Aziridine-modified amino alcohols as efficient modular catalysts for highly enantioselective alkenylzinc additions to aldehydes

Article abstract of DOI:10.1055/s-2007-973879

N-Tritylaziridino alcohols have been easily synthesized in a straightforward synthetic route from an inexpensive and easily available chiral pool. They were used in the enantioselective alkenylzinc additions to aldehydes furnishing the products in excelle

Full text of DOI:10.1055/s-2007-973879

LETTER
917
Aziridine-Modified Amino Alcohols as Efficient Modular Catalysts for Highly
Enantioselective Alkenylzinc Additions to Aldehydes
C
atalysts for High
n
ly Enantiosel
t
ective
o
A
lkenylzinc
n
A
dditions to
i
Aldehy
o
des L. Braga,*a Marcio W. Paixao,a,b Bernhard Westermann,*b Paulo H. Schneider,c Ludger A. Wessjohannb
a
Departamento de Química, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brazil
Fax +55(55)32208998; E-mail: albraga@quimica.ufsm.br
b
c
Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Received 1 November 2006
In connection with our current interests in the asymmetric
addition of organozinc reagents to aldehydes7 and encour-
aged by the recent successful developments in the enanti-
oselective arylzinc additon to aldehydes under MW
irradiation using aziridine-containing amino alcohols as
modular ligands,8 we demonstrated herein the utility of
these easy accessible ligand systems for the enantioselec-
tive addition of vinylzinc reagents to aldehydes.
Abstract: N-Tritylaziridino alcohols have been easily synthesized
in a straightforward synthetic route from an inexpensive and easily
available chiral pool. They were used in the enantioselective alke-
nylzinc additions to aldehydes furnishing the products in excellent
yields and stereoselectivities up to 97%.
Key words: asymmetric synthesis, allylic alcohols, vinyl addition,
alkenylzinc, aziridino alcohols
Ligands 1–3 can be prepared in high yields starting from
the appropriate amino acids, L-serine and L-threonine, re-
spectively.9 Due to the availability of the D-configured
amino acids, the corresponding enantiomers of ligand 1–
3 be can approached without any obstacles.
The catalytic enantioselective construction of carbon–car-
bon bonds is still one of the most challenging goals in or-
ganic chemistry.1 In this field, the enantioselective
addition of organometallic reagents to aldehydes appears
as an extremely attractive topic.2
With the target ligands in hand, we focused our attention
towards the optimization of the conditions of the C–C
coupling reaction. At first, effects of catalyst loading and
temperature were first investigated in detail for ligand 1
with 1-hexyne as the alkenylzinc precursor and benzalde-
hyde using toluene as solvent (Scheme 1, Table 1, entries
1–7).10
Chiral, nonracemic allylic alcohols are important interme-
diates for the synthesis of biologically and pharmaceuti-
cally active compounds due to the vast possibilities for
further stereoselective manipulations.3 The addition of
alkenylzinc derivatives to aldehydes is probably one of
the most efficient approach for this purpose. These orga-
nometallic reagents can be easily prepared in situ using
transmetalation protocols.4 In this context, Oppolzer and
Radinov introduced an elegant method where a vinylzinc
reagent was prepared in situ by regioselective hydrobora-
tion of terminal alkynes with dicyclohexylborane fol-
lowed by boron–zinc exchange.5
Table 1 Results for the Addition of Vinylzinc Species to Benzalde-
hyde under Various Conditions
Entry
Ligand
(mol%)
Temp
(°C)
Time
(h)
Yield
(%)a
ee
(%)b,c
1
2
1 (15)
1 (10)
1 (5)
–20
–20
–20
–20
–40
–78
–20
–20
–20
–20
18
18
18
18
24
36
18
18
18
18
88
87
83
72
68
36
84
82
79
93
93 (S)
92 (S)
85 (S)
79 (S)
92 (S)
94 (S)
90 (S)
91 (S)
46 (S)
95 (S)
Since, ligands which effectively catalyze the vinyl trans-
fer reactions to aldehydes have not been extensively stud-
ied.6 The search for efficient chiral ligands to generate
high enantioselectivities in such reactions still remains a
challenge in this area (Scheme 1).
