Diastereodivergent Synthesis of Fluorinated Cyclic β3-Amino Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b02759

The ability of 2-p-tolylbenzyl carbanions to behave as a source of chiral benzylic nucleophiles has been shown in its reaction with fluorinated imines. The process takes place with high levels of stereocontrol, rendering the corresponding amines as single diastereoisomers. Subsequent cross-metathesis followed by intramolecular aza-Michael reaction makes the synthesis of fluorinated homoproline derivatives bearing three stereogenic centers possible. Furthermore, the selectivity of the cyclization process can easily be tuned up in a diastereodivergent manner simply by changing the reaction conditions.

Full text of DOI:10.1021/acs.orglett.5b02759

Letter
pubs.acs.org/OrgLett
Diastereodivergent Synthesis of Fluorinated Cyclic β3‑Amino Acid
Derivatives
Isabel Aparici,† Marta Guerola,† Clemens Dialer,† Antonio Simon-Fuentes,† María Sanchez-Rosello,†,‡
́
́
́
Carlos del Pozo,*,† and Santos Fustero*,†,‡
†Departamento de Química Organ
‡Centro de Investigacion
Príncipe Felipe, Laboratorio de Molec
* Supporting Information
́
ica Universidad de Valencia, 46100 Burjassot, Spain
ulas Organicas, 46012 Valencia, Spain
́
́
́
S
ABSTRACT: The ability of 2-p-tolylbenzyl carbanions to
behave as a source of chiral benzylic nucleophiles has been
shown in its reaction with fluorinated imines. The process
takes place with high levels of stereocontrol, rendering the
corresponding amines as single diastereoisomers. Subsequent
cross-metathesis followed by intramolecular aza-Michael
reaction makes the synthesis of fluorinated homoproline
derivatives bearing three stereogenic centers possible.
Furthermore, the selectivity of the cyclization process can
easily be tuned up in a diastereodivergent manner simply by
changing the reaction conditions.
he synthesis of enantiomerically pure β-amino acid
fluorinated imidoyl chlorides as starting materials.8 The
sequence cross-metathesis (CM) with (−)-8-phenylmenthyl
acrylate followed by Dieckmann condensation and stereo-
selective imine reduction gave rise to the desired products.
Probably the most commonly employed strategy to prepare
these derivatives to date involves the late-stage nucleophilic
fluorination of adequately functionalized enantiomerically pure
cyclohexane- and cyclopentanecarboxylic acids.9 Very recently,
the synthesis of cis-2-amino-1-fluorocyclobutane-1-carboxylic
acid was accomplished by chemical resolution.10
To the best of our knowledge, no reports on the preparation
of enantiomerically pure fluorinated cyclic β2-aa have been
described to date,11 although two different strategies were
devised to access fluorine-containing β3-aa derivatives. The first
one involved a tandem nucleophilic addition−intramolecular
aza-Michael reaction (IMAMR) of aromatic sulfinyl imines
bearing a conjugated ester moiety at the ortho position.12 The
second one combined, in a tandem fashion, a CM reaction and
an IMAMR of fluorinated amides bearing a chiral conjugated
ester.13
T
derivatives is an area of intense research activity.1 This
structural motif is present in a wide variety of natural products
and biologically active compounds.2 Perhaps the most relevant
feature is that β-amino acids constitute the structural units of β-
peptides, compounds with high relevance in medicinal
chemistry.3 They fold into highly stable secondary structures
and show greater stability and resistance against degradation by
protease-type hydrolases as these enzymes only identify α-
amino acids.4 Despite their significance and the well-known
benefits that fluorine atoms often confer to organic molecules
modulating their biological properties,5 synthetic approaches to
access fluorinated β-amino acids in enantiomerically pure form
lag behind their α counterparts. Furthermore, most reported
examples focus on the synthesis of acyclic compounds.6
In general, fluorinated cyclic β-amino acids (β-aa) can be
classified into three constitutional isomers (β2-, β3-, and β2,3-aa)
with different structural features as shown in Figure 1.
The most frequent synthetic targets are β2,3-aa derivatives,
also known as 2-aminocycloalkanecarboxylic acids (2-ACACs),
probably due to their analogy with the naturally occurring
antifungal agent cispentacin.7 The first report dealing with the
synthesis of this class of β-amino acids in enantiomerically pure
form was developed by our research group, involving the use of
The enantioselective formation of C−C bonds at the
benzylic positions has been of great interest for many research
groups since benzylic stereogenic carbon atoms very often
appear in the framework of important organic molecules.14 The
use of benzyllithium carbanions stabilized by enantiopure o-
sulfinyl groups provided a facile solution to the creation of
benzylic stereocenters, facilitating diastereoselective reactions
with electrophiles by a 1,4-induction process.15
Received: September 23, 2015
Figure 1. Classification of fluorinated cyclic β-amino acids (β-aa).
