5-Phenylthio-1,3-oxazinan-4-ones via hetero Diels-Alder reactions: synthesis of (R)- and (S)-Duloxetines and Fluoxetines

Article abstract of DOI:10.1016/j.tet.2006.10.006

The synthesis of 5-phenylthio-1,3-oxazinan-4-ones, through a hetero Diels-Alder strategy, is described. The cycloadducts thus prepared have been shown to be useful intermediates for the synthesis of 1,3-aminoalcohols, valuable intermediates in the preparation of biologically significant molecules, e.g., optically active Duloxetines and Fluoxetines. In the course of this elaboration a novel microwave assisted desulfurization reaction is reported.

Full text of DOI:10.1016/j.tet.2006.10.006

Tetrahedron 62 (2006) 12270–12280
5-Phenylthio-1,3-oxazinan-4-ones via hetero Diels–Alder
reactions: synthesis of (R)- and (S)-Duloxetines
and Fluoxetines
a
b
Mauro Panunzio,a, Emiliano Tamanini, Elisa Bandini,
*
Eileen Campana,b Antonio D’Auriziob and Paola Vicennatib,
*
aI.S.O.F-C.N.R. Department of Chemistry, University of Bologna, ‘G. Ciamician’ Via Selmi 2, 40126 Bologna, Italy
bI.S.O.F-C.N.R. Via Gobetti 101, 40122 Bologna, Italy
Received 22 July 2006; revised 21 September 2006; accepted 5 October 2006
Available online 27 October 2006
Abstract—The synthesis of 5-phenylthio-1,3-oxazinan-4-ones, through a hetero Diels–Alder strategy, is described. The cycloadducts thus
prepared have been shown to be useful intermediates for the synthesis of 1,3-aminoalcohols, valuable intermediates in the preparation of
biologically significant molecules, e.g., optically active Duloxetines and Fluoxetines. In the course of this elaboration a novel microwave
assisted desulfurization reaction is reported.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
a hetero Diels–Alder strategy, may be adopted as useful
intermediates for the preparation of 1,3-aminoalcohols. In
continuation of our studies on the use of hetero Diels–Alder
strategy in the synthesis of heterocyclic compounds with
different substitution pattern and their use for the preparation
of acyclic derivatives we would like to present here our
recent results on the synthesis and use of the 5-phenylthio-
perhydrooxazinan-4-ones in the preparation of racemic and
optically active 1,3-aminoalcohols. Compared to the previ-
ously reported studies in the same field, we anticipated that
the synthesis of the 5-phenylthio-substituted oxazinan-4-
ones may have its importance if the position five of the het-
erocyclic adduct is substituted by an easily removable group,
as the thiophenyl one. Moreover, the intrinsic important reac-
tivity of this functionality would allow further elaborations,
e.g., introduction of an extra group and/or functionalities.
As an example, the parent acyclic b-hydroxy-a-phenylthio-
carboxy derivatives17–20 have been shown to be useful inter-
mediates for the synthesis of 1,3-aminoalcohols.21,22
Hetero Diels–Alder cycloaddition is a versatile strategy
for the synthesis of natural compounds containing six-
membered heterocyclic rings.1–9 Moreover, this strategy has
found important applications through the elaboration of the
cyclic adducts thus obtained to acyclic compounds with
a well-defined stereo- and regio-control of the present func-
tionalities. Reported herein is the application of hetero
Diels–Alder methodology to the synthesis of open-chain
compoundscontainingthe1,3-hydroxy-aminomoiety,which
is present in a large class of pharmaceutically important com-
pounds such as Duloxetine (CymbaltaÒ)10–12 and Fluoxetine
(ProzacÒ).13,14 Prozac and Cymbalta have been chosen as
target compounds being potent and highly selective inhibi-
tors of neutral serotonin-reuptake and among the most
important drugs for the treatment of psychiatric disorders
and metabolic problems. Last but not the least, their market
is very interesting from an industrial point of view.15 As a
matter of fact the establishment of new synthetic protocols,
which allow the building-up of small libraries, with an easily
obtainable different substitution pattern on the scaffold, is
of primary importance for researchers involved in the prepa-
ration and the study of this class of compounds. Recent
disclosure from these laboratories16 have demonstrated
that 5-unsubstituted perhydrooxazinan-4-ones, obtained via
2. Results and discussion
2.1. Synthesis of racemic 5-thiophenyl-1,3-oxazinan-
4-ones
5-Phenylthio-1,3-oxazinan-4-ones have been obtained
from the easily available 1,3-azadienes,23–28 prepared from
silylimines and ketenes, and using aldehydes as dienophiles.
In the present study, the starting azadiene is a neutral
Keywords: Hetero Diels–Alder; 1,3-Amino-alcohols; Prozac; Duloxetine.
* Corresponding authors. Tel.: +39 051 209 9508; fax: +39 051 209 9456;
e-mail addresses: mauro.panunzio@unibo.it; vicennati@isof.cnr.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.006

M. Panunzio et al. / Tetrahedron 62 (2006) 12270–12280
12271
3-trimethylsilyloxy-4-thioaryl-2-aza-1,3-diene, already used
in a previous study for the preparation of a b-lactam ring
by a 4p-conrotatory electrocyclization.29
mechanism (hetero Diels–Alder vs a competitive open-chain
Mukaiyama mechanism37) and taking into account that, as
already known,38–40 an equilibrium between the cyclic per-
hydrooxazinan-4-ones and the open-chain derivatives may
exist (Scheme 2), extra experiments were performed. Treat-
ment of pure 3a with an excess of BF3 etherate in methylene
chloride for 4 h at room temperature gives rise to a mixture
of 3a and 4a in 90/10 diastereomeric ratio as evaluated by 1H
NMR spectroscopic analysis. This is, in our opinion, a clear
evidence that some degree of isomerization could take place
after the formation of the Diels–Alder adduct thus suggest-
ing the exclusion of a different reaction mechanism (e.g., a
competitive Mukaiyama type addition–cyclization two-step
mechanism). A further confirmation of this working hypo-
thesis comes out from the results obtained when a hydroxy-
alkyl group, which should not favor the formation of a
positive charge, is present on the C2 stereocenter (hetero-
cyclic numbering). As a matter of fact in this case only
two products were obtained (vide infra): they have the
same basket conformation for the C2, C5, and C6 hydrogen
atoms and differ for opposite absolute configuration of these
centers. Nevertheless, it must be pointed out that these spec-
ulations are interesting from a mechanistic point of view but
useless from a practical one since this isomerization is
immaterial in our strategic plan because of the loss of the
C2 stereogenic center in the final products (see Schemes 3
and 4). For this reason no more investigations, so far, have
been undertaken.
In detail, reaction of the neutral azadiene 1 with an aldehyde
R1CHO 2, in the presence of a stoichiometric amount of
boron trifluoride etherate in dichloromethane (DCM) at
ꢀ78 ꢁC, gives rise to the formation of the expected 5-phe-
nylthio-1,3-oxazinan-4-ones 3 and 4 with various substitu-
tion patterns at the C2 and the C6 carbon atoms (Scheme 1
and Table 1).30–35 The results shown in Scheme 1 and Table 1
warrant some comments. (1) No traces of azedinones,
arising from a 4p-conrotatory electrocyclization, have
been detected in the crude reaction mixtures.29,36 (2) All
the reactions are completely regioselective. (3) The use of
an excess of Lewis acid does not influence the reaction
course since the value of the diastereomeric ratio as well
as that of the yield remains substantially untouched (Table 1
entry 2). (4) In all the experiments performed, irrespective of
the starting azadiene and the dienophilic aldehyde used,
a cis-relationship between the C5H and C6H is established,
shown by the relative coupling constants (Jcis¼2–4 Hz)
and NOE experiments. Careful analysis of the results
reported in Table 1 clearly allows to allocate, from the
stereochemical relationship of C2H–C5H–C6H, two groups
of cycloadducts: one (compounds 3a–3f) presenting the
three ring-protons in a basket conformation and an other
group (compounds 4a–4f) presenting the same cis-configu-
ration between the C5H and C6H but a trans-relationship be-
tween C2H and C5H as pointed out by the combined analysis
of coupling constants and NOEs. In order to ascertain if this
stereo-difference originates from a different cyclization
Ph
Ph
H
O
H
O
H
H
BF3
H
BF3
H
PhS
PhS
N
H
N
H
O
Ph
O
Ph
PhS
H
N
R
H
R
H
H
.
3a BF
.
4a BF
i
3
3
N
O
Ph
TMSO
R
H
OBF3
TMS
R1
H
1
PhS
R1
N
H
O
PhS
PhS
+
ii
O
O
N
H
R
N
H
O
O
R
Scheme 2.
3
4
Scheme 1. Reagents and conditions: (i) Ref. 29; (ii) R1CHO (2), DCM,
BF3$Et2O.
Ph
Ph
Ph
6
PhS
i
ii
iii
6
6
O
O
R
O
5
R
R1
5
5
R
Table 1. Synthesis of perhydrooxazinan-2-ones 3 and 4
2
2
2
N
H
N
H
R1
N
R1
CO2Me
O
O
O
Exps.
R
R1
Azadiene Products Ratio Ys, %a
1
2
Ph
Ph
Ph
Ph
S
1a
1a
3a/4a
3a/4a
90/10 35
74/26 33b
3a: R=Ph, R1=H
4a: R=H, R1=Ph
7a: R=Ph, R1=H
8a: R=H, R1=Ph
5a: R=Ph, R1=H
6a: R=H, R1=Ph
3
Ph
1a
3b/4b
40/60 38
4
5
6
p-MeO–Ph
o-TIPSO–Ph
Ph
Ph
Ph
Me
1b
1c
1a
3c/4c
3d/4d
3e/4e
80/20 55
85/15 48
50/50 51
CF3
Ph
Ph
Ph
OH
OH
O
Boc
iv
v
NH
Me
( )
10a
N
Me
Ph
N
NH
Me
-11a-Prozac
7
Ph
1a
3f/4f
40/60 41
9a
a
The yields have been calculated on the dienophilic aldehyde.
