Towards a total synthesis of quinocarcin: Diastereoselective synthesis of functionalized azepino[1,2-b]isoquinolines

Article abstract of DOI:10.1002/ejoc.200400231

1,3-Disubstituted tetrahydro-oxazolo-isoquinolinones 19a,b were obtained from phenylalanine in seven steps and 42% overall yield by Katritzky's benzotriazole method. The tricyclic oxazolidinone 19a was further converted into amino alcohol 10 by employing

Full text of DOI:10.1002/ejoc.200400231

FULL PAPER
Towards a Total Synthesis of Quinocarcin: Diastereoselective Synthesis of
Functionalized Azepino[1,2-b]isoquinolines
Oliver Koepler,[a] Sabine Laschat,*[b] Angelika Baro,[b] Peter Fischer,[b] Burkhard Miehlich,[b]
Marc Hotfilder,[c] and Christoph le Viseur[c]
Dedicated to Professor Johann Mulzer on the occasion of his 60th birthday
Keywords: Catalysis / Ene reaction / Lewis acids / Natural products / Nitrogen heterocycles
1,3-Disubstituted tetrahydro-oxazolo-isoquinolinones 19a,b
were obtained from phenylalanine in seven steps and 42%
overall yield by Katritzky’s benzotriazole method. The
tricyclic oxazolidinone 19a was further converted into amino
alcohol 10 by employing a chemoselective reduction of the
ester group with LiBH4/MeOH. Compound 10 and the cor-
responding 1-unsubstituted tetrahydroisoquinoline alcohol
11 were converted into aldehydes 27 and 33, which cyclized
in the presence of different Lewis acids to give the substi-
tuted azepino[1,2-b]isoquinolines 34 and 35, respectively,
which are key structural features of the alkaloid quinocarcin.
The stereoselectivities of the Lewis-acid-catalyzed hetero-
ene reaction are highly dependent on the substitution pat-
tern and the type of Lewis acid.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Among the class of tetrahydroisoquinoline alkaloids,
various members such as naphthyridinomycin (1),[1] ectein-
ascidin 743 (2),[2] and quinocarcin (3)[3] (Scheme 1) have re-
ceived increasing interest due to their potent cytotoxic
properties. Ecteinascidin 743, for example, is currently un-
dergoing phase II/III clinical trials.[2d] Although quinocar-
cin (3) seems to be the structurally simplest representative,
the two known enantioselective total syntheses require up
to 28 steps to establish the molecular skeleton.[4,5] Thus,
during our ongoing efforts in the field of alkaloid synthesis
we were interested in developing a general strategy which
would allow not only the total synthesis of (Ϫ)-quinocarcin
(3) itself, but also derivatives thereof.
According to the retrosynthetic analysis (Scheme 2) we
envisioned the cleavage of the hemiaminal in target com-
pound 3 followed by a retro SN2 reaction to afford the tri-
cyclic azepino[1,2-b]isoquinoline 4. The amino group and
the carboxylic acid in 4 may be traced back to an alcohol
and an alkene, respectively, in 5. As a key step for the for-
Scheme 1. Tetrahydroisoquinoline alkaloid derivatives 1Ϫ3
mation of the azepino[1,2-b]isoquinoline skeleton we de-
cided to use a Lewis-acid-catalyzed hetero-ene reaction of
precursor 6. Former results from our laboratory have
shown the synthetic utility of the Lewis-acid-catalyzed het-
ero-ene reaction of amino acid derivatives for the dia-
stereoselective synthesis of various nitrogen-containing het-
erocycles.[6,7] The cyclization precursor 6 may be available
from the tetrahydroisoquinoline derivative 7 and a func-
tionalized alkene 8.
[a]
Institut für Organische Chemie der Technischen Universität
Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
[b]
Institut für Organische Chemie der Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: (internat.) ϩ 49-711-685-4285
E-mail: sabine.laschat@oc.uni-stuttgart.de
[c]
Klinik und Poliklinik für Kinderheilkunde, Pädiatrische
Therefore, the current aim was to elaborate concise syn-
thetic routes to the building blocks 7 and 8 and, further-
Hämatologie/Onkologie,
Domagkstr. 9a, 48149 Münster, Germany
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S. Laschat et al.
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Nevertheless, the moderate yield prompted us to investi-
gate alternative routes towards compound 10. Beak,[9]
Meyers,[10] and Gawley[11] have reported that carbamates
or formamidines are suitable precursors for alkylation of
tetrahydroisoquinolines because these protecting groups on
the nitrogen atom are capable of stabilizing the intermediate
benzylic carbanion by a dipole-dipole interaction. Based on
these findings we chose the tricyclic oxazolidinone 13 as
a suitable alkylation precursor hoping that the carbamate
moiety would act both as protecting and activating group
(Scheme 4). According to a known procedure,[12] compound
13 was obtained by treatment of (S)-3-(hydroxymeth-
yl)tetrahydroisoquinoline (11) with NaOEt and diethyl car-
bonate in refluxing EtOH in 86% yield. However, upon de-
protonation of tricyclic oxazolidinone 13 with tBuLi at Ϫ78
°C in THF, and quenching with an excess of methyl iodide,
no trace of the desired alkylation product 15 was found.
Neither variation of base, reaction time or electrophile nor
addition of TMEDA or (Ϫ)-sparteine resulted in any con-
version of 13. In contrast, the structurally closely related
oxazolidinone 14 (Scheme 4), which is available from 2-
(benzylamino)ethanol (12) in 73% yield,[13] was cleanly
methylated under similar conditions to give product 16 in
83% yield. Presumably, the low reactivity of the tricyclic
oxazolidinone 13 as compared to 15 is caused by the restric-
ted conformation, which does not allow sufficient stabiliz-
ation of the intermediate carbanion. This observation is in
good agreement with the results of Beak, showing that an
orthogonal position of the lithiated carbanion relative to
the amide π-system is absolutely necessary for an optimum
stabilization;[13] in the case of 13 this geometry is obviously
not possible.
Scheme 2. Retrosynthetic pathway
more, to investigate the scope and limitations of the Lewis-
acid-catalyzed hetero-ene cyclization of derivatives 6. In
particular, it was of interest to see whether the Lewis acid
would interfere with additional coordinating groups at C-1
and C-2Ј of the tetrahydroisoquinolinecarbaldehyde 6 with
regard to diastereoselectivity. The results towards this goal
are discussed below.
Results and Discussion
Synthesis of 1,3-Disubstituted Tetrahydroisoquinolines
Previously we have reported the synthesis of trans-1,3-
disubstituted tetrahydroisoquinolines such as 10 by depro-
tonation of compound 9 with tBuLi at Ϫ78 °C, followed by
alkylation and subsequent two-step deprotection using HF/
pyridine and TFA, respectively.[8] Although the diastereo-
selectivities were high for various electrophiles, the yields
were low. When using 5  HCl for the deprotection of both
the TBS ether and carbamate the yield of amino alcohol 10
could be improved to 50% starting from 9 (Scheme 3).
Scheme 3. Preparation of trans-1,3-disubstituted tetrahydroisoqui-
noline 10; for other electrophiles see ref.[8]
Scheme 4. Alkylation of tricyclic oxazolidinone 13 and structurally
related compound 14
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Towards a Total Synthesis of Quinocarcin
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The alternative route to 1,3-disubstituted tetrahydroiso-
In the conversion of trans-ester 19a to tetrahydroisoquin-
quinoline via Katritzky’s benzotriazole methodology[14] is oline derivative 10 (Scheme 5) we first had to tackle the
shown in Scheme 5. -Phenylalaninol-derived oxazolidi- chemoselective reduction of the ester moiety while keeping
none 17 was condensed with ethyl glyoxylate and benzotria- the oxazolidinone ring intact. Whereas LiAlH4 resulted in
zole in refluxing toluene in the presence of TsOH to give cleavage and reduction of the oxazolidinone, the reduction
the Mannich-type adduct 18 in 84% yield. Treatment of of 19a with LiBH4 in the presence of equimolar amounts
compound 18 with TiCl4 in MeCN at 60 °C resulted in the of MeOH in THF at 50 °C[15] proceeded cleanly to give
formation of the iminium ion, which cyclized to the tricyclic alcohol 20a.
oxo-oxazolidine-carboxylate 19. In contrast to Katritzky’s
results, ester 19 was obtained as a diastereomeric mixture
of trans- and cis-configured products 19a and 19b (dr ϭ
91:9), respectively. This diastereomeric ratio could not be
changed by using other Lewis acids. However, partial epi-
merization of 19a,b was possible by deprotonation of trans-
ester 19a with BuLi (1.2 equiv.) in THF at Ϫ78 °C followed
by hydrolysis with 2,4,6-tri-tert-butylphenol (2 equiv.) as a
bulky proton source, giving 86% of a diastereomeric mix-
ture of 19a and 19b (66:34). Despite these limitations it
should be noted that both the Katritzky cyclization and the
epimerization can be performed easily on a multi-gram
scale.
Alcohol 20a was methylated with MeI in the presence of
NaH in THF at room temperature to give methyl ether 21a
in 91% yield. Subsequent basic hydrolysis yielded the amino
alcohol 10 in 93% yield.
Surprisingly, cis-oxazolidinone ester 19b displayed a dif-
ferent behavior when a similar reaction sequence was ap-
plied (Scheme 6). Upon treatment of 19b with LiBH4 and
equimolar amounts of MeOH in THF a mixture of the de-
sired alcohol 20b (38%) and the rearranged oxazolidinone
22 (13%) was isolated. After separation of compounds 20b
and 22 by flash chromatography, alcohol 20b was treated
with NaH and MeI, resulting in the formation of 21b (62%)
and the rearranged by-product 23 (16%). Due to the cis-1,3-
disubstitution pattern at the tetrahydroisoquinoline, under
basic conditions the hydroxymethylene group at C-1 can
easily undergo rearrangement by nucleophilic addition at
the oxazolidinone carbonyl group, followed by elimin-
ation.[16]
Scheme 6. Conversion of cis-ester 19b
It is surprising that the corresponding trans-ester 19a and
alcohol 20a did not undergo a similar rearrangement be-
cause they should be even more prone to such nucleophilic
displacement by the pendent hydroxy group. Rearrange-
ment occurs via tetrahedral tricyclic intermediates, as calcu-
lated by molecular modelling.[17] Due to a higher small-an-
gle strain, the trans intermediate derived from alcohol 20a
is less stable (ca. 2.5 kcal·molϪ1) than the cis intermediate
from 20b, leading to a higher activation barrier and thus
lower tendency to undergo nucleophilic displacement.
Scheme 5. Synthesis of 1,3-disubstituted tetrahydroisoquinoline 10
by benzotriazole methodology
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Synthesis of the Side-Chain Precursor
Cyclization precursors with a functionalized side chain
were prepared as shown in Scheme 9. The amino alcohols
10 and 11 were cleanly converted into the respective TBS
ethers 28a,b in good yields. According to a procedure by
Overman[20] the side chain was introduced by nucleophilic
ring-opening of the chiral epoxide 25 with tetrahydroisoqui-
nolines 28 in the presence of Et3Al, giving the correspond-
ing secondary alcohols 29a,b in 70% yield each.
According to a modified procedure by Mazzocchi,[18] 2-
methyl-1-propenylmagnesium bromide (24) was treated
with CuI (0.1 equiv.) in THF at Ϫ10 °C, then (S)-epichlo-
rohydrin was added at Ϫ78 °C and, after hydrolysis, aque-
ous workup and distillation, the chlorohydrin 8a was iso-
lated in 87% yield (Scheme 7). Upon addition of powdered
KOH and heating the mixture at 50 °C the desired epoxide
25 was obtained almost quantitatively by distillation from
the reaction mixture.
