A general methodology for the enantioselective synthesis of 1-substituted tetrahydroisoquinoline alkaloids

Article abstract of DOI:10.1002/ejoc.201000473

Starting from tricyclic lactam 2, which is easily accessible by cyclocondensation of δ-oxoester 1 with (R)-phenylglycinol, a three-step synthetic route to enantiopure 1-substituted tetrahydroisoquinolines, including 1-alkyl-, 1-aryl-, and 1-benzyltetrahydroisoquinoline alkaloids, as well as the tricyclic alkaloid (-)-crispine A, has been developed. The key step is a stereoselective α-amidoalkylation reaction using the appropriate Grignard reagent.

Full text of DOI:10.1002/ejoc.201000473

FULL PAPER
DOI: 10.1002/ejoc.201000473
A General Methodology for the Enantioselective Synthesis of 1-Substituted
Tetrahydroisoquinoline Alkaloids
Mercedes Amat,*[a] Viviane Elias,[a] Núria Llor,[a] Fabiana Subrizi,[a] Elies Molins,[b] and
Joan Bosch[a]
Dedicated to Prof. Dr. Antonio García Martínez on the occasion of his retirement
Keywords: Alkaloids / Heterocycles / Lactams / Asymmetric synthesis / Total synthesis
Starting from tricyclic lactam 2, which is easily accessible by
cyclocondensation of δ-oxoester 1 with (R)-phenylglycinol, a
three-step synthetic route to enantiopure 1-substituted tetra-
hydroisoquinolines, including 1-alkyl-, 1-aryl-, and 1-benzyl-
tetrahydroisoquinoline alkaloids, as well as the tricyclic alka-
loid (–)-crispine A, has been developed. The key step is a
stereoselective α-amidoalkylation reaction using the appro-
priate Grignard reagent.
also as useful key intermediates in the synthesis of more
complex alkaloids. This has stimulated the development of
a number of methodologies aimed at the enantioselective
synthesis of 1-substituted tetrahydroisoquinoline deriva-
tives[2] (Figure 1).
In previous work, we demonstrated that phenylglycinol-
derived oxazolopiperidone lactams are versatile scaffolds
that allow the regio- and stereocontrolled introduction of
substituents at different positions of the piperidine ring,
Introduction
The tetrahydroisoquinoline ring system is present in nu-
merous structurally diverse natural products exhibiting a
wide range of biological and pharmacological activities.[1]
In particular, simple 1-substituted tetrahydroisoquinolines
are of great interest not only as alkaloids themselves but
Figure 1. Selected 1-substituted tetrahydroisoquinoline alkaloids.
[a] Laboratory of Organic Chemistry, Faculty of Pharmacy, and
Institute of Biomedicine (IBUB), University of Barcelona,
Av. Joan XXIII s/n, 08028 Barcelona, Spain
Fax: +34-934-024-539
E-mail: amat@ub.edu
[b] Institut de Ciència de Materials de Barcelona (CSIC),
Campus UAB, 08193 Cerdanyola, Spain
Scheme 1. Natural and bioactive products prepared from phenyl-
glycinol-derived lactams.
Eur. J. Org. Chem. 2010, 4017–4026
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M. Amat, V. Elias, N. Llor, F. Subrizi, E. Molins, J. Bosch
FULL PAPER
thus providing access to enantiopure substituted piperidines
In contrast with related cis-oxazolopiperidone lactams,[8]
bearing virtually any type of substitution pattern, as minor cis lactam epi-2 did not undergo epimerization under
well as to quinolizidine, indolizidine, decahydroquinoline, acidic conditions (1.2  HCl, MeOH, r.t); isoquinolone 3
and complex piperidine-containing indole alkaloids[3] and trace amounts of dimer 4 were formed instead. This
(Scheme 1).
dimer was formed in 49% yield after prolonged acidic treat-
ment (1.2  HCl, MeOH, reflux, 66 h) of isoquinolone 3.
Results and Discussion
To further expand the synthetic potential of phenylgly-
cinol-derived oxazolopiperidone lactams, we report here a
general methodology for the enantioselective synthesis of 1-
substituted tetrahydroisoquinoline alkaloids. The applica-
tion of our enantiomeric scaffolding strategy[4] would sim-
ply require starting from an appropriate benzo-fused oxaz-
Initial attempts to carry out the α-amidoalkylation reac-
olopiperidone lactam and the subsequent stereocontrolled tion with a higher order cyanocuprate [Me2Cu(CN)Li2] in
introduction of the substituent at the 1-position of the the presence of BF3·Et2O[9] resulted in failure, leading ex-
tetrahydroisoquinoline ring by an asymmetric α-amidoalk- clusively to isoquinolone 3. However, treatment of lactam
ylation reaction.[5]
2 with an excess amount (3 equiv.) of methylmagnesium
Tricyclic lactam 2 was envisaged as the pivotal intermedi- chloride at 5 °C stereoselectively led to the expected 1-sub-
ate of our synthesis. It was prepared in 52% yield by cy- stituted tetrahydroisoquinolone 5a in 61% yield
clocondensation of aldehyde ester 1[6] with (R)-phenylgly- (Table 1).[10] Isoquinolone 3 was formed as a byproduct
cinol in refluxing toluene in the presence of a catalytic (17%). Higher temperatures resulted in the formation of in-
amount of p-TsOH (Scheme 2). The absolute configuration creasing amounts of 3, whereas when the reaction was car-
of lactam 2 was unambiguously determined by X-ray crys- ried out at a lower temperature the starting lactam was re-
tallographic analysis.[7] Minor amounts (6%) of lactam epi- covered to a considerable extent.
2, epimeric at the 2-position of the oxazolidine ring, were
also formed.
The observed retention of the configuration of the reac-
tive methine carbon can be rationalized by considering that
Scheme 2. Preparation of key tricyclic lactam 2.
Table 1. Enantioselective synthesis of 1-substituted tetrahydroisoquinolines.
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Enantioselective Synthesis of 1-Substituted Tetrahydroisoquinoline Alkaloids
the Grignard reagent coordinates with the oxygen atom of count previous transformations, this synthesis also consti-
the oxazolidine ring and that the subsequent intramolecular tutes a formal synthesis of the alkaloids (+)-O-methylarme-
delivery of the alkyl group occurs on the same face of the pavine,[18a,18b] zanoxyline,[19] and (–)-demethylcoclaurine
C–O bond of the incipient acyl iminium salt (Figure 2).[11]
[(–)-higenamine].[18d]
Similarly, the usefulness of this methodology in the syn-
thesis of 1-phenethyltetrahydroisoquinolines was demon-
strated by the preparation of 7g[20] from α-amidoalkylation
product 5g.
The procedure allows the preparation of tetrahydroiso-
quinolines and tetrahydroisoquinolones bearing a function-
alized C-1 substituent, for instance allyl[21] or 2-(1,3-dioxan-
2-yl)ethyl (Table 1, Entries h and i),[22] which can open ac-
cess to more complex tetrahydroisoquinoline alkaloids em-
Figure 2. Stereochemical outcome of the α-amidoalkylation reac-
tion.
As in related cis-substituted oxazolopiperidones,[11] bodying an additional ring. This was exemplified with the
minor cis lactam epi-2 was more reluctant to undergo α- synthesis of the pyrrolo[2,1-g]isoquinoline alkaloid cris-
amidoalkylation[12] than trans isomer 2 and, upon treatment pine A. The three-carbon fragment required for the con-
with MeMgCl, led to isoquinolone 3 as the major product struction of the pyrrolidine ring was incorporated in the α-
(50%); 2-methyltetrahydroisoquinoline 5a was formed in amidoalkylation step. Thus, reaction of lactam 2 with the
low yield (35%).
Grignard reagent derived from 2-(2-bromoethyl)-1,3-diox-
Removal of the phenylethanol moiety from lactam 5a ane (Scheme 3) gave 1-substituted tetrahydroisoquinolone.
was accomplished in excellent yield with sodium in liquid In this synthesis, the lactam carbonyl was reduced prior to
ammonia to give N-unsubstituted lactam 6a. Subsequent debenzylation to give tetrahydroisoquinoline 9 in excellent
reduction with borane generated in situ from NaBH4 and yield. Subsequent catalytic hydrogenation under acidic con-
iodine completed the enantioselective synthesis of (–)-sal- ditions brought about the hydrogenolysis of the exocyclic
solidine (7a).[13] Taking into account previous correlations, benzylic C–N bond, deprotection of the acetal function,
this synthesis also constitutes a formal synthesis of the alk- and closure of the pyrrolidine ring by reductive amination,
aloid (–)-carnegine.[14]
directly leading to crispine A[23] in 74% yield.
The above protocol provides general access to 1-alkyl-
substituted tetrahydroisoquinolines. Thus, reaction of lac-
tam 2 with ethylmagnesium bromide stereoselectively af-
forded (82% yield) lactam 5b, which was then debenzylated
and converted into (S)-1-ethyl-1,2,3,4-tetrahydroisoquin-
oline 7b in good overall yield, as in the above methyl series.
With the aim of demonstrating the potential of the meth-
odology for the synthesis of 1-aryl-, 1-benzyl-, and 1-phen-
ethyltetrahydroisoquinoline alkaloids, we applied the above
three-step sequence from lactam 2 using a variety of aryl-,
benzyl-, and phenethylmagnesium halides. The results are
summarized in Table 1 (Entries c–g). In all cases the α-
amidoalkylation reaction took place stereoselectively to
give a single 1-substituted tetrahydroisoquinolone deriva-
tive (i.e., 5c–g).[15]
Scheme 3. Enantioselective synthesis of (–)-crispine A.
Although the reductive cleavage of the exocyclic benzylic
C–N bond of 2-phenyl derivative 5c with Na/liq. NH3 oc-
curred with concomitant cleavage of the doubly benzylic
endocyclic C–N bond to give 2-benzyl-4,5-dimethoxyphen-
ylacetamide (8), a similar reduction from the meth-
Conclusions
Tricyclic (R)-phenylglycinol-derived lactam 2 has proven
oxyphenyl-substituted tetrahydroisoquinolones 5d and 5e to be a useful scaffold that provides general access to
satisfactorily led to the respective N-unsubstituted lactams enantiopure 1-substituted tetrahydroisoquinoline deriva-
6d and 6e in excellent yield. Subsequent reduction of the tives, including 1-alkyl-, 1-aryl-, and 1-benzyltetrahydroiso-
lactam carbonyl of 6d led to (–)-norcryptostyline II (7d), quinoline alkaloids as well as more complex alkaloids bear-
which constitutes a formal synthesis of the alkaloid (+)- ing the tetrahydroisoquinoline moiety (Scheme 4). The
cryptostyline II.[16] Similarly, lactam 6e was converted into enantioselective synthesis of 1-benzyltetrahydroisoquinol-
(–)-norcryptostyline III (7e), a known precursor of the alka- ines is of particular interest because these derivatives not
loid (+)-cryptostyline III.[17]
only play a pivotal role in the biosynthesis of numerous
The same set of sequential reductions (Na/liq. NH3 and alkaloids with a variety of skeletal types (e.g., aporphines,
then NaBH4/I2) was used to convert 2-benzyl derivative 5f cularines, protoberberines, and pavines) but have also been
into (–)-O,O-dimethylcoclaurine (7f).[18] Taking into ac- used as key synthetic precursors of such alkaloids.[24]
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M. Amat, V. Elias, N. Llor, F. Subrizi, E. Molins, J. Bosch
FULL PAPER
3 H, OCH3), 3.94 (s, 3 H, OCH3), 4.20 (dd, J = 9.0, 0.9 Hz, 1 H,
2-H), 4.47 (dd, J = 9.0, 6.3 Hz, 1 H, 2-H), 5.10 (d, J = 6.3 Hz, 1
H, 3-H), 5.90 (d, J = 2.1 Hz, 1 H, 10b-H), 6.71 (s, 1 H, 10-H), 7.10
(s, 1 H, 7-H), 7.15–7.25 (m, 5 H, ArH) ppm. 13C NMR (75.6 MHz,
CDCl3, 25 °C): δ = 38.1 (C-6), 55.9 (OCH3), 56.0 (OCH3), 58.6 (C-
3), 74.8 (C-2), 87.3 (C-10b), 106.5 (C-10), 110.1 (C-7), 123.0 (C-
6a), 125.0 (C-10a), 125.9 (C-o), 127.4 (C-p), 128.4 (C-m), 140.5 (C-
i), 148.0 (C-8), 149.2 (C-9), 165.2 (CO) ppm. HRMS: calcd. for
C19H19NO4 [M + H]+ 326.1386; found 326.1382.
