Base-catalyzed isomerization of 2-isoxazolines enables a two-step enantioselective synthesis of β-hydroxynitriles from enals

Article abstract of DOI:10.1021/jo1013788

The asymmetric synthesis of β-hydroxynitriles remains a challenge in organic synthesis. Herein we report a convenient synthesis of β-hydroxynitriles from enantiomerically enriched 3-unsubstituted 2-isoxazolines via a base-catalyzed ring-opening reaction that takes place without loss of enantiopurity. In combination with organocatalytic enantioselective synthesis of 3-unsubstituted 2-isoxazolines, the ring-opening enables a short 2-step synthesis of β-hydroxynitriles from α,β-unsaturated aldehydes in high enantiomeric purity.

Full text of DOI:10.1021/jo1013788

pubs.acs.org/joc
SCHEME 1. Synthesis of Enantiomerically Enriched
2-Isoxazolines from Enals
Base-Catalyzed Isomerization of 2-Isoxazolines
Enables a Two-Step Enantioselective Synthesis
of β-Hydroxynitriles from Enals
Antti Pohjakallio,† Petri M. Pihko,*,‡ and Jun Liu‡
†Department of Chemistry, Aalto University School of Science
and Technology, Kemistintie 1, FI-02150 Espoo, Finland, and
‡Department of Chemistry, University of Jyva€skyla€,
FI-40014 JYU, Finland
petri.pihko@jyu.fi
Received July 14, 2010
R,β-unsaturated nitriles,4 the nucleophilic opening of terminal
epoxides with cyanide,5 the enzymatic resolution of racemic
nitriles6 or the corresponding cyanoacetates,7 and the asym-
metric reduction of R-cyanoacetophenones.8 However, the
synthesis of β-hydroxynitriles bearing diverse alkylic sub-
stituents at the β-position with high enantioselectivity is still
challenging, and the best enantioselectivities are typically
obtained by resolution techniques.6
We have recently disclosed two methods for the prepara-
tion of 3-unsubstituted 2-isoxazolines in both racemic and
enantioselective manner from R,β-unsaturated aldehydes
and oximes (Scheme 1).9 These methods can be used to access
a diverse range of 2-isoxazolines bearing alkyl or substituted
alkyl substituents at the 5-position. In principle, these iso-
xazolines could be converted to β-hydroxynitriles via a base-
catalyzed isomerization reaction, first documented by Huisgen
and Christl10 in 1967. Although a number of 2-isoxazoline to
β-hydroxynitrile rearrangements have been reported, these
have been limited to isolated examples of special interest, partly
due to limitations in the synthesis of the parent heterocycles.11
In these examples, the isomerization has been effected by
The asymmetric synthesis of β-hydroxynitriles remains
a challenge in organic synthesis. Herein we report a con-
venient synthesis of β-hydroxynitriles from enantiomeri-
cally enriched 3-unsubstituted 2-isoxazolines via a base-
catalyzed ring-opening reaction that takes place without
loss of enantiopurity. In combination with organocatalytic
enantioselective synthesis of 3-unsubstituted 2-isoxazo-
lines, the ring-opening enables a short 2-step synthesis
of β-hydroxynitriles from R,β-unsaturated aldehydes in
high enantiomeric purity.
(5) Elenkov, M. M.; Hauer, B.; Janssen, D. B. Adv. Synth. Catal. 2006,
348, 579–585.
(6) For examples, see: (a) Kamal, A.; Ramesh Khanna, G. B.; Ramu, R.
