Synthesis of (+)-L-733,060, (+)-CP-99,994 and (2S,3R)-3-hydroxypipecolic acid: Application of an organocatalytic direct vinylogous aldol reaction

Article abstract of DOI:10.1039/c2ob06644k

The γ-butenolide obtained from an organocatalyzed, direct vinylogous aldol reaction of γ-crotonolactone and benzaldehyde serves as the key starting material in the expedient synthesis of a 3-hydroxy-2-phenyl piperidine intermediate which is converted to the target 2,3-disubstituted piperidines.

Full text of DOI:10.1039/c2ob06644k

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PAPER
Synthesis of (+)-L-733,060, (+)-CP-99,994 and (2S,3R)-3-hydroxypipecolic
acid: Application of an organocatalytic direct vinylogous aldol reaction†
Sunil V. Pansare* and Eldho K. Paul
Received 27th September 2011, Accepted 14th December 2011
DOI: 10.1039/c2ob06644k
The γ-butenolide obtained from an organocatalyzed, direct vinylogous aldol reaction of γ-crotonolactone
and benzaldehyde serves as the key starting material in the expedient synthesis of a 3-hydroxy-2-phenyl
piperidine intermediate which is converted to the target 2,3-disubstituted piperidines.
Introduction
Results and discussion
The piperidine motif is found in numerous biologically relevant
natural products1 as well as in medicinal and pharmaceutical
agents,2 and the synthesis of functionalized piperidines has
therefore continued to engage synthetic chemists over the years.3
Stereoselective routes to aryl substituted4 and hydroxylated
piperidines5 have been extensively investigated. In particular, the
biological activity and the synthesis of a variety of 2,3-disubsti-
tuted piperidines has attracted considerable interest. This is
perhaps best exemplified by the synthetic efforts directed
towards the neurokinin receptor antagonists (+)-L-733,0606 and
(+)-CP-99,994;7 as well as (2S,3R)-3-hydroxypipecolic acid,8 a
constituent of the antibiotic tetrazomine (Fig. 1). Herein, we
describe an organocatalysis based enantioselective synthesis of
these three targets.
The 2-substituted 3-hydroxy piperidine motif is accessible by
the rearrangement of 5-(1-aminoalkyl (or aminoaryl) butyrolac-
tones (Fig. 2).9 The aminobutyrolactones can, in turn, be
obtained from the corresponding hydroxy precursors, which are
typically obtained by stereoselective vinylogous Mukaiyama
aldol reactions of 2-siloxyfurans and aldehydes.10 However, a
much simpler route to stereodefined 5-(1-hydroxyalkyl/aryl)
butenolides involves the organocatalytic, direct vinylogous aldol
reaction of γ-crotonolactone (2(5H)-furanone) with aldehydes, a
reaction that has received attention only recently.11 Given the
structural similarities in the targets of the present study (Fig. 1),
it appeared that a suitably functionalized butyrolactone could
potentially be employed as a common synthetic precursor to
achieve most of the objectives. In addition, this synthetic strategy
would also highlight the utility of the organocatalytic direct
vinylogous aldol (ODVA) reaction (Fig. 2).
Our studies therefore began with the synthesis of 1 (Scheme 1)
and its conversion to (5S,6S)-5-hydroxy-6-phenylpiperidin-2-one
(3) which is an advanced precursor to (+)-L-733,060 and
(+)-CP-99,994. Initially, the direct vinylogous aldol reaction of
commercially available γ-crotonolactone and benzaldehyde was
examined in the presence of selected aminothiourea and amino-
squaramide catalysts derived from stilbenediamine, 1,2-cyclo-
hexane diamine and amines obtained from cinchona alkaloids.
Extensive optimization studies with these catalysts revealed the
aminosquaramide A12 as the most efficient catalyst in terms of
the yield, diastereoselectivity and enantioselectivity for the aldol
product.11c Thus, the direct vinylogous aldol reaction of γ-croto-
nolactone with benzaldehyde provided the butenolide 1 in good
yield and diastereoselectivity (74%, anti/syn = 8/1) and excellent
enantiomeric excess (>99% ee for the anti diastereomer) when
the reaction was conducted in dichloromethane at ambient temp-
erature (Scheme 1).
The aldol product 1 (as a diastereomeric mixture) was easily
converted to the lactam 3 via a series of simple transformations.
Hydrogenation of 1 to the butyrolactone 1a, subsequent mesyla-
tion of the secondary alcohol to give 1b and displacement of the
Department of Chemistry, Memorial University, St. John’s,
Newfoundland, Canada, A1B 3X7. E-mail: spansare@mun.ca
†Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra of all compounds and HPLC traces for compounds 5 and
CP-99,994. See DOI: 10.1039/c2ob06644k
Fig. 1 Biologically active 2,3-disubstituted piperidines targeted in this
study.
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with 3,5-bistrifluoromethylbenzylbromide followed by deprotec-
tion provided (+)-L-733,060 (9 steps from benzaldehyde, 24.8%
overall yield). The synthesis of (+)-CP-99,994 required the syn-
thesis of ketone 5 and subsequent reductive amination, and both
of these steps required detailed attention to the reaction con-
ditions. Oxidation of 4 with Dess–Martin periodinane provided
the 3-piperidinone 5 (77%, 94% ee). Notably, in our hands, the
enantiomeric excess of 5 was dependent on the method of oxi-
dation14 and the DMP procedure15 is by far the best for obtain-
ing 5 in good yield and high enantiomeric excess. Subsequent
oximation of 5 with methoxyamine by a significant modifi-
cation14 of the reported procedure15 (ethanol instead of pyridine
as the solvent) gave the corresponding oxime ether which was
reduced stereoselectively to the amine 6. Reductive amination of
6 with 2-methoxybenzaldehyde followed by deprotection pro-
vided CP-99,994.
