Enantioselective and Structure-Selective Diels-Alder Reactions of Unsymmetrical Quinones Catalyzed by a Chiral Oxazaborolidinium Cation. Predictive Selection Rules

Article abstract of DOI:10.1021/ja049323b

The chiral oxazaborolidinium cation 1 promotes Diels-Alder reactions between 2-triisopropylsilyloxy-1,3-butadiene and a number of unsymmetrical 1,4-benzoquinones in a highly enantioselective and structurally selective manner. The basis for the enantioselectivity is explained rationally in terms of a preferred type of transition-state assembly. Selection rules have been developed that allow the prediction of the principal reaction product of Diels-Alder reaction between unsymmetrical diene and quinone components. Copyright

Full text of DOI:10.1021/ja049323b

Published on Web 03/25/2004
Enantioselective and Structure-Selective Diels-Alder Reactions of
Unsymmetrical Quinones Catalyzed by a Chiral Oxazaborolidinium Cation.
Predictive Selection Rules
Do Hyun Ryu, Gang Zhou, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received February 6, 2004; E-mail: corey@chemistry.harvard.edu
The chiral cationic oxazaborolidinium ion 11,2 (and the corre-
sponding triflate3,4) are useful and potent catalysts for promoting a
wide variety of highly enantioselective Diels-Alder reactions.5 One
particularly important area of application is to the Diels-Alder re-
actions of unsymmetrical 1,4-benzoquinones and 1,3-dienes, which
is especially challenging because of the multiple requirements of
high enantioselectivity, orientational selectivity (i.e., only one of
the two possible modes of coupling the ends of the diene and dieno-
phile), and site-selectivity (i.e., reaction at only one of the two
CdC subunits of the quinone). Achievement of all these selectivities
with a broad range of dienes and 1,4-benzoquinones would be a
major advance since the quinone subcategory of the Diels-Alder
reaction is one of the most powerful versions of [4 + 2]-cycload-
dition and one of the most useful for the synthesis of many complex
natural products.6 In a previous paper we have described a number
of highly successful enantioselective reactions of 1,3-dienes with
1,4-benzoquinones in which one of the components is symmetrical.1
However, only a few cases were studied in which both components
were unsymmetrical.1 Some of these afforded a single chiral prod-
uct, but others gave a mixture of positional (or regio) isomers. We
describe herein a wide-ranging study of many different unsym-
metrical quinones with the test diene 2-triisopropylsilyloxy-1,3-bu-
tadiene that gave substantially one product with high enantiose-
lectivity. The results reported herein provide powerful guidance
for the use of catalytic enantioselective quinone Diels-Alder reac-
tions in the synthesis of complex targets. Taken together, they
allowed the development of predictive rules for the preferred course
of reactions between unsymmetrical 1,3-dienes and quinones, which
are summarized below. The selection rules also depend on the
predictive mechanistic model that has been derived previously.1,3,7
Table 1. Enantioselective Diels-Alder Reactions of Trisubstituted
1,4-Benzoquinones Catalyzed by 1 (0.2 Equiv)
a Isolated yield. b Enantioselectivities were determined by HPLC analysis.
c Absolute configuration proved by X-ray analysis. d Absolute configuration
determined by synthesis from product in entry 3. e Absolute configuration
assigned from optical rotatory data. f Absolute configuration, ref 1.
Table 1 summarizes the results of the Diels-Alder reactions
catalyzed by 1 (0.2 equiv) between 2-triisopropylsilyloxy-1,3-
butadiene (2) and five trisubstituted 1,4-benzoquinones. These
reactions all proceed with very good yields and enantioselectivities.
They all conform to the mechanistic path outlined at the top of
Table 1 in which the catalyst coordinates to the least sterically
shielded CdO lone pair, uniquely that which is syn to the
benzoquinone CR-H subunit, to produce the major enantiomer.1,3,7
Chromatographic analysis of the crude reaction mixtures and the
high yields of isolated pure product demonstrate that each of these
reactions is highly site-selective and regioselective as well as highly
enantioselective. The site selectivity indicates that diene attack on
the less substituted double bond is favored. In addition, the reactive
double bond is in each case syn to the catalyst-coordinated oxygen
lone pair. The orientational (or regio) selectivity can be explained
by attack of the nucleophilic end (C-1) of the 2-substituted diene
at the carbon â to the coordinated carbonyl, i.e., the olefinic carbon
expected to the most electrophilic in the quinone complex with
catalyst 1.
