A reasonably stereospecific multistep conversion of Boc-protected α-amino acids to Phth-protected β3-amino acids

Article abstract of DOI:10.1016/j.tetlet.2010.05.143

A method for the synthesis of β³-amino acids starting from α-amino acids is described. This conversion can be effected by an eight-step procedure which involves the transformation of the carboxylic group into an alkyne followed by a selenium-mediated conversion of the carbon-carbon triple bond to a Se-phenyl selenocarboxylate intermediate. The reactive Se-phenyl selenocarboxylate intermediates can be trapped with water, alcohols or the amine of an amino acid derivative to give β³-amino acids, β³-amino esters or mixed peptides, respectively. The whole transformations of the carboxylic group into an alkyne and of the alkyne group into β³-amino acids may not require purification of the intermediate products but a work-up and isolation procedure of crude materials.

Full text of DOI:10.1016/j.tetlet.2010.05.143

Tetrahedron Letters 51 (2010) 4121–4124
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A reasonably stereospecific multistep conversion of Boc-protected
a-amino
acids to Phth-protected b3-amino acids
b,
b
a
Andrea Temperini a, , Antonella Capperucci , Alessandro Degl’Innocenti , Raffaella Terlizzi ,
*
*
Marcello Tiecco a
a Dipartimento di Chimica e tecnologia del Farmaco, Sezione di Chimica Organica, Università di Perugia, via del Liceo 1, 06123 Perugia, Italy
b Dipartimento di Chimica, Università di Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
a r t i c l e i n f o
a b s t r a c t
A method for the synthesis of b3-amino acids starting from
a-amino acids is described. This conversion
Article history:
Received 30 March 2010
Revised 28 May 2010
Accepted 28 May 2010
Available online 2 June 2010
can be effected by an eight-step procedure which involves the transformation of the carboxylic group into
an alkyne followed by a selenium-mediated conversion of the carbon–carbon triple bond to a Se-phenyl
selenocarboxylate intermediate. The reactive Se-phenyl selenocarboxylate intermediates can be trapped
with water, alcohols or the amine of an amino acid derivative to give b3-amino acids, b3-amino esters or
mixed peptides, respectively. The whole transformations of the carboxylic group into an alkyne and of the
alkyne group into b3-amino acids may not require purification of the intermediate products but a work-
up and isolation procedure of crude materials.
Dedicated to Professor Saverio Florio on the
occasion of his 70th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
a-Amino acids
Selenium
Propargylic amines
b-Amino acids
The synthesis of b3-amino acids has attracted considerable
attention due to their important role in synthetic chemistry and
as key components of a variety of biologically active natural mole-
cules.1 In medicinal chemistry they represent key components of
drugs and b-lactams.2 b3-Amino acids also have considerable
importance in the study of biomimetic polymers which contain
both secondary and tertiary structure analogues to those of natural
proteins.3 Different approaches have been developed for the
an approach for the synthesis of the essential N-Boc propargylic
amines from the corresponding -amino aldehyde inter-
mediates 2.
Thus the commercially available N-Boc
3
a
a-amino acids 1a–d
were converted, under mild conditions, into the corresponding
Weinreb amide intermediates by the mixed anhydride method.9
These crude amides were directly reduced with 1.2 molar equiv
of lithium aluminium hydride10 to give the N-Boc a-amino alde-
hydes intermediates 2a–d. Because of their chemical and configu-
rational instability,11 the crude aldehydes 2 were directly used for
the reaction with the Bestmann–Ohira reagent, in the presence of
anhydrous potassium carbonate. The crude N-Boc propargylic
amines 3 were thus obtained. An analytical sample of compound
3a, ent-3a, 3c and ent-3c was used to detect the extent of the
synthesis of b3-amino acids starting from
a-amino acids as starting
materials because of their ready availability.4 In this field we have
recently introduced a facile synthesis of Se-phenyl selenocarboxy-
lates from readily accessible terminal alkynes.5 These results
induced us to devise a new stereospecific conversion of commer-
cially available optically active N-Boc
a-amino acids 1 into the N-
phthaloyl b-homologues 7 (Scheme 1).
racemization at the stereogenic
umn. Under the reaction conditions employed
and ent-1a as well as -serine ent-1c derivatives suffered a partial
a
-carbon by GC–MS on chiral col-
The key steps of this conversion are the synthesis of the optically
active N-Boc propargylic amines 3 from the a-amino acids 1 and the
formal oxidative-hydration of the C–C triple bond to give 7. General
methods for the stereoselective synthesis of 3 have been already
reported in the literature6 however, on the basis of previous expe-
rience,7 we envisioned that the use of the Bestmann–Ohira8
modification of the Seyferth–Gilbert reagent might constitute
L
- and -valine 1a
D
D
racemization. As evidenced in previous works12 these losses of
enantiopurity very likely occurred during the synthesis of the
aldehydes and/or during the work-up procedure, depending on
the structure. Since the Boc-amino-protecting group is not stable
under the reaction conditions employed for the conversion of the
C–C triple bond into the Se-phenyl selenocarboxylate group,5 com-
pounds 3 were treated with trifluoroacetic acid in dichlorometh-
ane to give the corresponding propargylic amine salts which
* Corresponding authors. Tel.: +39 075 5855121; fax: +39 075 5855116.
E-mail address: tempa@unipg.it (A. Temperini).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.143

