Enantioselective claisen rearrangements: Development of a first generation asymmetric acyl-claisen reaction

Full text of DOI:10.1021/ja015612d

J. Am. Chem. Soc. 2001, 123, 2911-2912
Enantioselective Claisen Rearrangements:
2911
Development of a First Generation Asymmetric
Acyl-Claisen Reaction
Tehshik P. Yoon and David W. C. MacMillan*
Department of Chemistry, UniVersity of California
Berkeley, California 94720
DiVision of Chemistry and Chemical Engineering
California Institute of Technology,
Pasadena, California 91125
Table 1. The Effect of Chiral Lewis Acid Structure on the
Enantioselective Acyl-Claisen Rearrangement
ReceiVed January 31, 2001
The development of an enantioselective catalytic Claisen
rearrangement1 remains an important yet elusive goal in chemical
synthesis.2 With this objective in mind, we recently reported the
acyl-Claisen rearrangement, a Lewis acid-catalyzed variant of the
Bellus reaction3 that utilizes acid chlorides and allylic amines in
the stereoselective synthesis of R,â-disubstituted-γ,δ-unsaturated
carbonyls (eq 1).4 In this communication, we demonstrate that
chiral Lewis acid
mol % time
%
%
entry complex
R
X
LA
(h)
yield eea
1
2
3
4
5
6
7
1
-
-
H
Cl
200
200
200
50
100
200
-
24
24
24
24
24
24
24
87
88
65
81
63
80
42
56
83
86
42
81
91
2a
2b
2c
2c
2c
-
Ph
Ph
p-MeOPh Cl
p-MeOPh Cl
p-MeOPh Cl
-
-
a Enantiomeric excess was determined by chiral GLC.
%, -20 °C, 24 h) was most successful in providing the Claisen
adduct (S)-3 in 87% yield and 56% ee (Table 1). Subsequent
optimization of ligand architecture for a series of magnesium
iodide derived complexes demonstrated that the (R,R)-Arbox
framework 2a was effective in affording (S)-3 in 88% yield and
83% ee (entry 2). Significantly, a number of 1,2-bis(oxazolinyl)-
aryl complexes have previously been reported;7 however, we
believe this study represents the first enantioselective transforma-
tion that successfully employs this class of ligand framework.
From an investigation of ligand substituent effects on reaction
efficiency, we determined that complexes that possess chlorine
moieties on the aryl backbone and methoxy substituents on the
phenyl oxazoline provide higher levels of enantiocontrol (entry
6, 91% ee). These substituent effects appear cumulative as
incorporation of only the chlorine moieties renders a less selective
process (cf. entries 3 and 6). It is important to note that
substoichiometric quantities of (R,R)-2c afford lower enantio-
selectivities (entry 4). We tentatively conclude that diminished
stereocontrol in this case arises from a competing nonmetal-
mediated rearrangement pathway. Indeed, control experiments
reveal that Claisen adduct 3 is formed with moderate efficiency
in the absence of Lewis acid (entry 7).8 The superior levels of
enantioselectivity exhibited by complex 2c (200 mol %) to afford
(S)-3 in 91% ee and 80% yield (entry 6) prompted us to select
this Lewis acid for further exploration.
Lewis acid architecture can play an important role in the design
of an enantioselective variant of this new [3,3]-sigmatropic bond
reorganization. Specifically, the Lewis acidic complexes 2 derived
from MgI2 and bis(oxazolinyl)aryl (Arbox) ligands provide a
highly effective asymmetric environment for a broad range of
acyl-Claisen rearrangements that employ chelating substrates. To
our knowledge, these studies collectively represent the first
example of an enantioselective acyl-Claisen reaction.
Our initial efforts toward an enantioselective Claisen process
were focused on the addition-rearrangement of benzyloxyacetyl
chloride with N-allylmorpholine in the presence of a variety of
chiral Lewis acids (eq 2). Given the demonstrated utility of
chelation as an organizational control element in asymmetric
catalysis,5 it was assumed that two-point coordination between
the chiral complex and an R-heteroatom-substituted allyl vinyl-
ammonium would engender a stereoselective process. A prelimi-
nary survey of “privileged ligand”-metal salt combinations6
revealed that the [Mg((R,R)-Ph-pybox)](I)2 complex 1 (200 mol
* Corresponding author. Current address: Division of Chemistry and
Chemical Engineering, California Institute of Technology, Pasadena, CA
91125.
(1) (a) Claisen, B. Chem. Ber. 1912, 45, 3157. For recent reviews on the
Claisen rearrangement, see: (b) Wipf, P. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter
7.2, p 827. (c) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron; Asymmetry
1996, 7, 1847. (d) Kallmerten, J.; Wittman, M. D. Stud. Nat. Prod. Chem.
1989, 3, 233. (e) Moody, C. J. AdV. Hetrocycl. Chem. 1987, 42, 203. (f) Ziegler,
F. E. Chem. ReV. 1988, 88, 1423. (g) Hill, R. K. In Asymmetric Synthesis;
Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, p 503.
(2) Three enantioselective metal-promoted Claisen variants have been
reported. Ireland-Claisen: (a) Corey, E. J.; Lee, D.-H. J. Am. Chem. Soc.
1991, 113, 4026. (b) Kazmaier, U.; Krebs, A. Angew. Chem., Int. Ed. Engl.
1995, 34, 2012. Oxonia-Claisen: (c) Maruoka, K.; Saito, S.; Yamamoto, H.
J. Am. Chem. Soc. 1995, 117, 1165.
The effect of acid chloride structure on enantioselectivity was
next evaluated. From the results summarized in Table 2, it is
evident that the capacity of the acid chloride to participate in metal
chelation is related to the enantiofacial discrimination of the [3,3]-
isomerization event. As expected, poorly chelating substrates such
as acetoxyacetyl and (tert-butyldimethylsilyloxy)acetyl chloride
(6) ComprehensiVe Asymmetric Catalysis; Jacobsen. E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Vols. 1-3.
(7) Bolm, C.; Wieckhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991,
124, 1173.
(8) As reported in our initial acyl-Claisen survey, we have not observed a
nonmetal-mediated process with alkyl-substituted acid chlorides (e.g. propionyl
chloride).4
(3) (a) Malherbe, R.; Bellus, D. HelV. Chim. Acta 1978, 61, 3096. (b)
Malherbe, R.; Rist, G.; Bellus, D. J. Org. Chem. 1983, 48, 860.
(4) Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc.
1999, 121, 9726.
(5) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
10.1021/ja015612d CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/02/2001

