Asymmetric Diels-Alder reactions of chiral cyclopropylidene imide dienophiles: Preparation of gem-dimethyl- and spirocyclopropane norbornyl carboxylic acids

Article abstract of DOI:10.1021/jo052516c

A highly efficient strategy has been developed for the rapid asymmetric synthesis of gem-dimethyl and spirocyclopropyl norbornyl carboxylic acids. The key transformation involved the unprecedented asymmetric Diels-Alder reaction of highly reactive β,β-cyc

Full text of DOI:10.1021/jo052516c

SCHEME 1
Asymmetric Diels-Alder Reactions of Chiral
Cyclopropylidene Imide Dienophiles: Preparation
of gem-Dimethyl- and Spirocyclopropane
Norbornyl Carboxylic Acids
Jeffrey T. Kuethe,* Dalian Zhao, Guy R. Humphrey,
Michel Journet, and Arlene E. McKeown
Department of Process Research, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New Jersey 07065
jeffrey_kuethe@merck.com
ReceiVed December 6, 2005
SCHEME 2
A highly efficient strategy has been developed for the rapid
asymmetric synthesis of gem-dimethyl and spirocyclopropyl
norbornyl carboxylic acids. The key transformation involved
the unprecedented asymmetric Diels-Alder reaction of
highly reactive â,â-cyclopropyl-R,â-unstaturated N-acylox-
azolidinones with cyclopentadiene affording the adducts in
high yield and de.
asymmetric catalytic Diels-Alder reactions, these methods have
remained mainly academic. In recent years, auxiliary-based
asymmetric Diels-Alder reactions have become particularly
attractive since many oxazolidinone auxiliaries are inexpensive,
commercially available in both optical antipodes, and can easily
be recovered and recycled after nondestructive cleavage from
the substrate. While monosubstituted (R1 ) H) and E-disub-
stituted (R1 * H) imide dienophiles 1 readily participate in both
auxiliary-based and catalytic Diels-Alder reactions with various
dienes, â,â-disubstituted imide dienophiles of type 3 exhibit poor
reactivity and generally give a mixture of all four possible
diastereomeric products (Scheme 1). Indeed, reaction of 3 with
cyclopentadiene was reported to only proceed at rt to give 4 as
a mixture of diastereomers in 38% combined yield.2a This poor
reactivity was attributed to steric influences where the Z-
substituent destabilizes the S-cis unsaturated carbonyl conforma-
tion.
The Diels-Alder reaction provides a highly efficient and
rapid means of constructing functionalized six-membered ring
systems often with complete control of the regio-, diastereo-,
and enantioselectivity. In particular, asymmetric Diels-Alder
reactions are among the most powerful and versatile organic
transformations in chemical synthesis.1 The pioneering work
of Evans2 using oxazolidinones derived from amino alcohols
as chiral auxiliaries has led to the discovery of a number of
chiral Lewis acid catalytic variants.1 In addition, recent develop-
ments employing organocatalysis have emerged as a remarkable
means of controlling enantioselective catalytic cycloaddition
reactions.3,4 Due to the limited availability, cost, and high
catalyst loading (typically 10-30 mol %) associated with most
(1) For recent reviews of enantioselective Diels-Alder reactions, see:
(a) Evans, D. A.; Johnson, J. S. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; Vol. 3, p 1177 and references therein. (b) Oppolzer, W. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New
York, 1991; Vol. 5. (c) Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92, 1007.
(d) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289. (e) Corey, E. J. Angew.
Chem., Int. Ed. 2002, 41, 1650.
Recently, we required an efficient route for the construction
of the gem-dimethylnorbornyl carboxylic acid 55 (Scheme 2).
We reasoned that an asymmetric Diels-Alder reaction between
the highly reactive â,â-cyclopropyl-R,â-unsaturated N-acylox-
(2) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238. (b) Evans, D. A.; Chapman, K. T.; Bisaha, J. Tetrahedron Lett.
1984, 25, 4071. (c) Evans, D. A.; Chapman, K. T.; Hung, D. T.; Kawaguchi,
A.; Bisaha, J. Angew. Chem., Int. Ed. Engl. 1987, 26, 1184.
(3) For reviews on organocatalysis, see: (a) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481. (b) List, B. Tetrahedron 2002, 58, 5573. (c)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (d) Acc.
Chem. Res. 2004, 37 (8) (special issue on organocatalysis). (e) Bolm, C.;
Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem., Int. Ed. 2005, 44, 1758.
