A General Entry to Antifeedant Sesterterpenoids: Total Synthesis of (+)-Norleucosceptroid A, (-)-Norleucosceptroid B, and (-)-Leucosceptroid K

Article abstract of DOI:10.1002/anie.201407788

The first asymmetric total synthesis of the antifeedant terpenoids (+)-norleucosceptroid A, (-)-norleucosceptroid B, and (-)-leucosceptroid K has been accomplished. This highly concise synthetic route was guided by our efforts to develop a platform for the collective synthesis of a whole family of antifeedant natural products. The synthesis features a Hauser-Kraus-type annulation followed by an unprecedented, highly efficient intramolecular dilactol aldol-type condensation reaction to produce the 5,6,5 skeleton. The developed synthetic route proceeds for norleucosceptroid A and B in 16 steps (longest linear sequence) from known compounds.

Full text of DOI:10.1002/anie.201407788

Angewandte
Chemie
DOI: 10.1002/anie.201407788
Terpenoid Synthesis
A General Entry to Antifeedant Sesterterpenoids: Total Synthesis
of (+)-Norleucosceptroid A, (À)-Norleucosceptroid B,
and (À)-Leucosceptroid K**
Cedric L. Hugelshofer and Thomas Magauer*
Dedicated to Professor Johann Mulzer and Professor Andrew G. Myers
Abstract: The first asymmetric total synthesis of the antifeed-
ant terpenoids (+)-norleucosceptroid A, (À)-norleucoscep-
troid B, and (À)-leucosceptroid K has been accomplished.
This highly concise synthetic route was guided by our efforts to
develop a platform for the collective synthesis of a whole
family of antifeedant natural products. The synthesis features
a Hauser–Kraus-type annulation followed by an unprece-
dented, highly efficient intramolecular dilactol aldol-type
condensation reaction to produce the 5,6,5 skeleton. The
developed synthetic route proceeds for norleucosceptroid A
and B in 16 steps (longest linear sequence) from known
compounds.
worm and are the first natural sesterterpenoids with biolog-
ical activity against plant-feeding insects and pathogens. The
concept of employing nontoxic antifeedant compounds to
protect plants from insect herbivores could emerge as an
alternative to conventional synthetic pesticides since the
former exhibit high specificity, quick degradation, and lack of
impact on nontarget organisms.[7]
The biological properties and novel chemical scaffolds of
leucosceptroids and many other sesterterpenoids[8] make
these natural products highly attractive targets for chemical
synthesis. Recently, Liu and co-workers[9] disclosed the first
total synthesis of leucosceptroid B, and Horne and co-work-
ers[10] reported an approach to the core of the leucosceptroids.
To date, a general and modifiable strategy that would allow
the collective synthesis of this natural product class (compris-
ing 23 members) is not yet available. Structurally, all members
of the leucosceptroid family of natural products share a highly
functionalized, synthetically challenging 5,6,5 framework that
differs in the oxidation state at C11 (OH, H) and the
substitution of the C14 ethyl linkage. These attributes were an
essential consideration in our initial retrosynthetic analysis of
the common ABC core structure and led us to focus on
disconnection of the central six-membered ring.
Herein, we describe an enantioselective synthetic route to
(+)-norleucosceptroid A (1), (À)-norleucosceptroid B (2),
and (À)-leucosceptroid K (3) that proceeds through the
convergent assembly of two building blocks of similar
complexity (Scheme 1). Our initial synthetic target was
fragment 4, which could be traced back to 5 through
disconnection of the substituents at C4, C5 and C6. The
ABC tricycle 5 contains the full retron for a simplifying
formal Diels–Alder reaction of the AB dienolate 6 and the C-
ring butenolide 7. We envisaged that both coupling partners
could be accessed from simple, readily available building
blocks.
T
he cotton bollworm (Helicoverpa armigera) and the beet
armyworm (Spodoptera exigua) are among the most destruc-
tive agricultural pests in nature and they affect vegetables and
other crops worldwide.[1] Protection against them has been
achieved by the use of sex-pheromone traps, insecticides, and
transgenic crops. However, resistance to insecticides has
developed over the last decade and new chemical agents are
necessary to prevent further crop damage from these pests.
