Oxidative nucleophilic substitution (SNOX) of the benzylic position as a tunable synthesis of tetrahydroisoquinoline natural alkaloid analogues

Article abstract of DOI:10.1002/ejoc.200700366

Synthetic investigations of 1,3-dichloro-5,6-dicyanobenzoquinone-mediated benzylic oxidation is reported for the synthesis of natural alkaloid analogues. Extensive explorations of the oxidative nucleophilic substitution of the benzylic position of β-phenylethylamine derivatives and the synthesis of functionalized tetrahydroisoquinolines of ecteinascidin 743 precursors have been carried out. Starting from L-DOPA, a tunable oxazolidinone group was installed under oxidative benzylic conditions. This derivative 13 was submitted to benzylic oxidation reactions using a wide range of carboxylic acids and subsequent chemical transformations of these compounds were attempted. Moreover, an efficient synthesis of an aromatic ketone derivative 20 was achieved and gave rise to tetrahydroisoquinoline 24 through a direct Pictet-Spengler cyclisation reaction. Subsequently, 24 was transformed into functionahzed α-amino alcohols 31a and 31b, precursors of ecteinascidin 743 analogues. In addition, in order to assess the viability of our synthetic strategy, the reaction of 24 with methyl thioglycolate was performed and the stereoselectivity confirmed by X-ray analysis of 33a. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700366

FULL PAPER
DOI: 10.1002/ejoc.200700366
Oxidative Nucleophilic Substitution (SNOx) of the Benzylic Position as a
Tunable Synthesis of Tetrahydroisoquinoline Natural Alkaloid Analogues
Sylvain Aubry,[a] Stéphane Pellet-Rostaing,*[a] and Marc Lemaire*[a]
Keywords: Alkaloids / Oxidation / Donor–acceptor systems / Nucleophilic substitution
Synthetic investigations of 1,3-dichloro-5,6-dicyanobenzo- pounds were attempted. Moreover, an efficient synthesis of
quinone-mediated benzylic oxidation is reported for the syn-
thesis of natural alkaloid analogues. Extensive explorations
of the oxidative nucleophilic substitution of the benzylic posi-
tion of β-phenylethylamine derivatives and the synthesis of
functionalized tetrahydroisoquinolines of ecteinascidin 743
an aromatic ketone derivative 20 was achieved and gave rise
to tetrahydroisoquinoline 24 through a direct Pictet–Spengler
cyclisation reaction. Subsequently, 24 was transformed into
functionalized α-amino alcohols 31a and 31b, precursors of
ecteinascidin 743 analogues. In addition, in order to assess
the viability of our synthetic strategy, the reaction of 24 with
methyl thioglycolate was performed and the stereoselectivity
confirmed by X-ray analysis of 33a.
precursors have been carried out. Starting from L-DOPA, a
tunable oxazolidinone group was installed under oxidative
benzylic conditions. This derivative 13 was submitted to ben-
zylic oxidation reactions using a wide range of carboxylic ac-
ids and subsequent chemical transformations of these com-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Many tetrahydroisoquinoline alkaloids and β-phenyl-
ethylamine derivatives that possess functions at the benzylic
position are of great biological interest.[1] Recently, one of
them, a new (+)-norepinephrine derivative, syncarpamide
(1), was isolated from the stem of Zanthoxylum syncarpum
and differs from most of the natural β-phenylethylamines
by the substitution of the benzylic position.[2] Moreover,
syncarpamide displays interesting potential antiplasmodial
activity.[2d,2e] Ecteinascidin 743 (2, Et 743), the most bioac-
tive member of the tetrahydroisoquinoline family,[3] isolated
from Caribbean tunicate Ecteinascidia turbinate[4] (Fig-
ure 1), revealed potent cytotoxic activity under phase II/III
clinical trials for various human cancer cell lines.[5] This im-
pressive architecture also exhibits a higher degree of oxi-
dation at the C-4 benzylic position. Moreover, azapodo-
phyllotoxin (3), structurally related to podophyllotoxin[6]
and tetrahydroisoquinoline derivatives, possesses a higher
degree of substitution at the benzylic position and has been
the subject of a methodological study to introduce requisite
functionalities at this position.[7]
Figure 1. Alkaloids oxidized at the benzylic position.
Since 2004, our laboratory has developed a new method-
ology directed towards the synthesis of Et 743 analogues.
We have reported the construction and the biological evalu-
ation of pentacyclic analogues of piperazine-core alkaloids
directed towards a general strategy for the construction of
Et 743 analogues[8] which could give rise to the synthesis of
many derivatives related to this family.[3] As a consequence
of these results, we became interested in the direct introduc-
tion of different functions at the benzylic position of a -
DOPA derivative in order to use these precursors for the
synthesis of natural tetrahydroisoquinoline analogues. In
this work we considered a new approach to the synthesis of
ecteinascidin precursors of the type 4 (Scheme 1). This pa-
[a] ICBMS, Institut de Chimie et Biochimie Moléculaires et Supra-
moléculaires, Laboratoire de Catalyse et Synthèse Organique,
43 boulevard du 11 Novembre 1918, Villeurbanne, F-69622,
France
Fax: +33-4-72431408
E-mail: marc.lemaire@univ-lyon1.fr
5212
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5212–5225

Synthesis of Tetrahydroisoquinoline Natural Alkaloid Analogues
Scheme 1. Retrosynthetic analysis of the piperazine pentacylic structure.
per deals with the preparation of compounds of type 6 and
an investigation of the use of 1,3-dichloro-5,6-dicyano-
Results and Discussion
benzoquinone (DDQ) for the oxidative nucleophilic substi-
To establish a template for the oxidative benzylic func-
tution (SNOx) of the benzylic position of a -DOPA deriva- tionalization of β-phenylethylamine derivatives, preliminary
tive in the synthesis of syncarpamide (1) and azapodophilo- studies with the commercially available -DOPA (8) were
toxin (3) analogues.
performed. First, protection of the sensitive amino acid and
DDQ is known to be a powerful reagent which has been incorporation of appropriate functional groups were carried
used extensively as an oxidant in organic synthesis and is out in five steps by standard chemical reactions. Thus, ox-
known to form charge-transfer complexes with aromatic azolidinone 13 was prepared by esterification of -DOPA
substrates.[9] To date, several studies involving the mono- in MeOH, followed by protection of the resulting amino
oxidation of the benzylic position of aromatic compounds group giving access to 10. Methylation of the aromatic hy-
mediated by DDQ have been realized. In 1965 Becker droxy groups[22b] and reduction of the ester function with
showed that DDQ is a specific reagent for the preparation LiBH4 in a mixture of MeOH/THF (1:3) afforded the corre-
of aromatic aldehydes and ketones.[10] The mechanism of sponding N-protected α-amino alcohol 12. Finally, intra-
6-hydroxy- and 6-methoxytetrahydronaphthalene oxidation molecular cyclization between the alcohol and the carba-
by DDQ to the corresponding ketone at the benzylic posi- mate function of 12 with SOCl2 in THF[7e] gave rise to 13
tion was also studied by Turner[11] and Lalonde[12] and their in an overall yield of 71% and up to 99% ee, as determined
co-workers. The formation of carbonyl derivatives was also by HPLC analysis (Chiracel OJ-H) of the racemic mixture
attempted with success for the selective oxidation of the prepared by the same synthetic pathway (Scheme 2).
side-chain at the C-3 position of indoles by Yonemitsu[13]
From compound 13, available on a multigram scale, oxi-
and Cook[14] and their co-workers. The benzylic oxidation dative benzylic substitution with DDQ and several carbox-
of polyaromatic compounds through the action of DDQ in ylic acid derivatives was attempted. Several ester derivatives
methanolic and acidic media has also been studied.[15] In were incorporated at the benzylic position of 13 in the pres-
the pavinan and isopavinan alkaloid series, DDQ also ence of 2 equivalents of DDQ at 60 °C in pure liquid car-
proved its efficiency in forming quinone methides as inter- boxylic acid or with an excess of solid carboxylic acid in
mediates in the synthesis of precursors of these polycyclic CH2Cl2 or CHCl3 which are reported to be efficient sol-
alkaloids.[16] More generally, Guy and Lemaire and co- vents for DDQ dehydrogenation (Scheme 2, Table 1).[23]
workers established the preparation of alkyl aryl ethers[17] Whatever the nature of the carboxylic acid, a mixture of
and alkylarylcarbinols[18] by mono-oxidation at the benzylic two diastereoisomers was obtained. Indeed, DDQ can re-
position using DDQ. An asymmetric version of this reac- move either of the two diastereotopic benzylic protons and
tion was also performed with a chiral substrate which in- the proximity of an asymmetric stereocentre induces a dif-
duced a difference in the rate of reaction between the dia- ference in the rate of reaction between these two protons.[19]
stereotopic benzylic protons.[19] This method was also de- The deep-blue coloration which appeared when the reagents
veloped for the direct formation of C–N bonds by azid- were first mixed and which disappeared as the reaction pro-
ation[20] and C–CN bonds by cyanation[21] of enriched ben- gressed is indicative of a charge-transfer interaction.[9a] In
zylic derivatives and aromatic steroids. More recently, ad- fact, substrate 13 acts as a donor and DDQ as an acceptor.
ditional studies concerning azapodophyllotoxin focused on The carboxylic acids act both as catalyst and as nucleophile
the acylation of the benzylic position with DDQ.[7] In ac- during oxidation mediated by DDQ. At the end of the reac-
cord with these studies, we report here an extensive explora- tion, precipitation of the by-product 2,3-dichloro-5,6-di-
tion of the functionalization of the benzylic position of β- cyanohydroquinone (DDHQ) occurred. However, when the
phenylethylamine derivatives and the synthesis of Et 743 reaction was carried out at room temperature, the deep-blue
analogue precursors under the efficient conditions required coloration persisted even after 96 h and the starting mate-
for the Pictet–Spengler cyclization starting from - rial was recovered. Finally, when the reaction was carried
DOPA.[22]
out in pure carboxylic acid such as acetic acid or acrylic
Eur. J. Org. Chem. 2007, 5212–5225
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5213

S. Aubry, S. Pellet-Rostaing, M. Lemaire
FULL PAPER
Scheme 2. Preparation and oxidation of oxazolidinone 13.
acid, complete disappearance of the donor–acceptor inter- to the assignments of the syn diastereoisomers (Table 2).
action and the precipitation of DDHQ were observed after Moreover, the carbon chemical shift of the stereocentre of
24 h at 60 °C. The corresponding diastereomeric mixtures the acetoxy derivative anti-14 (δ =75.8 ppm, from a 2:8 mix-
of ester 14 and 15 were obtained in good yields. However, ture of syn/anti diastereoisomers)[24] correlated with those
poor diastereomeric excesses were obtained (Table 1, en- described by Petrini and co-workers (δ = 75.4 ppm).[7e] In
tries 1 and 2). With solid carboxylic acids, reaction times fact, the chemical shift of the C–O bond for the carbon
and yields depended on the solubility of the acids in atom in syn-14 (δ = 77.6 ppm) appeared at a lower field in
CH2Cl2 or CHCl3 as well as their reactivity. In the case of the NMR spectra than those of the corresponding anti iso-
compounds 16, 17 and 18, the yields slightly decreased and mers (Table 2, entry 1).
the diastereomeric excess remained stable in favour of the
In addition, 19 displayed the same distinctive feature in
anti diastereoisomer (Table 1, entries 3–5). With phenylgly- terms of chemical displacement [δ(syn) = 80.2 ppm and
oxylic acid, better results were obtained in terms of reaction δ(anti) = 77.9 ppm] and the structural elucidation hypothe-
time and 19 was obtained in 96% yield (Table 1, entry 6). sis was corroborated by single-crystal X-ray analysis of syn-
Thus, the rate of the reaction was enhanced and the reac- 19[25] (Figure 2). Indeed, we observed the syn orientation of
tion took 12 hours. The attempt to introduce a glyoxalate both 7-H and 8-H in the X-ray structure of syn-19. The syn
function directly at the benzylic position of 13 with glyox- and anti isomers also displayed distinctive features in terms
ylic acid monohydrate was unsuccessful and gave rise to the of polarity. In the present series of compounds, 14 and 16–
formation of ketone 20 (Table 1, entry 7). In this case, the 19, the syn isomer is less polar than the anti isomer and
benzylic oxidation seems to be sensitive to several factors. consequently more easily isolated from the diastereoiso-
First, high concentrations of the nucleophile are necessary meric mixture.
to obtain a high yield and shorter reaction time. Secondly,
We then focused our efforts on the direct introduction of
the degree of substitution also depends on the carboxylic a carbonyl function at the benzylic position of 13 for a suit-
acid structure. Finally, acid activation of the donor–ac- able synthesis of α-amino alcohol compounds of type 6
ceptor complex seems important for the nucleophilic substi- (Scheme 3).
tution of 13 by carboxylic acids. Despite good yields, the
As already described for para-phenolic derivatives, the
stereoselectivity remained poor in many cases. Moreover, in oxidation of the benzylic position of 13 into ketone deriva-
the case of sterically hindered carboxylic acids such as tive 20 with DDQ was attempted in methanol solu-
trans-cinnamic or phenylglyoxylic acid poor diastereoselec- tion.[10,11,17] After 24 h at 60 °C with 2.2 equivalents of
tivities were also obtained.[19] Nevertheless, dioxidation was DDQ at a concentration of 0.4 mol/L, the formation of the
not observed, certainly due to the electron-withdrawing ef- corresponding methyl ether 21 was observed in 26% yield
fect of the first ester group introduced.[18]
as an inseparable 4:6 mixture of syn/anti diastereoisomers
In order to determine the configuration of the new ste- and 13 recovered in 45% yield (Table 3, entry 1). However,
reocentre at the benzylic position, we studied the chemical when the oxidation was carried out in a mixture of MeOH/
shift of the newly created stereocentre. The resonance signal H2O or THF/H2O (9:1), the starting material 13 was reco-
of this carbon atom in the anti isomers was upfield relative vered. After carrying out the reaction under a range of reac-
5214
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5212–5225

