Barbier-type diastereoselective allylation of α-amino aldehydes with an enantiopure 2-sulfinylallyl building block

Article abstract of DOI:10.1021/jo016068u

An optimized procedure for the diastereoselective allylation under aqueous Barbier conditions of a series of α-amino aldehydes with our new chiral building block (S_s)-3-chloro-2-(p-tolylsulfinyl)-1-propene [(S_s)-1a] to afford enantiomerically pure sulfinylamino alcohols in good yields and diastereoselectivites is reported. High levels of diastereoinduction can be achieved from α-amino aldehydes configurationally related to natural α-amino acids.

Full text of DOI:10.1021/jo016068u

308
J . Org. Chem. 2002, 67, 308-311
Sch em e 1
Ba r bier -Typ e Dia ster eoselective Allyla tion
of r-Am in o Ald eh yd es w ith a n En a n tiop u r e
2-Su lfin yla llyl Bu ild in g Block
Francesc Ma´rquez,†,‡ Rau´l Montoro,‡ Amadeu Llebaria,‡
Elena Lago,§ Elies Molins,§ and Antonio Delgado*,†,‡
ration of the starting R-amino aldehyde, a matched
double diastereoinduction can be envisaged. In addition,
the resulting sulfinylamino alcohols are versatile syn-
thetic intermediates in which the vinyl sulfinyl moiety
can be used, inter alia, as acceptor in inter or intramo-
lecular Michael additions8 with a vast array of nucleo-
philes.
Universitat de Barcelona, Facultat de Farma`cia, Unitat de
Quı´mica Farmace`utica, (Unitat Associada al CSIC) Avgda.
J oan XXIII, s/ n, 08028 Barcelona, Spain, Research Unit on
Bioactive Molecules (RUBAM), Departament de Quı´mica
Orga`nica Biolo`gica, Institut d’Investigacions Quı´miques i
Ambientals de Barcelona (IIQAB-C.S.I.C), J ordi Girona
18-26, 08034 Barcelona, Spain, and Institut de Cie`ncia de
Materials de Barcelona (CSIC), Campus Universitari de
Bellaterra, E-08193 Cerdanyola, Spain
Due to the chiral nature of both reactive counterparts
(R-amino aldehyde and sulfinyl allylic chloride), prelimi-
naryexperiments were aimed at determiningthe “matched”
pair in this allylation system. The serine-derived Garner’s
aldehyde (2) and its enantiomer (ent-2) were chosen for
this purpose. Thus, allylation of each of the above
enantiomers with (Ss)-1a under identical conditions
afforded higher diastereoinduction from L-amino alde-
hyde 2 (Table 1, entries 1 and 5). Therefore, R-amino
aldehydes derived from natural R-amino acids were used
throughout this work. In addition, the dramatic effect of
the chiral sulfoxide in this allylation system was made
evident from achiral sulfone 1b, whose reaction with
R-amino aldehyde 2 afforded adduct 16 in remarkable
lower diastereoselectivity (Table 1, entries 3 and 4).
However, chirality on both reaction partners seems to
be a requirement to reach high levels of diastereoinduc-
tion, since achiral N,N-diprotected glycinal derivative 3
(Table 2, entry 1) gave rise to a modest diastereomeric
ratio in comparison with the remaining enantiopure N,N-
diprotected amino aldehydes used in this study (see Table
2, entries 3-6).
Initial experiments with Garner’s aldehyde 2 and (Ss)-
1a under our previously described Barbier conditions,4
afforded the diastereomeric adducts 9 (Table 1, entry 1).
The configuration of the new stereogenic center for each
diastereomer was unambiguously determined by X-ray
diffraction analysis (see Supporting Information). Thus,
the new stereogenic center on the major diastereomer
was assigned as R, in agreement with our previous
studies on the allylation of (Ss)-1a with simple alde-
hydes.5 According to our working hypothesis, the ob-
served diastereoinduction in this allylation system can
be explained as a result of the competition between two
major transition states, that is, an open-chain one and a
cyclic one, each of them leading to a different diastere-
omer (Scheme 2). To address this issue, differences in
metal coordination on both types of transition states were
considered. Thus, while single metal-sulfoxide and
metal-carbonyl coordinations take place in the open
transition states, a double intramolecular metal-carbo-
adelgado@far.ub.es
Received August 29, 2001
Abstr a ct: An optimized procedure for the diastereoselective
allylation under aqueous Barbier conditions of a series of
R-amino aldehydes with our new chiral building block (Ss)-
3-chloro-2-(p-tolylsulfinyl)-1-propene [(Ss)-1a ] to afford enan-
tiomerically pure sulfinylamino alcohols in good yields and
diastereoselectivites is reported. High levels of diastereoin-
duction can be achieved from R-amino aldehydes configu-
rationally related to natural R-amino acids.
