Enantioselective synthesis of (+)-(S)-laudanosine and (-)-(S)-xylopinine

Article abstract of DOI:10.1002/ejoc.200500095

The study presents a new pathway for the enantioselective synthesis of benzylisoquinoline alkaloids. The key steps of the synthesis of (+)-(S)-laudanosine (1) and (-)-(S)-xylopinine (2) are a Sonogashira coupling that builds up the C1-C8a bond of the benzylisoquinoline skeleton, an intramolecular Ti-catalyzed hydroamination of an alkyne, and a subsequent enantioselective imine reduction according to Noyori's protocol.

Full text of DOI:10.1002/ejoc.200500095

FULL PAPER
Enantioselective Synthesis of (+)-(S)-Laudanosine and (–)-(S)-Xylopinine
Didin Mujahidin[a] and Sven Doye*[a]
Keywords: Alkaloids / Alkynes / Asymmetric Synthesis / Hydroamination / Titanium
The study presents a new pathway for the enantioselective
synthesis of benzylisoquinoline alkaloids. The key steps of
the synthesis of (+)-(S)-laudanosine (1) and (–)-(S)-xylopinine
(2) are a Sonogashira coupling that builds up the C1–C8a
bond of the benzylisoquinoline skeleton, an intramolecular
Ti-catalyzed hydroamination of an alkyne, and a subsequent
enantioselective imine reduction according to Noyori’s proto-
col.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
of an alkyne as the key step.[7] As the first two prominent
target molecules, we chose the opium alkaloids (+)-(S)-lau-
danosine (1)[8] and (–)-(S)-xylopinine (2).[9] For both com-
pounds, several asymmetric syntheses have been described
in the past.[10] However, in most cases, the benzylisoquino-
line framework was formed by Pictet–Spengler, Bischler–
Napieralski, or Pomeranz–Fritsch synthesis.
Ti-catalyzed hydroaminations of alkynes have attracted
much attention during the last few years.[1] While corre-
sponding reactions have extensively been used for the gener-
ation of small libraries of various classes of biologically
interesting compounds such as arylethylamines,[2] indoles,[3]
and tryptamine homologs,[4] to the best of our knowledge,
only one example of a natural product synthesis that applies
As outlined retrosynthetically in Scheme 1, our approach
a Ti-catalyzed hydroamination of an alkyne has been re- relies on the enantioselective reduction of imine 3, which
ported.[5,6] has already been described by Noyori et al.[11] In contrast
Since benzylisoquinoline alkaloids play an outstanding to the common synthesis of benzylisoquinoline alkaloids,
role among the various classes of natural products, we fo- the imine 3 was planned to arise from an intramolecular
cused on a synthetic approach towards the benzylisoquino- hydroamination reaction of aminoalkyne 4. Using this ap-
line framework that employs a Ti-catalyzed hydroamination proach, the C1–C8a bond can be formed by a Sonogashira
Scheme 1. Retrosynthesis of (+)-(S)-laudanosine (1) and (–)-(S)-xylopinine (2).
coupling[12] between the aryl iodide 5 and alkyne 6. Corre-
[a] Organisch-Chemisches Institut, Universität Heidelberg
spondingly, the typical electrophilic aromatic substitution
reaction which is usually employed for the formation of the
C1–C8a bond of benzylisoquinolines can be avoided. An
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: +49-6221-54-4205
E-mail: sven.doye@urz.uni-heidelberg.de
Eur. J. Org. Chem. 2005, 2689–2693
DOI: 10.1002/ejoc.200500095
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2689

D. Mujahidin, S. Doye
FULL PAPER
obvious advantage of this strategy is the fact that in con- action of commercially available homoveratrylamine (7)
trast to electophilic aromatic substitutions, the Pd-catalyzed with ethyl trifluoroacetate in THF at room temperature
Sonogashira coupling is facilitated by electron-withdrawing gave the N-protected trifluoroacetamide 8 cleanly in 99%
substituents located in the A-ring. Therefore, the Sonoga- yield. Subsequently, 8 was converted into 5 in 93% yield by
shira coupling/hydroamination approach is somehow com- iodination in the presence of I2 and HIO3 at 85 °C in a
plementary to the common electrophilic substitution ap- mixture of water and methanol.
proach. For future synthesis of benzylisoquinoline deriva-
The synthesis of alkyne fragment 6 is summarized in
tives with electron-deficient A-rings the new strategy might Scheme 3. Iodination of veratrol (9) in the presence of I2
be even superior to the old substitution-based procedures.
and HIO3 at 85 °C in a mixture of water and methanol
afforded 4-iodoveratrol (10) in 92% yield. Subsequent stan-
Results and Discussion
The synthesis of aryl iodide 5 was accomplished as de-
picted in Scheme 2, according to Tietze’s procedure.[13] Re-
Scheme 2. Synthesis of aryl iodide 5.
