Enantioselective synthesis of the pyrrolidine core of endothelin antagonist ABT-627 (Atrasentan) via 1,2-oxazines

Article abstract of DOI:10.1002/ejoc.200300234

Diastereoselective syntheses of the pyrrolidine core 6a of the endothelin antagonist ABT-627 (Atrasentan) either as a racemic mixture or as an enantiopure compound are presented. The crucial steps of these syntheses utilized the highly diastereoselective

Full text of DOI:10.1002/ejoc.200300234

FULL PAPER
Enantioselective Synthesis of the Pyrrolidine Core of Endothelin Antagonist
ABT-627 (Atrasentan) via 1,2-Oxazines
Monika Buchholz[a] and Hans-Ulrich Reißig*[a]
Keywords: Asymmetric synthesis / Hydrogenations / Inhibitors / Ring contraction / Nitrogen heterocycles
Diastereoselective syntheses of the pyrrolidine core 6a of the
oxazines 7 or 8, followed by trapping with ethyl cyanofor-
endothelin antagonist ABT-627 (Atrasentan) either as a ra- mate (ManderЈs reagent). The resulting 5,6-dihydro-4H-1,2-
cemic mixture or as an enantiopure compound are presented.
The crucial steps of these syntheses utilized the highly dia-
stereoselective conjugate addition of 1,3-benzodioxol-5-yl-
lithium to racemic 6H-1,2-oxazine 3 or enantiopure 6H-1,2-
oxazines were transformed into the 2,3,4-trisubstituted pyrro-
lidine 6a.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
Endothelins (ET-1, ET-2, and ET-3) constitute a family
of bicyclic peptides, each containing 21 amino acids, which
are potent vasoconstrictors and potent mitogens.[1] ET-1,
produced primarily by endothelial cells, has been implicated
as a contributing factor in many diseases. Two subtypes of
human endothelin receptors (ETA and ETB) exist, and it is
apparent from many studies that most of the actions of ET-
1 associated with pathological conditions are mediated by
ETA receptors, while the ETB receptors may mediate some
beneficial effects.[2] Animal models and human studies have
suggested that ET receptor antagonists may have beneficial
effects in the treatment of a number of different diseases,
such as heart failure, pulmonary hypertension, renal failure,
asthma, and as a therapeutic agent for cancers.[3] Selective
blocking of the ETA receptor subtype may be advantageous
in the treatment of these diseases. In 1996 a novel class of
non-peptide endothelin receptor antagonists containing a
substituted pyrrolidine ring was discovered at Abbott
Laboratories.[4] ABT-627 (Atrasentan, Scheme 1) is highly
potent and selective for the ETA receptor subtype. In the
following years, structure-activity studies were carried out
to increase the selectivity, binding affinity and metabolic
stability of ABT-627 by modification of the substituents on
the pyrrolidine ring.[2Ϫ5] Recent results demonstrate that
the selectivity and the metabolic stability can be improved
by variation of the substituents on the aromatic rings.[3]
Meanwhile, phase III clinical trials with Atrasentan for the
treatment of prostate cancer are in progress and phase II
trials for the treatment of other cancers are planned.[6]
Scheme 1. Retrosynthetic analysis of endothelin antagonist ABT-
627 (Atrasentan)
In the initial synthesis of ABT-627, the construction of
the pyrrolidine ring involves a Michael reaction between
ethyl (4-methoxybenzoyl)acetate and 3,4-(methylenedioxy)-
2Ј-nitrostyrene, followed by a reduction.[4] The disadvan-
tages of this method are poor diastereoselectivity and reso-
lution of the enantiomers at a late stage, either by treatment
of the carboxylic acid with a chiral oxazolidine and separ-
ation of the resulting diastereomers by chromatography, or
by generation of a chiral salt and separation of the dia-
stereomers by crystallisation. Wittenberger[7] and Pfau[8]
have developed enantioselective syntheses with the use of
a valine-derived oxazolidinone or of methylbenzylamine as
chiral auxiliaries. The pyrrolidine ring is formed either by a
[a]
Institut für Chemie Ϫ Organische Chemie,
Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
E-mail: hans.reissig@chemie.fu-berlin.de
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300234
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Enantioselective Synthesis of the Pyrrolidine Core of Atrasentan via 1,2-Oxazines
FULL PAPER
ring-contraction of
a 1,2-oxazine, prepared by dia-
stereoselective cyclization, or by a method similar to the
original synthesis, but now with employment of an enantio-
selective Michael-type reaction.
Retrosynthetic analysis (Scheme 1) shows that the pyr-
rolidine core of ABT-627 should also be available through
hydrogenolysis of a suitably substituted 1,2-oxazine, which
should be accessible from conjugate addition between 1,3-
benzodioxol-5-yllithium or an equivalent and a 6H-1,2-ox-
azine, followed by trapping of the intermediate with a car-
boxylating electrophile. In the key step,
a hetero-
DielsϪAlder reaction of an α-nitroso alkene should provide
the required 6H-1,2-oxazine. Conjugate additions of reac-
tive organolithium compounds and trapping of the inter-
mediates with electrophiles has proved to be an highly ef-
ficient and diastereoselective process, affording 4,5-trans/
5,6-trans-diastereomers either in large excess or exclus-
ively.[9,10] Introduction of chiral alkoxy groups at 6H-1,2-
oxazine permits the synthesis of enantiopure 1,2-oxazines
and products derived from them.[11]
Results and Discussion
Synthesis of the Racemic Pyrrolidine
We first examined the viability of the anticipated route
by a synthesis of rac-6a. This 2,3,4-trisubstituted pyrroli-
dine was prepared starting from 1-bromo-2-ethoxyethene
(1) and α-bromo-(p-methoxy)acetophenonoxime (2,
Scheme 2). Addition of sodium carbonate to the reaction
mixture causes a nitroso alkene to be formed in situ, and
this undergoes a hetero-DielsϪAlder reaction to yield a 5-
bromo-substituted 4H-1,2-oxazine. Its treatment with 1,8-
Scheme 2. Synthesis 2,3,4-trisubstituted pyrrolidines rac-6a and
rac-6b
diazabicyclo[5.4.0]undec-7-ene (DBU) furnished 6H-1,2- ently changed by column chromatography due to the acid-
oxazine 3 in 44% yield. Unfortunately, all attempts to im- catalysed equilibration. This behaviour has been discussed
prove the efficiency of this reaction were unsuccessful: nei- earlier and is only relevant for 4-alkoxycarbonyl-substituted
ther the use of a larger excess of the dienophile, in order 1,2-oxazines.[10]
to avoid side reactions of the reactive nitroso alkene, nor
The transformation of 1,2-oxazines into pyrrolidines by
modifications of the reaction conditions [different solvents cleavage of the NϪO bond with catalytically activated hy-
(CH2Cl2 or aqueous solution of LiCl), enhanced pressure drogen is a well known process.[14] Hydrogenolysis of rac-4
or temperature] had a positive effect. The relatively low with Pd/C as catalyst in the presence of Boc2O gave the
yield of the cycloaddition in relation to the reactions of protected pyrrolidine rac-5 in 64% yield as a mixture of
other nitroso alkenes, such as 1-alkoxycarbonyl- or 1-phe- diastereomers (80:20), which were easily separated by
nyl-substituted nitroso alkenes,[12] may be explained by the HPLC. The mechanism of this multi-step, one-pot process
electron-donating effect of the methoxy substituent, which involves a reductive cleavage of the NϪO bond, fragmen-
makes the transient nitroso alkene (derived from 2) an in- tation of the resulting semiacetal, reduction of the CϭN
ferior heterodiene for a DielsϪAlder reaction with inverse bond, recyclisation, and final reduction of the resulting cyc-
electron demand.
lic imine intermediate to afford the isolated pyrrolidine de-
Addition of 1,3-benzodioxol-5-yllithium to 6H-1,2-ox- rivative. In previous studies[15] it was shown that addition
azine 3 and trapping of the resulting intermediate with ethyl of Boc2O to the reaction mixture prevents the cleavage of
cyanoformate (Mander’s reagent[13]) provided 1,2-oxazine the benzylic CϪN bond of the pyrrolidine produced. This
rac-4 in moderate yield but with good diastereoselectivity acylating additive also results in a cleaner reaction and fa-
(d. r. 90:10). In accordance with previous results,[10] con- cilitates purification of products.
firmed by NMR spectroscopy, the configuration of the
The configurations of pyrrolidines rac-5a and rac-5b were
major isomer was assigned as 4,5-trans/5,6-trans and that assigned after cleavage of the protecting group with tri-
of the minor isomer 4,5-cis/5,6-trans. This recorded dia- fluoroacetic acid (TFA). Comparison with the known 2,3-
stereomeric ratio probably represents the equilibrium. For trans/3,4-trans-substituted pyrrolidine[4] and NOE measure-
crude rac-4 a ratio of 44:56 was recorded, which was appar- ments revealed that the major isomer has the desired 2,3-
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M. Buchholz, H.-U. Reißig
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trans/3,4-trans configuration, while the minor isomer is the
2,3-cis/3,4-trans product. The transformation of pyrrolidine
rac-6a into ABT-627 by N-alkylation and subsequent ester
hydrolysis was described previously.[4]
Synthesis of Enantiopure Pyrrolidine
The synthesis of enantiopure precursor (2R,3R,4S)-6a
was also achieved with 6H-1,2-oxazine 3 as starting mate-
rial. In a previous publication[11] we reported the synthesis
of related enantiopure 6H-1,2-oxazines by Lewis acid-cata-
lysed exchange of the 6-ethoxy group with (Ϫ)-menthol em-
ployed as chiral auxiliary. Treatment of 3 with either (ϩ)-
menthol or (Ϫ)-menthol furnished the expected pairs of
two diastereomers (d. r. 60:40). With (ϩ)-menthol and 3,
(6S)-7 is the slightly favoured diastereomer, whereas (6R)-8
is formed predominantly with (Ϫ)-menthol (Scheme 3). The
diastereomers can easily be separated by flash chromatogra-
phy or HPLC. On treatment of a pure compound with cata-
lytic amounts of acid the 60:40 mixture of isomers is formed
again, which in principle provides the opportunity to recy-
cle the undesired diastereomer.
Addition of 1,3-benzodioxol-5-yllithium to compounds 7
and 8, followed by trapping with ethyl cyanoformate,
yielded the desired compounds 9 and 10 with good dia-
Scheme 4. Conjugated addition of 1,3-benzodioxol-5-yllithium to
6-menthyloxy-substituted 6H-1,2-oxazines 7 and 8; (a) 1. LiAr2,
THF, Ϫ78 °C, 2. NCCO2Et, Ϫ78 °C, then EtOH
stereoselectivities (Scheme 4). Remarkably, the enantiomers
(6R)-8 and (6S)-7 are much less reactive towards the ad-
dition of an aryllithium compound than the enantiomers
(6R)-7 and (6S)-8, reflected both in lower yields and the
formation of side product 11, apparently generated by ad-
dition of the lithiated intermediate to a second 6H-1,2-ox-
azine. In general, the 6H-1,2-oxazines were added to an ex-
cess of the organolithium reagent (2.2 equiv.) over a period
of 35 to 60 min in order to avoid this side reaction. For the
reaction of (6S)-7 we therefore increased the addition time
(120 min) and the excess of the organolithium reagent (5
equiv.), but the yield of (6S)-9 was only slightly improved
and the formation of 11 could not be prevented. These
experiments clearly reveal that enantiomers (6R)-7 and
(6S)-8 are the compounds with matching configurations for
efficient attack of (bulky) aryllithium species, whereas their
diastereomers (6S)-7 and (6R)-8 apparently have mis-
matched configurations. As a consequence, the preferred
pathway to 1,2-oxazine with the required 6R configuration
uses (ϩ)-menthol as chiral auxiliary. The stereochemistry of
diastereomerically pure side product 11 was not established,
but a 4R,5S,6R configuration in both 1,2-oxazine rings of
this ‘‘dimer’’ is most likely for mechanistic reasons.
