Stereoselective synthesis of tetrahydroisoquinoline alkaloids: (-)-trolline, (+)-crispin A, (+)-oleracein e

Article abstract of DOI:10.1016/j.tet.2011.09.033

Tetrahydroisoquinoline alkaloids, (S)-(-)-trolline, (R)-(+)-crispin A, and (R)-(+)-oleracein E, have been synthesized stereoselectively from the both enantiomers of common intermediate (S)-4 and (R)-4. The key step in the synthesis include a stereoselecti

Full text of DOI:10.1016/j.tet.2011.09.033

Tetrahedron 67 (2011) 8648e8653
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Tetrahedron
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Stereoselective synthesis of tetrahydroisoquinoline alkaloids: (ꢀ)-trolline,
(þ)-crispin A, (þ)-oleracein E
*
Nobuyuki Kawai , Mika Matsuda, Jun’ichi Uenishi
Kyoto Pharmaceutical University, Misasagi Yamashina, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Tetrahydroisoquinoline alkaloids, (S)-(ꢀ)-trolline, (R)-(þ)-crispin A, and (R)-(þ)-oleracein E, have been
synthesized stereoselectively from the both enantiomers of common intermediate (S)-4 and (R)-4. The
key step in the synthesis include a stereoselective Bi(OTf)3-catalyzed intramolecular 1,3-chirality transfer
reaction of chiral non-racemic amino allylic alcohols (S)-6 and (R)-6 to construct both enantiomers of (E)-
1-propenyl tetrahydroisoquinoline 4.
Received 1 September 2011
Received in revised form 10 September 2011
Accepted 13 September 2011
Available online 16 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydroisoquinoline alkaloids
(S)-(ꢀ)-Trolline
(R)-(þ)-Crispin A
(R)-(þ)-Oleracein E
Bi(OTf)3-Catalyzed cyclization
1,3-Chirality transfer reaction
1. Introduction
HO
HO
HO
HO
MeO
MeO
N
N
N
Tetrahydroisoquinoline alkaloids, having a stereocenter at the
C-1 carbon, exist widely in nature and are compounds of extensive
interest due to their biological and pharmacological properties.1
Representative tetrahydroisoquinoline alkaloids, such as (S)-
(ꢀ)-trolline (1), (R)-(þ)-crispine A (2), (R)-(þ)-oleracein E (3),
shown in Fig. 1, have the tricyclic hydropyrrolo[2,1-a]isoquinoline
core structure with (R) and (S) configurations at the stereocenter.
(ꢀ)-Trolline,2 isolated from the flowers of Trollius chinensis, exhibits
antibacterial activity against respiratory bacteria, such as Staphy-
lococcus aureus, Staphylcoccus pneumonia, and Klesiella pneumoniae,
as well as antiviral activity against influenza viruses A and B.
(þ)-Crispine A shows significant cytotoxic activity against SKOV3,
KB, and HeLa human cancer lines.3 (þ)-Oleracein E (3),4 the anti-
pode of (ꢀ)-trolline, was isolated from Portulaca oleracea L and
exhibits DPPH-radical scavenging activity. Accordingly, significant
attention has been focused on the development of a general syn-
thetic approach to obtaining these alkaloids. Although several
asymmetric synthetic strategies have already been reported for the
preparation of the tricyclic hydropyrrolo[2,1-a]isoquinoline core of
the alkaloids,5e7 including the elegant strategy utilizing the ally-
lation of cyclic imines,6e,f the development of a stereoselective
synthetic methodology for producing both enantiomers of the al-
kaloids remains an extremely important.
O
O
H
H
H
(S)-(–)-Trolline
1
(R)-(+)-Crispine A
2
(R)-(+)-Oleracein E
3
Fig. 1. Tetrahydroisoquinoline alkaloids.
We have developed an intramolecular 1,3-chirality transfer re-
action of the chiral non-racemic-amino allylic alcohol for the syn-
thesis of chiral C-1 substituted tetrahydroisoquinolines.8 The
advantage of intramolecular 1,3-chirality transfer reaction has been
considered as the stereoselective synthesis of both enantiomers from
(S)- and (R)-chiral-amino allylic alcohols. In this paper, we describe
the asymmetric synthesis of the tricyclic tetrahydroisoquinoline al-
kaloids (S)-(ꢀ)-trolline (1), (R)-(þ)-crispine A (2), and (R)-(þ)-oler-
acein E (3) by Bi(OTf)3-catalyzed cyclization via 1,3-chirality transfer.
