Asymmetric Total Synthesis of (-)-Leuconoxine via Chiral Phosphoric Acid Catalyzed Desymmetrization of a Prochiral Diester

Article abstract of DOI:10.1021/ol5033865

The asymmetric total synthesis of (-)-leuconoxine has been achieved. The desymmetrization of a prochiral diester using a chiral phosphoric acid catalyst produced a highly enantioenriched lactam with excellent yield. The ring construction featuring an intr

Full text of DOI:10.1021/ol5033865

Letter
pubs.acs.org/OrgLett
Asymmetric Total Synthesis of (−)-Leuconoxine via Chiral Phosphoric
Acid Catalyzed Desymmetrization of a Prochiral Diester
Kazuhiro Higuchi,* Shin Suzuki, Reeko Ueda, Norifumi Oshima, Emiko Kobayashi, Masanori Tayu,
and Tomomi Kawasaki*
Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose, Tokyo 204-8588, Japan
S
* Supporting Information
ABSTRACT: The asymmetric total synthesis of (−)-leuco-
noxine has been achieved. The desymmetrization of a prochiral
diester using a chiral phosphoric acid catalyst produced a
highly enantioenriched lactam with excellent yield. The ring
construction featuring an intramolecular N-acyliminium
cyclization and the one-step pyrrolidone formation using Bestmann’s ylide was successfully accomplished.
he plant apocynaceae produces various biologically
important monoterpene indole alkaloids such as reser-
pine, ajmaline, and vinblastine. Therefore, it has attracted
attention as a medicinal resource over the centuries.1 Recently,
compounds 1−4 were isolated from apocynaceae. These are
attractive due to their complex structures, intriguing
bioactivities, and biosynthetic relationship (Figure 1). Leuco-
program of the N-acyliminium mediated ring construction for
alkaloid synthesis,3,4 we are interested in the chemoselective
cyclization of 6 toward seven-membered imine 4 or piperidine
5. Compound 6 is derived from the oxidation of indole 7. With
the aim of synthesizing chiral 1, we also planned the chiral
phosphoric acid catalyzed desymmetrization of prochiral diester
8. The desymmetrization of prochiral molecules to obtain chiral
products with an enzyme and organocatalyst is a powerful tool
in asymmetric syntheses. Chiral phosphoric acid catalysts5 have
recently attracted growing interest because of their easy tuning
and applicability to a wide range of substrates. Particularly, the
desymmetric ring opening reaction of acid anhydride6a and
bicyclic bislactone,6b and the desymmetric lactonization of
diesters6c have potential use in organic synthesis. However,
there is no example of asymmetric amidation7 by chiral
phosphoric acid catalysts; thus, we undertook the challenge of
desymmetric lactam cyclization of 8.
T
In 2013, Zhu et al.8 developed enantioselective total
syntheses of (−)-1 and (+)-2 by controlling the nucleophilicity
of amines within the α-diketone intermediate. In 2014,
Tokuyama et al.9 established powerful divergent syntheses of
( )-1 and 3 by the oxidative cyclic aminal formation and
diastereoselective ring closing metathesis. Here, we report the
asymmetric total synthesis of (−)-leuconoxine (1) using chiral
phosphoric acid catalyzed desymmetrization of prochiral diester
and N-acyliminium cyclization.10
In order to examine the desymmetrization, we first
synthesized prochiral diesters 8a and 8b (Scheme 1). Acylation
of tert-butyl acetoacetate using an acid chloride of 9 under basic
conditions afforded ester 10. The tert-butoxy carbonyl group in
10 was removed by treatment with TFA to give β-diketone 11
in 68% yield in three steps.11 Michael addition of 11 with
methyl acrylate produced β-diketo diester 12 in 56% yield
which was reduced under hydrogenation and cyclized into
diester 8a in 98% yield. Lactonization of 8a in the presence of
Figure 1. Leuconoxine (1) and retrosynthetic analysis.
