Concise synthesis of tylophorine

Article abstract of DOI:10.1016/j.tet.2013.02.014

The phenanthroindolizidine alkaloid tylophorine has been synthesized in the (R)- and racemic forms. One of the routes involves three steps from a known compound employing a Stevens rearrangement as the pivotal reaction. The phenanthrene moiety was constructed by either a base-catalyzed cyclization of 2-alkynylbiphenyls or a double Suzuki coupling of a 2,2′-dibromobiphenyl with vic-bis(pinacolatoboryl)alkene in other routes.

Full text of DOI:10.1016/j.tet.2013.02.014

Tetrahedron 69 (2013) 2996e3001
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Concise synthesis of tylophorine
*
Qi-Xian Lin, Tse-Lok Ho
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, 345 Ling Ling Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The phenanthroindolizidine alkaloid tylophorine has been synthesized in the (R)- and racemic forms.
One of the routes involves three steps from a known compound employing a Stevens rearrangement as
the pivotal reaction. The phenanthrene moiety was constructed by either a base-catalyzed cyclization of
2-alkynylbiphenyls or a double Suzuki coupling of a 2,20-dibromobiphenyl with vic-bis(pinacolatoboryl)
alkene in other routes.
Received 29 November 2012
Received in revised form 25 January 2013
Accepted 31 January 2013
Available online 8 February 2013
Ó 2013 Published by Elsevier Ltd.
Keywords:
Phenanthroindolizidine alkaloid
Tylophorine
Stevens rearrangement
Double Suzuki coupling
Symmetry for synthesis design
1. Introduction
works from our laboratories encompass elaboration of sesquiter-
penes, such as longifolene, occidol, tavacpallescensin, cuparene/her-
The pentacyclic alkaloid tylophorine (1) is present in Tylophora
indica, whose leaves having been used in India since ancient times
for the treatmentof asthma, bronchitis, rheumatism, and dysentery.1
First isolated in 1935,2 1 was shown to contain an indolizidine sub-
unit fused to a phenanthrene system, which heralded discovery of
homologous phenanthroquinolizidine alkaloids. At present more
than 60 members of the two families have been isolated and char-
acterized from plants of the Asclepiadaceae and Moraceae fami-
lies.1b,3 Because these substances possess outstanding biological and
pharmacological activities, including antitumor, anti-inflammatory,
antiviral, antibiotic, and cytotoxic effects, they make themselves
attractive synthetic targets.
bertene, b-cuparenone, platyphyllide, isocyano-neopupukeanane,
and of several alkaloids including cryptolepine/cryptotackiene,
anatoxin-a, nicotyrine, ellipticine, tangutorine, eburnamonine, and
tacamonine. Tylophorine was identified as one of our targets due to
its incorporation of a symmetrical phenanthrene moiety to permit
synthetic design based on either symmetrical biphenyls or phenan-
threne intermediates. Depicted in Schemes 1 and 2 are some of our
initial retrosynthetic ideas, which had undergone modification dur-
ing the subsequent investigation.
Since 1960, more than a dozen synthetic approaches for racemic
tylophorine and related compounds have been on records.4 For
assembly of enantiomeric tylophorine, after establishment of its
absolute configuration by a synthesis from glutamic acid,5a routes
that make use of chirons (proline,5b,f,h,i pyroglutamate5e) and chiral
auxiliaries or based on stereoselective reactions (Grignard addi-
tions5d and double Michael reactions5c) and asymmetric catalysis
(copper5g or palladium5k-catalyzed intramolecular alkene carboa-
mination) have been examined.
2. Discussion
Our interest in the synthesis of tylophorine was derived from the
relevance of molecular symmetry in synthetic design.6 Previous
Scheme 1. Retrosynthetic analysis (1).
* Corresponding author. E-mail address: tselokho@yahoo.com (T.-L. Ho).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.02.014

Q.-X. Lin, T.-L. Ho / Tetrahedron 69 (2013) 2996e3001
2997
Fig. 2. Synthesis of tylophorine starting from a twofold Suzuki coupling.
Scheme 2. Retrosynthetic analysis (2).
tylophorine precursor 12B that requires only a PicteteSpengler
reaction with acidic formaldehyde to complete another synthesis.
Access to 11B from N-benzylsuccinimide was based on a Barbier
propargylation12 and reduction with NaBH3CN under acidic
conditions.13
We also investigated some variants to the synthesis. Initially we
planned to pursue construction of two rings by a tandem Sonoga-
shiraeHeck coupling based on a 2,20-dihalobiphenyl. This effort did
not lead to the desired intermediate therefore a less ambitious
approach was adopted (Fig. 3). It started from a Sonogashira cou-
pling of 5-propargyl-1-benzyl-2-pyrrolidone 11B with 2-iodo-
4,5,30,40-tetramethoxybiphenyl (13)5f that is obtainable (54% yield)
from Suzuki coupling of 4,5-diiodo-1,2-dimethoxybenzene14 with
3,4-dimethoxyphenylboronic acid. The product 14 (96%) un-
derwent cyclization through isomerization to an allene by DBU15
resulted in the phenanthrene 4 (93% yield).
A succinct route to racemic tylophorine employs a symmetrical
9,10-bis(bromomethyl)phenanthrene 2A, which can be prepared by
two methods. The one starting from veratrole is via 2,20-dibromo-
4,40,5,50-tetramethoxybiphenyl (6)7 on successive treatment with
n-butyllithium, (THF)3CrCl3, and dimethyl acetylenedicarboxylate8
to deliver 34l was concluded on reduction with LiAlH4 (to 2B) and
bromination with PBr3. A more convenient protocol involves
preparation of 2C from veratrole in two steps in 49% yield by the
method of Weisgraber and Weiss,9 followed by benzylic bromina-
tion with NBS (yield 64%).
