Titanocene(III) chloride mediated formal synthesis of magnofargesin and 7′-epimagnofargesin

Article abstract of DOI:10.1016/j.tetlet.2012.09.103

Formal synthesis of two bioactive lignans, magnofargesin and 7′-epimagnofargesin has been accomplished in both racemic and optically active forms through titanocene(III) chloride (Cp₂TiCl) mediated radical induced cyclization reaction. Ti(III)

Full text of DOI:10.1016/j.tetlet.2012.09.103

Tetrahedron Letters 53 (2012) 6584–6587
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Tetrahedron Letters
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Titanocene(III) chloride mediated formal synthesis of magnofargesin and
70-epimagnofargesin
⇑
Pushkin Chakraborty, Samaresh Jana, Sumit Saha, Subhas Chandra Roy
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Formal synthesis of two bioactive lignans, magnofargesin and 70-epimagnofargesin has been accom-
plished in both racemic and optically active forms through titanocene(III) chloride (Cp2TiCl) mediated
radical induced cyclization reaction. Ti(III) species was generated in situ from the commercially available
titanocene dichloride (Cp2TiCl2) and activated zinc dust in dry THF.
Article history:
Received 1 September 2012
Revised 19 September 2012
Accepted 22 September 2012
Available online 28 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Radical cyclization
Epoxide
Titanocene(III) chloride
Magnofargesin
Epimagnofargesin
Due to widespread occurrence in nature and broad range of bio-
logical activities lignans have attracted the attention of organic
chemists in recent years. Magnofargesin (1) and its isomer 70-epi-
magnofargesin (2) are two furano lignans. Magnofargesin was first
isolated1 from the flower buds of Magnolia fargessi also known as
‘shin-i’, which has been used for many years in China and Japan
as materia medica. It has been shown that (ꢀ)-magnofargesin is
an antagonist of platelet-activating factor (PAF).2 Antagonists of
PAF have therapeutic potentiality for the treatment of asthma
and protective activity against ischemic injury.3
be easily synthesized from magnofargesin. In spite of such im-
mense biological importance, to the best of our knowledge only
one report by Wardrop and Fritz5 has been documented in the lit-
erature for the synthesis of magnofargesin (1) in a multi-step pro-
cess. In continuation of our ongoing research6 on the total
synthesis of natural products and related compounds through
titanocene(III) chloride (Cp2TiCl) mediated radical cyclization reac-
tions, we describe herein the formal synthesis of magnofargesin (1)
and 70-epimagnofargesin (2) in a concise and efficient route by
opening of epoxides using Cp2TiCl as the radical initiator. Ti(III)
species was generated in-situ from the readily available titanocene
dichloride (Cp2TiCl2) and activated zinc dust in dry THF.7
OMe
MeO
The epoxy alcohol 7 was prepared from 3,4,5-trimethoxybenz-
aldehyde (3) as depicted in Scheme 1. Compound 3 on vinyl Grig-
OH
7'
OMe
OMe
OH
9
nard reaction afforded the allyl alcohol
4 (86%) which on
8
7'
8'
9
1
MeO
MeO
epoxidation with m-CPBA afforded the epoxy alcohol 7 in only
25% yield as an inseparable mixture of two isomers in almost equal
ratio (1H NMR). The poor yield of the desired alcohol in this meth-
od prompted us to find out an alternative route to the epoxy alco-
hol 7 with an improved yield. Dihydroxylation8 of the allyl alcohol
4 with OsO4 and NMO in acetone–water (4:1) afforded the triol 5 in
good yield as a mixture of two isomers in 1:1 ratio. Selective tosy-
lation of the crude triol 5 with TsCl in pyridine furnished the tosyl-
ate 6 (44%). The treatment of the crude compound 6 with K2CO3 in
MeOH at room temperature9 afforded the terminal epoxide 7 in
92% yield as an inseparable mixture of two isomers in 1:1 ratio.
