Enantioselective Total Synthesis of Nitraria Alkaloids: (+)-Nitramine, (+)-Isonitramine, (-)-Isonitramine, and (-)-Sibirine via Asymmetric Phase-Transfer Catalytic α-Allylations of α-Carboxylactams

Article abstract of DOI:10.1021/acs.joc.0c02573

Many optically active 2-azaspirocyclic structures have frequently been found in biologically active natural products. In particular, Nitraria alkaloids, (+)-nitramine, (+)-isonitramine, (-)-isonitramine, and (-)-sibirine, have stereogenicity on their quat

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Enantioselective Total Synthesis of Nitraria Alkaloids: (+)-Nitramine,
(+)-Isonitramine, (−)-Isonitramine, and (−)-Sibirine via Asymmetric
Phase-Transfer Catalytic α‑Allylations of α‑Carboxylactams
Jewon Yang, Yohan Park, Sehun Yang, Geumwoo Lee, Min Woo Ha, Mi-hyun Kim, Suckchang Hong,
and Hyeung-geun Park*
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ABSTRACT: Many optically active 2-azaspirocyclic structures have frequently
been found in biologically active natural products. In particular, Nitraria
alkaloids, (+)-nitramine, (+)-isonitramine, (−)-isonitramine, and (−)-sibirine,
have stereogenicity on their quaternary carbon of the 2-azaspiro[5,5]undecane-7-
ol structure. To synthesize Nitraria alkaloids, we developed a new
enantioselective synthetic method for chiral α-quaternary lactams via the α-
alkylation of α-tert-butoxycarbonyl lactams. α-Alkylation of α-tert-butoxycarbox-
ylactams in the circumstances of phase-transfer catalytic (PTC) system (solid
KOH, toluene, and −40 °C) by virtue of the catalytic action of (S,S)-NAS
bromide (5 mol %) furnished the corresponding α-alkyl-α-tert-butoxycarbonyl
lactams in very high chemical (<99%) and enantioselectivity (<98% ee). Our
catalytic methodology was successfully applied for the enantioselective total
synthesis of Nitraria alkaloids. (+)-Isonitramine was obtained in 12 steps (98%
ee, 43% yield) from δ-valerolactam through enantioselective phase-transfer catalytic allylation, Dieckmann condensation, and
diastereoselective reduction as the key reactions. (−)-Sibirine and (+)-nitramine were prepared from (−)-isonitramine or its
intermediate. Switching the phase-transfer catalyst from (S,S)-NAS bromide to (R,R)-NAS bromide afforded (−)-isonitramine (98%
ee, 41% yield). (−)-Sibirine was synthesized by N-ethoxycarbonylation of (−)-isonitramine followed by reduction (98% ee, 14 steps,
32% yield). Furthermore, the diastereoselective reduction of (R)-2-benzhydryl-2-azaspiro[5.5]undecane-1,7-dione [(R)-15]
followed by reductive removal of the diphenylmethyl group successfully gave (+)-nitramine (98% ee, 11 steps, 40% yield).
INTRODUCTION
■
As a representative naturally occurred molecules, alkaloids
generally contain basic nitrogen atoms in their structures and
show various pharmacological activities.1 The promising
potentiality of pharmacological effects with alkaloids has
inspired many pharmaceutical companies to develop these
compounds or part of their structures as new drugs. A significant
number of alkaloids have cyclic or bicyclic skeletons. In
particular, many biologically important alkaloids with cyclic
ring core structures possess a 2-azaspirocyclic system, for
instance, polyzonimine, nitropolyzonamine, horsfiline, and
spirotryprostatin B (Figure 1).2 Among these compounds,
Nitraria alkaloids, (+)-nitramine, (+)-isonitramine, (−)-isonitr-
amine, and (−)-sibirine, also possess chiral quaternary carbon
centers on their 2-azaspiro[5,5]undecane-7-ol moieties.3 Recent
Figure 1. Azaspirocyclic alkaloids.
research revealed that an extract of Nitraria plants inhibits the
proliferation of cancer cell lines via the apoptotic pathway.4 As
Received: October 29, 2020
Published: January 19, 2021
part of our research programs for the development of new
anticancer therapeutics, we were interested in Nitraria alkaloids
and aimed to develop an efficient enantioselective synthetic
process of the 2-azaspirocyclic system as a platform skeleton.
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Most of the enantioselective synthetic approaches for Nitraria
alkaloids have employed chiral auxiliaries,5 chiral substrates,6 or
enzymatic resolution,7 which are not optimal for largescale
processes. However, there are only two reported catalytic
allylation methods using organopalladium catalysts.8 Herein, we
present a novel synthetic methodology for β-chiral pyrrolidine
and piperidine structures toward 2-azaspirocyclic systems
through asymmetric alkylation under phase-transfer catalysis
(PTC),9 and practical applications for the enantioselective total
synthesis of Nitraria alkaloids, (+)-nitramine, (+)-isonitramine,
(−)-isonitramine, and (−)-sibirine.10
Scheme 2. PTC Alkylation to Generate α-Quaternary
Lactams
RESULTS AND DISCUSSION
■
Our synthetic strategy for 2-azaspirocyclic system is the
enantioselective synthesis of α-quaternary lactams followed by
the subsequent cyclization and reduction as shown in Scheme 1.
Scheme 3. Synthesis of α-tert-Butylcarboxylactams (1−6)
Scheme 1. Synthetic Strategy for a Chiral 2-Azaspirocyclic
System
potential as a PTC substrate by α-benzylation under
representative PTC conditions [benzyl bromide (5.0 equiv),
50% KOH (aq, 5.0 equiv), 0 °C, toluene] in the presence of
chiral phase-transfer catalysts 7−13 (Figure 2)16,17 (Table 1).
As shown in Table 1, all catalysts smoothly afforded the α-
benzylated product (1b) with a variable range of enantiose-
lectivity (22−91% ee). Cinchona-derived catalysts (7−11)
showed low to moderate enantioselectivity (entries 1−5, 22−
51% ee). In contrast, binaphthyl-derived catalysts (12, 13)
exhibited higher enantioselectivities than the cinchona-derived
catalysts, and catalyst 12 gave the best result. Among the
solvents examined, toluene was superior to dichloromethane
and tetrahydrofuran (THF) in terms of enantioselectivity and
chemical yield (entries 6, 8, and 9). Additionally, the
enantioselectivity was not significantly dependent on the
reaction temperature. However, a lower temperature resulted
in a lower chemical yield, with a longer reaction time (entries 6,
13, and 14). Notably, use of the solid base at −40 °C gave faster
reaction times with both higher enantioselectivity and chemical
yield (entries 14−16). In fact, the PTC α-alkylation of N,N-
dialkyl-α-methylmalonamic tert-butyl esters to establish quater-
nary carbon centers gave disappointingly poor enantioselectiv-
ities (up to 65% chemical yield, 42% ee) due to the low acidity of
the α-proton. However, cyclic lactam system successfully
facilitated the formation of a lactam enolate species by alkali
base to afford the corresponding α-quaternary lactams in high
chemical yield and high enantioselectivity. Finally, solid KOH
(s-KOH) base under toluene at −40 °C in the presence of
catalyst 12 was chosen as the optimized reaction conditions for
the PTC α-alkylation of lactams (entry 15).
β-Chiral pyrrolidine or piperidine structures have been
previously synthesized via lactams.11 Generally, there are two
approaches. Introduction of the stereocenter prior to the
formation of lactams is popular, and few of the reverse cases have
been reported as a part of studies, such as α-substitution of
imides with aziridines12 or cyclic sulfamidates13 and α-arylation
of lactams via SNAr.14 However, there have been no methodical
studies on the direct α-alkylation of lactams as an enantiose-
lective method. Accordingly, we designed enantioselective α-
alkylation of lactams as a new and efficient approach to construct
β-chiral carbon on pyrrolidine and piperidine systems, as shown
in Scheme 1.
Enantioselective Synthesis of α-Quaternary Lactams.
In 2009, we reported the phase-transfer catalytic (PTC) α-
alkylation of N,N-dialkylmalonamic tert-butyl esters in the
presence of 1 mol % (S,S)-2,6-bis(3,4,5-trifluorophenyl)-
3,3′,5,5′-tetrahydro-4,4′-spirobi[dinaphtho[2,1-c:1′,2′-e]-
azepin]-4-ium bromide [(S,S)-NAS bromide (12)] to afford
highly enantioselective (S)-mono-α-alkylated products (up to
96% ee).15 To establish β-chiral pyrrolidine and piperidine
structures, we designed new PTC substrates, α-tert-butylcar-
boxy-N-alkyl lactams, as cyclized analogues of N,N-dialkylmalo-
namic tert-butyl esters (Scheme 2).
We first prepared α-carboxylactams 1−6 as substrates for
PTC α-alkylation (Scheme 3). Since the tert-butyl ester group
has been proven to be an essential functionality to ensure high
enantioselectivity in PTC α-alkylations, this moiety was
selected.16 α-tert-Butylcarboxylation of N-alkyl-γ-butyrolactams
or N-alkyl-δ-valerolactams using Boc2O under basic conditions
with lithium hexamethyldisilazide (LiHMDS) afforded the
corresponding α-tert-butylcarboxy-N-alkyl lactams (1−6, 78−
90%). One of the prepared lactams (1) was examined for its
We then expanded the structure of lactam substrates (1−6)
by varying the N-alkyl group. PTC α-benzylation of lactams was
performed under the optimized PTC conditions (Table 2). The
enantioselectivities dramatically relied upon the size of the N-
alkyl groups. Notably, the opposite tendency in enantioselec-
tivity was observed between the 5-membered lactam and 6-
membered lactam. As the size of the N-alkyl group in 5-
membered butyrolactams (1−3) increased, the enantioselectiv-
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Figure 2. Chiral phase-transfer catalysts (7−13).
Table 1. Optimization of Catalyst and Reaction Conditions
Table 2. Scope of Substrates in PTC α-Benzylation
b
c
temp
(°C)
time
(h)
yield
ee
entry cat.
base
solvent
(%)
(%)
1
2
3
4
5
6
7
8
7
8
9
50% KOH
50% KOH
50% KOH
50% KOH
50% KOH
50% KOH
50% KOH
50% KOH
50% KOH
50% NaOH
50% CsOH
50% K2CO3
50% KOH
50% KOH
s-KOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
0
0
0
0
0
0
0
0
0
0
0
0
−20
−40
−40
−40
−60
24
24
24
16
16
7
73
82
85
86
82
96
85
67
85
92
88
45
75
56
95
90
20
22
25
38
32
51
91
73
54
65
85
82
88
92
91
94
94
86
10
11
12
13
12
12
12
12
12
12
12
12
12
12
7
24
24
18
10
24
13
24
3
9
10
11
12
13
14
15
16
17
a
b
Isolated yields. The enantioselectivity was determined by HPLC
analysis of α-benzylated products using a chiral column (Chiralcel
OD-H) with hexane/2-propanol as eluents.
s-CsOH
s-KOH
24
24
a
b
c
0.1 mmol was used. Isolated yields. The enantiomeric excess was
lactams underwent α-alkylation with various activated electro-
philes to give the corresponding alkylated products with high
enantioselectivities, and δ-valerolactams gave slightly higher
enantioselectivities than γ-butyrolactams (Table 3). However,
the low reactivity of aliphatic alkyl halides did not allow them to
proceed with α-alkylation. We attempted to introduce a
heteroaromatic furan group into 6 by using bromomethylfuran.
However, the chemical yield (35%) and enantioselectivity
(<45% ee) were relatively low (data not shown). The high
enantioselectivities (up to 98% ee) confirmed that this synthetic
method is very efficient to prepare α-carboxy-α-alkyl lactams to
establish a 2-azaspirocyclic skeleton. X-ray crystallographic
analysis of 1d and 6d verified their absolute configurations as R
and S, respectively (Figure 3).18 We proposed the plausible
determined by HPLC analysis of the α-benzylated product (1b) using
a chiral column (Chiralcel OD-H) with hexane/2-propanol as the
eluent.
ities were decreased (1b, 94% ee; 2b, 75% ee, 3b, 68% ee). In
contrast, the larger N-alkyl group in 6-membered valerolactams
(4−6) showed the higher enantioselectivities (4b, 65% ee; 5b,
75% ee, 6b, 98% ee). We speculated that the N(1)-substituents
and the ring size might complement each other in the
conformational structure. The conformational change depend-
ing on the ring size and N-alkyl group might affect the efficient
binding process between lactam substrate and the catalyst 12.
With optimal substrates (1, 6) in hand, we next studied the
electrophile generality of enantioselective PTC alkylation. Both
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Table 3. Enantioselective Phase-Transfer Alkylation of 1 and 6 with Various Alkyl Halides
a
b
Isolated yields. The enantioselectivity was determined by HPLC analysis of the α-benzylated products (1a−e−6a−e) using a chiral column
c
(Chiralcel OD-H or Chiralpak AD-H) with hexanes/2-propanol as eluents. The absolute configuration was assigned by the X-ray analysis of 1d
and 6d, crystallized under n-hexane−EtOAc. The enantiopurity was determined by the corresponding methyl esters, prepared from 1e and 6e.
d
Figure 3. ORTEP structure of 1d and 6d showing thermal ellipsoids at the 50% probability level.
transition state model by a DFT-based conformational analysis
to account for the absolute configuration of 6d (Figure 4).19 p-
Bromobenzyl bromide might approach from the sterically less
hindered upper side of the lactam enolate anion formed ionic
complex with catalyst (S,S)-12, leading to the p-bromobenzy-
lated adduct (S)-6d in accord with X-ray analysis.
Enantioselective Synthesis of Nitraria Alkaloids. After
we established an enantioselective synthetic method for α-alkyl-
α-carboxylactams, tert-butyl N(1)-benzhydryl-α-allyl-δ-valero-
lactam (6a) was chosen for the total synthesis of Nitraria
alkaloids, namely, (+)-nitramine, (+)-isonitramine, (−)-isonitr-
amine, and (−)-sibirine. Retrosynthetically, we envisioned
access to Nitraria alkaloids, as shown in Scheme 4. The C−
OH chirality of Nitraria alkaloids can be installed by the
diastereoselective reduction of 15, which can be generated
through Dieckmann condensation of 14. Compound 14 can be
prepared by xanthate radical addition to the terminal alkene of
optically enriched 6a prepared from the enantioselective PTC α-
allylation of N(1)-benzhydryl-δ-valerolactam (6).
