A novel asymmetric phase-transfer-catalyzed γ-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary γ-carbon in good to excellent yields and good enantioselectivities (74-88% ee). The enantiomeric purity could be substantially enhanced to 94-95% ee by recrystallization. Both electron-withdrawing and electron-releasing substituents are well tolerated on the phthalide core as well as on the aromatic moiety of the alkylating agent. This methodology, enabling the introduction of an unfunctionalized group at the phthalide γ-position, fully complements previously reported organocatalytic strategies involving functionalized electrophiles, thus expanding the scope of accessible 3,3-disubstituted products. The high synthetic value of this asymmetric reaction has been proven by the formal synthesis of the naturally occurring alkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.
A novel asymmetric phase-transfer-catalyzed γ-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary γ-carbon in good to excellent yields and good enantioselectivities (74-88% ee). The enantiomeric purity could be substantially enhanced to 94-95% ee by recrystallization. Both electron-withdrawing and electron-releasing substituents are well tolerated on the phthalide core as well as on the aromatic moiety of the alkylating agent. This methodology, enabling the introduction of an unfunctionalized group at the phthalide γ-position, fully complements previously reported organocatalytic strategies involving functionalized electrophiles, thus expanding the scope of accessible 3,3-disubstituted products. The high synthetic value of this asymmetric reaction has been proven by the formal synthesis of the naturally occurring alkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.
The isobenzofuran-1(3H)-one core is a ubiquitous
pharmacophore incorporated in the structure of a large family of natural
products and synthetic analogues, known collectively as phthalides,
which display a considerably wide range of useful biological activities.[1,2] In addition, phthalides are also valuable intermediates for the
synthesis of several drugs and naturally occurring compounds such
as anthracyclines and other antibacterial and anticancer quinones,[3] phthalanes,[4] isocoumarins,[5] phthalazines,[6] and
others.[5,7] Despite the conspicuous efforts devoted
to the asymmetric syntheses of phthalides, typically performed through
the stereocontrolled formation of the lactone ring, the vast majority
of methods furnish 3-monosubstituted lactones, whereas enantioenriched
3,3-disubstituted derivatives containing a chiral γ-quaternary
carbon atom, also widely represented in nature (Figure ), remain elusive.[8]
Figure 1
Representative
natural 3,3-disubstituted phthalides with a chiral
γ-quaternary carbon atom.
Representative
natural 3,3-disubstituted phthalides with a chiral
γ-quaternary carbon atom.To this end, the stereocontrolled direct introduction of an electrophilic
group at the γ-position of a 3-substituted phthalide has recently
emerged as a viable alternative (Figure ).[9−14] In this context, γ-activated phthalide esters and nitriles
proved to be ideal substrates in reactions catalyzed by bifunctional
and polyfunctional base organocatalysts containing a thiourea moiety.
Such catalysts, which are tailor-made for functionalized electrophiles
capable to interact with hydrogen-bond donor groups, furnished excellent
results with imines,[10] Michael acceptors,[11] and Morita–Baylis–Hillman carbonates.[12,13] Remarkably, reactions with unfunctionalized alkylating agents, such
as alkyl halides, which lack hydrogen-bond acceptor groups, have never
been reported to date in asymmetric nor racemic version. For this
transformation, which would significantly expand the scope of accessible
3,3-disubstituted products, the abovementioned bifunctional base organocatalysts
do not appear suitable.
Figure 2
Enantioselective synthesis of 3,3-disubstituted
phthalides through
direct group insertion at the γ-position.
Enantioselective synthesis of 3,3-disubstituted
phthalides through
direct group insertion at the γ-position.It is well known that the most effective organocatalytic strategy
to achieve enantioselective alkylation of weakly acidic substrates
is asymmetric phase-transfer catalysis.[15] Although phthalide 3-carboxylic esters meet all the requirements,
their application in phase-transfer catalysis has not yet been explored.
In this article, we report the development of a novel phase-transfer-catalyzed
alkylation of phthalide 3-carboxylic esters, demonstrating the utility
of such a process in asymmetric synthesis.