Scheme 3. Synthesis of terminal alkyne 6.
Scheme 4. Final steps in the synthesis of laudanosine (1) and xylopinine (2).
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Enantioselective Synthesis of (+)-(S)-Laudanosine and (–)-(S)-Xylopinine
FULL PAPER
pounds as gauged by thin layer chromatography (TLC) and 1H
and 13C NMR spectroscopy. All products were characterized by 1H
NMR, 13C NMR, IR spectroscopy, and mass spectrometry (MS).
Additional characterization data were obtained by high-resolution
mass spectrometry (HRMS) and/or CHN elemental analysis. NMR
spectra were recorded with the following spectrometers: Bruker Av-
ance ARX 250, Bruker Avance DRX 300, Bruker AC 300, Bruker
dard Sonogashira coupling [2 mol-% Pd(PPh3)2Cl2, 4 mol-
% PPh3, 4 mol-% CuI, iPr2NH, 25 °C, 16 h] employing
TMS–acetylene (TMS = trimethylsilyl) led to the formation
of TMS-protected alkyne 11 in 92% yield. The desired build-
ing block 6 was finally obtained in 82% yield by deprotection
of 11 with K2CO3 in methanol at room temperature.
With 5 and 6 in hand, attention was now directed
towards the completion of the synthesis, as shown in
Scheme 4. Aryl iodide 5 and alkyne 6 were subjected to
1
Avance DRX 400, Bruker Avance DRX 500. All H NMR spectra
are reported in δ units ppm downfield from tetramethylsilane as
internal standard. All 13C NMR spectra are reported in δ units
standard Sonogashira coupling conditions [4 mol-% ppm relative to the central line of the triplet of CDCl3 at δ =
77.0 ppm. IR spectra were recorded with a Bruker Vector 22 spec-
trometer using an attenuated total reflection (ATR) method. Mass
spectra were recorded with a JEOL JMS-700 or a Finnigan TSQ
700 (EI) spectrometer with an ionization potential of 70 eV. Ele-
mental analyses were carried out with an Elementar Vario EL ma-
chine. ee values were determined by HPLC analysis carried out
with a Surveyor HPLC System Thermo (Chiralcel OD column).
Optical rotations were recorded with a Perkin–Elmer 241 polarime-
ter. Melting points are uncorrected. PE: light petroleum ether, b.p.
40–60 °C. MTBE: methyl tert-butyl ether.
Pd(PPh3)2Cl2, 8 mol-% PPh3, 8 mol-% CuI, iPr2NH, 25 °C,
16 h] to give the trifluoroacyl-protected alkyne 12 in 84%
yield. In this context, it is worth mentioning that in alkyne
12 the C1–C8a bond (vide supra) has already been estab-
lished. Liberation of the NH2 group under basic conditions
(KOH, MeOH, H2O, 25 °C, 20 h) delivered aminoalkyne 4
in 90% yield. This key intermediate was then subjected to
an intramolecular hydroamination reaction at 110 °C in tol-
[14]
uene by employing 10 mol-% Cp2TiMe2
as the catalyst.
To our delight, the hydroamination reaction proceeded
smoothly to produce imine 3 in 98% yield. After purifica-
tion by flash chromatography, imine 3 was enantioselecti-
vely reduced according to Noyori’s protocol by employing
1 mol-% (η6-p-cymene)[(1R,2R)-N-(p-tolylsulfonyl)-1,2-di-
phenylethylenediamine)]RuCl as the catalyst.[11] In good
agreement with Noyori’s results, the corresponding second-
ary amine 13 was obtained in 92% yield with 93% ee [(S)
configuration]. Amine 13 represents a single precursor for
the synthesis of both target molecules. (+)-(S)-Laudanosine
(1) was obtained from 13 by reductive amination (CH2O,
NaBH4, MeOH, H2O, 25 °C, 16 h) in 99% yield. Alterna-
tively, a final Pictet–Spengler cyclization of 13 by employing
aqueous CH2O and formic acid afforded (–)-(S)-xylopinine
(2) in 82% yield.
