Optically pure γ-butyrolactones and epoxy esters via two stereocentered HKR of 3-substituted epoxy esters: A formal synthesis of (-)-paroxetine, Ro 67-8867 and (+)-eldanolide

Article abstract of DOI:10.1039/c3ob27321k

The HKR of racemic anti- or syn-3-substituted epoxy esters catalyzed by a Co(iii)salen complex provides ready access to the corresponding enantioenriched 3,4-disubstituted γ-butyrolactones and 3-substituted epoxy esters. This strategy has been successfully employed in the formal synthesis of biologically active 3,4-disubstituted piperidine derivatives, (-)-paroxetine and Ro 67-8867 and a natural product, (+)-eldanolide.

Full text of DOI:10.1039/c3ob27321k

Organic &
Biomolecular Chemistry
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Optically pure γ-butyrolactones and epoxy esters via
two stereocentered HKR of 3-substituted epoxy esters:
a formal synthesis of (−)-paroxetine, Ro 67-8867 and
(+)-eldanolide†
Cite this: Org. Biomol. Chem., 2013, 11,
1280
Received 29th November 2012,
Accepted 4th January 2013
DOI: 10.1039/c3ob27321k
Dattatray A. Devalankar, Pratibha U. Karabal and Arumugam Sudalai*
www.rsc.org/obc
The HKR of racemic anti- or syn-3-substituted epoxy esters cata-
lyzed by a Co(III)salen complex provides ready access to the corre-
sponding enantioenriched 3,4-disubstituted γ-butyrolactones and
3-substituted epoxy esters. This strategy has been successfully
employed in the formal synthesis of biologically active 3,4-disub-
stituted piperidine derivatives, (−)-paroxetine and Ro 67-8867
and a natural product, (+)-eldanolide.
Introduction
The γ-butyrolactone skeleton represents an important core
structure in many biologically active natural products.1 In par-
ticular, certain functionalized chiral γ-butyrolactones are sex
attractant pheromones2 such as eldanolide 1 and some are uti-
lized as flavoring components.3 In addition, they are also
useful chiral synthons for accessing substituted piperidines,
which are ubiquitous structural motifs present in numerous
pharmaceuticals4 such as paroxetine 3 and Ro 67-8867 5
(Fig. 1). The enantiomerically pure epoxy esters 9 are also valu-
able ‘building blocks’ for the asymmetric synthesis of bioactive
natural products.5 Due to their interesting biological activity in
medicinal chemistry, an efficient catalytic method for the syn-
thesis of substituted γ-butyrolactones and epoxy esters from
commercially available materials is of current interest.6
Recent methods in the synthesis of chiral 3,4-disubstituted
γ-butyrolactones mainly include: (i) SmI2-mediated reductive
coupling of aldehydes with crotonates possessing 2-substituted
8-methoxy-1-naphthamides or N-methylephedrine as a chiral
auxiliary;7a,b (ii) lipase PS-mediated resolution of substituted
γ-butyrolactones7c and (iii) catalytic asymmetric cyclocarbony-
lation.7d On the other hand, the synthesis of chiral epoxy
esters has generally been reported from chiral pool resources.5
Fig. 1 Structure of biologically active γ-butyrolactone, substituted piperidines
and Co(III)salen catalyst.
However, the reported methods suffer from certain limitations
such as use of expensive catalysts, chiral pool resources, mul-
tiple steps or products obtained in low optical purity.
Jacobsen’s hydrolytic kinetic resolution (HKR) with chiral
cobalt catalysts has been comprehensively studied to obtain
chiral epoxides and diols of high ees in excellent yields.8
Despite impressive achievements, HKR has generally been
applied to the resolution of simple terminal epoxides with one
stereocentre.9 Quite recently, we have reported an elegant pro-
tocol involving a two-stereocentered Co-catalyzed HKR of
racemic terminal epoxides bearing adjacent C–O and C–N
binding substituents to furnish enantiopure syn or anti alkoxy
and azido epoxides and the corresponding 1,2-diols in high
optical purity (up to 99% ee).10 In the present work, it is of
interest to extend its scope to include terminal epoxides
bearing adjacent C–C binding substituents.
In this communication, we wish to report a flexible, novel
single-step method that employs Co-catalyzed HKR of racemic
3-substituted (aryl or alkyl) epoxy esters 7 with two stereo-
centres to produce substituted γ-butyrolactones 8 and epoxy
esters 9 in high optical purities (Scheme 1).
