Total synthesis of (±)-1-acetylaspidoalbidine and (±)-1-methylaspidospermidine

Article abstract of DOI:10.1002/adsc.201300756

(±)-1-Acetylaspidoalbidine and (±)-1- methylaspidospermidine were synthesized from protected tryptamine through the combination of an organocatalytic Diels-Alder reaction, a tandem stereoselective ring-opening reduction, and a double Michael addition.

Full text of DOI:10.1002/adsc.201300756

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DOI: 10.1002/adsc.201300756
Total Synthesis of (ꢀ)-1-Acetylaspidoalbidine and
(ꢀ)-1-Methylaspidospermidine
Jian Jina and Fayang G. Qiua,*
a
Guangzhou Institutes of Biomedicine and Health, The Chinese Academy of Sciences, 190 Kaiyuan Boulevard, The
Science Park of Guangzhou, Guangdong 510530, Peopleꢀs Republic of China
E-mail: qiu_fayang@gibh.ac.cn
Received: August 20, 2013; Published online: February 2, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300756.
Abstract: (ꢀ)-1-Acetylaspidoalbidine and (ꢀ)-1-
methylaspidospermidine were synthesized from
protected tryptamine through the combination of
an organocatalytic Diels–Alder reaction, a tandem
were first disclosed in 1963 by Djerassi[3] to have been
isolated from Vallesia dichotoma Ruiz et Pav in Peru,
and 1 was referred to as dehydroxyhaplocidine in
a more recent isolation.[4] More highly oxidized Aspi-
dosperma alkaloids share further hydroxylation of the
aromatic ring, a five-membered lactone versus a tetra-
hydrofuran ring, or further unsaturation in the six-
membered rings.
Owing to the structural complexity and potential
medicinal applications, the synthesis of the aspido-
spermine family of the indole alkaloids has elicited
substantial interest from the synthetic community. For
example, there are six total syntheses so far that have
been documented towards the construction of 1-
stereoselective
ring-opening
reduction,
and
a double Michael addition.
Keywords: Diels–Alder reaction; double Michael
addition; organocatalysis; stereoselectivity; trypta-
mine
The Aspidosperma alkaloid family contains more than acetylACTHNUTRGNEaNUG spidoalbidine and/or 1-methylaspidospermi-
250 compounds, many of which have important bio- dine. To briefly summarize the previous synthetic ef-
logical activities.[1] These compounds share a common forts, Ban[5] used a relatively complex intermediate
pentacyclic structure embedded in an indoline sub- that was developed in his previous investigations to
structure. In addition to these structural complexities, furnish 1-acetylaspidoalbidine; Overman[6] applied the
1-acetylaspidoalbidine (1) possesses a unique C19 aza-Cope rearrangement–Mannich cyclization reac-
N,O-acetal, as is shown in Figure 1.[2] 1-Acetylaspi- tions to achieve a general entry to Melodinus and As-
doalbidine (1) and 1-methylaspidospermidine (2) pidosperma alkaloids; Boger[7] relied on a powerful
Figure 1. Structures of (ꢀ)-1-acetylaspidoalbidine and (ꢀ)-1-methylaspidospermidine.
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Total Synthesis of (ꢀ)-1-Acetylaspidoalbidine
intramolecular [4+2]/ACHTGNUTREN[NUNG 3+2]cycloaddition cascade of ring. The retrosynthetic analysis is outlined in
a 1,3,4-oxadiazole in which the pentacyclic skeleton Scheme 1.
and all the stereochemical centers of the natural prod-
Since the aminal is the most sensitive functionality
ucts are assembled in a single synthetic operation; of 1, the construction of which should be arranged as
and Canesi[8] developed an oxidative 1,2- and 1,3- the last step via the oxidation of either the tertiary
alkyl shift process in a substituted phenol system as amine or the primary hydroxy group of the intermedi-
a key element for the synthesis of 1-acetylaspidoalbi- ate precursor. Construction of the latter may be
dine. Recently, Banwell reported a concise total syn- achieved from the pentacyclic aldehyde precursor 11
thesis[9] of acetylaspidoalbidine that is strategically after a chain elongation and reduction of the lactam
more convergent than the previous ones.
