Unified Total Synthesis of Pyrroloazocine Indole Alkaloids Sheds Light on Their Biosynthetic Relationship

Article abstract of DOI:10.1021/jacs.7b13484

The total synthesis of seven members of the lapidilectine and grandilodine family of alkaloids has been accomplished in racemic and enantiopure form without protection/deprotection of functional groups. The two key steps, an 8-endo-dig hydroarylation and a 6-exo-trig photoredox cyclization, were catalyzed using gold. A rationale for the formation of the cyclopropane ring of the lundurines is also provided.

Full text of DOI:10.1021/jacs.7b13484

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Article
Unified Total Synthesis of Pyrroloazocine Indole
Alkaloids Sheds Light on Their Biosynthetic Relationship
Fedor M. Miloserdov, Mariia S. Kirillova, Michael E. Muratore, and Antonio M. Echavarren
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b13484 • Publication Date (Web): 12 Feb 2018
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Unified Total Synthesis of Pyrroloazocine Indole Alkaloids
Sheds Light on Their Biosynthetic Relationship
Fedor M. Miloserdov,† Mariia S. Kirillova,† Michael E. Muratore,† and Antonio M. Echavarren†,‡*
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† 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).
Supporting Information Placeholder
ABSTRACT: The total synthesis of seven members of the lapidilectine and grandilodine family of alkaloids has been ac-
complished in racemic and enantiopure form without protection / deprotection of functional groups. The two key steps,
an 8-endo-dig hydroarylation and a 6-exo-trig photoredox cyclization, were catalyzed using gold. A rationale for the for-
mation
of
the
cyclopropane
ring
of
the
lundurines
is
also
provided.
oped. However, a synthetic approach to lapidilectine A-
type natural compounds 3-5 has not yet been disclosed.
Our interest in Kopsia indole alkaloids launched with the
discovery of a gold-catalyzed hydroarylation of alkynes
that allows a fast access to the pyrroloazocine indole core
of these natural compounds.7 Based on this strategy, we
developed a concise total synthesis of lundurines A–C.8
INTRODUCTION
Lapidilectines and grandilodines are indole alkaloids,
isolated from peninsular Malaysia species Kopsia grandi-
folia D. J. Middleton, that feature lactone (1, 2) or diester
motifs (3–7) (Figure 1).1,2 Together with tenuisines and the
cyclopropane-containing lundurines isolated from Kopsia
tenuis species,3 they represent a family of sixteen indole
alkaloids containing the common pyrroloazocine core.
Preliminary studies on the biological activity of lapidilec-
tines and grandilodines demonstrated their ability to
reverse multidrug resistance in vincristine-resistant can-
cer cells.2
Besides the synthetic challenge the pyrroloazocine indole
alkaloids pose,9,10 we were intrigued by the biosynthetic
relationships among the main classes of this family of
alkaloids, and in particular, fascinated by the origin of the
cyclopropane ring of the lundurines. Here we report a
unified total synthesis of seven members 1–7 of the lapidi-
lectine/grandilodine family streamlined by the use of two
gold-catalyzed reactions for the key cyclization steps.
With ready access to the main members of this natural
product family, we have examined their chemical inter-
conversions, uncovering that the cyclopropane ring can
arise from the photochemical decarboxylation of a lac-
tone. This photochemical origin differs from an early
biosynthetic hypothesis11 and is unprecedented among the
many pathways that have been elucidated for the biosyn-
thesis of cyclopropane-containing natural products.12
RESULTS AND DISCUSSION
We considered that compounds 1,2 and 3,4 might be bio-
synthetically connected through an oxidative decarboxy-
lation13 via carbocation A, which could become a key in-
termediate for the synthesis of lactone 8, or be treated
with a carbon nucleophile to construct the quaternary
stereocenter in 9 en route to diesters 3-7 (Scheme 1). The
diastereoselectivity of the latter transformation would be
controlled by the CO2Me moiety, which shields one face
of carbocation A from nucleophilic attack. Intermediate A
could be readily accessed from alkene 10, whose synthesis
was envisioned through a radical photoredox-catalyzed
1
Figure 1. Pyrroloazocine Indole Alkaloids.
