A straightforward route to functionalized trans-diels-alder motifs

Article abstract of DOI:10.1021/ja1073855

A sequence consisting of a Lewis acid-catalyzed Diels-Alder reaction on a 2-halocyclohexenone, followed by reductive alkylation, provides a route to trans-fused octalinones bearing angular methyl groups with functionality corresponding to that which would have been possible from a trans-directed Diels-Alder reaction.

Full text of DOI:10.1021/ja1073855

Published on Web 09/23/2010
A Straightforward Route to Functionalized trans-Diels-Alder Motifs
Jun Hee Lee,† Yandong Zhang,† and Samuel J. Danishefsky*,†,‡
Department of Chemistry, HaVemeyer Hall, Columbia UniVersity, 3000 Broadway, New York, New York 10027,
United States, and Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York
AVenue, New York, New York 10065, United States
Received August 16, 2010; E-mail: s-danishefsky@ski.mskcc.org
Abstract: A sequence consisting of a Lewis acid-catalyzed
Diels-Alder reaction on a 2-halocyclohexenone, followed by
reductive alkylation, provides a route to trans-fused octalinones
bearing angular methyl groups with functionality corresponding
to that which would have been possible from a trans-directed
Diels-Alder reaction.
The concept of prioritized strategic bond disconnection (SBD),
so well articulated by the Corey school, is clearly the most powerful
Figure 1
resource yet devised in guiding retrosynthetic analysis (RSA)1 en
route to complex targets. Recently, we have suggested an approach
to RSA which is complementary to the paradigm of strategic bond
disconnection. We refer to this mode of retrosynthesis as pattern
recognition analysis (PRA).2 Here, the thought exercise focuses
on identifying domains within the target. Particularly valuable is
the identification of patterns which are accessible by doable
chemistry. Indeed, the discernment of patterns around which a
synthesis might be organized may well provoke the discovery of
new reactions or reaction sequences to enable creation of the
molecular architecture inherent in the patterns.
We recently reported instances wherein this line of conjecture
could be reduced to practice, though in simplified form.7 The key
discovery was that, in a cis-decalinoid-like structure (3b), free
radical-mediated reduction of a bridgehead C-nitro function can
be achieved with inVersion of configuration (cf. 3b f 5b). While
this feasibility demonstration was certainly encouraging, all of the
functionality had come from the diene component. As dienophiles
we had exploited nitrocycloalkenes. For wider impact, it would be
helpful if the trans-Diels-Alder plan could be implemented with
valuable functionality from the dienophile which persists in the final
trans product.
At the planning stage, it had been hoped that the radical
generated upon reductive cleavage (3 f 4) could be trapped
with appropriate carbon-centered coupling partners so as to
produce junction carbon-carbon bonds in the ultimate trans-
fused system (5a). Unfortunately, a variety of projected methods
(Keck allylations,8 Giese conjugate additions, and trapping with
captodative agents9) failed, presumably for reasons of high steric
hindrance. Hence, we could only create a trans-fused product
bearing a hydrogen in place of the cis-disposed nitro group.
Another problem to be overcome was that nitrocycloalkenes are
rather sluggish dienophiles. Unfortunately, we have been unable
to prepare a compound such as 2-nitrocyclohex-2-enone, which
could well have been a much more reactive dienophile. Hence,
we were unable to “deliver” a keto group to the final trans-
decalinoid system.
One of the pillars of PRA is the notion of building cis-fused
ring systems via the Diels-Alder (DA) reaction.3 In PRA, the DA
cycloaddition is more than a specific reaction type. Rather, it really
implies an overall logic, encompassing a variety of post-DA forays.
The DA reaction has been a central implement in the field of
chemical synthesis, both in the construction of relatively small
molecules and for rather complex targets. The scope of PRA in
synthetic planning would be much enhanced if the overall logic of
the DA reaction could be marshalled to produce trans-fused
structures. In principle, the ideal solution to this challenge would
be to, somehow, change the stereochemical course of the DA
reaction such that the cycloaddition event is antarafacial4 (Figure
1, 2). While speculations about such a fascinating possibility
continue,5 we have been unable to generate any ideas of value along
these lines.
