A five-step synthesis of (±)-tylophorine via a nitrile-stabilized ammonium ylide

Article abstract of DOI:10.1021/jo3011045

The Stevens rearrangement of a nitrile-stabilized ammonium ylide is the key step of a very short and practical synthesis of the phenanthroindolizine alkaloid (±)-tylophorine. The method requires only five linear steps and is devoid of any protecting group manipulations.

Full text of DOI:10.1021/jo3011045

Note
pubs.acs.org/joc
A Five-Step Synthesis of ( )-Tylophorine via a Nitrile-Stabilized
Ammonium Ylide
Gunther Lahm, Alexander Stoye, and Till Opatz*
̈
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: The Stevens rearrangement of a nitrile-
stabilized ammonium ylide is the key step of a very short
and practical synthesis of the phenanthroindolizine alkaloid
( )-tylophorine. The method requires only five linear steps
and is devoid of any protecting group manipulations.
readily furnishes 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]-
isoquinoline (5) in 71% yield (Scheme 1).
main goal for the development of new synthetic methods
Ais the increase of efficiency in order to reduce the waste of
useful resources. Herein, we describe a very short and efficient
synthesis of the phenanthroindolizidine alkaloid ( )-tylo-
phorine (11) which only requires five linear steps, two or
even three of which can be performed in a one-pot procedure.
Veratrol, pyrrolidine, and biacetyl serve as readily available and
cheap starting materials.
Scheme 1. Preparation of Model Compound 5 by Stevens
Rearrangement of a Spirocyclic Ammonium Ylide
Tylophorine was first isolated from Tylophora indica1−3 and
has been demonstrated to possess a wide range of biological
activities such as anti-inflammatory,4 antiallergic,5,6 antiasth-
matic,5,6 antibacterial,7 antifungal,8 and antiviral.9 It has been
shown to be a potent inhibitor of eukaryotic protein
biosynthesis10 and to inhibit RNA transcription as well as the
action of several cyclins regulating the cell cycle.11 Despite the
extensive work on this compound and its congeners, no clear
picture for its detailed mode of action and the cellular target has
emerged so far.12 In addition to its effects on living systems,
tylophorine is an attractive target molecule for total synthesis
and the considerable number of published synthetic approaches
comes as no surprise.6,13−27 Among other methods, Comins’
approach using N-acyldihydropyridones as building blocks,27,28
Furstner's PtCl -catalyzed cycloisomerization,29 or the [2 + 2 +
̈
2
2] cyclotrimerization by Deiters30 have been used for the
construction of the pentacyclic core structure.
Transfer of this method to the preparation of 11 required
dibromide 7, which could be readily obtained by radical
bromination of dimethylphenanthrene 6. The elegant prepara-
tion of the latter material from veratrol and biacetyl in sulphuric
acid has been developed by Manson et al. who also discovered
the surprising importance of the exact acid concentration on
the outcome of the reaction.44 Reaction of 7 and 1 gave the
spirocyclic ammonium salt 8 in 68% yield which could be
converted to 11 in 85% yield over two steps without isolation
of the intermediate aminonitrile 10 (Scheme 2). Alternatively, 7
could be transformed into 11 in a one-pot procedure over three
steps in 49% yield.
In continuation of our studies on the synthesis of highly
enantiopure tylophorine by radical cyclization,31 we became
interested in a fast access to the racemic alkaloid. Model studies
on 1,2-bis(bromomethyl)benzene showed that its reaction with
2-cyanopyrrolidine (1), accessible by silver-catalyzed oxidation
of pyrrolidine to the pyrroline trimer and reaction with KCN
and HCl,32,33 furnishes the spirocyclic ammonium bromide 2 in
high yield. Treatment of this salt with KHMDS in THF at 0 °C
yields the nitrile-stabilized ammonium ylide,34−37 which readily
undergoes a Stevens-rearrangement37−43 to α-aminonitrile 4.
This material is unstable and eliminates HCN under formation
of the conjugated enamine which is prone to side reactions.
However, reduction of crude 4 with sodium cyanoborohydride
Received: May 29, 2012
Published: July 11, 2012
© 2012 American Chemical Society
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Note
(C5′), 62.4 (C1′), 27.2 (C3′), 20.2 (C4′) ppm. IR (ATR): 2941 (m,
br), 2876 (m), 1465 (w), 1441 (w), 1356 (w), 1242 (w, sh), 1216
(m), 746 (s) cm−1. ESI-MS (m/z): 199.13 (100) [M]+. ESI-HRMS:
calcd for [C13H15N2]+ 199.1235, found 199.1229.
