Utilization of whole cell mediated deracemization in a chemoenzymatic synthesis of enantiomerically enriched polycyclic chromeno[4,3-b] pyrrolidines

Article abstract of DOI:10.1039/c4ob00615a

Various aryl and alkyl substituted optically pure propargyl alcohols were obtained with excellent ee (up to >99%) and isolated yields (up to 87%) by deracemization using whole cells of Candida parapsilosis ATCC 7330. The whole cells show substrate specificity towards alkyl substituted propargyl alcohols and a switch in the enantioselectivity has been observed from 'R' to 'S' upon increasing the chain length. For the first time, enantiopure (R)-4-(3-hydroxybut-1-ynyl)benzonitrile, (R)-4-(biphenyl-4-yl)but-3-yn-2-ol, (S)-ethyl 3-hydroxy-5-phenylpent-4-ynoate and (S)-4-phenylbut-3-yne-1,2-diol were obtained using this strategy. Optically pure propargyl alcohol thus obtained was used as a chiral starting material in the synthesis of enantiomerically enriched poly-substituted pyrrolidines and a pyrrole derivative successfully demonstrating a chemoenzymatic route. This journal is

Full text of DOI:10.1039/c4ob00615a

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Biomolecular Chemistry
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Utilization of whole cell mediated deracemization
in a chemoenzymatic synthesis of enantiomerically
enriched polycyclic chromeno[4,3-b] pyrrolidines†
Cite this: Org. Biomol. Chem., 2014,
12, 4682
Thangavelu Saravanan,a Sushital Janaa and Anju Chadha*a,b
Various aryl and alkyl substituted optically pure propargyl alcohols were obtained with excellent ee (up to
>99%) and isolated yields (up to 87%) by deracemization using whole cells of Candida parapsilosis ATCC
7330. The whole cells show substrate specificity towards alkyl substituted propargyl alcohols and a switch
in the enantioselectivity has been observed from ‘R’ to ‘S’ upon increasing the chain length. For the first
time, enantiopure (R)-4-(3-hydroxybut-1-ynyl)benzonitrile, (R)-4-(biphenyl-4-yl)but-3-yn-2-ol, (S)-ethyl
3-hydroxy-5-phenylpent-4-ynoate and (S)-4-phenylbut-3-yne-1,2-diol were obtained using this strategy.
Optically pure propargyl alcohol thus obtained was used as a chiral starting material in the synthesis of
enantiomerically enriched poly-substituted pyrrolidines and a pyrrole derivative successfully demonstrat-
ing a chemoenzymatic route.
Received 22nd March 2014,
Accepted 1st May 2014
DOI: 10.1039/c4ob00615a
www.rsc.org/obc
Introduction
Pyrrolidines and their structural analogues have a significant
role in heterocyclic and natural product chemistry due to their
wide range of biological activities.1 Compounds containing the
hexahydrochromeno[4,3-b] pyrrolidine skeleton (Fig. 1, I) are
reported as acetylcholinesterase inhibitors2 where they exhibit
non-competitive antagonism on the muscular nicotinic
receptor and structurally resemble rivastigmine analogues.3 It
is interesting to know that natural compounds such as the
sceletium alkaloid A-4 and martinelline (Fig. 1, II & III)
contain a similar five membered heterocyclic ring system4 and
they were the first naturally occurring non-peptide bradykinin
B1 and B2 receptor antagonists.5 Given the importance of such
molecules, synthesis of these diversely substituted pyrrole/
pyrrolidine derivatives is an important research area in
synthetic and medicinal chemistry.
Fig. 1 Biologically important pyrrolidine derivatives.
[3 + 2] Dipolar cycloaddition is a powerful tool for the syn-
thesis of pyrrolidine derivatives.6,7 Furthermore, enantiopure
pyrrolidine synthesis is well established8 and includes
asymmetric 1,3-dipolar cycloaddition with chiral Lewis acids,
metallo- and organocatalysts.9,10 This study presents
a
chemoenzymatic synthesis of enantiomerically enriched pyrro-
lidines and a pyrrole via a chiral intermediate, i.e. enantiopure
propargyl alcohol obtained through whole cell mediated
deracemization followed by [3 + 2] dipolar cycloaddition of
O-propargylic salicylaldehyde with N-methyl amino esters
(Scheme 1).
