Asymmetric synthesis of cis-4- and trans-3-hydroxypipecolic acids

Article abstract of DOI:10.1002/ejoc.200701103

Enantioselective syntheses of cis-4- and trans-3-hydroxypipecolic acids from 2,3-epoxy-5-hexen-1-ol (7) are described. Regioselective C-3 or C-2 ring opening of the epoxide by the appropriate nitrogen nucleophile is the key step in each route. As enantiom

Full text of DOI:10.1002/ejoc.200701103

FULL PAPER
DOI: 10.1002/ejoc.200701103
Asymmetric Synthesis of cis-4- and trans-3-Hydroxypipecolic Acids
Carlos Alegret,[a] Xavier Ginesta,[a] and Antoni Riera*[a]
Keywords: Epoxidation / Asymmetric synthesis / Ring-opening / Natural products
Enantioselective syntheses of cis-4- and trans-3-hydroxypi- both enantiomers are equally accessible. This approach was
pecolic acids from 2,3-epoxy-5-hexen-1-ol (7) are described.
Regioselective C-3 or C-2 ring opening of the epoxide by the
appropriate nitrogen nucleophile is the key step in each
route. As enantiomerically enriched epoxy alcohols are read-
ily available in any configuration by Sharpless epoxidation,
also employed to synthesize the natural product baikiain and
the important synthetic intermediate trans-3-hydroxy-2-hy-
droxymethylpiperidine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Functionalized chiral piperidines are ubiquitous in na-
ture and are also pharmacologically important synthetic
products.[1] Hydroxylated piperidine alkaloids in organisms
possess a wide range of biological activities, mainly due to
their ability to mimic carbohydrate substrates in a variety
of enzymatic processes.[2] Cyclic α-amino acids are also
present in many biologically important compounds.[3] In
particular, hydroxypipecolic acids can be considered as ex-
panded hydroxylated homoprolines or as constrained serine
derivatives. As such, replacement of natural amino acids in
bioactive compounds with this fragment may affect the
physiological and pathological processes in which they are
involved.[4] Therefore, it is not surprising that much effort
has been directed towards the development of efficient syn-
theses of pipecolic acid derivatives.[5]
Figure 1. Structures of cis-4-hydroxypipecolic acid (1), trans-3-hy-
droxypipecolic acid (2) and trans-3-hydroxy-2-hydroxymehtylpiper-
idine (3).
(–)-cis-4-Hydroxypipecolic acid [(–)-1] (Figure 1), iso-
lated from the leaves of Calliandra pittieri and Strophantus
scandeus,[6] has been identified as a constituent of cyclopep-
tide antibiotics such as virginiamycin S2.[7] It has also been
employed as a precursor in the preparation of selective N-
methyl--aspartate (NMDA) receptor antagonists[8] and in
the synthesis of palinavir, a potent peptidomimetic-based
HIV protease inhibitor (Figure 2).[9]
(–)-trans-3-Hydroxypipecolic acid [(–)-2] is a nonnatural
cyclic β-hydroxy-α-amino acid that has been used as a pre-
cursor in the synthesis of (–)-swainsonine, a potent and spe-
cific inhibitor of α--mannosidase.[10] Its enantiomer (+)-2
is found in (+)-febrifugine, a potent antimalarial agent,[11]
Figure 2. The structures of palinavir, febrifugine, prosopinine and
swainsonine.
and its reduced derivative (+)-3 has been used for the prepa-
ration of (+)-prosopinine, which exhibits analgesic, anaes-
thetic and antibiotic activities.[12] Both cis-4-hydroxy-
pipecolic[8b,13] and trans-3-hydroxypipecolic[4b,11,14] acids, as
well as several N- and/or O-protected analogues of
3,[11,12,14a–d,15] have been the target of several synthetic stra-
tegies. However, the majority of these are racemic syntheses
or require either chiral building blocks or enzymatic resolu-
[a] Unitat de Recerca en Síntesi Asimètrica (URSA-PCB), Institute
for Research in Biomedicine (IRB, Barcelona) and De-
partament de Química Orgànica, Universitat de Barcelona,
Parc Científic de Barcelona, c/ Josep Samitier 1–5, 08028 Barce-
lona, Spain
Fax: +34-93-403-70-95
E-mail: ariera@pcb.ub.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 1789–1796
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Alegret, X. Ginesta, A. Riera
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tion. Indeed, only a few stereoselective syntheses in which with allylamine by using the conditions of Crotti,[21] fol-
all the stereogenic centres are constructed by asymmetric lowed by Boc protection, RCM (2ϫ4 mol-% of first gener-
synthesis have been reported for 1,[13l] 2 and 3.[14a–14d,14o,15e] ation Grubbs’ catalyst) and two-step oxidative cleavage of
During the past few years our research group has worked the diol (NaIO4 to yield the aldehyde, which is then oxid-
towards the synthesis of several types of amino acids and ized with sodium chlorite)[22] to avoid oxidation of the
cyclic amino alcohols by using epoxy alcohols as a source double bond. N-Boc baikiain (4)[23] was thus obtained in
of chirality,[16,17] because they are readily available in any 99%ee after recrystallization. Iodolactonization of 4 by
configuration through Sharpless epoxidation.[18] The C-2 standard procedures proceeded with excellent yield.[24] Io-
ring opening of an epoxy alcohol leads to 2-amino-1,3-diols dide elimination followed by lactone hydrolysis afforded the
with anti stereoselectivity, which is ideally suited for the desired N-protected cis-4-hydroxypipecolic acid (N-Boc-1)
preparation of trans-3-hydroxypipecolic acids by appropri- in good yield and excellent enantiomeric purity (Scheme 2).
ate cyclization. Alternatively, C-3 ring opening leads to 3-
amino-1,2-diols, which are amenable to the preparation of
pipecolic acids or derivatives through the use of ring-closing
metathesis (RCM).[19] We describe here the syntheses of cis-
4- and trans-3-hydroxypipecolic acids from 2,3-epoxy-5-
hexen-1-ol according to the retrosynthetic analysis outlined
in Scheme 1.
Scheme 2. Synthesis of N-Boc-cis-4-hydroxypipecolic acid (N-Boc-
1).
Epoxy alcohol 7 was subjected to a completely regiose-
lective C-2 ring opening to afford 12 (Scheme 3) in excellent
overall yield (86% over two steps).[25] Only 7% of the trans-
1
acylated isomer was observed by H NMR spectroscopy.
Cyclic carbamate 12 was deprotected under basic condi-
tions, and the resulting diol was protected by using TBSOTf
in high yield. Subsequent regioselective, oxidative hydrobor-
ation of the terminal olefin by using 9-BBN to afford 8a
also proceeded with good yield and high selectivity (95:5).