Leucosceptrum canum Smith (“Birdꢀs Coca Cola tree”)[2] and
Colquhounia coccinea var. mollisa, plants found in China and
Nepal, are remarkably resistant to herbivores and pathogens.
Extraction and isolation of the trichomes, flowers, and whole
leaves recently led to the discovery of novel sesterterpenoids,
designated leucosesterterpenone and leucosesterlactone,[3]
leucosceptroids A–O,[4] colquhounoids A–C,[5] and norleuco-
sceptroids A–C, which are classified as pentanor-sesterterpe-
noids.[6] In general, these compounds display potent antifeed-
ant activity against the cotton bollworm and the beet army-
[*] M. Sc. C. L. Hugelshofer, Dr. T. Magauer
Department of Chemistry and Pharmacy
Ludwig-Maximilians-University Munich
Butenandtstrasse 5–13, 81377 Munich (Germany)
E-mail: thomas.magauer@lmu.de
In the forward sense, the absolute configuration of
fragment 7 was set through a Sharpless asymmetric dihy-
droxylation reaction starting from 8 (Scheme 2).[11] As shown
by Corey, the p-methoxyphenyl directing group determined
the enantiofacial selectivity and was essential to provide 9 in
high enantiomeric excess (> 97% ee).[12] Oxidation of diol 9
using Parikh–Doering conditions[13] and homologation with
[**] We gratefully acknowledge financial support from the FCI (Liebig
Fellowship to T.M. and Kekulꢀ Mobility Fellowship to C.L.H.), the
DFG (Emmy-Noether Fellowship to T. M.) and Prof. Dirk Trauner.
We thank M. Sc. A. Ahlers and B. Sc. J. Tumpach for preliminary
synthetic studies, Dr. Peter Mayer (LMU Munich) for determination
of the X-ray structures, and Dr. David Barber, Dr. Jonathan Mortison,
and Dr. Ian Seiple for helpful discussions during the preparation of
this manuscript.
Bestmannꢀs ylide (Ph3P C C O)[14] formed the butenolide 7
= = =
in good overall yield.
The sequence for the preparation of 6 was initiated with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407788.
the degradation of inexpensive (R)-pulegone (10)[15] accord-
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Scheme 1. Selected members of the leucosceptroids family of natural
products: (+)-norleucosceptroid A (1), (À)-norleucosceptroid B (2),
and (À)-leucosceptroid K (3); and retrosynthetic analysis. PMP=
p-methoxyphenyl.
Scheme 2. 1) Preparation of C-ring butenolide 7. Reagents and con-
= =
ditions: a) SO3·pyridine, DMSO, NEt3, CH2Cl2, 238C, 87%; b) Ph3P C
=
C O, THF, 608C, 56%. 2) Preparation of AB segment 12. Reagents
and conditions: c) Tf2O, LDA, THF, À788C to 08C; d) DIBAL-H,
CH2Cl2, À788C to 238C, 58% over two steps; e) H2SO4/HCO2H,
Pd(PPh3)4, LiCl, (nBu)3N, MeCN, 708C, 98%. DIBAL-H=diisobutylalu-
minium hydride, DMSO=dimethyl sulfoxide, LDA=lithium diisopro-
pylamide.
Scheme 3. Fragment coupling to give the ABC tricycle 5. Reagents and
conditions: a) LHMDS, THF, then 7, À788C to À308C, d.r. =3:1;
b) Pd/C, H2, MeOH, 57% over two steps; c) DIBAL-H, CH2Cl2, À788C;
d) TFA, CH2Cl2, 4 ꢁ molecular sieves, 238C, then PDC, 238C; e) LDA,
THF, À788C, 69% over three steps. LHMDS=lithium hexamethyldisil-
azane, PDC=pyridinium dichromate, TFA=trifluoroacetic acid.
ing to a reported procedure.[16] A combination of lithium
diisopropylamide and triflic anhydride was superior to all
other investigated conditions (KHMDS/Tf2O; NEt3/Tf2O;
DIPEA/Tf2O; LDA/PhNTf2; LDA/Cominsꢀ reagent) for the
triflation of the known b-keto ester 11. Selective reduction of
the ester group was readily accomplished with diisobutylalu-
minium hydride to afford the allyl alcohol in 57% yield over
two steps. Palladium(0)-catalyzed insertion of carbon mon-
oxide,[17] generated in situ from the reaction of formic acid
with sulfuric acid,[18] gave the AB bicycle 12 in 98% yield.
