Useful Enantioselective Bicyclization Reactions Using an N-Protonated Chiral Oxazaborolidine as Catalyst

Article abstract of DOI:10.1021/ol035542a

(Equation Presented) Nine examples are reported of enantioselective [4 + 2] cycloaddition reactions of achiral, acyclic substrates to form chiral bicyclo[4.3.0]-nonane or bicyclo[4.4.0]decane derivatives.

Full text of DOI:10.1021/ol035542a

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3979-3982
Useful Enantioselective Bicyclization
Reactions Using an N-Protonated Chiral
Oxazaborolidine as Catalyst
Gang Zhou, Qi-Ying Hu, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received August 14, 2003
ABSTRACT
Nine examples are reported of enantioselective [4 + 2] cycloaddition reactions of achiral, acyclic substrates to form chiral bicyclo[4.3.0]-
nonane or bicyclo[4.4.0]decane derivatives.
N-Protonated oxazaborolidines such as 1 are outstandingly
powerful and useful cationic chiral catalysts for inter-
molecular enantioselective Diels-Alder reactions with achiral
substrates.1-4 Because of their potency, these catalysts effect
highly enantioselective reactions between a wide range of
dienes and dienophiles, including both acyclic and cyclic
dienes, R,â-enals, R,â-enones, R,â-unsaturated lactones, 1,4-
benzoquinones, and 1,4-benzoquinone monoketals. The
mechanistic model5,6 for these reactions allows the prediction
of the absolute stereochemistry of reaction products, another
useful aspect of this methodology. This paper deals with the
first application of N-protonated oxazaborolidine 1 to
enantioselective intramolecular Diels-Alder reactions with
achiral R,â-unsaturated aldehyde/1,3-diene and R,â-unsatu-
rated ester/1,3-diene derivatives as reactants. The literature
reports two instances of such a reaction with a chiral catalyst,
the conversion 2a f 3a in 46% ee and 80% ee and 2b f
3b in 84% yield and 92% ee.7-9
(1) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808-3809.
(2) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
9992-9993.
The intramolecular Diels-Alder reaction of the trienal 2b8
took place smoothly in the presence of 0.2 equiv of catalyst
(3) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388-6390.
(4) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650-1667.
(5) For R,â-enals, this model1 involves formyl C-H- -O hydrogen
bonding and π-π attractive interaction between the coordinated R,â-enal
and the proximate C-aryl substituent in 1. See: Corey E. J.; Lee, T. W. J.
Chem. Soc., Chem. Commun. 2001, 1321-1329.
(6) For R,â-unsaturated esters, lactones, and ketones with an R-C-H
unit, the model2 involves R-C-H- -O hydrogen bonding and π-π attractive
interaction between the coordinated dienophile and the proximate C-aryl
substituent in 1.
(7) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc. 1996,
118, 3049-3050.
(8) Furuta, K.; Kanemitsu, A.; Yamamoto, H.; Takaoka, S. Tetrahedron
Lett. 1989, 30, 7231-7232.
(9) In addition, several examples have been recorded of catalytic
enantioselective intramolecular Diels-Alder reactions with N-acyloxa-
zolidinone/trienes as reactants. See: (a) Iwasawa, N.; Sugimori, J.; Kawase,
Y.; Narasaka, K. Chem. Lett. 1989, 1947-1950. (b) Evans, D. A.; Johnson,
J. S. J. Org. Chem. 1997, 62, 786-787.
10.1021/ol035542a CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/17/2003

1 in CH2Cl2 at -78 °C after 4.5 days to give 93% yield of
the endo product 3b in 98% de and 90% ee.10 The
corresponding reaction occurred with the R-bromo trienal
2c (0.2 equiv of catalyst 1 in CH2Cl2 at -78 °C for 3 days)
intramolecular [4 + 2] cycloaddition leading to 6/6-fused
ring products as compared to the corresponding 6/5-fused
structures (which also is apparent in previous studies)12b,14
appears to be due to the less favorable [4 + 2] cycloaddition
stereoelectronics for 6/6-fused ring formation. It is interesting
in this connection that the intramolecular Diels-Alder
reaction of 8 to form 9 not only proceeds slowly relative to
2b f 3b (using 0.2 equiv of 1, no solvent, at -45 °C for 2
days) but also less stereoselectively (90% yield, 2:1 endo/
exo selectivity, 80% ee for 9 and 89% ee for the exo
diastereomer).15
to afford the endo product 3c in 98% de and 94% ee,11 [R]23
D
+136.3 (c ) 0.95, CHCl3).
