Complementary and stereodivergent approaches to the synthesis of 5-hydroxy- and 4,5-dihydroxypipecolic acids from enantiopure hydroxylated lactams

Article abstract of DOI:10.1002/ejoc.201201429

We describe two complementary and stereodivergent routes, from commercially available and inexpensive starting materials, for the synthesis of 4,5-dihydroxy- and 5-hydroxypipecolic acids based on the chemistry of lactam-derived enol phosphates. The synthesis of the 4,5-cis-4,5- dihydroxypipecolic acids required the preparation from 2-deoxy-D- and -L-ribose of the enantiopure cis-(4S,5R)- and -(4R,5S)-4,5-dihydroxy-δ-valerolactam, respectively. These new chiral synthons are potentially useful for the synthesis of other natural products. The key step is the Pd-catalyzed methoxycarbonylation reaction of the enol phosphates generated from these lactams. This reaction provided enecarbamate esters that were easily converted by stereoselective reduction to the target compounds. The synthesis of the 4,5-trans-4,5-dihydroxypipecolic acid, as well as of 5-hydroxypipecolic acids, was realized from a known (S)-5-hydroxy-δ-valerolactam derivative and, for the dihydroxylated compound, required a highly stereoselective allylic bromination reaction of the enecarbamate ester obtained by methoxycarbonylation of the enol phosphate. The preparation of the (4R,5S) enantiomer of the cis-4,5-dihydroxy-δ-valerolactam from 2-deoxy-L-ribose, alongside the fact that (R)-5-hydroxy-δ-valerolactam can be prepared from (R)-(-)-γ-hydroxymethyl-γ-butyrolactone, means our approach allows for the synthesis of all stereoisomers of these compounds, which can be employed as conformationally constrained scaffolds in drug discovery. The stereoselective synthesis of 5-hydroxy- and 4,5-dihydroxypipecolic acids was accomplished by sequential Pd-catalysed methoxycarbonylation and stereoselective reduction of enantiopure hydroxylated lactam-derived enol phosphates obtained from both enantiomers of commercially available γ-hydroxymethyl-γ- butyrolactone and 2-deoxyribose. Copyright

Full text of DOI:10.1002/ejoc.201201429

FULL PAPER
DOI: 10.1002/ejoc.201201429
Complementary and Stereodivergent Approaches to the Synthesis of 5-
Hydroxy- and 4,5-Dihydroxypipecolic Acids from Enantiopure Hydroxylated
Lactams
Dina Scarpi,*[a] Laura Bartali,[a] Andrea Casini,[a] and Ernesto G. Occhiato*[a]
Medicinal chemistry / Lactams / Nitrogen heterocycles / Alkaloids / Carbonylation / Palladium
We describe two complementary and stereodivergent routes,
from commercially available and inexpensive starting mate-
rials, for the synthesis of 4,5-dihydroxy- and 5-hydroxypipec-
olic acids based on the chemistry of lactam-derived enol
phosphates. The synthesis of the 4,5-cis-4,5-dihydroxypipec-
target compounds. The synthesis of the 4,5-trans-4,5-dihy-
droxypipecolic acid, as well as of 5-hydroxypipecolic acids,
was realized from a known (S)-5-hydroxy-δ-valerolactam de-
rivative and, for the dihydroxylated compound, required a
highly stereoselective allylic bromination reaction of the en-
ecarbamate ester obtained by methoxycarbonylation of the
enol phosphate. The preparation of the (4R,5S) enantiomer of
olic acids required the preparation from 2-deoxy-D- and -L-
ribose of the enantiopure cis-(4S,5R)- and -(4R,5S)-4,5-dihy-
droxy-δ-valerolactam, respectively. These new chiral syn-
thons are potentially useful for the synthesis of other natural
products. The key step is the Pd-catalyzed methoxycarb-
onylation reaction of the enol phosphates generated from
these lactams. This reaction provided enecarbamate esters
that were easily converted by stereoselective reduction to the
the cis-4,5-dihydroxy-δ-valerolactam from 2-deoxy-L-ribose,
alongside the fact that (R)-5-hydroxy-δ-valerolactam can be
prepared from (R)-(–)-γ-hydroxymethyl-γ-butyrolactone,
means our approach allows for the synthesis of all stereoiso-
mers of these compounds, which can be employed as confor-
mationally constrained scaffolds in drug discovery.
structural components of naturally occurring compounds
possessing noteworthy biological activity.[1a,1b] For example,
a 3-hydroxypipecolic acid (2) unit is found in the natural
antitumor antibiotic tetrazomine (Figure 2),[7] and 4-
Introduction
l-Pipecolic acid (1; Figure 1) is a cyclic naturally occur-
ring non-proteinogenic α-amino acid isolated from plants,
fungi, microorganisms and human physiological fluids.[1] It
is produced during the degradation of lysine and, in hu-
mans, it accumulates in the body fluids causing pipecolic
acidemia in subjects suffering from Zellweger syndrome,
neonatal adrenoleukodystrophy, and infantile Refsum dis-
ease.[2] A wide range of pharmacologically active com-
pounds with a pipecolic acid fragment in their structure are
known, for example the local anaesthetic analogue ropiva-
caine (Figure 2),[3] the immunosuppressive agents rapamy-
cin[1c,4] and FK506,[1c,5] and the antitumor antibiotic, sand-
ramycin.[6] Among its derivatives, 3-, 4-, and 5-hydroxy-sub-
stituted pipecolic acids 2–7 are natural compounds that
play an important role in medicinal chemistry either as mo-
lecular scaffolds and α-amino acid analogues for the prepa-
ration of conformationally restricted peptides and pharma-
ceutically active compounds or because they are essential
[a] Dipartimento di Chimica “Ugo Schiff”, Università degli Studi
di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Fax: +39-055-4573531
E-mail: dina.scarpi@unifi.it
ernesto.occhiato@unifi.it
Homepage: http://www.unifi.it/dipchimica/CMpro-v-p-
400.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201429.
Figure 1. Pipecolic acid (1) and natural mono- and polyhy-
droxylated pipecolic acids 2–12.
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Synthesis of 5-Hydroxy- and 4,5-Dihydroxypipecolic Acids
hydroxypipecolic acid (4) is incorporated in the structures pounds 10 and 11, as well as 8 and 9, were obtained by
of the HIV-protease inhibitor palinavir[8] (Figure 2) and Marlier,[16a] and later by Bleecker,[17] through stereoselective
some antagonists of the cholecystokinin hormone.[9] 4- oxidation of the natural compound l-baikiain, in a synthe-
Hydroxypipecolic acid (4) has also been used for the prepa- sis that required tedious chromatographic separations (in-
ration of one of the most potent and selective N-methyl-d- cluding an 8-day long elution) of the free acids. The N-
aspartic acid (NMDA) receptor antagonists, CGS20281.[10] tosyl-protected, 4,5-cis compounds 10 and 11 were more
Naturally occurring 4-hydroxypipecolic acid derivatives recently prepared by Chattopadhyay,[23] though no attempts
form the largest subgroup of substituted pipecolic acids and were made to remove the protecting group. Consequently,
include the cyclodepsipeptide antibiotic virginiamycin no practical and scalable syntheses of compounds 9–11
S2,[11] serotonin receptor antagonist damipipecoline[12] have been reported so far. Instead, the synthesis of pipecolic
(Figure 2), ovalin,[13] and a sulfate compound possessing acid 12, which was found to be a specific inhibitor of hu-
NMDA-receptor-agonistic activity.[14] Pseudoconhydrine man liver β-d-glucuronidase,[24] has been reported by
(Figure 2) is an example of a natural compound containing Fleet[25] and Kuzuhara.[21] The limited work towards these
a reduced 5-hydroxypipecolic acid skeleton.[15]
compounds is surprising, because just as monohydroxylated
pipecolic acids 2–7 have been used as frames around which
to build biologically active compounds, polyhydroxypipec-
olic acids 8–11 could be exploited in a similar fashion.
Moreover, the presence of an additional hydroxy group can
either provide further interactions with the target protein’s
active site or be functionalized to attain higher potency and
selectivity, as well as to modulate lipophilicity, which is an
important parameter in drug discovery.
With this in mind, we planned two complementary and
stereodivergent approaches for the synthesis of 4,5-dihy-
droxypipecolic acids, focusing on the more neglected com-
pounds 9–11, and their enantiomers. The strategy is based
on the chemistry of lactam-derived enol phosphates that
we have recently shown to be suited to the preparation of
enantiopure 4-hydroxypipecolic acids 4 and 5.[26,27] We re-
port our efforts in this paper, including a new synthesis of
both enantiomers of 5-hydroxypipecolic acids 6 and 7.
Results and Discussion
Our approach to the synthesis of compounds 4 and 5, as
well as other piperidine alkaloids, was based on the trans-
formation of suitable lactam 13 (Scheme 1) into ene-
carbamate ester 14 through a Pd-catalysed methoxycarb-
onylation reaction of the corresponding enol phosphates.[26]
The enecarbamate esters were then converted into cis- and
trans-4-hydroxypipecolic acids by exploiting the stereocon-
trol exerted by suitable OH-group protection during the re-
duction step. This methodology requires enantiopure hy-
droxylated-lactams as starting materials or, as an alterna-
tive, a racemate resolution at any stage of the synthesis. We
used both approaches for the synthesis of 4-hydroxypipec-
olic acids[27] and various piperidine alkaloids, such as gly-
cosidase inhibitors fagomine[27b,28] and 1-deoxymannojiri-
mycin.[29]
Figure 2. Some natural and synthetic compounds with embedded
pipecolic acid derivatives.
Owing to their widespread presence in nature and their
significant medicinal potential, there has been much interest
in developing synthetic strategies to attain enantiopure 3-,
4-, and 5-hydroxypipecolic acids 2–7.[1a–1b] Pipecolic acids
bearing two or three hydroxy groups are much less wide-
spread in nature and have been isolated from just a few
sources. 4,5-Dihydroxypipecolic acid (8; Figure 1) was ex-
tracted from the leaves of Derris elliptica,[16a] isomer 11
from D. elliptica[16a] and Calliandra haematocephala,[16b]
and compound 9 from the leaves of C. angustifolia and the
sap of C. confusa.[17] The cis,cis compound 10 has been de-
tected by GC–MS in extracts from Tetraberlinia polyphylla
together with 9 and isolated from the leaves of C. pittieri.[18]
Similarly, compound 12, isolated from the seeds of Baphia
racemosa, is the only natural trihydroxypipecolic acid
known.[19] Perhaps owing to their scarcity in nature, only a
limited number of total syntheses of polyhydroxypipecolic
acids have been reported so far, with a particular focus on
compound 8, as reported by Fleet,[20] Kuzuhara,[21] and
Scheme 1. Retrosynthetic analysis for hydroxylated pipecolic acids
Liebscher.[22] As for the other isomers, mixtures of com- 4–11.
