Chiral epoxides via borane reduction of 2-haloketones catalyzed by spiroborate ester: Application to the synthesis of optically pure 1,2-hydroxy ethers and 1,2-azido alcohols

Article abstract of DOI:10.1021/jo102294j

An enantioselective borane-mediated reduction of a variety of 2-haloketones with 10% spiroaminoborate ester 1 as catalyst is described. By a simple basic workup of 2-halohydrins, optically active epoxides are obtained in high yield and with excellent enantiopurity (up to 99% ee). Ring-opening of oxiranes with phenoxides or sodium azide is investigated under different reaction conditions affording nonracemic 1,2-hydroxy ethers and 1,2-azido alcohols with excellent enantioselectivity (99% ee) and in good to high chemical yield. 2011 American Chemical Society.

Full text of DOI:10.1021/jo102294j

NOTE
pubs.acs.org/joc
Chiral Epoxides via Borane Reduction of 2-Haloketones Catalyzed
by Spiroborate Ester: Application to the Synthesis of Optically Pure
1,2-Hydroxy Ethers and 1,2-Azido Alcohols
Kun Huang, Haiyang Wang, Viatcheslav Stepanenko, Melvin De Jesꢀus, Carilyn Torruellas,
Wildeliz Correa, and Margarita Ortiz-Marciales*
Department of Chemistry, University of Puerto Rico-H-umacao, CUH Station, Humacao, Puerto Rico 00791
S Supporting Information
b
ABSTRACT: An enantioselective borane-mediated reduction of a
variety of 2-haloketones with 10% spiroaminoborate ester 1 as catalyst
is described. By a simple basic workup of 2-halohydrins, optically active
epoxides are obtained in high yield and with excellent enantiopurity
(up to 99% ee). Ring-opening of oxiranes with phenoxides or sodium
azide is investigated under different reaction conditions affording
nonracemic 1,2-hydroxy ethers and 1,2-azido alcohols with excellent
enantioselectivity (99% ee) and in good to high chemical yield.
onracemic epoxides are recognized not only for their
biological importance,1 but also as key intermediates in
Spiroaminoborate ester 1 derived from diphenylprolinol was
highly effective for the reduction of a variety of aryl,15a-15d
heteroaryl,15e R-alkoxy,15f and aliphatic15g ketones providing the
desired secondary alcohols in excellent yield with excellent
enantioselectivity, higher or similar to Corey’s OAB (CBS
reagent). Presently, we are interested in the synthesis of non-
racemic R-aryloxy and R-amino alcohols as important chiral
building blocks for the preparation of neurobiological active
molecules. We, herein, describe a simple and convenient proce-
dure for the preparation of optically active epoxides in high yield
with excellent enantiopurity and their application to the synthesis
of optically pure β-hydroxy ethers and 1,2-azido alcohols.