Scheme 7. Synthesis of side-chain precursor 25
Synthesis of the Cyclization Precursors
The tetrahydroisoquinoline-carbaldehyde 27 with an un-
functionalized side chain and a methoxymethylene group
at C-1 was easily accessible from amino alcohol 10 by N-
alkylation with 5-methyl-4-hexenyl bromide in the presence
of CaO in DMF at room temperature[7] to give alcohol 26,
which was submitted to Swern oxidation,[19] yielding the
desired aldehyde 27[19d] (Scheme 8).
Scheme 9. Introduction of a chiral side chain; reagents and con-
ditions: (a) TBSCl, imidazole, DMAP, CH2Cl2, room temp., 16 h;
(b) AlEt3 (1.3 equiv.), 25, CH2Cl2, room temp., 16 h; (c) 1) NaOtBu
(1.2 equiv.), BnBr (1.5 equiv.), THF, room temp., 16 h; (d) TBAF
(3 equiv.), THF, room temp., 24 h; (e) (COCl)2, DMSO, NEt3,
CH2Cl2, Ϫ50 °C, 16 h
With regard to the Lewis-acid-catalyzed hetero-ene cycli-
zation a suitable protecting group for the alcohol moiety
was required. Preliminary studies revealed that benzyl-pro-
tected tetrahydroisoquinoline alcohols survived even a large
excess of strong Lewis acids. Thus, the secondary alcohols
29 were deprotonated with NaOtBu and protected with
benzyl bromide. Surprisingly, the benzylation reaction de-
pended strongly on the substitution pattern of the tetra-
hydroisoquinoline 29. Methoxymethylene-substituted 29a
underwent desilylation and subsequent benzylation of the
primary hydroxy group to yield benzyl ether 30 in 78%.
Replacing the base by NaH and a TBS ether by a TIPS
ether again led to benzyl ether 30. In contrast, the unsubsti-
tuted 29b gave the desired benzyl ether 31 in 60% yield with-
Scheme 8. Synthesis of unfunctionalized cyclization precursor 27
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Towards a Total Synthesis of Quinocarcin
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out any difficulty. We therefore focussed our further work Lewis acids SnCl4, TiCl4, ZnCl2 and EtAlCl2 (Entries 2Ϫ5),
on the 1-unsubstituted series. Swern oxidation of the pri- the use of BF3·OEt2 resulted in the formation of compound
mary alcohol 32, derived from the TBS ether 31 by depro- 34b as the major diastereomer (Entry 1). In contrast, Lewis-
tection with TBAF in 94% yield, provided aldehyde 33.[19d] acid-catalyzed cyclization of aldehyde 33 with a benzyl
ether in the side chain proceeded in favor of diastereomer
Lewis-Acid-Catalyzed Cyclizations
35b (Scheme 10) regardless of the Lewis acid. For example,
use of SnCl4 resulted in the formation of a diastereomeric
mixture (dr ϭ 83:17) in 88% yield, from which the major
diastereomer 35b was isolated in pure form after prepara-
tive HPLC in 30% yield. It should be noted that determi-
nation of the diastereomeric ratios of 35 was severely ham-
pered by decomposition during chromatography (GC and
HPLC). Therefore, the minor diastereomer of the SnCl4
cyclization could not be isolated and characterized. Similar
results were observed for other Lewis acids. One possible
reason for the lability of the secondary alcohol 35 might
be an acid-promoted elimination of water leading to the
conjugated diene. The stereochemical assignment of the
cyclization products is based on 2D NOE experiments of
all isolated diastereomers 34a,b and 35b.
When methoxymethylene-substituted aldehyde 27 was
treated with Lewis acid (2 equiv.) in CH2Cl2 for 20 h, a
mixture of diastereomeric azepino[1,2-b]isoquinolines
34aϪd was obtained (Scheme 10, Table 1).
In order to explain the stereochemical outcome of the
cyclization the following mechanistic rationale may be
drawn. As shown in Scheme 11, in the case of the stepwise
cyclization[6cϪ6e] of aldehyde 27 six different transition-state
geometries 36aϪf have to be considered: two half-chair geo-
metries with a monodentate Lewis acid (36a,b), two half-
chairs with a chelating Lewis acid (36c,d), and two half-
boat geometries with a monodentate and a bidentate Lewis
acid (36e,f). In this respect it should be noted that cycliza-
tions were incomplete when less than 2 equiv. of Lewis acid
were used. The only transition state which can be ruled out
first seems to be 36e as a result of steric interactions be-
tween the chelated Lewis acid and the axial isopropenyl
substituent. For small, nonchelating Lewis acids such as
BF3·OEt2 with a tetrahedral coordination sphere, transition
Scheme 10. Lewis-acid-catalyzed cyclization of derivatives 27 and
33[19d] to diastereomers 34aϪd and 35b, respectively; 40 h reaction
time in the conversion of 33
Table 1. Diastereoselective cyclization of tetrahydroisoquinoline-
carbaldehyde 27 in the presence of various Lewis acids
Entry[a][b] Lewis acid
Diastereomeric ratio (%)
Yield
(%)
34a
34b
34c
34d
1
2
3
4
5
BF3·OEt2
SnCl4
TiCl4
ZnCl2
EtAlCl2
10.0
92.0
88.9
89.4
88.0
90.0
5.1
4.7
9.8
8.3
Ͻ 0.1
2.9
0.7
Ͻ 0.1
Ͻ 0.1
Ͻ 0.1
Ͻ 0.1
5.8
0.8
3.7
78
90
60
89
90
[a]
[b]
For reaction conditions see Scheme 10. Diastereomeric ratios
were obtained by capillary GC and GC-MS of the crude products.
Yields refer to isolated yields.
As summarized in Table 1, the diastereomeric ratio was
strongly dependent on the Lewis acid. Whereas dia-
stereomer 34a, with a cis,trans configuration at C-11a, C-11
Scheme 11. Assumed transition state geometries 36aϪf in the
and C-10, was obtained as the major product with chelating Lewis-acid-catalyzed cyclization of aldehyde 27 to products 34
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S. Laschat et al.
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state 36b with the isopropenyl group in the equatorial posi- suitable tetrahydroisoquinoline-carbaldehydes 27 and 33 by
tion is probably favored rather than 36a, resulting in prod- a Lewis-acid-catalyzed hetero-ene cyclization. Whereas for
uct 34b as the major diastereomer. However, in the case of 1-methoxymethylene-substituted derivative 27, with an un-
larger chelating Lewis acids, transition state 36b is disfav- functionalized side chain, the major effect on stereoselectiv-
ored relative to 36a due to steric interactions between the ity is caused by the Lewis acid, the opposite result was ob-
Lewis acid and the equatorial substituent. In addition, tran- tained for aldehyde 33 with R ϭ H at C-1 and a benzyl
sition states 36c,d must be considered as well. For steric ether substituent in the side chain. In the latter case, the
reasons, transition states 36a,c seem to be most favorable, substituent dominates the stereochemistry regardless of the
both leading to diastereomer 34a.
Lewis acid. Unfortunately, due to synthetic difficulties both
For aldehyde 33, with a benzyloxy group in the side substituents in the same precursor could not be studied.
chain, transition-state geometries 37aϪf are conceivable With regard to application in the quinocarcin synthesis
(Scheme 12). Independent of the conformation of the tran- further work on these functionalized azepino[1,2-b]iso-
sition state, all geometries 37a,c,e with a 1,3-diaxial interac- quinolines 34 and 35 is necessary, in particular inversion of
tion between the benzyl ether and the isopropenyl group the stereochemistry at C-5. Studies towards this goal are
should be strongly disfavored (Scheme 12). Thus, the re- currently underway.
maining geometries 37b,d,f with an equatorial isopropenyl
substituent lead to the major diastereomer 35b. This means
Experimental Section
that the preference of different Lewis acids for different
transition states, for example nonchelating (37b) or chelat-
ing (37d or 37f), always gives the same stereochemical re-
sult.
General: The following compounds were prepared according to lit-
erature procedures: 9, 10,[8] 11,[7] 12,[12] 17 and 18.[14] Flash chroma-
tography was carried out using Merck SiO2 60 (particle size
230Ϫ400 mesh) with pentane and ethyl acetate (EtOAc) as eluents.
HPLC was performed using an MZ Analysetechnik silica gel-NH2
10-µm column (250 mm ϫ 32 mm). GC was carried out with a
HewlettϪPackard HP 6890 using an Agilent Technologies HP-5
column (30 m) and helium as the carrier gas.
(10aS)-1,5,10,10a-Tetrahydro[1,3]oxazolo[3,4-b]isoquinolin-3-one
(13): A solution of NaOEt (1 , 36.8 mL, 36.8 mmol) and diethyl
carbonate (22.3 mL, 184 mmol) was added dropwise to a solution
of 11 (3.00 g, 18.4 mmol) in abs. EtOH (150 mL), and the reaction
mixture was heated at reflux for 6 h. After cooling to room temp.
and hydrolysis with HOAc (20 mL), the solution was concentrated,
taken up in 10% HCl/H2O (5 mL) and extracted with CH2Cl2 (3
ϫ 20 mL). The combined organic layers were dried (MgSO4) and
concentrated under vacuum. Chromatography (SiO2; pentane/
EtOAc ϭ 3:1) gave 13 as a colorless solid (2.98 g, 15.8 mmol, 86%),
m.p. 134 °C. 1H NMR (400 MHz, CDCl3): δ ϭ 7.27Ϫ7.13 (m, 4
H, 6-H, 7-H, 8-H, 9-H), 4.82 (d, J ϭ 16.7 Hz, 1 H, 5-Ha), 4.58 (t,
J ϭ 8.5 Hz, 1 H, 1-Ha), 4.37 (d, J ϭ 16.7 Hz, 1 H, 5-Hb), 4.14 (dd,
J ϭ 8.5, J ϭ 5.1 Hz, 1 H, 1-Hb), 4.00Ϫ3.93 (m, 1 H, 10a-H), 2.94
(dd, J ϭ 15.3, J ϭ 4.4 Hz, 1 H, 10-Ha), 2.86 (dd, J ϭ 15.3, J ϭ
10.8 Hz, 1 H, 10-Hb) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
157.3 (CϭO), 131.6 (C-9a), 131.4 (C-5a), 129.4 (C-9), 127.0 (C-6),
126.8 (C-7), 126.4 (C-8), 68.4 (C-1), 51.1 (C-10a), 43.0 (C-5), 34.0
(C-10) ppm. IR (KBr): ν˜ ϭ 3021, 3005 (m, C-H aromat.), 2958,
2946, 2912 (m, CϪH aliphat.), 1747 (s, CϭO), 1455, 1436 (s, Cϭ
C aromat.), 1077, 1011 (s, CϪO), 780, 762 (m) cmϪ1. MS (EI):
m/z (%) ϭ 189 (54) [Mϩ], 144 (15) [C10H10Nϩ], 116 (27), 104 (100)
[C8H8ϩ], 91 (16) [C7H7ϩ].
Scheme 12. Assumed transition state geometries 37aϪf in the
Lewis-acid-catalyzed cyclization of aldehyde 33 to product 35b
Biological Assays
In vitro cytotoxicity studies against two different human
tumor cell lines RD-ES and CAD-ES1 (Ewing’s sar-
coma)[21] reveal that azepino[1,2-b]isoquinolines 34a,b and
35b are weakly active, displaying similar cytotoxicities
against both cell lines. The activity decreases in the order
35b Ͼ 34a Ͼ 34b (RD-ES) and 35b Ͼ 34b Ͼ 34a (CAD-
ES1).[22]
3-Benzyl-1,3-oxazolidin-2-one (14): A solution of NaOEt (1 ,
39.7 mL, 39.7 mmol) and diethyl carbonate (24.0 mL, 198 mmol)
was added dropwise to a solution of 12 (3.0 g, 19.8 mmol) in abs.
