Phosphine-catalyzed allylic substitution of Morita-Baylis-Hillman acetates: Synthesis of n-protected β-aminophosphonic acid esters

Article abstract of DOI:10.1021/jo061218s

(Chemical Equation Presented) A series of N-protected β-amino phosphonic acid esters have been prepared by phosphine-catalyzed allylic substitution of 2-(diethylphosphonyl)-substituted allylic acetates employing 4,5-dichlorophthalimide as nucleophilic par

Full text of DOI:10.1021/jo061218s

SCHEME 1. Plausible Catalytic Mechanism for the
Regioretentive Allylic Substitution of MBH Acetates via
Phosphine Catalysis
Phosphine-Catalyzed Allylic Substitution of
Morita-Baylis-Hillman Acetates: Synthesis of
N-Protected â-Aminophosphonic Acid Esters
HaeIl Park,† Chang-Woo Cho,‡ and Michael J. Krische*,‡
College of Pharmacy, Kangwon National UniVersity,
Chuncheon, 200-701, Republic of Korea, and Department of
Chemistry and Biochemistry, UniVersity of Texas at Austin,
Austin, Texas 78712
mkrische@mail.utexas.edu
ReceiVed June 13, 2006
regioretentive allylic substitution may be achieved through the
intervention of nucleophilic organocatalysts in successive SN2′-
SN2′ processes. The feasibility of this approach was first
indicated by the “two-stage” regioretentive substitution of MBH
acetates, wherein stoichiometric SN2′ displacement of the acetate
by DABCO is followed by treatment of the resulting DABCO
adduct with a heteroatom nucleophile that engages in a second
SN2′ displacement of DABCO.2 Concurrently, it was shown that
MBH carbamates and trichloroacetimidates undergo decarbox-
ylative rearrangement in the presence of substoichiometric
quantities of DABCO to afford products of regioretentive
amination.3 Later, (DHQD)2PHAL was shown to catalyze
regioretentive allylic substitution of MBH acetates with sodium
bicarbonate as nucleophile.4 The corresponding MBH alcohols
were produced in 25-42% yield and 54-92% enantiomeric
excess. In connection with our ongoing studies involving
nucleophilic phosphine organocatalysis,5 we recently reported
the first intermolecular organocatalytic allylic substitution
reactions of MBH acetates, wherein the N- and C-nucleophiles
4,5-dichlorophthalimide and 2-trimethylsilyloxyfuran were found
to generate allylic amines and γ-butenolides, respectively, with
retention of regiochemistry.5h,i These studies complement cor-
responding palladium-catalyzed allylic substitutions of MBH
acetates, which thus far are limited to phenol-based nucleophiles
and suffer from incomplete regioselection.6 Our collective
studies are consistent with a catalytic mechanism in which
generation of the electrophile-nucleophile ion pair B plays a
key role in suppressing direct addition of the nucleophile to
the less substituted enone moiety of the starting MBH acetate.
Generation of the electrophile-nucleophile ion pair B, in turn,
depends on the ability of acetate A to engage in acid-base
equilibria involving deprotonation of the pronucleophile, as in
the case of 4,5-dichlorophthalimide, or formation of anionic
hypervalent silicon adducts, as for 2-trimethylsilyloxyfuran.
Finally, an advantage associated with the use of P-centered
nucleophilic catalysts over N-based nucleophiles may reside in
activation of the enone B through internal coordination to
phosphorus (Scheme 1).7
A series of N-protected â-amino phosphonic acid esters have
been prepared by phosphine-catalyzed allylic substitution of
2-(diethylphosphonyl)-substituted allylic acetates employing
4,5-dichlorophthalimide as nucleophilic partner. These or-
ganocatalytic allylic substitutions exhibit exceptionally high
levels of regiospecificity by virtue of a tandem SN2′-SN2′
mechanism.
Although transition metal catalyzed substitutions of allylic
esters and carbonates have been extensively explored,1 orga-
nocatalytic variants of such transformations have only recently
begun to emerge.2-4,5h,i Through the use of allylic acetates
decorated with anion stabilizing groups, as exemplified by
Morita-Baylis-Hillman (MBH) acetates, ionic pathways for
† Kangwon National University.
‡ University of Texas at Austin.
(1) For a recent review, see: Trost, B. M. J. Org. Chem. 2004, 69, 5813.
