First enantioselective synthesis of methyl (+)-7-methoxyanodendroate, an antitubercular dihydrobenzofuran

Article abstract of DOI:10.1016/j.tetlet.2011.10.095

An enantioselective synthesis of methyl (+)-7-methoxyanodendroate was achieved utilising a Claisen rearrangement, a Grubbs cross-metathesis, and a Shi epoxidation-cyclisation sequence, confirming the absolute configuration assigned to the natural product.

Full text of DOI:10.1016/j.tetlet.2011.10.095

Tetrahedron Letters 52 (2011) 6988–6990
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First enantioselective synthesis of methyl (+)-7-methoxyanodendroate,
an antitubercular dihydrobenzofuran
⇑
Kylee M. Aumann, Natasha L. Hungerford, Mark J. Coster
Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan 4111, Queensland, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective synthesis of methyl (+)-7-methoxyanodendroate was achieved utilising a Claisen
rearrangement, a Grubbs cross-metathesis, and a Shi epoxidation–cyclisation sequence, confirming the
absolute configuration assigned to the natural product.
Received 8 September 2011
Revised 30 September 2011
Accepted 17 October 2011
Available online 20 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Methyl (+)-7-methoxyanodendroate
Cross-metathesis
Shi epoxidation
Claisen rearrangement
Natural product synthesis
Methyl (+)-7-methoxyanodendroate (1, Fig. 1) was first isolated,
in 2008, from Zanthoxylum wutaiense Chen, an evergreen shrub en-
demic to the Pingtung County in Taiwan, during an antituberculot-
ic bioactivity-guided screen of approximately 400 species of
Taiwanese plants.1 Compound 1 was shown to possess antituber-
cular activity against Mycobacterium tuberculosis H37Rv with a
cially available methyl vanillate (4) after allylation and Claisen
rearrangement of the resultant allyl ether.
The synthesis of our proposed Shi epoxidation substrate 6 be-
gan with the allylation of methyl vanillate (4),9 followed by the
Claisen rearrangement of allyl ether 5 to afford allylphenol 3 in
minimum inhibitory concentration of 35 l
g/mL. Its structure2
was elucidated using mass spectrometry, and 1D and 2D NMR
spectroscopic techniques. The absolute configuration at C2 was as-
signed as the (S)-enantiomer, after comparison of the specific rota-
tion of the natural product {½a D24
ꢀ
+31.7 (c 0.04, CHCl3)},1 with that
of (ꢁ)-(R)-anodendroic acid {½a D15
ꢀ
ꢁ35.2 (c 0.682, EtOH)}.3
The chiral 2-substituted 2,3-dihydrobenzofuran structure is
present in a number of biologically important compounds and
new enantioselective routes to these systems have recently been
described.4–7 Herein, our interest5,8 in dihydrobenzofuran synthe-
sis continues, and we report the first enantioselective synthesis
of 1, confirming the absolute configuration as methyl (+)-(S)
-7-methoxyanodendroate.
Figure 1. Methyl (+)-7-methoxyanodendroate (1).
Our retrosynthetic analysis (Scheme 1) proposed that the dihy-
drobenzofuran core of 1 could be derived from phenolic epoxide 2,
via base-promoted 5-exo-tet cyclisation. This epoxide would, in
turn, be accessed from allylphenol 3 via olefin cross-metathesis
to efficiently install the prenyl gem-dimethyl functionality,5 and
enantioselective epoxidation of the tri-substituted olefin utilising
the Shi protocol. Allylphenol 3 would be obtained from commer-
⇑
Corresponding author. Tel.: +61 7 3735 6037; fax: +61 7 3735 6001.
E-mail address: m.coster@griffith.edu.au (M.J. Coster).
Scheme 1. Retrosynthetic analysis of methyl (+)-7-methoxyanodendroate (1).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.095

