Stereoselective synthesis of β-hydroxy enamines, aminocyclopropanes, and 1,3-amino alcohols via asymmetric catalysis

Article abstract of DOI:10.1021/ja105435y

Tandem methods for the catalytic asymmetric preparation of enantioenriched β-hydroxy (E)-enamines and aminocyclopropanes are presented. The diastereoselective hydrogenation of enantioenriched (E)-trisubstituted hydroxy enamines to generate 1,2-disubstituted-1,3-amino alcohols is also outlined. These methods are initiated by highly regioselective hydroboration of N-tosyl-substituted ynamides with diethylborane to generate β-amino alkenyl boranes. In situ boron-to-zinc transmetalation generates β-amino alkenylzinc reagents. These functionalized vinylzinc intermediates are subsequently added to aldehydes in the presence of a catalyst derived from an enantioenriched amino alcohol (morpholino isoborneol, MIB). The catalyst promotes highly enantioselective C-C bond formation to provide β-hydroxy enamines in good isolated yields (68-86%) with 54-98% enantioselectivity. The intermediate zinc β-alkoxy enamines can be subjected to a tandem cyclopropanation to afford aminocyclopropyl carbinols with three continuous stereocenters in a one-pot procedure with good yields (72-82%), enantioselectivities of 76-94%, and >20:1 diastereomeric ratios. Diastereoselective hydrogenation of isolated enantioenriched β-hydroxy enamines over Pd/C furnished syn-1,2-disubstituted-1,3-amino alcohols in high yields (82-90%) with moderate to excellent diastereoselectivities. These methods were used in an efficient preparation of the enantioenriched precursor to PRC200-SS derivatives, which are potent serotonin-norepinephrine-dopamine reuptake inhibitors.

Full text of DOI:10.1021/ja105435y

Published on Web 09/20/2010
Stereoselective Synthesis of ꢀ-Hydroxy Enamines,
Aminocyclopropanes, and 1,3-Amino Alcohols via
Asymmetric Catalysis
Petr Valenta, Patrick J. Carroll, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received June 21, 2010; E-mail: pwalsh@sas.upenn.edu
Abstract: Tandem methods for the catalytic asymmetric preparation of enantioenriched ꢀ-hydroxy (E)-
enamines and aminocyclopropanes are presented. The diastereoselective hydrogenation of enantioenriched
(E)-trisubstituted hydroxy enamines to generate 1,2-disubstituted-1,3-amino alcohols is also outlined. These
methods are initiated by highly regioselective hydroboration of N-tosyl-substituted ynamides with dieth-
ylborane to generate ꢀ-amino alkenyl boranes. In situ boron-to-zinc transmetalation generates ꢀ-amino
alkenylzinc reagents. These functionalized vinylzinc intermediates are subsequently added to aldehydes
in the presence of a catalyst derived from an enantioenriched amino alcohol (morpholino isoborneol, MIB).
The catalyst promotes highly enantioselective C-C bond formation to provide ꢀ-hydroxy enamines in good
isolated yields (68-86%) with 54-98% enantioselectivity. The intermediate zinc ꢀ-alkoxy enamines can
be subjected to a tandem cyclopropanation to afford aminocyclopropyl carbinols with three continuous
stereocenters in a one-pot procedure with good yields (72-82%), enantioselectivities of 76-94%, and
>20:1 diastereomeric ratios. Diastereoselective hydrogenation of isolated enantioenriched ꢀ-hydroxy
enamines over Pd/C furnished syn-1,2-disubstituted-1,3-amino alcohols in high yields (82-90%) with
moderate to excellent diastereoselectivities. These methods were used in an efficient preparation of the
enantioenriched precursor to PRC200-SS derivatives, which are potent serotonin-norepinephrine-dopamine
reuptake inhibitors.
Scheme 1. Urabe’s Addition of Ynamide-Titanium Complexes to
Aldehydes To Form ꢀ-Hydroxy Enamines
1. Introduction
ꢀ-Hydroxy enamines are present in several natural and
unnatural products1-5 and are valuable synthetic intermediates.6-8
The absence of efficient catalytic enantioselective methods for
their preparation, however, impedes their wider utilization in
synthesis and drug discovery. Methods for the synthesis of
racemic ꢀ-hydroxy enamines have been introduced. Meyer
recently developed a five-step synthesis of ꢀ-hydroxy enamines
from ynamides.7,8 Derivatization followed by Wittig rearrange-
ment afforded amino alcohols, highlighting the utility of
ꢀ-hydroxy enamines. The only one-step method for the synthesis
of ꢀ-hydroxy enamines is Urabe’s reaction of ynamide-titanium
complexes with aldehydes (Scheme 1).6,9,10 Yields as high as
94% were achieved with moderate to excellent diastereoselec-
tivities (2:1 to <20:1) and good substrate scope. However, the
method requires the use of enantioenriched sulfonamide-based
auxiliaries that were synthesized in four steps, one of which
employed another chiral auxiliary.11
Given the challenges associated with the development of a
catalytic enantioselective version of this reaction, we considered
an alternative strategy for the stereoselective synthesis of
ꢀ-hydroxy enamines. Ynamides12,13 were chosen as precursors
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10.1021/ja105435y  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 14179–14190 14179

A R T I C L E S
Valenta et al.
Scheme 2. One-Pot Generation of (E)-Trisubstituted ꢀ-Hydroxy
Enamines
Scheme 3. Application of ꢀ-Hydroxy Enamine Derivatives in the
Synthesis of (A) Aminocyclopropyl Carbinols and (B) 1,3-Amino
Alcohols
because they can be easily prepared in one step from terminal
alkynes, amine derivatives, and copper catalysts in the presence
of oxygen following the method of Stahl and co-workers.14 As
outlined in Scheme 2, we envisioned hydroboration of ynamides
to generate ꢀ-amino vinyl boranes, boron-to-zinc transmetalation
of the resulting vinyl group, and catalytic enantioselective
carbonyl addition of the ꢀ-amino vinyl group to aldehydes to
afford zinc alkoxides. Simple protonation of these intermediates
was expected to provide ꢀ-hydroxy enamines as single double-
bond isomers with high ee (Scheme 2). As the catalyst for the
asymmetric addition of ꢀ-amino vinylzinc reagents to aldehydes,
we anticipated using enantioenriched amino alcohol derivatives,
which we15-19 and others20-29 have successfully employed in
the asymmetric addition of vinylzinc reagents to aldehydes.