We next investigated the synthesis of (2S,3R)-3-hydroxypipe-
colic acid. This particular diastereomer of 3-hydroxypipecolic
acid has been the subject of numerous investigations and it con-
tinues to attract interest from synthetic chemists.8a–f At the
outset, it seemed reasonable that direct oxidation of the phenyl
ring in the O-acetyl derivative of N-Boc-(2R,3R)-2-phenyl-3-
hydroxy piperidine16 (ent-4) would lead us to the pipecolic acid
target. However, attempted oxidation (RuCl3/NaIO4) of this sub-
strate invariably lead to a mixture of products, none of which
corresponded to the required carboxylic acid. Interestingly, a
change in the N-protecting group8c,17 was beneficial. Accord-
ingly, (2R,3R)-2-phenyl-3-hydroxy piperidine (7) was first con-
verted to the N,O-bis trifluoroacetyl derivative and the
trifluoroacetate ester was selectively replaced with an acetate to
provide 8 (89%). Oxidation of the phenyl ring in 8, with RuCl3/
NaIO4, now proceeded smoothly to provide the corresponding
carboxylic acid. Methanolysis of the trifluoroacetamide and the
Fig. 2 The organocatalytic direct vinylogous aldol route to functiona-
lized piperidines.
mesylate, with inversion of configuration, by azide anion gave
the azido butyrolactone 2. It should be mentioned that the
attempted mesylation of 1 exclusively resulted in its dehydration.
This unwanted side reaction is effectively prevented by prior
reduction of the double bond in 1. Reduction of the azide (H2,
Pd/C) generated a mixture of the corresponding amino butyrolac-
tone and the required piperidone 3 resulting from an intramole-
cular N-acylation of the amino lactone. Notably, hydrogenation
of the azide in the presence of a base (K2CO3) significantly
facilitated this rearrangement to directly provide 3 without any
residual amino lactone. At this stage, cis 3 was easily separated
from the minor (trans) diastereomer by flash chromatography
and all further transformations were carried out with diastereo-
merically pure cis 3.13 The overall conversion of 1 to 3 is quite
efficient (76% yield over four steps) and can be conducted
without purification of any of the intermediates. Reduction of the
piperidone 3 with borane6e provided the corresponding piper-
idine (3a, 96%) which was converted to the N-Boc derivative 4.
The conversion of 4 to the neurokinin receptor antagonist
targets was achieved by adaptation and some modification of
previously described methods (Scheme 2). O-Alkylation of 4
Scheme 1
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performed under an atmosphere of dry nitrogen using oven dried
glassware. Dichloromethane and tetrahydrofuran were distilled
from CaH2 and sodium/benzophenone respectively. Commercial
precoated silica gel plates were used for TLC. Silica gel for
column chromatography was 230–400 mesh. All melting points
are uncorrected. Optical rotations were measured at the sodium
D line on a digital polarimeter at ambient temperature. Com-
pounds 1, 4, 4a and 6a were prepared by literature methods. The
conversion of 4a to (+)-L-733,060 and of 6a to (+)-CP-99,994
was achieved by literature methods.
(S)-5-((R)-Hydroxy(phenyl)methyl)furan-2(5H)-one (1)11c
The literature procedure11c was adapted. To the catalyst A
(20 mol%, 1.00 g) was added benzaldehyde (970 μL,
9.14 mmol) followed by 2-(5H)-furanone (1.28 mL, 18.3 mmol)
and dichloromethane (5 mL). The mixture was stirred for 192 h
at room temperature. The mixture was diluted with ethyl acetate
(30 mL) and aqueous 2 M HCl (30 mL) was added. The organic
layer was separated and the aqueous layer was extracted with
ethyl acetate (2 × 30 mL). The combined extracts were dried
(Na2SO4), and concentrated in vacuo. The residue was purified
by flash chromatography (CH2Cl2/EtOAc, 10 : 1) to give 1 as a
pale yellow solid (1.73 g, 74%). The diastereomeric composition
Scheme 2
1
(anti : syn = 8 : 1) was determined by H NMR analysis of the
crude product. The enantiomeric excess was determined by
HPLC (Chiralpak AS-H, hexanes/2-propanol 90 : 10, 254 nm,
t1 = 32.6 min (minor anti), t2 = 37.7 min (minor syn), t3
=
53.1 min (major syn), t4 = 70.5 min (major anti). ee: > 99%
(anti)). In repeated experiments an ee range of 97 to >99% was
1
observed. Spectroscopic data (IR, H NMR, 13C NMR and MS)
for 1 is in agreement with that reported in the literature.11b,c
