A concise route to dihydrobenzo[b]furans: Formal total synthesis of (+)-lithospermic acid

Article abstract of DOI:10.1021/ol201130h

A sequence of Sonogashira coupling, Pd(II)-catalyzed carbonylative annulation, and benzofuran reduction (Mg, MeOH, NH₄Cl) provides a convergent and modular synthetic route to trans-2-aryl-2,3-dihydrobenzo[b]furan- 3-carboxylates, which are a structural feature of numerous biologically active natural products. This versatile strategy was applied to the formal total synthesis of the anti-HIV natural product (+)-lithospermic acid.

Full text of DOI:10.1021/ol201130h

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3376–3379
A Concise Route to Dihydrobenzo[b]furans:
Formal Total Synthesis of
(þ)-Lithospermic Acid
Joshua Fischer,† G. Paul Savage,‡ and Mark J. Coster*,†
Eskitis Institute for Cell And Molecular Therapies, Griffith University, Nathan 4111
Queensland, Australia and CSIRO Materials Science and Engineering, Private Bag 10,
Clayton 3169 Victoria, Australia
m.coster@griffith.edu.au
Received April 28, 2011
ABSTRACT
A sequence of Sonogashira coupling, Pd(II)-catalyzed carbonylative annulation, and benzofuran reduction (Mg, MeOH, NH4Cl) provides a
convergent and modular synthetic route to trans-2-aryl-2,3-dihydrobenzo[b]furan-3-carboxylates, which are a structural feature of numerous
biologically active natural products. This versatile strategy was applied to the formal total synthesis of the anti-HIV natural product (þ)-
lithospermic acid.
2-Aryl-2,3-dihydrobenzo[b]furans are a common struc-
tural feature of numerous natural products (e.g., 1ꢀ2,
Figure 1) exhibiting bioactivities, such as antimitotic,1
antiangiogenic,2 antioxidant,3 antimicrobial,4 and neuri-
togenic.5 Most natural products with this skeleton are 2,3-
trans configured,6 with many that were initially assigned
as cis-configured having their relative stereochemistry
revised.7
Considerable effort has been devoted to the synthesis of
2-aryl-2,3-dihydrobenzo[b]furans. Strategies employed for
Figure 1. Representative dihydrobenzo[b]furan natural
products.
† Griffith University.
‡ CSIRO Materials Science and Engineering.
(1) Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck,
the diastereoselective synthesis of these systems8 include
ꢀ
the biomimetic oxidation of phenylpropenes, the Schmidt
rearrangement, the rearrangement of chalcone epoxides,
and acid catalyzed [3 þ 2] cycloadditions of phenylpro-
penes with quinones.6 Enantioselective syntheses have
also been achieved via Rh(II)-catalyzed intramolecular
CꢀH insertions,9,10 with this approach affording a pre-
dominance of the cis-2,3-dihydrobenzo[b]furan.
A.; Lemiere, G. J. Med. Chem. 1999, 42, 5475–81.
(2) Apers, S.; Vlietinck, A; Pieters, L Phytochem. Rev. 2003, 2, 201–
217.
(3) Kikuzaki, H.; Kayano, S.; Fukutsuka, N.; Aoki, A.; Kasamatsu,
K.; Yamasaki, Y.; Mitani, T.; Nakatani, N. J. Agric. Food Chem. 2004,
52, 344–349.
ꢁ
(4) Pauletti, P. M.; Araujo, A. R.; Young, M. C. M.; Giesbrecht,
A. M.; Bolzani, V. S. Phytochemistry 2000, 55, 597–601.
(5) Shin, J. S.; Kim, Y. M.; Hong, S. S.; Kang, H. S.; Yang, Y. J.; Lee,
D. K.; Hwang, B. Y.; Ro, J. S.; Lee, M. K. Arch. Pharm. Res. 2005, 28,
1337–1340.
(6) Sefkow, M. Synthesis 2003, 2595–2625.
(7) Li, S.; Iliefski, T.; Lundquist, K; Wallis., A. F. A. Phytochemistry
1997, 46, 929–934.
