Diastereoselective synthesis of aliphatic α,α-difluoro- β3-amino esters via a sonocatalyzed Reformatsky reaction

Article abstract of DOI:10.1021/ol202969w

(R)-2-Phenylglycine ethyl ester was found to be a cheap and effective auxiliary for the preparation of aliphatic α,α-difluoro- β³-amino esters via a Reformatsky reaction performed under sonication conditions. The products were obtained in good to high yield and ≥96:4 dr, thus providing a new stereoselective route to this under-represented class of compounds. A facile one-pot removal of the phenylglycine moiety and concomitant Boc protection subsequently afforded the corresponding Boc-protected β³-amino esters in excellent yield.

Full text of DOI:10.1021/ol202969w

ORGANIC
LETTERS
2012
Vol. 14, No. 1
182–185
Diastereoselective Synthesis of Aliphatic
r,r-Difluoro-β3-Amino Esters via a
Sonocatalyzed Reformatsky Reaction
Taryn L. March,† Martin R. Johnston,† and Peter J. Duggan*,‡
School of Chemical and Physical Sciences, Flinders University, SA 5042, Australia, and
CSIRO Materials Science and Engineering, Bag 10, Clayton South,
Victoria 3169, Australia
peter.duggan@csiro.au
Received November 4, 2011
ABSTRACT
(R)-2-Phenylglycine ethyl ester was found to be a cheap and effective auxiliary for the preparation of aliphatic R,R-difluoro-β3-amino esters via a
Reformatsky reaction performed under sonication conditions. The products were obtained in good to high yield and g96:4 dr, thus providing a
new stereoselective route to this under-represented class of compounds. A facile one-pot removal of the phenylglycine moiety and concomitant
Boc protection subsequently afforded the corresponding Boc-protected β3-amino esters in excellent yield.
The ability to effect novel changes in the bioactivity
and physicochemical properties of a compound through
the inclusion of fluorine is well-known.1 R-Fluorinated
β3-amino acids in particular continue to attract interest for
their use as tools in peptide conformational studies2 and as
enzyme inhibitors,3 while they are also direct precursors to
the biologically important β-lactams.4
We recently reported an enantioselective tandem con-
jugate additionÀfluorination approach to R-fluoro-β3-
amino esters which can be extended to the synthesis of R,
R-difluoro-β3-amino esters;5 however, the most efficient
and versatile routes to R,R-difluoro-β3-amino acids typi-
cally employ a building block approach.6 The introduction
of a CF2 synthon with Reformatsky reactions involving
imines4f,g,7 or imine-type substrates8 together with ethyl
bromodifluoroacetate is among the most popular. The
majority of these literature reports focus primarily on the
use of imines derived from aromatic aldehydes, with high
yields and excellent dr values generally obtained. Aliphatic
imines, however, are notably more difficult to work with
† Flinders University.
‡ CSIRO Materials Science and Engineering.
(1) (a) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Biomedical
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U.; Stahl, M. ChemBioChem 2004, 5, 637. (c) Kirk, K. J. Fluorine Chem.
2006, 127, 1013. (d) Oyiliagu, C. E.; Novalen, M.; Kotra, L. P. Mini-Rev.
Org. Chem. 2006, 3, 99. (e) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (f) Hagmann, W. K.
J. Med. Chem. 2008, 51, 4359.
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Kobaiter, R.; Joyeau, R.; Wakselman, M. Tetrahedron: Asymmetry
1997, 8, 739. (c) Sato, K.; Tarui, A.; Matsuda, S.; Omote, M.; Ando,
A.; Kumadaki, I. Tetrahedron Lett. 2005, 46, 7679. (d) Tarui, A.; Kondo,
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r
10.1021/ol202969w
Published on Web 11/28/2011
2011 American Chemical Society