Enantiopure propargyl alcohols can be obtained by both
chemo- and biocatalytic methods. Oxidative kinetic resolu-
tion of rac-propargyl alcohols,11–13 asymmetric reduction of
aLaboratory of Bioorganic Chemistry, Department of Biotechnology, Indian Institute
of Technology Madras, Chennai 600 036, India
bNational Centre for Catalysis Research, Indian Institute of Technology Madras,
Chennai 600 036, India. E-mail: anjuc@iitm.ac.in; Fax: +91 44 2257 4102;
Tel: +91 44 2257 4106
†Electronic supplementary information (ESI) available: General experimental
procedure, spectral data, copies of 1H NMR and 13C NMR spectra, HPLC chromato-
grams and XRD data. CCDC 982489 and 982490. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4ob00615a
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Results & discussion
A variety of propargyl alcohols were synthesized and incubated
with C. parapsilosis ATCC 7330. The product was monitored for
deracemization. Preliminary studies which were carried out
with the model substrate rac-4-phenyl-3-butyne-2-ol 1a showed
low enantioselectivity (6% ee) under the previously optimized
conditions34 (6 mM of substrate in 50 mL water, 3 h, 25 °C).
Hence the reaction conditions (time & substrate concentration)
were re-optimized to obtain maximum ee and yield. Enantio-
selectivity improved to 89% by increasing the reaction time
from 3 h to 12 h. Furthermore the substrate concentration was
optimized in the range of 1 mM to 8 mM and reducing the
substrate loading (from 6 mM to 5 mM) led to a significant
increase in enantioselectivity giving up to >99%. To study the
generality of the biocatalytic deracemization with respect to
electronic effects and size of the substrate molecules, various
aryl and alkyl substituted propargyl alcohols were used under
the newly optimized reaction conditions.
Scheme 1 Synthetic route to synthesize pyrrolidine derivatives.
acetylenic ketones14–16 and enantioselective alkyne
additions to both aliphatic and aromatic aldehydes17–21
are the available chemical methods. Biocatalytic preparation
of enantiopure propargyl alcohols mainly involves
kinetic resolution,22–24 asymmetric reduction25 and
deracemization.26–28 Among the available strategies derace-
mization of racemates is an efficient methodology to
produce a single enantiomer in 100% theoretical yield
unlike resolution. In particular whole cell mediated derace-
mization has the advantage of eliminating the addition of
cofactors especially when stereoinversion of one enantiomer
to the other involves oxidation followed by reduction.
Reports on biocatalytic deracemization of propargyl alcohol
via stereoinversion are scarce in the literature. Ogawa et al.
reported the stereoinversion of rac-3-pentyn-2-ol to produce
both (R) and (S)-3-pentyn-2-ol using wet cells of Nocardia
fusca and Nocardia pseudosporangifera in 24 h and 72 h
respectively29 and the cofactor NADPH and glucose dehydro-
genase were added externally to the reaction medium.
As we have reported earlier, Candida parapsilosis ATCC 7330
is a versatile biocatalyst for deracemization30 and oxidative
kinetic resolution31 of secondary alcohols, asymmetric
reduction of prochiral ketones and imines,32 resolution of
N-acyl amino esters and acylation of anilines.33 Recently we
also reported the biocatalytic deracemization of sec-propargyl
hydroxy esters using the whole cells of C. parapsilosis ATCC
7330 with excellent ee (up to >99%) and isolated yields (up to
81%).34 Biocatalytic deracemization was shown by us to follow
a stereoinversion mechanism in which the biocatalyst is not
only enantioselective (i.e. preferring one enantiomer over the
other), but also stereoselective (i.e. inverting one enantiomer,
while the other remains intact).34,35 In the present study,
whole cells of C. parapsilosis ATCC 7330 were used for derace-
mization of various rac-aryl and alkyl substituted sec-
propargyl alcohols and the corresponding enantiopure
propargyl alcohols were obtained as the product thus increas-
ing the substrate repertoire of this whole cell system. An
enantiopure propargyl alcohol thus obtained was further
derivatized into polycyclic pyrolidines and a pyrrole derivative
(Scheme 1).
Biocatalytic deracemization of aryl substituted propargyl
alcohols
Both electron releasing p-CH3 and p-OCH3 substituted aryl pro-
pargyl alcohols gave the corresponding R-alcohols with excel-
lent ee (>99%) and yields (83 and 81% respectively) (Scheme 2,
2b & 2c). Electron withdrawing p-NO2 and p-CN substituted
aryl propargyl alcohols on deracemisation showed excellent ee
(>99%) and a slight decrease in yields (72 and 76%) compared
to the model substrate (Scheme 2, 2d & 2e).