The hydrogenolysis of 1,2-oxazine (6R)-9 was first carried
out under conditions as successfully applied to rac-4
(Scheme 2). However, no conversion was observed on use
either of Pd/C or of Pd(OH)2/C at atmospheric pressure, or
when higher pressure (50Ϫ60 bar) was employed. In all
cases the starting material was recovered unchanged. Fi-
nally, an excess of Raney nickel (ca. 1 g Raney Ni per mmol
Scheme 3. Synthesis of 6-menthyloxysubstituted 6H-1,2-oxazines 7
and 8
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Enantioselective Synthesis of the Pyrrolidine Core of Atrasentan via 1,2-Oxazines
FULL PAPER
Scheme 5. Hydrogenolysis of 9; (a) 70 bar H2, Raney nickel, Boc2O, EtOH/EtOAc
of 1,2-oxazine) under 50Ϫ70 bar of hydrogen in the pres-
ence of Boc2O provided the desired pyrrolidines 5. Interest-
ingly, a reaction employing lower amounts of Raney nickel
(ca. 0.5 g per mmol 1,2-oxazine) furnished pyrrole 12 as
major component (24%) accompanied by only small quan-
tities of pyrrolidine 5 (7%) (Scheme 5). These experiments
show that the reductive cleavage of the NϪO bond of 1,2-
oxazine 9 is strongly hampered by the bulky 6-menthyloxy
group. With Raney nickel the NϪO bond is cleaved, but the
subsequent reduction of the imine bond is relatively slow. If
this imine cyclizes, after elimination of menthol and hydro-
gen shift, pyrrole 12 is finally formed. Only if this imine is
reduced before cyclization can pyrrolidine 6 be formed. An
excess of Raney nickel apparently helps to direct the reac-
tion of this pathway.
Scheme 6. Hydrogenolysis of 10; (a) 50Ϫ60 bar H2, Raney nickel,
Boc2O, EtOH/EtOAc, 22 h
Thus, hydrogenolysis of (6R)-9 and (6S)-10 (mixture of
diastereomers a/b ϭ 90:10) under these conditions afforded
pyrrolidines 5 as mixtures of diastereomers, which could be
separated by HPLC (Schemes 5 and 6). Standard deprotec-
tion of 5a and 5b with trifluoroacetic acid finally provided
pyrrolidines 6a and 6b in good yields. The enantiomeric ex-
comparison of the chemical shifts of the protons at C-3. Be-
cause of the ring current of the vicinal aromatic rings at C-2
and C-4 the signal of the 2,3-trans compound is shifted to
higher field [3-Htrans δ ϭ 3.30Ϫ3.17 (m); 3-Hcis δ ϭ 3.48 (mc)].
The formation of the 2,3-trans products in moderate excess
cess of our target compound (2R,3R,4S)-6a was determined (dr, 70:30) may be interpreted in terms of a chelation mecha-
by transformation into the Mosher amide and HPLC com- nism in which complexation of the carbonyl and the imine
parison with this corresponding amide derived from rac-6a. group with the catalyst surface after NϪO cleavage of 9 re-
In both hydrogenolysis reactions (Schemes 5 and 6) the sults in a fixed conformation. The subsequent reduction of
2,3-trans/3,4-trans diastereomers moderately predominate. the imine unit occurs opposite to the bulky group R (rep-
The configurations of isomers 5c and 5d were assigned by resenting the residue of the intermediate), as illustrated in
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M. Buchholz, H.-U. Reißig
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ethoxyethene (1, 15.1 g, 100 mmol) were dissolved in tert-butyl
methyl ether (MtB) (200 mL) and dichloromethane (50 mL). To
start the reaction, freshly ground sodium carbonate (6.40 g,
60.0 mmol) was added, and the reaction mixture was stirred for 9
days at room temp., another portion of sodium carbonate (6.40 g,
60.0 mmol) being added after 3 days. The suspension was filtered
through a pad of Celite to remove inorganic salts. The resulting
filtrate was treated with DBU (2.40 mL, 15.9 mmol) and the mix-
ture was stirred for 16 h at room temp. The solution was then
washed with water (3 ϫ) and dried with Na2SO4. The solvent was
removed in vacuo, and the excess of 1 was distilled off by Kugelrohr
distillation. The residue was purified by column chromatography
(aluminium oxide, n-hexane/ethyl acetate, 4:1) to yield 1,2-oxazine
3 (1.03 g, 44%) as a colourless solid (m.p. 31Ϫ33 °C). 1H NMR
(250 MHz, CDCl3): δ ϭ 7.67 (d, J ϭ 9.2 Hz, 2 H, Ar), 6.94 (d, J ϭ
9.6 Hz, 2 H, Ar), 6.59 (d, J ϭ 9.8 Hz, 1 H, 4-H), 6.41 (dd, J ϭ 4.4,
9.8 Hz, 1 H, 5-H), 5.59 (d, J ϭ 4.4 Hz, 1 H, 6-H), 4.00, 3.69 (2 dq,
J ϭ 7.1, 9.6 Hz, 2 H, OCH2), 3.84 (s, 3 H, OCH3), 1.23 (t, J ϭ
7.1 Hz, 3 H, CH3) ppm. 13C NMR (125.8 MHz, CDCl3): δ ϭ 160.9
(s, COCH3), 153.5 (s, CϭN), 127.4 (d, Ar), 126.4 (d, C-5), 126.2
(s, Ar), 116.2 (d, C-4), 114.0 (d, Ar), 91.7 (d, C-6), 64.0 (t, OCH2),
55.3 (q, OCH3), 15.0 (q, CH3) ppm. IR (KBr): ν˜ ϭ 3070Ϫ2840
cmϪ1 (CϪH), 1610 (CϭN). C13H15NO3 (233.3) calcd. C 66.94, H
6.31, N 6.00; found C 66.86, H 6.43, N 5.83.
Scheme 7, to provide the observed major diastereomers. We
admit that this interpretation is speculative.
Scheme 7. Proposed chelation mechanism for the reduction of im-
ine intermediates during hydrogenolysis of 5,6-dihydro-4H-1,2-ox-
azines
Conclusion
In summary, we have described a fairly short new method
for the synthesis of enantiopure 2,3,4-trisubstituted pyrroli-
dines through the use of cheap and commercially available
auxiliaries and reagents. The core of endothelin antagonist
5a was prepared in five steps: (i) hetero-DielsϪAlder-reac-
tion with a 1-aryl-nitrosoalkene generated in situ, (ii) ex-
change of the ethoxy group by (ϩ)- or (Ϫ)-menthyloxy, fol-
lowed by separation of the diastereomers, (iii) conjugated
addition, (iv) hydrogenolysis, and (v) deprotection of the
pyrrolidine. Unfortunately, the overall efficiency of our
auxiliary-based method is diminished by the necessity to
separate the diastereomers formed. On the other hand, this
method makes both enantiomers available and it is in prin-
ciple highly flexible with respect to substituents at C-2 and
C-4 of the pyrrolidine ring, while the ethoxycarbonyl group
at C-3 may also be substituted by other moieties introduced
General Procedure A (Addition of 1,3-Benzodioxol-5-yllithium to
1,2-Oxazines 3, 7, and 8): tert-Butyllithium (1.5  solution in pen-
tane, 4.4 equiv.) was added at Ϫ78 °C to a solution of 5-bromo-
1,3-benzodioxole (2.2 equiv.) in THF (5 mL/mmol of 1,2-oxazine).
After the mixture had been stirred for 30 min, a solution of 1,2-
oxazine (1.0 equiv.) in THF (10 mL/mmol of 1,2-oxazine) was ad-
ded (addition time see below) and the mixture was stirred at Ϫ78
°C. Ethyl cyanoformate was then added, and the mixture was
stirred at Ϫ78 °C. Water or ethanol was added and the mixture
was allowed to warm to room temp. After addition of sat. aqueous
in the conjugate addition (step iii). Thus, many analogues ammonium chloride solution (10 mL/mmol of 1,2-oxazine) the
mixture was extracted with diethyl ether (2 ϫ 20 mL/mmol of 1,2-
oxazine), the combined extracts were dried (Na2SO4), and the sol-
vent was removed in vacuo. The crude product was purified by
column chromatography (neutral aluminium oxide).
of ABT-627 should be available by our route.
Experimental Section
t-5-(1,3-Benzodioxol-5-yl)-c-6-ethoxy-r-4-ethoxycarbonyl-3-(4-
methoxyphenyl)-5,6-dihydro-4H-1,2-oxazine (rac-4): According to
General Procedure A, a solution of 1,3-benzodioxol-5-yllithium
was prepared from 5-bromo-1,3-benzodioxole (442 mg, 2.20 mmol)
and tert-butyllithium (2.9 mL, 4.4 mmol). 1,2-Oxazine 3 (233 mg,
1.00 mmol) was added to this solution over a period of 60 min.
After the mixture had been stirred for an additional 15 min, ethyl
cyanoformate (0.30 mL, 3.10 mmol) was added and the reaction
mixture was stirred for 60 min. Water (1 mL) was then added, and
the mixture was allowed to warm to room temp. The crude product
(dr, 44:56) was purified by column chromatography (n-hexane/ethyl
acetate, 6:1) to yield 1,2-oxazine rac-4 (264 mg, 62%, dr 90:10) as
a yellowish solid, together with the starting material 3 (30 mg,
13%). 1,2-Oxazine rac-4 was recrystallized from n-hexane/ethyl
acetate to provide diastereomerically pure product (202 mg, 47%)
as colourless crystals (m.p. 127Ϫ128 °C). 1H NMR (270 MHz,
CDCl3): δ ϭ 7.61Ϫ7.57 (m, 2 H, Ph), 6.92Ϫ6.89 (m, 2 H, Ph),
6.78Ϫ6.74 (m, 3 H, Ph), 5.92 (s, 2 H, OCH2O), 5.28* (d, J ϭ
3.4 Hz, 0.1 H, 6-H), 5.10 (d, J ϭ 2.4 Hz, 0.9 H, 6-H), 4.25Ϫ3.80
(m, 4 H, OCH2, 5-H), 3.82 (s, 3 H, OCH3), 3.64 (d, J ϭ 2.0 Hz, 1
H, 4-H), 3.70Ϫ3.53 (m, 1 H, OCH2), 1.15 (t, J ϭ 7.1 Hz, 3 H,
CH3), 1.11 (t, J ϭ 7.3 Hz, 3 H, CH3) ppm. 13C NMR (62.9 MHz,
CDCl3): δ ϭ 169.6 (s, CϭO), 160.7 (s, COCH3), 152.8 (s, CϭN),
General: Unless otherwise stated, all reactions were performed un-
der argon atmosphere in flame-dried flasks by addition of the com-
ponents by syringe. All solvents were dried by standard procedures.