To develop a suitable procedure for the synthesis of epoxides, the
asymmetric reduction of R-chloroacetophenone was initially carried
N
diverse chemical transformations for the synthesis of chiral
auxiliaries, natural products, and chiral drugs.2,3 Moreover, chiral
epoxides have been recently used as catalysts for asymmetric in-
duction in the autocatalyzed organozinc addition to an alde-
hyde.4 Consequently, in the last 30 years, a variety of direct
epoxidation and resolution methods for the synthesis of en-
antiopure oxiranes have been successfully developed.5-8 More
convenient and efficient routes to prepare optically pure styrene
oxides involve the initial enzymatic9 or chemical asymmetric
reduction of R-halogenated acetophenones.10-12 Environmen-
tally friendly boron reagents have been used for the reduction of a
variety of R-haloketones and the halohydrins are easily converted
to nonracemic epoxides without racemization.11,12 These meth-
ods can be considered, essentially, as “one pot” procedures
valuable for substrates with sensitive groups due to the very mild
reaction conditions. The most recognized chiral catalysts for the
enantioselective borane-mediated reduction of unsymmetrical
ketones with outstanding and predictable stereoselectivities are
1,3,2-oxazaborolidines (OAB) derived from nonracemic 1,2-
amino alcohols.12 Nevertheless, the in situ prepared B-H oxaza-
borolidines are known to form side products diminishing in some
cases the effectiveness of the catalyst.13
out with 10% catalyst 1 and 0.7 equiv of BH3 DMS in THF at room
3
temperature, followed by treatment of the crude chlorohydrin with
2 N NaOH. The styrene oxide was afforded in good yield and
without racemization. To optimize the reaction conditions, R-Cl
and R-Br acetophenone were reduced under different catalytic loads
and borane sources, and subsequently, the crude halohydrins were
cyclized under basic conditions. Since BH3 DMS provides similar
3
enantioselectivity as BH3 THF, we consider its use more attractive
3
for a convenient method due to its low price and stability. In ad-
dition, the reduction of R-Br acetophenone afforded the corre-
sponding epoxide in higher enantiopurity than the chloro analogue,
providing 99% ee, and good chemical yield with 10% of catalyst 1,
A series of stable crystalline aminoborate esters, derived from a
variety of nonracemic 1,2-amino alcohols, ethylene glycol, and
inexpensive triisopropyl borate, were previously reported by our
group.14,15 The most effective and convenient aminoborate
complexes used as catalysts for the borane-mediated reduction
of ketones14,15a-15g and benzyl oximes15h are shown in Figure 1.
0.7 equiv of BH3 DMS in THF at room temperature for 0.5 h.
3
Received: October 8, 2010
Published: February 04, 2011
r
2011 American Chemical Society
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Table 1. Asymmetric Reduction of R-Haloketones for the
Synthesis of Epoxidesa
Figure 1. Representative aminoborate complexes.
Encouraged by the remarkable enantioselectivity obtained in
the synthesis of the styrene oxide using spiroaminoborate 1, we
explored its scope in the reduction of a variety of aromatic and
aliphatic R-halogenated ketones and their halohydrins conver-
sion to enantioenriched oxiranes. As indicated in Table 1,
R-haloacetophenones with Me, MeO, Cl, F, CN, and NO2 ring-
substituents (entries 1-10) were reduced to the S-2-bromo-1-
phenylethanols, which were transformed under basic conditions
to the S-epoxides in good to excellent yields and outstanding
enantioselectivities (97-99% ee). The presence of different
substituents on the aromatic ring has no significant effect on
the ee values (entries 2-10). However, the cyclization of 2-bromo-
4-methylphenyl-1-ethanol (entry 9) by treatment with 2 N NaOH
afforded the corresponding epoxide in lower yield. However,
the use of t-BuOK led us to the expected epoxide in good yield.
In addition, the R-bromocyclohexyl ethanone and R-bromo
adamanty ethanone afforded the epoxides in high yield and
excellent enantiomeric excess (entries 11 and 12).
The absolute configuration of the oxiranes was determined by
comparing the optical rotation with the literature values.8,10,11a,15f,16a
Racemic β-hydroxy ethers were prepared as standards for
HPLC analysis by the sodium borohydride reduction of
β-phenoxyketones (8).
Regioselective ring-opening of oxiranes with nucleophiles is
an important route to obtain a broad range of nonracemic 1,2-
substituted alcohols as intermediates for the synthesis of key
pharmaceutical compounds, as well as chiral catalysts.3,17-19 Opti-
cally active β-hydroxy ethers are valuable synthetic intermediates in
a wide variety of potentially bioactive compounds.2g,17a Although
asymmetric syntheses of terminal epoxides in high optical purity
are well established,5-8 efficient methods for the synthesis of non-
racemic β-aryloxy alcohols via epoxide ring-opening remains
limited.18 Thus, we were interested in studying the regioselective
ring-opening of enantiopure epoxides with phenols or phenoxides.
