Trans-hexahydrobenzoxazolidinones in the enantioselective synthesis of β2-amino acids containing proteinogenic side chains

Article abstract of DOI:10.1002/ejoc.201301834

The use of enantiopure trans-hexahydrobenzoxazolidinones as chiral auxiliaries in the enantioselective synthesis of two β²-amino acids containing proteinogenic side chains (β²-hPhenylalanine and β²-hLysine), in both enantiomeric forms, is described. Absolute configurations were assigned on the basis of X-ray diffraction analysis and chemical correlation methods.

Full text of DOI:10.1002/ejoc.201301834

FULL PAPER
DOI: 10.1002/ejoc.201301834
trans-Hexahydrobenzoxazolidinones in the Enantioselective Synthesis of
β2-Amino Acids Containing Proteinogenic Side Chains
Yamir Bandala,[a,b] Gloria Reyes-Rangel,[a] Arturo Obregón-Zúñiga,[a]
Carlos Cruz-Hernández,[a] Gerardo Corzo,[b] and Eusebio Juaristi*[a]
Keywords: Synthetic methods / Amino acids / Chiral auxiliaries / Enantioselectivity / Diastereoselectivity
The use of enantiopure trans-hexahydrobenzoxazolidinones
as chiral auxiliaries in the enantioselective synthesis of two
β2-amino acids containing proteinogenic side chains (β2-
hPhenylalanine and β2-hLysine), in both enantiomeric forms,
is described. Absolute configurations were assigned on the
basis of X-ray diffraction analysis and chemical correlation
methods.
the preparation of β2-amino acids carrying proteinogenic
side chains are available. In this report, we describe an ef-
ficient methodology for the synthesis of two β2-amino acids
containing side chains present in proteinogenic amino acids,
the hydrophobic amino acid side chain present in phenylal-
anine, and the hydrophilic amino acid side chain present in
lysine.
Juaristi and collaborators have demonstrated the conve-
nience of the use of enantiopure trans-hexahydrobenzo-
xazolidinones (R,R)-1 and (S,S)-1 (Figure 1) as efficient
and versatile chiral auxiliaries for the preparation of several
enantioenriched compounds such as carbinols,[13] sulfox-
ides,[14] aminophosphonic acids,[15] and β-amino acids con-
taining tryptophan[16] or tert-butyl[17] substituents. Based
on this precedent, we utilized enantiomerically pure (R,R)-1
and (S,S)-1 as starting materials, and employed the Curtius
rearrangement as a key step (see below), in the synthesis of
the target β2-amino acids.
Introduction
The fact that natural peptides control relevant aspects of
cellular function with high efficiency make them attractive
candidates in drug development.[1] Indeed, peptide-based
therapeutics for a wide variety of human diseases including
antiviral,[2] antimicrobial,[3] antiobesity,[4] neuroprotec-
tive,[5] anticancer,[6] and antihypertensive[7] agents have been
developed.
Peptides, when compared to small molecule drugs, have
the advantage of presenting higher potency and specificity
with fewer toxicological problems.[8] For example, peptides
are generally less immunogenic than recombinant proteins
and antibodies.[9] However, despite their great potential,
there are still some limitations for the use of peptides as
drugs. Major disadvantages are short half-life, rapid metab-
olism, and low in vivo stability from protease degradation,
which limits their oral administration.[10] In this context,
the pharmacological and physicochemical properties of
peptides can be improved by the presence of β-amino acids,
which are resistant to proteolytic enzymes; indeed, their in-
corporation in the peptidic sequence can drastically reduce
its rate of proteolytic degradation.[11] This feature has made
β-amino acids an important synthetic target for organic
chemists.
Figure 1. Enantiopure trans-hexahydrobenzoxazolidinones (R,R)-1
and (S,S)-1 used in this work.
Several methodologies for the synthesis of enantioen-
riched β-amino acids have appeared in the literature.[12]
Nevertheless, only a limited number of reports concerning
Results and Discussion
Chiral auxiliaries (R,R)-1 and (S,S)-1 were prepared
through ring opening of inexpensive cyclohexene oxide with
(S)-α-phenylethylamine[18] followed by chromatographic
separation of the resulting diastereomeric β-amino alcohols,
stereospecific cyclization, and removal of the phenylethyl
fragment.[13a] Enantiopure acylated derivatives 2 were gen-
erated in good yields by coupling between (R,R)-1 or (S,S)-
1 and hydrocinnamoyl chloride in the presence of nBuLi
[a] Departamento de Química, Centro de Investigación y de
Estudios Avanzados del Instituto Politécnico Nacional,
Apartado Postal 14-740, 07000 México, D. F., México
E-mail: juaristi@relaq.mx
http://www.relaq.mx/RLQ/EusebioJuaristi.html
[b] Instituto de Biotecnología, Universidad Nacional Autónoma de
México,
Apartado Postal 510-3, 62250 Cuernavaca, Morelos, México
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301834.
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(Method A, Scheme 1), whereas enantiopure derivatives 3 scopic analysis) induced by the trans-hexahydrobenzoxazol-
where formed by the coupling between (R,R)-1 or (S,S)- idinone chiral auxiliary.
1 and N-Boc-6-aminohexanoic acid (N-Boc-6-Ahx-OH) via
A transition state that is consistent with the observed
stereochemical course of the alkylation reaction is shown in
Scheme 2. It is suggested that the sodium cation is chelated
pivalic anhydride[19] (Method B, Scheme 1).
Scheme 1. N-Acylation of (R,R)-1 and (S,S)-1. Method A, for
(R,R)-2 and (S,S)-2: nBuLi, hydrocynnamoyl chloride, –20 °C.
Method B, for (R,R)-3 and (S,S)-3: N-Boc-6-aminohexanoic anhy-
dride, LiCl, –15 °C.
Diastereoselective Alkylation of 2 and 3
One of the most practical methods for the enantioselec-
tive synthesis of chiral molecules involves the diastereoselec-
tive alkylation of enolates for which the C=C faces are ren-
dered diastereotopic owing to the presence of chiral auxilia-
ries in the substrate. Thus, sodium enolates derived from
oxazolidinones 2 and 3 were prepared by treatment with
sodium hexamethyldisylazide (NaHMDS) at –78 °C in
tetrahydrofuran (THF), followed by alkylation at the same
temperature using 2.0 equiv. benzyl bromoacetate (slow ad-
dition to avoid an increase of temperature). Analysis of the
crude reaction mixture showed the presence of only one alk-
ylated product each for 4 and 5, indicating the high dia-
Figure 2. ORTEP diagrams of compounds (1R,2R,1ЈS)-4 (top) and
stereoselectivity (Ն 98% according to 1H NMR spectro- (1S,2S,1ЈR)-4 (bottom).[22]
Scheme 2. Proposed models for the diastereoselective alkylation of chiral N-acylated oxazolidinones. (a) (R,R)-2 and (R,R)-3; (b) (S,S)-2
and (S,S)-3. The solid arrow indicates the preferred trajectory during addition.