As our initial attempts at using 2A to alkylate the N-Boc derivative
of 2-lithiopyrrolidine were not successful, we turned to a strategy
involving formation of spirocyclic ammonium salts for a Stevens
rearrangement. Regioselective generation of the desired ammonium
ylide dictates the pyrrolidine nucleophile to contain an auxiliary
group at C-2 and reaction with 2-trimethylsilylpyrrolidine was
assayed using a fluoride base. The reaction did not proceed cleanly
therefore the N-Boc derivative of 2-tri-n-butylstannylpyrrolidine 910
was used instead. The free amine was released from 9 on treatment
with B-bromocatecholborane and sodium hydroxide, and its qua-
ternization to give 10 was carried out immediately by mixing with
2C. Stevens rearrangement on treatment 10 with n-butyllithium fi-
nally provide tylophorine in 37% yield (Fig. 1).
Fig. 3. Synthesis of racemic tylophorine involving a Sonogashira coupling.
The coupling-cyclization sequence was repeated with the
iodobiphenyl 13 and (R)-1-propargyl-2-oxopyrrolidinyl-5-methyl
t-butyldimethylsilyl ether (16) that was available from (R)-pyro-
glutamic acid.16 Note the different position of the propargyl
group in the pyrrolidine ring. As a chiral product 17 containing all
the skeletal carbon atoms was generated, the stage was set for
ring closure and removal of the excess oxygen functionalities.
In the event, a reaction sequence consisting of desilylation,
DesseMartin oxidation, cyclization, and a two-stage reduction
(Et3SiH, BF3$Et2O; LiAlH4) accomplished the task. (R)-(ꢀ)-Tylo-
phorine was isolated.
Fig. 1. Synthesis of tylophorine via Stevens rearrangement.
A second route we developed pertains to annulation by a two-
fold Suzuki coupling11 of 2,20-dibromo-4,5,40,50-tetramethox-
ybiphenyl (6) with pyrrolidone 5 derived from 11B and possessing
a (Z)-2,3-bis(pinacolatoboryl)-2-propenyl group at C-5 (Fig. 2). The
resulting phenanthrene 4 was then deoxygenated on reaction with
LiAlH4 to 12A and further N-debenzylated (H2, Pd/C) to provide the

2998
Q.-X. Lin, T.-L. Ho / Tetrahedron 69 (2013) 2996e3001
In summary, we have developed four routes for the efficient
3.1.2. 9,10-Bis(bromomethyl)-2,3,6,7-tetramethoxyphenanthrene
(2A) from 2C. A mixture of 2C (817 mg, 2.506 mmol), AIBN (42 mg,
0.256 mmol), NBS (989 mg, 5.556 mmol) in CCl4 (13 mL) was
refluxed for 8 h. On cooling to room temperature water was added
to the reaction mixture and the product was extracted into CH2Cl2,
which was washed with brine and dried over anhydrous Na2SO4.
The solvent was removed and flash chromatography on SiO2 (pe-
troleum ether/CH2Cl2, 1:2) afforded 2A (780 mg, 65%) as yellow
solid.
synthesis of tylophorine. This work further supports our belief
that symmetry consideration is meritorious in synthesis design.
Of interest is the method based on the Stevens rearrangement,
which we completed in 2010, has also been independently
conceived and pursued on a somewhat different precursor4q
(Fig. 4).
3.1.3. 5,6,9,10-Tetramethoxy-20-(tri-n-butylstannyl)-1,3-dihydrospiro
[dibenzo[e,g]isoindole-2,10-pyrrolidinium bromide (10). To a solution
of 9 (230 mg, 0.50 mmol) in CH2Cl2 (5 mL) was dropwise added B-
bromocatecholborane (0.2 M in CH2Cl2, 3 mL, 0.6 mmol), and after
10 min, 2 N NaOH (5 mL). It was followed by the addition of 2A
(240 mg, 0.5 mmol) in CH2Cl2 (12 mL). The resulting mixture was
stirred at room temperature for 4 h, separated into layers and the
aqueous phase extracted with CH2Cl2. The combined organic ex-
tract was dried over MgSO4, evaporated and purified by flash
chromatography on basic Al2O3 (CH2Cl2/MeOH, 80:1 to 15:1) to
afford 10 (220 mg, 0.32 mmol, 65%) as light yellow solid: mp
80e82 ꢁC; 1H NMR (300 MHz, CDCl3)
d 7.77 (s, 2H), 7.02 (s, 1H), 6.94
(s, 1H), 5.75 (d, J¼14.9 Hz, 1H), 5.28 (d, J¼14.0 Hz, 1H), 5.17 (d,
J¼14.6, 1H), 4.84 (d, J¼14.4 Hz, 1H), 4.31e4.37 (m, 2H), 4.14 (s, 6H),
4.03 (s, 6H), 3.71e3.77 (m, 1H), 2.37e2.58 (m, 4H), 0.83e1.04 (m,
18H), 0.66 (t, J¼7.0 Hz, 9H); 13C NMR (75 MHz, CDCl3)
d 149.7, 149.6,
149.5, 149.3, 125.9, 124.9, 123.80, 120.30, 120.21, 104.98, 104.80,
103.46, 103.40, 69.35, 68.87, 68.82, 68.16, 56.77, 56.58, 56.09, 56.0,
28.4, 27.3, 26.9, 22.6,13.2, 9.4; IR (KBr) 2954, 2924, 2852,1610,1520,
1496, 1481, 1431, 1248, 1199, 1158, 1038, 851, 768, 748 cmꢀ1; HRMS
þ
(ESI) calcd for C36H54ꢂSn NO4 676.3095, found 676.3122.
