Solvent-free asymmetric anhydride opening in a ball mill

Article abstract of DOI:10.1021/op6002743

The mechanochemical technique of ball milling has been applied to the asymmetric opening of meso-anhydrides, mediated by the cinchona alkaloid quinidine. A simple workup procedure affords the products, optically active dicarboxylic acid monoesters, in hig

Full text of DOI:10.1021/op6002743

Organic Process Research & Development 2007, 11, 592−597
Solvent-Free Asymmetric Anhydride Opening in a Ball Mill
Toni Rantanen, Ingo Schiffers, and Carsten Bolm*
Institut fu¨r Organische Chemie der RWTH Aachen, Landoltweg 1, D-52074 Aachen, Germany
Abstract:
tion and modification of inorganic solids.8 In contrast, in the
The mechanochemical technique of ball milling has been applied
to the asymmetric opening of meso-anhydrides, mediated by
the cinchona alkaloid quinidine. A simple workup procedure
affords the products, optically active dicarboxylic acid mo-
noesters, in high yields, with up to 64% ee. With most substrates
no column chromatography was needed. A range of various
alcohols, as well as anhydrides, reacted well thus demonstrating
the scope of this methodology. Even mixtures of purely solid
components react, and no solvent is required (except during
the workup). The possible use of almost equimolar amounts of
starting materials significantly simplifies the product isolation
compared to the standard solution reaction.
field of synthetic organic chemistry it has only found few
applications, which include oxidative 2-naphthol dimeriza-
tions,9 Heck-type cross-couplings,10 the protection of di-
amines,11 the preparation of phosphorus ylides,12 the metal-
free reductive benzylization of malononitrile,13 and the
functionalization of fullerenes.14 Our ball milling studies were
focused on the asymmetric proline-catalyzed aldol reaction
and the cinchona alkaloid-mediated asymmetric opening of
meso anhydrides.15 Herein, we describe details of the latter
transformation and demonstrate the scope of this methodol-
ogy.
Results and Discussion
The asymmetric opening of meso-anhydrides mediated by
the pseudoenantiomeric cinchona alkaloids quinine and
quinidine presents a versatile strategy for establishing
multiple stereogenic centers in a target molecule. Further-
more, the resulting functional groups of the products (di-
carboxylic acid monoesters) can selectively be manipulated
in subsequent transformations.16 As a consequence of detailed
optimization studies,17,18 products with up to 99% enantio-
meric excess (ee) can now be obtained in almost quantitative
yield (Scheme 1). Large-scale reactions have been reported
by various companies.16h,i, k,m
Introduction
The successful development of enantioselective catalysts,
which are applicable in the synthesis of complex molecules,
increases the demand for environmentally benign transforma-
tions1 to improve the sustainability of chemical processes.
On one hand, the scope of catalytic methods based on
nontoxic, small organic molecules has been expanded,2 and
on the other hand, the effective use of alternative reaction
media such as supercritical CO2,3 ionic liquids,4 or simply
water,5 which circumvent the problems associated with many
of the traditionally used volatile organic solvents, has been
demonstrated.6 However, by far the best “green” alternative
is, of course, to avoid the use of any solvent.7
With the vision that organocatalytic processes would
benefit from solvent-free reaction conditions, we initiated
an investigation of mechanochemical approaches for solvent-
free, asymmetric reactions catalyzed by small organic
molecules. The technique of ball milling has often been used
for grinding minerals into fine particles and for the prepara-
The mechanochemical solvent-free variant of the asym-
metric meso-anhydride opening presented here was per-
(6) For some recent reviews on the use of green solvents in organic synthesis,
see: (a) Andrade, C. K. Z.; Alves, L. M. Curr. Org. Chem. 2005, 9, 195-
218. (b) Sheldon, R. A. Green Chem. 2005, 7, 267-278. (c) Avalos, M.;
Babiano, R.; Cintas, P.; Jime´nez, J. L.; Palacios, J. C. Angew. Chem. 2006,
118, 4008-4012. Angew. Chem., Int. Ed. 2006, 45, 3904-3908.
(7) For an overview on solvent-free organic reactions, see: (a) Cave, G. W.;
Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159-2169. (b) Tanaka,
K. SolVent-Free Organic Synthesis; Wiley-VCH: Weinheim, 2003. For
organic solid-state reactions, see: (c) Kaupp, G.; Schmeyers, J.; Boy, J. J.
Prakt. Chem. 2000, 342, 269-280. (d) Kaupp, G. Top. Curr. Chem. 2005,
254, 945-183. (e) Kaupp, G. Cryst. Eng. Commun. 2006, 8, 794-804.
(8) (a) Kaupp, G.; Naimi-Jamal, M. R.; Ren, H.; Zoz H. In AdVanced
Technologies Based on Self-Propagating and Mechanochemical Reactions
for EnVironmental Protection; Cao, G., Delogu, F., Orru´, R., Eds.; Research
Signpost: Kerala, 2003; pp 83-100. (b) Kipp, S.; Sepela´k, V.; Becker, K.
D. Chem. Unserer Zeit 2005, 39, 384-392.
(9) Rasmussen, M. O.; Axelsson, O.; Tanner, D. Synth. Commun. 1997, 27,
4027-4030.
