A mild multistep conversion of n-protected α-amino acids into N-protected β3-amino acids utilizing the Nef reaction

Article abstract of DOI:10.1055/s-0032-1318344

Current methods of homologation of α-amino acids to β-amino acids have limitations. To overcome these shortfalls the Nef reaction has been utilized in the multistep synthesis of β³-amino acids from α-amino acids. In this approach, N-protected a

Full text of DOI:10.1055/s-0032-1318344

LETTER
▌747
lAetteMr ild Multistep Conversion of N-Protected α-Amino Acids into N-Protected
β3-Amino Acids Utilizing the Nef Reaction
Conversion of N-Protected α-Amino Acids into N-Protected β3-Amino Acids
Brad E. Sleebs,a,b Nghi H. Nguyen,c Andrew B. Hughes*c
a
The Walter and Eliza Hall Institute of Medical Research, Parkville 3010, Australia
b
Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
c
Department of Chemistry, La Trobe University, Victoria 3086, Australia
Fax +61(3)94791266; E-mail: tahughes@optusnet.com.au
Received: 19.10.2012; Accepted after revision: 12.02.2013
Perlmutter.6 The limitation of this method is the phospho-
Abstract: Current methods of homologation of α-amino acids to β-
rane reagent is relatively expensive and an N-Fmoc acid
amino acids have limitations. To overcome these shortfalls the Nef
reaction has been utilized in the multistep synthesis of β3-amino ac-
ids from α-amino acids. In this approach, N-protected amino alde-
chloride is required for the method to be viable (method
B, Scheme 1). And finally, Temperini et al.7 developed a
hydes, easily accessed from α-amino acids, were transformed into synthetic sequence using inexpensive reagents, via an al-
kyne to produce β3-amino acids (method D, Scheme 1).
However, eight synthetic steps were required.
the N-protected γ-amino nitroalkanes. The Nef reaction was then
used to smoothly convert the nitroalkanes into the corresponding N-
protected β3-amino acids without notable racemization.
R1
N2
Key words: amino acids, amino alcohols, amino aldehydes, nu-
cleophilic addition, enantioselectivity
R1
R1
PG
PG
PG
CO2H
N
N
CO2H
method A: Arndt–Eistert homologation
R1
N
H
H
H
O
The popularity of applications of β-amino acids as either
synthons in organic chemistry or in peptidomimetics in
bioorganic and medicinal chemistry is increasing. As a re-
sult a plethora of syntheses exist.1 Of these syntheses a
limited number of examples exist for the direct homologa-
tion of α-amino acids to β3-amino acids. The use of a ho-
mologation allows the chirality to be transferred to the β3-
amino acid product, and does not have the requirement to
use expensive, and sometimes toxic, chiral transfer re-
agents to install chirality in the final product.
R1
N2
R1
NNH2
Cl
2 steps
Fmoc
Fmoc
Fmoc
N
H
N
N
CO2H
H
H
O
O
method B: alternative diazoketone formation of Bio et al., adapted by
Perlmutter
R1
R1
R1
3 steps
CO2H
PG
CN
PG
H2N
⋅HCl
N
N
CO2H
method C: homologation by Caputo et al.
R1 R1
H
H
The most well-known procedure to perform the homolo-
gation of α-amino acids to β3-amino acids is the Arndt–Ei-
stert homologation (method A, Scheme 1).2,3 However,
this two-step transformation has limitations in the toxicity
and safe generation of diazomethane. As a result many al-
ternative procedures have appeared (Scheme 1). These
procedures have advantages and disadvantages. As a re-
sult there is still an unmet need to develop a novel strategy
that is mild, inexpensive, safe, possesses a limited number
of synthetic steps, and transfers the chirality of the α-ami-
no acid to the β3-amino acid product faithfully. The proto-
col of Caputo4 (method C, Scheme 1) has gone a long way
to achieving these idealities; however, the method re-
quires the use of cyanide. Further, hydrolysis of the nitrile
also results in loss of the N-protective group. An alterna-
tive to the use of diazomethane in the Arndt–Eistert ho-
mologation is the procedure by Bio et al.5 that utilizes N-
isocyano iminotriphenylphosphorane to produce diazoke-
tones in three steps. More recently, this method has been
applied to the homologation of N-Fmoc α-amino acids by
R1
5 steps
3 steps
Boc
Boc
CO2H
N
CO2H
N
PhthN
H
H
method D: homologation by Temperini et al.
