Asymmetric approach towards the total synthesis of (+)-actinopyllic acid

Article abstract of DOI:10.1016/j.tet.2017.02.058

This paper describes our efforts towards the asymmetric total synthesis of (+)-actinophyllic acid. Starting from the chiral oxazolidinone 9, an azocino [4,3-b]indolyl intermediate (5) possessing the A/B/C ring system and the C16 quaternary stereogenic center of actinophyllic acid has been synthesized. Key steps include a LHMDS-promoted condensation to establish the critical C2–C16 bond and a successive four-step transformation to assemble the eight-membered C-ring of the target molecule.

Full text of DOI:10.1016/j.tet.2017.02.058

Accepted Manuscript
Asymmetric approach towards the total synthesis of (+)-actinopyllic acid
Fei Xue, Tao Xiao, Min Li, Kai-Fang Zhang, Li-Ping He, Yong Qin, Xiao-Yu Liu, Dan
Zhang
PII:
S0040-4020(17)30206-5
10.1016/j.tet.2017.02.058
TET 28499
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 January 2017
Accepted Date: 25 February 2017
Please cite this article as: Xue F, Xiao T, Li M, Zhang K-F, He L-P, Qin Y, Liu X-Y, Zhang D, Asymmetric
approach towards the total synthesis of (+)-actinopyllic acid, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.02.058.
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Asymmetric Approach towards the Total
Synthesis of (+)-Actinopyllic Acid
Leave this area blank for abstract info.
Fei Xuea, Tao Xiaoa, Min Lia, Kai-Fang Zhanga, Li-Ping Heb,
Yong Qinb, Xiao-Yu Liub, and Dan Zhangb,
aInnovative Drug Research Centre (IDRC), School of
Pharmaceutical Sciences, Chongqing University,
Chongqing 401331, China
bKey Laboratory of Drug Targeting and Novel Delivery System
of the Ministry of Education, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China

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Tetrahedron
journal homepage: www.elsevier.com
Asymmetric Approach towards the Total Synthesis of (+)-Actinopyllic Acid
Fei Xuea, Tao Xiaoa, Min Lia, Kai-Fang Zhanga, Li-Ping Heb, Yong Qinb, Xiao-Yu Liub, and Dan Zhangb,
a
The Innovative Drug Research Centre (IDRC), School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
b
Key Laboratory of Drug Targeting and Novel Delivery System of the Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu
610041, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
This paper describes our efforts towards the asymmetric total synthesis of (+)-actinophyllic acid.
Starting from the chiral oxazolidinone 9, an azocino[4,3-b]indolyl intermediate (5) possessing
the A/B/C ring system and the C16 quaternary stereogenic center of actinophyllic acid has been
synthesized. Key steps include a LHMDS-promoted condensation to establish the critical C2–
C16 bond and a successive four-step transformation to assemble the eight-membered C-ring of
the target molecule.
Available online
Keywords:
Actinopyllic acid
Asymmetric Synthesis
Indole synthesis
2009 Elsevier Ltd. All rights reserved
.
Chiral oxazolidione
Alstonia actinophylla
1. Introduction
syntheses of actinophyllic acid were achieved by Overman et al
through a highly efficient aza-Cope-Mannich cascade strategy.2
Martin and coworkers documented a concise and elegant
In 2005, Carroll and coworkers reported
a
unique
monoterpernoid indole alkaloid (–)-actinophyllic acid 1 (Figure 1)
to be the active component of the leave extracts of Alstonia
actinophylla from Cape York Peninsula of Australia, with potent
carboxypeptidase U inhibitory activity (IC50 of 0.84 µM).1
Architecturally, actinophyllic acid possesses a highly compact
hexacyclic skeleton that is unprecedented among the known
monoterpernoid alkaloids. Specifically, its structure is
characterized by an azocino[4,3-b]indole moiety (A/B/C-ring), an
synthesis of (±)-actinophyllic acid via
a carbocation/π-
nucleophile cascade in 2013.3 Recently, a creative asymmetric
total synthesis of (–)-actinophyllic acid was reported by the
group of Kwon using a chiral phosphine-catalyzed [3+2]
annulation and subsequent novel ring formation sequance.4
Herein, we report our efforts towards the asymmetric total
synthesis of actinopyllic acid, leading to preparation of the key
azocino[4,3-b]indolyl intermediate 5 that contains the A/B/C ring
system and C15/C16 stereogenic centers of the target molecule.
1-azabicyclo[4.2.1]nonane unit (D/E-ring), and
a
highly
functionalized hemi-ketal F-ring, as well as five contiguous
stereogenic centers including one all-carbon quaternary center
(C16).
Cyclopropane-based strategy has proven to be a highly
versatile methodology in synthetic organic chemistry.6 Our group
previously developed a copper-catalyzed cyclopropanation/ring-
opening/iminium cyclization cascade (CRI reaction) on
tryptamine derivatives, which has allowed successful total
syntheses of several structurally intriguing indoline alkaloids
such as N-acetylardeemin, minfiensine, vincorine, and
communesin F.7 By analysis of the structure of actinophyllic acid,
we envisioned a cyclopropane-based [3+2] cycloaddition strategy
to construct the core of (+)-1. Retrosynthetically, the target
molecule could be accessed from intermediate 2 according to
Martin’s protocol,3 and 2 could be generated by deprotection and
hemi-ketalizaiton of acetonide 3 (Scheme 1). Acetonide 3 was
expected to be synthesized by an intramolecular [3+2]
cycloaddition of cyclopropane derivative 4, allowing efficient
construction of the D/E rings in a single step. Preparation of 4
could be realized by introducing the cyclopropyl side chain at
C20 from azocino[4,3-b]indolyl intermediate 5, which would
A
A
B
HN
NH
16 CO2H
B
21
21
HO2C 16
C
D
C
D
15
15
N
E
N
F
F
E
O
O
19
19
20
20
OH
(+)-actinophyllic acid ( )
HO
(–)-actinophyllic acid (1)
1
Figure 1. Structures of (–)- and (+)-actinophyllic acid.
The above-mentioned architectural features combined with its
potential medicinal applications make actinophyllic acid a
particularly attractive target for total synthesis.2–5 To date, three
synthetic groups have finished the total synthesis of actinophyllic
acid. The first racemic (2008) and asymmetric (2010) total

ACCEPTED MANUSCRIPT
2
Tetrahedron
arise from intermediate 6 by ring-opening of the oxazolidinone
Without separation of each diastereomer, 14 was subjected to a
two-step transformation including Dess-Martin oxidation and
hydroxymethylation13 with formaldehyde to give nitrobenzene
ketone derivative 15 in 87% overall yield. We found that
deprotection of the PMB group met with failure after the indole
ring was formed. Thus, removal of PMB protection was
performed at this stage using CAN in a mixed solvent of
CH3CN/H2O (v/v 1:1) at 0 °C, this was followed by indolization
under the hydrogenation conditions to furnish 16 in 63% yield for
two steps. DIBAL-H reduction of the ester functionality in 16
followed by treating the resultant diol with 2,2-
dimethoxypropane yielded the desired acetonide 6.
