Synthesis of novel optically pure quinolyl-β-amino alcohol derivatives from 2-amino thiophenol and chiral α-acetylenic ketones and their IBX-mediated oxidative cleavage to N-Boc quinolyl carboxamides

Article abstract of DOI:10.1016/S0957-4166(01)00308-1

A methodology directed toward the stereoselective synthesis of novel quinolyl glycines is presented. This strategy is based on the cyclocondensation reaction between 2-amino thiophenol 4 and chiral acetylenic ketones of the type 3 containing a latent α-amino acid functionality. The initially formed benzo[b][1,4]thiazepine derivatives 5, readily undergo sulphur extrusion in refluxing toluene to yield the corresponding 2,4-disubstituted quinolines 6. Subsequent oxazolidine ring opening followed by in situ re-protection of the amino group afforded the corresponding quinolyl-β-amino alcohols 8a-8f in enantiomerically pure form and good overall yields. The derivatives 8 are in principle suitable precursors for the synthesis of novel optically pure quinolyl glycines through oxidation of the alcohol side chain. However, these amino alcohol derivatives 8, did not afford the expected quinolyl glycines 10 using numerous oxidising agents and reaction conditions. Instead, by reacting 8 with the mild oxidising reagent IBX 11, an oxidative C-C cleavage leading to the N-Boc quinolyl carboxamides 12 took place.

Full text of DOI:10.1016/S0957-4166(01)00308-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1851–1863
Synthesis of novel optically pure quinolyl-b-amino alcohol
derivatives from 2-amino thiophenol and chiral a-acetylenic
ketones and their IBX-mediated oxidative cleavage to N-Boc
quinolyl carboxamides†
Gemma Cabarrocas,a Montserrat Ventura,a Miguel Maestro,b Jose´ Mah´ıab and
Jose´ M. Villalgordoa,*
aDepartament de Qu´ımica, Facultat de Cie`ncies, Universitat de Girona, Campus de Montilivi, E-17071 Girona, Spain
bServicios Xerais de Apoio a Investigacio´n, Universidade da Corun˜a, Campus da Zapateira s/n, E-15071 A Corun˜a, Spain
Received 8 June 2001; accepted 2 July 2001
Abstract—A methodology directed toward the stereoselective synthesis of novel quinolyl glycines is presented. This strategy is
based on the cyclocondensation reaction between 2-amino thiophenol 4 and chiral acetylenic ketones of the type 3 containing a
latent a-amino acid functionality. The initially formed benzo[b][1,4]thiazepine derivatives 5, readily undergo sulphur extrusion in
refluxing toluene to yield the corresponding 2,4-disubstituted quinolines 6. Subsequent oxazolidine ring opening followed by in
situ re-protection of the amino group afforded the corresponding quinolyl-b-amino alcohols 8a–8f in enantiomerically pure form
and good overall yields. The derivatives 8 are in principle suitable precursors for the synthesis of novel optically pure quinolyl
glycines through oxidation of the alcohol side chain. However, these amino alcohol derivatives 8, did not afford the expected
quinolyl glycines 10 using numerous oxidising agents and reaction conditions. Instead, by reacting 8 with the mild oxidising
reagent IBX 11, an oxidative CꢀC cleavage leading to the N-Boc quinolyl carboxamides 12 took place. © 2001 Published by
Elsevier Science Ltd.
1. Introduction
An important class of such non-proteinogenic amino
acids are the arylglycines.10 This type of a-amino acid is
present in many biologically active compounds such as
cephalosporins,11 penicillins, nocardicins12 and gly-
copeptidic antibiotics of the vancomycin group.13
Although several approaches have been reported for
The non-coded amino acids are a diverse range of
compounds whose synthesis in enantiomerically pure
form has attracted considerable attention in the last few
years.1,2 Interest in the development of synthetic meth-
ods toward the preparation of non-proteinogenic amino
acids has arisen due to the biological and toxicological
properties displayed by many of these compounds.3–5 In
addition, non-standard amino acids are valuable tools
for the creation of peptide or non-peptide based combi-
natorial libraries6 and incorporation of ‘unusual’ amino
acids into peptides or peptidomimetics often provides
biostability to the degradation by peptidases. The syn-
thesis of these types of substrates is therefore of interest
in the design of potential novel therapeutic agents.7–9
the asymmetric synthesis of
a number of aryl-
glycines,10,14 their application for the preparation of
heterocyclic analogues has been extended generally with
limited success in terms of efficiency and/or optical
purities. Recently, a remarkably successful approach
regarding the stereoselective synthesis of isoxazolyl a-
amino acids has been reported.15
a-Acetylenic ketones of the type 1 have been shown to
be highly versatile building blocks. These conjugated
ynones have proven to be very suitable substrates for
the synthesis of a wide range of heterocyclic systems,16–
25 including for instance the synthesis of the natural
* Corresponding author. Fax: +34 972 418 150; e-mail:
product
L
-lathyrine and related analogues.26 In addi-
jose.villalgordo@udg.es
†
tion, when properly functionalised, these types of com-
Taken in part from the Ph.D. Thesis of G.C., Universitat de
Girona, 1999.
pounds 1 have also proven to be very valuable
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00308-1

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G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
substrates for the preparation of highly structurally
diverse 2,4,6-trisubstituted pyrimidines by combinato-
rial and parallel synthesis methods.27,28 In view of the
great synthetic potential offered by these conjugated
ynones and in connection with our ongoing studies
dealing with the synthesis of non-proteinogenic aro-
matic and heteroaromatic a-amino acids in optically
active form, we recently described an efficient synthesis
of novel chiral a-acetylenic ketones 1 from naturally
occurring serine 229 (Scheme 1). Compounds 3, bearing
a latent a-amino acid moiety as a special structural
feature, were designed to readily incorporate a masked
amino acid functionality into a variety of relevant
heterocycles. Subsequent oxazolidine ring opening and
oxidation of the primary alcohol side chain should lead
to novel heteroarylglycines in optically active form. In
this context, we focussed our attention on the quinoline
nucleus and now report the full details of our studies
regarding the use of chiral a-acetylenic ketones 3 as
potential precursors of novel quinolyl glycines.
2. Results and discussion
When 2-amino thiophenol 4 was allowed to react in
anhydrous THF at −78°C with chiral a-alkynyl ketones
of the type 3 for a period of 3–12 h, followed by
acid-catalysed cyclisation at 0°C, the corresponding
seven-membered benzo[b][1,4]thiazepine derivatives 5a–
5f were isolated in excellent yields. In the single case of
5f, containing an aliphatic substituent, addition of
PPTS (as acidic catalyst) to effect cyclocondensation
was not necessary. These transformations leading to
5a–5f took place in a very efficient and clean manner.
Derivatives 5a–5f were stable enough to be subjected to
a rapid chromatographic filtration over a small plug of
silica to afford pure 5a–5f as yellow oils or foams,
allowing for structural determination and characterisa-
tion by standard spectroscopic techniques. However, on
standing for more than 24 h at rt, 5a–5f spontaneously
underwent partial sulphur extrusion to yield quinolines
6. In view of these results, in a second set of experi-
ments we moved directly onto 6a–6f by evaporating the
THF solution containing derivatives of type 5, adding
dry toluene, and heating under reflux for several hours.
By using this procedure, quinolines 6 were obtained
exclusively in very good yields (72–95% overall yields
for two steps) (Scheme 2, Tables 1 and 2).
O
R1
R2
At this stage, due to the known configurational stability
of the stereogenic centre of the oxazolidine ring in 3,
the synthetic sequence above described was expected to
be stereospecific. We checked the optical purity of the
isolated quinolines 6, and these were indeed found to be
enantiomerically pure (]95%) as determined by 1H
NMR analysis (200 MHz) in the presence of varying
amounts of Eu(hfc)3. In addition, we were able to
obtain crystals of 6c that were suitable for X-ray crys-
tallographic structure determination which confirmed
both the proposed structure and additionally that the
1
O
R
NH2
HO
OH
O
N
O
Boc
2
3
Scheme 1.
