Total synthesis of (±)-mimosifoliol by lateral lithiation

Article abstract of DOI:10.1016/j.tetlet.2013.01.040

A two-step protocol has been developed to allow the vinylation of diarylmethanes at the bridging CH₂ using lateral lithiation and formylation followed by a Wittig reaction. This methodology has been applied in the racemic synthesis of the natur

Full text of DOI:10.1016/j.tetlet.2013.01.040

Tetrahedron Letters 54 (2013) 1489–1490
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of ( )-mimosifoliol by lateral lithiation
⇑
Iustina Slabu, Steven B. Rossington, Patrick M. Killoran, Nicholas Hirst, James A. Wilkinson
Centre for Drug Design, Biochemistry and Cancer Research, University of Salford, Salford M5 4WT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step protocol has been developed to allow the vinylation of diarylmethanes at the bridging CH2
using lateral lithiation and formylation followed by a Wittig reaction. This methodology has been applied
in the racemic synthesis of the natural product mimosifoliol.
Received 3 October 2012
Revised 19 December 2012
Accepted 10 January 2013
Available online 16 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organolithium chemistry
Natural products
Total synthesis
Table 1
(+)-R-Mimosifoliol (1) is a neoflavonoid extracted from the
rootwood of Aeschynomene mimosifolia and has shown weak activ-
ity in a DNA-strand scission assay.1 Racemic ( )-mimosifoliol has
been synthesized in five steps via an o-quinone methide interme-
diate and subsequently, (+)-mimosifoliol was obtained via cycload-
dition of the same intermediate with a chiral enol ether (See
Fig. 1).2
Our group has previously utilized lateral lithiation protocols for
the asymmetric preparation of a range of diarylmethane deriva-
tives.3 We now report the racemic synthesis of the natural product
( )-1 using a lateral lithiation approach.
Results of lithiation/formylation reactionsa
Reagent
Additive
Yield of 3 (%)
ee
DMF
None
None
None
(À)-Sparteine
76
61
93
41
—
—
—
ca. 8%
N-Formylpiperidine
N-Formylmorpholine
N-Formylmorpholine
a
Conditions: sec-BuLi plus additive, Et2O, À20 °C, 1.5 h; formylating agent,
À78 °C to rt, 1 h.
OMe
OMe
OMe
Dꢀ
Eꢀ
The study began with work on a simple model system bearing
an ortho-methoxy substituent to allow coordination of lithium,
but none of the other oxygenation required for the natural product.
2-Benzylanisole (2) was subjected to lithiation using sec-butyl-
lithium in ether or THF and quenched with various formylating
agents (Table 1).4 This gave, under our best conditions, the formy-
lated product 3 in a 93% yield.5 The use of the chiral ligand (À)-
sparteine as an additive present in the reaction mixture before
addition of 2 gave disappointing results with a considerably
reduced yield and poor enantioselectivity as judged by the use of
O
Ph
4
Ph
Ph
3
2
Scheme 1. Vinylation of 2-benzylanisole. Reagents and conditions: (a) sec-BuLi,
Et2O, À20 °C, 1.5 h; N-formylmorpholine, À78 °C, 1 h, 93% (b) CH3PPh3Br, n-BuLi,
THF, À20 °C, 3 h, 88%.
OMe
O
OMe
Dꢀ
MeO
Eꢀ
MeO
7
Ph
5
HO
OMe
OMe
Ph
OMe
Fꢀ
MeO
(+) -1
Ph
MeO
MeO
8
6
Ph
Figure 1. Structure of (+)-mimosifoliol (1).
Scheme 2. Vinylation in the presence of a second methoxy group. Reagents and
conditions: (a) AlCl3, CH2Cl2, C6H5COCl, 0–5 °C, 4 h, 71% (b) Et3SiH, TFA, CH2Cl2,
reflux, 2 h, 80% (c) (i) sec-BuLi, Et2O, À78 °C, 2 h; N-formylmorpholine, À78 °C to rt,
3 h, 45%; (ii) CH3PPh3Br, THF, sec-BuLi, À15 °C, 3 h, 65%.
⇑
Corresponding author. Tel.: +44 161 295 4046.
E-mail address: j.a.wilkinson@salford.ac.uk (J.A. Wilkinson).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.040