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A. Temperini et al. / Tetrahedron Letters 51 (2010) 4121–4124
O
PO(OMe)2
a) i-BuOCOCl, NMM/ 0 °C
(MeO)NHMe.HCl/ EtOAc
b) LiAlH4/ THF/ RT
NHBoc
H
NHBoc
NHBoc
OH
N2
R
R
R
K2CO3/ MeOH/ 0 ºC
O
O
1
2
3
TsOH.H2O
PhthN
PhthN
R
a) CF3CO2H/ CH2Cl2
PhSeBr/ CuI
DMF/ RT
R
CH2Cl2/ 40 ºC
b) PhthNCO2Et
THF/ 80 ºC
SePh
4
5
PhthN
R
PhthN
R
O
O
H2O2
SePh
OH
THF/ RT
7
6
Scheme 1. Multistep synthesis of N-phthloyl-b3-amino acids 7 from N-Boc-
a-amino acids 1.
were then protected as N-phthaloyl derivatives 4. The reaction of
3c and ent-3c under the conditions reported above led to complete
acetonide decomposition to give the free hydroxy derivatives, as
already reported in the literature.13
Following this protocol the pure N-phthaloyl propargylic
amines 4 were obtained in good overall yields from 1 (Table 1).
HPLC analysis of compound 4b revealed that a partial racemization
then treated with hydrogen peroxide in tetrahydrofuran to give the
corresponding N-protected b3-amino acids 7 in good global yields
from 4. The results of these experiments are collected in Table 2.
As indicated in Scheme 2, the b3-amino acid derivatives of N-
phthaloyl propargylic amines 4c and ent-4c could not be obtained
because the treatment of their alkynyl phenyl selenide intermedi-
ates with p-toluenesulfonic acid monohydrate in refluxing dichlo-
romethane afforded lactones 8 and ent-8, respectively, in good
yields. The formation of these lactones is in agreement with previ-
ous observations15 which indicated that when an alkynyl phenyl
selenide holds an oxygen atom in a suitable position the reaction
with p-toluenesulfonic acid gives rise to a proton-induced ring-clo-
of the starting a-amino acid 1b occurred during the preparation of
the corresponding aldehyde. The enantiomeric ratios of com-
pounds 4d and ent-4d could not be determined since these
compounds did not show any separation on the chiral columns
employed.
The propargylic amines 4 were then converted14 into the corre-
sponding alkynyl phenyl selenide intermediates 5. These interme-
diates were obtained sufficiently pure to be directly employed in
the following step (Scheme 1). The treatment of 5 with an excess
of p-toluenesulfonic acid monohydrate in refluxing dichlorometh-
ane5 gave the Se-phenyl selenocarboxylates 6. Compounds 6 were
sure reaction affording c-lactones.
HPLC analysis of products 8 and ent-8 indicates that no racemi-
zation occurred during the conversion of 3c and ent-3c into
lactones 8 and ent-8, respectively. Moreover, analytical samples
of the crude Se-phenyl selenocarboxylate intermediates 6a, ent-
6a and 6b were converted5 into the corresponding N-protected
Table 1
Multistep conversion of N-Boc-a-amino acids 1 into the corresponding N-protected propargylic amines 4
a-Amino acids 1
N-Protected propargylic amines 4
era
Yieldb (%)
NHBoc
NPhth
1a
4a
86:14
85:15
77:23c
30
27
35
CO2H
ent-1a
1b
ent-4a
4b
NHBoc
CO2H
NPhth
Ph
Ph
NPhth
HO
NBoc
1c
4c
99:1
56
60
O
CO2H
ent-1c
ent-4c
77:23
NHBoc
NPhth
d
1d
4d
—
32
27
CbzNH
CbzNH
CO2H
4
4
d
ent-1d
ent-4d
—
a
b
c
Enantiomeric ratio determined by chiral GC–MS on a purified analytical sample of the corresponding intermediate 3.
Total yield calculated from 1.
Enantiomeric ratio of 4b determined by chiral HPLC.
d
Compounds 4d and ent-4d did not show any HPLC separation.

