Enantioselective total synthesis of (+)-lithospermic acid

Article abstract of DOI:10.1021/ol302273r

An enantioselective synthesis of (+)-lithospermic acid, a potent anti-HIV agent, has been accomplished in a convergent manner in nine steps. The synthesis features an enantioselective intramolecular oxa-Michael addition catalyzed by a quinidine derivative

Full text of DOI:10.1021/ol302273r

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5046–5049
Enantioselective Total Synthesis
of (þ)-Lithospermic Acid
Arun K. Ghosh,* Xu Cheng, and Bing Zhou
Department of Chemistry and Department of Medicinal Chemistry, Purdue University,
560 Oval Drive, West Lafayette, Indiana 47907, United States
akghosh@purdue.edu
Received August 15, 2012
ABSTRACT
An enantioselective synthesis of (þ)-lithospermic acid, a potent anti-HIV agent, has been accomplished in a convergent manner in nine steps.
The synthesis features an enantioselective intramolecular oxa-Michael addition catalyzed by a quinidine derivative, a hypervalent iodine-mediated
rearrangement of chromanone to dihydrobenzofuran, an enantioselective R-oxyamination, and an intermolecular CꢀH olefination.
Lithospermic acid (1) was first isolated from the root of
Lithospermum ruderale in 1963by Johnson and co-workers
(Figure 1).1 It was fully characterized as a trimer of caffeic
acid A in 1975 by Carmack et al. and Wagner et al.
independently.2,3 Lithospermic acid is an active ingredient
of the Chinese herb Danshen and shows important bio-
logical properties. It exhibited inhibitory activity on pro-
liferation and migration of rat vascular smooth muscle
cells.4 More recently, lithospermic acid showed anti-HIV
activity by inhibiting HIV-1 integrase with an IC50 value of
1.4 μM.5 Rosmarinic acid (2), the dimer of caffeic acid (3),
has shown an IC50 value of 5 μM against HIV-1 integrase.5
In view of its important biological properties, there has
been much interest in lithospermic acid. The first racemic
synthesis of heptamethyl lithospermate was reported by
JacobsonandRathsin1979.6 The first enantioselective syn-
thesis of (þ)-lithospermic acid was achieved by Bergman,
Ellman and co-workers using an asymmetric intramolecu-
lar alkylation via rhodium-catalyzed CꢀH activation.7 In
2011, Yu and co-workers reported the synthesis of (þ)-
lithospermic acidusinganintermolecularCꢀH olefination
reaction as the key step.8 Since then, two formal syntheses
were reported by Coster et al.9 and Hwu et al.10 As part of
our interest to explore anti-HIV properties of lithospermic
acid, we plan to devise an effective route that is amenable
to the preparation of structural variants. Herein, we report
our synthesis of (þ)-lithospermic acid.
Our retrosynthetic analysis of (þ)-lithospermic acid (1)
is outlined in Figure 2. Strategic disconnection of C1ꢀC7
results in dihydrobenzofuran 4 and acrylate derivative
5. We planned to utilize an intermolecular CꢀH olefina-
tion similar to Yu and co-workers8 to couple compounds
4 and 5. The functionalized dihydrobenzofuran 4 would be
(1) Johnson, G.; Sunderwirth, S. G.; Gibian, H.; Coulter, A. W.;
Gassner, F. X. Phytochemistry 1963, 2, 145–150.
(2) (a) Kelley, C. J.; Harruff, R. C.; Carmack, M. J. Org. Chem. 1976,
41, 449–455. (b) Kelley, C. J.; Mahajan, J. R.; Brooks, L. C.; Neubert, L. A.;
Breneman, W. R.; Carmack, M. J. Org. Chem. 1975, 40, 1804–1815.
(3) Wagner, H.; Whittmann, D.; Schafer, W. Tetrahedron Lett. 1975,
8, 547–550.
(4) Chen, L.; Wang, W.-Y.; Wang, Y.-P. Acta Pharm. Sinica 2009, 30,
1245–1252.
(5) (a) Abd-Elazem, I. S.; Chen, H. S.; Bates, R. B.; Huang, R. C. C.
Antiviral Res. 2002, 55, 91–106. (b) Tewtrakul, S.; Miyashiro, H.;
Nakmur, N.; Hattori, M.; Kawahata, T.; Otake, T.; Yoshnaga, T.;
Fujiwara, T. Phytother. Res. 2003, 17, 232–239.
(6) Jacobson, R. M.; Raths, R. A. J. Org. Chem. 1979, 44, 4013–4014.
(7) (a) O’Malley, S. J.; Tan, K. J.; Watzke, A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 13496–13497. (b) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655.
(8) Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767–5769.
(9) Fischer, J.; Savage, G. P.; Coster, M. J. Org. Lett. 2011, 13, 3376–
3379.
(10) Varadaraju, R. G.; Hwu, J. R. Org. Biomol. Chem. 2012, 10,
5456–5465.
r
10.1021/ol302273r
Published on Web 09/14/2012
2012 American Chemical Society

