Studies on asymmetric total synthesis of (?)-β-hydrastineviaa chiral epoxide ring-opening cascade cyclization strategy

Article abstract of DOI:10.1039/d0ra03038d

Herein, facile and enantioselective approaches to synthesize the core phthalide tetrahydroisoquinoline scaffold of (?)-β-hydrastineviaboth a CF₃COOH-catalyzed (86% ee) and KHMDS-catalyzed (78% ee) epoxide ring-opening/transesterification cascade cyclization from chiral epoxide under very mild conditions are described. The key elements include a highly enantioselective epoxidation using the Shi ketone catalyst and an intramolecular CF₃COOH-catalyzed cascade cyclization in one pot, and a late-stage C-3′ epimerization under MeOK/MeOH conditions as the key steps to achieve the first total synthesis of (?)-β-hydrastine (up to 81% ee).

Full text of DOI:10.1039/d0ra03038d

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Studies on asymmetric total synthesis of (ꢀ)-b-
hydrastine via a chiral epoxide ring-opening
cascade cyclization strategy†
Cite this: RSC Adv., 2020, 10, 18953
Jihui Li,a Tianxiao Wu,a Xinjing Song,a Yang Zheng,a Jiaxin Meng,a Qiaohua Qin,a
abc
a
and Maosheng Chenga
*
Yongxiang Liu,
Dongmei Zhao
Herein, facile and enantioselective approaches to synthesize the core phthalide tetrahydroisoquinoline
scaffold of (ꢀ)-b-hydrastine via both a CF3COOH-catalyzed (86% ee) and KHMDS-catalyzed (78% ee)
epoxide ring-opening/transesterification cascade cyclization from chiral epoxide under very mild
conditions are described. The key elements include a highly enantioselective epoxidation using the Shi
ketone catalyst and an intramolecular CF3COOH-catalyzed cascade cyclization in one pot, and a late-
stage C-30 epimerization under MeOK/MeOH conditions as the key steps to achieve the first total
synthesis of (ꢀ)-b-hydrastine (up to 81% ee).
Received 4th April 2020
Accepted 11th May 2020
DOI: 10.1039/d0ra03038d
rsc.li/rsc-advances
comprises a 1,2,3,4-tetrahydroisoquinoline and a phthalide ring
and these two units are linked together by two chiral centers at
their C-1 and C-30 carbons to form either erythro- or threo-isomer
Introduction
Natural products that feature multiple stereocenters and
complex molecular topologies hold a special fascination to
chemists. Phthalide tetrahydroisoquinoline alkaloids, such as
hydrastine1 (1, Fig. 1), are known to possess interesting and
diverse biological properties.2 In light of their fascinating
architectural attributes and unique structures, as well as
promising biological activities, phthalide tetrahydroisoquino-
line alkaloids have been attractive and challenging targets of
synthetic and medicinal chemists for decades. However, due to
the small quantities of the natural products including hydras-
tine (1), a comprehensive biological evaluation of this class of
alkaloids could not be accomplished. To accelerate further
investigation of pharmacological activities and SAR studies, we
embarked on the asymmetric total syntheses of this class of
alkaloids.
Hydrastine (1), originally isolated from Corydalis longipes3
has been used as an antiseptic,4 as a uterine hemostatic4 and as
a potent competitive antagonist at mammalian GABAA receptors
(CD50 0.16 mg kgꢀ1, i.v.).5 In 2016, (ꢀ)-b-hydrastine [(ꢀ)-b-1]
was found to exhibit potent antitumor activity against human
lung adenocarcinoma cells.6 Structurally, hydrastine (1)
(Fig. 1).7 Because of unique structural features and interesting
biological properties of hydrastine, the design of new protocols
for the construction of this privileged scaffold has attracted
considerable interest. Since the work for the synthesis of
hydrastine (1) by Robinson and co-workers using the direct
condensation strategy in 1931 (Scheme 1a),8 several synthetic
studies9,10 had been reported for the synthesis of hydrastine (1).