to the tertiary amine with concomitant reduction of
The studies described herein were not only formu- the aldehyde to the primary alcohol. The pentacyclic
lated to develop a general route to construct the Aspi- intermediate 11 may be synthesized through a tandem
dosperma alkaloids, but were seen to have the poten- Michael addition from the tricyclic enal 10, which
tial for applications toward other members of this sig- may be obtained via a stereoselective ring-opening re-
nificant family of alkaloids. In this communication, duction of indoline 7. Similar to what has been re-
we detail a concise route to 1-acetylaspidoalbidine ported by MacMillan,[10] indoline 7 is the result of
and 1-methylaspidospermidine, featuring a pivotal a pivotal intermolecular Diels–Alder reaction of an
organo-catalytic Diels–Alder reaction, which is simi- indolyldiene and propynal. The synthesis of the indo-
lar to what has been developed by MacMillan,[10] an lyldiene 6 may be realized from the protected trypta-
effective intramolecular double Michael addition and mine through a series of transformations (Scheme 2).
an iodine-induced formation of the tetrahydrofuran
Scheme 1. Retrosynthetic analysis.
Scheme 2. Synthesis of indoline 7.
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Jian Jin und Fayang G. Qiu
Scheme 3. Synthesis of lactam 11.
Based on the above analysis, the total synthesis of instance, when TMSI or aqueous HCl was used to
1 and 2 was designed to start from the tert-butoxycar- remove the Boc protecting group, the reaction turned
bonyltryptamine intermediate 3. The indole ring ni- into a complex mixture; when trifluoroacetic acid was
trogen was protected with PMBCl and sodium hy- used, the reaction led to esterification of the allylic al-
dride in DMF (!4) in 91% yield. The a-indolyl carb- cohol; When the Schotten–Bauman conditions were
anion generated through the low temperature depro- applied to the amidation, it was found that the selec-
tonation in THF with five equivalents of n-butyllithi- tivity between the amino group and the hydroxy
um, when quenched with DMF, afforded in 76% yield group was very poor. After a few unsuccessful at-
the desired indolecarboxaldehyde 5, which was then tempts, we decided to tackle the problem in a stepwise
olefinated via a conventional Wittig reaction to pro- manner. The problem was solved by leaving the ami-
vide the desired diene 6 in 84% yield.
dation process to a later stage. Thus, the tert-butoxy-
With the diene in hand,[10a] the pivotal Diels–Alder carbonyl protection was removed upon treatment
reaction is in place. Propynal was generated directly with TMSOTf at low temperatures. After protection
before use.[11] At this point, a variety of reaction con- of the primary alcohol with TBSCl, the free amine
ditions was examined. Initially, piperidinium acetate was reacted with acryloyl chloride to afford inter-
was tested but the reaction did not proceed at various mediate 8 in 66% combined yield for the three steps.
temperatures. Our attention was then turned to Mac- The next step was to reduce the aminal to the indo-
Millanꢀs catalyst, which is known to work well for line intermediate 9. The stereochemistry was con-
similar Diels–Alder reactions.[10a,b] Unfortunately, only trolled by taking advantage of the difference between
a low yield was obtained without any enantioselectivi- the thermodynamic stability of the cis- and trans-ACHTUNGTRENNUNG[5,6]
ty. This reaction was also tried with various Lewis fused ring systems. Following the treatment with tri-
acids, but no reaction was observed. Finally, the reac- fluoroacetic acid in acetonitrile and sodium cyanobor-
tion was found to work nicely to afford the tetracyclic ohydride, the TBS protecting group was removed
enal in a solvent system containing DMF and metha- using dilute aqueous hydrochloric acid in methanol to
nol. In this reaction, five equivalents of propynal was furnish in 87% overall yield the desired tricyclic inter-
used with dimethylamine hydrochloride being the cat- mediate 9, which was oxidized in 91% yield to the
alyst, although the reaction was incomplete even after corresponding enal with the proper set-up of all the
24 h. Since the resulting enal was unstable during the functionalities for the key tandem Michael addition.
following transformations, the aldehyde functionality However, no reaction occurred when the reaction
was reduced in situ with sodium borohydride in the mixture was treated with Na2CO3 in refluxing acetoni-
presence of cerium trichloride. The combined overall trile; when it was treated with MeONa in MeOH
yield was 87% based on recovered starting diene a complicated reaction mixture was obtained; on
(Scheme 3).
