Practical Stereoselective Synthesis of C3-Spirooxindole- and C2-Spiropseudoindoxyl-Pyrrolidines via Organocatalyzed Pictet-Spengler Reaction/Oxidative Rearrangement Sequence

Article abstract of DOI:10.1002/adsc.202001472

A stereoselective synthetic route to chiral C3-spirooxindole- and C2-spiropseudoindoxyl-pyrrolidines was accomplished by an enantioselective organocatalyzed Pictet-Spengler reaction of tryptamines and isotryptamines followed by a diastereoselective oxidative rearrangement using eco-friendly oxidants (i. e., NaOCl ? 5H₂O and Oxone). This sequential reaction enables rapid access to chiral C3-spirooxindole- and C2-spiropseudoindoxyl-pyrrolidines in a one-pot process. A Wnt signaling inhibitory assay of the prepared enantioenriched spiro compounds demonstrated that they exhibited moderate activities. (Figure presented.).

Full text of DOI:10.1002/adsc.202001472

UPDATES
DOI: 10.1002/adsc.202001472
Practical Stereoselective Synthesis of C3-Spirooxindole- and C2-
Spiropseudoindoxyl-Pyrrolidines via Organocatalyzed Pictet-
Spengler Reaction/Oxidative Rearrangement Sequence
Masaru Kondo,a Naoki Matsuyama,a Tin Z. Aye,a Irshad Mattan,a
Tomoyuki Sato,b Yoshinori Makita,b, c Masami Ishibashi,b Midori A. Arai,c
Shinobu Takizawa,a, d,* and Hiroaki Sasaia, d,*
a
The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan
Fax number: (+81) 6–6879-8469
E-mail: taki@sanken.osaka-u.ac.jp; sasai@sanken.osaka-u.ac.jp
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
Faculty of Science and Technology, Keio University 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223–8522, Japan
Artificial Intelligence Research Center, ISIR, Osaka University
b
c
d
Manuscript received: November 16, 2020; Revised manuscript received: February 19, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001472
and drug discovery because of their potent pharmaco-
Abstract: A stereoselective synthetic route to chiral
C3-spirooxindole- and C2-spiropseudoindoxyl-pyr-
logical activities, with example compounds including
fluorocurine,[5] mitragynine pseudoindoxyl,[6] and rau-
rolidines was accomplished by an enantioselective
niticine pseudoindoxyl[7] (Figure 1a). Various synthetic
organocatalyzed Pictet-Spengler reaction of trypt-
methods have been reported for the construction of
amines and isotryptamines followed by a diastereo-
chiral C3-spirooxindole-pyrrolidine[1c,8] and C2-spiro-
selective oxidative rearrangement using eco-friendly
pseudoindoxyl-pyrrolidine scaffolds[9] (Figure 1b). To
oxidants (i.e., NaOCl·5H2O and Oxone®). This
sequential reaction enables rapid access to chiral
date, the enantioselective syntheses of chiral spiroox-
indole-pyrrolidine frameworks have been mainly
C3-spirooxindole- and C2-spiropseudoindoxyl-pyr-
achieved using indole derivatives, with example routes
rolidines in a one-pot process. A Wnt signaling
including
the
cycloaddition
reactions
of
inhibitory assay of the prepared enantioenriched
spiro compounds demonstrated that they exhibited
moderate activities.
ylideneoxindoles[8f,i] and azaaurones,[10] the Michael
addition reactions of tryptamine-derived oxindoles,[11]
and the Pictet-Spengler (PS) reactions[12]/oxidative
rearrangements of tryptamine derivatives[13] in an
asymmetric manner. While the use of oxindole deriva-
tives as substrates is reliable, a multi-step preparation
of the oxindole scaffold is inevitable. In contrast, the
enantioselective PS reaction/diastereoselective oxida-
tive rearrangement of readily available tryptamine is
an attractive and rapid approach to chiral C3-spiroox-
indole-pyrrolidines because the oxindole moiety and
the chiral spiro center can be constructed simulta-
neously from chiral tetrahydro-β-carbolines. For exam-
Keywords: Squaramide catalyst; Spiro compound;
One-pot synthesis; Green oxidant; Wnt signaling
inhibitory activity
Introduction
Among the large family of biologically active ple, Jacobsen and Seidel independently contributed to
spirooxindoles,[1] C3-spirooxindole-pyrrolidines are the development of a highly enantioselective PS
found in a variety of natural compounds and pharma- reaction of non-protected tryptamines using their
ceuticals, such as horsfiline,[2] elacomine,[3] and spiro- unique organocatalysts.[12c,i] Furthermore, Tong and co-
tryptastatin A[4] (Figure 1a). In addition, C2-spiropseu- workers recently developed an oxidative rearrangement
doindoxyl-pyrrolidines, which are structural analogs of of tetrahydro-β-carbolines to yield C3-spirooxindole-
C3-spirooxindole-pyrrolidines, have recently received pyrrolidines, which employed a catalytic amount of
increasing attention in the fields of organic chemistry KBr, in addition to Oxone® as the terminal oxidant.[13k]
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Figure 1. (a) Selected examples of natural products and biologically active compounds containing the chiral C3-spirooxindole- and
C2-spiropseudoindoxyl-pyrrolidine skeletons. (b) Representative enantioselective syntheses of chiral C3-spirooxindole- and C2-
spiropseudoindoxyl-pyrrolidine skeletons. (c) This work: asymmetric syntheses of chiral C3-spirooxindole- and C2-spiropseudoin-
doxyl-pyrrolidine frameworks via a squaramide-catalyzed PS reaction/green oxidant-mediated diastereoselective oxidative
rearrangement sequence.
In 2011, Jacobsen and co-workers also reported that a 48% yield without any loss in enantiopurity.[14]
chiral thiourea catalyzed the highly enantioselective PS Although significant progress has been made in the
reaction of isotryptamines. Subsequent NBS-mediated syntheses of diverse spirooxindoles, a facile, eco-
oxidative rearrangement of tetrahydro-γ-carboline pro- friendly, and highly stereoselective strategy is still
vided the chiral C2-spiropseudoindoxyl-pyrrolidine in required. Thus, we herein describe a practical synthetic
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route to chiral C3-spirooxindole- and C2-spiropseu- actions of both tryptamine 1a and isotryptamine 5a
doindoxyl-pyrrolidines via an enantioselective PS were successfully catalyzed by organocatalyst 8, which
reaction of commercially available tryptamine and combined the steric bulks of the tert-butyl and
isotryptamine using the chiral squaramide as a single benzhydryl groups with squaramide as a strong hydro-
organocatalyst, and a subsequent diastereoselective gen-bonding donor. The absence of either component
oxidative rearrangement, wherein NaOCl·5H2O and had a detrimental effect on the enantioselectivity (see
Oxone® are employed as eco-friendly oxidants (Fig- Tables S1 and S2 in the Supporting Information).
ure 1c). In addition, we examine the feasibility of a
With the optimal reaction conditions in hand, we
one-pot process for this sequential reaction. Finally, examined the substrate scope for the PS reactions of
the ability of the newly obtained enantioenriched spiro tryptamines 1 or isotryptamines 5 with aldehydes 2 in
compounds to inhibit the Wnt signaling pathway is the presence of squaramide catalyst 8 and an appro-
examined.
priate acidic additive (succinic acid or benzoic acid)
(Scheme 2). Aliphatic and aromatic aldehydes, includ-
ing 1-hexanal, 3-phenylpropanal, and o-bromobenzal-
dehyde were suitable for this reaction, and products
3c–3e were obtained in moderate to good yields and
high enantioselectivities (54–85% yields, 79–95% ees).
In addition, methoxy-substituted tryptamine 1b was
Result and Discussion
Organocatalyzed Enantioselective Pictet-Spengler
Reactions of Tryptamine 1and Isotryptamine 5
Initially, to obtain the enantioenriched tetrahydro-β- smoothly converted into the desired spirooxindole 3f
carbolines 3, we tested the organocatalyzed enantiose- (99% yield, 85% ee). In the case of the enantioselec-
lective PS reaction of non-activated tryptamine 1a tive PS reaction of isotryptamine 5a, 1-hexanal, in
with isovaleraldehyde 2a based on previously reported addition to a range of sterically and electronically
methods.[12c] Following a comprehensive screening of different aromatic aldehydes, was applicable to the
the reaction conditions (see Table S1 in the Supporting present transformation, affording the desired products
Information), the tert-leucine-derived squaramide cata- 6c–6h in good yields (66–80%) and high enantiose-
lyst 8[15] (10 mol%), which was initially utilized in the lectivities (95–99% ees) after trituration with n-hexane.
enantioconvergent catalytic SN1 reaction by Jacobsen, When o-tolualdehyde and either isotryptamine 5b
allowed the reaction to proceed in toluene at 35 C to (R1 =OMe) or 5c (R1 =Br), bearing electron-donating
°
yield the desired product 3a in 89% yield and 90% ee or electron-withdrawing substituents, were employed
following Boc protection of the PS product (Sche- as substrates, the desired products 6i and 6j were
me 1a). Subsequently, based on the results presented in obtained in yields of 80% and 71%, and ee values of
Scheme 1a, we investigated the catalytic enantioselec- 98% and 81%, respectively. A variety of N-protecting
tive synthesis of the tetrahydro-γ-carbolines 6a using groups, including tosyl (Ts), allyloxycarbonyl (Alloc),
isotryptamine 5a and isovaleraldehyde 2a. The reac- and methoxycarbonyl, were successfully installed,
tion using 10 mol% of organocatalyst 8 in addition to providing the desired products 3g–3i and 6k in good
succinic acid provided the corresponding product 6a in yields (up to 88%) and good enantioselectivities (up to
90% yield and 79% ee. Replacement of the acidic 88% ee).
additive with benzoic acid significantly improved the
enantioselectivity to 92% ee, and after trituration with
Diastereoselective Oxidative Rearrangement of
n-hexane, 6a was obtained in 70% yield and 98% ee
Tetrahydro-β- and -γ-Carbolines 3 and 6
(Scheme 1b).[14,16] The highly enantioselective PS re-
To achieve the highly diastereoselective oxidative
rearrangement of tetrahydro-β-carboline 3 without any
loss in enantiopurity, a range of oxidative conditions
was examined (Scheme 3a). Among the various
oxidants subjected to screening, NaOCl·5H2O,[17]
which is a bench-stable and easily removable green
oxidant, efficiently promoted the oxidative rearrange-
ment of the Boc-protected tetrahydro-β-carboline 3a.
More specifically, in a DMF/H2O (2:1) mixed solvent
system, the desired spirooxindole 4a was obtained in
93% yield and in a highly diasetereoselective manner
with no reduction in the enantiopurity being observed
Scheme 1. Enantioselective PS reaction of tryptamine 1a and
isotryptamine 5a with isovarelaldehyde 2a catalyzed by chiral
squaramide catalyst 8 in the presence of an acidic additive.
Yields of 3a and 6a were determined by NMR analysis.
