A concise approach for the total synthesis of pseudolaric acid A

Article abstract of DOI:10.1021/ol200741j

A new strategy for the stereoselective total synthesis of natural product pseudolaric acid A (1) was accomplished in 16 steps from commercially available starting material, featuring a samarium diiodide (SmI₂)-mediated intramolecular alkene-ketyl radical cyclization and a ring-closing metathesis (RCM) reaction to stereoselectively cast the unusual trans-fused [5-7]-bicyclic core of pseudolaric acid A (1).

Full text of DOI:10.1021/ol200741j

ORGANIC
LETTERS
2
011
Vol. 13, No. 10
630–2633
A Concise Approach for the Total
Synthesis of Pseudolaric Acid A
2
†
Tao Xu, Chuang-chuang Li,* and Zhen Yang*
,†
,†,‡
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen, 518055 China, and State Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education and Beijing National Laboratory for Molecular Science (BNLMS),
College of Chemistry, Peking University, Beijing 100871, China
chuangli@pku.edu.cn, zyang@pku.edu.cn
Received March 19, 2011
ABSTRACT
A new strategy for the stereoselective total synthesis of natural product pseudolaric acid A (1) was accomplished in 16 steps from commercially
available starting material, featuring a samarium diiodide (SmI )-mediated intramolecular alkene-ketyl radical cyclization and a ring-closing
2
metathesis (RCM) reaction to stereoselectively cast the unusual trans-fused [5À7]-bicyclic core of pseudolaric acid A (1).
1
Pseudolarix kaempferi (pinaceae) is a Chinese folk
medicine for the treatment of fungal infections of skin
2
and nails. To date, over 20 natural products including
pseudolaric acid A (1) and structures 2À4 (Figure 1) have
been isolated from extracts of its root bark.
The structure of pseudolaric acid A has been estab-
3
lished by X-ray crystallographic analysis combined
with a circular dichroism (CD) excision chirality
4
method. The structure of pseudolaric acid A presents
a significant challenge to synthesis: a rarely seen trans-
fused [5À7]-bicyclic core substituted with an acetoxy
group and a lactone at the ring junction. Preliminary
biological assays show that pseudolaric acids exhibit
significant biological activities against fungi and multi-
drug-resistant tumors.
The structural complexity as well as biological signifi-
cance of the pseudolaric acids has attracted synthetic inter-
5
est worldwide; in particular, Chiu et al. have synthesized
Figure 1. Pseudolaric acids A, B, F, and H.
1
6
(
(
À)-1 (26 steps) and Trost et al. have synthesized (À)-2
7
28 steps), respectively, and several elegant model studies
have been reported. While the total syntheses of 1and 2have
been achieved, the need to develop more concise routes
remains in order to provide an ample supply of these
valuable compounds for the purpose of facilitating further
therapeutic investigations, since their availability from nat-
†
Peking University Shenzhen Graduate School.
Peking University.
‡
(
1) Chiu, P.; Leunga, L. T.; Kob, B. C. B. Nat. Prod. Rep. 2010, 27,
066.
2) (a) Ni, G.-P. Zhongguo Zhongyao Zazhi 1957, 3, 156. (b) Wu,
J. X.; Hu, R. S.; Yang, G. L. Chin. J. Dermatol. 1960, 8, 18.
1
1
(
ural resource is limited.
(
(
(
3) Yao, J.; Lin, X. Acta Chim. Sin. 1982, 40, 385.
4) Ying, B.; Xu, R.; Mi, J.; Han, J. Acta Chim. Sin. 1988, 46, 85.
5) Geng, Z.; Chen, B.; Chiu, P. Angew. Chem., Int. Ed. 2006, 45,
(6) (a) Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem. Soc. 2007,
129, 14556. (b) Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem. Soc.
2008, 130, 16424.
6
197.
1
0.1021/ol200741j r 2011 American Chemical Society
Published on Web 04/27/2011

