Functionalization of (2S)-Isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4- ones by a Suzuki-Miyaura Cross-Coupling Reaction Using Aryltrifluoroborate Salts: Convenient Enantioselective Preparation of α-Substituted β-Amino Acids

Article abstract of DOI:10.1002/ejoc.201000852

A simple protocol for the Pd(OAc)₂-catalyzed cross-coupling reaction of 1-benzoyl-(2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones with potassium aryltrifluoroborates was developed. The reaction is performed at 110°C with a ligand-free catalyst. In all cases, complete conversion of the 1-benzoyl-(2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-onesand aryltrifluoroborates into the C-C coupling products was observed within 30-360 min. It is noteworthy that a largevariety of groups present in the potassium aryltrifluoroborates (-CF₃, -OMe, -SEt, -CN, -CHO, -Cl, -Cbz, -NCbz,-OH, -CO₂H) could be tolerated. Hydrogenation of the endocyclic double bonds in the Suzuki-Miyaura products followed by acid hydrolysis afforded highly enantioenrichedα-aryl-substituted β-amino acids. We present a general approach for the synthesis of (2S)-isopropyl-5-aryl-2,3- dihydro-4(H)-pyrimidin-4-ones by Suzuki-Miyaura reaction of aryltrifluoroborate salts with(2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones in the presence of a palladium catalyst and a base. The arylated compounds were transformed into enantioenriched α-aryl-substituted β-amino acids. Copyright

Full text of DOI:10.1002/ejoc.201000852

FULL PAPER
DOI: 10.1002/ejoc.201000852
Functionalization of (2S)-Isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones
by a Suzuki–Miyaura Cross-Coupling Reaction Using Aryltrifluoroborate
Salts: Convenient Enantioselective Preparation of α-Substituted β-Amino Acids
Hélio A. Stefani,*[a] Monica F. Z. J. Amaral,[a] Gloria Reyes-Rangel,[b]
Jorge Vargas-Caporali,[b] and Eusebio Juaristi*[b]
Keywords: Palladium / Borates / Cross-coupling / Nitrogen heterocycles / Amino acids / Enantioselective synthesis
A simple protocol for the Pd(OAc)2-catalyzed cross-coupling
reaction of 1-benzoyl-(2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-
pyrimidin-4-ones with potassium aryltrifluoroborates was de-
veloped. The reaction is performed at 110 °C with a ligand-
free catalyst. In all cases, complete conversion of the 1-benz-
oyl-(2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones
and aryltrifluoroborates into the C–C coupling products was
observed within 30–360 min. It is noteworthy that a large
variety of groups present in the potassium aryltrifluoro-
borates (–CF3, –OMe, –SEt, –CN, –CHO, –Cl, –Cbz, –NCbz,
–OH, –CO2H) could be tolerated. Hydrogenation of the endo-
cyclic double bonds in the Suzuki–Miyaura products fol-
lowed by acid hydrolysis afforded highly enantioenriched
α-aryl-substituted β-amino acids.
Introduction
and high sensitivity to air and moisture. To solve these
problems, boronic acids and boronate esters have been re-
placed by organotrifluoroborate salts in several cross-cou-
pling reactions.[3]
Many types of cross-coupling reactions have been known
for several decades, and recent advances have greatly in-
creased their scope and practicality. This progress has had
a significant impact on academic research, and cross-cou-
pling reactions are now widely employed in a variety of syn-
thetic protocols, from the total synthesis of natural prod-
ucts to the preparation of relevant targets in bioorganic
chemistry, pharmaceuticals, agrochemicals, and polymers.
Indeed, transition-metal-catalyzed cross-coupling processes
are no longer considered out of the ordinary but have be-
come part of the everyday repertoire of the synthetic chem-
ist.[1]
In recent years, organoboron compounds have become
some of the most popular organometallic reagents for
carbon–carbon bond formation.[2] The great applicability of
organoboron compounds is due to several factors, such as
(1) compatibility with many functional groups in the sub-
strate, (2) availability of the desired reagents through hydro-
boration and transmetallation, (3) low toxicity of organ-
oboranes, (4) their ultimate degradation into environmen-
tally friendly boric acids, and (5) the handling and removal
of boron-containing byproducts is relatively simple com-
pared to the disposal of other organometallic reagents. The
most commonly used organoboron compounds are boronic
acids and boronate esters, but these compounds present
some drawbacks, such as their low stability, very high cost,
In particular, organotrifluoroborates are very useful rea-
gents in the Suzuki–Miyaura cross-coupling reaction, which
is among the most powerful and mild protocols currently
available for the formation of carbon–carbon bonds.[3,4]
Unlike their tricoordinate organoboron counterparts, these
tetracoordinate species are less prone to undergo protode-
boronation. Consequently, near-stoichiometric amounts of
the nucleophilic partner are employed for cross-coupling re-
actions. Furthermore, organotrifluoroborates provide sev-
eral additional advantages over the corresponding boronic
acids and boronate esters. For example, they are easily pre-
pared by the addition of inexpensive KHF2 to commercially
available organoboron compounds, and they can then be
stored indefinitely without special precaution due to the air-
and moisture-stable nature of these crystalline reagents.
Moreover, organotrifluoroborates are inert to many nucleo-
philic reagents such as cyanide, azide, amines, enolates, alk-
oxides, and organometallic reagents because the boron
atom in organotrifluoroborates does not have an empty p
orbital to interact with the incoming nucleophile.
In the last two decades, the synthesis of β-amino acids
has been of increasing interest, owing to their presence in
biologically active compounds, either in free form or as con-
stituents in various peptides. Indeed, β-amino acids are the
main components of several medicinally useful molecules.
For these reasons, numerous methodologies for the synthe-
sis of racemic and enantiomerically pure compounds have
emerged.[5]
[a] Faculdade de Ciências Farmacêuticas,
Universidade de São Paulo,
São Paulo, SP, Brasil
[b] Centro de Investigacion y de Estudios Avanzados del Instituto
Politécnico Nacional,
Apartado Postal 14-740, 07000 México, D. F., México
View this journal online at
wileyonlinelibrary.com
Eur. J. Org. Chem. 2010, 6393–6403
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6393

H. A. Stefani, E. Juaristi et al.
FULL PAPER
In this regard, perhydropyrimidin-4-one carboxylic acid
[(2S,6S)-1a] has been used as an efficient starting material
for the enantioselective synthesis of (R)- and (S)-α-substi-
tuted[6] and α,α-disubstituted β-amino acids.[7] Further-
more, several analogs of pyrimidinone (S)-2 have proven
useful for the asymmetric synthesis of β-substituted, α,β-
disubstituted, and β,β-disubstituted β-amino acids
(Scheme 1).[8]
Results and Discussion
In connection with our research interest in the preparation
and evaluation of potassium organotrifluoroborate salts as
intermediates in organic synthesis,[14] we wish to report here
a general procedure to convert (S)-5-substituted iodopyrim-
idinone precursors to enantiomerically pure β-amino acids.
Diastereomerically pure (2S,6S)-1b acid was prepared by
condensation of (S)-asparagine with isobutyraldehyde, fol-
lowed by in situ N-benzoylation (Scheme 3).[7a,15]
Scheme 3. Preparation of enantiopure (S)-2-isopropyl-5-iodopyr-
imidinone 3.
Treatment of perhydropyrimidin-4-one-6-carboxylic acid
(2S,6S)-1b with 2 equiv. of diacetoxyiodobenzene and
1 equiv. of iodine (DIB/I2), followed by addition of
BF3·Et2O (2 equiv.) to the resulting reaction mixture re-
sulted in the fast conversion of the (S)-pyrimidinone into
the corresponding 1-benzoyl-(2S)-isopropyl-5-iodo-2,3-di-
hydro-4(H)-pyrimidin-4-one (S)-3b, as the sole reaction
product in 78% yield (Scheme 3).
Scheme 1. Enantioselective synthesis of β-amino acids via chiral
pyrimidinones.
Recently, we reported that treatment of carboxylic acid
(2S,6S)-1a with diacetoxyiodobenzene/iodine (DIB/I2)[9] af-
forded a 1.6:1.0 mixture of iodoenone (S)-3a and enone (S)-
4a.[10] In view of the structural similarity between 5-iodo-
pyrimidinone (S)-3a and various 5-halouracils that show
antiviral activity,[11] reaction conditions were developed for
the decarboxylation/β-iodination of (2S,6S)-1a to provide
(S)-3a as the single product (Scheme 2).[12]
With the starting material in hand, optimization of the
reaction conditions for the cross-coupling of (S)-3b with
potassium aryltrifluoroborate salts[16] was undertaken. Ini-
Scheme 4. Cross-coupling of (S)-3b with potassium phenyltri-
fluoroborate.
Scheme 2. Preparation of 5-iodopyrimidinone (S)-3a.
Table 1. Effect of palladium catalyst on the Suzuki–Miyaura reac-
tion.[a]
The structural similarity of haloenones 3 and 5-halourac-
ils has suggested that they should present the same chemical
reactivity. For example, there are successful reports of the
application of Suzuki–Miyaura couplings to substitute the
halogen in 6-chloropurine derivatives.[13] Thus, iodopyrim-
idin-4-ones (S)-3 presented themselves as interesting sub-
strates for this kind of coupling. This paper reports the use
of pyrimidinone 3b as a substrate in Suzuki–Miyaura cross-
coupling reactions. The resulting products proved to be
suitable precursors to enantiomerically pure β-amino acids.
Herein, we describe the preparation of a variety of pyr-
imidinones 5a–q, which were obtained by the efficient cross-
coupling reaction of (S)-3b with a broad range of aryltri-
fluoroborates by using a simple reaction protocol that em-
ploys near stoichiometric amounts of the nucleophilic rea-
gent.
Entry
Catalyst
GC yield [%]
1
2
3
4
5
6
7
PdCl2
Pd(acac)2
Pd(PPh3)4
PdCl2(dppf)·CH2Cl2
Pd(OAc)2
66
74
52
84
84
n.r.
n.r.
–
NiCl2(dppe)
[a] The reaction was carried out with (S)-3b (0.50 mmol), BF3K
(0.60 mmol), Pd cat. (9 mol-%), and NaOH (1.0 mmol) in dioxane/
H2O (3:1, 5 mL) under a nitrogen atmosphere at reflux.
6394
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6393–6403

Enantioselective Preparation of α-Substituted β-Amino Acids
Table 2. Pd(OAc)2-catalyzed Suzuki–Miyaura reaction of (S)-3b (1 equiv.) with various potassium aryltrifluoroborates (1.2 equiv.).[a]
[a] The reaction was carried out with (S)-3b (0.50 mmol), BF3K (0.60 mmol), Pd(OAc)2 (9 mol-%), and K2CO3 (1.0 mmol) in dioxane/
H2O (3:1, 5 mL) under a nitrogen atmosphere at reflux. [b] Isolated yield.
Eur. J. Org. Chem. 2010, 6393–6403
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6395

H. A. Stefani, E. Juaristi et al.
FULL PAPER
tially, we conducted a palladium catalyst screening with Hydrogenation and Subsequent Hydrolysis of the Suzuki–
phenyltrifluoroborate salt (Scheme 4). Miyaura Products To Afford Highly Enantiomerically
A comparison of different palladium catalysts [PdCl2, Enriched α-Substituted β-Amino Acids
Pd(OAc)2, Pd(acac)2, Pd(PPh3)4, PdCl2(dppf), and NiCl2-
Hydrogenation of the endocyclic double bonds in aryl-
(dppe)] showed that Pd(OAc)2 (9 mol-%) was the best cata-
lyst for the reaction (Table 1, Entry 5). It should be men-
tioned that the reaction does not proceed in the absence of
a Pd catalyst (Table 1, Entry 6).
