An easy ABD→ABCD strategy to indolo[2,3-a]quinolizin-4-one. Synthesis of deplancheine and yohimbane

Article abstract of DOI:10.1016/j.tet.2004.11.005

The efficient synthesis of indolo[2,3-a]quinolizin-4-ones 2 is described in two steps via formal [3+3] cycloaddition reaction of α-sulfonyl tryptaminylacetamide 4 with various α,β-unsaturated esters 5 and the regioselective reduction of the resulting glut

Full text of DOI:10.1016/j.tet.2004.11.005

Tetrahedron 61 (2005) 585–591
An easy ABD/ABCD strategy to indolo[2,3-a]quinolizin-4-one.
Synthesis of deplancheine and yohimbane
b
b
b
Meng-Yang Chang,a, Chung-Yi Chen, Wen-Shang Chung, Min-Ruei Tasi
*
and Nein-Chen Changb,
*
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan, ROC
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC
Received 26 September 2004; revised 3 November 2004; accepted 4 November 2004
Available online 23 November 2004
Abstract—The efficient synthesis of indolo[2,3-a]quinolizin-4-ones 2 is described in two steps via formal [3C3] cycloaddition reaction of
a-sulfonyl tryptaminylacetamide 4 with various a,b-unsaturated esters 5 and the regioselective reduction of the resulting glutarimides 3 with
sodium borohydride then sequent further dehydrated cyclization in the presence of boron trifluoride etherate. The useful building block is
applied to synthesize deplancheine (1a) and yohimbane (1b).
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
into ene-lactam by the catalytic amount of boron trifluoride
etherate solution. This approach has been successfully
employed in the synthesis of 8a-epi-dendroprimine6a and 3-
PPP.7a Here, applications of this methodology have been
realized in the synthesis of indolo[2,3-a]quinolizine alka-
loid family with potential biological activities.
The development of synthetic methodology for constructing
the tetracyclic indolo[2,3-a]quinolizin-4-one type alkaloids
has attracted much attention1,2 for several decades because
of their important pharmacological properties.3 Recently,
we developed a facile methodology to produce a wide
variety of a-sulfonyl piperidine-2,6-diones (glutarimides)
by formal [3C3] cycloaddition reaction.4 We also explored
the application of these various glutarimides to different
clinical drugs and natural products.5–7 In the synthetic field
of piperidine-2,6-dione, the regioselective reduction of
asymmetrically substituted piperidine-2,6-dione to their
corresponding hydroxypiperidinone8–10 is an important
course to the formation of N-acyliminium ions.
In continuing the previous investigations and building upon
these observations on the chemistry of a-sulfonyl piperidine-
2,6-dione, we envisaged that a rapid entry into tetracyclic
indolo[2,3-a]quinolizin-4-one skeleton could be achieved
based on the formal [3C3] cycloaddition reaction between
a-sulfonyl tryptaminylacetamide and various a,b-unsaturated
esters, and the regioselective reduction of the resulting
piperidine-2,6-diones with sodium borohydride, followed by
further dehydration with the catalytic amount of boron
trifluoride etherate. Thus, the tetracyclic indolo[2,3-a]quino-
lizin-4-one system could be assembled in a key step by
Bischler–Napieralski cyclization to establish the C ring and
obtained as a single diastereomer in which the substituents at
C3 and C14 and C14 and C15 are trans to each other (Fig. 1).
However, it is difficult to generate specific N-acyliminium
ions from imide systems.1 Thus, it is important to select
appropriate piperidine-2,6-diones with a-sulfonyl group
that features higher selectivity in reduction. To solve the
imide reduction, we have developed the regioselective reduc-
tion with sodium borohydride to the various a-sulfonyl
piperidine-2,6-diones derived from the formal [3C3]
cycloaddition reaction under the milder condition (4–
7 8C). The resulting hydrolactam was sequent dehydrated
Keywords: Indolo[2,3-a]quinolizin-4-one; Formal [3C3] cycloaddition
reaction; Regioselective reduction; Deplancheine; Yohimbane.
* Corresponding authors. Tel.: C886 7 5919464; fax: C886 7 5919348
(M.-Y.C.); tel.: C886 7 5252000x3913; fax: C886 7 5253913 (N.-C.C.);
e-mail addresses: mychang@nuk.edu.tw; ncchang@mail.nsysu.edu.tw
Figure 1. Structural characteristics of deplancheine (1a) and yohimbane
(1b).
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.005

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M.-Y. Chang et al. / Tetrahedron 61 (2005) 585–591
Here, we also demonstrate the three-step technique toward
synthesis of deplancheine and yohimbane based on the
tetracyclic indolo[2,3-a]quinolizin-4-one skeleton.
acid sodium salt to give a-sulfonyl tryptaminylacetamide 4.
Compound 4 was deprotonated with sodium hydride to
produce the dianion intermediate. The dianion of 4 was
reacted with different a,b-unsaturated ester 5 to yield the
various piperidine-2,6-dione 3 with different substitent in an
efficient procedure.
