Enantiodivergent chemoenzymatic synthesis of 4-hydroxypiperidine alkaloids

Article abstract of DOI:10.1002/ejoc.201000837

An efficient chemoenzymatic synthesis of both enantiomers of fagomine, as well as of cis and trans-4-hydroxypipecolic acid is reported. The synthesis starts from commercial δ-valerolactam which, after a Pd-catalyzed methoxycarbonylation of the corresponding vinyl phosphate, is subjected to allylic oxidation to give a racemic 4-hydroxytetrahydropyridine derivative in 57% overall yield. This product is resolved by an enzyme-catalyzed esterification using immobilized lipases from Candida antarctica (Novozym 435) and Burkholderia cepacia (lipase PS Amano IM). The latter provides the corresponding R esters and the S alcohol in 95 and 94% ee, respectively. The S alcohol is then converted into L-fagomine by a stereoselective hydroboration/oxidation as key steps and the cis-(2R,4S)-4-hydroxypipecolic acid by stereoselective hydrogenation. The corresponding D-fagomine and cis-(2S,4R)-4-hydroxypipecolic acid, as well as trans-(2R,4R)-4-hydroxypipecolic acid can be prepared by the same strategy after hydrolysis of the R ester obtained by kinetic resolution. The lipase-catalyzed kinetic resolution of a racemic alcohol, readily obtained from commercial δ-valerolactam, is the key stepof an enantiodivergent synthesis of D- and L-fagomine as well as cis- and trans-4-hydroxypipecolic acid.

Full text of DOI:10.1002/ejoc.201000837

FULL PAPER
DOI: 10.1002/ejoc.201000837
Enantiodivergent Chemoenzymatic Synthesis of 4-Hydroxypiperidine Alkaloids
Laura Bartali,[a] Andrea Casini,[a] Antonio Guarna,[a] Ernesto G. Occhiato,*[a] and
Dina Scarpi[a]
Keywords: Alkaloids / Enzyme catalysis / Kinetic resolution / Lipase / Supported catalysts
An efficient chemoenzymatic synthesis of both enantiomers
of fagomine, as well as of cis and trans-4-hydroxypipecolic
acid is reported. The synthesis starts from commercial δ-val-
erolactam which, after a Pd-catalyzed methoxycarbonylation
of the corresponding vinyl phosphate, is subjected to allylic
oxidation to give a racemic 4-hydroxytetrahydropyridine de-
rivative in 57% overall yield. This product is resolved by an
enzyme-catalyzed esterification using immobilized lipases
from Candida antarctica (Novozym 435) and Burkholderia ce-
pacia (lipase PS Amano IM). The latter provides the corre-
sponding R esters and the S alcohol in 95 and 94% ee,
respectively. The S alcohol is then converted into L-fagomine
by a stereoselective hydroboration/oxidation as key steps
and the cis-(2R,4S)-4-hydroxypipecolic acid by stereoselec-
tive hydrogenation. The corresponding D-fagomine and cis-
(2S,4R)-4-hydroxypipecolic acid, as well as trans-(2R,4R)-4-
hydroxypipecolic acid can be prepared by the same strategy
after hydrolysis of the R ester obtained by kinetic resolution.
Thus, enantiodivergent methods that allow the preparation
of both enantiomers of fagomine and other iminosugars
could be advantageous for drug discovery.
Introduction
4-Hydroxylated piperidine alkaloids are a family of natu-
rally occurring compounds that includes, among the sim-
plest members, the glycosidase inhibitor -fagomine and
the non-proteinogenic α-amino acids cis- and trans-4-hy-
droxypipecolic acid. -Fagomine (1)[1] (Figure 1) is an imi-
nosugar that inhibits mammalian intestinal α-glucosidase
and β-galactosidase,[2] besides exhibiting strong antihyper-
glycemic effects in streptozocin-induced diabetic mice, and
potentiating glucose-induced insulin secretion.[3] Natural
and synthetic compounds derived from both enantiomers
of cis- and trans-4-hydroxypipecolic acids 2[4] and 3,[5] dis-
play important biological activity as antibiotics,[6] receptor
antagonists,[7] and HIV-protease inhibitors.[8] It is therefore
not surprising that several asymmetric syntheses of these
alkaloids have been reported so far.[9] For fagomine, how-
ever, most syntheses have been aimed at the preparation of
this iminosugar with -configuration, whereas the synthesis
of ent-1 has been reported only twice so far[9d,10] and, in
one case, only as a by-product.[10] In general, relatively little
attention has been paid to the -iminosugars, either due to
their supposed lack of biological activity or because of their
limited availability from natural sources. However, recent
studies of enzyme-inhibitor interactions have led to a recon-
sideration of -iminosugars for pharmaceutical purposes.[11]
Figure 1. Some 4-hydroxypiperidine alkaloids and the common
synthetic intermediate 4.
Results and Discussion
We have recently shown that compound 4, which can be
obtained through Pd-catalyzed methoxycarbonylation of a
suitable lactam-derived vinyl phosphate, is a useful building
block for the synthesis of the title alkaloids. With the intro-
duction of a bulky protecting group on the hydroxl group
of enantiopure (R)-4 (96% ee), (2S,4R)- and (2R,4R)-4-hy-
droxypipecolic acids 2 and 3 were obtained by stereocon-
trolled reduction of the enamine double bond,[12] whereas
the selective hydroboration of the same bond led to -fago-
mine (1).[13] With the goal of establishing a general pro-
cedure for the enantioselective synthesis of both enantio-
mers of 4-hydroxypiperidine alkaloids 1–3 from a common
precursor, we needed to obtain both antipodes of 4 in a
more convenient way than that previously reported,[12a]
which included eight steps starting from ethyl (R)- and (S)-
4-chloro-3-hydroxybutanoate and required the use of rela-
View this journal online at
[a] Dipartimento di Chimica “U. Schiff”, Università di Firenze,
via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Fax: +39-0554573531
E-mail: ernesto.occhiato@unifi.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000837.
wileyonlinelibrary.com
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5831

E. G. Occhiato et al.
FULL PAPER
tively large amounts of toxic NaCN and NiCl2·6H2O. To which was the best solvent for some 2-cyclohexen-1-ols[18a]
this end, we envisaged a chemo-enzymatic approach that and, more conventionally, in toluene.[23] In both solvents,
would enable the preparation of racemic 4 from commercial the best results were obtained with 4-chlorophenyl butyrate
δ-valerolactam in a short synthetic sequence (Scheme 1), (PCPB)[24] as the acyl donor (Table 1, entries 4 and 7).
followed by a lipase-catalyzed kinetic resolution of 4 to ob- Interestingly, we determined a low E value of about 20
tain both (R)-4 and (S)-4 enantiomers in enantiopure or when vinyl acetate was used (Table 1, entries 1 and 5),
enantio-enriched form.
which is almost identical to that measured for the kinetic
resolution of seudenol catalyzed by free CAL-B.[18c] With
2,2,2-trifluoroethyl butyrate (TFEB), besides low E values,
the reaction was slow and never reached 50% conversion
(Table 1, entries 2 and 6). With PCPB, we screened other
solvents (Table 1, entries 8–10), and found that anhydrous
tetrahydrofuran (THF) was optimal (Table 1, entry 10),
which is in accordance with the observation that solvents
with logP Ͻ 2 are most suitable for polar substrates.[25] In
this case, by increasing the amount of enzyme (Table 1, en-
try 11) and by using a 0.2  substrate concentration, we
eventually obtained an E value (135) that was only just suit-
able for effective kinetic resolution. We also tested vinyl bu-
tyrate as the acyl donor (Table 1, entry 12) under the same
conditions, but found that the E value decreased.
Scheme 1. Synthesis of racemic alcohols 4 and 9 from δ-valerolac-
tam.
In an attempt to further increase the enantiomeric ratio,
we assessed the kinetic resolution of n-butyl ester (Ϯ)-9. It
A three-step conversion of known lactam 5 into α,β-un- has been reported that enantioselectivity for the enzyme-
saturated ester 7 was thus realized by a Pd-catalyzed meth- catalyzed esterification with 2-cyclohexen-1-ols increases
oxycarbonylation of vinyl phosphate 6, which provided 7 in when a larger substituent is present at position 3.[20] How-
87% yield over two steps.[14] We also carried out the latter ever, under the best conditions, the esterification of (R)-9
reaction in the presence of an excess of n-butanol, thus ob- was very slow (27% conversion after 24 h, without proceed-
taining ester 8 in 63% yield.[15] Allylic oxidation of 7 and ing further) and so was unsuitable for synthetic purposes.
8 was carried out with N-bromosuccinimide (NBS) in the
Better results were obtained with lipase PS Amano IM,
presence of a catalytic amount of azobisisobutyronitrile although higher enzyme to substrate ratios (mg/mmol) were
(AIBN),[16] followed by hydrolysis with ZnCl2 in wet ace- required to reach acceptable conversions in reasonable
tone, which furnished (Ϯ)-4 and (Ϯ)-9 in 66 and 60% yield, times. The best result was obtained by carrying out the res-
respectively. As anticipated, this sequence provided (Ϯ)-4 in olution in the presence of PCPB in THF at a 0.8  substrate
a much higher overall yield (57%) than that obtained by concentration with 100 mg of lipase per mmol of (Ϯ)-4
using our previous route (24%) and, moreover, it was easily (E = 162; Table 1, entry 14). Under the same conditions,
scaled up.
with both vinyl acetate (Table 1, entry 16) and vinyl buty-
With sufficient amounts of racemic 4, we were ready to rate (Table 1, entry 17), the reaction was also highly enan-
study the kinetic resolution of this alcohol by means of li- tioselective, with measured E values of approximately 160
pases in organic media.[17] From the various commercially and enantiomeric excesses for both enantiomers of 4 com-
available lipases, we opted to use Candida antarctica lipase parable to those of commercial ethyl (3R)- and (3S)-4-
B (CAL-B) supported on acrylic resin (trade name Novo- chloro-3-hydroxybutanoate (96% ee) employed for the
zym 435), because it has been used on a few occasions, preparation of enantiopure (R)- and (S)-4,[12a] respectively.
either immobilized or free in solution, for the resolution of We thus applied the latter conditions to resolve a sufficient
carbacyclic allylic alcohols (e.g., seudenol) that structurally amount of (Ϯ)-4 (2.5 mmol) to proceed with the synthesis.
resemble compound 4.[18] The enantiomeric ratio E[19] After chromatographic separation of (R)-10b (45% yield,
ranged from 20 to 187 for those substrates depending on 95% ee) and (S)-4 (42% yield, 94% ee), pure (R)-4 (95%
the reaction conditions, thus allowing for an effective reso- yield) was obtained by hydrolysis of ester (R)-10b
lution. For similar reasons, we employed Burkholderia cepa- (Scheme 2), from which the synthesis of fagomine 1, as well
cia lipase[20] (immobilized on diatomaceous earth and com- as pipecolic acids 2 and 3, has already been reported.[12,13]
mercialized with the name of lipase PS Amano IM), which
The synthesis could then be extended to obtain the
has previously been exploited for the kinetic resolution of enantiomers, although in the case of ent-1 and ent-2 we
alcohols such as 3-ethyl-, 3-bromo-, and 3-nitro-2-cy- opted to use the bulky triisopropylsilyl (TIPS) group to pro-
clohexen-1-ol,[21] with E values from 49 to higher than 100. tect the 4-hydroxyl group, with the expectation of achieving
As in the case of simple secondary[22] and cyclic allylic greater stereoselectivity than previously observed.[26] After
alcohols,[18] the R enantiomer of 4 (Table 1) was preferen- protection of the 4-hydroxyl group as its TIPS ether (S)-11
tially acylated in all experiments. With CAL-B, we initially (Scheme 3), ester reduction with diisobutylaluminum hy-
screened various acyl donors in anhydrous acetonitrile, dride (DIBAL-H) gave alcohol (S)-12 in 73% yield. The
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4-Hydroxypiperidine Alkaloids
Table 1. Lipase-catalyzed kinetic resolution of (Ϯ)-4.