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02759
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Herein, we describe the stereoselective synthesis of
fluorinated homoproline derivatives containing three chiral
centers. The synthetic strategy to prepare these β3-aa
derivatives involved the reaction of 2-p-tolylsulfinyl benzyl
carbanions, generated in situ from sulfoxide 1, with fluorinated
imines 2. Previous work by our research group showed that
related processes take place with complete control of the
configuration at the two simultaneously created stereogenic
centers.16 The subsequent sequence CM, IMAMR, and
sulfoxide removal rendered the desired cyclic products 6 with
high levels of stereocontrol at the three generated stereocenters
(Scheme 1).
Table 1. Preparation of Enantiomerically Pure Fluorinated
Amines 3 and 4
a
a
b
entry
2
RF
R
3 (% yield)
4 (%, E/Z)
1
2
3
4
5
2a
2b
2c
2d
2e
CF3
CF3
H
3a (71)
3b (56)
3c (45)
3d (62)
3e (57)
4a (74, 8:1)
4b (76, 6:1)
4c (52, 5:1)
4d (50, 5:1)
4e (58, 7:1)
Scheme 1. Synthetic Strategy for the Synthesis of Cyclic
Me
H
Fluorinated β3-aa Derivatives
CF2Cl
CF3
2-furyl
Me
CF2H
a
b
Isolated yields after flash column chromatography. Diastereoiso-
1
meric ratios were determined by H NMR integration.
Table 2. IMAMR of Conjugated Esters 4
a
b
c
entry
4
conditions
5 (% yield)
ratio anti-5/syn-5
1
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
A
B
A
B
A
B
A
B
A
B
5a (78)
5a (88)
5b (70)
5b (78)
5c (82)
5c (72)
5d (73)
5d (63)
5e (90)
5e (86)
5:1
>1:99
7:1
2
3
4
>1:99
7:1
Deprotonation of sulfoxide (S)-1 at the benzylic position
with LDA at −78 °C and subsequent treatment with
trifluoromethyl aldimine 2a leads to the exclusive formation
of amine 3a in a highly selective manner in 71% yield when the
reaction is hydrolyzed at −78 °C.16c These optimized
conditions were extended to other fluorinated imines 2, giving
rise to the corresponding fluorinated amines 3 in moderate
yields as single diastereoisomers (Table 1).
5
6
>1:99
>99:1
>1:99
1.5:1
1:11
7
8
9
10
a
Conditions A: 4 (1 equiv), TBAF (1 equiv) in THF (0.1 M) for 1h at
rt. Conditions B: 4 (1 equiv), BF3·OEt2 (1 equiv) in DCM (0.1 M) for
b
While metathesis reactions involving sulfinyl amines are very
scarce in the literature, probably due to their basicity,17 in our
case, the CM reaction of substrates 3 with ethyl acrylate took
place in DCM at room temperature to render conjugated esters
4 in moderate to good yields as separable mixtures of E/Z
diastereoisomers (Table 1). The attenuated basicity of amines 3
due to the presence of the fluorinated substituents would
explain the success of the CM process under mild conditions.18
With conjugated esters 4 in hand, the next step in our study
was the evaluation of the IMAMR.19 Initially, the cyclization
was performed under basic conditions with compound 4a as
the model substrate. After several bases (TBAF, DBU, t-BuOK,
LiN(SiMe3)3, KN(SiMe3)3, NaH), temperatures (−78 °C, 0
°C, room temperature), and solvents (CH2Cl2, THF, toluene)
were tested, the best conditions to effect the cyclization entailed
the use of TBAF (tetrabutylammonium fluoride) as base in
THF at room temperature. Under these conditions, the
corresponding pyrrolidine 5a was achieved in good yield
(78%) and diastereoisomeric ratio (5:1), the anti isomer being
the major product (Table 2, entry 1). These conditions were
further extended to substrates 4, giving rise to the desired
1 h at rt. Isolated yields after flash column chromatography.
c
1
Diastereoisomeric ratios were determined by H NMR integration.
fluorinated homoproline derivatives 5 (Table 2, entries 3, 5,
and 7) in good yields (70−82%) and diastereoselectivities,
except for substrate 4e containing a CF2H moiety that led to an
almost equimolecular mixture of both isomers (Table 1, entry
9). The IMAMR was also evaluated in the presence of a Lewis
acid. When compound 4a was treated with BF3·OEt2, the
exclusive formation of the syn-5a isomer (88% yield) was
observed (Table 2, entry 2). This means that it is possible to
perform a diastereodivergent synthesis of both diastereoisomers
merely by changing the reaction conditions. Thus, these acidic
conditions for the IMAMR were applied to the rest of
substrates 4, and a highly diastereoselective cyclization took
place, giving fluorinated pyrrolidines syn-5 in good yields (63−
86%) (Table 2, entries 4, 6, 8, and 10).
