Bis(oxazoline) and bis(oxazolinyl)pyridine copper complexes as enantioselective Diels-Alder catalysts: Reaction scope and synthetic applications

Article abstract of DOI:10.1021/ja991191c

The scope of the Diels-Alder reaction catalyzed by bis(oxazoline) copper complexes has been investigated. In particular, [Cu((S,S)-t-Bu-box)](SbF₆)₂ (1b) has been shown to catalyze the Diels-Alder reaction between 3-propenoyl- 2-oxaz

Full text of DOI:10.1021/ja991191c

7582
J. Am. Chem. Soc. 1999, 121, 7582-7594
Bis(oxazoline) and Bis(oxazolinyl)pyridine Copper Complexes as
Enantioselective Diels-Alder Catalysts: Reaction Scope and
Synthetic Applications
David A. Evans,* David M. Barnes, Jeffrey S. Johnson, Thomas Lectka, Peter von Matt,
Scott J. Miller, Jerry A. Murry, Roger D. Norcross, Eileen A. Shaughnessy, and
Kevin R. Campos
Department of Chemistry & Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed April 14, 1999
Abstract: The scope of the Diels-Alder reaction catalyzed by bis(oxazoline) copper complexes has been
investigated. In particular, [Cu((S,S)-t-Bu-box)](SbF6)2 (1b) has been shown to catalyze the Diels-Alder reaction
between 3-propenoyl-2-oxazolidinone (2) and a range of substituted dienes with high enantioselectivity. This
cationic complex has also been employed in the catalysis of analogous intramolecular processes with good
success. The total syntheses of ent-∆1-tetrahydrocannabinol, ent-shikimic acid, and isopulo'upone, featuring
the use of this chiral catalyst in more complex Diels-Alder processes, are described. Similarly, the cationic
copper complex 9a, [Cu((S,S)-t-Bu-pybox)](SbF6)2, is effective in the Diels-Alder reactions of monodentate
acrolein dienophiles while the closely related complex, 9d [Cu((S,S)-Bn-pybox)](SbF6)2, is the preferred Lewis
acid catalyst for acrylate dienophiles in reactions with cyclopentadiene.
Introduction
Remarkable progress has been made in the development of
chiral Lewis acids as catalysts for enantioselective Diels-Alder
reactions.1 A number of systems have been reported that provide
excellent levels of selectivity; however, many of these are
limited in scope, such that only a handful of reacting partners
are accessible. For one to take full advantage of this powerful
transformation, more reactive catalysts are needed which provide
greater flexibility in the nature of the diene, as well as in the
substitution pattern on the dienophile. Previous reports from
this laboratory described the development of copper-based Lewis
acids as catalysts for enantioselective Diels-Alder2 reactions.3,4
These studies have demonstrated that [Cu((S,S)-t-Bu-box)]-
(SbF6)2 (1b) is an excellent catalyst for reactions between
cyclopentadiene and acrylimide 2 and substituted analogues
thereof (R ) Me, Ph, CO2Et),5 affording cycloadducts 3 with
(1) For reviews see: (a) Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92,
1007-1020. (b) Pindur, U.; Lutz, G.; Otto, C. Chem. ReV. 1993, 93, 741-
761. (c) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289-332. (d) Deloux, L.;
Srebnik, M. Chem. ReV. 1993, 93, 763-784. (e) Maruoka, K.; Yamamoto,
H. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York,
1993; pp 413-440. (f) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; John Wiley: New York, 1993; pp 212-217. (g) Oh, T.; Reilly,
M. Org. Prep. Proced. Int. 1994, 26, 129-158. (h) Lautens, M.; Klute,
W.; Tam, W. Chem. ReV. 1996, 96, 49-92.
(2) (a) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc. 1993,
115, 6460-6461. (b) Evans, D. A.; Lectka, T.; Miller, S. J. Tetrahedron
Lett. 1993, 34, 7027-7030. (c) Evans, D. A.; Murry, J. A.; von Matt, P.;
Norcross, R. D.; Miller, S. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 798-
800. (d) Previous paper, this issue.
Figure 1. PM-3-generated [Cu((S,S)-tert-Bu-box)](2+) complex 1b
bound to acrylimide 2 (ref 2d).
(3) For the use of these complexes in Mukaiyama aldol reactions see:
(a) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos,
K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-
685 and references therein. (b) Evans, D. A.; Burgey, C. S.; Kozlowski,
M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686-699 and references
therein.
(4) For the relative effectiveness of chiral Lewis acids derived from Cu-
(II) and Zn(II), see: Evans, D. A.; Kozlowski, M. C.; Tedrow, J. S.
Tetrahedron Lett. 1996, 37, 7481-7484.
enantioselectivities in excess of 94% at ambient temperatures
(eq 1).2 Mechanistic investigations support a scenario of
dienophile activation via bidentate coordination to a distorted
square planar copper center, a model that is consistent with the
absolute stereochemical outcome of all reactions investigated
to date (Figure 1). X-ray and computational structures of relevant
complexes have corroborated this model.6
10.1021/ja991191c CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/06/1999

Bis(oxazoline) and Bis(oxazolinyl)pyridine
J. Am. Chem. Soc., Vol. 121, No. 33, 1999 7583
Scheme 1
Among the systematically developed chiral Lewis acid
complexes, only the [Ti(TADDOL)]Cl2 catalysts have been
regularly employed in reactions of imide dienophiles with dienes
other than highly reactive cyclopentadiene derivatives.7 Like-
wise, only these complexes have been used to promote intramo-
lecular Diels-Alder reactions of imides.8 Indeed, despite notable
progress in the development of chiral Lewis acid catalysts, few
are sufficiently activating to promote the Diels-Alder reactions
either of more heavily substituted acyclic dienes9 or of their
intramolecular variants.10
asymmetric syntheses of ent-∆1-tetrahydrocannabinol (4), ent-
shikimic acid (5), and (-)-isopulo'upone (6).11 In the second
part of this study, the cationic Cu(II) complexes 8 and 9, derived
from the readily accessible bis(oxazolinyl)pyridyl (pybox) ligand
family 7,12 are evaluated as chiral catalysts for Diels-Alder
reactions with acrolein, methacrolein, bromoacrolein, and acry-
late ester dienophiles that are activated by single-point catalyst
coordination (eqs 2, 3).2c The results of this and other studies
indicate that these complexes are effective catalysts not only
for the Diels-Alder reaction but also for other processes.13
In the present investigation, the scope and synthetic utility
of [Cu((S,S)-t-Bu-box)](SbF6)2 (1b) in the catalysis of both intra-
and intermolecular imide-based Diels-Alder reactions are
described (Scheme 1).2a,2d,4 Included in this study are the
(5) Several other catalysts have also been reported to provide good to
excellent enantioselectivities in the reactions of cyclopentadiene with 2 and
with â-substituted acrylimides (R * H). Al: (a) Corey, E. J.; Imwinkelried,
R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc. 1989, 111, 5493-5495. Yb,
Sc: (b) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Tetrahedron
Lett. 1993, 34, 4535-4538. (c) Kobayashi, S.; Ishitani, H. J. Am. Chem.
Soc. 1994, 116, 4083-4084. (d) Kobayashi, S.; Ishitani, H.; Hachiya, I.;
Araki, M. Tetrahedron 1994, 50, 11623-11636. (e) Nishida, A.; Yamanaka,
M.; Nakagawa, M. Tetrahedron Lett. 1999, 40, 1555-1558. Zr: (f) Jaquith,
J. B.; Levy, C. J.; Bondar, G. V.; Wang, S. T.; Collins, S. Organometallics
1998, 17, 914-925 and references therein. Cu: (g) Ghosh, A. K.; Cho,
H.; Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 3687-3691 and
references therein. (h) Sagasser, I.; Helmchen, G. Tetrahedron Lett. 1998,
39, 261-264. Ni: (i) Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi, S.;
Yamamoto, H.; Tanaka, J.; Wada, E.; Curran, D. P. J. Am. Chem. Soc.
1998, 120, 3074-3088 and references therein. Zn: (j) Takacs, J. M.;
Quincy, D. A.; Shay, W.; Jones, B. E.; Ross, C. R. Tetrahedron: Asymmetry
1997, 8, 3079-3087 and references therein.
Results and Discussion
[Cu((S,S)-t-Bu-box)](SbF6)2-Catalyzed Cycloadditions. (A)
Catalyst Preparation. Solutions of the triflate complex [Cu-
((S,S)-t-Bu-box)](OTf)2 (1a) were prepared by stirring (S,S)-
tert-butyl-bis(oxazoline) (10)14 with Cu(OTf)2 in CH2Cl2 at room
temperature for 2-4 h (eq 4). In early work,2c,2d the analogous
hexafluoroantimonate catalyst [Cu((S,S)-t-Bu-box)](SbF6)2 (1b)
was prepared by vigorously stirring the ligand 10, CuCl2, and
(6) (a) ref 3b. (b) Evans, D. A.; Olhava, E. J.; Johnson, J. S.; Janey, J.
M. Angew. Chem., Int. Ed. Engl. 1998, 37, 3372-3375.
(7) (a) Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima,
M.; Sugimori, J. J. Am. Chem. Soc. 1989, 111, 5340-5345, and references
therein. (b) Corey, E. J.; Matsumura, Y. Tetrahedron Lett. 1991, 32, 6289-
6292. (c) Narasaka, K.; Tanaka, H.; Kanai, F. Bull. Chem. Soc. Jpn. 1991,
64, 387-391. (c) Narasaka, K.; Yamamoto, I. Tetrahedron 1992, 48, 5743-
5754. (d) Yamamoto, I.; Narasaka, K. Bull. Chem. Soc. Jpn. 1994, 67,
3327-3333. (e) Yamamoto, I.; Narasaka, K. Chem. Lett. 1995, 1129-1130.
(f) Tietze, L. F.; Ott, C.; Frey, U. Liebigs Ann. Chem. 1996, 63-67.
(8) (a) Iwasawa, N.; Sugimori, J.; Kawase, Y.; Narasaka, K. Chem. Lett.
1989, 1947-1950. (b) Narasaka, K.; Saitou, M.; Iwasawa, N. Tetrahe-
dron: Asymmetry 1991, 2, 1305-1318.
(9) For recent examples, see: (a) Hayashi, Y.; Rohde, J. J.; Corey, E. J.
J. Am. Chem. Soc. 1996, 118, 5502-5503. (b) Bruin, M. E.; Kundig, E. P.
Chem. Commun. 1998, 2635-2636. (c) Mikami, K.; Motoyama, Y.; Terada,
M. J. Am. Chem. Soc. 1994, 116, 2812-2820. (d) Yamamoto, H.; Ishihara,
K. J. Am. Chem. Soc. 1994, 116, 1561-1562. (e) Ishihara, K.; Kurihara,
H.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049-3050. (f) Reference
5g. (g) Ishihara, K.; Gao, Q. Z.; Yamamoto, H. J. Org. Chem. 1993, 58,
6917-6919 and references therein. (h) Corey, E. J.; Guzman-Perez, A.;
Loh, T. P. J. Am. Chem. Soc. 1994, 116, 3611-3612 and references therein.
(10) (a) References 8 and 9e. (b) Furuta, K.; Kanematsu, A.; Yamamoto,
H. Tetrahedron Lett. 1989, 30, 7231-7232.
(11) A portion of this work has been communicated. (a) Reference 2c.
(b) Evans, D. A.; Barnes, D. M. Tetrahedron Lett. 1997, 38, 57-58. (c)
Evans, D. A.; Johnson, J. S. J. Org. Chem. 1997, 62, 786-787. (d) Evans,
D. A.; Shaughnessy, E. A.; Barnes, D. M. Tetrahedron Lett. 1997, 38,
3193-3194.
(12) (a) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.; Itoh, K. J.
Am. Chem. Soc. 1994, 116, 2223-2224 and references therein. (b)
Nishiyama, H.; Kondo, M.; Nakamura, T.; Itoh, K. Organometallics 1991,
10, 500-508. The experimental procedure for the synthesis of the pybox
ligand may be found in this paper.
(13) For the application of these complexes to the catalysis of the aldol
reaction, see ref 3.
(14) For the synthesis of (S,S)-tert-butyl bis(oxazoline) (10), see Evans,
D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos, K. R.;
Woerpel, K. A. J. Org. Chem. 1998, 63, 4541-4544.