(8) Graening, T.; Thrun, F. Comprehensive Hetereocyclic Chemistry
III; Katritzky, A. R., Taylor, R. J. K., Ramsden, C. A., Scriven, E. F. V., Eds.;
Elsevier: 2008; Vol. 3, pp 553ꢀ561 and references cited therein.
r
10.1021/ol201130h
Published on Web 06/07/2011
2011 American Chemical Society

The closely related 2,3-disubstituted benzo[b]furans
have attracted extensive synthetic interest and also exhibit
a broad range of biological activities.11 Among synthetic
strategies for benzo[b]furans, Pd-catalyzed cyclizations are
particularly attractive, allowing for the simultaneous in-
stallation of a carbonyl substituent at C3, to give the 2,3-
disubstituted systems.12 Our approach would provide access
to both 2-arylbenzo[b]furan and 2-aryl-2,3-dihydrobenzo-
[b]furan-containing natural products and analogues. Key
toits success was developing a method toreduce the benzo-
[b]furan system to the corresponding trans-2,3-dihydro-
benzo[b]furan. The retrosynthetic strategy (Scheme 1)
highlights the concise and highly modular approach we
proposed to access these compounds.
10ꢀ1414 and aryl iodide 915 with arylalkynes 14ꢀ16
(Table 1). Traditional coupling conditions were well-suited
for generating diarylalkynes 17aꢀe (Method A); however
yields of 18b and 18c were improved by using the condi-
tions of Andrus et al.16 (Method B). Deacetylation of
17aꢀe was hampered by a competing side reaction that
produced unwanted protio-cyclized benzofurans, which
lacked the carbomethoxy functionality at the 3-position.
Cs2CO3 in MeOHꢀTHF at 0 °C, afforded ortho-hydro-
xydiarylalkynes 19aꢀe in good yield with no appreciable
protio-cyclization.
Table 1. Synthesis of ortho-Hydroxydiarylalkynes
Scheme 1. Retrosynthetic Analysis of 2-Aryl-2,3-dihydobenzo-
[b]furan-3-carboxylates (3)
product
product
entry ArI alkyne
R1
(yield, %) (yield, %)
1
2
3
4
5
6
7
8
8
8
8
8
8
9
9
9
10
11
12
13
14
14
15
16
Ph
17aa (98)
17ba (68)
19a (99)
19b (98)
19c (87)
19d (95)
19e (85)
20a (89)
20bc (94)
20c (89)
2-Np
We envisaged that dihydrobenzofuran 3 would be
formedby stereoselective reduction of benzofuran4, which
would be derived from ortho-hydroxydiarylalkyne 5, using
a carbonylative annulation reaction. Compound 5 would
be derivedfrom the Sonogashira coupling of protectedaryl
iodide 6 and arylalkyne 7. Initial investigations focused on
developing this route, using aryl iodides (8, 9) and terminal
alkynes (10ꢀ16). Subsequently, the utility of this method
was demonstrated by the formal total synthesis of the anti-
HIV natural product (þ)-lithospermic acid (1).
3,4,5-(MeO)3C6H2 17ca (84)
3,5-(MeO)2C6H3
4-(MeO)C6H4
4-(MeO)C6H4
3,4-(OCH2O)C6H3 18bb (97)
TIPS
18cb (77)
17da (77)
17ea (73)
18aa (100)
a Method A. b Method B. c The intermediate acetal was purified and
then deacetylated using Cs2CO3 in MeOHꢀTHF.
It was necessary, in the case of benzaldehydes 18aꢀc
(Table 1), to protect the aldehyde functionality in prepara-
tion for the carbonylative annulation and subsequent
reduction step. Thus, 18aꢀc were subjected to a one-
pot procedure that included protection of the aldehyde
as a cyclic acetal, followed by in situ methanolysis of the
acetate, to reveal the ortho-hydroxydiarylalkynes 20aꢀc.
The carbonylative annulation conditions of Kondo12a
and Scammells12b were well-suited to our systems (Table 2).