Trifluoroacetamide 8: At 25 °C, ethyl trifluoroacetate (10.58 g,
74.5 mmol) was added dropwise to a solution of homoveratrylam-
ine (7, 11.75 g, 65.0 mmol) in THF (325 mL). The mixture was
stirred at 25 °C for 2 h. Evaporation of the solvent under vacuum
gave 8 (17.98 g, 64.9 mmol, 99%) as a white solid. For the subse-
quent iodination, the product was used without further purifica-
tion. M.p. 81–82 °C. 1H NMR (500 MHz, CDCl3): δ = 2.82 (t, J =
7.0 Hz, 2 H), 3.57–3.61 (m, 2 H), 3.86 (s, 6 H), 6.36 (br. s, 1 H),
6.68 (d, J = 1.4 Hz, 1 H), 6.72 (dd, J = 1.7, 8.4 Hz, 1 H), 6.82 (d,
J = 8.0 Hz, 1 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3): δ =
34.5 (CH2), 41.1 (CH2), 55.8 (CH3), 55.9 (CH3), 111.5 (CH), 111.7
(CH), 115.8 (q, J = 288 Hz, CF3), 120.6 (CH), 130.0 (C), 148.2 (C),
149.2 (C), 157.1 (q, J = 37 Hz, C) ppm. IR: ν = 3426, 3319, 3116,
˜
3009, 2966, 2943, 2840, 1700, 1591, 1566, 1515, 1469, 1460, 1454,
1444, 1264, 1250, 1238, 1215, 1201, 1181, 1160, 1137, 1029,
805 cm–1. MS: m/z (%) = 277 (29) [M+], 164 (42), 151 (100), 113
(7), 107 (6), 91 (3), 78 (3). HRMS: calcd. (C12H14F3NO3) 277.0926;
found 277.0944. C12H14F3NO3 (277.2): calcd. C 51.99, H 5.09, N
5.05; found C 51.77, H 4.96, N 5.05.
Conclusions
Aryl Iodide 5: A solution of 8 (17.98 g, 64.9 mmol), I2 (6.57 g,
25.9 mmol), and HIO3 (2.29 g, 13.0 mmol) in a 3:1 mixture of
MeOH/H2O (650 mL) was heated to 85 °C for 48 h. After concen-
tration under vacuum, the residue was dissolved in CH2Cl2
(150 mL). The solution was washed with aqueous Na2SO3 (5%,
50 mL), H2O (100 mL) and brine (100 mL). The combined organic
layers were dried with MgSO4. After concentration under vacuum
and purification by flash chromatography (SiO2, PE/EtOAc, 4:1),
5 (24.42 g, 60.6 mmol, 93%) was isolated as a white solid. M.p.
In summary, we have presented a new pathway for the
enantioselective synthesis of benzylisoquinoline alkaloids.
The key steps of the synthesis of (+)-(S)-laudanosine (1)
and (–)-(S)-xylopinine (2) are a Sonogashira coupling that
builds up the C1–C8a bond of the benzylisoquinoline skel-
eton, an intramolecular Ti-catalyzed cyclization of an ami-
noalkyne, and a subsequent enantioselective imine re-
duction according to Noyori’s protocol.
1
122–123 °C. H NMR (250 MHz, CDCl3): δ = 2.97 (t, J = 7.0 Hz,
2 H), 3.55–3.64 (m, 2 H), 3.84 (s, 3 H), 3.85 (s, 3 H), 6.39 (br. s, 1
H), 6.69 (s, 1 H), 7.22 (s, 1 H) ppm. 13C NMR (125 MHz, DEPT,
CDCl3): δ = 39.0 (CH2), 40.0 (CH2), 55.9 (CH3), 56.2 (CH3), 87.9
(C), 112.6 (CH), 115.7 (q, J = 288 Hz, CF3), 121.9 (CH), 132.6 (C),
Experimental Section
General Remarks: All reactions were performed under argon in
flame dried Duran glassware (e.g. Schlenk tubes equipped with Tef-
lon stopcocks). Toluene was distilled under argon from molten so-
dium. CH2Cl2 and triethylamine were distilled from calcium hy-
dride. Formic acid was distilled from phthalic anhydride. Cp2TiMe2
was synthesized according to ref.[14] (η6-p-cymene)[(1R,2R)-N-
(p-tolylsulfonyl)-1,2-diphenylethylenediamine)]RuCl was synthe-
sized according to ref.[11] All other reagents were purchased from
commercial sources and were used without further purification.
Unless otherwise noted, yields refer to isolated yields of pure com-
148.6 (C), 149.6 (C), 157.1 (q, J = 37 Hz, C) ppm. IR: ν = 3434,
˜
2941, 2844, 1708, 1636, 1627, 1599, 1561, 1508, 1465, 1457, 1441,
1380, 1256, 1218, 1181, 1163, 1028, 858, 786, 727 cm–1. MS: m/z
(%) = 403 (62) [M+], 290 (50), 277 (100), 179 (3), 164 (5), 151 (8),
113 (6), 91 (2), 77 (4). HRMS: calcd. (C12H13F3INO3) 402.9892;
found 402.9866. C12H13F3INO3 (403.1): calcd. C 35.75, H 3.25, N
3.47; found C 35.97, H 3.34, N 3.51.
