Diastereoselective Synthesis of α,β′-Disubstituted Aminomethyl(2-carboxyethyl)phosphinates as Phosphinyl Dipeptide Isosteres

Article abstract of DOI:10.1021/ol801743d

(Chemical Equation Presented) A new and efficient method has been developed for the diastereoselective synthesis of unnatural dipeptide analogues containing the metabolically stable phosphinic moiety, NH₂XaaΨ [P(O)OHCH₂]XaaOH, which mimics the transition state of tetrahedral geometry of a scissile peptide bond in hydrolysis by protease. The method is based upon stereospecific Michael addition of stereodefined α-aminoalkyl- H-phosphinates to acrylates and subsequent diastereoselective alkylation at the β′-position of the resulting Michael adducts.

Full text of DOI:10.1021/ol801743d

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4347-4350
Diastereoselective Synthesis of
r,ꢀ′-Disubstituted
Aminomethyl(2-carboxyethyl)phosphinates
as Phosphinyl Dipeptide Isosteres
Takehiro Yamagishi, Hiroyuki Ichikawa, Terumitsu Haruki, and
Tsutomu Yokomatsu*
School of Pharmacy, Tokyo UniVersity of Pharmacy and Life Sciences, 1432-1
Horinouchi, Hachioji, Tokyo 192-0392, Japan
yokomatu@ps.toyaku.ac.jp
Received July 29, 2008
ABSTRACT
A new and efficient method has been developed for the diastereoselective synthesis of unnatural dipeptide analogues containing the metabolically
stable phosphinic moiety, NH2XaaΨ[P(O)OHCH2]XaaOH, which mimics the transition state of tetrahedral geometry of a scissile peptide bond
in hydrolysis by protease. The method is based upon stereospecific Michael addition of stereodefined r-aminoalkyl-H-phosphinates to acrylates
and subsequent diastereoselective alkylation at the ꢀ′-position of the resulting Michael adducts.
The backbone modification of bioactive peptides with
replacement of a scissile peptide bond in enzymatic hydroly-
sis is a well-established strategy for developing protease
inhibitors.1 Among the known isosteric modifications, several
studies have demonstrated that the use of phosphinyl
dipeptide isosteres (PDIs) can be a very effective approach
for the development of highly potent and selective inhibitors
of various Zn metalloproteases.2 PDIs contain the metaboli-
cally stable phosphinic moiety, NH2XaaΨ[P(O)OH-
CH2]XaaOH, which mimics the transition state for tetrahedral
geometry of a scissile peptide bond during enzymatic
hydrolysis (Figure 1). Although PDIs are of considerable
interest as a dipeptide building block in medicinal chemistry,
their application to the modification of bioactive peptides is
Figure 1. Structure of PDIs and transition states in the hydrolysis
of dipeptides.
(1) For reviews, see: (a) Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med.
Chem. 2000, 43, 305–341. (b) Babine, R. E.; Bender, S. L. Chem. ReV.
1997, 97, 1359–1472.
(2) (a) Collinsova´, M.; Jira´cek, J. Curr. Med. Chem. 2000, 7, 629. (b)
Yiotakis, A.; Geogiadis, D.; Matziari, M.; Makaritis, A.; Dive, V. Curr.
Org. Chem. 2004, 8, 1135. (c) Natchev, I. A. Tetrahedron 1991, 47, 1239.
(d) Moree, W. J.; van der Marel, G. A.; van Boom, J. H.; Liskamp, R. M. J.
Tetrahedron 1993, 49, 11055. (e) Mucha, A.; Kafarski, P.; Plenat, F.;
Cristau, H.-J. Tetrahedron 1994, 50, 12743. (f) Li, B.; Cai, S.; Du, D.-M.;
Xu, J. Org. Lett. 2007, 9, 2257.
limited due to the paucity of methods for preparing PDIs in
a highly stereocontrolled manner.
Classical methods for the synthesis of PDIs rely on the
Michael addition of N-protected silyl aminoalkylphosphinates
to R-substituted acrylate derivatives, followed by diastereo-
10.1021/ol801743d CCC: $40.75
Published on Web 09/10/2008
2008 American Chemical Society