Applying these conditions to ortho-hydroxydiarylalkynes
19aꢀe and 20aꢀc, moderate to excellent benzofuran pro-
duct yields were achieved for all but 20c (entry 8, Table 2).
Reaction rates were enhanced by heating to 40 °C; yet, this
had a detrimental effect on 22aꢀb yields, so these reactions
were conducted at rt. Interestingly, a methyl acetal bypro-
duct, resulting from trans-acetalization, was observed in the
cases of 1,3-dioxane substrates 20aꢀc.17
The diarylalkyne substrates were synthesized by Sono-
gashira coupling of aryl iodide 813 with arylalkynes
ꢁ
~ ꢁ ꢁ
(9) Garcıa-Munoz, S.; Alvarez-Corral, M.; Jimenez-Gonzalez, L.;
´
ꢁ
ꢁ
~
Lopez-Sanchez, C.; Rosales, A.; Munoz-Dorado, M.; Rodrı
guez-Garcıa,
´ ´
I. Tetrahedron 2006, 62, 12182–90.
(10) Natori, Y.; Tsutsui, H.; Sato, N.; Nakamura, S.; Nambu, H.;
Shiro, M.; Hashimoto, S. J. Org. Chem. 2009, 74, 4418–4421.
(11) For recent synthetic strategies, see: (a) Kao, C.-L.; Chern, J.-W.
J. Org. Chem. 2002, 67, 6772–6787. (b) Cho, C.-H.; Neuenswander, B.;
Lushington, G. H.; Larock, R. C. J. Comb. Chem. 2008, 10, 941–47.
(c) Duan, S.-F.; Shen, G.; Zhang, Z.-B. Synthesis 2010, 15, 2547–52.
(d) Bang, H. B.; Han, S. Y.; Choi, D. H.; Yang, D. M.; Hwang, J. W.; Lee,
H. S.; Jun, J.-G. Synth. Commun. 2009, 39, 506–515. (e) Scammells, P. J.;
Baker, S. P.; Beauglehole, A. R. Bioorg. Med. Chem. 1998, 6, 1517–1524.
(12) For examples, see: (a) Kondo, Y.; Sakamoto, T.; Yamanaka, H.
Heterocycles 1989, 29, 1013–1016. (b) Lutjens, H.; Scammells, P. J.
Tetrahedron Lett. 1998, 39, 6581–6584. (c) Nan, Y.; Miao, H.; Yang, Z.
Org. Lett. 2000, 2, 297–299.
(13) Miao, H.; Yang, Z Org. Lett. 2000, 2, 1765–68.
(14) Alkynes 10, 13, and 16 were commercially available. All other
alkynes were prepared from the corresponding aldehyde by the Coreyꢀ
Fuchs alkynylation procedure: Corey, E. J.; Fuchs, P. L. Tetrahedron
Lett. 1972, 36, 3769–3772.
(16) Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc.
1997, 119, 12159–12169.
(17) The methyl acetal counterparts could be separated by column
chromatography or carried on as a mixture with the 1,3-dioxane to the
subsequent step.