2912 J. Am. Chem. Soc., Vol. 123, No. 12, 2001
Communications to the Editor
Table 2. The Effect of Acid Chloride Structure on the
Enantioselective Acyl-Claisen Rearrangement
Experiments that probe the scope of the allyl morpholine
reaction component are summarized in Table 3. Significant
structural variation in the C(3)-allyl substituent is possible to
afford a diverse range of R,â-disubstituted-γ,δ-unsaturated car-
bonyls with excellent levels of diastereo- and enantioselectivity
(entries 4-8, 74-95% yield, 92:8 to 99:1 syn:anti, 86-97% ee).9
Incorporation of alkyl and aryl substituents at the C(2)-olefin
position is also readily tolerated without significant loss in enantio-
selectivity (entry 2, 78% yield, 91% ee; entry 3, 79% yield, 90%
ee). In accord with established Claisen methodology,1b comple-
mentary diastereomers can be accessed in enantioenriched form
by the appropriate selection of double bond geometry on the allyl
component. Thus, while (E)-(3-chloro-2-butenyl)morpholine yields
predominantly the syn Claisen product (entry 7, 95% yield, 98:2
syn:anti, 91% ee), the (Z) isomer affords the corresponding anti
product with similar levels of stereocontrol (entry 8, 74% yield,
3:97 syn:anti, 91% ee). Importantly, formation of the R,â-
unsaturated amide resulting from â-elimination of the chloride
substituent is not observed in either case, illustrating the mild
reaction conditions employed in this asymmetric Claisen process.
Finally, a demonstration of the utility of this new reaction to
provide enantioselective access to elusive acyclic structural motifs
is presented in the addition-rearrangement of 3,3-disubstituted allyl
morpholine 4 (eq 5). The central issue in this reaction is that of
entry
OR
OAc
OTBS
OPhCl-4
OPh
time (h)
% yield
% eea
1
2
3
4
5
6
20
20
20
20
24
24
44
67
59
48
28
80
37
38
71
78
80
91
OMe
OBn
a Enantiomeric excess was determined by chiral GLC or HPLC.
Table 3. Enantioselective Acyl-Claisen Rearrangement with
Representative Allyl Morpholines
Lewis acid controlled asymmetric construction of quaternary
carbon centers on an acyclic framework. As outlined in eq 5,
complex (R,R)-2c effectively translates the methyl-carboethoxy
substitution pattern on allylamine 4 with high levels of enantio-
control and stereospecificity to furnish the quaternary carbon
bearing Claisen adduct (S)-5 in 97% ee and 94:6 syn:anti
selectivity.10
In conclusion, we have developed the first enantioselective acyl-
Claisen rearrangement. Studies toward a catalytic variant of this
reaction are underway and will be reported in due course.
Acknowledgment. This paper is dedicated to Professor David A.
Evans on the occasion of his 60th birthday. T.P.Y. is grateful for an NSF
predoctoral fellowship. Financial support was provided by the NIH (R01
GM61214-01), the UC AIDS Research Program, and kind gifts from
Boehringer-Ingelheim, Dupont, Johnson and Johnson, and Merck.
Supporting Information Available: Experimental procedures and
spectral data for all compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA015612D
(9) In a representative procedure, the allylic morpholine (0.10 mmol, 0.025
M in CH2Cl2) and i-Pr2NEt (0.15 mmol) were added sequentially to a catalyst
solution (0.2 mmol) in CH2Cl2 at 23 °C. The resulting solution was cooled to
-20 °C before benzyloxyacetyl chloride (0.12 mmol, 1.0 M in CH2Cl2) was
added over 12 h. After an additional 12 h, the resulting solution was treated
with 1 N NaOH and extracted into EtOAc. The organics were dried (MgSO4)
and concentrated, and the ligand was precipitated with EtOH. The supernatant
was filtered, concentrated, and then purified by flash chromatography.
(10) Although one of the most common structural motifs found in organic
architecture, quaternary carbon stereogenicity remains a formidable challenge
to asymmetric synthesis. For an excellent review of enantioselective quaternary
carbon construction, see: Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int.
Ed. Engl. 1998, 37, 388.
a NR2 ) N-morpholine. b Ratios determined by chiral GLC or HPLC.
Absolute stereochemistry determined by chemical correlation or by
analogy. c Reaction performed with 200 mol % 2c.
(entries 1 and 2) exhibit only modest levels of stereocontrol
(e38% ee), while optimal levels of asymmetric induction were
obtained with ketene surrogates that contain Lewis basic R-alkoxy
substituents (entry 5, R ) Me, 80% ee; entry 6, R ) Bn, 91%
ee).