Preparation and use in amino acid synthesis of a new chiral glycine derivative - (R)- and (S)-tert-Butyl 2-tert-Butyl-4-methoxy-2,5-dihydroimidazole-1-carboxylate (BDI)

Article abstract of DOI:10.1002/(SICI)1099-0690(199807)1998:7<1337::AID-EJOC1337>3.0.CO;2-T

The title compound BDI is prepared on multigram scale, either by resolution of the precursor 2-tert-butylimidazolidin-4-one (from glycine amide and pivalaldehyde) through diastereomeric salts (Scheme 2) or by preparative chromatographic enantiomer separation on a chiral column. Lithiated BDI derivatives are highly nucleophilic species, combining the structural elements of a Li enaminate, of an enolether and of an N-Boc-enaminate (E, G). They react with complete diastereoselectivity (NMR analysis) from the face trans to the tert-butyl group. The electrophiles employed are primary and secondary alkyl, allyl, benzyl, and propargyl halides (Schemes 3 and 5), enoates (in Michael additions, Scheme 7), as well as aliphatic and aromatic aldehydes (in aldol additions, Scheme 8). When a third, exocyclic, stereocenter is formed in these reactions, there is a high degree of enantiomer differentiation (with tac. sec. halides, products 10-12) and of enantiotopic face differentiation (with enoates and aldehydes, products 40-50). The reactions are so clean that highly efficient in-situ double alkylations are feasible, in which the sequence of addition of the two different electrophiles determines the configuration at the newly formed stereogenic center (Scheme 5). In contrast to derivatives of previously reported chiral glycine reagents, the products from BDI are converted to methyl esters of amino acids under mild conditions and without concomitant formation (... and the need for recovery or removal) of a chiral auxiliary; the method is compatible with acid-sensitive side chains in the α-amino acids and α-branched α-amino acids to be synthesized (Schemes 4 and 6). The addition of Li-BDI to aldehydes furnishes, after hydrolysis, α-amino-β-hydroxy acids of erythro configuration (allo-threonine analogs, Scheme 8); a model for the stereochemical course of this reaction (rel. topicity unlike) is proposed, and compared with the corresponding conversions of analogous oxazolidinone and imidazolidinone Li enolates which occur with rel. topicity like.

Full text of DOI:10.1002/(SICI)1099-0690(199807)1998:7<1337::AID-EJOC1337>3.0.CO;2-T

FULL PAPER
Preparation and Use in Amino Acid Synthesis of a New Chiral Glycine
Derivative – (R)- and (S)-tert-Butyl 2-tert-Butyl-4-methoxy-2,5-
dihydroimidazole-1-carboxylate (BDI)Ƞ
Dieter Seebach* and Matthias Hoffmann
Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Zentrum,
Universitätstrasse 16, CH-8092 Zürich, Switzerland
Fax: (internat.) ϩ41(0)1/6321144
E-mail: seebach@org.chem.ethz.ch
Received February 16, 1998
Keywords: Amino acid synthesis / Chiral glycine building block / Dihydroimidazole
The title compound BDI is prepared on multigram scale,
either by resolution of the precursor 2-tert-butylimidazolidin-
4-one (from glycine amide and pivalaldehyde) through
diastereomeric salts (Scheme 2) or by preparative
so clean that highly efficient in-situ double alkylations are
feasible, in which the sequence of addition of the two
different electrophiles determines the configuration at the
newly formed stereogenic center (Scheme 5). In contrast to
chromatographic enantiomer separation on a chiral column. derivatives of previously reported chiral glycine reagents, the
Lithiated BDI derivatives are highly nucleophilic species, products from BDI are converted to methyl esters of amino
combining the structural elements of a Li enaminate, of an acids under mild conditions and without concomitant
enolether and of an N-Boc-enaminate (E, G). They react with
complete diastereoselectivity (NMR analysis) from the face
trans to the tert-butyl group. The electrophiles employed are
primary and secondary alkyl, allyl, benzyl, and propargyl
halides (Schemes 3 and 5), enoates (in Michael additions,
Scheme 7), as well as aliphatic and aromatic aldehydes (in
formation (... and the need for recovery or removal) of a chiral
auxiliary; the method is compatible with acid-sensitive side
chains in the α-amino acids and α-branched α-amino acids
to be synthesized (Schemes 4 and 6). The addition of Li-BDI
to aldehydes furnishes, after hydrolysis, α-amino-β-hydroxy
acids of erythro configuration (allo-threonine analogs,
Scheme 8); a model for the stereochemical course of this
reaction (rel. topicity unlike) is proposed, and compared with
aldol additions, Scheme 8). When
a third, exocyclic,
stereocenter is formed in these reactions, there is a high
degree of enantiomer differentiation (with rac. sec. halides, the corresponding conversions of analogous oxazolidinone
products 10–12) and of enantiotopic face differentiation (with and imidazolidinone Li enolates which occur with rel.
enoates and aldehydes, products 40–50). The reactions are topicity like.
Introduction
The non-catalytic methods of enantioselective amino acid
synthesis can be divided into two subgroups: those em-
ploying a chiral auxiliary and those using an enantiomer
separation, the most versatile strategy involving C,C-bond
formation with chiral glycine derivatives to which one or
two side chains are added stereoselectively[1]. The prototype
of the first group is the bis-lactim ether A: an amino acid
(usually valine, preferably tert-leucine) serves as the chiral
auxiliary, and two amino acid esters have to be separated
in the process of isolation of the desired product[2]
.
The most commonly used reagent of the second group is
the cyclic acetal B (Boc-BMI) prepared in enantiopure form
by resolution[3] of the non-Boc-protected precursor hetero-
cycle with mandelic acid[4][5]. The harsh conditions for hy- carboxylate, BDI)[7][8], combining the advantages of the
drolysis of Boc-BMI derivatives to the free amino acids can Schöllkopf reagent A with those of our Boc-BMI B: the
be circumvented by using the oxo-oxazolidine C (BOX) products of mono- and dialkylation are formed with ex-
which can be resolved[3][6] by chromatography on chiral tremely high stereoselectivity, hydrolysis of the heterocycle
stationary phases (CSP). We have developed a new and takes place under mildly acidic conditions, and the side
superior chiral glycine derivative D (R1 ϭ tBu, R2 ϭ CH3; product pivalaldehyde is volatile under evaporative solvent
tert-butyl 2-tert-butyl-4-methoxy-2,5-dihydroimidazole-1- removal during work-up.
Eur. J. Org. Chem. 1998, 1337Ϫ1351
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D. Seebach, M. Hoffmann
FULL PAPER
Preparation of Enantiopure BDI
Following the procedure outlined in Scheme 1 for rac-1,
the enantiopure (R)-1 is converted to (S)-BDI without loss
of configurational purity. BDI-analogs with protecting
groups other than Boc have, of course, also been prepared
from rac-[10] or from enantiopure imidazolidinone 1[15]. In
preliminary experiments, the (Z)-protected analog of BDI
turned out to be an inferior reagent for C,C-bond coup-
The two methods used by us to prepare larger amounts
(10Ϫ60 g) of BDI are the enantiomer separation on CSP of
BDI itself and the classical resolution of the imidazolidi-
none 1 through diastereomeric salt formation. The prep-
aration of rac-1 from commercial glycine amide and pivalal-
dehyde, its conversion to the Boc-derivative rac-2, and the
subsequent O-methylation with Meerwein salt to give rac-
BDI (Scheme 1), as well as the CSP enantiomer separation
of BDI and configurational assignment have been described
ling processes[11][13]
.
Alkylation of BDI through the Li-Enaminate E and Preparation of
Amino Acid Methyl Esters
in full detail elsewhere[9][10][11]
.
Racemic or enantiopure BDI was deprotonated with lith-
ium diisopropyl amide (LDA) to form the enaminate E,
which was alkylated with various electrophiles RX (Scheme
3). The halides used may be primary or secondary, propar-
gylic, allylic, or benzylic.
Scheme 1
Scheme 3. (Only one enantiomer of the rac products is shown)
The resolution of rac-1 with camphor sulfonic acid
(CSA), as described[7][11] originally, turned out not to be
applicable to large scale[12]. We therefore looked for other
chiral acids to use instead of or in addition to CSA. After
extensive experimentation (27 different carboxylic acids
were tested in four different solvents each!)[13], the pro-
cedure shown in Scheme 2 was chosen for the resolution[8]
:
the salt 3 precipitating from acetone/methanol and con-
sisting of the two diastereomeric u- and l-forms in a ca. 92:8
ratio is isolated, and the heterocycle liberated with aqueous
base, and then converted to the l-salt 4 with N-acetyl-(R)-
valine; this is so pure that no further crystallization is neces-
sary: the enantiopure imidazolidinone (R)-1 (enantiomer
ratio Ն 99.5:0.5) can be isolated by treatment with base.
Scheme 2
The overall yield of (R)-1[14] from rac-1 is ca. 34% of
The corresponding products of alkylation 5؊14 were
theory; (S)-1 can be prepared in the same way, since both generally isolated in good yields (of purified materials[16]
)
chiral acids are commercially available in either enantio- and, according to 1H-NMR spectroscopy of the crude
meric form.
products, in diastereopure form. Only with the least reactive
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Eur. J. Org. Chem. 1998, 1337Ϫ1351

New Chiral Glycine Derivative
FULL PAPER
halides, such as iodo cyclohexane, warming of the reaction Scheme 4. (Only one enantiomer of the rac product is shown)
mixture to the stability limit of the enaminate E (hours at
room temperature) was necessary. By nuclear Overhauser
effect (NOE) NMR measurements of the products and by
an X-ray crystal structure analysis[17], we confirmed that
of the two possible diastereoisomers the one with the new
substituent trans to the tert-butyl group at position 2 of the
heterocycle was formed exclusively[11]
.
The reactions of enaminate E with two equivalents of
rac-3-bromocyclopentene or rac-3-bromocyclohexene are
especially noteworthy: the corresponding products 10 and
11 are formed with diastereoisomer ratios of >98:2 and
1
91:9, respectively, as derived from the H-NMR spectra of
the crude products. We are sure that these alkylations,
again, occur exclusively from the face trans to the tert-butyl
group on the dihydroimidazole ring, and that the second
diastereoisomer formed besides 11 is epimeric at the stereo-
center in the aliphatic ring. A similar reaction with excess
rac-1-phenylethylbromide gave the dihydroimidazole deriva-
tive 12 with a diastereoisomer ratio of >98:2[18][19]. Thus,
the enaminate E has an unusually high enantiomer-differen-
tiating ability which leads to an efficient kinetic resolution
of racemic mixtures of allylic and benzylic halides. Unfortu-
nately, the configuration of the stereocenters in the aliphatic
rings of 10؊12 could not be determined so far (no crystals
suitable for X-ray analysis could be obtained).
In Situ Double Alkylation of BDI through the Li-Enaminate G and
Preparation of α-Branched Amino Acid Methyl Esters
Although the yields of analytically pure products 5؊14,
as given in Scheme 3, are not excellent[16], the conversions
in these alkylation reactions are complete (no BDI starting
The high nucleophilicity and the complete conversions in
material by thin-layer test of the crude reaction mixture), the monoalkylations of enaminate E gave us the confidence
signalling an excellent nucleophilicity of the Li enaminate to try in situ double alkylations by adding a second equiva-
E. This high reactivity is especially important for appli- lent of base after the first alkylation step to generate the Li-
cations of the new chiral glycine synthetic building block enaminate G with tetrasubstituted double bond. The low
BDI with in situ double alkylations (vide infra).
electrophilicity of the iminoester group in the dihydroimi-
Of course we had hoped to be able to hydrolyze BDI dazole ring enabled us to achieve this second deprotonation
derivatives to Boc-protected amino acid esters, and acids, with butyllithium (BuLi) (see Scheme 5).
ready for peptide synthesis. Inspite of many attempts, we
The gem. disubstituted products 21؊32 are formed in
did not succeed in finding conditions sufficiently acidic to yields which depend upon the degree of crowding. In all
cleave the imino ester functionality but not the Boc cases, the bath temperature was allowed to rise to 10Ϫ20°C
group[20]. Furthermore, we observed partial racemization in the second alkylation step. Polar impurities arising from
upon treatment of products of type 5؊14 with acid, aque- decomposition of enaminate G could be readily removed in
ous or non-aqueous. Therefore, we chose a two-step pro- the chromatographic purification of the products (the yields
cedure, first removing the Boc-group under aprotic con- in Scheme 5 refer to analytically pure samples).
1
ditions, and then cleaving the heterocycle hydrolytically. The
According to H-NMR spectroscopy of the crude prod-
Boc deprotection was achieved with trimethylsilyl trifl- ucts single diastereoisomers 21؊32 were formed. It was,
ate[21], and the resulting dihydroimidazoles hydrolyzed again, confirmed by NOE NMR measurements and by an
(without purification) to the free amino acid esters F under X-ray crystal structure analysis[25] that of the two possible
mildly acidic conditions. The overall yields of the two steps diastereoisomers the one with the substituent R2 trans to
range from 78 to 95%.
the tert-butyl group at position 2 of the dihydroimidazole
The crude-product methyl esters F are generally pure en- ring was formed exclusively[11]. Thus, the configuration of
ough to be used in subsequent reactions. In order to obtain the gem. disubstituted stereocenter can be determined by
analytically pure samples, however, the amino acid esters F the order of addition of the two electrophiles R1X and R2X.
were (Z)-protected[22] and the products 15 and 17؊20 puri- The unusually high nucleophilicity of the enaminate G is
fied by flash-chromatography (FC)[23]. Since all these com- demonstrated by the isopropylation of the benzyl derivative
pounds are oils, it was again not possible to determine the leading to an almost 60% yield of product 30.
configurations at the stereocenters in the β-positions of the
For the hydrolysis of the dialkylated dihydroimidazole
esters 17, 19, and 20. The amino acid derivatives thus ob- derivatives 21؊32 to the free amino acid esters of type H
tained were enantiopure[24]
.
the same concept as for the monoalkylated compounds
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Eur. J. Org. Chem. 1998, 1337Ϫ1351

D. Seebach, M. Hoffmann
FULL PAPER
Scheme 5. (Only one enantiomer of the rac adducts is shown)
in 2  TFA in H2O (0.5Ϫ4 d) for cleavage of the ring
(Scheme 6).
Scheme 6. (Only one enantiomer of the rac products is shown)
Since the conditions employed in the hydrolysis step are
so mild, the preparation of amino acid esters H with acid-
labile side chains is possible[26]. Like the “monosubstituted”
amino acid esters F, the gem. disubstituted esters H thus
obtained (yields ranging from 69 to 98%) were (Z) pro-
tected, and the products 33؊36 and 38 purified by FC in
order to obtain analytically pure samples. The crude ester
37 was purified by FC without prior protection of the free
amino group. All esters 33؊38 are isolated as oils. The di-
hydroimidazole rac-32 with the most congested substitution
could not be hydrolyzed under the mild reaction conditions
as outlined in Scheme 6. Since there is no acid-sensitive
group in 32, we used the harsh conditions of reflux in 6
 HCl to set the amino acid rac-39 free (purification by
crystallization from MeOH/H2O).
Michael Additions of the Li-Enaminate E to α,β-Unsaturated 2,6-
Di-tert-butyl-4-methoxyphenylesters I
The new chiral glycine derivative BDI was also tested in
Michael additions to α,β-unsaturated esters. We chose the
hindered 4-methoxyphenylesters I as the Michael acceptors
(Scheme 7), knowing that such derivatives with “sterically
protected but electronically activating” carbonyl groups are
5؊14 (Scheme 4) was chosen: the Boc-protecting group was ideal substrates to study this reaction. Hydroquinone-de-
removed first and then the heterocycle hydrolyzed without rived esters of this type can be cleaved by CeIV oxi-
prior purification. Both steps were performed under mild dation[19][27][28][29]
.
reaction conditions at room temperature: stirring in 1 
The esters I derived from crotonic, 4-methylpentenoic
TFA in CH2Cl2 (8 h) for the removal of the Boc-group and and cinnamic acid were added to Ϫ78°C cold solutions of
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Eur. J. Org. Chem. 1998, 1337Ϫ1351