4-Iodoveratrol (10): A solution of veratrol (9, 13.82 g, 100 mmol),
I2 (10.12 g, 40.0 mmol), and HIO3 (3.52 g, 20.0 mmol) in a 3:1 mix-
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D. Mujahidin, S. Doye
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ture of MeOH/H2O (1000 mL) was heated to 85 °C for 48 h. Then,
aqueous Na2SO3 (5%) was added until the iodine color disap-
peared. The mixture was extracted with CH2Cl2 (3×150 mL) and
the combined organic layers were dried with Na2SO4. After concen-
tration under vacuum and purification by Kugelrohr distillation,
10 (24.32 g, 92.1 mmol, 92%) was isolated as a yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 3.84 (s, 3 H), 3.85 (s, 3 H), 6.61 (d, J =
8.5 Hz, 1 H), 7.11 (d, J = 1.8 Hz, 1 H), 7.22 (dd, J = 1.8, 8.5 Hz,
1 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ = 55.9 (CH3),
ditional 16 h, saturated NH4Cl solution was added. The mixture
was extracted with CH2Cl2 (3×50 mL). The combined organic lay-
ers were dried with MgSO4 and concentrated under vacuum. After
purification by flash chromatography (SiO2, PE/EtOAc, 1:1), 12
(2.41 g, 5.51 mmol, 84%) was isolated as a yellow crystalline solid.
M.p. 164–165 °C. 1H NMR (250 MHz, CDCl3): δ = 3.10 (t, J =
6.6 Hz, 2 H), 3.66–3.74 (m, 2 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 3.91
(s, 3 H), 3.91 (s, 3 H), 6.48 (br. s, 1 H), 6.68 (s, 1 H), 6.85 (d, J =
8.3 Hz, 1 H), 7.02 (s, 1 H), 7.04 (d, J = 1.7 Hz, 1 H), 7.11 (dd, J =
56.1 (CH3), 82.3 (C), 113.2 (CH), 120.4 (CH), 129.8 (CH), 149.2 1.8, 8.2 Hz, 1 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ =
(C), 149.9 (C) ppm. IR: ν = 2955, 2930, 2836, 1583, 1503, 1460, 33.2 (CH2), 40.9 (CH2), 55.9 (CH3), 56.0 (CH3), 85.9 (C), 92.3 (C),
˜
1439, 1393, 1321, 1250, 1229, 1177, 1157, 1022, 838, 797, 762,
614 cm–1. MS: m/z (%) = 264 (83) [M+], 249 (26), 221 (31), 218
(18), 203 (17), 122 (19), 94 (100), 79 (33), 77 (23), 66 (24). HRMS:
calcd. (C8H9IO2) 263.9647; found 263.9647.
111.1 (CH), 112.1 (CH), 114.2 (CH), 114.8 (CH), 115.1 (C), 115.2
(C), 115.8 (q, J = 287 Hz, CF3), 124.7 (CH), 132.7 (C), 147.8 (C),
148.8 (C), 149.6 (C), 149.7 (C), 157.2 (q, J = 37 Hz, C) ppm. IR:
ν = 3331, 3008, 2934, 2836, 1704, 1603, 1576, 1518, 1467, 1452,
˜
1352, 1323, 1245, 1227, 1215, 1179, 1157, 1137, 1092, 1023, 1001,
809 cm–1. MS: m/z (%) = 437 (100) [M+], 369 (3), 324 (6), 311 (54),
281 (2), 267 (4), 253 (4), 213 (4), 201 (5), 161 (10), 150 (11), 113
(8). HRMS: calcd. (C22H22NO5F3) 437.1450; found 437.1445.
C22H22NO5F3 (437.4): calcd. C 60.41, H 5.07, N 3.20; found C
60.14, H 5.15, N 3.24.
TMS–Alkyne 11: Pd(PPh3)2Cl2 (282 mg, 0.40 mmol, 2 mol-%), CuI
(160 mg, 0.84 mmol, 4 mol-%), PPh3 (208 mg, 0.80 mmol, 4 mol-
%), and iPr2NH (60 mL) were placed in a round-bottomed flask.
After addition of 4-iodoveratrol (10, 5.28 g, 20.0 mmol), the mix-
ture was stirred at 25 °C for 30 min, and trimethylsilylacetylene
(1.96 g, 20.0 mmol) was then added. After this mixture had been
stirred at 25 °C for additional 16 h, a saturated NH4Cl solution
was added. The mixture was extracted with CH2Cl2 (3×50 mL).