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For the synthesis of 4,5-cis-4,5-dihydroxypipecolic acid hydropyran-2-one, or the intermediate aldonic acid, accord-
10 and 11, cis-4,5-dihydroxylated lactam 15 (Figure 3) is re- ing to Han et al.[31a,31b] We found a ratio of about 2.5:1 in
quired. Despite being a simple compound (and a potentially favour of 2-deoxy-d-ribonolactone, a ratio that did not
useful polyfunctionalized chiral synthon), the isolated change after heating at 50 °C.[32]
enantiomers of cis isomer 15 are unknown, and only the
The partial conversion of 18 into corresponding primary
synthesis of the racemic compound has been reported.[29] O-tosyl derivative 19 was realized by treatment with 4-tolu-
For the synthesis of 4,5-trans pipecolic acid 9, we envisaged enesulfonyl chloride (TsCl) in pyridine at –15 °C and then
a complementary route starting from enantiopure 5-hy- leaving at 0 °C for 5 h,[33] to give (+)-19 in 54% yield after
droxy δ-valerolactam 16, which was synthesised by Herdeis chromatography. This was the best yield we obtained under
from glutamic acid,[30] and in which the required 4-OH these conditions; prolonging the reaction times to com-
group could be installed at a later stage of the process. With pletely convert 18 into 19 led to partial tosylation of the
both enantiomers of glutamic acid (or the late synthetic in- secondary OH group. Similarly, several attempts at selec-
termediate, γ-hydroxymethyl-γ-butyrolactone) and 2-deoxy- tively converting the primary hydroxy group into a mesylate
ribose being commercially available, both approaches would (MsCl, Et3N, in CH2Cl2 at –30 °C) failed owing to the con-
also allow the preparation of the unnatural d-enantiomers current mesylation of the secondary alcohol, followed by
of target pipecolic acids 9–11. To obtain our target com- elimination of methanesulfonic acid during chromatog-
pounds, we first focused on the synthesis of enantiopure raphy. Instead, bromination of 18 by treatment with thionyl
cis-4,5-dihydroxy δ-valerolactam 15 from commercially bromide in anhydrous dimethylformamide (DMF) at room
available 2-deoxy-d-ribose, as well as its enantiomers from temperature occurred selectively at the primary position,
2-deoxy-l-ribose (Scheme 2). To this end, 2-deoxy-d-ribose but only gave lactone (+)-20 in 47% yield after chromatog-
17 was initially treated with Br2 in water for 5 d to give 2- raphy. However, it was possible to recover some of the unre-
deoxy-d-ribonolactone (+)-18 in excellent yield (88%) after acted starting material (31%) which was reacted again with
chromatography.[31] This compound proved stable in aprotic SOBr2 under the same conditions, providing bromolactone
solvents, but in protic ones, such as methanol, it slowly (+)-20 in 61% total yield.[34] Transformation of both 19 and
equilibrated to give a minor isomer, which could be the cor- 20 into 2-deoxy-5-azido-d-ribonolactone (+)-21 was ac-
responding six-membered lactone, cis-4,5-dihydroxytetra- complished by treatment with NaN3 in acetonitrile heated
to reflux, which provided key intermediate 21 in 87% (from
19) and 95% yield (from 20). Eventually, hydrogenation of
21 at atmospheric pressure over 10% Pd/C gave pure dihy-
droxylated lactam (4S,5R)-15 in 91% yield. By using the
same strategy of converting 2-deoxy-l-ribose (ent-17) into
corresponding bromide ent-20 (47% over two steps), and
further to ent-21 (97%), we were also able to prepare its
enantiomer (4R,5S)-15 in 43% overall yield.
Figure 3. Hydroxylated δ-valerolactams 15–16.
With lactam (4S,5R)-15 in hand, we proceeded with the
synthesis of 2,4-cis-4,5-cis-4,5-dihydroxypipecolic acid (10;
Scheme 3) by converting the lactam into enantiopure en-
Scheme 3. Synthesis of 4,5-dihydroxypipecolic acid 10. Reagents
and conditions: (a) 2,2-dimethoxypropane, pTsOH, MeOH, 55 °C,
1 h; (b) CH3OCOCl, nBuLi, –78 °C; (c) (PhO)2POCl, KHMDS,
THF, –78 °C; (d) 10% Pd(OAc)2, 20% Ph3P, CO, MeOH, Et3N,
DMF, 75 °C, 1 h; (e) H2 (1 atm), 10% Pd/C, NaHCO3, EtOAc, 4 h;
(f) 4 n HCl, reflux, 24 h.
Scheme 2. Synthesis of enantiopure lactam 15. Reagents and condi-
tions: (a) Br2, H2O, 25 °C, 5 d; (b) TsCl, pyridine, –15 °C, 2 h, then
0 °C, 5 h; (c) SOBr2, room temp., 4.5 h; (d) NaN3, CH3CN, 18-
crown-6 or 15-crown-5, reflux, 15–20 h; (e) H2 (1 atm), 10% Pd/C,
MeOH, 24 h.
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Synthesis of 5-Hydroxy- and 4,5-Dihydroxypipecolic Acids
ecarbamate ester 25 according to the procedure we reported
for the corresponding racemic compound.[29] Thus protec-
tion of (4S,5R)-15 as acetonide (–)-22 (92%), and then N-
protection as carbamate (–)-23 (84%) set the stage for the
quantitative generation of corresponding enol phosphate 24
by treatment of the lactam with potassium bis(trimethylsil-
yl)amide (KHMDS) at –78 °C in tetrahydrofuran (THF)
followed by the addition of diphenylchlorophosphate. Pd-
catalysed methoxycarbonylation reaction of the phosphate
in anhydrous DMF and at 1 atm was carried out at 75 °C
in the presence of an excess of MeOH to give key ester
intermediate (+)-25 in 78% yield after two steps.
We then subjected the enamine double bond of 25 to
heterogeneous catalytic hydrogenation over 10% Pd/C at
1 atm, which gave cis ester (–)-26 in quantitative yield and
with complete facial selectivity (by 1H NMR). Complete
deprotection in aqueous 4 n HCl at reflux temperatures
eventually concluded the first total synthesis of free l-pipec-
olic acid 10 in 27% overall yield in 9 steps and for which
we could measure the optical rotation.[35]
For the synthesis of the other 4,5-cis-dihydroxylated pip-
ecolic acid, compound 11 (Scheme 4), ent-25 that has been
prepared in 51% overall yield as reported for its enantio-
mer, was subjected to a conjugate reduction by Super-Hy-
dride (LiEt3BH) at –10 °C. After quenching the anion with
a saturated NaHCO3 solution, 1H NMR analysis of the
crude reaction mixture revealed the formation of a 2.6:1
mixture between thermodynamically more stable ester (–)-
27 and cis,cis isomer ent-26. The two diastereoisomers were
easily separated by chromatography to give pure 27 in 68%
yield and its minor isomer in 22% yield. On the basis of
Scheme 4. Synthesis of 4,5-dihydroxypipecolic acid 11 and ent-10.
Reagents and conditions: (a) 2,2-dimethoxypropane, pTsOH,
MeOH, 55 °C, 1 h; (b) CH3OCOCl, nBuLi, –78 °C; (c) (PhO)2-
POCl, KHMDS, THF, –78 °C; (d) 10% Pd(OAc)2, 20% Ph3P, CO,
MeOH, Et3N, DMF, 75 °C, 1 h; (e) H2 (1 atm), 10% Pd/C,
NaHCO3, EtOAc, 4 h; (f) LiEt3BH, THF, –10 °C, 70 min; (g) 4 n
HCl, reflux, 24 h; (h) TBAF, THF, 0 °C Ǟ room temp., 18 h.
our previous experience, the latter was subjected to epi- ing 5-unsubstituted enecarbamate ester was complete in
merization by treatment with tetra-n-butylammonium 15 min under the same conditions,[27b] complete consump-
fluoride (TBAF) in THF,[27d] which provided an approxi- tion of 32 occurred only after 1.5 h. On the other hand, we
mately 1:1 mixture of the two compounds (27 and ent-26) were glad to observe that allyl bromide 33 was obtained as
after 19 h at room temperature.[36] Further purification by a single trans diastereoisomer and with the two groups (Br
chromatography gave a total yield of target 27 of 78% over and OTBS) axially oriented. This assignment was made on
the two steps. Deprotection of 27 in 4 n HCl heated to re- the basis of the very low coupling constant values (less than
flux eventually provided pure 11 in quantitative yield,[37] 4 Hz) of protons 4-H and 5-H, which resonate at δ = 4.32
and analogous treatment of ent-26 provided the unnatural and 4.22 ppm almost as broad singlets, and the lack of any
enantiomer of 2,4-cis-4,5-cis isomer 10.
nOe correlations between 6-Hax and any of the two protons
As mentioned above, for the synthesis of 4,5-trans com- mentioned above. Our failed attempts to convert bromide
pound 9 we chose to introduce one of the hydroxy groups 33 into a 4,5-cis diol derivative by SN2 displacement of the
on the heterocyclic skeleton at a later stage of the synthesis, bromide with an O-nucleophile (e.g. AcOK in anhydrous
relying on preferential axial attack in the key allylic bromin- CH2Cl2 in the presence of 18-crown-6 at 25 °C or with Ac-
ation reaction step and the possible trans-directing effect by OLi in DMF at 45 °C) can be explained by the steric hin-
the bulky silyloxy group in compound 32 (Scheme 5).[38] drance from the large axially oriented OTBS group. Cat-
The synthesis of (+)-32 was realized starting from 5-OH- ionic processes were all successful in providing 4,5-trans
protected lactam 29, which was prepared from commer- diol derivative (–)-34, in particular treatment of 33 with sil-
cially available (S)-(+)-γ-hydroxymethyl-γ-butyrolactone ver acetate (2 equiv.) in glacial acetic acid furnished 34 in
(28) as reported.[30] After N-protection as the methyl carb- the highest yield (75% over the two steps).[40] Again, the
amate, compound (+)-30 was converted into the corre- trans stereochemical assignment of compound 34 is based
1
sponding enol phosphate 31 (99%) and then enecarbamate on the analysis of the coupling constants in its H NMR
ester 32 (82%) as usual. The allylic bromination of 32 was spectrum: both 4-H (δ = 4.95 ppm) and 5-H (δ = 3.91 ppm)
carried out by treatment with N-bromosuccinimide (NBS) protons possess very low coupling constants (less than
in the presence of catalyst azobis(isobutyronitrile) (AIBN) 3 Hz) that strongly indicate an equatorial relationship.
in a mixture of CCl4/CHCl3 heated to reflux.[39] Interest- Moreover, there is no nOe enhancement of 4-H and 5-H
ingly, whereas the bromination reaction of the correspond- when selecting 6-Hax in NOESY 1D experiments. The trans
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selectivity in both radical and cationic processes to give 33 4,5-trans compound (–)-36 (71% after chromatography)
and 34, respectively, can be only partially explained by and 2,4-cis-4,5-trans isomer 37. Unfortunately, it was not
using steric reasons, and stereoelectronic effects could play possible to isolate the minor isomer without traces of 36.
a major role in stabilizing the transition state.[38] The axial As expected, the effect of the bulky silyloxy group dictated
introduction of the bromine on the half-chair conformation which face of the double bond would be adsorbed on the
with the axial OTBS group at C-5 gives maximum π-overlap Pd-catalyst, although the stereoselectivity was lower than
in the allylic radical during the reaction. In addition, there we had hoped. When compound 32, lacking the 4-OH
is the possibility of further stabilization by hyperconjugative group, was hydrogenated, the selectivity was much higher
delocalization of the forming Br–C σ-bond with the σ* or- (Scheme 7), suggesting slight steric hindrance by the 4-OH
bital of C–OTBS bond (Scheme 6). The same interactions in 35, similarly to the 4-hydroxy-substituted com-
could also take place during the SN1 process leading exclu- pounds.[27d] Major isomer 36 was easily separated by
sively to trans acetate 34.
chromatography and deprotected in aqueous 4 n HCl at re-
flux temperatures to give target pipecolic acid 9 in quantita-
tive yield.[41]
Scheme 5. Synthesis of 4,5-dihydroxypipecolic acid 9 and ent-8.
