A strong-base induced [4 + 2] cycloaddition of homophthalic anhydrides with enolizable enones: A direct and efficient synthesis of peri-hydroxy aromatic compounds

Article abstract of DOI:10.1039/a807095d

A direct and efficient synthesis of peri-hydroxy aromatic compounds via a strong-base induced [4 + 2] cycloaddition of homophthalic anhydrides with α-phenylsulfinyl enolizable enones has been accomplished.

Full text of DOI:10.1039/a807095d

A strong-base induced [4+2] cycloaddition of homophthalic anhydrides with
enolizable enones: a direct and efficient synthesis of peri-hydroxy aromatic
compounds
Namakkal G. Ramesh, Kiyosei Iio, Akiko Okajima, Shuji Akai and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka 565-0871, Japan.
E-mail: kita@phs.osaka-u.ac.jp
Received (in Cambridge, UK) 11th September 1998, Accepted 28th October 1998
A direct and efficient synthesis of peri-hydroxy aromatic
compounds via a strong-base induced [4+2] cycloaddition of
homophthalic anhydrides with a-phenylsulfinyl enolizable
enones has been accomplished.
typical experiment, to a slurry of NaH in dry dioxane was added
a solution of homophtahlic anhydride 1a in dioxane. The
resulting slurry was stirred at room temperature for 30 min and
then for 20 min each at 80 °C and 120 °C (bath temperature).
Enone 2a was then added and the reaction mixture was stirred
for 20 min., cooled, quenched with aq. NH4Cl and extracted
with EtOAc. The crude reaction mixture, after evaporation of
the solvent, was treated with Ac2O and pyridine and left
overnight at room temperature. Column chromatography af-
forded the peri-hydroxy aromatic compound as its acetate 3a.
Subsequently, all the reactions were performed using the same
conditions, except for the final reaction time.
In the past two decades, considerable effort has been devoted to
the synthesis of biologically important polycyclic peri-hydroxy
aromatic compounds which include anthracyclines,1 freder-
icamycin A,2 granaticin,3 bostrycin,4 olivin5 and other poly-
cyclic antibiotics. Among the methods known for the construc-
tion of the key peri-hydroxy aromatic frameworks,6 the
strong-base induced [4+2] cycloaddition reaction of homo-
phthalic anhydrides to dienophiles7 continues to dominate, due
to the generality and efficiency of the reaction as well as ready
accessibility of the starting materials. An added advantage is the
direct synthesis of peri-hydroxy compounds in a single step.
The applicability of this methodology has already been realized
in the total synthesis of a variety of natural products such as
anthracyclines,1i,8 galtamycinone9 and dynemicin A.10 How-
ever, all these examples utilize non-enolizable dienophiles such
as quinone-type compounds or a,b-unsaturated esters.7b On the
other hand, the strong-base induced reaction of homophthalic
anhydride with enolizable enones such as cyclohex-2-en-1-one
or its b-substituted derivatives did not give any of the
cycloaddition products7b although in some cases the expected
product was obtained in low yield.11 This is probably due to
extensive enolization under the basic reaction condition, which
might in turn retard the cycloaddition step.
This base catalyzed [4+2] cycloaddition reaction was found
to be general for a range of substituted homophthalic anhydrides
1a–d as well as with different sulfinyl substituted enones 2a–e,
including that having an acetal functional group, affording the
respective products in moderate to good yields (Table 2).
Noteworthy is the success of the reaction with acyclic enone 2e,
which is a rewarding result given the report that no reaction was
observed between homophthalic anhydride and methyl but-
2-enoate.11a It is highly relevant that the reactions of homo-
phthalic anhydrides 1a and 1b with cyclohex-2-en-1-one and
cyclopent-2-en-1-one were not successful. The reactions under
identical conditions resulted only in complex mixtures and no
useful product could be isolated, indicating the possibility of a
base-induced enolization in these cases. Thus, it is clearly
evident that the sulfinyl group present at the a-position of the
enone moiety plays an important role in directing the course of
the reaction. Furthermore, the highlight of the reaction is the
rapid syn-elimination of the phenylsulfinyl moiety under the
reaction conditions, a unique characteristic of this functional
group,7d providing directly the peri-hydroxy aromatic com-
pounds in a single step. The advantages of the sulfinyl group are
emphasized by the fact that the strong-base induced reaction of
homophthalic anhydride with 2-bromocyclohex-2-en-1-one
was not successful. Reaction of 1a with 2-bromocyclohex-2-en-
1-one, under identical conditions for 7 h, afforded after
acylation acetate 3e in only 7% yield with the recovery of a
large amount of unreacted bromocyclohexenone. Use of an
additional equivalent of base (2.2 equiv.) in order to bring about
the trans-elimination of HBr from a possible non-aromatized
cycloadduct, did not lead to any significant improvement in the
yield. The reaction afforded, after 3 h, the acetate 3e in only
10% yield.
Since the discovery of this reaction by us in 1982,7a we have
been engaged in developing its variants and utilizing this
methodology for the synthesis of natural compounds. We have
now extended this reaction to enolizable enones. We reasoned
that the aforesaid problem could be readily overcome by the
introduction of a suitable functional group at the a-position of
the enone moiety which should be electron deficient in order to
increase dienophilicity and should also behave as a leaving
group, to provide directly the peri-hydroxy aromatic com-
pounds.
A number of functional groups such as Br, SPh, S(O)Ph,
SO2Ph were considered and among them, the sulfinyl group,
which fulfils the above-mentioned criteria, was found to be the
substituent of choice. Here we report an efficient, strong-base
induced [4+2] cycloaddition of various homophthalic anhy-
drides with a-sulfinyl substituted enones providing directly the
peri-hydroxy aromatic compounds in moderate to good
yields.
The homophthalic anhydrides 1a–d were prepared according
to the reported method.7 The strong-base induced reaction of
homophthalic anhydride 1a with 2-phenylsulfinylcyclopent-
2-en-1-one 2a was investigated in detail in order to optimize the
reaction conditions. Similar to our earlier work,7d we have
found that NaH is more suitable than other bases (ButOK, LDA
etc.). As can be seen from Table 1, among the various sets of
reaction conditions tried, use of 1.1 equiv. of NaH in refluxing
dioxane was adjudged the best, affording after acylation the
peri-hydroxy compound as its acetate 3a in good yield. In a
Table 1 Reaction of homophthalic anhydride 1a with the enone 2a in the
presence of NaH under various conditions
Yield of
Entry
Solvent
T/°C
Time
3aa (%)
1
2
3
4
THF
THF
room temp.
reflux
25 h
20
41
45
62
15 min
20 min
20 min
1,2-diethoxyethane reflux
1,4-dioxane reflux
a Isolated yields after column chromatography
Chem. Commun., 1998, 2741–2742
2741

