Enantioselective total synthesis of (-)-limaspermidine and formal synthesis of (-)-1-acetylaspidoalbidine

Article abstract of DOI:10.1021/jo402004f

Evolution of the synthetic strategy that culminated in the first asymmetric total synthesis of the Aspidosperma alkaloid limaspermidine is described. The successful enantioselective route to (-)-limaspermidine proceeds in 10 steps and with the isolation of only six intermediates using a Pd-catalyzed enantioselective decarboxylative allylation we have recently developed. This first enantioselective synthesis of (-)-limaspermidine establishes unambiguously its absolute configuration and allows the first asymmetric formal total synthesis of the Aspidoalbine alkaloid (-)-1-acetylaspidoalbidine.

Full text of DOI:10.1021/jo402004f

Article
pubs.acs.org/joc
Enantioselective Total Synthesis of (−)-Limaspermidine and Formal
Synthesis of (−)-1-Acetylaspidoalbidine
Shao-Xiong Zhang,† Xiao-Lei Shen,† Ze-Qian Li,† Li-Wei Zou, Feng-Qun Wang, Hong-Bin Zhang,
and Zhi-Hui Shao*
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology,
Yunnan University, Kunming 650091, People’s Republic of China
S
* Supporting Information
ABSTRACT: Evolution of the synthetic strategy that culminated in the first asymmetric total synthesis of the Aspidosperma
alkaloid limaspermidine is described. The successful enantioselective route to (−)-limaspermidine proceeds in 10 steps and with
the isolation of only six intermediates using a Pd-catalyzed enantioselective decarboxylative allylation we have recently developed.
This first enantioselective synthesis of (−)-limaspermidine establishes unambiguously its absolute configuration and allows the
first asymmetric formal total synthesis of the Aspidoalbine alkaloid (−)-1-acetylaspidoalbidine.
us to focus our attention on the asymmetric synthesis of
limaspermidine. Herein, we report the development of the first
catalytic enantioselective total synthesis of (−)-limaspermidine
and the determination of its absolute configuration. The
synthesis employs Pd-catalyzed enantioselective decarboxylative
allylation8 of carbazoleones we have recently developed9 as a
central enabling feature. This first enantioselective synthesis of
(−)-limaspermidine also allows the first asymmetric formal
total synthesis of Aspidoalbine alkaloid (−)-1-acetylaspidoalbi-
dine.10
INTRODUCTION
■
The natural product limaspermidine is an Aspidosperma
alkaloid1 isolated from the trunk bark of the small tree A.
rhombeosignatum MARKGRAF found growing in the Ven-
ezuelan Amazonas (Figure 1).2 The synthesis of limaspermi-
RESULTS AND DISCUSSION
■
Figure 1. Structures of limaspermidine and 1-acetylaspidoalbidine.
Very recently, we developed a novel palladium-catalyzed
decarboxylative allylation, enabling the first enantioselective
synthesis of carbazoleones 2 bearing a quaternary carbon center
(Figure 2a).9 We reasoned that enantioenriched carbazoleone
2a could be used as a starting point for a distinct approach
toward the synthesis of limaspermidine (Figure 2b). Crucial to
the success of this approach would be chemoselective oxidation
of the pentacycle 3 into the aldehyde 4. If this reaction were
successful, the reduction of the resulting aldehyde 4 with
LiAlH4 would provide directly the target limaspermidine. While
there are several methods available for the oxidation of an allyl
group into a −CH2CHO group, there are no precedents for
such chemoselective issues. Thus, we initially decided to utilize
rac-3 to explore this chemistry.
dine was first completed by Ban et al. in 1976, who obtained
limaspermidine as a racemic mixture.3 Since then, there have
been only a few successful total syntheses of this target. In
1991, the Overman group disclosed an elegant total synthesis of
limaspermidine, where a signature aza-Cope−Mannich rear-
rangement was used as the key reaction.4 During the course of
our studies, Banwell and co-workers reported an impressive
total synthesis of it wherein the B and D rings were formed in a
Raney cobalt-mediated tandem reductive cyclization process,5
and Canesi et al. described a nice new route to limaspermidine
(limaspermidine was not isolated) employing an oxidative shift
process in combination with a Fischer indole protocol.6 In all
these reports, however, limaspermidine was prepared in racemic
form, and an asymmetric total synthesis of this target has not
yet been realized. This background in conjunction with their
potential as precursors to a range of alkaloids, including those
of the aspidofractinine, kopsine, and vincadifformine series,7 led
The synthesis of rac-3 is shown in Scheme 1. Reduction of
the amide group of rac-5 prepared from rac-29 with LiAlH4 in
Received: September 10, 2013
Published: October 16, 2013
© 2013 American Chemical Society
11444
dx.doi.org/10.1021/jo402004f | J. Org. Chem. 2013, 78, 11444−11449

The Journal of Organic Chemistry
Article
Figure 2. (a) Our Pd-catalyzed decarboxylative allylation. (b) Working hypothesis for the enantioselective synthesis of limaspermidine.