The first total synthesis of (±)-lapidilectine B (1) was
achieved by Pearson in 25 steps.4 Only very recently, the
total syntheses of (+)-lapidilectine B (1)/(+)-grandilodine
C (2),5 and racemic grandilodine B (7)6 have been devel-
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cyclization of 11. This process was expected to favor the Scheme 2. Synthesis of Enantiopure Aldehyde Inter-
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1
2
3
4
5
6
7
8
formation of the product with an endo-methoxycarbonyl
group. Precursor 11 could ultimately be obtained from
aldehyde 12, whose 5-OMe-analogue was an intermediate
in our synthesis of the lundurines.8
mediate 12
O
NH2
N
Toluene, Et3N,
reflux;
20
N
+
H
O
CO2Me
then HCl
N
Scheme 1. Bioinspired Unified Retrosynthesis of
Lapidilectine/Grandilodine Family of Alkaloids
O
R
H
O
R = H, 83%, (±)ꢀ14a
R = cꢀC6H11, 83%, (–)ꢀ14b, 70% ee
13a, R = H
R
(+)ꢀ13b, R = cꢀC6H11
O
>99% ee a
O
O
P
OMe
O
epimerization
K2CO3
MeOH
9
OMe
N
R
3ꢀ5
6,7
N
N2
10
11
12
13
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O
O
[R]
+
O
N
1. AuCl (5+2 mol%)b
AcOH, CH2Cl2
N
N
CO2Me
CO2Me
9
N
CO2Me
CO2Me
N
O
A
N
O
2. NaHMDS
ClCO2Me
THF, 0 to 25 ºC
1,2
R
N
H
lactonization
CO2Me
R = H, 76%, (±)ꢀ17a
R = cꢀC6H11, 71%, (+)ꢀ17b
R
N
controls overall
diastereoselectivity
R = H, 91%, (±)ꢀ15a
8
H+
CO2Me
R = cꢀC6H11, 92%, (+)ꢀ15b
O
N
O
N
O
N
OsO4 (3 mol%), NMO
acetone, H2O;
photoredox
then NaIO4, acetone, H2O
O
Br
O
MeO2C
N
N
N
CO2Me
CO2Me
N
CO2Me
CO2Me
11
12
10
Unified total synthesis. The synthesis of advanced pyr-
roloazocine compound 12 was realized in both enanti-
opure and racemic form in 5 steps, on gram scale, from
commercially available tryptamine (Scheme 2). The first
O
N
CO2Me
(+)ꢀ12
91%, (±)ꢀ12
44%, (+)ꢀ12, >99% ee, 0.95 grams
(crystallization from 70% ee)
step in our synthetic sequence,
a
condensa-
a see Supporting Information for the synthesis of 13b. b Initial 5 mol%
of AuCl catalyst employed, then additional 2 mol% added after 0.5-1
hours to reach full conversion.14
tion/lactamization/Claisen rearrangement cascade of
oxoesters 13a,b with tryptamine occurred with high yield
(83%) and for (+)-13b with a good level of chirality trans-
fer from the allylic fragment to the C20 stereocenter
(>99% ee for 13b to 70% ee for (–)-14b).8,14 Aldehydes
14a,b underwent a Seyferth-Gilbert homologation to give
alkynes 15a,b.