K. M. Aumann et al. / Tetrahedron Letters 52 (2011) 6988–6990
6989
fully synthesised methyl ( )-7-methoxyanodendroate, an enantio-
selective strategy was investigated. Shi’s epoxidation protocol,
employing a chiral fructose-derived catalyst 7, seemed particularly
suitable, due to its proven ability to epoxidise enantioselectively
tri-substituted alkenes.15 Furthermore, Shi’s mechanism-based cor-
relation between catalyst configuration and resulting epoxide ste-
reochemistry suggested that we could obtain the desired epoxide
using the catalyst derived from naturally occurring D
-fructose.16
Attempts to generate chiral epoxide 2 from 6 using a standard
Shi epoxidation16 involving hydrogen peroxide as the oxidant (en-
try 2)17 resulted in substrate degradation. Whilst these results
were not ideal, they were not altogether unexpected. Previous
work within our group,5 and a lack of precedent in the literature,
suggests that Shi epoxidations on substrates bearing a free phenol,
such as 6, generally suffer from poor yields and stereoselectivities.
Accordingly, we sought to protect our phenol as a silyl ether. Wog-
gon et al. found that they achieved higher enantioselectivity in
their Shi epoxidation of a similar prenylphenol using bulkier silyl
ethers,18 so we sought to test this methodology on our system. Pro-
tection of phenol 6 as silyl ethers 8a–c proceeded smoothly in
excellent yields. Gratifyingly, epoxidation of the TBDPS ether 8a
using the Shi conditions again (entries 316 and 4,17 respectively)
gave the cyclised product 1 via epoxide 9a in good yields and
promising enantiomeric enrichment. Use of the H2O2-mediated
Shi epoxidation conditions17 (entry 4) provided a better yield.
However, attempts to optimise the conditions by altering the tem-
perature and ketone loading (entries 5–7) provided no significant
improvement in yield or ee. Likewise, other silyl protecting groups
(entries 8 and 9) failed to alter significantly the ee achieved, sug-
gesting that catalyst 7 is not ideally suited to epoxidation of our
substrate. Finally, application of the modified catalyst 10,
Scheme 2. Synthesis of prenylphenol 6.
99% yield, requiring no purification (Scheme 2). Cross-metathesis
of the terminal olefin with amylene (2-methylbut-2-ene) in the
presence of Grubbs’ 2nd generation catalyst furnished the desired
prenyl derivative 6.10 The crude reaction mixture was adsorbed
onto amino-bonded silica gel,11 and subjected to flash chromatog-
raphy (on regular silica gel). This proved to be the most effective
method for removing ruthenium contaminants.
With tri-substituted olefin 6 in hand, we turned our attention to
the proposed epoxidation–cyclisation sequence (Table 1). One-pot
achiral epoxidation–cyclisation of 6 with freshly distilled dim-
ethyldioxirane (DMDO) at 0 °C,12 followed by the direct addition
of base (entry 1)12,13 proceeded in excellent yield. Interestingly,
DMDO generated in situ14 caused degradation of our substrate
and no epoxide or cyclised product was detected. Having success-
Table 1
Synthesis of methyl (+)-7-methoxyanodendroate via enantioselective epoxidation, then cyclisation
Entry
Substrate
Epoxidation reagents
Epoxidation conditions
Cyclisation conditions
Yield of 1a (%)
eeb (%)
1
2
3
4
5
6
7
8
9
6
6
Freshly distilled DMDO (1.2 equiv), acetone
Method Bd (0.4 equiv of 7)
Method Ac (0.25 equiv of 7)
Method Bd (0.4 equiv of 7)
Method Bd (0.4 equiv of 7)
Method Bd (0.4 equiv of 7)
Method Bd (1.0 equiv of 7)
Method Bd (0.4 equiv of 7)
Method Bd (0.4 equiv of 7)
Method Df (0.15 equiv of 10)
0 °C, 30 min then rt, 16 h
4 °C, 14 h
0 °C, 1.5 h
Et3N, rt, 60 min
satd NaHCO3, rt, 60 min
78
—
62
84
(rac)
—
8a
8a
8a
8a
8a
8b
8c
8a
Method Ce (using 2 M NaOH, 30 min)
Method Ce (using satd NaHCO3, 70 min)
Method Ce (using 1 M NaOH, 15 min)
Method Ce (using 1 M NaOH, 15 min)
Method Ce (using 2 M NaOH, 30 min)
Method Ce (using satd NaHCO3, 70 min)
Method Ce (using satd NaHCO3, 70 min)
TBAF, THF, 0 °C to rt, 75 min
79
77
78
75
77
76
76
95
4 °C, 14 h
g
ꢁ15 °C, 7 h
63
rt, 1.5 h
84
87
81
79
69
0–6 °C, 2 h
4 °C, 14 h
4 °C, 14 h
10
0 °C, 22 h
a
b
c
Isolated yield.
ee values were determined by HPLC analysis using an AD-H column.
Method A: Ketone 7, nBu4NHSO4 (0.1 equiv), Oxone (1.5 equiv), K2CO3 (1 M, 6 equiv), buffer [Na2B4O7 (0.05 M), Na2EDTA (4 ꢂ 10ꢁ4 M)]: dimethoxymethane (DMM)–
CH3CN (2:2:1).
d
Method B: Ketone 7 and H2O2 (5.5 equiv) in buffer [2 M K2CO3 in 4 ꢂ 10ꢁ4 M Na2EDTA]–CH3CN–EtOH–CH2Cl2 (3:1:1:2).
e
f
Method C: TBAF, THF, 0 °C, 15 min then aqueous base, rt.
Method D: Ketone 10, nBu4NHSO4 (0.04 equiv), Oxone (1.5 equiv), K2CO3 (0.38 M, 2.4 equiv), pH 6 buffer [KOH (0.1 M):KH2PO4 (0.1 M):H2O (5.6:50:44.4)], DMM–CH3CN
(2:1).
g
Reaction did not proceed to completion, unreacted starting material (18%) was also recovered.