Dimer 4: A solution of 1.2  HCl in MeOH (6 mL) was added to
a solution of isoquinolone 3 (96 mg, 0.3 mmol) in MeOH (1 mL).
The mixture was heated at reflux for 66 h. The solvent was re-
moved, and the resulting solid was diluted with EtOAc. The solu-
tion was washed with saturated aqueous Na2CO3. The organic
phase was dried and concentrated to give a residue, which was puri-
fied by chromatography (7:3 Et2O/EtOAc to EtOAc) to afford 4
(47 mg, 49%) as a yellow oil. 1H NMR (400 MHz, CDCl3, 25 °C):
δ = 3.48 (s, 6 H, 2 OCH3), 3.64 (s, 6 H, 2 OCH3), 4.27 (dd, J =
13.0, 2.8 Hz, 2 H, 2 CH2OH), 4.43 (d, J = 10.8 Hz, 2 H, 2 CHCO),
4.44 (dd, J = 13.0, 3.6 Hz, 2 H, 2 CH2OH), 4.79 (d, J = 11.2 Hz,
2 H, 2 CHNCO), 5.68 (s, 2 H, 2 CH3OCCH), 5.73 (t, J = 2.9 Hz,
2 H, CHAr), 6.26 (s, 2 H, 2 CH3OCCH), 7.08 (d, J = 6.4 Hz, 4 H,
ArH), 7.14–7.23 (m, 6 H, ArH) ppm. 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ = 55.9 (OCH3), 56.0 (OCH3), 56.9 (CHCO), 58.5
(CHNCO), 58.7 (CHAr), 62.1 (CH2OH), 108.6 (CH3OCCH), 110.3
(CH3OCCH), 127.7 (C-p), 128.4 (C-o), 128.7 (CCHCO), 128.9 (C-
m), 131.5 (CCHN), 136.4 (C-i), 147.5 (CH3OC), 147.9 (CH3OC),
176.0 (CO) ppm. HRMS: calcd. for C38H38N2O8 [M + H]+
651.2706; found 651.2697.
Scheme 4. Enantiopure 1-substituted tetrahydroisoquinolines pre-
pared from common scaffold 2.
Experimental Section
General: Flash chromatography was carried out on SiO2 (silica gel
60, SDS, 0.04–0.06 mm) or (when indicated) by using a cartridge
containing amine-functionalized silica. Melting points were taken
with a Büchi apparatus and are uncorrected. Optical rotations were
measured with a Perkin-Elmer 241 polarimeter. High-resolution
mass spectra (HMRS; LC/MSD TOF Agilent Technologies) were
performed by Serveis Científico-Tècnics, Barcelona. Microanalyses
(Carlo Erba 1106 analyzer) were performed by Centre d’Investi-
gació i Desenvolupament (CSIC), Barcelona. Only noteworthy IR
absorptions (Perkin-Elmer 1600) are listed. NMR spectra were re-
corded with either a Varian Gemini-300 (300 and 75.4 MHz for 1H
General Procedure for the α-Amidoalkylation Reaction: The Grig-
nard reagent (3.0 equiv.) was added to a cooled (5 °C) solution of
oxazolopiperidone 2 (1 equiv.) in THF, and the mixture was stirred
at this temperature until the disappearance of the starting material
was observed by TLC. The reaction was quenched by the addition
of water, and the mixture was extracted with EtOAc. The combined
extracts were dried and concentrated to give the 1-substituted tetra-
hydroisoquinolones after flash chromatography.
1
and 13C, respectively) or Mercury-400 (400 and 100.6 MHz for H
and 13C, respectively) spectrometer.
(3R,10bS)-8,9-Dimethoxy-5-oxo-3-phenyl-2,3,6,10b-tetrahydro-5H-
oxazolo[2,3-a]isoquinoline (2): To a mixture of aldehyde-ester 1[6]
(1S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6,7-dimethoxy-1-methyl-3-
(993 mg, 4.2 mmol) and (R)-phenylglycinol (690 mg, 5.0 mmol) in oxo-1,2,3,4-tetrahydroisoquinoline (5a): Following the above general
anhydrous toluene (45 mL) containing 4 Å molecular sieves was
added a catalytic amount of p-TsOH. The mixture was heated at
reflux for 18 h with azeotropic elimination of water produced by a
Dean–Stark apparatus. The resulting suspension was concentrated
under reduced pressure to give a yellow foam. Flash chromatog-
raphy (Et2O to EtOAc) afforded lactam 2 (710 mg, 52%) and the
10b-epimer epi-2 (82 mg, 6%). Data for 2: White solid; m.p. 135–
procedure (reaction time 1.5 h), from lactam 2 (100 mg, 0.31 mmol)
and methylmagnesium chloride (3  in THF, 0.31 mL, 0.92 mmol)
in THF (12.5 mL) a brown oil was obtained. Flash chromatog-
raphy (7:3 Et2O/EtOAc, increasing polarity and 9:1 EtOAc/EtOH)
gave 5a (64 mg, 61%) as a yellow oil and isoquinolone 3 (17 mg,
17%) as a yellow-green foam. Data for 5a: [α]2D2 = +23.5 (c = 1.0,
CHCl ). IR (KBr): ν = 1629, 3400 cm–1
.
1H NMR (400 MHz,
˜
3
137 °C (Et2O). [α]2D2 = –136.6 (c = 1.0, CHCl ). IR (KBr): ν =
CDCl3, 25 °C): δ = 1.39 (d, J = 7.2 Hz, 3 H, CH3), 3.60 (d, J =
˜
3
1665 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 3.52 (d, J = 18.9 Hz, 1 H, 4-H), 3.76 (d, J = 18.9 Hz, 1 H, 4-H), 3.77 (s, 3 H,
19.2 Hz, 1 H, 6-H), 3.73 (dd, J = 19.2, 2.2 Hz, 1 H, 6-H), 3.88 (s,
OCH3), 3.86 (s, 3 H, OCH3), 4.28 (q, J = 7.2 Hz, 1 H, 1-H), 4.29
3 H, OCH3), 3.91 (s, 3 H, OCH3), 4.02 (dd, J = 9.0, 7.5 Hz, 1 H, (dd, J = 12.0, 8.4 Hz, 1 H, CH2OH), 4.30 (dd, J = 12.0, 5.2 Hz, 1
2-H), 4.58 (dd, J = 9.0, 7.5 Hz, 1 H, 2-H), 5.38 (t, J = 7.5 Hz, 1
H, 3-H), 6.02 (d, J = 2.2 Hz, 1 H, 10b-H), 6.66 (s, 1 H, 10-H), 6.99
(s, 1 H, 7-H), 7.35 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz,
H, CH2OH), 5.70 (dd, J = 8.4, 5.2 Hz, 1 H, CHAr), 6.38 (s, 1 H,
8-H), 6.66 (s, 1 H, 5-H), 7.18–7.30 (m, 5 H, ArH) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 23.2 (CH3), 37.3 (C-4), 55.6
CDCl3, 25 °C): δ = 36.9 (C-6), 56.0 (OCH3), 56.1 (OCH3), 58.6 (C- (OCH3), 56.0 (OCH3), 56.1 (C-1), 60.8 (CHAr), 63.3 (CH2OH),
3), 72.7 (C-2), 87.8 (C-10b), 107.7 (C-10), 109.8 (C-7), 122.5 (C- 107.7 (C-8), 110.3 (C-5), 123.1 (C-4a), 127.6 (C-o), 128.1 (C-p),
6a), 123.1 (C-10a), 126.0 (C-o), 127.7 (C-p), 128.8 (C-m), 139.3 (C- 128.7 (C-m), 130.5 (C-8a), 136.8 (C-i), 148.3 (C-7), 147.8 (C-6),
i), 148.4 (C-8), 149.7 (C-9), 166.2 (CO) ppm. HRMS: calcd. for
C19H19NO4 [M + H]+ 326.1386; found 326.1382. C19H19NO4
(325.36): calcd. C 70.14, H 5.89, N 4.31; found C 70.27, H 5.87, N
171.7 (CO) ppm. HRMS: calcd. for C20H23NO4 [M + H]+
342.1699; found 342.1695. C20H23NO4·1/4CH2Cl2 (362.64): calcd.
C 67.07, H 6.53, N 3.86; found C 67.13, H 6.65, N 3.81. Data for
4.08. Data for epi-2: [α]2D2 = +62.5 (c = 1.0, CHCl ). IR (KBr): ν =
3: IR (KBr): ν = 1652, 3269 cm–1. 1H NMR (400 MHz, CDCl3,
˜
˜
3
1667 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.45 (d, J = 25 °C): δ = 3.82 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 4.31 (dd, J
18.9 Hz, 1 H, 6-H), 3.60 (dd, J = 18.9, 2.1 Hz, 1 H, 6-H), 3.90 (s,
4020
= 12.4, 7.2 Hz, 1 H, CH2OH), 4.42 (dd, J = 12.4, 4.4 Hz, 1 H,
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Enantioselective Synthesis of 1-Substituted Tetrahydroisoquinoline Alkaloids
CH2OH), 6.12 (s, 1 H, 5-H), 6.26 (s, 1 H, 8-H), 6.47 (dd, J = 7.2,
5Ј-H), 6.72 (s, 1 H, 6Ј-H), 6.75 (s, 1 H, 8-H), 6.76 (s, 1 H, 5-H),
7.12–7.15 (m, 2 H, ArH), 7.26–7.32 (m, 3 H, ArH) ppm. 13C NMR
4.4 Hz, 1 H, CHAr), 6.59 (s, 1 H, 4-H), 7.33 (m, 5 H, ArH), 7.95
(s, 1 H, 1-H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 55.7 (100.6 MHz, CDCl3, 25 °C): δ = 37.4 (C-4), 55.8 (OCH3), 55.9
(OCH3), 55.8 (OCH3), 60.7 (CHAr), 62.9 (CH2OH), 100.6 (C-7),
(OCH3), 55.9 (OCH3), 56.0 (OCH3), 60.4 (C-1), 62.5 (CHAr), 62.6
103.6 (C-5), 107.6 (C-4), 114.2 (C-8a), 127.9 (C-m), 128.1 (C-p), (CH2OH), 108.1 (C-8), 109.5 (C-5), 110.1 (C-2Ј), 111.3 (C-5Ј),
128.9 (C-o), 135.3 (C-1), 137.4 (C-i), 140.6 (C-6), 147.7 (C-7), 155.0 118.3 (C-6Ј), 122.4 (C-4a), 127.9 (C-p), 128.4 (C-o), 128.6 (C-8a),
(C-4a), 160.5 (CO) ppm. EM (IQ+): m/z (%) = 326 (47), 325 (5),
206 (13), 138 (27), 122 (12) 121 (100).