New Chiral Glycine Derivative
FULL PAPER
Scheme 7. (Only one enantiomer of BDI and of the Michael ad-
Scheme 8. (Only one enantiomer of BDI and of the main diastereo-
isomer of the hydroxyalkylation products 43؊46, of the
bicyclic products 47؊50, and of the amino hydroxy acids
51 and 52 is shown)
ducts is shown)
rac-BDI enaminate, and the reactions were quenched after
3 h reaction time at this temperature (TLC sampling indi-
cating complete conversions). Work-up gave two dia-
stereoisomers in ratios of 94:6 for rac-40, 83:17 for rac-41,
and >98:2 for rac-42. The crude products were purified by
FC which led to the isolation of colorless solids in yields
ranging from 68Ϫ80%.
Based on the results of the mono- and dialkylations of
BDI, we are confident that the Michael-addition reactions
of the Li-enaminate E to the methoxyphenylesters I proceed
with complete diastereoselectivity trans to the tert-butyl
group at position 2 of the dihydroimidazole ring, and that
the minor diastereoisomer formed in the reaction leading
to rac-40 and rac-41 is epimeric at the exocyclic stereo-
center. The configurations of this stereocenter in the major
diastereoisomers are, as yet, unknown.
In order to determine the relative configurations at the
exocyclic stereocenters of the main aldol adducts, com-
pounds rac-43 and rac-46 were hydrolyzed to the corre-
sponding amino acids rac-51 and rac-52 as shown in
Scheme 8.
Comparison of the 1H-NMR spectra of the products rac-
51 and rac-52 with spectra found in the literature[31] re-
vealed that the amino hydroxy acids of erythro configura-
tion had been formed[34]. Hydrolysis of the corresponding
bicyclic products rac-47 and rac-50 under the same con-
ditions also led to the formation of products rac-51 and rac-
52. Furthermore, the relative configurations of the stereo-
centers in the bicyclic products rac-47 Ϫ rac-50 were also
verified to be as depicted in Scheme 8, using NOE 1H-
NMR spectroscopy[13]. The amount of epimer at the 1Ј-
position of 43؊46 and at the 4-position of the bicyclic car-
bamates 47؊50 varies from <2 to 33% and is given in the
Aldol Additions of the Li-Enaminate E from rac-BDI to Aldehydes
Aldol additions to rac-BDI were carried out in two differ-
Experimental Section[35]
Thus, it is clearly established that the reaction of lithiated
.
ent ways (Scheme 8): After reaction of enaminate E with BDI with aldehydes and subsequent hydrolysis lead to am-
isobutyric aldehyde, pivalaldehyde, cyclohexane carbal- ino hydroxy carboxylic acids of erythro configuration, i.e.
dehyde or benzaldehyde at Ϫ100°C for 5 min, followed by to analogs of allo-threonine (see 51 and 52 in Scheme 8).
low-temperature quenching, mainly the expected pro-
Using the Zimmerman-Traxler model[36], the approach
tonated primary adducts rac-43 Ϫ rac-46 were formed in of the trigonal centers of enaminate E and aldehyde and
yields ranging from 61Ϫ88%[30]. When, however, the alde- the primary adduct can be pictured as shown in J and K of
hyde was added at Ϫ78°C to the enaminate solution, and Scheme 9.
the reaction solution allowed to warm up to room tempera-
The cyclization of Li-alkoxides such as K to bicyclic car-
ture, the bicyclic compounds rac-47 Ϫ rac-50 were formed bamates (47Ϫ50) is a process which we have observed pre-
as the main products (yields between 26 and 79%). In both viously with analogous reactions of other N-alkoxycar-
ways of conducting the aldol addition, a mixture of the two bonyl-protected heterocyclic glycine derivatives[6][37]. For a
types of products was formed and easily separated by FC comparison, we also show in Scheme 9 the approach of
to give the pure compounds which were fully characterized. oxo-oxazolidine (L, M, X ϭ O) or oxo-imidazolidine (L,
The hydroxyalkylation products were thus obtained as col- M, X ϭ NCH3) Li enolates to aldehydes[38]. In this presen-
orless oils, the bicyclic compounds as amorphous solids.
tation, the surprising reversal of the relative topicity like
Eur. J. Org. Chem. 1998, 1337Ϫ1351
1341

D. Seebach, M. Hoffmann
FULL PAPER
drous CaCl2. The side arms of the reaction flasks were connected
to an Ar line by three-way taps. A positive pressure of Ar was
established by following the operation “flask evacuation/Ar intro-
duction” several times. Ϫ The electrophiles used for the reactions
were passed through a short column of basic Al2O3 prior to injec-
Scheme 9. Comparison of the stereochemical course of addition of
enaminate E and of BMI or BOX enolates to aldehydes
using the Zimmerman-Traxler model (only one enantio-
mer of the products and precursors is shown)
tion. Ϫ Diisopropylamine and triethylamine were distilled from
˚
CaH2 under Ar and stored over molecular thieves (4 A), solvents
for chromatography and work-up were distilled, all other solvents
were used as purchased from Fluka. Ϫ Thin layer chromatography
(TLC) analyses were performed on silica gel plates (Merck 60 F254
,
0.25 mm thickness), components were detected by UV light and/or
by dipping into a soln. of 5.25 g of N,N,NЈ,NЈ-tetramethyl-4,4Ј-
methylenebis[aniline] (TDM), 10.20 g of KI, 3.4 mg of ninhydrine,
23.6 ml of CH3CO2H and 310 ml of H2O followed by dipping into
hot water. Ϫ For flash chromatography (FC) Merck silica gel 60,
230Ϫ400 mesh was used. Ϫ Melting points were determined in
open capillaries in a Büchi 510 apparatus with Anschütz ther-
r.t.
mometers and are uncorrected. Ϫ Optical rotations [α]D were
measured with a Perkin Elmer 241 polarimeter using a 1.00 dm cell
at room temp. (ca. 22°C); concentration c (in g/100 ml) and solvent
in parenthesis. Ϫ Infrared spectra were recorded with a Perkin
Elmer FT-IR 1600 spectrometer. Ϫ 1H-NMR and 13C-NMR spec-
tra were recorded on a Varian XL 300 or a Gemini 300 (300 MHz/
75 MHz) and a Gemini 200 (200 MHz/50 MHz). CDCl3 was used
as solvent and as internal reference (δ ϭ 7.26/77.0) unless otherwise
stated. Coupling constants J are given in Hertz (Hz); multiplicities:
s ϭ singlet, d ϭ doublet, t ϭ triplet, q ϭ quartet, m ϭ multiplet.
Carbon multiplicities were assigned by DEPT techniques. Ϫ Mass
spectra were obtained on a Hitachi-Perkin-Elmer RMU-6M spec-
trometer. Ϫ Elemental analyses were performed by the “Mikroele-
mentaranalytisches Laboratorium der ETH Zürich”.
General Procedures (GPЈs)
Monoalkylations of tert-Butyl 2-tert-Butyl-4-methoxy-2,5-di-
hydroimidazole-1-carboxylate (BDI) (GP1): A soln. of 1 eq. of BDI
(usually ca. 5 mmol) in THF (15 ml) was cooled to Ϫ78°C. A
freshly prepared and precooled (Ϫ78°C) soln. of LDA (1.5 eq.) in
THF (15 ml) was slowly added. The reaction soln. was stirred at
Ϫ78°C for 40 min. The corresponding electrophile was then in-
jected using a syringe. After letting the reaction mixture warm up
to room temp. in 12 h, saturated NH4Cl soln. (75 ml) was added.
The aqueous phase was extracted three times with Et2O (100 ml),
and the combined organic phases washed with saturated NaCl soln.
(150 ml) and dried with anhydrous MgSO4. The solvent was re-
moved by rotary evaporation and the crude product purified by
FC.
with the enolates to unlike with the enaminate is directly
correlated to the exo-cyclic position of Li on oxygen in the
first case and its endo-cyclic position on nitrogen in the se-
Dialkylations of tert-Butyl 2-tert-Butyl-4-methoxy-2,5-dihydro-
imidazole-1-carboxylate (BDI) (GP2): A soln. of 1 eq. of BDI (usu-
ally ca. 5 mmol) in THF (15 ml) was cooled to Ϫ78°C. A freshly
prepared and precooled (Ϫ78°C) soln. of LDA (1.5 eq.) in THF
(15 ml) was slowly added. The reaction soln. was stirred at Ϫ78°C
for 40 min. The first electrophile was then injected using a syringe.
After letting the reaction warm up to room temp. in 12 h, it was
again cooled to Ϫ78°C. The same amount of BuLi as was used for
the preparation of the LDA soln. was added and the reaction mix-
ture stirred at Ϫ78°C for 40 min. The second electrophile was then
injected using a syringe. After letting the reaction warm up to room
temp. in 12 h, saturated NH4Cl soln. (75 ml) was added. The aque-
ous phase was extracted three times with Et2O (100 ml), and the
cond case[39]
.
This work is part of the ETH Dissertation Nr. 12387 of M. H.
We are greatful for the ongoing generous support of our research
by Novartis Pharma Ltd. We also thank S. Blank for preliminary
experiments and P. Seiler and B. Rheiner for X-ray crystal struc-
ture analyses.
Experimental Section
General Methods: THF used for alkylations was freshly distilled
from potassium/benzophenone ketyl under an inert gas atmosphere
of Ar. Flasks, stirring bars and hypodermic needles used for the combined organic phases washed with saturated NaCl soln. (150
generation and reactions of organolithium reagents were dried for
ca. 12 h at 150°C and allowed to cool in a desiccator over anhy-
ml) and dried with anhydrous MgSO4. The solvent was removed
by rotary evaporation and the crude product purified by FC.
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New Chiral Glycine Derivative
FULL PAPER
Hydrolysis of 4-Monosubstituted Methoxydihydroimidazoles and
ring the reaction for 5 min at Ϫ100°C, saturated NH4Cl soln. (75
Protection to the Corresponding (Z)-Protected Amino Acid Methyl ml) was added. The aqueous phase was extracted three times with
Esters (GP3): A soln. of the methoxydihydroimidazole in CH2Cl2 Et2O (100 ml), and the combined organic phases washed with satu-
was cooled to Ϫ15°C. TMSO-Tf (6 eq.) was added using a syringe
and the reaction soln. stirred for 12 h at Ϫ15°C. The reaction soln.
rated NaCl soln. (150 ml) and dried with anhydrous MgSO4. The
solvent was removed by rotary evaporation and the crude product
was diluted with an equal volume of saturated NaHCO3 soln., ex- purified by FC.
tracted three times with Et2O and the combined organic phases
Formation of Bicyclic Carbamates from rac-BDI and Aldehydes at
dried with anhydrous MgSO4. The solvent was removed by rotary
evaporation and the crude product dissolved in THF. 0.1 
CF3CO2H/H2O (2 eq.) was added and the reaction soln. stirred at
4°C for 4 d. The mixture was washed with half a volume of Et2O
(which was discarded), set to pH > 10 with a 10%-NH3 soln. and
the aqueous phase extracted three times with Et2O. The combined
organic phases were dried with anhydrous MgSO4. The solvent was
removed by rotary evaporation and the crude amino acid methyles-
ter dissolved in CH2Cl2. Benzylchloroformate (1.5 eq.) and 2 
NaOH (1.5 eq.) were added and the reaction stirred at room temp.
for 1 d. An equal volume of CH2Cl2 was added. The combined
organic phases were washed with half a volume of saturated
NaHCO3 soln. and dried with anhydrous MgSO4. The solvent was
removed by rotary evaporation and the crude product purified by
FC.
Ϫ78 to ϩ20°C (GP7): A soln. of 1 eq. of rac-BDI (usually ca. 5
mmol) in THF (15 ml) was cooled to Ϫ78°C. A freshly prepared
and precooled (Ϫ78°C) soln. of LDA (1.5 eq.) in THF (15 ml) was
slowly added. The reaction soln. was stirred at Ϫ78°C for 40 min.
The corresponding aldehyde (2.5 eq.) was then injected using a syr-
inge. After letting the reaction warm up to room temp., saturated
NH4Cl soln. (75 ml) was added. The aqueous phase was extracted
three times with Et2O (100 ml), and the combined organic phases
washed with saturated NaCl soln. (150 ml) and dried with anhy-
drous MgSO4. The solvent was removed by rotary evaporation and
the crude product purified by FC.
Hydrolysis of Aldol-Addition Products to the Corresponding
erythro Ͱ-Amino-β-hydroxy Carboxylic Acids (GP8): A sample of
aldol addition product was heated in 6  HCl at reflux for 12 h.
The reaction solution was extracted with Et2O and the phases sepa-
rated. The aqueous phase was evaporated on a rotary evaporator
and the crude product purified by ion exchange chromatography
on a Dowex 50Wϫ8 column with a 1%-NH3 soln. as eluent.
Hydrolysis of 4,4-Disubstituted Methoxydihydroimidazoles and
Protection to the Corresponding (Z)-Protected Amino Acid Methyl
Esters (GP4): A soln. of the methoxydihydroimidazole in 1 
CF3CO2H/CH2Cl2 was stirred at room temp. for 8 h. The reaction
solution was diluted with an equal volume of saturated NaHCO3
soln., extracted three times with Et2O and the combined organic
phases dried with anhydrous MgSO4. The solvent was removed by
rotary evaporation and the crude product dissolved in THF. 2 
CF3CO2H/H2O (8 eq.) was added and the reaction soln. stirred at
room temp. for 4 d. The mixture was washed with half a volume
of Et2O (which was discarded), set to pH > 10 with a 10%-NH3
soln. and the aqueous phase extracted three times with Et2O. The
combined organic phases were dried with anhydrous MgSO4. The
solvent was removed by rotary evaporation and the crude amino
acid methylester dissolved in CH2Cl2. Benzylchloroformate (1.5
eq.) and 2  NaOH (1.5 eq.) were added and the reaction stirred
at room temp. for 1 d. An equal volume of CH2Cl2 was added.
The combined organic phases were washed with half a volume of
saturated NaHCO3 soln. and dried with anhydrous MgSO4. The
solvent was removed by rotary evaporation and the crude product
purified by FC.
Enantiomer Resolution of rac-2-tert-Butylimidazolidin-4-one (rac-1)
through Diastereoisomeric Salt Formation
(R)-2-tert-Butylimidazolidin-4-onium-N-acetyl--valinate
(4):
Imidazolidinone rac-1 (30.0 g, 211 mmol) and (S)-(ϩ)-CSA (49.0
g, 211 mmol) were dissolved in acetone/MeOH (83:17, 1.7 l) at
reflux temp. After cooling to room temp. over night, colorless crys-
tals of unlike salt 3[11] (18.0 g, 23%) with a diastereoisomer ratio of
92.5:7.5 (determined by GC analysis of a sample of enriched 1 ob-
tained after basic hydrolysis of 3) were formed. The unlike salt 3
was dissolved in 2  NaOH (150 ml) and the solution three times
extracted with CH2Cl2 (250 ml). The organic phases were com-
bined, dried with anhydrous MgSO4 and the solvent removed using
a rotary evaporator. The free imidazolidinone 1 was isolated and
dissolved in AcOEt (300 ml) at reflux together with N-acetyl--
valine (7.65 g, 48 mmol). After cooling to room temp. over night,
colorless crystals of like salt 4 (10.72 g, 74%) with a diastereoisomer
ratio of >99.5:0.5 were isolated, m.p. 125.4Ϫ126.6°C. Ϫ IR (KBr):
3293m, 3077m, 2962m, 1719s, 1639s, 1541m, 1404m, 1376m, 1349m,
1321m, 1299m, 1152w, 1088w, 1056w, 975w, 843w, 757m. Ϫ 1H
NMR (300 MHz, CD3OD): δ ϭ 4.32 [s, 1 H, HC-C(Me)3], 4.30 (d,
J ϭ 6 Hz, 1 H, HC-COO), 3.44 [d, J ϭ 16 Hz, 1 H, H-C(5)], 3.36
[d, J ϭ 16 Hz, 1 H, H-C(5)], 2.22Ϫ2.10 (m, 1 H, HCMe2), 2.00 (s,
3 H, H3C-CO), 0.97 (d, J ϭ 3 Hz, 3 H, H3C-CH), 0.95 (d, J ϭ 3
Hz, 3 H, H3C-CH), 0.91 (s, 9 H, Me3-C). Ϫ 13C NMR (75 MHz,
CD3OD): δ ϭ 178.7, 175.2, 173.4, 81.0, 59.3, 36.4, 31.7, 24.7, 22.4,
19.6, 18.4. Ϫ C14H27N3O4 (301.39): calcd. C 55.79, H 9.03, N
13.94; found C 56.05, H 8.85, N 13.85.
Michael Additions with rac-tert-Butyl 2-tert-Butyl-4-methoxy-2,5-
dihydroimidazole-1-carboxylate (rac-BDI) (GP5): A soln. of 1 eq.
of rac-BDI (usually ca. 5 mmol) in THF (15 ml) was cooled to
Ϫ78°C. A freshly prepared and precooled (Ϫ78°C) soln. of LDA
(1.5 eq.) in THF (15 ml) was slowly added. The reaction soln. was
stirred at Ϫ78°C for 40 min. The corresponding Michael acceptor
(1.5 eq.) dissolved in THF was then injected using a syringe. After
stirring the reaction solution at Ϫ78°C for 3 h, saturated NH4Cl
soln. (75 ml) was added. The aqueous phase was extracted three
times with Et2O (100 ml), and the combined organic phases washed
with saturated NaCl soln. (150 ml) and dried with anhydrous
MgSO4. The solvent was removed by rotary evaporation and the
crude product purified by FC.
The free imidazolidinone (R)-(Ϫ)-1 was obtained after basic hy-
drolysis of like salt 4 as described above. All analytical data were
identical to the ones published in[11]
.
Hydroxyalkylation of rac-BDI at Ϫ100°C (GP6): A soln. of 1
eq. of rac-BDI (usually ca. 5 mmol) in THF (15 ml) was cooled to
Ϫ78°C. A freshly prepared and precooled (Ϫ78°C) soln. of LDA
(1.5 eq.) in THF (15 ml) was slowly added. The reaction soln. was
Monoalkylations of BDI
(2S,5S)-tert-Butyl 2-tert-Butyl-4-methoxy-5-prop-2-inyl-2,5-di-
hydroimidazole-1-carboxylate (5): The alkylation of (S)-(ϩ)-BDI
stirred at Ϫ78°C for 40 min and then cooled to Ϫ100°C. The corre- (1.35 g, 5.3 mmol) with propargylbromide (0.94 g, 7.9 mmol) was
sponding aldehyde (2.5 eq.) was injected using a syringe. After stir-
performed according to GP1. Purification of the crude product by
Eur. J. Org. Chem. 1998, 1337Ϫ1351
1343

