An alkaloid-mediated desymmetrization of meso-anhydrides via a nucleophilic ring opening with benzyl alcohol and its application in the synthesis of highly enantiomerically enriched β-amino acids

Article abstract of DOI:10.1016/S0957-4166(03)00579-2

The cinchona alkaloid-mediated opening of prochiral cyclic anhydrides in the presence of benzyl alcohol leading to optically active hemiesters is described. Structurally diverse anhydrides are converted into their corresponding benzyl monoesters with either enantiomer being obtained with up to 99 percent e.e. by using quinine or quinidine as the directing additive. A simple aqueous work-up protocol permits the isolation of the products in analytically pure form and the recovery of the alkaloids almost quantitatively. These hemiesters can be converted to N-protected β-amino esters by means of Curtius degradation of the corresponding acyl azides. Subsequent cleavage of both protecting groups by a single reaction step leads to the free β-amino acids in excellent yields. The efficiency of this procedure is demonstrated by the short asymmetric synthesis of the fungicide cis-pentacin delivering the amino acid with >99.7 percent enantiomeric excess.

Full text of DOI:10.1016/S0957-4166(03)00579-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3455–3467
An alkaloid-mediated desymmetrization of meso-anhydrides via a
nucleophilic ring opening with benzyl alcohol and its application
in the synthesis of highly enantiomerically enriched b-amino
acids
Carsten Bolm,* Ingo Schiffers, Iuliana Atodiresei and Christian P. R. Hackenberger
Institut fu¨r Organische Chemie der RWTH Aachen, Professor-Pirlet-Str. 1, D-52056 Aachen, Germany
Received 7 April 2003; accepted 27 May 2003
Dedicated to Professor H. Schwarz on the occasion of his 60th birthday
Abstract—The cinchona alkaloid-mediated opening of prochiral cyclic anhydrides in the presence of benzyl alcohol leading to
optically active hemiesters is described. Structurally diverse anhydrides are converted into their corresponding benzyl monoesters
with either enantiomer being obtained with up to 99% e.e. by using quinine or quinidine as the directing additive. A simple
aqueous work-up protocol permits the isolation of the products in analytically pure form and the recovery of the alkaloids almost
quantitatively. These hemiesters can be converted to N-protected b-amino esters by means of Curtius degradation of the
corresponding acyl azides. Subsequent cleavage of both protecting groups by a single reaction step leads to the free b-amino acids
in excellent yields. The efficiency of this procedure is demonstrated by the short asymmetric synthesis of the fungicide cis-pentacin
delivering the amino acid with >99.7% enantiomeric excess.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
introduced by Rovis6 and Fu.7 With respect to the
stereochemistry determining step, the existing methods
can be divided into two categories: First, anhydride
openings employing a chiral nucleophile, and second,
procedures using an achiral nucleophile in combination
with a chiral Lewis acid catalyst or a metal-free chiral
mediator: Whereas the first gives diastereomers, the
second only gives enantiomeric products (Fig. 1).
The asymmetric opening of a meso-anhydride by a
nucleophile is an efficient and versatile strategy to
establish multiple stereogenic centers in
a target
molecule,1 since the resulting functional groups can
selectively be manipulated in further reaction steps.
Therefore valuable building blocks for the synthesis of
natural products or biologically active substances can
be prepared in only one symmetry breaking operation
starting from easily accessible substrates. Impressive
examples of this include Carreira’s sequence to prepare
the cyclopentyl core of the axinellamines2 and Kraft’s
total synthesis of a new and powerful oxamacrolide-
musk odorant.3 The interest in the development of
selective methods has increased considerably within the
last 5 years and along with reliable concepts using
alcohols4 or amines,5 new approaches for the ring open-
ing with carbon-based nucleophiles have recently been
As chiral mediators cinchona alkaloids showed very
high enantioselectivities,8 and excellent procedures for
asymmetric methanolyses of anhydrides have been
developed.9 Recently, we reported on a simple and
highly enantioselective stoichiometric process, which
allowed the preparation of a wide variety of structurally
highly diverse mono methylesters in their pure form.9c,d
The mediator, which is used in stoichiometric quanti-
ties, can easily be recovered from the aqueous phase by
acid extraction and reused without loss of selectivity.
Both ester enantiomers are available in excellent yields
with up to 99% e.e. using either quinine or quinidine as
the directing additive. Comparable results were subse-
quently obtained by Deng et al.,9e who applied substoi-
* Corresponding author. Tel.: +49 241-8094 675; fax: +49 241-8092
391; e-mail: carsten.bolm@oc.rwth-aachen.de
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00579-2

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C. Bolm et al. / Tetrahedron: Asymmetry 14 (2003) 3455–3467
chiometric quantities10 of Sharpless’s biscinchona alka-
loid derivatives (DHQ)2AQN and (DHQD)2AQN.11,12
The mechanism of the alkaloid-mediated methanolysis
has not yet been fully elucidated. So far two general
models are discussed,13 although neither provides a
clear explanation for the cause in the distinction
between the enantiotopic carbonyl groups. On the one
hand, a nucleophilic catalyst is suggested in which the
alkaloid attacks the anhydride with the quinuclidine
nitrogen atom at one of the carbonyl groups.8c,9d This
mechanism is similar to the one accepted for the amine-
catalyzed kinetic resolution of secondary alcohols by
acylation.14 However on the other hand, the alkaloid
could serve as chiral base for the methanol molecule.8a
This proposal corresponds to the one suggested by
Wynberg for the asymmetric addition of thiols to
enones.15 Evidence has been found for both models.
However the kinetic isotope effect (kMeOH/kMeOD=2.3)
observed by Oda et al.8a supports the latter, while
Carloni’s detection of an anhydride-quinidine adduct
by mass spectroscopy16 indicates the formation of an
acylammonium-type intermediate.17
lem was solved by an acidic hydrolysis, which yielded
the hydrochloric salt of the fungicide. However, in this
case an additional ion exchange chromatography was
required to liberate the unprotected amino acid.36b In
order to circumvent these difficulties we have now
examined the use of other alcohols as nucleophiles in
the quinidine-mediated anhydride opening, which lead
to esters that can easily be cleaved under very mild
conditions.
As demonstrated earlier, the steric properties of a
nucleophile have a pronounced effect on the rate and
selectivity of the anhydride opening. Thus, almost no
reaction took place with more sterically hindered alco-
hols such as 2-propanol, even when they were used as
solvent.9d,19 Ethanol as the nucleophile exhibited a sig-
nificantly lower reactivity and selectivity when com-
pared to methanol.8a Accordingly, using anhydride 1 as
the model substrate, the reaction time had to be
increased from 60 to 108 h for achieving complete
conversion when methanol was substituted by ethanol
as the nucleophile (Table 1, entry 2). On the other
hand, 2,2,2-trifluoroethanol showed a considerable
reaction rate, but gave a product that was racemic
(entry 3). This result was analogous to the findings by
Oda, who found a significant decrease in e.e.8a It con-
trasted, however, the observations made by Deng in
studies of the openings of monosubstituted succinic
anhydrides. There, higher enantiomeric excesses were
achieved when the fluorinated alcohol was used as the
nucleophile.9f Since the irreversible Pd(0)-catalyzed
transfer of allyl to weakly basic morpholine offers the
possibility of a mild cleavage of allylic esters,24 the
synthesis of 5 with 97% e.e. (Table 1, entry 4) already
fulfilled the initially demanded criteria. However, tak-
ing into account the potentially tedious product purifi-
cation in an amino acid synthesis this sequence
appeared unsatisfactory.25 We therefore decided to
focus our attention on the establishment of a benzyl
ester functionality. The initial results proved promising.
Thus, using benzyl alcohols as the nucleophile, hemi-
esters 7 and 8 were obtained in analytically pure form
with 97% e.e. and in high yields (Table 1, entries 6–8).
In contrast to the nucleophiles described so far, the
required excess of the alcohol could not completely be
removed in vacuo after terminating the reaction. Never-
theless, the preparative advantage of a simple workup
without chromatographic product purification was
maintained for most products. Thus, an acidic wash
permitted the recovery of the alkaloid and a subsequent
As an extension of our work in this field, we demon-
strated the use of the methanolysis procedure in the
preparation of b-amino acids such as cis-pentacin
hydrochloride,18 g-amino alcohols,19 and vicinal
diamines.20 These applications were supplemented by
the synthetic work of others.2,16,21 Herein we report an
improvement in the existing procedure by using benzyl
alcohols as the nucleophile for the ring opening, which
substantially extends the scope of potential chemical
transformations. Furthermore, we demonstrate the use-
fulness of this new protocol in a highly efficient asym-
metric synthesis of cispentacin, which is a potent
fungicide that was independently isolated a decade ago
by two Japanese groups from Bacillus cereus and Strep-
tomyces setonii,22 and (−)-2-aminocyclobutane-1-car-
boxylic acid, which has recently been used for the
synthesis and structural investigation of a conforma-
tionally constrained b-dipeptide.23
2. Results and discussion
In our previous approach towards cispentacin, which
involved the meso-anhydride opening with methanol as
nucleophile, we observed epimerization of the amino
ester during its saponification. Consequently, a mixture
of diastereomeric products was obtained.18 The prob-
Figure 1. Stereoselective desymmetrization of meso-anhydrides by nucleophilic ring opening.

