Asymmetric approach to the pentacyclic skeleton of Aspidosperma alkaloids via enantioselective intramolecular 1,3-dipolar cycloaddition of carbonyl ylides catalyzed by chiral dirhodium(II) carboxylates

Article abstract of DOI:10.1016/j.tetlet.2009.03.142

This Letter describes asymmetric tandem carbonyl ylide formation-intramolecular 1,3-dipolar cycloaddition reaction of diazo imides containing a tethered indole catalyzed by chiral dirhodium(II) carboxylates as an approach to the pentacyclic skeleton of Aspidosperma alkaloids. The cycloaddition of carbonyl ylides derived from indolyl-substituted 2-diazo-5-imido-3-ketoesters under the influence of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh₂(S-TCPTTL)₄, provides cycloadducts in moderate yields and enantioselectivities of up to 66% ee as well as with perfect endo diastereoselectivity. This is the first example of asymmetric induction in an intramolecular cycloaddition of a carbonyl ylide across an indolyl π-bond.

Full text of DOI:10.1016/j.tetlet.2009.03.142

Tetrahedron Letters 50 (2009) 3675–3678
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Tetrahedron Letters
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Asymmetric approach to the pentacyclic skeleton of Aspidosperma alkaloids
via enantioselective intramolecular 1,3-dipolar cycloaddition of carbonyl
ylides catalyzed by chiral dirhodium(II) carboxylates
Hisanori Nambu, Mayuka Hikime, Janagiraman Krishnamurthi, Megumi Kamiya, Naoyuki Shimada,
*
Shunichi Hashimoto
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes asymmetric tandem carbonyl ylide formation–intramolecular 1,3-dipolar cycloaddition
reaction of diazo imides containing a tethered indole catalyzed by chiral dirhodium(II) carboxylates as an
approach to the pentacyclic skeleton of Aspidosperma alkaloids. The cycloaddition of carbonyl ylides derived
from indolyl-substituted 2-diazo-5-imido-3-ketoesters under the influence of dirhodium(II) tetrakis[N-tetra-
chlorophthaloyl-(S)-tert-leucinate], Rh2(S-TCPTTL)4, provides cycloadducts in moderate yields and enantiose-
lectivities of up to 66% ee as well as with perfect endo diastereoselectivity. This is the first example of
Received 19 February 2009
Revised 17 March 2009
Accepted 19 March 2009
Available online 25 March 2009
Keywords:
Carbonyl ylides
1,3-Dipolar cycloadditions
Chiral dirhodium(II) carboxylates
Vindorosine
asymmetric induction in an intramolecular cycloaddition of a carbonyl ylide across an indolyl p-bond.
Ó 2009 Elsevier Ltd. All rights reserved.
Over the past four decades, Aspidosperma alkaloids have been a
source of structurally intriguing target molecules that continue to
challenge the capabilities of contemporary organic synthesis. Efficient
and elegant strategies for the total synthesis of various members of
this alkaloid family have been reported.1,2 Padwa and co-workers
demonstrated that the tandem cyclic carbonyl ylide formation–1,3-
dipolar cycloaddition reaction3 of diazo imides catalyzed by
Rh2(OAc)4 isone of themostpowerful methods forthe rapid construc-
tion of the pentacyclic ABCDE framework of (ꢀ)-vindoline (1)4,5 and
(ꢀ)-vindorosine (2)6,7 (Eq. 1).8 The same group has accomplished
thetotalsynthesisof( )-aspidophytine9 employinganintramolecular
The synthetic utility of the carbonyl ylide cycloaddition strategy
has also been demonstrated in its application to the synthesis of a
variety of natural products.11 Over the past decade, considerable
effort has been directed to the development of an enantioselective
version of carbonyl ylide formation–1,3-dipolar cycloaddition cat-
alyzed by chiral dirhodium(II) complexes.12–15 In this process, the
chiral dirhodium(II) catalyst must be capable of associating with
carbonyl ylide intermediates in the cycloaddition step, because
catalyst-free carbonyl ylides are achiral. Hodgson and co-workers
were the first to demonstrate high levels of asymmetric induction
(up to 90% ee) in intramolecular cycloadditions of carbonyl ylides
1,3-dipolarcycloadditionofcarbonylylideacrosstheindole
p
-bond.10
derived from unsaturated a-diazo-b-ketoesters using binaphthol-
phosphate catalyst Rh2(R-DDBNP)4 (4) (Fig. 1).13a–c,f,h,i Recently,
we reported catalytic enantioselective intermolecular cycloaddi-
tions of 2-diazo-3,6-diketoesters-derived carbonyl ylides with
O
O
N
N
Rh2(OAc)4
O
O
N2
benzene, 50 ºC
N
O
N
Me
C12H25
C12H25
H
O
X
Me CO2Me
endo
X
X
O
N
CO2Me
X
H
O
N
H
5
N
C
O
E
14
D
O
122OH
(1)
O
O
O
O
A
B
N
Me
Rh Rh
P
R
N
OAc
O
3
H
H
CO2Me
Me CO2Me
R = OMe: (–)-vindoline (1)
R = H: (–)-vindorosine (2)
HO
Rh
Rh
X = Cl: Rh2(S-TCPTTL)4 (3a)
X = F: Rh2(S-TFPTTL)4 (3b)
X = H: Rh2(S-PTTL)4 (3c)
Rh2(R-DDBNP)4 (4)
* Corresponding author. Tel.: +81 11 706 3236; fax: +81 11 706 4981.