Tetrahedron: Asymmetry 2002, 13, 2039–2051. (b) Kamal, A.; Ramesh
Khanna, G. B.; Krishnaji, T.; Tekumalla, V.; Ramu, R. Tetrahedron:
Asymmetry 2005, 16, 1485–1494. (c) Fransson, A.-B. L.; Boren, L.; Pamies,
β-Hydroxynitriles are valuable synthetic intermediates in
chemical synthesis, allowing access to, e.g., β-hydroxy acids
and β-hydroxycarbonyl compounds.1 The synthesis of these
compounds in an enantioselective manner is still challenging,
and methods for the direct catalytic asymmetric synthesis of
β-hydroxynitriles are scarce. The currently available methods
for the synthesis of β-hydroxynitriles include the asymmetric
nitrile aldol reaction,2,3 the asymmetric hydroboration of
€
O.; Backvall, J.-E. J. Org. Chem. 2005, 70, 2582–2587. (d) Kamal, A.;
Ramesh Khanna, G. B.; Krishnaji, T.; Ramu, R. Tetrahedron: Asymmetry
2006, 17, 1281–1289.
(7) (a) Itoh, T.; Takagi, Y.; Nishiyama, S. J. Org. Chem. 1991, 56, 1521–
1524. (b) Itoh, T.; Mitsukura, K.; Kanphai, W.; Takagi, Y.; Kihara, H.;
Tsukube, H. J. Org. Chem. 1997, 62, 9165–9172. Itoh, T.; Mitsukura, K.;
Kanphai, W.; Takagi, Y.; Kihara, H.; Tsukube, H. J. Org. Chem. 1997, 62,
9165–9172.
(8) (a) Wang, G. Y.; Liu, X.-Y.; Zhao, G. Synlett 2006, 1150–1154. (b) Li,
Y.; Li, Z.; Li, F.; Wang, Q.; Tao, F. Org. Biomol. Chem. 2005, 3, 2513–2518.
(c) Liu, P. N.; Gu, P. M.; Wang, F.; Tu, Y. Q. Org. Lett. 2004, 6, 169–172.
(d) Watanabe, M.; Murata, K.; Ikariya, T. J. Org. Chem. 2002, 67, 1712–
1715. (e) Ankati, H.; Zhu, D.; Yang, Y.; Biehl, E. R.; Hua, L. J. Org. Chem.
(1) For selected examples of the use of chiral β-hydroxynitriles in natural
product synthesis, see: (a) Hijikuro, I.; Doi, T.; Takahashi, T. J. Am. Chem.
Soc. 2001, 123, 3716–3722. (b) Gogoi, S.; Barua, N. C.; Kalita, B. Tetra-
hedron Lett. 2004, 45, 5577–5579. (c) Wang, F.; Yue, J. Eur. J. Org. Chem.
ꢁ
2009, 74, 1658–1662. (f) Soltani, O.; Ariger, M. A.; Vasquez-Villa. H.;
ꢀ
2005, 2575–2579. (d) Pospisil, J.; Marko, I. E. J. Am. Chem. Soc. 2007, 129,
3516–3517.
ꢁ
Carreira, E. M. Org. Lett. 2010, 12, 2893-2895.
(9) (a) Pohjakallio, A.; Pihko, P. M. Synlett 2008, 827–830. (b) Pohjakallio,
(2) (a) Soai, K.; Mukaiyama, T. Bull. Chim. Soc. Jpn. 1979, 52, 3371–
3376. (b) Soai, K.; Hirose, Y.; Sakata, S. Tetrahedron: Asymmetry 1992, 3,
677–680. (c) Granander, J.; Eriksson, J.; Hilmersson, G. Tetrahedron:
Asymmetry 2006, 17, 2021–2027.
A.;Pihko, P. M. Chem. Eur. J. 2009, 15, 3960–3964. (c) Pohjakallio, A.; Pihko,
;
P. M.; Laitinen, U. M. Chem. Eur. J. DOI: 10.1002/chem.201000861.
(10) (a) Huisgen, R.; Christl, M. Angew. Chem. 1967, 79, 471. (b) Huisgen,
R.; Christl, M. Chem. Ber. 1973, 106, 3291–3311.
(3) For a truly catalytic asymmetric nitrile aldol reaction, see: Suto, Y.;
Tsuji, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2005, 7, 3757–3760.
