Enantioselective syntheses of conformationally rigid, highly lipophilic mesityl-substituted amino acids

Article abstract of DOI:10.1002/(SICI)1522-2675(20000510)83:5<972::AID-HLCA972>3.0.CO;2-9

Three N-Boc-protected amino acids substituted with a mesityl (=2,4,6- trimethylphenyl) group were synthesized in enantiomerically pure form, either by asymmetric epoxidation or by aminohydroxylation as the source of chirality. The 3-mesityloxirane-2-methanol 7, easily available in high enantiomer purity by Sharpless epoxidation, was converted into 3-{[(tert- butoxy)carbonyl]amino}-3-mesitylpropane-1,2-diol 9 by a regio- and stereoselective ring opening with an ammonia equivalent (sodium azide or benzhydrylamine), followed by hydrogenation and in situ treatment with (Boc)₂O (Boc=[(tert-butoxy)carbonyl]) (Scheme 3). Oxidative cleavage of the diol fragment in 9 afforded N-[(tert-butoxy)carbonyl]-α-mesitylglycine 1 of >99% ee. This amino acid was also prepared in enantiomerically pure form starting from 2,4,6-trimethylstyrene (11) by a regioselective Sharpless asymmetric aminohydroxylation, followed by a 2,2,6,6-tetramethylpiperidin-1- yloxyl (TEMPO)-catalyzed oxidation (Scheme 4). On the other hand, 1-[(tert- butoxy)carbonyl]-2-{{[(tert-butyl)dimethylsilyl]oxy}methyl}-3- mesitylaziridine 14 was prepared from 9 by a sequence involving selective protection of the primary alcohol (as a silyl ether), activation of the secondary alcohol as a mesylate, and base-induced (NaH) cyclization (Scheme 5). The reductive cleavage of the aziridine ring (H₂, Pd/C), followed by alcohol deprotection (Bu₄NF/THF) and oxidation (pyridinium dichromate (PDC)/DMF or (TEMPO)/NaClO) provided, in high yield and enantiomeric purity, N-[(tert-butoxy)carbonyl]-β-mesitylalanine 2. Alternatively, the regioselective ring opening of the aziridine ring of 14 with lithium dimethylcuprate, followed by silyl-ether cleavage and oxidation lead to N- [(tert-butoxy)carbonyl]-β-mesityl-β-methylalanine 3. A conformational study of the methyl esters of the N-Boc-protected amino acids 1 and 3 carried out by variable-temperature ¹H-NMR and semi-empirical (AM1) calculations shows the strong rotational restriction imposed by the mesityl group.

Full text of DOI:10.1002/(SICI)1522-2675(20000510)83:5<972::AID-HLCA972>3.0.CO;2-9

972
Helvetica Chimica Acta ± Vol. 83 (2000)
Enantioselective Syntheses of Conformationally Rigid, Highly Lipophilic
Mesityl-Substituted Amino Acids
by Eva Medina, Albert Moyano, Miquel A.PericaÁs*, and Antoni Riera*
Á
Á
Unitat de Recerca en Síntesi Asimetrica (URSA), Departament de Química Organica, Universitat de
Á
Barcelona, c/Martí i Franques, 1 ± 11, E-08028 Barcelona (e-mail: a.riera@qo.ub.es and mapericas@qo.ub.es)
Three N-Boc-protected amino acids substituted with a mesityl (ˆ2,4,6-trimethylphenyl) group were
synthesized in enantiomerically pure form, either by asymmetric epoxidation or by aminohydroxylation as the
source of chirality. The 3-mesityloxirane-2-methanol 7, easily available in high enantiomer purity by Sharpless
epoxidation, was converted into 3-{[(tert-butoxy)carbonyl]amino}-3-mesitylpropane-1,2-diol 9 by a regio- and
stereoselective ring opening with an ammonia equivalent (sodium azide or benzhydrylamine), followed by
hydrogenation and in situ treatment with (Boc)2O (Boc ˆ [(tert-butoxy)carbonyl]) (Scheme 3). Oxidative
cleavage of the diol fragment in 9 afforded N-[(tert-butoxy)carbonyl]-a-mesitylglycine 1 of > 99% ee. This
amino acid was also prepared in enantiomerically pure form starting from 2,4,6-trimethylstyrene (11) by a
regioselective Sharpless asymmetric aminohydroxylation, followed by a 2,2,6,6-tetramethylpiperidin-1-yloxyl
(TEMPO)-catalyzed oxidation (Scheme 4). On the other hand, 1-[(tert-butoxy)carbonyl]-2-{{[(tert-butyl)di-
methylsilyl]oxy}methyl}-3-mesitylaziridine 14 was prepared from 9 by a sequence involving selective protection
of the primary alcohol (as a silyl ether), activation of the secondary alcohol as a mesylate, and base-induced
(NaH) cyclization (Scheme 5). The reductive cleavage of the aziridine ring (H2, Pd/C), followed by alcohol
deprotection (Bu4NF/THF) and oxidation (pyridinium dichromate (PDC)/DMF or (TEMPO)/NaClO)
provided, in high yield and enantiomeric purity, N-[(tert-butoxy)carbonyl]-b-mesitylalanine 2. Alternatively,
the regioselective ring opening of the aziridine ring of 14 with lithium dimethylcuprate, followed by silyl-ether
cleavage and oxidation lead to N-[(tert-butoxy)carbonyl]-b-mesityl-b-methylalanine 3. A conformational study
of the methyl esters of the N-Boc-protected amino acids 1 and 3 carried out by variable-temperature 1H-NMR
and semi-empirical (AM1) calculations shows the strong rotational restriction imposed by the mesityl group.
1.Introduction. ± Peptides and proteins are mediators of multiple biological
processes, their activity being usually coupled to a given conformation. In the field of
small peptides, the absence of the multiple long-range interactions that stabilize protein
conformations has fostered the preparation of a myriad of synthetic analogues designed
to modify their conformational behavior and, consequently, their biological activity [1].
These modified peptides are finding increasing importance both as drugs (see, interalia,
[2]), and in structure-activity relationship studies [3]. One of the simplest approaches
to these modified peptides is the substitution of one or several amino acids by unnatural
residues [1 ± 6]1), and this strategy has also been applied in protein-structure/function
studies [7] by site-specific amino acid incorporation techniques [8].
The need for specifically designed amino acids as constituents of modified peptides
and proteins has stimulated the development of new synthetic methodologies for their
preparation in enantiomerically pure form [9], asymmetric synthesis being the most
1
)
For some examples of conformationally restricted peptides with unnatural amino acids, see [4]; for some
examples of modified peptides with hydrophobic amino acids, see [5].

Helvetica Chimica Acta ± Vol. 83 (2000)
973
practical and economical approach, especially in the case of very hydrophobic side-
chain residues, where the enzymatic resolution fails [10].
In recent years, we have been involved in the development of enantioselective
syntheses of several important types of N-Boc-amino acids [11 ± 14]. Among them,
arylglycines I [11], arylalanines II [12], and b-aryl-b-methylalanines III [12 ± 13] can be
prepared in a very straightforward and practical way from the corresponding
intermediates, the enantiomerically pure N-Boc-3-amino-1,2-diol IV. Compounds of
type IV are readily available by a regio- and stereospecific ring opening with an
ammonia synthetic equivalent [11 ± 15] of the corresponding epoxy alcohols of type V
which, in turn, can be prepared with full stereochemical control from allyl alcohols by
Sharpless epoxidation [16] (Scheme 1).
Scheme 1
Boc ˆ tBuOCO, P ˆ protecting group
The substitution of a phenyl by another aromatic group with different electronic or
steric characteristics is a well-established strategy in the synthesis of peptide or protein
analogues [4 ± 7]. In this context, amino acids containing in their side chain a 2,4,6-
trimethylphenyl (mesityl) group could be very useful in the preparation of more
hydrophobic and conformationally restricted analogues. Up to now, however, the use of
such residues has been rare, probably because of the difficulties encountered in the
preparation of enantiomerically pure amino acids that contain this group in the side
chain [17]. Whereas (2,4,6-trimethylphenyl)glycine (ˆa-mesitylglycine) has not been
described up to now, all attempts of enzymatic resolution of 3-(2,4,6-trimethylpheny-
l)alanine (ˆ b-mesitylalanine) have been reported to fail [17]. Notwithstanding,
several peptide analogues with very promising biological activity have been prepared in
which a phenylalanine is replaced by a b-mesitylalanine residue; however, the racemic
amino acid had to be introduced and the deprotected diastereoisomeric peptides
separated by HPLC [17][18]. On the other hand, several conformationally restricted

974
Helvetica Chimica Acta ± Vol. 83 (2000)
b-aryl-b-methylalanines have been used in structure-activity studies of biologically
important peptides [6][19], but whether the b-mesityl-b-methylalanine is a potentially
useful amino acid is still unknown.
We wish to report herein the successful enantioselective synthesis of three
important N-Boc-protected amino acids bearing a mesityl residue, i.e., N-[(tert-
butoxy)carbonyl]-a-mesitylglycine 1 (I, Arˆ mesityl), N-[(tert-butoxy)carbonyl]-b-
mesitylalanine 2 (II, Arˆ mesityl), and N-[(tert-butoxy)carbonyl] b-mesityl-b-meth-
ylalanine 3 (III, Arˆ mesityl), using a catalytic asymmetric reaction (Sharpless
epoxidation or aminohydroxylation) to introduce chirality. Moreover, the role of
the mesityl residue as a conformational lock (i.e., by increasing barriers for con-
former interconversion) in these amino acids was demonstrated by a combined NMR
and theoretical (AM1) conformational study of the methyl esters of compounds 1
and 3.
2.Results and Discussion. ± 2.1. Enantioselective Synthesis of N-Boc-Protected a-
Mesitylglycine 1. The synthesis of N-Boc-protected a-mesitylglycine 1 was initially
planned to make use of our previously described methodology for the preparation of a-
arylglycines [11b]. First of all, commercially available mesitaldehyde (ˆ2,4,6-
trimethylbenzaldehyde; 4) was converted into mesitylpropenol 6 by the standard
sequence of Wittig olefination (! 5) followed by diisobutylaluminium hydride
(DIBAL-H) reduction (Scheme 2). Subsequent catalytic asymmetric Sharpless epox-
idation [16] with diisopropyl l-tartrate afforded (2S,3S)-3-mesityloxirane-2-methanol
(7) in 63% yield and 88% ee. The high crystallinity of this epoxy alcohol allowed the
enantiomer excess to be increased up to 99% by repeated recrystallization from
hexanes.
Enantiomerically pure oxiranemethanol 7 was treated under Sharpless conditions
[20] (Ti(OiPr)4/CH2Cl2) using benzhydrylamine (ˆ(diphenylmethyl)amine) as an
Scheme 2
t
a) Ph3PCHCOOEt, CH2Cl2; 97%. b) DIBAL-H, Et2O; 86%. c) BuOOH, diisopropyl l-tartrate, Ti(OiPr)4,
CH2Cl2, À308, 63%.

