temperature, and
an aqueous solution of 4.532 g (69.6 mmol) of KCN was added. After stirring for 20 min and
extraction with Et2O, the organic phase was washed with H2O, dried over CaCl2, and concentrated to
1
furnish 2.93 g (content of 2c: 85% from H NMR, remaining material: 1c) of crude 2c.
Yellow crystals; 1H NMR (DMSO-d6, ꢃ, 200 MHz): 10.01, 9.34 (2s, 4(ph)-OH), 5(ph)-OH), 6.86
(s, 3H, 2, 6(ph)-H, CHOH), 5.57 (s, 1H, CHOH) ppm; 13C NMR (DMSO-d6, ꢃ, 50 MHz): 146.9,
142.6 (2s, C(ph)-4,5), 128.7, 120.6, 120.2 (3s, C(ph)-1,3,CN), 118.2, 112.3 (2d, C(ph)-2,6), 61.3
(d, CHOH) ppm.
(2S-(2ꢂ(RÃ),3aꢂ,4ꢀ, 7ꢀ, 7aꢂ))-2-Chloro-ꢂ((octahydro-7,8,8-trimethyl-4,7-methano-benzofuran-
2-yl)oxy)-4,5-di(phenylmethoxy)-benzeneacetonitrile (3a; C34H36ClNO4) and (2S-(2ꢂ(SÃ),3aꢂ,4ꢀ,
7ꢀ,7aꢂ))-2-chloro-ꢂ-((octahydro-7,8,8-trimethyl-4,7-methano-benzofuran)-2-yl)-oxy)-4,5-
di(phenylmethoxy)-benezeneacetonitrile (4a; C34H36ClNO4)
A solution of 29.8 g (content of 2a: 84%, 66.5 mmol) of crude 2a, 16.3g (43.51 mmol) of (MBE)2O,
and 450 mg of triphenylphosphine hydrobromide in 450 ml of CH2Cl2 was stirred for 30 min at room
temperature. 10 g of Na2SO4 were added, and stirring was continued for 2 h. The mixture was
washed with saturated NaHCO3 solution and H2O, dried over Na2SO2, ®ltered, and the solvent was
evaporated. The residue was crystallized from Et2O/PE and recrystallized from methanol to afford
16.5 g (44%) of a mixture 3a/4a. The mother liquor was concentrated to give 22.9 g which was

458
M. KnollmuÈller et al.
puri®ed by VFC (500 g, PE/Et2O (19:1) to yield 9.0 g (content of 3a/4a: 64%, remaining material:
1a), and 11.2 g (content of 3a/4a: 87%, remaining material: 1a). All these materials could be used for
the next step without further puri®cation.
1
3a/4a: Colorless crystals; H NMR (CDCl3, ꢃ, 200 MHz): 7.52±7.20 (m, 11H, 6(ph)-H, ph0,
ph00-H), 6.97 (s, H, 3(ph)-H), 5.79 (s, 0.5H, CHCN, 3a), 5.58 (s, 0.5H, CHCN, 4a), 5.41 (t, 0.5H, 2-H,
3a), 5.21 (t, 0.5H, 2-H, 4a), 5.18, 5.13 (2s, 4H, 2 CH2O), 4.18 (d, 0.5H, 7a-H, 4a), 3.88 (d, 0.5H,
7a-H, 3a), 2.46±0.78 (m, 17H, aliphatic-H, therein: 1.03, 0.99, 0.83 (3s, 9H, 3CH3)) ppm; 13C NMR
(CDCl3, ꢃ, 50 MHz): 150.3, 150.3, 148.0, 147.9 (4s, C(ph)-4,5), 136.4, 136.1 (2s, C(ph0, ph00)-1),
128.5, 128.0, 127.4, 127.1 (4d, 10C, C(ph0, ph00)-2, 3, 4, 5, 6), 125.0, 124.9, 124.1, 123.9 (4s, C(ph)-
1,2), 117.8, 117.2 (2s, CN), 115.5, 115.4, 115.1, 114.7 (4d, C(ph)-3, 6), 105.7, 103.3 (2d, C-2), 92.3,
92.2 (2d, C-7a), 71.5, 71.2 (2t, 2 OCH2), 63.4, 62.1 (2d, CHCN), 48.4, 48.3 (2d, C-4), 47.7, 47.6
(2s, C-7), 47.0 (s, C-8), 45.6, 45.3 (2d, C-3a), 38.8, 38.4 (2t, C-3), 32.1 (t, C-6), 28.7 (t, C-5), 22.8,
20.3, 11.4 (3q, 3CH3).
(2S-(2ꢂ(RÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-3-Chloro-ꢂ-((octahydro-7,8,8-trimethyl-4,7-methano-benzofuran-2-yl)-
oxy)-4,5-di(phenylmethoxy)-benzeneacetonitrile (3b; C34H36ClNO4) and (2S-(2ꢂ(SÃ),3aꢂ,4ꢀ,7ꢀ,
7aꢂ))-3-chloro-ꢂ((octahydro-7,8,8-trimethyl-4,7-methano-benzofuran-2-yl)-oxy)-4,5-di(phenylme-
thoxy)-benzeneacetonitrile (4b; C34H36ClNO4)
3b and 4b were prepared from 48.32 g (content of 2b: 94%, 120 mmol) of crude 2b in the same
manner as described for 3a/4a to give 65.26 g (91%) of a mixture 3b/4a. For analytical purposes, this
mixture was separated by VFC.
20
1
3b: Colorless oil; ‰ꢂŠ ˆ ꢁ64:0 (c ˆ 3.25, CH2Cl2); H NMR (CDCl3, ꢃ, 200 MHz): 7.52±7.29
D
(m, 10H, ph0, ph00-H), 7.12, 7.03 (2d, J ˆ 1.97 Hz, 2, 6(ph)-H), 5.50 (t, J ˆ 2.49 Hz, 1H, 2-H), 5.41
(s, 1H, CHCN), 5.16, 5.08 (2s, 4H, 2 CH2O), 3.82 (d, J ˆ 6.90 Hz, 1H, 7a-H), 2.39±0.78 (m, 17H,
aliphatic-H, therein: 1.03, 0.99, 0.83 (3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 153.3,
145.7 (2s, C(ph)-4,5), 136.7, 135.9 (2s, C(ph0)-1, C(ph00)-1), 130.08 (s, C(ph)-1), 129.2, 128.6, 128.5,
128.3, 128.2, 128.1, 127.5 (7d, ph0, ph00-2 3, 4, 5, 6, C(ph)-3), 121.3 (d, C(ph)-2), 117.2 (s, CN),
111.8 (d, C(ph)-6), 103.7 (d, C-2), 92.3 (d, C-7a), 75.0, 71.28 (2t, 2 OCH2), 64.6 (d, CHCN), 48.3
(d, C-4), 47.7 (s, C-7), 47.0 (s, C-8), 45.4 (d, C-3a), 38.4 (t, C-3), 32.2 (t, C-6), 28.7 (t, C-5), 22.8,
20.4, 11.5 (3q, 3 CH3) ppm.
20
1
4b: Colorless oil; ‰ꢂŠ ˆ ꢁ74:9 (c ˆ 0.89, CH2Cl2); H NMR (CDCl3, ꢃ, 200 MHz): 7.51±7.29
D
(m, 10H, ph0, ph00-H), 7.11, 7.01 (2d, J ˆ 1.97 Hz, 2(ph)-H, 6(ph)-H), 5.25 (s, 1H, CHCN), 5.13
(t, 1H, 2-H), 5.15, 5.07 (2s, 4H, 2 CH2O), 4.13 (d, J ˆ 7.49 Hz, 1H, 7a-H), 2.48±0.80 (m, 17H,
aliphatic-H, therein 1.03, 0.99, 0.83 (3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 153.1,
145.5 (2s, C(ph)-4, 5), 136.6, 135.7 (2s, C(ph0)-1, C(ph00)-1), 130.9 (s, C(ph)-1), 129.0 (s, C(ph)-3,
128.4, 128.3, 128.1, 128.0, 127.4 (6d, ph0, ph00-2, 3, 4, 5, 6), 121.0 (d, C(ph)-2), 118.0 (s, CN), 111.4
(d, C(ph)-6), 104.9 (d, C-2), 92.0 (d, C-7a), 74.8, 71.0 (2t, 2 OCH2), 65.1 (d, CHCN), 48.2 (d, C-4),
47.5 (s, C-7), 46.8 (s, C-8), 45.4 (d, C-3a), 38.6 (t, C-3), 32.0 (t, C-6), 28.6 (t, C-5), 22.8, 20.3, 11.3
(3q, 3 CH3) ppm.
(2S-(2ꢂ(RÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-3-Chloro-4,5-dihydroxy-ꢂ-((octahydro-7,8,8-trimethyl-4,7-methano-
benzofuran-2-yl)oxyl)-benzeneacetonitrile (3c; C20H24ClNO4) and (2S-(2ꢂ)(SÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-3-
chloro-4,5-dihydroxy-ꢂ-((octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)-oxy)-benzeneace-
tonitrile (4c; C20H24ClNO4)
A mixture of 2.9 g (content of 2c; 85%, 12.4 mmol) of crude 2c, 2.85 g (14.5 mmol) (MBE)2O,
140 mg of p-toluenesulfonic acid, and 1 g of Na2SO4 in 40 ml of Et2O was stirred for 12 h at room
temperature. The mixture was washed with saturated NaHCO3 solution and H2O, dried over Na2SO4,
and the solvent was evaporated. VFC (150 g, PE/Et2O (1:1)) yielded 0.33 g (11%) of recovered
starting material and 2.58 g (75%) of a mixture 3c/4c.