Once Pd(OAc)2 had been established as the best catalyst,
several organic and inorganic bases were tested as additives.
In the present system, inexpensive K2CO3 was the most ef-
fective (99%), although Cs2CO3 also afforded an excellent
yield (90%). Bases like Et3N, DIPEA, (iPr)2NH, and
NaOH all gave somewhat lower yields, in the 85–89%
range. When NaOH was used, dehalogenation of the start-
ing material leading to corresponding enone (S)-4b was ob-
served.
ated enones 5 with H2/Raney-Ni/AcOH/CH3OH at 80 °C
provided epimers (2S,5S)-23 and (2S,5R)-23 (cis-23 and
trans-23),[12] with the former product always predomina-
ting, as anticipated in terms of a more facile approach of
the reducing agent from the face of the double bond oppo-
site the isopropyl group[6,7] (Scheme 5).
Another reaction parameter investigated was the solvent.
When MeOH, CH3CN, and dry α,α,α-trifluorotoluene were
employed, the reaction did not proceed. The use of water
as solvent in ether mixtures like THF/H2O (5:1) and 1,4-
dioxane/H2O (3:1) afforded the desired product in 71 and
99% yield, respectively. The use of water as a solvent pro-
moted the formation of the coupled product in 50% yield;
however, we also observed the presence of enone (S)-4b as
a direct consequence of dehalogenation of the starting ma-
terial.
Finally, we tested catalyst loadings from 2.0 to 10 mol-%
and found that 9 mol-% of Pd(OAc)2 gave the best results.
When the amount of Pd(OAc)2 was less than 9 mol-%, the
yields were much lower.
Thus, it was concluded that the use of Pd(OAc)2 (9 mol-
%) as catalyst, in the presence of K2CO3 as base, in a
3:1 mixture of 1,4-dioxane/H2O and at 110 °C provided
the most suitable conditions for the cross-coupling of (S)-
3b (1 equiv.) with potassium aryltrifluoroborate (1.2
equiv.).
Scheme 5. Raney-Ni-catalyzed hydrogenation of the endocyclic
bond in the Suzuki–Miyaura cross-coupling products.
For example, cross-coupled product 5a (Ar = C6H5) was
hydrogenated for 24 h at 1500 psi of hydrogen pressure to
afford 23a in 73% yield as a 95:5 mixture of the cis and
trans diastereomers, which were separated by flash
chromatography. Following recrystallization of 23a, suitable
crystals were obtained, and the corresponding X-ray crys-
tallographic structure is shown in Figure 1. As shown in
this figure, the six-membered heterocycle adopts a confor-
mation that approaches a twisted chair.[17] The pseudo-axial
orientation of the phenyl ring is a consequence of allylic
strain.[18]
To demonstrate the efficiency of this cross-coupling reac-
tion, we explored its generality with a variety of aryltri-
fluoroborates 6–22. The results are summarized in Table 2.
The Pd0-catalyzed Suzuki reaction proved to be exception-
ally efficient. It is clear that this is a general method that
tolerates both electron-withdrawing and electron-donating
substituents on the aromatic ring of the aryltrifluoroborate.
In addition, even an ortho-methyl substituent at the aryltri-
fluoroborate afforded the corresponding product in moder-
ate yield (Table 2, Entry 11). This method was effective for
the aryltrifluoroborate containing a meta-hydroxy group,
giving a moderate yield and a mixture of products (Table 2,
Entry 13); however, no reaction was observed with organ-
otrifluoroborates 8 and 21. The reaction of 3-thiophenetri-
fluoroborate afforded the cross-coupled product in 78%
yield (Table 2, Entry 2), whereas 4-cyanophenyltrifluoro-
Figure 1. X-ray crystallographic structure and solid-state confor-
mation of (2S,5S)-23a.
Cross-coupled product 5g (Ar = 4-MeC6H4) was hydro-
borate and 4-chlorophenyltrifluoroborate afforded the genated for 48 h at 1800 psi of hydrogen pressure to afford
cross-coupled products in 60 and 59% yield, respectively 23b in 87% yield as essentially the pure cis diastereomer.
(Table 2, Entries 9 and 15). Additionally, the 4-formyltri- Similarly, cross-coupled product 5n (Ar = 4-tBuC6H4) was
fluoroborate afforded the desired product in 62% yield hydrogenated for 24 h at 1800 psi of hydrogen pressure to
(Table 2, Entry 10).
afford 23c in 67% yield as a 89:11 mixture of the cis and
6396
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6393–6403

Enantioselective Preparation of α-Substituted β-Amino Acids
Table 3. Hydrogenation of the Suzuki–Miyaura products.
Entry
Suzuki–Miyaura products
Hydrogenation products
(diastereomers)
Pressure H2 [psi]
Time [h]
Yield [%]
(cis and trans)
1[a]
2[b]
3[c]
4[d]
5[e]
5a (Ar = C6H5)
5g (Ar = 4-MeC6H4)
5n (Ar = 4-tBuC6H4)
5l (Ar = 2-naph)
(2S,5S)-23a/(2S,5R)-23a (95:5)
(2S,5S)-23b (pure)
(2S,5S)-23c/(2S,5R)-23c (89:11)
(2S,5S)-23d/(2S,5R)-23d (76:24)
(2S,5S)-23e/(2S,5R)-23e (92:8)
1500
1800
1800
1800
1800
24
48
24
24
24
73
87
67
77
56
5f (Ar = 4-MeOC6H4)
[a] The reaction was carried out with (2S)-5a (2.37 mmol) and Raney-Ni (7.6 g) under 1500 psi of H2 at 80 °C for 24 h. [b] The reaction
was carried out with (2S)-5g (2.39 mmol) and Raney-Ni (8.0 g) under 1800 psi of H2 at 80 °C for 48 h. [c] The reaction was carried out
with (2S)-5n (2.2 mmol) and Raney-Ni (8.3 g) under 1800 psi of H2 at 80 °C for 24 h. [d] The reaction was carried out with (2S)-5l
(2.47 mmol) and Raney-Ni (9.2 g) under 1800 psi of H2 at 80 °C for 24 h. [e] The reaction was carried out with (2S)-5f (2.34 mmol) and
Raney-Ni (8.2 g) under 1800 psi of H2 at 80 °C for 24 h.
trans diastereomers, which were separated by flash
chromatography. In another example, cross-coupled prod-
uct 5l (Ar = 2-naph) was hydrogenated for 24 h at 1800 psi
of hydrogen pressure to afford tetrahydro derivative 23d in
77% yield as a 76:24 mixture of the cis and trans dia-
stereomers, which were separated by flash chromatography.
Conclusions
In summary, a simple protocol for the Pd(OAc)2-cata-
lyzed Suzuki–Miyaura cross-coupling of (S)-2-isopropyl-5-
iodopyrimidinone with potassium aryltrifluoroborates has
been developed. The reaction is performed at 110 °C with
the use of a ligand-free catalyst. In all cases, complete con-
It should be noted that in addition to reduction of the en-
version of the (S)-5-iodoenones and aryltrifluoroborates
docyclic double bond, substrate 5l suffered partial hydro-
into the C–C coupling product was observed within 30–
360 min. It is noteworthy that all functional groups present
in the potassium aryltrifluoroborates (–CF3, –OMe, –SEt,
–CN, –CHO, –Cl, –CBz, –NCBz, –OH, –CO2H) could be
tolerated. Raney-Ni-catalyzed hydrogenation of Suzuki–
Miyaura products 5a, 5f, 5g, 5l, and 5n followed by acid-
catalyzed hydrolysis of main products (2S,5S)-23 afforded
genation of the aromatic naphthyl substituent. Finally,
cross-coupled product 5f (Ar = 4-MeOC6H4) was hydroge-
nated for 24 h at 1800 psi of hydrogen pressure to afford
23e in 56% yield as a 92:8 mixture of the cis and trans
diastereomers, which were separated by flash chromatog-
raphy (Table 3).
Major diastereomeric products cis-23a–d were then ex-
highly enantioenriched (S)-2-aryl-β-amino acids (S)-24a–d
posed to hydrolytic conditions (4  HCl at ca. 100 °C, tem-
in moderate yields. These results indicate that the cross-
perature controlled with air) under microwave irradiation
coupling Suzuki–Miyaura cross-coupling reaction between
(200–250 W) to afford (2S)-arylsubstituted β-amino acids
potassium aryltrifluoroborates and (S)-5-iodopyrimidinone
24a–d (Scheme 6).
generate products that are suitable precursors to enantio-
merically pure β-amino acids.
While the asymmetric synthesis of β3 β-amino acids is
well developed,[5] the preparation of β2 β-amino acids is
much less common.[5–7] Particularly difficult is the incorpo-
ration of aryl substituents α to the carboxylic group; thus,
the present strategy employing the Suzuki–Miyaura cou-
pling methodology for the enantioselective preparation of
suitable precursos of β2 β-amino acids is most relevant.
Scheme 6. Acid-catalyzed hydrolysis of (2S,5S)-23a–d in the prepa-
ration of (2S)-arylpropionic acids 24a–d.
Experimental Section
For example, cis-disubstituted (2S,5S)-23a (Ar = C6H5,
105 °C, 250 W, 90 min) was hydrolyzed to afford (S)-3-
Material and Methods: All air-sensitive and/or water-sensitive reac-
amino-2-phenylpropionic acid (24a) in 78% yield and tions were carried out with dry solvents under anhydrous condi-
tions under a nitrogen atmosphere. Standard syringe techniques
were applied for the transfer of dry solvents and air-sensitive rea-
gents. The reactions were monitored by TLC on Merck silica gel
(60 F254) by using UV light as a visualizing agent and 5% vanillin
in 10% H2SO4 with heating as a developing agent. Sigma–Aldrich
silica gel (particle size 0.040–0.063 mm) was used for flash
chromatography. NMR spectra of cross-coupling products 5a–q
were recorded with a Bruker DPX 300 (300 MHz) instrument by
using CDCl3 solvent. NMR spectra of hydrogenated products 23a–
e and β-amino acids 24a–d were recorded with Jeol Eclipse-400 or
Bruker Avance 300 DPX spectrometers in [D6]DMSO or D2O sol-
90%ee. On the other hand, (2S,5S)-23b [(Ar = 4-MeC6H4),
98 °C, 200 W, 6 h] was hydrolyzed to afford (S)-3-amino-2-
(4-methylphenyl)propionic acid (24b) in 48% yield and
95%ee. Similarly, (2S,5S)-23c [(Ar = 4-tBuC6H4), 98 °C,
200 W, 13 h] was hydrolyzed to afford (S)-3-amino-2-(4-tert-
butylphenyl)propionic acid (24c) in 65% yield and 78%ee.
Finally, (2S,5S)-23d [Ar = 2-(5,6,7,8-tetrahydronaphthalen-
2-yl), 98 °C, 200 Ws, 10 h] was hydrolyzed to afford (S)-3-
amino-2-(5,6,7,8-tetrahydronaphthalen-2-yl)propionic acid
(24d) in 17% yield and 76%ee.