noxine (1), isolated from stems and leaves of Leuconotis
eugenifolius in Indonesia,2 has the tetracyclic ring fused at the
aminal carbon and the adjacent quaternary carbon center. We
are interested in the inherent structure of 1 and planned the
retrosynthesis of 1 as shown in Figure 1. Pyrrolidone ring
formation using a phosphine ylide and subsequent hydro-
genation of 2 in the last stage lead to 1. Due to our ongoing
Received: November 21, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
Scheme 1. Syntheses of Prochiral Diester 8a and 8b
Table 1. Desymmetric Lactamization Using Chiral
Phosphoric Acids
temp
(°C)
a
entry
8
13
solvent
time yield of 7 (%)
er
1
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
b
a
a
a
a
a
a
a
b
c
d
e
f
DCM
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
rt
1 d
no reaction
a 44
−
2
THF
1 d
53:47
59:41
67:33
69:31
67:33
26:74
30:70
25:75
22:78
30:70
21:79
20:80
17:83
31:69
43:57
40:60
42:58
83:17
87:13
3
MeCN
DCE
10 d
4 d
a 52
4
a 99
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
8 h
a 96
6
8 h
a 95
7
2 h
a quant
a 98
8
15 h
20 h
1 h
9
a 99
10
11
12
13
14
15
16
17
18
19
20
a 96
g
h
i
7 h
a 97
1 h
a quant
a 96
0.8 h
6 d
i
a 89
j
reflux
reflux
reflux
reflux
reflux
80
1.5 h
0.8 h
0.8 h
0.3 h
11 h
4 d
a quant
a quant
b quant
b 96
k
f
DBU at rt afforded ( )-7a. The acetyl group in ( )-7a was
converted into an ethyl group by successive NaBH4 reduction
of ketone, chlorination, and radical reduction to produce
( )-7b. Finally, hydrolysis and the subsequent methylation led
to diester 8b in 76% yield in two steps.
h
l
a quant
a 94
l
a
Enantiomer ratios (er’s) were determined by HPLC.
Next, using the chiral phosphoric acids 13a−l (Figure 2), we
studied the desymmetrization of diesters 8 as shown in Table 1.
better ee’s (entries 8−12). Using the pentafluorophenyl group
13i at rt instead of toluene−reflux temperature enhanced the ee
but prolonged the reaction time significantly (entries 13 and
14). In addition, the effect of a sterically bulky group, such as
triisopropyl 13j and 9-anthryl 13k groups, resulted in low ee’s
(entries 15 and 16). In order to investigate the influence of the
acetyl carbonyl group in substrate 8a, the ethyl derivative 8b
was used and resulted in a substantial decline of ee’s (entries 17
and 18). This result suggests the importance of hydrogen
bonding between the phosphate and acetyl carbonyl group of
8a in the cyclization process.
Consequently, a desymmetrization using VAPOL (13l)12 at
80 °C and after stirring for 4 days provided the best
enantioselectivity (74% ee, entry 20). Optimized conditions
in hand, we continued the next transformation.
We next performed the transformation of 7a (75% ee) to
Kerr’s intermediate 1713 (Scheme 2). The conversion of an
acetyl derivative of 7a to an ethyl group in 7b was carried out
according to the same procedure as that shown in Scheme 1.
Ester 7b was reduced to alcohol 15 by sequential hydrolysis,
mixed-anhydride formation, and NaBH4 reduction in 83% yield
in three steps. After azidation of 15 using DPPA, NaN3, and
DBU,14 Staudinger reduction and subsequent Boc-protection
gave 16 in 87% yield in three steps. Then, the oxidation of
indole 16 to 17 resulted in the best yield (83%) using OXONE
according to Kerr’s method.13
Figure 2. Chiral phosphoric acids.