(17:1 dr, 88% ee). The use of other oxidants, such as
NBS, tBuOCl, Oxone®, and H2O2, gave 4a in moderate
to low yields (up to 59%). Under Tong’s reaction
conditions, the desired product 4a was obtained in a
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Scheme 3. Diastereoselective oxidative rearrangement of tetra-
hydro-β-carbolines 3a and 3b and tetrahydro-γ-carbolines 6a
and 6b.
diastereoselectivity, the yield was only 12% due to the
low reactivity of 6a, which contrasted to the use of
Oxone®, wherein 7a was obtained in 75% yield with a
good diastereoselectivity (10:1), and no reduction in
enantiopurity (Scheme 3b).[18] In addition, examination
of the protecting groups on the nitrogen atom
suggested that the electron-withdrawing Boc group
was crucial for the transformation because the reac-
tions of tetrahydro-β-carboline 3b and tetrahydro-γ-
carboline 6b bearing electron-donating methyl group
on the nitrogen atom significantly reduced the optical
purity (products 4b and 7b, respectively), likely due to
a retro-Mannich reaction of the products.[13g]
A plausible reaction mechanism for the present
oxidative rearrangement is proposed in Scheme 4; in
2021, Li and Sun reported a similar oxidative
rearrangement of tetrahydrocarbolines 3 and 6 to
produce spiroxindoles 4 and 7 using NIS as an
oxidant.[13k] Thus, the oxidative additon of water to
tetrahydro-β-carboline 3 results in the formation of
intermediate I, which is converted into C3-spiroox-
indole-pyrrolidine 4 through rearrangement. In our
system, NaOCl·5H2O readily promotes the addition of
OHÀ and X+ (Cl+) to generate intermediate Ia. Under
basic conditions (NaOCl·5H2O, pH 11),[19] the rear-
rangement of Ia subsequently occurs to give the
product (2’R,3S)-4 as the major product. However,
neutral oxidants (e.g., NBS, tBuOCl, and Oxone®/KBr)
lead to intermediates Ia and Ib (X =Br for NBS and
Oxone®/KBr; X =Cl for tBuOCl) via reversible
epimeraization of the imine precursors[13j] to give
diastereomers 4. We also found that NBS had a
Scheme 2. Substrate scope of the enantioselective PS reaction
catalyzed by 8. Yields are for the isolated compounds 3 and 6.
high yield but with a low diastereoselectivity (1.5:1 detrimental effect on yield due to promoting the
dr).[13k] Although the oxidative rearrangement of undesired bromination of the indole benzene ring.
tetrahydro-γ-carboline 6a with NaOCl·5H2O gave the Oxone® and H2O2 are inappropriate for this trans-
C2-spiropseudoindoxyl-pyrrolidine 7a with acceptable formation because these oxidants cannot generate
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Scheme 4. A plausible reaction mechanism for the oxidative rearrangements of tetrahydro-β-carbolines 3 and tetrahydro-γ-
carbolines 6.
intermediates. In the case of the oxidative rearrange- was determined to be 2’R,3S by single X-ray crystallo-
ment of tetrahydro-γ-carboline 6 using NaOCl·5H2O, graphic analysis (Figure 2),[20] and the absolute config-
unstable intermediates Ia’ and Ib’ form to produce uration of chiral spiropseudoindoxyl-pyrrolidine 7a
many by-products, thereby resulting in low yields of prepared using organocatalyst (S)-8 was assigned as
1
the desired compound 7. When Oxone® was used for 2S,2’S by comparison of its H NMR and optical
the reaction, intermediates IIa and IIb were smoothly rotation data with reported values.[14]
formed, and product 7a was obtained through a semi-
pinacol-type rearrangement.
The Asymmetric One-Pot Syntheses of Chiral
The substrate scope of the diastereoselective
C3-Spirooxindole- and C2-Spiropseudoindoxyl-Pyr-
oxidative rearrangement was then investigated using a
rolidines from Tryptamine and Isotryptamine
series of tetrahydro-β-carbolines 3 and tetrahydro-γ-
carbolines 6 with the desired eco-friendly oxidant After the successful development of the organocata-
(NaOCl·5H2O or Oxone®), as illustrated in Scheme 5. lyzed PS reaction/oxidative rearrangement sequence,
More specifically, tetrahydro-β-carbolines 3c–3e [R2 = we focused our attention on the asymmetric one-pot
n-pentyl (3c); phenethyl (3d); o-bromophenyl (3e)] syntheses of chiral C3-spirooxindole- and C2-spiro-
provided the corresponding products 4c–4e in moder- pseudoindoxyl-pyrrolidines from tryptamines and iso-
ate to good yields (42–81%) and high stereoselectiv- tryptamines (Scheme 6). For this purpose, each two-
ities (10:1–20:1 drs, and 82–93% ees). In addition, step reaction was attempted in a single vessel. To our
tetrahydro-γ-carbolines 6d–6h, which contain an delight, the enantioselective PS reaction of tryptamine
aromatic ring, were converted into the corresponding 1a with isovaleraldehyde, and the subsequent
products 7d–7h with excellent diastereoselectivities, NaOCl·5H2O-mediated oxidative rearrangement of
regardless of the electronic and steric properties of the tetrahydro-β-carboline 3a proceeded smoothly to
substrates (58–97% yields, >20:1 drs, 93–97% ees). afford the desired C3-spirooxindole-pyrrolidine 4a in a
The use of 5-substituted substrates 6i (R1 =OMe) and moderate yield (55%) with a high stereoselectivities
6j (R1 =Br) allowed the formation of spirocycles 7i (15:1 dr, 88% ee) without the isolation of 3a
and 7j in moderate yields (up to 63%) and with high (Scheme 6a). In addition, the one-pot transformation of
stereoselectivities yield (>20:1 dr, and 93% ee), while isotryptamine 5a with o-tolualdehyde into C2-spiro-
treatment with tetrahydrocarbolines 3f and 6c in the pseudoindoxyl-pyrrolidine 7g was achieved in 47%
presence of the appropriate oxidants furnished the yield, >20:1 dr, and 86% ee under the optimized
corresponding products 4f and 7c in good yields (up
to 86% yield) with acceptable diastereoselectivities
(7.3:1 dr) and high enantioselectivities (90% ee).
Furthermore, electron-withdrawing protecting groups,
such as Ts, CO2Me, and Alloc, were tolerated in the
highly diastereoselective oxidative rearrangement, af-
fording spiro compounds 4g–4i and 7k without any
loss in enantiopurity (51–76% yields, 15:1–>20:1 drs,
84–90% ees). Optically pure 4 and 7 were readily
obtained by recrystallization of the enantiomerically
enriched products. The absolute configuration of chiral
spirooxindole 4g prepared using organocatalyst (S)-8
Figure 2. ORTEP drawing of compound (2’R,3S)-4g with
ellipsoids at 50% probability (H atoms are omitted for clarity).
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Scheme 6. Asymmetric one-pot syntheses of the chiral C3-
spirooxindole- and C2-spiropseudoindoxyl-pyrrolidines 4a and
7g from tryptamine 1a and isotryptamine 5a.
one-pot syntheses of chiral C3-spirooxindole- and C2-
spiropseudoindoxyl-pyrrolidines from tryptamine and
isotryptamine.
Evaluation of the Activities of 4 and 7 for the
Inhibition of Wnt Signaling
To evaluate the biological activities of chiral spiroox-
indoles 4 and spiropseudoindoxyls 7, a Wnt signaling
inhibitory assay was employed, since we previously
found that oxindole derivatives exhibited potential to
inhibit the Wnt signaling pathway.[21a] The Wnt signal-
ing pathway plays an important role in the motility,
morphology, differentiation, and proliferation of cells.
In addition, various human cancers, such as colon
cancer, aberrantly activate the Wnt pathway.[21c] There-
fore, compounds that inhibit the Wnt signaling could
be considered potential candidates for anticancer
agents.[21] Thus, to survey the abilities of spiro products
4 and 7 to inhibit the Wnt signaling pathway, we
employed a TOP-Flash assay, which is a cell-based
reporter luciferase assay measuring TCF/β-catenin
transcription in the cell line STF/293 with LiCl as a
GSK-3β inhibitor to induce β-catenin accumulation
(see Supporting Information). Gratifyingly, spiro com-
pound (2S,2’S)-7g (>99% ee) inhibited TCF/β-catenin
transcription with an IC50 value of 2.2 μM, and was
found to exhibit a low cytotoxicity, in addition to low
inhibition of the FOP-Flash activity (Figure 3).[22,23]
Conclusion
Scheme 5. Substrate scope of the diastereoselective oxidative
rearrangement. Yields are for the isolated compounds 4 and 7.
The ee values in parentheses correspond to the ee values of
starting materials 3 and 6.
In conclusion, a facile enantioselective synthetic route
toward chiral C3-spirooxindole-pyrrolidines was de-
veloped via sequential processes involving the squar-
amide-catalyzed enantioselective Pictet-Spengler (PS)
reaction of tryptamines followed by the NaOCl·5H2O-
conditions (Scheme 6b). To the best of our knowledge, mediated diastereoselective oxidative rearrangement.
this is the first successful example of an asymmetric Using Oxone® as an alternative oxidant, this protocol
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catalyst 8 (0.01 mmol, 6.2 mg, 10 mol%), and succinic acid
(0.02 mmol, 2.4 mg, 20 mol%) were added. After the mixture
was stirred for 2 min under a nitrogen atmosphere, aldehyde 2
°
(0.11 mmol, 1.1 equiv.) was added and stirred at 35 C for 50 h.
The reaction mixture was treated with Boc2O (0.22 mmol,
°
48.0 mg, 2.2 equiv.) and stirred at 35 C for 3 h. The reaction
was quenched with water, and then the mixture was extracted
with EtOAc three times. The combined organic layer was
washed with brine and dried over Na2SO4. The solution was
concentrated under reduced pressure and the crude product was
purified by flash chromatography (EtOAc/n-hexanes=1:3) to
give the product 3.
Figure 3. Synthesized spiro compound 7g exhibiting inhibition
of the TCF/β-catenin transcriptional activity.
was also applicable to isotryptamines, affording chiral
C2-spiropseudoindoxyl-pyrrolidines in high diastereo-
and enantioselectivities. We found that the squaramide
catalyst was effective in the enantioselective PS
reaction of both non-protected tryptamines and iso-
General procedure for the organocatalyzed Pictet-
Spengler reaction of isotryptamine 5 with aldehyde
2
To a stirred solution of isotryptamine 5 (0.1 mmol, 1 equiv.),
tryptamines. Furthermore, our sequential reactions chiral squaramide 8 (0.01 mmol, 6.2 mg, 10 mol%) in toluene
(1 mL), a solution of benzoic acid (0.01 mmol, 1.2 mg,
10 mol%) in toluene (1 mL) and aldehyde 2 (0.11 mmol,
1.1 equiv.) were added. The resulting heterogeneous solution
were successfully applied to a one-pot system, provid-
ing the desired spiro compounds in a highly stereo-
selective manner. Moreover, the newly synthesized
enantioenriched spiro heterocycle was found to inhibit
the Wnt signaling pathway with almost no cytotoxicity.
Further application of this organocatalytic/oxidative
rearrangement sequence for the stereoselective con-
struction of complex heterocycles is ongoing in our
group, and the results will be presented in due course.
°
was stirred at 22 C for 1 h. The reaction mixture was treated
with Boc2O (0.22 mmol, 48.0 mg, 2.2 equiv.) and stirred at
°
22 C. After 30 min, the solvent was removed under reduced
pressure, and the resulting residue was triturated with n-hexane
(10 mL). The solid product was crashed out from the mixture in
n-hexane solution and filtrated to provide the desired N-Boc-
protected product 6.
Experimental Section
General procedure for oxidative rearrangement of
tetrahydro-β-carboline 3 using NaOCl·5H2O
General information
1H-, 13C-, and 19F-NMR spectra were recorded with a JEOL
JMN ECS400 FT NMR, JNM ECA 600 FT NMR or Bruker
AVANCE II (1H-NMR 400 MHz and 600 MHz, 13C-NMR 100,
125, 150 MHz, 19F-NMR 565 MHz). 1H NMR spectra are
reported as follows: chemical shift in ppm relative to the
chemical shift of CHCl3 (7.26 ppm) or CH3OH (3.31 ppm),
integration, multiplicities (s=singlet, d=doublet, t=triplet,
q=quartet, m=multiplet), and coupling constants (Hz). 13C-
NMR spectra reported in ppm relative to the central line of
triplet for CDCl3 (77 ppm) or CD3OD (49 ppm). Hexafluor-
obenzene was used as external standards for 19F-NMR. ESI-MS
spectra were obtained with JMS-T100LC (JEOL). Optical
rotations were measured with JASCO P-1030 polarimeter.
HPLC analyses were performed on a JASCO HPLC system
(JASCO PU 980 pump and UV-975 UV/Vis detector). FT-IR
spectra were recorded on a JASCO FT-IR system (FT/IR4100).
Absolute configuration was determined by Rigaku R-AXIS
RAPID 191R diffractometer using filtered CuÀ Kα radiation.
Column chromatography on SiO2 was performed with Kanto
Silica Gel 60 (40–100 μm). Commercially available organic and
inorganic compounds were used without further purification.