Scheme 1 Literature examples of the homologation of α-amino acids
to β3 amino acids. PG = protecting group; R1 = amino acid side chain.
There are numerous other homologation procedures,8
however, most are not applicable to β-amino acid synthe-
sis. The methods that are, produce substituted β2, β2,3 or
β2,2,3-amino acids,9 not β3-amino acids, the focus of the
work described here. One such example that produces a
hydroxy-substituted β2,3-amino acid is a method that in-
corporates the use of the Nef reaction (Scheme 2).10 To the
best of our knowledge the Nef reaction has not been used
in the production of β3-amino acids. It is proposed to per-
form a Henry reaction on an α-amino aldehyde. The hy-
droxyl group present on the Henry reaction product will
then be reductively eliminated, so a Nef reaction can be
exploited to enable the synthesis of β3-amino acids from
α-amino acids without racemization (Scheme 2). Prelimi-
nary results investigating the use and scope of the Nef re-
SYNLETT 2013, 24, 0747–0751
Advanced online publication: 06.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318344; Art ID: ST-2012-B0741-L
© Georg Thieme Verlag Stuttgart · New York

748
B. E. Sleebs et al.
LETTER
action in the production of β3-amino acids are described
herein.
R1
R1
R1
a
b
PG
PG
PG
N
R2
CO2H
1–7
N
R2
N
R2
To demonstrate the scope of the proposed synthetic route,
a small number of α-amino acid residues were selected
with different side-chain functionalities, N-nonmethyl-
ated and N-methylated, and in the presence of a few com-
mon N-protecting groups, such as Cbz, Boc, and Ts.
OH
O
8–14
15–21
Scheme 3 Conversion of N-protected α-amino acids into N-protect-
ed α-amino aldehydes. Reagents and conditions: (a) for 8–13: 1.
NMM, EtOCOCl, THF, –15 °C; 2. NaBH4, MeOH, H2O; for 14:
LiAlH4, THF, reflux, 2 h; (b) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C
(for PG, R1 and R2 refer to Table 1).
R1
R1
R1
PG
PG
CO2H
OH
PG
CO2H
N
R2
CO2H
N
R2
N
R2
(Scheme 3), in order to minimize racemization.13 Racemi-
zation of α-amino aldehydes can occur at room tempera-
ture in a short period, and to minimize racemization they
were used immediately in the next transformation. The
Swern reaction products 15–21 were immediately sub-
jected to a modified Henry reaction, using nitromethane in
the presence of potassium fluoride (Scheme 4).14 The use
of potassium fluoride, in place of a strong base usually
used in the Henry reaction, also minimized the risk of ra-
cemizing the α-amino aldehydes 15–21. The level of race-
mization was monitored only in the final β3-amino acid
product. The intermediate γ-amino β-hydroxy nitroal-
kanes 22–28 were obtained in mediocre to good yields
[37–70% (calculated from the starting amino alcohols 8–
14), Table 1].21 The β-hydroxy nitroalkanes 22–28 were
obtained as a mixture of diastereoisomers, and thus were
not characterized at this stage, but used directly in the next
transformation. The diastereoselectivity of the Henry re-
action was thus not important as the β-hydroxy stereocen-
ter was removed in the next step.
