First one-pot copper-catalyzed synthesis of α-hydroxy-β-amino acids in water. A new protocol for preparation of optically active norstatines

Article abstract of DOI:10.1021/jo034752y

α-Hydroxy-β-amino acids were synthesized with excellent yields for the first time in water and by a simple procedure based on a copper catalytic cycle, which included the recovery and reuse of the catalyst and is possible to realize by using only water as reaction medium.

Full text of DOI:10.1021/jo034752y

F ir st On e-P ot Cop p er -Ca ta lyzed Syn th esis of r-Hyd r oxy-â-Am in o
Acid s in Wa ter . A New P r otocol for P r ep a r a tion of Op tica lly
Active Nor sta tin es
Francesco Fringuelli,* Ferdinando Pizzo, Mauro Rucci, and Luigi Vaccaro*
Dipartimento di Chimica, Universita` di Perugia, 06123 Perugia, Italy
frifra@unipg.it; luigi@unipg.it
Received J une 3, 2003
R-Hydroxy-â-amino acids were synthesized with excellent yields for the first time in water and by
a simple procedure based on a copper catalytic cycle, which included the recovery and reuse of the
catalyst and is possible to realize by using only water as reaction medium.
In tr od u ction
Nonproteinogenic R-hydroxy-â-amino acids (isoserine
derivatives) are probably the most important members
of the â-amino acid family. They are the essential moiety
of a large number of well-known, naturally occurring
products that are endowed with powerful biological
activity.1 The most striking examples are the Taxol
derivatives,2 the immunological response modifier besta-
tin,3 and a number KNI protease inhibitors (Figure 1).1c
(+)-(2S,3R)-3-Amino-2-hydroxy-4-phenylbutanoic acid (1)
[(+)-phenylnorstatine] is one of the two amino acids that
constitute the dipeptide bestatin, and its (2S,3S) C-3
epimer 2 [(-)-allophenylnorstatine] is contained in two
tripeptides, the kynostatins (KNI)-227 and (KNI)-272,
which are highly potent HIV-1 protease inhibitors (Figure
2).4
As a result of the importance of the isoserine moiety,
several procedures have been developed to synthesize
R-hydroxy-â-amino acids in optically active form. These
methods include asymmetric catalytic synthesis, enzy-
matic kinetic resolution, and the use of chiral auxiliaries
and chiral building blocks.2b,5
F IGURE 1. Biologically active molecules containing R-hy-
droxy-â-amino acid units.
* To whom correspondence should be addressed. Fax: (+39) 075
5855560.
(1) (a) Curr Med. Chem. 1999, 6, entire volume. (b) Enantioselective
Synthesis of â-Amino Acids; J uaristi, E., Ed.; Wiley-VCH: New York,
1997. (c) Cardillo G.; Tomassini C. Chem. Soc. Rev. 1996, 117-127.
(2) (a) Kingston, D. G. Chem. Commun. 2001, 867-880. (b) Ojima,
I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927-954. (c) Georg, G.
I.; Chen, T. T.; Ojima, I.; Vyas, D. M. In Taxane Anticancer Agents:
Basic Science and Current Status; ACS Symposium Series 583; The
American Chemical Society: Washington, DC, 1999.
(3) Umezawa, H.; Aoyagi, T.; Suda, H.; Hamada, M.; Takeuchi, T.
J . Antibiot. 1976, 29, 97.
(4) (a) Mimoto, T.; Hattori, N.; Takaku, H.; Kisanuki, S.; Fukazawa,
T.; Terashima, K.; Kato, R.; Nojima, S.; Misawa, S.; Ueno, T.; Imai, J .;
Enomoto, H.; Tanaka, S.; Sakikawa, H.; Shintani, M.; Hayashi, H.;
Kiso, Y. Chem. Pharm. Bull. 2000, 48, 1310-1326. (b) Kiso, Y.;
Yamaguchi, S.; Matsumoto, H.; Mimoto, T.; Kato, R.; Nojima, S.;
Takaku, H.; Fukazawa, T.; Kimura, T.; Akaji, K. Arch. Pharm. 1998,
331, 87-89.