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β2-Amino Acids with Proteinogenic Side Chains
by both carbonyl oxygen atoms in a (Z)-configured enol- Removal of the Chiral Auxiliary
ate,[13,15,16,20] and that this well-defined structural arrange-
As the steric requirements around the carbamate chain
ment causes the electrophile to be incorporated from the
less sterically hindered face.[21] Accordingly, alkylation of
(R,R)-2 and (R,R)-3 takes place on the less sterically hin-
dered Re face, affording the corresponding product (4 or 5)
with S absolute configuration on the new stereogenic center.
On the other hand, when starting from the (S,S,Z) enolates,
alkylation takes place on the Si face, generating the corre-
sponding R configuration [according to the priority of the
substituents at C(α) for a system in which CH2CO2Bn Ͼ
R] (Scheme 2).
The absolute configuration of the newly created stereo-
genic center at C(α) in 4, was determined on the basis of
single-crystal X-ray diffraction analysis. The obtained struc-
ture (Figure 2) supports the conclusion that the alkylation
reaction takes place on the less sterically hindered face of
the enolates derived from N-acylated substrates (R,R)-2 and
(S,S)-2, as suggested in Scheme 2. The absolute configura-
tion in 5 was established by means of chemical correlation
as discussed below.
are significant in substrates 8 and 9, competition becomes
important for reagent attack at the endocyclic carbonyl
group.[23] Therefore, lithium hydroperoxide (LiOOH), which
is known to display greater exocyclic cleavage regioselectiv-
ity,[23] was used to carry out the removal of the N-acylox-
azolidinone chiral auxiliary. As anticipated, removal of the
auxiliary in (1S,2S,1ЈR)-8 and (1R,2R,1ЈS)-8 using LiOOH
generated in situ afforded (R)- and (S)-N-Cbz β2-amino ac-
ids (R)-10 and (S)-10 in 64 and 68% yields, respectively. By
the same token, hydrolysis of (1S,2S,1ЈR)-9 and
(1R,2R,1ЈS)-9 afforded N-Cbz β2-amino acids (R)-11 and
(S)-11 in 57 and 63% yields, respectively (Scheme 4). Recov-
ery of the chiral auxiliaries, enantiopure hexahydrobenz-
oxazolidinones (R,R)-1 and (S,S)-1, was achieved by means
of simple extraction procedures.
Hydrogenolysis and Curtius Rearrangement of Chiral
Derivatives 4 and 5
Carboxylic acids (1R,2R,1ЈS)-6 and (1R,2R,1ЈS)-7, the
required substrates for Curtius rearrangement, were pre-
pared by palladium-catalyzed hydrogenolysis of the benzyl
group in substrates (1R,2R,1ЈS)-4 and (1R,2R,1ЈS)-5. The
resulting carboxylic acids were treated with Et3N and di-
phenyl phosphoryl azide [(PhO)2P(O)N3] to provide the ex-
pected isocyanate intermediates, which were treated with
benzyl alcohol to generate the N-benzyloxycarbonyl (Cbz)
protected derivatives (1R,2R,1ЈS)-8 and (1R,2R,1ЈS)-9 in
good yields (Scheme 3).
Scheme 4. Removal of the chiral auxiliary by LiOOH to give (S)-
10 and (S)-11. A similar scheme applies to reactions carried out
with (1S,2S,1ЈR) substrates.
Free and Fmoc-Protected β2-Amino Acids 12 and 14
The use of trans-hexahydrobenzoxazolidinones as chiral
auxiliaries allows the preparation of highly enantioenriched
N-Cbz-protected β2-hPhe and β2-hLys (compounds 10 and
11). It was also possible to obtain these β2-amino acids in
free form, following removal of the N-Cbz protecting group
through catalytic hydrogenolysis. Indeed, treatment of (S)-
10 with 10% Pd/C on MeOH at 1 atm H2 and at room
temperature, generated (S)-12 in 90% yield and 96% enan-
tiomeric excess (Scheme 5).
Since the alkylation reaction of the sodium enolate de-
rived from substrate (R,R)-2 proceeds with at least 98% dia-
stereoselectivity (1H NMR detection limit, see above), the
96% enantiomeric excess determined for (S)-12 is probably
the result of the greater sensitivity of the HPLC method, or
a consequence of a small amount of epimerization during
the removal of the chiral auxiliary in substrate (1R,2R,1ЈS)-
8 under basic conditions (Scheme 4).
Finally, a two-step reaction procedure can be realized to
obtain Fmoc-β2-amino acid derivatives that are suitable for
solid-phase peptide synthesis. For example, catalytic hydro-
genation of (S)-11 followed by treatment with FmocOSuc
in the presence of NaHCO3, afforded the corresponding N-
Scheme 3. Hydrogenolysis of α-alkylated derivatives (1R,2R,1ЈS)-4
and (1R,2R,1ЈS)-5 and Curtius rearrangement of the corresponding
carboxylic acids 6 and 7. A similar scheme applies to reactions
carried out with the (1S,2S,1ЈR) enantiomers.
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Scheme 5. HPLC analysis of (S)-12 illustrating the efficiency of the present approach [Chirobiotic T column; MeOH/H2O (80:20); λ =
210 nm; flow = 0.6 mL/min].
Fmoc-protected β2-amino acid (S)-14 in 84% yield after ple and mild procedure. The application of X-ray diffrac-
two steps (Scheme 6). The close similarity between the op- tion analysis, as well as chemical correlation enabled the
tical rotation for homolysine derivative (S)-14 and the re- configuration of the products to be assigned. This route
ported value[24] suggests a very high enantiopurity in pre- provides access to both enantiomers of the free or the pro-
cursors (S)-11 and (S)-13 as well.
tected β2-amino acids containing benzyl and 4-aminobutyl
proteinogenic side chains. These β-amino acids should pro-
vide access to β-peptides with high biological potential.