To a stirred solution of tetrahydro-β-carboline 3 (0.073 mmol,
1 equiv.) in DMF (0.73 mL) and H2O (0.36 mL), sodium
hypochlorite pentahydrate (0.22 mmol, 36.2 mg, 3 equiv.) was
°
added. After stirring for 12 h at 30 C, the mixture was diluted
with water and extracted with EtOAc. The combined organic
layer was dried over Na2SO4 and concentrated under reduced
pressure. The crude residue was purified by silica gel column
chromatography (EtOAc:n-hexane=1:2) to give the desired
compound 4.
General procedure for oxidative rearrangement of
tetrahydro-γ-carboline 7 using Oxone®
To a stirred solution of tetrahydro-γ-carboline 6 (0.05 mmol,
1.0 equiv.), MeCN (0.8 mL) and H2O (0.2 mL), Oxone®
(0.075 mmol, 46.1 mg, 1.5 equiv.) was added. After stirring at
°
50 C for 3 h, the reaction mixture was diluted with water and
concentrated under reduced pressure. The mixture was extracted
with EtOAc, and the combined organic layer was dried over
Na2SO4. After the solvent was evaporated under reduced
pressure, the crude residue was purified by silica gel column
chromatography (EtOAc:n-hexane=1:2) to give the desired
product 7.
General procedure for the organocatalyzed Pictet-
Spengler reaction of tryptamine 1 with aldehyde 2
A flame dried test tube was charged with tryptamine 1
(0.1 mmol, 1 equiv.), MS 3A (50 mg). Then, toluene (2 mL),
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1372, 1280, 1128 cmÀ 1; HRMS (ESI) calcd for C32H30F6N3O3:
General procedure for the asymmetric one-pot syn-
thesis of chiral C3-spirooxindole-pyrrolidine 4a
from tryptamine 1a
m/z ([M+H+]) 618.2186, found 618.2187.
tert-Butyl (R)-1-isobutyl-1,3,4,9-tetrahydro-2H-pyri-
do[3,4-b]indole-2-carboxylate (3a)
A flame dried test tube was charged with tryptamine 1a
(0.1 mmol, 16.0 mg, 1 equiv.), MS 3A (50 mg). Then, toluene
(2 mL), catalyst 8 (0.01 mmol, 6.2 mg, 10 mol%), and succinic
acid (0.02 mmol, 2.5 mg, 20 mol%) were added. After the
mixture was stirred for 2 min under a nitrogen atmosphere,
isovaleraldehyde (0.11 mmol, 9.5 mg, 1.1 equiv.) was added
1
White solid, 27.6 mg, 84% yield; H, 13C NMR charts were
consistent with previously reported data.[13k] 1H NMR
(400 MHz, CDCl3) δ 7.76/7.71 (brs, 1H), 7.48–7.44 (m, 1H),
7.30 (d, J=7.6 Hz, 1H), 7.17–7.10 (m, 2H), 5.42–5.22 (m, 1H),
4.49–4.23 (m, 1H), 3.21–3.08 (m, 2H), 2.90–2.77 (m, 1H),
2.69–2.63 (m, 1H), 1.88–1.74 (m, 1H), 1.58–1.48 (m, 1H), 1.48
(s, 9H), 1.07 (d, J=6.0 Hz, 3H), 0.98 (d, J=6.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 155.28, 154.89, 135.84, 135.42,
134.84, 126.89, 121.73, 121.53, 119.52, 119.35, 118.11, 117.86,
110.71, 108.78, 108.16, 80.11, 79.66, 49.81, 49.16, 44.36,
43.82, 38.43, 37.12, 28.46, 25.17, 24.86, 23.37, 22.51, 21.47,
21.06; IR (KBr) 3292, 2952, 1660, 1415, 1170, 742 cmÀ 1;
HRMS (ESI) calcd for C20H28N2O2Na: m/z ([M+Na+])
351.2043, found 351.2042; [α]D25 =À 33.4 (c=0.14, in CHCl3
for 89% ee); HPLC Daicel ChiralPak AD-3 column, n-Hexane/
i-PrOH=10/1, 1.0 mL/min, λ=280 nm, tR=5.8 min (major
isomer) and 11.4 min (minor isomer).
°
and the solution was stirred 35 C for 50 h. The reaction mixture
was treated with Boc2O (0.22 mmol, 48.0 mg, 2.2 equiv.) and
°
stirred at 35 C for 3 h. The solution was concentrated under
reduced pressure, and then DMF (1 mL), H2O (0.5 mL), and
sodium hypochlorite pentahydrate (0.3 mmol, 49.4 mg, 3 equiv.)
°
were added. After stirring at 30 C for 12 h, the reaction mixture
was diluted water and extracted with EtOAc. The organic layer
was dried over Na2SO4 and concentrated under reduced
pressure. The crude residue was purified by silica gel column
chromatography (EtOAc:n-hexane=1:2) to give the desired
compound 4a (18.9 mg, 55%).
General procedure for the asymmetric one-pot syn-
thesis of chiral C2-spiropseudoindoxyl-pyrrolidine
7g from isotryptamine 5a
(R)-1-Isobutyl-2-methyl-2,3,4,9-tetrahydro-1H-pyri-
do[3,4-b]indole (3b)
To a stirred solution of isotryptamine 5a (0.05 mmol, 8.0 mg,
1 equiv.) and chiral squaramide 8 (5 μmol, 3.1 mg, 10 mol%) in
toluene (0.5 mL), a solution of benzoic acid (5 μmol, 0.61 mg,
10 mol%) in toluene (0.5 mL) and o-tolualdehyde (0.055 mmol,
6.6 mg, 1.1 equiv.) were added. After the resulting heteroge-
1H, 13C NMR charts were consistent with previously reported
data.[13k] 1H NMR (400 MHz, CDCl3) δ 7.67 (brs, 1H), 7.51–
7.48 (m, 1H), 7.33–7.29 (m, 1H), 7.17–7.07 (m, 2H), 3.63–3.61
(m, 1H), 3.24–3.17 (m, 1H), 2.93–2.81 (m, 2H), 2.70–2.63 (m,
1H), 2.48 (s, 3H), 1.99–1.90 (m, 1H), 1.78–1.70 (m, 1H), 1.61–
1.53 (m, 1H), 1.03–0.96 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ 135.70, 135.44, 127.29, 121.30, 119.27, 118.00, 110.60,
107.37, 57.56, 47.51, 43.20, 41.32, 25.25, 23.21, 22.68, 17.65;
HRMS (ESI) calcd for C16H23N2: m/z ([M+H+]) 243.1856,
found 243.1849; [α]D17 =À 8.4 (c=1.9, in CHCl3 for 82% ee);
HPLC Daicel ChiralPak AD-3 column, n-Hexane/i-PrOH=10/
1, 1.0 mL/min, λ=280 nm, tR=5.5 min (major isomer) and
7.6 min (minor isomer).
°
neous solution was stirred at 22 C for 1 h, Boc2O (0.11 mmol,
24.0 mg, 2.2 equiv.) was added and the mixture was stirred at
°
22 C for further 30 min. The organic solvent was evaporated
under reduced pressure. Then, MeCN (0.8 mL), H2O (0.2 mL),
and Oxone® (0.075 mmol, 46.1 mg, 1.5 equiv.) were added to
°
the crude residue and stirred at 50 C. After stirring for 3 h, the
mixture was diluted with water and concentrated under reduced
pressure, and then extracted with EtOAc. The separated organic
layer was dried over Na2SO4 and evaporated under reduced
pressure. The crude residue was purified by silica gel column
chromatography (EtOAc:n-hexane=1:2) to give the desired
product 7g (8.8 mg, 47%).
tert-Butyl (R)-1-pentyl-1,3,4,9-tetrahydro-2H-pyrido
[3,4-b]indole-2-carboxylate (3c)
(S)-squaramide catalyst (8) Catalyst 8 was obtained as a white
solid according to a previously reported procedure.[15] 1H, 13C
NMR charts were consistent with previously reported data. This
compound was observed as a 4:1 mixture of rotamers in
White solid, 23.2 mg, 68% yield; 1H NMR (400 MHz, CDCl3) δ
8.59/7.99 (brs, 1H), 7.52–7.45 (m, 1H), 7.30 (d, J=7.6 Hz,
1H), 7.17–7.00 (m, 2H), 5.39–5.09 (m, 1H), 4.56–4.20 (m, 1H),
3.26–3.01 (m, 1H), 2.89–2.74 (m, 1H), 2.67 (m, 1H), 1.88–1.67
(m, 2H), 1.64–1.12 (m, 15H), 1.00–0.73 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 155.31, 154.94, 146.74, 135.94, 135.20,
134.62, 126.85, 121.67, 121.40, 119.44, 119.18, 118.10, 117.84,
110.87, 110.77, 108.72, 107.79, 85.19, 79.88, 79.78, 51.54,
50.97, 38.68, 37.41, 35.09, 34.70, 31.80, 28.47, 27.37, 26.13,
25.83, 22.63, 22.49, 21.55, 21.19, 13.98; IR (KBr) 3330, 2935,
1665, 1418, 1164, 739 cmÀ 1; HRMS (ESI) calcd for
C21H30N2O2Na: m/z ([M+Na+]) 365.2199, found 365.2190;
[α]D25 =À 16.6 (c=0.12, in CHCl3 for 79% ee); HPLC Daicel
ChiralPak AD-3 column, n-Hexane/i-PrOH=10/1, 1.0 mL/min,
λ=280 nm, tR=7.6 min (major isomer) and 14.3 min (minor
isomer).
1
CD3OD. H NMR (400 MHz, CD3OD) δ 8.13 (s, 2H), 8.08 (s,
minor), 7.60–7.58 (s, 1H, mixture major/minor), 7.42–7.22 (m,
11H, mixture major/minor), 7.15–7.11 (m, 2H), 7.08–7.04 (s,
1H, mixture major/minor), 6.74 (s, minor), 5.39 (s, 1H), 5.36 (s,
minor), 3.03 (s, 3H), 2.77 (s, minor), 1.10 (s, 9H), 1.07 (s,
minor); 13C NMR (100 MHz, CD3OD) δ 185.6, 184.9 (minor),
182.1, 181.9 (minor), 173.1 (minor), 172.7, 170.4, 170.2
(minor), 164.3, 163.8 (minor), 142.3, 140.1, 139.4, 133.8 (q,
J
C-F =33.2 Hz), 130.5, 130.2, 129.7, 129.6, 129.2, 129.0, 128.4,
124.5 (d, JC-F =272 Hz), 119.1, 116.5, 66.4 (minor), 62.6, 61.5,
61.2 (minor), 54.8 (minor), 37.6, 37.1 (minor), 34.1, 32.2
(minor), 26.6; IR (KBr) 3237, 2973, 2371, 1576, 1496, 1454,
Adv. Synth. Catal. 2021, 363, 1–17
8
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tert-Butyl (R)-1-phenethyl-1,3,4,9-tetrahydro-2H-
pyrido[3,4-b]indole-2-carboxylate (3d)
(R)-1-Isobutyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido
[3,4-b]indole (3g)
1
1
Colorless oil, 37.7 mg, 85% yield; H NMR (400 MHz, CDCl3)
White solid, 25.6 mg, 67% yield; H, 13C NMR charts were
δ 7.74/7.60 (brs, 1H), 7.48–7.46 (m, 1H), 7.25–7.19 (m, 6H),
7.17–7.08 (m, 2H), 5.39–5.11 (m, 1H), 4.60–4.27 (m, 1H),
3.27–3.10 (m, 1H), 2.92–2.76 (m, 3H), 2.76–2.64 (m, 1H), 2.9–
2.0 (m, 2H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
155.38, 154.93, 141.64, 141.51, 135.96, 134.65, 133.92, 128.51,
128.25, 126.78, 126.04, 125.77, 124.28, 123.04, 121.76, 121.54,
119.46, 119.26, 118.16, 117.89, 110.89, 110.32, 108.89, 108.03,
80.00, 51.42, 50.76, 38.77, 37.71, 36.74, 36.40, 32.80, 32.45,
28.47, 21.47, 21.11; IR (KBr) 3363, 2917, 1664, 1423, 1233,
1166, 1002 cmÀ 1; HRMS (ESI) calcd for C24H28N2O2Na: m/z
([M+Na+]) 399.2048, found 399.2041; [α]D26 =À 42.9 (c=
0.14, in CHCl3 for 91% ee); HPLC Daicel ChiralPak AD-3
column, n-Hexane/i-PrOH=10/1, 1.0 mL/min, λ=280 nm,
tR=10.7 min (major isomer) and 25.0 min (minor isomer).
consistent with previously reported data.[24] 1H NMR (400 MHz,
CDCl3) δ 7.70 (brs, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.31–7.24 (m,
2H), 7.16–7.12 (m, 1H), 7.07–7.02 (m, 3H), 5.19 (m, 1H), 4.10
(dd, J=15.6 Hz, 7.2 Hz, 1H), 3.45–3.37 (m, 1H), 2.48–2.27 (m,
2H), 2.26 (s, 3H), 2.02–1.94 (m, 1H), 1.86–1.79 (m, 1H), 1.55–
1.50 (m, 1H), 1.08(d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 143.16, 137.95, 135.73, 133.55,
129.32, 126.75, 126.66, 121.81, 119.30, 117.98, 110.77, 107.33,
51.48, 44.94, 39.01, 24.65, 23.38, 21.99, 21.31, 19.51; IR (KBr)
3359, 1327, 1160, 734, 653, 583 cmÀ 1; HRMS (ESI) calcd for
C22H26N2O2SNa: m/z ([M+Na+]) 405.1607, found 405.1598;
[α]D23 =À 79.3 (c=0.19, in CHCl3 for 84% ee); HPLC Daicel
ChiralPak AD-3 column, n-Hexane/i-PrOH=7/1, 1.0 mL/min,
λ=280 nm, tR =13.2 min (major isomer) and 16.2 min (minor
isomer).