3
4
1 (2.5)
1 (10)
1 (10)
1 (10)
2 (10)
3 (10)
1 (10)
5
OH
nBu
i) Cy2BH
ii) ZnEt2
iii) Ligand
PhCHO
nBu
EtZn
6
Ph
nBu
7d
8
R1
R1
R
1 R = H, R1 = Ph
2 R = H, R1 = Et
3 R = Me, R1 = Ph
OH
Ligands:
N
9
Trit
10e
Scheme 1 Enantioselective synthesis of allylic alcohols
a Yield of isolated products.
b The ee values for allylic alcohols were measured by HPLC
(Chiralcel OD-H).
SYNLETT 2007, No. 6, pp 0917–0920
0
3.
0
4.
2
0
0
7
c Configuration determined by comparison with literature data.3d,6g
d A 1:1 mixture of toluene and hexane was used as solvent.
e Me2Zn was used instead of Et2Zn in transmetalation.
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973879; Art ID: S18206ST
© Georg Thieme Verlag Stuttgart · New York

918
A. L. Braga et al.
LETTER
Our studies had started employing catalyst loadings of 15 Table 2 Vinylzinc Addition to Various Aldehydes Catalyzed by
Ligand 111
mol% to achieve excellent levels of enantioselectivity
(entry 1). Decreased ligand loading to 10 mol% gave sim-
1 (10 mol%)
OH
R1CHO
+
MeZn
ilar results but reducing the catalyst loading to 5 mol% re-
sulted in a decrease in the enantioselectivity and yield
(entries 2 vs. 3). Further decrease of the catalyst loading
to 2.5 mol% caused a slight decrease in yield and in enan-
tioselectivity (entry 4). Lowering the reaction temperature
to –40 °C or –78 °C had a little effect on the selectivity;
instead, the reactivity was significantly decreased (entries
5 and 6).
R2
toluene
–20 °C, 18 h
R1
R2
Entry Terminal alkynes Aldehyde
Yield
ee
(R1)
(R2)
(%)a
94
96
92
83
86
89
88
97
89
(%)b,c
94 (S)
97 (S)
97 (S)
95 (S)
88 (S)
91 (S)
95 (S)
90 (S)
81 (S)
1
2
3
4
5
6
7
8
9
n-Hex
t-Bu
c-Hex
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Ph
Ph
The influence of the solvent was also examined. The use
of toluene is crucial for a high enantioselectivity, since a
lower ee was obtained by employing a mixture of tolu-
ene–hexane (entry 7). This fact is probably due to a poor
solubility of the reactive zinc species resulting from the
boron–zinc exchange reaction.6c
Ph
p-MeC6H4
p-OMeC6H4
p-ClC6H4
p-BrC6H4
p-MeCO2C6H4
o-BrC6H4
We decided to extend this study to other chiral aziridine
ligands. For this reason, the electronic and steric proper-
ties of the R and R1 groups have been briefly investigated.
Decreasing the size of the chiral ligand by switching from
1 (R1 = Ph) to 2 (R1 = Et) gave comparable yield and ee
(entries 2 vs. 8). However, variations in the R group have
shown that it plays a great impact on the enantioselectivity
of the reaction. The best result was achieved with the cat-
alyst 1 with R = H (entries 2 vs. 9). Therefore, one can as-
a Yield of isolated products.
b The ee (%) of allylic alcohols as measured by HPLC.
c Configuration determined by comparison with literature data.3d,6g
sume that steric factors play a dominant role in the enantioselectivity decreased compared to using benzalde-
stereochemical outcome in this series of ligands. We next hyde (entries 2 vs. 6–8). The presence of substituents at
examined alternative methods to generate the vinylzinc the ortho position of the aromatic aldehyde shows some
reagent. An improvement of the enantioselectivity was difference in the stereodifferentiation event. For example,
observed, when dimethylzinc was used in the transmeta- p-bromobenzaldehyde undergoes smooth vinyl addition,
lation step instead of diethylzinc (entry 10).
to achieve the corresponding product in 95% ee, while the
o-bromo derivative resulted in much lower enantioselec-
tivity (entries 7 vs. 9). This fact can be explained by the
influence of steric effects.
To study the generality of catalyst 1 we examined the
scope of the reactions catalyzed by this ligand by first
varying the structure of the vinylzinc reagent (Table 2).