7584 J. Am. Chem. Soc., Vol. 121, No. 33, 1999
EVans et al.
Table 1. Reaction of 2 with Cyclohexadiene Catalyzed by 1
AgSbF6 together in CH2Cl2 for 8-16 h; the AgCl precipitate
was removed by filtration through Celite to provide the active
catalyst solution. While catalyst solutions thus generated
provided high enantioselectivities, for operational convenience
an alternative and more reliable catalyst preparation has been
developed. Equimolar amounts of the bis(oxazoline) 10 and the
insoluble brown anhydrous CuCl2 were stirred in CH2Cl2 over
a period of 3 h, during which time a green solution of [Cu-
((S,S)-t-Bu-box)]Cl2 complex 11 was formed. This complex may
be isolated as its CH2Cl2 solvate in 99% yield after filtration
and concentration.15 This green powder can be stored indefinitely
at room temperature without decomposition. The active catalyst
solution was obtained by treating 11 with 2 equiv of AgSbF6
in CH2Cl2 for 3-4 h to afford [Cu((S,S)-t-Bu-box)](SbF6)2 (1b)
(eq 5). Filtration of the catalyst solution through Celite was
performed in the atmosphere. This catalyst preparation proved
to be operationally convenient and reproducible.
(eq 6)a
mol
%
endo/ endo
exob eec
catalyst
1a (X ) OTf)
temp (time)
yieldd
10
25 °C (40 h) 98:2 82% ee 90%
25 °C (5 h) 95:5 93% ee 90% (97%)
1b (X ) SbF6) 10 -10 °C (46 h) 96:4 95% ee 49%
1b (X ) SbF6) 10
1b (X ) SbF6)
1b (X ) SbF6)
1b (X ) SbF6)
5
2
1
25 °C (40 h) 95:5 89% ee (95%)
25 °C (40 h) 95:5 80% ee (78%)
25 °C (40 h) 95:5 74% ee (65%)
a Reactions run in CH2Cl2 with 10 equiv of diene. b Diastereomer
ratios determined by 1H NMR. c Enantiomer ratios determined by chiral
HPLC on the derived R-methylbenzyl amide. Major product absolute
stereochemistry assumed in analogy to 3. d Values refer to isolated
yields of cycloadducts. Numbers in parentheses refer to percent
conversion (GLC).
enantioselectivities of 80% and 74% ee, respectively (entries 5
and 6). The competing uncatalyzed thermal Diels-Alder
reaction between imide 2 and cyclohexadiene at 25 °C afforded
1% conversion to adduct 12 after 5 h and 7% conversion after
40 h, indicating that the erosion in enantioselectivity observed
with a lower catalyst concentration is not solely due to the
background reaction.
Complexes 1a (X ) OTf) and 1b (X ) SbF6) were also found
to catalyze cycloadditions between imide 2 and representative
acyclic dienes (Table 2). As in the case of cyclohexadiene, the
SbF6 catalyst generally provided higher selectivities and sig-
nificantly shorter reaction times than the triflate derivative. When
1a (X ) OTf) was employed, the reaction of piperylene with
imide 2 yielded a mixture of all eight possible stereo- and
regioisomers. The major cis regioisomer 13, accounting for 75%
of the product mixture, was formed in 86% ee (Table 2, entry
1). Recrystallization of the product mixture provided enantio-
merically pure material. When the reaction was repeated with
catalyst 1b (X ) SbF6), cycloadduct 13 was formed in 94% ee
and accounted for 83% of the product mixture (entry 2).
Similarly, trans,trans-2,4-hexadiene underwent a highly enan-
tioselective Diels-Alder reaction with imide 2 at room tem-
perature. Catalyst 1a (X ) OTf) afforded product 14 as a 78:
22 mixture of cis and trans isomers, and the cis product was
formed in 84% ee (entry 3). Catalyst 1b (X ) SbF6) provided
almost the same diastereoselectivity, while the reaction enan-
tioselectivity rose to 93% (entry 4).
The reaction between acrylimide 2 and 1-phenylbutadiene
was also investigated.18 When 10 mol % of catalyst 1a (X )
OTf) was employed at room temperature, the product was
isolated in 89% yield as a 2:1 mixture of cis and trans
cycloadducts with the cis isomer 15 being formed in 84% ee
(entry 5). When catalyst 1b (X ) SbF6) was employed at room
temperature, the metal center was reduced by the diene, resulting
in precipitation of metallic copper. However, when the reaction
was carried out at -20 °C, catalyst reduction was avoided,
permitting isolation of the product in 95% yield as a 85:15
mixture of cis/trans isomers, with the cis product formed in 97%
ee (entry 6). The reduction of catalyst 1b by 1-phenylbutadiene
at room temperature highlights the effect of the SbF6 counterions
(B) Alkyl-Substituted Dienes. With the high catalytic activity
of bis(oxazoline) copper complexes 1a and 1b established in
the Diels-Alder reactions of cyclopentadiene, attention was
directed to less reactive dienes, such as cyclohexadiene (Table
1, eq 6). Not unexpectedly, this reaction also exhibited a
significant counterion effect.16 While 10 mol % of triflate
catalyst 1a required 40 h to promote the reaction to complete
conversion at room temperature (82% ee, entry 1), the SbF6
complex 1b displayed substantially greater catalytic potency and
selectivity, requiring only 5 h at the same temperature (93%
ee, entry 2) for complete conversion.17 The observation that 1a
(X ) OTf) afforded higher diastereoselectivity (endo/exo ) 98:
2) was consistent with earlier observations, although the decrease
in diastereoselectivity with SbF6 catalyst 1b (endo/exo ) 95:5)
was not as pronounced as in the corresponding reaction of
cyclopentadiene (1a, endo 3/exo 3 ) 98:2; 1b, endo 3/exo 3 )
91:9).2c The temperature dependence of the SbF6 catalyst 1b
(25 °C, 93% ee; -10 °C, 95% ee) is low, and the decrease in
reaction rates at the lower temperatures is usually the determin-
ing issue in the selection of a given reaction temperature.
The enantioselectivity of the reaction between imide 2 and
cyclohexadiene erodes significantly when the catalyst loading
is lowered (Table 1, eq 6). In this respect, the cycloaddition
with cyclohexadiene was not as tolerant as the corresponding
reaction with cyclopentadiene.2c With 5 mol % of catalyst 1b
(X ) SbF6), adduct 12 was formed in 89% ee after 40 h at 25
°C (95% conv.; entry 4). Further reduction of catalyst to 2 and
1 mol % resulted in yet lower conversion and diminished
(15) The X-ray structure of [Cu((S,S)-tert-Bu-box)]Cl2‚CH2Cl2 has been
solved. See ref 2d.
(16) A counterion study was performed as in the previous paper (ref
2d). As observed in that study, the order of reactivity of the counterions
was SbF6 > PF6 > BF4 > OTf.
(17) The corresponding reactions with cyclopentadiene required 10 h
(catalyst 1a) and <4 h (catalyst 1b) at -78 °C. Reference 2c.
(18) Grummitt, O.; Becker, E. I. Organic Syntheses, CollectiVe Volume
IV; Rabjohn, N., Ed.; Wiley: New York, 1963; pp 771-775.

