Total synthesis of phenanthroindolizidine alkaloids via asymmetric deprotonation of N-Boc-pyrrolidine

Article abstract of DOI:10.1039/c3ra47465h

A concise and efficient enantioselective strategy to synthesize two typical phenanthroindolizidine alkaloids, 14-hydroxyantofine and antofine, was developed, featuring an asymmetric deprotonation/diastereoselective carbonyl addition sequence during which the formation of a chiral C-13a center and connection of pyrrolidine and phenanthrene moieties were achieved efficiently in one step. The absolute configuration of the C-13a stereocenter can be delicately controlled by using different enantiomers of sparteine, both of which are commercially available. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ra47465h

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Total synthesis of phenanthroindolizidine alkaloids
via asymmetric deprotonation of N-Boc-
pyrrolidine†
Cite this: RSC Adv., 2014, 4, 14979
*
Meng Deng, Bo Su, Hui Zhang, Yuxiu Liu and Qingmin Wang
A concise and efficient enantioselective strategy to synthesize two typical phenanthroindolizidine alkaloids,
14-hydroxyantofine and antofine, was developed, featuring an asymmetric deprotonation/
diastereoselective carbonyl addition sequence during which the formation of a chiral C-13a center and
connection of pyrrolidine and phenanthrene moieties were achieved efficiently in one step. The absolute
configuration of the C-13a stereocenter can be delicately controlled by using different enantiomers of
sparteine, both of which are commercially available.
Received 10th December 2013
Accepted 28th January 2014
DOI: 10.1039/c3ra47465h
www.rsc.org/advances
functionalization of pyrrolidine (Scheme 1).4 Although detailed
mechanistic studies have been done for this elegant and crea-
tive methodology,5 only a few successful applications in the
total synthesis of natural products and chiral drug molecules
have been reported, most of which used sinuous approaches to
realize the asymmetric functionalization.4d,e,6 To showcase the
efficiency and convenience of this methodology, we wish herein
to report a concise synthesis of (+)-14-hydroxyantone (2) and
(+)-antone (1a), both of which are enantiomers of these alka-
loids in nature (Fig. 1).
Introduction
Phenanthroindolizidine alkaloids, isolated mainly from Tylo-
phora, Cynanchun, Pergularia, and some genera of the Asclepia-
daceas family, have attracted continuous attention from both
the synthetic and pharmaceutical communities owing to their
unique structural features and low natural abundance, as well
as their noteworthy biological activities since the rst isolation
of (R)-tylophorine [(ꢀ)-1b] (Fig. 1) in 1935.1
In the past few decades, a number of impressive enantiose-
lective synthetic routes for phenanthroindolizidine alkaloids
have been reported.1c,2 As these alkaloids possess a stereogenic
center at the a position of the nitrogen atom, the chiron
approach starting with optical a-amino acids or their derivatives
has been widely used.1c,2b,d,e,h,i,k In addition, a few other
remarkable strategies have also been employed in recent years,
including the chiral auxiliary procedure,2j,3 asymmetric transi-
tion-metal-catalyzed intramolecular carboamination,2c,f enan-
tioselective phase-transfer alkylation,2a and proline-catalyzed
asymmetric a-aminoxylation of an aldehyde,2g etc. Although a
sustainable source of these alkaloids for bioactivity studies can
be provided by the approaches mentioned above, a more effi-
cient synthetic strategy is still desirable.
Results and discussion
Retrosynthetically, (+)-antone (1a) and (+)-14-hydroxyantone
(2) were envisioned to be accessible via Pictet–Spengler
Asymmetric deprotonation of N-Boc-pyrrolidine using
s-BuLi/(+)-sparteine, which gives a congurationally preferred
carbanion, followed by nucleophilic substitution/addition was
an attractive approach developed by Beak et al. for the direct
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, Nankai University, Collaborative Innovation Center
of Chemical Science and Engineering (Tianjin), Tianjin 300071, People's Republic of
China. E-mail: wang98h@263.net; wangqm@nankai.edu.cn
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectroscopic data for 5, 5a, 4c, 7a, 7b, 1a, and 2. HRMS (ESI) data for 5a, 4c,
7a, 7b, and 2. Chiral-HPLC chromatogram for 5, 2, 1a. See DOI:
10.1039/c3ra47465h
Fig. 1 Representative phenanthroindolizidine alkaloids and (+)-spar-
teine (L).