We found that the substituents on the propargylic position In summary, we have demonstrated an efficient catalytic
had a very little effect on the enantioselectivity of the re- enantioselective vinylation of aromatic aldehydes using
action. For example, n-hexylacetylene gave the corre- rigid chiral ligands readily available from common amino
sponding allylic alcohol in 94% ee and the bulky tert- acids. The reactive alkenylzinc species is generated in situ
butylacetylene gave the desired product in 97% ee (entries via a boron–zinc exchange and its reaction with aldehydes
1 vs. 2). Using cyclohexylacetylene, a very high enantio- gives access to several chiral allylic alcohols in high
meric excess of the corresponding product was achieved yields and ee. The selectivities are comparable to those
(entry 3). In fact, all substrates tested gave in general obtained with the best ligand known for this reaction.6
>90% ee.
Studies dealing with the mechanism of the reaction and
application of this catalyst system in other asymmetric
catalytic reactions are currently in progress in our labora-
tories.
Finally, we investigated the applicability of our ligand to
the addition of (E)-(3,3-dimethylbut-1-enyl) zinc to sever-
al aromatic aldehydes with diverse electronic and steric
properties (Table 2, entries 4–9). Reaction with p-tolu-
aldehyde underwent smooth vinyl addition in very high
enantiomeric excess in good yield (entry 4). When p-
methoxybenzaldehyde was employed, a decreased enan-
tiomeric excess of the corresponding product was
achieved (entry 5). On the other hand, when electron-
withdrawing groups were present in the aldehyde, the
Acknowledgment
We are grateful to CAPES and DAAD (German Academic Ex-
change Service) for travel grants as part of a PROBRAL project,
CNPq, and FAPERGS for financial support. We also acknowledge
CAPES for providing a PhD fellowship to M.W.P.
Synlett 2007, No. 6, 917–920 © Thieme Stuttgart · New York

LETTER
Catalysts for Highly Enantioselective Alkenylzinc Additions to Aldehydes
919
CDCl3): d = 146.79, 145.25, 143.44, 129.04, 127.77, 127.59,
127.22, 126.62, 126.55, 126.50, 126.04, 125.72, 73.95,
73.89, 41.46, 23.80. ESI-HRMS: m/z calcd for C34H29NO +
Na+: 490.2147; found: C34H29NO + Na+: 490.2141.
Compound 2: yield 74%; pale yellow oil; [a]D22 –82.8 (c 1,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.51–7.18 (m, 15
H), 3.05 (br s, 1 H), 1.94 (d, 1 H, J = 3.3 Hz), 1.62–1.43 (m,
1 H), 1.41–1.29 (m, 4 H), 1.14 (d, 1 H, J = 6.4 Hz), 0.73 (q,
6 H, J = 7.5 Hz). 13C NMR (75 MHz, CDCl3): d = 144.03,
129.37, 127.40, 126.68, 73.97, 70.82, 40.18, 31.93, 28.23,
23.51, 8.13, 7.73. ESI-HRMS: m/z calcd for C26H29NO +
Na+: 394.2141; found: C26H29NO + Na+: 394.2147
Compound 3: yield 82%; mp 174–176 °C; [a]D22 +22 (c 1,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.46–6.98 (m, 25
H), 3.05 (s, 1 H), 2.20 (d, 1 H, J = 6.7 Hz), 1.66 (q, 1 H,
J = 6.0 Hz), 1.19 (d, 3 H, J = 5.8 Hz). 13C NMR (75 MHz,
CDCl3): d = 148.39, 146.04, 143.80, 143.68, 129.34, 128.60,
127.80, 127.74, 127.29, 126.79, 126.64, 126.03, 125.52,
75.17, 73.50, 45.21, 31.99, 1376. ESI-HRMS: m/z calcd for
C35H31NO + Na+: 504.2303; found: C35H31NO + Na+:
504.2297.
References and Notes
(1) (a) Evans, D. A. Science 1988, 240, 420. (b) Noyori, R.;
Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
(c) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(d) Soai, K.; Shibata, T. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.;
Springer: Berlin, 1999, 911.
(2) (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757. (b) Pu, L.
Tetrahedron 2003, 59, 9873.
(3) (a) Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125,
10677. (b) Garcia, C.; Libra, E. R.; Carroll, P. J.; Walsh, P.