Results and Discussion
Our investigation began with a preliminary screening of chiral
phase-transfer catalysts (Figure ) in the reaction of substrate 15a with
benzyl bromide 16a (Table ). In the beginning, various cinchonidinium salts were
surveyed in toluene/KOH 50% aq (Table , entries 1–7), but although the anticipated
product 17aa was obtained in good yields and very short
reaction times in most cases, the enantioselectivities were disappointing,
with ee values not exceeding 24%.[16]
Figure 3
Phase-transfer
catalysts screened in the benzylation of 15a.
Phase-transfer
catalysts screened in the benzylation of 15a.Reaction conditions: 15a (0.05 mmol), 16a (0.06 mmol), catalyst (x mmol), KOH 50% aq (0.3 mL), toluene (0.5 mL).Isolated yields.Determined by chiral HPLC.Lygo’s chiral biphenyl azepinium salts 8–11(17) also led smoothly
to the desired product
with low ee values (entries 8–11). A small improvement was
observed with derivative 8. Finally, a striking enhancement
of enantioselectivity was achieved with Maruoka’s N-spiro C2-symmetric catalysts 12 and 13, even when applied at lower (5 mol %) loadings
(entries 12–13). A higher reaction rate and enantiomeric excess
were achieved with the latter derivative. A poor result was instead
observed with N,N-dibutyl ammonium
salt 14 (entry 14). A smaller catalyst amount led to
the decline of the enantiomeric excess (entry 15). Attempts to use
the corresponding benzyl and ethyl phthalide esters under conditions
described in Table , entry 13, resulted only in decomposition products.The X-ray
analysis of the major dextrorotatory enantiomer, produced
in the reaction catalyzed by (R,R)-configured catalyst 13, made it possible to determine
its absolute configuration as (R).[18]The effects of the aqueous base and the reaction
medium were next
studied (Table ).
Bases other than KOH required longer reaction times but led to improved
ee values (entries 2–5). Cesium aqueous bases, especially Cs2CO3 (entry 3), led to the best combination of ee
and yield in reasonable reaction times. Cs2CO3 50% aq was therefore used in the following runs. Both the reaction
rate and stereoselectivity were reduced in CH2Cl2 (entry 6), whereas good results were observed in ethereal solvents
(entries 7–8). However, the best results were generally achieved
in aromatic nonpolar solvents (entries 3 and 9–11). Both p- and o-xylene gave results almost identical
to toluene (cf. entries 10–11 with entry 3), suggesting their
use as alternative reaction media. However, toluene is easier to be
removed. Lower ee values were obtained in more polar solvents such
as chlorobenzene and fluorobenzene (entries 12–13). Conducting
the reaction in toluene at 0 °C did not yield any enhancement
of enantioselectivity (entry 14), whereas at −20 °C, no
traces of product were detected, even after 24 h (entry 15).
Reaction conditions: 15a (0.05 mmol), 16a (0.06 mmol), 13 (0.0025
mmol), aqueous base (50% w/w, 0.3 mL), toluene (0.5 mL).Isolated yields.Determined by chiral HPLC.Reaction performed at 0 °C.Reaction performed at −20
°C.With the optimized
reaction conditions displayed in Table , entry 3, we undertook the
study of process scope (Scheme ). Gratefully, uniformly good yields (65–96%) and enantioselectivities
(74–88% ee) were achieved with diversely substituted phthalide
esters 15a–15e and benzyl bromides 16a–16h. Both electron-withdrawing and
electron-releasing substituents were well tolerated at the 5- or 6-position
of the phthalide (products 17ba–17ea) as well as on the benzyl moiety (products 17ab–17ah). The presence of an ortho-methyl group
on the benzyl bromide partner (product 17ad) did not
affect the reactivity or the enantioselectivity. A good result was
also achieved in the reaction with allyl bromide (17ai, 54% yield, 84% ee).[19] It is worth noting
that no traces of hydrolysis byproducts were detected in all the cases
examined. In addition, we were delighted to find that products could
be easily enantioenriched up to >90% ee through recrystallization
from n-hexane. As examples, 17aa was
enantioenriched from 80 to 94% ee, and 17ai was enantioenriched
from 84 to 95% ee, with acceptable overall yields in both cases (66
and 51%, respectively).