treatment with t-BuOK in THF the reaction also
The seemingly straightforward combination of the turned into a complex mixture. When treated with po-
removal of the tert-butoxycarbonyl group and subse- tassium carbonate in acetonitrile, to our delight, the
quent amidation of 7 with acryloyl chloride had en- reaction proceeded cleanly to give the desired prod-
countered some difficulties. A complex mixture was uct in 88% isolated yield. Subsequent olefination of
obtained under a variety of reaction conditions. For the aldehyde functionality was realized using triphe-
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Total Synthesis of (ꢀ)-1-Acetylaspidoalbidine
Scheme 4. The total synthesis of (ꢀ)-1-actylaspidoalbidine and (ꢀ)-1-methylaspidospermidine.
nylmethoxymethylphosphonium chloride at low tem- multaneous methylation of the indolyl nitrogen atom,
peratures and KHMDS as the base. The resulting me- and hydrogenation of the terminal olefin, affording
thoxy vinyl ether was hydrolyzed to afford the elon- (ꢀ)-1-methylaspidospermidine (2) in 31% yield over
gated aldehyde, which provided the desired inter- 3 steps.
mediate hydroxylamine upon reduction with lithium
In conclusion, the total syntheses of (ꢀ)-1-acetylas-
aluminum hydride at room temperature (Scheme 4). pidoalbidine (1) and (ꢀ)-1-methylaspidospermidine
Palladium-catalyzed hydrogenolysis in methanol re- (2) were achieved in 16 and 13 linear steps (2.5% and
moved the PMB protective group. The combined 7.1% overall yield from intermediate 3). There are
overall yield was 55% for the four-step operation. At several notable features in this synthetic strategy: (i)
this point, there was only one known transformation the organocatalytic regioselective Diels–Alder reac-
toward the completion of the total synthesis of 1-ace- tion; (ii) the regio- and stereoselective reductive ring
tylaspidoalbidine. However, it was this last step that opening of the aminal; (iii) the steroecontrolled
had delayed the completion of the total synthesis for double Michael addition; (iv) the iodine-mediated tet-
about one year. As pointed out by Banwell,[9] the con- rahydrofuran ring formation; and (v) the acid-pro-
version reported by Ban[5b,12] et al. encountered diffi- moted in situ hydrogenolysis–methylation. All these
culties in our synthesis. Many other reaction condi- effective elements combined with mild reaction condi-
tions that seemed to work well for the oxidation of tions make this synthesis practicable.
other architectures containing a tertiary amine[13] did
not work. The major problem was irreproducibilty of
the reaction yield since numerous side products were
Experimental Section
detected under the reaction conditions. Fortunately,
iodination of the hydroxy group and subsequent in
situ cleavage of the iodine-oxygen bond led to the for-
mation of the desired tetrahydrofuran ring.[14] Since
this reaction produced more side products at pro-
General Methods
Tetrahydrofuran (THF) was dried over Na and diphenyl
ketone. Acetonitrile (MeCN) was dried over activated 4ꢂ
longed reaction times, it was quenched before going molecular sieves, and dimethylformamide (DMF) was dried
over calcium hydride. Dichloromethane (DCM), and trime-
thylsilyl trifluoromethanesulfonate (TMSOTf) were distilled
from calcium hydride immediately prior to use. Acetone
(Me2CO) was distilled from calcium chloride before use. 2-
Iodoxybenzoic acid (IBX) was synthesized according to lit-
erature procedures.[15] All reagents were of reagent grade
and used without purification unless otherwise noted. All re-
actions involving air- or moisture-sensitive reagents or inter-
mediates were performed under an inert atmosphere of ni-
trogen or argon in glassware that had been oven-dried. Re-
to completion. Thus, the unreacted starting material
was recovered and the net reaction yield was 21%.
At this point, we believed that our protocol may
also be good for the synthesis of (ꢀ)-1-methylaspido-
spermidine. Thus, aldehyde 11 was transformed into
terminal olefin 13 through a Wittig reaction using
methylenetriphenylphosphorane, and reduction of the
lactam functional group with LiAlH4. Acid-promoted
palladium-catalyzed hydrogenolysis of 13 in methanol
led to the removal of the PMB protective group, si- action temperatures referred to the temperature of the cool-
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Jian Jin und Fayang G. Qiu
ing/heating bath. Chromatography was performed using
a forced flow (flash chromatography) of the indicated sol-
vent system on 230–400 mesh silica gel (Silicycle flash F60)
according to the method of Still,[16] unless otherwise noted.