(5) (a) Boge, T. C.; Georg, G. I. In Enantioselective Synthesis of
â-Amino Acids; J uaristi, E., Ed.; Wiley-VCH: New York, 1997; pp
1-43. (b) For a recent summary of various synthetic approaches, see:
Aoyagi, Y.; J ain, R. P.; Williams, R. M. J . Am. Chem. Soc. 2001, 123,
3472-3477.
F IGURE 2. Some R-hydroxy-â-amino acids of biological
interest and their 1,2-epoxide precursors.
Among these procedures, the synthetic approach that
employs the nucleophilic ring opening of an appropriate
10.1021/jo034752y CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/13/2003
J . Org. Chem. 2003, 68, 7041-7045
7041

Fringuelli et al.
1,2-epoxide5b is, in principle, a very simple route that has
the advantage of using starting materials that are readily
available with high ee by using the Sharpless or the
J acobsen epoxidation of allylic alcohols6,7 or R,â-unsatur-
ated carboxylic esters,8 respectively. On the other hand,
this approach has the disadvantage that the ring opening
of the oxirane ring is generally not completely â-regiose-
lective. With alkyl substituents at C-â, a satisfactory
â-regioselectivity can be obtained by using a large
amount of catalyst (150-500%).9 All of the procedures
are carried out in organic solvents and have multiple
steps because, after the ring opening of the 1,2-epoxide,
further reactions are necessary to obtain the desired
R-hydroxy-â-amino acids, such as the oxidation of the
primary hydroxy group, the hydrolysis of the carboxylic
ester, or other transformations that require the isolation
and purification of all intermediates.
An efficient catalytic one-pot synthesis of â-alkyl and
â-arylisoserines starting from R,â-epoxycarboxylic acids
is to date not known and would be of interest for the
potential large-scale production of these compounds. In
addition, the pharmaceutical industry is showing enor-
mous interest in environmentally responsible procedures
that would allow simple and cost-effective syntheses of
target molecules.17
In this paper we report the first one-pot metal-
catalyzed synthesis of R-hydroxy-â-amino acids by azi-
dolysis of R,â-epoxycarboxylic acids and the in situ
reduction of the resulting â-azido-R-hydroxycarboxylic
acids intermediate, where the same metal catalyst cata-
lyzes both the oxirane ring opening by NaN3 and the
azido group reduction processes. To maximize the ef-
ficiency of the procedure, the whole process was per-
formed (i) solely in water without using any organic
solvents, (ii) on a gram scale, with (iii) recovery and (iv)
reuse of the catalyst.
To develop this idea, we needed a metal salt that, in
water, would be able (i) to catalyze anti-stereo- and
â-regioselectively the ring opening of a R,â-epoxycarboxy-
lic acid by NaN3, (ii) to chemoselectively catalyze the
reduction of azido group to amino by NaBH4 in high
yields, (iii) to form a boride complex20 that could be
quantitatively separated from the reaction mixture and
(iv) then be reused without loss in efficiency, and (v) to
make the procedure as simple as possible in view of
automating the process.
For several years we have been studying organic
reactions in water, and we have showed the advantages
related to its use as reaction medium and contributed to
the development of a benign organic synthesis.19 In all
cases, we have pointed out the crucial role that the pH
of the reaction medium plays in controlling the efficiency
of the processes.
We believe that the use of water as reaction medium
instead of an organic solvent optimizes the preparation
of the important family of R-hydroxy-â-amino acids and
is in perfect accord with the Click Chemistry principles
that were recently pointed out by Sharpless.18
Recently we have become engaged in a project aimed
at defining a new, environmentally friendly one-pot
protocol for synthesizing R-hydroxy-â-amino acids start-
ing from R,â-epoxycarboxylic acids. We began to study
the azidolysis of alkyl and aryl-1,2-epoxides and R,â-
epoxycarboxylic acids in water, showing that the pH of
the reaction medium directs the regioselectivity of the
reactions.12
(6) (a) J ohnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 101 and 476. (b)
Procter, G. In Asymmetric Synthesis; Oxford University Press: New
York, 1998. (c) Katsuki, T.; Mart´ın, V. S. Org. React. 1996, 48, 1-299.
(d) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780.
(7) Denis, J .-N.; Greene, A. E.; Serra, A. A.; Luche, M.-J . J . Org.
Chem. 1986, 51, 46-50.
