Spiroborate ester-mediated asymmetric synthesis of β-hydroxy ethers and its conversion to highly enantiopure β-amino ethers

Article abstract of DOI:10.1021/jo900666r

(Chemical Equation Presented) Borane-mediated reduction of aryl and alkyl ketones with α-aryl- and α-pyridyloxy groups affords β-hydroxy ethers in high enantiomeric purity (up to 99% ee) and in good yield, using as catalyst 10 mol % of spiroborate ester 1

Full text of DOI:10.1021/jo900666r

Spiroborate Ester-Mediated Asymmetric Synthesis of ꢀ-Hydroxy
Ethers and Its Conversion to Highly Enantiopure ꢀ-Amino Ethers
Kun Huang, Margarita Ortiz-Marciales,* Wildeliz Correa, Edgardo Pomales, and
Xaira Y. Lo´pez
Department of Chemistry, UniVersity of Puerto RicosHumacao, CUH Station,
Humacao, Puerto Rico 00791-4300
ortiz@quimica.uprh.edu
ReceiVed March 30, 2009
Borane-mediated reduction of aryl and alkyl ketones with R-aryl- and R-pyridyloxy groups affords
ꢀ-hydroxy ethers in high enantiomeric purity (up to 99% ee) and in good yield, using as catalyst 10 mol
% of spiroborate ester 1 derived from (S)-diphenylprolinol. Representative ꢀ-hydroxy ethers are successfully
converted to ꢀ-amino ethers, with minor epimerization, by phthalimide substitution under Mitsunobu’s
conditions followed by hydrazinolysis to obtain primary amino ethers or by imide reduction with borane
to afford ꢀ-2,3-dihydro-1H-isoindol ethers. Nonracemic Mexiletine and nAChR analogues with potential
biological activity are also synthesized in excellent yield by mesylation of key ꢀ-hydroxy pyridylethers
and substitution with five-, six-, and seven-membered ring heterocyclic amines.
Introduction
regioselectivity of the nucleophilic ring opening, usually, can
generate a mixture of products producing modest yields.3
Furthermore, the classic method of ring opening, usually,
requires high temperature and longer reaction time associated
with side reactions, such as isomerization, epimerization, and/
or rearrangement.1a,4 Recently, Wills and co-workers5 studied
the asymmetric transfer hydrogenation of functionalized ac-
etophenone by a ruthenium(II) catalyst with a tethering group
attachment from the basic nitrogen atom to the arene ligand.
They applied the method to the reduction of a ketone ether
obtaining the corresponding ꢀ-hydroxy ether in 95% ee. The
environmentally benign asymmetric reduction of functionalized
ketones mediated by 1,3,2-oxazaborolidines (OB) and other
chiral borane reagents has been extensively investigated by
Optically active ꢀ-hydroxy ethers are valuable building blocks
in organic synthesis, in particular for their transformation to
enantiopure ꢀ-amino ethers, which are important precursors in
the preparation of a wide variety of pharmaceutical compounds.1
Accordingly, various methods have been sought for the asym-
metric synthesis of ꢀ-hydroxy ethers, such as the enantioselec-
tive ring opening of epoxides catalyzed by chiral Salen
complexes2 and ring opening of optically active aryl oxiranes.1a
However, the steric and electronic factors controlling the
(1) (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. (b) Wright, J. T.; Gregory, T. F.; Heffner,
T. G.; Mackenie, R. G.; Pugsley, T. A.; Meulen, S. V.; Wise, L. D. Bioorg.
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Rizvi, R.; Shankar, B. B.; Duggar, S.; Clader, J.; McCombie, S. W.; Lin, S.;
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Bioorg. Med. Chem. Lett. 1996, 2069. (e) Cavalluzzia, M. M.; Catalanoa, A.;
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2004, 2756. (b) Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315.
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10.1021/jo900666r CCC: $40.75
Published on Web 05/04/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4195–4202 4195

Huang et al.
FIGURE 1. Spiroborate ester 1, Corey’s oxazaborolidines 2, Brown’s reagent 3, Zhao’s reagent 4, and TarB-X Singaram’s reagent 5.
SCHEME 1. Asymmetric Synthesis of Model ꢀ-Hydroxy Ether 7a
Corey6 and other groups (Figure 1).7,8 The B-H oxazaborolidine
(2a)-catalyzed reduction has been widely applied with high
enantioselectivity and predictable configuration to R-haloke-
tones,9 R-[(triorganosilyl)oxy] ketones,10a R-(2-pyranyl)oxy
ketones,10b R-sulfonyloxy ketones,10c R-amido ketones,10d dike-
tones,11 R-keto acetals,12 R,ꢀ-enones and ynones,13 R-azido
ketones,7h,j ketone esters,7f ketophosphonates,14 ꢀ-keto sulfides,
and sulfones.15 However, the in situ prepared B-H oxazaboro-
lidines may possibly form side products that can diminish the
efficiency of the catalyst.16 Although B-Me and B-n-Bu ox-
azaborolidines (2b, 2c) could overcome these disadvantages,
the use of relatively expensive trialkylboroxine or alkylboronic
acid and the careful purification procedure required for their
preparation make these reagents expensive for multigram
syntheses. The enantioselective reduction of ꢀ-keto ethers using
affordable and environmentally friendly chiral boron catalysts
is expected to be one of the most convenient methods for the
synthesis of optically active ꢀ-hydroxy ethers.
