Angewandte
Chemie
liquid chromatography (UPLC) measurements in the reac-
tion medium (98% formic acid) at various time intervals for
both (À)-(S,S)-8 and (Æ)-(S,S)-20.[11] The [M+H+] of the
observed reaction components in the evaporative light
scattering detector (ELSD) trace for (À)-(S,S)-8 corre-
sponded to monoformate and triformate adducts in the first
30 min of reaction; this indicates possible addition to C2 and/
or C13 in addition to the 1,1-disubstituted double bond prior
to cyclization. Substrate (Æ)-(S,S)-20 was routinely monitored
every few hours to observe the formation of monoformate
and diformate adducts in the ELSD trace; the formate peaks
gradually disappeared as the reaction proceeded to comple-
tion. For both substrates, the disappearance of all formate
intermediates was observed after 24 h with only product
remaining.[11]
The observed stereodivergent outcome (Scheme 4) may
be governed by steric interactions as represented in Figure 4.
Unfavorable steric interactions in cations 22b/23b, derived
from (À)-(S,S)-8, between the allyl group and the cyclo-
hexadiene ring system likely cause the equilibrium to favor
cations 22a/23a (Figure 4A). Because the cations are prox-
imal to the nucleophilic carbon at C3 in 22a/23a, we observe
dominant formation of the C-cyclized product. The prefer-
ence for O-cyclization in the case of (+)-(R,S)-8 may be
rationalized by the close proximity of the cation to the enol
depicted in the sterically favored conformation 24b (Fig-
ure 4B). The configuration depicted in 24a experiences
destabilizing steric interactions between the allyl substituent
and the cyclohexadiene core, thereby pushing the equilibrium
to favor 24b. Hence, 24b should react to afford O-cyclization
as the preferred stereodivergent outcome for diastereomer
(+)-(R,S)-8.
Scheme 6. Large-scale synthesis of (Æ)-clusianone potassium salt
(Æ)-1a. a) AlCl3, BzCl, CH2Cl2, 08C to RT, 3 h, 69%; b) K2CO3, nBu4NI,
allyl bromide, acetone, 758C, 16 h, 71%; c) 1,2-dichlorobenzene,
2108C, 12 h, 92%; d) LiHMDS, 10, THF/Tol=3:1, À208C to RT, 2 h,
67–83%, 1.3:1 d.r.; e) formic acid, 108C to RT, 48 h, 26–32%;
f) Grubbs second generation catalyst (20 mol%), isobutylene, À78 to
608C, 24 h, 81%.
access allyl clusianone 7. Finally, we developed a general
purification strategy for dearomatized phloroglucinols and
type B PPAP derivatives, thereby rendering our entire syn-
thesis column-free from phloroglucinol 9.[11] Further studies
regarding the synthesis and biological activity of PPAP
natural products and derivatives are in progress and will be
reported in due course.
Received: April 17, 2014
To conclude our study, we wished to demonstrate that our
synthesis of (Æ)-1 could be achieved on a gram-scale which is
not commonly reported for this class of compounds. The
difficulty associated with synthesizing large quantities of
PPAP natural products derives from their tendency to bind to
silica and form salts.[8d,11] Our final synthesis of racemic
clusianone (Æ)-1a utilized a general purification strategy for
dearomatized phloroglucinols and type B PPAPs,[11] where
the synthesis of acylphloroglucinol 9 and the subsequent
alkylative dearomatization were achieved on a multigram-
scale to provide 8 (30–37% over four steps, 1.3:1 d.r.,
Scheme 6). Without the need to separate diastereomers, the
key cyclization in formic acid was conducted on scales of up to
2 g where products were separated by basic extraction to
provide the potassium salt of allyl clusianone (Æ)-7a (26–
32%) as a single isomer.[11] Olefin metathesis proceeded in
81% yield using the Grubbs second generation catalyst[2c]
which was followed by basic workup to isolate more than
210 mg of racemic clusianone potassium salt (Æ)-1a. All salt
products could be converted to their conventional protonat-
ed, tautomeric forms by simple extraction with 1m HCl.
In conclusion, we have developed a scalable, asymmetric,
and stereodivergent synthesis of (À)-clusianone [(À)-1] in
only six steps from commercial starting materials. Protonative
cationic cyclization of 8 allowed selective access to five novel
architectures. Mechanistic studies[11] underscore the ability of
formic acid to mediate a unique biomimetic cyclization to
Published online: && &&, &&&&
Keywords: cationic cyclization · dearomatization · formic acid ·
.
natural products · PPAPs
[1] For reviews on total syntheses of PPAPs, see: a) R. Ciochina,
and Xanthones”: M. Dakanali, E. A. Theodorakis in Biomimetic
Organic Synthesis (Eds.: E. Poupon, B. Nay), Wiley-VCH,
[2] For recent syntheses of PPAPs, see: a) N. Biber, K. Mçws, B.
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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