D. Seebach, M. Hoffmann
FULL PAPER
FC (hexane/AcOEt, 15:1) gave 5 (1.08 g, 69%) as a colorless solid,
m.p. 71.8Ϫ72.2°C. Ϫ [α]D ϭ ϩ157.53 (c ϭ 0.97, CHCl3). Ϫ IR prop-2-ynyl)-2,5-dihydroimidazole-1-carboxylate (9): The alkylation
(2S,5S)-tert-Butyl 2-tert-Butyl-4-methoxy-5-(3-trimethylsilanyl-
r.t.
(KBr): 3274m, 2982m, 1685s, 1477w, 1453w, 1398m, 1368m, 1295w,
of (S)-(ϩ)-BDI (1.44 g, 5.6 mmol) with (3-chloroprop-1-inyl)tri-
1266m, 1177m, 1121m, 1076w, 1006m, 962w, 904w, 864w, 781m, methylsilane[40] (1.23 g, 8.4 mmol) was performed according to
1
668w. Ϫ H NMR (300 MHz, [D6]DMSO, 94.5°C): δ ϭ 5.19 [s, 1 GP1. Purification of the crude product by FC (hexane/AcOEt, 8:1)
H, H-C(2)], 4.28Ϫ4.25 [m, 1 H, H-C(5)], 3.82 (s, 3 H, H3C-O), 3.33 gave 9 (0.87 g, 42%) as a colorless solid, m.p. 81.0Ϫ81.4°C. Ϫ [α]
r.t.
(d, J ϭ 17 Hz, 1 H, H-CCϵC), 2.58 (s, 1 H, H-CϵC), 2.46 (d, J ϭ
17 Hz, 1 H, H-CCϵC), 1.43 (s, 9 H, Me3C-O), 0.87 [s, 9 H, Me3C-
ϭ ϩ172.22 (c ϭ 0.93, CHCl3). Ϫ IR (KBr): 2969m, 2179w,
D
1694s, 1674s, 1456w, 1392m, 1354s, 1300w, 1250m, 1168m, 1115m,
C(2)]. Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ 165.9, 152.6, 88.4, 1079w, 1010m, 980m, 903w, 864m, 841m, 782w, 758w. Ϫ H NMR
1
79.2, 78.5, 73.6, 59.6, 55.5, 27.8, 25.9, 20.4, 18.3. Ϫ MS (70 eV); (300 MHz, [D6]DMSO, 95.0°C): δ ϭ 5.17 [s, 1 H, H-C(2)], 4.28 [s,
m/z (%): 237 (15), 221 (5), 181 (100), 137 (64), 122 (6), 110 (3), 98
1 H, H-C(5)], 3.81 (s, 3 H, H3C-O), 3.38 (d, J ϭ 17 Hz, 1 H, H-
(5), 57 (95), 41 (18), 29 (6). Ϫ C16H26N2O3 (294.39): calcd. C 65.28, CCϵC), 2.46 (d, J ϭ 17 Hz, 1 H, H-CCϵC), 1.44 (s, 9 H, Me3C-
H 8.90, N 9.52; found C 65.35, H 8.83, N 9.52.
O), 0.86 [s, 9 H, Me3C-C(2)], 0.08 (s, 9 H, Me3Si). Ϫ 13C NMR
(75 MHz, [D6]DMSO): δ ϭ 165.9, 152.8, 101.8, 88.8, 79.2, 60.0,
55.5, 27.8, 25.9, 21.8, 19.6. Ϫ MS (70 eV); m/z (%): 367 (1) [Mϩ],
309 (28), 295 (7), 253 (100), 209 (91), 193 (5), 170 (4), 105 (7), 73
(3), 57 (6). Ϫ C19H34N2O3Si (366.58): calcd. C 62.25, H 9.35, N
7.64; found C 62.49, H 9.43, N 7.59.
rac-tert-Butyl 2-tert-Butyl-4-methoxy-5-trimethylsilanylmethyl-
2,5-dihydroimidazole-1-carboxylate (rac-6): The alkylation of rac-
BDI (2.10 g, 8.2 mmol) with trimethylsilylmethyliodide (2.64 g,
12.3 mmol) was performed according to GP1. Purification of the
crude product by FC (pentane/Et2O, 16:1) gave rac-6 (2.39 g, 85%)
as a colorless oil. Ϫ IR (CHCl3): 2976m, 2904w, 1669s, 1480w,
1448w, 1393s, 1367s, 1119m, 1074w, 997m, 913w, 879w, 840m. Ϫ 1H
NMR (300 MHz, CDCl3): δ ϭ 5.25Ϫ5.21 [br, 1 H, H-C(2)],
4.43Ϫ4.41 [br, 1 H, H-C(5)], 3.84 (s, 3 H, H3C-O), 1.48 (s, 10 H),
1.33 [dd, J ϭ 13 und 3 Hz, 1 H, H-C-Si(Me)3], 0.91 [s, 9 H, Me3C-
C(2)], 0.00 (s, 9 H, Me3Si). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
169.4, 153.4, 88.4, 79.9, 59.2, 55.0, 39.5, 28.5, 26.4, 19.2, 16.9, 0.0.
Ϫ MS (70 eV); m/z (%): 343 (1) [Mϩ], 285 (23), 271 (18), 229 (100),
185 (27), 153 (4), 125 (12), 89 (8), 81 (14), 73 (17), 57 (43), 41 (9),
29 (5). Ϫ C17H34N2O3Si (342.55): calcd. C 59.61, H 10.00, N 8.18;
found C 59.58, H 10.07, N 8.27.
(2S,5S)-tert-Butyl 2-tert-Butyl-5-cyclopent-2-enyl-4-methoxy-2,5-
dihydroimidazole-1-carboxylate (10): The alkylation of (S)-(ϩ)-BDI
(1.66 g, 6.5 mmol) with 3-bromocyclopentene[41] (2.38 g, 16.2
mmol) was performed according to GP1. Purification of the crude
product by FC (pentane/Et2O, 7:1) gave 10 (1.80 g, 86%) as a color-
less solid, m.p. 87.0Ϫ88.0°C. Ϫ IR (KBr): 2978m, 1688s, 1665s,
1475m, 1456m, 1396m, 1366s, 1356s, 1296m, 1271m, 1169m, 1120m,
1079m, 999m, 928w, 858w, 783w, 726w. Ϫ 1H NMR (300 MHz,
[D6]DMSO, 92.2°C): δ ϭ 5.63 [s, 1 H, H-C(2)], 5.14Ϫ5.10 (dd, 1
H), 4.36 (td, 1 H), 4.00Ϫ3.89 (br, 1 H), 3.69 (s, 3 H, H3C-O),
2.34Ϫ2.18 (m, 2 H), 1.95Ϫ1.85 (m, 1 H), 1.72Ϫ1.63 (m, 1 H), 1.42
(s, 9 H, Me3C-O), 1.22Ϫ1.14 (m, 1 H), 0.85 [s, 9 H, Me3C-C(2)].
rac-tert-Butyl 2-tert-Butyl-4-methoxy-5-oxiranylmethyl-2,5-dihy-
droimidazole-1-carboxylate (rac-7): The alkylation of rac-BDI (1.13
g, 4.4 mmol) with epibromohydrin (0.91 g, 6.6 mmol) was per-
formed according to GP1. Purification of the crude product by FC
(pentane/Et2O, 2:1) gave rac-7 (0.78 g, 56%) as a colorless solid,
m.p. 62.2Ϫ63.0°C. Ϫ IR (KBr): 2974m, 1687s, 1672s, 1482w,
1451w, 1395m, 1364s, 1267m, 1185m, 1139m, 1103m, 1082w, 1000m,
949w, 913w, 887w, 815w, 805w, 764w. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 5.29 [br, 1 H, H-C(2)], 4.36 [br, 1 H, H-C(5)], 3.90 (s,
3 H, H3C-O), 2.84Ϫ2.68 (m, 3 H), 2.53-2.46 (m, 1 H), 2.01Ϫ1.95
(m, 1 H), 1.48 (s, 9 H, Me3C-O), 0.92 [s, 9 H, Me3C-C(2)]. Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 167.8, 153.5, 88.8, 80.3, 59.4, 55.5,
47.9, 46.6, 39.3, 30.4, 28.4, 26.2. Ϫ MS (70 eV); m/z (%): 255 (12),
239 (4), 225 (11), 199 (100), 155 (29), 137 (3), 125 (6), 111 (35), 99
(10), 57 (8), 41 (4). Ϫ C16H28N2O4 (312.41): calcd. C 61.51, H 9.03,
N 8.97; found C 61.74, H 9.21, N 8.71.
Ϫ
13C NMR (75 MHz, [D6]DMSO): δ ϭ 166.6, 133.3, 131.3, 129.1,
128.5, 87.4, 79.1, 64.5, 63.1, 54.9, 31.2, 25.9, 23.4. Ϫ MS (70 eV);
m/z (%): 265 (21), 249 (4), 209 (55), 165 (7), 155 (12), 143 (65), 99
(83), 84 (3), 67 (24), 57 (100), 41 (28), 29 (13). Ϫ C18H30N2O3
(322.45): calcd. C 67.05, H 9.38, N 8.69; found C 66.84, H 9.45,
N 8.58.
(2S,5S)-tert-Butyl 2-tert-Butyl-5-cyclohex-2-enyl-4-methoxy-2,5-
dihydroimidazole-1-carboxylate (11): The alkylation of (S)-(ϩ)-BDI
(1.55 g, 6.1 mmol) with 3-bromocyclohexene[42] (2.44 g, 15.1 mmol)
was performed according to GP1. Purification of the crude product
by FC (pentane/Et2O, 7:1) gave 11 (1.62 g, 80%) as a colorless
solid, m.p. 81.8Ϫ82.6°C. Ϫ IR (KBr): 2971m, 1694s, 1669s, 1477m,
1449m, 1386m, 1364s, 1351s, 1295m, 1266m, 1184m, 1166m, 1107m,
1079m, 1046w, 997m, 964w, 947w, 910w, 869w, 782w, 713w, 667w. Ϫ
1H NMR (300 MHz, [D6]DMSO, 92.8°C): δ ϭ 5.69Ϫ5.50 (m, 2
H), 5.24Ϫ5.13 (m, 1 H), 4.23 (d, 1 H), 3.72 (s, 3 H, H3C-O),
3.45Ϫ3.36 (br, 1 H), 1.92 (br, 2 H), 1.77Ϫ1.61 (m, 2 H), 1.41 (s, 9
H, Me3C-O), 1.02Ϫ0.92 (m, 1 H), 0.86 [s, 9 H, Me3C-C(2)]. Ϫ 13C
NMR (75 MHz, [D6]DMSO): δ ϭ 128.6, 128.0, 125.8, 87.4, 79.2,
64.7, 54.9, 27.8, 25.9, 24.6, 24.4, 22.3, 21.2. Ϫ MS (70 eV); m/z (%):
279 (22), 263 (3), 223 (76), 179 (11), 155 (6), 143 (49), 99 (61), 81
(19), 57 (100), 41 (21), 29 (11). Ϫ C19H32N2O3 (336.47): calcd. C
67.82, H 9.59, N 8.33; found C 67.84, H 9.38, N 8.28.
(2S,5S)-tert-Butyl 5-(2-tert-Butoxycarbonylallyl)-2-tert-butyl-4-
methoxy-2,5-dihydroimidazole-1-carboxylate (8): The alkylation of
(S)-(ϩ)-BDI (1.16 g, 4.5 mmol) with tert-butyl 2-bromomethylacry-
late (1.50 g, 6.8 mmol) was performed according to GP1. Purifi-
cation of the crude product by FC (pentane/Et2O, 4:1) gave 8 (0.38
r.t.
g, 21%) as a colorless oil. Ϫ [α]D ϭ ϩ81.38 (c ϭ 1.09, CHCl3).
Ϫ IR (CHCl3): 2974m, 1697s, 1672s, 1631w, 1477w, 1456w, 1395m,
1369s, 1318w, 1169m, 1144m, 1077w, 1000m, 964w, 949w, 856w. Ϫ
1H NMR (300 MHz, [D6]DMSO, 95.0°C): δ ϭ 5.97 [s, 1 H, H-
C(2)], 5.33 (s, 1 H, H-CϭC), 5.12Ϫ5.11 (m, 1 H, H-CϭC),
(2S,5S)-tert-Butyl 2-tert-Butyl-4-methoxy-5-(1-phenylethyl)-2,5-
4.41Ϫ4.37 [m, 1 H, H-C(5)], 3.74 (s, 3 H, H3C-O), 2.78 (d, J ϭ 16 dihydroimidazole-1-carboxylate (12): The alkylation of (S)-(ϩ)-BDI
Hz, 1 H, H-C-CϭC), 1.44 (s, 9 H, Me3C-O), 1.40 (s, 9 H, Me3C- (0.71 g, 2.8 mmol) with rac-(1-bromoethyl)benzene (1.29 g, 6.9
O), 0.86 [s, 9 H, Me3C-C(2)]. Ϫ 13C NMR (75 MHz, [D6]DMSO): mmol) was performed according to GP1. Purification of the crude
δ ϭ 167.1, 165.4, 152.6, 137.1, 124.3, 87.9, 80.1, 79.3, 59.7, 55.3, product by FC (pentane/Et2O, 5:1) gave 12 (0.64 g, 64%) as a color-
27.8, 27.6, 26.0. Ϫ MS (70 eV); m/z (%): 397 (47) [Mϩ], 339 (35), less oil. Ϫ IR (CHCl3): 2977m, 1695s, 1667s, 1478w, 1448w, 1394m,
297 (10), 283 (21), 267 (6), 239 (31), 227 (22), 183 (100), 165 (32),
111 (11), 84 (6), 57 (21). Ϫ C21H36N2O5 (396.53): calcd. C 63.61, NMR (300 MHz, [D6]DMSO, 95.0°C): δ ϭ 7.31Ϫ7.15 (m, 5 H,
1368s, 1275w, 1164m, 1128m, 1079w, 992w, 955w, 882w, 854w. Ϫ 1H
H 9.15, N 7.06; found C 63.56, H 8.93, N 6.82.
arom. H), 5.17 [s, 1 H, H-C(2)], 4.47Ϫ4.45 (m, 1 H), 4.12Ϫ4.03 (br,
Eur. J. Org. Chem. 1998, 1337Ϫ1351
1344