Chemical Engineering and Process Development Division, National Chemical
Laboratory, Dr. Homi Bhabha Road, Pune 411008, India.
E-mail: a.sudalai@ncl.res.in; Fax: +91-02025902676
†Electronic supplementary information (ESI) available: Experimental details and
spectral data of all the new compounds. See DOI: 10.1039/c3ob27321k
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Table 2 Co-catalyzed HKR of racemic 3-substituted syn-epoxy esters
Scheme 1 Co-catalyzed HKR of racemic 3-substituted anti epoxy esters.
Lactones
Epoxides
11(a–d)
12(a–d)
Substrates
R ( ) – 10(a–d)
Yielda
(%)
eeb
(%)
Yielda
(%)
eeb
(%)
Entry
sc
Results and discussion
a
b
c
Phenyl
47
46
47
46
98
98
99
98
48
48
46
48
97
98
97
97
282
261
581
261
Initially, when HKR of racemic anti-3-substituted epoxy ester
7a was carried out with (S,S)-(salen)Co(OAc) complex
(0.5 mol%) and H2O (0.5 equiv.), the corresponding trans-3,4-
disubstituted γ-butyrolactone 8a (45%) and 3-substituted a Isolated yield after column chromatographic purification. b ee
4-Fluorophenyl
4-Chlorophenyl
4-Bromophenyl
6
d
determined by chiral HPLC. c The values for s (stereoselectivity factor)
were calculated using the equation s = ln[1 − c(1 + ee)]/ln[1 − c(1 −
epoxy ester 9a (48%) were isolated in high yields and optical
purity [8a (99% ee) and 9a (97% ee)]. The formation of γ-butyro-
ee)], where c and ee are conversion and enantiomeric excess of the
lactones can be explained on the basis of intramolecular lactone.11
cyclization of the chiral diol formed in situ with ester function-
ality. Encouraged by this result, we have examined its scope by
subjecting several racemic anti-3-substituted epoxy esters 7a–h
to HKR, which proceeded smoothly, with complete regio-
control, to give the respective enantioenriched trans-3,4-disub-
stituted γ-butyrolactones 8a–h and anti-epoxy esters 9a–h in
excellent ees (96 to 99% ee) and high yields (45 to 49%). The
results of such a study are shown in Table 1. The reaction thus
exhibited generality with respect to the degree of functionaliza-
tion of epoxides.
and syn-epoxy esters 12a–d were obtained in high yields and
ees up to 99%. The results of this study are presented in
Table 2.
The racemic anti- and syn-3-substituted epoxy esters (7 and
10), the substrates for HKR, were efficiently prepared in a
highly diastereoselective manner from the corresponding
allylic alcohols 13 by essentially following a three-step pro-
cedure:12 (i) Johnson–Claisen rearrangement13 of allylic alco-
hols 13 [MeC(OEt)3, hexanoic acid (catalytic), 80–150 °C] gave
acyclic olefinic acids 14; (ii) diastereoselective iodolactoniza-
tion of 14 gave trans or cis iodolactones (15 or 16) depending
upon the reaction conditions employed (for trans: I2, CH3CN,
0 °C, 24 h; for cis: I2, NaHCO3, CHCl3, 0 °C, 6 h); (iii) methano-
lysis of 15 or 16 under basic conditions produced the required
Similarly, when syn-3-substituted epoxy esters 10a–d were
subjected to HKR under identical reaction conditions, the cor-
responding chiral cis-3,4-disubstituted γ-butyrolactones 11a–d
Table 1 Co-catalyzed HKR of racemic 3-substituted anti-epoxy esters
racemic anti- or syn-3-substituted epoxy esters
7 or 10
(Scheme 2).
Lactones 8(a–h)
Epoxides 9(a–h)
Substrates
Entry R ( ) – 7(a–h)
Yielda
(%)
eeb,c Yielda
eeb,c
(%)
(%)
(%)
sd
a
b
c
d
e
f
Phenyl
45
46
45
46
99
99
98
96
97
97
99
96
48
49
48
48
47
48
48
48
97
99
98
96
96
96
97
96
500
535
245
124
200
170
581
146
4-Fluorophenyl
4-Chlorophenyl
4-Bromophenyl
4-Methoxyphenyl 48
Methyl
Benzyl
3-Phenylpropyl
46
47
48
g
h
a Isolated yield after column chromatographic purification. b ee
determined by chiral HPLC. c ee determined by Mosher’s ester analysis
for entries 8f and 9f. d The values for s (stereoselectivity factor) were
calculated using the equation s = ln[1 − c(1 + ee)]/ln[1 − c(1 − ee)],
where c and ee are conversion and enantiomeric excess of the
lactone.11
Scheme 2 Preparation of racemic 3-substituted anti/syn epoxy esters.