(8) Deng, L.; J acobsen, E. N. J . Org. Chem. 1992, 57, 4320-4323.
(9) Racemic â-alkyl-R,â-epoxycarboxylic acids and their ester deriva-
tives give azidolysis at C-â with LiN3 or NaN3 in organic medium in
the presence of an excess of Ti(i-OPr)4 (1.5 molar equiv),10 LiClO4 (5.0
molar equiv),11 or Mg(ClO4)2 (2.5 molar equiv).11 When the reaction is
carried out in water, the regioselectivity depends on the pH and on
the presence of a Lewis acid.12 Nonaromatic isoserines have been
prepared with excellent enantiomeric purity by the â-lactam synthon
method developed by Ojima,13 by using L-aspartic acid14 and Boc-L-
leucine15 as chiral building blocks, and by adding lithium (S)-(R-
methylbenzyl)benzylamide and (+)-camphorsulphonyl oxaziridine to
the tert-butyl cinnamate derivative.16
Metal salts such Cu(NO3)2, InCl3 and even AlCl3, once
believed to be unusable in water,12d were efficient cata-
lysts for a totally â-regio- and anti-stereoselective azi-
dolysis of R,â-epoxycarboxylic acids in aqueous medium,12
carried out with 5.0 molar equiv of NaN3 at pH 4.0, kept
constant for the entire reaction time. CoCl2, Zn(NO3)2,
and Ni(NO3)2 also gave good results but were not able to
completely control the regioselectivity of the process.12b
(10) Chong, J . M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1560-
1563.
(11) Azzena, F.; Crotti, P.; Favero, L.; Pineschi, M. Tetrahedron
1995, 48, 13409-13422.
(12) (a) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J . Org.
Chem. 1999, 64, 6094-6096. (b) Fringuelli, F.; Pizzo; Vaccaro, L.
Synlett 2000, 311-314. (c) Fringuelli, F.; Pizzo, F.; Vaccaro, L. J . Org.
Chem. 2001, 66, 3544-3548. (d) Fringuelli, F.; Pizzo, F.; Vaccaro, L.
J . Org. Chem. 2001, 66, 4719-4722.
(19) (a) Li, C. J .; Chang, T. H. In Organic Reactions in Aqueous
Media; Wiley: New York, 1997. (b) Organic Synthesis in Water; Grieco,
P. A., Ed.; Blackie Academic and Professional: London, 1998. (c)
Taticchi, A.; Fringuelli, F. In The Diels-Alder Reaction; Wiley: New
York, 2002. (d) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Eur.
J . Org. Chem. 2001, 439-455. (e) Attanasi, O. A.; De Crescentini, L.;
Filippone, P.; Fringuelli, F.; Mantellini, F.; Matteucci, M.; Piermatti,
O.; Pizzo, F. Helv. Chim. Acta 2001, 84, 513-525. (f) Fringuelli, F.;
Pizzo, F.; Vaccaro, L. Synthesis 2000, 646-650. (g) Amantini, D.;
Fringuelli, F.; Pizzo, F.; Vaccaro, L. J . Org. Chem. 2001, 66, 6734-
6737. (h) Fringuelli, F.; Matteucci, M.; Piermatti, O.; Pizzo, F.; Burla,
M. C. J . Org. Chem. 2001, 66, 4661-4666. (g) Amantini, D.; Fringuelli,
F.; Pizzo, F. J . Org. Chem. 2002, 67, 7238-7243.
(20) Combination of a metal salt of Cu, Ni, Co, Zn, Fe, etc. with
aqueous NaBH4 produces a finely divided black precipitate of the metal
boride.21,22 Borides can be dissolved in acidic water or in basic
ammoniac solution in the presence of oxygen. Because they actively
catalyze the decomposition of borohydrides, these borides have been
used as a practical source of H2.22c-e The role of the metal boride has
been studied, and it is generally thought that the metal boride acts as
a true catalyst, coordinating and activating the substrates towards the
reduction.22d,e
(13) (a) Ojima, I. Acc. Chem. Res. 1995, 28, 383-389. (b) Ojima, I.;
Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C.-M.; Brigaud, T.
