Two-component method to enantiopure quinolizidinones and Indolizidinones. Total synthesis of (-)-lasubine II.

Article abstract of DOI:10.1021/ol016802w

The reaction of iodides 1 and enantiopure beta-amino esters 2 mediated by potassium carbonate in acetonitrile at 65 degrees C provides quinolizidinones or indolizidinones 3, together with piperidines or pyrrolidines 4. Hydrolysis of 4 to the corresponding

Full text of DOI:10.1021/ol016802w

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3927-3929
Two-Component Method to Enantiopure
Quinolizidinones and Indolizidinones.
Total Synthesis of (−)-Lasubine II
Dawei Ma* and Wei Zhu
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
madw@pub.sioc.ac.cn
Received September 24, 2001
ABSTRACT
The reaction of iodides 1 and enantiopure â-amino esters 2 mediated by potassium carbonate in acetonitrile at 65 °C provides quinolizidinones
or indolizidinones 3, together with piperidines or pyrrolidines 4. Hydrolysis of 4 to the corresponding carboxylic acids followed by treatment
of acetic anhydride/triethylamine gives 3 in high yields. Using 3a as a key intermediate, (−)-lasubine II is synthesized in four steps.
Quinolizidine and indolizidine skeletons exist widely in many
biologically important natural products or artificial molecules.
The stereoselective formation of these skeletons has therefore
become an important objective for synthetic chemists in the
past decades.1,2 One of the powerful methods for producing
these skeletons is through the reduction of quinolizidinones
or indolizidinones. In addition, some alkaloids bearing the
quinolizidinone moiety such as myrtine3 have been found
in Nature. As a continuing effort on the synthesis from
enantiopure â-amino esters,4 we were interested in building
enantiopure quinolizidinones and indolizidinones using the
method shown in Scheme 1. The amino group of enantiopure
â-amino ester 25 first attacks the terminal carbon of methyl
7-halo-2-heptynoate 1a6 or methyl 7-halo-2-hexynoate 1b6
to form a secondary amine, which attacks the electron-
deficient triple bond to provide a heterocyclic intermediate.
The vinylogous anion generated in a Michael addition step
may attack the carbonyl group of 2 to give the bicyclic
product 3.
We noticed that the reaction sequence was crucial for this
strategy. If the amino group attacked the triple bond first,
Scheme 1
(1) For reviews, see: (a) Michael, J. P. Nat. Prod. Rep. 1993, 51. (b)
Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000, 2862. (c)
Michael, J. P. Nat. Prod. Rep. 1997, 605.
(2) For recent reports, see: (a) Comins, D. L.; Brooks, C. A.; Ingalls,
C. L. J. Org. Chem. 2001, 66, 2181. (b) Peroche, S.; Remuson, R.; Gelas-
Mialhe, Y.; Gramain, J.-C. Tetrahedron Lett. 2001, 42, 4617. (c) Potts, D.;
Stevenson, P. J.; Thompson, N. Tetrahedron Lett. 2000, 41, 275. (d) Michel,
P.; Rassat, A.; Daly, J. W.; Spande, T. F. J. Org. Chem. 2000, 65, 8908.
(e) Enders, D.; Thiebes, C. Synlett 2000, 1745. (f) Tang, X.-Q.; Montgomery,
J. J. Am. Chem. Soc. 1999, 121, 6098.
(3) Slosse, P.; Hootele, C. Tetrahedron Lett. 1978, 397.
10.1021/ol016802w CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/27/2001