1H and 13C NMR spectra were recorded on Bruker instruments
(AC, 500, WH 270, AC 250) in CDCl3 or C6D6 solution. The
chemical shifts are given relative to the TMS or to the CDCl3 signal
(δH ϭ 7.27, δC ϭ 77.0). Higher order NMR spectra were approxi-
mately interpreted as first-order spectra if possible. Missing signals
of minor isomers are hidden by signals of major isomers, or could
not be unambiguously identified due to low intensity. IR spectra
were measured with a Nicolet 5 SXC FT-IR spectrometer. The MS
and HRMS spectra were recorded with a Varian MAT 711 instru-
ment. Neutral aluminium oxide (activity III, Fluka/Merck) or silica
gel (0.040Ϫ0.063 mm, Fluka) were used for column chromatogra-
phy. Nucleosil 50-5 (Macherey & Nagel) was used for HPLC. Melt-
ing points (uncorrected) were measured with a Thermovar melting
point microscope from Reichert. Optical rotations were determined
with PerkinϪElmer 241 polarimeter at 20 °C. Starting materials
1[16] and 2[17] were prepared by literature procedures. All other
chemicals were commercially available and were used as received.
6-Ethoxy-3-(p-methoxyphenyl)-6H-1,2-oxazine (3): α-Bromo-(p-
methoxy)acetophenonoxime (2, 2.47 g, 10.1 mmol) and 1-bromo-2-
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Enantioselective Synthesis of the Pyrrolidine Core of Atrasentan via 1,2-Oxazines
FULL PAPER
148.1, 146.9, 132.4, 128.6 (4 s, Ar), 127.2, 113.8 (2 d, 3-Ar), 122.6*, Ethyl c-4-(1,3-Benzodioxol-5-yl)-r-2-(4-methoxyphenyl)pyrrolidine-t-
121.0, 108.5, 108.1, 108.0* (5 d, Ar), 101.1 (t, OCH2O), 98.3*, 97.7 3-carboxylate (rac-6a): According to General Procedure B, pyrroli-
(2 d, C-6), 64.2*, 63.5, 61.5, 60.9* (4 t, OCH2), 55.3 (OCH3), 42.5*,
42.3, 42.0*, 41.1 (4 d, C-4, C-5), 15.0*, 14.8, 13.8, 13.5* (4 q,
CH3) ppm, * signals of 3,4-cis isomer. IR (KBr): ν˜ ϭ 2980Ϫ2840
dine rac-5a (60 mg, 0.127 mmol), dissolved in TFA (1 mL), was
stirred for 1 h. After the aqueous workup, rac-6a (46 mg, 98%) was
obtained as a spectroscopically pure compound. Column chroma-
cmϪ1 (CϪH), 1730 (CϭO), 1610 (CϭN). C23H25NO7 (427.5): tography (SiO2, n-hexane/ethyl acetate, 1:2) yielded rac-6a (14 mg,
calcd. C 64.62, H 5.89, N 3.28; found C 64.40, H 5.79, N 3.23.
30%) as a colourless oil. 1H NMR (270 MHz, CDCl3): δ ϭ 7.34
(d, J ϭ 8.8 Hz, 2 H, Ar), 6.82Ϫ6.65 (m, 5 H, Ar), 5.91 (s, 2 H,
OCH2O), 4.45 (d, J ϭ 8.8 Hz, 1 H, 2-H), 4.04Ϫ3.88 (m, 2 H,
OCH2), 3.73 (s, 3 H, OCH3), 3.73Ϫ3.44 (m, 2 H, 4-H, 5-H), 3.18
(dd, J ϭ 6.3, 9.9 Hz, 1 H, 5-H), 2.88 (t, J ϭ 8.8 Hz, 1 H, 3-H),
1.97 (br.s, 1 H, NH), 1.09 (t, J ϭ 7.0 Hz, 3 H, CH3) ppm. The
Ethyl 4-(1,3-Benzodioxol-5-yl)-N-tert-butoxycarbonyl-2-(4-meth-
oxyphenyl)pyrrolidine-3-carboxylate (rac-5): A suspension of Pd
(10%)/C (50 mg) in ethanol (8 mL) was saturated with hydrogen.
1,2-Oxazine rac-4 (220 mg, 0.515 mmol) and di-tert-butyl dicar-
bonate (120 mg, 0.550 mmol) dissolved in ethyl acetate (8 mL) were
added, and the mixture was stirred under hydrogen at atmospheric
pressure and room temp. for 3 days. The suspension was then fil-
tered through Celite, eluting with ethyl acetate. The filtrate was
concentrated in vacuo and the crude product was purified by col-
umn chromatography (SiO2, n-hexane/ethyl acetate, 4:1) to yield a
mixture of isomers (5a/5b 80:20). Separation of the obtained iso-
mers by HPLC (solvent: n-hexane ϩ 15% ethyl acetate) yielded rac-
5a (81 mg), a mixture of 5a/5b (80:20, 51 mg), and rac-5b (23 mg,
total yield 64%) as colourless oils.
analytical data are in accordance with those given in ref.[8]
.
Ethyl t-4-(1,3-Benzodioxol-5-yl)-r-2-(4-methoxyphenyl)pyrrolidine-t-
3-carboxylate (rac-6b): According to General Procedure B, pyrrol-
idine rac-5b (20 mg, 0.043 mmol), dissolved in TFA (1 mL), was
stirred for 1 h. After the aqueous workup, rac-6b (16 mg, quant.,
colourless oil) was obtained as a spectroscopically pure compound.
1H NMR (270 MHz, CDCl3): δ ϭ 7.22 (d, J ϭ 8.8 Hz, 2 H, Ar),
6.92Ϫ6.70 (m, 5 H, Ar), 5.91 (s, 2 H, OCH2O), 4.66 (d, J ϭ 8.8 Hz,
1 H, 2-H), 4.80Ϫ3.52 (m, 4 H, OCH2, 4-H, 5-H), 3.77 (s, 3 H,
OCH3), 3.26 (dd, J ϭ 7.4, 8.8 Hz, 1 H, 5-H), 3.01 (mc, 1 H, 3-H),
0.80 (t, J ϭ 7.0 Hz, 3 H, CH3).
1
rac-5a: H NMR (500 MHz, CDCl3, 320 K): δ ϭ 7.14, 6.83 (2 d,
J ϭ 8.7 Hz, 2 H, 2 H, 2-Ar), 6.72Ϫ6.67 (m, 3 H, 4-Ar), 5.87 (s, 2
H, OCH2O), 4.97 (d, J ϭ 8.5 Hz, 1 H, 2-H), 4.20 (mc, 1 H, 5-H),
4.03 (q, J ϭ 7.1 Hz, 2 H, OCH2), 3.77 (s, 3 H, OCH3), 3.60Ϫ3.51
(m, 2 H, 4-H, 5-H), 3.04 (mc, 1 H, 3-H), 1.22 [br. s, 9 H, C(CH3)3],
1.06 (t, J ϭ 7.2 Hz, 3 H, CH3) ppm. 13C NMR (125.8 MHz,
CDCl3): δ ϭ 171.6 (s, CϭO), 158.6 (s, COCH3), 153.9 (s, CϭO),
147.8, 146.7, 133.3, 131.3 (4 s, Ar), 126.8, 126.5*, 120.7, 114.0*,
113.6, 108.3, 107.4 (7 d, Ar), 101.0 (t, OCH2O), 79.7 [s, C(CH3)3],
64.7 (d, C-2), 61.3 (d, C-3), 60.8 (t, OCH2), 55.1 (q, OCH3), 53.8
(t, C-5), 47.2 (d, C-4), 27.9 [q, C(CH3)3], 14.0 (q, CH3) ppm,
* signals of rotamer. IR (film): ν˜ ϭ 2980Ϫ2930 cmϪ1 (CϪH), 1730,
1695 (CϭO). C26H31NO7 (469.2): calcd. C 66.51, H 6.65, N 2.98;
found C 66.55, H 6.57, N 2.68.
General Procedure C (Preparation of 6-Menthyloxy-6H-1,2-ox-
azines 7؊8): BF3·OEt2 (2 equiv.) was added at Ϫ78 °C to a solution
of 1,2-oxazine 3 in CH2Cl2 (20 mL/mmol). After the mixture had
been stirred for 30 min, (ϩ)- or (Ϫ)-menthol (3 equiv.) was added
and the solution was allowed to warm to room temp. The reaction
mixture was stirred for 24 h, water (5 mL/mmol) was then added,
the phases were separated, the organic layer was dried (Na2SO4),
and the solvent was evaporated in vacuo. The crude product was
purified by column chromatography (neutral aluminium oxide, n-
hexane/ethyl acetate, 8:1). The diastereomers were separated by
HPLC (n-hexane ϩ5% ethyl acetate).
6-[(1S,2R,5S)-2-Isopropyl-5-methylcyclohexyloxy]-3-(p-methoxy-
phenyl)-6H-1,2-oxazine (7): According to General Procedure C,
(ϩ)-menthol (2.08 g, 13.3 mmol) was added to a solution of
1
rac-5b: H NMR (500 MHz, CDCl3, 320 K): δ ϭ 7.09, 6.81 (2 d,
BF3·OEt2 (1.11 mL, 8.86 mmol) and 1,2-oxazine
3 (1.03 g,
J ϭ 8.9 Hz, 2 H, 2 H, 2-Ar), 6.76Ϫ6.70 (m, 3 H, 4-Ar), 5.89 (s, 2
H, OCH2O), 5.23 (br. s, 1 H, 2-H), 4.12 (t, J ϭ 10.0 Hz, 1 H, 5-
H), 3.87 (dt, J ϭ 9.4, 11.4 Hz, 1 H, 4-H), 3.77 (s, 3 H, OCH3), 3.73
(q, J ϭ 7.1 Hz, 2 H, OCH2), 3.50 (t, J ഠ 11 Hz, 1 H, 5-H), 3.46
(dd, J ϭ 8.7, 11.4 Hz, 1 H, 3-H), 1.27 [br. s, 9 H, C(CH3)3], 0.96
(t, J ϭ 7.1 Hz, 3 H, CH3) ppm. 13C NMR (62.9 MHz, CDCl3):
δ ϭ 169.2 (s, CϭO), 159.0 (s, COCH3), 153.8 (s, CϭO), 147.9,
146.7, 132.7, 132.4* (3 s, Ar), 127.7, 121.0, 113.6*, 113.3, 108.4,
108.0 (6 d, Ar), 101.0 (t, OCH2O), 79.8 [s, C(CH3)3], 62.7 (d, C-2),
60.5 (t, OCH2), 56.7, 55.7* (2 d, C-3), 55.2 (q, OCH3), 53.7*, 52.9
(2 t, C-5), 43.1*, 42.3 (2 d, C-4), 28.2 [q, C(CH3)3], 13.8 (2 q, CH3)
ppm, * signals of a rotamer. IR (film): ν˜ ϭ 2980Ϫ2840 cmϪ1
(CϪH), 1740, 1695 (CϭO), 1610, 1585, 1250, 1180, 1040.