2. Results and discussion
2.1. Retrosynthetic approach to indolo[2,3-a]quinolizin-
4-one 2
In the next step, the piperidine-2,6-dione 3 was treated with
sodium borohydride followed by dehydration with boron
trifluoride etherate yielded the indolo[2,3-a]quinolizin-4-
one 2. According to related reports,12 regioselective
reduction with sodium borohydride was effected by the
a-substituted group at glutarimide ring. In our case,
chelation between a-sufonyl and adjacent carbonyl group
position of piperidine-2,6-dione 3 was induced by sodium
borohydride to produce the regioselective 6-hydroxy
piperidinone at 4–7 8C. The 6-hydroxy piperidinone was
dehydrated and intramolecularly cyclized with boron
trifluoride etherate to give 2 as a sole product. The two
steps from 3 to 2 gave 62–85% overall yield. Some
representative results are shown in Table 1.
We describe the stepwise reduction leading to tetracyclic
indolo[2,3-a]quinolizin-4-one 2 as illustrated in Scheme 1.
Table 1. The substitutents and yields of piperidine-2,6-diones 3 and
indolo[2,3-a]quinolizin-4-ones 2
Entry
Compound 2, R1, R2
R1ZH, R2ZH
R1ZH, R2ZCH3
R1ZH, R2ZCH2CH2CH2CH2–OH
R1ZH, R2ZCH2CH2CH2CH2–OBn 3d, 90
R1ZH, R2ZCH2CH2CH2CH2–OMs 3e, 56
R1ZH, R2ZCH(OCH3)2
R1ZH, R2ZCO2Et
R1ZCH3, R2ZH
3 (%)
2 (%)
1
2
3
4
5
6
7
8
9
10
3a, 72
3b, 84
3c, 80
2a, 74
2b, 81
2c, 82
2d, 85
2e, 69
2f, 81
2g, 62
2h, 80
2i, 84
2j, 78
Scheme 1. Retrosynthetic study of tetracyclic indolo[2,3-a]quinolizin-4-
one 2.
There are two remarkable steps for the synthesis of
compound 2. One is the rapid access to produce a wide
variety of a-sulfonyl piperidine-2,6-dione 3 with ABD-ring
by formal [3C3] cycloaddition reaction. The other is the
regioselective reduction of a-sulfonyl piperidine-2,6-dione
3 to a-sulfonyl hydroxypyridinone followed by acidic
dehydration. The approach for ABD/ABCD ring was
achieved by the dehydration and Bischler–Napieralski
cyclization under the acidic condition.
3f, 67
3g, 66
3h, 82
3i, 78
3j, 72
R1ZH, R2ZC6H5
R1Z(E)-ethylidene, R2ZH
The stereochemistry of 3j was established by X-ray
analysis.13 Reduction of the 2f to yield 6, fortunately, the
structure of 6 could be determined by single-crystal X-ray
analysis (Diagram 1).13 The relative stereochemical
relationship of three contiguous chiral centers on 6 can be
2.2. Three-step synthesis of indolo[2,3-a]quinolizin-4-one
2 from 4
The synthesis of indolo[2,3-a]quinolizin-4-one began from
the piperidine-2,6-diones 3 which were the cycloadducts of
formal [3C3] cycloaddition reaction as shown in Scheme 2.
Tryptamine was treated with chloroacetyl chloride and
triethylamine to produce a-chloro tryptaminylacetamide.
The chloro compound was treated with p-toluenesulfinic
Scheme 2. Synthesis of indolo[2,3-a]quinolizin-4-one 2.
Diagram 1. X-ray crystallography of 6.

M.-Y. Chang et al. / Tetrahedron 61 (2005) 585–591
587
confirmed as the trans orientation to each other. By the one-
pot intramolecular Bischler–Napieralski cyclization reac-
tion, we provide a rapid entry for constructing C-ring with
three contiguous chiral centers on the tetracyclic indolo[2,3-
a]quinolizin-4-one skeleton.
2.3. Synthesis of deplancheine (1a)
Deplancheine (1a) was isolated from the New Caledonian
plant Alstonia deplanchei van Heurck et Mueller Arg.
(Apocyanaceae) and assigned as the trans configuration on
the basis of an analogy with the majority of indole
alkaloids.14a After its structure elucidation, a number of
total syntheses were reported.14 Both deplancheine
and 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine15
are simple skeleton of indolo[2,3-a]quinolizine alkaloid
family with interesting biological functions. In structural
comparison, two alkaloids have a common characteristic
tetracycle framework comprised indole ABC ring and
their only difference is the exo-olefin substitutent of the
D-ring.
Scheme 4. Synthesis of yohimbane (1b).
3. Conclusion
In summary, a concise synthesis of tetracyclic indolo[2,3-
a]quinolizin-4-one 2 skeleton has been accomplished which
demonstrates the utility of the formal [3C3] cycloaddition
reaction of a-sulfonyl tryptaminylacetamide to provide the
D-ring and regioselective reduction of the resulting
piperidine-2,6-dione then followed by further dehydration
and intramolecular cyclization reaction to establish C-ring.
Syntheses of deplancheine (1a) and yohimbane (1b) are also
described using the methodology. Further applications of
the formal [3C3] cycloaddition reaction toward other
alkaloids will be reported in due course.