128.6 (C-m), 134.4 (C-1Ј), 136.2 (C-i), 147.9 (C-6), 148.5 (C-4Ј),
148.6 (C-7), 149.2 (C-3Ј), 171.6 (CO) ppm. HRMS: calcd. for
C27H29NO6 [M + H]+ 464.2073; found 464.2081. C27H29NO6·1/
4CHCl3 (493.37): calcd. C 66.34, H 5.98, N 2.84; found C 66.65,
H 6.33, N 2.49.
(1S)-1-Ethyl-2-[(1R)-2-hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-
1,2,3,4-tetrahydroisoquinoline (5b): Following the general procedure
(reaction time 6 h), from lactam 2 (400 mg, 1.23 mmol) in THF
(10 mL) and ethylmagnesium bromide (3  in Et2O, 1.23 mL,
3.68 mmol) a residue was obtained. Flash chromatography (1:1
Et2O/EtOAc) gave 5b (354 mg, 82%) as a yellow oil: [α]2D2 = +34.4
(1S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-1-
(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (5e): Fol-
lowing the general procedure (reaction time 20 min), from lactam
2 (500 mg, 1.54 mmol) in THF (10 mL) and 3,4,5-trimethoxyphen-
ylmagnesium bromide (0.5  in THF, 9.2 mL, 4.61 mmol) a residue
(c = 1.0, CHCl ). IR (KBr): ν = 1630, 3388 cm–1
.
1H NMR
˜
3
(400 MHz, CDCl3, 25 °C): δ = 0.72 (t, J = 7.2 Hz, 3 H, CH3), 1.66–
1.77 (m, 1 H, CH2), 1.79–1.89 (m, 1 H, CH2), 3.57 (d, J = 18.0 Hz, was obtained. Flash chromatography (Et2O/EtOAc, increasing po-
1 H, 4-H), 3.77 (s, 3 H, OCH3), 3.79 (d, J = 18.0 Hz, 1 H, 4-H), larity and 9:1 EtOAc/EtOH) gave 5e (370 mg, 49%) as a yellow
3.86 (s, 3 H, OCH3), 4.00 (dd, J = 9.6, 3.2 Hz, 1 H, 1-H), 4.23 (dd,
J = 11.6, 8.4 Hz, 1 H, CH2OH), 4.29 (dd, J = 11.6, 5.2 Hz, 1 H,
CH2OH), 5.66 (dd, J = 8.4, 5.2 Hz, 1 H, CHAr), 6.33 (s, 1 H, 8-
foam and 3 (135 mg, 27%). Data for 5e: [α]2D2 = +13.1 (c = 1.0,
CHCl ). IR (KBr): ν = 1684, 2930 cm–1
.
1H NMR (300 MHz,
˜
3
CDCl3, 25 °C): δ = 3.65 (d, J = 19.5 Hz, 1 H, 4-H), 3.75 (s, 3 H,
H), 6.67 (s, 1 H, 5-H), 7.10–7.30 (m, 5 H, ArH) ppm. 13C NMR OCH3), 3.77 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.80 (masked d,
(100.6 MHz, CDCl3, 25 °C): δ = 10.2 (CH3), 29.1 (CH2), 37.5 (C- 4-H), 3.81 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 5.17 (s, 1 H, 1-H),
4), 55.9 (OCH3), 56.1 (OCH3), 61.3 (C-1), 61.5 (CHAr), 63.4 3.98–4.08 (m, 2 H, CH2OH), 5.89 (dd, J = 8.7, 5.1 Hz, 1 H, CHAr),
(CH2OH), 109.3 (C-8), 110.3 (C-5), 123.7 (C-4a), 127.7 (C-o), 127.8 6.40 (s, 1 H, 2Ј-H), 6.46 (s, 2 H, 5-H, 8-H), 6.62 (s, 2 H, 6Ј-H),
(C-p), 127.8 (C-8a), 129.9 (C-m), 136.8 (C-i), 147.2 (C-7), 148.3 7.13–7.27 (m, 2 H, ArH), 7.29–7.31 (m, 3 H, ArH) ppm. 13C NMR
(C-6), 171.9 (CO) ppm. HRMS: calcd. for C21H25NO4 [M + H]+ (100.6 MHz, CDCl3, 25 °C): δ = 37.3 (C-4), 55.8 (OCH3), 55.9
356.1862; found 356.1872. C21H25NO4·1/4CHCl3 (385.28): calcd. C (OCH3), 56.0 (OCH3), 56.1 (OCH3), 56.2 (OCH3), 60.8 (C-1), 62.8
66.25, H 6.61, N 3.64; found C 66.13, H 6.64, N 3.53.
(CH2OH), 63.0 (CHAr), 103.3 (C-2Ј, C-6Ј), 108.1 (C-8), 110.0 (C-
5), 122.7 (C-4a), 128.1 (C-p), 128.4 (C-o), 128.6 (C-8a), 128.6 (C-
m), 136.1 (C-1Ј), 137.0 (C-i), 137.4 (C-4Ј), 147.9 (C-6), 148.6 (C-7),
153.4 (C-5Ј, C-3Ј), 172.0 (CO) ppm. HRMS: calcd. for C28H31NO7
[M + H]+ 494.2179; found 494.2183. C28H31NO7·1/4CHCl3
(523.40): calcd. C 64.83, H 6.02, N 2.68; found C 64.69, H 6.26, N
2.42.
(1S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-1-
phenyl-1,2,3,4-tetrahydroisoquinoline (5c): Following the general
procedure (reaction time 1 h), from lactam 2 (500 mg, 1.54 mmol)
in THF (10 mL) and phenylmagnesium chloride (2  in THF,
2.3 mL, 4.61 mmol) a residue was obtained. Flash chromatography
(Et2O/EtOAc increasing polarity and 9:1 EtOAc/EtOH) gave 5c
(415 mg, 67%) as a yellow oil and 3 (125 mg, 25%). Data for 5c:
(1S)-[(R)-2-Hydroxy-1-phenylethyl]-6,7-dimethoxy-1-(p-methoxy-
benzyl)-3-oxo-1,2,3,4-tetrahydroisoquinoline (5f): Following the ge-
neral procedure (reaction time 15 min), from lactam 2 (150 mg,
[α]2D2 = +16.7 (c = 1.0, CHCl ). IR (KBr): ν = 1629, 3388 cm–1. H
1
˜
3
NMR (300 MHz, CDCl3, 25 °C): δ = 3.66 (d, J = 19.8 Hz, 1 H, 4-
H), 3.71 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.84 (d, J = 19.8 Hz, 0.46 mmol) in THF (10 mL) and 4-methoxybenzylmagnesium chlo-
1 H, 4-H), 3.88–3.91 (m, 2 H, CH2OH), 5.26 (s, 1 H, 1-H), 5.96 (t, ride (0.25  in THF, 5.5 mL, 1.4 mmol) a residue was obtained.
J = 6.6 Hz, 1 H, CHAr), 6.41 (s, 1 H, 8-H), 6.58 (s, 1 H, 5-H), 7.15– Flash chromatography (3:7 hexane/EtOAc, increasing polarity and
7.30 (m, 10 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ
9:1 EtOAc/EtOH) gave 5f (129 mg, 63%) as a white foam and 3
= 37.2 (C-4), 55.8 (OCH3), 55.9 (OCH3), 59.9 (C-1), 62.2
(37 mg, 25%). Data for 5f: [α]2D2 = +41.5 (c = 1.0, CHCl3). IR
(CH2OH), 62.5 (CHAr), 108.6 (C-8), 110.0 (C-5), 122.3 (C-4a), (KBr): ν = 1630, 3393 cm–1. H NMR (400 MHz, CDCl , 25 °C):
1
˜
3
126.0 (C-o), 127.4 (C-p), 127.8 (C-p), 128.1 (C-m), 128.3 (C-o), δ = 2.84 (dd, J = 13.1, 8.5 Hz, 1 H, CHCH2Ar), 3.06 (dd, J = 13.1,
128.5 (C-8a), 128.8 (C-m), 136.7 (C-i), 143.0 (C-i), 147.8 (C-6), 3.4 Hz, 1 H, CHCH2Ar), 3.10 (d, J = 19.4 Hz, 1 H, 4-H), 3.39 (d,
148.0 (C-7), 171.9 (CO) ppm. HRMS: calcd. for C25H25NO4 [M +
J = 19.4 Hz, 1 H, 4-H), 3.51 (s, 3 H, OCH3C-4Ј), 3.69 (s, 3 H,
OCH3), 3.82 (s, 3 H, OCH3), 4.29 (dd, J = 8.5, 3.4 Hz, 1 H, 1-H),
4.35–4.44 (m, 2 H, CH2OH), 5.80 (s, 1 H, 5-H or 8-H), 5.85 (t, J
= 6.5 Hz, 1 H, CHAr), 6.53 (s, 1 H, 5-H or 8-H), 6.62 (s, 4 H, 2Ј-
H, 3Ј-H, 5Ј-H, 6Ј-H), 7.25–7.35 (m, 5 H, ArH) ppm. 13C NMR
(75.4 MHz, CDCl3, 25 °C): δ = 37.2 (C-4), 41.9 (C-1CH2), 55.2
(OCH3), 55.8 (OCH3), 55.9 (OCH3), 61.4 (C-1), 61.6 (CHAr), 63.6
(CH2OH), 109.2 (C-8), 109.7 (C-5), 113.5 (C-2Ј, C-6Ј), 124.2 (C-
4a), 127.2 (C-8a), 127.9 (C-o), 128.0 (C-p), 128.8 (C-m), 131.1 (C-
m), 131.1 (C-3Ј, C-5Ј), 136.9 (C-i), 146.8 (C-6), 148.2 (C-7), 158.5
(C-4Ј), 172.3 (CO) ppm. HRMS: calcd. for C27H29NO5 [M + H]+
448.2124; found 448.2130. C27H29NO5·3/4H2O (461.04): calcd. C
70.34, H 6.67, N 3.04; found C 70.03, H 6.42, N 2.87.
H]+ 404.1862; found 404.1875.
(1S)-1-(3,4-Dimethoxyphenyl)-2-[(1R)-2-hydroxy-1-phenylethyl]-6,7-
dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (5d): Following the
general procedure (reaction time 15 min), from lactam 2 (150 mg,
0.46 mmol) in THF (10 mL) and 3,4-dimethoxyphenylmagnesium
bromide (0.5  in THF, 2.8 mL, 1.4 mmol) a residue was obtained.
