Efficient asymmetric synthesis of trifluoromethylated β- aminophosphonates and their incorporation into dipeptides

Article abstract of DOI:10.1039/c2cc36702e

Addition of anions derived from dialkyl methylphosphonates to (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine afforded (Ss,R) addition adducts in moderate to good yield (53-75%) with excellent diastereoselectivity (94-95% de). After selective rem

Full text of DOI:10.1039/c2cc36702e

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Efficient asymmetric synthesis of trifluoromethylated
b-aminophosphonates and their incorporation into dipeptidesw
Kostiantyn V. Turcheniuk,a Kateryna O. Poliashko,a Valery P. Kukhar,a
Alexander B. Rozhenko,b Vadim A. Soloshonokcd and Alexander E. Sorochinsky*acd
Received 14th September 2012, Accepted 9th October 2012
DOI: 10.1039/c2cc36702e
Addition of anions derived from dialkyl methylphosphonates to
(Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine afforded
(Ss,R) addition adducts in moderate to good yield (53–75%)
with excellent diastereoselectivity (94–95% de). After selective
removal of the N-sulfinyl group, dipeptides containing enantio-
merically pure diethyl 2-amino-3,3,3-trifluoropropylphosphonate
were synthesized to investigate the influence of the trifluoromethyl
substituent on N-terminal coupling.
fluoroalkylated b-aminophosphonates are limited to some
procedures developed for addition of amines or ammonia to
a,b-unsaturated phosphonates,8 ring opening of trifluoromethyl
aziridine-2-phosphonates9 and addition of carbanions generated
from phosphonates to trifluoromethyl N-benzoyl and N-carbalkoxy
imines.10 To the best of our knowledge, there is only one
report in the literature dealing with preparation of optically
enriched fluoroalkylated b-aminophosphonates.11 This synthetic
route involves the reaction of enantiomerically pure N-(a-phenyl-
ethyl)trifluoroacetimidoyl chloride with carbanions derived from
dialkyl methylphosphonates, followed by a base-catalyzed [1,3]-
proton shift reaction of the intermediate N-substituted dialkyl
2-imino-3,3,3-trifluoropropylphosphonates and their isomeric
enamines with enantioselectivities in the range of 60–83% ee.
DBU-mediated isomerization of imine and enamine with
n-propyl ester groups gave the best result in terms of yield
and enantioselectivity.12 The isomeric azomethines thus formed
were hydrolyzed under mild conditions to the corresponding
optically enriched trifluoromethylated b-aminophosphonates.
However, in this report the absolute configuration of the
products remained undetermined.
Currently aminophosphonic acids and their derivatives are
recognized as fundamental compounds in the area of medicine,
biochemistry, and synthetic organic chemistry.1 Taking into
account that replacement of hydrogen atoms with fluorine atoms
in bioactive agents greatly influences the bioavailability by
improving the enzymatic stability and enhancing the lipophilicity
the fluorinated aminophosphonic acids and their derivatives are
becoming increasingly interesting for the development of enzyme
inhibitors and modification of peptides of natural and synthetic
origin.2 As a result a large number of fluorinated aminophosphonic
acid derivatives exhibiting enzyme inhibitory, antibiotic, anti-
bacterial, antiviral, antifungal, and herbicidal activities were
designed and synthesized.3 Among them fluoroalkylated
b-aminophosphonates have received less attention regardless
of the fact that they are phosphorus analogues of the corre
sponding b-fluoroalkyl-b-amino acids playing a key role in the
design of b-peptides,4 retropeptides5 and a new class of
proteasome inhibitors.6 The most general approach to racemic
fluoroalkylated b-aminophosphonates consists of reduction of
b-enaminophosphonates containing fluoroalkyl substituents
at the b position.7 Other methods for the synthesis of racemic
Considering the biological activities of the fluoroalkylated
b-aminophosphonic acid derivatives, the availability of these
compounds in enantiomerically pure form is highly desirable.
We reasoned that addition of carbanions derived from phos-
phonates to (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine,
which displays high-level reactivity, asymmetric induction and
is commercially available,13 might represent a general method
for the asymmetric synthesis of dialkyl 2-amino-3,3,3-trifluoro-
propylphosphonates. We report here the application of the
(Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine as a versatile
intermediate for the synthesis of dialkyl 2-amino-3,3,3-trifluoro-
propylphosphonates in optically pure form.
a Institute of Bioorganic Chemistry & Petrochemistry,
National Academy of Sciences of Ukraine, 1 Murmanskaya, Kiev,
Ukraine. E-mail: sorochinsky@bpci.kiev.ua;
As a starting point, the reaction of N-tert-butanesulfinyl
(3,3,3)-trifluoroacetaldimine (Ss)-1 and diethyl methylphos-
phonate 2b was investigated in THF using n-BuLi as a base.