Bis(oxazoline) and Bis(oxazolinyl)pyridine
J. Am. Chem. Soc., Vol. 121, No. 33, 1999 7585
Table 2. Diels-Alder Reactions of Imide 2 with Various Dienes Catalyzed by [Cu((S,S)-tert-Bu-box)]X2 (1)a
a Reactions run in CH2Cl2 with 10 mol % catalyst and 10 equiv of diene. b Diastereomer ratios determined by 1H NMR, or chiral GLC or HPLC.
c Enantiomer ratios determined by chiral GLC or chiral HPLC on the primary adduct or on the corresponding R-methylbenzyl amides or ethylthioesters.
See Experimental for details. d Values refer to isolated yields of cycloadducts. e Ratio refers to major cis: ∑ other isomers. f Major product absolute
stereochemistry assumed in analogy to cycloadducts 15 and 16. g Absolute stereochemistry assigned by independent synthesis. See text for details.
h Values refer to (1,4):(1,3) regioisomer ratio. i Major product stereochemistry proved by correlation to the benzyl ester derived from the cycloadduct
obtained from the Al-mediated reaction of a chiral dienophile. Reference 20.
in raising the Lewis acidity and, therefore, the reduction potential
of this catalyst.19 Fortunately, temperature control may be
effectively employed to contain this side reaction.
performed at an imide concentration of 0.2-0.3 M, it was found
that concentrations as high as 0.5 M afforded equivalent
results.21 Under these conditions, only 2 mol % catalyst was
required to promote the reaction to complete conversion in 13
h. Scale-up proceeded without incident; a 50 mmol scale reaction
yielded enantiomerically and diastereomerically pure cis cy-
cloadduct 15 in 80% yield after recrystallization (eq 7).
A decrease in enantioselectivity was noted with those dienes
which are not substituted at the 1-position. Both isoprene and
2,3-dimethylbutadiene exhibited good reactivity, yet in each case
the enantiomeric excess of the major cycloadduct was lower
than those observed for other dienes. The isoprene-derived 1,4-
regioisomer 16 was isolated in up to 64% ee (1,4:1,3 selectivity
g 96:4, entries 7 and 8), and the 2,3-dimethylbutadiene-derived
cycloadduct 17 was obtained in up to 65% ee (entries 9 and
10). The absolute stereochemistry of cycloadduct 16 was
determined by conversion to the known benzyl ester.20
The reason for the attenuated enantioselectivity in reactions
of isoprene and 2,3-dimethylbutadiene is unclear; however, we
postulate that steric interactions between the substituent methyl
groups and the catalyst lead to reaction largely via an exo
transition state. Supporting this hypothesis, we have found that
the catalyzed reaction of 1-acetoxybutadiene is endo-selective
(85:15) while that of 1-acetoxy-3-methylbutadiene favors the
exo product (73:27, vide infra). Furthermore, 1-vinylcyclohexene
provides a 1:1 mixture of endo and exo products (enantiose-
lectivities not determined). If the exo approach of dienes
unsubstituted at the 1-position is relatively nonselective, this
would explain the low enantioselectivities in entries 7-10. A
more detailed discussion of the effect of diene substituents on
reaction diastereoselectivity and enantioselectivity will be
presented later (vide infra).
To assay the selectivity of this reaction, we converted the
initially formed imide cycloadduct mixtures to the S-ethyl
thioesters by treatment with LiSEt (0 °C, THF).22 Enantiomer
and diastereomer ratios were then determined by chiral HPLC
analysis. During the course of this study, it was found that
prolonged exposure of the cis thioester 18 to LiSEt resulted in
equilibration to the derived trans isomer. Thus, cis imide 15
could be cleaved under either kinetic conditions to provide cis
thioester 18 (98:2, eq 8) or thermodynamic conditions to provide
the trans isomer 19 with excellent selectivity (95:5, eq 9). The
absolute stereochemical assignment of the 1-phenylbutadiene
cycloadduct was established by independent synthesis of cis
thioester 18 (eq 10). Lewis acid-mediated reaction of chiral
acrylate imide 2020 and 1-phenylbutadiene delivered crystalline
adduct 21 (mp >180 °C), whose relative stereochemistry was
established by X-ray analysis. Thiolate cleavage (LiSEt, THF,
The reaction of 1-phenylbutadiene with imide 2 was chosen
for further optimization. Whereas the above reactions were
(19) 1-(Tri-n-butylstannyl)butadiene (Go´mez, A. M.; Lo´pez, J. C.;
Frasier-Reid, B. Synthesis 1993, 943-944.) was subjected to the copper
catalyzed Diels-Alder reaction and was also found to reduce the catalyst
rapidly at -25 °C.
(20) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238-1256.
(21) The imide was insoluble at -20 °C at higher concentrations.
(22) Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1988, 29, 6141-
6144.

7586 J. Am. Chem. Soc., Vol. 121, No. 33, 1999
EVans et al.
0 °C, 2 h) provided thioester 18, which was identical to material
derived from the catalyzed reactions.
The relative stereochemistry of 22a (X ) OAc) was
determined by conversion to the crystalline ammonium car-
boxylate derivative 24 (eq 12). Treatment of the major isomer
22a with LiOOH25 under carefully monitored conditions (THF,
-5 °C, 15 min) selectively effected imide hydrolysis to provide
acid 23 in 85% yield. Treatment of 23 with dicyclohexylamine
in CH2Cl2 provided crystalline dicyclohexylammonium salt 24,
which was assigned the cis stereochemistry by X-ray analysis.
The reaction of imide 2 with 1-phenylthiobutadiene,26 em-
ploying 2 mol % SbF6 catalyst 1b at -20 °C, afforded
cycloadduct 22b (X ) SPh) with high endo selectivity (Table
3, entry 4, cis/trans ) 98:2; cis ee ) 98%). The cis isomer was
obtained diastereomerically and enantiomerically pure in 84%
yield by recrystallization. An X-ray structure of the product
confirmed both relative and absolute stereochemistry.
1-(Benzyloxycarbonylamino)butadiene27 also underwent reac-
tion with imide 2. In this case, 5 mol % of catalyst 1b was
required; cycloadduct 22c (X ) NHCbz) was obtained as a 72:
28 mixture of cis/trans isomers, from which the cis isomer was
isolated in 54% yield and in 90% ee (Table 3, entry 5). It appears
likely that the Lewis basic carbamate group associates with the
metal center of complex 1b,28 attenuating its Lewis acidity and
requiring the higher catalyst loading. The cis stereochemistry
of cycloadduct 22c (X ) NHCbz) was assigned by X-ray
analysis of racemic product obtained via a thermal reaction.
Synthesis of ent-∆1-Tetrahydrocannabinol (4). On the basis
of the results obtained with 1-acetoxybutadiene, we designed
an asymmetric synthesis of the cannabinols (Scheme 2). In this
(C) Heteroatom-Substituted Dienes. The [Cu((S,S)-t-Bu-
box)](SbF6)2 complex (1b) was then evaluated as a catalyst in
reactions with heteroatom-substituted dienes (eq 11, X ) OAc,
SPh, NHCbz). As with 1-phenylbutadiene, these dienes are
sensitive to oxidation by the catalyst, and to polymerization,
and the indicated reaction temperatures for these substrates
represent the highest temperature that the reactions may be run
without incurring these side reactions.
1-Acetoxybutadiene23 undergoes a clean reaction with acrylim-
ide 2 at 0 °C to yield adduct 22a (X ) OAc) (eq 11, Table
3).24 When run with 5 mol % catalyst, the reaction proceeded
Table 3. The Diels-Alder Reaction of Imide 2 with
1-Heteroatom-Substituted Butadienes (eq 11)a
Scheme 2
mol %
1b
cis/
cis
entry
diene
time (temp)b
transc eec yieldd
1
2
3
4
5
X ) OAc
X ) OAc
X ) OAc
X ) SPh
5% <23 h (0 °C)
85:15 98%e nd
85:15 96%e 75%
85:15 95%e nd
2%
1%
2%
24 h (0 °C)
48 h (0 °C)
24 h (-20 °C) 98:2 98%f 84%
24 h (0 °C)
X ) NHCbz 5%
72:28 90%g 54%
a Reactions were carried out in CH2Cl2 with 5 equiv of diene. b Time
required for complete conversion. c Diastereomer ratios and enantio-
meric excesses were determined by chiral HPLC. d Values refer to
isolated yields of cis adducts. e Ee of the trans isomer was 90%. f Ee
of the trans isomer was 89%. g Ee of the trans isomer was 97%.
to completion in less than 24 h at 0 °C to provide the product
as an 85:15 mixture of cis:trans isomers; the cis isomer was
formed in 98% ee. Reaction with 2 mol % catalyst required 24
h, and the enantioselectivity was only slightly eroded (entry 2).
In fact, the product was formed in 95% ee after 48 h when
employing only 1 mol % of the catalyst (entry 3). The cis adduct
could be isolated from these reaction mixtures in 75% yield by
chromatography. These results are especially significant as the
Me2AlCl-promoted reaction of 1-acetoxybutadiene with chiral
acrylimide 20 failed to provide any cycloadduct.
route, triol 25, the cyclization precursor to ent-∆1-tetrahydro-
cannabinol (4) arises via an acid- or metal-mediated addition
of olivetol (26) to the allylic oxygen functionality present in
cycloadduct 27, in turn derived from the catalyzed Diels-Alder
reaction of acrylimide 2 with 1-acetoxy-3-methylbutadiene.
(25) Evans, D. A.; Ellman, J. A.; Britton, T. C. Tetrahedron Lett. 1987,
28, 6141-6144.
(26) Hopkins, P. B.; Fuchs, P. L. J. Org. Chem. 1978, 43, 1208-1217.
(27) Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J. Org.
Chem. 1978, 43, 2164-2167.
(23) Bailey, W. J.; Barclay, R. J. Org. Chem. 1956, 21, 328-331.
(24) Diels-Alder reactions of 1-acetoxybutadiene with methacrolein and
juglone have been reported. See ref 9c.
(28) Evidence for N-coordination of amides has been reported. See: Cox,
C.; Ferraris, D.; Murthy, N. N.; Lectka, T. J. Am. Chem. Soc. 1996, 118,
5332-5333.