Flash chromatography (1:1 Et2O/EtOAc, increasing polarity and
9:1 EtOAc/EtOH) gave 5d (115 mg, 54%) as a yellow foam and 3
(50 mg, 33%). Data for 5d: [α]2D2 = +17.1 (c = 1.0, CHCl3). IR
1
(KBr): ν = 1634, 3406 cm–1. H NMR (400 MHz, CDCl , 25 °C):
˜
3
δ = 3.68 (d, J = 20.0 Hz, 1 H, 4-H), 3.73 (s, 3 H, OCH3), 3.79 (s,
3 H, OCH3), 3.83 (s, 3 H, CH3O), 3.86 (s, 3 H, CH3O), 3.87 (d, J
= 20.0 Hz, 1 H, 4-H), 3.95 (dd, J = 11.6, 8.4 Hz, 1 H, CH2OH), (1S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6,7-dimethoxy-3-oxo-1-phen-
4.01 (dd, J = 11.6, 5.2 Hz, 1 H, CH2OH), 5.18 (s, 1 H, 1-H), 5.93 ethyl-1,2,3,4-tetrahydroisoquinoline (5 g): Following the general
(dd, J = 8.4, 5.2 Hz, 1 H, CHAr), 6.37 (s, 1 H, 2Ј-H), 6.58 (s, 1 H, procedure (reaction time 40 min), from lactam 2 (400 mg,
Eur. J. Org. Chem. 2010, 4017–4026
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4021

M. Amat, V. Elias, N. Llor, F. Subrizi, E. Molins, J. Bosch
FULL PAPER
1.23 mmol) in THF (10 mL) and phenethylmagnesium chloride
(1  in THF, 3.69 mL, 3.69 mmol) a residue was obtained. Flash
chromatography (8:2 Et2O/EtOAc, increasing polarity and 9:1
EtOAc/EtOH) gave 5g (353 mg, 67 %) as a white foam and 3
133.9 (CH2CHCH2), 135.0 (C-1), 135.2 (CHCH2CHCH2), 140.9
(C-i), 146.9 (C-4), 147.5 (C-5) ppm. HRMS: calcd. for C28H37NO4
[M + H]+ 452.2801; found 452.2784. C28H37NO4·1/2H2O (460.61):
calcd. C 73.01, H 8.32, N 3.04; found C 73.24, H 8.13, N 2.75.
(68 mg, 17%). Data for 5g: [α]2D2 = +72.9 (c = 1.0, CHCl3). IR
(1S)-1-[2-(1,3-Dioxan-2-yl)ethyl]-2-[(1R)-2-hydroxy-1-phenylethyl]-
6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (5i): Following
the general procedure (reaction time 2.5 h), from lactam 2 (400 mg,
1.23 mmol) in THF (20 mL) and 2-(1,3-dioxan-2-yl)ethylmagne-
sium bromide (0.5  in THF, 7.4 mL, 3.69 mmol) a yellow solid
was obtained. Flash chromatography (1:1 Et2O/EtOAc, increasing
polarity and 9:1 EtOAc/EtOH) gave 5i (246 mg, 45%) as a yellow
foam and 3 (121 mg, 30%). Data for 5i: [α]2D2 = +38.5 (c = 1.0,
1
(KBr): ν = 1632, 3399 cm–1. H NMR (400 MHz, CDCl , 25 °C):
˜
3
δ = 1.92–2.07 (m, 1 H, CH2), 2.10–2.18 (m, 1 H, CH2), 2.25–2.36
(m, 1 H, CH2Ar), 2.50–2.57 (m, 1 H, CH2Ar), 3.59 (d, J = 18.8 Hz,
1 H, 4-H), 3.78 (s, 3 H, OCH3), 3.81 (d, J = 18.8 Hz, 1 H, 4-H),
3.87 (s, 3 H, OCH3), 4.10 (dd, J = 9.2, 2.8 Hz, 1 H, 1-H), 4.18–
4.23 (m, 2 H, CH2OH), 5.59 (dd, J = 7.6, 6.0 Hz, 1 H, CHAr),
6.34 (s, 1 H, 8-H), 6.69 (s, 1 H, 5-H), 7.01 (d, J = 13.2 Hz, 2 H, C-
2Ј, C-6Ј), 7.15 (m, 1 H, 4Ј-H), 7.20 (br. s, 2 H, C-3Ј, C-5Ј), 7.24–
7.26 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C):
δ = 31.5 (CH2Ar), 37.6 (C-4), 37.7 (CH2), 56.0 (OCH3), 56.1
(OCH3), 59.4 (C-1), 61.7 (CHAr), 63.3 (CH2OH), 109.1 (C-8),
110.5 (C-5), 123.9 (C-4a), 126.1 (C-4Ј), 127.8 (C-p), 127.8 (C-m),
128.1 (C-o), 128.3 (C-8a), 128.5 (C-2Ј, C-6Ј), 128.6 (C-3Ј, C-5Ј),
136.7 (C-i), 140.6 (C-1Ј), 147.3 (C-6), 148.4 (C-7), 171.9 (CO) ppm.
HRMS: calcd. for C27H29NO4 [M + H]+ 432.2175; found 432.2180.
C27H29NO4·3/4H2O (445.04): calcd. C 72.87, H 6.91, N 3.15; found
C 72.95, H 6.87, N 2.95.
CHCl ). IR (KBr): ν = 1632, 3399 cm–1 1H NMR (400 MHz,
.
˜
3
CDCl3, 25 °C): δ = 1.31 (dt, J = 13.6, 1.2 Hz, 2 H, 1Ј-H), 1.41–
1.46 (m, 2 H, OCH2CH2), 1.72–1.81 (m, 1 H, 2Ј-H), 1.92–2.06 (m,
1 H, 2Ј-H), 3.56 (d, J = 19.0 Hz, 1 H, 4-H), 3.68 (ddd, J = 15.2,
12.0, 3.6 Hz, 2 H, CH2CH2O), 3.75 (s, 3 H, OCH3), 3.79 (d, J =
19.0 Hz, 1 H, 4-H), 3.85 (s, 3 H, OCH3), 4.03 (m, 2 H, CH2CH2O),
4.40 (t, J = 4.8 Hz, 1 H, CHO2), 4.15 (dd, J = 10.0, 3.2 Hz, 1 H,
1-H), 4.23–4.32 (m, 2 H, CH2OH), 5.76 (dd, J = 8.0, 5.6 Hz, 1 H,
CHAr), 6.34 (s, 1 H, 8-H), 6.65 (s, 1 H, 5-H), 7.16 (d, J = 1.6 Hz,
1 H, ArH), 7.18 (d, J = 2.0 Hz, 1 H, ArH), 7.25–7.30 (m, 3 H,
ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 25.6 (C-1Ј),
30.3 (C-2Ј), 31.1 (CH2CH2O), 37.6 (C-4), 55.9 (OCH3), 56.0
(OCH3), 58.9 (C-1), 60.3 (CHAr), 63.1 (CH2OH), 66.7 (2
CH2CH2O), 101.6 (CHO2), 109.4 (C-8), 110.4 (C-5), 123.8 (C-4a),
127.7 (C-p), 127.8 (C-o), 128.1 (C-8a), 128.5 (C-m), 136.8 (C-i),
147.2 (C-6), 148.3 (C-7), 171.9 (CO) ppm. HRMS: calcd. for
C25H31NO6 [M + H]+ 442.2223; found 442.2219.
(1S)-1-Allyl-2-[(1R)-2-hydroxy-1-phenylethyl]-6,7-dimethoxy-3-
oxo-1,2,3,4-tetrahydroisoquinoline (5h): Following the general pro-
cedure (reaction time 2 h), from lactam 2 (200 mg, 0.6 mmol) in
THF (10 mL) and allylmagnesium bromide (1  in Et2O, 1.85 mL,
1.85 mmol) a yellow oil was obtained. Flash chromatography (95:5
tert-butyl methyl ether/EtOAc) gave 5h (92 mg, 42%) as a white oil
and 1-(2-allyl-2-hydroxy-4-pentenyl)-2-{1-[2-hydroxy-(1R)-phenyle-
thylamino]-3-butenyl}-4,5-dimethoxybenzene (10; 103 mg, 39%).
General Procedure for Na/liquid NH3 Reaction: Into a three-necked,
round-bottomed flask equipped with a cold-finger condenser
charged with dry ice/acetone was condensed NH3 at –78 °C. The
temperature was raised to –33 °C, and a solution of lactam 5 in
THF was added. Then, sodium metal was added in small portions
until the blue color persisted. After the mixture was stirred at
–33 °C for 1 min, the reaction was quenched by the addition of
solid NH4Cl until the blue color disappeared. The mixture was
stirred at room temperature for 4 h, poured into water, and ex-
tracted with Et2O. The combined organic extracts were dried and
concentrated to give a residue, which was purified by chromatog-
raphy.
Data for 5h: [α]2D2 = +16.8 (c = 1.0, CHCl ). IR (KBr): ν = 1637,
˜
3
3386 cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 2.18–2.33 (m,
1
1 H, CH2CH=), 2.39–2.60 (m, 1 H, CH2CH=), 3.54 (d, J =
19.5 Hz, 1 H, 4-H), 3.79 (d, J = 19.5 Hz, 1 H, 4-H), 3.76 (s, 3 H,
OCH3), 3.86 (s, 3 H, OCH3), 4.26 (m, 1 H, 1-H), 4.28 (dd, J =
11.4, 7.8 Hz, 1 H, CH2OH), 4.30 (dd, J = 11.4, 5.7 Hz, 1 H,
CH2OH), 4.90 (dd, J = 10.5, 1.8 Hz, 1 H, CH2=), 4.99 (td, J = 6.0,
1.8 Hz, 1 H, CH2=), 5.51 (m, 1 H, CH=), 5.68 (dd, J = 7.8, 5.7 Hz,
1 H, 1-H), 6.31 (s, 1 H, 8-H), 6.65 (s, 1 H, 5-H), 7.22–7.38 (m, 5
H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 37.6 (C-
4), 40.8 (CH2CH=), 55.8 (OCH3), 56.0 (OCH3), 60.1 (C-1), 61.3
(CHAr), 63.2 (CH2OH), 109.0 (C-8), 110.0 (C-5), 118.9 (CH2=),
123.6 (C-4a), 127.6 (C-p), 127.7 (C-o), 128.4 (C-m), 128.6 (C-8a),
133.0 (CH=), 136.8 (C-i), 147.1 (C-7), 148.2 (C-6), 171.8 (CO) ppm.
HRMS: calcd. for C22H25NO4 [M + H]+ 368.1862; found 368.1873.
C22H25NO4·1/2H2O (411.5): calcd. C 70.05, H 7.10, N 3.40; found
(1S)-6,7-Dimethoxy-1-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline
(6a): Operating as described in the general procedure, from 5a
(200 mg, 0.59 mmol) in THF (7 mL) and NH3 (50 mL) a clear ma-
roon residue was obtained. Flash chromatography (9:1 EtOAc/
EtOH) afforded 6a (110 mg, 85%) as a white solid. [α]2D2 = +10.0
C 66.69, H 6.70, N 3.55. Data for 10: IR (KBr): ν = 1638, 3073,
˜
(c = 1.0, CHCl ). IR (KBr): ν = 1668, 3217 cm–1 1H NMR
.
˜
3
1
3324 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 2.10–2.19 (m,
(400 MHz, CDCl3, 25 °C): δ = 1.51 (d, J = 6.4 Hz, 3 H, CH3), 3.48
(d, J = 20.0 Hz, 1 H, 4-H), 3.60 (d, J = 20.0 Hz, 1 H, 4-H), 3.87
(s, 6 H, 2 OCH3), 4.60 (m, 1 H, 1-H), 6.60 (s, 1 H, 8-H), 6.61 (s, 1
H, 5-H), 6.90 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 24.4 (CH3), 35.4 (C-4), 51.3 (C-1), 56.0 (OCH3), 56.1
(OCH3), 108.2 (C-8), 110.4 (C-5), 122.8 (C-4a), 127.8 (C-8a), 148.0
(C-6), 148.4 (C-7), 171.5 (CO) ppm. HRMS: calcd. for C12H15NO3
[M + H]+ 222.1124; found 222.1122. C12H15NO3 (221.25): calcd. C
65.14, H 6.83, N 6.33; found C 64.89, H 6.76, N 6.16.
