A purely synthetic, diversity amenable version of norephedrine thiols for the highly enantioselective diethylzinc addition to aldehydes

Article abstract of DOI:10.1055/s-2001-15142

A new β-aminothiol arising from purely synthetic yet enantiopure aminoalcohols has been prepared and successfully used in the addition of diethylzinc to aromatic aldehydes, yielding secondary alcohols in ee's up to 99%.

Full text of DOI:10.1055/s-2001-15142

LETTER
1155
A Purely Synthetic, Diversity Amenable Version of Norephedrine Thiols for
the Highly Enantioselective Diethylzinc Addition to Aldehydes
Ciril Jimeno, Albert Moyano, Miquel A. Pericàs,* Antoni Riera
Unitat de Recerca en Síntesi Asimètrica. Departament de Química Orgànica. Universitat de Barcelona. c/ Martí i Franquès 1-11, E-08028
Barcelona. Spain
Fax (+34) 933 397 878; E-mail: mapericas@qo.ub.es
Received 19 April 2001
opening with secondary amines and subsequent selective
Abstract: A new -aminothiol arising from purely synthetic yet
protection of the primary hydroxyl group.4a,b
enantiopure aminoalcohols has been prepared and successfully used
in the addition of diethylzinc to aromatic aldehydes, yielding sec-
ondary alcohols in ee’s up to 99%.
Key words: aminothiols, diethylzinc additions, enantioselective,
catalytic, aziridinium salt
Chiral ligands for asymmetric catalysis1,2 have been gen-
erally prepared from a limited chiral pool of readily avail-
able natural products.3 This fact does not allow in many
cases significant optimization of the catalytic properties
because of the difficulties associated to the synthetic ma-
nipulation of the starting natural product. To circumvent
this common problem, we have introduced several fami-
lies of modular aminoalcohols4,5 which can be readily pre-
pared through the stereospecific and regioselective ring
opening of enantiopure epoxides of synthetic origin.6
At this point, we realized that several aminothiols7 and
aminothioacetates8 had been synthesized starting from
(–)-norephedrine 1 (Scheme 1) and successfully used as
catalysts in the enantioselective addition of diethylzinc to
aromatic aldehydes, yielding chiral secondary alcohols of
high enantiomeric purity. Several sulfur-containing ami-
no acid derivatives have also been used as ligands in the
same reaction,9 in the asymmetric reduction of prochiral
ketones,9a,b,10 and in other processes.11
Scheme 2
All the individual reactions used in this synthesis are
known, so that the regio- and stereochemical outcome
could be predicted as indicated in Scheme 2. An important
advantage of this planning is that both enantiomers of 3
are equally accessible by simply changing the tartrate
enantiomer used as the catalytic ligand in the Sharpless
epoxidation leading to 5. Furthermore, these -aminothi-
ols 3 have another modulable group besides the amino
function; the protecting group of the primary alcohol is an
important source of diversity since its variation can give
rise to structures of very different bulkiness. We had pre-
viously observed that this factor exerts a deep influence
on the catalytic properties of the ligand4a,12 in aminoalco-
hols 4.
We report herein the successful application of these ideas
to the synthesis of the first members of a new family of
aminothiols and S-acetyl derivatives thereof, and the pre-
liminary results obtained in the addition of diethylzinc to
aldehydes using these compounds as chiral ligands.
Two different aminoalcohols 4 were used as starting ma-
terials, the NR2 substituent being specified as a piperidino
(4a) or a dibutylamino (4b) group. The protecting group
for the primary alcohol was initially chosen as a trityl,
since it has been observed in the related family of ami-
noalcohols 44a,b and in the recently developed regioiso-
meric family 612 that the very bulky trityl protecting group
provides superior results in catalytic applications.
Scheme 1
In line with previous experience in our group, which has
led to the development of highly efficient -aminoalcohol
ligands4 from enantiopure epoxyalcohols, we thought that
modular aminothiols could easily be prepared in the same
manner. Thus, we planned to synthesize norephedrine thi-
ol analogues 3 starting from (2R,3R)- or (2S,3S)-2-
alkoxy-3-dialkylamino-3-phenyl-2-propanols 4, which, in
turn, are prepared from epoxycinnamyl alcohol 5 (Scheme
2) through regioselective and stereospecific epoxide
Synlett 2001, No. 7, 1155–1157 ISSN 0936-5214 © Thieme Stuttgart · New York