Helvetica Chimica Acta ± Vol. 83 (2000)
975
ammonia surrogate but, quite unexpectedly, without success. In our hands, this is the
first epoxy alcohol that does not provide the corresponding aminodiol by treatment
with an amine and titanium tetraisopropoxide [11][14c][15]. Quite gratifyingly,
however, a totally regio- and stereospecific oxirane-ring opening took place with the
same amine but under Crottiꢀs conditions [21] (LiClO4/MeCN) to afford (2R,3R)-3-
(benzhydrylamino)-3-mesityl-1,2-diol 8 in 97% yield (Scheme 3). Catalytic hydro-
genolysis (Pd(OH)2/C) of 8 with in situ protection (Boc2O) afforded in 68% yield the
N-Boc-protected 3-amino-3-mesityl propane-1,2-diol 9, which is the key intermediate
in our approach to the synthesis of mesityl-substituted amino acids. An alternative
preparation of this key intermediate was performed using NaN3 as a synthetic
equivalent of ammonia. Thus, ring opening of the oxiranemethanol 7 under Crottiꢀs
conditions gave the corresponding azido diol, which was immediately hydrogenated
and protected to provide 9 in 62% overall yield (Scheme 3). The oxidative cleavage
(KMnO4/NaIO4) of the diol moiety of 9 led to the desired N-Boc-protected a-
mesitylglycine (À)-1 in 72% yield. The enantiomer purity was checked by HPLC
(Chiralcel OD) after reduction to (2R)-2-{[(tert-butoxy)carbonyl]amino}-2-mesityl-
ethanol (À)-10); the determined >99% ee was in good agreement with that of the
starting epoxy alcohol.
Scheme 3
Bzh ˆ Ph2CH, Boc ˆ tBuOCO
a) Ph2CHNH2, LiClO4, MeCN; 97%. b) H2, Pd(OH)2/C, (Boc)2O, AcOEt; 68%. c) NaN3, LiClO4, MeCN. d)
H2, Pd/C, (Boc)2O, MeOH; 62%, two steps. e) NaIO4, KMnO4, Na2CO3, dioxane, H2O; 72%.
Although these methodologies proved to highly reliably lead to enantiomerically
pure N-Boc-protected a-mesitylglycine, the synthesis of a-arylglycines recently
described by Reddy and Sharpless [22], based on the asymmetric aminohydroxylation
[23], would be an even shorter approach. Literature precedents, however, were not
encouraging since 2,4,6-trimethylstyrene (11) was not among the examples prepared by
Reddy and Sharpless and, more significantly, a recent report [24] described that this
reaction was sluggish, yielding, after 7.5 h, only 21% of N-Boc-protected (S)-2-amino-

976
Helvetica Chimica Acta ± Vol. 83 (2000)
2-mesitylethanol (‡)-10 in a poor 56% ee. Nevertheless, we decided to perform the
aminohydroxylation of 2,4,6-trimethylstyrene (11) with tert-butyl carbamate as a N-
source and bis(dihydroquininyl) phthalazine-1,4-diyl diether ((DHQ)2PHAL) as a
ligand. In our hands, the aminohydroxylation reaction worked reasonably well2),
affording the amino alcohol (‡)-10 in 44% yield as the predominant component of a
4 :1 mixture of regioisomers. The unwanted minor regioisomer was removed by
chromatography, and the initial 88% ee could be increased to 99% by crystallization
from Et2O. The 2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPO)-catalyzed oxidation
[25] of alcohol (‡)-10 provided the N-Boc-protected (S)-a-mesitylglycine (‡)-1 in
82% yield and with no decrease in optical purity.
Scheme 4
Boc ˆ tBuOCO
t
a) BuOCONH2, tBuOCl, (DHQ)2PHAL, K2OsO2(OH)4; 44%. b) TEMPO, NaClO, KBr, acetone; 82%.
Remarkably enough, both approaches reported here for the preparation of 1 allow
the synthesis of both enantiomers, the final configuration being determined simply by
the ligand used in the catalytic asymmetric epoxidation or aminohydroxylation.
2.2. Synthesis of N-Boc-Protected b-Mesitylalanines 2 and 3. The syntheses of the N-
Boc-protected b-mesitylalanine 2 and of b-mesityl-b-methylalanine 3 were envisaged to
proceed via the intermediacy of (2S,3R)-1-[(tert-butoxy)carbonyl] 2-{{[(tert-butyl)di-
methylsilyl]oxy}methyl}-3-mesitylaziridine (14). The latter was readily prepared from
the enantiomerically pure N-Boc-protected aminodiol 9 by a sequence involving the
protection of the primary-alcohol function as a tert-butyldimethylsilyl ether ( ! 12),
mesylation of the secondary-alcohol function ( ! 13), and treatment with NaH in THF
(Scheme 5). Hydrogenolytic cleavage of aziridine 14 was completely regioselective at
the benzylic position, leading almost quantitatively to N-Boc-protected (2S)-1-{[(tert-
butyl)dimethylsilyl]oxy] ± 3-mesitylpropan-2-amine 15. Bu4NF-Mediated cleavage of
the silyl ether ( ! 16) followed by oxidation of the primary alcohol afforded N-Boc-
protected b-mesitylalanine (À)-2 in excellent yield. The final oxidation step could be
performed either with pyridinium dichromate (PDC)/DMF [26] (92% yield) or with
sodium hypochlorite, TEMPO, and KBr [25] (95% yield). The optical purity of (À)-2
was checked by chiral HPLC of the corresponding methyl ester and, in good agreement
with the optical purity of the starting epoxy alcohol, was >99%, irrespective of the
oxidation protocol employed.
The synthesis of the sterically hindered N-Boc-protected amino acid (À)-3 was
planned to involve the ring opening of aziridine 14 by an appropriate C-nucleophile.
This could be achieved by treatment with lithium dimethylcuprate, although the target
2
)
We found that the Sharpless aminohydroxylation is extremely sensitive to the purity of the reagents.

Helvetica Chimica Acta ± Vol. 83 (2000)
977
Scheme 5
Boc ˆ tBuOCO, TBS ˆ tBuMe2Si,
Ms ˆ MeSO2
t
a) BuMe2SiCl, DMF, 1H-imidazole; 91% (12). b) MsCl, CH2Cl2, 4-(dimethylamino)pyridine (DMAP); 82%
(13). c) NaH, THF; 94% (14). d) H2, Pd/C, AcOEt; quant. (15). e) Bu4NF, THF; 82% (16). f) NaClO, TEMPO,
acetone 95% (2). g) Me2CuLi, Et2O; 48% (17). h) Bu4NF, THF; 86% (18). i) NaClO, TEMPO, KBr, acetone
91% (3).
O-protected amino alcohol was formed with moderate regioselectivity (2 :1), probably
due to the high steric shielding exerted by the two ortho-Me groups. The minor
regioisomer could be separated by chromatography, and the desired silyl ether 17 was
deprotected with Bu4NF in good yield ( ! 18). TEMPO-Catalyzed oxidation of 18
took place uneventfully as in the previous cases, leading to the N-Boc-protected
(2S,3S)-b-mesityl-b-methylalanine (À)-3 in excellent yield (Scheme 5).
2.3. Conformational Behavior of a-Mesitylglycine and b-Mesityl-b-methylalanine.
The usefulness of incorporating amino acids with conformational restrictions into
peptides as a method to study structure-function relationships has been stressed mainly
by Hruby and co-workers [6][19][27]3). Before including the new amino acids a-
mesitylglycine and b-mesityl-b-methyl-alanine in the toolkit for the construction of
modified peptides, it is important to know their conformational behavior in comparison
with that of their phenyl-substituted analogues. This can provide a clue as to how the
conformation of peptide chains will be modified by the inclusion of these amino acids.
To gather this knowledge, we decided to perform a conformational study of the
3
)
For asymmetric syntheses of b-aryl-b-methylalanines and tyrosines, see [28].

