Selective transformations of carbonyl functions in the presence of α,β-unsaturated ketones: Concise asymmetric total synthesis of decytospolides A and B

Article abstract of DOI:10.1021/ol501463p

Enones selectively react with a combination of PPh₃ and TMSOTf to produce phosphonium silyl enol ethers, which work as protective groups of enones during the reduction of other carbonyl functions and can be easily deprotected to regenerate parent enones at workup. Furthermore, the first ketone selective alkylations in the presence of enones were also accomplished. This in situ protection method was applied to concise asymmetric total syntheses of decytospolides A and B.

Full text of DOI:10.1021/ol501463p

Letter
pubs.acs.org/OrgLett
Selective Transformations of Carbonyl Functions in the Presence of
α,β-Unsaturated Ketones: Concise Asymmetric Total Synthesis of
Decytospolides A and B
Kenzo Yahata, Masaki Minami, Kei Watanabe, and Hiromichi Fujioka*
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: Enones selectively react with a combination of
PPh3 and TMSOTf to produce phosphonium silyl enol ethers,
which work as protective groups of enones during the
reduction of other carbonyl functions and can be easily
deprotected to regenerate parent enones at workup.
Furthermore, the first ketone selective alkylations in the
presence of enones were also accomplished. This in situ protection method was applied to concise asymmetric total syntheses of
decytospolides A and B.
ontrol of the reactivity of individual functional groups in
related carbonyl functions, ketones, and enones, there is no
Corganic compounds is a very important issue in organic general method for selective reduction of carbonyl functions in
the presence of α,β-unsaturated enones, let alone the method
for selective alkylation.
In our previous studies, we have developed procedures for
reversing the reactivity of carbonyl functions that relies on the
use of a combination of TMSOTf and phosphines to
temporarily protect aldehydes and ketones (Scheme 1 a).3 In
synthesis. For example, it is well-known that the order of
reactivity of carbonyl groups toward nucleophiles is generally
aldehyde > ketone > ester. Therefore, it is easy to react an
aldehyde in the presence of ketones and esters. In contrast, it is
difficult to react a ketone prior to an aldehyde. For the
achievement of such transformation, in some cases in situ
protection methods have been developed to alleviate this
problem,1 although intrusive multistep operations involving the
introduction and removal of protective groups are usually
required. However, in situ protection methods do not exist for
discriminating between two functions that have similar
reactivity, and then it is difficult to design selective reaction
for one of these two.
Scheme 1. In Situ Protection Method for Selective
Transformation
Ketones and α,β-unsaturated ketones display nearly identical
reactivity, although ketones generally have slightly higher
reactivity toward nucleophiles than enones. In the past, only
three different methods have been reported to describe
selective reductions of ketones in the presence of enones.2
Ward et al. described a ketone-selective reduction in the
presence of enones using NaBH4 in MeOH/CH2Cl2.2a Ranu et
al. realized that Zn(BH4)2 in DME can also be employed to
perform selective reductions of ketones.2b Although these
methods are applicable to selective reductions of aliphatic
ketones, they cannot be used to differenciate aromatic ketones
from enones owing to their highly similar reactivities. Maruoka
et al. described a procedure for chemoselective reductions of
saturated aldehydes and a ketone in the presence of unsaturated
carbonyls that employs a bulky tin hydride and Lewis acid.2c
Although this method was effective in the discrimination of
aldehydes, the yield of the ketone reduction was moderate. In
addition, the key organotin reagent needs to be prepared using
a multistep sequence.
these processes, aldehydes and ketones are temporarily
protected by being O,P-acetal-type phosphonium salt inter-
mediates. In the course of this study, we found that the PPh3
and TMSOTf combination, even when used in excess, does not
transform ketones to their corresponding phosphonium salts.
