Synthesis of (+)-septicine using intramolecular McMurry coupling: A Chiron approach

Article abstract of DOI:10.1080/00397911.2012.736004

Total synthesis of secophenanthroindolizidine alkaloid (+)-septicine 1 was accomplished using the McMurry coupling for the construction of indolizidine ring, using L-glutamicacid as chiral source. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.736004

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Synthesis of (+)-Septicine Using Intramolecular
McMurry Coupling; A Chiron Approach
K. Umamaheshwar Reddy a & A. Panasa Reddy a
a Department of Chemistry, University College of Engineering, Osmania University,
Hyderabad, India
Accepted author version posted online: 16 Apr 2013.
To cite this article: K. Umamaheshwar Reddy & A. Panasa Reddy (2013): Synthesis of (+)-Septicine Using Intramolecular
McMurry Coupling; A Chiron Approach, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.736004
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Synthesis of (+)-Septicine using intramolecular McMurry coupling; A Chiron
approach
K. Umamaheshwar Reddy1, A. Panasa Reddy1,
1Department of Chemistry, University College of Engineering, Osmania University,
Hyderabad, India
,. Tel: +91 984 9957268; Fax: +91 40 27095171; E-mail: reddypanasa@gmail.com
Abstract
Total synthesis of secophenanthroindolizidine alkaloid (+)-septicine 1 was accomplished
by using McMurry coupling for the construction of indolizidine ring using L-
glutamicacid as chiral source.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
KEYWORDS: N-alkylation, bromination, umpolung, McMurry coupling, reduction
INTRODUCTION
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Septicine 1 is Please cite the Supporting Information where appropriate in your
article.an prototype alkaloid of secophenanthroindolizidine group that was isolated by
Russel[1,2] from Ficus septica, a plant belonging to the Moraceae family. Septicine 1 is
considered to be a biogenetic precursor of the phenanthroindolizidine alkaloid
tylophorine 2 in which aryl rings are fused. Tylophorine was isolated from Tylophora
indica (Fig. 1), and has also been found in various plants of the Asclepipiadarceae
family.[1] Both enantiomers, (–)-septicine and (+)-septicine were isolated from natural
sources Ficus septica, Tylophora crebriflora3 and T. asthmatica respectively.[4] These
alkaloids show interesting physiological effects on the respiratory system[5a] as well as
wide range of biological properties such as cancer cell growth inhibition[5b] (in vitro and
in vivo), anti inflammatory activity,[6a] potential antitumor[6b] and anti-viral activity.[7]
Due to their biological importance, indolizidine alkaloids have attracted many synthetic
chemists.
In the past decade, a number of concise synthetic approaches of racemic and
enantiomerically pure septicine 1 have been reported in the literature[3,6,8] and few
approaches to discrete R- and S-enantiomers of septicine have also been published. First
enantioselective synthesis of septicine 1 was reported in 1969 by Russel and Hunziker.[3]
Their synthesis used L-prolinol as a building block and produced (–)-septicine. Comins et
al.,[8b] reported asymmetric synthesis of (–)-septicine using enantiopure N-
acyldihydropyridones as synthetic intermediates and other synthesis were mainly focused
on the synthesis of indolizine-5-one followed by reduction to furnish racemic spticine.8a,8c
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Although various methods were developed for the synthesis of septicine, these methods
have shortcomings like: lengthy procedures, low selectivity and yields.
RESULTS AND DISCUSSION
The strategy of our synthesis is convergent synthetic approach is depicted in the
Scheme 1. The indolizidine skeleton of the target molecule 1 could be constructed by
employing intramolecular McMurry coupling[9] of the appropriate diketone precursor 3,
which has been synthesized by forming C–C bond between bromo compound 4 and 5.
The requisite bromo compound 4 could be synthesized from the chiral fragment 6 in
sequential steps.
Based on retro synthetic analysis, the starting material of our synthesis was the t-
butyl silyl pyrrolidinone 6, which was synthesized from the commercially available L-
glutamic acid according to the reported literature (Scheme 2).[10] In the present synthesis
first N-alkylation of compound 6 with phenacyl bromide 7 was successfully carried out in
the presence of phenyl lithium in toluene under reflux conditions[11] to obtain compound
8. Subsequently carbonyl functionality of compound 8 was protected as 1,3-dithiane
[12]
using propane dithiol in the presence of BF3•OEt2
and concomitant deprotection of
TBDMS functionality occurred to give hydroxymethyl pyrrolidinone 9 in one pot.