In our ongoing studies on the use of sulfoxides as chiral
auxiliaries in organic synthesis,1-3 we have described (Ss)-
3-chloro-2-(p-tolylsulfinyl)-1-propene [(Ss)-1a ] as a new
chiral building block4 and its application for the diaste-
reoselective allylation of aldehydes under environmen-
tally friendly Barbier conditions.4,5 As far as the aldehyde
component is concerned, an interesting variation to widen
the potential of diversity inherent to this allylation
process relies on the use of enantiopure R-amino alde-
hydes as reaction partners. In this context, the use of
R-amino aldehydes in organic synthesis has increased
over the last years due to the development of efficient
preparative methods from the corresponding R-amino
acids or derivatives thereof.6 Along this line, we wish to
present our results on the allylation of enantiopure
R-amino aldehydes with (Ss)-1a under optimized Barbier
conditions (Scheme 1).Even though allylation of enan-
tiopure R-amino aldehydes with simple allyl derivatives
under Barbier conditions has been the subject of several
interesting reports,7 the use of (Ss)-1a as allylating agent
is attractive. Thus, by the proper choice of the configu-
* Corresponding author. Fax: int +34-932045904.
† Universitat de Barcelona.
‡ Institut d’Investigacions Qu´ımiques i Ambientals de Barcelona.
§ X-ray diffraction analysis: Institut de Cie`ncia de Materials de
Barcelona.
(1) Villar, J . M.; Delgado, A.; Llebaria, A.; Moreto´, J . M.; Molins,
E.; Miravitlles, C. Tetrahedron 1996, 52, 10525-10546.
(2) Henrich, M. L.; Delgado, A.; Molins, E.; Roig, A.; Llebaria, A.
Tetrahedron Lett. 1999, 40, 4259-4262.
(3) For the use of sulfoxides as chiral auxiliaries in organic synthesis,
see: Carren˜o, M. C. Chem. Rev. 1995, 95, 1717-1760.
(4) Ma´rquez, F.; Llebaria, A.; Delgado, A. Org. Lett. 2000, 2, 547-
549.
(5) Ma´rquez, F.; Llebaria, A.; Delgado, A. Tetrahedron Asymm. 2001,
12, 1625-1634.
(6) Steurer, S.; Podlech, J . Eur. J . Org. Chem. 1999, 1551-1560,
and references therein.
(7) Allylations with Zn : (a) Ru¨bsam, F.; Seck, S.; Giannis, A.
Tetrahedron 1997, 53, 2823-2834. (b) Gryko, D.; J urczak, J . Helv.
Chim. Acta 2000, 83, 2705-2711. (c) Hanessian, S.; Park, H.; Yang,
R. Y. Synlett 1997, 4, 353-354. Sn : refs 7a and 7b. In : ref 6 and (d)
Paquette, L. A.; Mitzel, T. M.; Isaac, M. B.; Crasto, C. F.; Schomer, W.
W. J . Org. Chem. 1997, 62, 4293-4301. (e) Steurer, S.; Podlech, J .
Adv. Synth. Catal. 2001, 343, 251-254
(8) We have already reported on the synthesis of enantioenriched
(S)-nicotine based on intramolecular Michael addition from a sulfiny-
lamino alcohol has been reported (see ref 5).
10.1021/jo016068u CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/14/2001

Notes
Ta ble 1. Allyla tion of Ser in a l Der iva tives 2 a n d en t-2
J . Org. Chem., Vol. 67, No. 1, 2002 309
Sch em e 2
dard system with no external additives (compare entries
1 and 2, Table 1). Moreover, since the Lewis acidity of
Zn, and thus its coordination ability, can be decreased
by coordination with iodide ions,5,10 we were pleased to
observe that the highest diastereoselectivity in the ally-
lation of 2 with (Ss)-1a was achieved by the combination
of NaI (3 equiv) and ZnCl2 (2 equiv) (entry 3, Table 1).
