Total synthesis of (±)-gusanlung D

Article abstract of DOI:10.1016/j.tet.2008.01.119

A new approach to the core structure of protoberberine alkaloid was described. Total synthesis of (±)-gusanlung D (2) was reported.

Full text of DOI:10.1016/j.tet.2008.01.119

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3483e3487
www.elsevier.com/locate/tet
Total synthesis of (ꢀ)-gusanlung D
*
Jung-Kai Chang, Nein-Chen Chang
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
Received 14 January 2008; received in revised form 31 January 2008; accepted 31 January 2008
Available online 3 February 2008
Abstract
A new approach to the core structure of protoberberine alkaloid was described. Total synthesis of (ꢀ)-gusanlung D (2) was reported.
Ó 2008 Elsevier Ltd. All rights reserved.
OH
1. Introduction
MeO
R2
R1
O
R3
R4
R3
R4
Polycyclic nitrogen containing heterocycles form the basic
skeleton of various alkaloids and physiologically active
drugs.1,2 Protoberberines are naturally occurring tetracyclic
isoquinoline alkaloids. The BischlereNapieralski process,3
PicteteSpengler sequence,4 and PomeranzeFritsch reaction5
were the major approaches for the synthesis of protoberberine
ring system 1 (Fig. 1).6 (ꢁ)-Gusanlung D isolated from
Acangelisia gusanlung H.S. Lo, by Zhang et al.7 in 1995 is
the first optically active natural protoberberine alkaloid unoxy-
genated at ring D. A number of elegant approaches to (ꢀ)-
gusanlung D (2) have been reported.8e11
N
N
Me
O
N
Bn
O
PG
O
O
Isoquinolinone 4
Oxyisoterihanine 5
3
skeleton
Figure 2. The application of 2-pyridones 3 to oxyisoterihanine 5 and isoquino-
linone 4.
investigated. In contrast to the existing synthetic approaches
for 1, ring D was built up in the last stage. Total synthesis
of (ꢀ)-gusanlung D was also reported.
Recently, we developed a new approach to isoquinolinone
skeleton 4 from 2-pyridones 3 and further applied to the syn-
thesis of oxyisoterihanine 5 (Fig. 2).12 To extend these results,
a new route to the core structure of protoberberine was
2. Results and discussion
2.1. Retrosynthesis of (ꢀ)-gusanlung D (2)
O
A
B
N
C
O
N
Our strategy for the synthesis of (ꢀ)-gusanlung D (2) was
shown in Scheme 1. The core structure of 2 was envisaged
to arise from tricyclic pyridone derivative 6. Pyridone 6 was
anticipated to derive from [3þ3] annulation adduct 7.
O
D
Protoberberine (1)
Gusanlung D (2)
ring system
2.2. Preparation of a key intermediate, tricyclic pyridone
derivative 6
Figure 1. The core structure of protoberberine alkaloids.
As shown in Scheme 2, glutarimide 7 was easily prepared
via stepwise [3þ3] annulation13 of a-sulfonyl acetamide 8
* Corresponding author.
E-mail address: ncchang@mail.nsysu.edu.tw (N.-C. Chang).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.119

3484
J.-K. Chang, N.-C. Chang / Tetrahedron 64 (2008) 3483e3487
O
O
O
O
O
O
A
B
O
N
C
O
N
O
MgBr
N
O
Br
NaH, THF
90%
N
N
O
O
Ts
THF
94%
D
Ts
Ts
6
12
Gusanlung D (2)
6
O
O
O
O
O
O
O
O
OMe
[ 3+3 ]
O
1) RCM, CH2Cl2, r.t.
A
N
O
O
N
C
O
HN
O
O
2) t-BuOK, t-BuOH
Ts
reflux
Ts
Ts
89% for two steps
7
8
9
14
13
Scheme 1. Retrosynthesis of (ꢀ)-gusanlung D (2).
