Total synthesis of (+)-lithospermic acid by asymmetric intramolecular alkylation via catalytic C-H bond activation

Article abstract of DOI:10.1021/ja052680h

The total synthesis of (+)-lithospermic acid is described. The efficient synthesis features an asymmetric alkylation via C-H bond activation to assemble the dihydrobenzofuran core of the natural product. This was accomplished via a chiral imine-directed C

Full text of DOI:10.1021/ja052680h

Published on Web 09/08/2005
Total Synthesis of (+)-Lithospermic Acid by Asymmetric Intramolecular
Alkylation via Catalytic C-H Bond Activation
Steven J. O’Malley, Kian L. Tan, Anja Watzke, Robert G. Bergman,* and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received April 25, 2005; E-mail: bergman@cchem.berkeley.edu; jellman@uclink.berkeley.edu
(+)-Lithospermic acid (+)-(1)1 has recently attracted considerable
Scheme 2. Synthesis of Z Olefin
interest due to its reported potent and nontoxic anti-HIV activity
that results from inhibition of HIV-1 integrase,2 which is an
intensively studied therapeutic target for the treatment of AIDS.
Though several groups have isolated (+)-lithospermic acid to study
its biological activity, its synthesis has not yet been reported. Herein
we report the first total synthesis of (+)-lithospermic acid using
asymmetric intramolecular alkylation via rhodium-catalyzed C-H
bond activation. The synthesis further provides the first example
of employing a chiral nonracemic imine as a directing group in a
C-H bond activation method.
The densely functionalized dihydrobenzofuran core of (+)-1
provides a formidable test of our recently developed method for
intramolecular alkylation via directed C-H bond activation.3 The
polyphenolic nature of (+)-lithospermic acid represents a further
synthetic challenge in that it requires an appropriate protecting group
strategy that allows late-stage global deprotection in the presence
of the labile C-9 ester and C-21 benzylic ether functional groups.
Corey-Fuchs olefination of 7 followed by double elimination
and trapping with methyl chloroformate provided ester 8 in excellent
yield (Scheme 2). A conjugate addition reaction with isovanillin
furnished 9, with a 1:1 methanol and pyridine solvent mixture
providing an optimized 3.2:1 ratio of Z:E isomers.6 After chroma-
tography and crystallization, the pure Z isomer was isolated in 59%
yield.
Upon conversion of aldehyde 9 to imine 6, the rhodium-catalyzed
intramolecular alkylation was next investigated (eq 1). Using
ferrocenyl-PCy2 (FcPCy2) as the ligand, dihydrobenzofuran 5 was
isolated solely as the cis isomer in 89% overall yield. This example
constitutes, by far, the most densely functionalized system to which
this C-H activation method has been applied.
We envisioned that global deprotection of heptamethyl litho-
spermic acid 2 would provide the most efficient route to (+)-
lithospermic acid (Scheme 1). Ester 2 could be prepared from acid
3 and alcohol 4, which can be made in two steps from commercially
available rosmarinic acid. Cinnamic acid 3 can be prepared by a
Knovenagel condensation and epimerization of dihydrobenzofuran
5. Using intramolecular alkylation via catalytic C-H bond activa-
tion, 5 should be accessible from imine 6, which would constitute
the first application of our C-H activation chemistry to natural
product synthesis.4,5
Unfortunately, chiral catalysts could not be identified that
provided satisfactory yields and/or enantioselectivities in this
cyclization. An alternative approach to inducing chirality in the
reaction involves using chiral amine auxiliaries to yield a dia-
stereoselective insertion of the prochiral olefin. Thus, a variety of
chiral nonracemic amines were screened in this reaction (Table 1).
Chiral benzylic amines proved to be the most effective (entries 1,
2, 5, and 6), with aminoindane 16 giving the best results, generating
the cyclization product in 63% yield and 76% ee after auxiliary
hydrolysis (entry 6). An increase in catalyst loading and reaction
time further improved the yield of the reaction without significantly
eroding the asymmetric induction (entry 7), while decreasing the
temperature was found to improve the selectivity but reduce the
yield significantly (entry 8). Thus, imine formation of 9 with (R)-
(-)-aminoindane followed by cyclization proceeded cleanly to give,
after hydrolysis, dihydrobenzofuran 5 in 88% yield with 73% ee.
Recrystallization of the product from benzene/pentane mixtures
provided the product in 56% yield as a single enantiomer. X-ray
structure analysis of a hydrazone derivative of 5 unambiguously
established the sense of induction in the cyclization reaction (see
Supporting Information).
Scheme 1. Retrosynthesis of (+)-Lithospermic Acid
Knovenagel condensation of 5 not only converted the aldehyde
to the desired cinnamic acid but also epimerized the C-20 position
to give the desired thermodynamically more stable anti diastereomer
9
13496
J. AM. CHEM. SOC. 2005, 127, 13496-13497
10.1021/ja052680h CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Asymmetric Cyclization Using Chiral Imines
Scheme 4. Completion of the Synthesis of (+)-Lithospermic Acid
entry
RNH2
T (
°C)
t (h)
% Rh
% FcPCy2
% 10a
% eeb
1
2
3
4
5
6
7
8
9
11
12
13
14
15
16
16
16
17
75
75
75
75
75
75
75
50
75
6
4
5
5
15
15
15
15
15
15