(15) See Supporting Information for the acetate protection of
2-iodoisovanillin, which was prepared according to: Markovich,
K. M.; Tantishaiyakul, V.; Hamada, A.; Miller, D. D.; Romstedt,
K. J.; Shams, G.; Shin, Y.; Fraundorfer, P. F.; Doyle, K.; Feller,
D. R. J. Med. Chem. 1992, 35, 466–479.
Org. Lett., Vol. 13, No. 13, 2011
3377

Table 2. Carbonylative Annulation and Mg-Mediated Benzofuran Reduction
product
product
(yield, %)a
entry
substrate
R1
R2
R3
(yield, %)
trans:cisb
1
2
3
4
5
6
7
8
19a
19b
19c
19d
19e
20a
20b
20c
Ph
H
H
H
H
H
H
21a (69)
21b (86)
21c (80)
21d (87)
21e (77)
22a (55)f
22b (75)h
22c (0)j
23a (84)c
23b (36)d
23c (79)
23d (66)e
23e (85)
24ag (74)
24bg (86)i
ꢀ
94:6
85:15
95:5
91:9
95:5
81:19
71:29
ꢀ
2-Np
H
3,4,5-(MeO)3C6H2
3,5-(MeO)2C6H3
4-(MeO)C6H4
4-(MeO)C6H4
3,4-(OCH2O)C6H3
TIPS
H
H
H
MeO
MeO
MeO
1,3-dioxan-2-yl
1,3-dioxan-2-yl
1,3-dioxan-2-yl
a Isolated yield of the trans-isomer. b Determined by 1H NMR of crude isolate. c Byproduct isolated, R1 = cyclohex-2-enyl (6%). d Byproducts
isolated, R1 = 1,2-dihydronaphthalen-2-yl (38%); R2 = 1,2,3,4-tetrahydronaphthalen-2-yl (24%). e Reduction byproduct isolated, R1 = 3,5-di-
methoxycyclohexa-2,5-dienyl (15%). f Accompanied by 8% of the trans-acetalized benzofuran product, analogous to 22a where R3 = CH(OMe)2.
g Acetal hydrolysis by aqueous workup led to the benzaldehyde (R3 = CHO) directly. h Accompanied by ca. 10% of the dimethyl acetal, where R3 =
CH(OMe)2. i Combined yield of cis and trans. j Trans-acetalized material isolated, analogous to 20c where R3 = CH(OMe)2.
Synthetic methods for reducing 2-arylbenzo[b]furan-
3-carboxylates to the corresponding 2-aryl-2,3-dihydrobenzo-
bond within an aromatic system. Early attempts at the
MgꢀMeOHreduction provedlow yielding and capricious,
apparently due to low and variable activity of the Mg and
the low solubility ofour substrates in MeOH. Adding THF
as a cosolvent alleviated solubility issues, but also resulted
in markedly less active Mg. Attempts to activate the Mg
surface by stirring vigorously (both neat and in solution),
by adding of I2 or 1,2-dibromoethane, or by prior treat-
ment with a dilute acid all proved inadequate. The intro-
duction of NH4Cl to the reaction mixture as an agent for
Mg activation22 was crucial to obtaining reproducible
results and, gratifyingly, enabled the use of THF as
cosolvent without deleterious effects on reaction rate and
yield. These conditions proved amenable to all the ben-
zofuran substrates (Table 2) in our investigation. The
reduction reactions initially proceed with some degree of
diastereoselectivity for thecis-isomers, which thenundergo
magnesium methoxide promoted epimerization to the
more thermodynamically stable trans-isomers, 23aꢀe
and 24aꢀb.23 Partial reduction of the pendant R1 aryl
group competed with the desired 2,3-reduction in some
substrates (Table 2, entries 1ꢀ2, 4). However, these un-
wanted reductions could be minimized by lowering the
reaction temperature from rt to ꢀ15 °C. To optimize
yields of the trans diastereomer the reaction mixture was
decanted from excess Mg when reduction was complete,
[b]furan-3-carboxylate are scarce. Juhasz et al.18b employed
ꢁ
catalytic hydrogenation over Pd/C in methanol to reduce
methyl 2-phenylbenzo[b]furan-3-carboxylate to the corre-
sponding cis-2,3-dihydrobenzo[b]furan in 11% yield.
While catalytic reduction of simpler benzofuran systems
has provided cis-dihyrobenzofurans,7 to our knowlegdge,
no methods for reducing 2,3-disubstituted benzo[b]furans
to the trans-dihydrobenzofuran have been reported. Com-
mon reduction conditions (e.g., H2/PdꢀC,18 chiral
“CuH”,19 TFA/Et3SiH20) applied to more complex ben-
zofurans of type 21 and 22 were not suitable for our
systems: either recovered starting material or complex
mixtures of products were obtained. Chemoselective re-
duction of R,β-unsaturated esters has been reported to
proceed using Mg in MeOH, even in systems in which the
double bond is part of an aromatic system.21 Our sub-
strates provided a considerable challenge, requiring
chemoselective reduction of a tetrasubstituted double
(18) (a) Tamura, K.; Kato, Y.; Ishikawa, A.; Kato, Y.; Himori, M.;
Yoshida, M.; Takashima, Y.; Suzuki, T.; Kawabe, Y.; Cynshi, O.;
Kodama, T.; Niki, E.; Shimizu, M. J. Med. Chem. 2003, 46, 3083–
ꢁ
ꢁ
3093. (b) Juhasz, L.; Szilagyi, L.; Antus, S.; Visy, J.; Zsila, F.; Simonyi,
M. Tetrahedron 2002, 58, 4261–4265.
(19) (a) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11253–11258. (b) Appella, D. H.; Moritani, Y.; Shintani, R.;
Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473–
9474.