Desulfonation of 2j with an excess of sodium amalgam
in methanol yielded the piperidinone. Without further
purification, reduction of the corresponding piperidinone
by lithium aluminum hydride produced the deplancheine
(1a) and its side product 7 in the ratio of 4:1. Under the
condition, the over-reduced product 7 was obtained. We
exchanged the sequence of the two-step to avoid the
problem but a similar result was still obtained. Although
Martin had provided the related reaction conditions to
solve the generated problems,16 we could not obtain the
desired sole 1a by the reported methods and the mixture
of 1a and 7 still was generated (Scheme 3).
4. Experimental
4.1. General
Dichloromethane (DCM) and tetrahydrofuran (THF) were
distilled prior to use. All other reagents and solvents were
obtained from commercial sources and used without further
purification. Reactions were routinely carried out under an
atmosphere of dry nitrogen with magnetic stirring. Products
in organic solvents were dried with anhydrous magnesium
sulfate before concentration in vacuo. All reported melting
temperatures are uncorrected.
Scheme 3. Synthesis of deplancheine (1a).
4.2. Procedure of formal [3C3] cycloaddition reaction
2.4. Synthesis of yohimbane (1b)
A solution of a-sulfonyl tryptaminylacetamide 4 (357 mg,
1.0 mmol) in THF (30 mL) was added to a rapidly stirred
suspension of sodium hydride (132 mg, 3.3 mmol, 60%) in
THF (40 mL). After the reaction mixture was stirred at rt for
15 min, a solution of a,b-unsaturated ester 5 (1.2 mmol) in
THF (10 mL) was added. The resulting mixture was
refluxed for 30 min, quenched with saturated ammonium
chloride solution (2 mL) in an ice bath, and concentrated
under reduced pressure. The residue was diluted with water
(10 mL) and extracted with ethyl acetate (3!20 mL). The
combined organic layers were washed with brine (2!
20 mL), dried over anhydrous magnesium sulfate, filtered
and evaporated. Purification on silica gel (hexane/ethyl
acetateZ4/1–2/1) produced glutarimides 3a–j in 56–90%
yield.5–7
Yohimbane (1b), allo-yohimbane, pseudo-yohimbane, and
3-epi-allo-yohimbane are simple skeleton of Rauwolfia
alkaloid family.17 The family possesses a wide range of
biological activities and has been served as an important
pharmacological tool. The interesting biological functions
have induced many attempts to synthesize these compounds
with pentacyclic ring system.18
We choose 2e as the starting material for synthesizing 1b as
shown in Scheme 4. Desulfonation of 2e with an excess of
6% sodium amalgam in methanol yielded the resulting
piperidinone 8. According to the Hua’s method, treatment of
8 with lithium diisopropylamide was furnished completely
to 9 via intramolecular alkylation.18s

588
M.-Y. Chang et al. / Tetrahedron 61 (2005) 585–591
4.3. Procedure of regioselective reduction [NaBH4] and
acidic dehydration [BF3-OEt2]
C23H24N2O3S: C, 67.62; H, 5.92; N, 6.86. Found: C,
67.66; H, 6.03; N, 7.02.
A solution of 3 (1.0 mmol) in a co-solvent of THF (10 mL)
and methanol (5 mL) was stirred at 4–7 8C. Sodium
borohydride (110 mg, 3.0 mmol) was added at 4–7 8C.
The mixture was stirred for 2 h at that temperature. Satur-
ated sodium bicarbonate solution (1 mL) was added to the
mixture and concentrated under reduced pressure. The resi-
due was diluted with water (5 mL) and extracted with DCM
(3!10 mL). The combined organic layers were washed
with brine (2!10 mL), dried over anhydrous magnesium
sulfate, filtered and evaporated. Without further purifi-
cation, the crude hydroxy-lactam was dissolved in DCM
(10 mL), and a catalytic amount of boron trifluoride etherate
(0.1 mL) and anhydrous magnesium sulfate (0.5 g) were
added. The mixture was stirred for 5 h at rt. Saturated
sodium bicarbonate solution (5 mL) was added to the
resulting mixture and concentrated under reduced pressure.
The residue was diluted with water (5 mL) and extracted
with DCM (3!10 mL). The combined organic layers were
washed with brine (2!10 mL), dried over anhydrous
magnesium sulfate, filtered and evaporated. Purification
on silica gel (hexane/ethyl acetateZ4/1–2/1) produced
tetracycles 2a–j in 62–85% yield.