(4) Lee, J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145–147.
(11) The synthesis of 3-unsubstituted 2-isoxazolines from alkenes and
fulminic acid or silyl nitronate has been limited to alkenes containing a
stabilizing substituent.
6712 J. Org. Chem. 2010, 75, 6712–6715
Published on Web 09/08/2010
DOI: 10.1021/jo1013788
r
2010 American Chemical Society

Pohjakallio et al.
JOCNote
TABLE 1. Comparison of Conditions for the Ring-Opening of 2-Isoxazoline 3aa
entry
solvent
base (mol %)
time
3 h
temp (°C)
[X]b
ee (3a)/ee (4a)
1
2
3
4
5
6
7
8
9
10
11
12
13
Et3N
Et3N
THF
MeOH
THF
toluene
MeCN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
solvent
solvent
rt
reflux
rt
0
0
n/d
n/d
80/70
80/79
91/91
n/d
n/d
n/d
n/d
n/d
3 h
KOtBu (2)
NaOMe (2)
KHMDS (130)d
Et3N (100)
Et3N (100)
Et3N (100)
Et3N (100)
DBU (100)
DBU (100)
DBU (25)
DBU (25)
10 min
45 min
60 min
3 h
3 h
3 h
3 h
3 h
30 min
30 min
10 min
100/97c
rt
100/88c
-15
reflux
reflux
rt
reflux
rt
reflux
reflux
85 /μw
100/58-91c
0
<10
0
40
90
100
100
100/94c
n/d
94/94e
94/94
aConditions: 0.1 mmol 3a, 0.5 mL solvent. bConversion (X) of 3a was determined by 1H NMR. p-Bromoanisole was used as the internal standard.
cIsolated yield. dThe use of catalytic amounts of KHMDS gave inferior results. eDetermined in conjunction with the telescoped experiment (see Scheme 2).
using triethylamine as solvent10,12,13 or as a catalytic14 or stoi-
chiometric15 reagent in methanol, toluene,16 and acetonitrile.17
The use of sodium methoxide in methanol18 has also been
reported in a single case. However, the general applicability
of these examples has not been demonstrated, since the reac-
tions have typically been carried out with either strained13,16
or electronically activated10,12,14,15,17,18 substrates, and the
issues of enantiomeric purity have not been addressed.
Herein we report a simple and effective catalytic protocol
that allows the rapid synthesis of enantiomerically enriched
β-hydroxynitriles from chiral 2-isoxazolines in excellent yields
and with full conservation of enantiomeric purity.
We initiated our study with the substrate 3a, containing an
alkyl chain at the 5-position. Initial attempts to generate the
β-hydroxynitrile 4a with triethylamine as the base and the
solvent were met with complete failure (Table 1, entries 1 and 2).
Consequently, several other base/solvent combinations were
screened (Table 1).
The base screen indicated that previously disclosed methods
were not directly applicable to nonactivated substrates such
as 3a. The suppressed reactivity of alkyl substrates was repor-
ted also by Huisgen and Christl.10b While strong anionic
bases such as KHMDS, KOt-Bu, or NaOMe (entries 3-5)
led to rapid reactions even at cold temperatures, the chemical
yields of these processes were often inconsistent and seemed
to be dependent on the quality of the base. We were also
concerned that the use of highly nucleophilic methoxide base
might be too restrictive in terms of functional group diversity
in the substrates. Furthermore, an even more worrying result
was obtained with KOt-Bu in THF, where a partial loss of
enantiomeric purity was observed (Table 1, entry 3). This result
was likely caused by the reversible retro-nitrile aldol reaction.
Turning to weaker nonanionic nitrogen bases, we found
that Et3N was only effective when an alcoholic solvent was
used (entries 6-9) and the reaction was heated to reflux, but
even then the reaction was quite sluggish.19 The use of a slightly
more basic 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) drama-
tically improved the rates. Under refluxing conditions, full
conversion of the starting material to the product was obser-
ved in 30 min, even when a catalytic amount of DBU was
used.20 The reaction could also be conducted very conveni-
ently in a microwave reactor: in a pressurized microwave vial
with 50 W heating power, full conversion was obtained within
10 min. 4a was isolated in excellent yield and unchanged
enantioselectivity (94% yield, 94% ee).
