A short, chemo-enzymatic synthesis of both enantiomers of trans-3-hydroxypipecolic acid

Article abstract of DOI:10.1002/ejoc.201402258

A short synthesis of both enantiomers of trans-3-hydroxypipecolic acid was based on the Suzuki-Miyaura reaction of a lactam-derived enol phosphate and the lipase-catalyzed kinetic resolution of the alcohol obtained by hydroboration/oxidation of the coupling product. The RuCl₃-catalyzed oxidation of the heteroaryl group introduced by the Suzuki-Miyaura coupling eventually afforded, in six or seven steps, the target compounds in 15-17% overall yield.

Full text of DOI:10.1002/ejoc.201402258

FULL PAPER
DOI: 10.1002/ejoc.201402258
A Short, Chemo-Enzymatic Synthesis of Both Enantiomers of
trans-3-Hydroxypipecolic Acid
Stefano Begliomini,[a] Lorenzo Sernissi,[a] Dina Scarpi,[a] and Ernesto G. Occhiato*[a]
Dedicated to C.I.N.M.P.I.S. on the occasion of its 20th anniversary
Keywords: Synthetic methods / Cross-coupling / Enzyme catalysis / Amino acids / Lactams
A short synthesis of both enantiomers of trans-3-hydroxy-
pipecolic acid was based on the Suzuki–Miyaura reaction of
a lactam-derived enol phosphate and the lipase-catalyzed
kinetic resolution of the alcohol obtained by hydroboration/
oxidation of the coupling product. The RuCl3-catalyzed
oxidation of the heteroaryl group introduced by the Suzuki–
Miyaura coupling eventually afforded, in six or seven steps,
the target compounds in 15–17% overall yield.
Introduction
Many natural compounds that display significant bio-
logical activity incorporate a pipecolic acid fragment as an
essential structural feature. Immunosuppressive agents ra-
pamycin[1] and FK506,[1a,2] antitumor antibiotics sandra-
mycin[3] and quinaldopeptin,[4] and cytotoxic apratoxin H[5]
contain simple pipecolic acid units. Cyclodepsipeptide anti-
biotic virginiamycin S2,[6] and serotonin-receptor antago-
nist damipipecoline[7] embody a 4-hydroxypipecolic acid,
whereas cis 3-hydroxypipecolic acid is embedded in the nat-
ural antitumor antibiotic tetrazomine (Figure 1).[8] Besides,
pipecolic acids play an important role in medicinal chemis-
try as either templates or α-amino acid analogues for the
preparation of conformationally restricted peptides[9] and
various pharmaceutically active compounds, such as local-
anesthetic analogue ropivacaine,[10] HIV protease inhibitor
Palinavir,[11] and one of the most potent and selective N-
methyl-d-aspartic acid (NMDA) receptor antagonists,
CGS20281.[12]
Owing to their widespread presence in nature and their
significant medicinal potential, there has been much interest
in the development of new methods for the asymmetric syn-
thesis of pipecolic acids.[13] In this context, trans- and cis-3-
hydroxypipecolic acids 1 and 2 are no exceptions because a
number of syntheses of both compounds have been re-
ported, also owing to the fact that 3-hydroxypiperidine is a
privileged scaffold in nature.[14a] As recently reviewed,
Figure 1. Natural 3-hydroxypipecolic acids and tetrazomine.
methods based on the use of starting material from the chi-
ral pool or that involve enantiomerically enriched reagents
or catalysts have been mainly exploited, with a few ad-
ditional tactics centered on the enzymatic resolution of ra-
cemic compounds.[14]
We have recently demonstrated that enantiopure 4-hy-
droxy-, 5-hydroxy- and 4,5-dihydroxypipecolic acids can be
efficiently prepared by Pd-catalyzed methoxycarbonylation
reaction of suitably functionalized lactam-derived enol
phosphates (Scheme 1, a).[15] By this strategy, racemic or
enantiopure lactams 3 are converted into enecarbamate es-
ters 4, which are then reduced to give target compounds 5.
As a consequence of this interest in pipecolic acids, we de-
cided to investigate if an analogous approach, but which
entails a Suzuki–Miyaura reaction instead of a carb-
onylative process to form the C–C bond at C2 (Scheme 1,
b), could efficiently provide trans-3-hydroxypipecolic acid
1. After hydroboration/oxidation of coupling product 6, an
enzymatic kinetic resolution should provide enantiopure in-
termediate 7, which is finally oxidized to target compound
1. Lipase-catalyzed resolutions have successfully been ex-
ploited for the synthesis of 3-hydroxypipecolic acids (both
[a] Dipartimento di Chimica “Ugo Schiff”, Università degli Studi
di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
E-mail: ernesto.occhiato@unifi.it
http://www.egocch.it/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402258.
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Synthesis of Both Enantiomers of trans-3-Hydroxypipecolic Acid
cis and trans) on only a few occasions, which involved pip-
eridin-3-ols with the 2-carboxyxlic group already installed
on the piperidine ring.[16] In our case, the resolution will be
attempted on a 2-aryl- or heteroaryl-substituted piperidin-
3-ol, with the advantage of obtaining enantiopure interme-
diates potentially useful for preparing biologically relevant
2-aryl-substituted piperidines.[17]
Scheme 2. Reagents and conditions: (a) (PhO)2POCl, KHMDS,
THF, –78 °C; (b) phenylboronic acid, (Ph3P)2PdCl2, Na2CO3 (2 m),
THF, 40 °C; (c) BH3·DMS, THF; then H2O2 (35%), EtOH, NaOH
(3 n), room temp.; (d) Et3N, DMAP, Ac2O, CH2Cl2, room temp.;
(e) NaIO4, RuCl3·xH2O, CCl4/MeCN/H2O, 0 °C.
Before attempting the enzymatic kinetic resolution of this
alcohol we wanted to test the RuCl3 catalyzed oxidation
reaction of the phenyl group and so, after acetylation reac-
tion of the OH group, we treated compound 12 under stan-
dard oxidative conditions.[23] To our disappointment, the
reaction carried out with a catalytic amount of RuCl3·xH2O
Scheme 1. Retrosynthetic analyses.-.