BF3$Et2O (5 equiv) has been used.
Scheme 3. Reagents and conditions: (i) MW, Nickel-Raney/EtOH; (ii)
LiHMDS, ClCOOMe, THF; (iii) LiAlH4/THF; (iv) Ref. 40; (v) Ref. 41.
b

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M. Panunzio et al. / Tetrahedron 62 (2006) 12270–12280
8b. Reduction of the amide functionality by means of
S
S
S
Ph2SiH2, in the presence of 1 mol % RhH(CO)(PPh3)3 in
THF,52 resulted in the production of the partially unstable
intermediates 9b and 10b. Ring opening by aqueous
hydrochloric acid furnished the corresponding aminol
11b. (ꢂ)-Duloxetine was obtained by means arylation of
11b according to a literature procedure (Scheme 4).50
PhS
6
6
6
O
O
i
O
ii
iii
5
5
R
R1
5
R
R
2
2
2
N
H
N
H
R1
N
R1
O
O
O
Me
3b: R=Ph, R1=H
4b: R=H, R1=Ph
7b: R=Ph, R1=H
5b: R=Ph, R1=H
6b: R=H, R1=Ph
8b: R=H, R1=Ph
2.3. Synthesis of optically active 5-thiophenyl-
substituted oxazinan-4-ones
S
S
S
OH
O
R
Owing to the different biological activity exhibited by
individual enantiomers of Prozac and Duloxetine, a number
of enantioselective syntheses of these important compounds
have been developed in recent years.53–55,50,56 In this section
we report the results obtained by our group in the synthesis
of optically active aminoalcohols 10a and 11b and,
therefore, of optically active (R)- and (S)-Fluoxetines and
Duloxetines [(R)-11a, (S)-11a and (R)-12b, (S)-12b, respec-
tively]. To reach this task and taking advantage of our
experience on the synthesis of optically active perhydro-
oxazinan-4-ones by hetero Diels–Alder strategy, we pre-
pared optically active azadiene 1d using, in its preparation,
the trimethylsilylimine derived from optically active (S)-
lactic aldehyde and the 2-phenylthioacetylchloride as source
of the ketene (Scheme 5). Reaction of the optically active
azadiene 1d with a range of aldehydes furnished two oxa-
zinan-4-ones 13 and 14 in diastereomeric ratios and yields
reported in Table 2. The two diastereoisomers presented
the same basket conformation for the protons on the hetero-
cyclic ring but an opposite absolute configuration of the C2,
C5, and C6 stereocenters.
iv
O
v
N
R1
NH
Me
NH
Me
Me
9b: R=Ph, R1=H
10b: R=H, R1=Ph
( )
-12b(Duloxetine)
11b
Scheme 4. Reagents and conditions. (i) aluminum amalgam, i-PrOH; (ii)
;
LiHMDS, MeI, THF; (iii) Ph2SiH2, RhH(CO)(PPh3)3, THF; (iv) HClaq
(v) Ref. 49.
2.2. Synthesis of racemic ( )-Prozac and ( )-Duloxetine
Having the desired perhydrooxazinones in hand, we fol-
lowed our strategic plan by elaboration of the diastereomeric
mixture of compounds 3a/4a and 3b/4b to the racemic (ꢂ)-
Prozac and (ꢂ)-Duloxetine, respectively.
The synthetic protocols are outlined in Schemes 3 and 4.
Compounds 3a and 4a were easily desulfurated by the use of
Nickel-Raney in a novel microwave-mediated41–45 desulfur-
ization reaction.18,46–49 Thus treatment of adducts 3a and 4a
with Raney-Nickel in a microwave oven allows to obtain, in
a very short time (2 min) and high yields (80% and 92%,
respectively), the corresponding desulfurated derivatives
5a and 6a. N-Carboxymethyl derivatives 7a and 8a were
obtained in quantitative yields by treatment of 5a and 6a
with methyl chloroformate and LiHMDS in THF. Reduction
of the amide and carboxymethyl functionalities with lithium
aluminum hydride gave rise to open-chain N-benzyl deriva-
tive 9a. Following already known procedures, this inter-
mediate was easily converted to the racemic Prozac via
hydrogenolysis of the benzyl group and arylation of the
hydroxy functionality.50 It must be stressed that the same
synthetic protocol, applied to the diastereomeric mixture
of 3a and 4a, gave the same results in terms of yields of
the overall process. By the same strategy, with slight modi-
fications, (ꢂ)-Duloxetine was prepared. Desulfuration of
oxazinan-4-ones 3b and 4b by the above reported micro-
wave-mediated Nickel-Raney methodology partially failed
when applied to these compounds giving rise to low yields
of the desired 5-unsubstituted derivatives 5b and 6b, proba-
bly due to side reactions on the thienyl ring. Different proce-
dures, known in the literature to give good results, failed
partially or completely. Finally we have found that desulfur-
ation with aluminum amalgam51 was the method of choice.
Once we prepared the derivatives 5b and 6b, their elabora-
tion to the final (ꢂ)-Duloxetine was a straightforward task.
Methylation by LiHMDS and methyl iodide gave rise, in
quantitative yields, to the N-methyl intermediates 7b and
PhS
OTIPS
H
H
i
ii
H
N
TMSO
O
OTIPS
1d
H
H
R
O
R
O
H
H
+
PhS
H
PhS
H
N
H
N
H
O
O
OTIPS
OTIPS
13
14
Scheme 5. Reagents and conditions: (i) Ref. 29; (ii) RCHO (2), DCM,
BF3$Et2O.
Table 2. Synthesis of oxazinan-4-ones 13 and 14
Exps.
R
Products
Ratioa
Ys, %b
1
2
Ph
S
13a/14a
13b/14b
50/50
60/40
81
90
3
4
Me
13c/14c
13d/14d
50/50
50/50
32
41
Boc
N
5
13e/14e
63/37
55
a
Diastereomeric ratios have been determined on the crude reaction mix-
tures to avoid enrichments in the course of purification processes.
The yields have been calculated on the dienophilic aldehyde.
b

M. Panunzio et al. / Tetrahedron 62 (2006) 12270–12280
12273
2.4. Synthesis of (R)- and (S)-Fluoxetines and (R)- and
(S)-Duloxetines
to the target (S)- and (R)-Fluoxetines has been already
described in a previous paper (Scheme 6).16 On the other
hand elaboration of compounds 13b and 14b to the (S)- and
(R)-Duloxetines was performed according to the protocol
described for the racemic compound. Thus, desulfuration
by means of aluminum amalgam followed by N-methylation
(LiHMDS, CH3I), amide functionality reduction, and final
arylation with fluoronaphthalene furnished the (S)- and
(R)-Duloxetines (Scheme 7).
Once again, having in hand the desired heterocyclic com-
pounds, we followed our strategic plan, aimed to obtain
enantiomerically pure (S)- and (R)-Fluoxetines and (S)-
and (R)-Duloxetines by elaboration of compounds 13a and
14a and compounds 13b and 14b to optically active amino-
alcohols (1S)-10a, (1R)-10a and (1S)-11b, (1R)-11b, respec-
tively. Conversion of compounds 13a and 14a to the (S)- and
(R)-Fluoxetines proved to be an easy task. Accordingly,
compounds 15a and 16a were easily obtained in quantitative
yields by desulfuration of 13a and 14a as already described
for the racemic derivatives by means of microwave assisted
Raney-Nickel delsufuration. Elaboration of 15a and 16a
3. Conclusions
In conclusion we have reported an extra contribution to
the applications of azadienes of type 1 in the synthesis of
valuable intermediates for the preparation of biologically
significant molecules. Moreover, the 5-thio-substituted cy-
clic adducts thus obtained may be considered as cyclic form
of a-thio-carboxylic acid derivatives and, accordingly, may
undergo further elaborations. Studies in this vein are cur-
rently in progress. Finally, the novel microwave assisted de-
sulfuration herein described, represents a valuable method,
alternative to those available for this task (e.g., use of expen-
sive and toxic tributyltin hydride). Its application to other
significant classes of compounds is in progress.
H
H
5
Ph
O
Ph
O
H
i
ii
6
H
H
PhS
2
N
N
H
O
O
H
OTIPS
OTIPS
(2R,6R)-15a
(2S,6S)-16a
CF3
(2R,5R,6S)-13a
(2S,5S,6R)-14a
H
H
H
Ph
O
4. Experimental
NHCH3
4.1. General procedures
(R)-Fluoxetine
H
H
All starting compounds, unless otherwise stated, were
purchased. Reactions were run under an atmosphere of dry
nitrogen or argon. FT-IR spectra were recorded on a Per-
kin–Elmer infrared spectrometer, mass spectra on Finnigan
MAT instrument, and NMR spectra on a Varian Mercury
400 MHz spectrometer using the residual signal of the sol-
vent as internal standard. Chemical shifts are reported in
the d scale and coupling constants (J) in hertz. Optical rota-
tions were recorded on a Perkin–Elmer Polarimeter 343.
Solvents were distilled and dried according to standard pro-
cedures. All the reactions were performed under a nitrogen
atmosphere.
(S)-Fluoxetine
Scheme 6. Reagents and conditions: (i) MW, Nickel-Raney/EtOH; (ii)
Ref. 16.
S
S
H
5
H
H
i
ii
6
O
O
H
H
PhS
2
N
H
N
H
O
O
OTIPS
OTIPS
(2R,6R)-15b
(2S,6S)-16b
(2R,5R,6R)-13b
H
(2S,5S,6S)-14b
H
4.2. General procedure (GP1) for the preparation of
1,3-oxazinan-4-ones 3a–3f and 4a–4f
S
H
S
H
Compound 1 (2 mmol), prepared according to literature,29
was dissolved in anhydrous CH2Cl2 (20 mL) and cooled at
ꢀ78 ꢁC. Aldehyde 2 (1 mmol), dissolved in methylene chlo-
ride (2 mL), was added followed by a slow addition of BF3
etherate (1 mmol) in CH2Cl2 (10 mL). The solution was
stirred overnight while the temperature was allowed to reach
room temperature. The mixture was poured into saturated
aqueous NaHCO3 and extracted with CH2Cl2. The organic
layers were dried and the solvent was removed in vacuum.