At this point the synthetic route diverges from the one
previously developed for the lundurines.8 Hydrogenation
of the double bond in 12 required carefully controlled
conditions14 in order to prevent over-reduction of the
indole into indoline. This was achieved with 10 wt% Pd/C
catalyst in EtOAc/CH2Cl2 to give 18 in 65–77% and 92%
brsm yields (Scheme 3). With aldehyde 18 in hand, we
focused on the development of an approach to an ester-
containing precursor for the radical cyclization. Current
methods to access α-halo esters by aldehyde homologa-
tion are essentially limited to cyanohydrin synthesis,
requiring several steps and harsh conditions. Thus, seek-
ing an alternative, our attention turned to the work of
Denmark et al., where α-hydroxy methyl esters were syn-
thesized from aldehydes and t-BuNC, in a Passerini-type
reaction, with an exceptional functional group tolerance.17
To apply this transformation to compound 18, we had to
account for the presence of several Lewis-basic centers in
the molecule, increasing the amount of SiCl4 (4.35 equiv
instead of 1.1 equiv) and raising the reaction temperature
(from –74 °C to –40 °C).14 The α-hydroxy ester 19 was
obtained in an excellent 88% yield, while the relatively
labile methylcarbamate remained intact (Scheme 3). Fi-
nally, bromide 11 was obtained in ca. 90% yield through
an Appel-type reaction using a modified protocol.14
The Au-catalyzed cyclization of 15 was found to be more
challenging than that of its 5-OMe derivative.8 In the
presence of the standard AuCl-based catalytic system, the
reaction stopped at an unsatisfactory ca. 60% conversion,
due to catalyst decomposition. With ligand-stabilized
cationic gold complex [IPrAu(NCCH3)]SbF6 (2 mol%), (±)-
15a undergoes the gold-catalyzed cyclization with a satis-
factory ca. 20:1 8-endo/7-exo selectivity. After subsequent
reaction with methyl chloroformate and crystallization
(removing traces of 7-exo product), (±)-17a was obtained
in 65% yield over two steps.14 Alternatively, in the pres-
ence of acetic acid, the AuCl catalyst was found to be
more stable,15 and full conversion could be achieved with
5+2 mol% catalyst loading (Scheme 2). The reaction pro-
ceeds with excellent 8-endo selectivity (>50:1 endo/exo),
and with high yield (16a,b, 76–82%). After introducing
the methylcarbamate, the exocyclic double bond of 17a,b
was cleaved by a one-pot OsO4/NaIO4 protocol to give
aldehyde 12 in racemic and enantioenriched form. For the
latter, the enantiomeric excess was enhanced from 70% to
>99% by crystallization from acetone, and its absolute
configuration was confirmed by high-resolution single
crystal X-ray diffraction.16
Scheme 3. Synthesis of α-Bromo Ester 11
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vation product, deep-purple trans-[Ru(bpy)2Br2]Br, was
isolated and structurally characterized.14
1
2
3
4
5
Scheme 4. Photoredox Cyclization of 11 into 10
O
O
[(dppmAuCl)2] (2 mol%)
Na2CO3, UV LEDs (365 nm)
N
N
6
7
8
CH3CN, 91%
dr >50:1
Br
CO Me
CO2Me
N
N
CO2Me
CO2Me
(–)/(±)ꢀ11
(–)/(±)ꢀ10
2
9
ꢀG‡ = 20.2 kcal/mol
+ e
– Br
– e
– H+
10
11
12
13
14
15
16
17
18
19
20
21
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O
O
(ꢀG‡ = 23.2 kcal/mol)a
ꢀG0 = 1.7 kcal/mol
N
N
(ꢀG0 = 7.5 kcal/mol)a
CO2Me
N
N
CO2Me
CO2Me
R1 CO2Me
R2a
The photoredox process to build the rigid azabicyclic
[4.2.2] skeleton was expected to be challenging, as it con-
sists of a rare 6-exo-trig radical spirocyclization onto an
indole through a transition state that cannot adopt a
chair-like conformation.18,19 Nevertheless, our initial study
+ e
+ H+
O
N
equatorial
position of
CO2Me
20
employing [Ru(bpy)3]Cl2 showed that 11 indeed under-
H
CO2Me
twist-boat-like
transition state
N
H
went cyclization to the key synthetic intermediate 10 with
excellent endo-diastereoselectivity, which most likely
originates from the CO2Me-group adopting an equatorial
position in a twist-boat-like transition state (Scheme 4).