4.3.3. 1-(4-Methylphenyl)sulfonyl-2-(4-hydroxy)butyl-
2,3,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-4-
one (2c). MpO230 8C (decomp.); IR (CHCl3) 3430,
1635 cmK1; EI-MS: C26H30N2O4S m/z (%)Z91 (100),
237 (54), 310 (8), 466 (MC, 1); HRMS (ESI, MCC1) calcd
for C26H31N2O4S 467.2004, found 467.2006; 1H NMR
(500 MHz, CDCl3) d 9.61 (br s, 1H), 7.86 (d, JZ8.5 Hz,
2H), 7.54 (d, JZ8.0 Hz, 1H), 7.47 (d, JZ8.0 Hz, 1H), 7.46
(d, JZ8.5 Hz, 2H), 7.26 (td, JZ1.0, 8.0 Hz, 1H), 7.16 (dd,
JZ1.0, 8.0 Hz, 1H), 5.50 (d, JZ6.5 Hz, 1H), 5.14 (ddd, JZ
1.5, 4.5, 11.5 Hz, 1H), 3.47 (d, JZ6.0 Hz, 1H), 3.28–3.18
(m, 2H), 2.97–2.84 (m, 3H), 2.80–2.73 (m, 1H), 2.51 (s,
3H), 2.38 (dt, JZ1.5, 16.0 Hz, 1H), 2.20–2.15 (m, 1H),
1.42–1.26 (m, 4H), 1.16–1.09 (m, 1H), 1.02–0.86 (m, 2H);
13C NMR (125 MHz, CDCl3) d 170.13, 146.45, 136.39,
132.78, 131.44, 130.50 (2!), 128.97 (2!), 126.22, 122.61,
119.86, 118.41, 111.60, 110.55, 69.50, 49.26, 44.27, 40.20,
34.40, 33.16, 32.65, 31.40, 23.66, 21.78, 20.53; Anal. Calcd
for C26H30N2O4S: C, 66.93; H, 6.48; N, 6.00. Found: C,
67.33; H, 6.54; N, 5.83.
4.3.4. 1-(4-Methylphenyl)sulfonyl-2-(4-benzoyloxy)butyl-
2,3,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-4-
one (2d). Mp 141–142 8C; IR (CHCl3) 3250, 1630 cmK1
;
4.3.1. 1-(4-Methylphenyl)sulfonyl-1,2,3,4,6,7,12,12b-
octahydro-1H-indolo[2,3-a]quinolizin-4-one (2a). Mp
258–260 8C; IR (CHCl3) 3240, 1610 cmK1; ESI-MS:
C22H22N2O3S m/z (%)Z58 (48), 136 (50), 149 (88), 238
(72), 391 (57), 395 (MCC1, 100); HRMS (ESI, MCC1)
calcd for C22H23N2O3S 395.1431, found 395.1436; 1H
NMR (400 MHz, CDCl3) d 9.75 (br s, 1H), 7.87 (d, JZ
8.3 Hz, 2H), 7.48 (d, JZ7.8 Hz, 1H), 7.44 (d, JZ8.2 Hz,
2H), 7.42 (d, JZ8.4 Hz, 1H), 7.21 (t, JZ8.0 Hz, 1H), 7.11
(t, JZ7.8 Hz, 1H), 5.39 (d, JZ8.3 Hz, 1H), 4.95 (dd, JZ
4.8, 13.2 Hz, 1H), 3.67–3.62 (m, 1H), 3.03–2.90 (m, 2H),
2.75–2.70 (m, 1H), 2.57 (dt, JZ4.5, 17.2 Hz, 1H), 2.49 (s,
3H), 2.20–2.12 (m, 1H), 2.07–1.97 (m, 1H), 1.95–1.88 (m,
1H); 13C NMR (100 MHz, CDCl3) d 169.32, 146.44,
136.11, 132.46, 131.49, 130.46 (2!), 129.29, 129.12,
126.47, 122.61, 119.85, 118.45, 111.65, 111.03, 64.32,
52.18, 42.75, 30.08, 22.10, 21.78, 20.56; Anal. Calcd for
C22H22N2O3S: C, 66.98; H, 5.62; N, 7.10. Found: C, 66.72;
H, 5.66; N, 7.31.
FAB-MS: C33H36N2O4S m/z (%)Z91 (100), 136 (66), 154
(61), 237 (52), 309 (14), 401 (4), 557 (MCC1, 7); HRMS
(ESI, MCC1) calcd for C33H37N2O4S 557.2474, found
1
557.2470; H NMR (400 MHz, CDCl3) d 9.56 (br s, 1H),
7.82 (d, JZ8.4 Hz, 2H), 7.52 (d, JZ7.8 Hz, 1H), 7.44 (d,
JZ8.3 Hz, 1H), 7.39 (d, JZ8.4 Hz, 1H), 7.36–7.12 (m, 7H),
5.47 (d, JZ6.5 Hz, 1H), 5.12 (dt, JZ2.9, 12.7 Hz, 1H), 4.31
(s, 2H), 3.46 (d, JZ6.5 Hz, 1H), 3.16 (t, JZ6.3 Hz, 2H),
2.91 (td, JZ3.6, 12.1 Hz, 1H), 2.84–2.74 (m, 3H), 2.44 (s,
3H), 2.36 (d, JZ15.6 Hz, 1H), 2.15–2.13 (m, 1H), 1.28–
1.07 (m, 4H), 0.94–0.89 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 170.20, 146.25, 138.37, 136.45, 132.97, 131.58,
130.45, 130.41, 130.12, 129.01 (2!), 128.36 (2!), 127.58,
127.56, 126.33, 122.59, 119.86, 118.45, 111.62, 110.54,
72.92, 69.61, 68.64, 49.36, 40.28, 34.24, 33.76, 32.67,
28.89, 23.04, 21.75, 20.57; Anal. Calcd for C33H35N2O4S:
C, 71.19; H, 6.52; N, 5.03. Found: C, 71.33; H, 6.82; N,
5.44.