On the other hand, Kozikowski et al.,4a Kim et al.,4b and Lee et
al.4c separately reported β-alkylation reactions of enones using
PPh3 and TBSOTf take place via initial phosphoniosilylation
processes. We then expected that the combination of PPh3 and
silyl triflate would react with α,β-unsaturated ketones selectively
in the presence of ketones. Although the phosphonium salts
were generated as reactive intermediates in the previous
As described above, although there are a few methodologies
succeeding in the selective transformation between closely
Received: May 21, 2014
Published: July 9, 2014
© 2014 American Chemical Society
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a
Table 1. Optimization of the Reaction Conditions
b
c
entry
R3SiOTf (equiv)
PPh3 (equiv)
reducing conditions
1a (%)
3a (%)
d
1
TBSOTf (1.2)
TBSOTf (1.5)
TESOTf (1.5)
TMSOTf (1.5)
1.2
1.5
1.5
1.5
DIBAL-H (2.0 equiv), −78 °C
DIBAL-H (2.0 equiv), −78 °C
DIBAL-H (2.0 equiv), −78 °C
DIBAL-H (2.0 equiv), −78 °C
DIBAL-H (1.0 equiv), −78 °C
NaBH4 (4.5 equiv), −78 °C
Zn(BH4)2 (1.0 equiv), −20 °C
57
75
78
82
41
68
59
97
94
99
82
d
2
d
3
e
4
f
i
5
45
fg
i
6 ,
47
i
fh
7 ,
18
a
b
c
d
1a (0.2 mmol) and 2a (0.2 mmol) were used. Isolated yield. Allylic alcohol was formed as byproduct in all entries. Isolated yield. TBAF (2
equiv) were used at workup. K2CO3 suspension in MeOH was used at workup. Reaction was performed in the absence of PPh3 and silyl triflate.
Ward conditions. CH2Cl2/MeOH (1:1) was used as a solvent. See ref 2a. Ranu conditions. DME was used as a solvent. See ref 2b. 2a was
e
f
g
h
i
recovered.
a
Table 2. Selective Reduction of Various Carbonyl Functions in the Presence of Enones
a
b
c
1 (0.2 mmol) and 2 (0.2 mmol) were used. Isolated yields were given in the parentheses. Protection was performed on 4c (0.6 mmol) with PPh3
d
e
(1.2 equiv) and TMSOTf (1.1 equiv) in CH2Cl2 (0.4 M) at −78 °C. TBAF (2.0 equiv) was used instead of sat. K2CO3/MeOH. Protection was
performed with PPh3 (1.5 equiv) and TMSOTf (1.7 equiv).
reports,4 we presumed that if the phosphonium silyl enol ethers
could survive during the transformation of remaining ketones,
an in situ protection method for discriminating between closely
related functional groups would be established (Scheme 1 b).
We began our study on the discrimination between enone 1a
and ketone 2a (Table 1). In light of previous reports,4 we first
chose TBSOTf and PPh3 as reagents for enone protection and
DIBAL-H as the reducing agent (Table 1, entry 1). Treatment
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of a mixture of 1a and 2a first with TBSOTf and PPh3 (1.2
equiv each) and then with DIBAL-H followed by TBAF
workup led to production of the ketone-reduced alcohol 3a
(97%) along with the recovered enone 1a (57%). Increasing
the amounts of PPh3 and TBSOTf to 1.5 equiv afforded a
higher yield of recovered 1a (Table 1, entry 2). The use of
TESOTf instead of TBSOTf resulted in a slightly higher 1a
recovery (Table 1, entry 3), and when TMSOTf was employed,
1a was recovered in the highest yield by using weakly basic
solvolysis conditions (K2CO3/MeOH) (Table 1, entry 4).
Nonselective reduction took place in the absence of pretreat-
ment with PPh3 and silyl triflate (Table 1, entry 5). We also
confirmed that the conditions reported previously by the Ward
group2a and the Ranu group2b did not work effectively in these
aromatic substrates (Table 1, entries 6 and 7).