ring and formation of the eight-membered C-ring. Since direct
formation of a congested indole-C2–quaternary-carbon bond is
challenging,8 we envisioned to firstly establish the C2–C16 bond
using malonate 7 and the known aldehyde 8,9 prior to
constructing the indole core. In turn, 7 could be prepared from
the known chiral oxazolidinone 9.10,11
A
NR
B
NH
NH
21
21
21
O
O
16
C
OH
RN
1
(+)-
N
N
15
20
15
D
15
O
O
5
E
5
O
19
19
6
20
19
O
O
OH
6
4
2
3
MeO
O
CO2Me
MeO2C
TBSO
16
15
( S)
15
A
NR
20
NH
O
B
O
N
21
3
N
21 Me
O
H
2
O
PMB
14
15
16
7
9
C
+
RN
14
15
20
O
3
21
NO2 Me
O
N
20
O
H
HO
R
5
6
8
O
Scheme 1. Retrosynthetic analysis of actinophyllic acid
2. Results and discussion
Our synthesis commenced with the preparation of the
substituted manolate intermediate 7 (Scheme 2). First of all,
using
oxazolidinone
a
modified literature protocol,10 the known chiral
9
was prepared in decagram scales from
commercially available (S)-4-amino-2-hydroxybutanoic acid over
3 steps (80% overall yield).11 Protection of the free amine using
PMB group, followed by desilylation of the resulting
intermediate 10 with TBAF, afforded alcohol 11 in 78% yield
over two steps. We next sought to install a leaving group at C15
in 11 for the further malonate displacement. Investigations on
various leaving groups including I, OTs, OTf, and ONs revealed
that the Ns-protected intermediate 12 gave the best results.
Specifically, treatment of 12 with dimethyl malonate and t-BuOK
delivered 7 smoothly with inverted C15 chirality in 90% yield
and 98.3% ee.12
Scheme 3. Reagents and conditions: (a) LiCl, DMSO/H2O (v/v 100:1),
reflux, 72%; (b) LHMDS, THF, –78 °C, 92%; (c) Dess-Martin periodinane,
DCM, 0 °C, 95%; (d) DBU, HCHO (aq 37%), THF, 0 °C, 92%; (e) CAN,
CH3CN/H2O (v/v 1:1), 0 o C → rt; (f) 20% Pd(OH)2/C, H2, 250 psi, MeOH, rt,
63% for two steps; (g) DIBAL-H, DCM, 0 oC, 65% (88% brsm); (h) 2,2-
dimethoxypropane,
THF,
reflux,
89%.
(LHMDS,
lithium
bis(trimethylsilyl)amide; CAN, ceric ammonium nitrate; DIBAL-H,
diisobutylaluminium hydride).
With a key C2–C16 bond formation and the indole core
secured, we next turned to assemble the eight-membered C-ring
of actinophyllic acid (Scheme 4). Converting the C21 methyl
group in 6 into an aldehyde was conducted by DDQ oxidation to
give 17 in 66% yield.14 The latter was subjected to Cbz-
protection of the oxazolidinone nitrogen atom to provide lactam
18 smoothly. Subsequent treatment of 18 with 1M NaOH in THF
at room temperature gave the ring-opening product 19 in
TBSO
HO
TBSO
15
a
b
O
O
O
N
N
N
H
87%
90%
PMB
PMB
9
10
11
CO2Me
MeO2C
NsO
O
excellent yield (95%). Finally,
a
successive four-step
16
(S)
c
d
transformation including Cbz deprotection, reductive amination,
Cbz re-protection, and carboxylic acid reduction was carried out
to secure the C-ring formation, thus giving rise to the stable
intermediate 5 in 50% overall yield.
15
N
90%
85%
O
N
PMB
12
PMB
7
Scheme 2. Reagents and conditions: (a) NaH, PMBCl, DMF, 0 °C → rt,
87%; (b) TBAF, THF, 0 °C → rt, 90%; (c) NsCl, Et3N, DCM, 0 °C, 85%; (d)
3. Conclusion
dimethyl malonate, t-BuOK, THF,
0 °C → rt, 90%. (PMBCl, 4-
In summary, a synthesis of the optically pure azocino[4,3-
b]indolyl intermediate 5 has been achieved using a LHMDS-
promoted condensation to establish the critical C2–C16 bond and
a successive four-step transformation to assemble the eight-
membered C-ring. Successful synthesis of this key intermediate
that possesses the A/B/C ring system and C15/C16 stereogenic
centers of (+)-actinophyllic acid will pave the way for exploring
our proposed cyclopropane-based [3+2] cycloaddition strategy.
methoxybenzyl chloride; TBAF, tetrabutylammonium fluoride; NsCl, p-
nitrobenzenesulfonyl chloride).
Successful preparation of the chiral building block 7 enabled
us to further investigate the synthesis of indole derivative 6
through C2–C16 bond formation and indolization (Scheme 3).
Considering the steric hindrance of the diester group at C16 may
impede the subsequent transformation, removal of one ester
group of diester 7 was manipulated under Krapcho condition,
delivering 13 in 72% yield. The desired C2–C16 bond formation
was then initiated by LHMDS-promoted condensation of chiral
oxazolidinone 13 with 2-(2-nitrophenyl) propanal 8,9 affording
alcohol 14 as a mixture of diastereomers in 92% combined yield.

ACCEPTED MANUSCRIPT
mL) at °C. The reaction was warmed to room temperature and
stirred until consumption of 10. This mixture was then quenched
with a solution of saturated aqueous solution of NH4Cl (200 mL)
at °C and diluted with EtOAc (200 mL). The layers were
separated and the aqueous layer was extracted with EtOAc (3 ×
200 mL). The combined organic layers were dried over Mg2SO4,
filtered and concentrated in vacuo. The residue was purified by
silica gel flash chromatography (petroleum ether/EtOAc = 1:1) to
give compound 11 (29.80 g, 90%) as white solid: mp 106 ‒
110 °C; [α]20D = ‒ 59.4 (c 0.2, CHCl3); 1H NMR (600 M, CDCl3)
δ 7.16 (d, J = 9.0 Hz, 2H), 6.87-6.85 (m, 2H), 4.43 – 4.37 (m,
3H), 4.20 – 4.19 (m, 1H), 3.79 (s, 3H), 3.25 – 3.21 (m, 1H), 3.17
– 3.13 (m, 1H), 2.41 – 2.38 (m, 1H), 1.95 – 1.91 (m, 1H); 13C
NMR (150 M, CDCl3) δ 174.7, 159.2, 129.5, 127.7, 114.1, 70.1,
55.2, 46.4, 42.8, 27.7; IR (KBr) 3416, 3322, 1669, 1442, 1317,
1247, 1111, 1032, 818, 729, 641 cm-1; HRMS m/z (M+Na)+
calcd for C12H15NNaO3 244.0944, found 244.0946.
Scheme 4. Reagents and conditions: (a) DDQ, DCM/H2O (v/v 20:1), 0 o C →
rt, 66%; (b) NaH, CbzCl, THF, 0 o C → rt, 81%; (c) 1M NaOH (aq), THF, rt,
95%; (d) Pd/C, H2, MeOH, 1 atm, rt; (e) 3 Å MS, MeOH, reflux; (f) NaBH4,
MeOH, 0 oC; then DIPEA, CbzCl, MeOH, 0 o C; (g) BH3·Me2S, THF, 30oC.