Scheme 3
acetate in this intermediate gave (2S,3R)-3-hydroxypipecolic
acid (58% from 8, Scheme 3).8c
(S)-Dihydro-5-((R)-(hydroxy(phenyl)methyl)furan-2(3H)-one
(1a)6e
Pd/C (10%, 75 mg) was added to a stirred solution of 1
(750 mg, 3.94 mmol) in EtOAc (10 mL). The reaction mixture
was stirred for 4 h at room temperature under a balloon filled
with H2. The mixture was filtered through Celite and the filter
cake was washed with EtOAc (2 × 30 mL). The combined
filtrates were concentrated in vacuo to provide 758 mg (99%) of
1a as a white solid (anti : syn = 8 : 1). IR: 3391, 1753, 1453,
1370, 1182, 1042, 992 cm−1; 1H NMR (500 MHz, CDCl3): anti
diastereomer: δ 7.39–7.32 (m, 5H, ArH), 5.13 (d, 1H, J = 2.7
Hz, CHOH), 4.72–4.65 (m, 1H, CHCH2), 2.59–2.50 (m, 2H,
CH2CvO, CHCH2), 2.5–2.4 (m, 1H, CH2CvO), 2.32–2.24 (m,
1H, CH2CH–O), 1.97–1.90 (m, 1H, CH2CH–O); Visible reson-
ances for the syn diastereomer: δ 4.65–4.60 (m, 1H, CHCH2),
2.06–2.01 (m, 1H, CH2CHO); 13C NMR (75 MHz, CDCl3): anti
diastereomer: δ 177.6 (CH2CO), 138.4 (ArC), 128.7 (ArC),
128.2 (ArC), 126.0 (ArC), 83.3 (CH2CHO), 73.5 (CHOH), 28.6
(CH2CO), 20.7 (CH2CHO); Visible resonances for the syn dia-
stereomer: δ 176.8 (CH2CO), 138.3 (ArC), 128.8 (ArC), 128.2
(ArC), 127.0 (ArC), 83.4 (CH2CHO), 77.2 (CHOH), 28.5
(CH2CO), 24.0 (CH2CHO); MS (EI pos): m/z: 193.1 (M + 1).
Conclusion
In conclusion, we have achieved the synthesis of three represen-
tative members of the 2,3-disubstituted class of bioactive piper-
idines from the butenolide 1. The syntheses developed in this
study are based on an organocatalytic vinylogous aldol reaction
as the pivotal step and are particularly concise.18 Notably, ketone
5 is also a starting material in the synthesis of spirocyclic NK-1
receptor antagonists.19,20 The methodology presented here has
potential relevance in the preparation of libraries of antagonists,
related to the those described here, by variation of the aldehyde
in the direct vinylogous aldol step. Current efforts focus on the
application of this methodology to other biologically relevant
piperidine-based natural products and their analogs.
Experimental section
All commercially available reagents were used without purifi-
cation. All reactions requiring anhydrous conditions were
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(S)-Dihydro-5-((R)-(methylsulfonyl)(phenyl)methyl)furan-2
white solid and 70 mg (10%) of the 5S,6R isomer as a white
solid.
(3H)-one (1b)6e
cis Diastereomer. Mp: 99 °C (lit.6b mp. 92 °C); IR: 3360,
Triethyl amine (626 μL, 4.5 mmol) was added slowly to an ice
cold solution of 1a (720 mg, 3.75 mmol) in CH2Cl2, followed
by the addition of methane sulfonyl chloride (349 μL,
4.5 mmol). The reaction mixture was stirred for 1 h at 0 °C and
water (20 mL) was added at 0 °C. The mixture extracted with
CH2Cl2 (2 × 20 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo to provide 1.1 g (>99%) of
1b as a yellow oil (anti : syn = 8 : 1) This was shown to be pure
by 1H NMR and was used in the next step without purification.
IR: 3027, 2938, 1775, 1351, 1171, 1031, 944, 912, 874,
3197, 2945, 1643, 1461, 1399, 1351, 1318, 1197, 1069, 986,
1
942 cm−1; H NMR (500 MHz, CDCl3): δ 7.44–7.41 (m, 2H,
ArH), 7.37–7.33 (m, 3H, ArH), 5.85 (br s, 1H, CONH), 4.67 (d,
1H, J = 2.7 Hz, CHAr), 4.08 (br s, 1H, CHOH), 2.76–2.69 (m,
1H, CH2CvO), 2.41–2.37 (m, 1H, CH2CvO), 2.15–2.13 (m,
1H, CHCH2), 2.04–2.01 (m, 1H, CHCH2), 1.69 (s, 1H, OH);
13C NMR (75 MHz, CDCl3): δ 172.3 (CvO), 137.9 (ArCipso),
129.2 (ArC), 128.7 (ArC), 127.0 (ArC), 66.2 (CHOH), 61.9
(CHAr), 26.7 (CHCH2), 26.07 (CH2CvO); MS (APCI, pos.)
m/z 192.1 (M + 1); HRMS (EI): 191.0950 (191.0946 calc. for
C11H13NO2 (M + H)); [α]2D3 = +55.3 (c 1.06, CH2Cl2), lit. [α]2D5
= +52.0 (c 1.1, CH2Cl2).6b
836 cm−1 1H NMR (500 MHz, CDCl3): anti diastereomer
;
(major): δ 7.35 (m, 5H), 5.73 (d, 1H, J = 3.9 Hz), 4.86–4.80
(m, 1H), 2.91 (s, 3H), 2.50–2.40 (m, 2H), 2.28–2.09 (m, 2H);
Visible resonances for the syn diastereomer (minor): δ 5.52
(d, 1H, J = 5.7 Hz), 2.89 (s, 3H); 13C NMR (75 MHz, CDCl3):
anti: δ 176.1, 133.5, 129.6, 129.1, 126.9, 82.8, 80.4, 39.0, 27.7,
22.1; syn: δ 176.0, 133.7, 130.0, 129.2, 127.5, 84.3, 80.3, 39.3,
27.9, 24.2; MS (API-ES) m/z 270.4 (M+); HRMS (CI):
271.0640 (271.0640 calc. for C12H15O5S, M + H).