Results and Discussion
The Suzuki–Miyaura coupling of lactam-derived enol and in the presence of NaIO4 (4 equiv.) in a CCl4/aceto-
phosphates and triflates has been extensively surveyed in nitrile/water mixture was sluggish, required the addition of
the past mainly by the group of Coudert and Gillaizeau[18] further oxidant, and yielded carboxylic acid 13 in a very
and by our own group,[19] and has found many applications low yield and in mixture with byproducts derived from
in the synthesis of natural and biologically active heterocy- over-oxidation at position 6. The oxidative degradation of
clic compounds.[20] We decided to use this reaction to install unsubstituted phenyl rings on similar systems has been re-
a masked carboxylic group at C2 mainly because the carb- ported for N-trifluoroacetyl-protected piperidines on-
onylative approach requires the availability and the manipu- ly,[17b,24] and never with N-Boc-protected analogues, which
lation of a toxic and expensive gas. Moreover, α,β-unsatu- are probably not compatible with the reaction conditions.
rated esters such as 4 are not suitable to install the 3-OH Although pipecolic acid 1 could formally be obtained from
group by hydroboration. Of course, this strategy involves a 11 after N deprotection and trifluoroacetylation,[24b] to
further oxidative step not required previously. To evaluate keep our synthesis as short as possible we decided to intro-
the feasibility of our approach, we first coupled enol phos- duce a more easily oxidized substituent at C2 from the be-
phate 9 (Scheme 2), obtained in 96% yield from commercial ginning. So, we opted for a more electron-rich furan, which
N-tert-butoxycarbonyl(Boc)-protected δ-valerolactam, with was established by the Pd-catalyzed coupling of N-Boc pro-
phenylboronic acid under conditions that worked best for tected valerolactam derivative 9 with 2-furanylboronic acid
the corresponding enol triflate.[19b] The reaction was carried (Scheme 3).
at 40 °C in the presence of (Ph3P)2PdCl2 (5 mol-%) in a
Also in this case the coupling was successful and pro-
tetrahydrofuran (THF) and Na2CO3 (2 m) mixture and it vided 14 in 82% yield over two steps, after chromatography.
was complete in 24 h to provide known dehydropiperidine Hydroboration of 14 was carried out both as reported
10 in 77% after chromatography. Hydroboration of 10 was above and with BH3·THF at 0 °C for 22 h, followed by oxi-
carried out with BH3·DMS at room temperature followed dation with trimethylamine N-oxide.[25] In both cases (Ϯ)-
by oxidation with H2O2 in alkaline medium,[21] which pro- 15 was obtained in good yield (83 and 85%, respectively),
vided racemic alcohol 11 in moderate yield (57%). The ex- although with the latter method purity of the crude reaction
pected trans stereochemistry in 11 (and similarly in 15, see mixture was higher. After acetylation, we tested the oxidat-
later) is easily assigned on the basis of very low coupling ive conditions on compound (Ϯ)-16 and were pleased to
constant values for protons at C2 and C3, which appear as obtain acid (Ϯ)-13 in good yield (70% after chromatog-
broad singlets at δ = 4.5 and 5.4 ppm, respectively, in the raphy) after 10 min at room temperature. Although analysis
1
1H NMR spectrum because of their equatorial orientation. of the H NMR spectrum of (Ϯ)-13 showed the presence
Both the aryl and OH groups are thus axially oriented, the of some unidentified impurities [this was true also for com-
former to remove the A(1,3) strain with the N-protecting pound (–)-13 and (+)-18, see later], after exhaustive hydrol-
group.[22]
ysis in HCl (6 n) at reflux temperatures, an appropriate
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S. Begliomini, L. Sernissi, D. Scarpi, E. G. Occhiato
FULL PAPER
B proved useful that gave an E value[29] around 50 when the
resolution was carried out in THF and with vinyl butyrate
as the acylant (Table 1, Entry 3). CAL-A proved less ef-
ficient but immobilized B. cepacia lipase did not appreci-
ably convert 15 into any of the products even with an excess
of acylant. This enzyme was the best in the kinetic resolu-
tion of 4-hydroxypipecolic acid derivatives[15b] and the same
enzyme (lipase PS-C, but immobilized on ceramic partic-
les)[28] provided the best results in the transesterification re-
action of a methyl 3-hydroxypipecolate.[16b,16e] So, although
the different immobilization forms resulted in differences,
the 2-heteroaryl group could play a role in the inefficacy of
this enzyme.
Scheme 3. Reagents and conditions: (a) (PhO)2POCl, KHMDS,
THF, –78 °C; (b) furanylboronic acid, (Ph3P)2PdCl2, Na2CO3 (2 m,
THF, 40 °C; (c) BH3·THF, 0 °C, THF; then Me3NO, THF, 65 °C;
(d) BH3·DMS, THF; then H2O2 (35%), NaOH (3 n), EtOH, r.t; (e)
The absolute configuration of residual substrate (–)-15
Et3N, DMAP, Ac2O, CH2Cl2, room temp.; (f) NaIO4, RuCl3·xH2O, was determined by converting it, on a small scale, into cor-
EtOAc/MeCN/H2O, 0 °C; (g) HCl (6 n), reflux, 3 h.
responding pipecolic acid (–)-1 (see later) and, by compari-
son of the optical rotation of its HCl salt ([α]2D1 = –14.9, c
work-up allowed us to obtain racemic 3-hydroxypipecolic = 1.4 in water),[30] we found that CAL-B catalyzes the acyl-
acid 1 in quantitative yield and excellent purity.
ation of the (2S,3S) substrate. Interestingly, CAL-B is
For the enzymatic kinetic resolution of racemic 15 we known to preferentially catalyze the acylation of the R
opted to test three commercially available immobilized li- alcohol in compounds like simple secondary and cyclic all-
pases, which we have successfully employed in the past for ylic alcohols,[26,31] but clearly this general rule cannot be
the enantioselective acylation reaction of 4-hydroxypipec- extended to our case owing to the presence of a second
olic acid precursors,[15b] CAL-B (Candida antarctica lipase vicinal stereocenter. CAL-A similarly has a stereopreference
B, supported on acrylic resin, trade name Novozym 435),[26] for the (2S,3S) enantiomer, whereas for the PS-AMANO-
CAL-A (C. antarctica lipase A on Immobead 150),[27] and IM-catalyzed resolution, owing to the low conversions, the
PS-AMANO-IM (Burkholderia cepacia lipase, immobilized ee values nor the absolute configuration of the resolution
diatomaceous earth).[28] As reported in Table 1, only CAL- products were calculated.