The crude epoxide 7 was used for the synthesis of 1 and 2 without
further purification. Thus, treatment of the epoxide 7 with sodium
hydride and the easily accessible propargyl bromide 8 at low
2'
O
4'
1
7
MeO
MeO
O
7
4
OMe
OMe
Magnofargesin (1)
7'-epimagnofargesin (2)
Biotransformation study of (ꢀ) magnofargesin by Spodoptera
litura larvae has been investigated thoroughly to obtain a useful
O-demethylated4 metabolite. (+)-Epimagnolin A,1b a growth inhib-
itory lignan against the larvae of Drosophila melanogaster, can also
⇑
Corresponding author.
E-mail address: ocscr@iacs.res.in (S.C. Roy).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.103

P. Chakraborty et al. / Tetrahedron Letters 53 (2012) 6584–6587
6585
O
m-CPBA
MgBr
CHCl3
MeO
MeO
MeO
CHO
THF
MeO
MeO
OH
OH
rt, 40 h
25%
rt, 3 h
86%
MeO
OMe
OMe
7
OMe
3
4
rt, 3 h
92%
OsO4, NMO rt, 16 h
acetone-water (4:1) 78%
K2CO3, MeOH
OTs
OH
TsCl, Py
CH2Cl2
OH
OH
OH
MeO
MeO
OH
MeO
MeO
rt, 36 h
44%
OMe
OMe
6
5
Scheme 1.
OMe
O
OMe
NaH/THF
Cp2TiCl
THF
0οC
MeO
MeO
OH
1
2
+
then
O
rt, 1.5 h
84%
(racemic, 1:1)
Br
MeO
MeO
OMe
MeO
MeO
7
O
8
rt, 8 h, 75%
OMe
9
Scheme 2.
temperature afforded the epoxide 9 as a mixture of two isomers
(1:1) in good yield (Scheme 2).
appeared as doublet at d 4.86 (J = 6.7 Hz) for one isomer and at d
5.08 (J = 4 Hz) for the other isomer. The 1H NMR of the crude
mixture was compared with the values reported in the literature
by Wardrop5 and it was found that both magnofargesin (1) and
70-epimagnofargesin (2) were formed in equal ratio. Due to
unavailability of the specific column used by Wardrop and Fritz,5
our attempts to separate two isomers 1 and 2 by preparative TLC
The radical cyclization of the crude epoxide 9 using titano-
cene(III) chloride (Cp2TiCl) in THF at room temperature afforded
a mixture of two isomers 1 and 2 in 1:1 ratio with 84% yield. The
ratio of the two isomers was determined from the 1H NMR spec-
trum of the crude cyclized product, where C-7 benzylic proton
O
NaH/
MgBr
THF
O
THF
OH
+
O
O
O
MeO
Br
65%
H
MeO
75%
(1:1)
11
12
10
OH
OH
O
O
TsCl/
Py
aq.TFA
O
DCM, overnight
73%
O
rt, 12 h
70%
MeO
MeO
14
13
O
O
OTs
OH
(R)
Cp2TiCl
THF
HO
NaH/THF
O
rt,overnight
80%
MeO
65%
O
MeO
MeO
17
15
16
Scheme 3.

6586
P. Chakraborty et al. / Tetrahedron Letters 53 (2012) 6584–6587
O
O
O
Major isomer
O
separeted
MeO
MeO
Br
BuLi, THF
MeO
MeO
MeO
OH
+
O
OH
53%
O
-40oC
MeO
OMe
H
OMe
OMe
O
19a
(3:1)
18
19
10
OH
OH
O
O
80% aq AcOH
40o
NaH
THF
MeO
O
C
MeO
MeO
O
MeO
71%
Br
OMe
OMe
81%
MeO
OMe
OMe
8
OMe
NaH
OMe
20a
21a
OMe
OTs
OH
O
O
MeO
MeO
Cp2TiCl
THF
MeO
MeO
TsCl, Py
O
1 + 2
THF
70%
DCM
78%
(optically active)
(1:1)
73%
OMe
OMe
OMe
OMe
OMe
23a
22a
OMe
Scheme 4.
and by HPLC [Column: 00G-4253-NO Luna 10u C 18(2); size-
(250 ꢁ 10) mm 10u micr.; eluent: methanol–water (80:20)] with
several solvent combinations were unsuccessful. So, we report here
the formal synthesis of magnofargesin (1) and 70-epimagnofargesin
(2) in racemic forms using radical cyclization strategy.
