Total synthesis of pipecolic acid and 1-: C -alkyl 1,5-iminopentitol derivatives by way of stereoselective aldol reactions from (S)-isoserinal

Article abstract of DOI:10.1039/c7ob02797d

A short synthesis of iminosugars and pipecolic acid derivatives has been realized through aldol addition of a pyruvate, a range of ketones and (S)-isoserinal, followed by catalytic reductive intramolecular amination. The stereoselective aldol reaction was achieved successfully by using tertiary amines or di-zinc aldol catalysts, thus constituting two parallel routes to optically pure products with good yields and high diastereo-selectivities. These carbohydrate analogues may be the inhibitors of potent glycosidases and glycosyltransferases.

Full text of DOI:10.1039/c7ob02797d

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Total Synthesis of Pipecolic Acid and 1-C-Alkyl 1,5-Iminopentitol
Derivatives by way of Stereoselective Aldol Reactions from (S)-
Isoserinal
Received 00th January 20xx,
Accepted 00th January 20xx
Sebastian Baś,*a Rafał Kusy,a Monika Pasternak-Suder,a Cyril Nicolas,b Jacek Mlynarskia,c and
Olivier R. Martinb
DOI: 10.1039/x0xx00000x
www.rsc.org/
A short synthesis of iminosugars and pipecolic acid derivatives has been realized through aldol addition of a pyruvate, a
range of ketones and (S)-isoserinal, followed by catalytic reductive intramolecular amination. The stereoselective aldol
reaction was achieved successfully by using tertiary amines or di-zinc aldol catalysts, thus constituting two parallel routes
to optically pure products with good yields and high diastereoselectivities. These carbohydrate analogues may be
inhibitors
of
potent
glycosidases
and
glycosyltransferases.
however, proceed through classical synthetic sequences
starting from natural sugars, although enantioselective
synthesis from non-sugar materials became also popular
recently.11 Enantiodivergent methods that result in optically
pure iminosugars are thus especially interesting and could be
of great advantage for the development of new glycosidase
inhibitors as drugs as well as for the study of the iminosugars
structure–bioactivity in interaction with glycosidases (SAR).12
Despite its synthetic interest and potential, utilization of the
direct catalytic aldol reaction in the realm of iminosugars has
been limited to only few examples. What is more, an
enzymatic approach for such aldol transformation was mainly
investigated during last decades.13 For example Class II
aldolase activated aldol reaction of pyruvic acid has been
exploited for the synthesis of pipecolic acid by Clapés et al
quite recently.14 A non-enzymatic protocol has been published
Introduction
Iminosugars refer to polyhydroxylated piperidines alkaloids, a
group of synthetic and naturally occurring sugar derivatives in
which the endocyclic oxygen is replaced by a nitrogen atom.1
The lack of an acetal function in most iminosugar derivatives
make them unable to undergo glycosidation reactions; instead
of this, they act as transition state analogues of the glycosyl
transfer process and manifest inhibitory activities against
various glycosidases.2 This feature has been exploited for the
development of new antiviral and anticancer drugs as well as
for the treatment of metabolic disorders such as type 1
Gaucher disease,3 or type 2 diabetes mellitus.4 Besides,
iminosugars have been also investigated in agriculture to
control insect and fungi population.5 Among iminosugars, the
group of hydroxylated pipecolic acids, which are non-
by Majewski et al. for the synthesis of 1-deoxy-
L-idonojirimycin
proteinogenic α
sources, display
-amino acids often isolated from natural
significant biological
activity.6
(
L
-DIJ) and related iminoalditols through proline-catalysed syn-
aldol reactions of protected dihydroxyacetone (DHA) and Cbz-
Hydroxypipecolic acids are useful scaffolds for the preparation
of medicinally valuable compounds like the antibiotic
tetrazomine,7 the HIV-protease inhibitor palinavir8 and
antagonists of the cholecistokinin (CCK) hormone.9 Owing to
widespread presence of iminosugars in Nature and their
significant medicinal potential, there is a strong demand for a
practical route providing an easy access to the hydroxylated
piperidine scaffold by asymmetric synthesis.10 Most strategies,
protected (S)-isoserinal acetonide 11; the latter compound is
available from commercial L-malic acid in a short synthetic
sequence.15 More recently, we presented another example of
application of 11 in syn-selective aldol reaction with
hydroxyacetone 10 and 1-hydroxy-2-octanone
9 as enolate
source and promoted by various amino acid-based catalysts.16
As a part of our continuing effort towards the synthesis of
natural products, we decided to investigate if a biomimetic
approach which entails an organocatalytic or class II aldolase
mimetic substrate activation could efficiently provide optically
pure aldols which could serve as precursors of iminosugar
skeletons. In this article we report the synthesis of pipecolic
acid derivative 1, iminosugars
stereocontrolled aldol reaction between optically pure (S)-
isoserinal acetonide 11 and appropriate hydroxyketones 10
or pyruvate as a key step (Scheme 1).