Experimental Section
General: Reagents and solvents employed in this work were high-
purity reagents. Glassware, needles, cannula, and magnetic bars
were dried in an oven at 120 °C for 24 h before use. Anhydrous
solvents were obtained by conventional methods. Purification of
organic products was achieved by means of flash chromatography
on 230–400 mesh silica gel. Melting points were measured with an
Electrothermal apparatus and are uncorrected. Optical rotations
were measured with a Perkin–Elmer polarimeter model 241, at λ
589 nm and 25 °C. 1H and 13C NMR spectra were recorded with
JEOL ECA 500 (500 MHz) or JEOL GSX-270 (270 MHz) spec-
trometers in CDCl3, [D6]DMSO or D2O with TMS as internal
1
standard. The multiplicity of H NMR signals is indicated by s =
singlet, d = doublet, t = triplet, and m = multiplet. IR spectra were
recorded with a Varian model 640 apparatus. Mass spectra were
registered with a Thermo Electron Trace-DSQ spectrometer at
20 eV. HRMS were recorded with an Agilent-MSD-TOF1069A
spectrometer. Elemental analyses were obtained with a Thermo-
Finnigan CHNS/O 1112 apparatus. HPLC analyses were carried
out with Waters 600 E equipment fitted with a UV/Vis Waters 2487
detector and Chirobiotic T (Daicel Chemical Ind., Ltd,
0.46ϫ25 cm) column, employing MeOH/H2O mixtures as mobile
phase.
Scheme 6. Two-step N-Fmoc protection of (S)-11 in the synthesis
of orthogonally protected β-amino acid (S)-14 suitable for solid-
phase peptide synthesis.
Conclusions
N-Acylation Procedure for the Preparation of 2: nBuLi (2.59 m in
hexane, 1 equiv.) was added to a cold (–20 °C) solution of enantio-
pure trans-hexahydrobenzoxazolidin-2-one 1 (1 equiv.) in anhy-
Enantiopure trans-hexahydrobenzoxazolidinones (R,R)-1
and (S,S)-1 are effective chiral auxiliaries for the enantiose-
lective synthesis of β2-hPhe and β2-hLys by means of a sim- drous THF and the resulting mixture was stirred for 30 min at
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β2-Amino Acids with Proteinogenic Side Chains
–20 °C. Hydrocinnamoyl chloride (1 equiv.) was then added over
15 min and the reaction mixture was stirred for 3.5 h at room tem-
perature, before the addition of saturated aqueous NH4Cl, H2O,
and EtOAc. The organic phase was separated and washed with
brine (100 mL), and each aqueous fraction was re-extracted with
EtOAc. The combined organic extracts were dried with anhydrous
Na2SO4 and concentrated under vacuum.
product was purified by flash chromatography (hexane/EtOAc,
80:20) to give the desired product (3.0 g, 85%); [α]2D5 = +55.0 (c =
1.2, CHCl3). The spectroscopic data are similar to those recorded
for enantiomeric (R,R)-3.
General Procedure for the Alkylation of 2: NaHMDS (1 m in hex-
ane, 1.1 equiv.) was added to a cold (–78 °C) solution of 2 (1 equiv.)
in anhydrous THF, and the resulting mixture was stirred for on
additional 60 min at –78 °C before the slow addition of a solution
of benzyl bromoacetate (2 equiv.) in anhydrous THF. The reaction
mixture was stirred for 12 h at –78 °C before the addition of satu-
rated aqueous NH4Cl and the resulting mixture was warmed to
room temperature, diluted with H2O and extracted with EtOAc.
The combined organic phases were dried with anhydrous Na2SO4
and concentrated under vacuum.
(3aR,7aR)-3-(3-Phenylpropanoyl)hexahydrobenzo[d]oxazol-2(3H)-
one [(R,R)-2]: The general procedure described above was followed
with (R,R)-1 (3.0 g, 21.3 mmol), and the crude product was purified
by flash chromatography (EtOAc/hexane, 80:20) to give the desired
product (4.4 g, 76%); m.p. 143–145 °C; [α]2D5 = –44.0 (c = 1.0,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.30–7.18 (m, 5 H), 3.82
(dt, J2 = 3.6, J1 = 11.6 Hz, 1 H), 3.53 (dt, J2 = 3.2, J1 = 11.0 Hz,
1 H), 3.32–3.24 (m, 1 H), 3.18–3.10 (m, 1 H), 3.04–2.92 (m, 2 H),
2.84–2.76 (m, 1 H), 2.25–2.18 (m, 1 H), 1.98–1.90 (m, 1 H), 1.88–
1.81 (m, 1 H), 1.68–1.58 (m, 1 H), 1.46–1.31 (m, 3 H) ppm. 13C
NMR (125.76 MHz, CDCl3): δ = 174.7, 154.8, 140.6, 128.6 (2 C),
128.5 (2 C), 126.3, 81.5, 63.2, 38.1, 30.5, 28.9, 28.5, 23.8, 23.6 ppm.
(S)-Benzyl 3-Benzyl-4-oxo-4-[(3aR,7aR)-2-oxohexahydrobenzo[d]ox-
azol-3(2H)-yl]butanoate [(1R,2R,1ЈS)-4]: The general procedure de-
scribed above was followed with (R,R)-2 (1.5 g, 5.3 mmol) and the
crude product was purified by flash chromatography (EtOAc/hex-
ane, 90:10) to give the desired product (1.6 g, 70 %); m.p. 120–
122 °C; [α]2D5 = –30.8 (c = 1.02, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 7.34–7.28 (m, 10 H), 5.0 (s, 2 H), 4.08 (tt, J2 = 3.8, J1
= 10.8 Hz, 1 H), 3.69 (dt, J2 = 3.5, J1 = 11.5 Hz, 1 H), 3.52 (dt, J2
= 3.3, J1 = 11.2 Hz, 1 H), 3.26 (dd, J2 = 4.0, J1 = 13.2 Hz, 1 H),
2.88 (dd, J2 = 11.0, J1 = 17.3 Hz, 1 H), 2.77–2.70 (m, 1 H), 2.46–
2.40 (m, 2 H), 2.22–2.16 (m, 1 H), 1.93–1.85 (m, 1 H), 1.83–1.75
(m, 1 H), 1.66–1.57 (m, 1 H), 1.40–1.31 (m, 2 H), 1.27–1.19 (m, 1
H) ppm. 13C NMR (125.76 MHz, CDCl3): δ = 176.8, 171.8, 154.6,
138.3, 135.7, 129.5 (2 C), 128.7 (2 C), 128.6 (2 C), 128.43 (2 C),
128.39, 126.8, 81.7, 66.6, 63.4, 42.7, 37.1, 35.6, 28.5, 28.4, 23.8,
IR: ν = 2946, 1783, 1766, 1693, 1452, 1373, 1309, 1230, 1208, 1147,
˜
1114, 1048, 1010, 938 cm–1. HRMS (ESI-TOF): calcd. for
C16H19NO3 + H+ 274.1437; found 274.1437. C16H19NO3 (273.33):
calcd. C 70.31, H 7.01, N 5.12; found C 70.48, H 7.21, N 5.14.