Among them, (ꢁ)-b-hydrastine and (ꢁ)-a-hydrastine were ob-
tained from the substituted b-phenylethylmethylamide of
a substituted phthalidecarboxylic acid by dehydrated ring-
closure and following reduction in 1950 (Scheme 1b),9 and the
semi-synthesis of (ꢁ)-b-hydrastine and (ꢁ)-a-hydrastine from
natural berberine was reported (Scheme 1c).10 In addition,
several other approaches11,12 to (ꢁ)-b-hydrastine and (ꢁ)-a-
hydrastine were reported, such as the electrochemical11a and
zinc-promoted reductive coupling11b (Scheme 1d). Alternatively,
the phthalide tetrahydroisoquinoline skeleton of hydrastine (1)
could also be synthesized through the Bischler–Napieralski
aKey Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education,
Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
E-mail: medchemzhao@163.com
bWuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016,
People's Republic of China
cInstitute of Drug Research in Medicine Capital of China, Benxi, 117000, People's
Republic of China
† Electronic supplementary information (ESI) available: Experimental details,
characterization data, NMR spectra and HPLC chromatograms for products. See
DOI: 10.1039/d0ra03038d
Fig. 1 The erythro- and threo-form of hydrastine (1).
RSC Adv., 2020, 10, 18953–18958 | 18953
This journal is © The Royal Society of Chemistry 2020

View Article Online
RSC Advances
Paper
Scheme 2 (a) Our previous work to the total synthesis of (ꢁ)-b-
hydrastine. (b) Our proposed synthetic strategy to the total synthesis of
(ꢀ)-b-hydrastine in this study.
synthesis of (ꢁ)-b-hydrastine via an SN1-like mechanism
(Scheme 2a).14 In order to investigate further applications of this
cascade cyclization strategy for enantioselective total syntheses
of phthalide tetrahydroisoquinoline alkaloids, we postulated
that the chiral epoxide was utilized as a key stereocontrol
element in addition to a reactivity control element to enantio-
selectively construct the phthalide tetrahydroisoquinoline
scaffold based on an SN1-type acid-catalyzed or an SN2-type
base-catalyzed cyclization strategy (Scheme 2b). As the Shi
ketone catalyst and other variants are synthetically acces-
sible,15,16 we have the ability to generate epoxide substrate
bearing the necessary stereochemistry based on the chosen
cascade direction. In this paper, we document the success of the
cascade cyclization strategy in the form of the rst enantiose-
lective total synthesis of (ꢀ)-b-hydrastine.
Scheme 1 The known strategic approaches to hydrastine. (a) The
direct condensation strategy. (b) The dehydrated ring-closure strategy.
(c) The semi-synthesis strategy. (d) The reductive coupling strategy. (e)
The Bischler–Napieralski cyclization strategy.
Results and discussion
In designing a synthetic route toward (ꢀ)-b-hydrastine, we
employed the chiral epoxide in order to control both the reac-
tivity and stereoselectivity and envisioned a crucial cascade
cyclization transformation, namely, an acid-catalyzed cascade
cyclization. Our retrosynthetic analysis of (ꢀ)-b-hydrastine was
outlined in Scheme 3. The target natural compound (ꢀ)-b-
hydrastine could be accessed from (ꢀ)-a-hydrastine via epime-
rization at C-30, and (ꢀ)-a-hydrastine could be obtained from
(ꢀ)-a-2 aer methylation. Then, we speculated that the phtha-
lide tetrahydroisoquinoline core of (ꢀ)-a-2 could be constructed
by an acid-catalyzed epoxide ring-opening/transesterication
cascade cyclization of the (R,R)-3, which could be prepared
from (E)-stilbene 4 by asymmetric epoxidation with Shi ketone
catalyst.15 Moreover, the stilbene 4 might be constructed from
iodide 5 and substituted styrene 6 by a Pd-catalyzed Heck
coupling reaction.14,17 The iodide 5 could be synthesized by
iodization of N-protected phenethylamine 7,14 which could be
obtained from commercially available vanillin (9). In addition,
reaction12 (Scheme 1e) in the similar fashion of the synthesis of
noscapine.13 Although these methods successfully achieved the
synthesis of hydrastine (1), an inherent drawback associated
with all of the above-mentioned strategies was the lack of
enantioselectivity. Thus, the efficient, practical and highly
enantioselective construction of phthalide tetrahydroisoquino-
line structures still constitutes a synthetic challenge. To our
best knowledge, no attempt to synthesize (ꢀ)-b-hydrastine
[(ꢀ)-b-1] with high enantioselectivity has been reported.
