Synthesis of type II β-turn surrogate dipeptides based on syn-α-amino-α,β-dialkyl-β-lactams

Article abstract of DOI:10.1021/ol048348c

(Chemical equation presented) The achiral bis(trimethylsilyl)methyl group acts as an efficient stereochemical determinant of the α-alkylation reaction in β-branched α-phenyloxazolidinyl- or α- diphenyloxazolidinyl-β-lactams and provides the first stereoco

Full text of DOI:10.1021/ol048348c

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4443-4446
Synthesis of Type II
Dipeptides Based on
â
-Turn Surrogate
syn-r-Amino-r,â-dialkyl-â-lactams
Claudio Palomo,*,† Jesus M. Aizpurua,*,† In˜aki Ganboa,† Ana Benito,†
Lourdes Cuerdo,† Raluca M. Fratila,† Azucena Jimenez,† Iraida Loinaz,†
Jose´ I. Miranda,† Kinga R. Pytlewska,† Andreea Micle,† and Anthony Linden‡
Departamento de Qu´ımica Organica-I, UniVersidad del Pais Vasco,
Facultad de Quimica, Apdo 1072, 20080 San Sebastian, Spain,
Organisch-chemisches Institut der UniVersita¨t Zu¨rich,Winterthurerstrasse 190,
CH-8057 Zu¨rich, Switzerland
qppaiipj@sc.ehu.es
Received August 19, 2004
ABSTRACT
The achiral bis(trimethylsilyl)methyl group acts as an efficient stereochemical determinant of the
r-alkylation reaction in
â
-branched
r
-phenyloxazolidinyl- or
r
-diphenyloxazolidinyl-
â
-lactams and provides the first stereocontrolled access to syn-
r
-amino-r,
â
-dialkyl(aryl)-â-
lactams. These products are readily transformed into type II
â
-turn mimetic surrogates 2B.
During the last two decades, â-turn peptidomimetics1 have
been sought as promising candidates for drug discovery due
to their ability to agonize or antagonize important biological
processes. We recently have established a novel approach
to the design of type II â-turn mimetics2 based on the
separation of restriction and recognition elements principle
using the -(R-alkyl-R-amino-â-lactam)-(glycine)- segment
as the betagenic (i + 1)-(i + 2)- central core (Figure 1).
In the same report, we provided MD and NMR conforma-
tional evidence that showed that only R-alkylated or syn-
R,â-dialkylated â-lactam peptides 1A and 1B stabilize
â-turned conformations in DMSO, whereas the R-unbranched
or anti-R,â-dialkylated â-lactam peptides collapse to open
conformations.
While the synthesis of dipeptide surrogates 2A has been
addressed for the first time in our laboratory3 using the
R-alkylation of N-[bis(trimethylsilyl)methyl]-â-lactams 4 as
a key step (Figure 2), the extension of this methodology to
† Universidad del Pais Vasco.
‡ Organisch-chemisches Institut der Universita¨t Zu¨rich.
(1) Kahn, M.; Eguchi, M. Synthesis of Peptides Incorporating â-Turn
Inducers and Mimetics. In Houben-Weyl, Methods of Organic Chemistry;
Felix, A., Moroder, L., Toniolo, C., Eds.; Thieme: Stuttgart, 2003; Vol.
E22c, pp 695-740 and references therein.
(2) Palomo, C.; Aizpurua, J. M.; Benito, A.; Miranda, J. I.; Fratila, R.
M.; Matute, C.; Domercq, M.; Gago, F.; Martin-Santamaria, S.; Linden,
A. J. Am. Chem. Soc. 2003, 125, 16243-16260.
Figure 1. â-Lactam peptide approach to type II â-turn mimetics.
10.1021/ol048348c CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/03/2004

