An enantioselective strategy for the synthesis of (S)-tylophorine via one-pot intramolecular schmidt/bischler-napieralski/imine-reduction cascade sequence

Article abstract of DOI:10.1021/jo302725q

A novel enantioselective strategy for the total synthesis of (S)-tylophorine was developed in an overall yield of 48% with more than 99% ee from readily avaliable azido acid and phenanthryl alcohol. This route features an Evans stereoselective alkylation and an unprecedented one-pot intramolecular Schmidt/Bischler-Napieralski/imine-reduction cascade sequence, in which three new bonds and two rings formed in 84% yield. The intramolecular Schmidt rearrangement of the azido aldehyde was proved to be racemization-free.

Full text of DOI:10.1021/jo302725q

Note
pubs.acs.org/joc
An Enantioselective Strategy for the Synthesis of (S)‑Tylophorine via
One-Pot Intramolecular Schmidt/Bischler−Napieralski/Imine-
Reduction Cascade Sequence
Bo Su,† Fazhong Chen,† and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, People’s Republic of China
S
* Supporting Information
ABSTRACT: A novel enantioselective strategy for the total synthesis of (S)-tylophorine was developed in an overall yield of
48% with more than 99% ee from readily avaliable azido acid and phenanthryl alcohol. This route features an Evans
stereoselective alkylation and an unprecedented one-pot intramolecular Schmidt/Bischler−Napieralski/imine-reduction cascade
sequence, in which three new bonds and two rings formed in 84% yield. The intramolecular Schmidt rearrangement of the azido
aldehyde was proved to be racemization-free.
fusion position.10 In most applications of this valuable
henanthroindolizidine and phenanthroquinolizidine alka-
Ploids represent a group of pentacyclic natural products, chemistry, ketones11 and carbocations12 (generally generated
from tertiary alcohols and olefins) are usually used as
which were mainly isolated from the Tylophora, Pergularia, and
Cynanchum species.1 To date, more than 60 members of this
class are known and have inspired increasing interest over the
past decade for their newfound potent anticancer2 and anti-
inflammatory activities.3 For example, tylophorine arrests
carcinoma cells in the G1 phase by downregulation of cyclin
A2 expression,4 while (R)-antofine exerts its cytotoxic effects
via cell cycle arrest in the G2/M phase.5 A surprising and
interesting find is that the unnaturally occurring (S)-
tylophorine is much more potent for the inhibition of cancer
cell growth.6 Consequently, a number of synthetic strategies
were developed,7 which include using chiral building
blocks,7b−d chiral auxiliary approach,7a enantioselective phase-
transfer alkylation, and enantioselective catalysis for intra-
molecular alkene carboamination.7e Intramolecular Diels−Alder
strategy was also employed, in which the DE ring was
constructed in one step. As a continuation of studies on the
synthesis and bioactivity evaluation,8 herein we report an
unprecedented one-pot intramolecular Schmidt/Bischler−
Napieralski/imine-reduction cascade sequence to construct
the DE ring of phenanthroindolizidine alkaloid.
electrophilic components, and seminal work has been done in
this area by Aube
́
9,11,13 and Pearson.12,14 In contrast, little work
has been done on the corresponding chemistry of aldehyde,
and it was always less efficient, mainly due to elimination and
the competition resulting from hydride or alkyl migration.15
Besides the concerns mentioned above, stereochemistry in the
intramolecular Schmidt rearrangement of aldehyde was also an
important noteworthy consideration. As shown in Scheme 1,
azido aldehyde (I), when activated by Lewis acid or Bronsted
acid, could lead to the formation of azidohydrin (III)
intermediate, which would furnish formamide (path a, alkyl
migration) and/or lactam (path b, hydride migration).
Although there was no precedent to the best of our knowledge,
we believe the resulting formamide or lactam, if activated by
suitable reagent, can produce electrophilic imine cation IV or
imine V respectively, which would be a valuable employable
synthetic intermediate in cascade reaction.