At this point, we explored two different pathways, de-
pending on the N-protecting group used prior to the cycli-
zation. With a benzyl protecting group, direct cyclization
under Mitsunobu conditions[26] yielded 3a (40%), but only
in moderate yield. This yield was improved by mesylation
of the primary alcohol and in situ cyclization. Subsequent
Scheme 1. Retrosynthetic analysis of pipecolic acid derivatives 1
and 2.
Results and Discussion
Our syntheses started from 2,3-epoxy-5-hexen-1-ol (7), hydrogenation of the benzyl group and simultaneous pro-
which was readily available by Sharpless epoxidation of 2,5- tection of the free amine with Boc2O gave compound 3b.[27]
hexadien-1-ol (prepared from propargyl alcohol and allyl
Alternatively, compound 3b was also obtained by chang-
bromide by using a modified literature procedure).[20] Enan- ing the protecting group before cyclization. Hydrogenation
tiomerically enriched 7 was obtained in 63% overall yield of the benzyl group of 8a, followed by protection of the free
(three steps) and 93%ee by working on a 50-g scale. It was amine with Boc2O, yielded compound 8b. Higher yields
then subjected to the five-step procedure shown in were obtained by performing these two reactions separately,
Scheme 2, which we developed in our preliminary com- because of the formation of an N-Bn–N-Boc byproduct,
munication, to yield N-Boc-protected baikiain (4).[17] The which was not hydrogenated under the reaction conditions.
sequence involves regioselective (10:1) C-3 ring opening With compound 8b in hand, the primary alcohol was acti-
1790
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1789–1796

Asymmetric Synthesis of cis-4- and trans-3-Hydroxypipecolic Acids
Experimental Section
General Methods: Dry solvents were distilled before use (DCM over
CaH; toluene, Et2O and THF over Na). All reagents were used as
received. All reactions were performed in flame-dried glassware un-
der an atmosphere of nitrogen. Optical rotations were measured at
room temperature (23 °C), and concentrations are reported in g per
100 mL. Infrared spectra were recorded by using NaCl films. 1H
NMR spectra were obtained at 400 MHz with tetramethylsilane as
internal standard. 13C NMR spectra were obtained at 100.6 MHz
and referenced to the solvent signal. Chemical shifts are recorded
in ppm. Signals marked with an asterisk correspond to rotamers.
Chromatographic separations were performed with SiO2 (70–
230 mesh) pretreated with NEt3 (2.5%v/v) by eluting with increas-
ing polarity mixtures of hexane/ethyl acetate. Compound 7 was pre-
pared according to a literature procedure.[20]
(2S,3S)-N-Allyl-N-tert-butoxycarbonyl-3-amino-5-hexen-1,2-diol
(6): To a solution of epoxy alcohol [(+)-7, 1.50 g, 13.2 mmol] in
acetonitrile (35 mL) was added LiClO4 (21.0 g, 195 mmol) with
stirring. After 15 min, allylamine (9.8 mL, 132 mmol) was added,
and the reaction was warmed to 65 °C. After 16 h, the solution was
cooled to room temperature and water (100 mL) was added. The
mixture was extracted with DCM (3ϫ100 mL). The combined or-
ganic layer was dried with MgSO4, and concentrated in vacuo and
then redissolved in MeOH (70 mL). To this solution was added
NaHCO3 (3.27 g, 39.6 mmol) and Boc2O (3.38 g, 15.5 mmol) in
acetonitrile (8 mL). After 16 h, the reaction mixture was filtered
and then concentrated in vacuo. The crude product was dissolved
in Et2O (60 mL), filtered again and concentrated in vacuo. Column
chromatography yielded 6 (2.11 g, 60 % yield over 2 steps) as a
colourless oil. Rf (hexane/EtOAc, 1:1) = 0.44. [α]D = +1.6 (c = 1.0,
Scheme 3. Synthesis of piperidines 3.
vated with MsCl so that it could undergo cyclization. Al-
though the use of NEt3 or catalytic 4-DMAP did not pro-
mote cyclization, treatment with stronger bases afforded pi-
peridine 3b in moderate-to-good yields (61–69% by using
NaH in THF/DMF or 72% by using tBuOK in THF). Fi-
nally, selective deprotection of the primary alcohol with
catalytic p-TsOH, followed by oxidation of the free alcohol
and total acidic hydrolysis, gave the trans-3-hydroxy-
pipecolic acid hydrochloride [(–)-2·HCl] in good yield[14c]
(Scheme 4).
CHCl ). IR (film): ν = 3424, 2932, 2979, 1694, 1667 cm–1. 1H NMR
˜
3
(400 MHz, CDCl3): δ = 1.46 (s, 9 H, OtBu), 2.40–2.54 (m, 1 H, 4-
Ha), 2.58–2.71 (m, 1 H, 4-Hb), 3.10 (br. s, 1 H, OH), 3.30 (br. s, 1
H, OH), 3.50–3.66 (m, 3 H, 1-H and 2-H), 3.70 (d, 3JH,H = 6.1 Hz,
2 H, NCH2CHCH2), 3.73–3.85 (m, 1 H, 3-H), 5.03–5.20 (m, 4 H,
CH2=CH-C), 5.69–5.82 (m, 2 H, CH2=CH-C) ppm. 13C NMR
(100 MHz, CDCl3): δ = 28.5 (OCMe3), 32.2 (CH2-2), 48.5
(NCH2CHCH2), 58.4 (CH-3), 63.4 (CH2-1), 73.6 (CH-2), 81.0
(OCMe3), 117.1 (CH2=CH-C), 117.3 (CH2=CH-C), 135.1
(CH2=CH-C), 135.5 (CH2=CH-C), 157.5 (NC=O) ppm. HRMS
(CI+): calcd. for C14H26NO4 272.1862; found 272.1858.
(S)-N-tert-Butoxycarbonyl-1-[(S)-1Ј,2Ј,3Ј,6Ј-tetrahydropyridin-2-yl]-
ethan-1,2-diol (5): To a stirring solution of a 6 (1.00 g, 3.71 mmol)
in dry DCM (400 mL) at room temperature was added the first
generation Grubbs catalyst (0.091 g, 3 mol-%) in dry DCM
(10 mL). After 4 h, the first generation Grubbs catalyst (0.091 g,
3 mol-%) in dry DCM (10 mL) was added again. After 15 h, the
solvent was evaporated in vacuo, and the crude product was puri-
fied by column chromatography to yield 5 (0.658 g, 73%) as a white
solid. Recrystallization of this solid from hot hexane gave 5 in
99%ee (determined by HPLC of a subsequently formed derivative).
Rf (hexane/EtOAc, 1:1) = 0.20. [α]D = +39.5 (c = 1.0, CHCl3). M.p.
Scheme 4. Synthesis of (–)-2·HCl.
