Phosphoric acid catalyzed desymmetrization of bicyclic bislactones bearing an all-carbon stereogenic center: Total syntheses of (-)-rhazinilam and (-)-leucomidine B

Article abstract of DOI:10.1002/anie.201405842

In the presence of a catalytic amount of an imidodiphosphoric acid, enantioselective desymmetrization of bicyclic bislactones by reaction with alcohols took place smoothly to afford enantiomerically enriched monoacids having an all-carbon stereogenic center. Concise catalytic enantioselective syntheses of both (-)-rhazinilam and (-)-leucomidine B were subsequently developed using (S)-methyl 4-ethyl-4-formylpimelate monoacid as a common starting material. Breaking symmetry: Achiral bislactones (1) undergo desymmetrization by reaction with alcohol in the presence of chiral imidodiphosphoric acids. The monoacids 2, having an all-carbon stereogenic center, were obtained in good to excellent yields and enantioselectivities. Concise total syntheses of (-)-rhazinilam and (-)-leucomidine B were subsequently developed using 2 as a common starting material.

Full text of DOI:10.1002/anie.201405842

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Angewandte
Communications
DOI: 10.1002/anie.201405842
Organocatalysis
Phosphoric Acid Catalyzed Desymmetrization of Bicyclic Bislactones
Bearing an All-Carbon Stereogenic Center: Total Syntheses of
(À)-Rhazinilam and (À)-Leucomidine B**
Jean-Baptiste Gualtierotti, Delphine Pasche, Qian Wang, and Jieping Zhu*
Abstract: In the presence of a catalytic amount of an
imidodiphosphoric acid, enantioselective desymmetrization
of bicyclic bislactones by reaction with alcohols took place
smoothly to afford enantiomerically enriched monoacids
having an all-carbon stereogenic center. Concise catalytic
enantioselective syntheses of both (À)-rhazinilam and (À)-
leucomidine B were subsequently developed using (S)-methyl
4-ethyl-4-formylpimelate monoacid as a common starting
material.
unit has, in our opinion, not been fully exploited. We assumed
that prior to designing and to executing any synthetic plan
using 1 as a key starting material, desymmetrization of this
prochiral synthon to the enantioenriched monoacid 2 was
a prerequisite. Previously, Amat, Bosch, et al. reported the
desymmetrization of prochiral 1 to the piperidinone deriva-
tive 6 by cyclocondensation of 1 with a stoichiometric amount
of (R)-phenylglycinol.[5] However, rapid and enantioselective
synthesis of 2a (R = Et) remained to be developed.[6] In
connection with our ongoing projects focused on the synthesis
of indole alkaloids,[7] we became interested in desymmetrizing
Kuehneꢀs aldehyde and its subsequent application in natural
product synthesis. We report herein that in the presence of
a catalytic amount of chiral phosphoric acid,[8,9] bicyclic
bislactones derived from diesters 1 are readily desymmetrized
to enantioenriched monoacids (2) having an all-carbon
stereogenic center. We also document a unified and divergent
synthesis of two structurally distinct monoterpene indole
alkaloids, (À)-rhazinilam (7) and (À)-leucomidine B (8),
using 2a (R = Et) as a common starting material (Figure 1).
To the best of our knowledge, desymmetrization of
dimethyl 4,4-disubstituted pimelate has never been reported.
Our initial attempts to differentiate the two enantiotopic ester
functions in 1 and the protected form 9 (Figure 2), using lipase
I
ntroduced by Kuehne in 1964,[1] dimethyl 4-ethyl-4-formyl-
pimelate (1a, R = Et; Figure 1) has been used as a key
starting material in the syntheses of vincamine (3),[1] 8-
oxovincatine (4),[2] vincadifformine (5),[3] and other mono-
terpene indole alkaloids.[4] However, the full potential of this
prochiral ten-carbon synthon, an equivalent of a monoterpene
Figure 2. Desymmetrization of Kuehne’s aldehyde and its derivatives.