Scheme 1. Attempts To Secure Pentacycle rac-3 en Route to Limaspermidine
Et2O at reflux afforded the amine rac-6 in 85% yield.
Interestingly, the LAH reduction reaction performed in THF
under reflux conditions resulted in the compound rac-6 in
much lower yield (21%) together with inseparable complexes.
Then rac-6 was debenzylated by a Birch reduction with Na/
NH3 to provide the free (NH)-indole rac-7 in almost
quantitative yield. Treatment of rac-7 with α-chloroacetyl
chloride in the presence of triethylamine delivered chloroamide
rac-8 in good yield (80%). The resulting acylated compound
rac-8 was transformed into an iodide, which subsequently
underwent Heathcock annulation11 to yield rac-3 in 70% yield,
setting the stage for the chemoselective oxidation reaction.
Unfortunately, all attempts, including ozonization (O3, CH2Cl2.
−78 °C then Me2S) and the osmate−periodate procedure
(K2OsO4·2H2O, NMO, THF/H2O (1/1) then NaIO4), led to
the formation of complex mixtures. Although the strategy of
introducing the hydroxyl group of limaspermidine at a later
stage failed, these results inspired us to adapt the approach with
a prehydroxylated compound, perhaps permitting elaboration
to the target limaspermidine.
Selective reduction of aldehyde rac-99 with NaBH4 in MeOH
afforded the alcohol rac-10 in 95% yield (Scheme 2).
Protection of the hydroxyl group with TBSCl and imidazole
produced the compound rac-11 in almost quantitative yield.
Although seemingly straightforward, reduction of the amide
rac-11 to the prehydroxylated amine rac-12 proved problem-
atic. Treatment of rac-11 with LiAlH4 in Et2O at reflux yielded
a mixture of the desired amine rac-12 and the unexpected
deprotected alcohol rac-13 in the ratio of 1.2:1. While the
alcohol rac-13 could be converted into silyl-protected rac-12 for
recycling by reaction with TBSCl and imidazole, this would
require additional tedious steps. Thus, we decided to give up
this route (Scheme 2). However, we recognized that the
alcohol 13 could serve as a suitable intermediate for the
11445
dx.doi.org/10.1021/jo402004f | J. Org. Chem. 2013, 78, 11444−11449

The Journal of Organic Chemistry
Article
Scheme 2. Attempts To Secure Prehydroxylated rac-12 en Route to Limaspermidine
Scheme 3. Completion of Enantioselective Synthesis of (−)-Limaspermidine
synthesis of limaspermidine. We then turned our attention to
developing a concise route to prepare 13 directly from
enantioenriched 2a.
the corresponding iodoamide, which was treated with AgOTf
to produce the desired cyclized product 18. Interestingly,
although the pentacycle rac-3 (Scheme 1) was stable to silica
gel column chromatography, this was not the case for the
structurally similar pentacycle 18. The attempt with neutral
Al2O3 failed to give pure pentacycle 18. Thus, once the
annulation reaction was complete, the resulting crude product
18 was treated with LiAlH4. To our delight, the target alkaloid
As shown in Scheme 3, reduction of the amide and aldehyde
groups of the compound 9 prepared from enantioenriched 2a
by a two-step route9 with LiAlH4 in Et2O at reflux delivered the
enantioenriched amino alcohol 13 in good yield (86%). Then
the compound 13 was debenzylated by a Birch reduction with
Na/NH3 to afford the free (NH)-indole 15 in 93% yield.
Protection of the hydroxyl group with TBDPSCl and imidazole
at room temperature gave the compound 16 in quantitative
yield, setting the stage for the E-ring annulation reaction again.
Reaction of the amine 16 with α-chloroacetyl chloride in the
presence of triethylamine occurred as expected. Unexpectedly,
the resulting acylated compound 17 partially decomposed
during the purification with silica gel column chromatography.