Conversion of compound 9 to bromo-derivative 4 was carried out via corresponding
mesylate intermediate. Compound 9 was treated with mesylchloride followed by
nucleophilic displacement with lithium bromide in acetone under reflux conditions to
furnish compound 4.[13] Our initial attempts to synthesize 4 through direct bromination of
hydroxymethyl pyrrolidinone 9 by using PBr3, CBr4/TPP was unsuccessful.
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The dithiane 5 was prepared from 3,4-dimethoxybenzaldehyde by treatment with
1,3-propane dithiol in the presence of BF3•OEt2,[12] which will facilitate umpolung
reactivity. The dithiane 5 reacted with n-BuLi and bromo compound 4 at –78oC to give
the alkylated dithiane 10 in 78% yield, which was then converted to the corresponding
diketone derivative 3 by reaction with mercuric oxide and mercuric chloride.[14]
With the key intermediate diketone 3 in hand, then we constructed indolizidinone
ring by forming tetra-substituted olefin system by employing intramolecular McMurry
coupling.[9] McMurry reaction is the reductive coupling of two carbonyl compounds to
produce olefin with low valent titanium. Compound 3 was subjected to the McMurry
reaction using titanium (0) generated from titanium(IV)chloride and activated zinc in
THF at 68oC in 24 h to afford the desired product 11 in 81% yield. Finally, reduction of
the amide function for 11 was achieved by using lithium aluminum hydride to furnish the
25
(+)-septicine 1 in 91% yield. The specific rotation of our synthetic (+)-septicine 1 [α]D
+169.2 (c 0.50 MeOH), is in good agreement with previously reported synthetic (–)-
septicine [α]D28 –172 (c 0.755, MeOH)8b and further supported by H and 13C NMR data
1
which were in agreement with literature.[8b] (+)-Septicine 1 can be readily converted to
(+)-Tylophorine 2 using reported protocol.[8b]
In conclusion, we have successfully demonstrated the synthesis of seco-
phenanthroindolizidine alkaloid (+)-septicine 1 and formal synthesis of (+)-tylophorine 2,
using intramolecular McMurry coupling as key reaction. The strategy of our synthesis is
convergent, efficient and thus could be used for the synthesis of other
phenanthroindolizidine alkaloids, which is currently under progress in our laboratory.
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EXPERIMENTAL SECTION
All the reactions were preformed in oven-dried (100oC) glassware under argon.
THF was freshly distilled from K. CH2Cl2 was freshly distilled from CaH2. The products
were purified by flash chromatography on 230–400 mesh silicagel. Yields refer to
analytically pure samples. 1H and 13C NMR spectra were recorded on a Bru¨ker AC-400
NMR. Chemical shifts (δ) are expressed in ppm relative to TMS as internal standard.
Thin layer chromatography’s were performed on merck silica gel plates with fluorescent
indicator and were visualized with UV-lamp at 254nm. IR spectra were recorded on
Thermo Scientific Nicolet 6700 FT-IR (solid). Mass spectra were recorded on Agilest
6140 single quade LC-MS coupled with Agilent 1200 series.
(S)-5-(Tert-Butyl-Dimethyl-Silanyloxymethyl)-1-[2-(3,4-Dimethoxy-Phenyl)-2-Oxo-
Ethyl]-Pyrrolidin-2-One (8)
To a mixture of 6 (6 g, 26.2 mmol) in dry toluene (36 mL), phenyl lithium (24.5 mL,
39.3 mmol) was dropwise added under nitrogen atmosphere at 0oC. After stirring 1 h at
ambient temperature a mixture of compound 7 (10.2 g, 39.3 mmol) in toluene (24 mL)
was added to the reaction mixture and mixture was heated under reflux for 16 h. The
solution was allowed to cool to room temperature water (30 mL) was added. The organic
layer was separated and aq-layer was extracted with EtOAc, combined total organic
extracts were washed with brine, dried over Na2SO4 and concentrated. The crude residue
was purified by flash silica gel column chromatography (EtOAc-hexane, 35:65) to afford
8 (7.15 g, 67%) as colorless liquid; [α]D25 +2.8 (c 1.0, EtOH); 1H NMR (400 MHz,
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CDCl3): δ = 7.59 (dd, 1 H, J = 2 Hz, 7.6 Hz), 7.50 (d, 1 H, J = 2 Hz), 6.88 (d, 1 H, J = 7.6
Hz), 5.15 (d, 1 H, J = 17.2 Hz), 4.52 (d, 1 H, J = 7.2 Hz), 3.94 (s, 3 H), 3.91 (s, 3 H),
3.89–3.82 (m, 1 H), 3.69 (dd, 1 H, J = 2 Hz, 10.8 Hz), 3.61 (dd, 1 H, J = 6 Hz, 10.8),
2.54–2.39 (m, 2 H), 2.23–2.13 (m, 1 H), 1.8–1.67 (m,1 H), 0.79 (s, 9 H), -0.02 (s, 6 H);
13C NMR (100 MHz, CDCl3): δ = 192.6, 176.07, 153.67, 149.11, 128.30, 122.62, 110.23,
110.16, 65.12, 59.67, 56.09, 58.98, 47.62, 59.99, 25.73, 21.28, 18.09, -5.59; IR (neat):
3252, 2929, 1688, 1665, 1584, 1442, 1266, 1023, 833, 772; MS (EI, 70eV): m/z =
408.2[M+1]; Anal. Calcd for C21H33NO5Si: C, 61.88; H, 8.16; N, 3.44. Found: C, 61.56;
H, 8.25; N, 3.41.