978
Helvetica Chimica Acta ± Vol. 83 (2000)
corresponding methyl esters 19 and 20, which were easily prepared from 1 and 3,
respectively, by treatment with MeI/KHCO3 in DMF.
In a-mesitylglycine derivatives, the only relevant dihedral angle is the one
corresponding to the rotation around the CÀC bond between the aromatic ring and
the methine moiety (c1). The conformational hypersurface of N-Boc-protected a-
mesitylglycine methyl ester 19 was explored with the RHF version of the semi-
empirical SCF-MO procedure AM1 [29] as implemented in the SPARTAN package of
programs [30]. In the minimum-energy conformer (see Fig. 1), the mesityl ring is
eclipsed with the methine CÀH bond to avoid the repulsions of the ortho-Me groups
with the methoxycarbonyl and Boc-amino groups. The dihedral angle c1 in the
minimum-energy conformation is 118. The rotation around the dihedral c1 was studied
by stepwise variation of this parameter (108 increments) with full optimization of all
other geometrical parameters. The resulting energetic profile (see Fig. 2) exhibits a
maximum around 908. Although the transition state corresponding to the rotation
could not be characterized, it is clear that, in the energetic maximum, the position of the
aromatic ring is perpendicular to the CÀH bond, and its energy is ca. 7.7 kcal molÀ1
above the minimum.
Fig. 1. AM1-Optimized structure of the minimum-energy conformer of N-Boc-
protected a-mesitylglycine methyl ester 19
The energy barrier associated with this rotation in 19 was measured by a variable-
1
temperature H-NMR experiment in CD2Cl2. Whereas at room temperature both
ortho-Me groups gave only one resonance at 2.36 ppm, this signal started broadening
on lowering the temperature (Fig. 3) and finally split into two resonances (at À908,
2s at d 2.11 and 2.47). The coalescence temperature was À66.58. According to well-

Helvetica Chimica Acta ± Vol. 83 (2000)
979
Fig. 2. Relative energies of N-Boc-protected a-mesitylglycine methyl ester 19 and N-Boc-protected a-phenyl-
glycine methyl ester as a function of the dihedral angle c1
known equations of dynamic NMR [31], this temperature was used to calculate the
activation free energy for the rotation: DG=ˆ À9.7 kcal molÀ1; this value is in good
agreement with the energetic barrier found by the coordinate driving at the semi-
empirical AM1 level.
For comparison, an analogous coordinate driving was performed at the same level
of theory for the a-phenylglycine methyl ester4). As it can be seen in Fig. 2, the shape
of the curve is fairly similar, both the minimum and the maximum being very close,
from the geometrical point of view, to the mesityl compound. The size of the barrier,
however, is much lower: only 2.0 kcal molÀ1. It can thus be concluded that the effect of
the two ortho-Me groups is almost exclusively an increase of the rotational barrier.
Thus, using a-mesitylglycine instead of a-phenylglycine would induce an important
conformational restriction in the side chain making the peptide topographically much
more constrained.
The conformational analysis of b-mesityl-b-methylalanine methyl ester 20 is more
complex since two significant dihedral angles c1 and c2 should be taken into account. A
systematic conformational search around the corresponding CÀC bonds led to the
characterization of three staggered conformers I ± III arising from the rotation of the
dihedral angle c1 (see Fig. 4). The most stable conformer I has the two H-atoms anti-
periplanar (c1 ˆ 169.48), although the energy difference between this conformer I and
the two synclinal ones is only 1.4 ± 1.6 kcal molÀ1. Quite interestingly, in all conformers
I ± III, the aromatic ring was eclipsed to the benzylic CÀH bond, the c2 dihedral angle
being in all cases close to 08. The arrangement of the mesityl ring is thus analogous to
the one found in the conformational analysis of a-mesitylglycine (Fig. 5).
4
)
The conformational rigidity of N-([tert-butoxy)carbonyl]-a-phenylglycine has allowed its use as an efficient
auxiliary reagent for the assignment of the absolute configuration of chiral primary amines by 1H-NMR
[32].

980
Helvetica Chimica Acta ± Vol. 83 (2000)
1
Fig. 3. Variable-temperature H-NMR spectrum of 19 in CD2Cl2
For each of the conformers I ± III, a coordinate driving was performed by a stepwise
change of the dihedral-angle value c2, with optimization of all other parameters, as
described for 19 (see Fig. 6). Interestingly enough, the value of c2 is very similar for all
three maxima, being ca. 90 ± 1108, and the energies of all three maxima are also very
Fig. 4. AM1-Calculated relative energies of the staggered conformers I ± III (dihedral angle c1) of N-Boc-
protected b-mesityl-b-methylalanine methyl ester 20

Helvetica Chimica Acta ± Vol. 83 (2000)
981
Fig. 5. AM1-Optimized structure of the minimum-energy con-
former of N-Boc-protected b-mesityl-b-methylalanine methyl
ester 20
similar, differing by less than 0.5 kcal molÀ1 5). An inspection of the geometry of these
maxima indicate that both ortho-Me groups simultaneously contribute to hinder the
rotation of the mesityl group: while one of them is interacting with the b-Me group, the
other interacts with the amino moiety. It is now easy to understand why the absence of
one of these ortho-Me groups gives rise to much lower energy barriers [28]. The energy
barrier of 14.8 kcal ´ molÀ1 was again estimated as the energy difference between the
minimum and the highest point of the plot (Fig. 6). The 1H-NMR spectrum (CDCl3) of
Fig. 6. Relative energies of N-Boc-protected-b-mesityl-b-methylalanine methyl ester 20 (starting from the three
staggered conformers I ± III of c1) and of N-Boc-protected b-methyl-b-phenylalanine methyl ester (conformer I,
c1 (HÀCÀCÀH) ˆ 1808) as the function of the dihedral angle c2
5
)
During the increase of c2 in the coordinate driving of conformer I, the dihedral angle c1 changed to a
synclincal conformation of type II. As a consequence, the final energy and geometry after a 1808 rotation
are not the initial ones.

982
Helvetica Chimica Acta ± Vol. 83 (2000)
1
Fig. 7. Variable-temperature H-NMR spectrum of 20 in CDCl3
methyl ester 20 exhibited already at room temperature two signals for the ortho-Me
groups (Fig. 7). On temperature increase, both signals smeared between 40 and 508, the
coalescence temperature being 458, which resulted in an activation free energy (DG=ˆ
16.2 kcal molÀ1) in excellent agreement with the calculated value. These values are in
the same range as those observed for b,2',6'-trimethyltyrosines [28], which have been
synthesized and incorporated into peptides for conformational and biological studies.
3.Conclusions. ± In summary, we have developed the first enantioselective
synthesis of N-Boc-protected a-mesitylglycines and b-mesitylalanines 1 ± 3 using
Sharpless asymmetric epoxidation and aminohydroxylation methodologies. Our
approach to b-mesitylalanines via N-Boc-protected 2-mesityl-3-[(silyloxy)methyl]azir-
idine 14 offers the additional advantage of allowing the preparation of configuration-
ally completely defined b-methyl-substituted analogues. According to variable-temper-
ature 1H-NMR studies and semi-empirical AM1 calculations, the conformation of the
mesityl group in these amino acids is very similar to that of the phenyl group in a-
phenylglycine and b-phenylalanine analogues, but the barriers to rotation around the
C(a/b)ÀC(aryl) bond are much higher in the mesityl derivatives. Thus, the incorpora-
tion of the N-Boc-protected-a-mesitylglycine 1, b-mesitylalanine 2, and b-mesityl-b-