Initially, the ring-opening of racemic 2-phenyloxirane was studied by
using sodium phenoxide in the presence of β-cyclodextrin in water
at 60 °C.18c However, the major product was 2-phenoxy-2-pheny-
lethanol (9a), produced by ring-opening at the benzylic position
contrary to the reported 2-aryloxy-1-phenylethanol (10a). The
compound 9a was identified by 1H NMR analysis and compared
with a standard sample of 10a prepared according to previous
reported procedure.15f Further analyses of the reaction mixture by
1H NMR showed 9a, 10a, and diol 11 in 100/8/88 ratio, and in
46%, 6%, and 38% isolated yield, respectively. For comparison
purposes, other substrates were also reinvestigated. See the Support-
ing Information.
a All the reactions were performed as reported in the experimental
procedure. b Purified by flash chromatography or Kugelrohr distillation.
c Determined by GC on a chiral column. d Determined by chiral HPLC
on the basis of β-hydroxyl ether. e t-BuOK was used in the epoxidation
reaction. f Determined by chiral HPLC.
(S)-β-hydroxy ethers 10 in good yield without racemization. As
indicated in Table 2, representative aromatic and aliphatic (S)-β-
hydroxy ethers were produced under the selected conditions with
outstanding enantiopurity (97% to >99% ee) and in moderate to
good isolated yields of pure products (entries 1-6).
Optically active 2-azido-2-aryl ethanols are well-known pre-
cursors for the synthesis of a broad variety of enantiopure
1,2-amino alcohols, which are essential building blocks in the
preparation of neurobiologically active compounds.3,17 Recently,
Qu and co-workers20a reported the preparation of racemic
1,2-diols and 1,2-azido alcohols by the ring-opening of epoxides
in hot water. Due to the importance of nonracemic 1,2-amino
alcohol, we were interested in studying the ring-opening reaction
of optically pure epoxides with NaN3. As indicated in Scheme 1,
when styrene epoxide (7a) and sodium azide were heated in
The low regioselectivity and poor yields in the previous
methods led us to search an alternative route for the synthesis
of the desired (S)-1,2-aryoxy ethanols 10. After various optimiza-
tion studies with different bases (K2CO3, NaOH, KOH, and
NaH) and solvents (CH3CN, THF, and DMF), in addition to
various temperatures and reaction times, it was found that the
treatment of epoxides 7 with phenol, previously treated with
NaH, in anhydrous DMF at 60 °C for 36 h, provided the desired
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NOTE
Table 2. Preparation of β-Hydroxy Ethers 10 from Epoxides 7
Scheme 1. Ring-Opening of Epoxides with NaN3 in Hot
Water
with inversion of configuration at the stereogenic center. Note-
worthy, this highly regioselective and enantioselective conver-
sion of styrene oxides to 1,2-azido alcohols was conducted under
mild and environmentally favorable conditions with only hot
water, providing a rapid access to important non-natural amino
alcohols, as well as to biological building blocks that can be used
for example in the click chemistry for the formation of chiral
triazoles or amides.21
In summary, the enantioselective reduction of 2-haloketones
with 10% of the spiroaminoborate ester 1 offers a convenient and
facile route for the synthesis of a variety of highly enantiopure
epoxides. The ring-opening of racemic styrene oxides by aryloxy
nucleophiles in hot water in the presence of β-cyclodextrin takes
place by a preferential nucleophilic attack to the benzylic position
providing 2-aryloxy-2-aryl ethanols as the mayor product. However,
the treatment of chiral epoxides with PhONa in anhydrous DMF at
60 °Cfor24-36 h gives mainly 1-aryl and 1-alkyl β-aryloxy ethanols
10 in outstanding ee and good chemical yield. In addition, remark-
able regioselective nucleophilic attack of NaN3 to (S)-epoxides in
hot water takes place affording optically pure (R)-2-azido-2-aryl
ethanols 13 with complete inversion of configuration in outstanding
enantiopurity (up to 99% ee) and in high yield.