Nef
reaction
2 steps
Henry
ref. 9
reductive
elimination
R1
R1
R1
NO2
reaction
PG
PG
PG
N
R2
N
R2
NO2
N
R2
O
OH
Scheme 2 Study proposed utilising the Nef reaction in the produc-
tion of β3-amino acids. PG = protecting group; R1 = amino acid side
chain; R2 = H, Me.
To enable the exploitation of the Nef reaction, the γ-amino
nitroalkane was required as a key synthon. It was pro-
posed this intermediate would be accessed from an elimi-
nation of the product obtained from the Henry reaction of
nitromethane with the α-amino aldehyde. The amino alde-
hyde will be accessed via a two-step process from the N-
protected α-amino acid (Scheme 2).
N-Protected amino alcohols 8–14 can be obtained using a
number of approaches. The approach used involved acti-
vating the N-protected α-amino acid 1–6 using N-methyl-
morpholine and ethyl chloroformate at –15 °C, followed
by the addition of sodium borohydride (Scheme 3).11 This
gave the N-protected amino alcohols 8–13 in good to ex-
cellent yields (76–86%, Table 1). The N-tosyl analogue 7
was converted into the amino alcohol 14 using LiAlH4.
R1
NO2
R1
NO2
R1
a
b
PG
PG
PG
N
N
N
R2
OH
R2
R2
O
15–21
22–28
29–35
Scheme 4 Conversion of α-amino aldehydes into γ-amino nitro-
alkanes. Reagents and conditions: (a) MeNO2 (4 equiv), KF (1 equiv),
i-PrOH, 0–25 °C, 8 h; (b) 1. Ac2O, cat. DMAP, Et2O 25 °C, 2 h; 2.
NaBH4, EtOH, 0 °C, 2 h (for PG, R1 and R2 refer to Table 1).
α-Amino aldehydes 15–21 can also be obtained by a vari-
ety of different methods,12 however, a Swern oxidation of
the amino alcohols 8–14 at low temperature was chosen
Table 1 Conversion of N-Protected α-Amino Acids 1–7 into Nitroalkanes 29–35
Entry
PG
R1
R2
α-Amino Yield of
acid
Amino
Yield of
Yield of
amino alcohol (%) aldehyde β-hydroxynitro alkane (%)a nitro alkane (%)
1
2
3
4
5
6
7
Cbz
Cbz
Boc
Boc
Cbz
Cbz
Ts
Me
H
1
2
3
4
5
6
7
8 80
9 86
15
16
17
18
19
20
21
22 63
23 60
24 40
25 60
26 55
27 70
28 37
29 70
30 53
31 48
32 65
33 60
34 63
35 55
Bn
H
CH2OBn
i-Pr
H
10 79
11 83
12 86
13 82
14 76
H
Bu
Me
Me
H
CH2CO2Bn
i-Bu
a Yield calcd from the starting amino alcohol.
Synlett 2013, 24, 747–751
© Georg Thieme Verlag Stuttgart · New York

LETTER
Conversion of N-Protected α-Amino Acids into N-Protected β3-Amino Acids
749
Table 2 Conversion of Nitroalkanes 29–35 into N-Protected β3-Amino Acids 36–42
Entry
PG
R1
R2
Nitro alkane
Yield of product (%) Found [α] (c)
Lit. [α] (c, solvent)
1
2
3
4
5
6
7
Cbz
Cbz
Boc
Boc
Cbz
Cbz
Ts
Me
H
29
30
31
32
33
34
35
36 75
37 67
38 60
39 67
40 69
41 70
42 76
–12.5 (1.04)
–30.0 (1.0)
+16.6 (1.05)
–20.0 (1.0)
+6.4 (3.1)
–15.7 (1.04, CHCl3)17
–36.0 (1.0, CHCl3)18
+15.1 (1.05, CHCl3)19
–20.3 (1.0, CHCl3)20
+5.5 (3.1, MeOH)3
+0.7 (1.0, MeOH)3
–12.5 (2.4, CH2Cl2)16
Bn
H
CH2OBn
i-Pr
H
H
Bu
Me
Me
H
CH2CO2Bn
i-Bu
+2.0 (1.0)
–30.5 (2.4)
In a one-pot process the β-hydroxy functionality on ni- equivocally that 42 was enantiopure, chiral HPLC was
troalkanes 22–28 was reductively eliminated using the performed. The N-tosyl analogue 42 possessed 99% enan-
conditions of Wollenberg et al.14 The hydroxy group was tiomeric excess.