The next best approach would be to conduct suprafacial DA
reactions, with the important caveat that one of the junction
substituents may be replaced by another group with overall
inVersion of configuration (3 f 5). In that case, a trans junction
would become available from the initial DA-derived cis junction.
In intermolecular DA reactions, the junction substituents of the
product arise from the dienophile. Hence, this type of exercise
would require the use of appropriate dienophiles, carrying substit-
uents amenable to inversion of configuration in the context of a
hindered ring junction.6
Figure 2
The starting point for the chemistry described here was the
finding that Lewis acid catalysis (cf. MeAlCl2) allows for rather
efficient Diels-Alder of 2-halocyclohex-2-enones and cyclopent-
2-enones (Figure 2, 6 + 7 f 8).10 The DA chemistry works with
a range of dienes. In this way, there are generated halogen functions
† Columbia University.
‡ Sloan-Kettering Institute for Cancer Research.
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10.1021/ja1073855  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Radical Debromination of R-Bromoketonesa 13
,
trapped by suitable carbon-based electrophiles.14 However, alky-
lation of a relatively reactive zinc enolate15 with methyl iodide could
not be realized. We next explored the possibility of a more reactive
lithium enolate as the reagent. Debromination was conducted with
lithium naphthalide.16
It will be recognized that here we were attempting what was
known in classical natural products chemistry as angular alkylation.
To generate the junction enolate, at the time of the historic Johnson
studies, it was necessary to insulate the R′ position from enolization
(cf. 20, Figure 3).11,17 Subsequently, House and Trost studied
angular alkylation on the simple enolate 21, derived from the
nonspecifically generated enol acetate. In the decalinoid series,
products were either primarily cis-fused or modestly trans-
selective.18 However, unlike the cases cited above, in our systems,
the R′ position would uniquely contain both a free R-methylene
group and a double bond parallel to the junction in an octalin
framework. We first investigated the direct methylation of two
R-bromoketone substrates. With methyl iodide as the electrophile,
reductive alkylation of substrate 10 did indeed occur, but the trans:
cis ratio was, at best, 3:1. In the hydrindanoid series (cf. 27), the
cis product was predominant (cis:trans ) 4:1).11 These results were
hardly in keeping with the goal of a stereoselective synthesis of
trans-fused bicyclic systems.
a Reaction conditions: To a mixture of R-bromoketone (1 equiv) and
AIBN (0.3 equiv) in degassed benzene (0.1 M) was added tri-n-butyltin
hydride (2 equiv), and the mixture was heated under reflux for 2 h.
b Isolated yield. c Determined by 1H NMR analysis. The relative
stereochemistry of the major isomer was confirmed by comparison with
the corresponding cis diastereomers, prepared through the
CH3AlCl2-catalyzed Diels-Alder reaction between cyclohex-2-enone
and the appropriately substituted 1,3-butadiene. d The corresponding cis
Figure 3
We next explored the use of iodomethyl phenyl sulfide as the
alkylating agent. This electrophile had been introduced by Trost in
a totally different context.19 Happily, its use resulted in dramatic
improvements in selectivity. As shown in Table 2, promising
stereoselectivity was accomplished even in the case of the hydrin-
denone (entry 6). In each case, the phenylthiomethyl group can be
converted to the methyl functionality through a high-yielding Raney
nickel reduction.
1
isomer was not detected within the limits of H and 13C NMR.
at the junction of cis-fused decalinoids (or hydrindanoids). We first
turned to the possibility of radical-mediated debromination (8 f
9). Parenthetically, it was of mechanistic interest to assess whether
the striking results we had observed above could be extended to
the bromine leaving group R to a ketone. The results, shown in
Table 1, are, indeed, quite encouraging.11 We note that the ratios
of trans to cis isomer in these experiments are even higher than
the corresponding ratios encountered in the reduction of the angular
nitro functions with the same radical-forming reagents. The
structures were assigned by preparation of reference samples of
cis-fused octalinones by Lewis acid-catalyzed Diels-Alder reactions
of cyclohex-2-enone itself with the appropriate dienes.11,12 In each
case, following debromination as described above, the minor
product corresponded to the reference cis sample. Explication of
the reasons for the higher levels of trans selectivity observed here
will require further study. In the context of the emergence of the
trans-Diels-Alder “logic”, valuable functionality (a keto group)
had been accommodated in the decalinoid product. It is well to
note that a number of these trans-fused products, though Very simple
structures, were preViously unknown in 2010 literature searches.