4.3.5. 1-(4-Methylphenyl)sulfonyl-2-(4-methylsulfonyl)-
butyl-2,3,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quino-
lizin-4-one (2e). Mp 211–212 8C; IR (CHCl3) 3230,
1640 cmK1; FAB-MS: C27H32N2O6S2 m/z (%)Z136 (60),
154 (61), 237 (100), 389 (9), 545 (MCC1, 19); HRMS
(ESI, MCC1) calcd for C27H33N2O6S2 545.1780, found
4.3.2. 1-(4-Methylphenyl)sulfonyl-2-methyl-2,3,6,7,12,12b-
hexahydro-1H-indolo[2,3-a]quinolizin-4-one (2b). MpO
260 8C (decomp.); IR (CHCl3) 3250, 1640 cmK1; EI-MS:
C23H24N2O3S m/z (%)Z91 (100), 237 (52), 252 (23), 408
(MC, 2); HRMS (EI, MC) calcd for C23H24N2O3S
1
1
408.1508, found 408.1505; H NMR (500 MHz, CDCl3) d
545.1781; H NMR (500 MHz, CDCl3) d 9.58 (br s, 1H),
9.55 (br s, 1H), 7.88 (d, JZ8.5 Hz, 2H), 7.53 (d, JZ7.5 Hz,
1H), 7.45 (d, JZ8.5 Hz, 3H), 7.24 (td, JZ1.0, 7.5 Hz, 1H),
7.16 (dd, JZ1.0, 7.5 Hz, 1H), 5.50 (d, JZ6.0 Hz, 1H), 5.16
(dt, JZ3.0, 12.5 Hz, 1H), 3.53 (d, JZ6.0 Hz, 1H), 2.97–
2.92 (m, 1H), 2.87–2.81 (m, 3H), 2.50 (s, 3H), 2.41–2.35
(m, 1H), 2.27 (ddd, JZ1.5, 3.5, 16.0 Hz, 1H), 0.90 (d, JZ
7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 169.82, 146.10,
136.29, 132.95, 131.54, 130.39 (2!), 128.80 (2!), 126.24,
122.45, 119.75, 118.31, 111.47, 110.37, 69.52, 49.59, 40.50,
35.72, 27.48, 21.67, 20.63, 20.48; Anal. Calcd for
7.87 (d, JZ8.0 Hz, 2H), 7.53 (d, JZ7.5 Hz, 1H), 7.47 (d,
JZ8.0 Hz, 3H), 7.25 (td, JZ1.0, 8.0 Hz, 1H), 7.15 (dd, JZ
1.0, 8.0 Hz, 1H), 5.50 (d, JZ6.0 Hz, 1H), 5.14 (ddd, JZ1.5,
4.5, 12.5 Hz, 1H), 3.93 (t, JZ6.5 Hz, 2H), 3.51 (d, JZ
6.5 Hz, 1H), 2.97–2.75 (m, 4H), 2.84 (s, 3H), 2.51 (s, 3H),
2.37 (dt, JZ2.0, 15.5 Hz, 1H), 1.39–1.26 (m, 4H), 1.16–
1.09 (m, 1H), 1.00–0.90 (m, 2H); 13C NMR (125 MHz,
CDCl3) d 169.89, 146.47, 136.36, 132.65, 131.39, 130.52
(2!), 128.89 (2!), 126.19, 122.54, 119.80, 118.34,
111.60, 110.43, 69.00, 68.13, 49.33, 40.26, 37.07, 34.17,

M.-Y. Chang et al. / Tetrahedron 61 (2005) 585–591
589
1
33.21, 32.54, 28.18, 22.25, 21.72, 20.48; Anal. Calcd for
C27H32N2O6S2: C, 59.54; H, 5.92; N, 5.14. Found: C, 58.96;
H, 6.31; N, 4.70.
470.1664, found 470.1662; H NMR (500 MHz, CDCl3) d
9.56 (br s, 1H), 7.79 (d, JZ8.0 Hz, 2H), 7.55 (d, JZ8.0 Hz,
1H), 7.47 (d, JZ8.0 Hz, 1H), 7.36 (d, JZ8.0 Hz, 2H), 7.26
(td, JZ1.0, 8.0 Hz, 1H), 7.17 (dd, JZ1.0, 8.0 Hz, 1H),
7.07–7.03 (m, 3H), 6.79–6.77 (m, 2H), 5.65 (d, JZ7.0 Hz,
1H), 5.11 (ddd, JZ1.5, 6.0, 12.5 Hz, 1H), 4.14–4.11 (m,
1H), 3.59 (dd, JZ5.0, 8.5 Hz, 1H), 3.05–2.97 (m, 2H),
2.90–2.80 (m, 2H), 2.62 (ddd, JZ1.5, 5.0, 16.5 Hz, 1H),
2.47 (s, 3H); 13C NMR (125 MHz, CDCl3) d 169.61, 146.05,
140.05, 136.50, 133.23, 131.44, 130.38 (2!), 128.83 (2!),
128.73 (2!), 127.25, 126.89 (2!), 126.41, 122.65, 119.89,
118.54, 111.62, 110.29, 68.76, 50.23, 41.02, 38.40, 36.84,
21.73, 20.31; Anal. Calcd for C28H26N2O3S: C, 71.46; H,
5.57; N, 5.95. Found: C, 71.66; H, 5.87; N, 6.33.
