Synthesis of α,α-disubstituted β-amino esters and peptide derivatives

Article abstract of DOI:10.1055/s-2002-19326

The synthesis of α,α-disubstituted β-amino esters and peptide derivatives from readily available 4-spiro-β-lactams 1 is described. The geminally disubstituted β-amino esters are obtained from the N-Boc spiro β-lactams 2 by treatment with potassium cyanide in methanol. Alternatively, the use of spiro β-lactams 2 as acylating agents of the amino group of C-protected amino acids, allowed its direct incorporation into a peptidic chain.

Full text of DOI:10.1055/s-2002-19326

LETTER
69
Synthesis of , -Disubstituted -Amino Esters and Peptide Derivatives
Synthesis of
,
d
-Disubstitut
u
ed -Amino
aEstersand
P
r
eptide
D
d
erivatives o Alonso, Carlos del Pozo, Javier González*
Departamento de Química Orgánica e Inorgánica, Universidad de Oviedo, 33071 Oviedo, Spain
Fax +34(985)103446; E-mail: FJGF@sauron.quimica.uniovi.es
Received 9 October 2001
which both the amino and the acid moieties are simulta-
neously protected, and therefore they are usually em-
ployed as precursors of -amino acids.8 It is interesting to
point out that a few synthetic methodologies to prepare
Abstract: The synthesis of , -disubstituted -amino esters and
peptide derivatives from readily available 4-spiro- -lactams 1 is de-
scribed. The geminally disubstituted -amino esters are obtained
from the N-Boc spiro -lactams 2 by treatment with potassium cya-
nide in methanol. Alternatively, the use of spiro -lactams 2 as acy- spiro -lactams have been described so far,9 and only in
lating agents of the amino group of C-protected amino acids,
allowed its direct incorporation into a peptidic chain.
one case they were employed as precursors of cyclic , -
disubstituted -amino acid derivatives (Figure 2).10
Key words: amino acids, lactams, peptides, ring opening, spiro
compounds
Ph
O
N
SO2Ph
N
RO
H
PhOC
S
-Amino acids have attracted a great deal of interest dur-
ing the last few years due to their presence in a wide num-
ber of natural products (e.g., the side chain of the
anticancer agent, taxol). On the other hand, and perhaps
even more interesting, recent results show that synthetic
-peptides ( -amino acids oligomers) present some inter-
esting features. They form much more stable secondary
structures than do their parents -peptides,1 and some of
them exhibit biological activity acting as inhibitors of
cholesterol and fat absorption2 or as antibiotics.3
R= H, Me, Et
Figure 2
At this point, we thought that 4-spiro -lactams 1, could
be useful intermediates for the preparation of -amino ac-
ids with , -cyclic disubstitution. These , -disubstituted
cyclic -amino acids present some new interesting struc-
tural features: a) their unsymmetrical (tetrahydrofuran
ring) , -disubstitution (almost all previously described
cyclic , - or , -disubstituted -amino acids bear a cy-
cloalkane ring);6,11 b) the presence of an oxygen atom in
the tetrahydrofuran ring, since oxygen could act as a hy-
drogen bond acceptor increasing the conformational -
peptide possibilities and their hydrogen bond interactions
with peptide receptors.