EPC Synthesis of Epinephrines and Norepinephrines
459
1
Colorless foam; H NMR (CDCl3, ꢃ, 200 MHz): 7.50±7.03 (b, 2H, 5(ph)-OH, 4(ph)-OH), 7.02,
7.00, 6.95 (3d, J ˆ 2.04 Hz, 4H, 2, 6(ph)-H), 5.45 (t, J ˆ 2.60 Hz, 0.5 H, 2-H, 3c), 5.37 (s, 0.5 H,
CHO, 3c), 5.21 (s, 0.5 H, CHO, 4c), 5.16 (t, J ˆ 4.34 Hz, 0.5 H, 2-H, 4c), 4.10 (d, J ˆ 7.50 Hz, 0.5 H,
7a-H, 4c), 3.84 (d, J ˆ 6.87 Hz, 0.5 H, 7a-H, 3c), 2.42±1.10 (m, 17H, aliphatic-H, therein: 0.98, 0.97,
0.92, 0.90, 0.79) (5s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 145.2, 145.1, 140.9, 140.8
(4s, C(ph)-4, 5), 126.8, 126.7, 120.2, 120.1 (4s, C(ph)-1,3), 119.7, 113.3, 113.2 (3d, C(ph)-2, 6),
118.2, 117.3 (2s, CN), 104.8, 103.6 (2d, C-2), 92.3 (d, C-7a), 65.2, 64.5 (2d, CHO), 48.4, 48.3
(2d, C-4), 47.8, 47.7 (2s, C-7), 47.0 (s, C-8), 45.5, 45.4 (2d, C-3a), 38.7, 38.4 (2t, C-3), 32.2 (t, C-6),
28.7, 28.7 (2t, C-5), 22.8, 20.4, 11.5, 11.4 (4q, 3 CH3) ppm.
(2S-(2ꢂ(RÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-2-Chloro-ꢂ((octahydro-7,8,8-trimethyl-4,7-methano-benzofuran-2-
yl)-oxy)-4,5-di(phenylmethoxy)-benzeneethanamine (5a; C34H40ClNO4) and (2S-(2ꢂ(SÃ),
3aꢂ,4ꢀ,7ꢀ,7aꢂ))-2-chloro-ꢂ-((octahydro-7,8,8-trimethyl-4,7-methano-benzofuran-2-yl)-
oxyl)-4,5-di(phenylmethoxy)-benzeneethanamine (6a; C34H40ClNO4)
1.032 g (29.6 mmol) of LiAlH4 were added rapidly in small portions to a solution of 16.5 g
(29.6 mmol) of 3a/4a in 250 ml of Et2O. After 30 min the mixture was cooled to 0ꢀC and quenched
with 26 ml of ice water. 102 ml of 10% NH4Cl solution were added; after ®ltering through a silica
pad, the aqueous layer was extracted thoroughly with Et2O. The combined organic phases were dried
over Na2SO4 and the solvent was evaporated to yield 10.8 g (65%) of 5a and 5.2 g (31%) of 6a after
VFC (320 g, Et2O (saturated with aqueous ammonia) gradient with methanol) and crystallization
from Et2O.
20
D
1
5a: Colorless crystals; m.p.: 123±125ꢀC; ‰ꢂŠ ˆ ꢁ0:2 (c ˆ 1, CH2Cl2); H NMR (CDCl3, ꢃ,
200 MHz): 7.51±7.22 (m, 10H, ph0,ph00-H), 7.08, 6.91 (2s, 2H, 3, 6(ph)-H), 5.23 (t, 1H, 2-H), 5.16,
5.11 (2s, 4H, 2 CH2O), 4.80 (dd, 1H, CHO), 3.59 (d, 1H, 7a-H), 2.88, 2.75 (2dd, 2H, CH2N),
2.30±0.75 (m, 17H, aliphatic-H, therein: 0.92, 0.81, 0.78 (3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ,
50 MHz): 148.3, 147.4 (2s, C(ph)-4, 5), 136.9, 136.6 (2S, C(ph0,ph00)-1), 131.7 (s, C(ph)-1), 128.4,
128.4, 127.8, 127.3, 127.2 (10C, C(ph0, ph00)-2,3,4,5,6),123.4 (s, C(ph)-2), 115.4, 114.7 (2d, C(ph)-3,
6), 105.0 (d, C-2), 91.5 (d, C-7a), 76.4 (d, CHO), 71.5, 71.3 (2t, 2 OCH2), 48.3 (d, C-4), 47.3
(s, C-7), 46.8 (s, C-8), 46.5 (t, CH2NH2), 45.7 (d, C-3a), 38.6 (t, C-3), 32.3 (t, C-6), 28.7 (t, C-5),
22.7, 20.4, 11.3 (3q, 3 CH3) ppm.
20
D
1
6a: Colorless crystals; m.p.: 99±101ꢀC; ‰ꢂŠ ˆ ꢁ136:4 (c ˆ 1, CH2Cl2); H NMR (CDCl3, ꢃ,
200 MHz): 7.50±7.22 (m, 10H, ph0, ph00-H), 6.91, 6.88 (2s, 2H, 3, 6(ph)-H), 5.17 (AB, 2H, CH2O),
5.11 (s, 2H, CH2O), 4.88 (dd, 1H, CHO), 4.80 (d, 1H, 2-H), 3.95 (d, 1H, 7a-H), 2.86, 2.66 (2dd, 2H,
CH2N), 2.38±0.75 (m, 17H, aliphatic-H, therein: 1.00, 0.91, 0.79 (3s, 9H, 3 CH3)) ppm; 13C NMR
(CDCl3, ꢃ, 50 MHz): 148.6, 147.3 (2s, C(ph)-4, 5), 136.8, 136.5 (2s, C(ph0, ph00)-1), 130.3 (s, C(ph)-1),
128.5, 128.4, 127.9, 127.8, 127.2, 127.2 (6d, C(ph0, ph00)-2, 3, 4, 5, 6), 124.4 (s, C(ph)-2), 115.6,
114.4 (2d, C(ph)-3, 6), 102.4 (d, C-2), 91.2 (d, C-7a), 75.2 (d, CHO), 71.3, 71.2 (2t, 2 OCH2), 48.4
(d, C-4), 47.6 (s, C-7), 47.3 (t, CH2N), 46.9 (s, C-8), 45.8 (d, C-3a), 38.5 (t, C-3), 32.3 (t, C-6), 28.8
(t, C-5), 22.8, 20.4, 11.5 (3q, 3 CH3) ppm.
(2S-(2ꢂ(RÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-3-Chloro-ꢂ-((octahydro-7,8,8-trimethyl-4,7-methano-benzofuran-2-yl)-
oxy)-4,5-di(phenylmethoxy)-benzeneethanamine (5b; C34H40ClNO4) and (2S-(2ꢂ(SÃ),
3aꢂ,4ꢀ,7ꢀ,7aꢂ))-3-chloro-ꢂ-((octahydro-7,8,8-trimethyl-4,7-methano-benzofuran-2-yl)-oxy)-4,5-
di(phenylmethoxy)-benzeneethanamine (6b; C34H40ClNO4)
64.68 g (116 mmol) of the mixture 3b/4b were treated in the same manner as described for 5a and 6a
to furnish 24.65 g (38%) of 5b and 16.05 g (25%) of 6b, Besides these two expected compounds,
4.4 g (7%) of (2S-(2ꢂ,3aꢂ,4ꢀ,7ꢀ,7aꢂ))-(octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)-3-
chloro-4,5-di(phenylmethoxy)benzoate (13) was isolated.

460
M. KnollmuÈller et al.
20
5b: Pale yellow oil; ‰ꢂŠ ˆ ꢁ12:8 (c ˆ 1.04, CH2Cl2); 1H NMR (CDCl3, ꢃ, 200 MHz): 7.52±7.22
D
(m, 10H, ph0, ph00-H), 6.99, 6.89 (2d, J ˆ 1.84 Hz, 2H, 2, 6(ph)-H), 5.28 (t, J ˆ 4.38 Hz, 1H, 2-H),
5.12, 5.03 (2s, 4H, 2 CH2O), 4.39 (t, J ˆ 5.40 Hz, 1H, CHO), 3.52 (d, J ˆ 7.08 ˆ Hz, 1H, 7a-H), 2.83
(d, J ˆ 5.40 Hz, 2H, CH2N), 2.34±0.70 (m, 17H, aliphatic-H, therein: 0.92, 0.81, 0.78 (3s, 9H,
3CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50MHz): 152.6, 143.7 (2s, C(ph)-4, C(ph)-5), 138.4, 137.1, 136.5,
128.5 (4s, C(ph, ph0, ph00)-1, C(ph)-3), 128.2 128.0, 128.0, 127.4 (4d, C(ph0, ph00)-2, 3, 4, 5, 6), 120.3
(d, C(ph)-2), 111.3 (d, C(ph)-6), 105.1 (d, C-2), 91.4 (d, C-7a), 79.5 (d, CHO), 74.9, 71.2 (2t, 2
OCH2), 48.3 (d, C-4), 47.5 (t, CH2N), 47.3 (s, C-7), 46.8 (s, C-8), 45.8 (d, C-3a), 38.7 (t, C-3), 32.3
(t, C-6), 28.8 (t, C-5), 22.8, 20.4, 11.4 (3q, 3 CH3) ppm.