4 H, 2 CH2CHCH2), 2.38–2.53 (m, 2 H, CHCH2CHCH2), 2.56 (d,
J = 14.8 Hz, 1 H, CH2Ar), 2.66 (d, J = 14.8 Hz, 1 H, CH2Ar), 3.57
(dd, J = 10.8, 8.0 Hz, 1 H, CH2OH), 3.67 (dd, J = 10.8, 4.4 Hz, 1
H, CH2OH), 3.85 (s, 3 H, OCH3), 3.86 (dd, J = 8.0, 4.4 Hz, 1 H,
CHAr), 3. 89 (s, 3 H, OCH3 ), 4.05 (t, J = 6.4 Hz, 1 H,
CHCH2CHCH2), 4.98–5.09 (m, 2 H, CHCH2CHCH2), 5.10–5.15
(m, 4 H, 2 CH2CHCH2), 5.64–5.72 (m, 1 H, CHCH2CHCH2),
5.74–5.84 (m, 2 H, 2 CH2CHCH2), 6.65 (s, 1 H, CH3OCCH), 6.85
(s, 1 H, CH3OCCH), 7.26–7.28 (m, 5 H, ArH) ppm. 13C NMR
(75.4 MHz, CDCl3, 25 °C): δ = 40.3 (CHCH2CHCH2), 40.4 (1S)-1-Ethyl-6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline
(CH2 Ar), 43.7 (CH2 CHCH2 ), 44.0 (CH2 CHCH2 ), 55.1 (6b): Operating as described in the general procedure, from 5b
(CHCH2CHCH2), 55.6 (OCH3), 55.7 (OCH3), 61.5 (CHAr), 66.3
(230 mg, 0.65 mmol) in THF (4 mL) and NH3 (30 mL) a residue
(CH2 OH), 73.3 (COH), 110.1 (C-3), 114.8 (C-6), 117.3 was obtained. Flash chromatography (EtOAc) afforded 6b (140 mg,
(CHCH2CHCH2), 118.5 (CH2CHCH2), 118.6 (CH2CHCH2), 127.0 92%) as a white oil. [α]2D2 = +21.7 (c = 0.57, CHCl ). IR (KBr): ν
˜
3
1
(C-2), 127.3 (C-m), 127.4 (C-p), 128.4 (C-o), 133.8 (CH2CHCH2),
= 1654, 2972 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 0.92
4022
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4017–4026

Enantioselective Synthesis of 1-Substituted Tetrahydroisoquinoline Alkaloids
1
(t, J = 8.0 Hz, 3 H, CH3), 1.81 (m, 2 H, CH2), 3.46 (d, J = 20.0 Hz, ν = 1674 cm–1. H NMR (400 MHz, CDCl , 25 °C): δ = 2.03–2.09
˜
3
1 H, 4-H), 3.62 (d, J = 20.0 Hz, 1 H, 4-H), 3.87 (s, 6 H, 2 OCH3), (m, 2 H, CH2), 2.62–2.70 (m, 2 H, CH2Ar), 3.48 (d, J = 20.0 Hz,
4.44 (m, 1 H, 1-H), 6.60 (s, 1 H, 8-H), 6.62 (s, 1 H, 5-H), 7.70 (br.
s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 9.1
(CH3), 31.7 (CH2), 35.2 (C-4), 55.9 (OCH3), 56.0 (OCH3), 57.2 (C-
1), 108.8 (C-8), 110.3 (C-5), 123.2 (C-4a), 126.2 (C-8a), 147.8 (C-
7), 148.4 (C-6), 171.9 (CO) ppm. HRMS: calcd. for C13H17NO3 [M
+ H]+ 236.1286; found 236.1280.
1 H, 4-H), 3.64 (d, J = 20.0 Hz, 1 H, 4-H), 3.86 (s, 3 H, OCH3),
3.87 (s, 3 H, OCH3), 4.60 (m, 1 H, 1-H), 6.60 (s, 2 H, 5-H, 8-H),
7.14–7.19 (m, 3 H, ArH), 7.25–7.28 (m, 2 H, ArH), 7.43 (m, 1 H,
NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 31.2
(CH2Ar), 35.4 (C-4), 40.5 (CH2), 55.7 (C-1), 56.0 (OCH3), 56.1
(OCH3), 108.7 (C-8), 110.5 (C-5), 123.2 (C-4a), 126.1 (C-8a), 126.3
(C-4Ј), 128.3 (C-3Ј), 128.5 (C-2Ј), 140.9 (C-1Ј), 147.9 (C-6), 148.5
(C-7), 171.7 (CO) ppm. HRMS: calcd. for C19H21NO3 [M + H]+
312.1599; found 312.1598.
(1S)-1-[3,4-(Dimethoxyphenyl)]-6,7-dimethoxy-3-oxo-1,2,3,4-
tetrahydroisoquinoline (6d): Operating as described in the general
procedure, from 5d (215 mg, 0.46 mmol) in THF (3 mL) and NH3
(35 mL) a residue was obtained. Flash chromatography (2:8 to 1:9
(1S)-1-Allyl-6,7-dimethoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline
(6h): Operating as described in the general procedure, from 5h
hexane/EtOAc) afforded 6d (121 mg, 77%) as a yellow foam. IR
1
(KBr): ν = 1647, 2920 cm–1. H NMR (400 MHz, CDCl , 25 °C): (80 mg, 0.22 mmol) in THF (2 mL) and NH3 (25 mL) a residue
˜
3
δ = 3.52 (d, J = 24.0 Hz, 1 H, 4-H), 3.66 (d, J = 24.0 Hz, 1 H, 4- was obtained. Flash chromatography (EtOAc) afforded 6h
H), 3.71 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3),
3.89 (s, 3 H, OCH3), 5.54 (s, 1 H, 1-H), 6.37 (s, 1 H, 2Ј-H), 6.65 (s,
1 H, 5Ј-H), 6.72 (s, 1 H, 6Ј-H), 6.83 (s, 1 H, 8-H), 6.84 (s, 1 H, 5-
(48.3 mg, 90%) as a yellow foam. [α]2D2 = –10.5 (c = 0.6, CHCl3).
IR (KBr): ν = 1667, 2918 cm–1
.
1H NMR (400 MHz, CDCl3,
˜
25 °C): δ = 2.45 (ddd, J = 14.0, 7.2, 7.2 Hz, 1 H, CH2), 2.57–2.61
H), 7.05 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, (m, 1 H, CH2), 3.47 (d, J = 20.0 Hz, 1 H, 4-H), 3.60 (d, J = 20.0 Hz,
25 °C): δ = 35.5 (C-4), 55.6 (OCH3), 55.7 (OCH3), 55.8 (OCH3), 1 H, 4-H), 3.88 (s, 6 H, 2 OCH3), 4.52 (m, 1 H, 1-H), 5.12–5.17
59.6 (C-1), 109.5 (C-8), 110.0 (C-5), 110.1 (C-2Ј), 110.9 (C-5Ј), (m, 2 H, =CH2), 5.69–5.79 (m, 1 H, CH=), 6.60 (s, 1 H, 8-H), 6.65
119.7 (C-6Ј), 123.0 (C-4a), 126.1 (C-8a), 134.2 (C-1Ј), 147.7 (C-6), (s, 1 H, 5-H), 6.80 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz,
148.5 (C-4Ј), 148.8 (C-7), 149.3 (C-3Ј), 170.8 (CO) ppm. HRMS:
CDCl3, 25 °C): δ = 35.4 (C-4), 43.2 (CH2), 55.5 (C-1), 55.9 (OCH3),
56.0 (OCH3), 108.6 (C-8), 110.4 (C-5), 119.9 (=CH2), 123.3 (C-4a),
125.6 (C-8a), 132.7 (CH=), 147.9 (C-6), 148.5 (C-7), 171.2 (CO)
ppm. HRMS: calcd. for C14H17NO3 [M + H]+ 248.1288; found
248.1278.
calcd. for C19H21NO5 [M + H]+ 344.1498; found 344.1491.
(1S)-6,7-Dimethoxy-3-oxo-1-[3,4,5-(trimethoxyphenyl)]-1,2,3,4-tetra-
hydroisoquinoline (6e): Operating as described in the general pro-
cedure, from 5e (150 mg, 0.30 mmol) in THF (2 mL) and NH3
(30 mL) a residue was obtained. Flash chromatography (EtOAc)
(1S)-1-[2-(1,3-Dioxan-2-yl)ethyl]-6,7-dimethoxy-3-oxo-1,2,3,4-tetra-
hydroisoquinoline (6i): Operating as described in the general pro-
afforded 6e (98 mg, 87%) as a yellow foam. IR (KBr): ν = 1663,
˜
2926 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.56 (d, J = cedure, from 5i (114 mg, 0.26 mmol) in THF (2 mL) and NH3
18.0 Hz, 1 H, 4-H), 3.71 (d, J = 18.0 Hz, 1 H, 4-H), 3.72 (s, 3 H,
(30 mL) a residue was obtained. Flash chromatography (9:1
OCH3), 3.76 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.83 (s, 3 H, EtOAc/EtOH) afforded 6i (78.5 mg, 92%) as a white solid. [α]2D2
=
OCH3), 3.84 (s, 3 H, OCH3), 5.25 (s, 1 H, 1-H), 6.41 (s, 2 H, 2Ј-H, +2.3 (c = 0.53, CHCl ). IR (KBr): ν = 1674, 3217 cm–1. H NMR
1
˜
3
6Ј-H), 6.66 (s, 1 H, 8-H), 6.73 (s, 1 H, 5-H), 7.25 (br. s, 1 H, NH)
(400 MHz, CDCl3, 25 °C): δ = 1.33 (dm, J = 13.2 Hz, 2 H, 2Ј-H),
ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 38.8 (C-4), 55.8 1.61–1.84 (m, 2 H, 1Ј-H), 1.87–1.94 (m, 1 H, CH2CH2O), 1.91–
(OCH3), 55.9 (OCH3), 56.0 (OCH3), 56.1 (OCH3), 60.0 (C-1), 60.1 2.11 (m, 1 H, CH2CH2O), 3.56 (d, J = 19.5 Hz, 1 H, 4-H), 3.60 (d,
(OCH3), 104.3 (C-8), 105.4 (C-2Ј, C-6Ј), 113.9 (C-5), 125.4 (C-4a), J = 19.5 Hz, 1 H, 4-H), 3.74 (td, J = 11.6, 0.8 Hz, 2 H, CH2CH2O),
131.2 (C-4Ј), 131.3 (C-8a), 133.4 (C-1Ј), 147.7 (C-6), 148.1 (C-7), 3.86 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.09 (ddd, J = 11.6, 4.8,
153.1 (C-3Ј, C-5Ј), 173.7 (CO) ppm. HRMS: calcd. for C20H23NO6
1.2 Hz, 2 H, CH2CH2O), 4.48–4.52 (br. m, 1 H, 1-H), 4.56 (t, J =
4.8 Hz, 1 H, CHO2), 6.59 (s, 1 H, 8-H), 6.65 (s, 1 H, 5-H), 7.18
(s.a., 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ =
25.7 (CH2CH2O), 30.5 (C-1Ј), 33.0 (C-2Ј), 35.3 (C-4), 55.6 (C-1),
55.9 (OCH3), 56.0 (OCH3), 66.8 (CH2O), 101.6 (CHO2), 108.8 (C-
8), 110.4 (C-5), 123.1 (C-4a), 126.6 (C-8a), 147.8 (C-6), 148.3 (C-
7), 171.4 (CO) ppm. HRMS: calcd. for C17H23NO5 [M + H]+
322.1655; found 322.1650.