C. Bolm et al. / Tetrahedron: Asymmetry 14 (2003) 3455–3467
3457
Table 1. Quinidine-mediated opening of anhydride 1 using
nene anhydride 25 were formed in a highly enantiose-
lective manner (entry 9). In contrast, the corresponding
methanolysis gave products with 18% e.e. difference.9d
Also the yields of 26 and ent-26 were significantly
higher than those of products which were obtained
from the opening of the same starting material with
methanol. This is due to a lower water solubility of the
benzyl hemiesters, which results in a reduced loss of
product during the aqueous workup. Since such oxatri-
cyclic molecules are known to react with basic
reagents,26 the second extraction procedure was omitted
and the products purified by chromatography (entries 9
and 10). The cleavage of the oxygen bridge offers an
access to carba-sugar derivatives,26a and investigations
for the development of asymmetric syntheses involving
the alkaloid-mediated anhydride opening are currently
in progress.
different alcoholsa
Entry
Alcohol
Hemiester E.e. (%)c Yield (%)
1
2
3
Methanol
Ethanol
2,2,2-Trifluoro-
ethanol
2
3
4
99
89
Rac.
99
97d
96
4
5
6
7
8
Allyl alcohol
Propargyl alcohol
Benzyl alcohol
Benzyl alcohol
p-Anisyl alcohol
5
6
7
97
79
97
96
97
97
97
92
93
93
ent-7e
The enantiomeric excesses of the benzyl esters were
determined by GC analysis of the appropriate lactones,
which were obtained by selective reduction of the ester
group with LiBEt3H followed by acid-catalyzed lac-
tonization.4a Since we had already established the abso-
lute configurations of the methanolysis products, the
retention times of the lactones derived from these
methyl esters permitted a direct assignment also for the
benzyl analogues. In all cases the stereochemical out-
come of the desymmetrization was uniform: the
quinidine-mediated ring opening of anhydrides gener-
ated the ester function at the carbonyl group indicated
in the scheme of Table 2. For the anhydrides containing
unsubstituted all-carbon backbones, this is the pro-S-
carbonyl group; due to the reversal of the CIP-priorities
it is the pro-R-carbonyl group of anhydrides 9, 25 and
27. In the same manner quinine always exhibited the
opposite selectivity. Due to this stereoselection rule
being strictly valid for a wide range of substrates,9d,18a
the absolute configurations of other alcoholysis prod-
ucts become highly predictable.
8
a All reactions were performed at −55°C for 60 h using 1.1 equiv. of
quinidine and 3.0 equiv. of alcohol in a toluene/CCl4 mixture (1:1),
0.2 M solution related to anhydride.
b For determination of the absolute configuration, see text and Ref.
9d.
c Determined by GC-analysis of the corresponding lactone using a
chiral stationary phase.
d Complete conversion was only achieved after 108 h.
e Quinine was used as chiral mediator.
mild basic extraction removed the remaining benzyl
alcohol. Furthermore, benzyl hemiester 7 nicely crystal-
lized from ether, allowing the enantiomeric excess to be
increased from a single recrystallization to >99% in
only a few hours. Diastereomeric quinine, which can be
considered as a pseudo-enantiomer of quinidine, gener-
ated ent-7 with 96% e.e. The opening with p-anisyl
alcohol ocurred analogously and gave the product with
97% e.e. in 93% yield (Table 1, entry 8).
In the methanolysis reaction, the highest enantiomeric
excesses were achieved with a solvent system consisting
of a 1:1 mixture of toluene and CCl4. However, combi-
nations of solvents without the potentially harmful
halogenated solvent27 were also applicable and gave
products with high e.e.4c,19 We now find that with
benzyl alcohol acting as a nucleophile, the anhydride
openings occured with almost the same enantioselectivi-
ties and yields in pure toluene, with the only difference
being that the quinine-mediated alcoholyses required
higher concentrations. The largest difference in enan-
tioselectivity between reactions performed in mixtures
of toluene/CCl4 (Table 3, entry 2) and pure toluene
(Table 2, entry 1) was De.e.=3% for ester ent-10. In
some cases, avoiding the use of CCl4 led to an even
slightly higher enantiomeric excess (Table 3, entries 3
and 5).
The ease of the benzyl ester deprotection by simple
hydrogenation performed after derivatization reactions
broadens the applicability of the alkaloid-mediated
anhydride opening favourably and encouraged us to
evaluate the scope of the benzyl alcoholysis. These
results are summarized in Table 2.
Under the conditions optimized in our primary investi-
gation,9c a large variety of bicyclic and tricyclic anhy-
drides were opened with benzyl alcohol to give
products in high yields and with impressive enantiose-
lectivities (up to 99% e.e.). In general, quinidine-medi-
ated ring openings furnished monoesters with slightly
higher enantiomeric excesses in comparison to the
quinine reactions. To our surprise, the difference in
enantioselectivity observed in the products was rather
low using benzyl alcohol as a nucleophile. For example,
both benzyl ester enantiomers derived from oxanorbor-
Next, we selected representative benzyl monoesters to
demonstrate that they are valuable intermediates for
the synthesis of highly enantiomerically enriched b-

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C. Bolm et al. / Tetrahedron: Asymmetry 14 (2003) 3455–3467
Table 2. Quinidine- and quinine-mediated opening of various meso-anhydrides with benzyl alcohola
Table 3. Opening of meso-anhydrides in toluene as solventa
Entry
Anhydride
Quinidine-mediated
E.e. (%)b
Quinine-mediated
E.e. (%)b
Hemiester
Yield (%)
Hemiester
Yield (%)
1
2
3
4
5
1
9
11
13
17
7
10
12
14
18
96
90
95
95
96
84
93
94
94
85
ent-7
95
85
90
94
93
90
86
90
90
86
ent-10
ent-12
ent-14
ent-18
a All reactions were performed at −55°C for 60 h using 1.1 equiv. of alkaloid and 3.0 equiv. of benzyl alcohol; for quinidine: in a 0.2 M solution
related to anhydride, for quinine: 0.1 M.
b Determined by GC-analysis of the corresponding lactones using a chiral stationary phase.

C. Bolm et al. / Tetrahedron: Asymmetry 14 (2003) 3455–3467
3459
amino acids.28 The increasing interest in such cyclic
b-amino acids29 results on the one hand from the fact
that many of these compounds show antibiotic, anti-
fungal, cytotoxic or other important biological proper-
ties in free form or as part of peptidic products.25,29,30
On the other hand Gellman’s reports on oligopeptidic
trans-2-aminocycloalkane carboxylic acid chains, which
can fold into stable helical structures,31 raised the
demand of efficient synthetic routes to b-amino acid
derivatives. Furthermore, cyclic b-amino acids are of
considerable significance in synthetic organic chemistry
for the preparation of pharmacologically active hetero-
cyclic products.29,32 For the synthesis of N-Cbz pro-
tected b-amino acid benzyl esters, the corresponding
dicarboxylic monoesters were activated by treatment
with ethyl chloroformate and triethylamine. Addition
of an aqueous solution of sodium azide afforded crude
acyl azides, which were dissolved in benzene and sub-
jected to thermal rearrangement. After removal of the
solvent, addition of the benzyl alcohol to a methylene
chloride solution of the resulting isocyanates in the
presence of triethylamine gave the desired amino ester
derivatives without purification of any of the intermedi-
ates.18 Finally, the ester and the carbamate protecting
groups were removed in a single step by a simple
hydrogenation, delivering the free b-amino acids in
excellent yields (Table 4).
The Pd/C-catalyzed deprotection step, which was per-
formed at 1 atm hydrogen, required a reaction time of
1–2 h until complete conversion occurred (monitored
by TLC). While carbonꢀcarbon double bonds in sub-
strates with a cyclohexene backbone do not react under
these conditions,18b,33 hydrogenation of the norbornene
amino ester 29 delivered the saturated amino acid 30
(Table 4, entry 1). Although quite expensive, racemic 30
is commercially available and was recently used in a
Ugi four-center three-component reaction to achieve
the appropriate b-lactams.34
As indicated by entry 2 in Table 4 the application of
this new protocol resulted in a simplified asymmetric
synthesis of cispentacin 32,35 an antifungal antibiotic
that was enantioselectively prepared first by Davies in
1993.36 The enantiomeric ratio of 97:3 was confirmed
by HPLC analysis of the corresponding amino ester 31,
using a racemic sample of this compound as reference.
