Total synthesis of (R)-tylophorine by using an asymmetric hydrogenation of the allyl alcohol

Article abstract of DOI:10.1016/j.tetlet.2018.04.052

An efficient synthesis of naturally occurring (R)-tylophorine is described. The alkaloid was prepared in seven steps from a known phenanthryl aldehyde with an overall yield of 14.2%. Asymmetric hydrogenation of an allyl alcohol was employed as a key step for installing a stereogenic center with good enantioselectivity (77% ee), and the ee value of the ω-chloro alcohol was improved to 95% by recrystallization. After azidation and oxidation of the enantio-enriched ω-chloro alcohol to the precursor of the Schmidt reaction, the chirality transfer in the stereospecific 1,2-migration furnished the chiral carbon in the alkaloid. Finally, a one-pot deformylation/Pictet-Spengler cyclization completed the total synthesis of (R)-tylophorine.

Full text of DOI:10.1016/j.tetlet.2018.04.052

Tetrahedron Letters 59 (2018) 2170–2172
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of (R)-tylophorine by using an asymmetric
hydrogenation of the allyl alcohol
⇑
⇑
Rui Li , Chun-Fang Liu, Chun-Jiao Yu, Peiming Gu
College of Chemistry & Chemical Engineering, Ningxia Engineering and Research Center for Natural Medicines, Ningxia University, Yinchuan 750021, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of naturally occurring (R)-tylophorine is described. The alkaloid was prepared in
seven steps from a known phenanthryl aldehyde with an overall yield of 14.2%. Asymmetric hydrogena-
tion of an allyl alcohol was employed as a key step for installing a stereogenic center with good enantios-
Received 8 March 2018
Revised 17 April 2018
Accepted 21 April 2018
Available online 24 April 2018
electivity (77% ee), and the ee value of the
x
-chloro alcohol was improved to 95% by recrystallization.
-chloro alcohol to the precursor of the Schmidt
After azidation and oxidation of the enantio-enriched
x
reaction, the chirality transfer in the stereospecific 1,2-migration furnished the chiral carbon in the
alkaloid. Finally, a one-pot deformylation/Pictet-Spengler cyclization completed the total synthesis of
(R)-tylophorine.
Keywords:
Tylophorine
Total synthesis
Asymmetric hydrogenation
Schmidt reaction
Ó 2018 Elsevier Ltd. All rights reserved.
OMe
Tylophorine 1 (Fig. 1), a phenanthroindolizidine alkaloid featur-
ing with a pentacyclic motif, was initially isolated from Tylophora
indica plant family.1 It exhibits remarkable antitumor,2 antiinflam-
matory,3 and antifungal activities,4 therefore many groups had
reported their synthesis of the racemate tylophorine,5 naturally
occurring (R)-tylophorine,6,7 and its antipode (S)-tylophorine.8,9
Most of the synthetic methods toward the optically active tylo-
phorine were based on the chiral materials or auxiliaries,6,8 and
only four different synthetic routes had been developed for con-
structing the stereogenic center of tylophorine via the catalytic
asymmetric reactions. The Pd-7a and Cu-catalyzed9b asymmetric
alkene carboamination reactions were used by Wolfe’s group and
Chemler’s group, and the corresponding intermediates for
synthesis of the enanito-enriched tylophorine were produced
with good enantioselectivities (88% ee and 81% ee, respectively).
Wang’s group had reported that the asymmetric allylation of an
aldehyde could be used as a key step for synthesis of (S)-
MeO
MeO
H
N
OMe
(R)-tylophorine 1
Fig. 1. Structure of naturally occurring tylophorine.
( )-antofine,10 another attractive phenanthroindolizidine alkaloid
for researchers. An intramolecular Schmidt reaction of the alkyl
azide with an aldehyde was served as a key conversion in our pre-
vious synthesis of ( )-antofine, and the Schmidt rearrangement
had been demonstrated as a stereospecific process, where the
stereochemistry of the migration group could be maintained.11
Therefore, the synthesis of optically active tylophorine could be
conveniently addressed if the enantio-enriched precursor of the
Schmidt reaction could be prepared.
tylophorine, affording
a
homoallylic alcohol with 86% ee.9a
Yamaoka and co-workers had reported the synthesis of (R)-
tylophorine based on an asymmetric transfer hydrogenation of a
cyclic imine for creating the chirality (84% ee).7b In this paper,
we present an enantioselective synthesis of the (R)-tylophorine
by using a catalytic asymmetric hydrogenation for installing the
stereogenic center.
With this in mind, we started the synthesis from the known
phenanthryl aldehyde 212 and
a substituted phosphonate 3
(Scheme 1). The aldehyde could be easily prepared according to
the literature12a through four steps conversion, and the
phosphonate 3 was obtained via the synthetic procedure we
reported.10 The Horner-Wadsworth-Emmons condensation of the
phenanthryl aldehyde 2 with phosphonate 3 was carried out in
Our synthesis of (R)-tylophorine employed the strategy analo-
gous to our previously reported method for preparation of the
⇑
Corresponding authors.
E-mail addresses: ruili@nxu.edu.cn (R. Li), gupm@nxu.edu.cn (P. Gu).
the presence of 2.0 equiv of NaH, affording the a,b-unsaturated ester
https://doi.org/10.1016/j.tetlet.2018.04.052
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.