Scheme 1
Scope of the Phase-Transfer-Catalyzed Alkylation
of Phthalide Esters–
The following reaction conditions
were applied unless otherwise specified: 15 (0.10 mmol), 16 (0.12 mmol), 13 (0.005) mmol, Cs2CO3 50% aq (0.6 mL), toluene (1.0 mL).
Isolated yields.
ee determined by chiral HPLC.
Values in parenthesis refer
to the product after recrystallization.
Allyl bromide (0.50 mmol) was used.
Scope of the Phase-Transfer-Catalyzed Alkylation
of Phthalide Esters–
The following reaction conditions
were applied unless otherwise specified: 15 (0.10 mmol), 16 (0.12 mmol), 13 (0.005) mmol, Cs2CO3 50% aq (0.6 mL), toluene (1.0 mL).Isolated yields.ee determined by chiral HPLC.Values in parenthesis refer
to the product after recrystallization.Allyl bromide (0.50 mmol) was used.During the scale-up optimization of this process we found
that
good yield and comparable enantioselectivity can be achieved at a
1 mmol scale by using only 2 mol % catalyst 13 (62%,
78% ee for product 17aa).It is reasonable to assume
that the observed enantioselectivity
comes from a preferential orientation of the substrate anion, generated
upon deprotonation of phthalide ester 15, within the
ion pair formed with the N-spiro C2-symmetric cation. Transition state models, based on
DFT calculations, have been previously reported for the benzylation
of N-(diphenylmethylene)glycine tert-butyl esters catalyzed by these Maruoka’s ammonium salts.
In these models, coulombic interactions as well as nonclassical hydrogen
bonds between both reactants and the two catalysts’ enantiotopic
fluorinated aromatic groups play a key role in dictating the mutual
orientation of the alkylating agent and the substrate anion.[20] Thus, building on these computed catalyst conformation
and interactions with the substrates, it is possible to tentatively
sketch a transition state for the alkylation of tert-butyl phthalide 3-carboxylate15a with benzyl bromide 16a, catalyzed by (R,R)-13 (Figure ). In this model, reaction occurs at the Si-face
of the substrate anion, accounting for the high selectivity observed
toward the (R)-17aa product.
Figure 4
Tentative transition
state model for the reaction between phthalide
3-carboxylic ester 15a and benzyl bromide 16a, catalyzed by (R,R)-13.
Tentative transition
state model for the reaction between phthalide
3-carboxylic ester 15a and benzyl bromide 16a, catalyzed by (R,R)-13.Then, to further stress the synthetic
significance of the present
methodology in gaining access to new enantioenriched phthalide compounds,
we focused on the enantioselective preparation of nitrile(R)-18, a key intermediate for the synthesis
of the naturally occurring spermidinealkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine (Scheme ).[7a,21] It should be noted that the control of the (R)-configuration
in 18 is an essential requirement to achieve the (13R)-configuration in the dihydroisoquinolinone moiety of
the target natural product. The original synthesis involved the preparation
and use of 18 as a racemate, leading to the target natural
product as a mixture of (9S,13R)
and (9S,13S) diastereomers, which
were separated only by tedious repeated flash chromatography.[7a] Our first synthesis of (R)-18 was accomplished in six steps starting from commercially
available parent phthalide, with an overall 28% yield and 95% ee (Scheme ). The enantioselective
allylation of 15a followed by fractional crystallization
afforded 17ai in 51% yield and 95% ee, as described before.
Then, de-tert-butylation, synthesis of primary amide 19, and subsequent dehydration[22] afforded (R)-18, a formal precursor
of (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.[23]
Scheme 2
Formal Synthesis of (+)-(9S,13R)-Hydroxyisocyclocelabenzine
Conclusions
In conclusion, the first asymmetric γ-alkylation
of phthalide
3-carboxylic esters has been herein described, affording 3,3-disubstituted
products incorporating benzyl and allyl groups with generally high
yields and good enantioselectivity. Excellent enantiomeric excesses
could be achieved by recrystallization. The present and previous studies[10] demonstrated that the carboxylic group can be
readily manipulated giving access to functionalized 3,3-disubstituted
phthalides that were previously unaccessible in enantioenriched form.