Table 2 NaH induced [4+2] cycloaddition reaction of various homophthalic anhydrides 1 with different sulfinyl substituted enones 2 in refluxing
dioxane
R1
O
O–
O
R1 AcO
O
S
R5
R5
(i) NaH, dioxane 120 oC (bath temp.)
O
Ph
+
+
R4
R4
(ii) Ac2O, pyridine, room temp., overnight
O
R3
R3
R2
1a–d
R2
3a–n
2a–e
Homophthalic anhydride
Dienophile
Product
3
Entry
1
1
R1
H
R2
2
R3
R4
R5
H
H
H
H
H
H
H
H
H
t/min
Yield (%)a
1a
1b
1c
1d
1a
1b
1c
1a
1b
1a
1b
1a
1b
1c
H
2a
2a
2a
2a
2b
2b
2b
2c
2c
2d
2d
2ec
2ec
2ec
–CH2–
–CH2–
–CH2–
–CH2–
20
20
20
20
20
20
20
20
20
3a
3b
3c
62
58
59
56
70
58
62
60
52
63
57
49
48
41
2
H
SPh
OMe
H
3
H
4
OBn
H
3d
3e
5
H
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)3–
–(CH2)3–
–(CH2)2–
–(CH2)2–
H
6
H
SPh
OMe
H
3f
7
H
3g
3h
3i
8
H
9
H
SPh
H
10
11
12
13
14
H
(CH2)2Xb 20
(CH2)2Xb 20
3j
H
SPh
H
3k
3l
H
Ph
Ph
Ph
H
H
H
90
H
SPh
H
180
210
3m
3n
H
OMe
H
a Isolated yields after column chromatography. b X = 1,3-dioxan-2-yl. c E:Z = ca. 6:1 mixture.
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The generality and efficiency of the reaction, ready availabil-
ity of the starting materials coupled with the unique activating
as well as leaving ability of the sulfinyl group renders this
method an attractive one for the synthesis of peri-hydroxy
aromatic compounds using enolizable enones. The application
of this methodology for the synthesis of natural products is in
progress and will be reported in a forthcoming paper.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science and Culture,
Japan (08245101) and Special Coordination funds of the
Science and Technology Agency of Japanese Govrnment. We
are grateful to the Japan Society for the Promotion of Science
for a postdoctoral fellowship to N. G. R.
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Communication 8/07095D
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Chem. Commun., 1998, 2741–2742