EtOH (150 mL), and the reaction mixture was heated at reflux for
6 h.The reaction was quenched with HOAc (50 mL) and the sol-
vents were evaporated. The residue was taken up in 2  HCl
(15 mL) and extracted with CH2Cl2 (3 ϫ 80 mL). The combined
organic layers were dried (MgSO4) and concentrated under vacuum
to give 14 as a colorless solid (2.56 g, 14 mmol, 73%), m.p. 78 °C.
1H NMR (400 MHz, CDCl3): δ ϭ 7.38Ϫ7.27 (m, 5 H, 7-H, 8-H,
Conclusion
We have shown that functionalized azepino[1,2-b]iso-
quinolines 34 and 35 can be prepared stereoselectively from 9-H, 10-H, 11-H), 5.23 (s, 2 H, 5-H), 4.29 (t, J ϭ 8.1 Hz, 2 H, 1-
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Towards a Total Synthesis of Quinocarcin
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H), 3.42 (t, J ϭ 8.1 Hz, 2 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 169.8 (CϭO, ester), 157.1 (C-3), 133.3 (C-9a), 129.9
CDCl3): δ ϭ 158.4 (CϭO), 135.7 (C-6), 128.7 (C-7, C-11), 128.0 (C-5a), 129.1 (C-6), 128.5 (C-8), 127.8 (C-9), 127.6 (C-7), 69.7 (C-
(C-8, C-10), 127.9 (C-9), 61.7 (C-1), 48.3 (C-5), 43.6 (C-4) ppm.
1), 62.0 (C-11), 57.7 (C-5), 52.4 (C-10a), 34.5 (C-10), 13.9 (C-12)
ppm. IR (film): ν˜ ϭ 3029 (m, CϪH aromat.), 2979, 2904 (m, CϪH
aliphat.), 1755, 1736 (s, CϭO, ester, oxazolidinone), 1490, 1415 (s,
CϭC aromat.), 1188, 1023 (s, CϪO), 755, 738 (m) cmϪ1. MS (EI):
m/z (%) ϭ 188 (100) [Mϩ Ϫ CH2COOC2H5], 144 (22) [C11H10Nϩ],
117 (24), 115 (17), 43 (66). C14H15NO4 (261.27): calcd. C 64.36, H
5.79, N 5.36; found C 63.94, H 5.99, N 5.02. GC: tR ϭ 12.26 min.
3-(1-Phenylethyl)-1,3-oxazolidin-2-one (16): A solution of tBuLi
(1.6 , 0.85 mL, 1.4 mmol) was added dropwise to a solution of 14
(177 mg, 1 mmol) in abs. THF (5 mL) in a Schlenk flask, and the
reaction mixture stirred at Ϫ78 °C for 5 h. After addition of MeI
(0.19 mL, 3 mmol), the reaction mixture was allowed to warm up
to room temp. (16 h), hydrolyzed with satd. NaHCO3 solution
(20 mL), and the aqueous layer was extracted with Et2O (3 ϫ
20 mL). The combined organic layers were dried (MgSO4), concen-
trated, and the residue purified by flash chromatography (SiO2;
pentane/EtOAc ϭ 2:1) to give 16 as a light-yellow oil (159 mg,
0.83 mmol, 83%). 1H NMR (400 MHz, CDCl3): δ ϭ 7.39Ϫ7.27 (m,
5 H, 7-H, 8-H, 9-H, 10-H, 11-H), 5.21 (q, J ϭ 7.1 Hz, 1 H, 5-H),
4.29 (ddd, J ϭ 9.2, J ϭ 8.5, J ϭ 6.8 Hz, 1 H, 1-Ha), 4.21 (ddd, J ϭ
9.2, J ϭ 8.5, J ϭ 6.8 Hz, 1 H, 1-Hb), 3.51 (ddd, J ϭ 9.2, J ϭ 8.5,
J ϭ 6.8 Hz, 1 H, 4-Ha), 3.05 (ddd, J ϭ 9.2, J ϭ 8.5, J ϭ 6.8 Hz, 1
H, 4-Hb), 1.58 (d, J ϭ 7.1 Hz, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 157.9 (CϭO), 139.4 (C-6), 128.7 (C-7, C-
11), 127.8 (C-9), 126.9 (C-8, C-10), 61.8 (C-1), 51.3 (C-5), 39.9 (C-
4), 16.2 (CH3) ppm.
(5S,10aS)-5-(Hydroxymethyl)-1,5,10,10a-tetrahydro[1,3]oxazolo-
[3,4-b]isoquinolin-3-one (20a): MeOH (4.70 mL, 385 mmol) was ad-
ded dropwise to a solution of LiBH4 (8.39 g, 385 mmol) in abs.
THF (270 mL). After stirring for 30 min, a solution of 19a (25.1 g,
96.1 mmol) in abs. THF (50 mL) was added, and the reaction mix-
ture was heated at 50 °C for 6 h, and then hydrolyzed with 3  HCl
(80 mL) with ice cooling. The organic solvent was removed under
vacuum, and the precipitate filtered off, washed with Et2O and
dried over P2O5 under high vacuum to give 20a as a colorless solid
(18.3 g, 83.5 mmol, 87%), m.p. 200 °C, [α]2D2 ϭ Ϫ68.3 (c ϭ 1.04,
MeOH). 1H NMR (400 MHz, [D6]DMSO): δ ϭ 7.35Ϫ7.33 (m, 1
H, 6-H), 7.26Ϫ7.16 (m, 3 H, 7-H, 8-H, 9-H), 5.00 (t, J ϭ 6.0 Hz,
1 H, OH), 4.70 (dd, J ϭ 5.9, J ϭ 4.4 Hz, 1 H, 5-H), 4.50 (t, J ϭ
8.2 Hz, 1 H, 1-Ha), 4.25Ϫ4.18 (m, 1 H, 10a-H), 4.14 (dd, J ϭ 8.2,
J ϭ 3.8 Hz, 1 H, 1-Hb), 3.76 (ddd, J ϭ 11.3, J ϭ 6.0, J ϭ 4.4 Hz,
1 H, 1Ј-Ha), 3.68 (ddd, J ϭ 11.3, J ϭ 5.8, J ϭ 5.8 Hz, 1 H, 1Ј-Hb),
2.96 (dd, J ϭ 16.4, J ϭ 4.6 Hz, 1 H, 10-Ha), 2.77 (dd, J ϭ 16.4,
J ϭ 11.0 Hz, 1 H, 10-Hb) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ ϭ 156.6 (CϭO), 133.2 (C-9a), 133.0 (C-5a), 129.3 (C-9), 126.9
(C-8), 126.8 (C-7), 126.3 (C-6), 68.0 (C-1), 64.4 (C-1Ј), 54.3 (C-5),
48.3 (C-10a), 33.0 (C-10) ppm. IR (KBr): ν˜ ϭ 3331 (br., OϪH),
2475 (s, OϪH, intramolecular H bond), 3063, 3032 (m, CϪH aro-
mat.), 2941, 2920, 2853 (m, CϪH aliphat.), 1715 (s, CϭO), 1605,
1484, 1455, 1433 (s, CϭC aromat.), 1064 (s, CϪO), 759, 718 (m)
Ethyl (5S,10aS)-3-Oxo-1,5,10,10a-tetrahydro[1,3]oxazolo[3,4-b]iso-
quinoline-5-carboxylate (19a): TiCl4 (10.8 mL, 98.5 mmol) was ad-
ded dropwise over 30 min to a solution of 18 (25.0 g, 65.7 mmol)
in MeCN (375 mL), and the reaction mixture heated at 60 °C for
40 h. After hydrolysis with water (150 mL) with ice cooling, the
layers were separated and the aqueous layer was extracted with
Et2O (4 ϫ 150 mL). The combined organic layers were washed suc-
cessively with 2  NaOH solution (2 ϫ 100 mL) and satd. NH4Cl
solution (2 ϫ 100 mL), and dried (MgSO4). The solvent was re-
moved under vacuum, and the residue chromatographed (SiO2;
pentane/EtOAc ϭ 2:1). In a first fraction (Rf ϭ 0.25) 19a was iso-
lated as a colorless solid (13.6 g, 52.1 mmol, 79%), m.p. 61 °C,
[α]2D2 ϭ Ϫ126.5 (c ϭ 1.1, CHCl3). In a second fraction (Rf ϭ 0.17)
its diastereomer 19b was obtained as a yellow oil (850 mg,
3.25 mmol, 5%), [α]2D2 ϭ Ϫ135.5 (c ϭ 1.08, CHCl3).
cmϪ1. MS (EI): m/z (%) ϭ 218 (8) [Mϩ Ϫ H], 188 (100) [Mϩ
Ϫ
CH2OH], 144 (44) [C11H10Nϩ], 117 (59), 115 (49). C12H13NO3
(219.24): calcd. C 65.74, H 5.98, N 6.39; found C 65.34, H 6.26,
N 6.22.
(5S,10aS)-5-(Methoxymethyl)-1,5,10,10a-tetrahydro[1,3]oxazolo-
[3,4-b]isoquinolin-3-one (21a): With ice cooling, MeI (19.6 mL,
314 mmol) and a solution of 20a (17.4 g, 78.6 mmol) in abs. THF
(45 mL) was added dropwise to a suspension of NaH (4.77 g,
121 mmol) in abs. THF (230 mL). The reaction mixture was stirred
at room temp. for 16 h prior to hydrolysis with satd. NH4Cl solu-
tion (30 mL). The organic solvent was removed, and the aqueous
layer extracted with CH2Cl2 (3 ϫ 100 mL). The combined extracts
were dried (MgSO4) and concentrated. The residue was purified by
flash chromatography (SiO2; pentane/EtOAc ϭ 5:1) to give 21a as
19a: 1H NMR (400 MHz, CDCl3): δ ϭ 7.58 (dd, J ϭ 5.4, J ϭ
3.6 Hz, 1 H, 6-H), 7.29Ϫ7.25 (m, 2 H, 7-H, 8-H), 7.17 (dd, J ϭ
5.4, J ϭ 3.8 Hz, 1 H, 9-H), 5.45 (s, 1 H, 5-H), 4.70 (t, J ϭ 8.3 Hz,
1 H, 1-Ha), 4.48 (dddd, J ϭ 11.3, J ϭ 8.3, J ϭ 6.4, J ϭ 4.3 Hz, 1
H, 10a-H), 4.21 (q, J ϭ 7.1 Hz, 2 H, 11-H), 4.14 (dd, J ϭ 8.3, J ϭ
6.3 Hz, 1 H, 1-Hb), 3.03 (dd, J ϭ 15.7, J ϭ 4.3 Hz, 1 H, 10-Ha),
2.88 (dd, J ϭ 15.7, J ϭ 11.1 Hz, 1 H, 10-Hb), 1.31 (t, J ϭ 7.1 Hz,
3 H, 12-H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 169.9 (CϭO,
ester), 156.9 (C-3), 131.8 (C-9a), 129.7 (C-9), 128.7 (C-5a), 128.1
(C-7), 127.4 (C-6), 127.1 (C-8), 69.2 (C-1), 61.9 (C-11), 54.9 (C-5),
49.2 (C-10a), 33.6 (C-10), 14.0 (C-12) ppm. IR (KBr): ν˜ ϭ 3068 (m,
CϪH aromat.), 2991, 2936, 2905 (m, CϪH aliphat.), 1758, 1725 (s,
CϭO, ester, oxazolidinone), 1477, 1408 (s, CϭC aromat.), 1068,
1016 (s, CϪO), 759, 715 (m) cmϪ1. MS (EI): m/z (%) ϭ 188 (100)
[Mϩ Ϫ CH2COOC2H5], 144 (21) [C11H10Nϩ], 117 (23), 44 (36).