Synthesis of Tetrahydroisoquinoline Natural Alkaloid Analogues
tion conditions, varying the solvents (CH2Cl2, CHCl3, H2O, an 8:2 mixture of HCO2H/H2O and 2.5 equivalents of
AcOH, HCO2H) and experimental procedures (Table 3), DDQ at a concentration of 0.4 mol/L after only 3 hours of
the best conditions for ketone formation were found to be heating at 60 °C (Table 3, entry 9). This also corroborated
Table 1. Benzylic oxidation of 13 by nucleophilic substitution of carboxylic acids.
1
[a] Time required for complete discoloration of the deep-blue charge-transfer complexes. [b] Determined by H NMR measurement of
the crude product.
Table 2. Chemical shifts (δ, ppm) of the C–O carbon atom in the
syn and anti diastereoisomers.
Entry
Compound
δC–O(syn)
δC–O(anti)
1
2
3
4
5
14
16
17
18
19
77.6
76.3
77.8
77.5
80.2
75.8[a]
74.9
75.9
76.0
77.9
[a] Determined from a 2:8 mixture of syn/anti diastereoisomers.
the need for acid activation to increase the rate of the oxi-
dative nucleophilic substitution of this type of compound.
With this efficient method in hand for the preparation of
ketone 20, the Pictet–Spengler cyclization was then
achieved with methyl dimethoxyacetate in refluxing CH2Cl2
Figure 2. X-ray crystal structure of syn-19.
Eur. J. Org. Chem. 2007, 5212–5225
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5215

S. Aubry, S. Pellet-Rostaing, M. Lemaire
FULL PAPER
Table 3. Benzylic oxidation of 13 to ketone 20.
reaction could be rationalized by the reaction proceeding
through the less hindered (E)-iminium isomer 23 (Fig-
ure 3).[26]
Entry Solvent[a]
Solvent Equiv. Time /h Isolated product:
ratio
DDQ
% yield
1
2
3
4
5
6
7
8
9
MeOH
100:0
90:10
90:10
90:10
90:10
90:10
80:20
100:0
2.2
2.2
2.2
2.2
2.2
2.5
2.5
2.5
2.5
24[b]
24[b]
24[b]
24[e]
16[e]
10[e]
10[f]
10[f]
3[f]
21: 26[c]
20: –[d]
MeOH/H2O
THF/H2O
CH2Cl2/H2O
CHCl3/H2O
AcOH/H2O
AcOH/H2O
HCO2H
20: –[d]
20: 59
20: 65
20/14: 51:17
20/14: 69:5
20: 49
Figure 3. Postulated transition state of the (E)-iminium isomer 23
leading to 22.
HCO2H/H2O 80:20
20: 84
[a] The reactions were performed at a substrate concentration of
0.4 mol/L. [b] The deep-blue coloration changed to dark red. [c]
The corresponding methyl ether 21 was obtained in 26% yield as
an inseparable 4:6 mixture of diastereoisomers and 13 recovered in
45% yield. [d] The starting material was recovered. [e] The deep-
blue coloration changed to dark brown and DDHQ precipitated.
[f] The deep-blue coloration turned to pale red and DDHQ precipi-
tated.
Upon exposure to Luche reduction conditions, the
ketone function of 22 was reduced by NaBH4 and
CeCl3·7H2O in a mixture of MeOH/THF (1:3) at –60 °C,
giving 24 in 92% yield.[27] This reaction proceeded with
complete stereoselectivity by hydride attack on the β face
and the stereochemistry of 24 was determined by single-
crystal X-ray analysis (Figure 4).[28] The hydride attack oc-
curred from the less hindered face, apparently due to the
steric hindrance imposed by the ester functionality, through
the activation of CeCl3. Indeed, in the absence of CeCl3,
the reduction was not complete, but the stereoselectivity re-
mained the same.
in the presence of BF3·Et2O, affording exclusively the 1,3-
trans-tetrahydroisoquinoline derivative 22 in 90% yield
(Scheme 4). No detectable traces of the corresponding cis
isomer were observed. The stereochemical outcome of this
Alcohol 24 was then protected as the TBDMS ether in
DMF in the presence of imidazole, giving 25 in 89% yield
(Scheme 4).[29] The selective reduction of ester 25 was
achieved with LiBEt3H in THF (super hydride®)[30] at room
temperature giving the corresponding primary alcohol with
the best results. The latter was immediately protected with
Scheme 3. Benzylic oxidation of 13 to ketone or ether derivatives.
Scheme 4. Synthesis of the fully protected diols 26 and 28.
5216
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5212–5225

Synthesis of Tetrahydroisoquinoline Natural Alkaloid Analogues
24 with methyl thioglycolate was realized under the condi-
tions established by Zhu and co-workers[32] (CF3CO2H/tol-
uene, 0.03 ), which gave rise to 31a and 31b in 92% yield
with a 9:1 diastereoselectivity (Scheme 6).
Figure 4. X-ray crystal structure of 24.
methoxymethyl chloride (MOMCl) in the presence of
iPr2NEt in CH2Cl2, affording 26 in 86% yield over two
steps without observation of oxazolidinone ring-opening,
which was confirmed by 2D NMR experiments (HMBC
and NOESY). The alcohol 24 was also protected with
ethoxymethyl chloride (EOMCl), affording 27 in 91% yield.
The ester function was then reduced with LiBEt3H to the
primary alcohol and protected with EOMCl, affording 28
in 88% yield over two steps.
Scheme 6. Synthesis of methyl thioglycolate derivatives 31a and
31b.
The stereoselectivity could be explained by nucleophilic
The oxazolidinone rings of 26 and 28 were then removed substitution process SN1 or SN2.[33] Competition between
(Scheme 5) following a method described previously (2  both these two mechanisms could also account for the ster-
NaOH, EtOH, 48 h).[31] After removal of the oxazolidinone eoselective outcome of this substitution. In the case of an
ring of 26, hydrolysis of the TBDMS ether function was SN1-type mechanism, the substitution would proceed
also observed. The resulting α-amino alcohols 29 and 30 through a carbocation or the equivalent p-quinone methide
were isolated in 65 and 79% yields respectively.
intermediate. The stereochemistry of 31a was corroborated
This method allowed the formation of differently pro- by X-ray single-crystal analysis (Figure 5).[34] The stereose-
tected α-amino alcohols substituted at the benzylic position lectivity seems to be influenced by the steric hindrance im-
and suitable for the synthesis of the piperazine systems posed by the ester function at the C-1 position and conse-
found in the ecteinascidin family. In addition, in order to quently the nucleophilic substitution of methyl thioglycolate
assess the viability of our synthetic strategy, the reaction of occurred from the β face.
Scheme 5. Synthesis of α-amino alcohols 29 and 30.
Eur. J. Org. Chem. 2007, 5212–5225
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5217

S. Aubry, S. Pellet-Rostaing, M. Lemaire
FULL PAPER
Service Central d’Analyses du CNRS (Solaize, France). Optical ro-
tations were measured at 23 °C using a Perkin–Elmer 241 polarime-
ter. Melting points were measured on a Kofler apparatus.
Methyl (S)-2-Amino-3-(3,4-dihydroxyphenyl)propanoate Hydrochlo-
ride (9):[36–38] Thionyl chloride (12 g, 0.101 mol) was slowly added
during 1 h to -DOPA (8) (10 g, 0.0507 mol) in dry methanol
(500 mL) stirred at 0 °C. The solution was then refluxed over a
period of 24 h before being cooled and co-evaporated with toluene
(100 mL) giving amine chlorohydrate 9 in 99% yield (12.55 g) as a
white solid, m.p. 174–175 °C (methanol/dichloromethane) (lit.:
172–174 °C,[36] 170–171 °C,[37] 170.5–171.5 °C[38]), [α]2D3 = +7.9
(methanol, c = 1) {lit.: [α]2D2 = +14.7 (methanol, c = 12.5)[38]}. H
1
NMR (300 MHz, D2O, 23 °C): δ = 6.78 (d, J = 8.2 Hz, 1 H, 5-H),
6.78 (d, J = 1.8 Hz, 1 H, 2-H), 6.68 (dd, J = 1.8, 8.1 Hz, 1 H, 6-
H), 4.35 (t, J = 6.6 Hz, 1 H, CH2CHN), 3.82 (s, 3 H, OCH3), 3.18
(dd, J = 5.9, 14.6 Hz, 1 H, CHAHBCHN), 3.06 (dd, J = 7.7,
14.6 Hz, 1 H, CHAHBCHN) ppm. 13C NMR (75 MHz, D2O,
23 °C): δ = 170.6 (C=O), 144.8 (ArC), 144.2 (ArC), 126.6 (ArC),
122.3 (ArCH), 117.4 (ArCH), 117.1 (ArCH), 54.8 (CH), 54.0
(OCH3), 35.4 (CH2) ppm. ESI-MS: m/z (%) = 212 (100) [M +
H]+. C10H14ClNO4 (247.68): calcd. C 48.49, H 5.70, N 5.66; found
C 48.24, H 5.42, N 5.36.
Figure 5. X-ray crystal structure of 33a.
Conclusions
To conclude, this report describes how a readily available
molecular template for the functionalization of β-phenyl-
ethylamine at the benzylic position by oxidative nucleophilic
substitution (SNOx) with DDQ can be achieved. New ana-
logues of syncarpamide (1) were prepared in six steps start-
ing from -DOPA with a wide range of functions directly
incorporated at the benzylic position (14–19). An improve-
ment in the oxidation conditions of the benzylic position
was also achieved with the necessary acid activation to yield
the corresponding ketone derivative 20. To assess the Pic-
tet–Spengler cyclization reaction we used 20, which served
Methyl (R)-2-(tert-Butoxycarbonylamino)-3-(3,4-dihydroxyphenyl)-
propanoate (10):[36,39,40] Triethylamine (0.0510 mol, 7.15 mL) and
di-tert-butyl dicarbonate (11.1 g, 0.0510 mol) were added to ester 9
(12.5 g, 0.0505 mol) in methanol (275 mL) at room temperature.
The solution was then stirred for 2 h. After completion (monitored
by TLC, n-heptane/ethyl acetate, 5:5), the solvent was evaporated
and the residue was acidified with 1  hydrochloric acid (50 mL) at
0 °C. The solution was then extracted with ethyl acetate
(3ϫ50 mL), the organic layer was dried with magnesium sulfate
as the probe. After several chemical modifications, the syn- and the solvents evaporated. The crude product was purified by
flash chromatography (silica gel, n-heptane/ethyl acetate, 5:5) giving
10 in 92% yield (14.1 g) as a white solid, m.p. 134–135 °C (meth-
anol) {lit.: 133–135 °C,[36] 140–141 °C (methanol/water),[39]
135 °C[40]}, Rf = 0.3 (n-heptane/ethyl acetate, 5:5), [α]2D3 = +6.9
thesis of α-amino alcohol precursors for the construction
of ecteinascidin analogues was accomplished. Our synthetic
approach differs from most of those previously reported
with respect to the introduction of a hydroxy group at the
C-4 benzylic position in the course of ecteinascidin 743 to-
tal synthesis.[35] We will apply this approach to the synthesis
of the fully functionalized core of the ecteinascidin family.
(methanol, c = 1) {lit.: [α]2D6 = +7.6 (methanol, c = 1.2),[36] [α]2D5
=
+7 (methanol, c = 1)[40]}. 1H NMR (300 MHz, CDCl3, 23 °C): δ =
6.75 (d, J = 8.1 Hz, 1 H, 5-H), 6.66 (br. s, 1 H, 2-H), 6.50 (dd, J =
1.8, 8.1 Hz, 1 H, 6-H), 5.08 (d, J = 8.2 Hz, 1 H, NH), 4.53 (m, 1
H, CH2CHN), 3.72 (s, 3 H, CO2CH3), 2.99 (dd, J = 5.6, 13.9 Hz,
1 H, CHAHBCHN), 2.90 (dd, J = 6.5, 13.9 Hz, 1 H, CHAHBCHN),
1.41 [s, 9 H, O(CH3)3] ppm. 13C NMR (75 MHz, CDCl3, 23 °C): δ
= 172.9 (C=O), 155.6 (NC=O), 144.0 (ArC), 143.1 (ArC), 128.1
(ArC), 121.4 (ArCH), 116.1 (ArCH), 115.4 (ArCH), 80.6 (C), 54.7
(CH), 52.4 (OCH3), 37.6 (CH2), 28.2 (3CH3) ppm. ESI-MS: m/z
(%) = 334 (100) [M + Na]+, 312 (28) [M + H]+, 256 (40) [M + H –
C4H8]+, 212 (36) [M + H – CO2C4H8]+. C15H21NO6·0.2H2O
(314.93): calcd. C 57.21, H 6.74, N 4.45; found C 57.18, H 6.96, N
4.12.
Experimental Section
General Methods: Reagents, starting material and solvents were
supplied by Aldrich, Acros, Lancaster, Alfa Aeser and Fluka, pur-
chased at the highest commercial quality and used without further
purification. All reactions were carried out under argon with dry
solvents under anhydrous conditions unless otherwise noted. NMR
spectra were recorded either on a Bruker AMX-300 (1H: 300 MHz;
13C: 75 MHz) or a Bruker DPX-500 (1H: 500 MHz; 13C: 125 MHz)
instrument using CDCl3 or (CD3)2SO as solvent. The chemical
shifts (δ, ppm) and coupling constants (Hz) are reported in the
standard fashion. In the NMR spectra, the nature of the carbon
atoms (C, CH, CH2, CH3) was determined by recording DEPT 135
spectra. The following abbreviations have been used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet, br. = broad. Electrospray ionization (ESI) mass spec-
trometry (MS) experiments were performed with a thermo Finni-
gan LCQ Advantage mass spectrometer. Analytical thin-layer
chromatography was effected on silica gel Merck 60 F254
(0.25 mm). Flash chromatography was performed on Merck Si 60
silica gel (40–63 µm). Elemental analyses were performed by the
Methyl (S)-2-(tert-Butoxycarbonylamino)-3-(3,4-dimethoxyphenyl)-
propanoate (11):[41] Compound 10 (14 g, 0.045 mol) and methyl io-
dide (27.5 g, 0.202 mol) were added to a stirred solution of dimeth-
ylformamide (100 mL) and potassium carbonate (55.9 g,
0.405 mol). The mixture was then stirred for 24 h. Monitoring by
TLC (n-heptane/ethyl acetate, 7:3) indicated the disappearance of
the starting material. The mixture was then filtered, extracted with
diethyl oxide (3ϫ60 mL) and washed twice with 1  hydrochloric
acid (20 mL). The organic layer was then dried with MgSO4, fil-
tered, evaporated and purified by flash chromatography (silica gel,
n-heptane/ethyl acetate, 9:1 Ǟ 7:3) giving 11 in 89% yield (13.6 g)
as a white solid, m.p. 77–78 °C (n-heptane/ethyl acetate) [lit.: 58–
5218
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5212–5225

