A modular rearrangement approach toward medicinally relevant phosphinic structures

Article abstract of DOI:10.1021/ol902004p

An unprecedented coupling of a P - C and a C - C bond-forming event In a practical operation was developed to access medicinally relevant phosphinic structures. The strategy relies on an Ireland-Claisen rearrangement triggered by the phospha-Michael addition of silyl phosphonltes to allyl acrylates. This protocol was extended to a more versatile three-component variant that utilizes phosphinic acids, acryloyl chlorides, and allylic alcohols as starting materials.

Full text of DOI:10.1021/ol902004p

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4696-4699
A Modular Rearrangement Approach
toward Medicinally Relevant Phosphinic
Structures
Vassilis Rogakos,† Dimitris Georgiadis,*,† Vincent Dive,‡ and
Athanasios Yiotakis*,†
Department of Chemistry, Laboratory of Organic Chemistry, UniVersity of Athens,
Panepistimiopolis Zografou 15771, Athens, Greece, and CEA, DSV, SerVice
d’Inge´nierie Mole´culaire des Prote´ines (SIMOPRO), Gif/YVette Cedex 91191, France
dgeorgia@chem.uoa.gr, yiotakis@chem.uoa.gr
Received August 28, 2009
ABSTRACT
An unprecedented coupling of a P-C and a C-C bond-forming event in a practical operation was developed to access medicinally relevant
phosphinic structures. The strategy relies on an Ireland-Claisen rearrangement triggered by the phospha-Michael addition of silyl phosphonites
to allyl acrylates. This protocol was extended to a more versatile three-component variant that utilizes phosphinic acids, acryloyl chlorides,
and allylic alcohols as starting materials.
The conjugate addition of phosphorus nucleophiles to
activated alkenes (phospha-Michael reaction) holds a fun-
damental position in organophosphorus chemistry.1 The
formation of a stable P-C bond through this process has
allowed access to a wide range of medicinally relevant
phosphorus peptidomimetics (Figure 1) that act as transition-
state analogue inhibitors of various proteases.2 In recent
Figure 1. Generic structure of a phosphinic peptide and standard
P-C bond disconnection.
years, several phosphinopeptidic Zn-metalloprotease inhibi-
tors with excellent selectivity profiles have been developed,
and in most of these cases, a P-Michael reaction stands at
the heart of their synthesis.3
† University of Athens.
‡ CEA, SIMOPRO.
(1) For reviews, see: (a) Enders, D.; Saint-Dizier, A.; Lannou, M.-I.;
Lenzen, A. Eur. J. Org. Chem. 2006, 29. (b) Lu, X.; Zhang, C.; Xu, Z.
Acc. Chem. Res. 2001, 34, 535. (c) Methot, J. L.; Roush, W. R. AdV. Synth.
Catal. 2004, 346, 1035.
On the other hand, the reversible addition of P(III)
nucleophiles to 1,4-conjugated systems is one of the most
prominent techniques to trigger transformation events on the
parent substrate, i.e., the formation of a new C-C bond.1b,c,4
Interestingly, coupling of P-C and C-C bond-forming
events during a P-Michael addition represents a challenge
hitherto scarcely addressed.5 As part of our ongoing research
on phosphinic peptidomimetics, we envisioned that the
(2) For reviews on phosphorous-containing peptidomimetics, see: (a)
Aminophosphonic and Aminophosphinic Acids: Chemistry and Biological
ActiVity; Kukhar, V. P., Hudson, H. R., Eds.; John Wiley & Sons: Chichester,
2000. (b) Collinsova´, M.; Jirácˇek, J. Curr. Med. Chem. 2000, 7, 629. (c)
Yiotakis, A.; Georgiadis, D.; Matziari, M.; Makaritis, A.; Dive, V. Curr.
Org. Chem. 2004, 8, 1135. (d) Palacios, F.; Alonso, C.; de los Santos, J. M.