After completion of the racemic synthesis of the mixture of 1
and 2, we turned our attention toward enantioselective synthesis
of the titled compounds starting from the easily accessible10 (R)-
2,3-O-cyclohexylideneglyceraldehyde (10). Initially, in a model
study, (R)-2,3-O-cyclohexylideneglyceraldehyde (10) was con-
verted into the epoxide 16 through a series of classical reactions
as depicted in Scheme 3. Finally, the epoxide 16 was subjected to
radical cyclization reaction using Cp2TiCl in THF to produce the cy-
clized compound 17.
sin (1) and 70-epimagnofargesin (2) was formed in equal ratio. Two
isomers 1 and 2 have already been separated by Wardrop and
Fritz5 in their racemic synthesis. Due to unavailability of the spe-
cific column used by Wardrop and Fritz, our attempts to separate
the two isomers 1 and 2 by preparative TLC and by HPLC [Column:
00G-4253-NO Luna 10u C 18(2); size-(250 ꢁ 10) mm 10u micr.;
eluent: methanol–water (80:20)] with several solvent combina-
tions were unsuccessful. So, we report here the formal synthesis
of magnofargesin (1) and 70-epimagnofargesin (2) in optically ac-
tive forms using radical cyclization strategy.
In conclusion, we have derived a new route for the formal syn-
thesis of bioactive lignans, magnofargesin and 70-epimagnofargesin
in both racemic and optically active forms by radical cyclization of
epoxides using titanocene(III) chloride as a radical source.
Then, we undertook the synthesis of optically active magno-
fargesin (1) and its isomer 70-epimagnofargesin (2) using the sim-
ilar radical strategy. Thus, 3,4,5-trimethoxybromobenzene (18)
was treated with n-BuLi in THF at ꢀ40 °C and then addition of
the aldehyde 10 afforded the alcohol 19 as a mixture of two diaste-
reomers11 in a ratio of 3:1 (Scheme 4). The major isomer 19a was
separated by column chromatography and was subjected to O-
alkylation with the bromo compound 8 in the presence of NaH in
THF to afford the compound 20a. Now, the deprotection of the
cyclohexylidene group with aq. AcOH furnished the diol 21a. Selec-
tive tosylation of the primary alcohol in 21a afforded 22a which on
treatment with NaH in THF afforded the epoxide 23a. Finally, the
radical cyclization of the epoxide 23a with Cp2TiCl in THF afforded
a mixture of two isomers in a ratio of 1:1.12 The ratio of the two
isomers was determined from the 1H NMR spectrum of the crude
cyclized product, where C-7 benzylic proton appeared as doublet
at d 4.86 (J = 6.7 Hz) for one isomer and at d 5.08 (J = 3.9 Hz) for
the other isomer. The 1H NMR of the crude mixture was compared
with the values reported in the literature by Wardrop5 in their
racemic synthesis and it was found that a mixture of magnofarge-
Acknowledgments
We thank DST, New Delhi for financial support. P.C., S.J., and S.S.
thank CSIR, New Delhi for awarding research fellowships.
References and notes
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Miyazawa, M.; Hiroyuki, K.; Kameoka, H. Phytochemistry 1996, 42, 531.