trans Diastereomer. IR: 3237, 2364, 1631, 1581, 1485, 1446,
1
1349, 1333, 1175, 1076, 945, 801 cm−1. H NMR (500 MHz,
CDCl3): δ 7.45–7.40 (m, 2H, ArH), 7.40–7.35 (m, 3H, ArH),
5.70 (br s, 1H, CONH), 4.69 (d, J = 2.8 Hz, 1H, CHAr), 4.10
(br s, 1H, CHOH), 2.72–2.82 (ddd, 1H, J = 18.0, 11.9, 6.5 Hz,
CH2CO), 2.40–2.45 (ddd, 1H, J = 18.0, 6.2, 2.8 Hz, CH2CO),
2.19–2.15 (m, 1H, CHCH2), 2.07–2.03 (m, 1H, CHCH2), 1.47
(br t, 1H, J = 1.5 Hz, OH); 13C NMR (75 MHz, CDCl3): δ 172.2
(CvO), 137.8 (ArCipso), 129.2 (ArC), 128.8 (ArC), 127.0
(ArC), 66.3 (CHOH), 61.9 (CHAr), 26.7 (CHCH2), 26.1
(CH2CvO); MS (APCI pos.): m/z 192.3 (M+); [α]D23 = +26.0
(c 1.0, MeOH); lit. [α]2D3 = +31.6 (c 0.75, MeOH).21
(S)-5-((S)-Azido(phenyl)methyl)-dihydrofuran-2(3H)-one (2)6e
Sodium azide (1.22 g, 18.7 mmol) was added to the crude mesy-
late (1.1 g, 4.1 mmol) in DMF (5 mL) and the mixture was
stirred at 80 °C for 4 h. The mixture was cooled to room temp-
erature and EtOAc (30 mL) was added followed by water
(30 mL). The resulting biphase was separated and the aqueous
layer was extracted with EtOAc (2 × 30 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated
in vacuo to provide 838 mg (>99%) of 2 as a yellow oil (syn :
(2S,3S)-2-Phenylpiperidin-3-ol (3a)6e
Borane-THF complex (4.7 mL, 4.68 mmol) was added to 3
(300 mg, 1.56 mmol), and the mixture was heated to reflux for
5 h. The mixture was cooled to 0 °C, aqueous HCl (3 M,
12 mL) was added and the mixture was stirred for 30 min. at
room temperature. The mixture was then concentrated in vacuo
to dryness under reduced pressure and the residue was basified
with 5% aqueous NaOH at 0 °C to pH ∼10. The resulting
mixture was extracted with EtOAc, dried (Na2SO4), and concen-
trated in vacuo to provide 3a as a white solid (267 mg, 96%).
This was shown to be pure by 1H NMR and was used in the next
step without purification.
1
anti = 8 : 1). This was pure by H NMR and was used in the
next step without purification.
IR: 2101, 1774, 1455, 1250, 1175, 1148, 1066, 990,
1
913 cm−1; H NMR (500 MHz, CDCl3): syn diastereomer: δ
7.44–7.35 (m, 5H), 4.71–4.61 (m, 1H), 4.60 (d, 1H, J = 5.9 Hz),
2.48–2.34 (m, 2H), 2.15–2.05 (m, 1H), 2.05–1.95 (m, 1H);
Visible resonances for the anti diastereomer: δ 4.90 (d, 1H, J
= 4.2 Hz), 2.58–2.45 (m, 2H), 2.25–2.15 (m, 2H); 13C NMR
(75 MHz, CDCl3): syn diastereomer: δ 176.2, 134.5, 129.2,
127.8, 127.2, 81.2, 68.5, 28.0, 24.6; Visible resonances for the
anti diastereomer: δ 176.4, 134.6, 129.1, 129.0, 81.4, 67.8,
28.1, 22.3; MS (EI pos.): m/z 218.1 (M + 1); HRMS (APCI
pos.): m/z 218.0972 (218.0930 calc. for C11H12N3O2 (M + H)).
Mp: 90–93 °C. IR: 3274, 2926, 2851, 1447, 1323, 1089,
1054, 1053, 989 cm−1 1H NMR (500 MHz, CDCl3): δ
;
7.35–7.32 (m, 3H), 7.32–7.24 (m, 2H), 3.86 (br s, 1H), 3.78 (br
s, 1H), 3.22–3.19 (m, 1H), 2.83–2.78 (dt, 1H, J = 2.8, 12.1 Hz),
2.02–1.92 (m, 1H), 1.89–1.84 (m, 1H), 1.74–1.67 (m, 1H),
1.52–1.48 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 142.0, 128.5,
127.3, 126.6, 68.9, 65.0, 47.5, 32.0, 19.9; MS (APCI, pos.): m/z
178.1 (M + 1); HRMS (EI): 177.1153 (177.1154 calc. for
C11H15NO); [α]2D3 = +66.4 (c 0.62, CHCl3).