Helvetica Chimica Acta ± Vol. 83 (2000)
983
methylalanine 3 into modified peptides should represent, besides an important increase
in lipophilicity, the introduction of a highly local constraint in the peptide conformation
without a significant change in the geometry of the minimum-energy conformer.
Experimental Part
General. THF and Et2O were distilled over Na/benzophenone and DMF and CH2Cl2 were distilled over
CaH2. The 2-ethenyl-1,3,5-trimethylbenzene (ˆ2,4,6-trimethylstyrene; 11) was prepared by Wittig olefination
of mesitaldehyde (4), yielding a product spectroscopically identical to the one described in [33]. Column
chromatography (CC): Et3N-pretreated (2.5% v/v) SiO2 (70 ± 230 mesh). Anal HPLC: Chiralcel ꢁ OD (25 cm)
or Chiralcel ꢁ ODR (25 cm) column; tR in min. [aD]: at r.t. (238); c in g/100 ml. M.p.: open capillary tubes;
uncorrected. IR Spectra: NaCl film or KBr pellet; nÄ in cmÀ1. NMR Spectra: at 200 or 300 MHz (1H) and 50.3 or
75.4 MHz (13C); 13C-multiplicities by DEPT; d in ppm rel. to SiMe4, J in Hz. MS: electron ionization (EI) or
chemical ionization (CI); in m/z (rel. %). High-resolution chemical ionization (CI) MS were performed by the
Â
Servicio de Espectrometría de Masas, Universidad de Cordoba. Elemental analyses were performed by the
Á
Servei dꢀAnalisis Elementals del CSIC de Barcelona.
Ethyl (2E)-3-(2,4,6-Trimethylphenyl)prop-2-enoate (5). To a soln. of ethyl (triphenylphosphoranyl)acetate
(26.4 g, 76 mmol) in CH2Cl2 (50 ml), mesitaldehyde (4; 10.2 g, 69 mmol) in CH2Cl2 (50 ml) was added. The
mixture was stirred under reflux for 24 h. After evaporation, the residual oil was submitted to CC (hexane/
AcOEt): 14.7 g (97%) of 5. M.p. 33 ± 358 ([34]: 36 ± 378). IR (NaCl): 2981, 2867, 1717. 1H-NMR (200 MHz,
CDCl3): 1.33 (t, J ˆ 7.0, 3 H); 2.26 (s, 3 H); 2.31 (s, 6 H); 4.26 (q, J ˆ 7.0, 2 H); 6.04 (d, J ˆ 16.6, 1 H); 6.87
(s, 2 H); 7.84 (d, J ˆ 16.6, 1 H). 13C-NMR (50 MHz, CDCl3): 14.2 (q); 20.88 (q); 20.95 (q); 60.3 (t); 123.0 (d);
‡
‡
129.0 (d); 130.8 (s); 136.7 (s); 138.1 (s); 143.0 (d); 166.9 (CˆO). EI-MS: 218 (34, M ), 203 (11, C13H15O2 , [M À
‡
‡
CH3] ), 173 (100, C12H13O2 ), 144 (74). Anal. calc. for C14H18O2: C 77.03, H 8.48; found: C 77.10, H 8.31.
(2E)-3-(2,4,6-Trimethylphenyl)prop-2-en-1-ol (6). To a soln. of 5 (6.0 g, 27.5 mmol) in Et2O (35 ml) at 08,
1m DIBALH in hexanes (55 ml, 55 mmol) was added. After 5 h stirring at r.t., the mixture was diluted with Et2O
(65 ml), cooled to 08, and quenched by careful addition of brine (65 ml). Then, 4m HCl (65 ml) was added
dropwise. The aq. layer was extracted with Et2O (3 Â 150 ml) and the combined org. phase dried (MgSO4) and
evaporated. The residue was submitted to CC (hexane/AcOEt): 4.2 g (86%) of 6. White solid. M.p. 58 ± 598. IR
(KBr): 3375, 2939, 1660, 1609, 1478, 1376. 1H-NMR (200 MHz, CDCl3): 1.77 (br. s, OH); 2.27 (s, 9 H); 4.32
(dd, J ˆ 5.6, 1.4, 2 H); 5.86 (dt, J ˆ 16.4, 5.6, 1 H); 6.56 (dt, J ˆ 16.4, 1.4, 1 H); 6.86 (s, 2 H). 13C-NMR (50 MHz,
‡
CDCl3): 20.8 (q); 64.0 (t); 128.5 (d); 128.7 (d); 133.3 (d); 133.3 (s); 135.8 (s); 136.2 (s). EI-MS: 176 (66, M ), 158
(24), 161 (15), 143 (87), 133 (100). Anal. calc. for C12H16O: C 81.77, H 9.15; found: C 81.61, H 9.20.
(2S,3S)-3-(2,4,6-Trimethylphenyl)oxirane-2-methanol (7). Dry powdered 4-Š molecular sieves (0.87 g) and
anh. CH2Cl2 (120 ml) under N2 was cooled to À308 (CO2/anisole bath). Then the following reagents were
introduced sequentially via cannula under stirring: (‡)-diisopropyl l-tartrate (285 mg, 1.22 mmol) in CH2Cl2
(10 ml), titanium tetraisopropoxide (0.24 ml, 0.81 mmol), and 2.8m tert-butyl hydroperoxide in isooctane (12 ml,
33.6 mmol). The mixture was stirred 1 h at À308, and a soln. of 6 (2.86 g, 16.25 mmol; previously recrystallized
in hexanes and stored for 24 h over 4-Š molecular sieves) in CH2Cl2 (5 ml) was added. After 8 h stirring at À308,
the reaction was quenched by addition of 10% NaOH soln. saturated with NaCl (1.3 ml) and Et2O (16 ml). The
mixture was allowed to warm to 108, and anh. MgSO4 (1.26 g) and Celite ꢁ (160 mg) were added. After 15 min
stirring at r.t., the mixture was filtered through a short Celite ꢁ pad. The solvents were evaporated and the excess
of tert-butyl hydroperoxide removed by azeotropic distillation with toluene (3 Â 100 ml). The crude was then
submitted to CC (hexanes/AcOEt): 1.98 g (63%) of 7 as a white solid of 88% ee. Three recrystallizations from
hexane afforded 0.8 g (26%) of enantiomerically pure 7. HPLC (Chiralcel OD-R, 0.5m aq. NaClO4/MeOH 3 :7,
flow 0.5 ml/min; tR (2R,3R) 21.68 and tR (2S,3S) 26.44): 99% ee. M.p. 104 ± 1058. [a]D ˆ ‡18.0 (c ˆ 1, CHCl3). IR
(KBr): 3380, 3310, 2954, 1611, 1455, 1380. 1H-NMR (300 MHz, CDCl3): 1.80 (dd, J ˆ 7.6, 5.4, OH); 2.27 (s, 3 H);
2.35 (s, 6 H); 3.16 (m, 1 H); 3.88 (ddd, J ˆ 12.8, 7.4, 4.2, 1 H); 3.97 (d, J ˆ 2.2, 1 H); 4.12 (ddd, J ˆ 12.8, 5.4, 2.6,
1 H); 6.83 (s, 2 H). 13C-NMR (75 MHz, CDCl3): 19.6 (q, MeÀC(2), MeÀC(6)); 20.9 (q); 54.4 (d); 59.7 (d); 61.5
‡
(t); 128.7 (d, C(3), C(5)); 130.2 (s, C(1)); 136.9 (s, C(2), C(6)); 137.4 (s, C(4)). EI-MS: 192 (56, M ), 161 (6),
147 (87), 132 (49), 117 (100). Anal. calc. for C12H16O2: C 74.97, H 8.39; found: C 74.90, H 8.34.
(2R,3R)-3-[(Diphenylmethyl)amino]-3-(2,4,6-trimethylphenyl)propane-1,2-diol (8). To a soln. of 7 (0.10 g,
0.52 mmol) in MeCN (1.3 ml), LiClO4 (0.86 g, 8.0 mmol) was added. After 10 min stirring, benzhydrylamine
(0.91 ml, 5.2 mmol) was added and the mixture heated at 658 for 24 h under N2. The mixture was then treated
with H2O (5 ml) and extracted with CH2Cl2 (3 Â 4 ml). The combined org. phase was dried (MgSO4) and

984
Helvetica Chimica Acta ± Vol. 83 (2000)
evaporated. To a soln. of the crude in Et2O, solid CO2 was added, and the precipitate was filtered off and washed
with more Et2O saturated with CO2. The solvent was evaporated and the crude submitted to CC (hexanes/
AcOEt): 0.19 g (97%) of 8. [a]D ˆ À25.6 (c 1, CHCl3). IR (NaCl): 3411, 2921, 1609, 1453, 1030, 702. 1H-NMR
(200 MHz, CDCl3): 1.7 (s, 3 H); 2.3 (s, 3 H); 2.5 (s, 3 H); 3.8 ± 4.2 (complex m, 6 H); 4.5 (s, 1 H); 6.9 (s, 1 H);
6.95 (s, 1 H); 7.2 ± 7.3 (m, 10 H). 13C-NMR (50 MHz, CDCl3); 20.8 (q); 20.9 (q); 21.06 (q); 59.9 (d); 64.4 (d); 66.4
(t); 72.5 (d); 127.0 (d); 127.2 (d); 127.3 (d); 127.5 (d); 128.5 (d); 128.7 (d); 129.7 (d); 131.3 (s); 131.4 (d); 135.8 (s);
‡
‡
‡
136.9 (s); 139.8 (s); 142.2 (s). CI-MS (CH4): 376 (100, [M ‡ 1] ). HR-CI-MS: 376.2273 (C25H30NO2 , [M ‡ 1] ;
calc. 376.2277).
(2R,3R)-3-{[(tert-Butoxy)carbonyl]amino}-3-(2,4,6-trimethylphenyl)propane-1,2-diol (9). From 8. A sus-
pension of 8 (189 mg, 0.5 mmol), di(tert-butyl) dicarbonate (143 mg, 0.65 mmol) and 15% Pd(OH)2/C (28 mg)
in MeOH (1.8 ml) was hydrogenated at r.t. and 1 atm until no starting material could be observed by TLC (ca. 2
days). The mixture was filtered and the filtrate evaporated. The residue was submitted to CC (hexanes/AcOEt):
105 mg (68%) of 9.
From 7. To a soln. of 7 (0.5 g, 2.60 mmol) in MeCN (13 ml), LiClO4 (6.9 g) was added. After 10 min stirring,
NaN3 (0.85 g, 13 mmol) was added and the mixture heated at 658 for 24 h under N2. The mixture was treated
with H2O (75 ml) and extracted with Et2O (3 Â 60 ml). The combined org. phase was dried (MgSO4) and
evaporated. The residue, composed mainly of (2R,3R)-3-azido-3-(2,4,6-trimethylphenyl)propane-1,2-diol
(0.59 g), was immediately dissolved in AcOEt (6 ml). This soln. was added to a suspension of di(tert-butyl)
dicarbonate (0.75 g, 3.43 mmol) and 10% Pd/C (59 mg) in AcOEt (1.2 ml) and hydrogenated at 1 atm until no
starting material could be observed by TLC (ca. 24 h). The mixture was filtered, the filtrate evaporated, and the
residue submitted to CC (hexanes/AcOEt): 0.5 g (62%) of 9. [a]D ˆ À61.3 (c ˆ 1, CHCl3). IR (NaCl): 3384,
2977, 1696, 1366, 853, 765. 1H-NMR (200 MHz, CDCl3): 1.41 (s, 9 H); 2.28 (s, 3 H); 2.4 (s, 6 H); 3.2 ± 3.9
(m, 4 H); 5.14 (m, 2 H); 6.84 (s, 2 H). 13C-NMR (50 MHz, CDCl3): 20.7 (q); 21.2 (q); 28.2 (q); 51.3 (d); 63.0 (t);
‡
73.0 (d); 80.4 (s); 130.3 (d); 132.2 (s); 137.2 (s, 2 C); 156.9 (s, CˆO). CI-MS (NH3): 310 (100, [M ‡ 1] ), 254
‡
‡
(59), 210 (2). HR-CI-MS: 310.2029 (C17H28NO4 , [M ‡ 1] ; calc. 310.2018).
(2S)-2-{[(tert-Butoxy)carbonyl]amino}-2-(2,4,6-trimethylphenyl)ethanol ((‡)-10). A soln. of tert-butyl
carbamate (363 mg, 3.1 mmol) in PrOH (3 ml) was sequentially treated with NaOH (122 mg, 3.05 mmol) in
H2O (7.5 ml) and tBuOCl (0.35 ml, 0.33 g, 3.05 mmol). After 5 min stirring, the soln. was cooled to 08, and a soln.
of (DHQ)2PHAL (0.040 g, 0.05 mmol, 5 mol-%) in PrOH (3.5 ml) was added (homogeneous mixture). Then
2,4,6-trimethylstyrene (11) (146 mg, 1 mmol) was added, followed by K2OsO2(OH)4 (14.8 mg, 0.04 mmol, 4 mol-
%). The mixture was stirred for 3 h at 08 (light green soln. ! light yellow), and the reaction was quenched with
sat. aq. NaHSO3 soln. (10 ml). The aq. phase was extracted with AcOEt (2 Â 10 ml), the combined org. phase
washed with brine (25 ml), dried (MgSO4), and evaporated to afford a crude product composed mainly of a
regioisomer mixture (4 :1) of amino alcohols and tert-butyl carbamate. The crude was submitted to CC
(hexanes/AcOEt), yielding 123 mg (44%) of (‡)-10 as a white solid of 88% ee. Crystallization from Et2O
provided enantiomerically pure (‡)-10. HPLC (Chiralcel ꢁ OD, 308, hexane iPrOH 98 :2, flow 1 ml/min; tR(2S)
17.83 and tR(2R) 20.37): >99% ee. M.p. 76 ± 778. [a]D ˆ ‡19.2 (c ˆ 1, CHCl3). IR (KBr): 3284, 2971, 1684, 1368,
1057. 1H-NMR (200 MHz, CDCl3): 1.42 (s, 9 H); 2.24 (s, 3 H); 2.4 (s, 6 H); 3.8 (m, 2 H); 4.1 (br. s, 1 OH); 5.05
(br. s, 1 H); 5.2 (br. s, NH); 6.8 (s, 2 H). 13C-NMR (50 MHz, CDCl3): 20.7 (q); 21.2 (q); 28.3 (q); 55.0 (d); 65.9
‡
(t); 80.0 (s); 130.2 (d); 132.0 (s); 136.0 (s, 2 C); 156.9 (s, CˆO). CI-MS (NH3): 298 (5, [M ‡ 18] ), 280 (100,
‡
[M ‡ 1] ). Anal. calc. for C16H25NO3: C 68.79, H 9.02, N 5.01; found: C 68.95, H 9.06, N 4.85.
2-{[(tert-Butoxy)carbonyl]amino}-2-(2,4,6-trimethylphenyl)acetic Acid (ˆ N-[(tert-Butoxy)carbonyl]-a-
mesitylglycine, 1). (2R)-Enantiomer (À)-1 from 9. A mixture of 9 (110 mg, 0.35 mmol), Na2CO3 (19 mg,
0.18 mmol), NaIO4 (304 mg, 1.42 mmol), and KMnO4 (11 mg, 0.07 mmol) in dioxane (1.5 ml) and H2O
(0.65 ml) was vigorously stirred at r.t. until no starting material could be observed by TLC (ca. 17 h). AcOEt
(10 ml) was added, and the mixture was acidified by addition of 2m HCl. The org. phase was washed with brine,
dried, and evaporated. The crude was dissolved in 1m NaHCO3 and the aq. phase washed with AcOEt, acidified,
and extracted again with AcOEt. The org. phase was then dried and evaporated: 75 mg (72%) of (À)-1. White
solid.
(2S)-Enantiomer (‡)-1 from (‡)-10. A soln. of (‡)-10 (84 mg, 0.3 mmol) in acetone (2.3 ml) was added to a
5% NaHCO3 soln. (0.8 ml). This magnetically stirred heterogeneous mixture was cooled to 08 and treated
sequentially with KBr (3.6 mg, 0.03 mmol) and TEMPO (50 mg, 0.33 mmol). Then, 0.63m NaClO (0.6 ml,
0.38 mmol) was added dropwise while the mixture was vigorously stirred and maintained at 08. After 1 h,
additional 0.63m NaClO (0.23 ml, 0.15 mmol) was added, and stirring was continued for 1 h at 08. Then, 5%
NaHCO3 soln. (1.2 ml) was added, and the acetone was evaporated. The aq. layer was washed twice with Et2O,

