Diastereoselective construction of chiral building blocks for the synthesis of indole alkaloids using an intramolecular Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2008.12.105

Highly diastereoselective construction of the chiral building blocks, with an allylic quaternary carbon stereogenic center, for the synthesis of indole alkaloids has been accomplished by employing a 1,4-chirality transfer via the intramolecular Heck react

Full text of DOI:10.1016/j.tetlet.2008.12.105

Tetrahedron Letters 50 (2009) 1279–1281
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective construction of chiral building blocks for the synthesis
of indole alkaloids using an intramolecular Heck reaction
*
Yuri Murakami, Masahiro Yoshida, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly diastereoselective construction of the chiral building blocks, with an allylic quaternary carbon ste-
reogenic center, for the synthesis of indole alkaloids has been accomplished by employing a 1,4-chirality
transfer via the intramolecular Heck reaction.
Received 1 December 2008
Revised 19 December 2008
Accepted 22 December 2008
Available online 8 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Since there are many biologically significant natural and unnat-
ural compounds with quaternary carbon stereogenic center(s),
developing new methodologies for the installation of this struc-
tural motif is an important issue in organic synthesis.1 In our pre-
vious papers, we described the development of a strategy for
constructing the chiral building blocks 6 (n = 1, 2; R = H) with a
quaternary center on a cyclohexenol ring by 1,4-chirality transfer
via a diastereoselective ring-closing metathesis of 4,2 and demon-
strated that they can be successfully applied to the asymmetric
syntheses of the indole alkaloids (ꢀ)-eburnamonine (1)3 (from 6;
n = 1, R = H), (ꢀ)-aspidospermine (2)4, and (ꢀ)-limaspermine (3)5
(from 6; n = 2, R = H).
To investigate the diastereoselectivity of the key IMH reaction,
we first prepared the racemic substrates 5a–c. As the protecting
group of the allylic alcohol moiety, we chose tert-butyldimethylsi-
lyl (TBS) on the basis of literature precedent.8 Regioselective reduc-
tive coupling of the alkynes 7 (n = 1,2) and the aldehydes with
CrCl2 and a catalytic amount of NiCl2 and triphenylphosphine in
aqueous DMF10 produced the allylic alcohols 8a–c. Claisen rear-
rangement of the corresponding vinyl ethers gave the aldehydes
9a–c, which were reacted with lithium trimethylsilylacetylide.
The resulting alcohols 10a–c were protected as TBS ethers to give
11
11a–c. They were then treated with NIS and AgNO3 to provide
the acetylenic iodides which were reduced with diimide, generated
Asymmetric creation of the quaternary center based on the
intramolecular Heck (IMH) reaction6 has been examined by many
groups with most of the efforts focusing on the asymmetric IMH
reaction using a chiral ligand.7 However, there have been very
few reports of strategies based on the 1,4-chirality transfer via
the IMH reaction of acyclic substrates. In 1999, Negishi et al. com-
municated a methodology for the construction of a quaternary
stereogenic center in cycloalkenols by a cyclic carbopalladation–
carbonylative esterification, and prepared 3,4,4-trisubstituted
cyclohexenols.8 In the conversion, it was found that 1,4-chirality
transfer occurred in as high as 98% diastereoselectivity. During
the course of our research on the development of an efficient strat-
egy for the preparation of the chiral building blocks 6 (4,4-disubsti-
tuted cyclohexenols),9 we envisaged that the intramolecular Heck
(IMH) reaction (sequential cyclic carbopalladation-reductive elim-
ination) of 5, possessing a terminal vinyl iodide and trisubstituted
alkene moieties, would play a pivotal role in our objective. In this
Letter, we report a diastereoselective strategy for assembling the
chiral building blocks 6 using the IMH reaction of compounds 5
(Scheme 1).
TMSO
H
N
N
OTBDPS
n
O
4: n=1, 2
diastereoselective
(–)-eburnamonine (1)
RCM
HO
R=H
n=1
OTBDPS
R=H
n
diastereoselective
intramolecular Heck
reaction
present
work
n=2
6: n=1, 2;
R
R=H, OMe
N
H
R1O
I
R3
OTBDPS
n
N
H
COR2
R1O
5: n=1, 2
R2
(—)-aspidospermine (2):
R1=Me, R2=Me, R3=H
(—)-limaspermine (3):
R1=H, R2=Et, R3=OH
* Corresponding author. Tel.: +81 88 6337287; fax: +81 88 6339575.
