Enantioselective construction and utilization of 2-(cyclohex-2-enyl)phenols

Article abstract of DOI:10.1055/s-1998-1844

Enantioselective construction of 2-(cyclohex-2-enyl)phenols from chiral equivalents of cyclohex-2-enols has been investigated by employing a concurrent retro-Diels-Alder reaction and Claisen rearrangement protocol. Utilizing the enantiomerically pure product obtained, the first enantiocontrolled synthesis of a phenolic natural sesquiterpene (+)-curcudiol, isolated from the marine sponge Didiscus flavus, has been demonstrated.

Full text of DOI:10.1055/s-1998-1844

1004
LETTERS
SYNLETT
Enantioselective Construction and Utilization of 2-(Cyclohex-2-enyl)phenols
Hiroyuki Konno and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81-22-217-6845
E-mail konol@mail.cc.tohoku.ac.jp
Received 22 May 1998
Abstract: Enantioselective construction of 2-(cyclohex-2-enyl)phenols
from chiral equivalents of cyclohex-2-enols has been investigated by
satisfactory yield (72%) as the single product. Dehydration prevailed in
32
the reaction of the endo-alcohol , [α]
3a
–43.7 (c 0.6, CHCl ), not
3
D
employing
a
concurrent retro-Diels-Alder reaction and Claisen
carrying a 4-substituent to give the elimination product
as a volatile oil and only 12% yield of the desired exo-ether , [α]
4a
in 76% yield
5a
26
rearrangement protocol. Utilizing the enantiomerically pure product
obtained, the first enantiocontrolled synthesis of a phenolic natural
sesquiterpene (+)-curcudiol, isolated from the marine sponge Didiscus
flavus, has been demonstrated.
D
+7.2 (c 2.5, CHCl ), was generated. In the reaction of the exo-alcohol
3c
3
carrying an anti-4-substituent, dehydration occurred exclusively to
4
afford a mixture of the two regioisomeric olefins,
and its ∆ -isomer,
5c
without generation of the aryl ether
having the exo-syn-1,4-
4c
stereochemistry. The observed specific ether formation in the reaction of
the endo-alcohol may be due to the steric repulsion between the
1
We have encountered difficulties in preservation of the original chiral
3b
integrity of chiral allyl alcohols in their conversion into chiral 2-
endo-syn-1,4-substituents which alleviates the antiperiplanar hydrogen
and oxygen-phosphorus disposition appropriate for the E2-elimination.
2
3,4
allylphenols through a sequential Mitsunobu aryl ether formation
5,6
and Claisen rearrangement. The enantiomeric purities of the products
Meanwhile, with
and which do not have the 1,4-steric interaction,
3c
3a
4,7
were diminished considerably in both the ether formation and the
the elimination rather than the substitution occurs to give the olefins as
observed (Scheme 2).
8
rearrangement steps. In relation to our recent development of a chiral
building block serving as chiral cyclohexenone, we examined the
synthesis of chiral 2-(cyclohex-2-enyl)phenols using the chiral
cyclohexenone synthon to extend its synthetic utility as the chiral
cyclohexenol equivalent. We wish to report here an enantio- and stereo-
selective construction of 2-(6-tert-butyldimethylsiloxy-2-cyclo-
hexenyl)phenol and its conversion into a natural phenolic sesquiterpene
9
(+)-curcudiol isolated from the marine sponge Didiscus flavus.
Since one major factor leading to loss of the original enantiomeric
purity was due to the racemization in the Mitsunobu coupling using
4
allylic alcohols, we first examined the coupling between 3-
methylphenol and each of the three non-allylic chiral cyclohexanols
serving as chiral cyclohex-2-enols to avoid the allylic racemization.
Thus, the enantiomerically pure ketone (+)-2, obtained by a chiral
I
8
BINAP-Rh -catalyzed asymmetrization of the meso-endiol bis-silyl
ether 1, was first transformed into the three substrates, chiral
cyclohex-2-enol equivalent 3a and syn-1,4 and anti-1,4 substituted
chiral cyclohex-2-enol equivalents, 3b and 3c (Scheme 1).
Scheme 2
We next examined the thermolysis of the aryl ethers. For comparison,
we prepared the endo-aryl ether , which could not be obtained directly
4c
from , by employing an alternative way from the same keto-ether
3c
.
2
Thus, , after desilylation, was exposed to NBS to form the bromo
2
ketone having an ether linkage which was then reduced from the convex
31
face to give the bromohydrin , m.p. 133–134 °C, [α]
+103.0 (c 1.1,
6
D
10
CHCl ). The Mitsunobu reaction of
with 4-nitrobenzoic acid,
6
3
followed by the hydrolysis of the resulting benzoate gave the exo-
29
alcohol , [α]
+67.2 (c 1.4, CHCl ), which on the second Mitsunobu
3
7
D
reaction furnished the endo-aryl ether
as the single stereoisomer.
8
During these two-fold Mitsunobu inversions, dehydration did not take
place at all, supporting the above-mentioned 1,4-repulsion explanation.
On reductive cleavage of the bromo-ether functionality followed by
silylation of the secondary hydroxy group, yielded the endo-aryl ether
8
30
Scheme 1
, [α]
+10.0 (c 1.4, CHCl ), bearing a syn-4-substituent (Scheme
3
4c
D
3).
The Mitsunobu reaction of these non-allylic alcohols with 3-
methylphenol was carried out in the presence of two equivalents each of
With the three substrates in hand, thermolysis was carried out in boiling
diphenyl ether to initiate the concurrent retro-Diels-Alder reaction and
11
diisopropyl azodicarboxylate (DIPAD) and triphenylphosphine (TPP) in
Claisen rearrangement. Thermolysis of
was completed within 30
4a
29
28
THF. Only the endo-alcohol , m.p. 128–130 °C, [α]
3b
–16.9 (c 1.1,
min to give the 2-(cyclohex-2-enyl)phenol
, [α]
10a
+102.1 (c 0.2,
D
D
CHCl ), carrying a syn-4-substituent furnished the expected exo-aryl
CHCl ), as the single product in 58% yield, whose enantiomeric purity
was determined to be 97% ee by hplc using a chiral column
3
3
34
ether , [α]
4b
+33.6 (c 1.2, CHCl ), carrying an anti-4-substituent in
D
3