Bis(oxazoline) and Bis(oxazolinyl)pyridine
J. Am. Chem. Soc., Vol. 121, No. 33, 1999 7587
The reaction of 1-acetoxy-3-methylbutadiene29 and imide 2
catalyzed by 1b (2 mol %, CH2Cl2, -20 °C, 18 h) afforded
cycloadduct 28 as a 73:27 mixture of diastereomers from which
the major diastereomer, initially formed in 98% ee, was isolated
enantiomerically pure by direct crystallization (mp 124-5 °C,
eq 13).30 When the reaction was performed on a 50 mmol scale,
28 crystallized from the unpurified reaction mixture, yielding
57% of enantiomerically and diastereomerically pure material.
An X-ray structure of adduct 28 established the anti relative
stereochemistry of the major diastereomer, formed via an exo
transition state. The stereochemical outcome of this reaction is
clearly opposite to that anticipated and will be discussed later
(vide infra).
dilution (0.003 M in CH2Cl2, p-toluenesulfonic acid, p-TSA)
afforded the cyclization substrate 25 in good yield (79%).31 The
synthesis was then completed through the precedented31,32
ZnBr2-promoted cyclization of 25 which was modified by the
addition of MgSO4. The product mixture was easily purified
by flash chromatography to provide a 72% yield of ent-∆1-
tetrahydrocannabinol (4). This procedure delivered 4 free from
contamination by isomeric products, which has been reported
to be a problem in previous syntheses.33 When the cyclization
was performed without MgSO4, an isomeric cannabinol deriva-
tive was obtained as a significant byproduct (25%). The use of
p-TSA as the cyclization promoter resulted in the formation of
significant amounts of ∆6-tetrahydrocannabinol via double-bond
isomerization. The spectroscopic data of synthetic (+)-∆1-
tetrahydrocannabinol was identical to the published data of the
natural product,32 with the exception of the rotation, which was
opposite in sign: [R]25D (literature) -150 (c 0.53, CHCl3); [R]25
D
(synthetic) +141 (c 0.55, CHCl3). This represents the first
synthesis of ent-∆1-tetrahydrocannabinol where absolute ste-
reocontrol in the natural product was not directly linked to the
chiral pool.
Synthesis of ent-Shikimic Acid (5). The Diels-Alder
reaction of acrylimide 2 with furan was also investigated (eq
14). Although 7-oxabicyclo[2.2.1]hept-2-enes are attractive
intermediates in organic synthesis,34 furan is generally held to
be a poor diene in Diels-Alder reactions,35 and only two
examples of catalytic asymmetric Diels-Alder reactions with
furan or substituted furans have been reported. One study
employed R-haloacroleins as the dienophiles,36 while the other
investigated the more reactive 3-(methylthio)furan as the diene
component.7e
Addition of LiOBn to cycloadduct 28 (6 equiv of LiOBn, 0
°C) effected transesterification of both imide and acetate
moieties to afford â-hydroxy ester 29 in 78% yield (Scheme
3); however, this product proved difficult to separate from excess
Scheme 3a
Table 4. The Diels-Alder Reaction of Imide 2 with Furan
(eq 14)a
entry
temp
time
conv.b
endo/exob
endo eec
1
2
3
-20 °C
-20 °C
-78 °C
24 h
2.5 h
42 h
98%
88%
97%
10:90
66:34
80:20
0%
59%
97%
a Reactions were carried out at the indicated temperature in CH2Cl2
with 10 equiv of furan. b Conversion and diastereomer ratios were
determined NMR spectroscopy. c Enantiomeric excess was determined
by chiral HPLC. Exo ee <20%.
a (a) Six equivalents of LiOBn, THF, 0 °C, 2.5 h; (b) 2 equiv of
LiOBn, THF, -20 °C, 3 h; (c) 6 equiv of MeMgBr, ether, 0 °C, 2 h;
(d) 26, p-TSA, CH2Cl2, 0 °C, 7 h; (e) ZnBr2, MgSO4, CH2Cl2, 20 °C,
5 h.
When the acrylimide-furan reaction (eq 14) was performed
under standard screening conditions (5 mol % catalyst 1b, -20
°C, 24 h), the product was obtained as a 9:1 mixture of exo/
endo isomers, both of which were racemic (Table 4, entry 1).
However, upon terminating the reaction after only 2.5 h (88%
benzyl alcohol. Alternatively, selective imide cleavage was
achieved under less forcing conditions (2 equiv of LiOBn, -20
°C) to provide ester 30 in 82% yield. Addition of excess
methylmagnesium bromide to 30 provided allylic alcohol 31
(80%). Acid-catalyzed alkylation of olivetol with 31 at high
(31) Stoss has provided the precedent for this transformation in the
cyclization of the isomeric allylic alcohol: Stoss, P.; Merrath, P. Synlett
1991, 553-554.
(32) (a) Petrzilka, T.; Haefliger, W.; Sikemeier, C. HelV. Chim. Acta
1969, 1102. (b) Archer, R. A.; Johnson, D. W.; Hagaman, E. W.; Moreno,
L. N.; Wenkert, E. J. Org. Chem. 1977, 42, 490-495.
(29) Reference 23. Attempts to form the diene through the rearrangement
of 2-methylbut-3-yn-2-ol with Ag(I) and acetic anhydride resulted in the
formation of a mixture of products which were difficult to separate. See:
(a) Banks, R. E.; Miller, J. A.; Nunn, M. J.; Stanley, P.; Weakley, T. J.;
Ullah, Z. J. Chem. Soc., Perkin Trans. 1 1981, 1096-1102. (b) Snider, B.
B.; Amin S. G. Synth. Commun. 1978, 8, 117.
(30) Reactions carried out at 0 °C were not as clean, while reactions at
temperatures lower than -20 °C did not exhibit improved diastereoselec-
tivity.
(33) (a) Razdan, R. K.; Dalzell, H. C.; Handrick, G. R. J. Am. Chem.
Soc. 1974, 96, 5860-5865. (b) Crombie, L.; Crombie, W. M. L.; Jamieson,
S. V.; Palmer, C. J. J. Chem Soc., Perkin Trans. 1 1988, 1243-1250.
(34) For reviews, see: (a) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.;
Thorpe, A. J. Chem. ReV. 1996, 96, 1195-1220. (b) Vogel, P.; Fattori, D.;
Gasparini, F.; Le Drian, C. Synlett 1990, 173-185.
(35) Brion, F. Tetrahedron Lett. 1982, 23, 5299-5302.
(36) Corey, E. J.; Loh, T.-P. Tetrahedron Lett. 1993, 34, 3979-3982.