Our research group has been exploring a unied acid-
catalyzed
epoxide
ring-opening/intramolecular
trans-
esterication cascade cyclization strategy for synthesis of
phthalide tetrahydroisoquinoline alkaloids, in which the C and
D rings are constructed simultaneously in one step.14 The
method was successfully applied to the diastereoselective total
18954 | RSC Adv., 2020, 10, 18953–18958
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Scheme 5 Total synthesis of (ꢀ)-b-hydrastine in method A.
Scheme 3 Retrosynthetic analysis of (ꢀ)-b-hydrastine.
Scheme 6 Synthesis of (R,R)-catalyst 13.
K2CO3 in a three-solvent system15,18 revealed that no trace of
desired epoxidation product (R,R)-3 was detected by NMR or LC-
MS (Table 1, entries 4–8). In addition, although a trace of desired
epoxidation product (R,R)-3 was detected when the reactions were
Scheme 4 Synthesis of substituted styrene 6.
ꢂ
conducted at ꢀ10 C for 2 h, the outcome was not substantially
improved (Table 1, entries 9–11). The all above-mentioned
unsuccessful asymmetric epoxidation with Shi catalyst 13 might
be attributed to the heterogeneous reactions. Considering the
importance of the reaction solvents, a two-solvent system was
researched according to the reported method (Table 1, entry 12),15
resulting in no improvement. However, using the increasing equiv.
of ketone 13 (3.0 equiv.) led to the almost complete consuming of
(E)-stilbene 4, which still produced a trace of desired (R,R)-3 for the
reason that the epoxide (R,R)-3 was postulated to strongly favor the
decomposition in the alkaline reaction environment at room
temperature for 24 h (Table 1, entry 13). Accordingly, subsequent
screening studies revealed that the yield of epoxide (R,R)-3 could be
drastically improved by proper selection of equiv. of ketone 13,
reaction temperatures and reaction times (Table 1, entries 14 and
15). Consequently, optimal yield (42% for two steps) and enan-
tiomeric excess (ee, 86%) of (ꢀ)-a-2 were obtained via epoxide
(R,R)-3 which was produced from (E)-stilbene 4 by an epoxidation
reaction with 3.0 equiv. of ketone 13 at 0 ꢂC for 4.5 h (Table 1, entry
14), and following CF3COOH-catalyzed cascade cyclization and N-
Boc deprotection in one pot.14 Additionally, other methods of
asymmetric epoxidation, using 30% H2O2 as oxidant19 (Table 1,
entries 16 and 17), did not improve yield and enantiomeric excess.
the styrene 6 could be derived from commercially available 2,3-
dimethoxybenzoic acid (8).
As shown in Scheme 4, our synthesis commenced with the
preparation of known (E)-stilbene 4, which was readily prepared
from 2,3-dimethoxybenzoic acid (8) in gram scale through a ve-
step sequence in our previous work14 (Scheme 4).