Scheme 2. Synthesis of ( )-Tylophorine in Five Linear
Steps
1,2,3,5,10,10a-Hexahydropyrrolo[1,2-b]isoquinoline (5). To
a stirred solution of 2′-cyanospiro[isoindoline-2,1′-pyrrolidin]-1′-ium
(2: 470 mg, 1.68 mmol) in dry THF (30 mL) was added KHMDS
(352 mg, 1.76 mmol, 1.1 equiv) dissolved in dry THF (2 mL) at 0 °C.
The reaction mixture was stirred at this temperature for 1.5 h. Ethanol
(8 mL) and NaCNBH3 (344 mg, 5.47 mmol, 3.3 equiv) were added,
and the solution was allowed to warm to room temperature before
AcOH (0.6 mL) was added dropwise. The reaction was stirred at room
temperature for 10 h, quenched with saturated aq NaHCO3 (30 mL),
and extracted with CHCl3 (3 × 40 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was partially dissolved in ice cooled EtOAc (10
mL). The remaining insoluble solid was filtered off by suction. The
filtrate was concentrated in vacuo to afford the title compound (207
mg, 71%) as a colorless liquid. Rf = 0.25 (CHCl3/EtOH = 9.5/0.5). 1H
NMR, COSY (400 MHz, CDCl3): δ = 7.14−7.05 (m, 4H, 4 × Ar−H),
4.12 (d, 2J = 14.6 Hz, 1H, Ha-5), 3.43 (d, 2J = 14.6 Hz, 1H, Hb-5), 3.28
(td, J = 8.7, 2.3 Hz, 1H, Ha-4), 2.99 (dd, J = 15.9, 3.8 Hz, 1H, Ha-10),
2.75−2.68 (m, 1H, Hb-10), 2.39−2.29 (m, 1H, H-1), 2.26 (pseudo-q, J
= 9 Hz, 1 H, Hb-4), 2.14−2.04 (m, 1H, Ha-2), 1.99−1.77 (m, 2H, H-
3), 1.61−1.51 (m, 1H, Hb-2) ppm. 13C NMR, HMBC, HSQC (75.5
MHz, CDCl3): δ = 135.1, 134.9 (C5a, C9a), 129.6 (CH), 126.7 (CH),
126.6 (CH), 125.8 (CH), 60.8 (C1), 56.0 (C5), 54.9 (C4), 36.1
(C10), 31.1 (C2), 21.6 (C3) ppm. IR (film): 2962 (s), 2782 (s), 1455
(m), 1381 (m), 1158 (m), 999 (m), 743 (s) cm−1. ESI-MS (m/z):
174.13 (100) [M + H]+. ESI-HRMS: calcd for [C12H16N]+ 174.1283,
found 174.1279.
2,3,6,7-Tetramethoxy-9,10-dimethylphenanthrene (6). The
title compound was prepared according to the method of Manson and
Musgrave.44 To a solution of veratrole (12.5 g, 90.9 mmol, 2.0 equiv)
in 70% aqueous sulfuric acid (150 mL) was added biacetyl (4.00 g,
46.5 mmol) dropwise with stirring during 0.5 h. The mixture was kept
at room temperature for 11 days and then filtered and washed with
water. The remaining solid was recrystallized from ethanol to afford
the title compound (11.2 g, 74%) as a white solid: Rf = 0.43
(cyclohexane/EtOAc = 1/1); mp 224−225 °C dec (lit.44,49 mp 222−
227 °C). 1H NMR, NOESY (400 MHz, CDCl3): δ = 7.74 (s, 2H, H-4,
H-5), 7.32 (s, 2H, H-1, H-8), 4.10 (s, 6H, C3-OCH3, C6-OCH3), 4.03
(s, 6H, C2-OCH3, C7-OCH3), 2.61 (s, 6H, C9-CH3, C10-CH3) ppm.
13C NMR, HMBC, HSQC (100.6 MHz, CDCl3): δ = 148.5 (C3,C6),
148.1 (C2, C7), 126.8 (C9, C10), 126.6 (C8a, C10a), 123.4 (C4a,
C4b), 105.2 (C4, C5), 103.2 (C8, C1), 56.0 (C3−OCH3, C6-OCH3),
55.8 (C2-OCH3, C7-OCH3), 16.2 (C9-CH3, C10-CH3) ppm. IR (film):
3010 (w), 2958 (m, br), 2836 (w), 1620 (m), 1519 (s), 1476 (s), 1422
(s), 1251 (s), 1213 (s), 1195 (s), 1156 (s), 841 (s) cm−1. FD-MS (m/
z): 326.5 (100) [M]+. Anal. Calcd for C20H22O4: C, 73.60; H, 6.79.
Found: C, 73.31; H, 7.08.