2. Miyazawa, M. Chem. Abstr. 1994, 121, 91784.
3. Singh, M.; Saraf, M. K. Drug Future 2001, 26, 883.
4. Kasahara, H.; Miyazawa, M.; Kameoka, H. phytochemistry 1996, 43, 1217.
5. Wardrop, D. J.; Fritz, J. Org. Lett. 2006, 8, 3659.
6. (a) Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem. 1998, 63, 2829; (b) Roy, S. C.;
Rana, K. K.; Guin, C. J. Org. Chem. 2002, 67, 3242; (c) Banerjee, B.; Roy, S. C.
Synthesis 2005, 2913; (d) Jana, S.; Guin, C.; Roy, S. C. Tetrahedron Lett. 2005, 46,
1155.
7. RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986.
8. Ghosh, S.; Bhaumik, T.; Sarkar, N.; Nayek, A. J. Org. Chem. 2006, 71, 9687.
9. Banwell, M. G.; Chand, S.; Savage, G. P. Tetrahedron: Asymmetry 2005, 16, 1645.
10. Sugiyama, T.; Sugawara, H.; Watanabe, M.; Yamashita, K. Agric. Biol. Chem.
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6587
11. (a) Saha, S.; Roy, S. C. Tetrahedron 2010, 66, 4278; (b) Chattopadhyay, A.;
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finally dried over Na2SO4. After removal of the solvent under reduced pressure
the crude residue obtained was purified by column chromatography over silica
gel (20% ethyl acetate in petroleum ether) to afford magnofargesin (1) and 70-
epimagnofargesin (2) as a mixture of two isomers in 1:1 ratio (213 mg, 73%). IR
12. Typical radical cyclization procedure for the synthesis of 1 and 2: a solution of
titanocene dichloride (564 mg, 2.28 mmol) in dry THF (25 mL, not
deoxygenated) was stirred with activated zinc dust (360 mg, 5.5 mmol) for
1 h under argon (activated zinc dust was prepared by washing 20 g of
commercially available zinc dust with 60 mL of 4 M HCl and thorough washing
with water and finally with dry acetone and then dried in vacuum). The
resulting green solution was then added dropwise to a stirred solution of the
epoxide 23a (290 mg, 0.70 mmol) in dry THF (25 mL) at room temperature
under argon during 1 h. The reaction mixture was stirred overnight and was
decomposed with 10% H2SO4 (10 mL). Most of the solvent was removed under
reduced pressure and the residue was extracted with diethyl ether (4 ꢁ 30 mL).
The combined ether layer was washed with saturated NaHCO3 (2 ꢁ 25 mL) and
(neat): 3510, 3010, 2923, 2850, 1593, 1514, 1461 cmꢀ1 1H NMR (500 MHz,
;
CDCl3); 2.96–2.98 (m, ½H, C8-H for 1), 3.40–3.49 (m, ½H, C8-H for 2), 3.82–
3.97 (m, 17 H, 5-OCH3, C9-H), 4.58–4.69 (m, 1H, C90-H for 2), 4.73–4.77 (m, 1/2
H, C90-H for 1), 4.86 (d, J = 6.7, 1/2H, C7-H for 1), 4.91–4.96 (m, 1/2H, C90-H for
1), 5.08 (d, J = 4 Hz, 1/2H, C7-H for 2), 6.40 (s, 1/2H, C70-H for 1), 6.47 (s, 1/2H,
C70-H for 2), 6.62 (s, 1H, C2-H and C6-H, for 2), 6.64 (s, 1H, C2-H and C6-H for
1), 6.71–6.74 (m, 1H, ArH), 6.81–6.86 (m, 1H, ArH), 6.89–6.93 (m, 1H, ArH); 13
C
NMR (125 MHz, CDCl3): d 153.5, 153.4, 149.0, 148.4, 138.8, 137.8, 129.4, 122.1,
121.8, 120.6, 111.6, 111.3, 103.3, 103.1, 84.6, 82.4, 73.1, 61.8, 61.0, 56.2, 56.0,
52.0; HRMS Calcd. for C23H28O7 (M++Na): 439.1727; found 439.1733.