Table 1. Lipase-catalyzed kinetic resolution of (Ϯ)-15.
Entry
Acylant[a]
Solvent[b]
CAL-B[g]
t
[h]
c[c]
[%]
(S,S)-16/17
ee [%][d]
(R,R)-15
ee [%][e]
E[f]
1
2
VA
VB
VB
VB
VB
DIPE
DIPE
THF
THF
TBME
19
17
25
19
17
58
60
45
46
57
50
42
91
89
50
75
99
81
75
98
6
11
53
39
12
3
4[h]
5
CAL-A[g]
6
7
VB
VA
THF
THF
24[i]
43
31
45
89
83
37
63
25
21
PS “Amano” IM[g]
8[h]
9
10
VA
VB
VB
DIPE
THF
TBME
39[i]
10
25
18
–
–
–
–
–
–
–
–
–
96[i]
52[i]
[a] VA: vinyl acetate, VB: vinyl butyrate. [b] Anhydrous solvents were used. [c] Reaction monitored by GLC and conversion determined
by 1H NMR spectroscopy. [d] Determined by HPLC analysis, after hydrolysis to (+)-15, on a HPLC Lux 5μ Cellulose-4 column
(250ϫ4.60 mm). [e] Determined by HPLC analysis on a HPLC Lux 5μ Cellulose-4 column (250ϫ4.60 mm). [f] E = enantiomeric ratio
calculated as reported in ref.[29]. [g] Reaction carried out on 0.4 mmol of substrate at 30 °C; substrate concentration: 0.8 m; enzyme (mg)/
substrate (mmol) ratio: 200 mg/mmol; 3.5 equiv. of acylant. [h] The reaction was carried out at 40 °C. [i] The reaction did not proceed
further and it was stopped.
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Eur. J. Org. Chem. 2014, 5448–5455

Synthesis of Both Enantiomers of trans-3-Hydroxypipecolic Acid
For the synthesis of (2R,3R)-3-hydroxypipecolic acid phosphates for the introduction of a C-2 substituent in the
(–)-1, resolution of (Ϯ)-15 was carried out on 200 mg of synthesis of pipecolic acids and the extension of this ap-
substrate and was stopped at a 57% of conversion to obtain proach to other piperidine derivatives is underway.
required (–)-(2R,3R)-15 in enantiopure form (99% ee) in
an acceptable yield (38% after chromatography). After the
lipase-catalyzed resolution, compound (–)-15 was acetyl-
Experimental Section
ated to give (–)-16 (90%) (Scheme 4) and then oxidized as
General: Chromatographic separations were performed under pres-
usual to afford (–)-13 in 72% yield after chromatography.
sure with silica gel 60 (Merck,70–230 mesh) by using flash column
Exhaustive deprotection was attained by treatment with
techniques; Rf values refer to TLC carried out on 0.25 mm silica
gel plates with the same eluent indicated for column chromatog-
HCl (6 n) at reflux temperatures to give (–)-(2R,3R)-1 as
the HCl salt in quantitative yield.
raphy. 1H NMR (400 and 200 MHz) and ppm. 13C NMR (50.33
and 100.4 MHz) spectra were recorded at 25 °C. Mass spectra were
carried out by direct inlet on a LCQ FleetTM Ion Trap LC/MS
system (Thermo Fisher Scientific) with an ESI interface in positive
mode. HPLC analyses were carried out with a Dionex Ultimate
3000 instrument. Compounds 10 and 14 are known.[19b]
tert-Butyl 6-[(Diphenoxyphosphoryl)oxy]-3,4-dihydropyridine-1(2H)-
carboxylate (9): A solution of potassium bis(trimethylsilyl)amide
(KHMDS) in toluene (0.5 m, 15.8 mL, 7.89 mmol) was diluted in
anhydrous THF (36 mL) and cooled to –78 °C. A solution of 8
(1.26 g, 6.31 mmol) in anhydrous THF (15 mL) was then added
dropwise, keeping the temperature below –70 °C, and the resulting
mixture was stirred for 1.5 h. A solution of diphenylchlorophos-
phate (1.63 mL, 7.89 mmol) in anhydrous THF (9 mL) was then
added dropwise and, after 1 h, the mixture was warmed to 0 °C.
Aqueous NaOH (10%, 150 mL) was slowly added and the product
extracted with Et2O (3ϫ100 mL). The combined organic extracts
were washed with NaOH (10%, 50 mL) and dried with K2CO3 for
40 min. After filtration and evaporation of the solvent, the crude
was purified with a short pad of silica gel (eluent: n-hexane/EtOAc,
3:1, 1% Et3N, Rf 0.30) to afford pure 9 in 96% yield as a pale
yellow oil (2.61 g, 6.05 mmol). 1H NMR (200 MHz): δ = 7.38–7.15
(m, 10 H, Ph), 5.10 (q, J = 3.3 Hz, 1 H, 3-H), 3.60–3.55 (m, 2 H,
6-H), 2.35–2.04 (m, 2 H, 4-H), 1.75–1.69 (m, 2 H, 5-H), 1.43 [s, 9
H, C(CH3)3] ppm.
Scheme 4. Reagents and conditions: (a) Et3N, DMAP, Ac2O,
CH2Cl2, room temp.; (b) NaIO4, RuCl3·xH2O, EtOAc/MeCN/H2O,
0 °C; (c) HCl (6 n), reflux, 3 h.