In addition to their intrinsic value, ꢀ-hydroxy enamines are
also potentially important synthetic intermediates for further
elaboration via alkoxide- and hydroxyl-directed diastereoselec-
tive reactions.30 Alkoxide-directed cyclopropanation of ꢀ-alkox-
ide enamines could provide access to aminocyclopropyl alcohols
(Scheme 3A). Enantioenriched aminocyclopropanes are phar-
macophores that are present in many natural products and
synthetic materials.31-33 As a result, their synthesis has attracted
significant attention.34-54 ꢀ-Hydroxy enamines are anticipated
to be useful precursors in the synthesis of enantioenriched 1,2-
disubstituted-1,3-amino alcohols (Scheme 3B), a class of
compounds that has garnered much interest because of their
biological activity.55-58
Herein we disclose the first one-pot catalytic asymmetric
synthesis of ꢀ-hydroxy enamines starting from readily available
ynamides. Through the approach outlined in Scheme 2, ꢀ-hy-
droxy enamines can be accessed in good to high yields with
good to excellent enantioselectivity as single double-bond
isomers. The intermediate ꢀ-alkoxide enamines can be subjected
to a tandem diastereoselective cyclopropanation to afford
aminocyclopropyl carbinols with high enantio- and diastereo-
selectivity. We have also developed an efficient diastereose-
lective hydrogenation of ꢀ-hydroxy enamines that leads to 1,2-
disubstituted-1,3-amino alcohols with high enantio- and
diastereoselectivities. This method has been applied to the
synthesis of PRC200-SS and its derivatives, which are potent
serotonin-norepinephrine-dopamine reuptake inhibitors.
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Stereoselective Synthesis of ꢀ-Hydroxy Enamines
A R T I C L E S
2. Experimental Section
134.50, 136.20, 136.32, 156.2. IR (neat): 3537 (OH), 2961, 2870,
1723, 1643, 1598, 1494, 1455, 1343, 1162, 1092, 1026, 814 cm-1
;
Representative procedures and characterization of the products
are described herein. Full experimental details and characterization
of all compounds are provided in the Supporting Information.
General Methods. Reactions involving dialkylzinc reagents were
performed under nitrogen using standard Schlenk or vacuum-line
techniques in oven-dried glassware. Hydrogenations were carried
out in magnetically stirred glass test tubes placed in a Parr high-
pressure hydrogenator. Chemicals were purchased from Aldrich or
Acros unless otherwise specified, and solvents were purchased from
Fisher Scientific. Toluene and hexanes were dried through alumina
columns. Aldehydes were distilled prior to use and stored under
nitrogen. Solutions of dimethylzinc and diethylzinc (2 M in toluene)
were prepared and stored in a Vacuum Atmospheres drybox.
Ynamides were synthesized according to Stahl’s procedure.14
N-Benzyl-N-ethynyl-4-methylbenzenesulfonamide was synthesized
using the method of Bruckner.59 Silica gel (230-400 mesh,
Silicycle) was used for air-flashed chromatography. Deactivated
silica gel was prepared by addition of 17 mL of Et3N to 1 L of
silica gel. The progress of reactions was monitored by thin-layer
chromatography (TLC) on Whatman precoated silica gel F-254
plates and visualized by UV light or ceric ammonium molybdate
stain. 1H NMR and 13C{1H} NMR spectra were obtained on Bruker
300, 360, 400, and 500 MHz Fourier transform spectrometers at
the University of Pennsylvania NMR facility. Chemical shifts are
reported in units of parts per million downfield from tetramethyl-
silane, and coupling constants are reported in hertz. IR spectra were
obtained using a PerkinElmer 1600 series spectrometer. High-
resolution mass spectrometry (HRMS) data were obtained on a
Waters liquid chromatography-time-of-flight (LC-TOF) mass
spectrometer (model LCT-XE Premier) using electrospray ionization
(ESI) in positive or negative mode, depending on the analyte.
Melting points were determined on a Unimelt Thomas-Hoover
melting point apparatus and are uncorrected.
HRMS-CI: m/z 458.1766 [(M + Na)+; calcd for C26H29NO3SNa,
458.1766].
General Procedure B. Asymmetric Aminovinylation of Al-
dehydes/Diastereoselective Cyclopropanation: N-Benzyl-N-
((1R,2R)-2-((R)-1-hydroxy-2-methylpropyl)cyclopropyl)-4-me-
thylbenzenesulfonamide (2a). A 10 mL Schlenk flask was charged
with a solution of N-benzyl-N-ethynyl-4-methylbenzenesulfonamide
(1.0 mL, 0.25 M in toluene, 0.25 mmol), and a solution of
diethylborane (0.25 mL, 1.0 M in toluene, 0.25 mmol) was added
dropwise at room temperature. The resulting solution was stirred
at room temperature for 20 min. The reaction flask was then cooled
to -78 °C, and Et2Zn (0.25 mL, 2.0 M in toluene, 0.5 mmol) was
added, after which the reaction mixture was stirred for 20 min.
(-)-MIB (3.0 mg, 0.012 mmol, 5 mol %) was added, and then
isobutyraldehyde (24 µL, 0.3 mmol) was added dropwise at -78
°C. The reaction flask was placed in a -30 °C isopropyl alcohol/
dry ice cold bath and allowed to warm to 0 °C over 12 h. The
solution was stirred at 0 °C until vinyl addition was complete, as
determined by TLC (typically 12 h). The volatile materials,
including the Et3B byproduct, were removed in vacuo at 0 °C. After
addition of hexanes (2 mL), the volatile materials were again
removed under reduced pressure. This step was repeated two more
times to ensure the complete removal of Et3B. A solution of Et2Zn
(0.63 mL, 2.0 M in toluene, 1.25 mmol) and neat CF3CH2OH (91
µL, 1.25 mmol) was added slowly at 0 °C, and the Schlenk flask
was wrapped in aluminum foil to exclude light. The resulting
mixture was stirred at 0 °C for 5 min, and then diiodomethane (101
µL, 1.25 mmol) was added. The stirring was continued at 0 °C for
40 h, after which the reaction mixture was quenched with brine (2
mL). The organic and aqueous layers were separated, and the
aqueous layer was extracted with 3 × 20 mL of diethyl ether. The
combined organic layers were then washed with 50 mL of water
and dried over MgSO4. The filtrate was concentrated under reduced
pressure, and the residue was chromatographed on deactivated silica
gel (10% ethyl acetate in hexanes) to afford 59 mg (80% yield) of
Caution! Dialkylzinc reagents are pyrophoric. Care and proper
laboratory attire must be used when handling them.
General Procedure A. Asymmetric Aminovinylation of Al-
dehydes with ꢀ-Amino Vinylzinc Reagents: (R)-(E)-N-Benzyl-
N-(3-hydroxy-4-methyl-2-phenylpent-1-enyl)-4-methylbenzene-
sulfonamide (1a). A 10 mL Schlenk flask was charged with a
solution of N-benzyl-N-(p-toluenesulfonyl)-2-phenylethynylamine
(1.0 mL, 0.25 M in toluene, 0.25 mmol), and a solution of
diethylborane (0.25 mL, 1.0 M in toluene, 0.25 mmol) was added
dropwise at room temperature. The resulting solution was stirred
at room temperature for 20 min. The reaction flask was then cooled
to -78 °C, and Et2Zn (0.25 mL, 2.0 M in toluene, 0.5 mmol) was
added, after which the reaction mixture was stirred for 20 min.