20
6b: Pale yellow oil; ‰ꢂŠ ˆ ꢁ114:2 (c ˆ 1.12, CH2Cl2); 1H NMR (CDCl3, ꢃ, 200 MHz):
D
7.55±7.23 (m, 10H, ph0, ph00-H), 6.92, 6.80 (2d, J ˆ 1.84 Hz, 2H, 2, 6(ph)-H), 5.13, 5.05 (2s, 4H,
2 CH2O), 4.94 (d, J ˆ 4.24 Hz, 1H, 2-H), 4.51 (t, J ˆ 5.71 Hz, 1H, CHO), 3.95 (d, J ˆ 7.55 Hz, 1H,
7a-H), 2.79 (d, J ˆ 5.71 Hz, 2H, CH2N), 2.45±0.72 (m, 17H, aliphatic-H, therein: 1.00, 0.91, 0.79
(3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 152.5, 143.8 (2s, C(ph)-4, C(ph)-5), 136.8,
136.0, 128.3 (3s, C(ph, ph0, ph00)-1, C(ph)-3), 128.1, 128.0, 127.9, 127.6, 127.0 (5d, C(ph0, ph00)-2, 3,
4, 5, 6), 120.3 (d, C(ph)-2), 111.2 (d, C(ph)-6), 101.8 (d, C-2), 90.9 (d, C-7a), 77.4 (d, CHO), 74.5,
70.6 (2t, 2 OCH2), 48.7 (t, CH2N), 48.0 (d, C-4), 47.3 (s, C-7), 46.5 (s, C-8), 45.6 (d, C-3a), 38.2
(t, C-3), 32.0 (t, C-6), 28.6 (t, C-5), 22.6, 20.2 11.3 (3q, 3 CH3) ppm.
1
13: IR (®lm): ꢄmax ˆ 2956 (s, C±H), 1782 (s, C=O), 1285 (s, C±O) cmꢁ1; H NMR (CDCl3, ꢃ,
200 MHz): 7.65, 7.58 (2d, 2H, 2, 6(ph)-H), 7.52±7.28 (m, 10H, ph0, ph00-H), 6.51 (d, 1H, 2-H), 5.15,
5.13 (2s, 4H, 2 CH2O), 4.14 (d, 1H, 7a-H), 2.5±0.75 (m, 17H, aliphatic-H, therein: 1.01, 0.98, 0.81
(3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 164.4 (s, CO), 152.6, 148.5 (2s, C(ph)-4, 5),
136.5, 136.0 (2s, C(ph0, ph00)-1), 128.6, 128.5, 128.3, 127.5, 126.4, 124.0 (2s, 5d, C(ph0, ph00)-2, 3, 4,
5, 6, C(ph)-1, 2, 3), 113.8 (d, C(ph)-6), 101.7 (d, C-2), 93.3 (d, C-7a), 75.0, 71.3 (2t, 2 CH2O), 48.3
(d, C-4), 47.8 (s, C-7), 47.0 (s, C-8), 45.1 (s, C-3a), 38.6 (t, C-3), 32.1 (t, C-6), 28.7 (t, C-5), 22.8,
20.4, 11.4 (3q, 3 CH3) ppm.
To get further evidence for the proposed structure of 13, 30 mg (0.054 mmol) were dissolved in
Et2O, and the solution was treated with methanol and 2 M HCl for 15 min at room temperature. The
solvent was evaporated, and 3 ml of 2 M NaOH were added to the residue. The precipitate was
®ltered off, 2 M HCl was added, and the product were extracted with Et2O. The organic layer was
dried over Na2SO4 and concentrated in vacuo. Recrystallization from ethanol afforded 11 mg (55%)
of 3-chloro-4,5-di(phenylmethoxy)benzoic acid (14).
1
Colorless crystals; m.p.: 173±178ꢀC; H NMR (CDCl3, ꢃ, 200 MHz): 7.79, 7.61 (2d, 2H, 2,
6(ph)-H), 7.50±7.28 (m, 10H, ph0, ph00-H), 5.17, 5.15 (2s, 4H, 2 CH2O); 13C NMR (CDCl3, ꢃ,
50 MHz): 169.9 (s, COOH), 152.6, 149.2 (2s, C(ph)-4, 5), 136.4, 135.7 (2s, C(ph0, ph00)-1), 128.9,
128.6, 128.4, 128.2, 128.2, 127.5, 124.9, 124.8 (2s, 6d, C(ph0, ph00)-2, 3, 4, 5, 6, C(ph)-1, 2, 3), 113.9
(d, C(ph)-6), 75.0, 71.2 (2t, 2 CH2O) ppm.
(2S-(2ꢂ(RÃ), 3aꢂ,4ꢀ,7ꢀ,7aꢂ))-(Phenylmethyl)-N-(2-(2-chloro-4,5-di(phenylmethoxy)-phenyl)-2-
((octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)-oxy)-ethyl)-carbamate (7a; C42H46ClNO6)
4.55 g (26.38 mmol) of benzyl chloroformate were added to a mixture of 10.8 g (19.21 mmol) of 5a
in 110 ml of CH2Cl2 and 11 ml of 2 M NaOH. The mixture was stirred for 30 min at room
temperature, the layers were separated, and the organic phase was washed with H2O, dried over
Na2SO4, and concentrated to give, after VFC (600 g, PE/Et2O (3:1)), 13.27 g (99%) of 7a.
20
1
Colorless foam; ‰ꢂŠ ˆ ‡99:3 (c ˆ 0.95, CH2Cl2); H NMR (CDCl3, ꢃ, 200 MHz): 7.55±7.29
(m, 15H, ph0, ph00, pH00D0-H) 7.08, 6.91 (2s, 2H, 3, 6 (ph)-H), 5.21 (t, 1H, 2-H), 5.16±5.11 (2s, 6H,
3 CH2O), 5.00±4.80 (dd, 1H, CHO), 3.69±3.48 and 3.21±3.08 (2m, 2H, CH2N, therein: 3.52 (d, 1H,
7a-H)), 2.23±0.75 (m, 17H, aliphatic-H, therein: 0.89, 0.81, 0.76 (3s, 9H, 3 CH3)) ppm; 13C NMR
(CDCl3, ꢃ, 50 MHz): 156.2 (s, HNCOO), 148.7, 147.6 (2s, C(ph)-4,5), 136.9, 136.6, 130.8 (3s, C(ph,

EPC Synthesis of Epinephrines and Norepinephrines
461
ph0, ph00, ph000)-1), 128.5, 128.4, 128.1, 127.9, 127.9, 127.4, 127.2 (7d, C(ph0, ph00, ph000)-2, 3, 4, 5, 6),
123.8 (s, C(ph)-2), 115.5 (d, C(ph)-3), 114.5 (d, C(ph)-6), 104.9 (d, C-2), 91.7 (d, C-7a), 71.7
(d, CHO), 71.7, 71.3 (2t, 2 OCH2), 66.7 (t, OCOCH2), 48.4 (d, C-4), 47.4 (d, C-7), 46.8 (s, C-8), 45.7
(d, C-3a), 45.7 (t, CH2NHCO), 38.6 (t, C-3), 32.3 (t, C-6), 28.8 (t, C-5), 22.8, 20.4, 11.3 (3q, 3
CH3) ppm.
(2S-(2ꢂ(RÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-(Phenylmethyl)-N-(2-(3-chloro-4,5-di(phenylmethoxy)-phenyl)-
2-((octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)-oxy)-ethyl)-carbamate
(7b; C42H46ClNO6)
24.31 g (43.24 mmol) of 5b in 300 ml of Et2O were treated in the same manner as described for 7a to
afford, after VFC (420 g, PE/Et2O (2:1)), 29.21 g (97%) of 7b
20
Colorless oil; ‰ꢂŠ ˆ ꢁ17:5 (c ˆ 1.1, CH2Cl2); 1H NMR (CDCl3, ꢃ, 200 MHz): 7.51±7.24
(m, 15H, ph0, ph00, ph00D0-H), 7.00, 6.90 (2d, 2H, 2, 6(ph)-H), 5.25 (t, J ˆ 5.25 Hz, 1H, 2-H), 5.11, 5.09,
5.03 (3s, 6H, 3 CH2O), 4.95 (b, 1H, NH), 4.54 (dd, 1H, CHO), 3.62±3.42, 3.33±3.14 (2m, 2H,
CH2N), 3.51 (d, 1H, 7a-H), 2.30±0.70 (m, 17H, aliphatic-H, therein: 0.90, 0.81, 0.78 (3s, 9H, 3
CH3)) ppm; 13C NMR (CDCl3,ꢃ, 50 MHz): 156.1 (s, HNCOO), 152.7, 143.9 (2s, C(ph)-4, C(ph)-5),
137.4, 136.9, 136.3 (3s, C(ph, ph0, ph00, ph000)-1), 128.4, 128.3, 128.1, 128.0, 127.9, 127.4 (s, 5d,
C(ph0, ph00, ph000)-2, 3, 4, 5, 6, C(ph)-3), 120.2 (d, C(ph)-2), 111.1 (d, C(ph)-6), 105.1 (d, C-2), 91.4
(d, C-7a), 76.2 (d, CHO), 74.8, 71.1 (2t, 2 OCH2), 66.6 (t, OCOCH2), 48.2 (d, C-4), 47.3 (s, C-7),
46.7 (s, C-8), 45.9 (t, CH2N), 45.6 (d, C-3a), 38.6 (t, C-3), 32.2 (t, C-6), 28.6 (t, C-5), 22.7, 20.3, 11.3
(3q, 3 CH3) ppm.
(2S-(2ꢂ(SÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-(Phenylmethyl)-N-(2-(2-chloro-4,5-di(phenylmethoxy)-phenyl)-2-
((octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy)-ethyl)-carbamate (8a; C42H46ClNO6)
8a was prepared from 6.61 g (11.76 mmol) of 6a in the same manner as described for 7a to give, after
crystallization from toluene/PE, 8.0 g (98%) of 8a.