Chem. ReV. 2005, 105, 899.
10.1021/ol902004p CCC: $40.75
Published on Web 09/23/2009
 2009 American Chemical Society

development of a modular protocol that would involve
tandem P-C/C-C bond formation would pave the way for
the combinatorial synthesis of diversified phosphinic scaf-
folds in a single operation (Scheme 1a). In this paper, we
Table 1. Condition Screening of Reaction between 2a and 3a
Scheme 1. (a) Tandem P-C/C-C Bond-Forming Approach. (b)
Proposed Tandem P-Michael/Ireland-Claisen Sequence
entry
silylating agent
base
4a/5aa
yielda (%)
1
2
3
4
5
6
7
8
9
HMDS
BSA
51:49
75:25
77:23
91:9
49:51
29:71
33:67
21:79
3:97
46
>99
>99
>99b
>99
>99
>99
>99
85
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
Et3N
i-Pr2EtN
DABCO
DBU
DMAP
NMM
DBN
imidazole
10
0:100
>99c
a Determined by 31P NMR spectroscopy of the crude mixtures. b Yield
of isolated product 4a, 85%. c Yield of isolated product 5a, 97%.
report a novel tandem P-C/C-C bond-forming reaction
based on the sequential P-Michael addition of silyl phos-
phonites to allyl acrylates followed by Ireland-Claisen
rearrangement and the extension of this transformation to a
more convergent three-component variant.
1) was observed upon silylation with N,O-bis(trimethylsilyl)ac-
etamide (BSA) (Table 1, entry 2). Interestingly, when TMSCl
was used the product distribution was highly dependent on the
amine employed each time. Gratifyingly, the combination of
TMSCl and Hunig’s base led to a 4a/5a ratio of 10:1 when 7
equiv of each reagent were used (Table 1, entry 4). Furthermore,
a wide screening of other amines in lieu of Hunig’s base led to
an unexpected observation: all the amines tested (except Et3N)
switched the 4a/5a ratio in favor of the Michael adduct 5a with
imidazole suppressing completely the formation of 4a (Table
1, entry 10). This remarkable tuning effect of the amine to the
reaction outcome can offer easy access to both scaffolds 4a
and 5a by using practically the same reaction setting.
NMR monitoring of the reaction between 2a and 3a revealed
that silyl ketene acetal 6 was the true precursor of the
rearrangement (Scheme 2). We observed that at -30 °C,
phosphonite 1a (δP ) 141.3 ppm) is slowly converted to an
intermediate showing two signals at δP ) 33.9 and 34.0 ppm
which are within the typical range of chemical shifts for P(V)
phosphinic esters (see the Supporting Information). Interestingly,
when the reaction was quenched with D2O after 48 h at -30
°C, compound 5a that had undergone quantitative deuterium
incorporation was obtained. This implies that the observed
intermediate corresponds to silyl ketene acetal 6 (E and Z
At the onset of our study, prompted by the work of Inanaga
et al. on the phosphine-catalyzed [3,3] rearrangement of allyl
acrylates to R-methylene-γ,δ-unsaturated carboxylic acids,6 we
reasoned that a similar [3,3] Ireland-Claisen rearrangement
could occur upon conjugate addition of in situ generated
trivalent bis(trimethylsilyl)phosphonites (1) to an allyl acrylate.
In this case, however, a stable P-C bond might be also formed
(Scheme 1b).7 Initial experiments to test our working hypothesis
were carried out with phosphinic acid 2a and allyl acrylate (3a)
as the Michael acceptor. After extensive experimentation, it was
revealed that the reaction outcome is dramatically affected by
the choice of silylation conditions. Silylation of 2a by HMDS
and subsequent addition of 3a at 25 °C led to the moderate
conversion of 2a to a 1:1 mixture of 4a and 5a (Table 1, entry
1). A significant improvement in both yield and 4a/5a ratio (3:
(3) For selected examples, see: (a) Dive, V.; Cotton, J.; Yiotakis, A.;
Michaud, A.; Vassiliou, S.; Jirácˇek, J.; Vazeux, G.; Chauvet, M.-T.;
Cuniasse, P.; Corvol, P. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 4330. (b)
Georgiadis, D.; Beau, F.; Czarny, B.; Cotton, J.; Yiotakis, A.; Dive, V.