Recrystallization of 31 increased the e.e. to >99.7%.
Table 4. Preparation of protected and unprotected alicyclic b-amino acids 29–35a

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C. Bolm et al. / Tetrahedron: Asymmetry 14 (2003) 3455–3467
In the first synthesis of the optically active cyclobutane
amino acid 34, Ortun˜o et al. used the methyl ester
analogue of ent-12 as a starting material, which was
prepared by pig liver esterase-catalyzed chemoselective
hydrolysis of the corresponding meso-diester.23 The
subsequent Curtius rearrangement afforded the amino
methyl ester equivalent to 33, whose saponification
required particularly mild reaction conditions due to its
tendency to epimerize. Finally, hydrolysis and hydro-
genation led to the highly hygroscopic free amino acid
34 with 91% e.e. in 73% yield. It is noteworthy that the
latter two reactions gave products, which were unsuit-
able for microanalysis.23b In light of these results, the
reaction sequence for the preparation of 34 presented in
Table 4 reveals a considerable improvement in terms of
product purity, enantioselectivity and yield. Since the
starting material used in both routes (cis-cyclobutane-
1,2-dicarboxylic diacid) is rather expensive, the latter
criterion (20% increase in yield) is particularly
noteworthy.
tion of the resulting benzyl monoester by
chromatography or recrystallization. Finally, we have
described the transformation of such hemiesters into
optically active b-amino acids through a reaction
sequence involving a Curtius degradation as a key step.
Their complete deprotection can be obtained in a single
step by simple hydrogenation enabling the isolation of
rather sensitive products. Currently, we are focusing
our efforts on the application of this improved desym-
metrization protocol toward the synthesis of b-peptides
and new diamine ligands for asymmetric catalysis and
highly organized pseudopeptidic systems.
3. Experimental
3.1. General information
Unless otherwise specified, all reagents were purchased
from commercial suppliers and used without further
purification. Toluene and THF were distilled from
sodium benzophenone ketyl radical, CH2Cl2 from CaH2
under Ar. All other solvents were reagent grade and
used as received. Unless otherwise noted all reactions
were carried out under argon using standard Schlenk
and vacuum line techniques. For the determination of
the enantiomeric ratios of the opening products, see
The results shown in Table 4 were obtained from
reactions towards amino acids performed on a 15 mmol
laboratory scale. However, due to the ease of all the
synthetic steps and the accessibility of the substrates,
larger quantities are just as easily manageable. Only in
a single case, the conversion of hemiester 10, did we
encounter difficulties. These were presumably due to
the donor-acceptor substituted cyclopropane core of
the corresponding b-amino acid which is prone to
undergo rapid ring opening reactions.37 Although the
Curtius degradation has frequently been applied with
such three-membered cyclic systems,23b,37d,38 35 was
only obtained with a low e.e. (entry 4). Most likely, this
partial racemization proceeded via an open-chain inter-
mediate, which then underwent a stereospecific ring
closure (as revealed by NMR spectroscopy). The insta-
bility of the three-membered ring also became apparent
in the attempted hydrogenolytic deprotection of 35 to
give the free amino acid. Even in the presence of HCl
the desired product was not obtained and the only
identifiable product (NMR spectroscopy) was the corre-
sponding ring-opened achiral g-amino acid. Along
these lines another interesting observation was made in
the hydrogenolytic deprotection of 33. In this case, the
corresponding free amino acid 34 was obtained in high
yield, when the hydrogenation was performed under
standard conditions. However, extending the reaction
time to 12 h also led to CꢀC bond cleavage. Thus, with
this substrate, the deprotection was substantially faster
than the ring-opening of the cycloalkyl backbone allow-
ing us to isolate the desired cyclobutane amino acid in
high yield.
1
Ref. 9d. H and 13C NMR spectra were obtained on a
Varian Gemini 300 or Inova 400 spectrometer and were
recorded relative to TMS as internal standard. Mass
spectra were measured on a Finnigan SSQ 7000 instru-
ment or on a Hewlett Packard GCMS apparatus-sys-
tem (Column HP-5 MS, 30 m×0.25 mm×0.25 mm; Mass
selective Detector 5973). HPLC analysis was performed
using a Chiralpak AD column, 4.6×250 mm, u=254
nm. Melting points were measured in open glass capil-
laries 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. All
microanalyses were conducted on a Heraeus CHN
RAPID instrument at the Institut fu¨r Organische
Chemie der RWTH Aachen.
3.2. General procedure for the alkaloid-mediated ring
opening of cyclic meso-anhydrides GP-1
Benzyl alcohol (0.310 mL, 3.0 mmol) was added drop-
wise to a stirred suspension of the anhydride (1.0
mmol) and the alkaloid (0.357 g, 1.1 mmol) in a 1:1
mixture of toluene and tetrachloromethane (5 mL in
the case of quinidine, 20 mL in the case of quinine) at
−55°C under argon. The reaction mixture was stirred at
this temperature for 60 h. During this period the mate-
rial gradually dissolved. Subsequently, the resulting
clear solution was concentrated in vacuo to dryness and
the resulting residue dissolved in ether (10 mL). The
solution was washed with 2 M HCl (3×3 mL), followed
by extraction of the aqueous phase with ether (5×5 mL)
and the combined organic layers extracted with a satu-
rated solution of sodium carbonate (5×15 mL). The
resulting aqueous phase was washed with ether (1×25
In conclusion, we have demonstrated that the desym-
metrization of easily accessible meso-anhydrides by cin-
chona alkaloid-mediated opening with benzyl alcohol is
applicable to a variety of structurally different sub-
strates and leads to the corresponding optically active
hemiesters with high enantioselectivities (up to 99%
e.e.). A simple reaction protocol has been developed
which allows the synthesis of either enantiomer selec-
tively, generally without the additional need of purifica-

C. Bolm et al. / Tetrahedron: Asymmetry 14 (2003) 3455–3467
3461
mL) in order to remove the traces of benzyl alcohol,
acidified with conc. HCl, extracted with CH2Cl2 (5×20
mL) and the organic layer dried over MgSO4, filtered
and concentrated providing the corresponding hemi-
ester. Analogously, the quinidine- and quinine-medi-
ated opening was performed in pure toluene using 5 or
10 mL solvent/mmol anhydride, respectively. The
results are summarized in Table 3. To recover the
alkaloid, the acidic aqueous phase was neutralized with
Na2CO3 and extracted with CH2Cl2. The combined
organic phases were dried over MgSO4 and filtered.
Evaporation of the solvent yielded the alkaloid almost
quantitatively.
(m, 1H), 5.87 (ddt, J=5.9, 10.4, 16.3 Hz, 1H), 6.21 (dd,
J=3.0, 5.5 Hz, 1H), 6.31 (dd, J=3.0, 5.5 Hz, 1H),
10.67 (br s, 1H); 13C NMR (75 MHz, CDCl3): l=46.4,
46.8, 48.3, 48.6, 49.0, 65.5, 118.5, 132.4, 134.6, 135.7,
172.3, 178.9; IR (KBr): 2980, 1736, 1703, 1342, 1261,
1216, 1173, 1153, 930 cm−1; EI-MS: m/z=222 (M+, 2),
204 (3), 176 (6), 165 (7), 157 (31), 139 (16), 137 (13), 119
(14), 99 (18), 91 (19), 66 (100), 65 (4). Anal. calcd for
C12H14O4 (229.24): C, 64.85; H, 6.35. Found: C, 64.79;
H, 6.35.
3.2.4.
(2R,3S)-3-endo-Propargyloxycarbonyl-bicy-
clo[2.2.1]hept-5-ene-2-endo-carboxylic acid 6. Com-
pound (2R,3S)-6 was obtained from the quinidine
opening of anhydride 1 in the presence of propargyl
alcohol in 97% yield: mp 115°C (rac), colorless oil;
3.2.1.