For example, we developed the enantioselective synthesis of a precursor
of (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.
Further synthetic applications of this methodology will be reported
by us in due course.
Experimental Section
General
Remarks
All the chemicals and solvents were
purchased from commercial suppliers and used without further purification.
Catalysts 1–4 and 12–14 are
commercially available, whereas catalysts 5–7(24) and 8–11(17a) were prepared following the general procedure described
in the literature. 5-Chloro-, 6-chloro-, 5-methoxy-, and 6-methoxyisobenzofuran-1(3H)-ones were prepared as described in the literature.[25] Reactions were monitored by analytical thin-layer
chromatography (TLC) on precoated silica gel plates (0.25 mm) and
visualized by UV light or by spraying KMnO4/ethanol or
ninhydrin/ethanol solutions and heating on a hot plate. Flash chromatography
was performed on silica gel 60 (particle size: 0.040–0.063
mm). 1H and 13C NMR spectra were recorded on
a Bruker Avance-600 MHz spectrometer and a Bruker Avance-400 MHz spectrometer
at room temperature in CDCl3, respectively. All the NMR
spectra were referenced to residual CHCl3 (7.26 ppm, 1H; 77.16 ppm, 13C). The following abbreviations
are used to indicate the multiplicity in NMR spectra: s = singlet;
d = doublet; dd = double doublet; t = triplet; bs = broad signal;
and m = multiplet. Coupling constants (J) are quoted
in Hertz. Optical rotations were measured on a Jasco P-2000 digital
polarimeter using WI (tungsten-halogen) lamp (λ = 589 nm). Enantiomeric
excesses were determined using a CHIRALPAK AS-H column (ϕ 0.46
cm × 25 cm) on a JASCO PU-4180 instrument equipped with a photodiode
array detector MD-4015 set at 220 nm. High-resolution mass spectra
(HRMS) were acquired using a Bruker solariX XR Fourier transform ion
cyclotron resonance mass spectrometer (Bruker Daltonik GmbH, Bremen,
Germany) equipped with a 7 T refrigerated actively shielded superconducting
magnet and with a LTQ Orbitrap XL Thermo Scientific. The samples were
ionized in positive-ion mode using a MALDI or ESI ionization source.
LDA was freshly prepared by adding a 2.5
M butyllithium solution in hexanes (11 mL, 27.5 mmol) to an anhydrous
solution of 0.5 M isopropylamine in THF (55 mL, 27.5 mmol) (28.0 mL)
at −78 ° C under a nitrogen atmosphere. The mixture was
stirred for 30 min at the same temperature, and then a solution of
isobenzofuran-1(3H)-one (2.49 g, 18.6 mmol) in anhydrous
THF (3.8 mL) was slowly added. The resulting mixture was stirred for
50 min at −78 °C under a nitrogen atmosphere. Then, the
reaction vessel was saturated with carbon dioxide (three freeze–pump–thaw
cycles followed by connection with a carbon dioxide balloon), and
stirring was kept at −78 °C for 2 h. Once reaction was
complete, NH4Cl saturated aqueous solution (15 mL) was
added dropwise, and then THF was removed under reduced pressure. The
mixture was basified with Na2CO3 saturated aqueous
solution until pH 9 and washed with AcOEt (2 × 20 mL). The aqueous
phase was acidified with concd HCl solution until pH 1, and the product
was extracted with AcOEt (3 × 50 mL). The combined organic phases
were dried over Na2SO4 and concentrated under
reduced pressure. The resulting crude phthalide 3-carboxylic acid
(3.31 g, 18.6 mmol) was dissolved in anhydrous CH2Cl2 (70 mL), and tert-butyl 2,2,2-trichloroacetimidate
(3.3 mL, 18.6 mmol) was added. The reaction mixture was stirred for
48 h under a nitrogen atmosphere, then diluted with CH2Cl2, and centrifuged. The supernatant solution was concentrated
under reduced pressure, and the crude residue was purified by flash
chromatography (silica gel; petroleum ether/ethyl acetate, 95:5 to
80:20), affording 15a as a white solid (4.36 g, 99% yield).