Circ. Res. 2003, 93, 148. (c) Devel, L.; Rogakos, V.; David, A.; Makaritis,
A.; Beau, F.; Cuniasse, P.; Yiotakis, A.; Dive, V. J. Biol. Chem. 2006,
281, 11152. (d) Chen, H.; Noble, F.; Coric, P.; Fournie-Zaluski, M.-C.;
Roques, B. P. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 12028. (e) Lauer-
Fields, J.; Brew, K.; Whitehead, J. K.; Li, S.; Hammer, R. P.; Fields, G. B.
J. Am. Chem. Soc. 2007, 129, 10408. (f) Liu, X.; Xu, X. E.; Tian, X.; Mazur,
A.; Ebetino, F. H. J. Organomet. Chem. 2002, 646, 212.
(5) For a phosphonium zwitterion isolated during a phosphine-catalyzed
Morita-Baylis-Hillman reaction, see: (a) Zhu, X.-F.; Henry, C. E.; Kwon,
O. J. Am. Chem. Soc. 2007, 129, 6722. For a tandem P-C/C-C bond-
forming reaction involving phosphides, see: (b) Hayashi, M.; Matsuura,
Y.; Watanabe, Y. Tetrahedron Lett. 2005, 46, 5135.
(4) For selected recent examples, see: (a) Zhu, G.; Chen, Z.; Jiang, Q.;
Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. (b) Wang,
L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem.
Soc. 2002, 124, 2402. (c) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc.
2003, 125, 4716. (d) Cho, C. W.; Krische, M. J. Angew. Chem., Int. Ed.
2004, 43, 6689. (e) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem.
Soc. 2005, 127, 9260. (f) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed.
2006, 45, 1426. (g) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007,
129, 10988. (h) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130,
5660.
(6) Hanamoto, T.; Baba, Y.; Inanaga, J. J. Org. Chem. 1993, 58, 299.
(7) For Ireland-Claisen rearrangements triggered by conjugate additions,
see: (a) Aoki, Y.; Kuwajima, I. Tetrahedron Lett. 1990, 31, 7457. (b)
Yamazaki, T.; Shinohara, N.; Kitazume, T.; Sato, S. J. Org. Chem. 1995,
60, 8140. (c) Eriksson, M.; Hjelmencrantz, A.; Nilsson, M.; Olsson, T.
Tetrahedron 1995, 51, 12631. (d) Takai, K.; Ueda, T.; Kaihara, H.; Sunami,
Y.; Moriwake, T. J. Org. Chem. 1996, 61, 8728. (e) Bausch, C. C.; Johnson,
J. S. J. Org. Chem. 2008, 73, 1575. For a relevant reaction with
oxasilacyclopentenes, see: (f) Calad, S. A.; Woeprel, K. A. J. Am. Chem.
Soc. 2005, 127, 2046.
Org. Lett., Vol. 11, No. 20, 2009
4697

Scheme 2
.