(R)-1-(2-Bromophenyl)-2-tosyl-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b]indole (3e)
Methyl (R)-1-isobutyl-1,3,4,9-tetrahydro-2H-pyrido
[3,4-b]indole-2-carboxylate (3h)
1
White solid, 26.1 mg, 54% yield; H, 13C NMR charts were
consistent with previously reported data.[24] 1H-NMR (400 MHz,
CDCl3) δ 7.82 (brs, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.65–7.61 (m,
1H), 7.43 (d, J=8.0 Hz, 1H), 7.25–7.21 (m, 2H), 7.17–7.11 (m,
5H), 7.09–7.05 (m, 1H), 6.56 (s, 1H), 4.07–4.01 (m, 1H), 3.76–
3.69 (m, 1H), 2.88–2.71 (m, 2H), 2.34 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 143.35, 140.05, 136.48, 136.10, 133.24,
130.98, 129.66, 129.54, 129.40, 127.86, 127.25, 126.23, 122.53,
122.37, 119.64, 118.23, 111.02, 108.67, 55.39, 42.30, 21.38,
20.55; IR (KBr) 3398, 1468, 1336, 1162, 768, 740, 658 cmÀ 1;
HRMS (ESI) calcd for C24H21BrN2O2SNa: m/z ([M+Na+])
503.0394, found 503.0396; [α]D20 =À 138.7 (c=0.12, in CHCl3
for 95% ee); HPLC Daicel ChiralPak IF column, n-Hexane/i-
PrOH=7/1, 1.0 mL/min, λ=280 nm, tR=19.0 min (minor
isomer) and 30.4 min (major isomer).
Colorless oil, 24.5 mg, 86% yield; H-NMR (400 MHz, CDCl3)
1
δ 7.75/7.71 (brs, 1H), 7.48–7.45 (m, 1H), 7.31 (d, J=5.2 Hz,
1H), 7.18–7.14 (m, 1H), 7.12–7.08 (m, 1H), 5.43–5.25 (m, 1H),
4.50–4.28 (m, 1H), 3.74 (s, 3H), 3.25–3.15 (m, 1H), 2.91–2.79
(m, 1H), 2.72–2.66 (m, 1H), 1.85–1.74 (m, 2H), 1.57–1.51 (m,
1H), 1.10–0.97 (m, 6H); 13C-NMR (100 MHz, CDCl3) δ 156.68,
156.32, 135.86, 134.97, 134.48, 126.83, 121.73, 121.57, 119.48,
119.34, 118.10, 117.88, 110.77, 108.51, 107.87, 52.77, 52.61,
49.94, 49.88, 44.20, 43.81, 38.10, 37.87, 25.04, 24.91, 23.39,
22.33, 22.01, 21.40, 20.96; IR (KBr) 3329, 2956, 2871, 1683,
1530, 1469, 1315, 1387, 1232, 1195, 751 cmÀ 1;; HRMS (ESI)
calcd for C17H23N2O2: m/z ([M+H+]) 287.1754, found
287.1750; [α]D26 =À 55.3 (c=0.19, in CHCl3 for 87% ee):
HPLC Daicel ChiralPak IBN-5 column, n-Hexane/i-PrOH=10/
1, 1.0 mL/min, λ=280 nm, tR=23.9 min (major isomer) and
32.4 min (minor isomer).
tert-Butyl (R)-1-isobutyl-5-methoxy-
1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-
2-carboxylate (3f)
Allyl (R)-1-isobutyl-1,3,4,9-tetrahydro-2H-pyrido
[3,4-b]indole-2-carboxylate (3i)
1
Colorless oil, 35.5 mg, 99% yield; H NMR (400 MHz, CDCl3)
White solid, 26.0 mg, 83% yield; 1H NMR (400 MHz, CDCl3) δ
7.89 (s, 1H), 7.48 (t, J=8.7 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H),
7.18–7.07 (m, 2H), 6.03–5.93 (m, 1H), 5.30–5.46 (m, 2H), 5.24
(d, J=10.5 Hz, 1H), 4.71–4.59 (m, 2H), 4.54–4.32 (m, 1H),
3.28–3.16 (m, 1H), 2.94–2.82 (m, 1H), 2.73–2.67 (m, 1H),
1.90–1.76 (m, 2H), 1.60–1.52 (m, 1H), 1.10–0.99 (m. 6H); 13C
NMR (100 MHz, CDCl3) δ 155.81, 155.47, 135.84, 134.93,
134.42, 133.03, 132.81, 126.85, 121.86, 121.70, 119.59, 119.46,
118.16, 117.95, 117.21, 110.79, 108.68, 108.07, 66.36, 66.08,
49.95, 49.86, 44.32, 43.89, 38.17, 37.88, 25.10, 24.90, 23.39,
22.39, 22.29, 21.50, 20.99; IR (KBr) 3323, 2955, 1679, 1602,
1417, 1229, 1196, 1129 cmÀ 1; HRMS (ESI) calcd for
C19H24N2O2Na: m/z ([M+Na+]) 335.1730, found 335.1732;
[α]D23 =À 49.1 (c=0.23, in CHCl3 for 86% ee); HPLC Daicel
ChiralPak AD-3 column, n-Hexane/i-PrOH=10/1, 1.0 mL/min,
λ=280 nm, tR=27.4 min (minor isomer) and 29.4 min (major
isomer).
δ 7.60/7.57 (brs, 1H), 7.19 (d, J=8.6 Hz, 1H), 6.92–6.91 (m,
1H), 6.80 (d, J=8.6 Hz, 1H), 5.40–5.19 (m, 1H), 4.48–4.23 (m,
1H), 3.85 (s, 3H), 3.20–3.07 (m, 1H), 2.86–2.73 (m, 1H), 2.64–
2.60 (m, 1H), 1.81–1.76 (m, 2H), 1.53–1.42 (m, 10H), 1.07 (d,
J=6.4 Hz, 3H), 0.98 (d, J=6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 155.20, 154.87, 154.09, 136.37, 135.74, 130.89,
127.29, 111.57, 111.41, 111.19, 108.94, 108.66, 108.00, 100.36,
80.10, 79.64, 55.94, 55.73, 55.48, 49.86, 49.18, 44.37, 43.85,
38.42, 37.11, 28.44, 25.16, 24.84, 23.35, 22.51, 21.51, 21.11; IR
(KBr) 3319, 2954, 1668, 1459, 1416, 1218, 1165 cmÀ 1; HRMS
(ESI) calcd for C21H30N2O3Na: m/z ([M+Na+]) 381.2154,
found 381.2159; [α]D27 =À 25.1 (c=0.11, in CHCl3 for 85%
ee); HPLC Daicel ChiralPak AD-3 column, n-Hexane/i-PrOH=
10/1, 1.0 mL/min, λ=280 nm, tR=6.4 min (major isomer) and
12.0 min (minor isomer).
Adv. Synth. Catal. 2021, 363, 1–17
9
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λ=280 nm, tR=10.4 min (major isomer) and 11.5 min (minor
isomer).
(S)-tert-Butyl 1-isobutyl-3,4-dihydro-1H-pyrido
[4,3-b]indole-2(5H)-carboxylate (6a)
1
White solid, 22.9 mg, 70% yield; H, 13C NMR charts were
consistent with previously reported data.[14] The compound exits
as a 3:1 mixture of rotamers. H NMR (400 MHz, CDCl3) δ
(S)-tert-Butyl 1-phenyl-3,4-dihydro-1H-pyrido
[4,3-b]indole-2(5H)-carboxylate (6d)
1
8.01 (brs, 1H), 7.91 (brs, 0.3H), 7.47 (d, J=7.8 Hz, 1.3H), 7.31
(d, J=7.3 Hz, 1.3H), 7.17–7.07 (m, 3H), 5.57 (m, 0.3H), 5.39
(d, J=8.7 Hz, 1H), 4.48 (dd, J=6.4 Hz, 1H), 4.27 (dd, J=
13.5, 5.3 Hz, 0.3H), 3.31–3.18 (m, 1.3H), 3.00–2.88 (m, 1.3H),
2.58 (dd, J=15.8, 3.4 Hz, 1.3H), 1.88–1.78 (m, 1.3H), 1.76–
1.63 (m, 2.6H), 1.52–1.46 (m, 11.7H), 1.20 (d, J=6.4 Hz,
3.9H), 1.00–0.94 (d, J=6.9 Hz, 3.9H); 13C NMR (100 MHz,
CDCl3) major rotamer: δ 155.35, 135.79, 131.98, 125.34,
121.39, 119.41, 117.70, 112.49, 110.86, 110.66, 80.01, 49.36,
44.40, 36.05, 28.48, 25.03, 23.89, 23.19, 22.22; selected minor
rotamer peaks: 37.31, 25.38; HRMS (ESI) calcd for
C20H28N2O2Na+: m/z ([M+Na+]) 351.2043, found 351.2031;
[α]D22 = +103.1 (c=0.12, in CHCl3 for 98% ee); HPLC Daicel
ChiralPak IBN-5 column, n-Hexane/i-PrOH=50/1, 1.0 mL/
min, λ=280 nm, tR=25.7 min (major isomer) and 35.1 min
(minor isomer).
1
White solid, 24.1 mg, 69% yield; H, 13C NMR charts were
consistent with previously reported data.[14] The compound
exists as a 3:2 mixture of rotamers. 1H NMR (400 MHz, CDCl3)
δ 8.07 (br s, 1H), 7.41–7.36 (m, 2H), 7.34 (d, J=7.6 Hz, 1H,),
7.31–7.24 (m, 3H), 7.16–7.12 (2H, m), 7.00 (t, J=7.6 Hz, 1H),
6.65 (brs, minor rotamer, 0.4H), 6.43 (brs, major rotamer,
0.6H), 4.39 (brs, major rotamer, 0.6H), 4.20 (brs, minor
rotamer, 0.4H), 3.15–3.04 (m, 2H), 2.70 (m, 1H), 1.55 (s, 9H);
13C NMR (100 MHz, CDCl3) major totamer: δ 154.68, 141.42,
135.86, 133.51, 128.17, 127.42, 126.16, 121.59, 119.64, 118.61,
110.64, 109.53, 80.27, 54.05, 36.53, 28.58, 23.48; selected
minor rotamer peaks: 52.87, 37.59; IR (KBr) 3292, 2937, 1654,
1462, 1419, 1366, 1295, 1253, 1234, 1164, 1147 cmÀ 1; HRMS
(ESI) calcd for C22H24N2O2Na: m/z ([M+Na+]) 371.1730,
found 371.1721; [α]D20 = +89.1 (c=0.16, in CHCl3 for 95%
ee); HPLC Daicel ChiralPak AD-3 column, n-Hexane/i-PrOH=
10/1, 1.0 mL/min, λ=280 nm, tR=7.5 min (minor isomer) and
8.5 min (major isomer).