E-mail address: hsmt@pharm.hokudai.ac.jp (S. Hashimoto).
Figure 1. Chiral dirhodium(II) catalysts.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.142

3676
H. Nambu et al. / Tetrahedron Letters 50 (2009) 3675–3678
H
N
arylacetylene, alkoxyacetylene, and styrene dipolarophiles using
Rh2(S-TCPTTL)4 (3a),16a,d,e the chlorinated analogue of Rh2(S-PTTL)4
(3c),17 wherein high levels of asymmetric induction (up to 99% ee)
as well as perfect exo diastereoselectivity for styrenes were
achieved.14d In this context, our interest was centered on an asym-
metric approach to the pentacyclic skeleton of 1 and 2 by means of
chiral dirhodium(II) complex-catalyzed carbonyl ylide formation–
a—d
e,f
HO2C
h
MeO2C
RO2C
CO2Me
10 O
11
N2
H
N
H
N
RO2C
O
O
O
8a—d
O
O
12a: R = Me
12b: R = t-Bu
12c: R = Bn
intramolecular cycloaddition across an indolyl p-bond. To the best
g
of our knowledge, no examples of an enantioselective version of
this sequence have been identified to date.18 Herein, we report
the first example of catalytic enantioselective intramolecular 1,3-
dipolar cycloaddition of carbonyl ylides derived from indolyl-
substituted 2-diazo-5-imido-3-ketoesters, wherein Rh2(S-TCPTTL)4
(3a) provides cycloadducts in up to 66% ee and with perfect endo
diastereoselectivity.
Our carbonyl ylide cycloaddition approach to 1 and 2 based on
Padwa’s effective route to the pentacyclic framework of 1 and 28 is
illustrated in Scheme 1. The construction of the D-ring would be
achieved by ring-closing metathesis (RCM) of diene 5. It was antic-
ipated that an ethyl group at C5 might be formed by ring opening
of the cyclopropyl ketone. On the basis of Padwa’s work,8 we envi-
sioned that Rh(II)-catalyzed reaction of indolyl-substituted 2-dia-
zo-5-imido-3-ketoester 7 would provide endo cycloadduct 6. The
carbonyl ylide precursor 7 could be formed through N-acylation
of diazo amide 8a with N-methylindole-3-acetyl chloride (9).10
12d: R = PhCH2CH2
N
Cl
i
8a—d
+
O
N2
O
N
N
O
Me
7a—d
Me
CO2R
9 (1.2 equiv)
Scheme 2. Reagents and conditions: (a) KOH, MeOH–H2O (3:1), 3 h; (b) SOCl2,
CH2Cl2, reflux, 1 h; (c) allylamine, Et3N, CH2Cl2, 0 °C, 0.5 h; (d) KOH, MeOH–H2O
(3:1), 2 h, 63% (4 steps); (e) CDI (1.1 equiv), THF, 1 h; (f) i-PrMgBr, RO2CCH2CO2H,
THF, 0.5–4 h, 85–90% (2 steps); (g) PhCH2CH2OH (3 equiv), toluene, 110 °C, 2 h, 76%;
(h) MsN3 (for 12a and 12b) or p-ABSA (for 12c and 12d), Et3N, CH3CN, 30 min, 78–
85%; (i) 4 Å MS (powder), CH2Cl2, reflux, 15–24 h, 54–70%.