(10) (a) Tullberg, E.; Peters, D.; Frejd, T. J. Organomet. Chem. 2004, 689, 3778-
3781. (b) Tullberg, E.; Schacher, F.; Peters, D.; Frejd, T. Synthesis 2006,
1183-1189.
(11) Kaupp, G.; Naimi-Jamal, M. R.; Stepanenko, V. Chem. Eur. J. 2003, 9,
4156-4160.
(12) Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V. K. J. Am. Chem.
Soc. 2002, 124, 6244-6245.
* To whom the correspondence should be addressed. Telephone: +49 241-
8094 675. Fax: +49 241-8092 391. E-mail: Carsten.Bolm@oc.rwth-aachen.de.
(1) Anastas, P. T., Warner, J. C., Eds. Green Chemistry: Theory and Practice;
Oxford University Press: Oxford, 1998.
(2) For some recent reviews on enantioselective organocatalysis, see: (a) Dalko,
P. I.; Moisan, L. Angew. Chem. 2004, 116, 5248-5286. Angew. Chem.,
Int. Ed. 2004, 43, 5138-5175. (b) Berkessel, A.; Gro¨ger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005. (c) Seayad, J.; List, B.
Org. Biomol. Chem. 2005, 3, 719-724. (d) Pihko, P. M. Angew. Chem.
2006, 118, 558-561. Angew. Chem., Int. Ed. 2006, 45, 544-547. (e) List,
B. Chem. Commun. 2006, 819-824.
(3) For recent reviews on the use of supercritical carbon dioxide as solvent in
catalysis, see: (a) Leitner, W. Acc. Chem. Res. 2002, 35, 746-756. (b)
Leitner, W. Pure Appl. Chem. 2004, 76, 635-644.
(4) For a recent overview on catalysis performed in ionic liquids, see: Zhang,
Z. C. In AdVances in Catalysis; Gates, B. C., Kno¨zinger, H., Eds.;
Elsevier: New York, 2006; Vol. 49, pp 153-237.
(5) For recent reviews on organic reactions in aqueous media, see: (a) Li,
C.-J. Chem. ReV. 2005, 105, 3095-3165. (b) Li, C.-J.; Chen, L. Chem.
Soc. ReV. 2006, 35, 68-82.
(13) Zhang, Z.; Gao, J.; Xia, J.-J.; Wang, G.-W. Org. Biomol. Chem. 2005, 3,
1617-1619.
(14) Wang, G.-W.; Zhang, T.-H.; Li, Y.-J.; Lu, P.; Zhan, H.; Liu, Y.-C.; Murata,
Y.; Komatsu, K. Tetrahedron Lett. 2003, 44, 4407-4409.
(15) Rodriguez, B.; Rantanen, T.; Bolm, C. Angew. Chem. 2006, 118, 7078-
7080. Angew. Chem., Int. Ed. 2006, 45, 6924-6926.
592
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development
10.1021/op6002743 CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/10/2007

Scheme 1. Alkaloid-mediated asymmetric opening of a
meso-anhydride under standard conditions using toluene as
solvent and methanol as nucleophile
Table 1. Mechanochemical asymmetric anhydride opening
with various alcohols as nucleophiles in a ball-milla
formed in a commercially available micromill (Fritsch
GmbH) with two 45-mL grinding bowls containing 5-mm
diameter balls, both composed of chemically inert and
nonabrasive zirconium oxide. Due to the friction between
the reaction components, milling balls, and reaction vessels
a slight temperature increase (above ambient temperature)
was observed. Consequently, a milling cycle involving a
rotational speed of 250 rpm for 25 min followed by a 5-min
cooling pause was selected, since the asymmetric meso-
anhydride opening is known to be temperature sensitive.19
This milling cycle was then repeated until the reaction was
complete.20 Initially, the reaction time was 36 h. Later, for
most substrates ball milling for 24 h was found to be
sufficient for complete conversion. In many cases all
reactants were solids.
First, reactions between anhydride 1 and various alcohols
were investigated. The results are summarized in Table 1.
a Reaction conditions: quinidine (1.1 mmol), anhydride 1 (1.0 mmol), alcohol
(1.0 mmol), ball milling, 250 rpm, milling cycle: 25 min milling/5 min break,
reaction time 24-36 h. b After column chromatography, if required; see text.
c Determined by chiral GC (Lipodex E) of the corresponding lactone. d In all
cases the products had (2R,3S) configuration. Comp. ref 17b. e Here, 3.0 equiv
of 4 were used. f Performed on a 5 mmol scale.
(16) For some reviews on the topic, see: (a) Willis, M. C. J. Chem. Soc., Perkin
Trans. I 1999, 1765-1784. (b) Spivey, A. C.; Andrews, B. I. Angew. Chem.
2001, 113, 3227-3230. Angew. Chem., Int. Ed. 2001, 40, 3131-3134. (c)
Chen, Y.; McDaid, P.; Deng, L. Chem. ReV. 2003, 103, 2965-2984. For
some examples in total synthesis utilizing this concept, see: (d) Starr, J.
T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 8793-8794.