Tetrahedron 1992, 48, 6985-7012. (c) Ojima, I.; Wang, H.; Wang, H.;
Ng, E. W. Tetrahedron Lett. 1998, 39, 923-926. (d) Ojima, I.; Wang,
T.; Delaloge, F. Tetrahedron Lett. 1998, 39, 3663-3666. (e) Ojima, I.;
Lin, S. J . Org. Chem. 1998, 63, 224-225.
(14) J efford, C. W.; McNulty, J .; Lu, Z.-H.; Wang, J . B. Helv. Chim.
Acta 1996, 79, 1203-1216.
(15) Alemany, C.; Bach, J .; Farra`s, J .; Garcia, J . Org. Lett. 1999, 1,
1831-1834.
(16) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J . Synlett 1993,
731-732.
(17) Rouhi, A. M. Chem. Eng. News 2002, 80 (16), 30-33.
(18) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004-2021.
7042 J . Org. Chem., Vol. 68, No. 18, 2003

Preparation of Optically Active Norstatines
TABLE 2. Cop p er -Ca ta lyzed Red u ction of
CHART 1. r,â-Ep oxyca r boxylic Acid s Utilized a n d
Cor r esp on d in g Azid o Acid s a n d Am in o Acid s
P r ep a r ed
â-Azid o-r-h yd r oxyca r boxylic Acid s 8 in Wa ter a
entry
azido acid
amino acid
yield (%)b
1
2
3
4
5
6
7
8
9
8a
8b
8b
8c
8c
8d
8e
8f
9a
9b
9b
9c
9c
9d
9e
9f
88
93
93c
93
94c
87
90
85
96
8g
9g
a
Cu(NO3)2 (10 mol %), NaBH4 (2.0 mol/eq), 0 °C, 30 min. b Yield
of the isolated product. c Yield obtained using the recovered
catalyst.
TABLE 3. Azid olysis of 1,2-Ep oxid e 7b in Wa ter w ith
Na N3 a t 65 °C for 1.5 h
TABLE 1. Meta l-Sa lt-Ca ta lyzed Red u ction s of Azid e 8b
to Am in e 9b in Wa ter
expt
catalysta
Cu(NO3)2
pH
NaN3 (mol/eq) R/â ratios
C (%)b
4.0c
4.0c
4.0c
d
5.0
1.5
1.5
5.0
1.5
<1/>99
>99
<1
>99
>99
>99
entry
catalyst
T (°C)
t (h)
C (%)a
<1
1
2
3
4
5
1
2
3
4
5
none
25
25
25
25
0
18
24
0.5
0.5
0.5
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
<1/>99
10/90
<1/>99
AlCl3
InCl3
26
>99
>99
d
CoCl2
Cu(NO3)2
a
10 mol %. b Conversion based on the GC analyses of the methyl
ester derivative. c Maintained fixed for all of the reaction time.
pH obtained by mixing the reagents and not regulated during
a
Conversion based on GC analyses of the methyl ester deriva-
d
tive.
the reaction.
Resu lts a n d Discu ssion s
without using any organic solvents. In all cases Cu(B)
was recovered by simple Bu¨chner filtration of the mother
liquors and reused without problems for a further reduc-
tion of an azidocarboxylic acid in aqueous medium (Table
2, entries 3 and 5). According to our plan to recycle the
catalyst we recovered Cu(B) and showed that is possible
to reconvert the solid to Cu2+ in water at pH 4.0. This
copper(II) aqueous solution was then used for the azi-
dolysis of 7b carried out under the above-mentioned
conditions (NaN3 5.0 molar equiv, pH fixed at 4.0, 65 °C,
1.5 h) followed by in situ reduction (NaBH4 2.0 molar
equiv, 0 °C, 0.5 h) of intermediate 8b. The whole process
worked well, and R-hydroxy-â-aminohexanoic acid (9b)
was isolated in 86% yield, but the excess of NaN3 used
in the azidolysis step hampered the recovery of Cu(B).
Indeed under basic conditions, the Cu2+/NaBH4 system
reduces NaN3 to NH3. Ammonia greatly lowers the Cu0/
CuII redox potential, making possible the oxidation of Cu-
To investigate the reduction step, â-azido-R-hydroxy-
hexanoic acid (8b) was chosen as reference compound and
was reduced to â-amino-R-hydroxyhexanoic acid (9b)
(Chart 1), by using the catalysts that gave the best results
in the azidolysis process.12 The results obtained by using
10 mol % of catalyst and 2.0 molar equiv of NaBH4 are
presented in Table 1.