(3aS,7aS)-3-(3-Phenylpropanoyl)hexahydrobenzo[d]oxazol-2(3H)-
one [(S,S)-2]: The general procedure described above was followed
with (S,S)-1 (4.0 g, 28.3 mmol) and the crude product was purified
by flash chromatography (EtOAc/hexane, 80:20) to give the desired
product (7.74 g, 75%); m.p. 146–148 °C; [α]2D5 = +45.3 (c = 1.01,
CHCl3). The spectroscopic data are similar to those recorded for
enantiomeric (R,R)-2.
23.6 ppm. IR: ν = 1785, 1728, 1695, 1453, 1380, 1339, 1256, 1192,
˜
1146, 1027, 1048, 938, 769, 754 cm–1. HRMS (ESI-TOF): calcd. for
C25H27NO5 + H+ 422.1961; found 422.1958. C25H27NO5 (421.49):
calcd. C 71.24, H 6.46, N 3.32; found C 71.58, H 6.60, N 3.35.
N-Acylation Procedure for the Preparation of 3: To a solution of
N-Boc-6-aminohexanoic acid (1.05 equiv.) in anhydrous THF, was
added Et3N (2.7 equiv.) at –15 °C. The solution was stirred at
–15 °C for 15 min before the addition of pivaloyl chloride
(1.05 equiv.). The resulting white suspension was stirred at –15 °C
for 2 h, before the addition of LiCl (1.2 equiv.) and enantiopure
hexahydrobenzoxazolidin-2-one 1 (1 equiv.) in anhydrous THF.
The mixture was warmed to room temperature and stirred for 18 h,
then treated with saturated aqueous NH4Cl, H2O, and EtOAc. The
organic phase was separated, washed with brine, and each aqueous
fraction was re-extracted with EtOAc. The combined organic
phases were dried with anhydrous Na2SO4 and concentrated under
vacuum.
(R)-Benzyl 3-Benzyl-4-oxo-4-[(3aS,7aS)-2-oxohexahydrobenzo[d]ox-
azol-3(2H)-yl]butanoate [(1S,2S,1ЈR)-4]: The general procedure de-
scribed above was followed with (S,S)-2 (2.5 g, 9.16 mmol) and the
crude product was purified by flash chromatography (EtOAc/hex-
ane, 9:1) to give the desired product (2.6 g, 67%); m.p. 120–121 °C;
[α]2D5 = +32.8 (c = 1, CHCl3). The spectroscopic data are similar to
those recorded for enantiomeric (1R,2R,1ЈS)-4.
General Procedure for Alkylation of 3: NaHMDS (1 m in THF,
2.2 equiv.) was added over 15 min to a cold (–78 °C) solution of 3
(1 equiv.) in anhydrous THF, and the resulting mixture was stirred
tert-Butyl 6-Oxo-6-[(3aR,7aR)-2-oxohexahydrobenzo[d]oxazol- for an additional 60 min at –78 °C before the slow addition by
3(2H)-yl]hexylcarbamate [(R,R)-3]: The general procedure de- using a cannula of a cold (–78 °C) solution of benzyl bromoacetate
scribed above was followed with (R,R)-1 (2.0 g, 14.2 mmol) and (2.2 equiv.) in anhydrous THF. The reaction mixture was stirred for
the crude product was purified by flash chromatography (hexane/
5 h at –78 °C, before the addition of saturated aqueous NH4Cl, and
the resulting mixture was warmed to room temperature, diluted
EtOAc, 80:20) to give the desired product (4.1 g, 77%); [α]2D5
=
–54.5 (c = 1.1, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 4.55 (br., with H2O, and extracted with EtOAc. The combined organic
1 H), 3.83 (ddd, J3 = 3.6, J2 = 11.5, J1 = 11.3 Hz, 1 H), 3.50 (ddd,
J3 = 3.3, J2 = 10.9, J1 = 10.9 Hz, 1 H), 3.07 (dt, J2 = 6.4, J1
phases were dried with anhydrous Na2SO4 and concentrated under
vacuum.
=
6.4 Hz, 2 H), 2.94–2.88 (m, 1 H), 2.79–2.73 (m, 2 H), 2.20–2.17 (m,
1 H), 1.90 (br., 1 H), 1.81 (br., 1 H), 1.67–1.57 (m, 3 H), 1.49–1.29
(m, 7 H), 1.39 (s, 9 H) ppm. 13C NMR (125.76 MHz, CDCl3): δ =
175.4, 156.0, 154.8, 81.4, 79.0, 63.1, 40.4, 36.3 (2 C), 29.8, 28.9,
(S)-Benzyl 7-(tert-Butoxycarbonylamino)-3-[(3aR,7aR)-2-oxoocta-
hydro-benzo[d]oxazole-3-carbonyl]heptanoate [(1R,2R,1ЈS)-5]: The
general procedure described above was followed with (R,R)-3
(2.8 g, 8.0 mmol) and the crude product was purified by flash
chromatography (hexane then hexane/EtOAc, 90:10) to give the de-
sired product (2.4 g, 60%); [α]2D5 = –4.5 (c = 1.1, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.33–7.25 (m, 5 H), 5.02 (s, 2 H), 4.60 (br.,
1 H), 3.81 (br., 1 H), 3.58 (ddd, J3 = 3.4, J2 = 11.5, J1 = 12.3 Hz,
1 H), 3.45 (ddd, J3 = 3.1, J2 = 11.1, J1 = 11.2 Hz, 1 H), 3.03 (br.,
2 H), 2.81 (dd, J2 = 10.4, J1 = 16.8 Hz, 1 H), 2.65 (d, J = 11.4 Hz,
1 H), 2.54 (dd, J2 = 4.0, J1 = 16.8 Hz, 1 H), 2.12 (d, J = 11.9 Hz,
28.4 (3 C), 26.3, 24.0, 23.7, 23.6 ppm. IR: ν = 3392, 2934, 2359,
˜
1801, 1686, 1519, 1384, 1366, 1336, 1304, 1255, 1221, 1174, 1143,
1121, 1054, 1019, 939 cm–1. HRMS (ESI-TOF): calcd. for
C18H30N2O5 + H+ 355.2227; found 355.2228.
