Synthesis of cyclobutane serine analogues

Article abstract of DOI:10.1021/jo048943s

(Chemical Equation Presented). In this paper, we describe a thermal [2 + 2] cycloaddition involving 2-acylaminoacrylates as electron-poor acceptor alkenes, a reaction that involves a Michael-Dieckmann-type process. The reaction gives rise to a new substit

Full text of DOI:10.1021/jo048943s

Synthesis of Cyclobutane Serine Analogues
nocycloalkanecarboxylic acids have been the focus of
many researchers, although the synthesis of substituted
1
-aminocyclobutanecarboxylic acids has not received the
Alberto Avenoza,* Jes u´ s H. Busto, Noelia Canal, and
Jes u´ s M. Peregrina*
6
same level of attention. Despite this, conformational
studies on model peptides with 1-aminocyclobutanecar-
boxylic acid residues have been published, indicating that
this type of amino acid derivative can be accommodated
in folded motifs commonly found in proteins and pep-
Departamento de Qu ı´ mica, Universidad de La Rioja,
Grupo de S ı´ ntesis Qu ı´ mica de La Rioja, U.A.-C.S.I.C.,
E-26006 Logro n˜ o, Spain
7
tides. Given these results, it appears likely that cyclobu-
alberto.avenoza@dq.unirioja.es
Received June 22, 2004
tane-R-amino acids could be used for the design of
conformationally restricted peptides and peptidomimet-
ics.
A few methods for the synthesis of 2-substituted
1
-aminocyclobutanecarboxylic acids have been described
8
in the last year. However, serine analogues that incor-
porate the cyclobutane skeleton (c Ser) have not been
4
synthesized to date. Taking into account that numerous
analogues of serine have been synthesized as acyclic and
cyclic compounds, filling this gap in our knowledge is an
attractive goal. We report here the first synthesis of both
4
two pairs of stereoisomers of c Ser.
In an effort to achieve the goal outlined above, we
envisioned that the reaction between 2-acylaminoacry-
lates and electron-rich donor alkenes could furnish the
desired four-ring system with oxygen substitution in the
In this paper, we describe a thermal [2 + 2] cycloaddition
involving 2-acylaminoacrylates as electron-poor acceptor
alkenes, a reaction that involves a Michael-Dieckmann-type
process. The reaction gives rise to a new substituted cy-
clobutane skeleton that can be transformed into amino acid
derivatives. For example, a number of transformations were
carried out to give the two pairs of stereoisomers of the
2
-position. The important role played by 2-amidoacrylates
in the field of novel amino acids has made these com-
pounds the subject of several synthetic studies. However,
9
these compounds have never been investigated in terms
of [2 + 2] reactions, although methyl acrylate, an olefin
acceptor, has been widely used as a starting material in
2
-hydroxycyclobutane-R-amino acid serine analogue (c4Ser);
compounds 22 and 23. This synthesis covers a gap in
knowledge in the broad field of restricted amino acids.
[
2 + 2] cycloadditions.10
Thermal (nonphotochemical) reactions of electron-rich
donor alkenes with electron-poor acceptor alkenes usually
lead to cyclobutanes via zwitterionic intermediates, and
in some cases, these intermediates could incorporate
The introduction of small-ring systems, especially
cyclobutane derivatives, as molecular building blocks has
recently gained increasing significance. However, amino
11
1
another alkeneselectron-poor or electron-richsto furnish
acids from the cyclobutane series have been investigated
12
a cyclohexane ring. Vinyl ethers and the most effective
2
very little. Prior to 1980, these amino acids were almost
ketene diethyl acetal have been used as electron-rich
olefins. As electron-poor olefins, the whole range of tri-
and tetrasubstituted ethylenes containing combinations
of ester (weak acceptor) and cyano (strong acceptor)
the only type of amino acids that had not been detected
3
in natural sources. The biological significance of 1-ami-
nocyclobutanecarboxylic acid derivatives has been well-
documented in several publications that provide evidence
of their extremely high activity as N-methyl-D-aspartate
(
5) Cativiela, C.; D ´ı az-de-Villegas, M. D. Tetrahedron: Asymmetry
(
NMDA) receptor agonists or antagonists attending the
1
998, 9, 3517-3599 and references therein.
4
substitution.
(6) Cativiela, C.; D ´ı az-de-Villegas, M. D. Tetrahedron: Asymmetry
000, 11, 645-732 and references therein.
2
In recent years, extraordinary advances in the syn-
thesis of new nonproteinogenic R,R-disubstituted amino
(
7) Balaji, V. N.; Ramnarayan, K.; Chan, M. F.; Rao, S. N. Peptide
Res. 1995, 8, 178-186.
