Enantioselective Total Syntheses of (-)-Rhazinilam, (-)-Leucomidine B, and (+)-Leuconodine F

Article abstract of DOI:10.1002/anie.201508906

A divergent total synthesis of three structurally distinct natural products from imine 9 was accomplished through an approach featuring: 1) a Pd-catalyzed decarboxylative cross-coupling, and 2) heteroannulation of 9 with bromoacetaldehyde and oxalyl chloride to give tetrahydroindolizine 6 and dioxopyrrole 7, respectively. The former was converted into (-)-rhazinilam, while the latter was converted into (-)-leucomidine B and (+)-leuconodine F. A substrate-directed highly diastereoselective reduction of a sterically unbiased double bond by using a homogeneous palladium catalyst was developed. A self-induced diastereomeric anisochronism (SIDA) phenomenon was observed for leucomidine B. Be divergent: Concise total syntheses of (-)-rhazinilam, (-)-leucomidine B, and (+)-leuconodine F were accomplished from the common intermediate A. A homogeneous palladium catalyst was exploited for the first time to accomplish a substrate-directed highly diastereoselective hydrogenation of a sterically unbiased double bond. A self-induced diastereomeric anisochronism (SIDA) phenomenon was observed for leucomidine B.

Full text of DOI:10.1002/anie.201508906

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International Edition: DOI: 10.1002/anie.201508906
German Edition: DOI: 10.1002/ange.201508906
Natural Product Synthesis
Enantioselective Total Syntheses of (À)-Rhazinilam, (À)-
Leucomidine B, and (+)-Leuconodine F
Dylan Dagoneau, Zhengren Xu, Qian Wang, and Jieping Zhu*
Abstract: A divergent total synthesis of three structurally
distinct natural products from imine 9 was accomplished
through an approach featuring: 1) a Pd-catalyzed decarboxy-
lative cross-coupling, and 2) heteroannulation of 9 with
bromoacetaldehyde and oxalyl chloride to give tetrahydroin-
dolizine 6 and dioxopyrrole 7, respectively. The former was
converted into (À)-rhazinilam, while the latter was converted
into (À)-leucomidine B and (+)-leuconodine F. A substrate-
directed highly diastereoselective reduction of a sterically
unbiased double bond by using a homogeneous palladium
catalyst was developed. A self-induced diastereomeric aniso-
chronism (SIDA) phenomenon was observed for leucomidi-
ne B.
ology, these natural products are all biogenetically derived
À
À
from vincadifformine (4). Cleavage of the C2 C7 and C2
C16 bonds were key steps for the conversion of 4 into 1 and 2,
À
respectively. On the other hand, formation of a N1 C21 bond
from the rhazinilam-type intermediate afforded the skeleton
of 3.[2,9]
The ability of nature to synthesize a collection of
structurally diverse natural products from a single intermedi-
ate has inspired chemists for years. We have recently
developed a unified approach to (À)-rhazinilam (1) and
(À)-leucomidine B (2).[6] The drawback of this approach was
the lack of stereocontrol in the creation of the C21 stereo-
genic center of (À)-leucomidine B (2).[10] Indeed, the lack of
diastereoselectivity in the nucleophilic addition of sterically
unbiased a,a-disubstituted imines is a recurrent problem
encountered in the synthesis of related indole alkaloids.[11] We
report herein a new strategy that allowed us to accomplish the
total syntheses of (À)-rhazinilam (1), (À)-leucomidine B (2),
and (+)-leuconodine F (3) from a cyclopentene derivative 5
with complete control of stereoselectivity.
T
he natural products (À)-rhazinilam (1),[1] (À)-leucomidi-
ne B (2),[2] and (+)-leuconodine F (3)[3] are members of the
monoterpene indole alkaloids (Figure 1). (À)-Rhazinilam (1),
with its unique axially chiral tetracyclic structure and potent
in vitro tubulin-binding properties,[4] has triggered substantial
synthetic efforts.[5,6] Total syntheses of (À)-leucomidine B (2)6
and (+)-leuconodine F (3)[7] have been reported and there
have been recent efforts towards the synthesis of members of
the leuconodine family of natural products, which have an
unusual [5.5.6.6]diazafenestrane system.[7,8] Although archi-
tecturally distinct, with different ring connectivity and top-
Our retrosynthetic analysis of 1, 2, and 3 is shown in
Scheme 1. In a forward sense, we envisaged reaching the
Figure 1. (À)-Rhazinilam (1), (À)-leucomidine B (2), and (+)-leucono-
dine F (3).