The retrosynthetic strategy for the synthesis of 1, 2, and 3 is
outlined in Scheme 1. In our previous report, Bi(OTf)3-catalyzed
cyclizations for the oxygen-substituted tetrahydroisoquinoline at
the 6 position afforded a high level of 1,3-chirality transfer by the
replacement of the methoxy group with the pivaloyl ester. There-
fore, the oxygen-functional group at the 6 position of the lactam 4
was selected as the pivaloyl ester. The construction of the tricyclic
system utilizes the RCM reaction or the standard lactam formation
from 5. The key step involves the construction of the chiral 1-
* Corresponding author. E-mail address: kawai@mb.kyoto-phu.ac.jp (N. Kawai).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.033

N. Kawai et al. / Tetrahedron 67 (2011) 8648e8653
8649
propenyl tetrahydroisoquinolines (S)-5 and (R)-5 from (S)-6 and
(R)-6, respectively, by the Bi(OTf)3-catalyzed 1,3-chirality transfer
reaction. The precursors (S)-6 and (R)-6 can be derived by the
SuzukieMiyaura cross coupling of 7 with chiral (E)-alkenyl boro-
nates (S)-8,9a (R)-8,9b which are readily prepared from the corre-
sponding alkyne by the hydroboration.
6
7
PivO
MeO
1, 2 and 3
1
N
O
R
(S)-4 R =
(R)-4 R =
H
H
for 1
for 2, 3
H
N
6
PivO
PivO
Boc
1,3-Chirality Transfer
Cyclization
N
Boc
MeO
7
MeO
1
R
R
(S)-5 R =
(R)-5 R =
H
H
(S)-6 R = OH
(R)-6 R = OH
Scheme 2. Synthesis of precursors (S)-6 and (R)-6.
H
R
N
PivO
MeO
Boc
O
B
O
+
Br
7
(S)-8 R = OTBS
OTBS
(R)-8 R =
Scheme 1. Retrosynthesis of alkaloids.
2. Results and discussion
Scheme 3. Bi(OTf)3-catalyzed cyclization.
The synthesis of 7, shown in Scheme 2, was initiated using the
bromide 9,10 readily prepared from a veratraldehyde in four steps.
Cyanation of 9 with NaCN in DMSO afforded 10 in 82% yield. The
hydroxy group of 10 was protected as the pivaloyl ester 11 in 80%
yield. Reduction of the nitrile with NaBH4 and a catalytic amount of
NiCl2 in MeOH followed by protection of the resultant amine with
Boc2O afforded 7 in 57% yield. The PdCl2(dppf)-catalyzed Suzu-
kieMiyaura cross coupling reaction of 7 and (S)-8 and (R)-8 in
aqueous solution at 80 ꢁC provided the corresponding products in
87% yield. Deprotection of the silyl ether by TBAF in THF at 4 ꢁC
afforded the corresponding alcohols (S)-6 and (R)-6 in 94% yield.11
With amino-alcohols (S)-6 and (R)-6 in hand, Bi(OTf)3-catalyzed
cyclization was executed, as shown in Scheme 3. Treatment ofꢁ(S)-6
formed from the desired product by oxidation, was obtained in 31%
yield instead of 3-pyrroline.12 The additive effect of Ti(OiPr)413 or 1,4-
benzoquinone14 in the reaction did not prevent the oxidation to
ꢀ
with 10 mol % of Bi(OTf)3 in the presence of MS-4 A, at ꢀ15 C, in
CH2Cl2, afforded the desired (E)-1-propenyl tetrahydroisoquinoline
in 79% yield. The optical purity of (S)-5 was determined by chiral
stationary phase HPLC analysis to be (S)/(R)¼94:6 by comparison
with the corresponding racemates, which was prepared by the
same route from racemic boronate 8. In a similar manner, (R)-5 was
obtained with a ratio of (R)/(S)¼93:7.
The initial strategy to construct the pyrrolidinone ring or pyrro-
lidine ring utilized an RCM reaction, as shown in Scheme 4. Depro-
tection of the N-Boc group of (S)-5 with TMSCl and NaI gave the
amine 12 in 91% yield. Conversion of the amine 12 to the acryl amide
under the standard conditions was followed by execution of the RCM
reaction under several conditions employing Grubbs catalysts;
however, no reaction took place. On the other hand, the RCM re-
action of the bis-allyl amine that was prepared from the amine 12
proceeded in the presence of 10 mol % of second generation Grubbs
catalyst in CH2Cl2. However, the pyrrole 14, which might have been
Scheme 4. RCM reaction.

8650
N. Kawai et al. / Tetrahedron 67 (2011) 8648e8653
afford the desired product. The use of other catalysts, such as Hov-
eydaeGrubbs and Schrock catalysts resulted in a non-improvement.
Transformation of the propenyl unit in (S)-5 to the propionate unit,
followed by the formation of lactam (S)-4 was subsequently explored,
as shown in Scheme 5. Oxidative cleavage of the alkenyl bond of (S)-5
with ozone followed by Wittig reaction of the resulting aldehyde with
phosphorane, and hydrogenation gave the saturated ester (S)-15 in
87% yield in two steps. Deprotection of the Boc group by TMSOTf fol-
lowed by treatment with Et3N gave lactam (S)-4 in 82% yield. Mean-
while, lactam (R)-4 was obtained from (R)-5 in the same three steps.
The spectra of synthetic 1 and 2 were in accordance with those
of natural (S)-(ꢀ)-trolline2 and (R)-(þ)-crispine A3, respectively.