Its enantiomer was instead prepared by stopping the res-
olution at a 45% conversion, thus obtaining (+)-(2S,3S)-17
in 91% ee (37% yield) and with a suitable protection al-
ready installed on 3-OH group. After usual oxidation and
exhaustive deprotection (Scheme 4), (+)-(2S,3S)-1 was ob-
tained in quantitative yield as the HCl salt and with optical
rotation consistent to that reported for this enantiomer.[32]
By treating the residual substrate of the enzymatic kinetic
resolution with further CAL-B and vinyl butyrate, and by
stopping the reaction at a 18% conversion, enantiopure
(–)-(2R,3R)-15 (32% yield) was provided, which was con-
verted into pipecolic acid (–)-1 as described above.
tert-Butyl 6-Phenyl-3,4-dihydropyridine-1(2H)-carboxylate (10):[19b]
Aqueous Na2CO3 (2 m, 14.7 mL, 29.4 mmol), (Ph3P)2PdCl2
(77.9 mg, 0.11 mmol) and phenylboronic acid (406 mg, 3.33 mmol)
were added to a solution of 9 (958 mg, 2.22 mmol) in THF
(30 mL). The reaction was stirred and heated at 40 °C for 24 h. The
reaction was diluted with H2O (35 mL) and the product extracted
with Et2O (3ϫ35 mL). The combined organic layers were dried
with K2CO3. After filtration and evaporation of the solvent, crude
10 was purified by flash chromatography (eluent: n-hexane, then n-
hexane/EtOAc, 20:1, Rf 0.30) to afford pure 10 (445 mg,
Conclusions
1
1.72 mmol) in 77% yield. H NMR (200 MHz): δ = 7.70–7.16 (m,
In conclusion, we have reported a very short (six or seven
steps) and facile synthesis of both enantiomers of trans 3-
hydroxypipecolic acid based on the Suzuki–Miyaura reac-
tion of a lactam-derived enol phosphate and the lipase-cata-
5 H, Ph), 5.31 (t, J = 3.7 Hz, 1 H, 5-H), 3.73–3.68 (m, 2 H, 2-H),
2.26 (dt, J = 6.6, 3.7 Hz, 2 H, 4-H), 1.91–1.78 (m, 2 H, 3-H), 1.05
[s, 9 H, C(CH3)3] ppm.
lyzed kinetic resolution of the alcohol obtained by hydro- tert-Butyl 3-Hydroxy-2-phenylpiperidine-1-carboxylate [(؎)-11]: A
solution of (CH3)2S·BH3 in THF (2 m, 375 μL, 0.75 mmol) was
added to a solution of 10 (129 mg, 0.5 mmol) in anhydrous THF
(1 mL) at 0 °C and under N2 atmosphere. The cooling bath was
removed and the mixture was stirred at room temperature for 5 h.
The reaction was cooled to 0 °C and EtOH (550 μL), NaOH (3 m,
440 μL) and H2O2 (35%, 200 μL) were added. The resulting mix-
ture was heated to reflux for 1 h and, after cooling, it was transfer-
red into a flask that contained ice. The product was extract with
Et2O (4ϫ4 mL) and the combined organic extracts were dried with
Na2SO4. After filtration and evaporation of the solvent, the residue
boration/oxidation of the coupling product. The best en-
zyme for the racemate resolution was supported Candida
antarctica lipase, which preferentially catalyzed the acyl-
ation of the alcohol with 3S absolute configuration. Then,
the RuCl3-catalyzed oxidation of the heteroaryl group in-
troduced by Suzuki–Miyaura coupling afforded the target
compounds, which are obtained in 15–17% overall yield.
Despite a further oxidative step being required, the Suzuki–
Miyara coupling strategy proved an excellent alternative to
the alkoxycarbonylative process on lactam-derived enol was purified by chromatography (n-hexane/EtOAc, 2:1, Rf 0.26) to
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S. Begliomini, L. Sernissi, D. Scarpi, E. G. Occhiato
FULL PAPER
give (Ϯ)-11 (79 mg, 0.28 mmol) in 57% yield as a white solid. H
NMR (400 MHz): δ = 7.37–7.34 (m, 2 H, Ph), 7.27–7.25 (m, 1 H,
Ph), 7.25–7.19 (m, 2 H, Ph), 5.37 (br. s, 1 H, 2-H), 4.52 (br. m, 1
1
into a flask that contained ice and the product was extracted with
Et2O (4ϫ18 mL). The combined organic extracts were dried with
Na2SO4. After filtration and evaporation of the solvent, the residue
H, 3-H), 4.12–4.07 (br. d, J = 13.3 Hz, 1 H, 6-Heq), 2.87 (td, J = was purified by chromatography (n-hexane/EtOAc, 3:1, Rf = 0.20)
13.3, 3.3 Hz, 1 H, 6-Hax), 1.98–1.87 (m, 2 H, 5-H and OH), 1.78– to give (Ϯ)-15 (222 mg, 0.83 mmol) in 83% yield as a pale yellow
1.73 (m, 1 H, 4-H), 1.66–1.58 (m, 1 H, 4-HЈ), 1.48 [s, 9 H,
C(CH3)3], 1.43–1.39 (m, 1 H, 5-HЈ) ppm. 13C NMR (100.32 MHz):
δ = 156.3 (C=O), 137.8 (Cipso, Ph), 128.4 (2 C, Ph), 126.5 (C, Ph),
126.0 (2 C, Ph), 79.8 [C(CH3)3], 67.2 (CH-OH), 60.0 (CH-Ph), 39.6
(C-6), 28.1 [C(CH3)3], 25.7 (C-4), 18.6 (C-5) ppm. MS (ESI): m/z
(%) = 577 (100) [2M + Na]+, 300 (20) [M + Na]+. C16H23NO3
(277.36): calcd. C 69.29, H 8.36, N 5.05; found C 69.31, H 8.25, N
5.26.
oil.
