Preparation of conformationally restricted β2,2- and β2,2,3-amino esters and derivatives containing an all-carbon quaternary center

Article abstract of DOI:10.1021/ol503432b

β-Amino acids are routinely incorporated into peptidic drugs to increase their stability and to incur conformational biases. However, the synthesis of highly substituted β-amino acids still represents a great challenge. A new approach to their preparation is reported involving a Vilsmeier-Haack reaction with nonaromatic carbon nucleophiles. The highly challenging preparation of contiguous tertiary and all-carbon quaternary centers was successfully used to generate several β^2,2,3-amino esters, such as derivatives of homoproline, homoalanine, and homopipecolinic esters.

Full text of DOI:10.1021/ol503432b

Letter
pubs.acs.org/OrgLett
Preparation of Conformationally Restricted β2,2- and β2,2,3-Amino
Esters and Derivatives Containing an All-Carbon Quaternary Center
Alexandre Romanens and Guillaume Belanger*
́
́ ́ ́ ́
Departement de Chimie, Universite de Sherbrooke, 2500 boulevard de l’Universite, Sherbrooke, Quebec J1K 2R1, Canada
S
* Supporting Information
ABSTRACT: β-Amino acids are routinely incorporated into peptidic
drugs to increase their stability and to incur conformational biases.
However, the synthesis of highly substituted β-amino acids still
represents a great challenge. A new approach to their preparation is
reported involving a Vilsmeier−Haack reaction with nonaromatic carbon
nucleophiles. The highly challenging preparation of contiguous tertiary
and all-carbon quaternary centers was successfully used to generate
several β2,2,3-amino esters, such as derivatives of homoproline,
homoalanine, and homopipecolinic esters.
t is well established that the use of β-amino acids in peptides
improves their metabolic lability and therefore enhances
Scheme 1. Most Common Approaches to the Construction
I
of β2,2-Amino Acids
their stability against proteolytic degradation.1 β-Peptides have
thus been used to mimic natural peptide-based drugs in
pharmacological studies. Not surprisingly, functionalized β-
amino acids are found in several antifungal2 and antibacterial3
bioactive molecules, as well as in antitumor agents.4 Moreover,
the fact that substituted β-amino acids, and in particular β2,2-
amino acids (or α,α-dialkyl-β-amino acids) and β2,2,3-amino
acids (or α,α,β-trialkyl-β-amino acids), are known to incur
restricted conformations to β-peptides has stimulated several
research groups to use them for the rational design of new
defined nanoscopic patterns such as helical secondary
structures and foldamers.5 However, their synthesis still
remains a high challenge in organic chemistry6 and, despite
the fact that this field has gained considerable attention over the
past decade, only a few synthetic approaches have been
developed, with the majority of them being of limited scope.
Scheme 1 exemplifies the most common approaches to the
construction of β2,2-amino acids (R2 ≠ H).7 The Mannich
addition (a) and the formation of β-lactams by cycloaddition
followed by ring opening (b) are among the most convergent
approaches.
While the cycloaddition strategy is limited by the steric bulk
of the substituents,8 the Mannich addition9 is restricted to the
use of an unsubstituted nucleophile (R2 = H), or specific
substituents (R2) on the nucleophile.10 Moreover, almost all of
these additions work only if these iminium ions are activated
with an electron-withdrawing group on either the iminium
carbon (R3)11 or nitrogen (R4).12
Figure 1. Accessible compounds via intermolecular Vilsmeier−Haack
reaction.
substitution at the β-position (R3 = H). Finally, Curtius
rearrangement of alkylated 1,4-diesters or derivatives (e) also
The other approaches to β2,2-amino acids mainly rely on
alkylation strategies. The amino group could be derived from
alkylated α-formylesters using a reductive amination (c)13 or
from nitrile reduction of alkylated cyanoesters or cyanoamides
(d).14 These two methods are inherently limited to no
Received: November 26, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503432b
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Synthesis of β2.2-Amino Esters
Table 2. Synthesis of β2,2- and β2,2,3-Amino Alcohols
serious difficulties are often encountered in the preparation of
the all-carbon quaternary center (with two R2 substituents).