All these results are consistent with the preference for
an open-chain transition state model in this allylation
process.11
a
(A): Zn dust (1.3 equiv), sat NH4Cl/THF (6:1), rt; (B): Zn dust
(1.3 equiv.), ZnCl2 (2 equiv), sat NH4Cl/THF (6:1), rt; (C): Zn dust
(1.3 equiv), ZnCl2 (2 equiv), NaI (3 equiv), sat NH4Cl/THF (6:1), 5
°C. Major diastereomer shown. c Diastereomeric ratio calculated
b
by 1H NMR from crude reaction mixtures.
Ta ble 2. Allyla tion of r-Am in oa ld eh yd es 3-8 w ith
(SS)-1a
These results led us to examine the suitability of other
R-amino aldehydes as allylation partners for (Ss)-1a . In
this context, it is well established that the tendency of
R-amino aldehydes toward racemization can be greatly
reduced, or even avoided, by the proper choice of protect-
ing groups on the nitrogen atom.12-14 Moreover, the effect
of nitrogen protection (N-monoprotected vs N,N-dipro-
tected derivatives) on the diastereoselectivity of the
allylations of R-amino aldehydes is well precedented in
the literature.7a,b,d,15 In general, N-monoprotected deriva-
tives afford lower diastereoselectivities than N,N-dipro-
tected ones due to the competition between a chelation-
controlled Cram model and a nonchelating Felkin-Ahn
model.16 This trend was also observed in our allylation
system when comparing alaninal derivatives 4 and 5
(Table 2, entries 2 and 3). As expected, the diastereose-
lectivity on the allylation of N-monoprotected 4 was lower
than that observed from 5, albeit the sense of diastere-
oinduction was not reversed. In this case, the operation
of a chelation-controlled open-chain model, as depicted
(9) A seven-membered cyclic transition state has been proposed for
the Lewis acid-catalyzed allylation of 2-(arylsulfinyl)allyl tributylstan-
nanes with aldehydes under strictly anhydrous conditions (see Mort-
lock, S. V.; Thomas, E. J . Tetrahedron 1998, 54, 4663-4672).
(10) Ito, A.; Kishida, M.; Kurusu, Y.; Masuyama, Y. J . Am. Chem.
Soc. 2000, 65, 494-498.
(11) This model is also valid to explain the observed diastereoin-
duction in the allylation of ent-2 (Table 1, entry 5). Thus, the R
configuration of the new stereocenter in the major diastereomer of 17
was inferred from X-ray diffraction analysis of the minor diastereomer
(see Supporting Information). The lower diastereoinduction observed
from ent-2 in comparison with 2 can be explained by the higher
contribution of the cyclic transition state (see Scheme 2) as a result of
the steric bias imposed by the opposite configuration of amino aldehyde
ent-2 in the open-chain transition state.
a
b
Major diastereomer shown. Diastereomeric ratio calculated
by 1H NMR from crude reaction mixture.
(12) Rapoport, H.; Lubell, W. D. J . Am. Chem. Soc. 1987, 109, 236-
nyl chelation can be postulated for the cyclic ones.9 As a
result, an efficient approach to favor the operation of the
open transition state would rely on the use of an external
Lewis acid for an additional carbonyl coordination. In this
context, the use of ZnCl2 (2 equiv) gave rise to an increase
on the diastereoselectivity in comparison with an stan-
239.
(13) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361-2364.
(14) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531-1545.
(15) Gryko, D.; Urbanczyk-Lipkoska, Z.; J urczak, J . Tetrahedron
1997, 53, 13373-13382.
(16) In some cases a reversal in the diastereoselectivity between
N-mono- and N,N-diprotected amino aldehydes has been observed (see
ref 7b, and references therein).

310 J . Org. Chem., Vol. 67, No. 1, 2002
Notes
Sch em e 3
Further studies addressed at the exploitation of the
synthetic potential of these building blocks are currently
underway in our laboratory and will reported in due
course.
Exp er im en ta l Section
Melting points are uncorrected. FT-IR spectra are reported
in cm-1
.