Method B: To a stirred solution of 14 (219 mg, 0.82 mmol) in anhy-
drous THF (40 mL), a solution of BH3·THF in THF (1 m,
2.87 mL, 2.87 mmol) was added at –78 °C under nitrogen atmo-
sphere. After 15 min, the temperature was raised to 0 °C and the
reaction was stirred for 20 h. Then the mixture was warmed to
room temperature and Me3NO was added. The reaction was heated
at 65 °C for 2 h. After cooling, EtOAc (80 mL) was added and the
organic layer was washed with brine (2ϫ40 mL) and dried with
anhydrous Na2SO4. Chromatography (n-hexane/EtOAc, 3:1, Rf =
0.20) afforded pure (Ϯ)-15 (187 mg, 0.7 mmol) in 85% yield as a
colorless oil. 1H NMR (400 MHz): δ = 7.35 (dd, J = 1.8, 0.6 Hz, 1
H, 5Ј-H), 6.33 (dd, J = 3.3, 1.8 Hz, 1 H, 4Ј-H), 6.11 (d, J = 3.3 Hz,
1 H, 3Ј-H), 5.34 (br. s, 1 H, 2-H), 4.34 (br. m, 1 H, 3-H), 4.04–4.00
(br. d, J = 13.1 Hz, 1 H, 6-Heq), 2.87 (td, J = 13.1, 3.1 Hz, 1 H, 6-
Hax), 2.01 (br. s, 1 H, OH), 1.93–1.73 (m, 3 H, 5-H, 4-H, 4-HЈ),
tert-Butyl 3-(Acetyloxy)-2-phenylpiperidine-1-carboxylate [(؎)-12]:
Et3N (70 μL, 0.5 mmol) and 4-dimethylaminopyridine (DMAP;
6.5 mg, 0.053 mmol) were added to a solution of alcohol (Ϯ)-11
(70 mg, 0.25 mmol) in CH2Cl2 dry (1 mL) under an N2 atmosphere.
The mixture was cooled to 0 °C and acetic anhydride (43 μL,
0.46 mmol) was slowly added. The cooling bath was removed and
the reaction was stirred at room temperature for 18 h. After di-
lution with CH2Cl2 (5 mL), NaHCO3 satd. (5 mL) was added and
the aqueous phase was extract with CH2Cl2 (3ϫ4 mL). The com- 1.47 [s, 9 H, C(CH3)3], 1.45–1.42 (m, 1 H, 5-HЈ) ppm. 13C NMR
bined organic layers were dried with Na2SO4. After filtration and
evaporation of the solvent, the residue was purified by chromatog-
raphy (n-hexane/EtOAc, 8:1, Rf = 0.24) to give (Ϯ)-12 (75 mg,
0.24 mmol) in 94% yield as a pale yellow oil. 1H NMR (400 MHz):
(100.32 MHz): δ = 156.1 (N-CO), 151.9 (C-2Ј), 141. 7 (C-5Ј), 110.2
(C-4Ј), 107.0 (C-3Ј), 80.2 [C(CH3)3], 66.1 (C-3), 56.2 (C-2), 40.0 (C-
6), 28.4 [C(CH3)3], 26.8 (C-4), 18.8 (C-5) ppm. MS (ESI): m/z (%)
= 557 (48) [2M + Na]+, 290 (100) [M + Na]+. C14H21NO4 (267.32):
δ = 7.38–7.34 (m, 2 H, Ph), 7.27–7.24 (m, 2 H, Ph), 5.53–5.51 (br. calcd. C 62.90, H 7.92, N 5.24; found C 62.64, H 7.89, N 5.37.
m, 1 H, 3-H), 5.49 (s, 1 H, 2-H), 4.17–4.11 (br. d, J = 13.3 Hz, 1
tert-Butyl 3-(Acetyloxy)-2-(furan-2-yl)piperidine-1-carboxylate [(؎)-
H, 6-Heq), 2.88 (td, J = 13.3, 3.3 Hz, 1 H, 6-Hax), 2.12 (s, 3 H,
16]: Prepared as reported above for (Ϯ)-12. Starting from alcohol
O=CCH3), 1.93–1.87 (m, 1 H, 5-H), 1.85–1.80 (m, 1 H, 4-H), 1.69–
(Ϯ)-15 (178 mg, 0.67 mmol), (Ϯ)-16 (160 mg, 0.6 mmol) was ob-
1.60 (m, 1 H, 4-HЈ), 1.45 [s, 9 H, C(CH3)3], 1.43–1.39 (m, 1 H, 5-
tained in 90% yield after chromatography (n-hexane/EtOAc, 6:1,
Rf = 0.21) as a colorless oil. H NMR (400 MHz): δ = 7.36 (dd, J
HЈ) ppm. 13C NMR (100.32 MHz): δ = 170.5 (O=CCH3), 156.0
(N-C=O), 137.6 (Cipso, Ph), 128.7 (2 C, Ph), 127 (C, Ph), 126.3 (2
1
= 1.8, 1.0 Hz, 1 H, 5Ј-H), 6.33 (dd, J = 3.3, 1.8 Hz, 1 H, 4Ј-H),
C, Ph), 79.8 [C(CH3)3], 70.1 (C-3), 57 (C-2), 39.7 (C-6), 28.4
6.15 (dd, J = 3.3, 1.0 Hz, 1 H, 3Ј-H), 5.44 (br. s, 1 H, 3-H), 5.32
[C(CH3)3], 23.9 (C-4), 21.3 (CH3C=O), 19.5 (C-5) ppm. MS (ESI):
(br. s, 1 H, 2-H), 4.07 (br. d, J = 12.7 Hz, 1 H, 6-Heq), 2.88 (br. t,
m/z (%) = 661 (100) [2M + Na]+, 342 (27) [M + Na]+. MS/MS
J = 12.7 Hz, 1 H, 6-Hax), 2.08 (s, 3 H, O=CCH3), 1.86–1.73 (m, 3
(ESI of [M + Na]+): m/z (%) = 342 (3) [M + Na]+, 286 (100), 242
H, 5-H, 4-H and 4-HЈ), 1.48–1.42 [s, 9 H, C(CH3)3 and m, 1 H, 5-
(9), 182 (11). C18H25NO4 (319.40): calcd. C 67.69, H 7.89, N 4.39;
found C 67.63, H 7.66, N 4.69.