Synthesis of (+)-Isonitramine. First, we started to
synthesize (+)-isonitramine. However, the enantioselectivity
of (S)-6a (87% ee) was not satisfactory. Fortunately, we were
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Scheme 5. Enantioselective PTC α-Allylation of 6
peroxide in 1,2-dichloroethane successfully gave (S)-17
(88%).22 The xanthate group was then readily removed by the
same procedure as the debromination step using tributyltin
hydride and AIBN, affording (R)-14 (96%). Cyclization was
attempted for the construction of a spirocyclic structure from
(R)-14 by Dieckmann condensation. However, the direct
Dieckmann condensation of (R)-14 failed due to steric
hindrance of the tert-butyl groups. Therefore, the tert-butyl
ester of (R)-14 was replaced with the methyl ester. The cleavage
of tert-butyl ester under acidic conditions with trifluoroacetic
acid (TFA) in dichloromethane followed by treatment with an
excess of diazomethane delivered (R)-18 (98%). Dieckmann
condensation of (R)-18 smoothly proceeded with LiHMDS in
tetrahydrofuran (THF) at 0 °C, generating spirocyclic
compound (S)-19 (98%).23,24 The removal of the ethyl carboxyl
group of (S)-19 was accomplished by hydrolysis with 50%
aqueous KOH in methanol and subsequent decarboxylation to
afford (S)-15 (93%).
Figure 4. Plausible transition-state model of p-bromobenzylation of 6;
(a) PTC, white ball and stick except for heteroatom (nitrogen, oxygen,
and fluoride); (b) enolate, green ball and stick except for heteroatom
(nitrogen, oxygen); (c) p-bromobenzyl bromide, cyan ball and stick
except for heteroatom (bromide).
Scheme 4. Retrosynthetic Analysis for Nitraria Alkaloids
Next, we aimed to establish the C(R)-OH configuration of
(+)-isonitramine via diastereoselective reduction of the ketone
group in (S)-15. The reduction of the diphenylmethyl group
removed analogue of (S)-15 using diisobutylaluminum hydride
(DIBAL) in THF at −78 °C has been previously reported,
reaching 87% de.5a,7b By adapting those reduction conditions,
(S)-15 was remarkably reduced to (S,R)-20 as a single
diastereomer (93%, >99% de). Then lactam (S,R)-20 was
readily reduced to piperidine (R,R)-21 by using excess LiAlH4 in
THF (90%). Finally, the catalytic hydrogenation of (R,R)-21
with Pd(OH)2 under H2 (1 atm) in methanol gave (+)-isonitr-
experienced at improving the enantioselectivity. During the total
synthesis of (−)-paroxetine, the enantioselectivity was improved
in the monoallylation of the N,N-diphenyl-malonamide ester by
switching the allyl bromide with 2-bromoallyl bromide as an
electrophile.20 Therefore, we attempted to use 2-bromoallyl
bromide instead of allyl bromide (Scheme 5). Gratifyingly, the
enantioselectivity of tert-butyl N(1)-benzhydryl-α-2-bromoall-
yl-δ-valerolactam (16) was successfully increased (87% ee to
98% ee), as was the chemical yield (87% to 93−95%). Although
a detailed mechanism has not been suggested yet for the
remarkable increase in enantioselectivity by attaching bromine,
the bulkier electrophile could make a more selective approach to
the either face of enolate 6 during complexation with quaternary
ammonium catalyst 12, establishing R or S chirality with higher
enantioselectivity.
Then we needed to remove the bromine atom in 16.
Accordingly, treatment of tributyltin hydride with (S)-16 in the
presence of azobisisobutyronitrile (AIBN) provided (S)-6a
(95%) (Scheme 6). Elongation of two carbons from the terminal
olefin moiety of (S)-6a was performed under radical
conditions.21 The addition of ethyl ethoxythiocarbonylsulfany-
lacetate to (S)-6a in the presence of a catalytic amount of lauroyl
23
23
amine {[α]D = +6.22 (c 1.16, CHCl3); [α]D = +5.8 (c 1.4,
CHCl3)6e} (87%). The total yield was 43% in 12 steps from δ-
valerolactam.
Synthesis of (−)-Isonitramine, (−)-Sibirine, and
(+)-Nitramine. We then attempted to synthesize (−)-sibirine
and (+)-nitramine. Since the chirality of the spiroquaternary
center in (−)-sibirine and (+)-nitramine is the same as that of
(−)-isonitramine, we aimed to prepare (−)-sibirine and
(+)-nitramine from (−)-isonitramine. Therefore, we employed
the same synthetic procedure as that of (+)-isonitramine, except
we used PTC catalyst (R,R)-12 instead of (S,S)-12 to create
reverse chirality. Accordingly, (−)-isonitramine {[αD25 = −6.14
(c 1.0, CHCl3); [α]D25 = −4.9 (c 1.1, CHCl3)6e} was successfully
synthesized from δ-valerolactam in 12 steps with a 41% overall
yield (Scheme 7). We needed an N-methylation step to
synthesize (−)-sibirine from the prepared (−)-isonitramine.
However, direct N-methylation by general approaches, such as
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Scheme 6. Synthesis of (+)-Isonitramine
a
The enantiopurity was determined by HPLC analysis of 16, 6a, and 20 using a chiral column (Chiralpak AD-H) with hexane/2-propanol as the
b
eluent. Absolute configuration was assigned by comparison of the specific optical rotation value with the literature value.
Scheme 7. Synthesis of (−)-Isonitramine, (−)-Sibirine, and (+)-Nitramine
a
The enantiopurity was determined by HPLC analysis of 16, 6a, and 20 using a chiral column (Chiralpak AD-H) with hexane/2-propanol as the
b
eluent. Absolute configuration was assigned by comparison of the specific optical rotation value with the literature value.
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CH3I/K2CO3 and dimethylsulfate/triethylamine (Et3N), did
not give successful results. Therefore, we ultimately chose a two-
step process via N-carbamate intermediates followed by
reduction (Table 4). N-Carbamations of (−)-isonitramine
Mitsunobu-type reactions using diethyl azodicarboxylate
(DEAD)-Ph3P-BzOH,22 Tf2O-KNO2,25 and Ms2O-AcOH26
from (6R,7S)-20 and (6S,7S)-21 failed to produce the
corresponding inversion products. We speculated that the
sterically hindered quaternary carbon centers of 20 and 21
inhibit SN2-type inversion with benzoate, nitrite, and acetate.
We then turned our attention to the diastereoselective
reduction of (R)-15. The diastereoselective reduction of N-
diphenylmethyl group removed analogue of (R)-15 was
reported for (+)-nitramine.5a However, we attempted to reduce
(R)-15 directly to obtain (R,R)-20 by shortening the total
number of steps. Previously, DIBAL could diastereoselectively
reduce (R)-15 to (R,S)-20 in THF at −78 °C. We examined
various reducing conditions (Table 5). Unfortunately, L-
Table 4. Synthesis of (−)-Sibirine from (−)-Isonitramine
entry
R
22−24 (%)
(−)-sibirine (%)
1
2
3
Et (22)
tert-Bu (23)
Bn (24)
95
84
74
78
68
46
Table 5. Diasteroselective Reduction of (R)-15
were performed by treating alkyl chloroformates under basic
conditions with Et3N in dichloromethane at 0 °C to provide the
corresponding carbamates (22−24, 74−95%). Finally, (−)-si-
birine {[α]D25 = −24.3 (c 0.5, CHCl3); [α]D25 = −23.1 (c 0.76,
CHCl3)6e} was prepared by the reduction of carbamates using
LiAlH4 under reflux conditions in THF (46−88%). Among the
prepared carbamates, ethyl carbamate afforded (−)-sibirine in
the highest chemical yield (98% ee, 14 steps, 32% overall yield).
The final Nitraria alkaloid, (+)-nitramine, is a diastereomer of
(−)-isonitramine. To date, many synthetic methods have been
developed for the synthesis of nitramine. However, only a few
cases of enantiomerically enriched nitramine have been
reported, and most of them introduced a chiral cyclohexanol
group prior to the construction of the piperidine structure of
nitramine. Our case was reversed, and we tried to prepare
(+)-nitramine in a few steps from spirocyclic intermediates (20
or 21) in the synthesis of (−)-isonitramine. As the configuration
of C(S)-OH of (−)-isonitramine needed to be inversed to
C(R)-OH, we first attempted to perform an inversion by
Mitsunobu-type reactions (Scheme 8). However, all trials with
entry
conditions
DIBAL
L-Selectride
NaBH4
NaCNBH4
Super-Hydride
Red-Al
yield (%)
(R,R)-20 /(R,S)-20
1
2
3
4
5
6
94
trace
75
58
NR
NR
1:>50
1:2.5
1:20
1:5
Selectride, NaBH4, and NaCNBH3 all afforded optically
enriched (R,S)-20, and no reaction was observed with Super-
Hydride and Red-Al. Finally, we employed LiAlH4 as a strong
and small reducing reagent to reduce both ketone and amide to
obtain (S,R)-21. Treatment of LiAlH4 with (R)-15 under THF,
surprisingly, afforded diastereoenriched (S,R)-21 (87%, dr 5:1).
We suggest that the DIBAL chelates with the amide carbonyl
group, delivering hydride to the upside direction of ketone to
form (R,S)-20; however, the LiAlH4 approach to ketone from
the less sterically hindered downside direction affords (R,R)-20
that is subsequently further reduced to (S,R)-21 (Figure 5).27
Scheme 8. Trials of the Inversion of C(S)-OH in 20 and 21
Figure 5. Plausible transition-state model of reduction of (R)-15
20
After separation, (+)-nitramine {[α]D = +14.2 (c 1.0,
CH2Cl2); [α]D = +21.4 (c 0.3, CH2Cl2)6e} was successfully
25
obtained by the catalytic hydrogenation of (S,R)-21 with
Pd(OH)2 in methanol (93%). The total yield of (+)-nitramine
was 40% in 11 steps from δ-valerolactam.
CONCLUSION
■
For the synthesis of Nitraria alkaloids, a novel synthetic method
for the enantioselective construction of α-alkylcarboxy lactams
that can be readily cyclized to an azaspirocyclic structure, was
developed. The enantioselective PTC α-alkylation of α-tert-
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(129 mg, 0.4 mmol) were added to a 100 mL round-bottom flask.
Toluene (10 mL) and KOH (1 g, pellet type) were added, respectively,
to the reaction mixture. After being stirred for 24 h, the reaction mixture
was diluted with EtOAc (200 mL), washed with brine (2 × 100 mL),
dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, hexane/
EtOAc = 3:1) to afford N(1)-benzhydryl-2-piperidone as a white solid
(915 mg, 95% yield): mp = 89−92 °C; 1H NMR (300 MHz, CDCl3) δ
7.40−7.22 (m, 11H), 3.04 (m, 2H), 2.59−2.58 (m, 2H), 1.83 (m, 4H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 138.8, 128.8, 128.4,
127.3, 59.6, 44.2, 32.6, 23.3, 21.2 ppm; IR (KBr) 3466, 3029, 2943,
1639, 1493, 1445, 1415, 1348, 1297, 1173, 1076, 1031, 747, 721, 700
cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C18H20NO]+ 266.1545,
found 266.1552.
General Procedure for α-tert-Butoxycarbonylation of Lactams
(1−6). Lithium bis(trimethylsilyl)amide 1.0 M in THF (20 mL, 19.9
mmol) was added slowly to a stirred solution of N(1)-benzhydryl-2-
piperidone (3.5 g, 13.3 mmol) in THF (35 mL) at −78 °C. Di-tert-butyl
dicarbonate (2.9 g, 13.3 mmol) in THF (5 mL) was added slowly to the
reaction mixture. After being stirred for 4 h, the reaction mixture was
quenched by addition of 0.1 M aqueous HCl. The reaction mixture was
diluted with ethyl acetate (250 mL), washed with brine (2 × 100 mL),
dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, hexane/
EtOAc = 8:1).
butoxycarbonyl lactams afforded α-alkyl-α-tert-butoxycarbonyl
lactams in high chemical (up to 99%) and optical yields (up to
98% ee). Our new catalytic system was successfully applied to
the synthesis of Nitraria alkaloids, namely, (+)-isonitramine,
(−)-isonitramine, (−)-sibirine, and (+)-nitramine. (+)-Isonitr-
amine and (−)-isonitramine were synthesized in 12 steps
(overall yield 43%, 98% ee; overall yield 41%, 98% ee,
respectively) from δ-valerolactam by enantioselective PTC 2-
bromoallylation, Dieckmann condensation, and diastereoselec-
tive reduction as key steps. (−)-Sibirine was synthesized by N-
ethoxycarbonylation of (−)-isonitramine followed by reduction
(overall yield 32% in 14 steps). The diastereoselective reduction
of (R)-2-benzhydryl-2-azaspiro[5.5]undecane-1,7-dione [(R)-
15] followed by reductive removal of the diphenylmethyl group
gave (+)-nitramine (overall yield 40% in 11 steps). The large-
scale synthesis of Nitraria alkaloids can aid in the investigation of
their systematic biological activities.
EXPERIMENTAL SECTION
General Methods. All reagents bought from commercial sources
were used as received. Organic solvents were concentrated under
■
reduced pressure using a Buchi rotary evaporator. Syringes, needles,
̈
and cannulae were oven-dried at 100 °C. As the commercially available
KOH was a pellet type, KOH should be ground to the powder form for
successful phase-transfer catalytic reaction and high enantiopurity.
Phase-transfer catalyst 12 was purchased from a commercial source
(Wako). TLC analyses were performed using Merck precoated TLC
plates (silica gel 60 GF254, 0.25 mm). Flash column chromatography
was carried out using E. Merck Kieselgel 60 (230−400 mesh).
Instruments (Hitachi, L-2130) and software (Hitachi, Version
LaChrom 8908800-07) were used for HPLC. The enantiomeric excess
(ee) of the products was determined by HPLC using 4.6 mm × 250 mm
Daicel Chiralpak AD-H column. Infrared (IR) spectra were recorded
on JASCO FT/IR-300E and PerkinElmer 1710 FT spectrometers.