tert-Butyl 6-Oxo-6-[(3aS,7aS)-2-oxohexahydrobenzo[d]oxazol-
3(2H)-yl]hexylcarbamate [(S,S)-3]: The general procedure described
above was followed with (S,S)-1 (1.4 g, 10 mmol) and the crude
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1 H), 1.84 (br., 1 H), 1.71 (br., 2 H), 1.57–1.53 (m, 1 H), 1.43–1.13
(R)-7-(tert-Butoxycarbonylamino)-3-[(3aS,7aS)-2-oxooctahydro-
(m, 8 H), 1.38 (s, 9 H) ppm. 13C NMR (125.76 MHz, CDCl3): δ = benzo-[d]oxazole-3-carbonyl]heptanoic Acid [(1S,2S,1ЈR)-7]: The ge-
177.1, 171.7, 156.0, 154.4, 135.8, 128.6 (2 C), 128.3 (3 C), 81.4, neral procedure described for 5 was followed with (1S,2S,1ЈR)-5
79.0, 66.5, 63.3, 40.2 (2 C), 36.4, 31.0, 29.8, 28.4 (3 C), 28.3 (2 C),
(2.3 g, 4.5 mmol) to give the desired product (1.8 g, 97%); [α]2D5
=
24.0, 23.7, 23.5 ppm. IR: ν = 3381, 2938, 1785, 1732, 1695, 1513,
+15.0 (c = 1.2, CHCl3). The spectroscopic data are similar to those
recorded for enantiomeric (1R,2R,1ЈS)-7.
˜
1454, 1365, 1340, 1306, 1250, 1214, 1165, 1113, 1028, 936 cm–1.
HRMS (ESI-TOF): calcd. for C27H38N2O7 + H+ 503.2751; found
503.2755.
General Procedure for the Preparation of Compounds 8 and 9
through Curtius Rearrangement: To a stirred solution of 6 or 7
(1 equiv.) and Et3N (2 equiv.) in anhydrous toluene was added di-
phenylphosphoryl azide [(PhO)2P(O)N3, 1.2 equiv] and BnOH
(2 equiv.). The mixture was heated at reflux for 3 h (compound 6)
or stirred for 1 h at room temperature and then heated at reflux
for an additional 2 h (compound 7). The toluene was evaporated
in vacuo and the residue was dissolved in EtOAc and 2 m HCl.
The organic phase was separated, washed with saturated solution
NaHCO3, dried with anhydrous Na2SO4, and concentrated under
vacuum.
(R)-Benzyl 7-(tert-Butoxycarbonylamino)-3-[(3aS,7aS)-2-oxoocta-
hydro-benzo[d]oxazole-3-carbonyl]heptanoate [(1S,2S,1ЈR)-5]: The
general procedure described above was followed with (S,S)-3 (3.0 g,
8.5 mmol) and the crude product was purified by flash chromatog-
raphy (hexane, then hexane/EtOAc, 90:10) to give the desired prod-
uct (2.2 g, 53%); [α]2D5 = +4.0 (c = 1.0, CHCl3). The spectroscopic
data are similar to those recorded for enantiomeric (1R,2R,1ЈS)-5.
General Procedure for Hydrogenolysis of Alkylated Products 4 and
5: A solution of compound 4 (10.9 mmol) or 5 (5.5 mmol) in
EtOAc (reagent grade, 100 mL) was stirred under H2 (1 atm) in the
presence of 10% Pd/C for 16 h (compound 4) or 24 h (compound
5). The mixture was filtered through Celite, washed with EtOAc,
and the filtrate was concentrated under vacuum.
Benzyl (S)-2-Benzyl-3-oxo-3-[(3aR,7aR)-2-oxohexahydrobenzo[d]ox-
azol-3(2H)-yl]propylcarbamate [(1R,2R,1ЈS)-8]: The general pro-
cedure described for 6 was followed with (1R,2R,1ЈS)-6 (886 mg,
2.7 mmol) and the crude product was purified by flash chromatog-
raphy (hexane/EtOAc, 90:10) to give the desired product (881 mg,
75%); m.p. 91–92 °C; [α]2D5 = –12 (c = 1, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.37–7.18 (m, 10 H), 5.06 (s, 2 H), 5.0–4.9
(br., 1 H), 4.12 (tt, J2 = 7.2, J1 = 14.2 Hz, 1 H), 3.75 (dt, J2 = 3.6,
J1 = 11.5 Hz, 1 H), 3.53–3.43 (m, 2 H), 3.42–3.32 (m, 1 H), 3.13
(dd, J2 = 6.2, J1 = 13.8 Hz, 1 H), 2.80–2.62 (m, 2 H), 2.20–2.12
(m, 1 H), 1.94–1.84 (m, 1 H), 1.84–1.74 (m, 1 H), 1.64–1.54 (m, 1
H), 1.42–1.24 (m, 3 H) ppm. 13C NMR (125.76 MHz, CDCl3): δ =
176.1, 156.2, 154.6, 138.3, 136.6, 129.2 (2 C), 128.6 (2 C), 128.24
(2 C), 128.21 (2 C), 128.0, 126.6, 81.4, 66.7, 63.4, 46.2, 42.3, 34.7,
(S)-3-Benzyl-4-oxo-4-[(3aR,7aR)-2-oxohexahydrobenzo[d]oxazol-
3(2H)-yl]butanoic Acid [(1R,2R,1ЈS)-6]: The general procedure de-
scribed for 4 was followed with (1R,2R,1ЈS)-4 (1.2 g, 2.8 mmol) and
the crude product was purified by crystallization (Et2O/hexane) to
give the desired product (887 mg, 95%); m.p. 116–118 °C; [α]2D5
=
–60 (c = 1, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.29–7.19
(m, 5 H), 4.05 (tt, J2 = 3.9, J1 = 10.7 Hz, 1 H), 3.94 (dt, J2 = 3.5,
J1 = 11.6 Hz, 1 H), 3.6 (dt, J2 = 3.3, J1 = 11.0 Hz, 1 H), 3.27 (dd,
J2 = 4.0, J1 = 13.2 Hz, 1 H), 2.85 (dd, J2 = 10.9, J1 = 17.6 Hz, 1
H), 2.80–2.74 (m, 1 H), 2.45–2.36 (m, 2 H), 2.28–2.22 (m, 1 H),
1.96–1.87 (m, 1 H), 1.87–1.77 (m, 1 H), 1.71–1.60 (m, 1 H), 1.49–
1.31 (m, 3 H) ppm. 13C NMR (125.76 MHz, CDCl3): δ = 178.0,
176.7, 154.6, 138.2, 129.5 (2 C), 128.6 (2 C), 126.8, 81.9, 63.5, 42.5,
28.5, 28.4, 23.8, 23.6 ppm. IR: ν = 3341, 3030, 2928, 2360, 1805,
˜
1724, 1677, 1524, 1406, 1326, 1309, 1255, 1236, 1206, 1141, 1039,
732, 713 cm–1. HRMS (ESI-TOF): calcd. for C25H28N2O5 + H+
437.2073; found 437.2070. C25H28N2O5 (436.51): calcd. C 68.79, H
6.47, N 6.42; found C 69.05, H 6.63, N 6.82.