(5S,6S)-5-Hydroxy-6-phenylpiperidin-2-one (3)6b
To a stirred solution of 2 (810 mg, 3.73 mmol) in methanol
(5 mL) was added K2CO3 (160 mg, 1.16 mmol) followed by Pd/
C (10%, 81 mg). The reaction mixture was stirred for 4 h at
room temperature under a balloon filled with H2 and then filtered
through a pad of Celite. The filter cake was washed with MeOH
(2 × 30 mL) and the combined filtrates were concentrated in
vacuo under reduced pressure to provide a yellow gum. This was
purified by flash chromatography on silica gel (CH2Cl2/MeOH,
95 : 5 as the eluant) to provide 564 mg (79%) of 3 as a fluffy
(2S,3S)-tert-Butyl 3-hydroxy-2-phenylpiperidine-1-carboxylate
(4)6b
Reaction of 3a (500 mg, 2.82 mmol) and di-tert-butyl dicarbo-
nate in the presence of triethylamine (431 μL, 3.1 mmol) and
DMAP (25 mg, 0.20 mmol) in dichloromethane (5 mL) by
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adaptation of the literature procedure6b followed by purification
of the crude product by flash chromatography on silica gel
(hexanes/ethylacetate, 7 : 3) provided 663 mg (85%) of 4 as a
(2S,3S)-tert-Butyl 3-amino-2-phenylpiperidine-1-carboxylate
(6)15
1
This was prepared by a modification of the reported procedure.15
To a stirred solution of ketone 5 (60 mg, 0.22 mmol) in ethanol
(0.5 mL) at room temperature, was added anhydrous pyridine
(26 μL, 0.33 mmol) followed by methoxylamine hydrochloride
(27 mg, 0.33 mmol) and the mixture was stirred at room temp-
erature for 30 min. Saturated aqueous NH4Cl (10 mL) was
added, the mixture was stirred for 30 min, and then extracted
with diethyl ether (3 × 30 mL). The combined organic layers
were dried (Na2SO4), and concentrated in vacuo to provide the
crude oxime methyl ether of 5 as a pale yellow oil (70 mg). This
was treated with BH3-THF (1 M soln. in THF; 651 μL,
0.63 mmol) under N2 and the solution was stirred at 50 °C for
4h. Saturated aqueous NH4Cl (10 mL) was added and the
mixture was extracted with CHCl3 (3 × 30 mL), dried (Na2SO4),
and concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel (CH2Cl2/MeOH, 9 : 1) to
provide 40 mg (67%) of 6 as a pale yellow oil. IR: 2931, 1682,
colorless oil. Spectroscopic data (IR, H NMR, 13C NMR and
MS) for 4 was in agreement with that reported in the literature.6b
(2S,3S)-tert-Butyl-3-(3,5-bis(trifluoromethyl)benzyloxy)-2-
phenylpiperidine-1-carboxylate (4a)6e
Reaction of the sodium salt of 4 (prepared from 60 mg,
0.216 mmol of 4) and sodium hydride (95%, 16 mg,
0.65 mmol) in DMF/THF (3 : 1, 1 mL) and bis(trifluoromethyl)
benzylbromide (100 mg, 0.33 mmol) at 0 °C for 16 h, by adap-
tation of the literature procedure,6e provided after purification of
the crude product by flash chromatography on silica gel
(hexanes/ethylacetate, 9 : 1) 57 mg (52%) of 4a as a colorless
1
oil. Spectroscopic data (IR, H NMR, 13C NMR and MS) for 4
was in agreement with that reported in the literature.6g
1407, 1362, 1252, 1147, 868 cm−1 1H NMR (500 MHz,
;
CDCl3): δ 7.44 (d, 2H, J = 7.3 Hz, ArH), 7.31–7.28 (m, 2H,
ArH), 7.26–7.23 (m, 1H, ArH), 5.20 (d, 1H, J = 6.0 Hz, CHAr),
4.01 (br d, 1H, J = 10.9 Hz, CHNH2), 3.20–3.11 (m, 2H,
NCH2), 1.88–1.65 (m, 4H, CH2CH2CH), 1.45 (br s, 2H, NH2),
1.36 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3): δ 155.4
(CO2tBu), 139.1 (ArC), 129.4 (2 × ArC), 128.2 (2 × ArC),
127.2 (ArC), 79.7 (OC(CH3)3), 60.6 (NCH), 51.2 (CHNH2),
39.8 (NCH2), 29.2 (NH2CHCH2), 28.3 (C(CH3)3), 24.4
(NCH2CH2); MS (EI pos.): m/z 277.2 (M + 1).
(2S,3S)-3-(3,5-Bis(trifluoromethyl)benzyloxy)-2-
phenylpiperidine ((+)-L-733,060)6b
Deprotection of 4a (46 mg, 0.09 mmol) with trifluoroacetic acid
(70 μL, 0.91 mmol) in CH2Cl2 (1 mL) by adaptation of the lit-
erature procedure6b provided 34 mg (92%) of (+)-L-733,060 as a
1
pale yellow liquid. Spectroscopic data (IR, H NMR, 13C NMR
and MS) for (+)-L-733,060 was in agreement with that reported
in the literature.6b
(2S,3S)-tert-Butyl 3-(2-methoxybenzylamino)-2-
phenylpiperidine-1-carboxylate (6a)15
(S)-tert-Butyl-3-oxo-2-phenylpiperidine-1-carboxylate (5)15
Reaction of 6 (16 mg, 0.06 mmol) and 2-methoxybenzaldehyde
(21 μL) to provide the imine and reduction of the imine with
sodium borohydride (13 mg, 0.35 mmol) by adaptation of the lit-
erature procedure22 followed by purification of the crude product
by flash column chromatography on silica gel (CH2Cl2/ethylace-
tate, 9 : 1) provided 18 mg (78%) of 6a as a pale yellow oil.