Having developed scalable routes to both ring fragments,
we concentrated our efforts on uniting 7 and the AB compo-
nent 12-derived lithium isofuran-1-olate 6, through a Hauser–
Kraus-type annulation (Scheme 3).[19,20] Predicting that the
reaction would proceed via the transition state shown in
Scheme 3, we expected the stereochemical outcome depicted
for the ABC tricycle 13. Although the stereodiscriminating
effect of the quaternary center at C14 in 7 was highly
uncertain at this stage, we hypothesized that the methyl group
at C10 of the AB segment 6 could reinforce the stereofacial
selectivity by approaching 7 with its sterically less-hindered
bottom face. Indeed, treatment of a solution of 6 in
tetrahydrofuran, prepared from 12 using lithium hexamethyl-
disilazane (2.2 equiv), with equimolar amounts of 7 (À788C to
À308C) led to the formation of enone 13 as a 3:1 mixture of
diastereomers. The proposed structure and relative stereo-
chemistry of 13 was unambiguously validated by single-crystal
X-ray diffraction. It was necessary to employ excess base to
trap 13 as the enolate in order to prevent a retro-Claisen
reaction from occurring. The formation of the minor diaste-
reomer can be rationalized by an exo approach of 6 from the
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lower face of 7 to give the corresponding enone, which
possesses the inverse stereochemistry at C5, C12, and C13
compared to 13, as shown by NMR analysis. We also found
that the use of degassed tetrahydrofuran for this transforma-
tion suppressed the formation of a p-hydroquinone byproduct
(see the Supporting Information) and increased the yield of
the reaction by approximately 20%.
Initial attempts to directly hydroxylate C5 and introduce
the methyl group at C6 were unsuccessful since overoxidation
prevailed. However, prior reduction of the enone allowed us
to develop an alternative approach that avoided the afore-
mentioned problem. Hydrogenation of 13[21] using palladium
on charcoal under 1 atm of hydrogen occurred exclusively
from the convex side of the molecule. After prolonged
reaction times or exposure of the crude reaction mixture to
triethylamine, we isolated a product with 13C NMR and IR
spectra that did not correspond to the expected ketone 14a.
From a molecular model, we concluded that the free hydroxyl
group at C12 was well disposed to form hemiacetal 14b, which
could in turn undergo a retro-Claisen condensation to give
dilactone 15. This reaction pathway was also supported by
data obtained from density functional theory (DFT) calcu-
lations at the B3LYP/6-31G(d) level of theory with the
Gaussian09 software suite.[22] Although ketone 14a was never
observed experimentally, the intermediate 14b could be
obtained as a single compound and fully characterized. As
above, upon exposure of hemiacetal 14b to mildly basic
(NEt3) or acidic (silica gel) conditions, clean transformation
to 15 was observed. To date, more than 4.7 g of dilactone 15
have been prepared in a single batch.
This rather unexpected reaction outcome was taken as
a chance to reform the 5,6,5 framework by developing an
unprecedented intramolecular dilactol aldol-type condensa-
tion within a complex molecular setting.[23] The synthesis of
the required dilactol motif through a twofold reduction of 15
(DIBAL-H, CH2Cl2, À788C) was highly efficient and gave 16
as a mixture of four diastereomers. Careful screening of the
reaction parameters (solvent, temperature, reagent) was
necessary to realize the intended one-pot condensation–
oxidation sequence to give 19. The optimized procedure
involved treating a solution of dilactol 16 in dichloromethane
containing 4 ꢁ molecular sieves with trifluoroacetic acid
(5 equiv) at 238C for 20 min, followed by the addition of
pyridinium dichromate to the intermediate 4-O-trifluoroace-
tyl acetal 18.[24] This afforded the tetracycle 19 as a single
diastereomer, the structure of which was unambiguously
confirmed by single-crystal X-ray diffraction. Excess acid was
required to prevent the reaction from stalling after the
intramolecular acetalization of 16 to 17. The most efficient
conditions for the opening of the ether bridge involved the
addition of lithium diisopropylamide (1.15 equiv) to a solution
of 19 in tetrahydrofuran at À788C, which afforded more than
3.0 g of a,b-unsaturated lactone 5 (69% yield over three
steps).