(e) Bernardi, A.; Arosio, D.; Dellavecchia, D.; Micheli, F. Tetrahedron:
Asymmetry 1999, 10, 3403-3407. (f) Bernardi, A.; Arosio, D.; Manzoni,
L.; Micheli, F.; Pasquarello, A.; Seneci, P. J. Org. Chem. 2001, 66, 6209-
6216. (g) Choi, C.; Tian, S.-K.; Deng, L. Synthesis 2001, 1737-1741. (h)
Mittendorf, J.; Buchholz, J.-B.; Fey, P.; Mohrs, K.-H. Synthesis 2003, 136-
140. (i) Mittendorf, J.; Kunisch, F.; Matzke, M.; Militzer, H.-C.; Schmidt,
A.; Scho¨nfeld, W. Bioorg. Med. Chem. Lett. 2003, 13, 433-436. (j) Basso,
A.; Banfi, L.; R. Riva, R.; Guanti, G. J. Org. Chem. 2005, 70, 575-579.
(k) Keen, S. P.; Cowden, C. J.; Bishop, B. C.; Brands, K. M. J.; Davies, A.
J.; Dolling, U. H.; Lieberman, D. R.; Stewart, G. W. J. Org. Chem. 2005,
70, 1771-1779. (l) Archambaud, S.; Aphecetche-Julienne, K.; Guingant,
A. Synlett 2005, 139-143. (m) Yue, T.-Y.; McLeod, D. D.; Albertson, K.
B.; Beck, S. R.; Deerberg, J.; Fortunak, J. M.; Nugent, W. A.; Radesca, L.
A.; Tang, L.; Xiang, C. D. Org. Process Res. DeV. 2006, 10, 262-271.
(17) (a) Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195-196. (b) Bolm,
C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000, 65, 6984-
6991. (c) Bolm, C.; Schiffers, I.; Atodiresei, I.; Hackenberger, C. P. R.
Tetrahedron: Asymmetry 2003, 14, 3455-3467. (d) Bolm, C.; Atodiresei,
I.; Schiffers, I. Org. Synth. 2005, 82, 120-125.
(18) (a) Shintani, R.; Fu, G. C. Angew. Chem. 2002, 114, 1099-1101. Angew.
Chem., Int. Ed. 2002, 41, 1057-1059. (b) Bercot, E. A.; Rovis, T. J. Am.
Chem. Soc. 2002, 124, 174-175. (c) Johnson, J. B.; Yu, R. T.; Fink, P.
Bercot, E. A.; Rovis, T. Org. Lett. 2006, 8, 4307-4310. For a substoichio-
metric version of this desymmetrization reaction based on the use of
Sharpless’ bis-cinchona alkaloid derivatives, see: (d) Chen, Y.; Tian, S.-
K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542-9543. (e) Chen, Y.; Deng,
L. J. Am. Chem. Soc. 2001, 123, 11302-11303.
(19) Since the alkaloid-mediated asymmetric anhydride opening is known to be
temperature sensitive, a control experiment with anhydride 1 and alcohol 4
in toluene at room temperature was performed. After 24 h the corresponding
product was obtained with 83% ee in 71% yield. An analogous experiment
performed at 60 °C led (quantitatively) to a racemate. A racemic product
was also obtained by reacting 1 and 4 in the absence of a solvent at 60 °C
(with a stirring bar).
At the beginning of the investigation, 3 equiv of alcohol
were used since reactions in toluene with equimolar amounts
of anhydride and nucleophile were known to be slow. To
our surprise, however, we found that in the ball mill 1 equiv
of nucleophile was sufficient for affording products in high
yields with essentially unchanged enantioselectivities (Table
1, entries 1 and 2). As a consequence of the reduced reagent
amount the workup procedure was simplified from a tedious
extraction sequence to a simple acidic wash yielding the
desired hemiesters in high purity.21 Scaling up the reaction
(Table 1, entry 3), afforded the product in high yield with a
slightly lower enantioselectivity, presumably due to increased
friction caused by the larger amount of solids in the reaction
vessel. Various alcohols proved applicable, and only in few
cases (Table 1, entries 7-9) was flash chromatography
necessary in order to remove unreacted alcohol and/or
anhydride. Generally, the conversion was higher than 95%,
and no side-products could be detected by GC or NMR
spectroscopy. The best results were achieved in reaction of
anhydride 1 with p-methyl and o-bromobenzyl alcohol (4
and 10) yielding the corresponding products 5 and 11 in
yields g91% with enantioselectivities of 60 and 64% ee,
respectively (Table 1, entries 2 and 6). Compared to the
results obtained in solution, the ee of product 3 stemming
(20) Performing the catalysis at a lower rotational speed resulted in an ineffective
mixing of the reactants and lower yields were observed. Milling without
the cooling pause of 5 min or using a higher rotational speed led to a decrease
in enantioselectivity presumably due to heating of the reaction vessel through
friction.
(21) For the workup of the small-scale reactions reported here, a relatively large
amount of solvent was used. Further optimization studies shall reveal the
minimal solvent quantity required for full product isolation. At the present
stage, the term “solvent-free” can only relate to the reaction itself.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
593

Table 2. Asymmetric anhydride opening with various
to 91%) and the enantioselectivities moderate (26-57% ee).