However, the reaction did not reach full conversion be-
cause of catalyst decomposition, and several other evalu-
ated catalytic systems did not provide a significant im-
provement.14 Remarkably, the digold photoredox catalyst
[(dppmAuCl)2] introduced by Barriault,21 showed an out-
standing efficiency leading to 10 in 91% yield (Scheme 4).
11H CO2Me
TSR1-R2a
a Values for exo-CO2Me isomer (R2b).
Alkene 10 was used as a precursor of benzylic carbocation
A, a common intermediate in the synthesis of both lac-
tones 1,2 and diesters 3-7 (Schemes 1 and 5). Under strong
acidic conditions (50% aqueous H2SO4), the styrene moie-
ty underwent protonation. The subsequent hydrolysis of
the ester, presumably involving cyclized cation A´ (see
below), led to the desired lactone 8 (Scheme 5). Forging
the quaternary carbon center bearing the benzylic CO2Me
group proved to be challenging. Besides the obvious in-
crease in molecular strain, this transformation goes in the
opposite direction to that of the proposed natural biosyn-
thetic scheme, in which the benzylic C–C bond is cleaved,
not constructed. Our scouting experiments suggested
that carbocation A undergoes proton elimination provid-
ing alkene 10 or lactonization into 8 faster than it reacts
with carbon nucleophiles (t-BuNC, TMSCN, anisole, or
1,3-dimethoxybenzene).14
The main challenge of the photoredox transformation
presumably arises from the lack of driving force for the
cyclization of the relatively stable α-CO2Me radical R1
into strained benzyl radicals R2a (endo-CO2Me) and R2b
(exo-CO2Me). DFT calculations22 provided ꢀG‡ values of
20.2 and 23.2 kcal/mol for the cyclization of R1 into R2a
and R2b, respectively, which is in accord with the ob-
served high endo-selectivity (Scheme 4). In addition, the-
se barriers indicate that the radical cyclization is a rela-
tively slow process, four to six orders of magnitude slower
than a standard 6-exo-trig cyclization of 6-hepten-1-yl
radical.14 Furthermore, from a thermodynamic point of
view, the open form of radical R1 was found to be even
more stable than the cyclized radical intermediates (ꢀG0 =
1.7 kcal/mol for R2a and 7.5 kcal/mol for R2b). This sug-
gests that the oxidation of benzylic radicals R2 is the
main driving force of the transformation that shifts the
equilibrium between R1 and R2. Both kinetic and ther-
modynamic data of the radical cyclization imply that R1
may accumulate in the reaction medium, causing side-
reactions and catalyst decomposition. For example, the
undesired reduction of R1 leads to 11H, which was isolat-
ed and identified as the main byproduct in both Au- and
Ru-catalyzed photoredox processes.14 This reduction into
11H naturally results in the oxidation of the photoredox
catalyst, and ultimately leads to the deactivation of the
catalytic system.23 For [Ru(bpy)3]Cl2 catalyst, such deacti-
We found that benzylic alcohol 20, accessible from 10 via
Mukaiyama hydration,24 can partake in
a Hosomi-
Sakurai-type allylation with allylTMS,25 providing the
desired product 9. Although promising, this result was
not suitable for application in the total synthesis because
9 was formed together with alkene 10 as an inseparable
mixture in ca. 1:2 ratio. Other allylic nucleophiles were
26
tested (Scheme 5), and allylSnBu3 demonstrated out-
standing efficiency (ca. 30:1 ratio of 9:10). Allylated prod-
uct 9 was obtained in 72% yield over two steps as a single
diastereomer (Scheme 6), confirming that the ester moie-
ty provides sufficient steric hindrance to favor the exclu-
sive attack of the nucleophile on one face of carbocation
A. Our attempts to perform a one-pot radical cyclization /
benzylic C–C bond construction were unsuccessful.14,27
The [(dppmAuCl)2]-catalyzed photoredox cyclization of 11
in the presence of nucleophiles such as TMSCN and al-
lylTMS led to elimination product 10. Employing al-
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lylSnBu3 (10 equiv) as nucleophile, this one-pot procedure
into methyl ester 25 by treatment with TMS-
1
2
3
4
provided a mixture of 9 and 10 in an unsatisfactory 1:2
diazomethane (80% yield over two steps).