R,â-Unsaturated esters are much less reactive in Lewis
acid catalyzed Diels-Alder reactions than the corresponding
R,â-unsaturated aldehydes, and this is probably why no
examples of efficient catalytic enantioselective intramolecular
reactions of this type appear in the literature.12 Nonetheless,
reaction of the triene ester 4 with 0.2 equiv of 1 (no solvent)
at 35 °C for 10 h resulted in formation of Diels-Alder adduct
5 in 75% yield (along with 20% of unchanged 4) in 98% de
and 93% ee.13 The results of this experiment are noteworthy
not only because this represents the first example of a highly
enantioselective Diels-Alder reaction of a triene ester but
also because the absolute stereochemical course of the
reaction is that predicted by the model.6 Although the
corresponding intramolecular Diels-Alder reaction of the
higher homologue 6 is also highly enantioselective under
the same conditions used for 4 f 5, to form 7 in 92% ee,
the reaction is considerably slower (with 0.2 equiv of 1 as
catalyst at 40 °C and with no solvent) and affords 41% yield
of 7 along with 45% of recovered 6.14 The lower rate of
The mixed ester, ethyl E-3,5-hexadienyl fumarate (10),
underwent intramolecular [4 + 2] cycloaddition (0.2 equiv
of 1, no solvent, 40 °C, 12 h) to afford the bicyclic lactone
11 in 71% yield (along with 10% recovered 10) with
complete diastereoselectivity and with 86% ee; [R]23 -50
D
(c ) 0.6, CHCl3).16 The absolute and relative configurations
of 11 were established by conversion of 11 to lactone triester
12 by the sequence: (1) dihydroxylation of the olefinic
linkage of 11 with OsO4-N-methylmorpholine N-oxide in
acetone-H2O and chromatographic purification of the result-
ing diol and (2) concurrent translactonization and esterifi-
cation by reaction with p-bromobenzoyl chloride in pyridine
(10) The exo/endo ratio and the enantioselectivity were determined for
3b by GC analysis using a J&W Scientific Cyclosil-B column (30 m ×
0.25 mm, 100 °C, 25 psi); retention times: 32.60 min (endo, major, 31.95
min (endo, minor), 26.75 min (exo isomer), 23.35 min (exo isomer). The
absolute configuration was determined by comparison of optical rotation
(14) The relative configuration for 7 was determined from 1H NMR NOE
data. The exo/endo ratio was determined by GC analysis using a J&W
Scientific Cyclosil-B column (30 m × 0.25 mm, 120 °C, 25 psi); retention
times: 16.1 min (endo, major), 17.2 min (exo, minor). Enantioselectivity
was determined by reduction with NaBH4 to the corresponding alcohol,
conversion to the (R)-MTPA ester derivative, and 1H NMR integration (500
MHz, CDCl3): δ 4.30 (dd, 1H, J ) 10.5, 3.5 Hz, major), 4.24 (dd, 1H, J
) 10.5, 3.5 Hz, minor). The absolute configuration was determined by
conversion of the Diels-Alder adduct to the known benzyl ester with lithium
with the known adduct,8 [R]20 +10 (c ) 1.06, CHCl3).