Synthesis of Tetrahydroisoquinoline Natural Alkaloid Analogues
60 °C (n-pentane)[41]], Rf = 0.4 (n-heptane/ethyl acetate, 1:1), [α]2D3
= +6.0 (methanol, c = 1) {lit.: [α]2D6 = +66 (dichloromethane, c =
CHAHBCHN, CHAHBCHN) ppm. 13C NMR (75 MHz, CDCl3,
23 °C): δ = 160.3 (NC=O), 149.5 (ArC), 148.5 (ArC), 128.9 (ArC),
1)[41]}. 1H NMR (300 MHz, CDCl3, 23 °C): δ = 6.72 (d, J = 7.9 Hz, 121.5 (ArCH), 112.6 (ArCH), 111.9 (ArCH), 69.9 (CH2), 56.3
1 H, 5-H), 6.56 (m, 2 H, 6-H, 2-H), 4.98 (br. d, J = 8.1 Hz, 1 H, (2OCH3), 54.2 (CH), 41.2 (CH2) ppm. ESI-MS: m/z (%) = 238
NH), 4.47 (dd, J = 6, 13.7 Hz, 1 H, CH2CHN), 3.78 (s, 6 H, 3- (100) [M + H]+. C12H15NO4 (237.25): calcd. C 60.75, H 6.37, N
OCH3, CO2CH3), 3.64 (s,
3
H, 4-OCH3), 2.94 (m,
1
H,
5.90; found C 60.41, H 6.380, N 5.85.
CHAHBCHN), 2.93 (t, J = 6 Hz, 1 H, CHAHBCHN), 1.34 [s, 9 H,
O(CH3)3] ppm. 13C NMR (75 MHz, CDCl3, 23 °C): δ = 172.8
(C=O), 155.4 (NC=O), 149.2 (ArC), 148.4 (ArC), 128.8 (ArC),
121.7 (ArCH), 112.7 (ArCH), 111.6 (ArCH), 80.2 (C), 56.2
(OCH3), 56.1 (OCH3), 54.8 (CH), 52.6 (OCH3), 38.2 (CH2), 28.7
(3CH3) ppm. ESI-MS: m/z (%) = 362 (100) [M + Na]+, 284 (22)
[M + H – C4H8]+, 240 (29) [M + H – CO2C4H8]+. C17H25NO6
(339.38): calcd. C 60.16, H 7.42, N 4.13; found C 59.84, H 7.32, N
4.11.
(R)-(3,4-Dimethoxyphenyl)[(R)-2-oxooxazolidin-4-yl]methyl Acetate
(syn-14) and (S)-(3,4-Dimethoxyphenyl)[(R)-2-oxooxazolidin-4-yl]-
methyl Acetate (anti-14): DDQ (0.479 g, 2.11 mmol) was added to
a suspension of 13 (0.25 g, 1.05 mmol) in acetic acid (2.6 mL) and
stirred at 60 °C for 24 h. After filtration of the precipitate the solu-
tion was diluted with dichloromethane (20 mL), washed with a sat-
urated sodium hydrogen carbonate aqueous solution (2ϫ15 mL)
and brine (10 mL), dried with magnesium sulfate and filtered. The
crude product was concentrated and purified by flash chromatog-
raphy (silica gel, cyclohexane/ethyl acetate, 7:3 Ǟ 5:5) giving syn-
14 and anti-14 in 82% yield (0.255 g) and as a 45:55 mixture of
syn/anti diastereoisomers. The less polar diastereoisomer syn-14
was separated in 26% yield (0.076 g) as a white solid, m.p. 160–
tert-Butyl [(S)-2-(3,4-Dimethoxyphenyl)-1-(hydroxymethyl)ethyl]-
carbamate (12):[41,42] Lithium borohydride (1.67 g, 0.0767 mol) was
added to a stirred solution of ester 11 (13 g, 0.0383 mol) in a 1:2
solution of methanol/tetrahydrofuran (200 mL) at 0 °C. The reac-
tion progress was then controlled by TLC (n-heptane/ethyl acetate,
5:5) until disappearance of the starting material. After 2 h of stir-
ring, the solution was diluted with dichloromethane and acidified
with 1  hydrochloric acid (50 mL) and water (50 mL) at 0 °C. The
organic layer was separated and the aqueous phase extracted with
dichloromethane (2ϫ50 mL). The organic layer was then dried
with magnesium sulfate, filtered, evaporated and purified by flash
chromatography (silica gel, n-heptane/ethyl acetate, 8:2 Ǟ 5:5) giv-
ing 12 in 92% yield (10.9 g) as a white solid, m.p. 91–92 °C (n-
heptane/ethyl acetate) [lit.: 65–67 °C (n-pentane),[41] 92–93 °C[42]],
Rf = 0.2 (n-heptane/ethyl acetate, 1:1), [α]2D3 = –19.6 (methanol, c =
0.3) {lit.: [α]2D6 = –26.7 (dichloromethane, c = 1),[41] [α]2D5 = –19.6 (c
= 0.3, methanol)[42]}. 1H NMR (300 MHz, CDCl3, 23 °C): δ = 6.56
(m, 3 H, 2-H, 5-H, 6-H, ArH), 4.87 (br. s, 1 H, NH), 4.47 (dd, J
= 6, 13.7 Hz, 1 H, CH2CHN), 3.86 (s, 3 H, 3-OCH3), 3.85 (s, 3 H,
4-OCH3), 3.83 (m, 1 H, CH2CHN), 2.94 (dd, J = 2.9, 11 Hz, 1 H,
CHAHBOH), 3.56 (dd, J = 5.8, 10.9 Hz, 1 H, CHAHBOH), 2.78 (d,
J = 7.1 Hz, 1 H, CHAHBCHN, CHAHBCHN), 2.63 (br. s, 1 H,
OH), 1.41 [s, 9 H, O(CH3)3] ppm. 13C NMR (75 MHz, CDCl3,
23 °C): δ = 156.6 (NC=O), 149.3 (ArC), 148.1 (ArC), 130.7 (ArC),
121.7 (ArCH), 112.8 (ArCH), 111.7 (ArCH), 80.1 (C), 64.6 (CH),
56.3 (OCH3), 56.2 (OCH3), 54.0 (CH), 37.6 (CH2), 28.8
(3CH3) ppm. ESI-MS: m/z (%) = 334 (100) [M + Na]+, 212 (6) [M
+ H]+, 256 (17) [M + H – C4H8]+, 212 (38) [M + H – CO2C4H8]+.
C16H25NO5 (311.37): calcd. C 61.72, H 8.09, N 4.50; found C
61.54, H 8.21, N 4.29.
(S)-4-(3,4-Dimethoxybenzyl)oxazolidin-2-one (13):[43] Thionyl chlo-
ride (16.05 g, 0.135 mol) was slowly added to alcohol 12 (10.5 g,
0.0337 mol) in dry tetrahydrofuran (230 mL) stirred at 0 °C. The
resulting solution was stirred at room temperature for 4 h. Then
the solution was diluted with dichloromethane (200 mL), washed
with a saturated sodium carbonate aqueous solution (3ϫ150 mL)
and brine (100 mL), dried with magnesium sulfate and filtered. The
crude product was purified by flash chromatography (silica gel, n-
heptane/ethyl acetate, 6:4 Ǟ 5:5) giving 13 in 81% yield (6.47 g) as
a white solid, m.p. 92–93 °C (ethyl acetate), Rf = 0.4 (ethyl acetate),
[α]2D3 = –51.6 (c = 1, dichloromethane). HPLC: Chiralcel OJ-H,
25ϫ0.4 i.d., Daicel; retention time = 40.19 min, eluent: n-heptane/
ethanol (60:40) isocratic conditions, flow 0.5 mL/min, UV 280 nm.
161 °C (n-heptane/ethyl acetate), Rf = 0.6 (ethyl acetate), [α]2D3
=
–54.4 (dichloromethane, c = 0.8). 1H NMR (500 MHz, CDCl3,
23 °C): δ = 6.97 (br. s, 1 H, NH), 6.91 (d, J = 8.2 Hz, 1 H, 6-H),
6.83 (m, 2 H, 2-H, 5-H), 5.62 (d, J = 7.1 Hz, 1 H, CHOCOCH3),
4.20 (m,
2 H, CHCHAHBO, OCH2CHN), 4.03 (m, 1 H,
CHCHAHBO), 3.87 (s, 3 H, 3-OCH3), 3.84 (s, 3 H, 4-OCH3), 2.10
(s, 3 H, CH3CO) ppm. 13C NMR (125 MHz, CDCl3, 23 °C): δ =
170.5 (OC=O), 160.2 (NC=O), 150.1 (ArC), 149.7 (ArC), 128.3
(ArC), 120.3 (ArCH), 111.7 (ArCH), 110.6 (ArCH), 77.6 (CH),
66.7 (CH2), 56.5 (CH), 56.4 (OCH3), 56.3 (OCH3), 21.4
(CH3CO) ppm. ESI-MS: m/z (%) = 318 (92) [M + Na]+, 296 (35)
[M + H]+, 236 (100) [M + H – CH3CO2H]+. C14H17NO6 (295.29):
calcd. C 56.94, H 5.80, N 4.74; found C 56.55, H 6.09, N 4.37.
(R)-(3,4-Dimethoxyphenyl)[(R)-2-oxooxazolidin-4-yl]methyl Acry-
late (cis-15) and (S)-(3,4-Dimethoxyphenyl)[(R)-2-oxooxazolidin-4-
yl]methyl Acrylate (anti-15): A suspension of 13 (0.25 g, 1.05 mmol)
in acrylic acid (2.6 mL) and DDQ (0.479 g, 2.11 mmol) was stirred
at 60 °C for 24 h. After filtration of the precipitate, the solution
was diluted with dichloromethane (20 mL), washed with a satu-
rated sodium hydrogen carbonate aqueous solution (2ϫ15 mL)
and brine (10 mL), dried with MgSO4 and filtered. The crude prod-
uct was concentrated and purified by flash chromatography (silica
gel, n-heptane/ethyl acetate, 7:3 Ǟ 5:5) giving syn-15 and anti-15
in 94% yield (0.304 g) as a colourless oil and as an inseparable
45:55 mixture of syn/anti diastereoisomers. ESI-MS: m/z (%) = 330
(22) [M + Na]+, 308 (19) [M + H]+, 236 (100) [M + H –
CH2CHCO2H]+. C15H17NO6 (307.29): calcd. C 58.63, H 5.58, N
4.56; found C 58.22, H 5.74, N 4.18.
(R)-(3,4-Dimethoxyphenyl)[(R)-2-oxooxazolidin-4-yl]methyl 3-Meth-
ylbut-2-enoate (syn-16) and (S)-(3,4-Dimethoxyphenyl)[(R)-2-oxoox-
azolidin-4-yl]methyl 3-Methylbut-2-enoate (anti-16): DDQ (0.479 g,
2.11 mmol) was added to a solution of 13 (0.25 g, 1.05 mmol) and
3,3-dimethylacrylic acid (2.11 g, 21.10 mmol) suspended in chloro-
form (2.6 mL). The resulting deep-blue mixture was stirred at 60 °C
for 36 h. After filtration of the precipitate, the solution was diluted
with dichloromethane (20 mL), washed with a saturated sodium
bicarbonate aqueous solution (2ϫ15 mL) and brine (10 mL), dried
with magnesium sulfate and filtered. The crude product was con-
1H NMR (300 MHz, CDCl3, 23 °C): δ = 6.78 (d, J = 8.1 Hz, 1 H, centrated and purified by flash chromatography (silica gel, n-hep-
5-H), 6.78 (d, J = 1.9 Hz, 1 H, 2-H), 6.68 (dd, J = 1.9, 7.9 Hz, 1 tane/ethyl acetate, 8:2 Ǟ 6:4) giving syn-16 (23%, 0.081 g) and
H, 6-H), 5.65 (br. s, 1 H, NH), 4.44 (t, J = 8.2 Hz, 1 H, CH2CHN), anti –16 (10%, 0.035 g) as white solids in 75% overall yield
4.13 (m, 1 H, CHCHAHBO), 4.05 (m, 1 H, CHCHAHBO), 3.87 (s, (0.265 g) as a 40:60 mixture of syn/anti diastereoisomers. Data for
3 H, 3-OCH3), 3.86 (s, 3 H, 4-OCH3), 3.06 (d, J = 6.8 Hz, 2 H,
compound syn-16: m.p. 70–71 °C (ethyl acetate), Rf = 0.7 (ethyl
Eur. J. Org. Chem. 2007, 5212–5225
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5219