HЈ] ppm. 13C NMR (100.32 MHz): δ = 170.3 (O=CCH3), 155.4 (N-
C=O), 151.1 (C-2Ј), 141.9 (C-5Ј), 110.3 (C-4Ј), 107.4 (C-3Ј), 80.0
tert-Butyl
6-(Furan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate
[C(CH3)3], 68.4 (C-3), 53.1 (C-2), 39.7 (C-6), 28.4 [C(CH3)3], 24.7
(14):[19b] Aqueous Na2CO3 (2 m, 24.4 mL, 48.8 mmol), (Ph3P)2- (C-4), 21.2 (O=CCH3), 19.5 (C-5) ppm. MS (ESI): m/z (%) = 641
PdCl2 (130 mg, 0.185 mmol) and 2-furanylboronic acid (621 mg,
5.55 mmol) were added to a solution of 9 (1.6 g, 3.73 mmol) in
THF (48 mL). The mixture was heated at 40 °C for 2 h, then was
diluted with H2O (68 mL) and the product extracted with Et2O
(3ϫ68 mL). The combined organic layers were dried with K2CO3.
After filtration and evaporation of the solvent, crude 14 was puri-
fied by flash chromatography (eluent: n-hexane/EtOAc, 20:1, then
n-hexane/EtOAc, 10:1, Rf 0.48) to afford pure 14 (755 mg,
(100) [2M + Na]+, 332 (69) [M + Na]+. MS/MS (ESI of [M +
Na]+): m/z (%) = 332 (10) [M + Na]+, 276 (100), 232 (15), 172 (11).
C16H23NO5 (309.36): calcd. C 62.12, H 7.49, N 4.53; found C
61.93, H 7.22, N 4.69.
3-(Acetyloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic Acid
[(؎)-13]: To a solution of NaIO4 (734 mg, 3.43 mmol) in EtOAc
(3.5 mL)/CH3CN (5.7 mL)/H2O (2.8 mL) cooled to 0 °C,
RuCl3·xH2O (2 mg, 0.01 mmol) was added. The reaction was left
stirred at 0 °C for 15 min, then a solution of (Ϯ)-16 (153 mg,
0.49 mmol) in EtOAc (2.8 mL) was slowly added. After 5 min at
0 °C, H2O (12 mL) was added and the product was extract with
EtOAc (2ϫ16 mL). The combined organic layers were dried with
anhydrous Na2SO4 and the crude product was purified by
1
3.03 mmol) in 82% yield. H NMR (200 MHz): δ = 7.32 (dd, J =
1.8, 0.7 Hz, 1 H, 5Ј-H), 6.35 (dd, J = 3.3, 1.8 Hz, 1 H,4Ј-H), 6.22
(d, J = 3.3 Hz, 1 H, 3Ј-H), 5.52 (t, J = 4.0 Hz, 1 H,5-H), 3.68–3.63
(m, 2 H, 2-H), 2.26 (td, J = 7.0, 4.0 Hz, 2 H, 4-H), 1.91–1.82 (m,
2 H, 3-H), 1.26 [s, 9 H, C(CH3)3] ppm.
tert-Butyl 2-(Furan-2-yl)-3-hydroxypiperidine-1-carboxylate [(؎)- chromatography (CH2Cl2/MeOH, 40:1 + 0.1% AcOH, Rf = 0.50)
15]. Method A: A solution of (CH3)2S·BH3 in THF (2 m, 1 mL, to give (Ϯ)-13 (98 mg, 0.34 mmol) in 70% yield as a yellow gummy
2 mmol) was added to a solution of 14 (250 mg, 1 mmol) in anhy- solid. H NMR (400 MHz): δ = (1:1 mixture of rotamers) = 10.78
1
drous THF (2 mL) at 0 °C under N2 atmosphere. The cooling bath
was removed and the mixture was stirred at room temperature for
4 h. The reaction was cooled to 0 °C and EtOH (1.1 mL), NaOH
(3 n, 900 μL) and H2O2 (35%, 390 μL) were added. The resulting
mixture was heated to reflux for 1 h. The solution was transferred
(br. s, 1 H, COOH), 5.43 (br. s, 1 H, 3-H, rotamer A), 5.34 (br. s,
1 H, 3-H, rotamer B), 5.07 (br. s, 2-H, rotamer A), 4.99 (br. s, 2-
H, rotamer B), 4.11 (br. d, J = 12.5 Hz, 1 H, 6-Heq, rotamer A),
3.97 (br. d, J = 12.5 Hz, 1 H, 6-Heq, rotamer B), 2.97 (br. t, J =
12.5 Hz, 1 H, 6-Hax, rotamer A), 2.85 (br. t, J = 12.5 Hz, 1 H, 6-
5452
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5448–5455

Synthesis of Both Enantiomers of trans-3-Hydroxypipecolic Acid
Hax, rotamer B), 2.06 (s, 3 H, O=CH3, rotamer A), 2.04 (s, 3 H,
O=CH3, rotamer B), 1.94–1.20 (m, 4 H, 4-H and 5-H, both rota-
mers) 1.45 [s, 9 H, C(CH3)3, rotamer A], 1.41 [s, 9 H, C(CH3)3,
rotamer B] ppm. 13C NMR (100.32 MHz): δ = (1:1 mixture of rota-
mers) = 177.3, 173.8 and 170.4 (COOH and O=CCH3, both rota-
mers), 156.3 (N-C=O, rotamer A), 155.3 (N-C=O, rotamer B), 80.7
[C(CH3)3], 67.9 (C-3, rotamer A), 67.3 (C-3, rotamer B), 57.9 (C-
2, rotamer A), 57.1 (C-2, rotamer B), 41.7 (C-6, rotamer A), 40.5
(C-6, rotamer B), 28.3 [C(CH3)3], 25.4 (C-4), 21.1 (O=CCH3, rot-
in THF (2.6 mL) at 30 °C was added CAL-B (400 mg). After
10 min, vinyl butyrate (889 μL, 7 mmol) was added and the reac-
tion was left to stir and monitored by GLC. After 25 h, the conver-
sion reached 45 % and the reaction was stopped by filtration
through a thin layer of Celite. After evaporation, the crude product
was purified by chromatography (n-hexane/EtOAc, 6:1 then n-hex-
ane/EtOAc, 3:1) to give (+)-17 (250 mg, 0.74 mmol, Rf 0.21) in 37%
yield (ee 91%), and (–)-15 (259 mg, 0.97 mmol, Rf 0.26). To a solu-
tion of (–)-15 (259 mg, 0.97 mmol) in THF (1.5 mL) at 30 °C was
amer A), 20.8 (O=CCH3, rotamer B), 18.9 (C-5, rotamer A), 18.8 added CAL-B (236 mg). After 10 min, vinyl butyrate (524 μL,
(C-5, rotamer B) ppm. MS (ESI): m/z (%) = 597 (100) [2M +
Na]+, 310 (96) [M + Na]+. MS/MS (ESI of [M + Na]+): m/z (%) =
310 (3) [M + Na]+, 254 (100), 210 (49). C13H21NO6 (287.31): calcd.