For this reason, chloroamide 17 was used directly in the next
step without further purification. Then the chloroamide 17
underwent a Finkelstein reaction with NaI/acetone to provide
(−)-limaspermidine ([α]D = −30.5° (c 0.5, CHCl3) was
20
obtained directly in one operation with reduction of the amide
and the imine groups and concomitant removal of the silyl
ether protecting group. All spectroscopic data (1H NMR and
13C NMR) of our synthetic (−)-limaspermidine were in accord
with those for ( )-limaspermidine reported previously (for a
comparison of 13C NMR chemical shifts, see Table 1 in the
Supporting Information).5 Thus, the first asymmetric total
synthesis of (−)-limaspermidine has been accomplished, thus
confirming unambiguously its absolute configuration.
11446
dx.doi.org/10.1021/jo402004f | J. Org. Chem. 2013, 78, 11444−11449

The Journal of Organic Chemistry
Article
Na2SO4. The solvent was removed by evaporation to dryness. The
The present route also constitutes the first formal
asymmetric total synthesis of the complex Aspidoalbine alkaloid
(−)-1-acetylaspidoalbidine,10 as this target can be synthesized
in two steps from limaspermidine.5
crude product was purified by flash chromatography (silica gel) to give
1
the compound rac-8 (269 mg, 80% yield). H NMR (CDCl3, 300
MHz): δ 1.22−1.39 (m, 2H), 1.49−1.82 (m, 4H), 1.83−1.93 (m,
0.38H), 1.97−2.20 (m, 1H), 2.25−2.42 (m, 1H), 2.48−2.63 (m, 1H),
2.64−2.73 (m, 1H), 2.76−2.89 (m, 0.72H), 3.54 (d, J = 13.5 Hz,
0.68H), 4.21 (dd, J = 12 Hz, 1.38H), 4.33 (s, 0.61H), 4.46 (m, 0.33H),
4.69 (s, 0.32H), 4.96−5.14 (m, 2H), 5.67 (s, 0.68H), 5.78 (m, 1H),
6.86−6.98 (m, 1H), 6.98−7.09 (m, 1H), 7.09−7.26 (m, 2H), 8.00 (br
s, 0.68H), 8.19 (br s, 0.31H). 13C NMR (CDCl3, 75 MHz): δ 19.6,
20.2, 21.6, 24.6, 25.5, 32.1, 36.7, 37.3, 37.8, 40.4, 40.7, 41.7, 41.9, 42.2,
53.1, 59.0, 106.8, 107.6, 110.5, 110.8, 118.1, 118.3, 118.4, 118.8, 119.7,
120.2, 121.3, 121.5, 126.2, 133.4, 133.9, 134.9, 135.0, 136.3, 166.1.
HRMS (EI): calcd for C20H23ClN2O [M]+ 342.1499, found 342.1505.
IR (KBr): v 3395, 3265, 2924, 1625, 1455, 1327, 1249, 1102, 996, 914,
743 cm−1.
CONCLUSION
■
In summary, we have developed the first enantioselective total
synthesis of the Aspidosperma alkaloid (−)-limaspermidine,
confirming its absolute configuration. Our synthesis features a
Pd-catalyzed asymmetric decarboxylative allylic alkylation that
we have recently developed. On the other hand, we have
accomplished the first asymmetric formal total synthesis of the
Aspidoalbine alkaloid (−)-1-acetylaspidoalbidine. Our synthetic
strategy also opens a pathway for the asymmetric syntheses of
other Aspidosperma alkaloids containing a functionalized two-
carbon unit at C-20.
Compound rac-3. To a solution of rac-8 (269 mg, 0.78 mmol) in
acetone (15 mL) was added NaI (1.18 g, 7.8 mmol, 10 equiv). The
reaction mixture was stirred under reflux for 2 h. EtOAc (50 mL) was
added, and the resulting solution was washed with H2O. The solvent
was removed by evaporation to dryness. The crude product was
dissolved in THF (15 mL), and AgOTf (400 mg, 1.56 mmol) was
added. The resulting mixture was stirred at room temperature for 0.5
h. EtOAc (10 mL) was added. The solution was washed with saturated
aqueous NaHCO3 and dried with Na2SO4. The solvent was removed
by evaporation to dryness, and the resulting crude product was
purified by flash chromatography (silica gel) to give the compound
rac-3 (167 mg, 70% yield). 1H NMR (CDCl3, 300 MHz): δ 1.44−1.68
(m, 5H), 1.71−1.83 (m, 2H), 2.21 (m, 1H), 2.54 (d, J = 1.2 Hz, 1H),
2.69−2.83 (m, 2H), 2.92−3.03 (m, 2H), 3.65 (s, 1H), 4.33 (m, 1H),
4.80 (d, J = 1.2 Hz, 1H), 4.98 (d, J = 1.8 Hz, 1H), 5.60 (m, 1H), 7.22
(m, 1H), 7.34 (m, 2H), 7.54 (m, 1H). 13C NMR (CDCl3, 75 MHz): δ
20.2, 24.1, 24.3, 34.3, 37.2, 38.7, 40.7, 41.2, 53.8, 69.2, 119.2, 120.5,
120.9, 126.2, 128.5, 131.9, 145.4, 154.5, 170.3, 186.6. HRMS (EI):
calcd for C20H22N2O [M]+ 306.1732, found 306.1734. IR (KBr): v
3297, 2935, 1678, 1456, 1286, 1243, 1047, 923, 748 cm−1.