Figure 1. Kuehne’s aldehyde and its use in natural product synthesis.
and esterase, met with failure (see the Supporting Informa-
tion).[10] Attempts to desymmetrize the eight-membered
cyclic anhydride 10 were equally unsuccessful. In the presence
of various organocatalysts, including Cinchona-alkaloid
derivatives[11] and BINOL-derived chiral phosphoric
acids,[12,13] reaction of 10 with methanol at À208C was very
slow, thus affording, after 48 h, the racemic monoacid 2a (R =
Et) in less than 20% yield. These results are in sharp contrast
to the facile desymmetrization of five- and six-membered
meso or prochiral anhydrides such as 11 (Figure 2), thus
indicating the challenges associated with the desymmetriza-
tion of 1.
[*] J.-B. Gualtierotti, D. Pasche, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304. 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
[**] We thank EPFL (Switzerland), the Swiss National Science Founda-
tion (SNSF), the Swiss National Centres of Competence in Research
NCCR-Chemical Biology, the COST action (CM0905), and the Swiss
State Secretariat for Education and Research for financial support.
Considering other substrates derived from Kuehneꢀs
aldehyde, which are susceptible to desymmetrization, we
turned our attention to the bicyclic bislactone 12a. In analogy
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405842.
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Chemie
to the anhydride 11, which is an excellent substrate for
desymmetrization, we hypothesized that 12a could be sim-
ilarly desymmetrized. The carbonyl carbon atoms in 12a are
certainly less electrophilic than those in 11, nevertheless we
assumed that the cascade fragmentation initiated by nucleo-
philic attack to one of the carbonyl groups in 12a could
provide a reasonable driving force to facilitate the occurrence
of the desired transformation. Although it has scarcely been
described in the literature,[14] 12a was easily synthesized from
1a (NaOH, then Ac2O) in 95% yield. The cis stereochemistry
of the bicyclic ring system was determined by X-ray crystal
structure analysis.[15,16]
Initial experiments on the desymmetrization of 12a using
methanol (2.0 equiv) as a nucleophile in the presence of
a chiral phosphoric acid (0.1 equiv; Figure 3) gave very
promising results (Table 1, entries 1–5). Reaction of 12a
with MeOH (2.0 equiv) at room temperature in the presence
of TRIP 13e (0.1 equiv) afforded the monoacid 2a in 95%
yield with an e.r. of 84:16 (entry 5). Interestingly, decreasing
the reaction temperature under otherwise identical reaction
conditions produced the monoacid with reduced enantiose-
lectivities (entries 5–7). Among the different solvents exam-
ined (entries 8–11), 1,4-dioxane turned out to be the solvent
of choice (entry 10). An additional increase in the enantio-
selectivity was observed with 13g[17] and 13h (entries 13 and
14).[18] Since we found that the imidodiphosphoric acid 13g,
reported by List and co-workers, was more easily recovered
from the reaction mixture than 13h (STRIP), it was chosen
for examining the scope of this novel desymmetrization
process. The 4S absolute configuration of 2a was determined
by X-ray crystal structure analysis of the corresponding 4-(4’-
bromophenyl)phenyl ester of 2a.[19]
As shown in Table 2, in addition to methanol (entry 1),
benzyl alcohol (entry 2) and isopropyl alcohol (entry 3) can
also act as nucleophiles to enantioselectively open 12, with
benzyl alcohol giving a slightly better result. The presence of
Table 2: Scope of the desymmetrization.
Entry R1
R2
R3
Product Yield [%] e.r.[b]
1
2
3
4
5
6
7
8
9
10
H
H
H
H
H
H
H
H
H
Et
Et
Et
vinyl
allyl
iPr
Ph
Me 2a
95
80
75
94
95
82
90
91
95
66
92:8
Bn
iPr
2b
2c
95.3:4.7
91.7:8.3
91:9
91.2:8.8
92.5:7.5
96.3:3.7
93.2:6.8
94.7:5.3
90.7:9.3
Me 2d
Me 2e
Me 2 f
Me 2g
Me 2h
CH2CH2SPh
CH2CH2CH2OBn Me 2i
Me 2j
Figure 3. Structure of chiral phosphoric acids derived from (S)-BINOL
and (S)-SPINOL.