E-mail address: shishido@ph.tokushima-u.ac.jp (Kozo Shishido).
Scheme 1. Strategies of the construction of chiral building blocks for the syntheses
of indole alkaloids.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.105

1280
Y. Murakami et al. / Tetrahedron Letters 50 (2009) 1279–1281
RCH2CHO, CrCl2
NiCl2, Ph3P, DMF
H2O, rt
1) ethyl vinyl ether
1) nBuLi,
THF, — 78 °C
HO
TMS
Hg(OCOCF3)2
R
reflux
OTBDPS
OHC
R
n
OTBDPS
n
n
OTBDPS
2) toluene, reflux
for 8a: 68%
for 8b: 62%
for 8c: 52%
2) TBSCl, imidazole
4-DMAP, CH2Cl2, rt
for 11a: 71% (2 steps)
for 11b: 73% (2 steps)
for 11c: 66% (2 steps)
8a: n=1, R=H
8b: n=2, R=H
8c: n=2, R=OMe
7 n=1,2
for 9a: 89% (2 steps)
for 9b: 84% (2 steps)
for 9c: 78% (2 steps)
9a-c
1) NIS, AgNO3
DMF, rt
TMS
R
TBSO
2) KO2C
N
R'O
I
2
AcOH, MeOH, rt
OTBDPS
n
OTBDPS
n
for 5a: 62% (2 steps)
for 5b: 54% (2 steps)
for 5c: 47% (2 steps)
5a: E/Z=2:1
5b: E/Z=2:1
5c: E/Z=1.5:1
10a-c: R'=H
11a-c: R'=TBS
R
Scheme 2. Preparation of the racemic substrates 5a–c for the IMH reaction.
Table 1
The IMH reactions of 5a–c
TBSO
TBSO
Pd(OAc)2
(10 mol%)
I
OTBDPS
OTBDPS
n
n
conditions
12a-c
R
5a-c
R
Entry
5
n
R
Conditions
Yield ,% of 12
de (%)
1
2
3
4
5
a
a
a
b
c
1
1
1
2
2
H
H
H
H
(o-Tol)3P, Et3N,CH3CN H2O, 80 °C, 6 h
(2-Furyl)3P, Et3N,CH3CN H2O, 80 °C, 4 h
(2-Furyl)3P, Et3N, CH3CN H2O, 100 °C, 1.5 h
(2-Furyl)3P, Et3N,CH3CN H2O, 80 °C, 4 h
(2-Furyl)3P, Et3N, CH3CN H2O, 80 °C, 3 h
83
96
90
94
94
94
95
95
92
95
OMe
mized conditions (entry 2) to give the cyclized products 12b,c12
in good yields and diastereoselectivities (entries 4 and 5).13
Next, we examined the effect of protecting groups (R in Table 2)
on the yield and diastereoselection. The results are shown in Table
2. It was found that the more sterically demanding protecting
groups provided higher yields and diastereoselectivities. In the
case of 5e,f, the results were comparable with those of 5a. When
the unprotected and the MOM-protected substrates 5g,h were
used (Table 2), the diastereoselectivity dropped significantly.
The structures of 12a,b thus obtained were confirmed by the
comparison of the 1H and 13C NMR data with those of the optically
active authentic compounds3–5 that were prepared previously by
us. As shown in Scheme 3, the cyclization process involves the dia-
stereoselective formation of the intermediate I1, which subse-
quently undergoes reductive elimination of the palladium
hydride species to give predominantly product 12 via the transi-
tion state T1. The diastereoselection attained in the cyclization step
from either the boat-like transition state T1 or T2 can be rational-
ized as a consequence of the allylic strain between the two transi-
tion states (T1 > T2).8 The decrease in de for 5g,h (entries 5 and 6 in
Table 2) may be due to the internal chelation of the hydroxy and
MOM groups with the palladium in the transition state T2, which
would collapse to form the undesired isomer 120. The structure
of 12c was deduced from the proposed mechanism (Scheme 3).