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bromide 4b was added. Gratifyingly, the desired coupled
product (ꢁ)-5 was obtained in a moderate yield. It is worth
noting that a main by-product 5a was isolated in a 22% yield,
which was believed to be produced from lithium–bromide
exchange9 of 4b with 2-lithio-N-Boc-pyrrolidine and subsequent
dimerization. To decrease the lithium–halogen exchange, 4b
was replaced by chloride 4a, which showed that 4a could give
better results (Table 1, entry 1).
Aer investigating the reactivity of N-Boc-pyrrolidine, it
was found that the asymmetric version was affected by the
use of chiral ligand (+)-sparteine (Table 1, entries 3 and 4).
Although great effort was made to optimize the reaction
conditions, unfortunately, the desired product 5 could only
be obtained in moderate enantiomeric excess and low yields.
The reason for the lower yield was proposed to be the steric
effect when the relatively bulky ligand was introduced. The
subsequent Pictet–Spengler cyclization proved to be effective,
giving antone (1a) in a high yield (91%) and moderate ee
(60%).
It was thought that the notable lithium–halogen exchange9
during the alkylation should be responsible for the unsat-
isfying yield and ee. To explore the mechanism, 2,2,6,6-tetra-
methylpiperidine 1-oxyl (TEMPO) was introduced into the
reaction system (Table 1, entry 5).10 Product 5 was gained in a
lower yield (23%) but a slightly raised ee (58%). Meanwhile,
radical trapping product 4c (Table 1) was isolated in an 18%
yield, which suggested a free radical process, as shown in
Scheme 2. Besides being generated by direct SN2 substitution
of chiral 3 with 4b, 5 could also be produced by free radical
Scheme 1 Asymmetric deprotonation of N-Boc-pyrrolidine using s-
BuLi/(+)-sparteine (L).
cyclization of compounds 5 (Table 1) and 7a/7b (Scheme 3),
respectively. Key intermediate 5 could be obtained by SN2
substitution of chiral 2-lithio-N-Boc-pyrrolidine (3) to 4a or 4b
(Table 1), and 7a/7b by a nucleophilic carbonyl addition of 3 to
phenanthryl aldehyde 6 (Table 1). The starting materials 4a,7a 4b
(ref. 2i) and 6 (ref. 7b) were readily available by using an efficient
and practical FeCl3-mediated oxidative coupling method for
constructing a polymethoxy-phenanthrene moiety developed by
our group.8
Initially, alkylation of N-Boc-pyrrolidine with bromide 4b
was put into practice, as shown in Table 1. To explore the
reactivity, tetramethylethylenediamine (TMEDA) was rst
employed as a ligand. Deprotonation of N-Boc-pyrrolidine with
s-BuLi/TMEDA gave (ꢁ)-2-lithio-N-Boc-pyrrolidine, then
Table 1 Synthesis of (+)-antofine (1a) by alkylation of N-Boc-pyrrolidine
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Scheme 2 Proposed mechanism of lithium–halogen exchange between 3 and 4b.
coupling aer the single electron transfer (SET) process were subjected to Pictet–Spengler cyclization conditions
between 3 and 4b, during which the racemization of chiral 3 separately. Interestingly, both isomers gave the same cycliza-
and dimerization of free radical intermediate 4r were tion product 2 in moderate yields (58%, 54%) and high ee
unavoidable. We declare that this SET mechanism is at least a (97%, 96%), and the other diastereomeric product was not
minor pathway but there must exist a lithium–halogen detected. It is believed that racemization at the C-14 stereo-
exchange pathway not involving SET.9,11
center occurred under the harsh acidic Pictet–Spengler cycli-
To avoid lithium–halogen exchange, a second strategy— zation conditions, so only one congurationally preferred
carbonyl addition of 3 to 6—was explored (Scheme 3). To our product was obtained. The NMR data of synthesized product 2
delight, treatment of N-Boc-pyrrolidine with s-BuLi/(+)-spar- were identical to those reported in literature.12 However, the
teine in diethyl ether gave chiral 3, which underwent reaction specic rotation of compound 2 was opposite to the natural
with phenanthryl aldehyde 6 to give the enantiomerically product, thus we conrmed that the absolute conguration of
enriched, diastereomeric intermediates 7a and 7b in 26% and 2 was (13aS, 14S). Aer dehydroxylation, 1a was obtained in a
61% yields, respectively. Then diastereoisomers 7a and 7b 96% yield and 98% ee.
