A highly efficient synthesis of the FGH ring of micrandilactone A. application of thioureas as ligands in the co-catalyzed Pauson-Khand reaction and Pd-catalyzed carbonylative annulation

Article abstract of DOI:10.1021/ol047394+

(Chemical Equation Presented) The functionalized FGH ring system of micrandilactone A was successfully constructed in high selectivity and good yields. The key reactions in our strategy are the Co-thiourea-catalyzed stereoselective, intramolecular Pauson-

Full text of DOI:10.1021/ol047394+

ORGANIC
LETTERS
2
005
Vol. 7, No. 5
85-888
A Highly Efficient Synthesis of the FGH
Ring of Micrandilactone A. Application
of Thioureas as Ligands in the
8
Co-catalyzed Pauson−Khand Reaction
and Pd-Catalyzed Carbonylative
Annulation
†
†
†
†
†
Yefeng Tang, Yandong Zhang, Mingji Dai, Tuoping Luo, Lujiang Deng,
,
†
,†,‡
Jiahua Chen,* and Zhen Yang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, College of Chemistry, Beijing 100871, China, Laboratory of Chemical
Genetics, Shenzhen Graduate School of Peking UniVersity, The UniVersity Town,
Shenzhen 518055, China, and ViVoQuest, Inc., 711 ExecutiVe BouleVard,
Valley Cottage, New York 10989
zyang@pku.edu.cn
Received December 20, 2004
ABSTRACT
The functionalized FGH ring system of micrandilactone A was successfully constructed in high selectivity and good yields. The key reactions
in our strategy are the Co thiourea-catalyzed stereoselective, intramolecular Pauson Khand reaction and Pd thiourea-catalyzed stereoselective,
−
−
−
intramolecular annulation.
Micrandilactone A (1) (Figure 1) was isolated from Scutel-
laria micrantha, a medicinal plant native to Yunnan province
of China, which was traditionally used for the treatment of
rheumatic lumbago and traumatic injury and related diseases.
The structure of micrandilactone A (1) has been confirmed
Micrandilactone A (1) is distinguished by its novel
triterpene framework, and a dense pattern of oxygenated
functionality. The molecule is bounded by 27 atoms of
carbon and oxygen. Thirteen carbons are stereogenic, and
1
4 carbons bear some forms of oxygenation. The biosyn-
thetically modified eight-membered D ring linked by a ketal
presents the potential problem for its synthesis with regard
to its unfavorable entropy, bond angle deformations, and
by spectroscopic data in conjunction with a single-crystal
X-ray analysis.1
†
Peking University.
VivoQuest, Inc.
(1) Li, R.; Zhao, Q.; Li, S.; Han, Q.; Sun, H.; Lu, Y.; Zhang, L.; Zheng,
Q. Org. Lett. 2003, 5, 1023.
‡
1
0.1021/ol047394+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/08/2005