Nuclear magnetic resonance (1H NMR and 13C NMR) spectra were
measured on JEOL JNM-LA 300 [300 MHz (1H), 75 MHz (13C)],
JEOL JNM-GSX 400 [400 MHz (1H), 100 MHz (13C)], and Bruker
AMX 500 [500 MHz (1H), 125 MHz (13C)] spectrometers using
CHCl3-d as solvent and are reported in ppm relative to CHCl3 (δ 7.24)
for 1H NMR and relative to the central CDCl3 (δ 77.23) resonance for
N(1)-Methyl-2-pyrrolidinone-3-carboxylic Acid tert-Butyl Ester
(1). Following the general procedure, the reaction was started from
N(1)-methyl-2-pyrrolidinone (1 mL, 10.3 mmol). After the mixture
was stirred for 4 h, 1 was obtained as a pale yellow oil (1.81 g, 88%
yield): 1H NMR (300 MHz, CDCl3) δ 3.47−3.39 (m, 1H), 3.32−3.22
(m, 2H), 2.82 (s, 3H), 2.34−2.11 (m, 2H), 1.43 (s, 9H) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 170.3, 169.6, 81.7, 47.8, 45.8, 29.8, 27.9,
22.5 ppm; IR (KBr) 3493, 2979, 1731, 1696, 1501, 1456, 1403, 1369,
1255, 1154, 844, 743 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C10H18NO3]+ 200.1287, found 200.1280.
N(1)-Benzyl-2-pyrrolidinone-3-carboxylic Acid tert-Butyl Ester (2).
Following the general procedure, the reaction was started from N(1)-
benzyl-2-pyrrolidinone (600 mg, 3.42 mmol). After the mixture was
stirred for 4 h, 2 was obtained as yellow oil (744 mg, 79% yield): 1H
NMR (300 MHz, CDCl3) δ 7.34−7.20 (m, 5H), 4.45 (q, J = 14.64 Hz,
2H), 3.38−3.32 (m, 2H), 3.22−3.14 (m, 1H), 2.34−2.11 (m, 2H), 1.47
(s, 9H) ppm; 13C{1H} NMR (126 MHz, CDCl3) δ 170.3, 169.5, 136.1,
128.7, 128.1, 127.6, 81.9, 49.6, 46.9, 45.2, 28.0, 22.3 ppm; IR (KBr)
3472, 2979, 2929, 1732, 1693, 1495, 1453, 1367, 1266, 1153, 1080, 843,
741, 702 cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C16H22NO3]+
276.1600, found 276.1603.
1
13C NMR. Coupling constants (J) in H NMR are reported in hertz.
Low-resolution mass spectra (MS) were recorded on a VG Trio-2 GC−
MS spectrometer, and high-resolution mass spectra (HRMS) were
measured on JEOL JMS-AX 505wA and JEOL JMS-HX/HX 110A
N(1)-Benzhydryl-2-pyrrolidinone-3-carboxylic Acid tert-Butyl
Ester (3). Following the general procedure, the reaction was started
from N(1)-benzhydryl-2-pyrrolidinone (700 mg, 2.78 mmol). After the
mixure was stirred for 4 h, 3 was obtained as a white solid (821 mg, 84%
yield): mp = 90−93 °C; 1H NMR (300 MHz, CDCl3) δ 7.33−7.18 (m,
10H), 6.56 (s, 1H), 3.41−3.33 (m, 1H), 3.09 (m, 1H), 2.29 (m, 1H),
2.20 (m, 1H), 1.46 (s, 9H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ
170.4, 169.4, 138.5, 138.2, 128.9, 128.6, 128.5, 128.1, 127.8, 127.5, 82.0,
59.0, 49.9, 42.9, 28.0, 22.6 ppm; IR (KBr) 2979, 1735, 1693, 1495,
1454, 1419, 1368, 1274, 1151, 1075, 1032, 842, 743, 701 cm−1; HRMS
(FAB) m/z [M + H]+ calcd for [C22H26NO3]+ 352.1913, found
352.1905.
N(1)-Methyl-2-piperidone-3-carboxylic Acid tert-Butyl Ester (4).
Following the general procedure, the reaction was started from N(1)-
methyl-2-piperidone (1 mL, 8.8 mmol). After the mixture was stirred
for 4 h, 4 was obtained as a pale yellow oil (1.46 g, 78% yield): 1H NMR
(300 MHz, CDCl3) δ 3.36−3.13 (m, 3H), 2.91 (s, 3H), 2.11−1.85 (m,
3H), 1.43 (s, 9H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 170.4,
166.3, 81.4, 49.9, 49.7, 34.8, 27.9, 25.2, 20.8 ppm; IR (KBr) 3485, 2940,
1731, 1647, 1504, 1455, 1394, 1367, 1331, 1257, 1210, 1152, 998, 850
cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C11H20NO3]+ 214.1443,
found 214.1447.
spectrometers. Melting points were measured on a Buchi B-540 melting
̈
point apparatus and are not corrected. Optical rotations were measured
on a JASCO DIP-1000 digital polarimeter. X-ray crystallographic data
was collected by Rigaku R-AXIS RAPID diffractometer using graphite-
monochromated Mo Kα radiation.
Enantioselective Synthesis of α-quaternary lactams. N(1)-
Benzhydryl-2-pyrrolidinone. γ-Butyrolactam (0.28 mL, 3.6 mmol), α-
bromodiphenylmethane (1.8 g, 7.2 mmol), and TBAB (129 mg, 0.4
mmol) were added to a 100 mL round-bottom flask. Toluene (10 mL)
and KOH (1 g, pellet type) were added, respectively, to the reaction
mixture. After being stirred for 24 h, the reaction mixture was diluted
with EtOAc (200 mL), washed with brine (2 × 100 mL), dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, hexane/EtOAc = 3:1)
to afford N(1)-benzhydryl-2-pyrrolidinone as a white solid (835 mg,
92% yield); mp = 136−139 °C; 1H NMR (300 MHz, CDCl3) δ 7.43−
7.22 (m, 10H), 6.68 (s, 1H), 3.25 (t, J = 6.96 Hz, 2H), 2.55 (t, J = 7.95
Hz, 2H), 2.13−2.03 (m, 2H) ppm; 13C{1H} NMR (126 MHz, CDCl3)
δ 175.0, 138.7, 129.1, 128.5, 128.5, 128.0, 127.6, 127.5, 58.5, 44.3, 31.1,
18.2 ppm; IR (KBr) 3029, 1686, 1495, 1453, 1416, 1282, 1215, 1077,
1031, 753, 737, 701 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C17H18NO]+ 252.1388, found 252.1397.
N(1)-Benzhydryl-2-piperidone. δ-Valerolactam (360 mg, 3.63
mmol), α-bromodiphenylmethane (1.8 g, 7.3 mmol), and TBAB
N(1)-Benzyl-2-piperidone-3-carboxylic Acid tert-Butyl Ester (5).
Following the general procedure, the reaction was started from N(1)-
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benzyl-2-piperidone (600 mg, 3.2 mmol). After the mixture was stirred
for 4 h, 5 was obtained as a pale yellow oil (743 mg, 81% yield): H
tert-Butyl (R)-1-Benzhydryl-3-benzyl-2-oxopyrrolidine-3-carbox-
ylate (3b). Following the general procedure, the reaction was started
from 3 (20 mg, 0.057 mmol) with benzyl bromide (0.033 mL, 0.29
mmol). After the mixture was stirred for 24 h, 3b was obtained as a pale
yellow viscous oil (23.9 mg, 95% yield). The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralcel OD-H,
1
NMR (300 MHz, CDCl3) δ 7.32−7.21 (m, 5H), 4.60 (dd, J1 = 97.8 Hz,
J2 = 14.82 Hz, 2H), 3.37 (t, J = 6.78 Hz, 1H), 3.28−3.12 (m, 2H), 2.15−
1.68 (m, 4H), 1.48 (s, 9H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ
170.4, 166.3, 137.0, 128.6, 127.9, 127.9, 127.3, 81.6, 50.2, 50.2, 47.0,
28.0, 25.3, 20.8 ppm; IR (KBr) 2936, 1730, 1647, 1494, 1453, 1367,
1256, 1151, 970, 850, 699 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C17H24NO3]+ 290.1756, found 290.1760.
N(1)-Benzhydryl-2-piperidone-3-carboxylic Acid tert-Butyl Ester
(6). Following the general procedure, the reaction was started from
N(1)-benzhydryl-2-piperidone (3.52 g, 13.26 mmol). After the mixture
was stirred for 4 h, 6 was obtained as a pale yellow oil (4.36 g, 90%
yield): 1H NMR (300 MHz, CDCl3) δ 7.36−7.19 (m, 11H), 3.44 (t, J =
6.48 Hz, 1H), 3.10−2.91 (m, 2H), 2.14−1.89 (m, 3H), 1.78−1.68 (m,
1H) 1.48 (s, 9H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 170.4,
166.6, 138.5, 138.4, 129.1, 128.6, 128.4, 128.4, 127.5, 127.3, 81.6, 59.8,
50.4, 43.8, 28.0, 24.9, 20.9 ppm; IR (KBr) 2977, 1730, 1644, 1495,
1454, 1392, 1367, 1256, 1148, 1078, 1032, 941, 850, 741, 700 cm−1;
HRMS (FAB) m/z [M + H]+ calcd for [C23H28NO3]+ 366.2069, found
366.2054.
General Procedure for Enantioselective Phase-Transfer Alkylation
of N-Protected tert-Butoxycarbonyl Lactams (1a−e−6a−e). Benzyl
bromide (0.06 mL, 0.5 mmol) was added to a solution of N(1)-methyl-
2-pyrrolidinone-3-carboxylic acid tert-butyl ester (1, 20 mg, 0.1 mmol)
and (S,S)-3,4,5-trifluorophenyl-NAS bromide (PTC 12, 4.6 mg, 0.005
mmol) in toluene (0.4 mL). At −40 °C, solid KOH (28 mg, 0.5 mmol)
was added to the reaction mixtures and stirred for 3 h. After the
powdered KOH was weighed, it was quickly added to the reaction
mixture. EYELA PSL-1400 was used for low-temperature stirring, and
the stirring rate was 7. The reaction mixture was diluted with ethyl
acetate (10 mL), washed with brine (2 × 2 mL), dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 10:1). The
absolute configurations were tentatively assigned as S or R based on the
absolute configurations of 1d and 6d confirmed by X-ray crystallo-
graphic analysis.
tert-Butyl (R)-3-Benzyl-1-methyl-2-oxopyrrolidine-3-carboxylate
(1b). Following the general procedure, the reaction was started from 1
(20 mg, 0.1 mmol) with benzyl bromide (0.06 mL, 0.5 mmol). After the
mxutre was stirred for 3 h, 1b was obtained as a pale yellow viscous oil
(27.6 mg, 95% yield). The enantioselectivity was determined by chiral
HPLC analysis (DAICEL Chiralcel OD-H, hexanes/2-propanol =
95:5), flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time, R
(major) 7.5 min, S (minor) 11.1 min, 94% ee: [α]D23 = +70.94 (c 0.43,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.29−7.19 (m, 5H), 3.20 (dd,
J1 = 63.6 Hz, J2 = 13.8 Hz, 2H), 3.24−3.16 (m, 1H), 2.75 (s, 3H), 2.60−
2.52 (m, 1H), 2.39−2.30 (m, 1H), 2.05−1.96 (m, 1H), 1.47 (s, 9H)
ppm; 13C{1H} NMR (126 MHz, CDCl3) δ 172.3, 170.9, 136.9, 130.1,
128.1, 126.7, 81.8, 57.3, 46.8, 38.9, 30.0, 27.9, 26.9 ppm; IR (KBr) 2977,
1734, 1694, 1497, 1454, 1403, 1368, 1254, 1160, 1032, 849, 703 cm−1;
HRMS (FAB) m/z [M + H]+ calcd for [C17H24NO3]+ 290.1756, found
290.1753.
hexanes/2-propanol = 95:5), flow rate = 1.0 mL/min, 23 °C, λ = 254
23
nm, retention time, major 5.6 min, minor 12.1 min, 68% ee. [α]D
=
+67.46 (c 0.32, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.38−7.20 (m,
13H), 6.87−6.84 (m, 2H), 6.60 (s, 1H), 3.30 (dd, J1 = 119.9 Hz, J2 =
13.74 Hz, 2H), 3.06−3.03 (m, 1H), 2.68−2.61 (m, 1H), 2.33−2.25 (m,
1H), 2.15−2.05 (m, 1H), 1.43 (s, 9H) ppm; 13C{1H} NMR (101 MHz,
CDCl3) δ 172.1, 171.0, 138.3, 138.0, 136.7, 130.6, 128.8, 128.4, 128.3,
128.3, 127.5, 127.3, 126.6, 81.9, 59.0, 57.5, 41.9, 38.3, 27.8, 26.6 ppm;
IR (KBr) 2978, 1736, 1689, 1495, 1452, 1422, 1368, 1256, 1157, 1100,
848, 738, 702 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C29H32NO3]+ 442.2382, found 442.2384.
tert-Butyl (S)-3-Benzyl-1-methyl-2-oxopiperidine-3-carboxylate
(4b). Following the general procedure, the reaction was started from
4 (20 mg, 0.094 mmol) with benzyl bromide (0.06 mL, 0.47 mmol).
After the mixture was stirred for 3 h, 4b was obtained as a pale yellow oil
(25.7 mg, 90% yield). The enantioselectivity was determined by chiral
HPLC analysis (DAICEL Chiralcel OD-H, hexanes/2-propanol =
95:5), flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time, major
6.7 min, minor 9.4 min, 65% ee: [α]D23 = +30.61 (c 0.71, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.29−7.22 (m, 5H), 3.64 (d, J = 13.35 Hz,
1H), 3.18−3.13 (m, 1H), 2.99−2.91 (m, 2H), 2.94 (s, 3H), 2.12−2.02
(m, 1H), 1.93−1.70 (m, 2H), 1.66−1.58 (m, 1H), 1.50 (s, 9H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 172.4, 168.6, 137.3, 130.8, 128.0,
126.5, 81.6, 55.8, 49.7, 40.9, 35.4, 29.6, 27.9, 19.9 ppm; IR (KBr) 2930,
1729, 1643, 1497, 1454, 1399, 1367, 1331, 1253, 1158, 1033, 850, 751,
704 cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C18H26NO3]+
304.1913, found 304.1910.
tert-Butyl (S)-1,3-Dibenzyl-2-oxopiperidine-3-carboxylate (5b).