Scheme 3 Synthesis of (+)-14-hydroxyantofine (2) and (+)-antofine (1a) by carbonyl addition of N-Boc-pyrrolidine.
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ꢂ
(60 mL) at ꢀ78 C was added s-BuLi (2.2 mL, 1.0 M in hexane,
1.1 equiv.). The following operation was in accordance with
procedure A.
Conclusions
In conclusion, a concise strategy to synthesize two typical phe-
nanthroindolizidine alkaloids, antone (1a) and 14-hydrox-
yantone (2), has been explored, featuring asymmetric
deprotonation of the N-Boc-pyrrolidine followed by reaction
with carbon electrophiles. For the alkylation of compound 3
with 4, a notable lithium–halogen exchange was observed,
which should account for the unsatisfying yield and ee. For the
carbonyl addition of 3 to 6, a gratifying result was obtained.
Product 2 was gained in a 47% total yield and 96–97% ee from 6
in two steps, then aer undergoing one more step 1a could be
obtained in a 96% yield and 98% ee.
Preparation of racemic 5 and 5a from 4a or 4b (Table 1, entries
1 and 2)
Taking 4a as an example (Table 1, entry 1), lithiation of N-Boc-
pyrrolidine was carried out according to procedure A, then a
suspension of 4a (317 mg, 1.0 mmol) in Et2O (10 mL) was added.
Purication by ash chromatography with 1/6 (v/v) EtOAc–
hexane, followed by recrystallization from 1.0 mL methanol
gave racemic 5 (280 mg, 62%) as a white solid; m.p. 150–152 ꢂC
(ref. 2b: 99–101 ꢂC). 1H NMR (400 MHz, CDCl3) d ¼ 8.33 (s, 1H,
Ar-H), 7.91 (s, 1H, Ar-H), 7.85 (d, J ¼ 2.0 Hz, 1H, Ar-H), 7.73 (d,
J ¼ 8.8 Hz, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 7.17 (dd, J ¼ 8.8, 2.0 Hz,
1H, Ar-H), 4.26 (m, 1H, N-CH, 2-H), 4.22 (s, 3H, OMe), 4.12 (s,
3H, OMe), 4.02 (s, 3H, OMe), 3.92 (m, 1H, Ar-CH2), 3.49 (m, 1H,
Ar-CH2), 3.32 (m, 1H, N-CH2, 5-H), 2.59 (m, 1H, N-CH2, 5-H),
2.02 (m, 1H, 3-H), 1.84 (m, 2H, 3-H, 4-H), 1.67 (m, 1H, 4-H), 1.51
(s, 9H, CH3) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 157.8, 154.7,
149.8, 148.7, 131.1, 130.6, 129.5, 127.3, 126.0, 125.7, 124.5,
115.2, 106.8, 103.9, 103.4, 78.9, 57.2, 56.7, 56.0, 55.6, 46.8, 38.6,
29.0, 28.6, 23.5 ppm. Filtering the insoluble solid out of the
organic/aqueous phase during the workup procedure gave 5a
(45 mg, 16%) as an off-white solid; m.p. 265–270 C. H NMR
(400 MHz, CDCl3) d ¼ 7.95 (s, 2H, Ar-H), 7.87 (d, J ¼ 2.4 Hz, 2H,
Ar-H), 7.74 (d, J ¼ 8.8 Hz, 2H, Ar-H), 7.58 (s, 2H, Ar-H), 7.37 (s,
2H, Ar-H), 7.20 (dd, J ¼ 8.7, 2.4 Hz, 2H, Ar-H), 4.12 (s, 6H, OMe),
4.04 (s, 6H, OMe), 3.87 (s, 6H, OMe), 3.57 (s, 4H, Ar-CH2) ppm;
13C NMR (100 MHz, CDCl3) d ¼ 157.9, 149.3, 148.7, 133.1, 130.3,
129.6, 126.8, 126.2, 124.8, 124.1, 115.5, 104.7, 104.7, 103.9, 56.0,
55.8, 55.6, 33.8 ppm. HRMS (ESI): calcd for C36H35O6 [M + H]+
563.2428, found 563.2423.