(S)-1-Isobutyl-2-methyl-2,3,4,5-tetrahydro-1H-pyri-
do[4,3-b]indole (6b)
1H NMR (400 MHz, CDCl3) δ 7.79 (brs, 1H), 7.46 (d, J=
7.6 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.14 (m, 2H), 3.82 (dd,
J=9.2, 4.4 Hz, 1H), 3.34–3.26 (m, 1H), 3.02–2.91 (m, 2H),
2.52–2.46 (m, 4H), 2.03–1.93 (m, 1H), 1.74–1.67 (m, 1H),
1.63–1.57 (m, 1H), 1.08 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 135.53, 130.78, 126.70,
121.06, 119.14, 118.11, 111.76, 110.60, 56.82, 44.81, 44.28,
41.61, 25.38, 23.76, 22.25, 18.39; IR (KBr) 3284, 2955, 1503,
1382, 1272, 1120 cmÀ 1; HRMS (ESI) calcd for C16H22N2Na: m/z
([M+Na+]) 415.2000, found 415.1996; [α]D18 =À 32.9 (c=
0.12, in CHCl3 for 83% ee); HPLC Daicel ChiralPak AD-3
column, n-Hexane/i-PrOH=10/1, 1.0 mL/min, λ=280 nm,
tR=5.6 min (major isomer) and 10.6 min (minor isomer).
(S)-tert-Butyl 1-(4-fluorophenyl)-3,4-dihydro-1H-
pyrido[4,3-b]indole-2(5H)-carboxylate (6e)
1
White solid, 24.9 mg, 68% yield; H, 13C NMR charts were
consistent with previously reported data.[14] The compound
exists as a 3:2 mixture of rotamers. 1H NMR (400 MHz, CDCl3)
δ 8.08 (brs, 1H), 7.37–7.33 (m, 3H), 7.14 (t, J=8.0 Hz, 1H),
7.09 (d, J=8.0 Hz, 1H), 7.02–6.94 (m, 3H), 6.58 (brs, minor
rotamer, 0.4H), 6.40 (brs, major rotamer, 0.6H), 4.38 (brs, major
rotamer, 0.6H), 4.23 (brs, minor rotamer, 0.4H), 3.11–3.00 (m,
2H), 2.77–2.69 (m, 1H), 1.54 (s, 9H); 13C NMR (100 MHz,
CDCl3) major rotamer: δ 162.14 (JC-F =203 Hz), 154.59,
137.26, 135.89, 133.61, 129.90, 125.96, 121.68, 119.68, 118.41,
114.94 (JC-F =16.8 Hz), 110.73, 109.32, 80.51, 53.39, 36.41,
28.57, 23.47; selected minor rotamer peaks: 52.27, 37.51; 19F
NMR (565 MHz, CDCl3) δ À 118.30; HRMS (ESI) calcd for
C22H23FN2O2Na: m/z ([M+Na+]) 389.1636, found 389.1633;
[α]D21 = +205.2 (c=0.2, in CHCl3 for 98% ee); HPLC Daicel
ChiralPak AD-3 column, n-Hexane/i-PrOH=10/1, 1.0 mL/min,
λ=280 nm, tR=6.7 min (minor isomer) and 8.8 min (major
isomer).
(S)-tert-Butyl 1-pentyl-3,4-dihydro-1H-pyrido[4,3-b]
indole-2(5H)-carboxylate (6c)
1
White solid, 22.7 mg, 66% yield; H, 13C NMR charts were
consistent with previously reported data.[14] The compound
exists as a 5:2 mixture of rotamers. 1H NMR (400 MHz, CDCl3)
δ 7.80 (brs, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.31 (d, J=7.8 Hz,
1H), 7.16–7.09 (m, 2H), 5.39–5.49 (m, 0.3H), 5.28 (d, J=
8.2 Hz, 0.7H, major rotamer), 4.50 (dd, J=13.5, 5.3 Hz, 0.7H,
major rotamer), 4.23–4.38 (m, 0.3H, minor rotamer), 3.23–3.16
(m, 1H), 3.00–2.92 (m, 1H), 2.62–2.58 (m, 1H), 2.02–1.90 (m,
1H), 1.80–1.67 (m, 1H), 1.59–1.40 (m, 2H), 1.48 (s, 9H), 1.38–
1.29 (m, 3H), 0.92 (t, J=6.9 Hz, 3H); 13C NMR (CDCl3,
125 MHz), major rotamer: δ 155.33, 135.83, 131.97, 125.44,
121.34, 119.36, 117.87, 112.26, 110.84, 79.80, 51.18, 36.17,
35.01, 31.84, 28.47, 26.46, 23.29, 22.78, 14.05; selected minor
rotamer peaks: 50.38, 37.47; HRMS (ESI) calcd for
C21H30N2O2Na: m/z ([M+Na+]) 365.2199, found 365.2188;
[α]D22 = +78.1 (c=0.16, in CHCl3 for 96% ee); HPLC Daicel
ChiralPak AD-3 column, n-Hexane/i-PrOH=20/1, 1.0 mL/min,
(S)-tert-Butyl 1-(4-chlorophenyl)-3,4-dihydro-1H-
pyrido[4,3-b]indole-2(5H)-carboxylate (6f)
1
White solid, 26.9 mg, 70% yield; H, 13C NMR charts were
consistent with previously reported data.[14] The compound
exists as a 2:1 mixture of rotamers. 1H NMR (CDCl3,
400 MHz): δ 8.41 (brs, 1H), 7.35–7.25 (m, 3H), 7.25–7.19 (m,
2H), 7.11–7.06 (m, 2H), 6.97 (t, J=8.0 Hz, 1H), 6.72–6.50
(brs, minor rotamer, 0.3H), 6.50–6.28 (brs, major rotamer,
0.6H), 4.51–4.31 (brs, major rotamer, 0.6H), 4.30–4.08 (brs,
minor rotamer, 0.3H), 3.07–2.93 (m, 2H), 2.65–2.61 (m, 1H),
1.54 (s, 9H); 13C NMR (CDCl3, 100 MHz), major rotamer: δ
154.67, 139.97, 135.92, 133.20, 129.62, 128.30, 125.87, 121.60,
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119.61, 118.30, 110.78, 108.74, 80.49, 53.48, 36.70, 28.54,
23.40; selected minor rotamer peaks: δ 52.53, 37.49; HRMS
(ESI) calcd for C22H23ClN2O2Na: m/z ([M+Na+]) 405.1340,
found 405.1336; [α]D18 = +152.4 (c=0.17, in CHCl3 for 95%
ee); HPLC Daicel ChiralPak AD-3 column, n-Hexane/i-PrOH=
10/1, 1.0 mL/min, λ=280 nm, tR=7.6 min (minor isomer) and
8.7 min (major isomer).
130.86, 130.71, 129.31, 127.46, 126.67, 125.33, 111.16, 110.98,
110.44, 101.11, 80.05, 55.88, 51.74, 37.51, 28.41, 23.13, 19.99;
IR (KBr) 3352, 2942, 1663, 1628, 1457, 1308, 1243, 1212,
1170,1141, 1114 cmÀ 1;HRMS (ESI) calcd for C24H28N2O3Na:
m/z ([M+Na+]) 415.1992, found 415.1988; [α]D23 = +216.7
(c=0.15, in CHCl3 for 98% ee); HPLC Daicel ChiralPak IF-3
column, n-Hexane/i-PrOH=97/3, 1.0 mL/min, λ=280 nm,
tR=23.1 min (minor isomer) and 34.6 min (major isomer).
(S)-tert-Butyl 1-o–tolyl-3,4-dihydro-1H-pyrido
[4,3-b]indole-2(5H)-carboxylate (6g)
(S)-tert-Butyl 8-bromo-1-o–tolyl-3,4-dihydro-1H-
pyrido[4,3-b]indole-2(5H)-carboxylate (6j)
1
White solid, 29.0 mg, 80% yield; H, 13C NMR charts were
consistent with previously reported data.[14] 1H NMR (CDCl3,
400 MHz): δ 8.07 (brs, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.25 (d,
J=6.4 Hz, 1H), 7.19–7.08 (m, 3H), 6.99–6.94 (m, 2H), 6.87 (d,
J=7.2 Hz, 1H), 6.67 (brs, 1H), 4.13 (brs, 1H), 3.17–3.11 (m,
2H), 2.71–2.64 (m, 1H), 2.64 (s, 3H), 1.50 (s, 9H); 13C NMR
(CDCl3, 100 MHz): δ 155.06, 138.66, 137.61, 135.72, 133.40,
130.71, 129.32, 127.49, 126.08, 125.27, 121.51, 119.55, 118.50,
110.58, 80.14, 51.51, 37.45, 28.40, 22.99, 20.04; IR (KBr)
3330, 1677, 1487, 1388, 1290, 1217, 1186, 1136, 1108 cmÀ 1;
HRMS (ESI) calcd for C23H26N2O2Na: m/z ([M+Na+])
385.1886, found 385.1882; [α]D20 = +89.1 (c=0.16, in CHCl3
for 99% ee); HPLC Daicel ChiralPak AD-3 column, n-Hexane/
i-PrOH=10/1, 1.0 mL/min, λ=280 nm, tR=5.5 min (minor
isomer) and 6.1 min (major isomer).
White solid, 31.4 mg, 71% yield; 1H NMR (400 MHz, CDCl3) δ
8.04 (brs, 1H), 7.24 (s, 1H), 7.20–7.15 (m, 4H), 6.97 (t, J=
7.6 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.60 (s, 1H), 4.22–4.18
(m, 1H), 3.23–3.04 (m, 2H), 2.65–2.55 (m, 4H), 1.49 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 154.99, 138.18, 137.78, 134.87,
134.45, 130.90, 129.14, 127.85, 127.69, 125.34, 124.41, 121.02,
112.90, 112.02, 110.41, 80.22, 51.71, 37.31, 28.40, 23.04,
19.98; IR (KBr) 3342, 2943, 1659, 1487, 1460, 1403, 1371,
1308, 1245, 1213, 1168, 1141, 1115 cmÀ 1; HRMS (ESI) calcd
for C23H25BrN2O2Na: m/z ([M+Na+]) 463.0992, found
463.0987; [α]D17 = +118.4 (c=0.15, in CHCl3 for 81% ee);
HPLC Daicel ChiralPak AD-3 column, n-Hexane/i-PrOH=20/
1, 1.0 mL/min, λ=280 nm, tR=7.7 min (mionor isomer) and
8.6 min (major isomer).