Figure 1. Structures of caffeic acid and derivatives (1ꢀ3).
constructed in an optically active form by a hypervalent
iodine-promoted rearrangement of optically active chro-
manone derivative 6. Such a chromanone can be prepared
in enantioselective manner by using either organometallic
chiral catalysts11 or organocatalysts.12 We planned to pre-
pare chromanone derivative 6 in optically active form by
an intramolecular oxa-Michael reaction catalyzed by a
chiral quinidine derivative followed by decarboxylation.
The requisite alkylidene β-keto ester 7 would be prepared
via Knoevenagel condensation of β-keto ester 8 with an
appropriately substituted benzaldehyde. The optically ac-
tive R-hydroxy ester core in 5 would be obtained by a
proline-catalyzed asymmetric R-oxyamination13 of dihy-
drocinnamaldehyde 9 as the key step.
As shown in Scheme 1, synthesis of alkylidene β-keto
ester 7 was accomplished by Knoevenagel condensation of
β-keto ester 8 and 3,4-dibromobenzaldehyde in the presence
of a catalytic amount of piperidinium acetate (5 mol %)
in benzene at reflux for 6 h.14 This provided 7 in 27%
yield on gram scale. Keto ester 7 was subjected to the oxa-
Michael reaction, catalyzed by chiral quinidine-derived
catalyst 10 at 23 °C for 48 h.12 The resulting product was
treated with 2 equiv of p-TsOH and heated at 80 °C for 2 h
to provide chromanone 6 in 97% yield.15 The enantiomeric
purity of 6 was shown to be 91% ee, and after single
recrystallization it could be improved up to 99% ee.
Figure 2. Retrosynthesis of (þ)-lithospermic acid.
Following the synthesis of chromanone 6, we then ex-
plored the key rearrangement of 6 to dihydrobenzofuran
11 using a reported protocol16 employing phenyliodine
diacetate (PIDA) as the oxidant in the presence of H2SO4
in trimethylorthoformate. These conditions did not
provide any appreciable amount of desired rearranged
product. However, we found that a combination of
phenyliodine bis(trifluoroacetate) (PIFA) and anhydrous
formic acid in trimethylorthoformate in the presence of
concentrated H2SO4 resulted in the desired ring contrac-
tion product dihydrobenzofuran 11 as a single product in
61% yield. Optical purity was fully retained in the product
(99% ee). Of particular note, the electron-withdrawing
bromines are important for this rearrangement. Our at-
tempted rearrangement of the corresponding dimethoxy
derivative provided a complex mixture of products. To
convert the dibromo derivative to the corresponding
phenols, we planned to carry out a Miyaura borylation
with pinacolborane.17 We first examined the coupling
reaction with Pd(MeCN)Cl2/SPhos catalytic systems.
These conditions resulted in only one C-Bpin bond
(11) (a) Korenaga, T.; Hayashi, K.; Akaki, Y.; Maenishi, R.; Sakai,
T. Org. Lett. 2011, 13, 2022–2025. (b) Han, F.; Chen, G.; Zhang, X.;
Liao, J. Eur. J. Org. Chem. 2011, 2928–2931.
(12) (a) Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc.
2007, 129, 3830–3831. (b) Wang, H.-F.; Cui, H.-F.; Chai, Z.; Li., P.;
Zheng, C.-W.; Yang, Y.-Q.; Zhao, G. Chem.;Eur. J. 2009, 15, 13299–
13303.
(13) (a) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125,
6038–6039. (b) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247–4250.
(c) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 10808–10809. (d) Hayashi, Y.; Yamaguchi, J.;
Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293–8296. (e) Kano,
T.; Mii, H.; Maruoka, K. Angew. Chem., Int. Ed. 2010, 49, 6638–6641.
(14) Wang, H.; Luo, J.; Han, X.; Lu, Y. Adv. Synth. Catal. 2011, 353,
2971–2975.
(16) (a) Prakash, O.; Tanwar, M. P. Bull. Chem. Soc. Jpn. 1995, 68,
1168–1171. (b) Juhasz, L.; Szilagyi, L.; Antus, S.; Visy, J.; Zsila, F.;
Simonyi, M. Tetrahedron 2002, 58, 4261–4265.
(17) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995,
60, 7508–7510. (b) Billingsley, K. L.; Buchwald, S. L. J. Org. Chem. 2008,
73, 5589–5591.
(15) Wang., H.-F.; Xiao, H.; Wang, X.-W.; Zhao, G. Tetrahedron
2011, 67, 5389–5394.
Org. Lett., Vol. 14, No. 19, 2012
5047