September 1998
SYNLETT
1005
Scheme 3
i
(CHIRALCEL OJ, 5% Pr OH-hexane) indicating about 1.5% loss of the
original chiral integrity of the starting keto-ether . The reaction was
2
found to proceed most easily with
, having no significant 1,4-
4b
interaction, to give 5-methyl-2-(6-siloxycyclohex-2-enyl)phenol
,
10b
31
[α]
–24.6 (c 0.5, CHCl ), stereo- and regioselectively, in 78% yield
3
D
as the single product within 30 min. In a shorter reaction time (~ 5 min),
a separable mixture of
and the aryl cyclohex-2-enyl ether
,
9b
10b
Scheme 4
33
[α]
+89.1 (c 0.7, CHCl ), was obtained though the reaction could not
3
D
be terminated definitely at the retro-Diels-Alder stage. Since none of the
14
31
xantate to give the primary alcohol , [α]
+5.6 (c 0.5, CHCl ), in
3
17
stereoisomers could be detected by hplc [after desilylation:
D
i
62% overall yield after reductive deacylation. Enantiomeric purity of
17
Microsorb(Si), 1% Pr OH-hexane] in the reaction of
, it was
9b
was determined to be >99% ee by hplc using a chiral column
(CHIRALCEL OJ, 3% Pr OH-hexane). By employing a sequence of
presumed that the original chiral integrity originated from the keto-ether
was preserved in the product . On the other hand, the thermolysis
i
2
10b
having a considerable 1,4-interaction took a
reactions involving oxidation, ether cleavage and esterification,
was
17
of the endo-aryl ether
4c
longer reaction time to give a separable 6:1 mixture of 5-methyl-2-(6-
siloxycyclohex-2-enyl)phenol and 3-methyl-2-(6-siloxycyclohex-2-
32
converted to the penultimate ester , [α]
18
+20.7 (c 0.2, CHCl ),
3
D
which was treated with excess methylmagnesium iodide to accomplish
12
in 45% total yield after 2.5 h. Although the reaction
15
30
the first enantiocontrolled synthesis of (+)-curcudiol , [α]
+9.9
+9.2 (c 10.8, CHCl )]. Overall yield of
19
enyl)phenol
13
D
22
(c 0.2, CHCl ), [natural: [α]
proceeded stereoselectively as none of the stereoisomers of
and
12
13
3
D
3
from was 44% (Scheme 5).
17
19
were detected by hplc analysis [after desilylation: Microsorb(Si), 1%
Pr OH-hexane], it lost regioselectivity to some extent. The observed
i
In summary, it was concluded that only the chiral cyclohex-2-enol
equivalent 3b bearing a syn-4-substituent was tolerable under the
Mitsunobu reaction and the concurrent retro-Diels-Alder and Claisen
rearrangement reaction protocol to give the 2-(cyclohex-2-enyl)phenol
differences in the regioselectivity among the allyl aryl ethers
,
and
4a b
were presumed to be due to the stereochemistry of the 4-substituent:
4c
,
, without having 1,4-interaction, were allowed to take the orbitally
4a b
12
16
favorable chair-like transition states
,
in the Claisen
b
9a
10b satisfactorily without losing the original chiral integrity of the
rearrangement to give the single products
,
, respectively, while
,
4c
10a b
having a considerable 1,4-interaction, was forced to take sterically
favorable two boat-like transition states to give rise to the mixture of
chiral starting material 2.
11
(Scheme 4).
References and Notes
the two regioisomers and
12
13
(1) Takano, S.; Akiyama, M.; Ogasawara, K. J. Chem. Soc., Perkin
Trans. 1 1985, 2447.
Having concluded the cyclohexenylphenol
compound accessible practically from the keto-ether via the syn-4-
to be the only
10b
2
substituted cyclohex-2-enol equivalent
through the Mitsunobu
3b
reaction and the concurrent retro-Diels-Alder and Claisen reaction, we
explored its utilization as chiral building block for the
(2) Goering, H. L.; Kimoto, W. I. J. Am. Chem. Soc., 1965, 87, 1748.
(3) Pertinent reviews, see: Mitsunobu, O. Synthesis 1981, 1. Hughes,
D. L. Org. React. 1992, 42, pp. 335-656. Hughes, D. L. Org. Prep.
Proc. Int. 1996, 28, 127.
a
enantiocontrolled construction of a natural phenolic sesquiterpene (+)-
9
curcudiol
isolated from the marine sponge Didiscus flavus. Thus,
19
27
(4) A discussion on the Mitsunobu reaction of cyclic allylic alcohols,
see: Shull, B. K.; Sakai, T.; Nichols, J. B.; Koreeda, M. J. Org.
Chem. 1997, 62, 8294.
the phenol
was first transformed into the methyl ether , [α]
14
10b
D
+131.7 (c 0.3, CHCl ), in 72% yield, which was sequentially
3
29
transformed into the monopivalate , [α]
15
–18.4 (c 0.9, CHCl ), in
3
D
73% yield through one-flask ozonolysis and reduction followed by
(5) Pertinent reviews, see: Rhoads, S. J.; Raulins, N. R. Org. React.
1975, 22, 1. Wipf, P. In “Comprehensive Organic Synthesis”
Trost, B. M.; Fleming, I.; Paquette, L. A. Eds. Pergamon Press,
Oxford, 1991, 5, pp. 827-874.
13
specific monoacylation. Reductive removal of the primary hydroxy
27
functionality of
via the tosylate afforded , [α]
16
–12.3 (c 0.3,
15
D
CHCl ), whose secondary oxygen functionality was removed via the
3