(2) For regioretentive substitutions of MBH acetates mediated by
stoichiometric DABCO, see: (a) Gong, J. H.; Kim, H. R.; Ryu, E. K.; Kim,
J. N. Bull. Korean Chem. Soc. 2002, 23, 789. (b) Kim, J. N.; Lee, H. J.;
Lee, K. Y.; Gong, J. H. Synlett 2002, 173.
(3) For regioretentive rearrangements of MBH acetates catalyzed by
DABCO, see: (a) Ciclosi, M.; Fava, C.; Galeazzi, R.; Orena, M.; Sepulveda-
Arques, J. Tetrahedron Lett. 2002, 43, 2199. (b) Galeazzi, R.; Martelli, G.;
Orena, M.; Rinaldi, S. Synthesis 2004, 2560.
(4) Kim, J. N.; Lee, H. J.; Gong, J. H. Tetrahedron Lett. 2002, 43, 9141.
(5) For phosphine-catalyzed transformations developed in our laboratory,
see: (a) Wang, L.-C.; Luiz, A.-L.; Agapiou, K.; Jang, H.-Y.; Krische, M.
J. J. Am. Chem. Soc. 2002, 124, 2402. (b) Agapiou, K.; Krische, M. J.
Org. Lett. 2003, 5, 1737. (c) Jellerichs, B. G.; Kong, J.-R.; Krische, M. J.
J. Am. Chem. Soc. 2003, 125, 7758. (d) Wang, J.-C.; Ng, S.-S.; Krische,
M. J. J. Am. Chem. Soc. 2003, 125, 3682. (e) Wang, J.-C.; Krische, M. J.
Angew. Chem., Int. Ed. 2003, 42, 5855. (f) Koech, P. K.; Krische, M. J. J.
Am. Chem. Soc. 2004, 126, 5350. (g) Luis, A.-L.; Krische, M. J. Synthesis
2004, 2579. (h) Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org. Lett. 2004, 6,
1337. (i) Cho, C.-W.; Krische, M. J. Angew. Chem., Int. Ed. 2004, 43, 6689.
In an effort to expand this emergent class of organocatalytic
allylic substitutions, the use of anion stabilizing groups in the
(6) Enantioselective Pd-catalyzed allylic alkylation of Morita-Baylis-
Hillman acetates has been reported but is restricted to phenol-based
nucleophiles and suffers from incomplete regioselection: (a) Trost, B. M.;
Toste, D. F. J. Am. Chem. Soc. 2000, 122, 3534. (b) Roy, O.; Riahi, A.;
He´nin, F.; Muzart, J. Tetrahedron 2000, 56, 8133. (c) Trost, B. M.; Thiel,
O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2002, 124, 11616. (d) Trost, B. M.;
Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003, 124, 13155.
10.1021/jo061218s CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/06/2006
7892
J. Org. Chem. 2006, 71, 7892-7894

TABLE 1. Optimization of Phosphine Catalyzed Allylic Amination
of Substrate 2b
entry
R
PPh3 (mol %)
T °C
solvent
THF
THF
THF
THF
1,4-dioxane
yield (%)
1
2
3
4
5
Me
Me
Et
Et
Et
20-100
20-100
20-100
40
25
65
25
65
110
nr
<10
trace
50
20
90
FIGURE 1. Enzyme inhibitors that embody â-aminophosphonic acid
ichiometric quantities of FeCl3 in acetonitrile solvent delivered
the phosphonyl-substituted allylic acetates 1b-6b in good to
excellent yields (Scheme 2).
substructures.