(2R,3S)-3-endo-Ethoxycarbonyl-bicyclo[2.2.1]-
hept-5-ene-2-endo-carboxylic acid 3. Compound
(2R,3S)-3 was obtained from the quinidine opening of
anhydride 1 in the presence of ethanol in 97% yield: mp
71°C (rac), colorless oil (en) lit.39 mp 74–75°C (rac);
1
[h]2D5=−1.4 (c 3.06, CHCl3); e.e.=79%; H NMR (300
MHz, CDCl3): l=1.34 (d, J=8.6 Hz, 1H), 1.50 (dt,
J=1.7, 8.6 Hz, 1H), 2.47 (t, J=2.5 Hz, 1H), 3.19–3.21
(m, 2H), 3.30 (dd, J=3.0, 10.1 Hz, 1H), 3.37 (dd,
J=3.2, 10.1 Hz, 1H), 4.53 (dd, J=2.5, 15.8 Hz, 1H),
4.67 (dd, J=2.5, 15.8 Hz, 1H), 6.21 (dd, J=3.0, 5.7 Hz,
1
[h]2D5=−5.8 (c 3.13, CHCl3); e.e.=89%; H NMR (300
MHz, CDCl3): l=1.20 (br t, J=7.2 Hz, 3H), 1.34 (br
d, J=8.6 Hz, 1H), 1.48 (dt, J=1.7, 8.6 Hz, 1H),
3.17–3.18 (m, 2H), 3.27 (dd, J=2.7, 10.1 Hz, 1H), 3.33
(dd, J=3.0, 10.1 Hz, 1H), 4.03 (dq, J=7.1, 10.8 Hz,
1H), 4.07 (dq, J=7.1, 10.8 Hz, 1H), 6.21 (dd, J=3.0,
5.7 Hz, 1H), 6.31 (dd, J=3.0, 5.7 Hz, 1H), 10.54 (br s,
1H); 13C NMR (75 MHz, CDCl3): l=14.3, 46.4, 46.8,
48.3, 48.7, 49.0, 60.6, 66.6, 134.6, 135.7, 172.6, 179.0;
IR (KBr): 2980, 1736, 1701, 1259, 1215, 1181 cm−1;
EI-MS: m/z=210 (M+, 1), 192 (5), 165 (24), 164 (11),
145 (36), 137 (13), 127 (9), 119 (21), 99 (22), 91 (22), 66
(100), 65 (11). Anal. calcd for C11H14O4 (210.23): C,
62.85; H, 6.71. Found: C, 62.83; H, 6.71.
1H), 6.34 (dd, J=3.0, 5.7 Hz, 1H), 10.70 (br s, 1H); 13
C
NMR (75 MHz, CDCl3): l=46.3, 46.9, 48.1, 48.4, 49.0,
52.1, 75.1, 77.9, 134.6, 135.8, 171.8, 178.5; IR (KBr):
3284, 1744, 1705, 1344, 1260, 1216, 1169, 1073 cm−1;
EI-MS: m/z=220 (M+, 1), 175 (3), 165 (5), 155 (22),
137 (13), 119 (12), 99 (20), 91 (16), 66 (100). Anal. calcd
for C12H12O4 (220.22): C, 65.45; H, 5.49. Found: C,
65.24; H, 5.60.
3.2.5. (2R,3S)-3-endo-Benzyloxycarbonyl-bicyclo[2.2.1]-
hept-5-ene-2-endo-carboxylic acid 7. Compound
(2R,3S)-3 was obtained from the quinidine opening of
anhydride 1 in 92% yield as a white solid: mp 120°C
(rac), 92°C (en); [h]2D5=+8.0 (c 1.95, CHCl3); e.e.=97%;
1H NMR (400 MHz, CDCl3): l=1.32 (d, J=8.5 Hz,
1H), 1.47 (dt, J=1.7, 8.5 Hz, 1H), 3.18 (br s, 2H),
3.30–3.32 (m, 2H), 5.00 (AB-system, J=12.4 Hz, 2H),
6.21 (dd, J=3.0, 5.7 Hz, 1H), 6.28 (dd, J=3.0, 5.7 Hz,
1H), 7.27–7.36 (m, 5H), 9.50 (br s, 1H); 13C NMR (100
MHz, CDCl3): l=46.4, 46.8, 48.4, 48.6, 49.0, 66.7,
128.4, 128.6, 128.7, 134.7, 135.7, 136.2, 172.5, 178.8; IR
(KBr): 3034, 2989, 2944, 1747, 1701, 1436, 1340, 1262,
1226, 1173, 1143, 1028 cm−1; EI-MS: m/z=272 (M+, 2),
254 (3), 226 (3), 181 (58), 163 (3), 137 (5), 119 (2), 91
(100), 66 (20). Anal. calcd for C16H16O4 (272.30): C,
70.57; H, 5.92. Found: C, 70.55; H, 6.01.
3.2.2.
(2R,3S)-3-endo-(2,2,2-Trifluorethoxycarbonyl)-
bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid 4. Com-
pound (2R,3S)-4 was obtained from the quinidine
opening of anhydride 1 in the presence of 2,2,2-trifl-
1
uoroethanol in 96% yield: mp 87.5°C (rac); H NMR
(300 MHz, CDCl3): l=1.37 (d, J=8.6 Hz, 1H), 1.54
(dt, J=1.7, 8.6 Hz, 1H), 3.22 (br d, J=10.1 Hz, 2H),
3.25 (dd, J=3.0, 10.1 Hz, 1H), 3.41 (dd, J=3.2, 10.1
Hz, 1H), 4.23 (dq, J=8.6, 12.6 Hz, 1H), 4.47 (dq,
J=8.6, 12.6 Hz, 1H), 6.21 (dd, J=3.0, 5.4 Hz, 1H),
6.34 (dd, J=3.0, 5.4 Hz, 1H), 10.39 (br s, 1H); 13C
NMR (75 MHz, CDCl3): l=46.1, 46.7, 47.7, 48.2, 48.8,
60.4 (q, J=36.5 Hz), 121.2 (q, J=277.0 Hz), 134.5,
135.6, 171.0, 178.5; IR (KBr): 2981, 1757, 1707, 1417,
1312, 1277, 1260, 1230, 1212, 1168, 1088 cm−1; EI-MS:
m/z=164 (12), 120 (12), 119 (9), 92 (36), 91 (100). Anal.
calcd for C11H11F3O4 (264.20): C, 50.01; H, 4.20.
Found: C, 50.28; H, 4.30.
3.2.6. (2S,3R)-3-endo-Benzyloxycarbonyl-bicyclo[2.2.1]-
hept-5-ene-2-endo-carboxylic acid ent-7. Compound
(2S,3R)-7 was obtained from the quinine opening of
anhydride 1 in 93% yield as a white solid; [h]2D5=−7.4 (c
1.00, CHCl3); e.e.=96%.
3.2.3. (2R,3S)-3-endo-Allyloxycarbonyl-bicyclo[2.2.1]-
hept-5-ene-2-endo-carboxylic acid 5. Compound
(2R,3S)-5 was obtained from the quinidine opening of
anhydride 1 in the presence of allyl alcohol in 97%
yield: mp 84°C (rac), colorless oil (en), lit.40 mp 83°C
3.2.7. (2R,3S)-3-endo-(4-Methoxy-benzyloxycarbonyl)-
bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid 8. Com-
pound (2R,3S)-8 was obtained from the quinidine
opening of anhydride 1 in the presence of p-anisyl
alcohol in 93% yield: mp 94°C (rac), colorless oil (en);
1
(rac); [h]2D5=−1.7 (c 3.20, CHCl3); e.e.=97%; H NMR
(300 MHz, CDCl3): l=1.34 (d, J=8.6 Hz, 1H), 1.49
(dt, J=1.7, 8.6 Hz, 1H), 3.18 (br s, 2H), 3.28–3.36 (m,
2H), 4.45 (ddt, J=1.5, 5.9, 13.1 Hz, 1H), 4.54 (ddt,
J=1.5, 5.9, 13.1 Hz, 1H), 5.17–5.22 (m, 1H), 5.25–5.32
1
[h]2D5=+7.3 (c 3.06, CHCl3); e.e.=97%; H NMR (300
MHz, CDCl3): l=1.32 (br d, J=8.6 Hz, 1H), 1.48 (dt,
J=1.7, 8.6 Hz, 1H), 3.18 (br d, J=8.9 Hz, 2H), 3.31-

3462
C. Bolm et al. / Tetrahedron: Asymmetry 14 (2003) 3455–3467
3.32 (m, 2H), 3.79 (s, 3H), 4.95 (AB-system, J=12.1
Hz, 2H), 6.22 (dd, J=3.0, 5.4 Hz, 1H), 6.28 (dd,
J=3.0, 5.4 Hz, 1H), 6.84–6.89 (m, 2H), 7.22–7.27 (m,
2H), 10.25 (br s, 1H); 13C NMR (75 MHz, CDCl3):
l=46.4, 46.8, 48.4, 48.6, 49.0, 55.5, 66.5, 114.1, 128.3,
130.4, 134.6, 135.8, 159.8, 172.5, 178.8; IR (KBr): 2952,
1733, 1706, 1516, 1265, 1215, 1165, 1073 cm−1; EI-MS:
m/z=302 (M+, 8), 121 (100), 91 (6). Anal. calcd for
C17H18O5 (302.32): C, 67.54; H, 6.00. Found: C, 67.49;
H, 6.08.
13C NMR (75 MHz, CDCl3): l=24.0, 29.0, 47.1, 66.1,
66.7, 128.4, 128.4, 128.7, 136.1, 173.9, 180.7; IR (Capil-
lary): 2961, 1736, 1706, 1183 cm−1; EI-MS: m/z=248
(M+, 8), 230 (6), 202 (9), 141 (46), 108 (100), 107 (89),
95 (19), 91 (87), 67 (27), 65 (16). Anal. calcd for
C14H16O4 (248.27): C, 67.73; H, 6.50. Found: C, 66.62;
H, 6.58.