Scheme 1
Figure 2. Stereochemical sense of the R-alkylation of R-(4-phenyl-
1,3-oxazolidin-3-yl)-â-lactams.
the preparation of syn-dialkyl dipeptides 2B is not obvious.
Indeed, Ojima and others4 have established that the asym-
metric alkylation of enolates generated by the deprotonation
of â-substituted monocyclic â-lactams invariably leads to
anti-R,â-dialkyl derivatives (e.g., 5f6).
Nevertheless, contrary to these general observations, we
have found2 that several structurally very similar â-substi-
tuted N-[bis(trimethylsilyl)methyl]-â-lactams can afford mainly
syn-R-alkylated products (e.g., 7f8). Herein we report the
first general synthesis of syn-R,â-dialkyl(aryl)-â-lactam
dipeptides 2B as well as a mechanistic model and experi-
mental evidence that accounts for the stereochemistry
observed as a function of the substituents borne by the
nitrogen atom of the â-lactam.
To study the scope and stereochemical outcome of the
R-alkylation reaction, a series of â-branched N-bis(trimeth-
ylsilyl)methyl-â-lactams were prepared from imines 9 and
mono- or diphenyloxazolidinylacetic acid chlorides, accord-
ing to the described methods (Scheme 1).5
As shown in Table 1, â-lactams 11-16 were completely
deprotonated within a few minutes with LDA in THF at -78
°C, and the resulting enolates were cleanly alkylated in fair
to good yields, either with activated benzyl and allyl
bromides or with primary normal alkyl iodides.6 Secondary
alkyl iodides failed to facilitate the reaction.
Inspection of the alkylation reaction of R-phenyloxazo-
lidinyl-â-lactams (11-13; R ) H; entries 1-9) led to the
identification of the structural factors governing the syn/anti
stereoselectivity. For instance, increasing the bulkiness of
the R2 group in the alkylating agent was found to improve
the syn ratio. This effect was apparent from the good
stereoselection observed for benzyl bromide (entries 1 and
5) or R-branched allyl bromides (entry 6), compared with
the almost equimolar diastereomeric mixtures obtained from
simple or â-substituted allyl bromides (entries 2, 4, and 7).
Small reactive electrophiles like methyl iodide or methyl
triflate (entries 3, 8, and 9) gave the poorer syn stereo-
selectivities. On the other hand, the aliphatic or aromatic
nature of the â-substituent (R1) seemed to exert a limited
but appreciable effect on the diastereoselection, with the
aliphatic groups giving uniformly higher ratios of syn isomers
(5) In contrast to conventional imines that only afford â-aryl-â-lactams
upon Staudinger [2 + 2] cycloaddition with aminoketenes, imines 9 give
either â-aryl-, â-alkyl-, or â-unsubstituted â-lactams in good yields and
excellent stereoselectivities; see: (a) Palomo, C.; Aizpurua, J. M.; Legido,
M.; Galarza, R.; Deya, P. M.; Dunogues, J.; Picard, J. P.; Ricci, A.; Seconi,
G. Angew. Chem., Int. Ed. Engl. 1996, 35, 1239-1241. (b) Palomo, C.;
Aizpurua, J. M.; Legido, M.; Mielgo, A.; Galarza, R. Chem. Eur. J. 1997,
3, 1432-1441.
(6) Although partial isomerization and decomposition was detected in
some instances for the lithium enolates of R-diphenyloxazolidinyl-â-lactams
(14-16; R ) Ph), this problem was solved by warming immediately the
mixtures of the enolates and alkyl halides from -78 to -30 °C. See
Supporting Information for details.
(3) (a) Palomo, C.; Aizpurua, J. M.; Galarza, R.; Benito, A.; Khamrai,
U.K.; Eikeseth, U.; Linden, A. Tetrahedron 2000, 56, 5563-5570. (b)
Palomo, C.; Aizpurua, J. M.; Benito, A.; Galarza, R.; Khamrai, U.K.;
Vazquez, J.; DePascual-Teresa, B.; Nieto, P. M.; Linden, A. Angew. Chem.,
Int. Ed. 1999, 38, 3056-3058.
(4) (a) Ojima, I.; Chen, H.-J. C.; Qiu, X. Tetrahedron 1988, 44, 5307-
5318. (b) Ojima, I. Acc. Chem. Res. 1995, 28, 383-389. (c) Ojima, I. In
The Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York,
1992; p 197. (d) Ho¨gberg, H.-E., Jr. In Houben-Weyl, StereoselectiVe
Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J.; Schaumann, E.;
Thieme: Stuttgart, 1996; E21 Vol. 2, p 791.
4444
Org. Lett., Vol. 6, No. 24, 2004