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H NMR and 13C NMR
spectra were recorded with a 300 or 400 MHz spectrophotometer.
Chemical shifts (δ) are expressed in ppm, and J values are given in Hz.
High-resolution mass spectrometry (HRMS) was recorded on a
spectrometer using a time-of-flight (TOF) analyzer. IR spectra were
obtained as KBr pellets. Optical rotations were measured on a
polarimeter. Flash column chromatography was performed on silica
gel (230−400 mesh). All chemicals and solvents were used as received
without further purification unless otherwise stated.
Compound rac-6. To a solution of the compound rac-59 (450 mg,
1.21 mmol) in Et2O (20 mL) was added LiAlH4 (276.9 mg, 7.3
mmol). The reaction mixture was stirred under reflux for 18 h. The
reaction was quenched with saturated aqueous NaHCO3. The reaction
mixture was extracted with DCM, and the extract was dried over
Na2SO4 and concentrated to dryness. The crude product was purified
by flash chromatography (silica gel) to give the pure compound rac-6
(367 mg, 85% yield). 1H NMR (CDCl3, 300 MHz): δ 1.35 (dd, J = 4.5
Hz, 1H), 1.40−1.59 (m, 3H), 1.67−1.83 (m, 2H), 1.92 (brs, 1H), 2.08
(m, 1H), 2.31 (m, 1H), 2.43−2.63 (m, 2H), 2.67 (m, 1H), 2.93 (m,
1H), 3.71 (s, 1H), 4.81 (d, J = 17.1 Hz, 1H), 4.91 (d, J = 9 Hz, 1H),
5.16 (dd, J = 16.8 Hz, 2H), 5.76 (m, 1H), 6.88 (d, J = 6.6 Hz, 2H),
7.01 (m, 2H), 7.15 (m, 4H), 7.56 (m, 1H). 13C NMR (CDCl3, 75
MHz): δ 19.2, 22.8, 24.8, 34.9, 42.0, 46.3, 56.4, 109.2, 111.8, 117.3,
117.7, 119.3, 120.9, 126.1, 127.1, 127.3, 128.8, 134.8, 135.5, 137.1,
137.9. HRMS (EI): calcd for C25H28N2 [M]+ 356.2252, found
356.2254. IR (KBr): v 3391, 2927, 1730, 1600, 1455, 1309, 1193,
1001, 914, 737 cm−1.
Compound rac-10. To a solution of the compound rac-99 (372.5
mg, 1 mmol) in MeOH (10 mL) was added NaBH4 (45 mg, 1.2
mmol) at 0 °C. The reaction mixture was stirred at room temperature
for 0.5 h. The reaction was quenched with saturated aqueous NH4Cl
(3 mL). The reaction mixture was extracted with DCM, and the
extract was dried over Na2SO4 and concentrated to dryness. The crude
product was purified by flash chromatography (silica gel) to give the
1
pure compound rac-10 (356 mg, 95% yield). H NMR (CDCl3, 300
MHz): δ 1.47−1.57 (m, 2H), 1.62−1.69 (m, 1H), 1.79−1.87 (m, 2H),
1.96−2.00 (m, 1H), 2.02 (s, 1H), 2.13−2.33 (m, 2H), 2.58−2.62 (m,
2H), 3.65 (t, J = 6.9 Hz, 2H), 4.44 (s, 1H), 5.16 (s, 2H), 5.88 (s, 1H),
6.87 (d, J = 6.3 Hz, 2H), 7.03−7.06 (m, 2H), 7.13−7.19 (m, 4H),
7.40−7.43 (m, 1H). 13C NMR (CDCl3, 75 MHz): δ 19.0, 25.8, 27.8,
28.0, 30.4, 33.7, 38.0, 46.5, 53.6, 58.6, 108.7, 109.7, 117.0, 120.0, 121.7,
126.0, 127.5, 128.9, 135.6, 137.1, 137.3, 171.0. HRMS (EI): calcd for
C24H26N2O2 [M]+ 374.1994, found 374.1993. IR (KBr): v 3448, 2937,
1642, 1460, 1060, 739 cm−1.
