Total synthesis of (-)-kopsinine by an asymmetric one-pot [N+2+3] cyclization

Article abstract of DOI:10.1002/asia.201200575

All together now: A common intermediate of Kopsia alkaloids was synthesized from cis-2,3-disubstituted piperidine, which was obtained with 98 % ee in 85 % yield using chiral diether-controlled asymmetric conjugate addition of lithium amide to indolepropenoate, followed by C,N dual alkylation with 1-chloro-3-iodopropane. The synthesis of (-)-kopsinine was accomplished via the intermediate in 9.0 % overall yield in 13 steps. Copyright

Full text of DOI:10.1002/asia.201200575

DOI: 10.1002/asia.201200575
Total Synthesis of (ꢀ)-Kopsinine by an Asymmetric One-Pot [N+2+3]
Cyclization
Shingo Harada,[b] Takeo Sakai,[b] Kiyosei Takasu,[b] Ken-ichi Yamada,[b]
Yasutomo Yamamoto,[a] and Kiyoshi Tomioka*[a]
One-pot processes, the sequential conjugation of multiple
bond-forming reactions, are powerful tools in organic syn-
thesis.[1] Conjugate addition[2] of lithium amide 2 to enoate 3
An asymmetric conjugate
addition of lithium N-benzyl-
trimethylsilylamide (2) was
ꢀ
forms an N C bond and generates lithium enolate 5, which
performed with tert-butyl N-
Boc-indole-3-propenoate (3)
using chiral diether 4 in tolu-
is further applicable as a carbonucleophile reacting in an
SN2 manner with alkyl halide. When the halide has two reac-
tion sites like dihalide 6, the initially introduced nitrogen
atom in 7 should undergo an intramolecular SN2 reaction to
form piperidine 8 (Scheme 1). This one-pot [N+2+3] cycli-
ene at ꢀ788C for 0.25 h to
afford, after quenching with saturated aqueous ammonium
chloride, 3-aminoester 9 with 97% ee in 89% yield (Table 1,
Table 1. Asymmetric conjugate aminolithiation followed by protonation.
Entry
T
t
Quench
Yield 9 ee 9 Yield 3 Yield 12
[8C]
[h]
[%]
[%] [%]
[%]
1
2
3
4
5
ꢀ78
ꢀ78
ꢀ78
ꢀ78
0.25 aq NH4Cl
89
89
93
97
96
97
97
95
2
0
0
39
5
1
0
0
0
12
3
1
3
aq NH4Cl
TMSCl
HCl/MeOH 54
ꢀ78; 1.5; HCl/MeOH 75
Scheme 1. One-pot [N+2+3] cyclization strategy. Bn=benzyl, TMS=tri-
methylsilyl, Boc=tert-butoxycarbonyl, Ind=indolyl, TBAF=tetrabutyl-
ammonium fluoride. X,Y=halide.
ꢀ40
ꢀ65
2
6
15
HCl/MeOH 91
98
2
3
zation, however, has not been realized, despite several re-
ports on sequential C-alkylation following conjugate addi-
tion of lithium amide.[3,4] We describe herein the total syn-
thesis of (ꢀ)-kopsinine (1)[5] using the asymmetric one-pot
[N+2+3] cyclization based on our asymmetric conjugate
aminolithiation[6] of a lithium amide with an enoate.
entry 1). Extension of the reaction time to 3 h did not affect
the results, giving 9 with comparable enantiomeric excess
and yield (Table 1, entry 2). The same reaction in the pres-
ence of internal chlorotrimethylsilane[6a] (TMSCl) gave 9
with 97% ee in 93% yield after 1 h (Table 1, entry 3). These
data indicated the completion of the conjugate aminolithia-
tion at ꢀ788C within 0.25 h.