the enamine intermediate generated would not be sufficiently
reactive to displace the primary halide. Accordingly, the
reactions of several halides 1a were tested with the â-amino
ester 2a under various conditions. As indicated in Table 1,
mixture was produced, or no reaction occurred in these cases
(entries 7 and 9). A higher reaction temperature was favored
for producing 3a but gave slightly lower total yields (compare
entries 4, 5 and 6, 10 and 11).
To make the present method more useful for the prepara-
tion of enantiopure quinolizidinones, we sought a method
to convert 4a to 3a. Initially, Michael’s procedure was
tested.7 Thus, 4a was hydrolyzed selectively with 1 equiv
of NaOH and the resultant sodium salt was treated with
methyl chloroformate. It was found that 3a was produced
but the yield was only about 40%. After some investigations,
we found that a stepwise method provided 3a in much better
yield (Scheme 2). Accordingly, hydrolysis of 4a followed
Table 1. Reaction of 1a with â-Amino Ester 2aa
Scheme 2
yield (%)b
entry
X
solvent
temp (°C)
time (h)
3a
4a
1
2
3
4
5
6
7
8
9
OMs
OTf
DMF
CH2Cl2
DMF
DMF
DMF
25
-15 to 0
40-50
40-50
25
70
25
25
25
24
12
12
12
24
2
10
12
12
36
24
c
5
16
30
25
33
d
21
e
44
48
65
30
32
39
26
I
I
I
I
I
I
I
I
I
DMF
EtOH
DMSO
C6H6
MeCN
MeCN
26
10
11
65
80
45
31
a Reaction condition: iodide (0.22 mmol), â-amino ester (0.22 mmol),
4 Å MS (50 mg) in 4 mL of solvent, Cs2CO3 (0.22 mmol) for entries 1 and
3, 2,6-lutidine (0.22 mmol) for entry 2, or K2CO3 (0.22 mmol) for entries
4-11. b Isolated yield. c 79% Michael product was isolated. d Complex
mixture was determined by TLC. e No reaction occurred.
by workup gave acid 5, which was converted into 3a in 71%
yield by treatment with methyl chloroformate/triethylamine,
or even higher yield by treatment with acetic anhydride/
triethylamine.8 This success implied that the present method
provided the quinolizidinone 3a in 82% total yield from 1ac
and 2a.
reaction of mesylate 1aa with 2a in DMF under the action
of Cs2CO3 provided the Michael addition product exclusively
(entry 1). However, when the more reactive triflate 1ab was
used as a substrate, the reaction in methylene chloride
mediated by 2,6-lutidine gave the desired quinolizidinone
3a in 5% yield, together with piperidine 4a in 65% yield
(entry 2). This result prompted us to try another more reactive
substrate, iodide 1ac. It was found that reaction of 1ac with
2a in DMF under the action of Cs2CO3 produced 3a in 16%
yield and 4a in 30% yield (entry 3). Switching the base from
Cs2CO3 to K2CO3 gave a better result (compare entries 3
and 4). Among the solvents tested, acetonitrile was best,
providing 3a and 4a in excellent yields (entry 10). Ethanol
and benzene were not suitable solvents because a complex
After optimizing the reaction, we tested the reaction scope
by varying the â-amino esters and the iodide. As summarized
in Table 2, alkyl-substituted â-amino esters also worked well
to provide the corresponding quinolizidinones and piperidines
in good yields. The ratios for 4 and 3 were from 1.25 to
2.27, and all piperidines 4 were converted into the corre-
sponding quinolizidinones in good yields under the condi-
tions noted in Scheme 2 (entries 1-5). Moreover, when ethyl
6-iodohexynoate was employed as the electrophilic reagent,
indolizidinones and pyrrolidizines were obtained. The ratios
for these two types of compounds were from 1/2.6 to 1/3
(entries 6-8). Hydrolysis of 4g, 4h, or 4i followed by
treatment with acetic anhydride/triethylamine afforded the
(4) (a) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. (b) Ma, D.; Xia, C.;
Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189. (c) Wang, Y.; Ma, D.
Tetrahedron: Asymmetry 2001, 12, 725. (d) Ma, D.; Sun, H. J. Org. Chem.
2000, 65, 6009. (e) Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503. (f) Ma, D.;
Sun, H. Tetrahedron Lett. 2000, 41, 1947. (g) Ma, D.; Sun, H. Tetrahedron
Lett. 1999, 40, 3609. (h) Ma, D.; Zhang, J. J. Chem. Soc., Perkin Trans. 1
1999, 1703. (i) Ma, D.; Zhang, J. Tetrahedron Lett. 1998, 39, 9067. (j)
Ma, D.; Jiang, J. Tetrahedron: Asymmetry 1998, 9, 1137. (k) Ma, D.; Jiang,
J. Tetrahedron: Asymmetry 1998, 9, 575.
(7) (a) Howard, A. S.; Gerrans, G. C.; Michael, J. P. J. Org. Chem. 1980,
45, 1713. (b) Michael, J. P.; Koning, C. B.; Gravestock, D.; Hosken, G.
D.; Howard, A. S.; Jungmann, C. M.; Krause, R. W. M.; Parsons, A. S.;
Pelly, S. C.; Stanbury, T. V. Pure Appl. Chem. 1999, 71, 979.
(8) Typical procedure: A solution of 4a (0.25 mmol), NaOH (1 mmol)
in 2 mL of ethanol and 1 mL of water was stirred at room temperature for
4 h before it was acidified to pH ) 4. Methylene chloride extractive workup
followed by solvent evaporation afforded the crude acid, which was
dissolved in 3 mL of THF. To this solution were added Et3N (1 mmol) and
a solution of Ac2O (0.5 mmol) in 1 mL of THF dropwise at 0 °C. The
resultant solution was stirred at room temperature for 12 h. Methylene
chloride extractive workup followed by chromatography provided 3a.
(5) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183.
(6) Kita, Y.; Okunaka, R.; Honda, T.; Shindo, M.; Taniguchi, M.; Kondo,
M.; Sasho, M. J. Org. Chem. 1991, 56, 119.
3928
Org. Lett., Vol. 3, No. 24, 2001