Compound rac-11. To a solution of the compound rac-10 (75
mg, 0.2 mmol) in DCM (3 mL) was added TBSCl (36 mg, 0.24 mmol,
1.2 equiv) and imidazole (41 mg, 0.6 mmol, 3 equiv). The reaction
mixture was stirred at room temperature overnight. Then saturated
aqueous NaCl (1 mL) was added, and the resulting mixture was
extracted with DCM. The organic phase was dried over Na2SO4 and
concentrated to dryness. The crude product was purified by flash
column chromatography (silica gel) to give the pure compound rac-11
(94 mg, 96% yield). 1H NMR (CDCl3, 300 MHz): δ 0.00 (s, 6H), 0.85
(s, 9H), 1.49−1.53 (m, 1H), 1.68−1.79 (m, 2H), 1.96−2.05 (m, 2H),
2.09−2.15 (m, 1H), 2.42−2.49 (m, 2H), 2.71−2.73 (m, 2H), 3.76 (t, J
= 6.6 Hz, 2H), 4.58 (s, 1H), 5.28 (s, 2H), 5.89 (s, 1H), 6.96 (d, J = 6.6
Hz, 2H), 7.14−7.16 (m, 2H), 7.24−7.29 (m, 4H), 7.50−7.53 (m, 1H).
13C NMR (CDCl3, 75 MHz): δ −5.4, 18.2, 19.1, 25.8, 25.9, 27.8, 30.5,
33.9, 38.0, 46.5, 53.8, 59.2, 108.8, 109.6, 117.0, 119.9, 121.7, 126.0,
127.5, 128.9, 135.7, 137.1, 137.4, 170.8. HRMS (EI): calcd for
Compound rac-7. To a solution of NH3 at −78 °C were slowly
added Na (237 mg, 10.3 mmol, 10 equiv) and the compound rac-6
(367 mg, 1.03 mmol) in THF (15 mL). The reaction mixture was
stirred at −78 °C for 0.5 h. The reaction was quenched with the
addition of MeOH. After NH3 evaporated at room temperature, the
crude product was purified by flash chromatography (silica gel) to give
1
the compound rac-7 (260 mg, 95% yield). H NMR (CDCl3, 400
MHz): δ 1.34 (m, 1H), 1.41−1.57 (m, 3H), 1.71 (m, 1H), 1.78 (m,
1H), 2.11 (m, 1H), 2.25 (m, 1H), 2.57−2.73 (m, 3H), 2.94 (m, 1H),
3.66 (s, 1H), 4.90 (d, J = 16.8 Hz, 1H), 4.96 (d, J = 10 Hz, 1H), 5.78
(m, 1H), 7.00 (m, 2H), 7.16 (m, 1H), 7.49 (m, 1H), 8.01 (s, 1H). 13C
NMR (CDCl3, 100 MHz): δ 19.9, 22.6, 24.9, 34.7, 34.9, 41.8, 46.1,
56.2, 110.6, 111.8, 117.4, 117.6, 119.3, 121.0, 127.3, 134.1, 134.7,
136.2. HRMS (EI): calcd for C18H22N2 [M]+ 266.1783, found
266.1791. IR (KBr): v 3397, 3288, 3058, 2931, 1729, 1631, 1443,
1296, 1104, 1007, 904, 735 cm−1.
Compound rac-8. To a solution of the compound rac-7 (260 mg,
0.98 mmol) in DCM (15 mL) was added Et3N (156 mg, 1.46 mmol,
1.5 equiv). To the resulting solution was added 2-chloroacetyl chloride
(73.8 μL, 0.98 mol, 1 equiv) at 0 °C. The reaction mixture was stirred
at room temperature for 2 h. The mixture was quenched with addition
of H2O (5 mL) and extracted with DCM and the extract dried with
11447
dx.doi.org/10.1021/jo402004f | J. Org. Chem. 2013, 78, 11444−11449

The Journal of Organic Chemistry
Article
C30H40N2O2Si [M]+ 488.2859, found 488.2866. IR (KBr): v 3447,
3201, 2937, 2858, 1653, 1461, 1417, 1086, 836, 734 cm−1.