selective protonation of the intermediate enolates.3 Alterna-
tively, diastereoselective reduction of dehydroalanyl phos-
phinyl peptide analogues with an asymmetric catalyst has
been applied.4 In these reactions, a mixture of four stereoi-
somers is usually formed upon using a racemic aminoalky-
lphosphinate as a starting material. The separation of the
mixture5 is necessary to isolate an individual diastereoisomer
showing the desired biological activity. Therefore, there is
room for the development of more stereoselective methods
for the preparation of PDIs.
phosphorus chirality. In the second reaction, cis-lithium
enolates bearing a cyclic chelated structure might be favor-
ably generated,9 and alkylation of the enolate is expected to
proceed in a highly diastereoselective manner induced by
the chirality of the phosphorus atom (Scheme 1). Herein,
we communicate our results.
According to the strategy, we first examined the Michael
addition of racemic R-aminoalkyl-H-phosphinates 4-10,
prepared according to our previously reported method,6 to
acrylates without a loss of phosphorus chirality (Table 1).
We have recently developed a general method for the
stereoselective synthesis of R-aminoalkyl-H-phosphinates 1
through alkylation of aminomethylphosphinate derivatives
having a bulky 1,1-diethoxyethyl functionality connected to
a phosphorus atom.6,7 In this method, the stereogenic center
at the R-carbon is highly controlled by the phosphorus
chirality.6,7 Asymmetric synthesis of this class of compounds
has also been successful through the same sequence utilizing
optically active aminomethylphosphinates.8 Thus, our in-
vestigations focused on developing a general method for the
diastereoselective synthesis of R,ꢀ′-disubstituted aminom-
ethyl(2-carboxyethyl)phosphinate derivatives 3, useful for the
Table 1. Michael Addition of 4-10 to t-Butyl Acrylatea
entry
substrate
product
yieldb (%)
1
2
3
4
5
6
7
4 (PG ) Cbz, R ) Bn)
5 (PG ) Bz, R ) Bn)
6 (PG ) Boc, R ) Bn)
7 (PG ) Ts, R ) Bn)
8 (PG ) Trs, R ) Bn)
9 (PG ) Trs, R ) i-Bu)
10 (PG ) Trs, R ) H)
11
12
13
14
15
16
17
93
78
90
83
92
67
99
Scheme 1
.
Strategy for Stereoselective Synthesis of PDI
Derivatives
a Reactions were carried out for 2-6 h. b Isolated yield.
Han and Zhao have recently established a magnesium
alkoxide-catalyzed Michael addition of P-chiral H-phosphi-
nates to electron-deficient alkenes, which proceeded in a
stereospecific manner with retention of phosphorus stereo-
chemistry.10 Thus, the Michael reaction of Ts-amide 7 to
t-butyl acrylate was examined using the conditions of Han
and Zhao (entry 4) because a large amount of Ts-amide 7 is
readily prepared. Accordingly, Ts-amide 7 was treated with
t-butyl acrylate in the presence of t-BuOMgBr (10 mol %)
at 0 °C in THF. Although this reaction provided the desired
adduct 14 as a single isomer as expected, chemical yield
was quite low (10%). However, the yield was significantly
improved to 83% upon utilizing 1 equiv of t-BuOMgBr
synthesis of PDIs, starting from highly stereodefined R-ami-
noalkyl-H-phosphinates 1 (Scheme 1).
(5) The method to separate inidividual phosphinic dipeptide stereoiso-
mers using HPLC was reported, see: Mucha, A.; Lammerhofer, M.; Lindner,
W.; Pawelczak, M.; Kafarski, P. Bioorg. Med. Chem. Lett. 2008, 18, 1550.
(6) Yamagishi, T.; Haruki, T.; Yokomatsu, T. Tetrahedron 2006, 62,
9210.
Our strategy for stereoselective synthesis of 3 is based on
the following two critical reactions: (1) Michael addition of
1 to acrylates without a loss of the phosphorus chirality and
(2) stereoselective alkylation of lithium enolates of the
resulting Michael adduct 2 under the influence of the
(7) For application of our methodology to the synthesis of R,R′-
diaminophosphinates and R-amino-R′-hydroxyphosphinates, see: (a) Kabou-
din, B.; Haruki, T.; Yamagishi, T.; Yokomatsu, T. Tetrahedron 2007, 63,
8199. (b) Kaboudin, B.; Haruki, T.; Yamagishi, T.; Yokomatsu, T. Synthesis
2007, 3226.
(3) For selected examples, see: (a) Makaritis, A.; Georgiadis, D.; Dive,
V.; Yiotakis, A. Chem.-Eur. J. 2003, 9, 2079. (b) Liu, X.; Hu, X. E.; Tian,
X.; Mazur, A.; Ebetino, F. H. J. Organomet. Chem. 2002, 646, 212–222.
(c) Cristau, H.-J.; Coulombeau, A.; Genevois-Borella, A.; Pirat, J.-L.
Tetrahedron Lett. 2001, 42, 4491. (d) Chen, H.; Noble, F.; Mothe, A.;
Meudal, H.; Coric, P.; Danascimento, S.; Roques, B. P.; George, P.; Fournie-
Zaluski, M.-C. J. Med. Chem. 2000, 43, 1398. (e) Allen, M. C.; Fuhrer,
W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989, 32, 1652.
(4) Parsons, W. H.; Patchett, A. A.; Bull, H. G.; Schoen, W. R.; Taub,
D.; Davidson, J.; Combs, P. L.; Springer, J. P.; Gadebusch, H.; Weissberger,
B.; Valiant, M. E.; Mellin, T. N.; Busch, R. D. J. Med. Chem. 1988, 31,
1772.
(8) Haruki, T.; Yamagishi, T.; Yokomatsu, T. Tetrahedron: Asymmetry
2007, 18, 2886.
(9) Alkylation of lithiun enolates derived from γ-amino esters and
δ-hydroxy esters was reported to proceed with high diastereoselectivity. In
these cases, selectivity were rationalized by cis-enolates bearing a cyclic
chelated structure. Reactions of γ-amino esters: (a) Hanessian, S.; Schaum,
R. Tetrahedron Lett. 1997, 38, 163. (b) Hanessian, S.; Margarita, R.
Tetrahedron Lett. 1998, 39, 5887. Reactions of δ-hydroxy esters: (c)
Narasaka, K.; Ukaji, Y. Chem. Lett. 1986, 59, 81. (d) Narasaka, K.; Ukaji,
Y.; Watanabe, K. Chem. Lett. 1986, 59, 1755. (e) Narasaka, K.; Ukaji, Y.;
Watanabe, K. Chem. Lett. 1987, 60, 1457.
(10) Han, L.-B.; Zhao, C.-Q. J. Org. Chem. 2005, 70, 10121.
4348
Org. Lett., Vol. 10, No. 19, 2008