3 and 4 by means of
8–
7
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Scheme 1 General concept of de novo synthesis of selected iminosugars via aldol reactions of isoserinal (S)-11.
this general observation due to their weak solubility in
Result and discussion
chloroform (Table 1, entry 5, 6). Catalyst 17 stay undissolved
during the whole reaction time, so obtained results cannot be
compared with others. Interestingly, achiral tertiary amines
were found to be inefficient in activation of this
transformation and resulted in very low yield and selectivity
(Table 1, entry 7, 8). Notably, the presence of 20 mol-%
tertiary amine at room temperature was necessary to reach
acceptable conversions in reasonable times wherein MTBE was
the solvent of choice (Table 1, entry 9–13). After careful tuning
In our previous work we have successfully employed proline-
based catalysts for the enantioselective aldol reaction of
aliphatic ketones
9 and 10 to afford aldol products 6b and 6c
with yield up to 43%, 67% and diastereoselectivity syn/anti
(3.4:1) and (8:1), respectively. However, we were unable to
activate by this method aromatic ketones like 2-hydroxy-
acetophenone.16 In an attempt to activate more demanding
substrates such as aromatic ketones or pyruvates and further
increase the yield and selectivity of the aldol reaction, we
assessed various types of non-amino acid catalysts. Easley
accessible optically pure tertiary amines: Cinchona alkaloids
12−16 were selected as first choice catalysts for efficient and
selective aldol reaction of (S)-11. In our previous works
Cinchona alkaloids have been exploited for the promotion of
aldol reaction of aromatic ketones17 and sterically hindered
pyruvates18 with various aldehydes. According to our
published data we screened various Cinchona alkaloids in the
of reaction conditions, catalyst 15 provided the desired anti-
5
product in 50% yield and a diastereoselectivity syn/anti ratio
(1:7.5) (Table 1, entry 9). Next our target was shifted to an
alternative route utilizing chiral zinc complexes as mimetics of
Class II aldolases, wherein bimetal-catalyst activate both
substrates donor and aldehyde in a chiral environment.20 We
chose the Zn/ProPhenol complex 18 developed by Trost which
is an excellent catalytic system for an array of enantioselective
aldol reactions.21 In this approach, both enantiomers of
complex 18 were investigated: they displayed
a
reaction of optically pure (S)-11 and pyruvate
7 to access both
match/mismatch effect with respect to chiral aldehyde (S)-11
similar to the Cinchona alkaloids. We were glad to observe that
efficiency and stereoselectivity (Table 1, entry 1–6). Starting
from the previously developed conditions19 we found that
pseudoenantiomeric pairs of Cinchona alkaloids showed a
match/mismatch effect toward the chiral aldehyde (S)-11. A
slightly higher yield and stereoselectivity in favour of the anti-
the reaction between
7 and (S)-11 promoted by (S,S)-18
catalyst proceeded smoothly and provided the aldol product in
40% yield with a selectivity comparable to that obtained for
15, favouring the anti-product in a (1:7) ratio (Table 1, entry
14). It is noteworthy that the (R,R)-enantiomer afforded nearly
the same yield (43%), but with a very low diastereoselectivity
syn/anti (1:1.3) (Table 1, entry 15). Solvent switch from THF to
isomer
5 was obtained by applying alkaloids with the
stereochemistry of 12 and 15 (Table 1 entry 1, 4) in
comparison to their pseudoenantiomers 13 and 14 which
afforded nonselective mixture of diastereomers (Table 1, entry
2, 3). Alkaloids with phenol group 16 and 17 did not match to
Toluene intermit the side reaction of pyruvate
7 self-
2 | J. Name., 2012, 00, 1-3
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ARTICLE
17e
(S,S)-18
Toluene
56
1/6
condensation a main source of impurities and side products,
but result with significant selectivity decrease (Table 1, entry
aIsolated yield. b Diastereomeric ratio determined by 1H NMR analysis
16). Presence of triphenylphosphine sulphide,
a
typical
c
of the product mixture. Reaction conditions: 7 (0.5 mmol), 11 (0.5
additive used together with ProPhenol catalyst 1820 was
beneficial for the selective product formation in Toluene which
manifested also in an increase of the yield up to 56% (Table 1,
entry 17).