The combined organic layers were dried with MgSO4 and concen-
trated under vacuum. After purification by flash chromatography
(SiO2, PE/MTBE, 3:1), 11 (4.31 g, 18.4 mmol, 92%) was isolated
as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 0.24 (s, 9 H),
3.87 (s, 3 H), 3.87 (s, 3 H), 6.76 (d, J = 8.3 Hz, 1 H), 6.96 (d, J =
1.8 Hz, 1 H), 7.07 (dd, J = 1.9, 8.3 Hz, 1 H) ppm. 13C NMR
(100 MHz, DEPT, CDCl3): δ = 0.0 (CH3), 55.8 (CH3), 55.9 (CH3),
92.3 (C), 105.2 (C), 110.8 (CH), 114.6 (CH), 115.3 (C), 125.4 (CH),
Aminoalkyne 4: Aqueous KOH (5 m, 11.0 mL, 55.0 mmol) was
added to a solution of 12 (2.37 g, 5.42 mmol) in MeOH (55 mL) at
0 °C. The cooling bath was removed and the mixture was stirred at
25 °C for 20 h. Then, the MeOH was removed under vacuum and
the residue was diluted with H2O (50 mL). After extraction with
CH2Cl2 (4×50 mL), the combined organic layers were dried with
MgSO4 and concentrated under vacuum. Purification by flash
chromatography (SiO2, EtOAc/MeOH, 1:1 + 3% NH3) gave 4
(1.66 g, 4.86 mmol, 90%) as a very hygroscopic pale brown solid.
Aminoalkyne 4 was stored as a solution in CH2Cl2 (100 mg/mL)
1
at 4 °C. H NMR (250 MHz, CDCl3): δ = 1.39 (s, 2 H), 2.90–2.97
148.5 (C), 149.7 (C) ppm. IR: ν = 3001, 2958, 2835, 2156, 1599,
˜
(m, 2 H), 3.01–3.08 (m, 2 H), 3.88 (s, 3 H), 3.89 (s, 6 H), 3.90 (s, 3
H), 6.73 (s, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 7.01 (s, 2 H), 7.11 (dd,
J = 1.9, 8.3 Hz, 1 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ
= 37.2 (CH2), 42.2 (CH2), 55.7 (CH3), 55.8 (CH3), 55.8 (CH3), 86.4
(C), 91.6 (C), 111.0 (CH), 112.4 (CH), 114.0 (CH), 114.6 (CH),
114.8 (C), 115.5 (C), 124.6 (CH), 134.1 (C), 147.1 (C), 148.6 (C),
1577, 1514, 1464, 1442, 1409, 1322, 1266, 1243, 1197, 1163, 1137,
1027, 951, 855, 765 cm–1. MS: m/z (%) = 234 (58) [M+], 219 (100),
203 (11), 162 (14), 151 (13), 138 (10), 113 (10), 109 (4), 95 (4), 77
(8). HRMS: calcd. (C13H18O2Si) 234.1076; found 234.1058.
C13H18O2Si (234.4): calcd. C 66.62, H 7.74; found C 66.57, H 7.82.
Alkyne 6: Anhydrous K2CO3 (138 mg, 1.00 mmol) was added to a
solution of 11 (2.41 g, 10.3 mmol) in MeOH (25 mL). After this
mixture had been stirred at 25 °C for 4 h, the solvent was evapo-
rated under vacuum. A saturated aqueous NaHCO3 was added to
the residue and the mixture was extracted with CH2Cl2 (3×50 mL).
The combined organic layers were dried with MgSO4 and concen-
trated under vacuum. After purification by flash chromatography
(SiO2, PE/MTBE, 1:1), 6 (1.37 g, 8.45 mmol, 82%) was isolated as
a white crystalline solid. M.p. 70–71 °C. 1H NMR (300 MHz,
CDCl3): δ = 3.00 (s, 1 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 6.79 (d, J =
8.3 Hz, 1 H), 6.98 (d, J = 1.8 Hz, 1 H), 7.10 (dd, J = 1.8, 8.3 Hz,
1 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ = 55.9 (CH3),
75.6 (CH), 83.7 (C), 110.9 (CH), 114.2 (C), 114.7 (CH), 125.4 (CH),
149.1 (C), 149.3 (C) ppm. IR: ν = 3360, 3003, 2939, 2830, 1599,
˜
1576, 1517, 1465, 1348, 1322, 1244, 1224, 1181, 1156, 1089, 1022,
996, 854, 813, 805, 764 cm–1. MS: m/z (%) = 341 (90) [M+], 326
(19), 312 (100), 297 (22), 281 (6), 267 (7), 253 (11), 225 (4), 216
(5), 204 (15), 190 (20) 161 (11), 151 (12), 113 (8). HRMS: calcd.
(C20H23NO4) 341.1627; found 341.1630.