Having accomplished the goal of synthesizing C1 keto-function-
alized trans-fused decalinoids via initiating Diels-Alder reaction,
we addressed the matter of inserting a carbon-carbon bond at the
junction position R to the ketone in the ultimate trans product. As
earlier efforts to accomplish this goal via radical-mediated trapping
experiments of the type described above had been unsuccessful
(vide supra), our next attempt in this regard was that of reductive
alkylation.
At this stage it is difficult to know whether the superior results
achieved with iodomethyl phenyl sulfide are primarily due to its
greater steric demands or suggest a subtle electronic effect in the
nature of the alkylation event. Preliminary experiments were done
in this regard. Thus, the relative rates of alkylation of iodomethyl
phenyl sulfide and methyl iodide were actually quite comparable
in competitive experiments.20
We established the stereostructures of our products by
preparing the authentic cis-fused compounds by Lewis acid-
catalyzed Diels-Alder cycloaddition of the appropriate diene
with the corresponding R-methylated cyclenones. In this way
we could rigorously assign the structures of the minor products
to the cis isomer.11 Accordingly, the major products are
established as trans. Again, it is instructive to note that these
simple trans-fused bicyclic structures, carrying an angular methyl
group, were previously unknown. In fact, on reflection, it would
not have been a straightforward matter to synthesize such
compounds by methodology previous to that which is described
here. This type of trans-Diels-Alder paradigm increases the
range of synthetically accessible structures with consequences
for library construction, as well as for the synthesis of intermedi-
ate structures en route to complex targets. A view of the direction
in which this type of chemistry can lead was gained by studying
the product of trans-piperylene with R-bromocyclohexenone. The
We began by studying zinc-induced debromination of the
R-bromoketone, hoping to generate a zinc enolate, which might be
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C O M M U N I C A T I O N S
Table 2. Methylation of R-Bromoketones
Figure 5
and its stereochemistry is known (35).11 Anticipating a Pummerer
rearrangement, we treated this compound with trifluoroacetic
anhydride. In fact, this reaction gave rise to 37, whose structure
was surmised from spectral and mechanistic considerations and
verified by a crystallographic determination.11 Presently, we cannot
assert the mechanism of this reaction in detail. Qualitatively, it
seems that an electrophilically activated sulfoxide could well
undergo heterolysis with capture of the thionium group by some
equivalent of π-cyclization followed by hydration to afford the
observed R-epoxide. The scope and mechanism of this very
surprising but high-yielding reaction are currently matters of great
importance in our laboratory.
In summary, the research described above generates what we
call trans-Diels-Alder equivalents endowed with exploitable
functionality. Application of these newly acquired capabilities, as
well as expansion of the trans-Diels-Alder logic, is an ongoing
matter in our laboratory.
Acknowledgment. This paper is dedicated to Prof. Jahyo Kang
(Sogang University) in celebration of his 60th birthday. We thank
Rebecca Wilson for editorial advice and Aaron Sattler and Wesley
Sattler (Parkin group, Columbia University) for X-ray experiments
(NSF, CHE-0619638). Support was provided by the NIH (HL25848
to S.J.D.).
a Solvent: DME. b Solvent: THF. c The cis isomer was not detected
by NMR. d The cis isomer was isolated in 15% yield.
major course of this reaction, though not by an impressive ratio
(6:1), is that of endo addition.10 Nonetheless, it produced
adequate amounts of exo compound for separate study in an
alkylation experiment. This led to a highly stereoselective
formation of the trans-fused thiophenyl compound (30)11 and,
by Raney nickel, the reduction to the angular methyl compound
(31, Figure 4).21
Supporting Information Available: Experimental procedures,
spectral data, and characterization data (PDF, CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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Figure 4
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