92–93 °C. IR (film): ν = 3418, 2975, 2931, 1693 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 1.48 (s, 9 H, OtBu), 2.26–2.40 (m, 1 H, 6Ј-
Ha), 2.62 (dd, JH,H = 16.7 Hz, JH,H = 5.0 Hz, 1 H, 6Ј-Hb), 3.34–
3.80 (m, 4 H, 3Ј-Ha, 1-H and 2-H), 4.05–4.23 (m, 2 H, 1Ј-H and
3Ј-Hb), 5.58–5.86 (m, 1 H, CH=CH), 5.76–5.86 (m, 1 H, CH=CH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 24.5 (CH2-6Ј), 28.5
(OCMe3), 41.5 (CH2-3Ј), 48.6 (CH-1Ј), 62.7 (CH2-2), 69.8 (CH-1),
81.1 (OCMe3), 122.2 (CH=CH), 123.5 (CH=CH), 157.0 (NC=O)
ppm. MS (FA+): m/z (%) = 266 (30) [M + Na]+, 244 (40)
2
3
Conclusions
We developed two enantioselective entries to cis-4- and
trans-3-hydroxypipecolic acids with complete control of the
stereochemistry of both stereogenic centres. Diversely pro-
tected piperidines 3, key intermediates for a variety of bio-
logically active products, were also synthesized.
Eur. J. Org. Chem. 2008, 1789–1796
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Alegret, X. Ginesta, A. Riera
[M + H]+, 188 [(M – 55)]+, 100. HRMS (CI+): calcd. for monitoring), the reaction mixture was cooled to room temperature,
FULL PAPER
C12H22NO4 244.1549; found 244.1555.
and DCM (5 mL) and a solution of aqueous KF (10%, 10 mL)
were added. After 30 min, the reaction mixture was filtered through
Celite. The aqueous layer was extracted with DCM, and the com-
bined organic layer was dried with MgSO4 and concentrated in
vacuo. The crude product was purified by flash chromatography to
yield 11 (0.195 g, 76%) as a white solid. Rf (hexane/EtOAc, 3:1) =
0.47. [α]D = –133.0 (c = 0.8, CHCl3) [ref.[13m] –136.9 (c = 1.075,
(S)-N-tert-Butoxycarbonylbaikiain (4): To a solution of 5 (6.05 g,
24.9 mmol) in THF/H2O (1:3, 75 mL) whilst stirring was added
NaIO4 (7.98 g, 37.3 mmol). After 2 h at room temperature (TLC
monitoring), H2O (50 mL) and EtOAc (50 mL) were added. The
aqueous layer was extracted with EtOAc (3ϫ20 mL). The com-
bined organic layer was dried with MgSO4 and concentrated in
vacuo. The crude product was used in subsequent chemistry with-
CHCl3)]. M.p. 142–144 °C (ref.[13m] 144–145 °C). IR (film): ν =
˜
1775, 1685 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.48 (s, 9 H,
1
out further purification. H NMR (200 MHz, CDCl3): δ =1.50 (s,
2
3
3
OtBu), 1.88 (dddd, JH,H = 13.7 Hz, JH,H = 11.6 Hz, JH,H
=
9 H, OtBu), 2.40–2.60 (m, 2 H, 3-H), 3.60–4.00 (m, 2 H, 6-H), 4.66
7.6 Hz, JH,H = 0.7 Hz, 1 H, 4-Ha), 1.95 (d, JH,H = 12.1 Hz, 1 H,
8-Ha), 2.01–2.12 (m, 1 H, 4-Hb), 2.26–2.35 (m, 1 H, 8-Hb), 3.12–
3.29 (m, 1 H, 3-Ha), 3.95–4.18 (m, 1 H, 3-Hb), 4.59–4.90 (m, 1 H,
1-H), 4.97 (t, 3JH,H = 5.1 Hz, 1 H, 5-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 28.4 (OCMe3), 28.8 (CH2-4), 36.8 (CH2-8), 38.1 (br.
s, CH2-3), 38.7* (br. s, CH2-3), 53.2 (br. s, CH-1), 53.9* (CH-1),
77.1 (CH-5), 81.3 (OCMe3), 153.9 (NC=O), 173.6 (COOC) ppm.
3
2
3
(m, 1 H, 2-H), 4.89* (d, JH,H = 6.8 Hz, 1 H, 2-H), 5.60–5.81 (m,
2 H, 4-H and 5-H), 9.54 (s, 1 H, COH) ppm.
The crude reaction of the aforementioned aldehyde was dissolved
in a mixture of THF (52 mL) and tBuOH (120 mL). To this solu-
tion was then added 2-methyl-2-butene (15.8 mL, 149 mmol) plus
an aqueous solution of NaH2PO4 (3.88 g, 32.3 mmol) and NaClO2
(80%, 3.65 g, 32.3 mmol) in water (17 mL). After 15 h, a solution
of aqueous NaHSO3 (5%, 120 mL) was added. The aqueous layer
was extracted with EtOAc (2ϫ70 mL), and the combined organic
layer was dried with MgSO4 and then concentrated in vacuo. The
crude product was recrystallized from hot hexane to afford pure 4
(3.50 g, 62%) as a white solid in 99%ee [HPLC of the methyl ester
saturated derivative, methyl (S)-N-tert-butoxycarbonylpipecolate;
Chiracel OD]. Rf (hexane/EtOAc, 2:1) = 0.14. [α]D = +7.6 (c = 1.2,
(2S,4R)-N-tert-Butoxycarbonyl-4-hydroxypipecolic Acid (N-Boc-1):
To a solution of 11 (0.050 g, 0.22 mmol) in dioxane (5 mL) was
added NaOH (0.010 g, 0.24 mmol) in water (2.5 mL). After 24 h
whilst stirring at room temperature, the reaction mixture was ex-
tracted with DCM, and the combined organic layer was dried with
MgSO4 and concentrated in vacuo. The crude product was purified
by flash chromatography to obtain N-Boc-1 (0.038 g, 70%) as a
white solid. [α]D = –67.3 (c = 0.25, CHCl3). M.p. 142–144 °C. IR
CHCl ). M.p. 113–115 °C. IR (film): ν = 2929, 1705, 1645 cm–1.