The characterization data matched those previously reported.[12a]1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 7.6, 1H),
7.58 (t, J = 7.6 Hz, 1H), 5.76 (s, 1H), 1.48 (s,
9H).
A mixture of 3-methoxybenzoic acid (0.76
g, 5.0 mmol), glyoxylic acid monohydrate (0.92 g, 10 mmol), concd
H2SO4 (0.55 mL, 10 mmol), and glacial acetic
acid (20.0 mL) was stirred at 80 °C. After 48 h, the reaction
mixture was cooled to room temperature and extracted with AcOEt (3
× 50 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure, affording
crude phthalide 3-carboxylic acid (0.56 g, 2.7 mmol). This solid was
dissolved in anhydrous CH2Cl2 (10 mL) and treated
with tert-butyl 2,2,2-trichloroacetimidate (0.59
g, 2.7 mmol) under a nitrogen atmosphere. After stirring for 48 h,
the reaction mixture was diluted with CH2Cl2 and centrifuged. The supernatant solution was concentrated under
reduced pressure, and the crude residue was purified by flash chromatography
(silica gel; petroleum ether/ethyl acetate, 95:5 to 80:20), affording 15b as a white solid (0.30 g, 23% yield). mp 89–90
°C. 1H NMR (400 MHz, CDCl3) δ 7.49
(d, J = 8.4 Hz, 1H), 7.30 (bs, 1H), 7.23 (d, J = 8.4, 1H), 5.68 (s, 1H), 3.85 (s, 3H), 1.46 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ
169.7, 165.6, 161.3, 136.8, 126.4, 123.2, 123.2, 107.7, 83.7, 77.4,
55.8, 27.8. HRMS (MALDI) m/z: [M
+ Na+] calcd for C14H16NaO5+, 287.0890; found, 287.0892.
To a solution of 3-oxo-1,3-dihydroisobenzofuran-1-carboxylic
acid, prepared as described above (0.2 g, 1.1 mmol), in anhydrous
ethanol (80 mL, 1.4 mmol), thionyl chloride (96 μL, 1.3 mmol)
was added. The resulting solution was stirred for 2 h at room temperature
under a nitrogen atmosphere. Next, the excess alcohol was evaporated,
and water (10 mL) was added to the residue. The mixture was extracted
with AcOEt (3 × 20 mL), and the combined organic phases were
dried over Na2SO4, filtered, and concentrated
under reduced pressure, affording 15f that was used without
further purification (0.22 g, 96% yield). The characterization data
of compounds 15f matched those previously reported.[26]1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.6 Hz, 1H), 7.75–7.64
(m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 5.87 (s, 1H),
4.28 (m, 2H), 1.30 (m, 3H).
Compound 15g was prepared
following the procedure
described for 15f, employing benzyl alcohol (140 mL,
1.4 mmol) that was used without further purification. Yield: 0.26
g (90% yield). The characterization data of compounds 15g matched those previously reported.[27]1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.5 Hz, 1H), 7.68 (m, 1H), 7.63–7.58 (m, 2H),
7.44–7.28 (m, 5H), 5.92 (s, 1H), 5.28 (d, J = 12.1 Hz, 1H), 5.22 (d, J = 12.1 Hz, 1H).
General
Procedure for the Enantioselective Alkylation of Phthalide
3-Carboxylic tert-Butyl Esters 15a–15e
To a solution of phthalide ester 15 (1.0 equiv, 0.1 mmol) in toluene (1 mL), contained in a 4 mL vial,
(R,R)-13 (0.05 equiv, 0.005 mmol), alkyl
bromide 16 (1.2 equiv, 0.12 mmol), and 50 % aqueous Cs2CO3 (0.6 mL) were added. The reaction mixture was
vigorously stirred (900 rpm) at room temperature for the time specified.
After completion (TLC), it was diluted with 1 M HCl (1 mL) and extracted
with CH2Cl2 (3 × 5 mL). The combined organic
phases were dried over Na2SO4 and concentrated
under reduced pressure. The crude residue was purified by flash chromatography,
affording products 17 as white solids.