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In this strategy, the relative stereochemistry is thus estab-
lished prior to the HKR step itself and in this way a simple
asymmetric reaction can be used to form enantiomerically
pure substituted γ-butyrolactones and epoxy esters with two
adjacent stereocentres.
Scheme 4 Synthesis of (+)-eldanolide.
Among the various applications of this two stereocentered
HKR, an enantioselective synthesis of 3,4-disubstituted piper-
idines [e.g. (−)-paroxetine 3 and Ro 67-88675] and natural
product (+)-eldanolide 1 attracted our attention due to their
pharmaceutical importance. For example, (−)-paroxetine 3, a
trans-3,4-disubstituted piperidine derivative, is used in the
treatment of depression, obsessive compulsive disorder and
panic disorder14 and its synthesis received considerable atten-
tion from synthetic chemists.4c,15 Our synthesis of 3 com-
mences from γ-butyrolactone 8b. Mesylation of 8b gave the
mesylate 17 which was converted to the corresponding azide
18 (NaN3, DMF, 80 °C) in 95% yield. Azide 18 was then sub-
jected to intramolecular reductive cyclization over Pd(OH)2/H2
(1 atm) to afford cis-3,4-disubstituted piperidinone core 19 in
98% yield. Reduction of 19 with BH3·SMe2 followed by in situ
N-benzyl protection gave cis-piperidine derivative 20 in 85%
yield. Swern oxidation of alcohol 20 gave ketone 21, which on
Wittig olefination with Ph3PvCHOMe15m produced enol ether
22 in 60% yield. Acid hydrolysis of 22 followed by NaBH4
reduction of the resulting aldehyde provided the known inter-
mediate N-benzyl amino alcohol 2,15q (overall yield 25% from
8b) thus constituting a formal synthesis of (−)-paroxetine 3
(Scheme 3). Ro 67-8867 5, a high affinity, selective and activity-
dependent antagonist of the N-methyl-D-aspartate (NMDA)
receptor, has been reported to selectively block an NMDA
receptor subtype in brain regions.16 Its key intermediate 417
was readily synthesized from an enantiomer of γ-butyrolactone
8g (obtained from HKR of 7g with (R,R)-Co salen as a catalyst)
by essentially following a similar sequence of reactions
described in Scheme 3: (i) mesylation (MsCl, Et3N, 0 °C);
(ii) azidation (NaN3, DMF, 80 °C); (iii) catalytic hydrogenation
[Pd(OH)2 (H2, 1 atm)] and (iv) BH3·SMe2-mediated reduction.
Finally, an elegant synthesis of natural product
(+)-eldanolide 1, a long range sex attractant isolated from the
male wing gland of African sugarcane stem borer Eldana
sacharina,2,18 was achieved by the regioselective ring opening
of chiral epoxide 9f with (Me)2CvCHMgBr in a single step
with an overall yield of 35% from 7f (Scheme 4).
The absolute configuration of both chiral γ-butyrolactones
8 and 11 and epoxy esters 9 and 12 was ascertained by compar-
ing optical rotations with those reported in the
literature.5d,7c,15q,17b,18e
Conclusion
In conclusion, the (salen)Co(III)-catalyzed HKR of racemic anti-
or syn-3-substituted epoxy esters provides a highly practical
route to the synthesis of substituted enantioenriched γ-butyro-
lactones and 3-substituted epoxy esters, key intermediates in
the synthesis of many bioactive molecules. This method has
been successfully demonstrated in the efficient formal syn-
thesis of (−)-paroxetine 3, Ro 67-8867 5 and (+)-eldanolide 1.
The reaction is convenient to carry out under mild conditions,
displaying a wide range of substrate scope. We believe that this
HKR strategy will find tremendous applications in the syn-
thesis of bioactive molecules owing to the flexible nature of
the synthesis of starting material and the ready availability of
Co-catalysts in both enantiomeric forms.