form of phosphonic esters was explored. Here, we disclose that
exposure of 2-(diethylphosphonyl)-substituted allylic acetates
1b-6b to 4,5-dichlorophthalimide in the presence of substo-
ichiometric quantities of triphenylphosphine results in regio-
retentive displacement of the acetate to afford â-(4,5-dichlo-
rophthalimido)-phosphonic acid esters 1c-6c.8 Protected â-ami-
no phosphonic acids of this type are potential precursors to
â-amino acid isosteres. As exemplified by the indicated inhibi-
tors of calpain I, human renin, HIV protease, and norstatine
renin, such compounds possessing â-aminophosphonic acid
substructures exhibit interesting and diverse biological properties
(Figure 1).9,10
The preparation of substrates 1b-6b for phosphine-catalyzed
allylic substitution was initially attempted using a MBH-type
vinylphosphonate-aldehyde coupling protocol.11 However, at-
tempted MBH-type couplings employing a range of different
nucleophilic promoters failed to provide the desired adducts 1a-
6a. Direct lithiation of the vinyl phosphonate mediated by LDA
in the presence of the aldehyde met with greater success.12 The
desired 2-(diethylphosphonyl)-substituted allylic alcohols 1a-
6a were obtained in moderate yield. Subsequent exposure of
alcohols 1a-6a to acetic anhydride in the presence of substo-
With substrates 1b-6b in hand, optimum conditions previ-
ously determined for the phosphine-catalyzed allylic substitution
of corresponding acrylate-based systems were examined.5h In
the event, introduction of triphenylphosphine to a THF solution
of 2b (R ) Me) and 4,5-dichlorophthalimide at ambient
temperature failed to provide the desired substitution product
2c, even at stoichiometric loadings of triphenylphosphine (Table
1, entry 1). A similar outcome was observed for reactions
performed at elevated temperatures in THF (65 °C) (Table 1,
entry 2). It was reasoned that 2b (R ) Me) might be a
suboptimal substrate as a result of facile dealkylation of the
methyl phosphonate via nucleophilic attack by triphenylphos-
phine, which would simultaneously consume the phosphine
catalyst. To challenge this hypothesis, the phosphine-catalyzed
allylic substitution of 2b (R ) Et) was examined. Indeed for
substrate 2b (R ) Et), trace quantities of the desired reaction
product 2c could be isolated from reactions performed at
ambient temperature (Table 1, entry 3), and for the reaction
performed at elevated temperature (65 °C) a 50% isolated yield
of phthalimide 2c was obtained at 40 mol % loadings of
triphenylphosphine (Table 1, entry 4). Finally, appreciating that
phosphonates are inherently less electrophilic than their carboxy
counterparts, the reaction of 2b (R ) Et) was investigated at
110 °C in dioxane solvent using 20 mol % loadings of
triphenylphosphine. The product of allylic substitution was
obtained in 90% yield with complete retention of regiochemistry
(Table 1, entry 5).
These optimized conditions were applied to diethylphos-
phonyl-substituted allylic acetates 1b-6b. The corresponding
allylic amination products 1c-6c were obtained in good to
excellent yields. In each case, the products appear as single
regioisomers, as determined by 1H NMR analysis. As expected
on the basis of the optimization study presented in Table 1,
high reaction temperatures were required for complete conver-
sion because of the diminished electrophilicity of the phospho-
nyl-substituted MBH acetates in comparison to those derived
from methyl acrylate and methyl vinyl ketone. Accordingly, for
less reactive substrates 1b and 6b, increased loadings of
triphenylphosphine were required. Exposure of 2c to the reaction
conditions in the presence of phthalimide does not result in
exchange with 4,5-dichlorophthalimide. Hence, it would appear
that regiochemistry is kinetically controlled (Table 2).
(7) For oxaphospholenes and related structures, see: (a) Ramirez, F.;
Madan, O. P.; Heller, S. R. J. Am. Chem. Soc. 1965, 87, 731. (b) Gorenstein,
D. G.; Westheimer, F. H. J. Am. Chem. Soc. 1967, 89, 2762. (c) Aksnes,
G.; Frøyen, P. Acta Chem. Scand. 1968, 22, 2347. (d) Gorenstein, D. G.;
Westheimer, F. H. J. Am. Chem. Soc. 1970, 92, 634. (e) Bentrude, W. G.;
Johnson, W. D.; Kahn, W. A. J. Am. Chem. Soc. 1972, 94, 923. (f) Arbuzov,
B. A.; Zoroastrova, V. M.; Tudrii, G. A.; Fuzenkova, A. V. Bull. Acad.
Sci. USSR DiV. Chem. Sci. 1973, 22, 2513. (g) Evans, D. A.; Hurst, K. M.;
Takacs, J. M. J. Am. Chem. Soc. 1978, 100, 3467. (h) Thalji, R. K.; Roush,
W. R. J. Am. Chem. Soc. 2005, 127, 16778.
(8) For an alternative approach to R-methylene â-amino phosphonic ester
derivatives, see: (a) Loreto, M. A.; Pompili, C.; Tardella, P. A. Tetrahedron
2001, 57, 4423. (b) Francavilla, M.; Gasperi, T.; Loreto, M. A.; Tardella,
P. A.; Bassetti, M. Tetrahedron Lett. 2002, 43, 7913.
(9) For a recent review, see: Palacios, F.; Alonso, C.; de los Santos, J.