GC: HP-5, temperature program: 16 °C minϪ1 gradient from 80 to
300 °C, tR ϭ 12.36 min.
a colorless solid (16.7 g, 71.6 mmol, 91%), m.p. 72.5 °C, [α]2D2
ϭ
Ϫ188.5 (c ϭ 1.24, CHCl3). 1H NMR (400 MHz, CDCl3): δ ϭ
7.26Ϫ7.21 (m, 3 H, 7-H, 8-H, 9-H), 7.14 (d, J ϭ 7.1 Hz, 1 H, 6-
H), 5.02 (t, J ϭ 4.3 Hz, 1 H, 5-H), 4.60 (t, J ϭ 8.6 Hz, 1 H, 1-Ha),
4.25 (dddd, J ϭ 10.8, J ϭ 8.6, J ϭ 4.5, J ϭ 4.2 Hz, 1 H, 10a-H),
4.13 (dd, J ϭ 8.6, J ϭ 4.2 Hz, 1 H, 1-Hb), 3.81 (dd, J ϭ 10.1, J ϭ
4.3 Hz, 1 H, 1Ј-Ha), 3.78 (dd, J ϭ 10.1, J ϭ 4.3 Hz, 1 H, 1Ј-Hb),
3.33 (s, 3 H, OCH3), 2.95 (dd, J ϭ 15.6, J ϭ 4.3 Hz, 1 H, 10-Ha),
19b: 1H NMR (400 MHz, CDCl3): δ ϭ 7.46 (dd, J ϭ 5.4, J ϭ 2.87 (dd, J ϭ 15.6, J ϭ 10.8 Hz, 1 H, 10-Hb) ppm. 13C NMR
3.6 Hz, 1 H, 6-H), 7.31Ϫ7.26 (m, 2 H, 7-H, 8-H), 7.19 (dd, J ϭ (100 MHz, CDCl3): δ ϭ 157.0 (CϭO), 132.6 (C-5a), 132.5 (C-9a),
4.9, J ϭ 3.6 Hz, 1 H, 9-H), 5.29 (s, 1 H, 5-H), 4.68 (t, J ϭ 8.4 Hz, 129.5 (C-6), 127.3 (C-9), 126.9 (C-8), 126.5 (C-7), 75.9 (C-1Ј), 68.5
1 H, 1-Ha), 4.25 (dd, J ϭ 9.6, J ϭ 8.4 Hz, 1 H, 1-Hb), 4.16 (q, J ϭ
7.1 Hz, 2 H, 11-H), 4.20Ϫ4.01 (m, 1 H, 10a-H), 3.14 (dd, J ϭ 14.4,
(C-1), 59.2 (OCH3), 52.3 (C-5), 49.4 (C-10a), 34.1 (C-10) ppm. IR
(KBr): ν˜ ϭ 3065, 3035, 3024 (m, CϪH aromat.), 2992, 2967, 2931,
J ϭ 11.4 Hz, 1 H, 10-Ha), 2.97 (dd, J ϭ 14.4, J ϭ 3.2 Hz, 1 H, 10- 2897 (m, CϪH aliphat.), 1745 (s, CϭO), 1435, 1417 (s, CϭC aro-
Hb), 1.22 (t, J ϭ 7.1 Hz, 3 H, 12-H) ppm. 13C NMR (100 MHz, mat.), 1103, 1020 (s, CϪO), 761, 750 (m) cmϪ1. MS (EI): m/z (%) ϭ
Eur. J. Org. Chem. 2004, 3611Ϫ3622
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3617

S. Laschat et al.
FULL PAPER
234 (2) [Mϩ ϩ H], 233 (1) [Mϩ], 188 (100) [Mϩ Ϫ CH2OCH3], 144 (SiO2; pentane/EtOAc ϭ 2:1; Rf ϭ 0.11) was obtained a mixture
(27) [C11H10Nϩ], 117 (32), 115 (24). C13H15NO3 (233.26): calcd. C of 21b and 23 in a ratio of 5:1 (83 mg, 0.36 mmol, 78%). 1H NMR
66.94, H 6.48, N 6.00; found C 66.63, H 6.55, N 5.67. GC: HP-5,
(400 MHz, CDCl3): δ ϭ 7.30Ϫ7.21 (m, 3 H, 7-H, 8-H, 9-H),
temperature program: 16 °C minϪ1 gradient from 80 to 300 °C, 7.17Ϫ7.14 (m, 1 H, 6-H), 4.79 (dd, J ϭ 4.6, J ϭ 2.4 Hz, 1 H, 5-
tR ϭ 11.7 min.
H), 4.52 (‘td’, J ϭ 6.6, J ϭ 0.9 Hz, 1 H, 1-Ha), 4.06 (dd, J ϭ 9.6,
J ϭ 4.6 Hz, 1 H, CH2OCH3), 4.06Ϫ4.02 (m, 1 H, 1-Hb), 4.02Ϫ3.94
(m, 1 H, 10a-H), 3.66 (dd, J ϭ 9.6, J ϭ 2.4 Hz, 1 H, CH2OCH3),
3.21 (s, 3 H, CH2OCH3), 2.97 (dd, J ϭ 14.1, J ϭ 10.0 Hz, 1 H, 10-
Ha), 2.89 (dd, J ϭ 14.1, J ϭ 3.0 Hz, 1 H, 10-Hb) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 156.7 (CϭO), 134.7 (C-5a), 133.8 (C-9a),
128.4 (C-6), 127.3 (C-9), 127.2 (C-8), 127.0 (C-7), 73.9 (C-1Ј), 68.4
(C-1), 59.2 (OCH3), 55.0 (C-5), 54.2 (C-10a), 34.1 (C-10) ppm. IR
(ATR): ν˜ ϭ 2995 (m, CϪH aromat.), 2977, 2955, 2924, 2891 (m,
CϪH aliphat.), 1733 (s, CϭO), 1491, 1474, 1407 (s, CϭC aromat.),
1103, 1075 (s, CϪO), 790, 760 (m) cmϪ1. MS (EI): m/z (%) ϭ 233
(1) [Mϩ], 201 (2) [Mϩ Ϫ 32], 188 (100) [Mϩ Ϫ CH2OCH3], 144
(25) [C11H10Nϩ], 117 (24), 115 (19).
[(1S,3S)-1-(Methoxymethyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]-
methanol (10): A 2  NaOH solution (200 mL) was added to a
solution of 21a (16.6 g, 71.0 mmol) in MeOH (200 mL), and the
reaction mixture heated at 80 °C for 4 h. The organic solvent was
removed, and the remaining aqueous layer extracted with CH2Cl2
(3 ϫ 80 mL). The combined extracts were dried (MgSO4) and con-
centrated to give 10 as a light-yellow solid (13.6 g, 67.5 mmol,
93%), m.p. 122 °C, [α]2D2 ϭ Ϫ26.7 (c ϭ 1.0, CHCl3). NMR spectro-
scopic data are in accordance with those in ref.[23]
(5R,10aS)-5-(Hydroxymethyl)-1,5,10,10a-tetrahydro[1,3]oxazolo-
[3,4-b]isoquinolin-3-one (20b): As described above for 20a, from 19b
(300 mg, 1.15 mmol) in abs. THF (5 mL), LiBH4 (100 mg,
4.60 mmol) in abs. THF (5 mL), MeOH (186 µL, 4.60 mmol), hy-
drolysis with 3  HCl (6 mL), and flash chromatography (SiO2;
pentane/EtOAc ϭ 1:1) by-product 22 was obtained in a first frac-
(2S)-1-Chloro-5-methylhex-4-en-2-ol (8a): A solution of 24 (0.5 ,
21.6 mL, 10.8 mmol) in Et2O was added dropwise to a suspension
of CuI (206 mg, 1.08 mmol) in abs. THF (40 mL) at Ϫ10 °C in a
Schlenk flask. After stirring at Ϫ10 °C for 45 min and then cooling
to Ϫ78 °C, (S)-epichlorohydrin (1.00 g, 10.81 mmol) was slowly ad-
ded. The reaction mixture was allowed to warm up to room temp.
(16 h) and hydrolyzed with satd. NH4Cl solution (15 mL). The
aqueous layer was extracted with Et2O (3 ϫ 10 mL), and the com-
bined organic layers were dried (MgSO4) and concentrated. The
residue was distilled under vacuum to give 8a as a colorless liquid
(1.39 g, 9.35 mmol, 87%), b.p. 82Ϫ85 °C/40 mbar, [α]2D2 ϭ ϩ8.3 (c ϭ
tion (Rf ϭ 0.19) as a yellow oil (32 mg, 0.15 mmol, 13%), [α]2D2
ϭ
Ϫ202.2 (c ϭ 1.05, CHCl3), and 20b in a second fraction (Rf ϭ 0.10)
as a colorless solid (95 mg, 0.43 mmol, 38%), m.p. 178 °C, [α]2D2
Ϫ174.5 (c ϭ 1.0, MeCN).
ϭ
1
20b: H NMR (400 MHz, [D6]DMSO): δ ϭ 7.36Ϫ7.22 (m, 4 H, 6-
H, 7-H, 8-H, 9-H), 4.84 (dd, J ϭ 6.7, J ϭ 5.6 Hz, 1 H, OH), 4.66
(dd, J ϭ 3.8, J ϭ 2.5 Hz, 1 H, 5-H), 4.55 (t, J ϭ 7.4 Hz, 1 H, 1-
Ha), 4.10Ϫ4.04 (m, 1 H, CH2OH), 4.03 (dd, J ϭ 10.8, J ϭ 7.4 Hz,
1 H, 1-Hb), 3.94 (dddd, J ϭ 10.8, J ϭ 10.6, J ϭ 7.4, J ϭ 3.7 Hz,
1 H, 10a-H), 3.63 (ddd, J ϭ 10.8, J ϭ 6.7, J ϭ 2.5 Hz, 1 H,
CH2OH), 2.94 (dd, J ϭ 14.2, J ϭ 10.6 Hz, 1 H, 10-Ha), 2.88 (dd,
J ϭ 14.2, J ϭ 3.7 Hz, 1 H, 10-Hb) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ ϭ 156.2 (CϭO), 135.2 (C-9a), 134.6 (C-5a), 128.2
(C-6), 127.5 (C-9), 126.6 (C-8), 126.5 (C-7), 68.0 (C-1), 62.9 (C-1Ј),
56.4 (C-5), 53.6 (C-10a), 33.3 (C-10) ppm. IR (KBr): ν˜ ϭ 3395 (br.,
OϪH), 3067, 3020, 3006 (m, CϪH aromat.), 2960, 2920, 2893 (m,
CϪH aliphat.), 1722 (s, CϭO), 1479, 1428 (s, CϭC aromat.), 1078
(m, CϪO), 762, 754 (m) cmϪ1. MS (EI): m/z (%) ϭ 219 (5) [Mϩ],
188 (100) [Mϩ Ϫ CH2OH], 144 (57) [C11H10Nϩ], 130 (9) [C9H8Nϩ],
117 (17), 115 (19). C12H13NO3 (219.24): calcd. C 65.74, H 5.98, N
6.39; found C 65.55, H 5.82, N 6.51.