On the basis of the rational analysis, we designed a one-pot
intramolecular Schmidt/Bischler−Napieralski/imine-reduction
cascade sequence to construct the DE ring of phenanthroindo-
Since the first intramolecular Schmidt reaction was reported
in 1991,9 it has become an important and effective strategy to
construct ring systems featuring a nitrogen atom at the ring
Received: December 20, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo302725q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Intramolecular Schmidt Rearrangement of Azido Aldehyde
Scheme 2. Retrosynthesis of (S)-Tylophorine
lizidine alkaloids. Using (S)-tylophorine as an example,
retrosynthetic analysis is shown in Scheme 2. The target
molecule could be accessible via reduction from imine cation 1,
which was envisioned to be produced from formamide 2
through Bischler−Napieralski reaction, while formamide 2
could be derived from azido aldehyde 3 via Schmidt reaction.
The stereogenic center of azido aldehyde 3 was planed to
introduce with the assistance of Evans stereoselective alkylation
from readily available phenanthryl bromide 4 and azido N-
acylated oxazolidinone 5.
Scheme 3. Synthesis of Key Intermediate Azido Aldehyde 3
Synthesis of the azido aldehyde 3 started with the coupling of
the known auxiliary 616 and azido acid 7,17 which gave N-
acylated oxazolidinone 5 under standard conditions18 (Scheme
3). Phenanthryl bromide 419 was prepared using the reported
method and used immediately without further purification due
to its instability. Stereoselective alkylation of compound 5 went
smoothly when KHMDS was used as base to give compound 9
as a single diastereomer (determined by NMR) after
purification by column chromatography, while other bases
such as LDA, LiHMDS, and NaHMDS proved to be less
effective. After reductive removal of the auxiliary with DIBAL-
H, azido aldehyde 3 was obtained.
With the key intermediate 3 in hand, we first investigated the
regioselectivity and stereochemistry of the intramolecular
Schmidt rearrangement (Scheme 4). After extensive conditions
screening, TiCl4 and CF3COOH were found to be effective for
promotion of the reaction, which furnished the desired
formamide 2 (formed via alkyl migration), and it is worth
noting that formamide 2 was stable enough for column
chromatographic purification. Fortunately, formation of lactam
(formed via H migration) was not detected, and no
racemization was found in this step.20 In order to execute the
desired cascade sequence in one pot, (CF3CO)2O was chosen
as the activating reagent for the Bischler−Napieralski reaction.
As expected, formamide 2 vanished 20 min after addition of
(CF3CO)2O, and then sodium borohydride was added to the
reaction mixture, which furnished (S)-tylophorine in 84%
isolated yield based on azido aldehyde 3 with an enantiomeric
excess of more than 99% (HPLC, Chiral AD, see Supporting
B
dx.doi.org/10.1021/jo302725q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 4. Completion of the Synthesis of (S)-Tylophorine
(25 mL/20 mL). KOH (1.12 g, 20 mmol) was added at 0 °C, and the
reaction mixture was stirred at room temperature overnight. The
reaction mixture was evaporated in vacuo, and residue was partitioned
between DCM and water. After extraction with DCM (50 mL × 2),
the aqueous phase was acidified to pH 1 with 1N aqueous HCl and
then extracted with EtOAc (50 mL × 3). The combined organic phase
was dried over Na2SO4 and concentrated to dryness to give azido acid
Information). The spectrum of our synthesized sample
matched well with reported data, and the optical rotation
([α]2D5 +82.8 (c 0.5, CHCl3)) is slightly higher than the
reported value (lit.7d [α]D22 +78.9 (c 0.5, CHCl3)).
In summary, we have developed a concise and novel
enantioselective strategy for the total synthesis of (S)-
tylophorine. Key features include (1) a stereoselective
alkylation to introduce the stereogenic center, which also
enables the synthesis of the antipode by converting the Evans
auxiliary; (2) an unprecedented one-pot Schmidt/Bischler−
Napieralski/Imine-reduction cascade sequence, in which three
new bonds and two rings formed in 84% yield; and (3) an
intramolecular Schmidt rearrangement that was proved to be
racemization-free, which may find further application in the
synthetic chemistry.
1
7 (1.22 g, 85%) as a light yellow oil: H NMR (400 MHz, CDCl3) δ
3.32 (t, J = 6.4 Hz, 1H), 2.41 (t, J = 7.2 Hz, 1H), 1.80−1.62 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 178.5, 51.0, 33.2, 28.2, 21.8.
