Highly convergent total synthesis of (+)-lithospermic acid via a late-stage intermolecular C-H olefination

Article abstract of DOI:10.1021/ja2010225

The total synthesis of (+)-lithospermic acid is reported, which exploits two successive C-H activation reactions as key steps. Rh-catalyzed carbene C-H insertion reaction utilizing Davies's catalyst was used to forge dihydrobenzofuran core, and a late-sta

Full text of DOI:10.1021/ja2010225

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Highly Convergent Total Synthesis of (þ)-Lithospermic Acid via a
Late-Stage Intermolecular CꢀH Olefination
Dong-Hui Wang and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
b
ABSTRACT: The total synthesis of (þ)-lithospermic acid
is reported, which exploits two successive CꢀH activation
reactions as key steps. Rh-catalyzed carbene CꢀH insertion
reaction utilizing Davies’s catalyst was used to forge dihy-
drobenzofuran core, and a late-stage intermolecular CꢀH
olefination coupled the olefin unit with the dihydrobenzo-
furan core to construct the molecule in a highly convergent
manner.
Figure 1. (þ)-Lithospermic acid (1).
ince its first isolation and characterization in 1975,1 lithos-
permic acid has been implicated as an active component in
S
Danshen, one of the most popular traditional herbs used in the
treatment of cardiovascular disorders, cerebrovascular diseases,
various types of hepatitis, chronic renal failure, and dysmenor-
rhea (Figure 1).2 Recent studies have shown that (þ)-lithosper-
mic acid (1) has potent and nontoxic anti-HIV activity.3 Not
surprisingly, the total synthesis of lithospermic acid and its
derivatives has attracted significant interest.4 Preparation of
racemic heptamethyl lithospermate was first reported by the
Jacobson group in 1979,5 while the first total synthesis of (þ)-
lithospermic acid was accomplished by the Ellman and Bergman
group,6 which elegantly showcased their CꢀH activation/hydro-
arylation reaction en route to the chiral dihydrobenzofuran core.
Herein, we report a synthesis of (þ)-lithospermic acid greatly
facilitated by two key CꢀH functionalization reactions, including
an intermolecular CꢀH olefination of arenes, through which the
dihydrobenzofuran core and the olefin unit are coupled at a late
stage of the synthesis to achieve the highest convergency.
Since demethylation of heptamethyl lithospermate through a
two-step deprotection sequence to give lithospermic acid had
already been demonstrated,6a we focused our efforts on the
assembly of hexamethyl lithospermate 2 (Figure 2). Inspired by a
number of total syntheses using CꢀH olefination of indoles and
pyrroles,7 we envisioned that 2 could be prepared by an inter-
molecular CꢀH olefination of acid 4 with acrylate 3, which
would put to the test our recently developed carboxyl-directed
CꢀH olefination reaction (Figure 2),8 especially in the presence
of other potentially more reactive electron-rich arenes and two
potentially racemizable chiral stereocenters (C20 and C21). This
disconnection would also enable a highly convergent approach
toward the synthesis of 2. Olefin 3 can be readily made in three
steps from commercially available rosmarinic acid. We decided to
construct the chiral dihydrobenzofuran 4 from diazo intermedi-
ate 6 through another CꢀH functionalization, an intramolecular
asymmetric CꢀH carbene insertion using Davies’s Rh(II)
catalyst9 and a chiral auxiliary developed by Fukuyama.10
Figure 2. Retrosynthesis of (þ)-lithospermic acid.
Following the above-mentioned synthetic plan, we began our
experimental efforts to prepare the diazo intermediate 6. We
initially attempted to use a 3,4-dimethoxybenzyl protecting
group for the phenol of phenylacetic acid 7; unfortunately, the
3,4-methoxybenzyl protecting group proved to be incompatible
with the synthetic sequence leading to this phenylacetic acid
skeleton (the 3,4-methoxylbenzyl moiety was cleaved under
oxidative conditions). Thus, we instead prepared 7 from readily
available o-eugenol in three steps (see Supporting Information).