Scheme 4. Functionalization of the leucosceptroids ABC core and total
synthesis of (+)-norleucosceptroid A (1), (À)-norleucosceptroid B (2),
and (À)-leucosceptroid K (3). Reagents and conditions: a) MeLi, CuI,
Et2O, À458C to À58C, 76%; b) DIBAL-H, CH2Cl2, À788C; c) MsCl,
NEt3, 1,2-dichloroethane, 758C, 53% over two steps; d) DMDO,
acetone, CH2Cl2, À788C to À308C, then AlCl3, 2-methyl-1-propenyl-
magnesium bromide, THF, CH2Cl2, À788C, 52%; e) PCC, CH2Cl2, 4 ꢁ
molecular sieves, 238C, 87%; f) CAN, pyridine, MeCN, H2O, 08C,
70%; g) DMP, NaHCO3, CH2Cl2, 238C, 66%; h) LHMDS, O2, P(OEt)3,
À788C to À358C; i) IBX, DMSO, 238C, 40% 1 and 10% 2 over two
steps; j) 24, KOtBu, THF, 08C, then 2, 08C to 238C, 70%. CAN=ceric
ammonium nitrate, DMDO=dimethyldioxirane, DMP=Dess–Martin
periodinane, IBX=2-iodoxybenzoic acid, MsCl=methanesulfonyl chlo-
ride, PCC=pyridinium chlorochromate.
unsuccessful, we envisioned introduction of the C5 hydroxy
group via enol ether 21. The addition of triethylamine
(7.5 equiv) to a solution of the crude lactol, derived from 20
by DIBAL-H reduction, and methanesulfonyl chloride
(3.5 equiv) in dichloroethane at 758C provided 21 in a repro-
ducible manner. These reaction conditions reduced formation
of the acetal byproduct that resulted from attack of the C12
hydroxy group on C4 (see the Supporting Information). The
epoxide obtained from the reaction of 21 with a solution of
dimethyldioxirane in acetone, prepared by the method
developed by Taber et al.,[25] was found to be highly unstable
and was readily hydrolyzed to the corresponding lactol. We
found that the addition of the crude epoxide product as
a solution in dichloromethane to a large excess of tris-(2-
methyl-1-propenyl) aluminum[26] in tetrahydrofuran at À788C
delivered the required vinylic appendage from the same side
as the epoxide to give the configuration at C4 and C5 depicted
in 4. The observed stereoselectivity of this transformation was
attributed to coordination of the organoaluminum reagent to
the epoxide to give the alanate and concomitant internal
Conjugate addition of excess dimethyl cuprate to 5
occurred with excellent diastereoselectivity at C6 and gave
rise to 20 as an inconsequential 4:1 mixture of kinetic and
thermodynamic epimers at C5 (Scheme 4). Since direct a-
hydroxylation followed by lactone reduction proved to be
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delivery of the propenyl nucleophile. Introduction of the
vinylic appendage at C4 occurred with opposite stereoselec-
tivity when a combination of copper(I) iodide and 2-methyl-1-
propenylmagnesium bromide was applied in the analogous
reaction.[27]
[1] a) K. M. Wu, Y. H. Lu, H. Q. Feng, Y. Y. Jiang, J. Z. Zhao,
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Subsequent oxidation of the sterically hindered alcohol
produced the configurationally stable ketone 4. We found that
H11 and H13 of 4 do not epimerize under basic conditions at
238C, however, since the b-hydroxy ketone is perfectly
aligned for an E2 elimination, dehydration takes place
under more forcing conditions (NEt3, MeOH, 458C).