Experimental section
General information
The melting points were determined using an X-4 binocular
microscope melting-point apparatus and were uncorrected. H
1
NMR spectra were obtained using a Bruker AV 400 spectrom-
eter. Chemical shis (d) were given in parts per million (ppm)
and were measured downeld from internal tetramethylsilane.
13C NMR spectra were recorded using a Bruker AV 400 instru-
ment (100 MHz) and CDCl3 as the solvent. Chemical shis (d)
were reported in parts per million. High-resolution mass
spectra were obtained using an FT-ICR MS spectrometer (Ion-
spec, 7.0 T). Optical rotations were measured using an Autopol
IV auto digital polarimeter (Rudolph Research Analytical). All
anhydrous solvents were dried and puried by standard tech-
niques just before use. All reagents were purchased from
commercial suppliers without further purication. Reactions
were monitored by thin layer chromatography on plates (GF254)
using UV light as a visualizing agent. (+)-Sparteine was
purchased from Aladdin Industrial Corporation. If not noted
otherwise, ash column chromatography used silica gel (200–
300 mesh).
1
ꢂ
Preparation of (+)-5 and 5a from 4a or 4b (Table 1, entries 3
and 4)
Taking 4a as an example (Table 1, entry 4), lithiation of N-Boc-
pyrrolidine was carried out according to procedure B and then a
suspension of 4a (317 mg, 1.0 mmol) in Et2O (10 mL) was added.
Purication by ash chromatography with 1/6 (v/v) EtOAc–
hexane, followed by recrystallization from 1.0 mL methanol
gave (+)-5 (150 mg, 33%) as a white solid. Chiral HPLC analysis
(Chiralcel AD-H column, i-PrOH : hexane ¼ 10 : 90, 1.0 mL
minꢀ1) showed that the product had an enantiomeric excess of
62%. Filtering the insoluble solid out of the organic/aqueous
phase during the workup procedure gave 5a (31 mg, 11%) as an
off-white solid. Other data were identical to those of racemic 5
and 5a in procedure A.
Procedure A: racemic deprotonation of N-Boc-pyrrolidine and
subsequent functionalization (Table 1, entries 1 and 2)
To a solution of TMEDA (278 mg, 2.4 mmol, 1.2 equiv.) and N-
Boc-pyrrolidine (344 mg, 2.0 mmol, 1.0 equiv.) in Et2O (60 mL)
at ꢀ78 ꢂC was added s-BuLi (2.2 mL, 1.0 M in hexane, 1.1 equiv.).
ꢂ
The reaction mixture was stirred for 4 h at ꢀ78 C, and then a
suspension of electrophile 4 or 6 (1.0 mmol, 0.5 equiv.) in Et2O
(10 mL) was added. The mixture was stirred for 4–6 h at ꢀ78 ꢂC,
then allowed to warm slowly to 0 ꢂC in 3 h. Workup consisted of
the addition of water (20 mL), extraction of the aqueous layer
with Et2O (2 ꢃ 10 mL), extraction of the combined Et2O extracts
with 5% phosphoric acid (2 ꢃ 10 mL) and brine (2 ꢃ 10 mL),
drying over anhydrous magnesium sulfate, ltration, and
concentration in vacuo.
