Concise Total Synthesis of Lundurines A-C Enabled by Gold Catalysis and a Homodienyl Retro-Ene/Ene Isomerization

Article abstract of DOI:10.1021/jacs.6b01428

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.

Full text of DOI:10.1021/jacs.6b01428

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Communication
Concise Total Synthesis of Lundurines A–C Enabled by Gold
Catal-ysis and a Homodienyl Retro-Ene / Ene Isomerization
Mariia S. Kirillova, Michael E. Muratore, Ruth Dorel, and Antonio M. Echavarren
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01428 • Publication Date (Web): 10 Mar 2016
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Concise Total Synthesis of Lundurines A–C Enabled by Gold
Catalysis and a Homodienyl Retro-Ene / Ene Isomerization
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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 Tarꢀ
ragona (Spain).
‡ Departament de Química Orgànica i Analítica, Universitat Rovira i Virgili, C/ Marcel·lí Domingo s/n, 43007 Tarragona (Spain).
Supporting Information Placeholder
lundurine family, including the first total synthesis of
racemic and enantiopure lundurine C, by constructing
the key lactam intermediate 4 in a single step by a conꢀ
densation / Claisen rearrangement followed by a gold(I)ꢀ
catalyzed intramolecular hydroarylation to form the 8ꢀ
membered ring5 (Scheme 1). In our initial plan, we exꢀ
pected that a transition metalꢀcatalyzed 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 acidꢀ
catalyzed pyrazoline formation. The endgame relied on
an unexpectedly facile vinylcyclopropane retroꢀene / ene
reaction that led to alkene migration, streamlining the
culmination of the synthesis.
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 vinylcyclopropane
retroꢀene / ene reaction that streamlines the endgame.
Lundurines 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 feaꢀ
ture a unique indolineꢀfused polyhydropyrroloazocine
and cyclopropyl moiety fused to the indoline (Figure 1).
Related alkaloids lacking the cyclopropane ring, such as
lapidilectam, lapidilectines, grandilodines, and tenꢀ
uisines, have also been isolated from plants of the
Kopsia genus.3
Scheme 1. Retrosynthetic Approach
For the synthesis of key chiral intermediate 5, we enviꢀ
sioned to condense oxoester 6 with commercially availꢀ
able 5ꢀmethoxytryptamine. This should lead to imine 7,
which should undergo lactamization to form pyrroliꢀ
dinones 8-Z and 8-E. Ultimately, 8-Z and 8-E could afꢀ
ford 5 through a Claisen rearrangement.6 For the enantiꢀ
oselective synthesis of 4, we proposed to build the C20
stereocenter by enantiodiscrimination through transfer of
chirality in the Claisen rearrangement (Scheme 2).
Figure 1. Lundurines A–C and related alkaloids.
The lundurines have recently attracted considerable atꢀ
tention,4 and the total syntheses of lundurine A and lunꢀ
durine B have been reported.4b–f However, all previous
approaches were lengthy, involving over twenty linear
synthetic steps, thus making the synthesis of large quanꢀ
tities of the natural products and / or analogues, for
broad biological assays, inconvenient.4bꢀf We now report
the expedient total synthesis of the three members of the
Scheme 2. Enantioselective Claisen Rearrangement
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oxidative cleavage sequence, that was performed oneꢀ
1
2
3
4
5
6
7
8
pot. Although aldehyde 11 may be isolated, it was rouꢀ
tinely 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 Xꢀray diffraction, confirming the C20 (S)ꢀ
configuration of all previous intermediates.