Deracemization
of
rac-4-(naphthalen-2-yl)but-3-yn-2-ol
showed low ee (27%) possibly due to steric reasons and the
bulky nature of the molecule (Scheme 2, 2f). This was also
seen in the case of the deracemization of (E)-methyl 2-hydroxy-
4-(naphthalen-1-yl)but-3-enoate using the whole cells of
C. parapsilosis ATCC 7330.35 However, the substrate 4-(biphenyl-
4-yl)but-3-yn-2-ol when subjected to deracemization gave
the R-enantiomer with excellent ee (>99%) and isolated yield
(76%) (Scheme 2, 2g). The possible reason could be that free
rotation is possible between the two phenyl rings unlike the
fused naphthyl ring. Another substrate 4-(9H-fluoren-2-yl)but-
3-yn-2-ol was designed where the free rotation of phenyl rings
was blocked by a –CH2 group. As anticipated the whole cells
gave low ee (23%) upon deracemization (Scheme 2, 2h).
Notably, the synthesis of enantiomerically pure (R)-4-(3-hydroxy-
but-1-ynyl)benzonitrile 2e and (R)-4-(biphenyl-4-yl)but-3-yn-2-ol
2g by biocatalytic deracemization is reported here for the first
time.
Biocatalytic deracemization of alkyl substituted propargyl
alcohols
Various alkyl substituted propargyl alcohols (Scheme 3) were
designed to study the effect of chain length towards C. parapsi-
losis ATCC 7330 mediated deracemization. As discussed earlier
the model substrate 4-phenyl-3-butyne-2-ol gave R-alcohol 2a
(>99% ee) in which the alkyl group is methyl. When methyl
was replaced by an ethyl group, i.e. 1-phenylpent-1-yn-3-ol, the
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Scheme 2 Deracemization of aryl substituted propargyl alcohols. Enantiomeric excess was determined by HPLC using chiral columns & isolated
yield is given in parentheses. Absolute configuration was determined by comparison of specific rotation and HPLC elution profile with the literature.
corresponding R-alcohol 2i was obtained with a slight decrease not mentioned) has been reported by Veliyev et al.39 Herein we
in ee (89% ee and 85% yield).
report for the first time, synthesis of enantiopure (S)-4-phenyl-
On increasing the chain length from propyl to pentyl, the but-3-yne-1,2-diol (Scheme 3, 2o) with excellent ee (>99%) and
corresponding S-alcohols 2j–2l were obtained with <10% ee for isolated yield (87%) via deracemization using whole cells of
all substrates in 12 h and ee for these substrates were further C. parapsilosis ATCC 7330. For this substrate the stereorecogni-
increased (62%, 48% & 40% ee respectively) by prolonging the tion (i.e. hydride transfer) is similar to the model substrate but
reaction time to 24 h. The alkyl chain length induced reversal absolute configuration is altered as per the CIP rules. Thus the
of stereoselectivity from R to S. When the alkyl groups are hydride from the cofactor is transferred to the ‘Re’ face of car-
small (methyl and ethyl) R-alcohols were obtained with moder- bonyl carbon resulting in the formation of S-enantiomer.30 rac-
ate to good ee, whereas a larger alkyl group (more hydro- Ethyl 3-hydroxy-5-phenylpent-4-ynoate (with ester functionality)
phobic) takes a longer reaction time and gives S-alcohols with was subjected to biocatalytic deracemization to obtain the opti-
low ee. Keinan et al.36 and Zhou et al.37 have reported similar cally pure S-alcohol 2p. To the best of our knowledge, synthesis
inversions of stereoselectivity with respect to chain length of (R)-ethyl 3-hydroxy-5-phenylpent-4-ynoate (92% ee & 95%
within structurally related substrates. A substrate with a cyclo- yield, 48 h) by asymmetric hydrogenations using tethered
hexyl group, i.e. rac-1-cyclohexyl-3-phenylprop-2-yn-1-ol, gave Ru(II)/TsDPEN-derived catalyst is the only example mentioned
the corresponding S-alcohol 2m in 24 h with poor ee (20%), in the literature so far.40 We report here for the first time,
which could be attributed to steric factors. When the cyclo- synthesis of optically pure (S)-ethyl 3-hydroxy-5-phenylpent-
hexyl group was replaced by a phenyl group, the S-alcohol 2n 4-ynoate 2p via biocatalytic deracemization with excellent ee
was obtained with excellent ee (>99%) and yield (79%) in 24 h. (>99%) and isolated yield (70%) in much lesser time (2 h) com-
Biocatalytic deracemization was carried out for rac-4-phenyl- pared to the reported chemical method (48 h).