first converted into an O-acetate, using acetic anhydride
In conclusion, a preliminary study converting α-amino ac-
and 4-dimethylamino pyridine, and then in the same pot
ids via a mild multistep synthesis, utilizing the Nef reac-
the O-acetate was reduced using sodium borohydride
tion, into β3-amino acids has been described. To obtain the
(Scheme 4). The one-pot procedure proceeded smoothly
Nef reaction synthon, γ-amino nitroalkanes 29–35, N-pro-
tected α-amino aldehydes 15–21 were converted into the
β-hydroxy-nitroalkanes 22–28 using the Henry reaction.
giving good yields (48–70%) of the nitroalkanes 29–35
(Table 2) after purification by column chromatography.22
The hydroxyl functionality was then reductively eliminat-
R1
NO2
R1
a
ed in a two-step process, to obtain the Nef synthons 29–
35. And finally the Nef reaction proceeded smoothly to
obtain a small selection of NH- and N-methyl N-protected
β3-amino acids 36–42. Residues were obtained without ra-
cemization of the chiral center. The overall conversion
from N-protected α-amino acids into the desired β3-amino
acids occurs in five steps. Although the number of syn-
thetic steps used here is greater than earlier methods, this
approach only requires the use of inexpensive and nontox-
ic reagents. Table 3 helps to facilitate comparison of the
current work with previous methods. Future studies will
focus on shortening the synthetic sequence and improving
synthetic yields, to further highlight that the Nef reaction
in the production of β3-amino acids is a viable alternative
to current homologation methods.
PG
PG
CO2H
N
R2
N
R2
29–35
36–42
Scheme 5 Conversion of γ-amino nitroalkanes into β3-amino acids.
Reagents and conditions: (a) NaNO2 (3 equiv), AcOH (10 equiv),
DMSO, 40 °C, 20 h (for PG, R1 and R2 refer to Table 2).
The nitroalkanes 29–35 were then converted into the β3-
amino acids using the Nef reaction carried out using the
conditions of Mioskowski et al.15 These conditions in-
volve the use of three equivalents of sodium nitrite and ten
equivalents of acetic acid in DMSO at 40 °C (Scheme
5).23 These conditions were applied to all residues and
produced the β3-amino acids 36–42 in good yields (60–
70%, Table 2). The enantiomeric purities of the β3-amino
acid products 36–42 obtained via the multistep sequence
were compared to literature optical rotation values (Table
2). The values for compounds 36–42 (Table 2, entries 1–
6) compared well. However, the N-tosyl analogue 42 (Ta-
ble 2, entry 7) did not compare well with the literature val-
ue.16 The optical rotation value for 42 is significantly
higher than that quoted in the literature. To prove un-
Acknowledgment
We thank La Trobe University for the provision of a postgraduate
scholarship awarded to N.H.N. and the NHMRC (App. 1010326)
for funding B.E.S.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Table 3 Comparison of Overall Yields for Conversion of α-Amino Acids into β3-Amino Acids
Residues
Homologation Methods
Arndt–Eistert
Caputo
Temperini
Current method
Cbz-β3-Ala
Cbz-β3-Val
Cbz-β3-Phe
72% (2 steps)
63%25 (2 steps)
77%26 (2 steps)
40%24 (5 steps)
28%24 (5 steps)
35%24 (5 steps)
–
26%
22%
20%
19%7 (8 steps)
–
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 747–751

750
B. E. Sleebs et al.
LETTER
(21) General Procedure B: Preparation of N-Protected β-
References and Notes
Hydroxy Nitroalkanes 22–28
(1) (a) Sleebs, B. E.; Van Nguyen, T. T.; Hughes, A. B. Org.