(DDQ, 2,3-dichloro-5,6-dicyanobenzoquinone; CbzCl, benzyl chloroformate;
MS, molecular sieves; DIPEA, N,N-diisopropylethylamine).
4.4. (S)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl 4-nitrobenzene
sulfonate (12)
Et3N (25.20 mL, 0.18 mol), DMAP (387.0 mg, 3.16 mmol)
and p-nitrobenzenesulfonyl chloride (26.05 g, 0.12 mol) were
successively added to a solution of compound 11 (20.00 g, 0.09
mol) in anhydrous CH2Cl2 (300 mL) at °C under N2. The reaction
mixture was then warmed to room temperature and stirred for 30
minutes before it was quenched with a solution of saturated
aqueous solution of NH4Cl (100 mL) at °C. The layers were
separated and the aqueous layer was extracted with CH2Cl2 (3 ×
100 mL). The combined organic layers were dried over Mg2SO4,
filtered and concentrated in vacuo. The residue was purified by
silica gel flash chromatography (petroleum ether/EtOAc = 1:1) to
give compound 12 (27.13 g, 85%) as pale yellow solid: mp 102 ‒
106 °C; [α]20D = ‒ 20.9 (c 0.3, CHCl3); 1H NMR (600 M, CDCl3)
δ 8.42 – 8.40 (m, 2H), 8.25 – 8.23 (m, 2H), 7.10 (d, J = 9.0 Hz,
2H), 6.85 – 6.84 (m, 2H), 5.18 – 5.15 (m, 1H), 4.37 – 4.31 (m,
2H), 3.79 (s, 3H), 3.79 – 3.31 (m, 1H), 3.21 – 3.17 (m ,1H), 2.58
– 2.55 (m, 1H), 2.28 – 2.24 (m, 1H); 13C NMR (150 M, CDCl3) δ
167.0, 159.4, 150.8, 142.3, 129.6, 129.5, 126.9, 124.3, 114.2,
78.4, 55.3, 46.6, 42.8, 26.2; IR (KBr) 3449, 1709, 1610, 1533,
1513, 1460, 1352, 1304, 1247, 1186, 1095, 1032m 988, 958, 842,
741, 618, 554 cm-1; HRMS m/z (2M+Na)+ calcd for
C36H36N4NaO14S2 835.1562, found 835.1550.
4. Experimental section
4.1. General procedure
All commercially available reagents were used without further
purification. All solvents were dried and distilled before use:
tetrahydrofuran was dried over sodium-benzophenone;
dichloromethane was distilled from calcium hydride; dimethyl
sulfoxide and dimethylformamide was distilled under reduced
pressure after drying over calcium hydride. Chromatography was
conducted by using 200-300 mesh silica gel. All new compounds
gave satisfactory spectroscopic analyses (IR, 1H NMR, 13C NMR,
HRMS). IR spectra were recorded on a FT IR spectrometer.
NMR spectra were recorded on a 400 and 600 MHz NMR
spectrometer. HRMS spectra were obtained by the FAB method.
4.2.
(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-methoxybenzyl)-
pyrrolidin-2-one (10)
Compound 9 (50.00 g, 0.23 mol) was dissolved in dry DMF
(400 mL) and cooled to °C. Sodium hydride (18.50 g, 0.46 mol,
60% in mineral oil) was added in small portions and the solution
was stirred at °C for 30 minutes followed by slow addition of 4-
methoxybenzyl chloride (40.90 mL, 0.30 mol).The reaction
mixture was then stirred at rt for 2 h before it was quenched with
a saturated aqueous solution of NH4Cl (200 mL) at °C and
diluted with EtOAc (200 mL). The layers were separated and the
aqueous layer was extracted with EtOAc (3 × 200 mL). The
combined organic layers were washed with water (2 × 100 mL),
brine (100 mL), dried over Mg2SO4, filtered and concentrated in
vacuo. The residue was purified by silica gel flash
4.5. Dimethyl (S)-2-(1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)
malonate (7)
Potassium tert-butoxide (8.90 g, 0.079 mol) was added in
small portions to a solution of dimethyl malonate (9.80 mL,
0.085 mol) in anhydrous THF (200 mL) at °C under N2. The
resulting suspension was stirred at this temperature for 1h before
a solution of compound 12 (20.00 g, 0.057 mol) in anhydrous
THF (100 mL) was added slowly over 0.5 h. The reaction was
then warmed to room temperature and stirred for 24 h. This
mixture was quenched with a solution of saturated aqueous
solution of NH4Cl (100 mL) at °C and diluted with EtOAc (100
mL). The layers were separated and the aqueous layer was
extracted with EtOAc (3 × 100 mL). The combined organic
layers were dried over Mg2SO4, filtered and concentrated in
vacuo. The residue was purified by silica gel flash
chromatography (petroleum ether/EtOAc
= 8:1) to give
compound 10 as pale yellow foam; [α]20 = ‒ 26.4 (c 0.5,
D
CHCl3); 1H NMR (600 M, CDCl3) δ 7.15 (d, J = 9.0 Hz, 2H),
6.83 (d, J = 9.0 Hz, 2H), 4.35 (s, 2H), 4.32 (t, J = 7.2 Hz, 1H),
3.76 (s, 3H), 3.20 – 3.17 (m, 1H), 3.07 – 3.05 (m, 1H), 2.26 –
2.23 (m, 1H), 1.87 – 1.84 (m, 1H), 0.90 (s, 9H), 0.17 (s, 3H),
0.15 (s, 3H); 13C NMR (150 M, CDCl3): δ 173.0, 159.0, 129.4,
128.2, 113.9, 71.1, 55.1, 46.2, 29.1, 25.7, ‒4.5, ‒5.2; IR (KBr)
3473, 2930, 2856, 1705, 1612, 1586, 1513, 1462, 1439, 1299,
1249, 1175, 1144, 838, 780 cm-1 ; HRMS m/z (M+Na+) calcd for
C18H29NNaO3Si 358.1809, found 358.1813.
chromatography (petroleum ether/EtOAc
= 1:1) to give
compound 7 (15.19 g, 80%) as pale yellow oil: [α]20D = + 12.0 (c
1
0.2, CHCl3); H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.4 Hz,
2H), 6.86 (d, J = 8.4 Hz, 2H), 4.46 (d, J = 14.8 Hz, 1H), 4.33 (d,
J = 14.8 Hz, 1H), 3.92 (d, J = 6.0 Hz, 1H), 3.80 (s, 3H), 3.79 (s,
3H), 3.72 (s, 3H), 3.23 – 3.13 (m, 3H), 2.26 – 2.05 (m, 1H), 2.04
– 1.97 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 173.0, 168.9,
4.3. (S)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidin-2-one (11).
Tetrabutylammonium fluoride (98.05 g, 0.37 mol) was added
to a solution of compound 10 (50.00 g, 0.15 mol) in THF (400

ACCEPTED MANUSCRIPT
4
Tetrahedron
168.2, 159.0, 129.4, 128.1, 113.9, 55.2, 52.7, 51.6, 46.2, 44.5,
The layers were separated and the aqueous layer was extracted
with EtOAc (3 × 200 mL). The combined organic layers were
dried over Mg2SO4, filtered and concentrated in vacuo. The
residue was purified by silica gel flash chromatography
(petroleum ether/EtOAc = 3:1) to give 14 (30.29 g, 92%) as pale
yellow oil, which was a mixture of isomers. The mixture of
isomers were used in next step directly without further separation.