The addition occurred smoothly with 2.0 equiv. of the lithium
diethyl methylphosphonate at À78 1C for 2 h giving rise to
N-sulfinyl aminophosphonate (Ss,R)-4b in 60% overall yield
and an excellent 97 : 3 diastereomeric ratio (Table 1, entry 1).
In order to optimize the reaction conditions the effects of
reaction parameters such as reactants ratio and reaction time
were briefly investigated. However, when 1.2 equiv. of lithium
Fax: +380 44 573-25-31; Tel: +380 44 558-25-52
b Institute of Organic Chemistry, National Academy of Sciences of
Ukraine, 5 Murmanskaya, Kiev, Ukraine
c Department of Organic Chemistry I, Faculty of Chemistry,
University of the Basque Country UPV/EHU, 20018 San Sebastian,
Spain
d Basque Foundation for Science, 48011, Bilbao, Spain
w Electronic supplementary information (ESI) available: Experimental
procedures, spectral data and copies of 1H, 13C, 19F and 31P NMR
spectra of all compounds. CCDC 876310. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2cc36702e
c
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Table 1 Synthesis of N-tert-butanesulfinyl 2-amino-3,3,3-trifluoro-
propylphosphonates (Ss,R)-4 from N-tert-butanesulfinyl (3,3,3)-tri-
fluoroacetaldimine (Ss)-1a
at 30–35 1C. The major diastereoisomers (Ss,R)-4 were then
isolated by flash chromatography on silica gel with diastereomeric
purity 96–98% de. Finally crystallisation of crude product
(Ss,R)-4b allowed us to obtain optically pure material which
was used in the next experiments. The stereochemistry of the
major diastereomer 4b was determined to be (Ss,R) by X-ray
analysis.14 The stereochemistry of the remaining products
4a,c,d was assigned by analogy.
According to the literature, the addition of phenylmagnesium
bromide, various aryllithium, phenyl boronic acids and ketone
enolates to imine (S)-1 proceeds via an open transition state
model where reagents preferably add to the imine from the less
hindered face occupied by the lone pair of electrons on sulfur to
afford the major diastereomer adducts.13 The stereochemical
outcome of the phosphonate carbanions addition to weakly
coordinating trifluoroacetaldimine (S)-1 is also consistent with
the open transition state model TS 1 to result in N-sulfinyl
b-aminophosphonates (Ss,R)-4 as major diastereomers (Fig. 1). It
is worth mentioning that addition of dialkyl methylphosphonates,
halomethylphosphonate as well as ethyl (1,1-diethoxyethyl)-
methylphosphinate carbanions to non-fluorinated aldehyde-
derived N-sulfinyl imines exhibited a similar stereochemical
outcome.15
Phosphonate
2
Base
3
Molar
ratio 1/2/3
Time deb
Yieldc
(%)
Entry
(h)
(%)
1
2
3
4
5
6
7
8
2b R = Et
2b R = Et
2b R = Et
2b R = Et
2b R = Et
2a R = Me n-BuLi 1.0 : 2.2 : 2.0 0.5
2c R = Pr n-BuLi 1.0 : 2.2 : 2.0 0.5
2d R = i-Pr n-BuLi 1.0 : 2.2 : 2.0 0.5
n-BuLi 1.0 : 2.2 : 2.0
n-BuLi 1.0 : 1.3 : 1.2
n-BuLi 1.0 : 2.8 : 2.5
LDA 1.0 : 2.2 : 2.0
2
2
2
2
94
90
92
93
94
95
94
94
60
20
48
56
n-BuLi 1.0 : 2.2 : 2.0 0.5
76 (58)d
53
68
75
a
The reactions were performed using the following procedure: a pre-cooled
to À78 1C THF solution of (S)-1 was quickly added to anions derived
from dialkyl methylphosphonate 2 and base at À78 1C. b Determined by
19F and 31P NMR analysis of the crude reaction mixtures. c Isolated yield
d
after chromatographic purification. Yield of optically pure material after
recrystallisation of the crude product.