Helvetica Chimica Acta ± Vol. 83 (2000)
985
acidified to pH 3 with 2m HCl, and extracted with AcOEt. The combined org. phase was washed with H2O and
brine, dried (MgSO4), and evaporated: 72 mg (82%) of (‡)-1. White solid.
Data of (À)-1. M.p. 55 ± 568. [a]D ˆ À142.4 (c ˆ 1, MeOH). IR (KBr): 3293, 2979, 1729, 1657, 1368.
1H-NMR (200 MHz, CDCl3): 1.4 (s, 9 H); 2.2 (s, 6 H); 2.4 (s, 3 H); 5.6 (br. s, 1 H); 8.3 (br. s, 1 H). 13C-NMR
(50 MHz, CDCl3): 20.2 (q); 20.8 (q); 27.9 (q); 54.0 (d); 81.5 (s); 129.9 (d); 136.9 (s); 137.0 (s); 157.5 (s); 173.6 (s).
‡
‡
CI-MS (NH3): 294 (12, [M ‡ 1] ), 311 (100, [M ‡ 18] ). Anal. calc. for C16H23NO4: C 65.50, H 7.90, N 4.77;
found: C 65.37, H 7.90, N 4.81.
Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-2-(2,4,6-trimethylphenyl)acetate (ˆ(2S)-N-[(tert-Butoxy)-
carbonyl]-a-mesitylglycine Methyl Ester; 19). (2S)-Enantiomer (‡)-1 (63 mg, 0.21 mmol) was dissolved in DMF
(0.35 ml), and KHCO3 (43 mg, 0.43 mmol) and MeI (21 ml, 1.16 mmol) were added. The mixture was stirred at
r.t. for 16 h, H2O was added, and the org. layer was extracted with Et2O (3 Â 3 ml). The combined org. phase was
washed successively with H2O (2 Â 2 ml), sat. Na2SO3 soln. and brine, dried (MgSO4), and evaporated and the
crude purified by CC (hexane/AcOEt): 48 mg (73%) of 19. Oil. IR (NaCl): 3442, 2977, 1742, 1719, 1613, 1393,
1368, 1161, 852. 1H-NMR (200 MHz, CDCl3): 1.4 (s, 9 H); 2.25 (s, 3 H); 2.4 (s, 6 H); 3.7 (s, 3 H); 5.4 (br. s, 1 H);
5.8 (br. d, 1 H); 6.8 (s, 2 H). 13C-NMR (50 MHz, CDCl3): 20.2 (q); 20.8 (q); 28.3 (q); 52.7 (q); 52.8 (d); 79.9 (s);
‡
129.8 (d); 131.3 (s); 136.7 (s, 2 C); 137.6 (s); 155.5 (s); 172.5 (s). CI-MS (NH3): 325 (95, [M ‡ 18] ), 308 (100,
‡
‡
‡
[M ‡ 1] ), 269 (24). HR-CI-MS: 307.1777 (C17H25NO4 , M ; calc. 307.1784).
(1R,2R)-3-{[(tert-Butyl)dimethylsilyl]oxy}-1-{[(tert-butoxy)carbonyl]amino}-1-(2,4,6-trimethylphenyl)-
propan-2-ol (12). To a soln. of 9 (0.99 g, 3.20 mmol) in DMF (17.8 ml), (tert-butyl)chlorodimethylsilane (0.53 g,
3.52 mmol) and 1H-imidazole (0.48 g, 7.04 mmol) were added. The mixture was stirred at r.t. and monitored by
TLC. After 24 h, H2O (20 ml) was added and the aq. phase extracted with Et2O (3 Â 15 ml). The combined org.
phase was washed with sat. aq. NH4Cl soln., dried (MgSO4), and evaporated. The crude product was purified by
CC (0 ± 15% AcOEt/hexane): 1.23 g (91%) of 12. Oil. [a]D ˆ À5.4 (c ˆ 1, CHCl3). IR (NaCl): 3421, 2931, 1700,
1366, 837. 1H-NMR (200 MHz, CDCl3): 0.18 (s, 6 H); 1.0 (s, 9 H); 1.4 (s, 9 H); 2.3 (s, 3 H); 2.5 (s, 6 H); 2.9 (br. s,
OH); 3.5 ± 4 (m, 3 H); 5.3 (br. d, 1 H); 5.6 (br. d, NH); 6.9 (s, 2 H). 13C-NMR (50 MHz, CDCl3): À5.4 (q); 18.2
(s); 20.7 (q); 21.2 (q); 25.9 (q); 28.4 (q); 53.8 (d); 64.9 (t); 72.5 (d); 130.2 (d); 132.7 (s); 136.6 (s); 155.1 (s). CI-
‡
‡
‡
MS (NH3): 424 (15, [M ‡ 1] ), 368 (32), 192 (100, C12H19NO ), 324 (19). HR-CI-MS: 424.2899 (C23H42NO4Si ,
‡
[M ‡ 1] ; calc. 424.2883).
(1R,2R)-2-{[(tert-Butoxy)carbonyl]amino}-1-{{[(tert-butyl)dimethylsilyl]oxy}methyl}-2-(2,4,6-trimethyl-
phenyl)ethyl Methanesulfonate (13). To a soln. of 12 (0.60 g, 1.42 mmol) in CH2Cl2 (1.8 ml) at À158, Et3N
(0.22 ml, 1.56 mmol), 4-(dimethylamino)pyridine (9 mg, 0.07 mmol), and methanesulfonyl chloride (0.12 ml,
1.56 mmol) were added. The mixture was allowed to warm to r.t. under stirring, and the reaction progress was
monitored by TLC. After ca. 5 h (no starting material detectable), CH2Cl2 (5 ml) was added, the org. phase
washed sequentially with cold 10% aq. HCl soln., sat. NaHCO3 soln., and H2O, dried (MgSO4), and evaporated,
and the crude product purified by CC (hexanes/AcOEt): 0.58 g (82%) of 13. White solid. M.p. 95 ± 968. [a]D
ˆ
‡5.0 (c ˆ 1.0, CHCl3). IR (KBr): 3267, 2931, 1702, 1366, 1177. 1H-NMR (200 MHz, CDCl3): 0.0 ± 0.02 (s, 6 H);
0.83 (s, 9 H); 1.26 (s, 9 H); 2.10 (s, 3 H); 2.22 (s, 6 H); 2.32 (s, 3 H); 3.85 (d, J ˆ 4, 2 H); 4.76 (m, 1 H); 5.32
(m, 1 H); 5.62 (br. d, NH); 6.70 (s, 2 H). 13C-NMR (50 MHz, CDCl3): À5.6 (q); 18.1 (s); 20.7 (q); 20.8 (q); 25.7
(q); 28.2 (q); 37.5 (q); 52.0 (d); 63.8 (t); 79.6 (s); 82.0 (d); 130.2 (d); 131.7 (s); 137.2 (s); 155.0 (s). CI-MS (NH3):
‡
‡
‡
502 (88, [M ‡ 1] ), 446 (100). HR-CI-MS: 444.1894 (C20H34NO6SSi , [M À C4H8 ‡ 1] ; calc. 444.1876).
(2S,3R)-1-[(tert-Butoxy)carbonyl]-2-{{[(tert-butyl)dimethylsilyl]oxy}methyl}-3-(2,4,6-trimethylphenyl)azi-
ridine (14). To a suspension of NaH (7.5 mmol; from 300 mg of a 55 ± 60% dispersion in paraffin, washed with
anh. hexane under N2) in THF (4 ml), a soln. of 13 (1.25 g, 2.5 mmol) in THF (7.7 ml) was added. After 3 h
stirring at r.t., the crude was carefully treated with H2O/AcOEt 1:1. The aq. phase was extracted with AcOEt
(3 Â 12 ml) and the combined org. phase dried (MgSO4) and evaporated. Purification of the crude by CC
(AcOEt/hexanes) gave 0.96 g (94%) of 14. White solid. M.p. 46 ± 478. [a]D ˆ À143.4 (c ˆ 1.1, CHCl3). IR
(NaCl): 2931, 1719, 1254, 1159, 837. 1H-NMR (200 MHz, CDCl3): 0.0 ± 0.01 (s, 6 H); 0.82 (s, 9 H); 1.40 (s, 9 H);
2.14 (s, 3 H); 2.3 (s, 6 H); 2.43 (m, 1 H); 3.40 (br. d, 1 H); 3.86 (dd, J ˆ 11.5, 3.6, 1 H); 4.10 (dd, J ˆ 11.5, 2.6,
1 H); 6.7 (s, 2 H). 13C-NMR (50 MHz, CDCl3): À5.4 (q); À5.3 (q); 18.4 (s); 20.0 (q); 20.8 (q); 25.9 (q); 28.2 (q);
39.1 (d); 46.0 (d); 59.7 (t); 80.7 (s); 128.8 (d); 130.3 (s); 136.5 (s); 137.4 (s); 159.9 (s). CI-MS (NH3): 406 (16,
‡
‡
‡
[M ‡ 1] ), 367 (97), 350 (100). HR-CI-MS: 406.2812 (C23H40NO3Si , [M ‡ 1] ; calc. 406.2777). Anal. calc. for
C23H39NO3Si: C 68.10, H 9.69, N 3.45; found: C 68.19, H 9.95, N 3.45.
(2S)-N-[(tert-Butoxy)carbonyl]-1-{[(tert-butyl)dimethylsilyl]oxy}-3-(2,4,6-trimethylphenyl)propan-2-amine
(15). A soln. of 14 (124 mg, 0.30 mmol) in AcOEt (1.5 ml) was added to a stirred suspension of 10% Pd/C
(15 mg) in AcOEt (0.6 ml) under H2: The mixture was hydrogenated at 1 atm (H2 balloon) for ca. 12 h (TLC
monitoring). Then, the suspension was filtered through Celite ꢁ and the latter washed thoroughly with AcOEt.