4.43 mmol). Purification of the crude product by chromatography
provided 1,2-oxazine 7 [1.19 g, 78%, (6S)/(6R) ϭ 60:40]. Separation
of the diastereomers by HPLC yielded (6R)-7 (433 mg, 28%) as
colourless crystals (m.p. 147Ϫ149 °C) and (6S)-7 (681 mg, 45%) as
colourless crystals (m.p. 107Ϫ108 °C).
[(6R)-7]: [α]2D0 ϭ Ϫ56.4 (c ϭ 1.34, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 7.66, 6.94 (2 d, J ϭ 8.8 Hz, 2 H, 2 H, Ar), 6.58 (d,
J ϭ 10.0 Hz, 1 H, 4-H), 6.41 (dd, J ϭ 4.4, 10.0 Hz, 1 H, 5-H), 5.62
(d, J ϭ 4.4 Hz, 1 H, 6-H), 3.84 (s, 3 H, OCH3), 3.61 (dt, J ϭ
4.2, 10.5 Hz, 1 H, 1Ј-H), 2.28 (mc, 1 H, 2Ј-H), 2.15Ϫ2.05 [m, 1 H,
CH(CH3)2], 1.65Ϫ0.83 (m, 7 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), 0.91 (d,
J ϭ 7.4 Hz, 3 H, 5Ј-CH3), 0.90, 0.83 [2 d, J ϭ 6.6 Hz, 6 H,
CH(CH3)2] ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 160.9 (s,
COCH3), 153.3 (s, CϭN), 127.5 (d, Ar), 126.6 (s, Ar), 126.0 (d, C-
5), 116.2 (d, C-4), 114.1 (d, Ar), 93.0 (d, C-6), 79.7 (d, C-1Ј), 55.3
(q, OCH3), 48.5 (d, C-2Ј), 42.2 (t, C-6Ј), 34.3 (t, C-4Ј), 31.7 (d, C-
5Ј), 25.6 [d, CH(CH3)2], 23.2 (t, C-3Ј), 22.1 (q, 5Ј-CH3), 21.1, 16.3
[2 q, CH(CH3)2] ppm. IR (KBr): ν˜ ϭ 3075Ϫ2850 cmϪ1 (CϪH),
1610, 1580 (CϭC, CϭN). C21H29NO3 (343.5): calcd. C 73.44, H
8.51, N 4.08; found C 73.34, H 8.38, N 4.03.
Mixture of Isomers: MS (EI, 80 eV): m/z (%) ϭ 469 (5) [Mϩ], 412
(33) [Mϩ Ϫ C4H9], 368 (100) [Mϩ Ϫ C5H9O2], 352 (17), 180 (34),
148 (58), 136 (31), 121 (9). HRMS (EI, 80 eV) C26H31NO7: calcd.
469.2101; found 469.2120.
General Procedure B (Deprotection of tert-Butyl Carbamates): Pyr-
rolidine 5 was dissolved in CH2Cl2, and TFA was added at 0 °C.
The mixture was stirred at room temp. and satd. sodium hydrogen
carbonate solution was then added. The mixture was diluted with
CH2Cl2 and washed with brine. The organic phase was dried
(Na2SO4), and the solvent was evaporated in vacuo.
[(6S)-7]: [α]2D0 ϭ ϩ94.8 (c ϭ 1.11, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 7.61, 6.92 (2 d, J ϭ 8.8 Hz, 2 H, 2 H, Ar), 6.57 (d,
J ϭ 9.6 Hz, 1 H, 4-H), 6.34 (dd, J ϭ 4.4, 9.6 Hz, 1 H, 5-H), 5.72
Eur. J. Org. Chem. 2003, 3524Ϫ3533
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3529

M. Buchholz, H.-U. Reißig
FULL PAPER
(d, J ϭ 4.4 Hz, 1 H, 6-H), 3.86Ϫ3.75 (m, 1 H, 1Ј-H), 3.82 (s, 3 H, ture was allowed to warm to room temp. The crude product was
OCH3), 2.16Ϫ2.11 (m, 1 H, 2Ј-H), 2.00Ϫ1.94 [m, 1 H, CH(CH3)2], purified by column chromatography (n-hexane/ethyl acetate, 8:1) to
1.67Ϫ0.78 (m, 7 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), 0.92 (d, J ϭ 6.6 Hz, 3 give 1,2-oxazine (6R)-9 (559 mg, 62%, 4,5-trans/4,5-cis ϭ 90:10) as
H, 5Ј-CH3), 0.80, 0.78 [2 d, J ϭ 6.6 Hz, 6 H, CH(CH3)2] ppm. 13C a colourless oil. The major isomer was isolated by HPLC (n-hexane
NMR (62.9 MHz, CDCl3): δ ϭ 160.8 (s, COCH3), 153.5 (s, CϭN),
127.3 (d, Ar), 126.6 (s, Ar), 126.5 (d, C-5), 116.1 (d, C-4), 114.1 (d,
ϩ 10% ethyl acetate) {[α]2D0 ϭ ϩ75.6 (c ϭ 0.93, CHCl3)}. 1H NMR
(270 MHz, CDCl3): δ ϭ 7.58, 6.90 (2 d, J ϭ 8.8 Hz, 2 H, 2 H, 3-
Ar), 88.0 (d, C-6), 74.8 (d, C-1Ј), 55.3 (t, OCH3), 48.1 (d, C-2Ј), Ar), 6.78Ϫ6.75 (m, 3 H, 5-Ar), 5.93 (s, 2 H, OCH2O), 5.36* (d,
40.2 (t, C-6Ј), 34.5 (t, C-4Ј), 31.4 (d, C-5Ј), 25.2 [d, CH(CH3)2], J ϭ 5.1 Hz, 0.1 H, 6-H), 5.07 (d, J ϭ 3.7 Hz, 0.9 H, 6-H), 4.19*
23.4 (t, C-3Ј), 22.6 (q, 5Ј-CH3), 20.8, 15.9 [2 q, CH(CH3)2] ppm. (d, J ϭ 7.4 Hz, 0.1 H, 4-H), 4.15Ϫ3.80 (m, 2 H, OCH2), 3.83 (s, 3
IR (KBr): ν˜ ϭ 2950Ϫ2865 cmϪ1 (CϪH), 1610, 1580 (CϭC,
CϭN). C21H29NO3 (343.5): calcd. C 73.44, H 8.51, N 4.08; found
C 73.39, H 8.24, N 4.09.
H, OCH3), 3.83Ϫ3.80 (m, 1 H, 5-H), 3.70 (d, J ϭ 3.7 Hz, 0.9 H,
4-H), 3.48 (dt, J ϭ 4.4, 10.3 Hz, 1 H, 1Ј-H), 2.30Ϫ2.22 (m, 1 H,
2Ј-H), 1.90Ϫ0.65 [m, 10 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H, contains at 1.09
(t, J ϭ 7.0 Hz, CH3)], 0.90, 0.67 (2 d, J ϭ 6.6 Hz, 3 H each, CH3),
0.83 (d, J ϭ 7.4 Hz, 3 H, CH3) ppm. 13C NMR (67.9 MHz,
CDCl3): δ ϭ 169.4 (s, CϭO), 160.7 (s, COMe), 152.9 (s, CϭN),
148.0, 146.9, 132.4, 128.4 (4 s, Ar), 127.3, 127.1*, 121.1, 113.8,
109.9*, 108.4, 108.1 107.6* (8 d, Ar), 101.0 (t, OCH2O), 100.1,
99.7* (2 d, C-6), 80.7*, 80.6 (2 d, C-1Ј), 61.3 (t, OCH2), 55.3, 55.0*
(2 q, OCH3), 48.8 (d, C-2Ј), 43.2 (d, C-5), 42.9*, 42.7 (2 d, C-4),
42.6 (t, C-6Ј), 34.3 (t, C-4Ј), 31.6 (d, C-5Ј), 25.3 (d, 2Ј-CH), 23.0 (t,
C-3Ј), 22.2 (q, 5Ј-CH3), 21.1, 21.0*, 16.0, 13.8 (4 q, CH3) ppm,
* signals of 4,5-cis-isomer. IR (film): ν˜ ϭ 2955Ϫ2870 cmϪ1 (CϪH),
1735 (CϭO). C31H39NO7 (537.6): calcd. C 69.25, H 7.31, N 2.61;
found C 69.12, H 7.37, N 2.61.
6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-3-(p-methoxy-
phenyl)-6H-1,2-oxazine (8): According to General Procedure C,
(Ϫ)-menthol (1.19 g, 7.68 mmol) was added to a solution of
BF3·OEt2 (0.64 mL, 5.21 mmol) and 1,2-oxazine
3 (597 mg,
2.56 mmol). Purification of the crude product by chromatography
provided 1,2-oxazine 8 [801 mg, 91%, (6R)/(6S) ϭ 60:40]. Separ-
ation of the diastereomers by HPLC yielded (6S)-8 (259 mg, 29%)
as colourless crystals (m.p. 145Ϫ146 °C) and (6R)-8 (459 mg, 52%)
as colourless crystals (m.p. 105Ϫ107 °C).
[(6S)-8]: [α]2D0 ϭ ϩ56.2 (c ϭ 1.0, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 7.66, 6.94 (2 d, J ϭ 8.8 Hz, 2 H, 2 H, Ar), 6.58 (d,
J ϭ 10.0 Hz, 1 H, 4-H), 6.41 (dd, J ϭ 4.8, 10.0 Hz, 1 H, 5-H), 5.62
(d, J ϭ 4.8 Hz, 1 H, 6-H), 3.84 (s, 3 H, OCH3), 3.61 (dt, J ϭ
4.4, 10.7 Hz, 1 H, 1Ј-H), 2.28 (mc, 1 H, 2Ј-H), 2.15Ϫ2.05 [m, 1 H,
CH(CH3)2], 1.65Ϫ0.83 (m, 7 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), 0.91 (d,
J ϭ 7.4 Hz, 3 H, 5Ј-CH3), 0.90, 0.83 [2 d, J ϭ 6.6 Hz, 6 H,
CH(CH3)2] ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ 160.9 (s,
COCH3), 153.3 (s, CϭN), 127.5 (d, Ar), 126.6 (s, Ar), 126.0 (d, C-
5), 116.2 (d, C-4), 114.1 (d, Ar), 93.0 (d, C-6), 79.8 (d, C-1Ј), 55.3
(q, OCH3), 48.5 (d, C-2Ј), 42.3 (t, C-6Ј), 34.4 (t, C-4Ј), 31.7 (d, C-
5Ј), 25.7 [d, CH(CH3)2], 23.3 (t, C-3Ј), 22.1 (q, 5Ј-CH3), 21.1, 16.3
[2 q, CH(CH3)2] ppm. IR (KBr): ν˜ ϭ 3075Ϫ2850 cmϪ1 (CϪH),
1610, 1580 (CϭC, CϭN). C21H29NO3 (343.5): calcd. C 73.44, H
8.51, N 4.08; found C 73.28, H 8.37, N 3.98.
