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Concise Total Synthesis of Lundurines A−C Enabled by Gold
Catalysis and a Homodienyl Retro-Ene/Ene Isomerization
Mariia S. Kirillova,† Michael E. Muratore,† Ruth Dorel,† and Antonio M. Echavarren*,†,‡
†

Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007
Tarragona, Spain
‡
Departament de Química Orgànica i Analítica, Universitat Rovira i Virgili, C/Marcel·lí Domingo s/n, 43007 Tarragona, Spain
S
* Supporting Information

intermediate 4 in a single step by a condensation/Claisen
rearrangement followed by a gold(I)-catalyzed intramolecular
hydroarylation to form the 8-membered ring5 (Scheme 1). In our

ABSTRACT: The total synthesis of lundurines A−C has
been accomplished in racemic and enantiopure forms in
11−13 and 12−14 steps, respectively, without protection/
deprotection of functional groups, by a novel tandem
double condensation/Claisen rearrangement, a gold(I)catalyzed alkyne hydroarylation, a cyclopropanation via
formal [3 + 2] cycloaddition/nitrogen extrusion, and a
remarkable olefin migration through a vinylcyclopropane
retro-ene/ene reaction that streamlines the endgame.

Scheme 1. Retrosynthetic Approach

L

undurines A (1), B (2), and C (3) were isolated from Kopsia
tenuis,1 a plant endemic to the north of Borneo, and show
interesting cytotoxicity.2 These alkaloids feature a unique
indoline-fused polyhydropyrroloazocine and cyclopropyl moiety
fused to the indoline (Figure 1). Related alkaloids lacking the
cyclopropane ring, such as lapidilectam, lapidilectines, grandilodines, and tenuisines, have also been isolated from plants of the
Kopsia genus.3
initial plan, we expected that a transition-metal-catalyzed
reaction of a carbene precursor of type I would lead to
intramolecular cyclopropanation of the indole nucleus. However,
a more effective solution was found using an acid-catalyzed
pyrazoline formation. The endgame relied on an unexpectedly
facile vinylcyclopropane retro-ene/ene reaction that led to
alkene migration, streamlining the culmination of the synthesis.
For the synthesis of key chiral intermediate 5, we envisioned
condensing oxoester 6 with commercially available 5-methoxytryptamine. This should lead to imine 7, which should undergo
lactamization to form pyrrolidinones 8-Z and 8-E. Ultimately, 8Z and 8-E could afford 5 through a Claisen rearrangement.6 For
the enantioselective synthesis of 4, we proposed building the C20
stereocenter by enantiodiscrimination through transfer of
chirality in the Claisen rearrangement (Scheme 2).
Examples of efficient transfer of chirality on flexible systems
featuring a “traceless” chiral auxiliary on the allyl fragment, and in
the absence of a Lewis acid, are scarce.7 Nonetheless, we
prepared a range of (S)-chiral alcohols by enzymatic resolution of
the racemic allylic alcohols,8 which were converted into the
desired chiral oxoesters 6 in a single step. The best transfer of

Figure 1. Lundurines A−C and related alkaloids.

The lundurines have recently attracted considerable attention,4 and the total syntheses of lundurine A and lundurine B
have been reported.4b−f However, all previous approaches were
lengthy, involving over 20 linear synthetic steps, thus making the
synthesis of large quantities of the natural products and/or
analogues, for broad biological assays, inconvenient.4b−f We now
report the expedient total synthesis of the three members of the
lundurine family, including the first total synthesis of racemic and
enantiopure lundurine C, by constructing the key lactam
© 2016 American Chemical Society

Received: February 8, 2016
Published: March 10, 2016
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DOI: 10.1021/jacs.6b01428
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Journal of the American Chemical Society