986
Helvetica Chimica Acta ± Vol. 83 (2000)
Evaporation yielded 122 mg (quant.) of crude, spectroscopically pure 15. [a]D ˆ À30.7 (c ˆ 1.0, CHCl3). IR
(NaCl): 3456, 2931, 1719, 1366, 1173, 837. 1H-NMR (200 MHz, CDCl3): 0.0 ± 0.01 (s, 6 H); 0.86 (s, 9 H); 1.33
(s, 9 H); 2.17 (s, 3 H); 2.28 (s, 6 H); 2.80 (m, 2 H); 3.42 (dd, J ˆ 9.8, 2.2, 1 H); 3.52 (dd, J ˆ 9.8, 3.6, 1 H); 3.74
(m, 1 H); 4.78 (br. d, NH); 6.76 (s, 2 H). 13C-NMR (50 MHz, CDCl3): À5.5 (q); À5.3 (q); 18.3 (s); 20.2 (q); 20.8
(q); 25.9 (q); 28.3 (q); 31.3 (t); 51.5 (d); 63.2 (d); 78.9 (s); 128.8 (d); 132.1 (s); 135.3 (s); 137.0 (s); 155.1 (s). CI-
‡
‡
‡
MS (NH3): 408 (37, [M ‡ 1] ), 407 (100, M ), 352 (36), 308 (11). HR-CI-MS: 408.2917 (C23H41NO3Si , [M ‡
‡
1] ; calc. 408.2934).
(2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(2,4,6-trimethylphenyl)propan-1-ol (16). To
a soln. of 15
(120 mg, 0.30 mmol) in THF (1.4 ml) at 08, a soln. of Bu4NF ´ H2O (0.14 g, 0.54 mmol) in THF (0.8 ml) was
added. The mixture was stirred at r.t. and monitored by TLC. After 60 min, the soln. was washed with H2O and
the org. layer extracted with Et2O. The combined org. phase was dried (MgSO4) and evaporated and the residue
purified by CC (AcOEt/hexanes): 70 mg (82%) of 16. White solid. M.p. 127 ± 1298. [a]D ˆ À51.8 (c ˆ 1.0,
1
CHCl3). IR (NaCl): 3363, 1688, 1532, 1175, 1005. H-NMR (200 MHz, CDCl3): 1.4 (s, 9 H); 2.24 (s, 3 H); 2.33
(s, 6 H); 2.8 (m, 2 H); 3.54 (dd, J ˆ 10.7, 5.3, 1 H); 3.66 (dd, J ˆ 10.7, 3.5, 1 H); 3.81 (m, 1 H); 6.83 (s, 2 H).
13C-NMR (50 MHz, CDCl3); 20.3 (q); 20.8 (q); 28.3 (q); 31.4 (t); 52.9 (d); 64.5 (t); 79.5 (s); 129.1 (d); 132.0 (s);
‡
135.6 (s); 136.8 (s); 157.0 (s). CI-MS (NH3): 294 (100, [M ‡ 1] ), 238 (59), 194 (15). Anal. calc. for C17H27NO3:
C 69.59, H 9.28, N 4.77; found: C 69.44, H 9.46, N 4.72.
(2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(2,4,6-trimethylphenyl)propanoic Acid (ˆ N-[(tert-Butoxy)car-
bonyl]-b-mesityl-l-alanine; (À)-2). Method A: A soln. of PDC (295 mg, 0.78 mmol) in DMF (0.6 ml) was added
to 16 (46 mg, 0.16 mmol) at r.t. under N2. After 24 h stirring, H2O (5 ml) and Et2O (5 ml) were added. The aq.
phase was extracted with Et2O (3 Â 3 ml) and the combined org. phase dried (MgSO4) and evaporated. The
crude was taken up with AcOEt and extracted with sat. NaHCO3 soln., the aq. layer washed with AcOEt, then
acidified with 2n HCl, and extracted with AcOEt, and the combined org. phase dried (MgSO4) and evaporated:
44 mg (92%) of (À)-2. White solid.
Method B: As described for (‡)-1, with 16 (30 mg, 0.10 mmol): 30 mg (95%) of (À)-2, spectroscopically
identical to the product obtained by Method A.
Data of (À)-2: M.p. 140 ± 1428. [a]D ˆ À20.2 (c ˆ 1.0, CHCl3). IR (NaCl): 3311, 1721, 1659, 1167, 756.
1H-NMR (200 MHz, CDCl3): 1.4 (s, 9 H); 2.24 (s, 3 H); 2.34 (s, 6 H); 3.06 ± 3.16 (m, 2 H); 4.52 (m, 1 H); 5.01
(br. d, NH); 6.83 (s, 2 H). 13C-NMR (50 MHz, CDCl3): 20.3 (q); 20.5 (q); 27.5 (q); 34.1 (d); 54.0 (t); 81 (s); 129.0
‡
(d); 130.5 (s); 136.0 (s); 138.0 (s); 156.5 (s); 175.0 (s) ppm. CI-MS (NH3): 325 (55, [M ‡ 18] ), 308 (41, [M ‡
‡
‡
‡
1] ), 269 (100). HR-CI-MS: 206.1118 (C17H25NO4 , [M À C5H9O2] ; calc. 206.1028).
Enantiomer Purity of (À)-2: To a mixture of (À)-2 (33 mg, 0.11 mmol) and KHCO3 (22 mg, 0.21 mmol) in
DMF (0.3 ml), MeI (27 ml, 0.43 mmol) was added by syringe. After 24 h stirring, H2O (2 ml) was added and the
aq. phase extracted with Et2O (3 Â 3 ml). The combined org. phase was washed with H2O (2 Â 2 ml), 5% aq.
Na2SO3 soln. (2 Â 2 ml), and brine (2 Â 2 ml), dried (MgSO4), and evaporated. The crude was chromatographed
(0 ± 5% AcOEt/hexanes): 27 mg (78%) of N-[(tert-butoxy)carbonyl]-b-mesityl-l-alanine methyl ester. HPLC
(Chiralcel ꢁ OD, 308, hexane/iPrOH 9 :1, flow 1 ml/min, l 254 nm): only one peak at tR 5.18; >99% ee; cf.
racemic sample: tR (2R) 4.20 and tR (2S) 5.19.
(2S,3S)-1-{[(tert-Butyl)dimethylsilyl]oxy}-2-[(tert-butoxy)carbonyl]-3-(2,4,6-trimethylphenyl)butan-2-amine
(17). A soln. of lithium dimethylcuprate was prepared by addition of 1.6m MeLi (4.4 mmol) in Et2O to a stirred
slurry of CuI (422 mg, 2.2 mmol) in anh. Et2O (7.5 ml) at 08 and stirring at 08 for a few minutes. To this soln. was
added via cannula a soln. of 14 (300 mg, 0.74 mmol) in Et2O (7.5 ml). The mixture was stirred under N2 at 08,
and sat. aq. NH4Cl soln. (8 ml) and NH4OH soln. (2 ml) were added. Then the org. layer was extracted with
more Et2O (3 Â 6 ml), the combined org. phase dried (MgSO4) and evaporated, and the residue submitted to
CC (hexanes/AcOEt): 150 mg of 17 (48%) and 75 mg (24%) of its regioisomer. 17: Colorless oil. [a]D ˆ À40.0
(c ˆ 0.5, CHCl3). IR (NaCl): 3457, 2931, 1717, 1366, 1175, 835. 1H-NMR (200 MHz, CDCl3): 0.0 ± 0.01 (s, 6 H);
0.84 (s, 9 H); 1.2 (s, 9 H); 1.2 (d, J ˆ 7.2, 3 H); 2.12 (s, 3 H); 2.19 (s, 3 H); 2.28 (s, 3 H); 3.50 (m, 1 H); 3.70
(m, 1 H); 3.95 (m, 2 H); 4.3 (br. d, NH); 6.69 (s, 2 H). 13C-NMR (50 MHz, CDCl3): À5.43 (q); À5.39 (q); 16.7
(q); 18.3 (s); 20.6 (q); 21.2 (q); 21.8 (q); 26.0 (q); 28.2 (q); 33.5 (d); 54.8 (d); 62.6 (t); 78.6 (s); 128.8 (d); 130.9
‡
(d); 135.0 (s); 136.7 (s); 137.1 (s); 155.0 (s). HR-CI-MS 422.3098 (C24H44NO3Si, [M ‡ 1] ; calc. 422.3090).
(2S,3S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(2,4,6-trimethylphenyl)butan-1-ol (18). As described for 16,
with 17 (70 mg, 0.17 mmol): 44 mg (86%) of 18. Colorless oil. [a]D ˆ À13.2 (c ˆ 1, CHCl3). IR (NaCl): 3457,
2931, 1717, 1366, 1175, 835. 1H-NMR (200 MHz, CDCl3): 1.30 (s, 9 H); 1.34 (d, J ˆ 7, 3 H); 2.23 (s, 3 H); 2.29
(s, 3 H); 2.35 (s, 3 H); 3.3 ± 3.6 (m, 1 H); 3.7 ± 3.8 (m, 1 H); 3.9 ± 4.1 (m, 2 H); 4.35 (br. s, 1 H); 6.8 (s, 2 H).
13C-NMR (50 MHz, CDCl3): 16.9 (q); 20.6 (q); 21.2 (q); 21.6 (q); 28.2 (q); 34.5 (d); 56.5 (d); 64.7 (t); 79.6 (s);