Among the available methods for the synthesis of -ami-
no acids ( - or -monosubstituted), just a few are suitable
for the preparation of , - and , -disubstituted ones.4
Seebach et al.5 have recently shown that , -disubstitu-
tion in -peptides leads to the formation of very stable
peptide secondary structures. In this context, especially
remarkable folding properties were observed in -pep-
Although -amino acids could be directly obtained from
N-alkyl or N-aryl -lactams by treatment with HCl (6 N)
at 100 ºC, we previously transformed the -lactams 1 to
the N-Boc derivatives 2 (Scheme 1). The presence of an
electron-withdrawing group, as the tert-butoxycarbonyl,
on the -lactam nitrogen allowed the cleavage of the
amide bond under milder reaction conditions. Oxidative
removal of the N-protecting p-methoxyphenyl group
(PMP) with ceric ammonium nitrate (CAN)12 and further
treatment with di-tert-butyldicarbonate [(Boc)2O] in the
presence of a catalytic amount of DMAP11 (Scheme 1)
lead to the formation of N-Boc -lactams 2. These com-
pounds were treated with a catalytic amount of potassium
cyanide in methanol to give the , -disubstituted -amino
esters 3 in high yields (Table 1).13
tides bearing
a
cyclic
, -disubstitution pattern
(Figure 1). These cyclic , -disubstituted -peptides
adopt unprecedented peptide secondary structures not
only in the -amino acid field, but also in realm of -pep-
tides.6
O
O
N
N
H
H
R
R
n
n= 0, 1, 2, 3
Figure 1
In this paper we describe the synthesis of cyclic , -dis-
ubstituted -amino esters and peptide derivatives employ-
ing 4-spiro -lactams 1 as starting materials (Scheme 1).7
-Lactams can be viewed as cyclic -amino acids, in
The Boc protecting group on the -amino ester 3a could
be easily removed by reaction with trifluoroacetic acid in
dichloromethane at 0 ºC affording the free amine, that was
directly coupled with a N-protected -amino acid to give
peptides 4 and 5 in good yields (Scheme 2).14 Unfortu-
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0069,0072,ftx,en;G14001ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

70
E. Alonso et al.
LETTER
opening promoter additive, to afford the dipeptide 6 in
good yield. No coupling reaction was observed with other
-amino esters under these experimental conditions. The
reactions were then carried out in DMF at 40 ºC in the
presence of 1.5 equiv of potassium cyanide as a ring open-
ing promoter, and 2 equiv of the amino ester, to give the
peptides 6–11 (Table 2).18 The 1:1 mixture of diastereo-
isomers obtained could be separated by column chroma-
tography in the case of peptides 7 and 8.19
O
X
R
Y
X
Y
X
R
R
i
iii
H3CO
NHBoc
N
N
ii
O
PMP
O
Boc
Y
1
2
3
PMP= p-Methoxyphenyl
Scheme 1 i) CAN, H2O/CH3CN, 0 °C, 30 min ii) (Boc)2O, DMAP
(cat.), CH3CN, 0 ºC to r.t., 16 h. (40–83%) two steps iii) KCN (cat.),
MeOH, r.t., 16 h
One of the most popular procedures to establish the abso-
lute configuration of a chiral secondary alcohol or a pri-
mary -substituted amine is the NMR approach,20
employing auxiliary reagents like -metoxy- -trifluorom-
ethylphenyl acetic acid (MTPA) introduced by Mosher.21
Table 1
, -Disubstituted -Amino Esters (3)
R
X
Y
Yield
93%
95%
95%
3a
3b
3c
C6H5–
O
CH2
CH2
O
R1
Y
X
R
O
R
i
C6H5CH=CH–
C6H5–
O
H3CO
N
NHBoc
N
H
X
CH2
O
O
Boc
Y
2
6-11
Scheme 3 i) KCN (1.5 equiv), -aminoester (2 equiv), DMF 40 ºC,
18 h. ii) Aqueous work up and chromatographic purification
nately, the 1:1 diastereoisomeric mixtures obtained could
not be separated by column chromatography.
Table 2 Peptides 6–11
The enhanced amide bond reactivity of the N-Boc -lac-
tams allowed its employment as acylating agent. Different
nucleophiles can be used to promote the ring opening of
the -lactam. Thus, -lactams can be directly coupled
with the amino group of an -aminoester15 or with an
alcohol16 to form a peptidic bond or an ester respectively.
The big influence of the steric hindrance at the 3- and 4-
positions of the N-Boc -lactams on its reactivity has also
been reported. In these cases, a ring opening promoter ad-
ditive like sodium azide17 or potassium cyanide12 is usual-
ly needed. In our case, we have observed the
aforementioned influence of the steric hindrance of sub-
stituents at 3- and 4-positions in the ring opening of N-Boc
-lactams. In addition, the influence of the steric hin-
drance of the substituent at C of the -amino ester em-
ployed as nucleophile in the ring opening, was also
observed.
