A convergent general strategy for the functionalized 2-Aryl cycloalkylfused chromans: Intramolecular hetero-diels-alder reactions of ortho-quinone methides

Article abstract of DOI:10.1002/chem.200902403

(Figure Presented) Five and six: 3, 4-Cyclopentyl- and cyclohexyl-fused 2-arylchromans could be readily prepared from the intramolecular hetero-Diels-Alder reactions of the corresponding ortho-quinone methide (o-QM) precursors tethered to the styrenes under mild reaction conditions. The products were obtained with good to excellent diastereoselectivity (up to > 99:1 dr; see scheme; MOM = methoxymethyl).

Full text of DOI:10.1002/chem.200902403

COMMUNICATION
DOI: 10.1002/chem.200902403
A Convergent General Strategy for the Functionalized 2-Aryl Cycloalkyl-
Fused Chromans: Intramolecular Hetero-Diels–Alder Reactions of
ortho-Quinone Methides
Jumreang Tummatorn,[a] Somsak Ruchirawat,[a, b] and Poonsakdi Ploypradith*[a, b]
Chroman is a core structure of flavonoids, which have
been shown to exhibit a wide array of biological activities.[1]
Palodesangren C (1; Scheme 1), a natural Diels–Alder
studied as an estradiol analogue.[4] Some tricyclic 2-aryl-3,4-
cycloalkyl-fused benzopyrans (4, 5; Scheme 1) were synthe-
sized and investigated for their high affinity to and selectivi-
ty for the estrogen receptor b over the a.[5,6]
Some synthetic methods have been developed for chro-
mans by hetero-Diels–Alder (HDA) reactions.[7] However,
despite the presence of the 2-aryl group in some natural
products and synthetic compounds, the synthesis of 2-aryl-
3,4-cycloalkyl-fused chromans has been relatively unex-
plored, partly due to the susceptible nature of styrenes to
polymerization. To date, the reported syntheses have been
largely performed for the 2-alkylcycloalkyl-fused chromans
and pyranobenzopyrans.[8] In addition, modifications on the
cycloalkyl-fused rings would be difficult because the cyclo-
alkyl or pyranyl moieties are nonfunctionalized. Moreover,
different strategies were required for cyclopentyl- and cyclo-
hexyl-fused compounds (4, 5).[6] Thus, developing a general
synthetic strategy for the tricyclic core of 2-aryl-3,4-cycloalk-
yl-fused chromans with defined stereocenters (C2, C3, and
C4) and functionalizable moieties on the cycloalkyl ring
would be pivotal.
Scheme 1. Examples of 2-arylcycloalkyl-fused chromans (shown with rel-
ative stereochemistry).
Recently, as part of our research in the use of solid-sup-
ported reagents in organic synthesis,[9] our group has report-
ed the successful generation of o-QMs and their intermolec-
ular HDA reactions with styrene derivatives under mild con-
ditions mediated by p-toluenesulfonic acid (p-TsOH) immo-
bilized on silica (PTS-Si) in toluene.[9d] We now envisioned
that PTS-Si could be employed to generate ortho-quinone
methide (o-QM), which, upon reacting intramolecularly
with the tethered dienophile (i.e., styrenes), could form the
tricyclic 2-aryl-3,4-cycloalkyl-fused chroman.
As shown retrosynthetically in Scheme 2, the precursors
for the intramolecular HDA reactions would be derived
from aldol condensation between the benzaldehyde deriva-
tive (6) and ketone (X=H; Y=Me) or the acetophenone
derivative (7) and the aldehyde (X=Me; Y=H). Synthesis
of these cycloalkyl-fused chroman systems would be highly
convergent and requires a similar strategy to assemble the
precursors for the intramolecular o-QM/HDA reactions.
adduct isolated from Brosimum rubescens, showed potent
inhibition of the binding of 5a-dihydrotestosterone (DHT)
with the androgen receptor.[2] Parvifolol A (2; Scheme 1), a
natural product isolated from Gnetum parvifolium, was eval-
uated for the inhibitory activity in the Maillard reaction
(protein glycation) associated with diabetic complications
and aging of the skin.[3] Compound 3 was synthesized and
[a] Dr. J. Tummatorn, Prof. Dr. S. Ruchirawat, Dr. P. Ploypradith
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute
Vipavadee-Rangsit Highway, Bangkok 10210 (Thailand)
Fax : (+662)574-2027
E-mail: poonsakdi@cri.or.th
[b] Prof. Dr. S. Ruchirawat, Dr. P. Ploypradith
Program in Chemical Biology, Chulabhorn Graduate Institute
Vipavadee-Rangsit Highway, Bangkok 10210 (Thailand)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902403.
