Tetrazolic acid functionalized dihydroindol: Rational design of a highly selective cyclopropanation organocatalyst

Article abstract of DOI:10.1021/jo070519e

(Chemical Equation Presented) Herein we wish to report our development of an improved catalyst (S)-(-)-indoline-2-yl-1H-tetrazole (1) for the enantioselective organocatalyzed cyclopropanation of α,β-unsaturated aldehydes with sulfur ylides. The new organo

Full text of DOI:10.1021/jo070519e

nation, using iodomethylzinc with C2-symmetric disulfonamide
ligands5 and Ti-taddolates.6
Tetrazolic Acid Functionalized Dihydroindol:
Rational Design of a Highly Selective
Cyclopropanation Organocatalyst
An increasingly important reaction type features a nucleophile
undergoing intermolecular Michael addition forming an enolate
followed by intramolecular ring closure accompanied by loss
of leaving group either present on the Michael acceptor or at
the nucleophile furnishing cyclopropanated product.7 This
reaction type is classified as a Michael initiated ring closure
(MIRC) reaction. The most commonly employed nucleophiles
in MIRC are R-halocarbanions,8 sulfur ylides,9 phosphorus
ylides,10 arsenium ylides,11 and telleronium ylides12 allowing a
range of structurally divergent substrates to be reacted, thus
creating a plethora of cyclopropane architectures.
In an important paper Ley et al. disclosed an intermolecular
asymmetric organocatalyzed cyclopropanation catalyzed by
quinine alkaloids.13 The reaction incorporates R-halocarbonyls,
R,â-unsaturated ketones, or esters coupled with an external base.
In another seminal paper, published by MacMillan et al., (S)-
(-)-indoline-2-carboxylic acid catalyzes the intermolecular
enantioselective organocatalytic cyclopropanation utilizing R,â-
unsaturated aldehydes as Michael acceptors, providing cyclo-
propated products in enantiomeric excesses up to 95%.14 The
proposed mechanistic postulate is based upon the concept of
directed electrostatic activation where the catalyst carboxylate
provides enantiofacial discrimination for the incoming nucleo-
phile accompanied by electrostatic association whereas selective
formation of a catalyst derived zwitterionic (Z)-iminum isomer
ensures a high degree of enantiocontrol. In line with our interest
in catalyst development for organocatalyzed reactions we
envisioned an improved catalyst that catalyzes the cyclopropa-
nation reaction with excellent diastereoselectivity and enantio-
selectivity. Second-generation catalyst, in which the carboxylic
acid of (S)-(-)-indoline-2-carboxylic acid is replaced by a
Antti Hartikka† and Per I. Arvidsson*,†,‡
Department of Biochemistry and Organic Chemistry, Uppsala
UniVersity, Box 576, SE-75123 Uppsala, Sweden, and DiscoVery
CNS & Pain Control, AstraZeneca R&D So¨derta¨lje,
S-151 85 So¨derta¨lje, Sweden
per.arVidsson@biorg.uu.se
ReceiVed March 13, 2007
Herein we wish to report our development of an improved
catalyst (S)-(-)-indoline-2-yl-1H-tetrazole (1) for the enan-
tioselective organocatalyzed cyclopropanation of R,â-
unsaturated aldehydes with sulfur ylides. The new organo-
catalyst readily facilitates the enantioselective organocatalytic
cyclopropanation, providing cyclized product in excellent
diastereoselectivities ranging from 96% to 98% along with
enantioselectivities exceeding 99% enantiomeric excess for
all reacted R,â-unsaturated aldehydes. The new catalyst
provides the best results so far reported for intermolecular
enantioselective organocatalyzed cyclopropanation.
(3) (a) Winstein, S.; Sonnenberg, J.; De Vries, L. J. Am. Chem. Soc.
1959, 81. 6523. (b) Winstein, S.; Sonnenberg, J. J. Am. Chem. Soc. 1961,
83, 3235. (c) Hoveyda, A. H.; Fu, G. C. Chem. ReV. 1993, 93, 1307. (d)
Corey, E. J.; Virgil, S. C. J. Am. Chem. Soc. 1990, 112, 6429. (e) Charette,
A. B.; Lebel, H. J. Org. Chem. 1995, 60, 2966.
(4) (a) Charette, A. B.; Coˆte´, B.; Marcoux, J.-F. J. Am. Chem. Soc. 1991,
113, 8166. (b) Mash, F. A.; Nelson, K. A. J. Am. Chem. Soc. 1985, 107,
8256. (c) Seebach, D.; Stucky, G. Angew. Chem., Int. Ed. 1988, 27, 1351.