Entry
Acylant reagent[a]
Solvent[b]
t [h]
Conv. [%][c]
(R)-10 ee [%][d] (S)-4 ee [%][e] E[f]
CAL-B[g]
1
2
VA
CH3CN
CH3CN
CH3CN
CH3CN
toluene
toluene
toluene
CH2Cl2
acetone
THF
21
72
43
18
16
28
15
72
72
23
4.5
3
45
83
90
94
84
56
82
88
85
95
94
96
90
64
–
–
21
TFEB
PCPB
PCPB
VA
TFEB
PCPB
PCPB
PCPB
PCPB
PCPB
VB[m]
36[h]
36[h]
54
31[i]
54[i]
59
3
4[j]
5
99
99
47
81
13
51
84
85
96
64
17
16
39
16
65
92
135
74
6
37[h]
50
7[j]
8
12[h]
35[h]
47
9
10[j]
11[k]
12[k,l]
THF
THF
47
52
PS “Amano” IM[n]
13
PCPB
PCPB
VA
THF
THF
THF
THF
THF
40
7
20
9
40[h]
45
97
97
94
97
96
65
79
54
80
93
130
162
56
163
168
14[o]
15
36[h]
45
16[o]
17[l,o]
VA[p]
VB[p]
6
49
[a] VA: vinyl acetate, TFEB: 2,2,2-trifluoroethyl butyrate, PCPB: 4-chlorophenyl butyrate, VB: vinyl butyrate. [b] Anhydrous solvents were
used. [c] Conversion determined by GLC (calibration trace in the Supporting Information) and 1H NMR spectroscopy. [d] Determined by
1
1H NMR analysis of the Mosher ester after hydrolysis. [e] Determined by H NMR analysis of the Mosher ester. [f] E = enantiomeric
ratio calculated as previously reported.[19] [g] Reaction carried out on 0.2–0.4 mmol of substrate at 30 °C; substrate concentration from
0.2 to 0.4 ; enzyme (mg)/substrate (mmol) ratio from 10 to 25; 2 equiv. of acylant reagent. [h] The reaction did not proceed further and
was stopped. [i] Calculated as: ln[1 – c(1 + eep)]/ln[1 – c(1 – eep)]. [j] Substrate concentration: 0.8 . [k] Enzyme (mg)/substrate (mmol)
ratio: 200. [l] Molecular sieve (4 Å, 130 mg/mmol) was used. [m] 2.5 equiv. [n] Reaction carried out on 0.2–0.4 mmol of substrate at 30 °C;
substrate concentration: 0.8 ; enzyme (mg)/substrate (mmol) ratio: 20; 2 equiv. of acylant reagent. [o] Enzyme (mg)/substrate (mmol)
ratio: 100. [p] 3.5 equiv.
Scheme 2. Formal synthesis of -fagomine 1 and pipecolic acids 2
and 3.
formation of variable amounts of cyclic carbamate (S)-13
(0–33%) depended on both the reaction work-up and
chromatographic conditions.[27] Because it was difficult to
completely separate (S)-12 from the cyclic urethane by
chromatography, the next protection step was carried out
on the mixture. Protection as the [2-(trimethylsilyl)ethoxy]-
Scheme 3. Synthesis of -fagomine ent-1.
methyl (SEM) ether proceeded uneventful and SEM ether
(S)-14 and (S)-13 – if present – were easily separated by
chromatography. Key intermediate (S)-14 was finally sub- chromatography. The major isomer (2S,3S,4S)-15, which
jected to hydroboration with BH3·THF followed by oxi- was obtained in 72% yield, was eventually deprotected to
dation with trimethylamine N-oxide (Me3NO) to give 15 as furnish ent-1 as its hydrochloride salt in 100% yield. Al-
an 8:1 mixture of diastereomers, which were separated by though the diastereoselectivity of the hydroboration was
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not higher than 8:1, because this reaction was almost the as reported,[12b] but from racemic starting material.[12a] Re-
last step of the synthesis, the effective loss of material duction of the ester group with DIBAL-H gave the corre-
through formation of the undesired isomer was low.
sponding alcohol (Ϯ)-17 (66%) as a mixture with cyclic ure-
We could assign the relative stereochemistry of the minor thane (Ϯ)-18, which could, in this case, be separated by
isomer of 15 obtained in the hydroboration/oxidation step chromatography. After protection as the SEM ether (70%
as 2,3-cis-3,4-cis [i.e., (2S,3R,4S)] based on the coupling yield), hydroboration of (Ϯ)-19 by BH3·THF followed by
constant values and on NOE experiments.[28] This unexpec- oxidation with Me3NO gave alcohol (Ϯ)-20 as an 8:1 dia-
ted assignment was confirmed by analysis of the products stereomeric mixture. This ratio was maintained in the
obtained after exhaustive deprotection in 2  aqueous HCl exhaustive hydrolysis to (Ϯ)-1, and analysis of the 1H NMR
and then neutralization with Ambersep 900 OH resin spectrum confirmed that the signals of the minor isomer
1
(Scheme 4), which provided a sample that generated a H corresponded, as in the previous case, to those reported for
NMR spectrum corresponding to that of 4-epi-fagomine,[29] 4-epi-fagomine. The reasons for the formation of this iso-
thus definitely confirming the all cis relative stereochemis- mer are unclear but, apparently, epimerization at C-3 in the
try for the minor isomer.
major diastereomer seems to have taken place at some
stage.
Given the spontaneous formation of cyclic urethane (S)-
13, we also envisaged a shorter route to ent-1 that entailed
the direct transformation of (S)-11 into (S)-13 (90%) by
treatment with K2CO3 in MeOH after reduction of 11 with
DIBAL-H (Scheme 6). This allowed us to avoid the need
for SEM-protection, thus further simplifying the synthetic
approach. The hydroboration/oxidation of the cyclic ure-
thane proceeded smoothly and provided alcohol 21 in 66%
yield after chromatography, with the same diastereomeric
ratio (8:1) to that obtained using the procedure described
above.[30] Exhaustive hydrolysis (HCl 6 , reflux, 30 h) fi-
nally gave ent-1 in quantitative yield.
Scheme 4. Conversion of the minor isomer (2S,3R,4S)-15 into ent-
4-epi-fagomine.
Interestingly, we measured the same relative amount of
the corresponding minor isomer when we carried out the
hydroboration/oxidation reaction on tert-butyl ether 19
(Scheme 5). The tert-butyl group had induced good facial
selectivity (18:1) in the hydrogenation of 16 to cis-4-hy-
droxypipecolic acid,[12b] so we were interested in evaluating
its effect in the hydroboration. Compound 16 was prepared
Scheme 6. Synthesis of compound 21 and ent-1·HCl.
The synthesis of 4-hydroxypipecolic acid ent-2 was real-
ized by hydrogenation of (S)-11 (Scheme 7), which provided
the diastereomerically pure cis compound (2R,4S)-22 in
quantitative yield. In this case, we managed to obtain a dia-
stereomeric ratio higher than that previously obtained (ca.
20:1); indeed, we could not detect any trace of the trans
Scheme 5. Synthesis of racemic 20.
Scheme 7. Synthesis of (2R,4S)-4-hydroxypipecolic acid.
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4-Hydroxypiperidine Alkaloids
1
Methyl 6-[(Diphenoxyphosphoryl)oxy]-3,4-dihydropyridine-1(2H)-
carboxylate (6): To a solution of potassium hexamethyldisilazide
(KHMDS; 20.8 mL, 0.5  in toluene, 10.4 mmol) in THF
(54.8 mL), cooled to –78 °C under a nitrogen atmosphere, was
added a solution of 5 (1.30 g, 8.3 mmol) in THF (21.7 mL), and
the resulting mixture was stirred for 1.5 h. A solution of (PhO)2P-
(O)Cl (2.1 mL, 10.38 mmol) in THF (17.1 mL) was added and the
reaction was stirred for 1 h at –78 °C before allowing the tempera-
ture to rise to 0 °C. NaOH (10%, 160 mL) was added and the mix-
ture was extracted with Et2O (3ϫ130 mL), washed with NaOH
(10%, 100 mL) and water (100 mL), and dried with anhydrous
K2CO3 for 1 h. After filtration and evaporation of the solvent
(without heating and leaving a small volume of solvent), the crude
phosphate was purified by chromatography (EtOAc/n-hexane, 1:3
containing 1% Et3N; Rf = 0.19) on a short layer of silica gel (4 cm
of silica gel on a column with internal diameter 4 cm) to give 6
compound in the H NMR spectrum of the crude reaction
mixture.[12] Exhaustive hydrolysis gave ent-2 as its hydro-
chloride salt in 100% yield.