A simple acidic wash gave pure products, and only in
reactions starting from anhydrides 15, 17, and 23 was flash
chromatography necessary in order to remove unreacted
alcohol and/or anhydride. A few more results are noteworthy.
For example, in solution studies anhydride 15 proved
unreactive, whereas under ball-milling conditions the asym-
metric anhydride opening with alcohol 4 as nucleophile
proceeded well, affording the corresponding hemiester 16
with 32% ee in 78% yield. No conversion of 3-methyl
glutaric acid anhydride (27) was observed after 24 h under
ball-milling conditions.
anhydrides using the ball-milla
The attempt to increase the enantioselectivity by using
greater than stoichiometric amounts of quinidine (2.0 equiv)
in the asymmetric anhydride opening of 1 with 4 led to no
improvement and afforded 5 with 60% ee in 90% yield.
Performing the reaction between 1 and 4 in a round-bottomed
flask under mixing with a simple stir bar gave results that
were difficult to reproduce.22 Generally, the yield of product
5 was lower, whereas the ee was higher than under ball-
milling conditions. These observations were, on one hand,
attributed to non-effective mixing of the solid components
and, on the other, to better temperature control, which
avoided warming of the reaction mixture. Trying to effect a
catalytic ball-milling reaction with 10 mol % of Sharpless’
bis(cinchona) alkaloid (DHQ)2AQN23 according to Deng’s
protocol18c,d led to products 3 and 5 in good yields (57 and
90%), but with significantly lower enantioselectivities (5 and
15%, respectively).
Conclusion
In summary, we have expanded the scope of the solvent-
free ball-milling methodology. The mechanically induced,
solid-state desymmetrization of meso-anhydrides mediated
by the cinchona alkaloid quinidine leads to optically active
hemiesters in high yields and moderate enantioselectivities.
Except for the workup, no solvent is required,21 and even
mixtures of purely solid components react. Compared to the
standard reaction performed in solution the possible use of
almost equimolar amounts of starting materials significantly
simplifies the product isolation.
a Reaction conditions: quinidine (1.1 mmol), anhydride (1.0 mmol), alcohol
4 (1.0 mmol), ball milling at 250 rpm, milling cycle: 25 min milling/5 min
break, reaction time 24-36 h. b After column chromatography, if required, see
text. c Determined after conversion into the corresponding lactone by GC using
a chiral column (Lipodex E). d For the determination of the absolute configu-
ration, see ref 17a. The one given for 16 is based on assuming an analogous
pathway of the anhydride opening as for the other substrates. e The ee was
determined from the methyl(p-methyl-benzyl)diester by HPLC using a chiral
column (see Experimental Section for details). f No conversion after 24 h.
from the anhydride opening of 1 with methanol was only
moderate (51%; entry 8), which was attributed to the phase
behavior and to the higher reaction temperature during the
catalysis in the ball mill. The attempted anhydride opening
with tert-butanol remained unsuccessful (entry 10), and only
traces of the product were observed.
On the basis of these results and taking into account that
other reactions with ortho-bromo-substituted benzyl alcohol
10 could potentially be hampered by steric interactions with
the substrates, para-substituted benzyl alcohol 4 was selected
as nucleophile for the subsequent studies. Table 2 sum-
marizes the data obtained from reactions of 4 with other
anhydrides.
Experimental Section
Unless otherwise specified, all reagents were purchased
from commercial suppliers and used without further purifica-
tion. Anhydride 15 was synthesized according to a known
procedure.24 The ball-milling experiments were performed
using a Fritsch Planetary Micro Mill model “Pulverisette 7”
with two 45-mL grinding bowls and 5-mm diameter grinding
balls made of zirconium oxide. H and 13C NMR spectra
were obtained on a Varian Gemini 300 or Inova 400
spectrometer and were recorded relative to CHCl3 as internal
standard. Mass spectra were measured on a Finnigan SSQ
1
(22) Interestingly, after stirring for some time, the solid reactants formed a sticky
paste in the reaction flask. This in turn hindered the efficient movement of
the stirring bar. An analogous behavior is observed in the ball mill. There,
however, the mixing is more efficient at this stage.
(23) (DHQ)2AQN: 1,4-bis(dihydroquinyl)anthraquinone.
(24) Fotins, J.; Smithrud, D. B. J. Org. Chem. 2005, 70, 4452-4459.
As shown in Table 2, the asymmetric anhydride opening
with (1 equiv of) p-methylbenzyl alcohol (4) in the presence
of (1.1 equiv of) quinidine also proceeded well with
substrates other than 1. Generally, the yields were high (up
594
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development

7000 instrument or on a Hewlett-Packard GC/MS apparatus-
system (column HP-5 MS, 30 m × 0.25 mm × 0.25 µm;
mass selective detector 5973). HPLC analysis was performed
using a Chiralpak OD-H column, 4.6 × 250 mm, λ ) 254
nm. For the determination of the enantiomeric ratios, the
hemiesters were reduced with LiBEt3H and cyclized to
lactones, which were then analyzed by GC.17b GC analysis
was performed using the chiral column Lipodex E (2,6-O-
dipentyl-3-O-butyryl-γ-CD) and the following conditions:
column head pressure: 1.0 bar N2; 100 °C (50 min), heating
rate 3.0 °C/min up to 180 °C (60 min); injector temperature
200 °C, detector temperature 250 °C. Melting points were
measured in open glass capillaries with a Bu¨chi-apparatus
and are uncorrected. Optical rotations were determined on a
Perkin-Elmer P241 instrument at rt (ca. 20 °C) using solvents
of Merck UVASOL-quality. Infrared spectra were recorded
on a Perkin-Elmer 1760 FT apparatus either as KBr pellets
or neat. All microanalyses were conducted on a Heraeus
CHN RAPID instrument at the Institut fu¨r Organische
Chemie der RWTH Aachen. Preparative column chroma-
tography: Merck silica gel 60, particle size 0.063-0.200
(230-400 mesh, flash). Analytical TLC: silica gel 60 F254
plates, Merck, Darmstadt. All experiments were conducted
at least twice to ensure reproducibility.