(5) (a) Imai, N.; Sakamoto, K.; Takahashi, H.; Kobayashi, S. Tetrahedron
Lett. 1994, 35, 7045. (b) Imai, N.; Takahashi, H.; Kobayashi, S. Chem.
Lett. 1994, 177. (c) Denmark, S. E.; O’Connor, S. P.; Wilson, S. R. Angew.
Chem., Int. Ed. 1998, 37, 1149. (d) Denmark, S. E.; O’Connor, S. P. J.
Org. Chem. 1997, 62, 584.
(6) (a) Charette, A. B.; Brochu, C. J. Am. Chem. Soc. 1995, 117, 11367.
(b) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc. 2001,
123, 12168. (c) A recent paper reported on Enantioselective Cyclopropa-
nation with TADDOL-Derived Phosphate Ligands, see: Charette, A. B.;
Voituriez, A. AdV. Synth. Catal. 2006, 348, 16-17, 2363.
(7) (a) Artaud, I.; Seyden-Penne, J.; Viout, P. Synthesis 1980, 34. (b)
Hudlicky, T.; Radesca, L.; Luna, H.; Anderson, F. E. J. Org. Chem. 1986,
51, 4746. (c) Caine, D. Tetrahedron 2001, 57, 2643.
(8) Hakam, K.; Thielman, M.; Thielman, T.; Winterfeldt, E. Tetrahedron
1987, 43, 2035.
(9) (a) Krollpfeiffer, F.; Hartmann, H. Chem. Ber. 1950, 83, 90. (b) Corey,
E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867. (c) Corey, E. J.;
Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(10) Bestmann, H. J.; Seng, F. Angew. Chem. 1962, 74, 154.
(11) Huang, Y.-Z.; Shen, Y. AdV. Organomet. Chem. 1982, 20, 115.
(12) Huang, Y.-Z.; Yong, T.; Zhou, Z.-L. Tetrahedron 1998, 54, 1667.
(13) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2004, 43, 4641.
(14) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
3240.
The cyclopropane unit is a frequently encountered structural
unit in many naturally occurring compounds. Synthetic meth-
odology enabling the construction of these highly strained
systems was thoroughly explored in the middle of the 20th
century whereas the enantioselective construction of diversely
substituted cyclopropane units has gained widespread interest
during the last 20 years.1
Early development in stereospecific cyclopropanation utilized
a Simmons-Smith type of process, in which iodomethylzinc
reagents2 generated by different methods allowed the enantio-
selective cyclopropanation of structurally diverse cyclic and
acyclic alkene systems to be carried out by utilizing the chiral
pool,3 chiral auxiliaries,4 and catalytic asymmetric cyclopropa-
† Uppsala University.
‡‡‡
‡ Discovery CNS & Pain Control, AstraZeneca R&D So¨derta¨lje.
(1) A thorough review has been published on the topic: Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977.
(2) (a) Hennion, G. F.; Sheehan, J. J. J. Am. Chem. Soc. 1949, 71, 1964.
(b) Wittig, G.; Wingler, F. Justus Liebigs Ann. Chem. 1961, 650, 18. (c)
Wittig, G.; Schwarzenbach, K. Angew. Chem. 1959, 71, 652. (d) Takai,
K.; Kakiuchi, T.; Utimoto, K. J. Org. Chem. 1994, 59, 2671.
10.1021/jo070519e CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007
5874
J. Org. Chem. 2007, 72, 5874-5877

TABLE 1. Solvent and Catalyst Screening for the Reaction
Depicted in Scheme 2
SCHEME 1. Synthesis of (S)-(-)-Indoline-2-yl-1H-tetrazole
(1)a
entrya
solvent
catalyst
yieldb (%)
dec (%)
eed (%)
1
2
3
4
5
6
CHCl3
CHCl3
CHCl3
DMF
DMSO
THF
1
2
7
1
1
1
82
74
84
34
32
69
96
95
88
75
80
93
99
89
43
-38
-32
83
a The reaction was conducted at 4 °C. b Isolated yield after column
chromatography. c Determined by 1H NMR analysis of crude reaction
mixture. d Determined by means of GLC analysis.
a Reagents and conditions: (a) Cbz-Cl, 2 M NaOH, 5 °C, 5 h; (b) Boc2O,
NH4HCO3, MeCN, pyridine, 68 h, room temperature; (c) cyanuric chloride,
DMF, 24 h, rt; (d) NaN3, ZnBr2, 2-Propanol, water, reflux; (e) Pd/C, H2(g),
AcOH:H2O (9:1), 60 °C.
