Asymmetric synthesis of quaternary α-amino acids using D-ribonolactone acetonide as chiral auxiliary

Article abstract of DOI:10.1016/S0957-4166(99)00457-7

We describe a new simple methodology to prepare enantiopure α,α- dialkylglycines based on the use of commercially available D-ribonolactone as a chiral auxiliary. Enantiopure α-methyl and α-butyl series are prepared through diastereoselective alkylation and subsequent Schmidt rearrangement of α,α-dialkylacetoacetates of D-ribonolactone acetonide. Absolute configuration was assigned through preparation of enantiopure 4,4- disubstituted 3-methyl-2-pyrazolin-5-ones.

Full text of DOI:10.1016/S0957-4166(99)00457-7

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4211–4224
Asymmetric synthesis of quaternary α-amino acids using
D-ribonolactone acetonide as chiral auxiliary
Marcial Moreno-Mañas, Elisenda Trepat, Rosa M. Sebastián and Adelina Vallribera ∗
Department of Chemistry, Universitat Autònoma de Barcelona, Cerdanyola, 08193 Barcelona, Spain
Received 24 September 1999; accepted 18 October 1999
Abstract
We describe a new simple methodology to prepare enantiopure α,α-dialkylglycines based on the use of
commercially available D-ribonolactoneas a chiral auxiliary. Enantiopure α-methyl and α-butyl series are prepared
through diastereoselective alkylation and subsequent Schmidt rearrangement of α,α-dialkylacetoacetates of D-
ribonolactone acetonide. Absolute configuration was assigned through preparation of enantiopure 4,4-disubstituted
3-methyl-2-pyrazolin-5-ones. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The high interest in the preparation of enantiomerically pure α,α-disubstituted glycines is based
on their remarkable properties as enzyme inhibitors1 and as conformational modifiers of peptides.2 In
particular the α-methyl series have been extensively studied.3
Due to the current interest in these compounds many synthetic methodologies have already been
developed.4 One synthetic approach is the use of cyclic derivatives such as Schöllkopf’s bis(lactim)ether,
prepared generally from L-tert-leucine and including two amino ester separations in the process of
isolation of desired products. Others cyclic substrates are Seebach’s oxazolidinones, imidazolidin-
ones and 2,5-dihydroimidazoles,5 their synthesis including classical resolution through diastereoiso-
meric salt formation or chromatographic separation on a chiral column. Nájera’s oxazinones and
tetrahydropyrazinones6 have also been used with real success. Also remarkable are the results of Davies,
who has used oxazolidinones derived from ferrocenecarbaldehyde and sodium (S)-alaninate,7 and the
work of Sandri using chiral morpholine derivatives.8 An alternative involves the palladium-catalyzed
asymmetric allylation of azlactones.9
A different approach is based on the diastereoselective alkylation of activated methylene groups in
open chain compounds (Fig. 1). Remarkable diastereoselective alkylations have been achieved for 2-
cyanoesters of enantiopure dicyclohexylsulfamoylisoborneol by Cativiela and co-workers10 (1, Z=CN).
∗
Corresponding author. E-mail: adelina.vallribera@blues.uab.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00457-7

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After the appropriate rearrangement process the diastereomerically pure α,α-dialkylcyanoacetate can be
elaborated to afford both enantiomers of the same amino acid. An alternative consists of the incorporation
of the chiral auxiliary in the form of an enamine 2. Koga has reported11 the alkylation of lithioenamines
derived from α-alkyl-β-ketoesters and (S)-valine tert-butyl ester. The α,α-dialkyl-β-ketoesters obtained
had been used by Georg et al. as intermediates to prepare α,α-disubstituted glycines.12 Fukumoto
et al. have worked on chiral derivatives of malonic acid. Precursors of amino acids are prepared
through diastereoselective alkylation of 8-phenylmenthyl α-alkylmalonic monoesters (1, Z=COOH)
followed by several transformations including a Curtius rearrangement.13 Herein we describe the use
of D-ribonolactone acetonide as a chiral auxiliary in the rearrangement of β-ketoacid derivatives, an
established strategy for the synthesis of quaternary α-amino acids.
Figure 1.
We have previously reported the preparation of enantiopure diphenylmethyl-, 9-fluorenyl- and
(1-adamantyl)glycines through cobalt mediated alkylation of (4R)- and (4S)-3-acetoacetyl-4-
benzyloxazolidin-2-ones (1, Z=acetyl, R1=H).14 Several dialkylation attempts on the same substrate
failed. However, alkylation of (−)-8-phenylmenthyl 2-methylacetoacetate affords 8-phenylmenthyl
2-alkyl-2-methylacetoacetates in a maximal diastereomeric ratio of 85:15.15 Subsequent elaboration to
amino acids failed, probably due to steric hindrance. These previous results led us to consider other
alcohols as chiral auxiliaries. We chose D-ribonolactone16 for two main reasons: (a) it is a commercially
available sugar derivative; and (b) being a primary alcohol, its ester might be easily manipulated (this
has failed in the case of (−)-8-phenylmenthol).
2. Results and discussion
2,3-O-Isopropylidene-17 and 2,3-O-cyclohexylidene-γ-D-ribonolactone18 had been prepared by re-
actions described previously in the literature. These protected lactones react with 2,2,6-trimethyl-1,3-
dioxen-4-one 5 in refluxing toluene (74–82% yield), followed by addition of potassium carbonate and
methyl iodide in acetone at 40°C to afford the corresponding 2-methyl acetoacetates 6 and 7 (Scheme 1).
We first studied the dialkylation process through generation of enolate with NaH at −78°C and subsequent
addition of benzyl bromide, and we obtained a similar d.r. for the two chiral auxiliaries. In the case of
cyclohexylidene protection we were unable to isolate the major diastereoisomer in pure form. Therefore,
we chose 2,3-O-isopropylidene-γ-D-ribonolactone as the chiral auxiliary.
Some attempts have been made to optimize the process: (a) other bases such as LDA, phosphazene
P4-t-Bu in n-hexane (C22H63N13P4) and sodium bis(trimethylsilyl)amide gave similar or worse d.r.s; and
(b) addition of N,N0-dimethylpropyleneurea (DMPU) or change of THF to DMPU, when using NaH, did
not give better results.
Alkylation of 6 with a series of alkyl halides furnished compounds 8a–d and 9a–d in reasonable
diastereomeric excesses (Table 1). The major diastereoisomers were isolated in pure form in all cases
except for R2=PhCH_CHCH2.
We were also interested in disubstituted glycines with one group different from methyl. Compound 12
was easily prepared from 2,3-O-isopropylidene-γ-D-ribonolactone acetoacetate with NaH in refluxing

M. Moreno-Mañas et al. / Tetrahedron: Asymmetry 10 (1999) 4211–4224
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Scheme 1.
Table 1
Results of diastereoselective dialkylation of 6 and 12 with a series of alkyl halides
THF and n-butyl iodide in 71% yield. Even with the bulkier n-butyl substituent high yields are obtained
in the dialkylation process (Table 1).
Table 2 summarizes the results for transesterification of pure diastereoisomers 8a,b,d–f. By using
an excess of titanium(IV) tetraethoxide in refluxing ethanol the corresponding enantiopure ethyl α,α-
dialkyl acetoacetates are obtained in excellent yields when R1=CH3. Experiments with sodium ethoxide
gave worse results. For a butyl substituent as in compounds 8e,f, less efficient reactivity was found, as
expected.