Recently, a series of air- and moisture-stable crystalline
spiroborate esters have been easily synthesized in our laboratory
from nonracemic 1,2-amino alcohols, ethylene glycol, and
inexpensive triisopropyl borate.17a,b Spiroborate ester 1 (Figure
1) derived from diphenyl prolinol, which was isolated and
characterized by X-ray, optical, and spectroscopical methods,
has demonstrated outstanding enantioselectivity for ketone
reductions.17c,d The facile and successful use of spiroborate ester
1 has prompted us to investigate its application for the reduction
of key ꢀ-keto ethers. Herein, we wish to report a highly efficient
synthesis of ꢀ-hydroxy ethers with excellent enantiomeric purity
in high yield and study its conversion to a wide variety of
ꢀ-amino ethers, Mexiletine and nAChR analogues.
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J. Am. Chem. Soc. 1987, 109, 7925. (b) Corey, E. J.; Helal, C. J. Angew. Chem.,
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1504. (b) Kanth, J. V. B.; Brown, H. C. Tetrahedron 2002, 58, 1069. (c) Liu,
D.; Shan, Z.; Zhou, Y.; Wu, X.; Qin, J. HelV. Chim. Acta 2004, 87, 2310. (d)
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Y.-M. Tetrahedron: Asymmetry 2006, 17, 1895. (f) Wang, G.; Hu, J.; Zhao, G.
Tetrahedron: Asymmetry 2004, 15, 807. (g) Gamble, M. P.; Studle, J. R.; Wills,
M. Tetrahedron Lett. 1992, 37, 2853. (h) Reddy, M. S.; Narender, Rao, M. K. R.
Tetrahedron 2007, 63, 331. (i) Eagon, S.; Kim, J.; Yan, K.; Haddenham, D.;
Singaram, B. Tetrahedron Lett. 2007, 48, 9025. (j) Bolm, C.; Felder, M.
Tetrahedron Lett. 1993, 34, 6041. (k) Bolm, C.; Seger, A.; Felder, M. Tetrahedron
Lett. 1993, 34, 8079. (l) Yadav, J. S.; Reddy, P. T.; Hashim, S. R. Synlett 2000,
1049. (m) Hu, J.; Zhao, G.; Yang, G.; Ding, Z. J. Org. Chem. 2001, 66, 303.
(8) (a) Cho, B. T. Tetrahedron 2006, 62, 7621. (b) Cho, B. T. Chem. Soc.
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Results and Discussion
The reduction of ketone ether 6a, as shown in Scheme 1,
was initially selected as a model substrate. Ketone 6a was readily
prepared in high yield by the treatment of 2-bromoacetophenone
(10) (a) Cho, B. T.; Chun, Y. S. J. Org. Chem. 1998, 63, 5280. (b) Cho,
B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1999, 10, 1843. (c) Cho, B. T.;
Yang, W. K.; Choi, O. K. J. Chem. Soc., Perkin Trans. 1 2001, 1204. (d) Cho,
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(b) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214.
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13, 697. (b) Cho, B. T.; Shin, S. H. Tetrahedron 2005, 61, 6959. (c) Cho, B. T.;
Kim, D. J. Tetrahedron: Asymmetry 2001, 12, 2043.
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Espinosa, S.; Ortiz, L. Tetrahedron: Asymmetry 2006, 17, 112. (b) Ortiz-
Marciales, M.; Stepanenko, V.; Correa, W.; De Jesu´s, M.; Espinosa, S. U.S.
Patent Application 11/512,599, August 30, 2006. (c) Stepanenko, V.; De Jesu´s,
M.; Correa, W.; Va´zquez, C.; Guzman, I.; Vazquez, C.; De la Cruz, W.; Ortiz-
Marciales, M.; Barnes, C. L. Tetrahedron Lett. 2007, 48, 5799. (d) Stepanenko,
V.; Ortiz-Marciales, M.; De Jesu´s, M.; Correa, W.; Va´zquez, C.; Ortiz, L.;
Guzma´n, I.; De la Cruz, W. Tetrahedron: Asymmetry 2007, 18, 2738.
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De Jesu´s, M.; Correa, W. J. Org. Chem. 2008, 73, 4017. (b) Huang, K.; Ortiz-
Marciales, M.; Stepanenko, V.; De Jesu´s, M.; Correa, W. J. Org. Chem. 2008,
73, 6928.
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Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880. (c) Tlahuext, H.; Santiesteban,
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24, 759. (e) Brown, J. M.; Guy, C.; Lloyd-Jones, G. C.; Layzell, T. P.