New Chiral Glycine Derivative
1 H), 3.64 (s, 3 H, H3C-O), 1.47 (s, 9 H, Me3C-O), 1.04 (d, J ϭ 7 167 (2), 152 (6), 140 (4), 124 (2), 105 (4), 88 (27), 86 (63), 84 (100),
FULL PAPER
Hz, 3 H, H3C-CPh), 0.86 [s, 9 H, Me3C-C(2)]. Ϫ 13C NMR (75
MHz, [D6]DMSO): δ ϭ 166.0, 153.1, 141.6, 128.3, 127.7, 126.9,
126.0, 87.4, 79.5, 67.0, 54.5, 36.9, 33.7, 27.9, 26.0. Ϫ MS (70 eV);
m/z (%): 361 (7) [Mϩ], 303 (44), 287 (7), 247 (100), 203 (19), 155
(16), 143 (44), 105 (41), 84 (16), 57 (18). Ϫ C21H32N2O3 (360.50):
calcd. C 69.97, H 8.95, N 7.77; found C 69.84, H 8.94, N 7.70.
73 (16), 57 (26).
rac-Methyl 2-Amino-3-(4-methoxyphenyl)propionate (rac-16):
The monosubstituted dihydroimidazole rac-14 (0.61 g, 1.6 mmol)
was deprotected with TMSO-Tf (2.16 g, 9.7 mmol) in CH2Cl2 (20
ml) according to GP3. The subsequent hydrolysis of the ring was
performed in 0.1  TFA/H2O (32 ml) and the purification of the
free amino acid methylester (0.32 g, 95%) by bulb-to-bulb destil-
lation (0.5 Torr, 165°C) gave rac-16 (0.19 g, 55%) as a colorless oil.
Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 7.09 (d, J ϭ 9 Hz, 2 H, arom.
H), 6.83 (d, J ϭ 9 Hz, 2 H, arom. H), 3.78 (s, 3 H, H3C-O), 3.70
(s, 3 H, H3C-O), 3.02 (dd, J ϭ 14 und 8 Hz, 1 H, H-CAr), 2.79
(dd, J ϭ 14 und 8 Hz, 1 H, H-CAr), 1.64 (br, 2 H, H2N).
(2S,5S)-tert-Butyl 2-tert-Butyl-5-cyclohexyl-4-methoxy-2,5-dihy-
droimidazole-1-carboxylate (13): The alkylation of (S)-(ϩ)-BDI
(1.68 g, 6.6 mmol) with iodocyclohexane (2.07 g, 9.8 mmol) was
performed according to GP1. Purification of the crude product by
FC (pentane/Et2O, 9:1) gave 13 (0.89 g, 40%) as a colorless solid,
r.t.
m.p. 82.2Ϫ82.6°C. Ϫ [α]D ϭ ϩ122.91 (c ϭ 0.90, CHCl3). Ϫ IR
(KBr): 2971m, 2928m, 2853m, 1693s, 1669s, 1476w, 1399m, 1354s,
1290m, 1256m, 1171m, 1109m, 1076w, 1004m, 970w, 941w, 853w,
783w, 710w. Ϫ 1H NMR (300 MHz, [D6]DMSO, 95.0°C): δ ϭ 5.13
[s, 1 H, H-C(2)], 4.07Ϫ4.05 [m, 1 H, H-C(5)], 3.79 (s, 3 H, H3C-
O), 1.72Ϫ1.64 (m, 3 H), 1.51Ϫ1.50 (m, 2 H), 1.42 (s, 9 H, Me3C-
O), 1.09Ϫ1.06 (m, 3 H), 0.85 [s, 9 H, Me3C-C(2)]. Ϫ 13C NMR (75
MHz, [D6]DMSO): δ ϭ 166.7, 153.3, 87.5, 79.0, 65.8, 55.0, 37.7,
34.1, 27.8, 25.9. Ϫ MS (70 eV); m/z (%): 339 (9) [Mϩ], 281 (28),
265 (6), 225 (100), 181 (44), 143 (14), 99 (13), 84 (4), 57 (7). Ϫ
C19H34N2O3 (338.49): calcd. C 67.42, H 10.12, N 8.28; found C
67.53, H 10.39, N 8.26.
(2S)-Methyl
Benzyloxycarbonylaminocyclopent-2-enylacetate
(17): The monosubstituted dihydroimidazole 10 (0.40 g, 1.3 mmol)
was deprotected with TMSO-Tf (1.67 g, 7.5 mmol) in CH2Cl2 (16
ml) according to GP3. The subsequent hydrolysis of the ring was
performed in 0.1  TFA/H2O (25 ml) and the protection of the free
amino acid methylester (0.16 g, 85%) thus obtained with benzyl-
chloroformate (0.32 g, 1.9 mmol) in CH2Cl2 (10 ml) and 2  NaOH
(1.4 ml). Purification of the crude protected amino acid ester by
FC (pentane/Et2O, 3:1) gave 17 (0.15 g, 41%) as a colorless oil. Ϫ
IR (CHCl3): 3431w, 3035w, 2954w, 1721s, 1509m, 1455w, 1438w,
1344w, 1062m, 1003w. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 7.36
(s, 5 H, arom. H), 5.96Ϫ5.92 (m, 1 H, H-CϭC), 5.50Ϫ5.46 (m, 1
H, H-CϭC), 5.11 (s, 3 H), 4.49Ϫ4.38 (m, 1 H), 3.75 (s, 3 H, H3C-
O), 3.37Ϫ3.12 (br, 1 H), 2.37Ϫ2.29 (br, 2 H), 2.17Ϫ1.85 (m, 1 H),
1.77Ϫ1.60 (m, 1 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 172.4,
136.3, 135.6, 133.7, 130.1, 128.5, 128.2, 67.1, 56.8, 52.2, 48.8, 47.9,
32.4, 32.0, 26.1, 24.8. Ϫ MS (70 eV); m/z (%): 230 (5), 223 (46),
186 (7), 162 (57), 138 (25), 122 (5), 115 (8), 108 (15), 91 (100), 79
(15), 67 (27). Ϫ C16H19NO4 (289.33): calcd. C 66.42, H 6.62, N
4.84; found C 66.39, H 6.72, N 4.61.
rac-tert-Butyl 2-tert-Butyl-4-methoxy-5-(4-methoxybenzyl)-2,5-
dihydroimidazole-1-carboxylate (rac-14): The alkylation of rac-BDI
(1.28 g, 5.0 mmol) with p-methoxybenzyliodide (1.86 g, 7.5 mmol)
was performed according to GP1. Purification of the crude product
by FC (pentane/Et2O, 7:1) gave rac-14 (1.69 g, 90%) as a colorless
oil. Ϫ IR (CHCl3): 2978m, 1672s, 1613w, 1514s, 1479w, 1444w,
1394s, 1368s, 1302w, 1127m, 1110m, 1074w, 1035w, 993m, 834w. Ϫ
1H NMR (300 MHz, [D6]DMSO, 100.0°C): δ ϭ 6.95 (d, J ϭ 3 Hz,
2 H, arom. H), 6.78 (d, J ϭ 3 Hz, 2 H, arom. H), 4.77 [s, 1 H, H-
C(2)], 4.46Ϫ4.43 [m, 1 H, H-C(5)], 3.76 (s, 3 H, H3C-O), 3.71 (s, 3
H, H3C-O), 3.57 (dd, J ϭ 15 und 5 Hz, 1 H), 2.82 (dd, J ϭ 15 und
5 Hz, 1 H), 1.45 (s, 9 H, Me3C-O), 0.83 [s, 9 H, Me3C-C(2)]. Ϫ 13C
NMR (75 MHz, [D6]DMSO): δ ϭ 166.5, 157.8, 130.5, 127.3, 113.3,
87.6, 79.3, 62.0, 54.8, 31.0, 27.9, 26.1. Ϫ MS (70 eV); m/z (%): 319
(25), 303 (4), 263 (59), 219 (17), 155 (5), 121 (100), 99 (15), 78 (4),
57 (74), 41 (16), 29 (9). Ϫ C21H32N2O4 (376.50): calcd. C 66.99, H
8.57, N 7.44; found C 67.11, H 8.30, N 7.27.
(2S)-Methyl Benzyloxycarbonylaminocyclohexylacetate (18): The
monosubstituted dihydroimidazole 13 (0.53 g, 1.6 mmol) was de-
protected with TMSO-Tf (2.09 g, 9.4 mmol) in CH2Cl2 (20 ml)
according to GP3. The subsequent hydrolysis of the ring was per-
formed in 0.1  TFA/H2O (31 ml) and the protection of the free
amino acid methylester (0.22 g, 81%) thus obtained with benzyl-
chloroformate (0.40 g, 2.4 mmol) in CH2Cl2 (15 ml) and 2  NaOH
(1.2 ml). Purification of the crude protected amino acid ester by
FC (pentane/Et2O, 4:1) gave 18 (0.27 g, 56%) as a colorless oil. Ϫ
r.t.
Hydrolysis of 4-Monosubstituted Methoxy-Dihydro-Imidazoles and
Preparation of the Corresponding Amino Acid Methyl Esters
[α]D ϭ ϩ17.38 (c ϭ 1.07, CHCl3). Ϫ IR (CHCl3): 3436w, 3032w,
2933s, 2856m, 1720s, 1514s, 1451m, 1342m, 1065m, 1028w. Ϫ 1H
NMR (200 MHz, CDCl3): δ ϭ 7.36 (s, 5 H, arom. H), 5.27 (d, J ϭ
9 Hz, 1 H, H-N), 5.11 (s, 2 H, HC-Ph), 4.31Ϫ4.27 (dd, J ϭ 9 und
5 Hz, 1 H, HC-CO2), 3.74 (s, 3 H, H3C-O), 1.77Ϫ1.55 (m, 6 H),
1.28Ϫ1.01 (m, 5 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 172.5,
156.2, 136.4, 128.6, 128.2, 67.1, 58.8, 52.1, 41.1, 29.5, 28.1, 26.0. Ϫ
MS (70 eV); m/z (%): 305 (6) [Mϩ], 271 (1), 246 (54), 223 (1), 202
(82), 170 (5), 162 (9), 154 (3), 138 (49), 115 (100), 91 (59), 79 (19),
65 (4), 55 (6). Ϫ C17H23NO4 (305.37): calcd. C 66.86, H 7.59, N
4.59; found C 66.70, H 7.46, N 4.43.
(2S)-Methyl 2-tert-Butoxycarbonylamino-5-trimethylsilanylpent-
4-ynecarboxylate (15): The monosubstituted dihydroimidazole 9
(0.27 g, 0.7 mmol) was deprotected with TMSO-Tf (0.98 g, 4.4
mmol) in CH2Cl2 (10 ml) according to GP3. The subsequent hy-
drolysis of the ring was performed in 0.1  TFA/H2O (15 ml) and
the protection of the free amino acid methylester (0.12 g, 78%)
thus obtained with di-tert-butyldicarbonate (0.24 g, 1.1 mmol) in
CH2Cl2 (5 ml) and Et3N (0.11 g, 1.1 mmol). Purification of the
crude protected amino acid ester by FC (pentane/Et2O, 7:1) gave
r.t.
15 (35 mg, 16%) as a colorless oil. Ϫ [α]D ϭ ϩ66.43 (c ϭ 0.28,
(2S)-Methyl
Benzyloxycarbonylaminocyclohex-2-enylacetate
CHCl3). Ϫ IR (CHCl3): 3437w, 2958m, 2177w, 1745s, 1711s, 1502s, (19): The monosubstituted dihydroimidazole 11 (0.71 g, 2.1 mmol)
1438m, 1368m, 1064m, 1012w, 845s. Ϫ 1H NMR (300 MHz, was deprotected with TMSO-Tf (2.81 g, 12.6 mmol) in CH2Cl2 (25
CDCl3): δ ϭ 5.29 (d, J ϭ 8 Hz, 1 H, H-N), 4.48Ϫ4.46 (m, 1 H, H-
CN), 3.77 (s, 3 H, H3C-O), 2.78 (dd, J ϭ 17 und 5 Hz, 1 H, H-
ml) according to GP3. The subsequent hydrolysis of the ring was
performed in 0.1  TFA/H2O (42 ml) and the protection of the free
CCϵC), 2.69 (dd, J ϭ 17 und 5 Hz, 1 H, H-CCϵC), 1.46 (s, 9 H, amino acid methylester (0.32 g, 89%) thus obtained with benzyl-
Me3C-O), 0.14 (s, 9 H, Me3Si). Ϫ 13C NMR (75 MHz, CDCl3): chloroformate (0.54 g, 3.2 mmol) in CH2Cl2 (20 ml) and 2  NaOH
δ ϭ 171.3, 155.2, 127.6, 100.8, 80.1, 52.4, 52.1, 28.2, 24.2. Ϫ MS
(1.6 ml). Purification of the crude protected amino acid ester by
(70 eV); m/z (%): 287 (1), 265 (1), 243 (3), 210 (4), 198 (1), 184 (6), FC (pentane/Et2O, 3:1) gave 19 (0.34 g, 54%) as a colorless oil. Ϫ
Eur. J. Org. Chem. 1998, 1337Ϫ1351
1345