M. Chem. ReV. 2005, 105, 899.
(10) For specific references of â-aminophosphonic acid analogues as
bioisosteres of biologically interesting natural products, see: (a) Tao, M.;
Bihovsky, R.; Wells, G. J.; Mallamo, J. P. J. Med. Chem. 1998, 41, 3912.
(b) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free, C. A.; Rogers, W.
L.; Smith, S. A.; DeForrest, J. M.; Oehl, R. S.; Petrillo, Jr., E. W. J. Med.
Chem. 1995, 38, 4557. (c) Zygmunt, J.; Gancarz, R.; Lejczak, B.; Wieczorek,
P.; Kafarski, P. Bioorg. Med. Chem. Lett. 1996, 6, 2989. (d) Wester, R. T.;
Chambers, R. J.; Green, M. D.; Murphy, W. R. Bioorg. Med. Chem. Lett.
1994, 4, 2005.
(11) Amri, H.; El Gaied, M. M.; Villieras, J. Synth. Commun. 1990, 20,
659.
(12) Nagaoka, Y.; Tomioka, K. J. Org. Chem. 1998, 63, 6428.
In summary, we report a concise synthetic approach to
N-protected â-aminophosphonates 1c-6c via phosphine-
J. Org. Chem, Vol. 71, No. 20, 2006 7893

SCHEME 2. Preparation of Substrates 1b-6b for Phosphine Catalyzed Allylic Substitution
TABLE 2. Phosphine Catalyzed Allylic Substitution of
including enantioselective variants of the present transformation
and application of this methodology toward the synthesis of
molecules of biological and medicinal interest that incorporate
the â-aminophosphonate substructures.
Phosphonyl-Substituted Morita-Baylis-Hillman Acetates 1b-6ba
Experimental Section
General Procedure for Preparation of Acetates 1b-6b. To
an acetonitrile solution (0.2 M) of alcohol 1a (1 mmol, 100 mol
%) at ambient temperature was added acetic anhydride (1.2 mmol,
120 mol %) followed by ferric chloride (0.05 mmol, 5 mol %).
The reaction vessel was allowed to stir for 30 min, at which point
saturated aqueous NaHCO3 solution was added until bubbling
ceased. The reaction mixture was partitioned between diethyl ether
and water. The aqueous layer was extracted with diethyl ether, and
the combined ethereal extracts were dried (MgSO4), filtered, and
evaporated onto silica gel. Purification by silica gel column
chromatography provides allylic acetate 1b.
General Procedure for Preparation of 4,5-Dichlorophthal-
imides 1c-6c. To a reaction vessel charged with acetate 1b (0.5
mmol, 100 mol %), 4,5-dichlorophthalimide (1.0 mmol, 200 mol
%), and PPh3 (0.1 mmol, 20 mol %) was added a dioxane (0.3 M).
The reaction vessel was placed in a heating bath at 110 °C and
was allowed to stir until complete consumption of 1b was observed
by TLC analysis, at which point the reaction mixture was evaporated
onto silica gel. Purification by silica gel column chromatography
provides phthalimide 1c.
a Cited yields are of isolated material. In all cases, >95:5 regioselection
is observed. See Experimental Section for a general procedure. b 40 mol %
loadings of PPh3 were used. c 20 mol % loadings of PPh3 were used.
Acknowledgment. The authors thank the Robert A. Welch
Foundation (F-1466) and the Herman Frasch Foundation (535-
HF02) for partial support of this research.
catalyzed allylic substitution of 2-(diethylphosphonyl)-substi-
tuted allylic acetates 1b-6b, employing 4,5-dichlorophthalimide
as a nucleophilic partner. Unlike the vast majority of metal-
catalyzed allylic substitutions,1 the phosphine-catalyzed trans-
formations exhibit exceptionally high levels of regiospecificity
by virtue of a tandem SN2′-SN2′ substitution mechanism. Future
studies will focus on the development of related transformations,
Supporting Information Available: Experimental details and
spectral data for all new compounds (1H NMR, 13C NMR, IR,
HRMS). This material is available free of charge via the Internet
at http://pubs.acs.org.
JO061218S
7894 J. Org. Chem., Vol. 71, No. 20, 2006