3.2.13. (1S,2R)-cis-2-Benzyloxycarbonyl-cyclopentane-1-
carboxylic acid ent-14. Compound (1S,2R)-14 was
obtained from the quinine opening of anhydride 13 in
89% yield as a colorless oil; [h]2D5=−1.3 (c 0.90, MeOH);
e.e.=95%.
3.2.8. (1S,2R)-cis-2-Benzyloxycarbonyl-3,3-dimethylcy-
clopropane-1-carboxylic acid 10. Compound (1S,2R)-10
was obtained from the quinidine opening of anhydride
9 in 95% yield: mp 79°C (rac), colorless oil (en); [h]2D5=
3.2.14. (1R,2S)-cis-2-Benzyloxycarbonyl-4,4-dimethylcy-
clopentane-1-carboxylic acid 16. Compound (1R,2S)-16
was obtained from the quinidine opening of anhydride
15 according to GP-1 with a modified work-up: the
crude product, obtained after washing the organic layer
with 2 M HCl and evaporation of the solvent, was
purified by column chromatography (pentane:EtOAc,
6:1 to 2:1) to give the hemiester 16 in 78% yield: mp
61°C (rac), colorless oil (en); [h]2D5=+4.2 (c 1.00,
MeOH); e.e.=97% [GC-analysis of the lactone:9d
1
−1.8 (c 1.58, CHCl3); e.e.=92%; H NMR (400 MHz,
CDCl3): l=1.26 (s, 3H), 1.41 (s, 3H), 1.98 (AB-system,
J=8.8 Hz, 2H), 5.15 (AB-system, J=12.1 Hz, 2H),
7.30–7.38 (m, 5H), 10.60 (br s, 1H); 13C NMR (100
MHz, CDCl3): l=15.6, 27.7, 28.4, 33.1, 33.1, 67.4,
128.6, 128.7, 128.8, 135.6, 170.7, 174.1; IR (KBr): 3042,
2961, 2881, 1741, 1691, 1502, 1445, 1257, 1191, 1097
cm−1; EI-MS: m/z=248 (M+, 7), 230 (1), 202 (1), 142
(5), 141 (3), 113 (19), 108 (7), 95 (4), 91 (100), 67 (3), 65
(6). Anal. calcd for C14H16O4 (272.30): C, 67.73; H,
6.50. Found: C, 67.67; H, 6.54.
1
Lipodex E, t1=68.2, t2=70.0 (major)]; H NMR (300
MHz, CDCl3): l=0.90 (s, 3H), 1.03 (s, 3H), 1.69–1.76
(dd, J=8.2, 13.4 Hz, 2H), 1.82–1.89 (dd, J=8.4, 11.4
Hz, 2H), 3.11–3.24 (m, 2H), 4.99 (AB-system, J=12.4
Hz, 2H), 7.20–7.30 (m, 5H), 9.40 (br s, 1H); 13C NMR
(75 MHz, CDCl3): l=29.0, 29.7, 38.8, 43.7, 46.3, 66.8,
128.4, 128.5, 128.7, 136.1, 174.2, 180.8; IR (KBr): 2958,
2930, 1736, 1702, 1285, 1207 cm−1; EI-MS: m/z=276
(M+, 4), 258 (5), 230 (6), 169 (45), 123 (10), 108 (100),
107 (16), 95 (31), 91 (67), 65 (10). Anal. calcd for
C16H20O4 (276.33): C, 69.54; H, 7.30. Found: C, 69.53;
H, 7.19.
3.2.9. (1R,2S)-cis-2-Benzyloxycarbonyl-3,3-dimethylcy-
clopropane-1-carboxylic acid ent-10. Compound
(1R,2S)-10 was obtained from the quinine opening of
anhydride 9 in 94% yield as a colorless oil: [h]2D5=+1.7
(c 1.00, CHCl3); e.e.=88%.
3.2.10. (1R,2S)-cis-2-Benzyloxycarbonyl-cyclobutane-1-
carboxylic acid 12. Compound (1R,2S)-12 was obtained
from the quinidine opening of anhydride 11 in 90%
yield: mp 72.5°C (rac), colorless oil (en), lit.41 mp 66°C
(rac); [h]2D5=−10.9 (c 1.75, MeOH); e.e.=93%; 1H
NMR (400 MHz, CDCl3): l=2.17–2.28 (m, 2H), 2.36–
2.45 (m, 2H), 3.41–3.49 (m, 2H), 5.11 (AB-system,
J=12.1 Hz, 2H), 7.26–7.36 (m, 5H), 10.10 (br s, 1H);
13C NMR (100 MHz, CDCl3): l=22.4, 22.5, 40.8, 40.9,
66.9, 128.4, 128.5, 128.7, 135.9, 173.1, 179.3; IR (KBr):
2955, 1744, 1700, 1336, 1307, 1242, 1189, 1055 cm−1;
EI-MS: m/z=234 (M+, 7), 216 (4), 188 (1), 127 (30),
110 (47), 108 (91), 99 (16), 91 (100), 82 (13), 77 (9), 66
(19), 55 (34). Anal. calcd for C13H14O4 (234.25): C,
66.66; H, 6.02. Found: C, 66.72; H, 6.02.
3.2.15. (1S,2R)-cis-2-Benzyloxycarbonyl-4,4-dimethylcy-
clopentane-1-carboxylic
acid
ent-16.
Compound
(1S,2R)-16 was obtained in the same manner from the
quinine opening of anhydride 15 in 83% yield as a
colorless oil; [h]2D5=−3.9 (c 1.00, MeOH); e.e.=95%.
3.2.16. (1R,2S)-cis-2-Benzyloxycarbonyl-cyclohexane-1-
carboxylic acid 18. Compound (1R,2S)-18 was obtained
from the quinidine opening of anhydride 17 in 88%
yield as a colorless oil; [h]2D5=+2.9 (c 1.95, CHCl3);
1
e.e.=95%; H NMR (400 MHz, CDCl3): l=1.36–1.56
(m, 4H), 1.76–1.80 (m, 2H), 2.01–2.07 (m, 2H), 2.86–
2.89 (m, 2H), 5.12 (AB-system, J=12.4 Hz, 2H), 7.26–
7.35 (m, 5H), 10.70 (br s, 1H); 13C NMR (100 MHz,
CDCl3): l=23.9, 24.0, 26.3, 26.5, 42.7, 42.8, 66.6,
128.3, 128.3, 128.7, 136.2, 173.6, 180.5; IR (Capillary):
3064, 3034, 2940, 2864, 1733, 1740, 1453, 1256, 1218,
1176 cm−1; EI-MS: m/z=262 (M+, 8), 244 (8), 216 (3),
155 (30), 108 (89), 107 (87), 91 (99), 81 (40), 45 (100).
Anal. calcd for C15H18O4 (262.30): C, 68.68; H, 6.92.
Found: C, 68.70; H, 6.98.
3.2.11. (1S,2R)-cis-2-Benzyloxycarbonyl-cyclobutane-1-
carboxylic acid ent-12. Compound (1S,2R)-12 was
obtained from the quinine opening of anhydride 11 in
85% yield as a colorless oil: [h]2D5=+11.5 (c 1.25,
MeOH); e.e.=90%.
3.2.12. (1R,2S)-cis-2-Benzyloxycarbonyl-cyclopentane-1-
carboxylic acid 14. Compound (1R,2S)-14 was obtained
from the quinidine opening of anhydride 13 in 93%
yield: mp 37.5°C (rac), colorless oil (en); [h]2D5=+0.6 (c
1.65, CHCl3), +1.8 (c 0.94, MeOH); e.e.=97%; 1H
NMR (300 MHz, CDCl3): l=1.56–1.71 (m, 1H), 1.79–
2.11 (m, 5H), 3.03–3.14 (m, 2H), 5.08 (AB-system,
J=12.4 Hz, 2H), 7.25–7.37 (m, 5H), 11.30 (br s, 1H);
3.2.17. (1S,2R)-cis-2-Benzyloxycarbonyl-cyclohexane-1-
carboxylic acid ent-18. Compound (1S,2R)-18 was
obtained from the quinine opening of anhydride 17 in
84% yield as a colorless oil; [h]2D5=−2.8 (c 1.09, CHCl3);
e.e.=93%.

C. Bolm et al. / Tetrahedron: Asymmetry 14 (2003) 3455–3467
3463
3.2.18. (1R,2S)-cis-2-Benzyloxycarbonyl-cyclohex-4-ene-
1-carboxylic acid 20. Compound (1R,2S)-20 was
obtained from the quinidine opening of anhydride 19 in
84% yield: mp 65–67°C (rac), colorless oil (en); [h]2D5=
3.2.23. (2S,3R)-3-exo-Benzyloxycarbonyl-bicyclo[2.2.1]-
hept-5-ene-2-exo-carboxylic acid ent-24. Compound
(2S,3R)-24 was obtained from the quinine opening of
anhydride 23 in 81% yield as a white solid; [h]2D5=+21.6
(c 1.00, CHCl3); e.e.=92%.