Scheme 1. A unified synthetic approach to (À)-rhazinilam (1), (À)-
leucomidine B (2), and (+)-leuconodine F (3).
bicycles 6 and 7 through heteroannulation of tetrahydropyr-
idine 9 with bromoacetaldehyde (10) and oxalyl chloride (11),
respectively. While tetrahydroindolizine 6 has been converted
into rhazinilam (1), reductive amination of 7 was expected to
afford leucomidine B (2). The key issue to be addressed
would be control of the C21 stereochemistry. Selective
reduction of the nitro group in 7 without triggering the
indolization, followed by macrolactamization would furnish 8,
which, upon transannular cyclization, would provide leuco-
[*] D. Dagoneau, Dr. Z. Xu, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique FØdØrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508906.
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nodine F (3). The imine 9 should be accessible through
structural reorganization of cyclopentene 5 through ozonol-
ysis and subsequent tandem Staudinger/Aza–Wittig reaction.
The cyclopentene 5 could in turn be synthesized through
a palladium-catalyzed decarboxylative coupling between the
potassium carboxylate 12 and the vinyl triflate 13.[12]
Synthesis of enantiomerically enriched 1,5,5-trisubstituted
cyclopentene 5 is detailed in Scheme 2. Pd-catalyzed asym-
Scheme 3. Total synthesis of (À)-rhazinilam (1). a) O3, NaHCO3
(0.30 equiv), CH2Cl2/MeOH (4/1), À788C, 2 min, then Ac2O
(4.0 equiv), Et3N (2.0 equiv), 08C to RT, 3 h, 92%; b) PPh3 (1.1 equiv),
CH3CN, 708C, 3 days; c) bromoacetaldehyde [10, 5.0 equiv, freshly
prepared as a dichloromethane solution (49 wt%)], NaHCO3
(6.0 equiv), 708C, 6 h, 76% from 20; d) H2, Pd/C, MeOH, RT, 30 min;
e) KOH, MeOH/H2O, RT, 12 h; f) EDCI, HOBt, Et3N, CH2Cl2, RT, 3 h,
79% over 3 steps. EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodii-
mide hydrochloride, HOBt=1-hydroxybenzotriazole.
Scheme 2. Synthesis of cyclopentene 5. a) [Pd2(dba)3] (2.5 mol%), (S)-
tBuPHOX (6.25 mol%), THF (c 0.067m), 258C, 3 h, 87% yield, 86%
ee; b) disiamyl borane (2.5 equiv), THF, 08C to RT, 2 h then H2O2/
NaOH, RT, 1 h; c) TBSCl (1.2 equiv), imidazole (1.5 equiv), DMF, RT,
12 h, 85% over 2 steps; d) LiHMDS (1.1 equiv), THF, À788C, 45 min
then PhNTf2 (1.2 equiv), À788C to RT, 12 h, 92%; e) potassium 2-(2-
nitrophenyl)acetate (12, 2.5 equiv), [{Pd(allyl)Cl}2] (5 mol%), XPhos
(15 mol%), diglyme, 1408C, 2 h, 52%; f) AcCl (0.20 equiv), MeOH, RT,
1 h; g) MsCl (1.2 equiv), Et3N (1.5 equiv), DMF, RT, 5 h then NaN3
(3.0 equiv), RT, 12 h, 84% over 2 steps. dba=1,5-diphenyl-1,4-penta-
dien-3-one, THF=tetrahydrofuran, TBS= tert-butyldimethylsilyl,
DMF=N,N-dimethylformamide, LiHMDS=lithium hexamethyldisil-
azide, Tf =triflate.
find that simply stirring an acetonitrile solution of 9 and
bromoacetaldehyde (10)[17] at 708C in the presence of a weak
base (NaHCO3) afforded tetrahydroindolizine 6 in excellent
yield. Mechanistically, the reaction might be initiated by N-
alkylation to give enamine aldehyde A, which undergoes
cyclization to give B. Dehydration of B followed by tautome-
rization would afford tetrahydroindolizine 6. We subse-
quently found that the Staudinger reduction/Aza–Wittig and
heteroannulation can be integrated into a one-pot reaction to
allow the direct conversion of 20 into 6 in 76% yield. Finally,
compound 6 was transformed into (À)-rhazinilam (1) in 79%
overall yield by following the standard reduction/hydrolysis/
metric decarboxylative allylation of the known b-ketoester 14
according to Stoltzꢀ method afforded (S)-2-allyl-2-ethylcyclo-
pentan-1-one (15) in 87% yield with 86% ee.[13] Hydrobora-
tion of 15 followed by oxidation of the resulting alkylborane
provided primary alcohol 16, which, without purification, was
directly converted into TBDMS ether 17 in 85% overall yield.