[M + H]+ 374.1603; found 374.1592.
(1S)-6,7-Dimethoxy-1-(p-methoxybenzyl)-3-oxo-1,2,3,4-tetrahydro-
isoquinoline (6f): Operating as described in the general procedure,
from 5f (95 mg, 0.21 mmol) in THF (2 mL) and NH3 (30 mL) a
residue was obtained. Flash chromatography (EtOAc to 95:5
EtOAc/EtOH) afforded 6f (58 mg, 85%) as a yellow foam. [α]2D2
=
1
–61.2 (c = 0.5, CHCl ). IR (KBr): ν = 1630, 2934 cm–1. H NMR
˜
3
(400 MHz, CDCl3, 25 °C): δ = 2.87 (d, J = 20.0 Hz, 1 H, 4-H),
2-Benzyl-4,5-dimethoxyphenylacetamide (8): Operating as described
2.91 (dd, J = 13.5, 6.0 Hz, 1 H, CH2), 3.03 (dd, J = 13.5, 4.0 Hz, in the general procedure, from 5c (100 mg, 1.17 mmol) in THF
1 H, CH2), 3.23 (d, J = 20.0 Hz, 1 H, 4-H), 3.77 (s, 1 H, OCH3), (2 mL) and NH3 (30 mL) a residue was obtained. Flash chromatog-
3.83 (s, 1 H, OCH3), 3.86 (s, 1 H, OCH3), 4.68 (m, 1 H, 1-H), 6.49 raphy (EtOAc) afforded 8 (20 mg, 28 %). IR (KBr): ν = 1629,
˜
1
(s, 1 H, 8-H), 6.55 (s, 1 H, 5-H), 6.76 (d, J = 8.2 Hz, 2 H, 2Ј-H), 2933 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 3.44 (s, 2 H,
6.86 (d, J = 8.2 Hz, 2 H, 3Ј-H), 6.95 (br. s, 1 H, NH) ppm. 13C CH2CO), 3.81 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.93 (s, 2 H,
NMR (100.6 MHz, CDCl3, 25 °C): δ = 35.0 (C-4), 44.5 (CH2), 55.2 CH2Ar), 5.20 (s, 1 H, NH2), 5.90 (s, 1 H, NH2), 6.70 (s, 1 H, 3-
(OCH3), 55.9 (C-1), 56.0 (OCH3), 57.3 (OCH3), 108.9 (C-8), 110.1
(C-5), 113.8 (C-3Ј), 123.9 (C-4a), 125.2 (C-2Ј), 127.8 (C-8a), 131.8 (100.6 MHz, CDCl3, 25 °C): δ = 38.8 (CH2Ar), 40.2 (CH2CO), 55.9
H), 6.75 (s, 1 H, 6-H), 7.10–7.25 (m, 5 H, ArH) ppm. 13C NMR
(C-1Ј), 147.7 (C-6), 148.4 (C-7), 158.5 (C-4Ј), 172.3 (CO) ppm.
(OCH3), 56.0 (OCH3), 113.8 (C-3), 114.2 (C-6), 125.5 (C-1), 126.3
HRMS: calcd. for C19H21NO4 [M + H]+ 328.1549; found 328.1532. (C-p), 128.5 (C-m), 128.6 (C-o), 131.6 (C-2), 140.3 (C-i), 147.8 (C-
4), 148.3 (C-5), 173.9 (CO) ppm. HRMS: calcd. for C17H19NO3 [M
(1S)-6,7-Dimethoxy-3-oxo-1-phenethyl-1,2,3,4-tetrahydroisoquinol-
ine (6g): Operating as described in the general procedure, from 5g
+ H]+ 286.1443; found 286.1437.
(100 mg, 0.23 mmol) in THF (2 mL) and NH3 (25 mL) a residue
was obtained. Flash chromatography (EtOAc) afforded 6g (56 mg,
79%) as a white foam. [α]2D2 = +16.0 (c = 1.0, CHCl3). IR (KBr):
General Procedure for the NaBH4–I2 Reduction Reactions: A solu-
tion of iodine (1 equiv.) in THF was slowly added to a cooled (0 °C)
suspension of NaBH4 (2.5 equiv.) in anhydrous THF, and the mix-
Eur. J. Org. Chem. 2010, 4017–4026
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4023

M. Amat, V. Elias, N. Llor, F. Subrizi, E. Molins, J. Bosch
FULL PAPER
ture was stirred at this temperature for 30 min. Then, a solution of
lactam 6 (1 equiv.) in THF was added to the solution (0 °C). The
resulting mixture was heated at reflux for 16 h and cooled to 0 °C.
MeOH (4 mL) was slowly added, and the stirring was continued at
room temperature for 30 min. The solvent was evaporated, and the
resulting solid was digested with 2  NaOH (30 min). The resulting
suspension was extracted with CH2Cl2, the combined organic ex-
tracts were dried and concentrated, and the residue was purified by
chromatography.
(–)-Norcryptostyline III (7e): Following the above general pro-
cedure, from lactam 6e (92 mg, 0.25 mmol) in THF (3 mL), NaBH4
(23.3 mg, 0.62 mmol) in THF (4 mL), and I2 (70.8 mg, 0.25 mmol)
in THF (3 mL), tetrahydroisoquinoline 7e (52 mg, 58%) was ob-
tained as a yellow oil after flash chromatography by using a car-
tridge containing amine-functionalized silica (7:3 Et2O/EtOAc).
[α]2D2 = –45.7 (c = 0.11, CHCl3) {ref.[16a] [α]D = –37.0 (CHCl3)}. IR
(KBr): ν = 2919 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
˜
2.74 (dt, J = 15.6, 4.5, 3.9 Hz, 1 H, 4-H), 2.90–3.00 (m, 1 H, 4-H),
3.07 (ddd, J = 11.7, 7.8, 3.9 Hz, 1 H, 3-H), 3.26 (dt, J = 11.7, 5.1,
4.5 Hz, 1 H, 3-H), 3.68 (s, 3 H, OCH3), 3.81 (s, 6 H, 2 CH3O), 3.85
(s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 5.01 (s, 1 H, 1-H), 6.26 (s, 1
H, 8-H), 6.47 (s, 2 H, 2Ј-H, 6Ј-H), 6.63 (s, 1 H, 5-H) ppm. 13C
NMR (75.4 MHz, CDCl3, 25 °C): δ = 27.9 (C-4), 41.5 (C-3), 55.8
(OCH3), 56.0 (OCH3), 56.2 (OCH3), 60.8 (OCH3), 61.2 (C-1), 106.4
(C-2Ј, C-6Ј), 110.8 (C-8), 111.3 (C-5), 126.7 (C-4a), 129.8 (C-8a),
137.7 (C-1Ј), 147.4 (C-6), 148.2 (C-7), 153.2 (C-3Ј, C-4Ј, C-5Ј) ppm.
HRMS: calcd. for C20H25NO5 [M + H]+ 360.1809; found 360.1809.
(–)-Salsolidine (7a): Following the above general procedure, from
lactam 6a (100 mg, 0.45 mmol) in THF (5 mL), NaBH4 (42.6 mg,
1.13 mmol) in THF (5 mL), and I2 (114 mg, 0.45 mmol) in THF
(4 mL), tetrahydroisoquinoline 7a (65 mg, 70%) was obtained as
an oil after flash chromatography (9:1 EtOAc/EtOH). [α]2D2 = –58.5
(c = 0.50, EtOH) {lit.[1b] [α]2D4 = –62.5 (c = 0.1, EtOH)}. IR (KBr):
1
ν = 3217 cm–1. H NMR (300 MHz, CDCl , 25 °C): δ = 1.43 (d, J
˜
3
= 6.5 Hz, 3 H, CH3), 1.78 (br. s, 1 H, NH), 2.60–2.68 (dt, J = 16.0,
4.8 Hz, 1 H, 4-H), 2.74–2.84 (ddd, J = 16.0, 8.4, 5.4 Hz, 1 H, 4-
H), 2.99 (ddd, J = 13.0, 8.4, 4.8 Hz, 1 H, 3-H), 3.24 (ddd, J = 13.0,
4.8 Hz, 1 H, 3-H), 3.87 (s, 6 H, 2 OCH3), 4.04 (q, J = 6.5 Hz, 1 H,
(–)-O,O-Dimethylcoclaurine (7f): Following the above general pro-
cedure, from lactam 6f (200 mg, 0.6 mmol) in THF (3 mL), NaBH4
1-H), 6.57 (s, 1 H, 8-H), 6.62 (s, 1 H, 5-H) ppm. 13C NMR (58 mg, 1.5 mmol) in THF (4 mL), and I2 (152 mg, 0.8 mmol) in
(100.6 MHz, CDCl3, 25 °C): δ = 22.8 (CH3), 29.5 (C-4), 41.8 (C- THF (3 mL), tetrahydroisoquinoline 7f (111 mg, 59 %) was ob-
3), 51.2 (C-1), 55.8 (OCH3), 55.9 (OCH3), 109.0 (C-8), 111.7 (C-
5), 126.8 (C-4a), 132.5 (C-8a), 147.2 (C-7), 147.3 (C-6) ppm.
tained as a yellow oil after flash chromatography by using a car-
tridge containing amine-functionalized silica (8:2 to 1:1 hexane/
EtOAc). [α]2D2 = –11.8 (c = 0.5, CHCl3) {ref.[18c] [α]2D2 = –19.9 (c =
(1S)-1-Ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (7b): Fol-
lowing the above general procedure, from lactam 6b (91 mg,
0.39 mmol) in THF (10 mL), NaBH4 (36 mg, 1.1 mmol) in THF
(4 mL), and I2 (99 mg, 0.39 mmol) in THF (4 mL), tetrahydroiso-
quinoline 7b (52 mg, 60 %) was obtained as an oil after flash
chromatography by using a cartridge containing amine-function-
alized silica (7:3 hexane/EtOAc to EtOAc). [α]2D2 = –47.4 (c = 0.3,
1, CHCl )}. IR (KBr): ν = 2932 cm–1. 1H NMR (400 MHz, CDCl ,
˜
3
3
25 °C): δ = 2.64–2.79 (m, 1 H, 3-H), 2.73 (ddd, J = 11.6, 6.0,
6.0 Hz, 1 H, 4-H), 2.86 (dd, J = 14.0, 9.5 Hz, 1 H, CH2Ar), 2.91
(ddd, J = 12.0, 6.0, 5.6 Hz, 1 H, 3-H), 3.15 (dd, J = 14.0, 4.5 Hz,
1 H, CH2Ar), 3.20 (ddd, J = 11.6, 11.6, 5.6 Hz, 1 H, 4-H), 3.80 (s,
1 H, OCH3), 3.82 (s, 1 H, OCH3), 3.86 (s, 1 H, OCH3), 4.11 (dd,
J = 9.5, 4.5 Hz, 1 H, 1-H), 6.59 (s, 1 H, 8-H), 6.63 (s, 1 H, 5-H),
6.86 (d, J = 8.5 Hz, 2 H, 3Ј-H), 7.16 (d, J = 8.5 Hz, 2 H, 5Ј-H)
ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 29.5 (C-4), 40.7
(CH2Ar), 41.5 (C-3), 55.3 (OCH3), 55.8 (OCH3), 55.9 (OCH3), 56.9
(C-1), 109.4 (C-8), 111.8 (C-5), 114.0 (C-3Ј), 127.3 (C-4a), 130.3
(C-2Ј), 130.5 (C-1Ј), 131.0 (C-8a), 147.0 (C-7), 147.4 (C-6), 158.3
(C-4Ј) ppm. HRMS: calcd. for C19H23NO3 [M + H]+ 314.1756;
found 314.1743.