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Table 2
Results of transesterification reaction
Schmidt rearrangement of 13 with sodium azide and methanesulfonic acid in dimethoxyethane
afforded acetamides 14 (Table 3). We have previously recommended the use of DME as an alternative
to the unsafe chlorinated solvents normally used in Schmidt rearrangement.20 Acetamides 14 were
hydrolyzed in refluxing 6 M HCl to give the amino acid hydrochlorides 15 in excellent yields (Table 3).
Table 3
Schmidt reaction of α,α-disubstituted acetoacetates 13 and posterior hydrolysis of acetamides 14
We have previously described a method for the preparation of enantiomerically pure (4R)-4-alkyl-
3,4-dimethyl-2-pyrazolin-5-ones 17 from (−)-8-phenylmenthyl (2R)-2-alkyl-2-methylacetoacetates 16
(Table 4).21 X-Ray diffraction studies on 16a and 16b showed R configuration at C-α. Accordingly, the
new stereogenic center of 17a and 17g was also R. Compounds 8a,b,d–f were converted into 17a,b,d–f
in excellent yields. Compound 17a obtained from 8a has the same [α]D as the one obtained from 16a.
The configuration of 17b,d–f was assigned by comparison of the circular dichroism with those of 17a
and 17g. All of them presented a strong negative Cotton effect. Therefore, the major diastereoisomers
obtained in the dialkylation process using D-ribonolactone acetonide as chiral auxiliary have R absolute

M. Moreno-Mañas et al. / Tetrahedron: Asymmetry 10 (1999) 4211–4224
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configuration at C-α, and consequently enantiopure hydrochlorides of (S)-α-alkylalanines, 15a,b,d, and
(S)-α-alkyl-α-butylglycines, 15e,f, had been prepared.
Table 4
Preparation of enantiomerically pure 4,4-disubstituted 2-pyrazolin-5-ones 17
In conclusion, we have developed a new simple method for the synthesis of enantiopure (S)-α,α-
disubstituted glycines using D-ribonolactone acetonide as a chiral auxiliary. The advantages of this
approach are: (a) the facility to obtain the chiral auxiliary (only protection of available material is needed);
(b) the fact that only one diastereomeric separation is needed (classical column chromatography); and (c)
the method allows the introduction of substituents bulkier than methyl.
3. Experimental
Melting points were determined with a Kofler Reichert apparatus and are uncorrected. Infrared spectra
were obtained on a Nicolet FT-IR 510 ZDX spectrophotometer. Proton and carbon magnetic resonance
spectra were recorded on a Bruker AC250 spectrometer using tetramethylsilane as internal standard.
Mass spectra were determined under electron impact at 70 eV. High resolution mass spectra were
registered in the Servicio de Espectrometría de Masas de la Universidad de Córdoba. Optical rotations
were recorded on a Propol polarimeter and circular dichroism on a Jasco J-715 apparatus.
3.1. 2,3-O-Isopropylidene-γ-D-ribonolactone 2-methylacetoacetate 6
A solution of 3 (5.00 g, 26.5 mmol) and 2,2,6-trimethyl-1,3-dioxen-4-one 5 (4.15 g, 29.2 mmol) in
toluene (50 mL) was heated under reflux for 24 h. The solvent was evaporated and diethyl ether was
added to the residue. The insoluble white solid was filtered off yielding 2,3-O-isopropylidene-γ-D-
ribonolactone acetoacetate (5.92 g, 82%); mp 62–63°C; [α]D=−42 (c=1.04, acetone); IR (KBr, cm−1)
1
2993, 2938, 1791, 1724; H NMR (250 MHz, CDCl3) δ 1.38 (s, 3H), 1.46 (s, 3H), 2.24 (s, 3H), 3.49
(s, 2H), 4.38 (dq, J=12.5 and J=2.9 Hz, 2H), 4.73–4.76 (m, 3H). Enol form: 1.98 (s), 4.97 (s), 11.72 (s);
13C NMR (62.5 MHz, CDCl3) δ 25.4, 25.5, 30.3, 49.6, 64.0, 75.0, 77.6, 79.6, 113.7, 166.0, 173.5, 200.0.
Anal. calcd for C12H16O7: C, 52.94; H, 5.92. Found: C, 53.18; H, 5.95.

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M. Moreno-Mañas et al. / Tetrahedron: Asymmetry 10 (1999) 4211–4224
Methyl iodide was added (3.39 g, 23.9 mmol) to a magnetically stirred mixture of 2,3-O-
isopropylidene-γ-D-ribonolactone acetoacetate (5.00 g, 18.4 mmol) and potassium carbonate (2.78 g,
20.2 mmol) in anhydrous acetone (50 mL). The mixture was heated at 40°C for 7 h, then it was filtered
and the solvent from the filtrate was evaporated. The oil residue was chromatographed on silica gel
under pressure, eluting with mixtures of increasing polarity of hexanes–ethyl acetate. Compound 6
(diastereomeric mixture) was obtained as a white solid (3.74 g, 71%); IR (KBr, cm−1) 2994, 2952, 1783,
1
1755, 1715, 1244, 1075; H NMR (250 MHz, CDCl3) δ 1.36 (d, J=7.3 Hz, 3H+3H), 1.40 (s, 3H+3H),
1.48 (s, 3H+3H), 2.23 (s, 3H), 2.25 (s, 3H), 3.54 (q, J=7.1 Hz, 1H), 3.55 (q, J=7.1 Hz, 1H), 4.30–4.48
(m, 2H+2H), 4.70–4.79 (m, 3H+3H); 13C NMR (62.5 MHz, CDCl3) δ 12.8, 12.9, 25.4, 26.6, 28.2, 28.4,
53.2, 64.0, 64.1, 75.0, 77.5, 79.4, 79.7, 113.8, 169.2, 169.4, 173.2, 173.3, 203.0, 203.7. Anal. calcd for
C13H18O7: C, 54.54; H, 6.34. Found: C, 54.55; H, 6.54.
3.2. 2,3-O-Cyclohexylidene-γ-D-ribonolactone 2-methylacetoacetate 7
Prepared as described for compound 6.
2,3-O-Cyclohexylidene-γ-D-ribonolactone acetoacetate was obtained in 74% yield as a white solid,
mp 82–83°C; [α]D=−53 (c=0.99, CHCl3); IR (KBr, cm−1) 2945, 2861, 1785, 1757, 1722, 1173, 1117;
1H NMR (250 MHz, CDCl3) δ 1.40–1.67 (m, 10H), 2.26 (s, 3H), 3.51 (s, 3H), 4.41 (dq, J=12.1 and
J=2.6 Hz, 2H), 4.73–4.76 (m, 3H). Enol form: 1.98 (s), 4.95 (s), 11.72 (s); 13C NMR (62.5 MHz, CDCl3)
δ 23.6, 23.7, 24.6, 30.3, 34.8, 36.2, 49.5, 64.0, 74.7, 77.1, 79.7, 114.5, 165.9, 173.6, 199.9. Enol form:
21.2, 62.6, 88.6, 177.5. Anal. calcd for C15H20O7: C, 57.69; H, 6.45. Found: C, 57.76; H, 6.52.
2,3-O-Cyclohexylidene-γ-D-ribonolactone 2-methylacetoacetate 7 was obtained as a diastereomeric
1
mixture in 69% yield as a white solid; IR (KBr, cm−1) 2938, 2854, 1785, 1750, 1715, 1166, 1117; H
NMR (250 MHz, CDCl3) δ 1.36 (d, J=7.3 Hz, 3H), 1.39 (d, J=6.6 Hz, 3H), 1.60–1.66 (m, 10H), 2.22 (s,
3H), 2.24 (s, 3H), 3.50 (q, J=7.3 Hz, 1H), 3.53 (q, J=7.3 Hz, 1H), 4.28–4.47 (m, 2H), 4.68–4.79 (m, 3H);
13C NMR (62.5 MHz, CDCl3) δ 12.8, 12.9, 23.6, 23.7, 24.7, 28.3, 28.4, 34.8, 34.9, 36.2, 53.2, 53.6, 64.0,
64.1, 74.7, 77.1, 79.6, 79.8, 114.6, 169.2, 169.4, 173.4, 173.5, 202.9, 203.7. Anal. calcd for C16H22O7:
C, 58.89; H, 6.79. Found: C, 58.68; H, 6.62.
3.3. 2,3-O-Isopropylidene-γ-D-ribonolactone 2-butylacetoacetate 12
2,3-O-Isopropylidene-γ-D-ribonolactone acetoacetate (5.00 g, 18.4 mmol) in anhydrous THF (12 mL)
was added to magnetically stirred NaH (60% suspension in mineral oil, 0.81 g, 20.2 mmol) in anhydrous
THF (10 mL) at room temperature and under nitrogen atmosphere. The reaction mixture was stirred
for 15 min, then a solution of butyl iodide (8.3 mL, 73.5 mmol) in anhydrous THF (10 mL) was
added. The mixture was heated under reflux for 24 h. THF was evaporated, and the residue partitioned
between CH2Cl2 and H2O. The aqueous layer was washed with CH2Cl2 (3×20 mL). The combined
dichloromethane extracts were dried with anhydrous sodium sulfate and the solvent was evaporated to
give a crude, which was chromatographed on silica gel under pressure, eluting with hexanes–diethyl
ether mixtures of increasing polarity to afford 4.32 g (71%) of a diastereomeric mixture of 12 as an oil;
1
IR (film, cm−1) 2959, 2938, 2868, 1792, 1750, 1715, 1152, 1082; H NMR (250 MHz, CDCl3) δ 0.90
(m, 3H+3H), 1.21–1.38 (m, 4H+4H), 1.40 (s, 3H+3H), 1.48 (s, 3H+3H), 1.77–1.89 (m, 2H+2H), 2.21 (s,
3H), 2.24 (s, 3H), 3.44 (t, J=7.3 Hz, 1H), 3.46 (t, J=7.3 Hz, 1H), 4.29–4.46 (m, 2H+2H), 4.68–4.82 (m,
3H+3H); 13C NMR (62.5 MHz, CDCl3) δ 13.6, 22.2, 22.3, 25.4, 26.6, 27.9, 28.0, 28.8, 28.9, 29.5, 59.4,
59.8, 63.9, 64.0, 75.0, 77.6, 79.4, 79.6, 113.8, 168.7, 168.8, 173.2, 173.3, 202.6, 203.2.