ratio.28
Scheme 6. Introduction of Benzylic CO2Me-group. X-
ray Structures of (±)-20 and (±)-24
Scheme 5. Lactonization of 10 and Benzylic Allylation
of 20
O
O
5
6
7
N
N
Mn(dpm)3 (5 mol%)
NaBH4 MS (4Å)
HO
EtOH, CH2Cl2, air
8
9
N
N
CO2Me
CO2Me
CO2Me
CO2Me
(–)/(±)ꢀ20
(–)/(±)ꢀ10
10
11
12
13
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15
16
17
18
19
20
21
22
23
24
25
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AllylSnBu3, BF3—Et2O
CH2Cl2, 0 ºC
72% (over two steps)
O
O
O
N
OsO4 (10 mol%)
NMO, NaIO4
CH2Cl2, tꢀBuOH, H2O;
N
then pyrrolidine
Na2CO3, NaIO4
tꢀBuOH, H2O
N
N
CO2Me
CO2Me
CO2Me
CO2Me
(+)/(±)ꢀ23
(–)/(±)ꢀ9
72%, one-pot
OsO4, NaIO4
Na2CO3
OsO4, NMO
NaIO4
O
O
O
N
N
N
N
H
N
CO2Me
N
CO2Me
CO2Me
CO2Me
21
22
O
O
O
1. KMnO4, K2CO3, NaIO4
N
N
CH2Cl2, tꢀBuOH, H2O
RO2C
2. TMSCHN2, CH2Cl2
MeOH, 80%
(over two steps)
N
N
CO2Me
CO2Me
CO2Me
CO2Me
(+)/(±)ꢀ23
Two-carbon degradations of allyl moieties to aldehydes
are typically performed through double-bond migra-
tion/ozonolysis sequence.29 However, low conversion and
difficult separation of isomeric alkenes made this strategy
impractical in our case. To circumvent this issue, we envi-
sioned to first cleave the double bond in 9 with
OsO4/NaIO4 to aldehyde 21, which could be further con-
verted to an enamine, that could undergo a second oxida-
tive cleavage (Scheme 6).30 Treating aldehyde 21 with
pyrrolidine afforded enamine 22 quantitatively (1H NMR),
which was then fragmented to aldehyde 23, under similar
oxidative conditions. A base (Na2CO3) was utilized in the
second C=C cleavage to efficiently generate the enamine
intermediate and suppress the retro-Stork enamine alkyl-
ation reaction, which results in the formation of alkene 10
and/or alcohol 20 byproducts.14 As both events involved
OsO4/NaIO4, we combined them, thereby developing a
novel one-pot degradation of an allyl group to the two-
carbon lower aldehyde homolog. With this strategy, 9 was
converted into 23 in 72% yield.31 The oxidation of alde-
hyde 23 to carboxylic acid 24 was hampered by the steric
hindrance of the substrate and the oxidative decarboxyla-
tion of the carboxylic acid product (see below). The oxi-
dation under Pinnick conditions32 was found to be less
selective, than that with KMnO4. Excess of oxidants
(KMnO4 and NaIO4) was employed to minimize the side
decarboxylation, presumably mediated by reduced man-
ganese species. Finally, carboxylic acid 24, was converted
R = H, (–)/(±)ꢀ24
R = Me, (–)/(±)ꢀ25
(±)ꢀ24
(±)ꢀ20
Seven pyrroloazocine indole alkaloids were accessed from
lactone 8 and diester 25 utilizing a unified end-game
strategy (Scheme 7). The introduction of a double bond in
(+)-8 and (–)-25 following Magnus’ thioamide sequence8,33
provided (+)-grandilodine C (2) and (–)-lapidilectam (4),
respectively. These results allowed us to revise the sign of
the optical rotation for lapidilectam (4) from the previ-
ously reported1b (+) to (–).14 Treatment of diester 4 under
basic conditions led to a ca. 3.5:1 mixture of 4 and 7,
which could be separated, affording (+)-grandilodine B
(7). The final reduction of amides 2, 4 and 7 with
Me3OBF4/NaBH4 led to (–)-lapidilectine
lapidilectine B (1) and (+)-isolapidilectine A (6),14 whilst (–
)-grandilodine (5) and unnatural (+)-
A (3), (+)-
A
dihydrolapidilectine B (26) were synthesized by direct
reduction of (–)-25 and (+)-8 with borane.
