Synthesis of isochromene-type scaffolds via single-flask diels-alder-[4 + 2]-annulation sequence of a silyl-substituted diene with menadione

Article abstract of DOI:10.1021/ol501329t

A sequential Diels-Alder reaction/silicon-directed [4 + 2]-annulation was developed to assemble hydroisochromene-type ring systems from menadione 2. In the first step, a Diels-Alder of the 1-silyl-substituted butadiene 1 with 2 furnished an intermediate cyclic allylsilane. Subsequently, TMSOTf promoted a [4 + 2]-annulation through trapping of an oxonium, generated by condensation between an aldehyde and the TBS protected alcohol resulted in the formation of a cis-fused hydroisochromene 13.

Full text of DOI:10.1021/ol501329t

Letter
pubs.acs.org/OrgLett
Synthesis of Isochromene-Type Scaffolds via Single-Flask Diels−
Alder-[4 + 2]-Annulation Sequence of a Silyl-Substituted Diene with
Menadione
Jihoon Lee and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library Development, Metcalf Center for Science and
Engineering, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: A sequential Diels−Alder reaction/silicon-
directed [4 + 2]-annulation was developed to assemble
hydroisochromene-type ring systems from menadione 2. In
the first step, a Diels−Alder of the 1-silyl-substituted butadiene
1 with 2 furnished an intermediate cyclic allylsilane.
Subsequently, TMSOTf promoted a [4 + 2]-annulation
through trapping of an oxonium, generated by condensation
between an aldehyde and the TBS protected alcohol resulted
in the formation of a cis-fused hydroisochromene 13.
ubstituted isochromene (2-benzopyran) frameworks are
frequently found in many natural products and bioactive
S
molecules.1 This class of molecules has inspired the develop-
ment of efficient synthetic methods for various isochromene-
type ring systems, and as a result, several useful methods have
been developed. The majority relies on an activation of alkyne
or olefin and subsequent addition of an oxygen atom.2
However, the efficient stereocontrolled synthesis of a fused
cyclic hydroisochromene skeleton still remains a useful
objective.3 Development of reaction processes that provide
access to heteroatom-bearing polycyclic scaffolds (isochro-
mene-like) would be a useful contribution to the field.
Furthermore, application of a divergent cyclization method to
diversity-oriented synthesis (DOS) would allow for a useful
method to establish novel and stereochemically well-defined
ring systems.
Figure 1. Proposed tandem Diels−Alder/annulation sequence.
Recently we reported a synthesis of hydrobenzofurans using
transannular cyclization of a tethered allylsilane, which was
rapidly prepared through an alkyne−alkyne reductive coupling
between a propargylsilane and terminal hydroxy-bearing olefin.4
Therein, we demonstrated that the tethered allylsilanes
participate in annulations, leading to the formation of trans-
fused hydrobenzofurans. Since allylsilanes have been shown to
be useful reaction partners in annulation reactions,5 allylsilanes
possessing a higher degree of structural complexity would also
be useful substrates in the construction of fused cyclic systems
by a silicon-directed annulation. Herein, we describe our studies
aimed at the development of a cascade cyclization utilizing an
organosilane compound to furnish a hydroisochromene
scaffold.
fused decalin. In the subsequent step, the resulting carbon
nucleophile will participate in a silicon-directed annulation in
the presence of an aldehyde to construct tetracyclic compound
6.
A similar idea had been previously employed in the tendem
processes, where polycyclic systems were successfully produced
through the reaction sequences involving Diels−Alder/
Schmidt,6 Diels−Alder/allylation,7 and IMDA/[3 + 2]-
annulation.8 Accordingly, we envisioned that a one-pot
Diels−Alder/[4 + 2]-annulation sequence would result in a
stereoselective approach to complex polycyclic scaffolds.
The development of this sequence began by establishing an
efficient and scalable synthesis of silicon-substituted 1,3-diene 1
(Scheme 1). Thus, 1-iodobutynol 79 underwent a copper-
In that regard, the use of a Diels−Alder reaction of a 1,4-
substituted butadiene with a paranaphthoquinone (Figure 1)
would afford a linear fused-tricyclic ring system bearing a
stereochemically well-defined allylsilane embedded in the cis-
Received: May 8, 2014
Published: June 11, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
we were unable to find an optimal condition for the DA
reaction using other types of dienes and dienophiles. For
example, the reactions using 2-ethyl substituted naphthoqinone
or cyclohexenone gave a low conversion or trace amount of
product, respectively.
Scheme 1. Preparation of Silicon-Substituted Diene 1
As such, we pursued a silicon-directed annulation to access a
stereochemically well-defined hydroisochromene skeleton and
explored the possibility of a one-pot Diels−Alder/annulation.
In these experiments, the reaction between 1 and 2 was
conducted prior to addition of aldehyde 4a to secure the
formation of allylsilane 3. After extensive screening of reaction
conditions, we learned that TMSOTf (2.0 equiv) was effective
in promoting the annulation with an aldehyde at −50 °C to
afford the fused pyran 13a, which was generated through
migration of the double bond in 6 into conjugation with the
carbonyl [66% yield as a single diastereomer (Table 2)].
Table 2. Optimization of One-Pot Sequential Diels−Alder/
mediated coupling with TMS-acetylene 8 to produce diyne 9.10
Selective reduction of the homopropargylic alkyne to an (E)-
alkene using LiAlH4 was followed by protodesilylation of the
resulting enyne without purification to provide 10 in 62%