3.1.4. Synthesis (ꢃ)-tylohporine (1) by Stevens rearrangement. To
a solution of 10 (76.4 mg, 0.10 mmol) in THF (4 mL) at ꢀ78 ꢁC was
add n-BuLi (2.5 M in hexane, 0.08 mL, 0.2 mmol) then warmed up to
ꢀ35 ꢁC and stirred for 18 h. Upon quenching with saturated
NaHCO3 the product was extracted into CH2Cl2. The combined or-
ganic extract was washed brine, dried over anhydrous Na2SO4,
concentrated, and purified by flash chromatography on SiO2
(CH2Cl2/MeOH, 20:1) to afford (ꢃ)-tylophorine 1 (15 mg, 37%) as
a light yellow solid: mp 284e286 ꢁC; 1H NMR (300 MHz, CDCl3)
Fig. 4. Synthesis of (R)-tylophorine involving a Sonogashira coupling.
3. Experimental section
3.1. General methods
NMR spectra were recorded with CDCl3 as solvent, at 300 and
75/100 MHz, respectively for 1H and 13C absorptions. Chemical shift
are in parts per million relative to 0 for TMS. Mass spectra including
HRMS were obtained with electron impact ionization at 70 eV or
electrospray ionization, where indicated. IR spectra were recorded
as neat films or KBr pellets (for solids). Melting points, determined
with a Laboratory Devices apparatus, are uncorrected.
d
7.78 (s, 2H), 7.25 (s, 1H), 7.08 (s, 1H), 4.61 (d, J¼14.4 Hz,1H), 4.11 (s,
6H), 4.04 (s, 6H), 3.67 (d, J¼15.0 Hz, 1H), 3.43e3.51 (m, 1H), 3.32 (d,
J¼15.8 Hz, 1H), 2.88e2.97 (m, 1H), 2.44e2.62 (m, 2H), 2.23e2.69
(m, 1H), 2.03e2.06 (m, 1H), 1.95e1.99 (m, 1H), 1.79e1.86 (m, 1H);
13C NMR (75 MHz, CDCl3)
d 148.6, 148. 5, 148.4, 126.0, 125.6, 124.1,
123.6, 123.3, 103.8, 103.2, 103.1, 102.9, 60.2, 56.0, 55.9, 55.8, 54.9,
53.4, 33.2, 31.0, 21.5; MS (ESI): m/z 394 (MþHþ); IR (KBr) 2951,
2922, 2854, 2830,1618, 1514, 1468, 1426, 1247,1212,1149,1018, 843,
3.1.1. 9,10-Bis(bromomethyl)-2,3,6,7-tetramethoxyphenanthrene
(2A) from 3. To a solution of 3 (249 mg, 0.6 mmol) in THF (15 mL) at
0 ꢁC was added LiAlH4 (137 mg, 3.6 mmol) in portions. After stirred
at room temperature for 3 h, the mixture was quenched with water,
filtered through Celite and evaporated to dryness to give a white
solid (2B) without further purification.
773 cmꢀ1
393.1938.
; HRMS (EI) calcd for C24H27NO4 393.1940, found
3.1.5. 1-Benzyl-5-hydroxy-5-(2-propynyl)pyrrolidin-2-one (11A). To
a mixture of N-benzylsuccinimide (946 mg, 5.0 mmol), Zn granule
(651 mg, 10.0 mmol) and PbBr2 (185 mg, 0.5 mmol) in anhydrous
THF (3.0 mL) under N2 was added propargyl bromide (0.6 mL,
7.7 mmol) dropwise over 15 min. The reaction mixture was stirred
at room temperature for 30 min, another portion of and propargyl
bromide (0.26 mL, 3.3 mmol) in anhydrous THF (7.0 mL) was added.
On further stirring for 24 h and quenching with saturated aq NH4Cl
(30.0 mL) the product was extracted into EtOAc, washed with brine,
dried over anhydrous Na2SO4, concentrated, and purified by flash
column chromatography on SiO2 (petroleum ether/acetone, 3:1) to
afford 11A (823 mg, 72%) as a white solid: mp 85e86 ꢁC; 1H NMR
Thus the solid was dissolved in toluene (30 mL) and treated with
PBr3 (60 mL, 0.63 mmol). After stirred at room temperature for 1.5 h,
the mixture was quenched with water and extracted with
dichloromethane. The combined organic extract was washed with
brine, dried over anhydrous Na2SO4, and concentrated under re-
duced pressure to give a crude residue that was purified by flash
column chromatography on SiO2 (petroleum ether/CH2Cl2, 1:2) to
afford 2A (246 mg, 85%) as a yellow solid: mp 246e248 ꢁC; 1H NMR
(300 MHz, CDCl3)
d
7.79 (s, 2H), 7.48 (s, 2H), 5.09 (s, 4H), 4.11 (s, 6H),
149.8, 149.1, 128.6, 125.5,
4.09 (s, 6H); 13C NMR (75 MHz, CDCl3)
d
124.0, 104.8, 103.1, 56.0, 55.9, 27.8; IR (KBr) 3001, 2931, 1620, 1480,
1466, 1457, 1439, 1252, 1197, 1043, 836, 787 cmꢀ1; HRMS (EI) calcd
for C20H20O4Br 481.9728, found 481.9725.
(300 MHz, CDCl3)
d 7.24e7.35 (m, 5H), 4.51 (s, 2H), 3.52 (s, 1H), 2.62
(dd, J¼2.4, 17.0 Hz, 1H), 2.38e2.57 (m, 4H), 2.06e2.16 (m, 1H), 2.00

Q.-X. Lin, T.-L. Ho / Tetrahedron 69 (2013) 2996e3001
2999
(s, 1H); 13C NMR (75 MHz, CDCl3)
91.2, 78.4, 71. 3, 42.4, 32.7, 30.2, 29.3; IR (KBr) 3269, 3208, 1956,
1667, 1498, 1452, 1413, 1359, 1179, 1144, 1084, 958, 715, 691 cmꢀ1
d
175.5, 137. 8, 128.4, 128.0, 127.6,
1035, 847, 700 cmꢀ1; HRMS (EI) calcd for C30H31NO5 485.2202,
found 485.2204.
;
HRMS (EI) calcd for C14H15NO2 229.1103, found 229.1104; Anal.