Preparation of (+)-5, 4c, and 5a from 4b (Table 1, entry 5)
Lithiation of N-Boc-pyrrolidine according to procedure B was
carried out, then a suspension of 4b (361 mg, 1.0 mmol,
0.5 equiv.) and TEMPO (624 mg, 4.0 mmol, 2.0 equiv) in Et2O
(10 mL) was added. Purication by ash chromatography with
Procedure B: asymmetric deprotonation of N-Boc-pyrrolidine
and subsequent functionalization (Table 1, entries 3–5)
To a solution of (+)-sparteine (563 mg, 2.4 mmol, 1.2 equiv.) and 1/10 (v/v) EtOAc–hexane gave (+)-5 (106 mg, 23%) as a
N-Boc-pyrrolidine (344 mg, 2.0 mmol, 1.0 equiv.) in Et2O white solid [chiral HPLC analysis (Chiralcel AD-H column,
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i-PrOH : hexane ¼ 10 : 90, 1.0 mL minꢀ1) showed that the d ¼ 158.0, 155.5, 149.6, 148.5, 133.0, 130.6, 130.3, 125.7, 125.3,
product had an enantiomeric excess of 58%]; and 4c (80 mg, 124.3, 121.5, 115.2, 105.6, 103.8, 103.3, 79.4, 70.2, 61.6, 56.7,
18%) as a white solid; m.p. 138–139 ꢂC. 1H NMR (400 MHz, 55.9, 55.6, 48.1, 28.6, 25.0, 24.1 ppm; HRMS (ESI): calcd for
CDCl3) d ¼ 7.93 (s, 1H, Ar-H), 7.86 (d, J ¼ 2.4 Hz, 1H, Ar-H), 7.81
C
27H33NNaO6 [M + Na]+ 490.2200, found 490.2197; and the
(d, J ¼ 8.8 Hz, 1H, Ar-H), 7.66 (s, 1H, Ar-H), 7.50 (s, 1H, Ar-H), major diastereomer 7b (286 mg, 61%) as a white foamy solid;
7.20 (dd, J ¼ 8.8, 2.4 Hz, 1H, Ar-H), 5.24 (s, 2H, Ar-CH2), 4.12 (s, m.p. 93–95 ꢂC; 1H NMR (400 MHz, CDCl3) d ¼ 7.97 (brs, 1H, Ar-
3H, OMe), 4.07 (s, 3H, OMe), 4.03 (s, 3H, OMe), 1.59–1.52 (m, H), 7.90 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.75 (d, J ¼ 8.8 Hz, 1H,
6H, CH2), 1.37 (s, 6H, CH3), 1.18 (s, 6H, CH3) ppm; 13C NMR Ar-H), 7.63 (brs, 1H, Ar-H), 7.17 (dd, J ¼ 8.8, 2.0 Hz, 1H, Ar-H),
(100 MHz, CDCl3) d ¼ 158.3, 149.3, 148.7, 131.0, 130.3, 129.2, 6.21 (brs, 1H, OH), 5.09 (brs, 1H, Ar-CH), 4.63 (brs, 1H, N-CH, 2-
126.4, 125.8, 125.0, 124.6, 115.4, 105.4, 103.9, 103.6, 78.4, 56.1, H), 4.10 (s, 3H, OMe), 4.08 (s, 3H, OMe), 3.99 (s, 3H, OMe), 3.42–
56.0, 55.6, 39.4, 32.9, 20.5, 17.0 ppm. HRMS (ESI): calcd for 3.50 (m, 2H, N-CH2, 5-H), 1.79–1.91 (m, 1H, 3-H), 1.66–1.76 (m,
C
27H36NO4 [M + H]+ 438.2639, found 438.2635. Filtering the 1H, 3-H), 1.54 (s, 9H, CH3), 1.37–1.47 (m, 2H, 4-H) ppm; 13C
insoluble solid out of the organic/aqueous phase during the NMR (100 MHz, CDCl3) d ¼ 158.6, 158.3, 149.0, 148.6, 133.0,
workup procedure gave 5a (34 mg, 12%) as an off-white solid. 131.0, 130.3, 126.0, 125.6, 125.2, 115.5, 106.0, 103.7, 103.7, 80.9,
Other data were identical to those of racemic 5 and 5a in 63.6, 56.0, 55.9, 55.5, 47.8, 29.0, 28.5, 24.1 ppm; HRMS (ESI):
procedure A.
calcd for C27H33NNaO6 [M + Na]+ 490.2200, found 490.2196.