but-3-yne-1,2-diol using whole cells of C. parapsilosis ATCC
7330. Asymmetric synthesis to obtain enantiopure 4-phenyl-
but-3-yne-1,2-diol is rarely reported in the literature using both
Chemoenzymatic synthesis of enantiomerically enriched
polycyclic pyrrolidine and pyrrole derivatives
chemo- and biocatalytic methods. Jeong et al. reported
osmium catalyzed asymmetric dihydroxylation of enynes using
multiple cinchona alkaloid derivatized chiral ligands to obtain
(R)-4-phenylbut-3-yne-1,2-diol with 73% ee and 91% yield.38
Microbial hydrolysis of acetylene epoxide using Aspergillus
niger to obtain the (R)-4-phenylbut-3-yne-1,2-diol (40% yield, ee
Asymmetric synthesis of pyrrolidines by chemical methods
using chiral reagents, metallo- and organo catalysts has been
well documented.8 Chemoenzymatic synthesis is an important
method to synthesize enantiomerically enriched pyrrolidines,
which employs an enzymatic reaction as well as derivatization
using chemical reagents.41–43 For example, Felluga et al. syn-
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Scheme 3 Deracemization of alkyl substituted propargyl alcohols. Enantiomeric excess was determined by HPLC using chiral columns. Isolated
yield is given in parentheses. Absolute configuration was determined by comparison of specific rotation and HPLC elution profile with the literature.
thesized both the enantiomers of the heterocyclic GABA ana-
Various achiral versions of intramolecular [3 + 2] cyclo-
logue 3-pyrrolidineacetic acid by a chemoenzymatic method addition of O-propargylic salicylaldehyde with amino acid
using two enantiocomplementary lipases (PLE & PPL) in the derivatives have been reported using chemical methods.4,48–50
desymmetric hydrolysis of 3-nitromethylglutaric acid diethyl Bashiardes et al. synthesized plurisubstituted pyrroles, pyrrol-
ester.44 Diversity oriented chemoenzymatic synthesis of func- izines and indolizines using intramolecular [3 + 2] cyclo-
tionalized pyrrolidines has been reported by Cerulli et al. addition reactions wherein the azomethine ylides were
through enzymatic monoacetylation using Amano PS lipase generated in the presence of the achiral/racemic O-substituted
followed by a diastereoselective multicomponent reaction.45 propargylic moiety.51,52 In the present study, we report for the
Asymmetric total synthesis of (−)-rosmarinecine was achieved first time, the intramolecular cycloaddition reaction of
by Nemoto et al. via lipase-catalyzed (immobilized CAL-B) enantiomerically enriched chiral intermediate (S-O-propargylic
domino reactions followed by the intramolecular [3 + 2] salicylaldehyde) to achieve the optically enriched pyrrolidines
dipolar cycloaddition reaction.46,47 Most of these chemoenzy- and a pyrrole derivative via a convenient chemoenzymatic
matic methods to prepare pyrrolidines involve lipase mediated approach.
resolution with limitations of producing the desired enantio-
mer in a maximum theoretical yield of 50% and they require the corresponding mesylate (3a) which undergoes SN2 substi-
long reaction times. tution with salicylaldehyde in DMF using potassium carbonate
Initially (R)-4-phenyl-3-butyne-2-ol 2a was converted into
Herein we describe a chemoenzymatic synthesis of enantio- as a base to obtain (S)-O-propargylic salicylaldehyde 4a in good
merically enriched polycyclic pyrrolidines via whole cell yield (72%) and ee (91%) (Scheme 4).
mediated deracemization of propargyl alcohol (>99% ee, 79%
Intramolecular cycloaddition of (S)-O-propargylic salicyl-
yield) followed by intramolecular [3 + 2] cycloaddition of O-pro- aldehyde 4a carried out by in situ generation of azomethine
pargylic salicylaldehyde. This whole cell mediated deracemiza- ylides from methyl sarcosinate 5a gave a mixture of tricyclic
tion method has the advantages of producing a single pyrrolidines 6a & 6b in 70% yield with 1 : 0.8 dr (Scheme 5).
enantiomer in maximum theoretical yield of 100% and does Both diastereomers were isolated by column chromatography
not require the external addition of expensive co-factors.
and fully characterized. The enantiopurity of both the isomers
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Scheme 4 Synthesis of (S)-O-propargylic salicylaldehyde.
was analysed by HPLC using a chiral stationary phase and
showed that the enantiopurity (ee 91%) was retained after
cyclization (Scheme 5).