9,10-Bis(bromomethyl)-2,3,6,7-tetramethoxyphenanthrene
(7). To a solution of 2,3,6,7-tetramethoxy-9,10-dimethylphenanthrene
(6: 500 mg, 1.53 mmol) in CCl4 (30 mL) were added N-
bromosuccinimide (550 mg, 3.10 mmol, 2.0 equiv) and a catalytic
amount of AIBN (30 mg). The mixture was refluxed for 18 h. It was
cooled to room temperature, filtered, and washed thoroughly with
water to afford the title compound (682 mg, 92%) as a yellow solid. Rf
= 0.40 (cyclohexane/EtOAc = 1/1). Mp: 222−223 °C dec. 1H NMR,
NOESY (400 MHz, CDCl3): δ = 7.79 (s, 2H, H-4, H-5), 7.50 (s, 2H,
H-1, H-8), 5.10 (s, 4H, 2 × CH2Br), 4.13 (s, 6H, C3−OCH3, C6−
OCH3), 4.10 (s, 6H, C2−OCH3, C7−OCH3) ppm. 13C NMR, HMBC,
HSQC (100.6 MHz, CDCl3): δ = 150.0 (C3, C6), 149.2 (C2, C7),
128.7 (C9, C10), 125.6 (C4a, C4b), 124.1 (C8a, C10a), 104.9 (C1,
C8), 103.2 (C4, C5), 56.1 (C3, C6), 56.0 (C2, C7), 27.9 (CH2Br)
ppm. IR (film): 2933 (w, br), 2827 (w), 1620 (m), 1514 (s), 1466 (s),
1424 (s), 1252 (s), 1197 (s), 1160 (m), 1042 (s), 837 (s) cm−1. FD-
MS (m/z) 486.2 (100) [M]+, 484.2 (78) [M]+, 482.3 (34) [M]+. Anal.
Calcd for C20H20Br2O4: C, 49.61; H, 4.16. Found: C, 49.37; H, 4.23.
In summary, a protecting group-free synthesis of racemic
tylophorine via Stevens rearrangement of a nitrile-stabilized
ammonium ylide has been developed. It comprises only five
linear steps and thus represents the shortest procedure known
so far. Moreover, it requires no chromatographic purifications.
While similar rearrangements on ammonium ylides stabilized
by carbonyl groups are known,45−48 the reductive removal of an
angular stabilizing group has never been reported to the best of
our knowledge.
EXPERIMENTAL SECTION
■
Pyrrolidine-2-carbonitrile (1) was prepared from pyrrolidine according
to the method of De Kimpe and Stevens et al.32
2′-Cyanospiro[isoindoline-2,1′-pyrrolidin]-1′-ium Bromide
(2). A mixture of 1,2-bis(bromomethyl)benzene (2.75 g, 10.4 mmol,
1.0 equiv) and DIPEA (1.80 mL, 10.6 mmol) in ethanol (6 mL) was
heated under reflux with stirring while pyrrolidine-2-carbonitrile (1:
1.01 g, 10.4 mmol, 1.0 equiv) was added dropwise. After the addition,
the mixture was heated under reflux for 12 h. Ethanol was removed
under reduced pressure. The residue was partially dissolved in acetone
(50 mL) for 30 min under reflux and filtrated while hot to afford the
title compound (2.1 g, 72%) as an orange solid. Mp: 178−179 °C dec.
1H NMR, COSY, NOESY (300 MHz, D2O): δ = 7.53−7.42 (m, 4H, 4
2
× Ar-H), 5.28 (d, J = 14.5 Hz, 1H, Ha-3), 5.26 (mc, 1H, H-2′), 5.14
2
(s, 2H, Ha-1, Hb-1), 5.06 (d, J = 14.5 Hz, 1H, Hb-3), 4.06−3.85 (m,
2H, Ha-5′, Hb-5′), 2.94−2.81 (m, 1H, Ha-3′), 2.75−2.63 (m, 1H, Hb-
3′), 2.51−2.40 (m, 2H, Ha-4′, Hb-4′) ppm. 13C NMR, HMBC, HSQC
(151 MHz, D2O): δ = 131.9 (C3a, C7a), 129.5 (CH), 129.4 (CH),
123.2 (CH), 123.1 (CH), 113.2 (CN), 67.6 (C1), 65.7 (C3), 64.4
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Note
2′-Cyano-5,6,9,10-tetramethoxy-1,3-dihydrospiro[dibenzo-
[e,g]isoindole-2,1′-pyrrolidin]-1′-ium Bromide (8). A mixture of
9,10-bis(bromomethyl)-2,3,6,7-tetramethoxyphenanthrene (7: 223
mg, 0.46 mmol, 1.0 equiv) and DIPEA (80 μL, 0.47 mmol, 1.0
equiv) in dry THF (10 mL) was heated under reflux with stirring while
pyrrolidine-2-carbonitrile (1: 45 mg, 0.47 mmol, 1.0 equiv) was added
dropwise. After the addition, the mixture was heated to reflux for 15 h.