Finally, the last step of our synthetic sequence was the
removal of the chiral auxiliary. Exposure of compounds 5 to
Raney Ni in THF for 15 min gave rise to the fluorinated
B
DOI: 10.1021/acs.orglett.5b02759
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
homoproline derivatives 6 in good yields as single isomers
Scheme 3. Role of Sulfoxide in the IMAMR
(Scheme 2).
Scheme 2. Chiral Auxiliary Removal on Compounds 5
The relative stereochemistry of final products 6 was
determined in both diastereoisomers anti-6b and syn-6b by
NOESY experiments. Thus, compound anti-6b showed two
NOE correlations: one between Ha and one Hc (Figure 3) and
The high selectivity achieved in the Lewis acid environment
could be attributed to the formation of a chelate with the boron
atom, with the participation of ester carbonyl, the sulfoxide, and
the nitrogen atom (Figure 2). This tight arrangement would
Figure 3. Determination of the relative stereochemistry of compounds
6.
another one between Ha and Hd, which indicates the cis relative
disposition of these H atoms and the ester group. On the other
hand, compound syn-6b also showed two NOE correlations:
one between Ha and Hc and a second one between Hc and Hb,
indicating the cis relative disposition between the three protons
(Figure 3). For the rest of compounds 6 an analogous
stereochemical assignment was assumed.
Figure 2. Rationalization of the stereochemical outcome in the
IMAMR.
In summary, stereocontrolled access to fluorinated homopro-
line derivatives has been achieved by taking advantage of the
ability of p-tolylbenzyl sulfinyl carbanions to undergo stereo-
selective addition to fluorinated imines. The chiral amines
obtained were then efficiently transformed into cyclic β3-amino
acid derivatives following the sequence CM-IMAMR. Interest-
ingly, a stereodivergent cyclization was performed by changing
the reaction conditions of the IMAMR. The role of the
sulfoxide auxiliary in the stereochemical outcome of the process
was also evaluated.
guide the addition of the nucleophile to the Re face of the
conjugated ester, leading to the formation of the syn product
under these conditions. On the other hand, the formation of
the anti product was implemented in basic medium. Under
these conditions, the nucleophilic addition would be controlled
by the steric requirements of the CF3 moiety, located in a
pseudoequatorial arrangement (Figure 2, TSA). In the
particular case of substrate 4e, the less sterically demanding
CF2H group enables the contribution of a competitive
transition state (Figure 2, TSB) with the chiral sulfoxide in
the pseudoequatorial position. This scenario would explain the
formation of an almost equimolecular amounts of diaster-
eoisomers syn- and anti-5e (Table 2, entry 9).
ASSOCIATED CONTENT
■
S
* Supporting Information
In order to verify the role of the sulfoxide moiety in the
diastereoselectivity of the process, an additional experiment was
designed. We envisioned that the removal of the chiral auxiliary
before cyclization would provide valuable information concern-
ing this point. To this end, compound 3b was treated with t-
Buli in order to remove the sulfoxide group. Then, the resulting
trifluoromethylamine 7 was reacted with ethyl acrylate under
the standard CM conditions and the corresponding unsaturated
ester 8 was cyclized in the presence of BF3·OEt2 to render
compound 6b (90% yield) as a 9:1 mixture of diastereoisomers,
with syn-6b being the major diastereomer (Scheme 3). This
drop in selectivity indicates that the presence of the sulfoxide,
which offers an additional coordination site to the Lewis acid,
probably plays an important role in the stereochemical
outcome of the cyclization process.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02759.
Experimental procedures, characterization data of all new
compounds, and NMR charts (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: carlos.pozo@uv.es.
*E-mail: santos.fustero@uv.es.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b02759
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) For the synthesis of alicyclic fluorinated β2-amino acids, see:
March, T. L.; Johnston, M. R.; Duggan, P. J.; Gardiner, J. Chem.
Biodiversity 2012, 9, 2410.