As can be seen, AlCl3 was ineffective, InCl3 was not
efficient, and furthermore the indium boride could not
been quantitatively recovered. At 25 °C, CoCl2 was a good
catalyst for the azido reduction to amino by NaBH4,19f
but it did not ensure a complete â-regioselectivity (84%)
in the azidolysis reaction of 7b.12b
The catalyst of choice for the reduction step was
Cu(NO3)2, which in aqueous medium and in the presence
of NaBH4 (pH > 10) allowed anti-R-hydroxy-â-aminohex-
anoic acid (9b) to be obtained exclusively in 0.5 h at 0 °C
with a 93% yield (Table 1, entry 5), isolated in pure form
by simple ion-exchange resin purification thereby avoid-
ing the use of any organic solvents. Because the
Cu(NO3)2/NaBH4 system had not been previously used
for the reduction of azides,23 this protocol was extended
to a number of R-hydroxy-â-azidocarboxylic acids (Table
2).
(B) to Cu2+ under air atmosphere and its dissolution in
2+ 24
water as Cu(NH3)4
,
thereby preventing its recovery
as a solid. In principle, Cu2+ could be recovered as an
amino complex, but this would require a longer proce-
dure.
We needed to go back and reinvestigate the azidolysis
of R,â-epoxycarboxylic acids in water, decreasing the
amount of NaN3.
By using only 1.5 molar equiv of NaN3, at 65 °C and
after 1.5 h, the results of the azidolysis of 7b were the
following (Table 3): (i) At fixed pH 4.0 the reaction works
only in the presence of the catalyst (Table 3, entries 2
and 3) and is again completely regio- and stereoselective
(Table 3, entry 3 vs 1). (ii) If the reaction was performed
at the pH obtained by simply mixing the reagents (pH
The reductions of 8 were fast (30 min at 0 °C), and the
amino-derivatives 9 were isolated in excellent yields
(21) The stoichiometry of boride does not conform to the ordinary
concepts of valence. In the case of copper boride, the molecular formula
strongly depends on the preparation temperature, and it is generally
reported as Cu(B).22a,b
(22) (a) Piton, J . P.; Vuillard, G.; Lundstroem, T. C. R. Acad. Sci.
Ser. C 1974, 278, 1495-1496. (b) Liaw, B. J .; Chen, Y. Z. Appl. Catal.,
A 2001, 2, 245-256. (c) Wade, R. C. J . Mol. Catal. 1983, 18, 273-297.
(d) Ganem, B.; Osby, J . O. Chem. Rev. 1986, 86, 763-780. (e) Osby, J .
O.; Heinzman, S. W.; Ganem, B. J . Am. Chem. Soc. 1986, 108, 67-72.
(23) A combination of CuSO4 and NaBH4 was used in methanol as
reducing system: Rao, H. S. P.; Siva, P. Synth. Commun. 1994, 24,
549-555.
(24) Cotton, F. A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M. In
Advanced Inorganic Chemistry, 6th ed.; Wiley & Sons: New York,
1999; pp 854-855.
J . Org. Chem, Vol. 68, No. 18, 2003 7043

Fringuelli et al.
TABLE 4. Azid olysis of Oxir a n es 7 in Wa ter Ca ta lyzed
by Cu (NO3)2 (10 m ol %) a n d Usin g Na N3 (1.5 m ola r equ iv)
SCHEME 1. Cop p er Ca ta lytic Cycle
1,2-epoxide
T (°C)
t (h)
azido-acida
yield (%)b,c
7a
7b
7c
7d
7e
7f
65
65
30
30
65
30
65
2
8a
8b
8c
8d
8e
8f
96
95
95
94
96
94
96
1.5
0.25
0.25
0.25
3
7g
4
8g
a
b
Only â-azido-R-hydroxy carboxylic acid was formed. Isolated
yield of g98% pure azido acid after workup. c In the absence of
catalyst no conversion was observed.