On the biosynthesis of pyrroloazocine indole alka-
loids. With the natural products and synthetic interme-
diates in hand, we studied the biosynthetic relationships
4
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of pyrroloazocine indole alkaloids. The initial proposal
Finally, it was noticed that despite their lower stability in
comparison with the corresponding pyrrolones,14 3-
pyrrolines (lundurine B, lapidilectines A,B, isolapidilecti-
ne A, tenuisine A) were isolated in significantly greater
amounts,1a,2 suggesting that the pyrrolones (lundurine A,
grandilodines B,C, lapidilectam, tenuisine C) could arise
from an autoxidation process. Indeed, synthetic lundurine
B8 spontaneously converted (> 50%) into lundurine A
upon storage under air for 16 months.
1
2
3
4
5
6
7
8
contains a rare oxidative decarboxylation of a methyl
ester in lapidilectine A-type diesters, followed by a het-
erolytic decarboxylation of the lactone, furnishing the
cyclopropane of the lundurines (Scheme 8).11,14 However,
to date, there is still no experimental support for this
hypothesis. To probe the first decarboxylation event we
attempted to transform diester 25 into alcohol 20, alkene
10, or directly into lactone 8. However, 25 was unreactive
to SET oxidation agents (CAN), and no oxidation peak
was observed (up to +2.0 V) by cyclic voltammetry. In
contrast, the sodium salt of carboxylic acid 24 (oxidative
potential peak of +0.9 V) underwent the desired oxidative
decarboxylation with CAN in the presence of MeOH.34
Under these conditions, a ca. 1:1 mixture of alkene 10 and
the methyl ether of 20 (20Me) was formed. Treatment of
this mixture with 50% aqueous sulfuric acid afforded
lactone 8 in 62% NMR yield (Scheme 8).
9
We suggest an alternative biosynthetic scheme, which
features carboxylic acids 28 as key intermediates and
homolytic mechanism for decarboxylation of lactone into
cyclopropane. The new proposal is summarized on
Scheme 8. It is in line with the experimentally observed
reactivity and additional DFT studies (see below).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
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42
43
44
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57
58
59
60
The new biosynthetic hypothesis starts with the hydroly-
sis of kopsijasminilam-type precursors to pyrroline-
containing carboxylic acids 28 (Scheme 8). The close
proximity between C20 and amide N atom in known
kopsijasminilam-type structures37 suggests that lactam
hydrolysis might involve N-acyl ammonium cations 29 as
key intermediates.38,39 Indeed, the DFT optimization22 of
kopsijasminilam-type structures with planar amide and
the carbocation at C20 led to more stable cations 29 that
have short C20–N distances (ca. 1.62 Å), non-planar nitro-
gen atoms and elongated amide C21–N bonds (ca. 1.52
Å).14 This geometry resembles the one previously reported
for N-alkylated twisted amides, which are prone to hy-
drolysis of N–CO bond.40
Next, the hypothesis of heterolytic cleavage of lactones to
cyclopropanes was tested. When lactone 8 was treated
with KCl in wet DMSO at 85 °C for 17 h,35 no cyclopropane
product was observed. This led us to consider an alterna-
tive mechanism for the generation of the cyclopropane
via homolytic photochemical decarboxylation of the γ-
lactone.36 To our delight, irradiation of lactone 8 with
UVb light (300 nm) or UVc light (254 nm) gave the corre-
sponding cyclopropane 27 in moderate NMR yield, with
UVb wavelength being more selective and efficient
(Scheme 8).