ACKNOWLEDGMENTS
■
́
We thank the Spanish Ministerio de Economıa y Compet-
itividad (CTQ-2013-43310-P) and Generalitat Valenciana
(GV/PrometeoII/2014/073) for financial support.
(12) (a) Fustero, S.; Albert, L.; Mateu, N.; Chiva, G.; Miro,
Gonzalez, J.; Acena, J. L. Chem. - Eur. J. 2012, 18, 3753. (b) Fustero,
S.; Moscardo,
Lett. 2010, 12, 5494.
(13) Fustero, S.; Bae
del Pozo, C. Synthesis 2012, 44, 1863.
(14) Rouhi, A. M. Chem. Eng. News 2003, 81, 45.
́
J.;
́
̃
́
́ ́
J.; Sanchez-Rosello, M.; Rodríguez, E.; Barrio, P. Org.
DEDICATION
■
́
́ ́ ́
z, C.; Sanchez-Rosello, M.; Asensio, A.; Miro, J.;
́
́
Luis Garcıa Ruano on the occasion of
Dedicated to Prof. Jose
his retirement.
(15) García-Ruano, J. L.; Carreno, M. C.; Toledo, M. A.; Aguirre, J.
̃
M.; Aranda, M. T.; Fischer, J. Angew. Chem., Int. Ed. 2000, 39, 2736.
(16) (a) García-Ruano, J. L.; Parra, A.; Alonso, I.; Fustero, S.; del
Pozo, C.; Arroyo, Y.; Sanz-Tejedor, A. Chem. - Eur. J. 2011, 17, 6142.
REFERENCES
■
(1) For recent reviews, see: (a) Kiss, L.; Fulop, F. Chem. Rev. 2014,
̈
̈
(b) Fustero, S.; del Pozo, C.; Catalan
V.; García-Ruano, J. L. Org. Lett. 2009, 11, 641. (c) García-Ruano, J. L.;
Aleman, J.; Catalan, S.; Marcos, V.; Monteagudo, S.; Parra, A.; del
Pozo, C.; Fustero, S. Angew. Chem., Int. Ed. 2008, 47, 7941.
(17) (a) Guerola, M.; Sanchez-Rosello, M.; Mulet, C.; del Pozo, C.;
Fustero, S. Org. Lett. 2015, 17, 960. (b) Fustero, S.; Monteagudo, S.;
Sanchez-Rosello, M.; Flores, S.; Barrio, P.; del Pozo, C. Chem. - Eur. J.
2010, 16, 9835.
(18) Fustero, S.; Simon
2015, 115, 871.
(19) For recent reviews of IMAMR, see: (a) San
Acena, J. L.; Simon-Fuentes, A.; del Pozo, C. Chem. Soc. Rev. 2014, 43,
7430. (b) Amara, Z.; Caron, J.; Joseph, D. Nat. Prod. Rep. 2013, 30,
1211. (c) Reyes, E.; Fernandez, M.; Uría, U.; Vicario, J. L.; Badía, D.;
́ ́
, S.; Aleman, J.; Parra, A.; Marcos,
114, 1116. (b) Fulop, F.; Martinek, T. A.; Tot
́
h, G. K. Chem. Soc. Rev.
̈
̈
2006, 35, 323. (c) Enantioselective Synthesis of β-Amino Acids, 2nd ed.;
Juaristi, E. C., Soloshonok, V. A., Eds.; Wiley−VCH: New York, 2005.
́
́
(d) Kuhl, A.; Hahn, M. G.; Dumie,
2005, 29, 89.
́
M.; Mittendorf, J. Amino Acids
́
́
(2) (a) Seebach, D.; Hook, D. F.; Glattli, A. Biopolymers 2006, 84, 23.
̈
́
́
(b) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206. (c) Liu, M.; Sibi,
M. P. Tetrahedron 2002, 58, 7991. (d) Frackenpohl, J.; Arvidsson, P. I.;
Schreiber, J. V.; Seebach, D. ChemBioChem 2001, 2, 445.
(3) (a) Cabrele, C.; Martinek, T.; Reiser, O.; Berlicki, L. J. Med.
Chem. 2014, 57, 9718. (b) Zeng, W.; Chen, Y.-L. Protein Pept. Lett.
2014, 21, 975. (c) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
Biodiversity 2004, 1, 1111. (d) Seebach, D.; Gardiner, G. Acc. Chem.
Res. 2008, 41, 1366.