(-)-MIB (3.0 mg, 0.012 mmol, 5 mol %) was added, and then
isobutyraldehyde (24 µL, 0.3 mmol) was added dropwise at -78
°C. The reaction flask was placed in a -30 °C cold bath and allowed
to warm to 0 °C over several hours. The solution was stirred at 0
°C until vinyl addition was complete, as determined by TLC
(typically 12 h). The reaction was then quenched by addition of
brine (2 mL). The organic and aqueous layers were separated, and
the aqueous layer was extracted with 3 × 20 mL of diethyl ether.
The combined organic layers were then washed with 50 mL of
water and dried over MgSO4. The filtrate was concentrated in vacuo,
and the residue was chromatographed on deactivated silica gel (10%
ethyl acetate in hexanes) to afford 107 mg (82% yield) of 1a as an
amorphous solid. [R]D20: -19.5 (c ) 1.0, CHCl3). 1H NMR (CDCl3,
360 MHz): δ 0.82 (d, 3H, J ) 7.0 Hz), 1.01 (d, 3H, J ) 7.0 Hz),
1.57 (sept., 1H, J ) 7.0 Hz), 2.07 (s, 3H), 3.84 (d, 1H, J ) 6.4
Hz), 4.27 (dd, 2H, J ) 21.3, 15.0 Hz), 6.54 (s, 1H), 6.94-7.02
(m, 4H), 7.09-7.19 (m, 7H), 7.29 (s, 1H), 7.84-7.90 (m, 2H).
13C{1H} NMR (CDCl3, 75 MHz): δ 27.65, 28.66, 35.45, 44.95,
77.47, 127.52, 127.66, 127.89, 128.81, 129.09, 129.62, 129.91,
1
2a as a yellow oil. [R]D20: -28.1 (c ) 0.5, CHCl3). H NMR
(CDCl3, 360 MHz): δ 0.68 (dd, 1H, J ) 14.32, 6.95 Hz), 0.74 (d,
3H, J ) 6.7 Hz), 0.77 (d, 3H, J ) 6.7 Hz), 1.00 (d, 1H, J ) 5.2
Hz), 1.09 (m, 1H), 1.52 (m, 1H), 2.00 (m, 1H), 2.42 (s, 3H), 3.16
(q, 1H, J ) 4.6 Hz), 4.18 (d, 1H, J ) 14.6 Hz), 4.38 (d, 1H, J )
14.6 Hz), 7.20-7.38 (m, 7H), 7.67-7.76 (m, 2H). 13C{1H} NMR
(CDCl3, 75 MHz): δ 9.90, 17.22, 18.94, 21.77, 23.69, 34.11, 34.44,
54.96, 74.52, 127.78, 127.86, 128.61, 128.65, 129.84, 135.68,
137.40, 143.67. IR (neat): 3538 (OH), 2960, 2873, 1598, 1495,
1455, 1341, 1163, 1093, 927, 815 cm-1. HRMS-CI: m/z 396.1604
[(M + Na)+; calcd for C21H27NO3SNa, 396.1609].
General Procedure C. Diastereoselective Hydrogenation of
ꢀ-Hydroxy Enamines with Aliphatic Substituents at the 3-Posi-
tion: N-Benzyl-N-(3-hydroxy-4-methyl-2-phenylpentyl)-4-me-
thylbenzenesulfonamide (3a). In a 10 × 75 mm glass test tube,
(E)-N-benzyl-N-(3-hydroxy-4-methyl-2-phenylpent-1-enyl)-4-me-
thylbenzenesulfonamide (44 mg, 0.1 mmol) was dissolved in
methanol (4 mL) at room temperature. The space above the solution
was purged with nitrogen to remove most of the air, and 10% Pd/C
(8 mg, 7 mol %) was added. The test tube was placed in a Parr
hydrogenator, and good stirring was confirmed before the apparatus
was closed. After the system was flushed three times with hydrogen,
it was pressured with hydrogen (9.65 MPa, 1400 psi), and the
reaction was stirred for 12 h at room temperature. After the
apparatus was opened, the Pd catalyst was removed via filtration
through a plug of Celite. The filtrate was concentrated under reduced
pressure, and the residue was chromatographed on silica gel (10%
ethyl acetate in hexanes) to afford 39 mg (90% yield) of 3a as an
amorphous solid. 1H NMR (CDCl3, 360 MHz): δ 0.36 (d, 3H, J )
6.6 Hz), 0.86 (d, 3H, J ) 6.6 Hz), 1.16 (sept., 1H, J ) 7.2 Hz),
2.41 (s, 3H), 2.73 (dd, 1H, J ) 14.3, 4.4 Hz), 3.08 (d, 1H, J ) 5.4
Hz), 3.48 (m, 1H), 3.74 (d, 1H, J ) 14.0 Hz), 3.96 (dd, 1H, J )
(59) Bruckner, D. Tetrahedron 2006, 62, 3809.
9
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A R T I C L E S
Valenta et al.
Scheme 4. Oppolzer’s Alkenylation of Aldehydes
Table 1. Examination of Various Electron-Withdrawing Groups on
the Ynamide
14.8, 11.7 Hz), 4.73 (d, 1H, J ) 14.0 Hz), 7.06-7.13 (m, 2H),
7.14-7.22 (m, 3H), 7.28-7.44 (m, 7H), 7.68-7.76 (m, 2H).
13C{1H} NMR (CDCl3, 75 MHz): δ 18.86, 20.21, 21.75, 31.15,
46.69, 53.51, 55.23, 75.25, 126.97, 127.43, 128.39, 128.48, 129.05,
129.24, 129.66, 130.11, 136.70, 139.05, 139.21, 143.80. IR (neat):
3532 (OH), 2924, 1599, 1494, 1330, 1156, 1094, 925, 814 cm-1
;
HRMS-CI: m/z 438.2111 [(M + H)+; calcd for C26H32NO3S,
438.2103].
General Procedure D. Diastereoselective Hydrogenation of
ꢀ-Hydroxy Enamines with Aromatic Substituents at the 3-Posi-
tion: N-Benzyl-N-(3-hydroxy-2,3-diphenylpropyl)-4-methylben-
zenesulfonamide (3d). In a 10 × 75 mm glass test tube,
(E)-N-benzyl-N-(3-hydroxy-2,3-diphenylprop-1-enyl)-4-methylben-
zenesulfonamide (47 mg, 0.1 mmol) was dissolved in ethyl acetate
(3 mL) at room temperature, and 10% Pd/C (8 mg, 7 mol %) was
added. The test tube was placed in a Parr hydrogenator at room
temperature, and good stirring was confirmed before the apparatus
was closed. After the system was flushed three times with hydrogen,
it was pressured with hydrogen (9.65 MPa, 1400 psi), and the
reaction was stirred for 12 h at room temperature. After the
apparatus was opened, the Pd catalyst was removed via filtration
through a plug of Celite. The filtrate was concentrated in vacuo,
and the residue was chromatographed on silica gel (10% ethyl
acetate in hexanes) to afford 43 mg (92% yield) of 3d as an
amorphous solid. 1H NMR (CDCl3, 360 MHz): δ 2.42 (s, 3H), 2.65
(m, 1H), 2.79 (d, 1H, J ) 4.3 Hz), 2.99 (dd, 1H, J ) 14.3, 6.1
Hz), 3.88 (d, 1H, J ) 14.5 Hz), 4.55 (d, 1H, J ) 14.5 Hz), 4.96 (t,
1H, J ) 4.3 Hz), 6.59-6.70 (m, 4H), 6.82-6.89 (m, 2H),
7.04-7.13 (m, 3H), 7.25-7.36 (m, 8H), 7.61-7.66 (m, 2H).