The reaction mixture was purified by flash chromatography
on silica gel. 5-Phenylthio-perhydrooxazin-4ones 3a–3f and
4a–4f were isolated in combined yields and diastereomeric
ratios reported in Table 1.
iv
iii
O
H
O
H
N
N
O
CH3
CH3
OTIPS
(2R,6R)-17b
OTIPS
(2R,6R)-19b
(2S,6S)-18b
(2S,6S)-20b
S
H
S
H
v
OH
O
NH
NHCH3
H3C
(R)-11b
(S)-11b
(R)-Duloxetine
(S)-Duloxetine
4.2.1. (2S*,5S*,6R*)-2,6-Diphenyl-5-phenylthio-[1,3]ox-
azinan-4-one 3a; (2R*,5S*,6R*)-2,6-diphenyl-5-phenyl-
thio-[1,3]oxazinan-4-one 4a. The crude reaction mixture
Scheme 7. Reagents and conditions. (i) aluminum amalgam, i-PrOH; (ii)
LiHMDS, MeI, THF; (iii) Ph2SiH2, RhH(CO)(PPh3)3, THF; (iv) HClaq
(v) Ref. 50.
;

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M. Panunzio et al. / Tetrahedron 62 (2006) 12270–12280
obtained from azadiene 1a (2 mmol) and benzaldehyde
(0.1 mL, 1 mmol) according to GP1 was subjected to col-
umn chromatography (1:1 EtOAc/cyclohexane) to give 3a
and 4a in 90/10 diastereomeric ratio and 35% overall yield.
(1:1 EtOAc/cyclohexane) to give 3c and 4c in 80/20 dia-
stereomeric ratio and 55% overall yield.
Compound 3c: pale yellow solid. Y¼44%. Mp 181–183 ꢁC.
IR (CHCl3): 1672 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
Compound 3a: pale yellow solid. Y¼32%. Mp 173–174 ꢁC.
d¼7.46–7.16 (m, 12H), 6.93 (d, J¼8.8 Hz, 2H), 6.45 (br s,
1H), 5.86 (s, 1H), 5.38 (d, J¼2.0 Hz, 1H), 3.83 (s, 3H),
3.80 (d, J¼2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d¼169.5, 160.8, 140.3, 136.9, 134.6, 133.2, 129.2, 128.8,
128.6, 128.1, 126.4, 125.9, 114.1, 85.8, 78.4, 55.4. MS
(m/z): 392 (M++1), 334, 316, 299, 285, 187, 162, 136, 105,
91, 77. E.A. Calcd for C24H23NO2S: C, 74.00; H, 5.95.
Found: C, 75.48; H, 6.07.
IR (CHCl3): 1674 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d¼7.60–7.10 (m, 15H), 6.30 (br s, 1H), 5.92 (s, 1H), 5.41
(d, J¼2.4 Hz, 1H), 3.82 (d, J¼2.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d¼169.1, 137.5, 136.9, 134.6, 133.2,
130.0, 128.8, 128.7, 128.1, 127.9, 127.8, 127.1, 125.9,
86.1, 78.6, 55.4. MS (m/z): 361, 255, 106, 91, 77. E.A. Calcd
for C22H19NO2S: C, 73.10; H, 5.30; N, 3.88. Found: C,
73.29; H, 5.33.
Compound 4c: pale yellow solid. Y¼11%. IR (CHCl3):
Compound 4a: Pale yellow oil. Y¼3%. IR (CHCl3):
1673 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d¼7.40–7.20
1667 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d¼7.78–7.00
(m, 12H), 6.90 (d, J¼8.6 Hz, 2H), 6.27 (br s, 1H), 5.96 (s,
1H), 5.38 (d, J¼3.8 Hz, 1H), 4.08 (d, J¼3.8 Hz, 1H), 3.80
(s, 3H). 13C NMR (100 MHz, CDCl3): d¼169.7, 160.7,
136.4, 134.6, 133.1, 130.3, 129.1, 128.5, 128.4, 128.0,
127.9, 127.1, 114.4, 82.1, 73.9, 55.6, 54.1. MS (m/z): 392
(M++1), 316, 299, 285, 281, 210, 136, 105, 91, 77. E.A.
Calcd for C24H23NO2S: C, 74.00; H, 5.95. Found: C,
75.48; H, 6.07.
(m, 15H), 6.53 (br s, 1H), 6.03 (s, 1H), 5.37 (d, J¼3.6 Hz,
1H), 4.03 (d, J¼3.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d¼169.4, 138.0, 136.1, 134.3, 132.9, 129.4,
128.8, 128.7, 128.3, 128.2, 127.7, 126.7, 126.6, 82.0, 73.6,
53.9. MS (m/z): 361, 255, 106, 91, 77. E.A. Calcd for
C22H19NO2S: C, 73.10; H, 5.30; N, 3.88. Found: C, 73.32;
H, 5.31.
4.2.2. (2S*,5S*,6S*)-2-Phenyl-6-(thiophen-2-yl)-5-phe-
nylthio-[1,3]oxazinan-4-one 3b; (2R*,5S*,6S*)-2-phenyl-
6-(thiophen-2-yl)-5-phenylthio-[1,3]oxazinan-4-one 4b.
The crude reaction mixture obtained from azadiene 1a
(2 mmol) and 2-thiophenecarboxaldehyde (0.093 mL,
1 mmol) according to GP1 was subjected to column chroma-
tography (4:6 EtOAc/cyclohexane) to give 3b and 4b in 40/
60 diastereomeric ratio and 38% overall yield.
4.2.4. (2S*,5S*,6R*)-2-(2-Triisopropylsilyloxyphenyl)-
6-phenyl-5-(phenylthio)-[1,3]oxazinan-4-one 3d;
(2R*,5S*,6R*)-2-(2-triisopropylsilyloxyphenyl)-6-phen-
yl-5-(phenylthio)-[1,3]oxazinan-4-one 4d. The crude reac-
tion mixture obtained from azadiene 1c (2 mmol) and
benzaldehyde (0.1 mL, 1 mmol) according to GP1 was sub-
jected to column chromatography (4:6 EtOAc/cyclohexane)
to give 3d and 4d in 85/15 diastereomeric ratio and 48%
overall yield.
Compound 3b: pale yellow oil. Y¼15%. IR (CHCl3):
1676 cmꢀ1. 1H NMR (400 MHz, CDCl3): d¼7.43 (m, 7H),
7.33 (dd, J1¼1.0 Hz, J2¼5.0 Hz, 1H), 7.24 (m, 3H), 7.06
(m, 1H), 7.01 (dd, J1¼3.4 Hz, J2¼5.0 Hz, 1H), 6.54 (br s,
1H), 5.93 (s, 1H), 5.60 (dd, J1¼0.6 Hz, J2¼2.4 Hz, 1H),
3.82 (d, J¼2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d¼168.8, 139.3, 137.1, 134.6, 132.9, 130.0, 128.9, 128.8,
127.8, 127.1, 126.37, 125.9, 125.5, 86.0, 76.3, 55.3. MS
(m/z): 368 (M++1), 323, 255, 212, 184, 152, 121, 106, 91,
77. E.A. Calcd for C21H19NOS2: C, 69.01; H, 5.24; N,
3.83. Found: C, 70.39; H, 5.34.
Compound 3d: pale yellow oil. Y¼41%. IR (CHCl3):
1674 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d¼7.62–6.85
(m, 14H), 6.36 (s, 1H), 6.22 (br s, 1H), 5.42 (d, J¼2.4 Hz,
1H), 3.84 (d, J¼2.4 Hz, 1H), 1.10 (m, 21H). 13C NMR
(100 MHz, CDCl3): d¼168.8, 153.0, 137.1, 134.6, 133.2,
130.3, 128.7, 128.1, 127.8, 127.6, 127.5, 127.2, 125.9,
121.5, 118.0, 80.5, 78.5, 55.5, 18.0, 12.9. MS (m/z): 534,
427, 385, 279, 234. E.A. Calcd for C32H41NO2SSi: C,
72.27; H, 7.77. Found: C, 74.44; H, 8.00.
Compound 4d: pale yellow oil. Y¼7%. IR (CHCl3):
Compound 4b: pale yellow oil. Y¼23%. IR (CHCl3):
1672 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d¼7.45–7.05
1675 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d¼7.50–7.38
(m, 14H), 6.33 (br s, 1H), 6.21 (s, 1H), 5.50 (d, J¼4.0 Hz,
1H), 4.10 (d, J¼4.0 Hz, 1H), 1.05 (m, 21H). 13C NMR
(100 MHz, CDCl3): d¼168.4, 153.4, 135.6, 134.4, 132.9,
130.1, 128.8, 128.5, 128.3, 127.7, 127.4, 126.6, 121.1,
118.5, 77.6, 75.1, 53.4, 18.0, 13.0. MS (m/z): 534, 427,
385, 279, 234. E.A. Calcd for C32H41NO2SSi: C, 72.27; H,
7.77. Found: C, 74.44; H, 8.00.
(m, 8H), 7.33 (br s, 1H), 7.26 (m, 4H), 7.14 (m, 1H), 7.05
(dd, J1¼3.2 Hz, J2¼5.2 Hz, 1H), 5.83 (s, 1H), 5.57 (d,
J¼4.8 Hz, 1H), 4.23 (dd, J1¼3.6 Hz, J2¼4.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3): d¼168.6, 137.6, 137.5, 134.4,
133.5, 129.7, 129.0, 128.8, 127.2, 126.8, 126.7, 81.6, 72.1,
53.4. MS (m/z): 366 (M+ꢀ1), 322, 255, 212, 186, 152,
121, 106, 77. E.A. Calcd for C21H19NOS2: C, 69.01; H,
5.24; N, 3.83. Found: C, 70.39; H, 5.34.