M. Moreno-Mañas et al. / Tetrahedron: Asymmetry 10 (1999) 4211–4224
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3.4. 2,3-O-Isopropylidene-γ-D-ribonolactone (2R)-2-benzyl-2-methylacetoacetate 8a+9a. General pro-
cedure for diastereoselective alkylation of compounds 6, 7, and 12
Compound 6 (4.65 g, 16.2 mmol) in anhydrous THF (12 mL) was added to magnetically stirred NaH
(60% suspension in mineral oil, 0.84 g (21.1 mmol)) in anhydrous THF (10 mL) at room temperature
and under nitrogen atmosphere. The reaction mixture was stirred for 15 min, cooled down to −78°C
and then a solution of benzyl bromide (4.17 g, 24.2 mmol) in anhydrous THF (10 mL) was added. The
reaction was allowed to warm to room temperature and was stirred for 12 h. THF was evaporated, and the
residue partitioned between CH2Cl2 and H2O. The aqueous layer was washed with CH2Cl2 (3×20 mL).
The combined dichloromethane extracts were dried with anhydrous sodium sulfate and the solvent was
evaporated to give a crude which was a mixture of 8a and 9a in a ratio ca. 75:25 determined by integration
1
of the H NMR signal of the CH3CO protons at δ 2.10 and 2.19. The crude was chromatographed on
silica gel under pressure, eluting with hexanes–diethyl ether mixtures of increasing polarity to afford 2.81
g (46%) of 8a and 1.04 g (17%) of 9a. Compound 8a: white solid; mp 101–103°C; [α]D=16 (c=1.09,
1
CHCl3); IR (KBr, cm−1) 1785, 1729, 1715; H NMR (250 MHz, CDCl3) δ 1.23 (s, 3H), 1.29 (s, 3H),
1.37 (s, 3H), 2.11 (s, 3H), 2.90 (d, J=13.1 Hz, 1H), 3.17 (d, J=13.1 Hz, 1H), 4.20–4.36 (m, 4H), 4.70 (t,
J=2.2 Hz, 1H), 7.06–7.27 (m, 5H); 13C NMR (62.5 MHz, CDCl3) δ 19.9, 25.5, 26.6, 26.7, 41.0, 61.1,
64.2, 74.9, 77.5, 79.1, 113.6, 127.0, 128.3 (2C), 130.1 (2C), 136.2, 171.3, 173.1, 204.9. Anal. calcd
for C20H24O7: C, 63.82; H, 6.43. Found: C, 63.70; H, 6.48. Compound 9a: white solid; mp 67–68°C;
1
[α]D=−39 (c=1.03, CHCl3); IR (KBr, cm−1) 1792, 1750, 1715; H NMR (250 MHz, CDCl3) δ 1.37 (s,
3H), 1.38 (s, 3H), 1.44 (s, 3H), 2.10 (s, 3H), 2.94 (d, J=13.1 Hz, 1H), 3.31 (d, J=13.1 Hz, 1H), 4.07 (dd,
J=12.4 and 2.7 Hz, 1H), 4.16 (d, J=5.8 Hz, 1H), 4.36 (dd, J=12.4 and 2.7 Hz, 1H), 4.44 (d, J=5.8 Hz,
1H), 4.67 (t, J=2.7 Hz, 1H), 7.12–7.22 (m, 5H); 13C NMR (62.5 MHz, CDCl3) δ 18.5, 25.4, 26.3, 26.5,
40.8, 61.0, 64.2, 74.9, 77.5, 79.2, 113.7, 127.1, 128.4 (2C), 130.0 (2C), 135.8, 171.3, 173.1, 204.7. Anal.
calcd for C20H24O7: C, 63.82; H, 6.43. Found: C, 63.86; H, 6.55.
3.5. 2,3-O-Isopropylidene-γ-D-ribonolactone (2R)-2-(4-bromobenzyl)-2-methylacetoacetate 8b
Prepared as for 8a as a white solid (38% yield), mp 94–95°C (hexanes–diethyl ether); [α]D=−13
1
(c=1.06, CHCl3); IR (KBr, cm−1) 2987, 2938, 1778, 1757, 1708, 1173, 1103; H NMR (250 MHz,
CDCl3) δ 1.30 (s, 3H), 1.39 (s, 3H), 1.47 (s, 3H), 2.18 (s, 3H), 2.95 (d, J=13.9 Hz, 1H), 3.18 (d, J=13.9
Hz, 1H), 4.20–4.52 (m, 4H), 4.74 (t, J=2.2 Hz, 1H), 6.96 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H); 13
C
NMR (62.5 MHz, CDCl3) δ 18.6, 25.5, 26.4, 26.6, 40.1, 60.9, 64.4, 75.0, 77.5, 79.3, 114.0, 121.3, 131.6
(2C), 131.8 (2C), 134.8, 171.1, 173.0, 204.4. Anal. calcd for C20H23O7Br: C, 52.76; H, 5.09. Found: C,
52.69; H, 5.09.
3.6. 2,3-O-Isopropylidene-γ-D-ribonolactone (2S)-2-(4-bromobenzyl)-2-methylacetoacetate 9b
Prepared as for 8a as a white solid (16% yield), mp 95–96°C (hexanes–diethyl ether); [α]D=−43
1
(c=0.98, CHCl3); IR (KBr, cm−1) 2987, 2938, 1792, 1750, 1715, 1173, 1082; H NMR (250 MHz,
CDCl3) δ 1.37 (s, 3H), 1.40 (s, 3H), 1.45 (s, 3H), 2.11 (s, 3H), 2.91 (d, J=13.9 Hz, 1H), 3.25 (d, J=13.9
Hz, 1H), 4.09 (dd, J=12.4 and 2.4 Hz, 1H), 4.22 (d, J=5.4 Hz, 1H), 4.37 (dd, J=12.4 and 2.4 Hz, 1H),
4.48 (d, J=5.4 Hz, 1H), 4.69 (t, J=2.4 Hz, 1H), 7.03 (d, J=6.5 Hz, 2H), 7.40 (d, J=6.5 Hz, 2H); 13C NMR
(62.5 MHz, CDCl3) δ 19.8, 25.5, 26.6, 29.6, 40.3, 60.8, 64.3, 74.8, 77.3, 79.1, 113.8, 121.1, 128.5, 131.4
(2C), 131.9 (2C), 135.1, 171.1, 173.1, 204.7. Anal. calcd for C20H23O7Br: C, 52.76; H, 5.09. Found: C,
52.89; H, 5.13.