(S)-1,5-Bis((2-(3,4-Dimethoxyphenyl)-1,3-Dithian-2-Yl) Methyl)Pyrrolidin-2-One
(10)
To a solution of 5 (0.8 g, 3.12 mmol) in dry THF (8 mL) was dropwise added n-BuLi (1.6
M in hexane 2.96 mL, 4.68 mmol) at –78oC and the resulting mixture was stirred at same
temperature for 30 min and a mixture of 4 (1.39 g, 3.12 mmol) in THF (10 mL) and
TMEDA (0.42 mL) were added at same temperature and the reaction mixture was
allowed to stir at –25oC for 3 h. The reaction was quenched by addition of saturated
NH4Cl solution and product was extracted with EtOAc. The combined organic phase was
washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash silica gel column chromatography (EtOAc-hexane,
35:65) to afford 10 (1.51 g, 78%) as light yellow gummy solid; [α]D25 –10.0 (c 1.0,
EtOH); 1H NMR (400 MHz, DMSO-d6): δ = 7.35 (s, 1 H), 4.08 (d, 1 H, J = 14.4 Hz),
3.79 (s, 3 H), 3.78 (s, 3 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.07–2.99 (m, 1 H), 2.85–2.70
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(m, 2 H), 2.63-2.5 (m, 3 H), 2.15-2.02 (m, 2 H), 1.95–1.68 (m, 6 H), 1.34–1.28 (m, 1 H),
0.90–0.82 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ = 175.3, 149.1, 148.9, 148.2, 148.2,
132.8, 132.3, 121.5, 121.5, 112.1, 112.0, 111.0, 110.9, 60.3, 56.7, 56.0, 55.9, 55.7, 51.1,
46.3, 28.4, 27.6, 27.5, 25.1, 24.8, 24.5; IR (neat): 3072, 2903, 1688, 1592, 1440, 1322,
1021, 863, 728; MS (EI, 70eV): m/z = 622.2 [M+1]; Anal. calcd. for C30H39NO5S4: C,
57.94; H, 6.32; N, 2.25. Found: C, 57.91; H, 6.34; N, 2.31.
(S)-1,2,8,8a-Tetrahydro-6,7-Bis(3,4-Dimethoxyphenyl)-Indolizin-3(5H)-One (11)
Under nitrogen atmosphere TiCl4 (0.94 mL, 5.53 mmol) was slowly added to a
suspension of activated zinc (16.8 g, mmol) in THF (40 mL) at 0oC. The resulting
mixture was refluxed for 1 h, cooled to room temperature and a mixture of 3 (0.5 g, 1.12
mmol) in dry THF (6 mL) was added drop wise by syringe to the reaction mixture and
the resulting mixture was refluxed for 24 h. After completion of reaction indicated by
TLC, the reaction mixture was cooled to room temperature and quenched with the
addition of water. Solids were filtered through celite pad and filtrate was extracted with
EtOAc and organic extracts were washed with water, brine and dried over anhydrous
Na2SO4, filtered. Filtrate was concentrated under reduced pressure, and the residue was
purified by flash silica gel column chromatography (EtOAc-hexane, 25:75) to afford 11
(0.37 g, 81%) as off-white semi solid; [α]D25 +158.1 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3): δ = 6.69–6.58 (m, 4 H), 6.50 (d, 1 H, J = 1.6 Hz), 6.46 (d, 1 H, J = 2 Hz), 4.74
(dd, 1 H, J = 2 Hz, 18.4 Hz), 3.95–3.88 (m, 1 H), 3.81 (s, 6 H), 3.79 (d,1 H, J = 18.4 Hz),
3.59 (s, 3 H), 3.58 (s, 3 H), 2.75 (dd, 1 H, J = 3.6 Hz, 16.8 Hz), 2.50 (t, 1 H, J = 8 Hz),
2.48–2.37 (m, 2 H), 1.86–1.75 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ = 173.91,
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148.39, 148.32, 147.94, 147.69, 134.47, 131.94, 131.76, 130.65, 121.17, 120.82, 112.82,
112.78, 110.77, 55.78, 55.68, 53.33, 44.24, 38.76, 30.05, 24.84; MS (EI, 70eV): m/z =
410.2 [M+1]; Anal. Calcd for C24H27NO5: C, 70.40; H, 6.65; N, 3.42. Found: C, 70.53; H,
6.50; N, 3.29.