˜
3
(film): ν = 3423, 2976, 2898, 1697, 1668 cm–1. 1H NMR (400 MHz,
˜
1H NMR (400 MHz, CDCl3): δ = 1.47 (s, 9 H, OtBu), 1.49* (s, 9
H, OtBu), 2.46–2.58 (m, 1 H, 3-Ha), 2.59–2.72 (m, 1 H, 3-Hb), 3.77
CDCl3): δ = 1.44 (s, 9 H, OtBu), 1.47* (s, 9 H, OtBu), 1.57–1.84
(m, 2 H, 3-Ha and 5-Ha), 1.89 (dd, 2JH,H = 13.8 Hz, 3JH,H = 6.3 Hz,
2
2
(d, JH,H = 19.6 Hz, 1 H, 6-Ha), 3.82* (d, JH,H = 18.5 Hz, 1 H, 6-
2
1 H, 5-Hb), 2.36–2.50 (m, 1 H, 2-Hb), 3.31 (dd, JH,H = 12.7 Hz,
Ha), 4.06 (d, 2JH,H = 17.1 Hz, 1 H, 6-Hb), 4.11* (d, 2JH,H = 17.9 Hz,
2
3
3JH,H = 11.7 Hz, 1 H, 6-Ha), 3.42* (dd, JH,H = 12.4 Hz, JH,H
=
3
3
1 H, 6-Hb), 4.92 (d, JH,H = 6.4 Hz, 1 H, 2-H), 5.10* (d, JH,H
=
11.7 Hz, 1 H, 6-Ha), 3.78 (d, JH,H = 12.0 Hz, 1 H, 6-Hb), 3.85*
2
5.9 Hz, 1 H, 2-H), 5.62–5.83 (m, 2 H, 4-H and 5-H) ppm. 13C
NMR (100 MHz, CDCl3) δ = 26.5 (CH2-3), 26.7* (CH2-3), 28.4
(OCMe3), 28.5* (OCMe3), 41.6 (CH2-C6), 42.3* (CH2-C6), 50.9
(CH-C1), 52.3* (CH-C1), 80.8 (OCMe3), 121.9 (CH=CH), 122.4*
(CH=CH), 124.3 (CH=CH), 124.7* (CH=CH), 156.1 (NC=O),
177.4 (COOH), 177.5* (COOH) ppm. HRMS (CI+): calcd. for
C11H18NO4 228.1236; found 228.1225.
(d, JH,H = 10.1 Hz, 1 H, 6-Hb), 4.18 (br. s, 1 H, 4-H), 4.63 (br. s,
2
1 H, 2-H), 4.80* (br. s, 1 H, 2 H), 5.93 (br. s, 2 H, OH) ppm. 13C
NMR (100 MHz, CDCl3) δ = 28.4 (OCMe3), 28.5* (OCMe3), 30.7
(CH2-5), 30.9* (CH2-5), 33.5 (CH2-3), 35.0 (CH2-6), 36.2* (CH2-
6), 50.3 (CH-2), 51.4* (CH-2), 63.4 (CH-4), 80.5 (OCMe3), 155.9
(NC=O), 156.3* (NC=O), 176.9 (COOH) ppm. MS (CI): m/z (%)
= 246 (30) [M + H]+, 190 [M – 55]+, 70, 146 [M – 99]+, 100. HRMS
(CI+): calcd. for C11H20NO5 246.1341; found 2446.1339.
C11H19NO5 (245.27): calcd. C 53.87, N 5.71, H 7.81; found C
54.25, N 5.47, H 7.88.
(1S,4S,5S)-N-tert-Butoxycarbonyl-4-iodo-6-oxa-7-oxo-2-azabicyclo-
[3.2.1]octane (10): To a solution of 4 (2.60 g, 11.4 mmol) in DCM
(50 mL) and water (100 mL) was added NaHCO3 (1.92 g,
22.9 mmol), iodide (8.71 g, 34.3 mmol) and KI (11.33 g,
68.6 mmol) whilst stirring. After 72 h, the reaction mixture was co-
oled to 0 °C and Na2S2O3 was gradually added until the yellow
colour of the solution disappeared. The aqueous layer was ex-
tracted with DCM (3ϫ100 mL), and the combined organic layer
was dried with MgSO4 and concentrated in vacuo. The crude prod-
uct was run through a short silica plug to afford 10 (3.96 g, 98%)
as a white solid. Rf (hexane/EtOAc, 3:1) = 0.50. M.p. 88–89 °C
(4S)-3-Benzyl-4-[(1R)-1-hydroxy-3-buthenyl]oxazolidin-2-one (12):
NEt3 (3.6 mL, 24.9 mmol) was added dropwise to a solution of
epoxide (+)-7 (1.32 g, 11.6 mmol) in Et2O (100 mL). After 15 min
stirring, benzyl isocyanate (2.1 mL, 17.4 mmol) was added, and the
reaction mixture was warmed to reflux. After 16 h, the reaction
was cooled to 0 °C, and a saturated solution of NH4Cl (100 mL)
was added. The organic layer was washed with a saturated solution
of NaCl (200 mL), dried with MgSO4 and concentrated in vacuo.
The crude product was purified by flash chromatography to obtain
(2R,3R)-N-Benzyl-5-hexen-2,3-epoxy-1-carbamate (2.69 g, 95%) as
a white solid. Rf (hexane/EtOAc, 2:3) = 0.45. M.p. 43–46 °C. [α]D
(ref.[22] 89–90 °C). IR (film): ν = 1799, 1703 cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = (s, 9 H, OtBu), 2.23–2.31 (m, 1 H, 8-Ha),
2
2.94 (d, JH,H = 12.8 Hz, 1 H, 8-Hb), 3.70–3.86 (m, 1 H, 3-Ha),
4.18–4.32 (m, 1 H, 3-Hb), 4.33–4.45 (m, 1 H, 4-H), 4.61–4.87 (m,
= +23.4 (c = 1.1, CHCl ). IR (film): ν = 3334, 2981, 2927, 1708,
˜
3
3
1 H, 1-H), 4.96 (t, JH,H = 4.8, Hz, 1 H, 5-H) ppm. 13C NMR
1529, 1242 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.35 (dd, JH,H
3
(100 MHz, CDCl3): δ = 19.6 (br. s, CH-4), 20.3* (br. s, CH-4) 28.3
(OCMe3), 34.0 (br. s, CH2-8), 34.2* (br. s, CH2-8), 47.7 (br. s, CH2-
3), 48.9* (br. s, CH2-3), 53.4 (br. s, CH-1), 54.1* (br. s, CH-1), 80.1
(br. s, CH-5), 81.9 (OCMe3), 153.6 (NC=O), 172.4 (COOC) ppm.