5
acids has allowed the development of peptidomimetics
(8) (a) Volk, F.-J.; Wagner, M.; Frahm, A. W. Tetrahedron: Asym-
metry 2003, 14, 497-502. (b) Truong, M.; Lecornu e´ , F.; Fadel, A.
Tetrahedron: Asymmetry 2003, 14, 1063-1072. (c) Koch, C.-J.; H o¨ fner,
G.; Polborn, K.; Wanner, K. T. Eur. J. Org. Chem. 2003, 2233-2242.
(9) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1988, 159-
172.
(10) (a) Brannock, K. C.; Burpitt, R. D.; Thweatt, J. G. J. Org. Chem.
1964, 29, 940-941. (b) Amice, Ph.; Coina, J. M. Bull. Soc. Chim. Fr.
1974, 1015-1019. (c) Kniep, C. S.; Padias, A. B.; Hall, H. K., Jr.
Tetrahedron 2000, 56, 4279-4288.
(11) (a) Huisgen, R. Acc. Chem. Res. 1977, 10, 117-124. (b) Huisgen,
R. Acc. Chem. Res. 1977, 10, 199-206.
(12) (a) Hall, H. K., Jr. Angew. Chem., Int. Ed. Engl. 1983, 22, 440-
455. (b) Hall, H. K., Jr.; Padias, A. B. Acc. Chem. Res. 1990, 23, 3-9.
(c) Srisiri, W.; Padias, A. B.; Hall, H. K., Jr. J. Org. Chem. 1994, 59,
5424-5435. (d) Johnston, K.; Padias, A. B.; Bates, R. B.; Hall, H. K.,
Jr. Langmuir 2003, 19, 6416-6421.
and pseudopeptides. In this sense, substituted 1-ami-
*
To whom correspondence should be addressed. Fax: +34 941
2
99655.
(
1) (a) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103,
1
1
485-1537. (b) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103,
449-1483.
(2) (a) Avontins, F. Russ. Chem. Rev. 1993, 62, 897-906. (b) Gaoni,
Y. Org. Prep. Proced. Int. 1995, 27, 185-212.
3) Bell, H. A.; Qureshi, M. Y.; Pryce, R. J.; Janzen, D. H.; Lemke,
P.; Clardy, J. J. Am. Chem. Soc. 1980, 102, 1409-1412.
4) (a) Gaoni, Y.; Chapman, A. G.; Parvez, N.; Pook, P. C.-K.; Jane,
(
(
D. E.; Watkins, J. C. J. Med. Chem. 1994, 37, 4288-4296. (b) Allan,
R. D.; Hanrahan, J. R.; Hambley, T. W.; Johnston, G. A. R.; Mewett,
K. N.; Mitrovic, A. D. J. Med. Chem. 1990, 33, 2905-2915.
10.1021/jo048943s CCC: $30.25 © 2005 American Chemical Society
330
J. Org. Chem. 2005, 70, 330-333
Published on Web 12/02/2004

TABLE 1. Reactivity of Electron-Poor Acceptor Alkenes
H2CdCR1R2 and Ketene Diethyl Acetal
yielda
(%)
entry
R
1
R
2
equiv solvent
product
b
c
1
2
CN
H
H
2
1
tBuOH cyclobutane
62, 27
b
c
CO
2
Me
CH
CH
3
CN cyclobutane
Cl cyclohexane
44, 60,
d
6
3
e
f
3
4
5
6
7
8
9
CN
CN
CN
CO
5.5
1
2
3
2
47
85
2
Me
CH
CN cyclohexane
t
CO
2
H
NHAc 2 + 8 BuOH
i
t
CONH Pr NHAc 2 + 8 BuOH
t
CO
CO
CO
CO
CO
2
2
2
2
2
Me
Me
Me
Me
Me
NHAc 10
NHAc 5 + 5 BuOH cyclobutane
cyclobutane
BuOH cyclobutane
11
25
9
t
NHAc 5 + 5g Bu
2
O
t
1
1
0
1
NHBz 2 + 8 BuOH cyclobutane (1) 51
NHAc 2 + 8g BuOH cyclobutane (2) 64
t
a
Yield after column chromatography. See ref 10c. c See ref
b
d
f
1
0b. See ref 10a. e See ref 15. See ref 12. g The last 8 equiv were
added as a solution in BuOH by syringe pump over 90 min.
t
SCHEME 1. Thermal [2 + 2] Cycloaddition of
Methyl 2-Acylaminoacrylate and Ketene Diethyl
Acetal
FIGURE 1. Evaluation of LUMO energies for various acceptor
olefins and HOMO energy of ketene diethyl acetal.
completed by syringe pump (8 equivalents dissolved in
t
BuOH added over 90 min) the yield reached 64%, a
better result than in the cases of acrylonitrile and methyl
acrylate.