O
N
O
N
O
Boc
SH
S
Boc
+
NH2
N
R
R
5a-5f
4
3a-3f
O
N
Boc
R
N
6a-6f
Scheme 2.

G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
Table 1. Benzo[b][1,4]thiazepine derivatives 5a–5f
1853
Table 2. Chiral quinolyl oxazolidine derivatives 6a–6f
this derivative 9 was assessed by 1H NMR and found to
crystals were enantiomerically pure. It was then
assumed that they had the expected absolute configura-
tion. This assumption was extended to the complete
series of synthesised compounds 6a–6f (Fig. 1).
be diastereoisomerically pure (Scheme 3, Table 3).
In addition, we were able to grow crystals of 8f of
adequate quality for an X-ray crystallographic structure
determination that confirmed the proposed structure
and showed that 8f was enantiomerically pure. It was
then assumed that they had the expected absolute
configuration. This assumption was extended to the
complete series of synthesised N-Boc-b-amino alcohol
derivatives 8a–8f (Fig. 2).
After sulphur extrusion, we then proceeded to selec-
tively cleave the oxazolidine ring in 6 without affecting
the N-protecting group. After trying a number of dif-
ferent conditions, 8 was obtained by treatment of 6
with p-toluenesulphonic acid in dry MeOH at rt; how-
ever, the yields were very low (ꢀ10%). Alternatively,
treatment of 6a–6f with TFA in MeOH at 0°C afforded
the corresponding amino alcohols 7a–7f which were not
isolated but were re-protected in situ to afford N-Boc-
protected chiral b-amino alcohols 8a–8f in very good
overall yields. For the particular case 8b, we did pre-
pare the corresponding Mosher’s ester derivative 9 from
the crude reaction mixture. The enantiomeric excess of
With a good and reliable procedure in our hands to
efficiently prepare optically active quinolyl-b-amino
alcohols of type 8, we proceeded to further study the
critical oxidation step of the lateral chain containing
the primary alcohol moiety. This transformation should
afford the initially targeted novel optically active
quinolyl glycines. To achieve this transformation we

1854
G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
Figure 1. ORTEP plot of the molecular structure of 6c with 30% probability ellipsoids42 (Table 5).
Figure 2. ORTEP plot of the molecular structure of 8f with 30% probability ellipsoids42 (Table 5).

G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
1855
OH
O
NH2
N
Boc
TFA
MeOH / 0°C
N
R
N
R
6a-6f
7a-7f
H
N
HO
Boc
R
p-TsOH
(Boc)2O / r.t.
NaHCO3(sat.) / Dioxane 1:1
MeOH / r.t.
Low yields
N
85-93%
8a-8f
For 8b
O
H
N
O
Boc
MeO
CF3
O
N
O
9
Scheme 3.
Table 3. Chiral N-Boc-protected quinolyl-b-amino alcohol derivatives 8a–8f
acids30 we selected several different methods to carry
out this transformation. Thus, when chiral b-amino
alcohol derivatives of the type 8 were allowed to react
with either dilute aqueous KMnO4,31,32 TEMPO/
initially attempted a direct oxidative strategy to the
corresponding carboxylic acid. From the large amount
of available data reported in the literature regarding the
direct oxidation of primary alcohols to carboxylic

1856
G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
NaClO33 or with RuCl3/NaIO4 (Sharpless oxidation)34–36
very complex mixtures of products were obtained. Only
in the case of using TEMPO/NaClO, the presence of car-
boxylic acids of type 10 could be detected but only in trace
amounts. In view of these discouraging results, we decided
to use a milder oxidative method that could account for
the partial oxidation of 8 to the corresponding aldehydes
9 that in turn would be further oxidised to the correspond-
ing a-amino acids 10 under stronger oxidising conditions.
However, when we attempted the partial oxidation of chi-
ral b-amino alcohol derivatives 8 to the corresponding
aldehydes 9 under Swern oxidation conditions,37–39 com-
plex reaction mixtures were also obtained. Finally, we
found that when the N-Boc-protected amino alcohol
derivatives 8a, 8c, 8e were allowed to react with 2
equiv. of 1-hydroxy-1-oxo-benzo[d][1,2]iodoxol-3-one40
11 (IBX) at 75°C in DMSO, a clean transformation lead-
ing to the formation of N-Boc quinolyl carboxamides of
type 12 took place instead of the formation of the alde-
hydes 9 or the acids 10 (Scheme 4, Table 4).
O
H
N
Partial Oxidation
H
Boc
R
N
9
O
H
H
N
N
HO
Boc
HO
Boc
R
Direct Oxidation
N
R
N
8
10
O
I
OH
H
N
O
O
O
O
R
A plausible mechanism that could account for the forma-
tion of quinolyl carboxamides of type 12 is depicted in
Scheme 5.
O
11
DMSO / 75°C
N
63-68%
12a-12c
Thus, IBX 11 would initially oxidise amino alcohol
derivatives 8 to the corresponding aldehydes 9. These
aldehydes 9, through their enol form 13, would react with
another molecule of 11 to give spicrocyclic intermediate
14, which would undergo CꢀC bond cleavage affording
carboxamides 12 in addition to o-iodosobenzoic acid 16
and formic acid 15. This mechanism has been proposed in
analogy to those suggested for chromium(VI)-based
reagents where CꢀC bond cleavage is known to occur fre-
quently in the case of readily enolisable aldehydes.41 To
the best of our knowledge, however, this is the first time
that IBX is reported to promote such oxidative CꢀC
cleavage of readily enolisable aldehydes.
Scheme 4.
tives are of particular interest, since they can serve as
novel building blocks for biologically active molecules or
they can be used as chiral ligands for asymmetric transfor-
mations. In addition, compounds 8 could be in principle
adequate precursors for the synthesis of novel chiral
quinolyl glycines 10. However, under a variety of reaction
conditions using different oxidising reagents we were
unable obtain our initially targeted a-amino acids of type
10. In the best case, we discovered that substrates of the
type 8 underwent oxidative CꢀC bond cleavage with mild
oxidising agent 11, presumably through the enol form of
the corresponding aldehyde 9. A mechanism to explain
such a transformation has been proposed. Nevertheless,
the idea of incorporating latent a-amino acid functional-
ities into relevant core structures such as quinolines
through acetylenic ketones of type 3 proved successful. At
present, new acetylenic ketones incorporating other
masked a-amino acid functionalities into their structure
that could avoid the critical oxidation step are being stud-
ied intensively in our laboratories and the results will be
reported in due course.
3. Conclusion
In summary, we have shown that chiral a-acetylenic
ketones of the type 3, containing a masked a-amino acid
group can serve as valuable synthetic intermediates to
incorporate this structural motif into heterocycles such as
quinolines. In consequence, an efficient and straightfor-
ward synthesis of novel optically active quinolyl-b-amino
alcohols of the type 8 has been developed. These deriva-
Table 4. N-Boc quinolyl carboxamide derivatives 12a–12c prepared

G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
1857
R
R
R
O
IBX, 11
HO
Boc
Boc
Boc
N
H
N
H
N
H
HO
H
H
8
9
13
R
HO
H
NHBoc
O
OH
O
O
O
I
HO
O
H
HN
I
O
+
R
O
Boc
13
11
14
I
O
H
H2O
R
N
HCOOH
+
+
Boc
COOH
O
16
15
12
R = 2-Substituted Quinolines
Scheme 5.
4. Experimental
4.1. General methods
model. Crystal data and details on the data collection
and refinement are summarised in Table 5.
