Catalytic Enantioselective Hetero Diels-Alder Reactions of α,β-Unsaturated Acyl Phosphonates with Enol Esters

Full text of DOI:10.1021/ja980423p

J. Am. Chem. Soc. 1998, 120, 4895-4896
4895
Table 1. Cycloaddition of Acyl Phosphonates 3a-d and Enol
Ethers Catalyzed by 1 and 2 (eqs 2 and 3)
Catalytic Enantioselective Hetero Diels-Alder
Reactions of r,â-Unsaturated Acyl Phosphonates
with Enol Ethers
David A. Evans* and Jeffrey S. Johnson
Department of Chemistry and Chemical Biology
HarVard UniVersity
Cambridge, Massachusetts 02138
ReceiVed February 6, 1998
Previous reports from this laboratory have documented the
utility of cationic C2-symmetric Cu(II)bis(oxazoline)1 complexes
1 and 2 as chiral Lewis acids capable of catalyzing a number of
Diels-Alder2 and aldol3 reactions with high enantioselectivities.
In these processes, the unifying organizational motif is that the
substrate undergoing activation is capable of chelating to the chiral
cationic Cu(II) catalyst, a condition that frequently affords high
enantioselection.4 The purpose of this paper is to present our
findings that R,â-unsaturated acyl phosphonates undergo enan-
tioselective hetero Diels-Alder reactions5 with enol ethers
catalyzed by chiral Cu(II) complexes 1 and 2 to afford cyclic
enol phosphonates (eq 1), chemical entities that are shown to be
useful building blocks for asymmetric synthesis.
enol
product
yield
(%)c
ee
entry
R
ethera
catalyst
(endo/exo)b
(%)b
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Ph
4
4
4
4
6
8
8
4
6
4
6
6
1a
1b
2a
2b
1a
1b
1b
2b
2a
2b
1b
1b
5a (99:1)
5a (69:1)
89
84
85
100
91
55
100
98
100
99
79
98
99
93
94
93
95
92
89
98
93
96
90
97
5a (>99:1)
5a (>99:1)
7a (>99:1)
9a (98:2)
9a (93:7)d
5b (167:1)
7b (171:1)
5c (146:1)
7c (98:2)
Ph
10
11
12
i-Pr
i-Pr
OEt
7d (>99:1)
a Reaction conducted with 3 equiv of enol ether relative to 3.
b Determined by capillary GLC or chiral HPLC (see the Supporting
Information). c Isolated yield. d Reaction run at -40 °C.
complex (1a) (10 mol % catalyst, CH2Cl2, 48 h, -78 °C) afforded
cycloadduct 5a in 89% yield with exceptional stereoselectivity
(entry 1; endo/exo ) 99:1, 99% ee). In contrast to previous
studies,2b reaction with [Cu((S,S)-tert-Bu-box)](SbF6)2 complex
(1b) afforded cycloadduct 5a (84%) in moderately lower dias-
tereo- and enantioselectivities (entry 2), although the expected
rate acceleration was observed (48 h for 1a vs 22 h for 1b).9
Interestingly, [Cu((R,R)-Ph-box)](X)2 complexes 2, possessing the
opposite stereochemistry of 1, afforded the same antipode of 5a,
again in high stereoselectivity and yield (entries 3 and 4).10,11 It
is of some practical import that the cycloaddition between 3a
The selection of acyl phosphonates for this study was made
on the premise that favorable acyl phosphonate-catalyst associa-
tion might be achieved via complexation between the vicinal CdO
and PdO functional groups. Indeed, it was found that complexes
1 and 2 activate acyl phosphonates 3a-d to the extent that they
undergo facile cycloaddition reactions with electron-rich alkenes
(Table 1).6-8 The reaction of ethyl vinyl ether (4) with crotonyl
phosphonate 3a in the presence of [Cu((S,S)-tert-Bu-box)](OTf)2
(7) Hetero Diels-Alder reactions of R,â-unsaturated carbonyls with enol
ethers: (a) McRae, K. J.; Rizzacasa, M. A. J. Org. Chem. 1997, 62, 1196-
1197. (b) Dondoni, A.; Kniezo, L.; Martinkova, M.; Imrich, J. Chem. Eur. J.
1997, 3, 424-430. (c) Wada, E.; Pei, W.; Yasuoka, H.; Chin, U.; Kanemasa,
S. Tetrahedron 1996, 52, 1205-1220 and references therein. (d) Tietze, L.
F.; Schneider, C.; Grote, A. Chem. Eur. J. 1996, 2, 139-148 and references
therein. (e) Gaudenzi, L. D.; Apparao, S.; Schmidt, R. R. Tetrahedron 1990,
46, 277-290 and references therein. (f) Boger, D. L.; Robarge, K. D. J. Org.
Chem. 1988, 53, 5796-5798. (g) Boger, D. L.; Robarge, K. D. J. Org. Chem.
1988, 53, 3373-3377.