because of their instability and hence receive much less
attention; the limited examples that do appear in the
literature often suffer from poor to moderate yields
and unsatisfactory dr values. The lack of progress in this
area is surprising considering that the side chains of
most naturally occurring amino acids are aliphatic in
nature. The highly stereoselective but moderate yielding
HondaÀReformatsky reaction4c,d,9 is among the most
promising; however, it requires a rhodium catalyst and
diethyl zinc. We desired a more general method for the
preparation of aliphatic R,R-difluoro-β3-amino acids that
was applicable to a wide variety of substrates, uses only
simple and readily available reagents, and is amenable to
large-scale synthesis. Our efforts toward extending the
Reformatsky reaction to the successful preparation of
these compounds are reported herein.
Application of the Reformatsky methodology to the
synthesis of R,R-difluoro-β3-amino acids presents two
immediate problems, namely, the relative unreactivity of
imines (cf. carbonyl compounds) and the instability of the
Reformatsky reagent BrZnCF2CO2Et, which is typically
generated in refluxing THF yet rapidly decomposes under
these conditions.10 The application of ultrasound, which
has long been used as a tool in organic synthesis11;and
indeed the Reformatsky reaction itself12;offered a solu-
tion to both problems: first, sonication of the reaction
mixture can greatly enhance the reactivity of poor electro-
philes in the Reformatsky reaction when compared to
standard reflux conditions,13 and second, the BrZnCF2-
CO2Et species is relatively stable when generated under
ultrasonic conditions, extending its half-life.4b While ultra-
sound has been successfully used in Reformatsky reactions
involving either imines or ethyl bromodifluoroacetate
alone, its use for reactions employing both reagents
together for the preparation of R,R-difluoro-β3-amino
esters is previously unreported.
Amines derived from the chiral pool represent the most
common chiral auxiliaries employed in this type of Re-
formatsky reaction, and amino acid derivatives capable of
forming highly chelated transition states, such as those
based on (R)-phenylglycinol, generally give the highest
degree of asymmetric induction.4f,6,8,14 Given that enan-
tiopure sources of phenylglycinol can be prohibitively
expensive on a large scale, the cheaper (R)-phenylglycine
methyl ester was chosen as an alternative. The suscept-
ibility of phenylglycine derivatives to epimerize at the
R-carbon often precludes their use as chiral auxiliaries;
however, they previously have been reported to show
extremely high stereocontrol in organometallic enolate
condensations15 and Barbier-type allylations.16
Using isovaleraldehyde as a model substrate, (E)-phe-
nylglycine imine 317 was prepared in quantitative yield
using anhydrous Na2SO4 as a desiccant. The mixture was
filtered and the crude imine subsequently added to a THF
solutionof BrZnCF2CO2Et(4), which was prepreparedvia
the addition of ethyl bromodifluoroacetate to a sonicating
suspension of zinc and catalytic I2. After 15 min of sonica-
tion followed by acidic workup, 1H NMR analysis of the
crude reaction mixture revealed the desired β-amino ester
was present as a 96:4 mixture of diastereomers (Table 1,
entry 1). The major isomer, tentatively assigned the (S)
configuration at C3 in line with analogous phenylglycine
systems,4f,6,8,13a,14 was subsequently isolated in 53% yield
after chromatography. Importantly, no cyclized β-lactam
product, which is commonly produced during the Refor-
matsky reaction, was evident in the spectrum of the crude
material. Increasing the reaction time to 30 min and
decreasingtheamountof ethylbromodifluoroacetate from
2 to 1.5 equiv improved the yield to 64%. The dr was
unchanged after this prolonged reaction period, attesting
to the configurational stability of the phenylglycine moiety
under these relatively mild reaction conditions. Reactant
concentration appeared to have a negligible effect on the
reaction outcome.
(5) (a) Duggan, P. J.; Johnston, M.; March, T. L. J. Org. Chem. 2010,
75, 7365. (b) Andrews, P. C.; Bhaskar, V.; Bromfield, K. M.; Dodd,
A. M.; Duggan, P. J.; Duggan, S. A. M.; McCarthy, T. D. Synlett 2004,
791.
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~
(6) Mikami, K.; Fustero, S.; Sanchez-Rosello, M.; Acena, J. L.;
Soloshonok, V. A.; Sorochinsky, A. Synthesis 2011, 3045.
As shown in Table 1, performing the experiment with
other typical Reformatsky solvents such as diethyl ether
and toluene resulted in inferior yields and diastereomeric
ratios. Surprisingly, the traditionally poorer solvents
DCM and acetonitrile gave results almost comparable to
THF, while the use of DMSO and DMF resulted largely in
decomposition. Under the same reaction conditions, the
use of the more common (R)-phenylglycinol auxiliary
(7) (a) Angelastro, M. R.; Bey, P.; Mehdi, S.; Peet, N. Bioorg. Med.
Chem. Lett. 1992, 2, 1235. (b) Marcotte, S.; Pannecoucke, X.; Feasson,
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N. N.; Ball, R. G. J. Org. Chem. 2002, 67, 8276. (d) Sorochinsky, A.;
Voloshin, N.; Markovsky, A.; Belik, M.; Yasuda, N.; Uekusa, H.; Ono,
T.; Berbasov, D. O.; Soloshonok, V. A. J. Org. Chem. 2003, 68, 7448. (e)
Sorochinsky, A.; Soloshonok, V. A. J. Fluorine Chem. 2010, 131, 127.
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Ohno, H.; Fujii, N. Tetrahedron 2008, 64, 4332.
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T. J. Chem. Soc. Rev. 1997, 26, 443.
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Licandro, E.; Papagni, A. Tetrahedron 1996, 52, 4849. (b) Shankar,
B. B.; Kirkup, M. P.; McCombie, S. W.; Clader, J. W.; Ganguly, A. K.
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2002, 50, 307. (b) Otaka, A.; Watanabe, J.; Yukimasa, A.; Sasaki, Y.;
Watanabe, H.; Kinoshita, T.; Oishi, S.; Tamamura, H.; Fujii, N. J. Org.
Chem. 2004, 69, 1634. (c) Niida, A.; Tomita, K.; Mizumono, M.;
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Kieboom, A. P. G; Spek, A. L.; van Koten, G. Tetrahedron: Asymmetry
1993, 4, 1441. (b) van Maanen, H. L.; Kleijn, H.; Jastrzebski, J. T. B. H.;
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Org. Lett., Vol. 14, No. 1, 2012
183