Calcd for C14H15NO2: C, 73.74; H, 6.59; N, 6.11. Found: C, 73.25; H,
6.67; N, 6.06.
3.1.9. 1-Benzyl-2-[(2,3,6,7-tetramethoxyphenanthren-9-yl)-methyl]
pyrrolidine (12A). To a suspension of 4 (89 mg, 0.18 mmol) in an-
hydrous THF (15 mL) at 0 ꢁC was added LiAlH4 (35 mg, 0.92 mmol)
in portions. After refluxed for 3 h, the mixture was cooled,
quenched with aq Na2SO4 and filtered through Celite. The filtrate
was concentrated, and purified by flash column chromatography on
SiO2 (CH2Cl2/MeOH, 40:1) to afford 12A (71 mg, 83%) as a white
3.1.6. 1-Benzyl-5-(2-propynyl)-2-pyrrolidinone (11B). To a solution
of 11A (1.147 g, 5.0 mmol) in anhydrous MeOH (25 mL) was added
bromophenol blue (3 drops, 1 mg/mL) and NaBH3CN (320 mg,
5.1 mmol). The solution was adjusted to pH w3 with 6 N HCl and
stirred at room temperature for 1.5 h. After neutralized with 6 N
NaOH, the mixture was evaporated. The residue was shaken in
a mixture of water and EtOAc, separated and the organic solution
was washed with brine, dried over anhydrous Na2SO4 and con-
centrated. Flash column chromatography on SiO2 (petroleum ether/
acetone, 4:1) afforded 11A (182 mg) and 11B (803 mg, 90% brsm),
the latter as a white solid: mp 95e96 ꢁC; 1H NMR (300 MHz, CDCl3)
solid: mp 105e106 ꢁC; 1H NMR (300 MHz, CDCl3)
d 7.80 (s, 1H), 7.74
(s, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.26e7.38 (m, 5H), 7.16 (s, 1H), 4.27
(d, J¼12.6 Hz, 1H), 4.10 (s, 3H), 4.08 (s, 3H), 4.01 (s, 3H), 3.99 (s, 3H),
3.57 (d, J¼12.6 Hz, 1H), 3.33 (d, J¼12.3 Hz, 1H), 2.97e3.03 (m, 2H),
2.90 (d, J¼12.9 Hz, 1H), 2.18e2.23 (m, 1H), 1.63e1.75 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 148.8, 148.7, 148.4, 139.4, 131.7, 129.0, 128.3,
127.0, 126.3, 125.6,124.9,124.8,123.6,107.9, 104.8,103.3, 102.7, 64.3,
59.2, 56.0, 56.0, 55.8, 55.8, 54. 5, 38.8, 31.0, 22.0; IR (KBr) 3001,
2934, 2832, 1619, 1508, 1475, 1429, 1253, 1201, 1151, 1039, 772,
d
7.22e7.36 (m, 5H), 5.06 (d, J¼15.3 Hz, 1H), 3.99 (d, J¼15.0 Hz, 1H),
þ
3.59 (td, J¼4.7, 12.9 Hz, 1H), 2.56e2.68 (m, 1H), 2.37e2.48 (m, 3H),
699 cmꢀ1; HRMS (ESI) calcd for C30H34NO4 472.2482, found
2.11e2.23 (m, 1H), 1.91e2.02 (m, 2H); 13C NMR (75 MHz, CDCl3)
472.2494.
d
175.2, 136.3, 128.7, 127.9, 127.5, 79.2, 71.1, 55.2, 44.1, 30.0, 23.4,
23.0; IR (KBr) 3288, 2935, 1684, 1579, 1496, 1419, 1305, 1251, 1166,
1084, 704 cmꢀ1; HRMS (EI) calcd for C14H15NO 213.1154, found
213.1151; Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found:
C, 78.80; H, 7.23; N, 6.45.
3.1.10. 2-[(2,3,6,7-Tetramethoxyphenanthren-9-yl)methyl]-pyrroli-
dine (12B). A suspension of 12A (48 mg, 0.101 mmol) and 10% Pd/C
(53.7 mg, 0.05 mmol) in anhydrous THF (5 mL) was stirred under H2
(1 atm) for 2 days. The mixture was filtered through Celite and the
residue was washed with MeOH (containing 3% NH3$H2O). The
liquid was evaporated and the product was purified by flash col-
umn chromatography on SiO2 (CH2Cl2/MeOH/Et3N, 20:1:1) to af-
ford 12B (36.8 mg, 96%) as a colorless oil: 1H NMR (300 MHz, CDCl3)
3.1.7. (Z)-1-Benzyl-5-[2,3-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)allyl-2-pyrrolidinone (5). To
a solution of 11B (215 mg,
1.01 mmol) in degassed DMF (10 mL) were added [B(pin)]2 (280 mg,
1.10 mmol) and (Ph3P)4Pt (101 mg, 0.08 mmol) sequentially. After
stirring at 80 ꢁC for 24 h the mixture was cooled to room temper-
ature, diluted with EtOAc (30 mL), washed with brine, and dried
over anhydrous MgSO4. Evaporation and purification by flash col-
umn chromatography on SiO2 (petroleum ether/acetone, 3:1) afford
5 (390 mg, 85%) as a white solid: mp 178e179 ꢁC; 1H NMR
d
7.69 (s, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.12 (s, 1H), 5.15
(br s, 1H), 4.04 (s, 3H), 4.03 (s, 6H), 3.97 (s, 3H), 3.64e3.66 (m, 1H),
3.41 (dd, J¼7.0, 13.8 Hz, 1H), 3.13e3.25 (m, 2H), 2.94e3.02 (m, 1H),
1.82e1.93 (m, 2H), 1.59e1.80 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
148.8, 148.8, 148.7, 148.6, 130.3, 126.1, 125.1, 124.8, 124.7, 123.7,
107.9, 104.5, 103.2, 102.5, 59.1, 56.2, 56.0, 55.9, 55.8, 45.8, 38.3, 31.1,
24.2; IR (KBr) cmꢀ1 3416, 2958, 2835, 1620, 1510, 1475, 1429, 1254,
1150, 1040, 843, 772, 733 cmꢀ1; HRMS (EI) calcd for C23H27NO4
381.1940, found 381.1941.