’ EXPERIMENTAL SECTION
General Procedure for Asymmetric Reduction and Epox-
idation. To a solution of spiroaminoborate ester 115 (64 mg, 0.2
mmol) in dry THF (5 mL) was added BH3 DMS (0.14 mL, 10 M, 1.4
3
mmol) at room temperature under N2 atmosphere, and the solution was
stirred for 30 min. A solution of the 2-haloketone (2 mmol) in dry THF
(4 mL) was added dropwise for 1 h. After the addition was complete, the
reaction mixture was stirred for 30 min, cooled at 0 °C, and quenched
with MeOH (5 mL). The solvents were removed under reduced
pressure, and the residue was treated with 2 N NaOH (5 mL) in THF
(10 mL) for 2 h. After an aqueous workup the residue was purified by
flash column chromatography on silica.
Typical Procedure for the Preparation of Enantiopure
β-Hydroxy Ethers: (S)-(þ)-1-(3-Methoxyphenyl)-2-phenox-
yethanol (10j). To a dried, three-necked, 25 mL, round-bottomed flask
charged with NaH (30.3 mg, 1.2 mmol, 1.2 equiv, 95%) in anhydrous DMF
(2 mL) was added dropwise PhOH (94.1 mg, 1.0 mmol) in anhydrous
DMF (2 mL) at ambient temperature under nitrogen. After the mixture was
stirred for 10 min, a solution of epoxide 7j (150.2 mg, 1.0 mmol) in
anhydrous DMF (2 mL) was added dropwise. The mixture was stirred at
60 °C for 24 h and after aqueous workup the residue was purified by
preparative TLC. The desired product was obtained in 82% yield (200 mg)
as a colorless oil; 98% ee, determined by chiral HPLC analysis.
a The products were obtained by preparative TLC. b Determined by
HPLC (Chiralcel OD-H). c Reaction time 36 h.
water at 60 °C for 3.5 h, 2-azido-2-phenyl ethanol 12a was
formed as the main product with only a trace amount of
regioisomer 13a, as determined by GC-MS and 1H NMR
analyses of the crude product. The ratio of 12a and 13a by
GC-MS analysis was 95.4:4.6. After purification by preparative
TLC, it was afforded (S)-12a in 91% yield and 99% ee, based on
HPLC analysis on a chiral column. Since highly enantiopure (S)-
1-phenyl-2-azido ethanol was obtained, and more significantly,
with complete inversion of configuration, the reaction was
carried out with the p-chlorostyrene oxide 7d to demonstrate
the generality of this valuable ring-opening reaction. According
to the analysis by GC-MS, the ratio of 2-azidoarylethanol 12d to
13d was 93:7. Remarkably, 12d was isolated in excellent yield
(88%) and its optical purity was 98% ee. The stereochemistry of
these compounds was confirmed by full spectroscopic analysis
and optical rotation. Interestingly, this transformation only
slightly decreased the enantioselectivities of compounds 12a
(99% ee) and 12d (98% ee), obtaining the 2-azido-1-arylethanols
General Procedure for the Preparation of 2-Azido-2-ary-
lethanols. To a stirred suspension of epoxide (1 mmol) in distilled
water (6 mL) in a 25 mL flask with condenser was added sodium azide
(2 mmol, 130 mg). The mixture was stirred for 3.5 h at 60 °C and then
20 mL of water was added. The product was isolated by preparative
TLC.
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NOTE
’ ASSOCIATED CONTENT
(13) (a) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Carroll,
J. D.; Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880. (b)
Brown, J. M.; Guy, C.; Lloyd-Jones, G. C.; Layzell, T. P. Tetrahedron:
Asymmetry 1993, 4, 2151. (c) Stepanenko, V.; Ortiz-Marciales, M.;
Barnes, C. E.; Garcia, C. Tetrahedron Lett. 2006, 47, 7603.
(14) Stepanenko, V.; Ortiz-Marciales, M.; Barnes, C. L.; Garcia, C.