13C{1H} NMR (CDCl3, 75 MHz): δ 21.78, 52.15, 54.66, 55.36,
72.28, 127.09, 127.32, 127.53, 128.16, 128.33, 129.03, 129.10,
129.62, 130.05, 134.51, 136.12, 136.79, 138.21, 143.83, 158.61.
IR (neat): 3519 (OH), 2919, 1611, 1513, 1454, 1331, 1246, 1156,
1103, 1034, 928 cm-1. HRMS-CI: m/z 494.1760 [(M + Na)+; calcd
for C29H29NO3SNa, 494.1766].
allylic alcohols, and we have applied it to the synthesis of R-
and ꢀ-amino acid derivatives,61,62 epoxy alcohols,16,17,63 and
cyclopropyl and vinylcyclopropyl alcohols.19,64,65 This method
works well with terminal and internal alkynes, and we have
shown that ethoxy ethynyl ether can also be employed.18,66 It
was not clear at the outset whether the uncatalyzed hydrobo-
ration of internal ynamides would proceed with high regiose-
lectivity; only hydroboration of terminal ynamides had previ-
ously been reported to proceed with good regioselectivity.67,68
Our synthesis of ꢀ-hydroxy enamines involves the application
of Oppolzer’s procedure to ynamides, which are readily available
using Stahl’s copper-catalyzed oxidative coupling of alkynes
with amines.14 The phenyl-substituted ynamides shown in Table
1 were synthesized using amines with an electron-withdrawing
group (EWG) on the nitrogen. The presence of the EWG is
important for the synthesis and stabilization of the ynamides
and the resulting ꢀ-hydroxy enamines.
3. Results and Discussion
3.1. Asymmetric Synthesis of ꢀ-Hydroxy Enamines. Our
interest in enantiomerically enriched ꢀ-hydroxy enamines with
stereodefined double bonds stems from their potential utility in
medicinal chemistry and as synthetic intermediates. We therefore
set out to develop a highly enantioselective, practical, and
efficient one-pot method for their generation.
3.1.1. Optimization of Enantioselective ꢀ-Aminovinylation
of Aldehydes. For the synthesis of enantioenriched ꢀ-hydroxy
enamines, we envisaged use of Oppolzer’s method20 for the key
C-C bond-forming step. On the basis of Srebnik’s observation60
that alkenyl boranes undergo reversible transmetalation with
dialkylzinc reagents to generate vinylzinc intermediates, Op-
polzer20 developed a catalytic asymmetric synthesis of allylic
alcohols involving hydroboration of alkynes, transmetalation of
the vinyl group to zinc, and enantioselective addition to
aldehydes to afford enantioenriched allylic alcohols (Scheme
4). We15-19 and others20-29 have used this method to make
The ꢀ-hydroxy enamine synthesis begins with hydroboration
of an ynamide using diethylborane and transmetalation of the
vinylborane with Et2Zn to generate the ꢀ-amino vinylzinc
intermediate. The aldehyde alkenylation is then performed in
(61) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002,
124, 12225.
(62) Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 10677.
(63) Lurain, A. E.; Maestri, A.; Kelly, A. R.; Carroll, P. J.; Walsh, P. J.
J. Am. Chem. Soc. 2004, 126, 13608.
(64) Kim, H. Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc.
2009, 131, 954.
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2010, 132, 402.
(66) Valenta, P.; Drucker, N. A.; Bode, J. W.; Walsh, P. J. Org. Lett.
2009, 11, 2117.
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8473.
(60) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449.
(68) Hoffmann, R. W.; Bruckner, D. New J. Chem. 2001, 25, 369.
9
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Stereoselective Synthesis of ꢀ-Hydroxy Enamines
A R T I C L E S
Table 2. Optimization of Yield and Enantioselectivity in the
Synthesis of ꢀ-Hydroxy Enamines
Table 3. Substrate Scope of the Asymmetric One-Pot Generation
of (E)-Trisubstituted ꢀ-Hydroxy Enamines
entry
R12BH
R22Zn
isolated yield (%)
ee (%)
1
2
3
4
5
BH3 ·SMe2
9-BBN
Cy2BH
Et2BH
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Me2Zn
trace
44
78
82
80
-
82
92
92
91
Et2BH
the presence of a catalyst derived from Nugent’s isoborneol-
based amino alcohol ligand MIB.69 As illustrated in Table 1,
the yield of the addition product is strongly dependent on the
nature of the EWG. Although the Boc group resulted in
formation of the desired addition product, the isolated yield did
not exceed 25% (entry 1). Use of more strongly electron-
withdrawing carbonyl groups on the nitrogen, such as trifluo-
roacetyl or imide, did not result in formation of the ꢀ-hydroxy
enamine product (entries 2 and 3), perhaps because the
borohydride added to the carbonyl group. In contrast, the more
robust tosyl group led to formation of the ꢀ-hydroxy enamine
in 82% yield (entry 4). The tosyl group serves a dual role in
the chemistry: it both enables the generation of the product in
good yield and prevents elimination of the ꢀ-hydroxy enamine.
Decomposition via elimination eventually affords R,ꢀ-unsatur-
ated aldehydes after reaction with water.
To perform the analogous asymmetric addition, we used a
catalyst derived from enantiomerically pure (-)-MIB (Table
2), which is readily prepared in three steps or can be pur-
chased.70 With the general procedure for entry 4 of Table 1,
several hydroborating agents were examined (Table 2). After
the hydroboration and addition of the dialkylzinc reagent, (-)-
MIB (5 mol %) and isobutyraldehyde were added. When
BH3 ·SMe2 was used in the hydroboration, only trace addition
product was observed (entry 1). Use of 9-BBN resulted in
formation of the ꢀ-hydroxy enamine in 44% yield with 82% ee
(entry 2). Screening combinations of diethyl- and dicyclohexyl-
borane with diethyl- and dimethylzinc (entries 3-5) led to the
identification of diethylborane and diethylzinc as the optimal
combination, with formation of the ꢀ-hydroxy enamine in 82%
yield and 92% ee. It is noteworthy that under the reaction
conditions the addition of Et2Zn to the aldehyde was very slow
relative to the reaction of the vinylzinc species and that a yield
of less than 5% for the ethyl addition product was observed.
The optimized conditions in Table 2 were then used to determine
the substrate scope, as outlined in the following section.