= 5.5 Hz, 3JH,H = 5.5 Hz, 2 H, 4-H), 2.94 (dt, 3JH,H = 5.0 Hz, 3JH,H
= 1.6 Hz, 1 H, CH2 CHOCHCH2 ) , 2 . 9 9– 3. 04 (m, 1 H,
2
3
CH2CHOCHCH2), 3.95 (dd, JH,H = 12.2 Hz, JH,H = 6.2 Hz, 1
H, 1-Ha), 4.37 (d, 3JN,H = 6.0 Hz, 2 H, NHCH2Ph), 4.42 (dd, 2JH,H
3
(1S,5R)-N-tert-Butoxycarbonyl-6-oxa-7-oxo-2-azabicyclo[3.2.1]-
octane (11): To a solution of 10 (0.400 g, 0.65 mmol) in benzene
(6 mL) was added tributyltin hydride (0.192 mL, 0.72 mmol) and a
small amount of AIBN whilst stirring. After 5 h at 85 °C (TLC
= 12.2 Hz, JH,H = 3.1 Hz, 1 H, 1-Hb), 5.01–5.20 (m, 2 H, 6-H),
3
3
3
5.80 (tdd, JH,H = 17.0 Hz, JH,H = 10.3 Hz, JH,H = 6.6 Hz, 1 H,
5-H), 7.25–7.37 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, CDCl3):
δ = 35.7 (CH2-4), 45.3 (NHCH2Ph), 55.3 (CH2CHOCHCH2), 55.4
1792
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1789–1796

Asymmetric Synthesis of cis-4- and trans-3-Hydroxypipecolic Acids
(CH2CHOCHCH2), 65.1 (CH2-1), 118.0 (CH2-6), 127.6 (CHar), H, SitBu), 0.89 (s, 9 H, SitBu), 2.24–2.35 (m, 1 H, 4-Ha), 2.40 (ddd,
3
3
127.7 (CHar), 128.8 (CHar), 132.7 (CH-5), 138.4 (Car), 156.2 2JH,H = 14.1 Hz, JH,H = 7.1 Hz, JH,H = 7.1 Hz, 1 H, 4-Hb), 2.73
3
3
(OCONH) ppm. HRMS (CI+): calcd. for C14H18NO3 248.1287; (dd, JH,H = 10.5 Hz, JH,H = 5.7 Hz, 1 H, 2-H), 3.66 (m, 2 H, 1-
2
2
found 248.1282.
H), 3.77 (d, JH,H = 13.0 Hz, 1 H, NCHHPh), 3.82 (d, JH,H
=
13.4 Hz, 1 H, NCHHPh), 3.83–3.89 (m, 1 H, 3-H), 4.98–5.10 (m,
To a solution of the aforementioned epoxycarbamate (2.64 g,
10.69 mmol) in THF (250 mL) was added sodium bis(trimethyl-
silyl)amide (2.15 g, 11.76 mmol) in THF (50 mL). After 15 min stir-
ring, DCM (40 mL) was added, and the reaction mixture was
washed with a saturated solution of NH4Cl (40 mL). The organic
layer was dried with MgSO4 and concentrated in vacuo. The crude
product was purified by flash chromatography to afford a 12.7:1
regioisomeric mixture with 12 as the major isomer (2.40 g, 91%)
as a colourless oil. Rf (hexane/EtOAc, 2:3) = 0.45. [α]D = +5.14 (c
3
3
3
2 H, 6-H), 5.84 (tdd, JH,H = 17.3 Hz, JH,H = 10.1 Hz, JH,H
=
7.1 Hz, 1 H, 5-H), 7.20–7.26 (m, 1 H, p-Ph), 7.27–7.35 (m, 4 H, o-
Ph and m-Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = –5.3 (SiMe),
–5.2 (SiMe), –4.3 (SiMe), –4.2 (SiMe), 18.3 (SiCMe3), 18.4
(SiCMe3), 26.1 (SiCMe3), 26.1 (SiCMe3), 37.1 (CH2-4), 52.9
(HNCH2Ph), 62.2 (CH2-1), 63.2 (CH-2), 72.4 (CH-3), 116.8 (CH2-
6), 126.9 (CH-p-Ph), 128.3 (CHar), 128.4 (CHar), 136.2 (CH-5),
141.2 (Car) ppm. MS (CI): m/z (%) = 450 (100) [M + H]+, 434 [M –
15]+, 50, 392 [M – 57]+, 40. HRMS (CI+): calcd. for C25H48NO2Si2
450.3224; found 450.3229.
= 0.56, CHCl ). IR (film): ν = 3418, 2922, 2857, 1731, 1435 cm–1.
˜
3
1H NMR (400 MHz, CDCl3): δ = 2.05 (ddd, 2JH,H = 12.8 Hz, 3JH,H
3
2
= 6.2 Hz, JH,H = 6.2 Hz, 1 H, 2Ј-Ha), 2.15 (ddd, JH,H = 15.1 Hz,
(2S,3R)-N-Benzyl-2-amino-1,3-bis(tert-butyldimethylsilyloxy)hexan-
6-ol (8a): To a solution of 9 (0.240 g, 0.545 mmol) in THF (1 mL)
at –78 °C was added 9-BBN (0.4  in hexane, 4.1 mL, 1.63 mmol)
dropwise. The reaction mixture was then warmed to room tempera-
ture over 4 h and then left to stir overnight. After 24 h, EtOH
(0.3 mL), a solution of aqueous NaOH (6 , 0.1 mL) and H2O2
(33%, 9.2 mL) were added, and the reaction mixture was warmed
to 50 °C and stirred for 1 h. After that, the reaction was allowed
to cool to room temperature, and it was then dried with K2CO3
and concentrated. The crude product was purified by column
chromatography to afford compound 8a (0.206 g, 81% over 2 steps)
as a colourless oil. Rf (hexane/EtOAc, 1:1) = 0.53. [α]D = +13.9 (c
3JH,H = 7.6 Hz, JH,H = 7.6 Hz, 1 H, 2Ј-Hb), 2.53 (br. s, 1 H, OH),
3
3
3
3
3.65 (ddd, JH,H = 8.8 Hz, JH,H = 6.5 Hz, JH,H = 1.8 Hz, 1 H, 4-
3
3
3
H), 3.90 (ddd, JH,H = 5.8 Hz, JH,H = 5.8 Hz, JH,H = 1.8 Hz, 1
H, 1Ј-H), 4.20 (dd, JH,H = 8.9 Hz, JH,H = 8.9 Hz, 1 H, 5-Ha),
2
3
4.28 (d, 2JH,H = 15.3 Hz, 1 H, NCHHPh), 4.36 (dd, 2JH,H = 8.6 Hz,
3JH,H = 6.4 Hz, 1 H, 5-Hb), 4.73 (d, JH,H = 15.3 Hz, 1 H,
2
3
NCHHPh), 5.04–5.13 (m, 2 H, 4Ј-H), 5.72 (tdd, JH,H = 17.6 Hz,
3JH,H = 10.6 Hz, JH,H = 7.0 Hz, 1 H, 3Ј-H), 7.28–7.39 (m, 5 H,
3
Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 36.8 (CH2-2Ј), 46.6
(NCH2Ph), 58.4 (CH-4), 62.2 (CH2-5), 67.1 (CH-1Ј), 118.7 (CH2-
4Ј), 128.2 (CHar), 128.2 (CHar), 129.1 (CHar), 133.4 (CH-3Ј), 136.2
(Car), 159.3 (OCONH) ppm. HRMS (CI+): calcd. for C14H18NO3
248.1287; found 248.1282.
