Highly Enantioselective diels-alder reactions of maleimides catalyzed by activated chiral oxazaborolidines

Article abstract of DOI:10.1021/ol902865d

[Chemical equation presented] Diels-Alder reactions of various combinations of maleimides and 1,3-dienes with cationic oxazaborolidines as catalysts have been shown to be highly efficient and enantioselective.

Full text of DOI:10.1021/ol902865d

ORGANIC
LETTERS
2010
Vol. 12, No. 3
632-635
Highly Enantioselective Diels-Alder
Reactions of Maleimides Catalyzed by
Activated Chiral Oxazaborolidines
Santanu Mukherjee and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received December 11, 2009
ABSTRACT
Diels-Alder reactions of various combinations of maleimides and 1,3-dienes with cationic oxazaborolidines as catalysts have been shown to
be highly efficient and enantioselective.
A series of studies in these laboratories have demonstrated
that activation of oxazaborolidine 1 by protonation,1 methy-
lation2 or complexation with aluminum bromide3 generates
cationic species (Figure 1) which are very effective as
philes have been employed and excellent levels of diaste-
reoselectivity and enantioselectivity have been achieved.4
With the goal of expanding the dienophile scope of
Diels-Alder reactions promoted by activated oxazaboro-
lidines, we recognized that maleimides as dienophiles would
lead to useful compounds. Although maleimides have been
successfully utilized as the dienophile component for dias-
tereoselectiVe Diels-Alder reactions with a number of chiral
dienes,5 development of general catalytic enantioselective
variants has remained elusive. In 1994, we reported the first
catalytic asymmetric Diels-Alder reaction of maleimides
using a diazaluminolidine-based catalyst6 and applied this
method for the enantioselective total synthesis of gracilins
B and C.7 Although a high level of enantioselectivity was
Figure 1. Chiral oxazaborolidine and its activated derivatives.
(4) Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2100–2117, Also see:
Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650–1667.
(5) (a) Tripathy, R.; Carroll, P. J.; Thornton, E. R. J. Am. Chem. Soc.
1991, 113, 7630–7640. (b) Menezes, R. F.; Zezza, C. A.; Sheu, J.; Smith,
M. B. Tetrahedron Lett. 1989, 30, 3295–3298, and the references therein.
(6) Corey, E. J.; Sarshar, S.; Lee, D.-H. J. Am. Chem. Soc. 1994, 116,
12089–12090.
catalysts for asymmetric cycloaddition reactions, particularly
Diels-Alder processes. A wide range of dienes and dieno-
(1) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808–3809.
(2) Canales, E.; Corey, E. J. Org. Lett. 2008, 10, 3271–3273.
(3) Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129,
1498–1499.
(7) Corey, E. J.; Letavic, M. A. J. Am. Chem. Soc. 1995, 117, 9616–
9617.
10.1021/ol902865d  2010 American Chemical Society
Published on Web 01/11/2010