Conclusions
We have shown that both CAL-B and lipase PS AM-
ANO IM are suitable for conducting effective kinetic reso-
lution of racemic alcohol 4 which, in turn, is prepared by a
short and efficient route starting from commercially avail-
able δ-valerolactam. After Pd-catalyzed methoxycarbon-
ylation of the corresponding vinyl phosphate, allylic oxi-
dation gives the key racemic alcohol 4 in 57% yield over
four steps. The lipase-catalyzed esterification of this alcohol
by Burkholderia cepacia (lipase PS Amano IM), in particu-
lar, then provides the corresponding (R)-butyrate and the
(S)-alcohol in 95 and 94% ee, respectively. These com-
pounds can be converted into both enantiomers of fagom-
ine and all stereoisomers of 4-hydroxypipecolic acid
through an elaboration of the enamine double bond. Thus,
-fagomine was obtained in 37% yield through stereoselec-
tive hydroboration, whereas cis-(2S,4R)-4-hydroxypipecolic
acid was obtained in quantitative yield by catalytic hydro-
genation. Other 4-hydroxypiperidine alkaloids can be pre-
pared by using this approach and the results will be re-
ported in due course.
1
(3.20 g, 99%) as a pale-yellow oil. H NMR (CDCl3, 400 MHz): δ
= 7.37–7.32 (m, 4 H, ArH), 7.26–7.17 (m, 6 H, ArH), 5.10 (q, J =
2.9 Hz, 1 H, 3-H), 3.64–3.61 (m, 2 H, 6-H), 3.56 (s, 3 H, OCH3),
2.18–2.04 (m, 2 H, 4-H), 1.76–1.69 (m, 2 H, 5-H) ppm. 13C NMR
(CDCl3, 100.4 MHz): δ = 154.7 (s, CO), 150.5 (s, 2 C, CAr), 140.0
(s, C-2), 129.8 (d, 4 C, CAr), 125.5 (d, 2 C, CAr), 120.1 (d, 4 C,
C
Ar), 100.4 (d, C-3), 53.1 (q, OCH3), 45.7 (t, C-6), 22.6 (t, C-4),
21.6 (t, C-5) ppm. ESI-MS: m/z (%) = 390 (6) [M + 1]+, 346 (100),
265 (21). C19H20NO6P (389): calcd. C 58.61, H 5.18, N 3.60; found
C 58.34, H 5.00, N 3.27.
Dimethyl 5,6-Dihydropyridine-1,2(4H)-dicarboxylate (7): Phosphate
6
(2.87 g, 7.38 mmol) was immediately dissolved in DMF
(19.4 mL), and Pd(OAc)2 (166 mg, 0.738 mmol) and Ph3P (388 mg,
1.48 mmol) were added. The solution was stirred for 10 min under
a CO atmosphere (balloon), then Et3N (2.0 mL, 14.76 mmol) and
MeOH (12.0 mL, 295.2 mmol) were added and stirring was contin-
ued at 55 °C (external bath) for 3 h under static CO pressure. The
solution was diluted with water (200 mL), extracted with Et2O
(6ϫ150 mL) and dried with Na2SO4. After filtration and evapora-
tion of the solvent, the oily residue was purified by chromatography
(EtOAc/n-hexane, 1:2; Rf = 0.20) to give 7 (1.29 g, 88%) as a thick
pale-yellow oil. 1H NMR (CDCl3, 200 MHz): δ = 6.04 (t, J =
4.0 Hz, 1 H, 3-H), 3.73 (s, 3 H, OCH3), 3.67 (s, 3 H, OCH3), 3.61–
3.55 (m, 2 H, 6-H), 2.25–2.16 (m, 2 H, 4-H), 1.84–1.72 (m, 2 H, 5-
H) ppm. 13C NMR (CDCl3, 50.33 MHz): δ = 164.9 (s, CO), 154.3
(s, CO), 132.2 (s, C-2), 122.8 (d, C-3), 53.1 (q, OCH3), 52.0 (q,
OCH3), 43.6 (t, C-6), 22.9 (t, C-4), 22.7 (t, C-5) ppm. MS: m/z (%)
= 199 (29) [M]+, 167 (11), 140 (30), 80 (20), 68 (29), 59 (100).
C9H13NO4 (199): calcd. C 54.26, H 6.58, N 7.03; found C 54.29,
H 6.33, N 6.86.
Experimental Section
General: Chromatographic separations were performed under pres-
sure on silica gel 60 (Merck, 70–230 mesh) using flash-column tech-
niques; Rf values refer to TLC carried out on 0.25-mm silica gel
plates using the same eluent indicated for the column chromatog-
raphy. THF was distilled from Na/benzophenone. Commercial an-
hydrous DMF was used. 1H NMR (400 and 200 MHz) and 13C
NMR (50.33 and 100.4 MHz) spectra were recorded at 25 °C. Mass
spectra were carried out either by direct inlet on a LCQ Fleet Ion-
Trap LC/MS system (Thermo Fisher Scientific) with an electro-
spray ionization (ESI) interface in the positive mode, or by electron
ionization (EI) at 70 eV. CAL-B was purchased from Sigma–Ald-
rich and had a reported activity Ն10.000 U/g. Lipase PS Amano
IM has a reported activity Ն500 U/g. Compound 5 is known.[31]
Methyl 2-Oxopiperidine-1-carboxylate (5): To a solution of methyl
2-Butyl 1-Methyl 5,6-Dihydropyridine-1,2(4H)-dicarboxylate (8):
2-oxopiperidine-1-carboxylate (991 mg, 10 mmol) in THF (92 mL), Phosphate 6 (327 mg, 0.84 mmol), prepared as described above,
cooled to –78 °C, nBuLi (6.3 mL, 1.6  in hexane, 10 mmol) was was immediately dissolved in DMF (2.2 mL), and Pd(OAc)2
slowly added. The mixture was stirred at –78 °C for 15 min and
then methyl chloroformate (850 µL, 11 mmol) was added dropwise.
After 10 min, the solution was allowed to reach 0 °C, satd. aq.
NaHCO3 (50 mL) was added and the organic layer was separated.
The aqueous layer was extracted with CH2Cl2 (2ϫ40 mL) and the
combined organic extracts were dried with Na2SO4 and the sol-
vents evaporated. The residue was purified by flash chromatog-
(19 mg, 0.084 mmol) and Ph3P (44 mg, 0.168 mmol) were added.
The solution was stirred for 10 min under a CO atmosphere (bal-
loon), then Et3N (233 µL, 1.68 mmol) and nBuOH (3.1 mL,
33.6 mmol) were added and stirring was continued at 55 °C (exter-
nal bath) for 3 h under static CO pressure. The solution was diluted
with water (23 mL), extracted with Et2O (6ϫ23 mL) and dried
with Na2SO4. After filtration, cyclohexane (27 mL) was added and
the solvent was evaporated. The oily residue was purified by
raphy (n-hexane/EtOAc, 1:1; Rf
= 0.27) to give 5 (1.30 g,
1
8.27 mmol, 83%) as a white solid. H NMR (CDCl3, 400 MHz): δ chromatography (EtOAc/n-hexane, 1:4; Rf = 0.28) to give 8
= 3.84 (s, 3 H, OCH3), 3.74–3.71 (m, 2 H, 6-H), 2.54–2.50 (m, 2
(128 mg, 63%) as a thick pale-yellow oil. 1H NMR (CDCl3,
H, 3-H), 1.85–1.80 (m, 4 H, 4-H and 5-H) ppm. 13C NMR (CDCl3, 400 MHz): δ = 6.06 (t, J = 3.9 Hz, 1 H, 3-H), 4.17 (t, J = 6.6 Hz,
100.4 MHz): δ = 171.2 (s, CO), 155.0 (s, CO), 53.8 (q, OCH3), 46.5
(t, C-6), 34.8 (t, C-3), 22.6 (t, C-4), 20.3 (t, C-5) ppm. ESI-MS: m/z
(%) = 158 (9) [M + 1]+, 126 (100), 82 (49).
2 H, OCH2), 3.70 (s, 3 H, OCH3), 3.64–3.60 (m, 2 H, 6-H), 2.25–
2.21 (m, 2 H, 4-H), 1.85–1.79 (m, 2 H, 5-H), 1.68–1.61 (m, 2 H,
CH2), 1.44–1.34 (m, 2 H, CH2), 0.93 (t, J = 6.6 Hz, 3 H, CH3)
Eur. J. Org. Chem. 2010, 5831–5840
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E. G. Occhiato et al.
FULL PAPER
ppm. 13C NMR (CDCl3, 100.4 MHz): δ = 164.8 (s, CO), 154.6 (s,
(53 µL) was added and the reaction was left under vigorous stirring
CO), 132.7 (s, C-2), 122.7 (d, C-3), 64.9 (t, OCH2), 53.1 (q, OCH3),
and monitored by GC. After 9 h the conversion was 45% and the
43.7 (t, C-2), 30.6 (t, CH2CH2CH3), 22.9 (t, C-4), 22.7 (t, C-5), 19.1 reaction was stopped by filtration through a thin layer of Celite.
(t, CH2CH3), 13.7 (q, CH3) ppm. ESI-MS: m/z (%) = 242 (2) [M After evaporation, the crude product was purified by chromatog-
+ 1]+, 168 (100). C12H19NO4 (241): calcd. C 59.73, H 7.94, N 5.81;
found C 59.55, H 7.71, N 5.94.
raphy (EtOAc/n-hexane, 1:1) to give (R)-10a (Rf = 0.53; 23 mg,
39%; 97% ee) and (S)-4 (Rf = 0.30; 24 mg, 48%; 80% ee).
(R)-10a: [α]2D5 = +214 (c = 1.15, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 5.90 (d, J = 4.1 Hz, 1 H, 3-H), 5.28 (pseudo q, J =
4.3 Hz, 1 H, 4-H), 4.10 (dt, J = 13.3, 4.1 Hz, 1 H, 6-H), 3.79 (s, 3
H, OCH3), 3.73 (s, 3 H, OCH3), 3.28 (ddd, J = 13.3, 6.8, 6.0 Hz,
1 H, 6-HЈ), 2.04 (s, 3 H, CH3CO), 1.98–1.94 (m, 2 H, 5-H) ppm.
13C NMR (CDCl3, 100.4 MHz): δ = 170.0 (s, CO), 164.7 (s, CO),
153.9 (s, CO), 135.3 (s, C-2), 116.3 (d, C-3), 63.5 (d, C-4), 53.4 (q,
OCH3), 52.5 (q, OCH3), 40.5 (t, C-6), 29.1 (t, C-5), 21.0 (q, CH3)
ppm. MS: m/z (%) = 257 (14) [M]+, 225 (40), 198 (49), 183 (60),
152 (76), 94 (100). C11H15NO6 (257): calcd. C 51.36, H 5.88, N
5.45; found C 51.08, H 5.95, N 5.56.