6990
K. M. Aumann et al. / Tetrahedron Letters 52 (2011) 6988–6990
described by Shi19 and Vidal-Ferran20 using the conditions20,6
described in entry 10 gave product 1 in excellent enantiomeric ex-
cess (95% ee), as determined by chiral HPLC (AD-H column, 20–80%
isopropanol in hexane, 1 mL.minꢁ1, Rt (major) = 13.2 min, Rt (min-
or) = 7.2 min), and 69% yield. The spectroscopic data (1H and 13C
NMR, HRMS) and specific rotation for the synthetic material
References and notes
1. Huang, H.-Y.; Ishikawa, T.; Peng, C.-F.; Tsai, I.-L.; Chen, I.-S. J. Nat. Prod. 2008, 71,
1146–1151.
2. The synthesis of racemic 1 has been described, but no spectroscopic data was
reported: Ishii, H.; Ishikawa, T.; Chen, I.-S.; Lu, S.-T. Tetrahedron Lett. 1982, 23,
4345–4348.
3. Kawase, Y.; Yamaguchi, S.; Inoue, O.; Sannomiya, M.; Kawabe, K. Chem. Lett.
1980, 1581–1584.
{½a 2D5
ꢀ
+60.4 (c 0.54, CHCl3)} confirmed the assigned (S)-configura-
tion of the natural product.
4. Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010, 328, 1376–1379.
5. Magolan, J.; Coster, M. J. J. Org. Chem. 2009, 74, 5083–5086.
6. (a) Jiang, H.; Hamada, Y. Org. Biomol. Chem. 2009, 7, 4173–4176; (b) Jiang, H.;
Sugiyama, T.; Hamajima, A.; Hamada, Y. Adv. Synth. Catal. 2011, 353, 155–162.
7. Pelly, S. C.; Govender, S.; Fernandes, M. A.; Schmalz, H.-G.; de Koning, C. B. J.
Org. Chem. 2007, 72, 2857–2864.
In summary, we have developed the first enantioselective total
synthesis of the naturally occurring dihydrobenzofuran, methyl
(+)-7-methoxyanodendroate (1) in five steps from commercially
available methyl vanillate (4), with an overall yield of 65%, and
an ee of 95%. This synthesis confirms the structure and absolute
configuration of the natural product as methyl (+)-(S)-7-methoxy-
anodendroate. Furthermore, it is efficient and scalable, and paves
the way for future structure–activity relationship studies.
8. Fischer, J.; Savage, G. P.; Coster, M. J. Org. Lett. 2011, 13, 3376–3379.
9. Wilson, S. C.; Howard, P. W.; Forrow, S. M.; Hartley, J. A.; Adams, L. J.; Jenkins, T.
C.; Kelland, L. R.; Thurston, D. E. J. Med. Chem. 1999, 42, 4028–4041.
10. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.
11. DavisilÒ amino-bonded Silica gel 60A, 30–40
lm, was employed.
12. Murray, R. W.; Singh, M. Org. Synth. 1998, Coll. vol. 9, 288–293. 1997, 74, 91–96.
13. Lindsey, C. C.; Gómez-Diaz, C.; Villalba, J. M.; Pettus, T. R. R. Tetrahedron 2002,
58, 4559–4565.
14. Curci, R.; Fiorentino, M.; Troisi, L.; Edwards, J. O.; Pater, R. H. J. Org. Chem. 1980,
45, 4758–4760.
Acknowledgements
15. For reviews on the Shi epoxidation, see: (a) Frohn, M.; Shi, Y. Synthesis 2000,
1979–2000; (b) Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 3958.
16. Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,
11224–11235.
We thank the Australian Research Council for funding
(DP0986795) and Dr. Jakob Magolan for preparing ketone 7.
17. Shu, L.; Shi, Y. Tetrahedron 2001, 57, 5213–5218.
18. Chapelat, J.; Buss, A.; Chougnet, A.; Woggon, W.-D. Org. Lett. 2008, 10, 5123–
5126.
Supplementary data
19. (a) Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792–8793; (b) Wang,
B.; Wu, X.-Y.; Wong, O. A.; Nettles, B.; Zhao, M.-X.; Chen, D.; Shi, Y. J. Org. Chem.
2009, 74, 3986–3989.
20. Nieto, N.; Molas, P.; Benet-Buchholz, J.; Vidal-Ferran, A. J. Org. Chem. 2005, 70,
10143–10146.
Supplementary data (experimental procedures and character-
ization data for all new compounds; 1H and 13C NMR spectra for
all new compounds; chiral HPLC traces for Table 1) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.10.095.