Experimental section
A general experimental procedure for hydrolytic kinetic
resolution (HKR) of 3-substituted epoxy esters (7a–h and 10a–d)
To
a
solution of (R,R)- or (S,S)-(salen)Co(II)complex
(0.024 mmol, 0.5 mol%) in toluene (1 mL), acetic acid (0.014 g,
0.24 mmol) was added. It was allowed to stir at 25 °C in open
air for 30 min during which time the color changed from
orange-red to a dark brown and it was then concentrated
under reduced pressure to get the Co(III)-salen complex-6 as a
brown colored solid. To this racemic 3-substituted epoxy esters
7/10 (4.85 mmol) and H2O (0.043 g, 2.42 mmol) were added at
0 °C. The reaction was allowed to warm to 25 °C and stirred for
12 h. After completion of the reaction (monitored by TLC), the
crude product was purified by column chromatography over
silica gel to give chiral epoxy esters 9a–g and 12a–d [solvent
Scheme 3 Formal synthesis of (−)-paroxetine.
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system; petroleum ether–ethyl acetate (9 : 1)] and chiral γ-butyro- 0.5 mL min−1, 254 nm); retention time: tmajor = 10.51 and
lactones 8a–g and 11a–d [solvent system; petroleum ether–ethyl tminor = 13.84 min.
acetate (1 : 1)] in pure form.
(R)-Methyl 3-((R)-oxiran-2-yl)-3-phenylpropanoate (12a)
Yield: 48%, colorless liquid; [α]2D5 = +17.3 (c 1, CHCl3); IR:
(4S, 5R)-5-(Hydroxymethyl)-4-phenyldihydrofuran-2(3H)-one
1
(CHCl3, cm−1) 1736; H NMR (200 MHz, CDCl3) δ 2.47 (dd, J =
(8a)
Yield: 45%, colorless solid; m.p.: 82 °C; [α]2D5 = −25.4 (c 1,
2.6, 4.9 Hz, 1H), 2.58–2.83 (m, 3H), 3.14 (m, 1H), 3.26–3.36 (m,
1H), 3.63 (s, 3H), 7.20–7.32 (m, 5H); 13C NMR (50 MHz,
CDCl3): δ 36.50, 42.89, 45.67, 51.56, 54.43, 127.20, 127.87,
128.53, 139.46, 171.80; HRMS (m/z): calculated [M + H]+ for
C12H15O3: 207.1016; found: 207.1028; optical purity: 97% ee
determined by (OD-H column, n-hexane–2-propanol (90 : 10),
0.5 mL min−1, 254 nm); retention time: tminor = 13.68 and
tmajor = 14.93 min.
CHCl3); IR: (CHCl3, cm−1) 1778, 3443; 1H NMR (200 MHz,
CDCl3) δ 2.04 (br s, 1H), 2.80 (dd, J = 9.9, 17.8 Hz, 1H), 3.10
(dd, J = 9.1, 17.8 Hz, 1H), 3.63–3.77 (m, 2H), 3.93–3.99 (m, 1H),
4.53 (m, 1H), 7.24–7.40 (m, 5H); 13C NMR (50 MHz, CDCl3):
δ 37.23, 41.92, 61.73, 87.23, 127.19, 127.67, 129.12, 139.38,
176.30; HRMS (m/z): calculated [M + H]+ for C11H13O3:
193.0859; found: 193.0859; optical purity: 99% ee determined
by HPLC analysis (Chiral OD-H column, n-hexane-2-propanol
(50 : 50), 0.5 mL min−1, 254 nm); retention time: tmajor = 10.15
and tminor = 11.35 min.
((2R, 3S)-3-(4-Fluorophenyl)-5-oxotetrahydrofuran-2-yl)methyl
methanesulfonate (17)
Yield: 92%, colorless liquid; [α]2D5 = −31.9 (c 1, CHCl3); IR:
1
(CHCl3, cm−1) 1789; H NMR (200 MHz, CDCl3) δ 2.74 (dd, J =
(R)-Methyl 3-((S)-oxiran-2-yl)-3-phenylpropanoate (9a)
9.7, 17.8 Hz, 1H), 3.05 (dd, J = 9.1, 18.1 Hz, 1H), 3.08 (s, 3H),
3.64 (q, J = 9.1 Hz, 1H), 4.27–4.49 (m, 2H), 4.61 (m, 1H),
7.04–7.13 (m, 2H), 7.22–7.29 (m, 2H); 13C NMR (50 MHz,
CDCl3): δ 36.75, 37.70, 41.89, 67.53, 82.94, 116.14 (d, J =
21.6 Hz), 128.93 (d, J = 8.1 Hz), 133.76 (d, J = 3.3 Hz), 162.36
(d, J = 248.1 Hz), 174.04; HRMS (m/z): calculated [M + H]+ for
C12H14FO5S: 289.0540; found: 289.0536.