D
(11) Enantioselectivity was determined by reduction with NaBH4 to the
corresponding alcohol, conversion to the (R)-MTPA ester derivative and
1H NMR integration (500 MHz, CDCl3): δ 3.57 (s, MeO, 3H, minor, 3.55
(s, MeO, 3H, major; 19F NMR integration (376.2 MHz, CDCl3): δ -71.79
(s, CF3, major), -71.89 (s, CF3, minor). The absolute configuration of adduct
3c follows from its high dextrorotation ([R]23D +136) by application of the
confirmational preference/R-bromocarbonyl correlation (see, Corey, E. J.;
Ursprung, J. J. J. Am. Chem. Soc. 1955, 77, 3667-3668), from analogy
with 3b, and from the mechanistic model.5
benzyl oxide and measurement of optical rotation, [R]23 +6.9 (c ) 1.00,
D
CHCl3); see, Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1988, 110, 1238-1256.
(15) The exo/endo ratio and the enantioselectivity were determined by
GC analysis using a J&W Scientific Cyclosil-B column (30 m × 0.25 mm,
120 °C, 25 psi), retention times: 21.99 min (exo, minor), 25.00 min (exo,
major), 27.33 min (endo, minor), 28.28 min (endo, major). The absolute
configuration of 9 was assigned by analogy with 3b and 3c.
(12) See, for example: (a) Roush, W. R.; Gillis, H. R.; Ko, A. I. J. Am.
Chem. Soc. 1982, 104, 2269-2283. (b) Wullf, W. D.; Powers, T. S. J.
Org. Chem. 1993, 58, 2381-2393.
(13) The relative configuration for 5 was determined from 1H NMR NOE
data. The exo/endo ratio was determined by GC analysis using a J&W
Scientific Cyclosil-B column (30 m × 0.25 mm, 100 °C, 25 psi); retention
times: 18.4 min (endo, major) 23.2 min (exo, minor). Enantioselectivity
was determined by reduction with NaBH4 to the corresponding alcohol,
conversion to the (R)-MTPA ester derivative and 1H NMR integration (500
MHz, CDCl3): δ 4.13 (dd, 1H, J ) 11.0, 4.5 Hz, major), 4.38 (dd, 1H, J
) 11.0, 4.5 Hz, minor). The absolute configuration was determined from
(16) Diastereoselectivity was determined by 1H NMR analysis and
relative configuration was deduced from NOE data. Enantioselectivity were
determined by GC analysis of the partly reduced product using a J&W
Scientific Cyclosil-B column (30 m × 0.25 mm, 130 °C, 25 psi, retention
times: 23.9 min (endo, major), 24.6 min (endo, minor). The formation of
11 from 10 can be understood in terms of an exo-COOEt selectivity in the
[4 + 2] cycloaddition (with 1 coordinating to the COOEt group). The same
diastereoselectivity has been noted for the Et2AlCl-catalyzed cyclization
of 10 by: Chen, C.-Y.; Hart; D. J. J. Org. Chem. 1993, 58, 3840-3849.
the rotation of the known12 corresponding alcohol, [R]23 +38 (c ) 1.00,
D
CHCl3).
3980
Org. Lett., Vol. 5, No. 21, 2003

containing 4-(dimethylamino)pyridine at 23 °C for 24 h, (3)
recrystallization of 12 from hexane-benzene (10:1), and (4)
single-crystal X-ray analysis which revealed the absolute
structure as 12. The three-step synthesis of the bridged-ring
lactone 12 from the achiral precursor with the creation of
two rings and five stereocenters provides one illustration of
the power of the enantioselective methodology based on the
chiral catalyst 1.
the transformation 16 f 17 was considerably slower than
13 f 14. Reaction of 16 catalyzed by 0.2 equiv of 1 at 40
°C, neat, for 12 h produced 17 as major product (90% ee)
in 4:1 excess over the minor diastereomeric byproduct
(corresponding cis-fused structure).18 Treatment of 17 with
THF-aqueous HCl produced the trans decalone 18, [R]27
D
+26 (c ) 1.1, CHCl3).
The nine substrates for the intramolecular Diels-Alder
reactions described above were synthesized readily using
well-known methodology. Specifically, aldehydes 2b and 2c
were made from the corresponding ethyl esters by reduction
COOEt f CH2OH (DIBAL-H) followed by Swern oxidation.