mmol), catalyst (0.1 mmol) in solvent (1.0 mL) at rt. dReaction
conditions: 7 (0.5 mmol), 11 (0.5 mmol), catalyst 18 (20 mol%) in dry
solvent (1.5 mL) under argon at -20 °C. eReaction performed at -20 °C
for 60 h in dry solvent (1.5 mL) with triphenylphosphine sulfide (0.15
mmol) and 4Å MS (100 mg) as additives.
Table 1. Catalyst screening for the aldol reactions of pyruvic
ester
7
and isoserinal (S)-11
.
After this initial catalyst screening, we next explored the
generality of the elaborated strategy with various
N
N
N
N
OH
OH
OH
OH
hydroxyketones (i.e.,
evaluating catalyst 15 and 18 for the reaction of the (2-
hydroxyacetyl)furan and aldehyde (S)-11 (Table 2, entry 1−3).
8–10). We initiated this work by
MeO
MeO
N
N
N
N
8
12
13
cinchonidine (CD)
14
15
cinchonine (CN)
quinine (QN)
quinidine (QD)
The experiments soon revealed that the developed catalysts
were the key for successful activation of aromatic ketones with
yields up to 83−92 %. Although catalyst 15 (30 mol%) afforded
a yield above 80%, the content of the main isomer (2R,3R,4S)-
6a did not exceed 50% in products mixture (Table 2, entry 1).
Because of the presence of rotamers caused by the N-Cbz
protecting group, it was difficult to determine the ratio of
other isomers from the NMR spectra. A similar investigation
was made for catalyst 18, wherein both enantiomers of the
catalyst resulted in yield above 90%. Application of the (S)-
configured catalyst 18, however, resulted in the loss of
stereoselectivity, apparently as a result of a mismatched pair
formed between the chiral pocket of catalyst and the aldol
reaction undergoing substrates (Table 2, entry 2).
Alternatively, (R,R)-18 with the appropriate configuration
promoted the formation of the aldol product 6a having the
expected configuration (2R,3R,4S), with a selectivity of (4:1)
(Table 2, entry 3). Furthermore, we decided to investigate if an
analogous approach could promote efficiently aldol reactions
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Zn
O
Zn
Ph
N
N
O
O
N
O
Zn
Zn
OH
OH
N
O
N
O
N
HO
HO
N
N
16
cupreine
17
cupreidine
(S,S)-18
(R,R)-18
O
20 mol%
catalyst
OH
O
O
O
(S)
O
OMe
OMe
+
(R)
NCbz
CbzN
solvent, 60h
O
O
O
O
11
5
7
entry
1c
catalyst
12(CN)
13(CD)
14(QN)
15(QD)
16
solvent
CHCl3
yield (%)a
27
syn/antib
1/4
2c
CHCl3
20
1/2.6
1/1
3c
CHCl3
23
4c
CHCl3
30
1/7
5c
CHCl3
16
1/7
of ketones
9 and 10 which we have successfully employed in
6c
17
CHCl3
7
1/1.5
1/2.4
1/1.5
1/7.5
1/6
the past (Table 2, entry 4–9).16 As anticipated, this
methodology provided product 6b in a much higher yield
(79%) than that obtained using our previous route (43%) and,
moreover, the diastereoselectivity was increased from 3.4:1 to
9:1 syn/anti (Table 2, entry 4−6). We were glad to observe the
highest dr (9:1) for the quinidine (15)–activated reaction,
although it required an extremely long reaction time (14 d)
(Table 2, entry 4). For ketone 10 the reaction was faster (72 h),
but resulted in lower selectivity (Table 2, entry 7).The
match/mismatch effect of catalyst 18 enantiomers was
maintained also for both ketones (Table 2, entry 5, 6, 8, 9).