Then, alkylation of enolate 5 as the second step was ex-
amined. After the aminolithiation at ꢀ788C for 1.5 h and
then at ꢀ408C for 2 h, alkylation was performed at ꢀ408C
for 4 h by the addition of 3-tert-butyldimethylsilyloxypropyl
iodide (6a; X=I, Y=OTBS) in dimethylformamide[7]
(DMF; 233 equiv) to give, after treatment with TBAF to
remove the TBS group, 10 with 95% ee as a sole diastereo-
mer in 60% yield and enoate 11 in 18% yield (Table 2,
entry 1). N,N’-Dimethylpropyleneurea (DMPU; 133 equiv)
was a better co-solvent, giving 10 with 95% ee in 73% yield
and 11 in 13% yield (Table 2, entry 2). Surprisingly, 11 was
[a] Dr. Y. Yamamoto, Prof. Dr. K. Tomioka
Faculty of Pharmaceutical Sciences
Doshisha Womenꢀs College of Liberal Arts
Kodo, Kyotanabe 610-0395 (Japan)
Fax : (+81)774-65-8658
E-mail: tomioka@pharm.kyoto-u.ac.jp
[b] S. Harada, Dr. T. Sakai, Prof. Dr. K. Takasu, Prof. Dr. K. Yamada
Graduate School of Pharmaceutical Sciences
Kyoto University
Yoshida, Sakyo, Kyoyo 606-8501 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200575.
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COMMUNICATION
Table 2. Asymmetric conjugate aminolithiation followed by alkylation.[a]
for 0.5 h to remove the N-TMS group, and finally heating
with saturated aqueous sodium bicarbonate at 1008C for 1 h
to accomplish cyclization by N-alkylation,[10] giving 8 with
98% ee in 85% yield (Scheme 3). Treatment with TBAF at
758C for 3 h after the alkylation also gave 8 in same yield.
Entry
Conditions
Co-solvent
t
Yield 10 ee
Yield 11
[h] [%] [%] [%]
1
2
3
ꢀ788C, 1.5 h; DMF
ꢀ408C, 2 h
4
2
2
60
73
89
95
95
98
18
13
2
Scheme 3. One-pot synthesis of piperidine 8 by [N+2+3] cyclization.
ꢀ788C, 1.5 h; DMPU
ꢀ408C, 2 h
ꢀ658C, 15 h
DMPU
[a] TBS=tert-butyldimethylsilyl, DMF=dimethylformamide.
obtained in a significant yield, despite the results in Table 1,
entries 1–3 indicating that 3 was completely consumed after
the aminolithiation at ꢀ788C for 0.25 h.
The quenching method significantly affected the product
yield in the conjugate amination. The addition of methanolic
hydrogen chloride after the aminolithiation for 1.5 h at
ꢀ788C and 2 h further at ꢀ408C gave 9 with 95% ee in
75% yield, recovered enoate 3 in 5% yield and indole-3-
propenote 12 in 12% yield (Table 1, entry 5), consistent
with the result of the above-mentioned alkylation in the
presence of DMPU (Table 2, entry 2; 73% 10 and 13% 11).
Surprisingly, the reaction at ꢀ788C for 3 h afforded 9 with
97% ee in only 54% yield, and 3 was recovered in 39%
yield (Table 1, entry 4). The chemical yield was improved by
performing the reaction at ꢀ658C for 15 h, giving 9 with
98% ee in 91% yield (Table 1, entry 6).
Having truly established conditions for the aminolithia-
tion, we carried out alkylation of enolate 5 after the amino-
lithiation at ꢀ658C for 15 h by the addition of 6a in DMPU
(133 equiv) and 2 h further reaction at ꢀ408C to afford 10
with 98% ee in 89% yield (Table 2, entry 3). The reaction
with mesyl chloride converted 10 into piperidine 8[8] in 98%
yield (Scheme 2).
Scheme 4. Construction of pentacyclic intermediate (ꢀ)-18. HMDS=hex-
amethyldisilazide, HMPA=hexamethylphosphoramide.
