Synthesis of enantiomerically pure (S)- and (R)-fluoxetine (Prozac) via a hetero Diels-Alder strategy

Article abstract of DOI:10.1016/j.tetasy.2004.09.009

A new route to enantiomerically pure (R)- and (S)-fluoxetine is described using a hetero Diels-Alder strategy.

Full text of DOI:10.1016/j.tetasy.2004.09.009

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3489–3493
Synthesis of enantiomerically pure (S)- and
(R)-fluoxetine (ProzacÒ) via a hetero Diels–Alder strategy
Mauro Panunzio,a,* Katia Rossi,a Emiliano Tamanini,a,*
Eileen Campanab and Giorgio Martellib
aISOF-CNR Dipartimento di Chimica ‘‘G. Ciamician’’ Via Selmi 2, I-40126 Bologna, Italy
bISOF-CNR Via Gobetti 101, I-40122 Bologna, Italy
Received 22 July 2004; accepted 7 September 2004
Abstract—A new route to enantiomerically pure (R)- and (S)-fluoxetine is described using a hetero Diels-Alder strategy.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Fluoxetine, marketed as racemate under the trade name
ProzacÒ, is a potent and highly selective inhibitor of
neutral serotonin-reuptake and is among the most
important drugs for the treatment of psychiatric disor-
ders and metabolic problems.1 Due to its market value
and the different pharmacological activities displayed
by analogues of fluoxetine, several synthetic methods,
including the enantioselective synthesis of both enantio-
mers, have been reported.2–4 To the best of our knowl-
edge, there has been no report in the literature about
the synthesis of fluoxetine in racemic or enantiomeri-
cally pure form, using a hetero Diels–Alder strategy.5–9
As part of our ongoing research program on hetero
Diels–Alder reactions for the synthesis of useful inter-
mediates in the preparation of biologically active mole-
cules, using as a diene counterpart azadiene 1, we
anticipated that a hetero Diels–Alder (HDA) strategy
would represent a powerful tool in the synthesis of a
three carbon-chain segment10 characterized by the pres-
ence at positions 1 and 3 of the amino and hydroxy
functionalities. Moreover, this strategy may offer con-
siderable opportunities for synthetic manipulations,
including the building-up of a library of analogues of
fluoxetine. Herein we report our preliminary results on
the synthesis of enantiomerically pure (S)- and (R)-
fluoxetine.
Our strategic plane starts from the synthesis11–13 of
azadiene 1 prepared according to an already described
procedure.14–18 Reaction of diene 1 with benzaldehyde
under BF3-etherate mediated reaction conditions, gave
rise to four isomeric products 2, 3, 4 and 5 in 82%
combined yields (Scheme 1). Flash chromatography of
the crude reaction mixture allowed the separation
of the two couples of diastereomeric Diels–Alder
adducts: the adducts 2 and 3 and the adducts 4 and 5
(Scheme 1). All attempts to isolate the epimeric couples
of perhydroxazin-2-ones (2 from 3 and 4 from 5),
although immaterial in our strategic plane (see below),
failed so far. Careful analysis by 1H NMR, NOEÕs
experiments,19 GC–mass spectra of the two diastereo-
meric couples allowed the attribution to each isomer
of the structure depicted in Scheme 1.20 The diastereo-
selectivity of the initial Diels–Alder cycloaddition looks
very poor. This lack of diastereoselectivity could be
explained assuming that the formation of the cycload-
ducts takes place via a competitive stepwise mecha-
nism.21 Final confirmation of the exact attribution was
obtained by processing each couple (2, 3 and 4, 5) to
the known aminols 14 and 15. It is clear that each couple
of epimers was characterized by the same absolute con-
figuration at the C-6 stereocentre and a different config-
uration at the C-2 stereocentre (Scheme 1). This different
configuration of the C-2 stereocentre is irrelevant to our
strategic plan since the stereocentre in C-2 will be de-
stroyed in the final step (Scheme 2). Elaboration of the
two epimeric mixtures to (S) and (R)-fluoxetine was
*
Corresponding authors. Tel.: +39 051 209 9508; fax: +39 051 209
9456; e-mail: mauro.panunzio@unibo.it
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.009

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M. Panunzio et al. / Tetrahedron: Asymmetry 15 (2004) 3489–3493
13.2
H
H
Ph
Ph
H
H
Ph
Ph
14.8
8.6
H
ii
O
6
O
O
6
H
O
5
H
+
H
5
+
2
2
N
H
3
41
N
H
2
O
N
O
N
Me
6
O
O
OTIPS
Me
7
OTIPS
:
OTIPS
OTIPS
59
i
N
TMSO
32%
Ph
OTIPS
13.6
1
H
H
H
H
Ph
3.8
H
Ph
Ph
15.9
ii
O
6
6
O
O
O
5
5
H
H
H
2
+
+
2
N
H
N
Me
N
H
N
Me
O
O
O
O
OTIPS
OTIPS
OTIPS
:
OTIPS
4
54
8
5
46
9
50%
Scheme 1. Reagents and conditions: (i) BF3, PhCHO, CH2Cl2, À78°C to rt; (ii) LiHDSA, MeI, THF, 0°C.