Reagents and conditions: (a) CH3OCOCl, nBuLi, –78 °C;
(b) (PhO)2POCl, KHMDS, THF, –78 °C; (c) 10% Pd(OAc)2, 20%
Ph3P, CO, MeOH, Et3N, DMF, 75 °C, 40 min; (d) NBS, AIBN,
CCl4/CHCl3 (9:1), reflux, 1.5 h; (e) silver acetate, AcOH, 15 min,
25 °C; (f) MeONa, MeOH, 0 °C, 1 h; (g) H2 (1 atm), 10% Pd/C,
NaHCO3, EtOAc, 20 h; (h) 4N HCl, reflux, 24 h.
Scheme 7. Synthesis of 5-hydroxypipecolic acid 6, ent-6 and 7. Rea-
gents and conditions: (a) H2 (1 atm), 10% Pd/C, NaHCO3, EtOAc,
21 h; (b) 3 n HCl, CH3CN, 25 °C, 2 h; (c) 4 n HCl, reflux, 24 h;
(d) LiEt3BH, THF, –10 °C, 70 min.
Owing to a lack of high-field NMR studies on 4,5-dihy-
droxypipecolic acids, we also performed NOESY 1D and
2D experiments to assess the spatial orientation of the three
substituents on the piperidine ring. As depicted in Figure 4,
in all cases the carboxylic group at the 2-position is equato-
rially oriented, as indicated by the nOe cross-peak between
2-H (axially oriented) and 6-Hax, thus dictating the spatial
orientation of the two hydroxy groups. In compound 9, the
two protons at C-4 and C-5 give rise to almost broad sing-
lets with very low coupling constants (J Ͻ 3.5 Hz) at δ =
4.04 and 3.94 ppm, consistent with their equatorial posi-
tion. In compound 10, a nOe correlation exists between 2-
Scheme 6. Stereochemistry in the allylic oxidation of compound 32
and substitution of 33.
After removal of the acetyl group to give (–)-35, the ene- H and 4-H, indicating an equatorial orientation of the 4-
carbamate ester was hydrogenated under standard condi- OH group. In this compound, only 5-H appears as a broad
1
tions to yield a 3.1:1 mixture (by H NMR) of 2,4-trans- singlet at δ = 4.16 ppm consistent with an axial position for
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Synthesis of 5-Hydroxy- and 4,5-Dihydroxypipecolic Acids
the 5-OH group. The reverse situation applies to compound onylation of the enol phosphate generated from 15, which
11, for which we found a nOe correlation between 3-Hax provided an enecarbamate ester that was easily converted,
and 5-H, and it was the equatorially oriented 4-H (δ = by stereoselective reduction, either to 10 or 11 (obtained in
4.13 ppm) that had a very low coupling constant value. The 27 and 17% yield, respectively, over ten steps). The synthe-
equatorial orientation of 5-OH is further confirmed by the sis of 4,5-trans-4,5-dihydroxypipecolic acid was instead real-
high value for the 3J coupling between 5-H and 6-Hax ized through a highly stereoselective allylic bromination re-
(10 Hz), consistent with an axial orientation of 5-H.
action of the enecarbamate ester obtained by methoxycarb-
onylation of the enol phosphate derived from a known 5-
hydroxy-δ-valerolactam derivative. After substitution to
give the 4-hydroxylated derivative, reduction of the double
bond and subsequent hydrolysis provided target compound
9 (in 22% yield over 8 steps). Although in this work we did
not specifically focus on the preparation of the unnatural
enantiomers of 10 and 11, we have set the stage for their
synthesis because we have prepared the enantiopure precur-
sor 15 from both 2-deoxy-d- and l-ribose. Similarly, the
same route can furnish unnatural enantiomers of 9 and 6–
7, because the precursor (R)-(–)-γ-hydroxymethyl-γ-butyro-
lactone is commercially available. This approach allows the
synthesis of several hundred mg of final compound, and
the potential of these 4,5-dihydroxypipecolic acids as con-
formationally constrained scaffolds in medicinal chemistry
can now be assessed.
Figure 4. Nuclear Overhauser effects in dihydroxypipecolic acids
9–11.
Having assessed our approach to the synthesis of 4,5-
dihydroxypipecolic acids 9–11, we were tempted to exploit
5-silyloxy-protected compound 32 (and its enantiomer) for
the preparation of both cis- and trans-5-hydroxypipecolic
acid 6 and 7, although their synthesis has been reported.[42]
Thus, hydrogenation of 32 provided cis compound 38 (95%
yield, stereochemical attribution based on nOe correlation
3
between 3-Hax and 5-H and a large J value between 6-Hax
and 5-H in a compound with the 2-CO2Me group axially
oriented) in a 8:1 ratio with its trans isomer. This was re-
moved from the mixture by chromatography after O-depro-
tection to give compound cis 39 as a single diastereoiso-
mer.[42g,42h,43] After N-deprotection in 4 n HCl at reflux
temperatures, pure cis-5-hydroxypipecolic acid 6 was ob-
tained in 43% overall yield from 29. Conjugate reduction
of the double bond in ent-32 showed poor stereoselectivity,
providing the thermodynamically less stable trans isomer
(40) in a 1:1.5 ratio with cis compound ent-38. This ratio is
easily explained considering the forced axial orientation of
the 2-CO2Me group necessary to remove the A1,3 strain
with the N-protection.[44] In trans compound 40 the 5-
OTBS group is axially oriented and thus less favoured for
the 1,3-diaxial repulsive interaction with 3-H. As above, de-
protection gave free alcohols ent-39 and 41, which, after
chromatographic separation, were quantitatively converted
into ent-6 and natural pipecolic acid 7.
Experimental Section
General: Chromatographic separations were performed under pres-
sure on silica gel by using flash-column techniques; Rf values refer
to thin-layer chromatography (TLC) carried out on 25-mm silica
gel plates (Merck F254), with the same eluent as indicated for the
column chromatography. 1H NMR and 13C NMR spectroscopic
data were recorded with a Mercury 400 instrument in CDCl3 solu-
tion, unless otherwise stated. Solvent references were set at δ = 7.26
(CDCl3), 4.79 (D2O), 3.31 (CD3OD), and 2.50 ppm ([D6]DMSO).
Mass spectra were carried out by direct inlet on a LCQ FleetTM
Ion Trap LC/MS system (Thermo Fisher Scientific) with an electro-
spray ionization (ESI) interface in the positive mode. Microanaly-
ses were carried out with a Perkin–Elmer 2400/2 elemental analyser.
Optical rotations were determined with a JASCO DIP-370 instru-
ment.
(4S,5R)-4-Hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one [(+)-
18]: Bromine (4.0 mL, 78.0 mmol) was slowly added to a solution
of 2-deoxy-d-ribose (17; 2.01 g, 15.0 mmol) in water (12 mL). The
flask was then sealed and the red solution was stirred at room tem-
perature for 5 d. After dilution with water (10 mL), Ag2CO3 was
added until the solution reached pH 7 (complete decolourization
occurred). The suspension was filtered through a Celite pad and
the filtrate evaporated under vacuum. The residue was purified by
Conclusions
In this work we have demonstrated the flexibility and
ease of our approach to the synthesis of polyhydroxylated flash chromatography (eluent: EtOAc/MeOH, 10:1; Rf 0.50) afford-
ing pure lactone 18 (1.74 g, 88%) as a colourless oil.[31a,32] [α]1D8
=
pipecolic acids based on lactam-derived enol phosphates. In
a few steps, from commercially available and inexpensive
starting materials, we were able to prepare three isomers
of 4,5-dihydroxypipecolic acid and the two isomers of the
simpler 5-hydroxy derivative. The synthesis of 4,5-cis-4,5-
dihydroxypipecolic acids required the preparation from 2-
deoxy-d- (and L) ribose of enantiopure cis-4,5-dihydroxy-
δ-valerolactam 15, which is a new compound that may be
useful in the syntheses of other natural products. The key
+3.05 (c = 1.14, CH3OH) {ref.[32] [α]2D5 = +2.17 (c = 0.6, CH3OH);
ref.[45] [α]2D2 = +3.50 (c = 0.8, CH3OH)}. [α]2D4 = +19.2 (c = 1.33,
H2O) {ref.[31a] [α]2D2 = +19.9 (c = 0.71, H2O)}. 1H NMR ([D6]-
DMSO, 400 MHz): δ = 5.52 (d, J = 4.1 Hz, 1 H, CHOH), 5.10 (t,
J = 5.5 Hz, 1 H, CH2OH), 4.33–4.27 (m, 2 H, 4-H and 5-H), 3.62–
3.53 (m, 2 H, CH2OH), 2.85 (dd, J = 17.6, 6.2 Hz, 1 H, 3-H),
2.26 (dd, J = 17.6, 2.1 Hz, 1 H, 3-HЈ) ppm. 1H NMR (CD3OD,
400 MHz): δ = 4.42 (dt, J = 6.6, 2.3 Hz, 1 H, 4-H), 4.36 (X part
of an ABX system, m, 1 H, 5-H), 3.73 (AB part of an ABX system,
step in the process was the Pd-catalysed methoxycarb- J = 12.5, 3.3 Hz, 2 H, CH2OH), 2.91 (dd, J = 18.0, 6.8 Hz, 1 H,
Eur. J. Org. Chem. 2013, 1306–1317
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1311

D. Scarpi, L. Bartali, A. Casini, E. G. Occhiato
FULL PAPER
3-H), 2.37 (dd, J = 18.0, 2.5 Hz, 1 H, 3-HЈ) ppm. 13C NMR ([D6]- suspension heated to reflux until completion (in all 15 h). After
DMSO, 100.32 MHz): δ = 177.1 (s, CO), 89.2 (d, C5), 68.7 (d, C4), cooling to room temperature, the suspension was filtered through
61.7 (t, CH2OH), 38.9 (t, C3) ppm. 13C NMR (CD3OD,
a Celite pad and the filtrate concentrated under vacuum. The resi-
100.32 MHz): δ = 178.6 (s, CO), 90.2 (d, C5), 69.7 (d, C4), 62.5 (t, due was purified by flash chromatography (eluent: n-hexane/
CH2OH), 39.2 (t, C3) ppm. MS (ESI): m/z (%) = 101 (19) [M+
–
EtOAc, 2:3; Rf 0.23), affording pure azide 21 (401 mg, 87%) as a
31], 43 (100). C5H8O4 (132.11): calcd. C 45.46, H 6.10; found C
45.35, H 6.39.
colourless oil.
From Bromide 20: Bromide 20 (580 mg, 2.97 mmol) was dissolved
in anhydrous acetonitrile (13 mL) under a nitrogen atmosphere.
Next 15-crown-5 ether (118 μL, 0.59 mmol) and NaN3 (387 mg,
2.0 equiv.) were rapidly added and the mixture was heated to reflux.