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Franchini, C.; Tortorella, V.; Conte Camerino, D. Mol. Pharmacol. 2000, 57,
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Luca, A.; Pierno, S.; Natuzzi, F.; Franchini, C.; Duranti, A.; Lentini, G.;
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4196 J. Org. Chem. Vol. 74, No. 11, 2009

Spiroborate-Mediated Asymmetric Synthesis of ꢀ-Hydroxy Ethers
TABLE 1. Optimization Studies for the Asymmetric Reduction of
other important ꢀ-amino ethers are neuronal nicotinic acetyl-
choline receptor (nAChRs) agonists, which are a group of
ligand-gated ion channels that hold significant promise as
therapeutic targets for the treatment of central nervous system
(CNS) and peripheral nervous system disorders.20 As shown in
Figure 2, the ꢀ-amino pyridyl ethers A-84534 (11),21 ABT-
594 (12),22 NIDA52189 (13),23 and related compounds have
been investigated as potential drug candidates. Recently, we
reported a new methodology for the synthesis of novel Mexi-
letine analogues by the reduction of benzylated oxime ethers
with excellent enantiopurity.18b As part of our ongoing pro-
grams, we are interested in developing alternative methodologies
for the synthesis of a variety primary ꢀ-amino pyridyl ethers
with possible neurobiological activity. Since ꢀ-hydroxy ethers
are easily converted into ꢀ-amino ethers employing the Mit-
sunobu reaction24 with only slight decrease in enantioselectiv-
ity,25 we were interested in the synthesis of Mexiletine and
nAChRs analogues from the previously prepared optically pure
ꢀ-hydroxy pyridyl ethers.
As outlined in Table 3, the optically pure alcohols 7 were
readily transformed into 14 by a stereospecific substitution
reaction of the hydroxyl group with phthalimide employing a
typical Mitsunobu procedure. After hydrazinolysis of phthal-
imido ethers 14, the desired bioactive ꢀ-amino ethers were
obtained with inversion of configuration at the stereogenic center
in moderate to good yields. Chiral HPLC analysis indicated high
enatiomeric purity of the ꢀ-amino ethers 14 (95-99% ee) (Table
3 entries 1-6), with only a slight racemization. Interestingly,
adamantyl and pyridyl ethers are also suitable substrates for
this transformation, demonstrating the efficiency and the
functional tolerance of this reaction toward phenoxy and pyridyl
groups.
ꢀ-Keto Ether 6aa
entry
borane
cat 1 (equiv) solvent yield (%)b ee (%)c
1
2
3
4
5
6
BH3 ·DMS
BH3 ·DMS
BH3 ·DMS
BH3 ·DMS
BH3 ·BACH
BH3 ·THF
0.01
0.05
0.1
0.1
0.1
THF
THF
THF
dioxane
THF
71
83
96
96
67
91
23
66
98
65
99
98
0.1
THF
a Unless otherwise stated, reactions were performed on a 2 mmol
scale: 1 equiv of ketone, 0.7 equiv of BH3 in THF at 25 °C for 1 h.
b Purified by flash column chromatography. c Determined by chiral
HPLC (Chiralcel OD-H column).
with K2CO3 (1.5 equiv) and 2,6-dimethylphenol (1.5 equiv) in
DMF at room temperature for 24 h.18 To establish the most
advantageous conditions, different catalytic loads (Table 1,
entries 1-3), dioxane as an alternative solvent and the use of
other borane sources (entries 4-6), were evaluated. Initially,
the reduction of ketone 6a with BH3 ·DMS in THF at 25 °C
using 1, 5, and 10% of catalyst 1 was investigated. A remarkable
increase in enantioselectivity and eficiency of the reaction was
achieved with 10% of catalyst, providing the alcohol 7a in 98%
ee and 96% isolated yield. Dioxane was found as an unsuitable
solventforthereaction,givingonly65%ee.AlthoughBH3 ·BACH-
EI (borane N-ethyl-N-isopropylaniline complex) and BH3 ·THF
provided 99 and 98% ee, respectively, BH3 ·DMS was more
attractive due to its low price and stability.