4.2.5. (2S*,5S*,6R*)-6-Methyl-2-phenyl-5-phenylthio-
[1,3]oxazinan-4-one 3e; (2R*,5S*,6R*)-6-methyl-2-phenyl-
5-phenylthio-[1,3]oxazinan-4-one 4e. The crude reaction
mixture obtained from azadiene 1a (2 mmol) and acetalde-
hyde (0.056 mL, 1 mmol) according to GP1 was subjected
to column chromatography (6:4 EtOAc/cyclohexane) to
give 3e and 4e in 50/50 diastereomeric ratio and 51% overall
yield.
4.2.3. (2S*,5S*,6R*)-2-(4-Methoxy-phenyl)-6-phenyl-5-
phenylthio-[1,3]oxazinan-4-one 3c; (2R*,5S*,6R*)-2-(4-
methoxy-phenyl)-6-phenyl-5-phenylthio-[1,3]oxazinan-
4-one 4c. The crude reaction mixture obtained from
azadiene 1b (2 mmol) and benzaldehyde (0.1 mL, 1 mmol)
according to GP1 was subjected to column chromatography

M. Panunzio et al. / Tetrahedron 62 (2006) 12270–12280
12275
Compound 3e: pale yellow oil. Y¼25%. IR (CHCl3):
1672 cmꢀ1. 1H NMR (400 MHz, CDCl3): d¼7.70 (m, 2H),
7.45–7.23 (m, 8H), 6.69 (br s, 1H), 5.74 (s, 1H), 4.34 (dq,
J1¼6.4 Hz, J2¼2.8 Hz, 1H), 3.51 (d, J¼2.8 Hz, 1H), 1.57
(d, J¼6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d¼169.7, 137.8, 135.1, 133.3, 130.2, 129.3, 129.0, 128.0,
127.3, 86.2, 74.2, 54.6, 18.6. MS (m/z): 299, 255, 122,
106. E.A. Calcd for C17H17NO2S: C, 68.20; H, 5.72; N,
4.68. Found: C, 68.34; H, 5.73.
reaction mixture was purified by flash chromatography
(3:7 EtOAc/cyclohexane) to give the desired product 5a in
80% yield.
4.3.1. (2S*,6S*)-2,6-Diphenyl-[1,3]oxazinan-4-one 5a.
Pale yellow oil. IR (Nujol): 1653 cmꢀ1
.
1H NMR
(400 MHz, CDCl3): d¼7.51 (m, 2H), 7.43–7.30 (m, 8H),
6.57 (br s, 1H), 5.92 (s, 1H), 5.02 (m, 1H), 2.75 (m, 2H).
13C NMR (100 MHz, CDCl3): d¼168.8, 139.6, 137.7,
129.9, 128.8, 128.7, 128.3, 126.9, 125.6, 85.7, 76.6, 39.1.
MS (m/z): 253, 175, 147, 131, 118, 104, 78. E.A.
Calcd for C16H15NO2: C, 75.87; H, 5.97. Found: C, 75.96;
H, 5.98.
Compound 4e: yellow solid. Y¼26%. Mp 147–148 ꢁC. IR
(CHCl3): 1677 cmꢀ1
.
1H NMR (400 MHz, CDCl3):
d¼7.61 (m, 2H), 7.50–7.15 (m, 8H), 6.67 (br s, 1H), 5.97
(s, 1H), 4.34 (m, 1H), 3.82 (d, J¼3.6 Hz, 1H), 1.48 (d,
J¼6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d¼169.0,
138.7, 134.4, 132.8, 129.7, 129.3, 129.1, 128.0, 126.8,
82.0, 69.0, 54.1, 16.8. MS (m/z): 299, 255, 122, 105, 91,
77. E.A. Calcd for C17H17NO2S: C, 68.20; H, 5.72; N,
4.68. Found: C, 68.30; H, 5.71.
4.3.2. (2R*,6S*)-2,6-Diphenyl-[1,3]oxazinan-4-one 6a.
The crude reaction mixture obtained from 5-phenylsul-
fanyl-perhydrooxazinone 4a, according to GP2, was sub-
jected to a short column chromatography (3:7 EtOAc/
cyclohexane) to give 6a in 92% overall yield.
4.2.6. tert-Butyl-3-[(2S*,5S*,6R*)-4-oxo-2-phenyl-5-
(phenylthio)-[1,3]oxazinan-6-yl]-1H-indole-1-carboxyl-
ate 3f; tert-butyl-3-[(2R*,5S*,6R*)-4-oxo-2-phenyl-5-
(phenylthio)-[1,3]oxazinan-6-yl]-1H-indole-1-carboxyl-
ate 4f. The crude reaction mixture obtained from azadiene
1a (2 mmol) and tert-butyl-3-formyl-1H-indole-1-carboxyl-
ate (245 mg, 1 mmol) according to GP1 was subjected to
column chromatography (4:6 EtOAc/cyclohexane) to give
3f and 4f in 40/60 diastereomeric ratio and 41% overall
yield.
Pale yellow oil. IR (Nujol): 1653 cmꢀ1. 1H NMR (400 MHz,
CDCl3): d¼7.60–7.30 (m, 10H), 6.54 (br s, 1H), 5.95 (s, 1H),
5.05 (dd, 1H, J1¼7.2 Hz, J2¼5.8 Hz), 2.86 (m, 2H). 13C
NMR (75 MHz, CDCl3): d¼169.6, 139.2, 138.4, 129.2,
128.7, 128.6, 128.3, 126.7, 126.1, 81.8, 70.2, 37.6. MS
(m/z): 253, 175, 147, 131, 118, 104, 78. E.A. Calcd for
C16H15NO2: C, 75.87; H, 5.97. Found: C, 75.99; H, 5.60.
4.3.3. (2S*,6S*)-Methyl 4-oxo-2,6-diphenyl-1,3-oxazi-
nane-3-carboxylate 7a. To a solution of 5a (253 mg,
1.0 mmol) in THF (10 ml) at 0 ꢁC was added LiHMDS
(1 M in THF, 1.0 mmol, 1.0 ml). The reaction mixture was
stirred for 20 min, then methyl chloroformate (8 mmol,
0.62 ml) was added. Stirring was maintained for 2 h at the
same temperature. A saturated solution of NH4Cl was added
and the mixture was extracted with CH2Cl2. The organic
phases were dried on Na2SO4 and concentrated in vacuum.
The carbamate 7a was obtained in quantitative yield and
used as such for the next step.
Compound 3f: yellow oil. Y¼16%. IR (CHCl3): 1737,
1
1673 cmꢀ1. H NMR (400 MHz, CDCl3): d¼7.75 (s, 1H),
7.60–7.05 (m, 14H), 6.21 (br s, 1H), 6.00 (s, 1H), 5.63 (dd,
J1¼2.0 Hz, J2¼0.8 Hz, 1H), 4.04 (d, J¼2.0 Hz, 1H), 1.66
(s, 9H). 13C NMR (100 MHz, CDCl3): d¼169.2, 149.8,
137.7, 134.5, 133.2, 130.3, 129.1, 128.9, 128.0, 127.9,
127.4, 124.8, 124.7, 123.0, 119.0, 118.1, 116.9, 115.7,
86.5, 84.2, 74.7, 54.1, 28.4. MS (m/z): 399 (M+ꢀt-Boc),
334, 255, 202, 106, 91, 77. E.A. Calcd for C29H28N2O4S:
C, 69.58; H, 5.64; N, 5.60. Found: C, 69.75; H, 5.62.
Compound 7a: pale yellow oil. IR (Nujol): 1731,
1702 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d¼7.50–7.20
Compound 4f: pale yellow solid. Y¼25%. Mp 102–104 ꢁC.
IR (CHCl3): 1738, 1673 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d¼7.84 (s, 1H), 7.50–7.15 (m, 14H), 6.83 (br s, 1H), 5.78
(s, 1H), 5.67 (dd, J1¼4.8 Hz, J2¼0.8 Hz, 1H), 4.41
(d, J¼4.8 Hz, 1H), 1.71 (s, 9H). 13C NMR (100 MHz,
CDCl3): d¼168.7, 149.4, 137.7, 135.4, 134.2, 132.4,
129.6, 128.9, 128.8, 128.7, 127.6, 126.8, 125.2, 124.9,
122.9, 119.1, 115.4, 114.4, 84.3, 81.7, 70.0, 52.4, 28.1. MS
(m/z): 456, 422, 399, 334, 255, 202, 186, 131, 107, 91, 77.
E.A. Calcd for C29H28N2O4S: C, 69.58; H, 5.64; N, 5.60.
Found: C, 69.77; H, 5.62.
(m, 10H), 6.41 (s, 1H), 5.06 (dd, 1H, J1¼7.2 Hz,
J2¼5.8 Hz), 3.67 (s, 3H), 2.97 (m, 2H). 13C NMR
(100 MHz, CDCl3): d¼167.4, 152.8, 138.4, 138.2, 129.3,
128.5, 128.4, 128.3, 126.8, 125.5, 89.5, 75.2, 53.5, 41.5.
MS (m/z): 311, 234, 223. E.A. Calcd for C18H17NO4: C,
69.44; H, 5.50. Found: C, 70.83; H, 5.61.
4.3.4. (2R*,6R*)-Methyl 4-oxo-2,6-diphenyl-1,3-oxazi-
nane-3-carboxylate 8a. The crude reaction mixture ob-
tained from product 6a according to the procedure used
for 7a gave 8a in quantitative yield, which was used as
such for the next step.
4.3. MW-mediated desulfurization reaction: prepara-
tion of 5a as general procedure (GP2)
Compound 8a: pale yellow oil. IR (Nujol): 1731,
1702 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d¼7.50–7.20
5-Phenylsulfanyl-perhydrooxazinone
3a
(87 mg,
(m, 10H), 6.96 (s, 1H), 4.83 (m, 1H), 3.91 (s, 3H), 2.87
(m, 2H). 13C NMR (100 MHz, CDCl3): d¼167.4, 153.0,
139.4, 137.3, 129.13, 128.9, 128.7, 128.4, 126.5, 125.6,
86.1, 69.7, 54.1, 40.9. MS (m/z): 311, 234, 223. E.A.
Calcd for C18H17NO4: C, 69.44; H, 5.50. Found: C, 70.83;
H, 5.61.