The specific rotations of synthetic 1 (½a D25
ꢀ204.1 (c 0.4, MeOH))
ꢂ
and 2 (½a 2D5
þ92.7 (c 0.8, CHCl3)) were in agreement with the data
ꢂ
of natural (ꢀ)-trolline (½a D25
ꢂ
ꢀ197 (c 0.8, MeOH))2 and (þ)-crispine
A (½a 2D5
ꢂ
þ100.4 (c 1.0, CHCl3)),6a respectively.
3. Conclusions
In summary, the total synthesis of (S)-(ꢀ)-trolline (1), (R)-
(þ)-crispine A (2), and (R)-(þ)-oleracein E (3) was achieved from 9
in ten and eleven steps, respectively. The Bi(OTf)3-catalyzed cycli-
zations via 1,3-chirality transfer have been shown to be potentially
useful for the stereoselective synthesis of C-1 substituted tetrahy-
droisoquinoline alkaloids. Synthesis of additional analogs of alka-
loids and their biological tests are currently underway.
1) O3 then PPh3, CH2Cl2
–78 °C to 0 ºC, 15 min
then Ph3P=CHCO2Me
rt, 30 min
PivO
MeO
PivO
MeO
N
N
Boc
Boc
H
H
2) Pd/ C, H2, MeOH
rt, 12 h
CO2Me
(S)-15, (R)-15
4. Experimental section
4.1. General methods
(S)-5, (R)-5
87% (2 steps)
TMSOTf
CH2Cl2
PivO
MeO
All melting points were measured on a Yanaco MP-J3 and are
uncorrected. The infrared spectra were recorded on a JASCO FT/IR-
400. 1H and 13C NMR spectra were recorded on a JEOL JNM-AL 500,
or Varian Inova Unity XL-400, or JEOL JNM-AL 300 spectrometer in
N
O
then Et3N
rt, 42 h
82%
H
(S)-4, (R)-4
parts per million downfield from tetramethylsilane (TMS,
d scale)
Scheme 5. Lactam formation.
with the solvent resonances as internal standards. Optical rotations
were measured on a JASCO P-2200. Chiral HPLC analysis was per-
formed on a JASCO PU-2080 and UV-2075 or Shimazu 6A. Mass
spectrometric was recorded on a JEOL JMS-GC MATE, or JEOL JMS-
SSX 102A QQ. Elemental analyses was recorded on a PerkineElmer
2400 (N241-03) CHN analyzer. All reactions were carried out under
an N2 atmosphere with dry, freshly distilled solvents under anhy-
drous conditions, unless otherwise noted. All reactions were
monitored by thin-layer chromatography carried out on 0.25 mm E.
Merck silica gel plates (60F254) using UV light as visualizing agent
and phosphomolybdic acid and heat as developing agents. Nacalai
silica gel 60 (0.040e0.063 cm) was used for flash column chro-
matography. Preparative thin-layer chromatography (PTLC) sepa-
rations were carried out on self-made 0.3 mm with Wakogel B-5F.
THF was distilled from sodium/benzophenone ketyl. MeCN (ace-
tonitrile), DCM (CH2Cl2) were distilled from calcium hydride. Pyr-
idine and DMSO were distilled from CaH2 under reduced pressure.
All reagents were purchased from Aldrich, TCI, Nacalai, Wako,
Kishida, or Kanto Chemical Co. Ltd.
Finally, deprotection of the pivaroly and methyl groups of (S)-4 by
the treatment with BBr3 in CH2Cl2 was achieved to afford (S)-
(ꢀ)-trolline (1) in 81% yield as shown in Scheme 6. On the other hand,
reduction of (S)-4 with LiAlH4 in THF followed by the methylation of
the resulting catechol with TMSCHN2 provided the antipode of nat-
ural isomer of (R)-(þ)-crispine A, ent-2, in 80% yield in two steps. The
synthesis of (R)-(þ)-crispine A (2), and (R)-(þ)-oleracein E (3) have
been accomplished by the same sequences from (R)-4.
PivO
MeO
HO
HO
BBr3, CH2Cl2
N
N
O
O
rt, 10 min
81%
H
H
1
(S)-4
1) LiAlH4, THF
reflux, 10 min
MeO
MeO
4.1.1. 2-Bromo-5-hydroxy-4-methoxyphenyl-acetonitrile (10)15. To
the stirred solution of NaCN (866 mg, 17.7 mmol) in DMSO (25 ml)
was added the solution of 9 (4.75 g, 16.1 mmol) in DMSO (20 ml) at
room temperature, and the resultant mixture was stirred at the same
temperature for 5 min. The reaction mixture was poured into H2O
and the aqueous layer was extracted with EtOAc. The organic layer
was washed with brine, dried over MgSO4, filtered, and evaporated.