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For n=2, alkylation of ethyl acetoacetate with cinnamyl
bromide using NaH as base gave 11 in 87% yield, which
was subjected to saponification/decarboxylation conditions
with KOH to provide 12 in 88% yield. The benzaldehyde 6
could be readily prepared.[9d] The acetophenone 7 was pre-
pared in three steps from 2,4-dihydroxyacetophenone via 13.
With both fragments of each cycloalkyl-fused chromans in
hand, the aldol condensations of respective pairs were stud-
ied (Scheme 4). Alcohol 10 was oxidized to the aldehyde
Scheme 2. Retrosynthetic analysis for the cycloalkyl-fused chromans.
MOM=methoxymethyl.
Our efforts then focused on 1) the syntheses of styrene-con-
taining fragments of different chain length, 2) the aldol con-
densation, and 3) the o-QM/HDA reactions.
As depicted in Scheme 3, the requisite styrene-containing
fragments could be easily prepared. For n=1, we first antici-
pated that ketone 8[10] could be used in the aldol condensa-
Scheme 4. Aldol condensation/reduction/acetylation/o-QM/HDA reac-
tions and proposed exo transition states, providing the chromans as race-
mates (shown with relative stereochemistry). DMAP=4-dimethylamino-
pyridine.
Scheme 3. Synthesis of styrene-containing fragments 12, 14, and aceto-
phenone derivative 7. LAH=lithium aluminum hydride.
using Dess–Martin periodinane (DMP). The crude aldehyde
was used directly in the aldol condensation with the enolate
of acetophenone 7, giving 14 in 42% yield. For n=2, aldol
condensation of the methyl ketone 12 with benzaldehyde 6
gave 15 in 65% yield.
tion with benzaldehyde 6. However, regioselective genera-
tion of kinetic enolate of 8 by lithium diisopropylamide
(LDA) was difficult. The presence of the styrene moiety
rendered the a-methylene protons more acidic and deproto-
nation of these protons became competitive with that of the
a-methyl protons. Thus, an alternative pair for aldol conden-
sation was considered and the target styrene-containing
fragment would contain the aldehyde group rather than the
ketone. Such a fragment could be synthesized starting from
the Sonogashira coupling between iodobenzene and but-3-
yn-1-ol, which gave the product 9 in 92% yield. The trans-
styrene moiety was installed by LAH reduction of the
alkyne, giving 10 in 98% yield.
After some experimentation,[11] it was found that borohy-
dride reduction of the ketone followed by a one-pot acetyla-
tion and PTS-Si-mediated o-QM/HDA reaction sequence in
toluene occurred smoothly for both substrates, providing the
products 16 and 17 in 50 and 65% yields over two steps, re-
spectively. Subsequent base-mediated cleavage of the ace-
tates followed by DMP oxidation furnished the ketones 18
and 19 in 76 and 93% yields over two steps, respectively.
Compound 19 was obtained as a single isomer, suggesting
that the o-QM/HDA reaction occurred with high stereose-
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Functionalized 2-Aryl Cycloalkyl-Fused Chromans
COMMUNICATION
lectivity. Compound 18, on the other hand, was obtained as
À
a 77:23 (Ha/Hb) mixture of C4-epimers. The C3 C4 trans re-
lationship in the major product of 18 and in compound 19
suggested the exo transition states 20 and 21.[8]
Our new method also allowed easy access to other modifi-
cations on the cyclohexyl ring. The b-hydroxy ketone 15 was
oxidized by DMP to the 1,3-diketone 22 in 82% yield,
which underwent bis-methylation to give the product 23 in
87% yield (Scheme 5). Subsequent borohydride reduction
Scheme 6. Synthesis of C2-modified cyclohexyl-fused chroman. DIBAL-
H=diisobutylaluminum hydride.