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3.7. 2,3-O-Isopropylidene-γ-D-ribonolactone 2-cinnamyl-2-methylacetoacetate 8c+9c
Prepared as for 8a as a mixture of diastereoisomers (71% yield); IR (KBr, cm−1) 2987, 2945, 1792,
1
1750, 1715, 1216, 1173, 1082; H NMR (250 MHz, CDCl3) δ 1.34 (s, 3H), 1.35 (s, 3H), 1.41 (s,
3H+3H), 1.46 (s, 3H), 1.47 (s, 3H), 2.16 (s, 3H), 2.18 (s, 3H), 2.59–2.80 (m, 2H+2H), 4.20–4.46 (m,
2H+2H), 4.57–4.77 (m, 3H+3H), 5.92–6.12 (m, 1H+1H), 6.44 (d, J=15.3 Hz, 1H), 6.46 (d, J=15.3 Hz,
1H), 7.21–7.34 (m, 5H+5H); 13C NMR (62.5 MHz, CDCl3) δ 18.9, 19.4, 25.4, 26.1, 26.3, 26.6, 38.5,
39.0, 60.2, 64.3, 64.4, 75.0, 77.5, 79.4, 79.5, 113.8, 122.8, 123.6, 126.2, 127.6, 128.5, 134.3, 134.8, 136.6,
171.4, 173.2, 204.7, 204.9. Anal. calcd for C22H26O7: C, 65.66; H, 6.51. Found: C, 65.70; H, 6.51.
3.8. 2,3-O-Isopropylidene-γ-D-ribonolactone (2R)-2-methyl-2-(2-naphthylmethyl)acetoacetate 8d
Prepared as for 8a as a white solid (47% yield), mp 108–109°C (hexanes–diethyl ether); [α]D=6
1
(c=1.01, CHCl3); IR (KBr, cm−1) 2996, 2965, 1788, 1735, 1216, 1083; H NMR (250 MHz, CDCl3)
δ 1.12 (s, 3H), 1.36 (s, 3H), 1.39 (s, 3H), 2.21 (s, 3H), 3.14 (d, J=13.5 Hz, 1H), 3.41 (d, J=13.5 Hz,
1H), 4.00–4.33 (m, 4H), 4.66 (t, J=2.2 Hz, 1H), 7.17–7.21 (m, 1H), 7.42–7.54 (m, 3H), 7.76–7.82 (m,
3H); 13C NMR (62.5 MHz, CDCl3) δ 18.7, 25.2, 26.4, 26.6, 41.0, 61.3, 64.4, 74.9, 75.0, 79.2, 113.7,
126.0, 126.4, 127.5, 127.6, 128.0, 128.1, 128.8, 132.3, 133.3, 133.4, 171.4, 173.1, 204.7. Anal. calcd for
C24H26O7: C, 67.59; H, 6.15. Found: C, 67.45; H, 6.22.
3.9. 2,3-O-Isopropylidene-γ-D-ribonolactone (2S)-2-methyl-2-(2-naphthylmethyl)acetoacetate 9d
Prepared as for 8a as a white solid (12% yield), mp 105–107°C (hexanes–diethyl ether); [α]D=−47
1
(c=1.06, CHCl3); IR (KBr, cm−1) 2966, 2938, 1799, 1750, 1715, 1159, 1082; H NMR (250 MHz,
CDCl3) δ 1.19 (s, 3H), 1.39 (s, 3H), 1.45 (s, 3H), 2.12 (s, 3H), 3.11 (d, J=13.9 Hz, 1H), 3.48 (d, J=13.9
Hz, 1H), 3.93 (d, J=5.4 Hz, 1H), 4.05 (dd, J=12.4 and 2.6 Hz, 1H), 4.34 (dd, J=12.4 and 2.6 Hz, 1H), 4.37
(d, J=5.4 Hz, 1H), 4.61 (t, J=2.6 Hz, 1H), 7.24–7.28 (m, 1H), 7.44–7.48 (m, 2H), 7.62 (s, 1H), 7.74–7.82
(m, 3H); 13C NMR (62.5 MHz, CDCl3) δ 20.2, 25.4, 26.6, 26.8, 41.2, 61.3, 64.3, 74.8, 77.3, 79.1, 113.7,
126.0, 126.4, 127.6 (2C), 127.8, 128.2, 129.0, 132.3, 133.3, 133.8, 171.5, 173.1, 205.0. Anal. calcd for
C24H26O7: C, 67.59; H, 6.15. Found: C, 67.55; H, 6.15.
3.10. 2,3-O-Isopropylidene-γ-D-ribonolactone (2R)-2-(4-bromobenzyl)-2-butylacetoacetate 8e
Prepared as for 8a as a white solid (44% yield), mp 64–65°C (pentane–diethyl ether); [α]D=6 (c=1.06,
CHCl3); IR (KBr, cm−1) 2994, 2952, 2875, 1785, 1757, 1715, 1187, 1110; 1H NMR (250 MHz, CDCl3)
δ 0.92 (t, J=7.3 Hz, 3H), 1.02–1.36 (m, 4H), 1.39 (s, 3H), 1.47 (s, 3H), 1.79 (m, 2H), 2.13 (s, 3H), 3.04
(d, J=13.8 Hz, 1H), 3.11 (d, J=13.8 Hz, 1H), 4.18 (dd, J=12.4 and J=2.9 Hz, 1H), 4.26–4.33 (m, 1H),
4.32 (d, J=5.8 Hz, 1H), 4.48 (d, J=5.8 Hz, 1H), 4.73 (t, J=2.9 Hz, 1H), 6.88–6.92 (m, 2H), 7.38–7.43 (m,
2H); 13C NMR (62.5 MHz, CDCl3) δ 13.7, 22.9, 25.5, 26.1, 26.6, 27.1, 30.8, 37.1, 64.4, 64.8, 75.0, 77.5,
79.2, 114.0, 121.3, 131.4 (2C), 131.6 (2C), 135.0, 170.9, 173.0, 204.1. Anal. calcd for C23H29O7Br: C,
55.54; H, 5.88. Found: C, 55.53; H, 6.07.
3.11. 2,3-O-Isopropylidene-γ-D-ribonolactone (2S)-2-(4-bromobenzyl)-2-butylacetoacetate 9e
Prepared as for 8a as a white solid (15% yield), mp 72–74°C (pentane–diethyl ether); [α]D=−29
1
(c=1.12, CHCl3); IR (KBr, cm−1) 2987, 2959, 2924, 2868, 1785, 1764, 1715, 1159, 1075; H NMR
(250 MHz, CDCl3) δ 0.92 (t, J=6.9 Hz, 3H), 0.99–1.12 (m, 2H), 1.17–1.36 (m, 2H), 1.39 (s, 3H), 1.44