129.84, 133.1, 135.4, 136.3, 138.2. HRMS (EI): calcd for C33H40N2Osi
20
[M]+ 508.2910, found 508.2914. [α]D = −6.5° (c 0.5, CHCl3). IR
Compound rac-12. To a solution of the compound rac-11 (98
mg, 0.2 mmol) in Et2O (15 mL) was added LAH (46 mg, 1.2 mmol, 6
equiv). The reaction mixture was stirred at reflux overnight. The
reaction was quenched with saturated aqueous NaHCO3 (2 mL). The
reaction mixture was extracted with DCM, and the extract was dried
over Na2SO4 and concentrated to dryness. The crude product was
purified by flash chromatography (silica gel) to give the pure
compound rac-12 (45 mg, 47% yield) together with the alcohol rac-
13 (27 mg, 38% yield). 1H NMR (CDCl3, 300 MHz): δ 0.01 (s, 6H),
0.87 (s, 9H), 1.30−1.37 (m, 1H), 1.55−1.64 (m, 3H), 1.72−1.77 (m,
2H), 1.86 (d, J = 11.1 Hz, 1H), 2.46−2.51 (m, 1H), 2.73−2.79 (m,
3H), 2.99−3.03 (m, 1H), 3.73 (t, J = 7.2 Hz, 2H), 3.82 (s, 1H), 5.28
(s, 2H), 7.03 (d, J = 6.6 Hz, 2H), 7.11−7.14 (m, 2H), 7.21−7.30 (m,
4H), 7.67−7.70 (m, 1H). 13C NMR (CDCl3, 100 MHz): δ −5.4, 18.2,
19.5, 22.4, 25.1, 25.9, 34.2, 34.9, 39.8, 46.1, 46.4, 56.8, 59.3, 109.1,
111.4, 117.8, 119.3, 120.9, 126.1, 127.1, 127.2, 128.8, 135.6, 137.1,
137.9. HRMS (EI): calcd for C30H42N2OSi [M]+ 474.3066, found
474.3055. IR (KBr): v 3444, 2945, 2851, 1638, 1458, 1401, 1094, 743
cm−1.
(KBr): v 3417, 3207, 2936, 2859, 1617, 1460, 1423, 1103, 742, 700
cm−1.
Synthesis of (−)-Limaspermidine. To a solution of the
compound 16 (101.6 mg, 0.2 mmol) in DCM (4 mL) was added
Et3N (15 mg, 0.3 mmol, 1.5 equiv). To the resulting solution was
added 2-chloroacetyl chloride (15.0 μL, 0.2 mol, 1 equiv) at 0 °C. The
reaction mixture was stirred at room temperature for 2 h. The mixture
was quenched with addition of H2O (1.5 mL) and extracted with
DCM, and the extract was dried with Na2SO4. The solvent was
removed by evaporation to dryness. The crude product was used
without further purification. To a solution of the crude compound
obtained above in acetone (5 mL) was added NaI (210 mg, 1.4
mmol). The reaction mixture was stirred under reflux for 2 h. EtOAc
(5 mL) was added, and the resulting solution was washed with H2O.
The solvent was removed by evaporation to dryness. The crude
product was dissolved in THF (5 mL), and AgOTf (72 mg, 0.28
mmol) was added. The resulting mixture was stirred at room
temperature for 0.5 h. EtOAc (10 mL) was added. The solution was
washed with saturated aqueous NaHCO3 and dried with Na2SO4. The
solvent was removed by evaporation to dryness, and the resulting
crude product was used without further purification. To a solution of
this crude product in THF (5 mL) was added LAH (17.3 mg, 0.46
mmol). The reaction mixture was stirred at room temperature for 0.5
h and under reflux overnight. H2O (35 μL), KOH (35 μL, 15%
aqueous), and H2O (100 μL) were added in sequence. The resulting
slurry was filtered and rinsed with THF. The crude product was
purified by flash chromatography (silica gel) to give (−)-limaspermi-
dine (13 mg, 22% yield over four steps). 1H NMR (CDCl3, 300
MHz): δ 7.01 (d, J = 7.2 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 6.66 (t, J =
7.2 Hz, 1H), 6.56 (d, J = 7.8 Hz, 1H), 3.56 (m, 1H), 3.47 (m, 2H),
3.05 (m, 1H), 2.25 (m, 3H), 1.97 (m, 3H), 1.74−1.62 (m, 5H), 1.46−
1.42 (m, 3H), 1.24−1.12 (m, 2H), 1.03 (m, 1H). 13C NMR (CDCl3,
75 MHz): δ 21.7, 24.3, 28.2, 29.8, 35.5, 38.5, 40.5, 52.8, 53.4, 53.7,
Compound 13. To a solution of the compound 99 (187 mg, 0.5
mmol) in Et2O (20 mL) was added LAH (114 mg, 3 mmol, 6 equiv).