SCHEME 2. Catalyst and Solvent Screening
known bio-isostere15 such as tetrazolic acid, was expected to
improve enantioselectivity as a consequence of increased steric
bulk while retaining important structural functionality associated
with the proposed directed electrostatic activation mechanistical
postulate.
Since the introduction of tetrazolic acids in enantioselective
organocatalyzed reactions by Ley,16 Yamamoto,17 and our-
selves18 the number of applications where catalysts containing
tetrazol acid moieties has significantly increased in literature
displaying the profound impact of tetrazolic acid based catalysts
in asymmetric organocatalyzed reactions.19 Thus, herein we
report our development of an improved catalyst for the orga-
nocatalyzed asymmteric cyclopropanantion, initially discovered
by MacMillan, containing a tetrazolic acid moiety instead of
the carboxylic acid of (S)-(-)-indoline-2-carboxylic acid.
The new organocatalyst 1 was synthesized from commercially
available (S)-(-)-indoline-2-carboxylic acid, according to Scheme
1. The synthesis commenced from Cbz protection of (S)-(-)-
indoline-2-carboxylic acid20 with use of Schotten-Baumann
conditions21 to give the Cbz protected (S)-(-)-indoline-2-
carboxylic acid (3), which was subsequently converted to the
corresponding primary amide (4)22 by in situ activation of the
carboxylic acid followed by dehydration furnishing the nitrile
(5).23The nitrile was then further converted to the corresponding
protected tetrazole (6) utilizing the “click chemistry” protocol
developed in the Sharpless laboratory.24 The target compound
1 was obtained after catalytic hydrogenation and purification
by a solid-phase catch and release procedure followed by
recrystallization to give pure product.25
Catalyst 1 and tetrazolic acid containing catalyst 718 along
with the original catalyst 2 were assessed in the benchmark
reaction of crotonaldehyde and sulfur ylide to furnish product
in various yields, diastereoselectivities, and enantioselectivities.
The results clearly indicate that chloroform was the solvent of
choice providing the products in high enantiomeric excesses
whereas high dielectric constant solvents render products of low
optical purity as concluded in the previous study.14 More
importantly, this initial screening indicated that catalyst 1 offered
higher enantioselectivity compared to catalyst 2 (Table 1, entries
1 and 2).
After initial catalyst and solvent screening the substrate scope
was investigated (Table 2,, entries 1-7, catalyst 1; and Table
3, entries 1-7, catalyst 2).26The novel catalyst 1 provides
products in slightly higher isolated yields compared to reactions
catalyzed by 2 but more importantly renders products of
significantly higher optical purity for all investigated R,â-
unsaturated aldehydes (Table 2 and 3, entries 1-7). Catalyst 1
facilitates the reactions between straight chain R,â-unsaturated
aldehydes and stabilized aromatic sulfur ylides with excellent
diastereo- and enantioselectivity, see products 8a-10a (Table
2, entries 1-3) compared to catalyst 2, which renders products
of lower optical purity (Table 3, entries 1-3). Notably, a
(15) For a thorough review of the topic see: Herr, R. J. Bioorg. Med.
Chem. 2002, 10, 3379.
(16) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 3, 558.
(17) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem., Int. Ed. 2004, 43, 1983.
(18) (a) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004,
15, 1831. (b) Hartikka, A.; Arvidsson, P. I. Eur. J. Org. Chem. 2005, 4287.
(19) (a) Dodda, R.; Zhao, C.-G. Org. Lett. 2006, 8, 21, 4911. (b) Kumarn,
S.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2006, 30, 3211. (c) Chowdari,
N, S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III Org.
Lett. 2006, 8, 2839. (d) Mitchell, C. E. T.; Brenner, S. E.; Garcia-Fortanet,
J.; Ley, S. V. Org. Biomol. Chem. 2006, 4, 2039. (e) Samanta, S.; Zhao,
C.-G. Tetrahedron Lett. 2006, 47, 3383. (f) Suri, J. T.; Mitsumori, S.;
Albertshofer, K.; Tanaka, F.; Barbas, C. F., III J. Org. Chem. 2006, 71,
3822. (g) Limbach, M. Chem. BiodiVersity 2006, 3, 119. (h) Knudsen, K.
R.; Mitchell, C. E. T.; Ley, S. V. Chem. Commun. 2006, 1, 66. (i) Ibrahem,
I.; Zou, W.; Casas, J.; Sunden, H.; Cordova, A. Tetrahedron 2006, 62, 357.
(j) Grondal, C.; Enders, D. Tetrahedron 2006, 62, 329. (k) Mitchell, C. E.