Ethyl
(6R)-5-(1,3-Benzodioxol-5-yl)-6-[(1R,2S,5R)-2-isopropyl-5-
methylcyclohexyloxy]-3-(4-methoxyphenyl)-5,6-dihydro-4H-1,2-
oxazine-4-carboxylate [(6R)-10]: According to General Procedure
A, a solution of 1,3-benzodioxol-5-yllithium was prepared from 5-
bromo-1,3-benzodioxole (222 mg, 2.10 mmol) and tert-butyllithium
(1.7 mL, 2.2 mmol). 1,2-Oxazine (6R)-8 (172 mg, 0.501 mmol) was
added to this solution over a period of 35 min. After the mixture
had been stirred for an additional 30 min, ethyl cyanoformate
(0.15 mL, 1.53 mmol) was added and the reaction mixture was
stirred for 60 min. Ethanol (0.3 mL) was then added and the mix-
ture was allowed to warm to room temp. The crude product was
purified by column chromatography (n-hexane/ethyl acetate, 8:1) to
give 1,2-oxazine (6R)-10 (56 mg, 21%, 4,5-trans/4,5-cis ϭ 85:15) as
a colourless oil and a mixture of bis-1,2-oxazine (6R)-11 and ethyl
benzodioxole-5-carboxylate (53 mg, calcd. yield of (6R)-11 19%).
Bis-1,2-oxazine (6R)-11 (yellowish solid, m.p. 72Ϫ79 °C) was puri-
[(6R)-8]: [α]2D0 ϭ Ϫ93.8 (c ϭ 1.0, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 7.63, 6.92 (2 d, J ϭ 8.8 Hz, 2 H, 2 H, Ar), 6.57 (d,
J ϭ 9.6 Hz, 1 H, 4-H), 6.34 (dd, J ϭ 4.4, 9.6 Hz, 1 H, 5-H), 5.72
(d, J ϭ 4.4 Hz, 1 H, 6-H), 3.86Ϫ3.75 (m, 1 H, 1Ј-H), 3.82 (s, 3 H,
OCH3), 2.16Ϫ2.11 (m, 1 H, 2Ј-H), 2.00Ϫ1.94 [m, 1 H, CH(CH3)2],
1.67Ϫ0.78 (m, 7 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), 0.92 (d, J ϭ 6.6 Hz, 3
H, 5Ј-CH3), 0.80, 0.78 [2 d, J ϭ 6.6 Hz, 6 H, CH(CH3)2] ppm. 13C
NMR (62.9 MHz, CDCl3): δ ϭ 160.9 (s, COCH3), 153.5 (s, CϭN),
127.3 (d, Ar), 126.6 (s, Ar), 126.5 (d, C-5), 116.1 (d, C-4), 114.1 (d,
Ar), 88.1 (d, C-6), 74.8 (d, C-1Ј), 55.3 (t, OCH3), 48.1 (d, C-2Ј),
40.2 (t, C-6Ј), 34.5 (t, C-4Ј), 31.4 (d, C-5Ј), 25.2 [d, CH(CH3)2],
23.5 (t, C-3Ј), 22.6 (q, 5Ј-CH3), 20.8, 16.0 [2 q, CH(CH3)2] ppm.
IR (KBr): ν˜ ϭ 2950Ϫ2840 cmϪ1 (C-H), 1610, 1580 (CϭC, CϭN).
C21H29NO3 (343.5): calcd. C 73.44, H 8.51, N 4.08; found C 73.48,
H 8.42, N 4.02.
1
fied by HPLC (n-hexane ϩ 10% ethyl acetate). (6R)-10: H NMR
(270 MHz, CDCl3): δ ϭ 7.50, 6.87 (2 d, J ϭ 8.8 Hz, 2 H, 2 H, 3-
Ar), 6.77Ϫ6.70 (m, 3 H, 5-Ar), 5.89 (s, 2 H, OCH2O), 5.38* (d,
J ϭ 2.9 Hz, 0.15 H, 6-H), 5.16 (d, J ϭ 2.2 Hz, 0.85 H, 6-H),
4.18Ϫ4.05 (m, 1 H, OCH2), 3.89Ϫ3.77 (m, 2 H, OCH2, 5-H), 3.80
(s, 3 H, OCH3), 3.64 (dt, J ϭ 3.7, 10.7 Hz, 1 H, 1Ј-H), 3.61 (d, J ϭ
2.2 Hz, 1 H, 4-H), 2.17Ϫ1.94 (m, 1 H, 2Ј-H), 1.64Ϫ0.73 [m, 10 H,
3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H, contains at 0.99 (t, J ϭ 7.0 Hz, CH3)], 0.87,
0.82 (2 d, J ϭ 6.6 Hz, 3 H each, CH3), 0.81 (d, J ϭ 7.4 Hz, 3 H,
CH3) ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 169.1 (s, CϭO),
160.6 (s, COMe), 154.7*, 153.0 (2 s, CϭN), 148.1, 147.6*, 147.0*,
146.9, 133.1, 130.1*, 129.2, 128.5* (8 s, Ar), 127.2, 126.9*, 122.8*,
121.0, 113.8, 109.1*, 108.4, 108.2, 107.8* (9 d, Ar), 101.0 (t,
Ethyl
(6R)-5-(1,3-Benzodioxol-5-yl)-6-[(1S,2R,5S)-2-isopropyl-5- OCH2O), 95.0, 93.5* (2 d, C-6), 80.5, 74.2* (2 d, C-1Ј), 61.3, 60.3*
methylcyclohexyloxy]-3-(4-methoxyphenyl)-5,6-dihydro-4H-1,2-
oxazine-4-carboxylate [(6R)-9]: According to General Procedure A,
(2 t, OCH2), 55.3 (q, OCH3), 48.0*, 47.8 (2 d, C-2Ј), 42.7, 42.6* (2
d, C-5), 41.2, 41.0* (2 d, C-4), 40.2 (t, C-6Ј), 34.4*, 34.3 (2 t, C-
a solution of 1,3-benzodioxol-5-yllithium was prepared from 5- 4Ј), 31.4, 31.2* (2 d, C-5Ј), 25.5*, 24.4 (2 d, 2Ј-CH), 23.0*, 22.6 (2
bromo-1,3-benzodioxole (738 mg, 3.67 mmol) and tert-butyllithium t, C-3Ј), 22.3 (q, 5Ј-CH3), 21.3, 21.0*, 15.5*, 15.4, 13.7, 13.5* (6 q,
(4.9 mL, 7.3 mmol). 1,2-Oxazine (6R)-7 (573 mg, 1.67 mmol) was CH3) ppm, * signals of 4,5-cis-isomer. IR (film): ν˜ ϭ 3055Ϫ2870
added to this solution over a period of 45 min. After the mixture
cmϪ1 (CϪH), 1735 (CϭO), 1610 (CϭN). MS (EI, 80 eV):
had additionally been stirred for 30 min, ethyl cyanoformate m/z (%) ϭ 537 (5) [Mϩ], 398 (7), 382 (12) 366 (14), 353 (22), 220
(0.49 mL, 5.01 mmol) was added, and the reaction mixture was
stirred for 60 min. Ethanol (0.8 mL) was then added and the mix-
(100). HRMS (EI, 80 eV) C31H39NO7: calcd. 537.2727; found
537.2748.
3530
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3524Ϫ3533

Enantioselective Synthesis of the Pyrrolidine Core of Atrasentan via 1,2-Oxazines
Ethyl 5-(1,3-Benzodioxol-5-yl)-6,6Ј-bis[(1R,2S,5R)-2-isopropyl-5- (2.9 mL, 4.4 mmol). 1,2-Oxazine (6S)-8 (343 mg, 1.00 mmol) was
FULL PAPER
methylcyclohexyloxy]-3,3Ј-bis(4-methoxyphenyl)-5,6,5Ј,6Ј-tetra- added to this solution over a period of 60 min. After the mixture
hydro-4H,4HЈ-[4,5Ј]bi-1,2-oxazinyl-4Ј-carboxylate [(6R)-11]: [α]2D0
ϩ2.8 (c ϭ 1.01, CHCl3). H NMR (270 MHz, CDCl3): δ ϭ 7.70, (0.30 mL, 3.10 mmol) was added and the reaction mixture was
7.63, (2 d, J ϭ 8.8 Hz, 2 H, 2 H, Ar), 6.92 (t, J ϭ 8.8 Hz, 4 H, stirred for 60 min. Ethanol (0.3 mL) was then added and the mix-
ϭ
had additionally been stirred for 15 min, ethyl cyanoformate
1
Ar), 6.71Ϫ6.60 (m, 3 H, Ar), 5.90 (s, 2 H, OCH2O), 4.71 (d, J ϭ
ture was allowed to warm to room temp. The crude product was
5.2 Hz, 1 H, 6Ј-H), 4.67 (d, J ϭ 7.4 Hz, 1 H, 6-H), 4.08 (d, J ϭ purified by column chromatography (n-hexane/ethyl acetate, 10:1)
1.5 Hz, 1 H, 4Ј-H), 4.03Ϫ3.90, 3.81Ϫ3.73 (2 m, 1 H each, OCH2),
3.84, 3.83 (2 s, 3 H each, OCH3), 3.59 (dt, J ϭ 3.9, 10.7 Hz, 1 H,
1ЈЈ-H), 3.47 (dt, J ϭ 4.4, 10.3 Hz, 1 H, 1ЈЈ-H), 3.30 (mc, 1 H, 4-
to give 1,2-oxazine (6S)-10 (306 mg, 57%, 4,5-trans/4,5-cis ϭ 90:10)
as a colourless oil. The major isomer was isolated by HPLC (n-
hexane ϩ 10% ethyl acetate) {[α]2D0 ϭ Ϫ69.6 (c ϭ 0.79, CHCl3)}.