Reacting 7 with pyrrolidinyl (S)-lactamide under Mitsunobu
conditions appended the lactamide-type chiral auxiliary 8 in 83%
Received: February 1, 2011
Published: March 28, 2011
r
2011 American Chemical Society
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COMMUNICATION
Scheme 1. Synthesis of Dihydrobenzofuran Carboxylic
Acid 4a
Table 1. Synthesis of Hexamethyl Lithospermate 2
Pd(OAc)2
(mol %)
entry
time (h)
ligand
yield (%)
1
2
3
4
5
5
5
2
12
24
2
5 mol % BQ
31
50
93
91
5 mol % BQ
10 mol % Ac-Ile-OH
4 mol % Ac-Ile-OH
10
to assemble the lithospermic acid backbone at a late stage in a
highly convergent manner, several potential complications could
jeopardize such an approach. First, the presence of multiple
electron-rich and hence reactive arenes could cause nonselective
CꢀH olefination reactions. Second, the two chiral centers
adjacent to the esters (C20 and C21) could be prone to
racemization under the reaction conditions. Third, intermolecu-
lar CꢀH olefination of two relatively large fragments involves
considerable entropy costs compared to previous intramolecular
CꢀH olefinations used in synthesis.7 Finally, the carboxyl
directing group is pointing away from the target CꢀH bonds
with an approximate dihedral angle of 50° (estimated using
ChemBio 3D). Nonetheless, despite these disadvantages, we
hoped that combination of the directing power of the carbonyl
group of carboxyl potassium salt and ligand acceleration8 could
deliver this late-stage CꢀH olefination process.
a Reagents and conditions: (a) pyrrolidinyl (S)-lactamide (1.2 equiv),
PPh3 (1.2 equiv), DEAD (1.2 equiv), toluene, 0 to 23 °C, 2 h; (b) H2
(balloon), Pd/C (5 mol %), MeOH, 23 °C, 12 h; (c) 3,4-dimethox-
ybenzyl bromide (1.45 equiv), K2CO3 (2 equiv), THF (2 equiv), 80 °C,
overnight, 71% over three steps; (d) p-ABSA (2 equiv), DBU (2 equiv),
MeCN, 0 to 23 °C, 24 h, 82%; (e) Rh2(S-DOSP)4 (0.5 mol %), CH2Cl2,
23 °C, 2 h, 85%, dr 8:1; (f) Ba(OH)2 8H2O (1.1 equiv), THF/MeOH
3
(1:1), 0 to 23 °C, 4 h, 86%.
Scheme 2. Synthesis of Acrylate 3a
Consistent with our hypothesis, olefination of 4 with 3, when
carried out in the presence of 5 mol % of Pd(OAc)2, 5 mol % of
Ac-Ile-OH, and 2 equiv of KHCO3 in a solution of tert-amyl
alcohol at 85 °C for 2 h under 1 atm O2, afforded the desired
product 2 in 93% isolated yield (Table 1, entry 3). Catalyst
loading can be lowered to 2 mol % with prolonged reaction time
(entry 4). In the absence of Ac-Ile-OH ligand, olefination of 4
under the optimized conditions also proceeded, albeit giving
significantly lower yields (entries 1, 2). This late-stage coupling
of two structurally complex substrates represents the most
sophisticated application of arene CꢀH olefination to date and
demonstrates the broad applicability of this transformation to
natural product synthesis. Mechanistically, these results further
showcase the directing power of weak coordination of Pd(II)
with the carbonyl group of the carboxyl potassium salt formed
in situ.
To confirm the structure of 2, we converted 2 into two
previously characterized derivatives, dimethyl ester 11 and diacid
12 (Scheme 3). Treatment of monomethyl ester 2 with diazo-
methane gave dimethyl ester 11 in 96% yield. Treatment of 2 or
11 under Nicolaou’s hydrolysis conditions afforded diacid 12 in
91% yield.12 1H and 13C NMR spectra of 11 and 12 were in good
agreement with those reported by Ellman and Bergman (see
Supporting Information).6a
a Reagents and conditions: (a) Me2SO4 (10 equiv), K2CO3 (10 equiv),
acetone, reflux, 10 h, 97%; (b) NaOMe (1 equiv), MeOH, 23 °C, 2 h,
88%; (c) acrylic acid (1.5 equiv), EDC-HCl (2 equiv), DMAP (2 equiv),
CH2Cl2, 0 to 23 °C, 91%.
yield (Scheme 1).11 Removal of the benzyl group gave the
corresponding phenol in quantitative yield, which was then
protected with 3,4-dimethoxybenzyl bromide in the presence
of K2CO3 to provide the cyclization precursor 9 in 86% yield.