Having optimized the reaction conditions, the reduction of a
variety of ꢀ-keto aryl and pyridyl ethers with aliphatic and
aromatic substituents was accomplished. Table 2 illustrates the
optical rotation, yield, and enantiomeric excess for the prepared
enantiopure secondary alcohols. In general, the ꢀ-hydroxy ethers
were afforded in 92-99% ee and with excellent yield. Generally,
steric and electronic effects of the substituents attached to both
aromatic rings on the enantioselectivity of the reaction were
not observed. For example, ꢀ-aryl keto ethers bearing both
electron-withdrawing and electron-donating groups on the aryl
groups afford excellent enantioselectivities (entries 1-7). It is
important to note that the reduction of aliphatic ꢀ-keto ethers
containing cyclohexanyl and adamantyl groups provides the
desired alcohols in 93 and 99% ee, respectively, and in high
yield (entries 8 and 9). It should be pointed out that 1.7 equiv
of BH3 ·DMS is needed for the reduction of pyridyl ethers
because one borane molecule coordinates to the pyridine
nitrogen. Surprisingly, the ꢀ-keto 2-pyridyl ethers (entries 10,
11, and 13), which could bring forth a nonselective intramo-
lecular borane reduction, afford excellent enantioselectivities
in good to high yields. The 3-pyridyl ethers also offered high
enantiopurity and excellent yields (entries 12-14). The absolute
configuration of products was determined by comparison with
the optical rotations of corresponding known compounds.1a
Optically active ꢀ-amino aryl ethers display a key role in
the treatment of neuromuscular disorders (Figure 2).1 The
commercial Mexiletine, as a racemate 8, is used as an anti-
arrhythmic and analgesic oral drug,1a but due to side effects,
such as dizziness, heartburn, nausea, nervousness, trembling,
and unsteadiness, its use is limited. The optically active
Mexiletine analogue (R)-9 is more potent than the more active
(R)-Mexiletine isomer.1a,e The racemic potent ꢀ-blocker of
voltage-gated K+ channels 10 was recently discovered, using
structure-based virtual screening in combination with electro-
physiological assays in rat hippocampal neurons.19f In addition,
On the basis of similar structural features present in the
nAChRs agonist, we investigated the reduction of phthalimide
ethers 14 to obtain 2,3-dihydro-1H-isoindol derivatives
(Scheme 2). BH3 · DMS in THF (8 equiv) was employed for
the imide reduction. After the mixture was refluxed for 1.5 h,
the reaction was quenched with MeOH at 0 °C. As evidenced
by TLC analysis, the starting material was consumed and
only one compound was observed. Surprisingly, amide 16j,
formed by monoreduction of the phthalimide ether, was
identified by NMR analysis as the initial partial reduction
product. After the reaction time was extended to 8 h, the
target product 17j was obtained in 71% yield.
Under the previous optimized conditions, representative
substrates were reduced to 2,3-dihydro-1H-isoindol derivatives
(20) (a) Karlin, A. Nat. ReV. Neurosci. 2002, 3, 102. (b) Lloyd, G. K.;
Williams, M. J. Pharmacol. Exp. Ther. 2000, 29, 2–461. (c) Tonder, J. E.; Olesen,
P. H. Curr. Med. Chem. 2001, 8, 651. (d) Jensen, A. A.; Frolund, B.; Liljefors,
T.; Krogsgaard- Larsen, P. J. Med. Chem. 2005, 48, 4705.
(21) Tonder, J. E.; Olesen, P. H. Curr. Med. Chem. 2001, 8, 651.
(22) (a) Bannon, A. W.; Decker, M. W.; Holladay, M. W.; Curzon, P.;
Donnelly-Roberts, D.; Puttfarcken, P. S.; Bitner, R. S.; Diaz, A.; Dickenson,
A. H.; Porsolt, R. D.; Williams, M.; Arneric, S. P. Science 1998, 279, 77. (b)
Holladay, M. W.; Wasicak, J. T.; He, Y.; Ryther, K. B.; Bannon, A. W.; Buckley,
M. J.; Kim, D. B.; Decker, M. W.; Anderson, D. J.; Campbell, J. E.; Kuntzweiler,
T. A.; Donnelly-Roberts, D. L.; Piattoni-Kaplan, M.; Briggs, C. A.; Williams,
M.; Arneric, S. P. J. Med. Chem. 1998, 41, 407. (c) Abreo, M. A.; Lin, N.-H.;
Garvey, D. S.; Gunn, D. E.; Hettinger, A.-M.; Wasicak, J. T.; Pavlik, P. A.;
Martin, Y. C.; Donnelly-Roberts, D. L.; Anderson, D. J.; Sullivan, J. P.; Williams,
M.; Arneric, S. P.; Holladay, M. W. J. Med. Chem. 1996, 39, 817.
(23) Gao, Y.; Horti, A. G.; Kuwabara, H.; Ravert, H. T.; Hilton, J.; Holt,
D. P.; Kumar, A.; Alexander, M.; Enres, C. J.; Wong, D. F.; Dannals, R. F.
J. Med. Chem. 2007, 50, 3814.
(24) Mitsunobu, O. Synthesis 1981, 1.
(25) (a) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.;
Grabowski, E. J. J. J. Org. Chem. 1993, 58, 5886. (b) Chen, C.-P.; Prasad, K.;
Repic, O. Tetrahedron Lett. 1991, 32, 7175.
J. Org. Chem. Vol. 74, No. 11, 2009 4197

Huang et al.
TABLE 2. Asymmetric Reduction of ꢀ-Keto Aryl and Pyridyl Ethersa
a Unless otherwise stated, reactions were performed on a 2 mmol scale: 1 equiv of ketone, 0.7 equiv of BH3 ·DMS in THF at 25 °C for 1 h. b Optical
rotation in CHCl3. c Purified by flash chromatography column. d Determined by chiral HPLC analysis on a Chiralcel OD-H column. e Determined by
HPLC analysis of acetyl derivative on a Chiralcel OD-H column. f It used 1.7 equiv of BH3 ·DMS.
a rapid access to novel amides and amino acids with potential
biological applications.