128.3, 129.0, 132.7, 134.2, 135.4, 137.7, 172.1, 178.3; IR
(KBr): 2974, 1730, 1676, 1519, 1330, 1294, 1191, 1043,
797 cm-1; EI-MS: m/z ) 286 (M+, 4), 268 (4), 240 (3),
170 (4), 121 (3), 105 (100), 91 (4), 77 (4), 66 (4). Anal.
calcd for C17H18O4 (286.32): C, 71.31; H, 6.34. Found: C,
71.19; H, 6.29.
(2R,3S)-3-endo-p-Nitrobenzyloxycarbonyl-bicyclo[2.2.1]-
hept-5-ene-2-endo-carboxylic Acid (7). The compound was
isolated as a slightly yellow solid according to GPR 1 using
anhydride 1, p-nitrobenzyl alcohol (6), and quinidine: mp
dec; [R]25 ) -11.4 (c 3.70, CDCl3); ee ) 40% as
D
determined by GC analysis of the corresponding lactone; 1H
NMR (400 MHz, CDCl3): δ ) 1.36 (d, J ) 8.5 Hz, 1H),
1.52 (dt, J ) 1.7, 8.8 Hz, 1H), 3.20 (br s, 2H), 3.31-3.39
(m, 2H), 5.10 (AB-system, J ) 13.3 Hz, 2H), 6.19 (dd, J )
2.7, 5.7 Hz, 1H), 6.28 (dd, J ) 3.0, 5.7 Hz, 1H), 7.46 (d, J
) 8.8 Hz, 2H), 8.19 (d, J ) 8.8 Hz 2H); 13C NMR (100
MHz, CDCl3): δ ) 46.3, 46.6, 48.1, 48.2, 48.9, 64.9, 123.6,
128.5, 134.4, 135.4, 143.0, 147.5, 171.8, 177.9; IR (KBr):
3076, 2983, 1703, 1602, 1515, 1430, 1338, 1192, 842 cm-1;
EI-MS: m/z ) 317 (M+, 4), 284 (6), 256 (8), 252 (54), 137
(26), 136 (29), 119 (10), 91 (13), 66 (100). Anal. calcd for
C16H15NO6 (317.29): C, 60.57; H, 4.77; N, 4.41. Found: C,
60.55; H, 4.42; N, 4.24.
General Procedure for the Anhydride Opening in the
Ball Mill (GPR 1). In a clean, dry, ball-milling vessel 60
zirconium oxide balls, the anhydride (1 mmol), quinidine
[1.1 equiv or 0.1 equiv of (DHQ)2AQN], and the alcohol
(1.0 equiv) were sequentially added. The vessel was closed
and the milling started (ball-milling cycle: 250 rpm, 25-
min milling time, 5-min pause). This milling cycle was
repeated until the reaction was complete. The mixture was
then carefully transferred into a separation funnel using first
2 N HCl (2 × 15 mL) and then EtOAc (3 × 20 mL). The
organic phase was separated and washed with 2 N HCl (3
× 15 mL). The combined aqueous fractions were extracted
with EtOAc (1 × 20 mL). After drying of the combined
organic fractions (MgSO4), the solvent was evaporated. If
required, the product was purified by flash chromatography.
(2R,3S)-3-endo-Methoxycarbonyl-bicyclo[2.2.1]-hept-
5-ene-2-endo-carboxylic Acid (3). The compound was
isolated as a colorless solid according to GPR 1 using
anhydride 1 and methanol with quinidine as mediator. The
analytical data is in accordance with the ones already
published.17b
(2R,3S)-3-endo-p-Thiomethoxybenzyloxycarbonyl-bi-
cyclo-[2.2.1]-hept-5-ene-2-endo-carboxylic Acid (9). The
compound was isolated as a colorless oil according to GPR
1 using anhydride 1, p-thiomethoxybenzylalcohol (8), and
quinidine: [R]25 ) +1.6 (c 4.18, CDCl3); ee ) 55% as
D
determined by GC analysis of the corresponding lactone; 1H
NMR (300 MHz, CDCl3): δ ) 1.32 (d, J ) 8.7 Hz, 1H),
1.47 (dt, J ) 1.7, 8.7 Hz, 1H), 2.45 (s, 3H), 3.17 (br s, 2H),
3.30-3.34 (m, 2H), 4.95 (AB-system, J ) 12.2 Hz, 2H),
6.21 (dd, J ) 2.8, 5.6 Hz, 1H), 6.28 (dd, J ) 2.9, 5.6 Hz,
1H), 7.21 (s, 4H), 10.73 (br s, 1H); 13C NMR (75 MHz,
CDCl3): δ ) 15.5, 46.0, 46.4, 48.0, 48.2, 48.6, 65.9, 126.3,
128.8, 132.4, 134.2, 135.3, 138.4, 172.1, 178.5; IR (KBr):
2976, 1718, 1177, 804 cm-1; EI-MS: m/z ) 318 (M+, 17),
153 (4), 137 (100), 122 (6), 99 (2), 91 (3). Anal. calcd for
C17H18O4S (318.38): C, 64.13; H, 5.70. Found: C, 63.84;
H, 6.08.
