Development of an expedient intramolecular Pauson-Khand reaction approach to stereoselectively construct the trans-decalin with a C1 quaternary chiral center

Article abstract of DOI:10.1039/c3cc45170d

Stereoselective synthesis of the trans-decalin subunit with a defined C1 quaternary chiral center has been achieved by the Pauson-Khand reaction (PKR) as a key step. The developed chemistry offers an alternative to the IMDA reaction that has been used for the syntheses of trans-decalin based biologically active natural products. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc45170d

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Development of an expedient intramolecular Pauson–
Khand reaction approach to stereoselectively construct
the trans-decalin with a C1 quaternary chiral center†
Li-Li Shi,a Hong-Juan Shen,a Li-Chao Fang,a Jun Huang,a Chuang-Chuang Li*a and
Zhen Yang*ab
Cite this: Chem. Commun., 2013,
49, 8806
Received 11th July 2013,
Accepted 31st July 2013
DOI: 10.1039/c3cc45170d
www.rsc.org/chemcomm
Stereoselective synthesis of the trans-decalin subunit with a defined Equisetin (4)5 was isolated from the white mold Fusarium
C1 quaternary chiral center has been achieved by the Pauson–Khand equiseti and found to have antibiotic and HIV activities.6
reaction (PKR) as a key step. The developed chemistry offers an
Because of their structural features and biological properties,
alternative to the IMDA reaction that has been used for the syn- much activity has been directed toward the chemical syntheses of
theses of trans-decalin based biologically active natural products.
these natural products, and the Diels–Alder reaction has most
commonly been used for the construction of their trans-decalin
trans-Decalin subunits occur in many biologically active natural fragments.7 However, one of the vexing problems in the synthesis
products. For example, (+)-fusarisetin A1 (1, Fig. 1) represents of trans-decalin via the Diels–Alder reaction is that of correlating
an emerging class of anti-cancer agents structurally related to the configuration of the C1 with the resident stereochemistry of the
the members of the cytochalasin family of fungal metabolites.2 polycyclic domain.8 Research in this particular area has provided
Tetrodecamycin (2)3 is isolated from methanolic extracts of considerable insights into the general synthesis of trans-decalin,
Streptomyces nashvillensis MJ885-mF8, and has activity against and shown that the chirality of this quaternary carbon center is
Gram positive bacteria. Chlorothricolide (3)4 belongs to spirotetro- heavily dependent on the substituents on the dienes and dieno-
nate antibiotics, and has activity against Gram positive bacteria. philes used in the Diels–Alder reaction. The development of
alternative strategies for the stereoselective syntheses of this type
of trans-decalin subunits is therefore highly desirable.
We recently investigated the Co-mediated Pauson–Khand reac-
tions (PKRs) of enynes for the construction of 6–6–5 tricyclic and 6–6
bicyclic skeletons. We found out that the PK reaction of enyne A was
an efficient method for synthesizing cyclopentenone B bearing a
quaternary carbon in high yield under mild conditions (Scheme 1).9
This result inspired us to explore the feasibility of generating
trans-decalin subunits in natural products (such as 1–4 in Fig. 1)
via the PKR as the key step.
We envisaged that trans-decalin C (Fig. 2) could be derived
from cyclopentenone B via oxidative cleavage of the C ring.
Cyclopentenone B, in turn, was expected to be stereoselectively
constructed from propargylic alcohol10 based enyne A via the
PKR by taking advantage of transition state A0.11 We assumed
that the methyl group occupying the axial position would accelerate
Fig. 1 Naturally occurring decalin based natural products.
coordination of its internal olefin with the alkyne–Co2(CO)6
complex moiety, giving a favorable product B. Herein we report
a Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
E-mail: chuangli@pku.edu.cn, zyang@pku.edu.cn
b Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education and Beijing National Laboratory for Molecular Science (BNLMS), and
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
† Electronic supplementary information (ESI) available: Experimental section.
CCDC 949493. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3cc45170d
Scheme 1 (TMTU)/Co2(CO)8-catalyzed Pauson–Khand Reaction.
c
8806 Chem. Commun., 2013, 49, 8806--8808