Imine 3: A solution of 4 in CH2Cl2 (6.83 mL, c = 100 mg/mL,
2.00 mmol) was transferred to a Schlenk tube and the solvent was
removed under vacuum. Then, toluene (0.5 mL) and a solution of
Cp2TiMe2 (0.54 mL, c = 0.37 mol/L in toluene, 0.20 mmol, 10 mol-
%) were added. The reaction mixture was heated to 110 °C for 16
h. After the obtained brown liquid had been allowed to reach room
temperature, the solvent was removed under vacuum. Purification
of the residue by flash chromatography (SiO2, EtOAc + 4% NEt3)
148.6 (C), 149.9 (C) ppm. IR: ν = 3428, 3259, 3250, 3007, 2971,
˜
2939, 2843, 1597, 1579, 1511, 1452, 1446, 1408, 1323, 1263, 1240,
1152, 1138, 1035, 1026, 860, 821, 810, 730, 621 cm–1. MS: m/z (%)
= 162 (100) [M+], 147 (21), 119 (10), 91 (14), 76 (8), 65 (6). HRMS:
calcd. (C10H10O2) 162.0681; found 162.0659. C10H10O2 (162.2):
calcd. C 74.06, H 6.21; found C 73.66, H 6.14.
1
provided 3 (669 mg, 1.96 mmol, 98%) as a yellow solid. H NMR
(250 MHz, CDCl3): δ = 2.63 (t, J = 7.7 Hz, 2 H), 3.71 (t, J =
7.7 Hz, 2 H), 3.74 (s, 3 H), 3.81 (s, 3 H), 3.82 (s, 3 H), 3.87 (s, 3
H), 3.97 (s, 2 H), 6.64 (s, 1 H), 6.74–6.86 (m, 3 H), 6.98 (s, 1 H)
ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ = 25.3 (CH2), 40.3
Alkyne 12: Pd(PPh3)2Cl2 (186 mg, 0.26 mmol, 4 mol-%), CuI (CH2), 43.7 (CH2), 55.6 (CH3), 55.8 (CH3), 55.9 (CH3), 56.0 (CH3),
(101 mg, 0.53 mmol, 8 mol-%), PPh3 (138 mg, 0.51 mmol, 8 mol-
%), and iPr2NH (19 mL) were placed in a round-bottomed flask.
After addition of aryl iodide 5 (2.66 g, 6.60 mmol), the mixture was
110.5 (CH), 110.7 (CH), 111.4 (CH), 111.7 (CH), 119.6 (C), 120.7
(CH), 128.5 (C), 132.7 (C), 147.7 (C), 148.1 (C), 149.3 (C), 153.0
(C), 169.6 (C) ppm. IR: ν = 2992, 2934, 2832, 2803, 1609, 1589,
˜
stirred at 25 °C for 30 min, and alkyne 6 (1.07 g, 6.60 mmol) was 1515, 1465, 1449, 1416, 1374, 1326, 1301, 1262, 1233, 1173, 1154,
then added. After this mixture had been stirred at 25 °C for ad- 1138, 1154, 1138, 1111, 1026, 983, 950, 862, 821, 805, 787, 766,
2692
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Enantioselective Synthesis of (+)-(S)-Laudanosine and (–)-(S)-Xylopinine
FULL PAPER
698, 546 cm–1. MS: m/z (%) = 341 (3) [M+], 340 (4), 326 (4), 194
(7), 193 (79), 192 (100), 177 (14), 176 (33), 151 (19), 148 (15), 147
(10), 131 (8), 118 (6), 106 (4). HRMS: calcd. (C20H23NO4)
341.1627; found 341.1592.
graphy (SiO2, EtOAc/NEt3, 99:1), (–)-(S)-xylopinine (2, 44 mg,
0.12 mmol, 82%) was isolated as a cream-colored solid. M.p.