J. J. Am. Chem. Soc. 2003, 125, 3210. (c) Jeon, S.-J.;
Walsh, P. J. J. Am Chem. Soc. 2003, 125, 9544. (d) Lurain,
A. E.; Carroll, P. J.; Walsh, P. J. J. Org. Chem. 2005, 70,
1262. (e) Kim, H. Y.; Lurain, A. E.; Garcia-Garcia, P.;
Carroll, P. J.; Walsh, P. J. J. Am Chem. Soc. 2005, 127,
13138. (f) Lurain, A. E.; Maestri, A.; Kelly, A. R.; Carroll,
P. J.; Walsh, P. J. J. Am Chem. Soc. 2005, 126, 13608.
(4) (a) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988,
29, 5645. (b) Oppolzer, W.; Radinov, R. N. Tetrahedron
Lett. 1991, 32, 5777.
(11) General Procedure for the Alkenylzinc Addition to
Aldehydes
(5) (a) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75,
10. (b) Oppolzer, W.; Radinov, R. N.; El-Sayed, E. J. Org.
Chem. 2001, 66, 4766.
Cyclohexene (608 mL, 3.0 mmol) was added under argon at
0 °C to a magnetically stirred solution of borane dimethyl-
sulfide complex (142 mL, 1.5 mmol) in toluene (1 mL). After
2 h at 0 °C the alkyne (1.5 mmol) was added and the mixture
was stirred for 30 min at r.t. The mixture was cooled to
–78 °C and a solution of Et2Zn (2 mL, 1 mmol, 1.0 M in
toluene) or Me2Zn solution (1.5 mL, 3 mmol, 2 M in toluene)
was added slowly to this and after 1 h at –78 °C, a toluene
solution of ligand (0.1 mL, 1 M in toluene, 0.1 mmol) was
added. After warming from –78 °C to –30 °C over a period
of 1 h, toluene (1 mL) and the aldehyde (1 mmol) were added
and the mixture was stirred for 18 h at –20 °C. The reaction
mixture was quenched with H2O, Et2O was added and the
organic layer was subsequently extracted with brine. The
organic layer was dried over MgSO4 and the solvent was
removed in vacuo. The residue was purified through column
chromatography on silica gel to provide the enantio-
merically pure allyl alcohol.
(6) (a) Soai, K.; Takahashi, K. J. Chem. Soc., Perkin Trans. 1
1994, 1257. (b) Shibata, T.; Nakatsui, K.; Soai, K. Inorg.
Chim. Acta 1999, 296, 33. (c) Dahmen, S.; Bräse, S. Org.
Lett. 2001, 3, 4119. (d) Ji, J.-X.; Qiu, L.-Q.; Yip, C.-W.;
Chan, A. S. C. J. Org. Chem. 2003, 68, 1589. (e) Chen, Y.
K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
12225. (f) Tseng, S.-L.; Yang, T.-K. Tetrahedron:
Asymmetry 2005, 16, 773. (g) Sprout, C. M.; Richmond, M.
L.; Seto, C. T. J. Org. Chem. 2005, 70, 7408.
(h) Richmond, M. L.; Sprout, C. M.; Seto, C. T. J. Org.
Chem. 2005, 70, 8835.
(7) For some representative examples, see: (a) Braga, A. L.;
Appelt, H. R.; Schneider, P. H.; Silveira, C. C.; Wessjohann,
L. A. Tetrahedron: Asymmetry 1999, 10, 1733. (b) Braga,
A. L.; Paixão, M. W.; Lüdtke, D. S.; Silveira, C. C.;
Rodrigues, O. E. D. Org. Lett. 2003, 5, 2635. (c) Braga, A.
L.; Milani, P.; Paixão, M. W.; Zeni, G.; Rodrigues, O. E. D.;
Alves, E. F. Chem. Commun. 2004, 2488. (d) Braga, A. L.;
Lüdtke, D. S.; Vargas, F.; Paixão, M. W. Chem. Commun.
2005, 2512. (e) Braga, A. L.; Lüdtke, D. S.; Schneider, P.
H.; Vargas, F.; Schneider, A.; Wessjohann, L. A.; Paixão, M.
W. Tetrahedron Lett. 2005, 45, 7827.
Conditions for Determining Enantiomeric Excess by
HPLC Analysis
All measurements were performed at a 20 °C column
temperature using a UV detector at 219 nm.
(S,E)-1-Phenylhept-2-en-1-ol (Table 1, entries 1–10):
Chiralcel OD-H column eluted with hexane–2-PrOH (99:1)
at 1.0 mL/min; tR = 22.0 min for R and tR = 32.3 min for S.