(4) For organocatalysis in asymmetric Diels-Alder reactions, see: (a)
Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243. (b) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 2458. (c) Kim, K. H.; Lee, S.; Lee, D.-W.; Ko, D.-H.; Ha,
D.-C. Tetrahedron Lett 2005, 46, 5991.
(5) The enantiomer of acid 5 has been reported to have cytotoxic effects
on cancer cell lines, see: Jaeger, W.; Paesler, B.; Buchgauer, G.; Chiba, P.
Pharmazie 1995, 50, 619.
10.1021/jo052516c CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/09/2006
2192
J. Org. Chem. 2006, 71, 2192-2195

SCHEME 3
SCHEME 4
a mixture of 11 and 1.6 equiv of cyclopentadiene at -75 °C.
HPLC analysis of the crude reaction mixture revealed the
formation of 4 diastereomeric products in a ratio of 91:1.9:6.6:
0.5 (12/13/14/15) and in a combined yield of 97%.10 The desired
endo adduct 12 was obtained in diastereomerically pure form
(> 99:1, 80% isolated yield) by recrystallization of the crude
reaction mixture from either n-heptane or cyclohexane. The
relative and absolute stereochemistry of 12 was unambiguously
established by single-crystal X-ray analysis.11 It should also be
noted that the use of Me2AlCl in either heptane or hexanes gave
slightly higher de than Et2AlCl solutions, and the use of either
of these Lewis acids as solutions in toluene resulted in a
substantial erosion in de.
azolidinones of type 7 and cyclopentadiene could offer a rapid
method for the preparation of spirocyclopropyl norbornyl
carboxylic acid 6.6,7 Since the cyclopropane ring can be
considered as a gem-dimethyl surrogate, this approach was
particularly attractive and would circumvent the poor diaste-
reoselective Diels-Alder reaction of 3. In this paper, we
document a practical and highly efficient synthesis of 5 and 6
via the unprecedented asymmetric Diels-Alder reactions of
chiral cyclopropylidene imide dienophiles 7 with cyclopenta-
diene.
Inspired by previous reports from these laboratories,12 we
examined the Diels-Alder reaction of the conformationally
constrained cyclopropylidene imide dienophile 18. Dienophile
18 was prepared in excellent overall yield by the procedure
outlined in Scheme 4. After considerable optimization, it was
discovered that slow addition of NEt3 to a mixture of mesyl
acid 8, LiCl, pivalyl chloride, and aminoindanone 16 in THF
at -10 to -20 °C followed by the addition of water afforded
the highly crystalline intermediate 17 in 88% yield. Subsequent
reaction with NEt3 in THF at 45-50 °C gave 18 in 85% overall
yield. This two-step process eliminated undesired Michael
addition products resulting from the addition of either chloride
or pivalic acid to the reactive cyclopropenyl imide double
bond.6,13 The Diels-Alder reaction of 18 was conducted below
-70 °C with 1.4 equiv of Me2AlCl in the presence of 1.6 equiv
of cyclopentadiene and provided a mixture of endo product 19
and exo product 20 as the exclusive products in a 97.3:2.7 ratio
in near-quantitative yield. There were no detectable amounts
of any other diastereomeric products by either proton NMR or
HPLC analysis of the crude reaction mixture. Attempts to
upgrade the diastereomeric ratio of 19 by crystallization from
a number of solvent systems only resulted in a net upgrade of
the undesired exo product 20, and this mixture was used crude
without purification.
Our first challenge was preparation of the required cyclo-
propylidene imide dienophile (Scheme 3). Reaction of the
known mesyl acid 88 with oxalyl chloride followed by treatment
with the lithium salt of oxazolidinone 10 under standard
conditions2a afforded the desired cyclopropylidene imide di-
enophile 11 in <30% isolated yield. No acylated intermediates
bearing a mesyloxy group were identified in the crude reaction
mixture. Elimination of the mesyl group of 8 by treatment with
45% KOH in water followed by an extractive workup gave
cyclopropenyl acid 9 in 97% isolated yield. Treatment of the
acid chloride of acid 9 with the lithium salt of oxazolidinone
10 was equally unsuccessful, giving 11 in <30% yield. In each
of these cases, significant unidentified impurities resulting from
apparent ring-opening of the cyclopropyl group were observed.
Reaction of 9 with pivaloyl chloride in the presence of LiCl,
NEt3, and oxazolidinone 10 afforded the desired 11 in an
unoptimized 75% yield.9 The product was conveniently obtained
by direct crystallization from the crude reaction mixture. The
Diels-Alder reaction of 11 with cyclopentadiene was conducted
by slow addition of 1.4 equiv of Me2AlCl (1 M in hexanes) to
(6) For a review on the synthesis of various alkylidenecyclopropanes,
see: Brandi, A.; Goti, A. Chem. ReV. 1998, 98, 589.