1006
LETTERS
SYNLETT
Scheme 5
(6) Quite recently, a catalytic asymmetric protocol for the formation
of allyl aryl ethers and their Claisen rearrangements has been
disclosed, see: Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998,
120, 815.
(12) Fleming, I. In Frontier Orbitals and Organic Chemical Reactions,
J. Wiley & Sons, London, 1976.
(13) Guanti, G.; Narisano, E.; Podgorski, T.; Thea, S.; Williams, A.
Tetrahedron 1990, 46, 7081.
(7) Sakagami, H.; Samizu, K.; Kamikubo, T.; Ogasawara, K. Synlett
1996, 163.
(14) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans 1,
1975, 1574. Barton, D. H. R.; Crich, D.; Löbberding, A.; Zard, S.
Z. Tetrahedron 1986, 42, 2329.
(8) Hiroya, K.; Kurihara, Y.; Ogasawara, K. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2287.
(15) Racemic synthesis of curcudiol, see: Ono, M.; Yamamoto, Y.;
(9) Wright, A. E.; Pomponi, S. A.; McConnell, O. J.; Kohmoto, S.;
Todoroki, R.; Akita, H. Heterocycles 1994, 37, 181.
McCarthy, P. J. J. Nat. Prod. 1987, 50, 976.
(16) The corresponding cyclopent-2-enyl ether lost some of the
original chiral integrity under the same concurrent retro-Diels-
Alder and Claisen conditions, see: Sugahara, T.; Ogasawara, K.
Tetrahedron: Asymmetry in press.
(10) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(11) Sugahara, T.; Ogasawara, K. Synlett 1996, 319.