(R)-4-Isopropyloxazolidin-2-one (6).17 To a solution of D-
valinol (2.0 g, 20 mmol) in diethylcarbonate (4.76 g, 40 mmol) in a 50
mL round flask equipped with a short-path distillation apparatus was
added potassium carbonate (0.28 g, 2 mmol). The reaction mixture
was heated to 130 °C for 3 h. Brine (50 mL) was added to the residue
and then extracted with DCM (50 mL × 2). After concentration in
vacuo, a light yellow oil was obtained, to which ether (20 mL) was
added. Compound 6 (2.03 g, 79%) precipitated as a white crystalline
solid: mp 75−76 °C, lit.17 67−70 °C; [α]D25 −14.2 (c 4.1, CHCl3), lit.17
EXPERIMENTAL SECTION
■
[α]2D2 −13.1 (c 4.2, CHCl3); H NMR (400 MHz, CDCl3) δ 6.79 (s,
1
General Information. The melting points were determined with
an X-4 binocular microscope melting-point apparatus and are
uncorrected. 1H NMR spectra were obtained by using Bruker AV
400 spectrometer. Chemical shifts (δ) are given in parts per million
(ppm) and were measured downfield from internal tetramethylsilane.
13C NMR spectra were recorded by using a Bruker AV 400 instrument
(100 MHz) and CDCl3 as solvent. Chemical shifts (δ) are reported in
parts per million. High-resolution mass spectra were obtained with an
FT-ICR MS spectrometer (Ionspec, 7.0 T). Optical rotations were
measured with a Autopol IV auto digital polarimeter (Rudolph
Research Analytical). The enantiomeric excesses were determined by
HPLC with a Chiralcel AD-H column using an Agilent 1100
instrument. All anhydrous solvents were dried and purified by
standard techniques just before use. All reagents were purchased
from commercial suppliers without further purification. Reactions were
monitored by thin layer chromatography on plates (GF254) using UV
light as visualizing agent. If not noted otherwise, flash column
chromatography used silica gel (200−300 mesh).
1H), 4.44 (t, J = 8.8 Hz, 1H), 4.10 (dd, J = 8.8, 6.4 Hz, 1H), 3.61 (dd,
J = 13.6, 6.8 Hz, 1H), 1.73 (dq, J = 13.6, 6.8 Hz, 1H), 0.97 (d, J = 6.8
Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H).
(R)-3-(5-Azidopentanoyl)-4-isopropyloxazolidin-2-one (5).
To a solution of compound 6 (5.2 g, 40 mmol) in THF (100 mL)
was added n-BuLi (20 mL, 48 mmol, 2.4 M in THF) dropwise at −78
°C under an atmosphere of Ar. The mixture was stirred at this
temperature for 30 min. In another flask, azide acid 7 (6.9 g, 48 mmol)
and triethylamine (9.4 mL, 68 mmol) were taken in THF (150 mL) at
0 °C, to which pivaloyl chloride (6.3 g, 52 mmol) was added slowly.
After 30 min of stirring at this temperature, the lithio-oxazolidinone
was added to this freshly formed mixed anhydride. The mixture was
quenched with saturated aqueous ammonium chloride and extracted
with EtOAc (50 mL × 3). The combined organic layer was washed
with saturated aqueous NaHCO3 (100 mL), saturated aqueous NH4Cl
(100 mL), and brine (100 mL), dried over Na2SO4, and concentrated
in vacuo. The residue was purified by flash chromatography on silica
gel to give compound 5 (8.2 g, 82%) as a coloress oil: [α]2D5 −68.2 (c
5-Azidopentanoic Acid (7).16 To a solution of bromo acid
methyl ester (1.94 g, 10 mmol) in acetone/water (15 mL/5 mL) was
added sodium azide (1.3 g, 20 mmol), and then the reaction mixture
was heated under reflux overnight. After removal of the solvent in
vacuo, residue was partitioned between DCM and water. After
separation, aqueous phase was extracted with DCM (50 mL × 3), and
the combined organic extracts were washed with water, brine, dried
over Na2SO4 and evaporated to dryness to give azido ester as colorless
oils, which without further purification was dissolved in MeOH/water
1
3.14, CHCl3); H NMR (400 MHz, CDCl3) δ 4.50−4.38 (m, 1H),
4.28 (dd, J = 9.0, 2.8 Hz, 1H), 4.22 (dd, J = 9.0, 2.8 Hz, 1H), 3.32 (t, J
= 6.5 Hz, 2H), 3.10−2.85 (m, 2H), 2.43−2.33 (m, 1H), 1.82−1.63 (m,
4H), 0.92 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.6, 154.1, 77.4, 77.1, 76.8, 63.4, 58.4, 51.1,
34.9, 28.4, 28.3, 21.5, 18.0, 14.7; HRMS (ESI) calcd for
C11H18N4NaO3 (M + Na)+ 277.1271, found 277.1269.