0.24 mmol), Nickel-Raney (0.6 g), and EtOH (6 mL) were
mixed in a 30 mL reaction tube. The tube was sealed and
positioned in the reaction cavity. The sealed reaction was
irradiated at 150 W for 2 min. The reaction mixture was
filtered on Celite, and the solvent evaporated. The crude

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M. Panunzio et al. / Tetrahedron 62 (2006) 12270–12280
4.3.5. Procedure for the preparation of aminol 10a.
4.3.5.1. Step 1: 3-(N-benzyl-N-methylamino)-1-
phenyl-propan-1-ol 9a. Carbamate 7a and/or 8a (1 mmol)
were dissolved in anhydrous Et2O (10 mL) at 0 ꢁC. Lithium
aluminum hydride (LAH, 1 M in Et2O, 4 mmol) was added
and the mixture was stirred for 2 h. NaOH (10 mL, 5 N) was
added and the aqueous phase was washed with ethyl acetate.
The extracts were treated with HCl 1 N; aqueous phase was
neutralized with NaOH 5 N (pH¼10–12) and extracted with
CH2Cl2. The organic phase was dried over Na2SO4 and the
solvent evaporated. Product 9a so obtained was used without
purification for the next step of the synthesis.
NH4Cl was added, the organic solvent removed in vacuo,
and the obtained aqueous solution extracted with EtOAc.
The organic phases were collected, dried on Na2SO4, and
concentrated in vacuo. The reaction mixture was purified
by flash chromatography on silica gel, eluting with CH2Cl2/
cyclohexane/EtOAc 50/30/20. Compound 7b was obtained
in 55% overall yield calculated from product 3b.
Pale yellow oil. IR (CHCl3): 1644 cmꢀ1
.
1H NMR
(400 MHz, CDCl3): d¼7.4 (m, 5H), 7.29 (dd, J1¼1.2 Hz,
J2¼5.2 Hz, 1H), 7.05 (dd, J1¼1.2 Hz, J2¼4.4 Hz, 1H),
6.97 (dd, J1¼4.4 Hz, J2¼5.2 Hz, 1H), 5.78 (s, 1H), 5.23
(dd, J1¼2.8 Hz, J2¼12.0 Hz, 1H), 3.05 (dd, J1¼12.0 Hz,
J2¼16.8 Hz, 1H), 2.90 (dd, J1¼2.8 Hz, J2¼16.8 Hz, 1H),
2.63 (s, 3H). 13C NMR (100 MHz, CDCl3): d¼171.1,
142.0, 136.9, 129.8, 128.8, 127.6, 126.7, 125.9, 125.0,
91.0, 71.9, 39.8, 29.8. MS (m/z): 273, 259, 196, 167, 137,
118, 110, 91, 77. Anal. Calcd for C15H15NO2S: C, 65.91;
H, 5.53. Found: C, 65.81; H, 5.52.
Pale yellow oil. IR (Nujol): 3243, 2946, 2843, 1602 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d¼7.0–7.6 (m, 10H), 4.97
(dd, J1¼3.9 Hz, J2¼7.5 Hz, 1H), 3.70 (d, J¼12.7 Hz, 1H),
3.53 (d, J¼12.7 Hz, 1H), 2.87 (m, 1H), 2.66 (m, 1H), 2.32
(s, 3H), 1.94 (m, 2H). 13C NMR (75 MHz, CDCl3):
d¼144.8, 137.6, 129.0, 128.1, 128.0, 127.2, 126.7, 125.4,
75.4, 62.6, 56.2, 41.6, 34.4. MS (m/z): 255, 134, 120, 91.
Anal. Calcd for C17H21NO: C, 79.96; H, 8.29. Found: C,
80.01; H, 8.31.
4.4.3. Synthesis of (2R*,6S*)-2-phenyl-6-(thiophen-2-yl)-
[1,3]oxazinan-4-one 6b. Product 6b, obtained from 4b ac-
cording to GP3, was used for the methylation step without
any purification. Identification was performed on an aliquot
of the crude reaction mixture prior to purification by a short
flash chromatography on silica gel (5:3:2 CH2Cl2/cyclo-
hexane/EtOAc).
4.3.5.2. Step 2: hydrogenolysis of 9a. Hydrogenolysis of
compound 9a according to literature procedure furnished
aminol 10a in 78% yield. Spectra are just similar to the
literature data.50
4.4. Desulfurization reaction by Al/HgCl2 amalgam:
preparation of 5b as general procedure (GP3)
Pale yellow oil. IR (CHCl3): 1671 cmꢀ1 1H NMR
.
(400 MHz, CDCl3): d¼7.45–7.00 (m, 8H), 6.72 (br s, 1H),
5.84 (s, 1H), 5.34 (t, J¼6.0 Hz, 1H), 2.96 (m, 2H). 13C
NMR (100 MHz, CDCl3): d¼168.5, 142.0, 137.8, 129.6,
128.9, 126.9, 126.8, 126.5, 125.8, 81.0, 67.8, 37.0. MS
(m/z): 259, 181, 154, 147, 137, 118, 106, 85, 77. Anal. Calcd
for C14H13NO2S: C, 64.84; H, 5.05. Found: C, 65.01; H, 5.07.
Aluminum (4.0 g) and 50 mL of a solution of HgCl2 (1% in
H2O) were stirred for 1 min, the mixture was decanted and
the residue was washed with water. The amalgam so pre-
pared was added to a solution of compound 3b (335 mg,
0.9 mmol) in i-PrOH (50 ml) under inert atmosphere. The
reaction was stirred overnight until the disappearance of
starting materials (TLC test). The mixture was filtered
through Celite and the solvent was removed in vacuo. Prod-
uct 5b so obtained was used for the next step without any
purification. An aliquot of the crude reaction mixture was
utilized for identification of 5b after purification by a short
flash chromatography on silica gel (5:3:2 CH2Cl2/cyclo-
hexane/EtOAc).
4.4.4. Synthesis of (2R*,6S*)-N-methyl-2-phenyl-6-(thio-
phen-2-yl)-[1,3]oxazinan-4-one 8b. Crude 6b was methyl-
ated, following the procedure used for 7b, to give 8b, after
a short column chromatography (CH2Cl2/cyclohexane/
EtOAc 50/30/20) in 58% overall yield calculated from prod-
uct 4b.
Pale yellow oil. IR (CHCl3): 1645 cmꢀ1
.
1H NMR
(400 MHz, CDCl3): d¼7.42 (m, 3H), 7.37 (d, J¼2.0 Hz,
2H), 7.29 (dd, J1¼1.6 Hz, J2¼5.2 Hz, 1H), 6.95 (dd,
J1¼3.2 Hz, J2¼5.2 Hz, 1H), 6.90 (m, 1H), 6.72 (br s, 1H),
5.78 (s, 1H), 5.12 (dd, J1¼6.0 Hz, J2¼8.4 Hz, 1H), 2.94
(m, 2H), 2.85 (s, 3H). 13C NMR (100 MHz, CDCl3):
d¼166.6, 142.1, 136.4, 129.5, 128.6, 127.4, 126.7, 125.94,
125.13, 87.6, 66.6, 38.3, 31.1. MS (m/z): 273, 196, 188,
168, 137, 118, 110, 97, 77. Anal. Calcd for C15H15NO2S:
C, 65.91; H, 5.53. Found: C, 68.82; H, 5.51.
4.4.1. (2S*,6S*)-2-Phenyl-6-(thiophen-2-yl)-[1,3]oxa-
zinan-4-one 5b. Pale yellow oil. IR (CHCl3): 1670 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d¼7.50–6.95 (m, 8H), 6.37
(br s, 1H), 5.93 (s, 1H), 5.27 (dd, J1¼4.0 Hz, J2¼11.2 Hz,
1H), 2.95 (dd, J1¼11.2 Hz, J2¼17.2 Hz, 1H), 2.86 (dd,
J1¼4.0 Hz, J2¼11.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d¼168.2, 142.1, 137.3, 130.1, 128.9, 126.9,
126.7, 125.9, 125.0, 85.7, 72.7, 38.9. MS (m/z): 259, 181,
154, 147, 137, 118, 106, 85, 77. Anal. Calcd for
C14H13NO2S: C, 64.84; H, 5.05. Found: C, 64.96; H, 5.06.
4.4.5. Synthesis of aminol rac-11b. Ph2SiH2 (0.46 mL,
2.5 mmol) and RhH(CO)(PPh3)3 (1%) were added to a solu-
tion of 7b or 8b (273 mg, 1.0 mmol) in THF (10 mL) at room
temperature and the stirring maintained for 15 h. Disappear-
ance of starting material was verified by TLC (CH2Cl2/
cyclohexane/EtOAc 50/30/20). Aqueous HCl (1 M, 2.50 mL)
was added to the crude reaction mixture and the stirring
maintained at the same temperature for 4 h. The organic
solvent was removed in vacuo and the obtained aqueous
4.4.2. (2S*,6S*)-N-Methyl-2-phenyl-6-(thiophen-2-yl)-
[1,3]oxazinan-4-one 7b. To a solution of crude 5b
(0.9 mmol) in THF (10 mL) at 0 ꢁC was added LHMDSA
(1 M in THF, 0.9 mL). The reaction was stirred for 20 min,
MeI (0.45 mL, 7.2 mmol) was added and the solution
warmed to room temperature. Stirring was maintained for
1.5 h at the same temperature. A saturated solution of

M. Panunzio et al. / Tetrahedron 62 (2006) 12270–12280
12277
solution extracted with Et2O. The aqueous phase was
basified with NH4OH (pH¼10) and then extracted with
CH2Cl2. The organic phases were dried over Na2SO4 and
the solvent evaporated.
crude reaction mixture obtained from azadiene 1d (2 mmol)
and 2-thiophenecarboxaldehyde (0.093 mL, 1 mmol) ac-
cording to GP5 was subjected to column chromatography
(2:8 EtOAc/cyclohexane) to give 13b and 14b in 60/40
diastereomeric ratio and 90% overall yield.
Compound rac-11b was obtained in 95% yield calculated
from product 7b. Spectral data are identical to the product
obtained from 19b or 20b (see below).