S. Aubry, S. Pellet-Rostaing, M. Lemaire
FULL PAPER
acetate), [α]2D3 = –56.3 (dichloromethane, c = 0.65). 1H NMR
J = 8.6 Hz, 1 H, 6-H), 6.87 (d, J = 8.2 Hz, 1 H, 5-H), 6.84 (d, J =
(500 MHz, CDCl3, 23 °C): δ = 6.90 (dd, J = 1.9, 8.2 Hz, 1 H, 6- 1.2 Hz, 1 H, 2-H), 5.88 (m, 1 H, COCH2CHCH2), 5.77 (br. s, 1
H), 6.84 (m, 2 H, 2-H, 5-H), 6.23 (br. s, 1 H, NH), 5.74 [m, 1 H,
(CH3)2CCHCO2], 5.61 [d, J = 7.3 Hz, 1 H, CHOCOCHC(CH3)2],
4.22 (dd, J = 8.5, 17 Hz, 1 H, CHCHAHBO), 4.18 (m, 1 H,
OCH2CHN), 4.08 (dd, J = 4.7, 16.8 Hz, 1 H, CHCHAHBO), 3.84
H, NH), 5.73 (d, J = 6 Hz, 1 H, CHOCOCH3), 5.19 (br. s, 1 H,
COCH2CHCHAHB), 5.17 (d, J = 5.4 Hz, 1 H, COCH2CH-
CHAHB), 4.38 (t, J = 8.8 Hz, 1 H, CHCHAHBO), 4.29 (m, 1 H,
CHCHAHBO), 4.29 (m, 1 H, OCH2CHN), 3.86 (s, 3 H, 3-OCH3),
(s, 3 H, 3-OCH3), 3.82 (s, 3 H, 4-OCH3), 2.07 (d, J = 1.0 Hz, 3 H, 3.85 (s,
CH3), 1.85 (d, J = 1.0 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz, CHAHBCHCH2, COCHAHBCHCH2) ppm. 13C NMR (125 MHz,
CDCl3, 23 °C): 165.6 (OC=O), 159.7 (NC=O), 159.7 CDCl3, 23 °C): δ = 170.8 (OC=O), 159.5 (NC=O), 150.0 (ArC),
[C(CH3)2], 149.9 (ArC), 149.7 (ArC), 128.8 (ArC), 119.9 (ArCH), 149.7 (ArC), 129.9 (CH), 128.1 (ArC), 119.7 (CH2), 119.6 (ArCH),
3 H, 4-OCH3), 3.15 (d, J = 6.6 Hz, 2 H, CO-
δ
=
115.5 [(CH3)2CCHCO2], 111.8 (ArCH), 110.3 (ArCH), 76.3 (CH),
66.7 (CH2), 56.6 (CH), 56.4 (OCH3), 56.3 (OCH3), 27.9 (CH3), 20.8
(CH3) ppm. ESI-MS: m/z (%) = 358 (100) [M + Na]+, 236 (28) [M
111.8 (ArCH), 110.2 (ArCH), 75.9 (CH), 66.9 (CH2), 56.4 (CH),
56.4 (OCH3), 56.3 (OCH3), 39.5 (CH2) ppm. ESI-MS: m/z (%) =
344 (100) [M + Na]+, 236 (258) [M + H – H2CCHCH2CO2H]+.
+ H – (CH3)2CCHCO2H]+. C17H21NO6 (335.35): calcd. C 60.89, C16H19NO6 (321.33): calcd. C 59.81, H 5.96, N 4.36; found C
H 6.31, N 4.18; found C 60.81, H 6.61, N 3.90. Data for compound
anti-16: m.p. 64–65 °C (ethyl acetate), Rf = 0.6 (ethyl acetate),
[α]2D3 = +16.2 (dichloromethane, c = 0.4). 1H NMR (500 MHz,
CDCl3, 23 °C): δ = 6.93 (dd, J = 1.9, 8.2 Hz, 1 H, 6-H), 6.87 (m,
2 H, 2-H, 5-H), 5.77 [br. s, 1 H, (CH3)2CCHCO2], 5.73 [d, J =
6.9 Hz, 1 H, CHOCOCHC(CH3)2], 5.02 (br. s, 1 H, NH), 4.46 (t,
J = 8.8 Hz, 1 H, CHCHAHBO), 4.35 (dd, J = 5, 9.1 Hz, 1 H,
CHCHAHBO), 4.19 (m, 1 H, OCH2CHN), 3.91 (s, 3 H, 3-OCH3),
3.89 (s, 3 H, 4-OCH3), 2.17 (d, J = 0.9 Hz, 3 H, CH3), 1.94 (d, J
= 0.6 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz, CDCl3, 23 °C): δ
= 165.5 (OC=O), 160.2 (NC=O), 159.0 [C(CH3)2], 149.9 (ArC),
149.8 (ArC), 128.9 (ArC), 119.8 (ArCH), 115.3 [(CH3)2CCHCO2],
111.8 (ArCH), 110.1 (ArCH), 74.9 (CH), 67.4 (CH2), 56.5 (CH),
56.4 (OCH3), 56.4 (OCH3), 28.0 (CH3), 20.9 (CH3) ppm. ESI-MS:
m/z (%) = 358 (100) [M + Na]+, 236 (25) [M + H – (CH3)2-
CCHCO2H]+. C17H21NO6 (335.35): calcd. C 60.89, H 6.31, N 4.18;
found C 60.78, H 6.60, N 3.90.
59.39, H 6.06, N 4.10.
(R)-(3,4-Dimethoxyphenyl)[(R)-2-oxooxazolidin-4-yl]methyl Cinna-
mate (syn-18) and (S)-(3,4-Dimethoxyphenyl)[(R)-2-oxooxazolidin-
4-yl]methyl Cinnamate (anti-18): DDQ (0.479 g, 2.11 mmol) was
added to a solution of 13 (0.25 g, 1.05 mmol) and anti-cinnamic
acid (3.13 g, 21.10 mmol) suspended in chloroform (2.6 mL). The
resulting deep-blue mixture was stirred at 60 °C for 36 h. After fil-
tration of the precipitate, the solution was diluted with dichloro-
methane (20 mL) and washed with a saturated sodium hydrogen
carbonate aqueous solution (2ϫ15 mL) and brine (10 mL), dried
with magnesium sulfate and filtered. The crude product was con-
centrated and purified by flash chromatography (silica gel, n-hep-
tane/ethyl acetate, 8:2 Ǟ 5:5) giving syn-18 (26%, 0.105 g) and anti-
18 (15%, 0.060 g) as white solids in 72% overall yield (0.290 g) and
as a 40:60 mixture of syn/anti diastereoisomers. Data for compound
syn-18: m.p. 88 °C (chloroform), Rf = 0.8 (ethyl acetate), [α]2D3
=
+17.5 (dichloromethane, c = 1.1). 1H NMR (500 MHz, CDCl3,
23 °C): δ = 7.72 (d, J = 16.1, Hz 1 H, C6H5CHCHCOO), 7.90 (m,
2 H, 2Ј-H, 6Ј-H), 7.38 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 6.94 (dd, J = 1.4,
8.5 Hz, 1 H, 6-H), 6.86 (m, 2 H, 2-H, 5-H), 6.48 (d, J = 16.1 Hz, 1
H, C6H5CHCHCO2), 6.14 (br. s, 1 H, NH), 5.72 [d, J = 6.9 Hz, 1
H, CHO(CO)C2H2C6H5], 4.29 (m, 1 H, OCH2CHN), 4.28 (m, 1
H, CHCHAHBO), 4.11 (m, 1 H, CHCHAHBO), 3.89 (s, 3 H, 3-
OCH3), 3.86 (s, 3 H, 4-OCH3) ppm. 13C NMR (125 MHz, CDCl3,
23 °C): δ = 166.3 (OC=O), 159.6 (NC=O), 150.1 (ArC), 149.8
(ArC), 146.8 (CHalkene), 134.5 (ArC), 131.1 (ArCH), 129.3
(2ArCH), 128.7 (2ArCH), 128.4 (ArC), 119.9 (ArCH), 117.4
(CHalkene), 111.9 (ArCH), 110.3 (ArCH), 77.5 (CH), 66.8 (CH2),
56.6 (CH), 56.5 (OCH3), 56.3 (OCH3) ppm. ESI-MS: m/z (%) =
406 (100) [M + Na]+, 236 (12) [M + H – C6H5C2H2CO2H]+.
C21H21NO6 (383.39): calcd. C 65.79, H 5.52, N 3.65; found C
65.78, H 5.62, N 3.55. Data for compound anti-18: m.p. 77–78 °C
(R)-(3,4-Dimethoxyphenyl)[(R)-2-oxooxazolidin-4-yl]methyl But-3-
enoate (syn-17) and (S)-(3,4-Dimethoxyphenyl)[(R)-2-oxooxazolidin-
4-yl]methyl But-3-enoate (anti-17): A suspension of 13 (0.25 g,
1.05 mmol), but-3-enoic acid (1.82 g, 1.80 mL, 21.1 mmol) and
DDQ (0.479 g, 2.11 mmol) in chloroform (0.86 mL) was stirred at
60 °C for 36 h. After filtration of the precipitate, the solution was
diluted with dichloromethane (20 mL), washed with a saturated so-
dium bicarbonate aqueous solution (2ϫ15 mL) and brine (10 mL),
dried with magnesium sulfate and filtered. The crude product was
concentrated and purified by flash chromatography (silica gel, n-
heptane/ethyl acetate, 8:2 Ǟ 6:4) giving syn-17 (22%, 0.075 g) and
anti-17 (13%, 0.044 g) as white solids in 73% overall yield (0.247 g)
and as a 45:55 mixture of syn/anti diastereoisomers. Data for com-
pound syn-17: m.p. 50–51 °C (dichloromethane), Rf = 0.7 (ethyl
acetate), [α]2D3 = –63.4 (dichloromethane, c = 0.5). 1H NMR
(500 MHz, CDCl3, 23 °C): δ = 6.90 (dd, J = 1.9, 8.2 Hz, 1 H, 6- (dichloromethane), Rf = 0.7 (ethyl acetate), [α]2D3 = –75.0 (dichloro-
H), 6.84 (m, 3 H, 2-H, 5-H, NH), 5.89 (m, 1 H, COCH2CHCH2), methane, c = 0.6). 1H NMR (500 MHz, CDCl3, 23 °C): δ = 7.73
5.64 (d, J = 7.6 Hz, 1 H, CHOCOCH3), 5.16 (br. s, 1 H,
COCH2CHCHAHB), 5.13 (dd, J = 1.2, 5.3 Hz, 1 H, COCH2CH-
CHAHB), 4.21 (m, 2 H, CHCHAHBO, OCH2CHN), 4.05 (m, 1 H,
(d, J = 16.1 Hz, 1 H, C6H5CHCHCO2), 7.90 (m, 2 H, 2Ј-H, 6Ј-H),
7.38 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 6.95 (dd, J = 1.7, 8.4 Hz, 1 H, 6-
H), 6.87 (m, 2 H, 2-H, 5-H), 6.47 (d, J = 16.1 Hz, 1 H,
CHCHAHBO), 3.87 (s, 3 H, 3-OCH3), 3.86 (s, 3 H, 4-OCH3), 3.14 C6H5CHCHCOO), 5.82 [d, J = 6.6 Hz, 1 H, CHO(CO)C2H2C6H5],
(dd, J = 6.9, 16.7 Hz, 1 H, COCHAHBCHCH2), 3.14 (dd, J = 7.0, 5.30 (br. s, 1 H, NH), 4.48 (m, J = 8.8 Hz, 1 H, CHCHAHBO),
16.7 Hz, 1 H, COCHAHBCHCH2) ppm. 13C NMR (125 MHz, 4.38 (dd, J = 4.7, 9.1 Hz, 1 H, CHCHAHBO), 4.26 (m, 1 H,
CDCl3, 23 °C): δ = 171.0 (OC=O), 160.2 (NC=O), 150.1 (ArC), OCH2CHN), 3.89 (s, 3 H, 3-OCH3), 3.87 (s, 3 H, 4-OCH3) ppm.
149.8 (ArC), 130.2 (CH), 128.2 (ArC), 120.2 (ArCH), 119.4 (CH2), 13C NMR (125 MHz, CDCl3, 23 °C): δ = 166.2 (OC=O), 159.2
111.8 (ArCH), 110.5 (ArCH), 77.8 (CH), 66.7 (CH2), 56.6 (CH), (NC=O), 150.1 (ArC), 149.8 (ArC), 147.0 (CHalkene), 134.4 (ArC),
56.4 (OCH3), 56.3 (OCH3), 39.3 (CH2) ppm. ESI-MS: m/z (%) =
131.2 (ArCH), 129.4 (2ArCH), 128.7 (2ArCH), 128.4 (ArC), 119.8
(ArCH), 117.2 (CHalkene), 111.8 (ArCH), 110.3 (ArCH), 76.0 (CH),
344 (100) [M + Na]+, 236 (258) [M + H – H2CCHCH2CO2H]+.
C16H19NO6·H2O (339.34): calcd. C 56.63, H 6.24, N 4.13; found C 67.3 (CH2), 56.5 (CH), 56.4 (OCH3), 56.4 (OCH3) ppm. ESI-MS:
56.60, H 6.16, N 4.18. Data for compound anti-17: m.p. 45–46 °C
m/z (%) = 406 (100) [M + Na]+, 236 (6) [M + H – C6H5C2H2-
CO2H]+. C21H21NO6·0.25CH2Cl2 (404.62): calcd. C 63.02, H 5.31,
N 3.46; found C 62.78, H 5.62, N 3.78.
(dichloromethane), Rf = 0.6 (ethyl acetate), [α]2D3 = +56.9 (dichloro-
1
methane, c = 2). H NMR (500 MHz, CDCl3, 23 °C): δ = 6.87 (d,
5220
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5212–5225