7588 J. Am. Chem. Soc., Vol. 121, No. 33, 1999
EVans et al.
conversion), the endo product, formed in 59% ee, was now
found to be the predominant product diastereomer (endo/exo,
66:34), (entry 2). These results suggested that at -20 °C, the
reaction was reversible. Accordingly, when the reaction was
carried out at -78 °C, the endo/exo ratio climbed to 80:20,
while the endo isomer was formed in 97% ee (entry 3). A 20
mmol scale reaction yielded enantiomerically pure endo isomer
32 in 67% yield after recrystallization.
To demonstrate the utility of this reaction, we undertook a
synthesis of shikimic acid, an intermediate in the plant biosyn-
thesis of aromatic amino acids and quinic acid.37 Previous
syntheses of racemic shikimic acid and related derivatives have
originated from Diels-Alder adducts of furan with acryloni-
trile38 and methyl acrylate.39 On the basis of precedent estab-
lished in these studies, imide 32 was converted to its derived
methyl ester 33 via the intermediate S-ethyl thioester [(a)
LiSEt;22 (b) Cs2CO3, MeOH] in 93% overall yield (Scheme 4).40
exhibited spectroscopic data comparable to that of a natural
sample, with the exception of the rotation, which was opposite
in sign [R]25D -150 (c ) 0.80, MeOH); [R]25D (synthetic) +142
(c ) 0.80, MeOH)]. This synthesis again established that the
absolute sense of induction in the Diels-Alder reaction was
consistent with the proposed model.2
Effect of Diene Substitution on Reaction Selectivity. The
unanticipated turnover in diastereoselectivity between the reac-
tions of 1-acetoxybutadiene and 1-acetoxy-3-methylbutadiene
may be understood as the result of a steric interaction in the
latter case between the 3-methyl group and the ligand in the
endo trajectory. A qualitative examination of models of the endo
and exo transition states for this reaction (Figure 2) suggests
that the 3-substituent, X, encounters nonbonding interactions
with the chiral bis(oxazoline) ligand in the endo transition state.
It follows that a steric interaction between the ligand and the
methyl substituent on the diene in the endo transition state could
account for the turnover in diastereoselectivity from the corre-
sponding reaction of 1-acetoxybutadiene (vide supra).43
Examination of thermal and catalyzed diastereoselectivities
provides further evidence for a steric interaction between the
3-methyl group and the catalyst in the endo transition state. The
catalyzed reactions of 1-acetoxybutadiene (85:15 endo/exo) were
slightly more endo-selective than the thermal reaction (75:25).
Other dienes behaved similarly.44 However, 1-acetoxy-3-me-
thylbutadiene showed a greater exo preference in the catalyzed
reaction (73:27 exo/endo) than in the thermal reaction (60:40
endo/exo).
Scheme 4a
a (a) LiSEt, THF, -20 °C; (b) Cs2CO3, MeOH, 0 °C; (c) LiHMDS,
THF, -78 to 0 °C, then TBSOTf, 2,6-lutidine, -78 °C; (d) OsO4,
NMO, THF, H2O, 0 °C; (e) TBAF, THF; (f) TMSOK, THF, then IR-
120, H2O.
LiHMDS-promoted ring opening of 33 resulted in isolation of
substantial amounts of methyl benzoate; therefore, a modifica-
tion of the procedure of Campbell was employed in which the
lithium alkoxide was trapped in situ with TBSOTf to provide
silyl ether 34 in 90% yield.40 Dihydroxylation (OsO4, NMO,
THF, H2O) of 34 proceeded with good diastereoselectivity (10:
1) to deliver diol 35 (74%), which was desilylated (TBAF, THF)
in 97% yield to provide ent-methyl shikimate. Although the
saponification of methyl shikimate is reported to be capricious
due to varying amounts of aromatized byproducts,37 it was found
that potassium trimethylsilanolate41 cleanly afforded ent-shikimic
acid (5) in 90% yield after purification by ion-exchange
chromatography (Amberlyst IR-120, H2O).42 This material
Figure 2. Endo and exo approaches of 1-acetyoxybutadienes to
catalyst-bound imide dienophile.
The effect of a 3-methyl substituent on reactions of 1-acet-
oxybutadienes is anticipated to be general. In particular, this
steric effect could explain the anomolously low selectivities
obtained in reactions of 2,3-dimethylbutadiene (65% ee) and
isoprene (60% ee, Table 2). Both of these dienes are presumed
to approach the catalyst-bound imide largely via an exo
transition state. If the catalyst is incapable of imparting high
selectivities to the exo trajectory, then a lower enantioselectivity
would be anticipated (in these cases, endo and exo transition
states give rise to the same product).
The question then arises as to why the exo trajectory of 2,3-
dimethylbutadiene and isoprene would be unselective while that
of 1-acetoxy-3-methylbutadiene is very selective (97% ee). We
postulate that the presence of the (1E)-substitution provides a
steric interaction with the ligand that is missing in the other
(37) For a brief review of the role of shikimic acid in plant biosynthesis
and the syntheses of the shikimates, see Campbell, M. M.; Sainsbury, M.;
Searle, P. A. Synthesis 1993, 179-193.
(38) Rajapaksa, D.; Keay, B. A.; Rodrigo, R. Can. J. Chem. 1984, 6,
826-827.
(39) (a) Campbell, M. M.; Kaye, A. D.; Sainsbury, M. Tetrahedron Lett.
1983, 24, 4745-4746. (b) Campbell, M. M.; Kaye, A. D.; Sainsbury, M.;
Yavarzadeh, R. Tetrahedron Lett. 1984, 25, 1629-1630. (c) Campbell, M.
M.; Kaye, A. D.; Sainsbury, M.; Yavarzadeh, R. Tetrahedron 1984, 40,
2461-2470. (d) Campbell, M. M.; Sainsbury, M.; Yavarzadeh, R. Tetra-
hedron 1984, 40, 5063-5070.
(40) Attempts to open cycloadduct 32 under basic conditions (LiHMDS,
TBSCl, or TBSOTf, Et3N) to the derived cyclohexadienol proved unsat-
isfactory.
(43) An exo-selective Diels-Alder reaction has been designed on the
basis of steric interactions between an approaching diene and an imidizo-
lidinonyl carbene dienophile in the endo transition state. See: Powers, T.
S.; Jiang, W.; Su, J.; Wulff, W. D.; Waltermire, B. E.; Rheingold, A. L. J.
Am. Chem. Soc. 1997, 119, 6438-6439.
(44) 1-Phenylbutadiene: thermal ) 82:18 endo/exo; catalyzed ) 85:15
endo/exo. 1-Phenylthiobutadiene: thermal ) 65:35 endo/exo; catalyzed )
98:2 endo/exo. 1-Benzyloxycarbonylaminobutadiene: thermal ) 49:51
endo/exo; catalyzed ) 72:28 endo/exo.
(41) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831-
5834.
(42) Pawlak, J. L.; Berchtold, G. A. J. Org. Chem. 1987, 52, 1765-
1771.

Bis(oxazoline) and Bis(oxazolinyl)pyridine
J. Am. Chem. Soc., Vol. 121, No. 33, 1999 7589
Scheme 5a
a (a) DIBAL, Et2O, 0 °C; 1 M HCl; (b) 38, NaHMDS, THF, 0 °C to
25 °C; (c) 38, Et3N, LiCl, CH3CN, 25 °C; (d) (E)-â-styryliodide,
(PhCN)2PdCl2 (3 mol %), DMF, 25 °C; (e) DMSO, (COCl)2, CH2Cl2,
-78 °C; Et3N, to 0 °C; (f) CrCl2, CHI3, dioxane/THF (6:1), 25 °C; (g)
(E)-â-styryltributyltin, (PhCN)2PdCl2 (3 mol %), DMF, 25 °C; (h)
DIBAL, CH2Cl2, 0 °C; (i) 38, (i-Pr)2NEt, LiCl, CH3CN, 25 °C.
Figure 3. Minor exo approaches of 2,3-dimethylbutadiene and of
1-acetoxy-3-methylbutadiene to [Cu((S,S)tert-Bu-box)(imide)].
two cases. As shown in Figure 3, the disfavored exo approach
of 2,3-dimethylbutadiene to the catalyst-bound imide does not
encounter substantial steric interaction with the ligand. However,
1-acetoxy-3-methylbutadiene does contact the ligand substituent
in the disfavored exo approach.
If the preceding analysis is correct, then one would anticipate
the exo enantioselectivities of (1E)-substituted dienes to be high,
while the exo selectivities of (1Z)-substituted dienes should be
lower. In fact, these expectations are borne out. The trans
products of the reactions of 1-acetoxybutadiene (90% ee),
1-phenylthiobutadiene (89% ee), and 1-(benzyloxycarbonylami-
no)butadiene (97% ee) were formed with high enantioselectivity
(Table 3).45 However, the exo products of cyclohexadiene (29-
53% ee) and furan (<20% ee, Table 4) were generated relatively
unselectively.
(A) Intramolecular Diels-Alder Reactions. Prior to this
investigation, only a handful of studies had been reported which
described catalytic asymmetric intramolecular Diels-Alder
(IMDA) reactions.8,9e,10 Of these, only one catalytic system has
been reported to effect the enantioselective IMDA reaction of
unsaturated trienimides such as 36.8 Our interest in this class
of reactions extends back some years, having reported previously
that chiral trienimides undergo highly diastereoselective IMDA
reactions when mediated by dimethyaluminum chloride.20 We
speculated that complexes 1a and 1b would possess sufficient
Lewis acidity and facial discrimination to effect an enantiose-
lective version of this cycloaddition reaction.
37 (eq 15), whose synthesis has been described by Roush.46
Reduction of 37, followed by Horner-Emmons homologation
with phosphonate reagent 38, itself prepared via an Arbuzov
reaction of 2-(bromoacetyl)-3-oxazolidinone and trimethyl phos-
phite, provided 36. The higher homologue 40 was prepared via
a similar olefination of aldehyde 39 (eq 16).47 Trienimide 43,
the phenyl-substituted variant of 36, was synthesized via the
following sequence: Pd(0)-catalyzed coupling of vinylstannane
4148 and (E)-iodostyrene to afford dienic alcohol 42, oxidation
under Swern conditions,49 and immediate homologation with
phosphonate 38 (eq 17). The higher homologue 48 was accessed
beginning with Takai olefination50,51 of aldehyde ester 4452 to
give vinyl iodide 45, which underwent Pd(0)-catalyzed coupling
with (E)-â-tributylstannylstyrene to afford dienic ester 46.
Reduction with DIBAL, oxidation, and Horner-Emmons ho-
mologation led to the desired trienimide 48 (eq 18).
(46) Roush, W. R.; Gillis, H. R.; Ko, A. I. J. Am. Chem. Soc. 1982,
104, 2269-2283.
(47) We have prepared 39 on a small scale (<1 g) via Pd(0) coupling of
vinyltributylstannane with iodide 45, followed by DIBAL reduction and
Swern oxidation in analogy to the preparation on 47. This route is probably
not amenable to large-scale preparation. For an alternate preparation, see
Roush, W. R.; Hall, S. E. J. Am. Chem. Soc. 1981, 103, 5200-5211.
(48) Kalivretenos, A.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1991,
56, 2883-2894.
The synthesis of the requisite trienimides is outlined in
Scheme 5. Trienimide 36, possessing a three-carbon tether
between the diene and dienophile, was prepared from nitrile
(49) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(50) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
(51) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497-
4513.
(52) Claus, R. E.; Schreiber, S. L. Organic Syntheses, CollectiVe Volume
VII; Freeman, J. P., Ed.; Wiley: New York, 1990; p 168-171.
(45) It was not possible to accurately assay the enantioselectivity of the
trans product of 1-phenylbutadiene reactions, due to epimerization during
the thiolate cleavage reaction.