Prep. Proced. Int. 2009, 41, 429. (b) Juaristi, E.
Enantioselective Synthesis of β-Amino Acids; Wiley-VCH:
Weinheim, 2005, 2nd ed.. (c) Liu, M.; Sibi, M. P.
Tetrahedron 2002, 58, 7991. (d) Juaristi, E.; Lopez-Ruiz, H.
Curr. Med. Chem. 1999, 6, 983. (e) Cole, D. C. Tetrahedron
1994, 50, 9517.
(2) (a) Hughes, A. B.; Sleebs, B. E. Aust. J. Chem. 2008, 61,
131. (b) Müller, A.; Vogt, C.; Sewald, N. Synthesis 1998,
837. (c) Plucinska, K.; Liberek, B. Tetrahedron 1987, 43,
3509. (d) Seebach, D.; Kimmerlin, T. Helv. Chim. Acta
2003, 86, 2098. (e) Seebach, D.; Overhand, M.; Matinoni,
B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta
1996, 79, 913. (f) Seebach, D.; Podlech, J. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 471. (g) Seebach, D.; Podlech, J.
Liebigs Ann. 1995, 1217. (h) Sleebs, B. E.; Hughes, A. B.
Aust. J. Chem. 2006, 58, 778. (i) Sleebs, B. E.; Hughes, A.
B. Synth. Commun. 2009, 39, 48.
(3) Sleebs, B. E.; Hughes, A. B. Helv. Chim. Acta 2006, 89,
2611.
(4) Caputo, R.; Cassano, E.; Longobardo, L.; Palumbo, G.
Tetrahedron 1995, 51, 12337.
(5) Bio, M. M.; Javadi, G.; Song, Z. J. Synthesis 2005, 19.
(6) Perlmutter, P.; Poster at the Univeristy of Melbourne
Organic Synthesis Symposium, 2011.
(7) Temperini, A.; Capperucci, A.; Degl’Innocenti, A.; Terlizzi,
R.; Tiecco, M. Tetrahedron Lett. 2010, 51, 4121.
(8) (a) Li, J. Name Reactions for Homologation; Wiley-VCH:
Weinheim, 2009, Parts 1 and 2. (b) Katritzky, A. R.;
Bobrov, S. ARKIVOC 2005, (x), 174.
Oxalyl chloride (9.56 mmol) was dissolved in CH2Cl2 (20
mL), the mixture was cooled to –78 °C, and a solution of dry
DMSO (19.1 mmol) in CH2Cl2 (5 mL) was added dropwise
during 15 min. The N-protected amino alcohol 8–14 (4.78
mmol) in CH2Cl2 (15 mL) was added dropwise during 10
min, the resulting solution was stirred for 10 min at –78 °C,
and a solution of Et3N (28.7 mmol) in CH2Cl2 (20 mL) was
added dropwise during 15 min. After 20 min, H2O (5.0 mL)
was added to the vigorously stirred solution at –78 °C. The
resulting slurry was poured in Et2O (50 mL) and washed
with 20% aq KHSO4 (2 × 30 mL), the layers were separated,
and the aqueous layer was back-extracted with Et2O (2 × 50
mL). The combined organic layers were washed with brine
(2 × 50 mL), dried (MgSO4), and the solvent was removed
under reduced pressure (at <20 °C) to afford the crude
aldehyde 15–21, which was immediately used in the next
reaction without any further purification.