Many biologically important compounds contain a hetero-
cyclic ring in their structure, and many piperidine derivatives
are also in clinical and preclinical studies.26 Our interest in the
synthesis of nicotinic analogues prompted us to investigate the
direct substitution of the hydroxyl group with secondary cyclic
amines, such as pyrrolidine, piperidine, or azepane. Considering
the efficiency and convenience of the Mitsunobu reaction, we
initially explored this procedure (Scheme 3). Unfortunately, no
FIGURE 2. Mexiletine and neuronal nicotinic acetylcholine receptors
agonist.
product was observed even by increasing the reaction temper-
ature and time, and only starting materials were observed by
TLC. Consequently, an alternative route was searched.
One of the most common methods for the preparation of
tertiary heterocyclic amine is the displacement of a sulfonated
17 using 8 equiv of BH3 ·DMS in anhydrous THF for 10 h. As
shown in Table 4, various chiral 2,3-dihydro-1H-isoindol
derivatives were provided in good to high yields. Moreover,
by control of the reaction time, selective reduction can provide
(26) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
4198 J. Org. Chem. Vol. 74, No. 11, 2009

Spiroborate-Mediated Asymmetric Synthesis of ꢀ-Hydroxy Ethers
TABLE 3. Asymmetric Synthesis of ꢀ-Amino Ethers from Optically Pure Alcohols
a Purified by flash chromatography column. b Determined by chiral HPLC (Chiralcel OD-H column). c Determined by HPLC analysis of acetyl
derivative on a chiral Chiralcel OD-H column.
SCHEME 2. Reduction of Representative Phthalimide 14j
product was 98% ee. As desired, the reaction took place
stereoselectively via an SN2 process as the optical purity of 19b
is even higher than the enantiopurity of the starting alcohol (S)-
7l (97% ee). Under similar condition, various secondary aliphatic
amines and substrates were examined. As shown in Table 5,
pyrrolidine, piperidine, and azepane derivatives are obtained in
good yields, providing a rapid access to new nicotinic acetyl-
choline receptor (nAChRs) analogues in high optical purity.
intermediate with the secondary aliphatic amines. To investigate
the possibility of this transformation with complete inversion
of configuration, optically active alcohol 7a (Table 5) was
chosen as a model. The mesylate (S)-18a was prepared by
conventional treatment of alcohol with mesyl chloride in the
presence of Et3N. Considering the instability of mesylate 18a
on the chromatographic columm, this intermediate was used
without further purification and was treated directly with
pyrrolidine in acetonitrile. To our delight, the desirable product
19a was obtained in 83% yield for the two steps. A baseline
separation of the racemic sample was not satisfactory for chiral
GC and HPLC analysis; however, a good baseline separation
was achieved for the chiral HPLC analysis of racemic compound
19b. As indicated in Table 5 (entry 3), the optical purity of this
Conclusions
Spiroborate ester 1 demonstrated to be an excellent catalyst
for the facile enantioselective borane reduction of representative
ꢀ-keto aryl and pyridylethers using 10% of catalytic load in
THF at room temperature. A wide range of aliphatic and
aromatic ꢀ-hydroxy ethers were afforded in optically pure form
in up to 99% ee and in high yield. Electronic factors or steric
effects in the aryl or pyridyl rings do not affect significantly
the enantioselectivity of the spiroborate ester-mediated reduction.
The nonracemic ꢀ-hydroxy ethers were successfully converted
to ꢀ-amino ethers with negligible epimerization by phthalimide
substitution under Mitsunobu’s conditions. By a facile imide
hydrazinolysis, representative primary aryl and alkyl amino
J. Org. Chem. Vol. 74, No. 11, 2009 4199

Huang et al.
TABLE 4. Synthesis of Novel nAChRs Analogues by Reduction of
Optically Active Lactame 14
TABLE 5. Synthesis of ꢀ-Novel Heterocyclic Ethers
a Purified by column chromatography on silica gel.
SCHEME 3. Attempted Substitution of the Hydroxyl Group
with Pyrrolidine by Mitsunobu’s Method
a CHCl3 as solvent. b Purified by flash chromatography column.
c Determined by chiral HPLC (Chiralcel AD-H column).
ethers were achieved in good yield. Complete phthalimide
reduction with borane provided the corresponding ꢀ-2,3-dihydro-
1H-isoindol derivatives in good yield. In addition, the partial
imide reduction can afford important ꢀ-amide ethers, which by
hydrolysis can be transformed to aromatic ortho-secondary
amino acids with a ꢀ-aryl and pyridyloxy moiety. In addition,
nonracemic novel Mexiletine and nAChR analogues with
potential biological activity were synthesized in enantiopure
form and excellent yields by mesylation of key ꢀ-hydroxy
pyridylethers and in situ substitution with pyrrolidine, piperidine,
and azepane to form, respectively, five-, six-, and seven-
membered ring heterocyclic amino ethers.
during 1 h by a syringe pump. The resulting mixture was stirred
for another 1 h. Then, the reaction mixture was cooled with an
ice-bath and quenched with MeOH (3 mL). The solvents were
removed under reduced pressure, and to the residue was added
1 N HCl (10 mL). The aqueous phase was extracted with ether
(3 × 30 mL), and the combined organic phases were washed
with brine and dried over Na2SO4. After solvent removal under
reduced pressure and purification by silica gel column chroma-
tography, the corresponding ꢀ-hydroxy ethers (7) were provided.