Synthesis of Tetrahydroisoquinoline Natural Alkaloid Analogues
(R)-(3,4-Dimethoxyphenyl)[(R)-2-oxooxazolidin-4-yl]methyl 2-Oxo-
2-phenylacetate (syn-19) and (S)-(3,4-Dimethoxyphenyl)[(R)-2-
oxooxazolidin-4-yl]methyl 2-Oxo-2-phenylacetate (anti-19): A sus-
pension of oxazolidin-2-one 13 (0.25 g, 1.05 mmol), DDQ (0. 479 g,
2.11 mmol) in dichloromethane (2.6 mL) and phenylglyoxylic acid
(2.53 g, 8.43 mmol) was stirred at 60 °C for 12 h. After filtration of
the pale brown precipitate, the solution was diluted with dichloro-
methane (20 mL) and washed with a saturated sodium hydrogen
carbonate aqueous solution (2ϫ15 mL) and brine (10 mL), dried
with magnesium sulfate and filtered. The crude product was con-
centrated and purified by flash chromatography (silica gel, n-hep-
tane/ethyl acetate, 8:2 Ǟ 5:5) giving syn-19 (29%, 0.117 g) and anti-
19 (22%, 0.089 g) as white solids in 96% overall yield (0.390 g) and
as a 45:55 mixture of syn/anti diastereoisomers. Data for compound
syn-19: m.p. 178–179 °C (dichloromethane), Rf = 0.8 (ethyl ace-
tate), [α]2D3 = –72 (dichloromethane, c = 1). 1H NMR (500 MHz,
CDCl3, 23 °C): δ = 7.90 (d, J = 7.2 Hz, 2 H, 2Ј-H, 6Ј-H), 7.64 (t,
J = 7.9 Hz, 1 H, 4Ј-H), 7.47 (t, J = 7.9 Hz, 2 H, 3Ј-H, 5Ј-H), 7.01
(d, J = 1.5, 8.2 Hz, 1 H, 6-H), 6.92 (d, J = 1.3 Hz, 1 H, 2-H), 6.90
(d, J = 8.2 Hz, 1 H, 5-H), 6.26 (br. s, 1 H, NH), 5.82 [d, J = 8.2 Hz,
1 H, CHO(CO)2C6H5], 4.35 (m, 1 H, OCH2CHN), 4.25 (t, J =
9.0 Hz, 1 H, CHCHAHBO), 4.09 (dd, J = 5.3, 9.1 Hz, 1 H,
CHCHAHBO), 3.91 (s, 3 H, 3-OCH3), 3.90 (s, 3 H, 4-OCH3) ppm.
13C NMR (125 MHz, CDCl3, 23 °C): δ = 185.6 (ArC=O), 162.8
(OC=O), 159.3 (NC=O), 150.6 (ArC), 150.0 (ArC), 135.6 (ArCH),
132.6 (ArC), 130.5 (2ArCH), 129.4 (2ArCH), 126.8 (ArC), 120.7
(ArCH), 111.8 (ArCH), 110.4 (ArCH), 80.2 (CH), 66.3 (CH2), 56.5
(OCH3), 56.4 (OCH3), 56.1 (CH) ppm. MS-ESI: m/z (%) = 408
(100) [M + Na]+, 386 (57) [M + H]+, 236 (83) [M + H – C6H5CO-
CO2H]+. C20H19NO7 (385.37): calcd. C 62.33, H 4.97, N 3.63;
found C 61.96, H 5.03, N 3.57. Data for compound anti-19: m.p.
(s, 3 H, 4-OCH3) ppm. 13C NMR (125 MHz, CDCl3, 23 °C): δ =
193.4 (C=O), 159.4 (NC=O), 155.0 (ArC), 150.3 (ArC), 126.7
(ArC), 123.1 (ArCH), 110.9 (ArCH), 110.8 (ArCH), 67.2 (CH2),
56.8 (OCH3), 56.7 (OCH3), 56.5 (CH) ppm. ESI-MS: m/z (%) =
252 (100) [M + H]+. C12H13NO5 (251.24): calcd. C 57.37, H 5.22,
N 5.58; found C 57.67, H 5.48, N 5.28.
(4R)-4-[(3,4-Dimethoxyphenyl)(methoxy)methyl]oxazolidin-2-one
(21): DDQ (0.422 g, 1.86 mmol) was added to oxazolidinone 13
(0.2 g, 0.844 mmol) in MeOH (2.1 mL) and the solution stirred at
60 °C for 24 h. The dark-red solution was then diluted with dichlo-
romethane (10 mL), washed with a saturated sodium hydrogen car-
bonate aqueous solution (3ϫ10 mL) and brine (15 mL), dried with
magnesium sulfate and filtered. The crude product was concen-
trated and purified by flash chromatography (silica gel, n-heptane/
ethyl acetate, 7:3) giving 21 in 26% yield (0.059 g) as a pale-yellow
oil and as an inseparable 4:6 mixture of syn/anti diastereoisomers.
ESI-MS: m/z (%) = 290 (100) [M + Na]+. C13H17NO5·0.1H2O
(269.08): calcd. C 57.97, H 6.32, N 5.20; found C 57.55, H 6.53, N
4.93.
Methyl (5S,10aR)-7,8-Dimethoxy-3,10-dioxo-1,5,10,10a-tetrahydro-
3H-oxazolo[3,4-b]isoquinoline-5-carboxylate (22): BF3·Et2O (11.3 g,
79.6 mmol) was added to a stirred solution of ketone 20 (1.0 g,
3.98 mmol) and methyl dimethoxyacetate (1.07 g, 79.7 mmol) in
dichloromethane (42 mL), and the mixture was stirred at reflux for
4 h. After cooling, the solution was diluted with dichloromethane
(50 mL), washed with a saturated sodium hydrogen carbonate
aqueous solution (100 mL) and brine (20 mL), dried with magne-
sium sulfate and filtered. The crude product was concentrated and
purified by flash chromatography (silica gel, cyclohexane/ethyl ace-
tate, 6:4) giving 22 in 90% yield (1.15 g) as a pale-yellow solid, m.p.
79–80 °C (ethyl acetate), Rf = 0.6 (AcOEt), [α]2D3 = –78.0 (dichloro-
methane, c = 0.5). 1H NMR (300 MHz, CDCl3, 23 °C): δ = 7.34
(s, 1 H, 5-H), 6.79 (s, 1 H, 8-H), 5.44 (s, 1 H, CHCO2Me), 4.71
(dd, J = 5.9, 8.9 Hz, 1 H, OCH2CHN), 4.49 (m, 2 H, CHCHAHBO,
CHCHAHBO), 3.74 (s, 3 H, 7-OCH3), 3.50 (s, 3 H, OCH3), 3.68 (s,
3 H, 6-OCH3) ppm. 13C NMR (75 MHz, CDCl3, 23 °C): δ = 190.8
(C=O), 169.4 (CO2Me), 157.1 (NC=O), 155.2 (ArC), 150.2 (ArC),
131.6 (ArC), 122.9 (ArC), 109.8 (ArCH), 108.8 (ArCH), 65.6
(CH2), 56.9 (CH), 56.6 (OCH3), 56.5 (OCH3), 55.4 (CH), 53.6
(OCH3) ppm. ESI-MS: m/z (%) = 344 (100) [M + Na]+, 322 (26)
[M + H]+. C15H15NO7 (321.28): calcd. C 56.08, H 4.71, N 4.36;
found C 55.98, H 4.79, N 4.18.
169–170 °C (dichloromethane), Rf = 0.7 (ethyl acetate), [α]2D3
=
+23.2 (dichloromethane, c = 0.6). 1H NMR (500 MHz, CDCl3,
23 °C): δ = 7.89 (d, J = 7.3 Hz, 2 H, 2Ј-H, 6Ј-H), 7.52 (t, J =
7.5 Hz, 1 H, 4Ј-H), 7.48 (t, J = 7.8 Hz, 2 H, 3Ј-H, 5Ј-H), 6.97 (d,
J = 8.2 Hz, 1 H, 6-H), 6.90 (d, J = 1.9 Hz, 1 H, 2-H), 6.88 (d, J =
8.2 Hz, 1 H, 5-H), 5.91 [d, J = 4.2 Hz, 1 H, CHO(CO)2C6H5], 5.63
(br. s, 1 H, NH), 4.47 (t, J = 8.6 Hz, 1 H, CHCHAHBO), 4.35 (m,
1 H, CHCHAHBO), 4.31 (m, 1 H, OCH2CHN), 3.88 (s, 3 H, 3-
OCH3), 3.86 (s, 3 H, 4-OCH3) ppm. 13C NMR (125 MHz, CDCl3,
23 °C): δ = 185.7 (ArC=O), 163.0 (OC=O), 159.1 (NC=O), 150.4
(ArC), 150.0 (ArC), 135.7 (ArCH), 132.4 (ArC), 130.4 (2ArCH),
129.5 (2ArCH), 127.1 (ArC), 120.2 (ArCH), 111.8 (ArCH), 110.0
(ArCH), 77.9 (CH), 67.1 (CH2), 56.5 (OCH3), 56.4 (OCH3), 56.2
(CH) ppm. ESI-MS: m/z (%) = 408 (77) [M + Na]+, 236 (100) [M
+ H – C6H5COCO2H]+. C20H19NO7·0.2H2O (388.97): calcd. C
61.76, H 4.99, N 3.60; found C 61.56, H 5.10, N 3.56.
Methyl (5S,10S,10aR)-10-Hydroxy-7,8-dimethoxy-3-oxo-1,5,10,10a-
tetrahydro-3H-oxazolo[3,4-b]isoquinoline-5-carboxylate (24):
A
solution of ketone 22 (0.120 g, 0.374 mmol) and CeCl3·7H2O
(0.417 g, 1.12 mmol) in tetrahydrofuran/methanol (2.7+0.9 mL)
was cooled to –65 °C and treated with solid NaBH4 (0.018 g,
0.411 mmol). After 0.5 h at –60 °C, the reaction mixture was di-
luted with dichloromethane (10 mL) and quenched with 1  hydro-
chloric acid (2 mL). The aqueous layer was extracted twice with
dichloromethane (2ϫ5 mL). Combined extracts were washed with
brine (5 mL), dried with magnesium sulfate and filtered. The crude
product was concentrated and purified by flash chromatography
(silica gel, n-heptane/ethyl acetate, 6:4) giving 24 in 92% yield
(0.111 g) as a white solid, m.p. 219–220 °C (dichloromethane), Rf
(R)-4-(3,4-Dimethoxybenzoyl)oxazolidin-2-one (20): DDQ (2.40 g,
10.6 mmol) was added to oxazolidinone 13 (1 g, 4.22 mmol) in for-
mic acid/water (8.48:2.12 mL). The resulting solution was stirred at
60 °C for 3 h. After filtration of the precipitate, the solution was
diluted with dichloromethane (50 mL), washed with a saturated
NaHCO3 aqueous solution (4ϫ50 mL) and brine (40 mL), dried
with magnesium sulfate and filtered. The crude product was con-
centrated and purified by flash chromatography (silica gel, n-hep-
tane/ethyl acetate, 6:4 Ǟ 5:5) giving 20 as a white solid in 84%
yield (0.900 g), m.p. 168–169 °C (dichloromethane), Rf = 0.5 (ethyl
acetate), [α]2D3 = +44.4 (dichloromethane, c = 0.5). 1H NMR
(500 MHz, CDCl3, 23 °C): δ = 7.49 (d, J = 1.9 Hz, 1 H, 2-H), 7.34
(dd, J = 1.9, 8.5 Hz, 1 H, 6-H), 6.92 (d, J = 8.2 Hz, 1 H, 5-H), 5.89
(br. s, 1 H, NH), 5.22 (dd, J = 6.6, 10 Hz, 1 H, OCH2CHN), 4.80
= 0.6 (ethyl acetate), [α]2D3 = –75.2 (methanol, c = 0.5). H NMR
1
[500 MHz, (CD3)2SO, 23 °C]: δ = 7.15 (s, 1 H, 5-H), 7.00 (s, 1 H,
8-H), 6.10 (d, J = 6.9 Hz, 1 H, OH), 5.27 (s, 1 H, CHCO2Me), 4.73
(t, J = 8.5 Hz, 1 H, CHCHAHBO), 4.47 (t, J = 7.9 Hz, 1 H,
CHOH), 4.38 (dd, J = 6.6, 9.8 Hz, 1 H, CHCHAHBO), 3.93 [dd, J
(t, J = 9.8 Hz, 1 H, CHCHAHBO), 4.43 (dd, J = 5.7, 9.8 Hz, 1 H, = 8.2, 15.4 Hz, 1 H, CH(OH)CHN], 3.76 (s, 3 H, 6-OCH3), 3.75
CHCHAHBO), 3.97 (s, 3 H, 3-OCH3), 3.94 (s, 3 H, 3-OCH3), 3.86 (s, 3 H, OCH3), 3.74 (s, 3 H, 7-OCH3) ppm. 13C NMR [125 MHz,
Eur. J. Org. Chem. 2007, 5212–5225
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5221