CF3
H
H
Ph
Ph
H
H
Ph
Ph
Ph
Ph
i
i
ii
iii
O
O
OH
O
6 + 7
H
H
+
N
N
Me
NH
Me
NH
Me
Me
OTIPS
OTIPS
10
11
14
(R)-Fluoxetine
CF3
H
H
H
H
Ph
Ph
ii
iii
O
8 + 9
O
OH
O
H
H
+
N
Me
N
Me
NH
Me
NH
Me
OTIPS
OTIPS
12
13
15
(S)-Fluoxetine
Scheme 2. Reagents and conditions: (i) Ph2SiH2, RhH(CO)(PPh3)3; (ii) HClaq; (iii) 4-Cl-Benzotrifluoride, NaH, DMSO, Ref. 23.
our next task. Accordingly, epimeric mixtures of com-
pounds 2 and 3, and 4 and 5 were treated with LiHMD-
SA and methyl iodide in order to get the corresponding
N-methyl derivatives 6, 7 and 8, 9 in quantitative yields.
Reduction of carboxy functionality occurred with diphe-
nyl silane in the presence of catalytic amount of tris(tri-
phenylphosphine)rhodium(I) carbonyl hydride22 to give
the perhydrooxazines, respectively, in yields up to 98%.
Due to their relative instability, the crude reaction mix-
tures of 10, 11 and 12, 13 were used as such in the next
step of our process. Accordingly, final mild ring opening
of these compounds by means of diluted HCl furnished
the enantiomerically pure (1R)-amino alcohol 14 pre-
senting super imposable spectroscopic properties,
including [a]D, with the literature data, in 60% (for ami-
no alcohol 14) and 67% (for amino alcohol 15) overall
yields based on the epimeric mixtures 2 and 3, and 4
and 5, respectively. Final conversion of intermediates
14 and 15 to the title compounds was achieved accord-
ing to literature procedures.23
3. Conclusion
In conclusion we have developed a straightforward con-
vergent synthesis of both enantiomers of fluoxetine by a
hetero Diels–Alder approach. As anticipated, we feel
that this approach is highly adaptable to a parallel syn-
thesis of 3-amino-1-propanol derivatives and allows the
introduction of high molecular diversity at position 1 of
the carbonic skeleton and in the choice of the N- and O-
substituents in the final compounds. Work in this field,
as well as developing high stereocontrol in the first step
of our strategic plan is currently underway.
4. Experimental
1H NMR and 13C NMR spectra were recorded in
CDCl3 on Varian 200MHz or on Varian Gemini
300MHz or on Varian Mercury 400MHz spectrometers.
Chemical shifts are reported in the d scale and coupling

M. Panunzio et al. / Tetrahedron: Asymmetry 15 (2004) 3489–3493
3491
constants (J) reported in hertz. Infrared spectra were
recorded on a Perkin–Elmer spectrum BX spectropho-
tometer. Mass spectra were recorded on Finnigan
MAT GCQ spectrometer. Solvents were distilled
according to standard procedure before use.