Deprotonation of ketone 17 followed by trapping of the
resulting enolate with N-phenylbis(trifluoromethanesulfoni-
mide) afforded the desired vinyl triflate 13 in 92% yield. The
decarboxylative coupling of 13 with potassium carboxylate 12
afforded 18 in 52% yield in spite of the steric hindrance
around the vinyl triflate unit. Treatment of a methanol
solution of 18 with a catalytic amount of in situ generated
hydrochloric acid[14] afforded alcohol 19, which was trans-
formed into azide 5 via the mesylate intermediate.
Conversion of cyclopentene 5 into (À)-rhazinilam (1) is
depicted in Scheme 3. Ozonolysis of cyclopentene 5 in
CH2Cl2/MeOH solution buffered with NaHCO3, followed
by treatment of the crude ozonolysis product with acetic
anhydride and triethylamine,[15] afforded the keto ester 20 in
92% yield. The one-pot Staudinger reduction/cyclization of
20 (MeCN, 708C, 3 days) provided the tetrahydropyridine 9 in
86% isolated yield. We noted that imine 9 was sufficiently
stable to be purified by flash column chromatography. While
condensation of 1-alkyl-3,4-dihydroisoquinolines with a-halo
ketones has been exploited for the synthesis of pyrrolo[2,1-
a]isoquinolines,[16] heteroannulation of imines with bromoa-
cetaldehyde has, to the best of our knowledge, never been
examined. After much experimentation, we were pleased to
macrolactamization sequence[6]
.
The total synthesis of (À)-leucomidine B (2) is shown in
Scheme 4. Cyclocondensation between imine 9 and oxalyl
chloride (11, 1.1 equiv) in the presence of Et3N afforded the
desired dioxopyrrole 7 in quantitative yield after acidic
workup.[18] Owing to hindered rotation around the C7 C8
À
bond, compound 7 was isolated as a mixture of two
inseparable atropisomers. While indolization of 7 to give
natural product 2 proceeded without problems under a variety
of reductive conditions, control of the diastereoselectivity
turned out to be challenging owing to the insignificant steric
difference between the neighboring ethyl and 2-methoxycar-
bonylethyl groups. For example, heterogeneous catalytic
hydrogenation of 7 in the presence of Pd/C afforded (À)-
leucomidine B (2) and its C21 epimer in a 1:1 ratio. A similar
result was obtained by using aqueous TiCl3 as the reduc-
tant.[19] The reagent-controlled enantioselective reduction of 7
was also examined. CuH-catalyzed 1,4-reduction with
Ph2SiH2 as the reducing agent in the presence of a variety
of chiral ligands afforded the 1,4-reduction product in
excellent yield,[20] but the diastereoselectivity never exceeded
1.3:1.
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To reach (+)-leuconodine F (3) from 7, we needed to
chemoselectively reduce the nitro group without touching the
2,3-dioxopyrrole and to avoid condensation of the resulting
aniline with the neighboring carbonyl function. Owing to the
high electrophilicity of the dioxopyrrole unit,[26] masking the
carbonyl unit was deemed necessary and 1,4-conjugate
addition of methanol to b,g-unsaturated a-keto amide was
thought to be ideal. The resulting adduct would be sufficiently
stable under the neutral or mild basic conditions planned for
the macrolactamization but the electrophilicity of C2 and C21
are readily revealed under acidic conditions for the subse-
quent transannular cyclization.
Scheme 4. Total synthesis of (À)-leucomidine B (2). a) Et3N
(2.5 equiv), CH2Cl2, 08C to RT, 1 h, quantitative; b) KOH, THF/H2O,
87%; c) H2 (1 atm), Pd(TFA)2 (10 mol%), CF3CH2OH, 08C to RT, 12 h;
then reflux; then TMSCHN2 (5.0 equiv), 08C, 15 min, 71% from 21.
TFA=trifluoroacetic acid, TMS=trimethylsilyl.