A solution of diester 8 and 10 mol % chiral phosphoric acid
(13a−k) in solvents was heated under reflux to give lactam 7 in
good to excellent yields. The nonpolar and high-boiling solvent
afforded a better product yield and enantiomer ratio (er)
(entries 1−5). Using catalysts 13a and 13b (R = H) in toluene,
the reaction gave (−)-7a in 38% ee and 34% ee, respectively
(entries 5 and 6). The presence of 13c (R = Ph) shortened the
reaction time to 2 h and increased the ee value (entry 7). Upon
use of 3,5-disubstituted (13d−f) and 4-substituted phenyl
catalysts (13g,h), the electron-withdrawing substituents gave
Then, we studied N-acyliminium cyclization using ( )-17 to
tetracyclic compound 5 which has an aminal moiety next to the
quaternary carbon center (Table 2). In the presence of PPTS
under refluxing toluene for 24 h, sequential Boc group removal
B
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Finally, the total synthesis of (−)-leuconoxine (1) was
completed as shown in Scheme 3. Under the optimized
Scheme 2. Synthesis of 2-Hydroxy Indolinone 17
Scheme 3. Asymmetric Total Synthesis of (−)-Leuconoxine
(1)
Table 2. N-Acyliminium Cyclization
cyclization conditions (Table 2), (+)-17 was converted to
(+)-5b in 56% yield without loss of chirality. The one-step
formation of γ-butyrolactam was accomplished by the treat-
ment of indolinone 5b using Bestmann’s ylide16 to give
(+)-melodinine E17 (2, 83% yield, 74% ee). The hydrogenation
of 2 took place from the convex face of (+)-2 to afford
(−)-leuconoxine (1) (90% yield, 74% ee), which was
recrystallized into its optically pure form (>99% ee). Synthetic
(−)-1 displayed physical and spectroscopic data identical in all
respects to those reported for the natural product.2
In conclusion, we have accomplished the asymmetric total
synthesis of (−)-leuconoxine (1). In the presence of a chiral
phosphoric acid catalyst, the desymmetrization of a prochiral
diester produced a highly enantioenriched lactam in excellent
yield. Ring construction steps featuring the N-acyliminium
mediated intramolecular piperidine cyclization and the one-step
pyrrolidone formation using Bestmann’s ylide were achieved
successfully. Application of this methodology to the synthesis of
more complicated natural products is in progress in our
laboratory.
time
entry
reagents (equiv)
PPTS (1.0)
solvent
temp (°C)
(h)
yields (%)
1
2
toluene
MeOH
reflux
reflux
24
30
4 quant
4 62
PPTS (1.0),
HC(OMe)3 (10)
3
Tf2O (1.5),
TEA (2.0)
CH2Cl2
−78 to 0
1
17 63,
5a 11,
5b 9
4
5
6
7
Tf2O (1.5),
TEA (2.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0 to rt
0 to rt
0 to rt
0 to rt
1
1
1
2
5b 50
5b 62
5b 50
5b 67
Tf2O (1.5),
DIEA (2.0)
Tf2O (1.5),
DBU (2.0)
Tf2O (1.5),
2,6-lutidine (2.0)
ASSOCIATED CONTENT
■
and condensation with ketone provided mersicarpine (4) in
quantitative yield (entry 1). The addition of HC(OMe)3 did
S
* Supporting Information
15
not give the desired product 5 (entry 2). In order to accelerate
the elimination of the hydroxyl group, the application of acid
anhydride was tested. When Tf2O and TEA were added at −78
°C and the reaction mixture was stirred at 0 °C for 1 h, the
desired acyliminium formation and intramolecular cyclization
occurred to generate compounds 5a and 5b in 11% and 9%
yield, respectively, along with recovered 17 (63% yield) (entry
3). When these reagents were added at 0 °C and the mixture
was stirred at rt, the reaction afforded 5b as a sole product in
50% yield without diastereomer formation (entry 4). An
evaluation of other bases (entries 5−7) revealed that 2,6-
lutidine produced a good yield in this transformation (entry 7).
Experimental procedures and analysis data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: khiguchi@my-pharm.ac.jp.
*E-mail: kawasaki@my-pharm.ac.jp.
Notes
The authors declare no competing financial interest.
C
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Letter
ACKNOWLEDGMENTS
■
We thank N. Eguchi, T. Koseki, and S. Yamada of the Analytical
Center of our University for microanalysis, NMR, and mass
spectral measurements.
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