Eur. J. Org. Chem. 2010, 6393–6403
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6397

H. A. Stefani, E. Juaristi et al.
FULL PAPER
1
vent. Chemical shifts are reported in δ relative to (CH3)4Si for H
and CDCl3 for 13C NMR spectroscopy. Ratios of mixtures of dia-
stereomers were determined by peak integration in the 1H NMR
spectra of the crude products. Infrared (IR) spectra were obtained
from CHCl3 solutions using a Varian 3100 FTIR spectrophotome-
ter or Perkin–Elmer Spectrum GX instrument. Mass spectra (MS)
were measured with Shimadzu GC–MS-QP5050A or Hewlett–
Packard Model 5989 mass spectrometer. HRMS spectra were mea-
sured with a Bruker Daltonics Micro TOF (direct inlet probe) or
HPLC coupled to a MSD TOF Agilent Technologies Mod. 1969A
instrument. Microwave heating was carried out with a single mode
cavity Discover Microwave synthesizer (CEM Corporation, NC).
The crystallographic structure and corresponding data were ob-
tained with an Enraf–Nonius Kappa CCD diffractometer. CCDC-
784491 [(2S,5S)-23a] contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif. Elemental analyses were obtained by using
a Thermo Finnigan CHNS-1112 instrument.
and the reaction progress was monitored by TLC and GC. When
the reaction was complete, the reaction mixture was cooled and
then extracted with ethyl acetate (3ϫ50 mL). The organic layers
were combined and dried with MgSO4, and the solvent was re-
moved on a rotary evaporator to furnish a viscous oil. The product
was purified by column chromatography (ethyl acetate/hexane, 1:1)
to afford the cross-coupled product as a solid (see Table 2).
1-Benzoyl-(2S)-isopropyl-5-phenyl-2,3-dihydro-4(1H)-pyrimidin-4-
one (5a): Yield: 86 %, pale-yellow crystals, m.p. 173.2–174.8 °C,
[α]2D0 = +325.2 (c = 1, CHCl3). 1H NMR (300 MHz, CDCl3) δ =
7.48–7.59 (m, 6 H), 7.42 (dd, J = 8.1, 1.5 Hz, 2 H), 7.27–7.34 (m,
3 H), 6.66 (d, J = 4.38 Hz, 1 H), 5.68 (t, J = 6 Hz, 1 H), 2.36–2.43
(m, 1 H), 1.09 (d, J = 6.7 Hz, 3 H), 1.01 (d, J = 6.9 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.6, 163.7, 134.5; 133.6, 133.1,
131.6, 128.8 (2 C), 128.4 (2 C), 128.3 (2 C), 128.2, 127.7 (2 C),
116.9, 69.1, 33.0, 18.4, 17.6 ppm. MS (EI): m/z (%) = 320 (1)
[M]+, 277 (14), 105 (100), 89 (2), 77 (28), 51 (4), 43 (2). IR: ν =
˜
3396, 3053, 2992, 2859, 1652, 1607 cm–1. HRMS (ESI-TOF): calcd.
for C20H20N2O2 + H+ 321.1603; found 321.1611.
General Procedure for the Synthesis of the Potassium Aryltrifluoro-
borates:[19] The procedure for the synthesis of the potassium phen-
yltrifluoroborate is representative. A solution of phenylmagnesium
bromide 0.5  (10 mmol, 1.0 equiv.) in dry THF (20 mL) was co-
oled to –30 °C under a nitrogen atmosphere and trimethylborate
(1.24 g, 12 mmol, 1.2 equiv.) was added dropwise. The solution was
stirred at –30 °C for 1 h, after which it was warmed to room tem-
perature for 1 h. A saturated aqueous solution of potassium hydro-
gen difluoride (3.12 g, 40 mmol, 4.0 equiv.) was added at –10 °C to
the vigorously stirred solution. The resulting mixture was allowed
to stir for 1 h at –10 °C, after which it was warmed to room tem-
perature for 1 h. The solvent was removed under reduced pressure,
and the resulting white solid was dried under high vacuum for 2 h
to remove all water. The solid was then washed with acetone and
hot acetone. The resulting organic solution was filtered, and the
solvent was removed to afford a fluffy white solid. This solid was
then dissolved in hot acetone and precipitated with diethyl ether,
after which the solution was cooled to –20 °C to induce complete
precipitation of the solid. The potassium phenyltrifluoroborate was
collected as a white crystalline solid.
1-Benzoyl-(2S)-isopropyl-5-(thiophen-3-yl)-2,3-dihydro-4(1H)-pyr-
imidin-4-one (5b): Yield: 78 %, pale-yellow crystals, m.p. 163.5–
165.0 °C, [α]2D0 = +476.6 (c = 1, CHCl3). 1H NMR (300 MHz,
CDCl3) δ = 7.75 (d, J = 2.9 Hz, 1 H), 7.46–7.59 (m, 5 H), 7.36 (s,
1 H), 7.24–7.26 (m, 1 H), 7.13 (d, J = 5.0 Hz, 1 H), 6.9 (s, 1 H),
5.65 (s, 1 H), 2.31–2.43 (m, 1 H), 1.07 (d, J = 6.7 Hz, 3 H), 0.99
(d, J = 6.8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.3,
163.4, 133.3, 132.9, 132.8, 131.4, 128.6 (2 C), 128.3 (2 C), 125.7,
125.0, 123.0, 112.0, 68.7, 32.6, 18.2, 17.5 ppm. IR: ν = 3398, 3045,
˜
2989, 2862, 1670, 1608 cm–1. HRMS (ESI-TOF): calcd. for
C18H18N2O2S + H+ 327.1167; found 327.1193.
1-Benzoyl-5-(4-fluorophenyl)-(2S)-isopropyl-2,3-dihydro-4(1H)-pyr-
imidin-4-one (5d): Yield: 73 %, pale-yellow crystals, m.p. 152.0–
153.0 °C, [α]2D0 = +461.2 (c = 1, CHCl3). 1H NMR (300 MHz,
CDCl3) δ = 7.59–7.49 (m, 5 H), 7.39 (dd, J = 8.4, 5.76 Hz, 2 H),
7.21 (s, 1 H), 7.01 (t, J = 8.5 Hz, 2 H), 6.8 (s, 1 H), 5.67 (s, 1 H),
2.32–2.43 (m, 1 H), 1.08 (d, J = 6.6 Hz, 3 H), 1.00 (d, J = 6.6 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.6, 163.6, 162.1 (d,
3
J = 247 Hz, C-F), 134.5, 133.0, 131.7, 130.05 (d, J = 8.4 Hz, C-
F), 129.6 (d, 4J = 2.77 Hz, C-F), 128.8 (2 C), 128.4 (2 C), 115.8,
115.2 (d, J = 21.82 Hz, C-F), 69.2, 33.0, 18.4, 17.6 ppm. MS (EI):
m/z (%) = 338 (2) [M]+, 295 (16), 105 (100), 77 (37), 51 (5), 43 (2).
1-Benzoyl-5-iodo-(2S)-isopropyl-2,3-dihydro-4(H)-pyrimidin-4-one
(3b):[12] A suspension of the carboxylic acid (2S,6S)-1a[15b]
(1.0 mmol), DIB (644 mg, 2.0 mmol), and iodine (253 mg,
1.0 mmol) in CH2Cl2 (20 mL) was stirred at ambient temperature
until TLC showed disappearance of the starting material (4–4.5 h).
BF3·OEt2 (0.25 mL, 2 equiv.) was added, and the resulting mixture
was stirred for 1 h. Following the addition of CH2Cl2 (20 mL), the
reaction mixture was washed with 5 % aqueous Na2S2O3
(4 ϫ 15 mL), 3 % aqueous NaHCO3 (2 ϫ 10 mL), and brine
(2ϫ10 mL), dried with anhydrous Na2SO4, and evaporated to af-
ford the desired iodoenone as a yellow syrup that was purified by
flash chromatography. Yield: 78%, m.p. 218–220 °C. [α]2D5 = +389.2
IR: ν = 3398, 3042, 2990, 2857, 1663, 1624 cm–1. HRMS (ESI-
˜
TOF): calcd. for C20H19FN2O2 + H+ 339.1509; found 339.1529.
1-Benzoyl-(2S)-isopropyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-
4(1H)-pyrimidin-4-one (5e): Yield: 72%, pale-yellow crystals, m.p.
212.5–214.0 °C, [α]2D0
= +227.5 (c =
1, CHCl3). 1H NMR
(300 MHz, CDCl3) δ = 7.47–7.64 (m, 9 H), 7.32 (s, 1 H), 6.72 (d,
J = 4.5 Hz, 1 H), 5.69 (t, J = 6.0 Hz, 1 H), 2.33–2.44 (m, 1 H),
1.08 (d, J = 6.9 Hz, 3 H), 1.01 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3) δ = 168.5, 163.1, 137.0, 135.6, 132.5, 131.7, 129.4
(q, J = 32.4 Hz), 128.7 (2 C), 128.3 (2 C), 128.2 (2 C), 125.0 (q, J
= 3.75 Hz), 123.8 (q, J = 271 Hz), 115.0, 69.1, 32.9, 18.1, 17.3 ppm.
MS (EI): m/z (%) = 388 (1) [M]+, 345 (9), 105 (100), 77 (26), 51
1
(c = 1, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.50–7.59 (m, 6
H), 6.95 (d, J = 4.5 Hz, 1 H), 5.6 (t, J = 6 Hz, 1 H), 2,26–2.36 (m,
1 H), 1.04 (d, J = 6.7 Hz, 3 H), 0.96 (d, J = 6.7 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 169.0, 161.2, 142.0, 132.7, 131.4,
128.7 (2 C), 128.1 (2 C), 68.7, 32.4, 18.3, 17.6 ppm.
(4), 43 (10). IR: ν = 3403, 3023, 2995, 2863, 1684, 1646, 1311 cm–1.
˜
HRMS (ESI-TOF): calcd. for C21H19F3N2O2 + H+ 389.1477;
found 389.1495.
General Procedure for the Suzuki–Miyaura Cross-Coupling Reac-
tions: To a 50-mL round-bottom flask under a nitrogen atmosphere
was added potassium aryltrifluoroborate (1.2 mmol), (S)-5-iodo-
1-Benzoyl-(2S)-isopropyl-5-(4-methoxyphenyl)-2,3-dihydro-4(1H)-
pyrimidinone (5f): Yield: 95 %, greenish crystals, m.p. 188.1–
189.7 °C, [α]2D0 = +315.2 (c = 1, CHCl3). 1H NMR (300 MHz,
pyrimidinone (1.0 mmol, 370 mg), Pd(OAc)2 (9 mmol-%, CDCl3) δ = 7.45–7.59 (m, 5 H), 7.35 (d, J = 8.7 Hz, 2 H), 7.16 (s,
20.02 mg), K2CO3 (2 mmol, 276 mg), and degassed dioxane/H2O
(3:1, 16 mL). The reaction mixture was heated to reflux at 110 °C,
1 H), 6.85 (d, J = 8.7 Hz, 2 H), 6.47 (d, J = 4.2 Hz, 1 H), 5.66 (t,
J = 5.9 Hz, 1 H), 3.83 (s, 3 H), 2.33–2.42 (m, 1 H), 1.08 (d, J =
6398
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6393–6403

Enantioselective Preparation of α-Substituted β-Amino Acids
6.6 Hz, 3 H), 1.00 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3) δ = 168.6, 164.0, 159.3, 137.5, 133.5, 133.2, 131.6, 129.5 (2
C), 128.8 (2 C), 128.4 (2 C), 116.6, 113.8 (2 C), 69.0, 55.3, 32.9,
18.4, 17.7 ppm. MS (EI): m/z (%) = 350 (4) [M]+, 307 (4), 105 (100),
13C NMR (75 MHz, CDCl3) δ = 17.7, 18.4, 20.4, 32.8, 69.3, 117.6,
125.8, 128.2 (2 C), 128.2, 128.7 (2 C), 129.9, 130.2, 131.5, 133.23,
133.29, 135.8, 137.6, 163.1, 168.6 ppm. MS (EI): m/z (%) = 334 (1)
[M]+, 291 (12), 105 (100), 77 (28), 71 (7), 43 (38), 40 (8). IR: ν =
˜
77 (25), 51 (3), 43 (2). IR: ν = 3422, 3027, 3995, 2875, 1670, 1617, 3403, 3041, 2985, 2943, 2886, 1670, 1616 cm–1. HRMS (ESI-TOF):
˜
1245 cm–1. HRMS (ESI-TOF): calcd. for C21H22N2O3 + H+
351.1709; found 351.1740.
calcd. for C21H22N2O2 + H+ 335.1760; found 335.1748.