(4) (a) Kudo, F.; Miyanaga, A.; Eguchi, T. Nat. Prod. Rep. 2014, 31,
1056. (b) Hodges, J. A.; Raines, R. T. J. Am. Chem. Soc. 2005, 127,
15923. (c) Golbik, R.; Yu, C.; Weyher-Stingl, E.; Huber, R.; Moroder,
L.; Budisa, N.; Schiene-Fischer, C. Biochemistry 2005, 44, 16026.
́
-Fuentes, A.; Barrio, P.; Haufe, G. Chem. Rev.
̈
́
́
chez-Rosello, M.;
́
̃
́
Carrillo, L. Curr. Org. Chem. 2012, 16, 521. (d) Wang, J.; Li, P.; Choi,
P. Y.; Chan, A. C. S.; Kwong, F. Y. ChemCatChem 2012, 4, 917.
(d) Jackel, C.; Seufert, W.; Thust, S.; Koksch, B. ChemBioChem 2004,
̈
5, 717.
(5) For selected reviews, see: (a) Wang, J.; San
́
chez-Rosello,
́
M.;
Acena, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok,
̃
V. A.; Liu, H. Chem. Rev. 2014, 114, 2432. (b) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Muller,
K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(6) For recent reviews of the synthesis of fluorinated β-amino acids,
see: (a) Qiu, X.-L.; Qing, F.-L. Eur. J. Org. Chem. 2011, 2011, 3261.
(b) Mikami, K.; Fustero, S.; San
Soloshonok, V.; Sorochinsky, A. Synthesis 2011, 19, 3045. (c) Acena, J.
L.; Simon-Fuentes, A.; Fustero, S. Curr. Org. Chem. 2010, 14, 928.
́
́ ́
chez-Rosello, M.; Acena, J. L.;
̃
̃
(d) Sorochinsky, A.; Soloshonok, V. J. Fluorine Chem. 2010, 131, 127.
(7) (a) Konishi, M.; Nishio, M.; Saitoh, K.; Miyaki, T.; Oki, T.;
Kawaguchi, H. J. Antibiot. 1989, 42, 1749. (b) Oki, T.; Hirano, M.;
Tomatsu, K.; Numata, K.; Kamei, H. J. Antibiot. 1989, 42, 1756.
(c) Iwamoto, T.; Tsujii, E.; Ezaki, M.; Fujie, A.; Hashimoto, S.;
Okuhara, M.; Kohsaka, M.; Imanaka, H.; Kawabata, K.; Inamoto, Y.;
Sakane, K. J. Antibiot. 1990, 43, 1. (d) Kawabata, K.; Inamoto, Y.;
Sakane, K.; Iwamoto, T.; Hashimoto, S. J. Antibiot. 1990, 43, 513.
(8) (a) Fustero, S.; San
L.; del Pozo, C.; Fernan
2006, 8, 4633. (b) Fustero, S.; San
Fernandez, B.; Asensio, A.; Sanz-Cervera, J. F.; del Pozo, C. J. Org.
Chem. 2009, 74, 3414.
(9) (a) Kiss, L.; Forro,
2011, 2011, 4993. (b) Kiss, L.; Forro,
Biomol. Chem. 2011, 9, 6528. (c) Nonn, M.; Kiss, L.; Hanninen, M.
́
chez-Rosello,
dez, B.; Bartolome,
chez-Rosello,
́
M.; Sanz-Cervera, J. F.; Acena, J.
̃
́
́
A.; Asensio, A. Org. Lett.
M.; Acena, J. L.;
́
́
̃
́
́
E.; Fustero, S.; Fulop, F. Eur. J. Org. Chem.
̈
̈
́
E.; Fustero, S.; Fulop, F. Org.
̈
̈
̈
M.; Sillampaa, R.; Fulop, F. Chem. Biodiversity 2012, 9, 2571. (d) Kiss,
̈
̈
̈
̈
L.; Nonn, M.; Sillampaa, R.; Fustero, S.; Fulop, F. Beilstein J. Org.
̈
̈
̈
̈
Chem. 2013, 9, 1164. (e) Kiss, L.; Nonn, M.; Forro,
́
E.; Sillampaa, R.;
̈ ̈
Fustero, S.; Fulop, F. Eur. J. Org. Chem. 2014, 2014, 4070. (f) Nonn,
̈
̈
M.; Kiss, L.; Haukka, M.; Fustero, S.; Fulop, F. Org. Lett. 2015, 17,
̈
̈
1074.
(10) Hassoun, A.; Grison, C. M.; Gillot, R.; Boddaert, T.; Aitken, D.
J. New J. Chem. 2015, 39, 3270.
D
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