Figure 2. Synthesis of FGH ring 8.
onstrated chemistries illustrate the feasibility of our proposed
synthetic strategy toward the total synthesis of micrandilac-
tone A.
Scheme 1 summarized the synthesis of 6 by the Co-
mediated PKR. The synthesis of enyne 5 commenced with
2 8
Scheme 1. Co CO -Mediated PKR To Synthesize 6
Figure 1. Retrosynthetic analysis of micrandilactone A.
destabilizing transannular interactions created by this medium
2
sized ring. Therefore, micrandilactone A (1) is a challenging
and attractive target for total synthesis.
Figure 1 shows the bond disconnections that lead to a
convergent strategy employed in our synthetic program.
Retrosynthetic disassembly of micrandilactone A (1) leads
to 2 by cleavage of three C-O bands and two C-C bonds.
Synthetically, these bonds could be assembled by a tandem
ketalization and the Pd-catalyzed carbonylative annulation,
followed by methylation to install the methyl group at C-25.
Compound 2 in turn could be retrosynthetically traced back
to 3 and 4, which have the necessary functionalities to affect
the subsequent union of 3 and 4 through the Wittig reaction
diol 9, which was first protected as its mono-TPS ether, and
then reacted with acid 10. Thus, 6 was obtained in 80% yield
7
2 8
by treatment of 5 with Co CO (1.2 equiv).
However, there were two major issues associated with this
PKR. First, although the above Co-mediated intramolecular
PKR works well, an excess amount of Co
used to ensure high yield, which is too expensive for total
synthesis. Second, the quality of commercially available Co
CO is sometimes unreliable, making it difficult to use for a
large-scale synthesis.
2 8
CO had to be
2
-
3
to form the top C11-C12 bond, and the olefin metathesis
8
4
or McMurry coupling to form the bottom C15-C16 bond
of the eight-membered D ring. Thus, the resulting D ring
could be utilized to construct diketone 2.
We report herein an efficient synthetic approach to
stereoselectively construct the framework of FGH ring
(
5) Recent reviews of the Pauson-Khand reaction: (a) Schore, N. E. In
ComprehensiVe Organometallic Chemistry II; Hegedus, L. S., Ed.; Perga-
mon: Oxford, 1995; Vol. 12, p 703. (b) Geis, O.; Schmalz, H. G. Angew.
Chem., Int. Ed. 1998, 37, 911. (c) Jeong, N. In Transition Metals In Organic
Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany,
(
Figure 2), featuring the Co-thiourea-catalyzed intra-
1
998; Vol. 1, p 560. (d) Brummond, K. M.; Kent, J. L. Tetrahedron 2000,
5
molecular Pauson-Khand reaction (PKR), and the Pd-
thiourea-catalyzed tandem alkoxycarbonylation. The dem-
56, 3263. (e) Bo n˜ aga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 60, 9795.
(6) (a) James, D. E.; Stille, J. K. J. Am. Chem. Soc. 1976, 98, 1810. (b)
Semmelhack, M. F.; Bozell, J. J.; Sato, T.; Wulff, W.; Spiess, E.; Zask, A.
J. Am. Chem. Soc. 1982, 104, 5850. (c) Semmelhack, M. F.; Bodurow, C.;
Baum, M. Tetrahedron Lett. 1984, 25, 3171. (d) Tamaru, Y.; Kobayashi,
T.; Kawamura, S.-I.; Ochiai, H.; Hojo, M.; Yoshida, Z.-I. Tetrahedron Lett.
1985, 26, 3207. (e) Semmelhack, M. F.; Epa, W. R.; Cheung, A. W.-H.;
Gu, Y.; Kim, C.; Zhang, N.; Lew, W. J. Am. Chem. Soc. 1994, 116, 7455.
(f) Gracza, T.; J a¨ ger, V. Synthesis 1994, 1359. (g) Boukouvalas, J.; Fortier,
G.; Radu, I.-I. J. Org. Chem. 1998, 63, 916. (h) Paddon-Jones, G. C.;
McErlean, C. S. P.; Moore, C. J.; K o¨ nig, W.; Kitching, W. J. Org. Chem.
2001, 66, 7487.
6
(2) (a) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95. (b)
For an review, see: Patasis, N. A.; Patane, M. A. Tetrahedron 1992, 48,
5
757.
(3) (a) Schwab, P.; Grubbs, R. H. Ziller, J. W. J. Am. Chem. Soc. 1996,
1
18, 100. (b) O′Dell, R.; McConville, D. H.; Hofmeister, G. E.; Schrock,
R. R. J. Am. Chem. Soc. 1994, 116, 3414. (c) F u¨ rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012. (d) Tsang, P. W. C.; Jernelius, J. A.; Cortez, G.
A.; Weatherhead, G. S.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2003, 125, 2591.
(7) (a) Marco-Contelles, J.; Ruiz, J. Tetrahedron Lett. 1998, 39, 6393.
(b) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263. (c) Bo n˜ aga,
L. V. R.; Krafft, M. E. Tetrahedron 2004, 60, 9795.
(
4) (a) McMurry, J. E. Chem. ReV. 1989, 89, 1513. (b) McMurry, J. E.
Acc. Chem. Res. 1983, 16, 405.
886
Org. Lett., Vol. 7, No. 5, 2005