coupling of diazo amides 8 with acid chloride 9 using a variety of
bases resulted in the recovery of starting materials 8, we prepared
diazo imides 7 according to the procedure of Weinstock.10,23 Thus,
N-acylation of 8a–d with 9 in the presence of 4 Å molecular sieves
(MS) as an acid scavenger in CH2Cl2 at reflux provided the desired
diazo imides 7a–d in 54–70% yields.
a-Diazo-b-ketoester 8a could be prepared from commercially
available dimethyl 1,1-cyclopropanedicarboxylate (11).
The carbonyl ylide cycloaddition precursors 7a–d were pre-
pared from 11 as shown in Scheme 2. Selective saponification of
11 followed by condensation with allylamine via the acid chloride
and saponification of the methyl ester provided carboxylic acid 10
in 63% yield. Treatment of 10 with 1,10-carbonyldiimidazole (CDI)
followed by reaction with the dianion derived from a variety of half
esters of malonic acid afforded the corresponding b-ketoesters
12a–c in 85–90% yields.19 2-Phenylethyl ester derivative 12d was
prepared by transesterification of tert-butyl b-ketoester 12b with
2-phenylethanol.20 Diazo transfer to 12a–d with methanesulfonyl
azide21 (for 12a and 12b) or p-acetamidebenzenesulfonyl azide22
(p-ABSA) (for 12c and 12d) using Et3N as a base in CH3CN gave
On the basis of our previous work,14d we initially explored the
reaction of methyl ester 7a using 1 mol % of Rh2(S-TCPTTL)4
(3a)16a,d,e (Table 1, entry 1). The reaction in
a,a,a-trifluorotoluene
at 60 °C proceeded to completion within 1 h, giving endo cycload-
duct 6a in 42% yield, along with 42% of bicyclic epoxide 13a.24 The
endo stereochemistry of 6a was established by the 1H NOE be-
tween the C5 cyclopropyl group proton and C14–H (Fig. 2). The
enantiomeric excess of 6a was determined to be 37% by HPLC using
a Daicel Chiralcel OD-H column.25 The enantiomeric purity of
epoxide 13a, ½a 2D2
ꢀ 8:0 (c 0.80, CHCl3), was not determined. Trans-
ꢁ
formation of epoxide 13a to cycloadduct 6a under the same condi-
tions did not occur, suggesting that the cycloaddition did not
proceed via formation of epoxide 13 as an intermediate. We next
examined the effect of the ester moiety. The use of tert-butyl ester
7b increased the product yield at the expense of enantioselectivity
(66% yield, 20% ee, entry 2). Gratifyingly, the use of benzyl ester 7c
greatly improved the enantioselectivity to provide cycloadduct 6c
in 50% yield with 63% ee (entry 3), whereas a low level of asym-
metric induction was obtained in the reaction of 2-phenylethyl es-
ter 7d (36% ee, entry 4). Using the benzyl ester 7c, we evaluated the
performance of Rh2(S-TFPTTL)4 (3b)16b,c and Rh2(S-PTTL)4 (3c).17
Catalysis with Rh2(S-TFPTTL)4 (3b) exhibited lower product yield
and enantioselectivity than those found with Rh2(S-TCPTTL)4 (3a)
(42% yield, 53% ee, entry 5). The use of Rh2(S-PTTL)4 (3c) enhanced
the product yield, but there was a marked decrease in enantiose-
lectivity (55% yield, 22% ee, entry 6). A survey of solvents with 3a
a-diazo-b-ketoesters 8a–d in 78–85% yields. Since attempted
N
C
N
H
E
D
5
RCM
A
OH
B
N
Me
R
OAc
CO2Me
R
N
OAc
H
H
Me CO2Me
HO
R = OMe: (–)-vindoline (1)
5
R = H: (–)-vindorosine (2)
O
N
O
O
N
cat. Rh(II)
O
R
N
Me
N2
R
N
O
revealed that
a,a,a-trifluorotoluene was the optimal solvent for
O
H
Me CO2Me
this cycloaddition in terms of both product yield and enantioselec-
tivity (entry 3 vs entries 7 and 8). Lowering the reaction tempera-
ture to 40 °C led to a modest improvement in enantioselectivity,
though a slight drop in product yield was observed (43% yield,
66% ee, entry 9). The reaction at 80 °C resulted in a decrease in
enantioselectivity with the same product yield (50% yield, 57%
ee, entry 10).