Proposed Mechanistic Pathway
Table 2. P-Michael/Claisen Reaction between Phosphinic Acids
and Allyl Acrylatesa
isomers) which cannot rearrange at -30 °C. In addition, the
absence of any other intermediates in the reaction mixture at
-30 °C suggests that a rapid Arbuzov-type rearrangement of
primary adducts (zwitterions A and oxaphosphalenes B have
been proposed)8 toward secondary adduct 6 precedes the
sigmatropic rearrangement. This observation rules out possible
rearrangement of A or B, a hypothesis that could be valid on
the basis of recent work by Woerpel et al. on similar isosteric
oxasilacyclopentenes.7f When imidazole was used as a depro-
tonating base, no deuterium incorporation was observed upon
D2O addition at -30 °C, which suggests that intermediate 6 is
internally quenched by imidazole.HCl. This result may explain
the absence of rearranged product observed at entry 10 of Table
1. When we followed the fate of 6 at room temperature in the
TMSCl/i-Pr2EtN system, we observed that this was fully
consumed within 5 h to give a new major resonance at δP )
33.5 ppm and a minor at δP ) 33.8 ppm. Upon quenching with
D2O, a 10:1 mixture of 4a/5a was obtained in which 5a was
not labeled. Obviously, 6 affords 7 upon rearrangement or, to
a lesser extent, 8 upon protonation by i-Pr2EtN.HCl and the
final product distribution reflects the relative rate of these two
processes which is clearly in favor of the sigmatropic rear-
rangement under the described conditions.
The scope of this P-Michael/Claisen tandem process was
studied by testing a wide range of acrylates with diverse
substitution patterns. It should be emphasized that in all cases,
target compounds of type 4 were easily isolated from minor
Michael-adduct byproducts of type 5 by standard column
chromatography, thus satisfying our initial requirement for a
synthetically useful protocol. Substituents at C-1 or C-3 of the
allylic part of 3 do not affect the efficiency of the formation of
rearranged products 4 (Table 2, entries 1, 3, and 4).9 Moreover,
comparison of entries 3 and 4 of Table 2 shows that a phenyl
group at C-3 position benefits the rearrangement process,
possibly due to a better stabilization of the pericyclic reaction
transition state. Slightly inferior yields for products of type 4
were observed with a C-2 substituent on the allylic chain (Table
2, entries 2 and 5). This protocol was also able to provide
synthetically useful allenyl-substituted phosphinate 4g by
a Conditions: 2, 3 (1.1 equiv), i-Pr2EtN (7 equiv), CH2Cl2, then TMSCl
(7 equiv) at -78 °C, warm to rt, 24 h. b Yield of isolated product. c dr:
70:30 (4d), 65:35 (4e), 90:10 (4f). d Reaction time 48 h.
replacing the starting allyl acrylate with propargyl acrylate.
Furthermore, a very interesting application of this process relies
on the preparation of phosphinic scaffolds with an all-carbon
quaternary center at the R-position (Table 2, entries 7 and 8).
Such structures can be of great medicinal interest since double
substitution of peptidomimetics is a well-known medicinal
(8) Evans, D. A.; Hurst, K. M.; Takacs, J. M. J. Am. Chem. Soc. 1977,
100, 3467.
4698
Org. Lett., Vol. 11, No. 20, 2009

technique to obtain conformationally restricted bioactive com-
pounds.10 These unique phosphinic structures can be easily
obtained by using allyl acrylates bearing an R-substituent. To
our knowledge, this protocol represents the first general synthetic
method for phosphinic peptide-like structures with a quaternary
R-carbon.11
Table 3. One-Pot Three-Component Synthesis of Compounds 4a
Cbz-protected R-aminophosphinic acids (2b) can be also
used in this reaction, although the yield of the rearranged
product is lower (4j/5j ) 55:45 in the crude mixture) due to
a negative effect of the vicinal amide hydrogen (Table 2,
entry 9).12 Although the role of this amide hydrogen in the
final 4j/5j ratio is not completely understood, the 6-atom
distance between the amide hydrogen and the nucleophilic
carbon of silyl ketene acetal 6j could imply an increased
susceptibility to protonation due to intramolecular proton
transfer, as it is depicted in Figure 2. This is further supported
yielda
product (%)
entry phosphinic acid -R1
-R2
1
2
3
2a
2a
2a
2a
2a
2c
-H -CHdCH2
-H -C(Me)dCH2
-H -CHdCHPh (E)
-H -Ct CH
-Bn -CHdCH2
-H -CHdCH2
4a
4c
4d
4g
4h
4k
80
54
91
67
87
76
4
5b
6
a Yield of isolated product. b Reaction time 48 h.