After 8 h a further amount of NaN3 (0.5 equiv.) was added and the
suspension heated to reflux until completion (20 h; TLC monitor-
ing). After cooling to room temperature, the suspension was fil-
tered through a mixed silica gel/Celite pad and the filtrate concen-
trated under vacuum. Azide 21 (443 mg, 95%) was obtained as a
(2S,3S)-(3-Hydroxy-5-oxotetrahydrofuran-2-yl)methyl
4-Methyl-
benzenesulfonate [(+)-19]: A solution of lactone 18 (850 mg,
6.4 mmol) in freshly distilled pyridine (20 mL) was cooled to –15 °C
(external) and, after 15 min, TsCl (1.15 equiv.) was rapidly added
and the mixture left to stir at –15 °C for 2 h and at 0 °C for 5 h.
The solvent was then removed under vacuum and the residue taken
up in water (20 mL); the product was extracted with EtOAc (4ϫ
20 mL) and the combined organic extracts washed with 0.5 m HCl
(2ϫ 20 mL), water (20 mL) and dried with anhydrous Na2SO4. Af-
ter filtration and evaporation of the solvent, crude 19 was obtained
and purified by flash chromatography (eluent: n-hexane/EtOAc,
2:3; Rf 0.19), affording pure O-tosylate 19 as a white solid (990 mg,
54%). M.p. 56.0–57.9 °C (ref.[33] 56–58 °C). [α]2D0 = +36.5 (c = 0.89,
CHCl3) {ref.[33] [α]2D0 = +39.6 (c = 5.3, CH2Cl2); ref.[46] [α]2D0 = +32.1
colourless oil and no further purification was required. [α]2D5
=
+100.5 (c = 0.39, CHCl3). 1H NMR (400 MHz): δ = 4.51–4.45 (m,
2 H, 4-H, 5-H), 3.64 (AB part of an ABX system, J = 13.3, 3.9 Hz,
2 H, CH2N3), 2.96 (dd, J = 18.2, 6.8 Hz, 1 H, 3-H), 2.55 (dd, J =
18.2, 3.9 Hz, 1 H, 3-HЈ) ppm. 13C NMR (100.32 MHz): δ = 175.8
(s, CO), 85.5 (d, C5), 69.0 (d, C4), 51.8 (t, CH2N3), 37.8 (t,
C3) ppm. MS/MS (ESI of [M + 1]+): m/z (%) = 158 (100) [M+
1]. C5H7N3O3 (157.13): calcd. C 38.22, H 4.49, N 26.74; found C
37.96, H 4.72, N 26.56.
+
1
(c = 3.2, CH2Cl2)}. H NMR (400 MHz): δ = 7.76 (d, J = 8.2 Hz,
2 H, Ar), 7.37 (d, J = 8.4 Hz, 2 H, Ar), 4.62–4.58 (m, 1 H, 3-H),
4.51–4.48 (m, 1 H, 2-H), 4.29 (dd, J = 11.3, 3.3 Hz, 1 H, CH2OTs),
4.16 (dd, J = 11.3, 3.5 Hz, 1 H, CH2OTs), 2.90 (dd, J = 18.2,
7.2 Hz, 1 H, 4-H), 2.64 (br. s, 1 H, OH), 2.53 (dd, J = 18.2, 3.7 Hz,
1 H, 4-HЈ), 2.46 (2, 3 H, CH3) ppm. 13C NMR (100.32 MHz): δ =
174.1 (s, CO), 145.7 (s, Ar), 131.8 (s, Ar), 130.2 (d, 2 C, Ar), 128.0
(d, 2 C, Ar), 83.6 (d, C2), 68.9 (d, C3), 67.8 (t, CH2OTs), 37.7 (t,
C4), 21.7 (q, CH3) ppm. MS (ESI): m/z (%) = 286 (100) [M]+, 115
(6). C12H14O6S (286.30): calcd. C 50.34, H 4.93; found C 49.94, H
5.06.
(4S,5R)-4,5-Dihydroxypiperidin-2-one [(–)-15]: Azide 21 (840 mg,
5.35 mmol) was dissolved in anhydrous methanol (35 mL) under a
nitrogen atmosphere. Then, 10% Pd/C catalyst (3mol-%) was
added and the reaction flask flushed first with N2 and then with
hydrogen and left under a hydrogen atmosphere (balloon) at room
temperature for 24 h. The suspension was filtered through a Celite
pad and the filtrate concentrated under vacuum, affording pure
lactam 15 as a white solid (638 mg, 91%) with spectroscopic data
identical to those of the racemic compound.[29] M.p. 160.9–
162.0 °C. [α]2D4 = –17.8 (c = 0.62, CH3OH). 1H NMR (D2O,
400 MHz): δ = 4.21–4.15 (m, 2 H, 4-H, 5-H), 3.46 (dd, J = 13.0,
4.3 Hz, 1 H, 6-HЈ), 3.37 (dd, J = 13.0, 5.1 Hz, 1 H, 6-HЈЈ), 2.68
(dd, J = 17.5, 5.5 Hz, 1 H, 3-HЈ), 2.50 (dd, J = 17.5, 7.8 Hz, 1 H,
3-HЈЈ) ppm. C5H9NO3 (131.13): calcd. C 45.80, H 6.92, N 10.68;
found C 45.96, H 6.75, N 10.36.
(4S,5S)-5-(Bromomethyl)-4-hydroxydihydrofuran-2(3H)-one
[(+)-
20]: A solution of lactone 18 (850 mg, 6.4 mmol) in anhydrous
DMF (9.5 mL) was cooled to 0 °C and thionyl bromide (595 μL,
7.7 mmol) was added dropwise. After 2 min the cooling bath was
removed and the orange solution was left to stir for 4.5 h. The
reaction was quenched by adding anhydrous methanol (332 μL)
and, after 10 min, water (95 mL). The product was extracted with
EtOAc (4ϫ 80 mL) and the combined organic extracts were dried
with anhydrous Na2SO4. After filtration and evaporation of the
solvent, crude 20 was obtained and purified by flash chromatog-
raphy (eluent: n-hexane/EtOAc, 1:1; Rf 0.25). Pure bromide 20
(587 mg, 47%) was obtained as a colourless oil. The aqueous layer
was concentrated under vacuum and the residue chromatographed
(eluent: EtOAc, Rf 0.21) to give alcohol 18 (262 mg). This was
treated again with SOBr2 as reported above providing pure 20
(181 mg) in a total yield of 61%. [α]2D6 = +12.5 (c = 1.22, EtOAc).
1H NMR (400 MHz): δ = 4.63–4.58 (m, 1 H, 4-H), 4.58–4.53 (m,
1 H, 5-H), 3.61 (dd, J = 11.2, 3.9 Hz, 1 H, CH2Br), 3.53 (dd, J =
11.2, 6.0 Hz, 1 H, CH2Br), 2.99 (dd, J = 18.4, 7.2 Hz, 1 H, 3-H),
(4R,5S)-4-Hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one [(–)-
ent-18]: Prepared as reported above for (+)-18. Starting from 2-
deoxy-l-ribose (ent-17; 700 mg, 5.22 mmol) pure lactone ent-18
(545 mg, 79%) was obtained as a colourless oil. [α]2D3 = –17.1 (c =
1.04, H2O). Analytical and spectroscopic data as reported above.
(4R,5R)-5-(Bromomethyl)-4-hydroxydihydrofuran-2(3H)-one
[(–)-
ent-20]: Prepared as reported above for its enantiomer from lactone
ent-18 (450 mg, 3.40 mmol). Bromide ent-20 (398 mg, 60%) was ob-
tained as a colourless oil. [α]2D3 = –12.1 (c = 0.9, EtOAc). Analytical
and spectroscopic data as above.
(4R,5S)-5-Azidomethyl-4-hydroxydihydrofuran-2-one
[(–)-ent-21]:
J = 18.4, 3.9 Hz, 1
H, 3-HЈ) ppm. 13C NMR
Prepared as reported above for its enantiomer from bromide (–)-
ent-20 (306 mg, 1.57 mmol). Pure azide ent-21 (239 mg, 97%) was
obtained as a colourless oil. [α]2D2 = –98.2 (c = 1.12, CHCl3). Ana-
lytical and spectroscopic data as reported above.
2.58 (dd,
(100.32 MHz): δ = 175.7 (s, CO), 85.6 (d, C5), 70.1 (d, C4), 37.9
(t, CH2Br), 31.5 (t, C3) ppm. MS (ESI): m/z (%) = 219 (45) [M +
Na]+, 217 (47) [M + Na]+. C5H7BrO3 (195.01): calcd. C 30.79, H
3.62; found C 30.85, H 3.93.
(4R,5S)-4,5-Dihydroxypiperidin-2-one [(+)-ent-15]: Prepared as re-
ported above for its enantiomer, starting from azide ent-21 (239 mg,
1.52 mmol). Pure lactam (4R,5S)-15 was obtained as a white solid
(185 mg, 93%). [α]2D3 = +17.2 (c = 1.1, CH3OH). Analytical and
spectroscopic data as reported above.
(4S,5R)-5-Azidomethyl-4-hydroxydihydrofuran-2-one [(+)-21] from
Tosylate 19: Tosylate 19 (825 mg, 2.88 mmol) was dissolved in an-
hydrous acetonitrile (12.5 mL) under a nitrogen atmosphere. Next
18-crown-6 ether (152 mg, 0.58 mmol) and NaN3 (280 mg,
1.5 equiv.) were rapidly added and the mixture was heated to reflux.
After 7 h a further amount of NaN3 (0.2 equiv.) was added and the
(3aR,7aS)-2,2-Dimethyltetrahydro[1,3]dioxolo[4,5-c]pyridin-6(3aH)-
one [(–)-22]: Lactam (4S,5R)-15 (630 mg, 4.80 mmol) was dissolved
1312
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1306–1317

Synthesis of 5-Hydroxy- and 4,5-Dihydroxypipecolic Acids
in anhydrous methanol (4.3 mL) and a catalytic amount of p-tolu-
enesulfonic acid was added (183 mg, 0.96 mmol) followed by 2,2-
dimethoxypropane (10.6 mL, 86 mmol). The mixture was warmed
at 55 °C for 2.5 h and, after cooling, diluted with MeOH (4.5 mL)
and neutralized with K2CO3 (73 mg, 0.53 mmol). After filtration
through a Celite pad and evaporation of the solvent, crude 22 was
obtained and purified by flash chromatography (eluent: CH2Cl2/
(3aR,7aS)-Dimethyl 2,2-Dimethyl-3a,7a-dihydro[1,3]dioxolo[4,5-c]-
pyridine-5,6(4H)-dicarboxylate [(+)-25]: In a round-bottomed flask
a solution of phosphate 24 (1.68 g, 3.64 mmol), Pd(OAc)2 (82 mg,
0.36 mmol) and Ph3P (191 mg, 0.73 mmol) in anhydrous DMF
(8.6 mL) under a nitrogen atmosphere was prepared. The flask was
flushed and saturated with carbon monoxide and, after 10 min,
Et3N (1.0 mL, 7.28 mmol) and anhydrous CH3OH (5.9 mL,
MeOH, 20:1; Rf 0.18), affording pure 22 as a white powder 146 mmol) were added. The mixture was saturated with CO (bal-
(756 mg, 92%) with spectroscopic data identical to those of the
racemic compound.[29] M.p. 118.2–119.2 °C. [α]2D4 = –121.9 (c =
0.75, CHCl3). 1H NMR (400 MHz): δ = 5.85 (br. s, 1 H, NH), 4.69
(ddd, J = 7.2, 4.1, 2.7 Hz, 1 H, 4-H), 4.45–4.41 (m, 1 H, 5-H), 3.38
(ddd, J = 14.3, 5.9, 2.3 Hz, 1 H, 6-HЈ), 3.28 (dt, J = 14.3, 2.5 Hz,
1 H, 6-HЈЈ), 2.66 (ddd, J = 15.6, 2.7, 1.4 Hz, 1 H, 3-HЈ), 2.37 (dd,
loon) and heated at 75 °C (external bath) for 1 h. After cooling,
water (86 mL) was added and the product extracted with Et2O (4ϫ
50 mL). The combined organic extracts were dried with Na2SO4.