(2R,3S)-3-endo-o-Bromobenzyloxycarbonyl-bicyclo-
[2.2.1]-hept-5-ene-2-endo-carboxylic Acid (11). The com-
pound was isolated as a colorless solid according to GPR 1
using anhydride 1, o-bromobenzyl alcohol (10), and quini-
dine: mp 112 °C (en); [R]25D ) +0.4 (c 1.99, CDCl3); ee )
64% as determined by GC analysis of the corresponding
lactone; 1H NMR (400 MHz, CDCl3): δ ) 1.34 (d, J ) 8.6
Hz, 1H), 1.49 (dt, J ) 1.6, 8.5 Hz, 1H), 3.20 (br s, 2H),
3.35 (dq, J ) 3.0, 8.1 Hz, 2H), 5.10 (AB-system, J ) 12.9
Hz, 2H), 6.23 (dd, J ) 2.8, 5.5 Hz, 1H), 6.29 (dd, J ) 3.0,
5.5 Hz, 1H), 7.13-7.20 (m, 1H), 7.26-7.32 (m, 1H), 7.35-
7.40 (m, 1H), 7.52-7.57 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ ) 46.3, 46.6, 48.1, 48.2, 48.8, 66.0, 123.4, 127.4,
129.5, 130.0, 132.6, 134.5, 135.3, 171.8, 177.8; IR (KBr):
3400, 2980, 1744, 1436, 1341, 1257, 1171, 1077, 1025, 754,
669 cm-1; EI-MS: m/z ) 352/350 (M+, 5), 287/285 (21),
181 (18), 171/169 (100), 137 (24), 107 (13), 90 (24), 66
(2R,3S)-3-endo-p-Methylbenzyloxycarbonyl-bicyclo-
[2.2.1]-hept-5-ene-2-endo-carboxylic Acid (5). The com-
pound was isolated as a colorless oil according to GPR 1
using the anhydride 1, p-methylbenzyl alcohol (4), and
quinidine: [R]25 ) +5.3 (c 2.68, CDCl3); ee ) 61% as
D
determined by GC analysis of the corresponding lactone:
Lipodex E, t1 ) 84.4 min, t2 ) 84.9 min (major); 1H NMR
(400 MHz, CDCl3): δ ) 1.33 (d, J ) 8.5 Hz, 1H), 1.49 (dt,
J ) 1.8, 8.5 Hz, 1H), 2.35 (s, 3H), 3.19 (d, J ) 8.8 Hz, 2H),
3.30-3.36 (m, 2H), 4.98 (AB-system, J ) 12.4 Hz, 2H),
6.23 (dd, J ) 3.0, 5.5 Hz, 1H), 6.30 (dd, J ) 3.0, 5.5 Hz,
1H), 7.12-7.24 (m, 4H), 9.70 (br s, 1H); 13C NMR (100
MHz, CDCl3): δ ) 21.2, 46.1, 46.6, 48.1, 48.3, 48.7, 66.3,
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
595

(97). Anal. calcd for C16H15BrO4 (351.18): C, 54.72; H, 4.31.
Found: C, 54.89; H, 4.46.
(2R,3S)-3-exo-p-Methylbenzyloxycarbonyl-bicyclo[2.2.1]-
hept-5-ene-2-exo-carboxylic Acid (18). The compound was
isolated as a colorless solid according to GPR 1 using
anhydride 17, p-methylbenzyl alcohol (4), and quinidine: mp
97-98 °C (en); [R]25D ) -10.7 (c 1.88, CDCl3); ee ) 57%
as determined by GC analysis of the corresponding lactone:
Lipodex E, t1 ) 79.1 min, t2 ) 80.1 min (major); 1H NMR
(300 MHz, CDCl3): δ ) 1.52 (dt, J ) 1.5, 9.1 Hz, 1H),
2.16 (d, J ) 8.9 Hz, 1H), 2.35 (s, 3H), 2.62-2.73 (m, 2H),
3.09-3.19 (m, 2H), 5.05 (AB-system, J ) 12.1 Hz, 2H),
6.18-6.27 (m, 2H), 7.16 (d, J ) 7.9 Hz, 2H), 7.24 (d, J )
8.1 Hz, 2H), 10.62 (br s, 1H); 13C NMR (75 MHz, CDCl3):
δ ) 21.1, 45.3, 45.4, 45.7, 47.3, 47.4, 66.6, 128.4, 129.1,
132.6, 137.8, 137.9, 138.0, 173.2, 179.8; IR (KBr): 2977,
1730, 1436, 1334, 1258, 1173, 1023, 803, 716 cm-1; EI-
MS: m/z ) 286 (M+, 7), 268 (3), 240 (1), 165 (5), 122 (52),
105 (100), 91 (13), 77 (11), 66 (20). Anal. calcd for C17H18O4
(286.32): C, 71.31; H, 6.34. Found: C, 71.29; H, 6.22.
