Diversity-oriented synthesis of fused pyran γ-lactones via an efficient Pd-thiourea-catalyzed alkoxycarbonylative annulation

Article abstract of DOI:10.1021/ol802115u

(Chemical Equation Presented) We reported herein a diversity-oriented synthesis of a range of fused pyran-γ-lactones that was effected through a versatile Pd-thiourea complex-catalyzed intramolecular alkoxycarbonylative annulation.

Full text of DOI:10.1021/ol802115u

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5163-5166
Diversity-Oriented Synthesis of Fused
Pyran γ-Lactones via an Efficient
Pd-Thiourea-Catalyzed
Alkoxycarbonylative Annulation
Zhengtao Li,† Yingxiang Gao,† Zhaodong Jiao,† Na Wu,†
David Zhigang Wang,*,† and Zhen Yang*,†,‡
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Shenzhen Graduate School of Peking UniVersity, Shenzhen 518055, China, and Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education and Beijing National Laboratory for Molecular Science (BNLMS), College
of Chemistry and the State Key Laboratory of Natural and Biomimetic Drugs, School
of Pharmaceutical Science, Peking UniVersity, Beijing 100871, China
zyang@pku.edu.cn
Received September 10, 2008
ABSTRACT
We reported herein a diversity-oriented synthesis of a range of fused pyran-γ-lactones that was effected through a versatile Pd-thiourea
complex-catalyzed intramolecular alkoxycarbonylative annulation.
Fused pyran-γ-lactones are common structural motifs among
many classes of natural products,1 and some of them possess
significant biological activities. For example, crisamicin A
(1),2 frenolicin B (2),3 medermycin (3),4 griseusin A (4),5
and BE-54238B (5)6 belong to a family of potent pyranon-
aphthoquinone antibiotics that feature prominently various
stereochemically complex fused pyran-γ-lactone core struc-
tures (Figure 1).
Among the several variants for synthesis of fused pyran-
γ-lactones,7 the Pd-mediated tandem carbonylative annula-
tion invented by Semmelhack and co-workers stands out as
a valuable synthetic method.8 The protocol offers an efficient
entry to highly functionalized fused pyran-γ-lactones B from
benzylic alcohols A (Figure 2); however, a stoichiometric
amount of Pd reagent8n,o was employed. In addition, carbo-
nylative annulation mediated by Pd(II) was thought to
proceed through an alkoxypalladium(II) intermediate9 which
may undergo oxidation to afford a ketone,10 thereby interfer-
ing with the desired annulation reaction pathway. Since we
† Shenzhen Graduate School of Peking University.
‡ Peking University.
(1) (a) Friedrichsen, W. In ComprehensiVe Heterocyclic Chemistry II;
Bird, C. W., Ed.; Pergamon Press: Oxford, 1996; Vol. 2, pp 351. (b)
Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127.
(2) Iwai, Y.; Kora, A.; Takahashi, Y. J. Antibiot. 1978, 31, 959.
(3) Bergy, M. E. J. Antibiot. 1968, 21, 454. (b) Hoeksema, H.; Krueger,
W. C. J. Antibiot. 1976, 29, 704.
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Nakata, M. J. Antibiot. 1991, 44, 901.
(7) (a) Tatsuta, K. J. Synth. Org. Chem. Jpn. 1984, 42, 497. (b) Dawe,
R. D.; Fraser-Reid, B. J. Org. Chem. 1984, 49, 522. (c) Brimble, M. A.;
Neville, D.; Duncalf, L. J. Tetrahedron Lett. 1998, 39, 5647. (d) Brimble,
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(5) Fang, X.-P.; erson, J. E.; Chang, C.-J.; Fanwick, P. E.; McLaughlin,
J. L. J. Chem. Soc., Perkin Trans 1 1990, 1655.
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S.; Kojiri, K.; Suda, H. J. Antibiot. 2000, 53, 26.
10.1021/ol802115u CCC: $40.75
Published on Web 10/16/2008
2008 American Chemical Society

Scheme 1. Possible Mechanistic Pathways Involved in Pd/
TMTU-Catalyzed Alkoxycarbonylative Annulation
Figure 1. Bioactive pyranonaphthoquinone antibiotics.
were interested in diversity-oriented synthesis of pyranon-
aphthoquinone antibiotics, further study of this powerful
reaction in a catalytic manner and profile of the reaction
scope is an essential step toward this goal. Herein we describe
that TMTU-Pd(OAc)2 is an efficient catalyst system promot-
ing carbonylative annulation for the formation of structurally
diverse fused pyran-γ-lactones.
decomposition, presumably because of its oxidative degrada-
tion.
We recently identified that TMTU (tetramethyl thiourea)
was an efficient ligand in Co2(CO)8 and PdCl2 catalyzed
Pauson-Khand reactions11 and AuCl3-catalyzed cycloalky-
lation of aryl epoxides.12 The stability of TMTU-ligated
transition-metal complexes toward air and moisture,13 to-
gether with its cheap price and commercial availability,
inspired us to explore Pd-TMTU complex in this Pd-
catalyzed carbonylative annulation.
Figure 2. Pd(II)-mediated carbonylative annulation.
The feasibility of Pd-TMTU as a unique catalyst has been
demonstrated in the construction of a fused pyran-γ-lactone,
a key intermediate in our total synthesis of crisamicin A.9
To further study catalyst precursors and solvent effect on
the outcome of this carbonylative annulation, we had
screened several catalyst precursors including Pd(OAc)2,
Our study employed compound 6 as a model substrate to
test its annulation with both stoichiometric and catalytic
amounts of palladium according to the published
procedures;8j,n,o however, we found that in most of the cases
starting material either yielded complex mixture or underwent
Table 1. Pd/TMTU-Catalyzed Annulationa
yieldb (%)
entry
catalyst system
Pd(OAc)2 (equiv)
thiourea (equiv)
time (h)
7
8
total
dr
1
2
3
4
5
Pd(OAc)2 + TMTU
PdCl2 + TMTU
Pdl2 + TMTU
[PdCl(C3H5)]2 + TMTU
PdCl2(PPh3)2 + TMTU
0.1
0.1
0.1
0.05
0.1
0.1
0.1
0.1
0.1
0.1
12
12
12
12
12
83
11
94
7.5
5.8
5.9
5.4
58 (70)c
23 (59)c
43 (66)c
10 (12)c
4 (10)c
8 (12)c
68 (82)c
27 (69)c
51 (78)c
trace
a Reaction conditions: substrate 6, PdLn (0.1 equiv), thiourea, and CuCl2 (2.5 equiv) were combined in THF, and the mixture was allowed to react under
a balloon pressure of CO at the indicated time. b Isolated yield. c Based on recovery of SM.
5164
Org. Lett., Vol. 10, No. 22, 2008