(S)-tert-Butyl 1-(naphthalen-1-yl)-3,4-dihydro-1H-
pyrido[4,3-b]indole-2(5H)-carboxylate (6h)
(S)-1-(o-Tolyl)-2-tosyl-2,3,4,5-tetrahydro-1H-pyrido
[4,3-b]indole (6k)
1
1
White solid, 30.0 mg, 75% yield; H, 13C NMR charts were
White solid, 36.6 mg, 88% yield; H, 13C NMR charts were
consistent with previously reported data.[14] The compound
exists as a 2:1 mixture of rotamers. 1H NMR (CDCl3,
400 MHz): δ 8.88 (d, J=8.4 Hz, 1H), 8.04 (brs, 1H), 7.91 (d,
J=8.4 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.64 (t, J=8.0 Hz,
1H), 7.55 (t, J=7.6 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.32 (m,
1H), 7.22 (t, J=7.6 Hz, 1H), 7.14 (t, J=6.8 Hz, 1H), 7.09–7.05
(m, 2H), 6.95 (t, J=8.0 Hz, 1H), 4.14–4.01 (m, 1H), 3.14–3.09
(m, 2H), 2.68 (d, J=12.4 Hz, 1H), 1.54 (s, 9H); 13C NMR
(CDCl3, 150 MHz): major rotamer: δ 154.99, 136.45, 135.84,
133.99, 132.27, 128.49, 127.66, 126.37, 125.67, 124.95, 121.56,
119.59, 118.72, 110.68, 110.19, 80.06, 51.10, 37.89, 28.48,
23.49; selected minor rotamer peaks: δ 37.20, 22.64; IR (KBr)
3381, 2925, 1665, 1601, 1448, 1409, 1366, 1292, 1160, 1140,
1099 cmÀ 1;HRMS (ESI) calcd for C26H26N2O2Na: m/z ([M+
Na+]) 421.1886, found 421.1882; [α]D17 = +87.8 (c=0.2, in
CHCl3 for 95% ee); HPLC Daicel ChiralPak AD-3 column, n-
Hexane/i-PrOH=10/1, 1.0 mL/min, λ=280 nm, tR=5.3 min
(minor isomer) and 7.4 min (major isomer).
consistent with previously reported data.[25] 1H NMR (400 MHz,
CDCl3) δ 7.78 (brs, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.27–7.24 (m,
2H), 7.18–7.07 (m, 3H), 7.00–6.90 (m, 4H), 6.84 (dd, J=7.6,
0.8 Hz, 1H), 6.70 (s, 1H), 3.89 (dd, J=14.8, 6.0 Hz, 1H), 3.47–
3.39 (m, 1H), 2.80 (s, 3H), 2.59–2.44 (m, 2H), 2.29 (s, 3H);
13C-NMR (100 MHz, CDCl3) δ 142.92, 137.71, 137.66, 137.55,
135.69, 131.57, 131.09, 129.18, 128.92, 127.91, 127.07, 125.59,
125.42, 121.76, 119.66, 118.06, 110.52, 109.49, 53.47, 38.43,
21.36, 21.26, 20.13; IR (KBr) 3398, 1459, 1325, 1155,
741 cmÀ 1; HRMS (ESI) calcd for C25H24N2O2SNa: m/z ([M+
Na+]) 439.1451, found 439.1444; [α]D22 = +43.2 (c=1.35, in
CHCl3 for 88% ee); HPLC Daicel ChiralPak AD-3 column, n-
Hexane/i-PrOH=10/1, 1.0 mL/min, λ=280 nm, tR=30.2 min
(minor isomer) and 33.0 min (major isomer).
tert-Butyl (2’R,3S)-2’-isobutyl-2-oxospiro[indoline-
3,3’-pyrrolidine]-1’-carboxylate (4a)
1
White solid, 23.3 mg, 93% yield (17:1 dr); H, 13C NMR charts
were consistent with previously reported data.[13k] 1H NMR
(400 MHz, CDCl3) δ 7.80 (brs, 1H), 7.25–7.20 (m, 1H), 7.07–
7.00 (m, 2H), 6.88 (d, J=7.6 Hz, 1H), 4.13–3.68 (m, 3H),
2.54–2.43 (m, 1H), 2.07–2.00 (m, 1H), 1.90–1.70 (m, 1H),
1.52–1.28 (m, 11H), 0.88–0.73 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 178.55, 154.67, 139.45, 134.66, 128.06, 122.86,
122.44, 109.84, 80.16, 63.48, 55.71, 43.78, 40.08, 35.41, 33.84,
28.49, 25.03, 22.95, 22.63; IR (KBr) 3247, 2957, 1704, 1620,
1473, 1369, 1331, 1232, 1119, 747 cmÀ 1; HRMS (ESI) calcd for
C20H28N2O3Na: m/z ([M+Na+]) 367.1992, found 367.1997;
(S)-tert-Butyl 8-methoxy-1-o–tolyl-3,4-dihydro-1H-
pyrido[4,3-b]indole-2(5H)-carboxylate (6i)
1
White solid, 31.4 mg, 80% yield; H, 13C NMR charts were
consistent with previously reported data.[14] 1H NMR (400 MHz,
CDCl3) δ 7.89 (brs, 1H), 7.14–7.25 (m, 3H), 6.97 (t, J=7.3 Hz,
1H), 6.89–6.87 (m, 1H), 6.78 (dd, J=8.7, 2.3 Hz, 1H), 6.71–
6.60 (m, 1H), 6.52 (brs, 1H), 4.14–4.10 (m, 1H), 3.68 (s, 3H),
3.14–3.03 (m, 2H), 2.69–2.56 (m, 4H), 1.47 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 155.05, 154.00, 138.61, 137.63, 134.21,
Adv. Synth. Catal. 2021, 363, 1–17
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[α]D25 =À 19.7 (c=0.21, in CHCl3 for 88% ee); HPLC Daicel
ChiralPak AD-3 column, n-Hexane/i-PrOH=20/1, 1.0 mL/min,
λ=280 nm, tR=11.4 min (minor isomer) and 18.9 min (major
isomer).
(2’R,3S)-2’-(2-Bromophenyl)-1’-tosylspiro[indoline-
3,3’-pyrrolidin]-2-one (4e)
White solid, 15.3 mg, 42% yield (>20:1 dr); 1H NMR
(400 MHz, CDCl3) δ 8.73 (brs, 1H), 7.66–7.64 (m, 1H), 7.59
(m, 3H), 7.46–7.40 (m, 2H), 7.38–7.35 (m, 3H), 7.19 (d, J=
8.2 Hz, 2H), 7.16–7.12 (m, 1H), 4.50 (s, 1H), 3.12 (t, J=
7.0 Hz, 2H), 2.87 (t, J=7.0 Hz, 2H), 2.38 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 187.4, 143.2, 140.6, 136.8, 136.7, 133.4,
131.7, 131.0, 129.5, 128.4, 128.0, 127.8, 127.4, 126.9, 122.2,
121.3, 121.1, 119.3, 112.2, 43.7, 25.2, 21.5; IR (KBr) 3324,
3060, 2925, 1622, 1469, 1326, 1279, 1156, 746 cmÀ 1; HRMS
(ESI) calcd for C24H21BrN2O3SNa: m/z ([M+Na+]) 519.0348,
found 519.0341; [α]D20 =À 58.9 (c=0.14, in CHCl3 for 93%
ee); HPLC Daicel ChiralPak AD-3 column, n-Hexane/i-PrOH=
7/1, 1.0 mL/min, λ=265 nm, tR=34.2 min (minor isomer) and
47.2 min (major isomer).
(2’R*,3S*)-2’-Isobutyl-1’-methyl-spiro[indoline-3,3’-
pyrrolidin]-2-one (4b)
1
Colorless oil, 13.4 mg, 71% yield and 0% ee (7.5:1 dr); H-
NMR (400 MHz, CDCl3) δ 8.27 (brs, 1H), 7.39 (d, J=7.6 Hz,
1H), 7.19 (t, J=7.6 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 6.87 (d,
J=7.2 Hz, 1H), 3.31 (t, J=7.6 Hz, 1H), 2.73–2.70 (m, 1H),
2.63–2.57 (m, 1H), 2.41 (s, 3H), 2.35–2.29 (m, 1H), 2.07–2.02
(m, 1H), 1.22–1.18 (m, 1H), 1.25–1.14 (m, 2H), 0.98–0.94 (m,
1H), 0.75 (d, J=6.4 Hz, 3H), 0.52 (d, J=6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ182.72, 140.13, 133.38, 127.64,
125.40, 122.42, 109.42,71.52, 57.22, 56.01, 40.49, 38.70, 36.64,
24.79, 23.85, 21.89; HRMS (ESI) calcd for C16H23N2O: m/z
([M+H+]) 259.1805, found 259.1797
tert-Butyl (2’R,3R)-2’-isobutyl-5-methoxy-2-oxospiro
[indoline-3,3’-pyrrolidine]-1’-carboxylate (4f)
Colorless oil, 21.9 mg, 80% yield (4.2:1 dr); 1H-NMR
(400 MHz, CDCl3) δ 8.49 (brs, 1H), 6.83–6.74 (m, 2H), 6.71–
6.61 (m, 1H), 4.11–3.85 (m, 2H), 3.76 (s, 3H), 3.73–3.64 (m,
1H), 2.60–2.32 (m, 1H), 2.11–1.97 (m, 1H), 1.97–1.74 (m, 1H),
1.75–1.60 (m, 2H), 1.47 (s, 9H), 1.41–1.29 (m, 1H), 0.93–0.70
(m, 6H); 13C NMR (150 MHz, CDCl3) 177.9, 157.1, 136.0,
132.4, 125.5, 125.0, 112.8, 109.9, 80.2, 63.5, 56.1, 55.8, 43.7,
40.2, 34.0, 28.5, 25.0, 23.0, 22.6 ; IR (KBr) 3205, 2955, 1705,
1659, 1501, 1412, 1367, 1339, 1209, 1111, 1038, 747 cmÀ 1;
HRMS (ESI) calcd for C21H30N2O4Na: m/z ([M+Na+])
397.2098, found 397.2088; [α]D27 = +38.2 (c=0.13, in CHCl3
for 87% ee); HPLC (Chiral AD-3 column), n-Hexane/i-PrOH=
7/1, 1.0 mL/min, λ=280 nm, tR=7.1 min (major isomer) and
16.8 min (major isomer).
tert-Butyl (2’R,3S)-2-oxo-2’-pentylspiro[indoline-
3,3’-pyrrolidine]-1’-carboxylate (4c)
Colorless oil, 20.1 mg, 77% yield (10:1 dr); 1H NMR
(400 MHz, CDCl3) δ 7.82 (brs, 1H), 7.26–7.20 (m, 1H), 7.11–
6.99 (m, 2H), 6.88 (d, J=8.0 Hz, 1H), 4.10–3.69 (m, 3H),
2.60–2.32 (m, 1H), 2.07–2.00 (m, 1H), 1.96–1.63 (m, 2H), 1.45
(s, 9H), 1.33–0.95 (m, 6H), 0.89–0.71 (m, 3H): 13C NMR
(100 MHz, CDCl3) δ 179,34 178.56, 154.74, 139.48, 134.70,
133.88, 128.02, 122.84, 122.38, 109.79, 79.88, 65.29, 55.80,
44.89, 43.85, 35.42, 33.84, 31.67, 31.29, 28.43, 26.29, 22.50,
13.85; IR (KBr) 3250, 2957, 1732, 1695, 1620, 1472, 1393,
1334, 1174, 1125, 747 cmÀ 1; HRMS (ESI) calcd for
C21H30N2O3Na: m/z ([M+Na+]) 381.2149, found 381.2141;
[α]D25 =À 14.8 (c=0.12, in CHCl3 for 82% ee); HPLC Daicel
ChiralPak AD-3 column, n-Hexane/i-PrOH=10/1, 1.0 mL/min,
λ=280 nm, tR=5.4 min (minor isomer) and 6.7 min (major
isomer).
(2’R,3S)-2’-Isobutyl-1’-tosylspiro[indoline-3,3’-pyr-
rolidin]-2-one (4g)
1
White solid, 20.1 mg, 69% yield; H, 13C NMR charts were
1
tert-Butyl (2’R,3S)-2-oxo-2’-phenethylspiro[indoline-
3,3’-pyrrolidine]-1’-carboxylate (4d)
consistent with previously reported data. H-NMR (400 MHz,
CDCl3) δ 7.84 (d, J=8.4 Hz, 2H), 7.46–7.39 (m, 3H), 7.19–
7.14 (m, 1H), 6.90–6.86 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 6.52
(d, J=7.2 Hz, 1H), 4.03–3.93 (m, 2H), 3.80–3.75 (m, 1H), 2.49
(s, 3H), 2.10–1.97 (m, 2H), 1.85–1.78 (m, 1H), 1.70–1.62 (m,
1H), 1.11–1.01 (m, 1H), 0.75 (d, J=6.4 Hz, 3H), 0.64 (d, J=
6.4 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 178.81, 143.80,
139.60, 135.41, 131.77, 129.88, 128.41, 127.69, 122.77, 122.36,
109.81, 65.44, 56.85, 48.04, 42.00, 37.40, 24.89, 23.59, 21.60,
21.17; IR (KBr) 3172, 2956, 1700, 1473, 1351, 1163, 670, 661,
570 cmÀ 1; HRMS (ESI) calcd for C22H26N2O3SNa: m/z ([M+
Na+]) 421.1564, found 421.1557. [α]D23 =À 46.8 (c=0.17, in
CHCl3 for 84% ee); HPLC (Chiral AD-3 column), n-Hexane/i-
PrOH=7/1, 1.0 mL/min, λ=280 nm, tR=24.2 min (major
isomer) and 35.9 min (minor isomer).