7590 J. Am. Chem. Soc., Vol. 121, No. 33, 1999
EVans et al.
Scheme 6
was deduced by appropriate NOE experiments; the structure of
51 was confirmed by X-ray analysis. The absolute stereochem-
ical assignments of 51 and 52 were made by analogy to 49.
(B) Synthesis of (-)-Isopulo'upone (6). A synthesis of (-)-
isopulo'upone (6), isolated in 1993 from mollusks NaVarax
inermis and Bulla Gouldiana, provided an interesting test of
substrate complexity for the IMDA process.53 Preparation of
the cyclization substrate was initiated by the Pd(0)-catalyzed
coupling of vinyl iodide 53 with vinylstannane 41 to afford the
desymmetrized (E,E)-diene 54 (Scheme 7).54 Swern oxidation
of 54 afforded an aldehyde that was immediately treated with
phosphonate 38 (NaHMDS, THF) to afford trienimide 55 in
77% yield (2 steps) as a separable 27:1 mixture of (E) and (Z)
isomers.
With the requisite trienimide 55 in hand, cycloaddition to
the desired adduct 56 was achieved with 5 mol % of the SbF6
catalyst 1b (24 h, 25 °C) in 81% yield. The cycloaddition
proceeded with high diastereo- and enantioselectivity (>99:1
endo/exo, 96% ee), delivering the isopulo'upone skeleton with
all four contiguous stereogenic centers established in the correct
relative and absolute configuration (vide infra). Imide 56 was
transformed to its derived thioester 57 in 91% yield by treatment
with LiSEt (THF, 0 °C, 15 min).22 Reduction of the thioester
to aldehyde 58 using Pd(0)/triethylsilane55 was plagued by
concomitant saturation of the olefin; however, a modification
in which Lindlar’s catalyst was employed52 in the presence of
an excess of a “sacrificial” olefin, 1-decene, allowed the
transformation to be conducted without detectable alkene
reduction, cleanly affording 58 without the need of purification.
Treatment of this aldehyde with methylmagnesium chloride
(THF, -78 °C) and subsequent silyl ether deprotection (1% HCl/
EtOH, 10 min, 25 °C) afforded diol 59 in 90% yield (3 steps)
as an 8:1 mixture of diastereomers at the newly formed hydroxyl
stereocenter. An X-ray crystal structure of 59 confirmed the
relative stereochemical assignments made previously.11c While
inconsequential to the study at hand, the major product observed
in this addition reaction is consistent with the diastereomer
predicted by the Felkin-Ahn model.56 The diastereomeric
mixture of diols 59 was oxidized to a single keto aldehyde 60
(83%), then treated with the ylide derived from tributylphos-
phonium salt 61 to afford (-)-isopulo'upone (6) with excellent
chemo- and stereoselectivity (E/Z ) 12:1) and yield (90%).57
The spectral data (1H, 13C, IR, HRMS) for 6 matched those
reported for the natural product, while the absolute stereochem-
ical assignment of the Diels-Alder reaction was confirmed by
Our initial studies focused on the reaction of 36 with the
triflate complex 1a (Scheme 6, eq 19). After 5 days at room
temperature (10 mol % 1a, CH2Cl2), only 17% conversion to
cycloadduct 49 was observed (1H NMR spectroscopy); however,
by employing SbF6 catalyst 1b (10 mol %, 25 °C, CH2Cl2), we
isolated the desired cycloadduct as a single diastereomer in 89%
yield and 86% ee after 24 h. The relative and absolute
configuration of this adduct was established by transformation
to the known benzyl ester ([R]25 -23.8 (c ) 0.90, CHCl3))
D
whose absolute configuration had been previously established.20
By way of comparison, the optimal conditions for the chiral
oxazolidinone-derived triene variant of 36, promoted by di-
methylaluminum chloride, afforded a 97:3 mixture of endo
isomers (endo/exo, >99:1) in 65% yield.20 The similar endo
face selectivities observed between the enantioselective and
diastereoselective reactions render these two processes quite
competitive.
On the basis of our results with trienimide 36, we were
disappointed to find that the higher homologue 40 failed to
undergo cycloaddition with SbF6 catalyst 1b to a significant
degree after extended reaction times (>1 week) (eq 20). This
was especially surprising in light of the facility with which chiral
variants of 40 undergo cycloaddition.20 The reason for this
anomolous behavior has not been identified.
the specific rotation: [R]25 (synthetic) -143 (c ) 0.38,
D
hexane); [R]25D (lit.) -119 (c ) 0.40, hexane).53a Thus, the sense
(53) (a) Spinella, A.; Alvarez, L. A.; Cimino, G. Tetrahedron 1993, 49,
3203-3210. (b) A racemic synthesis of isopulo'upone has appeared:
Matikainen, J.; Kaltia, S.; Hase, T. Synth. Commun. 1995, 25, 195-201.
(c) Racemic and auxiliary-mediated asymmetric syntheses of pulo'upone
(exocyclic double bond out of conjugation) have appeared: (i) Burke, S.
D.; Piscopio, A. D.; Buchanan, J. L. Tetrahedron Lett. 1988, 29, 2757-
2960. (ii) Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T. M.; Bernardinelli,
G. Tetrahedron Lett. 1988, 29, 5885-5888. (iii) Sugahara, T.; Iwata, T.;
Yamaoka, M.; Takano, S. Tetrahedron Lett. 1989, 30, 1821-1824.
(54) Synthesis of 53 and 41 from 5-hexyn-1-ol: (a) TBSCl, Et3N, DMAP
(cat.), CH2Cl2, rt, 1.5 h (86%); (b) (i) Cp2ZrH(Cl), toluene, rt, 12 h; (ii)
N-iodosuccinimide, rt, 18 h (88%); (c) (i) n-BuLi, THF, -78 °C; Bu3SnCl;
(ii) TBAF, THF, rt, 12 h (61%). See ref 48.
(55) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112,
7050-7051.
(56) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61-
70.
(57) Earlier attempts to execute this reaction with the analogous
phosphonate-derived reagent 2-pyr-CH(M)P(O)(OMe)2 (M ) Li, Na, K)
led to proton transfer-induced intramolecular aldol addition of 60.
The illustrated phenyl-substituted dienes 43 and 48 uniformly
afforded better reactivity and enantioselectivity than their
unsubstituted counterparts 36 and 40 in the IMDA process. Upon
treatment of trienimide 43 with 5 mol % of catalyst 1b, under
the usual reaction conditions (CH2Cl2, rt), cyclization to the
desired adduct 51 was observed after only 5 h with complete
diastereoselectivity in 86% yield and 92% ee (eq 21). The higher
homologue 48 was transformed in 97% yield (10 mol % 1b) to
the corresponding cycloadduct 52 as a mixture of diastereomers
(endo/exo ) 84:16), with the endo isomer delivered in 97% ee
and the exo in >95% ee (eq 22). From these results, it may be
deduced that a longer diene tether allows greater conformational
flexibility, eroding reaction diastereoselectivity. As expected,
the phenyl group enhanced diene reactivity, manifested in the
divergent outcomes using unsubstituted 40 versus phenyl-
substituted 48. The relative stereochemistry of each cycloadduct