The scope of the optimized protocol was then screened
with a structurally diverse set of enantioenriched 2-isoxazo-
lines, readily accessible from R,β-unsaturated aldehydes and
oximes9c (Table 2). A range of substrates bearing different
substituents in the 5-position of the isoxazoline could readily
be converted into the corresponding β-hydroxynitriles, inclu-
ding a 5,5-disubstituted isoxazoline 3g bearing a tertiary
center (entry 7). Different protecting groups (silyl, benzyl,
Cbz) were found to readily withstand the reaction conditions
(entries 3, 5, and 6), and even the unsaturated ester side chain
present in 3h afforded a good yield of the product; however,
in this case, the ring-opening reaction (entry 8) had to be
conducted at room temperature with methanol as the solvent
to avoid transesterification and to suppress the internal
conjugate addition of 4h to form tetrahydropyrans.21
Finally, we conducted the synthesis of 4a as a direct two-
step protocol without purification of the 2-isoxazoline product.
This telescoped protocol afforded the product in 73% overall
yield and 94% enantiomeric excess (Scheme 2).
As a conclusion, we have demonstrated that under optimized
conditions, base-catalyzed isomerization of 3-unsubstituted
(12) Das, N. B.; Torssell, K. B. G. Tetrahedron 1983, 39, 2247–2253.
€
(14) Galley, G.; Jones, P. G.; Patzel, M. Tetrahedron: Asymmetry 1996, 7,
2073–2082.
(15) Ogamino, T.; Nishiyama, S. Tetrahedron 2003, 59, 9419–9423.
(16) Irngartinger, H.; Weber, A. Tetrahedron Lett. 1997, 38, 2075–2076.
(17) Lukevics, E.; Dirnens, V.; Kemme, A.; Popelis, J. J. Organomet.
Chem. 1996, 521, 235–244.
(18) (a) Andersen, S.; Das, N. B.; Jørgensen, R. D.; Kjeldsen, G.;
Knudsen, J. S.; Sharma, S. C.; Torssell, K. B. G. Acta. Chem. Scand. B
1982, 36, 1–14. (b) Yashiro, A.; Nishida, Y.; Kobayashi, K.; Ohno, M.
Synlett 2000, 361–362.
(13) Brand, U.; Hunig, S. Liebigs Ann. 1996, 585–592.
€
(19) Other solvents reported in the literature, such as toluene and aceto-
nitrile, did not work at all with Et3N as the base.
(20) Interestingly, DBU was reported to be ineffective in the ring opening
of a [60]fullereno[1,2-d]isoxazole. See ref 16.
(21) (a) The formation of the side products could not be completely
suppressed, and this is the likely reason for the slightly lower yield obtained
with 2h compared to other substrates. (b) In addition to MeOH and EtOH as
the solvents, the reaction of 1h in less nucleophilic solvent, i-PrOH, was also
attempted. However, only a very slow reaction was observed, even upon heating.
J. Org. Chem. Vol. 75, No. 19, 2010 6713

Pohjakallio et al.
JOCNote
TABLE 2. Synthesis of Enantioenriched β-Hydroxynitriles from 2-Isoxazolinesa
aConditions: (a) 1 mmol of 2-isoxazoline, 0.25 mmol of DBU, 4 mL of EtOH; (b) 1 mmol of 2-isoxazoline, 0.25 mmol of DBU, 4 mL of MeOH.