led to dr values of 71:29, 60:40, and 57:43, respectively.
This is likely caused by a disruption of the highly che-
lated transition state postulated to be responsible for the
high stereoselectivity seen in this type of Reformatsky
reaction;18 an open transition state would result in indis-
criminate attack by the Reformatsky reagent, affording a
mixture of isomers.
Table 1. Reaction of Phenylglycine-Derived Imines with Re-
formatsky Reagent 4 in Various Solventsa
Lastly, as a comparison to traditional Reformatsky
conditions the imine 3b was added to 4 in refluxing THF
(Scheme 1). This resulted in an undesirable 63:37 mixture
of β-amino ester (5b) and β-lactam (6), which were isolated
in 57 and 34% yields, respectively.
Scheme 1. Preparation of 5b under “Classical” Reflux Condi-
tions
entry
R
solvent
THFd
product
yield (%)b
drc
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
53
96:4
THF
64
96:4
3
diethyl ether
1,4-dioxane
toluene
DCM
45
80:20
95:5
4
19
5
21
75:25
86:14
85:15
6
52
7
MeCN
DMSO
DMF
47
Application of the sonocatalyzed Reformatsky reaction
to C-alkyl imines derived from a range of aldehydes
generally produced pleasing results (Table 2), with a high
degree of diastereoselectivity obtained for each β-amino
ester. Yields were typically between 66 and 76% with
imines bearing simple linear or branched alkyl chains,
while β-amino ester 7e was obtained in 97% yield from
4-pentenal. The sterically hindered cyclohexyl derivative
7d was obtained in a lower 46% yield, although almost
exclusively as a single isomer. For imines derived from
heteroatom-functionalized aldehydes (entries 7À9), reac-
tion conditions were modified slightly to counter the
increased sensitivity of these substrates. Phthalimide 7f
was obtained in a synthetically useful 45% yield with the
use of a 2:1 diethyl ether/THF mixed solvent system, which
had no negative impact on the diastereoselectivity of the
reaction. The TBSO group was found to be relatively
unstable under sonicating conditions; however, by adding
the imine to 4 (preprepared using sonication) and simply
stirring the mixture at rt, 7g and 7h could be obtained in
53 and 60% yields, respectively. It was also found that scal-
ing the preparation of 7g and 7h up to gram quantities had
minimal impact on yield or dr.
8
trace
25
9
59:41
96:4
10
11
THF
72
tBu
THF
48
86:14
a Reaction stoichiometry: aldehyde (1.0 mmol), amine (1.0 mmol),
Zn 3.0 mmol), I2 (0.2 mmol), BrCF2CO2Et (1.5 mmol). b Isolated yield
from 2. c Determined from crude reaction mixture by integration of the
1H NMR esonances due to R-proton of phenylglycine moiety. d 2 equiv
of BrCF2CO2Et used, sonicated for 15 min.
furnished the corresponding β-amino ester in only 9%
yield. This was largely a result of poor imine formation,
even with prolonged reaction times.
During these experiments, the transesterified product
(5b) was continually evident in small quantities (10À15%)
in the 1H NMR spectra of the crude material. To eliminate
this problem, both the tert-butyl and ethyl ester of (R)-
phenylglycine were used in the Reformatsky reaction
(entries 10 and 11). While the tert-butyl ester gave a
disappointing 48% yield and 86:14 dr, use of the ethyl
ester gave a yield of 72% and excellent dr of 96:4.
With the ethyl ester of (R)-phenylglycine providing
superior results, a one-pot reaction that did not involve
preformation of the Reformatsky reagent was investi-
gated. This furnished the desired β-amino ester in a similar
71% yield, although the dr dropped to 82:18. One possible
explanation for this drop may involve isomerization of the
imine double bond by ultrasound before attack of the
organozinc species; addition to the (Z)-imine would result
in the (3R) isomer.
Removal of the phenylglycine moiety with concomitant
Boc protection was achieved in excellent yield under
standard hydrogenolysis conditions using Pearlman’s cata-
lyst (Table 3). With crystalline samples of the Reformatsky
adducts (5aÀc, 7aÀh) unavailable for X-ray crystallo-
graphic analysis, a comparison of the optical rotations of
Itwasalsoof interesttodetermineifthe incorporation of
Lewis acids into the reaction mixture would enhance the dr
for the addition of 4 to imine 3b; however, the inclusion of
(18) (a) Wu, M. J.; Pridgen, L. N. J. Org. Chem. 1991, 56, 1340. (b)
Mokhallalati, M. K.; Wu, M. J.; Pridgen, L. N. Tetrahedron Lett. 1993,
34, 47.
(19) Fuertes-Perez, Y.; Kelly, A. M.; Fossey, J. S.; Powell, M. E.;
Bull, S. D.; James, T. D. Nat. Protoc. 2008, 3, 210.
1 equiv of ZnBr2, BF3 OEt2, or TiCl4 to the reaction mixture
3
184
Org. Lett., Vol. 14, No. 1, 2012