Helvetica Chimica Acta ± Vol. 83 (2000)
987
‡
129.3 (d); 131.2 (d); 135.5 (s); 135.7 (s); 138 (s); 155.9 (s); 178.0 (s). EI-MS: 325 (8, [M ‡ 18] ), 308 (100, [M ‡
‡
‡
‡
1] ). HR-CI-MS: 307.2137 (C18H29NO3 , M ; calc. 307.2147).
(2S,3S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(2,4,6-trimethylphenyl)butanoic Acid (ˆ(3S)-N-[(tert-But-
oxy)carbonyl]-b-mesityl-b-methyl-l-alanine; (À)-3). As described for (À)-2 (Method B), with 18 (45 mg,
0.15 mmol): 43 mg (91%) of (À)-3. Colorless oil. [a]D ˆ À23.6 (c ˆ 2, CHCl3). IR (NaCl): 3745, 3313, 2929,
1719, 1654, 1457, 835. 1H-NMR (300 MHz, CDCl3): 1.3 (s, 9 H); 1.41 (d, J ˆ 5, 3 H); 2.24 (s, 3 H); 2.34 (s, 6 H);
2.38 (s, 6 H); signal of a rotamer; 3.4 ± 3.8 (m, 1 H); 4.4 ± 4.8 (m, 1 H); 6.9 (s, 2 H). 13C-NMR (75 MHz, C7D8;
signals marked with an asterisk correspond to a rotamer; the other signals are slightly split): 16.5 (q); 20.6 (q);
21.4 (q); 21.8 (q); 27.7 (q); 28.1 (q)*; 36.6 (d); 38.1 (d)*; 57.7 (d); 80.1 (s); 80.2 (s)*; 129.3 (d); 131.4 (d); 134.1 (s);
‡
135.0 (s); 136.2 (s); 136.6 (s); 155.8 (s); 156.0 (s)*; 176.0 (s)*, 178 (s)*. EI-MS: 283 (100, [M ‡ 18] ), 322 (47,
‡
[M ‡ 1] ), 266 (6), 283 (78).
Methyl (2S,3S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(2,4,6-trimethylphenyl)butanoate (ˆ(3S)-N-[(tert-
Butoxy)carbonyl]-b-mesityl-b-methyl-l-alanine Methyl Ester; 20). As described for 19, (À)-3 (39 mg,
1
0.12 mmol): 27 mg (68%) of 20. Oil. IR (KBr): 3379, 1746, 1717, 1495, 1167. H-NMR (300 MHz, CDCl3): 1.3
(s, 9 H); 1.35 (d, 3 H); 2.30 (s, 3 H); 2.32 (s, 3 H); 2.39 (s, 3 H); 3.4 ± 3.6 (br. m, 1 H); 3.8 (s, 3 H); 4.4 ± 4.6
(br., 2 H); 6.8 (s, 2 H). 13C-NMR (75 MHz, CDCl3): 16.5 (q); 20.2 (q); 21.1 (q); 21.6 (q); 28.1 (q); 30.9 (q); 52.0
(d); 57.3 (d); 79.9 (s); 129.40 (s); 129.44 (d); 131.5 (d); 134.1 (s); 136.2 (s); 136.8 (s); 155.5 (s); 174.2 (s). CI-MS
‡
‡
‡
‡
(NH3): 353 (24, [M ‡ 18] ), 336 (100, [M ‡ 1] ). HR-CI-MS: 336.2147 (C19H30NO4 , [M ‡ 1] ; calc. 336.2175).
Financial support from DGICYT (PB98-1246 and PB97-0939) and from CIRIT (1998SGR 00005) is
gratefully acknowledged. E.M. thanks Universitat de Barcelona for a predoctoral fellowship.
REFERENCES
[1] J. Rizo, L. M. Gierasch, Annu. Rev. Biochem. 1992, 61, 387; A. S. Dutta, in ꢂAmino Acids, Peptides and
Proteinsꢀ, The Royal Society of Chemistry, 1998, Vol. 29, p. 175.
[2] A. S. Dutta, Adv. Drug Res. 1991, 21, 145; V. J. Hruby, D. Patel, in ꢂPeptides: Synthesis, Structures, and
Applicationsꢀ, Ed. B. Gutte, Academic Press, San Diego, 1995, p. 247; C. McMartin, Handb. Exp.
Pharmacol. 1994, 110, 371; D. J. A. Crommelin, G. Storm, Eur. J. Pharm. Sci. 1994, 2, 17; U. B. Kompella,
V. H. L. Lee, Adv. Drug Delivery Rev. 1992, 8, 115; D. J. Begley, J. Pharm. Pharmacol. 1996, 48, 136.
[3] G. R. Marshall, D. D. Beusen, G. V. Nikiforovich, in ꢂPeptides: Synthesis, Structures, and Applicationsꢀ. Ed.
B. Gutte, Academic Press, San Diego, 1995, p. 193.
[4] S. Salvadori, S. D. Bryant, C. Bianchi, G. Balboni, V. Scaranari, M. Attila, L. H. Lazarus, J. Med. Chem.
1993, 36, 3748; H. Josien, S. Lavielle, A. Brunissen, M. Saffroy, Y. Torrens, J. C. Beaujouan, J. Glowinski, G.
Chassaing, J. Med. Chem. 1994, 37, 1586; K. Hsieh, T. R. LaHann, R. C. Speth, J. Med. Chem. 1989, 32, 898.
[5] S. Sagan, H. Josien, P. Karoyan, A. Brunissen, G. Chassaing, S. Lavielle, Bioorg. Med. Chem. 1996, 4, 2167;
L. Ranjalahy-Rasoloarijao, R. Lazaro, P. Daumas, F. Heitz, J. Pept. Protein Res. 1989, 33, 273; Y. Yabe, C.
Miura, Y. Baba, S. Sawano, Chem. Pharm. Bull. 1978, 26, 993; M. Rodriguez, N. Bernad, M. C. Galas, M. F.
Lignon, J. Laur, A. Aumelas, J. Martinez, Eur. J. Med. Chem. 1991, 26, 245; Z. Prochazka, J. Slaninova,
Collect. Czech. Chem. Commun. 1995, 60, 2170; T. J. Tucker, W. C. Lumma, A. M. Naylor-Olsen, S. D.
Lewis, R. Lucas, R. M. Freidinger, A. M. Mulichak, Z. Chen, L. C. Kuo, J. Med. Chem. 1997, 40, 830; L.
Cheng, C. A. Goodwin, M. F. Schully, V. V. Kakkar, G. Claeson, J. Med. Chem. 1992, 35, 3364; W. L. Cody,
J. X. He, P. L. DePue, L. A. Waite, D. M. Leonard, A. M. Sefler, J. S. Kaltenbronn, S. J. Haleen, D. M.
Walker, M. A. Flynn, K. M. Welch, E. E. Reynolds, A. M. Doherty, J. Med. Chem. 1995, 38, 2809; R.
Schmidt, D. Vogel, C. Mrestani-Klaus, W. Brandt, K. Neubert, N. N. Chung, C. Lemieux, P. W. Schiller, J.
Med. Chem. 1994, 37, 1136.
[6] A. W. Burgess, Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2649; V. J. Hruby, Biopolymers 1993, 33, 1073; V. J.
Hruby, F. Al-Obeidi, W. Kazmierski, Biochem. J. 1990, 268, 249; M. D. Shenderovich, K. E. Kover, G. V.
Nikiforovich, D. Jiao, V. J. Hruby, Biopolymers 1996, 38, 141.
[7] T. Hohsaka, D. Kajihara, Y. Ashizuka, H. Murakami, M. Sisido, J. Am. Chem. Soc. 1999, 121, 34.
[8] C. J. Noren, S. J. Anthony-Cahill, M. C. Griffith, P. G. Schultz, Science (Washington D.C.) 1989, 244, 182.
[9] R. O. Duthaler, Tetrahedron 1994, 50, 1539; Y. Ohfune, Acc. Chem. Res. 1992, 25, 360; R. M. Williams,
ꢂSynthesis of Optically Active a-Amino Acidsꢀ, Pergamon Press, Oxford, 1989; Ed. M. J. OꢀDonnell,
Tetrahedron 1988, 44, 5253 ± 5614; G. C. Barrett, in ꢂAmino Acids, Peptides and Proteinsꢀ, The Royal
Society of Chemistry, 1998, Vol. 29, p. 1.