Proton nuclear magnetic resonance (1H NMR) and carbon
nuclear magnetic resonance (13C NMR) spectra were ob-
tained at the indicated field strengths as solutions in CDCl3.
Chemical shifts were referenced to the deuterated solvent
(e.g., for CDCl3, d=7.26 ppm and 77.0 ppm for 1H and
13C NMR, respectively) and reported in parts per million
(ppm, d) relative to tetramethylsilane (TMS, d=0.00 ppm).
Coupling constants (J) are reported in Hz and the splitting
abbreviations used are: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet.
Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by using column chromatography (EA/
hexane 1/20) to give 8 as a white foam; yield: 1.159 g (66%
1
over 3 steps): H NMR (400 MHz, CDCl3): d=7.10 (t, J=
8.5 Hz, 3H, indoline ArH, PMB ArH), 6.95 (tt, J=13.6,
6.8 Hz, 1H, indoline ArH), 6.78 (d, J=8.7 Hz, 2H, PMB
ArH), 6.67 (t, J=7.1 Hz, 1H, indoline ArH), 6.40 (dd, J=
16.7, 10.1 Hz, 1H, CH=CHH), 6.30 (dd, J=16.7, 2.2 Hz, 1H,
CH=CHH), 6.13 (d, J=7.8 Hz, 1H, indoline ArH), 5.75 (s,
1H, CH=C), 5.63 (dd, J=10.0, 2.2 Hz, 1H, CH=CHH), 5.04
(d, J=16.8 Hz, 1H, PMB ArCHH), 4.80 (d, J=16.5 Hz, 1H,
PMB ArCHH), 4.01 (s, 2H, CH2OTBS), 3.76 (s, 3H,
OCH3), 3.66 (m, 1H), 3.54–3.41 (m, 1H), 3.02 (dt, J=14.1,
5.1 Hz, 1H), 2.51–2.29 (m, 2H), 2.18–1.80 (m, 3H), 0.89 [s,
9H, OSiC
ACHTUNTGRENNG(U CH3)3ACHTUNGTREN(NUGN CH3)2], 0.04 [d, J=2.9 Hz, 6H, OSiC-
A
CHTUNGTRENNUNG
Indoline 7
158.03, 148.45, 137.23, 131.88, 131.56, 130.29, 128.08, 127.47,
127.41, 121.81, 121.67, 117.54, 113.67, 108.06, 92.20, 66.21,
56.00, 55.17, 47.78, 47.38, 35.09, 25.88, 25.16, 22.69, 18.36,
ꢁ5.29, ꢁ5.35; HR-MS (ESI): m/z=531.3031, exact mass cal-
culated for [M+H]+ (C32H42N2O3Si): 531.3037.
To a solution of 6 (2.22 g, 5.5 mmol) in DMF/MeOH (2 mL/
2 mL) was added Me2NH·HCl (2.3 mg, 0.028 mmol) in one
portion. The resulting solution was stirred for 10 min before
the addition of propynal[11] (1.48 g, 27.5 mmol). The reaction
mixture was stirred at room temperature for 24 h and then
cooled to 08C. CeCl3·7H2O (20.49 g, 55 mmol) in MeOH
(20 mL) was added in one portion, followed by NaBH4
(2.08 g, 55 mmol). After being stirred for 10 min, the reac-
tion mixture was diluted with ethyl acetate (100 mL), and
washed with water (50 mL). The aqueous layer was extract-
ed with ethyl acetate (50 mLꢃ2), and the combined organic
layers were washed with brine, dried over Na2SO4, and then
concentrated under reduced pressure. The residue was puri-