(300 MHz, CDCl3)
d 7.23e7.32 (m, 5H), 5.91 (s, 1H), 5.04 (d,
J¼15.2 Hz, 1H), 3.96 (d, J¼15.2 Hz, 1H), 3.51e3.60 (m, 1H), 2.79 (dd,
J¼1.5, 12.9 Hz, 1H), 2.28e2.52 (m, 2H), 2.06 (d, J¼12.0 Hz, 1H),
1.91e2.00 (m, 1H), 1.68e1.79 (m, 1H), 1.26 (s, 12H), 1.18 (s, 12H); 13C
NMR (75 MHz, CDCl3)
d
174.8, 150.1, 150.0, 136.5, 134.5, 134.4, 134.2,
3.1.11. Synthesis of (ꢃ)-tylophorine (1) by PicteteSpengler re-
action. To a solution of amine 12B (36.5 mg, 0.10 mmol) in EtOH
(2.5 mL) was added a formalin solution (0.55 mL, 7.34 mmol) and
134.1, 128.3, 127.8, 127.1, 83.6, 83.3, 55.7, 43.7, 42.9, 29.5, 24.6, 24.5,
23.2; IR (KBr) 2980, 2934, 1677, 1615, 1496, 1423, 1348, 1228, 1139,
973, 850, 705 cmꢀ1; HRMS (EI) calcd for C26H29NO510B2 465.3087,
found 465.3091; Anal. Calcd for C26H29NO5B2: C, 66.84; H, 8.41; N,
3.00. Found: C, 66.79; H, 8.29; N, 2.83.
concentrated HCl (55
mL, 0.66 mmol) successively. The reaction
mixture was refluxed for 2 days in the dark, evaporated to dryness,
and treated with 20% KOH (5 mL). The aqueous phase was extracted
with CH2Cl2, washed with brine and dried over anhydrous Na2SO4.
Filtration, concentration, and purification by flash column chro-
matography on SiO2 (CH2Cl2/MeOH, 20:1) afforded (ꢃ)-tylophorine
1 (31.5 mg, 84%) as a light yellow solid: mp 284e286 ꢁC.
3.1.8. Synthesis of 1-benzyl-5-[(2,3,6,7-tetramethoxyphenan-thren-
9-yl)methyl]-2-pyrrolidinone (4) by double Suzuki coupling. A solu-
tion of 6 [Ref. 3] (44 mg, 0.10 mmol) and 5 (56 mg, 0.12 mmol) in
THF (2 mL) was successively treated with (dppf)PdCl2 (7.4 mg,
0.01 mmol) and 3 N K3PO4 (0.2 mL, 0.6 mmol) under N2, and stirred
at 60 ꢁC for 3 days. Dilution with saturated NH4Cl was followed by
extraction with CH2Cl2. The combined organic extract was washed
with brine, dried over anhydrous Na2SO4, concentrated, and puri-
fied by flash column chromatography on SiO2 (petroleum ether/
acetone, 3:1) to afford 4 (24 mg, 50%) as a white solid: mp
3.1.12. 1-Benzyl-5-[3-(4,40,5,50-tetramethoxybiphenyl-2-yl)-2-
propynyl]-2-pyrrolidinone (14). To
a solution of 13 (200 mg,
0.50 mmol) and 11B (132 mg, 1.30 mmol) in anhydrous PhMe
(4 mL) under N2 were added piperidine (1.0 mL, 10.1 mmol),
(Ph3P)2PdCl2 (36 mg, 0.05 mmol), CuI (20 mg, 0.10 mmol) se-
quentially. The resulting mixture was stirred at 50 ꢁC for 18 h, di-
luted with water, and extracted with CH2Cl2. The combined organic
extract was washed with brine, dried over anhydrous Na2SO4,
concentrated, and purified by flash column chromatography on
SiO2 (petroleum ether/acetone, 5:1e3:1) to afford 14 (232 mg, 96%)
as a white foam: mp 69e71 ꢁC; 1H NMR (300 MHz, CDCl3)
258e260 ꢁC; 1H NMR (300 MHz, CDCl3)
d 7.79 (s, 1H), 7.74 (s, 1H),
7.36 (s, 1H), 7.26e7.33 (m, 3H), 7.20 (d, J¼7.3 Hz, 2H), 7.15 (s, 1H),
6.92 (s, 1H), 5.22 (d, J¼15.6 Hz, 1H), 4.10 (s, 3H), 4.09 (s, 3H), 4.03 (s,
3H), 3.89e3.99 (m, 2H), 3.67 (dd, J¼3.8, 13.2 Hz, 1H), 3.55 (s, 3H),
2.73e2.81 (m, 1H), 2.52e2.62 (m, 1H), 2.35e2.46 (m, 1H), 1.79e1.87
(m, 2H); 13C NMR (75 MHz, CDCl3)
d
175.2, 148.9, 148.7, 148.7, 148.3,
d
7.26e7.33 (m, 3H), 7.20 (d, J¼7.6 Hz, 2H), 7.04e7.07 (m, 2H), 6.95
136.3, 128.6, 128.4, 127.3, 127.2, 125.8, 125.6, 124.8, 124.7, 123.6,
107.7, 103.7, 103.1, 102.4, 55.9, 55.8, 55.8, 55.7, 55.3, 43.9, 37.4, 29.7,
24.1; IR (KBr) 2925, 2837, 1686, 1610, 1512, 1475, 1426, 1257, 1150,
(s, 1H), 6.92 (d, J¼8.5 Hz, 1H), 6.82 (s, 1H), 4.99 (d, J¼15.2 Hz, 1H),
3.92 (d, J¼15.2 Hz, 1H), 3.92 (s, 6H), 3.91 (s, 3H), 3.88 (s, 3H), 3.54
(td, J¼4.6, 12.9 Hz, 1H), 2.51 (d, J¼5.0 Hz, 2H), 2.28e2.47 (m, 2H),

3000
Q.-X. Lin, T.-L. Ho / Tetrahedron 69 (2013) 2996e3001
1.98e2.08 (m, 1H), 1.73e1.82 (m, 1H); 13C NMR (75 MHz, CDCl3)
175.1, 149.0, 148.2, 148.1, 147.6, 137.2, 136.4, 133.3, 128.6, 127.8,
127.4, 121.5, 115.3, 113.1, 112.6, 112.3, 110.8, 85.6, 82.7, 56.0, 55.9,
55.5, 44.0, 29.9, 24.1, 23.5; IR (KBr) 3062, 2933, 2835, 1685, 1602,
1504, 1440, 1252, 1211, 1173, 1025, 858, 763 cmꢀ1; HRMS (EI) calcd
for C30H31NO5 485.2202, found 485.2206.