20
1
Colorless crystals; m.p.: 98±101ꢀC; ‰ꢂŠ ˆ ꢁ101:0 (c ˆ 0.95, CH2Cl2); H NMR (CDCl3, ꢃ,
200 MHz): 7.50±7.23 (m, 15H, ph0, ph00, ph0D00-H), 6.91 (s, 2H, 3, 6(ph)-H), 5.40±5.25 (bs, 1H, NH),
5.16±5.08 (3s, 6H, 3 CH2O) 5.02±4.92 (dd, 1H, CHO), 4.85±4.75 (dd, 1H, 2-H), 3.95 (d, 1H, 7a-H),
3.63±3.48 and 3.21±3.08 (2m, 2H, CH2N), 2.38±0.75 (m, 17H, aliphatic-H), therein: 0.98, 0.89, 0.75
(3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 156.2 (s, HNCOO), 148.9, 147.5 (2s, C(ph)-4,
5), 136.8, 136.5, 129.4 (3s, C(ph, ph0, ph00, ph000)-1), 128.5, 128.4, 128.0, 127.8, 127.4, 127.2 (6d,
17C, C(ph0, ph00, ph000)-2, 3, 4, 5, 6), 124.5 (s, C(ph)-2), 115.6 (d, C(ph)-3), 114.3 (d, C(ph)-6), 103.2
(d, C-2), 91.4 (d, C-7a), 73.1 (d, CHO, 71.4, 71.3 (2t, 2 OCH2), 66.6 (t, OCOCH2), 48.4 (d, C-4),
47.6 (d, C-7), 46.9 (s, C-8), 45.8 (d, C-3a), 45.8 (t, CH2NHCO), 38.5 (t, C-3), 32.3 (t, C-6), 28.8
(t, C-5), 22.8, 20.4, 11.5 (3q, 3 CH3) ppm.
(2S-(2ꢂ(SÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-(Phenylmethyl)-N-(2-(3-chloro-4,5-di(phenylmethoxy)-phenyl)-2-
((octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)-oxy)-ethyl)-carbamate
(8b; C42H46ClNO6)
15.85 g (28.20 mmol) of 6b were treated in the same manner as described for 7a to yield 18.13 g
(93%) of 8b.
20
Colorless oil; ‰ꢂŠ ˆ ꢁ87:9 (c ˆ 1.19, CH2Cl2); 1H NMR (CDCl3, ꢃ, 200 MHz): 7.53±7.25
D
(m, 15H, ph0, ph00, ph000-H), 6.99, 6.84 (2s, 2H, 2, 6(ph)-H), 5.29 (b, 1H, NH), 5.12, 5.10, 5.04 (3s,
6H, 3 CH2O), 4.96 (d, J ˆ 3.79 Hz, 1H, 2-H), 4.66 (dd, J1 ˆ 8.74 Hz, J2 ˆ 3.55 Hz, 1H, CHO), 3.94
(d, J ˆ 7.33 Hz, 1H, 7a-H), 3.60±3.44, 3.26±3.10 (2m, 2H, CH2N), 2.42±0.78 (m, 17H, aliphatic-H,
therein: 0.95, 0.91, 0.81 (3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 156.2 (s, HNCOO),

462
M. KnollmuÈller et al.
152.9, 144.3 (2s, C(ph)-4, C(ph)-5), 137.0, 136.3, 136.0 (3s, C(ph, ph0, ph00, ph000)-1), 128.7, 128.5,
128.4, 128.2, 128.0, 128.0, 127.9, 127.5 (7d, s, C(ph0, ph00, ph000)-2, 3, 4, 5, 6, C(ph)-3), 120.5
(d, C(ph)-2), 111.4 (d, C(ph)-6), 102.7 (d, C-2), 91.4 (d, C-7a), 75.3 (d, CHO), 74.9, 71.1 (2t, 2
OCH2), 66.6 (t, OCOCH2), 48.3 (d, C-4), 47.6 (s,C-7, 47.2 (t,CH2N), 46.8 (s, C-8), 45.8 (d, C-3a),
38.5 (t, C-3), 32.3 (t, C-6), 28.8 (t, C-5), 22.8, 20.4, 11.5 (3q, 3 CH3) ppm.
(2S-(2ꢂ(RÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-(Phenylmethyl)-N-(2-(2-chloro-4,5-di(phenylmethoxy)-phenyl)-
2-((octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy)-ethyl)-N-methylcarbamate
(9a; C43H48ClNO6)
A solution of lithium diisopropylamide in 30 ml of THF [39], prepared from 3.21 g (30.49 mmol)
of diisopropylamine (freshly distilled from Na) and 11.23 ml of a 2.5 M solution of n-butyl
lithium (30.5 mmol) in THF at ꢁ30ꢀC, was added slowly to a solution of 13.27 g (19.06 mmol) of
7a in 185 ml of THF at ꢁ30ꢀC. It was stirred for 30 min at this temperature, the cooling bath
was removed, and 6.4 ml (95.3 mmol) of methyl iodide, freshly distilled from potassium carbonate,
was added. After 12 h, the mixture was cooled to 0ꢀC, quenched with 25 ml of ice water and
50 ml saturated NaHCO3 solution, and stirred for 15 min. Most of the THF was distilled off, and the
residue was distributed between H2O and Et2O. The organic layer was washed with H2O, dried
over Na2SO4, and yielded, after concentration under diminished pressure, 12.9 g (content of 9a:
70%; remaining material: 7a) of crude 9a which was used for the next step without further
puri®cation. For analytical purposes, 200 mg of this material were puri®ed by CC (4 g, PE/Et2O
(3:1)) to give pure 9a.
20
Colorless oil; ‰ꢂŠ ˆ ‡67:1 (c ˆ 0.9, CH2Cl2); 1H NMR (CDCl3, ꢃ, 200 MHz): 7.55±7.29
(m, 15H, ph0, ph00, ph00D0-H), 7.29±7.08, 6.91, 6.85 (m, 2s, 2H, 3,6(ph)-H), 5.21 (t, 1H, 2-H), 5.16±5.11
(m, 6H, 3 CH2O), 5.00±4.80 (dd, 1H, CHO), 3.69±3.48 and 3.21±3.08 (2m, 2H, CH2N therein: 3.52
(d, 1H, 7a-H)), 2.92, 2.85 (2s, 3H, NCH3), 2.23±0.75 (m, 17H, aliphatic-H, therein: 0.89, 0.81, 0.76
(3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 156.0 (s, NCOO), 148.2, 147.4 (2s, C(ph)-4,
5), 136.6, 136.3, 131.2 (3s, C(ph, ph0, ph00, ph000)-1), 128.1, 128.0, 127.8, 127.6, 127.5, 127.3, 127.0,
126.9 (8d, C(ph0, ph00, ph000)-2, 3, 4, 5, 6), 123.8, 123.3 (2s, C(ph)-2), 115.0 (d, C(ph)-3), 114.1
(d, C(ph)-6), 105.0 (d, C-2), 91.2 (d, C-7a), 73.1, 72.7 (2d, CHO), 71.3, 71.0 (2t, 2 OCH2), 66.8, 66.5
(2t, OCOCH2), 53.4 (t, CH2N), 48.0 (d, C-4), 47.0 (s, C-7), 46.5 (s, C-8), 45.4 (t, C-3a), 38.2 (t, C-3),
36.1, 35.5 (2q, NCH3), 32.0 (t, C-6), 28.4 (t, C-5), 22.5, 20.1, 11.0 (3q, 3 CH3 ) ppm.
(2S-(2ꢂ(RÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-(Phenylmethyl)-N-(2-(3-chloro-4,5,-di(phenylmethoxy)-phenyl)-
2-((octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)-oxy)-ethyl)-N-methylcarbamate
(9b; C43H48ClNO6)
28.68 g (41.20 mmol) of 7b were treated in the same manner as described for 9a to yield, after VFC
(420 g, Et2O/PE (1:3)), 28.55 g (97%) of 9b.
20
1
Colorless oil; ‰ꢂŠ ˆ ꢁ24:3 (c ˆ 1.81, CH2Cl2); H NMR (CDCl3, ꢃ, 200 MHz): 7.50±7.20 (m,
D
15H, ph0, ph00, ph000-H), 7.02, 6.91, 6.96, 6.78 (4s, 2H, 2,6(ph)-H), 5.22-4.92 (m, 7H, 3 CH2O, 2-H),
4.75±4.64, 4.61±4.51 (2m, 1H, CHO), 3.60±3.40 (m, 2H, CH2N), 3.30, 3.12 (2d, J ˆ 8.43 and
8.46 Hz, resp., 1H, 7a-H), 2.91, 2.88 (2s, 3H, NCH3), 2.30±0.70 (m, 17H, aliphatic-H, therein: 0.90,
0.81, 0.78 (3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 156.0 (s, HNCOO), 152.7, 143.8
(2s, C(ph)-4), C(ph)-5), 138.0, 137.0, 136.4 (3s, C(ph, ph0, ph00, ph000)-1), 128.5, 128.3, 128.2, 128.0,
127.9, 127.6, 127.5 (5d, 2s, C(ph0, ph00, ph000)-2, 3, 4, 5, 6, C(ph)-3), 120.2, 120.1 (2d, C(ph)-2),
111.1, 110.9 (2d, C(ph)-6), 105.7 (d, C-2), 91.4 (d, C-7a), 77.3, 76.6 (2d, CHO), 74.9, 71.2 (2t, 2
OCH2), 67.3, 66.9 (2t, OCOCH2), 55.2 (t, CH2N), 48.4 (d, C-4), 47.3 (s, C-7), 46.8 (s, C-8), 45.7
(d, C-3a), 38.7 (t, C-3), 36.6, 36.3 (2q, NCH3), 32.3 (t, C-6), 28.8 (t, C-5), 22.8, 20.4, 11.4 (3q, 3
CH3) ppm.