4.3.6. 1-(4-Methylphenyl)sulfonyl-2-dimethoxymethyl-
2,3,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-4-
one (2f). Gum; IR (CHCl3) 3330, 1618 cmK1; ESI-MS:
C25H28N2O5S m/z (%)Z75 (100), 237 (30), 468 (MC, 2);
HRMS (ESI, MC) calcd for C25H28N2O5S 468.1719, found
1
468.1719; H NMR (500 MHz, CDCl3) d 9.48 (br s, 1H),
7.86 (d, JZ8.0 Hz, 2H), 7.52 (d, JZ7.5 Hz, 1H), 7.46–7.42
(m, 3H), 7.24 (t, JZ8.0 Hz, 1H), 7.14 (t, JZ8.0 Hz, 1H),
5.50 (d, JZ6.0 Hz, 1H), 5.16–5.12 (m, 1H), 3.99 (d, JZ
7.5 Hz, 1H), 3.95 (d, JZ6.0 Hz, 1H), 3.08 (s, 3H), 2.95–
2.89 (m, 1H), 2.85–2.76 (m, 3H), 2.79 (s, 3H), 2.54 (d, JZ
16.5 Hz, 1H), 2.48 (s, 3H), 2.41–2.38 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 169.64, 164.11, 136.35, 132.70,
131.22, 130.29 (2!), 129.16 (2!), 126.32, 122.40,
119.68, 118.37, 111.48, 110.67, 104.31, 64.03, 55.29,
53.54, 49.49, 40.53, 36.38, 30.59, 21.73, 20.54.
4.3.10.
3-Ethylidene-1-(4-methylphenyl)sulfonyl-
2,3,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-4-
one (2j). MpO260 8C (decomp.); s: C24H24N2O3S m/z
(%)Z91 (100), 169 (30), 249 (33), 264 (61), 420 (MC, 5);
HRMS (EI, MC) calcd for C24H24N2O3S 420.1508, found
1
420.1504; H NMR (500 MHz, CDCl3) d 9.80 (br s, 1H),
7.91 (d, JZ8.5 Hz, 2H), 7.49 (d, JZ8.0 Hz, 1H), 7.48 (d,
JZ8.5 Hz, 2H), 7.41 (d, JZ8.0 Hz, 1H), 7.21 (td, JZ1.0,
8.0 Hz, 1H), 7.12 (td, JZ1.0, 8.0 Hz, 1H), 6.78 (qd, JZ1.5,
7.0 Hz, 1H), 5.38 (d, JZ8.5 Hz, 1H), 4.89 (dd, JZ4.5,
12.5 Hz, 1H), 3.74–3.69 (m, 1H), 3.13–3.06 (m, 1H), 3.01
(td, JZ3.5, 12.0 Hz, 1H), 2.82 (dd, JZ4.5, 13.5 Hz, 1H),
2.72 (d, JZ13.5 Hz, 1H), 2.53 (s, 3H), 2.51–2.45 (m, 1H),
1.60 (dd, JZ1.5, 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 165.25, 146.39, 135.92, 135.04, 132.24, 131.52, 130.36
(2!), 129.33 (2!), 126.41, 125.63, 122.46, 119.68,
118.38, 111.53, 111.05, 63.47, 52.59, 43.65, 24.07, 21.76,
20.37, 13.51; Anal. Calcd for C24H24N2O3S: C, 68.55; H,
5.75; N, 6.66. Found: C, 68.37; H, 5.47; N, 6.83.
4.3.7. 1-(4-Methylphenyl)sulfonyl-2-ethoxycarbonyl-
2,3,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-4-
one (2g). Gum; IR (CHCl3) 3345, 2531 cmK1; ESI-MS:
C25H26N2O5S m/z (%)Z236 (100), 310 (41), 466 (MC, 11);
HRMS (ESI, MC) calcd for C25H26N2O5S 466.1562, found
1
466.1557; H NMR (500 MHz, CDCl3) d 9.17 (br s, 1H),
7.88 (d, JZ8.0 Hz, 2H), 7.51 (d, JZ8.0 Hz, 1H), 7.47 (d,
JZ8.0 Hz, 2H), 7.43 (d, JZ8.0 Hz, 1H), 7.23 (t, JZ7.5 Hz,
1H), 7.14 (t, JZ7.5 Hz, 1H), 5.32 (d, JZ8.0 Hz, 1H), 4.54
(dd, JZ5.0, 13.0 Hz, 1H), 4.03–3.99 (m, 1H), 3.97 (q, JZ
7.0 Hz, 2H), 3.20–3.16 (m, 1H), 3.11–3.05 (m, 1H), 2.90–
2.83 (m, 2H), 2.62 (dd, JZ3.5, 13.5 Hz, 1H), 2.52 (s, 3H),
2.04 (dd, JZ5.5, 13.5 Hz, 1H), 1.09 (t, JZ7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 170.26, 169.26, 146.69, 136.21,
132.99, 130.69 (2!), 130.02, 129.44, 129.21 (2!), 126.54,
122.61, 119.76, 118.57, 111.47, 109.24, 67.46, 60.85, 52.21,
41.02, 38.43, 32.09, 21.81, 20.75.