M. Moreno-Mañas et al. / Tetrahedron: Asymmetry 10 (1999) 4211–4224
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(s, 3H), 1.86–1.93 (m, 3H), 2.04 (s, 3H), 2.83 (d, J=13.5 Hz, 1H), 3.32 (d, J=13.5 Hz, 1H), 3.93–4.00
(m, 2H), 4.30–4.39 (m, 2H), 4.64 (t, J=2.2 Hz, 1H), 7.02 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H); 13
C
NMR (62.5 MHz, CDCl3) δ 13.8, 22.9, 25.6, 25.8, 26.7, 27.3, 33.2, 37.7, 64.3, 65.1, 74.9, 77.5, 79.0,
113.8, 121.1, 131.5 (2C), 131.8 (2C), 135.7, 171.0, 173.1, 204.5. Anal. calcd for C23H29O7Br: C, 55.54;
H, 5.88. Found: C, 55.59; H, 6.06.
3.12. 2,3-O-Isopropylidene-γ-D-ribonolactone (2R)-2-butyl-2-(2-naphthylmethyl)acetoacetate 8f
Prepared as for 8a as a white solid (47% yield), mp 38–40°C (hexanes–diethyl ether); [α]D=−4
(c=1.01, CHCl3); IR (KBr, cm−1) 2959, 2868, 1792, 1750, 1715, 1180, 1152, 1082; 1H NMR (250 MHz,
CDCl3) δ 0.94 (t, J=7.3 Hz, 3H), 1.11 (s, 3H), 1.38 (s, 3H), 1.11–1.38 (m, 4H), 1.69–1.88 (m, 2H), 2.15
(s, 3H), 3.29 (AB, J=13.9 Hz, 2H), 3.91 (d, J=5.8 Hz, 1H), 4.12 (dd, J=12.4 and J=2.5 Hz, 1H), 4.24 (d,
J=5.8 Hz, 1H), 4.26 (dd, J=12.4 and J=2.5 Hz, 1H), 4.64 (t, J=2.5 Hz, 1H), 7.12–7.16 (m, 1H), 7.41–7.49
(m, 3H), 7.75–7.81 (m, 3H); 13C NMR (62.5 MHz, CDCl3) δ 13.7, 22.9, 25.2, 26.0, 26.5, 27.1, 30.8,
37.8, 64.3, 65.1, 74.8, 77.4, 79.1, 113.7, 126.0, 126.4, 127.5, 127.6, 127.8, 128.0, 128.5, 132.3, 133.3,
133.5, 171.3, 173.0, 204.4. Anal. calcd for C27H32O7: C, 69.21; H, 6.88. Found: C, 69.33; H, 6.72.
3.13. 2,3-O-Isopropylidene-γ-D-ribonolactone (2S)-2-butyl-2-(2-naphthylmethyl)acetoacetate 9f
Prepared as for 8a as a white solid (7% yield), mp 112–114°C (hexanes–diethyl ether); [α]D=36
1
(c=1.15, CHCl3); IR (KBr, cm−1) 2959, 2868, 1792, 1736, 1708, 1237, 1089; H NMR (250 MHz,
CDCl3) δ 0.92 (t, J=7.3 Hz, 3H), 1.13 (s, 3H), 1.35 (s, 3H), 1.11–1.40 (m, 4H), 1.87–1.99 (m, 2H), 2.04
(s, 3H), 3.27 (AB, J=13.9 Hz, 2H), 3.66 (d, J=5.8 Hz, 1H), 3.89 (dd, J=11.7 and J=2.2 Hz, 1H), 4.27 (d,
J=5.8 Hz, 1H), 4.28 (dd, J=11.7 and J=2.2 Hz, 1H), 4.52 (t, J=2.9 Hz, 1H), 7.25 (dd, J=8.7 and J=2.02
Hz, 1H), 7.39–7.48 (m, 2H), 7.60 (s, 1H), 7.76–7.79 (m, 3H); 13C NMR (62.5 MHz, CDCl3) δ 13.7,
22.8, 25.3, 25.8, 26.5, 27.3, 33.2, 38.3, 64.1, 65.3, 74.7, 77.1, 78.9, 113.4, 125.9, 126.3, 127.4 (2C),
127.7, 128.0, 128.7, 132.1, 133.2, 134.1, 171.1, 173.1, 204.6. Anal. calcd for C27H32O7: C, 69.21; H,
6.88. Found: C, 69.20; H, 6.66.
3.14. 2,3-O-Cyclohexylidene-γ-D-ribonolactone 2-benzyl-2-methylacetoacetate 10+11
Prepared as for 8a as a mixture of diastereoisomers; IR (KBr, cm−1) 2938, 2861, 1785, 1743, 1722,
1
1124, 1110; H NMR (250 MHz, CDCl3) δ major diastereoisomer: 1.30 (s, 3H), 1.39–1.62 (M, 10H),
2.19 (s, 3H), 2.98 (d, J=13.8 Hz, 1H), 3.24 (d, J=13.8 Hz, 1H), 4.18–4.35 (M, 5H), 4.72 (t, J=2.9 Hz,
1H), 7.06–7.26 (M, 5H); 1H NMR (250 MHz, CDCl3) δ minor diastereoisomer: 1.38 (s, 3H), 1.52–1.61
(m, 10H), 2.10 (s, 3H), 2.93 (d, J=13.5 Hz, 1H), 3.31 (d, J=13.5 Hz, 1H), 4.07 (dd, J=12.4 and 2.2 Hz,
4H), 4.45 (d, J=5.8 Hz, 1H), 4.68 (t, J=2.2 Hz, 1H), 7.12–7.23 (m, 5H); 13C NMR (62.5 MHz, CDCl3)
δ 18.6, 19.9, 23.6, 23.8, 24.7, 26.4, 26.8, 34.9, 36.2, 40.8, 41.1, 61.1, 64.3, 74.7, 77.1, 79.3, 79.4, 114.5,
127.1, 127.2, 128.5, 130.1, 130.2, 135.9, 171.4, 173.3, 204.7. Anal. calcd for C23H28O7: C, 66.33; H,
6.78. Found: C, 66.39; H, 6.80.
3.15. Ethyl (2R)-2-benzyl-2-methyl-3-oxobutanoate 13a. General procedure for transesterification reac-
tion
A solution of 8a (1.00 g, 2.6 mmol) and Ti(OEt)4 (1.21 g, 5.3 mmol) in ethanol (40 mL) was refluxed
for 5 h. The solution was evaporated and the crude solid was purified by column chromatography on
silica gel under pressure, eluting with a mixture of hexanes–ethyl acetate. Product 13a was obtained

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as a colorless oil (0.57 g, 92%): bp 125°C/0.07 mmHg; [α]D=66 (c=0.64, CHCl3) (lit.11,19 [α]D=62.5
1
(c=0.42, CHCl3)); IR (film, cm−1) 2994, 1743, 1715; H NMR (250 MHz, CDCl3) δ 1.25 (t, J=6.6 Hz,
3H), 1.29 (s, 3H), 2.17 (s, 3H), 3.05 (d, J=13.9 Hz, 1H), 3.27 (d, J=13.9 Hz, 1H), 4.18 (m, 2H), 7.06–7.27
(m, 5H); 13C NMR (62.5 MHz, CDCl3) δ 13.9, 18.9, 26.4, 40.3, 60.7, 61.3, 126.8, 128.2 (2C), 130.1 (2C),
136.4, 172.3, 205.3. Anal. calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.89; H, 7.95.
3.16. Ethyl (2R)-2-(4-bromobenzyl)-2-methyl-3-oxobutanoate 13b
Prepared as for 13a (90% yield); bp 150°C/0.07 mmHg; [α]D=61 (c=1.12, CHCl3); IR (film, cm−1)
2987, 2938, 1729, 1715, 1180, 1110; 1H NMR (250 MHz, CDCl3) δ 1.25 (t, J=7.3 Hz, 3H), 1.28 (s, 3H),
2.16 (s, 3H), 2.99 (d, J=13.9 Hz, 1H), 3.22 (d, J=13.9 Hz, 1H), 4.18 (dq, J=7.3 Hz and J=3.3 Hz, 2H),
6.96–7.00 (m, 2H), 7.35–7.39 (m, 2H); 13C NMR (62.5 MHz, CDCl3) δ 13.9, 19.0, 26.4, 39.8, 60.6,
61.5, 120.8, 131.3 (2C), 131.8 (2C), 135.5, 172.1, 205.0. Anal. calcd for C14H17BrO3: C, 53.69; H, 5.47.
Found: C, 53.75; H, 5.51.
3.17. Ethyl (2R)-2-methyl-2-(naphthylmethyl)-3-oxobutanoate 13d
Prepared as for 13a (93% yield); bp 175°C/0.07 mmHg; [α]D=57 (c=1.27, CHCl3); IR (film, cm−1)
3058, 2980, 2938, 1743, 1715, 1223, 1187, 1096; 1H NMR (250 MHz, CDCl3) δ 1.24 (t, J=6.9 Hz, 3H),
1.33 (s, 3H), 2.19 (s, 3H), 3.21 (d, J=13.1 Hz, 1H), 3.44 (d, J=13.1 Hz, 1H), 4.19 (q, J=6.9 Hz, 2H),
7.19–7.25 (m, 1H), 7.40–7.47 (m, 2H), 7.56 (s, 1H), 7.71–7.80 (m, 3H); 13C NMR (62.5 MHz, CDCl3) δ
14.0, 19.1, 26.5, 40.5, 60.9, 61.4, 125.6, 126.0, 127.5 (2), 127.7, 128.3, 128.9, 132.3, 133.3, 134.1, 172.4,
205.4. Anal. calcd for C18H20O3: C, 76.03; H, 7.09. Found: C, 75.89; H, 7.26.
3.18. Ethyl (2R)-2-(4-bromobenzyl)-2-butyl-3-oxobutanoate 13e
Prepared as for 13a (reaction time 48 h, 37% yield); bp 150°C/0.07 mmHg; [α]D=33 (c=1.10, CHCl3);
1
IR (film, cm−1) 2959, 2931, 2868, 1736, 1715, 1194; H NMR (250 MHz, CDCl3) δ 0.90 (t, J=6.9 Hz,
3H), 0.96–1.42 (m, 7H), 1.69–1.87 (m, 2H), 2.10 (s, 3H), 3.05 (d, J=14.2 Hz, 1H), 3.18 (d, J=14.2 Hz,
1H), 4.08–4.25 (m, 2H), 6.90 (d, J=2.9 Hz, 2H), 6.95 (d, J=2.9 Hz, 2H); 13C NMR (62.5 MHz, CDCl3)
δ 13.8, 13.9, 22.9, 25.9, 27.1, 31.1, 36.6, 61.3, 64.5, 120.7, 131.3 (2C), 131.5 (2C), 135.6, 171.8, 204.8.
Anal. calcd for C17H23O3Br: C, 57.47; H, 6.53. Found: C, 57.79; H, 6.46.
3.19. Ethyl (2R)-2-butyl-2-(2-naphthylmethyl)-3-oxobutanoate 13f
Prepared as for 13a (reaction time 48 h, 49% yield); [α]D=32 (c=1.50, CHCl3); IR (film, cm−1) 3058,
2959, 2931, 2868, 1736, 1715, 1187; 1H NMR (250 MHz, CDCl3) δ 0.84 (t, J=7.3 Hz, 3H), 1.14 (t, J=7.3
Hz, 3H), 1.09–1.28 (m, 4H), 1.70–1.82 (m, 2H), 2.04 (s, 3H), 3.26 (AB, J=13.9 Hz, 2H), 3.99–4.18 (m,
2H), 7.07–7.12 (m, 2H), 7.31–7.39 (m, 2H), 7.44 (s, 1H), 7.63–7.72 (m, 3H); 13C NMR (62.5 MHz,
CDCl3) δ 13.9, 14.0, 22.9, 26.1, 27.2, 31.2, 37.4, 61.2, 64.9, 125.6, 126.0, 127.5 (2C), 127.8, 128.0,
128.6, 132.3, 133.3, 134.2, 172.1, 205.2. Anal. calcd for C21H26O3: C, 77.27; H, 8.03. Found: C, 76.91;
H, 7.78.