D. Seebach, M. Hoffmann
FULL PAPER
IR (CHCl3): 3682w, 3436w, 3015w, 2944w, 1723s, 1600w, 1513s,
1456m, 1436m, 1062m. Ϫ H NMR (300 MHz, [D6]DMSO): δ ϭ calcd. C 60.63, H 10.18, N 7.86; found C 60.37, H 10.12, N 7.87.
139 (6), 112 (2), 95 (6), 73 (4), 57 (6). Ϫ C18H36N2O3Si (356.58):
1
7.36 (s, 5 H, arom. H), 5.79Ϫ5.74 (m, 1 H, H-CϭC), 5.58Ϫ5.54
(2S,5S)-tert-Butyl 2-tert-Butyl-5-cyclopropylmethyl-4-methoxy-5-
(m, 1 H, H-CϭC), 5.06 (s, 2 H, HC-Ph), 4.01 (m, 1 H), 3.65 (s, 3
methyl-2,5-dihydroimidazole-1-carboxylate (23): The double alky-
H, H3C-O), 1.95 (br, 2 H), 1.72Ϫ1.63 (m, 2 H), 1.51Ϫ1.44 (m, 1
lation of (S)-(ϩ)-BDI (2.09 g, 8.2 mmol) with MeI (1.74 g, 12.2
H), 1.36Ϫ1.29 (m, 1 H). Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ
mmol) and cyclopropylmethylbromide (1.65 g, 12.2 mmol) accord-
171.9, 156.1, 136.8, 129.1, 128.3, 127.7, 127.6, 65.5, 58.3, 57.7, 51.6,
ing to GP2 and purification of the crude product by FC (pentane/
36.6, 25.2, 24.3, 20.7. Ϫ MS (70 eV); m/z (%): 286 (3), 260 (20),
r.t.
Et2O, 13:1) gave 23 (2.17 g, 82%) as a colorless oil. Ϫ [α]D
ϭ
244 (8), 223 (15), 212 (2), 200 (13), 178 (14), 168 (6), 162 (39), 152
(78), 132 (5), 120 (7), 108 (11), 91 (100), 81 (37). Ϫ C17H21NO4
(303.36): calcd. C 67.31, H 6.98, N 4.62; found C 67.35, H 7.27,
N 4.92.
ϩ75.78 (c ϭ 1.52, CHCl3). Ϫ IR (CHCl3): 2977m, 1694s, 1480w,
1458w, 1392w, 1366s, 1346s, 1172m, 1123w, 1053m, 1020w, 998w,
920w, 858w. Ϫ 1H NMR (300 MHz, [D6]DMSO, 93.6°C): δ ϭ 5.13
[s, 1 H, H-C(2)], 3.79 (s, 3 H, H3C-O), 1.43 (s, 9 H, Me3C-O), 1.36
[s, 3 H, H3C-C(5)], 1.22Ϫ1.09 (m, 1 H), 0.89 [s, 9 H, Me3C-C(2)],
0.36Ϫ0.21 (m, 3 H), 0.18Ϫ0.02 (m, 2 H). Ϫ 13C NMR (75 MHz,
[D6]DMSO): δ ϭ 168.3, 154.4, 87.6, 78.9, 67.2, 54.9, 37.4, 27.8,
26.5, 23.6, 5.4, 3.8, 2.1. Ϫ MS (70 eV); m/z (%): 325 (2) [Mϩ], 267
(21), 251 (5), 225 (1), 211 (100), 167 (38), 157 (4), 152 (1), 113 (7),
57 (5). Ϫ C18H32N2O3 (324.46): calcd. C 66.63, H 9.94, N 8.63;
found C 66.44, H 9.93, N 8.56.
(2S)-Methyl 2-Benzyloxycarbonylamino-3-phenylbutyrate (20):
The monosubstituted dihydroimidazole 12 (1.13 g, 3.1 mmol) was
deprotected with TMSO-Tf (4.17 g, 18.7 mmol) in CH2Cl2 (35 ml)
according to GP3. The subsequent hydrolysis of the ring was per-
formed in 0.1  TFA/H2O (62 ml) and the protection of the free
amino acid methylester (0.55 g, 91%) thus obtained with benzyl-
chloroformate (0.80 g, 4.7 mmol) in CH2Cl2 (15 ml) and 2  NaOH
(2.3 ml). Purification of the crude protected amino acid ester by
FC (hexane/AcOEt, 8:1) gave 20 (0.68 g, 66%) as a colorless oil. Ϫ
IR (CHCl3): 3432w, 3032w, 1723s, 1510s, 1454m, 1438w, 1342m,
1076w, 1028w. Ϫ 1H NMR (300 MHz, [D6]DMSO): δ ϭ 7.33Ϫ7.20
(m, 10 H, arom. H), 4.93 (s, 2 H, HC-Ph), 4.29 (m, 1 H), 3.63 (s,
3 H, H3C-O), 1.19 (d, J ϭ 7 Hz, 3 H, H3C-CPh). Ϫ 13C NMR (75
MHz, [D6]DMSO): δ ϭ 172.1, 155.7, 142.6, 136.8, 128.2, 128.1,
127.5, 65.3, 62.8, 59.6, 51.6, 18.5. Ϫ MS (70 eV); m/z (%): 268 (2),
236 (1), 223 (7), 192 (2), 176 (30), 162 (7), 117 (4), 105 (100), 91
(33), 79 (10). Ϫ C19H21NO4 (327.38): calcd. C 69.71, H 6.47, N
4.28; found C 69.72, H 6.45, N 4.17.
rac-tert-Butyl 5-Benzyl-2-tert-butyl-4-methoxy-5-methyl-2,5-di-
hydroimidazole-1-carboxylate (rac-24): The double alkylation of
rac-BDI (1.99 g, 7.8 mmol) with MeI (1.65 g, 11.6 mmol) and
benzylbromide (1.99 g, 11.6 mmol) according to GP2 and purifi-
cation of the crude product by FC (pentane/Et2O, 9:1) gave rac-24
(2.28 g, 91%) as a colorless solid, m.p. 112.4Ϫ113.2°C. Ϫ IR (KBr):
2964m, 2892w, 1708s, 1682s, 1477w, 1451m, 1385m, 1364s, 1344s,
1292m, 1256w, 1174m, 1128m, 1092w, 1051s, 985m, 913w, 862w,
774w, 749w, 713w, 697m, 631w. Ϫ 1H NMR (300 MHz, [D6]DMSO,
93.6°C): δ ϭ 7.28Ϫ7.18 (m, 3 H, arom. H), 7.02 (d, J ϭ 6 Hz, 2
H, arom. H), 4.51 [s, 1 H, H-C(2)], 3.75 (s, 3 H, H3C-O), 3.72Ϫ3.53
(br, 1 H), 2.73 (d, J ϭ 15 Hz, 1 H), 1.58 [s, 3 H, H3C-C(5)], 1.50
(s, 9 H, Me3C-O), 0.83 [s, 9 H, Me3C-C(2)]. Ϫ 13C NMR (75 MHz,
[D6]DMSO): δ ϭ 167.4, 167.2, 153.5, 152.9, 136.1, 129.5, 129.3,
128.0, 127.8, 126.6, 87.4, 79.5, 68.8, 68.3, 54.8, 41.2, 37.6, 37.0,
27.9, 26.8, 23.8. Ϫ MS (70 eV); m/z (%): 303 (10), 287 (3), 247
(100), 229 (4), 213 (4), 203 (98), 181 (4), 169 (17), 160 (6), 113 (7),
91 (13), 57 (5). Ϫ C21H32N2O3 (360.50): calcd. C 69.97, H 8.95, N
7.77; found C 69.95, H 9.01, N 7.74.
Dialkylations of BDI
rac-tert-Butyl 2-tert-Butyl-5-ethyl-4-methoxy-5-methyl-2,5-dihy-
droimidazole-1-carboxylate (rac-21): The double alkylation of rac-
BDI (2.00 g, 7.8 mmol) with MeI (1.66 g, 11.7 mmol) and EtI
(1.82 g, 11.7 mmol) according to GP2 and purification of the crude
product by FC (pentane/Et2O, 9:1) gave rac-21 (1.84 g, 79%) as a
colorless oil. Ϫ IR (CHCl3): 2976m, 1687s, 1480w, 1458w, 1392w,
1366s, 1350s, 1296w, 1171m, 1104w, 1068m, 1021w, 996w, 915w,
rac-tert-Butyl
5-Allyl-2-tert-butyl-4-methoxy-5-(3-trimethylsil-
1
865w. Ϫ H NMR (300 MHz, [D6]DMSO, 93.6°C): δ ϭ 4.51 [s, 1
anylprop-2-inyl)-2,5-dihydroimidazole-1-carboxylate (rac-25): The
double alkylation of rac-BDI (2.55 g, 9.9 mmol) with allylbromide
(1.80 g, 14.9 mmol) and (3-chloroprop-1-inyl)trimethylsilane[40]
(2.19 g, 14.9 mmol) according to GP2 and purification of the crude
product by FC (hexane/AcOEt, 15:1) gave rac-25 (2.15 g, 53%) as
a colorless oil. Ϫ IR (CHCl3): 2977m, 2178w, 1682s, 1480w, 1446w,
1337s, 1172m, 1140w, 1030w, 1009m, 921w, 845s, 644w. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 5.99Ϫ5.79 (br, 1 H), 5.23Ϫ5.18 (m, 1 H),
5.09Ϫ4.95 (m, 2 H), 3.84 (s, 3 H, H3C-O), 3.33Ϫ3.23 (br, 1 H),
2.78Ϫ2.38 (m, 3 H), 1.47 (s, 9 H, Me3C-O), 0.92 [s, 9 H, Me3C-
C(2)], 0.09 (s, 9 H, Me3Si). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
167.0, 154.5, 133.7, 117.9, 89.5, 80.1, 55.5, 42.3, 37.4, 28.3, 27.1. Ϫ
MS (70 eV); m/z (%): 407 (8) [Mϩ], 389 (3), 349 (38), 333 (8), 293
(100), 249 (55), 233 (9), 193 (6), 73 (24), 57 (30).
H, H-C(2)], 3.75 (s, 3 H, H3C-O), 3.68Ϫ3.57 (br, 1 H), 2.75 (d, J ϭ
15 Hz, 1 H), 1.58 [s, 3 H, H3C-C(5)], 1.50 (s, 9 H, Me3C-O), 0.83
[s, 9 H, Me3C-C(2)]. Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ
167.9, 154.3, 87.6, 78.9, 67.7, 55.3, 37.4, 29.0, 27.8, 26.4, 23.6, 7.5.
Ϫ MS (70 eV); m/z (%): 241 (12), 225 (5), 185 (100), 141 (25), 125
(1), 114 (4). Ϫ C16H30N2O3 (298.43): calcd. C 64.40, H 10.13, N
9.39; found C 64.23, H 10.36, N 9.46.
(2S,5S)-tert-Butyl 2-tert-Butyl-4-methoxy-5-methyl-5-trimethyl-
silanylmethyl-2,5-dihydroimidazole-1-carboxylate (22): The double
alkylation of (S)-(ϩ)-BDI (2.08 g, 8.1 mmol) with MeI (1.73 g, 12.2
mmol) and trimethylsilylmethyliodide (2.61 g, 12.2 mmol) accord-
ing to GP2 and purification of the crude product by FC (pentane/
Et2O, 11:1) gave 22 (2.33 g, 80%) as a colorless oil. Ϫ IR (CHCl3):
2977m, 1692s, 1480w, 1457w, 1392m, 1365s, 1344s, 1297w, 1123w,
rac-tert-Butyl 2-tert-Butyl-5-cyclohexylmethyl-4-methoxy-5-meth-
1072w, 1046m, 996w, 909w, 872m, 839m. Ϫ 1H NMR (300 MHz, yl-2,5-dihydroimidazole-1-carboxylate (rac-26): The double alky-
[D6]DMSO, 95.0°C): δ ϭ 5.07 [s, 1 H, H-C(2)], 3.78 (s, 3 H, H3C- lation of rac-BDI (2.01 g, 7.8 mmol) with iodomethylcyclohexane
O), 1.81 (d, J ϭ 15 Hz, 1 H, H-CSiMe3), 1.48 [s, 3 H, H3C-C(5)], (2.63 g, 11.7 mmol) and MeI (1.67 g, 11.7 mmol) according to GP2
1.44 (s, 9 H, Me3C-O), 1.08 (d, J ϭ 15 Hz, 1 H, H-CSiMe3), 0.89
and purification of the crude product by FC (pentane/Et2O, 14:1)
[s, 9 H, Me3C-C(2)], 0.07 (s, 9 H, Me3Si). Ϫ 13C NMR (75 MHz, gave rac-26 (2.03 g, 71%) as a colorless oil. Ϫ 1H NMR (300 MHz,
[D6]DMSO): δ ϭ 211.9, 170.4, 154.4, 88.2, 80.4, 79.8, 65.8, 55.9,
[D6]DMSO, 93.6°C): δ ϭ 5.08 [s, 1 H, H-C(2)], 3.74 (s, 3 H, H3C-
38.7, 29.0, 27.8, 0.0. Ϫ MS (70 eV); m/z (%): 357 (2) [Mϩ], 299 O), 2.20 (d, J ϭ 15 Hz, 1 H), 1.71Ϫ1.48 (m, 10 H), 1.43 (s, 9 H,
(18), 285 (14), 243 (100), 213 (4), 199 (23), 183 (1), 167 (7), 153 (2), Me3C-O), 1.28Ϫ1.03 (m, 5 H), 0.92 [s, 9 H, Me3C-C(2)]. Ϫ 13C
1346
Eur. J. Org. Chem. 1998, 1337Ϫ1351

New Chiral Glycine Derivative
FULL PAPER
NMR (75 MHz, [D6]DMSO): δ ϭ 168.9, 88.1, 79.2, 54.7, 46.0, double alkylation of (S)-(ϩ)-BDI (0.97 g, 3.8 mmol) with 3,5-di-
37.3, 35.0, 34.6, 34.3, 32.9, 32.5, 32.0, 27.7, 27.1, 26.1, 25.9, 25.7, methoxybenzyliodide (1.58 g, 5.7 mmol) and isopropyliodide (0.97
25.6. Ϫ MS (70 eV); m/z (%): 335 (100), 291 (27), 251 (4), 239 (15), g, 5.7 mmol) according to GP2 and purification of the crude prod-
207 (10), 195 (40), 155 (8), 111 (22), 97 (5), 84 (10), 57 (9).
uct by FC (pentane/Et2O, 5:1) gave 30 (0.97 g, 57%) as a colorless
solid, m.p. 80.6Ϫ81.8°C. Ϫ IR (KBr): 2970m, 1702s, 1676s, 1606s,
1459m, 1428m, 1388m, 1370m, 1322s, 1286m, 1193s, 1174m, 1154s,
1122m, 1096w, 1063m, 1013m, 904w, 837m, 794w, 698w. Ϫ 1H
NMR (300 MHz, [D6]DMSO, 92.0°C): δ ϭ 6.36 (s, 2 H, arom. H),
6.28 (s, 1 H, arom. H), 4.84 [s, 1 H, H-C(2)], 3.85 (s, 3 H, H3C-O),
3.67 (s, 6 H, H3C-O), 3.18Ϫ3.03 (m, 2 H), 2.65Ϫ2.59 (m, 1 H, H-
CMe2), 1.48 (s, 9 H, Me3C-O), 1.07 (d, J ϭ 7 Hz, 3 H, H3C-CH),
0.73 (d, J ϭ 7 Hz, 3 H, H3C-CH), 0.40 [s, 9 H, Me3C-C(2)]. Ϫ 13C
NMR (75 MHz, [D6]DMSO): δ ϭ 165.0, 160.2, 155.2, 139.4, 108.2,
99.3, 87.5, 79.3, 75.9, 54.8, 37.0, 35.6, 27.8, 26.2, 18.3, 17.1. Ϫ MS
(70 eV); m/z (%): 391 (21), 375 (3), 335 (15), 305 (5), 291 (100), 249
(8), 197 (3), 151 (32), 139 (4), 57 (12). Ϫ C25H40N2O5 (448.60):
calcd. C 66.94, H 8.99, N 6.24; found C 67.18, H 8.73, N 6.33.
(2S,5R)-tert-Butyl 5-Allyl-2-tert-butyl-5-cyclohex-1-enylmethyl-
4-methoxy-2,5-dihydroimidazole-1-carboxylate (27): The double al-
kylation of (S)-(ϩ)-BDI (1.60 g, 6.2 mmol) with 1-bromometh-
ylcyclohexene (1.64 g, 9.4 mmol) and allylbromide (1.13 g, 9.4
mmol) according to GP2 and purification of the crude product by
FC (pentane/Et2O, 15:1) gave 27 (1.96 g, 80%) as a colorless oil. Ϫ
[α]Dr.t. ϭ ϩ12.90 (c ϭ 0.93, CHCl3). Ϫ IR (CHCl3): 2974m, 2933m,
1692s, 1477w, 1446w, 1390m, 1369s, 1333s, 1169m, 1108w, 1010m,
1
923w. Ϫ H NMR (300 MHz, [D6]DMSO, 92.2°C): δ ϭ 5.47 [br,
1 H, H-C(2)], 5.43Ϫ5.28 (m, 1 H), 5.05Ϫ4.93 (m, 3 H), 3.77 (s, 3
H, H3C-O), 2.26Ϫ2.19 (m, 1 H), 1.99Ϫ1.90 (m, 4 H), 1.57Ϫ1.47
(m, 4 H), 1.43 (s, 9 H, Me3C-O), 0.89 [s, 9 H, Me3C-C(2)]. Ϫ 13C
NMR (75 MHz, [D6]DMSO): δ ϭ 133.1, 131.7, 125.9, 119.5, 87.7,
79.3, 71.1, 54.9, 44.5, 37.1, 29.6, 27.8, 26.9, 24.8, 22.2, 21.2. Ϫ MS
(70 eV); m/z (%): 333 (19), 295 (5), 277 (99), 249 (4), 233 (15), 193
(6), 183 (2), 139 (41), 111 (5), 95 (11), 67 (5), 57 (100), 41 (21), 29
(10). Ϫ C23H38N2O3 (390.57): calcd. C 70.73, H 9.81, N 7.17; found
C 70.75, H 9.70, N 7.20.
rac-tert-Butyl 2-tert-Butyl-5-cyclohexylmethyl-5-(3,5-dimethoxy-
benzyl)-4-methoxy-2,5-dihydroimidazole-1-carboxylate
(rac-31):
The double alkylation of rac-BDI (0.90 g, 3.5 mmol) with 3,5-di-
methoxybenzyliodide (1.46 g, 5.2 mmol) and iodomethylcyclohex-
ane (1.17 g, 5.2 mmol) according to GP2 and purification of the
crude product by FC (pentane/Et2O, 6:1) gave rac-31 (0.93 g, 53%)
as a colorless solid, m.p. 97.8Ϫ98.6°C. Ϫ IR (KBr): 2975m, 2924m,
2856m, 1701s, 1679m, 1611m, 1596m, 1462m, 1431w, 1390w, 1368m,
1331s, 1291m, 1204m, 1165m, 1148m, 1121w, 1066w, 1014m, 905w,
844m, 692w. Ϫ 1H NMR (300 MHz, [D6]DMSO, 92.0°C): δ ϭ 6.31
(s, 3 H, arom. H), 5.01 [s, 1 H, H-C(2)], 3.80 (s, 3 H, H3C-O), 3.68
(s, 6 H, H3C-O), 3.04Ϫ2.89 (m, 2 H), 2.18 (d, J ϭ 14 Hz, 1 H),
1.63Ϫ1.48 (m, 5 H), 1.44 (s, 9 H, Me3C-O), 1.17Ϫ0.79 (m, 7 H),
0.59 [s, 9 H, Me3C-C(2)]. Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ
167.3, 160.1, 138.7, 108.4, 98.9, 87.8, 79.2, 70.8, 54.8, 43.1, 37.1,
34.5, 32.8, 27.7, 26.5, 26.0. Ϫ MS (70 eV); m/z (%): 445 (16), 429
(2), 389 (11), 345 (100), 295 (10), 251 (24), 239 (6), 195 (18), 151
(37), 111 (7), 57 (21). Ϫ C29H46N2O5 (502.69): calcd. C 69.29, H
9.22, N 5.57; found C 69.36, H 9.11, N 5.42.
(2S,5R)-tert-Butyl 2-tert-Butyl-5-ethyl-4-methoxy-5-(4-methoxy-
benzyl)-2,5-dihydroimidazole-1-carboxylate (28): The double alky-
lation of (S)-(ϩ)-BDI (1.28 g, 5.0 mmol) with p-methoxybenzyliod-
ide (1.86 g, 7.5 mmol) and EtI (1.17 g, 7.5 mmol) according to GP2
and purification of the crude product by FC (pentane/Et2O, 7:1)
r.t.
gave 28 (1.42 g, 70%) as a colorless oil. Ϫ [α]D ϭ ϩ74.41 (c ϭ
0.93, CHCl3). Ϫ IR (CHCl3): 2974m, 1694s, 1612w, 1513s, 1460w,
1392w, 1368m, 1334s, 1107w, 1092w, 1036w, 1004m. Ϫ 1H NMR
(300 MHz, [D6]DMSO, 100.0°C): δ ϭ 7.05 (d, J ϭ 8 Hz, 2 H,
arom. H), 6.79 (d, J ϭ 8 Hz, 2 H, arom. H), 4.99 [s, 1 H, H-C(2)],
3.80 (s, 3 H, H3C-O), 3.70 (s, 3 H, H3C-O), 3.06 (d, J ϭ 14 Hz, 1
H, H-CAr), 3.00 (d, J ϭ 14 Hz, 1 H, H-CAr), 2.33Ϫ2.21 (m, 1 H,
H-CMe), 1.60Ϫ1.48 (m, 1 H, H-CMe), 1.43 (s, 9 H, Me3C-O), 0.62
[s, 9 H, Me3C-C(2)], 0.57 (t, J ϭ 8 Hz, 3 H, Me-CH2). Ϫ 13C NMR
(75 MHz, [D6]DMSO): δ ϭ 166.4, 158.1, 131.3, 128.9, 113.5, 87.8,
79.2, 72.8, 55.0, 41.3, 36.9, 28.7, 27.7, 26.3. Ϫ MS (70 eV); m/z (%):
347 (16), 331 (3), 291 (59), 247 (9), 227 (11), 183 (14), 171 (7), 121
(100), 111 (3), 78 (4), 57 (70), 41 (16), 29 (8). Ϫ C23H36N2O4
(404.55): calcd. C 68.29, H 8.97, N 6.92; found C 68.45, H 8.68,
N 6.83.
rac-tert-Butyl 5-Benzyl-2-tert-butyl-5-cyclohexylmethyl-4-meth-
oxy-2,5-dihydroimidazole-1-carboxylate (rac-32): The double alky-
lation of rac-BDI (2.07 g, 8.1 mmol) with benzylbromide (2.08 g,
12.1 mmol) and iodomethylcyclohexane (2.72 g, 12.1 mmol) ac-
cording to GP2 and purification of the crude product by FC (pen-
tane/Et2O, 13:1) gave rac-32 (2.26 g, 63%) as a colorless oil. Ϫ IR
(CHCl3): 2923s, 2851m, 1687s, 1492w, 1477w, 1451m, 1390m, 1339s,
1169m, 1118m, 1077w, 1010m, 908w, 856w. Ϫ 1H NMR (300 MHz,
[D6]DMSO, 93.6°C): δ ϭ 7.23Ϫ7.14 (m, 5 H, arom. H), 5.02 [s, 1
H, H-C(2)], 3.78 (s, 3 H, H3C-O), 3.11Ϫ2.99 (m, 2 H), 2.20 (d, J ϭ
15 Hz, 1 H), 1.64Ϫ1.46 (m, 6 H), 1.43 (s, 9 H, Me3C-O), 1.18Ϫ0.73
(m, 6 H), 0.60 [s, 9 H, Me3C-C(2)]. Ϫ 13C NMR (75 MHz,
[D6]DMSO): δ ϭ 167.5, 136.8, 130.5, 127.9, 126.4, 87.9, 79.3, 70.7,
54.7, 43.2, 42.7, 37.0, 34.4, 32.8, 32.4, 27.7, 26.6, 26.0, 25.8, 25.6.
Ϫ MS (70 eV); m/z (%): 385 (8), 369 (2), 351 (1), 329 (100), 295
(7), 285 (49), 251 (19), 239 (7), 195 (22). Ϫ C27H42N2O3 (442.64):
calcd. C 73.26, H 9.56, N 6.33; found C 73.14, H 9.68, N 6.21.
(2S,5R)-tert-Butyl 5-Allyl-2-tert-butyl-5-(3,5-dimethoxybenzyl)-
4-methoxy-2,5-dihydroimidazole-1-carboxylate (29): The double al-
kylation of (S)-(ϩ)-BDI (1.63 g, 6.3 mmol) with 3,5-dimethoxy-
benzyliodide (2.65 g, 9.5 mmol) and allylbromide (1.15 g, 9.5
mmol) according to GP2 and purification of the crude product by
FC (pentane/Et2O, 5:1) gave 29 (1.47 g, 52%) as a colorless oil. Ϫ
IR (CHCl3): 2978m, 1699s, 1597s, 1458m, 1430m, 1368s, 1333s,
1153s, 1063m, 1011m, 928w, 856w. Ϫ 1H NMR (300 MHz,
[D6]DMSO, 92.2°C): δ ϭ 6.34Ϫ6.31 (m, 3 H, arom. H), 5.42Ϫ5.36
(m, 1 H), 5.06Ϫ5.00 (m, 2 H), 4.90 [s, 1 H, H-C(2)], 3.82 (s, 3 H,
H3C-O), 3.69 (s, 6 H, H3C-O), 3.13Ϫ2.96 (m, 3 H), 2.32Ϫ2.25 (m,
1 H), 1.46 (s, 9 H, Me3C-O), 0.57 [s, 9 H, Me3C-C(2)]. Ϫ 13C NMR
(75 MHz, [D6]DMSO): δ ϭ 165.8, 160.2, 154.5, 138.6, 131.5, 119.7,
108.3, 99.1, 87.6, 79.5, 72.1, 54.9, 41.8, 36.8, 27.8, 26.3. Ϫ MS (70
eV); m/z (%): 389 (20), 333 (16), 305 (4), 289 (100), 249 (9), 195
(7), 151 (42), 139 (8), 57 (63), 41 (15), 29 (7). Ϫ C25H38N2O5
(446.59): calcd. C 67.24, H 8.58, N 6.27; found C 67.44, H 8.62,
N 6.48.
Hydrolysis of 4,4-Disubstituted Methoxy-Dihydro-Imidazoles and
Preparation of the Corresponding Amino Acid Methylesters
rac-Methyl 2-Benzyloxycarbonylamino-2-methylbutyrate (rac-33):
The disubstituted dihydroimidazole rac-21 (0.89 g, 3.0 mmol) was,
according to GP4, deprotected in 1  TFA/CH2Cl2 (46 ml) and
hydrolyzed in 2  TFA/H2O (12 ml) to give the free amino acid
methylester (0.33 g, 85%). After protection of the amino group with
benzylchloroformate (0.76 g, 4.5 mmol) in CH2Cl2 (14 ml) and 2 
NaOH (2.2 ml), the crude product was purified by FC (pentane/
(2S,5S)-tert-Butyl 2-tert-Butyl-5-(3,5-dimethoxybenzyl)-5-iso-
propyl-4-methoxy-2,5-dihydroimidazole-1-carboxylate (30): The
Eur. J. Org. Chem. 1998, 1337Ϫ1351
1347