This reaction represents the first time that alkyl
-acylaminoacrylates have been reacted with an electron-
2
rich olefin to afford the cyclobutane ring in a good yield.
In an effort to explain this reactivity of methyl 2-acet-
amidoacrylate, and taking into account that the reaction
groups have been used. When monosubstituted acceptor
alkenes are used, the donor alkene must be highly
is driven by HOMO-donor olefin and LUMO-aceptor
12c,14a
olefin,
we compared the LUMO energies for several
12b
reactive. Acrylonitrile and methyl acrylate do not react
with vinyl ethers under these conditions but do react with
ketene diethyl acetal to form cyclobutanes, as recently
shown by Hall, Jr., and co-workers, to give 62% and 44%
acceptor olefins at the B3LYP/6-31+G(d) theory level for
16
optimized geometries using the Gaussian 98 package.
The value for the LUMO energy of methyl 2-acetami-
doacrylate is -1.71 eV, for methyl acrylate (monoacti-
vated olefin) it is -1.57 eV and for dimethyl 2-methyl-
enemalonate (diactivated olefin) the LUMO energy is
10c
yield, respectively (Table 1, entries 1 and 2).
Bearing in mind the information outlined above, we
recently reported a communication about the reaction
between 2-acylaminoacrylates and ketene diethyl ac-
-
2.03 eV. The difference EHOMO - ELUMO for methyl
2
-acetamidoacrylate (4.26 eV) is located between the
1
3
etal. Several sets of conditions were applied to this
reaction (Table 1) following previous work on thermal
monoactivated (4.40 eV) and diactivated (3.94 eV) olefins
and it appears reasonable to believe that the reactivity
of methyl 2-acetamidoacrylate will be similar or superior
to that of methyl acrylate. Moreover, the formation of the
cyclohexane derivatives, as occur in entries 3 and 4 in
Table 1, was not observed (Figure 1).
With the aim of obtaining both pairs of stereoisomers
4
of c Ser, we attempted the transformation of the diethyl
acetal group of compound 2 into the corresponding
ketone. However, all attempts to remove the protecting
group, including treatment with formic acid, were unsuc-
11
14
[
Jr.
2 + 2] cycloadditions by Huisgen, Scheeren and Hall,
1
2
The mechanism proposed for the thermal [2 + 2]
cycloaddition between acrylates and ketene diethyl acetal
involves zwitterionic intermediates, so that we attempted
t
the reaction in two solvents ( BuOH and Bu
2
O), obtaining
better yields when a polar solvent was used (entries 8
and 9, Table 1). Reaction did not occur for entries 5 and
i
6
in Table 1 (R
1
) CO
2
H or CONH Pr and R
2
) NHAc).
When the ketene diethyl acetal was added in one portion
the best result afforded only 11% yield of compound 2
(
15) Stille, J. K.; Chung, D. C. Macromolecules 1975, 8, 114-121.
(
Scheme 1). The use of inhibitors10c such as DABCO and
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millan, J. M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaroni, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonz a´ lez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Replogle, E. S.; Pople, J. A. Gaussian 98, Revisions A.7 and A.11;
Gaussian, Inc.: Pittsburgh, PA, 1998.
3
-tert-butyl-4-hydroxy-5-methylphenyl sulfide (SULFIDE)
furnished similar yields. Nevertheless, when the ketene
diethyl acetal was added in two portions the yield
increased to 25%. Unexpectedly, when the addition was
(
13) Avenoza, A.; Busto, J. H.; Canal, N.; Peregrina, J. M. Chem.
Commun. 2003, 1376-1377.
(
14) (a) Scheeren, H. W.; van Rossum, A. J. R.; Nivard, R. J. F.
Tetrahedron 1983, 39, 1345-1353. (b) Scheeren, J. W. Recl. Trav.
Chim. Pays-Bas 1986, 105, 71-84.