Preparation of 1a from (+)-5
Preparation of 2 from 7a
(+)-5 (45 mg, 0.1 mmol, 62% ee) provided by the above proce- To a solution of 7a (94 mg, 0.2 mmol) in ethanol (5 mL) was
dure (Table 1, entry 4) was dissolved in ethanol (2 mL). Conc. added conc. HCl (0.5 mL, 36–38%), the reaction mixture was
HCl (0.5 mL, 36–38%) and formaldehyde solution (0.5 mL, 37%) heated under reux for 1 h, then formaldehyde solution (2.0 mL,
were then added and the reaction mixture was heated under 37%) was added, and the reaction mixture was heated under
reux for 12 h under an Ar atmosphere. Aer removing most of reux for 56 h under an Ar atmosphere. Aer removing most of
the ethanol, aqueous NaOH (1.0 M, 10 mL) was added and the the ethanol, aqueous NaOH (1.0 M, 10 mL) was added and the
mixture was extracted with CH2Cl2 (3 ꢃ 10 mL), and the mixture was extracted with CH2Cl2 (3 ꢃ 10 mL), and the
combined organic layer was dried over anhydrous Na2SO4, combined organic layer was dried over anhydrous Na2SO4,
ltered and concentrated in vacuo. Purication of the residue by ltered and concentrated in vacuo. Purication of the residue by
ash chromatography with 20/1 (v/v) CH2Cl2–CH3OH gave 1a ash chromatography with 20/1 (v/v) CH2Cl2–CH3OH gave 2
(33 mg, 91%) as a white solid; m.p. 215–217 ꢂC (ref. 2h: 209–211 (44 mg, 58%) as a light-yellow solid; m.p. 221–223 ꢂC. [a]2D6
¼
11
ꢂC). Chiral HPLC analysis (Chiralcel AD-H column, +197.4 (c 0.23, CHCl3); {ref. 12: m.p. 237–239 C, [a]D ¼ ꢀ217.1
i-PrOH : hexane ¼ 50 : 50, 1.0 mL minꢀ1) showed that the (c 0.23, CHCl3)}; chiral HPLC analysis (Phenomenex Lux Cellu-
product had an enantiomeric excess of 60%. 1H NMR (400 MHz, lose-1 column, i-PrOH : CH3CN (0.1% Et3N) ¼ 5 : 95, 1.0 mL
CDCl3) d ¼ 7.92 (s, 1H, Ar-H), 7.91 (d, J ¼ 2.4 Hz, 1H, Ar-H), 7.83 minꢀ1) showed that the product had an enantiomeric excess of
ꢂ
1
(d, J ¼ 9.2 Hz, 1H, Ar-H), 7.32 (s, 1H, Ar-H), 7.21 (dd, J ¼ 9.2, 2.4 97%. H NMR (400 MHz, CDCl3) d ¼ 7.86 (s, 1H, Ar-H), 7.84 (s,
Hz, 1H, Ar-H), 4.71 (d, J ¼ 14.8 Hz, 1H, 9-H), 4.11 (s, 3H, OMe), 1H, Ar-H), 7.72 (d, J ¼ 2.0 Hz, 1H, Ar-H), 7.03 (d, J ¼ 9.2 Hz, 1H,
4.07 (s, 3H, OMe), 4.02 (s, 3H, OMe), 3.71 (d, J ¼ 14.8 Hz, 1H, 9- Ar-H), 6.85 (dd, J ¼ 9.2, 2.0 Hz, 1H, Ar-H), 4.94 (s, 1H, 14-H), 4.79
H), 3.44–3.50 (m, 1H, 13a-H), 3.40–3.33 (m, 1H, 14-H), 2.85–2.96 (brs, 1H, OH), 4.15 (s, 3H, OMe), 4.11 (s, 3H, OMe), 4.02 (s, 3H,
(m, 1H, 14-H), 2.42–2.50 (m, 2H, 11-H), 2.19–2.26 (m, 1H, 13-H), OMe), 3.55 (d, J ¼ 15.6 Hz, 1H, 9-H), 3.16–3.20 (d, J ¼ 15.6 Hz, 1H,
2.00–2.06 (m, 1H, 13-H), 1.89–1.94 (m, 1H, 12-H), 1.75–1.79 (m, 9-H), 3.13–3.16 (m, 1H, 11-H), 2.35–2.42 (m, 2H, 13a-H, 12-H),
1H, 12-H) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 157.4, 149.4, 2.17–2.25 (m, 1H, 11-H), 2.07–1.95 (m, 1H, 12-H), 1.95–1.85 (m,
148.3, 130.2, 127.1, 126.8, 125.6, 124.3, 124.2, 123.5, 114.9, 2H, 13-H) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 157.7, 149.4,
104.7, 104.0, 103.8, 60.2, 56.0, 55.9, 55.5, 55.1, 53.9, 33.8, 31.3, 148.3, 130.5, 127.7, 127.2, 126.8, 124.2, 123.7, 122.8, 114.6, 105.2,
21.6 ppm.
104.0, 103.3, 65.4, 64.8, 56.1, 55.9, 55.4, 55.3, 53.4, 24.0, 21.6 ppm.