1-Benzoyl-(2S)-isopropyl-5-(naphthalen-2-yl)-2,3-dihydro-4(1H)-pyr-
imidin-4-one (5l): Yield: 70%, yellow-greenish crystals, m.p. 189.2–
191.0 °C, [α]2D0 = +405.1 (c = 1, CHCl3). 1H NMR (300 MHz,
CDCl3) δ = 7.9 (s, 1 H), 7.79 (d, J = 8.4 Hz, 3 H), 7.43–7.63 (m, 8
1-Benzoyl-(2S)-isopropyl-5-p-tolyl-2,3-dihydro-4(1H)-pyrimidin-4-
one (5g): Yield: 72 %, pale-yellow crystals, m.p. 161.0–162.8 °C,
[α]2D0 = +355.9 (c = 1, CHCl3). 1H NMR (300 MHz, CDCl3) δ =
7.45–7.54 (m, 5 H), 7.31 (d, J = 8.1 Hz, 1 H), 7.19 (s, 1 H), 7.13 H), 7.36 (s, 1 H), 6.87 (d, J = 4.2 Hz, 1 H), 5.7 (s, 1 H), 2.39–2.50
(d, J = 8.1 Hz, 2 H), 6.61 (d, J = 3.3 Hz, 1 H), 5.66 (s, 1 H), 2.35– (m, 1 H), 1.12 (d, J = 6.69 Hz, 3 H), 1.04 (d, J = 6.84 Hz, 3 H) ppm.
2.42 (m, 1 H), 2.32 (s, 3 H), 1.08 (d, J = 6.9 Hz, 3 H), 1.00 (d, J = 13C NMR (75 MHz, CDCl3): δ = 168.6, 163.6, 134.8, 133.19,
6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3) δ = 168.3, 163.3,
133.11, 132.7, 131.7, 131.1, 128.8 (2 C), 128.5 (2 C), 128.0, 127.7,
137.4, 133.8, 132.9, 131.3, 130.4, 128.7 (2 C), 128.6 (2 C), 128.2 (2 127.5, 127.4, 126.1 (3 C), 116.8, 69.3, 33.0, 18.4, 17.7 ppm. MS
C), 128.0 (2 C), 116.6, 68.9, 32.7, 20.9, 18.2, 17.4 ppm. MS (EI):
(EI): m/z (%) = 370 (4) [M]+, 327 (6), 105 (92), 77 (28), 71 (6), 44
m/z (%) = 334 (3) [M]+, 291 (14), 105 (100), 77 (27), 51 (3), 43 (2).
(100), 43 (30). IR: ν = 3413, 3028, 2940, 2895, 1680, 1635 cm–1.
˜
IR: ν = 3404, 3025, 2994, 2940, 2886, 1670, 1624 cm–1. HRMS
HRMS (ESI-TOF): calcd. for C24H22N2O2 + H+ 371.1760; found
371.1790.
˜
(ESI-TOF): calcd. for C21H22N2O2 + H+ 335.1760; found 335.1789.
1-Benzoyl-5-[4-(ethylthio)phenyl]-(2S)-isopropyl-2,3-dihydro-4(1H)- 1-Benzoyl-5-(3-hydroxyphenyl)-(2S)-isopropyl-2,3-dihydro-4(1H)-
pyrimidin-4-one (5h): Yield: 65%, pale-yellow crystals, m.p. 182.8–
pyrimidin-4-one (5m): Yield: 72 %, yellow crystals, m.p. 123.2–
184.5 °C, [α]2D0 = +356.7 (c = 1, CHCl3). 1H NMR (300 MHz,
125.0 °C, [α]2D0 = +405.1 (c = 1, MeOH). 1H NMR (300 MHz,
CDCl3) δ = 7.46–7.59 (m, 5 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.24– [D6]DMSO) δ = 9.31 (d, J = 1.2 Hz, 1 H), 8.54 (d, J = 4.44 Hz, 1
7.27 (m, 3 H), 6.76 (d, J = 4.5 Hz, 1 H), 5.66 (s, 1 H), 2.92 (q, J = H), 7.54–7.58 (m, 5 H), 7.17 (s, 1 H), 7.07 (t, J = 7.98 Hz, 1 H),
7.5 Hz, 2 H), 2.31–2.43 (m, 1 H), 1.23–1.36 (m, 3 H), 1.08 (d, J = 6.9 (s, 1 H), 6.78 (d, J = 7.17 Hz, 2 H), 6.65 (d, J = 8.01 Hz, 1 H),
6.7 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 168.3, 163.2, 136.2, 134.0, 132.8, 131.4, 130.7, 128.6
(2 C), 128.4 (2 C), 128.3 (2 C), 128.2 (2 C), 115.9, 68.9, 32.7, 27.2,
5.39 (s, 1 H), 2.14–2.26 (m, 1 H), 0.97 (d, J = 6.27 Hz, 3 H), 0.90
(d, J = 6.45 Hz, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
168.4, 162.5, 157.3, 135.8, 134.2, 133.7, 131.8, 129.3, 129.2 (2 C),
18.1, 17.4, 14.1 ppm. MS (EI): m/z (%) = 380 (5) [M]+, 337 (7), 105 128.7 (2 C), 119.1, 116.6, 115.6, 114.7, 68.5, 33.2, 18.8, 18.1 ppm.
(100), 77 (26), 51 (3), 43 (3). IR: ν = 3393, 3058, 2991, 2945, 2898,
MS (EI): m/z (%) = 336 (1) [M]+, 293 (10), 105 (100), 77 (27),
1668, 1630 cm–1. HRMS (ESI-TOF): calcd. for C22H24N2O2S + H+ 44 (16), 41 (4). HRMS (ESI-TOF): calcd. for C20H20N2O3 + H+
˜
381.1637; found 381.1605.
337.1552; found 337.1599.
1-Benzoyl-5-(4-benzonitrile)-(2S)-isopropyl-2,3-dihydro-4(1H)-pyr-
1-Benzoyl-5-(4-tert-butylphenyl)-(2S)-isopropyl-2,3-dihydro-4(1H)-
imidin-4-one (5i): Yield: 30%, white crystals, m.p. 194.9–196.2 °C, pyrimidin-4-one (5n): Yield: 75 %, white crystals, m.p. 220.5–
[α]2D0 = +160.8 (c = 1, CHCl3). 1H NMR (300 MHz, CDCl3) δ = 222.4 °C, [α]2D0 = +382.6 (c = 1, CHCl3). 1H NMR (300 MHz,
7.51–7.58 (m, 9 H), 7.36 (s, 1 H), 6.94 (s, 1 H), 5.68 (s, 1 H), 2.33– CDCl3) δ = 7.35–7.59 (m, 1 H), 7.22 (m, 5 H), 6.23 (s, 1 H), 5.67
2.40 (m, 1 H), 1.07 (d, J = 6.6 Hz, 3 H), 1.00 (d, J = 6.7 Hz, 3 (s, 1 H), 2.35–2.42 (m, 1 H), 1.27 (s, 9 H), 1.08 (d, J = 6.6 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3) δ = 168.7, 163.1, 153.8, H), 1.00 (d, J = 6.78 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
138.4, 136.3, 132.6, 132.0 (2 C), 129.0 (2 C), 128.7 (2 C), 128.4 (2 δ = 168.6, 163.4, 150.8, 134.1, 133.2, 131.6, 130.6, 128.8 (2 C), 128.4
C), 118.7, 114.6, 111.0, 69.3, 33.2, 18.3, 17.5 ppm. MS (EI): m/z (2 C), 127.9 (2 C), 125.3 (2 C), 115.4, 69.2, 34.5, 33.0, 31.3 (3 C),
(%) = 345 (4) [M]+, 302 (7), 105 (100), 77 (28), 51 (5), 43 (3). IR: 18.4, 17.6 ppm. MS (EI): m/z (%) = 376 (1) [M]+, 233 (10), 105
ν = 3410, 3055, 2951, 2898, 2227, 1688, 1625 cm–1. HRMS (ESI-
(100), 77 (19), 57 (3), 43 (4). IR: ν = 3409, 3028, 2992, 2895, 2835,
˜
˜
TOF): calcd. for C21H19N3O2 + H+ 346.1556; found 346.1593.
1675, 1632 cm–1. HRMS (ESI-TOF): calcd. for C24H28N2O2 + H+
377.2229; found 377.2211.
1-Benzoyl-5-(4-formylphenyl)-(2S)-isopropyl-2,3-dihydro-4(1H)-pyr-
imidin-4-one (5j): Yield: 62 %, yellowish crystals, m.p. 170.1–
172.0 °C, [α]2D0 = +266.4 (c = 1, CHCl3). 1H NMR (300 MHz,
1-Benzoyl-5-(4-chlorophenyl)-(2S)-isopropyl-2,3-dihydro-4-(1H)-pyr-
imidin-4-one (5o): Yield: 59 %, pale-yellow crystals, m.p. 161.9–
CDCl3) δ = 9.98 (s, 1 H), 7.84 (d, J = 8.01 Hz, 2 H), 7.49–7.64 (m, 162.6 °C, [α]2D0 = +362.1 (c = 1, CHCl3). 1H NMR (300 MHz,
7 H), 7.39 (s, 1 H), 6.71 (d, J = 4.56 Hz, 1 H), 5.69 (t, J = 5.64 Hz, CDCl3): δ = 1.01 (d, J = 6.84 Hz, 3 H), 1.08 (d, J = 6.69 Hz, 3 H),
1 H), 2.34–2.45 (m, 1 H), 1.09 (d, J = 6.69 Hz, 3 H), 1.02 (d, J = 2.32–2.42 (m, 1 H), 5.66 (s, 1 H), 6.47 (d, J = 4.47 Hz, 1 H), 7.26–
6.84 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ = 191.7, 168.6,
7.30 (m, 3 H), 7.37 (d, J = 8.58 Hz, 2 H), 7.47–7.59 (m, 5 H) ppm.