4.4. Reduction of compound 2f
Lithium aluminum hydride (20 mg, 0.5 mmol) was added to
a solution of 2f (94 mg, 0.2 mmol) in THF (10 mL) at 0 8C.
The mixture was stirred for 2 h at rt, quenched with
saturated ammonium chloride solution (1 mL) under cool-
ing, and then concentrated. The residue was diluted with
water (15 mL) and extracted with ethyl acetate (3!30 mL).
The organic layer was washed with brine and water, dried,
filtered and concentrated to produce crude compound.
Purification on silica gel (hexane/ethyl acetateZ2/1–1/1)
produced 6 (56 mg, 62%).
4.3.8. 1-(4-Methylphenyl)sulfonyl-3-methyl-2,3,6,7,12,12b-
hexahydro-1H-indolo[2,3-a]quinolizin-4-one (2h). Mp 183–
184 8C; IR (CHCl3) 3230, 1630 cmK1; EI-MS: C23H24N2O3S
m/z (%)Z130 (74), 143 (100), 267 (4), 408 (MC, 1); HRMS
(EI, MC) calcd for C23H24N2O3S 408.1508, found
1
408.1507; H NMR (500 MHz, CDCl3) d 9.71 (br s, 1H),
7.88 (d, JZ8.0 Hz, 2H), 7.52 (d, JZ7.5 Hz, 1H), 7.46 (d,
JZ8.0 Hz, 2H), 7.45 (d, JZ7.5 Hz, 1H), 7.24 (td, JZ1.0,
8.0 Hz, 1H), 7.15 (dd, JZ1.0, 8.0 Hz, 1H), 5.41 (d, JZ
8.0 Hz, 1H), 5.02–4.99 (m, 1H), 3.81 (dd, JZ7.5, 14.0 Hz,
1H), 2.96–2.87 (m, 2H), 2.78–2.69 (m, 2H), 2.51 (s, 3H),
2.10–2.08 (m, 1H), 1.80–1.75 (m, 1H), 1.07 (d, JZ7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 173.38, 146.29,
136.15, 132.51, 131.29, 130.41 (2!), 129.12 (2!),
126.33, 122.47, 119.71, 118.36, 111.55, 110.82, 62.46,
51.05, 42.02, 33.06, 28.75, 21.72, 20.48, 15.92; Anal. Calcd
for C23H24N2O3S: C, 67.62; H, 5.92; N, 6.86. Found: C,
67.87; H, 6.22; N, 6.99.
4.4.1. 1-(4-Methylphenyl)sulfonyl-2-dimethoxymethyl-
2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizidine (6).
1H NMR (300 MHz, CDCl3) d 9.48 (br s, 1H), 7.85 (d, JZ
9.0 Hz, 1H), 7.48 (d, JZ6.0 Hz, 2H), 7.41–7.36 (m, 3H),
7.20–7.07 (m, 2H), 4.60 (br d, JZ8.4 Hz, 1H), 4.41 (br s,
1H), 3.81 (br d, JZ6.3 Hz, 1H), 3.16 (s, 3H), 3.09–2.54 (m,
6H), 2.88 (s, 3H), 2.45 (s, 3H), 2.21–2.05 (m, 2H), 1.87–
1.84 (m, 1H) Single-crystal X-ray diagram:13 crystal of 6
was grown by slow diffusion of ethyl acetate into a solution
of 6 in dichloromethane to yield orange prisms. The
compound crystallizes in the monoclinic crystal system,
4.3.9. 1-(4-Methylphenyl)sulfonyl-2-phenyl-2,3,6,7,12,12b-
hexahydro-1H-indolo[2,3-a]quinolizin-4-one (2i). MpO
260 8C (decomp.); IR (CHCl3) 3240, 1645 cmK1; EI-MS:
C28H26N2O3S m/z (%)Z91 (100), 169 (25), 223 (11), 314
(10), 470 (MC, 1); HRMS (EI, MC) calcd for C28H26N2O3S
˚
˚
space group. P21/n(#14), aZ13.701 (2)A, bZ9.718 (3)A,
3
˚
˚
cZ17.823 (3)A, bZ100.81 (1)8, VZ2330.8 (8) A , ZZ4,
dcalcdZ1.295 mg/m3, F(000)Z968.00, 2g range 20 (8.7–
14.08), RZ0.116.

590
M.-Y. Chang et al. / Tetrahedron 61 (2005) 585–591
4.5. Reduction of compound 2j
HRMS (EI, MC) calcd for C20H26N2O4S 390.1613, found
390.1616; H NMR (400 MHz, CDCl3) d 8.02 (br s, 1H),
1
Sodium amalgam (Na/Hg, 300 mg) was added to a stirred
solution of 2j (210 mg, 0.5 mmol) in methanol (15 mL), and
vigorously stirred for 2 h at rt The residue was filtered and
washed with methanol (2!10 mL). The combined organic
layers were concentrated to obtain the crude products.