1
1.20, CHCl3). H NMR (400 MHz, CDCl3): δ ϭ 5.14 (m, 1 H, 4-
H), 3.82 (ddd, J ϭ 13.0, J ϭ 6.6, J ϭ 3.7 Hz, 1 H, 2-H), 3.63 (dd,
J ϭ 11.1, J ϭ 3.7 Hz, 1 H, 1-Ha), 3.50 (dd, J ϭ 11.1, J ϭ 6.6 Hz,
1 H, 1-Hb), 2.31Ϫ2.28 (m, 3 H, 3-H, OH), 1.73 (d, J ϭ 1.1 Hz, 3
H, 6-H), 1.65 (s, 3 H, 7-H) ppm. 13C NMR (100 MHz, CDCl3):
δ ϭ 135.7 (C-5), 118.5 (C-4), 71.4 (C-2), 49.6 (C-1), 33.0 (C-3), 25.8
(C-6), 17.9 (C-7) ppm. IR (film): ν˜ ϭ 3384 (br., OH), 3048 (CϪH
olefin), 2969, 2916, 2860, 2731 (s, CϪH aliphat.), 1673, 1648 (Cϭ
C olefin), 1437 (OϪH), 1053 (s, CϪO) cmϪ1. MS (EI): m/z (%) ϭ
150 (12) [C7H13ClOϩ], 148 (35) [Mϩ], 81 (47) [C6H9ϩ], 69 (100)
[C5H9ϩ], 41 (94) [C3H5ϩ].
(2S)-2-(3-Methylbut-2-enyl)oxirane (25): A mixture of 8a (1.24 g,
8.34 mmol) and powdered KOH (565 mg, 10.1 mmol) was heated
in a distillation apparatus under vacuum until product 25 distilled
off as a colorless liquid (934 mg, 8.33 mmol, 99%), b.p. 48Ϫ50 °C/
1
22: H NMR (400 MHz, CDCl3): δ ϭ 7.21Ϫ7.17 (m, 2 H, 7-H, 8-
140 mbar, [α]2D2 ϭ ϩ23.2 (c ϭ 1.31, CHCl3). H NMR (400 MHz,
1
H), 7.14Ϫ7.10 (m, 1 H, 6-H), 6.92Ϫ6.88 (m, 1 H, 9-H), 5.02 (t,
J ϭ 8.3 Hz, 1 H, 5-H), 4.80 (t, J ϭ 8.3 Hz, 1 H, 1-Ha), 4.17 (t, J ϭ
8.3 Hz, 2 H, 1-Hb, OH), 3.96 (br. s, 2 H, CH2OH), 3.60 (dddd, J ϭ
11.1, J ϭ 5.7, J ϭ 4.0, J ϭ 3.9 Hz, 1 H, 11-H), 3.08 (dd, J ϭ 16.3,
J ϭ 11.1 Hz, 1 H, 10-Ha), 2.68 (dd, J ϭ 16.3, J ϭ 3.9 Hz, 1 H, 10-
Hb) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 157.2 (CϭO), 133.8
(C-5a), 133.5 (C-9a), 129.4 (C-6), 127.8 (C-7), 127.1 (C-8), 124.1
(C-9), 69.1 (C-1), 62.2 (CH2OH), 56.7 (C-5), 55.0 (C-11), 30.3 (C-
10) ppm. IR (film): ν˜ ϭ 3419 (br., O-H), 3066, 3028, (m, CϪH
aromat.), 2910 (m, CϪH aliphat.), 1747 (s, CϭO), 1476, 1457 (s,
CϭC aromat.), 1083 (m, CϪO), 762, 746 (m) cmϪ1. MS (EI): m/z
(%) ϭ 188 (100) [Mϩ Ϫ CH2OCH3], 144 (23) [C11H10Nϩ], 117 (29),
115 (21). C12H13NO3 (219.24): calcd. C 65.74, H 5.98, N 6.39;
found C 65.46, H 5.92, N 6.11.
C6D6): δ ϭ 5.14 (m, 1 H, 4-H), 2.65 (dddd, J ϭ 5.4, J ϭ 5.4, J ϭ
3.8, J ϭ 2.5 Hz, 1 H, 2-H), 2.33 (dd, J ϭ 5.4, J ϭ 3.8 Hz, 1 H, 1-
Ha), 2.18Ϫ2.11 (m, 1 H, 3-Ha), 2.14 (dd, J ϭ 5.4, J ϭ 2.5 Hz, 1 H,
1-Hb), 2.06Ϫ1.99 (m, 1 H, 3-Hb), 1.59 (d, J ϭ 1.0 Hz, 3 H, 6-H),
1.43 (s, 3 H, 7-H) ppm. 13C NMR (100 MHz, C6D6): δ ϭ 134.1 (C-
5), 119.2 (C-4), 51.4 (C-2), 45.9 (C-1), 31.4 (C-3), 25.7 (C-6), 17.7
(C-7) ppm. IR (film): ν˜ ϭ 3048 (CϪH olefin), 2981, 2918, 2859,
2734 (s, CϪH aliphat.), 1675 (CϭC olefin), 1111 (s, CϪO), 836
(CϪH olefin) cmϪ1. MS (EI): m/z (%) ϭ 112 (29) [Mϩ], 97 (50)
[C6H9Oϩ], 81 (42) [C5H5Oϩ], 79 (83) [C6H7ϩ], 69 (93) [C5H9ϩ], 67
(92) [C5H7ϩ], 41 (100) [C3H5ϩ].
[(1S,3S)-1-(Methoxymethyl)-2-(5-methyl-4-hexenyl)-1,2,3,4-tetra-
hydroisoquinolin-3-yl]methanol (26): CaO (1.00 g, 18.1 mmol) was
added to a solution of 10 (1.50 g, 7.24 mmol) in DMF (12 mL) in
a Schlenk flask, followed by addition of 6-bromo-2-methylhex-2-
ene (1.39 g, 7.83 mmol) over 5 min, and the reaction mixture stirred
at room temp. for 3 d. Additional CaO (1.00 g, 18.1 mmol) was
then added, and the reaction mixture stirred for a further 7 d. After
(5R,10aS)-5-(Methoxymethyl)-1,5,10,10a-tetrahydro[1,3]oxazolo-
[3,4-b]isoquinolin-3-one (21b): As described above for 21a, from
MeI (0.29 mL, 4.56 mmol), 20b (100 mg, 0.46 mmol) in abs. THF
(5 mL), and NaH (27 mg, 0.69 mmol) in abs. THF (5 mL), hydroly-
sis with satd. NH4Cl solution (8 mL) and flash chromatography
3618
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3611Ϫ3622

Towards a Total Synthesis of Quinocarcin
FULL PAPER
dilution with CH2Cl2 and filtration through Celite, the solvent was
removed under vacuum, and remaining DMF by azeotropic distil-
inert gas to a solution of the appropriate 28 (1.00 mmol) in abs.
CH2Cl2 (10 mL), and the reaction mixture stirred for 30 min. After
lation with toluene. The residue was purified by flash chromatogra- addition of 25 (1.00 mmol), the reaction mixture was stirred at
phy (SiO2; pentane/EtOAc ϭ 5:1 and 3:1) to give 26 as a yellow oil room temp. for 16 h, and then hydrolyzed with 2  NaOH solution
(1.23 g, 4.05 mmol, 56%). NMR spectroscopic data are in accord- (5 mL). The aqueous layer was extracted with CH2Cl2 (3 ϫ 10 mL).
ance with those in ref.[23]
The combined organic layers were dried (MgSO4), concentrated,
and the residue was purified by flash chromatography on SiO2 to
give products 29.
(1S,3S)-1-(Methoxymethyl)-2-(5-methyl-4-hexenyl)-1,2,3,4-tetra-
hydroisoquinoline-3-carbaldehyde
(27):
DMSO
(0.82 mL,
11.55 mmol) in abs. CH2Cl2 (4 mL) was added dropwise over
30 min to a solution of (COCl)2 (0.52 mL, 5.94 mmol) in abs.
CH2Cl2 (15 mL) at Ϫ50 °C. After stirring for 15 min, a solution of
26 (700 mg, 2.31 mmol) in abs. CH2Cl2 (10 mL) was added drop-
wise over 45 min, and the reaction mixture was stirred at Ϫ50 °C
for 16 h. Et3N (1.7 mL) was added dropwise over 30 min, the reac-
tion mixture stirred for a further 15 min and then allowed to warm
up to room temp. The organic layer was washed with water (3 ϫ
50 mL) and dried (MgSO4). The solvent was removed under vac-
uum to give 27 (699 mg, quant.). NMR spectroscopic data are in
accordance with those in ref.[23]
(1S,2ЈS,3S)-3-(tert-Butyldimethylsilyloxymethyl)-2-(2Ј-hydroxy-5Ј-
methylhex-4Ј-enyl)-1-(methoxymethyl)-1,2,3,4-tetrahydroiso-
quinoline (29a): From 28a (1.00 g, 3.11 mmol), Et3Al (2.1 mL,
4.04 mmol) and 25 (300 mg, 3.11 mmol), after flash chromatogra-
phy with pentane/EtOAc (20:1), 29a was obtained as a colorless oil
(944 mg, 2.18 mmol, 70%), Rf ϭ 0.19, [α]2D2 ϭ ϩ18.6 (c ϭ 1.37,
1
CHCl3). H NMR (400 MHz, CDCl3): δ ϭ 7.18Ϫ7.15 (m, 3 H, 5-
H, 6-H, 7-H), 7.14Ϫ7.11 (m, 1 H, 8-H), 5.19Ϫ5.15 (m, 1 H, 4Ј-H),
3.94 (dd, J ϭ 8.6, J ϭ 4.5 Hz, 1 H, 1-H), 3.82 (dd, J ϭ 10.2, J ϭ
6.2 Hz, 1 H, CH2OSi), 3.72Ϫ3.67 (m, 2 H, 2Ј-H, CH2OSi), 3.64
(dd, J ϭ 10.2, J ϭ 8.6 Hz, 1 H, CH2OCH3), 3.54 (dd, J ϭ 10.2,
J ϭ 4.5 Hz, 1 H, CH2OCH3), 3.41 (s, 3 H, OCH3), 3.35Ϫ3.28 (m,
1 H, 3-H), 2.66Ϫ2.64 (m, 2 H, 4-H), 2.42Ϫ2.32 (m, 2 H, 1Ј-H),
2.23Ϫ2.16 (m, 1 H, 3Ј-Ha), 2.07Ϫ2.00 (m, 1 H, 3Ј-Hb), 1.67 (d, J ϭ
1.3 Hz, 3 H, 7Ј-H), 1.57 (d, J ϭ 0.8 Hz, 3 H, 6Ј-H), 0.88 [s, 9 H,
C(CH3)3], 0.10 [s, 3 H, Si-(CH3)2], 0.09 [s, 3 H, Si-(CH3)2] ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 136.1 (C-5Ј), 134.4 (C-4a), 133.5
(C-8a), 129.6 (C-8), 128.8 (C-5), 126.8 (C-7), 126.3 (C-5), 120.5 (C-
4Ј), 76.2 (CH2OCH3), 67.2 (C-2Ј), 65.4 (CH2OSi), 61.2 (C-1), 59.4
(OCH3), 54.3 (C-3), 52.8 (C-1Ј), 33.6 (C-3Ј), 26.8 (C-4), 26.2
[C(CH3)3], 26.1 (C-6Ј), 18.5 [C(CH3)3], 18.2 (C-7Ј), Ϫ5.1 (Si-CH3),
Ϫ5.0 (Si-CH3) ppm. IR (ATR): ν˜ ϭ 3540 (br., OϪH), 2954, 2926,
2883 (m, CϪH aliphat.), 1451 (s, CϭC aromat.), 1100 (s), 1006
Silylation of Compounds 10 and 11. General Procedure: TBSCl
(26.0 mmol) was added to a solution of 10 or 11 (24.0 mmol), imi-
dazole (60.0 mmol) and DMAP (1.23 mmol) in abs. CH2Cl2
(40 mL), and the reaction mixture stirred at room temp. for 16 h.