162.9, 139.8, 136.1, 135.3, 132.7, 131.9, 129.6 (2 C), 128.9 (2 C), 13C NMR (75 MHz, CDCl3): δ = 17.6, 18.4, 33.0, 69.3, 115.5,
128.6 (2 C), 128.5 (2 C), 115.2, 69.4, 33.1, 18.4, 17.5 ppm. MS (EI): 128.4, 128.46, 128.49, 128.9, 129.5, 131.8, 132.0, 132.9, 133.7,
m/z (%) = 348 (2) [M]+, 305 (9), 278 (3), 105 (100), 77 (32), 71 (32), 134.7, 163.1, 168.6 ppm. MS (EI): m/z (%) = 354 (1) [M]+, 311 (6),
56 (4), 51 (4). IR: ν = 3420, 3055, 2952, 2883, 1699, 1647,
277 (1), 105 (100), 77 (26), 51 (4). IR: ν = 3495, 3026, 2964, 2915,
˜
˜
1593 cm–1. HRMS (ESI-TOF): calcd. for C21H20N2O3 + H+
349.1552; found 349.1537.
2869, 1685, 1664 cm– 1 . HRMS (ESI-TOF): calcd. for
C20H19ClN2O2 + H+ 355.1213; found 355.1215.
1-Benzoyl-(2S)-isopropyl-5-o-tolyl-2,3-dihydro-4(1H)-pyrimidin-4-
one (5k): Yield: 66 %, pale-yellow crystals, m.p. 198.7–200.5 °C,
[α]2D0 = +338.9 (c = 1, CHCl3). 1H NMR (300 MHz, CDCl3) δ =
1-Benzoyl-(2S)-isopropyl-5-[4-(N-CBz)-phenyl]-2,3-dihydro-4(1H)-
pyrimidin-4-one (5q): Yield: 62 %, yellow-greenish crystals, m.p.
114.5–116.3 °C, [α]2D0
= +316.5 (c =
1, CHCl3). 1H NMR
7.46–7.57 (m, 5 H), 7.12–7.22 (m, 3 H), 7.06 (d, J = 6.9 Hz, 2 H), (300 MHz, CDCl3) δ = 7.44–7.54 (m, 5 H), 7.30–7.35 (m, 9 H),
6.27 (d, J = 4.74 Hz, 1 H), 5.69 (s, 1 H), 2.48–2.57 (m, 1 H), 2.26 7.18 (s, 1 H), 6.68 (s, 1 H), 6.20 (d, J = 4.8 Hz, 1 H), 5.59 (s, 1 H),
(s, 3 H), 1.16 (d, J = 6.69 Hz, 3 H), 1.03 (d, J = 6.84 Hz, 3 H) ppm. 5.17 (s, 2 H), 2.28–2.39 (m, 1 H), 1.03 (d, J = 6.7 Hz, 3 H), 0.96
Eur. J. Org. Chem. 2010, 6393–6403
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6399

H. A. Stefani, E. Juaristi et al.
FULL PAPER
(d, J = 6.81 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.6,
163.8, 153.4, 137.6, 136.0, 134.0, 133.1, 131.7, 128.9, 128.8, 128.6
(3 C), 128.48 (2 C), 128.40 (2 C), 128.3 (2 C), 118.5, 116.3, 69.0,
67.0, 32.9, 18.4, 17.6 ppm. MS (EI): m/z (%) = 469 (1) [M]+, 318
stereomer (2S,5S)-23b was determined by HPLC (Chiralcel OD-H,
hexane/EtOH = 90:10, 220 nm, 1 mL/min) to predominate by a
99.7:0.3 ratio over the trans (2S,5R)-23b isomer. Data for major
diastereomer (2S,5S)-23b: Yield: 697 mg (87%), m.p. 168–170 °C
(6), 105 (100), 77 (32), 71 (25), 56 (4), 44 (19), 43 (10). IR: ν = (MeOH/H2O), [α]2D5 = –99 (c = 1, CHCl3). 1H NMR (500 MHz,
˜
3403, 3029, 2990, 2889, 1734, 1697, 1663 cm–1. HRMS (ESI-TOF):
calcd. for C28H27N3O4 + H+ 470.2080; found 470.2099.
[D6]DMSO, 120 °C): δ = 8.06 (s, 1 H, NH), 7.44 (s, 5 H, ArH),
7.06 (d, J = 7.9 Hz, 2 H, ArH), 7.0 (d, J = 8.0 Hz, 2 H, ArH), 5.17
(br., 1 H, *CH), 4.03 (br., 1 H, *CH), 3.60 (dd, J = 7.1, 11.6 Hz,
1 H, CH2), 3.41 (dd, J = 12.0, 12.75 Hz, 1 H, CH2), 2.24 (s, 3 H,
CH3), 2.20–2.12 (m, 1 H, CH), 1.03 (d, J = 6.6 Hz, 3 H, CH3), 0.92
(d, J = 6.8 Hz, 3 H, CH3 ) ppm. 1 3C NMR (125.76 MHz,
[D6]DMSO, 120 °C): δ = 170.3, 169.6, 136.6, 136.1, 135.4, 130.3,
General Procedure for the Hydrogenation of the Suzuki–Miyaura
Cross-Coupled Products: In a hydrogenation flask and under a ni-
trogen atmosphere, the required amount of aryl-substituted pyrim-
idinone, methanol (60 mL), Raney-Ni (1.0 g per 100 mg of hetero-
cycle), and acetic acid (1.5 mL) were added. The resulting mixture
was pressurized to 1500–1800 psi of hydrogen and stirred mechani-
cally at 80 °C for 24–48 h. The reaction mixture was filtered, and
the filtrate was concentrated on a rotary evaporator. The residue
was dissolved in ethyl acetate and washed with a saturated solution
of potassium and sodium tartrate. The organic phase was dried
(anhydrous Na2SO4) and concentrated on a rotary evaporator to
afford the crude product, which was purified by flash chromatog-
raphy.
129.4, 129.0, 127.1, 68.8, 47.9, 34.6, 20.9, 19.1, 18.7 ppm. IR: ν =
˜
3197, 3062, 2971, 2883, 1666, 1639, 1411, 1317, 1279, 1129,
1010 cm–1. MS (EI): m/z (%) = 336 (1.1) [M]+, 294.1 (9.5), 293
(49.6), 230 (3), 132 (14.3), 105 (100), 77 (41). HRMS (ESI-TOF):
calcd. for C21H24 N2 O2 + H+ 337.1910; found 337.1916.
C21H24N2O2 (336.43): calcd. C 74.97, H 7.19, N 8.33; found C
74.97, H 7.53, N 8.22.
(2S,5S)-1-Benzoyl-5-(4-tert-butylphenyl)-2-isopropyltetrahydropyr-
imidin-4(1H)-one [(2S,5S)-23c]: Following the general procedure,
(S)-5n (829 mg, 2.20 mmol) and Raney-Ni (8.3 g) under 1800 psi of
H2 were heated with mechanical stirring at 80 °C for 24 h to give
a diastereomeric mixture of products (561 mg, 67% yield) in an
89:11 cis/trans ratio. After purification, these diastereomers were
separated by flash chromatography (ethyl acetate/hexane, 70:30).
Data for major diastereomer (2S,5S)-23c: Yield: 502 mg (60%),
m.p. 140–141 °C (MeOH/H2O), [α]2D5 = –91.5 (c = 1, CHCl3). 1H
NMR (400 MHz, [D6]DMSO, 120 °C): δ = 8.06 (s, 1 H, NH), 7.47
(s, 5 H, ArH), 7.30 (d, J = 8.4 Hz, 2 H, ArH), 7.07 (d, J = 8.4 Hz,
2 H, ArH), 5.20 (d, J = 5.6 Hz, 1 H, *CH), 4.05 (br., 1 H, *CH),
3.63 (dd, J = 7.1, 11.6 Hz, 1 H, CH2), 3.46 (dd, J = 11.9, 13.7 Hz,
1 H, CH2), 2.27–2.15 (m, 1 H, CH), 1.27 (s, 9 H, CH3), 1.06 (d, J
= 6.6 Hz, 3 H, CH3), 0.94 (d, J = 6.8 Hz, 3 H, CH3) ppm. 13C
NMR (100.5 MHz, [D6]DMSO, 120 °C): δ = 170.3, 169.7, 150.1,
136.2, 135.4, 130.3, 129.0, 128.8, 127.1, 125.6, 89.9, 68.8, 47.9, 45.7,
(2S,5S)-1-Benzoyl-2-isopropyl-5-phenylperhydropyrimidin-4-one-
[(2S,5S)-23a]: Following the general procedure, (S)-5a (760 mg,
2.37 mmol) and Raney-Ni (7.6 g) under 1500 psi of hydrogen were
heated with mechanical stirring at 80 °C for 24 h to afford a dia-
stereomeric 95:5 mixture (561 mg, 73% yield). After purification,
the cis and trans diastereomeric products were separated by flash
chromatography (ethyl acetate/hexane, 70:30). Data for major dia-
stereomer (2S,5S)-23a: Yield: 531 mg (69 %), m.p. 217–218 °C
(CH2Cl2/Hexane), [α]2D5 = –84.5 (c = 1, CHCl3). HPLC (Chiralcel
OD-H, hexane/EtOH = 90:10, 220 nm, 1 mL/min): tR = 29.63 min.
1H NMR (500 MHz, [D6]DMSO, 120 °C): δ = 8.09 (s, 1 H, NH),
7.45 (s, 5 H, ArH), 7.28–7.25 (m, 2 H, ArH), 7.22–7.18 (m, 1 H,
ArH), 7.14–7.12 (m, 2 H, ArH), 5.18 (s, 1 H, CH), 4.05 (s, 1 H,
CH), 3.67 (dd, J = 7.1, 11.7 Hz, 1 H, CH2), 3.45 (dd, J = 12.0,
13.5 Hz, 1 H, CH2), 2.20–2.18 (m, 1 H, CH), 1.04 (d, J = 6.7 Hz,
3 H, CH3), 0.92 (d, J = 6.7 Hz, 3 H, CH3) ppm. 13C NMR
(125.76 MHz, [D6]DMSO, 120 °C): δ = 170.3, 169.5, 138.4, 136.1,
130.3, 130.2, 129.0, 128.8, 127.3, 127.1, 68.8, 48.3, 45.6, 34.6, 19.1,
34.6, 31.6, 19.1, 18.7 ppm. IR: ν = 3199, 2961, 1668, 1650, 1403,
˜
1277, 1209, 1012 cm–1. MS (EI): m/z (%) = 379 (1) [M + 1]+, 335
(66), 272 (6), 159 (6), 145 (4), 105 (100), 77 (2). C24H30N2O2
(378.51): calcd. C 76.16, H 7.99, N 7.40; found C 76.03, H 8.17, N
7.21.
18.7 ppm. IR: ν = 3266, 2927, 1727, 1663, 1636, 1433, 1388, 1319,
˜
1273 cm–1. MS (EI): m/z (%) = 322 (1) [M]+, 279 (78), 216 (5), 175
(3), 118 (5), 105 (100), 77 (5). C20H22N2O2 (322.40): calcd. C 74.51,
H 6.88, N 8.69; found C 74.73, H 6.92, N 8.91. Data for minor
diastereomer (2S,5R)-23a: Yield: 30 mg (4 %), m.p. 86–88 °C
(CH2Cl2/Hexane), [α]2D5 = +53.2 (c = 0.63, CHCl3). HPLC (Chi-
(2S,5S)-1-Benzoyl-2-isopropyl-5-(5,6,7,8-tetrahydronaphthalen-2-
yl)perhydropyrimidin-4-one [(2S,5S)-23d]: Following the general
procedure, (S)-5l (916 mg, 2.47 mmol) and Raney-Ni (9.2 g) under
1800 psi of H2 were heated with mechanical stirring at 80 °C for
24 h to give a diastereomeric 76:24 mixture (713 mg, 77% yield).