Without further purification, lithium aluminum hydride
(20 mg, 0.5 mmol) was added to a solution of the resulting
compound in THF (10 mL) at 0 8C. The mixture was stirred
for 2 h at rt, quenched with saturated ammonium chloride
solution (1 mL) under cooling, and then concentrated. The
residue was diluted with water (15 mL) and extracted with
ethyl acetate (3!30 mL). The organic layer was washed
with brine and water, dried, filtered and concentrated to
produce crude compound. The crude products were slowly
recrystallized sequentially from the mixture by the solvent
system of hexane and ethyl acetate (v/vZ1/3–1/1) to yield
1a (50 mg, 40%) and 7 (13 mg, 10%).
7.48 (d, JZ7.8 Hz, 1H), 7.33 (d, JZ7.8 Hz, 1H), 7.20–7.09
(m, 2H), 5.15–5.12 (m, 1H), 4.81–4.78 (m, 1H), 4.28–4.22
(m, 1H), 4.27 (t, JZ6.0 Hz, 2H), 3.00 (s, 3H), 3.04–2.77 (m,
4H), 2.56–2.49 (m, 1H), 2.12–2.05 (m, 1H), 1.81–1.75 (m,
1H), 1.56–1.38 (m, 6H). The 8 (40 mg, 0.1 mmol), dissolved
in dried THF (5 mL), was added a solution of lithium
diisopropylamide (LDA) which was generated in situ from
diisopropylamine (200 mg, 2.0 mmol) in dried THF
(10 mL) and n-butyllithium (1.6 M, 1 mL, 1.6 mmol) at
K78 8C. After storage of this mixture for 30 min, acetic
acid (0.5 mL) in THF (5 mL) was added. The reaction
mixture was stirred at K78 8C for an additional 5 min, and
the reaction was quenched with saturated aqueous sodium
bicarbonate (15 mL). The liquid layers were separated, and
aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried,
and concentrated. The residue was chromatographed on
silica gel (ethyl acetate/methanolZ20/1) produced 9
1
(18 mg, 60%). The H NMR data was in accordance with
the reported in the literature.
4.5.1. (E)-3-Ethylidene-1,2,3,4,6,7,12,12b-octahydro
indolo[2,3-a]quinolizidine (1a), (deplancheine).10,11 EI-
MS: C17H20N2 m/z (%)Z108 (100), 143 (25), 158 (16), 252
(MC, 34); HRMS (EI, MC) calcd for C17H20N2 252.1621,
1
found 252.1622; H NMR (500 MHz, CDCl3) d 7.83 (br s,
5. Supplementary Material
1H), 7.47 (d, JZ7.0 Hz, 1H), 7.29 (d, JZ7.5 Hz, 1H), 7.14–
7.08 (m, 2H), 5.38 (br d, JZ3.5 Hz, 1H), 3.29 (br d, JZ
12.0 Hz, 1H), 3.16 (br d, JZ12.0 Hz, 1H), 3.07–3.03 (m,
2H), 2.99–2.91 (m, 3H), 2.70 (dd, JZ6.0, 16.0 Hz, 1H),
2.59 (br s, 1H), 2.39 (t, JZ11.0 Hz, 1H), 2.32–2.27 (m, 1H),
1.61 (d, JZ6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d
136.31, 134.49, 134.32, 128.82, 121.05, 119.29, 117.54,
114.93, 112.72, 110.42, 63.87, 63.61, 55.51, 36.48, 35.03,
Additional spectroscopic data for compounds 3a–j, 2a–j, 6,
7, 8, 1a (1H NMR in CDCl3) were supported.
Acknowledgements
The authors would like to thank the National Science
Council (NSC 93-2113-390-004) of the Republic of China
for financial support.
1
24.55, 14.39. The H NMR spectral data of 1a were in
accordance with those reported in the literature.
4.5.2. Trans-3-ethyl-1,2,3,4,6,7,12,12b-octahydroin-
dolo[2,3-a]quinolizidine (7).14j EI-MS: C17H22N2 m/z
(%)Z118 (29), 169 (63), 225 (19), 253 (100), 254 (MC,
76); HRMS (EI, MC) calcd for C17H22N2 254.1778, found
254.1779; 1H NMR (500 MHz, CDCl3) d 7.4 (br s, 1H), 7.48
(d, JZ7.5 Hz, 1H), 7.29 (d, JZ8.0 Hz, 1H), 7.13 (t, JZ
7.0 Hz, 1H), 7.09 (t, JZ7.0 Hz, 1H), 3.15 (d, JZ11.5 Hz,
1H), 3.12–3.00 (m, 3H), 2.73 (dd, JZ4.5 Hz, 1H), 2.63 (td,
JZ4.5 Hz, 11.5 Hz, 1H), 2.09 (dq, JZ3.0, 13.0 Hz, 1H),
2.02 (t, JZ11.5 Hz, 1H), 1.94 (d, JZ12.0 Hz, 1H), 1.71–
1.64 (m, 1H), 1.58 (q, JZ11.0 Hz, 1H), 1.32–1.23 (m, 2H),
1.12–1.04 (m, 1H), 0.95 (t, JZ7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 135.99, 135.00, 127.36, 121.20,
119.27, 118.05, 110.73, 107.96, 61.70, 60.25, 53.44,
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2004.11.
005
References and notes
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