Enantioselective and regioselective pyrone Diels-Alder reactions of vinyl sulfones: Total synthesis of (+)-cavicularin

Article abstract of DOI:10.1002/anie.201406621

The total synthesis of (+)-cavicularin is described. The synthesis features an enantio- and regioselective pyrone Diels-Alder reaction of a vinyl sulfone to construct the cyclophane architecture of the natural product. The Diels-Alder substrate was prepared by a regioselective one-pot three-component Suzuki reaction of a non-symmetric dibromoarene. The total synthesis of (+)-cavicularin features an enantio- and regioselective Diels-Alder reaction of a pyrone with a vinyl sulfone. The substrate for this transformation is prepared by a regioselective one-pot three-component Suzuki reaction of a non-symmetric dibromoarene.

Full text of DOI:10.1002/anie.201406621

Angewandte
Chemie
DOI: 10.1002/anie.201406621
Asymmetric Synthesis
Enantioselective and Regioselective Pyrone Diels–Alder Reactions of
Vinyl Sulfones: Total Synthesis of (+)-Cavicularin**
Peng Zhao and Christopher M. Beaudry*
Abstract: The total synthesis of (+)-cavicularin is described.
The synthesis features an enantio- and regioselective pyrone
Diels–Alder reaction of a vinyl sulfone to construct the
cyclophane architecture of the natural product. The Diels–
Alder substrate was prepared by a regioselective one-pot three-
component Suzuki reaction of a non-symmetric dibromoarene.
T
he Diels–Alder cycloaddition[1] is a protean organic reac-
tion; the variety of dienes and dienophiles that participate is
practically endless. Moreover, the enantioselective Diels–
Alder reaction[2] is a well-developed process for the asym-
metric construction of stereogenic carbon centers. Many
complex target molecules have been made using the enantio-
selective Diels–Alder reaction.[3]
a-Pyrones are useful dienes for Diels–Alder reactions.[4,5]
Not surprisingly, enantioselective a-pyrone Diels–Alder reac-
tions exist. Enantioselective Diels–Alder reactions that
involve a-pyrone dienes fall into three well-defined subtypes
as exemplified in Scheme 1: 1) normal-electron-demand
Diels–Alder reactions of 5-hydroxy-a-pyrones and electron-
deficient alkenes promoted by cinchona alkaloid[6] or amino-
indanol-derived[7] catalysts (Scheme 1a), 2) inverse-electron-
demand Diels–Alder reactions of 5-acyl-a-pyrones and elec-
tron-rich alkenes (Scheme 1b),[8] and 3) normal-electron-
demand Diels–Alder reactions of 2H-pyran-2,5-diones with
electron-deficient alkenes catalyzed by a cinchona-based
thiourea (Scheme 1c).[9]
Scheme 1. Enantioselective Diels–Alder reactions of a-pyrones.
BINOL=1,1’-bi-2-naphthyl, Tf=trifluoromethanesulfonyl.
rigidified molecular architecture, cavicularin displays confor-
mational chirality.
Our interest in the Diels–Alder reaction of a-pyrones
arose from the observation that a-pyrone Diels–Alder
reactions with alkynes (or alkyne equivalents) are followed
by retro-Diels–Alder events that deliver phenyl rings.[10] The
enantioselective a-pyrone Diels–Alder reaction could, in
principle, be used in an intramolecular context for an
enantioselective cyclophane synthesis (Scheme 1d); however,
such a strategy has not been reported. We evaluated this
concept in an enantioselective synthesis of cavicularin.
Cavicularin (Scheme 2) is a cyclophane natural product
that was isolated from the liverwort Cavicularia densa.[11] The
natural product displays a strained molecular architecture;
crystallographic studies of cavicularin show that the A ring is
distorted in a boat-shaped configuration. As a result of the
Cavicularin has captured the attention of synthetic
chemists, and the groups of Harrowven,[12] Baran,[13]
Fukuyama,[14] Suzuki,[15] and our own[16] have reported
syntheses of cavicularin. The synthesis by Suzuki and co-
workers featured an elegant use of a chiral sulfoxide auxiliary
for the synthesis of (À)-cavicularin. Herein, we report the first
synthesis of (+)-cavicularin using enantioselective catalysis.
Consideration of the enantioselective a-pyrone Diels–
Alder reactions depicted in Scheme 1 suggested that an
asymmetric Diels–Alder reaction of a hydroxy-a-pyrone
would serve in an enantioselective cavicularin synthesis.
Specifically, phenol 4 may be the product of an enantiose-
lective Diels–Alder cycloaddition of 5 (Scheme 2). It was
presumed that 5 may undergo enantioselective cycloaddition
in the presence of cinchona-based catalysts to give enan-
tioenriched 6. We anticipated that the regiochemical outcome
would be the result of interactions between the electrophilic
C5 position of the vinyl sulfone moiety and the presumed
nucleophilic C6 position of the a-pyrone motif.[16] Bicyclic
compound 6 may undergo elimination of phenylsulfinic acid
to produce 7. Unsaturated bicycles such as 7 undergo rapid
retro-Diels–Alder reactions to produce arenes such as 8.[10]
Key intermediate 5 could then be prepared from terphenyl 8.