The residue was purified by silica gel column chromatography (15%
EtOAc in hexane) to give 10 (3.2 g, 82%) as a colorless solid. Rf¼0.50
(S)-4
N
2) TMSCHN2, MeOH
rt, 21.5 h
H
ent-2
80% (2 steps)
PivO
MeO
MeO
MeO
1) LiAlH4, THF
N
N
O
(50% EtOAc in hexane); 1H NMR (500 MHz, CDCl3)
(s, 1H), 5.63 (s, 1H), 3.90 (s, 3H), 3.73 (s, 2H).
d 7.07 (s, 1H), 7.04
2) TMSCHN2, MeOH
80% (2 steps)
H
H
2
(R)-4
4.1.2. 2-Bromo-5-(2,2-dimethylpropanoyloxy)-4-methoxy-phenyl-
acetonitrile (11). To the stirred solution of 10 (4.57 g, 18.9 mmol) in
DCM (25 ml) were added pyridine (5.5 ml, 68.0 mmol), DMAP
(230 mg, 1.89 mmol), and pivaloyl chloride (2.8 ml, 22.7 mmol) at
0 ꢁC, and the resultant mixture was stirred at room temperature for
20 h. The reaction mixture was quenched with satd NH4Cl aq and
the aqueous layer was extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, filtered, and evaporated. The
HO
BBr3
(R)-4
N
O
CH2Cl2
81%
HO
H
3
Scheme 6. Completion of the synthesis of alkaloids 1, 2, 3, and ent-2.

N. Kawai et al. / Tetrahedron 67 (2011) 8648e8653
8651
residue was purified by silica gel column chromatography (20%
NMR (125 MHz, CDCl3)
d
176.7,156.0,149.9,139.4,136.3,134.7,128.9,
EtOAc in hexane) to give 11 (4.93 g, 80%) as a colorless solid. Rf¼0.75
126.1,123.9,110.4, 79.5, 68.4, 56.0, 41.3, 39.0, 33.5, 28.4, 27.2, 23.2; IR
(CHCl3, cmꢀ1) 3019, 2979, 1747,1703; EI-MS m/z 421 (Mþ); EI-HRMS
calcd for C23H35NO6 m/z 421.2464, found: 421.2467.
(50% EtOAc in hexane); mp 115e117 ꢁC; 1H NMR (500 MHz, CDCl3)
d
7.17 (s, 1H), 7.15 (s, 1H), 3.81 (s, 3H), 3.76 (s, 2H), 1.36 (s, 9H); 13
C
NMR (125 MHz, CDCl3) d 176.2,151.8, 139.9, 123.8, 121.8, 120.1,116.9,
116.9, 56.3, 39.1, 27.1, 24.0; IR (CHCl3, cmꢀ1) 3022, 2253, 2976, 1753;
EI-MS m/z 325 (Mþ); EI-HRMS calcd for C14H16BrNO3 m/z 325.0313,
found: 325.0309; Anal. Calcd for C14H16BrNO3: C, 51.55; H, 4.94; N,
4.29. Found: C, 51.74; H, 5.12; N, 4.24.
4.1.5. (1S)-(E)-N-Boc-6-(2,2-dimethyl-propanoyl-oxy)-7-meth oxy-
1-(prop-1-enyl)-1,2,3,4-tetrahydro-isoquinoline ((S)-5). To the mix-
ꢀ
ture of Bi(OTf)3 (2.4 mg, 3.73
m
mol) and MS-4 A (31 mg) in DCM
(0.4 ml) was added the solution of (S)-6 (15.7 mg, 0.037 mmol) in
DCM (0.4 ml) at ꢀ15 ꢁC, and the resultant mixture was stirred at
the same temperature for 1 h. The reaction mixture was quenched
with satd NaHCO3 aq and filtered, the aqueous layer was extracted
with EtOAc, and the organic layer was washed with brine, dried
over MgSO4, filtered, and evaporated. The residue was purified by
preparative thin-layer chromatography (20% EtOAc in hexane) to
give (S)-5 (11.8 mg, 79%) as a colorless solid. Mp <30 ꢁC; Rf¼0.50
4.1.3. N-Boc-N-[2-(2-bromo-5-(2,2-dimethylpropanoyloxy)-4-
methoxyphenyl)ethyl]amine (7). To the stirred solution of 11
(120 mg, 0.37 mmol) in MeOH (6.0 ml) were added Boc2O (104 mg,
0.48 mmol), NiCl2$6H2O (4.4 mg, 0.018 mmol), and NaBH4 (95 mg,
2.58 mmol) at 0 ꢁC, and the resultant mixture was stirred at room
temperature for 1 h. The reaction mixture was quenched with satd
NaHCO3 aq and the aqueous layer was extracted with EtOAc. The
organic layer was washed with brine, dried over MgSO4, filtered,
and evaporated. The residue was purified by silica gel column
chromatography (5% Et2O in benzene) to give 7 (89.8 mg, 57%) as
a colorless solid. Rf¼0.43 (10% Et2O in benzene); mp 125e126 ꢁC; 1H
(20% EtOAc in hexane); ½a D20
ꢂ
þ109.0 (c 1.00, CHCl3); 1H NMR
(CDCl3, 500 MHz)
d
6.75 (s, 1H), 6.64 (s, 1H), 5.58 (dd, J¼15.5,
5.5 Hz, 1H), 5.52e5.47 (m, 2H), 4.10 (m, 1H), 3.74 (s, 3H), 3.11 (m,