Herein, we report a novel intermolecular Vilsmeier−Haack-
type addition of nonaromatic carbon nucleophiles onto
activated amides followed by in situ reduction16 to efficiently
generate all-carbon quaternary centers in a racemic version
(Scheme 1f). This strategy rapidly gives access to β2,2- and
a
DCE: 1,2-dichloroethane; DTBMP: 2,6-di-tert-butyl-4-methyl-
b
pyridine; Tf2O: trifluoromethanesulfonic anhydride. The addition
of AcOH (10 equiv) was required to significantly improve the yield.
Scheme 2. Undesired Retro-Mannich Reaction
β
2,2,3-amino esters (1 and 2, respectively) and acids (3 and 4,
respectively), as well as to 1,3-amino alcohols 5 (Figure 1).17
β2,2-Amino esters were synthesized from silylated ketene
acetals 7 and formamides 6 (Table 1). The reaction was very
high yielding when performed with a variety of N-
benzylformamides (entries 1−3). Cyclic formamides could
also be used successfully (entries 4−8). Hindered nucleophiles
derived from methyl cyclohexanecarboxylate (entry 6) or
lactones (entries 7 and 8) also furnished the desired β2,2-amino
esters in good to excellent yields.
The construction of β2,2,3-amino esters, bearing a tertiary
center adjacent to the quaternary carbon, turned out to be a lot
more challenging. Delightfully, the nucleophilic addition took
place smoothly. However, problems arose during the attempted
reduction of the resulting iminium ion 9 (Scheme 2). After
hydride addition, β-amino ester 2 spontaneously underwent a
retro-Mannich reaction in situ, presumably driven by steric
lead to the desired unnatural amino acid.15 In all cases,
restrictions concerning the synthesis of starting materials lead
to a lack of versatility in the nature of the substituents (R) and
B
DOI: 10.1021/ol503432b
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Synthesis of β2,2,3-Amino Esters
Table 5. Debenzylation of β2,2 and β2,2,3-Amino Esters
a
The hydrogenation was run over 2 days in order to remove both
benzyls.
side reaction, as successfully demonstrated in Table 2, leading
to the corresponding 1,3-amino alcohols derivatives 5.
In sharp contrast with Mannich reactions reported to work
with iminium ions bearing no more than one substituent on
carbon,9 we showed that amides other than formamides were
impeccably compatible with our method, leading to highly
congested β2,2,3-amino alcohols (entries 1−4). Another
remarkable advantage of our method is the great reactivity of
the iminium ion resulting from the amide activation. In fact, we
could perform the addition of silyl enol ethers of esters (7b,
entries 5 and 6) and even of aldehydes (13a, entries 7 and 8)
and obtain the same products (5e and 5f) in comparable yields.
Mannich additions using the latter nucleophiles are usually not
working and require the more reactive enol ethers of esters.
The undesired retro-Mannich reaction (Scheme 2, 2 to 10)
could be suppressed using another strategy. We envisaged that
reduction of iminium ion 9 in a slightly acidic medium would
secure the protonation of the resulting amine 2 as it is
generated, thus preventing the cleavage to 10. After
optimization, it was revealed that acetic acid worked charmingly
well, as exemplified in Table 3. Homoproline esters (entries 1
and 2) and homopipecolinic esters (entry 3) bearing a
quaternary center were successfully prepared, as well as a
series of acyclic β2,2,3-amino esters (entries 4−6).
Table 4. Saponification to β2,2 and β2,2,3-Amino Acids
The free acid derivatives were obtained essentially in
quantitative yields from treatment of methyl esters with
potassium trimethylsilanolate (KOTMS, Table 4).
Furthermore, the free amine derivatives were obtained upon
hydrogenolysis of the corresponding benzylamino compounds
(Table 5). The reaction proceeded under H2 pressure in high
to quantitative yields.