(8) For general references on the hetero Diels-Alder reaction, see: (a)
Boger, D. L. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 451-512. (b) Boger, D. L.;
Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis;
Academic Press: San Diego, CA, 1987.
(9) Representative procedure for catalyzed cycloadditions: To a 0.02 M
solution of 0.1 equiv of [Cu((S,S)-tert-Bu-box)](SbF6)2 in CH2Cl2 at -78 °C
was added sequentially acyl phosphonate 2 (1.0 equiv) and enol ether (3.0
equiv). After the reaction was complete, the reaction mixture was partitioned
between 20 mL of EtOAc and 10 mL of 2:1 (v/v) 3 M NH4OH/saturated
aqueous NaCl. After extraction, the combined organic extracts were dried
(MgSO4), filtered, and concentrated in Vacuo. A small aliquot was analyzed
by capillary GC and chiral HPLC to determine the de and ee, respectively, of
the cycloaddition. Flash chromatography on silica gel afforded the pure
cycloadducts.
(1) The bis(oxazoline) ligands will be abbreviated as box in the following
discussion. Syntheses of the (S,S)-tert-butyl-box and (S,S)-phenyl-box ligands
are included in the Supporting Information. For catalyst preparation, see ref
2d, footnote 6, or the Supporting Information.
(2) (a) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc. 1993,
115, 6460-6461. (b) Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R.
D.; Miller, S. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 798-800. (c) Evans,
D. A.; Kozlowski, M. C.; Tedrow, J. S. Tetrahedron Lett. 1996, 37, 7481-
7484. (d) Evans, D. A.; Barnes, D. M. Tetrahedron Lett. 1997, 38, 57-58.
(e) Evans, D. A.; Johnson, J. S. J. Org. Chem. 1997, 62, 786-787. (f) Evans,
D. A.; Shaughnessy, E. A.; Barnes, D. M. Tetrahedron Lett. 1997, 38, 3193-
3194.
(3) (a) Evans, D. A.; Murry, J. A. J. Am. Chem. Soc. 1996, 118, 5814-
5815. (b) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W.
C. J. Am. Chem. Soc. 1997, 119, 7893-7894.
(4) Those substrates that appear to effectively chelate with these Lewis
acids are R,â-unsaturated imide dienophiles in Diels-Alder reactions (ref 2)
and R-alkoxy aldehydes, R-diketones, and glyoxylate and pyruvate esters in
aldol reactions (ref 3).
(10) In practice, [Cu((S,S)-Ph-box)](X)2 (ent-2a, X ) OTf; ent-2b, X )
SbF6) were used to afford cycloadducts ent-5, ent-7, and ent-9. For the sake
of clarity, we have chosen to show the (S,S)-tert-Bu ligand and the (R,R)-Ph
ligand affording the same products. The source of this divergent stereochemical
outcome is not apparent at this time and is the subject of continuing
investigation.
(5) Formal hetero Diels-Alder reactions between electron-rich dienes and
pyruvate have recently been reported with these complexes: Johannsen, M.;
Jørgensen, K. A. J. Chem. Soc., Chem. Commun. 1997, 2169-2170.
(6) Cycloadditions of an R,â-unsaturated acyl phosphonate with alkylidene
dithianes have been reported: Schuster, T.; Evans, S. A., Jr. Phosphorous,
Sulfur, Silicon 1995, 103, 259-271.
(11) Cu[(S,S)-Bn-box)](SbF6)2 afforded ent-5a in 58% ee (98:2 endo/exo);
Cu[(S,S)-i-Pr-box)](SbF6)2 afforded ent-5a in 39% ee (97:3 endo/exo).
S0002-7863(98)00423-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/29/1998

4896 J. Am. Chem. Soc., Vol. 120, No. 19, 1998
Communications to the Editor
and ethyl vinyl ether could be conducted with as little as 0.2 mol
% of catalyst 2b with minimal drop in yield and no loss of
stereoselectivity (93% yield, endo/exo > 99:1, 93% ee). Con-
sistent with previous observations,2c,3b complexes 1 and 2 may
be employed as effective catalysts over a broad range of
temperatures as evidenced by an enantioselectivity/temperature
profile (eq 1, 1a, -78 °C, endo/exo ) 99:1, 99% ee; -20 °C,
endo/exo ) 97:3, 94% ee; 25 °C, endo/exo ) 95:5, 89% ee).12
Scheme 1a
Cyclic enol ethers also undergo stereoselective reactions with
acyl phosphonate 3a.13 Specifically, 2,3-dihydrofuran (6) reacted
with 3a in the presence of [Cu((S,S)-tert-Bu-box)](OTf)2 complex
(1a) to deliver bicyclic enol phosphonate 7a (entry 5), while the
reaction of 2,3-dihydropyran (8) and 3a afforded adduct 9a (entry
6), both in good diastereo- and enantioselectivities. The hetero
Diels-Alder reaction was general with respect to the â-substituent
on the unsaturated acyl phosphonate (entries 8-12). Of particular
merit is the fact that phenyl (entries 8 and 9), isopropyl (entries
10 and 11), and alkoxy (entry 12) substituents may all be tolerated
with no loss in selectivity for the derived cycloadducts.14
Cycloadduct 5b has been produced on multigram scale using 2.5
mol % of catalyst 2b, indicating the preparative utility of the
reaction.
