Asymmetric total synthesis of antiochic acid

Article abstract of DOI:10.1021/ol800499p

(Chemical Equation Presented) The first asymmetric total synthesis of antiochic acid using bioinspired polyene cyclization strategy is described. Both good yield and good asymmetric induction were obtained.

Full text of DOI:10.1021/ol800499p

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2143-2145
Asymmetric Total Synthesis of
Antiochic Acid
Yu-Jun Zhao and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371
teckpeng@ntu.edu.sg
Received March 5, 2008
ABSTRACT
The first asymmetric total synthesis of antiochic acid using bioinspired polyene cyclization strategy is described. Both good yield and good
asymmetric induction were obtained.
Antiochic acid 1 and its biosynthetically related polycyclic
diterpenes represent a vast multitude in the fascinating realm
Scheme 1. Retrosynthetic Analysis of 1
of terpenoids.1 Furthermore, they have interesting structures
and biological activities (Scheme 1).1,2 The antiochic acid 1
possessed several synthetic challenging structural features,
including multisubstituted tricyclic core, two quaternary
chiral centers, and the styrene type side chain. Although
several racemic syntheses of abietane diterpenes have been
reported,3,4 antiochic acid 1 had not surrendered to any total
(1) Isolation and microbiological transformations of related analogues:
Ulubelen, A.; Miski, M.; Mabry, T. J. J. Nat. Prod 1981, 44, 119.
(2) (a) Avhan, U.; Mahmut, M.; Candan, J.; Fak, E. Doga Bilim Derg.,
Seri C 1984, 8, 109–115. (b) Sepu´lveda, B.; Astudillo, L.; Rodr´ıguez, J. A.;
Ya´n˜ez, T.; Theoduloz, C.; Schmeda-Hirschmann, G. Pharmacol. Res. 2005,
52, 429–437. (c) Ukiya, M.; Akihisa, T.; Tokuda, H.; Hirano, M.; Oshikubo,
M.; Nobukuni, Y.; Kimura, Y.; Tai, T.; Kondo, S.; Nishino, H. J. Nat.
Prod. 2002, 65, 462–465
.
(3) Previous syntheses of dehydroabietic acid and its analogues: (a) Stork,
G.; Schulenberg, J. W. J. Org. Chem. 1962, 84, 284–292. (b) Ireland, R. E.;
Kierstead, R. C. J. Org. Chem. 1962, 84, 703–704. (c) van Tamelen, E. E.;
Zawacky, S. R.; Russell, R. K.; Carlson, J. G. J. Am. Chem. Soc. 1983,
105, 142–143. (d) Corey, E. J.; Tius, M. A.; Das, J. J. Am. Chem. Soc.
E. J. J. Am. Chem. Soc. 1999, 121, 9999–10003. (g) Corey, E. J., Jr. J. Am.
Chem. Soc. 1996, 118, 11982–11983, and references therein. (h) van Tamlen,
E. E.; Hwu, J. R. J. Am. Chem. Soc. 1983, 105, 2490–2491, and references
therein. (i) Bogensta¨tter, M.; Limberg, A.; Overman, L. E.; Tomasi, A. L.
J. Am. Chem. Soc. 1999, 121, 12206–12207. (j) Pattenden, G.; Gonzalez,
M. A.; McCulloch, S.; Walter, A.; Woodhead, S. J. Proc. Natl. Acad. Sci.
2004, 101, 12024–12029, and references therein. (k) Smith, A. B., III;
Kinsho, T. Tetrahedron Lett. 1996, 37, 6461–6464. (l) Justicia, J.; Oller-
Lopez, J. L.; Campan˜a, A. G.; Oltra, J. E.; Cuerva, J. M.; Bun˜uel, E.;
Cardenas, D. J. J. Am. Chem. Soc. 2005, 127, 14911–14921. (m) Snider,
B. B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1998, 63, 7945–7952.
(n) Yang, D.; Ye, X. Y.; Gu, S.; Xu, M. J. Am. Chem. Soc. 1999, 5579–
1980, 102, 1743–1744
.
(4) Recent progress in total synthesis using polyene cyclization strategy:
Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900–903. (b)
Kurdyumov, A. V.; Hsung, R. P. J. Am. Chem. Soc. 2006, 128, 6272–
6273. (c) Uyanik, M.; Ishibashi, H.; Ishihara, K.; Yamamoto, H. Org. Lett.
2005, 7, 1601–1604. (d) Uyanik, M.; Ishihara, K.; Yamamoto, H. Org. Lett.
2006, 8, 5649–5652, and early references cited therein. (e) Johnson, W. S.;
Plummer, M. S.; Reddy, S. P.; Bartlett, W. R. J. Am. Chem. Soc. 1993,
115, 515–521, and references therein. (f) Huang, A. X.; Xiong, Z.; Corey,
5580
.
10.1021/ol800499p CCC: $40.75
Published on Web 04/26/2008
2008 American Chemical Society