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3.20. Ethyl (2S)-2-acetylamino-2-methyl-3-naphthylpropanoate 14d. General procedure for Schmidt
rearrangement
Methanesulfonic acid (5.8 mL) was added dropwise to a stirred mixture of ketoester 13d (1.30 g, 4.6
mmol) and DME (5 mL) cooled at −30°C. Sodium azide (0.89 g, 13.7 mmol) was then added portionwise.
When the evolution of nitrogen ceased the mixture was left at room temperature for 24 h. More DME
(10 mL) and 30% aqueous ammonia were added until pH ca. 9. The mixture was partitioned between
dichloromethane and water. The organic layer was dried and evaporated. The residue was purified through
silica gel eluting with hexanes–ethyl acetate mixtures of increasing polarity to afford 14d (1.13 g, 82%)
as an oil: bp 200°C/0.07 mmHg; [α]D=51 (c=0.97, CHCl3); IR (film, cm−1) 3290, 1736, 1652; 1H NMR
(250 MHz, CDCl3) δ 1.24 (t, J=7.3 Hz, 3H), 1.60 (s, 3H), 1.86 (s, 3H), 3.28 (d, J=13.8 Hz, 1H), 3.56 (d,
J=13.8 Hz, 1H), 4.15 (q, J=7.3 Hz, 2H), 6.10 (broad s, 1H), 7.07–7.11 (m, 1H), 7.33–7.39 (m, 2H), 7.43
(s, 1H), 7.62–7.72 (m, 3H); 13C NMR (62.5 MHz, CDCl3) δ 14.1, 23.4, 23.9, 40.9, 61.1, 61.8, 125.6,
125.9, 127.5 (2C), 128.0, 128.6, 132.3, 133.3, 134.1, 169.6, 173.9. Anal. calcd for C18H21NO3: C, 72.22;
H, 7.07; N, 4.68. Found: C, 71.81; H, 7.34; N, 4.33.
3.21. Ethyl (2S)-2-acetylamino-2-methyl-3-phenylpropanoate 14a
Prepared as for 14d (82% yield); colorless oil, bp 175°C/0.07 mmHg; [α]D=53 (c=1.02, CHCl3) (lit.13b
[α]D=49 (c=0.56, CHCl3)); IR (KBr, cm−1) 3290, 3065, 3030, 2987, 2938, 1736, 1659, 1117; 1H NMR
(250 MHz, CDCl3) δ 1.32 (t, J=7.3 Hz, 3H), 1.66 (s, 3H), 1.95 (s, 3H), 3.19 (d, J=13.5 Hz, 1H), 3.56 (d,
J=13.5 Hz, 1H), 4.22 (dq, J=7.3 and J=3.3 Hz, 2H), 6.10 (broad s, 1H), 7.04–7.26 (m, 5H); 13C NMR
(62.5 MHz, CDCl3) δ 14.0, 23.2, 23.8, 40.8, 60.9, 61.6, 126.7, 128.0 (2C), 129.8 (2C), 136.5, 169.5,
173.8.
3.22. Ethyl (2S)-2-acetylamino-3-(4-bromophenyl)-2-methylpropanoate 14b
Prepared as for 14d (63% yield); white solid, mp 69–71°C; [α]D=42 (c=0.95, CHCl3); IR (KBr, cm−1)
1
3459–3170, 3065, 2980, 2938, 1736, 1652, 1490, 1117; H NMR (250 MHz, CDCl3) δ 1.33 (t, J=7.3
Hz, 3H), 1.66 (s, 3H), 1.96 (s, 3H), 3.15 (d, J=13.1 Hz, 1H), 3.59 (d, J=13.1 Hz, 1H), 4.06–4.25 (m, 2H),
6.04 (broad s, 1H), 6.85 (d, J=8.04 Hz, 2H), 7.30 (d, J=8.04 Hz, 2H); 13C NMR (62.5 MHz, CDCl3)
δ 14.1, 23.4, 24.1, 40.1, 61.1, 61.9, 120.9, 131.3 (2C), 131.5 (2C), 135.7, 169.5, 173.7. Anal. calcd for
C14H18NO3Br: C, 51.23; H, 5.53; N, 4.27. Found: C, 51.34; H, 5.49; N, 4.27.
3.23. Ethyl (2S)-2-acetylamino-2-(4-bromobenzyl)hexanoate 14e
Prepared as for 14d (43% yield); white solid, mp 88–89°C; [α]D=61 (c=1.15, CHCl3); IR (KBr, cm−1)
1
3268, 2959, 2952, 2869, 1736, 1637, 1208; H NMR (250 MHz, CDCl3) δ 0.88 (t, J=6.9 Hz, 3H),
0.88–1.00 (m, 1H), 1.16–1.37 (m, 3H), 1.34 (d, J=6.9 Hz, 3H), 1.71–1.88 (m, 1H), 1.97 (s, 3H), 2.61
(dt, J=12.8 and J=4.4 Hz, 1H), 3.03 (d, J=13.1 Hz, 1H), 3.74 (d, J=13.1 Hz, 1H), 4.13–4.34 (m, 2H),
6.19 (broad s, 1H), 6.90 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H); 13C NMR (62.5 MHz, CDCl3) δ
13.9, 14.1, 22.4, 24.3, 26.4, 35.0, 39.8, 61.9, 65.8, 120.8, 131.3 (4C), 135.7, 169.3, 173.2. Anal. calcd for
C17H24BrNO3: C, 55.14; H, 6.53; N, 3.78. Found: C, 55.24; H, 6.53; N, 3.58.
3.24. Ethyl (2S)-2-acetylamino-2-(2-naphthylmethyl)hexanoate 14f
Prepared as for 14d as a white solid (41% yield), mp 72–74°C; [α]D=83 (c=0.99, CHCl3); IR (KBr,
1
cm−1) 3281, 3058, 2956, 2861, 1740, 1645, 1549, 1205; H NMR (250 MHz, CDCl3) δ 0.90 (t, J=7.3

