Total synthesis of leucosceptroids a and B

Article abstract of DOI:10.1002/anie.201410134

Leucosceptroids A and B are sesterterpenoids with potent antifeedant and antifungal activities. A more efficient gram-scale total synthesis of leucosceptroid B and the first total synthesis of leucosceptroid A are presented. The key transformations include an aldol reaction between a substituted dihydrofuranone and an (S)-citronellal-derived aldehyde, a SmI₂-mediated intramolecular ketyl-olefin radical cyclization, and final-stage alcohol oxidation.

Full text of DOI:10.1002/anie.201410134

Angewandte
Chemie
DOI: 10.1002/anie.201410134
Terpenoids
Total Synthesis of Leucosceptroids A and B**
Sheng Guo, Jie Liu, and Dawei Ma*
Abstract: Leucosceptroids A and B are sesterterpenoids with
potent antifeedant and antifungal activities. A more efficient
gram-scale total synthesis of leucosceptroid B and the first total
synthesis of leucosceptroid A are presented. The key trans-
formations include an aldol reaction between a substituted
dihydrofuranone and an (S)-citronellal-derived aldehyde,
a SmI2-mediated intramolecular ketyl–olefin radical cycliza-
tion, and final-stage alcohol oxidation.
by the same group from Leucosceptrum canum and Colqu-
hounia coccinea var. mollis, and these were named leuco-
sceptroids C–O,[2] colquhounoids A–C,[3] and norleucoscep-
troids A–C.[4] Most of these show significant antifeedant
activity, which could explain why the corresponding plant is
rarely attacked by herbivores and only occasionally by
pathogens. This finding may shed new light on crop protec-
tion, and these sesterterpenoids could serve as lead com-
pounds for developing conceptually novel pesticides.
I
n 2010, Li and co-workers reported the isolation of
The interesting chemical structures and biological activ-
ities of the leucosceptroids and related sesterterpenoids
attracted the immediate attention of the synthetic community.
In 2011, the Horne group reported synthetic studies toward
the core structure of leucosceptroids A–D, with the employ-
ment of an intramolecular Diels–Alder reaction to install the
fused tricyclic hydrindane ring system.[5] Two years later, Liu
and co-workers achieved the first total synthesis of leuco-
sceptroid B in 2.7% overall yield from commerically unavail-
able (S)-5-methyl-5,6-dihydro-2H-pyran-2-one.[6] Recently,
Magauer and Hugelshofer accomplished the first total syn-
thesis of norleucosceptroids A and B.[7] Herein, we describe
a more efficient and scalable route for assembling leucoscep-
troid B and the first total synthesis of leucosceptroid A.
As outlined in Figure 2, we assumed that 1 could be
elaborated from 2 through deprotonation and oxidation. The
trans-hydrindanone skeleton in 2 offers an additional syn-
thetic challenge because the corresponding cis isomer may be
the more stable one and the energetic difference between
these two isomers is quite low.[8] Indeed, poor conversion for
epimerization of the cis isomer 2 greatly reduced the synthetic
efficiency in the leucosceptroid B synthesis developed by Liu
and co-workers.[6] To avoid this problem of isomerization, we
planned to obtain a trans-hydrindanol intermediate first and
leucosceptroids A and B (Figure 1) from glandilar trichomes
of Leucosceptrum canum. Preliminary biological evaluation
revealed that these two sesterterpenoids have potent anti-
feedant activity (against the beet armyeorm and cotton
bollworm) and antifungal effects (against four strains of
agricultural pathogenic fungi, including Colletotrichum musae
and Rhizoctonia solani).[1] In the following years, several
additional structurally related sesterterpenoids were isolated
Figure 1. Structures of the leucosceptroids and related sesterterpe-
noids.
[*] S. Guo, J. Liu, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic & Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
E-mail: madw@mail.sioc.ac.cn
[**] We are grateful to the National Basic Research Program of China
(973 Program, grant 2010CB833200), Chinese Academy of Sciences
and the National Natural Science Foundation of China (grant
21132008 & 20921091) for their financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410134.
Figure 2. Retrosynthetic analysis of leucosceptroids A and B.
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subsequently convert it into 2 at the final step. Consequently,
triol 3, which could be assembled by a SmI2-mediated 6-exo
cyclization of ketone 4, became our next synthetic target . The
installation of 4 could be achieved by an aldol reaction of
dihydrofuranone 5 and aldehyde 6, which could be prepared
by using aldehyde 7 and (S)-citronellal (8), respectively, as the
chiral pools.
molecular allylation of aldehyde 16 worked well according to
MacMillan’s SOMO-organocatalysis procedure,[14] delivering
the aldehyde 6 in 89% yield (6 g scale) and with high
diasteroselectivity (33:2:1 for 6 and two other isomers).