3.1.2. Substrate Scope of the Synthesis of ꢀ-Hydroxy Enam-
ines. To determine the scope and limitations of our one-pot
synthesis of enantioenriched ꢀ-hydroxy enamines, a series of
aldehydes and ynamides were tested using the conditions from
entry 4 of Table 2. As shown in Table 3, the asymmetric
vinylation reaction is compatible with a range of ynamides and
aldehydes. Initially, ynamides derived from phenylacetylene
a Enantioselectivities were determined by HPLC.
were employed (entries 1-8). With this coupling partner,
aliphatic aldehydes with R-branching underwent additions with
enantioselectivities of >90% and yields of 73-82% (entries 1
and 2). With dihydrocinnamaldehyde, which lacks R-branching,
a significant decrease in enantioselectivity to 54% was observed
(entry 3). The R,ꢀ-unsaturated aldehyde cyclohexenecarboxal-
dehyde afforded the corresponding ꢀ-hydroxy enamine in 70%
yield with 92% enantioselectivity (entry 4). This product also
contains an allylic alcohol, which is a useful functional group
for further elaboration.30 Aromatic aldehydes proved to be
excellent substrates, undergoing the reaction with enantiose-
lectivities of 91-98% and yields >80% (entries 5-7). The
heteroaromatic 3-furancarboxaldehyde resulted in formation of
the product in 68% yield with 89% enantioselectivity (entry
8). The ynamide with a 2-benzofuranyl substituent also exhibited
excellent enantioselectivities in the asymmetric addition to
isobutyraldehyde (91% ee; entry 9) and 4-methylbenzaldehyde
(98% ee; entry 10). Yields of >80% were achieved in both cases.
Comparison of the enantioselectivities for phenyl- and 2-ben-
zofuranyl-substituted ynamides (entries 1-8 vs entries 9 and
10) suggests that the addition does not strongly depend on the
nature of the aryl group.
(69) Nugent, W. A. Chem. Commun. 1999, 1369.
(70) Chen, Y. K.; Jeon, S.-J.; Walsh, P. J.; Nugent, W. A. Org. Synth.
2005, 82, 87.
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A R T I C L E S
Valenta et al.
Scheme 5. (A) Barrett’s and (B) de Meijere’s Syntheses of
The n-Bu-substituted ynamide underwent addition with
representative aliphatic and aromatic aldehydes with high levels
of enantioselectivity. Thus, with isobutyraldehyde and benzal-
dehyde, the addition products were obtained with 93 and 96%
enantioselectivity, respectively (entries 11 and 12). The yields
were >80% in both cases. The parent ynamide (R ) H) was
also a useful coupling partner, as shown in entries 13-17. With
the aliphatic aldehydes isobutyraldehyde and cyclohexanecar-
boxaldehyde, the yields were 80 and 77%, respectively, and
the corresponding enantioselectivities were g93% (entries 13
and 14). Bulky pivaldehyde reacted with high enantioselectivity
(93%), albeit in decreased yield (67%; entry 15). Not surpris-
ingly, aliphatic aldehydes lacking R-branching were difficult
substrates with (-)-MIB (entries 16 and 17), as with most amino
alcohol catalysts.71-82 Isovaleraldehyde and phenylacetaldehyde
gave enantioselectivities of 76 and 83%, respectively. Presum-
ably, the advent of more enantioselective catalysts will enable
additions to these challenging substrates to occur with higher
stereoselectivities. As indicated in entry 1 of Table 1, the Boc-
protected ynamide gave a low yield. Nonetheless, the product
formed upon addition to 2-naphthaldehyde in the presence of
(-)-MIB had an ee of 97% (Table 3, entry 18).
Aminocyclopropyl Carbinols
In order for a method to be useful, scalability must be
demonstrated. As shown in eq 1, the phenyl-substituted ynamide
and isobutyraldehyde were used in the catalytic asymmetric
ꢀ-amimo vinylation to afford 1.5 g of ꢀ-hydroxy enamine 1a
(92% ee).
The absolute stereochemistry of a derivative of 1b was
determined by single-crystal X-ray diffraction (see the Sup-
porting Information and section 3.2). Accordingly, the (-)-MIB-
based catalyst promoted the formation of (R)-hydroxy enamines,
consistent with the transition state proposed by Noyori83,84 for
the asymmetric alkylation of aldehydes with dialkylzinc reagents
and the amino alcohol-based catalyst derived from DAIB. The
stereochemistry of the remaining entries in Table 3 was assigned
by analogy. It is noteworthy that coordination to zinc by the
heteroatoms, such as the nitrogens present in the ynamides and
the oxygens of the sulfonamides and benzofuryl groups (entries
9 and 10), was not problematic in the enantioselective vinyl
addition step. Finally, only the E isomer of the ꢀ-hydroxy
enamine was observed in each case by 1H NMR spectroscopy,
indicating that isomerization of the double bond does not occur
during the transmetalation, addition, workup, and purification
steps. As will be seen in subsequent sections, the conservation
of the double-bond geometry of the enamine is essential for
diastereoselective elaboration of these products.
3.2. Tandem Asymmetric ꢀ-Aminovinylation of Aldehydes/
Diastereoselective Cyclopropanation. Cyclopropylamines con-
tinue to attract interest because of their abundance in natural pro-
ducts and biologically active compounds,31 including several com-
mercial medications.85-93 As a result, many methods for syn-
thesizing the aminocyclopropyl moiety have been developed.34-54
Direct methods for the effective synthesis of functionalized enantio-
and diastereoenriched cyclopropylamines remain elusive, however.