(S,E)-1-Phenylnon-2-en-1-ol (Table 2, entry 1): Chiralcel
OD-H column eluted with hexane–2-PrOH (99:1) at 1.0 mL/
min; tR = 20.7 min for R and tR = 32.3 min for S.
(S,E)-4,4-Dimethyl-1-phenylpent-2-en-1-ol (Table 2,
entry 2): Chiralcel OD-H column eluted with hexane–2-
PrOH (99:1) at 1.0 mL/min; tR = 14.1 min for R and tR = 22.3
min for S.
(S,E)-3-Cyclohexyl-1-phenylprop-2-en-1-ol (Table 2,
entry 3): Chiralcel OD-H column eluted with hexane–2-
PrOH (99:1) at 1.0 mL/min; tR = 21.9 min for R and tR = 33.2
min for S.
(S,E)-(4-Tolylphenyl)-4,4-dimethylpent-2-en-1-ol
(Table 2, entry 4): Chiralcel OD-H column eluted with
hexane–2-PrOH (98:2) at 0.5 mL/min; tR = 18.3 min for R
and tR = 20.5 min for S.
(8) Braga, A. L.: Paixao, M. W.; Westermann, B.; Schneider, P.
H.; Wessjohann, L. A.; Chem. Eur. J., in press.
(9) General Procedure for the Synthesis of Ligands 1–3
The Grignard reagent (25 mmol) in THF (10 mL, 2.5 M
solution) was added dropwise over a period of 10 min to a
solution of the appropriate aziridine ester (5 mmol) in 10 mL
of THF. After 1.5 h the reaction was quenched with sat. aq
NH4Cl (30 mL) followed by the evaporation of the organic
solvents. The residue was extracted with Et2O (3 × 50 mL)
and the combined organic layers were dried (MgSO4) and
concentrated to give the product. The crude product was
purified by flash column chromatography on silica (hexane–
EtOAc, 12:1); Et3N was added to the eluent to prevent
detritylation of the product during the purification
procedure. Recrystallization was achieved from MeOH–
Et3N by a hot solution.
(10) Compound 1: yield 70%; mp 133.5–134.5 °C; [a]D22 –78.8
(c 1, CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.45–7.34 (d,
2 H, J = 7.3 Hz), 7.32–7.12 (m, 8 H), 7.09–7.04 (m, 15 H),
4.44 (br s, 1 H), 2.38 (dd, 1 H, J = 6.2, 3.1 Hz), 2.08 (d, 1 H,
J = 3.1 Hz), 1.32 (d, 1 H, J = 6.2 Hz). 13C NMR (75 MHz,
(S,E)-1-(4-Methoxyphenyl)-4,4-dimethylpent-2-en-1-ol
(Table 2, entry 5): Chiralcel OD-H column eluted with
hexane–2-PrOH (99:1) at 1.0 mL/min; tR = 25.5 min for R
and tR = 32.5 min for S.
Synlett 2007, No. 6, 917–920 © Thieme Stuttgart · New York

920
A. L. Braga et al.
LETTER
(S,E)-Methyl 4-(1-hydroxy-4,4-dimethylpent-2-
enyl)benzoate (Table 2, entry 8): Chiralcel OD-H column
eluted with hexane–2-PrOH (95:5) at 1.0 mL/min; tR = 13.7
min for S and tR = 14.8 min for R.
(S,E)-(4-Chlorophenyl)-4,4-dimethylpent-2-en-1-ol
(Table 2, entry 6): Chiralcel AD-H column eluted with
hexane–2-PrOH (95:5) at 1.0 mL/min: tR = 7.15 min for R
and tR = 8.14 min for S.
(S,E)-(4-Bromophenyl)-4,4-dimethylpent-2-en-1-ol
(Table 2, entry 7): Chiralcel AD-H column eluted with
hexane–2-PrOH (95:5) at 1.0 mL/min: tR = 7.64 min for R
and tR = 9.07 min for S.
(S,E)-(2-Bromophenyl)-4,4-dimethylpent-2-en-1-ol
(Table 2, entry 9): Chiralcel OD-H column eluted with
hexane–2-PrOH (97:7) at 1.0 mL/min: tR = 13.2 min for R
and tR = 15.7 min for S.
Synlett 2007, No. 6, 917–920 © Thieme Stuttgart · New York

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