The cis and trans diastereomeric products were separated by flash
chromatography (ethyl acetate/hexane, 70:30). Data for major dia-
stereomer (2S,5S)-23d: Yield: 538 mg (58 %), m.p. 151–153 °C
(CH2Cl2/Hexane), [α]2D5 = –86 (c = 1, CHCl3). 1H NMR (300 MHz,
[D6]DMSO, 120 °C): δ = 7.99 (s, 1 H, NH), 7.46 (s, 5 H, ArH),7.01–
6.8 (m, 3H Ar H), 5.20 (d, J = 7.2 Hz, 1 H, *CH), 4.03 (dd, J =
6.0, 12.6 Hz, 1 H, *CH), 3.56 (dd, J = 6.4, 11.5 Hz, 1 H, CH2),
3.46 (dd, J = 11.7, 12.9 Hz, 1 H, CH2), 2.66 (s, 4 H, CH2), 2.27–
2.13 (m, 1 H, CH), 1.72 (s, 4 H, CH2), 1.05 (d, J = 6.6 Hz, 3 H,
CH3), 0.94 (d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75.5 MHz,
[D6]DMSO, 120 °C): δ = 170.2, 169.86 137.2, 136.1, 136.0, 135.3,
130.2 129.4, 129.1, 128.9, 127.0, 126.1, 68.8, 48.0, 45.6, 34.5,
ralcel OD-H, hexane/EtOH = 90:10, 220 nm, 1 mL/min): tR
=
35.30 min. 1H NMR (500 MHz, [D6]DMSO): δ = 8.65 (d, J =
3.3 Hz, 1 H, NH), 7.35–7.05 (m, 6 H, ArH), 6.93 (s, 2 H, ArH),
6.60 (d, J = 7.2 Hz, 2 H, ArH), 5.54 (d, J = 6.8 Hz, 1 H, CH), 3.90
(dd, J = 3.0, 13.5 Hz, 1 H, CH), 3.50–3.40 (m, 2 H, CH2), 2.2–2.1
(m, 1 H, CH), 1.03 (d, J = 6.2 Hz, 3 H, CH3), 0.91 (d, J = 6.4 Hz,
3 H, CH3) ppm. 13C NMR (125.76 MHz, [D6]DMSO): δ = 170.8,
169.1, 140.1, 135.5, 129.8, 128.9, 128.6, 128.5, 127.4, 126.7, 66.3,
47.5 (2 C), 34.1, 19.2, 18.6 ppm. MS (EI): m/z (%) = 322 (3.2) [M]
+, 279 (73), 216 (11.6), 175 (1.9), 118 (3.5), 106 (7.5), 105 (100), 77
(4.3). IR: ν = 3200, 2965, 2360, 2162, 1979.1667, 1643, 1410, 1390,
˜
698 cm–1. HRMS (ESI-TOF): calcd. for C20H22N2O2 + H+
323.1754; found 323.1746.
(2S,5S)-1-Benzoyl-2-isopropyl-5-(4-methylphenyl)tetrahydropyrim-
idin-4-one [(2S,5S)-23b]: Following the general procedure, (S)-5g
(800 mg, 2.39 mmol) and Raney-Ni (8.0 g) under 1800 psi of H2
were heated with mechanical stirring at 80 °C for 48 h to give essen-
tially one diastereomer (697 mg, 87% yield). Indeed, the cis dia-
29.2,28.9 23.1, 19.0, 18.6 ppm. IR: ν = 3209, 2932, 2162, 1667,
˜
1639, 1430, 1361, 1313, 1216, 1014 cm–1. MS (EI): m/z (%) = 376
(5) [M]+, 333 (100), 305 (9), 229 (42), 172 (12), 105 (98). HRMS
(ESI-TOF): calcd. for C24H28N2O2 + H+ 377.2223; found 377.2213.
Data for minor diastereomer (2S,5R)-23d: Yield: 175 mg (19%),
6400
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6393–6403

Enantioselective Preparation of α-Substituted β-Amino Acids
foam, [α]2D5 = +64 (c = 1, CHCl3). 1H NMR (300 MHz, [D6]DMSO,
120 °C): δ = 8.02 (s, 1 H, NH), 7.31–7.19 (m, 3 H, ArH), 6.90 (d,
J = 4.6 Hz, 1 H ArH), 6.82–6.68 (m, 4 H, ArH), 5.44 (br., 1 H,
ArH), 7.14–7.10 (m, 2 H, ArH), 3.86 (t, J = 7.5 Hz, 1 H, CH), 3.37
(dd, J = 13.1, 7.6 Hz, 1 H, CH2), 3.13 (dd, J = 13.1, 7.4 Hz, 1 H,
CH2) ppm. 13C NMR (125.76 MHz, D2O): δ = 174.6 (C=O), 134.3
*CH), 3.83 (dd, J = 4.8, 14 Hz, 1 H, CH2), 3.7 (br., 1 H, CH), 3.48 (Cipso), 129.6 (CHAr), 128.9 (CHAr), 128.3 (CHAr), 48.5 (CH),
(s, 1 H, CH2), 2.68–2.54 (m, 4 H, CH2), 2.20–2.13 (m, 1 H, CH), 41.1 (CH2) ppm. HPLC [Chirobiotic T column, EtOH/H2O =
1.78–1.68 (m, 4 H, CH2), 1.03 (d, J = 6.75 Hz, 3 H, CH3), 0.93 (d,
J = 6.7 Hz, 3 H, CH3) ppm. 13C NMR (125.76 MHz, [D6]DMSO,
120 °C): δ = 170.7, 169.3, 137.2, 137.1, 136.04, 136.01, 129.0,
128.4,128.3, 127.0, 126.9, 125.7, 67.7, 47.4, 47.0, 34.4, 29.4, 29.3,
50:50, 210 nm, 1 mL/min; er = 5:95 (R/S)]: tR = 6.93 (minor, R),
11.32 (major, S) min.
rac-3-Amino-2-phenylpropionic Acid (rac-24a): This compound was
prepared according to a literature procedure[22] to obtain rac-24a
in an overall yield of 42%. Spectroscopic and physical data were
consistent with the literature values.
28.9, 23.3, 23.2, 18.9, 18.6 ppm. IR: ν = 3202, 2926, 2855, 1665,
˜
1643, 1446, 1408, 1389, 1311, 1277, 1020 cm–1. MS (EI): m/z (%)
= 376 (12) [M]+, 333 (100), 305 (9), 270 (15), 229 (13), 172 (7), 105
(82). HRMS (ESI-TOF): calcd. for C24H28N2O2 + H+ 377.2223;
found 377.2225.
(S)-3-Amino-2-(4-methylphenyl)propionic Acid [(S)-24b]: Following
general procedure A (105 °C, 250 W, 90 min), (2S,5S)-23b (100 mg,
0.3 mmol) afforded (S)-24b (26 mg, 48% yield) as a powder, which
1-Benzoyl-(2S)-isopropyl-(5S)-(4-methoxyphenyl)perhydropyrimidin-
4-one, (2S,5S)-23e: Following the general procedure, (S)-5f
(820 mg, 2.34 mmol) and Raney-Ni (8.2 g) under 1800 psi of H2
were heated with mechanical stirring at 80 °C for 24 h to give a
diastereomeric 92:8 cis/trans mixture (459 mg, 56% yield). The dia-
stereomeric products were separated by flash chromatography
(ethyl acetate/hexane, 70:30). Data for major diastereomer (2S,5S)-
2e: Yield: 423 mg (51%), m.p. 188–189 °C (CH2Cl2/hexane), [α]2D5
was crystallized from methanol/ether. M.p. 229–230 °C, [α]2D5
=
1
–54.2 (c = 0.48, 1  HCl). H NMR (500 MHz, D2O): δ = 6.97 (d,
J = 8.2 Hz, 2 H, ArH), 6.9 (d, J = 8.1 Hz, 2 H, ArH), 3.75 (t, J =
7.4 Hz, 1 H, CH), 3.28 (dd, J = 13.2, 7.7 Hz, 1 H, CH2), 3.0 (dd,
J = 13.0, 7.5 Hz, 1 H, CH2), 2.0 (s, 3 H, CH3) ppm. 13C NMR
(125.76 MHz, D2O): δ = 174.7 (C=O), 139.1 (Cipso), 131.0 (Cipso),
130.0 (CHAr), 128.1 (CHAr), 48.0 (CH), 41.0 (CH2), 20.1
(CH ) ppm. IR: ν = 2922, 2858, 2756, 2624, 2162, 1624, 1570, 1512,
˜
3
1
= –107 (c = 1, CHCl3). H NMR (400 MHz, [D6]DMSO, 120 °C):
1380 cm–1. HRMS (ESI-TOF): calcd. for C10H13N1O2 + H+
180.1019; found 180.1026. HPLC [Chirobiotic T column, EtOH/
H2O = 50:50, 210 nm, 1 mL/min; er = 2.5:97.5 (R/S)]: tR = 6.46
(minor, R), 10.33 (major, S) min. MS (EI): m/z (%) = 179 (14) [M+],
162 (18), 150 (86), 132 (100), 117 (48), 105 (88), 91 (39), 77 (56).
δ = 8.04 (s, 1 H, NH), 7.46 (s, 5 H, ArH), 7.06 (d, J = 8.8 Hz, 2
H, ArH), 6.85 (d, J = 8.6 Hz, 2 H, ArH), 5.19 (d, J = 6.6 Hz, 1 H,
*CH), 4.05 (br., 1 H, *CH), 3.74 (s, 3 H, CH3), 3.62 (dd, J = 7.1,
11.6 Hz, 1 H, CH2), 3.44 (dd, J = 12.0, 13.5 Hz, 1 H, CH2), 2.26–
2.14 (m, 1 H, CH), 1.05 (d, J = 6.5 Hz, 3 H, CH3), 0.94 (d, J =
6.8 Hz, 3 H, CH3) ppm. 13C NMR (100.5 MHz, [D6]DMSO,
120 °C): δ = 170.3, 169.8, 159.2, 136.2, 130.5, 130.3, 130.2, 129.0,
rac-3-Amino-2-(4-methylphenyl)propionic Acid (rac-24b): Following
general procedure B (10 d), (2S,5S)-23b (100 mg, 0.3 mmol) af-
forded rac-24b (28 mg, 53% yield) as a powder, which was crys-
tallized from methanol/diethyl ether. M.p. 226–228 °C. 1H NMR
(500 MHz, D2O): δ = 6.71 (d, J = 8.3 Hz, 2 H, ArH), 6.68 (d, J =
8.3 Hz, 2 H, ArH), 3.5 (t, J = 7.4 Hz, 1 H, CH), 3.02 (dd, J =
13.02, 7.7 Hz, 1 H, CH2), 2.78 (dd, J = 12.9, 7.6 Hz, 1 H, CH2),
1.7 (s, 3 H, CH3) ppm. 13C NMR (125.76 MHz, D2O): δ = 174.4
(C=O), 138.9 (Cipso), 130.8 (Cipso), 129.8 (CHAr), 127.9 (CHAr),
127.1, 114.7, 68.9, 55.9, 47.5, 45.7, 34.6, 19.1, 18.7 ppm. IR: ν =
˜
3199, 3062, 2966, 1666, 1639, 1514, 1421, 1318, 1279, 1242 cm–1.
MS (EI): m/z (%) = 352 (3) [M]+, 309 (63), 281 (31), 205 (32), 148
(16), 105 (100), 83 (8). C21H24N2O3 (352.43): calcd. for
C21H24N2O3 C 71.57, H 6.86, N 7.95; found C 71.19, H 7.24, N
7.98.