1H), 2.79 (m, 1H), 2.60 (m, 1H), 1.67 (d, J¼6.0 Hz, 3H), 1.47 (s, 9H),
1.34 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 176.7, 154.4, 149.7, 138.7,
NMR (CDCl3, 500 MHz)
3.68 (s, 3H), 3.24 (td, J¼6.6, 6.6 Hz, 2H), 2.77 (t, J¼6.6 Hz, 2H), 1.34
(s, 9H), 1.25 (s, 9H); 13C NMR (125 MHz, CDCl3)
176.3, 155.8, 150.3,
d
7.01 (s, 1H), 6.78 (s, 1H), 4.56 (br s, 1H),
133.6, 130.6, 127.4, 126.9, 122.5, 111.7, 79.5, 56.3, 55.9, 38.9, 37.0,
28.4, 27.7, 27.1, 17.5; Enantiometric excess: 88%, determined by
HPLC (Daicel Chiralcel OD-H, hexane/isopropanol¼98.75/1.25,
flow rate 0.3 ml/min, T¼20 ꢁC, 254 nm): tS¼20.8 min ((S)-5),
tR¼26.1 min ((R)-5); IR (CHCl3, cmꢀ1) 3019, 2978, 1748, 1683, 1216;
EI-MS m/z 403 (Mþ); EI-HRMS calcd for C23H33NO5 m/z 403.2358,
found: 403.2367; Anal. Calcd for C23H33NO5: C, 68.46; H, 8.24; N,
d
139.4, 130.6, 124.6, 120.7, 116.8, 79.1, 56.2, 40.2, 39.0, 35.4, 28.3, 27.1;
IR (CHCl3, cmꢀ1) 3018, 2978, 2935, 1753, 1706; EI-MS m/z 429 (Mþ);
EI-HRMS calcd for C19H28BrNO5 m/z 429.1150, found: 429.1155;
Anal. Calcd for C19H28BrNO5: C, 53.03; H, 6.56; N, 3.25. Found: C,
53.11; H, 6.29; N, 3.45.
3.47. Found: C, 68.49; H, 8.28; N, 3.51. (R)-5: ½a D20
ꢀ100.0 (c 1.00,
ꢂ
CHCl3).
4.1.4. (3S)-(E)-N-Boc-N-[2-[5-(2,2-dimethyl-propanoyl-oxy)-2-(3-
hydroxybut-1-enyl)-4-methoxy-phenyl]ethyl]amine ((S)-6). To a stir-
red solution of 7 (24 mg, 0.056 mmol) in 1,4-dioxane (1.0 ml) were
added boronate (S)-8 (23 mg, 0.07 mmol), NaHCO3 (14 mg,
0.167 mmol), and H2O (0.5 ml). After the addition of PdCl2(dppf)
4.1.6. (1S)-(E)-6-(2,2-Dimethylpropanoyl)-7-methoxy-1-(prop-1-
enyl)-1,2,3,4-tetrahydro-isoquinoline ((S)-12). To a stirred solution
of (S)-5 (113 mg, 0.28 mmol) in MeCN (5 ml) were added NaI
(84 mg, 0.56 mmol) and TMSCl (70 mL, 0.56 mmol) at room tem-
(2.3 mg, 2.79
m
mol), the mixture was stirred at 80 ꢁC for 2 h. The
perature, and the resultant mixture was stirred at the same tem-
perature for 2 h. The reaction mixture was filtered and the filtrate
was evaporated. The residue was purified by preparative thin-layer
chromatography (10% MeOH in CHCl3) to give (S)-12 (77.0 mg, 91%)
reaction mixture was poured into H2O and the aqueous layer was
extracted with EtOAc. The organic extracts was washed with brine
and dried over MgSO4, filtered, and evaporated. The residue was
purified by preparative thin-layer chromatography (5% EtOAc in
hexane) to give (3S)-(E)-N-Boc-N-[2-[5-(2,2-dimethyl-propanoyl-
oxy)-2-(3-tert-butyl dimethylsilyloxy-but-1-enyl)-4-methoxy-ph-
enyl]ethyl]-amine(26 mg, 87%) as a colorless oil. Rf¼0.63 (20% EtOAc
as a yellow oil. Rf¼0.36 (10% MeOH in CHCl3); ½a D20
þ13.0 (c 0.83,
ꢂ
CHCl3); 1H NMR (500 MHz, CDCl3)
d 6.76 (s, 1H), 6.61 (s, 1H), 5.80
(dq, J¼15.3, 6.4 Hz, 1H), 5.65 (ddd, J¼15.3, 7.5, 1.5 Hz, 1H), 4.68 (d,
J¼7.5 Hz, 1H), 4.51 (br s, 1H), 3.73 (s, 3H), 3.32 (m, 1H), 3.17 (m, 1H),
2.93e2.78 (m, 2H), 1.76 (d, J¼6.4 Hz, 3H), 1.34 (s, 9H); 13C NMR
in hexane); ½a 2D0
ꢂ
ꢀ23.6 (c 1.00, CHCl3); 1H NMR (CDCl3, 500 MHz)
d
6.99 (s, 1H), 6.77 (s, 1H), 6.73 (d, J¼15.5 Hz, 1H), 6.06 (dd, J¼15.5,
(125 MHz, CDCl3) d 176.8, 149.6, 139.4, 132.7, 132.2, 129.7, 125.5,
5.5 Hz, 1H), 4.55 (br s, 1H), 4.49 (qd, J¼5.5, 5.5 Hz, 1H), 3.81 (s, 3H),
3.31e3.21 (m, 2H), 2.83e2.72 (m, 2H),1.43 (s, 9H),1.35(s, 9H),1.31 (d,
J¼6.4 Hz, 3H), 0.93 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR
122.9, 111.4, 58.1, 56.0, 40.0, 39.0, 27.2, 26.6, 17.8; IR (neat, cmꢀ1
)
2969, 1750, 1620, 1509, 1271, 1122; EI-MS m/z 303 (Mþ); EI-HRMS
calcd for C18H25NO3 m/z 303.1834, found: 303.1826.