Initially, we had expected that the system would be under
Curtin−Hammett conditions, as a result of a fast equilibrium
between 8-Z and 8-E. However, in a closely related model
system, we isolated the E- and Z-pyrrolidinones (2.6:1 ratio),
which did not undergo equilibration after being heated at 100 °C
in 1:2 toluene−Et3N for several hours.10 Presumably, the major
8-E pyrrolidinone reacts preferentially through a boat-like
transition state TSE‑boat to form (S)-5, whereas the minor isomer
8-Z reacts through TSZ‑chair (Scheme 2).11
Aldehyde 5 was immediately homologated into the corresponding alkyne 4 employing the Ohira−Bestmann reagent (4a
88%; 4f 84%, 89:11 er), setting the stage for the key 8-endo-dig
gold(I)-catalyzed hydroarylation (Scheme 3). This was accomplished with perfect 8-endo selectivity with 5 mol % AuCl (9a
83%; 9f 79%, 89:11 er). Compound 9f was crystallized to obtain
virtually enantiopure material (mother liquor, 56%, > 99:1 er).
The methyl carbamate at the indole nitrogen was then
introduced (10a 80%; 10f 88%), and the exocyclic olefin was
converted to the corresponding aldehyde via a dihydroxylation/
oxidative cleavage sequence, that was performed in one pot.
Although aldehyde 11 may be isolated, it was routinely converted
without further purification into tosyl hydrazone 12 ((±)-12,
91% and (+)-12, 79% from 10). The absolute configuration of
(+)-12 was determined by single crystal X-ray diffraction,
confirming the C20 (S)-configuration of all previous intermediates.
Initial attempts to form 14a by various transition-metalcatalyzed procedures4f were unsuccessful. However, 14b was
formed through deprotonation of the hydrazone and generation
of the corresponding diazo compound, although we were not
able to obtain yields higher than 20−25%, the main products
being the undesired vinyl-substituted tetracycles 13a−b
(Scheme 4). Most surprising was the fact that in 14b12,13 the

Scheme 2. Enantioselective Claisen Rearrangement

chirality was achieved with R = c-pentyl (89:11 er). It is important
to note that the use of basic conditions turned out to be essential
to avoid the Pictet−Spengler type reaction that would form
tetrahydro β-carbolines.9 Thus, mixtures of pyridine/toluene or
Et3N/toluene proved to be optimal, affording high yields of
lactam (R = H: 5a 74%; R = c-pentyl, 5f 84%) (Scheme 3).
Scheme 3. Synthesis of (+)-9f and Hydrazone (+)-12a

Scheme 4. Indole Cyclopropanation and Olefin Isomerization

a

double bond had migrated to the opposite side of the
hexahydroazocine ring. We also isolated pyrazoline 15,12 which
is the first example of a formal [3 + 2] dipolar cycloadduct
between a diazocompound and an indole. By performing a
formal [3 + 2] cycloaddition of tosyl hydrazone 12 in the
presence of BF3·OEt2 as the Lewis acid,14 we obtained 14a in
79−80% yield. Remarkably, this product of direct cyclopropanation (14a) could be converted in essentially quantitative
yield into its isomer 14b by simple heating at 155 °C for 2 h.

CYLview depiction of the X-ray crystal structure of (+)-12.
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Hydrogenation of 16 using PtO2 as the precatalyst gave
lundurine C (3), albeit in a rather low yield (44%), while
hydrogenation of the olefin of 14a prior to borane reduction of
the lactam was unsuccessful. Gratifyingly, the ready access to 14b
led to a considerably more efficient synthesis of 3 and, more
importantly, provided an entry to the synthesis of lundurines A
(1) and B (2). Hence, the first total synthesis of 3 could be
completed in two steps from 14b, by reduction of the enaminone
double bond with NaBH3CN19 in the presence of formic acid to
form saturated lactam 18, followed by a second reduction with
BH3·SMe2 (Scheme 7). Surprisingly, enantiopure lundurine C

The puzzling isomerization of 14a most likely proceeds by a
homodienyl retro-ene rearrangement15 via 1,4-diene II, followed
by the reverse process to form 14b (Scheme 5). This type of
Scheme 5. Migration of the Olefin from 14a to 14b via
Homodienyl Retro-Ene/Ene Rearrangementa

Scheme 7. Synthesis of Lundurines A−Ca

a

Numbers in parentheses correspond to relative free energies in kcal·
mol−1 (B3LYP/6-31G(d), solvent = toluene).

transformation has been studied before in cyclic and bicyclic
systems, leading irreversibly to skipped dienes.16 The homodienyl retro-ene rearrangement of bicyclo[5.1.0]octen-2-ene has
been reported to take place at 150−170 °C, to furnish 1,4cyclooctadiene with an activation energy of ca. 33 kcal·mol−1.16d
The reverse process, the formation of vinyl cyclopropanes from
skipped dienes under thermal conditions, has only one precedent
in the oxy-homodienyl rearrangement, which requires a
temperature of ca. 260 °C (activation energies of 41−43.5 kcal·
mol−1).17 However, according to DFT calculations, the two
transition states for the hydrogen shifts in our system have much
lower barriers (ca. 29.5 kcal·mol−1) and the formation of a more
stable conjugated enaminone drives the equilibrium toward the
formation of 14b.18
Isomers 14a and 14b behave very differently in their reactions
with borane. Thus, whereas 14a reacted with excess BH3·SMe2
by exclusive reduction of the lactam to give 16 (56%), 14b led to
an unexpected and remarkably inert heptacyclic diborane 17
(Scheme 6).

a

CYLview depictions of the X-ray crystal structures of iodide salt 19
and lundurine A ((−)-1), with absolute configurations.