= 1.1, CHCl ). IR (film): ν = 2953, 2928, 2856, 1471, 1255,
˜
3
1097 cm–1. H NMR (400 MHz, CDCl3): δ = 0.04 (s, 3 H, SiMe),
1
0.06 (s, 3 H, SiMe), 0.06 (s, 3 H, SiMe), 0.06 (s, 3 H, SiMe), 0.89
(2S,3R)-N-Benzyl-2-amino-5-hexen-1,3-diol (13): Compound 12
(1.56 g, 6.33 mmol) was dissolved in MeOH/water (9:1, 125 mL).
A solution of aqueous NaOH (6 , 30 mL) was added, and the
reaction mixture was stirred under reflux overnight. After 22 h, the
reaction mixture was cooled to room temperature and then concen-
trated in vacuo. The aqueous mixture was extracted with Et2O
(3 ϫ 50 mL), and the combined organic layer was dried with
MgSO4 and concentrated in vacuo. Compound 13 (1.22 g, 87%)
was thus obtained as a colourless oil, which was used in the next
step without further purification. Rf (hexane/EtOAc, 2:3) = 0.20.
(s, 9 H, SitBu), 0.89 (s, 9 H, SitBu), 1.50–1.80 (m, 4 H, 4-H and 5-
H), 2.74 (dd, JH,H = 10.8 Hz, JH,H = 5.4 Hz, 1 H, 2-H), 3.61 (t,
3
3
2
3
3JH,H = 6.0 Hz, 2 H, 6-H), 3.67 (dd, JH,H = 17.3 Hz, JH,H
=
10.4 Hz, 1 H, 1-Ha), 3.69 (dd, JH,H = 16.9 Hz, JH,H = 10.3 Hz, 1
2
3
H, 1Hb), 3.74 (d, JH,H = 12.8 Hz, 1 H, NCHHPh), 3.82 (d, JH,H
= 12.8 Hz, 1 H, NCHHPh), 3.85–3.88 (m, 1 H, 3-H), 7.20–7.27 (m,
1 H, p-Ph), 7.27–7.35 (m, 4 H, o-Ph and m-Ph) ppm. 13C NMR
(100 MHz, CDCl3): δ = –5.3 (SiMe), –5.2 (SiMe), –4.3 (SiMe), –4.3
(SiMe), 18.2 (SiCMe3), 18.3 (SiCMe3), 26.1 (SiCMe3), 28.5
(CH2CH2), 28.8 (CH2CH2), 52.9 (HNCH2Ph), 61.7 (CH2-1), 63.0
(CH-6), 63.1 (CH-2), 71.8 (CH-3), 127.1 (CH-p-Ph), 128.4 (CHar),
128.5 (CHar), 140.8 (Car) ppm. MS (CI): m/z (%) = 468 (95) [M +
H]+, 452 [M – 15]+, 36, 264 [M – 203]+, 100. HRMS (CI+): calcd.
for C25H50NO3Si2 468.3329; found 468.3326.
2
2
IR (film): ν = 3407, 2889, 1640, 1453, 1045 cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = 2.20–2.37 (m, 2 H, 4-H), 2.66 (dd, 3JH,H
9.5 Hz, JH,H = 4.5 Hz, 1 H, 2-H), 3.69–3.78 (m, 2 H, 1-H), 3.72
=
3
2
3
(dd, JH,H = 11.0 Hz, JN,H = 5.4 Hz, 1 H, NCHHPh), 3.75 (dd,
2JH,H = 11.0 Hz, JN,H = 4.3 Hz, 1 H, NCHHPh), 3.79–3.91 (m, 1
3
(2S,3R)-N-tert-Butoxycarbonyl-2-amino-1,3-bis(tert-butyldimethyl-
silyloxy)hexan-6-ol (8b): A mixture of 8a (0.200 g, 0.428 mmol) and
Pd(OH)2 (20 wt.-% on carbon, 0.020 g, 10 wt.-%) in MeOH (3 mL)
was stirred under an atmosphere of H2. After 24 h, the mixture was
filtered through Celite and then concentrated in vacuo. The crude
product was dissolved in EtOAc (3 mL) and Boc2O (0.121 g,
0.556 mmol) was added. The resulting solution was stirred at room
H, 3-H), 5.10–5.19 (m, 2 H, 6-H), 5.82 (tdd, 3JH,H = 17.1 Hz, 3JH,H
3
= 10.2 Hz, JH,H = 7.1 Hz, 1 H, 5-H), 7.23–7.30 (m, 2 H,
CHarCarCHar), 7.30–7.35 (m, 3 H, CHarCHarCHar) ppm. 13C NMR
(100 MHz, CDCl3): δ = 38.6 (CH2-4), 51.6 (HNCH2Ph), 60.6
(CH2-1), 60.9 (CH-2), 71.0 (CH-3), 118.2 (CH2-6), 127.4 (CHar),
128.4 (CHar), 128.7 (CHar), 134.9 (CH-5), 140.2 (Car) ppm.
(2S,3R)-N-Benzyl-2-amino-1,3-bis(tert-butyldimethylsilyloxy)-5-hex- temperature for 16 h and then concentrated. The crude product was
ene (9): A solution of diol 13 (0.97 g, 4.38 mmol), lutidine (1.5 mL,
13.15 mmol) and tert-butyldimethylsilyl triflate (2.52 mL,
10.96 mmol) in DCM (35 mL) was stirred for 2 h (TLC monitor-
ing). Water (35 mL) was then added, and the resulting mixture was
purified by flash chromatography to afford 8b (0.161 g, 79% over
2 steeps) as a colourless oil. Rf (hexane/EtOAc, 3:1) = 0.45. [α]D
=
–2.3 (c = 0.8, CHCl ). IR (film): ν = 3452, 2955, 2930, 2858, 1721,
˜
3
1706 cm–1. H NMR (400 MHz, CDCl3): δ = 0.05 (s, 3 H, SiMe),
1
washed with a saturated aqueous solution of NaHCO3 (35 mL). 0.06 (s, 3 H, SiMe), 0.07 (s, 3 H, SiMe), 0.07 (s, 3 H, SiMe), 0.89
The combined organic layer was dried with MgSO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography to yield compound 9 (1.90 g, 96%) as a colourless
oil. Rf (hexane/EtOAc, 4:1) = 0.95. [α]D = +9.8 (c = 1.2, CHCl3). IR
(s, 9 H, SitBu), 0.90 (s, 9 H, SitBu), 1.43 (s, 9 H, OtBu), 1.54–1.58
(m, 4 H, 4-H and 5-H), 3.55–3.71 (m, 4 H, 2-H, 1-Ha and 6-H),
3.74–3.80 (m, 1 H, 1-Hb), 3.83–3.89 (m, 1 H, 3-H), 4.71 (br. d,
3JN,H = 7.5 Hz, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ
= –5.4 (SiMe), –5.1 (SiMe), –4.7 (SiMe), –4.1 (SiMe), 18.2
(SiCMe3), 18.4 (SiCMe3), 26.0 (SiCMe3), 26.1 (SiCMe3), 27.6
(film): ν = 2929, 2857, 1471, 1255, 1094 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 0.03 (s, 6 H, SiMe2), 0.05 (s, 6 H, SiMe2), 0.88 (s, 9
Eur. J. Org. Chem. 2008, 1789–1796
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1793

C. Alegret, X. Ginesta, A. Riera
FULL PAPER
(CH2CH2), 28.6 (OCMe3), 29.4 (CH2CH2), 54.6 (CH-2), 61.7 (2ϫ2 mL). The combined organic layer was dried with MgSO4 and
(CH2-1), 63.1 (CH2-6), 71.0 (CH-3), 79.4 (SiCMe3), 156.0 (NC=O) then concentrated in vacuo. The crude product was purified by
ppm. MS (CI): m/z (%) = 478 (15) [M + H]+, 378 [M – 99]+, 100.