The requisite esters were prepared by two-carbon Wittig
coupling from E-5,7-octadienal that was made by the
sequence shown in Scheme 1. Substrate 4 was also prepared
The catalytic enantioselective [4 + 2] cyclization of the
siloxydiene-R,â-unsaturated esters 13a and 13b to 14a and
14b, respectively, was also investigated. The transformation
13a f 14a occurred cleanly with 0.2 equiv of 1 in CH2Cl2
(0.3 M) at -50 °C for 2 days and -20 °C for 1 day to give
14a in 93% yield, 99% de and 96% ee.17 The conversion of
13b to 14b was effected in 92% yield, 6:1 dr and 92% ee
with 0.2 equiv of 1 in CH2Cl2 at 0 °C for 2 days.17 Products
Scheme 1
14a and 14b were converted to the same keto ester 15, [R]27
D
+40 (c ) 1.1, CHCl3) by exposure to a solution of aqueous
HCl-THF. Treatment of 15 with DBU in C6H6 at 80 °C for
2 h resulted in complete conversion to the 6/5 cis-fused
hydrindanone. The absolute configuration of 15 was estab-
lished by transformation into (+)-(octahydro-1-inden-4-yl)-
methanol, [R]27D +30 (c ) 0.6, CHCl3), using the sequence
(1) ethylenethioketal formation (ethanedithiol-BF3‚Et2O,
CH2Cl2), (2) reduction of COOMe to CH2OH with LiAlH4
in ether at 23 °C for 2 h, and (3) Raney nickel desulfurization
in EtOH at reflux for 8 h. An authentic sample of (+)-
(octahydro-1-inden-4-yl)methanol was synthesized from 5
by catalytic hydrogenation and carboxyl f CH2OH reduction
by LiAlH4. An advantage of using 13b over 13a derives from
the greater stability of the former which allows the reaction
to be conducted at 0 °C.
from E-5,7-octadienal by Wittig condensation. Substrate 6
was similarly made from E-6,8-nonadienal whose synthesis
and the further transformation to 8 are outlined in Scheme
2. In our experience, the synthetic pathways summarized in
Scheme 2
The construction of the decalin system from silyloxy-
diene-R,â-unsaturated ester 16, homologous reaction to 13
f 14, was also investigated. As expected from the relative
rates of cyclization of substrates 4 and 6, as discussed above,
(17) The relative stereochemistry of products 14a and 14b was deter-
mined from analysis of 1H NMR/NOE data. The exo/endo ratio and
enantioselectivity were determined by GC analysis of the desilylation
product 15 using a J&W Scientific Cyclosil-B column (30 m × 0.25 mm,
150 °C, 25 psi), retention times: 16.29 min (exo), 16.88 min (exo), 17.71
min (endo, major), 18.63 min (endo, minor). The absolute configuration
was determined by chemical correlation, as described.
Schemes 1 and 2 are simpler and more effective than the
previously described routes to such Diels-Alder substrates.
The synthesis of 10 is summarized in Scheme 3.
The synthesis of the silyloxydienes 13a and 13b was
accomplished by the sequence shown in Scheme 4. Substrate
Org. Lett., Vol. 5, No. 21, 2003
3981

Scheme 3
Scheme 4
16 was synthesized in an analogous manner from 7,7-
dimethoxyheptanal (from ozonization of cycloheptene).
The experiments described above support the proposition
that the oxazaborolidine 1 is a useful reagent for the Diels-
Alder bicyclization of a variety of achiral triene substrates
to form chiral bicyclo[4.3.0]nonane or bicyclo[4.4.0]decane
derivatives with good yields and high enantioselectivities.
Since the chiral ligand from which 1 is prepared, diphenyl-
prolinol, is easily and efficiently recovered for reuse in each
of the nine cases reported herein, this methodology is
attractive for multistep synthesis. Another important feature
is the predictability of absolute configuration of the internal
Diels-Alder products. In each case described above, the
mechanistic model accurately predicts the stereochemical
course of the bicyclization reaction. The operational de-
tails of catalyst preparation and application to the bi-
cyclization process are given in the illustrative procedures
below.19,20
Acknowledgment. This research was assisted financially
by funding from Pfizer, Inc. We are grateful to Dr. Do Hyun
Ryu for helpful advice and Dr. Richard Staples for the X-ray
determination of structure 12.