As shown in Scheme 5, we then turned our attention to
synthesize the (E)-stilbene 4, the precursor for asymmetric epoxi-
dation, which could be prepared in gram scale from commercially
available 9 in three steps in our previously reported manner
(Scheme 5).14 With substrate 4 in hand, our next goal was the
efficient asymmetric epoxidation with Shi catalyst 13
(Scheme 6)15,16 to obtain (R,R)-3 as the key precursor for the
proposed acid-catalyzed cascade cyclization.14 Various conditions
were screened with (E)-stilbene 4 (Table 1). Initially, treating (E)-
stilbene 4 with ketone 13 in the conditions of our previously re-
ported achiral epoxidation (Table 1, entry 1),14 as well as further
changing solvent system17 and increasing the equiv. of ketone 13
(Table 1, entries 2 and 3), failed to give (R,R)-3 (Table 1, entries 1–
3). Unfortunately, more extensive investigation of the asymmetric
epoxidation reaction using various equiv. of ketone 13, Oxone and
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 18953–18958 | 18955

View Article Online
RSC Advances
Paper
Table 1 Optimization of asymmetric epoxidation of (E)-stilbene 4 for
the acid-catalyzed cascade cyclization
Entrya
Ketone 13 (equiv.)
Conditionsb
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
3.0
3.0
5.0
0.3
0.3
1.6
2.0
3.0
3.0
1.6
1.6
0.3
3.0
3.0
1.0
3.0
3.0
A
B
B
C
NDe
NDe
NDe
NDe
NDe
NDe
NDe
NDe
Traceh
Traceh
Traceh
NDe
Tracej
42
—
—
—
—
—
—
—
—
—
—
—
—
—
86
79
58
71
Scheme 7 Syntheses of (E)-stilbenes 16a–c.
D
furnished (ꢀ)-b-hydrastine [(ꢀ)-b-1] with 81% ee, which was in
agreement with authentic reference standards for this natural
product1 (see the ESI†).
Df
Df
Df
Df,g
Df,g
Dg
E
Therefore, (ꢀ)-b-hydrastine had been synthesized with
a high enantiomeric excess (81% ee) by using CF3COOH-
catalyzed cascade cyclization reaction and C-30 epimerization
under MeOK/MeOH conditions as the key steps (Scheme 5).
Inspired by the ring-opening reaction of epoxides in basic
conditions via an SN2-type mechanism,20 we also assumed that
the core phthalide tetrahydroisoquinoline scaffold with the R
and S congurations at C-1 and C-30 could be enantioselectively
structured based on a base-catalyzed epoxide ring-opening/
transesterication cascade cyclization strategy in order to
avoid the late-stage epimerization reaction at C-30. Corre-
spondingly, the chiral epoxide with (S,S) congurations was
chosen as the substrate to direct the cascade reaction under
basic conditions. To test the working hypothesis, initially, we
prepared a series of racemic model substrates [(ꢁ)-17] through
DMDO-mediated epoxidation14 from the corresponding (E)-
stilbenes (16), which were subjected to base-catalyzed cascade
cyclization model reactions. Similarly, the precursors 16 for
epoxidation were prepared in three steps, namely, N-protection,
I2/CF3COOAg-mediated iodination and following Pd-catalyzed
Heck coupling reaction (Scheme 7).
With the (E)-stilbenes 16a–c in hand, we focused our atten-
tion on the base-catalyzed cascade cyclization model reactions.
Initially, we chosen triuoroacetyl21 as the N-protection group to
examine the reactivity in the presence 60% NaH21 in 1,4-
dioxane, unfortunately, leading to no desired cyclization
product (ꢁ)-b-18a (Table 2, entry 1). Aer that, we further
optimized the reaction conditions of the model reaction, and
the results were summarized in Table 2. Using (ꢁ)-17a as the
model substrate, rstly, extensive screening of different bases
(KHMDS, LDA, and n-BuLi), solvents (THF and 1,4-dioxane),
and reaction temperatures resulted in no desired (ꢁ)-b-18a or
the decomposition of (ꢁ)-17a (Table 2, entries 2–7). In our
opinion, it was probably due to that the electron-withdrawing
ability of triuoroacetyl group was not strong enough to fulll
the deprotonation process of amino in the presence of strong
bases, and then failing to facilitate desired cascade cyclization
reaction. In light of the above reason, the 4-(triuoromethyl)
benzenesulfonyl, a much stronger electron-withdrawing group,
9
10
11
12i
13
14k
15k
16m
17m
E
F
Fl
G
24
25
40
H
a
b
Substrate 4 (0.1 mmol). Condition A: Oxone (5.6 equiv.), NaHCO3
(18.9 equiv.), CH3CN–CH2Cl2–H2O (v/v/v ¼ 1 : 4 : 5), 0 ꢂC, 48 h.