D. Seebach, M. Hoffmann
FULL PAPER
Et2O, 4:1). The amino acid ester rac-33 (0.26 g, 33%) was isolated
arom. H), 7.22Ϫ7.15 (m, 3 H, arom. H), 6.98Ϫ6.95 (m, 2 H, arom.
H), 5.49Ϫ5.40 (br, 1 H, H-N), 5.17 (d, J ϭ 12 Hz, 1 H), 5.08 (d,
as a colorless oil. Ϫ IR (CHCl3): 3417w, 3032w, 1720s, 1506s,
1
1453m, 1375w, 1337w, 1315m, 1161w, 1089m, 1045m. Ϫ H NMR J ϭ 12 Hz, 1 H), 3.74 (s, 3 H, H3C-O), 3.40 (d, J ϭ 13 Hz, 1 H),
(300 MHz, CDCl3): δ ϭ 7.37Ϫ7.29 (m, 5 H, arom. H), 5.59Ϫ5.57
3.17 (d, J ϭ 13 Hz, 1 H), 1.63 (s, 3 H, H3C-CN). Ϫ 13C NMR (75
(br, 1 H, H-N), 5.08 (s, 2 H, H-CPh), 3.74 (s, 3 H, H3C-O), MHz, CDCl3): δ ϭ 174.1, 154.7, 136.7, 136.1, 129.9, 128.5, 128.3,
2.15Ϫ2.11 (m, 1 H, H-CMe), 1.88Ϫ1.76 (m, 1 H, H-CMe), 1.57 (s, 128.1, 127.0, 66.5, 60.9, 52.6, 41.9, 23.7. Ϫ MS (70 eV); m/z (%):
3 H, H3C-CN), 0.80 (t, J ϭ 7 Hz, 3 H, H3C-CH2). Ϫ 13C NMR 310 (2), 284 (5), 268 (2), 236 (12), 224 (4), 192 (20), 176 (12), 160
(75 MHz, CDCl3): δ ϭ 174.7, 154.6, 136.6, 128.5, 128.1, 128.0,
(2), 132 (2), 121 (3), 91 (100), 65 (9). Ϫ C19H21NO4 (327.38): calcd.
66.4, 60.6, 52.6, 30.1, 23.0, 8.4. Ϫ MS (70 eV); m/z (%): 222 (2), C 69.71, H 6.47, N 4.28; found C 69.85, H 6.54, N 4.18.
206 (13), 181 (3), 162 (20), 130 (3), 108 (11), 91 (100), 79 (6). Ϫ
C14H19NO4 (265.31): calcd. C 63.38, H 7.22, N 5.28; found C
63.33, H 7.42, N 5.57.
(2R)-Methyl 2-Amino-2-(4-methoxybenzyl)butyrate (37): The
disubstituted dihydroimidazole 28 (0.62 g, 1.5 mmol) was, accord-
ing to GP4, deprotected in 1  TFA/CH2Cl2 (23 ml) and hydrolyzed
in 2  TFA/H2O (6 ml) to give the free amino acid methylester,
which was purified by FC (Et2O/pentane, 2:1). The amino acid es-
ter 37 (0.22 g, 60%) was isolated as a colorless oil. Ϫ IR (CHCl3):
3414w, 3008w, 2957m, 2862w, 1717s, 1612m, 1512s, 1455m, 1346m,
1278m, 1108m, 1085m, 1024s, 909w. Ϫ 1H NMR (200 MHz,
CDCl3): δ ϭ 6.85 (d, J ϭ 8 Hz, 2 H, arom. H), 6.70 (d, J ϭ 8 Hz,
2 H, arom. H), 3.78 (s, 6 H, H3C-O), 3.56 (d, J ϭ 14 Hz, 1 H, H-
CAr), 3.02 (d, J ϭ 14 Hz, 1 H, H-CAr), 1.45Ϫ1.28 (m, 2 H, H2C-
CN), 0.89 (t, J ϭ 7 Hz, 3 H, H3C-CH2). Ϫ 13C NMR (50 MHz,
CDCl3): δ ϭ 173.7, 158.5, 154.3, 136.9, 130.6, 128.5, 113.6, 66.1,
65.5, 55.1, 52.5, 40.2, 35.3, 29.6, 26.3, 22.4, 13.8. Ϫ MS (70 eV);
m/z (%): 205 (1), 149 (2), 144 (3), 122 (13), 121 (100), 108 (6), 91
(37), 77 (3), 65 (2).
(2S)-Methyl 2-Benzyloxycarbonylamino-2-methyl-3-trimethylsil-
anylpropionate (34): The disubstituted dihydroimidazole 22 (0.75 g,
2.1 mmol) was, according to GP4, deprotected in 1  TFA/CH2Cl2
(32 ml) and hydrolyzed in 2  TFA/H2O (8 ml) to give the free
amino acid methylester (0.27 g, 69%). After protection of the am-
ino group with benzylchloroformate (0.59 g, 3.5 mmol) in CH2Cl2
(11 ml) and 2  NaOH (1.8 ml), the crude product was purified by
FC (pentane/Et2O, 5:1). The amino acid ester 34 (0.20 g, 30%) was
isolated as a colorless oil. Ϫ IR (CHCl3): 3072w, 2931w, 2859m,
2740w, 1693s, 1609s, 1472w, 1428m, 1391w, 1304w, 1165w, 1113s,
1092s, 1016w, 822m. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
7.36Ϫ7.29 (m, 5 H, arom. H), 5.72Ϫ5.61 (br, 1 H, H-N), 5.07 (s, 2
H, H-CPh), 3.72 (s, 3 H, H3C-O), 1.63 (s, 3 H, H3C-CN), 1.61 (d,
J ϭ 15 Hz, 1 H, H-CSiMe3), 1.24 (d, J ϭ 15 Hz, 1 H, H-CSiMe3),
0.03 (s, 9 H, Me3Si). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 176.2,
155.3, 137.3, 129.2, 128.9, 128.8, 67.2, 59.5, 53.3, 27.8, 27.5. Ϫ MS
(70 eV); m/z (%): 308 (6), 264 (24), 220 (33), 204 (4), 173 (10), 157
(5), 128 (2), 114 (6), 91 (100), 73 (11). Ϫ C16H25NO4Si (323.46):
calcd. C 59.41, H 7.79, N 4.33; found C 59.27, H 7.76, N 4.47.
(2R)-Methyl 2-Benzyloxycarbonylamino-2-(3,5-dimethoxybenz-
yl)pent-4-encarboxylate (38): The disubstituted dihydroimidazole
29 (0.15 g, 0.3 mmol) was, according to GP4, deprotected in 1 
TFA/CH2Cl2 (5 ml) and hydrolyzed in 2  TFA/H2O (2 ml) to give
the free amino acid methylester (0.09 g, 98%). After protection of
the amino group with benzylchloroformate (85 mg, 0.5 mmol) in
CH2Cl2 (2 ml) and 2  NaOH (0.3 ml), the crude product was
purified by FC (pentane/Et2O, 2:1). The amino acid ester 38 (86
mg, 69%) was isolated as a colorless oil. Ϫ IR (CHCl3): 3690w,
3413w, 3008w, 2955w, 2839w, 1716s, 1597s, 1503s, 1457m, 1431m,
(2S)-Methyl 2-Benzyloxycarbonylamino-3-cyclopropyl-2-methyl-
propionate (35): The disubstituted dihydroimidazole 23 (0.68 g, 2.1
mmol) was, according to GP4, deprotected in 1  TFA/CH2Cl2 (32
ml) and hydrolyzed in 2  TFA/H2O (8 ml) to give the free amino
acid methylester (0.26 g, 79%). After protection of the amino group
with benzylchloroformate (0.54 g, 3.1 mmol) in CH2Cl2 (10 ml) and
2  NaOH (1.6 ml), the crude product was purified by FC (hexane/
AcOEt, 10:1). The amino acid ester 35 (0.30 g, 49%) was isolated
1
1345m, 1153s, 1068s, 1027m, 994w, 928w, 836w. Ϫ H NMR (300
MHz, [D6]DMSO, 94.5°C): δ ϭ 7.50 (s, 1 H, H-N), 7.41Ϫ7.31 (m,
5 H, arom. H), 6.37 (s, 1 H, arom. H), 6.20 (s, 2 H, arom. H),
5.83Ϫ5.69 (m, 1 H, H-CϭC), 5.14Ϫ5.02 (m, 4 H), 3.66 (s, 6 H,
H3CO-Ar), 3.60 (s, 3 H, H3CO-CO), 3.15 (d, J ϭ 13 Hz, 1 H, H-
CAr), 2.95 (d, J ϭ 13 Hz, 1 H, H-CAr), 2.44 (dd, J ϭ 10 und 7
Hz, 1 H, H2C-CϭC), 2.33 (dd, J ϭ 10 und 7 Hz, 1 H, H2C-Cϭ
C). Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ 172.4, 160.0, 154.6,
137.9, 136.9, 132.5, 128.3, 127.8, 127.7, 119.0, 108.2, 98.6, 65.3,
62.5, 54.9, 51.8. Ϫ MS (70 eV); m/z (%): 413 (1) [Mϩ], 305 (9), 289
(13), 262 (6), 249 (7), 218 (4), 195 (12), 177 (4), 152 (90), 139 (22),
108 (23), 91 (100), 79 (24). Ϫ C23H27NO6 (413.47): calcd. C 66.81,
H 6.58, N 3.39; found C 66.98, H 6.82, N 3.45.
r.t.
as a colorless oil. Ϫ [α]D ϭ ϩ15.06 (c ϭ 0.83, CHCl3). Ϫ IR
(CHCl3): 3417w, 3007w, 2954w, 1728s, 1502s, 1452s, 1374w, 1327m,
1
1062s, 1028w. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 7.37Ϫ7.30 (m,
5 H, arom. H), 5.76Ϫ5.75 (br, 1 H, H-N), 5.09 (s, 2 H, H-C-Ph),
3.74 (s, 3 H, H3C-O), 2.16Ϫ2.02 (m, 1 H), 1.68Ϫ1.61 (m, 4 H),
0.61Ϫ0.56 (m, 1 H), 0.46Ϫ0.38 (m, 2 H), 0.09Ϫ0.01 (m, 2 H). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 174.8, 154.7, 136.6, 128.5, 128.1,
66.5, 60.4, 52.5, 41.9, 23.4, 6.1, 4.0, 3.7, 1.0. Ϫ MS (70 eV); m/z
(%): 232 (6), 200 (2), 192 (4), 188 (7), 184 (5), 181 (3), 169 (1), 156
(13), 140 (4), 129 (3), 108 (15), 91 (100), 81 (21). Ϫ C16H21NO4
(290.34): calcd. C 66.19, H 6.94, N 4.82; found C 66.12, H 7.02,
N 4.91.
rac-2-(Cyclohexylmethyl)phenylalanine (rac-39): The disubsti-
tuted dihydroimidazole rac-32 (0.94 g, 2.1 mmol) was heated in 6
 HCl (25 ml) at reflux for 14 h. After evaporation of the solvent
using a rotary evaporator and crystallization of the crude product
from MeOH/H2O, the hydrochloride of rac-39 (0.57 g, 91%) was
isolated as an amorphous solid. The analytical data were identical
rac-Methyl
2-Benzyloxycarbonylamino-2-methyl-3-phenylprop-
ionate (rac-36): The disubstituted dihydroimidazole rac-24 (0.84 g,
2.6 mmol) was, according to GP4, deprotected in 1  TFA/CH2Cl2
(39 ml) and hydrolyzed in 2  TFA/H2O (10 ml) to give the free
amino acid methylester (0.45 g, 89%). After protection of the am-
ino group with benzylchloroformate (0.66 g, 3.9 mmol) in CH2Cl2
(12 ml) and 2  NaOH (2.0 ml), the crude product was purified by
to those published in ref.[43]
.
Michael Additions of BDI to α,β-Unsaturated Phenol Esters
rac-tert-Butyl 2-tert-Butyl-5-[2-(2,6-di-tert-butyl-4-methoxyphen-
FC (hexane/AcOEt, 9:1). The amino acid ester rac-36 (0.37 g, 44%) oxycarbonyl)-1-methylethyl]-4-methoxy-2,5-dihydroimidazole-
was isolated as a colorless oil. Ϫ IR (CHCl3): 3415w, 3032w, 2954w, 1-carboxylate (rac-40): After the reaction of rac-BDI (1.49 g, 5.8
1719s, 1504s, 1452s, 1375w, 1328m, 1280m, 1113m, 1078s, 1059s,
mmol) with 2,6-di-tert-butyl-4-methoxyphenylbut-2-encarboxy-
986w. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 7.39Ϫ7.31 (m, 5 H, late[19] (2.65 g, 8.7 mmol) according to GP5, the crude product
1348
Eur. J. Org. Chem. 1998, 1337Ϫ1351