After hydrolysis with satd. NH4Cl solution (100 mL), the aqueous
layer was extracted with CH2Cl2 (3 ϫ 50 mL). The combined or-
ganic layers were washed successively with satd. NaHCO3 solution
(100 mL) and brine (100 mL), dried (MgSO4), and concentrated.
The residue was chromatographed (SiO2; pentane/EtOAc ϭ 15:1)
to give products 28.
(1S,3S)-3-(tert-Butyldimethylsilyloxymethyl)-1-(methoxymethyl)-
1,2,3,4-tetrahydroisoquinoline (28a): From 10 (1.2 g, 5.79 mmol),
imidazole (0.96 g, 14.12 mmol), DMAP (0.06 g, 0.43 mmol) and
TBSCl (0.92 g, 6.12 mmol) 28a was obtained as a colorless oil
(1.78 g, 5.54 mmol, 96%), Rf ϭ 0.20, [α]2D2 ϭ Ϫ17.7 (c ϭ 1.31,
(m), 834 (s, CϪH olefin), 775, 740 (s, 1,2-disubst. aromat.) cmϪ1
.
MS (EI): m/z (%) ϭ 388 (100) [Mϩ Ϫ CH2OCH3], 334 (12)
[C19H32NO2Siϩ], 288 (12) [Mϩ Ϫ CH2OCH3 Ϫ CH2OSi(C3H7)3],
144 (23) [C10H10Nϩ], 130 (12) [C9H8Nϩ].C23H43NO3Si (433.70):
calcd. C 68.89, H 9.85, N 3.34; found C 68.82, H 10.04, N 3.24.
1
CHCl3). H NMR (400 MHz, CDCl3): δ ϭ 7.06Ϫ6.99 (m, 4 H, 5-
H, 6-H, 7-H, 8-H), 4.17 (dd, J ϭ 10.0, J ϭ 3.8 Hz, 1 H, 1-H), 3.65
(dd, J ϭ 9.6, J ϭ 4.0 Hz, 1 H, 1ЈЈ-Ha), 3.48 (dd, J ϭ 10.0, J ϭ
9.8 Hz, 1 H, 1Ј-Ha), 3.43 (dd, J ϭ 9.6, J ϭ 8.3 Hz, 1 H, 1ЈЈ-Hb),
3.39 (dd, J ϭ 9.8, J ϭ 3.8 Hz, 1 H, 1Ј-Hb), 3.33 (s, 3 H, OCH3),
3.18Ϫ3.11 (m, 1 H, 3-H), 2.65 (br. s, 1 H, NH), 2.56 (dd, J ϭ 15.9,
J ϭ 3.9 Hz, 1 H, 4-Ha), 2.44 (dd, J ϭ 15.9, J ϭ 10.7 Hz, 1 H, 4-
Hb), 0.84 [s, 9 H, C(CH3)3], 0.09 (s, 3 H, SiϪCH3), 0.01 (s, 3 H,
SiϪCH3) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 134.9 (C-4a),
134.8 (C-8a), 129.3 (C-8), 127.2 (C-5), 126.5 (C-6), 125.6 (C-7), 74.8
(C-1Ј), 67.1 (C-1ЈЈ), 58.9 (O-CH3), 55.2 (C-1), 48.6 (C-3), 31.6 (C-
4), 25.8 [C(CH3)3], 18.2 [C(CH3)3], Ϫ5.3 (SiϪCH3), Ϫ5.4 (SiϪCH3)
ppm. IR (ATR): ν˜ ϭ 3335 (NϪH), 3063, 3021 (m, CϪH aromat.),
2954, 2926, 2885, 2854 (s, CϪH aliphat.), 1675, 1492, 1454 (s, Cϭ
C aromat.), 1104, 1053 (s, CϪO), 833 (s, CϪH olefin), 773, 740 (s,
(2ЈS,3S)-3-(tert-Butyldimethylsilyloxymethyl)-2-(2Ј-hydroxy-5Ј-
methylhex-4Ј-enyl)-1,2,3,4-tetrahydroisoquinoline (29b): From 28b
(247 mg, 0.89 mmol), Et3Al (0.58 mL, 1.16 mmol) and 25 (100 mg,
0.89 mmol), after flash chromatography with pentane/EtOAc
(10:1), 29b was obtained as a colorless oil (243 mg, 0.62 mmol,
70%), Rf ϭ 0.24, [α]2D2 ϭ ϩ23.2 (c ϭ 1.31, CHCl3). 1H NMR
(400 MHz, CDCl3): δ ϭ 7.15Ϫ7.08 (m, 3 H, 5-H, 6-H, 7-H),
7.03Ϫ7.00 (m, 1 H, 8-H), 5.19 (‘tq’, J ϭ 7.2, J ϭ 1.0 Hz, 1 H, 4Ј-
H), 3.89 (d, J ϭ 15.9 Hz, 1 H, 1-Ha), 3.80 (d, J ϭ 15.9 Hz, 1 H, 1-
Hb), 3.77 (dd, J ϭ 10.4, J ϭ 6.8 Hz, 1 H, 1ЈЈ-Ha), 3.73Ϫ3.67 (m, 1
H, 2Ј-H), 3.18Ϫ3.12 (m, 1 H, 3-H), 3.55 (dd, J ϭ 10.4, J ϭ 6.3 Hz,
1 H, 1ЈЈ-Hb), 2.97 (dd, J ϭ 16.5, J ϭ 5.5 Hz, 1 H, 4-Ha), 2.78 (dd,
J ϭ 13.1, J ϭ 3.0 Hz, 1 H, 1Ј-Ha), 2.67 (dd, J ϭ 16.5, J ϭ 5.1 Hz,
1 H, 4-Hb), 2.50 (dd, J ϭ 13.1, J ϭ 10.6 Hz, 1 H, 1Ј-Hb), 2.27Ϫ2.20
(m, 1 H, 3Ј-Ha), 2.13Ϫ2.04 (m, 1 H, 3Ј-Hb), 1.71 (d, J ϭ 1.0 Hz, 3
H, 7Ј-H), 1.62 (s, 3 H, 6Ј-H), 0.88 [s, 9 H, C(CH3)3], 0.02 [s, 6 H,
Si-(CH3)2] ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 134.1 (C-5Ј),
133.7 (C-4a), 133.5 (C-8a), 129.1 (C-5), 126.5 (C-6), 126.3 (C-7),
125.7 (C-8), 119.9 (C-4Ј), 67.0 (C-2Ј), 62.7 (C-1ЈЈ), 59.8 (C-1Ј), 59.7
(C-3), 51.1 (C-1), 33.4 (C-3Ј), 29.3 (C-4), 25.8 [C(CH3)3], 25.8 (C-
6Ј), 18.2 [C(CH3)3], 17.9 (C-7Ј), Ϫ5.4 (Si-CH3), Ϫ5.5 (Si-CH3)
ppm. IR (film): ν˜ ϭ 3452 (br., OH), 3064, 3046, 3023 (m, CϪH
aromat.), 2954, 2928, 2905, 2897 (s, CϪH aliphat.), 1496 (m), 1104
(s), 1036 (m), 836 (s, CϪH olefin), 776 (s, 1,2-disubst. aromat.)
1,2-disubst. aromat.) cmϪ1. MS (EI): m/z (%) ϭ 276 (100) [Mϩ
Ϫ
CH2OCH3], 260 (38) [Mϩ Ϫ CH2OCH3 Ϫ CH3], 218 (15)
[C12H16NOSiϩ], 176 (23) [Mϩ Ϫ CH2OSi(CH3)2C(CH3)3], 144 (29)
[C10H10Nϩ]. C18H31NO2Si (321.50): calcd. C 68.89, H 9.85, N 3.34;
found C 68.81, H 10.04, N 3.24.
(3S)-3-(tert-Butyldimethylsilyloxymethyl)-1,2,3,4-tetrahydroiso-
quinoline (28b): From 11 (2.00 g, 12.3 mmol), imidazole (2.04 g,
30.0 mmol), DMAP (0.08 g, 0.61 mmol) and TBSCl (1.96 g,
13.0 mmol) 28b was obtained as a colorless oil (3.21 g, 11.6 mmol,
94%), Rf ϭ 0.10, [α]2D2 ϭ Ϫ47.3 (c ϭ 1.00, CH2Cl2). NMR spectro-
scopic data are in accordance with those in ref.[23]
N-Alkylation of Compounds 28. General Procedure: A solution of
Et3Al (2  in toluene, 1.30 mmol) was added dropwise under an
cmϪ1. MS (EI): m/z (%) ϭ 374 (1) [Mϩ Ϫ 15], 290 (30) [Mϩ
C6H11O], 258 (25) [Mϩ Ϫ C6H15SiO], 244 (100) [Mϩ Ϫ C7H17SiO],
Ϫ
Eur. J. Org. Chem. 2004, 3611Ϫ3622
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3619

S. Laschat et al.
FULL PAPER
130 (24) [C9H8Nϩ]. C23H39NO2Si (389.65): calcd. C 70.90, H 10.09,
N 3.59; found C 70.71, H 10.44, N 3.51.
(ATR): ν˜ ϭ 3064, 3026 (m, CϪH aromat.), 2954, 2927, 2882, 2855
(s, CϪH aliphat.), 1675, 1496 (s, CϭC aromat.), 1092, 1069 (s,
CϪO), 833 (s, CϪH olefin), 773, 738 (s, 1,2-disubst. aromat.) cmϪ1
.
MS (EI): m/z (%) ϭ 334 (100) [Mϩ Ϫ C7H16SiO], 290 (30) [Mϩ
Ϫ
(1S,2ЈS,3S)-3-(Benzyloxymethyl)-2-(2Ј-hydroxy-5Ј-methylhex-4Ј-
enyl)-1-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline (30): A solu-
tion of 29a (300 mg, 0.69 mmol) in abs. THF (5 mL) was added to
a suspension of NaH (33 mg, 0.83 mmol) in abs. THF (5 mL) with
ice cooling, and the reaction mixture stirred for 30 min. After ad-
dition of BnBr (90 µL, 0.76 mmol), the reaction mixture was stirred
at room temp. for 16 h and then hydrolyzed with satd. NH4Cl solu-
tion (10 mL). The aqueous layer was extracted with Et2O (3 ϫ
10 mL), and the combined organic layers were dried (MgSO4) and
C6H11O], 91 (9) [C7H7ϩ]. C23H39NO2Si (479.8): calcd. C 75.10, H
9.45, N 2.92; found C 74.85, H 9.51, N 2.78.