Dimethyl
[(؎)-4]:
4-Hydroxy-5,6-dihydropyridine-1,2(4H)-dicarboxylate
solution of (1.29 g, 6.49 mmol), NBS (1.47 g,
A
7
8.24 mmol) and a catalytic amount of AIBN (90 mg, 0.55 mmol)
in a 9:1 mixture of CCl4 and CHCl3 (224 mL) was heated to reflux
with vigorous stirring for 15 min. After cooling, the reaction mix-
ture was diluted with CHCl3 (180 mL), washed with water
(200 mL) and the solvents evaporated. The yellow oil thus obtained
was dissolved in 96% aqueous acetone (113 mL) and ZnCl2 (3.67 g,
26.93 mmol) was added to the solution portionwise over 4 h. After
6 h, the reaction mixture was diluted with CHCl3 (130 mL), washed
with water (300 mL), satd. aq. NaHCO3 (300 mL) and brine
(300 mL), and dried with Na2SO4. After filtration and evaporation
of the solvent, the crude product was purified by chromatography
(EtOAc/n-hexane, 2:1 containing 0.5% Et3N; Rf = 0.33) to give
(S)-4: [α]2D5 = –113 (c = 1.91, CHCl3). Spectroscopic data as re-
ported above for (Ϯ)-4.
Kinetic Resolution with PS “AMANO” IM Lipase
1
(Ϯ)-4 (920 mg, 66%) as a thick pale-yellow oil. H NMR (CDCl3,
Dimethyl
(R)-4-(Butyryloxy)-5,6-dihydropyridine-1,2(4H)-dicarb-
400 MHz): δ = 5.96 (dd, J = 3.9, 1.0 Hz, 1 H, 3-H), 4.31–4.27 (m,
1 H, 4-H), 4.05 (dt, J = 13.1, 4.1 Hz, 1 H, 6-H), 3.79 (s, 3 H,
OCH3), 3.73 (s, 3 H, OCH3), 3.30 (ddd, J = 13.2, 9.2, 5.5 Hz, 1 H,
oxylate [(+)-10b] and (S)-4-Hydroxy-5,6-dihydropyridine-1,2(4H)-
dicarboxylate [(–)-4]: To a solution of (Ϯ)-4 (538 mg, 2.5 mmol) in
THF (3.1 mL) at 30 °C, was added lipase PS “AMANO” IM
(250 mg) under an N2 atmosphere. After 20 min, vinyl butyrate
(1.1 mL) was added and the reaction was left under vigorous stir-
ring and monitored by GC. After 6.5 h, the conversion reached
50% and the reaction was stopped by filtration through a thin layer
of Celite. After evaporation, the crude product was purified by
chromatography (EtOAc/n-hexane, 1:2) to give (R)-10b (Rf = 0.60;
321 mg, 45%; 95% ee) and (S)-4 (Rf = 0.15; 226 mg, 42%; 94%
ee).
(R)-10b: [α]2D5 = +206 (c = 0.82, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 5.91 (d, J = 4.1 Hz, 1 H, 3-H), 5.31 (pseudo q, J =
3.9 Hz, 1 H, 4-H), 4.10 (dt, J = 13.1, 4.1 Hz, 1 H, 6-H), 3.79 (s, 3
H, OCH3), 3.74 (s, 3 H, OCH3), 3.28 (ddd, J = 13.1, 8.8, 6.2 Hz,
1 H, 6-HЈ), 2.27 (t, J = 7.0 Hz, 2 H, OCH2), 1.94–1.98 (m, 2 H, 5-
H), 1.60–1.68 (m, 2 H, CH2), 0.94 (t, J = 7.3 Hz, 3 H, CH3) ppm.
13C NMR (CDCl3, 100.4 MHz): δ = 172.7 (s, CO), 164.7 (s, CO),
153.9 (s, CO), 135.2 (s, C-2), 116.6 (d, C-3), 63.2 (d, C-4), 53.5 (q,
OCH3), 52.5 (q, OCH3), 40.5 (t, C-6), 36.2 (t, CH2CH2CH2), 29.3
(t, C-5), 18.4 (t, CH2CH3), 13.6 (q, CH3) ppm. MS: m/z (%) =
286 (12) [M + 1]+, 253 (21), 198 (59), 183 (77), 152 (58), 94 (100).
C13H19NO6 (285): calcd. C 54.73, H 6.71, N 4.91; found C 54.58,
H 6.93, N 5.12.
6-HЈ), 1.96–1.85 (m,
2
H, 5-H) ppm. 13C NMR (CDCl3,
100.4 MHz): δ = 165.1 (s, CO), 154.0 (s, CO), 133.6 (s, C-2), 120.4
(d, C-3), 61.2 (d, C-4), 53.4 (q, OCH3), 52.5 (q, OCH3), 40.1 (t, C-
6), 32.1 (t, C-5) ppm. MS: m/z (%) = 215 (38) [M]+, 183 (79), 155
(59), 127 (47), 114 (49), 97 (74), 59 (100). C9H13NO5 (215): calcd.
C 50.23, H 6.09, N 6.51; found C 50.48, H 5.79, N 6.22.
2-Butyl 1-Methyl 4-Hydroxy-5,6-dihydropyridine-1,2(4H)-dicarb-
oxylate [(؎)-9]: A solution of 8 (128 mg, 0.53 mmol), NBS (119 mg,
0.67 mmol) and a catalytic amount of AIBN (7.4 mg, 0.045 mmol)
in a 9:1 mixture of CCl4 and CHCl3 (18.1 mL) was heated to reflux
with vigorous stirring for 15 min. After cooling, the reaction mix-
ture was diluted with CHCl3 (15 mL), washed with water (17 mL)
and the solvents were evaporated. The yellow oil thus obtained
was dissolved in 96% aqueous acetone (15 mL) and ZnCl2 (300 g,
2.20 mmol) was added to the solution portionwise over 4 h. After
6 h, the reaction mixture was diluted with CHCl3 (10 mL), washed
with water (24 mL), satd. aq. NaHCO3 (24 mL) and brine (24 mL),
and dried with Na2SO4. After filtration and evaporation of the sol-
vent, the crude product was purified by chromatography (EtOAc/
n-hexane, 2:1, containing 0.5% Et3N; Rf = 0.41) to give (Ϯ)-9
(82.2 mg, 60%) as a thick pale-yellow oil. 1H NMR (CDCl3,
400 MHz): δ = 5.94 (d, J = 3.5 Hz, 1 H, 3-H), 4.32–4.26 (m, 1 H,
4-H), 4.18 (t, J = 6.6 Hz, 2 H, OCH2), 4.04 (dt, J = 13.1, 4.3 Hz,
1 H, 6-H), 3.72 (s, 3 H, OCH3), 3.30 (ddd, J = 13.1, 9.8, 4.5 Hz, 1
H, 6-HЈ), 1.96–1.86 (m, 2 H, 5-H), 1.69–1.61 (m, 2 H, CH2), 1.44–
1.35 (m, 2 H, CH2), 0.94 (t, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR
(CDCl3, 100.4 MHz): δ = 164.6 (s, CO), 154.1 (s, CO), 134.0 (s, C-
2), 120.3 (d, C-3), 65.4 (t, OCH2), 61.4 (d, C-4), 53.3 (q, OCH3),
40.2 (t, C-6), 32.2 (t, C-5), 30.5 (t, CH2CH2CH3), 19.1 (t,
CH2CH3), 13.7 (q, CH3) ppm. ESI-MS: m/z (%) = 258 (1)
[M + 1]+, 240 (60), 202 (24), 184 (100), 127 (8). C12H19NO5 (257):
calcd. C 56.02, H 7.44, N 5.44; found C 56.13, H 7.23, N 5.08.
(S)-4: [α]2D5 = –132 (c = 0.78, CHCl3). Spectroscopic data as re-
ported above for (Ϯ)-4.
Dimethyl (R)-4-Hydroxy-5,6-dihydropyridine-1,2(4H)-dicarboxylate
[(+)-4]: To a solution of (+)-10b (215 mg, 0.75 mmol) in anhydrous
MeOH (7.2 mL) cooled in an ice bath, MeONa (40.5 mg,
0.75 mmol) was added and the reaction was stirred for 5 h at 0 °C
under an N2 atmosphere. Glacial acetic acid (0.340 mL) was added
and the MeOH was evaporated. The residue was diluted with water
(70 mL), extracted with EtOAc (4ϫ70 mL) and dried with
Na2SO4. After filtration and evaporation of the solvent, the crude
product was purified by chromatography (EtOAc/n-hexane, 1:1,
containing 0.5% Et3N; Rf = 0.30) to give (R)-4 (153 mg, 95%) as
a thick pale-yellow oil. [α]2D5 = +134 (c = 0.67, CHCl3). Spectro-
scopic data as reported above for (Ϯ)-4.
Kinetic Resolution with PS “AMANO” IM Lipase
Dimethyl (R)-4-Acetoxy-5,6-dihydropyridine-1,2(4H)-dicarboxylate
[(+)-10a] and Dimethyl (S)-4-Hydroxy-5,6-dihydropyridine-1,2(4H)-
dicarboxylate [(–)-4]: To a solution of (Ϯ)-4 (49.6 mg, 0.23 mmol)
in THF (300 µL) at 30 °C, was added lipase PS “AMANO” IM
(23 mg) under an N2 atmosphere. After 20 min, vinyl acetate
Dimethyl (S)-4-Triisopropylsilyloxy-5,6-dihydropyridine-1,2(4H)-di-
carboxylate [(–)-11]: To a stirred solution of (S)-4 (207 mg,
5836
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5831–5840

4-Hydroxypiperidine Alkaloids
0.975 mmol) in anhydrous DMF (2.6 mL) were added imidazole
(148 mg, 2.17 mmol) and TIPSCl (306 µL, 1.45 mmol) and the re-
action was stirred for 5 h at 40 °C (external bath) under an N2
atmosphere. After cooling to r.t., water (25 mL) was added and
the solution was extracted with Et2O (4ϫ25 mL). The combined
organic layers were washed with brine (25 mL) and dried with
Na2SO4. After filtration and evaporation of the solvent, the oily
residue was purified by chromatography (EtOAc/n-hexane, 1:4; Rf
= 0.19) to give (S)-11 (327 mg, 91%) as a thick colorless oil. [α]2D0
= –125.2 (c = 0.97, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 5.92
(dd, J = 3.9, 0.8 Hz, 1 H, 3-H), 4.35 (pseudo q, J = 3.9 Hz, 1 H,
4-H), 3.98 (dt, J = 12.9, 4.1 Hz, 1 H, 6-H), 3.79 (s, 3 H, OCH3),
3.72 (s, 3 H, OCH3), 3.34 (ddd, J = 12.9, 10.3, 3.5 Hz, 1 H, 6-HЈ),
1.94–1.83 (m, 2 H, 5-H), 1.06 (s, 18 H and 3 H, TIPS) ppm. 13C
NMR (CDCl3, 100.4 MHz): δ = 165.3 (s, CO), 154.2 (s, CO), 132.4
(s, C-2), 122.2 (d, C-3), 62.0 (d, C-4), 53.3 (q, OCH3), 52.3 (q,
OCH3), 40.3 (t, C-6), 33.2 (t, C-5), 18.0 (q, 6 C, CH3 of TIPS),
12.2 (d, 3 C, CH of TIPS) ppm. ESI-MS: m/z (%) = 394 (11) [M
+ Na]+, 296 (22), 220 (100), 62 (14). C18H33NO5Si (371): calcd. C
58.19, H 8.95, N 3.77; found C 57.86, H 8.98, N 3.83.