O
O
with methyl acrylate 9. Regioselective reduction of C6 car-
bonyl in 7 provided hydroxylactam 10.14 Without purification,
10 was converted to tricyclic product 11 in the presence of
BF3$OEt2. Bromination and dehydrobromination of 11 with
NBS and excessive amount of sodium methoxide furnished
an a,b-unsaturated lactam, which was then further oxidized
with DDQ15 to yield the corresponding tricyclic pyridone 6.
N
O
Pd/C, HCO2NH4
MeOH, reflux
61%
Gusanlung D (2)
Scheme 3. Completion of the total synthesis of (ꢀ)-gusanlung D (2).
3. Conclusion
2.3. Total synthesis of (ꢀ)-gusanlung D (2)
In summary, we have developed a new route to the tetracyclic
protoberberine ring system. The characteristic feature of this ap-
proach is the construction of ring D at the final stage. By chang-
ing the substituents on allyl group, this process has the potential
to produce protoberberine derivatives with various substituents
on ring D. The application of this method to the synthesis of pro-
toberberine alkaloids corytenchirine and ophiocarpine is cur-
rently underway in our laboratory and will be reported in future.
With the key intermediate 6 in hand, we then focused our at-
tention on the construction of ring D in (ꢀ)-gusanlung D (2)
(Scheme 3). Treatment of 6 with allylmagnesium bromide pro-
vided 1,4-addition adduct 12,16 which was further allylated with
sodium hydride and allyl bromide to produce the diallyl enlac-
tam 13.16 Performing RCM reaction on 13 with first generation
Grubbs catalyst followed by dehydrosulfonation produced pro-
toberberine derivative 14. Presumably, after sequential RCM
reaction and dehydrosulfonation of 13, a spontaneous oxidation
arises to form 14. Finally, protoberberine derivative 14 was
treated with HCO2NH4 in the presence of PdeC in MeOH,17
and the desired reduced adduct (ꢀ)-gusanlung D (2) was ob-
tained in 61% yield. The spectral data of 2 were in agreement
with those reported in the literature.7e11
4. Experimental
4.1. General
Melting points were determined with melting point appara-
tus and are uncorrected. 1H NMR and 13C NMR were recorded
O
O
O
OMe
O
N
O
[ 3+3 ]
NaH, THF
HN
O
O
O
6
Ts
Ts
93%
9
8
7
O
O
O
O
NaH, LAH
THF
BF3 OEt2
N
O
HO
N
O
CH2Cl2
-10 °C
83% for two steps
Ts
Ts
11
10
O
O
1) NBS. NaOMe
2) DDQ
N
O
81%
Ts
6
Scheme 2. Synthesis of tricyclic pyridone 6.

J.-K. Chang, N.-C. Chang / Tetrahedron 64 (2008) 3483e3487
3485
on Varian VRX 500 spectrometer. NMR spectra were recorded
in CDCl3 (1H at 500 MHz and 13C at 125 MHz), and chemical
shifts are expressed in parts per million (d) relative to internal
Me4Si.
Tetrahydrofuran was distilled prior to use. All other re-
agents and solvents were obtained from commercial sources
and were used without any further purification. Reactions
were routinely carried out under an atmosphere of dry nitrogen
with magnetic stirring. Solutions of products in organic
solvents were dried with anhydrous magnesium sulfate before
concentration under vacuum.