(7) For the use of alkylidenecyclopropanes as dienophiles in racemic
Diels-Alder reactions, see: (a) Heiner, T.; Michalski, S.; Gerke, K.; Kuchta,
G.; Buback, M.; de Meijere, A. Synlett 1995, 355. (b) Seyed-Mahdavi, F.;
Teichmann, S.; De Meijere, A. Tetrahedron Lett. 1986, 27, 6185. (c)
Spitzner, D.; Engler, A.; Wagner, P.; de Meijere, A.; Bengtson, G.; Simon,
A.; Peters, K.; Peters, E.-M. Tetrahedron 1987, 43, 3213. (d) Hadjiarapo-
glou, L.; Klein, I.; Spitzner, D.; de Meijere, A. Synthesis 1996, 525.
(8) Limbach, M.; Dalai, S.; de Meijere, A. AdV. Synth. Catal. 2004, 346,
760.
(10) The assignment of products 13-15, which were not isolated, was
based on NMR experiments on the crude reaction mixture.
(11) See the Supporting Information.
(12) Davies, I. W.; Senanayake, C. H.; Castonguay, L.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1995, 36, 7619.
(13) For catalytic hydrogenation of a similar spirocyclopropyl norbornyl
system, see: Gream, G. E.; Pincombe, C. F. Aust. J. Chem. 1974, 27, 543.
(9) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
J. Org. Chem, Vol. 71, No. 5, 2006 2193

SCHEME 5
SCHEME 6
(Scheme 6). Treatment of 25 with Me2AlCl in the presence of
cyclopentadiene at low temperature resulted in no reaction. Upon
warming to rt and stirring for 12 h, conversion to adducts 26-
29 was noted. The reaction afforded the expected mixture of
diastereomers 26-29 in a 53:35:3.5:2.5 ratio and 79% combined
yield.14 This result demonstrated that the conformationally
constrained cis-aminoindanone auxiliary provided a bias for
approach of the dienophile, although no real facial selectivity
was observed. Transfer hydrogenation of the crude reaction
mixture (Pd/C, cyclohexene, reflux) followed by fractional
crystallization from heptane gave the major product 30 in 25%
overall yield from 25. Hydrolysis of 30 with lithium peroxide
gave 5 in 95% isolated yield.
In summary, we have outlined a highly efficient and practical
asymmetric method for the preparation of both gem-dimethyl
and spirocyclopropyl norbornyl carboxylic acids 5 and 6 with
complete control of both the regio- and absolute stereochemistry.
This protocol provides enantiopure 5 in just six synthetic steps
from readily available mesyl acid 8, requires no chromatographic
separations, and the chiral auxiliary can be recovered and
recycled. The unprecedented selectivity of the highly reactive
â,â-cyclopropyl-R,â-unsaturated N-acyloxazolidinones 11 and
18 in the Diels-Alder reactions with cyclopentadiene offer their
use in the asymmetric preparation of other novel carbo- and
heterocyclic systems.
Reduction of the double bond in the Diels-Alder adducts
12 and 19 was accomplished by either catalytic hydrogenation
over 10% Pd/C or transfer hydrogenation over 10% Pd/C
employing cyclohexene (Scheme 5). In both cases, reduced
compounds 21 and 22 were obtained in quantitative yield. Under
these reaction conditions, no detectable amounts of over-
reduction of the cyclopropane ring to the gem-dimethyl ana-
logues was observed, even upon prolonged reaction. At this
stage, the diastereomeric purity of 22 could be upgraded to
>99:1 by crystallization from heptane (80% overall yield from
18). The relative and absolute stereochemistry of 22 was
unambiguously established by single-crystal X-ray analysis.11
Hydrolysis of either 21 or 22 was performed with LiOOH,
prepared from 2 equiv of LiOH and 3 equiv of H2O2 in a THF/
water solvent system.2 Upon reaction completion, the excess
peroxide was quenched with sodium sulfite, and THF was
removed under reduced pressure leaving an aqueous slurry of
the auxiliary which could be isolated by filtration in >95%
recovered yield and in analytically pure form. The resulting
aqueous layer was made acidic with concentrated HCl and
crystalline acid 6 was obtained in 95% yield and in analytically
pure form after filtration and drying. Finally, catalytic hydro-
genation of acid 6 over PtO2 in acetic acid for 24 h gave the
desired gem-dimethylnorbornyl carboxylic acid 5 in 99% yield.13
Interestingly, reduction of 22 under a number of standard
conditions including LiBH4, NaBH4, or LiAlH4 provided a
mixture of alcohol 23 (80%) and amide 24 (20%) where
reduction of the oxazolidinone carbonyl was competitive with
reduction of the N-acyl carbonyl. Similar results were also
observed for 21. On the other hand, in situ borane reduction of
6 gave alcohol 23 in 97% yield.