S. Aubry, S. Pellet-Rostaing, M. Lemaire
(CD3)2SO, 23 °C]: δ = 171.1 (CO2Me), 157.2 (NC=O), 149.7 (ArC), CHAHBOCH2OCH3, CHAHBOCH2OCH3), 3.87 (s, 3 H, 7-OCH3),
FULL PAPER
148.8 (ArC), 131.6 (ArC), 120.8 (ArC), 110.4 (ArCH), 109.9
(ArCH), 68.9 (CH), 68.9 (CH2), 56.6 (CH), 56.5 (OCH3), 56.3
3.85 (s, 3 H, 6-OCH3), 3.22 (s, 3 H, CH2OCH3), 0.98 [9 H,
(CH3)3CSi], 0.26 (3 H, CH3Si), 0.18 (3 H, CH3Si) ppm. 13C NMR
(OCH3), 55.1 (CH), 53.7 (OCH3) ppm. ESI-MS: m/z (%) = 346 (125 MHz, CDCl3, 23 °C): δ = 157.0 (NC=O), 148.6 (ArC), 148.5
(100) [M + Na]+, 306 (12) [M + H – H2O]+, 246 (9) [M + H – (ArC), 130.2 (ArC), 124.4 (ArC), 109.0 (ArCH), 108.7 (ArCH),
H2O – HCO2Me]+, 202 (6) [M + H – H2O – HCO2Me – CO2]+.
C15H17NO7 (323.30): calcd. C 55.73, H 5.30, N 4.33; found C
55.58, H 5.31, N 4.18.
96.3 (CH2), 70.5 (CH), 70.1 (CH2), 67.0 (CH2), 56.5 (OCH3), 56.3
(OCH3), 56.0 (CH), 55.8 (OCH3), 52.6 (CH), 26.0 [(CH3)3CSi], 18.3
(CSi), –3.5 (CH3Si), –3.5 (CH3Si) ppm. ESI-MS: m/z (%) = 476
(38) [M + Na]+ , 454 (100) [M + H]+, 422 (41) [M + H –
CH3OH]+. C22H35NO7Si (453.60): calcd. C 58.25, H 7.78, N 3.09;
found C 58.10, H 7.80, N 2.99.
(5S,10S,10aR)-10-(tert-Butyldimethylsilyloxy)-5-(hydroxymethyl)-
7,8-dimethoxy-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-
3-one (25): A solution of alcohol 24 (0.200 g, 0.619 mmol), tert-
butyldimethylsilyl chloride (0.559 g, 3.72 mmol) and imidazole Methyl (5S,10S,10aR)-10-(Ethoxymethoxy)-7,8-dimethoxy-3-oxo-
(0.506 g, 7.43 mmol) in dry dimethylformamide (2 mL) was stirred
at room temperature for 12 h. The reaction was quenched by add-
ing a saturated ammonium chloride aqueous solution (10 mL). The
aqueous layer was extracted with dichloromethane (3ϫ10 mL).
The combined extracts were dried with magnesium sulfate and fil-
tered. The crude product was concentrated and purified by flash
chromatography (silica gel, n-heptane/ethyl acetate, 8:2) giving 25
in 89% yield (0.241 g) as a white solid, m.p. 145 °C (n-heptane), Rf
1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinoline-5-carboxylate
(27): Ethoxymethyl chloride (0.117 g, 1.24 mmol) was added to a
solution of 24 (0.200 g, 0.619 mmol) and diisopropylethylamine
(0.798 g, 6.19 mmol) in dichloromethane (4 mL) and the reaction
mixture was heated at 60 °C for 18 h. After cooling to room tem-
perature, the solution was diluted with dichloromethane (10 mL),
washed with water (10 mL) and brine (10 mL), dried with magne-
sium sulfate and filtered. After evaporation, the crude residue was
purified by flash chromatography (silica gel, n-heptane/ethyl ace-
tate, 8:2) to give 27 in 91% yield (0.215 g) as a colourless oil, Rf =
0.8 (ethyl acetate), [α]2D3 = –10.4 (dichloromethane, c = 1). 1H NMR
(500 MHz, CDCl3, 23 °C): δ = 7.00 (s, 1 H, 8-H), 6.97 (s, 1 H, 5-
= 0.8 (ethyl acetate), [α]2D3 = –46.4 (dichloromethane, c = 0.5). H
1
NMR (500 MHz, CDCl3, 23 °C): δ = 7.01 (s, 1 H, 8-H), 6.97 (s, 1
H, 5-H), 5.31 (s, 1 H, CHCO2Me), 4.68 (t, J = 8.5 Hz, 1 H,
CHCHAHBO), 4.64 (d, J = 8.8 Hz, 1 H, CHOSi), 4.33 (dd, J =
6.6, 8.5 Hz, 1 H, CHCHAHBO), 4.17 (dd, J = 8.2, 15.1 Hz, 1 H, H), 5.31 (s, 1 H, CHCO2 Me), 4.95 (d, J = 7.3 Hz, 1 H,
CH2CHN), 3.87 (s, 3 H, 6-OCH3), 3.85 (s, 3 H, 7-OCH3), 3.77 (s,
3 H, OCH3), 0.97 [9 H, (CH3)3CSi], 0.27 (3 H, CH3Si), 0.18 (3
H, CH3Si) ppm. 13C NMR (125 MHz, CDCl3, 23 °C): δ = 170.2
(CO2Me), 156.9 (NC=O), 149.3 (ArC), 148.7 (ArC), 129.8 (ArC),
120.4 (ArC), 109.4 (ArCH), 108.9 (ArCH), 70.7 (CH), 68.3 (CH2),
OCHAHBO), 4.90 (d, J = 7.2 Hz, 1 H, OCHAHBO), 4.76 (dd, J =
7.2, 9.1 Hz, 1 H, CHCHAHBO), 4.47 (m, 2 H, CHOCH2OC2H5,
CHCHAHBO), 4.17 (m, 1 H, CH2CHN), 3.87 (s, 3 H, 7-OCH3),
3.86 (s, 3 H, 6-OCH3), 3.76 (s, 3 H, OCH3), 3.72 (m, 1 H, OCH2O-
CHAHBCH3), 3.60 (m, 1 H, OCH2OCHAHBCH3), 1.25 (t, J =
56.2 (OCH3), 56.0 (OCH3), 55.6 (CH), 54.8 (CH), 53.0 (OCH3), 7.1 Hz, 3 H, OCH2OCH2CH3) ppm. 13C NMR (125 MHz, CDCl3,
25.8 [(CH3)3CSi], 18.2 (CSi), –3.6 (CH3Si), –3.8 (CH3Si) ppm. ESI- 23 °C): δ = 170.4 (CO2Me), 157.3 (NC=O), 149.8 (ArC), 149.4
MS: m/z (%) = 460 (100) [M + Na]+, 306 (33) [M + H – (CH3)3- (ArC), 127.3 (ArC), 121.5 (ArC), 109.8 (ArCH), 109.7 (ArCH),
C(CH3)2SiOH]+. C21H31NO7Si (437.19): calcd. C 57.64, H 7.14, N
3.20; found C 57.46, H 7.07, N 2.92.
96.7 (CH2), 78.2 (CH), 69.3 (CH2), 64.8 (CH2), 56.5 (OCH3), 56.3
(OCH3), 54.9 (CH), 54.8 (CH), 53.3 (OCH3), 15.4 (CH3) ppm. ESI-
MS: m/z (%) = 404 (100) [M + Na]+, 306 (31) [M + H – C2H5O-
CH2OH]+, 246 (30) [M + H – C2H5OCH2OH – HCO2Me]+, 202
(22) [M + H – C2H5OCH2OH – HCO2Me – CO2]+. C18H23NO8
(381.38): calcd. C 56.69, H 6.08, N 3.67; found C 56.38, H 6.15, N
3.48.
(5S,10S,10aR)-10-(tert-Butyldimethylsilyloxy)-7,8-dimethoxy-5-
[(methoxymethoxy)methyl]-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]-
isoquinolin-3-one (26): A 1  solution of lithium triethylborohydride
in tetrahydrofuran (1.83 mL, 1.83 mmol) was added to a solution
of ester 25 (0.200 g, 0.457 mmol) in tetrahydrofuran (12 mL). The
reaction mixture was allowed to stir for 5 min and then quenched
with a saturated ammonium chloride aqueous solution (10 mL)
and stirred for an additional 10 min. The aqueous layer was ex-
tracted with dichloromethane (4ϫ10 mL). The combined organic
layers were dried with magnesium sulfate, filtered and concentrated
under reduced pressure. The crude residue was then engaged in the
next step without further purification. At 0 °C, diisopropylethylam-
ine (0.177 g, 1.371 mmol) was added to a solution of the primary
alcohol in dichloromethane (2 mL). The reaction mixture was
stirred for 5 min and methoxymethyl chloride (0.055 g,
0.686 mmol) was added dropwise. The solution was then stirred for
12 h at room temperature. The reaction was quenched with H2O
(10 mL) and the aqueous layer extracted with dichloromethane
(2ϫ10 mL). The combined organic layers were dried with magne-
sium sulfate, filtered and concentrated under reduced pressure. The
crude residue was purified by flash chromatography (silica gel, n-
heptane/ethyl acetate, 8:2) to give 26 in 86% yield (0.178 g) as a
colourless oil, Rf = 0.8 (ethyl acetate), [α]2D3 = –51.7 (dichlorometh-
10-(Ethoxymethoxy)-5-[(ethoxymethoxy)methyl]-7,8-dimethoxy-
1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one (28): A
1  solution of lithium triethylborohydride in tetrahydrofuran
(1.05 mL, 1.05 mmol) was added to a solution of ester 27 (0.100 g,
0.262 mmol) in tetrahydrofuran (7.5 mL). The reaction mixture was
allowed to stir for 5 min and then quenched with a saturated am-
monium chloride aqueous solution (5 mL) and stirred for an ad-
ditional 10 min. The aqueous layer was extracted with dichloro-
methane (3ϫ5 mL). The combined organic layers were dried with
magnesium sulfate, filtered and concentrated under reduced pres-
sure. The crude residue was then engaged in a protection step with-
out further purification. At 0 °C, diisopropylethylamine (0.110 g,
0.850 mmol) was added to a solution of the primary alcohol in
dichloromethane (2 mL). The reaction mixture was stirred for
5 min and ethoxymethyl chloride (0.040 g, 0.425 mmol) was added
dropwise. The solution was then stirred for 12 h at room tempera-
ture. The reaction was quenched with H2O (10 mL) and the aque-
ous layer extracted with dichloromethane (2ϫ10 mL). The com-
bined organic layers were dried with magnesium sulfate, filtered
1
ane, c = 0.65). H NMR (500 MHz, CDCl3, 23 °C): δ = 6.97 (s, 1
H, 5-H), 6.70 (s, 1 H, 8-H), 4.91 (t, J = 4.4 Hz, 1 H, CHCH2OCH2- and concentrated under reduced pressure. The crude residue was
OCH3), 4.62 (m, 2 H, CHOSi, CH2OCHAHBOCH3), 4.55–4.51 (m, purified by flash chromatography (silica gel, n-heptane/ethyl ace-
1 H, CH2OCHAHBOCH3, CHCHAHBO), 4.38 (dd, J = 3.8, 8.8 Hz,
1 H, CHCHAHBO), 3.96 (m, 1 H, CH2CHN), 3.90 (m, 1 H,
tate, 8:2) to give 28 in 88% yield (0.095 g) as a colourless oil, Rf =
0.8 (ethyl acetate), [α]2D3 = –27.1 (dichloromethane, c = 0.19). 1H
5222
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5212–5225