988
Helvetica Chimica Acta ± Vol. 83 (2000)
[10] V. I. Tararov, T. F. Saveleva, N. Y. Kuznetsov, N. S. Ikonnikov, S. A. Orlova, Y. N. Belokon, M. North,
Tetrahedron: Asymmetry 1997, 8, 79 ± 83; H. Josien, A. Martin, G. Chassaing, Tetrahedron Lett. 1991, 32,
6547; V. G. Beylin, H. G. Chen, J. Dunbar, O. P. Goel, W. Harter, M. Marlatt, J. G. Topliss, Tetrahedron Lett.
1993, 34, 953; M. P. Sibi, P. K. Deshpande, A. J. La Loggia, J. W. Christensen, Tetrahedron Lett. 1995, 36,
8961; H. G. Chen, V. G. Beylin, M. Marlatt, B. Leja, O. P. Goel, Tetrahedron Lett. 1992, 33, 3293.
Â
Á
[11] a) M. Poch, M. Alcon, A. Moyano, M. A. Pericas, A. Riera, Tetrahedron Lett. 1993, 34, 7781; b) E. Medina,
Á
A. Vidal-Ferran, A. Moyano, M. A. Pericas, A. Riera, Tetrahedron: Asymmetry 1997, 8, 1581.
Á
[12] E. Medina, A. Moyano, M. A. Pericas, A. Riera, J. Org. Chem. 1998, 63, 8574.
Â
Á
[13] M. Pasto, A. Moyano, M. A. Pericas, A. Riera, J. Org. Chem. 1997, 62, 8425.
Â
Á
Â
[14] M. Pasto, A. Moyano, M. A. Pericas, A. Riera, Tetrahedron: Asymmetry 1995, 6, 2329; b) P. Castejon, M.
Â
Á
Â
Pasto, A. Moyano, M. A. Pericas, A. Riera, Tetrahedron Lett. 1995, 36, 3019; c) P. Castejon, A. Moyano,
Á
Â
Á
M. A. Pericas, A. Riera, Chem.±Eur. J. 1996, 2, 1001; d) P. Castejon, A. Moyano, M. A. Pericas, A. Riera,
Â
Á
Tetrahedron 1996, 52, 7063; e) M. Pasto, A. Moyano, M. A. Pericas, A. Riera, Tetrahedron: Asymmetry
Â
Â
Á
1996, 7, 243; f) M. Pasto, P. Castejon, A. Moyano, M. A. Pericas, A. Riera, J. Org. Chem. 1996, 61, 6033;
Â
Á
g) M. Pasto, A. Moyano, M. A. Pericas, A. Riera, Tetrahedron Lett. 1998, 39, 1233; h) N. Aguilar, A.
Á
Moyano, M. A. Pericas, A. Riera, J. Org. Chem. 1998, 63, 3560.
Á
[15] M. Canas. M. Poch, X. Verdaguer, A. Moyano, M. A. Pericas, A. Riera, Tetrahedron Lett. 1991, 32, 6931.
[16] Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune, K. B. Sharpless, J. Am. Chem. Soc. 1987, 109,
5765; T. Katsuki, V. S. Martín, Org. React. 1996, 48, 1.
[17] J. J. Nestor, T. L. Ho, R. A. Simpson, B. L. Horner, G. H. Jones, G. I. McRae, B. H. Vickery, J. Med. Chem.
1982, 25, 795; J. Porter, J. Dykert, J. Rivier, Int. J. Peptide Protein Res. 1987, 30, 13.
[18] M. Zertova, Z. Prochazka, J. Slaninova, T. Barth, P. Majer, M. Lebl, Collect. Czech. Chem. Commun. 1993,
58, 2751; J. Hlavacek, J. Pirkova, M. Zertova, J. Pospisek, L. Maletinska, J. Slaninova, Collect. Czech. Chem.
Commun. 1993, 56, 2761; J. Hlavacek, J. Pirkova, P. Majer, M. Zertova, L. Maletinska, J. Slaninova, Collect.
Czech. Chem. Commun. 1991, 56, 2991.
[19] V. J. Hruby, G. Toth, C. A. Gherig, L.-F. Kao, R. Knapp, G. K. Lui, H. I. Yamamura, T. H. Kramer, P. Davis,
Â
T. F. Burks, J. Med. Chem. 1991, 34, 1823; X. Qian, M. D. Shenderovich, K. E. Köver, P. Davis, R. Horvath,
T. Zalewska, H. I. Yamamura, F. Porreca, V. J. Hruby, J. Am. Chem. Soc. 1996, 118, 7280.
[20] M. Caron, K. B. Sharpless, J. Org. Chem. 1985, 50, 1557.
[21] M. Chini, P. Crotti, F. Macchia, J. Org. Chem. 1991, 56, 5939; M. Chini, P. Crotti, L. A. Flippin, F. Macchia, J.
Org. Chem. 1991, 56, 7043.
[22] K. L. Reddy, K. B. Sharpless, J. Am. Chem. Soc. 1998, 120, 1207.
[23] G. Li, H.-T. Chang, K. B. Sharpless, Angew. Chem., Int. Ed. 1996, 35, 451; G. Li, H. H. Angert, K. B.
Sharpless, Angew. Chem., Int. Ed. 1996, 35, 2813; J. Rudolph, P. C. Sennhenn, C. P. Vlaar, K. B. Sharpless,
Angew. Chem., Int. Ed. 1996, 35, 2810; A. E. Rubin, K. B. Sharpless, Angew. Chem., Int. Ed. 1997, 36, 2637;
M. Bruncko, G. Schlingloff, K. B. Sharpless, Angew. Chem., Int. Ed. 1997, 36, 1483.
[24] P. Obrien, S. A. Osborne, D. D. Parker, J. Chem. Soc., Perkin Trans. 1 1998, 2519.
[25] P. L. Anelli, C. Biffi, F. Montanari, S. Quici, J. Org. Chem. 1987, 52, 2559.
[26] E. J. Corey, G. Schmidt, Tetrahedron Lett. 1979, 399.
[27] D. Jiao, K. C. Russell, V. J. Hruby, Tetrahedron 1993, 49, 3511.
[28] R. Dharanipragada, E. Nicolas, G. Toth, V. J. Hruby, Tetrahedron Lett. 1989, 30, 6841; R. Dharanipragada,
K. VanHulle, A. Bannister, S. Bear, S. Kennedy, V. J. Hruby, Tetrahedron 1992, 48, 4733; M. J. Burk, M. F.
Gross, J. P. Martinez, J. Am. Chem. Soc. 1995, 117, 9375; F. A. Davis, C.-H. Liang, H. Liu, J. Org. Chem.
1997, 62, 3796; W. Yuan, V. J. Hruby, Tetrahedron Lett. 1997, 38, 3853; X. Qian, K. C. Russell, L. W. Boteju,
V. J. Hruby, Tetrahedron 1995, 51, 1033; X. Li, H. Wu, V. J. Hruby, Tetrahedron: Asymmetry 1995, 6, 83.
[29] M. J. S. Dewar, E. G. Zoebisch, E. F. Healy, J. J. P. Stewart, J. Am. Chem. Soc. 1985, 107, 3902.
[30] ꢂSPARTAN, Version 5.1.1ꢀ, Wavefunction, Inc., 18401 Von Karman Ave., Suite 370, Irvine, CA, 92612.
[31] H. Friebolin, ꢂBasic One- and Two-Dimensional NMR Spectroscopyꢀ, 2nd edn.; VCH Publishers, New
York, 1993.
Â
[32] J. M. Seco, E. QuinÄoa, R. Riguera, J. Org. Chem. 1999, 64, 4669.
Â
[33] J. Zwegers, E. Marechal, Bull. Soc. Chim. Fr. 1972, 1157.
[34] R. C. Fuson, N. Thomas, J. Org. Chem. 1953, 18, 1762.
Received January 21, 2000