achieved, the range of these reactions appeared restricted to
reactive dienes and maleimides bearing a bulky aromatic
N-substituent. Recently Tan and co-workers reported a
method for catalytic enantioselective Diels-Alder reaction
of maleimides with 3-hydroxy-2-pyrones promoted by an
amino alcohol-based organocatalyst.8
These earlier studies were carried out with only C2V-
symmetrical maleimides as dienophile. The objective of the
present work was the development of a general catalytic
asymmetric Diels-Alder reaction with both symmetrical and
unsymmetrical components. The previously proposed ster-
eochemical models4 via pretransition state assemblies analo-
gous to 4 (Figure 2) predicted that position selectivity,
enantioselectivity, and diastereoselectivity were likely.
The absolute stereochemistry of the product was determined
by comparison of optical rotation with the value reported
previously for a sample of known absolute configuration.10
The absolute stereochemistry of 6a is consistent with the
model shown in Figure 2. Enantiopurity could be improved
to >99% ee after a single recrystallization from hexanes/
EtOAc. Further studies established that the same reaction
promoted by the AlBr3-activated catalyst 311 provided endo-
product 6a with even higher selectivity (98% ee) than with
catalyst 2b (see Table 1, entry 2).
Encouraged by the preliminary results, we decided to study
the substrate scope of this reaction both in terms of
maleimide and diene. We first examined the viability of
various unsymmetrical maleimides with different steric and
electronic properties (Table 1). In general, 2-bromo-
substituted maleimides were found to be more reactive than
the corresponding 2-methyl-substituted analogs. Endo-
products were obtained exclusively in all cases with excellent
ee. This method is not limited to maleimides with bulky
N-aromatic substituent: Diels-Alder reaction of N-benzyl
and N-ethyl maleimides provided products with 93-99% ee
(entry 3, 5-6).
After demonstrating success with various maleimides and
cyclopentadiene as the diene, we turned our attention to other
dienes with the results summarized in Table 2. Reactions
with less reactive dienes such as cyclohexadiene or isoprene
provided the corresponding products 7 and 8 in high yield
and ee (entries 1-5), using in some of these cases higher
reaction temperatures or longer reaction times. Although the
product derived from isoprene and N-phenylmaleimide (8a)
was obtained with high ee (entry 5), the corresponding
reaction with N-benzylmaleimide (to form 8b) was only
moderately enantioselective, even with AlBr3-activated cata-
lyst 3 (entry 6 and 7). On the other hand, reactive dienes
such as 2-triisopropylsilyloxy-1,3-butadiene reacted ef-
ficiently with N-phenylmaleimide 5f in the presence of
20 mol % catalyst 3 to produce the Diels-Alder product 9a
in high yield and excellent ee (entry 8).
Figure 2. Expected pretransition state assembly for the Diels-Alder
reaction of maleimides.
Initial studies focused on a reaction between cyclopenta-
diene with 2-methyl-N-phenylmaleimide 5a in the presence
of 20 mol % catalyst 2b (Scheme 1).9 In a typical procedure,
Scheme 1. Asymmetric Diels-Alder Reaction of
2-Methyl-N-phenylmaleimide with Cyclopentadienea
Methylcyclopentadiene, obtained by thermal cracking of
the dimer as a 1:1 mixture of 1- and 2-methyl isomers, was
also used as diene for reaction with N-phenylmaleimide 5f
(10) Adams, D. J.; Blake, A. J.; Cooke, P. A.; Gill, C. D.; Simpkins,
N. S. Tetrahedron 2002, 58, 4603–4615. Also see Supporting Information.
(11) Typical experimental procedure: A 0.25 M solution of oxazaboro-
lidine 1 in toluene (0.5 mL; 0.125 mmol) was placed in a 10 mL oven- and
flame-dried Schlenk tube and the solvent was removed under reduced
pressure. Then 0.2 mL of abs. CH2Cl2 was added and the resulting clear
solution was cooled to -25 °C (dry ice/iso-propanol) under positive nitrogen
pressure. A solution of AlBr3 (0.1 mL of 1.0M in CH2Br2; 0.1 mmol) was
added, and the reaction mixture was stirred at -25 °C for 25 min. The
resulting green solution was cooled to -78 °C (dry ice/iso-propanol), and
a solution of maleimide 5a (94 mg; 0.5 mmol) in 0.4 mL abs. CH2Cl2 was
added. At this point, cyclopentadiene (0.21 mL; 2.5 mmol) was added down
the wall of the flask over a period of two hours and stirred at -78 °C. The
reaction was monitored by TLC and judged to be complete within 8 h.
Triethylamine (0.1 mL) was added to the reaction mixture followed Et2O
(2 mL), allowed to warm to ambient temperature and filtered through a
Celite pad. The filtrate was concentrated in vacuo and the residue purified
by silica gel column chromatography using hexanes/EtOAc (5:1 to 3:1) to
obtain, as a white crystalline solid, the desired product 6a (117 mg, 0.46
mmol, 92% yield; mp 124-125 °C). For further details about determination
of enantiomeric purity by HPLC-analysis, see Supporting Information.
a Values in parentheses correspond to the sample obtained after single
recrystallization.
slow addition of 5.0 equivalents of cyclopentadiene over two
hours to a solution of 2b and 5a in dichloromethane (final
concentration is 0.5 M with respect to 5a) at -78 °C and
further reaction at this temperature for 8 h afforded the endo-
product 6a in 92% yield as a single diastereomer in 93% ee.
(8) Soh, J. Y.-T.; Tan, C.-H. J. Am. Chem. Soc. 2009, 131, 6904–6905.
(9) Twenty mol percent catalyst was used typically for faster reaction.
It is possible to reduce the catalyst loading to 10 mol % without affecting
the reaction yield and enantioselectivity. However, in these cases reactions
must be carried out in more concentrated solution (1.0 M instead of 0.5
M).
Org. Lett., Vol. 12, No. 3, 2010
633