Synthesis of Tetrahydroisoquinoline Natural Alkaloid Analogues
NMR (500 MHz, CDCl3, 23 °C): δ = 6.95 (s, 1 H, 5-H), 6.67 (s, 1
H, 8-H), 4.95 (d, J = 7.3 Hz, 1 H, OCHAHBO), 4.90 (d, J = 7.2 Hz,
1 H, OCHAHBO), 4.89 (m, 1 H, CHCH2OCH2OC2H5), 4.65 (d, J
= 6.6 Hz, 1 H, OCHAЈHBЈO), 4.60 (m, 1 H, CHCHAHBO), 4.56 (d,
(dichloromethane/methanol, 10:1), [α]2D3 = +35.4 (dichloromethane,
c = 1). 1H NMR (500 MHz, CDCl3, 23 °C): δ = 6.86 (s, 1 H, 5-H),
6.62 (s, 1 H, 8-H), 4.81 (s, 2 H, OCHAHBO), 4.72 (d, J = 6.6 Hz,
1 H, OCHAЈHBЈO), 4.68 (d, J = 6.6 Hz, 1 H, OCHAЈHBЈO), 4.44
J = 6.6 Hz, 1 H, OCHAЈHBЈO), 4.52 (m, 1 H, CHCHAHBO), 4.49 (d, J = 5.4 Hz, 1 H, CHOCH2OC2H5), 4.09 (dd, J = 3.8, 7.6 Hz, 1
(m, 1 H, CHOCH2OC2H5), 4.15 (m, 1 H, CH2CHN), 3.93–3.87 H, CHCH2OCH2OC2H5), 3.85 (s, 3 H, 7-OCH3) 3.84 (s, 3 H, 6-
(m, 2 H, CHAHBOCH2OC2H5, CHAHBOCH2OC2H5), 3.86 (s, 6 OCH3), 3.81 (m, 1 H, CHAHBOCH2OC2H5), 3.76 (dd, J = 4.0,
H, 6-OCH3, 7-OCH3), 3.74–3.68 (m, 1 H, OCH2OCHAHBCH3), 10.2 Hz, 1 H, CHAHBOCH2OC2H5), 3.72–3.67 (m, 2 H, OCH2O-
3.64–3.58 (m, 1 H, OCH2OCHAHBCH3), 3.46–3.36 (m, 1 H, OCH-
CHAHBCH3, OCH2OCHAHBCH3), 3.65 (m, 1 H, CHCHAHBO),
2OCHAЈHBЈCH3, OCH2OCHAЈHBЈCH3), 1.24 (t, J = 7.0 Hz, 3 H, 3.60–3.55 (m, 2 H, OCH2OCHAЈHBЈCH3, OCH2OCHAЈHBЈCH3),
OCH2OCH2CH3), 1.12 (t, J = 6.9 Hz, 3 H, OCH2OCH2- 3.52 (m, 1 H, CHCHAHBO), 3.31 (m, 1 H, CH2CHN), 2.68 (br. s,
CHЈ3) ppm. 13C NMR (125 MHz, CDCl3, 23 °C): δ = 156.9
(NC=O), 148.9 (ArC), 148.7 (ArC), 127.2 (ArC), 125.4 (ArC),
109.4 (ArCH), 108.7 (ArCH), 96.3 (CH2), 94.9 (CH2), 77.9 (CH),
69.9 (CH2), 67.9 (CH2), 64.3 (CH2), 63.5 (CH2), 56.1 (OCH3), 56.0
2 H, NH, OH), 1.24 (t, J = 6.9 Hz, 3 H, OCH2OCH2CH3), 1.19
(t, J = 7.1 Hz, 3 H, OCH2OCH2CHЈ3) ppm. 13C NMR (125 MHz,
CDCl3, 23 °C): δ = 148.8 (ArC), 148.1 (ArC), 128.2 (ArC), 127.1
(ArC), 112.0 (ArCH), 108.9 (ArCH), 95.4 (CH2), 94.7 (CH2), 73.2
(OCH3), 54.3 (CH), 52.0 (CH), 15.1 (2CH3) ppm. ESI-MS: m/z (%) (CH), 70.9 (CH2), 64.0 (CH2), 63.6 (CH2), 62.0 (CH2), 56.0
= 434 (100) [M + Na]+, 412 [M + H]+, 366 (11) [M + H –
(OCH3), 55.9 (OCH3), 55.8 (CH), 53.0 (CH), 15.2 (2CH3) ppm.
C2H5OH]+. C20H29NO8 (411.45): calcd. C 58.38, H 7.10, N 3.40; ESI-MS: m/z (%) = 408 (4) [M + Na]+, 386 (100) [M + H]+, 310
found C 58.19, H 7.16, N 3.23.
(70) [M + H – C2H5OCH2OH]+, 264 (27) [M + H – C2H5O-
CH2OH – C2H5OH]+, 202 (14) [M + H – C2H5OCH2OH – C2H5O-
CH2OH]+. C19H31NO7·0.3H2O (390.86): calcd. C 58.33, H 8.08, N
3.58; found C 58.34, H 8.05, N 3.44.
(1S,3R,4S)-3-(Hydroxymethyl)-6,7-dimethoxy-1-[(methoxymeth-
oxy)methyl]-1,2,3,4-tetrahydroisoquinolin-4-ol (29): A 2  solution
of sodium hydroxide (0.9 mL) was added to a solution of 26
(0.100 g, 0.221 mmol) in ethanol (1.8 mL). This solution was de-
gassed by bubbling through a stream of N2(g) and then heated for
48 h at 90 °C. After cooling to room temperature, the solution was
diluted with dichloromethane (6 mL) and brine (3 mL) was added.
After separation of the organic layer, the aqueous layer was ex-
tracted with dichloromethane (3ϫ5 mL). The combined extracts
were dried with sodium sulfate, filtered and concentrated under
reduced pressure. The crude residue was recrystallized from dichlo-
romethane giving 29 in 65% yield (0.045 g) as a white solid, m.p.
209–210 °C (dichloromethane), Rf = 0.1 (dichloromethane/meth-
anol, 10:1), [α]2D3 = –17.8 (dichloromethane/methanol, 8:2, c = 0.5).
1H NMR [500 MHz, CDCl3/MeOD (10:1), 23 °C]: δ = 6.97 (s, 1
H, 5-H), 6.47 (s, 1 H, 8-H), 4.61 (d, J = 6.6 Hz, 2 H, OCHAHBO),
4.58 (d, J = 6.6 Hz, 2 H, OCHAHBO), 4.28 (d, J = 9.5 Hz, 1 H,
CHOH), 4.01 (dd, J = 3.8, 9.4 Hz, 1 H, CHCH2OCH2OCH3), 3.83
(dd, J = 4.1, 11.0 Hz, 1 H, CHCHAHBO), 3.76 (s, 3 H, 6-OCH3)
3.74 (s, 3 H, 7-OCH3), 3.71 (br. s, 3 H, NH, 2OH), 3.69 (m, 1 H,
CHAHBOCH2OCH3), 3.58 (dd, J = 3.7, 11.1 Hz, 1 H, CHAHB-
OCH2OC2H5), 3.49 (dd, J = 7.6, 11 Hz, 1 H, CHCHAHBO), 3.29
(s, 3 H, CHCH2OCH2OCH3), 2.96 (m, 1 H, CH2CHN) ppm. 13C
NMR [125 MHz, CDCl3/MeOD (10:1), 23 °C]: δ = 148.4 (ArC),
148.1 (ArC), 130.5 (ArC), 125.9 (ArC), 110.0 (ArCH), 108.9
(ArCH), 96.6 (CH2), 69.4 (CH2), 67.4 (CH), 63.1 (CH2), 55.8
(OCH3), 55.7 (OCH3), 55.4 (OCH3), 55.3 (CH), 54.2 (CH) ppm.
ESI-MS: m/z (%) = 314 (100) [M + H]+, 296 (85) [M + H –
H2O]+, 264 (35) [M + H – H2O – CH3OH]+. C15H23NO6·CH2Cl2
(397.28): calcd. C 48.25, H 6.33, N 3.52; found C 47.86, H 6.25, N
3.69.
Methyl (5S,10R,10aR)-7,8-Dimethoxy-10-(2-methoxy-2-oxoethyl-
thio)-3-oxo-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinoline-5-
carboxylate (31a) and Methyl (5S,10S,10aR)-7,8-Dimethoxy-10-(2-
methoxy-2-oxoethylthio)-3-oxo-1,5,10,10a-tetrahydro-3H-oxazolo-
[3,4-b]isoquinoline-5-carboxylate (31b): A solution of methyl thio-
glycolate (0.036 g, 0.341 mmol) in dry toluene (5.16 mL) was added
to a solution of trifluoroacetic acid (5.16 mL) containing the ben-
zylic alcohol 24 (0.100 g, 0.310 mmol) at 0 °C and stirred for 1 h.
The reaction mixture was diluted with dichloromethane (10 mL)
and washed with a saturated sodium carbonate aqueous solution
(5 mL) and brine (4 mL). The organic layer was dried with magne-
sium sulfate and filtered. The crude product was concentrated and
purified by flash chromatography (silica gel, n-heptane/ethyl ace-
tate, 8:2) giving 31a (0.090 g, 71%) and 31b (0.010 g, 8%) as white
solids in 92% overall yield (0.117 g) and as a 9:1 mixture of dia-
stereoisomers 31a/31b. Data for compound 31a: m.p. 157–158 °C
(dichloromethane), Rf = 0.6 (ethyl acetate), [α]2D3 = –147.0 (dichlo-
1
romethane, c = 0.6). H NMR (500 MHz, CDCl3, 23 °C): δ = 7.03
(s, 1 H, 8-H), 6.84 (s, 1 H, 5-H), 5.29 (s, 1 H, CHCO2Me), 4.83 (m,
1 H, CHCHAHBO), 4.67–4.59 (m, 2 H, CHCHAHBO, CH2CHN),
4.17 (br. s, 1 H, CHSCH2CO2Me), 3.87 (s, 6 H, 7-OCH3, 6-OCH3),
3.77 (s, 3 H, OCH3), 3.67 (s, 3 H, OCH3), 2.98 (s, 2 H,
SCH2CO2Me) ppm. 13C NMR (100 MHz, CDCl3, 23 °C): δ =
170.6 (CO2Me), 170.2 (CO2Me), 157.1 (NC=O), 149.3 (2ArC),
125.2 (ArC), 120.9 (ArC), 112.6 (ArCH), 109.3 (ArCH), 66.8
(CH2), 56.1 (OCH3), 56.0 (OCH3), 54.7 (CH), 53.6 (CH), 53.0
(OCH3), 52.7 (OCH3), 45.8 (CH), 31.8 (CH2) ppm. ESI-MS: m/z
(%) = 434 (100) [M + Na]+, 306 (59) [M + H – HSCH2CO2Me]+,
{(1S,3R,4S)-4-(Ethoxymethoxy)-1-[(ethoxymethoxy)methyl]-6,7-di- 246 (79) [M + H – HSCH2CO2Me – HCO2Me]+, 202 (66) [M +
methoxy-1,2,3,4-tetrahydroisoquinolin-3-yl}methanol (30): A 2 
solution of sodium hydroxide (1 mL) was added to a solution of
28 (0.200 g, 0.486 mmol) in ethanol (4 mL). This solution was de-
gassed by bubbling through a stream of N2(g) and then heated for
48 h at 90 °C. After cooling to room temperature, the solution was
diluted with dichloromethane (10 mL) and brine (5 mL) was added.
After separation of the organic layer, the aqueous layer was ex-
tracted with dichloromethane (3ϫ5 mL). Combined extracts were
dried with sodium sulfate, filtered, concentrated under reduced
pressure and purified by flash chromatography (silica gel, dichloro-
methane/methanol, 10:1) giving 30 in 79% yield (0.142 g) as a pale-
yellow solid, m.p. 68 °C (n-heptane/dichloromethane), Rf = 0.6
H – HSCH2CO2Me – HCO2Me – CO2]+. C18H21NO8S (411.43):
calcd. C 52.55, H 5.14, N 3.40; found C 52.46, H 5.23, N 3.39.
Data for compound 31b: m.p. 64–65 °C (tetrahydrofuran), Rf = 0.7
(ethyl acetate), [α]2D3 = –105.7 (dichloromethane, c = 0.4). 1H NMR
(500 MHz, CDCl3, 23 °C): δ = 7.37 (s, 1 H, 5-H), 6.99 (s, 1 H, 8-
H), 5.38 (s, 1 H, CHCO2Me), 4.77 (t, J = 8.3 Hz, 1 H,
CHCHAHBO), 4.47 (m, 1 H, CH2CHN), 4.47 (dd, J = 5.3, 8.8 Hz,
1 H, CHCHAHBO), 3.90 (s, 6 H, 7-OCH3, 6-OCH3), 3.87 (s, 1 H,
CHSCH2CO2Me), 3.80 (s, 3 H, OCH3), 3.65 (s, 3 H, OCH3), 3.17
(d, J = 15.1 Hz, 1 H, SCH2CO2Me), 3.13 (d, J = 15.3 Hz, 1 H,
SCH2CO2Me) ppm. 13C NMR (125 MHz, CDCl3, 23 °C): δ =
170.5 (CO2Me), 170.3 (CO2Me), 156.6 (NC=O), 149.6 (ArC), 149.0
Eur. J. Org. Chem. 2007, 5212–5225
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5223

S. Aubry, S. Pellet-Rostaing, M. Lemaire
FULL PAPER
A. Pellegrino, J. Jimeno, H. Hendriks, M. D’Incalci, G. Fair-
cloth, R. Giavazzi, Clin. Cancer Res. 1998, 4, 1977–1983; f)
D. P. Ryan, J. G. Supko, J. P. Eder, M. V. Seiden, G. Demetri,
T. J. Lynch, A. J. Fischman, J. Davis, J. Jimeno, J. W. Clark,
Clin. Cancer Res. 2001, 7, 231–242; g) N. Takashi, W. Li, D.
Banerjee, Y. Guan, Y. Wada-Takahashi, M. F. Brennan, T. C.
Chou, K. W. Scotto, J. R. Bertino, Cancer Res. 2002, 62, 6909–
6915; h) G. J. Aune, T. Furuta, Y. Pommier, Anti-Cancer Drugs
2002, 13, 545–555; i) J. Y. Blay, A. Le Cesne, J. Verweij, M.
Scurr, C. Seynaeve, S. Bonvalot, P. Hogendoorn, J. Jimeno, V.
Evrard, M. van Glabbeke, I. Judson, Eur. J. Cancer 2004, 40,
1327–1331; j) L. Zelek, A. Yovine, E. Brain, F. Turpin, A.
Taamma, M. Riofrio, M. Spielman, J. Jimeno, J. L. Misset, Br.
J. Cancer 2006, 94, 1610.
a) I. Jardine, Anticancer Aganents Based on Natural Products
Models, Academic Press, New York, 1980, vol. 3, pp. 319–351;
b) H. F. Stähelin, A. Von Wartburg, Cancer Res. 1991, 51, 5–
15; c) R. S. Ward, Synthesis 1992, 719–730; d) C. Canel, R. M.
Moraes, F. E. Dayan, D. Ferreira, Phytochemistry 2000, 54,
115–120.
a) K. Tomioka, Y. Kubota, K. Koga, J. Chem. Soc. Chem.
Commun. 1989, 1622–1624; b) K. Tomioka, Y. Kubota, K.
Koga, Tetrahedron 1993, 49, 1891–1900; c) J.-O. Bosmans, J.
Van der Eycken, M. Vandewalle, Tetrahedron Lett. 1989, 30,
3877–3880; d) H. L. Pearce, N. J. Bach, T. L. Cramer, Tetrahe-
dron Lett. 1989, 30, 907–910; e) E. Marcantoni, M. Petrini, R.
Profeta, Tetrahedron Lett. 2004, 45, 2133–2136.
a) S. Aubry, S. Pellet-Rostaing, B. Fenet, M. Lemaire, Tetrahe-
dron Lett. 2006, 47, 1319–1323; b) S. Aubry, J. Fourn-
ier dit Chabert, S. Pellet-Rostaing, S. Ducki, M. Lemaire, Bi-
oorg. Med. Chem. Lett. 2007, 17, 2598–2602.
a) D. Walker, J. D. Hiebert, Chem. Rev. 1967, 67, 153–195; b)
A. B. Turner, Synthetic Reagents (Ed.: J. S. Pizey), Wiley, New
York, 1977, vol. 3, pp. 193–225.
a) H. D. Becker, J. Org. Chem. 1965, 30, 982–989; b) H. D.
Becker, J. Org. Chem. 1969, 34, 1203–1210.
J. W. A. Findlay, A. B. Turner, J. Chem. Soc. C 1971, 23–29.
F. D. Ramdayal, D. J. Kiemle, R. T. Lalonde, J. Org. Chem.
1999, 64, 4607–4609.
a) Y. Oikawa, T. Yoshioka, K. Mohri, O. Yonemitsu, Heterocy-
cles 1979, 12, 1457–1462; b) Y. Oikawa, O. Yonemitsu, J. Org.
Chem. 1977, 42, 1213–1216.
a) K. Narayanan, J. M. Cook, Heterocycles 1991, 32, 2005–
2014; b) M. Cain, R. Mantei, J. M. Cook, J. Org. Chem. 1982,
47, 4933–4936; c) T. J. Hagen, K. Narayanan, J. Names, J. M.
Cook, J. Org. Chem. 1989, 54, 2170–2178.
a) P. P. Fu, R. G. Harvey, Chem. Rev. 1978, 78, 317–361; b)
P. P. Fu, C. Cortez, K. B. Sukumaran, R. G. Harvey, J. Org.
Chem. 1979, 44, 4265–4271; c) H. Lee, R. G. Harvey, J. Org.
Chem. 1983, 48, 749–751; d) H. Lee, R. G. Harvey, J. Org.
Chem. 1988, 53, 4587–4589; e) R. E. Lehr, P. L. Kole, K. D.
Tschappat, Tetrahedron Lett. 1986, 27, 1649–1652.
K. C. Rice, W. C. Ripka, J. Reden, A. Brossi, J. Org. Chem.
1980, 45, 601–607.
M. Bouquet, A. Guy, M. Lemaire, J.-P. Guetté, C. R. Acad.
Sci., Ser. IIc: Chim. 1984, 299, 1389–1390.
(ArC), 124.2 (ArC), 123.2 (ArC), 111.1 (ArCH), 110.1 (ArCH),
66.8 (CH2), 56.3 (OCH3), 56.2 (OCH3), 54.8 (CH), 53.5 (CH), 53.1
(OCH3), 52.8 (OCH3), 46.9 (CH), 30.6 (CH2) ppm. ESI-MS: m/z
(%) = 434 (100) [M + Na]+, 306 (30) [M + H – HSCH2CO2Me]+,
246 (35) [M + H – HSCH2CO2Me – HCO2Me]+, 202 (26) [M +
H – HSCH2CO2Me – HCO2Me – CO2]+. C18H21NO8S (411.43):
calcd. C 52.55, H 5.14, N 3.40; found C 52.42, H 5.13, N 3.07.
Acknowledgments
The authors wish to thank the Ministère de l’Enseignement Supéri-
eur et de la Recherche for a Ph. D. grant to S. A. and Dr. Christine
Clozel-Fox for correcting the manuscript. Pr. René Faure is grate-
fully acknowledged for the analysis of X-ray single-crystal struc-
tures and his resourses.
[6]
[7]
[1] a) K. W. Bentley, The isoquinoline Alkaloids, Harvard Aca-
demic Publisher, Amsterdam, 1998; b) K. W. Bentley, Nat.
Prod. Rep. 2003, 20, 342–365; c) K. W. Bentley, Nat. Prod. Rep.
2004, 21, 395–424; d) K. W. Bentley, Nat. Prod. Rep. 2005, 22,
249–268; e) K. W. Bentley, Nat. Prod. Rep. 2006, 23, 444–463.
[2] a) V. A. Facundo, S. M. De Morais, R. Braz Filho, I. J.
de A. Matos, R. T. Souza, Rev. Bras. Farm. 1997, 78, 57–59; b)
V. A. Facundo, S. M. De Morais, M. I. L. Machado, F. J. de A.
Matos, L. C. M. Da frota, J. Essent. Oil Res. 1999, 11, 426–
428; c) S. M. De Morais, V. A. Facundo, R. Braz Filho, J. Ess-
ent. Oil Res. 2002, 14, 274–275; d) S. A. Ross, G. N. N. Sultana,
C. L. Burandt, M. A. ElSohly, J. P. J. Marais, D. Ferreira, J.
Nat. Prod. 2004, 67, 88–90; e) S. A. Ross, M. A. Al-Azeib, K. S.
Krishnaveni, F. R. Fronczek, C. L. Burandt, J. Nat. Prod. 2005,
68, 1297–1299.
[8]
[9]
[3] For a review, see: J. Scott, R. M. Williams, Chem. Rev. 2002,
[10]
102, 1669–1730.
[4] a) K. L. Rinehart, T. G. Holt, N. L. Fregeau, T. J. Perun Jr,
D. S. Seigler, G. R. Wilson, L. S. Shield, Pure Appl. Chem.
1990, 62, 1277–1280; b) K. L. Rinehart, T. G. Holt, N. L. Fre-
geau, P. A. Keifer, F. Sun, H. Li, D. G. Martin, J. Org. Chem.
1990, 55, 4512–4515; c) A. E. Wright, D. A. Forleo, G. P. Gun-
awardana, S. P. Gunasekera, F. E. Koehn, O. J. McConnel, J.
Org. Chem. 1990, 55, 4508–4512; d) R. Sakai, K. L. Rinehart,
Y. Guan, A. H.-J. Wang, Proc. Natl. Acad. Sci. U.S.A. 1992,
89, 11456–11460; e) R. Sakai, E. Jares-Erijaman, I. Manzan-
ares, M. V. Elipe, K. L. Rinehart, J. Am. Chem. Soc. 1996, 118,
9017–9023; f) K. Suwanboriux, K. Chapurant, S. Amnuoypol,
S. Pummangura, A. Kubo, N. Saito, J. Nat. Prod. 2002, 65,
935–937.
[5] a) L. Zelek, A. Yovine, B. Etienne, J. Jimeno, A. Taama,
C. Martin, M. Spielmann, E. Cvitkovic, J. L. Misset, Ecteinac-
sidin-743 in taxane/Antracycline pretreated advanced/metastatic
breast cancer patients: preliminary results with the 24 h con-
tinuous infusion Q3 week schedule, presented at the American
Society of Clinical Oncology, 36th Annual Meeting, New Orle-
ans, 20–23 May, 2000, Abstract number 592; b) S. Delaloge, A.
Yovine, A. Taama, P. Cottu, M. Riofrio, E. Raymond, E.
Brain, M. Marty, J. Jimeno, E. Cvitkovic, J. L. Misset, Prelimi-
nary evidence of activity of Ecteinascidin-743 (ET-743) in
heavily pretreated patients with bone and soft tissue sarcomas,
presented at the American Society of Clinical Oncology, 36th
Annual Meeting, New Orleans, 20–23 May, 2000, Abstract
number 2181; c) A. Le Cesne, I. Judson, J. Y. Blay, J. Radford,
A. van Oosterom, P. Lorigan, E. Rodenhuis, E. Donato Di Pa-
oula, M. Van Glabbeke, J. Jimeno, J. Verweij, Phase II of ET-
743 in advance soft tissue sarcoma in adult: a STBSG-EORTC
trial, presented at the American Society of Clinical Oncology,
36th Annual Meeting, New Orleans, 20–23 May, 2000, Abstract
number 2182; d) E. Izbicka, R. Lawrence, E. Raymond, G.
Eckhardt, G. Faircloth, J. Jimeno, G. Clark, D. D. Von Hoff,
Annals Oncol. 1998, 9, 981–987; e) G. Valoti, M. I. Nicoletti,
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
M. Bouquet, A. Guy, M. Lemaire, J.-P. Guetté, Synth. Com-
mun. 1985, 15, 1153–1157.
a) M. Lemaire, A. Guy, D. Imbert, J.-P. Guetté, J. Chem. Soc.
Chem. Commun. 1986, 741–742; b) A. Guy, A. Lemor, D. Im-
bert, M. Lemaire, Tetrahedron Lett. 1989, 30, 327–330; c) M.
Lemaire, A. Guy, D. Imbert, J.-P. Guetté, New J. Chem. 1991,
15, 379–384.
a) A. Guy, A. Lemor, J. Doussot, M. Lemaire, Synthesis 1988,
900–902; b) A. Guy, J. Doussot, M. Lemaire, Synthesis 1991,
460–462.
a) M. Lemaire, J. Doussot, A. Guy, Chem. Lett. 1988, 1581–
1584; b) A. Guy, J. Doussot, J.-P. Guetté, R. Garreau, M. Le-
maire, Synlett 1992, 821–822.
[20]
[21]
5224
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5212–5225