Existing routes for preparing aminocyclopropyl carbinols suffer
from either low yields94 (Scheme 5A) or low diastereoselectivities95,96
(Scheme 5B) or are not enantioselective.97-99
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9
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Stereoselective Synthesis of ꢀ-Hydroxy Enamines
A R T I C L E S
Scheme 6. Asymmetric and Diastereoselective One-Pot
Generation of Aminocyclopropyl Carbinols
Table 4. Enantio- and Diastereoselective One-Pot Generation of
Aminocyclopropyl Carbinols
Because aminocyclopropyl carbinols can serve as precursors
to compounds of biological relevance,52,100-102 their direct
enantio- and diastereoselective synthesis is desirable. Our
approach to the catalytic enantio- and diastereoselective syn-
thesis of aminocyclopropyl carbinols is based on our prior efforts
involving the diastereoselective directed cyclopropanation of
allylic alcohols.19,64,65 At the outset of this study, however, it
was not clear how the nitrogen of the enamine would impact
the reactivity of the double bond toward cyclopropanation or
whether it would affect the diastereoselectivity. A search of the
literature revealed very few examples of Simmons-Smith
cyclopropanations of enamines.50,103 Nonetheless, we attempted
the tandem asymmetric aminovinylation/diastereoselective cy-
clopropanation. Hydroboration of the ynamide, transmetalation,
and asymmetric addition to the aldehyde according to our
synthesis of ꢀ-hydroxy enamines generated the zinc ꢀ-alkoxy
enamine intermediate (Scheme 6). The alkoxide complex was
then subjected to a directed Simmons-Smith cyclopropanation
using a carbenoid introduced by Shi.104,105
The generation of the Shi modified carbenoid involves the
reaction of CF3CH2OH with diethylzinc to form the monoalkox-
ide complex CF3CH2OZnEt. Reaction of this intermediate with
diiodomethane results in the formation of the Shi carbenoid,
CF3CH2OZnCH2I. Upon combining CF3CH2OZnCH2I with zinc
ꢀ-alkoxy enamine intermediates, we were pleased to see the
formation of the desired cyclopropyl amines as single diaster-
eomers, although the yields were moderate. As we have
observed with other systems,19,64,65 the cyclopropanation pro-
ceeds in low to moderate yield in the presence of triethylborane,
a byproduct formed during transmetalation of the ꢀ-aminovinyl
group from boron to zinc (Scheme 6). To achieve high yields,
the triethyborane was removed from the reaction mixture before
the cyclopropanation step. Removal of the volatile triethylborane
was accomplished by subjecting the reaction mixture to reduced
pressure. The best results were obtained with addition of hexanes
to the residue followed by removal of the volatile materials
under reduced pressure. This procedure was performed three
times. Under these conditions, aliphatic aldehydes (entries 1-5,
Table 4) underwent the addition/cyclopropanation sequence with
the terminal ynamide in 72-82% isolated yields, 76-94%
enantioselectivities, and excellent diastereoselectivities (>20:1
in all cases).
a Determined by HPLC of the intermediate enamines. b Determined
by 1H NMR analysis of the crude reaction mixture. c Reaction time
60 h.
Under our current conditions, the tandem reaction is capri-
cious when the sequence is initiated with substituted ynamides.
Although we were able to generate a trisubstituted aminocy-
clopropyl carbinol (entry 6), the isolated yield was low (28%)
and the reaction time long (60 h). Cyclopropanation of ꢀ-alkoxy
enamines generated from aromatic aldehydes or aryl-substituted
ynamides did not proceed; instead, ꢀ-hydroxy enamines were
isolated.
The diastereomeric ratios in Table 4 were determined by 1H
NMR analysis of the crude reaction products. The absolute and
relative configurations of 2f were determined by X-ray diffrac-
tion (see the Supporting Information). The structure revealed
that cyclopropanation occurred syn to the carbinol, as observed
inthecyclopropanationofallylicalcoholsviatheSimmons-Smith
cyclopropanation.19,64,65,106,107 A possible transition state for the
directed cyclopropanation is illustrated in Figure 1.106,107
The aminovinylation/cyclopropanation method introduced
above affords aminocyclopropyl carbinols containing trans-
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A R T I C L E S
Valenta et al.
Crabtree’s124 and Wilkinson’s125 catalysts resulted in loss of
the hydroxyl group, probably by elimination to form an R,ꢀ-
unsaturated iminium intermediate. This intermediate could then
undergo subsequent hydrogenation, resulting in formation of
the observed alkyl sulfonamide 4 (entries 1-6). These examples
illustrate the sensitivity of ꢀ-hydroxy enamines to elimination
even under very mild conditions. We next turned to common
heterogeneous catalysts. PtO2 did not catalyze the hydrogenation
at room temperature but caused decomposition of the hydroxy
enamine at elevated temperature or pressure (entries 7-9). On
the other hand, rhodium on alumina (5 mol %) was completely
inactive (entry 10). Palladium on carbon (10 mol %) was the
most promising catalyst, providing the desired 1,3-amino alcohol
as the major product. Atmospheric pressure at room temperature
(entry 11) or above (entry 12) was not sufficient for full
conversion, so a higher pressure was used (entries 13 and 14).
With 10 mol % Pd/C catalyst in methanol at a hydrogen pressure
of 8 MPa, the reaction provided an isolated yield of 90% with
excellent diastereoselectivity (>20:1; entry 14). Unlike the
ꢀ-hydroxy enamines with aliphatic carbinols, which undergo
highly diastereoselective reductions in methanol, we found that
the enamine hydrogenation of substrates with benzylic hydroxyl
groups led to elimination/reduction in methanol. Therefore, the
choice of the solvent was crucial and dependent on the
substituent attached to the carbinol. We reasoned that protic
solvents would hydrogen bond to the hydroxyl group of the
ꢀ-hydroxy enamine and facilitate the elimination pathway. To
reduce elimination, ꢀ-hydroxy enamines with aromatic carbinols
were hydrogenated in aprotic solvents. After a screen of several
solvents, ethyl acetate was determined to be the most effective.
Interestingly, hydrogenation of ꢀ-hydroxy enamines with ali-
phatic carbinols in ethyl acetate resulted in lower conversions
(entry 15) than in methanol.
Figure 1. Proposed transition states for diastereoselective cyclopropanation
of ꢀ-alkoxy enamines. The interaction of R with the substituents is
responsible for the diastereoselectivity.
disubstituted cyclopropane motifs. The products are formed in
good yields with good to excellent enantioselectivities and very
high diastereoselectivities. This one-pot procedure results in the
generation of three C-C bonds and three continuous stereo-
centers and is conducted without isolation of any intermediates.
3.3. Synthesis of Amino Alcohols. 1,3-Amino alcohols are
common structural motifs in many biologically active com-
pounds55-58 and are extensively used in asymmetric synthesis
as both chiral ligands and auxiliaries.108 Many methods for the
synthesis of enantio- and diastereoenriched 1,3-disubstituted-
1,3-amino alcohols are available.109-113 In contrast, the stereo-
selective synthesis 1,2-disubstituted-1,3-amino alcohols remains
a significant challenge.6,114-122 The best approach to enantioen-
riched 1,2-disubstituted-1,3-amino alcohols is addition of lithium
arylacetonitriles to aldehydes,123 which leads to ꢀ-hydroxy
nitriles with moderate enantio- and diastereoselectivities. This
method employs greater than stoichiometric amounts of chiral
ligand. Efficient methods for the synthesis of enantio- and
diastereoenriched 1,2-disubstituted-1,3-amino alcohols would
facilitate their use in medicinal chemistry and asymmetric
catalysis. We envisioned a catalytic diastereoselective hydro-
genation of ꢀ-hydroxy enamines as a straightforward route to
1,2-disubstituted-1,3-amino alcohols.