When NMR was recorded in deuterated solvents (CDCl3
&
CD3OD), a trace amount of pyrrole derivative, 7a (10%) was
observed due to the aromatization. Bashiardes et al. reported a
similar type of intermediate formation in the synthesis of
tricyclic pyrroles via azomethine ylide based cycloaddition
reaction.51
After complete characterization, both the diastereomers 6a
& 6b were converted into the pyrrole derivative 7a using Pd/C
in ethyl acetate under reflux conditions in 87% yield and 91%
ee. Initially, the feasibility of the reaction was examined
using rac-4-phenyl-3-butyne-2-ol and the reaction proceeded
smoothly to afford the corresponding cyclized products, rac-6a
& 6b and aromatized pyrrole rac-7a. The compounds rac-6b &
7a were crystallized and subjected for single crystal X-ray
crystallographic analysis (Fig. 2 and 3). The relative stereo-
chemistry of 6b was assigned from these crystal data (Fig. 2) in
which the methine protons (H7 & H9; H9 & H12) are anti to
each other. Likewise, NOE analysis was carried out to assign
Fig. 2 X-ray crystallographic ORTEP diagram of 6b.
the relative stereochemistry of 6a which showed that the
methine protons (H7, H9 & H12) are syn to one another.
In order to obtain a tetracyclic pyrrolidine with a quaternary
chiral center, intramolecular cycloaddition of azomethine
ylides generated from aldehyde 4a and methyl prolinate 5b
(Scheme 5) afforded the cycloadducts 8a & 8b (inseparable)
with good yield (78%) in 1 : 0.6 dr and the enantiomeric excess
was found to be 91% for each. The relative stereochemistry of
the diastereomers 8a & 8b was assigned by NOE experiments.
In major diastereomer 8a, the methine protons H7 & H9 are
syn to each other, whereas in minor diastereomers 8b the
methine protons H7 & H9 are anti to each other (Scheme 5).
Notably, the intramolecular cycloaddition of (S)-O-propargylic
Scheme 5 Chemoenzymatic synthesis of enantiomerically enriched pyrrolidines and a pyrrole derivative.
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(Merck1.05554). All chemicals used were of analytical grade
and distilled prior to use. HPLC analysis was carried out on a
Jasco PU-1580 liquid chromatograph with a PDA detector
using Chiralcel OJ-H, OD-H, AD-H, OB-H (Daicel, 4.6 ×
250 mm) and Lux 5u Amylose-2 (Phenomenex, 4.6 × 250 mm)
chiral columns. Hexane–2-propanol was used as the mobile
phase. Optical rotations were determined on an AutopalR
digital polarimeter. X-ray crystallographic analysis was per-
formed with a Bruker AXS Kappa APEX II single crystal CCD
Diffractometer with graphite-monochromated Mo Kα radiation
(λ = 0.71073 Å) at room temperature.
Growth conditions for C. parapsilosis ATCC 733053
C. parapsilosis ATCC 7330 was grown in yeast malt broth
medium (50 mL) in 250 mL Erlenmeyer flasks incubated at
25 °C, 200 rpm. The cells were harvested by centrifuging the
14 h culture broth at 10 000 rpm for 10 min at 4 °C and sub-
sequent washing with distilled water. The process was repeated
twice and the wet cells were used for biotransformation.
Fig. 3 X-ray crystallographic ORTEP diagram of 7a.
salicylaldehyde 4a with both amino esters (5a & 5b) resulted in
the formation of the syn adduct as a major product.
Typical procedure for deracemization of rac-propargyl alcohols
using the whole cells of C. parapsilosis ATCC 733034,54
Conclusions
The substrate rac-4-phenyl-3-butyne-2-ol (5 mM) dissolved in
ethanol (1 mL) was added into a Erlenmeyer flask containing
A broad variety of aryl and alkyl substituted propargyl alcohols
were deracemized to the corresponding optically pure alcohols the harvested C. parapsilosis ATCC 7330 cells (12 g) in water
(50 mL). The reaction was carried out in an orbital shaker at
200 rpm and 25 °C for 12 h. After incubation, the product
with excellent ee (up to >99%) and isolated yield (up to 87%)
using whole cells of Candida parapsilosis ATCC 7330. Enantio-
pure (R)-4-(3-hydroxybut-1-ynyl)benzonitrile, (R)-4-(biphenyl- formed was isolated using ethyl acetate and the organic layer
was dried over anhydrous sodium sulphate. The solvent was
removed by evaporation and the optically pure (R)-4-phenyl-3-
4-yl)but-3-yn-2-ol, (S)-ethyl 3-hydroxy-5-phenylpent-4-ynoate
and (S)-4-phenylbut-3-yne-1,2-diol were obtained with excellent
enantioselectivity via biocatalytic deracemization and are butyne-2-ol 2a was obtained as a yellow liquid after purifi-
cation by silica gel column chromatography using hexane–
ethyl acetate (90 : 10) as a mobile phase eluent (79% yield).