We recently reported that thiourea is an effective ligand
8
in the Pd-catalyzed carbonylation reactions. The observed
Scheme 4. Carbonylative Annulation of 13
beneficial effect of thiourea as a ligand to incorporate CO
into scaffolds prompted us to apply it in the catalytic PKR.
To this end, we identified TMTU (tetramethyl thiourea) as
9
an effective ligand in the co-catalyzed PKR, and under the
optimal conditions 6 was obtained in 75% yield (Scheme
2).
Scheme 2. Pd-Thiourea-Catalyzed PKR To Synthesize 6
This failure led us to explore thioureas A11 (Scheme 4) as a
ligand in this Pd-catalyzed carbonylative annulation due to
its successful employment in our carbonylative reactions.8
The reaction proceeded as indicated in Scheme 4. As
expected, the desired product 15 was formed in 25% yield,
together with 30% of 16. Though a variety of conditions
were screened, no improvement was observed. Interestingly,
when we used 14 as a substrate, 16 was formed exclusively
under identical conditions.
Realizing an effective way to synthesize 6, we started to
work on the construction of FGH ring 8 (Figure 2). To this
end, 6 was first converted to its corresponding alcohol by
Luche reduction and then silylated with TBSCl and imidazole
to give 11 in 89% overall yield. Compound 11 was further
reduced with DIBAL-H, and the resulting alcohol was
c,8d
oxidized with MnO
of 12 with vinylmagnesium bromide afforded 13 and 14 in
6% yield as diastereoisomers. The stereochemistry of 13
2 2
in Et O to give aldehyde 12. Vinylation
8
Based on our proposed mechanistic interpretation,12 the
double bond in cyclopentene 13 seems to be detrimental to
the desired reaction, and its removal would be beneficial.
Thus, we transformed 13 into its corresponding epoxide 7
was established by a NMR study of its derivative (see the
Supporting Information for details), and its counterpart 14
was converted to 13 by an oxidation-reduction process
(Scheme 3).
by regioselective epoxidation with m-CPBA in CH
our delight, compound 8 was obtained in 95% yield (Scheme
) when 7 was reacted under the optimized carbonylative
2 2
Cl . To
5
Scheme 3. Synthesis of Compound 13
conditions (see the Supporting Information).
Scheme 5. Synthesis of Compound 8
The stereochemistryof the synthesized compound 8 was
confirmed by spectroscopic data in conjunction with single-
crystal X-ray analysis (Figure 3).
(8) (a) Yang, N.; Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297. (b) Miao,
H.; Yang, Z. Org. Lett. 2000, 2, 1765. (c) Dai, M.; Wang, C.; Dong, G.;
Xiang, J.; Luo, Y.; Liang, B.; Chen, J.; Yang, Z. Eur. J. Org. Chem. 2003,
4
346. (d) Dai M.; Liang, B.; Wang, C.; You, Z.; Xiang, J.; Dong, G.; Chen,
J.; Yang, Z. AdV. Synth. Catal. 2004, 346, 1669.
9) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org.
Lett. in press.
(
With 13 in hand, we then tested its Pd-catalyzed carbon-
ylative cyclization. However, our attempts to obtain 15 from
3 (Scheme 4) under the previously reported catalytic
(10) (a) Semmelhack, M. F.; Bozbll, J. J.; Keller, L.; Sato, T.; Spiess,
E. J.; Wulff, W.; Zask, A. Tetrahedron 1985, 41, 5803. (b) Kraus, G. A.;
Li, J.; Gordon, M. S.; Jensen, J. H. J. Am. Chem. Soc. 1993, 115, 5859. (c)
Hayes, P. Y.; Kitching, W. J. Am. Chem. Soc. 2002, 124, 9718.
1
1
0
system in THF under atmospheric pressure of CO at 50
C were unsuccessful due to complete decomposition of 13.
(11) Dai, M.; Liang, B.; Wang, C.; Chen. J.; Yang. Z. Org. Lett. 2004,
°
6, 221.
Org. Lett., Vol. 7, No. 5, 2005
887

Acknowledgment. We gratefully acknowledge financial
support of this work by the National Science Foundation of
China (Grants 20472002 and 20325208) and VivoQuest, Inc.,
through the sponsored research program.
Supporting Information Available: Experimental pro-
1
3
cedure and NMR and C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL047394+
(12) To understand the formation of compounds 15 and 16, we proposed
the following catalytic cycle. Although less evident. we speculated that the
overall process for the formation of 15 may involve the attack of 13 on the
PdCl2 to generate complex A, followed by insertion of CO to give
intermediate B. Intramolecular nucleophilic addition of the primary alcohol
to the resulting acylpalladium complex B leads to formation of intermediate
D through C, which might undergo reductive elimination to produce the
five-membered lactone 15 and palladium(0). The palladium(0) is then
oxidized with CuCl2 to palladium(II), completing the catalytic cycle. On
the other hand, the resulting intermediate B in the above catalytic cycle
might also competitively undergo the allylic rearrangement to afford E,
which could lead to formation of 16 through the downstream addition-
elimination process, followed by chloride displacement of the activated
homoallylic alcohol F. The proposed catalytic cycle is shown below:
Figure 3. X-ray structure of compound 8.
We then moved to the stage to construct 18 with the
essential functionalities presented in FGH ring of micrandi-
lactone A. To achieve a mild condition to generate diol 18
from its epoxide precursor 8, we first carried out desilylation,
and the resulting primary alcohol was then selectively
protected as its silyl ether. Thus, the remained secondary
alcohol could be selectively oxidized to ketone 17 by Dess-
Martin periodide. As a result, this activated epoxide ring
opened fairly easily, and the reaction was expected to occur
through the S
treatment of 17 with silica gel (Scheme 6).
N
2-type trans-opening to give the diol 18 by
13
Scheme 6. Synthesis of Compound 8b
In summary, a convergent approach for the construction
of the FGH ring system of micrandilactone A (3 rings, 6
stereogeneic carbons including 2 quartery carbons) was
successfully accomplished in 15 steps. We demonstrated the
unique role of thioureas in the co-catalyzed stereoselective,
intramolecular PKR and the Pd-catalyzed stereoselective,
intramolecular alkoxycarbonylation. The illustrated chem-
istries show the feasibility of our proposed strategy toward
the total synthesis of micrandilactone A, which is currently
underway in our laboratories.
(
13) (a) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983,
9, 2323. (b) Hanson, R. M. Chem. ReV. 1991, 91, 437. (c) Kotsuki, H.;
Shimanouchi, T.; Ohshima, R.; Fujiwara, S. Tetrahedron 1998, 54, 2709.
3
888
Org. Lett., Vol. 7, No. 5, 2005