Experimental Section
Melting points are uncorrected. All solvents and reagents were
used as received from commercial sources. Analytical samples were
obtained by chromatography on silica gel using an ethyl acetate-
hexanes mixture as the eluent unless otherwise specified.
(3S,8aR)-3-(3′R,4′S,6′S)-5′,1′′-Spirocyclopropane(bicyclo[2.2.1]-
hepten-4′-yl)carbonyl-3,3a,8,8a-tetrahydroindeno[1,2-d]oxazol-
2-one (19). To a -75 °C solution of 40.0 g (157 mmol) of 18 in
300 mL of CH2Cl2 was added 16.6 g (249 mmol) of freshly distilled
cyclopentadiene. To the resulting mixture was added dropwise 218
mL (218 mmol) of a 1 M solution of Me2AlCl in hexane at such
a rate that the internal temperature was maintained below -67 °C.
After 30 min, the reaction mixture was quenched by being poured
slowly into 300 mL of 1 M HCl, the biphasic solution was mixed
well for 30 min, and the layers were separated. The aqueous layer
(14) No attempt was made to isolate the individual diastereomers, and
structural assignments were based on NMR experiments and analogy to
products 13-15.
We also thought it worth investigating the Diels-Alder
reaction of dimethyl imide 25 as a more direct approach to 5
2194 J. Org. Chem., Vol. 71, No. 5, 2006

was extracted with 50 mL of CH2Cl2. The combined extracts were
concentrated under reduced pressure to give 49.1 g (97%) of a 97.3:
2.7 mixture of 19/20 which was used in the next reaction without
further purification. An analytical sample could be obtained by
recrystallization from cyclohexane to give 19 as a white solid: mp
of lithium hydroxide hydrate in 30 mL of water at such a rate that
the internal temperature did not rise above 5 °C. The resulting
mixture was stirred at 5 °C for 1.5 h, allowed to warm to rt, and
quenched by slowly pouring the reaction mixture into a solution
of 39.0 g (309 mmol) of Na2SO3 in 130 mL of water at 10 °C. The
mixture was stirred for 30 min, and the THF was removed under
reduced pressure. The resulting slurry was stirred at rt for 12 h
and filtered. The wet cake was washed with water and dried under
vacuum/N2 sweep for 12 h to provide 13.0 g (95%) of 16 as an
analytically pure white solid. The filtrate was transferred to a 500
mL flask and made acidic (pH ) 1) with concd HCl. The slurry of
the crystalline acid 6 was stirred for 1 h at rt and filtered. The wet
cake was washed with water and dried under vacuum/N2 sweep
for 12 h to provide 12.3 g (95%) of 6 as a white solid: mp 73-74
°C; [R]23D +67.4 (c 0.024, EtOH); 1H NMR (CDCl3, 400 MHz) δ
0.30 (m, 1H), 0.51 (m, 1H), 0.61 (m, 1H), 0.96 (m, 1H), 1.44 (m,
1
139-140 °C (cyclohexane); H NMR (CDCl3, 400 MHz) δ 0.58
(m, 1H), 0.70 (m, 3H), 1.57 (d, 1H, J ) 8.2 Hz), 1.91 (d, 1H, J )
8.2 Hz), 2.13 (s, 1H), 3.28 (s, 1H), 3.36 (d, 2H, J ) 3.4 Hz), 4.19
(d, 1H, J ) 3.4 Hz), 5.22 (m, 1H), 5.88 (d, 1H, J ) 6.9 Hz), 5.99
(m, 1H), 6.45 (m, 1H), 7.29 (m, 3H), 7.56 (d, 1H, J ) 7.4 Hz); 13
C
NMR (CDCl3, 100 MHz) δ 9.2, 11.9, 28.6, 38.1, 48.9, 49.7, 49.9,
53.1, 63.2, 77.9, 125.3, 127.1, 128.2, 129.8, 133.1, 137.7, 139.6,
139.7, 152.9, 173.7. Anal. Calcd for C20H19NO2: C, 74.75; H, 5.96;
N, 4.36. Found: C, 74.79; H, 5.94; N, 4.31.