Condition B: Oxone (5.0 equiv.), NaHCO3 (15.5 equiv.), Bu4NHSO4
(5 mol%), CH3CN–aq. Na2EDTA (4 ꢃ 10ꢀ4 M) (v/v ¼ 1.5 : 1), 0 ꢂC,
2.0 h. Condition C: Oxone (2.02 equiv.), K2CO3 (4.04 equiv.),
Bu4NHSO4 (5 mol%), CH3CN–DMM–0.05 M aq. Na2HPO4–0.05 M aq.
KH2PO4 (pH ¼ 7.0) (v/v/v ¼ 1 : 2 : 1), 0 ꢂC, 24 h. Condition D: Oxone
(1.38 equiv.), K2CO3 (5.8 equiv.), Bu4NHSO4 (5 mol%), CH3CN–DMM–
0.05 M Na2B4O7$10H2O of aq. Na2EDTA (4 ꢃ 10ꢀ4 M) solution (v/v/v ¼
1 : 2 : 2), 0 ꢂC, 1.5 h. Condition E: Oxone (1.38 equiv.), K2CO3 (5.8
equiv.), Bu4NHSO4 (5 mol%), CH3CN–0.05 M Na2B4O7$10H2O of aq.
Na2EDTA (4 ꢃ 10ꢀ4 M) solution (v/v ¼ 3 : 2), 0 ꢂC to rt, 24 h.
Condition F: Oxone (4.6 equiv.), K2CO3 (18.6 equiv.), Bu4NHSO4
(5 mol%), CH3CN–0.05 M Na2B4O7$10H2O of aq. Na2EDTA (4 ꢃ 10ꢀ4
M) solution (v/v ¼ 3 : 2, 25 mL), 0 ꢂC, 4.5 h. Condition G: 30% H2O2
(30 equiv.), CH3CN–1.0 M K2CO3 in 4 ꢃ 10ꢀ4 M of EDTA (v/v ¼ 2 : 1),
0
ꢂC, 36 h. Condition H: 30% H2O2 (30 equiv.), CH3CN–EtOH–CH2Cl2
(v/v/v ¼ 1 : 1 : 2), 2.0 M K2CO3 in 4 ꢃ 10ꢀ4 M of EDTA, 0 ꢂC, 36 h.
c
d
Isolated yield of (ꢀ)-a-2. The enantiomeric excess was determined
e
by chiral HPLC (Chiralpak IH). The epoxide (R,R)-3 was not detected
by TLC and the starting material 4 was recovered. Oxone (1.38
f
g
equiv.) and K2CO3 (5.8 equiv.) were used. The reactions were
h
stopped aer 2 h for ꢀ10 ꢂC. Most of the starting material 4 was
i
j
recovered. Substrate 4 (1.0 mmol). Most of the epoxide (R,R)-3 was
k
l
decomposed. Substrate 4 (0.3 mmol). The reactions were stopped
aer 8 h for 0 ꢂC. m Substrate 4 (0.4 mmol). DMM ¼ dimethoxymethane.
With highly enantioselective (ꢀ)-a-2 in hand, we were pleased to
synthesize (ꢀ)-b-hydrastine [(ꢀ)-b-1] using already established
conditions for two transformations.14 The N-methylation of (ꢀ)-a-2
occurred under classic Eschweiler–Clarke reaction conditions,14
thus yielding (ꢀ)-a-hydrastine [(ꢀ)-a-1]. Remarkably, without
purication of (ꢀ)-a-2, (ꢀ)-a-hydrastine was prepared from 4 in the
three-step yield of 30% (see Scheme 5). Finally, a late-stage epi-
merization of (ꢀ)-a-1 at C-30 under MeOK/MeOH conditions
18956 | RSC Adv., 2020, 10, 18953–18958
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 2 Optimization of racemic model substrates [(ꢁ)-17] for the base-catalyzed cascade cyclization
Entrya
17
Base (equiv.)