1H and 13C NMR spectra were obtained in CDCl3
1
solutions at 200 MHz (for H) and 50 MHz (for 13C), respectively,
unless otherwise indicated. Chemical shifts are reported in delta
(δ) units, parts per million (ppm) relative to the singlet at 7.24
ppm of CDCl3 for 1H and in ppm relative to the center line of a
triplet at 77.0 ppm of CDCl3 for 13C. Solvents were distilled prior
to use and dried by standard methods.18 Usual reaction workup
consists of extraction of the aqueous phase with an organic sol-
vent, washings with brine, drying of the extracts over Na2SO4,
filtration, and evaporation to dryness. A detailed experimental
procedure for the synthesis of (SS)-1a is described in ref 5. For
the synthesis of aldehyde 6, see Supporting Information.
Gen er a l P r oced u r e for th e Allyla tion of Ald eh yd es w ith
(SS)-1a . NaI (670 mg, 4.5 mmol) is added portionwise to a
solution of (SS)-1a (320 mg, 1.5 mmol) in THF (1 mL) under Ar.
After stirring for 5 min at room temperature, a solution of the
requisite aldehyde (1.5 mmol) in THF (0.5 mL) was added
followed by portionwise addition of ZnCl2 (610 mg, 3 mmol) and
sat. aqueous NH4Cl solution (7.5 mL). The reaction mixture was
then cooled in an ice-water bath, and Zn dust (150 mg, 2.3
mmol) was added portionwise. After stirring at 0 °C for 2 h, the
reaction mixture was extracted with CH2Cl2/Et2O (1:2, 10 mL)
and worked up in the usual way to obtain an oil which was
purified by flash chromatography to give the desired sulfiny-
lamino alcohol.
Sch em e 4
Com p ou n d 9. Obtained from aldehyde 213 in 75% yield as a
80:20 mixture of diastereomers. HRMS, calcd for C21H31NO5S:
409.192295. Found: 409.192614. Major diastereomer: [R]D
+11.8 (c, 0.51, CHCl3); mp: 106-107 °C. IR (film): 3380; 1695,
1049. 1H NMR (300 MHz, C6D6, 60 °C): 1.30 (s, 9H, C(CH3)3);
1.39 (s, 3H, CH3); 1.54 (s, 3H, CH3); 1.97 (s, 3H, CH3Ar); 2.16
(dd, 1H, J 1 ) 9 Hz, J 2 ) 15 Hz); 2.48 (dd, 1H, J 1 ) 10.3 Hz, J 2
) 15 Hz,); 3.58 (dd, 1H, J 1 ) 6.6 Hz, J 2 ) 9 Hz, CH2O); 3.84-
4.00 (m, 4H); 5.7 (broad. 1H, dCH2); 5.92 (s, 1H, dCH2); 6.88
(2H, AA′ of AA′BB′: J ) 7.8 Hz and H arom m-SO); 7.47 (BB′ of
AA′BB′, 2H, J ) 7.8 Hz, and H arom. o-SO). 13C NMR (75.4 MHz,
C6D6, 60 °C): 21.0, 27.0, 28.3, 32.8, 62.2, 65.0, 71.7, 80.2, 94.4,
120.6, 125.4, 129.9, 140.8, 141.1, 153.6, 190.0. For X-ray
coordinates, see below. Minor diastereomer: [R]D -50.0 (c, 0.72,
acetone); mp: 121-122 °C. IR (film): 3350, 1697, 1054. 1H NMR
(300 MHz, C6D6, 60 °C): 1.25 and 1.30 (3H, rotamers), 1.39 (9H),
1.53 (3H), 1.97 and 1.94 (3H), 2.27 (1H), 2.45 (1H), 3.70 (1H),
3.91-4.14 (3 × 1H), 4.88 (1H), 5.42 (1H), 5.71 and 5.75 (1H,
rotamers), 6.85-6.89 (2H), 7.42 and 7.43 (2H, rotamers). 13C
NMR (75.4 MHz, C6D6, 60 °C): 21.0, 27.0, 28.3, 28.4, 33.0, 61.4,
64.2, 71.6, 80.0, 94.4, 121.6, 125.1, 130.0, 141.2. For X-ray
coordinates, see below.
in Scheme 3, would also account for the formation of the
minor diastereomer of 11.
Configurational assignments of diastereomers 11 were
carried out by their independent conversion into oxazo-
lidines 18 and NOE measurements from selected protons
(Scheme 4).