dry dichloromethane (20 mL) was treated with BF3$OEt2
(0.5 mL, 3.6 mmol) at ꢁ10 ꢃC. After 15 h, the resulting mix-
ture was diluted with saturated aqueous NaHCO3 and
extracted with dichloromethane (2ꢂ20 mL). The combined or-
ganic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and evaporated. Purification on silica gel
(n-hexane/ethyl acetate¼2:1e1:1) produced 11 (1.2 g, 83%
for two steps), which was recrystallized from n-hexane/ethyl
1
acetate as a white solid. H NMR (500 MHz, CDCl3): d 7.85
(d, J¼8.5 Hz, 2H), 7.35 (d, J¼8.5 Hz, 2H), 6.64 (s, 1H), 6.56 (s,
1H), 5.92 (s, 2H), 4.68 (dd, J¼4.0, 10.5 Hz, 1H), 4.61 (dt,
J¼4.0, 12.5 Hz, 1H), 4.04 (t, J¼8.5 Hz, 1H), 2.90e2.85 (m,
1H), 2.78e2.72 (m, 1H), 2.65e2.49 (m, 4H), 2.44 (s, 3H),
1.74e1.66 (m, 1H); 13C NMR (125 MHz, CDCl3) d 161.5,
146.6, 146.5, 144.6, 136.7, 129.4 (2C), 129.1 (2C), 129.0, 128.2,
108.6, 105.0, 101.1, 65.5, 56.5, 40.5, 29.3, 28.6, 21.7, 19.9; IR
(CHCl3, cmꢁ1): 1632; HRMS (ESI) calcd for C21H22NO5S
(Mþþ1) 400.1219, found 400.1220; mp: 89.4e91.3 ꢃC.
4.2. Preparation of a key intermediate, tricyclic pyridone
derivative 6
4.2.1. 1-(2-Benzo[1,3]dioxol-5-yl-ethyl)-3-(4-toluene-
sulfonyl)piperidine-2,6-dione (7)
A solution of a-toluenesulfonyl acetamide 8 (5.0 g,
13.8 mmol) in dry THF (100 mL) was added to a rapidly
stirred suspension of sodium hydride (1.7 g, 41.4 mmol,
60%) in dry THF (20 mL). After the reaction mixture was
stirred at room temperature for 30 min, a solution of a,b-un-
saturated ester 9 (1.3 g, 15.2 mmol) in dry THF (80 mL) was
slowly added over 4 h. The resulting mixture was stirred for
another 4 h, quenched with saturated ammonium chloride so-
lution (25 mL) in an ice bath, and concentrated under reduced
pressure. The residue was diluted with water (25 mL) and
extracted with ethyl acetate (3ꢂ70 mL). The combined or-
ganic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and evaporated. Purification on silica gel
(n-hexane/ethyl acetate¼4:1e2:1) produced glutarimide 7
(5.35 g, 93%) as a colorless oil. 1H NMR (500 MHz,
CDCl3) d 7.75 (d, J¼8.0 Hz, 2H), 7.40 (d, J¼8.0 Hz, 2H),
6.73e6.72 (m, 1H), 6.71 (s, 1H), 6.66e6.64 (m, 1H), 5.92
(s, 2H), 4.08 (t, J¼4.0 Hz, 1H), 3.95 (t, J¼7.0 Hz, 2H),
3.24e3.17 (m, 1H), 2.79e2.69 (m, 4H), 2.48 (s, 3H), 2.34e
2.27 (m, 1H); 13C NMR (125 MHz, CDCl3) d 170.5, 164.8,
147.6, 146.1, 145.8, 134.9, 131.9, 129.9 (2C), 129.0 (2C),
121.8, 109.4, 108.2, 100.8, 65.6, 41.6, 33.4, 29.2, 21.8, 17.8;
IR (CHCl3, cmꢁ1): 1728, 1677; HRMS (ESI, Mþþ1) calcd
for C21H22NO6S 416.1168, found 416.1166.