Tetrahedron Lett. 2009, 50, 995.
S
Supporting Information. Characterization data of all
b
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(15) (a) Stepanenko, V.; Ortiz-Marciales, M.; Correa, W.; De Jesꢀus,
M.; Espinosa, S.; Ortiz, L. Tetrahedron: Asymmetry 2006, 17, 112. (b)
Ortiz-Marciales, M.; Stepanenko, V.; Correa, W.; De Jesꢀus, M.; Espinosa,
S. U.S. Patent Application 11/512,599, August 30, 2006. (c) Stepanenko,
V.; De Jesꢀus, M.; Correa, W.; Vꢀazquez, C.; Guzmꢀan, I.; Vꢀazquez, C.;
De la Cruz, W.; Ortiz-Marciales, M.; Barnes, C. L. Tetrahedron Lett. 2007
48, 5799. (d) Stepanenko, V.; Ortiz-Marciales, M.; De Jesꢀus, M.; Correa,
W.; Vꢀazquez, C.; Ortiz, L.; Guzmꢀan, I.; De la Cruz, W. Tetrahedron:
Asymmetry 2007, 18, 2738. (e) Stepanenko, V.; De Jesꢀus, M.; Correa,
W.; Bermꢀudez, L.; Vꢀazquez, C.; Guzmꢀan, I.; Ortiz-Marciales, M.
Tetrahedron: Asymmetry 2009, 20, 2659. (f) Huang, K.; Ortiz-Marciales,
M.; Correa, W.; Loꢀpez, X. Y.; Pomales, E. J. Org. Chem. 2009, 74, 4195.
(g) Stepanenko, V.; Huang, K.; Ortiz-Marciales, M. Org. Synth. 2010, 87,
26. (h) Huang, K.; Ortiz-Marciales, M. Org. Synth. 2010, 87, 36 and
references cited therein.
(16) (a) Schaus, S.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 1307. (b) Ready, J. M.; Jocobsen, E. N. J. Am. Chem. Soc.
1999, 121, 6086.
(17) (a) Franchini, C.; Carocci, A.; Catalano, A. A.; Cavalluzzi,
M. M.; Corbo, F.; Lentini, G.; Scilimati, A.; Scilimati, A.; Tortorella,
P.; Camerino, D. C.; Luca, A. J. Med. Chem. 2003, 46, 5238–5248. (b)
For an extensive review on the enantioselective ring opening of epoxides,
see: Schneider, C. Synthesis 2006, 3919.
Corresponding Author
*E-mail margarita.ortiz1@upr.edu
’ ACKNOWLEDGMENT
Financial support by the National Institute of Health through
their MBRS (GM 08216) and NIH-INBRE (NC P20 RR-
016470) grants is greatly appreciated. The NIH-INBRE and
NIH-RISE, NIH-MARC, NSF-AMP undergraduate student’s
support is also gratefully acknowledged.
’ REFERENCES
(1) Hatakeyama, S.; Ochi, N.; Takano, S. Chem. Pharm. Bull. 1993,
41, 1358.
^
(2) (a) Hudlicky, T.; Tian, X.; Kinigsberger, K.; Rouden, J. J. Org.
Chem. 1994, 59, 4037. (b) Satake, A.; Shimizu, I.; Yamamoto, A. Synlett
1995, 64. (c) Shao, H.; Zhu, Q.; Goodman, M. J. Org. Chem. 1995, 60,
790. (d) Schmidt, B.; Kunz, O.; Biernat, A. J. Org. Chem. 2010, 75, 2389.
(3) For a review on the reactivity of epoxides, see: Schneider, C.
Synthesis 2006, 3919.
(4) Kawasaki, T.; Shimizu, M.; Sato, I.; Soai, K. Tetrahedron:
Asymmetry 2004, 15, 3699.
(18) (a) Fan, R. H.; Hou, X. L. J. Org. Chem. 2003, 68, 726. (b)
Chem, J.; Shum, W. Tetrahedron Lett. 1995, 36, 2379. (c) Surendra, K.;
Krishnaveni, S. S.; Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem. 2003, 68,
4994–4995.