(1R,2S)-cis-2-p-Methylbenzyloxycarbonyl-cyclohexane-
1-carboxylic Acid (20). The compound was isolated as a
colorless oil according to GPR 1 using anhydride 19,
(2R,3S)-3-endo-Cinnamoyloxycarbonyl-bicyclo[2.2.1]-
hept-5-ene-2-endo-carboxylic Acid (13). The compound
was isolated as a colorless oil according to GPR 1 using
anhydride 1, cinnamyl alcohol (12), and quinidine: [R]25
D
) +2.6 (c 1.66, CDCl3); ee ) 50% as determined by GC
analysis of the corresponding lactone; 1H NMR (300 MHz,
CDCl3): δ ) 1.24 (d, J ) 8.7 Hz, 1H), 1.41 (dt, J ) 1.7,
8.6 Hz, 1H), 3.03-3.15 (m, 2H), 3.15-3.29 (m, 2H), 4.47-
4.67 (m, 2H), 6.10-6.29 (m, 3H), 6.47-6.59 (m, 1H), 7.13-
7.38 (m, 5H), 10.19 (br s, 1H); 13C NMR (75 MHz,
CDCl3): δ ) 46.1, 46.4, 48.0, 48.3, 48.7, 65.1, 123.2, 126.6,
127.8, 128.4, 133.8, 134.4, 135.4, 136.2, 172.1, 178.6; IR
(KBr): 3852, 3743, 2361, 2339, 1696, 1550, 672 cm-1; EI-
MS: m/z ) 298 (M+, 3), 280 (2), 182 (3), 117 (100), 115
(14), 91 (8). Anal. calcd for C18H18O4 (298.32): C, 72.47;
H, 6.08. Found: C, 72.70; H, 5.96.
(2R,3S)-3-endo-Isopropoxycarbonyl-bicyclo[2.2.1]-hept-
5-ene-2-endo-carboxylic Acid (14). The compound was
isolated as a colorless solid according to GPR 1 using
anhydride 1, isopropyl alcohol, and quinidine: mp 87 °C
(en); [R]25D ) -0.4 (c 2.24, CDCl3); ee ) 13% as determined
by GC analysis of the corresponding lactone; 1H NMR (300
MHz, CDCl3): δ ) 1.13 (d, J ) 6.4 Hz, 3H), 1.17 (d, J )
6.2 Hz, 3H), 1.29 (d, J ) 8.7 Hz, 1H), 1.44 (dt, J ) 1.8, 8.6
Hz, 1H), 3.10-3.18 (m, 2H), 3.18-3.32 (m, 2H), 4.89 (sept,
J ) 6.3 Hz, 1H), 6.19 (dd, J ) 3.0, 5.4 Hz, 1H), 6.26 (dd,
J ) 3.0, 5.4 Hz, 1H), 11.00 (br s, 1H); 13C NMR (75 MHz,
CDCl3): δ ) 21.4, 21.7, 46.2, 46.5, 48.0, 48.6, 48.7, 67.8,
134.3, 135.3, 171.7, 178.7; IR (KBr): 2976, 2360, 1709,
1339, 1209, 1101, 909, 717 cm-1; EI-MS: m/z ) 224 (M+,
1), 206 (1), 182 (2), 164 (15), 137 (12), 117 (33), 99 (20),
66 (100). Anal. calcd for C12H16O4 (224.25): C, 64.27; H,
7.19. Found: C, 64.23; H, 7.20.
p-methylbenzyl alcohol (4), and quinidine: [R]25 ) +0.7
D
(c 1.65, CDCl3); ee ) 26% as determined by GC analysis
of the corresponding lactone: Lipodex E, t1 ) 75.9 min
1
(major), t2 ) 76.9 min; H NMR (400 MHz, CDCl3): δ )
1.34-1.62 (m, 4H), 1.72-1.84 (m, 2H), 1.98-2.12 (m, 2H),
2.34 (s, 3H), 2.82-2.91 (m, 2H), 5.19 (AB-system, J ) 12.2
Hz, 2H), 7.15 (d, J ) 7.9 Hz, 2H), 7.22 (d, J ) 8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3): δ ) 21.3, 23.7, 23.8,
26.1, 26.3, 42.48, 42.51, 66.3, 128.1, 129.0, 132.9, 137.7,
173.2, 179.8; IR (KBr): 2938, 2863, 1710, 1217, 1177, 733
cm-1; EI-MS: m/z ) 276 (M+, 21), 248 (12), 230 (6), 186
(5), 155 (16), 122 (75), 121 (100), 105 (76). Anal. calcd for
C16H20O4 (276.33): C, 69.54; H, 7.30. Found: C, 69.28; H,
7.52.