White solid, 23.0 mg, 81% yield (>20:1 dr); 1H-NMR
(400 MHz, CDCl3) δ 8.94 (brs, 1H), 7.25–7.14 (m, 3H), 7.05–
7.01 (m, 2H), 6.92 (d, J=6.8 Hz, 1H), 4.14–3.78 (m, 3H),
2.64–2.38 (m, 3H), 2.33–2.15 (m, 2H), 2.11–2.04 (m, 2H), 1.47
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.35, 154.66, 141.87,
139.34, 134.52, 133.76, 128.30, 125.72, 123.03, 125.72, 123.03,
122.52, 109.91, 80.14, 79.76, 65.50, 64.71, 55.78, 44.93, 44.06,
35.55, 34.09, 33.54, 33.16, 32.80, 28.47 cmÀ 1; IR (KBr) 3275,
2970, 1716, 1671, 1412, 1168, 1124, 887 cmÀ 1; HRMS (ESI)
calcd for C24H28N2O3Na: m/z ([M+Na+]) 415.1992, found
415.1996. [α]D20 = +22.1 (c=0.17, in CHCl3 for 90% ee);
HPLC Daicel ChiralPak AD-3 column, n-Hexane/i-PrOH=7/1,
1.0 mL/min, λ=280 nm, tR=6.3 min (minor isomer) and
8.5 min (major isomer).
Adv. Synth. Catal. 2021, 363, 1–17
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Methyl (2’R,3S)-2’-isobutyl-2-oxospiro[indoline-3,3’- (2S*,2’S*)-2’-Isobutyl-1’-methyl-spiro[indoline-2,3’-
pyrrolidine]-1’-carboxylate (4h)
pyrrolidin]-3-one (7b)
1
Colorless oil, 16.7 mg, 76% yield (15:1 dr); 1H, 13C NMR charts
were consistent with previously reported data.[13k] 1H NMR
(400 MHz, CDCl3) δ 8.76 (brs, 1H), 7.22 (t, J=8.2 Hz, 1H),
7.13–7.01 (m, 2H), 6.92 (d, J=7.8 Hz, 1H), 4.20–3.95 (m, 1H),
3.94–3.79 (m, 2H), 3.74 (s, 3H), 2.61–2.36 (m, 1H), 2.10–2.03
(m, 1H), 1.94–1.62 (m, 2H), 1.40–1.28 (m, 1H), 0.80 (d, J=
6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 178.96, 178.23,
155.62, 139.54, 134.35, 133.38, 128.21, 123.00, 122.47, 109.84,
63.60, 55.69, 52.46, 44.54, 40.17, 39.69, 35.56, 33.89, 25.15,
23.15, 22.55, 21.96; IR (KBr) 3250, 2956, 1703, 1677, 1620,
1454, 1387, 1335, 1119, 750 cmÀ 1; HRMS (ESI) calcd for
C17H22N2O3Na: m/z ([M+Na+]) 325.1530, found 325.1526;
[α]D25 =À 10.4 (c=0.12, in CHCl3 for 88% ee); HPLC (Chiral
AD-3 column), n-Hexane/i-PrOH=10/1, 1.0 mL/min, λ=
280 nm, tRt (minor isomer)=8.3 min, t (major isomer)=
10.0 min.
Yellow solid, 8.6 mg, 67% yield and 0% ee (>20:1 dr); H
NMR (400 MHz, CDCl3) δ 7.57 (d, J=7.8 Hz, 1H), 7.42 (t, J=
7.3 Hz, 1H), 6.82–6.74 (m, 2H), 5.22 (brs, 1H), 3.21 (td, J=
8.9, 2.7 Hz, 1H), 2.52–2.42 (m, 2H), 2.39–2.28 (m, 5H), 1.93–
1.85 (m, 1H), 1.32–1.18 (m, 2H), 1.08 (m, 1H), 0.80–0.64 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 202.7, 160.3, 137.2, 124.6,
120.1, 118.3, 111.6, 74.9, 71.7, 54.7, 40.2, 37.4, 36.2, 25.7,
23.7, 22.2; IR (KBr) 3210, 2954, 1620, 1492, 1469, 1320, 1241,
1097, 1037 cmÀ 1; HRMS (ESI) calcd for C16H23N2O: m/z ([M+
H+]) 259.1805, found 259.1799.
(2S,2’S)-tert-Butyl 2’-pentyl-3-oxospiro[indoline-
2,3’-pyrrolidine]-1’-carboxylate (7c)
1
Yellow solid, 15.4 mg, 86% yield (7.3:1 dr); H NMR (CDCl3,
400 MHz): δ 7.61 (d, J=8.0 Hz, 1H), 7.44–7.48 (m, 1H), 6.88–
6.83 (m, 2H), 4.63 (brs, 1H), 3.92 (t, J=6.8 Hz, 2H), 3.43–3.36
(m, 1H), 2.21–2.14 (m, 1H), 1.93–1.61 (m, 2H), 1.48 (s, 9H),
1.20–1.18 (m, 6H), 1.07–1.01 (m, 1H), 0.77 (t, J=6.6 Hz, 3H);
13C NMR (CDCl3, 100 MHz): δ 201.58, 159.91, 155.07, 137.20,
124.86, 119.63, 119.09, 112.10, 79.83, 73.54, 60.10, 44.57,
44.50, 40.71, 35.27, 28.48, 24.86, 23.41, 22.20. IR (KBr) 3287,
2929, 1690, 1672, 1621, 1470, 1403, 1366, 1172, 1146 cmÀ 1;
HRMS (ESI) calcd for C21H30N2O3Na: m/z ([M+Na+])
381.2149, found 381.2138; [α]D17 =À 6.9 (c=0.30, in CHCl3
for 90% ee); HPLC Daicel ChiralPak ODÀ H column, n-
Hexane/i-PrOH=20/1, 1.0 mL/min, λ=390 nm, tR=11.8 min
(major isomer) and 21.5 min (minor isomer).
Allyl (2’R,3S)-2’-isobutyl-2-oxospiro[indoline-3,3’-
pyrrolidine]-1’-carboxylate (4i)
Colorless oil, 17.2 mg, 72% yield (>20:1 dr); 1H-NMR
(400 MHz, CDCl3) δ 8.63 (brs, 1H), 7.25–7.21 (m, 1H), 7.14–
7.01 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.09–5.77 (m, 1H),
5.50–5.01 (m, 2H), 4.72–4.50 (m, 2H), 4.23–3.68 (m, 3H),
2.64–2.37 (m, 1H), 2.14–1.99 (m, 1H), 1.97–1.65 (m, 2H),
1.60–1.19 (m, 1H), 0.81 (d, J=5.6 Hz, 6H); 13C-NMR
(100 MHz, CDCl3) δ 178.90, 178.16, 154.91, 154.64, 139.53,
139.28, 134.35, 133.39, 133.08, 132.76, 128.22, 123.01, 122.50,
117.98, 117.37, 109.82, 66.16, 65.82, 63.61, 55.69, 55.54,
44.58, 44.37, 40.17, 39.64, 35.55, 33.89, 29.65, 25.14, 23.17,
22.74, 22.45, 21.96; IR (KBr) 3159, 3082, 2960, 1700, 1620,
1474, 1108, 999, 929, 753 cmÀ 1; HRMS (ESI) calcd for
C19H24N2O3Na: m/z ([M+Na+]) 351.1687, found 351.1684
[α]D2 =À 11.8 (c=0.13, in CHCl3); HPLC Daicel ChiralPak
AD-3 column, n-Hexane/i-PrOH=20/1, 1.0 mL/min, λ=
280 nm, tR=7.2 min (minor isomer) and=9.1 min (major
isomer).
(2S,2’S)-tert-Butyl 2’-phenyl-3-oxospiro[indoline-
2,3’-pyrrolidine]-1’-carboxylate (7d)
Yellow solid, 12.9 mg, 71% yield (>20:1 dr); 1H NMR (CDCl3,
400 MHz): δ 7.60 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H),
7.31–7.24 (m, 3H), 7.07–7.05 (m, 2H), 6.81 (t, J=7.2 Hz, 1H),
6.59 (d, J=7.2 Hz, 1H), 4.90 (brs, 1H), 4.03–4.15 (m, 2H),
3.83–3.73 (m, 1H), 2.35–2.17 (m, 1H), 2.16–2.04 (m, 1H),
1.43–1.14 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 201.76,
159.85, 154.43, 139.25, 137.30, 128.34, 127.61, 126.19, 124.76,
119.87, 119.27, 111.97, 73.73, 65.70, 64.10, 44.73, 32.97,
28.03; IR (KBr) 3342, 2979, 1693, 1681, 1621, 1393, 1168,
1134, 754 cmÀ 1; HRMS (ESI) calcd for C22H24N2O3Na: m/z ([M
+Na+]) 387.1679, found 387.1669; [α]D17 =À 12.0 (c=0.28, in
CHCl3 for 96% ee); HPLC Daicel ChiralPak AD-3 column, n-
Hexane/i-PrOH=20/1, 1.0 mL/min, λ=390 nm, tR=29.6 min
(minor isomer) and 33.4 min (major isomer).
(2S,2’S)-tert-Butyl 2’-isobutyl-3-oxospiro[indoline-
2,3’-pyrrolidine]-1’-carboxylate (7a)
Yellow solid, 12.9 mg, 75% yield (10:1 dr); 1H, 13C NMR charts
were consistent with previously reported data.[14] 1H NMR
(CDCl3, 400 MHz): δ 7.59 (d, J=7.6 Hz, 1H), 7.44 (t, J=
7.6 Hz, 1H), 6.88–6.80 (m, 2H), 4.97 (brs, 1H), 4.02 (t, J=
6.4 Hz, 1H), 3.93 (m, 1H), 3.41–3.34 (m, 1H), 2.23–2.12 (m,
1H), 1.92–1.86 (m, 1H), 1.63–1.59 (m, 1H), 1.51–1.39 (m,
10H), 1.32–1.23 (m, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.78 (d, J=
6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 201.58, 159.91,
155.07, 137.20, 124.86, 119.63, 119.09, 112.10, 79.83, 73.54,
60.10, 44.57, 44.50, 40.71, 35.27, 28.48, 24.86, 23.41, 22.20;
HRMS (ESI) calcd for C20H28N2O3Na: m/z ([M+Na+])
367.1998, found 367.1996; [α]D17 =À 7.0 (c=0.32, in CHCl3
for 94% ee); HPLC Daicel ChiralPak ODÀ H column, n-
Hexane/i-PrOH=20/1, 1.0 mL/min, λ=390 nm, tR=10.9 min
(major isomer), 15.7 min (minor isomer).
(2S,2’S)-tert-Butyl 2’-(p–fluorophenyl)-3-oxospiro
[indoline-2,3’-pyrrolidine]-1’-carboxylate (7e)
Yellow solid, 13.7 mg, 72% yield (>20:1 dr); 1H NMR
(400 MHz, CDCl3) δ 7.60 (d, J=7.5 Hz, 1H), 7.39–7.35 (m,
1H), 7.09–7.03 (m, 2H), 6.97 (m, 2H), 6.82 (t, J=7.5 Hz, 1H),
6.61 (d, J=8.4 Hz, 1H), 4.90 (s, 1H), 4.15–4.03 (m, 2H), 3.79–
3.73 (m, 1H), 2.37–2.30 (m, 1H), 2.10–2.03 (m, 1H), 1.48–1.18
(m, 9H); 13C NMR (100 MHz, CDCl3) δ 201.37, 162.21 (JC-F
=
245 Hz), 159.74, 154.44, 137.46, 134.96, 127.78 (JC-F =7.7 Hz),
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124.77, 119.80, 119.38, 115.21 (JC-F =20.9 Hz), 111.97, 80.03,
73.87, 72.63, 65.57, 65.36, 44.81, 33.07, 28.09; 19F NMR
(565 MHz, CDCl3) δ À 118.33, À 118.70; IR (KBr) 3341, 2972,
1693, 1672, 1619, 1382, 1173, 1157, 1098, 755 cmÀ 1; HRMS
(ESI) calcd for C22H23FN2O3Na: m/z ([M+Na+]) 415.2000,
found 415.1996; [α]D20 =À 12.2 (c=0.14, in CHCl3 for 98%
ee); HPLC Daicel ChiralPak AD-3 column, n-Hexane/i-PrOH=
10/1, 1.0 mL/min, λ=390 nm, tR=8.8 min (minor isomer) and
10.4 min (major isomer).