Scheme 3. Synthesis of (+)-9f and hydrazone (+)-12a
9
NH2
MeO
10
11
12
13
14
15
16
17
18
19
20
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O
Toluene / py 1:2
reflux, 40 h (for 5a
N
N
H
)
MeO
+
Toluene / Et3N 1:2
reflux, 16 h (for 5f)
CO2Me
N
O
H
O
O
R = H, 74% (5a)
R = c-C5H9, 84% (5f)
R
6
R
O
O
N
AuCl
(5 mol %)
K2CO3, MeOH
25 ºC, 3–5 h
N
MeO
MeO
O
P
MeO
O
CH2Cl2
25 ºC, 5 h
N
N
H
H
MeO
R
R = H, 88% (4a)
R = H, 83% (9a
)
N2
R
R = c-C5H9, 84% (4f)
R =
c
-C5H9, 79%, 89:11 er
(
9f
)
56%, >99:1 er (after crystallization)
Examples of efficient transfer of chirality on flexible
systems featuring a “traceless” chiral auxiliary on the
allyl fragment, and in the absence of 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 chirality
was achieved with R = cꢀpentyl (89:11 er). It is imꢀ
portant to note that the use of basic conditions turned out
to be essential in order to avoid the PictetꢀSpengler type
reaction that would form tetrahydro βꢀcarbolines.9 Thus,
mixtures of pyridine / toluene or Et3N / toluene proved
to be optimal, affording high yields of lactam (R = H: 5a
74%; R = cꢀpentyl, 5f 84%), (Scheme 3).
O
O
N
i. OsO4, NMO
acetone / H2O
1.5–6 h, 25 ºC
N
NaHMDS or
LDA,
MeO
MeO
ClCO2Me
O
N
N
THF
0 to 25 ºC
2 h
ii. NaIO4
CO2Me
CO2Me
acetone / H2O
0.5 h, 25 ºC
R
11
R = H, 80% (10a
)
R = c-C5H9, 88% (10f
)
O
N
TsNHNH2
p-TsOH (cat.)
MeO
CH2Cl2, 25 ºC
5–10 min
=
N
N
NHTs
CO2Me
(±)-12, 91% from 10a
(+)-12, 79% from 10f
Initially, we had expected that the system would be unꢀ
der CurtinꢀHammett conditions, as a result of a fast equiꢀ
librium between 8-Z and 8-E. However, in a closely reꢀ
lated model system, we isolated the Eꢀ and Zꢀ
pyrrolidinones (2.6:1 ratio), which did not undergo equiꢀ
libration after being heated at 100 °C in 1:2 tolueneꢀ
Et3N for several hours.10 Presumably, the major 8-E pyrꢀ
rolidinone reacts preferentially through a boatꢀlike tranꢀ
sition state TSE-boat to form (S)ꢀ5, whereas the minor
isomer 8-Z reacts through TSZ-chair (Scheme 2).11
a CYLview depiction of the Xꢀray crystal structure of (+)ꢀ12.
Initial attempts to form 14a by various transitionꢀmetal
f
catalyzed procedures4 were unsuccessful. However, 14b
was formed through deprotonation of the hydrazone and
generation of the corresponding diazo compound, altꢀ
hough we were not able to obtain yields higher than 20–
25%, the main products being the undesired vinylꢀ
substituted tetracycles 13a–b (Scheme 4). Most surprisꢀ
ing was the fact that in 14b12,13 the double bond had miꢀ
grated to the opposite side of the hexahydroazocine ring.
We also isolated pyrazoline 15,12 which is the first exꢀ
ample 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 presꢀ
ence of BF3·OEt2 as the Lewis acid,14 we obtained 14a
in 79–80% yield. Remarkably, this product of direct cyꢀ
clopropanation (14a) could be converted in essentially
quantitative yield into its isomer 14b by simple heating
at 155 °C for 2 h.
Aldehyde 5 was immediately homologated into the corꢀ
responding alkyne 4 employing OhiraꢀBestmann reagent
(4a 88%; 4f 84%, 89:11 er), setting the stage for the key
8ꢀendoꢀdig gold(I)ꢀcatalyzed hydroarylation (Scheme 3).