(125 MHz, CDCl3)
d 176.6, 155.8, 149.8, 139.4, 136.5, 134.5, 128.9,
124.8, 124.1, 110.2, 79.1, 69.3, 56.0, 41.2, 39.0, 32.5, 28.4, 27.2, 25.9,
24.7, 18.3, ꢀ4.6, ꢀ4.7; IR (neat, cmꢀ1) 3399, 2959, 1754, 1714; EI-MS
m/z 535 (Mþ); EI-HRMS calcd for C29H49NO6Si m/z 535.3329, found:
535.3334. To a stirred solution of (3S)-(E)-N-Boc-N-[2-[5-(2,2-
dimethyl-propanoyl-oxy)-2-(3-tert-butyldimethylsilyloxy-but-1-
enyl)-4-methoxy-phenyl]ethyl]amine (26 mg, 0.048 mmol) in THF
(2.6 ml) was added TBAF (0.073 ml, 1.0 M) at 0 ꢁC, and the resultant
mixture was stirred at 4 ꢁC for 4 h. The reaction mixture was
quenched with satd NH4Cl aq and the aqueous layer was extracted
with EtOAc, and the organic layer was washed with brine, dried over
MgSO4, filtered, and evaporated. The residue was purified by silica
gel column chromatography (40% EtOAc in hexane) to give (S)-6
4.1.7. 5,6-Dihydro-8-(2,2-dimethylpropanoyloxy)-9-methoxy pyrrolo
[2,1-a]isoquinoline (14)16. To a stirred solution of (S)-12 (13.4 mg,
0.044 mmol) in MeCN (0.5 ml) were added NaH (1.8 mg,
0.044 mmol, 60% in oil) and 3-bromopropene (4.2 mL, 0.049 mmol)
at room temperature, and the resultant mixture was stirred at 40 ꢁC
for 35 min. The reaction mixture was quenched with satd NH4Cl aq
and the aqueous layer was extracted with the solution (10% MeOH
in EtOAc). The organic layer was washed with brine, dried over
MgSO4, filtered, and evaporated. The residue was purified by pre-
parative thin-layer chromatography (10% EtOAc in hexane) to give
(1S)-(E)-2-allyl-6-(2,2-dimethylpropanoyl)-7-methoxy-1-(prop-1-
enyl)-1,2,3,4-tetrahydro-isoquinoline (12.4 mg, 82%) as a yellow oil.
(19 mg, 94%) as a colorless oil. Rf¼0.48 (50% EtOAc in hexane); ½a D20
ꢂ
Rf¼0.36 (10% EtOAc in hexane); 1H NMR (300 MHz, CDCl3)
d 6.72 (s,
þ6.2 (c 1.00, CHCl3); 1H NMR (CDCl3, 500 MHz)
d
6.97 (s,1H), 6.87 (d,
1H), 6.63 (s, 1H), 5.91 (dddd, J¼17.1, 10.0, 7.2, 5.5 Hz, 1H), 5.65 (dq,
J¼15.3, 6.3 Hz, 1H), 5.47 (ddq, J¼15.3, 8.1, 1.5 Hz, 1H), 5.25e5.11 (m,
2H), 3.97 (d, J¼8.1 Hz, 1H), 3.73 (s, 3H), 3.45 (m, 1H), 3.14e2.96 (m,
2H), 2.88e2.71 (m, 2H), 2.53 (m, 1H), 1.76 (dd, J¼6.3, 1.5 Hz, 3H),
J¼15.7 Hz, 1H), 6.76 (s, 1H), 6.09 (dd, J¼15.7, 5.4 Hz, 1H), 4.77 (br s,
1H), 4.51 (m, 1H), 3.80 (s, 3H), 3.33e3.16 (m, 2H), 3.02 (br s, 1H),
2.79e2.72 (m, 2H),1.43 (s, 9H),1.37 (d, J¼6.4 Hz, 3H),1.35 (s, 9H); 13C

8652
N. Kawai et al. / Tetrahedron 67 (2011) 8648e8653
1.35 (s, 9H). To
dimethylpropan-oyl)-7-methoxy-1-(prop-1-enyl)-1,2,3,4-
a
stirred solution of (1S)-(E)-2-allyl-6-(2,2-
1H), 2.85 (m, 1H), 2.70e2.44 (m, 4H), 1.87 (m, 1H), 1.35 (s, 9H); 13
NMR (100 MHz, CDCl3) 176.8, 173.1, 150.2, 139.4, 135.4, 125.8,
C
d
tetrahydro-isoquinoline (12.4 mg, 0.0361 mmol) in DCM (2 ml) was
added Grubbs catalyst second generation (9.2 mg, 0.011 mmol) at
room temperature, the resultant mixture was stirred at the same
temperature for 22 h. The reaction mixture was filtered and the
filtrate was evaporated. The residue was purified by preparative
thin-layer chromatography (10% EtOAc in hexane) to give 14
(3.3 mg, 31%) as a blue oil. Rf¼0.80 (10% EtOAc in hexane); 1H NMR
123.1, 108.7, 56.7, 56.1, 39.0, 36.9, 31.7, 27.6, 27.6, 27.2; IR (CHCl3,
cmꢀ1) 3018, 1749, 1680, 1510, 1123; EI-MS m/z 317 (Mþ); EI-HRMS
calcd for C18H23NO4 m/z 317.1627, found: 317.1622; Anal. Calcd for
C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C, 67.81; H, 7.21; N,
4.20. (R)-4: ½a 2D0
þ175 (c 1.0, CHCl3).