reported here for the first time. The whole cells showed sub-
strate specificity towards alkyl substituted propargyl alcohols,
notably the extended alkyl chain length induced reversal of The ee was found to be >99%, as determined by HPLC using
the chiral OJ-H column. The yield of the isolated product was
79%. The rest of the propargyl alcohols were used as substrates
stereoselectivity from ‘R’ to ‘S’. Deracemized optically pure
(R)-4-phenyl-3-butyne-2-ol was used as chiral starting
a
material for the first time to prepare enantiomerically enriched for deracemization under the same reaction conditions
(Scheme 1 and 2). Under identical conditions control experi-
ments were done in parallel without the whole cells.
pyrrolidines and a pyrrole derivative with good ee (91%) via a
chemoenzymatic approach.
Synthesis of (R)-4-phenylbut-3-yn-2-yl methanesulfonate
3a.22 (R)-4-Phenyl-3-butyne-2-ol 2a (1 mmol) and triethylamine
(2 mmol) were dissolved in dichloromethane (5 mL) at −78 °C.
Mesylchloride (2 mmol) was added slowly. The reaction
mixture was stirred at −78 °C for 1 h and then warmed to
Experimental section
General methods
C. parapsilosis ATCC 7330 was purchased from ATCC Mana- room temperature slowly. The mixture was quenched with
ssas, VA 201018, USA and maintained at 4 °C in yeast malt saturated aqueous sodium bicarbonate solution (5 mL). The
agar medium that contained 5 g L−1 peptic digest of animal organic phase was separated and the aqueous layer was
tissue, 3 g L−1 malt extract, 3 g L−1 yeast extract, 10 g L−1 dex- extracted with methylene chloride (10 mL × 3). The combined
trose and 20 g L−1 agar. The entire chemicals for media prepa- organic phases were washed with water and dried over sodium
ration were purchased locally. 1H and 13C NMR spectra were sulfate. The solids were filtered off, and the solvent was
recorded on a Bruker AV-400 and Bruker AVANCE III 500 MHz removed under reduced pressure to give (R)-4-phenylbut-3-yn-
spectrometers. Chemical shifts are expressed in ppm values 2-yl methanesulfonate 3a as a light brown liquid which was
using TMS as an internal standard. Infrared spectra were used for the next step without purification.
recorded on a Shimadzu IR 470 instrument. Mass spectra were
recorded on
TOF micro mass spectrometer. TLC 4a.48 To a solution of K2CO3 (1.5 mmol) and salicylaldehyde
was carried out on Kieselger 60 F254 aluminium sheets (0.5 mmol) in 3 mL of dry DMF, (R)-4-phenylbut-3-yn-2-yl
Synthesis of (S)-2-(4-phenylbut-3-yn-2-yloxy)benzaldehyde
a
Q
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methanesulfonate 3a in DMF (2 mL) was added dropwise. The 1.0 mL min−1; retention times 25.8 min (major) and 34.2 min
reaction mixture was stirred at room temperature for 6 h and (minor)]; [α]2D5 = +5.4 (c 1, CHCl3).
subsequently cooled to 0 °C. Then the reaction was quenched
(S)-2-(4-Phenylbut-3-yn-2-yloxy)benzaldehyde
(4a). Yield
by addition of 10 mL of a sat. NH4Cl solution. This solution 72%; 91% ee; pale yellow liquid; 1H NMR (400 MHz, CDCl3):
was exacted with diethyl ether (10 mL × 3). The combined 2.12 (3H, d, J = 6.4 Hz), 5.49 (1H, q, J = 6.4 Hz), 6.60 (1H, dd,
organic phases were washed with water (2 × 20 mL) and dried J = 8 & 1.2 Hz), 7.35–7.39 (1H, m), 7.56–7.62 (4H, m), 7.66–7.69
over Na2SO4. After the removal of the solvent under reduced (2H, m), 7.84–7.89 (1H, m), 8.16 (1H, dd, J = 7.6 & 1.6 Hz),
pressure, the crude mixture was purified by column chromato- 10.84 (1H, d, J = 1.2 Hz); 13C NMR (100 MHz, CDCl3): 22.2,
graphy using hexane–ethyl acetate (97 : 03) as a mobile phase 65.6, 86.7, 87.2, 114.9, 121.5, 122.0, 125.8, 128.2, 128.3, 128.7,
eluent to afford (S)-2-(4-phenylbut-3-yn-2-yloxy)benzaldehyde 131.7, 135.6, 160.0, 189.9; IR (ν, cm−1): 3076, 2990, 1686, 1479,
4a as a slightly yellow oil.