One of the advantages of using the tert-butanesulfinyl group
in aminophosphonates synthesis was that it could be removed
under mild acidic conditions with complete chemoselectivity
thus allowing further transformation. By performing the
desulfinylation reaction of (Ss,R)-4b at room temperature with
4 N HCl solution in alcohol the b-aminophosphonate (R)-5
could be isolated in high yield (Scheme 1). b-Aminophosphonate
(R)-5 was further quantitatively transformed upon refluxing in
10 N hydrochloric acid to free b-aminotrifluoropropylphosphonic
acid (R)-6, which was isolated in the usual manner by the addition
of propylene oxide. Because application of fluoroalkyl a- and
b-aminophosphonates in peptide design is still in the early
stages of development,16 we decided to focus on incorporation
of enantiopure trifluoromethylated b-aminophosphonate
(R)-5 into peptide chains by coupling with N-Cbz-L-alanine
and N-Cbz-L-phenylalanine. As we anticipated that nucleophilicity
of the nitrogen atom of b-aminophosphonate (R)-5 was decreased
by the neighbouring electron-withdrawing trifluoromethyl group,
the activation of the Cbz-protected natural amino acids was
achieved by exploiting a mixed anhydrides method, recently
developed for N-terminal coupling of a-trifluoromethyl
a-amino acids.17 According to 19F NMR as well as 31P NMR
analysis the diastereoisomerically pure N-Cbz protected
b-aminophosphonic dipeptide derivatives (S,R)-7 and (S,R)-8
were conveniently obtained in good yield by this procedure.
Coupling time was 18 h and purification of (S,R)-7 and (S,R)-8
was easily carried out by crystallization.
diethyl methylphosphonate 2b was employed, the yield of
(Ss,R)-4b was significantly decreased with lower diastereos-
electivity (Table 1, entry 2). On the other hand using 2.5 equiv.
of lithium diethyl methylphosphonate obviously decreased the
yield and had little effect on the diastereomeric ratio (Table 1,
entry 3). In another experiment the use of LDA as a base only
led to a slight decrease in yield of the product (Ss,R)-4b under
the reaction conditions employed (Table 1, entry 3). The
screening of the reaction time demonstrated that transformation
could be carried out for 0.5 h and reducing the reaction time
resulted in increase in yield to a synthetically useful level while not
decreasing diastereoselectivity (Table 1, entry 5). Interestingly,
formation of side products decreased when pre-cooled THF
solution of (S)-1 was quickly added in one portion to lithium
diethyl methylphosphonate at À78 1C. Based on these results,
we speculated that the diastereoselectivity of the reaction was
kinetically controlled and the addition product was not stable
under reaction conditions.
We then examined the effect of the phosphonate ester
groups on the diastereoselectivity of addition to imine (S)-1.
In general, various phosphonates 2a,c,d participated successfully in
the reaction under optimised reaction conditions providing the
corresponding addition products (Ss,R)-4a,c,d in moderate to good
yields and excellent diastereoselectivities (Table 1, entries 6–8). The
use of the least hindered dimethyl methylphosphonate 2a gave
addition product with diastereoisomeric ratio similar to that found
for the diisopropyl methylphosphonate 2d albeit in lower yield.
Similar diastereoselectivity for dimethyl and diisopropyl phos-
phonates indicated that the stereochemical outcome of addition
reactions was independent of the alkyl moieties. The presence of
excess of dialkyl methylphosphonates 2 complicated the isola-
tion of the N-sulfinyl b-aminophosphonates (Ss,R)-4 by flash
chromatography on silica gel. To avoid this problem the crude
products were dried using a high vacuum pump (0.5 mm Hg)
Fig. 1 Proposed transition state model for the diastereoselective
addition of phosphonate carbanions to N-tert-butanesulfinyl (3,3,3)-
trifluoroacetaldimine (Ss)-1.
c
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Scheme 1 Deprotection of N-sulfinyl b-aminophosphonate (Ss,R)-4b and peptide coupling of b-aminophosphonate (R)-5 with N-Cbz-L-alanine
and N-Cbz-L-phenylalanine.
In summary, we have developed an asymmetric synthesis
of 2-amino-3,3,3-trifluoropropylphosphonate esters via the
addition of anions derived from dialkyl methylphosphonates
to (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine as
chiral auxiliary. The excellent diastereoselectivity, good yield
and short reaction time are the noteworthy advantages of the
described method. Synthesis of phosphonodipeptides from
enantiomerically pure 2-amino-3,3,3-trifluoropropylphosphonate
ester using a coupling reaction at the deactivated N-terminal
position was successfully performed.
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This study was financially supported in part by Ukrainian
National Academy of Sciences (Grant 02-03-12). A sample
of (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine was
generously donated by TOSOH F-TECH, Inc., Japan.
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c
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Chem. Commun.