178–180 °C. [α]2D2 = –262 (c = 0.10, CHCl3) {ref.[9]: [α]D = –297
1
(CHCl3)}. H NMR (300 MHz, CDCl3): δ = 2.57–2.69 (m, 2 H),
2.84 (dd, J = 11.5, 15.1 Hz, 1 H), 3.09–3.16 (m, 2 H), 3.24 (dd, J
= 3.7, 15.8 Hz, 1 H), 3.59 (dd, J = 3.7, 11.4 Hz, 1 H), 3.67 (d, J =
14.3 Hz, 1 H), 3.85 (s, 3 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 3.89 (s, 3
H), 3.95 (d, J = 14.7 Hz, 1 H), 6.58 (s, 1 H), 6.62 (s, 1 H), 6.66 (s,
1 H), 6.74 (s, 1 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ =
29.1 (CH2), 36.4 (CH2), 51.4 (CH2), 55.8 (CH3), 55.9 (CH3), 56.0
(CH3), 56.1 (CH3), 58.3 (CH2), 59.6 (CH), 108.6 (CH), 109.1 (CH),
111.4 (CH), 111.5 (CH), 126.3 (C), 126.4 (C), 126.8 (C), 129.8 (C),
(–)-(S)-Norlaudanosine (13): A 5:2 mixture of HCOOH and NEt3
(1.5 mL) was added to a suspension of imine 3 (1.02 g, 3.00 mmol)
and (η6-p-cymene)[(1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenylethy-
lenediamine)]RuCl (19 mg, 0.03 mmol) in DMF (6.0 mL). After the
mixture had been stirred at 25 °C for 7 h, a saturated aqueous
Na2CO3 solution (30 mL) was added. The resulting mixture was
extracted with CH2Cl2 (3×30 mL) and the combined organic layers
were dried with MgSO4. After concentration under vacuum and
purification by flash chromatography (SiO2, EtOAc/MeOH, 4:1 +
1% NH3), 13 (951 mg, 2.77 mmol, 92%, 93% ee, HPLC: hexane/
2-propanol/diethylamine, 55:45:0.1, 0.5 mL/min) was isolated as a
yellow oil. [α]2D5 = –23.6 (c = 0.85, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 2.65–2.76 (m, 2 H), 2.82–2.95 (m, 2 H), 3.14–3.24 (m,
2 H), 3.83 (s, 3 H), 3.86 (s, 3 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 4.13
(dd, J = 4.4, 9.2 Hz, 1 H), 6.59 (s, 1 H), 6.66 (s, 1 H), 6.75–6.84
(m, 3 H) ppm. 13C NMR (75 MHz, DEPT, CDCl3): δ = 29.5 (CH2),
41.0 (CH2), 42.2 (CH2), 55.9 (CH3), 55.9 (CH3), 56.0 (CH3), 56.8
(CH3), 78.7 (CH), 101.7 (C), 109.4 (CH), 111.3 (CH), 111.8 (CH),
112.4 (CH), 121.4 (CH), 127.4 (C) 131.4 (C), 147.0 (C), 147.5 (C),
147.4 (C), 147.5 (C), 147.5 (C), 147.7 (C) ppm. IR: ν = 3435, 2931,
˜
2833, 1612, 1518, 1464, 1384, 1350, 1329, 1260, 1241, 1205, 1144,
1102, 1005, 856, 787, 769 cm–1. MS: m/z (%) = 355 (94) [M+], 354
(34), 340 (11), 316 (4), 267 (5), 251 (5), 206 (10), 199 (7), 190 (22),
164 (100), 151 (14), 121 (10), 112 (12). HRMS: calcd. (C21H25NO4)
355.1784; found 355.1778.
Acknowledgments
Generous support by Professor E. Winterfeldt and Professor H. M.
R. Hoffmann is most gratefully acknowledged. We further thank
the Deutscher Akademischer Austausch Dienst (DAAD Fellowship
for D. M.), the Deutsche Forschungsgemeinschaft, the Fonds der
Chemischen Industrie and the Dr. Otto Röhm Gedächtnisstiftung,
Darmstadt for financial support of our research.
147.7 (C), 148.6 (C) ppm. IR: ν = 3330, 2997, 2934, 2833, 1509,
˜
1585, 1515, 1464, 1412, 1379, 1320, 1266, 1157, 1140, 112, 1028,
945, 859, 811, 729 cm–1. MS: m/z (%) = 343 (2) [M+], 342 (9), 341
(24), 326 (15), 266 (3), 206 (17), 193 (74), 192 (100), 177 (12), 176
(27), 162 (5), 151 (16), 131 (6). HRMS: calcd. (C20H25NO4)
343.1784; found 343.1717.
[1] For reviews, see: a) I. Bytschkov, S. Doye, Eur. J. Org. Chem.
2003, 935–946; b) S. Doye, Synlett 2004, 1653–1672; c) A.
Odom, Dalton Trans. 2005, 225–233.
[2] a) H. Siebeneicher, S. Doye, Eur. J. Org. Chem. 2002, 1213–
1220; b) I. Bytschkov, H. Siebeneicher, S. Doye, Eur. J. Org.
Chem. 2003, 2888–2902.
[3] H. Siebeneicher, I. Bytschkov, S. Doye, Angew. Chem. 2003,
115, 3151–3153; Angew. Chem. Int. Ed. 2003, 42, 3042–3044.
[4] V. Khedkar, A. Tillack, M. Michalik, M. Beller, Tetrahedron
Lett. 2004, 45, 3123–3126.
[5] P. L. McGrane, T. Livinghouse, J. Org. Chem. 1992, 57, 1323–1324.
[6] For a synthesis of (+)-preussin based on a stoichiometric imi-
dotitanium–alkyne [2+2]-cycloaddition, see: P. L. McGrane, T.
Livinghouse, J. Am. Chem. Soc. 1993, 115, 11485–11489.
[7] A synthesis of the isoquinoline framework that involves a Pic-
tet–Spengler reaction of an imine obtained by Ti-catalyzed hy-
droamination of 1-hexyne has been described: Z. Zhang, L. L.