fied by using column chromatography (ethyl acetate/hexane
1/10 to 1/5) to give 7 as a white powder; yield: 1.54 g (60%;
87% based on recovered starting material). 1H NMR
(400 MHz, CDCl3): d=7.14–7.06 (m, 3H, ArH), 6.96 (t, J=
7.5 Hz, 1H, indoline ArH), 6.84–6.79 (m, 2H, ArH), 6.64 (t,
J=7.1Hz, 1H), 6.13 (d, J=7.6 Hz, 1H, indoline ArH), 6.06*
(d, J=7.6, indoline ArH), 5.81 (s, 1H, CH=C), 4.86 (d, J=
16.4 Hz, 1H, PMB ArCHH), 4.78* (d, J=16.5 Hz, PMB
ArCHH), 4.65 (d, J=16.5 Hz, 1H, PMB ArCHH), 4.49* (d,
J=16.2 Hz, PMB ArCHH), 4.04 (d, J=5.6 Hz, 2H,
CH2OH), 3.77 (s, 3H, OCH3), 3.72–3.25 (m, 2H), 2.67–2.21
Allyl alcohol 9
To a solution of 8 (1.159 g, 2.2 mmol) in MeCN (10 mL) was
added trifluoroacetic acid (423 mg, 4.3 mmol) in one por-
tion. After the mixture had been stirred for 10 min,
NaBH3CN (148 mg, 2.2 mmol) was added in one portion,
and the mixture was stirred for 10 min before MeOH
(5 mL) and aqueous solution of HCl (3M, 1 mL) were
added. The solution was stirred for 5 min and then neutral-
ized with saturated NaHCO3, diluted with ethyl acetate
(10 mL), and washed with water. The aqueous layer was ex-
tracted with ethyl acteate (10 mL), and the combined organ-
ic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was puri-
fied by column chromatography (MeOH/CH2Cl2 1/40) to
give 9 as a white foam; yield: 787 mg (86%). 1H NMR
(400 MHz, CDCl3): d=7.22 (d, J=8.6 Hz, 2H, PMB ArH),
7.07–6.98 (m, 2H, indoline ArH), 6.85 (d, J=8.6 Hz, 2H,
PMB ArH), 6.66 (t, J=7.3 Hz, 1H, indoline ArH), 6.42 (d,
J=8.1 Hz, 1H, indoline ArH), 6.21 (dd, J=16.8, 1.2 Hz, 1H,
HC=CHH), 5.96 (dd, J=16.8, 10.3 Hz, 1H, HC=CHH), 5.60
(dd, J=10.3, 1.2 Hz, 1H, HC=CHH), 5.52 (s, 2H, CH=C,
NHCO), 4.39 (d, J=15.6 Hz, 1H, PMB ArCH), 4.14 (d, J=
15.6 Hz, 1H, PMB ArCH), 3.97 (s, 2H, CH=CCH2OH), 3.80
(s, 3H, OCH3), 3.68–3.64 (m, 1H), 3.45–3.29 (m, 2H), 2.12–
1.70 (m, 6H); 13C NMR (125 MHz, CDCl3): d=165.49,
158.64, 150.80, 137.89, 134.66, 130.79, 130.45, 128.51, 127.97,
126.26, 125.87, 122.59, 117.68, 113.95, 107.62, 66.68, 66.38,
55.24, 49.55, 46.63, 38.77, 36.09, 22.41, 20.94; HR-MS (ESI):
m/z=419.2324, exact mass calculated for [M+H]+
(C26H30N2O3): 419.2329.
(m, 3H), 2.03–1.79 (m, 3H), 1.45 [s, 9H, CACHTNUGTRNEG(UN CH3)3]; HR-MS
(ESI): m/z=463.2583, exact mass calculated for [M+H]+
(C28H34N2O4): 463.2591.
Acrylamide 8
To a solution of 7 (1.536 g, 3.3 mol) in dry MeCN (10 mL) at
ꢁ308C was added TMSOTf (2.938 g, 13.3 mmol) dropwise.
