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standard silica gel purification techniques rapidly decomposes
4. Finally, the synthesis could be scaled to give 600 mg batches
of 4 in 25% overall yield and in seven steps.
mediary radical species,[18] the addition is trans-selective and
the product could be identified as (À)-palustrol (13).[18]
Next, we evaluated direct oxidative cyclization modes of bi-
cyclogermacrene which should provide a manifold to further
rearranged terpenoids. Indeed, exposure of 4 to mCPBA at am-
bient temperature led to a very fast consumption of starting
material (Scheme 5). Putative epoxide 14 could not be detect-
ed. Instead, its tricyclic compound 15, identified as (+)-spathu-
lenol,[19] was isolated as a sole product in 57% yield. Conforma-
tionally enforced selective epoxidation triggers the intramolec-
ular cyclization and subsequent elimination to give the exo-
double bond of 15. With the often observed simultaneous
presence of both spathulenol and bicyclogermacrene in their
Synthesis of (+)-ledene and the terpenoids (+)-viridiflorol,
(À)-palustrol and (+)-spathulenol
Earlier work[8] and modelling of bicyclogermacrene conforma-
tions[14] clearly indicate a higher accessibility and reactivity of
the olefin moiety proximal to the cyclopropyl group towards
electrophilic reagents. A brief exposure of bicyclogermacrene
(4) to mildly acidic conditions induced a fast cyclization
(Scheme 3). For instance, the terpene (+)-ledene (11)[15] is
Scheme 5. Oxidative cyclization of bicyclogermacrene (4) to (+)-spathulenol
(15). mCPBA=meta-chloroperbenzoic acid.
Scheme 3. Cationic cyclization of bicyclogermacrene (4) to (+)-ledene (11).
formed in a virtually quantitative manner upon exposure to di-
luted hydrothiocyanic acid (a wider range of other acids pro-
vides 11 as well). The intermediate carbenium ion 4c under-
goes exclusive endo-elimination forming the tetrasubstituted
olefin.
natural sources, a similar oxidative pathway probably occurs in
the spathulenol biosynthesis.[20]
Biomimetic approach to meroterpenoids: Synthesis of psi-
guadial A, C and D
Ledene 11 was next exposed to different hydration strat-
egies to access different aromadendranols. For instance, hydro-
boration of 11 with borane followed by oxidative workup pro-
vided (+)-viridiflorol (12) with a cis-configured ring junction in
78% yield (Scheme 4). The reaction is completely regio- and
diastereoselective resulting from an approach of BH3 from the
more accessible convex face and an orientation of the borane
away from the ring junction. To alter the diastereoselectivity of
the hydration event, we exposed 11 to Mukaiyama’s cobalt-
catalyzed phenylsilane/O2 hydration method.[16] Intriguingly,
these conditions reverse the regiochemistry providing the hy-
droxyl group at the ring junction. Presumable due to the inter-
We next turned our focus towards meroterpenoids that are po-
tentially built from a coupling process involving a bicycloger-
macrene unit and an electron-rich aromatic phloroglucinol
part. The aromatic part derives from the polyketide metabo-
lism and constitutes a condensation product between doubly
formylated phloroglucinol 16 and an aliphatic or aromatic al-
dehyde. Knoevenagel-type condensation gives o-quinone me-
thide 17 (Scheme 6). Such o-quinone methides are reactive
substrates engaging in hetero-Diels–Alder reactions as previ-
ously shown for related meroterpenoids.[7,21] However, the
highly stabilized carbenium ion 18 (generated by loss of water
from the aldol intermediate or by protonation of 17) might
allow for alternative and divergent pathways. While such a cyc-
lization pathway might be stereochemically less clean, it could
allow for typical carbocation rearrangements providing addi-
tional products.
In this respect, members of the psiguadial and macrocarpal
structural family could be targeted by using bicyclogermacrene
4 in the cationic cyclization cascade.[6b,7] For instance, psigua-
dial D could be reached by the direct hetero-Diels–Alder path-
way and psiguadial A might originate from the electrophilic
cascade cyclization (Scheme 7). After the initial cyclization step
leading to tertiary carbenium 23, either direct Wagner–Meer-
wein shift or elimination similar to the aforementioned synthe-
sis of ledene followed by a protonation would give carbenium
ion 24. Subsequent intramolecular attack of the phenolic OH
group would give psiguadial A (1).
Scheme 4. Selective hydration of (+)-ledene provides (+)-viridiflorol (12)
and (À)-palustrol (13). acac=acetylacetonate.
Chem. Eur. J. 2014, 20, 1 – 7
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