3.3.2. Substrate Scope of the Diastereoselective Hydrogena-
tion of ꢀ-Hydroxy Enamines. The results of the diastereoselec-
tive hydrogenation of ꢀ-hydroxy enamines are shown in Table
6. Catalytic hydrogenation of ꢀ-hydroxy enamines with aliphatic
(entries 1, 2, 3, 7, and 9) or aromatic (entries 4, 5, 6, 8, and 10)
carbinol substituents and aromatic (entries 1-6) or heteroaro-
matic (entries 7 and 8) substituents at the 2-position led to 1,2-
disubstituted-1,3-aminoalcohols in good isolated yields (80-92%)
with excellent diastereoselectivities (>20:1). With an alkyl group
at the 2-position of the ꢀ-hydroxy enamine, however, the
diastereoselectivity was only moderate (entries 9 and 10). The
3.3.1. Diastereoselective Hydrogenation of ꢀ-Hydroxy Enam-
ines. Our initial efforts to reduce ꢀ-hydroxy enamines focused
on homogeneous hydrogenation catalysts and variation of the
solvent, hydrogen pressure, and reaction time (Table 5). Both
(108) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. ReV. 2007, 107, 767.
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1
diastereomeric ratios in Table 6 were determined by H NMR
analysis of the crude reaction products. The ee’s of the
ꢀ-hydroxy enamines 1a, 1e, and 1j were determined before the
hydrogenation to be 92, 91, and 98%, respectively. Their
hydrogenation products 3a, 3e, and 3j were found to have ee’s
of 91, 90, and 95%, respectively. The absolute and relative
stereochemistries in Table 6 are based on the X-ray structural
determination of 3a, which revealed that the hydrogenation is
syn-selective (see the Supporting Information).
The diastereoselective outcome of the hydrogenation can be
rationalized by conformational analysis of the ꢀ-hydroxy
enamine when it is associated with the surface of the palladium
catalyst (Figure 2, left). The ꢀ-hydroxy enamine binds to the
surface of the catalyst through coordination of the hydroxyl
group. The substrate then adopts a conformation that minimizes
(110) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835.
(111) Cho, B. T.; Kim, N. Synth. Commun. 1995, 25, 167.
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2343.
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37, 1044.
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(115) Laumer, J. M.; Kim, D. K.; Beak, P. J. Org. Chem. 2002, 67, 6797.
(116) Liu, C.; Hashimoto, Y.; Saigo, K. Tetrahedron Lett. 1996, 37, 6177.
(117) Cherkauskas, J. P.; Klos, A. M.; Borzilleri, R. M.; Sisko, J.; Weinreb,
S. M.; Parvez, M. Tetrahedron 1996, 52, 3135.
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Chem. 1995, 60, 7511.
(119) Carlier, P. R.; Lo, C. W. S.; Lo, M. M. C.; Wan, N. C.; Williams,
I. D. Org. Lett. 2000, 2, 2443.
(120) Gotor, V.; Dehli, J. R.; Rebolledo, F. J. Chem. Soc., Perkin Trans.
1 2000, 307.
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Tagarelli, A.; Bartoli, G. Eur. J. Org. Chem. 2002, 2924.
(122) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi,
M.; Rinaldia, S.; Sambria, L. Tetrahedron Lett. 2001, 42, 8811.
(123) Carlier, P. R.; Lam, W. W. F.; Wan, N. C.; Williams, I. D. Angew.
Chem., Int. Ed. 1998, 37, 2252.
(124) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
(125) Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J. Chem.
Soc. A 1966, 1711.
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Stereoselective Synthesis of ꢀ-Hydroxy Enamines
A R T I C L E S
Table 5. Optimization of the Diastereoselective Hydrogenation of ꢀ-Hydroxy Enamines
entry
catalyst (mol %)/solvent
pressure (MPa)
temp. (°C)
time (h)
producta
isolated yield (%)
drb
1
2
3
4
5
6
7
8
Crabtree’s cat. (10)/CH2Cl2
Crabtree’s cat. (10)/1:1 MeOH:CH2Cl2
Crabtree’s cat. (10)/1:1 MeOH:CH2Cl2
Crabtree’s cat. (10)/1:1 MeOH:CH2Cl2
Wilkinson’s cat. (1.0)/benzene
Wilkinson’s cat. (10)/benzene
PtO2 (10)/MeOH
PtO2 (10)/MeOH
PtO2 (10)/MeOH
5% Rh/Al2O3 (10)/AcOEt
10% Pd/C (10)/MeOH
10% Pd/C (10)/MeOH
0.1
0.1
1.0
8.0
0.1
1.0
0.1
0.1
8.0
1.0
0.1
0.1
1.0
8.0
8.0
20
20
20
20
20
20
20
50
20
20
20
50
20
20
20
12
12
5
4
4
4
4
NR
4
NR
dec
dec
NR
3a
3a
3a
3a
3a
40
50
50
60
0
60
0
0
-
-
-
12
12
12
12
12
12
12
12
5
-
-
-
-
-
9
0
0
-
10
11
12
13
14
15
-
10
14
55
90
14
>20:1
>20:1
>20:1
>20:1
>20:1
10% Pd/C (10)/MeOH
10% Pd/C (10)/MeOH
10% Pd/C (10)/AcOEt
12
12
12
a NR, only starting material recovered; dec, starting material decomposed to an inseparable mixture. b Determined by 1H NMR analysis of the crude
reaction mixture.
Table 6. Diastereoselective Hydrogenation of ꢀ-Hydroxy Enamines
a Determined by 1H NMR analysis of the crude reaction mixture. b 91% ee (HPLC). c 90% ee (HPLC). d 95% ee. For aliphatic R1, MeOH; for
e
aromatic R1, EtOAc.
unfavorable interactions between R1 and the hydroxyl group,
as would be predicted for the free substrate in solution. The
dihydrogen is then delivered to give the syn product. It is
possible to disfavor the association of the hydroxyl group with
the metal catalyst by introduction of a bulky protecting group.
In this case, the two conformers differ in steric interactions,
one having iPr-Ph interactions and the other OTBS-Ph
interactions (Figure 2, right). The difference in the energies of
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A R T I C L E S
Valenta et al.
Figure 2. (A) Proposed conformation of hydroxy enamines on the surface of the catalyst to rationalize the syn-selective hydrogenation. (B) The conformation
of the TBS-protected ꢀ-hydroxy enamine slightly favors the anti diastereomer.
Scheme 7. Synthesis of the Key Intermediate 8 in the Synthesis of
PRC200-SS and Derivatives
the conformers is not sufficient for good diastereoselection,
resulting in a 0.7:1 syn/anti mixture of diastereomers in case of
TBS and an 1:1 mixture in case of TIPS. It is noteworthy that
the N-benzyl group is not hydrogenolysed under these reaction
conditions.