Table 2 summarizes the results of five reactions, catalyzed by 1
(0.2 equiv), between 2-triisopropylsilyloxy-1,3-butadiene and vari-
ous 2,3- or 2,6-disubstituted 1,4-benzoquinones. In entries 1 and
2, the quinones are C2 symmetric so that there is no issue of
orientational selectivity. The major product results from coordina-
tion of catalyst to the least shielded oxygen lone pair (a) and
addition of diene to the less substituted CdC. The absolute
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C O M M U N I C A T I O N S
Table 2. Enantioselective Diels-Alder Reactions of 2,3- or
2,6-Disubstituted 1,4-Benzoquinones and
2-Triisopropylsilyloxy-1,3-butadiene Catalyzed by 1 (0.2 Equiv)
Table 3. Enantioselective Diels-Alder Reactions of Unsubstituted
or Monosubstituted 1,4-Benzoquinones and
2-Triisopropylsilyloxy-1,3-butadiene Catalyzed by 1 (0.2 Equiv)
a Isolated yield. b Enantioselectivities were determined either by HPLC
or 1H NMR MTPA analysis. c Absolute configuration proved by X-ray
analysis. d Absolute configuration assigned from optical rotatory data.
e Absolute configuration from chemical correlation.
a Isolated yield. b Enantioselectivities were determined either by HPLC
or 1H NMR MTPA analysis. c Absolute configuration determined by X-ray
analysis. d Absolute configuration assigned from optical rotatory data. e In
addition, 3% of the regioisomer was formed.
configurations of the products shown correspond to those expected
from the mechanistic model. In the remaining cases of Table 2
(entries 3-5), although each of the reactants is unsymmetrical, good
site-selectivity and regio- and enantioselectivity are observed. In
each case the favored pathway is that predicted for catalyst
coordination to the oxygen lone pair that is labeled a. Entry 3 of
Table 2 is an especially interesting example, since that reaction
was not totally regioselective, with the product shown being formed
in 84% yield and the regioisomer in 15% yield. In this case the
major pathway involves catalyst coordination to the more basic
oxygen (lone pair a), whereas the minor, regioisomeric product
results from coordination to the sterically less screened lone pair
of the other oxygen. Examples 4 and 5 of Table 2 illustrate an
interesting new selectivity in catalyst coordination that results in
the favoring of the pathway for [4 + 2]-cycloaddition at the double
bond that is syn to the coordinated lone pair a. Coordination to
lone pair b would have led to the enantiomer of the observed
product. Methoxy substituents on the quinone exert two important
effects because of their strong electron donation into the π-system
of the catalyst-quinone complex: (1) methoxy greatly favors
catalyst complexation at the carbonyl â to the methoxy group (the
more basic oxygen) and (2) methoxy lowers the electrophilicity of
the olefinic carbon to which it is attached so much that that CdC
of the quinone is unreactive.
is syn to the coordination site. In remaining cases (Table 3, entries
2-4), the favored site of diene attack is the less substituted CdC
subunit, catalyst coordination occurs to the lone pair of the oxygen
â to the electron-supplying substituent, and the product is that
expected from addition of diene syn to that coordination site.
The data summarized in this study allowed the derivation of the
following set of selection rules for Diels-Alder reactions of unsym-
metrical 1,3-butadienes with unsymmetrical 1,4-benzoquinones,
which when used together are predictive of the structure and abso-
lute configuration of the predominant product with 1 as a chiral
catalyst.
(1) For a quinone carbonyl flanked by CR-H and CR-R, the
major product will result from catalyst coordination preferentially
at the oxygen lone pair on the C-H side (a) rather than the C-R
side (b) because a is sterically more accessible than b.
(2) Catalyst coordination at the more basic of the two 1,4-quinone
oxygens will predominate, and this mode will lead to the preferred
Diels-Alder adduct.
Table 3 presents the results of experiments on the Diels-Alder
reactions with 0.2 equiv of 1, 2-triisopropylsilyloxy-1,3-butadiene,
and 1,4-benzoquinone or three monosubstituted 1,4-benzoquinones.
For the parent 1,4-benzoquinone (entry 1), the observed predomi-
nating enantiomer accords with the model shown in the heading of
Table 3, with endo addition of the diene to that double bond which
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C O M M U N I C A T I O N S
(3) If a double bond of the quinone in 1,3-diene addition bears
two hydrogens, it will be more reactive than that bearing substituent-
(s), especially one or two π-electron donor groups.
(4) For monosubstituted 1,4-quinones (or p-benzoquinone itself),
the major product pathway will involve coordination of catalyst at
CdO syn to the HCdCH subunit that undergoes [4 + 2]-cycload-
dition.