Analytical samples of these isomers were obtained by preparative
41.7, 22.0; IR (KBr) 2965, 2871, 1738, 1676, 1513, 1462, 1438,
1247, 1176, 1088, 1048, 881, 810, 756 cm-1; HRMS m/z
(M+Na)+ calcd for C17H21NNaO6 358.1261, found 358.1262. The
ee value (98%) was determined by HPLC (AS-H, isopropanol :
n-hexane = 40 : 60, flow rate 1.0 mL/min, λ = 254 nm), tmajor
8.89 min, tminor = 11.65 min.
=
thin-layer chromatography. Isomer 14a: pale yellow oil; [α]20
=
4.6. Methyl (S)-2-(1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)
acetate (13)
D
– 29.2 (c 0.25, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.65 (d, J
= 7.8 Hz, 1H), 7.60 – 7.56 (m, 2H), 7.36 – 7.33 (m, 1H), 7.21 (d,
J = 8.4 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2 H), 6.10 (d, J = 8.4 Hz,
1H), 4.49 (d, J = 15.0 Hz, 1H), 4.46 – 4.43 (m, 1H), 4.38 (d, J =
14.4 Hz, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 3.37 – 3.35 (m, 1H),
3.24 – 3.22 (m, 2H), 2.93 (td, J = 9.0 Hz, 3.0 Hz, 1H), 2.62 (t, J =
3.6 Hz, 1H), 2.01 – 1.96 (m, 1H), 1.77 – 1.70 (m, 1H), 1.48 (d, J
= 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 175.7, 172.1,
158.1, 138.3, 132.6, 129.5, 128.9, 127.9, 127.2, 114.1, 74.9, 55.3,
52.1, 49.9, 46.5, 45.4, 39.8, 38.2, 23.3, 18.7; IR (neat) 3200,
2952, 1732, 1651, 1523, 1512, 1461, 1435, 1355, 1242, 1172,
LiCl (1.38 g, 0.33 mol), H2O (2 mL) was added to a solution
of compound 7 (52.00 g, 0.155 mol) in DMSO (200 mL). The
resulting mixture was refluxed for 2 h. This mixture was then
cooled to room temperature and diluted with H2O (100 mL) and
EtOAc (100 mL). The layers were separated and the aqueous
layer was extracted with EtOAc (3 × 100 mL). The combined
organic layers were washed with water (2 × 100 mL), brine (100
mL), dried over Mg2SO4, filtered and concentrated in vacuo. The
residue was purified by silica gel flash chromatography
(petroleum ether/EtOAc = 4:1) to give compound 13 (30. 98 g,
1031, 853, 732 cm-1
;
HRMS m/z (M+Na)+ calcd for
72%) as pale yellow oil: [α]20D = – 3.0 (c 0.2, CHCl3); H NMR
1
C24H28N2NaO7 479.1789, found 479.1793. Isomer 14b: pale
(400 MHz, CDCl3) δ 7.16 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.4 Hz,
2H), 4.44 – 4.35 (m, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 3.21 – 3.17
(m, 2H), 2.96 – 2.86 (m, 2H), 2.44 (dd, J = 8.8 Hz, 16.0 Hz, 1H),
2.31 – 2.38 (m, 1H), 1.72 – 1.67 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 174.7, 172.5, 159.1, 129.5, 128.5, 114.0, 55.3, 51.7,
46.3, 44.6, 38.7, 35.5, 25.0; IR (KBr) 3454, 1736, 1681, 1513,
1439, 1247, 1175, 1111, 1031, 821, 579 cm-1 ; HRMS m/z
(M+Na)+ calcd for C15H19NNaO4 300.1206, found 300.1204.
yellow oil; [α]20 = – 24.0 (c 0.05, CHCl3); H NMR (600 MHz,
1
D
CDCl3) δ 7.77 (d, J = 8.4 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.38 –
7.34 (m, 2H), 7.17 (d, J = 7.8 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H),
5.68 (d, J = 4.8 Hz, 1H), 4.44 (d, J = 14.4 Hz, 1H), 4.34 (d, J =
14.4 Hz, 1H), 4.08 (dd, J = 10.2 Hz, 4.8 Hz, 1H), 3.77 (s, 3H),
3.68 (s, 3H), 3.60 – 3.57 (m, 1H), 3.20 – 3.14 (m, 2H), 2.73 –
2.69 (m ,1H), 2.33 (d, J = 5.4 Hz, 1H), 2.01 – 1.99 (m, 1H), 1.64
– 1.60 (m, 1H), 1.50 (d, J = 7.2 Hz, 3H) ; 13C NMR (150 MHz,
CDCl3) δ 175.1, 171.7, 159.1, 150.4, 139.2, 132.7, 129.5, 128.2,
128.0, 127.1, 124.5, 114.0, 55.2, 51.6, 49.2, 46.4, 44.8, 44.6, 38.8,
23.5, 20.0; IR (neat) 3200, 2952, 1732, 1651, 1523, 1512, 1461,
1435, 1355, 1242, 1172, 1031, 853, 732 cm-1; HRMS m/z
(M+Na)+ calcd for C24H28N2NaO7 479.1789, found 479.1786.
4.7. 2-(2-nitrophenyl)propanal (8)
Methyl 2-(2-nitrophenyl)propanoate (18.00 g, 0.086 mol),
which was prepared according to Hanna’s procedure,15 was
dissolved in anhydrous toluene (200 mL) and cooled to –78 °C.
A 1.5 M solution of DIBAL-H (57.10 mL, 0.086 mol) in toluene
was dropwise added under N2. The resulting solution was stirred
at –78 °C for 2 h. Then the reaction was quenched with MeOH
(20 mL) and saturated aqueous potassium sodium tartrate (50 mL)
at –78 °C. This resulting suspension was warmed to room
temperature, stirred for 0.5 h, diluted with EtOAc (100 mL) and
filtered through Celite. The filtrate was extracted with with
EtOAc (3 × 100 mL). The combined organic layers were dried
over Mg2SO4, filtered and concentrated in vacuo. The residue
was purified by silica gel flash chromatography (petroleum
ether/EtOAc = 4:1) to give compound 8 (10.00 g, 65%) as pale
yellow oil: 1H NMR (CDCl3, 400Hz) δ 9.77 (s, 1H), 7.99 – 8.01
(d, J = 8 Hz, 1H), 7.63 – 7.67 (m, 1H), 7.46 – 7.50 (m, 1H), 7.32-
7.34 (d, J = 8.0 Hz, 1H), 4.27 – 4.29 (dd, J = 14.4 Hz, 7.2 Hz,
1H), 1.59 – 1.61 (d, J = 6.8 Hz, 3H); 13C NMR (100MHz, CDCl3)
δ 194.4, 128.6, 128.3, 125.4, 123.5, 120.2, 43.3, 9.5; IR (neat)
2950ꢀ 1730ꢀ 1521ꢀ 1346ꢀ 1206ꢀ 1061ꢀ 851ꢀ 786ꢀ
744ꢀ 704ꢀ 674ꢀ 591 cm-1; HRMS m/z (M+Na)+ calcd for
C9H9NNaO3 202.0475, found 202.0475.