CH2Cl2) {ref.[25] [α]2D2 = –51.9 (c = 2.1, CH Cl )}. IR (KBr): ν =
˜
2
2
2930 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.02 (t, J =
7.6 Hz, 3 H, CH3), 1.67–1.78 (m, 1 H, CH2), 1.90 (dddd, J = 14.4,
7.2, 7.2, 3.2 Hz, 1 H, CH2), 2.40 (s, 1 H, NH), 2.67 (dt, J = 16.2,
5.2 Hz, 1 H, 3-H), 2.77 (dt, J = 16.2, 6.0 Hz, 1 H, 3-H), 2.98 (ddd,
J = 12.4, 7.6, 4.8 Hz, 1 H, 4-H), 3.24 (dt, J = 12.4, 5.2 Hz, 1 H, 4-
H), 3.85 (s, 6 H, 2 OCH3), 3.85 (m, 1 H, 1-H), 6.57 (s, 1 H, 8-H),
6.62 (s, 1 H, 5-H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ
= 10.9 (CH3), 29.0 (CH2), 29.4 (C-4), 41.1 (C-3), 55.8 (OCH3), 56.0
(1S)-6,7-Dimethoxy-1-phenylethyl-1,2,3,4-tetrahydroisoquinoline
(OCH3), 56.7 (C-1), 109.2 (C-8), 111.7 (C-5), 127.1 (C-4a), 131.0 (7g): Following the above general procedure, from lactam 6g
(C-8a), 147.2 (C-7), 147.3 (C-6) ppm. HRMS: calcd. for
(250 mg, 0.8 mmol) in THF (3 mL), NaBH4 (76 mg, 2.0 mmol) in
THF (4 mL), and I2 (203 mg, 0.8 mmol) in THF (3 mL), tetra-
hydroisoquinoline 7g (183 mg, 77%) was obtained as a colorless oil
after flash chromatography (SiO2 previously washed with 8:2 Et3N/
EtOAc; 8:2 to 1:1 Et2O/EtOAc as eluent). [α]2D2 = –23.4 (c = 0.25,
C13H19NO2 [M + H]+ 222.1494; found 222.1488.
(–)-Norcryptostyline II (7d): Following the above general procedure,
from lactam 6d (90 mg, 0.26 mmol) in THF (3 mL), NaBH4
(24.8 mg, 0.66 mmol) in THF (4 mL), and I2 (66.5 mg, 0.26 mmol)
in THF (3 mL), tetrahydroisoquinoline 7d (58 mg, 69%) was ob-
tained as a yellow oil after flash chromatography by using a car-
tridge containing amine-functionalized silica (1:1 hexane/EtOAc).
CHCl ). IR (KBr): ν = 2955 cm–1. 1H NMR (400 MHz, CDCl3,
˜
3
25 °C): δ = 2.04–2.17 (m, 2 H, CH2), 2.66–2.89 (m, 4 H, CH2Ar,
4-H), 3.02 (ddd, J = 12.0, 7.2, 5.6 Hz, 1 H, 3-H), 3.27 (ddd, J =
12.0, 5.6, 5.6 Hz, 1 H, 3-H), 3.82 (s, 3 H, OCH3), 3.85 (s, 3 H,
OCH3), 4.00 (dd, J = 8.0, 2.8 Hz, 1 H, 1-H), 6.57 (s, 2 H, 5-H, 8-
H), 7.17–7.31 (m, 5 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3,
25 °C): δ = 29.1 (CH2Ar), 32.4 (C-4), 38.1 (CH2), 40.9 (C-3), 55.1
(C-1), 55.8 (OCH3), 56.0 (OCH3), 109.2 (C-8), 111.8 (C-5), 125.9
(C-4Ј), 127.0 (C-4a), 128.4 (C-2Ј, C-3Ј), 128.5 (C-8a), 142.2 (C-4Ј),
147.3 (C-6), 147.4 (C-7) ppm. HRMS: calcd. for C19H23NO2 [M +
H]+ 298.1807; found 298.1802.
[α]2D2 = –33.8 (c = 0.36, CHCl3) {ref.[5a] [α]1D8 = –37 (c = 0.26,
1
CHCl )}. IR (KBr): ν = 2923 cm–1. H NMR (400 MHz, CDCl ,
˜
3
3
25 °C): δ = 2.75 (dt, J = 15.2, 4.4 Hz, 1 H, 4-H), 2.96 (ddd, J =
15.2, 4.8, 4.8 Hz, 1 H, 4-H), 3.06 (ddd, J = 13.2, 8.8, 4.8 Hz, 1 H,
3-H), 3.24 (ddd, J = 13.2, 4.8 Hz, 1 H, 3-H), 3.65 (s, 3 H, OCH3),
3.83 (s, 3 H, OCH3), 3.87 (s, 6 H, OCH3), 5.00 (s, 1 H, 1-H), 6.27
(s, 1 H, 8-H), 6.62 (s, 1 H, 5-H), 6.79 (s, 1 H, 2Ј-H), 6.80 (s, 1 H,
6Ј-H), 6.82 (s, 1 H, 5Ј-H) ppm. 13C NMR (75.4 MHz, CDCl3,
25 °C): δ = 29.1 (C-4), 42.1 (C-3), 55.8 (OCH3), 55.9 (OCH3), 56.0 (1S)-1-[2-(1,3-Dioxan-2-yl)ethyl]-2-[(1R)-2-hydroxy-1-phenylethyl]-
(OCH3), 61.3 (C-1), 110.7 (C-2Ј), 110.9 (C-5Ј), 111.4 (C-8), 111.8 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9): LiAlH4 (96 mg,
(C-5), 121.3 (C-6Ј), 127.4 (C-4a), 129.8 (C-8a), 136.9 (C-i), 147.0 2.54 mmol) was slowly added to a suspension of AlCl3 (113 mg,
(C-6), 147.7 (C-4Ј), 148.4 (C-7), 149.0 (C-3Ј) ppm. HRMS: calcd.
0.85 mmol) in THF (6 mL) at –78 °C and the mixture was stirred
for 2 h. Then, a solution of tetrahydroisoquinolone 5i (170 mg,
for C19H23NO4 [M + H]+ 330.1705; found 330.1691.
4024
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4017–4026

Enantioselective Synthesis of 1-Substituted Tetrahydroisoquinoline Alkaloids
[2]
For reviews, see: a) E. Anakabe, D. Badía, L. Carrillo, E.
Reyes, J. L. Vicario, “Chiral β-Amino alcohols and Derivatives
in the Asymmetric Synthesis of Tetrahydroisoquinolines” in
Targets in Heterocyclic Systems (Eds.: O. A. Attanasi, D. Spi-
nelli), Italian Society of Chemistry, 2002, vol. 6, pp. 270–311;
b) J. L. Vicario, D. Badía, L. Carrillo, J. Etxebarria, Curr. Org.
Chem. 2003, 7, 1775–1792; c) M. Chrzanowska, M. D. Rozwa-
dowska, Chem. Rev. 2004, 104, 3341–3370; d) E. L. Larghi, M.
Amongero, A. B. J. Bracca, T. S. Kaufman, Arkivoc 2005, 12,
98–153; e) Z. Czarnocki, A. Siwicka, J. Szawkato, Curr. Org.
Chem. 2005, 2, 301–331.
For reviews on the use of amino alcohol derived oxazolopiperi-
done lactams, see: a) A. I. Meyers, G. P. Brengel, Chem. Com-
mun. 1997, 1–8; b) M. D. Groaning, A. I. Meyers, Tetrahedron
2000, 56, 9843–9873; c) C. Escolano, M. Amat, J. Bosch, Chem.
Eur. J. 2006, 12, 8198–8207; d) S. N. Gaskell, L. J. Duffy, S. M.
Allin, Nat. Prod. Commun. 2008, 3, 1825–1838; for more recent
work, see: e) M. Amat, O. Bassas, N. Llor, M. Cantó, M. Pérez,
E. Molins, J. Bosch, Chem. Eur. J. 2006, 12, 7872–7881; f) M.
Amat, M. M. M. Santos, O. Bassas, N. Llor, C. Escolano, A.
Gómez-Esqué, E. Molins, S. M. Allin, V. McKee, J. Bosch, J.
Org. Chem. 2007, 72, 5193–5201; g) M. Amat, R. Griera, R.
Fabregat, J. Bosch, Angew. Chem. Int. Ed. 2008, 47, 3348–3351;
h) M. Amat, A. Gómez-Esqué, C. Escolano, M. M. M. Santos,
E. Molins, J. Bosch, J. Org. Chem. 2009, 74, 1205–1211; i) M.
Amat, N. Llor, B. Checa, E. Molins, J. Bosch, J. Org. Chem.
2010, 75, 178–189; j) M. Amat, M. Pérez, S. Proto, T. Gatti, J.
Bosch, Chem. Eur. J., DOI: 10.1002/chem.201000421.
T. C. Coombs, M. D. Lee IV, H. Wong, M. Armstrong, B.
Cheng, W. Chen, A. F. Moretto, L. S. Liebeskind, J. Org.
Chem. 2008, 73, 882–888.
For related approaches from oxazolotetrahydroisoquinolines,
see: a) M. Yamato, K. Hashigaki, N. Qais, S. Ishikawa, Tetra-
hedron 1990, 46, 5909–5920; b) K. Hashigaki, K. Kan, N. Qais,
Y. Takeuchi, M. Yamato, Chem. Pharm. Bull. 1991, 39, 1126–
1131; c) A.-C. Carbonnelle, V. Gott, G. Roussi, Heterocycles
1993, 36, 1763–1769; d) K. Umetsu, N. Asao, Tetrahedron Lett.
2008, 49, 2722–2725.
J. M. Gardiner, M. R. Bryce, P. A. Bates, M. B. Hursthouse, J.
Org. Chem. 1990, 55, 1261–1266.