(entry 4). The stereochemistry of 14 was ascertained by
single-crystal X-ray analysis, suggesting the stereochemistry
at the phosphorus atom was retained without epimerization
in accordance with Han’s report.10 Through this methodol-
ogy, R-aminoalkyl(2-carboxyethyl)phosphinates 11-13 and
15-17 bearing Bz, Boc, Cbz, and 2,4,6-triisopropylbenze-
nesulfonyl (Trs) groups on the nitrogen atom could be
prepared without a loss of phosphorus chirality in good
yields, respectively (entries 1-7).
To elucidate the scope of this methodology, alkylations
of the lithium enolate generated from 15 with several
electrophiles were examined (Table 3). Reactions with
Table 3. Reactions of 15 with Several Electrophiles
Having requisite 11-17 in hand, alkylations of their
enolates with benzyl bromide (BnBr) as a model electrophile
were next investigated to determine the influence of the
nitrogen protecting group (PG) on diastereoselectivity (Table
2). Thus, compound 11 having a conventional Cbz protecting
entry
RX
temp (°C)
product dra yieldb (%)
1
2
3
4
5
MeI
allylBr
methallylBr -78
-78
-78
23
24
25
26
27
24:1
21:1
29:1
14:1
17:1
82
83
69
62
84
i-BuI
-78 to rt
propargylCl -78 to -20
Table 2. Reactions of 11-15 with Benzyl Bromide
a Determined by 31P NMR analysis. b Isolated yield.
relatively active alkyl halides including methyl iodide, allyl
bromide, and methallyl bromide proceeded at -78 °C to give
alkylation products 23-25 in good yields (entries 1-3).
However, increasing the temperature from -78 °C to rt or
-20 °C was necessary in reactions using i-butyl iodide and
propargyl chloride (entries 4 and 5). In all cases, excellent
diastereoselectivity (14:1-29:1) was observed (entries 1-5).
Recently, a propargyl side chain at the P1′ position proved
to be a versatile functionality for divergent synthesis of
phosphinic peptides bearing an isoxazole ring, which is
expected to interact favorably with the S1′ pocket of
metalloproteases.3a However, highly stereoselective synthesis
of phosphinic dipeptide units having a propargyl side chain
at the P1′ position is a difficult task as seen in a previous
study.3a Therefore, the remarkably high diastereoselectivity
(17:1) observed in the alkylation with propargyl chloride is
noteworthy (entry 5).
entry
substrate
product
dr(a:b)a
yieldb (%)
1
2
3
4
5
11 (PG ) Cbz)
12 (PG ) Bz)
13 (PG ) Boc)
14 (PG ) Ts)
15 (PG ) Trs)
18
19
20
21
22
1.1:1
3.4:1
4.5:1
4.0:1
21:1
93
78
90
83
92
a Determined by 31P NMR analysis. b Combined yield of each isomer.
group was treated with LHMDS (3 equiv) in THF at -78
°C, and the resulting enolate was alkylated with BnBr (3.2
equiv) at the same temperature. This alkylation reaction was
completed within 2 h to give a 1.1:1 mixture of 18a and
18b in 93% yield (entry 1). Modest diastereoselectivity (3.4:1
to 4.5:1) was observed when substrates 12-14 bearing Bz,
Boc, and a Ts protecting group, respectively, were alkylated
under the same conditions (entries 2-4).11 It is noteworthy
that a bulky Trs protecting group of 15 markedly influenced
diastereoselectivity, and 22a was preferably produced in an
excellent diastereoselectivity (21:1) in a 92% yield under
the same conditions (entry 5). Determination of the stereo-
chemistry of alkylation product 21a was accomplished by
X-ray crystallographic analysis. The stereochemistries of
18a-20a and 22a were inferred based on their analogous
spectroscopic data (1H NMR and 31P NMR) to those of 21a.
To survey the origin of the high diastereoselectivity,
diastereoselectivity for benzylation of 17 having no stereo-
genic center at the R-position was analyzed in comparison
with that of 16, which possesses a bulky i-butyl group at
the R-position (Scheme 2). Our survey revealed that dias-
Scheme 2
(11) A similar benzylation of 14 was also attempted using LiCl (6 equiv)
as an additive, which has previously been elucidated to enhance the reactivity
of lithium enolates and have an influence on the diastereoselectivity of their
alkylation reactions by changing the aggregated states. However, the
selectivity was deteriorated to 21a:21b ) 3:1. For LiCl-mediated reactions
of lithium enolates with electrophiles, see: (a) Seebach, D.; Grundler, H.;
Shoda, S.-I. HelV. Chim. Acta 1991, 74, 197. (b) Myers, A. G.; Gleason,
J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc. 1997, 119, 656. (c) Myers,
A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason,
J. L. J. Am. Chem. Soc. 1997, 119, 6496. (d) Lee, J.; Choi, W. B.; Lynch,
J. E.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 3679.
tereoselectivity might be highly dependent upon the chirality
at the phosphorus atom rather than the R-position, since both
reactions provided desired benzylation products 28 and 29
in high diastereoselectivity (14:1 vs 18:1) without significant
differences.
Before incorporating R,ꢀ′-disubstituted aminomethyl(2-
carboxyethyl)phosphinates obtained into a peptide sequence,
Org. Lett., Vol. 10, No. 19, 2008
4349