4.9. Methyl 2-(hydroxymethyl)-2-((S)-1-(4-methoxybenzyl)-2-
oxopyrrolidin-3-yl)-4-(2-nitrophenyl)-3-oxopentanoate (15)
The aforementioned mixture (14, 30.00 g, 0.066 mol) was
dissolved in CH2Cl2 (300 mL) and cooled to 0 °C. Dess-Martin
periodinane (41.81 g, 0.098 mol) was added in small portions and
the suspension was stirred at 0 °C for 3 h. The reaction mixture
was quenched with saturated aqueous Na2S2O3 (100 mL) and
saturated aqueous NaHCO3 (100 mL).The layers were separated
and the aqueous layer was extracted with CH2Cl2 (3 × 200 mL).
The combined organic layers were dried over Mg2SO4, filtered
and concentrated in vacuo. The residue was purified by silica gel
flash chromatography (petroleum ether/EtOAc = 2:1) to give β-
ketoester (28.47 g, 95%) as pale yellow foam, which was a
1
mixture of inseparable isomers: H NMR (600 MHz, CDCl3) δ
7.83 – 7.79 (m, 1H), 7.54 – 7.48 (m, 1H), 7.38 – 7.33 (m, 1.5H),
7.26 – 7.24 (m, 0.3 H), 7.09 – 7.07 (m, 2H), 6.79 – 6.75 (m, 2H),
4.68 – 4.61 (m, 0.5 H), 4.53 – 4.50 (m, 0.4 H), 4.35 – 4.19 (m,
2H), 4.09 – 4.01 (m, 0.4 H), 3.96 (d, J = 12.0 Hz, 0.3 H), 3.85 (d,
J = 10.8 Hz, 0.3 H), 3.69 – 3.62 (m, 4H), 3.55 (s, 0.6 H), 3.52 (s,
0.4 H), 3.36 (s, 1H), 3.29 – 3.26 (m, 0.3 H), 3.14 – 3.04 (m,
2.5H), 2.10 – 2.07 (m, 1H), 1.74 – 1.72 (m, 1H), 1.52 – 1.46 (m,
2H), 1.39 (d, J = 10.2 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ
202.9, 202.8, 202.6, 202.0, 173.3, 173.2, 168.9, 168.5, 167.9,
159.1, 159.0, 149.6, 149.3, 149.2, 134.2, 134.1, 133.9, 133.8,
133.4, 133.0, 132.9, 130.5, 130.4, 130.2, 130.1, 129.4, 129.3,
128.5, 128.4, 128.3, 128.2, 128.1, 124.9, 124.8, 124.7, 124.6,
114.0, 113.9, 60.3, 57.3, 57.2, 56.1, 55.2, 53.6, 52.6, 52.4, 52.1,
48.3, 47.3, 47.2, 46.6, 46.1, 44.7, 44.6, 44.5, 43.2, 42.2, 41.8,
41.3, 25.7, 22.8, 22.4, 22.3, 21.7, 20.9, 17.9, 17.6, 17.5, 14.1; IR
(neat) 2953, 1720, 1678, 1523, 1511, 1435, 1344, 1242, 1173,
4.8.
Methyl
3-hydroxy-2-((S)-1-(4-methoxybenzyl)-2-
oxopyrrolidin-3-yl)-4-(2-nitrophenyl)pentanoate (14)
Compound 13 (20.00 g, 0.072 mol) was dissolved in
anhydrous THF (200 mL) and cooled to –78 °C. A 1M solution
of LHMDS in THF (76.0 mL, 0.076 mol) was added dropwise
under N2 and the resulting mixture was maintained at –78 °C for
1 h. Then a solution of aldehyde 8 (14.21 g, 0.792 mol) in
anhydrous THF (100 mL) was slowly added. After stirring for 3
h, the reaction was quenched with a solution of a saturated
aqueous NH4Cl (200 mL) at –78 °C and warmed to room
temperature. This mixture was diluted with EtOAc (200 mL).

ACCEPTED MANUSCRIPT
1032, 788, 724, 701, 525 cm-1; HRMS m/z (M+Na)+ calcd for
C24H26N2NaO7 477.1632, found 477.1631.
stirred in a pressure vessel under hydrogen (250 psi) for 36 h at
room temperature. Then the mixture was filtered through Celite
and the filtrate was concentrated in vacuo. The residue was
purified by silica gel flash chromatography (petroleum
ether/EtOAc = 1:1) to give 16 (6.75 g, 63% from 15) as a pair of
diastereomers, which were used directly in next step without
further separation. The analytical samples of the two isomers 16a
and 16b were obtained by preparative thin-layer chromatography.
The above β-ketoester (20.00 g, 0.044 mol) was dissolved in
THF (200 mL) and cooled to 0 °C. DBU (1.32 mL, 8.81 mmol)
was added and the resulting solution was stirred at 0 °C for 15
minutes before a solution of 37% aqueous HCHO (37.00 mL,
0.44 mol) was added. After 1h, this reaction mixture was
quenched with saturated aqueous CuSO4 (100 mL) and diluted
with EtOAc (100 mL).The layers were separated and the aqueous
layer was extracted with EtOAc (3 × 100 mL). The combined
organic layers were dried over Mg2SO4, filtered and concentrated
in vacuo. The residue was purified by silica gel flash
chromatography (petroleum ether/EtOAc = 1:1) to give 15 (19.61
g, 92%) as pale yellow oil, which was a mixture of isomers. The
mixture of isomers were used in next step directly without further
separation. Analytical samples of the major isomers was obtained
by preparative thin-layer chromatography. Inseparable isomers
A: pale yellow oil; 1H NMR (600 MHz, CDCl3) δ 7.92 – 7.89 (m,
2H), 7.81 (d, J = 8.0 Hz, 1H), 7.64 – 7.53 (m, 3H), 7.46 – 7.41
(m, 4H), 7.37 – 7.30 (m, 2H), 7.26 – 7.23 ( m, 2H), 7.15 (d, J =
8.4 Hz, 4H) , 6.91 – 6.84 (m, 6H), 6.11 (d, J = 9.6 Hz, 1H), 4.84
(q, J = 6.8 Hz, 1H), 4.75 (q, J = 6.8 Hz, 1H), 4.60 (q, J = 6.8 Hz,
1H), 4.48 – 4.36 (m, 8H), 4.32 – 4.28 (m, 2H), 4.22 – 4.19 (m,
1H), 4.04 (d, J = 8.8 Hz, 1H), 3.94 (d, J = 6.8 Hz), 3.82 (s, 3H),
3.79 (s, 6H), 3.76 (s, 3H), 3.45 (s, 3H), 3.40 (s, 3H), 3.36 – 3.29
(m, 2H), 3.23-3.08 (m, 6H), 2.97 (t, J = 9.6 Hz, 1H), 2.24 – 2.11
(m, 2H), 1.86 – 1.72 (m, 4H), 1.60 – 1.56 (m, 6H), 1.47 (d, J =
6.8 Hz, 3H)ꢁ13C NMR (150 MHz, CDCl3) δ 206.0, 202.8, 202.2,
174.6, 173.3, 173.3, 169.8, 169.1, 167.9, 159.2, 159.1, 159.0,
149.6, 149.3, 149.0, 135.9, 134.2, 133.9, 133.4, 132.9, 132.5,
130.6, 130.2, 129.5, 129.4, 129.3, 128.4, 128.2, 128.1, 127.8,
127.2, 114.1, 114.0, 67.5, 66.7, 57.3, 56.8, 55.3, 52.8, 52.4, 52.3,
48.6, 48.2, 46.6, 46.2, 45.1, 44.7, 44.6, 43.2, 42.0, 41.8, 29.7,
22.8, 22.3, 22.1, 21.4, 18.0, 17.7; IR (neat) 2952, 1683, 1524,
1512, 1458, 1351, 1243, 1175, 1030, 732, 701 cm-1; HRMS m/z
(M+Na)+ calcd for C25H28N2NaO8 507.1738, found 507.1739.