C
dx.doi.org/10.1021/jo302725q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
mp 281−283 °C, lit.7b mp 280−283 °C, lit.8b mp 282−284 °C; H
1
9-(Bromomethyl)-2,3,6,7-tetramethoxyphenanthrene (4).
To a solution of compound 8 (4.9 g, 15 mmol) in DCM (300 mL)
was added PBr3 (6.1 g, 22.5 mmol in DCM (40 mL)) dropwise
through a constant pressure funnel at 0 °C. The reaction mixture was
stirred at this temperature for 2 h and then quenched with ice−water
(200 mL). After separation, the organic layer was washed with ice−
water (200 mL × 5) and brine (200 mL), dried over Na2SO4, and
concentrated in vacuo to give bromide 4 (5.6 g, 14.4 mmol, 96%) as a
white solid: mp 207−209 °C, lit.19 195−197 °C; 1H NMR (400 MHz,
CDCl3) δ 7.75 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.12
(s, 1H), 4.93 (s, 2H), 4.10 (s, 3H), 4.09 (s, 3H), 4.08 (s, 3H), 3.99 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 149.9, 149.3, 149.0, 148.7,
128.7, 126.4, 125.6, 125.2, 124.0, 108.4, 104.9, 103.3, 102.7, 56.1, 56.1,
56.0, 55.9, 33.8.
NMR (400 MHz, CDCl3) δ 7.83 (s, 2H), 7.31 (s, 1H), 7.16 (s, 1H),
4.63 (d, J = 14.7 Hz, 1H), 4.12 (s, 6H), 4.06 (s, 6H), 3.68 (d, J = 14.6
Hz, 1H), 3.48 (t, J = 8.1 Hz, 1H), 3.37 (d, J = 16.1 Hz, 1H), 2.97−2.86
(m, 1H), 2.48 (d, J = 8.8 Hz, 2H), 2.25 (d, J = 5.6 Hz, 1H), 2.04 (d, J
= 7.5 Hz, 1H), 1.94 (s, 1H), 1.79 (d, J = 9.7 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 148.7, 148.5, 148.4, 126.3, 126.1, 125.9, 124.4, 123.6,
123.4, 104.0, 103.4, 103.3, 103.1, 60.2, 56.1, 55.9, 55.8, 55.2, 54.0, 33.8,
31.3, 21.6; [α]D25 +82.8 (c 0.5, CHCl3), lit.7b [α]2D2 +78.9 (c 0.5,
CHCl3); ee >99%, determined by HPLC; HRMS (ESI) calcd for
C24H29NO4 (M + H)+ 394.2018, found 394.2022.
ASSOCIATED CONTENT
■
S
* Supporting Information
(R)-3-((S)-5-Azido-2-((2,3,6,7-tetramethoxyphenanthren-9-
yl)methyl)pentanoyl)-4-isopropyloxazolidin-2-one (9). To a
solution of compound 5 (0.8 g, 3.1 mmol) in THF (50 mL) was
added KHMDS (3.4 mL, 3.4 mmol, 1 M in THF) via a syringe
dropwise at −78 °C under an atmosphere of Ar. One hour later,
bromide 4 (1.2 g, 2.9 mmol in THF (80 mL)) was added slowly via a
syringe. The reaction mixture was stirred at this temperature overnight
and then quenched with aqueous saturated ammonium chloride. After
separation, the aqueous layer was extracted with EtOAc (100 mL × 3).