The realization of the aforementioned synthetic plan is
shown in Scheme 5. Stirring a methanol solution of 7 in the
presence of DIPEA at room temperature, followed by
trapping of the resulting enol with an excess amount of
The substrate-directed diastereoselective reduction was
next examined by taking advantage of the coordinating ability
of the carboxylic acid group. Hydrogenation (1.0 atm H2) of
carboxylic acid 21 in the presence of Crabtreeꢀs catalyst or
hydride reduction with Strykerꢀs reagent CuH/Ph2SiH2 led
only to recovery of the starting material. Gratifyingly, treat-
ment of a trifluoroethanol (TFE) solution of 21 with Pd-
(TFA)2 under hydrogen atmosphere (1.0 atm)[21] at 08C
afforded a mixture of aniline 22 and indole 23, which, after
heating to reflux, was converted into a single compound 23
with a diastereomeric ratio of 92:8. Addition of an excess of
TMSCHN2 (5.0 equiv) to the above reaction mixture at 08C
furnished, after column chromatography, the diastereomeri-
cally pure (À)-leucomidine B (2) in 71% isolated yield. As
expected, reduction of ester 7 under identical conditions
afforded leucomidine B (2) and its C21 epimer without
noticeable diastereoselectivity owing to the poor coordinating
ability of the ester function.[22] It is worth noting that
hydrogenation of 21 in the presence of Pd/C or Pd(OH)2/C
afforded a 1:1 diastereomeric mixture of tetracycle 23. We
also synthesized the (Æ)-leucomidine B (2) by following the
same synthetic route and obtained an X-ray crystal structure
of (Æ)-2 that confirmed the relative stereochemistry between
C20 and C21. A heterodimer was formed in the crystal
packing of (Æ)-2 (Figure 2),[23] which nicely explains the
concentration dependence of the [a]D value of our enantio-
merically enriched (À)-2 in apolar solvent [89% ee, [a]D =
À21 (c 1.0, CHCl3) [a]D = À29 (c 0.3, CHCl3); lit.2 [a]D = À18
(c 0.3, CHCl3)].[24] In addition, a self-induced diastereomeric
anisochronism (SIDA) phenomenon was observed for leuco-
midine B (see the Supporting Information).[7,25]
Scheme 5. Total synthesis of (+)-leuconodine F (3). a) DIPEA, MeOH,
RT, 1 h, then TMSCHN2, 08C to RT, 30 min, 93%; b) KOH, MeOH/
H2O, RT, 12 h; c) H2, Pd/C, MeOH, RT, 1 h; d) EDCI, HOBt, Et3N,
CH2Cl2, RT, 12 h, then TFA, RT, 4 h, 53% from 24. DIPEA=diisopropyl-
ethylamine.
trimethylsilyldiazomethane afforded exclusively the 1,4-
adduct 24 in 93% yield of isolated product (Scheme 5).
Saponification of the methyl ester followed by hydrogenation
of the nitro group furnished amino acid 25, which, without
purification, underwent EDCI-mediated lactamization to
provide 26 as a mixture of diastereomers. Upon addition of
TFA to the above mixture, a highly diastereoselective trans-
annular cyclization took place to afford (+)-leuconodine F
(3) as a single diastereomer in 53% overall yield from 24. The
physical and spectroscopic data for our synthetic compound
were identical to those reported for the natural product.
In conclusion, we developed a novel divergent total
synthesis of three natural products, namely (À)-rhazinilam (1,
12 steps, 16.4% overall yield), (À)-leucomidine B (2, 12 steps,
14.5% overall yield), and (++)-leuconodine F (3, 14 steps,
11.6% overall yield) from readily available (Æ)-allyl 1-ethyl-
2-oxocyclopentane-1-carboxylate (14). Heteroannulation of
tetrahydropyridine 9 with bromoacetaldehyde (10) and oxalyl
chloride (11), respectively, was successfully developed for the
construction of the functionalized bicycles, which were
subsequently diverged to three skeletally different natural
products. A homogeneous palladium catalyst was exploited
for the first time to accomplish a substrate-directed highly
diastereoselective hydrogenation of a sterically unbiased
double bond. We anticipate that this method will find
applications in the synthesis of other monoterpene indole
alkaloids.
Figure 2. X-ray structure of (Æ)-leucomidine B (2).
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Keywords: asymmetric synthesis · divergent synthesis ·
domino cyclization · heteroannulation · indole alkaloids
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Received: September 23, 2015
Published online: October 20, 2015
Angew. Chem. Int. Ed. 2016, 55, 760 –763
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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