yield.11 Regioselective hydrosilylation of 10 was conducted
utilizing [Pt(DVDS)]-PtBu3 (Chandra’s catalyst12) 11 to afford
silane-substituted diene 12 in 93% yield as a single
regioisomer.13
Annulation
a
b
c
entry
A
B (equiv)
temp (°C)
yield (%)
At that point, it seemed that the selection of a proper
protecting group for the hydroxy group in 12 would be crucial
for a successful annulation reaction,14 as it has to be
spontaneously removed after the Diels−Alder reaction to
generate an oxocarbenium ion with an aldehyde under the
given reaction conditions. In our earlier three-component
propargylation reaction utilizing allenylsilanes,15 the TBS ether
successfully participated in the formation of an oxonium ion
with an aldehyde promoted by TMSOTf. In our initial study,
therefore, TBS was determined to be the protecting group for
the terminal hydroxy group to afford diene 1.
An initial Lewis acid screening determined that bidentate
aluminum-based promoters16 efficiently affected the reaction to
give 3 in a useful yield and as a single regioisomer (Table 1).17
A series of reactions using other Lewis acids [BF3·OEt2, TiCl4,
and Cu(OTf)2] provided inferior results in terms of reaction
efficiency, while thermal conditions in refluxing benzene
without Lewis acid activation gave no reaction. Unfortunately,
1
2
3
4
5
6
AlCl3
−
0 to 25
−78 to 25
−78 to 25
0 to 25
−50
−
17
AlCl3
BF3·OEt2 (1.2)
TiCl4 (1.0)
AlCl3
ta
AlCl3
ln(OTf)3 (1.0)
TMSOTf (2.0)
TMSOTf (2.0)
17
40
66
AlCl3
MeAlCl2
−50
a
The reactions were conducted at 0.2 M concentration of 1 in CH2Cl2.
0.5 equiv of Lewis acid was used. Purification yield after column
chromatography on SiO2. ta = trace amount.
b
c
The scope of the process was evaluated with a range of
aldehydes, while employing the optimized conditions. The DA
was carried out in the presence of MeAlCl2, and aldehyde 4 and
TMSOTf were subsequently added to the reaction mixture at
−50 °C to furnish the desired fused-cyclic compounds (Scheme
2). The sequence using aldehydes 4b and 4c showed similar
reactivity to the reaction of isobutylaldehyde 4a and resulted in
the formation of products 13b and 13c in 63% and 60% yield,
respectively, as a single diastereomer. Also, 2-ethylbutyrl-
aldehyde proved to be a good reaction partner in this reaction
sequence, which gave 13d in 65% yield. Given the observed
results from the reaction of 4a, 4b, 4c, and 4d, it was concluded
that α-branched aldehydes served as excellent reaction partners
in this annulation sequence.
Table 1. Diels−Alder Reactions of Diene 1 with Dienophiles
2
Additionally, valeraldehyde 4e, a linear aldehyde, gave the
desired cyclic compound 13e in 40% yield. The effect of β-
branching on the annulations was also examined using
isovaleraldehyde 4f. However, this trial provided 13f in 30%
yield albeit as a single diastereomer. In addition, the reaction of
cyclopropanecarboxaldehyde 4g proceeded with unidentified
side reactions and gave the product 13g in only 24% yield.
Utilization of aromatic aldehydes under the optimal reaction
conditions provided a mixture of unidentified reaction
products.
a
b
entry
LA
none
solvent
temp (°C)
yield (%)
1
2
3
4
benzene
CH2Cl2
CH2Cl2
CH2Cl2
80
25
25
25
nr
ta
Me2AlCl
MeAlCl2
AlCl3
77
60
a
The reactions were conducted under 0.2 M concentration of 1.
Purification yield after column chromatography on SiO2. nr = no
reaction; ta = trace amount.
b
Through the extensive experiments to elucidate the scope of
this reaction sequence, it was turned out that the 2-alkyl
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Organic Letters
Letter
group in a pseudoequatorial orientation to help minimize
destabilizing 1,3-diaxial interactions that would develop in a
chair−chair conformation. Subsequent boat to chair inter-
conversion then aligns the C−Si σ-bond with the empty p-
orbital (T2) that maximizes the electron-donating effect of the
silyl group (β-silicon effect). Elimination of the silicon group
followed by isomerization of the double bond into conjugation
gave the cis-fused cyclic compound 13.
Scheme 2. One-Pot Diels−Alder-Annulation Sequence with
a
Various Aldehydes (4b−4g)
We have described a one-pot sequential Diels−Alder/
annulation sequence employing a silyl-substituted diene that
rapidly assembles a complex tetracyclic scaffold bearing a cis-
fused hydroisochromene. Experiments aimed at the develop-
ment of an asymmetric variant will allow access to
enantioenriched fused-cyclic scaffolds, and studies to broaden
the reaction scope will be the focus of future studies.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for new
compounds 1−13g are provided. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: panek@bu.edu.
Notes
The authors declare no competing financial interest.
a
Isolated yield after purification by SiO2 chromatography.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the NIGMS
CMLD initiative (P50-GM067041). We are grateful to Dr. Paul
Ralifo, Dr. Norman Lee, and Dr. Jeffrey Bacon (Chemical
Instrumentation Center at Boston University) for helpful
discussions and assistance with NMR, HRMS, and X-ray
crystallographic analysis experiments.
substituent on naphthoquinone is crucial in a successful
annulation reaction.18 The DA reaction using naphthoquione
as the diene part proceeded to form an adduct in 73% yield, but
formation of the desired isochromene-type scaffold was not
observed in the subsequent annulation step. Although the DA/
annulation sequence exhibits limitations in reaction scope, this
strategy assembles a high degree of complexity through simple
manipulations with various aliphatic aldehydes, which allows for
rapid establishment of a focused chemical library.
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