Compound 13b: pale yellow oil. Y¼54%. [a]2D0 +33.5 (c 2.9,
CHCl3). IR (CHCl3): 1672 cmꢀ1 1H NMR (400 MHz,
.
CDCl3): d¼7.36 (m, 3H), 7.20 (m, 3H), 7.01 (m, 2H), 6.20
(br s, 1H, NH), 5.46 (d, J¼2.0 Hz, 1H), 5.09 (d, J¼3.6 Hz,
1H), 4.19 (dq, J1¼3.6 Hz, J2¼6.0 Hz, 1H), 3.71 (d,
J¼2.0 Hz, 1H), 1.26 (d, J¼6.0 Hz, 3H), 1.07 (m, 21H).
13C NMR (100 MHz, CDCl3): d¼168.80, 139.61, 135.80,
132.32, 128.84, 127.60, 126.28, 126.03, 125.52, 85.51,
75.69, 68.72, 56.16, 18.02, 15.88, 12.14. MS (m/z): 492,
448, 379, 336, 187. Anal. Calcd for C25H37NO3S2Si: C,
61.06; H, 7.58. Found: C, 61.20; H, 7.63.
4.5. General procedure (GP5) for the preparation
of 1,3-oxazinan-4-ones 13a–13e and 14a–14e
Azadiene 1d (2 mmol), prepared according to literature from
(2S)-triisopropylsilyloxy-propanal and 2-(phenylthio)acetyl
chloride28 5, was dissolved in anhydrous CH2Cl2 (20 mL)
and cooled at ꢀ78 ꢁC. Aldehyde 2 (1 mmol) in methylene
chloride (2 mL) was added followed by a slow addition of
BF3 etherate (1 mmol) in CH2Cl2 (10 mL). The solution
was stirred overnight while the temperature was allowed to
reach room temperature. The mixture was poured into satu-
rated aqueous NaHCO3 and extracted with CH2Cl2. The
organic layers were dried and the solvent was removed in
vacuum. The reaction mixture was purified by flash chroma-
tography on silica gel. 5-Phenylthio-perhydrooxazin-4ones
13a–13e and 14a–14e were isolated in combined yields
and diastereomeric ratios reported in Table 2.
Compound 14b: pale yellow oil. Y¼36%. [a]2D0 ꢀ58.6 (c 2.5,
CHCl3). IR (CHCl3): 1685 cmꢀ1 1H NMR (400 MHz,
.
CDCl3): d¼7.42–7.20 (m, 6H), 7.02–6.98 (m, 2H), 6.33
(br s, 1H, NH), 5.41 (dd, J1¼1.2 Hz, J2¼2.4 Hz, 1H), 4.60
(d, J¼8.0 Hz, 1H), 3.77 (d, J¼2.4 Hz, 1H), 3.68 (m, 1H),
1.31 (d, J¼6.4 Hz, 3H), 1.08 (m, 21H). 13C NMR
(100 MHz, CDCl3): d¼167.68, 139.66, 134.16, 133.56,
128.71, 127.96, 126.51, 125.54, 124.75, 87.66, 76.07,
71.35, 55.16, 19.43, 18.12, 12.58. MS (m/z): 491, 446,
379, 336, 217, 186. Anal. Calcd for C25H37NO3S2Si: C,
61.06; H, 7.58. Found: C, 61.18; H, 7.60.
4.5.1. (2R,5R,6S)-2-[(S)-1-Triisopropylsilyloxyethyl]-6-
phenyl-5-(phenylthio)-[1,3]oxazinan-4-one 13a;
(2S,5S,6R)-2-[(S)-1-triisopropylsilyloxyethyl]-6-phenyl-
5-(phenylthio)-[1,3]oxazinan-4-one 14a. The crude reac-
tion mixture obtained from azadiene 1f (2 mmol) and benz-
aldehyde (0.1 mL, 1 mmol) according to GP5 was subjected
to column chromatography (3:7 EtOAc/cyclohexane) to give
13a and 14a in 50/50 diastereomeric ratio and 81% overall
yield.
4.5.3. (2R,5R,6S)-2-[(S)-1-Triisopropylsilyloxyethyl]-6-
methyl-5-(phenylthio)-[1,3]oxazinan-4-one 13c;
(2S,5S,6R)-2-[(S)-1-triisopropylsilyloxyethyl]-6-methyl-
5-(phenylthio)-[1,3]oxazinan-4-one 14c. The crude reac-
tion mixture obtained from azadiene 1f (2 mmol) and
acetaldehyde (0.056 mL, 1 mmol) according to GP5 was
subjected to column chromatography (2:8 EtOAc/cyclohex-
ane) to give 13c and 14c in 50/50 diastereomeric ratio and
32% overall yield.
Compound 13a: colorless oil. Y¼41%. [a]2D0 13.0 (c 0.7,
CHCl3). IR (CHCl3): 1677 cmꢀ1 1H NMR (400 MHz,
.
CDCl3): d¼7.45–7.05 (m, 10H), 6.22 (br s, 1H), 5.25 (d,
J¼2.0 Hz, 1H), 5.08 (d, J¼2.8 Hz, 1H), 4.23 (m, 1H), 3.69
(d, J¼2.8 Hz, 1H), 1.31 (d, J¼7.2 Hz, 3H), 1.05 (s, 21H).
13C NMR (100 MHz, CDCl3): d¼169.1, 136.7, 135.0,
132.8, 128.7, 128.0, 127.9, 127.6, 126.0, 85.3, 77.8, 68.8,
56.3, 18.0, 17.9, 15.9, 12.1. MS (m/z): 486, 442, 399, 379,
336, 239, 211, 188, 135, 77. E.A. Calcd for C27H39NO3SSi:
C, 66.76; H, 8.09; N, 2.88. Found: C, 66.86; H, 8.11.
Compound 13c: pale yellow oil. Y¼16%. [a]2D0 40.0 (c 2.1,
CHCl3). IR (CHCl3): 1670 cmꢀ1 1H NMR (400 MHz,
.
CDCl3): d¼7.65 (m, 2H), 7.40–7.18 (m, 3H), 6.10 (br s,
1H), 4.90 (d, J¼3.2 Hz, 1H), 4.20 (dq, J1¼6.0 Hz,
J2¼1.8 Hz, 1H), 4.06 (dq, J1¼6.4 Hz, J2¼3.2 Hz, 1H),
3.46 (d, J¼1.8 Hz, 1H), 1.50 (d, J¼6.0 Hz, 3H), 1.11 (d,
J¼6.4 Hz, 3H), 1.05 (s, 21H). 13C NMR (100 MHz,
CDCl3): d¼169.4, 135.6, 132.4, 129.0, 127.5, 85.4, 73.2,
68.8, 55.1, 18.0, 17.9, 15.7, 12.1. MS (m/z): 423, 408, 380,
362, 336, 223, 187, 149, 77. E.A. Calcd for C22H37NO3SSi:
C, 62.37; H, 8.80; N, 3.31. Found: C, 62.40; H, 8.83.
Compound 14a: colorless oil. Y¼40%. [a]2D0 ꢀ41.5 (c 2.0,
CHCl3). IR (CHCl3): 1676 cmꢀ1 1H NMR (400 MHz,
.
CDCl3): d¼7.40–7.07 (m, 10H), 6.35 (br s, 1H), 5.22 (d,
J¼2.4 Hz, 1H), 4.58 (d, J¼8.0 Hz, 1H), 3.77 (m, 1H), 3.76
(d, J¼2.4 Hz, 1H), 1.35 (d, J¼5.6 Hz, 3H), 1.05 (s, 21H).
13C NMR (100 MHz, CDCl3): d¼168.2, 145.4, 137.0,
133.7, 128.9, 128.6, 128.2, 127.8, 125.7, 87.6, 78.0, 71.5,
55.2, 19.5, 18.1, 18.0, 12.6. MS (m/z): 486, 442, 379, 336,
284, 239, 211, 188, 135, 77. E.A. Calcd for C27H39NO3SSi:
C, 66.76; H, 8.09; N, 2.88. Found: C, 66.82; H, 8.10.
Compound 14c: pale yellow oil. Y¼16%. [a]2D0 ꢀ40.7 (c
1.35, CHCl3). IR (CHCl3): 1667 cmꢀ1
.
1H NMR
(400 MHz, CDCl3): d¼7.65 (m, 2H), 7.25 (m, 3H), 6.25
(br s, 1H), 4.39 (d, J¼7.2 Hz, 1H), 4.14 (dq, J1¼6.4 Hz,
J2¼2.4 Hz, 1H), 3.50 (m, 1H), 3.45 (d, J¼2.4 Hz, 1H),
1.50 (d, J¼6.4 Hz, 3H), 1.21 (d, J¼6.0 Hz, 3H), 1.05 (s,
21H). 13C NMR (100 MHz, CDCl3): d¼168.3, 134.5,
133.4, 128.8, 127.7, 87.5, 73.4, 71.3, 54.5, 19.3, 18.1,
18.0, 12.6. MS (m/z): 423, 408, 380, 362, 336, 222, 186,
149, 77. E.A. Calcd for C22H37NO3SSi: C, 62.37; H, 8.80;
N, 3.31. Found: C, 62.42; H, 8.84.
4.5.2. (2R,5R,6R)-2-[(S)-1-Triisopropylsilyloxyethyl]-6-
(thiophen-2-yl)-5-(phenylthio)-[1,3]oxazinan-4-one 13b;
(2S,5S,6S)-2-[(S)-1-triisopropylsilyloxyethyl]-6-(thio-
phen-2-yl)-5-(phenylthio)-[1,3]oxazinan-4-one 14b. The

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M. Panunzio et al. / Tetrahedron 62 (2006) 12270–12280
4.5.4. (2R,5R,6S)-2-[(S)-1-Triisopropylsilyloxyethyl]-6-
(naphthalen-2-yl)-5-(phenylthio)-[1,3]oxazinan-4-one
13d; (2S,5S,6R)-2-[(S)-1-triisopropylsilyloxyethyl]-6-
(naphthalen-2-yl)-5-(phenylthio)-[1,3]oxazinan-4-one
14d. The crude reaction mixture obtained from azadiene 1f
(2 mmol) and 2-naphthaldehyde (156 mg, 1 mmol) accord-
ing to GP5 was subjected to column chromatography (3:7
EtOAc/cyclohexane) to give 13d and 14d in 50/50 diastereo-
meric ratio and 41% overall yield.