Yield: 48%, colorless liquid; [α]2D5 = −12.7 (c 1, CHCl3); IR:
1
(CHCl3, cm−1) 1736; H NMR (200 MHz, CDCl3) δ 2.55 (dd, J =
2.6, 4.8 Hz, 1H), 2.72–3.12 (m, 5H), 3.60 (s, 3H), 7.20–7.34 (m,
5H); 13C NMR (50 MHz, CDCl3): δ 37.37, 44.96, 46.95, 51.64,
55.29, 127.32, 127.67, 128.76, 139.89, 171.88; HRMS (m/z): cal-
culated [M + H]+ for C12H15O3: 207.1016; found: 207.1014;
optical purity: 97% ee determined by HPLC analysis (OD-H
column, n-hexane–2-propanol (90 : 10), 0.5 mL min−1
254 nm); retention time: tminor = 10.28 and tmajor = 11.24 min.
,
(4S, 5R)-5-(Azidomethyl)-4-(4-fluorophenyl)dihydrofuran-2-
(3H)-one (18)
Yield: 95%, colorless liquid; [α]2D5 = −89.2 (c 1, CHCl3); IR:
(CHCl3, cm−1) 1789, 2105; 1H NMR (200 MHz, CDCl3) δ 2.71
(dd, J = 9.9, 17.8 Hz, 1H), 3.03 (dd, J = 8.9, 17.7 Hz, 1H),
3.26–3.71 (m, 3H), 4.51 (m, 1H), 7.02–7.11 (m, 2H), 7.18–7.26
(m, 2H); 13C NMR (50 MHz, CDCl3): δ 36.91, 42.95, 51.86,
84.31, 116.52 (d, J = 21.6 Hz), 128.83 (d, J = 8.1 Hz), 134.02 (d,
J = 3.3 Hz), 162.32 (d, J = 247.7 Hz), 174.08; HRMS (m/z): calcu-
lated [M + H]+ for C11H11FN3O2: 236.0830; found: 236.0829.
(4S, 5R)-4-(4-Fluorophenyl)-5-(hydroxymethyl)dihydrofuran-2-
(3H)-one (8b)
Yield: 46%, colorless solid; m.p.: 90 °C; [α]2D5 = −23.2 (c 1,
CHCl3); IR: (CHCl3, cm−1) 1777, 3439; 1H NMR (200 MHz,
CDCl3) δ 2.21 (dd, J = 5.8, 7.3 Hz, 1H), 2.72 (dd, J = 9.7, 17.7
Hz, 1H), 3.03 (dd, J = 9.1, 17.7 Hz, 1H), 3.58–3.78 (m, 2H),
3.91–4.01 (m, 1H), 4.48 (m, 1H), 7.01–7.10 (m, 2H), 7.21–7.28
(m, 2H); 13C NMR (50 MHz, CDCl3): δ 37.30, 41.22, 61.56,
87.21, 116.24 (d, J = 21.6 Hz), 128.89 (d, J = 8.1 Hz), 135.01 (d,
J = 2.9 Hz), 162.10 (d, J = 246.6 Hz), 176.15; HRMS (m/z): calcu-
lated [M + H]+ for C11H12FO3: 211.0765; found: 211.0766;
Optical purity: 99% ee determined by HPLC analysis (Chiral
(4S, 5R)-4-(4-Fluorophenyl)-5-hydroxypiperidin-2-one (19)
Yield: 98%, colorless solid; m.p.: 176 °C; [α]2D5 = +74.7 (c 1,
MeOH); IR: (CHCl3, cm−1
)
1636, 1652, 3439; 1H NMR
(200 MHz, MeOH-d4) δ 2.33 (dd, J = 5.6, 17.3 Hz, 1H), 2.82 (dd,
J = 12.2, 29.5 Hz, 1H), 3.11 (m, 1H), 3.25 (m, 1H), 3.48 (dd, J =
2.9, 13.0 Hz, 1H), 4.02 (m, 1H), 6.90–6.99 (m, 2H), 7.25–7.32
(m, 2H); 13C NMR (50 MHz, MeOD4): δ 33.46, 42.97, 50.19,
67.27, 115.93 (d, J = 21.6 Hz), 130.81 (d, J = 7.7 Hz), 138.64,
163.41 (d, J = 243.5 Hz), 174.57; HRMS (m/z): calculated
OJ-H column, n-hexane–2-propanol (50 : 50), 0.5 mL min−1
254 nm); retention time: tminor = 10.72 and tmajor = 11.28 min.