This was accomplished with perfect 8ꢀendo selectivity
with 5 mol% AuCl (9a 83%; 9f 79%, 89:11 er). Comꢀ
pound 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 converted
to the corresponding aldehyde via a dihydroxylation /
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(ca. 29.5 kcal·mol–1) and the formation of a more stable
Scheme 4. Indole Cyclopropanation and Olefin Isom-
erization
1
2
conjugated enaminone drives the equilibrium towards
the formation of 14b.18
3
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 remarkꢀ
ably inert heptacyclic diborane 17 (Scheme 6).
4
5
6
7
8
9
Scheme 6. Reduction of 14a–b with boranea
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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Scheme 5. Migration of the Olefin from 14a to 14b
via Homodienyl Retro-ene / Ene Rearrangementa
a CYLview depiction of the Xꢀray crystal structure of (±)ꢀ17.
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 reducꢀ
tion 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
589
lundurine C (3) presented an optical rotation ([αD = –
589
1.1 ± 0.6°, CHCl3, c 0.98, 300K] and [αD = –6.2 ±
0.8°, CH2Cl2, c 0.3, 301K]) differing significantly from
589
the one reported for the natural product [αD = – 25°,
CHCl3, c 0.067],1,2 although chiral HPLC analysis of our
synthetic sample of lundurine C left no doubt with reꢀ
gards to its enantiopurity. Furthermore, we prepared
crystalline quaternary ammonium iodide 19, whose abꢀ
solute configuration was established by Xꢀray crystalꢀ
lography. 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 on the measurement.
a
Numbers in parenthesis correspond to relative free energies in
kcal·mol–1 (B3LYP/6ꢀ31G(d), solvent = toluene).
The puzzling isomerization of 14a most likely proceeds
by a homodienyl retroꢀene rearrangement15 via 1,4ꢀdiene
II, followed by the reverse process to form 14b (Scheme
5). This type of transformation has been studied before
in cyclic and bicyclic systems, leading irreversibly to
skipped dienes.16 The homodienyl retroꢀene rearrangeꢀ
ment of bicyclo[5.1.0]octenꢀ2ꢀene has been reported to
take place at 150ꢀ170 °C, to furnish 1,4ꢀcyclooctadiene
Lundurines A (1) and B (2) were both prepared in three
additional steps from 18, by thiolation / Cꢀsulfinylationꢀ
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
pꢀtoluenesulfinyl chloride, in the presence of Hünig’s
base, to generate in situ an αꢀsulfinyl thiolactam.20 Upon
heating at 80 °C, a Copeꢀtype elimination gave thiolunꢀ
durine A (22). Oxidation of 22 with mꢀCPBA at –78 °C
d
with an activation energy of ca. 33 kcal·mol–1.16 The
reverse process, the formation of vinyl cyclopropanes
from skipped dienes under thermal conditions, has only
one precedent in the oxyꢀhomodienyl rearrangement,
which requires a temperature of ca. 260 °C (activation
energies of 41ꢀ43.5 kcal·mol–1).17 However, according to
DFT calculations, the two transition states for the hyꢀ
drogen shifts in our system have much lower barriers
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produced (–)ꢀlundurine A (1) in 69% yield, while treatꢀ sis endeavors, serendipity also played a significant role
1
2
3
4
5
6
7
8
ment of 22 with iodomethane followed by sodium boroꢀ
hydride gave (–)ꢀlundurine B (2) in 71% yield. Interestꢀ
ingly, unlike stated in the isolation and previous syntheꢀ
ses, racemic and enantiopure 1 are crystalline solids and
we have also obtained the crystal structure of this natural
product, which confirms its absolute configuration and
the one of the whole family of natural compounds.
in the discovery of a new transformation in which a
double bond migrates by means of a homodienyl retroꢀ
ene / ene rearrangement, which streamlined the access to
this family of alkaloids.
ASSOCIATED CONTENT
Supporting Information. All procedures and characteriza-
tion data for compounds 1–3, 4a,f–6a,f, 9a,f–10a,f and 11–22.