ꢂ
4.1.10. (S)-Trolline (1) and (R)-oleracein E (3). To a stirred solution
of (S)-4 (31.6 mg, 0.10 mmol) in DCM (2 ml) was added BBr3 (28 L,
(300 MHz, CDCl3)
d
7.07 (s, 1H), 6.83 (s, 1H), 6.67 (dd, J¼2.6, 1.7 Hz,
m
1H), 6.46 (dd, J¼3.7, 1.5 Hz, 1H), 6.21 (dd, J¼3.7, 2.6 Hz, 1H), 4.05 (t,
J¼6.4 Hz, 2H), 3.64 (s, 3H), 2.98 (t, J¼6.4 Hz, 2H), 0.37 (s, 9H); IR
(neat, cmꢀ1) 2972, 1748, 1711, 1505, 1127; EI-MS m/z 299 (Mþ); EI-
HRMS calcd for C18H21NO3 m/z 299.1521, found: 299.1515.
0.30 mmol), and the resultant mixture was stirred at room tem-
perature for 10 min. The reaction mixture was quenched with H2O
and the aqueous layer was extracted with the solution (25% MeOH
in CHCl3). The organic layer was washed with brine, dried over
MgSO4, filtered, and evaporated. The residue was purified by silica
gel column chromatography (5% MeOH in CHCl3) to give 1 (17.6 mg,
4.1.8. (1S)-N-Boc-6-(2,2-dimethylpropanoyloxy)-7-methoxy-1-(3-
methoxy-3-oxopropyl)-1,2,3,4-tetrahydro-isoquinoline ((S)-15). The
stirred solution of (S)-5 (368 mg, 0.912 mmol) in DCM (15 ml) was
bubbled a stream of ozone at ꢀ78 ꢁC for 2 min. N2 gas was bubbled
through the reaction mixture for 5 min, and the reaction mixture
was stirred for 15 min at 0 ꢁC after the addition of PPh3 (915 mg,
2.74 mmol). After the addition of methyl (triphenylphosphor-
anylidene)acetate (957 mg, 3.65 mmol), the resulting mixture was
stirred at room temperature for 30 min the reaction mixture was
quenched with satd NH4Cl aq and the aqueous layer was extracted
with EtOAc. The organic layer was washed with brine, dried over
MgSO4, filtered, and evaporated. The residue was passed through
a short column of silica gel. After the removal of solvent, the residue
dissolved in MeOH (15 ml) and treated with Pd on carbon (40 mg).
The mixture was stirred at room temperature for 12 h under the
atmosphere of H2 gas and diluted with CHCl3, filtrated, then
evaporated. The residue was purified by silica gel column chro-
matography (10% EtOAc in hexane) to give (S)-15 (355 mg, 87% in
two steps) as a colorless solid. Mp 60e66 ꢁC; Rf¼0.23 (10% EtOAc in
81%) as a colorless solid: ½a D20
ꢂ
ꢀ204 (c 0.44, MeOH), lit.,2 ½a D20
ꢀ197
ꢂ
(c 0.8, MeOH); 1H NMR (400 MHz, DMSO-d6)
d 8.80 (br s, 2H), 6.51
(s, 1H), 6.49 (s, 1H), 4.57 (t, J¼7.8 Hz, 1H), 3.95 (m, 1H), 2.91 (m, 1H),
2.63e2.46 (m, 3H), 2.40 (m, 1H), 2.21 (m, 1H), 1.59 (m, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 172.0, 144.2, 144.0, 128.4, 123.7, 115.4, 111.7,
55.6, 36.6, 31.3, 27.4, 27.3; IR (MeOH, cmꢀ1) 3121, 2726, 1666, 1278;
EI-MS m/z 219 (Mþ); EI-HRMS calcd for C12H13NO3 219.0895, found:
219.0891. Compound 3: ½a D20
ꢂ
þ187 (c 0.44, MeOH), lit.,4 ½a D20
þ61.1
ꢂ
(c 0.32, MeOH).