synthesis yet. To mimic terpenoids biosynthesis, we are
interested in using the polyene cyclization strategy for the
total synthesis of 1. Herein, we reported the asymmetric total
synthesis of 1 using a bioinspired polyene cyclization
reaction.5 This method allows the construction of tricyclic
core of 1 with stereochemical control of up to five chiral
centers in single step (Scheme 2).
group. Treatment of alcohol 4 with Ac2O in the presence of
DMAP and pyridine followed by removal of TIPS protecting
group using TBAF furnished key intermediate 9 in 87%
yield.
Scheme 3a
Scheme 2
aSee ref 11.
The stereochemistry of the tricyclic core 5 could be
predicted according to cyclization protocol previously es-
tablished in our laboratory.5 Four chiral centers were formed
on the carbocyclic ring with the absolute stereochemistry
perfectly matching the natural product 1. The stereochem-
istries were further confirmed from X-ray structure analyses
of cyclization products 5, 7, and 8 (Schemes 2 and 3). The
following transition state (as shown in Figure 1) was
proposed to account for the observed stereochemistry.5
Our strategy focused on the development of an efficient
method for the construction of tricylic core 1. It can be
envisaged that tricyclic alcohol 5 generated from the polyene
cyclization could be converted into alcohol 4 once the side
chain was cleaved (Scheme 1).6We expected that alcohol 4
could be converted into compound 3 using an elimination
reaction. The alkene moiety of 3 could be readily cleaved upon
ozonolysis. Finally, reduction followed by Suzuki coupling of
aryl bromide 2 with vinyl boronate could render 1.7
(9) Compound 7 was confirmed to be the THF formation product of 8.
The formation yield of 7 was moderate partially because the minor isomer
20 was resistant to cyclization condition and could be recovered.
Our synthetic efforts commenced with the reaction of
polyene 68 with chiral acetal A in the presence of SnCl4 at
-70 °C (Scheme 2). The desired tricyclic adduct 5 was
obtained in 56% yield with a diastereomeric ratio of 9:1.
Although the minor byproduct 79 was obtained in 10% yield,
we did not detect any of the benzene ring cyclization
regioisomer.
Swern oxidation10 of the alcohol 5 followed by treatment
with concentrated KOH solution for 24 h provided alcohol
4 (77% yield, 80% ee11) over two steps (Scheme 3). The
enantioselectivity was much higher than the previous reported
system (52% ee) probably due to existence of the OTIPS
(5) Zhao, Y. J.; Chng, S. S.; Loh, T. P. J. Am. Chem. Soc. 2007, 129,
492–493.
(6) (a) Johnson, W. S.; Elliott, J. D.; Hanson, G. J. Am. Chem. Soc.
1984, 106, 1138–1139. (b) Mori, A.; Fujiwara, J.; Maruoka, K.; Yamamoto,
H Tetrahedron Lett. 1983, 24, 4581–4584.
(10) Sharma, A. K.; Swern, D. Tetrahedron Lett. 1974, 15, 1503–1506.
(11) The enantiomeric excess value of 4 was determined on the basis
of compound 17 as shown below:
(7) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866–
867.
(8) Polyene 6 was synthesized over seven steps as shown below:
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Org. Lett., Vol. 10, No. 11, 2008

Scheme 4
Figure 1
.
Without further delay, alcohol 9 was subjected to Swern
oxidation, followed by Pinnick oxidation12 and methylation
using Steglich’s method13 (Scheme 4). The desired product
ester 10 was obtained in 74% yield over three steps.
Treatment of 10 with methanolic potassium carbonate gave
alcohol 11. Bromination of alcohol 11 using PBr3 afforded
benzylic bromide, which was immediately subjected to
t-BuOK and DMF without purification to provide alkene 3
in 40% yield over two steps. C-C bond cleavage of alkene
3 afforded ketone 2 in 56% yield with 80% ee. Ketone 2
was reduced to alcohol using NaBH4 to afford 12 as single
isomer in 80% yield. Suzuki coupling of 12 and 2-prope-
nylboronate in the presence of 5 mol% Pd(PPh3)4 gave 13
in 84% yield. Lastly, hydrolysis of methyl ester 13 using
LiOH and KOH in hot methanol completed the total synthesis
of antiochic acid 1.
of constructing polycyclic terpenoids with diverse function-
alities as building blocks for terpenoid synthesis.
Acknowledgment. This paper is dedicated to Professor
Elias J. Corey (Harvard University) on the occasion of his
80th birthday. We thank Dr. Yong-Xin Li (Nanyang Tech-
nological University) for X-ray analyses. We gratefully
acknowledge the Nanyang Technological University and the
Singapore Ministry of Education Academic Research Fund
Tier 2 (No. T206B1221) for financial support of this research.
In summary, we have developed an asymmetric total
synthesis of antiochic acid which demonstrates the power
of bioinspired polyene cyclization in the total synthesis of
natural products. This synthesis also revealed the feasibility
Supporting Information Available: Additional experi-
ment procedures, spectral data for reaction products, and four
CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. (1947-1973)
1973, 27, 888–890. (b) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. K.
Tetrahedron 1981, 37, 2091–2096.
(13) (a) Neises, B.; Steglich, W. Angew. Chem. 1978, 90, 556–557. (b)
Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394–2395.
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