After the reaction mixture had been slowly warmed up to
room temperature, saturated NaHCO3 (30 mL) was added,
and then the mixture was diluted with ethyl acetate
(50 mL), washed with water and brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was
dissolved in dry DCM (10 mL), imidazole (221 mg,
3.3 mmol) and TBSCl (497 mg, 3.3 mmol) were added. After
being stirred for 1 hour, the reaction mixture was diluted
with ethyl acetate (20 mL), washed with water and brine,
dried over Na2SO4, and concentrated under reduced pres-
sure. The residue was dissolved in dry DCM (10 mL), pyri-
dine (391 mg, 4.95 mmol) and acryloyl chloride (448 mg,
4.95 mmol) were added. The reaction mixture was stirred
for 1 hour and then washed with water, brine, dried over
Aldehyde 10
To a dimethyl sulfoxide (5 mL) solution of 9 (787 mg,
1.9 mmol) was added IBX (644 mg, 2.3 mmol) and NaHCO3
(193 mg, 2.3 mmol) in one portion. The reaction mixture
was stirred at room temperature for 3 h before it was diluted
with ethyl acetate (20 mL) and water (50 mL). The aqueous
layer was extracted with ethyl acetate (20 mLꢃ2). The com-
bined organic layers were washed with water and brine,
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COMMUNICATIONS
Total Synthesis of (ꢀ)-1-Acetylaspidoalbidine
dried over Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by using column chromatog-
raphy (ethyl acetate/hexane, 1/4) to give 10 as a gray foam;
one portion. The mixture was stirred at room temperature
for 4 h and then quenched with saturated aqueous Na2SO4,
diluted with ethyl acetate, washed with water, brine, and
concentrated under reduced pressure. The residue was dis-
solved in MeOH/3M HCl (5 mL/0.5 mL) and Pd/C (10 mg)
was added. The mixture was stirred under H2 for 10 min,
and filtered. The filtrate was diluted with DCM (10 mL),
washed with saturated NaHCO3, dried over Na2SO4, and
concentrated under reduced pressure. The residue was puri-
fied by using column chromatography (DCM/MeOH, 100/
1 to 20/1) to give 12 as a white solid; yield: 262 mg (55%
1
yield: 748 mg (91%). H NMR (400 MHz, CDCl3): d=9.41
(s, 1H, CHO), 7.20 (d, J=8.6 Hz, 2H, PMB ArH), 7.08 (m,
2H, ArH), 6.85 (d, J=8.6 Hz, 2H, PMB ArH), 6.71 (t, J=
7.2 Hz, 1H, indoline ArH), 6.50 (s, 1H, CH=CCHO), 6.47
(d, J=7.8 Hz, 1H, indoline ArH), 6.22 (dd, J=17.0, 1.3 Hz,
1H, CH=CHH), 5.96 (dd, J=17.0, 10.3 Hz, 1H, CH=CHH),
5.62 (dd, J=10.3, 1.2 Hz, 1H, CH=CHH), 5.51 (s, 1H, NH),
4.40 (d, J=15.8 Hz, 1H, PMB Ar CHH), 4.14 (d, J=
15.8 Hz, 1H, PMB Ar CHH), 3.87–3.77 (m, 4H), 3.35 (dd,
J=14.0, 7.6 Hz, 2H), 2.28–2.01 (m, 5H), 1.72–1.64 (m, 2H);
13C NMR (125 MHz, CDCl3): d=193.68, 165.45, 158.75,
152.43, 151.27, 139.94, 131.08, 130.55, 129.84, 128.92, 128.47,
126.47, 123.04, 118.07, 114.02, 108.19, 66.12, 55.21, 49.64,
48.04, 37.34, 35.92, 21.47, 16.49; HR-MS (ESI): m/z=
439.2171, exact mass calculated for [M+H]+ (C26H28N2O3):
417.2173.
1
over 4 steps). H NMR (400 MHz, CDCl3): d=7.09 (d, J=
7.3 Hz, 1H), 7.01 (td, J=7.6, 1.2 Hz, 1H), 6.73 (td, J=7.4,
0.8 Hz, 1H), 6.64 (d, J=7.7 Hz, 1H), 3.71–3.42 (m, 4H),
3.22–2.97 (m, 2H), 2.40–2.18 (m, 3H), 2.13–1.91 (m, 2H),
1.82–1.60ACTHNUGRTNEUNG(m, 4H), 1.54–1.40 (m, 3H), 1.33–1.14 (m, 2H),
1.03 (d, J=13.8 Hz, 1H), 0.89 (dd, J=12.6, 7.0 Hz, 1H);
13C NMR (125 MHz, CDCl3): d=149.48, 135.23, 127.35,
122.74, 119.17, 110.49, 70.69, 65.33, 58.64, 53.74, 73.47, 52.84,
40.50, 38.55, 35.48, 35.41, 28.22, 24.32, 21.70; HR-MS (ESI):
m/z=299.2118, exact mass calculated for [M+H]+
(C19H26N2O): 299.2118.