HRMS (CI+): calcd. for C23H52NO5Si2 478.3384; found 478.3366.
flash chromatography to provide the desired mesylate (0.048 g,
99%), which was used immediately. To a mixture tBuOK (0.023 g,
0.207 mmol) in THF (0.7 mL) at 0 °C was added a solution of the
aforementioned mesylate (0.048 g, 0.086 mmol) in THF (0.7 mL).
After 10 min, the reaction mixture was allowed to warm to room
temperature over 1.5 h (TLC monitoring). Water was then added
(1 mL), and the aqueous layer was extracted with Et2O (3ϫ3 mL).
The combined organic layer was dried with MgSO4 and then con-
centrated in vacuo. The crude product was purified by flash
chromatography to yield 3b (0.029 g, 73%) as a colourless oil. Rf
(hexane/EtOAc, 3:1) = 0.89. [α]D = +12.5 (c = 1.4, CHCl3). IR
(2S,3R)-N-Benzyl-2-tert-butyldimethylsilyloxymehtyl-3-tert-butyldi-
methylsilyloxypiperidine (3a)
Procedure A: To a solution of alcohol 8a (0.090 g, 0.192 mmol) and
PPh3 (0.101 g, 0.385 mmol) in toluene (1 mL) at 0 °C was added
DIAD (0.075 mL, 0.385 mmol) dropwise. The mixture was then
warmed to room temperature and left to stir overnight. Et2O
(1 mL) was then added, and the resulting solution was washed with
a saturated solution of NaHCO3 (2ϫ1 mL), dried with MgSO4
and concentrated. The crude product was dissolved in Et2O (1 mL)
and treated with hexane, and the resulting mixture was filtered to
remove the triphenylphosphane oxide. The solvent was evaporated
off, and the crude product was purified by flash chromatography
to yield 3a (0.035 g, 40%) as a colourless oil.
(film): ν = 2954, 2929, 2857, 1697, 1415 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 0.04 (s, 3 H, SiMe), 0.05 (s, 3 H, SiMe), 0.06 (s, 3 H,
SiMe), 0.07 (s, 3 H, SiMe), 0.88 (s, 9 H, SitBu), 0.89 (s, 9 H, SitBu),
1.25–1.37 (m, 1 H, 5-Ha), 1.45 (s, 9 H, OtBu), 1.53–1.71 (m, 2 H,
3
4-H), 1.85–1.99 (m, 1 H, 5-Hb), 2.66 (dd, 2JH,H = 13.0 Hz, JH,H
=
12.0 Hz, 1 H, 6-Ha), 3.52–3.61 (m, 1 H, NCHHPh), 3.66 (dd, 2JH,H
= 9.8 Hz, JH,H = 9.5 Hz, 1 H, NCHHPh), 3.87–4.25 (m, 3 H, 2-
Procedure B: A mixture of alcohol 8a (0.100 g, 0.214 mmol) and
activated, powdered, 4-Å molecular sieves (0.40 g) in pyridine
(2.1 mL) was stirred at room temperature for 10 min. MsCl
(0.025 mL, 0.321 mmol) was then added, and the reaction mixture
was warmed to 100 °C and stirred for 3 h (TLC monitoring). The
mixture was then diluted with DCM (2 mL), filtered through Celite
and concentrated. The crude product was purified by flash
chromatography to yield 3a (0.049 g, 51%) as a colourless oil. Rf
3
H and 3-H) ppm. 13C NMR (100 MHz, CDCl3): δ = –5.2 (SiMe2),
–4.8 (SiMe2), 18.2 (SiCMe3), 18.3 (SiCMe3), 19.0 (CH2-5), 25.9
(SiCMe3), 26.0 (SiCMe3), 27.4 (CH2-4), 28.6 (OCMe3), 39.5 (CH2-
6), 59.5 (CH-2), 61.3 (CH2OTBS), 64.7 (CH-3), 79.4 (OCMe3),
155.8 (NC=O) ppm. MS (ES+): m/z (%) = 461 (100) [M + H]+,
361 [M – 99]+, 80. HRMS (ESI+): calcd. for C23H50NO4Si2
460.3273; found 460.3269.
(hexane/EtOAc, 3:1) = 0.89. [α]D = +3.2 (c = 1.7, CHCl3). IR (film):
1
ν = 2954, 2928, 2856, 1727, 1462, 1257 cm–1. H NMR (400 MHz,
(2S,3R)-N-tert-Butoxycarbonyl-2-hydroxymethyl-3-tert-butyldi-
methylsilyloxypiperidine (3c): A mixture of 3b (0.061 g,
0.136 mmol) and p-toluenesulfonic acid (10 mol-%, 0.003 g,
˜
CDCl3): δ = 0.03 (s, 3 H, SiMe), 0.04 (s, 3 H, SiMe), 0.07 (s, 3 H,
SiMe), 0.07 (s, 3 H, SiMe), 0.89 (s, 9 H, SitBu), 0.91 (s, 9 H, SitBu),
1.30–1.42 (m, 2 H, 4-Ha and 5-Ha), 1.59–1.71 (m, 1 H, 4-Hb or 5- 0.014 mmol) in MeOH (3 mL) was stirred at room temperature for
2
Hb), 1.85–1.94 (m, 1 H, 4-Hb or 5-Hb), 2.02 (dd, JH,H = 9.9 Hz,
2 h (TLC monitoring). DCM (6 mL) and a saturated aqueous solu-
3JH,H = 9.6 Hz, 1 H, 6-Ha), 2.28–2.38 (m, 1 H, 2-H), 2.62–2.71 (m, tion of NaHCO3 (2 mL) were then added, and the aqueous layer
2
1 H, 6-Hb), 3.36 (d, JH,H = 13.9 Hz, 1 H, CHHOTBS), 3.60–3.68 was extracted with DCM (3ϫ2 mL). The combined organic layer
2
3
(m, 1 H, 3-H), 3.79 (dd, JH,H = 10.7 Hz, JN,H = 5.2 Hz, 1 H,
was dried with MgSO4 and concentrated. The crude product was
purified by flash chromatography to yield 3c (0.035 g, 74%) as a
2
3
NCHHPh), 4.04 (dd, JH,H = 10.7 Hz, JN,H = 3.5 Hz, 1 H,
2
NCHHPh), 4.29 (d, JH,H = 13.8 Hz, 1 H, CHHOTBS), 7.20 (t, colourless oil. Rf (hexane/EtOAc, 3:1) = 0.32. [α]D = +24.3 (c =
3JH,H = 7.1 Hz, 1 H, p-Ph), 7.28 (t, JH,H = 7.4 Hz, 2 H, o-Ph),
0.7, CHCl ). IR (film): ν = 3445, 2953, 2929, 2857, 1694, 1668 cm–1.