(dd, 1H, J1 = 10.8, J2 = 17.6Hz), 1.24 (d, 3H,
J = 6.0Hz), 1.06 (m, 21H); 13C NMR (100MHz,
CDCl3), d: 168.73, 139.61, 128.72, 128.39, 125.56,
84.88, 76.09, 68.64, 39.75, 17.95, 15.74, 12.08; MS
(m/z): 378, 334, 316, 202, 188, 131.
4.1. (2R,6R)-2-((S)-1-Triisopropylsilyloxyethyl)-6-phenyl-
1,3-oxazinan-4-one 2, (2S,6R)-2-((S)-1-triisopropylsilyl-
oxyethyl)-6-phenyl-1,3-oxazinan-4-one 3, (2R,6S)-2-((S)-
1-triisopropylsilyloxyethyl)-6-phenyl-1,3-oxazinan-4-one
4 and (2S,6S)-2-((S)-1-triisopropylsilyloxyethyl)-6-phen-
yl-1,3-oxazinan-4-one 5
Compound 3: IR (neat, cmÀ1): 3201, 2942, 2866, 1675,
1463; 1H NMR (400MHz, CDCl3), d: 7.37 (m, 5H),
6.39 (br s, 1H), 5.14 (pt, 1H, J = 5.6Hz), 4.36 (dd, 1H,
J1 = 1.2, J 2 = 6.4Hz), 3.97 (qt, 1H, J = 6.4Hz), 2.85
(dd, 1H, J1 = 5.6, J2 = 16.8Hz), 2.75 (dd, 1H,
J1 = 6.4, J2 = 16.8Hz), 1.23 (d, 3H, J = 6.4Hz), 1.06
(m, 21H); 13C NMR (100MHz, CDCl3), d: 168.46,
138.66, 128.72, 128.39, 126.53, 83.32, 72.16, 70.54,
36.53, 19.69, 18.05, 12.51; MS (m/z): 334, 202, 187 131.
A solution of (2S)-2-(triisopropylsilyloxy)-N-(trimethyl-
silyl) propanimine was prepared by the dropwise addi-
tion of lithium bis(trimethylsilyl)amide (1M in THF,
1.10mmol, 1.10mL) to a cooled (0 °C) hexane solution
(5mL) of (2S)-2-(triisopropylsilyloxy)propionaldehyde
(0.23g, 1.00mmol). The reaction mixture was stirred
for 40min at the same temperature. Trimethylsilyl chlo-
ride (1.10mmol, 0.15mL) was added in one portion and
this solution stirred for 15min at 0°C and then for 1h at
room temperature. The mixture was cooled at 0°C and
triethylamine (2.20mmol, 0.30mL) added in one por-
tion. After stirring this mixture for 5min at 0°C, acetyl
chloride (1.10mmol, 78 lL) was slowly added by syr-
inge. Stirring was maintained for 15min at 0°C and then
1.5h at room temperature. The yellow solution was fil-
tered through Celite and the solvent removed in vacuo
to give 3-trimethylsilyloxy-2-azadiene 1 as a yellow oil.
IR (neat, cmÀ1): 2944, 2867, 1684, 1577, 1464. 1H
NMR (300MHz, CDCl3), d: 7.83 (d, 1H, J = 6.0Hz),
4.45 (m, 1H), 4.42 (s, 1H), 4.19 (s, 1H), 1.34 (d, 3H,
J = 6.6Hz), 1.02 (m, 21H), 0.21 (s, 9H).
4.2. (2R,6S)-tert-Butyl 2-((S)-1-triisopropylsilyloxy-
ethyl)-4-oxo-6-phenyl-1,3-oxazinane-3-carboxylate 16
and (2S,6S)-tert-butyl 2-((S)-1-triisopropylsilyloxyethyl)-
4-oxo-6-phenyl-1,3-oxazinane-3-carboxylate 17
t-Boc derivatives were obtained, in quantitative yields,
by the addition of t-Boc anhydride (2.0equiv, 436mg),
TEA (2.0equiv, 0.3mL) and DMAP (cat.) to a CH 2Cl2
(10mL) solution of perhydrooxazin-2-one 4 and 5
(1.00mmol, 377mg) at room temperature. The solution
obtained was stirred for 12h. The reaction was
quenched with a saturated solution of NH4Cl and ex-
tracted with CH2Cl2. The collected organic phases were
dried over Na2SO4 and the solvent removed in vacuo.