TABLE 5. On e-P ot Cu (NO3)2-Ca ta lyzed Syn th esis in
Wa ter of (()-r-Hyd r oxy-â-a m in o Acid s25
TABLE 6. On e-P ot P r ep a r a tion of Op tica lly Active
Nor sta tin es
a
b
65 °C, 1.5 h.25 0 °C, 0.5 h.25 c Yield of isolated product.
d
Optical purity of the 1,2-epoxide starting material (4 ) 90% ee;
5 ) 95% ee; 6 ) 93% ee).
ered by filtering the aqueous heterogeneous mixture. The
aqueous layer was charged on an ion-exchange resin to
furnish the final R-hydroxy-â-amino acid without using
any organic solvent. The fine black Cu(B) precipitate was
redissolved in water at pH 4.0 under air atmosphere
(Scheme 1), and this solution was reused by adding the
oxirane 7 and NaN3 to repeat the cycle again. The
catalyst was used for five cycles on a 1-, 10-, and 100-
mmol scale without loss of its efficiency and was always
completely recovered. The final amino acids were ana-
lyzed by Atomic Absorption Spectrophotometry before
and after ion exchange purification, and no traces of
a
b
See experimental procedure.25 Yield of isolated product.
4.3) and not regulated during the reaction, the conversion
was quantitative, and again a complete â-regioselectivity
was found (Table 3, entry 5 vs 4). This last result is very
important in view of an automation of the process.
This simplified azidolysis protocol was extended to
a variety of R,â-epoxycarboxylic acids 7; high yields
and a complete â-regioselectivity were always obtained
(Table 4).
The definitive one-pot protocol was defined and ex-
tended to a variety of oxiranes (Table 5). The copper
catalytic cycle25 (Scheme 1) started when 10 mol % of
Cu(NO3)2 catalyzed the azidolysis of a R,â-epoxycarboxylic
acid in the presence of 1.5 molar equiv of NaN3. At the
end of this step (30 or 65 °C, 0.25-4 h), 2.0 molar equiv
of NaBH4 was added at 0 °C with the immediate
formation of black Cu(B), followed by the azido group
reduction (30 min). Copper is then quantitatively recov-
(25) In a typical procedure, 1.300 g (10.0 mmol) of an R,â-epoxy-
hexanoic acid (7b) was dissolved in water (10 mL). Powdered NaN3
(0.975 g, 15 mmol) and 10 mL of an aqueous solution 0.1 M of Cu-
(NO3)2 were added under stirring (resulting pH 4.3-4.5), and the
mixture was warmed to 65 °C. After 1.5 h (ca. pH 5.5) the reaction
mixture was cooled to 0 °C, and NaBH4 was added portion-wise (0.757
g, 20 mmol). After 30 min at 0 °C the reaction mixture was filtered,
and the copper boride was separated quantitatively. The aqueous
mother liquors were acidified to red (indicator paper) with a few drops
of concentrated HCl and charged on an ion-exchange resin Dowex
50WX8-400. Eluting with NH4OH 0.1 M, the 2-hydroxy-3-aminohex-
anoic acid (9b) was isolated in 86% yield as a white crystalline solid.
Recovered Cu(B) was dissolved in 20 mL of a water solution at pH
4.0, and the procedure was repeated. The catalyst was used four times
without decreasing its efficiency. The structures of the products were
confirmed by usual analyses; see Supporting Information.
7044 J . Org. Chem., Vol. 68, No. 18, 2003

Preparation of Optically Active Norstatines
copper were found (sensitivity > 0.5 ppm), confirming the
complete recovery of the catalyst.
Ack n ow led gm en t. The Ministero dell’Universita` e
della Ricerca Scientifica e Tecnologica (MURST), the
Consiglio Nazionale delle Ricerche (CNR), and the
Universita` degli Studi di Perugia are thanked for
financial support.
Finally, the procedure was applied to the synthesis of
optically active alkylisoserines of biological interest: (+)-
phenylnorstatine (1), (-)-allophenylnorstatine (2), and
(-)-alloethylnorstatine (3) starting from the correspond-
ing optically active R,â-epoxycarboxylic acids 4,26 5,29 and
6,32 respectively (Table 6).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
The optically active norstatines 1,33 2,35 and 332 were
isolated in 72-83% overall yields, and the enantiomeric
excesses (90-95%) were found to be consistent with those
of the corresponding starting materials. These results
proved, as expected, that the process proceeds with the
preservation of the purity of the chiral centers.