Scheme 7. Endgame: Diversification of Intermediates (+)-8 and (–)-25 into Seven Natural Products of the Lapidi-
lectine/Grandilodine Family. X-ray Structures of (±)-1, (±)-3, (±)-4, (±)-5, (±)-7
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Scheme 8. Cyclopropane Formation by Stepwise Decarboxylation of Acid 24 and Lactone 8. Original and New
Proposal for the Origin of the Cyclopropane of Lundurines
1
2
3
Original biosynthetic proposal:a
4
5
N
N
N
N
N
MeO2C
HO
O
O
R
R
O
R
R
R
O
6
7
8
9
– CO2
N
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Lapidilectine B
Tenuisine A
Lundurine B
Lapidilectine A
via heterolytic pathway
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental results:
O
O
O
O
N
N
N
N
H2SO4 (50% aq)
HO2C
MeO
CAN, Na2CO3
CH2Cl2, MeOH
O
O
+
62% NMR yield
(over two steps)
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
8
24
10
20Me
10:20Me = ca. 1:1
h
ν
Time
O
O
Yield of 27 (bcsm)
N
2.5 h
20 min
1 h
20 min
10 d
no reaction
23% (66%)
34% (47%)
14% (26%)
6% (11%)
N
UVa (350 nm)
UVb (300 nm)
UVb (300 nm)
UVc (254 nm)
Sunlight
h
ν
O
O
MeOHꢀd4 (for UV)
neat (for sunlight)
N
N
CO2Me
CO2Me
– CO2
8
27
bcsm = based on conversion of starting material
New biosynthetic proposal:
X
N
21
N
HO2C
21
O
N
R
MeO2C
R = H
R
20
20
OH
N
N
N
CO2Me
21
+
N
CO2Me
MeO2C
CO2Me
O
N
CO2Me
28
via
20
CO2Me
21
N
20
Kopsijasminilam-type
precursor (R = H, OMe)
X = H2
X = O
R
O2
[O]
CO2Me
endoꢀCO2Me
Lapidilectine A
Isolapidilectine A
Lapidilectam
Grandilodine B
– CO2
–MeOH
group
DFT, R = H
endoꢀCO2Me
CO2Me
29
O
N
N
N
O
N
O
O
O2
R
UVb
R
R
O
R
– CO2
N
N
N
N
CO2Me
CO2Me
CO2Me
R = OMe
CO2Me
Lundurine B
Lundurine A
Lapidilectine B
Tenuisine A
Grandilodine C
Tenuisine C
O2
via radical pathway
a Simplified version. For the full scheme see Supporting Information and ref. 11.