The diastereoisomers 16 and 17 were separated by flash
chromatography on silica gel (eluents cyclohexane/ethyl
acetate 9:1).
Compound 16: oil. [a]D = +20.3 (c = 0.89, CHCl3); IR
(neat, cmÀ1): 2939, 2859, 1772, 1719, 1447, 1387, 1367;
1H NMR (300MHz, CDCl3), d: 7.40(m, 5H), 5.90
(dd, 1H, J1 = 6.0, J2 = 9.0Hz), 5.44 (d, 1H, J = 2.7Hz),
4.55 (m, 1H), 2.73 (m, 2H), 1.56 (s, 9H), 1.40(d, 3H,
J = 6.6Hz), 1.12 (m, 21H); 13C NMR (75MHz, CDCl3),
d: 167.46, 151.36, 140.69, 128.68, 128.17, 125.56, 87.09,
83.18, 72.63, 71.15, 41.62, 27.98, 19.02, 18.08, 12.70.
Anal. Calcd for C26H43NO5Si: C, 65.37; H, 9.07. Found:
C, 65.42; H, 9.09.
To a cooled (À78°C) solution of PhCHO (1.00mmol,
0.102mL) in CH2Cl2 (10mL) was added BF3–Et2O
(1.00equiv, 0.160mL). The mixture was stirred for
10min and then 3-trimethylsilyloxy-2-azadiene
1
(2.0equiv, 2.00mmol in 5mL of CH Cl2) slowly added.
2
The reaction mixture was stirred for 8h while the tem-
perature was allowed to reach room temperature. The
reaction was quenched with a saturated solution of
NaHCO3 (aq), extracted with CH2Cl2, the organic phase
dried over Na2SO4 and the solvent removed in vacuo.
The crude reaction mixture was chromatographed on
silica gel (eluents cyclohexane/ethyl acetate 6/4) and
the oily products separated as the couple of diastereoiso-
mers 2, 3 and 4, 5 in a 40:60 ratio and 82% overall yield.
Within each couple the ratio between the two isomers
was 59:41 for the 2, 3 couple and 54:46 for the 4, 5
couple.
Compound 17: oil. [a]D = À103.9 (c = 0.79, CHCl3); IR
(neat, cmÀ1): 2943, 2866, 1775, 1718, 1457, 1391, 1369;
1H NMR (300MHz, CDCl3), d: 7.40(m, 5H), 5.56 (d,
1H, J = 2.4Hz), 4.90(dd, 1H, J1 = 3.0, J2 = 11.0Hz),
4.32 (m, 1H), 2.80(m, 2H), 1.58 (s, 9H), 1.29 (d, 3H,
J = 6.3Hz), 1.10(m, 21H); 13C NMR (75MHz, CDCl3),
d: 168.09, 151.67, 139.29, 128.49, 127.98, 125.29, 89.22,
83.89, 73.22, 69.22, 42.09, 27.82, 17.96, 16.87, 12.44.
Anal. Calcd for C26H43NO5Si: C, 65.37; H, 9.07. Found:
C, 65.40; H, 9.08.
1
A careful analysis of the H and 13C NMR (400MHz),
making large use of decoupling and NOEÕs technique
allowed the attributions of each series of signals to the
corresponding isomer.
4.3. Synthesis of oxazinones 4 and 5 form t-Boc deriva-
tives 16 and 17 (Scheme 3)
Compound 2: IR (neat, cmÀ1): 3201, 2942, 2866, 1675,
1463; 1H NMR (400MHz, CDCl3), d: 7.30(m, 5H),
6.37 (br s, 1H), 5.07 (d, 1H, J = 3.6Hz), 4.86 (dd, 1H,
J1 = 4.4, J2 = 10.8Hz), 4.19 (dq, 1H, J1 = 3.6,
J2 = 6.0Hz), 2.68 (dd, 1H, J1 = 4.4, J2 = 17.6Hz), 2.61
To a solution of t-Boc derivative 16 (or 17) (1mmol) in
CH2Cl2 (5mL) was added a solution of CF3COOH 20%
in CH2Cl2 (5mL). The solution was stirred for 5min at
room temperature and then quenched with NaHCO3

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M. Panunzio et al. / Tetrahedron: Asymmetry 15 (2004) 3489–3493
1
mixture was controlled by H NMR analysis and used
without purification for the next step. Yield >98%.