Preparation of 7a/7b from 6
Preparation of 2 from 7b
Lithiation of N-Boc-pyrrolidine was carried out according to To a solution of compound 7b (219 mg, 0.47 mmol) in ethanol
procedure B, then a suspension of 6 (296 mg, 1.0 mmol) in Et2O (12 mL) was added conc. HCl (1.0 mL, 36–38%), the reaction
(10 mL) was added. Purication by ash chromatography with mixture was heated under reux for 1 h, then formaldehyde
1/4 (v/v) EtOAc–hexane gave the minor diastereomer 7a (122 mg, solution (4.0 mL, 37%) was added and the reaction mixture was
26%) as a white solid; m.p.195–197 ꢂC. 1H NMR (400 MHz, heated under reux for 60 h under an Ar atmosphere. Workup
CDCl3) d ¼ 8.14 (s, 1H, Ar-H), 7.88–7.75 (m, 4H, Ar-H), 7.18 (dd, was similar to the above procedure and purication by ash
J ¼ 8.8, 2.0 Hz, 1H, Ar-H), 6.11 (s, 1H, Ar-CH), 4.28–4.35 (m, 1H, chromatography gave 2 (95 mg, 54%) as a light-yellow solid. [a]D26
N-CH, 2-H), 4.18 (s, 3H, OMe), 4.08 (s, 3H, OMe), 4.01 (s, 3H, ¼ +191.6 (c 0.23, CHCl3); chiral HPLC analysis (Phenomenex Lux
OMe), 3.40–3.48 (m, 2H, N-CH2, 5-H), 2.43–2.47 (m, 1H, 3-H), Cellulose-1 column, i-PrOH : CH3CN (0.1% Et3N) ¼ 5 : 95,
2.07–2.15 (m, 1H, 3-H), 1.93–2.02 (m, 1H, 4-H), 1.64–1.72 (m, 1.0 mL minꢀ1) showed that the product had an enantiomeric
1H, 3-H), 1.53 (s, 9H, CH3) ppm; 13C NMR (100 MHz, CDCl3) excess of 96%. Other data were identical to those above.
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A. Z. Feng, Z. W. Wang and Q. M. Wang, J. Org. Chem., 2010,
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Preparation of 1a from 2
Two parts of 2 (44 + 95 mg, 0.367 mmol) prepared from 7a and
7b were gathered and dissolved in triuoroacetic acid (4 mL),
then triethylsilane (0.36 g, 3.1 mmol) was added, and the
resulting mixture was stirred at room temperature for 12 h in
the dark. The solvent was made basic with aqueous NaOH
(2.0 M, 40 mL) and extracted with CH2Cl2 (3 ꢃ 20 mL), and the
combined organic layer was dried over anhydrous Na2SO4,
ltered and concentrated in vacuo. Purication of the residue by
ash chromatography using basic alumina (200–300 mesh) with
40/1 (v/v) CH2Cl2–CH3OH gave 1a (127 mg, 96%) as a white
solid. Chiral HPLC analysis (Chiralcel AD-H column,
i-PrOH : hexane ¼ 50 : 50, 1.0 mL minꢀ1) showed that the
product had an enantiomeric excess of 98%. [a]2D5 ¼ +80.9
(c 0.45, CHCl3); {ref. 2h: [a]2D0 ¼ +85 (c 2.0, CHCl3); 99% ee}; other
data were identical to those of 1a prepared from 5.
´
D. David, L. Stephane, C. Axel, D. Eric and G. Pierre, Eur. J.
Org. Chem., 2010, 1943–1950.
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552–560; (b) D. Hoppe and T. Hense, Angew. Chem., Int.
Ed., 1997, 36, 2282–2316.
Acknowledgements
This work was supported by the National Key Project for Basic
Research (2010CB126106), the National Natural Science Foun-
dation of China (21132003, 21121002, 21372131, 21002053),
Tianjin Natural Science Foundation (11JCZDJC20500), and the
Specialized Research Fund for the Doctoral Program of Higher
Education (20130031110017).
6 For examples: (a) R. T. Watson, V. K. Gore, K. R. Chandupatla,
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14984 | RSC Adv., 2014, 4, 14979–14984
This journal is © The Royal Society of Chemistry 2014