1
a Cu-mediated oxidative deformylation, an Otera
3
At our laboratories, we aimed to develop a strategy to
rapidly establish the trans-fused [5À7]-bicyclic core in a
stereoselective manner, which would constitute a founda-
tion for the synthesis of pseudolaric acids A and B. We also
envisaged that the generated bicyclic core could be further
elaborated by the installation of suitable functionalities so
as to accomplish other family members of pseudolaric
acids, such as 2À4 shown in Figure 1.
6
,14
lactonization
(HWE) reaction.
and a HornerÀWadsworthÀEmmons
We commenced from preparing the key intermediate 7
(Scheme 1). Diene 7 was synthesized in 82% yield via
alkylation of the dianion derived from ketoester 5 with
1
5
allyl bromide 6. Compound 7 then underwent a
Michael addition with acrolein in the presence of
NaOMe to give aldehyde 8 in 67% yield. Then, upon
the treatment of aldehyde 8 with Wittig reagent 9, 10 was
obtained in 73% yield. We also envisaged that asym-
metric synthesis of either enantiomer of intermediate 10
could in principle be achieved via the asymmetric
1
6
Michael addition by 7.
Scheme 1. Synthesis of Intermediate 10
Figure 2. Synthetic analysis.
Figure 2 outlines our strategy on the disconnection of
pseudolaric acid A (1). Key steps thereof include the
formation of trans-fused bicyclic core by a SmI -mediated
2
8
9
alkeneÀketyl radical cyclization and a RCM reaction.
1
0
The former has been widely applied in syntheses given it
1
1
may create not only high yield but also stereoselectivity,
and the latter has been regarded as one of the most
powerful reactions in natural product synthesis. The
rest of the major challenges, namely the construction of
lactone and side chain were intended to be addressed by
1
2
We then explored the route for the synthesis of 2-hydro-
xycyclopentanecarboxylate 11a (Scheme 2). Although SmI2-
mediated acyclic alkeneÀketyl radical cyclization had been
widely used to construct structurally diverse natural product
scaffolds, the stereoselective synthesis of the trans-fused
17
(
7) (a) Pan, B.; Chang, H.; Cai, G.; Guo, Y. Pure Appl. Chem. 1989,
1, 389. (b) Hu, Y.; Ou, L.; Bai, D. Tetrahedron Lett. 1999, 40, 545.
c) Hu, Y. H.; Ou, L. G.; Wang, X. L.; Bai, D. L. Chin. Chem. Lett. 1999,
1
1
[
chemical outcome of SmI -mediated cyclization tends to be
5À7]-bicyclic core however remains rare. As the stereo-
6
(
2
18
0, 281. (d) Ou, L.; Hu, Y.; Song, G.; Bai, D. Tetrahedron 1999, 55,
3999. (e) Jiang, X. T.; Ou, L. G.; Han, D. M.; Zhai, Y. F.; Bai, D. L.
Chin. Chem. Lett. 2001, 12, 113. (f) Wu, B.; Karle, J. M.; Watkins, E. B.;
Avery, M. A. Tetrahedron Lett. 2002, 43, 4095. (g) L. A. Paquette, L. A.;
Pettigrew, J. D. Synthesis 2009, 379. (h) Pettigrew, J. D.; Paquette, L. A.
Heterocycles 2010, 99.
highly solvent-, additive- and substrate-dependent, we
therefore attempted to apply this reaction to synthesize 11a.
To this end, we initially profiled the SmI -mediated
2
alkene-ketyl radical annulation reaction in the solvents of
THF, acetonitrile, and DME, respectively. Unfortunately,
poor diastereoselectivity was observed in all those cases with
low yields (see the Supporting Information for details).
Based on the knowledge that additives such as HMPA
(
2
8) For reviews of SmI -induced transformations, see: (a) Molander,
A. G.; Harris, C. R. Tetrahedron 1998, 54, 3321. (b) Molander, A. G.;
Harris, C. R. Chem. Rev. 1996, 96, 307. (c) Edmonds, D. J.; Johnson, D.;
Procter, D. J. Chem. Rev. 2004, 104, 3371.
(9) (a) Grubbs, R. H.; Fu, G. C. J. Am. Chem. Soc. 1992, 114, 5426.
(
b) Grubbs, R. H.; Schwab, P.; France, M. B.; Ziller, J. W. Angew.
Chem., Int. Ed. 1995, 34, 2039. (c) Schrock, R. R.; Murdzek, J. S.; Bazan,
G. C.; Robbins, J.; Dimare, M.; O’Regan, M. J. Am. Chem. Soc. 1990,
12, 3875. (d) Bazan, G. C.; Oskam, J. H.; Cho, H.-N.; Park, L. Y.;
Schrock, R. R. J. Am. Chem. Soc. 1991, 113, 6899. (e) Armstrong, S. K.
J. Chem. Soc., Perkin Trans. 1 1998, 371.
or DMPU may increase the reduction potential of SmI
2
t
and cosolvents such as MeOH or BuOH as proton source
may affect the efficiency of quenching intermediate anions
1
1
9
in reactions, we carried out the SmI -mediated cyclization
2
t
in the presence of HMPA (10 equiv) and BuOH (10 equiv).
(10) (a) Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic
Synthesis using Samarium Diiodide: A Practical Guide; RSC Publishing:
Cambridge, 2010. (b) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew.
Chem., Int. Ed. 2009, 48, 7140. (c) Edmonds, D. J.; Johnston, D.;
Procter, D. J. Chem. Rev. 2004, 104, 3371.
(13) (a) Rheenen, V. V. Tetrahedron Lett. 1969, 985. (b) Nitta, I.;
Haruyama, T.; Fujimori, S.; Inoue, S.; Ueno, H. Bull. Chem. Soc. Jpn.
(
11) (a) Cui, K.; Liao, H.; Yao, Z. 11th Tetrahedron Symposium,
010, Beijing, China, PSC113; (b) Wei, G.18th IUPAC International
Conference on Organic Synthesis, Bergen, Norway, 2010, Poster No. 032-
43.
12) (a) Tannert, R.; Milroy, L.-G.; Ellinger, B.; Hu, T.-S.; Arndt
1
985, 58, 1081.
2
(14) Otera, J.; Danoh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307.
(15) Snider, B. B.; Dombroski, M. A. J. Org. Chem. 1987, 52, 5487.
(16) (a) Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem.,
5
(
H.-D.; Waldmann, H. J. Am. Chem. Soc. 2010, 132, 3063. (b) Smith,
A. B., III; Bosanac, T.; Basu, K. J. Am. Chem. Soc. 2009, 131, 2348.
(
Int. Ed. 2006, 45, 4301. (b) Hermann, K.; Wynberg, H. J. Org. Chem.
1979, 44, 2238.
(17) (a) Hutton, T. K.; Wuir, K. W.; Procter, D. J. Org. Lett. 2003, 5,
4811. (b) Molander, G. A.; McWilliams, J. C.; Noll, B. C. J. Am. Chem.
Soc. 1997, 119, 1265. (b) Enholm, E. J.; Satici, H.; Trivellas, A. J. Org.
Chem. 1989, 54, 5841.
c) F u€ rstner, A.; Nevado, C.; Waser, M.; Tremblay, M.; Chevrier, C.;
Teply, F.; Aissa, C.; Moulin, E.; M u€ ller, O. J. Am. Chem. Soc. 2007, 129,
9150. (d) Trost, B. M.; Dong, G.; Vance, J. A. J. Am. Chem. Soc. 2007,
129, 4540. (e) Li, Y,l; Hale, K. J. Org. Lett. 2007, 9, 1267. (f) Yang, Z. Q.;
Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J.
J. Am. Chem. Soc. 2004, 126, 7881.
(18) (a) Enholm, E. J.; Satici, H.; Trivellas, A. J. Org. Chem. 1994, 54,
5841. (b) Suzuki, K.; Nakata, T. Org. Lett. 2002, 4, 3943.
Org. Lett., Vol. 13, No. 10, 2011
2631