EPC Synthesis of Epinephrines and Norepinephrines
463
(2S-(2ꢂ(SÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-(Phenylmethyl)-N-(2-(2-chloro-4,5-di(phenylmethoxy)-phenyl)-2-
((octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)-oxy)-ethyl)-N-methylcarbamate
(10a; C43H48ClNO6)
10a was prepared from 7.89 g (11.33 mmol) of 8a in the same manner as described for 9a to yield
20
8.2 g (quant.) of 10a. Colorless foam; ‰ꢂŠ ˆ ꢁ93:2 (c ˆ 3.48, CH2Cl2); 1H NMR (CDCl3, ꢃ,
200 MHz): 7.55±7.29 (m, 15H, ph0, ph00, ph0D00-H) 7.28±7.08, 6.91, 6.85 (m, 2s, 2H, 3,6(ph)-H), 5.21
(t, 1H, 2-H), 5.16±5.11 (m, 6H, 3 CH2O), 5.00±4.80, (dd, 1H, CHO), 3.69±3.48 and 3.21±3.08 (2m,
2H, CH2N, therein: 3.52 (d, 1H, 7a-H)), 2.90, 2.85 (2s, 3H, NCH3), 2.23±0.75 (m, 17H, aliphatic-H,
therein: 0.89, 0.81, 0.76 (3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 155.7 (s, NCOO),
148.2, 146.9 (2s, C(ph)-4, 5), 136.2, 135.9, 129.3 (3s, C(ph, ph0, ph00, ph000)-1), 127.9, 127.8, 127.7,
127.4, 127.2, 127.1 (6d C(ph0, ph00, ph000)-2, 3, 4, 5, 6), 124.1, 123.9 (2s, C(ph)-2), 115.0 (d, C(ph)-3),
113.8, 113.7 (2d, C(ph)-6), 101.3 (d, C-2), 90.5 (d, C-7a), 70.7, 70.5 (2d, CHO), 70.6, 70.3 (2t, 2
OCH2), 66.4, 66.3 (2t, OCOCH2), 52.8 (t, CH2N), 47.8 (d, C-4), 46.9 (s, C-7), 46.3 (s, C-8), 45.2
(d, C-3a), 37.9 (t, C-3), 35.4, 34.1 (2q, NCH3), 31.7 (t, C-6), 28.3 (t, C-5), 22.3, 19.9, 11.0 (3q, 3
CH3) ppm.
Ã
2-((octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)-oxy)-ethyl)-N-methylcarbamate
(2S-(2ꢂ(S ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-(Phenylmethyl)-N-(2-(3-chloro-4,5-di(phenylmethoxy)-phenyl)-
(10b; C43H48ClNO6)
17.12 g (24.59 mmol) of 8b were treated in the same manner as described for 9a to yield, after VFC
(250 g, Et2O/PE(1:3)), 10.8 g (63%) of 10b.
20
D
Colorless oil; ‰ꢂŠ ˆ ꢁ86:8 (c ˆ 0.85, CH2Cl2); 1H NMR (CDCl3, ꢃ, 200 MHz): 7.52±7.25
(m, 15H, ph0, ph00, ph000-H), 7.01, 6.85, 6.90, 6.65 (4s, 2H, 2,6(ph)-H), 5.20±4.77 (m, 8H, 3 CH2O,
2-H, CHO), 3.88, 3.81 (2d, J ˆ 7.80 and 8.41 Hz, resp., 1H, 7a-H), 3.53±3.19 (m, 2H, CH2N), 2.95
(s, 3H, NCH3), 2.35±0.75 (m, 17H, aliphatic-H, therein: 1.00, 0.91, 0.80 (3s, 9H, 3 (CH3)) ppm; 13
C
NMR (CDCl3, ꢃ, 50 MHz): 156.1, 155.9 (2s, HNCOO), 152.8, 144.1 (2s, C(ph)-4, C(ph)-5), 136.9,
136.7, 136.6, 136.3, 136.2 (5s, C(ph, ph0, ph00, ph000)-1), 128.6, 128.3, 128.1, 127.9, 127.6, 127.4,
125.9, 125.6 (5d, 2s, C(ph0, ph00, ph000)-2, 3, 4, 5, 6, C(ph)-3), 120.5, 120.3 (2d, C(ph)-2), 111.4, 111.2
(2d, C(ph)-6), 101.6 (d, C-2), 91.1 (d, C-7a), 74.1, 73.9 (2d, CHO), 74.7, 70.9 (2t, 2 OCH2), 67.1,
66.8 (2t, OCOCH2), 55.3 (t, CH2N), 48.2 (d, C-4), 47.4 (s, C-7), 46.8 (s, C-8), 45.8 (d, C-3a), 38.4
(t, C-3), 36.3, 35.9 (2q, NCH3), 32.2 (t, C-6), 28.8 (t, C-5), 22.8, 20.4, 11.4 (3q, 3 CH3) ppm.
(S)-(Phenylmethyl)-N-(2-(2-chloro-4,5-di(phenylmethoxy)-phenyl)-2-hydroxyethyl)-
N-methylcarbamate (11a; C31H30ClNO5)
To a solution of 12.9 g of crude 9a (12.71 mmol of 9a and 5.56 mmol of 7a) in 120 ml of methanol
and 30 ml of Et2O, 3.7 ml of 4.5 M HCl in Et2O were added, and the mixture was stirred for 45 min at
room temperature. The mixture was treated with 120 ml of saturated NaHCO3/H2O, and the solvent
was evaporated. The residue was distributed between Et2O and H2O, and the combined organic
layers were washed with H2O and dried over Na2SO4. Evaporation of the solvent followed by VFC
(100 g, PE/Et2O (1:1)) afforded 6.3 g (93%) of crude 11a as colorless oil which crystallized from
Et2O/PE (1:1) to give 4.5 g (67%) of 11a.
20
D
Colorless crystals; m.p.: 97±99ꢀC; ‰ꢂŠ ˆ ‡45:2 (c ˆ 1, CH2Cl2; 1H NMR (CDCl3, ꢃ,
200 MHz): 7.45±7.2 (m, 15H, ph0, ph00, ph000-H), 6.9 (s, 2H, 3, 6(ph)-H), 5.21±4.99 (m, 7H,
3 CH2O and CHOH), 4.38 (bs, 1H, OH), 3.75±3.36 (2dd, 2H, CH2N), 2.87 (s, 3H, NCH3) ppm;
13C NMR (CDCl3, ꢃ, 50 MHz): 158.0 (s, CH3-NCOO), 148.2, 147.2 (2s, C(ph)-4, 5), 136.4, 136.2,
131.0 (3s, 4C, C(ph, ph0 ph00, ph000)-1), 128.1, 127.8, 127.6, 127.5, 127.1, 126.9 (6d, 15C, C(ph0, ph00,
ph000)-2, 3, 4, 5, 6), 122.0 (s, C(ph)-2), 115.5 (d; C(ph)-3), 113.2 (d, C(ph)-6), 71.1, 71.0 (2t, 2
OCH2), 70.3 (d, CHOH), 67.3 (t, OCOCH2), 55.7 (t, CH2N), 35.5 (q, NCH3) ppm.

464
M. KnollmuÈller et al.
(R)-(Phenylmethyl)-N-(2-(2-chloro-4,5-di(phenylmethoxy)-phenyl)-2-hydroxyethyl)-
N-methylcarbamate (ent-11a; C31H30ClNO5)
ent-11a was prepared from 22.52 g (31.70 mmol) of 10a in the same manner as described for 11a
to give 16.87 g (100%) of crude ent-11a as colorless oil. Crystallization from Et2O/PE (1:1)
20
afforded 13.5 g (80%) of ent-11a. Colorless crystals; m.p.: 97±99ꢀC; ‰ꢂŠ ˆ ꢁ45:2 (c ˆ 1, CH2Cl2);
D
1H NMR (CDCl3, ꢃ, 200 MHz): 7.45±7.2 (m, 15H, ph0, ph00, ph000-H), 6.9 (s, 2H, 3, 6(ph)-H),
5.21±4.99 (m, 7H, 3 CH2O and CHOH), 4.38 (bs, 1H, OH) 3.75±3.36 (2dd, 2 H, CH2N), 2.87
(s, 3H, NCH3) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 158.0 (s, CH3-NCOO), 148.2, 147.8 (2s,
C(ph)-4, 5) 136.4, 136.2, 131.0 (3s, 4C, C(ph, ph0, ph00, ph000)-1), 128.1, 127.8, 127.6, 127.5, 127.1,
126.9 (6d, 15C, C(ph0, ph00, ph000)-2, 3, 4, 5, 6), 122.0 (s, C(ph)-2), 115.5 (d; C(ph)-3), 113.2
(d, C(ph)-6), 71.1, 71.0 (2t, 2 OCH2), 70.3 (d, CHOH), 67.3 (t, OCOCH2), 55.7 (t, CH2N), 35.5
(q, NCH3) ppm.
(S)-(Phenylmethyl)-N-(2-(3-chloro-4,5-di(phenylmethoxy)-phenyl)-2-hydroxyethyl)-
N-methylcarbamate (11b; C31H30ClNO5)
4.75 g (6.69 mmol) of 9b was treated as described for 11a to give, after VFC (25 g, PE/Et2O) (1:2),
3.55 g (99%) of 11b as colorless oil, which was crystallized from Et2O/PE to furnish 2.9 g (82%) of
20
11b. Colorless crystals; m.p.: 88±90ꢀC; ‰ꢂŠ ˆ ‡24:0 (c ˆ 0.97, CH2Cl2); 1H NMR (CDCl3 ꢃ,
200 MHz) : 7.50±7.25 (m, 15H, ph0, ph00, ph00D0-H), 7.02±6.90, 6.84±6.76 (2b, 2H, 2, 6(ph)-H), 5.15,
5.10, 5.04 (3s, 6H, 3, CH2O), 4.89, (b, 1H, CHO) 3.45 (m, 2H, CH2N), 2.85 (s, 3H, NCH3) ppm;
13C NMR (CDCl3, ꢃ, 50 MHz): 158.0 (s, HNCOO), 153.0, 143.9 (2s, C(ph)-4, C(ph)-5), 138.8,
136.9, 136.3 (3s, C(ph, ph0, ph00, ph000)-1), 128.6, 128.5, 128.2, 128.0, 127.8, 127.5 (5d, s, C(ph0, ph00,
ph000)-2, 3, 4, 5, 6, C(ph)-3) 119.5 (d, C(ph)-2), 110.2 (d, C(ph)-6), 74.9, 71.0 (2t, 2 OCH2), 72.7
(d, CHO), 67.5 (t, OCOCH2), 57.6 (t, CH2N), 36.2 (q, N-CH3) ppm.