While there was clearly room for improvement, we next exam-
ined the cyclopropane ring opening of cycloadduct 6c (Scheme 3).
After considerable experimentation, we found that treatment of
6c with trimethylsilyl iodide (TMSI)26 led to the formation of
CO2Me
6
7
N2
H
H
MeO2C
N
HO
N
O
O
O
O
O
10
8a
+
Cl
O
R
N
Me
MeO2C
CO2Me
9
11
Scheme 1. Synthetic strategy.

H. Nambu et al. / Tetrahedron Letters 50 (2009) 3675–3678
3677
Table 1
Enantioselective intramolecular 1,3-dipolar cycloaddition of 2-diazo-5-imido-3-ketoesters 7a–d catalyzed by chiral dirhodium(II) carboxylatesa
O
O
O
O
N
Rh2(S-TCPTTL)4
(1 mol %)
N
N
N
+
O
O
+
O
O
N
Me
N2
N
O
N
Me
N
Me
O
O
CO2R
O
H
RO2C
Me CO2R
CO2R
Rh
6
13
7
endo
Entry
Diazo imide 7
Rh(II) catalyst
Solvent
Temperature (°C)
Time (h)
Cycloadduct 6
Epoxide 13
R
Yieldb (%)
eec (%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7c
7c
7c
7c
7c
7c
Me
t-Bu
Bn
Rh2(S-TCPTTL)4 (3a)
Rh2(S-TCPTTL)4 (3a)
Rh2(S-TCPTTL)4 (3a)
Rh2(S-TCPTTL)4 (3a)
Rh2(S-TFPTTL)4 (3b)
Rh2(S-PTTL)4 (3c)
Rh2(S-TCPTTL)4 (3a)
Rh2(S-TCPTTL)4 (3a)
Rh2(S-TCPTTL)4 (3a)
Rh2(S-TCPTTL)4 (3a)
CF3C6H5
CF3C6H5
CF3C6H5
CF3C6H5
CF3C6H5
CF3C6H5
Toluene
(CH2Cl)2
CF3C6H5
CF3C6H5
60
60
60
60
60
60
60
60
40
80
1
1
1
1
1
1
1
2
3
1
6a
6b
6c
6d
6c
6c
6c
6c
6c
6c
42
66
50
48
42
55
44
42
43
50
37
20
63
36
53
22
60
44
66
57
13a
13b
13c
13d
13c
13c
13c
13c
13c
13c
42
trace
27
37
4
16
21
17
34
23
PhCH2CH2
Bn
Bn
Bn
Bn
Bn
Bn
10
a
All reactions were carried out as follows: a solution of 7 (0.1 mmol) in the indicated solvent (1 mL) was added over 5 min to a solution of Rh(II) catalyst (1 mol %) in the
indicated solvent (1 mL) at the indicated temperature.
b
Isolated yield.
Determined by HPLC.
c
rected at improving the enantioselectivity and product yield as
well as the total synthesis of (ꢀ)-vindorosine are currently in
H
H
H
H
N
progress.
O
14
H
1.2%
O
O
Acknowledgments
N
O
3.6%
H
O
5
H
This research was supported, in part, by a Grant-in-Aid for Sci-
entific Research on Priority Areas 18032002 from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT). J.K.
thanks the Japan Society for the Promotion of Science (JSPS) for
postdoctoral fellowships. We thank S. Oka, M. Kiuchi, and T. Hirose
of the Center for Instrumental Analysis at Hokkaido University for
mass measurements and elemental analysis.
H
H
6a
Figure 2. Key NOE interactions for cycloadduct 6a.
O
N
O
N
N
Supplementary data
R
a
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.142.
O
O
N
H
H
Me
Me CO2Bn
Me3SiO CO2Bn
14: R = I
6c (66% ee)
b
References and notes
15: R = H
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cycloaddition of carbonyl ylides derived from the diazo decompo-
sition of indolyl-substituted 2-diazo-5-imido-3-ketoesters under
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3678
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