Solvent
Temp. (ꢂC)
T (h)
Yieldb (%)
c
1
2
3
4
5
6
7
8
17a
17a
17a
17a
17a
17a
17a
17b
17b
17b
17c
17c
17c
17c
17c
17c
17c
60% NaH (2.5)
KHMDS (1.2)
KHMDS (1.2)
KHMDS (1.2)
KHMDS (1.2)
LDA (1.2)
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Dry THF
Dry THF
Dry THF
Dry THF
Dry THF
1,4-Dioxane
Dry THF
Dry THF
0–65
0–65
0–84
0–65
0 to rt
0–65
ꢀ78 to rt
0–65
0–65
0–65
0–65
0–65
0–84
0–65
0–65
0–60
0–60
12
12
12
12
12
12
12
12
12
5.0
12
12
12
12
24
12
5.0
—
NDd
c
—
NDd
NDd
c
—
c
n-BuLi (1.2)
—
KHMDS (1.2)
KHMDS (1.5)
KHMDS (1.5)
KHMDS (1.5)
NaHMDS (1.5)
KHMDS (1.5)
60% NaH (2.5)
60% NaH (2.5)
60% NaH (2.5)
60% NaH (1.5)
11
10
9
10
11
12
13
14
15
16
17
30
NDd
Dry THF
NDd
c
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
—
15
10
16
19
a
The substrate 16 (0.1 mmol) was dissolved in solvent and then the base was added in dropwise. b Isolated yield of (ꢁ)-b-18 in two steps. c Most of
d
the epoxide (ꢁ)-17 was decomposed. The (ꢁ)-b-18 was not detected by TLC and the epoxide (ꢁ)-17 was recovered. NaHMDS ¼ sodium
bis(trimethylsilyl)amide. KHMDS ¼ potassium bis(trimethylsilyl)amide. LDA ¼ lithium diisopropylamide.
was used and the corresponding (ꢁ)-17b was subjected to the benzenesulfonyl might lead to lower yields, a mesyl-protected
model reactions (Table 2, entries 8–10). To our delight, the model substrate (ꢁ)-17c was prepared for further investigation
desired cyclization product (ꢁ)-b-18b was generated in 11% of model reactions (Table 2, entries 11–17). The results revealed
yield when the reactionꢂ was carried out by action of 1.0 M that no (ꢁ)-b-18c was delivered from (ꢁ)-17c in both KHMDS
KHDMS in THF at 0–65 C for 12 h (Table 2, entry 8). Encour- and NaHMDS conditions (Table 2, entries 11–13). However, the
aged by this result, we further optimized the reaction conditions model substrate (ꢁ)-17c was conducted to 60% NaH in 1,4-
by changing reaction solvent and temperature. As displayed in dioxane, resulting in the desired (ꢁ)-b-18c in 15% yield (Table 2,
Table 2, the reaction solvent had little effect on the yield of entry 14). Moreover, attempts were made to improve the yields
(ꢁ)-b-18b (Table 2, entry 9). A decrease in the reaction time from by extending the reaction time, lowering the reaction tempera-
12 h to 5 h resulted in a three-time increase in yield for the same ture and decreasing the equiv. of NaH, but the improvement
reaction solvent and temperature (Table 2, entry 10). In addi- was not signicant (Table 2, entries 16–17). Finally, the optimal
tion, considering that the steric hindrance of 4-(triuoromethyl) conditions were determined to be the model substrate (ꢁ)-17b
in THF at 0–65 ꢂC for 5 h in the presence of KHMDS (1.5 equiv.)
with stirring (Table 2, entry 10).
Based on the abovementioned results, the (E)-stilbene 16b was
smoothly transformed to phthalide-tetrahydroisoquinoline-
containing scaffold (ꢀ)-b-18b in 8% (30% brsm) yield over two
steps with the enantiomeric excess (ee) of 78% (Scheme 8), where
asymmetric epoxidation of 16b with Shi catalyst ent-13 (ref. 15 and
Scheme 8 Synthesis of the phthalide tetrahydroisoquinoline core of
(ꢀ)-b-hydrastine in method B.