(R)-(Phenylmethyl)-N-(2-(3-chloro-4,5-di(phenylmethoxy)-phenyl)-2-hydroxyethyl)-
N-methylcarbamate(ent-11b; C31H30ClNO5)
This was prepared from 3.06 g (4.31 mmol) of 10b in the same manner as described for 11a to give
2.15 g (93%) of ent-11b, which was recrystallized from PE/Et2O (1:1) to afford 1.85 g (80%) of
ent-11b.
20
Colorless crystals; m.p.: 88±90ꢀC; ‰ꢂŠ ˆ ꢁ24:8 (c ˆ 0.95, CH2Cl2); 1H NMR (CDCl3 ꢃ,
D
200 MHz): 7.50±7.25 (m, 15H, ph0, ph00, ph000-H), 7.03±6.86, 6.84±6.72 (2b, 2H, 2,6(ph)-H), 5.18,
5.09, 5.05 (3s, 6H, 3 CH2O), 4.88 (b, 1H, CHO), 3.47 (m, 2H, CH2N), 2.88 (s, 3H, NCH3) ppm; 13
C
NMR (CDCl3, ꢃ, 50 MHz): 158.0 (s, HNCOO), 153.0, 143.8 (2s, C(ph)-4, C(ph)-5), 138.8, 136.9,
136.4, 136.3 (4s, C(ph, ph0, ph00, ph000)-1), 128.6, 128.5, 128.2, 128.0, 127.8, 127.5 (5d, s, C(ph0, ph00,
ph000)-2, 3, 4, 5, 6, C(ph)-3), 119.5 (d, C(ph)-2), 110.2 (d, C(ph)-6), 74.9, 71.0 (2t, 2 OCH2), 72.6
(d, CHO), 67.4 (t, OCOCH2), 57.6 (t, CH2N), 36.2 (q, N-CH3) ppm.
(S)-2-Chloro-ꢀ,4,5-trihydroxy-N-methylbenzeneethanamine hydrochloride (12a; C9H13Cl2NO3)
To a solution of 1.20 g (2.256 mmol) of 11a in 60 ml of methanol, 120 mg of Pd/C (10%) and 5.02 ml
of 0.4486 M HCl in Et2O were added. The mixture was hydrogenated at 400 kPa in a Parr apparatus
for 12.5 min, cooled to 0ꢀC, the catalyst was ®ltered off, and the solvent was evaporated under
diminished pressure below 30ꢀC. CCl4 was added to the residue, and the solvent was distilled off
again. The addition of CCl4 followed by evaporation was repeated twice before the residue was
treated with 125 ml of a mixture of acetone and ethyl acetate (4:1). The precipitate was ®ltered off
and afforded, after drying in a desiccator, 480 mg (84%) of 12a.

EPC Synthesis of Epinephrines and Norepinephrines
465
20
D
Colorless crystals; m.p.: 174±175ꢀC (decomp); ‰ꢂŠ ˆ ‡57:8 (c ˆ 1, MeOH); 1H NMR (D2O, ꢃ,
200 MHz): 7.05, 6.93 (2s, 2H, 3,6(ph)-H), 5.32±5.28 (dd, 1H, CHOH). 3.34±3.15(m, 2H, CH2N),
2.81 (s, 3H, N-CH3) ppm; 13C NMR (D2O, ꢃ, 50 MHz): 147.0, 145.6 (2s, C(ph)-4,5), 130.6,
124.1 (2s, C(ph)-1,2), 119.0, 116.1 (2d, C(ph)-3, 6), 67.5 (d, CHOH), 55.4 (t, CH2N), 35.1
(q, NCH3) ppm.
(R)-2-Chloro-ꢀ,4,5-trihydroxy-N-methylbenzeneethanamine hydrochloride (ent-12a; C9H13Cl2NO3)
ent-12a was prepared from 1.20 g (2.256 mmol) of ent-11a in the same manner as described for 12a
to give 480 mg (84%) of ent-12a.
20
D
1
Colorless crystals; m.p.: 174±175ꢀC (decomp.); ‰ꢂŠ ˆ ꢁ58:4 (c ˆ 1, MeOH); H NMR (D2O,
ꢃ, 200 MHz): 7.05, 6.93 (2s, 2H, 3,6(ph)-H), 5.32±5.28 (dd, 1H, CHOH), 3.34±3.15 (m, 2H, CH2N),
2.81 (s, 3H, N-CH3) ppm; 13C NMR (D2O, ꢃ, 50 MHz): 147.0, 145.6 (2s, C(ph)-4, 5), 130.6, 124.1
(2s, C(ph)-1, 2), 119.0, 116.1 (2d, C(ph)-3, 6), 67.5 (d, CHOH), 55.4 (t, CH2N), 35.1 (q, NCH3) ppm.
(S)-3-Chloro-ꢀ,4,5-trihydroxy-N-methylbenzeneethanamine hydrochloride (12b; C9H13Cl2NO3)
12b was prepared from 2.13 g (4.00 mmol) of 11b in the same manner as described for 12a to give
0.96 mg (94%) of 12b.
20
1
Colorless foam; ‰ꢂŠ ˆ ‡50:4 (c ˆ 0.43, MeOH); H NMR (D2O, ꢃ, 200 MHz): 6.84, 6.73 (2d,
D
2H, 3, 5(ph)-H), 4.79 (t, 1H, CHOH), 3.18 (m, 2H, CH2N), 2.70 (s, 3H, N±CH3) ppm; 13C NMR
(D2O, ꢃ, 50 MHz): 142.8, 137.8 (2s, C(ph)-4, 5), 129.6, 118.5 (2s, C(ph)-1, 3), 115.8, 109.3
(2d, C(ph)-2, 6), 65.1 (d, CHOH), 51.7 (t, CH2N), 30.3 (q, NCH3) ppm.
(R)-3-Chloro-ꢀ,4,5-trihydroxy-N-methylbenzeneethanamine hydrochloride (ent-12b; C9H13Cl2NO3)
ent-12b was prepared from 1.27 g (2.39 mmol) of ent-11b in the same manner as described for 12a to
give 450 mg (74%) of ent-12b.
20
Colorless foam; ‰ꢂŠ ˆ ꢁ50:5 (c ˆ 0.43, MeOH); 1H NMR (D2O, ꢃ, 200 MHz): 6.84, 6.73
D
(2d, 2H, 3,5(ph)-H), 4.79 (t, 1H, CHOH), 3.18 (m, 2H, CH2N), 2.70 (s, 3H, N±CH3) ppm; 13C NMR
(D2O, ꢃ, 50 MHz): 142.8, 137.8 (2s, C(ph)-4, 5), 129.6, 118.5 (2s, C(ph)-1, 3), 115.8, 109.3 (2d,
C(ph)-2, 6), 65.1 (d, CHOH), 51.7 (t, CH2N), 30.3 (q, NCH3) ppm.
2-Chloro-4,5-dihydroxy-ꢀ-methoxy-N-methylbenzeneethanamine hydrochloride
(15a; C10H15Cl2NO3)
15a was prepared from 30 mg (0.056 mmol) of 11a in the same manner as described for 12a, but
instead of keeping the temperature of the water bath below 30ꢀC, it was raised up to 90ꢀC for 2 h
yield: 13 mg (100%) of 15a.
1
Colorless oil; H NMR (D2O, ꢃ, 200 MHz): 7.16, 7.09 (2d, 2H, 3,6(ph)-H), 5.12±5.01 (dd, 1H,
CHO), 3.47±3.32 (m, 2H, CH2N, therein:, 3.44 (s, 3H, OCH3)), 2.95 (s, 3H, NCH3) ppm; 13C NMR
(D2O, ꢃ, 50 MHz): 142.9, 141.5 (2s, C(ph)-4, 5), 122.6, 120.9 (2s, C(ph)-1, 2), 114.6, 111.9
(2d, C(ph)-3, 6), 72.4 (d, CHO), 54.1 (t, CH2), 50.0 (q, OCH3), 30.6 (q, N±CH3) ppm.
3-Chloro-4,5-dihydroxy-ꢀ-methoxy-N-methylbenzeneethanamine hydrochloride
(15b; C10H15Cl2NO3)
A solution of 30 mg (0.12 mmol) of 12b in 3 ml of anhydrous methanol was treated with 3 ml of
9 M HCl in Et2O for four days at 25ꢀC. The solvent was evaporated to afford 30 mg (95%) of 15b.

466
M. KnollmuÈller et al.
1
Colorless oil; H NMR (D2O, ꢃ, 200 MHz): 6.84, 6.71 (2d, 2H, 2, 6(ph)-H), 4.35 (t, 1H, CHO),
3.16±3.07 (m, 2H, CH2N, therein: 3.15 (s, 3H, OCH3)), 2.65 (s, 3H, NCH3) ppm; 13C NMR (D2O, ꢃ,
50 MHz): 148.1, 143.3 (2s, C(ph)-4, 5), 131.6 (s, C(ph)-1), 123.7 (s, C(ph)-3), 121.9, 115.1
(2d, C(ph)-2, 6), 79.8 (d, CHO), 58.6 (q, OCH3), 55.8 (t, CH2), 35.2 (q, N±CH3) ppm.
(S)-2-Chloro-ꢀ-hydroxy-4,5-di(phenylmethoxy)benzeneethanamine hydrochloride
(16; C22H23Cl2NO3)
A solution of 0.6 g (1.07 mmol) of 5a in a mixture of 12 ml of methanol and 3.6 ml of Et2O was
treated with 0.22 ml of 4.5 M HCl in Et2O at 0ꢀC. After 0.5 h additional 0.1 ml of 4.5 M HCl in Et2O
were added, and the mixture was stirred for 0.5 h. The mixture was treated with saturated NaHCO3,
extracted with Et2O, and the organic layer was dried over Na2SO4 and concentrated under
diminished pressure. The residue was dissolved in a mixture of Et2O and methanol and cooled to
0ꢀC. Addition of a solution of HCl in Et2O afforded, after ®ltration and drying, 0.38 g (85%) of 16.