hexane, 1:4; Rf = 0.19) to give (S)-13 (89 mg, 90%) as a white solid;
m.p. 95.3–96.9 °C. 1H NMR (CDCl3, 400 MHz): δ = 4.91–4.83 (m,
3 H, 8-H and CH2O), 4.45–4.40 (m, 1 H, 7-H), 3.75 (dt, J = 12.3,
4.3 Hz, 1 H, 5-H), 3.49 (td, J = 12.3, 3.7 Hz, 1 H, 5-HЈ), 1.95 (dq,
J = 13.5, 3.9 Hz, 1 H, 6-H), 1.77–1.68 (m, 1 H, 6-HЈ), 1.06 (s, 18
H and 3 H, TIPS) ppm. 13C NMR (CDCl3, 100.4 MHz): δ = 156.0
(s, CO), 135.6 (s, C-8a), 97.4 (d, C-8), 66.2 (t, CH2O), 61.0 (d, C-
7), 35.5 (t, C-5), 30.0 (t, C-6), 18.0 (q, 6 C, CH3 of TIPS), 12.3 (d,
3 C, CH of TIPS) ppm. ESI-MS: m/z (%) = 312 (12) [M + 1]+, 169
(65), 138 (100). C16H29NO3Si (311): calcd. C 61.69, H 9.38, N 4.50;
found C 61.37, H 9.11, N 4.64.
Methyl (4S)-6-[2-(Trimethylsilyl)ethoxymethoxymethyl]-4-triisopro-
pylsilyloxy-3,4-dihydropyridine-1(2H)-carboxylate [(–)-14]: To
a
stirred solution of (S)-12 (209 mg, 0.61 mmol) in anhydrous
CH2Cl2 (2.7 mL) were added DIPEA (315 µL, 1.84 mmol) and
SEMCl (294 µL, 1.66 mmol) and the reaction was stirred for 16 h
at 30 °C (external bath). After cooling to r.t., CH2Cl2 (12 mL) was
added and the solution was washed with water (2ϫ12 mL). The
organic layer was dried with Na2SO4 and, after filtration and evap-
oration of the solvent, the oily residue was purified by chromatog-
raphy (EtOAc/n-hexane, 1:6; Rf = 0.36) to give (S)-14 (221 mg,
77%) as a thick colorless oil. If (S)-13 is present in the mixture
with the alcohol, the former can be easily separated from (S)-14 by
Methyl (4S)-6-(Hydroxymethyl)-4-triisopropylsilyloxy-3,4-dihydro-
pyridine-1(2H)-carboxylate [(–)-12]: To
a solution of (S)-11
(325 mg, 0.876 mmol) in anhydrous Et2O (26 mL), cooled to
–78 °C, was added dropwise a solution of DIBAL-H (2.2 mL,
0.89  in n-hexane, 1.96 mmol) whilst stirring under an N2 atmo-
sphere. After 1 h, the reaction mixture was warmed to 0 °C and
stirred for 30 min. Then satd. NH4Cl was added until a solid
formed and the mixture was filtered through a Celite layer. The
phases were separated and the organic layer was dried with
Na2SO4, filtered and concentrated. The crude product was purified
by chromatography (EtOAc/n-hexane, 1:3; Rf = 0.25) on a short
layer of silica gel (3 cm of silica gel in a column with internal dia-
meter 4 cm) to give (S)-12 (219 mg, 73%) as a pale-yellow oil. Com-
pound (S)-12 was obtained in variable mixtures with compound
(S)-13 (0–33 mol-%). In these cases, complete separation by
chromatography of (S)-12 from (S)-13 was not possible and the
mixture was subjected to the next reaction without further purifica-
tion. [α]2D2 = –45.7 (c = 0.30, CHCl3). 1H NMR (CDCl3, 400 MHz):
δ = 5.22 (d, J = 4.1 Hz, 1 H, 5-H), 4.31–4.24 (m, 1 H, 4-H and 1
H, CH2OH), 4.17 (dd, J = 12.3, 9.1 Hz, 1 H, CH2OH), 3.94 (ddd,
J = 12.7, 5.3, 3.7 Hz, 1 H, 2-H), 3.77 (s, 3 H, OCH3), 3.42 (ddd, J
= 12.7, 9.7, 4.1 Hz, 1 H, 2-HЈ), 1.87–1.78 (m, 2 H, 3-H), 1.06 (s,
18 H and 3 H, TIPS) ppm. 13C NMR (CDCl3, 100.4 MHz): δ =
154.7 (s, CO), 139.2 (s, C-6), 115.9 (d, C-5), 65.0 (t, CH2OH), 62.0
(d, C-4), 53.2 (q, OCH3), 40.8 (t, C-2), 32.4 (t, C-3), 18.1 (q, 6 C,
CH3 of TIPS), 12.3 (d, 3 C, CH of TIPS) ppm. ESI-MS: m/z (%)
= 366 (6) [M + Na]+, 192 (100), 170 (4). C17H33NO4Si (343): calcd.
C 59.44, H 9.68, N 4.08; found C 59.75, H 9.44, N 4.23.
chromatography (EtOAc/hexane, 1:6; Rf = 0.17). (S)-14: [α]2D3
=
–95.8 (c = 0.88, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 5.31 (d,
J = 3.3 Hz, 1 H, 5-H), 4.67 (AB system, J = 6.8 Hz, 2 H, OCH2O),
4.52 (d, J = 13.1 Hz, 1 H, part of an AB system, C6-CH2O), 4.38
(d, J = 13.1 Hz, 1 H, part of an AB system, C6-CH2O), 4.28
(pseudo q, J = 4.3 Hz, 1 H, 4-H), 3.93 (ddd, J = 12.7, 5.3, 3.7 Hz,
1 H, 2-H), 3.77 (s, 3 H, OCH3), 3.65–3.61 (m, 2 H, OCH2), 3.39
(ddd, J = 12.7, 9.4, 4.2 Hz, 1 H, 2-HЈ), 1.86–1.78 (m, 2 H, 3-H),
1.06 (s, 18 H and 3 H, TIPS), 0.96–0.93 (m, 2 H, CH2TMS), 0.01
(s, 9 H, TMS) ppm. 13C NMR (CDCl3, 100.4 MHz): δ = 154.2 (s,
CO), 136.8 (s, C-6), 115.0 (d, C-5), 93.9 (t, OCH2O), 67.9 (t,
CH2O), 65.2 (t, OCH2), 62.5 (d, C-4), 52.8 (q, OCH3), 41.4 (t, C-
2), 33.4 (t, C-3), 18.0 (q, 6 C, CH3 of TIPS), 18.0 (t, CH2TMS),
12.3 (d, 3 C, CH of TIPS), –1.4 (q, 3 C, CH3 of TMS) ppm. ESI-
MS: m/z (%) = 496 (4) [M + Na]+, 322 (100). C23H47NO5Si2 (473):
calcd. C 58.31, H 10.00, N 2.96; found C 58.02, H 10.37, N 2.91.
Methyl (2S,3S,4S)-3-Hydroxy-4-triisopropylsilyloxy-2-[2-(trimethyl-
silyl)ethoxymethoxymethyl]piperidine-1-carboxylate [(+)-15]: To a
stirred solution of (S)-14 (191 mg, 0.455 mmol) in anhydrous THF
(21 mL), under an N2 atmosphere and cooled to –78 °C, was added
a solution of BH3·THF (1.55 mL, 1.0  in THF, 1.55 mmol). After
5 min, the flask was submerged in an ice bath and left at 0 °C for
20 h. Then, under vigorous stirring, trimethylamine N-oxide
(Me3NO; 410 mg, 5.47 mmol) was added and, after mounting a
condenser, the reaction was heated at 65 °C (external bath) for 2 h.
After cooling, EtOAc (52 mL) was added and the organic layer was
washed with brine (2ϫ21 mL) and dried with anhydrous Na2SO4.
Chromatography (CH2Cl2/MeOH, 40:1) afforded (2S,3S,4S)-15
(161 mg, 72%; Rf = 0.15) and (2S,3R,4S)-15 (18 mg, 8%; Rf = 0.20)
as colorless oils.
(S)-7-Triisopropylsilyloxy-1,5,6,7-tetrahydro[1,3]oxazolo[3,4-a]-
pyridin-3-one [(–)-13]: To a solution of (S)-11 (119 mg, 0.32 mmol)
in anhydrous Et2O (10 mL), cooled to –78 °C, was added dropwise
a solution of DIBAL-H (0.8 mL, 0.89  in n-hexane, 0.70 mmol)
whilst stirring under an N2 atmosphere. After 1 h, the reaction mix-
ture was warmed to 0 °C and stirred for 30 min. Then satd. NH4Cl
was added until a solid formed, then the mixture was filtered
through a Celite layer, the phases were separated and the organic
layer was dried with Na2SO4, filtered and concentrated. To a solu-
tion of the crude alcohol product in CH3OH (5 mL), K2CO3
(430 mg) was added under vigorous stirring and, after 50 min, the
mixture was filtered and concentrated. Water (5 mL) was added
and the solution was extracted with CH2Cl2 (5ϫ5 mL). The or-
ganic layer was washed with brine (10 mL), dried with Na2SO4,
and the crude product was purified by chromatography (EtOAc/n-
1
(2S,3S,4S)-15: [α]2D1 = +2.95 (c = 0.91, CHCl3). H NMR (CDCl3,
400 MHz): δ = 4.65 (d, J = 6.7 Hz, 1 H, part of an AB system,
OCH2O), 4.62 (d, J = 6.7 Hz, 1 H, part of an AB system, OCH2O),
4.43 (br. s, 1 H, 2-H), 4.03 (dd, J = 10.7, 8.9 Hz, 1 H, C6-CH2O),
3.99 (m, 1 H, 4-H), 3.93 (br. d, J = 13.3 Hz, 1 H, 6-Heq), 3.81 (br.
s, 1 H, 3-H), 3.70 (s, 3 H, OCH3), 3.70 (dd, J = 10.7, 5.7 Hz, 1 H,
C6-CH2O), 3.65–3.59 (m, 1 H, OCH2), 3.57–3.50 (m, 1 H, OCH2),
3.24 (td, J = 13.3, 2.5 Hz, 1 H, 6-Hax), 2.09–1.97 (m, 2 H, 5-Hax
and OH), 1.54 (br. dd, J = 14.0, 2.1 Hz, 1 H, 5-Heq), 1.07 (s, 18 H
Eur. J. Org. Chem. 2010, 5831–5840
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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E. G. Occhiato et al.