The reaction mixture was stirred at reflux for 36 h. The reaction was
quenched with saturated aqueous NaHCO3. The reaction mixture was
extracted with DCM, and the extract was dried over Na2SO4 and
concentrated to dryness. The crude product was purified by flash
chromatography (silica gel) to give the pure compound 13 (155 mg,
86% yield). 1H NMR (CDCl3, 300 MHz): δ 1.42−1.52 (m, 5H),
1.59−1.69 (m, 2H), 2.12 (s, 1H), 2.49−2.70 (m, 4H), 2.77 (s, 1H),
3.56−3.71 (m, 2H), 3.82 (s, 1H), 5.15 (s, 2H), 6.88 (d, J = 6.9 Hz,
2H), 7.00−7.03 (m, 2H), 7.11−7.18 (m, 4H), 7.49−7.52 (m, 1H); 13C
NMR (CDCl3, 75 MHz): δ 19.3, 22.6, 29.7, 33.3, 34.6, 41.6, 44.4, 46.4,
56.4, 58.9, 109.3, 111.1, 117.8, 119.4, 121.0, 126.1, 126.8, 127.3, 128.8,
135.7, 137.2, 137.9. HRMS (EI): calcd for C24H28N2O [M]+ 360.2202,
20
58.6, 65.3, 70.6, 110.5, 119.2, 122.7, 127.4, 135.2, 149.5. HRMS (EI):
found 360.2199. [α]D = +7.7° (c 0.5, CHCl3). IR (KBr): v 3410,
20
calcd for C19H26N2O [M]+ 298.2045, found 298.2041. [α]D
=
2927, 2843, 1641, 1609, 1455, 1043, 737 cm−1.
−30.5° (c 0.5, CHCl3). IR (KBr): v 3444, 2929, 1601, 1544, 1470,
Compound 15. To a solution of NH3 at −78 °C were slowly
added Na (64.4 mg, 2.8 mmol, 10 equiv) and the compound 13 (100
mg, 0.28 mmol) in THF (10 mL). The reaction mixture was stirred
−78 °C for 0.5 h. The reaction was quenched with the addition of
MeOH (1 mL). After NH3 evaporated at room temperature, the crude
product was purified by flash chromatography (silica gel) to give the
1392, 1037, 898, 755 cm−1.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving 1H NMR and 13C NMR spectra of the
compounds rac-6, rac-7, rac-8, rac-3, rac-10, rac-11, rac-12,
13, 15, 16, and limaspermidine. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
compound 15 (69.7 mg, 93% yield). H NMR (CDCl3, 400 MHz): δ
1.40−1.42 (m, 3H), 1.44−1.49 (m, 2H), 1.59−1.70 (m, 2H), 2.10 (s,
1H), 2.53−2.59 (m, 2H), 2.66−2.69 (m, 1H), 2.77 (s, 1H), 3.61−3.65
(m, 1H), 3.67−3.69 (m, 1H), 3.71−3.75 (m, 1H), 6.98−7.05 (m, 2H),
7.17−7.18 (m, 1H), 7.43−7.45 (d, J = 7.5 Hz, 1H), 7.97 (s, 1H). 13C
NMR (CDCl3, 100 MHz): δ 20.1, 22.7, 28.2, 33.0, 34.7, 41.8, 44.4,
56.3, 59.0, 110.7, 111.5, 117.6, 119.4, 121.1, 127.1, 134.3, 136.3.
HRMS (EI): calcd for C17H22N2O [M]+ 270.1732, found 270.1737.
AUTHOR INFORMATION
Corresponding Author
*Z.-H.S.: e-mail, zhihui_shao@hotmail.com; fax, (+86)871-
5035538; tel, (+86)871-5031119.
■
20
[α]D = +8.9° (c 0.5, CHCl3). IR (KBr): v 3399, 3284, 2929, 1629,
1459, 1319, 1047, 894, 745 cm−1.