3
˜
3
3
3
7.36 (dd, JH,H = 7.5 Hz, JH,H = 7.2 Hz, 2 H, m-Ph) ppm. 13C
NMR (100 MHz, CDCl3): δ = –5.2 (SiMe), –5.2 (SiMe), –4.4
(SiMe), –3.9 (SiMe), 18.2 (SiCMe3), 18.3 (SiCMe3), 26.1 (SiCMe3),
1H NMR (400 MHz, CDCl3): δ = 0.05 (s, 3 H, SiMe), 0.08 (s, 3 H,
SiMe), 0.89 (s, 9 H, SitBu), 1.30–1.38 (m, 1 H, 5-Ha), 1.45 (s, 9 H,
2
3
OtBu), 1.55–1.65 (m, 2 H, 4-H), 1.92 (dtd, JH,H = 17.1 Hz, JH,H
26.1 (SiCMe3), 29.4 (CCH2CH2C), 33.1 (CCH2CH2C), 50.9 (CH2- = 12.5 Hz, JH,H = 4.5 Hz, 1 H, 5-Hb), 2.84 (dd, JH,H = 12.8 Hz,
3
2
6), 58.6 (CH2OTBS), 62.3 (NCH2Ph), 68.7 (CH-3), 69.9 (CH-2), 3JH,H = 12.4 Hz 1 H, 6-Ha), 3.63 (dd, JH,H = 11.0 Hz, JH,H
=
2
3
2
3
126.6 (CH-p-Ph), 128.2 (CH-m-Ph), 129.0 (CH-o-Ph), 140.8 (Car) 6.3 Hz, 1 H, CHHOH), 3.71 (dd, JH,H = 10.0 Hz, JH,H = 8.5 Hz,
ppm. MS (CI): m/z (%) = 450 (45) [M + H]+, 434 [M – 15]+, 40,
304 [M – 145]+, 100. HRMS (CI+): calcd. for C25H48NO2Si2
450.3224; found 450.3224.
1 H, CHHOH), 3.86–3.90 (m, 1 H, 3-H), 3.98 (d, 2JH,H = 11.4 Hz,
3
3
1 H, 6-Hb), 4.17 (dd, JH,H = 7.9 Hz, JH,H = 6.3 Hz, 1 H, 2-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = –4.9 (SiMe), –4.7 (SiMe),
18.1 (SiCMe3), 19.4 (CH2-5), 25.9 (SiCMe3), 28.4 (CH2-4), 28.6
(OCMe3), 39.8 (CH2-6), 60.2 (CH-2), 60.9 (CH2OH), 65.4 (CH-3),
79.8 (OCMe3), 156.4 (NC=O) ppm. MS (CI): m/z (%) = 346 (71)
[M + H]+, 290 [M – 55]+, 80, 246 [M – 99]+, 100. HRMS (CI+):
calcd. for C17H36NO4Si 346.2414; found 346.2408.
(2S,3R)-N-tert-Butoxycarbonyl-2-tert-butyldimethylsilyloxymethyl-
3-tert-butyldimethylsilyloxypiperidine (3b)
Procedure A: A mixture of 3a (0.048 g, 0.107 mmol), Boc2O
(0.030 g, 0.139 mmol) and Pd(OH)2 (20 wt.-% on carbon, 0.005 g)
in EtOAc (1 mL) was stirred under an atmosphere of H2. After
20 h (TLC monitoring), the mixture was filtered through Celite and
then concentrated in vacuo. The crude product was purified by
flash chromatography to afford 3b (0.026 g, 53% over 2 steeps) as
a colourless oil.
(2R,3R)-3-Hydroxypipecolic Acid Hydrochloride [(–)-2·HCl]: A
mixture of NaIO4 (0.037 g, 0.174 mmol) and RuCl3·H2O (0.002 g,
0.009 mmol, 10 % mol.) in acetonitrile/CCl4/H2O (1:1:10, 1 mL)
was stirred at room temperature. After 45 min, 3c (0.030 g,
0.087 mmol) in acetonitrile (0.5 mL) was added. NaIO4 (0.019 g,
0.087 mmol) was then added, and the reaction mixture was left to
stir for 30 min (TLC monitoring). The reaction mixture was filtered
Procedure B: To a mixture of alcohol 8b (0.041 g, 0.086 mmol) and
NEt3 (0.024 mL, 0.171 mmol) in DCM (1.5 mL) at 0 °C was added
MsCl (0.010 mL, 0.128 mmol). After 30 min at this temperature the through Celite, washed with EtOAc, dried with MgSO4 and con-
reaction mixture was allowed to warm to room temperature over centrated. The crude product was purified by flash chromatography
30 h (TLC monitoring). A mixture of water/Et2O (1:1, 2 mL) was
then added, and the organic layer was extracted with Et2O
(SiO2). The O-protected hydroxy acid was treated with aqueous
HCl (6 , 2 mL) at 70 °C for 2 h. The reaction mixture was then
1794
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1789–1796

Asymmetric Synthesis of cis-4- and trans-3-Hydroxypipecolic Acids
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extracted with Et2O (2 mL), dried with MgSO4 and concentrated
to yield (–)-2·HCl (0.010 g, 63% over 2 steps) as a solid. [α]D
=
–13.5 (c = 0.3, H2O) [ref.[14c] +14.2 for (+)-2·HCl (c = 0.95, H2O)].
1H NMR (400 MHz, D2O): δ = 1.64–1.83 (m, 2 H, 4-Ha and 5-
Ha), 1.96–2.10 (m, 2 H, 4-Hb and 5-Hb), 3.07–3.15 (m, 1 H, 6-Ha),
[10]
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3
3.36–3.43 (m, 1 H, 6-Hb), 3.81 (d, JH,H = 7.5 Hz, 1 H, 2-H), 4.16
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1
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and 9–13.
Acknowledgments
We thank Ministerio de Educación y Ciencia (MEC) (CTQ2005–
000623) for financial support. C. A. and X. G. thank DURSI (Ge-
neralitat de Catalunya) and Universitat de Barcelona, respectively,
for fellowships.
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Received: November 21, 2007
Published Online: February 12, 2008
1796
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1789–1796