Lewis acid catalyst will play a role in determining the magnitude
of this transition-state coordination effect, it is not surprising that
different Lewis acids show regioselectivities that diverge from those
observed with catalyst 1. For example, in the case of Table 1, entry
2, an 86:14 mixture of (()-regioisomeric adducts is obtained at
-78 °C with EtAlCl2 as a catalyst, whereas only one adduct is
formed with 1 as catalyst.9
We believe that the catalytic enantioselective Diels-Alder
reactions of quinones described herein with catalyst 1 demonstrate
a major advance in synthetic methodology that will prove to have
broad utility.10 The availability of a mechanistic model and a reliable
set of selection rules that allow prediction of the structure and
absolute configuration of the principal reaction product adds further
to the usefulness of the catalyst 1 in the planning of syntheses.
Details of the determination of enantioselectivity and absolute
configuration of the various products along with several interesting
synthetic transformations of the Diels-Alder adducts are presented
in Supporting Information.
(5) C(1) of 2-triisopropylsilyloxy-1,3-butadiene (2), the more
nucleophilic end of the diene, will attach to the carbon â to the
carbonyl group that coordinates with the catalyst, i.e., the more
electrophilic carbon.
(6) The preferred three-dimensional transition state corresponds
to the endo arrangement of diene and catalyst-coordinated quinone.1
We have tested these rules by examining a number of their
consequences experimentally. For instance, rule 1 predicts that
catalyst 1 will not be effective for tetrasubstituted 1,4-benzoquino-
nes. In fact, the reaction of tetramethyl-1,4-benzoquinone with
2-triisopropylsilyloxy-1,3-butadiene in the presence of 0.2 equiv
of catalyst 1 is exceedingly slow at -78 °C. When the reaction
was conducted at -40 °C for 16 h, the resulting 1:1 Diels-Alder
adduct (35% yield) was totally racemic, indicating that the reaction
may occur as a result of proton transfer from catalyst 1 to the
quinone rather than by coordination at boron.
Acknowledgment. We are grateful to Pfizer, Inc., for a generous
grant.
Supporting Information Available: Information is provided on
the analysis and characterization of reaction products to determine
structure, enantioselectivity, and absolute configuration (PDF, CIF).
X-ray diffraction data are provided for the products in Table 1, entries
2 and 5; for the product in Table 2, entry 5; and the products in Table
3, entries 1 and 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388-6390.
(2) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org. Lett. 2003, 5, 3979-3982.
(3) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 9992-
9993.
Rules 1, 2, and 5 allow the prediction that the reaction of 6-[tert-
butyldimethylsilyloxy]-1,4-naphthoquinone (3) with 2 under ca-
talysis by 1 will generate adduct 4 as the principal Diels-Alder
product. In fact, the reaction was found to give 4 of >99%
enantiomeric purity in a 92:8 predominance over the regioisomeric
adduct (95% total yield after 16 h at -78 °C in CH2Cl2 with 0.2
equiv of 1 as catalyst), in full accord with expectations based on
the above selection rules.8 The underlying basis for rule 2 may
derive from the possibility that stronger coordination of catalyst 1
to the more basic of the two quinone carbonyls lowers the energy
of the transition state more than that of the complex ground state.
(4) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808-
3809.
(5) For a recent review of this area, see: Corey, E. J. Angew. Chem., Int. Ed.
2002, 41, 1650-1667.
(6) For background literature, see: Breuning, M.; Corey, E. J. Org. Lett. 2001,
3, 1559-1562.
(7) Corey, E. J.; Lee, T. W. J. Chem. Soc., Chem. Commun. 2001, 1321-
1329.
(8) Diels-Alder reaction of 2 with the methoxy analogue of quinone 3 and
catalyst 1 was less regioselective and afforded the 7-methoxy analogue
of 4 and the 6-methoxy regioisomer in a ratio of 76:24. The lower
selectivity in this case relative to 4 is understandable in view of the stronger
π-electron donation from OTBS vs methoxy in the quinone substrates.
(9) As is well known, thermal quinone Diels-Alder reactions with unsym-
metrical components are relatively nonregioselective. For instance, for
the case of Table 1, entry 2, the thermal reaction at 110 °C affords a
43:56 mixture of (()-regioisomers with that shown in Table 1 being the
minor component.
(10) The Mikami binaphthol-TiCl4-molecular sieves system is a known catalyst
for enantioselective Diels-Alder addition of 1,3-dienes to quinones; for
a leading reference, see: White, J. D.; Choi, Y. HelV. Chim. Acta, 2002,
85, 4306-4327. In addition, pybox lanthanide catalysts have recently been
applied to quinones having a methoxycarbonyl substituent; see: Evans,
D. A.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10162-10163.
It is important to note in this context that the coordination of catalyst
to the carbonyl persists not only in the transition state but even in
the Diels-Alder adduct. Because the steric requirements of the
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