Table 5. Crystallographic data for 6c and 8f
All commercially available chemicals were used as pur-
chased, except THF and Toluene that were distilled over
Na/benzophenone prior to use. Melting points (capil-
lary tube) were measured with a Gallenkamp apparatus
and are uncorrected. IR spectra were recorded on a
Mattson-Galaxy Satellite FT-IR. 1H and 13CNMR spec-
tra were recorded at 200 and 50 MHz, respectively, on
a Bruker DPX200 Advance instrument with TMS as
internal standard. MS spectra were recorded on a VG
Quattro instrument in the positive-ionisation FAB
mode, using 3-NBA or 1-thioglycerol as the matrix or in
a Hewlett–Packard 5989A instrument for electron-
impact (70 eV) mode. Elemental analyses were per-
formed on an apparatus from Thermo instruments,
model EA1110-CHNS. Optical rotation measurements
were performed on a Perkin–Elmer 241 polarimeter.
Analytical TLC was performed on precoated TLC
plates, silica gel 60 F254 (Merck). Flash chromatography
purifications were performed on silica gel 60 (230–400
mesh, Merck). X-Ray data were collected on a Bruker
SMART CCD area-detector diffractometer with
graphite-monochromated Mo Ka radiation (u=0.71073
Data/compound
6c (Fig. 1)
8f (Fig. 2)
Empirical formula
Formula weight
Space group
Crystal system
Z
C23H26N2O2S
410.52
P21
Monoclinic
2
9.351(2)
10.561(4)
11.992(3)
112.863(13)
1091.4(6)
1.294
C22H32N2O2
372.5
P2(1)2(1)2(1)
Orthorhombic
4
5.069(1)
15.743(1)
27.667(1)
90
2208.7(1)
1.121
,
a (A)
,
b (A)
,
c (A)
i (°)
3
,
V (A )
z(calcd) (g/cm3)
vcalcd (mm−1
F (000)
)
0.174
436
0.70173
298(2)
0.074
808
0.70173
298(2)
,
Radiation (Mo Ka) (A)
T (K)
Crystal size (mm)
Crystal colour
Reflections measured
Independent reflections
0.45×0.40×0.25 0.50×0.15×0.05
Colourless
4627
3197
(Rint=0.0170)
0.958/0.926
Pale brown
9389
3887
(Rint=0.0409)
0.996/0.964
Max./min. transmission
coefficients
Data/restrains/parameters
,
A) operating at rt, using the phi–omega scan method.
3197/1/263
3887/0/245
1.5–25.0
1.119
Absorption corrections were applied using SADABS.43
The structures were solved by the direct method using
SHELXS-9744 and were refined by the least-squares
method on F2. All non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were included in geo-
metrically calculated positions and refined using a riding
q Range for data collection 1.8–25.0
Goodness-of-fit
Final R1, wR2 indicesa
[I\2|(I)]
1.061
0.0413, 0.1079
0.0534, 0.1247
a R1=ꢀꢁꢁFoꢁ−ꢁFcꢁꢁ/ꢀꢁFoꢁ and wR2={ꢀ[w(Fo2−Fc2)2]/ꢀ[w(Fo2)2]}1/2
.

1858
G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
Crystallographic data (excluding structure factors) for
the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 161478
(for 6c) and CCDC 161479 (for 8f). Copies of the data
can be obtained free of charge on application to:
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: (+44)1223-336-033; e-mail: deposit@ccdc.cam.
ac.uk).
(600 mg, 1.61 mmol), 4 (246 mg, 1.93 mmol) and PPTS
(83 mg, 0.32 mmol) afforded 5b as a yellow foam (741
mg, 96%); [h]2D0 −21.5 (c 0.72, MeOH); IR (KBr, w,
cm−1): 2976m, 2926m, 2856m, 1699s, 1626w, 1591w,
1571w, 1487m, 1443m, 1370s, 1296m, 1249s, 1210w,
1
1168m, 1100m, 1038m, 937w, 850w, 810w, 761m; H
NMR (CDCl3): l 7.65–7.10 (m, 6H, CHarom.), 6.87 (d,
J=8 Hz, 1H, CHarom.), 6.49 (s, 1H), 6.05 (s, 2H,
OCH2O), 4.6 (s, br., 1H, CH), 4.21 (dd, J=9.1 Hz,
J%=6.9 Hz, 1H, CH2O), 3.99 (s, br., 1H, CH2O), 1.80–
1.25 (m, br., 15H); 13C NMR (CDCl3, doubling of
some signals observed): l 164.3+163.6 (s, CꢁN), 151.6,
150.6, 150.0, 149.7 (4s, Carom.+NCO), 148.2, 133.5 (2s,
Carom.), 132.0, 130.9, 129.2, 128.8 (4d, CHarom.), 128.2+
127.5 (s, Carom.), 126.4+126.2, 124.7+124.0, 123.4+123.0,
107.8+107.4 (4d, CHarom.), 101.9+101.5 (t, OCH2O),
95.2+94.6 (s, C(CH3)2), 80.8+80.4 (s, C(CH3)3), 67.5+
67.2 (t, CH2O), 63.2 (d, CH), 28.3+28.0 (q, C(CH3)3),
26.9+26.1 (q, C(CH3)2), 24.6+23.4 (q, C(CH3)2); MS
(EI, 70 eV) m/e: 480 (M+, 5), 448 (25), 334 (14), 333
(53), 317 (10), 304 (23), 83 (10), 71 (10), 69 (13), 57
(100).
4.2. Synthesis of benzo[b][1,4]thiazepine derivatives 5a–5f
and quinoline derivatives 6a–6f. General procedure
Into a cooled (−78°C) solution of 3 in anhydrous THF
(2.1 mL/mmol), another solution of 2-amino thiophe-
nol 4 (1.2 equiv.) in THF (1 mL/mmol), was added
dropwise. The reaction mixture was stirred at −78°C
until total consumption of 3 (3–12 h, monitored by
TLC). The reaction was slowly warmed to 0°C, and 20
mol% of pyridinium p-toluenesulphonate (PPTS) was
added (except for 3f). After stirring at 0°C for 8–15 h
(monitored by TLC), the mixture was partitioned
between 0.1 M phosphate buffer (pH 7.1) and AcOEt.
The organic layer was separated, dried over MgSO4
(anhyd.), the solvent eliminated under reduced pressure
(T <35°C), and the resulting residue purified through a
short silica-gel column (hexanes/AcOEt as eluent) to
afford pure 5a–5f. These compounds 5a–5f were dis-
solved in dry toluene (3 ml/mmol) and refluxed for
12–15 h. Evaporation of the solvent and flash chro-
matography of the resulting residue (n-hexane/AcOEt
as eluent) afforded pure 6a–6f.
4.2.3. Benzo[b][1,4]thiazepine 5c. According to the gen-
eral procedure described above, reaction between 3c
(850 mg, 2.54 mmol), 4 (382 mg, 3.05 mmol) and PPTS
(127 mg, 0.50 mmol) afforded 5c as a yellow foam (1.07
g, 96%); [h]2D0 −83.0 (c 0.97, MeOH); IR (film, w, cm−1):
3294w, 3260w, 3069w, 2977m, 2932, 2875m, 1699s,
1624w, 1567m, 1456m, 1422m, 1371s, 1301d, 1245m,
1205w, 1168m, 1097m, 1057m, 939w, 849m, 807w,
1
761m, 713m, 676w; H NMR (DMSO-d6, T=60°C): l
7.85 (dd, J=5.1 Hz, J%=1 Hz, 1H, CHarom.), 7.61 (dd,
J=3.6 Hz, J%=1 Hz, 1H, CHarom.), 7.50–7.25 (m, 5H,
CHarom.), 6.85 (s, 1H), 4.74 (dd, J=7.0 Hz, J%=3.8 Hz,
1H, CH), 4.29 (dd, J=9.2 Hz, J%=7.0 Hz, 1H, AB sys.,
CH2O), 3.91 (dd, J=9.2 Hz, J%=3.8 Hz, 1H, AB sys.,
CH2O), 1.81 (s, 3H, C(CH3)2), 1.60 (s, 3H, C(CH3)2),
1.38 (s, br., 9H, C(CH3)3); 13C NMR (DMSO-d6, T=
60°C): l 159.2 (s, CꢁN), 151.4, 150.8, 148.9, 145.0 (4s,
Carom.+NCO), 131.7, 130.9, 129.1, 128.9, 127.6 (5d,
CHarom.), 126.7 (s, Carom.), 126.6, 125.8, 123.5 (3s,
CHarom.), 94.0 (s, C(CH3)2), 79.3 (s, C(CH3)3), 66.9 (t,
CH2O), 62.4 (d, CH), 27.5 (q, C(CH3)2), 25.6 (q,
C(CH3)2), 23.8 (q, C(CH3)3); MS (FAB+) m/e: 444
([M+2]+, 28), 443 ([M+1]+, 100), 442 ([M]+, 23), 387
(33), 329 (21), 268 (32), 267 (51), 218 (22).