,
(4S, 5S)-5-(Hydroxymethyl)-4-phenyldihydrofuran-2(3H)-one
(11a)
Yield: 47%, colorless thick liquid; [α]D25 = −76.56 (c 1, CHCl3); [M + H]+ for C11H13FNO2: 210.0925; found: 210.0925.
IR: (CHCl3, cm−1) 1780, 3440; 1H NMR (200 MHz, CDCl3) δ
(3R, 4S)-1-Benzyl-4-(4-fluorophenyl)piperidin-3-ol (20)
2.30 (br s, 1H), 2.87 (dd, J = 8.9, 17.4 Hz, 1H), 3.04 (dd, J = 8.3,
17.4 Hz, 1H), 3.34–3.60 (m, 2H), 3.90 (q, J = 8.2 Hz, 1H), 4.79 Yield: 85%, colorless solid; m.p.: 114 °C; [α]2D5 = +37.0 (c 1,
(m, 1H), 7.22–7.37 (m, 5H); 13C NMR (50 MHz, CDCl3): δ 34.56, CHCl3); IR: (CHCl3, cm−1
)
1509, 2936, 3446; 1H NMR
43.16, 62.10, 86.37, 127.66, 127.84, 128.93, 136.46, 176.72; (200 MHz, CDCl3) δ 1.66 (m, 1H), 2.15–2.36 (m, 2H), 2.35 (d,
HRMS (m/z): calculated [M + H]+ for C11H13O3: 193.0859; J = 11.3 Hz, 1H), 2.59 (d, J = 12.3 Hz, 1H), 3.06 (dd, J = 7.0, 30.4
found: 193.0859; optical purity: 98% ee determined by Hz, 2H), 3.61 (s, 2H), 3.86 (s, 1H), 6.94–6.98 (m, 2H), 7.24–7.32
HPLC analysis (OJ-H column, n-hexane-2-propanol (50 : 50), (m, 7H); 13C NMR (50 MHz, CDCl3): δ 26.35, 45.80, 53.36,
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60.20, 62.61, 68.94, 115.10 (d, J = 20.8 Hz), 127.52, 128.47, (+)-Eldanolide (1)
129.17, 129.39 (d, J = 6.9 Hz), 137.28, 138.77, 161.59 (d, J =
Yield: 74%, colorless liquid; [α]2D5 = +48.5 (c 1, MeOH) {lit.18e
243.5 Hz); Anal. Calcd for C18H20FNO requires C, 75.76; H,
7.06; N, 4.91; found C, 75.78; H, 7.01; N, 4.82%.
1
[α]2D0 +48.2 (c 1.15, MeOH)}; IR: (CHCl3, cm−1) 1781; H NMR
(200 MHz, CDCl3) 1.12 (d, J = 6.6 Hz, 3H), 1.64 (s, 3H), 1.73 (s,
3H), 2.10–2.42 (m, 4H), 2.66 (m, 1H), 4.07 (q, J = 6.2 Hz, 1H),
5.17 (m, 1H); 13C NMR (50 MHz, CDCl3): δ 17.81, 18.02, 25.88,
32.20, 35.09, 37.05, 86.94, 118.02, 135.41, 176.18; Anal. Calcd
for C10H16O2 requires C, 71.39; H, 9.59; found C, 71.20; H,
9.42%.
(3S, 4S)-4-Benzylpiperidin-3-ol (4)
Yield: 80%, colorless solid; m.p.: 95.5 °C; [α]2D5 = −34.8 (c 1,
CHCl3) {lit.17b [α]D20 −36.6 (c 1, CHCl3)}; IR: (CHCl3, cm−1) 2923,
1
3441; H NMR (200 MHz, MeOH-d4) δ 1.29 (m, 1H), 1.64 (m,
2H), 2.27 (d, J = 13.43 Hz, 1H), 2.45 (m, 2H), 2.61 (dd, J = 7.02,
13.12 Hz, 1H), 2.94–3.01 (m, 2H), 3.53 (s, 1H), 7.05–7.10 (m,
3H), 7.13–7.16 (m, 2H); 13C NMR (50 MHz, CDCl3): δ 26.60,
39.64, 42.10, 54.13, 60.53, 66.34, 127.14, 129.45, 130.34,
141.62; HRMS (m/z): calculated [M + H]+ for C12H18NO:
192.1383; found: 192.1384.