lutidine, product 12a was obtained in 78% yield in two
steps.
The observed diastereoselectivity suggested that the
Scheme 2. Synthesis of Compound 13
2
0
dipolar repulsion between Sm-associated ketyl radical
anion and the ester groupforcedthe transition state A asits
favorable conformation as depicted in Scheme 2. As a
result of that, 11a came out as the major product.
With 12a in hand, we moved on to construct the
azulene 13 via RCM. To this end, 12a was treated with
Grubbs II catalyst to perform an RCM reaction. To our
delight, the desired product 13 was formed in excellent yield.
The stereochemistry of 13 has been confirmed via the X-ray
crystallographic analysis of its derivative 14, which was
generated from 13 via Dibal-H reduction. We attributed
this successful RCM reaction to the favorable conformation
of substrate 12a, in which the two-terminal olefins occupy
equatorial positions, which would facilitate the proposed
annulation (see 3D structure of 12a in Scheme 2).
Scheme 3. Synthesis of 17
We next focused on advancing the intermediate 13
(
Scheme 3). To generate ketone 17, it was essential to
perform an oxidative one-carbon degradation of 13. Scheme
illustrates our strategy involving a selective DIBAL-H
4
reduction of 13 to alcohol 15, an oxidative of the alcohol into
aldehyde 16, and a copper-dipyridine mediated oxidative
11
deformylation to give 17 in 85% yield.
Having assembled the [5,7]-bicyclic core structure, we
turned our attention to completing the total synthesis as
illustrated in Scheme 4. Thus, 17 was first treated with
(trimethylsilyl)ethynyl)lithium to afford a tertiary alco-
hol 18, which upon treatment with Otera catalyst
[ BuSn(NCS) ] O in toluene, generated lactone 19 after
2 2
TBAF-mediated desilylation.
We then designed two reactions independent of each other
to achieve the total synthesis (Scheme 4). We first explored
21
olefin-exchange metathesis as a key step toward the total
The annulated products11a and 11b were obtained in 76%
combined yield. While the yield for the annulated products
was fine, the trans/cis stereoselectivity was unsatisfactory
n
13
(
ca. 1:1, trans/cis). We then ran the reaction in the presence
t
of BuOH (10 equiv) without addition of HMPA, and the
reaction turned out to be very slow. We finally performed
the annulation reaction in the presence of HMPA (10 equiv)
synthesis. To this end, 19 was converted into its correspond-
ing acetate 20 in 75% yield by treatment with Sc(OTf) /
3
t
without addition of BuOH. To our delight, the desired
product 11a was formed as the major product (ca. 10:1,
trans/cis). Subsequently, after the silylation with TMSOTf/
22
Ac O, and the formed acetylene in 20 was selectively
2
(
20) Inui, M.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2007, 9, 469.
(
21) (a) Choi, T.-L.; Lee, C. W.; Chatterjee, A. K.; Grubbs, R. H.
J. Am. Chem. Soc. 2001, 123, 10417. (b) Wang, Y.; Romo, D. Org. lett.
002, 4, 3231. (c) Morita, A.; Kuwahara, S. Tetrahedron Lett. 2007, 48,
3163.
(22) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Am.
Chem. Soc. 1995, 117, 4413.
2
(
19) (a) Flowers, R. A., II. Synlett 2008, 1427. (b) Dahlen, A.;
Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393. (c) Hutton, T. K.;
Muir, K.; Procter, D. J. Org. Lett. 2002, 4, 2345.
2
632
Org. Lett., Vol. 13, No. 10, 2011