Synthesis of Tetrahydroisoquinoline Natural Alkaloid Analogues
[22] a) For a review, see: E. D. Cox, J. M. Cook, Chem. Rev. 1995,
95, 1797; b) S. Aubry, S. Pellet-Rostaing, R. Faure, M. Lemaire,
J. Heterocycl. Chem. 2006, 43, 139–148.
[23] A. Ohki, T. Nishiguchi, K. Fukuzumi, Tetrahedron 1979, 35,
1737–1743.
[24] The chemical shift of the benzylic carbon was determined from
the 13C NMR spectrum of a 80:20 mixture of trans-14/cis-14
recorded on a Bruker DPX-500 spectrometer (1H: 500 MHz;
13C: 100 MHz).
[25] X-ray crystal structure analysis of syn-19: Colourless crystal
from CH2Cl2; size [mm]: 0.80ϫ0.20ϫ0.05; formula
C20H19NO7, M = 385.37; data set collected with a Nonius-
KappaCCD diffractometer; orthorhombic; space group:
M = 411.42; data set collected with a Nonius-KappaCCD dif-
fractometer; monoclinic; space group: P21; a = 4.8190(1), b =
16.8130(7), c = 11.8460(5) Å; β = 96.707(2)°; V = 953.22(6) Å3;
Z = 2; ρ = 1.433 gcm–3; 2θmax = 55.6°; λ(Mo-Kα) = 0.71073 Å;
T = 294 K; 3747 measured reflections; 3597 [IϾ2σ(I)]; µ(Mo-
Kα) = 0.216 mm–1; Tmin = 0.881, Tmax = 0.918; SHELXTL; 252
parameters; hydrogen atoms calculated and refined as riding
atoms; R = 0.030, wR = 0.085; refinement of F2 against all
reflections; ∆ρmax = 0.19, ∆ρmin = –0.21 eÅ–3. CCDC-641202
contains the supplementary crystallographic data for this pa-
per. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
P212121; a = 7.2720(3), b = 16.0890(9), c = 16.341(1) Å; V = [35] a) E. J. Corey, D. Y. Gin, R. S. Kania, J. Am. Chem. Soc. 1996,
1911.9(2) Å3; Z = 4; ρ = 1.339 gcm–3; 2θmax = 55.8°; λ(Mo-
Kα) = 0.71073 Å; T = 291 K; 4340 measured reflections; 2736
118, 9202–9203; b) E. J. Martinez, E. J. Corey, Org. Lett. 2000,
2, 993–996; c) A. Endo, T. Kann, T. Fukuyama, Synlett 1999,
1103–1105; d) A. Endo, A. Yanagisawa, M. Abe, S. Tohma, T.
Kan, T. Fukuyama, J. Am. Chem. Soc. 2002, 124, 6552–6554;
e) C. Cuevas, M. Pérez, M. J. Martín, J. L. Chicharro, C.
Fernández-Rivas, M. Flores, A. Francesch, P. Gallego, M. Zar-
zuelo, F. de la Calle, J. García, C. Polanco, I. Rodríguez, I.
Manzanares, Org. Lett. 2000, 2, 2545–2548; f) R. Menchaca,
V. Martínez, A. Rodríguez, N. Rodríguez, M. Flores, P. Gal-
lego, I. Manzanares, C. Cuevas, J. Org. Chem. 2003, 68, 8859–
8866; g) N. Saito, K. Tashiro, Y. Maru, K. Yamaguchi, A.
Kubo, J. Chem. Soc. Perkin Trans. 1 1997, 53–69; h) N. Saito,
H. Kamayachi, M. Tachi, A. Kubo, Heterocycles 1999, 51, 9–
12; i) N. Saito, M. Tachi, R. Seki, H. Kamayachi, A. Kubo,
Chem. Pharm. Bull. 2000, 48, 1549–1557; j) N. Saito, R. Seki,
N. Kameyama, R. Sugimoto, A. Kubo, Chem. Pharm. Bull.
2003, 51, 821–831; k) B. Zhou, S. Edmonson, J. Padron, S. J.
Danishefsky, Tetrahedron Lett. 2000, 41, 2039–2042; l) B.
Zhou, J. Guo, S. J. Danishefsky, Tetrahedron Lett. 2000, 41,
2043–2046; m) S. Zheng, C. Chan, T. Furuuchi, B. J. D. Wright,
B. Zhou, J. Guo, S. J. Danishefsky, Angew. Chem. Int. Ed. 2006,
45, 1754–1759; n) X. Chen, J. Chen, M. De Paolis, J. Zhu, J.
Org. Chem. 2005, 70, 4397–4408; o) J. Chen, X. Chen, M. Bois-
Choussy, J. Zhu, J. Am. Chem. Soc. 2006, 128, 87; p) X. Chen,
J. Chen, M. Bois-Choussy, J. Zhu, Synthesis 2006, 4081–4086;
q) J. Chen, X. Chen, M. Willot, J. Zhu, Angew. Chem. Int. Ed.
2006, 45, 8028–8032; r) C. Rondot, P. Retailleau, J. Zhu, Org.
Lett. 2007, 9, 247–250; s) W. Jin, S. Metebo, R. M. Williams,
Org. Lett. 2003, 5, 2095–2098; t) D. Fishlock, R. M. Williams,
Org. Lett. 2006, 8, 3299–3301; u) S. Chandrasekhar, N. R.
Reddy, Y. S. Rao, Tetrahedron 2006, 62, 12098–12107.
[IϾ2σ(I)]; µ(Mo-Kα) = 0.102 mm–1; Tmin = 0.923, Tmax
=
0.995; SHELXTL; 253 parameters; hydrogen atoms calculated
and refined as riding atoms; R = 0.053, wR = 0.137; refinement
of F2 against all reflections; ∆ρmax = 0.28, ∆ρmin = –0.22 eÅ–3.
CCDC-628764 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[26] a) A. R. Katritzky, J. Cobo-Domingo, B. Yang, P. J. Steel, Tet-
rahedron: Asymmetry 1999, 10, 255–263; b) O. Koepler, S. Las-
chat, A. Baro, P. Fischer, B. Miehlich, M. Hotfilder, C. le Vis-
eur, Eur. J. Org. Chem. 2004, 3611–3622.
[27] J.-L. Luche, J. Am. Chem. Soc. 1978, 100, 2226–2227.
[28] X-ray crystal structure analysis of 26: Colourless crystal from
CH2Cl2; size [mm]: 0.50ϫ0.40ϫ0.25; formula C15H17NO7, M
= 323.30; data set collected with a Nonius-KappaCCD dif-
fractometer; orthorhombic; space group: P212121;
a =
7.7550(2), b = 11.9840(5), c = 16.0200(7) Å; V = 1488.8(1) Å3;
Z = 4; ρ = 1.442 gcm–3; 2θmax = 55.8°; λ(Mo-Kα) = 0.71073 Å;
T = 291 K; 3432 measured reflections; 2970 [IϾ2σ(I)]; µ(Mo-
Kα) = 0.116 mm–1; Tmin = 0.945, Tmax = 0.971; SHELXTL;
209 parameters; alcoholic hydrogen atom clearly evidenced on
Fourier difference map; all other hydrogen atoms calculated
and refined as riding atoms; R = 0.044, wR = 0.115; refinement
of F2 against all reflections; ∆ρmax = 0.23, ∆ρmin = –0.32 eÅ–3.
CCDC-628658 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[29] X.-M. Zhou, K. J.-H. Lee, J. Cheng, S.-S. Wu, H.-X. Chen, X.
[36] S. N. Banerjee, C. Ressler, J. Org. Chem. 1976, 41, 3056–3058.
Guo, Y.-C. Cheng, K.-H. Lee, J. Med. Chem. 1994, 37, 287– [37] K. Vogler, H. Baumgartner, Helv. Chim. Acta 1952, 35, 1776–
292.
1780.
[30] H. C. Brown, S. Krishnamurthy, J. Am. Chem. Soc. 1973, 95,
[38] N. Bodor, K. D. Sloan, T. Higuchi, K. Sasahara, J. Med. Chem.
1977, 20, 1435–1445.
1669–1671.
[31] a) M. Katoh, H. Inoue, A. Suzuki, T. Honda, Synlett 2005,
2820–2822; b) M. Katoh, H. Inoue, A. Suzuki, T. Honda, Het-
erocycles 2007, 72, 497.
[32] M. De Paolis, J. Blankenstein, M. Bois-Choussy, J. Zhu, Org.
Lett. 2002, 4, 1235–1238.
[39] E. A. Rudd, W. C. Cunnigham, J. W. Thanassi, J. Med. Chem.
1979, 22, 233–237.
[40] A. Gaucher, L. Dutot, O. Barbeau, W. Hamchaoui, M. Waksel-
man, J.-P. Mazaleyrat, Tetrahedron: Asymmetry 2005, 16, 857–
864.
[33] a) T. Hashiyama, H. Inoue, M. Takeda, K. Aoe, K. Kotera, J.
Chem. Soc. Perkin Trans. 1 1985, 421–427; b) H. D. H.
Showalter, R. T. Winters, A. D. Sercel, A. Michel, Tetrahedron
Lett. 1991, 32, 2849–2852; c) A. Elomri, S. Mitaku, S. Michel,
A. L. Skaltsounis, F. Tillequin, M. Koch, A. Pierre, N. Guil-
baud, S. Léonce, L. Kraus-Berthier, Y. Rolland, G. Atassi, J.
Med. Chem. 1996, 39, 4762–4766.
[41] E. García, S. Arrasate, A. Ardeo, E. Lete, N. Sotomayor, J.
Org. Chem. 2005, 70, 10368–10374.
[42] R. D. Clark, J. Berger, C.-H. Lee, J. M. Muchowski, Heterocy-
cles 1987, 26, 1291–1302.
[43] D. C. Humber, N. C. Cammack, J. A. V. Coates, D. C. Orr, R.
Storer, G. G. Weingarten, M. P. Weir, J. Med. Chem. 1992, 35,
3081–3084.
[34] X-ray crystal structure analysis of 33a: Colourless crystal from
CH2Cl2; size [mm]: 0.60ϫ0.50ϫ0.40; formula C18H21NO8S,
Received: April 23, 2007
Published Online: August 23, 2007
Eur. J. Org. Chem. 2007, 5212–5225
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5225