Alternatively, after cyclocondensation has been
effected, THF was removed under reduced pressure (T
<35°C), dry toluene (3 ml/mmol) added to the residue,
and the mixture refluxed for 12–15 h. Work-up identi-
cal as above afforded pure 6a–6f (Tables 1 and 2).
4.2.1. Benzo[b][1,4]thiazepine 5a. According to the gen-
eral procedure described above, reaction between 3a
(200 mg, 0.60 mmol), 4 (121.6 mg, 0.973 mmol) and
PPTS (30.5 mg, 0.12 mmol) afforded 5a as a yellow
foam (251 mg, 95%); [h]2D0 −46.9 (c 0.64, MeOH); IR
(KBr, w, cm−1): 3060w, 2979m, 2931m, 2875w, 1701s,
1626w, 1570w, 1455m, 1370s, 1296w, 1259m, 1210w,
1
1168m, 1101m, 1060m, 851m, 762m, 694m; H NMR
(DMSO-d6, T=60°C): l 8.1–7.3 (m, 9H, CHarom.), 6.76
(s, 1H), 4.80–4.75 (m, 1H), 4.31 (dd, 1H, J=9.2 Hz,
J%=7 Hz, AB sys., CH2O), 3.94 (dd, 1H, J=9.2 Hz,
J%=7 Hz, AB sys., CH2O), 1.78 (s, 3H, C(CH3)2), 1.60
(s, 3H, C(CH3)2), 1.40 (s, br., 9H, C(CH3)3); 13C NMR
(DMSO-d6, T=60°C): l 164.2 (s, CꢁN), 151.2, 150.8,
149.2, 138.3 (4s, Carom.+NCO), 131.6, 130.5, 129.0,
128.1 (4d, CHarom.), 127.1 (s, Carom.), 126.9, 126.4,
125.6, 124.4 (4d, CHarom.), 94.0 (s, C(CH3)2), 79.4 (s,
C(CH3)3), 66.9 (t, CH2O), 62.4 (d, CH), 27.5 (q,
C(CH3)3), 25.7, 23.7 (2q, C(CH3)2); MS (EI, 70 eV)
m/e: 436 (M+, 5), 289 (20), 262 (13), 261 (30), 57 (100).
4.2.4. Benzo[b][1,4]thiazepine 5d. According to the gen-
eral procedure described above, reaction between 3d
(150 mg, 0.47 mmol), 4 (70.63 mg, 0.56 mmol) and
PPTS (24.5mg, 0.097 mmol) afforded 5d as a yellow oil
(0.114 g, 57%); [h]2D0 −90.4 (c 1.34, MeOH); IR (film, w,
cm−1): 3131w, 3058w, 2980w, 2932m, 2877w, 1737w,
1700s, 1626w, 1592w, 1562w, 1477m, 1456m, 1370s,
1303w, 1251m, 1207w, 1166m, 1093m, 1053m, 1012w,
944w, 919w, 809w, 850m, 758m, 676w; 1H NMR
(DMSO-d6, T=60°C): l 7.96 (dd, J=1.8 Hz, J%=0.8
Hz, 1H, CHarom.), 7.55–7.30 (m, 4H, CHarom.), 7.16 (dd,
J=3.4 Hz, J%=0.8 Hz, 1H, CHarom.), 6.77 (dd, J=3.4
Hz, J%=1.8 Hz, 1H, CHarom.), 6.75 (s, 1H, CHarom.),
4.71 (dd, J=7.0 Hz, J%=3.6 Hz, 1H, CH), 4.27 (dd,
4.2.2. Benzo[b][1,4]thiazepine 5b. According to the gen-
eral procedure described above, reaction between 3b

G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
1859
J=9.2 Hz, J%=7.0 Hz, 1H, AB sys., CH2O), 3.88 (dd,
J=9.2 Hz, J%=3.6 Hz, 1H, AB sys., CH2O), 1.80 (s,
3H, C(CH3)2), 1.59 (s, 3H, C(CH3)2), 1.36 (s, br., 9H,
C(CH3)3); H NMR (DMSO-d6, T=60°C): l 154.9 (s,
CꢁN), 152.5, 151.7, 150.8, 149.1 (4s, Carom.+NCO),
145.5, 131.8, 129.2, 126.7 (4d, CHarom.), 125.9 (s,
0.81, MeOH); IR (KBr, w, cm−1): 3063w, 2981m,
2932m, 2890w, 2863w, 1698s, 1685s, 1602m, 1550w,
1496w, 1475w, 1452w, 1386s, 1365m, 1264m, 1243m,
1205w, 1167m, 1097m, 1053m, 1031w, 945w, 885w,
1
1
853m, 809w, 771m, 692m, 619w; H NMR (DMSO-d6,
T=60°C): l 8.30–8.25 (m, 4H, CHarom.), 7.95–7.60 (m,
6H, CHarom.), 5.95–5.90 (m, 1H, CH), 4.75–4.65 (m,
1H, CH2O), 3.94 (d, J=9 Hz, 1H, CH2O), 1.96 (s, 3H,
C(CH3)2), 1.76 (s, 3H, C(CH3)2), 1.30 (s, br., 9H,
C(CH3)3); 13C NMR (DMSO-d6, T=60°C): l 153.3,
151.1 (2s, Carom.), 148.3 (s, NCO), 147.7, 138.7 (2s,
Carom.), 125.8, 123.0, 113.1, 112.0 (4d, CHarom.), 94.1 (s,
C(CH3)2), 79.4 (s, C(CH3)3), 66.8 (t, CH2O), 62.5 (d,
CH), 27.5 (q, C(CH3)2), 25.6 (q, C(CH3)2), 23.8 (q,
C(CH3)3); MS (EI, 70 eV) m/e: 428 ([M+2]+, 1), 427
([M+1]+, 3), 426 ([M]+, 10), 293 (10), 279 (27), 252 (18),
251 (55), 57 (100).
C
arom.), 129.7, 129.2, 129.1, 128.6, 126.4, 126.2 (6d,
CHarom.), 124.3 (s, Carom.), 122.7, 113.7 (d, CHarom.),
93.8 (s, C(CH3)2), 79.3 (s, C(CH3)3), 68.8 (t, CH2O),
56.7 (d, CH), 27.4 (q, C(CH3)3), 26.1, 23.4 (2q,
C(CH3)2); MS (EI, 70 eV) m/e: 405 ([M+1]+, 10), 404
([M]+, 4), 333 (11), 289 (42), 57 (100). Anal. calcd for
C25H28N2O3 (404.50): C, 74.23; H, 6.98; N, 6.93.
Found: C, 73.95; H, 7.20; N, 7.14%.