We next investigated the aldol reaction of dihydrofur-
anone 5 with aldehyde 6. Initially, we attempted to condense
the lithium enolate of ketone 5 (with LiHMDS or LDA) with
aldehyde 6 and found that no desired aldol product was
produced, presumably because of the steric hindrance of the
two reactants and the thermodynamically favored retroaldol
reaction. After some experimenting, we discovered that
treatment of ketone 5 with (Hex)2BCl and Et3N at À788C[15]
followed by the addition of 6 gives the adduct 17 in 78% yield
and with high diastereoselectivity (13:1.5:1 for 17 and two
other isomers; Scheme 2). The success of the aldol reaction
under these conditions is ascribed to the stability of the
We commenced our total synthesis by assembling the
required dihydrofuranone 5 and aldehyde 6 (Scheme 1). The
Scheme 1. Reagents and conditions: a) EtMgBr, CuCl, 508C, then 3-
bromoprop-1-yne; b) AuPPh3Cl, AgOTf, 85% for 2 steps; c) nBuLi,
THF, À788C, then (iPrO)3TiCl; then (R)-2,2-dimethyl-1,3-dioxolane-4-
carbaldehyde 7, 78%; d) Fe(acac)3, MeMgBr, THF, 85%; e) Dowex 50
W/H+ acid resin, MeOH, 78%; f) TBDPSCl, Imidazole, DMF, 88%;
g) PhSeCl, K2CO3, THF, À788C, then HOAc/NaOAc, H2O2, 78%;
h) O3, MeOH, Me2S, À788C then Ph3P=CHCH2TMS, 59%; i) Dess–
Martin periodinane, CH2Cl2, 87%; j) 5% (2S,6S)-2-tert-butyl-3-methyl-5-
benzyl-4-imidazoildinone trifluoroactate, CAN, NaHCO3, H2O, DME,
89%, d.r.=33:2:1. THF=tetrahydrofuran, TBDPS=tert-butyldiphenyl-
silyl, DMF=N,N-dimethylformamide, TMS=trimethylsilyl, CAN=ceric
ammonium nitrate, DME=1,2-dimethoxyethane.
Scheme 2. Reagents and conditions: a) (Hex)2BCl, NEt3, THF, À788C
to 08C, 78%; b) SmI2, HMPA, THF, tBuOH; c) TMSCl, DMAP,
imidazole, DMF, 90%; d) SmI2, HMPA, THF, H2O, then HF·Py.
HMPA=hexamethylphosphoramide, DMAP=4-dimethylaminopyri-
dine, Py=pyridine.
derived ketol borate complexes. With alcohol 17 in hand, the
stage was set for the crucial SmI2-mediated intramolecular
ketyl–olefin radical cyclization.[16] Accordingly, we treated 17
with SmI2 in THF/HMPA/tBuOH and obtained the 5/7/5
tricyclic compound 19, together with some decomposed
products. This result was rather unexpected because similar
substrates have been reported to give 6-exo cyclization
products.[16] We thought that this observation might result
from the steric hindrance of the 6-membered ketyl ring unit
that was generated from chelation of the SmIII cation by the b-
hydroxyl group (conformer A, Figure 3), which might inhibit
6-exo cyclization and force the reaction to proceed through 7-
endo-trig cyclization. Based on this assumption, we decided to
protect the free hydroxyl group with TMS. After treatment of
the resulting silyl ether 18 with SmI2 and subsequent
desilylation, we found that the reaction still gave the 7-
endo-trig cyclization product 20[13] as the major product,
although the 6-exo cyclization product 21 could be isolated in
40% yield and with poor diastereoselectivity (Scheme 2).