C 54.35, H 7.37, N 4.88; found C 54.11, H 7.19, N 4.95.
4.13 mmol) was added and the reaction was left to stir vigorously
and monitored by GLC. When the conversion reached 18% the
reaction was stopped by filtration through a thin layer of Celite.
After evaporation, the crude product was purified by chromatog-
raphy (n-hexane/EtOAc, 3:1, Rf 0.26) to give enantiopure (–)-15
(171 mg, 0.64 mmol) in 32% yield as a colorless oil.
3-Hydroxypiperidine-2-carboxylic Acid Hydrochloride [(؎)-1·HCl]:
A solution of (Ϯ)-13 (93 mg, 0.32 mmol) in HCl (6 n, 9 mL) was
heated to reflux for 2 h. The reaction was then cooled to room
temperature and the solvent was evaporated under vacuum. The
residue was triturated with Et2O (2ϫ5 mL), and the organic phase
was discarded to obtain (Ϯ)-1·HCl (100%) as a pale yellow solid.
1H NMR (400 MHz): δ = 3.95–3.91 (m, 1 H, 3-H), 3.66 (d, J =
8.2 Hz, 2-H), 3.20–3.15 (m, 1 H, 6-H), 2.91–2.85 (m, 1 H, 6-HЈ),
1.86–1.78 (m, 2 H, 4-H and 5-H), 1.59–1.44 (m, 2 H, 4-HЈ and 5-
HЈ) ppm. 13C NMR (100.32 MHz): δ = 169.6 (COOH), 65.5 (C-3),
60.7 (C-2), 42.6 (C-6), 28.9 (C-4), 18.6 (C-5) ppm.
(+)-17: [α]2D3 = +31.7 (c = 0.82, CHCl3). H NMR (400 MHz): δ =
1
7.36 (d, J = 1.2 Hz, 1 H, 5Ј-H), 6.33 (dd, J = 3.1, 2.0 Hz, 1 H, 4Ј-
H), 6.15 (dd, J = 2.0, 1.2 Hz, 1 H, 3Ј-H), 5.42 (br. s, 1 H, 3-H),
5.34 (br. s, 1 H, 2-H), 4.08 (br. d, J = 12.5 Hz, 1 H, 6-Heq), 2.88
(br. t, J = 12.5 Hz, 1 H, 6-Hax), 2.32 (t, J = 7.4 Hz, 2 H, OC-
OCH2CH2), 1.86–1.76 (m, 3 H, 5-H, 4-H and 4-HЈ), 1.72–1.60 (m,
2 H, -CH2CH2CH3), 1.47–1.44 [s, 9 H, C(CH3)3 and m, 1 H, 5-
HЈ] ppm. 13C NMR (100.32 MHz): δ = 173.0 (O=CCH2), 155.4 (N-
C=O), 151.2 (C-2Ј), 142.1 (C-5Ј), 110.4 (C-4Ј), 107.4 (C-3Ј), 80.0
[C(CH3)3], 68.2 (C-3), 53.3 (C-2), 39.8 (C-6), 36.5 (O=CCH2CH2),
28.5 [C(CH3)3], 24.8 (C-4), 19.7 (C-5), 18.6 (-CH2CH2CH3), 13.8
(-CH2CH3) ppm. MS (ESI): m/z (%) = 697 (100) [2M + Na]+, 360
(28) [M + Na]+. C18H27NO5 (337.41): calcd. C 64.07, H 8.07, N
4.15; found C 63.78, H 7.93, N 4.22.
Kinetic Resolution of (؎)-15 with CAL-B
tert-Butyl (R,R)-2-(Furan-2-yl)-3-hydroxypiperidine-1-carboxylate
[(–)-15]: To a solution of (Ϯ)-15 (200 mg, 0.74 mmol) in diisopropyl
ether (940 μL) at 30 °C was added CAL-B (148 mg). After 10 min,
vinyl butyrate (330 μL, 2.6 mmol) was added and the reaction was
left to stir and monitored by GLC. After 17 h, the conversion
reached 57% and the reaction was stopped by filtration through a
thin layer of Celite. After evaporation, the crude product was puri-
fied by chromatography (n-hexane/EtOAc, 6:1, then n-hexane/
EtOAc, 3:1, Rf 0.26) to give (–)-15 (75 mg, 0.28 mmol) in 38% yield
(99% ee).