Bis(oxazoline) and Bis(oxazolinyl)pyridine
J. Am. Chem. Soc., Vol. 121, No. 33, 1999 7591
Scheme 7a
a (a) Four mole percent Pd2(dba)3‚CHCl3, DMF, rt, 16 h; (b) DMSO, (COCl)2, CH2Cl2, -78 °C; Et3N, to -40 °C; (c) 38, NaHMDS, THF, rt,
26 h; (d) 5 mol % 1b, CH2Cl2, rt, 24 h; (e) LiSEt, THF, 0 °C, 15 min; (f) Et3SiH, 5% Pd/CaCO3/PbO/quinoline, 1-decene, acetone, rt, 2 h; (g)
MeMgCl, THF, -78 °C; (h) 1% HCl/EtOH, rt, 10 min; (i) 61, n-BuLi, THF, -20 °C, then 60 rt, 45 min.
of induction that all catalyzed trienimide IMDA reactions
reported in this study is consistent with our proposed model
(Figure 1).6
It is noteworthy that the enantioselectivity of observed for
the key step (55 f 56) in this synthesis (96%) is significantly
greater than that observed for the analogous reaction lacking
alkyl substitution on the diene terminus (Scheme 7, eq 19, 86%
ee). We thus conclude that this family of cationic Cu(2+)
catalysts should also be effective for similarly substituted
enantioselective IMDA processes.
AgSbF6 in CH2Cl2 for several hours at room temperature (eq
25). The resulting AgCl precipitate was removed by filtration
through a plug of cotton in air to provide blue or green catalyst
solutions of 9a-9d.
Structural studies were undertaken on both the triflate and
SbF6 complexes 8b and 9b as their derived crystalline hydrates
(62 and 63) to determine the nature of both metal center
architecture and counterion involvement (eqs 26, 27).6
[Cu((S,S)-pybox)](SbF6)2 Catalyzed Cycloadditions. In
conjunction with the development of [Cu(t-Bu-box)](X)2 com-
plexes as chelating chiral Lewis acids, the evaluation of related
square planar Cu(2+) complexes derived from bis(oxazolinyl)-
pyridine (pybox) ligands was also undertaken.58 In the absence
of counterion involvement, the cationic trigonal planar com-
plexes 8 and 9 would be expected to bind Lewis bases in the
ligand plane, creating a sterically differentiated environment for
the two π-surfaces of a coordinated dienophile (eq 23).
The impact of counterion on the aquo complexes is docu-
mented in the X-ray structures of 62 and 633a provided in Figure
4. The X-ray structure of 62 clearly substantiates that the triflate
counterions are associated with the metal center to varying
degrees (Cu-OTf ) 2.359 and 2.489 Å). On the other hand,
the structure of the bis(aquo) SbF6 complex 63 adopts the
expected square pyramidal geometry with the more tightly
bound water located in the equatorial plane (Cu-OH2 ) 1.985
Å) and the second bound water more loosely coordinated in
the apical position (Cu-OH2 ) 2.179 Å). Both of these
structures support the premise that the coordination of a carbonyl
Lewis base to either complex would be expected to occur in
the more Lewis basic site in the ligand plane as previously
projected (eq 23).
(A) Catalyst Preparation. Solutions of the (S,S)-pybox lig-
ands 7a-7c in CH2Cl2 were complexed with Cu(OTf)2 to form
blue solutions of the chiral triflate complexes 8a-8c (eq 24).
(B) Acrolein Dienophiles. [Cu(pybox)](OTf)2 complexes
8a-c serve as chiral Lewis acids in the reactions of methac-
rolein9,59 with cyclopentadiene (Table 5, eq 28). With 5 mol %
of the tert-butyl pybox catalyst 8a, exo cycloadduct 64 (X )
Me, 96:4) was obtained in 85% ee (entry 1); however, extended
reaction times (116 h) were required for complete conversion.
The isopropyl pybox catalyst 8b provided lower selectivity
(entry 2), and a reversal in absolute sense of induction was
observed with the phenyl-substituted ligand (entry 3). This latter
result suggests the existence of a possible substituent-related
The analogous SbF6 complexes were also prepared through
complexation of the pybox ligand with CuCl2 and 2 equiv of
(58) Four-coordinate Cu(II) complexes exhibit a strong tendency toward
square planar geometries. See: Hathaway, B. J. in ComprehensiVe
Coordination Chemistry; Wilkinson, G., Ed.; Pergamon Press: New York;
1987; Vol. 5, Chapter 53.
(59) (a) Bao, J.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1993,
115, 3814-3815. (b) Corey, E. J.; Loh, T. P. J. Am. Chem. Soc. 1991, 113,
8966-8967. (c) Hashimoto, S.; Komeshima, N.; Koga, K. J. Chem. Soc.,
Chem. Commun. 1979, 437-438.

7592 J. Am. Chem. Soc., Vol. 121, No. 33, 1999
EVans et al.
Figure 4. Crystallographic structures of the [Cu((S,S)-i-Pr-pybox)](H2O)n]X2 complexes 62 and 63 along with selected bond lengths and angles.
Table 5. Reaction of 2-Substituted Acrolein Derivatives with
the reaction of methacrolein at -40 °C (Table 5, entry 6). The
Cyclopentadiene Catalyzed by [Cu((S,S)-R-pybox)](X)2 (eq 28)a
benzyl catalyst 9d was comparable to the tert-butyl derivative,
providing the cycloadduct in 90% ee (entry 9). This phenyl-
alanine-derived ligand is an attractive alternative to the more
expensive tert-leucine variant. Similar trends were observed with
2-bromoacrolein: the best result was provided by tert-butyl
catalyst 9a (96% ee, entry 10), although the benzyl ligand
catalyst
dienophile (temp) timeb exo/endoc exo eed
afforded comparable enantioselection (95% ee, entry 11).
The preceding data document the importance of counterion
selection in achieving a sufficiently reactive metal center to
deliver a practical level of catalytic activity. The qualitative
kinetic data for these two catalysts (Table 5) is also consistent
with the X-ray structure of the triflate aquo complex 62 shown
in Figure 2 that illustrates the fact the triflate counterions
associate with the metal center. Accordingly, we speculate that
the Lewis acidity of the triflate-based catalysts 8 is being
buffered by the triflate counterion. In conclusion, these data
support the conclusion that the SbF6 complexes 9 are comparable
to other catalysts reported in the literature for this family of
reactions.9,59
(C) Acrylate Dienophiles. This class of dienophiles has been
studied under the influence of both stoichiometric61 and
catalytic62 conditions with metalloid chiral Lewis acid catalysts.
They were also evaluated in the Diels-Alder reaction with
cyclopentadiene with the chiral pybox complexes [Cu((S,S)-
pybox)](SbF6)2 9a-9d (Table 6, eq 29). This reaction was
stereoregular, producing the same enantiomer (R) regardless of
the pybox or ester substituent. tert-Butyl acrylate (R′ ) CMe3)
proved to be the optimal substrate (entries 1-4). A survey of
the ligands revealed that benzyl pybox catalyst 9d provided the
best selectivity (92% ee, entry 4), while the others (9a-c)
provided selectivities in the range of 83-88% ee (entries 1-3).
Methyl acrylate and phenyl acrylate underwent cycloadditions
with lower selectivities (entries 5 and 6, respectively). The
absolute stereochemistry was determined by reduction of the
esters to the corresponding alcohols and comparison of optical
rotation to literature values.63
8a (R ) CMe3)
Z ) Me (-20 °C) 116 h
97:3
96:4
94:6
96:4
97:3
97:3
96:4
96:4
96:4
98:2
98:2
85% (S)
52% (S)
39% (R)
78% (R)
87% (R)
92% (S)
72% (S)
49% (R)
90% (S)
96% (R)
95% (R)
8b (R ) CHMe2) Z ) Me (-20 °C)
23 h
80 h
12 h
60 h
8 h
8c (R ) Ph)
Z ) Me (-20 °C)
Z ) Br (-20 °C)
Z ) Br (-40 °C)
Z ) Me (-40 °C)
8a (R ) CMe3)
8a (R ) CMe3)
9a (R ) CMe3)
9b (R ) CHMe2) Z ) Me (-40 °C)
6 h
9c (R ) Ph)
9d (R ) Bn)
9a (R ) CMe3)
9d (R ) Bn)
Z ) Me (-40 °C)
Z ) Me (-40 °C)
Z ) Br (-78 °C)
Z ) Br (-78 °C)
6 h
6 h
12 h
12 h
a Reactions were carried out in CH2Cl2 with 5 equiv of diene. b Time
required for >95% conversion. c The diastereomer ratio was determined
by GLC analysis. d Enantiomeric excesses were determined as follows:
methacrolein: GLC analysis after conversion to the acetal of (-)-
(2R,4R)-pentanediol; 2-bromoacrolein, GLC analysis after conversion
to the dimethyl acetal.
electronic effect imparted to the reaction by the aryl moiety.
The tert-butyl catalyst 8a was also employed in the reaction of
cyclopentadiene with the more reactive 2-bromoacrolein (entries
4 and 5). At -40 °C, the exo cycloadduct 64 (X ) Br) was
formed with enantioselectivities as high as 87%. The absolute
sense of induction (as shown) in each instance was determined
by comparison of rotations to literature values.60
While these data indicated that the pybox-Cu(II) complexes
afforded the architecture necessary for asymmetric induction,
the long reaction times severely limit practical applications of
this system. Although the triflate counterion had been chosen
on the assumption that the [Cu(pybox)](OTf)2 complex would
dissociate upon substrate binding, this postulate was tested
through the evaluation of the less coordinating counterions BF4,
PF6, and SbF6. From this screen, the SbF6 catalysts 9 (eq 25)
were found to provide optimal reactivity, without sacrificing
reaction enantioselectivity. For example, the tert-butyl-substi-
tuted complex 9a proved to be optimal, affording 92% ee in
(61) (a) Seebach, D.; Beck, A. K.; Imwinkelreid, R.; Roggo, S.;
Wonnacott, A. HelV. Chim. Acta 1987, 70, 954-974. (b) Devine, P.; Oh,
T. J. Org. Chem. 1992, 57, 396-399.
(62) (a) Hawkins, J. M.; Loren, S. J.; Nambu, M. J. Am. Chem. Soc.
1994, 116, 1657-1660. (b) Maruoka, K.; Conception, A. B.; Yamamoto,
H. Bull. Chem. Soc. Jpn. 1992, 65, 3501-3503.
(60) Methacrolein/cyclopentadiene adduct: ref 9c. 2-Bromoacrolein/
cyclopentadiene adduct: (c) ref 59b.
(63) Berson, J. A.; Walia, J. S.; Remanick, A.; Suzuki, S.; Warnhoff, P.
R.; Willner, D. J. Am. Chem. Soc. 1961, 83, 3986.