H), 3.24Ϫ3.19 (m, 1 H, 5Ј-H), 3.16 (dd, J ϭ 3.3, 7.4 Hz, 1 H, 1H NMR (270 MHz, CDCl3): δ ϭ 7.60, 6.91 (2 d, J ϭ 9.0 Hz, 2
5-H), 2.28Ϫ2.17, 2.12Ϫ2.02 (2 m, 1 H each, 2ЈЈ-H), 1.62Ϫ0.63,
H, 2 H, 3-Ar), 6.78Ϫ6.75 (m, 3 H, 5-Ar), 5.91 (s, 2 H, OCH2O),
5.36* (d, J ϭ 5.2 Hz, 0.1 H, 6-H), 5.07 (d, J ϭ 3.7 Hz, 0.9 H, 6-
0.47Ϫ0.32 (m, 35 H, CH, CH2, CH3) ppm. 13C NMR (67.9 MHz,
CDCl3): δ ϭ 168.6 (s, CϭO), 161.3, 160.9 (2 s, COMe), 165.4, H), 4.20Ϫ3.90 (m, 2 H, OCH2), 3.81 (s, 2.7 H, OCH3), 3.79* (s,
159.1, 147.9, 146.6, 135.0, 127.9 (6 s, CϭN, Ar), 128.1, 127.8, 121.4, 0.3 H, OCH3), 3.81Ϫ3.79 (m, 1 H, 5-H), 3.73* (d, J ϭ 6.6 Hz, 0.1
114.1, 113.8, 108.5, 108.3 (7 d, Ar), 101.0 (t, OCH2O), 100.6, 95.4 H, 4-H), 3.70 (d, J ϭ 2.9 Hz, 0.9 H, 4-H), 3.48 (dt, J ϭ 4.3,
(2 d, C-6), 77.5, 76.2 (2 d, C-1ЈЈ), 61.3 (t, OCH2), 55.2 (q, OCH3),
47.8, 47.5, 43.3, 42.3 (4 d, C-4, C-5), 39.8, 39.3 (2 t, C-6Ј), 34.3 (t,
10.8 Hz, 1 H, 1Ј-H), 2.29Ϫ2.24 (m, 1 H, 2Ј-H), 1.90Ϫ0.65 (m, 10
H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H, contains at 1.08 (t, J ϭ 7.3 Hz, CH3)],
C-4Ј), 31.2, 31.1 (2 d, C-5Ј), 25.2, 24.9 (2 d, 2Ј-CH), 23.0, 22.9 (2 0.90, 0.82 (2 d, J ϭ 6.9 Hz, 3 H each, CH3), 0.68 (d, J ϭ 7.7 Hz,
t, C-3ЈЈ), 22.1, 22.0, 21.1, 21.0, 15.9, 13.6 (6 q, CH3) ppm. IR
3 H, CH3) ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 169.3 (s,
(KBr): ν˜ ϭ 2925Ϫ2870 cmϪ1 (CϪH), 1740 (CϭO), 1610 (CϭN). CϭO), 160.7 (s, COMe), 152.9 (s, CϭN), 148.0, 146.9, 132.4, 128.4
MS (EI, 80 eV): m/z (%) ϭ 880 (3) [Mϩ], 741 (6), 709 (37), 571 (4 s, Ar), 127.3, 127.1*, 122.6*, 121.1, 113.8, 109.3*, 108.4, 108.0*,
(25), 401 (64), 379 (100), 306 (41), 280 (67), 270 (54), 246 (93), 149
108.1 (9 d, Ar), 101.0 (t, OCH2O), 100.1, 99.7* (2 d, C-6), 80.7*,
(71). HRMS (EI, 80 eV) C52H68N2O10: calcd. 880.4874; found 80.5 (2 d, C-1Ј), 61.3, 61.0* (2 t, OCH2), 55.3 (q, OCH3), 48.8,
880.4854.
48.6* (2 d, C-2Ј), 43.2, 43.0* (2 d, C-5), 42.9*, 42.7 (2 d, C-4), 42.6
(t, C-6Ј), 34.3 (t, C-4Ј), 31.6 (d, C-5Ј), 25.3 (d, 2Ј-CH), 23.0 (t, C-
3Ј), 22.2 (q, 5Ј-CH3), 21.1, 16.0, 13.8*, 13.6 (4 q, CH3) ppm,
* signals of 4,5-cis-isomer. IR (film): ν˜ ϭ 2955Ϫ2870 cmϪ1 (C-H),
1735 (CϭO). C31H39NO7 (537.6): calcd. C 69.25, H 7.31; N 2.61;
found C 68.78, H 7.22, N 2.32.
Ethyl
(6S)-5-(1,3-Benzodioxol-5-yl)-6-[(1S,2R,5S)-2-isopropyl-5-
methylcyclohexyloxy]-3-(4-methoxyphenyl)-5,6-dihydro-4H-1,2-
oxazine-4-carboxylate [(6S)-9]: According to General Procedure A,
a solution of 1,3-benzodioxol-5-yllithium was prepared from 5-
bromo-1,3-benzodioxole (901 mg, 4.48 mmol) and tert-butyllithium
(6.0 mL, 9.0 mmol). 1,2-Oxazine (6S)-7 (308 mg, 0.897 mmol) was
added to this solution over a period of 120 min. After addition of
ethyl cyanoformate (0.54 mL, 5.51 mmol) the reaction mixture was
stirred for 60 min. Ethanol (1.0 mL) was then added and the mix-
General Procedure D (Hydrogenolysis of 1,2-Oxazines under Pres-
sure): 1,2-Oxazine and di-tert-butyl dicarbonate were dissolved in
ethyl acetate and added to a suspension of Raney nickel (50% in
water, Acros) in dry ethanol. The reaction mixture was stirred in
an autoclave under hydrogen pressure (times and pressures given
below) at room temp. The suspension was then filtered through
Celite, eluting with ethyl acetate. The filtrate was concentrated in
vacuo and the crude product was purified by column chromatogra-
phy.
1
ture was allowed to warm to room temp. The H NMR spectrum
shows a mixture of (6S)-9 and (6S)-11 (70:30). Purification by col-
umn chromatography (n-hexane/ethyl acetate, 8:1) yielded 1,2-ox-
azine (6S)-7 (154 mg, 32%, 4,5-trans/4,5-cis ϭ 85:15) as a colourless
oil. Bis-1,2-oxazine (6S)-11 was not isolated in this experiment.
(6S)-9: 1H NMR (250 MHz, CDCl3): δ ϭ 7.52, 6.90 (2 d, J ϭ
8.8 Hz, 2 H each, 3-Ar), 6.80Ϫ6.72 (m, 3 H, 5-Ar), 5.92 (s, 2 H,
OCH2O), 5.40* (d, J ϭ 2.9 Hz, 0.15 H, 6-H), 5.20 (d, J ϭ 2.2 Hz,
0.85 H, 6-H), 4.29Ϫ4.09 (m, 1 H, OCH2), 3.92Ϫ3.81 (m, 2 H,
OCH2, 5-H), 3.82 (s, 3 H, OCH3), 3.67 (dt, J ϭ 3.7, 10.7 Hz, 1 H,
1Ј-H), 3.64 (d, J ϭ 2.2 Hz, 1 H, 4-H), 2.22Ϫ2.01 (m, 1 H, 2Ј-H),
1.66Ϫ0.76 [m, 10 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H, contains at 1.02 (t,
J ϭ 7.4 Hz, CH3)], 0.89, 0.85 (2 d, J ϭ 6.6 Hz, 3 H each, CH3), 0.83
(d, J ϭ 7.4 Hz, 3 H, CH3) ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ
169.1 (s, CϭO), 160.6 (s, COMe), 153.0 (s, CϭN), 148.0, 146.8,
133.1, 129.2 (4 s, Ar), 127.2, 126.9*, 122.9*, 121.0, 113.7, 109.9*,
108.4, 108.2, 107.6* (9 d, Ar), 101.0 (t, OCH2O), 94.9, 93.5* (2 d,
C-6), 74.2* (d, C-1Ј), 61.3, 60.8* (2 t, OCH2), 55.3 (q, OCH3), 48.0*
,
Hydrogenolysis of (6R)-9: According to General Procedure D, 1,2-
oxazine (6R)-9 (488 mg, 0.908 mmol, dr 90:10), di-tert-butyl dicar-
bonate (250 mg, 1.13 mmol) and Raney nickel (ഠ 1 g) in ethanol/
ethyl acetate (1:1, 30 mL) were stirred under hydrogen pressure (ഠ
70 bar) for 3 days. The crude product was purified by column chro-
matography (SiO2, n-hexane/ethyl acetate, 4:1) to yield a mixture
of isomers (dr, 60:24:10:6). Separation of the isomers by HPLC (n-
hexane ϩ 3% 2-propanol) provided (2R,3R,4S)-5a (161 mg, 38%)
and (2S,3R,4S)-5b (75 mg, 18%) as colourless oils, (2S,3S,4S)-5c
(28 mg, 6.5%) as a colourless solid (m.p. 115Ϫ122 °C) and
(2R,3S,4S)-5d (15 mg, 3.5%) as a colourless solid (m.p. 130Ϫ138
°C).
(2R,3R,4S)-5a: [α]2D0 ϭ Ϫ4.4 (c ϭ 0.84, CHCl3). 1H NMR
(500 MHz, C6D6, 351 K): δ ϭ 7.21 (d, J ϭ 8.5 Hz, 2 H, 3-Ar),
6.80Ϫ6.77 (m, 2 H, 3-Ar), 6.66 (d, J ϭ 1.6 Hz, 1 H, 5-Ar), 6.54 (d,
J ϭ 7.9 Hz, 1 H, 5-Ar), 6.50 (dd, J ϭ 1.6, 7.9 Hz, 1 H, 5-Ar), 5.34,
5.33 (2 d, J ϭ 1.5 Hz, 2 H, OCH2O), 5.21 (br. d, J ϭ 8.8 Hz, 1 H,
2-H), 4.26 (mc, 1 H, 5-H), 3.77 (q, J ϭ 7.1 Hz, 2 H, OCH2), 3.51
47.8 (2 d, C-2Ј), 42.8, 42.6* (2 d, C-5), 41.2, 41.0 (2 d, C-4), 40.2
(t, C-6Ј), 34.4*, 34.3 (2 t, C-4Ј), 31.4, 31.2* (2 d, C-5Ј), 25.5*, 24.4
(2 d, 2Ј-CH), 23.0*, 22.6 (2 t, C-3Ј), 22.3 (q, 5Ј-CH3), 21.3, 21.0*,
15.3, 13.7 (4 q, CH3) ppm, * signals of 4,5-cis isomer.
Ethyl
(6S)-5-(1,3-Benzodioxol-5-yl)-6-[(1R,2S,5R)-2-isopropyl-5- (mc, 1 H, 5-H), 3.44 (dt, J ϭ 7.3, 11.3 Hz, 1 H, 4-H), 3.14 (dd, J ϭ
methylcyclohexyloxy]-3-(4-methoxyphenyl)-5,6-dihydro-4H-1,2-
oxazine-4-carboxylate [(6S)-10]: According to General Procedure
A, a solution of 1,3-benzodioxol-5-yllithium was prepared from 5-
bromo-1,3-benzodioxole (442 mg, 2.20 mmol) and tert-butyllithium
8.8, 11.3 Hz, 1 H, 3-H), 1.29 (s, 9 H, CH3), 0.73 (t, J ϭ 7.1 Hz, 3
H, CH3) ppm. 13C NMR (125 MHz, C6D6, 351 K): δ ϭ 171.6 (s,
CϭO), 159.6 (s, COCH3), 153.9 (s, CϭO), 148.5, 147.4, 136.2,
132.5 (4 s, Ar), 127.4, 121.8, 114.4, 108.6, 108.1 (5 d, Ar), 101.0 (t,
Eur. J. Org. Chem. 2003, 3524Ϫ3533
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3531

M. Buchholz, H.-U. Reißig
FULL PAPER
OCH2O), 79.2 [s, C(CH3)3], 65.5 (d, C-2), 61.9 (d, C-3), 60.6 (t, J ϭ 8.6 Hz, 1 H, 3-H), 2.16 (br. s, 1 H, NH), 1.11 (t, J ϭ 7.1 Hz,
OCH2), 54.9 (q, OCH3), 54.8 (t, C-5), 47.9 (d, C-4), 28.3 [q,
3 H, CH3) ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 173.8 (s, Cϭ
C(CH3)3], 14.0 (q, CH3) ppm. IR (film): ν˜ ϭ 2975Ϫ2835 cmϪ1 O), 158.9 (s, COCH3), 147.8, 146.2, 136.4, 134.3 (4 s, Ar), 127.7,
(CϪH), 1730, 1695 (CϭO). C26H31NO7 (469.2): calcd. C 66.45, H
6.66, N 2.98; found C 66.37, H 6.58, N 2.86.