3.3.3. Enantio- and Diastereoselective Formal Synthesis of
Derivatives of PRC200-SS. The 1,2-disubstituted-1,3-amino
alcohol moiety is present in many biologically active com-
pounds, such as the antidepressants venlafaxine (Effexor, Wyeth)
and desvenlafaxine (Pristiq, Wyeth), which are both serotonin-
norepinephrine reuptake inhibitors (SNRIs). Most antidepres-
sants prescribed at the present time target serotonergic and
noradrenergic neurotransmission, resulting in enhanced dopam-
ine neurotransmission. Inhibitors that influence the combination
of serotonergic, noradrenergic, and dopaminergic neurotrans-
mission (SNDRIs) can result in significant improvement of
depressive symptoms. There are no approved SNDRIs on the
market to date, but several are in development. One family of
SNDRIs includes PRC200-SS126-129 and its derivatives.130 To
demonstrate the utility of our methods, we performed a short
formal enantio- and diastereoselective synthesis of derivatives
of PRC200-SS.130 Our synthesis (Scheme 7) starts with the
copper-catalyzed oxidative coupling of commercially available
under 1 atm hydrogen provided the syn product 7 with high
2-naphthylacetylene with N-methyltoluene sulfonamide, which
diastereoselectivity (dr ) 10.8:1 by 1H NMR analysis) in 65%
proceeded in 87% yield. Hydroboration of the resulting 2-naph-
yield with 95% ee (entry 4). When a higher hydrogen pressure
thyl ynamide 5 with diethylborane followed by transmetalation
(entry 5) or higher catalyst loading (entry 6) was applied, partial
hydrogenation of the 2-naphthyl group was observed, and 7′
was the major product. The structure of 7′ was confirmed by
to zinc and enantioselective addition to benzaldehyde promoted
by the (+)-MIB-based catalyst provided ꢀ-hydroxy enamine 6
in high yield (92%) with excellent enantioselectivity (97%).
X-ray diffraction (see the Supporting Information). The di-
Because of the presence of the N-methyl group in place of the
astereomers formed in entry 4 were easily separable by column
chromatography, allowing isolation of the pure syn isomer.
N-benzyl group that appears in the examples in Tables 1-5,
the hydrogenation of ꢀ-hydroxy enamine 6 under the original
Detosylation with sodium naphthalenide afforded 8 in 89%
conditions (Table 7, entry 1) or related conditions (entries 2
yield. Biologically active chloride, fluoride, and azide derivatives
and 3) provided only mediocre diastereoselectivity for 7 (2:1).
can be obtained from the common intermediate 8, as shown in
However, an additional screen of heterogeneous catalysts
Scheme 8.130 Mitsunobu reaction of 7 and subsequent hydrolysis
afforded 9 in 79% yield with 95% ee (Scheme 9). After the
revealded that use of 20% Pd(OH)2/C (6 mol %) in methanol
detosylation, PRC200-SS was isolated in 76% yield.
(126) Shaw, A. M.; Boules, M.; Zhang, Y.; Williams, K.; Robinson, J.;
In contrast to the original nine-step synthesis of 8 (Scheme
Carlier, P. R.; Richelson, E. Eur. J. Pharmacol. 2007, 555, 30.
10), which involves resolution of racemic intermediate 10 and
late-stage separation of diastereomers (Scheme 10, step 8), our
procedure is highly efficient and both enantio- and diastereo-
selective, affording 8 in four steps from commercially available
materials in 46% overall yield. Although the original anti-
selective nitrile aldol method allows the synthesis of PRC200-
SS, the absolute configuration of the carbinol must be inverted
to prepare the bioactive chloride, fluoride, and azide derivatives.
(127) Liang, Y.; Shaw, A. M.; Boules, M.; Briody, S.; Robinson, J.;
Oliveros, A.; Blazar, E.; Williams, K.; Zhang, Y.; Carlier, P. R.;
Richelson, E. J. Pharmacol. Exp. Ther. 2008, 327, 573.
(128) Carlier, P. R.; Lo, M. M. C.; Lo, P. C. K.; Richelson, E.; Tatsumi,
M.; Reynolds, I. J.; Sharma, T. A. Bioorg. Med. Chem. Lett. 1998,
8, 487.
(129) Richelson, E.; Carlier, P. R. PCT Int. Appl. 2003, 45, WO
2003007929.
(130) Richelson, E.; Fauq, A. H. PCT Int. Appl. 2009, 107, WO
2009089479.
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Stereoselective Synthesis of ꢀ-Hydroxy Enamines
A R T I C L E S
Table 7. Optimization of Diastereoselective Hydrogenation of ꢀ-Hydroxy Enamine 6
entry
catalyst (mol %)/solvent
pressure (MPa)
time (h)
major product
isolated yield (%)
dra
1
2
3
4
5
6
10% Pd/C (10)/AcOEt
10% Pd/C (10)/MeOH
10% Pd/C (10)/MeOH
10% Pd(OH)2/C (6)/MeOH
10% Pd(OH)2/C (10)/MeOH
10% Pd(OH)2/C (20)/MeOH
8.0
0.1
8.0
0.1
8.0
0.1
5
48
5
48
8
7
7
7
7
7′
7′
48
64
83
65
78
68
2:1
4:1
2:1
10.8:1
2:1
48
3:1
a
1
Determined by H NMR analysis of the crude reaction mixture.
Scheme 8. Known Conversion of 8 to Bioactive Derivatives
Scheme 10. Carlier’s Synthesis of PRC200-SS and Derivatives
Scheme 9. Conversion of 7 to 9 and PCR200-SS
ꢀ-hydroxy enamines are obtained in high yields with good to
excellent ee’s. We have shown that ꢀ-hydroxy enamines are
viable substrates for alkoxy- and hydroxyl-directed reactions.
An efficient catalytic enantio- and diastereoselective method for
the synthesis of aminocyclopropyl carbinols has also been
outlined. This convenient one-pot method enables the synthesis
of aminocyclopropyl carbinols in good yields with good to
excellent enantioselectivities and excellent diastereoselectivities.
Additionally, an efficient syn-diastereoselective hydrogenation
of ꢀ-hydroxy enamines has been developed that leads to 1,2-
disubstituted-1,3-amino alcohols, a common structural motif in
many biologically active compounds. This method has made
possible the efficient synthesis of the precursor to PRC200-SS
derivatives, which are potent serotonin-norepinephrine-dopamine
reuptake inhibitors.
Our syn-selective method opens the door to the direct synthesis
of PRC200-SS derivatives without the need for a Mitsunobu
reaction.
4. Summary and Outlook
Herein has been presented the first general catalytic and highly
enantioselective method of synthesis of ꢀ-hydroxy enamines.
The versatility of this method is demonstrated by its wide
substrate scope, as it can be used to combine aliphatic, R,ꢀ-
unsaturated, aromatic, or heteroaromatic aldehydes with ali-
phatic, aromatic, or heteroaromatic ynamides. The resulting
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A R T I C L E S
Valenta et al.
Acknowledgment. This work was financially supported by the
NIH (National Institute of General Medical Sciences GM58101)
and the NSF (CHE-0848467). Funds for instrumentation were
provided by the NIH (1S10RR023444) for a mass spectrometer
and NSF (CHE-0840438) for an X-ray diffractometer. We thank
Dr. Hun Young Kim for preliminary results and Prof. Marisa C.
Kozlowski for use of the hydrogenation apparatus. P.V. thanks the
Isabel and Alfred Bader Foundation for a graduate fellowship.
Supporting Information Available: Experimental procedures,
synthesis and full characterization of new compounds, conditions
for resolution of racemates, and crystallographic data (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA105435Y
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