(S,S)-3-(Butyryloxy)-1-(tert-butoxycarbonyl)piperidine-2-carb-
oxylic Acid [(+)-18]: Prepared as reported above for (Ϯ)-13. Start-
ing from (+)-17 (190 mg, 0.56 mmol), product (+)-18 (114 mg,
65%) was obtained as a yellow gummy solid. [α]2D0 = +12.4 (c =
1
1.1, CHCl3). H NMR (400 MHz): δ = (1:1 mixture of rotamers)
= 9.17 (br. s, 1 H, COOH), 5.45 (br. s, 1 H, 3-H, rotamer A), 5.36
(br. s, 1 H, 3-H, rotamer B), 5.09 (br. s, 2-H, rotamer A), 5.00 (br.
s, 2-H, rotamer B), 4.14 (br. d, J = 12.3 Hz, 1 H, 6-Heq, rotamer
A), 3.99 (br. d, J = 12.3 Hz, 1 H, 6-Heq, rotamer B), 3.00 (br. t, J
= 12.3 Hz, 1 H, 6-Hax, rotamer A), 2.86 (br. t, J = 12.3 Hz, 1 H,
6-Hax, rotamer B), 2.31–2.30 (br. m, 2 H, O=CH2CH3, both rota-
mers), 1.67–1.60 (br. m, 2 H, CH2CH2CH3), 1.47 [s, 9 H, C-
(CH3)3, rotamer A], 1.43 [s, 9 H, C(CH3)3, rotamer B], 1.94–1.20
(m, 4 H, 4-H and 5-H, both rotamers), 0.96–0.93 (br. m, 3 H,
CH2CH3) ppm. 13C NMR (100.32 MHz): δ = 173.8, 172.9 and
172.7 (COOH and O=CCH2, both rotamers), 156.1 (N-C=O, rot-
amer A), 155.3 (N-C=O, rotamer B), 80.7 [C(CH3)3], 67.4 (C-3,
rotamer A), 67.3 (C-3, rotamer B), 57.9 (C-2, rotamer A), 57.1 (C-
2, rotamer B), 41.6 (C-6, rotamer A), 40.3 (C-6, rotamer B), 36.3
(O=CCH2CH2), 28.2 [C(CH3)3], 25.4 (C-4), 18.9 (C-5, rotamer A),
18.8 (C-5, rotamer B), 18.5 (CH2CH2CH3, rotamer A), 18.4
(CH2CH2CH3, rotamer B), 13.6 (CH2CH3) ppm. MS (ESI): m/z
(%) = 984 (100) [3M + K]+, 669 (70) [2M + K]+, 653 (59) [2M +
Na]+, 338 (19) [M + Na]+. C15H25NO6 (315.36): calcd. C 57.13, H
7.99, N 4.44; found C 57.45, H 7.81, N 4.28.
(–)-15: [α]1D8 = –77.3 (c = 1.1, CHCl3). Spectroscopic data identical
to those reported above for (Ϯ)-15.
tert-Butyl (R,R)-3-(Acetyloxy)-2-(furan-2-yl)piperidine-1-carboxyl-
ate [(–)-16]: Prepared as reported above for (Ϯ)-16. Starting from
(–)-15 (70 mg, 0.26 mmol), (–)-16 (72 mg, 0.23 mmol) was obtained
after chromatography (n-hexane/EtOAc, 6:1, Rf 0.21) in 90% yield
as a colorless oil. [α]2D1 = –45.9 (c = 1.0, CHCl3). Spectroscopic data
identical to those reported above for (Ϯ)-16.
(R,R)-3-(Acetyloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic
Acid [(–)-13]: Prepared as reported above for (Ϯ)-13. Starting from
(–)-16 (70 mg, 0.23 mmol), (–)-13 (49 mg, 0.17 mmol) was obtained
after chromatography (CH2Cl2/MeOH, 20:1 with 0.1% AcOH, Rf
0.19) in 72% yield. [α]2D2 = –15.7 (c = 1.0, CHCl3). Spectroscopic
data identical to those reported above for (Ϯ)-13.
(R,R)-3-Hydroxypiperidine-2-carboxylic Acid Hydrochloride [(–)-
1·HCl]:[30] Prepared as reported above for (Ϯ)-1·HCl. Starting from
(–)-13 (49 mg, 0.17 mmol), (–)-1·HCl (31 mg, 0.17 mmol) was ob-
tained as a light yellow solid in quantitative yield. [α]2D1 = –14.9 (c
= 1.4, water). Spectroscopic data identical to those reported above
for (Ϯ)-1·HCl.
(S,S)-3-Hydroxypiperidine-2-carboxylic Acid Hydrochloride [(+)-
1·HCl]:[32] Prepared as reported above for (Ϯ)-1·HCl. Starting from
(+)-18 (100 mg, 0.32 mmol), compound (+)-1·HCl (58 mg,
0.32 mmol) was obtained as a light yellow solid. [α]2D1 = +13.7 (c =
0.7, water). Spectroscopic data as reported above for (Ϯ)-1·HCl.
Two-Step Lipase-Catalyzed Kinetic Resolution of (؎)-15
tert-Butyl (R,R)-2-(Furan-2-yl)-3-hydroxypiperidine-1-carboxylate
[(–)-15] and tert-Butyl (S,S)-3-(Butyryloxy)-2-(furan-2-yl)piperidine-
1-carboxylate [(+)-17]: To a solution of (Ϯ)-15 (540 mg, 2 mmol)
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR and 13C NMR spectra for all new
Eur. J. Org. Chem. 2014, 5448–5455
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5453

S. Begliomini, L. Sernissi, D. Scarpi, E. G. Occhiato
FULL PAPER
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Acknowledgments
Dott. Andrea Casini is acknowledged for carrying out preliminary
experiments and Università di Firenze for financial support. Am-
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www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5448–5455

Synthesis of Both Enantiomers of trans-3-Hydroxypipecolic Acid
B. Danieli, G. Palmisano, S. Riva, M. Santagostino, Tetrahe-
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[29] The enantioselectivity in an enzymatic kinetic resolution pro-
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between the specificity constants (kcat/KM) of the enzyme for
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rotation values are [α]2D3 = +14.5 (c = 0.4, H2O), see: a) B.
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Wang, R.-H. Liu, Eur. J. Org. Chem. 2009, 2845; and [α]2D5
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X. Ginesta, A. Riera, Eur. J. Org. Chem. 2008, 1789.
+14.2 (c = 0.95, H2O), see: b) N. Liang, A. Datta, J. Org.
Chem. 2005, 70, 10182.
Received: March 13, 2014
Published Online: June 16, 2014
Eur. J. Org. Chem. 2014, 5448–5455
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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