(2R,3S)-3-endo-p-Methylbenzyloxycarbonyl-1,2,3,4-tet-
rahydro-1,4-methano-naphthalene-2-carboxylic Acid (16).
The compound was isolated as a colorless oil according to
GPR 1 using anhydride 15, p-methylbenzyl alcohol (4), and
quinidine. In order to determine the ee, the initial product
was converted into the corresponding methyl(p-methylben-
zyl)diester by DCC-coupling. This compound was then
analyzed by HPLC using a chiral column (Chiralcel OD-H
column, 90:10 heptane/2-propanol, 0.5 mL/min, 15.0 min
major, 17.9 min minor). The absolute configuration of 16 is
based on assuming an analogous pathway of the anhydride
opening as for the other substrates: [R]25D ) +14.8 (c 2.22,
CDCl3); ee ) 32%; 1H NMR (400 MHz, CDCl3): δ ) 1.72
(d, J ) 9.1 Hz, 1H), 1.86 (dt, J ) 1.5, 9.1 Hz, 1H), 2.35 (s,
3H), 3.44-3.49 (m, 2H), 3.62 (br s, 2H), 4.82 (AB-system,
J ) 12.1 Hz, 2H), 7.04-7.26 (m, 8H), 9.70 (br s, 1H); 13C
NMR (100 MHz, CDCl3): δ ) 21.3, 47.46, 47.52, 47.65,
47.77, 49.8, 66.2, 123.1, 123.3, 126.0, 126.1, 128.5, 129.0,
132.7, 137.7, 143.4, 143.7, 171.0, 176.6; IR (KBr): 3742,
3017, 2975, 2355, 1720, 1520, 1175, 757 cm-1; EI-MS: m/z
) 336 (M+, 36), 318 (5), 220 (11), 215 (17), 141 (19), 122
(22), 116 (49), 105 (100), 91 (5). Anal. calcd for C21H20O4
(336.38): C, 74.98; H, 5.99. Found: C, 74.64; H, 6.33.
(1R,2S)-cis-2-p-Methylbenzyloxycarbonyl-cyclohex-4-
ene-1-carboxylic Acid (22). The compound was isolated as
a colorless oil according to GPR 1 using anhydride 21,
p-methylbenzyl alcohol (4), and quinidine: [R]25 ) -0.7
D
(c 3.21, CDCl3); ee ) 55% as determined by GC analysis
of the corresponding lactone: Lipodex E, t1 ) 78.4 min
1
(major), t2 ) 79.0 min; H NMR (400 MHz, CDCl3): δ )
2.31-2.46 (m, 5H), 2.52-2.68 (m, 2H), 3.05-3.14 (m, 2H),
5.10 (AB-system, J ) 12.1 Hz, 2H), 5.64-5.73 (m, 2H),
7.15 (d, J ) 8.0 Hz, 2H), 7.22 (d, J ) 8.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3): δ ) 21.2, 25.6, 25.8, 39.60, 39.62,
66.5, 124.9, 125.1, 128.1, 129.0, 132.7, 137.8, 172.8, 179.4;
IR (KBr): 3850, 3748, 3681, 3428, 2949, 2364, 2343, 2224,
1700, 1548, 1181, 662 cm-1; EI-MS: m/z ) 274 (M+, 4),
256 (3), 228 (3), 121 (5), 105 (100), 79 (7). Anal. calcd for
C16H18O4 (274.31): C, 70.06; H, 6.61. Found: C, 70.03; H,
6.71.
(1S,2R)-cis-2-p-Methylbenzyloxycarbonyl-3,3-dimeth-
ylcyclopropane-1-carboxylic Acid (24). The compound was
isolated as a colorless oil according to GPR 1 using
anhydride 23, p-methylbenzyl alcohol (4), and quinidine:
[R]25D ) +0.3 (c 2.16, CDCl3); ee ) 46% as determined by
596
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development

GC analysis of the corresponding lactone: Lipodex E, t1 )
71.6 min, t2 ) 72.7 min (major); H NMR (300 MHz,
(13), 105 (100), 77 (7). Anal. calcd for C15H18O4 (262.30):
C, 68.68; H, 6.92. Found: C, 68.70; H, 6.64.
1
CDCl3): δ ) 1.26 (s, 3H), 1.41 (s, 3H), 1.97 (s, 2H), 2.35
(s, 3H), 5.11 (AB-system, J ) 12.1 Hz, 2H), 7.17 (d, J )
8.2 Hz, 2H), 7.25 (d, J ) 8.2 Hz, 2H), 9.79 (br s, 1H); 13C
NMR (75 MHz, CDCl3): δ ) 15.3, 21.1, 27.3, 28.0, 32.8,
32.9, 67.0, 128.5, 129.2, 132.3, 138.1, 170.4, 173.7; IR
(KBr): 2954, 2355, 1729, 1446, 1176, 1109, 808 cm-1; EI-
MS: m/z ) 262 (M+, 8), 162 (1), 141 (2), 121 (17), 113
Acknowledgment
We are grateful to the Fonds der Chemischen Industrie
and to the Deutsche Forschungsgemeinschaft (DFG) within
the SPP 1179 (‘Organocatalysis’) for financial support.
Received for review December 18, 2006.
OP6002743
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
597