(S)-1-Adamantan-1-yl-2-phenoxyethanol (7i): White solid; mp
65-66 °C; yield 96% (262 mg); >99% ee; [R]20 ) +41 (c 1.5,
D
Experimental Section
1
CHCl3); H NMR (400 MHz, CDCl3) δ 1.7-1.83 (m, 12H), 2.08
(m, 3H), 2.38 (br s, 1H, OH), 3.58 (m, 1H), 3.98 (m, 1H), 4.19 (m,
1H), 6.97-7.04 (m, 3H), 7.32-7.37 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 28.4, 35.7, 37.2, 38.4, 68.6, 114.7, 121.1, 129.5, 158.7;
IR ν (cm-1) 3454, 2912, 2893, 2848, 1600, 1585, 1497, 1450, 1298,
1241, 1172, 1086, 1048, 1034, 1022, 986, 895, 880, 814, 749, 688;
ESI HRMS m/z calcd for C18H24NaO2 (M + Na)+ 295.1674, found
295.1666. Enantiomeric excess was determined by HPLC with a
General Procedure for the Reduction of ꢀ-Keto Ethers
(6a-6i). To a dried 50 mL reaction tube under N2 were added
catalyst 117a (65 mg, 0.2 mmol) and anhydrous THF (4 mL).
Then, BH3 · DMS (0.14 mL, 10.0 M) was added in one portion.
The resulting mixture was stirred at room temperature for 30
min until a transparent solution was observed. A solution of
ꢀ-keto ether18 (2 mmol) in THF (3 mL) was added dropwise
4200 J. Org. Chem. Vol. 74, No. 11, 2009

Spiroborate-Mediated Asymmetric Synthesis of ꢀ-Hydroxy Ethers
Chiralpak OD-H column (95:5 hexane/2-propanol), 0.5 mL/min,
254 nm, minor enantiomer tR ) 16.65 min, major enantiomer tR )
26.69 min.
69.5, 114.7, 120.8, 129.5, 159.0; IR ν (cm-1) 3371, 3308, 2901,
2893, 2849, 1727, 1599, 1587, 1498, 1467, 1449, 1301, 1285, 1243,
1179, 1077, 1038, 1031, 1018, 990, 960, 900, 879, 815, 755, 691;
ESI HRMS m/z calcd for C18H26NO (M + H)+ 272.2009, found
272.2015. Enantiomeric excess was determined by HPLC for acetyl
derivative with a Chiralpak OD-H column (96:4 hexane/2-propanol),
0.4 mL /min, 254 nm, major enantiomer tR ) 43.11 min, minor
enantiomer tR ) 47.73 min.
General Procedure for the Reduction of ꢀ-Keto Pyridyl
Ethers (6j-6m). To a dried 50 mL reaction tube under N2 were
added catalyst 1 (65 mg, 0.2 mmol) and anhydrous THF (4 mL).
Then, BH3 · DMS (0.34 mL, 10.0 M) was added in one portion.
The resulting mixture was stirred at room temperature for 30
min until a transparent solution was observed. A solution of
ꢀ-keto pyridyl ethers (2 mmol) in THF (4 mL) was added
dropwise during 1 h by a syringe pump. The resulting mixture
was stirred overnight. Then, the reaction mixture was cooled
with an ice-bath and quenched with MeOH (5 mL). After the
mixture was refluxed for 3 h, the solvents were removed under
reduced pressure and the residue was purified by silica gel
column chromatography.
(R)-2-(6-Methylpyridin-3-yloxy)-1-phenylethylamine (15l): Col-
orless oil; yield 66% (136 mg); 97% ee; [R]20 ) -37 (c 1.3,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 1.98 (br s, 2H), 2.52 (s,
3H), 3.98 (m, 1H), 4.13 (m, 1H), 4.47 (m, 1H), 7.07-7.15 (m,
2H), 7.33-7.50 (m, 5H), 8.23 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 23.4, 55.2, 74.5, 122.1, 123.3, 126.9, 127.9, 128.7, 136.9,
141.6, 150.8, 152.9; IR ν (cm-1) 3368, 3291, 3060, 3026, 2923,
2866, 1599, 1572, 1484, 1454, 1387, 1287, 1265, 1240, 1212, 1122,
1023, 825, 759, 702; ESI HRMS m/z calcd for C14H17N2O (M +
H)+ 229.1341, found 229.1351. Enantiomeric excess was deter-
mined by HPLC for acetyl derivative with a Chiralcel OD-H column
(9:1 hexane/2-propanol), 0.5 mL /min, 254 nm, major enantiomer
tR ) 46.32 min, minor enantiomer tR ) 55.8 min.