(3S,8aR)-3-(3′S,4′S,6′R)-5′,1′′-Spirocyclopropane(bicyclo[2.2.1]-
heptan-4′-yl)carbonyl-3,3a,8,8a-tetrahydroindeno[1,2-d]oxazol-
2-one (22). To a solution of 49.1 g (151.12 mmol) of crude 19 in
150 mL of EtOAc was added 159 mL (1.57 mol) of cyclohexene
followed by 5.00 g of 10% Pd/C (wet, Degussa type E101 NE/W).
The mixture was then heated to reflux for 1.5 h, cooled to rt, and
filtered through a pad of Celite. The solvent was removed under
reduced pressure, and the residue (HPLC assay 49.4 g, 100%) was
suspended in 275 mL of heptane. The mixture was heated to reflux
and then cooled to 45 °C, at which point the product began to
crystallize. The resulting slurry was reheated to 50 °C and stirred
for 30 min, cooled to 45 °C and stirred for 30 min, and then allowed
to cool to rt. After being stirred for 2 h at rt, the solid was collected
by filtration to give 43.8 g (89%) of a 98:2 mixture of 22 and the
corresponding exo isomer. The resulting solid was slurried in 220
mL of heptane and heated to reflux and then allowed to cool slowly
to rt. The resulting solid was then collected by filtration and was
washed with 25 mL of cold heptane to afford 39.5 g (80% overall)
of 22 as a diastereomerically pure white solid: mp 88-89 °C
5H), 1.75 (m, 2H), 2.67 (s, 1H), 2.78 (m, 1H), 11.8 (br s, 1H); 13
C
NMR (CDCl3, 100 MHz) δ 7.8, 15.6, 23.7, 26.7, 27.6, 39.3, 52.6,
46.7, 51.7, 179.8. Anal. Calcd for C10H14O2: C, 72.26; H, 8.49.
Found: C, 72.27; H, 8.74.
(1S,3R,6S)-3,3-Dimethylbicyclo[2.2.1]heptane-2-carboxylic Acid
(5). To a solution of 5.00 g (30.1 mmol) of 6 in 35 mL of acetic
acid was added 200 mg of PtO2. The resulting mixture was stirred
at 65 °C at 40 psi H2 for 24 h and then cooled to rt. The reaction
mixture was filtered through Celite eluting with EtOAc. The solvent
was removed under reduced pressure, and the crude product was
recrystallized from MeOH/H2O to provide 5.01 g (99%) of 5 as a
colorless solid: mp 46-47 °C; [R]23 + 10.1 (c 0.0203, EtOH);
D
1H NMR (CDCl3, 400 MHz) δ 1.05 (s, 3H), 1.13 (s, 3H), 1.25-
1.44 (m, 3H), 1.68 (m, 2H), 1.86 (m, 1H), 1.97 (m, 1H), 2.37 (m,
1H), 2.44 (m, 1H), 12.0 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 21.5, 22.9, 24.6, 32.0, 37.6, 38.5, 40.9, 49.1, 56.2, 180.7. Anal.
Calcd for C10H16O2‚1/4 H2O: C, 69.53; H, 9.63. Found: C, 69.82;
H, 9.66.
1
(heptane); H NMR (CDCl3, 400 MHz) δ 0.26 (m, 1H), 0.59 (m,
1H), 0.69 (m, 1H), 0.80 (m, 1H), 1.30 (m, 1H), 1.31-1.57 (m,
4H), 1.75 (m, 1H), 1.90 (m, 1H), 2.75 (m, 1H), 3.36 (m, 2H), 3.89
(m, 1H), 5.22 (m, 1H), 5.92 (m, 1H), 7.28 (m, 3H), 7.68 (d, 1H,
J ) 7.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 9.1, 16.5, 23.9, 26.5,
28.4, 38.1, 39.9, 42.8, 47.3, 50.9, 63.3, 76.8, 125.2, 127.2, 128.2,
129.8, 139.6, 152.8, 173.9.
(1S,3R,6S)-2,1′-Spirocyclopropane(bicyclo[2.2.1]heptane)-1′-
carboxylic Acid (6). To a 0 °C solution of 25.0 g (77 mmol) of 22
in 125 mL of THF was added 26.3 g (232 mmol) of a 30% solution
of H2O2. To the resulting solution was added 4.87 g (116 mmol)
Acknowledgment. We thank Lisa DiMichele and Peter G.
Dormer of Merck & Co., Inc., for valuable NMR assistance.
Supporting Information Available: Experimental details,
characterization data for all new compounds, X-ray crystallographic
data, and ORTEP diagrams for 12 and 22. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO052516C
J. Org. Chem, Vol. 71, No. 5, 2006 2195