R-oxyamino aldehyde was exposed to the Pinnick
oxidation conditions to give rise to R-substituted
acid. Treatment of the resulting acid with SOCl2 in
methanol furnished methyl ester 15. Methyl ester 15
was obtained in 98% ee and 34% yield in a three-step
sequence without any purification of intermediates.
Reaction of ester 15 with acryloyl chloride and Et3N in
the presence of a catalytic amount of DMAP provided
5, the other partner for the intermolecular CꢀH ole-
fination reaction.
Scheme 1. Synthesis of Dihydrobenzofuran 4
Scheme 2. Synthesis of Acrylate 5
Scheme 3. Synthesis of Lithospermic Acid
formation along with other undesired products. Subsequent
optimization attempts with other phosphine ligands proved
ineffective. However, the use of a palladium N-heterocyclic
carbene (NHC) catalytic system, PEPPSI (12),18 provided
the desired coupling product bis-borane 13 in 57% yield.
Treatment of 13 with aqueous NaOH and H2O2, followed
by protection of the resulting diol with dimethoxypropane
in the presence of a catalytic amount of p-TsOH, afforded
isopropylidene derivative 14 in 76% yield for the two steps.
Subsequent saponification of methyl ester 14 with aqueous
barium hydroxide at 23 °C furnished carboxylic acid 4 for
the intermolecular CꢀH olefination reaction.
Previous syntheses of R-hydroxyesters for lithospermic
acid involved the hydrolysis of rosmarinic acid, limiting
substrate scope. We planned to use the proline catalyzed
R-oxyamination of an aldehyde to introduce the hydroxyl
group, which would expand the diversity of the substrate
scope. Optically active synthesis of acrylate derivative 5 is
shown in Scheme 2 using aldehyde 9 as starting material.
This was subjected to an R-oxyamination protocol devel-
oped by MacMillan and co-workers.13c The resulting
The coupling of dihydrobenzofuran 4 and acrylate 5
involved an intermolecular CꢀH olefination reaction sim-
ilar to that utilized by Wang and Yu in their synthesis.8
As shown in Scheme 3, using the reported Ac-Ile-OH/
Pd(OAc)2 combination, coupling product 16 was obtained
as the only product in 89% yield (brsm). Hydrolysis of 16
with the trimethyltin hydroxide reagent as described by
(18) Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Hadei, N.; Nasielski,
J.; O’Brien, C. J.; Valente, C. Chem.;Eur. J. 2007, 13, 150–157.
5048
Org. Lett., Vol. 14, No. 19, 2012

Nicolaou and co-workers19 afforded diacid 17 in 95%
yield. Treatment of diacid 17 with TMSI-quinoline7a and
subsequent exposure to aqueous trifluoroacetic acid (TFA)
provided synthetic (þ)-1 in 34% yield. The spectroscopic
data of our synthetic (þ)-lithospermic acid {[R]D23 = þ75
(c 0.2, MeOH)} are in complete agreement with those of
the natural product.1,2
In summary, we have accomplished an enantioselective
synthesis of (þ)-lithospermic acid. The synthesis features a
number of interesting transformations. The chromanone
derivative 6 was prepared by an organocatalytic reaction
using a quinidine derivative with high enantioselectivity
and isolated yield. Hypervalent iodine-promoted rearrange-
ment of chromanone 6 proceeded to provide dihydro-
benzofuran 11 with retention of configuration. The syn-
thesis also features a functional group transformation of
dibromobenzene to a bis pinacol borane derivative by
a Pd-catalyzed reaction with a PEPPSI ligand. Fur-
thermore, we have utilized an efficient asymmetric
R-oxyamination of an aldehyde to prepare R-hydroxy
ester required for 1, offering variations of substrate
scope for analogs. The current synthesis is amenable
to a variety of structural analogs of lithospermic acid for
optimization of HIV-integrase activity. Further research is
in progress in our laboratory.
Acknowledgment. Financial support of this work was
provided by the National Institutes of Health (GM53386).
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR spectra for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina,
B. S. Angew. Chem., Int. Ed. 2005, 44, 1378–1382.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5049