The Supporting Information is available free of charge on the
ACS Publications website.
Scheme 7. Synthesis of lundurines A–Ca
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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O
AUTHOR INFORMATION
Corresponding Author
aechavarren@iciq.es
Funding Sources
No competing financial interests have been declared.
N
MeO
N
CO2Me
14b
19 (92%)
ACKNOWLEDGMENT
NaBH3CN
(±)-18 89%
THF / HCO2H
(–)-18 90%
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.
MeI, 25 ºC
25 to 40 ºC, 6 h
O
3 h
i. BH3•SMe2, THF
25 ºC, 3 h
N
N
MeO
MeO
ii. AcOH, 0 to
25 ºC, 0.5 h
N
N
CO2Me
CO2Me
(±)-3 80%
(–)-3 84%
18
(–)-Lundurine C (3)
Lawesson's
reagent
(±)-21 98%
(–)-21 96%
REFERENCES
toluene
90 °C, 1 h
S
N
S
O
S
Cl
Tol
N
iPr2NEt
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MeO
MeO
CH2Cl2
–20 °C to 80 ºC, 4 h
N
N
(±)-22 75%
(–)-22 68%
CO2Me
CO2Me
22
21
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i. MeI, 50 ºC, 2 h
ii. NaBH4, MeOH
0 to 25 °C, 2.5 h
(–)-2
72%
m-CPBA
CH2Cl2
N
–78 °C, 0.5 h
MeO
(–)-1 69%
N
CO2Me
(–)-Lundurine A (1)
(–)-Lundurine B
(2)
a CYLview depictions of the Xꢀray crystal structures of iodide salt
19 and lundurine A ((–)ꢀ1), with absolute configurations.
In conclusion, we have developed a unified approach
towards the synthesis of lundurines A–C, including the
first enantioselective total synthesis of lundurine C, takꢀ
ing advantage of a gold(I)ꢀcatalyzed 8ꢀendoꢀdig selecꢀ
tive 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 bioꢀ
logical evaluation as well as for its extension to the synꢀ
thesis of other Kopsia alkaloids. Worthy of note is the
implementation of a practical chirality transfer in a comꢀ
plex tandem transformation and the new intramolecular
cyclopropanation of indoles by formation of a pyrazoꢀ
line by formal [3+2] cycloaddition in the presence of a
Lewis acid. Finally, as often encountered in total syntheꢀ
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1
2
10. To simulate the real reaction conditions, we added ca. 1 equiv of
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3
4
5
6
7
8
9
12. See Supporting Information for the Xꢀray structure.
13. (a) The absolute structure high resolution data were collected
using Molybdenum radiation and applying methodology deꢀ
scribed in: EscuderoꢀAdán, E. C.; BenetꢀBuchholz, J. B.; Ballesꢀ
ter, P. Acta Cryst. 2014, B70, 660–668. The absolute configuraꢀ
tion was determined reliably with a Flack13b value based on Parꢀ
sons’ quotients13c of 0.00(8) R1 value for the structure of 2.86%.
(b) Flack, H. D. Acta Cryst. 1983, A39, 876–881. (c) Parsons, S.;
Flack, H. Acta Cryst. 2004, A39, S61.
14. (a) Frank, É.; Mucsi, Z.; Zupkó, I.; Réthy, B.; Falkay, G.; Schneiꢀ
der, G.; Wölfling, J. J. Am. Chem. Soc 2009, 131, 3894–3904. (b)
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2334.
17. Klärner, F.ꢀG.; Rüngeler, W.; Maifeld, W. Angew. Chem. 1981,
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18. A dyotropic rearrangement of 14a into 14b is highly unlikely,
since the computed barrier of activation for this process would lie
very high (>80 kcal·mol–1). See Supporting Information.
19. Yazici, A.; Pyne, S. G. Org. Lett. 2013, 15, 5878–5881.
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