X
Y
R
R1
Rto.a
82%b
66%c
6
O
CH2
CH2
CH2
CH2
O
C6H5–
C6H5–
C6H5–
H–
7a,b
8a,b
9
O
CH3–
O
(CH3)2CHCH2– 56%c
O
C6H5CH=CH– CH3–
64%d
53%d
10
11
CH2
CH2
C6H5–
C6H5–
CH3–
O
(CH3)2CHCH2– 49%d
a Yield referred to the mixture of stereoisomers.
b Reaction carried out without KCN at r.t.
c Separable stereoisomers.
d Not separable stereoisomers.
Therefore, we removed the Boc protecting group of dias-
tereoisomers 7b and 8a. Reaction of the amines with both
enantiomers of Mosher’s acid chloride (MTPACl)
(Scheme 4) gave the diastereoisomeric amides 11-14. The
difference in the H NMR chemical shifts values (
Due to the spiro substitution at the 4-position of our -lac-
tams 2, we initially assumed that it would be necessary to
use a ring-opening promoter for the coupling reaction
with different -amino esters (Scheme 3). This assump-
tion was true for all cases except for the glycine methyl es-
ter, which was coupled at r.t. in DMF without any ring
1
=
–
(R)MTPA) of the methoxy group of the diastereoi-
(S)MTPA
someric MTPA amides, were employed to determine the
absolute configuration of compounds 7b and 8a
(Figure 3). The influence of the phenyl ring anisotropy on
the C of the MTPA amide in the chemical shift value of
methoxy group, allowed us to establish the absolute con-
figuration of this chiral centre. We assume that the differ-
ence in chemical shift observed in the methoxy group of
compounds 11,12 and 13,14, is due to the anisotropic
shielding produced by the C aromatic ring depending
upon the absolute stereochemistry of this chiral centre as
can be seen in the model proposed by Mosher et al.
(Scheme 4).20a This result, in conjunction with previous
O
O
Ph
O
NHBoc
i
H3CO
N
3a
H
R1
ii
4: R1=CH3-
5: R1=Bn-
81%
76%
Scheme 2 i) TFA, CH2Cl2 0 ºC to r.t., 2 h ii) HOBT, DCC, BocN-
HCH(R1)CO2H, THF, 0 ºC to r.t., 16 h
Synlett 2002, No. 1, 69–72 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of , -Disubstituted -Amino Esters and Peptide Derivatives
71
upfield relative to
CH3
R2
O
O
Ph
O
O
Ph
H
N
H3CO
CF3
i
N
N
7b or 8a
CF3
H
H
Ph
OCH3
Cα
ii
O
O
H
(S)-(-)
11: R2=CH3-; MTPA- R-(+)
12: R2=CH3-; MTPA-S-(-)
∆δ= 15 Hz
CH3
O
Ph
H
N
13: R2=(CH3)2CHCH2 ; MTPA- R-(+)
14: R2=(CH3)2CHCH2 ; MTPA- S-(-)
CF3
∆δ= -12 Hz
Cα
O
H
(R)-(+)
Scheme 4 i) TFA, CH2Cl2, 0 ºC to r.t., 2 h ii) (+or –) MTPA acid chloride (1.2 equiv), NEt3, CH2Cl2, r.t., 16 h
2 mmol) in toluene (5 mL). The reaction mixture was
refluxed overnight, cooled to r.t., and diluted with CH2Cl2
(30 mL). The resultant solution was washed with 5%
NaHCO3(20 mL) and brine (20 mL). The organic layer was
dried (Na2SO4) and concentrated in vacuo. Flash
NOE experiments on the starting spiro -lactam that re-
vealed the cis relative stereochemistry of the 3- and 4-
substituents, allowed us to establish the absolute stere-
ochemistry of the peptide derivatives (Figure 2).
chromatography over silica gel (EtOAc–hexanes) of the
crude reactions afforded the final spiro -lactams 1.