cyclohexyl-fused chroman systems. The use of PTS-Si in tol-
uene was critical to suppress styrene polymerization. In ad-
dition, all stereocenters at C2, C3, and C4 were installed
with good to excellent stereocontrol in a single step. The ap-
proach is flexible for a number of modifications and the key
steps are compatible with the modified substrates to provide
structurally diverse analogues. In addition, the presence of
bromine and a methoxy group on the aromatic ring allowed
further modifications, such as those required for installing
the coumarin moiety in palodesangren C. Applications of
this strategy to synthesize other natural products will be re-
ported in due course.
Scheme 5. Synthesis of modified cyclohexyl-fused chroman.
and one-pot acetylation/o-QM/HDA reactions provided a
mixture of tricyclic alcohol 24 and acetate 25 in 63% com-
bined yields over 2 steps. Treatment of the acetate with
NaOMe followed by DMP oxidation gave the ketone 26 as
a single isomer in 91% yield over 2 steps. The alcohol 24
was also oxidized to the ketone by DMP in 96% yield.
In addition, modification at C2 as a quaternary center was
performed. Aldol condensation between ethyl acetate and
acetophenone using LDA followed by CeCl3–NaI-mediated
dehydration[12] gave the a,b-unsaturated ester 27 in 62%
yield (Scheme 6). Subsequent DIBAL-H reduction fur-
nished the alcohol 28 in 87% yield, which was converted to
the cinnamyl bromide by using CBr4 and PPh3. Alkylation
of the bromide with ethyl acetoacetate, saponification/decar-
boxylation, and aldol condensation gave ketone 31 via 29
and 30. Reduction and one-pot acetylation/o-QM/HDA re-
actions provided the tricyclic chroman acetate 32 in 66%
yield over 2 steps. Cleavage of the acetate followed by DMP
oxidation gave ketone 33 in 87% yield over 2 steps as a
single isomer with the C2-methyl group syn to the C4-H.
In summary, we have developed a highly efficient and
general strategy for the synthesis of cycloalkyl-fused chro-
man systems by the PTS-Si-mediated o-QM/HDA reactions,
which proceeded in 50–66% yields in combination with the
preceding reduction and acetylation. The generality of this
strategy was demonstrated to provide the cyclopentyl- and
Experimental Section
General procedure for HDA reactions of o-QMs: NaBH4 (1.1 equiv) was
added to a solution of precursor compounds (14, 15, 23, 31) (1 equiv) in
MeOH (1 mLmmolÀ1) at room temperature and then the resulting mix-
ture was stirred for 30 min. After removal of the solvent, H2O was added
to the residue and it was extracted with EtOAc. The combined organic
phase was washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated under a vacuum to give a crude alcohol product. This crude
product was dissolved in toluene (1 mLmmolÀ1), followed by the addition
of DMAP (2.5 equiv), and the reaction mixture was stirred until com-
pletely dissolved. Acetyl chloride (2.5 equiv) was added dropwise to this
solution and then the reaction was stirred vigorously overnight. PTS-Si
(1.2 equiv) was added to this mixture at room temperature. The reaction
mixture was monitored by TLC analysis. After completion, the resulting
mixture was filtered and the solid was washed with EtOAc. The com-
bined organic layers were evaporated and the residue was purified by
flash chromatography on silica to yield 2-arylcycloalkyl-fused chroman
acetates (16, 17, 25, 32) and 2-arylcycloalkyl-fused chromanol (24).
Acknowledgements
Financial support from the Thailand Research Fund (TRF; BRG5100813
for P.P.) is gratefully acknowledged.
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Keywords: chromans · cycloaddition · cyclization · quinone
methides · stereoselective reactions
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[11] Direct conversion of the alcohol in compounds 14 and 15 to the ace-
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others. Subjecting 15 directly for the o-QM/HDA reaction gave 19
in low yield (20%). Treating the 1,3-diol from the borohydride re-
duction with PTS-Si in toluene or p-TsOH in methanol (ref. [8a–d])
gave no desired tricyclic alcohol.
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Received: August 31, 2009
Published online: December 28, 2009
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