1452, 1287, 1233, 757, 691; HRMS: m/z, calcd mass: 273.0886
[(M + Na)+], found: 273.0894 [(M + Na)+]. The compound was
resolved by HPLC analysis at 25 °C, using a CHIRALCEL OD-H
column [hexanes–2-propanol = 98 : 02, 1.0 mL min−1, retention
Typical experimental procedure for the cycloaddition of
(S)-2-(4-phenylbut-3-yn-2-yloxy)benzaldehyde 4a51,52
To a solution of O-propargylic salicylaldehyde 4a (0.5 mmol) in times 6.7 min (major) and 7.9 min (minor)]; [α]2D5 = +14.8 (c 1,
dry toluene were added hydrochloride of amino ester 5a CHCl3).
(0.75 mmol) and diisopropyl ethyl amine (0.75 mmol). The
(4S)-Methyl 1,4-dimethyl-3-phenyl-1,2,4,9b-tetrahydrochro-
resulting solution was heated to reflux and the progress of the meno[4,3-b]pyrrole-2-carboxylate (6a). Yield 39%; 91% ee; pale
reaction was monitored by TLC. After completion, the excess yellow liquid; 1H NMR (400 MHz, CD3OD): 0.98 (3H, d, J =
solvent was removed under reduced pressure and the crude 6.4 Hz), 2.79 (3H, s), 3.61 (3H, s), 4.96 (1H, dd, J = 5.2 &
mixture was purified by silica gel column chromatography 1.2 Hz), 4.97 (1H, d, J = 5.2 Hz), 5.44 (1H, qt, J = 6.4 & 1.2 Hz),
using hexane–ethyl acetate (95 : 05) as a mobile phase eluent 6.60 (1H, dd, J = 8 & 1.2 Hz), 7.06–7.08 (1H, m), 7.16–7.17 (1H,
to provide pyrrole 6a and 6b. The cyclo adducts 8a and 8b were m), 7.18–7.19 (1H, m), 7.28–7.38 (4H, m), 7.41–7.43 (1H, m);
also obtained under the identical reaction conditions.
13C NMR (100 MHz, CD3OD): 19.7, 38.2, 52.2, 70.3, 74.1, 79.7,
Synthesis of (S)-methyl 1,4-dimethyl-3-phenyl-1,4-dihydro- 119.9, 123.8, 125.7, 129.0, 129.4, 129.5, 129.8, 130.9, 132.4,
chromeno[4,3-b]pyrrole-2-carboxylate 7a.55 To a solution of 6a 134.8, 143.0, 154.2, 173.0; IR (ν, cm−1): 3061, 2978, 1735, 1482,
and 6b (0.3 mmol) in ethyl acetate 10% Pd/C was added and 1452, 1387, 1286, 757, 700; HRMS: m/z, calcd mass: 336.1594
refluxed for 6 h. Then the mixture was filtered to remove the [(M + H)+], found: 336.1601 [(M + H)+]. The compound was
Pd/C and the resulting solution was evaporated under reduced resolved by HPLC analysis at 25 °C, using a CHIRALCEL AD-H
pressure. The crude mixture was then purified by column column [hexanes–2-propanol = 95 : 05, 1.0 mL min−1, retention
chromatography on silica gel to give pyrrole (S)-7a.
times 9.3 min (major) and 11.6 min (minor)]; [α]2D5 = +70.0 (c 1,
CH3OH).
Spectral data
(4S)-Methyl 1,4-dimethyl-3-phenyl-1,2,4,9b-tetrahydrochro-
(R)-4-(Naphthalen-2-yl)but-3-yn-2-ol (2f). Yield 75%; 27% meno[4,3-b]pyrrole-2-carboxylate (6b). Yield 31%; 91% ee;
1
ee; colourless solid; Mp 98–99 °C; H NMR (500 MHz, CDCl3): viscous liquid; 1H NMR (400 MHz, CD3OD): 1.52 (3H, d, J = 6.8
1.60 (3H, d, J = 6.4 Hz), 2.02 (1H, s), 4.81 (1H, q, J = 6.5 Hz), Hz), 2.78 (3H, s), 3.64 (3H, s), 4.93 (1H, d, J = 4 Hz), 5.11 (1H,
7.46–7.50 (3H, m), 7.76–7.82 (3H, m), 7.96 (1H, m); 13C NMR qd, J = 6.8 & 1 Hz), 5.13 (1H, d, J = 4 Hz), 6.81 (1H, dd, J = 8.4 &
(125 MHz, CDCl3): 24.4, 59.0, 84.4, 91.3, 119.9, 126.5, 126.7, 1.2 Hz), 6.98 (1H, td, J = 7.2 & 0.8 Hz), 7.17–7.18 (1H, m),
127.7, 128.0, 128.4, 131.6, 132.8, 132.9; IR (ν, cm−1): 3443, 7.27–7.29 (2H, m), 7.35–7.37 (1H, m), 7.40–7.42 (2H, m);
3060, 2973, 2878, 2226, 1265, 1103, 801, 764, 712; HRMS: m/z, 7.43–7.45 (1H, m); 13C NMR (100 MHz, CD3OD): 19.2, 38.3,
calcd mass: 219.0780 [(M + Na)+], found: 219.0781 [(M + Na)+]. 52.4, 66.2, 71.4, 78.5, 119.1, 122.4, 126.6, 128.6, 129.4, 129.8,
The compound was resolved by HPLC analysis at 25 °C, using 130.0, 130.9, 133.7, 134.8, 140.0, 153.8, 172.7; IR (ν, cm−1):
a CHIRALCEL OJ-H column [hexanes–2-propanol = 90 : 10, 2961, 2352, 1727, 1485, 1452, 1387, 1217, 762, 700; HRMS: m/z,
1.0 mL min−1; retention times 25.1 min (major) and 29.2 min calcd mass: 336.1594 [(M + H)+], found: 336.1598 [(M + H)+].