Scaled-up Procedure for the Enantioselective
Alkylation of Phthalide
Ester 15a
To a solution of phthalide ester15a (234 mg, 1.00 mmol) in toluene (10 mL), contained in a
50 mL round-bottom flask, (R,R)-13 (22
mg, 0.020 mmol), benzyl bromide (205 mg, 1.20 mmol), and 50% aqueous
Cs2CO3 (6.6 mL) were added. The reaction mixture
was vigorously stirred (900 rpm) at room temperature for 20 h followed
by addition of 1 M HCl (20 mL) and extraction with CH2Cl2 (3 × 50 mL). The combined organic phases were dried
over Na2SO4 and concentrated under reduced pressure.
The crude residue was purified by flash chromatography (silica gel;
petroleum ether/ethyl acetate, 98:2 to 80:20), affording 17aa as a white solid (201 mg, 62% yield). The % ee was determined by
chiral HPLC, as described above (78% ee).
Recrystallization of Compound 17aa
Compound 17aa (26.5 mg, 82% yield,
80% ee) was dissolved in hot hexane
(1 mL), and the resulting solution was cooled down at 4 °C. After
20 h, crystals of racemate were formed. The supernatant solution was
separated and concentrated under reduced pressure, affording enantioenriched 17aa (21.9 mg, 66% yield). [α]D20 = +37.2
(c 0.20, CHCl3). The % ee was determined
by chiral HPLC, as described above (94% ee).
Recrystallization of Compound 17ai
Compound 17ai (14.8 mg, 54% yield,
84% ee) was dissolved in hot hexane
(1 mL), and the resulting solution was cooled down at 4 °C. After
20 h, crystals of racemate were formed. The supernatant solution was
separated and concentrated under reduced pressure, affording enantioenriched 17ai (14.0 mg, 51% yield). [α]D20 +55.6 (c 1.0, CHCl3). The % ee was determined by chiral
HPLC, as described above (95% ee).
Formal Synthesis of (+)-(9S,13R)-13-Hydroxyisocyclocelabenzine
To a solution of 17ai (26.1
mg, 0.12 mmol, 95% ee after recrystallization, see above) in anhydrous
CH2Cl2 (0.65 mL), trifluoroacetic acid (0.12
mL) was added dropwise. After stirring for 8 h, the mixture was concentrated
under reduced pressure, affording carboxylic acid 25 as
a white solid (28.0 mg), which was used in the next step without further
purification.Carboxylic acid 25 was dissolved
in dioxane (0.1 mL), and aqueous ammonia (0.2 mL) was added dropwise
at 0 °C. Once the addition was complete, the mixture was allowed
to warm to room temperature, and H2O (0.2 mL) was added.
The resulting reaction mixture was stirred for 2 h and then extracted
with CH2Cl2 (3 × 5 mL). The combined organic
phases were dried over Na2SO4 and concentrated
under reduced pressure. The crude residue was passed through a silica
gel short path by eluting with ethyl acetate, affording 19 as a colorless oil (21.0 mg, 74% yield). [α]D20 +93.2 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3) δ 7.86–7.82 (m, 2H),
7.71 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 6.57 (bs, 1H), 5.84 (bs, 1H), 5.54 (m, 1H), 5.18–5.01
(m, 2H), 3.11 (dd, J = 14.2, 7.4 Hz, 1H), 2.80 (dd, J = 14.2, 6.8 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 170.9, 170.0, 148.0, 135.0, 130.0,
129.4, 125.5, 124.4, 123.5, 121.2, 87.9, 42.0. The % ee was determined
by chiral HPLC (CHIRALPAK AS-H column, n-hexane/i-PrOH = 90:10, 0.5 mLmin–1): τminor = 18.6 min, τmajor = 46.6 min (95% ee).
HRMS (ESI) m/z: [M + H+] calcd for C12H12O3N+, 218.0812; found, 218.0814.
Figure 1
Figure 2
Figure 3
Scheme 1
Figure 4
Scheme 2