(400 MHz, CDCl3): d¼7.65 (s, 1H), 7.40–7.00 (m, 9H),
6.38 (br s, 1H), 5.41 (dd, J1¼2.4 Hz, J2¼1.2 Hz, 1H), 4.66
(d, J¼7.2 Hz, 1H), 3.97 (d, J¼2.4 Hz, 1H), 3.76 (m, 1H),
1.68 (s, 9H), 1.35 (d, J¼6.4 Hz, 1H), 1.11 (s, 21H). 13C
NMR (100 MHz, CDCl3): d¼167.8, 149.6, 135.3, 133.8,
133.5, 132.5, 128.5, 127.8, 127.7, 124.6, 124.1, 122.7,
118.7, 116.8, 115.4, 87.8, 83.9, 74.1, 71.4, 53.6, 28.2,
19.5, 18.1, 18.0, 12.6. MS (m/z): 567 (M+ꢀt-Bu), 379,
336, 230, 188, 77. E.A. Calcd for C34H50N2O5SSi: C,
65.14; H, 8.04; N, 4.47. Found: C, 65.41; H, 8.07.
Compound 13d: pale yellow oil. Y¼20%. [a]2D0 ꢀ39.7
(c 1.40, CHCl3). IR (CHCl3): 1678 cmꢀ1
.
1H NMR
4.5.6. (2R,6R)-2-[(S)-1-Triisopropylsilyloxyethyl]-6-
phenyl-[1,3]oxazinan-4-one 15a. The crude reaction mix-
ture obtained from desulfurization of 13a, according to
GP2, was subjected to column chromatography (3:7
EtOAc/cyclohexane) to give 15a in 98% overall yield. Spec-
troscopic data are superimposable with the published ones.16
(400 MHz, CDCl3): d¼7.82 (m, 5H), 7.50 (m, 2H), 7.38
(m, 1H), 7.05 (m, 5H), 6.26 (br s, 1H), 5.41 (d, J¼2.6 Hz,
1H), 5.15 (d, J¼3.6 Hz, 1H), 4.29 (dq, J1¼6.4 Hz,
J2¼3.6 Hz, 1H), 3.83 (d, J¼2.6 Hz, 1H), 1.36 (d,
J¼6.4 Hz, 3H), 1.08 (s, 21H). 13C NMR (100 MHz,
CDCl3): d¼169.1, 134.8, 134.1, 132.9, 132.8, 132.7, 128.6,
128.1, 127.8, 127.7, 127.6, 126.2, 126.1, 125.2, 123.4,
85.5, 78.0, 68.8, 56.0, 18.1, 18.0, 16.0, 12.1. MS (m/z):
535, 379, 336, 289, 261, 187. E.A. Calcd for C31H41NO3SSi:
C, 69.49; H, 7.71; N, 2.61. Found: C, 69.63; H, 7.73.
4.5.7. (2S,6S,)-2-[(S)-1-Triisopropylsilyloxyethyl]-6-
phenyl-[1,3]oxazinan-4-one 16a. The crude product ob-
tained from desulfurization of 14a according to GP2 was
subjected to column chromatography (3:7 EtOAc/cyclohex-
ane) to give 16a in 90% overall yield. Spectra are just similar
to literature data.16
Compound 14d: pale yellow oil. Y¼21%. [a]2D0 ꢀ14.2
(c 1.70, CHCl3). IR (CHCl3): 1677 cmꢀ1 1H NMR
.
(400 MHz, CDCl3): d¼7.85 (m, 5H), 7.55 (m, 2H), 7.38
(m, 1H), 7.22–7.05 (m, 5H), 6.42 (br s, 1H), 5.37 (d,
J¼2.2 Hz, 1H), 4.65 (d, J¼7.6 Hz, 1H), 3.90 (d, J¼2.2 Hz,
1H), 3.85 (m, 1H), 1.43 (d, J¼6.4 Hz, 3H), 1.12 (s, 21H).
13C NMR (100 MHz, CDCl3): d¼168.1, 134.3, 134.1,
133.7, 132.9, 132.8, 128.5, 128.1, 127.9, 127.8, 127.7,
127.6, 126.2, 126.1, 124.9, 123.2, 87.6, 78.2, 71.5, 55.0,
19.6, 18.1, 18.0, 12.6. MS (m/z): 535, 379, 336, 289, 261,
187. E.A. Calcd for C31H41NO3SSi: C, 69.49; H, 7.71; N,
2.61. Found: C, 69.62; H, 7.71.
4.5.8. (2R,6R)-2-[(S)-1-Triisopropylsilyloxyethyl]-6-
(thiophen-2-yl)-[1,3]oxazinan-4-one 15b. Product 15b, ob-
tained from 13b according to GP3 was used for the next step
without any purification. An aliquot of the crude reaction
mixture was utilized for identification of 15b after purifica-
tion by flash chromatography on silica gel (2:8 EtOAc/cyclo-
hexane).
Compound 15b: pale yellow oil. [a]2D0 +1.9 (c 1.3, CHCl3).
IR (CHCl3): 1666 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d¼7.33 (d, J¼5.2 Hz, 1H), 7.05 (d, J¼3.6 Hz, 1H), 7.00
(dd, J1¼3.6 Hz, J2¼5.2 Hz, 1H), 6.38 (br s, 1H, NH), 5.11
(dd, J1¼6.0 Hz, J2¼9.6 Hz, 1H), 5.07 (d, J ¼3.6 Hz, 1H),
4.19 (dq, J¼3.6 Hz, 6.4 Hz, 1H), 2.77 (m, 2H), 1.19 (d,
J¼6.4 Hz, 3H), 1.07 (m, 21H). 13C NMR (100 MHz,
CDCl3): d¼168.18, 142.26, 126.77, 125.88, 124.88, 84.91,
72.13, 68.61, 39.66, 18.01, 15.69, 12.14. MS (m/z): 384,
340, 322, 202, 187. Anal. Calcd for C19H33NO3SSi: C,
59.49; H, 8.67. Found: C, 60.68; H, 8.84.
4.5.5. tert-Butyl-3-[(2R,5R,6S)-2-[(S)-1-triisopropylsilyl-
oxyethyl]-4-oxo-5-(phenylthio)-[1,3]oxazinan-6-yl]-1H-
indole-1-carboxylate 13e; tert-butyl-3-[(2S,5S,6R)-2-[(S)-
1-triisopropylsilyloxyethyl]-4-oxo-5-(phenylthio)-
[1,3]oxazinan-6-yl]-1H-indole-1-carboxylate 14e. The
crude reaction mixture obtained from azadiene 1d
(2 mmol) and tert-butyl-3-formyl-1H-indole-1-carboxylate
(245 mg, 1 mmol) according to GP2 was subjected to col-
umn chromatography (3:7 EtOAc/cyclohexane) to give 13e
and 14e in 63/37 diastereomeric ratio and 55% overall yield.
4.5.9. (2S,6S)-2-[(S)-1-Triisopropylsilyloxyethyl]-6-(thio-
phen-2-yl)-[1,3]oxazinan-4-one 16b. Product 16b, ob-
tained from 14b according to GP3 was used for the next
step without any purification. An aliquot of the crude reac-
tion mixture was utilized for identification of 16b after puri-
fication by flash chromatography on silica gel (2:8 EtOAc/
cyclohexane).
Compound 13e: pale yellow oil. Y¼35%. [a]2D0 +24 (c 0.5,
CHCl3). IR (CHCl3): 1738, 1674 cmꢀ1
.
1H NMR
(400 MHz, CDCl3): d¼7.70 (s, 1H), 7.42–6.98 (m, 9H),
6.23 (br s, 1H), 5.46 (dd, J1¼2.2 Hz, J2¼1.2 Hz, 1H), 5.14
(d, J¼3.2 Hz, 1H), 4.23 (dq, J1¼3.2 Hz, J2¼6.4 Hz, 1H),
3.92 (d, J¼2.2 Hz, 1H), 1.68 (s, 9H), 1.30 (d, J¼6.4 Hz,
3H), 1.08 (s, 21H). 13C NMR (100 MHz, CDCl3):
d¼168.7, 149.5, 135.2, 134.4, 132.4, 128.5, 127.4, 124.6,
122.6, 118.6, 116.5, 115.4, 85.6, 83.9, 73.7, 68.8, 54.5,
28.1, 18.0, 17.9, 15.9, 12.1. MS (m/z): 567 (M+ꢀt-Bu),
525, 473, 379, 336, 230, 188, 77. E.A. Calcd for
C34H50N2O5SSi: C, 65.14; H, 8.04; N, 4.47. Found: C,
65.41; H, 8.07.
Compound 16b: pale yellow oil. [a]2D0 ꢀ1.3 (c 2.1, CHCl3).
IR (CHCl3): 1666 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d¼7.32 (dd, J1¼1.6 Hz, J2¼4.8 Hz, 1H), 6.99 (m, 2H),
6.53 (br s, NH), 5.05 (dd, J1¼6.4 Hz, J2¼8.4 Hz, 1H),
4.62 (d, J¼6.4 Hz, 1H), 3.87 (m, 1H), 2.78 (m, 2H), 1.32
(d, J¼6.0 Hz, 3H), 1.07 (m, 21H). 13C NMR (100 MHz,
CDCl3): d¼167.52, 142.48, 126.70, 125.72, 124.36, 87.33,
72.32, 71.20, 38.95, 19.61, 18.06, 12.59. MS (m/z): 384,
340, 322, 202, 187. Anal. Calcd for C19H33NO3SSi: C,
59.49; H, 8.67. Found: C, 60.68; H, 8.84.