J. Org. Chem, Vol. 70, No. 1, 2005 331

SCHEME 2a
a
Key: (a) formic acid 88%, 35 °C, 65%; (b) LiBH4, Et2O, 0 °C to rt, 90%; (c) TBDPSCl, imidazole, CH2Cl2, rt, 86%; (d) 0.5 N HCl, THF,
rt, 35%; (e) 0.5 N HCl, THF, rt, 90%; (f) TBDPSCl, imidazole, DMF, 50 °C, 97%; (g) NaBH4, EtOH/THF, 0 °C, 91%; (h) benzyl 2,2,2-
trichloroacetimidate, triflic acid, Et2O, 0 °C to rt, 40%; (i) NaH, BnBr, Bu4NI, THF, rt, 20% of 10 and 16% of 9a; (j) acetic anhydride,
DMAP, pyridine, rt, 96%; (k) MOMCl, DIEA, 0 °C to rt, 60%; (l) TBAF, THF, 0 °C to rt, 72% of 11a, 30% of 11b and 60% of 11c; (m) Jones
reagent, acetone, 0 °C, 70% of 12a, 72% of 12b and 80% of 12c; (n) CH2N2, Et2O, rt, 95% of 13a, 93% of 13b, and 73% of 13c.
cessful (Scheme 2). The electron-withdrawing character
of the carboxylate group facilitates the stabilization of
the carbanion to force the retro-Dieckmann-type reaction.
This process led to the acyclic product, a new glutamic
acid derivative (3) whose structure was unambiguously
determined by X-ray diffraction. In these cases, the usual
procedure to avoid this opening reaction involves reduc-
tion of the methyl ester group to a primary alcohol.
protecting groups. Acetylation of the alcohol in the
presence of acetic anhydride and DMAP in pyridine
provided the acetylated compound 9b in 96% yield. The
use of the MOMCl as the protecting agent in diisopro-
pylethylamine (DIEA) gave compound 9c in 60% yield
(Scheme 2).
The next reaction sequence on the three protected
alcohols (benzyl, acetyl, and methoxymethyl derivatives
9a, 9b, and 9c, respectively) involved cleavage of the silyl
group with TBAF, oxidation in the presence of Jones
reagent and isolation of the target compoundssthe
desired carboxylic acid derivatives 12a, 12b, and 12c.
Deprotection of the silyl group gave moderate yields in
the cases of benzyl and methoxymethyl derivatives.
However, difficulties were encountered in obtaining the
alcohol from the acetyl compound. In this case, the acetyl
group underwent multiple transacetylations to give
several acetylated derivatives. This phenomenon could
be favored by the short distance between the hydroxyl
and amino groups. The oxidation stage gave moderate
yields in all cases. In the last step, purification of the
target compounds was achieved through esterification
with diazomethane to obtain, after column chromatog-
Therefore, compound 2 was reduced using LiBH
to give the corresponding cyclobutylmethanol 4 (Scheme
).
An attempt at direct oxidation of the alcohol group and
4 2
in Et O
2
hydrolysis of the ketal group by treatment with Jones
reagent furnished a complex mixture of compounds.1
Protection of the alcohol group with tert-butyldiphenyl-
silyl chloride (TBDPSCl) gave compound 5 in good yield.
This compound was subsequently hydrolyzed to ketone
0b
6
by treatment with HCl in THF. A better yield was
obtained when this process was inverted, i.e., first the
hydrolysis to obtain the keto alcohol 7 and then the
protection with tert-butyldiphenylsilyl chloride (Scheme
2
).
The reduction of the ketone group of compound 6 on
raphy, the pure (1R*,2R*)-Ac-c
3a, 13b, and 13c. The best yield was obtained for the
methoxymethyl derivative, with (1R*,2R*)-Ac-c Ser-
OMOM)-OMe (13c) isolated in a 9% overall yield from
methyl 2-acetamidoacrylate (Scheme 2).
It was desirable to obtain the other stereoisomer of
1R*,2R*)-c Ser; protected (1R*,2S*)-c Ser in which the
4
Ser(OR)-OMe derivatives
the opposite side to the silyl group, due to the spatial
requirement of this group, gave alcohol 8 as a single
stereoisomer. The stereochemistry of this compound was
assigned unambiguously by NOE experiments and X-ray
diffraction (Scheme 2).
1
4
(
Protection of the secondary alcohol with BnI in the
presence of NaH gave benzylated alcohol 9a in low yield
and furnished compound 10 from deprotection of silyl
(
4
4
hydroxyl group is located cis with respect to the amino
group. It was envisioned that this goal could be achieved
by activating the alcohol group of compound 8 to give
group and benzylation of the primary alcohol. The use
of benzyl 2,2,2-trichloroacetimidate (BTCA)17 as the
protecting reagent led to a better yield of the required
compound 9a. An attempt to improve the yield of the
protection step was made by testing two additional
(
17) Handbook of Reagents for Organic Synthesis. Activating Agents
and Protecting Groups; Pearson, A. J., Roush, W. J., Eds.; John Wiley
& Sons: 1999.