4.2.5. Benzo[b][1,4]thiazepine 5e. According to the gen-
eral procedure described above, reaction between 3e
(775 mg, 1.85 mmol), 4 (279 mg, 2.22 mmol) and PPTS
(93 mg, 0.37 mmol) afforded 5e as a yellow foam (0.914
g, 94%); [h]2D0 −157.6 (c 1.03, MeOH); IR (film, w, cm−1):
3057w, 2973m, 2934m, 2876m, 1698s, 1626w, 1573m,
1503m, 1457m, 1411w, 1372s, 1339m, 1256m, 1206w,
1
1170m, 1126m, 1064w, 1006w, 849m, 762m, 699w; H
4.2.8. Quinolyl oxazolidine 6b. By following the general
procedure described above, 6b was isolated in 85% yield
as a colourless solid; mp 164–165°C; [h]2D0 −139.7 (c
1.03, MeOH); IR (KBr, w, cm−1): 3082w, 2983m, 2904w,
2876w, 1693s, 1601m, 1552w, 1500m, 1449m, 1383s,
1307w, 1247m, 1165m, 1095m, 1042m, 939w, 878w,
NMR (DMSO-d6, T=60°C): l 7.55–7.30 (m, 6H,
CHarom.), 6.76 (s, 1H, CHarom.), 4.77 (dd, J=6.9 Hz,
J%=3.3 Hz, 1H, CH), 4.35–4.10 (m, 2H, CH2O), 3.98 (s,
6H, 2×CH3O), 3.89 (s, 3H, CH3O), 1.80 (s, 3H,
C(CH3)2), 1.60 (s, 3H, C(CH3)2), 1.37 (s, br., 9H,
C(CH3)3); 13C NMR (DMSO-d6, T=60°C): l 163.3 (s,
CꢁN), 153.1, 150.9, 150.6, 149.1 (4s, Carom.+NCO),
140.9, 133.5 (2s, Carom.), 131.6, 128.9 (2d, CHarom.),
127.1 (s, Carom.), 126.2, 125.6, 122.6, 105.8 (4s, CHarom.),
93.9 (s, C(CH3)2), 79.3 (s, C(CH3)3), 66.8 (t, CH2O),
62.6 (d, CH), 59.8, 56.1 (2q, 3xCH3O), 27.4 (q,
C(CH3)2), 25.8 (q, C(CH3)2), 24.1 (q, C(CH3)3); MS
(FAB+) m/e: 528 ([M+2]+, 31), 527 ([M+1]+, 100), 526
([M]+, 14), 471 (28), 391 (18), 327 (12), 326 (46), 279
(15).
1
847m, 814m, 762m, 696w; H NMR (DMSO-d6, T=
60°C): l 8.20–8.15 (m, 2H, CHarom.), 7.90–7.65 (m, 5H,
CHarom.), 7.18 (d, J=8.2 Hz, 1H, CHarom.), 6.21 (s, 2H,
OCH2O), 5.90–5.85 (m, 1H, CH), 4.75–4.65 (m, 1H,
CH2O), 3.95–3.90 (m, 1H, CH2O), 1.95 (s, 3H,
C(CH3)3), 1.74 (s, 3H, C(CH3)3), 1.30 (s, br. 9H,
C(CH3)3); 13C NMR (DMSO-d6, T=60°C): l 154.7,
151.2 (2s, Carom.), 148.6, 148.2, 148.0, 147.7 (4s, Carom.
+
NCO), 133.1 (s, Carom.), 129.6, 129.3, 126.0 (3d,
CHarom.), 124.2 (s, Carom.), 122.7, 120.7, 113.4, 108.4,
106.4 (5d, CHarom.), 101.2 (t, OCH2O), 93.8 (s,
C(CH3)2), 79.3 (s, C(CH3)3), 68.8 (t, CH2O), 56.8 (d,
CH), 27.5 (q, C(CH3)3), 26.1 (q, C(CH3)2), 23.5 (q,
C(CH3)2); MS (EI, 70 eV) m/e: 449 ([M+1]+, 11), 448
([M]+, 38), 377 (14), 334 (21), 333 (85), 317 (14), 303
(15), 291 (13), 289 (12), 274 (14), 57 (100). Anal. calcd
for C26H28N2O5 (448.51): C, 69.63; H, 6.29; N, 6.25.
Found: C, 69.36; H, 6.47; N, 6.03%.
4.2.6. Benzo[b][1,4]thiazepine 5f. According to the gen-
eral procedure described above, reaction between 3f
(500 mg, 1.48 mmol) and 4 (258 mg, 2.07 mmol) (no
addition of PPTS) afforded 5f as a yellow oil (0.497 g,
76%); [h]2D0 −79.1 (c 1.11, MeOH); IR (film, w, cm−1):
3059w, 2957m, 2930m, 2859m, 1704s, 1631m, 1607w,
1581w, 1459m, 1371s, 1261m, 1170m, 1205w, 1095m,
1063m, 944w, 850m, 806w, 762m, 678w, 590w; 1H
NMR (DMSO-d6, T=60°C): l 7.50–7.10 (m, 4H,
CHarom.), 6.29 (s, 1H), 4.70–4.55 (m, 1H, CH), 4.23 (dd,
J=9.2 Hz, J%=7.0 Hz, 1H, AB sys., CH2O), 3.82 (dd,
J=9.2 Hz, J%=3.4 Hz, 1H, AB sys., CH2O), 2.65–2.55
(m, 2H), 1.85–1.35 (m, 23H), 0.98 (t, J=6.8 Hz, 3H);
13C NMR (DMSO-d6, T=60°C): l 161.4 (s, CꢁN),
150.7, 149.5, 149.2 (3s, Carom.+NCO), 131.6, 128.9 (2d,
CHarom.), 127.3 (s, Carom.), 126.2, 125.9, 125.4 (3d,
CHarom.), 93.9 (s, C(CH3)2), 79.2 (s, C(CH3)3), 66.9 (t,
CH2O), 62.2 (d, CH), 40.2, 37.7, 30.7, 28.4 (4t, CH2),
27.5, 25.9 (2q, C(CH3)2), 24.2 (q, C(CH3)3), 21.6 (t,
CH2), 13.4 (q, CH3); MS (EI, 70 eV) m/e: 446 ([M+2]+,
1), 445 ([M+1]+, 3), 57 (100).
4.2.9. Quinolyl oxazolidine 6c. By following the general
procedure described above, 6c was isolated in 86% yield
as a colourless solid; mp 204–205°C; [h]2D0 −199.8 (c
0.84, MeOH); IR (KBr, w, cm−1): 3074w, 2979m, 2930w,
2879w, 1685s, 1605m, 1551w, 1454w, 1428m, 1392s,
1364m, 1262m, 1239m, 1168m, 1096m, 1072w, 1052m,
875w, 831w, 809w, 767m, 730m, 690w; 1H NMR
(C6D6, T=60°C): l 8.36 (d, J=8.5 Hz, 1H, CHarom.),
8.09 (s, 1H, CHarom.), 7.90 (d, J=3.8 Hz, 1H, CHarom.),
7.62 (d, J=8.5 Hz, 1H, CHarom.), 7.55–7.45 (m, 1H,
CHarom.), 7.35–7.25 (m, 1H, CHarom.), 7.16 (d, J=5 Hz,
1H, CHarom.), 6.95 (dd, J=5 Hz, J%=3.8 Hz, 1H,
CHarom.), 5.56 (dd, J=7.4 Hz, J%=3.2 Hz, 1H, CH),
4.21 (dd, J=8.8 Hz, J%=7.4 Hz, 1H, AB sys., CH2O),
3.74 (dd, J=8.8 Hz, J%=3.2 Hz, 1H, AB sys., CH2O),
2.11 (s, 3H, C(CH3)2), 1.81 (s, 3H, C(CH3)2), 1.26 (s,
br., 9H C(CH3)3); 13C NMR (C6D6, T=60°C): l 153.4,
4.2.7. Quinolyl oxazolidine 6a. By following the general
procedure described above, 6a was isolated in 92% yield
as a colourless solid; mp 132–133°C; [h]2D0 −182.0 (c

1860
G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
152.8, 150.1, 149.2, 147.2 (5s, Carom.+NCO), 131.8,
130.1, 129.3, 129.0, 126.7, 126.6 (6d, CHarom.), 126.2 (s,
Carom.), 123.1, 115.0 (2d, CHarom.), 95.8 (s, C(CH3)2),
80.8 (s, C(CH3)3), 70.2 (t, CH2O), 58.6 (d, CH), 28.9 (q,
C(CH3)3), 27.4, 24.8 (2q, C(CH3)2); MS (FAB+) m/e:
412 ([M+2]+, 26), 411 ([M+1]+, 100), 410 ([M]+, 15), 355
(42), 295 (41), 281 (16), 279 (12), 253 (17), 252 (17), 251
(13), 238 (20), 237 (16), 236 (34), 225 (18), 212 (27).