1156
C. Jimeno et al.
LETTER
cern on the catalytic activity of ligands 3a and 8a,b. Grat-
ifyingly enough, the results of the initial trials in additions
of diethylzinc to benzaldehyde15 (Scheme 4) with -ami-
nothioacetates were excellent (Table 1, entries 1 and 2);
addition took place with very high conversion and selec-
tivity when 8a was used, and enantioselectivities of 96%
were achieved. The reaction was carried out in anhydrous
toluene at 0 ºC for five hours, using a 5 mol% of 8a (or
whatever any other ligand used) and 2 equivalents of 1 M
diethylzinc solution in hexanes, besides the corresponding
aldehyde (1 equiv). Conversions were lower when the
dibutylamino-containing ligand 8b was used, but ee was
still high (95% ee).
Most interestingly, -aminothiol 3a turned out to be an
even better ligand, and the addition product to benzalde-
hyde was found to be of 99% ee (entry 3). Other aromatic
aldehydes (entries 4-6) also showed excellent reactivity
towards the diethylzinc addition (99% conversion and se-
lectivity were observed), and led to the corresponding al-
cohols in 98-99% ee. When an aliphatic aldehyde, as
n-heptanal, was tested, the resulting alcohol was only of
66% ee (entry 8), although total conversion and selectivity
were achieved. This is not surprising when results previ-
ously obtained with other aminothiols are taken into ac-
Scheme 3
Under these restrictions, the preparation of our target mol-
ecules was achieved through the sequence of reactions in-
dicated in Scheme 3. Mesylation of the alcohol at 0 ºC in
the presence of two equivalents of triethylamine led to
formation of an intermediate aziridinium salt 713 that was
not isolated but treated in situ with a 10% aqueous solu-
tion of potassium thioacetate for 24 hours. After extrac-
tive work-up, aminothioacetate 8a was isolated in
excellent yield, in chemically pure form without further
purification. In the case of 8b, however, it was necessary
to purify the S-acetyl derivative by column chromatogra-
phy, and therefore yield was somewhat lower (58%). The
regiochemistry was determined by MS-EI, and ions only
compatible with fragmentation of the drawn structures
were clearly observed. This is in accordance with the fact
that the benzylic carbon atom in the aziridinium interme-
diate is the most reactive towards nucleophilic attack.
Aminothioacetate 8a was then reduced to the free thiol
3a14 with a commercial 1 M DIBALH solution in hexanes
in good yield.
count.7 Finally, an
-unsaturated aldehyde was tested
(entry 7), and the corresponding allylic alcohol was found
to be of 99% ee.
Scheme 4
In conclusion, we have developed the first members of a
new family of modular, synthetic analogues of norephe-
drine aminothiol ligands. Compound 3a shows excellent
catalytic activity and enantioselectivity in the addition re-
action of diethylzinc to aromatic aldehydes, yielding sec-
ondary alcohols in 98-99% ee.
Due to the important steric effects exerted by the trityl
group and, therefore, to the big difference with respect to
the norephedrine derived aminothiol 2, we had some con-
Table 1 Diethylzinc Additions to Aldehydes using 5% of 8a-b or 3a.
a Calculated by GC ( -DEXTM 120). b Absolute configuration assigned according to the
elution order in the chiral capillary column. c The acetate derivative was analyzed.
Synlett 2001, No. 7, 1155–1157 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Purely Synthetic, Diversity Amenable Version of Norephedrine Thiols
1157
(9) a) Trentmann, W.; Mehler, T.; Martens, J. Tetrahedron:
The influence on catalytic activity of the steric effects cre-
ated by the primary hydroxyl-protecting group in 3 is cur-
rently being investigated in our laboratories, and full data
on the structural effects of aminothiols on their catalytic
behavior will be reported soon.
Asymmetry 1997, 8, 2033. b) Kossenjans, M.; Martens, J.
Tetrahedron: Asymmetry 1998, 9, 1409. c) Juanes, O.;
Rodríguez-Ubis, J. C.; Brunet, E.; Pennemann, H.;
Kossenjans, M.; Martens, J. Eur. J. Org. Chem. 1999, 3323.
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b) Xingshu, L.; Rugang, X. Tetrahedron: Asymmetry 1996, 7,