This was prepared by a modification of the reported procedure.15
Dess–Martin periodinane (642 mg, 1.5 mmoles) was added to a
solution of the crude alcohol 4 (140 mg, 0.50 mmol) in CH2Cl2
(3 mL) and the mixture was stirred at room temperature for 1 h.
Saturated aqueous sodium bicarbonate (10 mL) was added, the
organic layer was separated and the aqueous layer was extracted
with CHCl3 (3 × 30 mL). The combined organic layers were
washed with saturated brine (30 mL), dried (Na2SO4), and con-
centrated in vacuo. The residue was purified by flash chromato-
graphy (hexanes/EtOAc, 8 : 2) to give 106 mg (77%) of 5 as a
1
Spectroscopic data (IR, H NMR, 13C NMR and MS) for 6a is
in agreement with that reported in the literature.15
HPLC (Chiralpak OD-H, hexanes/2-propanol 90 : 10, 210 nm,
tminor = 4.64 min, tmajor = 5.20 min; ee = 93%.
1
pale yellow liquid. Spectroscopic data (IR, H NMR, 13C NMR
(2S,3S)-N-(2-Methoxybenzyl)-2-phenylpiperidin-3-amine
and MS) for 5 is in agreement with that reported in the
((+)-CP-99,994)15
literature.20
IR: 2974, 1690, 1401, 1361, 1247, 1154 (br), 1105, 1031,
Reaction of 6a (18 mg, 0.05 mmol) in conc. aqueous HCl/
methanol (1 : 1 v/v, 1 mL) by adaptation of the literature pro-
cedure15 provided 12 mg (92%) of (+)-CP-99,994 as a pale
yellow oil. Spectroscopic data (IR, 1H NMR, 13C NMR and MS)
for 6a is in agreement with that reported in the literature.15
HPLC (Chiralpak OD-H, hexanes/2-propanol 90 : 10, 210 nm,
1
967 cm−1; H NMR (500 MHz, CDCl3): δ 7.37–7.20 (m, 5H,
ArH), 5.65 (br s, 1H, CHAr), 4.08 (br s, 1H, CH2N), 3.34–3.30
(br m, 1H, CH2N), 2.51–2.40 (m, 2H, CH2CvO), 1.98–1.88
(m, 2H, CH2CH2CvO), 1.43 (br s, 9H, C(CH3)3); 13C NMR
(75 MHz, CDCl3): δ 205.5 (CH2CvO), 155.0 (N–CvO), 135.6
(ArC), 128.9 (ArC), 127.6 (ArC), 125.4 (ArC), 80.7 (C(CH3)3),
65.9 (br, CHAr), 40.1 (br, NCH2), 37.3 (CH2CvO), 28.2
(C(CH3)3), 22.8 (CH2CH2N); HRMS (EI pos.): 275.1525
(275.1521 calc. for C16H21NO3); HPLC: Chiralpak AD-H,
tmajor = 6.27 min, tminor = 9.75 min; ee = 94%
N-Trifluoroacetyl-(2S,3R)-3-acetoxy-2-phenylpiperidine (8)8c
hexanes/2-propanol 99 : 1, 254 nm, tmajor = 33.9 min, tminor
35.7 min.; ee = 94% ee.
=
To an ice cold solution of the aminoalcohol 7 (ent-3a, 500 mg,
2.82 mmol; prepared as described for 3a, but with the
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enantiomer of catalyst A) in CH2Cl2 (30 mL) containing Et3N
(2.3 mL, 16.9 mmol) and dimethylaminopyridine (17 mg,
0.14 mmol) was added triflouroacetic anhydride (1.6 mL,
11.3 mmol). The solution was stirred at room temperature for
12 h, water was added and the solution was extracted with
CH2Cl2 and the combined extracts were dried (Na2SO4), and
concentrated in vacuo. The residue was dissolved in THF
(30 mL), K2CO3 (770 mg, 5.57 mmol) was added and the
mixture was stirred for 36 h at room temperature. Water was
added and the mixture was extracted with CH2Cl2 and the com-
bined extracts were dried (Na2SO4) and concentrated in vacuo.
The residue was purified by flash chromatography (hexanes/
EtOAc, 7 : 3) to provide 715 mg (93%) of the trifluoroacetamide
derivative of 7 as a pale yellow oil. This was dissolved in
CH2Cl2 (30 mL), Et3N (1.57 mL, 11.29 mmol) and dimethyl-
aminopyridine (15 mg, 0.12 mmol) were added and the solution
was cooled to 0 °C. Acetic anhydride (0.53 mL, 5.19 mmol) was
added and the reaction mixture was stirred at room temperature
for 12 h. Water was added and the mixture was extracted with
CH2Cl2. The combined extracts were dried (Na2SO4), and con-
centrated in vacuo. The crude product was purified by flash
chromatography (hexanes/EtOAc, 8 : 2) to provide 795 mg
(89%) of 8 as a pale yellow oil.
agreement with that reported in the literature.8e Mp. 231–235 °C
(lit.8a mp 233–238 °C) [α]D23 −53.5 (c 0.6, H2O); lit. [α]D25 −53.8
(c 0.6, H2O).8a
Acknowledgements
Financial support from the Natural Sciences and Engineering
Research Council of Canada and the Canada Foundation for
Innovation is gratefully acknowledged.