1
+11.0 (c 1.13, MeOH); e.e.=94%; H NMR (300 MHz,
CDCl3): l=2.32–2.43 (m, 2H), 2.52–2.68 (m, 2H),
3.08–3.13 (m, 2H), 5.13 (AB-system, J=12.4 Hz, 2H),
5.64–5.72 (m, 2H), 7.26–7.37 (m, 5H), 10.10 (br s, 1H);
13C NMR (75 MHz, CDCl3): l=25.8, 26.0, 39.8, 39.9,
66.8, 125.3, 125.4, 128.3, 128.4, 128.7, 136.1, 173.3,
180.0; IR (Capillary): 3031, 2924, 1735, 1707, 1296,
1255, 1190, 1163 cm−1; EI-MS: m/z=260 (M+, 1), 242
(13), 214 (11), 169 (4), 123 (18), 107 (5), 91 (100), 79
(26), 65 (9). Anal. calcd for C15H16O4 (260.29): C,
69.22; H, 6.20. Found: C, 68.83; H, 6.27.
3.2.24. (2S,3R)-3-exo-Benzyloxycarbonyl-7-oxabicyclo-
[2.2.1]hept-5-ene-2-exo-carboxylic acid 26. Compound
(2S,3R)-26 was obtained from the quinidine opening of
anhydride 25 according to GP-1 with a modified work-
up: the crude product, obtained after washing the
organic layer with 2 M HCl and evaporation of the
solvent, was purified by column chromatography
(CH2Cl2:Et2O, 1:1, +1% AcOH) to give the hemiester
26 in 84% yield as a white solid: mp 121°C (rac), 123°C
1
(en); [h]2D5=−27.8 (c 3.23, MeOH). e.e.=99%; H NMR
(300 MHz, CDCl3): l=2.86 (AB-system, J=8.9 Hz,
2H), 5.11 (AB-system, J=12.4 Hz, 2H), 5.25 (br s, 1H),
5.32 (br s, 1H), 6.43–6.48 (m, 2H), 7.28–7.38 (m, 5H),
8.50 (br s, 1H); 13C NMR (75 MHz, CDCl3): l=46.9,
47.3, 67.2, 80.4, 80.7, 128.4, 128.5, 128.6, 135.5, 136.4,
136.8, 171.1, 176.8; IR (KBr): 3022, 1737, 1677, 1334,
1313, 1288, 1214, 1198, 1168, 1008 cm−1; EI-MS: m/z=
228 (1), 206 (19), 139 (9), 121 (6), 108 (23), 107 (81), 100
(55), 91 (100), 79 (30), 68 (90), 65 (26), 55 (12), 51 (14).
Anal. calcd for C15H14O5 (274.24): C, 65.69; H, 5.15.
Found: C, 65.69; H, 5.33.
3.2.19. (1S,2R)-cis-2-Benzyloxycarbonyl-cyclohex-4-ene-
1-carboxylic acid ent-20. Compound (1S,2R)-20 was
obtained from the quinine opening of anhydride 19 in
84% yield as a colorless oil; [h]2D5=−12.1 (c 1.00,
MeOH); e.e.=95%.
3.2.20. (1R,2S)-cis-2-Benzyloxycarbonyl-4,5-dimethylcy-
clohex-4-ene-1-carboxylic acid 22. Compound (1R,2S)-
22 was obtained from the quinidine opening of
anhydride 21 in 88% yield: mp 81–83°C (rac), colorless
oil (en); [h]2D5=+1.9 (c 4.87, CHCl3); e.e.=98%; 1H
NMR (300 MHz, CDCl3): l=1.60 (s, 6H), 2.27–2.30
(m, 2H), 2.44–2.55 (m, 2H), 3.03–3.07 (m, 2H), 5.13
(AB-system, J=12.4 Hz, 2H), 7.25–7.37 (m, 5H), 9.80
(br s, 1H); 13C NMR (75 MHz, CDCl3): l=19.1, 19.2,
31.9, 32.1, 40.5, 40.6, 66.7, 124.2, 124.3, 128.2, 128.3,
128.7, 136.2, 173.4, 180.1; IR (Capillary): 2916, 2859,
1736, 1706, 1255, 1197, 1173 cm−1; EI-MS: m/z=288
(M+, 12), 270 (3), 242 (5), 197 (33), 179 (15), 151 (86),
107 (100), 91 (92), 79 (8), 65 (15). Anal. calcd for
C17H20O4 (288.34): C, 70.81; H, 6.99. Found: C, 70.70;
H, 6.64.
3.2.25. (2R,3S)-3-exo-Benzyloxycarbonyl-7-oxabicyclo-
[2.2.1]hept-5-ene-2-exo-carboxylic acid ent-26. Com-
pound (2R,3S)-26 was obtained in the same manner
from the quinine opening of anhydride 25 in 77% yield
as a white solid; [h]2D5=+29.8 (c 1.00, MeOH); e.e.=
94%.
3.2.26. (2S,3R)-3-exo-Benzyloxycarbonyl-7-oxabicyclo-
[2.2.1]heptane-2-exo-carboxylic acid 28. Compound
(2S,3R)-28 was obtained from the quinidine opening of
anhydride 27 according to GP-1 with a modified work-
up: the crude product, obtained after washing the
organic layer with 2 M HCl and evaporation of the
solvent, was purified by column chromatography
(CH2Cl2:Et2O, 1:1, +1% AcOH) to give the hemiester
28 in 79% yield as a white solid: mp 135°C (rac), 126°C
(en), lit.42 mp 122–124°C (rac); [h]2D5=−10.8 (c 1.00,
3.2.21. (1S,2R)-cis-2-Benzyloxycarbonyl-4,5-dimethylcy-
clohex-4-ene-1-carboxylic acid ent-22. Compound
(1S,2R)-22 was obtained from the quinine opening of
anhydride 21 in 87% yield as a colorless oil; [h]2D5=−2.3
(c 1.00, CHCl3); e.e.=97%.
1
MeOH); e.e.=96%; H NMR (400 MHz, CDCl3): l=
3.2.22. (2R,3S)-3-exo-Benzyloxycarbonyl-bicyclo[2.2.1]-
hept-5-ene-2-exo-carboxylic acid 24. Compound
(2R,3S)-24 was obtained from the quinidine opening of
anhydride 23 in 95% yield: mp 115°C (rac), 77°C (en);
1.42–1.48 (m, 2H), 1.70–1.78 (m, 2H), 2.95 (AB-system,
J=9.4 Hz, 2H), 4.81–4.89 (m, 2H), 5.00 (AB-system,
J=12.4 Hz, 2H), 7.21–7.30 (m, 5H), 8.20 (br s, 1H); 13
C
NMR (100 MHz, CDCl3): l=29.3, 52.5, 52.6, 67.3,
78.7, 78.9, 128.5, 128.6, 128.8, 135.7, 170.8, 176.5; IR
(KBr): 2982, 1736, 1681, 1332, 1301, 1196, 1001 cm−1;
EI-MS: m/z=276 (M+, 1), 258 (9), 169 (10), 141 (5),
123 (25), 108 (77), 91 (100), 79 (18), 68 (19), 65 (15).
Anal. calcd for C15H16O5 (276.28): C, 65.21; H, 5.84.
Found: C, 65.32; H, 5.96.
1
[h]2D5=−24.6 (c 1.17, CHCl3); e.e.=96%; H NMR (300
MHz, CDCl3): l=1.50 (dt, J=1.7, 9.1 Hz, 1H), 2.13
(d, J=9.1 Hz, 1H), 2.64 (dd, J=1.7, 9.6 Hz, 1H), 2.69
(dd, J=1.7, 9.6 Hz, 1H), 3.10–3.13 (m, 2H), 5.06
(AB-system, J=12.4 Hz, 2H), 6.21 (br t, J=1.7 Hz,
2H), 7.26–7.37 (m, 5H), 10.40 (br s, 1H); 13C NMR (75
MHz, CDCl3): l=45.6, 45.8, 46.1, 47.7, 47.8, 67.0,
128.4, 128.5, 128.8, 136.0, 138.2, 138.3, 173.5, 180.2; IR
(KBr): 2979, 1744, 1694, 1437, 1327, 1259, 1223, 1186,
1151, 1018 cm−1; EI-MS: m/z=272 (M+, 3), 254 (7), 226
(1), 181 (5), 165 (9), 163 (7), 120 (9), 108 (47), 91 (100),
66 (40). Anal. calcd for C16H16O4 (272.30): C, 70.57; H,
5.92. Found: C, 70.67; H, 5.99.
3.2.27.