Minor isomer 16a: pale yellow foam. [α]20 = ‒51.6 (c 0.1,
D
CHCl3); 1H NMR (600 MHz, CDCl3) δ 9.66 (brs, 1H), 7.50 (d, J
= 7.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 7.2 Hz, 7.8
Hz, 1H), 7.09 (t, J = 8.4 Hz, 7.2 Hz, 1H), 5.85 (brs, 1H), 4.35 (q,
J = 6.0 Hz, 1H), 4.27 (brs, 1H), 4.27 – 4.23 (m, 1H), 3.81 (s, 3H),
3.59 – 3.56 (m, 1H), 3.37 – 3.32 (m, 2H), 2.30 – 2.26 (m, 1H),
2.24 (s, 3H), 2.11 – 2.04 (m, 1H); 13C NMR (150 MHz, CDCl3)
178.2, 173.0, 135.1, 132.3, 128.8, 122.1, 119.1, 118.3, 111.0,
107.4, 66.8, 55.1, 52.6, 45.5, 40.6, 24.7, 9.1; IR (KBr) 3385,
2952, 1732, 1678, 1460, 1435, 1385, 1333, 1238, 1047, 742 cm-1;
HRMS m/z (M+Na)+ calcd for C17H20N2NaO4 339.1315, found
339.1317. Major isomer 16b: pale yellow foam. [α]20 = +23.0
D
1
(c 0.04, CHCl3); H NMR (400 MHz, CDCl3) δ 9.68 (brs, 1H),
7.53 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 7.2 Hz, 1H), 7.10 (t,
J = 8.0 Hz, 7.6 Hz, 1H), 5.59 (brs, 1H), 5.23 (brs, 1H), 4.66 –
4.63 (m, 1H), 4.30 – 4.27 (m, 1H), 3.81 (s, 3H), 3.64 (t, J = 8.8
Hz, 1H), 3.29 – 3.26 (m, 1H), 3.04 – 3.02 (m, 1H), 2.53 – 2.50
(m, 1H), 2.24 (s, 3H), 2.08 – 2.02 (m, 1H); 13C NMR (150 MHz,
CDCl3) δ 178.4, 173.4, 134.9, 129.9, 128.7, 122.2, 119.1, 118.3,
111.1, 109.3, 66.8, 54.0, 52.8, 46.1, 40.5, 24.8, 9.7; IR (KBr)
3385, 2952, 1732, 1678, 1460, 1435, 1385, 1333, 1238, 1047,
742 cm-1; HRMS m/z (M+Na)+ calcd for C17H20N2NaO4
339.1315, found 339.1317.
4.11. (S)-3-(2,2-dimethyl-5-(3-methyl-1H-indol-2-yl)-1,3-dioxan-
5-yl)pyrrolidin-2-one (6)
The mixture (6.00 g, 0.019 mol) of 16a and 16b was dissolved
in anhydrous CH2Cl2 (300 mL) and cooled to 0 °C. A solution of
1.5 M DIBAL-H (75 mL, 0.11 mol) in toluene was dropwise
added under N2. The resulting solution was stirred at 0 °C for 4h.
Then the reaction was quenched with MeOH (30 mL) and
saturated aqueous potassium sodium tartrate (100 mL) at 0 °C.
This resulting suspension was stirred for 0.5 h, diluted with
CH2Cl2 (100 mL) and filtered through Celite. The filtrate was
extracted with with CH2Cl2 (3 × 100 mL). The combined organic
layers were dried over Mg2SO4, filtered and concentrated in
vacuo. The residue was recrystallized from CH2Cl2 to give diol
(2.50 g) as white solid. The filtrate was concentrated in vacuo
and the residue was purified by silica gel flash chromatography
(petroleum ether/EtOAc = 1:3) to give diol (1.50 g) and the
starting material (1.00 g). The two portions of diol (4.00 g, 65%,
1
Inseparable isomers B: pale yellow oil; H NMR (600 MHz,
CDCl3) δ 7.87 – 7.83 (m, 2H), 7.54 – 7.53 (m, 4H), 7.39 – 7.34
(m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.89
(d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.91 – 4.84 (m, 2H),
4.53 – 4.48 (m, 2H), 4.40 – 4.37 (m, 1H), 4.29 – 4.21 (m, 3H),
3.99 – 3.89 (m, 4H), 3.81 (s, 3H), 3.80 (s, 3H), 3.70 (s, 3H), 3.41
(m, 1H), 3.37 (s, 3H), 3.33 – 3.13 (m, 6H), 2.01 – 1.85 (m, 4H),
1.58 – 1.54 (m, 6H); 13C NMR (150 MHz, CDCl3) δ 206.2, 205.8,
173.9, 173.8, 170.8, 169.7, 159.1, 149.0, 148.9, 134.2, 132.8,
132.6, 129.6, 129.5, 129.4, 129.3, 128.0, 127.9, 127.6, 124.8,
124.6, 114.0, 67.6, 66.8, 65.3, 64.4, 55.3, 52.7, 52.5, 48.1, 56.3,
46.2, 46.0, 44.9, 44.8, 44.2, 43.5, 21.7, 21.6, 20.8, 20.6; IR (neat)
2953, 1683, 1524, 1512, 1458, 1351, 1300, 1243, 1175, 1059,
1030, 786, 730, , 700 cm-1; HRMS m/z (M+Na)+ calcd for
C25H28N2NaO8 507.1738, found 507.1736.
brsm 88%) was combined. Diol: mp 185 ‒ 189 °C; [α]20
=
D
1
‒57.3 (c 0.3, CHCl3) ; H NMR (400 MHz, CDCl3) δ 9.37 (brs,
1H), 7.51 (d, J = 7.6 Hz, 1H), 7.31 (J = 7.6 Hz, 1H), 7.16 (t, J =
6.8 Hz, 8.0 Hz, 1H), 7.09 (t, J = 7.6 Hz, 7.2 Hz, 1H), 5.87 (brs,
1H), 4.99 – 4.98 (m, 1H), 4.40 (d, J = 4.4 Hz, 1H), 4.25 – 4.18
(m, 2H), 4.10 – 4.05 (m, 1H), 3.43 – 3.25 (m, 4H), 2.39 (s, 3H),
2.18 – 2.05 (m ,1H), 1.94 – 1.81 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 1679.4, 135.0, 134.4, 129.4, 121.8, 119.0, 117.9, 110.9,
107.2, 67.3, 63.9, 48.2, 46.8, 40.9, 24.7, 10.2; IR (KBr) 3374,
2950, 1667,1462, 1332, 1294, 1050, 743 cm-1; HRMS m/z
(M+Na)+ calcd for C16H20N2NaO3 311.1366, found 339.1366.