(S)-1,2,3,5,8,8a-Hexahydro-6,7-Bis(3,4-Dimethoxy-Phenyl)Indolizine (1)
To a solution of compound 11 (0.2 g, 0.292 mmol) in THF (10 mL) was slowly added
lithium aluminum hydride (2.0M in THF, 0.23 mL, 0.436 mmol) at 0oC over 10 min. The
resulting mixture was stirred for 1 h at room temperature. The reaction mixture was
quenched by addition of water at 0oC and solids were filtered through the celite. Filtrate
was extracted with EtOAc and washed with brine, dried over anhydrous Na2SO4, filtered.
Solvent was removed under vacuo and crude residue was purified by column
chromatography on silica gel (MeOH/CH2Cl2, 2:98) to furnish 1 (0.105 g, 91%) as pale
yellow solid;Optical purity was estimated as >99% using Chiracel OJ-H column
0.2%DEA, in 20% EtOH in Hexane, with flow rate of 1ml/min, λ=254nm; mp: 131-132
oC;[α]D25 +169.2 (c 0.50, MeOH); 1H NMR (400 MHz, CDCl3): δ = 6.68-6.63 (m, 4 H),
6.54 (d, 1 H, J = 1.2 Hz), 6.51 (d, 1 H, J = 1.2 Hz), 3.92 (d, 1 H, J = 16 Hz), 3.80 (s, 6
H), 3.59 (s, 3 H), 3.57 (s, 3 H), 3.34 (m, 1 H), 3.15–3.08 (m, 1 H), 2.75 (d, 1 H, J = 15
Hz), 2.48– 2.43 (br m, 2 H), 2.33–2.32 (br m, 1 H), 2.20– 2.09 (br m, 1 H), 2.06–2.01
(m, 1 H), 1.90–1.80 (m, 1 H),1.63–1.25 (m, 1 H); 13CNMR (100 MHz, CDCl3): δ =
148.3, 148.1, 147.5, 147.3, 134.9, 133.4, 132.9, 132.3, 121.0, 120.7, 113.0, 112.8, 110.7,
110.6, 60.4, 57.3, 55.7, 55.6, 54.1, 38.2, 30.7, 29.6, 21.4; IR (neat): 1599, 1580, 1511,
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1459, 1242, 1020, 995, 778 cm-1; MS (EI, 70eV): m/z = 396 ([M+1]+); EI-HRMS m/z
calculated for C24H29NO4 395.21, found 396.2175.
ACKNOWLEDGMENTS
The authors acknowledge the Osmania University for providing the research facility and
IICT for analytical data. And also thankful to Head of the Department and Vice
Chancellor of Osmania University for constant support and encouragement.
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Figure 1. Natural Indolizidine alkaloids
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Scheme 1. Retrosynthetic analysis of septicine (1)
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Scheme 2. Reagents and conditions: (i) PhLi ,Toluene, 0oC–rt, 1 h, reflux 16 h, 67%; (ii)
1,3-propane dithiol, BF3•OEt2, CH2Cl2, rt, 15 h, 84%; (iii) (a) MsCl, Et3N, CH2Cl2, rt, 2
h, 94%; (b) LiBr, acetone, reflux, 8 h, 78%; (iv) n-BuLi, TMEDA, Int-5, THF, –78oC to
–20oC, 2 h, 78%; (v) Hg2O, HgCl2, CH3CN-H2O, rt, 16h, 75%; (vi) anhyd. TiCl4, Zn,
THF, 24 h, reflux, 81%; (vii) LiAlH4, 0oC–rt, 1 h, 91%.
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