4.2.3. 3-(4-Toluenesulfonyl)-6,7-dihydro[1,3]dioxolo[4,5-g]-
pyrido[2,1-a]isoquinolin-4-one (6)
To a solution of 11 (1.2 g, 3.0 mmol) in CH3CN (30 mL) was
added sequentially sodium methoxide (340 mg, 6.3 mmol) and
N-bromosuccinimide (590 mg, 3.3 mmol). The resulting mix-
ture was stirred for 6 h at that temperature. The reaction mixture
was filtered and the organic solvents were removed under re-
duced pressure. The residue was diluted with water (30 mL)
and extracted with ethyl acetate (3ꢂ50 mL). The combined or-
ganic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and evaporated. Without further purification,
the solution of the residue in toluene (40 mL) was added DDQ
(1.0 g, 4.5 mmol). The resulting mixture was refluxed for 1
day. After removal of the precipitates by filtration, a large
amount of 5% NaOH was added to the filtrate and the mixture
was extracted with dichloromethane (3ꢂ50 mL). The combined
organic layers were washed with 5% NaOH, dried over anhy-
drous MgSO4, filtered, and evaporated. Purification on silica
gel (dichloromethane/methanol¼200:1e100:1) produced pyri-
done derivative 6 (960 mg, 81% for two steps) as a yellow solid.
1H NMR (500 MHz, CDCl3): d 8.38 (d, J¼8.0 Hz, 1H), 8.02 (d,
J¼8.0 Hz, 2H), 7.31 (d, J¼8.0 Hz, 2H), 7.17 (s, 1H), 6.72 (s,
1H), 6.63 (d, J¼8.0 Hz, 1H), 6.05 (s, 2H), 4.18 (t, J¼6.5 Hz,
2H), 2.84 (t, J¼6.5 Hz, 2H), 2.41 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 157.1, 150.9, 149.5, 147.8, 144.0,
141.6, 137.1, 132.1, 129.2 (2C), 129.0 (2C), 126.4, 121.6,
108.1, 105.8, 102.0, 100.7, 39.2, 27.5, 21.6; IR (CHCl3,
cmꢁ1): 1656; HRMS (ESI) calcd for C21H18NO5S (Mþþ1)
396.0906, found 396.0907; mp: 181.1e182.8 ꢃC. Anal. Calcd
for C21H17NO5S: C, 63.79; H, 4.33; N, 3.54. Found: C, 63.78;
H, 4.24; N, 3.61.
4.2.2. 3-(4-Toluenesulfonyl)-1,2,3,6,7,12b-hexahydro-[1,3]-
dioxolo[4,5-g]pyrido[2,1-a]isoquinolin-4-one (11)
A solution of glutarimides 7 (1.5 g, 3.6 mmol) in dry THF
(60 mL) was added to a rapidly stirred suspension of sodium
hydride (220 mg, 5.4 mmol, 60%) in dry THF (10 mL). After
the reaction mixture was stirred at room temperature for
15 min, lithium aluminum hydride (160 mg, 4.0 mmol) was
slowly added in an ice bath. After the reaction mixture was
stirred for 2 h, quenched with saturated ammonium chloride
solution (10 mL) at the same temperature, filtered and then
concentrated under reduced pressure. The residue was diluted
with water (40 mL) and extracted with ethyl acetate
(3ꢂ60 mL). The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and evaporated.