To obtain the optically active building blocks 12a–c, the alkynyl
alcohols 10a–c were oxidized with Dess–Martin periodinane to
give the ketones 14a–c, which were reduced with the chiral oxaz-
aborolidine 15 and BH3ꢁTHF14 to produce the optically active (S)-
11a–c with enantiomeric excesses of 92%, 90%, and 82%, respec-
tively. According to the procedures for racemate synthesis, they
were then converted to (S)-5a–c via three steps, which were sub-
jected to the IMH reactions to give the optically active 12a–c. On
Table 2
The IMH reactions of 5d–h
RO
Pd(OAc)2 (10 mol%) RO
(2-furyl)3P, Et3N
I
OTBDPS
OTBDPS
CH3CN, H2O
80 °C, 4~6h
5a, d-h
12a, d-h
Yield (%)
Entry
5
R
12
de (%)
1
2
3
4
5
d
e
f
g
h
Me
d
g
f
g
h
89
89a
88
52
85
83
86a
93
46
65
TMS
TES
H
MOM
a
For the desilylated product.
in situ from potassium azodicarboxylate and acetic acid, to give the
desired 5a–c with terminal Z-vinyl iodide and trisubstituted alkene
(mixture of E/Z isomers) moieties (Scheme 2).
With the requisite substrates 5a–c in hand, we then examined
the cyclization to find the optimum conditions for obtaining higher
yields and diastereoselectivities. The results are summarized in Ta-
ble 1. Initially, 5a was treated with Pd(OAc)2 (10 mol %), (o-tol)3P,
and Et3N in aqueous acetonitrile at 80 °C to give 12a in 83% yield
with 94% de (entry 1). When (2-furyl)3P was used as a ligand,
12a was obtained in higher yield and diastereoselectivity (entry
2). A higher reaction temperature led to a lower yield of the prod-
uct (entry 3). Other substrates 5b,c were treated with the opti-

Y. Murakami et al. / Tetrahedron Letters 50 (2009) 1279–1281
1281
Ln
Pd
Ln
Pd
R1O
R1O
I
I
R2
R3
H
R2
R3
H
R3
R1O
H
R1O
H
R1O
I
T1
Pd/Ln
I1
R2
12
R3
R2
R3
5
R3
R2
R3
R2
Pd
R1O
R1O
I
I
Pd
Ln
Ln
R2
12'
I2
T2
Scheme 3. Proposed mechanism for the IMH reaction.
Ph
H
Ph
sperma indole alkaloids based on a 1,4-chirality transfer via the
IMH reaction has been demonstrated. The IMH reaction proceeded
with high diastereoselectivity to provide the 4,4-disubstituted
cyclohexenols, possessing an allylic quaternary carbon stereogenic
center, in excellent yields. The methodology described here holds
considerable promise for the synthesis of natural products with
quaternary carbon centers.
TMS
R
O
Dess-Martin
N
O
B
15
periodinane
Me
10a-c
BH3•THF, THF
–78 °C
for 15a: 78% (2 steps) ; 92%ee
for 15b: 84% (2 steps) ; 90%ee
for 15c: 81% (2 steps) ; 82%ee
OTBDPS
n
14a-c
TMS
R
R'O
Acknowledgment
OTBDPS
n
16a-c
This work was supported in part by a Grant-in-Aid for program
for Promotion of Basic and Applied Researches for Innovations in
Bio-oriented Industry.
TBSO
3 steps shown
in Scheme 2
I
OTBDPS
n
for 5a: 64% (3 steps)
for 5b: 49% (3 steps)
for 5c: 42% (3 steps)
R
References and notes
(S)-5a-c
1. For reviews, see: (a) Fuji, K. Chem. Rev. 1993, 93, 2037; (b) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
2. Fukuda, Y.; Sasaki, H.; Shindo, M.; Shishido, K. Tetrahedron Lett. 2002, 43,
2047.