After filtration and evaporation of the solvent, crude 25 was puri-
fied by flash chromatography (eluant: n-hexane/EtOAc, 2:1, 1%
Et3N; Rf 0.27) to afford pure 25 as a thick colourless oil (770 mg,
J = 15.6, 4.1 Hz, 1 H, 3-HЈЈ), 1.45 (s, 3 H, CH3), 1.34 (s, 3 H, 78%). The spectroscopic data were identical to those of the racemic
CH3) ppm. C8H13NO3 (171.19): calcd. C 56.13, H 7.65, N 8.18;
found C 56.04, H 7.32, N 8.30.
compound.[29] [α]2D6 1.12, CHCl3). 1H NMR
= +40.0 (c =
(400 MHz): δ = 6.20 (d, J = 3.7 Hz, 1 H, 3-H), 4.58 (dd, J = 6.2,
3.7 Hz, 1 H, 4-H), 4.30 (ddd, J = 7.6, 6.2, 4.1 Hz, 1 H, 5-H), 3.95
(dd, J = 13.5, 4.1 Hz, 1 H, 6-Heq), 3.80 (s, 3 H, OCH3), 3.73 (s, 3
H, OCH3), 3.36 (dd, J = 13.5, 7.6 Hz, 1 H, 6-Hax), 1.43 (s, 3 H,
CH3), 1.38 (s, 3 H, CH3) ppm. C12H17NO6 (271.27): calcd. C 53.13,
H 6.32, N 5.16; found C 53.32, H 6.26, N 4.99.
(3aR,7aS)-Methyl 2,2-Dimethyl-6-oxotetrahydro[1,3]dioxolo[4,5-c]-
pyridine-5(4H)-carboxylate [(–)-23]:
A solution of lactam 22
(750 mg, 4.38 mmol) in dry THF (44 mL) was cooled to –78 °C
and a 1.6 m solution of nBuLi (2.74 mL, 4.38 mmol) was slowly
added, keeping the temperature below –70 °C during the addition.
The mixture was stirred for 15 min and then methyl chloroformate
(338 μL, 4.38 mmol) was added dropwise. After 10 min, the cooling
bath was removed and the mixture allowed to warm to 0 °C. Satu-
rated NaHCO3 (20 mL) and water (20 mL) were added and the
product extracted with dichloromethane (4ϫ 15 mL). The com-
bined organic extracts were dried with Na2SO4, filtered and evapo-
rated in vacuo to give crude 23. After purification by flash
chromatography (eluent: n-hexane/EtOAc, 1:2; Rf 0.32) pure 23 was
obtained as a white solid (843 mg, 84%) with spectroscopic data
identical to those of the racemic compound.[29] M.p. 70.2–72.1 °C.
[α]2D4 = –63.9 (c = 0.91, CHCl3). 1H NMR (400 MHz): δ = 4.64
(ddd, J = 7.6, 3.5, 2.7 Hz, 1 H, 4-H), 4.54–4.49 (m, 2 H, 5-H, 6-
HЈ), 3.88 (s, 3 H, OCH3), 3.30 (dd, J = 15.0, 2.3 Hz, 1 H, 6-HЈЈ),
2.85 (dd, J = 16.0, 2.7 Hz, 1 H, 3-HЈ), 2.49 (dd, J = 16.0, 3.5 Hz,
1 H, 3-HЈЈ), 1.38 (s, 3 H, CH3), 1.32 (s, 3 H, CH3) ppm. C10H15NO5
(229.23): calcd. C 52.40, H 6.60, N 6.11; found C 52.55, H 6.77, N
6.01.
(3aR,6S,7aS)-Dimethyl 2,2-Dimethyltetrahydro[1,3]dioxolo[4,5-c]-
pyridine-5,6(4H)-dicarboxylate [(–)-26]: A suspension of NaHCO3
(155 mg, 1.84 mmol, 2.5 equiv.) and 10% Pd/C (126 mg,
0.12 mmol, 0.16 equiv.) in EtOAc (19.4 mL) was flushed with hy-
drogen and vigorously stirred under a hydrogen atmosphere for
30 min. A solution of 25 (200 mg, 0.74 mmol) in EtOAc (1.7 mL)
was then added and the resulting mixture flushed and stirred under
hydrogen (balloon) at room temperature for 4 h. After filtration
through a Celite pad, the filtrate was concentrated under vacuum
to give pure 26 as a colourless oil (195 mg, 97%). The spectroscopic
data were identical to those of the racemic compound.[29] [α]2D5
=
–7.1 (c = 0.93, CHCl3). 1H NMR (400 MHz) (1.3:1 mixture of
rotamers): δ = 4.54 (t, J = 6.4 Hz, 1 H, 2-H, major), 4.40 (t, J =
6.8 Hz, 1 H, 2-H, minor), 4.29–4.15 (m, 2 H, 4-H, 5-H, both rota-
mers + 1 H, 6-Heq minor), 3.99 (dd, J = 13.9, 6.2 Hz, 1 H, 6-Heq,
major), 3.74 (s, 3 H, CO2CH3), 3.72 (s, 3 H, NCO2CH3, major),
3.68 (s, 3 H, NCO2CH3, minor), 3.33 (dd, J = 13.9, 8.2 Hz, 1 H,
6-Hax, major), 3.26 (dd, J = 13.7, 8.2 Hz, 1 H, 6-Hax, minor), 2.38–
2.16 (m, 2 H, 3-HЈ, 3-HЈЈ), 1.43 (s, 3 H, CH3), 1.32 (s, 3 H,
CH3) ppm. C12H19NO6 (273.28): calcd. C 51.06, H 7.14, N 4.96;
found C 50.92, H 7.18, N 4.72.
(3aR,7aS)-Methyl 6-(Diphenoxyphosphoryloxy)-2,2-dimethyl-3a,7a-
dihydro-4H-[1,3]dioxolo[4,5-c]pyridine-5(4H)-carboxylate (24):
A
solution of 0.5 m KHMDS in toluene (9.2 mL, 4.6 mmol) was di-
luted in anhydrous THF (19 mL) and cooled to –78 °C. A solution
of 23 (840 mg, 3.66 mmol) in anhydrous THF (11 mL) was then
added dropwise, keeping the temperature below –70 °C, and the
resulting mixture was stirred for 1.5 h. A solution of diphenyl-
chlorophosphate (948 μL, 4.6 mmol) in anhydrous THF (5.6 mL)
was then dropwise added and, after 1 h, the mixture was allowed
to warm at 0 °C. Aqueous 5% NaOH (70 mL) was slowly added
and the product extracted with Et2O (3ϫ 40 mL). The combined
organic extracts were washed with 5% NaOH (60 mL) and dried
with K2CO3 for 30 min. After filtration and evaporation of the sol-
vent, the crude was purified over a short pad of silica gel (eluent:
n-hexane/EtOAc, 2:1 buffered with 1% Et3N; Rf 0.29) affording
pure 24 as a colourless oil (1.68 g, 99%). This product was used
immediately for the next step. Spectroscopic data were identical to
those of the racemic compound.[29] 1H NMR (400 MHz): δ = 7.38–
7.32 (m, 4 H, Ph), 7.28–7.17 (m, 6 H, Ph), 5.33 (dd, J = 4.5, 2.7 Hz,
1 H, 5-H), 4.68 (ddd, J = 6.4, 4.5, 2.1 Hz, 1 H, 4-H), 4.30 (ddd, J
= 6.4, 5.7, 3.1 Hz,1 H, 3-H), 3.81 (dd, J = 13.5, 5.7 Hz, 1 H, 2-HЈ),
3.68 (dd, J = 13.5, 3.1 Hz, 1 H, 2-HЈЈ), 3.58 (s, 3 H, OCH3), 1.42
(s, 3 H, CH3), 1.35 (s, 3 H, CH3) ppm.
(2S,4S,5R)-4,5-Dihydroxypipecolic Acid [(–)-10·HCl]:
A 25 mm
solution of compound 26 (187 mg, 0.68 mmol) in aqueous 4 n HCl
was heated to reflux temperatures for 24 h. After cooling, the sol-
vent was concentrated under vacuum. The residue was triturated
with cold diethyl ether and then dried under vacuum until constant
a weight was obtained. Pure acid (–)-10 was obtained as the hydro-
chloride salt (135 mg, quantitative) and as a white solid. M.p.
167 °C (dec.). [α]2D4 = –29.0 (c = 0.54, H2O). [α]2D8 = –25.3 (c = 0.54,
2N HCl). 1H NMR (400 MHz, D2O): δ = 4.15 (br. s, 1 H, 5-H),
4.10 (dd, J = 12.1, 3.7 Hz, 1 H, 2-H), 4.04 (ddd, J = 10.9, 4.3,
2.9 Hz, 1 H, 4-H), 3.51 (dd, J = 13.5, 3.9 Hz, 1 H, 6-Heq), 3.25 (dd,
J = 13.9, 1.8 Hz, 1 H, 6-Hax), 2.36 (dt, J = 13.7, 4.1 Hz, 1 H, 3-
Heq), 2.19–2.10 (m, 1 H, 3-Hax) ppm. 13C NMR (100.4 MHz,
D2O): δ = 170.5 (s, CO), 66.7 (d, C-5), 64.4 (d, C-4), 55.3 (d, C-2),
46.7 (t, C-6), 27.6 (t, C-3) ppm. MS/MS (ESI of
[M + 1]+): m/z (%) = 162 (2) [M+ + 1], 144 (53), 116 (100), 98 (25).
C6H13ClNO4 (197.62): calcd. C 36.47, H 6.63, N 7.12; found C
36.38, H 6.85, N 7.03.
(3aS,7aR)-2,2-Dimethyltetrahydro[1,3]dioxolo[4,5-c]pyridin-6-
(3aH)-one [(+)-ent-22]: Prepared as reported for (–)-22, starting
Eur. J. Org. Chem. 2013, 1306–1317
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1313

D. Scarpi, L. Bartali, A. Casini, E. G. Occhiato
FULL PAPER
from (+)-15 (185 mg, 1.41 mmol) and affording pure (+)-22
(217 mg, 90%) as a white solid. [α]2D4 = +122.2 (c = 0.80, CHCl3).
Analytical and spectroscopic data as reported above.
(eluent: n-hexane/EtOAc, 2:1) afforded pure 27 (19 mg, 46%) and
ent-26 (18 mg, 44%) as thick colourless oils.
(2S,4R,5S)-4,5-Dihydroxypipecolic Acid [(–)-11·HCl]: Prepared as
reported for (–)-10, starting from 27 (145 mg, 0.53 mmol) and ob-
taining pure (–)-11 as the hydrochloride salt (104 mg, 99%) as a
white solid. M.p. 253 °C (dec.). [α]2D5 = –10.7 (c = 0.53, 2N HCl).