Ph Me
[a] All reactions were performed on a 0.1 mmol scale, R3OH (2.0 equiv),
13g (0.1 equiv) in 1,4-dioxane (c 0.1m), RT. [b] Determined by SFC
analysis on a chiral stationary phase (see the Supporting Information for
full details).
Table 1: Desymmetrization of bicyclic bislactone 12a: Survey of catalytic
conditions.
substituents such as vinyl, allyl, isopropyl, phenyl 2-(thiophe-
noxy)ethyl, and 3-(benzyloxy)propyl at the C4a-position was
well tolerated, thus affording, after methanolysis, the corre-
sponding enantiomerically enriched aldehydes 2d–
i (entries 4–9) and ketone 2j (entry 10) in good to excellent
yields and enantioselectivities.
Entry
Cat.
Solvent
T [8C]
e.r.[b]
1
2
3
4
5
6
7
8
13a
13b
13c
13d
13e
13e
13e
13e
13e
13e
13e
13 f
13g
13h
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
THF
1,4-dioxane
TBME
1,4-dioxane
1,4-dioxane
1,4-dioxane
RT
RT
RT
RT
RT
À10
À60
RT
RT
RT
55:45
65:35
65:35
80:20
84:16
75:25
55:45
86:14
88:12
89:11
85:15
80:20
92:8
Total syntheses of (À)-rhazinilam (7)[20,21] and (À)-leuco-
midine B (8)[22] were next envisaged using 2a as a starting
material. Retrosynthetically, 7 can be prepared from 14 by
a reduction and macrolactamization sequence (Scheme 1).
The tetrahydroindolizine 14 could in turn be obtained by
a formal [3+2] cycloaddition between the allylbromide 15 and
tetrahydropyridine (R)-16.[21b,c] Likewise, (À)-leucomidine B
(8) could be accessed by a facile indolization of 17 which was
in turn thought to be accessible by condensation of (R)-16
with the a-ketoester 18.
9
10
11
12
13
14
RT
RT
RT
RT
92:8
The synthesis of (R)-16, a common starting material to
both natural products, is shown in Scheme 2. Protection of the
aldehyde in 2a was found to be more difficult than it might
appear. After a number of unsuccessful trials, the aldehyde
[a] All reactions were run at 0.1 mmol scale at RT, methanol (2.0 equiv),
catalyst (0.1 equiv), c 0.1m. [b] e.r. was determined by SFC analysis on
a chiral stationary phase (see the Supporting Information for full details).
TBME=tert-butyl methyl ether, THF=tetrahydrofuran.
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Scheme 1. Retrosynthetic analysis of (À)-rhazinilam (7) and (À)-leuco-
midine B (8).
Scheme 3. Total synthesis of (À)-rhazinilam (7). a) DMF, 1008C;
b) Ag2CO3, toluene, 1108C, 1 h, 60% for two steps; c) Pd/C, H2,
MeOH; d) KOH, MeOH/H2O (1:1) e) EDC, DMAP, NEt3, CH2Cl2, 80%
for three steps. DMAP=4-(N,N-dimethyl)pyridine, EDC=1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide.
A total synthesis of (À)-leucomidine B (8), isolated in
2012 by Morita,[22] has not been reported. Our synthesis
started by condensation of methyl 3-(2-nitrophenyl)-2-oxo-
propanoate (18)[26] with (R)-16. Simply heating (R)-16 and 18
afforded the [3+2] annulation product 17 as a mixture of two
diastereomers (d.r. = 1:1) in 70% yield (Scheme 4). The
Scheme 2. Synthesis of the tetrahydropyridine 16. a) Ethanedithiol,
Hf(OTf)4, (0.05 equiv), CH2Cl2, 95%; b) LiBH4, THF; c) TMSCHN2,
MeOH, 95% for two steps; d) MsCl, NEt3, CH2Cl2; e) NaN3
(2.0 equiv), DMF, 508C, 83% for two steps; f) IBX, TBAB, AcOH/
DMSO/H2O (1:8:1); g) PPh3, THF/H2O (9:1), 60% for two steps.