Ph
H
O
iii
ii
H
8
9
4
5
N
Boc
16
Ph
O
i
4.5. (2R,6S)-2-((S)-1-Triisopropylsilyloxyethyl)-3-
methyl-6-phenyl-1,3-oxazinan-4-one 8 and (2S,6S)-2-((S)-
1-triisopropylsilyloxyethyl)-3-methyl-6-phenyl-1,3-oxaz-
inan-4-one 9
OTIPS
4 + 5
H
O
iii
ii
H
N
Boc
Following the same procedure but using 4 and 5, com-
pounds 8 and 9 were prepared in quantitative yields.
O
OTIPS
17
Compound 8: oil. [a]D = À15.2 (c = 1.50MeOH); IR
1
(neat, cmÀ1): 3201, 2942, 2866, 1675, 1463; H NMR
Scheme 3. Reagents and conditions: (i) (t-Boc)2O, TEA, DMAP
(98%); (ii) CF3COOH (20% in DCM) 98%; (iii) see Scheme 1.
(200MHz, CDCl3), d: 7.30(m, 5H), 5.61 (pt, 1H,
J = 6.2Hz), 4.91 (d, 1H, J = 2.2Hz), 4.22 (m, 1H), 2.90
(s, 3H), 2.62 (m, 2H), 1.26 (d, 3H, J = 6.6Hz), 1.01
(m, 21H); 13C NMR (50MHz, CDCl3), d: 167.42,
139.74, 128.69, 128.19, 126.02, 88.85, 72.40, 69.74,
37.88, 30.47, 18.86, 18.05, 12.48; MS (m/z): 338
(M+À43), 216, 190, 131. Anal. Calcd for C22H37NO3Si:
C, 67.47; H, 9.52. Found: C, 67.54; H, 9.54.
satd after which it was extracted with CH2Cl2. The
organic phases were dried over Na2SO4 and concen-
trated in vacuo to give product 4 (or 5) in quantitative
yield (Scheme 3).
Compound 4: oil. [a]D = +49.5 (c = 0.80, CHCl3); IR
Compound 9: oil. [a]D = À62.5 (c = 0.92 CHCl3); IR
1
(neat, cmÀ1): 3201, 2942, 2866, 1675, 1463; H NMR
1
(neat, cmÀ1): 3201, 2944 2871, 1675, 1463; H NMR
(400MHz, CDCl3), d: 7.35 (m, 5H), 6.22 (br s, 1H),
5.26 (dd, 1H, J1 = 3.6, J2 = 6.0Hz), 4.57 (d, 1H,
J = 3.2Hz), 3.96 (dq, 1H, J1 = 3.2, J2 = 6.0Hz), 2.91
(dd, 1H, J1 = 6.0, J2 = 17.2Hz), 2.79 (dd, 1H, J1 = 3.6,
J2 = 17.2Hz), 1.19 (d, 3H, J = 6.0Hz), 0.90(m, 21H);
13C NMR (100MHz, CDCl3), d: 168.98 137.77,
128.68, 128.58, 127.08, 80.35, 72.75, 68.90, 35.38,
18.09, 17.09, 11.98. MS (m/z): 334, 202, 187, 131. Anal.
Calcd for C21H35NO3Si: C, 66.80; H, 9.34. Found: C,
66.88; H, 9.35.