Without purification, a solution of above crude product in
4.3. Total synthesis of (ꢀ)-gusanlung D (2)
4.3.1. 2-Allyl-3-(4-toluenesulfonyl)-2,3,6,7-tetrahydro-[1,3]-
dioxolo[4,5-g]pyrido[2,1-a]isoquinolin-4-one (12)
To a solution of 6 (560 mg, 1.4 mmol) in dry THF (15 mL)
was added allylmagnesium bromide (2.8 mmol) in one portion

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J.-K. Chang, N.-C. Chang / Tetrahedron 64 (2008) 3483e3487
by syringe. The resulting mixture was stirred at room temper-
ature for 1.5 h. After the reaction was accomplished (moni-
tored by TLC), the reaction mixture was quenched with
water (15 mL) and filtered through Celite. The mixture was
extracted with ethyl acetate (3ꢂ20 mL) and dried with anhy-
drous MgSO4, filtered, and concentrated. The crude product
was purified by silica gel chromatography (n-hexane/ethyl
acetate¼4:1e2:1) produced 12 (582 mg, 94%) as a yellow
residue in t-BuOH (25 mL) was added t-BuOK (130 mg,
1.1 mmol) and then heated to reflux for 24 h. The organic sol-
vent was evaporated under reduced pressure and the residue
was extracted with water (15 mL) and ethyl acetate
(3ꢂ20 mL). The combined organic layer was dried with anhy-
drous MgSO4, filtered, and concentrated. The crude product
was purified by silica gel chromatography (n-hexane/ethyl
acetate¼4:1e2:1) to afford protoberberine derivative 14
(194 mg, 89% for two steps) as a white solid. 1H NMR
(500 MHz, CDCl3): d 8.42 (d, J¼8.0 Hz, 1H), 7.63 (t,
J¼7.0 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H), 7.44 (t, J¼7.0 Hz,
1H), 7.27 (s, 1H), 6.85 (s, 1H), 6.73 (s, 1H), 6.03 (s, 2H),
4.35 (t, J¼6.0 Hz, 2H), 2.92 (t, J¼6.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d 162.1, 148.7, 147.4, 137.4, 136.7,
132.3, 130.3, 127.9, 126.3, 126.0, 124.6, 123.7, 108.0,
105.1, 101.9, 101.5, 39.7, 28.6; IR (CHCl3, cmꢁ1): 1650;
HRMS (ESI) calcd for C18H14NO3 (Mþþ1) 292.0974, found
292.0973; mp: 183.1e184.5 ꢃC. Anal. Calcd for C18H13NO3:
C, 74.22; H, 4.50; N, 4.81. Found: C, 74.21; H, 4.54; N, 4.72.
1
oil. H NMR (500 MHz, CDCl3): d 7.69 (d, J¼8.0 Hz, 2H),
7.18 (d, J¼8.0 Hz, 2H), 6.79 (s, 1H), 6.53 (s, 1H), 5.95 (d,
J¼8.5 Hz, 2H), 5.74e5.66 (m, 1H), 5.45 (d, J¼7.0 Hz, 1H),
5.13e5.07 (m, 2H), 4.04e4.00 (m, 2H), 3.57e3.51 (m, 1H),
3.39 (m, 1H), 2.65e2.60 (m, 2H), 2.34e2.30 (m, 1H), 2.30
(s, 3H), 2.14e2.08 (m, 1H); 13C NMR (125 MHz, CDCl3):
d 160.4, 147.9, 146.9, 145.1, 135.4, 134.1, 133.3, 129.3
(2C), 129.0 (2C), 128.6, 122.8, 119.1, 107.6, 104.3, 101.9,
101.2, 70.3, 39.2, 38.3, 31.9, 28.6, 21.5; IR (CHCl3, cmꢁ1):
1645; HRMS (ESI) calcd for C24H24NO5S (Mþþ1)
438.1375, found 438.1376.
4.3.2. 2,3-Diallyl-3-(4-toluenesulfonyl)-2,3,6,7-tetrahydro-
[1,3]dioxolo[4,5-g]pyrido[2,1-a]isoquinolin-4-one (13)
4.3.4. 5,6,13,13a-Tetrahydro[1,3]dioxolo[4,5-g]isoquino-
[3,2-a]isoquinolin-8-one (2)
A solution of 12 (581 mg, 1.3 mmol) in dry THF (15 mL)
was added to a rapidly stirred suspension of sodium hydride
(100 mg, 2.7 mmol, 60%) in dry THF (5 mL). After the reac-
tion mixture was stirred at room temperature for 15 min, allyl
bromide (0.23 mL, 2.7 mmol) was added. The resulting mix-
ture was stirred for 12 h, quenched with water (3 mL), and
concentrated under reduced pressure. The residue was diluted
with water (10 mL) and extracted with ethyl acetate
(3ꢂ20 mL). The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and evaporated.