T.; Brenner, S. E.; Ley, S. V. Chem. Commun. 2005, 42, 5346. (l) Sunden,
H.; Ibrahem, I.; Eriksson, L.; Cordova, A. Angew. Chem., Int. Ed. 2005,
44, 4877. (m) Kumarn, S.; Shaw, D. M.; Longbottom, D. A.; Ley, S. V.
Org. Lett. 2005, 7, 4189.
(24) (a) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525. (b)
Huisgen, R. Pure Appl. Chem. 1989, 61, 613.
(20) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53,
2861.
(21) Bergmann, M.; Zervas, L. Chem. Ber. 1932, 65, 1192.
(22) (a) Pozdnev, V. F. Tetrahedron Lett. 1995, 36, 7115.
(23) (a) Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61, 7398. (b)
Olah, G. A.; Narang, S.; Fung, A. P.; Gupta, G. B. Synthesis 1980, 8, 657.
(25) Almquist, G. R.; Chao, W.; White-Jennings, C. J. Med. Chem. 1985,
28, 1067.
(26) Both catalytic systems were assessed as in the previous report (ref
14), which allowed correlation of the relative and absolute stereochemistry
of products generated by catalyst (1) from the retention time of products in
GC or HPLC generated from catalytic system 2.
J. Org. Chem, Vol. 72, No. 15, 2007 5875

TABLE 2. Scope of Organocatalytic Ylide-Cyclopropanation
Depicted in Scheme 3a,b
TABLE 3. Scope of Organocatalytic Ylide-Cyclopropanation
Depicted in Scheme 4a,b
a The reactions are performed at -10 °C unless otherwise stated. b These
results are reproductions of those experiments performed by MacMillan et
al. in their original study,14 and gave comparable results. The main purpose
of these reproductions was to obtain reference material for assigning relative
and absolute configuration of product. c The reaction is performed at 4 °C.
d Isolated yield after column chromatography. e de (diastereomeric excess)
a The reactions are performed at -10 °C unless otherwise stated.
b Relative and absolute configuration was assigned through correlation of
obtained products to reference substances generated with catalyst 2.14
c Isolated yield after column chromatography. d de (diastereomeric excess)
1
is determined by H NMR or GLC analysis and ee (enantiomeric excess)
1
is determined by H NMR or GLC analysis and ee (enantiomeric excess)
is determined by GLC or HPLC analysis.
is determined by GLC or HPLC analysis. e The reaction is performed at
4 °C.
SCHEME 3. Scope of Organocatalytic
Ylide-Cyclopropanation with Catalyst 1
substantial difference is observed for the nonreactive substrate
crotonaldehyde (Tables 2 and 3, entry 3). Here the novel catalyst
1 furnishes product 10a in 85% isolated yield accompanied by
99% enantiomeric excess and 96% diasteromeric excess whereas
the existing catalyst gave the product 10b in 67% isolated yield
with 89% ee and 95% de. The R,â-unsaturated terminal
allylether aldehyde (Table 2, entries 4 and 5) is converted to
the cyclopropanated products 11a and 12a by catalyst 1 in
enantiomeric excesses exceeding 99% whereas catalyst 2
provide products 11b and 12b in enantiomeric excesses ranging
from 88% to 91% (Table 3, entries 4 and 5). The terminally
unsaturated R,â-unsaturated aldehyde investigated also gave the
product 13a in higher enantiomeric excess with catalyst 1, as
compared with catalyst 2 (Tables 2 and 3, entry 6). An aromatic
R,â-unsaturated aldehyde was also reacted successfully yielding
product 14a in >99% enantiomeric excess for catalyst 1, while
catalyst 2 furnished the product 14b in 93% enantiomeric excess.
The new catalyst obviously adapts well to the directed electro-
static activation mechanistic postulate, as indicated by the
excellent results for the enantioselective organocatalytic cyclo-
SCHEME 4. Scope of Organocatalytic
Ylide-Cyclopropanation with Catalyst 2
propanation, where the observed increase in enantioselectivity
correlates to the increased steric bulk imposed by the larger
tetrazolic acid, as compared to the normal carboxylic acid
functionality.