synthesis of these natural products, and those synthetic routes
involve multiple processes.8
Our synthetic route for the target natural products was
summarized in Scheme 3. Corey−Bakshi−Shibata reduction9 of
Scheme 3. Asymmetric Total Synthesis of Decytospolides A
and B
The generality of this method was explored (Table 2). The
results showed that pretreatment with PPh3 and TMSOTf can
be used to protect not only aromatic enones 1a and 1b but also
the aliphatic enone 1c in selective reductions of various ketones
2b,e,i and even the easily enolizable ketone 2h. Moreover, by
using this procedure, selective reduction of esters 2d,f,
including α,β-unsaturated ester 2j, and Weinreb amide 2g
proceeded smoothly to produce the corresponding alcohols
and aldehyde in high yields (Table 2, entries 1 and 3−9). A
pyridyl ketone 2c and unprotected indolyl ester 2k could also
be reduced selectively (Table 2, entries 2 and 10). Moreover,
acid-labile TBS and MOM groups could tolerate the reaction
conditions (Table 2, entries 5 and 8). The reaction was then
applied to the selective reduction of substrates possessing both
enone and other carbonyl moieties in the same molecule
(Table 2, entries 11−15). The ketone groups in aliphatic and
aromatic keto-enones 4a and 4b were reduced selectively to
afford the corresponding alcohols 5a and 5b in high yields
(Table 2, entries 11 and 12). In addition, even the highly
hindered ketone moiety in 4c, which also contains an acid-labile
benzylidene acetal group, was reduced in excellent yield leaving
the enone and the acetal groups intact (Table 2, entry 13). The
ester and Weinreb amide moieties in 4d and 4e were also
reduced in the presence of enone groups (Table 2, entries 14
and 15).
commercially available 2-pentyl-2-cyclopenten-1-one (9) af-
forded a chiral allylic alcohol. Protection of the hydroxyl group
with BOM group was followed by a one-pot ozonolysis−Wittig
reaction sequence to give the key keto-enone 11.10 Following
in situ protection of the enone group, diastereo- and
chemoselective reduction of ketone moiety in 11 with Red-
Al11,12 proceeded smoothly, and 12, which has desired
stereochemistry, was constructed by DBU-promoted isomer-
ization. It is notable that the chiral center in 11 was not
epimerized through this sequence of reactions. Finally, BOM
group in 12 was detached by hydrogenolysis to give
decytospolide A (7), which was acetylated to afford
decytospolide B (8). These enantioselective syntheses were
accomplished in six and seven steps from commercially
available cyclopentenone 9, with overall yields of 47% for
decytospolide A and 46% for decytospolide B.
In conclusion, a convenient and versatile in situ protection
method for enones has been developed. The process,
performed by using a combination of PPh3 and TMSOTf,
generates phosphonium silyl enol ether intermediates. This
method can be employed to discriminate between enones and
ketones. By using this procedure, the first ketone selective
alkylation reactions of a keto-enone were developed. Finally, we
demonstrated the asymmetric total synthesis of decytospolides
A and B by using the developed method as a key reaction. The
route employed for the preparation of these natural products is
the most concise and efficient of those developed thus far.
Additional investigations of the applicability of other reagents
and the protection of α,β-unsaturated carbonyl substrates
having other substituent patterns are currently underway.
Scheme 2. Ketone-Selective Allylation (eq 1) and
Reformatsky Reaction (eq 2)
It is noteworthy that the in situ protection method could also
be applied to ketone selective alkylation reactions of keto-
enone (Scheme 2). In(0)-mediated Barbier-type allylation5 and
Reformatsky reaction6 of 4a afforded the ketone-selective
alkylated products 6a and 6b, respectively, in high yields. These
are the first methods of ketone selective alkylation reactions of
keto-enones.
To demonstrate the synthetic utility of this method, we
carried out the asymmetric total synthesis of decytospolides A
(7) and B (8), which were isolated from Cytospora sp., an
endophytic fungus from Ilex canariensis.7 Decytospolide B (8)
shows in vitro cytotoxic activity toward tumor cell lines A549
and QGY. To date, two reports exist describing the total
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedures and spectroscopic data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: fujioka@phs.osaka-u.ac.jp.
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Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the Hoansha
Foundation, the Uehara Memorial Foundation, and a Grant-
in-Aid for Scientific research from the ministry of Education,
Culture, Sports, Sciences, and Technology of Japan. K.Y. is
grateful for financial support from the Japan Society for the
Promotion of Science Research Fellow
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