Notes and References
1 (a) R. Remuson and Y. Gelas-Mialhe, Mini-Rev. Org. Chem., 2008, 5,
193; (b) T. Reynolds, Phytochemistry, 2005, 66, 1399; (c) D. O’Hagan,
Nat. Prod. Rep., 2000, 17, 435 and references therein.
2 P. S. Watson, B. Jiang and B. Scott, Org. Lett., 2000, 2, 3679 and refer-
ences therein.
3 Selected recent reviews: (a) S. Källström and R. Leino, Bioorg. Med.
Chem., 2008, 16, 601; (b) C. De Risi, G. Fanton, G. P. Pollini,
C. Trapella, F. Valente and V. Zanirato, Tetrahedron: Asymmetry, 2008,
19, 131; (c) C. Escolano, M. Amat and J. Bosch, Chem.–Eur. J., 2006,
12, 8198; (d) M. G. P. Buffat, Tetrahedron, 2004, 60, 1701.
4 D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103,
893.
5 Selected reviews: (a) M. S. M. Pearson, M. Mathe-Allainmat, V. Fargeas
and J. Lebreton, Eur. J. Org. Chem., 2005, 2159; (b) P.-Q. Huang,
Synlett, 2006, 1133.
6 For selected, recent syntheses of (+)-L-733,060 see: (a) N. M. Garrido,
M. Garcia, M. R. Sanchez, D. Diez and J. G. Urones, Synlett, 2010, 387;
(b) S. Prevost, P. Phansavath and M. Haddad, Tetrahedron: Asymmetry,
2010, 21, 16; (c) J. L. Bilke, S. P. Moore, P. O’Brien and J. Gilday, Org.
Lett., 2009, 11, 1935; (d) R.-H. Liu, K. Fang, B. Wang, M.-H. Xu and
G.-Q. Lin, J. Org. Chem., 2008, 73, 3307; (e) L. Emmanuvel and
A. Sudalai, Tetrahedron Lett., 2008, 49, 5736; (f) F. A. Davis and
T. Ramachandar, Tetrahedron Lett., 2008, 49, 870 and references therein
(g) S. K. Cherian and P. Kumar, Tetrahedron: Asymmetry, 2007, 18, 982.
7 For selected recent syntheses of CP-99,994, see: (a) R. Fu, B. Zhao and
Y. Shi, J. Org. Chem., 2009, 74, 7577; (b) F. A. Davis and Y. Zhang,
Tetrahedron Lett., 2009, 50, 5205; (c) M. Ahari, A. Perez, C. Menant,
J.-L. Vasse and J. Szymoniak, Org. Lett., 2008, 10, 2473 and references
therein. Also see refs. 6a,d.
8 For selected, recent syntheses of (2S,3R)-3-hydroxypipecolic acid, see:
(a) V.-T. Pham, J.-E. Joo, Y.-S. Tian, Y.-S. Chung, K.-Y. Lee, C.-Y. Oh
and W.-H. Ham, Tetrahedron: Asymmetry, 2008, 19, 318;
(b) H. S. Chung, W. K. Shin, S. Y. Choi, Y. K. Chung and E. Lee, Tetra-
hedron Lett., 2010, 51, 707; (c) A. Cochi, B. Burger, C. Navarro, D.
G. Pardo, J. Cossy, Y. Zhao and T. Cohen, Synlett, 2009, 2157;
(d) B. Wang and R.-H. Liu, Eur. J. Org. Chem., 2009, 17, 2845;
(e) Y. Yoshimura, C. Ohara, T. Imahori, Y. Saito, A. Kato, S. Miyauchi,
I. Adachi and H. Takahata, Bioorg. Med. Chem., 2008, 16, 8273;
(f) S. K. Chattopadhyay, S. P. Roy and T. Saha, Synthesis, 2011, 2664
and references therein.
IR: 1743, 1687, 1451, 1370, 1235, 1193, 1045 cm−1 1H
;
NMR (500 MHz, CDCl3): Major rotamer: δ 7.49–7.26 (m,
5H), 5.99 (d, 1H, J = 5.7 Hz), 5.25–5.20 (m, 1H), 3.83 (br d,
1H, J = 14.0 Hz), 3.19–3.13 (m, 1H), 2.17–2.11 (m, 1H), 2.0 (s,
3H), 1.85–1.83 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 169.6,
135.4, 128.9, 128.7, 128.0, 128.0, 127.8, 116.6 (q, J = 288.0
Hz), 55.5, 41.2 (q, J = 3.4 Hz), 24.9, 23.9, 21.1; Minor
1
rotamer: H NMR (500 MHz, CDCl3), visible resonances: 5.55
(d, J = 5.3 Hz, 1H), 4.37 (d, J = 11.8 Hz, 1H), 2.78–2.72 (dt,
1H, J = 4.1, 13.3 Hz). 13C NMR (75 MHz, CDCl3), visible reso-
nances: δ 169.7 (COCH3), 156.5 (q, J = 36.1 Hz), 135.0, 72.4,
70.6, 57.7, 38.8, 23.5, 21.1; MS (APCI pos.): m/z 316.1
(M + 1); HRMS (CI+): m/z 316.1154 (316.1161 calc. for
C15H17NO3F3 (M + H)).