FULL PAPER
and 3 H, TIPS), 0.94–0.87 (m, 2 H, CH2TMS), 0.01 (s, 9 H, TMS) (؎)-17: 1H NMR (CDCl3, 400 MHz): δ = 5.14 (d, J = 3.5 Hz, 1
ppm. 13C NMR (CDCl3, 100.4 MHz): δ = 157.3 (s, CO), 94.4 (t,
H, 5-H), 4.34–4.26 (m, 1 H, CH2OH), 4.16–4.07 (m, 1 H, CH2OH),
OCH2O), 68.8 (d, C-3), 68.6 (d, C-2), 65.0 (t, OCH2), 64.4 (d, C- 4.00–3.95 (m, 1 H, 4-H), 3.92 (ddd, J = 12.9, 5.1, 3.7 Hz, 1 H, 2-
4), 57.3 (t, CH2O), 52.7 (q, OCH3), 34.4 (t, C-6), 28.2 (t, C-5), 18.1
(t, CH2TMS), 18.1 and 18.0 (q, 6 C, CH3 of TIPS), 12.2 (d, 3 C,
CH of TIPS), –1.4 (q, 3 C, CH3 of TMS) ppm. ESI-MS: m/z (%)
= 514 (10) [M + Na]+, 414 (100), 366 (55), 344 (35), 336 (33).
C23H49NO6Si2 (491): calcd. C 56.17, H 10.04, N 2.85; found C
55.89, H 10.23, N 2.68.
H), 3.76 (s, 3 H, OCH3), 3.44–3.32 (m, 1 H, 2-HЈ), 1.90–1.75 (m,
2 H, 3-H), 1.21 [s, 9 H, (CH3)3C] ppm.
(؎)-18: 1H NMR (CDCl3, 400 MHz): δ = 4.82 (qt, J = 8.2, 1.9 Hz,
2 H, CH2O), 4.79–4.76 (m, 1 H, 8-H), 4.16–4.11 (m, 1 H, 7-H),
3.76–3.68 (m, 1 H, 5-H), 3.43 (td, J = 11.9, 3.9 Hz, 1 H, 5-HЈ),
1.86 (dq, J = 13.7, 3.9 Hz, 1 H, 6-H), 1.80–1.70 (m, 1 H, 6-HЈ),
1.22 [s, 9 H, (CH3)3C] ppm. 13C NMR (CDCl3, 100.4 MHz): δ =
156.0 (s, CO), 135.7 (s, C-8a), 97.1 (d, C-8), 74.1 [s, C(CH3)3], 66.2
(t, CH2O), 60.2 (d, C-7), 35.9 (t, C-5), 29.2 (t, C-6), 28.4 [q, 3 C,
(CH3)3C] ppm. ESI-MS: m/z (%) = 212 (3) [M + 1]+, 156 (100).
C11H17NO3 (211): calcd. C 62.54, H 8.11, N 6.63; found C 62.33,
H 8.40, N 6.21.
1
(2S,3R,4S)-15: H NMR (400 MHz, CDCl3): δ = 4.68–4.65 (m, 2
H, OCH2O), 4.52–4.48 (m, 1 H, 2-H), 4.23–4.20 (m, 1 H, 4-H),
3.97 (pseudo d, J = 7.0 Hz, 2 H, 7-H), 3.84 (br. d, 1 H, 6-Heq),
3.69 (s, 3 H, OCH3), 3.73–3.67 (m, 1 H, 3-H), 3.66–3.51 (m, 2 H,
OCH2CH2TMS), 3.18 (pseudo td, J = 15.4, 3.1 Hz, 6-Hax), 2.69
(d, J = 9.2 Hz, 1 H, OH), 1.85–1.65 (m, 2 H, 5-H), 1.16–1.00 (m,
21 H, TIPS), 0.93–0.87 (m, 2 H, CH2-TMS), 0.02 (s, 9 H, TMS)
ppm.
Methyl
4-tert-Butoxy-6-[2-(trimethylsilyl)ethoxymethoxymethyl]-
3,4-dihydropyridine-1(2H)-carboxylate [(؎)-19]: To a stirred solu-
tion of (Ϯ)-17 (100 mg, 0.41 mmol) in anhydrous CH2Cl2 (1.8 mL)
were added DIPEA (210 µL, 1.23 mmol) and SEMCl (196 µL,
1.11 mmol) and the reaction was stirred for 22 h at 30 °C (external
bath). After cooling to r.t., CH2Cl2 (8 mL) was added and the solu-
tion was washed with water (2ϫ8 mL). The organic layer was dried
with Na2SO4 and, after filtration and evaporation of the solvent,
the oily residue was purified by chromatography (EtOAc/n-hexane,
1:10; Rf = 0.16) to give (Ϯ)-19 (107 mg, 70%) as a thick colorless
(2S,3S,4S)-2-(Hydroxymethyl)piperidine-3,4-diol [L-Fagomine HCl
Salt] [(–)-ent-1·HCl]:[32] A suspension of (2S,3S,4S)-15 (69 mg,
0.14 mmol) in 2  aq. HCl (17 mL) was heated to reflux for 18 h.
After cooling to r.t., the mixture was washed with Et2O
(3ϫ10 mL), concentrated, and triturated with acetone (2ϫ2 mL)
to give ent-1·HCl (25 mg, 100%) as a pale-yellow solid after 12 h
under vacuum. [α]2D1 = –12.0 (c = 0.26, H2O). 1H NMR (400 MHz,
D2O, ref. line at δ = 4.65 ): δ = 3.82 (dd, J = 12.5, 3.1 Hz, 1 H,
part of an ABX system, CH2OH), 3.79 (dd, J = 12.5, 5.1 Hz, 1 H,
part of an ABX system, CH2OH), 3.62 (ddd, J = 14.0, 10.1, 4.7 Hz,
1 H, 4-H), 3.43 (pseudo t, J = 10.1 Hz, 1 H, 3-H), 3.34 (br. d, J =
12.1 Hz, 1 H, 6-Heq), 3.05–2.96 (m, 1 H and 1 H, 2-H and 6-Hax),
2.13–2.08 (m, 1 H, 5-Heq), 1.67–1.60 (m, 1 H, 5-Hax) ppm.
1
oil. H NMR (CDCl3, 400 MHz): δ = 5.20 (d, J = 3.5 Hz, 1 H, 5-
H), 4.67 (AB system, J = 7.0 Hz, 2 H, OCH2O), 4.42 (s, 2 H, C6-
CH2O), 4.01 (pseudo q, J = 3.9 Hz, 1 H, 4-H), 3.83 (ddd, J = 12.9,
6.4, 3.7 Hz, 1 H, 2-H), 3.71 (s, 3 H, OCH3), 3.64–3.60 (m, 2 H,
OCH2), 3.43 (ddd, J = 12.9, 9.6, 3.0 Hz, 1 H, 2-HЈ), 1.58–1.55 (m,
2 H, 3-H), 1.20 [s, 9 H, (CH3)3C], 0.95–0.91 (m, 2 H, CH2TMS),
0.01 (s, 9 H, TMS) ppm. 13C NMR (CDCl3, 100.4 MHz): δ = 154.2
(s, CO), 137.3 (s, C-6), 115.1 (d, C-5), 94.1 (t, OCH2O), 73.9 [s,
C(CH3)3], 68.2 (t, CH2O), 65.2 (t, OCH2), 61.9 (d, C-4), 52.7 (q,
OCH3), 42.2 (t, C-2), 32.8 (t, C-3), 28.4 [q, 3 C, (CH3)3C], 18.1 (t,
CH2TMS), –1.4 (q, 3 C, CH3 of TMS) ppm. ESI-MS: m/z (%) =
396 (11) [M + Na]+, 322 (100). C18H35NO5Si (373): calcd. C 57.87,
H 9.44, N 3.75; found C 57.76, H 9.59, N 3.43.
(2S,3R,4S)-2-(Hydroxymethyl)piperidine-3,4-diol [ent-4-epi-Fagom-
ine] [(2S,3R,4S)-1]:[33]
A suspension of (2S,3R,4S)-15 (4 mg,
8.1 µmol) in 2  aq. HCl (1 mL) was heated to reflux for 8 h. After
cooling to r.t., the mixture was washed with Et2O (3ϫ1 mL), con-
centrated, and triturated with acetone (2ϫ0.15 mL) to give
(2S,3R,4S)-1·HCl (1.3 mg, 88%) as a pale-yellow solid after 12 h
under vacuum. 1H NMR (400 MHz, D2O): δ = 3.97–3.95 (m, 1 H,
3-H), 3.78 (ddd, J = 11.9, 5.5, 2.9 Hz, 1 H, 4-H), 3.74–3.70 (m, 2
H, 7-H), 3.34 (ddd, J = 13.1, 4.7, 2.3 Hz, 1 H, 6-Heq), 3.21 (pseudo
dd, J = 8.2, 5.5 Hz, 1 H, 2-H), 2.94 (pseudo td, J = 13.1, 3.90 Hz,
1 H, 6-Hax), 1.97–1.80 (m, 2 H, 5-H) ppm. The D2O solution of
(2S,3R,4S)-1·HCl was then treated with Ambersep 900 OH resin
Methyl
(2S,3S,4S)-4-tert-Butoxy-3-hydroxy-2-[2-(trimethylsilyl)-
ethoxymethoxymethyl]piperidine-1-carboxylate [(؎)-20]: To a solu-
tion of (Ϯ)-19 (107 mg, 0.286 mmol) in anhydrous THF (13.4 mL),
under an N2 atmosphere and cooled to –78 °C, was added a solu-
tion of BH3·THF (970 µL, 1.0  in THF, 0.97 mmol). After 5 min,
the flask was submerged in an ice bath and left at 0 °C for 20 h.