332 J. Org. Chem., Vol. 70, No. 1, 2005

SCHEME 3a
a
Key: (a) MsCl, DIEA, CH2Cl2, 0-40 °C, 95%; (b) Et3N, DMF, 130 °C, 99%; (c) 0.1 N HCl, THF, rt, 98%; (d) silica gel, CH2Cl2, rt, 76%;
(
e) MOMCl, DIEA, 0 °C to rt, 82%; (f) TBAF, THF, 0 °C to rt, 60%; (g) Jones reagent, acetone, 0 °C, 80%; (h) CH2N2, Et2O, rt, 60%.
SCHEME 4a
compound 14, and then carrying out the nucleophilic
displacement with an oxygen nucleophile. On the basis
of our experience with similar cyclic compounds, we ruled
out the use of the typical Mitsunobu reaction. As an
alternative, the mesylated compound 14 was obtained
with MsCl and DIEA in CH
2
Cl
2
, and an S
N
2 reaction was
) in DMF.
attempted with ammonium benzoate (BzONH
4
This gave a mixture of two compounds corresponding to
the inverted alcohol and oxazoline 15, both in a low yield,
but did not give any benzoate derivative. In view of this
fact, and in order to generate the intramolecular dis-
placement of the oxygen from the acetamide group, we
carried out the reaction in DMF and in the presence of
a Key: (a) 3 N HCl, 60 °C, 47% of 22 and 59% of 23.
Finally, we explored the possibility of removing the
protecting groups without damaging the cyclobutane
structure. Therefore, after several conditions tested, we
obtained the corresponding cyclobutane amino acids 22
and 23 from 13c and 21, respectively, as hydrochloride
derivatives using controlled acid hydrolysis (Scheme 4).
In conclusion, we have developed a thermal [2 + 2]
cycloaddition on dehydroamino acid derivatives that
involves a Michael-Dieckmann-type reaction. The spe-
cial reactivity has been discussed in terms of frontier
orbital theory. The result of the reaction is a new
cyclobutane skeleton that can be incorporated into amino
acid derivatives. As an example of this application, the
Et
3
N, which gave oxazoline 15 as the only product
1
8
(Scheme 3).
Compound 15 is extremely unstable, and purification
proved impossible. Hydrolysis of 15 was therefore per-
formed in the presence of 0.1 N HCl to give compound
1
6, in which the amine group is free and the alcohol is
acetylated. With the aim of following a similar synthetic
pathway to that described for compound 13c, it was
necessary to obtain the corresponding compound in which
the alcohol was free and the amino group acetylated. The
equilibrium of the transacetylation reaction was dis-
placed to the desired compound (17) by treatment with
silica gel. The structure of this compound was unambigu-
ously determined by X-ray diffraction (Scheme 3).
The protection of alcohol 17 with MOMCl in the
presence of DIEA furnished compound 18 in 82% yields
higher than the yield obtained for the protection of
alcohol 8, which had a trans disposition with respect to
the amino group. The route described to obtain methyl
ester 13c from compound 9c was also employed for
obtaining methyl ester 21 from compound 18, i.e., depro-
tection of the silyl group, Jones oxidation, and treatment
two pairs of stereoisomers of the amino acid c
4
Ser were
obtained so much as protected derivatives (compounds
3c and 21) as well as hydrochloride forms (compounds
2 and 23).
1
2
Acknowledgment. We thank the Ministerio de
Ciencia y Tecnolog ´ı a (project PPQ2001-1305) and the
Universidad de La Rioja (project API-03/04). J.H.B.
thanks the Ministerio de Ciencia y Tecnolog ´ı a for a
Ramon y Cajal contract and N.C. thanks the Gobierno
de La Rioja for a doctoral fellowship.
Supporting Information Available: Experimental pro-
1
13
with diazomethane to furnish the (1R*,2S*)-Ac-c
OMOM)-OMe (21) in 8% overall yield from methyl
-acetamidoacrylate (Scheme 3).
4
Ser-
cedures for all compounds, copies of H and C NMR spectra
1
1
1
13
and H- H and H- C correlations for most of the compounds
obtained, and NOE data for compound 8. X-ray data for
compounds 3, 8, and 17 (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(
2
(
18) Avenoza, A.; Cativiela, C.; Fern a´ ndez-Recio, M. A.; Peregrina,
J. M. Tetrahedron: Asymmetry 1996, 7, 721-728.
JO048943S
J. Org. Chem, Vol. 70, No. 1, 2005 333