(20) (a) Rupprecht, K. M.; Boger, J.; Hoogsteen, K.; Nachbar, R. B.;
Springer, J. P. J. Org. Chem. 1991, 56, 6180–6188. (b) Lanzilotti, A. E.;
Littell, R.; Fanshawe, W. J.; McKenzie, T. C.; Lovell, F. M. J. Org.
Chem. 1979, 44, 4809–4813.
(21) (a) Boyle, E. A.; Mangan, F. R.; Markwell, R. E.; Smith, S. A.;
Thomson, M. J.; Ward, R. W.; Wyman, P. A. J. Med. Chem. 1986, 29,
894–898. (b) Youn, I. K.; Yon, G. H.; Pak, C. S. Tetrahedron Lett. 1986,
27, 2409–2410. (c) Lee, G. H.; Youn, I. K.; Choi, E. B.; Lee, H. K.; Yon,
G. H.; Yang, H. C.; Pak, C. S. Curr. Org. Chem. 2004, 8, 1263–1287.
(22) (a) Elder, A. M.; Rich, D. H. Org. Lett. 1999, 1, 1443–1446.
(b) Leduc, A. B.; Kerr, M. A. Eur. J. Org. Chem. 2007, 237–240.
(c) Okabe, K.; Natsume, M. Tetrahedron 1991, 47, 7615–7624.
(23) Notably, the JH2-H3 values were not a useful diagnostic tool for
distinguishing the cis and trans isomers in these systems. Instead, the
anisotropic effect of the C-2 aryl group causes chemical shifts of 3-CH
and CO2CH3 which are diagnostic for cis versus trans isomers (refs 7, 9,
and 18b). Thus, the trans compound displayed an upfield 3-CH reso-
nance, compared to the cis isomer.
3378
Org. Lett., Vol. 13, No. 13, 2011

allowing the magnesium methoxide reaction mixture to
warm to rt, whereupon epimerization to the predominantly
trans-isomer resulted. The protected aldehyde in 22aꢀb
was unmasked by aqueous acid workup to directly afford
the aldehyde products 24aꢀb.
(2S,3S,20R)-31 and the corresponding (2R,3R,20R)-dia-
stereomer. The diastereomeric pair was separable by
HPLC, providing diasteromerically pure 31. All spectro-
scopic data obtained matched those reported by Bergman,
Ellman and co-workers.30a
(þ)-Lithospermic acid (1) was first isolated from Lithos-
permum ruderale in 196324 and its structure elucidated in
1975.25 (þ)-Lithospermic acid (1) has also been isolated
from Salvia miltiorrhiza (Danshen), a popular herb in
traditional Chinese medicine,26 and from many other
sources.27 It was not until 2002 that it was found to be a
potent HIV integrase inhibitor.28 Importantly, 1 was
devoid of the collateral toxicity that plagued many other
integrase inhibitors. Previous approaches to the synth-
esis of 1 include the HBr-promoted cyclization used by
Raths and co-workers, resulting in the synthesis of
racemic heptamethyl lithospermate,29 and the CꢀH
bond activation strategies used by Bergman, Ellman
and co-workers, and also by Yu and co-workers for
the first total syntheses of (þ)-lithospermic acid.30
Sonogashira coupling of aryl iodide 9 and arylalkyne
2531 proceeded in 75% yield (Scheme 2). Sonogashira
coupling, followed by protection of the aldehyde and
removal of the acetate using Cs2CO3 in MeOHꢀTHF, gave
the ortho-hydroxydiarylalkyne 26. Subjecting 26 to carbo-
nylative annulation generated the desired tetrasubstituted
benzofuran 27 in good yield. The previously developed
conditions proved well-suited for reducing 27 to give the
desired 2,3-dihydrobenzo[b]furan 28 (81%, ca. 3:1 trans:
cis), following an acidic workup to remove the cyclic
Scheme 2. Synthesis of (þ)-Heptamethyl Lithospermate (31)
€
acetal protecting group. Knovenagel condensation
of aldehyde 28 with malonic acid, and concomitant
epimerization at C-3, gave cinnamic acid 29 with im-
proved dr (ca. 6:1 2,3-trans:2,3-cis), which was subse-
quently coupled with known alcohol 3030a to afford
The two-step conversion of 31 to 1, involving ester
hydrolysis followed by global demethylation, has been
reported,30a and hence the synthesis of (þ)-heptamethyl
lithospermate (31) presented here constitutes a formal
total synthesis of (þ)-lithospermic acid (1).