(minor)]; [α]2D5 = +2.2 (c 1, CHCl3).
The compound was resolved by HPLC analysis at 25 °C, using
(R)-4-(9H-Fluoren-2-yl)but-3-yn-2-ol (2h). Yield 85%; 23% ee; a CHIRALCEL AD-H column [hexanes–2-propanol = 95 : 05,
1
pale yellow solid; Mp 139–140 °C; H NMR (400 MHz, CDCl3): 1.0 mL min−1, retention times 12.4 min (minor) and 18.0 min
1.58 (3H, d, J = 6.4 Hz), 3.87 (2H, s), 4.79 (1H, d, J = 6.4 Hz), (major)]; [α]2D5 = −36.8 (c 0.5, CH3OH).
7.31 (1H, td, J = 7.2 Hz & 1.2 Hz), 7.36–7.38 (1H, m), 7.45 (1H,
(S)-Methyl 1,4-dimethyl-3-phenyl-1,4-dihydrochromeno[4,3-
dt, J = 8 Hz & 0.8 Hz), 7.58–7. 60 (2H, m); 13C NMR (100 MHz, b]pyrrole-2-carboxylate (7a). Yield 87%; 91% ee; colorless
CDCl3): 24.7, 36.9, 59.2, 84.9, 91.1, 119.9, 120.4, 120.8, 125.3, solid; Mp 128–129 °C; 1H NMR (400 MHz, CDCl3): 1.21 (3H, d,
127.1, 127.4, 128.5, 130.7, 141.1, 142.2, 143.3, 143.7; IR J = 6.4 Hz), 3.54 (3H, s), 4.19 (3H, s), 5.29 (1H, q, J = 6.4 Hz),
(ν, cm−1): 3476, 2985, 2257, 1407, 829, 769, 733; HRMS: m/z, 7.00–7.01 (2H, m), 7.17–7.22 (1H, m), 7.24–7.27 (2H, m),
calcd mass: 235.1117 [(M + H)+], found: 235.1113 [(M + H)+]; 7.29–7.34 (1H, m), 7.35–7.39 (2H, m); 7.63 (1H, dd, J = 7.6 &
the compound was resolved by HPLC analysis at 25 °C, using 1.2 Hz); 13C NMR (100 MHz, CDCl3): 21.4, 35.5, 50.8, 71.2,
a CHIRALCEL OJ-H column [hexanes–2-propanol = 90 : 10, 117.7, 118.6, 121.1, 121.4, 121.8, 122.5, 126.8, 127.7, 128.4,
4688 | Org. Biomol. Chem., 2014, 12, 4682–4690
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128.7, 129.0, 129.6, 135.1, 153.1, 162.2; IR (ν, cm−1): 3061,
2974, 1697, 1454, 1435, 752; HRMS: m/z, calcd mass: 334.1438
[(M + H)+], found: 334.1428 [(M + H)+]. The compound was
resolved by HPLC analysis at 25 °C, using a CHIRALCEL AD-H
column [hexanes–2-propanol = 98 : 02, 1.0 mL min−1, retention
times 5.4 min (major) and 6.2 min (minor)]; [α]2D5 = −32.4
(c 0.5, CH3OH).
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Acknowledgements
Thangavelu Saravanan thanks the Indian Institute of Technol-
ogy Madras (IITM) and the University Grants Commission,
India, for the fellowship. We thank Dr Sudhadevi for XRD ana-
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