36.9, 35.2, 28.6, 28.5, 23.8, 23.6 ppm. IR: ν = 2939, 1795, 1734,
˜
1699, 1404, 1381, 1327, 1308, 1260, 1218, 1194, 1144, 1121, 1048,
1029, 937, 767, 717 cm–1 . HRMS (ESI-TOF): calcd. for
C18H21NO5 + H+ 332.1495; found 332.1492.
Benzyl (R)-2-Benzyl-3-oxo-3-[(3aS,7aS)-2-oxohexahydrobenzo[d]ox-
azol-3(2H)-yl]propylcarbamate [(1S,2S,1ЈR)-8]: The general pro-
cedure described for 6 was followed with (1S,2S,1ЈR)-6 (3.3 g,
10.06 mmol) and the crude product was purified by flash
chromatography (hexane/EtOAc, 90:10) to give the desired product
(3.5 g, 80%); m.p. 92–94 °C; [α]2D5 = +14.2 (c = 1, CHCl3). The
spectroscopic data are similar to those recorded for enantiomeric
(1R,2R,1ЈS)-8.
(R)-3-Benzyl-4-oxo-4-[(3aS,7aS)-2-oxohexahydrobenzo[d]oxazol-
3(2H)-yl]butanoic Acid [(1S,2S,1ЈR)-6]: The general procedure de-
scribed for 4 was followed with (1S,2S,1ЈR)-4 (4.5 g, 10.9 mmol)
and the crude product was purified by crystallization (Et2O/hex-
ane) to give the desired product (3.5 g, 96%); m.p. 118–120 °C;
[α]2D5 = +60.4 (c = 1.01, CHCl3). The spectroscopic data are similar
to those recorded for enantiomeric (R,R,S)-6.
Benzyl {(S)-6-tert-Butoxycarbonylamino-2-[(3aR,7aR)-2-oxooctahy-
drobenzo[d]oxazole-3-carbonyl]-hexyl}carbamate [(1R,2R,1ЈS)-9]:
The general procedure described for 7 was followed with
(1R,2R,1ЈS)-7 (1.4 g, 3.3 mmol) and the crude product was purified
by flash chromatography (hexane/EtOAc, 90:10 to 80:20) to give
(S)-7-(tert-Butoxycarbonylamino)-3-[(3aR,7aR)-2-oxooctahydro-
benzo[d]oxazole-3-carbonyl]heptanoic Acid [(1R,2R,1ЈS)-7]: The ge-
neral procedure described for 5 was followed with (1R,2R,1ЈS)-5
1
the desired product (1.1 g, 64%); [α]2D5 = –3.3 (c = 0.9, CHCl3). H
(2.4 g, 4.7 mmol) to give the desired product (1.9 g, 97%); [α]2D5
=
NMR (500 MHz, CDCl3): δ = 7.35–7.27 (m, 5 H), 5.20 (br., 1 H),
5.0 (br., 2 H), 4.60 (br., 1 H), 3.80–3.72 (m, 2 H), 3.56–3.46 (m, 2
H), 3.38–3.20 (m, 1 H), 3.12–3.00 (m, 2 H), 2.70 (br., 1 H), 2.16
(br., 1 H), 1.90–1.26 (m, 12 H), 1.40 (s, 9 H) ppm. 13C NMR
(125.76 MHz, CDCl3): δ = 176.7, 156.4, 156.1, 154.6, 136.6, 128.5
(2 C), 128.1 (3 C), 81.3, 79.1, 66.7, 63.3, 44.6, 42.5, 39.9, 30.0, 28.4
–14.5 (c = 1.1, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.60 (br.,
1 H), 4.58 (br., 1 H), 3.89 (ddd, J3 = 3.5, J2 = 11.5, J1 = 11.4 Hz,
1 H), 3.80–3.75 (m, 1 H), 3.55 (ddd, J3 = 3.3, J2 = 11.0, J1
=
10.9 Hz, 1 H), 3.08 (br., 2 H), 2.83–2.73 (m, 2 H), 2.55 (dd, J2 =
4.4, J1 = 17.1 Hz, 1 H), 2.21 (m, 1 H), 1.91 (br., 1 H), 1.83 (br., 1
H), 1.78–1.71 (m, 1 H), 1.67–1.59 (m, 1 H), 1.49–1.31 (m, 8 H),
1.41 (s, 9 H) ppm. 13C NMR (125.76 MHz, CDCl3): δ = 177.2,
177.1, 156.1, 154.5, 81.7, 79.2, 63.4, 40.2, 40.1, 36.1, 30.8, 29.8,
(3 C), 28.4 (2 C), 27.9, 23.9, 23.7, 23.5 ppm. IR: ν = 3353, 2933,
˜
2360, 1782, 1693, 1519, 1455, 1365, 1306, 1234, 1167, 1144, 1036,
937 cm–1. HRMS (ESI-TOF): calcd. for C27H39N3O7 + H+
518.2860; found 518.2866.
28.5, 28.4 (4 C), 24.0, 23.8, 23.5 ppm. IR: ν = 3354, 2936, 2359,
˜
1785, 1699, 1521, 1455, 1365, 1306, 1253, 1203, 1165, 1114, 1028,
936 cm–1. HRMS (ESI-TOF): calcd. for C20H32N2O7 + H+
413.2282; found 413.2273.
Benzyl {(R)-6-tert-Butoxycarbonylamino-2-[(3aS,7aS)-2-oxooctahy-
drobenzo[d]oxazole-3-carbonyl]hexyl}carbamate [(1S,2S,1ЈR)-9]:
2280
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2275–2283

β2-Amino Acids with Proteinogenic Side Chains
The general procedure described for 7 was followed with
(1S,2S,1ЈR)-7 (1.9 g, 4.4 mmol) and the crude product was purified
by flash chromatography (hexane/EtOAc, 90:10 to 80:20) to give
the desired product (1.5 g, 66%); [α]2D5 = +3.6 (c = 1.1, CHCl3).
The spectroscopic data are similar to those recorded for enantio-
meric (1R,2R,1ЈS)-9.