To a solution of crude aldehyde 15–21 and nitromethane
(19.1 mmol, 4 equiv) in i-PrOH (30 mL), cooling to 0 °C,
was added KF (4.78 mmol, 1 equiv). The reaction mixture
was warmed to r.t. and stirred for 8 h, H2O (50 mL) was
added, and the aqueous layer was extracted with Et2O
(3 × 20 mL). The organic layers were washed with H2O (50
mL), dried (MgSO4), and concentrated in vacuo. The crude
product was subjected to flash column chromatography,
eluting with 10–35% EtOAc–hexane to give a
diastereomeric mixture of nitro alcohols 22–28. The
diastereomeric mixture of β-hydroxy nitroalkanes 22–28
were not characterized and were used directly in the next
reaction.
(9) (a) Boto, A.; Hernández, R.; Saavedra, C. J. Synlett 2010,
659. (b) Moumne, R.; Lavielle, S.; Karoyan, P. J. Org.
Chem. 2006, 71, 3332. (c) Moumne, R.; Lavielle, S.;
Karoyan, P.; Curie, M.; Jussieu, P.; Cedex, P. Tetrahedron
2006, 21. (d) Saavedra, C.; Hernandez, R.; Boto, A.;
Alvarez, E. J. Org. Chem. 2009, 74, 4655. (e) Saavedra, C.
J.; Boto, A.; Hernandez, R. Org. Biomol. Chem. 2012, 10,
4448. (f) Saavedra, C. J.; Hernández, R.; Boto, A.; Álvarez,
E. Tetrahedron Lett. 2006, 47, 8757.
(10) (a) Lei, L. J.; He, X. C. Org. Prep. Proced. Int. 2005, 37,
555. (b) Sasai, H.; Kim, W.-S.; Suzuki, T.; Shibasaki, M.;
Mitsuda, M.; Hasegawa, J.; Ohashi, T. Tetrahedron Lett.
1994, 35, 6123.
(11) (a) Kokotos, G. Synthesis 1990, 299. (b) Rodriguez, M.;
Llinares, M.; Doulut, S.; lleitr, A.; Mwtmez, J. Tetrahedron
Lett. 1991, 32, 923.
(12) Hili, R.; Baktharaman, S.; Yudin, A. Eur. J. Org. Chem.
2008, 5201.
(13) Konradi, A. W.; Kemp, S. J.; Pedersen, S. F. J. Am. Chem.
Soc. 1994, 116, 1316.
(14) Wollenberg, R. H.; Miller, S. J. Tetrahedron Lett. 1978, 19,
3219.
(15) Matt, C.; Wagner, A.; Mioskowski, C. J. Org. Chem. 1997,
62, 234.
(16) Howson, W.; Osborn, H. M. I.; Sweeney, J. J. Chem. Soc.,
Perkin Trans. 1 1995, 19, 2439.
(17) Arvidsson, P. I.; Frackenpohl, J.; Seebach, D. Helv. Chim.
Acta 2003, 86, 1522.
(18) Patil, B. S.; Vasanthakumar, G.-R.; Suresh Babu, V. V.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
2005, 12, 2611.
(19) Matthews, J. L.; Gademann, K.; Jaun, B.; Seebach, D. J.
Chem. Soc., Perkin Trans. 1 1998, 20, 3331.
(20) Patil, B. S.; Suresh Babu, V. V. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 2005, 12, 2611.
(22) General Procedure C: Preparation of N-Protected γ-
Amino Nitroalkanes 29–35
To the β-hydroxy nitroalkane 22–28 (1.79 mmol) was added
dry Et2O (20 mL), followed by Ac2O (3.58 mmol) and
DMAP (0.18 mmol). The reaction mixture was stirred at
25 °C for 2 h, and the solvent was evaporated in vacuo. To
the resulting crude residue was added 1 N ethanolic NaBH4
(4 mL) at 0 °C with stirring for 2 h (monitored by TLC). The
mixture was acidified with 0.5 N HCl and extracted with
Et2O (3 × 20 mL), and the organic layers were washed with
H2O (1 × 20 mL). The crude was subjected to flash column
chromatography, eluting with 10–30% EtOAc–hexane to
give the nitroalkanes 29–35.