Although cis-hydrindanones were calculated to be thermo-
dynamically more stable,[28] and as is corroborated by the
structures of most leucosceptroid natural products, (+)-nor-
leucosceptroid A (1) features an AB-cis-BC-trans fusion in
which intramolecular hemiacetal formation preserves this
conformation from epimerization to the AB-cis-BC-cis
system.
Cleavage of the p-methoxyphenyl ether in 4 with cer-
ic(IV) ammonium nitrate followed by oxidation of the
primary alcohol 22 with Dess–Martin periodinane afforded
(+)-11-deoxynorleucosceptroid A (23), which has not yet
been isolated from natural sources.[29] Regioselective a-
hydroxylation (LHMDS, O2, P(OEt)3)[30] of 22 afforded two
C11 hydroxylated products, which were directly oxidized
under mild conditions (IBX, DMSO)[31] without prior purifi-
cation. NMR analysis of the resulting product mixture
revealed that a-hydroxylation had occurred with high stereo-
selectivity. However, we also recognized that partial epimer-
ization of H13 to the thermodynamically more stable AB-cis-
BC-cis fusion had spontaneously taken place during the a-
hydroxylation step. Column chromatography on silica gel thus
gave (+)-norleucosceptroid A (1), as well as minor amounts
of (À)-norleucosceptroid B (2). Finally, the union of 2 with
phosphonate 24[32] gave rise to (À)-leucosceptroid K (3) in
70% yield. The spectroscopic data (1H and 13C NMR, HRMS,
[a]D) for 1–3, which are the unnatural enantiomers, were in
full agreement with those reported for the naturally occurring
substances.
[8] D. T. Hog, R. Webster, D. Trauner, Nat. Prod. Rep. 2012, 29,
752 – 779.
[9] X. Huang, L. Song, J. Xu, G. Zhu, B. Liu, Angew. Chem. Int. Ed.
2013, 52, 952 – 955; Angew. Chem. 2013, 125, 986 – 989.
[10] J. Xie, Y. Ma, D. A. Horne, J. Org. Chem. 2011, 76, 6169 – 6176.
[11] H. C. Kolb, M. S. Van Nieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483 – 2547.
[12] The use of a tert-butyldimethylsilyl group led to the erosion of
enantioselectivity in the Sharpless asymmetric dihydroxylation
reaction. Mosher ester analysis revealed that the undesired (S)-
enantiomer was formed in low enantiomeric excess (ca. 20%).
For a detailed analysis: E. J. Corey, A. Guzman-Perez, M. C.
Noe, J. Am. Chem. Soc. 1995, 117, 10805 – 10816.
[13] J. R. Parikh, W. Doering, J. Am. Chem. Soc. 1967, 89, 5505 –
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[14] We were surprised to find that the use of Bestmannꢀs Ylide for
the synthesis of butenolides from a-hydroxy aldehydes is, to our
knowledge, unprecedented in the literature; a) R. Schobert, Org.
Synth. 2005, 82, 140 – 146; b) H. J. Bestmann, D. Sandmeier,
Angew. Chem. Int. Ed. Engl. 1975, 14, 634; Angew. Chem. 1975,
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[15] For practical reasons, we started from inexpensive (R)-pulegone.
(S)-Pulegone can be prepared from (S)-citronellol: E. J. Corey,
H. E. Ensley, J. W. Suggs, J. Org. Chem. 1976, 41, 380 – 381.
[16] a) J. N. Marx, L. R. Norman, J. Org. Chem. 1975, 40, 1602 – 1606;
b) H. Niwa, K. Kunitani, T. Nagoya, K. Yamada, Bull. Chem.
Soc. Jpn. 1994, 67, 3094 – 3099.
In summary, a general enantioselective synthesis of
antifeedant (pentanor-)sesterterpenoids has been developed.
This enabled the preparation of three representative anti-
feedant leucosceptroids; (+)-norleucosceptroid A (1),
(À)-norleucosceptroid B (2), and (À)-leucosceptroid K (3);
in a convergent manner with a high level of efficiency. The
ability to prepare the ABC tricycle 5 on a multigram scale
(3.0 g) paves the way for the synthesis of the remaining
leucosceptroids. This work also highlights the fact that the
intramolecular aldol condensation of dilactols could be
a useful method for organic synthesis. A collective synthesis
of the leucosceptroid family and unnatural derivatives thereof
is currently underway in our laboratories.