THF was removed under reduced pressure and the residue was
recrystallized from methanol to afford the title compound (159 mg,
68%) as a beige solid. Mp: 258−260 °C dec. 1H NMR, COSY,
NOESY (400 MHz, DMSO-d6): δ = 8.13 (s, 2H, H-7, H-8), 7.29 (s,
1H, H-4), 7.17 (s, 1H, H-11), 5.73 (d, 2J = 14.7 Hz, 1H, Ha-3), 5.67−
at room temperature for 15 h, quenched with saturated aq NaHCO3
(25 mL), and extracted with CHCl3 (3 × 30 mL). The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was washed with EtOAc (50 mL).
The remaining solid was dissolved in CHCl3 (30 mL), cooled to 0 °C,
and filtered. The CHCl3 filtrate was concentrated in vacuo to afford
the title compound (119 mg, 49%) as a pale yellow solid. Mp: 277−
280 °C dec (lit.50 mp 275−282 °C). The spectroscopic data were
identical with those of the sample prepared by method a.
ASSOCIATED CONTENT
* Supporting Information
General methods and spectra for compounds 2, 5, 6−8, and 11.
This material is available free of charge via the Internet at
http://pubs.acs.org
■
S
2
5.53 (m, 3H, Ha-1, Hb-1, H-2′), 5.55 (d, J = 14.7 Hz, 1H, Hb-3),
4.18−4.11 (m, 1H, Ha-5′), 4.11−4.02 (m, 1H, Hb-5′), 4.07 (s, 6H, C6-
OCH3, C9-OCH3), 3.97 (s, 3H, C5-OCH3), 3.95 (s, 3H, C10-OCH3),
2.91−2.80 (m, 1H, Ha-3′), 2.77−2.66 (m, 1H, Hb-3′), 2.48−2.39 (m,
2H, Ha-4′, Hb-4′) ppm. 13C NMR, HMBC, HSQC (151 MHz
DMSO-d6): δ = 149.7 (C5, C10), 149.2 (C6), 149.1 (C9), 124.9
(C3a), 124.8 (C11b), 124.6 (C3b, C11a), 119.8 (C7a, C7b), 114.4
(CN), 105.4 (C4), 105.3 (C11), 104.7 (C7, C8), 68.3 (C1), 66.9
(C3), 65.2 (C5′), 63.4 (C2′), 56.1 (C6−OCH3, C9−OCH3), 55.8
(C15−OCH3), 55.7 (C10-OCH3), 27.1 (C3′), 20.4 (C4′) ppm. IR
(ATR): 3397 (w, br), 2939 (w, br), 2337 (w), 1614 (w), 1520 (m),
1481 (s), 1250 (s), 1213 (w), 1158 (m), 1040 (m, sh), 1021 (m), 857
(m) cm−1. ESI-MS (m/z): 419.20 (100) [M]+. ESI-HRMS: calcd for
[C25H27N2O4]+ 419.1971, found 419.1969.
AUTHOR INFORMATION
Corresponding Author
*E-mail: opatz@uni-mainz.de.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Rhineland-Palatinate Center for Integrated
Natural Products Research for helpful discussions as well as
Dr. J. C. Liermann (Mainz) for NMR spectroscopy and Dr. N.
Hanold (Mainz) for mass spectrometry.
rac-Tylophorine (11). (a) To a stirred solution of 2′-cyano-
5,6,9,10-tetramethoxy-1,3-dihydrospiro[dibenzo[e,g]isoindole-2,1′-pyr-
rolidin]-1′-ium bromide (8: 160 mg, 0.32 mmol) in dry THF (10 mL)
was added KHMDS (70 mg, 0.35 mmol, 1.1 equiv) dissolved in dry
THF (1 mL) at 0 °C. The reaction mixture was stirred at this
temperature for 1.5 h. Ethanol (1 mL) and NaCNBH3 (66 mg, 1.05
mmol, 3.3 equiv) were added, and the solution was allowed to warm to
room temperature before AcOH (0.12 mL) was added dropwise. The
reaction was stirred at room temperature for 13 h, quenched with
saturated aq NaHCO3 (15 mL), and extracted with CHCl3 (3 × 25
mL). The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was washed with
EtOAc (50 mL), and the remaining solid was dissolved in CHCl3 (30
mL), cooled to 0 °C, and filtered. The CHCl3 filtrate was concentrated
in vacuo to afford the title compound (107 mg, 85%) as a pale yellow
solid. Rf = 0.28 (CH2Cl2/EtOH = 10/1). Mp: 279−281 °C dec (lit.50
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mp 275−282 °C). H NMR, COSY (400 MHz, CDCl3): δ = 7.83 (s,
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