(8) Palomo, C.; Aizpurua, J. M.; Ganboa, I. In Enantioselective
Synthesis of -Amino Acids; Juaristi, E., Ed.; Wiley-VCH.:
NY, 1997, 280–357.
(9) See: (a) Ikeda, M.; Uchino, T.; Ishibashi, H.; Tamura, Y.;
Kido, M. J. Chem. Soc. Chem. Commun. 1984, 758. (b) Le
Blanc, S.; Pete, J.; Piva, O. Tetrahedron Lett. 1992, 33,
1993. (c) Bateson, J. H.; Guest, A. W. Tetrahedron Lett.
1993, 34, 1799. (d) Anklam, S.; Liebscher, J. Tetrahedron
1998, 54, 6369. (e) Croce, P. D.; Ferraccioli, R.; La Rosa, C.
Tetrahedron 1995, 34, 9385. (f) Croce, P. D.; Ferraccioli,
R.; La Rosa, C. Tetrahedron 1999, 55, 201. (g) Croce, P.
D.; La Rosa, C. Tetrahedron Asymmetry 1999, 10, 1193.
(10) Croce, P. D.; La Rosa, C. Heterocycles 2000, 53, 2653.
(11) Palomo, C.; Oiarbide, M.; Bindi, S. J. Org. Chem. 1998, 63,
2469.
S, (R)
O
Ph
R, (S)
NHBoc
H3CO
7b, (7a)
N
H
O
O
R, (S)
O
Ph
S, (R)
NHBoc
H3CO
8a, (8b)
N
H
O
O
Figure 3 Assignment of the stereochemistry of the peptides 7b and
8a. Peptides 7a and 8b are in parentheses
(12) Floyd, D. M.; Fritz, A. W.; Plusec, J.; Weaver, E. R.;
Cimarusti, C. M. J. Org. Chem. 1982, 42, 5160.
In conclusion, we have shown the synthetic utility of the
readily available 4-spiro -lactams in the synthesis of new
, -cyclic disubstituted -amino esters and peptide deriv-
atives. These compounds have been shown as useful pre-
cursors for the construction of -peptides with new
folding patterns.
(13) Typical experimental procedure for 3: To a stirred solution
of the N-Boc -lactam 2 (1 mmol) in MeOH (10 mL) was
added a catalytic amount of potassium cyanide (10–15%
mol). After the consumption of the starting material
(monitored by TLC), the methanol was removed in vacuo,
10 mL of NaHCO3 (5%) and 10 mL of EtOAc were then
added. The aqueous solution was extracted with EtOAc (2
15 mL). The mixed organic layers were washed with brine
(2 25 mL) and dried over anhydrous Na2SO4 and
concentrated in vacuo. The crude oil was submitted to a short
silica gel column chromatography (1:1, EtOAc–hexanes) to
afford 3a–c. Data for 3a: IR (KBr): 3465, 1736, 1686, 1095
cm–1; 1H NMR (300 MHz, CDCl3): 1.36 (s, 9 H), 1.64 (m,
1 H), 1.86 (m, 2 H), 2.08 (m, 1 H), 3.74 (s, 3 H), 3.86 (m, 2
H), 5.04 (d, J = 10.0 Hz, 1 H), 5.79 (broad d, J = 10.0 Hz, 1
H), 7.29 (m, 5 H). 13C NMR (75 MHz, CDCl3): 174.2,
154.6, 137.8, 128.2, 127.8, 127.4, 88.2, 79.1, 69.5, 58.6,
52.2, 33.2, 27.9, 24.7. HRMS calcd for C14H16NO4 262.1077
(M+– C4H9), found 262.1079.
References
(1) Koert, U. Angew. Chem., Int. Ed. Engl. 1997, 36, 1836.
(2) Werder, M.; Hauser, H.; Abele, S.; Seebach, D. Helv. Chim.
Acta 1999, 82, 1774.
(3) (a) Porter, E. A.; Wang, X.; Lee, H.; Weisblum, B.; Gellman,
S. H. Nature 2000, 404, 565. (b) Liu, D.; DeGrado, W. F. J.
Am. Chem. Soc. 2001, 123, 7553. (c) Hamuro, Y.;
Scheneider, J. P.; DeGrado, W. F. J. Am. Chem. Soc. 1999,
121, 12200.