(3) presented an optical rotation ([αD589 = −1.1 ± 0.6°, CHCl3, c
0.98, 300 K] and [αD589 = −6.2 ± 0.8°, CH2Cl2, c 0.3, 301 K])
differing significantly from the one reported for the natural
product [αD589 = −25°, CHCl3, c 0.067],1,2 although chiral
HPLC analysis of our synthetic sample of lundurine C left no
doubt with regards to its enantiopurity. Furthermore, we
prepared crystalline quaternary ammonium iodide 19, whose
absolute configuration was established by X-ray crystallography.
The discrepancy in the value of the optical rotation may arise
from the very low concentration at which the natural product was
measured originally that induced a significant error in the
measurement.
Lundurines A (1) and B (2) were both prepared in three
additional steps from 18, by thiolation/C-sulfinylation−elimination and either oxidation or reduction (Scheme 7).
Intermediate 18 was first subjected to Lawesson’s reagent to
form thiolactam 21, which then reacted with p-toluenesulfinyl
chloride, in the presence of Hünig’s base, to generate in situ an α-

Scheme 6. Reduction of 14a−b with Boranea

a

CYLview depiction of the X-ray crystal structure of (±)-17.
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sulfinyl thiolactam.20 Upon heating at 80 °C, a Cope-type
elimination gave thiolundurine A (22). Oxidation of 22 with mCPBA at −78 °C produced (−)-lundurine A (1) in 69% yield,
while treatment of 22 with iodomethane followed by sodium
borohydride gave (−)-lundurine B (2) in 72% yield.
Interestingly, unlike stated in the isolation and previous
syntheses, racemic and enantiopure 1 are crystalline solids and
we have also obtained the crystal structure of this natural
product, confirming its absolute configuration and the one of the
whole family of natural compounds.
In conclusion, we have developed a unified approach toward
the synthesis of lundurines A−C, including the first enantioselective total synthesis of lundurine C, taking advantage of a
gold(I)-catalyzed 8-endo-dig selective hydroheteroarylation to
build the polyhydroazocine ring. Our synthesis of the lundurines
is the shortest and most efficient to date (12−14 steps from
known chiral alcohol 20f,21 6.6% overall yield for lundurine C
and 3% overall yield for lundurines A and B, >99:1 er) and is
perfectly suited to the preparation of analogues for biological
evaluation as well as its extension to the synthesis of other Kopsia
alkaloids. Worthy of note is the implementation of a practical
chirality transfer in a complex tandem transformation and the
new intramolecular cyclopropanation of indoles by formation of
a pyrazoline by formal [3 + 2] cycloaddition in the presence of a
Lewis acid. Finally, as often encountered in total synthesis
endeavors, serendipity also played a significant role in the
discovery of a new transformation in which a double bond
migrates by means of a homodienyl retro-ene/ene rearrangement, which streamlined the access to this family of alkaloids.

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ASSOCIATED CONTENT

S
* Supporting Information

The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b01428.
Crystallographic data files (ZIP)
All procedures and characterization data for compounds
1−3; 4a,f−6a,f; 9a,f−10a,f; and 11−22 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*aechavarren@iciq.es
Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS
We thank MINECO (Severo Ochoa Excellence Accreditation
2014-2018 (SEV-2013-0319), project CTQ2013-42106-P), the
European Research Council (Advanced Grant No. 321066), the
AGAUR (2014 SGR 818 and predoctoral fellowship to M.S.K.),
and the ICIQ Foundation. M.E.M. acknowledges the receipt of a
COFUND postdoctoral fellowship (Marie Curie program). We
also thank Dr. Fedor Miloserdov for helpful discussions and the
ICIQ X-ray diffraction unit for the crystal structures.

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DOI: 10.1021/jacs.6b01428
J. Am. Chem. Soc. 2016, 138, 3671−3674