General Procedure for the Hydrolysis of (2S,5S)-23
47.7 (CH), 40.8 (CH ), 20.0 (CH ) ppm. IR: ν = 3125, 3026, 2956,
˜
2
3
Method A: In a 50-mL round-bottom flask was placed the required
2923, 2184, 1727, 1647, 1622, 1568, 1512, 1394 cm–1. HRMS (ESI-
perhydropyrimidinone (2S,5S)-23a–d (100 mg), 4  HCl (13 mL), TOF): calcd. for C10H13N1O2 + H+ 180.1019; found 180.1030.
and 1,4-dioxane (2 mL). The resulting mixture was placed inside a
microwave apparatus adapted with a reflux condenser and irradi-
ated with 200–250 W for 1.5–12 h at 98–105 °C by using an air-
cooling system to control the temperature. The reaction mixture
was allowed to reach room temperature and was then extracted
with CH2Cl2 (3ϫ20 mL). The aqueous phase was concentrated un-
der reduced pressure, and the residue was purified by flash silica
gel chromatography (230–400 mesh) using 2-propanol/methanol/
NH4OH (5:2:1) as eluent.[20]
HPLC (Chirobiotic T column, EtOH/H2O = 50:50, 210 nm, 1 mL/
min): tR = 6.4 (R), 11.02 (S) min. MS (EI): m/z (%) = 179 (16)
[M+], 162 (46), 150 (100), 132 (96), 117 (76), 105 (98), 91 (50), 77
(46).
(S)-3-Amino-2-(4-tert-butylphenyl)propionic Acid [(S)-24c]: Follow-
ing general procedure A (98 °C, 200 W, 13 h), (2S,5S)-23c (100 mg,
0.26 mmol) afforded (S)-24c (34 mg, 65% yield) as a powder, which
was crystallized from methanol/diethyl ether. M.p. 249–251 °C,
[α]2D5 = –78.22 (c = 0.45, 1  HCl). 1H NMR (500 MHz, D2O): δ =
7.18 (d, J = 8.2 Hz, 2 H, ArH), 6.96 (d, J = 8.3 Hz, 2 H, ArH),
3.73 (t, J = 7.5 Hz, 1 H, CH), 3.25 (dd, J = 13.0, 7.9 Hz, 1 H, CH2),
Method B: A solution of compound (2S,5S)-23a–d (100 mg) in 1,4-
dioxane (2 mL) and 12  HCl (3 mL) was heated in a sealed am-
poule at 100 °C for 8–12 d. The resulting mixture was cooled to
room temperature and extracted with CH2Cl2 (3ϫ10 mL), and the
aqueous phase was concentrated under reduced pressure to afford
a solid, which was purified by flash chromatography using 2-propa-
nol/methanol/NH4OH (5:2:1) as eluent.[20] Further evaporation af-
forded the corresponding amino acid.
2.99 (dd, J = 12.88, 7.0 Hz, 1 H, CH2), 0.92 (s, 9 H, CH3) ppm. 13
C
NMR (125.76 MHz, D2O): δ = 174.6 (C=O), 152.4 (Cipso), 131.3
(Cipso), 128.0 (CHAr), 126.5 (CHAr), 47.9 (CH), 41.0 (CH2), 33.9
(C), 30.3 (CH ) ppm. IR: ν = 2954, 2901, 2768, 2655, 2162, 1625,
˜
3
1575, 1525, 1384 cm–1. MS (EI): m/z (%) = 221 (11) [M]+, 192 (100),
177 (39), 174 (23), 159 (40), 136 (68), 131 (12), 57 (38). HRMS
(ESI-TOF): calcd. for C13H20N1O2 222.1488; found 222.1493.
HPLC [Chirobiotic T column, EtOH/H2O = 50:50, 210 nm, 1 mL/
min; er = 11:89 (R/S)]: tR = 7.13 (minor, R), 15.57 (major, S) min.
(S)-3-Amino-2-phenylpropionic Acid [(S)-24a]: Following general
procedure A (98 °C, 200 W, 6 h), (2S,5S)-23a (100 mg,0.31 mmol)
afforded (S)-24a (40 mg, 78% yield) as a powder, which was recrys-
tallized from methanol/ether. M.p. 236–238 °C, [α]2D5 = –81.7 (c =
0.2, H2O) {ref.[21] [α]2D0 = –81 (c = 0.2, H2O), 94%ee for the S
rac-3-Amino-2-(4-tert-butylphenyl)propionic Acid (rac-24c): Follow-
ing general procedure B (8 d), (2S,5S)-23c (100 mg, 0.26 mmol) af-
forded rac-24c (10 mg, 17% yield) as a powder, which was crys-
1
enantiomer}. H NMR (500 MHz, D2O): δ = 7.23–7.15 (m, 3 H,
Eur. J. Org. Chem. 2010, 6393–6403
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6401

H. A. Stefani, E. Juaristi et al.
FULL PAPER
tallized from methanol/diethyl ether. M.p. 244–246 °C. 1H NMR
(500 MHz, D2O): δ = 7.23 (d, J = 7.7 Hz, 2 H, ArH), 7.0 (d, J =
7.83 Hz, 2 H, ArH), 3.77 (t, J = 7.3 Hz, 1 H, CH), 3.29 (dd, J =
12.5, 8.0 Hz, 1 H, CH2), 3.04 (dd, J = 12.8, 7.2 Hz, 1 H, CH2),
0.97 (s, 9 H, CH3) ppm. 13C NMR (125.76 MHz, D2O): δ = 174.6
(C=O), 152.5 (Cipso), 131.4 (Cipso), 128.0 (CHAr), 126.5 (CHAr),
Ling, M. Yoshida, P. S. Mariano, J. Org. Chem. 1996, 61, 4439–
4449.
[3]
For reviews on organotrifluoroborate salts, see: a) S. Darses,
J. P. Genet, Eur. J. Org. Chem. 2003, 4313–4327; b) G. A. Mo-
lander, R. Figueroa, Aldrichimica Acta 2005, 38, 49–56; c)
G. A. Molander, N. Ellis, Acc. Chem. Res. 2007, 40, 275–286;
d) H. A. Stefani, R. Cella, A. S. Vieira, Tetrahedron 2007, 63,
3623–3658; e) S. Darses, J. P. Genet, Chem. Rev. 2008, 108,
288–325.
For reviews on the Suzuki–Miyaura reaction, see: a) H. Dou-
cet, Eur. J. Org. Chem. 2008, 2013–2030; b) D. Benito-Gara-
gorri, K. Kirchner, Acc. Chem. Res. 2008, 41, 201–213; c) M.
Sasaki, H. Fuwa, Synlett 2004, 1851–1874; d) S. Kotha, K.
Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633–9695.
For monographs, see: a) E. Juaristi (Ed.), Enantioselective Syn-
thesis of β-Amino Acids, Wiley, New York, 1997; b) E. Juaristi,
V. Soloshonok, Enantioselective Synthesis of β-Amino Acids,
2nd ed., Wiley, New York, 2005; for additional review articles,
see: c) E. Juaristi, D. Quintana, J. Escalante, Aldrichimica Acta
1994, 27, 3–11; d) D. C. Cole, Tetrahedron 1994, 50, 9517–9582;
e) G. Cardillo, C. Tomasini, Chem. Soc. Rev. 1996, 25, 117–
128; f) E. Juaristi, H. López-Ruiz, Curr. Med. Chem. 1999, 6,
983–1004; g) S. Abele, D. Seebach, Eur. J. Org. Chem. 2000, 1–
15; h) F. Fülöp, Chem. Rev. 2001, 101, 2181–2204; i) M. Liu,
M. P. Sibi, Tetrahedron 2002, 58, 7991–8035; j) F. Gnad, O.
Reiser, Chem. Rev. 2003, 103, 1603–1623; k) J.-A. Ma, Angew.
Chem. Int. Ed. 2003, 42, 4290–4299; l) N. Sewald, Angew.
Chem. Int. Ed. 2003, 42, 5794–5795; m) G. Lelais, D. Seebach,
Biopolymers 2004, 76, 206–243; n) M. Palko, K. Lorand, F.
Fülöp, Curr. Med. Chem. 2005, 12, 3063–3083; o) N. M. Gar-
rido, D. Diez, S. H. Domínguez, M. García, M. R. Sánchez,
S. G. Davies, Tetrahedron: Asymmetry 2006, 17, 2183–2186; p)
A. Dondoni, A. Massi, Acc. Chem. Res. 2006, 39, 451–463; q)
D. J. Ager (Ed.), “Synthesis of Non-Natural Amino Acids” in
Handbook of Chiral Chemicals, 2nd ed., DSM Pharma Chemi-
cals, Raleigh, NC, 2006; r) D. Seebach, A. K. Beck, S. Capone,
G. Deniau, U. Groselj, E. Zass, Synthesis 2009, 1–32; s) Y. Ban-
dala, E. Juaristi in Amino Acids, Peptides and Proteins in Or-
ganic Chemistry (Ed.: A. B. Hughes), Wiley, Weinheim, 2009,
pp. 291–366; t) K. Lorand, E. Forro, F. Fülöp in Amino Acids,
Peptides and Proteins in Organic Chemistry (Ed.: A. B.
Hughes), Wiley, Weinheim, 2009, pp. 367–409; u) B. E. Sleebs,
T. T. van Nguyen, A. B. Hughes, Org. Prep. Proced. Int. 2010,
41, 429–478.
a) E. Juaristi, D. Quintana, M. Balderas, E. García-Pérez, Tet-
rahedron: Asymmetry 1996, 7, 2233–2246; b) C. G. Avila-Ortiz,
G. Reyes-Rangel, E. Juaristi, Tetrahedron 2005, 61, 8372–8381.
a) E. Juaristi, M. Balderas, Y. Ramírez-Quirós, Tetrahedron:
Asymmetry 1998, 9, 3881–3888; b) E. Juaristi, M. Balderas, H.
López-Ruiz, V. M. Jiménez-Pérez, M. L. Kaiser-Carril, Y.
Ramírez-Quiróz, Tetrahedron: Asymmetry 1999, 10, 3493–
3505.
a) J. P. Konopelski, K. S. Chu, G. R. Negrete, J. Org. Chem.
1991, 56, 1355–1357; b) E. Juaristi, J. Escalante, B. Lamatsch,
D. Seebach, J. Org. Chem. 1992, 57, 2396–2398; c) K. S. Chu,
G. R. Negrete, J. P. Konopelski, F. J. Lakner, W. Nam-Tae,
M. M. Olmstead, J. Am. Chem. Soc. 1992, 114, 1800–1812; d)
E. Juaristi, J. Escalante, J. Org. Chem. 1993, 58, 2282–2285; e)
R. Amoroso, G. Cardillo, C. Tomasini, P. Tortoreto, J. Org.
Chem. 1992, 57, 1082–1087; f) G. Cardillo, A. Tolomelli, C. To-
masini, Tetrahedron 1995, 51, 11831–11840; g) J. Escalante, E.
Juaristi, Tetrahedron Lett. 1995, 36, 4397–4400; h) F. Beaulieu,
J. Arora, V. Vieth, N. J. Taylor, B. J. Chapell, V. Snieckus, J. Am.
Chem. Soc. 1996, 118, 8727–8728; i) E. Juaristi, H. López-Ruiz,
D. Madrigal, Y. Ramírez-Quirós, J. Escalante, J. Org. Chem.
1998, 63, 4706–4710; j) D. Seebach, A. Boog, W. B. Schweizer,
Eur. J. Org. Chem. 1999, 335–360; k) E. Castellanos, G. Reyes-
Rangel, E. Juaristi, Helv. Chim. Acta 2004, 87, 1016–1024; l) M.