Lactam 11
To a solution of 10 (748 mg, 1.8 mmol) in dry MeCN
(50 mL) was added anhydrous sodium carbonate (2.48 g,
18 mmol) in one portion. The mixture was stirred at 808C
under nitrogen for 6 h and then filtered. The filtrate was
concentrated under reduced pressure and the residue was
purified by column chromatography (DCM/MeOH, 60/1 to
20/1) to give 11 as a white solid; yield: 661 mg (88%):
1H NMR (400 MHz, CDCl3): d=9.43 (s, 1H, CHO), 7.25 (d,
J=8.2 Hz, 2H, PMB, ArH), 7.18–6.96 (m, 2H, indoline
ArH), 6.88 (d, J=8.4 Hz, 2H, PMB ArH), 6.70 (t, J=
7.3 Hz, 1H, indoline ArH), 6.41 (d, J=7.8 Hz, 1H, indoline
ArH), 4.39 (d, J=14.4 Hz, 2H, PMB ArHH, CHNCO), 4.00
(d, J=14.6 Hz, 1H, PMB ArCH), 3.82 (s, 3H, OCH3), 3.75–
3.60 (m, 1H), 3.45–3.50 (m, 1H), 3.12 (dd, J=9.1, 5.0 Hz,
1H), 2.66–2.51 (m, 1H), 2.28–2.45 (m, 2H), 2.01–1.93 (m,
1H), 1.84–1.63 (m, 3H), 1.57–1.45 (m, 1H), 1.40–1.20 (m,
2H); 13C NMR (125 MHz, CDCl3): d=201.30, 167.85,
158.94, 150.34, 129.54, 129.00, 128.85, 128.78, 122.49, 118.12,
114.09, 107.70, 63.62, 60.84, 55.28, 53.63, 48.00, 47.77, 43.53,
34.76, 27.65, 27.07, 21.56, 20.26; HR-MS (ESI): m/z=
417.2166, exact mass calculated for [M+H]+ (C26H28N2O3):
417.2173.
(ꢀ)-1-Acetylaspidoalbidine (1)
To a solution of 12 (18 mg, 0.06 mmol) in CH2Cl2 (1 mL)
was added 2M NaOH in water (2 mL). The mixture was
cooled to 08C and AcCl (0.1 mL) was added. The reaction
mixture was stirred for one hour and then separated. The or-
ganic layer was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was dis-
solved in CHCl3 (1 mL). To this solution was added I2
(19 mg, 0.06 mmol) and saturated NaHCO3 (1 mL). The
mixture was stirred at room temperature for 4 h and diluted
with DCM (10 mL), washed with saturated Na2S2O3 and
brine, dried over Na2SO4, and then concentrated under re-
duced pressure. The residue was purified by using column
chromatography (ethyl acetate/hexane, 0.5/1 to 2/1) to give
(ꢀ)-1-Acetylaspidoalbidine (1) as a colorless solid; yield:
1
4.2 mg (21% over 2 steps). H NMR (400 MHz, CDCl3): d=
8.14 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.19 (td,
J=7.6, 1.1 Hz, 1H), 7.05 (td, J=7.6, 1.0 Hz, 1H), 4.16 (t, J=
8.5 Hz, 1H), 4.13–4.02 (m, 1H), 3.86 (dd, J=10.7, 5.1 Hz,
1H), 3.02 (td, J=8.8, 4.4 Hz, 1H), 2.96–2.88 (m, 1H), 2.79
(dd, J=15.5, 6.9 Hz, 1H), 2.65 (d, J=11.0 Hz, 1H), 2.25 (s,
3H), 2.0–2.25 (m, 1H), 1.99–1.64 (m, 6H), 1.50–1.58 (m,
1H), 1.47–1.31 (m, 2H), 1.26 (dd, J=12.5, 5.5 Hz, 1H);
13C NMR (125 MHz, CDCl3): d=168.05, 141.12, 137.76,
127.35, 124.77, 124.66, 117.77, 102.01, 68.82, 64.97, 58.21,
48.90, 43.92, 39.63, 37.11, 34.73, 33.09, 26.45, 25.37, 23.35,
21.06; HR-MS (ESI): m/z=339.2064, exact mass calculated
for [M+H]+ (C21H26N2O2): 339.2067.