[*] P. Zhao, Prof. Dr. C. M. Beaudry
Department of Chemistry, Oregon State University
Corvallis, OR 97331 (USA)
E-mail: christopher.beaudry@oregonstate.edu
[**] Financial Support from Oregon State University is acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406621.
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Scheme 3. Reagents and Conditions: a) [Pd(PPh3)4], K3PO4, DMSO,
708C, 52%; b) [Pd(PPh3)4], K3PO4, KBr, dioxane, H2O, 558C;
c) Grubbs II catalyst, CH2Cl2, 508C, 95%; d) H2 (600 psi), Pd/C,
EtOAc, 608C, 87%. pin=pinacolato.
Scheme 2. Retrosynthetic analysis of (+)-cavicularin.
Suzuki conditions. When dibromide 11 was consumed (as
observed by thin-layer chromatography (TLC)), boronic ester
10 was added, and the reaction proceeded to completion. This
three-component coupling gave terphenyl 8 in good yields,
and no regioisomers were isolated. To the best of our
knowledge, this is the first regioselective one-pot three-
component Suzuki reaction of a dibromoarene.
Terphenyl 8 underwent ring-closing metathesis and sub-
sequent phenanthrene hydrogenation to give 14.[26] The
synthetic route to 14 consisted of three steps and proceeded
in 52% overall yield from known building blocks.
With convenient access to 14, the material was advanced
to the Diels–Alder substrate (Scheme 4). A one-pot phos-
phorylation/Horner–Wadsworth–Emmons reaction was fol-
lowed by a deprotection, pyrone conjugate addition,[27]
elimination sequence delivering Diels–Alder substrate 5.
The regiochemical preference of 3,4-dioxygenated
a-pyrones in Diels–Alder reactions was previously unknown;
however, we anticipated that bond formation would occur
between the C5 and C6 carbon atoms of 5. Heating of 5
induced the Diels–Alder cycloaddition. Presumably, the
initial cycloaddition gave 16. Elimination of phenylsulfinic
acid led to 17, and retro-Diels–Alder reaction to liberate CO2
gave 18. No intermediates were observed in the reaction, and
the order of elimination events is inconsequential. Evidently,
the resonance contribution from the additional hydroxy
group of the pyrone in 5 resulted in the undesired regiochem-
ical preference in the initial cycloaddition, and the undesired
meta-substituted aryl ring was observed as the only product
(18).[28]
Our first objective was to develop an efficient synthesis of
8. The terphenyl architecture of 8 suggested that Suzuki
reactions[17] would be well suited for its construction from
starting materials 9–11. One option for the assembly of
intermediate 8 would be to use distinct halogen atoms that
undergo chemoselective cross-couplings (e.g., 11, where X1 =
I and X2 = Br).[18]
A conceptually different strategy developed for hetero-
aromatic systems makes use of the different reactivity of non-
symmetry-related bromides (e.g., 11, where X1 = X2 =
Br).[18a,19] Handy and co-workers found that in polybromi-
nated heteroarenes, the more reactive bromide can be
predicted by the 1H NMR chemical shifts of the non-
halogenated congener.[20] However, there are no examples
of non-symmetric dibromoarenes participating in this type of
reaction. The predicted chemical shifts[21] for 3-vinylanisole
suggested that the bromide substituent at the C10’ position of
11 would be more reactive.
Gratifyingly, subjecting dibromide 11[22] to boronic ester
10[23] under Suzuki reaction conditions induced a regioselec-
tive cross-coupling forming 12 as a single regioisomer
(Scheme 3). A combination of 2D NMR techniques revealed
that although dibromide 11 reacted regioselectively, biphenyl
12 possessed the undesired connectivity.[24] Fortunately, when
boronic ester 11 was first coupled with 9, the reaction was
again completely selective and produced 13 in good yield.
Subjecting 13 to boronic ester 10 under the same Suzuki
reaction conditions gave the desired terphenyl 8 with the
correct regiochemistry.
Cinchona-based catalysts did not reverse the regiochem-
ical outcome, and 18 was still formed (conditions e). How-
ever, in the presence of quinidine, the reaction occurred at
lower temperature (1008C) than the background reaction
The successful sequential Suzuki couplings suggested that
a one-pot Suzuki reaction[25] would be possible to construct 8
in one step. In the event, 11 was coupled with 9 using standard
2
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threne 22. Deprotection and addition to pyrone 15
led to the formation of 23. Oxidation, olefination,
and removal of the MOM ether[29] gave Diels–Alder
substrate 19.