The benzyl group of 8 was replaced with a hydroxyethyl
group through hydrogenolysis[11] and N-hydroxyethylation[12]
to give 13 in 96% yield (Scheme 4). By heating 13 in metha-
nol at reflux with sulfuric acid, removal of the Boc group
and methyl esterification simultaneously proceeded to pro-
vide 14 in 89% yield. Claisen condensation[13] of 14 was ac-
complished by treating the dianion 15, generated by the de-
protonation of 14 using lithium hexamethyldisilazide,[14] with
four equivalents of the lithium enolate of methyl acetate 16
in THF at room temperature for 20 h, giving ketoester 17 in
72% yield. Mesylation of 17 and subsequent treatment with
potassium tert-butoxide gave (ꢀ)-18,[15] a common pentacy-
clic intermediate for Kopsia alkaloids,[5h] in 61% yield.
Scheme 2. Construction of piperidine 8.
A one-pot [N+2+3] piperidine formation was realized by
sequential asymmetric conjugate aminolithiation, stereose-
lective C-alkylation with 1-chloro-3-iodopropane (6b; X=I,
Y=Cl)[9] in the presence of DMPU at ꢀ408C for 2 h, heat-
ing with saturated aqueous ammonium chloride at 1008C
Because only racemic 18 has been reported,[5h] (ꢀ)-kopsi-
nine (1) was synthesized to confirm the absolute configura-
tion of synthesized optically pure 18 (Scheme 5). Thus, 18
was converted into enoate 19 in high yield according to
Wenkert and Pestchankerꢀs three-step procedure reported
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Total Synthesis of (ꢀ)-Kopsinine
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Scheme 5. Transformation to (ꢀ)-kopsinine (1). DME=dimethoxy-
ethane.
for racemic synthesis;[5j] the ketone moiety was reduced with
sodium borohydride, followed by mesylation and elimina-
tion using potassium hydride. Oxidation with lead tetraace-
tate at 08C for 45 min and Diels–Alder cyclization of the re-
sulting diene 20 with vinyl sulfone gave 21 in 61% yield.
The sulfone moiety was reductively removed by Raney
nickel to give (ꢀ)-kopsinine (1) in 62% yield. The specific
rotation of the synthetic 1, ½aꢁ2D1 =ꢀ60.2 (c=0.51, CHCl3),
was in good agreement with those reported for natural
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1
([a]D =ꢀ69.0ꢂ3 (c=0.856, CHCl3))[5c] and synthetic
1 (½aꢁD23 =ꢀ65.8 (c=1.13, CHCl3)).[5g] The asymmetric total
synthesis was accomplished in 9.0% overall yield in 13 steps
from 3.
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In summary, the yield of asymmetric conjugate aminoli-
thiation was significantly affected by the quenching method,
and the use of methanolic hydrogen chloride was important
to probe completion of the reaction accurately. We accom-
plished the asymmetric total synthesis of (ꢀ)-kopsinine,
which validates the utility of our one-pot [N+2+3] cycliza-
tion strategy to construct chiral piperidine derivatives.
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Acknowledgements
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We are grateful to JSPS and JST for financial support.
Keywords: asymmetric synthesis · chiral ligands · domino
reactions · lithium amide · total synthesis
Received: June 27, 2012
Published online: && &&, 0000
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COMMUNICATION
Asymmetric Synthesis
Shingo Harada, Takeo Sakai,
Kiyosei Takasu, Ken-ichi Yamada,
Yasutomo Yamamoto,
Kiyoshi Tomioka*
&&&& — &&&&
Total Synthesis of (ꢀ)-Kopsinine by an
Asymmetric One-Pot [N+2+3] Cycli-
zation
All together now: A common inter-
mediate of Kopsia alkaloids was syn-
thesized from cis-2,3-disubstituted
piperidine, which was obtained with
98% ee in 85% yield using chiral
diether-controlled asymmetric conju-
gate addition of lithium amide to indo-
lepropenoate, followed by C,N dual
alkylation with 1-chloro-3-iodopro-
pane. The synthesis of (ꢀ)-kopsinine
was accomplished via the intermediate
in 9.0% overall yield in 13 steps.
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www.chemasianj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!