DMF=N,N-dimethylformamide, DMSO=dimethylsulfoxide, IBX=
o-iodoxybenzoic acid, Ms=methanesulfonyl, TBAB=tetra-n-butylam-
moniumfluoride, TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl.
was converted into the 1,3-dithiolane 19 in 95% yield.[23]
Chemoselective reduction of the ester to the alcohol
(LiBH4) and susbsequent esterification of the carboxylic
acid afforded 20. The primary alcohol was subsequently
transformed into the azide 22 via the mesylate intermediate
21. Deprotection of the dithiolane was realized using
Scheme 4. Total synthesis of (À)-leucomidine B (8). a) Toluene, 908C,
80%; b) Pd/C, H2, then toluene, 1108C, 40% of 8 +40% of its C21
epimer (d.r. =1:1).
a
modified literature procedure (IBX, TBAB, AcOH,
DMSO/H2O) to afford the azido aldehyde 23.[24] Staudinger
reduction of the azide and subsequent intramolecular aza-
Wittig reaction converted 23 into the cyclic imine 16 in 60%
yield. By using BH3 instead of LiBH4 for the chemoselective
reduction of the acid function, the compound 19 was
converted into ent-16 following exactly the same synthetic
sequence.
The total synthesis of (À)-rhazinilam (7) was accom-
plished as shown in Scheme 3. Heating a DMF solution of 15
and (R)-16 afforded the imminium salt 24, which upon
heating in toluene in the presence of freshly prepared Ag2CO3
(2.0 equiv) furnished 14 in 60% overall yield.[21b,c,25] The
compound 14 turned out to be air sensitive, therefore, the
oxidative annulation had to be performed under a strictly
inert atmosphere. Hydrogenation of the nitro group to give
the amine, and subsequent saponification and lactamization
provided 7 in 80% overall yield. The synthetic 7 displayed
physical and spectroscopic data identical in all respects to
those reported for the natural product.
reaction was most probably initiated by the intermolecular
Mannich reaction and subsequent intramolecular transami-
dation of the resulting Mannich adduct 25. The compound 17
1
existed exclusively as the enol form. However, the H NMR
spectra of the two purified diastereomers are more compli-
cated than expected because of the presence of atropisomers
2
2
À
around the C(sp ) C(sp ) bond. Hydrogenation of 17 fol-
lowed by heating a toluene solution of the crude aniline
afforded 8 and its C21 epimer in 80% overall yield (d.r. =
1:1). The two epimers were readily separable and one of the
diastereomers displayed physical and spectroscopic data
identical in all respects to those reported for 8[27] {Synthetic:
[a]D À18.6 (c 0.3, CHCl3); natural: [a]D À18 (c 0.3, CHCl3)}.
We have also synthesized (+)-leucomidine B (ent-8) from ent-
16 by using exactly the same synthetic scheme {[a]D + 14.3
(c 0.3, CHCl3)}. Therefore, the 20R,21S absolute configura-
tion of 8, initially assigned based on detailed NMR and CD
spectra studies, was confirmed by the present total synthesis.
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Rowland, G. B. Rowland, E. Rivera-Otero, J. C. Antilla, J. Am.
In summary, we developed a new strategy for the
desymmetrization of prochiral diesters 1 via the bicyclic
bislactone surrogates 12. In the presence of the chiral
imidodiphosphoric acid 13g, desymmetrization of the bislac-
tones 12 with an alcohol took place smoothly to afford the
enantiomerically enriched 4-substituted-4-formylpimelate
monoacids 2 in good to excellent yields and good enantiose-
lectivities. The utility of 2 as chiral building blocks in natural
products synthesis was illustrated by the development of
a concise total synthesis of (À)-razinilam (7) and the first total
synthesis of (À)-leucomidine B (8).
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Received: June 2, 2014
Revised: June 24, 2014
Published online: July 22, 2014
Keywords: alkaloids · natural products · organocatalysis ·
.
synthetic methods · total synthesis
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