H), 3.40–3.31 (m, 2 H), 3.06 (br., 2 H), 2.60 (br., 1 H), 1.66–1.18
(m, 7 H), 1.41 (s, 9 H) ppm. 13C NMR (67 MHz, CDCl3): δ =
179.1, 156.6 (2 C), 136.4, 128.6 (2 C), 128.2 (3 C), 79.3, 66.9, 45.5,
41.6, 40.1, 29.7, 29.3, 28.4 (3 C), 24.0 ppm. IR: ν = 3331, 2933,
˜
1693, 1519, 1454, 1365, 1248, 1165, 986 cm–1. HRMS (ESI-TOF):
calcd. for C20H30N2O6 + H+ 395.2176; found 395.2179.
General Procedure for the Preparation of Derivatives 10: The reac-
tion was carried out in two steps: To a stirred solution of
(S)-2-[(Benzyloxycarbonylamino)methyl]-6-(tert-butoxycarbonyl-
amino)hexanoic Acid [(S)-11]: The general procedure described
LiOH·H2O (2 equiv., 1.14 mmol) in a mixture of THF/H2O (1:1 above was followed with (1R,2R,1ЈS)-9 (1.1 g, 2.1 mmol) and the
v/v, 8.0 mL) was added H2O2 (30% aqueous solution, 4 equiv.) at
0 °C, and the resulting mixture was stirred at 0 °C for 3 min. In a
second flask, a stirred solution of 8 (1 equiv., 0.7 mmol) in THF
(8.0 mL) was cooled to 0 °C before the quick addition by using a
cannula of the solution of H2O2. The reaction mixture was stirred
at 0 °C for 30 min before the addition of Na2SO3 (4 equiv.) in H2O.
The mixture was stirred a 0 °C for an additional 30 min, treated
with H2O, and extracted with EtOAc. The aqueous phase was
acidified to pH 2 with 1 m HCl at 0 °C to give a white solid precipi-
tate, which was extracted with EtOAc. The organic phase was sepa-
rated, washed with saturated solution of sodium and potassium
tartrate, dried with anhydrous Na2SO4, filtered, and concentrated
under vacuum.
crude product was purified by flash chromatography (hexane/
EtOAc, 80:20 to 60:40) to give the desired product (526 mg, 63%);
[α]2D5 = +4.0 (c = 1.5, CHCl3). The spectroscopic data are similar
to those recorded for enantiomeric (R)-11.
General Procedure for Preparation of β2-Amino Acids (R)-12 and
(S)-12: The product 10 (116 mg, 0.37 mmol) was dissolved in
MeOH (reagent grade, 15 mL) and stirred with 10% Pd/C under
an H2 atmosphere (1 atm) at room temp. for 16 h. A precipitate
corresponding to the β-amino acid, which is insoluble in methanol,
was observed. The reaction mixture was treated with MeOH/
NH4OH (8:2, 20 mL) and stirred for 20 min. The mixture was fil-
tered through Celite, washed with MeOH/NH4OH (8:2), and the
filtrate was concentrated under vacuum.
(R)-2-Benzyl-3-(benzyloxycarbonylamino)propanoic Acid [(R)-10]:
The general procedure described above was followed with
(1S,2S,1ЈR)-8 (300 mg, 0.7 mmol) and the crude product was puri-
fied by flash chromatography (CH2Cl2/MeOH, 9:1) to give the de-
sired product (130 mg, 64%) as a foam; [α]2D5 = +2.3 (c = 1, CHCl3).
1H NMR (500 MHz, [D6]DMSO, 100 °C): δ = 7.35–7.1 (m, 10 H),
6.90 (br., 2 H), 5.01 (s, 2 H), 3.30–3.21 (m, 1 H), 3.20–3.11 (m, 1
H), 2.83–2.73 (m, 3 H) ppm. 13C NMR (125.76 MHz, [D6]DMSO,
100 °C): δ = 174.9, 156.6, 139.8, 137.8, 129.2 (2 C), 128.8 (2 C),
128.7 (2 C), 128.1, 128.0 (2 C), 126.6, 66.0, 47.5, 42.9, 35.8 ppm.
(R)-3-Amino-2-benzylpropanoic Acid [(R)-12]: The general pro-
cedure described above was followed with (R)-10 (116 mg,
0.37 mmol) and the crude product was purified by flash chromatog-
raphy (iPrOH/MeOH/NH4OH, 3:2:1) to give the desired product
(60 mg, 89%); m.p. 228–230 °C; [α]2D5 = +15.7 (c = 1.01, 1M HCl).
1H NMR (500 MHz, D2O): δ = 7.14–7.09 (m, 2 H), 7.07–7.00 (m,
3 H), 3.00–2.93 (m, 1 H), 2.90–2.84 (m, 2 H), 2.82–2.69 (m, 2
H) ppm. 13C NMR (125.76 MHz, D2O): δ = 176.0, 137.2, 129.0 (2
C), 128.8 (2 C), 127.2, 44.3, 39.6, 35.3 ppm. HRMS (ESI-TOF):
calcd. for C10H13NO2 + H+ 180.1019; found 180.1020. Enantio-
meric ratio 98:2 [determined by HPLC (Chirobiotic T; MeOH/
H2O, 80:20; 210 nm; 0.6 mL/min): tR = 11.99 (major R enantio-
mer), 16.21 (minor S enantiomer) min].
IR: ν = 3324, 3030, 2359, 1703, 1520, 1454, 1252, 1141, 734,
˜
696 cm–1. HRMS (ESI-TOF): calcd. for C18H19NO4 + H+
314.1383; found 314.1386.
(S)-2-Benzyl-3-(benzyloxycarbonylamino)propanoic Acid [(S)-10]:
The general procedure described above was followed with
(1R,2R,1ЈS)-8 (300 mg, 0.7 mmol) and the crude product was puri-
fied by flash chromatography (CH2Cl2/MeOH, 9:1) to give the de-
sired product (156 mg, 68%) as a foam; [α]2D5 = –2.5 (c = 1, CHCl3).
The spectroscopic data are similar to those recorded for enantio-
meric (R)-10.