the dynamically controlled product 4. This hypothesis was
supported by our observation that only 4 was isolated when
the reaction was run in wet acetonitrile.
With quinolizidinone 3a in hand, we developed a facile
route to (-)-lasubine II11 as outlined in Scheme 4. Hydrolysis
Table 2. Synthesis of Enantiopure Quinolizidinones and
Indolizidinonesa,9
Scheme 4
product (yield (%))b
entry
n
R
R1
R2
3
4
4 to 3
1
2
3
4
5
6
7
8
1
1
1
1
1
0
0
0
n-Pr
c-hexyl
H
H
H
Me 3b (34) 4b (42)
84
73
85
79
89
77
72
80
Et
3c (24) 4c (55)
3d (31) 4d (51)
n-hexyl Et
i-Pr
H
H
Arc
H
Me 3e (28) 4e (55)
Me 3a (43) 4f (39)
Me 3g (22) 4g (66)
Arc
n-Pr
H
Et
3h (24) 4h (63)
4i (62)
H
i-Pr
Me 3i (24)
a Reaction condition: iodide (0.22 mmol), â-amino ester (0.22 mmol),
K2CO3 (0.22 mmol), 4 Å MS (50 mg) in 4 mL of MeCN, stirred at 65 °C
for 36 h. b Isolated yield. c Ar ) 3,4-dimethoxyphenyl.
corresponding indolizidinones in 72% to 80% yields. When
these results are taken together, it is obvious that the present
method provides an efficient protocol for preparing enan-
tiopure quinolizidinones and indolizidinones.
On the basis of Harris’s and Henin’s report,10 we proposed
a possible mechanism for the formation of 3 and 4 as
illustrated in Scheme 3. After the SN2 reaction of 1 and 2
of 3a with aqueous potassium hydroxide followed by
decarboxylation provided the enone 8 in 66% yield. Hydro-
genation of 8 afforded the alcohol 9, which was subjected
to Mitsunobu conversion to give (-)-lasubine II. Its optical
rotation value ([R]D20 -46 (c 2.1, MeOH)) was close to that
20
reported ([R]D -41 (c 2.7, MeOH)).11c The overall yield
for this total synthesis from the â-amino ester 2a was about
36%.
Scheme 3
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (Grants 29725205 and 29972049), and Qiu Shi
Science & Technologies Foundation for their financial
support.
Supporting Information Available: Experimental pro-
cedures and characterizations for compounds 3, 4, 8, and 9
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL016802W
(9) Typical procedure: To a mixture of 4 Å MS (50 mg), anhydrous
K2CO3 (0.22 mmol), and â-amino ester (0.22 mmol) in 4 mL of CH3CN
was added iodide 1 (0.22 mmol). The suspension was heated at 65 °C for
32 h before it was subjected to ether workup. Chromatography of the crude
products afforded 3 and 4.
(10) (a) Walter, P.; Harris, T. W. J. Org. Chem. 1978, 43, 4250. (b)
Henin, J.; Vercauteren, J.; Mangenot, C.; Henin, B.; Nuzillard, J. M.;
Guilhem, J. Tetrahedron 1999, 55, 9817.
(11) Isolation: (a) Fuji, K.; Yamada, T.; Fujita, E.; Murata, H. Chem.
Pharm. Bull. 1978, 26, 2515. Racemic synthesis: (b) Pilli, R. A.; Dias, L.
C.; Maldaner, A. O. J. Org. Chem. 1995, 60, 717, and references therein.
Enantioselective synthesis: (c) Chalard, P.; Remuson, R.; Gelas-Mialhe,
Y.; Gramain, J.-C. Tetrahedron: Asymmetry 1998, 9, 4361. (d) Ukaji, Y.;
Ima, M.; Yamada, T.; Inomata, K. Heterocycles 2000, 52, 563. (e) Davis,
F. A.; Chao, B. Org. Lett. 2000, 2, 2623.
took place to form the secondary amine 6, intramolecular
Michael addition occurred to provide the intermediate 7.
There were two possibilities for 7 to process the further
conversion. One was intramolecular condensation to afford
the thermodynamically controlled product 3, another one was
performing inter- or intramolecular proton abstraction to give
Org. Lett., Vol. 3, No. 24, 2001
3929