Following the general procedure, the reaction was started from 5 (20
mg, 0.07 mmol) with benzyl bromide (0.042 mL, 0.35 mmol). After the
mixture was stirred for 24 h, 5b was obtained as a pale yellow oil (18.7
mg, 70% yield). The enantioselectivity was determined by chiral HPLC
analysis (DAICEL Chiralcel OD-H, hexanes/2-propanol = 95:5), flow
rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time, major 8.3 min,
23
1
minor 14.2 min, 75% ee: [α]D = +8.75 (c 0.40, CHCl3); H NMR
(300 MHz, CDCl3) δ 7.30−7.17 (m, 10 H), 4.58 (dd, J1 = 149.13 Hz, J2
= 14.76 Hz, 2H), 3.33 (dd, J1 = 222.51 Hz, J2 = 13.08 Hz, 2H), 3.11−
3.04 (m, 1H), 2.88−2.79 (m, 1H), 2.07−1.98 (m, 1H), 1.87−1.67 (m,
3H), 1.49 (s, 9H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 172.5,
168.5, 137.2, 137.1, 131.0, 128.4, 128.0, 128.0, 127.1, 126.5, 81.8, 56.0,
50.6, 47.0, 41.0, 29.6, 28.0, 19.9 ppm; IR (KBr) 2932, 1730, 1642, 1494,
1453, 1366, 1253, 1154, 1075, 1031, 850, 736, 702 cm−1; HRMS (FAB)
m/z [M + H]+ calcd for [C24H30NO3]+ 380.2226, found 380.2221.
tert-Butyl (S)-1-Benzhydryl-3-benzyl-2-oxopiperidine-3-carboxy-
late (6b). Following the general procedure, the reaction was started
from 6 (20 mg, 0.054 mmol) with benzyl bromide (0.032 mL, 0.27
mmol). After the mixture was stirred for 24 h, 6b was obtained as a
white solid (19.2 mg, 88% yield). The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralcel OD-H,
hexanes/2-propanol = 95:5), flow rate = 1.0 mL/min, 23 °C, λ = 254
nm, retention time, S (major) 5.2 min, R (minor) 10.1 min, 98% ee: mp
= 89−91 °C; [α]D23 = +71.61 (c 0.86, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.40−7.27 (m, 14H), 7.09−7.06 (m, 2H), 3.39 (dd, J1 =
244.95 Hz, J2 = 13.35 Hz, 2H), 3.03−2.96 (m, 1H), 2.61−2.53 (m, 1H),
2.09−1.82 (m, 4H), 1.44 (s, 9H) ppm; 13C{1H} NMR (76 MHz,
CDCl3) δ 172.4, 168.7, 138.5, 138.2, 137.0, 130.7, 129.1, 128.3, 128.1,
128.0, 128.0, 127.2, 127.0, 126.3, 81.6, 60.1, 55.8, 43.7, 41.3, 29.6, 27.8,
20.1 ppm; IR (KBr) 2935, 1733, 1637, 1495, 1454, 1367, 1293, 1253,
1149, 1032, 850, 751, 702 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C30H34NO3]+ 456.2539, found 456.2544.
tert-Butyl (R)-1,3-Dibenzyl-2-oxopyrrolidine-3-carboxylate (2b).
Following the general procedure, the reaction was started from 2 (20
mg, 0.072 mmol) with benzyl bromide (0.043 mL, 0.37 mmol). After
the mixture was stirred for 20 h, 2b was obtained as a white solid (24.3
mg, 92% yield). The enantioselectivity was determined by chiral HPLC
analysis (DAICEL Chiralcel OD-H, hexanes/2-propanol = 95:5), flow
rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time, major 8.7 min,
minor 14.4 min, 71% ee: mp = 98−101 °C; [α]D23 = +58.54 (c 1.12,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.30−7.20 (m, 8H), 7.11−
7.08 (m, 2H), 4.38 (dd, J1 = 101.37 Hz, J2 = 14.61 Hz, 2H); 3.25 (dd, J1
= 73.41 Hz, J2 = 13.74 Hz, 2H), 3.19−3.11 (m, 1H) 2.66−2.59 (m,
1H), 2.32−2.23 (m, 1H), 2.05−1.96 (m, 1H) 1.45 (s, 9H) ppm;
13C{1H} NMR (126 MHz, CDCl3) δ 172.1, 170.9, 136.9, 136.1, 130.4,
128.5, 128.2, 128.0, 127.4, 126.7, 81.9, 57.5, 46.9, 44.3, 38.7, 27.9, 26.8
ppm; IR (KBr) 2927, 1735, 1692, 1495, 1454, 1368, 1256, 1157, 1100,
848, 736, 702 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C23H28NO3]+ 366.2069, found 366.2081.
tert-Butyl (R)-3-Allyl-1-methyl-2-oxopyrrolidine-3-carboxylate
(1a). Following the general procedure, the reaction was started from
1 (20 mg, 0.1 mmol) with allyl bromide (0.042 mL, 0.5 mmol). After
the mixture was stirred for 8 h, 1a was obtained as yellow oil (22.0 mg,
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92% yield). The enantioselectivity was determined by chiral HPLC
analysis (DAICEL Chiralpak AD-H, hexanes/2-propanol = 98.5:1.5),
flow rate = 1.0 mL/min, 23 °C, λ = 217 nm, retention time, S (minor)
(m, 7H), 7.22−7.07 (m, 4H), 5.79−5.65 (m, 1H), 5.13−5.04 (m, 2H),
3.10−3.03 (m, 1H), 2.97−2.80 (m, 2H), 2.53−2.46 (m, 1H), 2.10−
1.92 (m, 2H), 1.84−1.58 (m, 2H), 1.44 (s, 9H) ppm; 13C{1H} NMR
(101 MHz, CDCl3) δ 172.1, 169.1, 138.8, 138.5, 133.9, 129.4, 128.4,
128.3, 127.5, 127.2, 118.9, 81.7, 60.1, 54.4, 43.7, 40.7, 29.5, 27.9, 20.1
ppm; IR (KBr) 2977, 1733, 1640, 1495, 1434, 1367, 1304, 1253, 1202,
1149, 1032, 1002, 919, 845, 739, 701 cm−1; HRMS (FAB) m/z [M +
H]+ calcd for [C26H32NO3]+ 406.2382, found 406.2372.
tert-Butyl (S)-1-Benzhydryl-3-(4-methylbenzyl)-2-oxopiperidine-
3-carboxylate (6c). Following the general procedure, the reaction
was started from 6 (20 mg, 0.054 mmol) with 4-methylbenzyl bromide
(50 mg, 0.27 mmol). After the mixture was stirred for 24 h, 6c was
obtained as a pale yellow solid (21.1 mg, 84% yield). The
enantioselectivity was determined by chiral HPLC analysis (DAICEL
Chiralcel OD-H, hexane/2-propanol = 95:5), flow rate = 1.0 mL/min,
23 °C, λ = 254 nm, retention time, S (major) 5.7 min, R (minor) 9.1
min, 98% ee: mp = 92−95 °C; [α]D23 = +26.39 (c 0.96, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.25−7.15 (m, 8H), 7.03−6.91 (m, 7H),
3.21 (dd, J1 = 243.24 Hz, J2 = 13.47 Hz, 2H), 2.83−2.79 (m, 1H), 2.43
(m, 1H), 2.25 (s, 3H), 1.92−1.78 (m, 4H), 1.42 (s, 9H) ppm; 13C{1H}
NMR (126 MHz, CDCl3) δ 172.7, 168.8, 138.7, 138.4, 136.0, 134.0,
130.8, 129.5, 128.8, 128.5, 128.3, 128.1, 127.3, 127.2, 81.8, 60.2, 56.0,
43.9, 41.0, 29.7, 28.0, 21.1, 20.3, 1.02 ppm; IR (KBr) 2930, 1734, 1638,
1495, 1455, 1367, 1291, 1254, 1149, 1117, 1032, 854, 804, 703 cm−1;
HRMS (FAB) m/z [M + H]+ calcd for [C31H36NO3]+ 470.2695, found
470.2691.
23
15.2 min, R (major) 16.6 min, 82% ee: [α]D = +23.71 (c 0.63,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 5.75−5.61 (m, 1H), 5.13−
5.06 (m, 2H), 3.41−3.36 (m, 1H), 3.25−3.20 (m, 1H), 2.85 (s, 3H),
2.68−2.61 (m, 1H), 2.51−2.44 (m, 1H), 2.34−2.28 (m, 1H), 2.04−
1.95 (m, 1H), 1.43 (s, 9H) ppm; 13C{1H} NMR (76 MHz, CDCl3) δ
172.2, 170.8, 133.6, 118.8, 81.7, 55.8, 47.1, 38.1, 27.9, 27.4 ppm; IR
(KBr) 2978, 2929, 1736, 1695, 1499, 1434, 1404, 1368, 1306, 1252,
1155, 1073, 1001, 920, 848 cm−1; HRMS (FAB) m/z [M + H]+ calcd
for [C13H22NO3]+ 240.1600, found 240.1606.
tert-Butyl (R)-1-methyl-3-(4-methylbenzyl)-2-oxopyrrolidine-3-
carboxylate (1c). Following the general procedure, the reaction was
started from 1 (20 mg, 0.1 mmol) with 4-methylbenzyl bromide (93
mg, 0.5 mmol). After the mixture was stirred for 6 h, 1c was obtained as
a pale yellow solid (32.0 mg, 99% yield). The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralcel OD-H,
hexanes/2-propanol = 99.5:0.5), flow rate = 1.0 mL/min, 23 °C, λ =
254 nm, retention time, R (major) 20.2 min, S (minor) 34.2 min, 94%
ee: mp = 96 °C; [α]D23 = +36.33 (c 1.50, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.08−7.01 (m, 4H), 3.13 (dd, J1 = 64.53 Hz, J2 = 13.83 Hz,
2H), 3.19−3.13 (m, 1H), 2.73 (s, 3H), 2.60−2.50 (m, 1H), 2.34−2.30
(m, 1H), 2.82 (s, 3H), 2.02−1.92 (m, 1H), 1.44 (s, 9H) ppm; 13C{1H}
NMR (126 MHz, CDCl3) δ 172.5, 171.1, 136.2, 133.7, 130.06, 128.9,
81.8, 57.4, 46.9, 38.5, 30.1, 27.9, 26.9, 21.0 ppm; IR (KBr) 2977, 2927,
1735, 1694, 1499, 1452, 1403, 1368, 1306, 1255, 1161, 1037, 848, 817
cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C18H26NO3]+ 304.1913,
found 304.1904.
tert-Butyl (S)-1-Benzhydryl-3-(4-bromobenzyl)-2-oxopiperidine-
3-carboxylate (6d). Following the general procedure, the reaction
was started from 6 (40 mg, 0.108 mmol) with 4-bromobenzyl bromide
(136 mg, 0.54 mmol). After the mixture was stirred for 24 h, 6d was
obtained as a white solid (52.5 mg, 91% yield). The enantioselectivity
was determined by chiral HPLC analysis (DAICEL Chiralcel OD-H,
hexane/2-propanol = 95:5), flow rate = 1.0 mL/min, 23 °C, λ = 217 nm,
retention time, S (major) 5.3 min, R (minor) 7.0 min, 96% ee: mp =
tert-Butyl (R)-3-(4-Bromobenzyl)-1-methyl-2-oxopyrrolidine-3-
carboxylate (1d). Following the general procedure, the reaction was
started from 1 (20 mg, 0.1 mmol) with 4-bromobenzyl bromide (125
mg, 0.5 mmol). After the mixture was stirred for 5 h, 1d was obtained as
a white solid (36.4 mg, 99% yield). The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralcel OD-H,
hexanes/2-propanol = 98:2), flow rate = 1.0 mL/min, 23 °C, λ = 254
nm, retention time, R (major) 12.0 min, S (minor) 13.7 min, 92% ee:
23
1
116−117 °C; [α]D = +17.39 (c 1.0, CHCl3); H NMR (300 MHz,
CDCl3) δ 7.29−7.25 (m, 8H), 7.21−7.19 (m, 3H), 7.06 (d, J = 8.4 Hz,
2H), 6.99−6.96 (m, 2H), 3.27 (dd, J1 = 244.4 Hz, J2 = 13.4 Hz, 2H),
2.96−2.92 (m, 1H), 2.55−2.49 (m, 1H), 2.00−1.76 (m, 4H), 1.47 (s,
9H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 172.4, 168.5, 138.5,
138.2, 136.1, 132.7, 131.2, 129.3, 128.4, 128.3, 128.3, 127.6, 127.3,
120.6, 82.1, 60.3, 55.9, 44.0, 40.8, 29.7, 28.0, 20.3 ppm; IR (KBr) 2933,
1733, 1637, 1486, 1455, 1367, 1253, 1149, 1074, 1032, 1013, 851, 811,
739, 702 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C30H33BrNO3]+ 534.1644, found 534.1633.
23
1
mp = 97−100 °C; [α]D = +65.03 (c 1.0, CHCl3); H NMR (300
MHz, CDCl3) δ 7.35 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 3.27−
3.24 (m, 1H), 3.17 (dd, J1 = 65.0 Hz, J2 = 13.9 Hz, 2H), 2.74 (s, 3H),
2.33−2.25 (m, 1H), 1.96−1.87 (m, 1H), 1.43 (s, 9H) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 172.1, 170.7, 136.0, 132.0, 131.3, 120.8,
82.1, 57.2, 46.9, 38.1, 30.1, 27.9, 26.8 ppm; IR (KBr) 2977, 2928, 1734,
1694, 1488, 1454, 1404, 1368, 1304, 1255, 1157, 1105, 1073, 1013, 848
cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C17H23BrNO3]+
368.0861, found 368.0856;.
tert-Butyl (S)-1-Benzhydryl-3-(naphthalen-2-ylmethyl)-2-oxopi-
peridine-3-carboxylate (6e). Following the general procedure, the
reaction was started from 6 (20 mg, 0.054 mmol) with 2-
(bromomethyl)naphthalene 96% (60 mg, 0.27 mmol). After the
mixture was stirred for 24 h, 6e was obtained as a white solid (21.4 mg,
78% yield). The enantioselectivity was determined by the correspond-
ing methyl ester of (S)-66e: mp = 156−158 °C; [α]D23 = +4.44 (c 1.0,
tert-Butyl (R)-1-Methyl-3-(naphthalen-2-ylmethyl)-2-oxopyrroli-
dine-3-carboxylate (1e). Following the general procedure, the reaction
was started from 1 (20 mg, 0.1 mmol) with 2-(bromomethyl)-
naphthalene 96% (115 mg, 0.5 mmol). After the mixture was stirred for
24 h, 1e was obtained as a white solid (30.1 mg, 89% yield). The
enantioselectivity was determined by the corresponding methyl ester of
(R)-1e: mp = 143−145 °C; [α]D23 = +96.58 (c 0.25, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.80−7.64 (m, 4H), 7.46−7.30 (m, 3H), 3.35
(dd, J1 = 63.03 Hz, J2 = 13.8 Hz, 2H), 3.21−3.13 (m, 1H), 2.72 (s, 3H),
2.56−2.48 (m, 1H), 2.38−2.29 (m, 1H), 2.08−1.99 (m, 1H), 1.46 (s,
9H) ppm; 13C{1H} NMR (126 MHz, CDCl3) δ 172.4, 171.0, 134.6,
133.3, 132.3, 128.9, 128.5, 127.7, 127.6, 127.6, 126.0, 125.6, 81.9, 57.5,
47.0, 39.0, 30.1, 28.0, 27.0 ppm; IR (KBr) 2976, 1733, 1692, 1498,
1452, 1403, 1368, 1253, 1157, 847, 752 cm−1; HRMS (FAB) m/z [M +
H]+ calcd for [C21H26NO3]+ 340.1913, found 340.1911.