Purification on silica gel (n-hexane/ethyl acetate¼4:1e2:1)
produced 13 (570 mg, 90%) as a yellow oil. 1H NMR
(500 MHz, CDCl3): d 7.63 (d, J¼8.0 Hz, 2H), 7.14 (d,
J¼8.0 Hz, 2H), 6.80 (s, 1H), 6.53 (s, 1H), 5.94 (d,
J¼6.0 Hz, 2H), 5.78e5.70 (m, 1H), 5.66e5.57 (m, 1H),
5.42 (d, J¼3.5 Hz, 1H), 5.27e5.22 (m, 2H), 5.19e5.14 (m,
2H), 4.07e4.03 (m, 1H), 3.55e3.50 (m, 1H), 3.35 (dd,
J¼5.0, 14.0 Hz, 1H), 3.12e3.08 (m, 1H), 2.86e2.77 (m,
3H), 2.73e2.62 (m, 2H), 2.28 (s, 3H); 13C NMR (125 MHz,
CDCl3): d 163.5, 147.7, 146.8, 144.8, 136.1, 135.8, 133.2,
131.9, 129.7 (2C), 129.1 (2C), 128.1, 122.9, 120.5, 117.7,
107.6, 104.3, 104.1, 101.2, 73.3, 39.9, 36.0, 34.1, 32.3, 28.6,
21.5; IR (CHCl3, cmꢁ1): 1647; HRMS (ESI) calcd for
C27H28NO5S (Mþþ1) 478.1689, found 478.1687.
A suspension of 14 (194 mg, 0.67 mmol) and PdeC (10%,
10 mg) in methanol (20 mL) was vigorously stirred and a solu-
tion of HCO2NH4 (423 mg, 6.7 mmol) in distilled water
(3 mL) was slowly added. The reaction mixture was refluxed
for 5 h with stirring and then filtered on Celite. Water
(20 mL) was added and the mixture extracted with dichloro-
methane (3ꢂ30 mL). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered,
and evaporated. Purification on silica gel (n-hexane/ethyl
acetate¼4:1e2:1) gave gusanlung D (2) (119 mg, 61%) as
a white solid. 1H NMR (500 MHz, CDCl3): d 8.14 (d,
J¼8.0 Hz, 1H), 7.34e7.45 (m, 2H), 7.25 (d, J¼8.0 Hz, 1H),
6.73 (s, 1H), 6.67 (s, 1H), 6.03 (s, 2H), 4.95e5.01 (m, 1H),
4.82e4.90 (m, 1H), 3.08e3.15 (m, 1H), 2.91e2.99 (m, 3H),
2.84e2.89 (m, 1H); 13C NMR (125 MHz, CDCl3): d 162.2,
146.7, 146.5, 137.2, 131.8, 129.0, 128.8, 128.6, 128.5,
127.3, 126.8, 108.6, 105.8, 101.1, 55.3, 38.7, 38.2, 29.6; IR
(CHCl3, cmꢁ1): 1640; HRMS (ESI) calcd for C18H16NO3
(Mþþ1) 294.1131, found 294.1129; mp: 175.9e177.6 ꢃC.
Acknowledgements
The authors would like to thank the National Science Coun-
cil of the Republic of China for financial support.
4.3.3. 5,6-Dihydro[1,3]dioxolo[4,5-g]isoquino[3,2-a]-
isoquinolin-8-one (14)
Supplementary data
Diallyl compound 13 (360 mg, 0.75 mmol) in dry dichloro-
methane (50 mL) was added to 1st generation Grubbs catalyst
[(C6H11)3P]2Cl2RuC2H3Ph (62 mg, 0.075 mmol, 10 mol %),
and the mixture was allowed to react for 12 h at room temper-
ature. After the reaction was finished (monitored by TLC), the
mixture was quenched with water (20 mL) and extracted with
dichloromethane (2ꢂ30 mL) and dried with anhydrous
MgSO4, filtered, and concentrated. To the solution of the
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.01.119.
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