Pd(OAc)2 (10 mol%)
(1S, 4S)-(–)-12a : 95%
(1S, 4R)-(–)-12b : 91%
(1S, 4S)-12c : 91%
(2-furyl)3P, Et3N
(S)-5a-c
CH3CN, H2O, 80 °C
3. Murakami, Y.; Shindo, M.; Shishido, K. Synlett 2005, 664.
4. Fukuda, Y.; Shindo, M.; Shishido, K. Org. Lett. 2003, 5, 749.
5. Fukuda, Y.; Shindo, M.; Shishido, K. Heterocycles 2004, 62, 787.
6. For a reviews, see: (a) Overman, L. E. Pure Appl. Chem. 1994, 66, 1423; (b)
Negishi, E.; Coperet, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996, 96, 365; (c)
Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009; (d) Link, J. T. Org.
React. 2002, 60, 157; (e) Guiry, P. J.; Kiely, D. Curr. Org. Chem. 2004, 8, 781.
7. For reviews, see: (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945;
(b) Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533; For
representative references: (c) Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem.
1989, 54, 4738; (d) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6477; (e) Oestreich, M.; Sempere-Culler, F.; Machotta, A.
B. Angew. Chem., Int. Ed. 2005, 44, 149; (f) Dounay, A. B.; Overman, L. E.;
Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127, 10186.
PPTS, EtOH
(1S, 4S)-12a
(1S, 4R)-12b
(1S, 4S)-6a: n=1, R=H : 86%
(1S, 4R)-6b: n=2, R=H : 87%
reflux
HO
1) HCl (aq.)
dioxane, 56%
OTBDPS
3
(1S, 4S)-12c
2) NaBH4, EtOH
97%
OH 13
Scheme 4. Syntheses of the chiral building blocks.
8. Coperet, C.; Negishi, E. Org. Lett. 1999, 1, 165.
9. In Ref. 8, an example of the reaction producing the TBS-ether of 4-methyl-4-
carbomethoxycyclohexenol, which has been converted to the Colvin-Raphael
lactone, was demonstrated.
10. (a) Takai, K.; Sakamoto, S.; Isshiki, T. Org. Lett. 2003, 5, 653; (b) Takai, K.;
Sakamoto, S.; Isshiki, T.; Kokumai, T. Tetrahedron 2006, 62, 7534.
11. Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett 1994, 485.
12. The reaction of 5c was performed using a mixture of E/Z isomers (ca. 1.5:1).
Attempted reactions for the separated isomers under the same reaction
conditions resulted in similar results; for the E-isomer, 94%, 95% de; for the Z-
isomer, 93%, 97% de.
13. Typical experimental procedure: To a stirred solution (1.0 M) of 5 (1 equiv) in
CH3CN/H2O (10:1) were added Pd(OAc)2 (10 mol %), phosphine ligand
(20 mol %), and Et3N (2 equiv), and the resulting mixture was stirred at 80–
100 °C for 1.5–6 h. After removal of the solvent, the residue was
chromatographed on silica gel column (AcOEt/hexane = 1:20) to give the
cyclized product 12.
exposure of 12a,b to PPTS in ethanol, selective desilylation oc-
curred to give 6a,b in good yields. The optical rotations of the syn-
thetic 6a,b (92% and 90% ee, respectively) showed good agreement
with those of the authentic materials; for 6a, ½a D30
ꢂ
–25.6 (CHCl3, c
–32.7 (CHCl3, c
1.10){lit.3
½
a 3D0
ꢂ
ꢂ
–27.7 (CHCl3, c 1.12)}; for 6b, ½a D30
ꢂ
0.50){lit.4 ½a 3D0
–36.6 (CHCl3, c 0.90)}. The methyl enol ether moiety
of 12c was hydrolyzed with HCl (aq), and the resulting hydroxy
aldehyde was reduced with NaBH4 to give the diol 13 {½a D30
ꢂ
–61.4
(CHCl3, c 0.02)}. It could subsequently serve as a useful chiral
building block for the synthesis of limaspermine 3 and related
alkaloids (Scheme 4).
14. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925.
In summary, a strategy for the preparation of three types of chi-
ral building blocks for the syntheses of the eburna and the aspido-