Scheme 9 Synthesis of (S,S)-catalyst ent-13.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 18953–18958 | 18957

View Article Online
RSC Advances
Paper
16) (Scheme 9) delivered (S,S)-17b, and the resulting epoxide
underwent KHMDS-catalyzed cascade cyclization to give corre-
sponding (ꢀ)-b-18b. Aer that, the total synthesis of (ꢀ)-b-
hydrastine would be completed through the N-deprotection and
the known methylation14 reaction. Regarding to the late-stage N-
deprotection of (ꢀ)-b-18b, several conditions, such as Mg/MeOH,22
SmI2/THF,23 Na-naphthalide/THF,24 had been screened, but failing
to afford (ꢀ)-b-2 (see the ESI†) and further studies on the late-stage
N-deprotection are still in progress.
U. P. Singh, R. N. Jha, V. B. Pandey and M. B. Pandey, Folia
Microbiol., 2003, 48, 363–368.
4 K. Goswami, V. Yadava, V. Padmanabhan and S. Banerjee,
Acta Crystallogr., 1993, 49, 504–506.
5 J. Huang and G. A. R. Johnston, Br. J. Pharmacol., 1990, 99,
727–730.
6 B. Guo, X. Li, S. Song, M. Chen, M. Cheng, D. Zhao and F. Li,
Oncol. Rep., 2016, 35, 2246–2256.
7 (a) M. Shamma and V. S. Georgiev, Tetrahedron Lett., 1974,
15, 2339–2342; (b) K. Iwasa, M. Kamigauchi, M. Sugiura
and N. Takao, J. Nat. Prod., 1987, 50, 1083–1088.
8 E. Hope, F. L. Pyman, F. G. P. Remfry and R. Robinson, J.
Chem. Soc., 1931, 236–247.
Conclusions
In conclusion, we have completed an efficient and stereo-
controlled approach to total synthesis of the phthalide tetra-
hydroisoquinoline alkaloid (ꢀ)-b-hydrastine [(ꢀ)-b-1]. The key
elements include a high enantioselective epoxidation using the
Shi ketone catalyst and an intramolecular acid-catalyzed
cascade cyclization in one pot, and a late-stage epimerization.
Furthermore, it should be noted that the facile and enantiose-
lective construction of the core phthalide tetrahydroisoquino-
line scaffold was made possible by the CF3COOH-catalyzed or
KHMDS-catalyzed epoxide ring-opening cascade cyclization
from chiral epoxide under very mild conditions. In this reac-
tion, the phthalide tetrahydroisoquinoline scaffold was enan-
tioselectively constructed with one C–N bond and one C–C bond
formed simultaneously. Efforts toward the asymmetric total
syntheses of other phthalide tetrahydroisoquinoline alkaloids,
such as (ꢀ)-a-noscapine, and the structure-related alkaloids, are
currently ongoing in our laboratory. To conclude, the chemistry
described herein would serve as an efficient alternative strategy
to synthesize biologically active phthalide tetrahydroisoquino-
line alkaloids and their derivatives.
9 R. D. Haworth, A. R. Pinder and R. Robinson, Nature, 1950,
165, 529.
10 (a) J. L. Moniot and M. Shamma, J. Org. Chem., 1979, 44,
4337–4342; (b) J. L. Moniot and M. Shamma, J. Am. Chem.
Soc., 1976, 98, 6714–6715.
11 (a) T. Shono, Y. Usui and H. Hamaguchi, Tetrahedron Lett.,
1980, 21, 1351–1354; (b) T. Shono, H. Hamaguchi,
M. Sasaki, S. Fujita and K. Nagami, J. Org. Chem., 1983, 48,
1621–1628; (c) K. Orito, M. Miyazawa, R. Kanbayashi,
M. Tokuda and H. Suginome, J. Org. Chem., 1999, 64,
6583–6596.
12 L. Na, D. Zhao, S. Song, L. Sun and M. Cheng, Acta Chim. Sin.,
2011, 69, 356–361.