Under vigorous stirring, trimethylamine N-oxide (Me3NO; 258 mg,
3.43 mmol) was added and, after mounting a condenser, the reac-
tion was heated at 65 °C (external bath) for 2 h. After cooling,
EtOAc (25 mL) was added and the organic layer was washed with
brine (2ϫ14 mL) and dried with anhydrous Na2SO4. Chromatog-
1
until pH 9 and filtered through a Celite layer. The H NMR spec-
trum of the resulting ent-4-epi-fagomine was directly recorded in
this solution: 1H NMR (400 MHz, D2O): δ = 3.74 (br. s, 1 H),
3.61–3.53 (m, 1 H), 3.48 (t, J = 7.1 Hz, 2 H), 2.93 (dt, J = 13.2,
3.1 Hz, 1 H), 2.61 (td, J = 6.9, 5.2 Hz, 1 H), 2.52–2.40 (m, 1 H),
1.58–1.57 (m, 2 H) ppm.
Methyl 4-tert-Butoxy-6-(hydroxymethyl)-3,4-dihydropyridine-1(2H)-
carboxylate [(؎)-17]: To a solution of (Ϯ)-16 (335 mg, 1.23 mmol) raphy (EtOAc/n-hexane, 1:10) afforded (Ϯ)-19 (73 mg, 65%; Rf =
in anhydrous Et2O (35 mL), cooled to –78 °C, was added dropwise
0.15) as a 8:1 mixture of epimers. 1H NMR (CDCl3, 400 MHz)
a solution of DIBAL-H (3.7 mL, 1  in n-hexane, 3.7 mmol) whilst (major epimer): δ = 4.68 (AB system, J = 6.8 Hz, 2 H, OCH2O),
stirring under an N2 atmosphere. After 1 h, the reaction mixture
was heated to 0 °C and stirred for 30 min. Then satd. Na2SO4 was
added until a solid formed and the mixture was filtered through a
Celite layer. The phases were separated and the organic layer was
dried with Na2SO4, filtered and concentrated. The crude product
was purified by chromatography (EtOAc/n-hexane, 1:2; Rf = 0.25)
to give (Ϯ)-17 (200 mg, 66%; Rf = 0.23) as a pale-yellow oil, which
was immediately used in the next step. A pure sample of cyclic
urethane (Ϯ)-18 (18 mg, 10%; Rf = 0.37) was obtained by
chromatography and characterized.
4.35 (br. s, 1 H, 2-H), 3.91 (dd, J = 10.5, 7.8 Hz, 1 H, C6-CH2O),
3.77 (dd, J = 10.5, 6.2 Hz, 1 H, C6-CH2O), 3.73 (br. s, 1 H, 6-Heq),
3.70 (s, 3 H, OCH3), 3.70–3.55 (m, 3 H, 4-H and O-CH2CH2TMS),
3.19 (td, J = 13.3, 2.9 Hz, 1 H, 6-Hax), 2.05–1.94 (m, 1 H, 5-Hax),
1.60 (br. s, 1 H, OH), 1.40 (br. dd, J = 13.7, 2.5 Hz, 1 H, 5-Heq),
1.22 [s, 9 H, (CH3)3C], 0.96–0.91 (m, 2 H, CH2TMS), 0.02 (s, 9 H,
TMS) ppm. 13C NMR (CDCl3, 100.4 MHz): δ = 157.2 (s, C=O),
94.7 (t, OCH2O), 74.2 [s, C(CH3)3], 68.4 (d, C-3), 67.1 (d, C-2),
65.1 (t, OCH2), 64.9 (d, C-4), 57.6 (t, CH2O), 52.7 (q, OCH3), 35.2
(t, C-6), 30.3 (t, C-5), 28.1 [q, 3 C, (CH3)3C], 18.1 (t, CH2TMS),
5838
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5831–5840

4-Hydroxypiperidine Alkaloids
–1.4 (q, 3 C, CH3 of TMS) ppm. ESI-MS: m/z (%) = 414 (10) [M
Preparation of Mosher’s Esters. Typical Procedure: To a solution of
+ Na]+, 358 (81), 314 (100). C18H37NO6Si (391): calcd. C 55.21, H (+)-4 (22 mg, 0.102 mmol) in CCl4 (913 µL) and pyridine (913 µL)
9.52, N 3.58; found C 55.33, H 9.19, N 3.24.
was added (S)-(+)-α-methoxy-α-trifluoromethylphenylacetic acid
chloride [(S)-(+)-MPTA-Cl] (30 µL, 0.160 mmol) whilst stirring un-
der an N2 atmosphere. After 18 h, water (20 mL) was added and
the mixture was extracted with Et2O (3ϫ20 mL). The combined
organic layers were washed with 5% aq. citric acid (20 mL), H2O
(20 mL), satd. aq. NaHCO3 (20 mL), H2O (20 mL) and finally
dried with Na2SO4. After filtration and evaporation of the solvent,
(7S,8S,8aS)-8-Hydroxy-7-(triisopropylsilyloxy)hexahydro[1,3]-
oxazolo[3,4-a]pyridin-3-one (21): To a stirred solution of (S)-13
(46 mg, 0.15 mmol) in anhydrous THF (7 mL), under an N2 atmo-
sphere and cooled to –78 °C, was added a solution of BH3·THF
(0.5 mL, 1.0  in THF, 0.5 mmol). After 5 min, the flask was sub-
merged in an ice bath and left at 0 °C for 20 h. Under vigorous
stirring, trimethylamine N-oxide (132 mg, 1.75 mmol) was added
and, after mounting a condenser, the reaction was heated at 65 °C
(external bath) for 2 h. After cooling, EtOAc (17 mL) was added
and the organic layer was washed with brine (2ϫ7 mL) and dried
with anhydrous Na2SO4. Chromatography (CH2Cl2/MeOH, 40:1)
afforded (7S,8S,8aS)-21 (33 mg, 66%; Rf = 0.15) as a 8:1 mixture
1
the product obtained was sufficiently pure for H NMR analysis.
Supporting Information (see also the footnote on the first page of
this article): Copies of 1H and 13C NMR spectra of all compounds,
1H NMR spectra for stereochemical assignment to the minor iso-
mer (2S,3R,4S)-15, and the calibration trace for GLC analysis.
1
of epimers. H NMR (CDCl3, 400 MHz) (major epimer): δ = 4.41
Acknowledgments
(dd, J = 8.9, 8.0 Hz, 1 H, 1-H), 4.26 (dd, J = 8.9, 4.3 Hz, 1 H, 1-
HЈ), 3.89 (ddd, J = 13.7, 5.1, 1.8 Hz, 1 H, 5-H), 3.69 (ddd, J =
11.3, 8.6, 4.3 Hz, 1 H, 7-H), 3.53 (ddd, J = 9.5, 8.0, 4.3 Hz, 1 H,
8a-H), 3.28 (td, J = 9.5, 1.6 Hz, 1 H, 8-H), 2.90 (td, J = 13.7,
3.3 Hz, 1 H, 5-HЈ), 1.97–1.91 (m, 1 H, 6-H), 1.64–1.53 (m, 1 H, 6-
HЈ), 1.08 (s, 18 H and 3 H, TIPS) ppm. 13C NMR (CDCl3,
100.4 MHz): δ = 157.0 (s, CO), 76.1 (d, C-8), 74.4 (d, C-8a), 65.5
(t, C-1), 57.2 (d, C-7), 39.2 (t, C-5), 32.4 (t, C-6), 18.0 (q, 6 C, CH3
of TIPS), 12.5 (d, 3 C, CH of TIPS) ppm. ESI-MS: m/z (%) = 352
(8) [M + Na]+, 156 (100). C16H31NO4Si (329): calcd. C 58.32, H
9.48, N 4.25; found C 58.11, H 9.67, N 4.32.
Amano Enzyme Inc. is acknowledged for generously providing us
with a free sample of lipase PS Amano IM. Professor Alberto
Brandi is acknowledged for useful suggestions and the University
of Florence for financial support.
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Dimethyl 4-(Triisopropyloxy)piperidine-1,2-dicarboxylate [(+)-22]:
To a suspension of NaHCO3 (16 mg, 0.19 mmol) in anhydrous
EtOAc (1.5 mL), Pd/C 10% (13.1 mg, 0.012 mmol) was added and
the suspension was stirred for 30 min under an H2 atmosphere (bal-
loon). A solution of (S)-11 (26.2 mg, 0.077 mmol) in anhydrous
EtOAc (680 µL) was added and the reaction was stirred at r.t. for
6 h. The reaction was stopped by filtration through a thin layer of
Celite and the solvent was evaporated to give (2R,4S)-22 (26 mg,
100%) as a thick colorless oil. [α]2D3 = +11.6 (c = 1.06, CHCl3). H
1
NMR (CDCl3, 400 MHz): δ = 4.80 (br. d, J = 6.6 Hz, major rot-
amer, 2-H), 4.64 (br. d, J = 6.6 Hz, minor rotamer, 2-H), 4.19 (br.
quint, J = 2.5 Hz, 1 H, 4-H), 3.96 (br. d, J = 12.0 Hz, minor rot-
amer, 6-Heq), 3.83 (br. d, J = 10.9 Hz, major rotamer, 6-Heq), 3.72
and 3.69 (s, 3 H and 3 H, two rotamers, OCH3), 3.56–3.44 (m, 1
H, 6-Hax), 2.50–2.40 (br. m, 1 H, 3-Heq), 1.86 (br. dd, J = 13.7,
7.2 Hz, 1 H, 3-Hax), 1.78–1.55 (m, 2 H, 5-H), 1.04 (s, 18 H and 3
H, TIPS) ppm. 13C NMR (CDCl3, 100.4 MHz): δ = 171.9 (s, CO),
157.1 and 156.6 (s, two rotamers, CO), 63.8 (d, C-4), 52.8 (d, C-2),
51.9 (q, OCH3), 51.2 and 50.9 (q, two rotamers, OCH3), 35.9 and
35.7 (t, two rotamers, C-6), 33.9 and 33.8 (t, two rotamers, C-3),
32.4 and 32.2 (t, two rotamers, C-5), 18.0 and 17.9 (q, 6 C, CH3 of
TIPS), 12.2 (q, 3 C, CH of TIPS) ppm. ESI-MS: m/z (%) = 374 (6)
[M + 1]+, 314 (100). C18H35NO5Si (373): calcd. C 57.87, H 9.44,
N 3.75; found C 57.73, H 9.52, N 3.89.