Gratifyingly, heating of 19 in the presence of
cinchona-based catalysts resulted in the desired
cycloaddition, producing 4 as a single regioisomer
(Scheme 6). Presumably, the initial cycloaddition
gives intermediate 24, which undergoes elimination
of phenylsulfinic acid followed by elimination of CO2
in a retro-Diels–Alder process. The order of the
elimination events is inconsequential, and no inter-
mediates were observed.[28]
The phenolic functional group in 4 was sensitive
to chromatography, so the crude material from the
Diels–Alder reaction was directly treated with Tf2O
to give the corresponding triflate 25, which was
reduced and dealkylated to give cavicularin.
We surveyed cinchona-based catalysts that pro-
mote enantioselective reactions. In the presence of
cinchona alkaloid derivative 26, the reaction to give
25 was enantioselective (e.r. = 89:11). To the best of
Scheme 4. Reagents and Conditions: a) (EtO)2P(O)Cl, LDA, THF, À788C, then
(CH2O)n, THF, 08C, 68%; b) BCl3, C6(Me)5H, CH2Cl2, À408C, 90%; c) 15,
Cs2CO3, MeCN, 658C, then TFA, CH2Cl2, 08C, 56%; d) BHT, o-DCB, 2408C, 29%;
e) quinidine, EtOAc, 1008C, 46%. BHT=tert-butylhydroxytoluene, LDA=lithium
diisopropylamide, MOM=methoxymethyl, o-DCB=ortho-dichlorobenzene,
TFA=trifluoroacetic acid.
(2408C). Furthermore, a modest level of enantioselectivity
(e.r. = 58:42) was observed. Although this was not the desired
regioisomer, the ability of the cinchona alkaloid amine to
increase the rate of the reaction and deliver modest enantio-
selectivity suggested that an enantioselective Diels–Alder
cascade of an a-pyrone to form a cyclophane was possible.
The regiochemical outcome of the reaction of 5 revealed
that the C3 position was the nucleophilic position of the
pyrone. A convenient approach to recover the desired
connectivity was to change the substitution pattern of the
vinyl sulfone.
Isomeric Diels–Alder substrate 19 was therefore prepared
(Scheme 5). Three-component Suzuki coupling of 20, 11, and
10 gave terphenyl 21 in good yield as a single regioisomer.
Ring-closing metathesis and reduction gave dihydrophenan-
Scheme 6. Reagents and Conditions: a) 26, EtOAc, 3 ꢀ molecular
sieves, 458C; b) Tf2O, CH2Cl2, 08C, 45% (2 steps); c) NH4CO2H, Pd/C,
MeOH, 708C, quant.; d) BBr3, CH2Cl2, 80%.
our knowledge, this is the first example of an asymmetric
intramolecular Diels–Alder reaction with an a-pyrone.
Reduction and dealkylation of triflate (+)-25 gave (+)-cav-
icularin without erosion of enantiopurity.
In conclusion, the enantioselective synthesis of (+)-cav-
icularin has been reported. The synthesis features two novel
reactions: a regioselective one-pot three-component Suzuki
reaction of a dibromoarene to form a highly substituted
terphenyl, and the first intramolecular enantioselective
Diels–Alder reaction of an a-pyrone to construct the cyclo-
phane architecture of (+)-cavicularin. The twelve-step syn-
thesis proceeded in 7.3% overall yield from the known
building blocks 10, 11, and 20.
Scheme 5. Reagents and Conditions: a) [Pd(PPh3)4], K3PO4, KBr, diox-
ane, H2O, 558C; b) Grubbs II catalyst, CH2Cl2, 508C, 44% (2 steps);
c) H2 (600 psi), Pd/C, EtOAc, 84%; d) BCl3, C6(Me)5H, CH2Cl2, À408C,
89%; e) 15, Cs2CO3, MeCN, 658C, 72%; f) (COCl)2, DMSO, Et3N,
CH2Cl2, À788C, 87%; g) PhSO2CH2P(O)(OEt)2, LiHMDS, THF, À788C,
99%; h) TFA, CH2Cl2, 08C, 100%. LiHMDS=lithium hexamethyldisila-
zide, TBS=tert-butyldimethylsilyl.
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[22] Prepared from the corresponding known aldehyde (see the
Supporting Information).
[23] Boronic esters 9, 10, and 20 were known from our racemic
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Received: June 26, 2014
Published online: && &&, &&&&
Keywords: asymmetric synthesis · catalysis · chirality ·
.
cross-coupling · Diels–Alder reaction
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Communications
Asymmetric Synthesis
P. Zhao, C. M. Beaudry*
&&&& — &&&&
Enantioselective and Regioselective
Pyrone Diels–Alder Reactions of Vinyl
Sulfones: Total Synthesis of
(+)-Cavicularin
The total synthesis of (+)-cavicularin
features an enantio- and regioselective
Diels–Alder reaction of a pyrone with
a vinyl sulfone. The substrate for this
transformation is prepared by a regiose-
lective one-pot three-component Suzuki
reaction of a non-symmetric dibromo-
arene.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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