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.80−6.86 (m, 18H), 3.49
(dd, J1 = 249.63 Hz, J2 = 13.29 Hz, 2H), 2.90−2.85 (m, 1H), 2.41−2.40
(m, 1H), 2.21−1.89 (m, 4h) ppm; 13C{1H} NMR (126 MHz, CDCl3) δ
172.7, 168.7, 138.6, 138.3, 134.9, 133.3, 132.4, 129.7, 129.3, 129.2,
128.4, 128.3, 128.2, 127.9, 127.7, 127.6, 127.3, 127.2, 125.8, 125.5, 82.0,
60.2, 56.2, 44.0, 41.5, 29.9, 28.0, 20.3 ppm; IR (KBr) 2933, 1732, 1638,
1495, 1454, 1367, 1252, 1150, 824, 751, 701 cm−1; HRMS (FAB) m/z
[M + H]+ calcd for [C34H36NO3]+ 506.2695, found 506.2709.
Methyl (R)-1-Methyl-3-(naphthalen-2-ylmethyl)-2-oxopyrroli-
dine-3-carboxylate (1e′). Trifluoroacetic acid (1 mL) was added to
a solution of 1e (20 mg, 0.059 mmol) in dichloromethane (1 mL). The
reaction mixture was stirred for 1 h at room temperature and
concentrated in vacuo. The reaction mixture was used for the next
step without purification. Toluene/methanol = 5:2 solution (1 mL) and
(trimethylsilyl)diazomethane 2.0 M in diethyl ether solution (0.096
mL, 0.19 mmol) were added, respectively, to the reaction mixture. The
reaction mixture was stirred for 1 h and quenched with AcOH, and the
solvent was evaporated. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 3:1) to afford 1e′ as a
tert-Butyl (S)-3-Allyl-1-benzhydryl-2-oxopiperidine-3-carboxy-
late (6a). Following the general procedure, the reaction was started
from 6 (20 mg, 0.054 mmol) with allyl bromide (0.023 mL, 0.27
mmol). After the mixture was stirred for 24 h, 6a was obtained as a white
solid (19.1 mg, 87% yield). The enantioselectivity was determined by
chiral HPLC analysis (DAICEL Chiralpak AD-H, hexanes/2-propanol
= 90:10), flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time, S
23
(major) 8.1 min, R (minor) 13.6 min, 87% ee: mp = 66−68 °C; [α]D
1
= +36.53 (c 0.6, CHCl3); H NMR (300 MHz, CDCl3) δ 7.35−7.26
4384
https://dx.doi.org/10.1021/acs.joc.0c02573
J. Org. Chem. 2021, 86, 4375−4390

The Journal of Organic Chemistry
pubs.acs.org/joc
Featured Article
1
white solid (18.4 mg, 99% yield). The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralpak AD-H,
hexanes/2-propanol = 95:5), flow rate = 1.0 mL/min, 23 °C, λ = 254
nm, retention time, R (major) 26.4 min, S (minor) 37.2 min, 91% ee:
mp = 119−122 °C; [α]D23 = +73.12 (c 0.82, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.80−7.64 (m, 4H), 7.47−7.40 (m, 2H), 7.30 (dd, J1 =
8.43 Hz, J2 = 1.65 Hz, 1H), 3.78 (s, 3H), 3.40 (dd, J1 = 58.41 Hz, J2 =
13.74 Hz, 2H), 3.20−3.12 (m, 1H), 2.72 (s, 3H), 2.51−2.39 (m, 2H),
2.14−2.04 (m, 1H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 172.3,
171.8, 134.0, 133.4, 132.4, 128.8, 128.3, 127.8, 127.7, 127.6, 126.1,
125.7, 56.9, 52.8, 46.8, 39.5, 30.1, 27.0 ppm; IR (KBr) 3473, 2952,
1739, 1691, 1499, 1435, 1404, 1243, 1104, 863, 825, 751 cm−1; HRMS
(FAB) m/z [M + H]+ calcd for [C18H20NO3]+ 298.1443, found
298.1452.
Methyl (S)-1-Benzhydryl-3-(naphthalen-2-ylmethyl)-2-oxopiper-
idine-3-carboxylate (6e′). Trifluoroacetic acid (1 mL) was added to a
solution of 6e (20 mg, 0.0395 mmol) in dichloromethane (1 mL). The
reaction mixture was stirred for 1 h at room temperature and
concentrated in vacuo. The reaction mixture was used for the next
step without purification. Toluene/methanol = 5:2 solution (1 mL) and
(trimethylsilyl)diazomethane 2.0 M in diethyl ether solution (0.096
mL, 0.19 mmol) were added, respectively, to the reaction mixture. The
reaction mixture was stirred for 1 h and quenched with AcOH, and the
solvent was evaporated. The residue was purified by column
chromatography (silica gel, hexanes/EtOAc = 3:1) to afforded 6e′ as
a white solid (18.1 mg, 99% yield). The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralpak AD-H,
hexanes/2-propanol = 85:15), flow rate = 1.0 mL/min, 23 °C, λ = 254
nm, retention time, R (minor) 21.3 min, S (major) 67.3 min, 98% ee:
mp = 51−53 °C; [α]D23 = −3.58 (c 0.69, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.82−7.65 (m, 5H), 7.49−7.44 (m, 2H), 7.35−7.26 (m, 4H),
7.23−7.14 (m, 3H), 7.09−7.04 (m, 2H), 6.95−6.93 (m, 2H), 3.57 (dd,
J = 243.06 Hz, J = 13.29 Hz, 2H), 3.81 (s, 3H), 2.91−2.87 (m, 1H),
2.48−2.39 (m, 1H), 2.07−1.79 (m, 4H) ppm; 13C{1H} NMR (76
MHz, CDCl3) δ 174.2, 168.4, 138.5, 138.2, 134.5, 133.4, 132.4, 129.6,
129.3, 129.2, 128.4, 128.3, 128.2, 127.9, 127.7, 127.5, 127.4, 127.2,
125.9, 125.6, 60.5, 56.0, 52.7, 44.1, 41.2, 29.8, 20.1 ppm; IR (KBr) 2926,
2854, 1739, 1637, 1495, 1455, 1356, 1242, 1201, 1120, 821, 752, 700
cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C31H30NO3]+ 464.2226,
found 464.2237.
min, R (minor) 13.6 min, 98% ee: mp = 66−68 °C; H NMR (300
MHz, CDCl3) δ 7.35−7.26 (m, 7H), 7.22−7.07 (m, 4H), 5.79−5.65
(m, 1H), 5.13−5.04 (m, 2H), 3.10−3.03 (m, 1H), 2.97−2.80 (m, 2H),
2.53−2.46 (m, 1H), 2.10−1.92 (m, 2H), 1.84−1.58 (m, 2H), 1.44 (s,
9H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 169.1, 138.8,
138.5, 133.91, 129.4, 128.4, 128.3, 127.5, 127.2, 118.9, 81.7, 60.1, 54.4,
43.7, 40.7, 29.5, 27.9, 20.1 ppm; IR (KBr) 2977, 1733, 1640, 1495,
1434, 1367, 1304, 1253, 1202, 1149, 1032, 1002, 919, 845, 739, 701
cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C26H32NO3]+ 406.2382,
found 406.2372.
Ethyl Ethoxythiocarbonylsulfanylacetate. To the solution of
ethylchloroacetate (1 mL, 9.38 mmol) in acetone (20 mL) was
added potassium ethyl xanthogenate (1.8 g, 11.26 mmol). The resulting
mixture was stirred at room temperature for 0.5 h. The reaction mixture
was diluted with ethyl acetate (100 mL), washed with brine (2 × 20
mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
hexane/EtOAc = 60:1) to afford xanthate (1.8 g, 92% yield) as a yellow
oil: 1H NMR (300 MHz, CDCl3) δ 4.62 (q, J = 7.1 Hz, 2H), 4.19 (q, J =
7.1 Hz, 2H), 3.89 (s, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz,
3H) ppm; 13C{1H} NMR (126 MHz, CDCl3) δ 212.6, 167.8, 70.5,
61.9, 37.9, 14.1, 13.6 ppm; IR (KBr) 2982, 1740, 1444, 1366, 1297,
1229, 1152, 1113, 1050, 890, 864 cm−1; HRMS (FAB) m/z [M + H]+
calcd for [C7H13O3S2]+ 209.0306, found 209.0297.
tert-Butyl (3S)-1-Benzhydryl-3-{5-ethoxy-2-[(ethoxycarbono-
thioyl)thio]-5-oxopentyl}-2-oxopiperidine-3-carboxylate [(S)-17].
Under argon gas, ethyl ethoxythiocarbonylsulfanylacetate (471 mg,
2.26 mmol) was added to a stirred solution of (S)-6a (460 mg, 1.13
mmol) and lauroyl peroxide (84 mg, 0.21 mmol) in dry 1,2-
dichloroethane (5 mL). The reaction mixture was refluxed for 2.5 h.
The reaction mixture was cooled to room temperature and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 15:1) to afford (S)-17
(613 mg, 88% yield) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ
7.37−7.25 (m, 11H), 4.60−4.51 (m, 2H), 4.06 (q, J = 7.1 Hz, 2H),
3.70−3.64 (m, 1H), 3.17−3.11 (m, 1H), 3.03−2.96 (m, 1H), 2.61−
1.65 (m, 10 H), 1.44 (s, 9H), 1.36 (q, J = 7.1 Hz, 3H), 1.21 (q, J = 7.1
Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 214.2, 213.9,
173.0, 172.0, 171.8, 169.0, 168.6, 138.9, 138.5, 138.4, 129.7, 129.7,
128.5, 128.4, 128.3, 128.2, 127.7, 127.4, 127.1, 82.3, 82.2, 69.9, 61.8,
60.4, 60.3, 55.5, 54.8, 47.5, 47.0, 44.0, 43.9, 38.9, 37.9, 32.0, 31.4, 31.2,
31.1, 29.46, 28.5, 27.9, 27.9, 20.2, 20.2, 14.2, 13.8 ppm; IR (KBr) 2979,
1732, 1639, 1454, 1368, 1294, 1214, 1150, 1112, 1051, 846, 739, 702
cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C33H44NO6S2]+
614.2610, found 614.2605.
tert-Butyl (R)-1-Benzhydryl-3-(5-ethoxy-5-oxopentyl)-2-oxopi-
peridine-3-carboxylate [(R)-14]. Under argon gas, tributyltin hydride
(0.26 mL, 0.98 mmol) was added to a stirred solution of (S)-17 (500
mg, 0.82 mmol) in dry toluene (10 mL). AIBN (27 mg, 0.164 mmol)
was added to the reaction mixture, and the mixture was refluxed for 1 h.
The reaction mixture was cooled to room temperature and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 10:1) to afford (R)-14
(389 mg, 96% yield) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ
7.36−7.18 (m, 11H), 4.09 (q, J = 7.1 Hz, 2H), 3.11−3.05 (m, 1H),
2.91−2.84 (m, 1H), 2.30−2.25 (m, 2H), 2.11−1.96 (m, 3H), 1.84
∼.160 (m, 7H), 1.43 (s, 9H), 1.25−1.20 (m, 3H) ppm; 13C{1H} NMR
(101 MHz, CDCl3) δ 173.7, 172.4, 169.5, 138.9, 138.5, 129.3, 128.4,
128.3, 128.3, 127.6, 127.7, 81.6, 60.2, 60.0, 54.8, 43.7, 35.9, 34.2, 29.8,
27.9, 25.3, 24.0, 20.3, 14.2 ppm; IR (KBr) 2933, 1734, 1641, 1495,
1455, 1368, 1295, 1251, 1156, 1032, 848, 738, 702 cm−1; HRMS (FAB)
m/z [M + H]+ calcd for [C30H40NO5]+ 494.2906, found 494.2915.