The combined organic phase was washed with brine (100 mL × 2),
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to give compound 9
(1.4 g, 2.4 mmol, 84%) as a white solid: mp 69−71 °C; [α]2D5 −26.5 (c
1
Copies of H and 13C NMR spectra for compounds 3−7, 9,
and (S)-tylophorine, and HPLC for (S)-tylophorine and
racemic tylophorine. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wang98h@263.net; wangqm@nankai.edu.cn.
■
Author Contributions
†These authors contributed equally to this work.
Notes
1
1.35, CHCl3); H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.75 (s,
The authors declare no competing financial interest.
1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.14 (s, 1H), 4.63−4.53 (m, 1H),
4.49−4.42 (m, 1H), 4.20 (t, J = 8.8 Hz, 1H), 4.11 (s, 3H), 4.11 (s,
6H), 4.10−4.06 (m, 1H), 4.01 (s, 3H), 3.58 (dd, J = 13.2, 8.0 Hz, 1H),
3.20 (t, J = 6.8 Hz, 2H), 3.12 (dd, J = 13.2, 8.0 Hz, 1H), 2.12−2.01 (m,
1H), 1.94−1.83 (m, 1H), 1.64−1.43 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.8, 153.6, 149.1, 149.0, 148.89, 148.8, 130.1, 126.1,
126.0, 125.4, 124.9, 124.0, 108.0, 105.1, 103.4, 102.8, 62.9, 58.4, 56.2,
56.1, 56.0, 56.0, 51.2, 42. 6, 36.8, 29.0, 28.3, 26.8, 17.9, 13.8; HRMS
(ESI) calcd for C30H36N4NaO7 (M + Na)+ 587.2476, found 587.2479.
(S)-5-Azido-2-((2,3,6,7-tetramethoxyphenanthren-9-yl)-
methyl)pentanal (3). To a solution of compound 9 (0.60 g, 1.06
mmol) in DCM (80 mL) was added DIBAL-H (3.2 mL, 3.2 mmol, 1
M in hexane) at −78 °C under an atmosphere of Ar. The reaction
mixture was stirred at this temperature overnight and then quenched
with aqueous saturated ammonium chloride. After separation, the
aqueous layer was extracted with DCM (50 mL × 2). The combined
organic phase was washed with brine (100 mL × 2), dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel to give azido aldehyde 3 (0.40 g,
87%) as a white solid: mp 86−88 °C; [α]2D5 −22.2 (c 1.03, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 9.77 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H),
7.78 (s, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 7.18 (s, 1H), 4.14 (s, 3H),
4.13 (s, 3H), 4.06 (s, 3H), 4.04 (s, 3H), 3.51 (dd, J = 14.6, 7.0 Hz,
1H), 3.32−3.20 (m, 2H), 3.09 (dd, J = 14.6, 7.0 Hz, 1H), 2.90−2.82
(m, 1H), 1.94−1.84 (m, 1H), 1.77−1.67 (m, 2H), 1.65−1.55 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 204.1, 149.2, 149.0, 148.8, 129.9,
ACKNOWLEDGMENTS
■
We are grateful to the National Key Project for Basic Research
(2010CB126106), the National Natural Science Foundation of
China (21132003, 21121002), the Tianjin Natural Science
Foundation (11JCZDJC20500), and the National Key
Technology Research and Development Program
(2011BAE06B05, 2012BAK25B03-3) for generous financial
support for our programs. We thank China Agricultural
University for supplying some chemical reagents.
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dropwise manner at room temperature. Thirty minutes later, azido
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vacuo. The residue was purified by column chromatography on basic
Al2O3 to give (S)-tylophorine (112 mg, 0.28 mmol) as a white solid:
D
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Note
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(20) The formamide 2 could be isolated for the use of monitoring
the process of the reaction, and no racemization occurred, which was
demonstrated by chiral HPLC of (S)-tylophorine and a racemic
sample (see Supporting Information).
E
dx.doi.org/10.1021/jo302725q | J. Org. Chem. XXXX, XXX, XXX−XXX