1490
I. Slabu et al. / Tetrahedron Letters 54 (2013) 1489–1490
TBSO
MeO
OMe
O
HO
OMe
TBSO
MeO
OMe
a)
b)
MeO
11
Ph
9
10
c)
HO
OMe
TBSO
OMe
TBSO
MeO
OMe
d)
e)
MeO
MeO
1
13
12
Ph
Ph
Ph
Scheme 3. Total synthesis of ( )-mimosifoliol. Reagents and conditions: (a) DMAP, imidazole, DMF, TBSCl, 0 °C to rt, 16 h, 90% (b) AlCl3, CH2Cl2, C6H5COCl, 0–5 °C, 4 h, 74% (c)
AlCl3, NaBH4, Et2O, reflux, 4 h, 90% (d) (i) sec-BuLi, THF, À78 °C, N-formylpiperidine, 16 h, 42% (ii) CH3PPh3Br, THF, n-BuLi, À20 °C, 50% (e) TBAF, THF, rt, 4 h, 90%.
the chiral shift reagent TFAE in the 1H NMR. This will be optimized
in future work. Conversion of 3 into the vinyl product 4 was
effected in 88% yield using a Wittig protocol (Scheme 1).6 Carbox-
ylation of the organolithium derived from 2 was also efficient, but
the two-step conversion of the resulting carboxylate into aldehyde
3 was considered too clumsy.
resulted. Future work will be directed towards the asymmetric
synthesis of this natural product either by using chiral ligands or
a chiral auxiliary.
Acknowledgment
The next model study involved a second methoxy group para to
the first (Scheme 2). 1,4-Dimethoxybenzene (5) was ortho-lithiated
under a variety of conditions, but quenching of the organolithium
with benzyl bromide failed to produce any of the desired diaryl-
methane 6. An alkylation catalysed by bismuth acetate according
to the method of Rueping was also unsuccessful in our hands.7 Ac-
cess to 6 was provided by a two-step route using Friedel–Crafts
acylation followed by reduction of the resulting ketone 7.8 This
provided 6 in a 57% yield over two steps. Lithiation of 6 proceeded
smoothly giving high levels of deuterium incorporation when
quenched with deuterium oxide. Formylation was more difficult,
but by using N-formylmorpholine, we were able to isolate the
product in 45% yield.9 Conversion into the vinylated product 8
was more efficient giving a 65% yield.
Completion of the total synthesis of ( )-mimosifoliol required a
masked hydroxyl group to be carried through the synthesis. To this
end, compound 9 was protected with a tert-butyldimethylsilyl
group giving 10 (Scheme 3).10 This was acylated and the resulting
ketone 11 reduced to give lithiation precursor 12. Careful control of
the temperature of the Friedel–Crafts reaction was required to
avoid accidental deprotection. The vinylation protocol gave just a
21% yield for the two steps. This reflects the difficulty in clean lat-
eral lithiation of highly oxygenated substrates which we have ob-
served in the past.11 This provided 13 which was deprotected to
give the natural product in six steps from starting material 9.
Our sample of ( )-mimosifoliol gave data identical to those re-
ported other than for optical rotation.
We acknowledge financial support from Kidscan for I.S.
References and notes
1. Fullas, F.; Kornberg, L. J.; Wani, M. C.; Mall, M. E.; Farnsworth, N. R.;
Chagwedera, T. E.; Kinghorn, A. D. J. Nat. Prod. 1996, 59, 190–192.
2. (a) Tuttle, K.; Rodriguez, A. A.; Pettus, T. R. R. Synlett 2003, 2234–2236; (b)
Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2004, 69, 9196–9203.
3. Wilkinson, J. A.; Rossington, S. B.; Ducki, S.; Leonard, J.; Hussain, N. Tetrahedron
2006, 62, 1833. and references cited therein.
4. Typical procedure for formylation reaction:
2-Benzylanisole (1 equiv) was dissolved in dry Et2O (10 mL) and cooled to
À20 °C, when sec-BuLi 1.4 M in cyclohexane (1.5 equiv) was added dropwise.
The reaction was stirred at À20 °C for 2 h under an inert atmosphere. The
mixture was cooled to À78 °C and the formylating agent (2 equiv) in dry Et2O
(5 mL) was added dropwise. The reaction was allowed to warm to room
temperature, and monitored by TLC (petroleum ether/EtOAc, 9:1). The reaction
was quenched with saturated aqueous NH4Cl (10 mL), diluted with Et2O
(10 mL), separated and the aqueous layer extracted with Et2O (3 Â 20 mL). The
combined organics were washed with 10% HCl (20 mL), H2O (2 Â 30 mL) and
brine (2 Â 30 mL), dried and the solvent removed to afford the crude product.
The pure aldehyde was separated by flash column chromatography.
5. Hill, G.; Harris, F. L. J. Org. Chem. 1977, 42, 3306–3307.
6. (a) Alexakis, A.; El Hajjaji, S.; Polet, D.; Rathgeb, X. Org. Lett. 2007, 9, 3393–
3395; (b) Polet, D.; Rathgeb, X.; Falciola, C. A.; Langlois, J.-B.; El Hajjaji, S.;
Alexakis, A. Chem. Eur. J. 2009, 15, 1205–1216; (c) Selim, K. B.; Matsumoto, Y.;
Yamada, K.-I.; Tomioka, K. Angew. Chem., Int. Ed. 2009, 48, 8733–8735.
7. Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv. Synth. Catal. 2006, 348,
1033–1037.
8. Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995, 60, 1066–1069.
9. All new compounds gave satisfactory spectral data.
10. 2,5-Dimethoxyphenol (9) is commercially available but at an extremely high
price. It was therefore prepared by
a Baeyer–Villiger reaction from the
corresponding aldehyde according to the procedure of Meiji Dairies
Corporation, EP1854777A, 2007; Chem. Abstr. 2006, 145, 314653.
In conclusion, a method has been developed which allows effi-
cient vinylation of diarylmethane precursors using organolithium
chemistry and the racemic synthesis of a natural product has
11. Rossington, S. B. Ph.D. Dissertation, University of Salford, 2004.