Methyl (R)-1-Benzhydryl-3-(5-ethoxy-5-oxopentyl)-2-oxopiperi-
dine-3-carboxylate [(R)-18]. Trifluoroacetic acid (2 mL) was added
to a solution of (R)-14 (490 mg, 0.99 mmol) in dichloromethane (2
mL). The reaction mixture was stirred for 0.5 h at room temperature
and concentrated in vacuo. The residue was used for the next step
without purification. Toluene/methanol = 5:2 solution (4 mL) and
(trimethylsilyl)diazomethane 2.0 M in diethyl ether solution (1.65 mL,
3.3 mmol) were added, respectively, to the reaction mixture. The
Synthesis of (+)-Isonitramine. tert-Butyl (S)-1-Benzhydryl-3-(2-
bromoallyl)-2-oxopiperidine-3-carboxylate [(S)-16]. Following the
synthetic procedure of compound 6a, the reaction was started from 6
(100 mg, 0.274 mmol) with 2,3-dibromopropene (0.13 mL, 1.37
mmol). After the mixture was stirred for 24 h, (S)-16 was obtained as a
white solid (126.1 mg, 95% yield). The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralpak AD-H,
hexane/2-propanol = 90:10), flow rate = 1.0 mL/min, 23 °C, λ = 254
nm, retention time, S (major) 7.2 min, R (minor) 14.5 min, 98% ee: mp
23
1
= 75−77 °C; [α]D = +21.45 (c 1.0, CHCl3); H NMR (300 MHz,
CDCl3) δ 7.42−7.14 (m, 11H), 5.57 (d, J = 51.3 Hz, 2H), 3.25 (dd, J1 =
171.57 Hz, J2 = 14.9 Hz, 2H), 3.20−3.13 (m, 1H), 2.98−2.89 (m, 1H),
2.29−2.02 (m, 3H), 1.84−1.76 (m, 1H), 1.45 (s, 9H) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 171.6, 168.1, 138.7, 138.2, 129.8, 128.6,
128.3, 128.3, 128.2, 127.7, 127.1, 121.8, 82.3, 60.5, 55.1, 45.9, 44.0,
29.1, 27.9, 20.5 ppm; IR (KBr) 2934, 1731, 1640, 1496, 1455, 1431,
1393, 1368, 1254, 1202, 1148, 1032, 900, 843, 740, 701 cm−1; HRMS
(FAB) m/z [M + H]+ calcd for [C26H31BrNO3]+ 484.1487, found
484.1494.
tert-Butyl (S)-3-Allyl-1-benzhydryl-2-oxopiperidine-3-carboxy-
late [(S)-6a]. Under argon gas, tributyltin hydride (0.42 mL, 1.6l
mmol) was added to a stirred solution of (S)-16 (650 mg, 1.34 mmol)
in dry toluene (10 mL). AIBN (44 mg, 0.268 mmol) was added to the
reaction mixture, and the mixture was refluxed for 3 h. The reaction
mixture was cooled to room temperature and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
hexanes/EtOAc = 20:1) to afford (S)-6a (516 mg, 95% yield) as a pale
yellow solid. The enantioselectivity was determined by chiral HPLC
analysis (DAICEL Chiralpak AD-H, hexane/2-propanol = 90:10), flow
rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time, S (major) 8.1
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reaction mixture was stirred for 0.5 h and quenched with AcOH, and the
solvent was evaporated. The residue was purified by column
chromatography (silicagel, hexane/EtOAc = 5:1) to afford (R)-18
(440 mg, 98% yield) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ
7.36−7.18 (m, 11H), 4.09 (q, J = 7.1 Hz, 2H), 3.72 (s, 3H), 3.11−3.04
(m, 1H), 2.91−2.83 (m, 1H), 2.31−2.26 (m, 2H), 2.16−1.57 (m,
10H), 1.26−1.20 (m, 3H) ppm; 13C{1H} NMR (76 MHz, CDCl3) δ
173.9, 173.6, 169.1, 138.8, 138.5, 129.4, 128.5, 128.4, 128.2, 127.6,
127.2, 60.3, 60.2, 54.5, 52.5, 44.0, 35.7, 34.1, 29.8, 25.3, 24.1, 20.2, 14.2
ppm; IR (KBr) 2951, 1734, 1641, 1494, 1454, 1244, 1201, 1119, 1031,
738, 702 cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C27H34NO5]+
452.2437, found 452.2443.
mixture was quenched with addition of one drop of saturated aqueous
NH4Cl solution and 50% aqueous NaOH solution alternately until no
hydride remained. The suspension was filtered, and the precipitate was
washed with dichloromethane (50 mL), dried over anhydrous K2CO3,
filtered again, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 20:1) to afford
(R,R)-21 (69 mg, 90% yield) as a white solid: mp = 103−105 °C; 1H
NMR (300 MHz, CDCl3) δ 7.43−7.13 (m, 11H), 4.10 (s, 1H), 3.54
(dd, J1 = 11.1 Hz, J2 = 3.6 Hz, 1H), 2.93 (d, J = 10.8 Hz, 1H), 2.72 (d, J =
11.4 Hz, 1H), 2.26−2.08 (m, 2H), 1.88−0.77 (m, 12H) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 142.4, 142.3, 128.9, 128.7, 128.5, 127.6,
127.5, 127.1, 127.1, 126.5, 80.2, 66.3, 53.4, 37.4, 29.5, 28.6, 24.3, 23.2,
20.4 ppm; IR (KBr) 3334, 3027, 2927, 2856, 1598, 1493, 1452, 1305,
1174, 1091, 1028, 969, 881, 760, 746, 704 cm−1; HRMS (FAB) m/z [M
+ H]+ calcd for [C23H30NO]+ 336.2327, found 336.2321.
Ethyl (6S)-2-Benzhydryl-1,7-dioxo-2-azaspiro[5.5]undecane-8-
carboxylate [(S)-19]. To the solution of (R)-18 (400 mg, 0.886
mmol) in dry THF (5 mL) at 0 °C under argon gas was slowly added
LHMDS 1.0 M solution in THF (1.8 mL, 1.8 mmol). The resulting
mixture was stirred for 0.5 h. The reaction mixture was quenched with
saturated NH4Cl solution and diluted with ethyl acetate (50 mL),
washed with brine (2 × 10 mL), dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 6:1) to afford (S)-19 (364
(+)-Isonitramine. To the mixture of (R,R)-21 (53 mg, 0.15 mmol)
and palladium hydroxide on carbon (10 mg, 20 wt %) in dry MeOH (2
mL) was added H2 gas. The resulting mixture was stirred for 3 h. The
reaction mixture was filtered by Celite 545, washed with MeOH, and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, CHCl3/MeOH:25% aq. NH4OH =
46:50:4) to afford (+)-isonitramine (23 mg, 87% yield) as a white
1
mg, 98% yield) as a pale yellow oil: H NMR (300 MHz, CDCl3) δ
23
1
7.36−7.09 (m, 11H), 4.26−4.07 (m, 2H), 3.04−2.94 (m, 2H), 2.37−
2.20 (m, 4H), 2.04−1.46 (m, 7H), 1.30−1.20 (m, 3H) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 172.8, 172.7, 172.0, 138.8, 138.6, 129.6,
129.1, 128.9, 128.6, 128.4, 128.4, 127.3, 99.2, 60.5, 48.7, 44.5, 34.0,
32.5, 22.5, 20.1, 18.4, 14.3 ppm; IR (KBr) 2940, 1740, 1638, 1495,
1453, 1398, 1375, 1300, 1246, 1207, 1032, 920, 813, 754, 702 cm−1;
HRMS (FAB) m/z [M + H]+ calcd for [C26H30NO4]+ 420.2175, found
420.2171.
solid; mp = 102−104 °C; [α]D = +6.22 (c 1.16, CHCl3); H NMR
(400 MHz, CDCl3) δ 3.8−3.3 (br s, 2H), 3.62 (dd, J1 = 11.2 Hz, J2 = 3.4
Hz, 1H), 3.02−3.00 (m, 1H), 2.92 (d, J = 11.2 Hz, 1H), 2.59 (td, J1 =
11.2 Hz, J2 = 3.1 Hz, 1H), 2.49 (d, J = 11.2 Hz, 1H), 2.22−2.19 (m,
1H), 2.09−1.97 (m, 1H),1.70−1.67 (m, 2H), 1.56−1.46 (m, 2H),
1.38−1.33 (m, 2H), 1.29−1.12 (m, 3H), 1.09−1.05 (m, 1H), 0.97−
0.90 (m, 1H) ppm; 13C{1H} NMR (126 MHz, CDCl3) δ 79.7, 59.3,
46.6, 36.3, 36.2, 29.9, 28.0, 24.3, 22.2, 20.2 ppm; IR (KBr) 3376, 2930,
2858, 1590, 1451, 1358, 1283, 1135, 1066, 993, 885, 839 cm−1; HRMS
(FAB) m/z [M + H]+ calcd for [C10H20NO]+ 170.1545, found
170.1543.
(S)-2-Benzhydryl-2-azaspiro[5.5]undecane-1,7-dione [(S)-15]. To
the solution of (S)-19 (300 mg, 0.715 mmol) in MeOH (2 mL) was
added 50% aqueous KOH solution (2 mL). Resulting mixture was
refluxed for 2 h. The reaction mixture was evaporated, diluted with
dichloromethane (50 mL), washed with brine (2 × 10 mL), dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, hexane/EtOAc = 6:1)
Synthesis of (−)-Isonitramine. tert-Butyl (R)-1-Benzhydryl-3-(2-
bromoallyl)-2-oxopiperidine-3-carboxylate [(R)-16]. 2,3-Dibromo-
propene (0.14 mL, 1.37 mmol) was added to a solution of N(1)-
benzhydryl-2-piperidone-3-carboxylic acid tert-butyl ester 6 (100 mg,
0.274 mmol) and (R,R)-3,4,5-trifluorophenyl-NAS bromide [(R,R)-12,
12.5 mg, 0.014 mmol] in toluene (1.0 mL). At −40 °C, solid KOH
(76.8 mg, 1.37 mmol) was added to the reaction mixture and stirred for
24 h. EYELA PSL-1400 was used for low-temperature stirring, and the
stirring rate was 7. The reaction mixture was diluted with ethyl acetate
(10 mL), washed with brine (2 × 2 mL), dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. After purification by column
chromatography (silica gel, hexane/EtOAc = 20:1), compound (R)-16
was obtained as a pale yellow oil (123.7 mg, 93% yield). The
enantioselectivity was determined by chiral HPLC analysis (DAICEL
Chiralpak AD-H, hexane/2-propanol = 90:10), flow rate = 1.0 mL/min,
23 °C, λ = 254 nm, retention time, S (minor) = 7.1 min, R (major) =
13.0 min, 98% ee: [α]D20 = −14.9 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.21−7.34 (m, 11H), 5.66 (s, 1H), 5.49 (d, J = 1.4 Hz, 1H),
3.55 (d, J = 14.6 Hz, 1H), 3.14−3.20 (m, 1H), 2.92−3.00 (m, 2H),
2.03−2.16 (m, 3H), 1.76−1.82 (m, 1H), 1.46 (s, 9H) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 171.8, 168.2, 139.0, 138.4, 130.0, 128.8,
128.5, 128.5, 128.4, 127.9, 127.4, 122.0, 82.5, 60.7, 55.3, 46.1, 44.2,
29.3, 28.2, 20.7 ppm; IR (KBr) 3726, 2978, 2934, 2359, 2298, 1731,
1642, 1432, 1368, 1254, 1149, 772, 701 cm−1; HRMS (FAB) m/z [M +
H]+ calcd for [C26H31BrNO3]+ 484.1487, found 484.1493.
tert-Butyl (R)-3-Allyl-1-benzhydryl-2-oxopiperidine-3-carboxy-
late [(R)-6a]. Under argon gas, tributyltin hydride (0.33 mL, 1.24
mmol) was added to a stirred solution of (R)-16 (500 mg, 1.03 mmol)
in dry toluene (8 mL). AIBN (0.2 M in toluene, 1.03 mL, 0.206 mmol)
was added to the reaction mixture, and the mixture was refluxed for 3 h.
The reaction mixture was cooled to room temperature and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 20:1) to afford (R)-6a
(403 mg, 96% yield) as a clear oil. The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralpak AD-H,
hexane/2-propanol = 90:10), flow rate = 1.0 mL/min, 23 °C, λ = 254
nm, retention time, S (minor) = 7.8 min, R (major) = 12.8 min, 98% ee:
23
to afford (S)-15 (231 mg, 93% yield) as a pale yellow viscous oil: [α]D
= +28.39 (c 0.85, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.36−7.19
(m, 11H), 3.09−3.01 (m, 1H), 2.88−2.79 (m, 1H), 2.70−2.56 (m,
2H), 2.52−2.42 (m, 1H), 2.38−2.30 (m, 1H), 2.03−1.57 (m, 8H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 210.7, 170.1, 138.9, 138.4,
129.5, 128.4, 128.4, 127.5, 127.1, 60.5, 58.2, 43.9, 38.9, 37.2, 31.0, 29.7,
26.4, 20.7, 19.4 ppm; IR (KBr) 2927, 2865, 1705, 1634, 1494, 1452,
1349, 1299, 1180, 1134, 1080, 735, 702 cm−1; HRMS (FAB) m/z [M +
H]+ calcd for [C23H26NO2]+ 348.1964, found 348.1951.
(6S,7R)-2-Benzhydryl-7-hydroxy-2-azaspiro[5.5]undecan-1-one
[(S,R)-20]. To the solution of (S)-15 (110 mg, 0.317 mmol) in dry THF
(3 mL) at −78 °C under argon gas was slowly added DIBALH 1 M in
THF solution (0.95 mL, 0.95 mmol). The resulting mixture was stirred
for 0.5 h. The reaction mixture was quenched with saturated NaHSO4
solution, diluted with dichloromethane (25 mL), washed with brine (2
× 5 mL), dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography (silica gel,
hexanes/EtOAc = 3:1) to afford (S,R)-20 (103 mg, 93% yield, dr =
50:1) as a colorless oil. The enantioselectivity was determined by chiral
HPLC analysis (DAICEL Chiralpak AD-H, hexanes/2-propanol =
90:10), flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time,
1
6S,7R (major) 11.9 min, 6R,7S (minor) 23.3 min, 98% ee: H NMR
(300 MHz, CDCl3) δ 7.34−7.13 (m, 11H), 4.34−4.30 (m, 1H), 2.98−
2.94 (m, 2H), 2.15−1.35 (m, 12H) ppm; 13C{1H} NMR (101 MHz,
CDCl3) δ 175.4, 139.1, 138.9, 129.0, 128.5, 128.4, 127.3, 127.3, 73.9,
60.7, 49.1, 44.3, 33.2, 29.7, 29.0, 24.4, 21.9, 19.9, 8.6 ppm; IR (KBr)
3420, 2927, 2858, 1735, 1611, 1495, 1452, 1357, 1293, 1199, 1058, 735,
704 cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C23H28NO2]+
350.2120, found 350.2108.
(6R,7R)-2-Benzhydryl-2-azaspiro[5.5]undecan-7-ol [(R,R)-21]. To
the solution of (S,R)-20 (80 mg, 0.229 mmol) in dry THF (2 mL)
under argon gas was slowly added LiAlH4 1 M in THF solution (2.3 mL,
2.3 mmol). The resulting mixture was refluxed for 1 h. The reaction
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Featured Article
[α]D20 = −33.6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.19−
7.35 (m, 11H), 5.66−5.77 (m, 1H), 5.04−5.12 (m, 2H), 3.04−3.09 (m,
1H), 2.81−2.90 (m, 2H), 2.50 (dd, J1 = 13.7 Hz, J2 = 8.2 Hz, 1H),
1.94−2.06 (m, 2H), 1.77−1.84 (m, 1H), 1.66−1.75 (m, 1H), 1.44 (s,
9H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 172.4, 169.3, 139.0,
138.7, 134.1, 129.6, 128.6, 128.5, 128.5, 127.8, 127.4, 119.2, 82.0, 60.3,
54.6, 44.0, 40.9, 29.7, 28.1, 20.3 ppm; IR (KBr) 2976, 2934, 1732, 1641,
1496, 1455, 1368, 1253, 1149, 919, 845, 701 cm−1; HRMS (FAB) m/z
[M + H]+ calcd for [C26H32NO3]+ 406.2382, found 406.2383.
tert-Butyl (3R)-1-Benzhydryl-3-{5-ethoxy-2-[(ethoxycarbono-
thioyl)thio]-5-oxopentyl}-2-oxopiperidine-3-carboxylate [(R)-17].