(200MHz, CDCl3), d: 7.30(m, 5H), 4.82 (d, 1H,
J = 2.5Hz), 4.78 (dd, 1H, J1 = 2.2, J2 = 11.4Hz), 4.22
(m, 1H), 2.88 (s, 3H), 2.80–2.42 (m, 2H), 1.16 (d, 3H,
J = 6.2Hz), 1.00 (m, 21H); 13C NMR (50MHz, CDCl3),
d: 168.51, 139.87, 128.60, 127.85, 125.43, 90.75, 73.59,
68.84, 40.17, 29.57, 18.21, 16.54, 12.60; MS (m/z): 338
(M+À43), 216, 190, 131. Anal. Calcd for C22H37NO3Si:
C, 67.47; H, 9.52. Found: C, 67.35; H, 9.50.
4.6. (2R,6R)-2-((S)-1-Triisopropylsilyloxyethyl)-3-
methyl-6-phenyl-1,3-oxazinane 10 and (2S,6R)-2-((S)-1-
triisopropylsilyloxyethyl)-3-methyl-6-phenyl-1,3-oxazin-
ane 11
Compound 5: oil. [a]D = À37.3 (c = 0.82, CHCl3); IR
1
(neat, cmÀ1): 3201, 2942, 2866, 1675, 1463; H NMR
(400MHz, CDCl3), d: 7.36 (m, 5H), 6.53 (br s, 1H),
4.83 (dd, 1H, J1 = 3.6, J2 = 12.0Hz), 4.61 (d, 1H,
J = 6.8Hz), 3.90(m, 1H), 2.71 (dd, 1H, J 1 = 3.6,
J2 = 17.2Hz), 2.59 (dd, 1H, J1 = 12.0, J2 = 17.2Hz),
1.33 (d, 3H, J = 6.4Hz), 1.09 (m, 21H). 13C NMR
(100MHz, CDCl3), d: 168.10, 139.86, 128.63, 128.17,
125.44, 87.51, 76.04, 71.45, 39.29, 19.72, 18.11, 12.65;
MS (m/z): 334, 202, 187, 131. Anal. Calcd for
C21H35NO3Si: C, 66.80; H, 9.34. Found: C, 66.92 H,
9.38.
Ph2SiH2 (2.5equiv, 0.461mL) and RhH(CO)(PPh3)3
(1%) were added to a solution of 6 and 7 (1.0mmol,
391mg) in THF (10mL) at room temperature and the
stirring maintained for 15h. THF was removed in vacuo,
HCl (1M) added and the reaction extracted with Et2O.
The aqueous phase was neutralized with NaOH (5M)
(pH = 10–12) and then extracted with Et2O. The organic
phases were dried over Na2SO4 and the solvent evapo-
rated. The crude reaction mixture obtained was used
without purification for the last step of the synthesis.
4.4. (2R,6R)-2-((S)-1-Triisopropylsilyloxyethyl)-3-
methyl-6-phenyl-1,3-oxazinan-4-one 6 and (2S,6R)-2-
((S)-1-triisopropylsilyloxyethyl)-3-methyl-6-phenyl-1,3-
oxazinan-4-one 7
Following the same protocol but using a solution of 8
and 9, compounds 12 and 13 were prepared.
4.7. (R)-3-(Methylamino)-1-phenylpropan-1-ol 14
To a solution of 2 and 3 (1.00mmol, 377mg) in THF
(10mL) at 0 °C was added HMDSLA (1M in THF,
1.0equiv, 1.0mL). The reaction was stirred for 20min,
MeI (8equiv, 0.498mL) added and the solution warmed
to room temperature. Stirring was then maintained for
2h at the same temperature. A saturated solution of
NH4Cl was added, the organic solvent removed in vacuo
and the obtained aqueous solution extracted with
AcOEt. The organic phases were collected, dried over
Na2SO4 and concentrated in vacuo. The crude reaction
To a solution of 10 and 11 in MeOH (10mL) was added
HCl (1M) (5mL/mmol) and the mixture heated at 90°C
for 1.5h. The solution was cooled at room temperature,
after which MeOH was removed in vacuo and the aque-
ous solution extracted with Et2O. The aqueous solution
was neutralized with NaOH (5M) and extracted with
CH2Cl2. The organic phases were collected, dried over
Na2SO4 and the solvent removed in vacuo to give prod-

M. Panunzio et al. / Tetrahedron: Asymmetry 15 (2004) 3489–3493
3493
9. Weinreb, S. M. Heterodienophile Additions to Diene In
Comprehensive Organic Synthesis; Paquette, L. A., Ed.;
Pergamon: Oxford, 1991; Vol. 5, p 401.