Table 1. Catalytic Enantioselective Diels-Alder Reactions of
Table 2. Catalytic Enantioselective Diels-Alder Reactions of an
Cyclopentadiene with Various Maleimidesa
Assortment of Dienes and Maleimidesa
a Reactions were carried out using 20 mol % catalyst and 5 equiv of
cyclopentadiene at 0.5 M in CH2Cl2 with respect to the dienophiles. b In
all cases, endo-products were obtained in >99:1 dr. Enantiomeric excesses
were determined by HPLC or GC using chiral column (see Supporting
Information). Absolute configuration of products 6b-e were assigned in
analogy to 6a.
in the presence of catalyst 2b (Scheme 2).12 Although two
position isomeric13 endo-products (10 and 11) were formed
from the methylcyclopentadiene mixture in a 6:1 ratio with
high enantiomeric excess, they were easily separated by
chromatography on silica gel.
a Reactions were carried out with 20 mol % catalyst and 5 equiv of
diene at 0.5 M in CH2Cl2 with respect to the dienophiles except where
noted. b When applicable, endo-products were obtained in >99:1 dr.
Enantiomeric excesses were determined by HPLC or GC using chiral column
(see Supporting Information). Absolute configuration of the products were
assigned in analogy to 6a. c Reaction was carried out neat. d Reaction was
carried out at 1.0 M concentration. e Diene (1.5 equiv) was used.
Encouraged by the excellent results obtained with cationic
oxazaborolidines as catalysts for Diels-Alder reactions of
(12) Experimental procedure for the Diels-Alder reaction of 5f and
methylcyclopentadiene: A 0.25M solution of oxazaborolidine 1 in toluene
(0.5 mL; 0.125 mmol) was placed in a 10 mL oven- and flame-dried Schlenk
tube and the solvent was removed under reduced pressure. Then 0.3 mL of
abs. toluene was added and the resulting clear solution was cooled to -25
°C (dry ice/iso-propanol) under positive nitrogen pressure. A solution of
Tf2NH (0.2 mL of 0.5M in abs. toluene; 0.1 mmol) was added, and the
resulting solution was stirred at -25 °C for 25 min. The reaction mixture
was cooled to -78 °C (dry ice/iso-propanol), and methylcyclopentadiene
(∼1:1 mixture of 1- and 2-methyl isomers; 0.5 mL; 5.0 mmol) was slowly
added down the wall of the flask over 15 min. At this point a solution of
maleimide 5f (87 mg; 0.5 mmol) in 0.3 mL abs. toluene and 0.2 mL abs.
CH2Cl2 was added over a period of two hours. The reaction was monitored
by TLC and judged to be complete within 2 h; reaction mixture was diluted
with Et2O (2 mL), brought to ambient temperature and filtered through a
Celite pad. The filtrate was concentrated to a colorless oil. 1H-NMR analysis
of the crude product revealed a 6:1 ratio of 10 and 11. Purification by silica
gel column chromatography using hexanes/EtOAc (5:1 to 4:1 to 3:1)
afforded, as colorless crystals, 10 (mp 141-143 °C) and 11 (mp 193-195
°C). For further details about determination of enantiomeric purity by HPLC-
analysis, see Supporting Information.
maleimides, we investigated briefly the possibility that
unsymmetrical maleic anhydrides might also participate in
Scheme 2. Enantioselective Diels-Alder Reaction of
Methyl-cyclopentadienes with N-Phenylmaleimide 5f
(13) For a recent report on asymmetric Diels-Alder reactions of
substituted cyclopentadiene see: Payette, J. N.; Yamamoto, H. J. Am. Chem.
Soc. 2007, 129, 9536–9537.
634
Org. Lett., Vol. 12, No. 3, 2010