Anal. calcd for C23H26N2O3S (410.53): C, 67.29; H,
6.38; N, 6.82; S, 7.81 Found: C, 67.52; H, 6.09; N, 6.96;
S, 8.11%.
1561w, 1509w, 1457m, 1376s, 1365f, 1254m, 1205w,
1171m, 1096m, 1053m, 949w, 857m, 810w, 760m; H
1
NMR (DMSO-d6, T=60°C): l 8.15–8.05 (m, 2H,
CHarom.), 7.85–7.60 (m, 2H, CHarom.), 7.30 (s, 1H,
CHarom.), 5.81 (dd, J=7.2 Hz, J%=2.6 Hz, 1H, CH),
4.66 (dd, J=9 Hz, J%=7.2 Hz, 1H, AB sys., CH2O),
3.85 (dd, J=9 Hz, J%=2.6 Hz, 1H, AB sys., CH2O),
3.01 (t, J=7.3 Hz, 2H), 1.89 (s, br., 4H), 1.72 (s, 3H,
C(CH3)2), 1.50–1.30 (m, 16H), 0.95 (t, J=7 Hz, 3H);
13C NMR (DMSO-d6, T=60°C): l 161.5, 151.1, 147.5,
147.2 (4s, Carom.+NCO), 129.0, 128.6, 125.4 (3d,
CHarom.), 123.8 (s, Carom.), 122.6, 116.5 (2d, CHarom.),
93.7 (s, C(CH3)2), 79.1 (s, C(CH3)3), 68.8 (t, CH2O),
56.6 (d, CH), 38.1, 30.7, 28.4, 28.0 (4t, CH2), 27.5 (q,
C(CH3)3), 25.9, 23.5 (2q, C(CH3)2), 21.5 (t, CH2), 13.4
(q, CH3); MS (EI, 70 eV) m/e: 413 ([M+1]+, 1), 412
([M]+, 1), 342 (10), 286 (12), 57 (100). Anal. calcd for
C25H36N2O3 (412.57): C, 72.78; H, 8.80; N, 6.79.
Found: C, 72.49; H, 8.96; N, 7.04%.
4.2.10. Quinolyl oxazolidine 6d. By following the gen-
eral procedure described above, 6d was isolated in 71%
yield as a pale yellow solid; mp 161–162°C; [h]2D0 −127.4
(c 0.94, MeOH); IR (KBr, w, cm−1): 2981w, 2932w,
2900w, 1691s, 1604m, 1552w, 1500w, 1454w, 1390s,
1261m, 1166m, 1094m, 1051w, 1012w, 855w, 814w,
1
752m, 599w; H NMR (DMSO-d6, T=60°C): l 8.20–
7.65 (m, 6H, CHarom.), 7.34 (d, J=3.2 Hz, 1H, CHarom.),
6.80–6.75 (m, 1H, CHarom.), 5.90–5.85 (m, 1H, CH),
4.75–4.65 (m, 1H, CH2O), 3.91 (dd, J=9 Hz, J%=2.6
Hz, 1H, CH2O), 1.95 (s, 3H, C(CH3)2), 1.74 (s, 3H,
C(CH3)2), 1.31 (s, br., 9H, C(CH3)3); 13C NMR
(DMSO-d6, T=60°C): l 153.2, 151.1 (2s, Carom.), 148.4
(s, NCO), 147.8, 147.7 (2s, Carom.), 144.6, 129.5, 129.3,
126.1 (4d, CHarom.), 124.3 (s, Carom.), 122.8, 112.4,
112.2, 109.6 (4d, CHarom.), 93.8 (s, C(CH3)2), 79.3 (s,
C(CH3)3), 68.7 (t, CH2O), 56.7 (d, CH), 27.5 (q,
C(CH3)3), 26.0, 23.4 (2q, C(CH3)2); MS (EI, 70 eV)
m/e: 395 ([M+1]+, 1), 394 ([M]+, 4), 279 (22), 57 (100).
Anal. calcd for C23H26N2O4 (394.46): C, 70.03; H, 6.64;
N, 7.10. Found: C, 70.22; H, 6.39; N, 7.36%.
4.3. Synthesis of quinolyl-b-amino alcohol derivatives
8a–8f. General procedure
To a cooled (0°C) solution of 6a–6f in MeOH (0.7
mL/mmol), TFA (3 mL/mmol) was added dropwise.
After stirring for 2 h at 0°C and overnight at rt, TFA
was removed under a gentle stream of argon. The
resulting residue was re-dissolved in a 1:1 mixture diox-
ane/NaHCO3 (satd), (12 mL/mmol), cooled at 0°C and
(Boc)2O (3.3 equiv.) added in one portion. The reaction
mixture was stirred at 0°C for 4 h and overnight at rt.
The mixture was partitioned between H2O and AcOEt,
the organic layer separated and dried over MgSO4
(anhyd.). Removal of the solvent and purification of the
resulting residue by flash chromatography (hexanes/
AcOEt as eluent) afforded pure 8a–8f (Table 3).
4.2.11. Quinolyl oxazolidine 6e. By following the general
procedure described above, 6e was isolated in 89% yield
as a yellowish solid; mp 114–115°C; [h]2D0 −139.2 (c 0.75,
MeOH); IR (KBr, w, cm−1): 2977m, 2932m, 1700s,
1600m, 1551w, 1504m, 1461m, 1423w, 1367s, 1244m,
4.3.1. Quinolyl b-amino alcohol 8a. By following the
general procedure described above, 8a was isolated in
93% yield as a colourless solid; mp 164–165°C; [h]D20
−71.4 (c 0.82, MeOH); IR (KBr, w, cm−1): 3400br.,
3354m, 3230m, 3070w, 2972w, 2934w, 2875w, 1684s,
1609m, 1537m, 1447w, 1392w, 1367m, 1283m, 1252m,
1171m, 1065m, 1031w, 884w, 861w, 757m, 692m, 646w;
1H NMR (CDCl3): l 8.20–7.35 (m, 10H, CHarom.), 5.80
(s, br., 1H, NH), 5.56 (s, br., CH), 4.10–3.80 (m, 2H,
CH2O), 3.24 (s, br., 1H, OH), 1.47 (s, br., 9H,
C(CH3)3); 13C NMR (CDCl3): l 156.7, 155.8, 148.1,
146.3 (4s, Carom.+NCO), 139.0 (s, Carom.), 130.1, 129.6,
129.4, 128.7, 127.5, 126.7 (6d, CHarom.), 124.8 (s,
Carom.), 122.4, 116.2 (2d, CHarom.), 80.4 (s, C(CH3)3),
64.8 (t, CH2O), 52.5 (d, CH), 28.3 (q, C(CH3)3); MS
(EI, 70 eV) m/e: 365 ([M+1]+, 1), 364 ([M]+, 1), 233
(13), 57 (100). Anal. calcd for C22H24N2O3 (364.44): C,
72.50; H, 6.64; N, 7.69. Found: C, 72.73; H, 6.82; N,
7.42%.
