Organic Letters
Letter
subsequent addition of DBU furnished fused pyridine 3 in
good yield.
first. However, our experiences in the methyl pyridine series
suggested that the internal olefin would be inert to traditional
Wacker oxidation conditions and led to our speculation that it
would be possible to convert the exocyclic olefin of 8 to a
methyl ketone which, in turn, might then be elaborated to
carboxylic acid 9 via a Lieben Haloform reaction (see Scheme
5).
Having completed the tricyclic core, we turned attention to
the remaining largely oxidative modifications of the periphery.
To this end, we attempted to advance 3 via palladium-
mediated Wacker type oxidations but did not observe any
appreciable product formation. After considerable experimen-
tation, we discovered an iron-catalyzed variant recently
developed by Han to be very effective in delivering the
corresponding ketone (6).5 With ketone 6 in hand, the stage
was set for a seemingly simple methylenation to 2. However,
typical Wittig olefination conditions using cryogenic temper-
atures and strong bases led to consistently low yields of the
desired product and the predominant return of starting
material. Presuming ketone enolizability as the culprit, we
turned to conditions originally developed by Conia (employing
sodium tert-amylate), and effectively deployed by Dauben to
overcome issues with both substrate sterics and acidity.6 In the
event, exposure of 6 to methyltriphenylphosphonium bromide
and potassium tert-butoxide in toluene at reflux furnished the
desired exocyclic methylene (2) in good yield.7 Unfortunately,
efforts to install the vicinal hydroxyl unit were met with little or
extraordinarily sluggish reactivity.8 Additionally, oxidation of
the methylpyridine on compounds 3 and 6 also proved
remarkably challenging, resulting in either undesirable or no
reactivity.9
Scheme 5. Evolution of an Oxidation Strategy
Much to our chagrin, it was found that exposure of 8 to
traditional Wacker oxidation conditions resulted in no
reaction. Efforts to push this chemistry led to the serendipitous
discovery that exposure of 8 to 2 equiv of PdCl2, under an
atmosphere of O2, results in the selective cleavage of the
external olefin giving rise to pyridinecarboxaldehyde 10;
neither oxidation to the corresponding acid nor reaction of
the internal olefin was observed under these conditions.
Intrigued by this reactivity we explored the literature for similar
observations and discovered pioneering work performed by
Spencer and Gaunt, who, when working on styrene-type
compounds, found that 2 equiv of PdCl2 were able to effect
anti-Markovnikov selectivity in the Wacker oxidation.11
Further, Spencer noted spontaneous degradation of the anti-
Markovnikov aldehydes to analogous benzaldehydes in the
presence of O2. Indeed, exposure of 8 to Spencer’s conditions
using degassed solvents and an inert atmosphere produced
anti-Markovnikov aldehyde 11 (see Scheme 5). Isolation of 11
and resubmission to the original, oxygenated, reaction
conditions again furnished 10. Notably, conditions akin to
those used by Spencer and Gaunt (2 equiv of PdCl2 in the
presence of O2) were also found to produce 10; however, the
efficiency of this transformation was increased by incorpo-
ration of CuCl.
Unable to advance methylpyridine substrates to the
corresponding ester, we decided to modify our plan. As
illustrated in Scheme 4, we focused on altering the 6π-azatriene
Scheme 4. Synthesis of Vinyl Pryidine (8) and Revision of
Retrosynthesis
With pyridinecarboxaldehyde 10 in hand, we employed a
standard Pinnick oxidation followed by treatment with
TMSCHN2 to provide the requisite methyl ester (12)
(Scheme 6).12 Based on previous success, we turned to the
iron-catalyzed Wacker-type oxidation to produce ketone 13
which, with this substrate, was accompanied by a mixture of
diastereomeric alcohols (14) that were isolated and converted
to 13 via a Swern oxidation.13 A modification of the Wittig
olefination was employed to furnish exomethylene 15.6,7
Lastly, dihydroxylation, with potassium osmate dihydrate and
NMO,14 provided a 1:3 mixture of diastereomers favoring the
undesired diastereomer of ent-plagiochianin B (16).15
Separation of the diastereomers allowed for comparison of
NOESY data which supported the isolation chemist’s proposed
relative stereochemistry of plagiochianin B. Furthermore,
analysis of the optical rotation of our synthetic product aided
electrocyclization substrate so as to deliver a more malleable
vinylpyridine intermediate (8), an approach that was
advantaged by continued efforts from Zhai.4b Selective
oxidations of the external and internal olefins would then
deliver 1b. While implementing this revised strategy, it was
found that exposure of enal 4 to benzoyloxy propargylamine
(7), with minor alteration to conditions reported by Zhai,
delivered the corresponding vinylpyridine (8) in useful yields.
With the vinyl pyridine 8 in hand, we turned toward
effecting a selective oxidation of the terminal olefin in the
presence of the presumably more electron-rich internal one.
Precedent regarding electrophilic oxidation strategies such as
ozonolysis10 suggested the internal olefin would likely react
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Org. Lett. 2021, 23, 1243−1246