20
D
1
Colorless crystals; m.p.: 171±172ꢀC; ‰ꢂŠ ˆ ‡40:4 (c ˆ 0.2, CH3OH); H NMR (DMSO-d6, ꢃ,
200 MHz): 8.2 (s, 3H, NH3Cl), 7.50±7.25 (m, 11H, ph-H), 7.12 (s, 1H, ph-H), 6.23 (d, J ˆ 4.8 Hz,
1H, OH), 5.25±5.03 (m, 5H, 2 CH2O, CHOH), 3.00±2.70 (m, 2H, CH2N) ppm; 13C NMR (DMSO-d6,
ꢃ, 50 MHz): 148.4, 147.5 (2s, C(ph)-4, 5), 136.9, 136.7, 131.2 (3s, C(ph, ph0, ph00)-1), 128.4, 127.9,
127.6, 127.5 (4d, 10C, C(ph0, ph00)-2, 3, 4, 5, 6), 122.0 (s, 1C, C(ph)-2), 114.8, 113.4 (2d, C(ph)-3, 6),
70.4, 70.3 (2t, 2 OCH2), 65.8 (d, CHOH), 43.8 (t. CH2N) ppm.
(R)-2-Chloro-ꢀ-hydroxy-4,5-di(phenylmethoxy)benzeneethanamine hydrochloride
(ent-16; C22H23Cl2NO3)
ent-16 was prepared from 1.11 g (1.97 mmol) of 6a in the same manner as described for 16 to give
0.61 g (74%) of ent-16.
20
D
Colorless crystals; m.p.: 172±173ꢀC; ‰ꢂŠ ˆ ꢁ38:3 (c ˆ 0.17, CH3OH); 1H NMR (DMSO-d6, ꢃ,
200 MHz): 8.2 (s, 3H, NH3Cl), 7.50±7.25 (m, 11H, ph-H), 7.12 (s, 1H, ph-H), 6.23 (d, J ˆ 4.8 Hz,
1H, OH), 5.25±5.03 (m, 5H, 2 CH2O, CHOH), 3.00±2.70 (m, 2H, CH2N) ppm; 13C NMR (DMSO-d6,
ꢃ, 50 MHz): 148.4, 147.5 (2s, C(ph)-4, 5), 136.9, 136.7, 131.2 (3s, C(Ph, Ph0, Ph00)-1), 128.4, 127.9,
127.6, 127.5 (4d, 10C, C(ph0, ph00)-2, 3, 4, 5, 6), 122.0 (s, 1C, C(ph)-2), 114.8, 113.4 (2d, C(ph)-3, 6),
70.4, 70.3 (2t, 2 OCH2), 65.8 (d, CHOH), 43.8 (t, CH2N) ppm.
(S)-2-Chloro-ꢀ,4,5-trihydroxybenzeneethanamine hydrochloride (17; C8H11Cl2NO3)
20 mg of Pd/C (10%) was added to a solution of 244 mg (0.58 mmol) of 16 in 10 ml of methanol; the
mixture was hydrogenated at 400 kPa in a Parr apparatus for 15 min, cooled to 0ꢀC, the catalyst was
®ltered off, and the solvent was evaporated under diminished pressure at a H2O bath temperature
below 30ꢀC. CCl4 was added to the residue, and the solvent was distilled off again. The addition of
CCl4 followed by evaporation was repeated twice before the residue was treated with 125 ml of a
mixture of acetone and ethyl acetate (4:1). The precipitate was ®ltered off and afforded, after drying
in a desiccator, 97 mg (70%) of 17.
20
D
Colorless crystals; m.p.: 152±156ꢀC; ‰ꢂŠ ˆ ‡70:2 (c ˆ 0.1, CH3OH); 1H NMR (D2O, ꢃ,
200 MHz): 7.04, 6.91 (2s, 2H, 3, 6(ph)-H), 5.20 (dd, J1 ˆ 7 Hz, J2 ˆ 2.6 Hz, 1H, CHOH), 3.27 (dd,
13
J1 ˆ 13 Hz, J2 ˆ 2.6 Hz, 1H, CHHN), 3.10 (dd, J1 ˆ 13 Hz, J2 ˆ 7 Hz, 1H, CHHN) ppm;
NMR
(D2O/DMSO-d6, ꢃ, 50 MHz): 146.6, 145.3 (2s, C(ph)-4, 5), 130.4 (s, C(ph)-1), 123.8 (s, C(ph)-2),
118.5 (d, C(ph)-3), 115.8 (d, C(ph)-6), 67.8 (d, CHOH), 45.7 (t, CH2N) ppm.
(R)-2-Chloro-ꢀ,4,5-trihydroxybenzeneethanamine hydrochloride (ent-17; C8H11Cl2NO3)
ent-17 was prepared from 250 mg (0.59 mmol) of ent-16 in the same manner as described for 17 to
yield 95 mg (66%) of ent-17.

EPC Synthesis of Epinephrines and Norepinephrines
467
20
D
Colorless crystals; m.p.: 156±160ꢀC; ‰ꢂŠ ˆ ꢁ65:0 (c ˆ 0.1, CH3OH); 1H NMR (D2O, ꢃ,
200 MHz): 7.04, 6.91 (2s, 2H, 3, 6(ph)-H), 5.20 (dd, J1 ˆ 7 Hz, J2 ˆ 2.6 Hz, 1H, CHOH), 3.27 (dd,
J1 ˆ 13 Hz, J2 ˆ 2.6 Hz, 1H, CHHN), 3.10 (dd, J1 ˆ 13 Hz, J2 ˆ 7 Hz, 1H, CHHN) ppm; 13C NMR
(D2O/DMSO-d6, ꢃ, 50 MHz): 146.5, 145.2 (2s, C(ph)-4, 5), 130.3 (s, C(ph)-1), 123.7 (s, C(ph)-2),
118.5 (d, C(ph)-3), 115.7 (d, C(ph)-6), 67.8 (d, CHOH), 45.6 (t, CH2N) ppm.
(S)-4-(2-((Benzenesulfonyl)-methylamino)-1-hydroxyethyl)-5-chloro-1,2-phenylene
dibenzenesulfonate (18a; C27H24ClNO9S3)
1.2 ml (0.71 mmol) of benzenesulfonylchloride were added to a solution of 50 mg (0.197 mmol) of
12a in 15 ml of 0.25 M NaOH at 10ꢀC. The mixture was allowed to reach room temperature and
stirred for 4 h. Then, 1 ml of 0.25 M NaOH and 0.6 ml (0.35 mmol) of benzenesulfonylchloride were
added. After stirring for one hour and extraction with CH2Cl2, the organic phase was washed with
H2O, dried over Na2SO4, and concentrated. The excess of benzenesulfonylchloride was removed by
CC (5 g, PE/Et2O (2:3)) to yield 68 mg (54%) of 18a.
20
Colorless crystals; m.p.: 55±57ꢀC; ‰ꢂŠ ˆ ‡40:1 (c ˆ 0.53, CH2Cl2); 1H NMR (CDCl3, ꢃ,
200 MHz): 7.75±7.47 (m, 15H, ph0, ph00, ph00D0-2, 3, 4, 5, 6) 7.35, 7.26 (2s, 2H, 3, 6(ph)-H), 5.25±5.12
(dd, 1H, CHO), 3.39 (bs, 1H, OH), 3.2±3.11 (m, 2H, CH2N), 2.87 (s, 3H, NCH3) ppm; 13C NMR
(CDCl3, ꢃ, 50 MHz): 140.4, 140.1, 138.4, 136.6, 134.8, 134.4, 134.3, 132.7, 129.3, 129.0, 128.9,
128.8, 128.1, 126.9, 124.9, 123.1 (10d, 6s, aromatic C), 67.9 (d, CHO), 55.3 (t, CH2N), 36.6
(q, N±CH3) ppm.
(R)-4-(2-((Benzenesulfonyl)-methylamino)-1-hydroxyethyl)-5-chloro-1,2-phenylene
dibenzenesulfonate (ent-18a; C27H24ClNO9S3)
ent-18a was prepared from 50 mg (0.197 mmol) of ent-12a in the same manner as described for 18a
to give 70 mg (54%) of ent-18a.
20
Colorless crystals; m.p.: 55±57ꢀC; ‰ꢂŠ ˆ ꢁ39:2 (c ˆ 0.94, CH2Cl2); 1H NMR (CDCl3, ꢃ,
200 MHz): 7.75±7.47 (m, 15H, ph0, ph00, ph00D0-H), 7.35, 7.26 (2s, 2H, 3, 6(ph)-H), 5.25±5.12 (dd, 1H,
CHO), 3.39 (bs, 1H, OH), 3.2±3.11 (m, 2H, CH2N), 2.87 (s, 3H, NCH3) ppm; 13C NMR (CDCl3, ꢃ,
50 MHz): 140.4, 140.1, 138.4, 136.6, 134.8, 134.4, 134.3, 132.7, 129.3, 128.9, 128.9, 128.9,128.1,
126.9, 124.9, 123.1 (10d, 6s, aromatic-C), 67.9 (d, CHO), 55.3 (t, CH2N), 36.6 (q, NCH3) ppm.
(S)-5-(2-(Acetylmethylamino)-1-hydroxyethyl)-3-chloro-1,2-phenylene diacetate
(18b; C15H18ClNO6)
1.2 ml of acetic anhydride were added slowly to a mixture of 30 mg (0.118 mmol) of 12b, 7 ml of
H2O, 0.6 ml of chloroform, and 2.0 g of NaHCO3. After stirring for further 30 min and extraction
with chloroform, the combined organic extracts were dried over Na2SO4 and concentrated in vacuo.
CC (1.0 g, Et2O: EtOAc (1:1)) afforded 24 mg (59%) of 18b.