120.4, 113.9, 108.2, 107.5 (5 d, Ar), 100.9 (t, OCH2O), 66.7 (d, C-
2), 61.4, 60.6 (2 t, C-5, OCH2), 55.3, 54.6, 50.6 (q, 2 d, OCH3, C-
3, C-4), 14.2 (q, CH3) ppm. MS (EI, 80 eV): m/z (%) ϭ 369 (36)
[Mϩ], 340 (13), 324 (13), 221 (4), 149 (100). C21H23NO5 (369.4):
calcd. C 68.28, H 6.28, N 3.79; found C 67.88, H 6.19, N 3.79. The
analytical data are in accordance with those given in ref.[8]
(2S,3R,4S)-5b: [α]2D0 ϭ ϩ49.8 (c ϭ 0.84, CHCl3). 1H NMR
(500 MHz, C6D6, 351 K): δ ϭ 7.15Ϫ7.14, 6.77Ϫ6.75 (2 m, 2 H
each, Ar), 6.65Ϫ6.64 (m, 1 H, Ar), 6.55Ϫ6.53 (m, 2 H, Ar), 5.32
(s, 2 H, OCH2O), 5.32Ϫ5.30 (br. s, 1 H, 2-H), 4.15 (mc, 1 H, 5-H),
3.92 (q, J ϭ 10.2 Hz, 1 H, 4-H), 3.57, 3.53 (2 dq, J ϭ 7.1, 10.9 Hz,
2 H, OCH2), 3.47 (t, J ϭ 10.7 Hz, 1 H, 5-H), 3.32 (s, 3 H, OCH3),
3.32Ϫ3.28 (m, 1 H, 3-H), 1.34 (br. s, 9 H, CH3), 0.69 (t, J ϭ 7.1 Hz,
3 H, CH3) ppm. 13C NMR (125.8 MHz, C6D6, 351 K): δ ϭ 168.9
(s, CϭO), 159.7 (s, COCH3), 153.7 (s, CϭO), 148.5, 147.2, 133.7
(3 s, Ar), 128.4, 128.0, 121.3, 113.9, 108.5, 108.4 (s, 5 d, Ar), 101.0
(t, OCH2O), 79.2 [s, C(CH3)3], 63.4 (d, C-2), 60.3 (t, OCH2), 56.8
(d, C-3), 54.8 (q, OCH3), 53.7 (t, C-5), 43.2 (d, C-4), 28.4 [q,
C(CH3)3], 13.8 (q, CH3) ppm. IR (film): ν˜ ϭ 2980Ϫ2900 cmϪ1
(CϪH), 1740, 1695 (CϭO), 1610 (CϭC). MS (EI, 80 eV): m/z
(%) ϭ 469 (18) [Mϩ], 412 (21) [Mϩ Ϫ C4H9], 368 (87) [Mϩ Ϫ Boc],
180 (39), 148 (63), 136 (43), 121 (18), 57 (100) [C4H9ϩ]. HRMS
(EI, 80 eV) C26H31NO2: calcd. 469.2101; found 469.2143.
Deprotection of (2R,3R,4S)-5b: According to General Procedure B,
the protected pyrrolidine (2S,3R,4S)-5b [31 mg, 0.066 mmol, con-
tains 10% of 2R diastereomer)] was dissolved in CH2Cl2 (1 mL),
and TFA (1 mL) was added. The mixture was stirred for 5 h. After
aqueous workup (2S,3R,4S)-6b (20 mg, 82%) was obtained as a
colourless oil. 1H NMR (270 MHz, CDCl3): δ ϭ 7.25, 6.85 (2 d,
J ϭ 8.8 Hz, 2 H, 2 H, 2-Ar), 6.78Ϫ6.75 (m, 3 H, 4-Ar), 4.66 (d,
J ϭ 8.8 Hz, 1 H, 2-H), 3.79 (s, 3 H, CH3), 3.80Ϫ3.57 (m, 4 H,
OCH2, 4-H, 5-H), 3.27 (dd, J ϭ 7.4, 8.8 Hz, 1 H, 5-H), 3.02 (mc,
1 H, 3-H), 2.33 (br. s, 1 H, NH), 0.83 (t, J ϭ 7.4 Hz, 3 H, CH3)
ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 172.9 (s, CϭO), 158.9 (s,
COCH3), 147.8, 146.3, 135.7, 131.9 (4 s, Ar), 128.2, 120.5, 113.4,
108.3, 107.7 (5 d, Ar), 100.9 (t, OCH2O), 65.9 (d, C-2), 60.3 (t,
OCH2), 58.2 (t, C-5), 55.3 (q, OCH3), 48.7 (d, C-4), 13.7 (q,
CH3) ppm.
(2S,3S,4S)-5c: [α]2D0 ϭ ϩ23.9 (c ϭ 0.95, CHCl3). 1H NMR
(270 MHz, CDCl3): δ ϭ 7.19 (mc, 2 H, Ar), 6.87 (d, J ϭ 8.8 Hz, 2
H, Ar), 6.72Ϫ6.60 (m, 3 H, Ar), 5.93 (s, 2 H, OCH2O), 5.26Ϫ5.01
(m, 1 H, 2-H), 4.03Ϫ3.88, 3.72Ϫ3.64 (2 m, 5 H, OCH2, 4-H, 5-H),
3.80 (s, 3 H, OCH3), 3.30Ϫ3.17 (m, 1 H, 3-H), 1.48*, 1.22 [2 s, 9
H, C(CH3)3], 1.05 (t, J ϭ 7.0 Hz, 3 H, CH3) ppm. 13C NMR
(67.2 MHz, CDCl3): δ ϭ 166.1 (s, CϭO), 158.7 (s, COCH3), 154.3
(s, CϭO), 147.7, 146.6, 135.3 (3 s, Ar), 126.9, 120.6, 113.7, 108.1,
107.9 (5 d, Ar), 100.9 (t, OCH2O), 79.8 [s, C(CH3)3], 61.1, 59.0 (2
d, C-2, C-3), 60.5 (t, OCH2), 55.2 (q, OCH3), 51.5 (t, C-5), 44.0 (d,
C-4), 29.6*, 28.1 [2 q, C(CH3)3], 13.9 (q, CH3) ppm, * signals of
rotamer. IR (KBr): ν˜ ϭ 2985Ϫ2875 cmϪ1 (CϪH), 1720, 1700
(CϭO). MS (EI, 80 eV): m/z (%) ϭ 469 (10) [Mϩ], 413 (26) (Mϩ
Ϫ C4H8], 368 (100) [Mϩ Ϫ Boc], 148 (45), 57 (65) [C4H9ϩ].
4-(1,3-Benzodioxol-5-yl)-3-ethoxycarbonyl-2-(4-methoxyphenyl)-
pyrrole (12): According to General Procedure D, 1,2-oxazine (6R)-9
(493 mg, 0.917 mmol, dr 90:10), di-tert-butyl dicarbonate (300 mg,
1.38 mmol) and Raney nickel (ഠ 400 mg) in ethanol/ethyl acetate
(1:1, 20 mL) were stirred under hydrogen pressure (ഠ 50 bar) for 3
days. Purification by column chromatography (SiO2, n-hexane/ethyl
acetate, 4:1) yielded pyrrolidine 5 (31 mg, 7%, mixture of isomers)
and pyrrole 12 (82 mg, 24%) as colourless solids (m.p. 122Ϫ123
°C).
Pyrrole 12: 1H NMR (250 MHz, CDCl3): δ ϭ 8.41 (br. s, 1 H,
NH), 7.46 (d, J ϭ 8.8 Hz, 2 H, Ar), 6.94Ϫ6.78 (m, 5 H, Ar), 6.69
(d, J ϭ 2.2 Hz, 1 H, 5-H), 5.95 (s, 2 H, OCH2O), 4.07 (q, J ϭ
7.0 Hz, 2 H, OCH2), 3.83 (s, 3 H, OCH3), 1.04 (t, J ϭ 7.0 Hz, 3
H, CH3) ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 164.6 (s, CϭO),
159.5 (s, COCH3), 147.0, 146.2, 137.0, 129.5, 127.4, 124.9 (6 s, Ar,
C-2, C-3, C-4), 130.1, 122.2, 116.6, 113.6, 109.9, 107.7 (6 d, Ar, C-
5), 100.8 (t, OCH2O), 59.7 (t, OCH2), 55.3 (q, OCH3), 13.8 (q,
CH3) ppm. IR (KBr): ν˜ ϭ 3300 cmϪ1 (NϪH), 1680, 1670 (CϭO).
C21H19NO5 (365.4): calcd. C 69.03, H 5.24, N 3.83; found C 68.88,
H 5.30, N 3.77.
1
(2R,3S,4S)-5d: H NMR (270 MHz, CDCl3): δ ϭ 7.16, 6.80 (2 d,
J ϭ 8.8 Hz, 2 H, 2 H, 2-Ar), 6.75Ϫ6.66 (m, 3 H, Ar), 5.92 (s, 2 H,
OCH2O), 5.26Ϫ5.24* (m, 0.36 H, 2-H), 5.15 (d, J ϭ 7.4 Hz, 0.64
H, 2-H), 4.36Ϫ4.03, 3.70Ϫ3.59, 355Ϫ3.48 (3 m, 6 H, OCH2, 3-H,
4-H, 5-H), 3.78 (s, 3 H, OCH3), 1.47*, 1.14 [2 s, 9 H, C(CH3)3],
0.74 (t, J ϭ 7.0 Hz, 3 H, CH3) ppm. 13C NMR (67.2 MHz, CDCl3):
δ ϭ 169.9 (s, CϭO), 158.5 (s, COCH3), 154.5 (s, CϭO), 147.6,
146.3, 131.7, 131.1 (4 s, Ar), 127.5, 120.3, 112.9, 108.1, 107.9 (5 d,
Ar), 100.9 (t, OCH2O), 79.6 [s, C(CH3)3], 63.9, 56.5 (2 d, C-2, C-
3), 59.9 (t, OCH2), 55.2 (q, OCH3), 50.0 (t, C-5), 44.5 (d, C-4),
28.4*, 27.9 [2 q, C(CH3)3], 13.6 (q, CH3) ppm, * signals of rotamer.
MS (EI, 80 eV): m/z (%) ϭ 469 (13) [Mϩ], 413 (30) [Mϩ Ϫ C4H8],
368 (100) [Mϩ Ϫ Boc], 148 (67).