(2R,4S)-4-Hydroxypiperidine-2-carboxylic Acid [(–)-ent-2·HCl]:[34]
A suspension of (2R,4S)-22 (26 mg, 0.077 mmol) in 2  aq. HCl
(9.3 mL) was heated to reflux for 20 h. After cooling to r.t., the
reaction was washed with Et2O (3ϫ5 mL), concentrated and tritu-
rated with acetone (2ϫ1 mL) to give ent-2·HCl (14 mg, 100%) as
a pale-yellow solid after 12 h under vacuum; m.p. 200–203 °C (de-
comp). [α]2D5 = –7.0 (c = 0.38, MeOH). 1H NMR (D2O, 400 MHz):
δ = 4.07 (dd, J = 9.4, 3.9 Hz, 1 H, 2-H), 4.06–4.00 (m, 1 H, 4-H),
3.59 (td, J = 12.7, 4.1 Hz, 1 H, 6-Heq), 3.12 (td, J = 12.7, 3.3 Hz,
1 H, 6-Hax), 2.18 (br. d, J = 14.2 Hz, 1 H, 5-Heq), 2.56 (br. d, J =
13.8 Hz, 1 H, 3-Heq), 1.83–1.74 (m, 1 H, 5-Hax), 1.73–1.63 (m, 1
H, 3-Hax) ppm.
[9] For the most recent syntheses of 4-hydroxypipecolic acids, see
ref.[12] and: a) C.-S. Sun, Y.-S. Lin, D.-R. Hou, J. Org. Chem.
2008, 73, 6880; b) C. Alegret, X. Ginesta, A. Riera, Eur. J. Org.
Chem. 2008, 1789; c) P. Merino, V. Mannucci, T. Teieroli, Eur.
J. Org. Chem. 2008, 3943. For the most recent syntheses of
fagomine, see: d) N. Kumari, B. G. Reddy, Y. D. Vankar, Eur.
Eur. J. Org. Chem. 2010, 5831–5840
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5839

E. G. Occhiato et al.
FULL PAPER
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DЈEnrico, S. DЈAlonzo, S. Pedatella, G. Palumbo, Org. Lett.
2007, 9, 3473, and reference cited therein.
were poorer with this solvent than with more polar ones, see:
R. Gómez, A. Alcudia, L. S. Liebeskind, Org. Lett. 2001, 3,
3381. Furthermore, alcohol 4 was insoluble in hexane so the
conditions reported for seudenol by Rotticci et al.[18b] could
not be applied.
[24] PCPB was prepared as reported: A.-B. L. Fransson, Y. Xu, K.
Leijondahl, J.-E. Bäckvall, J. Org. Chem. 2006, 71, 6309.
[25] N. Armesto, M. Ferrero, S. Fernández, V. Gotor, J. Org. Chem.
2002, 67, 4978, and references cited therein.
[10]
[11]
[26] The diastereomeric ratio achieved in the double-bond hydro-
boration step was 13:1 with
a 4-OTBS group. A dia-
stereomerically pure compound was obtained only after
chromatography in 70% yield, see ref.[13]
[27] Work-up with satd. aq. NH4Cl and use of chromatographic
eluent without bases minimized the formation of (S)-13.
[28] Although the minor isomer (2S,3R,4S)-15 was obtained in im-
pure form after chromatographic separation from the major
isomer (2S,3S,4S)-15, it could be well-characterized. First,
there is no trans-diaxal relationship between any proton pair
among 2-H, 3-H, 4-H, and 5-H. Proton 4-H resonates at δ =
4.22 ppm as a multiplet with J Ͻ 3.0 Hz. This is in accordance
with an equatorial position of 4-H, which was confirmed by a
NOESY 1D experiment (mixing time 800 ms), which showed
no correlation between 4-H and any of the 7-H protons. A
NOE relationship does instead exist between protons 7-H and
the axial 6-H, which is consistent with an axial orientation of
the C-2 side chains [2-alkyl groups on the tetrahydropyridine
ring are axially oriented to remove the A(1,3) strain with the N-
protecting group, see: D. L. Comins, S. P. Joseph, in: Advances
in Nitrogen Heterocycles (Ed.: C. J. Moody), JAI Press, Green-
wich, CT, 1996, vol. 2, p. 251–294]. Furthermore, a NOE rela-
tionship is seen between 7-H and the proton of the OH group
at C-3. The proton at C-3 should therefore be axially oriented
(and thus shielded and resonates at δ = 3.7 ppm, which is partly
covered by the OMe group’s signal). The hydrolysis of
(2S,3R,4S)-15 provided an epimer of ent-1·HCl in which the 4-
H proton is clearly axially oriented because it resonates as a
ddd with a coupling constant Jax–ax = 11.9 Hz with the axial
5-H. Proton 3-H is, instead, equatorially oriented and, in fact,
is strongly deshielded (δ = 3.96 ppm) and resonates as a mul-
tiplet with low coupling constant values (J Ͻ 3 Hz) due to
equatorial–axial relationships with both 2-H and 4-H. This as-
signment was supported by observed NOE effects between 2-
H, 4-H, and axial 6-H.
[12]
a) E. G. Occhiato, D. Scarpi, A. Guarna, Eur. J. Org. Chem.
2008, 524; b) E. G. Occhiato, D. Scarpi, A. Guarna, S. Tabasso,
A. Deagostino, C. Prandi, Synthesis 2009, 3611.
L. Bartali, D. Scarpi, A. Guarna, C. Prandi, E. G. Occhiato,
Synlett 2009, 913; Erratum: Synlett 2010, 239.
The preparation of the N-Boc analogous of 7 and some 4-OH-
protected derivatives by a RCM-based methodology has re-
cently been reported, see: K. F. W. Hekking, D. C. J. Waalboer,
M. A. H. Moelands, F. L. van Delft, F. P. J. T. Rutjes, Adv.
Synth. Catal. 2008, 350, 95.
Interestingly, such a Pd-catalyzed carbonylative approach to
the preparation of α,β-unsaturated esters with alcohols other
than methanol, to the best of our knowledge, has no precedent.
[13]
[14]
[15]
[16]
K. Mochida, T. Hirata, Chem. Pharm. Bull. 1988, 36, 3642.
[17] An analogous approach to the synthesis of all four stereoiso-
mers of 4-hydroxypipecolic acid that exploited lipase AY 30
from Candida rugosa has been reported, but this involved the
lipase-catalyzed separation of diastereomers at a stage where
both stereocenters at C-2 and C-4 of the piperidine ring were
already installed. See: R. C. Lloyd, M. E. B. Smith, D. Brick,
S. J. C. Taylor, D. A. Chaplin, R. McCague, Org. Process Res.
Dev. 2002, 6, 762.
[18] a) S. Akai, K. Tanimoto, Y. Kita, Angew. Chem. Int. Ed. 2004,
43, 1407; b) D. Rotticci, T. Norin, K. Hult, Org. Lett. 2000, 2,
1373; c) C. Orrenius, T. Norin, K. Hult, G. Carrea, Tetrahe-
dron: Asymmetry 1995, 6, 3023.
[19] The enantioselectivity in an enzymatic kinetic resolution process
is expressed by the enantiomeric ratio, E, which is the ratio be-
tween the specificity constants (kcat/KM) of the enzyme for the
competing R and S enantiomers: E = (kcat/KM)R/(kcat/KM)S. E
was calculated using the formula E = ln[(1 – ees)/(1 + ees/eep)]/
ln[(1 + ees)/(1 + ees/eep)]. J. L. L. Rakels, A. J. J. Straathof,
J. Heijnen, J. Enzyme Microb. Technol. 1993, 15, 1051.
[20] Formerly known and used as Pseudomonas cepacia lipase. Li-
pase Amano AK (from Pseudomonas fluorescens) has also been
successfully used for the kinetic resolution of differently substi-
tuted 2-cyclohexen-1-ol derivatives in acetonitrile, see: H. Hagi-
wara, T. Nakano, H. Uda, Bull. Chem. Soc. Jpn. 1993, 66,
3110.
[29] Reported proton spectrum for 4-epi-fagomine: 1H NMR
(300 MHz, D2O): δ = 3.74 (br. s, 1 H), 3.60–3.50 (m, 1 H), 3.47
(dd, J = 6.7, 3.4 Hz, 2 H), 2.91 (td, J = 12.9, 3.3 Hz, 1 H), 2.57
(td, J = 6.9, 5.2 Hz, 1 H), 2.49–2.39 (m, 1 H), 1.56–1.49 (m, 2
H). H. Takahata, Y. Banba, H. Ouchi, H. Nemoto, A. Kato,
I. Adachi, J. Org. Chem. 2003, 68, 3603.
[30] Despite previously reported discouraging results with similar
substrates, we tried the hydroboration of (S)-13 with a more
hindered borane such as cyclohexylborane; however, only unre-
acted starting material was recovered, see: T. Luker, H. Hiem-
stra, W. N. Speckamp, J. Org. Chem. 1997, 62, 3592.
[21] a) J. Doussot, A. Guy, R. Garreau, A. Falguières, C. Ferroud,
Tetrahedron: Asymmetry 2000, 11, 2259; b) G. Carrea, B. Dan-
ieli, G. Palmisano, S. Riva, M. Santagostino, Tetrahedron:
Asymmetry 1992, 3, 775.
[31] N. Casamitjana, V. López, A. Jorge, J. Bosch, E. Molins, A.
Roig, Tetrahedron 2000, 56, 4027.
[22] a) B. A. Persson, A. L. E. Larsson, M. Le Ray, J.-E. Bäckvall,
[32] See ref.[10,13] for compound (+)-1·HCl.
J. Am. Chem. Soc. 1999, 121, 1645; b) M.-J. Kim, Y. I. Chung, [33] See ref.[29] for 4-epi-fagomine.
Y. K. Choi, H. K. Lee, D. Kim, J. Park, J. Am. Chem. Soc.
2003, 125, 11494, and references cited therein.
[23] Toluene was used in the lipase-mediated kinetic resolution of
5-hydroxy-5,6-dihydro-2(1H)-pyridones. In our case, the results
[34] For compound (+)-2·HCl, see: C. Herdeis, W. Engel, Arch.
Pharm. (Weinheim, Ger.) 1992, 325, 419, and ref.[12]
Received: June 9, 2010
Published Online: August 31, 2010
5840
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