Finally, a small representative series of N,N-dipro-
tected R-amino aldehydes 6-8 was chosen to show the
scope of this allylation system (Table 2, entries 4-6). In
all cases, the expected allylation adducts 13-15 were
obtained in good yields and diastereoselectivities and the
configuration of the major diastereomer was inferred
from the above considerations. It is worth mentioning,
that the stereochemical integrity of the R-amino aldehyde
was preserved in all the examples here studied, as
evidenced by the observation (by 1H NMR of crude
mixtures) of only two diastereomers instead of four, as
it would be expected if epimerization of the R-amino
aldehyde had taken place.17
Com p ou n d 10. Obtained from aldehyde 319 in 90% yield as
a 75:25 mixture of diastereomers. HRMS, calcd for C24H31
-
NO4S: 429.197369. Found: 429.198013, [R]D +10.0 (c, 0.25,
CHCl3); IR (film): 3392, 2976, 2928, 1692, 1048. Major diaste-
reomer: 1H NMR (200 MHz, CDCl3): 1.42 (s, 9H, (CH3)3), 2.02-
2.37 (m, 2H), 3.01-3.35 (m, 2H), 3.95 (m, 1H), 4.20-4.71 (m,
2H, CH2Ar), 5.75 (broad, 1H, dCH2), 6.08 (broad, 1H, dCH2),
7.11-7.44 (m, 9H). 13C NMR (75.4 MHz, CDCl3): Major dias-
tereomer: 21.4, 28.3, 34.3, 52.2, 80.9, 122.2, 125.1, 127.2, 128.5,
129.9, 138.1, 138.2, 141.7, 151.9, 156.9.
Com p ou n d 11. Obtained from aldehyde 420 in 82% yield as
a 75:25 mixture of diastereomers. HRMS, calcd for C18H28NO4S
(M+ + 1): 354.173905. Found: 354.172827. Major diastere-
omer: [R]D +28.2 (c, 0.62, acetone). IR (film): 3458, 1710, 1045.
In summary, an optimized procedure for the diaste-
reoselective allylation of a series of R-amino aldehydes
with (SS)-1a under aqueous Barbier conditions to afford
enantiomerically pure sulfinylamino alcohols in good
yields and diastereoselectivites is reported. The diaste-
reoselectivity of the process has been optimized by a
judicious choice of additives and reaction conditions.
Interestingly, R-amino aldehydes configurationally re-
lated to natural R-amino acids afford “matched” diaste-
reoinduction with (SS)-1a as a counterpart.
(18) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, 1988.
(19) Lutz, C.; Lutz, V.; Knochel, P. Tetrahedron 1998, 54, 6385-
6402.
(17) The stereochemical integrity of the sulfinyl allylic chloride in
this allylation system had been previously proven (see ref 5).
(20) J urczak, J .; Gryko, D.; Kobrzycka, E.; Gruza, H.; Prokopowicz,
P. Tetrahedron 1998, 54, 6051-6064.

Notes
J . Org. Chem., Vol. 67, No. 1, 2002 311
1H NMR (300 MHz, C6D6, 60 °C): 0.95 (d, 3H, J ) 6.9 Hz, 3H),
1.40 (s, 9H, C(CH3)3), 1.97 (s, 3H), 2.09 (dd, 1H, J 1 ) 7,5 Hz, J 2
) 15,3 Hz), 2.26 (ddd, 1H, J 1 ) 0.9 Hz, J 2 ) 4.2 Hz, J 3 ) 15.3
Hz,), 3.54-3.79 (m, 3 × 1H), 4.50 (d, 1H, J ) 8.4 Hz), 5.55 (s,
1H, dCH2), 5.82 (s, 1H, dCH2), 6.89 (AA′ of AA′BB′, 2H, J ) 8
Hz), 7.43 (BB′ of AA′BB′, 2H, J ) 8 Hz). 13C NMR (75.4 MHz,
C6D6): 16.0, 21.0, 28.4, 33.3, 50.6, 73.0, 78.7, 121.7, 125.3, 129.9,
139.9, 141.1, 152.4, 155.8. Minor diastereomer: [R]D -60.3 (c,
15.6 Hz), 2.35 (m, 1H), 3.03 (m, 1H), 3.28 (broad, 1H), 3.78
(broad, 1H), 4.00 (m, 1H), 5.75 (broad, 1H, dCH2), 5.97 (broad,
1H, dCH2), 6.90 (AA′ of AA′BB′, 2H, J ) 8 Hz), 7.43 (BB′ of
AA′BB′, 2H, J ) 8 Hz). 13C NMR (75.4 MHz, C6D6): 21.0, 24.1,
27.2, 28.5, 32.2, 47.8, 62.8, 71.9, 79.3, 119.7, 125.5, 129.8, 141.0,
141.5, 154.0. Minor diastereomer: 1H NMR (300 MHz, C6D6, 60
°C): 1.39 (s, 9H, C(CH3)3), 1.88-1.94 (m, 1H), 1.97 (s, 3H), 2.14-
2.24 (m, 1H), 3.67-3.72 (m, 1H), 3.87-3.94 (m, 1H), 5.53 (broad,
1H, dCH2), 5.83 (broad, 1H, dCH2), 7.35 (AA′ of AA′BB′, 2H, J
) 8,1 Hz). 13C NMR (75.4 MHz, C6D6): 25.7, 29.9, 28.5, 34.1,
46.9, 62.0, 74.5, 116.9, 125.3, 141.2, 154.9.