Treatment of 9 with diazo transfer reagent in the presence of
DBU at room temperature afforded diazo compound 6 in 82%
yield,9d which was isolated and immediately treated with 0.5 mol %
of Davies’s catalyst, Rh2(S-DOSP)4. Gratifyingly, the CꢀH
insertion reaction proceeded smoothly at room temperature
and provided the trans-dihydrobenzofuran core 10 in good yield
and diastereoselectivity (85%, 8:1 dr). Both CH2Cl2 and hexanes
were found to be effective solvents for the cyclization reaction.
Basic hydrolysis conditions afforded the carboxylic acid 4 in
86% yield.
Next, we prepared the acrylate coupling partner 3 (Scheme 2).
Alcohol 5 was synthesized by pentamethylation of rosmarinic
acid and subsequent hydrolysis.6a By treating alcohol 5 with
acrylic acid in the presence of EDC and DMAP at room
temperature, acrylate 3 was obtained in 91% yield. Compound
3 is stable when stored at 0 °C.
With carboxylic acid 4 and acrylate 3 in hand, we were ready to
test the key CꢀH olefination step. While this strategy promised
These results encouraged us to perform the two-step de-
methylation procedure that would complete the synthesis of the
natural product. Conversion of monoacid 2 to diacid 12 under
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COMMUNICATION
Scheme 3. Completion of the Synthesis of (þ)-Lithospermic
of lithospermic acid was given in 1963, see:(b) Johnson, G.; Sunderwirth,
S. G.; Gibian, H.; Coulter, A. W.; Gassner, F. X. Phytochemistry 1963,
2, 145.
Acida
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Pharmacol. 2005, 45, 1345. (d) Lu, Y.; Foo, L. Y. Phytochemistry 2002,
59, 117. (e) Watzke, A.; O’Malley, S. J.; Bergman, R. G.; Ellman, J. A.
J. Nat. Prod. 2006, 69, 1231.
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Antiviral Res. 2002, 55, 91. (b) Shigematsu, T.; Tajima, S.; Nishikawa, T.;
Murad, S.; Pinnell, S. R.; Nishioka, I. Biochim. Biophys. Acta, Gen. Subj.
1994, 1200, 79.
(4) For recent syntheses of structually related members of rosmari-
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a Reagents and conditions: (a) Me3SnOH (3 equiv), 1,2-dichloroethane,
80 °C, 24 h, 91%; (b) 1-trimethylsilylquinolinium iodide (40 equiv),
neat, 130 °C, 3 h, 31%; (c) CH2N2, Et2O, 0 °C, 10 min, 96%.
Nicolaou’s conditions12 and subsequent treatment of diacid 12
with TMSIꢀquinoline6a gave the natural product (þ)-lithosper-
mic acid (1) in 31% yield (Scheme 3).
In summary, total synthesis of (þ)-lithospermic acid was
accomplished in 12 steps and 11% overall yield from o-eugenol.
The highly convergent strategy employed was made possible by
two CꢀH functionalization reactions, including a late-stage Pd-
catalyzed intermolecular CꢀH olefination reaction accelerated
by the amino acid ligand Ac-Ile-OH, the most sophisticated
application to date of arene CꢀH olefination to the synthesis of
complex natural products.
(11) Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima, S.
Tetrahedron 1989, 45, 5767.
’ ASSOCIATED CONTENT
(12) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S.
Angew. Chem., Int. Ed. 2005, 44, 1378.
S
Supporting Information. Experimental procedures and
b
characterization of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
’ ACKNOWLEDGMENT
We gratefully acknowledge the National Institutes of Health
(NIGMS, 1 R01 GM084019-01A1) and National Science Foun-
dation under the Center of Chemical Innovation in Stereoselec-
tive CꢀH Functionalization (CHE-0943980), and Amgen for
financial support. We are thankful for predoctoral fellowships
from the China Scholarship Council (D.-H.W.). We thank Prof.
P. S. Baran, Prof. H. M. L. Davies, Dr. T. Newhouse, and
D. Sarlah for valuable discussions and Dr. Shun Su for helping
with the isolation of final product on prep. HPLC.
’ REFERENCES
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Breneman, W. R.; Carmack, M. J. Org. Chem. 1975, 40, 1804. The name
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