Table 2. Application of the Sonocatalyzed Reformatsky Reac-
tion Conditions to Imines Derived from Aliphatic Aldehydes
Table 3. Removal of the Phenylglycine Auxiliary under Hy-
drogenolysis Conditions and Concomitant Boc Protection
entry
R
product
isolated yield (%)
entry
R
product
yield (%)a
drb
1
2
3
4
5
6
iBu
iPr
8a
8b
8c
8d
8e
8f
93
82
95
88
81
95
1
2
3
4
5
6
7
8
9
iBu
iPr
5b
7a
7b
7c
7d
7e
7f
72
96:4
98:2
94:6
96:4
98:2
97:3
96:4
96:4
96:4
CH3(CH2)6
Ph(CH2)2
66
CH3(CH2)6
Ph(CH2)2
cC6H11
70
TBSO(CH2)3
TBSO(CH2)2
75
46
CH2dCH(CH2)2
phthal(CH2)3
TBSO(CH2)3
TBSO(CH2)2
97
45c
53d
60d
7g
7h
formed imines to be between 90:10 and 95:5 (see Support-
ing Information).
a Isolated yield from the aldehyde. b Determined from crude reaction
mixture by integration of the 1H NMR resonances due to R-proton of
phenylglycine moiety. c Diethyl ether/THF (2:1) used as the solvent.
d Magnetic stirring used upon addition of imine.
In conclusion, we have developed a highly stereoselective
sonocatalyzed Reformatsky reaction using inexpensive
(R)-phenylglycine ethyl ester as a chiral auxiliary for the
preparation of aliphatic R,R-difluoro-β3-amino esters with
dr g 96:4. The reaction proceeds in good yield without the
need for additional catalysts or additives and is compatible
with sensitive functional groups. The Reformatsky adducts
are easily deprotected under standard conditions and re-
protected as the Boc derivatives to give substrates amenable
to further functionalization.
known compounds (8b and 8e) was performed. While the
magnitude of the rotations for 8b ([R]20 = À5; lit.14b
D
[R]22D = À13.9) and 8e ([R]20D = À3; lit.9 [R]23D = À10.9)
was significantly smaller than those reported previously,
the sign of the rotation supports the assigned (3S) stereo-
chemistry of the products.
The stereochemical purity of a selection of Boc-pro-
tected amino esters (8a,c,d) was analyzed using the method
of James and Bull19 following Boc cleavage with TFA. The
method involves the in situ derivatization of the crude
amine with 2-formylphenylboronic acid and (S)-BINOL
and integration of the two diastereomeric imino protons
present in the 1H NMR spectrum of the mixture, found in
the region of 8.2À8.7 ppm. In the case of the amine derived
from 8d, a dr for the imine of 96:4 was obtained. Other
substrates subjected to the same treatment displayed par-
tial overlap of key resonances; however, crude estimates
based on these spectra generally put dr values of the in situ
Acknowledgment. We are grateful to Flinders University
for providing a Research Scholarship to T.M. and CSIRO
for providing a scholarship top-up for T.M. and research
funding. The Australian Research Council is acknowledged
for LIEF funding (LEO668489) for NMR spectrometers.
Supporting Information Available. Experimental details,
characterization data, and 1H and 13C NMR spectra for all
new compounds, as well as experimental details and spectra
for er determination of β-amino esters. This material is avai-
lable free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
185