(S)-3-Amino-2-benzylpropanoic Acid [(S)-12]: The general pro-
cedure described above was followed with (S)-10 (130 mg,
0.42 mmol) and the crude product was purified by flash column
chromatography (iPrOH/MeOH/NH4OH, 3:2:1) to give the desired
product (67 mg, 90%); m.p. 227–229 °C; [α]2D5 = –16.5 (c = 1, 1M
HCl) [ref.[26] [α]2D5 = –16.0 (c = 1, 1M HCl)]. The spectroscopic data
are similar those recorded for enantiomeric (R)-12. HRMS (ESI-
TOF): calcd. for C10H13NO2 + H+ 180.1019; found 180.1019. En-
antiomeric ratio 98:2 [determined by HPLC (Chirobiotic T;
MeOH/H2O, 80:20; 210 nm; 0.6 mL/min): tR = 12.51 (minor R
enantiomer), 15.00 (major S enantiomer) min.
General Procedure for Preparation of Fmoc-β2-amino Acids 14: The
corresponding substrate 11 (1 equiv.) was dissolved in EtOH and
stirred with 10% Pd/C under an H2 atmosphere (1 atm) at room
temp. for 15 h. The catalyst Pd/C was filtered off, washed with
EtOH, and the filtrate was concentrated under vacuum. The hydro-
genation process was repeated under the same conditions for an
additional 24 h. The slightly yellow foam (corresponding to β2-
amino acid 13) was dissolved in a THF/H2O (1:1 v/v) mixture and
cooled to 0 °C, then FmocOSuc (1 equiv.) in THF/H2O (1:1 v/v)
and NaHCO3 (10 equiv.) in THF/H2O (1:1 v/v) were added. The
reaction mixture was stirred for 3 h at room temp., then the solvent
was removed under vacuum. The aqueous phase was washed with
diethyl ether, cooled to 0 °C, and acidified (pH 2) with solid
KHSO4 before extraction with CH2Cl2 and EtOAc. The organic
phases were combined and dried under anhydrous Na2SO4, filtered,
General Procedure for the Preparation of Derivatives 11: To a solu-
tion of 9 (1 equiv.) in a mixture of THF/H2O (3:1, v/v) at 0 °C and
under vigorous stirring, was added dropwise a cold (0 °C) solution
of 30% H2O2 (10 equiv.), followed by solid LiOH·H2O (2.3 equiv.).
The mixture was stirred for 3 h at 0 °C, warmed to room tempera-
ture, and stirred for an additional 1 h. After completion of the reac-
tion, the solution was cooled to 0 °C and basified to pH 10 with
1.5 m Na2SO3. Solvents were removed under reduced pressure and
the resulting mixture was diluted in H2O and extracted with EtOAc
to recover the chiral auxiliary. The aqueous layer was cooled to
0 °C and carefully acidified (pH 2) with solid KHSO4. The re-
sulting solution was extracted with EtOAc, dried with anhydrous
Na2SO4, filtered, and concentrated under vacuum.
(R)-2-[(Benzyloxycarbonylamino)methyl]-6-(tert-butoxycarbonyl-
amino)hexanoic Acid [(R)-11]: The general procedure described
above was followed with (1S,2S,1ЈR)-9 (1.5 g, 2.9 mmol) and the
crude product was purified by flash chromatography (hexane/
EtOAc, 80:20 to 60:40) to give the desired product (526 mg, 57%);
[α]2D5 = –4.0 (c = 1.5, CHCl3). 1H NMR (270 MHz, CDCl3): δ =
7.33–7.27 (m, 5 H), 5.36 (br., 1 H), 5.09 (m, 2 H), 4.52–4.68 (m, 1 and the solvents evaporated under vacuum.
Eur. J. Org. Chem. 2014, 2275–2283
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2281

E. Juaristi et al.
FULL PAPER
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(R)-2-({[(9H-Fluoren-9-yl)methoxy]carbonylamino}methyl)-6-(tert-
butoxycarbonylamino)hexanoic Acid [(R)-14]: The general pro-
cedure described above was followed with (R)-11 (242 mg,
0.61 mmol) and crude product was purified by flash chromatog-
raphy (CH2Cl2/MeOH, 98:2 to 90:10) to give the desired product
(236 mg, 80%, two steps); [α]2D5 = –4.3 (c = 0.58, CHCl3) [ref.[25]
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1
[α]2D5 = –4.6 (c = 0.54, CHCl3)]. H NMR (500 MHz, CDCl3): δ =
7.76–7.73 (m, 2 H), 7.55–7.57 (m, 2 H), 7.41–7.36 (m, 2 H), 7.32–
7.27 (m, 2 H), 5.41–5.32 (m, 1 H), 4.66 (br., 1 H), 4.51 (m, 1 H),
4.37–4.35 (m, 1 H), 4.23–4.18 (m, 1 H), 3.46–3.35 (m, 1 H), 3.10
(br., 3 H), 2.64 (br., 1 H), 2.35 (br., 1 H), 1.70–1.24 (m, 6 H), 1.42
(s, 9 H) ppm. 13C NMR (125.76 MHz, CDCl3): δ = 178.9, 158.0,
156.6, 143.9 (2 C), 141.3 (2 C), 127.7 (2 C), 127.1 (2 C), 125.1 (2
C), 120.0 (2 C), 79.4, 66.9, 47.2, 45.3, 41.6, 40.0, 29.9, 28.5 (3 C),
[5]
[6]
[7]
[8]
25.4, 24.0 ppm. IR: ν = 3365, 2934, 2359, 1698, 1519, 1449, 1365,
˜
1248, 1164, 993 cm–1. HRMS (ESI-TOF): calcd. for C27H34N2O6
+ H+ 483.2489; found 483.2490.
(S)-2-({[(9H-Fluoren-9-yl)methoxy]carbonylamino}methyl)-6-(tert-
butoxycarbonylamino)hexanoic Acid [(S)-14]: The general procedure
described above was followed with (S)-11 (121 mg, 0.31 mmol) and
the crude product was purified by flash chromatography (CH2Cl2/
MeOH, 98:2 to 90:10) to give the desired product (125 mg, 84%,
two steps); [α]2D5 = +4.4 (c = 0.57, CHCl3) [ref.[24] [α]rDt = +4.8 (c =
0.54, CHCl3)]. The spectroscopic data are similar to those recorded
for enantiomeric (R)-14.
[9]
[10]
Supporting Information (see footnote on the first page of this arti-
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8, 10, and 12; chromatographic data for compounds (R)-12, (S)-12,
and rac-12; NMR spectroscopic data for enantiomeric compounds
3, 5, 7, 9, 11, 13, and 14.
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Acknowledgments
The authors are grateful to the Mexican Consejo Nacional de Cien-
cia y Tecnología (CONACyT)) for financial support through grants
130826 and 153606. Y. B. is also indebted to the Dirección General
de Asuntos del Personal Académico and to the Instituto de Biotec-
nología (UNAM) for a postdoctoral fellowship.
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Received: December 9, 2013
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