Angewandte
Communications
Chemie
pyrolysis of 11 milligrams of 1 in a sealed tube produced
2.4 milligrams of chloranthalactone A (6),[10] also named
shizukanolide B,[11] and a trace amount of the diene 7,
whose structure was originally assigned as 7a (Figure 1b).[1]
However, we found that cycloaddition between 7b, an
analogue of 7a, and either 6 or 8, could not be realized
under either thermal or Lewis acid catalysis conditions
(Figure 1c).[9b] This failure is not surprising if one considers
the intrinsically electric character in both components of the
cycloaddition and steric repulsion between them in the
transition state. The compound 7b decomposes at 1408C,
and its thermal lability prompted us to question the validity of
the proposed molecular structure of the diene 7 from
pyrolysis of 1 at such a high temperature as 2508C. After
accomplishing the total synthesis of the proposed structure
7a,[12] we discovered curiously that the characterization data
of the synthetic 7a showed significant discrepancies with
those of the diene 7 reported by Kawabata et al., whereas the
NMR data of synthetic 7a and 7b were similar (Figur-
es 1b,c).[12] This exploration showed that the proposed
biosynthesis is not supported by experiment because of the
misassigned structure of 7. Moreover, the feasibility of the
decomposition of 1 indicates the irreversibility of the thermal
pyrolysis in Figure 1b, which sheds doubt on the thermody-
namic preference of the cycloaddition in the proposed
biohypothesis involving cycloaddition between 6 and 7. All
of the above observations and analyses indicate that the
originally proposed biosynthesis for the formation of linde-
nane sesquiterpenoid [4+2] dimers needs to be modified.
Inspired by our biomimetic total synthesis of bolivia-
nine,[13] we began to consider a modified biosynthesis with
cycloaddition between an either electron-normal or electron-
deficient dienophile (10) and an electron-rich diene conju-
gated with a furan (11; Figure 1d). Biogenetically, both diene
and dienophile could be formed from natural lindenane
precursors bearing a furan ring, such as lindenene (9) and its
natural analogues.[14] This hypothesis can be partially sup-
ported by prevalent co-occurrence of eudesmane sesquiter-
penoids, involving a furan motif, with eudesmane sesquiter-
penoids, involving a lactone motif. Eudesmane sesquiterpe-
noids are biosynthetically associated with lindenane sesqui-
terpenoids and both can be simultaneously isolated as
secondary metabolites of plants from the genus Chloran-
thus.[2] Biosynthetically, this electronic advantage in Diels–
Alder reactivity might surpass the steric repulsion between 10
and 11 in the transition state. Then oxidative elaboration of
the furan in 12 to a tetrasubstituted alkene could be rendered
at a late stage of the biosynthesis.
Scheme 1. Synthesis of the dienophile 24. BPSCl=tert-butyldiphenyl-
silyl chloride, brsm=based on recovery of the starting material,
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, LiHMDS=lithium hexame-
thyldisilazide, LDA=lithium diisopropylamide, MOM=methoxy-
methyl, THF=tetrahydrofuran, Ts=4-toluenesulfonyl.
Based on the above strategy, we started with the synthesis
of 10 starting with 13 (Scheme 1). The steric effect of the b-
oriented cyclopropane made the direct asymmetric trans-
formation from 13 into 16 nonproductive. Thus hydrobora-
tion-oxidation afforded the alcohol 15, the C4 stereochemis-
try of which was inverted through a sequence of oxidation,
isomerization, and reduction to produce 16. Protection of the
primary alcohol with BPSCl and ketal removal furnished 17,
which was subjected to aldol reaction to afford 18. Acetyla-
tion of the tertiary alcohol,[8h,i] and the subsequent DBU/LiBr
elimination smoothly produced 23. The presence of LiBr is
crucial to avoid the competitive formation of 20’ from 20. This
effect can be ascribed to activation of the ester in 21 with
LiBr, as a mild Lewis acid, to accelerate the lactone
formation. Finally, switching of the protective group from
BPS to MOM achieved the dienophile fragment 24.
To achieve the diene 11, 13 was first converted into 25
through removal of the ketal and alkene isomerization
(Scheme 2A). Silyl enol ether formation and Saegusa–Ito
oxidation resulted in the formation of 26.[16] Introducing an
OH a to the ketone and protecting it as a MOM ether
afforded 28. To invert the stereochemistry at C9, 28 was
subjected to thermal conditions in the presence of both DBU
and LiBr to achieve equilibrium. At this stage, 29 was isolated
in either 51% yield, or 65% yield based on recovery of 28.
The presence of a catalytic amount of a lithium salt
(20 mol%) was essential. Otherwise, only trace amounts of
29 could be obtained, even with 10 equivalents of DBU.
Installing an iodine atom on the less hindered alkene
delivered 30, which was reacted with the organoborate 31
through Suzuki cross-coupling to afford 32.[17] Chemoselec-
tive dihydroxylation at the least hindered and most electron-
rich double bond delivered 33. Treatment of 33 with acid was
anticipated to produce the diene fragment 34 through furan
formation and alkene isomerization.
Accordingly, retrosynthetic analysis revealed our target
molecules, 4 and 5, can be derived from the precursor 12 by
oxidative furan elaboration and other routine transformations
(Figurer1d). Notably, realizing the chemo-, regio-, and
stereoselectivities simultaneously is challenging in the [4+2]
cycloaddition toward 12, let alone the potential steric
repulsion between the carbonyl at C12 in 10 and Me (C13)
in 11 in the transition state. Both 10 and 11 might be prepared
from the known compound 13, which is accessible in six steps
from commercially available verbenone (14) on a ten-gram
scale given our improved procedure.[15]
2
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Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!
Yuan, Changchun