CCDC-770769 (for 2) contains the supplementary crystallo-
graphic 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
0.39 mmol) in anhydrous THF (6 mL) was slowly added. The stir-
ring was continued at –78 °C for 20 h, and the reaction was
quenched with water. The aqueous layer was extracted with
CH2Cl2, and the combined organic extracts were dried and concen-
trated to give a residue, which was purified by chromatography
(Et2O to 1:1 Et2O/EtOAc) to afford tetrahydroisoquinoline 9
(144 mg, 87%). [α]2D2 = –37.1 (c = 1.03, CHCl ). IR (KBr): ν =
˜
3
3399 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.26–1.31 (m,
1
1 H, C1CH2), 1.49–1.52 (m, 1 H, OCH2CH2), 1.53–1.62 (m, 1 H,
CH2CHO2), 1.76–1.82 (m, 1 H, CH2CHO2), 1.83–1.93 (m, 1 H,
OCH2CH2), 1.97–2.09 (m, 1 H, C1CH2), 2.27 (s, 1 H, OH), 2.43
(dd, J = 17.0, 5.0 Hz, 1 H, 4-H), 2.97 (ddd, J = 17.0, 12.0, 6.0 Hz,
1 H, 4-H), 3.20 (dd, J = 13.5, 6.0 Hz, 1 H, 3-H), 3.31 (dd, J = 13.5,
5.0 Hz, 1 H, 3-H), 3.37 (dd, J = 9.6, 4.4 Hz, 1 H, 1-H), 3.64–3.67
(m, 2 H, 2 OCH2CH2), 3.68–3.73 (m, 1 H, CHAr), 3.75 (s, 3 H,
OCH3), 3.83 (s, 3 H, OCH3), 3.81–3.86 (m, 2 H, 2 OCH2CH2), 3.95
(dd, J = 10.8, 6.0 Hz, 1 H, CH2OH), 4.05 (dd, J = 10.8, 4.8 Hz, 1
H, CH2OH), 4.40 (t, J = 4.8 Hz, 1 H, CHO2), 6.28 (s, 1 H, 8-H),
6.55 (s, 1 H, 5-H), 7.28–7.29 (m, 5 H, ArH) ppm. 13C NMR
(75.4 MHz, CDCl3, 25 °C): δ = 22.5 (CH2CH2O), 25.6 (C-4), 30.7
(C-1Ј), 32.1 (C-2Ј), 39.0 (C-3), 55.6 (OCH3), 55.7 (OCH3), 57.6 (C-
1), 64.0 (CH2OH), 64.5 (CHAr), 66.6 (OCH2CH2), 102.1 (CHO2),
110.5 (C-8), 111.3 (C-5), 125.4 (C-4a), 127.4 (C-p), 128.2 (C-o),
128.6 (C-m), 130.3 (C-8a), 140.9 (C-i), 146.9 (C-6), 147.1 (C-7)
ppm. HRMS: calcd. for C25H33NO5 [M + H]+ 428.2437; found
428.2424.
[3]
[4]
[5]
(S)-(–)-Crispine A: A solution of tetrahydroisoquinoline 9 (110 mg,
0.26 mmol) in EtOH (12 mL) and 1.0  aqueous HCl (0.5 mL) con-
taining 10% Pd/C (15 mg) was hydrogenated with vigorous stirring
at room temperature and atmospheric pressure for 3 d. The catalyst
was removed by filtration, the solvent was concentrated under vac-
uum, and the resulting oil was purified by chromatography with a
cartridge containing amine-functionalized silica (1:1 hexane/
EtOAc) to give crispine A (45 mg, 74%). [α]2D2 = –100.1 (c = 0.32,
CHCl3) {ref.[26] [α]2D2 = –96 (c = 0.25, CHCl )}. IR (KBr): ν =
˜
3
[6]
[7]
2922 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.69–1.78 (m,
1
1 H, 1-H), 1.82–1.99 (m, 2 H, 2-H), 2.30–2.38 (m, 1 H, 1-H), 2.63
(ddd, J = 17.0, 8.0, 8.0 Hz, 1 H, 6-H), 2.69 (m, 1 H, 5-H), 2.74 (m,
1 H, 3-H), 3.00 (ddd, J = 12.4, 9.6, 5.6 Hz, 1 H, 3-H), 3.07 (ddd,
J = 17.0, 8.0, 4.0 Hz, 1 H, 6-H), 3.18 (dddd, J = 17.2, 11.2, 6.4,
2.8 Hz, 1 H, 5-H), 3.49 (m, 1 H, 10b-H), 3.85 (s, 6 H, OCH3), 6.57
(s, 1 H, 10-H), 6.61 (s, 1 H, 7-H) ppm. 13C NMR (75.4 MHz,
CDCl3, 25 °C): δ = 22.3 (C-2), 27.9 (C-6), 30.6 (C-3), 48.2 (C-3),
53.1 (C-5), 55.9 (OCH3), 56.0 (OCH3), 62.8 (C-10b), 108.8 (C-10),
111.3 (C-7), 126.1 (C-6a), 130.5 (C-10a), 147.3 (C-8), 147.4 (C-9)
ppm. HRMS: calcd. for C14H19NO2 [M + H]+ 234.1494; found
234.1486.
[8]
a) M. Amat, J. Bosch, J. Hidalgo, M. Cantó, M. Pérez, N. Llor,
E. Molins, C. Miravitlles, M. Orozco, J. Luque, J. Org. Chem.
2000, 65, 3074–3084; b) M. Amat, C. Escolano, A. Gómez-
Esqué, O. Lozano, N. Llor, R. Griera, E. Molins, J. Bosch,
Tetrahedron: Asymmetry 2006, 17, 1581–1588; c) M. Amat, M.
Pérez, A. T. Minaglia, D. Passarella, J. Bosch, Tetrahedron:
Asymmetry 2008, 19, 2406–2410.
[9]
M. Amat, N. Llor, J. Hidalgo, C. Escolano, J. Bosch, J. Org.
Chem. 2003, 68, 1919–1928.
[10]
[11]
The use of MeMgBr resulted in a lower yield (42%) of α-ami-
doalkylation product 5a.
For related α-amidoalkylation reactions from oxazolopiperi-
done lactams, see: M. Amat, C. Escolano, N. Llor, M. Huguet,
M. Pérez, J. Bosch, Tetrahedron: Asymmetry 2003, 14, 1679–
1683; see also ref.[8b]
Acknowledgments
Financial support from the Ministry of Science and Innovation,
Spain (Project CTQ2009-07021/BQU) and the AGAUR, Genera-
litat de Catalunya (Grant 2009-SGR-111) is gratefully acknowl-
edged.
[12]
[13]
This behavior can be explained in terms of the stereoelectronic
effect: P.-Q. Huang, Synlett 2006, 1133–1149.
For a review, see: a) T. S. Kaufman, Tetrahedron: Asymmetry
2004, 15, 1203–1237; for more recent work, see: b) T. Kanem-
itsu, Y. Yamashita, K. Nagata, T. Itoh, Synlett 2006, 1595–
1597; c) F. Werner, N. Blank, T. Opatz, Eur. J. Org. Chem. 2007,
3911–3915; d) C. Li, J. Xiao, J. Am. Chem. Soc. 2008, 130,
13208–13209.
[1] a) J. D. Phillipson, M. F. Roberts, M. H. Zenk (Eds.), The
Chemistry and Biology of Isoquinoline Alkaloids, Springer,
Berlin, 1985; b) Atta-ur-Rahman (Ed.), Handbook of Natural
Products Data, Elsevier, Amsterdam, 1994, vol. 3; c) D. Jack,
R. Williams, Chem. Rev. 2002, 1669–1730; d) P. M. Dewick in
Medicinal Natural Products, Wiley, Chichester, 2002, pp. 315–
346; e) K. W. Bentley, Nat. Prod. Rep. 2006, 23, 444–463 and
previous reviews in this series.
[14]
For a review, see: A. B. J. Bracca, T. S. Kaufman, Tetrahedron
2004, 60, 10575–10610.
Eur. J. Org. Chem. 2010, 4017–4026
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4025

M. Amat, V. Elias, N. Llor, F. Subrizi, E. Molins, J. Bosch
FULL PAPER
[15] The α-amidoalkylation failed when p-methoxyphenylzinc io-
dide was used, lactam 2 was recovered along with variable
amounts of isoquinolone 3.
[16] For previous enantioselective syntheses, see: a) A. Brossi, S.
Teitel, Helv. Chim. Acta 1971, 54, 1564–1571; b) M. J. Munch-
hof, A. I. Meyers, J. Org. Chem. 1995, 60, 7086–7087; c) H.
Suzuki, S. Aoyagi, C. Kibayashi, Tetrahedron Lett. 1995, 36,
6709–6712; see also ref.[5a,5d]
[17] For previous enantioselective syntheses, see: a) G. Gosmann,
D. Guillaume, H.-P. Husson, Tetrahedron Lett. 1996, 37, 4369–
4372; b) V. Samano, J. A. Ray, J. B. Thompson, R. A.
Mook Jr., D. K. Jung, C. S. Koble, M. T. Martin, E. C. Bi-
gham, C. S. Regitz, P. L. Feldman, E. E. Boros, Org. Lett. 1999,
1, 1993–1996; see also ref.[16a]
[18] For previous enantioselective syntheses, see: a) N. Yamazaki,
H. Suzuki, S. Aoyagi, C. Kibayashi, Tetrahedron Lett. 1996,
37, 6161–6164; b) R. Pedrosa, C. Andrés, J. M. Iglesias, J. Org.
Chem. 2001, 66, 243–250; c) P. Allef, H. Kunz, Heterocycles
2007, 74, 421–436; d) M. K. Pyo, D.-H. Lee, D.-H. Kim, J.-H.
Lee, J.-C. Moon, K. C. Chang, H. S. Yun-Choi, Bioorg. Med.
Chem. Lett. 2008, 18, 4110–4114; see also ref.[13c]
yl}-4,5-dimethoxybenzene (10) was isolated as a byproduct
(39%).
[22]
[23]
Treatment of lactam 2 with allyltrimethylsilane in the presence
of TiCl4 or with 2-(1,3-dioxolan-2-yl)ethylzinc iodide led to iso-
quinolone 3, and the starting lactam was partly recovered in
the latter case.
For previous enantioselective syntheses, see: a) T. R. Wu, M.
Chong, J. Am. Chem. Soc. 2006, 128, 9646–9647; b) J. Szawk-
ato, S. J. Czarnocki, A. Zawadzka, K. Wojtasiewicz, A. Leniew-
ski, J. K. Maurin, Z. Czarnocki, J. Drabowicz, Tetrahedron:
Asymmetry 2007, 18, 406–413; c) S. M. Allin, S. N. Gaskell,
J. M. R. Towler, P. C. B. Page, B. Saha, M. J. McKenzie, W. P.
Martin, J. Org. Chem. 2007, 72, 8972–8975; d) T. Kanemitsu,
Y. Yamashita, K. Nagata, T. Itoh, Heterocycles 2007, 74, 199–
203; e) G.-H. Hou, J.-H. Xie, P.-C. Yan, Q.-L. Zhou, J. Am.
Chem. Soc. 2009, 131, 1366–1367.
[24]
a) T. Kametani in The Total Synthesis of Natural Products (Ed.:
J. ApSimon), Wiley, New York, 1977, vol. 3, pp. 1–272; b) M. J.
Munchhof, A. I. Meyers, J. Org. Chem. 1996, 61, 4607–4610;
see also ref.[1a,1d]
[25] R. P. Polniaszek, C. R. Kaufman, J. Am. Chem. Soc. 1989, 111,
[19] S. V. Kini, M. M. V. Ramana, Tetrahedron Lett. 2004, 45,
4171–4173.
[20] For the enantioselective synthesis of the enantiomer, see:
K. Th. Wanner, I. Praschak, Heterocycles 1989, 29, 29–33.
[21] In this series, the polyallylated compound 1-(2-allyl-2-hydroxy-
4-pentenyl)-2-{1-[2-hydroxy-(1R)-phenylethylamino]-3-buten-
4859–4863.
[26] I. W. Southon, J. Buckingham, Dictionary of Alkaloids, Chap-
man and Hall, London, 1989, p 261.
Received: April 7, 2010
Published Online: June 11, 2010
4026
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4017–4026