10. Hilborn, J. W.; Lu, Z.-H.; Jurgens, A. R.; Fang, Q. K.;
Byers, P.; Wald, S. A.; Senanayake, C. H. Tetrahedron
Lett. 2001, 42, 8919–8921.
uct 14 as a pure enantiomer. Yield: 60%, 14: oil.
[a]D = +37.5 (c = 1.2, CHCl3). IR (neat, cmÀ1): 3303,
3061, 2938, 2854, 1492. H NMR (300MHz, CDCl3),
d: 7.30(m, 5H), 4.95 (dd, 1H, J1 = 3.3, J2 = 8.7Hz),
4.20(br s, 2H), 2.88 (m, 2H), 2.46 (s, 3H), 1.85 (m,
2H). 13C NMR (75MHz, CDCl3), d: 145.02, 128.14,
126.86, 125.54, 75.27, 50.21, 36.75, 35.82.
1
11. Jayakumar, S.; Ishar, M. P.; Mahajan, M. P. Tetrahedron
2002, 58, 379–471.
12. Barluenga, J.; Suarez-Sobrino, A.; Lopez, L. A. Aldrichim.
Acta 1999, 32, 4–15.
4.8. (S)-3-(Methylamino)-1-phenylpropan-1-ol 15
13. Panunzio, M.; Vicennati, P. From 3-Trialkylsilyloxy-2-
aza-1,3-dienes to Biological Interesting Molecules through
Cyclization Reactions. In Recent Research Development in
Organic Chemistry; Pandalai, S. G., Ed.; Transworld
Research Network: Trivandrum, India, 2002; Vol. 6, pp
683–707.
This compound was prepared starting from the diaste-
reomeric mixture 8 and 9, following the protocol de-
scribed for compound 14. Yield: 67%.
Compound 15: oil. [a]D = À36.0( c = 1.0, CHCl3); IR
14. Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.;
Panunzio, M. Synlett 1999, 1735–1738.
1
(neat, cmÀ1): 3303, 3061, 2938, 2854, 1492; H NMR
(300MHz, CDCl3), d: 7.30(m, 5H), 4.95 (dd, 1H,
J1 = 3.3, J2 = 8.7Hz), 4.20(br s, 2H), 2.88 (m, 2H), 2.46
(s, 3H), 1.85 (m, 2H); 13C NMR (75MHz, CDCl3), d:
145.02, 128.14, 126.86, 125.54, 75.27, 50.21, 36.75, 35.82.
15. Sainte, F.; Serckx-Poncin, B.; Ghosez, L. J. Am. Chem.
Soc. 1982, 104, 1428–1430.
16. Ghosez, L.; Bayard, P.; Nshimyumukiza, P.; Gouverneur,
V.; Sainte, F.; Beaudegnies, R.; Rivera, M.; Frisque-
Hesbain, A. M.; Wynants, C. Tetrahedron 1995, 51,
11021–11042.
17. Ntirampebura, D.; Ghosez, L. Tetrahedron Lett. 1999, 40,
7079.
Acknowledgements
18. Ntirampebura, D.; Ghosez, L. Synthesis 2002, 2043–
2052.
E.T. thanks GSK-(Verona, Italy) for financial support.
We are indebted to Dr. Elisa Bandini for helpful discus-
19. No NOEÕs effects between the C2H and C6H were
observed for products 3 and 4. The NOEÕs effect, between
the C2H and C6H, for product 2 was determined by
identifying and irradiating the corresponding signals in the
1H NMR spectra of the mixture of isomers 2 and 3.
20. A confirmation of the correct structuresÕ attributions
depicted in Scheme 1 come from the sequence of reactions
reported (Scheme 3). Unfortunately, due to difficulty in
separating the two Boc derivatives of 2 and 3 by flash
chromatography, this sequence could not be repeated for
those last compounds.
1
sion on H, 13C NMR data interpretations.
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