Alcohol 12
To a mixture of Ph3PCH2OCH3Cl (548 mg, 1.6 mmol) in dry
THF (10 mL) at ꢁ308C under nitrogen was added KHMDS
(1.6 mL, 1M in THF) dropwise. After the mixture had ben
stirred for 30 min at the same temperature, 11 (661 mg,
1.6 mmol) in dry THF (10 mL) was added slowly. The reac-
tion mixture was gradually warmed up to 08C, and saturate
NH4Cl (5 mL) was added. The resulting mixture was diluted
with ethyl acetate (20 mL), washed with water, brine, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was dissolved in Me2CO (10 mL) and p-TsOH
(10 mg) was added in one portion. The reaction mixture was
stirred at room temperature for 12 h and then neutralized
with saturated NaHCO3 (5 mL), diluted with ethyl acetate,
washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was dissolved in dry
ether (20 mL), and LiALH4 (61 mg, 1.6 mmol) was added in
(ꢀ)-1-Methylaspidospermidine (2)
To a mixture of Ph3PCH3Br (47 mg, 0.13 mmol) in dry THF
(2 mL) at ꢁ308C was added KHMDS (0.26 mL, 1M in
THF) dropwise. After this mixture had been stirred for
30 min at the same temperature, 11 dissolved in dry THF
(2 mL) was added dropwise. The reaction mixture was grad-
ually warmed up to 08C, and saturated NH4Cl (5 mL) was
added. The resulting mixture was diluted with ethyl acetate
(20 mL), washed with water, brine, dried over Na2SO4, and
Adv. Synth. Catal. 2014, 356, 340 – 346
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
345

COMMUNICATIONS
Jian Jin und Fayang G. Qiu
concentrated under reduced pressure. The residue was dis-
[2] H. Auterhoff, Arch. Pharm. 1968, 301, 956–956.
solved in dry ether (20 mL), and LiALH4 (3.4 mg,
0.09 mmol) was added in one portion. The mixture was
stirred at room temperature for 4 h and then quenched with
saturated aqueous Na2SO4, diluted with ethyl acetate,
washed with water, brine, and concentrated under reduced
pressure. The residue was dissolved in MeOH (5 mL) before
Pd/C (10 mg), formaldehyde (0.01 mL, 37% in water) were
added. The mixture was stirred under H2 for 30 min. HCl
(3M, 0.2 mL) was then added to the mixture, which was
stirred for another 1 hour and filtered. The filtrate was dilut-
ed with DCM (10 mL), washed with saturated NaHCO3,
dried over Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by using column chromatog-
raphy (ethyl acetate/hexane, 1/10 to 1/5) to give 2 as a white
[3] A. Walser, C. Djerassi, Helv. Chim. Acta 1965, 48, 391–
404.
[4] A.-C. Mitaine, K. Mesbah, B. Richard, C. Petermann,
S. Arrazola, C. Moretti, M. Zꢄches-Hanrot, L. Le Men-
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[8] K. C. Guꢅrard, A. Guꢅrinot, C. Bouchard-Aubin, M.-
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1
solid; yield: 5.6 mg (31% over 3 steps). H NMR (400 MHz,
CDCl3): d=7.06 (t, J=7.6 Hz, 1H), 7.01 (d, J=7.4 Hz, 1H),
6.63 (t, J=7.4 Hz, 1H), 6.37 (d, J=7.7 Hz, 1H), 3.41 (d, J=
4.5 Hz, 1H), 3.23–2.96 (m, 2H), 2.74 (s, 3H), 2.39–2.13 (m,
3H), 2.01–1.81 (m, 2H), 1.80–1.36 (m, 7H), 1.35–1.03 (m,
3H), 0.94–0.78 (m, 1H), 0.60 (t, J=7.3 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=150.55, 136.87, 127.21, 122.14, 117.09,
106.38, 71.75, 71.23, 53.83, 53.02, 52.59, 39.12, 35.50, 34.50,
[9] S. H. Tan, M. G. Banwell, A. C. Willis, T. A. Reekie,
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1
31.46, 30.07, 22.95, 21.99, 21.80, 6.79. The H and 13C data
for synthetic (ꢀ)-1-methylaspidospermidine (2) were consis-
tent with those reported.[7a] HR-MS (ESI): m/z=297.2323,
exact mass calculated for [M+H]+ (C20H29N2): 297.2325.
Acknowledgements
[13] F. He, Y. Bo, J. D. Altom, E. Corey, J. Am. Chem. Soc.
1999, 121, 6771–6772.
This work was supported by the National Natural Science
Foundation of China (Grant # 21072191).
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346
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 340 – 346