Nahrwold, A. Stoncius, A. Penner, B. Neumann, H.-G.
Stammler, N. Sewald, Beilstein J. Org. Chem. 2009, 5, 43–49.
47.9 (CH), 41.1 (CH ), 34.0 (C), 30.4 (CH ) ppm. IR: ν = 2955,
˜
2
3
2926, 2863, 2649, 2162, 1731, 1623, 1566, 1524, 1387 cm–1. MS
(EI): m/z (%) = 222 (8) [M + 1]+, 192 (100), 177 (50), 174 (25),
159 (39), 136 (64), 131 (12), 57 (34). HRMS (ESI-TOF): calcd.
for C13H20N1O2 222.1488; found 22.1491. HPLC (Chirobiotic T
column, EtOH/H2O = 50:50, 210 nm, 1 mL/min): tR = 7.23 (R),
16.50 (S) min.
[4]
[5]
(S)-3-Amino-2-(5,6,7,8-tetrahydronaphthalen-2-yl)propionic
Acid
[(S)-24d]: Following general procedure A (98 °C, 200 W, 10 h),
(2S,5S)-23d (100 mg, 0.265 mmol) afforded (S)-24d (10 mg, 17%)
as a powder, which was recrystallized from methanol/diethyl ether.
M.p. 224–225 °C, [α]2D5 = –28.8 (c = 0.52, 1  HCl). 1H NMR
(500 MHz, D2O): δ = 6.69 (d, J = 7.8 Hz, 1 H, ArH), 6.61 (s, 2 H,
ArH), 3.56 (t, J = 7.5 Hz, 1 H, CH), 3.12 (dd, J = 13.1, 7.9 Hz, 1
H, CH2), 2.86 (dd, J = 13.3, 6.85 Hz, 1 H, CH2), 2.25 (s, 4 H, CH2),
1.31–1.22 (m, 4 H, CH2) ppm. 13C NMR (125.76 MHz, D2O): δ
= 174.6 (C=O), 138.7 (Cipso), 138.1 (Cipso), 131.1 (Cipso), 130.0
(CHAr), 128.5 (CHAr), 125.0 (CHAr), 47.9 (CH2), 40.9 (CH), 28.5
(CH ), 28.3 (CH ), 22.33 (CH ), 2.30 (CH ) ppm. IR: ν = 2924,
˜
2
2
2
2
2855, 2756, 2623, 1728, 1634, 1558, 1496, 1373 cm–1. MS (EI): m/z
(%) = 220 (11) [M+ + 1], 190 (100), 172 (57), 145 (30), 131 (12), 89
(6). HRMS (ESI-TOF): calcd. for C13H17N1O2 + H+ 220.1332;
found 220.1343. HPLC [Chirobiotic T column, EtOH/H2O =
50:50, 210 nm, 1 mL/min; er = 12:88 (R/S)]: tR = 7.6 (minor, R),
10.4 (major, S) min.
rac-3-Amino-2-(5,6,7,8-tetrahydronaphthalen-2-yl)propionic
Acid
(rac-24d): Following general procedure B (10 d), (2S,5S)-23d
(100 mg, 0.265 mmol) afforded rac-24d (33 mg, 56% yield) as a
powder, which was recrystallized from methanol/diethyl ether. M.p.
1
230–232 °C. H NMR (500 MHz, D2O): δ = 6.9 (d, J = 7.6 Hz, 1
H, ArH), 6.83 (s, 2 H, ArH), 3.77 (t, J = 7.5 Hz, 1 H, CH), 3.34
(dd, J = 8.0, 7.5 Hz, 1 H, CH2), 3.08 (dd, J = 13.1, 7.0 Hz, 1 H,
CH2), 2.47 (s, 4 H, CH2), 1.49 (s, 4 H, CH2) ppm. 13C NMR
(125.76 MHz, D2O): δ = 174.7 (C=O), 138.9 (Cipso), 138.4 (Cipso),
131.4 (Cipso), 130.2 (CHAr), 128.7 (CHAr), 125.2 (CHAr), 48.1
(CH), 41.0 (CH2), 28.7 (CH2), 28.5 (CH2), 22.5 (CH2), 22.47
[6]
[7]
(CH ) ppm. IR: ν = 3015, 2926, 2855, 2362, 2176, 1728, 1629, 1560,
˜
2
1500, 1396, 1288 cm–1. MS (EI): m/z (%) = 220 (15) [M + 1]+, 190
(100), 172 (66), 145 (41), 131 (14), 89 (6). HRMS (ESI-TOF): calcd.
for C13H17N1O2 + H+ 220.1332; found 220.1339. HPLC (Chiro-
biotic T column, EtOH/H2O = 50:50, 210 nm, 1 mL/min): tR = 7.5
(R), 10.5 (S) min.
[8]
Acknowledgments
The authors are grateful for the support of the Fundação de Am-
paro à Pesquisa do Estado de São Paulo (07/59404–2) and Con-
selho Nacional de Desenvolvimento Científico e Tecnológico for a
fellowship (300613/2007–5, 134722/2008–6). We are also indebted
to Consejo Nacional de Ciencia y Tecnología, Mexico for financial
support (60366-Q).
[1] Special issue dedicated to cross-coupling reactions: S. L. Buch-
wald (Guest Ed.), Acc. Chem. Res. 2008, 41, 1439–1564.
[2] a) D. S. Matteson, Stereodirected Synthesis with Organobor-
anes, Springer, Berlin, 1995; b) A. Pelter, K. Smith, H. C.
Brown, Borane Reagents, Academic Press, London, 1988; c) R.
6402
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6393–6403

Enantioselective Preparation of α-Substituted β-Amino Acids
[9]
4012; j) G. V. Botteselle, T. L. S. Hough, R. C. Venturoso, R.
Cella, A. S. Vieira, H. A. Stefani, Aust. J. Chem. 2008, 61, 870–
873; k) A. S. Vieira, P. F. Fiorante, T. L. S. Hough, F. P. Fer-
reira, D. S. Lüdtke, H. A. Stefani, Org. Lett. 2008, 10, 5215–
5218; l) F. V. Singh, H. A. Stefani, Synlett 2008, 20, 3221–3225.
[15] a) E. Juaristi, D. Quintana, Tetrahedron: Asymmetry 1992, 3,
723–726; b) E. Juaristi, Handbook of Reagents for Organic Syn-
thesis. Chiral Reagents for Asymmetric Synthesis (Ed.: L. A. Pa-
quette), Wiley, Chichester, 2003, pp. 53–56; c) S. A. Hopkins,
T. A. Ritsema, J. P. Konopelski, J. Org. Chem. 1999, 64, 7885–
7889.
[16] a) G. A. Molander, B. Biolatto, J. Org. Chem. 2003, 68, 4302–
4314; b) G. A. Molander, B. Biolatto, Org. Lett. 2002, 4, 1867–
1870.
[17] Y. Ramírez-Quirós, M. Balderas, J. Escalante, D. Quintana, I.
Gallardo, D. Madrigal, E. Molins, E. Juaristi, J. Org. Chem.
1999, 64, 8668–8680.
[18] D. Seebach, B. Lamatsch, A. K. Beck, M. Dobler, M. Egli, R.
Fitzi, M. Gautschi, B. Herradón, P. C. Hidber, J. J. Irwin, R.
Locher, M. Maestro, T. Meetzke, A. Mouriño, E. Pfammatter,
D. A. Plattner, C. Schickli, W. B. Schweiser, P. Seifer, G. Stucky,
W. Petter, J. Escalante, E. Juaristi, D. Quintana, C. Miravitlles,
E. Molins, Helv. Chim. Acta 1992, 75, 913–934.
[19] a) G. A. Molander, B. W. Katona, F. Machrouhi, J. Org. Chem.
2002, 67, 8416–8423; b) S. Darses, G. Michaud, J.-P. Genêt,
Eur. J. Org. Chem. 1999, 1875–1883.
A. Boto, R. Hernández, E. Suárez, J. Org. Chem. 2000, 65,
4930–4937.
M. A. Iglesias-Arteaga, C. G. Avila-Ortiz, E. Juaristi, Tetrahe-
dron Lett. 2002, 43, 5297–5300.
a) Y. F. Shealy, C. A. O’Dell, W. M. Shannon, G. Arnett, J.
Med. Chem. 1983, 26, 156–161; b) H. G. Howell, P. R. Brod-
fuehrer, S. P. Brundidge, D. A. Benigni, C. Sapino, J. Org.
Chem. 1988, 53, 85–88; c) L. M. v. Beauchamp, B. L. Serling,
J. E. Kelsey, K. K. Biron, P. Collins, J. Selway, J.-C. Lin, H. J.
Schaeffer, J. Med. Chem. 1988, 31, 144–149.
[10]
[11]
[12] B. R. Díaz-Sánchez, M. A. Iglesias-Arteaga, R. Melgar-
Fernández, E. Juaristi, J. Org. Chem. 2007, 72, 4822–4825.
[13] N. Alonso, O. Caamano, F. Fernández, X. García-Mera, M.
Morales, J. E. Rodríguez-Borges, E. De Clercq, Synthesis 2008,
1845–1852.
[14] a) R. Cella, R. C. Venturoso, H. A. Stefani, Tetrahedron Lett.
2008, 49, 16–19; b) H. A. Stefani, R. C. Guadagnin, A. F.
Keppler, A. S. Vieira, J. V. Comasseto, C. A. Suganuma, G. V.
Botteselle, A. L. Braga, Beilstein J. Org. Chem. 2008, 4, 1–4; c)
A. Bellomo, D. Gonzalez, H. A. Stefani, J. Organomet. Chem.
2008, 693, 1136–1142; d) A. S. Vieira, R. C. Guadagnin, P. F.
Fiorante, F. P. Ferreira, H. A. Stefani, Tetrahedron 2008, 64,
3306–3314; e) M. W. Paixão, M. Weber, H. A. Stefani, A. L.
Braga, J. B. Azeredo, A. M. Deobald, Tetrahedron Lett. 2008,
49, 2366–2370; f) A. S. Vieira, P. F. Fiorante, J. Zukerman-
Schpector, D. Alves, G. V. Botesselle, H. A. Stefani, Tetrahe-
dron 2008, 64, 7234–7241; g) R. C. Guadagnin, C. Suganuma,
A. S. Vieira, R. Cella, H. A. Stefani, Tetrahedron Lett. 2008,
49, 4713–4716; h) F. V. Singh, M. Weber, R. C. Guadagnin,
H. A. Stefani, Synlett 2008, 12, 1889–1893; i) A. L. Braga, T.
Barcellos, M. W. Paixão, A. M. Deobald, M. Godoy, H. A. Ste-
fani, R. Cella, A. Sharma, Organometallics 2008, 27, 4009–
[20] A. J. Mota, E. Castellanos, E. Juaristi, Org. Prep. Proced. Int.
2003, 35, 414–417.
[21] N. J. A. Martin, X. Cheng, B. List, J. Am. Chem. Soc. 2008,
130, 13862–13863.
[22] R. H. Prager, K. Schafer, Aust. J. Chem. 1997, 50, 813–823.
Received: June 14, 2010
Published Online: October 7, 2010
Eur. J. Org. Chem. 2010, 6393–6403
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6403