CDCl3)
d
7.08 (d, J¼1.5 Hz, 1H), 7.04 (dd, J¼1.8, 8.2 Hz, 1H), 6.99 (s,
d
1H), 6.91 (d, J¼8.2 Hz, 1H), 6.83 (s, 1H), 4.80 (d, J¼17.5, 1H), 3.94 (s,
3H), 3.92 (s, 6H), 3.91 (s, 3H), 3.71 (d, J¼17.9 Hz, 1H), 3.61 (dd, J¼2.6,
10.3 Hz, 1H), 3.41e3.50 (m, 2H), 2.38e2.47 (m, 1H), 2.24e2.34 (m,
1H), 1.89e1.99 (m, 1H), 1.75e1.86 (m, 1H), 0.85 (s, 9H), 0.01 (s, 6H);
13C NMR (75 MHz, CDCl3)
d 174.4, 148.9, 147.9, 147.8, 147.3, 137.2,
133.0, 121.0, 114.6, 112.4, 112.4, 111.9, 110.2, 84.1, 83.3, 62.6, 57.5,
3.1.13. 1-Benzyl-5-((2,3,6,7-tetramethoxyphenanthren-9-yl)-
methyl)-2-pyrrolidinone (4) from isomerization. A solution of 14
(242 mg, 0.50 mmol) and DBU (120 mL, 0.78 mmol) in anhydrous
55.6, 55.6, 55.5, 30.6, 30.1, 25.3, 20.6, 17.6, ꢀ6.0; IR (KBr) 2997, 2932,
2856, 2216, 1693, 1602, 1504, 1463, 1254, 1028, 858, 780 cmꢀ1
HRMS (EI) calcd for C30H41NO6Si 539.2703, found 539.2706.
;
NMP (5 mL) was refluxed for 3 h. The mixture was cooled, con-
centrated in vacuo, and purified by flash column chromatography
on SiO2 (petroleum ether/acetone, 3:1e2:1) to afford 4 (222 mg,
92%) as a white solid: mp 258e260 ꢁC.
3.1.17. (R)-5-(t-Butyldimethylsiloxymethyl)-1-[(2,3,6,7-tetramethoxy-
phenanthren-9-yl)methyl]-2-pyrrolidinone (18A). A solution of 17
(219 mg, 0.40 mmol) and DBU (100 mL, 0.65 mmol) in anhydrous
NMP (4 mL) was refluxed for 1.5 h, cooled and concentrated in
3.1.14. (R)-5-(t-Butyldimethylsiloxymethyl)-2-pyrrolidinone (15). To
vacuo. Flash column chromatography on SiO2 (petroleum ether/
a
solution of (R)-5-hydroxymethyl-2-pyrrolidinone (2.5 g,
acetone, 3:1) afforded 18A (191 mg, 87%) as a white foam: mp
20
21.5 mmol) in anhydrous CH2Cl2 (25 mL) were added TBSCl (3.9 g,
26.0 mmol) and imidazole (2.2 g, 32.5 mmol) successively. The
resulting mixture was stirred at room temperature for 4 h,
quenched with H2O (10 mL) and separated into layers. The organic
phase was washed with water, brine, dried over Na2SO4, and
evaporated to afford 15 (4.98 g, 100%) as a colorless oil, which
proved to be homogeneous. [
(300 MHz, CDCl3)
78e80 ꢁC; [
a]
D
ꢀ99.4 (c 0.60, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.81 (s,1H), 7.77 (s,1H), 7.67 (s,1H), 7.46 (s,1H), 7.18 (s,1H), 5.60 (d,
J¼14.6 Hz, 1H), 4.26 (d, J¼14.7 Hz, 1H), 4.12 (s, 3H), 4.11 (s, 3H), 4.03
(s, 6H), 3.82 (dd, J¼3.2, 10.5 Hz, 1H), 3.53 (dd, J¼2.7, 10.5 Hz, 1H),
3.35e3.37 (m, 1H), 2.53e2.65 (m, 1H), 2.32 (dt, J¼7.0, 16.7 Hz, 1H),
1.82e1.90 (m, 2H), 0.88 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR
20
a]
ꢀ46.8 (c 0.72, CHCl3); 1H NMR
(75 MHz, CDCl3) d 175.0, 149.3, 149.0, 148.8, 148.7, 127.9, 126.1, 125.4,
D
d
6.14 (br s, 1H), 3.70e3.78 (m, 1H), 3.60 (dd,
124.8, 124.8, 124.6, 108.0, 105.3, 102.9, 102.6, 62.8, 57.6, 56.2, 56.0,
55.9, 55.8, 43.6, 30.6, 25.7, 21.5,18.1, ꢀ6.0; IR (KBr) 2995, 2855, 2362,
1681, 1614, 1514, 1473, 1437, 1257, 1148, 1033, 837, 776 cmꢀ1; HRMS
(EI) calcd for C30H41NO6Si, 539.2703, found 539.2705.