Acknowledgements
DAD and PUK thanks CSIR, New Delhi for the award of a
Senior Research Fellowship. The authors are also thankful to
Dr V. V. Ranade, Chair, Chemical Engineering and Process
Development Division for his constant encouragement and
support.
(S)-1-Benzyl-4-(4-fluorophenyl)piperidin-3-one (21)
Yield: 80%, colorless liquid; [α]2D5 = +11.0 (c 1, CHCl3); IR:
1
(CHCl3, cm−1) 1722; H NMR (200 MHz, CDCl3) 2.14–2.25 (m,
2H), 2.51–2.64 (m, 1H), 2.89 (d, J = 13. 9 Hz, 1H), 3.03–3.10 (m,
1H), 3.37 (dd, J = 1.5, 13.9 Hz, 1H), 3.51 (t, J = 9.2 Hz, 1H), 3.63
(s, 2H), 6.97–7.14 (m, 4H), 7.31 (m, 5H); 13C NMR (50 MHz,
CDCl3): δ 32.74, 51.97, 54.36, 62.45, 64.46, 115.31 (d, J = 11.5
Hz), 127.52, 128.47, 129.17, 130.22 (d, J = 8.4 Hz), 133.67,
136.91, 161.79 (d, J = 247.4 Hz), 205.18; Anal. Calcd for
C18H18FNO requires C, 76.30; H, 6.40; N, 4.94; found C, 76.58;
H, 6.32; N, 4.88%.
References
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(S)-1-Benzyl-4-(4-fluorophenyl)-3-(methoxymethylene)
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Yield: 60%, colorless liquid; [α]2D5 = +7.0 (c 1, CHCl3); IR:
(CHCl3, cm−1) 1603, 1675, 2933; 1H NMR (200 MHz, CDCl3)
1.78 (m, 1H), 1.98 (m, 1H), 2.21 (m, 1H), 2.64 (d, J = 12.3 Hz,
1H), 2.90 (d, J = 11.6 Hz, 1H), 3.16 (d, J = 10.3 Hz, 1H), 3.42 (s,
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12.3 Hz, 1H), 5.14 (s, 1H), 6.92 (m, 2H), 7.14–7.42 (m, 7H); 13C
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63.01, 114.99 (d, J = 21.2 Hz), 117.53, 126.93, 128.14, 129.39,
129.82 (d, J = 7.6 Hz), 137.75, 137.93, 143.24, 161.88 (d, J =
246.6 Hz); Anal. Calcd for C20H22FNO requires C, 77.14; H,
7.12; N, 4.50; found C, 77.24; H, 7.15; N, 4.41%.
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methanol (2)
Yield: 72%, colorless liquid; [α]2D5 = −15.2 (c 1, CHCl3) {lit.15q
[α]D20 −16.0 (c 0.8, CHCl3)}; IR: (CHCl3, cm−1) 3424; 1H NMR
(200 MHz, CDCl3): δ 1.45–1.90 (m, 3H), 1.95–2.11 (m, 3H), 2.32
(m, 1H), 2.98 (m, 1H), 3.18–3.26 (m, 2H), 3.37 (dd, J = 2.5, 11.2
Hz, 1H), 3.54 (d, J = 13.2 Hz, 1H), 3.63 (d, J = 13.2 Hz, 1H), 6.98
(m, 2H), 7.17 (m, 2H), 7.34 (m, 5H); 13C NMR (50 MHz,
CDCl3): δ 29.77, 44.24, 44.36, 53.92, 57.36, 63.43, 64.34, 115.42
(d, J = 21.2 Hz), 127.14, 128.22, 128.86, 129.31, 138.15, 140.20
(d, J = 3.0 Hz), 161.59 (d, J = 245.0 Hz); Anal. Calcd for
C19H22FNO requires C, 76.22; H, 7.41; N, 4.68; found C, 76.23;
H, 7.35; N, 4.61%.
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