(18) The exo/endo ratio and the enantioselectivity were determined by
GC analysis using a J&W Scientific Cyclosil-B column (30 m × 0.25 mm,
135 °C, 25 psi), retention times: 36.33 min (exo), 37.26 min (exo), 41.28
min (endo, major), 41.70 min (endo, minor). The absolute configuration
was assigned from the dextrorotation of 18 and also by analogy with
dextrorotatory ketone 15.
Supporting Information Available: Experimental data
are given for the preparation of substrates and for the internal
[4 + 2] cycloaddition reactions that are described herein.
X-ray data for 12 are also included. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Preparation of Catalyst 1. A 100-mL, two-necked, round-bottomed
flask equipped with a stir bar, a glass stopper, and a 50-mL pressure-
equalizing addition funnel (containing a cotton plug and ca. 10 g of 4 Å
molecular sieves, and functioning as a Soxhlet extractor) fitted on top with
a reflux condenser and a nitrogen inlet adapter was charged with (S)-(-)-
R,R-diphenyl-2-pyrrolidinemethanol (41 mg, 0.16 mmol), tri-o-tolylboroxine
(19 mg, 0.054 mmol), and 30 mL of toluene. The resulting solution was
heated to reflux (bath temperature ∼ 145 °C). After 4 h, the reaction mixture
was cooled to ca. 60 °C and the addition funnel and condenser were quickly
replaced with a short-path distillation head. The mixture was concentrated
by distillation (air-cooling) to a volume of ca. 10 mL. This distillation
protocol was repeated three times by re-charging with 3 × 10 mL of toluene.
The solution was then allowed to cool to room temperature and the
distillation head was quickly replaced with a nitrogen inlet adapter.
Concentration at (ca. 0.1 Torr for 30 min afforded the corresponding
oxazaborolidine as a clear oil. To the neat waxlike oxazaborolidine precursor
(0.16 mmol, theoretical) at -78 °C was added dropwise a solution of
trifluoromethanesulfonimide (0.200 M in CH2Cl2, freshly prepared, 667 µL,
0.133 mmol). After 10-15 min at -20 °C, a colorless homogeneous solution
of cationic catalyst 1 was obtained.
OL035542A
(20) Synthesis of (+)-(4R,3aR,7aR)-4-Methyl-2,3,3a,4,5,7a-hexahydro-
1H-indene-4-carboxaldehyde (3b). To a CH2Cl2 solution of 0.2 equiv of
the freshly prepared catalyst 1 was added neat enal 2b (109 mg, 0.665 mmol)
at -78 °C. The reaction mixture was stirred at -78 °C for 108 h and then
quenched by addition of 100 µL of Et3N. After the mixture had warmed to
room temperature, the residue was purified directly by silica gel chroma-
tography (elution with hexane then hexanes-ether 20:1) to afford the Diels-
Alder adduct 6 (101 mg, 93%) as a colorless oil: [R]20D ) +10 (c ) 1.06,
CHCl3, 98% de, 90% ee); TLC (hexanes-EtOAc, 4:1), Rf ) 0.30; 1H NMR
(500 MHz, CDCl3) 9.48 (s, 1H, CHO), 5.84 (d, J ) 10.3 Hz, 1H, H7),
5.59 (dq, J ) 2.6, 10.2 Hz, 1H, H6), 2.44 (dq, J ) 3.4, 18.1 Hz, 1H), 1.90
(m, 2H), 1.78 (dq, J ) 2.0, 18.0 Hz, 1H), 1.70 (m, 2H), 1.54(m, 2H), 1.18
(m, 2H), 1.01 (s, 3H, Me); 13C NMR (125 MHz, CDCl3) δ 205.8, 129.5,
124.5, 47.9, 46.6, 39.4, 33.6, 28.9, 23.8, 22.3, 12.6; MS m/e 164.0 (M+);
FTIR (film) 3019, 2957, 2870, 1725, 1684, 1456, 1397, 1267 cm-1
.
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Org. Lett., Vol. 5, No. 21, 2003