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Hz, 3H), 0.82–1.05 (m, 2H), 1.26–1.46 (m, 2H), 1.38 (t, J=7.3 Hz, 3H), 1.85–1.95 (m, 1H), 1.98 (s, 3H),
2.70 (dt, J=13.9 and 4.4 Hz, 1H), 3.60 (AB, J=13.2 Hz, 2H), 4.21–4.36 (m, 2H), 6.18 (s, 1H), 7.14–7.18
(m, 1H), 7.42–7.45 (m, 2H), 7.50 (s, 1H), 7.70–7.81 (m, 3H); 13C NMR (62.5 MHz, CDCl3) δ 13.9,
14.2, 22.5, 24.3, 26.5, 35.1, 40.6, 61.9, 66.2, 125.5, 125.9, 127.5 (3C), 127.9, 128.4, 132.4, 133.4, 134.3,
169.4, 173.5; Anal. calcd for C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C, 73.82; H, 7.80; N, 4.05.
3.25. (S)-α-Benzylalanine hydrochloride 15b. General procedure for acid hydrolysis
A mixture of 0.49 g of 14a in 6 M HCl was heated at reflux for 24 h. After cooling at room temperature
a precipitate was formed and filtered, yielding 15a as a white solid (0.33 g, 81%); mp 160–164°C (d);
[α]D=−7 (c=1.22, H2O); IR (KBr, cm−1) 3184–2446, 1736, 1237, 1194; 1H NMR (250 MHz, CDCl3) δ
1.48 (s, 3H), 3.12 (s, 2H), 7.21–7.36 (m, 5H), 8.49 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 21.9, 42.3,
59.9, 127.6, 128.7 (2C), 130.5 (2C), 134.1, 172.3. Anal. calcd for C10H14ClNO2: C, 55.69; H, 6.54; N,
6.49. Found: C, 55.52; H, 6.62; N, 6.07.
3.26. (S)-α-(4-Bromobenzyl)alanine hydrochloride 15b
Prepared as for 15a (81% yield) as a white solid; mp 161–163°C (d); [α]D=−8 (c=1.05, H2O); IR
1
(KBr, cm−1) 3297–2671, 1757, 1511, 1490, 1173; H NMR (250 MHz, CDCl3) δ 1.49 (s, 3H), 3.13 (s,
2H), 7.21 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 8.55 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 22.1,
41.4, 59.7, 121.1, 131.5 (2C), 132.7 (2C), 133.5, 172.2. Anal. calcd for C10H13BrClNO2: C, 40.77; H,
4.45; N, 4.75. Found: C, 40.60; H, 4.38; N, 4.52.
3.27. (S)-α-(2-Naphthylmethyl)alanine hydrochloride 15d
Prepared as for 15a (76% yield) as a white solid; mp 170–174°C (d); [α]D=5 (c=1.14, EtOH); IR
1
(KBr, cm−1) 3395–2503, 1743, 1525, 1209; H NMR (250 MHz, CDCl3) δ 1.56 (s, 3H), 3.32 (s, 2H),
7.37–7.40 (m, 1H), 7.47–7.54 (m, 2H), 7.79–7.92 (m, 4H), 8.59 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ
22.1, 42.4, 60.0, 126.2, 126.4, 127.7, 127.9, 128.1, 128.4, 129.4, 131.7, 132.5, 133.1, 172.4. Anal. calcd
for C14H16ClNO2·H2O: C, 59.26; H, 6.39; N, 4.94. Found: C, 59.12; H, 6.46; N, 4.80.
3.28. (S)-α-(4-Bromobenzyl)-α-butylglycine hydrochloride 15e
Prepared as for 15a (73% yield) as a white solid; mp 169–173°C (d); [α]D=7 (c=1.06, EtOH); IR (KBr,
cm−1) 3662–2347, 1722, 1511, 1209; 1H NMR (250 MHz, CDCl3) δ 0.86 (t, J=7.0 Hz, 3H), 1.22–1.50
(m, 4H), 1.69–1.92 (m, 2H), 3.07 (d, J=14.2 Hz, 1H), 3.15 (d, J=14.2 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H),
7.53 (d, J=8.0 Hz, 2H), 8.35 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 13.8, 22.3, 25.0, 35.5, 40.3, 63.2,
121.1, 131.5 (2C), 133.0 (2C), 133.4, 171.8. Anal. calcd for C13H19BrClNO2·1/2H2O: C, 45.16; H, 5.79;
N, 4.05. Found: C, 44.88; H, 5.80; N, 3.94.
3.29. (S)-α-Butyl-α-(2-naphthylmethyl)glycine hydrochloride 15f
Prepared as for 15a (65% yield) as a white solid; mp 110–112°C (d); [α]D=−3 (c=0.90, EtOH); IR
1
(KBr, cm−1) 3698–2341, 1729, 1511, 1216; H NMR (250 MHz, CDCl3) δ 0.88 (t, J=6.9 Hz, 3H),
1.25–1.33 (m, 3H), 1.52–1.59 (m, 1H), 1.84–2.01 (m, 2H), 3.36 (s, 3H), 7.44–7.54 (m, 3H), 7.81–7.92
(m, 4H), 8.47 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 14.6, 25.1, 25.9, 36.4, 42.1, 64.3, 126.8, 127.0,