1
1170m, 1128m, 1098m, 1051w, 1005w, 851w, 765m; H
NMR (DMSO-d6, T=60°C): l 8.30–8.15 (m, 2H,
CHarom.), 7.95–7.80 (m, 2H, CHarom.), 7.75–7.65 (m, 1H,
CHarom.), 7.55 (s, 2H, CHarom.), 5.89 (dd, J=7.0 Hz,
J%=2.6 Hz, 1H, CH), 4.71 (dd, J=8.9 Hz, J%=7 Hz,
1H, CH2O), 4.02 (s, 6H, 2×CH3O), 4.00–3.95 (m, 1H,
CH2O), 3.91 (s, 3H, CH3O), 1.96 (s, 3H, C(CH3)2), 1.75
(s, 3H, C(CH3)2), 1.32 (s, br., 9H, C(CH3)3); 13C NMR
(DMSO-d6, T=60°C): l 155.6, 153.8, 151.8 (3s, Carom.),
148.9 (s, NCO), 148.4, 140.3, 134.7 (3s, Carom.), 130.4,
130.0, 126.9 (3d, CHarom.), 124.9 (s, Carom.), 123.4,
114.4, 105.4 (3d, CHarom.), 94.5 (s, C(CH3)2), 80.0 (s,
C(CH3)3), 69.5 (t, CH2O), 60.6 (q, CH3O), 57.56 (d,
CH), 56.6 (q, 2×CH3O), 28.2 (q, C(CH3)3), 26.6, 24.2
(2q, C(CH3)2); MS (FAB+) m/e: 495 ([M+1]+, 100), 494
([M]+, 59), 440 (17), 439 (64), 438 (10), 379 (21), 365
(24), 363 (10), 296 (10). Anal. calcd for C28H34N2O6
(494.58): C, 68.00; H, 6.93; N, 5.66. Found: C, 68.26;
H, 6.64; N, 5.83%.
4.3.2. Quinolyl b-amino alcohol 8b. By following the
general procedure described above, 8b was isolated in
90% yield as a colourless solid; mp 180–181°C; [h]D20
−85.3 (c 0.99, MeOH); IR (KBr, w, cm−1): 3400br.,
3074w, 2979w, 2927w, 2888w, 1679s, 1604m, 1505s,
1451m, 1366m, 1249s, 1167m, 1104w, 1040m, 934w,
4.2.12. Quinolyl oxazolidine 6f. By following the general
procedure described above, 6f was isolated in 72% yield
as a yellowish oil; [h]2D0 −88.3 (c 0.89, MeOH); IR (film,
w, cm−1): 3065w, 2957m, 2929m, 2858m, 1702s, 1605m,

G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
1861
873w, 759m, 635w; 1H NMR (CDCl3): l 8.10 (d, J=8.2
Hz, 1H, CHarom.), 7.90 (d, J=8.2 Hz, 1H, CHarom.),
7.75–7.45 (m, 5H, CHarom.), 6.90 (d, J=8.6 Hz, 1H,
CHarom.), 6.06 (s, 2H, OCH2O), 5.83 (d, J=6.8 Hz, 1H,
NH), 5.51 (s, br., 1H, CH), 4.05–3.80 (m, 2H, CH2O),
3.75–2.80 (s, br., 1H, OH), 1.47 (s, br., 9H, C(CH3)3);
13C NMR (CDCl3): l 156.0, 155.7, 148.9, 148.2, 148.0
(5s, Carom.), 146.0 (s, NCO), 133.4 (s, Carom.), 129.9,
129.6, 126.4 (3d, CHarom.), 124.6 (s, Carom.), 122.3,
(100). Anal. calcd for C20H22N2O4 (354.40): C, 67.78;
H, 6.26; N, 7.90. Found: C, 67.49; H, 6.49; N, 7.71%.
4.3.5. Quinolyl b-amino alcohol 8e. By following the
general procedure described above, 8e was isolated in
91% yield as a yellowish solid; mp 159–160°C; [h]D20
−80.6 (c 0.94, MeOH); IR (KBr, w, cm−1): 3500br.,
3490m, 3344m, 2971m, 2938m, 2866d, 2834w, 1681s,
1598m, 1534m, 1505m, 1459, 1425m, 1362s, 1276m,
1246m, 1170m, 1130s, 1096w, 1063m, 1005m, 859w,
121.8, 115.8, 108.4, 107.7 (5d, CH
), 101.4 (t,
arom.
1
OCH2O), 80.3 (s, C(CH3)3), 64.8 (t, CH2O), 52.6 (d,
CH), 28.3 (q, C(CH3)3); MS (EI, 70 eV) m/e: 409
([M+1]+, 4), 408 ([M]+, 14), 334 (17), 322 (11), 321 (21),
278 (10), 277 (49), 190 (10), 57 (100). Anal. calcd for
C23H24N2O5 (408.45): C, 67.63; H, 5.92; N, 6.86.
Found: C, 67.41; H, 6.18; N, 6.67%.
759m, 647w; H NMR (CDCl3): l 8.18 (d, J=8.2 Hz,
1H, CHarom.), 7.99 (d, J=8.2 Hz, 1H, CHarom.), 7.75–
7.50 (m, 3H, CHarom.), 7.31 (s, 2H, CHarom.), 5.71 (d,
J=7 Hz, 1H, NH), 5.59 (s, br., 1H, CH), 4.15–4.10 (m,
2H, CH2O), 4.0 (s, 6H, 2×CH3O), 3.95 (s, 3H, CH3O),
2.98 (s, br., 1H, OH), 1.46 (s, br., 9H, C(CH3)3); 13C
NMR (CDCl3): l 156.5, 155.6, 153.5, 148.3, 146.0,
139.6, 135.0 (6s, Carom.+NCO), 130.3, 129.6, 126.6 (3d,
CHarom.), 124.8 (s, Carom.), 122.4, 116.0, 105.0 (3d,
CHarom.), 80.3 (s, C(CH3)3), 64.9 (t, CH2O), 60.9 (q,
CH3O), 56.3 (q, 2×CH3O), 52.8 (d, CH), 28.3 (q,
C(CH3)3); MS (FAB+) m/e: 455 ([M+1]+, 100), 454
([M]+, 52), 399 (36), 381 (12), 323 (29). Anal. calcd for
C25H30N2O6 (454.52): C, 66.06; H, 6.65; N, 6.16.
Found: C, 66.24; H, 6.42; N, 5.95%.
4.3.3. Quinolyl b-amino alcohol 8c. By following the
general procedure described above, 8c was isolated in
91% yield as a colourless solid; mp 183–184°C; [h]D20
−81.8 (c 0.80, MeOH); IR (KBr, w, cm−1): 3400br.,
3348m, 3241m, 3070w, 2972w, 2931w, 2874w, 1682s,
1605m, 1536m, 1458w, 1427w, 1368m, 1283m, 1254m,
1169m, 1065m, 1032w, 878w, 836w, 757m, 706m, 644w;
1H NMR (CD3OD): l 8.36 (d, J=8.4 Hz, 1H,
CHarom.), 8.24 (d, J=8.4 Hz, 1H, CHarom.), 8.17 (s, 1H,
CHarom.), 8.05 (dd, J=3.7 Hz, J%=1.1 Hz, 1H,
CHarom.), 7.95–7.70 (m, 3H, CHarom.), 7.37 (dd, J=5.1
Hz, J%=3.7 Hz, 1H, CHarom.), 5.74 (s, br., 1H, CH),
4.14 (dd, J=11.4 Hz, J%=4.6 Hz, AB sys., 1H, CH2O),
3.97 (dd, J=11.4 Hz, J%=6.9 Hz, AB sys., 1H, CH2O),
1.63 (s, br., 9H, C(CH3)3); 13C NMR (CD3OD): l
158.2, 153.9, 149.7, 149.2, 146.4 (5s, Carom.+NCO),
131.2, 130.7, 130.2, 129.5, 127.9, 127.7 (6d, CHarom.),
127.0 (s, Carom.), 124.4, 116.7 (2d, CHarom.), 81.0 (s,
C(CH3)3), 65.6 (t, CH2), 54.4 (d, CH), 29.0 (q,
C(CH3)3); MS (FAB+) m/e: 372 ([M+2]+, 24), 371 ([M+
1]+, 100), 370 ([M]+, 13), 315 (32), 297 (14), 284 (14),
283 (15), 254 (12), 239 (27), 236 (10), 212 (12). Anal.
calcd for C20H22N2O3S (370.47): C, 64.84; H, 5.99; N,
7.56; S, 8.66. Found: C, 64.61; H, 6.22; N, 7.33; S,
8.92%.