Schafer, Org. Lett. 2003, 5, 4733–4736.
[8] Römpp Lexikon Naturstoffe, 10th ed. (Eds.: B. Fugmann, S.
Lang-Fugmann, W. Steglich), Georg Thieme Verlag, Stuttgart,
1997, p. 79–80.
[9] J. Schmutz, Helv. Chim. Acta 1959, 42, 335–343.
[10] For a recent review on the asymmetric synthesis of isoquinoline
alkaloids, see: M. Chrzanowska, M. D. Rozwadowska, Chem.
Rev. 2004, 104, 3341–3370.
[11] N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J.
Am. Chem. Soc. 1996, 118, 4916–4917.
[12] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 16, 4467–4470; b) K. Sonogashira, in: Comprehensive Or-
ganic Synthesis (Eds.: B. M. Trost, I. Fleming), Pergamon
Press, Oxford, 1991, vol. 3, p. 521–549.
(+)-(S)-Laudanosine (1): Aqueous CH2O (2.0 mL, c = 37%) was
added to a solution of 13 (330 mg, 0.96 mmol) in MeOH (6.0 mL).
After this mixture had been stirred at 25 °C for 3 h, NaBH4
(400 mg, 10.57 mmol) was slowly added. Subsequently, the reaction
mixture was stirred at 25 °C for additional 16 h. Then, saturated
aqueous NH4Cl (25 mL) was added and the mixture was extracted
with CH2Cl2 (3×30 mL). The combined organic layers were dried
with MgSO4 and the solvent was evaporated under vacuum. After
purification by flash chromatography (SiO2, MTBE/MeOH/NEt3,
95:3:3), (+)-(S)-laudanosine (1, 340 mg, 0.95 mmol, 99%) was iso-
lated as a cream-colored solid. M.p. 88–89 °C. [α]2D2 = +87 (c =
0.70, EtOH) {ref.[8]: [α]D = +103 (EtOH)}. 1H NMR (300 MHz,
CDCl3): δ = 2.53 (s, 3 H), 2.56–2.60 (m, 1 H), 2.71–2.85 (m, 3 H),
3.10–3.18 (m, 1 H), 3.56 (s, 3 H), 3.66–3.70 (m, 1 H), 3.77 (s, 3 H),
3.82 (s, 3 H), 3.83 (s, 3 H), 6.04 (s, 1 H), 6.54 (s, 1 H), 6.58–6.63
(m, 2 H), 6.75 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR (75 MHz,
DEPT, CDCl3): δ = 25.5 (CH2), 40.8 (CH2), 42.6 (CH3), 47.0
(CH2), 55.5 (CH3), 55.7 (CH3), 55.7 (CH3), 55.9 (CH3), 64.8 (CH),
111.0 (CH), 111.1 (CH), 111.2 (CH), 113.0 (CH), 121.8 (CH), 126.0
(C), 129.2 (C), 132.5 (C), 146.3 (C), 147.2 (C), 147.3 (C), 148.5 (C)
ppm. IR: ν = 2993, 2915, 2789, 1607, 1516, 1466, 1451, 1374, 1334,
˜
1281, 1265, 1227, 1204, 1155, 1142, 1104, 1029, 1018, 861,
818 cm–1. MS: m/z (%) = 358 (80) [M+ + H], 342 (3), 307 (22), 289
(11), 222 (3), 206 (100), 204 (18), 190 (10). HRMS: calcd.
(C21H28NO4) 358.2018; found 358.2000. C21H27NO4 (357.4): calcd.
C 70.56, H 7.61, N 3.92; found C 70.28, H 7.61, N 3.98.
(–)-(S)-Xylopinine (2): A mixture of aqueous CH2O (0.8 mL, c =
37%), HCOOH (1.2 mL), and 13 (52 mg, 0.15 mmol) was heated
to 90 °C for 2 h. After the resulting mixture had cooled to 25 °C,
saturated aqueous NaHCO3 was added until pH Ͼ 7 was reached.
The mixture was then extracted with CH2Cl2 (3×15 mL). The com-
bined organic layers were dried with MgSO4 and the solvent was
evaporated under vacuum. After purification by flash chromato-
[13] a) L. F. Tietze, R. Schimpf, Synthesis 1993, 876–880; b) H. O.
Wirth, O. Königstein, W. Kern, Justus Liebigs Ann. Chem.
1960, 634, 84–104.
[14] N. A. Petasis, in: Encyclopedia of Reagents for Organic Synthe-
sis (Ed.: L. A. Paquette), John Wiley & Sons, New York, 1995,
vol. 1, p. 470–473.
Received: February 4, 2005
Eur. J. Org. Chem. 2005, 2689–2693
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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