(2R,3S)-3-exo-Benzyloxycarbonyl-7-oxabicy-
clo[2.2.1]heptane-2-exo-carboxylic acid ent-28. Com-
pound (2R,3S)-28 was obtained in the same manner
from the quinine opening of anhydride 27 in 85% yield
as a white solid; [h]2D5=+10.5 (c 1.05, MeOH); e.e.=
90%.

3464
C. Bolm et al. / Tetrahedron: Asymmetry 14 (2003) 3455–3467
3.3. General procedure for the preparation of N-Cbz
tem, J=12.4 Hz, 2H), 5.25 (d, J=8.4 Hz, 1H), 7.26–
7.39 (m, 10H); 13C NMR (75 MHz, CDCl3): l=22.1,
27.8, 32.1, 46.8, 54.3, 66.4, 66.6, 128.1, 128.2, 128.2,
128.5, 128.6, 135.8, 136.5, 155.8, 174.1; IR (KBr): 3333,
2950, 1719, 1688, 1529, 1455, 1319, 1244, 1184, 1044
cm−1; EI-MS: m/z=353 (M+, 2), 262 (3), 218 (4), 156
(53), 138 (14), 107 (42), 91 (100); Anal. calcd for
C21H23NO4 (353.41): C, 71.37; H, 6.56; N, 3.96. Found:
C, 71.09; H, 6.75; N, 4.18.
protected amino acid benzyl esters GP-2
Ethyl chloroformate (2.86 mL, 30 mmol) was added to
a mixture of the appropriate monoester (15 mmol) and
Et3N (6.27 mL, 45 mmol) in dry THF (25 mL) at
−20°C. The reaction mixture was stirred at this temper-
ature for 1 h. An aqueous solution of NaN3 (2.93 g, 45
mmol; in 18 mL water) was added at −10°C. The
temperature was gradually increased to rt and stirring
continued for 2 h. The mixture was diluted with water
and extracted with ethyl acetate. The organic phase was
washed with aq. NaHCO3, dried over MgSO4, filtered
and concentrated providing the corresponding acyl
azide. The crude acyl azide was dissolved in anhydrous
benzene (18 mL) and heated under reflux for 2 h. After
removal of the benzene, benzyl alcohol (1.55 mL, 15
mmol) and Et3N (4.18 mL, 30 mmol) were added to a
solution of the isocyanate in dry CH2Cl2 (20 mL). The
reaction mixture was heated under reflux for 4 h.
Evaporation of the solvent delivered an oily residue,
which was purified by column chromatography provid-
ing the corresponding N-protected amino acid benzyl
ester.
3.3.3. (1R,2S)-cis-2-Benzyloxycarbonylamino-cyclobu-
tane-1-carboxylic acid benzyl ester 33. Compound
(1R,2S)-33 was synthesized according to GP-2 by the
reaction of the dicarboxylic acid monoester ent-12 with
benzyl alcohol. The crude reaction product was purified
by flash chromatography (pentane:EtOAc, 6:1) deliver-
ing 33 in 74% yield as a colorless oil: e.e.=93% [HPLC-
analysis: Chiralpak AD at rt, n-heptane:2-PrOH=95:5,
0.5 mL/min, 254 nm, t1=38.9 min (major), t2=45.0
min]; [h]2D5=−61.6 (c 5.00, CHCl3); 1H NMR (400
MHz, CDCl3): l=1.97–2.03 (m, 2H), 2.23–2.33 (m,
1H), 2.35–2.38 (m, 1H), 3.45 (s, 1H), 4.57 (p, J=8.8
Hz, 1H), 5.05 (AB-system, J=12.2 Hz, 2H), 5.13 (AB-
system, J=12.4 Hz, 2H), 5.69 (d, J=8.8 Hz, 1H),
7.29–7.38 (m, 10H); 13C NMR (100 MHz, CDCl3):
l=19.0, 30.2, 45.6, 46.5, 66.7, 67.0, 128.3, 128.4, 128.5,
128.7, 128.8, 136.0, 136.6, 155.4, 174.2; IR (Capillary):
3350, 2952, 1724, 1515, 1334, 1251, 1213, 1169, 1049
cm−1; EI-MS: m/z=311 (4), 220 (5), 204 (14), 177 (7),
132 (8), 107 (7), 91 (100). Anal. calcd for C20H21NO4
(339.39): C, 70.78; H, 6.24; N, 4.13. Found: C, 70.64;
H, 6.17; N, 4.41.
3.3.1. (2S,3R)-3-exo-Benzyloxycarbonylamino-bicyclo-
[2.2.1]hept-5-ene-2-exo-carboxylic acid benzyl ester 29.
Compound (2S,3R)-29 was synthesized according to
GP-2 by the reaction of the dicarboxylic acid
monoester 24 with benzyl alcohol. The crude reaction
product was purified by flash chromatography
(petroleum ether:EtOAc, 4:1) delivering 29 in 72% yield
as a white solid: mp 44°C (en); e.e.=93% [HPLC-anal-
ysis: Chiralpak AD at rt, n-heptane:2-propanol=94:6,
0.5 mL/min, 254 nm, t1=30.1 min, t2=46.8 min
3.3.4. (1R,2S)-cis-2-Benzyloxycarbonylamino-3,3-dime-
thylcyclopropane-1-carboxylic acid benzyl ester 35.
Compound (1R,2S)-35 was synthesized according to
GP-2 by the reaction of the dicarboxylic acid
monoester 10 with benzyl alcohol. The crude reaction
product was purified by flash chromatography (pen-
tane:EtOAc, 6:1) delivering 35 in 70% yield as a color-
less oil: e.e.=19% [HPLC-analysis: Chiralpak AD at rt,
n-heptane:2-PrOH=94:6, 0.7 mL/min, 254 nm, t1=
17.8 min, t2=21.3 min (major)]; [h]2D5=−7.3 (c 5.00,
1
(major)]; [h]2D5=+17.4 (c 2.63, CHCl3); H NMR (300
MHz, CDCl3): l=1.57 (dt, J=1.7, 9.4 Hz, 1H), 1.97
(d, J=9.4 Hz, 1H), 2.69 (d, J=8.4 Hz, 1H), 2.73 (br s,
1H), 2.95 (br s, 1H), 4.03 (t, J=8.4 Hz, 1H), 4.95–5.13
(m, 4H), 5.52 (d, J=9.6 Hz, 1H), 6.15–6.25 (m, 2H),
7.24–7.38 (m, 10H); 13C NMR (75 MHz, CDCl3): l=
44.7, 46.2, 46.7, 48.8, 53.5, 66.8, 67.0, 128.3, 128.4,
128.5, 128.7, 128.8, 135.9, 136.8, 137.5, 138.7, 158.0,
174.3; IR (KBr): 3352, 2978, 1718, 1529, 1337, 1267,
1252, 1235, 1189, 1032 cm−1; EI-MS: m/z=353 (M+, 1),
262 (9), 218 (39), 91 (100). Anal. calcd for C23H23NO4
(353.41): C, 71.37; H, 6.56; N, 3.96. Found: C, 71.46;
H, 6.92; N, 4.01.
1
CHCl3); H NMR (400 MHz, CDCl3): l=1.13 (s, 3H),
1.20 (s, 3H), 1.69 (d, J=7.7 Hz, 1H), 3.20 (t, J=7.4 Hz,
1H), 5.09 (br s, 2H), 5.11 (br s, 2H), 6.26 (d, J=6.0 Hz,
1H), 7.27–7.37 (m, 10H); 13C NMR (100 MHz, CDCl3):
l=13.5, 26.2, 26.6, 27.9, 41.5, 66.8, 67.1, 128.3, 128.5,
128.6, 128.7, 128.8, 136.0, 136.8, 157.1, 171.5; IR (Cap-
illary): 3401, 2957, 1725, 1510, 1344, 1221, 1154, 1065
cm−1; EI-MS: m/z=353 (M+, 1), 262 (9), 218 (39), 91
(100). Anal. calcd for C21H23NO4 (353.41): C, 71.37; H,
6.56; N, 3.96. Found: C, 71.46; H, 6.92; N, 4.01.
3.3.2. (1R,2S)-cis-2-Benzyloxycarbonylamino-cyclopen-
tane-1-carboxylic acid benzyl ester 31. Compound
(1R,2S)-31 was synthesized according to GP-2 by the
reaction of the dicarboxylic acid monoester ent-14 with
benzyl alcohol. The crude reaction product was purified
by flash chromatography (pentane:EtOAc, 4:1) deliver-
ing 31 in 77% yield as a white solid: mp 55°C (rac),
77°C (en); e.e.=94% (99.7% after recrystallization)
[HPLC-analysis: Chiralpak AD at rt, n-heptane:2-
propanol=90:10, 0.8 mL/min, 254 nm, t1=14.9 min
3.4. General procedure for the synthesis of the free
b-amino acids GP-3
A solution of the N-protected b-amino acid benzyl ester
in dry MeOH was hydrogenated over 10% Pd/C for 1–2
h at rt and at 1 atm. The complete conversion of the
reaction was monitored by TLC, the catalyst was
removed by filtration through Celite, washed with
MeOH and the filtrate was evaporated to give the
corresponding free amino-acid.