1
1.25, acetone). IR (film): 3436, 1708, 1048, 1029. H NMR (300
MHz, C6D6, 60 °C): 1.14 (d, 3H, J ) 6.6 Hz), 1.35 (s, 9H,
C(CH3)3), 1.97 (s, 3H), 2.08-2.25 (m, 2H), 3.41 (dt, 1H, J 1 ) 1.8
Hz, J 2 ) 9 Hz), 3.77 (m, 1H), 4.85 (d, 1H, J ) 9.6 Hz), 4.99
(broad, 1H, NH), 5.14 (s, 1H, dCH2), 5.55 (s, 1H, dCH2), 6.88
(AA′ of AA′BB′, 2H, J ) 8 Hz), 7.34 (BB′ of AA′BB′, 2H, J ) 8
Hz). 13C NMR (75.4 MHz, C6D6): 19.1, 21.0, 28.4, 36.6, 50.7, 73.9,
78.2, 123.7, 124.8, 130.0, 139.0, 141.1, 153.7, 155.9.
Com p ou n d 16. Obtained from condensation of aldehyde 2
with sulfone 1b in 82% yield as a 60:40 mixture of diastereomers
following the above general procedure. HRMS, calcd for C21H31
-
NO6S: 425.187210. Found: 425.188823. IR (film): 3501, 1697,
1
1366, 1135. Major diastereomer: H NMR (300 MHz, C6D6, 60
Com p ou n d 12: Obtained from aldehyde 520 in 70% yield as
a 93:7 mixture of diastereomers. HRMS, calcd for C25H33NO4S:
443.213031. Found: 443.213234; [R]D +50.0 (c, 0.45, acetone);
mp: 94-96 °C. Major diastereomer: IR (film): 3390, 1687, 1029.
1H NMR (300 MHz, C6D6, 60 °C): 1.17 (d, 3H, J ) 6.9 Hz), 1.32
(s, 9H, C(CH3)3), 1.98 (s, 3H, CH3), 2.11 (dd, 1H, J 1 ) 7.5 Hz, J 2
) 15.3 Hz), 2.33 (dd, 1H, J 1 ) 4,5 Hz, J 2 ) 15.3 Hz), 3.67 (m,
1H), 4.02 (m, 1H), 4.28 (m, 2H), 5.44 (s, 1H, dCH2), 5.90 (s, 1H,
dCH2), 6.89 (AA′ of AA′BB′, 2H, J ) 8 Hz), 7.02-7.20 (m, 5H),
7.44 (BB′ of AA′BB′, 2H, J ) 8 Hz). 13C NMR (75.4 MHz, C6D6,
60 °C): 21.0, 28.4, 34.6, 50.7, 58.3, 73.2, 80.0, 125.5, 127.2, 127.8,
128.6, 129.9, 140.0, 140.7, 141.1, 153.5, 156.4. Minor diastere-
omer (selected signals from the mixture of diastereomers): 1H
NMR (300 MHz, C6D6, 60 °C): 1.12 (d, 3H, J ) 6,9 Hz), 1.27 (s,
9H, C(CH3)3), 4.43 (A of AB, 1H, J ) 16 Hz), 4.60 (B of AB, 1H,
J ) 16 Hz), 5.39 (s, 1H, dCH2), 5.77 (s, 1H, dCH2).