General Procedure for the Synthesis of Compounds 16 and
17 via Borane Reduction. To a stirred solution of 14 (1 mmol) in
anhydrous THF under nitrogen was added BH3 ·DMS (0.8 mL, 10
M, 8 mmol). Compound 16 was produced after the mixture was
refluxed for 1.5 h. Compound 17 was formed by complete reduction
when the mixture was refluxed overnight. In both cases, the reaction
mixtures were slowly quenched with 5 mL of MeOH at 0 °C. The
corresponding products were isolated after the solvents were
evaporated under reduced pressure, and the residue was purified
by silica gel column chromatography.
(R)-2-(1-Adamantan-1-yl-2-phenoxyethyl)-2,3-dihydroisoin-
dol-1-one (16i): White solid; mp 148-150 °C; yield 81% (313
mg); 1H NMR (400 MHz, CDCl3) δ 1.70-1.82 (m, 9H), 1.88 (m,
3H), 2.09 (m, 3H), 4.37 (m, 2H), 4.58 (m, 3H), 6.89-7.0 (m, 3H),
7.29 (m, 2H), 7.45-7.60 (m, 3H), 7.95 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 28.5, 36.9, 40.3, 64.5, 114.8, 121.1, 122.5, 123.9,
127.9, 129.5, 131.2, 141.6, 158.6; IR ν (cm-1) 3039, 2918, 2899,
2875, 2850, 1731, 1676, 1597, 1498, 1483, 1448, 1401, 1303, 1288,
1246, 1218, 1175, 1164, 1018, 989, 947, 896, 879, 834, 815,796,
753, 735, 688; ESI HRMS m/z calcd for C26H30NO2 (M + H)+
388.2277, found 388.2299.
(R)-2-(1-Adamantan-1-yl-2-phenoxyethyl)-2,3-dihydro-1H-
isoindole (17i): Colorless oil; yield 65% (121 mg); 1H NMR (400
MHz, CDCl3) δ 1.72-1.77 (m, 9H), 1.88 (m, 3H), 2.06 (m, 3H),
2.89 (m, 1H), 4.36 (m, 6H), 6.89-6.99 (m, 3H), 7.21 (m, 4H),
7.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 28.7, 37.3, 38.2,
40.2, 57.7, 64.9, 67.7, 114.6, 120.6, 122.1, 126.2, 129.4, 140.6,
158.8; IR ν (cm-1) 2961, 2899, 2846, 1693, 1598, 1587, 1495, 1468,
1448, 1360, 1344, 1300, 1258, 1240, 1170, 1152, 1135, 1077, 1031,
1017, 858, 796, 739, 689; ESI HRMS m/z calcd for C26H32NO (M
+ H)+ 374.2484, found 374.2491.
(S)-2-(6-Chloropyridin-2-yloxy)-1-phenylethanol (7j): White
solid; mp 85-86 °C; yield 88% (659 mg); 99% ee; [R]20D ) +48
1
(c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 3.12 (br s, 1H),
4.41 (m, 1H), 4.60 (m, 1H), 5.19 (m, 1H), 6.78 (m, 1H), 6.98 (m,
1H), 7.35 (m, 1H), 7.44 (m, 2H), 7.53 (m, 2H), 7.62 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 72.2, 72.9, 109.4, 116.9, 126.3, 128.1,
128.6, 140, 141, 148.3, 163.2; IR ν (cm-1) 3368, 2988, 2941, 1588,
1559, 1493, 1433, 1407, 1296, 1261, 1159, 1082, 1056, 1021, 1006,
983, 921, 899, 788, 756, 701; ESI HRMS m/z calcd for
C13H12ClNNaO2 (M + Na)+ 272.0454, found 272.0454. Enantio-
meric excess was determined by HPLC with a Chiralpak OD-H
column (9:1 hexane/2-propanol), 0.5 mL/min, 254 nm, major
enantiomer tR ) 16.72 min, minor enantiomer tR ) 20.54 min.
General Procedure for the Synthesis of Compounds 14 via
a Mitsunobo Reaction. To a mixture of the optically pure alcohol
(2 mmol), phthalimide (441 mg, 3 mmol), and triphenylphosphine
(786 mg, 3 mmol) in 20 mL of anhydrous THF under N2 at room
temperature was added dropwise a solution of DIAD (603 mg, 3
mmol) in anhydrous THF (10 mL). The resulting mixture was stirred
until TLC indicated that the alcohol was consumed. The solvent
was removed under reduced pressure, and the residue was purified
by silica gel column chromatography, affording the corresponding
imide.