the N-terminal protecting group must be removed. Thus,
deprotection of the Trs group of 22a was examined (Scheme
3). Although the reported deprotection protocols using (1)
treated with SmI2 in THF to give 18a in a modest overall
yield. Finally, hydrogenolysis of 18a over Pearlman’s catalyst
provided free amine 31 in a 74% yield.
In summary, we have developed a novel method for the
stereoselective synthesis of R,ꢀ′-disubstituted aminomethyl(2-
carboxyethyl)phosphinates starting from R-aminoalkyl-H-
phosphinates having high diastereomerical purity. The feature
of this method is that all stereogenic centers are highly
controlled by the chirality of the phosphorus atom. Since
both enantiomers of R-aminoalkyl-H-phosphinates are now
available in high optical purity,8 the present method is
applicable to the synthesis of optically active R,ꢀ′-disubsti-
tuted aminomethyl(2-carboxyethyl)phosphinate derivatives.
Synthesis of the optically active analogues and their incor-
poration to a peptide sequence as a phosphinyl dipeptide
isostere are now in progress.
Scheme 3
Acknowledgment. This work was partially supported by
a grant for private universities from The Promotion and
Mutual Aid Corporation for Private Schools of Japan and
the Ministry of Education, Culture, Sports, Science, and
Technology. The authors wish to thank Mr. Haruhiko Fukaya
(the analytical center of this university) for the X-ray
crystallographic analysis.
sodium with liquid NH3,12 (2) SmI2,13 and (3) 4,4-di-tert-
butylbiphenyl with lithium14 were applied, a desired free
amine product could not be obtained in each case. However,
facile removal of the Trs group was achieved through
application of the Knowles method.15 Accordingly, 22a was
carbamated with CbzCl, and the resulting carbamate 30 was
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds,
and X-ray analysis data for compounds 14 and 21a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1988, 53, 2367.
(13) Vedejs, E.; Lin, S. J. Org. Chem. 1994, 59, 1602.
(14) Neipp, C. E.; Humphrey, J. M.; Martin, S. F. J. Org. Chem. 2001,
66, 531.
(15) For SmI2-mediated removal of the sulfonyl group of N-benzoyl
benzenesulfonamide derivatives, see: Knowles, H.; Parsons, A. F.; Pettifer,
R. M. Synlett. 1997, 271.
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