(24) Johnson, G.; Sunderwirth, S. G.; Gibian, H.; Coulter, A. W.;
Gassner, F. X. Phytochemistry 1963, 2, 145–150.
(25) (a) Kelley, C. J.; Mahajan, J. R.; Brooks, L. C.; Neubert, L. A.;
Breneman, W. R.; Carmack, M. J. Org. Chem. 1975, 40, 1804–1815.
(b) Wagner, H.; Wittman, D.; Schaffer, W. Tetrahedron Lett. 1975, 16,
547–550.
(26) (a) Lu, Y.; Foo, L. Y. Phytochemistry 2002, 59, 117–140.
(b) Jiang, R.-W.; Lau, K.-M.; Hon, P.-M.; Mak, T. C. W.; Woo,
K.-S.; Fung, K.-P. Curr. Med. Chem. 2005, 12, 237–246. (c) Kang,
H. S.; Chung, H. Y.; Jung, J. H.; Kang, S. S.; Choi, J. S. Arch. Pharm.
Res. 1997, 20, 496–500.
(27) A small selection includes: (a) Lin, Y.-L.; Wang, C.-N.; Shiao,
Y.-J.; Liu, T.-Y.; Wang, W.-Y. J. Chin. Chem. Soc. 2003, 50, 1079–1083.
(b) Lin, Y.-L.; Chang, Y.-Y.; Kuo, Y.-H.; Shiao, M.-S. J. Nat. Prod.
2002, 65, 745–747. (c) Yamamoto, H.; Inoue, K.; Yazaki, K. Phyto-
chemistry 2000, 53, 651–657. (d) Fukui, H.; Yazaki, K.; Tabata, M.
Phytochemistry 1984, 23, 2398–2399.
We have demonstrated a versatile, modular synthetic
approach to 2-aryl-2,3-dihydrobenzo[b]furans via Mg-
mediated reduction of benzo[b]furans and demonstrated
its use in natural product synthesis with a synthesis of
(þ)-heptamethyl lithospermate (31) in 7 steps and in 8.4%
overall yield from 9, constituting a formal total synthesis of
the anti-HIV natural product (þ)-lithospermic acid (1).
Acknowledgment. We thank the Australian Research
Council for funding (DP556187), the CSIRO for a scholar-
ship to J.F., and Dr. Natasha Hungerford (Griffith
University) for assisting in preparing of this manuscript.
(28) Abd-Elazem, I. S.; Chen, H. S.; Bates, R. B.; Huang, R. C. C.
Antiviral Res. 2002, 55, 91–106.
(29) Jacobsen, R. M.; Raths, R. A. J. Org. Chem. 1979, 44, 4013–
4014.
Supporting Information Available. Experimental pro-
1
(30) (a) O’Malley, S. J.; Tan, K. L.; Watzke, A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 13496–13497. (b) Wang, D.-H.;
Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767–5769.
(31) Pelter, A.; Ward, R. S.; Little, G. M. J. Chem. Soc., Perkin Trans. 1
1990, 2775–90.
cedures, product characterization data, and H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 13, 2011
3379