13 Z. Varga, G. Blasko, G. Dornyei and C. Szantay, Acta Chim.
Hung., 1991, 128, 831–837.
14 J. Li, Y. Liu, X. Song, T. Wu, J. Meng, Y. Zheng, Q. Qin,
D. Zhao and M. Cheng, Org. Lett., 2019, 21, 7149–7153.
15 (a) Z.-X. Wang, Y. Tu, M. Frohn, J.-R. Zhang and Y. Shi, J. Am.
Chem. Soc., 1997, 119, 11224–11235; (b) Y. Tu, Z.-X. Wang
and Y. Shi, J. Am. Chem. Soc., 1996, 118, 9806–9807.
16 (a) J. Kang, G. J. Lim, S. K. Yoon and M. Y. Kim, J. Org. Chem.,
1995, 60, 564–577; (b) S. Mio, Y. Kumagawa and S. Sugai,
Tetrahedron, 1991, 47, 2133–2144.
Conflicts of interest
There are no conicts to declare.
17 D. Shabashov and O. Daugulis, Org. Lett., 2006, 8, 4947–4949.
18 B. Wang, X.-Y. Wu, O. A. Wong, B. Nettles, M.-X. Zhao,
D. Chen and Y. Shi, J. Org. Chem., 2009, 74, 3986–3989.
19 (a) L. Shu and Y. Shi, Tetrahedron, 2001, 57, 5213–5218; (b)
L. Shu and Y. Shi, Tetrahedron Lett., 1999, 40, 8721–8724.
20 (a) T. Angelini, F. Fringuelli, D. Lanari, F. Pizzo and
L. Vaccaro, Tetrahedron Lett., 2010, 51, 1566–1569; (b)
N. Oguni, Y. Miyagi and K. Itoh, Tetrahedron Lett., 1998,
39, 9023–9026; (c) D. L. Fox, A. A. Robinson, J. B. Frank
and R. N. Salvatore, Tetrahedron Lett., 2003, 44, 7579–7582.
21 D. Knight, S. L. E. Overman and G. Pairaudeau, J. Am. Chem.
Soc., 1995, 117, 5776–5788.
22 (a) C. Qi, F. Hasenmaile, V. Gandon and D. Lebœuf, ACS
Catal., 2018, 8, 1734–1739; (b) M. Nagamoto, T. Yanagi,
T. Nishimura and H. Yorimitsu, Org. Lett., 2016, 18, 4474–
4477.
23 V. Pace, J. P. Rae and D. J. Procter, Org. Lett., 2014, 16, 476–
479.
Acknowledgements
We gratefully acknowledge the Program for Innovative Research
Team of the Ministry of Education and the Program for Liaon-
ing Innovative Research Team in University.
References
1 G. Blasko, D. J. Gula and M. Shamma, J. Nat. Prod., 1982, 45,
105–122.
2 (a) S. Y. Yin, Y. M. Kim, J. J. Lee, C. M. Jin, Y. J. Yang,
S.-K. Park, S. K. Yoo and M. K. Lee, Biol. Pharm. Bull., 2007,
30, 1547–1550; (b) S. Y. Yin, Y. M. Kim, J. J. Lee, C. M. Jin,
Y. J. Yang, J. J. Ma, M. H. Kang, M. Kai and M. K. Lee,
Neuropharmacology, 2004, 47, 1045–1052; (c) M. K. Lee,
Y. H. Zhang, J. S. Shin and S. S. Lee, Med. Sci. Res., 1997,
25, 619–620.
24 N. Chakor, S. Dallavalle, L. Scaglioni and L. Merlini, Eur. J.
Org. Chem., 2010, 6217–6223.
3 (a) R. N. Jha, M. B. Pandey, A. K. Singh, S. Singh and
V. P. Singh, Nat. Prod. Res., 2009, 23, 250–255; (b) M. Goel,
18958 | RSC Adv., 2020, 10, 18953–18958
This journal is © The Royal Society of Chemistry 2020