[17] G. T. Crisp, A. G. Meyer, J. Org. Chem. 1992, 57, 6972 – 6975.
[18] The CO apparatus (similar to an H-tube) does not require
special laboratory equipment. See the Supporting Information
for details and the experimental setup.
[19] D. Mal, P. Pahari, Chem. Rev. 2007, 107, 1892 – 1918.
[20] Alternatively, the reaction can be described as a formal [4+2]
cycloaddition: Substituted furans, in particular isofurans, are
notoriously inefficient dienes in Diels–Alder reactions. Activa-
tion with high pressure is often required: a) C. O. Kappe, S. S.
Murphree, A. Padwa, Tetrahedron 1997, 53, 14179 – 14233;
b) C. L. Hugelshofer, T. Magauer, Synthesis 2014, 1279 – 1296.
Received: July 31, 2014
Published online: && &&, &&&&
Keywords: Claisen reaction · leucosceptroids ·
.
natural products · terpenoids · total synthesis
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[21] The 3:1 diastereomeric mixture of enones was used for this
purpose. The spontaneous autoxidation in air and low solubility
of both diastereomers in several solvent mixtures made the
purification of 13 inefficient and time-consuming at this stage.
The dilactones obtained in the following step could be easily
separated.
[26] Tris-(2-methyl-1-propenyl) aluminum was prepared in situ by
adding a threefold excess of 2-methyl-1-propenylmagnesium
bromide to a suspension of aluminum trichloride in tetrahydro-
furan at 08C.
[27] I. Singh, O. Seitz, Org. Lett. 2006, 8, 4319 – 4322.
[28] H. L. Gorson, S. Freeman, T. Hudlicky, Synthesis 2005, 2911 –
2914.
[29] The Li group is actively searching for novel leucosceptroids
natural products, including 11-deoxynorleucosceptroid A.
[30] a) E. J. Corey, H. E. Ensley, J. Am. Chem. Soc. 1975, 97, 6908 –
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[31] Oxidation of the 1,5-diol was found to be challenging since
overoxidation of the formed lactol readily occurred under
a variety of conditions. E. J. Corey, A. Palani, Tetrahedron
Lett. 1995, 36, 3485 – 3488.
[22] Gaussian09, RevisionA.02, M. J. Frisch, et al., Gaussian, Inc.,
Wallingford CT, 2009.
[23] For two examples of inspiring intramolecular aldol condensa-
tions in natural product synthesis under almost neutral aprotic
conditions: a) E. J. Corey, R. L. Danheiser, S. Chandrasekaran,
P. Siret, G. E. Keck, J. L. Gras, J. Am. Chem. Soc. 1978, 100,
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2012, 489, 278 – 281.
[24] Labeling studies with CF3CO2D and CD3OD showed that this
highly reactive intermediate is formed from the oxonium ion; an
enol ether is not involved.
[25] D. F. Taber, P. W. Dematteo, R. A. Hassan, Org. Synth. 2013, 90,
350 – 357.
[32] D. C. Harrowven, J. D. Wilden, M. J. Tyte, M. B. Hursthouse, S. J.
Coles, Tetrahedron Lett. 2001, 42, 1193 – 1195.
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Angewandte
Communications
Communications
Terpenoid Synthesis
C. L. Hugelshofer,
T. Magauer*
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A General Entry to Antifeedant
Sesterterpenoids: Total Synthesis of
(+)-Norleucosceptroid A, (À)-
Norleucosceptroid B, and (À)-
Leucosceptroid K
Totally terpenoid: A general asymmetric
synthetic route to antifeedant leuco-
sceptroids was developed. Highlights are
a stereoselective annulation reaction and
an unprecedented intramolecular dilactol
condensation to construct the tricyclic
carbon skeleton. The convergent
approach enabled us to synthesize mul-
tigram quantities of an advanced inter-
mediate, which was converted into
(+)-norleucosceptroid A, (À)-norleuco-
sceptroid B, and (À)-leucosceptroid K.
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!