Com p ou n d 13. Obtained from aldehyde 6 in 75% yield as a
88:12 mixture of diastereomers. HRMS, calcd for C27H37NO4S:
471.2443162. Found: 471.242911; [R]D +6.78 (c, 0.56, CHCl3).
IR (film): 3382, 1687, 1031. Major diastereomer: 1H NMR (200
MHz, CDCl3): 0.75-1.05 (broad, 6H, (CH3)2 rotamers), 1.42 (s,
9H, (CH3)3), 1.72 (m, 1H), 2.01-2.19 (m, 2H), 2.36 (s, 3H), 3.95
(broad, 1H), 4.09 (broad, 1H, A of AB), 4.41 (broad, 1H), 4.61
(broad, 1H, B of AB), 5.48 (broad, 1H, dCH2), 5.91 (broad, 1H,
dCH2), 7.32-7.42 (m, 9H). 13C NMR (50.3 MHz, CDCl3): 20.2,
20.6, 28.3, 34.6, 54.1, 69.3, 74.1, 80.4, 119.8, 125.3, 125.5, 127.2,
127.7, 128.6, 129.7, 138.5, 141.1, 152.1, 156.7. Minor diastere-
omer (selected signals from the mixture of diastereomers): 1H
NMR (200 MHz, CDCl3): 3.39 (s, 3H), 5.67 (broad, 1H, dCH2),
6.02 (broad, 1H, dCH2).
°C): 1.30 (s, 9H, C(CH3)3); 1.37-1.53 (m, 6H); 1.91 (s, 3H), 2.23-
2.34 (m, 1H), 2.54-2.62 (m, 1H), 3.56-3.67 (m, 1H), 3.83 (broad,
1H), 3.82-4.40 (m, 3 × 1H), 5.78 (broad, 1H, dCH2), 6.38 (broad,
1H, dCH2), 6.83 (AA′ of AA′BB′, 2H, J ) 8,1 Hz), 7.30-7.77 (m,
2H). 13C NMR (75.4 MHz, C6D6, 60 °C): 21.1, 26.9, 28.3, 33.9,
62.4, 65.2, 71.9, 80.5, 94.5, 125.4, 125.7, 128.7, 129.9, 137.2,
144.0, 148.6. Most relevant signals for the minor diastereomer
(taken from the mixture of isomers): 1H NMR: 1.90 (s, 3H), 4.18
(broad, 1H), 6.35 (broad, 1H, dCH2). 13CNMR: 28.4, 64.3, 144.2,
148.4.
Com p ou n d 17. Obtained from commercially available alde-
hyde ent-2b in 75% yield as a 60:40 mixture of diastereomers.
HRMS, calcd for C21H31NO5S: 409.192295. Found: 409.192990.
Major diastereomer: [R]D +92.4 (c, 0.80, acetone); mp: 105-
108 °C. IR (film): 3382, 1697, 1052. 1H NMR (300 MHz, C6D6,
60 °C): 1.26 and 1.30 (s, 3H, rotamers), 1.39 (s, 9H, C(CH3)3),
1.53 (s, 3H), 1.98 (s, 3H), 2.12 (dd, 1H, J 1 ) 9.6 Hz, J 2 ) 15 Hz),
2.40-2.50 (m, 1H), 3.58-3.64 (m, 1H), 3.91-4.14 (m, 3 × 1H),
4.21 (broad, 1H, OH), 5.61 (broad, 1H, dCH2), 5.95 (broad, 1H,
dCH2), 6.91 (AA′ of AA′BB′, 2H, J ) 8,1 Hz), 7.49 (BB′ of AA′BB′,
2H, J ) 8,1 Hz). 13C (75.4 MHz, CDCl3): 21.3, 24.0, 26.4 and
27.0 (rotamers); 28.2, 32.6, 61.5, 64.4, 71.9, 81.2, 94.0 and 94.2
(rotamers), 119.8, 125.3, 129.9, 140.8, 141.1, 151.4, 154. Minor
diastereomer: [R]D +9.7 (c, 0.75, acetone; mp: 88-90 °C. IR
(film): 3382, 1050, 1014. 1H NMR (300 MHz, C6D6, 60 °C): 1.25
(s, 9H, C(CH3)3), 1.39 and 1.47 (s, 3H rotamers), 1.64 (s, 3H);
1.96 (s, 3H); 2.22 (dd, 1H, J 1 ) 10.2 Hz, J 2 ) 14.7 Hz), 2.40 (d,
1H, J 1 ) 14.7 Hz), 3.61 (dd, 1H, J 1 ) 5.7 Hz, J 2 ) 9 Hz), 3.71-
3.85 (m, 2 × 1H), 4.07 (broad, 1H), 4.70 (broad, 1H), 5.36 (broad,
1H, dCH2), 5.68 (broad, 1H, dCH2), 6.86 (AA′ of AA′BB′, 2H, J
) 8,1 Hz), 7.39 (BB′ of AA′BB′, 2H, J ) 8,1 Hz). 13C NMR (75.4
MHz, CDCl3): 21.3, 26.4, 28.2, 33.9 and 34.8 (rotamers), 61.6,
64.7 and 65.5 (rotamers), 71.7, 80.0 and 80.7, 94.1, 122.3 and
123.6 (rotamers), 124.9, 129.9, 137.9, 141.6, 152.4. For X-ray
coordinates, see below.