30
15
15
53
68
<10
0
37
63
88c
31
3
48
50
18
22
24
4
5
5
to the corresponding acid. Although standard saponification condi-
tions did not result in selective hydrolysis of the two methyl esters
over the C-9 ester linkage, diacid 18 could be obtained in excellent
yield by employing a recently reported protocol for the hydrolysis
of methyl esters10 using Me3SnOH (Scheme 4). Subsequent
treatment of this diacid with sublimed TMSI quinoline adduct
resulted in removal of the five ether methyl groups to provide (+)-
lithospermic acid in 35% yield.
5
50
76
73
80
nd
6
5
20
20
20
10
5
5
a Yields based on 1H NMR integration relative to 2,6-dimethoxytoluene
as an internal standard. b Enantiomeric excess determined after hydrolysis
of 10 with 1 N HCl (aq) using chiral HPLC. c Isolated yield of the product
after hydrolysis and column chromatography.
In summary, an efficient, asymmetric synthesis of (+)-litho-
spermic acid was accomplished in 10 steps and 5.9% overall yield.
The asymmetric intramolecular alkylation to provide 5 is the first
example of chiral imine-directed C-H bond activation and
represents the first application of our C-H activation method to
natural product synthesis. Due to this efficient synthesis, the
preparation of lithospermic acid analogues for evaluation as HIV-1
integrase inhibitors is also in progress.
Scheme 3. Synthesis of Heptamethyl Lithospermic Acid
Acknowledgment. This work was supported by the NIH
GM069559 (to J.A.E.) and 5F32GM071207-02 (to S.O.M.) and
the Director and Office of Energy Research, Office of Basic Energy
Sciences, Chemical Sciences Division, U.S. Department of Energy,
under Contract DE-AC03-76SF00098 (to R.G.B.). We thank Dr.
Frederick J. Hollander and Dr. Allen G. Oliver of the Berkeley
CHEXray facility for solving the X-ray crystal structure of the
hydrazone derivative used to determine the absolute configuration
of 5. We thank Dr. Reema K. Thalji for her chiral imine studies in
similar cyclization reactions.
Supporting Information Available: Complete experimental details
and spectral data for all compounds described (PDF, CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
Table 2. Model Global Deprotection
References
(1) (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) Kelley, C.
J.; Harruff, R. C.; Carmack, M. J. Org. Chem. 1976, 41, 449-455. For
other references dealing with the isolation and study of lithospermic acid,
see: (c) Lin, Y. L.; Wang, C. N.; Shiao, Y. J.; Liu, T. Y.; Want, W. Y.
J. Chin. Chem. Soc. 2003, 50, 1079-1083. (d) Lin, Y. L.; Chang, Y. Y.;
Kuo, Y. H.; Shiao, M. S. J. Nat. Prod. 2002, 65, 745-747. (e) Yamamoto,
H.; Inoue, K.; Yazaki, K. Phytochemistry 2001, 53, 651-657. (f) Fukui,
H.; Yazaki, K.; Tabata, M. Phytochemistry 1984, 23, 2398-2399.
(2) Abd-Elazem, I. S.; Chen, H. S.; Bates, R. B.; Huang, R. C. C. AntiViral
Res. 2002, 55, 91-106.
as the major product in 85% yield (Scheme 3).7,8 Esterification of
3 with alcohol 4 was accomplished with N-(3-dimethylamino-
propyl)-N′-ethylcarbodiimide hydrochloride (EDC) and 4-(di-
methylamino)pyridine (DMAP) to provide heptamethyl lithospermic
acid 2 in 80% yield.
Completion of the synthesis required removal of five ether and
two ester methyl groups to arrive at (+)-lithospermic acid. To model
this final reaction, the deprotection of pentamethyl rosmarinic acid
was studied, and it was found that numerous conditions gave only
decomposition products (Table 2). Using Brossi’s conditions,9 in
which iodotrimethylsilane (TMSI) and quinoline are precomplexed,
pentamethyl rosmarinic acid was converted back to rosmarinic acid
in 57% yield (entry 7).
(3) (a) Thalji, R. K.; Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2004,
126, 7192-7193. (b) Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2003, 5, 1301-1303. (c) Thalji, R. K.; Ahrendt, K. A.; Bergman, R.
G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 9692-9693.
(4) For use of our method to the synthesis of a drug candidate, see 3b.
(5) For other examples of total syntheses using C-H activation, see: (a)
Davies, H. M. L.; Jin, Q. Tetrahedron: Asymmetry 2003, 14, 941-949.
(b) Wehn, P. M.; DuBois, J. J. Am. Chem. Soc. 2002, 124, 12950-12951.
(c) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D. J. Am.
Chem. Soc. 2002, 124, 11856-11857. (d) Johnson, J.; Sames, D. J. Am.
Chem. Soc. 2000, 122, 6321-6322. (e) Harris, P. W. R.; Woodgate, P.
D. J. Organomet. Chem. 1997, 530, 211-223.
(6) Hamed, E. A. Ind. J. Chem. 1998, 37B, 1202-1206.
(7) Detterbeck, R.; Hesse, M. HelV. Chim. Acta 2003, 86, 343-360.
(8) Cyclization of (E)-9, though capable of directly establishing the desired
anti relationship in 3, was not thoroughly investigated because it was the
minor isomer produced and was found to cyclize less efficiently.
(9) Minamikawa, J.; Brossi, A. Tetrahedron Lett. 1978, 34, 3085-3086.
(10) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. Angew.
Chem., Int. Ed. 2005, 44, 1378-1382.
Unfortunately, final deprotection of 2 using the TMSI/quinoline
conditions led only to decomposition of the starting material. Ring
opening of the dihydrobenzofuran through â-elimination of the C-21
phenoxy group proved to be a major decomposition pathway. This
could be minimized, however, by converting the C-20 methyl ester
JA052680H
9
J. AM. CHEM. SOC. VOL. 127, NO. 39, 2005 13497