TBAF desilylation followed by acetylation with in situ
removal of MEM group, the target product 1 was
obtained in 80% as a racemic form. The synthetic
Scheme 4. Synthesis of Compound 20
1
material has been fully characterized, and its H NMR
1
and C NMR spectra are identical to those of the
3
5
natural products.
Scheme 5. Total Synthesis of Pseudolaric Acid A
hydrogenated to give 21 in 76% yield. While various cross-
metathesis conditions were screened for the coupling of 21
and 22, unfortunately, none generated the desired pseudo-
laric acid A (1). In most of these cases, only the homocoupling
product of 22 was obtained.
We then attempted a strategy to make pseudolaric acid
A via a Sonogashira reaction, followed by selective hydro-
genation as key steps. To this end, acetylene 19 was
coupled with vinyl iodide 23 under the typical Sonogashira
reaction conditions. As a result, enyne 24 was generated in
In summary, we have developed a concise approach for
the stereoselective synthesis of 1 with the unusual trans-
fused [5À7]-bicyclic core in 16 steps involving a SmI -
2
mediated intramolecular alkene ketyl radical cyclization
and a ring closing metathesis (RCM) reaction as key steps.
The work described herein exhibits a robust synthetic
strategy for the rapid construction of the core structure
of pseudolaric acids, which expectedly may be exploited to
yield various analogues of pseudolaric acids. Asymmetric
total synthesis of pseudolaric acid A based upon these key
findings is currently underway in our laboratory.
9
6% yield. However, when enyne 24 was subjected to the
action of several known selective hydrogenation protocols,
the desired product could not be generated.
We ultimately elected to synthesize the target molecule 1
via an HWE reaction as the key reaction (Scheme 5). To
2
this end, ketone 17 was reacted with BnOCH Li to give a
3
2
tertiary alcohol in 87% yield, which subsequently under-
went lactonization by the treatment with Otera catalyst to
furnish lactone 25 in 78% yield in two steps.
Acknowledgment. This work was funded by the Na-
tional Science Foundation of China (Grant Nos.
20225318, 20325208, and 20902007). We also thank the
National Science and Technology Major Project “Devel-
opment of Novel Vaccines, Antibodies and Therapeutic
Agents against Influenza Infection” (2009ZX10004-016),
the National Basic Research Program of China (973
Program, Grant No. 2010CB833201), and the Shenzhen
Basic Research Program (Nos. JC200903160352A,
JC201005260097A, and CXB201005260053A).
The observed diastereoselectivity thereof was presum-
ably attributed to the chelation of catonic lithium with
ketone and the carbonyl of methyl ester (see 17a in
Scheme 5), which guided the nucleophile to attack the
ketone from its top face with less steric hindrance.
2
4
25
Finally, a deprotection Àoxidation sequence effi-
ciently transformed 25 to 26, which was then reacted
with an HWE reagent 27 to afford product 28. After
(
23) (a) Verma, V. A.; Arasappan, A.; Njoroge, F. G. Tetrahedron
Supporting Information Available. Experimental pro-
Lett. 2010, 51, 4284. (b) Kaufman, T. S. Synlett 1997, 1377. (c) Johnson,
C. R.; Medich, J. R. J. Org. Chem. 1988, 53, 4131.
1
13
cedures and H and C NMR spectra, as well as X-ray
data for compound 14 (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(24) Majetich, G.; Grove, J. L. Org. Lett. 2009, 11, 2904.
(25) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1
994, 639.
Org. Lett., Vol. 13, No. 10, 2011
2633