(major), t2=19.2 min]; [h]2D5=−41.1 (c 1.83, CHCl3); H
NMR (300 MHz, CDCl3): l=1.55–1.85 (m, 3H), 1.89–
2.03 (m, 3H), 3.05 (q, J=7.2 Hz, 1H), 4.24–4.34 (m,
1H), 5.04 (AB-system, J=18.3 Hz, 2H), 5.06 (AB-sys-
1

C. Bolm et al. / Tetrahedron: Asymmetry 14 (2003) 3455–3467
3131.
3465
3.4.1. (2S,3R)-3-exo-Amino-bicyclo[2.2.1]heptane-2-exo-
carboxylic acid 30. Compound (2S,3R)-30 was synthe-
sized from the b-amino ester 29 according to GP-3 in
97% yield as a white solid: mp (dec) >250°C (rac), (dec)
>250°C (en), lit.43 mp 275–278°C (rac); [h]2D5=−8.0 (c
2. Starr, J. T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 8793.
3. Kraft, P.; Cadalbert, R. Synthesis 1998, 1662.
4. Recent reports: (a) Jaeschke, G.; Seebach, D. J. Org.
Chem. 1998, 63, 1190; (b) Gottwald, K.; Seebach, D.
Tetrahedron 1999, 55, 723; (c) Uozumi, Y.; Yasoshima,
K.; Miyachi, T.; Nagai, S. Tetrahedron Lett. 2001, 42,
411; (d) Dai, W.-M.; Yeung, K. K. Y.; Chow, C. W.;
Williams, I. D. Tetrahedron: Asymmetry 2001, 12, 1603.
5. Recent reports: (a) Jones, I. G.; Jones, W.; North, M.
Synlett 1997, 63; (b) Hibbs, D. E.; Hursthouse, M.;
Jones, I. G.; Jones, W.; Malik, K. M. A.; North, M. J.
Org. Chem. 1998, 63, 1496.
1
1.40, H2O); H NMR (300 MHz, D2O): l=1.16–1.18
(m, 2H), 1.23 (d, J=10.9 Hz, 1H), 1.43–1.60 (m, 2H),
1.66 (d, J=10.9 Hz, 1H), 2.30 (s, 1H), 2.42 (s, 1H), 2.53
(d, J=7.9 Hz, 1H), 3.30 (d, J=7.9 Hz, 1H); 13C NMR
(75 MHz, D2O): l=25.8, 28.0, 33.5, 41.1, 41.9, 51.3,
54.7, 178.9; IR (KBr): 3424, 2955, 2676, 1632, 1537,
1395, 1367, 1316 cm−1; EI-MS: m/z=155 (M+, 70), 138
(13), 127 (52), 110 (43), 82 (45), 70 (100), 56 (90).
HRMS for C8H13NO2: calcd 155.0946, Found:
155.0945.
6. Rovis, T.; Bercot, E. A. J. Am. Chem. Soc. 2002, 124,
174.
3.4.2.
(1R,2S)-cis-2-Amino-cyclopentane-1-carboxylic
7. Shintani, R.; Fu, G. C. Angew. Chem. 2002, 114, 1099;
Angew. Chem., Int. Ed. 2002, 41, 1057.
acid 32. Compound (1R,2S)-32 was synthesized from
the b-amino ester 31 according to GP-3 in 98% yield as
a white solid: mp (dec) 194°C (rac), (dec) 192°C (en),
lit.36b mp 194–197°C (en); [h]D25=−10.1 (c 2.81, H2O),
8. For fundamental studies see: (a) Hiratake, J.; Inagaki,
M.; Yamamoto, Y.; Oda, J. J. Chem. Soc., Perkin Trans.
1 1987, 1053; (b) Hiratake, J.; Yamamoto, Y.; Oda, J. J.
Chem. Soc., Chem. Commun. 1985, 1717; (c) Aitken, R.
A.; Gopal, J. Tetrahedron: Asymmetry 1990, 1, 517; (d)
Aitken, R. A.; Gopal, J.; Hirst, J. A. J. Chem. Soc.,
Chem. Commun. 1988, 632.
9. (a) Mittendorf, J.; Arold, H.; Fey, P.; Matzke, M.; Mil-
itzer, H.-C.; Mohrs, K.-H. Patent DE 4400749A1, 1994,
Chem. Abstr. 1994, 121, 83988u; (b) Mittendorf, J. Patent
EP0805145A1, 1997, Chem. Abstr. 1997, 127, 339100g; (c)
Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195;
(d) Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J.
Org. Chem. 2000, 65, 6984; (e) Chen, Y.; Tian, S.-K.;
Deng, L. J. Am. Chem. Soc. 2000, 122, 9542; (f) Chen,
Y.; Deng, L. J. Am. Chem. Soc. 2001, 123, 11302; (g)
Wo¨ltinger, J.; Krimmer, H.-P.; Drauz, K. Tetrahedron
Lett. 2002, 43, 8531.
lit.35f [h]D25=−9.6 (c 1.00, H2O); H NMR (300 MHz,
1
D2O): l=1.52–1.74 (m, 4H), 1.86–2.00 (m, 2H), 2.71
(dt, J=6.4, 8.4 Hz, 1H), 3.56 (dt, J=4.2, 6.4 Hz, 1H);
13C NMR (75 MHz, D2O): l=21.3, 28.0, 29.5, 47.6,
53.0, 180.8; IR (KBr): 3420, 2955, 1627, 1577, 1506,
1461, 1440, 1411, 1311, 1122, 1073 cm−1; EI-MS: m/z=
129 (M+, 12), 100 (8), 82 (7), 69 (7), 56 (100). Anal.
calcd for C6H11NO2 (129.16): C, 55.80; H, 8.58; N,
10.84. Found: C, 55.52; H, 8.46; N, 11.19.
3.4.3.
(1R,2S)-cis-2-Amino-cyclobutane-1-carboxylic
acid 34. Compound (1R,2S)-34 was synthesized from
the b-amino ester 33 according to GP-3 in 93% yield as
a white solid: mp (dec) 130°C (en), lit.44 mp (dec)
129–132°C (rac), lit.23b mp (dec) 130°C (en); [h]2D5=
1
−80.0 (c 1.00, H2O); H NMR (300 MHz, D2O): l=
10. A direct comparison of the two approaches in view of
their preparative advantages remains difficult at the
present time. The stoichiometric procedure can be easily
transfered to a 50–60 mmol scale without any restrictions.
Then, the cost of the required amount of quinine is about
4-18 times lower than the one of the (DHQ)2AQN cata-
lyst (Aldrich). In this context see also Ref. 25.
1.90–2.00 (m, 1H), 2.07–2.30 (m, 3H), 3.09–3.17 (m,
1H), 3.79–3.86 (m, 1H); 13C NMR (75 MHz, D2O):
l=21.1, 25.0, 41.3, 45.5, 181.0; IR (KBr): 3433, 2956,
2190, 1541, 1405, 1293 cm−1; MS (FAB): 114 (M+−H);
Anal. calcd for C5H9NO2 (115.13): C, 52.16; H, 7.88;
N, 12.17. Found: C, 51.80; H, 7.97; N, 11.81.
11. (DHQD)2AQN: 1,4-Bis(dihydroquinidyl)anthraquinone,
(DHQ)2AQN: 1,4-bis(dihydroquinyl)anthraquinone.
12. For leading reviews on the use of those alkaloid deriva-
tives in asymmetric dihydroxylations of olefins, see: (a)
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483; (b) Kolb, H. C.; Sharpless, K.
B. In Transition Metals for Organic Synthesis, Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2, p.
219; (c) Marko´, I. E.; Svendsen, J. S. In Compressive
Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin 1999, p. 713; (d)
Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New
York, 2000; p. 357; (e) Bolm, C.; Hildebrand, J. P.;
Mun˜iz, K. In Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: New York, 2000; p. 399.
13. (a) For a detailed discussion see Ref. 1b; (b) for early
mechanistic studies on the reaction of cyclic anhydrides
and tert-amines (in water), see: Kluger, R.; Hunt, J. C. J.
Am. Chem. Soc. 1989, 111, 3325.
Acknowledgements
We are grateful to the Deutsche Forschungsgemein-
schaft (DFG) within the Collaborative Research Center
(SFB) 380 ‘Asymmetric Synthesis by Chemical and
Biological Methods’ and the Fonds der Chemischen
Industrie for financial support. C.P.R.H. acknowledges
the Fonds der Chemischen Industrie and the BMBF for
a pre-doctoral stipend. We also thank Nicole Brendgen
and Susi Gru¨nebaum for experimental contributions.
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