[(2ЈS,3S)-2-(2Ј-Benzyloxy-5Ј-methylhex-4Ј-enyl)-1,2,3,4-tetrahydro-
isoquinolin-3-yl]methanol (32): A solution of TBAF (1  in THF/
5% H2O, 1.05 mL, 1.05 mmol) was added to a solution of 31
(170 mg, 0.35 mmol) in THF (5 mL), and the reaction mixture
stirred at room temp. for 24 h. After hydrolysis with water (10 mL),
concentrated. The residue was chromatographed (SiO2; pentane/ the layers were separated, and the aqueous layer was extracted with
EtOAc ϭ 3:1) to give 30 as a colorless oil (221 mg, 0.54 mmol,
Et2O (4 ϫ 8 mL). The combined organic layers were dried (MgSO4)
78%), Rf ϭ 0.21, [α]2D2 ϭ ϩ16.5 (c ϭ 1.09, CHCl3). 1H NMR and concentrated. The product 32 (122 mg, 0.33 mmol, 94%) was
(400 MHz, CDCl3): δ ϭ 7.31Ϫ7.25 (m, 4 H, 3ЈЈ-H, 7ЈЈ-H, 4ЈЈ-H, dried under high vacuum and used without further purification,
6ЈЈ-H), 7.23Ϫ7.18 (m, 1 H, 5ЈЈ-H), 7.11Ϫ7.05 (m, 3 H, 6-H, 7-H,
8-H), 7.04Ϫ7.00 (m, 1 H, 5-H), 5.12Ϫ5.07 (m, 1 H, 4Ј-H), 4.52 (d, δ ϭ 7.31Ϫ7.24 (m, 4 H, 3ЈЈ-H, 7ЈЈ-H, 4ЈЈ-H, 6ЈЈ-H), 7.22Ϫ7.18 (m,
J ϭ 11.9 Hz, 1 H, 1ЈЈ-Ha), 4.48 (d, J ϭ 11.9 Hz, 1ЈЈ-Hb), 3.88 (dd, 1 H, 5ЈЈ-H), 7.08Ϫ7.05 (m, 2 H, 6-H, 7-H), 7.00Ϫ6.98 (m, 1 H, 5
[α]2D2 ϭ ϩ31.6 (c ϭ 1.14, CHCl3). 1H NMR (400 MHz, CDCl3):
J ϭ 8.7, J ϭ 4.5 Hz, 1 H, 1-H), 3.66Ϫ3.59 (m, 2 H, 2Ј-H, CH2OH), H), 6.94Ϫ6.92 (m, 1 H, 8-H), 5.08Ϫ5.03 (m, 1 H, 4Ј-H), 4.59 (d,
3.59 (dd, J ϭ 10.1, J ϭ 8.7 Hz, 1 H, CH2OCH3), 3.49Ϫ3.43 (m, 2 J ϭ 11.7 Hz, 1 H, 1ЈЈ-Ha), 4.48 (d, J ϭ 11.7 Hz, 1 H, 1ЈЈ-Hb), 3.81
H, 3-H, CH2OH), 3.45 (dd, J ϭ 10.1, J ϭ 4.5 Hz, 1 H, CH2OCH3),
(s, 2 H, 1-H), 3.58Ϫ3.52 (m, 2 H, 2Ј-H, OH), 3.48 (d, J ϭ 2.4 Hz,
3.33 (s, 3 H, OCH3), 2.59Ϫ2.58 (m, 2 H, 4-H), 2.34Ϫ2.26 (m, 2 H, 1 H, CH2OH), 3.46 (d, J ϭ 5.1 Hz, 1 H, CH2OH), 3.15 (dddd, J ϭ
1Ј-H), 2.16Ϫ2.08 (m, 1 H, 3Ј-Ha), 2.00Ϫ1.93 (m, 1 H, 3Ј-Hb), 1.59 8.3, J ϭ 8.3, J ϭ 5.7, J ϭ 5.6 Hz, 1 H, 3-H), 2.67Ϫ2.64 (m, 1 H,
(d, J ϭ 1.0 Hz, 3 H, 7Ј-H), 1.50 (d, J ϭ 1.0 Hz, 3 H, 6Ј-H) ppm. 4-Ha), 2.61 (d, J ϭ 5.9 Hz, 1 H, 1Ј-Ha), 2.42Ϫ2.40 (m, 1 H, 4-Hb),
13C NMR (100 MHz, CDCl3): δ ϭ 138.2 (C-2ЈЈ), 135.5 (C-5Ј), 2.38Ϫ2.36 (m, 1 H, 1Ј-Hb), 2.25Ϫ2.11 (m, 2 H, 3Ј-H), 1.60 (d, J ϭ
133.9 (C-4a), 133.2 (C-8a), 129.2 (C-5), 128.5 (C-7), 128.4 (C-4ЈЈ, 1.0 Hz, 3 H, 7Ј-H), 1.50 (d, J ϭ 1.0 Hz, 3 H, 6Ј-H) ppm. 13C NMR
C-6ЈЈ), 127.7 (C-3ЈЈ, C-7ЈЈ), 127.6 (C-5ЈЈ), 126.5 (C-8), 126.0 (C-6), (100 MHz, CDCl3): δ ϭ 138.1 (C-2ЈЈ), 133.9 (C-4a), 133.7 (C-8a),
120.1 (C-4Ј), 75.8 (CH2OCH3), 73.2 (C-1ЈЈ), 72.1 (CH2OH), 66.9 133.5 (C-5Ј), 128.6 (C-5), 128.0 (C-4ЈЈ, C-6ЈЈ), 127.6 (C-3ЈЈ, C-7ЈЈ),
(C-2Ј), 60.9 (C-1), 59.1 (OCH3), 52.5 (C-1Ј), 51.8 (C-3), 33.2 (C- 127.3 (C-5ЈЈ), 126.7 (C-8), 126.1 (C-6), 125.7 (C-7), 119.3 (C-4Ј),
3Ј), 26.8 (C-4), 25.8 (C-7Ј), 17.9 (C-6Ј) ppm. IR (ATR): ν˜ ϭ 3453 77.1 (C-2Ј), 71.2 (C-1ЈЈ), 62.0 (CH2OH), 58.7 (C-3), 53.0 (C-1Ј),
(br., O-H), 3061, 3028 (m, CϪH aromat.), 2963, 2913, 2856 (s, 51.9 (C-1), 30.5 (C-3Ј), 25.9 (C-4), 25.5 (C-7Ј), 17.6 (C-6Ј) ppm. IR
CϪH aliphat.), 1492, 1451 (s, CϭC aromat.), 1098, 1028 (s, CϪO),
(ATR): ν˜ ϭ 3486 (br., OϪH), 3068, 3056, 3022 (m, CϪH aromat.),
2976, 2953, 2886 (s, CϪH aliphat.), 1500, 1471 (s, CϭC aromat.),
1068 (s, CϪO), 823 (s, CϪH olefin) cmϪ1. MS (EI): m/z (%) ϭ 365
(1) [Mϩ], 334 (42) [Mϩ Ϫ CH2OH], 176 (100) [C14H10NOϩ], 146
833 (s, CϪH olefin) cmϪ1. MS (EI): m/z (%) ϭ 364 (100) [Mϩ
CH2OCH3], 288 (20) [Mϩ Ϫ CH2OH Ϫ C7H7], 376 (10) [Mϩ
Ϫ
Ϫ
CH2OCH3 Ϫ 54], 144 (13) [C10H10Nϩ], 130 (15) [C9H8Nϩ], 91 (56)
[C7H7ϩ]. C26H35NO3 (409.57): calcd. C 76.25, H 8.61, N 3.42; (10) [C10H12Nϩ], 132 (12) [C9H10Nϩ], 117 (10), 105 (10), 91 (26)
found C 76.39, H 8.58, N 3.33.
[C7H7ϩ]. C23H39NO2Si (365.51): calcd. C 78.86, H 8.55, N 3.83;
found C 78.68, H 8.64, N 3.78.
(2ЈS,3S)-2-(2Ј-Benzyloxy-5Ј-methylhex-4Ј-enyl)-3-(tert-butyldi-
methylsilyloxymethyl)-1,2,3,4-tetrahydroisoquinoline (31): As de-
scribed above for 30, from 29b (500 mg, 1.28 mmol) in abs. THF
(8 mL), NaOtBu (148 mg, 1.54 mmol) in abs. THF (8 mL), BnBr
(2ЈS,3S)-2-(2Ј-Benzyloxy-5Ј-methylhex-4Ј-enyl)-1,2,3,4-tetra-
hydroisoquinoline-3-carbaldehyde (33): As described above for 27,
from 32 (120 mg, 0.33 mmol), DMSO (148 µL, 1.64 mmol),
(220 µL, 1.93 mmol), after chromatography with pentane/EtOAc (COCl)2 (57 µL, 0.84 mmol) and NEt3 (250 µL) 33 was obtained
(20:1), 31 was obtained as a colorless oil (221 mg, 0.46 mmol, 60%
(119 mg, quant.). 1H NMR (400 MHz, C6D6): δ ϭ 9.65 (d, J ϭ
1.1 Hz, 1 H, CHO), 7.43Ϫ7.41 (m, 2 H, 3ЈЈ-H, 7ЈЈ-H), 7.29Ϫ7.25
referred to reacted 29b), Rf ϭ 0.21, [α]2D2 ϭ ϩ57.6 (c ϭ 1.18,
CHCl3). 1H NMR (400 MHz, CDCl3): δ ϭ 7.36Ϫ7.34 (m, 2 H, 3ЈЈ- (m, 2 H, 4ЈЈ-H, 6ЈЈ-H), 7.21Ϫ7.17 (m, 1 H, 5-H), 7.10Ϫ7.07 (m, 2
H, 7ЈЈ-H), 7.31Ϫ7.24 (m, 3 H, 4ЈЈ-H, 5ЈЈ-H, 6ЈЈ-H), 7.16Ϫ7.09 (m, H, 6-H, 7-H), 7.00Ϫ6.98 (m, 1 H, 8-H), 6.89Ϫ6.84 (m, 1 H, 8-H),
3 H, 5-H, 6-H, 7-H), 6.99Ϫ6.97 (m, 1 H, 8-H), 5.19 (‘tq’, J ϭ 7.2, 5.38Ϫ5.33 (m, 1 H, 4Ј-H), 4.58 (d, J ϭ 12.0 Hz, 1 H, 1ЈЈ-Ha), 4.54
J ϭ 1.2 Hz, 1 H, 4Ј-H), 4.63 (s, 2 H, 1ЈЈ-H), 3.84 (d, J ϭ 15.4 Hz, (d, J ϭ 12.0 Hz, 1 H, 1ЈЈ-Hb), 4.06 (d, J ϭ 16.0 Hz, 1 H, 1-Ha),
1 H, 1-Ha), 3.80Ϫ3.76 (m, 1 H, CH2OSi), 3.78 (d, J ϭ 15.4 Hz, 1 3.74 (d, J ϭ 16.0 Hz, 1 H, 1-Hb), 3.59 (ddd, J ϭ 6.3, J ϭ 6.1, J ϭ
H, 1-Hb), 3.63Ϫ3.57 (m, 1 H, 2Ј-H), 3.48 (dd, J ϭ 10.1, J ϭ 7.5 Hz, 4.5 Hz, 1 H, 2Ј-H), 3.26 (ddd, J ϭ 6.0, J ϭ 5.7, J ϭ 1.1 Hz, 1 H,
1 H, CH2OSi), 3.08 (dddd, J ϭ 7.5, J ϭ 5.3, J ϭ 5.1, J ϭ 4.8 Hz,
3-H), 2.90 (dd, J ϭ 16.6, J ϭ 5.7 Hz, 1 H, 4-Ha), 2.84 (dd, J ϭ
1 H, 3-H), 2.98 (dd, J ϭ 16.3, J ϭ 5.5 Hz, 1 H, 4-Ha), 2.87 (dd, 13.6, J ϭ 4.5 Hz, 1 H, 1Ј-Ha), 2.77 (dd, J ϭ 13.6, J ϭ 6.1 Hz, 1 H,
J ϭ 13.7, J ϭ 6.7 Hz, 1 H, 1Ј-Ha), 2.76 (dd, J ϭ 13.7, J ϭ 4.5 Hz,
1 H, 1Ј-Hb), 2.73 (dd, J ϭ 16.3, J ϭ 4.8 Hz, 1 H, 4-Hb), 2.35Ϫ2.23
1-Hb), 2.76 (dd, J ϭ 16.6, J ϭ 6.3 Hz, 1 H, 4-Hb), 2.42 (t, J ϭ
6.3 Hz, 2 H, 3Ј-H), 1.75 (d, J ϭ 0.9 Hz, 3 H, 7Ј-H), 1.63 (s, 3 H,
(m, 2 H, 3Ј-H), 1.71 (d, J ϭ 1.2 Hz, 3 H, 7Ј-H), 1.61 (d, J ϭ 0.9 Hz, 6Ј-H) ppm. 13C NMR (100 MHz, C6D6): δ ϭ 202.6 (CϭO), 139.9
3 H, 6Ј-H), 0.87 [s, 9 H, SiϪC(CH3)3], 0.01 [s, 6 H, Si-(CH3)2] ppm. (C-2ЈЈ), 134.9 (C-5Ј), 133.5 (C-4a), 132.9 (C-8a), 129.2 (C-5), 128.7
13C NMR (100 MHz, CDCl3): δ ϭ 139.2 (C-2ЈЈ), 135.0 (C-5Ј), (C-4ЈЈ, C-6ЈЈ), 128.1 (C-5ЈЈ), 128.0 (C-3ЈЈ, C-7ЈЈ), 127.8 (C-4), 127.1
134.3 (C-8a), 133.2 (C-4a), 128.9 (C-5), 128.2 (C-4ЈЈ, C-6ЈЈ), 127.7 (C-8), 126.9 (C-6), 126.6 (C-7), 121.2 (C-4Ј), 78.9 (C-2Ј), 71.8 (C-
(C-3ЈЈ, C-7ЈЈ), 127.3 (C-4ЈЈ), 126.3 (C-8), 126.1 (C-6), 125.4 (C-7), 1ЈЈ), 67.4 (C-3), 58.3 (C-1Ј), 53.4 (C-1), 31.7 (C-3Ј), 26.8 (C-4), 26.1
120.5 (C-4Ј), 78.2 (C-2Ј), 71.5 (C-1ЈЈ), 62.9 (CH2OSi), 59.6 (C-3),
(C-7Ј), 18.2 (C-6Ј) ppm. MS (EI): m/z (%) ϭ 361 (1) [Mϩ Ϫ 2],
58.5 (C-1Ј), 52.2 (C-1), 31.4 (C-3Ј), 29.9 (C-4), 25.9 [C(CH3)3], 25.8 332 (25) [Mϩ Ϫ 2 Ϫ CHO], 270 (30) [Mϩ Ϫ 2 Ϫ C7H7], 172 (84)
(C-7Ј), 18.2 [C(CH3)3], 17.9 (C-6Ј), Ϫ5.4 [Si(CH3)2] ppm. IR [C11H10NOϩ], 144 (48) [C10H10Nϩ], 91 (100) [C7H7ϩ].