A. Temperini et al. / Tetrahedron Letters 51 (2010) 4121–4124
4123
Table 2
Bn
PhthN
R
O
THF/ RT
Et3N
Multistep preparation of enantiomerically enriched N-protected b3-aminoacids
from N-protected propargylic amines 4
7
+
SePh
ClH3N CO2Me
N-Protected
propargylic
amines 4
N-Protected b3-amino acids 7
Yielda (%)
erb
6d
PhthN
R
O
Bn
CO2Me
+
PhSeSePh
N
PhthN
CO2H
H
10
4a
63
65
87:13
83:17
53% (d.r. = 88:12)
R = CbzNH-(CH2)4-
ent-4a
ent-7a
PhthN
Scheme 3. Formation of mixed
calculated from 4d. The diastereoisomeric mixed
67% global yield from ent-6d by the same procedure.
a
/b-dipeptide 10 from intermediate 6d. Global yield
CO2H
4b
76
77:23
a
/b-dipeptide 11 was obtained in
Ph
7b
PhthN
c
4d
50
56
—
CbzNH
CO2H
The whole transformations of 1 into 4 and of 4 into 7 may not re-
quire purification of the intermediate products but a work-up and
isolation procedure of crude materials: there are solvent changes
from EtOAc to THF to MeOH to CH2Cl2 to THF on the way from 1
to 4 and from DMF to CH2Cl2 to THF on the way from 4 to 7. It is
worth noting that the entire synthetic procedure is of general
application since different functionalities present in the substrates
such as phenyl, hydroxy, phthaloyl and benzyloxycarbonyl groups
are tolerated under the reaction conditions employed. Modifica-
tions of the above strategy to minimize the loss of enantiomeric
4
c
ent-4d
ent-7d
—
a
b
c
Total yield calculated from 4.
Determined by chiral HPLC on the corresponding methyl ester derivatives.
Enantiomeric ratio was determined by proton magnetic resonance analysis of
b-dipeptide.
the corresponding mixed
a
purity of the starting a-amino acids are currently under investiga-
tion in our laboratory.
PhthN
NPhth
4c
i
HO
HO
O
O
8
ii
Acknowledgements
51% (e.r. = 98:2)
Financial support from MIUR, National Projects PRIN 2007, Con-
sorzio CINMPIS, Bari and University of Perugia is gratefully
acknowledged.
PhthN
NPhth
i
O
O
ii
Supplementary data
ent-4c
ent-
8
53% (e.r. = 77:23)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.143.
Scheme 2. Formation of lactone 8 from 4c and lactone ent-8 from ent-4c. Reagents
and conditions: (i) PhSeBr (1.1 equiv), CuI (2 equiv), DMF, rt, 48 h; (ii) p-TsOH
(2 equiv), CH2Cl2, 70 °C, 4 h.
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