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Table 2 Syntheses of cyclopentanones 8a–8j
Reaction
time (h)
Yielda
(%)
Entry Substrate
Product
Fig. 2 Synthetic analysis.
1
10
0
0
Table 1 Synthesis of cyclopentanaphthalenone 6
2
3
4
5
6
7
8
15
10
10
15
10
20
11
Co2(CO)8
(equiv.)
Temperature
(1C)
Yield
(%)
Entry
Additive (equiv.)
75
65
57
38
40
23
1
2
3
4
5
6
7
8
9
1.2
1.2
1.2
1.2
1.2
1.2
0.95
0.5
1.2
—
110
110
110
110
110
110
110
110
110
66
32
53
54
62
80
49
40
51
CyNH2 (3)
TMTU (3)
Me2S (3)
NMO (3)
TMANO (3)
TMANO (3)
TMANO (3)
TMANO (3)/2H2O (6)
our results regarding the stereoselective construction of the
trans-decalin fragment via the PKR as the key step.
It was first necessary to develop an understanding of the scope
and limitations of the planned PK reaction, because no evidence
existed in the literature of this reaction being used for the synthesis
of cyclopentenones. Enyne 5 was selected as a substrate to perform
the reaction (see ESI† for the synthesis of enyne 5). Initially, the PK
reaction of enyne 5 was carried out with a stoichiometric amount of
Co2(CO)8 at 110 1C under a CO atmosphere, to our delight, the
desired product 6 was obtained in 66% yield (entry 1 in Table 1).
The relative stereochemistry of the C3 chiral center in 6 was
determined by examination of its NMR spectrum.
We then began to examine the effects of additives on the outcomes
of the PKRs (see Table 1 for detail). We used CyNH2 12 to cleave the Co
complex, and obtained 6 in 32% yield (entry 2). We next employed
tetramethylthiourea (TMTU)9a,13 to accelerate the PKR; however, the
reaction was sluggish (3d) with the formation of annulated product 6
in 53% yield (entry 3). We then tested Me2S14 and NMO15 as additives,
and improved yields were obtained (entries 4 and 5). We finally used
trimethylamine N-oxide (TMANO);16 we found that TMANO was the
most effective promoter for the PKR, and 6 was obtained in 80% yield
when 1.2 equiv. of Co2(CO)8 were used (entry 6). It is worthwhile
mentioning that attempts to use catalytic amounts of Co2(CO)8 or to
use TMANO/2H2O as an additive led to low yields (entries 7–9).
With the optimized annulation conditions for synthesis of cyclo-
pentanone 6 with the essential C1 quaternary chiral center in hand,
we next investigated the substituent effect on the outcomes of
the PKRs. To this end, enynes 7a–7j were made and annulated
9
6
85
75
10
10.5
a
Isolated yield.
c
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(entries 6, 7, and 10).
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the S configuration occupy favorable equatorial positions in the pro-
posed chair-like transition state (see Fig. 2). (4) A low yield was
obtained when C3 did not have an alkoxyl group (entry 8). (5) Replace-
ment of the cyclohexene moieties in the enynes (entries 3–8) with
cyclohexane moieties (entries 9 and 10) improved the yields.
Since compounds 8c–8j hold the tricyclic cyclopentenone of
(+)-fusarisetin A (1), thus, the developed synthetic strategy, featuring
the PK reaction, opens up an alternative and novel pathway for the
total synthesis of (+)-fusarisetin A (1).17 To further explore the
synthetic utility of the developed PKR in the construction of decalin
subunits in natural products, such as 2–4 (Fig. 1), we selected 8j as a
test substrate for its synthetic transformation into decalin 10. To
this end, 8j was converted into its corresponding silyl ether, followed
by oxidation with oxone in the presence of 18-crown-6 and NaHCO3
to afford the hydroxyl ketone 9 as a pair of diastereoisomers in 88%
yield over two steps. Thus, after oxidative cleavage with Pb(OAc)4, 9
was successfully converted to aldehyde 10 in 52% yield (Scheme 2).
In conclusion, we have developed a novel and concise method
for stereoselective syntheses of cyclopentanones 6 and 8c–8j, using
an intramolecular PKR as the key step. We have also achieved the
synthetic transformation of cyclopentenone 6 into decalin 10 with
the essential C1 quaternary stereogenic center. The developed
chemistry offers an alternative to the IMDA reaction that has been
used for the syntheses of trans-decalin based natural products, and
is applicable to their analogue synthesis for biological evaluation.
This work was supported by the National Science Foundation of
China (Grant no. 91013004), National 973 Program (2012CB722602)
and 863 Program (2013AA092903).
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8808 Chem. Commun., 2013, 49, 8806--8808
This journal is The Royal Society of Chemistry 2013