Since the problem might be caused by strong repulsive
interaction between the axial-orientated b-OTMS and the
olefin moiety (conformer B, Figure 3), we speculated that if
ketone 22, which has an a-OTMS unit, was used, cyclization
coupling of 3-bromoprop-1-yne and the cuprous salt gener-
ated from enynol 9 produced a diyne, which was treated with
a gold catalyst in the presence of silver triflate to afford furan
10 in 85% yield.[9] After the transformation of 10 into
a titanium acetylide complex, Felkin–Anh addition of the
aldehyde 7 was carried out to provide anti-adduct 11 in 78%
yield and with 7:1 diastereoselectivity.[10] Next, iron-catalyzed
carbometalation of propargylic alcohol 11 with MeMgBr
proceeded smoothly to deliver allyl alcohol 12,[11] which was
deprotected and the liberated primary alcohol reprotected
with TBDPSCl to give diol 13. Finally, PhSeCl-mediated
cyclization of 13 led to the diastereoselective formation of
substituted tetrahydrofuran 14,[12,13] the structure of which
was confirmed by X-ray crystallography. Without isolation, 14
could be directly oxidized with H2O2 to furnish dihydrofur-
anone 5 in 78% yield. In a parallel procedure, (S)-citronellal
(8) was subjected to oxidative cleavage and subsequent Wittig
olefination to produce olefin 15, which was converted into
aldehyde 16 through DMP oxidation. Pleasingly, the intra-
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Figure 3. Possible stereochemical outcomes for SmI2-mediated cycliza-
tion.
might proceed through conformer C, in which the OTMS
group in the equatorial position would not affect the 6-exo
cyclization. Furthermore, this conformer would give the
product with correct stereochemistry for synthesizing target
molecules at the two newly created stereocenters.
Scheme 3. Reagents and conditions: a) Me4NB(OAc)3H, AcOH,
MeCN, 89%; b) DMAP, AcCl, pyridine; c) IBX, DMSO, 77% for 2
steps; d) LiBH4, THF, 85%; e) IBX, DMSO; f) TMSCl, DMAP, imida-
zole, 62% for 2 steps; g) SmI2, HMPA, H2O, THF, then HF·Py, 89%;
h) IBX, DMSO; i) iPrPPh3I, nBuLi, THF, À788C to RT, 92% for 2 step;
j) (COCl)2, DMSO, DIPEA, toluene, À758C to RT, 80%;k) LDA, O2,
P(OEt)3, À78 to À358C, 60%. IBX=2-iodoxybenzoic acid, DMSO=di-
methyl sulfoxide, DIPEA=N,N-diisopropylethylamine, LDA=lithium
diisopropylamide. Crystal structure: red oxygen, blue hydrogen.
With this idea in mind, we attempted to revise the
stereochemistry of the aldol reaction step but we found that
none of the desired a-hydroxyl product could be obtained
under various conditions. We thus had to reach our goal
indirectly, as demonstrated in Scheme 3. Reduction of 17 with
Me4NB(OAc)3H afforded diol 23, which was subjected to
regioselective acylation and subsequent oxidation of the
remained hydroxyl group to produce ketone 24 in 69%
overall yield. LiBH4 reduction of 24 provided the alcohol with
the desired stereochemistry and the resultant diol was
selectively oxidized with IBX to deliver ketone 22 after
protection with TMSCl. To our delight, the SmI2-mediated
cyclization of 22 worked well, producing the desired triol 3[13]
in 89% yield as a single product after desilylation. Finally,
selective oxidation of the primary alcohol in 3 followed by
Wittig olefination gave rise to diol 25, which was converted
into 2 through Swern oxidation. This route is scalable, as
evident from the fact that more than 1.2 g of 2 could be
obtained. Furthermore, regioselective a-hydroxylation
(LDA, then O2 and P(OEt)3)[7,17] of 2 delivered leucoscep-
troid A in 60% yield.
In conclusion, by using a substituted dihydrofuranone and
a (S)-citronellal-derived aldehyde, with an SmI2-mediated
intramolecular ketyl–olefin radical cyclization and final-stage
alcohol oxidation as the key steps, we accomplished a more
efficient and scalable synthesis of leucosceptroid B (5.6%
overall yield for 18 linear steps from commercially available
enynol 9) and the first total synthesis of leucosceptroid A.
Leucosceptroid B could serve as the starting material for
synthesizing other members of the leucosceptroid family and
our synthetic route could be used for assembling a wide range
of leucosceptroid analogues. Our findings thus provide a basis
for further structure–activity relationship (SAR) studies of
these antifeedant compounds and the subsequent develop-
ment of new pesticides.
Keywords: aldol reaction · cyclization · natural products ·
.
sesterterpenoids · total synthesis
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Terpenoids
The sesterterpenoids leucosceptroids A
and B are plant secondary metabolites
with potent antifeedant and antifungal
activities. A convergent and scalable
synthesis of leucosceptroids A and B was
achieved by employing an aldol reaction
and an SmI2-mediated intramolecular
ketyl–olefin radical cyclization as the key
steps.
S. Guo, J. Liu, D. Ma*
&&&& — &&&&
Total Synthesis of Leucosceptroids A and
B
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