4.1.11. (R)-Crispine A (2) and ent-2. To a stirred solution of 4
(30 mg, 0.095 mmol) in THF (2 ml) was added LiAlH4 (17.9 mg,
0.47 mmol), and the resultant mixture was refluxed for 10 min. The
reaction mixture was quenched with satd Na2SO4 aq and filtered,
the filtrate was evaporated. The residue dissolved in MeOH (2 ml)
and treated with TMSCHN2 (2.2 ml, 0.6 M) at room temperature,
the resultant mixture was stirred at the same temperature for
21.5 h. After the removal of solvent, the residue was purified by
neutral aluminum column chromatography (50% EtOAc in hexane)
hexane); ½a 2D0
ꢂ
þ76.9 (c 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz); the
compound exists as a 1.5:1 mixture of carbamate rotamers; signals
to give 2 (17.7 mg, 80%) as a colorless solid. Mp 53e55 ꢁC; ½a D20
ꢂ
corresponding to the major rotamer:
d
6.74 (s, 2H), 5.06 (m, 1H),
þ92.7 (c 0.86, CHCl3), lit.,6a
½
a 2D0
ꢂ
þ100.4 (c 1.0, CHCl3); 1H NMR
4.20 (m, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.05 (m, 1H), 2.82 (m, 1H),
2.61 (m, 1H), 2.54e2.38 (m, 2H), 2.15e1.97 (m, 2H), 1.46 (s, 9H), 1.35
(s, 9H); representative signals corresponding to the minor rotamer:
(CDCl3, 400 MHz) d 6.60 (s, 1H), 6.56 (s, 1H), 3.84 (s, 3H), 3.84 (s,
3H), 3.42 (t, J¼8.2 Hz, 1H), 3.18 (m, 1H), 3.10e2.98 (m, 2H), 2.73 (m,
1H), 2.63 (m, 1H), 2.56 (m, 1H), 2.31 (m, 1H), 1.99e1.80 (m, 2H), 1.71
d
6.74 (s, 2H), 5.17 (m, 1H), 3.95 (m, 1H), 3.80 (s, 3H), 3.70 (s, 3H),
(m, 1H); 13C NMR (100 MHz, CDCl3)
d 147.3, 147.2, 130.9, 126.2, 111.3,
3.19 (m, 1H), 2.82 (m, 1H), 2.58 (m, 1H), 2.54e2.38 (m, 2H),
108.8, 62.9, 56.0, 55.9, 53.1, 48.3, 30.5, 28.0, 22.2; IR (CHCl3, cmꢀ1
)
2.15e1.97 (m, 2H), 1.46 (s, 9H), 1.35 (s, 9H); 13C NMR (100 MHz,
3019, 2938, 2400, 1611, 1512, 1254; EI-MS m/z 234 (MþþH); EI-
CDCl3); signals corresponding to both rotamers:
d 176.8, 173.6,
HRMS (CIþ) calcd for C14H20NO2 m/z 234.1494, found: 234.1490.
155.1, 154.6, 149.5, 138.8, 135.6, 135.3, 126.6, 126.3, 122.8, 122.6,
111.2, 111.0, 80.1, 79.7, 56.0, 53.9, 53.3, 51.5, 39.0, 38.1, 36.3, 31.4,
31.0, 30.6, 28.3, 27.6, 27.3, 27.1; IR (CHCl3, cmꢀ1) 2970, 2935, 1753,
1733, 1691; EI-MS m/z 449 (Mþ); EI-HRMS calcd for C24H35NO7 m/z
449.2413, found: 449.2418; Anal. Calcd for C24H35NO7: C, 64.12; H,
ent-2: ½a 2D0
ꢀ91.9 (c 0.58, CHCl3).
ꢂ
Acknowledgements
This research was supported by a grant from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT), and
Japan Society for the Promotion of Science (JSPS). (Nos. 22790023
and 21590030).
7.85; N, 3.12. Found: C, 64.36; H, 7.86; N, 3.09. (R)-15: ½a D20
ꢀ76.9 (c
ꢂ
1.00, CHCl3).
4.1.9. (10bS)-8-(2,2-Dimethylpropanoyloxy)-9-methoxy-1,5,6,10b-
tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one ((S)-4). To a stirred
solution of 15 (60.9 mg, 0.14 mmol) in DCM (6 ml) were added
References and notes
TMSOTf (75 mL, 0.406 mmol), and after a while, Et3N (113 mL,
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at the same temperature for 42 h. The reaction mixture was
quenched with satd NH4Cl aq and the aqueous layer was extracted
with EtOAc. The organic layer was washed with brine, dried over
MgSO4, filtered, and evaporated. The residue was purified by silica
gel column chromatography (10% MeOH in CHCl3) to give (S)-4
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d
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N. Kawai et al. / Tetrahedron 67 (2011) 8648e8653
9. (a) (S)-8 (98% ee) was prepared from ethyl-
8653
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