(19) Huang, K.; Ortiz-Marciales, M.; Stepanenko, V.; De Jesꢀus, M.;
Correa, W. J. Org. Chem. 2008, 73, 6928.
(20) (a) Wang, Z.; Cui, Y.-T.; Xu, Z.-B.; Qu, J. J. Org. Chem. 2008, 73,
2270. (b) Kiasat, A. R.; Badri, R.; Zargar, B.; Sayyahi, S. J. Org. Chem.
2008, 73, 8382.
(5) (a) Sharpless Angew. Chem., Int. Ed. 2002, 41, 2024. (b) Katsuki,
T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5976. (c) Zhang, W.;
Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed.
2005, 44, 4389. (d) Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007,
129, 286.
(6) (a) Brandes, B. D.; Jacobsen, N. E. J. Org. Chem. 1994, 59, 4378.
(b) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–299. (c) Jacobsen,
E. N. Acc. Chem. Res. 2000, 33, 421. (d) Matsumoto, K.; Oguma, T.;
Katsuki, T. Angew. Chem., Int. Ed. 2009, 48, 7432.
(21) (a) Sletten, E. M.; Bertozzi, C. R. Angew. Chem., Int. Ed. 2009,
48, 6974. (b) Best, M. D. Biochemistry 2009, 48, 6571.
(7) (a) Burke, C. P.; Shi, Y. J. Org. Chem. 2007, 72, 4093. (b) Wong,
O.; Shi, Y. Chem. Rev. 2008, 108, 3958.
(8) (a) Jin, H.; Li, Z.; Dong, X. Org. Biomol. Chem. 2004, 2, 408. (b)
Minireview: Finey, N. S. Chem. Biol. 1998, 5, 74.
(9) (a) For a recent review on the asymmetric reduction of ketones
with biocatalysts, see: Nakamura, K.; Yamanaka, R.; Matsuda, T.;
Harada, T. Tetrahedron: Asymmetry 2003, 14, 2659. (b) Podea, P. V.;
Paizs, C.; To-sa, M. I.; Irimie, F. D. Tetrahedron: Asymmetry 2008, 19,
1959. (c) McCubbin, J. A.; Maddess, M. L.; Lautens, M. Synlett 2008, 289.
(d) Tr€aff, A.; Bogꢀar, K.; Warner, M.; B€ackvall, J.-A. Org. Lett. 2008, 10, 4807.
(10) (a) Lee, D.-M.; Kwak, S. H.; Lee, K.-I. Bull. Korean Chem. Soc.
2009, 30, 1317. (b) Haak, R. M.; Berthiol, F.; Jerphagnon, T.; Gayet,
A. J. A.; Tarabiono, C.; Postema, C. P.; Ritleng, V.; Pfeffer, M.; Janssen,
D. B.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. J. Am. Chem. Soc.
2008, 130, 13508.
(11) (a) Cordes, D. B.; Kwong, T. J.; Morgan, K. A.; Singaram, B.
Tetrahedron Lett. 2006, 47, 349. (b) Chung, J. Y. L.; Cvetovich, R.;
Amato, J.; McWilliams, J. C.; Reamer, R.; DiMichel, L. J. Org. Chem.
2005, 70, 3592.
(12) (a) Itsuno, S.; Ito, K. J. Org. Chem. 1984, 49, 555. (b) Corey,
E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861. (c) Choi,
O. K.; Cho, B. T. Tetrahedron: Asymmetry 2001, 12, 903. (d) Cho, B. T.
Chem. Soc. Rev. 2009, 443 and references cited therein. (e) Glushkov,
V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2004, 73, 581 and references
cited therein. (f) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986 and references cited therein. (g) Corey, E. J.; Bakshi, R. K.; Shibata,
S. J. Am. Chem. Soc. 1987, 109, 5551.
1886
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