Scheme 2
Table 1. R-Alkylation of â-Substituted â-Lactams 11-16
entry
R
product
R2-X
yield (%)a syn:antib
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
H
H
H
H
H
H
H
H
17
18
19
20
21
22
23
24
24
25
26
27
28
29
30
31
31
32
33
PhCH2Br
CH2dCHCH2Br
MeI
CMe2dCHCH2Br
PhCH2Br
CH2dCMeCH2Br
CH2dCHCH2Br
MeI
82
91
90
80
84
67
85
75
c
67
72d
92
78
85
58
70e
82d
81
84d
>98:2
67:33
53:47
60:40
90:10
93:7
50:50
10:90
30:70
>98:2
95:5
>98:2
>98:2
>98:2
>98:2
71:29
95:5
H
MeOTf
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
PhCH2Br
CH2dCHCH2Br
PhCH2Br
2NaphthCH2Br
CH2dCHCH2Br
nBuI
MeI
MeI
PhCH2Br
MeI
>98:2
73:27
isomers 42 and 43, whereas desilylation of bis-silyl-R,â-
dialkyl-â-lactams 17 or 21 gave the corresponding syn
isomers. These results were meaningful, not only because
they clearly stated the necessity of a second trimethylsilyl
group to reach any syn selectivity but also because they
anticipated the obtention of either syn or anti isomers from
the same starting N-bis(trimethylsilyl)methyl-â-lactam by
simply desilylating the N-substituent before the alkylation
step.
a Yield of the pure mixture of syn and anti products. b Determined by
1H NMR (500 MHz) analysis of the reaction crude. Configurations were
assessed by NOE experiments and X-ray crystallography (compounds 28
and 30; see Supporting Information). c Yield not determined. d Enolate
trapping carried out at -30 °C for 16 h. d Enolate trapping carried out at
-78 °C for 16 h.
than their aromatic counterparts (compare entries 1, 2, and
3 with entries 5, 7, and 8, respectively). Our finding was
that incorporation of a second phenyl group in the oxazo-
lidinone ring (R-diphenyloxazolidinyl-â-lactams 14-16; R
) Ph) significantly enhanced the syn stereoselectivity in all
instances, including those involving simple allyl and normal
alkyl groups, and provided a convenient preparative entry
to the desired R-amino syn-R,â-dialkyl(aryl)-â-lactams.
Transformation of R-diphenyloxazolidinyl-â-lactams into
the dipeptide surrogates of type 2B was carried out unevent-
fully, Scheme 2, by hydrogenolytic removal of the diphen-
yloxazolidinone ring and simultaneous Boc protection of the
R-amino-â-lactam group, followed by the elaboration of the
N-bis(trimethylsilyl)methyl moiety to the N-carboxymethyl
group. For example, Boc-(â-lactam)-(Gly)-H fragments 36
and 37 were obtained in overall yields of 73 and 65%,
respectively.
A preliminary RHF/PM37 conformational analysis of the
putative lithium enolates (Figure 3) arising from the depro-
tonation of two â-methyl-â-lactam models (R ) H and R )
Scheme 3
To gain insight into the specific syn stereodirecting effect
exerted by the bis(trimethylsilyl) methyl and diphenyl-
oxazolidinyl groups on the alkylation reactions disclosed
above, we (a) explored the behavior of N-trimethylsilyl-
methyl-â-lactams bearing less hindered groups at the nitrogen
atom and (b) conducted computational modeling of the
respective intermediate â-lactam lithium enolates.
We found (Scheme 3) that reaction of N-bis-silyl-â-lactams
11 and 13 with cesium fluoride or tetra-n-butylammonium
fluoride, respectively, resulted in clean mono- or didesilyl-
ation of the bis(trimethylsilyl)methyl moiety to provide the
â-lactams 38-41 in high yields. R-Benzylation of N-tri-
methylsilylmethyl-â-lactams 38 and 39 under conditions
identical to those used above afforded exclusively the anti
Org. Lett., Vol. 6, No. 24, 2004
4445

were characterized with the â-lactam nitrogen pyramidal-
ized.8 As expected, for the more stable conformations (II),
the bis(trimethylsilyl)methyl group and the â-substituent
(Me) were located at opposite faces of the â-lactam ring.
Moreover, in these conformers, one of the SiMe3 groups
shielded the back face of the enolate, thereby inhibiting the
formation of anti-R,â-dialkylated products. Finally, the
second 5-phenyl group borne by the oxazolidinone ring in
enolate II (R ) Ph) caused a partial rotation of the 4-phenyl
group with respect to II (R ) H), which is consistent with
the greater syn stereoselectivity observed for R-diphenyl-
oxazolidinyl-â-lactams with respect to the monophenyl
counterparts.
In summary, the R-alkylation of â-substituted R-phenyl-
oxazolidinyl-N-bis(trimethylsilyl)methyl-â-lactams represents
the first method for preparing enantiopure syn-R-amino-R,â-
dialkyl(aryl)-â-lactams, which are suitable intermediates for
the synthesis of type II â-turn dipeptide surrogates.
Acknowledgment. This work was supported by Spanish
Ministerio de Educacio´n y Ciencia (MEC; Project BQU2002-
01737). Grants from Gobierno Vasco to A.B. and I.L. and
from European Commission (Marie Curie HMPT-CT-2000-
00173) to R.M.F., A.M., and K.R.P. are acknowledged.
Figure 3. Comparison of the calculated RHF/PM3 structures of
the lithium enolates of â-methyl â-lactam models (R ) H) and (R
) Ph). Some hydrogen atoms are omitted for clarity.
Supporting Information Available: Preparation proce-
dures and physical and spectroscopic data for compounds
17-43 and crystallographic data in CIF format and ORTEP
diagrams of 28 and 30. This material is available free of
charge via the Internet at http://pubs.acs.org.
Ph) was conducted, assuming a lithium cation chelated by
the oxazolidinone carbonyl oxygen atom and solvated by
the THF solvent. In each case, two significant energy minima
OL048348C
(7) MacSpartan Plus, version 1.2.2; Wavefunction, Inc: Irvine, CA. The
actual origin of the discrimination between the syn and anti alkylation paths
is given by the energy differences of the respective transition states and
not necessarily by the relative stability of the enolate intermediates.
(8) For crystallographic evidence concerning the tetrahedral character
of the nitrogen atom in lactams and amides, see: (a) Laube, T.; Dunitz, J.
D.; Seebach, D. HelV. Chim. Acta 1985, 68, 1373-1393. (b) Laube, T.;
Seebach, D. Chem. Ber. 1985, 118, 764-773.
4446
Org. Lett., Vol. 6, No. 24, 2004