Carboxylic acids 28 can be further converted into methyl
esters lapidilectine A and isolapidilectine A. These com-
pounds were previously proposed as precursors to lac-
tones. Our experimental results suggest that this scenario
is unlikely, but carboxylic acids 28 might undergo an
oxidative decarboxylation/lactonization leading to the
formation of lactones lapidilectine B and tenuisine A. The
proximity of the lactone carbonyl group and the pyrroline
nitrogen atom in lapidilectine B (2.5 Å, X-ray structure,
Scheme 7) suggests a possible intramolecular assistance of
the latter in the lactonization process. While we were not
able to obtain amino-acid 28 or its 14,15-dihydro analogue
to test this hypothesis experimentally, our DFT calcula-
tions22 support this possibility. On one hand, open ben-
zylic carbocation A is more stable than closed carbocation
A´ by 5.3 kcal/mol (Scheme 9). This suggests that the
lactonization of lactam derivatives is hampered by this
unfavorable equilibrium. Experimentally, we indeed ob-
served that this transformation only takes place efficiently
in a strongly acidic medium, and that under milder condi-
tions the major pathway observed is towards elimination
product 10. On the other hand, pyrroline-containing cati-
on B´ benefits from additional stabilization by the nitro-
gen and, in this scenario, is more stable than open ben-
zylic cation B by 5.6 kcal/mol.41 This, in turn, suggests
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that the lactonization of pyrroline derivatives should be a conversion into the cyclopropane present in the lun-
1
favorable natural process.
durines.
2
3
4
5
6
7
8
9
The subsequent decarboxylation into cyclopropane may
be a light-induced process, as was demonstrated experi-
mentally for 8. Tenuisine A, after a photochemical decar-
boxylation, would give lundurine B, featuring a 3-
pyrroline fragment. This transformation presumably pro-
ceeds with the initial excitation of the arene system (ab-
sorption band at 290 nm in 1, 2 and 8), that results in the
homolytic cleavage of the benzylic C–O bond, which is
perpendicular to the aromatic system. Irradiation of a
thin film of neat 8 between two quartz plates with sun-
light over 10 days also showed formation of 27, suggesting
the relevance of the photochemical decarboxylation in the
biosynthetic scheme and the sufficiency of UVb light to
trigger this transformation.42
ASSOCIATED CONTENT
Supporting Information
Additional details, theoretical calculations, experimental
procedures, characterization data (PDF). Crystallographic
data (CIF).
AUTHOR INFORMATION
Corresponding Author
aechavarren@iciq.es
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ORCID
Fedor M. Miloserdov: 0000-0002-7906-4650
Mariia S. Kirillova: 0000-0003-1628-4186
Michael E. Muratore: 0000-0002-3298-9381
Antonio M. Echavarren: 0000-0001-6808-3007
Finally, pyrrolines might undergo allylic oxidation, pro-
ducing pyrrolones. As the decarboxylation of lactone and
allylic oxidation do not require any specific enzyme, the
corresponding compounds could have been formed after
collection of the plant material, and be even artefacts of
the isolation process.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Agencia Estatal de Investigación (CTQ2016-75960-
P MINECO/AEI/FEDER, UE), AEI-Severo Ochoa Excellence
Accreditation 2014-2018, SEV-2013-0319), the European Re-
search Council (Advanced Grant No. 321066), the AGAUR
(2014 SGR 818 and predoctoral fellowship to M.S.K.), and
CERCA Program / Generalitat de Catalunya for financial
support. M.E.M. acknowledges the receipt of a COFUND
postdoctoral fellowship (Marie Skłodowska-Curie actions).
We also thank the ICIQ X-ray diffraction unit for the crystal-
lographic studies.
Scheme 9. Relative Stability of Cation Intermediates
A, A´ and B, B´.
O
O
N
N
O
+
OMe
+
ꢀG0 = 5.3 kcal/mol
N
N
CO2Me
CO2Me
CO2Me
A
B
A´
B´
14
15
14
REFERENCES
N
N
15
O
+
OMe
+
ꢀG0
= –5.6 kcal/mol
N
N
CO2Me
CO2Me
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CONCLUSIONS
In summary, we have developed concise total syntheses
(11-19 steps) of enantiomerically pure (+)-lapidilectine B
(1), (+)-grandilodine C (2), (–)-lapidilectine A (3), (–)-
lapidilectam (4), (–)-grandilodine
A
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