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128.4, 128.7, 129.5, 130.5, 132.5, 133.2, 133.8, 172.7. Anal. calcd for C17H22ClNO2·H2O: C, 62.66; N,
4.30. Found: C, 62.88; N, 4.59.
3.30. (4R)-4-Benzyl-3,4-dimethyl-2-pyrazolin-5-one 17a. General procedure for preparation of 2-
pyrazolin-5-ones 17a,b,d–g
A solution of 0.20 g (0.5 mmol) of 8a and 0.27 g (5.3 mmol) of hydrazine hydrate in ethanol (8 mL)
was heated at 140°C in a closed reactor for 24 h. After cooling at room temperature, the solvent was
evaporated and the residue was chromatographed on silica gel under pressure with hexanes–ethyl acetate
as eluent, to afford 17a (0.10 g, 92%) as a white solid; mp 99–101°C (hexanes–diethyl ether); [α]D=−180
(c=1.20, CHCl3) (lit.15 [α]D=−186 (c=1.24, CHCl3)); IR (KBr, cm−1) 3163, 1708, 1666; 1H NMR (250
MHz, CDCl3) δ 1.34 (s, 3H), 2.05 (s, 3H), 2.84 (d, J=13.8 Hz, 1H), 3.12 (d, J=13.8 Hz, 1H), 7.08–7.26
(m, 5H), 8.03 (s, 1H, NH); 13C NMR (62.5 MHz, CDCl3) δ 14.2, 20.3, 41.2, 53.5, 127.2–128.9 (5C),
135.3, 163.4, 179.6.
3.31. (4R)-4-(4-Bromobenzyl)-3,4-dimethyl-2-pyrazolin-5-one 17b
Prepared as for 17a from 8b as a white solid (86% yield); mp 52–54°C (hexanes–diethyl ether);
1
[α]D=−144 (c=1.01, CHCl3); IR (KBr, cm−1) 3227, 2924, 2854, 1701; H NMR (250 MHz, CDCl3)
δ 1.33 (s, 3H), 2.04 (s, 3H), 2.78 (d, J=13.9 Hz, 1H), 3.05 (d, J=13.9 Hz, 1H), 6.97 (d, J=8.1 Hz, 2H),
7.34 (d, J=8.1 Hz, 2H), 8.16 (s, 1H, NH); 13C NMR (62.5 MHz, CDCl3) δ 14.1, 20.2, 40.4, 53.4, 121.3,
130.6, 131.5, 134.2, 163.0, 179.3. HRMS: calcd for C12H13BrN2O: 280.0224 and 282.0207. Found:
280.0211 and 282.0191.
3.32. (4R)-3,4-Dimethyl-4-(2-naphthylmethyl)-2-pyrazolin-5-one 17d
Prepared as for 17a from 8d as a white solid (75% yield); mp 131–133°C (hexanes–diethyl ether);
[α]D=−211 (c=0.88, CHCl3); IR (KBr, cm−1) 3191, 3093, 2973, 2917, 2840, 1708, 1680, 773; 1H NMR
(250 MHz, CDCl3) δ 1.40 (s, 3H), 2.09 (s, 3H), 3.00 (d, J=13.5 Hz, 1H), 3.30 (d, J=13.5 Hz, 1H),
7.21–7.26 (m, 1H), 7.42–7.48 (m, 2H), 7.57 (s, 1H), 7.69–7.79 (m, 3H), 7.92 (s, 1H, NH); 13C NMR
(62.5 MHz, CDCl3) δ 14.3, 20.4, 41.3, 53.6, 125.8, 126.0, 127.1, 127.5, 127.8 (2C), 128.0, 132.5, 132.9,
133.3, 163.4, 179.6. Anal. calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found: C, 76.08; H, 6.63;
N, 11.07.
3.33. (4R)-4-(4-Bromobenzyl)-4-butyl-3-methyl-2-pyrazolin-5-one 17e
Prepared as for 17a from 8e as a white solid (74% yield); mp 133–135°C (pentane–diethyl ether);
[α]D=−88 (c=1.04, CHCl3); IR (KBr, cm−1) 3198, 3086, 2959, 2931, 2861, 1701; 1H NMR (250 MHz,
CDCl3) δ 0.86 (t, J=7.3 Hz, 3H), 0.92–1.34 (m, 4H), 1.58–1.70 (m, 1H), 1.79–1.92 (m, 1H), 2.01 (s, 3H),
2.77 (d, J=13.5 Hz, 1H), 3.03 (d, J=13.5 Hz, 1H), 6.96 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 8.52 (s,
1H, NH); 13C NMR (62.5 MHz, CDCl3) δ 13.7, 14.4, 22.6, 26.2, 34.6, 40.3, 58.5, 121.2, 130.7, 131.4,
134.0, 162.0, 178.7; Anal. calcd for C15H19BrN2O: C, 55.74; H, 5.92; N, 8.67. Found: C, 55.76; H, 5.70;
N, 8.30.

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3.34. (4R)-4-Butyl-3-methyl-4-(2-naphthylmethyl)-2-pyrazolin-5-one 17f
Prepared as for 17a from 8f as a white solid (70% yield); mp 87–88°C (pentane–diethyl ether);
[α]D=−127 (c=1.01, CHCl3); IR (KBr, cm−1) 3234, 3058, 2959, 2931, 2861, 1701; 1H NMR (250 MHz,
CDCl3) δ 0.88 (t, J=7.3 Hz, 3H), 0.93–1.43 (m, 6H), 1.73 (dt, J=12.0 and J=4.3 Hz, 1H), 1.68 (dt, J=12.0
and J=4.3 Hz, 1H), 2.07 (s, 3H), 3.13 (AB, J=13.9 Hz, 2H), 7.21–7.25 (m, 1H), 7.41–7.45 (m, 3H), 7.90
(s, 1H, NH); 13C NMR (62.5 MHz, CDCl3) δ 13.7, 14.5, 22.6, 26.2, 34.7, 41.1, 58.6, 125.7, 125.9, 127.2,
127.5, 127.8, 127.9, 132.4, 132.7, 133.2, 162.3, 179.1. HRMS: calcd for C19H22N2O: (M+1) 295.1796.
Found: 295.1810.
Acknowledgements
Financial support from DGICYT (Ministry of Education and Science of Spain; project PB93-0896
and predoctoral grant to E.T.) and from CIRIT (Generalitat de Catalunya; project SGR98-0056 and
predoctoral grant to M.R.S) is gratefully acknowledged.
References
1. Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 238–264.
2. Cheng, H.; Keitz, P.; Jones, J. B. J. Org. Chem. 1994, 59, 7671–7676.
3. Toniolo, C.; Formaggio, F.; Crisma, M.; Valle, G.; Boesten, W. H. J.; Schoemaker, H. E.; Kamphuis, J.; Temussi, P. A.;
Becker, E. L.; Précigoux, G. Tetrahedron 1993, 49, 3641–3653.
4. (a) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517–3599 (report 40). (b) Duthaler, R.
O. Tetrahedron 1994, 50, 1539–1650 (report 349). (c) Williams, R. M. Synthesis of Optically Active α-Amino Acids;
Pergamon Press: Oxford, 1989. (d) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225–227.
5. Seebach, D.; Hoffman, M. Eur. J. Org. Chem. 1998, 1337–1351.
6. (a) Chinchilla, R.; Falvello, L. R.; Nájera, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 995–997. (b) Abellán, T.; Nájera, C.;
Sansano, J. M. Tetrahedron: Asymmetry 1998, 9, 2211–2214.
7. Alonso, F.; Davies, S. G.; Elend, A. S.; Haggitt, J. L. J. Chem. Soc., Perkin Trans. 1 1998, 257–264.
8. Carloni, A.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1998, 9, 2987–2998.
9. Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed. Engl. 1997, 36, 2635–2637.
10. (a) Cativiela, C.; Díaz-de-Villegas, M. D.; Galvez, J. A. Tetrahedron: Asymmetry 1994, 5, 261–268. (b) Cativiela, C.; Díaz-
de-Villegas, M. D.; Galvez, J. A. Tetrahedron 1994, 50, 9837–9846. (c) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron
1995, 51, 5921–5928. (d) Badorrey, R.; Cativiela, C.; Díaz-de-Villegas, M. D.; Galvez, J. A.; Lapeña, Y. Tetrahedron:
Asymmetry 1997, 8, 311–317.
11. Ando, K.; Takemasa, Y.; Tomioka, K.; Koga, K. Tetrahedron 1993, 49, 1579–1588.
12. Georg, G. I.; Guan, X.; Kant, J. Tetrahedron Lett. 1988, 29, 403–406.
13. (a) Ihara, M.; Takahashi, M.; Niitsuma, H.; Taniguchi, N.; Yasui, K.; Fukumoto, K. J. Org. Chem. 1989, 54, 5413–5415.
(b) Ihara, M.; Takahashi, M.; Niitsuma, H.; Taniguchi, N.; Yasui, K.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1991,
525–535.
14. Gálvez, N.; Moreno-Mañas, M.; Vallribera, A.; Molins, E.; Cabrero, A. Tetrahedron Lett. 1996, 37, 6197–6200.
15. Moreno-Mañas, M.; Sebastián, R. M.; Vallribera, A.; Molins, E.; Espinosa, E. Tetrahedron: Asymmetry 1997, 8,
1525–1527.
16. For reviews on the use of carbohydrates as chiral auxiliaries, see: (a) Kunz, H.; Rück, K. Angew. Chem., Int. Ed. Engl.
1993, 32, 336–358. (b) Hultin, P. G.; Earle, M. A.; Sudharshan, M. Tetrahedron 1997, 53, 14823–14870 (report 432).
17. Hough, L.; Jones, J. K. N.; Mitchell, D. L. Can. J. Chem. 1958, 36, 1720–1728.
18. Beer, D.; Meuwly, R.; Vasella, A. Helv. Chim. Acta 1982, 65, 2570–2582.
19. Kato, K.; Suemune, H.; Sakai, K. Tetrahedron 1994, 50, 3315–3326.
20. Gálvez, N.; Moreno-Mañas, M.; Sebastián, R. M.; Vallribera, A. Tetrahedron 1996, 52, 1609–1616.
21. Moreno-Mañas, M.; Sebastián, R. M.; Vallribera, A.; Molins, E.; Espinosa, E. Tetrahedron: Asymmetry 1997, 8,
1525–1527.