In conclusion, the present study has established a new
method for the synthesis of unnatural β-amino esters bearing an
all-carbon quaternary center (β2,2-amino esters) and even the
very challenging contiguous all-carbon quaternary and tertiary
centers (β2,2,3-amino esters) which are essentially not accessible
from usual methods. The corresponding β-amino acids and 1,3-
amino alcohols were also prepared efficiently. The development
decompression.18 An ensuing reduction of the resulting iminum
ion 10 led to the isolated corresponding amine 11.
We rationalized that the undesired retro-Mannich reaction
could be suppressed using two different strategies. The first one
was to perform the reduction of iminium 9 using a much
stronger reducing agent, such as LiAlH4. The latter reduced the
ester group on intermediate 9 or 2 prior to any retro-Mannich
C
DOI: 10.1021/ol503432b
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Organic Letters
Letter
Org. Lett. 2008, 10, 3583. (d) Moumne,
Lavielle, S.; Rudler, H.; Karoyan, P. Tetrahedron Lett. 2007, 48, 8277.
(e) Deiana, L.; Zhao, G.-L.; Dziedzic, P.; Rios, R.; Vesely, J.; Ekstrom,
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of a chiral version of our method is underway and will be
published in due course.
̈
́
J.; Cordova, A. Tetrahedron Lett. 2010, 51, 234. For N-activation with
ASSOCIATED CONTENT
* Supporting Information
■
a sulfonyl group, see: (f) Tiong, E. A.; Gleason, J. L. Org. Lett. 2009, 8,
1725. (g) Delgado-Rebollo, M.; Moreno, R.; Fructos, M. R.; Prieto, A.
Eur. J. Org. Chem. 2013, 31. For N-activation with a sulfinyl group,
see: (h) Davis, A.; Theddu, N. J. Org. Chem. 2010, 75, 3814.
(i) Almansa, R.; Collados, J. F.; Guijarro, D.; Yus, M. Tetrahedron:
Asymmetry 2010, 1421. (j) Yang, C.-F.; Shen, C.; Wang, J.-Y.; Tian, S.-
K. Org. Lett. 2012, 14, 3092. For N-activation with a hydroxyphenyl
group complexed with a Lewis acid, see: (k) Ishitani, H.; Ueno, M.;
Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180.
S
Experimental procedures, characterization data, and copies of
1
the H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(13) (a) Charrier, J.; Pierard, F. Pat. Appl. WO2009023269, 2009.
(b) Lin, D.; Deng, G.; Wang, J.; Ding, X.; Jiang, H.; Liu, H. J. Org.
Chem. 2010, 75, 1717.
*E-mail: Guillaume.Belanger@USherbrooke.ca.
Notes
́
(14) (a) Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A. J. Org.
Chem. 1994, 59, 2497. (b) Gaucher, A.; Zuliani, Y.; Cabaret, D.;
Wakselman, M.; Mazaleyrat, J.-P. Tetrahedron: Asymmetry 2001, 12,
2571. (c) Hansen, T.; Alst, T.; Havelkova, M.; Strøm, M. B. J. Med.
Chem. 2010, 53, 595.
(15) Duan, J. J.W.; Chen, L.; Lu, Z.; Jiang, B.; Asakawa, N.;
Sheppeck, J. E., II; Liu, R. Q.; Covington, M. B.; Pitts, W.; Kim, S.-H.;
Decicco, C. P. Bioorg. Med. Chem. Lett. 2007, 17, 266.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the Natural Science and
Engineering Research Council (NSERC) of Canada and the
■
́
Universite de Sherbrooke. A Center in Green Chemistry and
Catalysis (CGCC) fellowship to A.R. is also gratefully
acknowledged.
(16) For an intramolecular version developed in our laboratory, see:
(a) Bel
Barabe,
Gauthier, R.; Men
71, 704.
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anger, G.; Larouche-Gauthier, R.; Men
F. Org. Lett. 2005, 7, 4431. (b) Bel
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DOI: 10.1021/ol503432b
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