4.10. Methyl 3-hydroxy-2-(3-methyl-1H-indol-2-yl)-2-((S)-2-
oxopyrrolidin-3-yl)propanoate (16)
Ceric ammonium nitrate (36.18 g, 0.066 mmol) was added in
small portions to a solution of compound 15 (16.00 g, 0.033 mol)
in CH3CN/H2O (200 mL, v/v = 3:1) at 0 °C. The resulting
solution was stirred at 0 °C for 3 h. This reaction mixture was
then quenched by saturated aqueous Na2S2O3 (100 mL) and
diluted with EtOAc (100 mL). The layers were separated and the
aqueous layer was extracted with EtOAc (3 × 100 mL). The
combined organic layers were dried over Mg2SO4, filtered
through a silica gel pad, and concentrated in vacuo. The residue
was directly dissolved in MeOH (200 mL) and Pd(OH)2/C (2.00
g, 20% Pd on carbon, wet) was added. The reaction mixture was
The above diol (2.50 g, 8.67 mmol) was dissolved in
anhydrous THF (100 mL). 2, 2-dimethyoxypropane (8.51 mL,
69.36 mmol) and p-TsOH (149.3 mg, 0.87 mmol) was added
successively. The resulting mixture was heated to reflux for 5 h
and quenched with saturated aqueous NaHCO3 (100 mL) at 0 °C.

ACCEPTED MANUSCRIPT
6
Tetrahedron
The suspension was diluted with H2O (5 mL) and EtOAc (50
118.8ꢀ 113.6ꢀ 111.7ꢀ 64.1ꢀ 63.1ꢀ 43.9ꢀ 43.8ꢀ 41.3ꢀ
26.5ꢀ 21.2ꢀ 20.8ꢁ IR (neat) 3280ꢀ 2920ꢀ 1779ꢀ 1718ꢀ
mL). The layers were separated and the aqueous layer was
extracted with EtOAc (3 × 100 mL). The combined organic
layers were dried over Mg2SO4, filtered and concentrated in
vacuo. The residue was purified by silica gel flash
chromatography (petroleum ether/EtOAc = 2:1) give compound
1646ꢀ 1444ꢀ 1374ꢀ 1285ꢀ 1197ꢀ 829ꢀ 728ꢀ 697 cm-1
;
HRMS m/z (M+Na)+ calcd for C27H28N2NaO6 499.1840, found
499.1836.
4.17.
(S)-4-(((benzyloxy)carbonyl)amino)-2-(5-(3-formyl-1H-
6 (2.53 g, 89%) as white foam: [α]20D = ‒32.4 (c 1.1, CHCl3); H
1
indol-2-yl)-2,2-dimethyl-1,3-dioxan-5-yl)butanoic acid (19).
NMR (400 MHz, CDCl3) δ 8.91 (brs, 1H), 7.52 (d, J = 8.0 Hz,
1H), 7.29 (d, J = 8.4Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 5.48 (brs,
1H), 5.18 (d, J = 12.0 Hz, 1H), 4.39 (s, 2H), 4.10 (d, J = 12.0 Hz,
1H), 3.58 (dd, J = 11.8 Hz, 8.4 Hz, 1H), 3.30 – 3.28 (m, 1H),
3.10 (t, J = 9.2 Hz, 1H), 2.37 – 2.34 (m, 4H), 1.88 – 1.83 (m, 1H),
1.50 (s, 3H), 1.46 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 180.1,
135.2, 131.6. 128.9, 121.7, 118.7, 117.8, 110.8, 108.3, 98.1, 65.9,
64.3, 41.8, 41.7, 39.6, 27.3, 23.6, 20.2, 10.0; IR (neat) 3300,
2923, 1676, 1459, 1372, 1257, 1197, 1091, 834, 732, 701, 522
cm-1 ; HRMS m/z (M+Na)+ calcd for C19H24N2NaO3 351,1679,
found 351.1678.
A 1M solution of aqueous NaOH (0.57 mL, 0.57 mmol) was
added to a solution of compound 24 (136.0 mg, 0.29 mmol) in
THF (10 mL). After stirring at room temperature for 1 h, the
reaction was cooled to 0 °C, and a 10% aqueous solution of citric
acid was added to adjust the pH value to 6. This mixture was
diluted with H2O (3 mL) and EtOAc (10 mL). The layers were
separated and the aqueous layer was extracted with EtOAc (3 ×
20 mL). The combined organic layers were dried over Mg2SO4,
filtered and concentrated in vacuo. The residue was purified by
silica gel flash chromatography (CH2Cl2/MeOH = 10:1) to give
compound 19 as colorless oil. [α]20 = ‒2.5 (c 0.2, CH3OH);1H
D
4.12. (S)-2-(2,2-dimethyl-5-(2-oxopyrrolidin-3-yl)-1,3-dioxan-5-
NMR(600 M, CD3OD): δ 10.33 (s, 1H), 7.18 (d, J = 5.6 Hz, 1H),
7.29 – 7.28 (m, 1H), 7.26 – 7.17 (m, 7H), 4.96 (s, 2H), 4.64 (d, J
= 12.8 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H), 4.42 – 4.36 (m, 2H),
3.13 – 2.95 (m, 2H), 2.93 – 2.92 (m, 1H), 2.07 – 2.02 (m, 1H),
1.68 – 1.59 (m, 2H), 1.48 (s, 3H), 1.40 (s, 3H); 13C NMR (150
MHz, CD3OD) 187.0ꢀ 176.3ꢀ 158.7ꢀ 150.9ꢀ 138.3ꢀ 136.6,
129.4, 128.9, 128.7, 124.3, 123.6, 120.8, 115.0, 112.9, 100.1,
67.4, 66.6, 64.7, 44.6, 40.3, 28.9, 27.4, 20.7; IR (neat) 3343,
2486, 1699, 1634, 1455, 1396, 1199, 1115, 970 cm-1 ; HRMS
m/z (M+Na)+ calcd for C27H30N2NaO7 517.1945, found 517.1942.
yl)-1H-indole-3-carbaldehyde (17)
DDQ (64.0 mg, 2.80 mmol) was added in small portions to a
solution of compound 6 (460.0 mg, 1.40 mmol) in DCM/H2O (42
mL, v/v = 20 : 1) at 0 °C. The resulting dark green solution was
warmed to room temperature and stirred for 5h. This reaction
mixture was then quenched with saturated aqueous NaHCO3 (30
mL) and diluted with CH2Cl2 (30 mL). The layers were separated
and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were washed with saturated
aqueous NaHCO3 (30 mL), bine (30 mL)), dried over Mg2SO4,
filtered and concentrated in vacuo. The residue was purified by
silica gel flash chromatography (petroleum ether/EtOAc = 1:1)
4.18.