(3S)-N-Benzyloxycarbonyl-3-amino-1-nitrobutane (29)
The β-hydroxy nitroalkane 22 (0.48 g, 1.79 mmol) was
transformed according to the General Procedure C, which
afforded the desired nitro alkane 29 as a clear oil
29
(crystallized on standing; 0.31 g, 70%); mp 45–48 °C; [α]D
+9.2, (c 2.71, MeOH). HRMS (ESI+): m/z calcd for
C12H16N2O4 [M + H]+: 253.1183; found: 253.1184. IR
(NaCl): νmax = 3392 (NH), 3349, 3336 (CH), 1680 (CO),
1550 (NO2), 1242, 1064, 897 cm–1. 1H NMR (300 MHz,
CDCl3, 300 K): δ = 7.32 (5 H, s, ArH), 5.06 (2 H, s,
ArCH2O), 4.78 (1 H, d, J = 7.3 Hz, NH), 4.43–4.37 (2 H, m,
CH2NO2), 3.82 (1 H, br s, NCH), 2.19–2.08 (2 H, m,
CH2CH2NO2), 1.20 (3 H, d, J = 6.6 Hz, CHCH3). 13C NMR
(75 MHz, CDCl3, 300 K): δ = 155.9 (CO), 136.2, 136.2 (aryl
C), 128.6, 128.2, 128.1 (aryl CH), 72.7 (CH2NO2) 66.9
(ArCH2O), 45.1 (NCH), 34.4 (CH2CH2NO2), 21.2 (CHCH3).
(23) General Procedure D – Preparation of the N-Protected β-
Amino Acids 36–42
To a solution of nitroalkane 29–35 (0.79 mmol) in DMSO (2
mL) was added NaNO2 (2.37 mmol) and AcOH (7.9 mmol),
and the reaction was heated to 40 °C for 20 h. After cooling
to r.t., 1 N HCl was added to the yellow solution, stirring for
Synlett 2013, 24, 747–751
© Georg Thieme Verlag Stuttgart · New York

LETTER
Conversion of N-Protected α-Amino Acids into N-Protected β3-Amino Acids
751
another 15 min, and the aqueous was extracted with Et2O
(3 × 15 mL). The organic layers were washed with H2O
according to the General Procedure D, and afforded the
desired β-amino acid 36 as a white solid (140 mg, 75%);
[α]D24 –12.5 (c 1.0, CHCl3); lit. [α]D27 –15.7 (c 1.0, CHCl3).17
1H NMR (300 MHz, CDCl3, 300 K): δ = 7.33–7.29 (5 H, m,
ArH), 5.32 (1 H, NH), 5.08 (2 H, s, ArCH2O), 4.10 (1 H,
HNCH), 2.57 (2 H, s, CH2), 1.26 (3 H, d, J = 6.7 Hz, CH3).
(24) Sutherland, A.; Willis, C. L. J. Org. Chem. 1998, 63, 7764.
(25) Gopi, H. N.; Roy, R. S.; Raghothama, S.; Karle, I. L.;
Balaaram, P. Helv. Chim. Acta 2002, 85, 3313.
(2 × 20 mL) and extracted with sat. NaHCO3 solution
(3 × 15 mL). The aqueous layers were acidified to pH 2 with
2 N HCl and then re-extracted with EtOAc (3 × 15 mL). The
organic extracts were dried (MgSO4) and evaporated in
vacuo. The residue was subjected to flash column
chromatography, gradient eluting with 10–40% EtOAc–
hexane to afford the N-protected β-amino acids 36–42.
(3S)-N-Benzyloxycarbonyl-3-aminobutanoic Acid 36
Nitroalkane 29 (199 mg, 0.79 mmol) was transformed
(26) Patil, B. S.; Vasanthakumar, G.-R.; Babu, V. V. S. Synth.
Commun. 2003, 33, 3089.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 747–751

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