(R)-2-(1-Adamantan-1-yl-2-phenoxyethyl)isoindole-1,3-di-
one (14i): Colorless oil; yield 86% (345 mg); reaction time 72 h;
1H NMR (400 MHz, CDCl3) δ 1.7-1.77 (m, 9H), 1.82-1.88 (m,
3H), 2.06 (m, 3H), 4.43 (m, 2H), 5.02 (m, 1H), 6.88 (m, 2H), 6.96
(m, 1H), 7.26 (m, 2H), 7.77 (m, 2H), 7.84 (m, 1H), 7.92 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 28.3, 28.4, 36.8, 37.1, 37.2, 38.4,
40.1, 60.8, 63.0, 115, 121, 123.1, 123.4, 129.4, 131.6, 133.8, 134.0,
158.6, 169.5; IR ν (cm-1) 3512, 3039, 2900, 2847, 1773, 1710,
1599, 1587, 1496, 1450, 1392, 1345, 1241, 1171, 1076, 1032, 1013,
986, 874, 751, 736, 716, 690; ESI HRMS m/z calcd for C26H28NO3
(M + H)+ 402.2069, found 402.2079.
General Procedure for the Synthesis of ꢀ-Amino Ether 15
via Hydrazinolysis. To a stirred solution of 14 (1 mmol) in 5
mL of EtOH was added 50-60% N2H4 (256 mg, 8 mmol). The
resulting mixture was refluxed for 3 h. The precipitated solid
was filtered off, and the solvent was removed under reduced
pressure. The residue, dissolved in ether, was extracted with 2
N HCl, and the aqueous phase was treated with 2 N NaOH until
pH >12. The aqueous phase was extracted with ether (3 × 20
mL), and the combined organic phases were dried over Na2SO4
and evaporated under reduced pressure to give the target product.
For the amine of 15i, 15j, and 15l, because of their water
solubility, the desired products were obtained, directly, by silica
gel column chromatography.
General Procedure for the Synthesis of 18. To a two-neck
round-bottom flask under nitrogen was added a solution of the
nonracemic alcohol (2 mmol) in anhydrous CH2Cl2 (20 mL) and
Et3N (1.7 mL, 10 mmol). The mixture was cooled to 0 °C, and
MsCl (0.46 mL, 6 mmol) was added dropwise for 0.5 h by a syringe
pump. The resulting solution was stirred until TLC indicated that
the starting material was consumed (about 30 min). Water (20 mL)
was added to quench the reaction, and the aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic phases
were washed with brine, dried over MgSO4, and concentrated under
reduced pressure at 25 °C, affording the crude product.
(R)-1-Adamantan-1-yl-2-phenoxyethylamine (15i): White solid;
General Procedure for the Synthesis of 19. To the crude
sulfonate intermediate 18 (2 mmol) in 10 mL of CH3CN at room
temperature was added the corresponding heterocyclic amine (5
equiv). The resulting mixture was stirred overnight. The solvent
was evaporated under reduced pressure, and the residue was purified
by silica gel column chromatography.
mp 61-62 °C; yield 86% (465 mg); >99% ee; [R]20 ) -29 (c
D
1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.48 (br s, 2H),
1.72-1.81 (m, 12H), 2.07 (m, 3H), 2.78 (m, 1H), 3.82 (m, 1H),
4.22 (m, 1H), 4.50 (m, 1H), 6.96-7.01 (m, 2H), 7.31-7.35 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 28.5, 35.3, 37.3, 38.9, 59.5,
J. Org. Chem. Vol. 74, No. 11, 2009 4201

Huang et al.
(R)-2-Methyl-5-(2-phenyl-2-piperidin-1-ylethoxy)pyridine (19b):
Acknowledgment. We thank NIH for the financial support
through their MBRS (GM 08216), INBRE (NC P20 RR-
016470), and NSF-ADVANCE (SBE-0123645). Support for
undergraduate scholars from the NIH-INBRE, NIH-RISE, NIH-
MARC, and NSF-AMP programs is also gratefully acknowledged.
Colorless oil; yield 87% (259 mg); 98% ee; [R]20 ) -13 (c 1.3,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 1.45 (m, 2H), 1.62 (m,
4H), 2.52 (m, 7H), 3.80 (m, 1H), 4.32 (m, 1H), 4.42 (m, 1H),
7.05-7.13 (m, 2H), 7.33-7.40 (m, 5H), 8.2 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 23.4, 24.5, 26.3, 52.2, 69.2, 70.4, 122.4, 123.3,
127.5, 128.3, 128.5, 137.2, 150.5, 152.9; IR ν (cm-1) 3374, 3059,
3028, 2931, 2853, 2799, 2755, 1600, 1572, 1485, 1471, 1452, 1387,
1266, 1239, 1212, 1175, 1118, 1027, 992, 912, 827, 758, 723, 699;
ESI HRMS m/z calcd for C19H25N2O (M + H)+ 297.1967, found
297.1968. Enantiomeric excess was determined by HPLC with a
Chiralcel AD-H column (95:5 hexane/2-propanol), 0.5 mL/min, 254
nm, major enantiomer tR ) 17.65 min, minor enantiomer tR ) 19.62
min.
Supporting Information Available: Experimental data and
full characterization of new and known compounds, and spectral
and chromatographic data of starting materials and enantiopure
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO900666R
4202 J. Org. Chem. Vol. 74, No. 11, 2009