Under argon gas, ethyl ethoxythiocarbonylsulfanylacetate (1.23 g,
5.92 mmol) was added to a stirred solution of (R)-6a (1.2 g, 2.96
mmol) and lauroyl peroxide (236 mg, 0.59 mmol) in dry 1,2-
dichloroethane (13 mL). The reaction mixture was refluxed for 2.5 h.
The reaction mixture was cooled to room temperature and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 15:1) to afford (R)-17
(1.62 g, 89% yield) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ
7.19−7.33 (m, 11H), 4.51−4.67 (m, 2H), 4.10 (qd, J1 = 7.2 Hz, J2 = 3.7
Hz, 2H), 3.90−3.98 (m, 1H), 3.06−3.11 (m, 1H), 2.85−2.92 (m, 1H),
2.36−2.56 (m, 4 H), 2.09−2.21 (m, 2H), 1.84−2.07 (m, 3H), 1.72−
1.79 (m, 1H), 1.42 (s, 9H), 1.38 (t, J = 7.1 Hz, 3H), 1.21−1.25 (m, 3H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 214.4, 173.2, 172.1, 169.2,
139.1, 138.8, 129.9, 128.6, 128.5, 127.7, 127.4, 82.5, 70.1, 60.6, 60.6,
55.0, 47.2, 44.1, 38.1, 32.2, 31.6, 29.9, 28.7, 28.1, 20.5, 14.4, 14.0 ppm;
IR (KBr) 2979, 2932, 1732, 1640, 1455, 1368, 1212, 1150, 1112, 1050,
846, 702 cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C33H44NO6S2]+
614.2610, found 614.2610.
tert-Butyl (S)-1-Benzhydryl-3-(5-ethoxy-5-oxopentyl)-2-oxopiper-
idine-3-carboxylate [(S)-14]. Under argon gas, tributyltin hydride
(0.52 mL, 1.95 mmol) was added to a stirred solution of (R)-17 (1 g,
1.63 mmol) in dry toluene (20 mL). AIBN (0.2 M in toluene, 1.63 mL,
0.326 mmol) was added to the reaction mixture, and the mixture was
refluxed for 1 h. The reaction mixture was cooled to room temperature
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 10:1) to afford (S)-14
(740 mg, 92% yield) as clear oil. 1H NMR (400 MHz, CDCl3) δ 7.18−
7.32 (m, 11H), 4.09 (q, J = 7.2 Hz, 2H), 3.07 (ddd, J1 = 12.3 Hz, J2 = 5.3
Hz, J3 = 3.9 Hz, 1H), 2.83−2.90 (m, 1H), 2.28 (td, J1 = 7.4 Hz, J2 = 1.8
Hz, 2H), 1.93−2.11 (m, 3H), 1.67−1.82 (m, 3H), 1.59−1.66 (m, 2H),
1.43 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 173.9, 172.6, 169.7, 139.1, 138.7, 129.5, 128.6, 128.5, 128.5,
127.8, 127.4, 81.8, 60.4, 60.2, 54.9, 43.8, 36.1, 34.4, 30.0, 28.1, 25.5,
24.2, 20.5, 14.5 ppm; IR (KBr) 3725, 2977, 2935, 2349, 2308, 1736,
1641, 1456, 1368, 1252, 1157, 848, 701 cm−1; HRMS (FAB) m/z [M +
H]+ calcd for [C30H40NO5]+ 494.2906, found 494.2909.
Methyl (S)-1-Benzhydryl-3-(5-ethoxy-5-oxopentyl)-2-oxopiperi-
dine-3-carboxylate [(S)-18]. Trifluoroacetic acid (4 mL) was added
to a solution of (S)-14 (1 g, 2.03 mmol) in dichloromethane (4 mL).
The reaction mixture was stirred for 0.5 h at room temperature and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 3:1) and concentrated
in vacuo for the next step. Toluene/methanol = 5:2 solution (8 mL)
and (trimethylsilyl)diazomethane 2.0 M in diethyl ether solution (2.00
mL, 4.0 mmol) were added, respectively, to the reaction mixture. The
reaction mixture was stirred for 0.5 h, quenched with AcOH, and the
solvent was evaporated. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 5:1) to afford (S)-18
(869 mg, 95% yield) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ
7.26−7.36 (m, 6H), 7.20−7.21 (m, 5H), 4.10 (q, J = 7.2 Hz, 2H), 3.73
(s, 3H), 3.05−3.11 (m, 1H), 2.84−2.91 (m, 1H), 2.29 (td, J1 = 7.5 Hz,
J2 = 1.5 Hz, 2H), 2.03−2.16 (m, 2H), 1.70−1.99 (m, 3H), 1.57−1.66
(m, 3H), 1.33−1.45 (m, 1H), 1.22−1.25 (m, 3H) ppm; 13C{1H} NMR
(101 MHz, CDCl3) δ 174.2, 173.8, 169.3, 138.9, 138.6, 129.6, 128.7,
128.6, 128.3, 127.8, 127.4, 60.5, 60.4, 54.6, 52.7, 44.2, 35.8, 34.3, 30.0,
25.4, 24.3, 20.3, 14.4 ppm; IR (KBr) 2951, 1732, 1643, 1455, 1433,
1245, 1200, 1175, 1031, 703 cm−1; HRMS (FAB) m/z [M + H]+ calcd
for [C27H34NO5]+ 452.2437, found 452.2441.
Ethyl (6R)-2-benzhydryl-1,7-dioxo-2-azaspiro[5.5]undecane-8-
carboxylate [(R)-19]. To the solution of (S)-18 (500 mg, 1.11
mmol) in dry THF (6.25 mL) at 0 °C under argon gas, LHMDS 1.0 M
solution in THF (2.2 mL, 2.2 mmol) was slowly added. The resulting
mixture was stirred for 0.5 h. The reaction mixture was quenched with
saturated NH4Cl solution, diluted with ethyl acetate (50 mL), washed
with brine (2 × 10 mL), dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 6:1) to afford (R)-19
(455 mg, 98% yield) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ
7.24−7.33 (m, 7H), 7.18−7.28 (m, 4H), 4.16−4.24 (m, 2H), 3.03 (d, J
= 3.7 Hz, 2H), 2.22−2.32 (m, 4H), 1.80−1.93 (m, 5H), 1.53−1.54 (m,
3H), 1.26−1.31 (m, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ
172.8, 172.0, 138.8, 138.6, 129.1, 128.6, 128.4, 128.4, 127.3, 99.2, 60.5,
48.7, 44.5, 34.0, 32.5, 22.5, 20.1, 18.4, 14.3 ppm; IR (KBr) 2929, 2854,
1740, 1638, 1454, 1376, 1301, 1246, 1207, 1032, 920, 813, 756, 702
cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C26H30NO4]+ 420.2175,
found 420.2173.
(R)-2-Benzhydryl-2-azaspiro[5.5]undecane-1,7-dione [(R)-15]. To
the solution of (R)-19 (450 mg, 1.07 mmol) in MeOH (3 mL) was
added 1 M aqueous KOH solution (3 mL). The resulting mixture was
refluxed for 3 h. The reaction mixture was quenched with saturated
NH4Cl solution, diluted with dichloromethane (70 mL), washed with
brine (2 × 15 mL), dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 6:1) to afford (R)-15
25
(335 mg, 90% yield) as clear viscous oil: [α]D = −21.07 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.20−7.36 (m, 11H), 3.06 (dt,
J1 = 12.0 Hz, J2 = 5.5 Hz, 1H), 2.82−2.88 (m, 1H), 2.58−2.69 (m, 2H),
2.44−2.51 (m, 1H), 2.35 (qd, J1 = 6.6 Hz, J2 = 4.0 Hz, 1H), 1.87−2.03
(m, 3H), 1.57−1.85 (m, 5H) ppm; 13C{1H} NMR (101 MHz, CDCl3)
δ 210.9, 170.2, 139.0, 138.6, 129.6, 128.6, 128.5, 127.7, 127.3, 60.6,
58.4, 44.1, 39.0, 37.3, 31.1, 26.6, 20.9, 19.5 ppm; IR (KBr) 2936, 2866,
1704, 1635, 1495, 1453, 1300, 1207, 1180, 1080, 1032, 929, 870, 771,
735, 702 cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C23H26NO2]+
348.1964, found 348.1962.
(6R,7S)-2-Benzhydryl-7-hydroxy-2-azaspiro[5.5]undecan-1-one
[(R,S)-20]. To the solution of (R)-15 (110 mg, 0.317 mmol) in dry THF
(3 mL) at −78 °C under argon gas was slowly added 1 M DIBAL-H in
THF solution (0.95 mL, 0.95 mmol). The resulting mixture was stirred
for 0.5 h, quenched with saturated Rochelle salt solution, diluted with
dichloromethane (25 mL), washed with brine (2 × 5 mL), dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, hexane/EtOAc = 3:1)
to afford (R,S)-20 (104 mg, 94% yield, dr = 50:1) as colorless oil. The
enantioselectivity was determined by chiral HPLC analysis (DAICEL
Chiralpak AD-H, hexane/2-propanol = 90:10), flow rate = 1.0 mL/min,
23 °C, λ = 254 nm, retention time, 6S,7R (minor) = 13.7 min, 6R,7S
(major) = 24.8 min, 98% ee: 1H NMR (400 MHz, CDCl3) δ 7.14−7.34
(m, 11H), 4.32 (d, J = 10.5 Hz, 1H), 2.92−3.00 (m, 2H), 1.95−2.02
(m, 2H), 1.67−1.84 (m, 8H), 1.18−1.49 (m, 5H) ppm 13C{1H} NMR
(101 MHz, CDCl3) δ 175.6, 139.3, 139.1, 129.2, 128.7, 128.6, 127.5,
127.4, 74.0, 60.8, 49.3, 44.5, 33.4, 29.9, 29.1, 24.6, 22.1, 20.1, 20.1 ppm;
IR (KBr) 3428, 2936, 2862, 1611, 1495, 1453, 1431, 1296, 1198, 1055,
763, 735, 704 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C23H28NO2]+ 350.2120, found 350.2118.
(6S,7S)-2-Benzhydryl-2-azaspiro[5.5]undecan-7-ol [(S,S)-21]. To
the solution of (R,S)-20 (200 mg, 0.572 mmol) in dry THF (5 mL)
under argon gas was slowly added 1 M LiAlH4 in THF solution (5.7 mL,
5.7 mmol). The resulting mixture was refluxed for 1 h and quenched by
adding one drop of saturated aqueous NH4Cl solution and 50%
aqueous NaOH solution alternately until no hydride remained. The
suspension was filtered, and the precipitate was washed with
dichloromethane (10 mL), dried over anhydrous K2CO3, filtered
again, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 20:1) to afford (S,S)-21
25
(177 mg, 92% yield) as a pale yellow oil: [α]D = −75.73 (c 0.28,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.14−7.43 (m, 11H), 4.11 (s,
1H), 3.56 (dd, J1 = 11.2 Hz, J2 = 3.9 Hz, 1H), 2.95 (d, J = 8.2 Hz, 1H),
2.73 (d, J = 11.4 Hz, 1H), 2.09−2.27 (m, 2H), 1.67−1.87 (m, 4H),
4387
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1.46−1.60 (m, 2H), 1.10−1.41 (m, 6H), 0.80−1.01 (m, 2H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 142.6, 142.5, 129.1, 128.9, 127.8,
127.7, 127.3, 127.3, 80.5, 66.5, 53.6, 37.6, 37.4, 29.9, 29.7, 28.8, 24.5,
23.4, 20.6 ppm; IR (KBr) 3308, 3026, 2928, 2859, 2801, 1598, 1492,
1452, 1305, 1174, 1129, 1092, 1029, 969, 934, 881, 761, 746, 705 cm−1;
HRMS (FAB) m/z [M + H]+ calcd for [C23H30NO]+ 336.2327, found
336.2329.
(−)-Sibirine. To the solution of (S,S)-22 (40 mg, 0.166 mmol) in dry
THF (1 mL) under argon gas was slowly added 1 M LiAlH4 in THF
solution (1.66 mL, 1.66 mmol). The resulting mixture was stirred at
room temperature for 1 h and quenched with 5% aqueous hydrochloric
acid (1 mL). The resulting mixture was extracted with dichloromethane
(2 mL), and the aqueous layer was neutralized with 2 M aqueous
sodium hydroxide (2 mL). The resulting mixture was extracted with
dichloromethane (3 × 2 mL), and the combined organic layers were
washed with brine (3 mL), dried over anhydrous MgSO4, and filtered.
The solvent was removed under reduced pressure to provide
(−)-Isonitramine. To the mixture of (S,S)-21 (50 mg, 0.15 mmol)
and palladium hydroxide on carbon (10 mg, 20 wt %) in dry MeOH (2
mL) was added H2 gas. The resulting mixture was stirred for 3 h, filtered
by Celite 545, washed with MeOH, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, CHCl3/
MeOH/25% aq NH4OH = 46:50:4) to afford (−)-isonitramine (23
mg, 92% yield) as a white solid: mp = 94−95 °C; [α]D25 = −6.14 (c =
1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.64 (dd, J1 = 11.2 Hz, J2
= 3.4 Hz, 1H), 3.00−3.04 (m, 1H), 2.92 (d, J = 11.4 Hz, 1H), 2.58 (td,
J1 = 11.4 Hz, J2 = 3.4 Hz, 1H), 2.50 (d, J = 11.0 Hz, 1H), 2.22 (d, J = 14.2
Hz, 1H), 2.04 (qt, J1 = 12.7 Hz, J2 = 4.9 Hz, 1H), 1.66−1.73 (m, 2H),
1.44−1.57 (m, 2H), 1.33−1.40 (m, 2H), 1.16−1.28 (m, 2H), 1.04 (td,
J1 = 13.3 Hz, J2 = 5.5 Hz, 1H), 0.91−0.98 (m, 1H) ppm; 13C{1H} NMR
(101 MHz, CDCl3) δ 80.6, 60.9, 47.4, 36.9, 36.4, 30.0, 28.9, 24.5, 23.2,
20.5 ppm; IR (KBr) 3308, 2924, 2853, 1462, 1378, 1281, 1219, 1078,
994, 886, 772 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C10H20NO]+ 170.1545, found 170.1541.