enantioselective [4 + 2] additions. We are unware of previ-
ous examples of enantioselective Diels-Alder reactions with
maleic anhydride-type substrates. Indeed the reaction of cit-
raconic anhydride 12 with cyclopentadiene and 20 mol %
of catalyst 2b in dichloromethane afforded the endo-product
13 in 75% yield14 and 91% ee (Scheme 3).15
Scheme 4. New Method for the Preparation of Precatalyst 1
Scheme 3
.
Enantioselective Diels-Alder Reaction of Citraconic
Anhydride 12 with Cyclopentadiene
standard azeotropic condensation reaction between 16 and
o-tolylboroxine17 because it is faster, simpler and leads to
pure 1.18 Precatalyst 1 synthesized via this new method was
used for the enantioselective Diels-Alder reactions reported
in this paper.
In summary, cationic oxazaborolidines are extremely
efficient catalysts for enantioselective Diels-Alder reactions
of maleimides and 1,3-dienes. The scope of the method is
broad and the reactions are generally enantiocontrolled and
diastereoselective.
Finally, we have developed an alternative method for the
preparation of oxazaborolidine 1, which involves the reaction
of easily accessible dibromo(o-tolyl)borane 15 with (S)-1,1-
diphenylpyrrolidinemethanol 16 in the presence of 2 equiv
of Hu¨nig’s base in benzene (Scheme 4).16 Simple filtration
of the resulting HBr salt with exclusion of air and moisture
gave rapid access to 1. This new method is superior to the
Acknowledgment. We thank Dr. Nathan Wallock of Sigma-
Aldrich Co. for a gift of the precatalyst 1 and triflimide.
(14) Reaction was slow and interrupted before completion (approxi-
mately 80% conversion).
(15) For determination of enantiomeric purity and absolute configuration,
see Supporting Information.
Supporting Information Available: Experimental pro-
cedures, and spectral and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Experimental procedure for the preparation of 1: (S)-1,1-Diphe-
nylpyrrolidinemethanol 15 (697 mg; 2.75 mmol) was placed in a 25 mL
oven- and flame-dried round bottom flask together with 2.5 mL abs. benzene
and Hu¨nig’s base (0.96 mL; 5.50 mmol) under nitrogen. A solution of
dibromo(o-tolyl)borane 14 (720 mg; 2.75 mmol) in 2.5 mL abs. benzene
was added via syringe over 30 min at rt. After the addition was complete,
the resulting white suspension was heated at 40 °C for 1 h. The reaction
mixture was cooled to ambient temperature and the precipitate was filtered
through a sintered glass funnel under nitrogen. The filtrate was concentrated
under reduced pressure to a pale yellow oil, which was taken in abs. toluene
to make a 0.25M solution of 1 and used subsequently for Diels-Alder
experiments. Also see Supporting Information.
OL902865D
(17) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
9992–9993.
(18) Also see: Chein, R. J.; Yeung, Y.-Y.; Corey, E. J. Org. Lett. 2009,
11, 1611–1614.
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