J O034752Y
(29) E)-4-Phenyl-2-buten-1-ol, used for preparing 5, was synthesized
by standard DIBAL-reduction of the corresponding R,â-unsaturated
ethyl ester,30 which was prepared following the recently reported
procedure31 where carboethoxymethyltriphenylphosphonium bromide
(1.0 equiv) was added to a THF mixture of phenylacetaldehyde (1.0
equiv) and sodium acetate (1.2 equiv) and refluxed for 2 h (93% yield,
after silca gel column chromatography). Sharpless asymmetric
epoxidation6c,d and RuCl3/periodic acid oxidation28 of the alcohol then
allowed 5 to be obtained with 95% ee (measured by HPLC analysis on
a chiral stationary phase and 1H NMR analysis of the Mosher ester;
see Supporting Information) (comparable to that obtained in the
original procedures).6c,d
Con clu sion s
In conclusion, anti- and syn-R-hydroxy-â-amino acids
were synthesized in excellent yields from R,â-epoxycar-
boxylic acids using for the first time a one-pot copper-
catalyzed azidolysis-reduction process that includes the
recovery and reuse of the catalyst. The whole process has
been performed solely in water, and considering that it
plays an essential role in the recovery of copper boride
and in its reconversion into Cu2+ at pH 4.0, water is the
only reaction medium in which the process here pre-
sented can be carried out.
(30) Miller, A. E. G.; Biss, J . W.; Schwartzman, L. H. J . Org. Chem.
1959, 24, 627-630.
(31) Hon, I.-S.; Lee, I.-F. Tetrahedron 2000, 56, 7893-7902.
(32) Epoxycarboxylic acid 6 was prepared by Sharpless asymmetric
epoxidation6c,d and RuCl3/periodic acid oxidation28 of trans-2-hexenol
with 93% ee (measured by 1H NMR analysis of the Mosher ester)
(comparable to that obtained in the original procedures).6c,d Compound
20
3: mp > 230 °C (dec) and [R]d ) -11.7 (c ) 0.52 in 1 N HCl).
(33) Mp ) 236-237 °C and [R]20 ) +29.6 (c ) 0.25 in 1 N HCl)
D
(26) Z)-4-Phenyl-2-buten-1-ol, used to prepare 4, was synthesized
according to the procedure advised by Nicolaou.27 Sharpless asym-
metric epoxidation of the alcohol followed by RuCl3/periodic acid
Sharpless oxidation28 allowed 4 to be obtained with 90% ee (measured
by HPLC analysis on a chiral stationary phase and 1H NMR analysis
of the Mosher ester; see Supporting Information) (comparable to those
obtained in the original procedures).6c,d
(27) Nicolaou, K. C.; Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.;
Leresche, J . E.; Tsuri, T.; Yoshimitsu, N.; De Riccardis, F. Chem. Eur.
J . 1995, 1, 467-494.
(28) Carlsen, P. H.; Katsuki, T.; Mart´ın, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936-3938.
[lit.14 mp ) 235-237 °C and [R]20 ) +29.9 (c ) 0.214 in 1 N HCl;
D
lit.34 mp ) 236-237 °C and [R]20 ) 29.2 (c ) 0.25 1 N HCl). HPLC
D
analysis on a chiral stationary phase, performed on the N-acetyl-
methylester derivative, confirmed the enantiomeric purity of the
starting epoxyalcohol 4 (Supporting Information).
(34) Kobayashi, Y.; Takemoto, Y.; Kamijo, T.; Harada, H.; Ito, Y.;
Terashima, S. Tetrahedron 1992, 48, 1853-1868.
(35) Mp ) 236-237 °C and [R]20D ) -5.2 (c ) 0.56 in 1 N HCl) [lit.16
[R]20 ) -5.4 (c ) 0.51 in 1 N HCl). HPLC analysis on a chiral
D
stationary phase, performed on the N-acetyl-methylester derivative,
confirmed the enantiomeric purity of the starting epoxyalcohol 5
(Supporting Information).
J . Org. Chem, Vol. 68, No. 18, 2003 7045