phosphinic acids. The reaction involves an Ireland-Claisen
rearrangement triggered by the P-Michael addition of silyl
phosphonites to allyl acrylates, both formed in situ. This unique
tandem P-C/C-C bond-forming reaction allows the prepara-
tion of diverse phosphinic peptidomimetic structures in a single
step and gives access to unprecedented R,R-disubstituted
scaffolds that can be of great interest for the development of
conformational-constrained bioactive compounds. In fact, all
compounds of type 4 reported herein are potential inhibitors of
zinc-metallocarboxypeptidases, a large family of exopeptidases
that are involved in a wide range of physiological process, as
well as, in numerous human pathologies.13 It is also noteworthy
thatthismethodrepresentsthefirstapplicationofanIreland-Claisen
rearrangement in a three-component synthetic protocol. Studies
on the scope and the development of an asymmetric version of
this process are currently underway.
Figure 2. Intramolecular interaction at 6j that may accelerate its
deactivation.
by the fact that when the bis-protected aminophosphinic
analogue 2c was employed, the yield of the rearranged
product was increased in levels comparable to those obtained
with phenylphosphinic acid (Table 2, entry 10).
Although the development of the reported protocol follows
the spirit of our initial concept, it still does not enable us to
assemble the target compounds by three independent compo-
nents that will correspond to the phosphinic part, the propionyl
backbone part, and the side-chain part. Obviously, the two latter
components are brought together in the final structure by an
allyl acrylate that needs to be synthesized separately. Therefore,
our next goal was to merge the allyl acrylate preparation with
the P-Michael addition/Ireland-Claisen rearrangement protocol
in an one pot three-component process. A crucial feature of
the developed method that allowed us to perform this combina-
tion was the tolerance of the process to the presence of
i-Pr2EtN·HCl. We reasoned that such a characteristic would
permit the in situ formation of allyl acrylates by acryloyl
chloride and simple allylic alcohols mediated by Hunig’s base.
Indeed, addition of TMSCl and a phosphinic acid in a reaction
mixture consisting of acryloyl chloride, an allylic alcohol, and
Hunig’s base successfully provided the target structures in high
yields. In all cases, the desired products were obtained with
high efficiency, comparable to that of the two-component
protocol. Some examples of this novel transformation are shown
in Table 3.
Acknowledgment. This work was supported by funds
from the European Commision (FP6RT, Cancer Degradome
project, LSHC-CT-2003-503297) and from the Special
Account for Research Grants of University of Athens.
Supporting Information Available: Full experimental
1
details, characterization data, and copies of H, 13C and 31P
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL902004P
(9) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc.
1976, 98, 2868.
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Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bos, M.; Cook, C. M.; Fry,
D. C.; Graves, B. J.; Hatada, M.; Hill, D. E.; Kahn, M.; Madison, V. S.;
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33, 1699. (d) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789.
(11) For the only literature report of a relevant phosphinopeptidic
structure, see: McKittrick, B. A.; Stamford, A. W.; Weng, X.; Ma, K.;
Chackalamannil, S.; Czarniecki, M.; Cleven, R. M.; Fawzi, A. B. Bioorg.
Med. Chem. Lett. 1996, 6, 1629.
In conclusion, we have developed a novel and practical
reaction sequence which enables the rapid assembly of me-
dicinally relevant phosphinic structures starting from readily
available acryloyl chlorides, allylic or propargylic alcohols and
(12) Smith, A. B.; Ducry, L.; Corbett, R. M.; Hirschmann, R. Org. Lett.
2000, 2, 3887–3890.
(13) Gomis-Ru¨th, F. X. Crit. ReV. Biochem. Mol. Biol. 2008, 43, 319.
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