J¼4.1, 10.0 Hz, 1H), 3.43 (dd, J¼7.3, 10.0 Hz, 1H), 2.30e2.36 (m, 2H),
2.09e2.21 (m, 1H), 1.67e1.79 (m, 1H), 0.87 (s, 9H), 0.04 (s, 6H); 13C
NMR (75 MHz, CDCl3)
d
178.6, 66.4, 55.7, 29.9, 25.7, 22.7, 18.0, ꢀ5.6;
MS (ESI): m/z 230 (MþHþ); IR (KBr) 3220, 3103, 2931, 2858, 1702,
1464, 1256, 1119, 1032, 838, 777, 665 cmꢀ1; HRMS (ESI) calcd for
C11H24NO2Siþ 230.1570, found 230.1568; Anal. Calcd for C11H23NO2:
C, 57.59; H, 10.11; N, 6.11. Found: C, 57.47; H, 10.36; N, 5.72.
3.1.18. (R)-5-Hydroxymethyl-1-[(2,3,6,7-tetramethoxyphenanthren-
9-yl)methyl]-2-pyrrolidinone (18B). To a solution of 18A (184 mg,
0.34 mmol) in anhydrous THF (3.5 mL) at 0 ꢁC was added TBAF
(0.50 mL, 1.0 M in THF, 0.50 mmol), stirred for 2 h and then
quenched with saturated NH4Cl (2 mL). The mixture was parti-
tioned between CHCl3 and water, and the aq phase was extracted
with CHCl3. The combined organic phase was washed with brine,
dried over anhydrous Na2SO4, evaporated, and purified by flash
column chromatography on SiO2 (CH2Cl2/MeOH, 40:1) to afford
3.1.15. (R)-5-(t-Butyldimethylsiloxymethyl)-1-(2-propynyl)-2-
pyrrolidinone (16). To a solution of 15 (2.42 g, 10.6 mmol) in an-
hydrous THF (12.5 mL) was added NaH (0.51 g, 60% suspension in
mineral oil, 12.7 mmol) in portions at room temperature. After
stirring for 0.5 h under N2, propargyl bromide (1.7 mL, 21.7 mmol)
was added via syringe. The resulting mixture was kept at room
temperature for 24 h, quenched with saturated NH4Cl (10 mL),
extracted with CH2Cl2, washed with brine, and dried over anhy-
drous Na2SO4. After removal of solvent the crude product was pu-
rified by flash column chromatography on SiO2 (petroleum ether/
18B (128 mg, 95%) as a white solid: mp 251e253 ꢁC; [
a]
20 ꢀ97.3 (c
D
0.56, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.81 (s, 1H), 7.76 (s, 1H),
7.62 (s, 1H), 7.51 (s, 1H), 7.18 (s, 1H), 5.43 (d, J¼14.1 Hz, 1H), 4.34 (d,
J¼14.1 Hz, 1H), 4.11 (s, 6H), 4.03 (s, 6H), 3.81 (d, J¼10.0 Hz, 1H),
3.43e3.49 (m, 2H), 2.59e2.67 (m, 1H), 2.36e2.41 (m, 1H), 2.12 (br s,
EtOAc, 8:1) to afford 16 (2.56 g, 90%) as a light yellow oil: [
a
]
20 ꢀ21.3
1H), 1.94e1.96 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 175.6, 149.6,
D
(c 0.55, CHCl3); 1H NMR (300 MHz, CDCl3)
d
4.60 (d, J¼17.9 Hz, 1H),
149.2, 149.1, 148.9, 127.9, 126.4, 125.6, 125.0, 124.7, 124.6, 108.2,
105.1, 103.2, 102.6, 62.6, 58.4, 56.4, 56.1, 56.0, 55.9, 44.4, 30.6, 21.1;
IR (KBr) 3531, 2932, 2837, 1655, 1614, 1513, 1477, 1414, 1258, 1149,
1031, 837, 776 cmꢀ1; HRMS (EI) calcd for C24H27NO6, 425.1838,
found 425.1839.
3.87e3.91 (m, 1H), 3.79 (dd, J¼3.5, 10.8 Hz, 1H), 3.73 (d, J¼17.6 Hz,
1H), 3.63 (dd, J¼3.8, 10.8 Hz, 1H), 2.42e2.53 (m, 1H), 2.27e2.39 (m,
1H), 2.20 (s, 1H), 2.05e2.16 (m, 1H), 1.82e1.92 (m, 1H), 0.88 (s, 9H),
0.06 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 175.0, 78.1, 71.9, 63.6, 58.3,
30.4, 30.3, 25.7, 21.1, 18.1, ꢀ5.6; IR (KBr) 3312, 3233, 2930, 2857,
2111, 1692, 1471, 1417, 1359, 1253, 1115, 838, 778, 662 cmꢀ1; HRMS
(EI) calcd for C14H25NO2Si 267.1655, found 267.1652; Anal. Calcd
for C14H25NO2Si: C, 62.87; H, 9.42; N, 5.24. Found: C, 62.86; H, 9.41;
N, 5.24.