Com p ou n d 14. Obtained from aldehyde 721 in 75% yield as
a 93:7 mixture of diastereomers. HRMS, calcd for C31H37NO4S:
519.2443162. Found: 519.245881. [R]D -7.18 (c, 0.97, CHCl3).
IR (film): 3419, 3041, 2921, 2850, 1654, 1250, 1178. Major dia-
stereomer: 1H NMR (200 MHz, CDCl3): 1.46 (broad, 9H, (CH3)3),
1.94 (m, 1H), 2.25 (m, 1H), 2.38 (s, 3H), 2.88 (m, 1H), 3.13 (m,
1H), 3.23 (m, 1H), 3.32 (broad, 1H), 3.93 (broad, 1H), 4.36 (m,
1H), 5.25 (s, 1H, dCH2), 5.81 (s, 1H, dCH2), 7.01-7.44 (m, 14H);
13CNMR (50.3 MHz, CDCl3): 21.2, 28.3, 31.2, 33.2, 53.9, 65.1,
73.7, 80.7, 119.9, 125.1, 126.1, 127.0, 127.2, 127.8, 128.3, 128.4,
129.2, 129.6, 129.8, 137.9, 141.4, 151.6, 157.0. Minor diastere-
omer (selected signals from the mixture of diastereomers): 1H
NMR (200 MHz, CDCl3): 3.85 (m, 1H), 3.32 (m, 1H).
Ack n ow led gm en t. Financial support from Direc-
cio´n General de Ensen˜anza Superior, Ministerio de
Educacio´n y Cultura (PB97-1171), and Comissionat per
a Universitats i Recerca, Generalitat de Catalunya
(Projects 1999SGR00080 and 1999SGR00187) is grate-
fully acknowledged. F.M. is also grateful to Ministerio
de Educacio´n y Cultura for a predoctoral fellowship.
Com p ou n d 15. Obtained from commercially available alde-
hyde 8 in 79% yield as a 91:9 mixture of diastereomers. HRMS,
calcd for C20H29NO4S: 379.181731. Found: 379.182965. Major
diastereomer: [R]D +30 (c, 1.14, acetone). IR (film): 3405, 1689,
1045. 1H NMR (300 MHz, C6D6, 60 °C): 1.17-1.68 (m, 4H), 1.38
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis of aldehyde 6 and oxazolidines cis- and
trans-18; copies of 1H and/or 13C NMR spectra for compounds
9-12 and 14-18; X-ray coordinates for 9 (major isomer), 9
(minor isomer), and 17 (minor isomer). This material is
available free of charge via the Internet at http://pubs.acs.org.
(s, 9H, C(CH3)3), 1.98 (s, 3H), 2.07 (dd, 1H, J 1 ) 8.7 Hz, J 2
)
(21) (a) Hormuth, S.; Reibig, H.; Dorsch, D. Liebigs Ann. Chem.
1994, 121-127. (b) Dondoni, A.; Perrone, D.; Merino, P. J . Org. Chem.
1995, 60, 8074-8080.
J O016068U