Compound 14e: pale yellow oil. Y¼20%. [a]2D0 ꢀ42.8
1
(c 1.12, CHCl3). IR (CHCl3): 1737, 1671 cmꢀ1. H NMR

M. Panunzio et al. / Tetrahedron 62 (2006) 12270–12280
12279
4.5.10. (2R,6R)-N-Methyl-2-[(S)-1-triisopropylsilyloxy-
ethyl]-6-(thiophen-2-yl)-[1,3]oxazinan-4-one 17b. Crude
15b was methylated according to the procedure described
for 7b. After column chromatography (3:7 EtOAc/cyclo-
hexane) 17b was obtained in 65% overall yield calculated
from product 13b.
4.5.12.2. Step 2: (R)-3-(methylamino)-1-(thiophen-2-
yl)propan-1-ol (R)-11b. Aqueous HCl (1 M, 2.50 mL)
was added to the crude THF solution of 19b and the stirring
maintained at the same temperature for 4 h. The organic sol-
vent was removed in vacuo and the obtained aqueous solu-
tion extracted with Et2O. The aqueous phase was basified
with NH4OH (pH¼10) and then extracted with CH2Cl2.
The organic phases were dried over Na2SO4 and the solvent
evaporated.
Compound 17b: pale yellow oil. [a]2D0 +36.3 (c 2.7, CHCl3).
IR (CHCl3): 1644 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d¼7.31 (dd, J1¼1.6 Hz, J2¼4.8 Hz, 1H), 7.00 (m, 2H),
5.03 (dd, J1¼5.6 Hz, J2¼8.4 Hz, 1H), 4.96 (d, J¼0.8 Hz,
1H), 4.16 (dq, J1¼0.8 Hz, J2¼6.4 Hz, 1H), 3.06 (s, 3H),
2.76 (m, 2H), 1.17 (d, J¼6.4 Hz, 3H), 1.06 (m, 21H). 13C
NMR (100 MHz, CDCl3): d¼167.45, 142.42, 126.66,
125.63, 124.53, 90.83, 71.14, 70.44, 40.26, 29.65, 18.03,
16.70, 12.19. MS (m/z): 397, 354, 216, 137. Anal. Calcd
for C20H35NO3SSi: C, 60.41; H, 8.87. Found: C, 62.22; H,
9.14.
The crude reaction mixture was subjected to column chro-
matography (ethyl acetate/MeOH/NH4OH 80/19/1) to give
(S)-11b in 68% overall yield calculated on 17b.
Compound (R)-11b: pale yellow oil. [a]2D0 +13.7 (c 2.5,
EtOH) [lit. [a]D +13.3 (c 1.05, MeOH)57]. IR (CHCl3):
1
3302, 3103, 2939, 2853, 2793, 1473, 1315 cmꢀ1. H NMR
(400 MHz, CDCl3): d¼7.20 (dd, J1¼1.2 Hz, J2¼4.8 Hz,
1H), 6.96 (dd, J1¼4.0 Hz, J2¼5.2 Hz, 1H), 6.91 (d,
J¼1.2 Hz, 1H), 5.19 (dd, J1¼2.8 Hz, J2¼8.4 Hz, 1H), 2.94
(m, 1H), 2.89 (m, 1H), 2.44 (s, 3H), 1.95 (m, 2H). 13C
NMR (100 MHz, CDCl3): d¼149.64, 126.53, 123.70,
122.31, 71.92, 50.12, 36.73, 35.88. MS (m/z): 170, 153,
138, 127, 110, 97, 88. Anal. Calcd for C8H13NOS: C,
56.11; H, 7.65. Found: C, 56.21; H, 7.66.
4.5.11. (2S,6S)-N-Methyl-2-[(S)-1-triisopropylsilyloxy-
ethyl]-6-(thiophen-2-yl)-[1,3]oxazinan-4-one 18b. Crude
16b was methylated according to the procedure described
for 7b. After column chromatography (3:7 EtOAc/cyclo-
hexane) 18b was obtained in 54% overall yield calculated
from product 14b.
Compound 18b: pale yellow oil. [a]2D0 ꢀ67.4 (c 2.2, CHCl3).
The same procedure was applied for the preparation of (S)-
11b via reduction product 20b. (S)-11b was obtained in
60% overall yield from 18b.
IR (CHCl3): 1646 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d¼7.29 (dd, J1¼2.4 Hz, J2¼3.6 Hz, 1H), 6.98 (m, 2H),
5.02 (dd, J1¼3.6 Hz, J2¼10.0 Hz, 1H), 4.87 (d, J¼2.4 Hz,
1H), 4.25 (dq, J1¼2.4 Hz, J2¼6.4 Hz, 1H), 2.94 (s, 3H),
2.81 (m, 2H), 1.19 (d, J¼6.4 Hz, 3H), 1.08 (m, 21H). 13C
NMR (100 MHz, CDCl3): d¼167.32, 142.87, 126.60,
125.48, 123.93, 90.84, 70.56, 68.87, 39.90, 29.43, 18.05,
16.57, 12.46. MS (m/z): 397, 354, 216, 137. Anal. Calcd for
C23H41NO3SSi: C, 62.82; H, 9.40. Found: C, 62.70; H, 9.38.
4.5.12.3. Step 1: (2S,6S)-[(S)-1-(triisopropylsilyl-
oxy)ethyl]-3-methyl-6-(thiophen-2-yl)-1,3-oxazinane 20b.
Compound 20b: pale yellow oil. [a]2D0 ꢀ17.8 (c 2.3,
CHCl3). IR (CHCl3): 2944, 2865, 1463 cmꢀ1 1H NMR
.
(400 MHz, CDCl3): d¼7.23 (dd, J1¼2.8 Hz, J2¼3.6 Hz,
1H), 6.96 (m, 2H), 4.73 (dd, J1¼2.8 Hz, J2¼11.6 Hz, 1H),
4.15 (m, 1H), 3.92 (d, J¼4.0 Hz, 1H), 3.07 (ddd,
J1¼1.6 Hz, J2¼4.4 Hz, J3¼14.4 Hz, 1H), 2.88 (dt,
J1¼3.2 Hz, J2¼13.2 Hz, 1H), 2.37 (s, 3H), 2.13 (m, 1H),
1.71 (m, 1H), 1.28 (d, J¼6.0 Hz, 3H), 1.06 (m, 21H). 13C
NMR (100 MHz, CDCl3): d¼146.17, 126.24, 124.31,
122.89, 96.83, 75.32, 68.14, 54.65, 37.22, 29.81, 18.77,
18.17, 12.60. MS (m/z): 383, 340, 235, 182, 123. Anal. Calcd
for C20H37NO2SSi: C, 62.61; H, 9.72. Found: C, 64.49; H,
9.99.
4.5.12. Synthesis of optically pure aminoalcohols (R)-11b
and (S)-11b.
4.5.12.1. Step 1: (2R,6R)-[(S)-1-(triisopropylsilyl-
oxy)ethyl]-3-methyl-6-(thiophen-2-yl)-1,3-oxazinane 19b.
Ph2SiH2 (0.46 mL, 2.5 mmol) and RhH(CO)(PPh3)3 (1%)
were added to a solution of 17b (1.0 mmol) in THF
(10 mL) at room temperature and the stirring maintained
for 15 h. Disappearance of starting material was verified by
TLC (CH2Cl2/cyclohexane/ethyl acetate 50/30/20). An ali-
quot of the solution was utilized for identification of the
reduction product 19b after removing the solvent and fast
purification by a short flash chromatography eluting with
cyclohexane/ethyl acetate 90:10 (saturated with NH3 (g)).
4.5.12.4. Step 2: (S)-3-(methylamino)-1-(thiophen-2-
yl)propan-1-ol (S)-11b. [a]2D0 ꢀ12.0 (c 3.0, EtOH). IR
(CHCl3): 3302, 3103, 2939, 2853, 2793, 1473, 1315 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d¼7.20 (dd, J1¼1.2 Hz,
J2¼4.8 Hz, 1H), 6.96 (dd, J1¼4.0 Hz, J2¼5.2 Hz, 1H),
6.91 (d, J¼1.2 Hz, 1H), 5.19 (dd, J1¼2.8 Hz, J2¼8.4 Hz,
1H), 2.94 (m, 1H), 2.89 (m, 1H), 2.44 (s, 3H), 1.95 (m,
2H). 13C NMR (100 MHz, CDCl3): d¼149.64, 126.53,
123.70, 122.31, 71.92, 50.12, 36.73, 35.88. MS (m/z): 170,
153, 138, 127, 110, 97, 88. Anal. Calcd for C8H13NOS: C,
56.11; H, 7.65. Found: C, 57.23; H, 7.88.
Compound 19b: pale yellow oil. [a]2D0 +35.7 (c 1.0, CHCl3).
1
IR (CHCl3): 2944, 2865, 1463 cmꢀ1. H NMR (400 MHz,
CDCl3): d¼7.23 (dd, J1¼1.6 Hz, J2¼4.8 Hz, 1H), 6.96 (m,
2H), 4.75 (dd, J1¼2.0 Hz, J2¼11.2 Hz, 1H), 3.99 (m, 1H),
3.92 (d, J¼5.2 Hz, 1H), 3.06 (ddd, J1¼2.0 Hz, J2¼4.4 Hz,
J3¼12.8 Hz, 1H), 2.88 (dt, J1¼2.8 Hz, J2¼12.8 Hz, 1H),
2.40 (s, 3H), 2.13 (m, 1H), 1.64 (m, 1H), 1.28 (d,
J¼6.8 Hz, 3H), 1.06 (m, 21H). 13C NMR (100 MHz,
CDCl3): d¼145.80, 126.12, 124.35, 123.43, 97.06, 75.38,
70.46, 54.80, 36.62, 30.51, 18.78, 18.12, 12.27. MS (m/z):
383, 340, 235, 182, 123. Anal. Calcd for C20H37NO2SSi:
C, 62.61; H, 9.72. Found: C, 64.49; H, 9.99.
Acknowledgements
A.D. thanks Farchemia (Treviglio, Italy) for financial sup-
port. M.P., recipient of a grant STM (CNR-Rome) is

12280
M. Panunzio et al. / Tetrahedron 62 (2006) 12270–12280
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