In conclusion, the novel catalyst 1 was synthesized through
well-established methodology consisting of a dihydroindol
5876 J. Org. Chem., Vol. 72, No. 15, 2007

(1R,2R,3S)-2-Allyloxymethyl-3-(4′-bromobenzoyl)cyclopro-
panecarbaldehyde (12a; Table 2, entry 5). 5 was prepared
according to general procedure from (2E)-4-(allyloxy)but-2-enal
(64 mg; 0.508 mmol), 2-(dimethyl-λ4-sulfanylidene)-1-(4′-bro-
mophenyl)-ethanone, and (S)-(-)-indoline-2-yl-1H-tetrazole (1) to
give the pure product as a colorless oil (34.1 mg; 83% yield; 99%
ee; 23:1 dr) after column chromatography (silica gel, 10% Et2O in
framework coupled to a tetrazolic acid. The structural features
ensure necessary functionality enabling the catalyst to highly
selectively catalyze the enantioselective organocatalytic cyclo-
propanation in excellent enantiomeric excesses, i.e., over 99%
ee, for all reacted R,â-unsaturated aldehydes and sulfur ylides
attempted. At the same time the catalyst furnishes the products
in acceptable to high yields and with comparable diastereose-
lectivities to the previously reported catalyst. Increased enan-
tioselective induction can be rationalized by the larger steric
bulk imposed by the deprotonated tetrazolic acid enhancing
enantiofacial discrimination of the incoming nucleophile well
in accordance with the directed electrostatic activation mecha-
nistic postulate depicted by MacMillan. The system is robusts
no dry solvents are needed in the catalytic reactionssand the
catalyst can be stored neat or in chloroform solution without
any detectable decomposition. The results convincingly show
that carboxylic acid substitution to the corresponding tetrazolic
acid indeed has a beneficial effect in terms of asymmetric
induction.
1
n-pentane), Rf 0.06. H NMR (500 MHz, CDCl3) δ 9.38 (d, J )
6.34 Hz, 1H), 7.9-7.86 (m, 2H), 7.64-7.61 (m, 1H), 5.88 (ddt, J
) 17.2, 10.4, 5.6 Hz, 1H), 5.27 (dq, J ) 17.2, 1.57 Hz, 1H), 5.21
(ddq, J ) 10.4, 1.59, 1.21 Hz, 1H), 4.03-4.00 (m, 2H), 3.74 (dd,
J ) 10.4, 4.59 Hz, 1H), 3.55 (dd, J ) 10.4, 5.5 Hz, 1H), 3.19 (dd,
J ) 8.81, 6.11 Hz, 1H), 2.78-2.72 (m, 1H), 2.34 (dt, 8.82, 6.21).
13C NMR (100 MHz, CDCl3) δ 27.9, 30.3, 31.8, 36.5, 68.4, 71.9,
117.5, 130.0 (2C), 132.0 (2C), 134.1, 135.5, 194.7, 198.5. [R]D
-16.9 (c 1.0, CHCl3). The enantiomeric excess and diastereomeric
excess were determined by GLC, using column coated with chiral
stationary phase (30 m × 0.25 mm), column (200 °C isotherm for
130 min), ramp to (220 °C by 10 °C), hold 0.5 min. Major
diastereomer: major enantiomer tr ) 32.6 min and minor enanti-
omer tr ) 33.3 min Minor diastereomer: major enantiomer tr )
18.5 min and minor enantiomer tr ) 17.3 min. MS (EI) m/z (rel
intensity) 323 ([M + 1]+, 7), 325 (7), 283 (5), 281 (8), 280 (1),
253 (97), 252 (16), 251 (100), 250 (4), 185(53), 184(8), 183(55),
182(2), 157(22), 156(4), 155(21), 154(1).
Experimental Section
General Procedure for Catalytic Asymmetric Cyclopropa-
nation. To a 30 mL flask equipped with a magnetic stirring bar
was added the aldehyde (0.508 mmol) and chloroform (21 mL).
The mixture was cooled to the desired temperature and stirred for
an additional 20 min. To the chilled mixture was then added either
(S)-(-)-indoline-2-carboxylic acid (2) (4.2 mg; 0.026 mmol) or (S)-
(-)-indoline-2-yl-1H-tetrazole (1) (4.8 mg; 0.026 mmol) followed
by either 2-(dimethyl-λ4-sulfanylidene)-1-phenylethanone (23 mg;
0.127 mmol) or 2-(dimethyl-λ4-sulfanylidene)-1-(4′-bromophenyl)-
ethanone (33 mg; 0.127mmol). The homogeneous solution was
stirred between 24 and 48 h after which the cold solution was
filtered through a pad of silica eluting with diethyl ether. The filtrate
was concentrated under reduced pressure to give crude products
as yellow oils, which were further purified by means of column
chromatography.
Acknowledgment. This work was supported by Veten-
skapsrådet (The Swedish Research Council).
Supporting Information Available: Experimental procedures,
1H NMR and 13C NMR spectra of all synthesized compounds,
and HPLC and GLC-MS traces for enantioselectivity determina-
tion. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070519E
J. Org. Chem, Vol. 72, No. 15, 2007 5877