(2S,3R)-3-Hydroxypiperidine-2-carboxylic acid8e
To a mixture of 8 (150 mg, 0.475 mmol) in carbon tetrachloride
(0.75 mL), acetonitrile (0.75 mL) and water (1.1 mL), were
added sodium periodate (1.53 g, 7.13 mmol) and ruthenium
chloride (5 mg, 0.024 mmol) and the mixture was stirred vigour-
ously at ambient temperature for 20 h. The mixture was filtered
through a pad of Celite and the residue was rinsed several times
with CH2Cl2. The black filtrates were combined, dried (Na2SO4)
and concentrated in vacuo. The residue obtained was dissolved
in methanol (5 mL), K2CO3 (393 mg, 2.84 mmol) was added
and the mixture was stirred at room temperature for 12 h. The
resulting solution was concentrated in vacuo and the residue was
dissolved in aqueous HCl (1 M, 1 mL). This solution was
applied to a column of Dowex 50Wx8 resin (200–400 dry mesh)
and the column was eluted with deionized water (250 mL) fol-
lowed by aqueous ammonia (3 M). Fractions containing the
product were concentrated in vacuo to provide 40 mg (58%) of
(2S,3R)-3-hydroxypiperidine-2-carboxylic acid as a white solid.
Spectroscopic data (IR, 1H NMR, 13C NMR and MS) is in
9 G. W. J. Fleet, N. G. Ramsden and D. R. Witty, Tetrahedron Lett., 1988,
29, 2871. Also see ref. 6e.
10 Recent review: G. Casiraghi, L. Battistini, C. Curti, G. Rassu and
F. Zanardi, Chem. Rev., 2011, 111, 3076.
11 (a) H. Ube, N. Shimada and M. Terada, Angew. Chem., Int. Ed., 2010,
49, 1858; (b) Y. Yang, K. Zheng, J. Zhao, J. Shi, L. Lin, X. Liu and
X. Feng, J. Org. Chem., 2010, 75, 5382; (c) S. V. Pansare and E. K. Paul,
Chem. Commun, 2011, 47, 1027.
12 H. Konishi, T. Y. Lam, J. P. Malerich and V. H. Rawal, Org. Lett., 2010,
12, 2028.
13 For an alternative approach to 3 via azide 2 but employing the Shi asym-
metric epoxidation as the key step, see ref. 6e.
14 Oxidation of 4 with IBX or IBX/DMSO with heating led to 5 with dimin-
ished ee as compared to 4. Swern oxidation of 4 is reported to provide 5
without racemization (ref. 20,22). In the present study, Swern oxidation
of 4 (96% ee) provided 5 with 76% ee. Oximation of 5 obtained in situ
from the Swern oxidation of 4 (ee of 4 (93%), eventually provided
CP-99,994 with 60% ee. Similarly, the reaction of 5 (87% ee) with meth-
oxylamine hydrochloride in pyridine as the solvent (ref. 15) subsequently
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provided CP-99,994 with 50% ee. Changing the solvent to ethanol and
employing only the necessary amount of pyridine was found to be impor-
tant for minimizing the racemization of 5. Likewise, direct imination of 5
with the appropriate amine (ref. 6a), with or without Lewis acid catalysis,
eventually provided racemic CP-99,994. These observations suggest that
5 is prone to racemization if it is heated or exposed to excess base and
that the extent of racemization, under these conditions, may depend on
variables that are difficult to regulate.
17 (a) M. Haddad and M. Larcheveque, Tetrahedron: Asymmetry, 1999,
10, 4231; (b) A. Lemire and A. B. Charette, J. Org. Chem., 2010, 75,
2077.
18 The synthesis of (+)-L-733,060 reported in ref. 6c (80% ee, separation of
a 3(1 diastereomeric mixture of a key intermediate) is shorter, but the dia-
stereoselectivity (8(1 for 1) and enantioselectivity (97% ee) of the present
synthesis is higher.
19 P. E. Maligres, M. M. Waters, J. Lee, R. A. Reamer, D. Askin, M.
S. Ashwood and M. Cameron, J. Org. Chem., 2002, 67, 1093.
20 J. J. Kulagowski, N. R. Curtis, C. J. Swain and B. J. Williams, Org. Lett.,
2001, 3, 667.
21 J. M. Andrès, R. Pedrosa and A. Pèrez-Encabo, Tetrahedron Lett., 2006,
47, 5317.
15 M. Atobe, N. Yamazaki and C. Kibayashi, J. Org. Chem., 2004, 69,
5595.
16 Prepared as described for 3 by employing the enantiomer of catalyst A.
For the RuCl3/NaIO4 oxidation of N-Boc pyrrolidones, see: J. Clayden,
C. J. Menet and K. Tchabanenko, Tetrahedron, 2002, 58, 4727; For oxi-
dation of N-Boc piperidines, see: N. Liang and A. Datta, J. Org. Chem.,
2005, 70, 10182.
22 P.-Q. Huang, L.-X. Liu, B.-G. Wei and Y.-P. Ruan, Org. Lett., 2003, 5,
1927.
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