3.1.19. Pentacyclic hydroxylactam 19. To a solution of 18B (108 mg,
0.25 mmol) in anhydrous CH2Cl2 (7 mL) at 0 ꢁC was added
DesseMartin periodinane (208 mg, 0.49 mmol). The resulting
slurry was stirred at room temperature for 2 h, treated with 2-
propanol (1 mL), diluted with saturated aq NaHCO3, and extracted
with CH2Cl2. The organic phase was washed with brine, dried over
anhydrous Na2SO4, and concentrated to afford a white residue. This
crude aldehyde was dissolved in anhydrous CH2Cl2 (7.5 mL) at 0 ꢁC,
and treated with TFA (0.25 mL, 3.25 mmol) for 2 h, then diluted
with CH2Cl2, and washed with saturated NaHCO3. The aqueous
phase was further extracted with CH2Cl2 and the combined organic
phase was wash with brine, dried over anhydrous Na2SO4, con-
centrated under reduced pressure. Flash column chromatography
3.1.16. (R)-5-(t-Butyldimethylsiloxymethyl)-1-[3-(30,4,40,5-tetrame-
thoxybiphenyl-2-yl)prop-2-ynyl]-2-pyrrolidinone (17). Under N2, to
a solution of 13 (400 mg, 1.00 mmol) and 16 (350 mg, 1.30 mmol) in
anhydrous PhMe (8 mL) were added piperidine (2.0 mL,
20.2 mmol), (Ph3P)2PdCl2 (70 mg, 0.10 mmol) and CuI (21 mg,
0.11 mmol) sequentially. The resulting mixture was stirred at 50 ꢁC
for 24 h, diluted with water, and extracted with CH2Cl2. The com-
bined organic phase was washed with brine, dried over anhydrous
Na2SO4, and concentrated. Flash column chromatography on SiO2
(petroleum ether/acetone, 5:1) afforded 17 (516 mg, 0.96 mmol,
on SiO2 (CH2Cl2/acetone, 3:1e1:1) gave 19 (82 mg, 76%) as a white
20
solid: mp 285e287 ꢁC; [
a
]
ꢀ144.6 (c 0.52, CHCl3); 1H NMR
D
96%) as a yellow oil: [
a
]
20 ꢀ34.2 (c 0.64, CHCl3); 1H NMR (300 MHz,
(300 MHz, CDCl3) d 7.63 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 6.43 (s, 1H),
D

Q.-X. Lin, T.-L. Ho / Tetrahedron 69 (2013) 2996e3001
3001
5.01 (s, 1H), 4.82 (d, J¼17.2 Hz, 1H), 4.16 (d, J¼17.3 Hz, 1H), 4.08 (s,
References and notes
3H), 4.06 (s, 3H), 4.04 (s, 3H), 3.79 (d, J¼8.2 Hz, 1H), 3.62 (br s, 1H),
3.52 (s, 3H), 2.41e2.74 (m, 3H), 2.14e2.26 (m, 1H); 13C NMR
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3. (a) Li, Z.; Jin, Z.; Huang, R. Synthesis 2001, 2365e2379; (b) Bhakuni, D. S. J. Indian
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(75 MHz, CDCl3)
d 175.3, 148.8, 148.7, 148.3, 126.8, 124.7, 123.9,
123.2, 122.4, 104.4, 102.7, 102.6, 102.2, 65.4, 58.3, 55.9, 55.7, 55.5,
40.7, 30.7,18.9; MS (EI): IR (KBr) 3470, 3060, 2960, 2832,1666,1620,
1514, 1470, 1425, 1250, 1148, 1018, 834, 726 cmꢀ1; HRMS (EI) calcd
for C24H25NO6 423.1682, found 423.1676.
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3.1.20. Synthesis of (R)-(ꢀ)-tylophorine (1) from 19. A solution of 19
(85 mg, 0.20 mmol) in anhydrous CH2Cl2 (6 mL) was stirred with
BF3$Et2O (0.13 mL, 1.02 mmol) and Et3SiH (0.17 mL, 1.05 mmol) at
ꢀ78 ꢁC for 2 h. The mixture was brought to room temperature and
kept for another 19 h, neutralized with saturated NaHCO3 (3 mL),
extracted with CH2Cl2, washed with brine, dried over anhydrous
Na2SO4, and concentrated. To the white residue was suspended in
anhydrous THF (18 mL) at 0 ꢁC and LiAlH4 (38.1 mg, 1.00 mmol) was
cautiously added. After refluxing for 1 h it was cooled, quenched
with Na2SO4$10H2O and filtered through Celite. The filtrate was
concentrated and purified by flash column chromatography on SiO2
(CH2Cl2/MeOH, 20:1) to afford (R)-(ꢀ)-tylophorine (1) (67.1 mg,
5. (a) Buckley, T. F., III; Rapoport, H. J. Org. Chem. 1983, 48, 4222e4232; (b)
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20
85%) as a light yellow solid: mp 283e285 ꢁC; [
a]
ꢀ80.0 (c 0.14,
D
CHCl3). Lit4
d
[
a
]
D
ꢀ76.0 (c 0.10, CHCl3); 1H NMR (300 MHz, CDCl3)
30
7.81 (s, 2H), 7.29 (s, 1H), 7.13 (s, 1H), 4.63 (d, J¼14.9 Hz, 1H), 4.11 (s,
€
Furstner, A.; Kennedy, J. W. J. Chem.dEur. J. 2006, 12, 7398e7410; (g) Zeng, W.;
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(d, J¼14.9 Hz, 1H), 2.93 (dd, J¼10.8, 14.9 Hz, 1H), 2.45e2.54 (m, 2H),
2.20e2.30 (m, 1H), 2.02e2.09 (m, 1H), 1.93e1.99 (m, 1H), 1.72e1.86
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(m, 1H); 13C NMR (75 MHz, CDCl3)
d 148.6, 148.5, 148.4, 126.0, 125.6,
124.1, 123.6, 123.3, 103.8, 103.2, 103.1, 102.9, 60.2, 56.0, 55.9, 55.8,
54.9, 53.4, 33.2, 31.0, 21.5; IR (KBr) 2950, 2919, 2869, 2830, 1618,
1514, 1469, 1427, 1247, 1212, 1149, 1018, 843, 774 cmꢀ1; HRMS (EI)
calcd for C24H27NO4 393.1946, found 393.1940.
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Acknowledgements
Contents of this paper are abstracted from the Ph.D. Thesis
[B200818003508028] submitted by Q.-X.L. to the Shanghai In-
stitute of Organic Chemistry on October 10, 2010. The authors are
most grateful to Professor Henry N.C. Wong for allowing the work
done under his auspices at the Shanghai-Hong Kong Joint Labora-
tory at SIOC. We also thank the Croucher Foundation for financial
support.
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