New Chiral Glycine Derivative
FULL PAPER
(diastereoisomer ratio of 94:6 with respect to the exocyclic stereoc-
(48), 57 (13). Ϫ C37H54N2O6 (622.85): calcd. C 71.35, H 8.74, N
enter as determined by 1H-NMR spectroscopy) was purified by FC 4.50; found C 71.31, H 8.66, N 4.41.
(pentane/Et2O, 6:1) giving rac-40 (2.61 g, 80%) as an amorphous
solid, m.p. 150.8Ϫ152.2°C. Ϫ IR (CHCl3): 2964s, 1754m, 1692s,
1595m, 1456m, 1395m, 1364s, 1303m, 1277m, 1149s, 1062m, 995w.
Ϫ
Aldol Additions of BDI to Aldehydes
Preparation of erythro Adducts
1H NMR (200 MHz, CDCl3): δ ϭ 6.88 (s, 2 H, arom. H),
rac-tert-Butyl 2-tert-Butyl-5-(1-hydroxy-2-methylpropyl)-4-meth-
oxy-2,5-dihydroimidazole-1-carboxylate (rac-43): The aldol addition
of rac-BDI (2.06 g, 8.0 mmol) to isobutyric aldehyde (1.45 g, 20.0
mmol) according to GP6 and purification of the crude product
(erythro/threo ϭ 86:14 according to 1H-NMR spectroscopy) by FC
(hexane/AcOEt, 6:1) gave rac-43 (1.14 g, 61%) as an amorphous
solid, m.p. 87.8Ϫ88.6°C. Ϫ IR (CHCl3): 3573w, 2978s, 1691s,
1478m, 1445m, 1395s, 1368s, 1265m, 1164m, 1131s, 1076w, 993m,
943w, 888w, 854w. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 5.27 [d,
J ϭ 3 Hz, 1 H, H-C(2)], 4.45Ϫ4.34 (m, 2 H), 3.90 (s, 3 H, H3C-
O), 2.55 (d, J ϭ 11 Hz, 1 H, HO-CH), 1.69Ϫ1.56 (m, 1 H, H-
CMe2), 1.48 (s, 9 H, Me3C-O), 0.99Ϫ0.79 (m, 15 H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 167.4, 153.6, 88.5, 80.6, 73.2, 64.5, 55.5,
39.4, 30.0, 28.4, 26.3, 20.3, 17.5. Ϫ MS (70 eV); m/z (%): 271 (8),
255 (5), 229 (4), 215 (8), 197 (48), 171 (8), 153 (59), 143 (80), 111
(8), 99 (100), 84 (9), 57 (17). Ϫ C17H32N2O4 (328.45): calcd. C
62.17, H 9.82, N 8.53; found C 61.93, H 9.67, N 8.43.
5.40Ϫ5.39 [br, 1 H, H-C(2)], 4.37Ϫ4.34 [br, 1 H, H-C(5)], 3.93 (s,
3 H, H3C-O), 3.81 (s, 3 H, H3C-O), 3.52Ϫ3.36 (br, 1 H), 2.98Ϫ2.63
(m, 2 H), 1.45 (s, 9 H, Me3C-O), 1.34 (s, 18 H, Me3C-Ar), 0.94 [s,
9 H, Me3C-C(2)], 0.82 (d, J ϭ 7 Hz, 3 H, H3C-CΗ). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 173.2, 166.7, 156.3, 153.9, 143.5, 143.4,
141.7, 111.7, 88.5, 80.2, 65.5, 55.3, 39.5, 39.2, 35.5, 31.4, 31.3, 28.2,
26.2, 13.5. Ϫ MS (70 eV); m/z (%): 503 (10), 487 (3), 445 (2), 403
(94), 347 (32), 269 (21), 225 (100), 205 (4), 181 (13), 167 (54), 125
(36), 99 (21), 57 (17). Ϫ C32H52N2O6 (560.77): calcd. C 68.54, H
9.35, N 5.00; found C 68.67, H 9.32, N 5.05.
rac-tert-Butyl 2-tert-Butyl-5-[1-(2,6-di-tert-butyl-4-methoxyphen-
oxycarbonylmethyl)-2-methylpropyl]-4-methoxy-2,5-dihydroimid-
azole-1-carboxylate (rac-41): After the reaction of rac-BDI (1.38 g,
5.4 mmol) with 2,6-di-tert-butyl-4-methoxyphenyl 4-methylpent-2-
encarboxylate[19] (2.69 g, 8.1 mmol) according to GP5, the crude
product (diastereoisomer ratio of 83:17 with respect to the exocyclic
stereocenter as determined by 1H-NMR spectroscopy) was purified
by FC (hexane/AcOEt, 15:1) giving rac-41 (2.16 g, 68%) as an
amorphous solid, m.p. 52.6Ϫ53.8°C. Ϫ IR (CHCl3): 2964s, 1754m,
1692s, 1590m, 1446m, 1395m, 1364s, 1297m, 1139s, 1062m, 1000m,
rac-tert-Butyl 2-tert-Butyl-5-(1-hydroxy-2,2-dimethylpropyl)-4-
methoxy-2,5-dihydroimidazole-1-carboxylate (rac-44): The aldol ad-
dition of rac-BDI (1.28 g, 5.0 mmol) to pivalaldehyde (1.08 g, 12.5
mmol) according to GP6 and purification of the crude product
(erythro/threo ϭ >98:2 according to 1H-NMR spectroscopy) by FC
(hexane/AcOEt, 10:1) gave rac-44 (0.14 g, 8%) as an amorphous
solid, m.p. 86.2Ϫ87.2°C. Ϫ IR (CHCl3): 3676w, 3485w, 2976s,
1703m, 1662s, 1479m, 1394s, 1367s, 1334s, 1165m, 1122m, 1080m,
1
954w, 928w, 903w, 872w. Ϫ H NMR (300 MHz, [D6]DMSO): δ ϭ
6.81 (s, 2 H, arom. H), 5.18 [d, J ϭ 3 Hz, 1 H, H-C(2)], 4.45Ϫ4.42
[m, 1 H, H-C(5)], 3.81 (s, 3 H, H3C-O), 3.73 (s, 3 H, H3C-O),
2.66Ϫ2.60 (m, 1 H), 1.67Ϫ1.60 (m, 1 H), 1.39 (s, 9 H, Me3C-O),
1.27 (s, 18 H, Me3C-Ar), 0.87 (d, J ϭ 7 Hz, 3 H, H3C-CΗ), 0.84
[s, 9 H, Me3C-C(2)], 0.74 (d, J ϭ 7 Hz, 3 H, H3C-CΗ). Ϫ 13C
NMR (75 MHz, [D6]DMSO): δ ϭ 173.1, 167.4, 167.1, 155.8, 152.9,
143.0, 141.1, 111.4, 87.4, 79.3, 62.4, 55.1, 54.9, 37.7, 35.1, 35.0,
31.0, 30.8, 27.8, 26.0, 25.8, 22.0, 17.4. Ϫ MS (70 eV); m/z (%): 531
(10), 515 (3), 487 (3), 473 (2), 431 (100), 375 (43), 297 (16), 253
(88), 236 (37), 221 (16), 195 (51), 181 (8), 153 (44), 126 (7), 99 (15),
57 (18). Ϫ C34H56N2O6 (588.83): calcd. C 69.35, H 9.59, N 4.76;
found C 69.44, H 9.70, N 4.89.
1
997s, 926w, 878w. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 5.23 [s, 1
H, H-C(2)], 4.48 [d, J ϭ 7 Hz, 1 H, H-C(5)], 3.83 (s, 3 H, H3C-O),
3.25Ϫ3.14 (m, 1 H), 3.12Ϫ3.02 (m, 1 H), 1.48 (s, 9 H, Me3C-O),
1.02 (s, 9 H, Me3C-COH), 0.96 [s, 9 H, Me3C-C(2)]. Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 166.7, 157.6, 89.7, 81.7, 63.1, 55.5, 36.6,
35.8, 28.4, 26.3, 26.1. Ϫ MS (70 eV); m/z (%): 285 (7), 269 (3), 229
(35), 211 (4), 199 (23), 185 (18), 155 (5), 143 (100), 99 (46), 84 (7),
57 (7). Ϫ C18H34N2O4 (342.48): calcd. C 63.13, H 10.01, N 8.18;
found C 63.16, H 9.92, N 8.12.
rac-tert-Butyl 2-tert-Butyl-5-[2-(2,6-di-tert-butyl-4-methoxyphen-
oxycarbonyl)-1-phenylethyl]-4-methoxy-2,5-dihydroimidazole-
1-carboxylate (rac-42): After the reaction of rac-BDI (1.70 g, 6.6
mmol) with 2,6-di-tert-butyl-4-methoxyphenyl 3-phenylacrylate[44]
(3.65 g, 10.0 mmol) according to GP5, the crude product (dia-
stereoisomer ratio of >98:2 with respect to the exocyclic stereo-
center as determined by 1H-NMR spectroscopy) was purified by
FC (hexane/AcOEt, 17:1) giving rac-42 (2.90 g, 70%) as an
amorphous solid, m.p. 89.6Ϫ90.8°C. Ϫ IR (CHCl3): 3680w, 2968s,
1756m, 1672s, 1591m, 1479m, 1447m, 1416m, 1395m, 1367s, 1298w,
1262w, 1177m, 1136s, 1105m, 1062m, 1024w, 990w, 960w, 872w. Ϫ
1H NMR (300 MHz, [D6]DMSO, 94.0°C): δ ϭ 7.27Ϫ7.22 (m, 3
H, arom. H), 7.13Ϫ7.11 (m, 2 H, arom. H), 6.80 (s, 1 H, arom. H),
6.77 (s, 1 H, arom. H), 4.72Ϫ4.68 (br, 1 H), 4.56 (s, 1 H), 3.86 (s,
3 H, H3C-O), 3.74 (s, 3 H, H3C-O), 3.31 (d, J ϭ 7 Hz, 2 H), 1.48
(s, 9 H, Me3C-O), 1.28 (s, 9 H, Me3C-Ar), 1.07 (s, 9 H, Me3C-Ar),
0.81 [s, 9 H, Me3C-C(2)]. Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ
172.0, 171.9, 166.2, 165.4, 155.7, 152.7, 152.2, 143.0, 142.9, 141.1,
137.8, 137.5, 128.7, 128.2, 127.9, 127.8, 127.1, 111.2, 87.4, 87.1,
79.5, 65.7, 65.3, 55.2, 54.9, 37.3, 36.8, 36.3, 35.0, 34.7, 31.0, 30.8,
27.9, 27.8, 26.2, 26.0. Ϫ MS (70 eV); m/z (%): 623 (3) [Mϩ], 565
(11), 549 (3), 523 (10), 465 (77), 409 (24), 331 (21), 311 (7), 287
rac-tert-Butyl 2-tert-Butyl-5-(cyclohexylhydroxymethyl)-4-meth-
oxy-2,5-dihydroimidazole-1-carboxylate (rac-45): The aldol addition
of rac-BDI (2.19 g, 8.5 mmol) to cyclohexane carbaldehyde (2.39 g,
21.3 mmol) according to GP6 and purification of the crude product
(erythro/threo ϭ 67:33 according to 1H-NMR spectroscopy) by FC
(pentane/Et2O, 2:1) gave rac-45 (1.07 g, 62%) as an amorphous
solid, m.p. 143.2Ϫ145.0°C. Ϫ IR (CHCl3): 3675w, 3569w, 2930s,
2856m, 1694s, 1672s, 1479w, 1447m, 1395m, 1368s, 1263m, 1168m,
1131m, 1077w, 991m, 949w, 930w, 890w, 856w. Ϫ 1H NMR (300
MHz, CDCl3): δ ϭ 5.28 [d, J ϭ 3 Hz, 1 H, H-C(2)], 4.43Ϫ4.41 (m,
2 H), 3.91 (s, 3 H, H3C-O), 2.57 (d, J ϭ 11 Hz, 1 H, HO-CH),
1.72Ϫ1.65 (m, 5 H), 1.48 (s, 9 H, Me3C-O), 1.21Ϫ1.15 (m, 6 H),
0.92 [s, 9 H, Me3C-C(2)]. Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
167.6, 153.5, 88.5, 80.5, 72.8, 64.2, 55.5, 39.9, 39.4, 30.3, 28.3, 27.4,
26.9, 26.5, 26.2. Ϫ MS (70 eV); m/z (%): 311 (9), 295 (3), 255 (7),
237 (100), 211 (6), 193 (35), 155 (11), 143 (86), 111 (9), 99 (99), 84
(13). Ϫ C20H36N2O4 (368.52): calcd. C 65.19, H 9.85, N 7.60; found
C 65.05, H 9.81, N 7.63.
The bicyclic compound rac-49 (0.21 g, 15%) with a diastereoiso-
mer ratio of >98:2 was also formed during this reaction.
rac-tert-Butyl 2-tert-Butyl-5-(hydroxyphenylmethyl)-4-methoxy-
(100), 255 (9), 236 (57), 205 (10), 187 (43), 155 (31), 131 (64), 99 2,5-dihydroimidazole-1-carboxylate (rac-46): The aldol addition of
Eur. J. Org. Chem. 1998, 1337Ϫ1351 1349