PdCl2, PdI2, PdCl2(PPh3)2, and PdCl2(dppf) in various
solvents, such as THF, benzene, DMF, and CH3CN.
Table 2. Pd/Thiourea-Catalyzed Annulationa
The catalytic activities of these Pd complexes were
examined by generating the Pd complex in situ from the
reaction of a catalyst precursor with TMTU. As indicated in
Table 1, Pd(OAc)2 was proved to be the best catalyst
precursor for the formation of TMTU-Pd(OAc)2 complex
in the presence of NH4OAc and propylene oxide (PO)9 in
THF, and lactones 7 and 8 were obtained in high yield (94%)
with a cis/trans ratio of 7.5 (entry 1).
With the optimized conditions in hand, we started to profile
the substrates’ substitutent effect (Figure 2) on the outcome
of annulation and suspected that the hydrogen at the allylic
position might play a critical role in the entire carbonylative
annulation process. We envisioned that the allylic alcohol-
derived enyl Pd complex D (Scheme 1) could undergo an
intramolecular nucleophilic addition across the double bond
to give intermediate E (path A). A sequential CO insertion-
reductive elimination events on the alkyl-Pd species E then
would deliver the fused pyran γ-lactones G and H.
On the other hand, intermediate D could either undergo a
Pd-mediated oxidation9 to yield the ketone I and various
byproducts decomposed thereafter (path B)14 or be subject
to a double-bond migration to form certain types of
intermediates which might lead to decomposition.15 Based
on this analysis, we believed that the relative rate between
paths A and B could be critical in the proposed carbonylative
annulation and the substitutent of R group should play a
pivotal role to control the speed for the formation of
intermediate E. To support our analysis, two groups of
compounds 11-14 (entries 1-4 in Table 2) and 15-18
(entries 5-8) were selected as suitable precursors to probe
the steric effect of R groups on the annulation, and their
annulated results were summarized in Table 2. In general,
the primary benzylic alcohol-derived substrates (entires 1-4)
appeared to give products in higher yields than those
secondary alcohol-derived substrates (entries 5-8). It was
worthy of noting that the substitution on the benzylic position
seemed to have a marked influence not only on the yields
but also on the reaction diastereoselectivities (entries 5-8).
A substitution at the benzylic position generally favored the
cis-lactones, and when chirality at this position was matched
with that at the allylic position, the corresponding cis-lactone
was exclusively formed (entries 6 and 8). It should be added
here that both cis- and trans-lactones were readily separated;
thus, this protocol offered a stereochemically flexible solution
to construct diverse pyran-fused lactones.16
To further confirm that the lability of intermediate D
accounts for the failure for the desired reaction, we then
synthesized substrates 17 and 18 by replacing the allylic
hydrogen with a methyl group, which would prevent the
proposed oxidative degradation. As expected, the desired
products were obtained in high yields, indicating the allylic
hydrogen indeed plays a pivotal role in the Pd-catalyzed
carbonylative annulation.
It appeared to be reasonable that in a substrate structure
an increase of steric size of its benzylic R3 group could retard
the formation of the bicyclic intermediate E, and the presence
a Reaction conditions: substrate (0.5 mmol), Pd(OAc)2 (0.05 mmol),
TMTU (0.05 mmol), CuCl2 (2.5 mmol), and NH4OAc (1.0 mmol) in THF
at 50 °C for 12 h. b Isolated yield.
Org. Lett., Vol. 10, No. 22, 2008
5165

of allylic hydrogen could promote the oxidation pathway B;
therefore, both factors under otherwise similar molecular
settings should pose a detrimental effect on reaction yield.
In summary, we have established Pd/TMTU to be an
efficient and general catalytic system in promoting alkoxy-
carbonylative annulation to generate interesting fused pyran
γ-lactones in high yields. This simple catalyst was readily
accessible and applicable to a wide range of substrates
bearing useful stereochemical information, thus advancing
this important methodology. We believe that this enabling
methodology should find utility in diversity- and target-
oriented synthesis of biologically significant pyran γ-lactone-
derived molecules.
Acknowledgment. We thank Dr. Yefeng Tang (Depart-
ment of Chemistry, The Scripps Research Institute) and Mr.
Mingji Dai (Department of Chemistry, Columbia University)
for their contributions in initiating this research program and
Professor Jacques Muzart (Universite´ de Reims Champagne-
Ardenne) for the helpful suggestion for the proposed mech-
anism of the carbonylative reaction. This work was funded
by the National Science Foundation of China (Grants
20672004 and 20521202) and the 973 Basic Science
Research Program (No.2007CB516802).
Supporting Information Available: Experimental pro-
cedure and 1H NMR and 13C NMR spectra This material is
available free of charge via the Internet at http://pubs.acs.org.
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