3620
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3611Ϫ3622

Towards a Total Synthesis of Quinocarcin
FULL PAPER
Cyclization of Compounds 27 and 33 to Azepine Derivatives 34 and
(5S,8S,10R,11S,11aS)-8-Benzyloxy-10-isopropenyl-5,7,8,9,10,
35. General Procedure: The appropriate Lewis acid (Table 1, 2 11,11a,12-octahydroazepino[1,2-b]isoquinolin-11-ol (35b): Crude
equiv.) was added over 45 min, with ice cooling, to a solution of yield: 88%; yield after HPLC: 35 mg, 0.10 mmol, 30%, yellow oil;
27 (270 mg, 0.90 mmol) or 33 (115 mg, 0.32 mmol) in abs. CH2Cl2 GC: HP-5, temperature program 8 °C minϪ1, gradient from 80 to
(10 mL), and the reaction mixture stirred at room temp. for 24 h.
300 °C, tR ϭ 13.03 min, [α]2D2 ϭ ϩ37.3 (c ϭ 2.18, CHCl3). 1H NMR
After hydrolysis with 2  NaOH solution (10 mL), the aqueous (400 MHz, C6D6): δ ϭ 7.16Ϫ7.01 (m, 7 H, 2-H, 3-H, 3Ј-H, 4Ј-H,
layer was extracted with CH2Cl2 (5 ϫ 10 mL). The combined or-
ganic layers were dried (MgSO4) and concentrated. The residue was
5Ј-H, 6Ј-H, 7Ј-H), 6.99Ϫ6.97 (m, 1 H, 1-H), 6.92Ϫ6.90 (m, 1 H, 4-
H), 5.01Ϫ5.00 (m, 1 H, 14-Ha), 4.97Ϫ4.96 (m, 1 H, 14-Hb), 4.23
filtered through basic Al2O3 with hexane/iPrOH (3:1) as eluent, (d, J ϭ 12.1 Hz, 1 H, 1Ј-Ha), 4.07 (d, J ϭ 12.1 Hz, 1 H, 1Ј-Hb),
chromatographed (SiO2; hexane/iPrOH/NEt3 ϭ 17:1:1) and finally
purified by HPLC with hexane/iPrOH (17:1) as eluent.
3.67 (d, J ϭ 1.9 Hz, 1 H, 11-H), 3.59Ϫ3.54 (m, 1 H, 8-H), 3.58 (d,
J ϭ 14.4 Hz, 1 H, 5-Ha), 3.23 (d, J ϭ 14.4 Hz, 1 H, 5-Hb),
2.81Ϫ2.72 (m, 2 H, 12-Ha, 11a-H), 2.74 (dd, J ϭ 12.9, J ϭ 2.5 Hz,
1 H, 7-Ha), 2.63 (dd, J ϭ 12.9, J ϭ 6.5 Hz, 1 H, 7-Hb), 2.55 (ddd,
J ϭ 11.9, J ϭ 2.3, J ϭ 1.9 Hz, 1 H, 10-H), 2.37 (dd, J ϭ 13.1, J ϭ
3.8 Hz, 1 H, 12-Hb), 1.94 (dd, J ϭ 1.4, J ϭ 0.8 Hz, 3 H, 15-H),
1.89 (dd, J ϭ 14.3, J ϭ 2.0 Hz, 1 H, 9-Ha), 1.77 (ddd, J ϭ 14.3,
J ϭ 6.6, J ϭ 2.3 Hz, 1 H, 9-Hb) ppm. 13C NMR (100 MHz, C6D6):
δ ϭ 149.5 (C-13), 139.1 (C-12a), 137.7 (C-4a), 136.4 (C-2Ј), 128.5
(C-2), 127.9 (C-3Ј), 127.7 (C-4Ј, C-6Ј), 127.6 (C-7Ј), 127.4 (C-3),
127.3 (C-1), 126.0 (C-5Ј), 125.6 (C-4), 110.9 (C-14), 75.9 (C-8), 75.0
(C-11), 70.4 (C-1Ј), 62.1 (C-7), 62.0 (C-11a), 55.4 (C-5), 45.8 (C-
10), 33.5 (C-12), 27.8 (C-9), 22.5 (C-15) ppm. IR (ATR): ν˜ ϭ 3421
(br., OH), 3064, 3027 (CϪH aromat.), 2918, 2855 (CϪH aliphat.),
1641, 1495 (s, CϭC aromat.), 1088, 1061 (s, CϪO), 738 (1,2-di-
subst. aromat.) cmϪ1. TMS derivative: MS (EI): m/z (%) ϭ 435 (2)
(5S,10S,11S,11aS)-10-Isopropenyl-5-(methoxymethyl)-5,7,8,9,
10,11,11a,12-octahydroazepino[1,2-b]isoquinolin-11-ol (34a): Crude
yield: 81%; yield after HPLC: 54 mg, 0.18 mmol, 20%, yellow oil;
GC: HP-5, temperature program 8 °C minϪ1, gradient from 80 to
300 °C, tR ϭ 17.00 min, [α]2D2 ϭ Ϫ20.1 (c ϭ 1.97, MeCN). 1H NMR
(400 MHz, C6D6): δ ϭ 7.15Ϫ7.13 (m, 2 H, 3-H, 4-H), 7.06Ϫ7.03
(m, 1 H, 2-H), 6.99Ϫ6.97 (m, 1 H, 1-H), 4.79Ϫ4.80 (m, 1 H, 14-
Ha), 4.75Ϫ4.76 (m, 1 H, 14-Hb), 4.02 (t, J ϭ 5.6 Hz, 1 H, 5-H),
3.61 (dd, J ϭ 9.6 , J ϭ 5.6 Hz, 1 H, 16-Ha), 3.55 (d, J ϭ 2.5 Hz, 1
H, 11-H), 3.31 (dd, J ϭ 9.6, J ϭ 5.6 Hz, 1 H, 16-Hb), 3.29 (ddd,
J ϭ 9.5, J ϭ 4.3, J ϭ 3.6 Hz, 1 H, 11a-H), 3.03 (s, 3 H, OCH3),
2.93Ϫ2.99 (m, 2 H, 7-Ha, 7-Hb), 2.78 (dd, J ϭ 15.9, J ϭ 9.5 Hz, 1
H, 12-Ha), 2.53 (dd, J ϭ 15.9, J ϭ 4.3 Hz, 1 H, 12-Hb), 2.35 (d,
J ϭ 11.4 Hz, 1 H, 10-H), 2.08Ϫ1.97 (m, 1 H, 9-Ha), 1.63 (s, 3 H,
CH3), 1.69Ϫ1.50 (m, 2 H, 8-Ha, 8-Hb), 1.49Ϫ1.41 (m, 1 H, 9-Hb)
ppm. 13C NMR (100 MHz, C6D6): δ ϭ 150.8 (C-13), 137.9 (C-12a),
135.1 (C-4a), 129.1, 127.8, 126.6, 125.7 (C-1, C-2, C-3, C-4), 110.2
(C-14), 75.7 (C-16, C-11), 64.7 (C-5), 60.2 (C-11a), 58.7 (OCH3),
52.7 (C-7), 47.2 (C-10), 32.9 (C-12), 30.3 (C-8), 25.9 (C-9), 22.2 (C-
15) ppm. IR (ATR): ν˜ ϭ 3416 (br., OH), 3065, 3022 (C-H aromat.),
2923 (CϪH aliphat.), 1604, 1493 (s, CϭC aromat.), 1111 (s, CϪO),
750 (1,2-disubst. aromat.) cmϪ1. MS (EI): m/z (%) ϭ 256 (100)
[C17H22NOϩ], 146 (13) [C10H12Nϩ], 130 (12) [C9H8Nϩ], 115 (7)
[C9H7ϩ], 55 (6) [C4H7ϩ]. MS (CI, CH4): m/z (%) ϭ 302 (85) [Mϩ
ϩ1], 270 (14) [C18H24NOϩ], 256 (100) [C17H22NOϩ].
[Mϩ], 420 (4) [Mϩ Ϫ CH3], 392 (3) [Mϩ Ϫ 43], 344 (27) [Mϩ
Ϫ
91], 184 (87), 172 (80) [C12H14Nϩ], 146 (53) [C10H12Nϩ], 132 (100)
[C9H10Nϩ], 91 (80) [C7H7ϩ].
Acknowledgments
Generous financial support by the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie and the Ministerium
für Wissenschaft, Forschung und Kunst des Landes Baden-
Württemberg is gratefully acknowledged. We would like to thank
Dr. T. Beuerle (TU Braunschweig) and Dr. P. Rösner (Landeskrimi-
nalamt Kiel) for their skilful help with GC-MS analyses.
(5S,10R,11S,11aS)-10-Isopropenyl-5-(methoxymethyl)-5,7,8,9,10,
11,11a,12-octahydroazepino[1,2-b]isoquinolin-11-ol (34b): From 27
and BF3·OEt2; crude yield: 80%; yield after HPLC: 41 mg,
0.14 mmol, 12%, yellow oil, tR ϭ 17.54, [α]2D2 ϭ ϩ6.0 (c ϭ 0.90,
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Received April 5, 2004
3622
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www.eurjoc.org
Eur. J. Org. Chem. 2004, 3611Ϫ3622