(4) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1.
(5) Seebach, D.; Abele, S.; Sifferlen, T.; Hänggi, M.; Gruner, S.;
Seiler, P. Helv. Chim. Acta 1998, 81, 2218.
(6) Abele, S.; Seiler, P.; Seebach, D. Helv. Chim. Acta 1999, 82,
1559.
(14) The Practice of Peptide Synthesis; Bodanszky, M.
Bodanszky, A., Ed.; 2nd ed, Springer Lab Manual: 1994.
(15) Ojima, I.; Sun, C. M.; Park, Y. H. J. Org. Chem. 1994, 59,
1249.
(16) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun,
C. M.; Brigaud, T. Tetrahedron 1992, 48, 6985.
(7) Typical experimental procedure for 1: To a solution of the
imine (2 mmol) and dry Et3N (0.41 mL, 3 mmol) in dry
refluxing toluene (15 mL) was added dropwise a solution of
the corresponding 2- or 3-tetrahydrofuroyl chloride (0.269 g,
Synlett 2002, No. 1, 69–72 ISSN 0936-5214 © Thieme Stuttgart · New York

72
E. Alonso et al.
LETTER
(17) Palomo, C.; Aizpurua, J. M.; Galarza, R.; Mielgo, A. Chem.
Commun. 1996, 633.
Hz, 1 H), 6.56 (broad d, J = 9 Hz, 1 H), 6.87 (broad d, J = 9.2
Hz, 1 H), 7.27 (m, 5 H). 13C NMR (75 MHz, CDCl3):
173.7, 171.7, 155.2, 138.6, 127.6, 127.5, 127.1, 87.6, 79.1,
69.6, 59.4, 52.0, 49.9, 41.3, 34.6, 28.1, 25.4, 24.7, 22.6, 21.5.
HRMS calcd for C14H16NO4 448.2573 (M+), found
448.2576.
(18) Typical experimental procedure for 7-13: To a solution of
the N-Boc -lactam 2 (1 mmol) in dry DMF (10 mL) at 40
ºC was added 2 mmol of the corresponding amino ester and
(77 mg, 1.5 equiv) of KCN. After stirring the solution during
16 h, brine (10 mL) was added. The solution was extracted
with EtOAc (2 15 mL) and the mixed organic layers were
washed with 5% NaHCO3 (15 mL), 1 N HCl (15 mL) and
brine (25 mL). The organic layer was dried over anhydrous
Na2SO4 and concentrated in vacuo. Flash chromatography
over silica gel (EtOAc-hexanes) of the crude reactions
afforded the final dipeptides 6-11. Data for 8a: [ ]D 20 = –
30.8 (c = 0.76, CHCl3); IR (KBr): 3323, 1731, 1697, 1646
cm–1; 1H NMR (300 MHz, CDCl3): 0.89 (d, J = 6.2 Hz, 6
H), 1.38 (s, 9 H), 1.50 (m, 3 H)1.82 (m, 1 H), 2.24 (m, 1 H),
3.58 (s, 3 H), 3.98 (m, 2 H), 4.45 (m, 1 H), 4.76 (d, J = 9.2
(19) Compound letter were assigned according to their Rf values
in column chromatography (silica gel Merck 230-400 mesh,
1:1, hexane-EtOAc as eluent). Rf 7a<7b; Rf 8a<8b.
(20) See for example: (a) Dale, J. A.; Mosher, H. S. J. Am. Chem.
Soc. 1972, 95, 512. (b) Trost, B. M.; Belletire, J. L.;
Godleski, S.; McDougal, P. G.; Balkovec, J. M. J. Org.
Chem. 1986, 51, 2370. (c) Latypov, S. K.; Seco, J. M.;
Quiñoá, E.; Riguera, R. J. Am. Chem. Soc. 1998, 120, 877.
(21) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543.
Synlett 2002, No. 1, 69–72 ISSN 0936-5214 © Thieme Stuttgart · New York