Benzyl
(S)-5-(hydroxymethyl)-2',2'-dimethyl-1,4,5,7-
give compound 17 (316.0 mg, 66%) as pale yellow foam. [α]20
tetrahydrospiro[azocino[4,3-b]indole-6,5'-[1,3]dioxane]-2(3H)-
D
= ‒77.5 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 10.34 (s,
1H), 10.08 (brs, 1H), 8.22 – 8.20 (m, 1H), 7.42 – 7.40 (m, 1H),
7.36 – 7.27 (m, 2H), 5.88 (brs, 1H), 4.84 – 4.81 (d, J = 12.0 Hz,
1H), 4.28 (d, J = 11.6 Hz, 1H), 3.89 – 3.84 (m, 1H), 3.31 – 3.24
(m, 1H), 3.17 (t, J = 9.6 Hz, 1H), 2.21 – 2.14 (m, 1H), 1.80 –
1.72 (m, 1H), 1.57 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 185.1, 178.1, 147.4, 134,7, 127.8, 123.6, 122.7, 120.0,
115.0, 111.5, 99.0, 65.3, 63.9, 42.0, 41.8, 39.6, 25.3, 24.1, 22.5;
IR (neat) 3285, 2924, 1683ꢀ 1636ꢀ 1455, 1374ꢀ1264, 1198ꢀ
830, 734, 667 cm-1; HRMS m/z (M+Na)+ calcd for
C19H22N2NaO4 365.1472, found 365.1471.
carboxylate (5).
A mixture of compound 19 (90.0 mg, 0.18 mmol)) and
Pd/C (10% Pd on carbon, wet, 50 mg) in MeOH (5 mL) was
stirred at room temperature under 1.0 atm pressure of H2 for 0.5 h.
Then the mixture was filtered through Celite and the filtrate was
concentrated in vacuo. The residue was dissolved in MeOH (10
mL), and 3 Å molecular sieves (200 mg) was added. The
resulting suspension was heated to reflux overnight before it was
cooled to room temperature and filtered. Then this filtrate was
cooled to 0 °C. NaBH4 (7.0 mg, 0.18 mmol) was added slowly.
After stirring at 0 °C for 0.5 h, DIPEA (95.0 ꢀL, 0.55 mol),
CbzCl (62.0 ꢀL, 0.44 mol) was added successively. The resulting
mixture was stirred for 1 h and concentrated in vacuo. This
residue was diluted with H2O (5 mL) and EtOAc (5mL). Then a
10% aqueous solution of citric acid was added to adjust the pH
value to 6. The layers were separated and the aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic layers
were dried over Mg2SO4, filtered and concentrated in vacuo. The
resulting crude acid was directly dissolved in anhydrous THF (10
mL), borane dimethyl sulfide complex (0.10 mL, 1.09 mmol)
was added dropwise under N2 at room temperature. The resulting
mixture was stirred at 35 °C for 10 h before it was quenched with
saturated aqueous NH4Cl (5 mL) at °C. This suspension was
diluted with H2O (10 mL) and EtOAc (10 mL). The layers were
separated and the aqueous layer was extracted with EtOAc (3 ×
20 mL). The combined organic layers were dried over Mg2SO4,
filtered and concentrated in vacuo. The residue was purified by
silica gel flash chromatography (petroleum ether/EtOAc = 2:1) to
give compound 5 (42.0 mg, 50% from 19) as pale yellow foam:
4.16. Benzyl (S)-3-(5-(3-formyl-1H-indol-2-yl)-2,2-dimethyl-1,3-
dioxan-5-yl)-2-oxopyrrolidine-1-carboxylate (18).
NaH (47.0 mg, 0.17 mmol, 60% in mineral oil) was added in
small portions to a solution of compound xx in anhydrous THF
(15 mL) at 0 °C. The resulting suspension was stirred at this
temperature for 1h before CbzCl (0.2 mL, 1.40 mmol) was added
dropwise. After 1 h, the reaction mixture was quenched with
saturated aqueous NH4Cl (10 mL) and diluted with EtOAc (10
mL). The layers were separated and the aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic layers
were dried over Mg2SO4, filtered and concentrated in vacuo. The
residue was purified by silica gel flash chromatography
(petroleum ether/EtOAc = 4:1) to give compound 18 (181.0 mg,
81%) as pale yellow oil: [α]20 = ‒37.7 (c 0.3, CHCl3); 1H NMR
D
(600 MHz, CDCl3) δ 10.3 (s, 1H), 9.95 (brs, 1H), 8.09 – 8.07 (m,
1H), 7.43 – 7.39 (m, 1H), 7.38 – 7.26 (m, 8H), 5.28 – 5.21 (m,
2H), 4.89 (d, J = 12.0 Hz, 1H), 4.71 (d, J = 12.6 Hz, 1H), 4.35 –
4.26 (m, 3H), 3.74 (t, J = 10.2 Hz, 1H), 3.59 – 3.55 (m, 1H), 2.04
– 2.02 (m, 1H), 1.68 – 1.63 (m, 1H), 1.58 (s, 3H), 1.35 (s, 3H).
13C NMR (150 MHz, CDCl3) δ 184.8, 173.7ꢀ 151.0, 147.2ꢀ
135.0, 134.4ꢀ128.6ꢀ 128.5ꢀ 128.4ꢀ 128.3ꢀ 123.6ꢀ 122.7ꢀ
[α]20 = +152.0 (c 0.2, CHCl3); 1H NMR (600 MHz, CDCl3, two
D
rotamers) δ 9.31 (s, 1H), 9.29 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H),
7.48 (d, J = 7.8 Hz, 1H), 7.40 – 7.31 (m, 10 H), 7.19 – 7.13 (m,

ACCEPTED MANUSCRIPT
3H), 7.03 (m, 1H), 5.23 – 5.19 (m, 2H), 5.15 – 5.12 (m, 2H), 5.06
(d, J = 15.6 Hz, 1H), 5.00 (d, J = 15.6 Hz, 1H), 4.63 (d, J = 15.0
Hz, 1H), 4.33 – 4.28 (m, 2H), 4.17 –4.09 (m, 5H), 3.97 – 3.90 (m,
4H), 3.70 (m, 2H), 3.58 – 3.55 (m, 2H), 3.30 (m, 1H), 3.10 (m,
1H), 2.49 (m, 2H), 2.40 (m, 1H), 2.20 (m, 1H), 1.86 (m, 2H),
1.57 (m, 2H), 1.49 (d, J = 3.6 Hz, 6H), 1.46 (d, J = 3.6 Hz, 6H)
ppm. 13C NMR (150 MHz, CDCl3) δ 156.0, 155.9, 139.7, 139.5,
136.9, 136.8, 134.8, 134.7, 128.5, 128.2, 128.0, 127.9, 122.2,
122.1, 121.9, 119.7, 119.5, 118.9, 118.3, 118.0, 110.9, 110.6,
106.9, 106.4, 100.2, 100.1, 67.8, 67.7, 67.3, 67.1, 66.0, 65.2, 64.7,
64.5, 64.4, 64.3, 43.2, 43.1, 43.0, 42.1, 41.7, 41.6, 39.5, 29.7,
28.4, 27.7, 25.3, 24.9, 22.5, 22.1 ppm. IR (neat) 3396ꢀ 2938ꢀ
1668ꢀ 1456ꢀ 1418ꢀ 1372ꢀ 1254ꢀ 1196ꢀ 1167ꢀ 1027ꢀ
832ꢀ 731ꢀ 697ꢀ 609ꢀ 522 cm-1 ; HRMS m/z (M+Na)+ calcd
for C27H32N2NaO5 487.2203, found 487.2200.
Acknowledgements
This work was supported by grants from the NSFC (21321061,
21202209 and 21132006), excellent young scientist foundation of
Sichuan University (2016SCU04A10)
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