1H NMR (400 MHz, D2O): δ = 4.20 (dd, J = 10.9, 3.9 Hz, 1 H, 2-
H), 4.13–3.99 (br. m, 1 H, 4-H), 3.98 (ddd, J = 9.8, 4.1, 2.7 Hz, 1
H, 5-H), 3.33 (dd, J = 12.5, 4.3 Hz, 1 H, 6-Heq), 3.19 (dd, J = 12.5,
10.0 Hz, 1 H, 6-Hax), 2.39 (ddd, J = 15.0, 5.9, 4.1 Hz, 1 H, 3-Heq),
2.11–2.04 (ddd, J = 15.0, 11.0, 2.5 Hz, 1 H, 3-Hax) ppm. 13C NMR
(100.4 MHz, D2O): δ = 171.1 (s, CO), 66.7 (d, C-5), 64.6 (d, C-4),
51.7 (d, C-2), 42.3 (t, C-6), 29.8 (t, C-3) ppm. MS/MS (ESI of [M
+ 1]+): m/z (%) = 162 (21) [M+ + 1], 144 (100), 116 (25), 98 (69).
C6H13ClNO4 (197.62): calcd. C 36.47, H 6.63, N 7.12; found C
36.34, H 6.88, N 6.99.
(3aS,7aR)-Methyl 2,2-Dimethyl-6-oxotetrahydro[1,3]dioxolo[4,5-c]-
pyridine-5(4H)-carboxylate [(+)-ent-23]: Prepared as reported for
(–)-23, starting from (+)-22 (207 mg, 1.21 mmol) and affording
pure (+)-23 (227 mg, 82%) as a white solid. [α]2D3 = +64.1 (c = 0.91,
CHCl3). Analytical and spectroscopic data as reported above.
(3aS,7aR)-Dimethyl 2,2-Dimethyl-3a,7a-dihydro[1,3]dioxolo[4,5-c]-
pyridine-5,6(4H)-dicarboxylate [(–)-ent-25]: Prepared as reported
for (+)-25, in two steps, starting from (+)-23 (227 mg, 0.99 mmol)
and affording pure (–)-25 (185 mg, 69%) as colourless oil. [α]2D5
=
–39.3 (c = 0.78, CHCl3). Analytical and spectroscopic data as re-
ported above.
(3aS,6R,7aR)-Dimethyl 2,2-Dimethyltetrahydro[1,3]dioxolo[4,5-c]-
pyridine-5,6(4H)-dicarboxylate [(+)-ent-26] and (3aS,6S,7aR)-Di-
methyl 2,2-Dimethyltetrahydro[1,3]dioxolo[4,5-c]pyridine-5,6(4H)-
dicarboxylate [(–)-27]: A solution of (–)-ent-25 (185 mg, 0.68 mmol)
in anhydrous THF (2.5 mL) was cooled to –10 °C and Super-Hy-
dride (1 m solution in THF, 820 μL, 0.82 mmol) was slowly added.
After 70 min, the temperature was raised to 0 °C and the mixture
stirred for 5 min, before being cooled again to –10 °C and
quenched by saturated NaHCO3 solution (8 mL). The product was
extracted with CH2Cl2 (5ϫ 15 mL) and the combined organic ex-
tracts were washed once with water (25 mL) and dried with anhy-
drous Na2SO4. After filtration and evaporation of the solvent, the
crude 2.6:1 mixture of 27 and ent-26 was obtained. The two dia-
stereoisomers were separated by flash chromatography (eluent: n-
hexane/EtOAc, 2:1), affording pure 27 (126 mg, 68%) and ent-26
(41 mg, 22%) as thick colourless oils.
(2R,4R,5S)-4,5-Dihydroxypipecolic Acid [(+)-ent-10·HCl]: Prepared
as reported for (–)-10, starting from ent-26 (18 mg, 0.065 mmol)
and obtaining pure (+)-ent-10 as the hydrochloride salt (13 mg,
quantitative). [α]2D4 = +26.1 (c = 0.65, 2N HCl).
(5S)-Methyl
5-(tert-Butyldimethylsilanyloxy)-2-oxopiperidine-1-
carboxylate [(+)-30]: Prepared as reported for (–)-23, starting from
29 (2.22 g, 9.68 mmol) and affording, after purification by flash
chromatography (n-hexane/EtOAc, 2:1; Rf 0.25), pure (+)-30
(1.98 g, 71%) as a white solid. M.p. 64.1–65.0 °C (ref.[42g] m.p.
68 °C). [α]2D1 = +17.2 (c = 1.07, CHCl3) {ref.[42g] [α]2D0 = +10.9 (c =
1.0, MeOH)}. 1H NMR (CDCl3, 400 MHz): δ = 4.20–4.15 (m, 1
H, 5-H), 3.86 (s, 3 H, OCH3), 3.75 (ddd, J = 13.3, 4.7, 1.6 Hz, 1
H, 6-H), 3.68 (dd, J = 13.3, 3.7 Hz, 1 H, 6-HЈ), 2.75 (ddd, J = 17.4,
9.6, 6.8 Hz, 1 H, 3-H), 2.46 (dt, J = 17.4, 6.0 Hz, 1 H, 3-HЈ), 2.05–
1.92 (m, 1 H, 4-H), 1.90–1.81 (m, 1 H, 4-H), 0.87 [s, 9 H, SiC-
Compound (+)-ent-26: [α]2D5 = +8.0 (c = 0.64, CHCl3).
(CH3)3], 0.08 [s,
6
H, Si(CH3)2] ppm. 13C NMR (CDCl3,
Compound (–)-27: [α]2D7 = –113.4 (c = 0.96, CHCl3). 1H NMR
(400 MHz, 1.4:1 mixture of rotamers): δ = 4.52 (dd, J = 11.9,
5.7 Hz, 1 H, 2-H, major), 4.47–4.42 [m, 2 H, 2-H (minor) and 4-H
(both rotamers)], 4.31 (dm, J = 8.0 Hz, 1 H, 5-H, minor), 4.28 (dm,
J = 7.8 Hz, 1 H, 5-H, major), 4.20 (dd, J = 14.6, 2.0 Hz,1 H, 6-
Heq minor), 4.07 (dd, J = 15.0, 2.0 Hz, 1 H, 6-Heq, major), 3.72 (s,
3 H, CO2CH3, major), 3.71 (s, 3 H, CO2CH3, minor), 3.70 (s, 3 H,
NCO2CH3, major), 3.67 (s, 3 H, NCO2CH3, minor), 3.14 (dd, J =
15.0, 2.0 Hz, 1 H, 6-Hax, major), 3.09 (dd, J = 14.6, 1.8 Hz, 1 H,
6-Hax, minor), 2.38–2.28 (m, 1 H, 3-H), 1.78–1.69 (m, 1 H, 3-HЈ),
1.37 (s, 3 H, CH3), 1.30 (s, 3 H, CH3) ppm. 13C NMR (100.4 MHz,
mixture of rotamers): δ = 173.1 (s, CO2Me), 156.7 and 156.3 (s,
NCO2Me), 108.5 and 108.4 [s, C(CH3)2], 72.6 and 72.5 (d, C-4),
69.7 (d, C-5), 52.9 and 52.8 (d, C-2), 52.2 (q, OCH3), 50.9 and 50.8
(q, OCH3), 42.4 and 42.1 (t, C-6), 27.9 and 27.6 (t, C-3), 26.2 and
26.1 (q, CH3), 24.2 and 24.1 (q, CH3) ppm. MS/MS (ESI of [M +
1]+): m/z (%) = 274 (3) [M+ + 1], 242 (45), 216 (100), 214 (22), 184
(7), 156 (5). C12H19NO6 (273.28): calcd. C 51.06, H 7.14, N 4.96;
found C 50.88, H 7.28, N 4.80.
100.4 MHz): δ = 170.8 (s, CO), 154.9 (s, NCO2Me), 64.1 (d, C-5),
53.9 (q, OCH3), 52.9 (t, C-6), 30.8 (t, C-3), 28.6 (t, C-4), 25.6 [q, 3
C, SiC(CH3)3], 17.8 [(s, SiC(CH3)3], –4.9 [(q, 2 C, Si(CH3)2] ppm.
MS/MS (ESI of [M + 1]+): m/z (%) = 288 ([M+ + 1], 19), 256 (65),
156 (86), 147 (27), 114 (100). C13H25NO4Si (287.49): calcd. C 54.32,
H 8.77, N 4.87; found C 54.26, H 8.50, N 4.88.
(3S)-Methyl 6-[(Diphenoxyphosphoryl)oxy]-3-(tert-butyldimethylsil-
anyloxy)-3,4-dihydropyridine-1(2H)-carboxylate (31): Prepared as
reported for 24, starting from 30 (1.97 g, 6.85 mmol) and affording,
after purification by chromatography (EtOAc/n-hexane, 1:3, + 1%
Et3N; Rf 0.55), phosphate 31 (3.52 g, 99%) as a pale yellow oil that
was immediately used in the next step. 1H NMR (CDCl3,
400 MHz): δ = 7.37–7.32 (m, 4 H, CHarom), 7.28–7.13 (m, 6 H,
CHarom), 5.04 (q, J = 3.1 Hz, 1 H, 3-H), 4.04–3.99 (m, 1 H, 5-H),
3.76 (dd, J = 12.5, 5.6 Hz, 1 H, 6-H), 3.55 (s, 3 H, OCH3), 3.40
(dd, J = 12.5, 2.1 Hz, 1 H, 6-HЈ), 2.36 (dq, J = 18.1, 4.3 Hz, 1 H,
4-H), 2.06 (dq, J = 18.1, 3.5 Hz, 1 H, 4-HЈ), 0.86 [s, 9 H, SiC-
(CH3)3], 0.06 [s, 3 H, Si(CH3)2], 0.05 [s, 3 H, Si(CH3)2] ppm. 13C
NMR (CDCl3, 100.4 MHz): δ = 155.3 (s, CO), 150.5 (s, 2 C, Carom),
139.6 (s, C-2), 129.8 (d, 4 C, Carom), 125.5 (d, 2 C, Carom), 120.1
(d, 4 C, Carom), 98.2 (d, C-3), 64.7 (d, C-5), 53.0 (q, OCH3), 51.4
(t, C-6), 32.0 (t, C-4), 25.6 [q, 3 C, SiC(CH3)3], 18.0 [s, SiC-
(CH3)3], –5.00 [q, 2 C, Si(CH3)2] ppm. MS/MS (ESI of [M + 1]+):
m/z (%) = 520 ([M+ + 1], 11), 476 (100), 379 (10), 344 (8).