a Key: (a) 10 mol % OsO4, N-methylmorpholine N-oxide, t-BuOH/
H2O (10:1); (b) HCl(g)/MeOH, reflux; (c) pyridinium p-toluenesulfonate
(cat.), 4:1 acetone/H2O, reflux; (d) 5 mol % Sm(OTf)3, MeOH, reflux.
single diastereomer in 95% ee, indicating that both cycloaddition
processes are highly stereoselective.
The electron-withdrawing capability of the phosphonate group
manifests itself when acyl phosphonates 3 undergo reaction with
dienes. Specifically, when acyl phosphonate 3a was treated with
cyclopentadiene in the presence of complex 1b, two products were
obtained in quantitative yield (10/11 ) 35:65, eq 4). The expected
The sense of asymmetric induction observed for all reported
reactions catalyzed by the [Cu((S,S)-tert-Bu-box)](X)2 complexes
(1) is consistent with the intervention of catalyst-acyl phospho-
nate complex 12 in direct analogy to the related Diels-Alder
imide-derived catalyst-dienophile complex 13.2 In contrast, we
have no adequate model that rationalizes the sense of asymmetric
induction for the analogous [Cu((S,S)-Ph-box)](X)2 complexes (2).
The cycloadducts described in this study afford useful chiral
synthons (Scheme 1). Upon treatment of 5 with protic (anhydrous
HCl) or Lewis (Sm(OTf)3) acid in MeOH, solvolysis of the lactol
ethyl ether and decomposition of the intermediate enol phospho-
nate occurred to deliver acetal esters which, after brief treatment
with aqueous acid (PPTS, acetone/H2O), afforded aldehydic esters
in good overall yield. Oxo esters 14a-c are formally conjugate
adducts of aldehyde enolates with â-substituted acrylates, a
process for which no catalytic asymmetric variant exists. Bicyclic
enol phosphonates were also transformed into useful compounds.
Under the influence of catalytic quantities of Sm(OTf)3 in MeOH,
adduct 7a was transformed to lactol methyl ether 15 in 91% yield.
Alkoxy-substituted adduct 7d undergoes a similar Lewis acid
catalyzed solvolysis reaction, but undergoes elimination of EtOH
to afford R,â-unsaturated ester 16, formed exclusively as the E
isomer, in 89% yield. The double bond in the cyclic enol
phosphonate may also be manipulated. Reaction of cycloadduct
5a under standard dihydroxylation conditions (cat. OsO4, NMO,
tert-BuOH/H2O) afforded lactone 17 as a single diastereomer.
In summary, the stereoselective hetero Diels-Alder reaction
between R,â-unsaturated acyl phosphonates and enol ethers
catalyzed by C2-symmetric Cu(II)bis(oxazoline) complexes re-
ported in this study provides access to a range of useful
bifunctional chiral synthons not readily accessible by other current
reaction methodology.
Diels-Alder adduct 10 was obtained as the minor product (endo/
exo ) 87:13, endo ee ) 84%). Surprisingly, the major reaction
product 11 was the result of an inverse electron demand hetero
Diels-Alder reaction in which cyclopentadiene acted as the
dienophile in the cycloaddition process. To our knowledge, this
is the first example of cyclopentadiene behaving as the 2π
component in a hetero [4π + 2π] reaction with an unsaturated
carbonyl compound.15 Enol phosphonate 11 was isolated as a
(12) Complex 2a catalyzed the same reaction and gave the following ee-
temperature profile: -78 °C, > 99:1 endo/exo, 94% ee; -20 °C, >99:1 endo/
exo, 86% ee. At 25 °C, catalyst decomposition and low conversion (<40%)
was observed.
(13) The optimal catalyst is reported for each particular reaction; however,
we have observed that any of the four catalysts (1 or 2) will consistently
catalyze the indicated cycloadditions in >80% ee. See the Supporting
Information.
(14) The absolute configurations of 5a-c, 7a, and 10 were unambiguously
determined either by X-ray crystallography or by correlation with structures
of known configuration as described in the Supporting Information.
(15) For a hetero Diels-Alder reaction between an aryl imine and
cyclopentadiene, see: Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37,
7357-7360.
Acknowledgment. Support has been provided by the NIH, the NSF,
and Merck. J.S.J. acknowledges an NSF Predoctoral Fellowship (1994-
1997) and a Pharmacia & Upjohn Graduate Fellowship (1997). X-ray
analysis was performed by Mr. Kevin R. Campos.
Supporting Information Available: Ligand syntheses, experimental
procedures, spectral data for all compounds, and stereochemical proofs
(16 pages, print/PDF). See any current masthead page for ordering
information and Web access instructions.
JA980423P