2779. c) Xingshu, L.; Rugang, X. Tetrahedron: Asymmetry
1997, 8, 2283.
Acknowledgement
(11) a) Brunner, H.; Becker, R.; Riepl, G. Organometallics 1984,
3, 1354. b) Griffin, J. H.; Kellogg, R. J. Org. Chem. 1985, 50,
3261.
(12) Jimeno, C.; Moyano, A.; Pericàs, M. A.; Riera, A. Manuscript
in preparation.
This research was supported by MEC (grant PB98-1246) and DUR-
SI (grant 2000SGR00019). CJ thanks Generalitat de Catalunya for
a pre-doctoral fellowship.
References and Notes
(13) Anderson, S. R.; Ayers, J. T.; De Vries, K. M.; Ito, F.;
Mendenhall, D.; Vanderplas, B. C. Tetrahedron: Asymmetry
1999, 10, 2655; and references cited therein.
(1) a) Asymmetric Catalysis in Organic Synthesis. Noyori, R.
(Ed.); John Wiley & Sons, New York 1994. b) Catalytic
Asymmetric Synthesis. Ojima, I. (Ed.); VCH, New York 1993.
(2) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1050.
(3) For compilations of natural and non-natural enantioselective
catalysts and auxiliaries, see, for example: a) Blaser, H. U.
Chem. Rev. 1992, 92, 935. b) Chiral Auxiliaries and Ligands
in Asymmetric Synthesis. Seyden-Penne, J. (Ed.); John Wiley
& Sons, New York 1995.
(4) a) Vidal-Ferran, A.; Moyano, A.; Pericàs, M. A.; Riera, A. J.
Org. Chem. 1997, 62, 4970. b) Vidal-Ferran, A.; Moyano, A.;
Pericàs, M. A.; Riera, A. Tetrahedron Lett. 1997, 38, 8773.
c) Solà, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.;
Pericàs, M. A.; Riera, A.; Álvarez-Larena, A.; Piniella, J. F. J.
Org. Chem. 1998, 63, 7078. d) Reddy, K. S.; Solà, L.;
Moyano, A.; Pericàs, M. A.; Riera, A. J. Org. Chem. 1999, 64,
3969. e) Reddy, K. S.; Solà, L.; Moyano, A.; Pericàs, M. A.;
Riera, A. Synthesis 2000, 165.
(5) For applications of aminoalcohols in catalysis, see: Fache, F;
Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000,
100, 2159.
(6) a) Katsuki, T.; Martín, V. S. Org. React. 1996, 48, 1.
b) Johnson, R. A.; Sharpless, K. B. in Catalytic Asymmetric
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(14) A solution of 4 (0.817 g, 1.71 mmol) in CH2Cl2 (3 mL) under
N2 at 0 °C was treated with Et3N (0.788 mL, 5.64 mmol) and
MsCl (0.219 mL, 2.82 mmol). After 2 hours, 10% aq AcSK (5
mL, 6.57 mmol) was added, the mixture was allowed to warm
up to r.t., and stirring was continued for 24 h. Water and
CH2Cl2 (10 mL each) were added, the organic phase was
separated, and the aqueous one extracted with CH2Cl2 (2 10
mL). The combined organic extracts were dried (Na2SO4) and
the solvent evaporated to afford pure 8a (0.880 g, 96% yield)
as an amorphous solid. Next, to a solution of 8a (0.400 g,
0.750 mmol) in anhydrous Et2O (5 mL) under N2, DIBALH
(1.6 mL, 1M in hexanes) was added dropwise at 78 °C.
Stirring was continued for 6 hours, while the temperature
slowly increased to 20 °C. Methanol (5 mL) was carefully
added at 78 °C, the reaction mixture was allowed to warm up
to room temperature, and the solvents evaporated. The residue
was purified by column chromatography on silica gel
(hexanes / AcOEt 95:5) to afford 3a (0.252 g, 68% yield) as
an amorphous solid. Data for 3a: [ ]D22 = -48.8 (c 1.18,
CHCl3); 1H NMR (300 MHz, CDCl3) = 1.24 (m, 6H), 2.32
(m, 4H), 3.08 (m, 1H), 3.35 (m, 2H), 4.21 (d, J = 7Hz, 1H),
7.12-7.50 (m, 20H); 13C NMR (75 MHz, CDCl3) = 24.6,
26.6, 44.3, 51.7, 61.1, 70.6, 87.1, 125.6, 126.9, 127.6, 127.7,
127.8, 128.7, 142.6, 143.9; HRMS (CI, NH3): Calcd for
C33H36NOS: 494.2518; Found: 494.2505.
(15) Typical experimental procedure: 10 mg (0.02 mmol) of 3a
was dissolved in 1 mL of anhydrous toluene, under nitrogen
atmosphere. A 1 M diethylzinc solution in hexanes (0.8 mL,
0.80 mmol) was added dropwise, and, after cooling the
mixture at 0 °C, benzaldehyde (42 mg, 0.40 mmol) was added
via syringe. Five hours later, the reaction was quenched with
sat. aq. NH4Cl, extracted with CH2Cl2 (3 10 mL) and the
combined organic phases dried over Na2SO4. After filtration,
the organic solution was analyzed by GC ( -DEXTM 120):
Conversion was found to be 98%, selectivity was higher than
99%, and ee was 99%.
Article Identifier:
1437-2096,E;2001,0,07,1155,1157,ftx,en;G05301ST.pdf
Synlett 2001, No. 7, 1155–1157 ISSN 0936-5214 © Thieme Stuttgart · New York