(3aS,6S,7aR)-Dimethyl 2,2-Dimethyltetrahydro[1,3]dioxolo[4,5-c]-
pyridine-5,6(4H)-dicarboxylate [(–)-27]:
A solution of ent-26
(40 mg, 0.15 mmol) in anhydrous THF (2.2 mL) was cooled to 0 °C
and TBAF (1.0 m solution in THF, 330 μL, 0.33 mmol) was added
dropwise. The ice bath was removed and the mixture stirred at
room temperature for 18 h. Water (5.5 mL) was added and the
product extracted with EtOAc (4ϫ 6 mL). The combined organic
extracts were washed once with saturated NH4Cl (7 mL), brine
(7 mL) and dried with anhydrous Na2SO4. After filtration and
evaporation of the solvent, a crude 1:1 mixture of 27 and ent-26
was obtained. Separation of the mixture by flash chromatography
(5S)-Dimethyl 5-(tert-Butyldimethylsilanyloxy)-5,6-dihydropyridine-
1,2(4H)-dicarboxylate [(+)-32]: Prepared as reported for (+)-25,
starting from phosphate 31 (3.52 g, 6.77 mmol) and affording, after
purification by chromatography (EtOAc/n-hexane, 1:4; Rf 0.27),
pure 32 (1.83 g, 82%) as a thick pale yellow oil. [α]1D9 = +5.27 (c =
0.99, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 6.06 (t, J = 3.9 Hz,
1314
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1306–1317

Synthesis of 5-Hydroxy- and 4,5-Dihydroxypipecolic Acids
1 H, 3-H), 4.06–4.02 (m, 1 H, 5-H), 3.77 (s, 3 H, OCH3), 3.70 (s,
3 H, OCH3), 3.59 (dd, J = 12.7, 6.2 Hz, 1 H, 6-H), 3.52 (dd, J =
12.7, 2.7 Hz, 1 H, 6-HЈ), 2.44 (ddd, J = 19.3, 5.5, 3.7 Hz, 1 H, 4-
3.89 (m, 1 H, 4-H), 3.88–3.86 (m, 1 H, 5-H), 3.79 (s, 3 H, OCH3),
3.70 (s, 3 H, OCH3), 3.24 (dd, J = 12.9, 1.4 Hz, 1 H, 6-HЈ), 0.84
[s, 9 H, SiC(CH3)3], 0.09 [s, 3 H, Si(CH3)2], 0.07 [s, 3 H, Si-
H), 2.13 (dt, J = 19.3, 4.3 Hz, 1 H, 4-HЈ), 0.86 [s, 9 H, SiC- (CH3)2] ppm. 13C NMR (CDCl3, 100.4 MHz): δ = 164.8 (s, CO),
(CH3)3], 0.07 [s,
6
H, Si(CH3)2] ppm. 13C NMR (CDCl3,
155.1 (s, NCO), 133.5 (s, C-2), 119.2 (d, C-3), 69.9 (d, C-4), 67.1
(d, C-5), 53.2 (q, OCH3), 52.4 (q, OCH3), 46.4 (t, C-6), 25.5 [q, 3
100.4 MHz): δ = 164.7 (s, CO), 155.2 (s, NCO), 132.1 (s, C-2), 121.4
(d, C-3), 64.5 (d, C-5), 53.1 (q, OCH3), 52.1 (q, OCH3), 49.7 (t, C- C, SiC(CH3)3], 17.9 [s, SiC(CH3)3], –5.0 [q, 1 C, Si(CH3)2], –5.1 [q,
6), 33.2 (t, C-4), 25.6 [q, 3 C, SiC(CH3)3], 18.0 [s, SiC(CH3)3], –5.00
1 C, Si(CH3)2] ppm. MS/MS (ESI of [M + 1]+): m/z (%) = 346 (21)
[q, 2 C, Si(CH3)2] ppm. MS: m/z (%) = 329 (100) [M+], 298 (7). [M+ + 1], 328 (47), 314 (100), 296 (17). C15H27NO6Si (345.46):
C15H27NO5Si (329.46): calcd. C 54.68, H 8.26, N 4.25; found C
54.87, H 8.27, N 4.13.
calcd. C 52.15, H 7.88, N 4.05; found C 52.08, H 8.05, N 3.95.
(2S,4R,5R)-Dimethyl 5-(tert-Butyldimethylsilyloxy)-4-hydroxypiper-
idine-1,2-dicarboxylate [(–)-36]: Prepared as reported for (–)-26,
starting from 35 (650 mg, 1.88 mmol) and leaving the mixture to
stir under a hydrogen atmosphere for 24 h. After filtration through
a Celite pad and removal of the solvent under vacuum, a crude
3:1 mixture of 36 and 37 was obtained. Major diastereoisomer 36
(346 mg, 53%) was obtained in pure form by flash chromatography
(eluent: n-hexane/Et2O, 2:3; Rf 0.25), as a thick colourless oil. The
fraction containing the mixture of both isomers 36 and 37 was
further purified by using chromatography to give an addition yield
of pure 36 (117 mg; overall yield 71%). [α]2D5 = –39.6 (c = 0.95,
(4R,5R)-Dimethyl 4-Acetyloxy-5-(tert-butyldimethylsilanyloxy)-5,6-
dihydropyridine-1,2(4H)-dicarboxylate [(–)-34]: A solution of 32
(906 mg, 2.75 mmol), N-bromosuccinimide (622 mg, 3.49 mmol)
and a catalytic amount of AIBN (77 mg, 0.47 mmol) in a 9:1 mix-
ture of CCl4 and CHCl3 (99 mL) was heated to reflux under vigor-
ous stirring for 1.5 h. After cooling, the mixture was diluted with
CHCl3 (80 mL), washed with water (90 mL) and concentrated un-
der vacuum to give crude bromide 33 as a yellow oil that was imme-
diately used for the next step without further purification. 1H
NMR (CDCl3, 400 MHz): δ = 6.09 (dd, J = 4.3, 1.0 Hz, 1 H, 3-
H), 4.33–4.30 (m, 1 H, 4-H), 4.27–4.24 (m, 1 H, 5-H), 4.11 (dd, J
= 12.1, 4.1 Hz, 1 H, 6-H), 3.80 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3),
1
MeOH). H NMR (400 MHz, 1.1:1 mixture of rotamers): δ = 5.01
(d, J = 6.2 Hz, 1 H, 2-H, major), 4.85 (d, J = 6.2 Hz, 1 H, 2-H,
minor), 4.21 (dd, J = 13.0, 3.9 Hz, 1 H, 6-Heq, minor), 4.03 (dd, J
= 13.8, 3.5 Hz, 1 H, 6-Heq, major), 3.75 and 3.70 (s, 6 H, CO2CH3
and NCO2CH3, both rotamers), 3.41–3.35 (m, 2 H, 4-H and 5-H),
2.85 (dd, J = 13.8, 10.1 Hz, 1 H, 6-Hax, major), 2.77 (dd, J = 13.0,
10.1 Hz, 1 H, 6-Hax, minor), 2.53–2.47 (m, 1 H, 3-Heq), 2.33 (dd,
J = 14.6, 1.2 Hz, 1 H, OH), 1.74–1.66 (m, 1 H, 3-Hax), 0.90 [s, 9
H, SiC(CH3)3], 0.12 [s, 6 H, Si(CH3)2] ppm. 13C NMR (100.4 MHz,
mixture of rotamers): δ = 171.2 and 171.1 (s, CO2Me), 156.4 and
155.9 (s, NCO2Me), 73.2 and 73.1 (d, C-4), 71.4 (d, C-5), 53.9 and
53.7 (d, C-2), 53.2 and 53.1 (q, OCH3), 52.6 and 52.5 (q, OCH3),
46.2 and 46.1 (t, C-6), 32.0 and 31.7 (t, C-3), 25.7 [q, 3 C, SiC-
(CH3)3], 18.0 [s, SiC(CH3)3], –4.5 [q, 1 C, Si(CH3)2], –4.7 [q, 1 C,
Si(CH3)2] ppm. MS/MS (ESI of [M + 1]+): m/z (%) = 348 (27) [M+
+ 1], 316 (100), 288 (72). C15H29NO6Si (347.48): calcd. C 51.85, H
8.41, N 4.03; found C 51.51, H 8.60, N 4.35.
3.53 (d,
J = 12.1, Hz, 1 H, 6-HЈ), 0.83 [s, 9 H, SiC-
(CH3)3], 0.08 [s, 6 H, Si(CH3)2] ppm.
Silver acetate (688 g, 4.13 mmol) was added to a solution of 33
(898 mg, 2.20 mmol) in glacial CH3CO2H (115 mL) and the re-
sulting mixture stirred at room temperature for 15 min. The suspen-
sion was then filtered through a Celite pad and the filtrate diluted
with Et2O (300 mL), washed with saturated NaHCO3 to neutralize
(6ϫ 150 mL) and dried with anhydrous Na2SO4. After filtration
and evaporation of the solvent, crude 34 was obtained and purified
by flash chromatography (EtOAc/n-hexane, 1:4, Rf 0.30), affording
pure 34 (1.03 g, 75% over two steps) as a thick pale yellow oil.
Compound (–)-34: [α]2D5 = –149.6 (c = 1.06, CHCl3). 1H NMR
(CDCl3, 400 MHz): δ = 5.90 (dd, J = 4.1, 1.4 Hz, 1 H, 3-H), 4.96–
4.94 (m, 1 H, 4-H), 4.08 (dd, J = 13.3, 4.5 Hz, 1 H, 6-H), 3.91–
3.89 (m, 1 H, 5-H), 3.79 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 3.19
(dd, J = 13.3, 1.4 Hz, 1 H, 6-HЈ), 2.06 (s, 3 H, CH3CO), 0.83 [s, 9
H, SiC(CH3)3], 0.11 [s, 3 H, Si(CH3)2], 0.07 [s, 3 H, Si(CH3)2] ppm.
13C NMR (CDCl3, 100.4 MHz): δ = 169.5 (s, CH3CO), 164.4 (s,
CO), 155.0 (s, NCO), 135.1 (s, C-2), 115.4 (d, C-3), 67.9 (d, C-4),
67.3 (d, C-5), 53.3 (q, OCH3), 52.4 (q, OCH3), 47.0 (t, C-6), 25.4
[q, 3 C, SiC(CH3)3], 20.9 (q, CH3CO), 17.7 [s, SiC(CH3)3], –5.0 [q,
1 C, Si(CH3)2], –5.3 [q, 1 C, Si(CH3)2] ppm. MS/MS (ESI of [M +
23]+): m/z (%) = 410 ([M+ + 23], 12), 350 (8), 328 (83), 296 (41),
292 (100). C17H29NO7Si (387.50): calcd. C 52.69, H 7.54, N 3.61;
found C 52.83, H 7.87, N 3.43.
(2S,4R,5R)-4,5-Dihydroxypipecolic Acid [(–)-9·HCl]: Prepared as
reported for (–)-10, starting from 36 (410 mg, 1.18 mmol) and ob-
taining pure (–)-9 as the hydrochloride salt (233 mg, quantitative).
M.p. 252 °C (dec.). [α]2D1 = –18.2 (c = 0.57, 2N HCl). 1H NMR
(400 MHz, D2O): δ = 4.17 (dd, J = 11.5, 4.1 Hz, 1 H, 2-H), 4.06–
4.01 (br. m, 1 H, 4-H), 3.97–3.92 (br. m, 1 H, 5-H), 3.43 (dd, J =
13.5, 2.0 Hz, 1 H, 6-Heq), 3.30 (dd, J = 13.5, 3.5 Hz, 1 H, 6-Hax),
2.32–2.17 (m, 2 H, 3-H) ppm. 13C NMR (100.4 MHz, D2O): δ =
174.2 (s, CO), 67.4 (d, C-4), 67.1 (d, C-5), 54.8 (d, C-2), 47.0 (t, C-
6), 30.3 (t, C-3) ppm. MS/MS (ESI of [M + 1]+): m/z (%) = 162 (7)
[M+ + 1], 144 (16), 126 (5), 116 (100), 98 (19). C6H13ClNO4
(197.62): calcd. C 36.47, H 6.63, N 7.12; found C 36.26, H 6.85, N
7.00.