Synthesis of (−)-Sibirine. (6S,7S)-Ethyl 7-Hydroxy-2-
azaspiro[5.5]undecane-2-carboxylate [(S,S)-22]. Ethyl chlorofor-
mate (0.19 mL, 1.99 mmol) was added to the stirred solution of
(−)-isonitramine (112.5 mg, 0.665 mmol) in dichloromethane (3 mL).
Trimethylamine (0.46 mL, 3.32 mmol) was added, and the mixture was
stirred for 0.5 h. After completion of the reaction as confirmed by thin-
layer chromatography, the mixture was concentrated in vacuo. The
residue was purified by column chromatography (silica gel, hexane/
EtOAc = 10:1) to afford (S,S)-22 (152 mg, 95% yield) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 4.09 (q, J = 7.2 Hz, 2H), 3,80−3.55 (br,
25
(−)-sibirine as a colorless oil (24 mg, 78% yield): [α]D = −24.3 (c
= 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.59 (dd, J1 = 11.4 Hz, J2
= 3.7 Hz, 1H), 2.79 (d, J = 8.2 Hz, 1H), 2.57 (d, J = 11.4 Hz, 1H), 2.21
(s, 3H), 1.87 (d, J = 11.0 Hz, 2H), 1.67−1.74 (m, 2H), 1.45−1.55 (m,
2H), 1.37 (tt, J1 = 10.1 Hz, J2 = 3.4 Hz, 2H), 1.14−1.28 (m, 3H), 0.86−
1.01 (m, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 80.8, 70.3,
56.6, 46.7, 37.4, 29.9, 29.7, 27.9, 24.6, 23.4, 20.6 ppm; IR (KBr) 2925,
1220, 772 cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C11H22NO]+
184.1701, found 184.1694.
Synthesis of (+)-Nitramine. (6S,7R)-2-Benzhydryl-2-azaspiro-
[5.5]undecan-7-ol [(S,R)-21]. To the solution of (R)-15 (200 mg,
0.576 mmol) in dry THF (5 mL) under argon gas was slowly added 1 M
LiAlH4 in THF solution (5.7 mL, 5.7 mmol). The resulting mixture was
refluxed for 1 h and quenched with adding one drop of saturated
aqueous NH4Cl solution and 50% aqueous NaOH solution alternately
until no hydride left. The suspension was filtered, and the filtered
solution was washed with dichloromethane (10 mL), dried over
anhydrous K2CO3, filtered again, and concentrated in vacuo. The
residue was purified by prep TLC (silica gel, dichloromethane/acetone
= 49:1) to afford (S,R)-21 (142 mg, 74% yield) and (S,S)-21 (28 mg,
15% yield) as a colorless oil: [α]D25 = +132.0 (c 0.40, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.14−7.42 (m, 11H), 4.07 (s, 1H), 3.52 (d, J = 9.8
Hz, 1H), 3.21 (d, J = 9.2 Hz, 1H), 2.91 (s, 1H), 2.25 (d, J = 11.6 Hz,
1H), 1.48−1.89 (m, 7H), 1.02−1.24 (m, 8H), 0.88 (d, J = 7.3 Hz, 2H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 142.4, 142.1, 128.7, 127.9,
127.4, 127.3, 127.0, 79.5, 77.4, 77.2, 58.1, 53.5, 39.0, 37.0, 32.6, 29.7,
24.4, 23.9, 21.0 ppm; IR (KBr) 2928, 2858, 2804, 1492, 1452, 1220,
772, 705 cm−1; HRMS (FAB) m/z [M + H]+ calcd for [C23H30NO]+
336.2327, found 336.2331.
1H), 3.46 (s, 1H), 3.33 (q, J = 13.3 Hz, 2H), 3.15−3.00 (br, 1H), 1.75−
1.25 (m, 11H), 1.22 (t, J = 7.2 Hz, 3H), 1.04−1.10 (m, 1H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 156.2, 73.1, 61.3, 51.8, 44.8, 38.1,
30.2, 30.0, 28.0, 22.6, 20.9, 20.7, 14.9 ppm; IR (KBr) 2937, 2864, 1678,
1442, 1269, 1240, 1220, 772 cm−1; HRMS (FAB) m/z [M + H]+ calcd
for [C13H24NO3]+ 242.1756, found 242.1749.
(+)-Nitramine. To the mixture of (S,R)-21 (50 mg, 0.15 mmol) and
palladium hydroxide on carbon (10 mg, 20 wt %) in dry MeOH (2 mL)
was added H2 gas (1 atm). The resulting mixture was stirred for 3 h,
filtered by Celite 545, washed with MeOH, and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
CHCl3/MeOH/25% aq NH4OH = 46:50:4) to afford (+)-nitramine
(23 mg, 93% yield) as a yellow solid: mp = 96−97 °C; [α]D20 = +14.2 (c
= 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 3.96 (dd, J1 = 5.7 Hz,
J2 = 1.6 Hz, 1H), 3.57 (dd, J1 = 10.1 Hz, J2 = 4.1 Hz, 1H), 3.48 (d, J =
11.9 Hz, 1H), 3.02 (td, J1 = 7.5 Hz, J2 = 3.8 Hz, 1H), 2.63 (td, J1 = 11.3
Hz, J2 = 3.6 Hz, 1H), 2.40 (d, J = 11.9 Hz, 1H), 2.00−2.16 (m, 1H),
1.73−1.86 (m, 2H), 1.46−1.69 (m, 3H), 1.16−1.39 (m, 7H), 0.99−
1.08 (m, 1H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 77.6, 52.0,
46.6, 37.8, 36.8, 35.9, 32.2, 29.7, 24.0, 23.2, 21.0 ppm; IR (KBr) 2923,
2851, 1454, 1220, 777 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C10H20NO]+ 170.1545, found 170.1543.
Computational Method for Docking Model. Every 3D structure of
the single species except for Maruoka catalyst [(S,S)-12] was built using
the LigPrep of Schrodinger Suite. The 3D structure of (S,S)-12 was
built based on the X-ray crystallography published ref 17c. These 3D
structures were used as initial inputs in the Jaguar of ab initio program
with density-functional theory. All geometry optimizations were
performed using the B3LYP-D3 functional and 6-31G** basis set.
The optimal geometry was validated by checking the imaginary
frequency. In order to propose a transition state, the optimized species
were combined in 3D Cartesian space and manually adjusted through
translation and rotation. The proposed pose could be chosen between
the crash and known length between PTCs and substrates in literature.
The optimal geometry of product 15-R was calculated in the Jaguar of
ab initio program with density-functional theory (the B3LYP-D3
(6S,7S)-tert-Butyl 7-Hydroxy-2-azaspiro[5.5]undecane-2-carbox-
ylate [(S,S)-23]. Di-tert-butyl dicarbonate (135 mg, 0.62 mmol) was
added to the stirred solution of (−)-isonitramine (35 mg, 0.207 mmol)
in dichloromethane (700 μL). Trimethylamine (144 μL, 1.03 mmol)
was added, and the mixture was stirred for 0.5 h. After completion of the
reaction as confirmed by thin-layer chromatography, the mixture was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexanes/EtOAc = 10:1) to afford (S,S)-
23 (47 mg, 84% yield) as colorless oil: 1H NMR (400 MHz, CDCl3) δ
3.70−3.50 (br, 1H), 3.49 (q, J = 3.5 Hz, 1H), 3.30 (s, 2H), 3.15−3.00
(s, 1H), 1.43 (s, 9H), 1.75−1.05 (m, 12H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 155.2, 79.2, 77.2, 73.1, 51.6, 37.9, 30.1, 29.8, 29.7, 28.4,
22.3, 20.7, 20.6 ppm; IR (KBr) 2930, 2860, 1670, 1431, 1365, 1277,
1220, 1164, 772 cm−1; HRMS (FAB) m/z [M + H]+ calcd for
[C15H28NO3]+ 270.2069, found 270.2067.
(6S,7S)-Benzyl 7-Hydroxy-2-azaspiro[5.5]undecane-2-carboxy-
late [(S,S)-24]. Benzyl chloroformate (80 μL, 0.567 mmol) was
added to the stirred solution of (−)-isonitramine (32 mg, 0.189 mmol)
in dichloromethane (700 μL). Trimethylamine (132 μL, 0.945 mmol)
was added, and the mixture was stirred for 0.5 h. After completion of the
reaction as confirmed by thin-layer chromatography, the mixture was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexanes/EtOAc = 10:1) to afford (S,S)-
24 (42 mg, 74% yield) as colorless oil: 1H NMR (400 MHz, CDCl3) δ
7.36−7.25 (m, 5H), 5.11 (s, 2H), 3.85−3.60 (br, 1H), 3.55−3.25 (m,
3H), 3.20−2.95 (br, 1H), 1.85−1.00 (m, 12H) ppm; 13C{1H} NMR
(101 MHz, CDCl3) δ 155.7, 136.9, 128.4, 127.9, 127.8, 77.2, 73.0, 66.9,
51.8, 44.8, 38.0, 30.0, 29.8, 29.7, 22.5, 20.6 ppm; IR (KBr) 2930, 2860,
1680, 1442, 1220, 913, 772 cm−1; HRMS (FAB) m/z [M + H]+ calcd
for [C18H26NO3]+ 304.1913, found 304.1915.
4388
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functional and 6-31G** basis set to consider 3D dispersion correction
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02573.
■
sı
Spectral data of all new compounds including 1H,
13C{1H} NMR spectra and HPLC analysis graph under
optimization conditions, X-ray crystallographic data of 1d
and 6d, computational data for p-bromobenzylation of 6
(PDF)
AUTHOR INFORMATION
Corresponding Author
Hyeung-geun Park − Research Institute of Pharmaceutical
Sciences and College of Pharmacy, Seoul National University,
Gwanak-gu, Seoul 08826, Republic of Korea; orcid.org/
0000-0002-9645-8221; Phone: +82-2-880-7821, ext 8264;
Email: hgpk@snu.ac.kr; Fax: +82-2-888-0649
■
Authors
(4) Boubaker, J.; Bhouri, W.; Ben Sghaier, M.; Bouhlel, I.; Skandrani,
I.; Ghedira, K.; Chekir-Ghedira, L. Leaf extracts from Nitraria retusa
promote cell population growth of human cancer cells by inducing
apoptosis. Cancer Cell Int. 2011, 11, 37.
Jewon Yang − Research Institute of Pharmaceutical Sciences and
College of Pharmacy, Seoul National University, Gwanak-gu,
Seoul 08826, Republic of Korea
Yohan Park − College of Pharmacy, Inje Institute of
Pharmaceutical Sciences and Research, Inje University,
Gimhae, Gyeongnam 50834, Republic of Korea; orcid.org/
0000-0001-6844-2241
Sehun Yang − Research Institute of Pharmaceutical Sciences and
College of Pharmacy, Seoul National University, Gwanak-gu,
Seoul 08826, Republic of Korea
Geumwoo Lee − Research Institute of Pharmaceutical Sciences
and College of Pharmacy, Seoul National University, Gwanak-
gu, Seoul 08826, Republic of Korea
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Syntheses of Sibirine, Nitramine, and Isonitramine. Heterocycles 1987,
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K.; Iwata, C. Highly Enantioselective Construction of a Quaternary
Carbon Centre by the Pummerer-type Reaction: A Total Synthesis of
(−)-Sibirine. J. Chem. Soc., Chem. Commun. 1991, 1409−1411.
(c) Francois, D.; Lallemand, M. C.; Selkti, M.; Tomas, A.; Kunesch,
N.; Husson, H. P. Expeditious Enantioselective Biomimetic Synthesis
of the Nitraria Alkaloids (+)-Isonitramine and (−)-Sibirine. Angew.
Chem., Int. Ed. 1998, 37, 104−105. (k) Koreeda, M.; Wang, Y.; Zhang,
L. 6-Exo-spiro (Alkoxycarbonylamino)methyl Radical Cyclization:
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(6) (a) Quirion, J. C.; Grierson, D. S.; Royer, J.; Husson, H. P.
Asymmetric synthesis XV: Enantiospecific Synthesis of (+) and (−)
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1988, 29, 3311−3314. (b) Tanner, D.; He, H. M. Enantioselective
Total Synthesis of (+)-Nitramine. Tetrahedron 1989, 45, 4309−4316.
(c) Kim, D.; Choi, W. J.; Hong, J. Y.; Park, I. Y.; Kim, Y. B. An
Asymmetric Synthesis of (+)-Isonitramine by ‘Triple Allylic Strain-
Controlled’ Intramolecular SN2′ Alkylation. Tetrahedron Lett. 1996, 37,
1433−1434. (d) Koreeda, M.; Wang, Y.; Zhang, L. 6-Exo-spiro
(Alkoxycarbonylamino)methyl Radical Cyclization: Highly Regio- and
Stereoselective Synthesis of (−)-Sibirine. Org. Lett. 2002, 4, 3329−
3332. (e) Pandey, G.; Kumara, C. P.; Burugu, S. K.; Puranik, V. G.
Enantioselective Total Syntheses of (−)-Isonitramine, (−)-Sibirine,
and (+)-Nitramine by Ring-Closing Metathesis. Eur. J. Org. Chem.
2011, 2011, 7372−7377.
(7) (a) Westermann, B.; Scharmann, G.; Kortmann, J. PLE-catalyzed
Resolution of α-substituted β-Ketoesters Application to the Synthesis
of (+)-Nitramine and (−)-Isonitramine. Tetrahedron: Asymmetry 1993,
4, 2119−2122. (b) Keppens, M.; De Kimpe, N. Enantioselective Total
Syntheses of the Nitraria Alkaloids (−)-Nitramine and (+) -Isonitr-
amine. J. Org. Chem. 1995, 60, 3916−3918. (c) Yamane, T.; Ogasawara,
K. Enantio- and Stereo-controlled Synthesis of the Nitraria Alkaloids,
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11, 1726−1730.
Min Woo Ha − College of Pharmacy, Jeju National University,
Jeju 63243, Republic of Korea
Mi-hyun Kim − College of Pharmacy, Gachon University,
Incheon 21936, Republic of Korea; orcid.org/0000-0002-
2718-5637
Suckchang Hong − Research Institute of Pharmaceutical
Sciences and College of Pharmacy, Seoul National University,
Gwanak-gu, Seoul 08826, Republic of Korea; orcid.org/
0000-0003-4975-9192
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02573
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
(NRF) of Korea (2019R1A2C-1005678) and the BK21 Plus
Program in 2020. We thank Dr. Jae Kyun Lee for X-ray
crystallography of 1d and 6d.
REFERENCES
■
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NOTE ADDED AFTER ASAP PUBLICATION
Figure 1 was corrected on January 20, 2021.
■
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