4.3.6. Quinolyl b-amino alcohol 8f. By following the
general procedure described above, 8f was isolated in
85% yield as a colourless solid; mp 132–133°C; [h]D20
−33.4 (c 0.99, MeOH); IR (KBr, w, cm−1): 3500br.,
3353m, 3180m, 2957m, 2926m, 2857, 1689s, 1604w,
1525m, 1465w, 1367w, 1281w, 1246m, 1174m, 1086m,
1
1059m, 888w, 766m, 640w; H NMR (CDCl3): l 7.89
(d, J=7.9 Hz, 1H, CHarom.), 7.75 (d, J=7.9 Hz, 1H,
CH), 7.55–7.20 (m, 3H, CHarom.), 5.76 (d, J=7.4 Hz,
1H, NH), 5.53 (s, br., 1H, CH), 4.40–4.20 (s, br., 1H,
OH), 4.12 (s, br., 2H, CH2O), 2.85–2.75 (m, 2H),
1.75–1.30 (m, 17H), 0.90 (t, J=6.2 Hz, 3H, CH3); 13C
NMR (CDCl3): l 162.6, 156.0, 147.8, 146.5 (4s, Carom.
NCO), 129.6, 129.2, 126.3 (3d, CHarom.), 124.6 (s,
arom.), 122.7, 118.8 (2d, CHarom.), 80.6 (s, C(CH3)3),
+
C
65.1 (t, CH2O), 52.9 (d, CH), 39.4, 32.1, 30.4, 29.5 (4t,
CH2), 28.7 (q, C(CH3)3), 22.9 (t, CH2), 14.5 (q, CH3);
MS (EI, 70 eV) m/e: 373 ([M+1]+, 2), 372 ([M]+, 1), 302
(45), 246 (25), 241 (34), 229 (17), 228 (100), 57 (83).
Anal. calcd for C22H32N2O3 (372.50): C, 70.94; H, 8.66;
N, 7.52. Found: C, 71.15; H, 8.44; N, 7.79%.
4.3.4. Quinolyl b-amino alcohol 8d. By following the
general procedure described above, 8d was isolated in
74% yield as a yellowish solid; mp 170–171°C; [h]D20
−63.4 (c 0.84, MeOH); IR (KBr, w, cm−1): 3500br.,
3376m, 3349m, 3081w, 3301m, 2980w, 2931w, 2875w,
1685s, 1608m, 1511m, 1461w, 1393w, 1366m, 1284m,
1247m, 1170m, 1091w, 1061m, 1019d, 883d, 759m,
4.4. Synthesis of quinolyl carboxamide derivatives 12a–
12c. General procedure
1
618w; H NMR (CDCl3): l 8.13 (d, J=8.2 Hz, 1H,
To a pre-heated (75°C) solution of the corresponding
amino alcohol 8 in DMSO (3.8 mL/mmol), IBX 11 (2
equiv.) was added and the reaction mixture stirred at
75°C for 5 h. After cooling to rt, the mixture was
partitioned between H2O and ether. The layers were
separated and the aqueous extracted further with ether.
The combined organic layers were washed once with
NaHCO3 (satd) and the separated organic layer dried
over MgSO4 (anhyd.), and filtered. Removal of the
solvent and purification of the resulting residue by flash
chromatography (hexanes/AcOEt as eluent) afforded
pure 12a–12c (Table 4).
CHarom.), 8.02 (d, J=8.2 Hz, 1H, CHarom.), 7.82 (s, 1H,
CHarom.), 7.75–7.50 (m, 3H, CHarom.), 7.26 (d, J=3.4
Hz, 1H, CH), 6.63 (dd, J=3.4 Hz, J%=1.6 Hz, 1H,
CHarom.), 5.60 (s, br., 2H, CH+NH), 4.11 (s, br., 2H,
CH2O), 2.39 (s, br., 1H, OH), 1.49 (s, br., 9H,
C(CH3)3); 13C NMR (CDCl3): l 155.5, 152.8, 148.0,
147.4, 146.3 (5s, Carom., NCO), 143.9, 129.6, 129.1,
126.2 (4d, CHarom.), 124.5 (s, Carom.), 122.3, 114.5,
112.2, 110.5 (4d, CHarom.), 80.2 (s, C(CH3)3), 64.7 (t,
CH2O), 52.5 (d, CH), 28.3 (q, C(CH3)3); MS (EI, 70
eV) m/e: 355 ([M+1]+, 1), 354 ([M]+, 2), 223 (15), 57

1862
G. Cabarrocas et al. / Tetrahedron: Asymmetry 12 (2001) 1851–1863
4.4.1. Quinolyl carboxamide 12a. According to the gen-
eral procedure described above, reaction between 8a
(150 mg, 0.41 mmol) and IBX 11 (231 mg, 0.82 mmol)
afforded 0.096 g (67%) of 12a as a colourless solid; mp
147–148°C; IR (KBr, w, cm−1): 3450br., 3166w, 3065w,
2979w, 2982w, 2855w, 1767m, 1750s, 1682m, 1592m,
1519m, 1499m, 1459w, 1370m, 1344w, 1229m, 1141s,
1050w, 1032w, 935m, 847w, 769m, 692m, 653w; 1H
NMR ((CD3)2CO): l 10.20 (s, br., 1H, NH), 8.55–7.70
(m, 10H, CHarom.), 1.51 (s, 9H, C(CH3)3); 13C NMR
((CD3)2CO): l 169.7 (s, CO), 157.4, 151.0, 149.6, 143.9,
139.9 (5s, Carom.+NCO), 131.3, 131.2, 131.0, 130.0,
128.6, 128.5, 126.0 (7d, CHarom.), 124.5 (s, Carom.), 117.6
(d, CHarom.), 82.8 (s, C(CH3)3), 28.3 (q, C(CH3)3); MS
(FAB+) m/e: 349 ([M+1]+, 54), 348 ([M]+, 4), 293 (19),
275 (10), 250 (19), 249 (100), 248 (19), 205 (18), 204
(17). Anal. calcd for C21H20N2O3 (348.40): C, 72.40; H,
5.79; N, 8.04. Found: C, 72.66; H, 5.61; N, 8.28%.
Acknowledgements
Generous financial support from the Ministerio de Edu-
cacio´n y Ciencia (Spain) through project PB98-0451,
Universitat de Girona through project UdG98-452,
Medichem SA (Barcelona) and Roviall Qu´ımica SL
(Murcia) is gratefully acknowledged. Thanks are also
given to Dr. Llu¨isa Matas (Servei d%Ana`lisi, Universitat
de Girona) for recording the NMR spectra and micro-
analysis. One of us (G.C.) thanks the Ministerio de
Educacio´n
fellowship.
y
Ciencia (Spain) for a pre-doctoral
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