(4R,5R)-Dimethyl 5-(tert-Butyldimethylsilanyloxy)-4-hydroxy-5,6-
dihydropyridine-1,2(4H)-dicarboxylate [(–)-35]: A solution of 34
(1.03 g, 2.66 mmol) in anhydrous MeOH (29 mL) was cooled to
0 °C and MeONa (144 mg, 2.66 mmol) was rapidly added. The
mixture was stirred at 0 °C for 1 h, acidified by adding glacial acetic
acid (380 μL, 6.65 mmol) and the solvent removed under vacuum
without heating. The residue was diluted with water (260 mL) and
the product extracted with Et2O (5ϫ 110 mL). The combined or-
ganic extracts were dried with Na2SO4. After filtration and evapo-
ration of the solvent, crude 35 was obtained and purified by
chromatography (EtOAc/n-hexane, 1:2; Rf 0.20) to give pure 35
(670 mg, 73%) as a thick colourless oil. [α]2D1 = –111.4 (c = 1.13,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 5.96 (dd, J = 3.9,
(2S,5S)-Dimethyl 5-(tert-Butyldimethylsilanyloxy)piperidine-1,2-di-
carboxylate [(–)-38]: Prepared as reported for (–)-26, starting from
32 (920 mg, 2.79 mmol) and leaving the mixture to stir under a
hydrogen atmosphere for 21 h. After filtration through a Celite pad
and removal of the solvent under vacuum, the residue was purified
by flash chromatography (eluent: n-hexane/EtOAc, 6:1; Rf 0.24),
affording pure 38 (878 mg, 95%) as a colourless oil, containing a
small amount of the trans diastereoisomer. [α]3D0 = –24.5 (c = 0.74,
MeOH) {ref.[42g] [α]2D0 = –15.4 (c = 1.0, MeOH)}. 1H NMR
(400 MHz, 1.3:1 mixture of rotamers, dr 8:1): δ = (ppm): 4.88 (d,
1.2 Hz, 1 H, 3-H), 3.99 (dd, J = 12.9, 4.5 Hz, 1 H, 6-Heq), 3.92– J = 4.4 Hz, 1 H, 2-H, major), 4.72 (d, J = 5.1 Hz, 1 H, 2-H, minor),
Eur. J. Org. Chem. 2013, 1306–1317
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1315

D. Scarpi, L. Bartali, A. Casini, E. G. Occhiato
FULL PAPER
4.17 (dd, J = 12.9, 4.9 Hz, 1 H, 6-Heq, minor), 3.99 (dd, J = 12.9, (2R,5R)-5-Hydroxypipecolic Acid [(+)-ent-6·HCl]: Prepared as re-
4.9 Hz, 1 H, 6-Heq, major), 3.74 and 3.70 (s, 6 H, CO2CH3 and ported for (–)-10, starting from ent-39 (138 mg, 0.64 mmol) and
NCO2CH3, both rotamers), 3.60–3.51 (m, 1 H, 5-H), 2.75 (dd, J =
12.9, 10.5 Hz, 1 H, 6-Hax, major), 2.67 (dd, J = 12.9, 10.5 Hz, 1 H,
6-Hax, minor), 2.31–2.23 (m, 1 H, 3-Heq), 1.88–1.81 (m, 1 H, 4-
Heq), 1.74–1.62 (m, 1 H, 3-Hax), 1.31–1.19 (m, 1 H, 4-Hax), 0.87 [s,
9 H, SiC(CH3)3], 0.07 [s, 3 H, Si(CH3)2], 0.06 [s, 3 H, Si-
(CH3)2] ppm. 13C NMR (100.4 MHz, mixture of rotamers): δ =
171.6 (s, CO2Me), 156.7 and 156.2 (s, NCO2Me), 67.4.2 and 67.2
(d, C-5), 53.7 and 53.4 (d, C-2), 53.1 (q, OCH3), 52.4 and 52.3 (q,
OCH3), 48.5 and 48.3 (t, C-6), 31.1 and 31.0 (t, C-3), 25.8 [q, 3 C,
SiC(CH3)3], 25.4 and 25.0 (C-4), 18.1 [s, SiC(CH3)3], –4.7 [q, 2 C,
Si(CH3)2] ppm. MS (ESI): m/z (%) = 332 (100) [M+ + 1].
C15H29NO5Si (331.48): calcd. C 54.35, H 8.82, N 4.23; found C
54.19, H 9.02, N 3.99.
obtaining pure (+)-ent-6 as the hydrochloride salt (115 mg, quanti-
tative). [α]2D4 = +21.2 (c = 1.1, H2O). The spectroscopic data were
identical to those of (–)-6.
(2S,5R)-5-Hydroxypipecolic Acid [(–)-7·HCl]: Prepared as reported
for (–)-10, starting from 41 (74 mg, 0.34 mmol) and obtaining pure
(–)-7 as the hydrochloride salt (62 mg, quantitative). [α]2D3 = –9.5 (c
= 0.59, H2O) {ref.[47] [α]2D0 = –9.7 (c = 0.9, H2O); ref.[42g] for (2R,5S)
[α]2D0 = +8.6 (c = 1.0, H2O)}. 1H NMR (400 MHz, D2O): δ = 4.05–
3.98 (m, 2 H, 2-H and 5-H), 3.54 (dd, J = 12.5, 4.1 Hz, 1 H, 6-
Heq), 2.94 (dd, J = 12.5, 9.4 Hz, 1 H, 6-Hax), 2.46–2.38 (m, 1 H, 3-
H), 2.18–2.11 (m, 1 H, 4-H), 1.96–1–85 (m, 1 H, 3-HЈ), 1.72–1.62
(m, 4-HЈ) ppm.
Supporting Information (see footnote on the first page of this arti-
(2S,5S)-Dimethyl 5-Hydroxypiperidine-1,2-dicarboxylate [(–)-39]: A
solution of compound 38 (878 mg, 2.65 mmol) in acetonitrile
(80 mL) was cooled to 0 °C and aqueous 3 n HCl was added drop-
wise (80 mL). After 10 min the ice bath was removed and the mix-
ture was left to stir at room temperature for 2 h. Saturated
NaHCO3 solution was then slowly added until complete neutraliza-
tion and the product extracted with EtOAc (5ϫ 160 mL). The com-
bined organic extracts were dried with anhydrous Na2SO4. After
filtration and evaporation of the solvent, crude 39 was obtained
and purified by flash chromatography (eluent: n-hexane/EtOAc,
2:3; Rf 0.35), affording pure 39 as a single diastereoisomer (448 mg,
78%) as a colourless oil. [α]2D4 = –40.3 (c = 0.42, MeOH) {ref.[42g]
[α]2D0 = –24.1 (c = 1.0, MeOH)}. 1H NMR (400 MHz, 1.3:1 mixture
of rotamers): δ = 4.88 (d, J = 5.5 Hz, 1 H, 2-H, major), 4.73 (d, J
= 4.9 Hz, 1 H, 2-H, minor), 4.27 (br. d, J = 12.3 Hz, 1 H, 6-Heq,
minor), 4.13 (br. d, J = 12.5 Hz, 1 H, 6-Heq, major), 3.74 (s, 3 H,
CO2CH3), 3.73 and 3.69 (s, 3 H, NCO2CH3), 3.67–3.59 (m, 1 H,
5-H), 2.20 (br. t, J = 11.9 Hz, 1 H, 6-Hax, major), 2.71 (br. t, J =
11.7 Hz, 1 H, 6-Hax, minor), 2.29 (br. d, J = 14.1 Hz, 1 H, 3-Heq),
2.01–1.93 (m, 2 H, OH and 4-Heq), 1.77–1.68 (m, 1 H, 3-Hax), 1.28–
1.18 (m, 1 H, 4-Hax) ppm.
1
cle): H and 13C NMR spectra for all new compounds.
Acknowledgments
Financial support from University of Florence is acknowledged.
Dr. Maurizio Passaponti is acknowledged for technical assistance.
Ente Cassa di Risparmio di Firenze is acknowledged for granting
a 400 MHz NMR instrument.
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(2S,5S)-5-Hydroxypipecolic Acid [(–)-6·HCl]: Prepared as reported
for (–)-10, starting from (–)-39 (100 mg, 0.46 mmol) and obtaining
pure (–)-6 as the hydrochloride salt (83 mg, 99%). [α]2D3 = –20.8 (c
= 1.6, H2O) {ref.[42g] [α]2D0 = –21.9 (c = 1.0, H2O)}. 1H NMR
(400 MHz, D2O): δ = 4.22 (br. s, 1 H, 5-Heq), 4.02 (dd, J = 11.7,
3.7 Hz, 1 H, 2-Hax), 3.38 (dt, J = 13.5, 1.9 Hz, 1 H, 6-Heq), 3.25
(dd, J = 13.5, 1.6 Hz, 1 H, 6-Hax), 2.22–1.83 (m, 4 H, 3-H and 4-
H) ppm.
(2R,5R)-Dimethyl 5-Hydroxypiperidine-1,2-dicarboxylate [(+)-ent-
39] and (2S,5R)-Dimethyl 5-Hydroxypiperidine-1,2-dicarboxylate
[(–)-41]: Reduction of ent-32 (520 mg, 1.58 mmol) was performed
as reported for (–)-ent-25, affording, after chromatographic purifi-
cation, a 1.5:1 mixture of ent-38 and 40 (392 mg, 75%). Removal
of the O-silyl group was performed on the mixture as reported
above for (–)-39, affording, after chromatographic separation, pure
ent-39 (138 mg, 54%) and (–)-41 (74 mg, 29%) as colourless oils.
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Compound ent-39: [α]2D3 = +39.1 (c = 0.91, MeOH).
Compound 41: Rf 0.21. [α]2D4 = –49.1 (c = 0.58, MeOH). H NMR
1
(400 MHz, 1.2:1 mixture of rotamers): δ = 4.98 (br. d, J = 4.7 Hz,
1 H, 2-H, major), 4.85 (br. s, 1 H, 2-H, minor), 4.15 (br. d, J =
14.4 Hz, 1 H, 6-Heq, minor), 4.03 (br., 1 H, 5-Heq), 3.98 (br. d, J
= 13.7 Hz, 1 H, 6-Heq, major), 3.74 (s, 3 H, CO2CH3), 3.73 and
3.71 (s, 3 H, NCO2CH3), 3.26 (br. d, J = 13.7 Hz, 1 H, 6-Hax,
major), 3.17 (br. d, J = 14.4 Hz, 1 H, 6-Hax, minor), 2.25–2.12 (m,
1 H, 3-H), 2.10–1.95 (m, 1 H, 4-H), 1.85–1.63 (m, 2 H, OH and 4-
HЈ), 1.58–1.45 (m, 1 H, 3-HЈ) ppm.
1316
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1306–1317

Synthesis of 5-Hydroxy- and 4,5-Dihydroxypipecolic Acids
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[32] We observed this by recording the spectrum of 18 in CD3OD.
The signals associated with the minor isomer are the following:
1H NMR (CD3OD, 400 MHz): δ = 3.98 (ddd, J = 9.4, 7.0,
3.3 Hz, 1 H), 3.71 (dd, J = 11.3, 3.9 Hz, 1 H), 3.57 (dd, J =
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3.3 Hz, 1 H), 2.42 (dd, J = 15.4, 9.4 Hz, 1 H) ppm, which seems
consistent with the structure of the pyran-2-one derivative. The
1H and 13C NMR spectra of compound 18, recorded both in
CD3OD and [D6]DMSO, are identical to those reported in the
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Received: October 26, 2012
Published Online: January 21, 2013
Eur. J. Org. Chem. 2013, 1306–1317
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1317