1135, 754 cmÀ 1; HRMS (ESI) calcd for C26H26N2O3Na: m/z ([M
+Na+]) 437.1836, found 437.1823; [α]D19 = +13.1 (c=0.26,
in CHCl3 for 93% ee); HPLC Daicel ChiralPak AD-3 column,
n-Hexane/i-PrOH=10/1, 1.0 mL/min, λ=390 nm, tR=
12.1 min (major isomer) and 15.7 min (minor isomer).
tert-Butyl (2S,2’S)-5-methoxy-3-oxo-2’-(o–tolyl)spiro
[indoline-2,3’-pyrrolidine]-1’-carboxylate (7i)
Yellow solid, 12.8 mg, 63% yield (>20:1 dr); 1H NMR
(400 MHz, CDCl3) δ 7.24–7.14 (m, 3H), 7.04–7.07 (m, 3H),
6.58 (d, J=8.7 Hz, 1H), 5.17 (brs, 1H), 4.03 (m, 1H), 3.92–
(2S,2’S)-tert-Butyl 2’-(p–chlorophenyl)-3-oxospiro
[indoline-2,3’-pyrrolidine]-1’-carboxylate (7f)
3.80 (m, 2H), 3.77 (s, 3H), 1.99 (s, 3H), 1.47–1.12 (m, 9H); 13
C
Yellow solid, 19.4 mg, 97% yield (>20:1 dr); 1H NMR
(400 MHz, CDCl3) δ 7.59 (d, J=7.5 Hz, 1H), 7.39–7.35 (m,
1H), 7.24 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.5 Hz, 2H), 6.81 (t,
J=7.5 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H), 4.88 (s, 1H), 4.22–
4.02 (m, 2H), 3.78–3.72 (m, 1H), 2.27 (s, 1H), 2.09–2.02 (m,
1H), 1.55–0.88 (m, 9H); 13C NMR (150 MHz, CDCl3) δ 201.25,
159.67, 154.36, 137.91, 137.54, 133.20, 128.42, 127.57, 124.81,
119.73, 119.45, 112.01, 80.12, 73.79, 72.15, 65.44, 63.83,
44.77, 33.27, 28.03; IR (KBr) 3337, 1697, 1664, 1620, 1405,
1170, 1146, 756 cmÀ 1; HRMS (ESI) calcd for C22H23ClN2O3Na:
m/z ([M+Na+]) 421.1289, found 421.1280; [α]D20 =À 11.4 (c=
0.13, in CHCl3 for 94% ee); HPLC Daicel ChiralPak AD-3
column, n-Hexane/i-PrOH=10/1, 1.0 mL/min, λ=390 nm,
tR=8.7 min (minor isomer) and 13.6 min (major isomer).
NMR (150 MHz, CDCl3) δ 202.80, 156.00, 154.12, 153.59,
138.36, 136.07, 130.26, 127.93, 127.36, 126.24, 125.18, 119.64,
113.57, 104.63, 79.57, 74.21, 61.04, 60.01, 55.74, 44.30, 33.20,
28.45, 27.95, 19.37; IR (KBr) 3347, 2972, 1690, 1494, 1394,
1224, 1131, 734 cmÀ 1; HRMS (ESI) calcd for C24H28N2O4Na:
m/z ([M+Na+]) 431.1941, found 431.1929; [α]D24 =À 19.0 (c=
0.11, in CHCl3 for 93% ee); HPLC Daicel ChiralPak AD-3
column, n-Hexane/i-PrOH=20/1, 1.0 mL/min, λ=390 nm,
tR=18.7 min (major isomer) and 29.0 min (minor isomer).
tert-Butyl (2S,2’S)-5-bromo-3-oxo-2’-(o–tolyl)spiro
[indoline-2,3’-pyrrolidine]-1’-carboxylate (7j)
Yellow solid, 13.4 mg, 59% yield (>20:1 dr); 1H NMR
(400 MHz, CDCl3) δ 7.71 (d, J=1.4 Hz, 1H), 7.44 (d, J=
8.7 Hz, 1H), 7.23–7.14 (m, 3H), 7.09 (d, J=6.9 Hz, 1H), 6.53
(d, J=8.7 Hz, 1H), 5.25–5.09 (br, 1H), 3.97–4.11 (m, 2H),
3.89–3.71 (m, 1H), 2.29–2.09 (m, 2H), 1.99 (s, 3H), 1.46–1.13
(m, 9H); 13C NMR (150 MHz, CDCl3) δ 201.11, 158.53,
154.02, 139.93, 138.29, 135.99, 130.76, 130.35, 127.55, 127.37,
126.39, 125.16, 120.70, 113.36, 111.33, 79.71, 73.67, 72.29,
60.58, 59.64, 43.93, 32.54, 28.44, 27.94, 19.43; IR (KBr) 3330,
2970, 1690, 1619, 1474, 1390, 1175, 725 cmÀ 1; HRMS (ESI)
calcd for C23H25BrN2O3Na: m/z ([M+Na+]) 479.0946, found
479.0929; [α]D17 = +51.0 (c=0.11, in CHCl3 for 82% ee);
HPLC Daicel ChiralPak AD-3 column, n-Hexane/i-PrOH=20/
1, 1.0 mL/min, λ=390 nm, tR=11.4 min (major isomer) and
28.2 min (minor isomer).
(2S,2’S)-tert-Butyl 2’-o–tolyl-3-oxospiro[indoline-
2,3’-pyrrolidine]-1’-carboxylate (7g)
Yellow solid, 11.2 mg, 59% yield (>20:1 dr); 1H NMR (CDCl3,
400 MHz): δ 7.60 (d, J=8.0 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H),
7.09 (d, J=7.2 Hz, 2H), 6.95–6.93 (m, 2H), 6.81 (t, J=7.6 Hz,
1H), 6.61 (d, J=8.0 Hz, 1H), 4.84 (brs, 1H), 4.17–4.00 (m,
2H), 3.83–3.71 (m, 1H), 2.33 (s, 3H), 2.23–2.11 (m, 2H), 1.16–
1.45 (m, 9H); 13C NMR (CDCl3, 100 MHz): δ 202.6, 160.1,
154.0, 138.5, 137.4, 136.0, 130.1, 127.3, 126.2, 125.1, 124.8,
119.1, 119.0, 111.7, 79.5, 73.0, 60.5, 43.9, 32.4, 27.9, 19.3.; IR
(KBr) 3320, 2976, 1690, 1670, 1620, 1471, 1408, 1363, 1168,
1133, 751 cmÀ 1; HRMS (ESI) calcd for C23H26N2O3Na: m/z ([M
+Na+]) 401.1836, found 401.1824; [α]D17 =À 50.7 (c=0.14, in
CHCl3 for 97% ee); HPLC Daicel ChiralPak AD-3 column, n-
Hexane/i-PrOH=20/1, 1.0 mL/min, λ=390 nm, tR=16.9 min
(major isomer) and=20.0 min (minor isomer).
(2S,2’S)-2’-(o-Tolyl)-1’-tosylspiro[indoline-2,3’-pyr-
rolidin]-3-one (7k)
Yellow solid, 11.0 mg, 51% yield (>20:1 dr); 1H NMR (CDCl3,
600 MHz): δ 7.75 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H),
7.47 (d, J=7.6 Hz, 1H), 7.37 (m, 2H), 7.33 (t, J=8.0 Hz, 1H),
7.27–7.23 (m, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.07 (d, J=7.6 Hz,
1H), 6.76 (t, J=7.2 Hz, 1H), 6.55 (d, J=8.2 Hz, 1H), 5.01 (s,
1H), 3.97 (s, 1H), 3.76–3.87 (m, 2H), 2.48 (s, 3H), 2.20–2.15
(m, 1H), 2.07–1.93 (m, 4H); 13C NMR (150 MHz, CDCl3) δ
201.86, 159.89, 143.72, 137.56, 137.16, 135.65, 134.06, 130.44,
129.58, 128.00, 127.77, 126.74, 126.40, 124.88, 119.36, 118.70,
111.78, 72.86, 62.51, 45.93, 33.65, 21.70, 19.43; IR (KBr)
3387, 2925, 1690, 1619, 1492, 1469, 1341, 1163, 754 cmÀ 1;
HRMS (ESI) calcd for C25H24N2O3SNa: m/z ([M+Na+])
455.1408, found 455.1385; [α]D24 = +101.2 (c=0.11, in CHCl3
for 90% ee); HPLC Daicel ChiralPak AD-3 column, n-Hexane/
(2S,2’S)-tert-Butyl 2’-(1-naphtyl)-3-oxospiro
[indoline-2,3’-pyrrolidine]-1’-carboxylate (7h)
Yellow solid, 12.1 mg, 58% yield (>20:1 dr); 1H NMR (CDCl3,
400 MHz): δ 7.83–7.80 (2H, m), 7.67–7.60 (1H, m), 7.50 (t, J=
7.8 Hz, 2H), 7.44 (d, J=6.6 Hz, 1H), 7.40 (t, J=7.2 Hz, 1H),
7.23–7.15 (m, 2H), 6.85–6.76 (m, 1H), 6.34–6.28 (m, 1H),
5.84–5.76 (brs, 1H), 4.16–4.11 (m, 1H), 3.93–3.76 (m, 2H),
2.29–2.25 (m, 2H), 1.49–0.99 (m, 9H). 13C NMR (150 MHz,
CDCl3) δ 202.53, 160.18, 159.11, 154.66, 154.26, 137.35,
136.16, 135.13, 133.62, 133.34, 131.32, 128.53, 128.26, 126.01,
125.81, 125.29, 125.15, 124.77, 123.10, 122.80, 119.22, 111.93,
80.14, 79.67, 73.29, 71.91, 60.14, 59.14, 44.08, 32.75, 32.01,
28.46, 27.87; IR (KBr) 3331, 2976, 1696, 1670, 1620, 1393,
Adv. Synth. Catal. 2021, 363, 1–17
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i-PrOH=7/1, 1.0 mL/min, λ=390 nm, tR=17.0 min (minor
isomer) and 26.8 min (major isomer).
Cheng, Y. Ishihara, B. Tan, C. F. Barbas, III, ACS Catal.
2014, 4, 743; e) M. Xia, R.-Z. Ma, J. Heterocycl. Chem.
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M. U. Rahman, N. K. Nyola, Synth. Commun. 2016, 46,
1643; h) G.-J. Mei, F. Shi, Chem. Commun. 2018, 54,
6607; i) X. Fang, C.-J. Wang, Org. Biomol. Chem. 2018,
16, 2591.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP18 K14221 in Early-Career Scientists, JP18KK0154 in
Promotion of Joint International Research (Fostering Joint
International Research(B)), JST CREST Grant Number
JPMJCR20R1, Iketani Science and Technology Foundation,
Research Foundation for Opto-Science and Technology, Daiichi
Sankyo Foundation of Life, Hoansha Foundation, Iwatani
foundation and AIRC-Grant 2019. We acknowledge the techni-
cal staff of the Comprehensive Analysis Center of ISIR, Osaka
University (Japan). We thank Dr. Shun Saito for FOP-Flash
assay. We also thank Nippon Light Metal Company for
providing large amount of NaOCl·5H2O.
[9] Y. Ji, X. He, C. Peng, W. Huang, Org. Biomol. Chem.
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Practical Stereoselective Synthesis of C3-Spirooxindole- and
C2-Spiropseudoindoxyl-Pyrrolidines via Organocatalyzed
Pictet-Spengler Reaction/Oxidative Rearrangement Sequence
Adv. Synth. Catal. 2021, 363, 1–17
Dr. M. Kondo, N. Matsuyama, T. Z. Aye, Dr. I. Mattan, T.
Sato, Y. Makita, Prof. M. Ishibashi, Prof. M. A. Arai, Dr. S.
Takizawa*, Prof. H. Sasai*