Hydrogenolysis of (6S)-10: According to General Procedure D, 1,2-
oxazine (6S)-10 (244 mg, 0.455 mmol, dr 90:10), di-tert-butyl dicar-
bonate (119 mg, 0.545 mmol) and Raney nickel (ഠ 200 mg) in etha-
nol/ethyl acetate (1:1, 20 mL) were stirred under hydrogen pressure
(50Ϫ60 bar) for 22 h. The crude product was purified by column
chromatography (SiO2, n-hexane/ethyl acetate, 4:1). Separation of
the isomers by HPLC (n-hexane ϩ 20% ethyl acetate) yielded
(2S,3S,4R)-5a (68 mg, 31%), (2R,3S,4R)-5b (31 mg, 14%) and a
third isomer of 5 (9 mg, 4%) with unknown configuration, as
colourless oils.
Deprotection of (2R,3R,4S)-5a: According to General Procedure B,
protected pyrrolidine (2R,3R,4S)-5a (161 mg, 0.340 mmol) was dis-
solved in CH2Cl2 (2 mL), and TFA (2 mL) was added. The mixture
was stirred for 3 h. Column chromatography (SiO2, n-hexane/ethyl
acetate, 15:85) yielded (2R,3R,4S)-6a (92 mg, 73%) as a colourless
oil. [α]2D0 ϭ ϩ57.7 (c ϭ 0.98, CHCl3)* [ref[8]: ϩ57.7 (c ϭ 7.68,
EtOH)], * Because of the poor solubility of the compound in EtOH
we used CHCl3 as solvent. 1H NMR (270 MHz, CDCl3): δ ϭ 7.36,
(2S,3S,4R)-5a: [α]2D0 ϭ ϩ4.3 (c ϭ 0.49, CHCl3). 1H NMR
(500 MHz, CDCl3, 323 K): δ ϭ 7.16, 6.85 (2 d, J ϭ 8.6 Hz, 2 H
each, 2-Ar), 6.75Ϫ6.70 (m, 3 H, 4-Ar), 5.91 (s, 2 H, OCH2O), 4.96
6.88 (2 d, J ϭ 8.8 Hz, 2 H, 2 H, 2-Ar), 6.82 (s, 1 H, 4-Ar), 6.73 (s, (br. s, 1 H, 2-H), 4.22 (mc, 1 H, 5-H), 4.04 (q, J ϭ 7.1 Hz, 2 H,
2 H, 4-Ar), 5.92 (s, 2 H, OCH2O), 4.47 (d, J ϭ 8.6 Hz, 1 H, 2-H),
4.06 (q, J ϭ 7.1 Hz, 2 H, OCH2), 3.80 (s, 3 H, OCH3), 3.68Ϫ3.51
OCH2), 3.79 (s, 3 H, OCH3), 3.62Ϫ3.54 (m, 2 H, 4-H, 5-H), 3.05
(mc, 1 H, 3-H), 1.20 [br. s, 9 H, C(CH3)3], 1.07 (t, J ϭ 7.1 Hz, 3
(m, 2 H, 4-H, 5-H), 3.20 (dd, J ϭ 6.6, 10.3 Hz, 1 H, 5-H), 2.90 (t, H, CH3) ppm. 13C NMR (125.8 MHz, CDCl3, 323 K): δ ϭ 171.7
3532
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 3524Ϫ3533

Enantioselective Synthesis of the Pyrrolidine Core of Atrasentan via 1,2-Oxazines
FULL PAPER
bayashi, Y. Mitsui, Y. Yazaki, K. Goto, Nature 1988, 332,
411Ϫ415.
G. Liu, K. J. Henry, B. G. Szczepankiewicz, M. Winn, N. S.
Kozmina, S. A. Boyd, J. Wasicak, W. von Geldern, J. R. Wu-
Wong, W. J. Chiou, D. B. Dixon, B. Nguyen, K. C. Marsh, T.
J. Opgenorth, J. Med. Chem. 1998, 41, 3261Ϫ3275 and refer-
ences therein.
H.-S. Jae, M. Winn, T. W. von Geldern, B. K. Sorensen, W. J.
Chiou, B. Nguyen, K. C. Marsh, T. J. Opgenorth, J. Med.
Chem. 2001, 44, 3978Ϫ3984.
(s, CϭO), 158.9 (s, COCH3), 153.9 (s, CϭO), 148.0, 146.9, 135.5,
131.7 (4 s, Ar), 126.8, 120.7, 113.6, 108.4, 107.5 (5 d, Ar), 101.0 (t,
OCH2O), 79.7 [s, C(CH3)3], 64.8 (d, C-2), 61.4 (d, C-3), 60.8 (t,
OCH2), 55.3 (q, OCH3), 54.1 (t, C-5), 47.4 (d, C-4), 28.1 [q,
C(CH3)3], 14.1 (q, CH3) ppm. MS (EI, 80 eV): m/z (%) ϭ 469 (10)
[Mϩ], 412 (27) [Mϩ Ϫ C4H9], 368 (100) [Mϩ Ϫ Boc], 352 (12), 180
(25), 148 (35), 136 (28), 57 (22). HRMS (EI, 80 eV) C26H31NO7:
calcd. 469.2101; found 469.2142.
[2]
[3]
[4]
(2R,3S,4R)-5b: 1H NMR (500 MHz, CDCl3, 323 K):
δ ϭ
M. Winn, T. W. von Geldern, T. J. Opgenorth, H. Jae, A. S.
Tasker, S. A. Boyd, J. A. Kester, R. A. Mantei, R. Bal, B. K.
Sorensen, J. R. Wu-Wong, W. J. Chiou, D. B. Dixon, E. I. No-
vosad, L. Hernandez, K. C. Marsh, J. Med. Chem. 1996, 39,
1039Ϫ1048.
7.10Ϫ7.09 (m, 2 H, 2-Ar), 6.82 (d, J ϭ 8.7 Hz, 2 H, 2-Ar),
6.77Ϫ6.71 (m, 3 H, 4-Ar), 5.91 (s, 2 H, OCH2O), 5.31*, 5.20 (2 br.
s, 1 H, 2-H), 4.14 (mc, 1 H, 5-H), 3.88 (dt, J ϭ 8.9, 11.3 Hz, 1 H,
4-H), 3.78 (s, 3 H, OCH3), 3.74 (q, J ϭ 7.1 Hz, 2 H, OCH2),
3.53Ϫ3.46 (m, 2 H, 3-H, 5-H), 1.26*, 1.21 [2 br. s, 9 H, C(CH3)3],
0.98 (t, J ϭ 7.1 Hz, 3 H, CH3) ppm. 13C NMR (125.8 MHz,
CDCl3, 323 K): δ ϭ 169.2 (s, CϭO), 159.1 (s, COCH3), 153.8 (s,
CϭO), 147.9, 146.7, 132.9 (3 s, Ar), 127.8, 121.0, 113.5, 108.4,
108.0 (5 d, Ar), 101.0 (t, OCH2O), 79.8 [s, C(CH3)3], 62.8 (d, C-2),
60.5 (t, OCH2), 56.9 (d, C-3), 55.2 (q, OCH3), 53.0 (t, C-5), 43.1*,
42.5 (2 d, C-4), 28.2 [q, C(CH3)3], 13.8 (q, CH3) ppm, * signals of
[5a] H.-S. Jae, M. Winn, D. B. Dixon, K. C. Marsh, B. Nguyen,
[5]
T. J. Opgenorth, T. W. von Geldern, J. Med. Chem. 1997, 40,
[5b]
3217Ϫ3227.
T. W. von Geldern, A. S. Tasker, B. K. So-
rensen, M. Winn, B. G. Szczepankiewicz, D. B. Dixon, W. J.
Chiou, L. Wang, J. L. Wessale, A. Adler, K. C. Marsh, B.
Nguyen, T. J. Opgenorth, J. Med. Chem. 1999, 42, 3668Ϫ3678.
[5c]
G. Liu, N. S. Kozmina, M. Winn, T. W. von Geldern, W. J.
Chiou, D. B. Dixon, B. Nguyen, K. C. Marsh, T. J. Opgenorth,
J. Med. Chem. 1999, 42, 3679Ϫ3689.
Abbott Laboratories website, http://www.abbott.com.
S. J. Wittenberger, M. A. McLaughlin, Tetrahedron Lett. 1999,
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G. Revial, S. Lim, B. Viossat, P. Lemoine, A. Tomas, A. F.
Duprat, M. Pfau, J. Org. Chem. 2000, 65, 4593Ϫ4600.
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M. Buchholz, H.-U. Reißig, Synthesis 2002, 1412Ϫ1422.
M. Buchholz, F. Hiller, H.-U. Reißig, Eur. J. Org. Chem.
2002, 2838Ϫ2843.
rotamer. MS (EI, 80 eV): m/z (%) ϭ 469 (3) [Mϩ], 412 (4) [Mϩ
Ϫ
[6]
[7]
C4H9], 368 (16) [Mϩ Ϫ Boc], 284 (6), 148 (14), 57 (35). HRMS (EI,
80 eV) C26H31NO7: calcd. 469.2101; found 469.2144.
[8]
[9]
1
Third isomer of 5: H NMR (500 MHz, CDCl3, 323 K): δ ϭ 7.18,
6.86 (2 d, J ϭ 8.6 Hz, 2 H, 2 H, 2-Ar), 6.73Ϫ6.60 (m, 3 H, 4-Ar),
5.91 (s, 2 H, OCH2O), 5.14 (d, J ϭ 8.5 Hz, 1 H, 2-H), 4.05Ϫ3.96
(m, 2 H, 5-H, 4-H), 3.93 (q, J ϭ 7.1 Hz, 2 H, OCH2), 3.80 (s, 3 H,
OCH3), 3.68Ϫ3.58 (m, 1 H, 5-H), 3.21 (mc, 1 H, 3-H), 1.22 [br. s,
9 H, C(CH3)3], 1.06 (t, J ϭ 7.2 Hz, 3 H, CH3) ppm.
[10]
[11]
[12]
[13]
K. Homann, J. Angermann, M. Collas, R. Zimmer, H.-U.
Reißig, J. Prakt. Chem. 1998, 340, 649Ϫ655.
L. N. Mander, S. P. Sethi, Tetrahedron Lett. 1983, 24,
5425Ϫ5428.
Acknowledgments
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C. Hippeli, H.-U. Reißig, Liebigs Ann. Chem. 1990,
475Ϫ481. [14b] R. Zimmer, M. Hoffmann, H.-U. Reißig, Chem.
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H.-U. Reißig, R. Zimmer, Synlett 1995, 1014Ϫ1016.
Generous support by the Deutsche Forschungsgemeinschaft (Gra-
duiertenkolleg ‘‘Struktur-Eigenschafts-Beziehungen bei Heterocy-
clen’’), the Fonds der Chemischen Industrie, and the Schering AG
is most gratefully acknowledged. We thank Dr. R. Zimmer for help
during preparation of this manuscript.
[14c]
J. Angermann, K. Homann,
[14d]
K.
Paulini, A. Gerold, H.-U. Reißig, Liebigs Ann. 1995, 667Ϫ671.
M. Buchholz, Dissertation, Freie Universität Berlin, 2002.
K. S. Y. Lau, M. Schlosser, J. Org. Chem. 1978, 43, 1595Ϫ1598.
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Received April 11, 2003
[15]
[16]
[17]
[1]
M. Yanagisawa, H. Kurihara, S. Kimura, Y. Tomobe, M. Ko-
Eur. J. Org. Chem. 2003, 3524Ϫ3533
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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