SCHEME 2. A Telescoped Two-Step Protocol for the Synthesis
of β-Hydroxynitrile 4a
1.00 mmol, 100 mol %) in EtOH (4 mL) in a microwave glass
vessel was added DBU (35 μL, 0.25 mmol, 25 mol %). The
resulting mixture was heated in a microwave reactor with
constant power (50 W, 10 mL sealed vessel) at 83 °C, using air
cooling to adjust the temperature. After the reaction was
complete (indicated by TLC), the solution was concentrated
to a volume of ca. 1 mL with a rotary evaporator and then
diluted with EtOAc (20 mL). The resulting solution was washed
with 1 M HCl (5 mL) and the aqueous layer was back-extracted
with EtOAc (5 mL). The combined organic layers were washed
with brine (10 mL), dried (Na2SO4), and concentrated. Purifica-
tion of the residue by column chromatography (27% EtOAc/
hexane) afforded the product 4a as a pale yellow solid (164 mg,
95%, 94% ee by HPLC). Mp 44-46 °C (lit.22 mp 42-43 °C);
Rf 0.33 (50% EtOAc in hexane); [R]D þ13.5 (c 1.0, CH2Cl2, 94%
2-isoxazolines can be used efficiently in the asymmetric synth-
esis of β-hydroxynitriles. The ring-opening proceeds under
fairly mild conditions with catalytic amounts of amine base
(DBU) in methanol or ethanol. Heating the reaction results
in fast reaction rates, but for sensitive substrates, the reaction
can also be conducted at rt. Importantly, the enantiomeric
purity of the 2-isoxazoline is fully conserved in the process,
enabling a simple two-step synthesis of β-hydroxynitriles
directly from the R,β-unsaturated aldehydes, even without
purification of the intermediates. The implementation of the
full protocol from R,β-unsaturated aldehydes to β-hydro-
xynitriles on supported catalysts has been initiated.
1
ee) {lit.22 [R]D þ20 (c 1.6, CHCl3, >99% ee)}; H NMR (400
MHz, CDCl3) δ 7.34-7.27 (m, 2H), 7.25-7.18 (m, 3H), 3.94
(qn, 1H, J = 5.8 Hz), 2.82 (ddd, 1H, J1 = 5.9 Hz, J2 = 8.5 Hz,
J3 = 14.0 Hz), 2.71 (td, 1H, J1 = 8.0 Hz, J2 = 14.0 Hz), 2.55
(dd, 1H, J1 = 4.8 Hz, J2 = 16.7 Hz), 2.50 (dd, 1H, J1 = 6.4 Hz,
J2 = 16.7 Hz), 2.35 (br s, 1H), 2.0-1.84 (m, 2H). The analytical
data correspond to those reported in the literature.22 The enantio-
meric purity was determined by HPLC analysis with a Daicel
Chiralcel OD column (25 cm) along with precolumn (5 cm).
Eluent: 10% 2-propanol in hexane. Flow rate: 0.7 mL/min. λ =
254 nm. Major isomer: tr=38.3 min. Minor isomer: tr 31.6 min.
Acknowledgment. TEKES (National Agency for Technol-
ogy and Innovation), the Graduate School of Organic
Chemistry and Chemical Biology, Finnish Cultural Foundation,
Experimental Section
General Procedure for the Ring-Opening of Isoxazolines under
Microwave Conditions: Synthesis of (R)-3-Hydroxy-5-phenyl-
pentanenitrile 4a. To a solution of 2-isoxazoline 3a (173 mg,
(22) Wang, D.-F.; Yue, J.-M. Eur. J. Org. Chem. 2005, 2575–2579.
6714 J. Org. Chem. Vol. 75, No. 19, 2010

Pohjakallio et al.
JOCNote
and Academy of Finland (Project No. 123813) are ac-
knowledged for material and financial support. We thank
Dr. Jari Koivisto for NMR assistance. Ulla Laitinen and
Essi Karppanen are acknowledged for their experimental
contributions.
Supporting Information Available: General experimental
methods, full experimental details, characterization data, copies
of NMR spectra, microwave heating profiles, and HPLC chro-
matograms. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 19, 2010 6715