D. Seebach, M. Hoffmann
rac-BDI (2.05 g, 8.0 mmol) to benzaldehyde (2.13 g, 20.0 mmol) mmol) and benzaldehyde (2.29 g, 21.6 mmol) according to GP7
FULL PAPER
according to GP6 and purification of the crude product (erythro/
and purification of the crude product (diastereoisomer ratio of
threo ϭ 91:9 according to 1H-NMR spectroscopy) by FC (pentane/ >98:2 with respect to the stereocenter at C(1) as determined by 1H-
Et2O, 3:1) gave rac-46 (2.54 g, 88%) as an amorphous solid. All NMR spectroscopy) by FC (hexane/AcOEt, 9:1) gave rac-50 (0.65
analytical data were identical to those published in ref.[11]
.
g, 26%) as a colorless solid, m.p. 135.4Ϫ135.8°C. Ϫ IR (KBr):
2968m, 1747s, 1653s, 1459m, 1445m, 1385m, 1363m, 1331m, 1303m,
1255w, 1236m, 1213w, 1160m, 1065m, 1001m, 983m, 926m, 887w,
795w, 770w, 758m, 740m, 695m. Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 7.36Ϫ7.34 (m, 3 H, arom. H), 7.18Ϫ7.15 (m, 2 H, arom. H),
5.71 (d, J ϭ 9 Hz, 1 H), 5.17 (d, J ϭ 3 Hz, 1 H), 4.82 (dd, J ϭ 9
und 3 Hz, 1 H), 3.35 (s, 3 H, H3C-O), 0.97 (s, 9 H, Me3C-C). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 166.4, 162.2, 135.4, 129.1, 128.5,
125.9, 93.3, 79.3, 66.1, 55.8, 36.9, 25.2. Ϫ MS (70 eV); m/z (%):
231 (73), 187 (100), 155 (10), 130 (52), 117 (5), 103 (19), 90 (7), 77
(12), 70 (4), 57 (12), 41 (14), 29 (9). Ϫ C16H20N2O3 (288.35): calcd.
C 66.65, H 6.99, N 9.72; found C 66.90, H 7.08, N 9.54.
Preparation of Bicyclic Carbamates
rac-5-tert-Butyl-1-isopropyl-7-methoxy-5,7a-dihydro-1H-imidazo-
[1,5-c]oxazol-3-one (rac-47): The reaction of rac-BDI (2.01 g, 7.9
mmol) and isobutyric aldehyde (1.42 g, 19.6 mmol) according to
GP7 and purification of the crude product (diastereoisomer ratio
of >98:2 with respect to the stereocenter at C(1) as determined by
1H-NMR spectroscopy) by FC (pentane/Et2O, 3:1) gave rac-47
(0.72 g, 36%) as a colorless oil. Ϫ IR (CHCl3): 2968m, 2873w,
1755s, 1651s, 1464w, 1444w, 1366m, 1341m, 1319m, 1276m, 1135w,
1
1087w, 1061w, 1028m, 986m, 954w, 920w, 882w. Ϫ H NMR (300
MHz, CDCl3): δ ϭ 5.10 (s, 1 H), 4.50 (s, 2 H), 3.92 (s, 3 H, H3C-
O), 2.15Ϫ2.02 (m, 1 H, H-CMe2), 1.08 (d, J ϭ 8 Hz, 3 H, H3C-
CH), 0.95 (s, 9 H, Me3C-C), 0.93 (d, J ϭ 8 Hz, 3 H, H3C-CH). Ϫ
13C NMR (50 MHz, CDCl3): δ ϭ 167.1, 162.5, 92.8, 82.7, 63.9,
56.5, 36.7, 29.4, 25.1, 19.9, 16.3. Ϫ MS (70 eV); m/z (%): 239 (1),
211 (3), 197 (100), 153 (94), 138 (9), 125 (5), 111 (13), 99 (27),
57 (4).
The aldol adduct rac-46 (1.63 g, 52%) with erythro/threo > 98:2
was also formed during this reaction.
Preparation of erythro-Ͱ-Amino-β-hydroxy Acids
erythro-2-Amino-3-hydroxy-4-methylpentanoic Acid (rac-51): The
aldol adduct rac-43 (0.13 g, 0.4 mmol) was hydrolyzed in 6  HCl
(10 ml) according to GP8. After purification of the crude product
by ion exchange chromatography (Dowex 50Wx8) the amino acid
rac-51 (57 mg, 97%) was isolated as an amorphous solid. All ana-
The aldol adduct rac-43 (0.12 g, 5%) with erythro:threo > 98:2
was also formed during this reaction.
lytical data were identical to those published in ref.[32]
.
rac-1,5-Di-tert-butyl-7-methoxy-5,7a-dihydro-1H-imidazo[1,5-c]-
oxazol-3-one (rac-48): The reaction of rac-BDI (2.27 g, 8.8 mmol)
and pivalaldehyde (1.91 g, 22.1 mmol) according to GP7 and purifi-
cation of the crude product (diastereoisomer ratio of >98:2 with
respect to the stereocenter at C(1) as determined by 1H-NMR spec-
troscopy) by FC (pentane/Et2O, 5:1) gave rac-48 (1.87 g, 79%) as
a colorless solid, m.p. 86.6Ϫ87.4°C. Ϫ IR (KBr): 2966m, 1749s,
1648s, 1438w, 1364m, 1331m, 1317m, 1277m, 1238m, 1157w, 1104w,
1028w, 1007w, 984m, 881w, 795w, 758w. Ϫ 1H NMR (300 MHz,
[D6]DMSO): δ ϭ 4.93 (d, J ϭ 3 Hz, 1 H), 4.79 (dd, J ϭ 9 und 3
Hz, 1 H), 4.63 (d, J ϭ 9 Hz, 1 H), 3.87 (s, 3 H, H3C-O), 0.96 (s, 9
H, Me3C-C), 0.88 (s, 9 H, Me3C-C). Ϫ 13C NMR (75 MHz,
[D6]DMSO): δ ϭ 167.0, 161.3, 91.3, 85.4, 63.1, 56.3, 36.3, 33.4,
24.8, 24.6. Ϫ MS (70 eV); m/z (%): 253 (1), 211 (50), 155 (6), 99
(100), 84 (4), 69 (14), 57 (12), 41 (17), 29 (7). Ϫ C14H24N2O3
(268.36): calcd. C 62.66, H 9.01, N 10.44; found C 62.89, H 8.89,
N 10.35.
erythro-2-Amino-3-hydroxy-3-phenylpropionic Acid (rac-52): The
aldol adduct rac-46 (0.54 g, 1.5 mmol) was hydrolyzed in 6  HCl
(15 ml) according to GP8. After purification of the crude product
by ion exchange chromatography (Dowex 50Wx8) the amino acid
rac-52 (0.25 g, 92%) was isolated as an amorphous solid. All ana-
lytical data were identical to those published in ref.[33]
.
Ƞ
Dedicated to Professor Wolfgang Steglich on the occasion of
his 65th birthday.
[1]
[2]
R. M. Williams, Synthesis of Optically Active α-Amino Acids,
1st ed., Pergamon Press, Oxford, 1989. Ϫ R. O. Duthaler, Tetra-
hedron 1994, 50, 1539Ϫ1650. For a most recent paper on amino
acid synthesis by the OЈDonnel methodology see: E. J. Corey,
F. Xu, M. C. Noe, J. Am. Chem. Soc. 1997, 119, 12414.
U. Schöllkopf, Tetrahedron 1983, 39, 2085Ϫ2091.
Ϫ U.
Schöllkopf, Pure & Appl. Chem. 1983, 55, 1799Ϫ1806. Ϫ U.
Schöllkopf in Topics in Current Chemistry (Ed.: F. L. Boschke),
Springer Verlag, Berlin, 1983, vol. 109, p. 65Ϫ85.
The aldol adduct rac-44 (0.11 g, 5%) with erythro/threo > 98:2
was also formed during this reaction.
...with recycling of the undesired enantiomer[4][5][6]
.
[3]
[4]
[5]
R. Fitzi, D. Seebach, Tetrahedron 1988, 44, 5277Ϫ5292.
Review: D. Seebach, A. R. Sting, M. Hoffmann, Angew. Chem.
1996, 108, 2880Ϫ2921; Angew. Chem. Int. Ed. 1996, 35,
2708Ϫ2748.
J. N. Kinkel, U. Gysel, D. Blaser, D. Seebach, Helv. Chim. Acta
1991, 74, 1622Ϫ1635. Ϫ D. Blaser, D. Seebach, Liebigs Ann.
Chem. 1991, 1067Ϫ1078. Ϫ D. Seebach, T. Gees, F. Schuler,
Liebigs Ann. Chem. 1993, 785Ϫ799.
Preliminary communication: S. Blank, D. Seebach, Angew.
Chem. 1993, 105, 1780Ϫ1781; Angew. Chem. Int. Ed. 1993, 32,
1765Ϫ1766.
Abstract of a poster: M. Hoffmann, D. Seebach, Chimia 1997,
51, 90Ϫ92.
rac-5-tert-Butyl-1-cyclohexyl-7-methoxy-5,7a-dihydro-1H-imid-
azo[1,5-c]oxazol-3-one (rac-49): The reaction of rac-BDI (2.27 g,
8.8 mmol) and cyclohexane carbaldehyde (2.49 g, 22.2 mmol) ac-
cording to GP7 and purification of the crude product (diastereoiso-
mer ratio of 67:33 with respect to the stereocenter at C(1) as deter-
mined by 1H-NMR spectroscopy) by FC (hexane/AcOEt, 7:1) gave
rac-49 (1.10 g, 78%) as a colorless solid, m.p. 125.2Ϫ126.4°C. Ϫ IR
(CHCl3): 3682w, 3026w, 2933m, 2862w, 1754s, 1651s, 1600w, 1446w,
1380w, 1364w, 1344m, 1323m, 1277m, 1139w, 1062w, 1010w, 990m,
[6]
[7]
[8]
[9]
1
928w. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 5.09 (s, 1 H), 4.50 (s,
M. Hoffmann, S. Blank, D. Seebach, E. Küsters, E. Schmid,
Chirality 1998, 10, 217Ϫ222.
D. Seebach, M. Hoffmann, A. R. Sting, J. N. Kinkel, M.
Schulte, E. Küsters, J. Chromatogr. A 1998, 796, 299Ϫ307.
S. Blank, Diss. ETH Nr. 10193, Zürich, Switzerland, 1993.
...mainly due to the fact that it was difficult to exceed enan-
tiomer ratios above 97:3.
M. Hoffmann, Diss. ETH Nr. 12387, Zürich, Switzerland, 1997.
The absolute configuration of (R)- and (S)-1 was determined
from the X-ray crystal structure of the salt 3 (P. Seiler, X-ray
service of our laboratory)[11]. It also follows from the compari-
2 H), 3.92 (s, 3 H, H3C-O), 1.80Ϫ1.60 (m, 6 H), 1.26Ϫ1.13 (m, 5
H), 0.96 (s, 9 H, Me3C-C). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
167.2, 162.4, 92.8, 82.0, 63.8, 56.5, 39.1, 36.7, 30.4, 26.7, 26.1, 25.9,
25.5, 25.2. Ϫ MS (70 eV); m/z (%): 237 (100), 193 (44), 166 (4), 155
(10), 111 (9), 99 (41). Ϫ C16H26N2O3 (294.39): calcd. C 65.28, H
8.90, N 9.52; found C 65.43, H 9.00, N 9.60.
[10]
[11]
[12]
[13]
[14]
rac-5-tert-Butyl-7-methoxy-1-phenyl-5,7a-dihydro-1H-imidazo-
[1,5-c]oxazol-3-one (rac-50): The reaction of rac-BDI (2.21 g, 8.6
1350
Eur. J. Org. Chem. 1998, 1337Ϫ1351

New Chiral Glycine Derivative
FULL PAPER
son of amino acid esters, synthesized from BDI, with authentic
enantiopure samples of known configuration.
far, and also than many other synthetic methods found in the
literature (for an overview see ref.[1][5]).
[15]
[27]
[28]
For the isolation and characterization of the racemic as well as
D. Seebach, E. Pfammatter, V. Gramlich, T. Bremi, F. Kühnle,
S. Portmann, I. Tironi, Liebigs. Ann. Chem. 1992, 1145Ϫ1151.
For results and a detailed mechanistic discussion of Michael
additions to di-tert-butylphenol esters see ref.[19] and references
to HeathcockЈs and CookeЈs work therein.
of the enantiopure (Z)-analogs of 2 and of BDI see ref.[10]
.
[16]
[17]
[18]
Most mono- and dialkylated BDI derivatives are oils which may
partially decompose upon distillation. The yields given in
Scheme 3 and 5 refer to analytically pure chromatographed
samples.
[29]
See also our other papers on carbonyl derivatives with “steri-
cally protected but electronically active” CO groups, reference
The structure of enantiopure 14 (Scheme 3) with p-nitrobenzyl
instead of p-methoxybenzyl as the substituent was determined
by B. Rheiner, as part of the requirements in a crystallography
course at ETH Zürich, 1992.
With Li-Boc-BMI, Fitzi had obtained the product of alkylation
with rac-1-phenylethylbromide in 68% yield and with a dia-
stereoisomer ratio of 92.5:7.5[4]; see the mechanistic discussion
in footnote 43 of [19]. For another enantiomer differentiation
of an alkyl halide by a chiral oxazoline see: A. I. Meyers, K.
Kamata, J. Am. Chem. Soc. 1976, 98, 2290Ϫ2294.
K. Suzuki, D. Seebach, Liebigs Ann. Chem. 1992, 51Ϫ61.
Various amounts and concentrations of hydrochloric acid, tri-
fluoro acetic acid (TFA) and acidic ion exchange resin in aque-
ous methanol, aqueous THF and water were tested.
Y. Hamada, S. Kato, T. Shioiri, Tetrahedron Lett. 1985, 26,
3223Ϫ3226.
The amino acid methyl ester obtained after hydrolysis of di-
hydroimidazole derivative 9 was Boc-protected in order to avoid
possible loss of the acetylenic Me3Si-protection under the con-
ditions of introducing the (Z) group. Only the amino acid ester
rac-16 could be obtained in analytically pure form as such
(bulb-to-bulb destillation at high vacuum). A protection of the
amino functionality followed by flash chromatography was
therefore not necessary in this case. In all other cases (also with
the α-branched amino acid esters shown in Scheme 6) the (Z)
protecting group was introduced in order to obtain analytically
pure samples of the esters F and H.
10 in ref.[19]
.
[30]
[31]
[32]
At this temperature pivalaldehyde reacted very slowly with en-
aminate E, giving rise to the product rac-44 in only 8% yield.
For erythro-hydroxyleucine see ref.[32] and for erythro-hydroxy-
phenylalanine see ref.[33]
.
K. J. Hale, S. Manaviazar, V. M. Delisser, Tetrahedron 1994,
50, 9181Ϫ9188.
[33]
[34]
A. Saeed, D. W. Young, Tetrahedron 1992, 48, 2507Ϫ2514.
For other methods developed by our group to prepare α-amino
β-hydroxy acids of erythro configuration see: D. Seebach, E.
Juaristi, D. D. Miller, C. Schickli, T. Weber, Helv. Chim. Acta
1987, 70, 237Ϫ261 and S. Blank, D. Seebach, Liebigs Ann.
Chem. 1993, 889Ϫ896.
[19]
[20]
[21]
[22]
[35]
The two diastereomeric Li-alkoxides formed in the original ad-
dition step are expected to cyclize with different rates, and, in-
deed, the ratios of epimers detected in the two types of products
43Ϫ46 and 47Ϫ50 are different.
H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957,
79, 1920Ϫ1923.
[36]
[37]
D. Blaser, S. Y. Ko, D. Seebach, J. Org. Chem. 1991, 56,
6230Ϫ6233 and D. Blaser, Diss. ETH Nr. 9527, Zürich, Switzer-
land, 1991.
For a detailed mechanistic discussion see refs.[5][19], and: D. See-
bach, T. Maetzke, W. Petter, B. Klötzer, D. A. Plattner, J. Am.
Chem. Soc. 1991, 113, 1781Ϫ1786.
[38]
[39]
[40]
In both cases we would interpret the axial position of the alde-
hyde R group as a consequence of avoidance of a gauche re-
[23]
[24]
Formation of diketopiperazines by dimerization of amino acid
methyl esters F was not observed. The poor overall yields of
(Z)-protected esters (see Experimental Part) is partially due to
losses caused by water-solubility of the esters F.
lationship between the R and the N-CO2R group[38]
.
This electrophile was prepared according to the experimental
procedure described on page 66 in: L. Brandsma, H. D. Verkru-
ijsse, Synthesis of Acetylenes, Allenes and Cumulenes Ϫ A Lab-
oratory Manual, Elsevier, Amsterdam, 1981.
-Alanine, -valine, and -phenylalanine methyl ester (as ob-
tained from (S)-(ϩ)-BDI) were characterized by gas chromatog-
raphy following the literature procedure: S. Abdalla, E. Bayer,
H. Frank, Chromatographia 1987, 23, 83Ϫ85.
[41]
This electrophile was prepared in analogy with the experimental
procedure for the preparation of 3-bromocyclohexene described
on page 401 in: A. Vogel, Textbook of Practical Organic Chemis-
try, Longman, New York, 1978.
The crystal structure of the product with R1 ϭ CH2C6H5, R2 ϭ
CH3 (5-epi-24) was determined by B. Rheiner, as part of the
requirements in a crystallography course at ETH Zürich, 1992.
The methodology of using BDI as a chiral building block in
amino acid synthesis clearly employs milder hydrolysis con-
ditions than all the other methods developed in our group, so
[25]
[26]
For the preparation of this electrophile see ref.[41]
.
[42]
[43]
[44]
A. Studer, D. Seebach, Liebigs Ann. Chem. 1995, 217Ϫ222.
M. P. Cooke, J. Org. Chem. 1986, 51, 1637Ϫ1638.
[98064]
Eur. J. Org. Chem. 1998, 1337Ϫ1351
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