Compound 16. To a solution of the compound 15 (90 mg, 0.33
mmol) in DCM (10 mL) were added imidazole (34.5 mg, 0.5 mmol,
1.5 equiv), DMAP (8 mg, 0.066 mmol, 0.2 equiv), and TBDPSCl (110
mg, 0.4 mmol, 1.2 equiv). The reaction mixture was stirred at room
temperature for 1.5 h. Then saturated aqueous NH4Cl (5 mL) was
added, and the resulting mixture was extracted with DCM. The
organic phase was dried over Na2SO4 and concentrated to dryness.
The crude product was purified by flash column chromatography
Author Contributions
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the NSFC
(21162034, 21372193, 21362040) and the Government of
Yunnan Province (2012FB114, 2013Y362).
1
(silica gel) to give the pure compound 16 (164.6 mg, 98% yield). H
NMR (CDCl3, 400 MHz): δ 0.89 (s, 9H), 1.09−1.14 (m, 1H), 1.31−
1.36 (m, 2H), 1.50−1.66 (m, 4H), 1.95−1.97 (m, 1H), 2.37−2.45 (m,
1H), 2.58−2.61 (m, 1H), 2.96−3.02 (m, 2H), 3.44−3.52 (m, 2H),
3.72 (d, J = 10.2 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz,
1H), 7.19−7.26 (m, 5H), 7.30−7.34 (m, 2H), 7.41−7.46 (m, 4H),
7.58 (d, J = 7.5 Hz, 1H), 9.72−9.76 (m, 1H), 10.69 (s, 1H). 13C NMR
(CDCl3, 100 MHz): δ 17.9, 19.0, 19.4, 24.3, 26.8, 33.2, 34.3, 38.0,
44.7, 55.4, 59.6, 102.9, 111.9, 117.9, 119.0, 120.9, 125.4, 127.7, 129.78,
REFERENCES
■
(1) (a) Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1998; Vol. 51, Chapter 1. (b) Lopchuk, J. M. Prog.
Heterocycl. Chem. 2011, 23, 1.
(2) Medina, J. D.; Di Genova, L. Planta Med. 1979, 37, 165.
11448
dx.doi.org/10.1021/jo402004f | J. Org. Chem. 2013, 78, 11444−11449

The Journal of Organic Chemistry
Article
(3) Honma, Y.; Ohnuma, T.; Ban, Y. Heterocycles 1976, 5, 47.
(4) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem.
Soc. 1991, 113, 2598.
(5) Tan, S. H.; Banwell, M. G.; Willis, A. C.; Reekie, T. A. Org. Lett.
2012, 14, 5621.
(6) Guerard, K. C.; Guerinot, A.; Bouchard-Aubin, C.; Menard, M.-
́ ́ ́
A.; Lepage, M.; Beaulieu, M. A.; Canesi, S. J. Org. Chem. 2012, 77,
2121.
(7) Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, CA, 1998; Vol. 50, p 343.
(8) For reviews on decarboxylative allylation: (a) You, S.-L.; Dai, L.-
X. Angew. Chem., Int. Ed. 2006, 45, 5246. (b) Mohr, J. T.; Stoltz, B. M.
Chem. Asian J. 2007, 2, 1476. (c) Trost, B. M. J. Org. Chem. 2004, 69,
5813. (d) Hong, A. Y.; Stoltz, B. M. Eur. J. Org. Chem. 2013, 2745.
(e) Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem.
Rev. 2011, 111, 1846. For pioneering contributions, see: (f) Behenna,
D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044. (g) Trost, B.
M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846.
(9) Li, Z.; Zhang, S.; Wu, S.; Shen, X.; Zou, L.; Wang, F.; Li, X.;
Peng, F.; Zhang, H.; Shao, Z. Angew. Chem., Int. Ed. 2013, 52, 4117.
For Lupton’s elegant work, see: Gartshore, C. J.; Lupton, D. W. Angew.
Chem., Int. Ed. 2013, 52, 4113.
(10) Boger used his signature [4 + 2]/[3 + 2] cycloaddition
methodology for the only nonracemic total synthesis of (+)-1-
acetylaspidoalbidine. This elegant synthesis employed a semiprepar-
ative Daicel ChiralCel OD column to separate the enantiomers of the
racemic key precursor: Campbell, E. L.; Zuhl, A. M.; Liu, C. M.; Boger,
D. L. J. Am. Chem. Soc. 2010, 132, 3009.
(11) Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000, 65, 2642.
11449
dx.doi.org/10.1021/jo402004f | J. Org. Chem. 2013, 78, 11444−11449