1
Colorless oil; H NMR (CDCl3, ꢃ, 200 MHz): 7.36, 7.15 (2d, J ˆ 1.74 Hz, 2H, 2,6(ph)-H), 4.93
(d, J ˆ 5.86 Hz, 1H, CHO, therein: 4.93 (b, 1H, COH), 3.72±3.21 (m, 2H, CH2), 2.96, 2.83 (2s, 3H,
N±CH3), 2.32, 2.28 (2s, 6H, 2 OCOCH3), 2.10 (s, NCOCH3) ppm.
(R)-5-(2-(Acetylmethylamino)-1-hydroxyethyl)-3-chloro-1,2-phenylene diacetate
(ent-18b; C15H18ClNO6)
ent-18b was prepared from 25 mg (0.098 mmol) of ent-12b in the same manner as described for 18b
to give 23 mg (68%) of ent-18b.

468
M. KnollmuÈller et al.
1
Colorless oil; H NMR (CDCl3, ꢃ, 200 MHz): 7.36, 7.15 (2d, J ˆ 1.74 Hz, 2H, 2,6(ph)-H, 4.93
(d, J ˆ 5.86 Hz, 1H, CHOH, therein: b, 1H, CHOH), 3.72±3.21 (m, 2H, CH2), 2.96, 2.83 (2s, 3H,
N±CH3), 2.32, 2.28 (2s, 6H, 2 OCOCH3), 2.10 (s, NCOCH3) ppm.
(S)-4-(2-(Acetylmethylamino)-1-hydroxyethyl)-5-chloro,1,2-phenylene diacetate
(18c; C15H18ClNO6)
18c was prepared from 25 mg (0.098 mmol) of 12a in the same manner as described for 18b to afford
22 mg (67%) of 18c.
Colorless oil; 1H NMR (CDCl3, ꢃ, 200 MHz): 7.5, 7.21 (2d, 2H, 3, 6(ph)-H), 5.26±5.01 (dd, 1H,
CHO), 3.75±3.65 (m, 2H, CH2N), 2.83 (s, 3H, NCH3), 2.28 (s, 6H, 2 COOCH3), 2.11 (s, 3H,
NCOCH3) ppm.
(R)-4-(2-(Acetylmethylamino)-1-hydroxyethyl)-5-chloro-1,2-phenylene diacetate
(ent-18c; C15H18ClNO6)
ent-18c was prepared from 15 mg (0.059 mmol) of ent-12a in the same manner as described for 18b
to give 12 mg (59%) of ent-18c.
Colorless oil; 1H NMR (CDCl3, ꢃ, 200 MHz): 7.50, 7.21 (2d, 2H, 3,6(ph)-H), 5.26±5.01 (2d, 1H,
CHO), 3.75±3.65 (m, 2H, CH2N), 2.83 (s, 3H, NCH3), 2.28 (s, 6H, 2 COOCH3), 2.11 (s, 3H,
NCOCH3) ppm.
(2S-(2ꢂ(RÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-4-(2-((Benzenesulfonyl)-methyl)-amino)-1-((octahydro-7,8,8-
trimethyl-4,7-methanobenzofurane)-2-yl)-oxy)-ethyl)-5-chloro-1,2-phenylene
dibenzenesulfonate (19a; C39H42ClNO10S3)
A mixture of 35 mg (0.055 mmol) of 18a, 103 mg (0.274 mmol) of (MBE)2O, and a catalytic amount
of p-toluenesulfonic acid in 5 ml of CH2Cl2 was stirred for 2 h in the presence of some Na2SO4. Solid
NaHCO3 was added, the mixture was ®ltered, and the solvent was evaporated. CC (10 g, PE/Et2O
(3:2)) and recrystallization from n-hexane/2-propanol afforded 36 mg (80%) of 19a.
20
1
Colorless crystals; m.p: 133±135ꢀC; ‰ꢂŠ ˆ ‡7:43 (c ˆ 1.52, CH2Cl2); H NMR (CDCl3, ꢃ,
200 MHz): 7.80±7.44 (m, 15H, ph0, ph00, ph00D0-H) 7.26, 7.25 (2s, 2H, 3,6(ph)-H), 5.23 (d, 1H, 2-H),
5.11±4.07 (dd, 1H, CHO), 3.44 (d, 1H, 7a-H), 3.29±3.01 (m, 2H, CH2N), 2.88 (s, 3H, NCH3),
2.35±0.75 (m, 17H, aliphatic-H, therein: 0.88, 0.78, 0.75 (3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ,
50 MHz): 139.5, 139.3, 138.9, 137.4, 134.5, 134.3, 134.0, 133.9, 132.0, 129.4, 128.6, 128.6, 128.5,
127.9, 127.8, 126.7, 124.3, 123.5 (11d, 7s, aromatic-C), 105.9 (d, C-2), 91.0 (d, C-7a), 73.6 (d, CHO),
53.7 (t, CH2N) 47.9 (d, C-4), 46.8 (s, C-7), 46.3 (s, C-8), 45.0 (d, C-3a), 38.4 (t, C-3), 36.5 (q, NCH3),
31.4 (t, C-6), 28.1 (t, C-5), 22.2, 19.8, 10.7 (3q, 3 CH3) ppm.
(2S-(2ꢂ(RÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-5-(2-(Acetylmethylamino)-1-((octahydro-7,8,8-trimethyl-4,7-
methanobenzofurane-2-yl)-oxy)-ethyl)-3-chloro-1,2-phenylene diacetate (19b; C27H36ClNO7)
103 mg (0.27 mmol) of (MBE)2O, a catalytic amount of p-toluenesulfonic acid, and Na2SO4 were
added to 24 mg (0.070 mmol) of 18b in 2 ml CH2Cl2. The mixture was stirred for 90 min at room
temperature, an excess of NaHCO3 was added, and the solids were ®ltered off. The excess of
(MBE)2O was removed by CC (0.8 g, PE/Et2O (2:1), then methanol) to furnish 33 mg (90%) of 19b.
1
Colorless oil; H NMR (CDCl3, ꢃ, 200 MHz): 7.34, 7.28, 7.10, 7.09 (4d, 2H, 2, 6(ph)-H), 5.17
(dd, 1H, 2-H), 4.78, 4.61 (2dd, 1H, CHO), 3.60±3.15 (m, 3H, CH2N, 7a-H), 2.96, 2.90 (2s, 3H,
N±CH3), 2.35±0.70 (m, 26H, aliphatic-H, therein: 2.32, 2.28 (2s, 6H, 2 OCOCH3), 2.09, 2.02 (2s,
3H, NCOCH3), 0.88, 0.79, 0.72 (3s, 9H, 3 CH3)) ppm.

EPC Synthesis of Epinephrines and Norepinephrines
469
(2S-(2ꢂ(SÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-4-(2-((Benzenesulfonyl)-methyl)-amino)-1-((octahydro-7,8,8-
trimethyl-4,7-methanobenzofurane-2-yl)-oxy)-ethyl)-5-chloro-1,2-phenylene
dibenzenesulfonate (20a; C39H42ClNO10S3)
20a was prepared from 30 mg (0.047 mmol) of ent-18a in the same manner as described for 19a to
give 31 mg (78%) of 20a.
20
1
Colorless foam; ‰ꢂŠ ˆ ꢁ43:08 (c ˆ 2.11, CH2Cl2); H NMR (CDCl3, ꢃ, 200 MHz): 7.80±7.45
D
(m, 15H, ph0, ph00, ph000-H) 7.26, 7.25 (2s, 2H, 3,6(ph)-H), 5.21±5.17 (dd, 1H, CHO), 4.84 (d, 1H,
2-H), 3.94 (d, 1H, 7a-H), 3.37±3.07 (m, 2H, CH2N), 2.91 (s, 3H, NCH3), 2.35±0.80 (m, 17H,
aliphatic-H, therein: 0.97, 0.90, 0.80 (3s, 9H, 3 CH3)) ppm; 13C NMR (CDCl3, ꢃ, 50 MHz): 140.4,
140.1, 138.6, 138.0, 137.4, 134.7, 134.6, 134.5, 133.0, 132.4, 131.2, 129.2, 129.1, 128.9, 128.4,
127.2, 127.1, 125.3, 123.8, 123.3 (14d, 6s, aromatic-C), 102.4 (d, C-2), 91.5 (d, C-7a), 71.5 (d, CHO),
53.7 (t, CH2N), 48.2 (d, C-4), 47.5 (s, C-7), 46.9 (s, C-8), 45.5 (d, C-3a), 38.5 (t, C-3), 36.2
(q, NCH3), 32.2 (t, C-6), 28.7 (t, C-5), 22.7, 20.4, 11.4 (3q, 3 CH3) ppm.
(2S-(2ꢂ(SÃ),3aꢂ,4ꢀ,7ꢀ,7aꢂ))-5-(2-(Acetylmethylamino)-1-((octahydro-7,8,8-trimethyl-4,7-
methanobenzofurane-2-yl)-oxy)-ethyl)-3-chloro-1,2-phenylene diacetate (20b; C27H36ClNO7)
20b was prepared from 23 mg (0.067 mmol) of ent-18b in the same manner as described for 19b to
give 31 mg (89%) of 20b
1H NMR (CDCl3, ꢃ, 200 MHz): 7.32, 7.28, 7.10, 7.08 (4d, 2H, 2,6(ph)-H), 5.05±4.89 (m, 2H,
2-H, CHO), 3.79 (d, 1H, 7a-H), 3.69±3.22 (m, 2H, CH2), 3.00, 2.97 (2s, 3H, NCH3), 2.40±0.70
(m, 26H, aliphatic-H), therein: 2.30, 2.27 (2s, 6H, 2 OCOCH3), 2.09, 2.06 (2s, 3H, NCOCH3), 0.94,
0.86, 0.74 (3s, 9H, 3 CH3) ppm.
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Received October 7, 1998. Accepted (revised) October 28, 1998