R. Li et al. / Tetrahedron Letters 59 (2018) 2170–2172
2171
OMe
OMe
OMe
OMe
OMe
MeO
MeO
a
MeO
b
MeO
c
O
O
H
H
OEt
Cl
OH
Cl
OH
Cl
MeO
MeO
MeO
MeO
MeO
2
5
4
6
OMe
OMe
OMe
OMe
OMe
d
OMe
OMe
MeO
MeO
f
MeO
e
O
H
N
H
H
H
g
OH
N3
N
N3
OHC
MeO
MeO
MeO
MeO
9
8
1
7
OMe
OMe
OMe
OMe
i -Pr
OMe
MeO
MeO
O
N
O
P
EtO
O
H
Pr- i
N
EtO
NH
OEt
Cl
Ir complex =
Ir
N
10
3
OMe
O
BARF
Scheme 1. Synthesis of (R)-tylophorine.
OMe
OMe
OMe
MeO
MeO
MeO
5 mol%
Rh* or Ir* cat
OH
Cl
OH
50 bar H2, CH2Cl2,
rt, 24 h
Cl
5
6
MeO
OMe
Ligands for the chiral Ir catalysts:
i -Pr
N
Ir
PPh2
N
O
Pr- i
N
PPh2
N
Bn
O
R
N
I-a: R = Ph (20% ee, >99% conv.)
I-b: R = i-Pr (15% ee, >99% conv.)
I-c: R = t-Bu (24% ee, >99% conv.)
III-a: (20% ee, >99% conv.)
O
BARF
Me
Bn Bn
IV-a: Ir complex
(Strem 77-5030)
O
O
[71% ee, >99% conv. (CH2Cl2, 50 bar)]
[54% ee, 12% conv. (CHCl3, 50 bar)]
[58% ee, 22% conv. (ClCH2CH2Cl, 50 bar)]
[55% ee, 85% conv. (CH2Cl2, 30 bar)]
[77% ee, >99% conv. (CH2Cl2, 60 bar)]
[77% ee, >99% conv. (CH2Cl2, 70 bar)]
N
PR2
Ph
II-a: R = Ph (34% ee, >99% conv.)
II-b: R = Cy (27% ee, >99% conv.)
Ligands for the chiral Rh catalysts :
Ph
Et
Et
PR'2
R2P
Me
Fe
P
P
MeO
MeO
PAr2
PAr2
Ph
Ph
Et
Et
H
P
P
VIII-a: R = R' = Cy (59% ee, 19% conv)
VIII-b: R = Ph, R' = tBu (<10% conv)
Ph
V-a: R = Ph (34% ee, 60% conv)
V-b: R = 4-OMe-3,5-tBu-Ph
(25% conv)
VIII-c: R = 4-OMe-3,5-Me-Ph,
VI-a: (42% ee, 70% conv) VII-a: (<10% conv)
R' = Cy (<10% conv)
Scheme 2. Optimization for the asymmetric hydrogenation of the allyl alcohol 5.

2172
R. Li et al. / Tetrahedron Letters 59 (2018) 2170–2172
4 in 70% yield with absolute control of the stereochemistry of the
double bond, and only the E isomer of the ester 4 was observed.
Reduction of 4 with potassium borohydride and lithium chloride
could smoothly offer an allyl alcohol 5 in 65% yield, and the reaction
should be carefully monitored, as excess reduction of the C@C bond
had been observed. The asymmetric hydrogenation of alkenes pro-
vides an efficient and reliable method for producing chiral com-
pounds.13 The primary screening of the commercially available Rh
and Ir catalysts revealed that the Ir-complex catalyzed hydrogena-
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]
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tion of an allyl alcohol was employed for installing a stereogenic
center, and a stereospecific shift of the chiral carbon finally com-
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tylophorine was prepared through seven steps from the known
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This work was supported by the National Natural Science
Foundation of China (Nos 21262024, 21662027), the Program for
Leading Talents of Ningxia Province (KJT2015002).
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.04.052.