Bis(oxazoline) and Bis(oxazolinyl)pyridine
J. Am. Chem. Soc., Vol. 121, No. 33, 1999 7593
alkyldichoroborane-methyl crotonate complex.61a Unfortunately,
qualitative analysis of the nonbonding interactions in catalyst-
acrylate complex 68 leads to the wrong stereochemical predic-
tion for the course of the cycloaddition (eq 33). An alternative
model that is consistent with the stereochemical outcome of
the reaction follows from the less symmetrical complex 69 (eq
34). As illustrated, the Si-enantioface of the dienophile may be
exposed through rotation of the complexed acrylate about the
Cu-O bond.
Table 6. Reaction of Acrylate Esters with Cyclopentadiene
Catalyzed by [Cu((S,S)-R-pybox)](SbF6)2 9 (eq 29)a
entry
catalyst
ester
endo/exob
endo eeb
1
2
3
4
5
6
9a (R ) CMe3)
9b (R ) CHMe2)
9c (R ) Ph)
9d (R ) Bn)
9d (R ) Bn)
9d (R ) Bn)
R′ ) CMe3
R′ ) CMe3
R′ ) CMe3
R′ ) CMe3
R′ ) Me
96:4
98:2
96:4
98:2
95:5
92:8
84%
88%
83%
92%
85%
44%
R′ ) Ph
a Reactions were carried out in CH2Cl2 with 5 equiv of diene.
b Diastereomer ratios and enantiomeric excesses were determined by
chiral GLC.
(D) Models for Diels-Alder Reactions of Monodentate
Dienophiles. Simple models that correlate catalyst-dienophile
structure with dienophile face selectivity are provided below
(eq 30, 31). On the basis of the crystal geometry of the [Cu-
((S,S)-i-Pr-pybox)(H2O)2](SbF6)2 complex (63) (Figure 2), it is
presumed that aldehyde dienophiles coordinate to the copper
center in a square planar geometry. The principal uncertainty
in the prediction of the stereochemical outcome of the reaction
is associated with the reacting dienophile conformation which
presents options for cycloaddition out of either the s-cis or
s-trans conformation. The relative reactivity of s-cis and s-trans
acrolein64 complexes has been addressed at the ab initio level
by Houk and co-workers, who find that the lower LUMO
energies of the s-cis conformer favor reaction out of this less
stable conformer65 through both the exo and endo transition
states.66 This projection, when integrated into the proposed
model for the reactive conformation of the coordinated dieno-
phile (66), leads to a clear prediction for the stereochemical
course of the exo- (eq 30) and endo-selective (eq 31) Diels-
Alder reactions with cyclopentadiene. Our experimental results
on the exo-selective reactions with methacrolein and bromoac-
rolein (Table 5) and the endo-selective cycloaddition with
acrolein (eq 32) are consistent with this model.
Conclusion
Although a number of chiral metal catalysts have been
described which are capable of promoting Diels-Alder reactions
of cyclopentadiene, the results in this report demonstrate that
bis(oxazoline) copper complexes, particularly hexafluoroanti-
monate complex [Cu((S,S)-t-Bu-box)](SbF6)2 (1b), are highly
effective at promoting reactions of acyloxazolidinone-derived
dienophiles with less reactive dienes. With this catalyst, a wide
range of cyclic and linear dienes react with imide 2 in greater
than 90% ee. The application of this catalyst to intramolecular
cycloadditions has also proven to be possible. The power of
the Diels-Alder reaction lies in its ability to assemble ring
systems and multiple contiguous stereocenters quickly. Due to
the reactivity of catalyst 1b and the high degree of asymmetric
induction which it imparts, the complex product cycloadducts
that are now available have been utilized in efficient syntheses
of ent-∆1-tetrahydrocannabinol (4), ent-shikimic acid (5), and
isopulo′upone (6).
We have also extended the scope of the copper-catalyzed
Diels-Alder reaction to include monodentate dienophiles. The
SbF6 pybox catalysts [Cu((S,S)-t-Bu-pybox)](SbF6)2 (9a) and
[Cu((S,S)-Bn-pybox)](SbF6)2 (9d) have been found to catalyze
the Diels-Alder reactions of acrolein and acrylate dienophiles
with high enantioselectivities.
The observations made in the study of the Diels-Alder
reaction, especially the efficacy of chelating dienophiles, have
provided the foundation for new enantioselective Cu(II)-
(64) X-ray structures for the following aldehyde complexes have been
reported: (a) Methacrolein/BF3 complex: Corey, E. J.; Loh, T.-P.; Sarshar,
S.; Azimioara, M. D. Tetrahedron Lett. 1992, 33, 6945-6948. (b)
2-Heptenal/SnCl4 complex: Denmark, S. E.; Almstead, N. G. J. Am. Chem.
Soc. 1993, 115, 3133-3139. (c) Methacrolein/RuLn complex: Carmona,
D.; Cativiela, C.; Elipe, S.; Lahoz, F. J.; Lamata, M. P.; Pilar, M.; de Viu,
L. R.; Oro, L. A.; Vega, C.; Viguri, F. Chem. Commun. 1997, 2351-2352.
(d) Methacrolein/RuLn complex: Ku¨ndig, E. P.; Saudan, C. M.; Bernar-
dinelli, G. Angew. Chem., Int. Ed. Engl. 1999, 38, 1220-1222.
(65) Such a Curtin-Hammett scenario has been proposed for a catalyzed
Diels-Alder reaction between 2-bromoacrolein and cyclopentadiene. Corey,
E. J.; Loh, T.-P.; Roper, T. D.; Azimioara, M. D.; Noe, M. C. J. Am. Chem.
Soc. 1992, 114, 8290-8292.
The construction of a model for the acrylate-catalyst complex
has been aided by the ab initio-based force field modeling of
the transition states of these reactions by Houk and co-workers.67
This study concludes that the reacting geometry for this metal-
complexed dienophile is s-trans with the metal complexed to
the oxygen lone pair syn to the double bond as depicted below
(eqs 33, 34). This is also the observed geometry of the Hawkins
(66) Birney, D. M.; Houk, K. N. J. Am. Chem. Soc. 1990, 112, 4127-
4133.
(67) de Pascual-Teresa, B.; Gonzalez, J.; Asensio, A.; Houk, K. N. J.
Am. Chem. Soc. 1995, 117, 4347-4356.

7594 J. Am. Chem. Soc., Vol. 121, No. 33, 1999
EVans et al.
Figure 5. Representative Cu(box) and Cu(pybox) catalyst-substrate complexes implicated in enantioselective reactions.
catalyzed reactions. The requirement of substrate chelation has
not hindered these endeavors. As evidenced by Figure 5,
reactions catalyzed by bis(oxazoline) Cu(II) complexes span a
broad range of important enantioselective bond constructions
and have yielded many chiral synthons useful to organic
chemists.68
Acknowledgment. Support has been provided by the NIH,
the NSF, and Merck. The NIH BRS Shared Instrumentation
Grant Program 1-S10-RR04870 and the NSF (CHE 88-14019)
are acknowledged for providing NMR facilities.
(68) (a) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617-2618.
(b) Evans, D. A.; Willis, M. C.; Johnston, J. N. Org. Lett. 1999, 1, in press.
(c) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, in press. (d) Evans, D.
A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am. Chem. Soc. 1999,
121, 1994-1995. (e) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc. 1998,
120, 4895-4896. (f) Thorhauge, J.; Johannsen, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2404-2406. (g) Johannsen, M.; Yao, S.;
Graven, A.; Jørgensen, K. A. Pure Appl. Chem. 1998, 70, 1117-1122. (h)
Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay, S. W. J.
Am. Chem. Soc. 1998, 120, 5824-5825. (i) Yao, S. L.; Johannsen, M.;
Audrain, H.; Hazell, R. G.; Jørgensen, K. A. J. Am. Chem. Soc. 1998, 120,
8599-8605.
Supporting Information Available: Experimental proce-
dures and spectral data for all compounds are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA991191C