Surprisingly, aldol reaction of hydroxyacetone 10 exhibited
higher selectivity for 6c when promoted by (S,S)-18 than its
7c
Quinuclidine
DBU
CHCl3
24
8c
CHCl3
6
9c
15
MTBE
AcOEt
THF
50
10c
11c
12c
13c
14d
15d
16d
15
33
15
44
1/7
15
Toluene
1,4-Dioxane
THF
37
1/5
15
47
1/4
(S,S)-18
(R,R)-18
(S,S)-18
40
1/7
THF
43
1/1.3
1/2.5
enantiomer (Table 2, entry 8, 9), whereas in case of ketone
mismatch effect was unaltered (Table 2, entry 5, 6).
9
Toluene
42
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ARTICLE
Table 2. Reactivity of Hydroxyketones 8–10.
Journal Name
entry
ketone
main product
catalyst
yield (%)a
drb
(2R,3R,4S)-6:other 6
1c
2d
15
83
92
1:1
(S,S)-18
1:1
3d
4e
5d
(R,R)-18
15
92
41
76
4:1
9:1
(S,S)-18
1.4:1
6d
7c
(R,R)-18
79
48
4:1
3:2
15
8d
9d
(S,S)-18
(R,R)-18
72
58
9:1
1:1
aIsolated yield. bDiastereomeric ratio determined by 1H NMR analysis of the product mixture. cReaction
conditions: ketone (0.5 mmol), 11 (0.5 mmol), catalyst 15 (30 mol%) in MTBE (1.0 mL) at rt for 72 h.
dReaction conditions: ketone (0.5 mmol), 11 (0.5 mmol), catalyst 18 (20 mol%) in dry THF (1.5 mL) under
argon at 5 °C for 12 h. eReaction time of 14 days with other conditions like in c.
During our investigation on these aliphatic ketones, an This unexpected phenomenon can be explained by the
unexpected solvent effect on the aldol reaction efficiency was different solubility of the ketones in these solvents. The less
observed. In dry THF, aldol reaction of
9 proceeded smoothly polar ketone 9 is dissolved better in nonpolar Toluene in
and provided 6b in 79% yield with a (4:1) diastereoselectivity, compare to THF whereas the opposite is true for ketone 10. Of
whereas in dry toluene no product was observed (Table 3, note, possible formation of aggregates between ketones and
entry 1, 2). An opposite situation was observed for ketone 10 catalyst 18 in inappropriate solvents could result in aldol
(Table 3, entry 3, 4) wherein dry Toluene promoted the reaction acceleration.
synthesis of aldol 6c while THF prevented this process.
All in all, the stereochemical outcome observed for both type
of catalysts, which mainly produced adducts with the same
configuration, might be consistent with similar mechanisms
based on the generation of the enolate from pyruvic ester or
ketone. In case of tertiary amines the tight complex between
the enolate and the chiral catalyst is formed as an ions pair.
The thus formed chiral enolate-catalyst pair attacks the chiral
aldehyde according to Felkin–Anh principles (Scheme 2a). This
model suggests also that the steric constraints imposed by
larger substituents of reagents coordinated to catalyst and
complex cavity determine which face of the aldehyde is
preferentially exposed to the enolate nucleophile (Scheme 2b).
Therefore, the asymmetric induction occurs during the
approach of the nucleophile to the chiral acceptor electrophile
which results in the formation of aldols having one precise
configuration predominantly. The zinc catalysts 18 activation
mode can be compared mechanistically to the type II
Table 3. Solvent Effect on Aldol Reactions.
entry
1c
ketone
solvent yield (%)a
drb
(2R,3R,4S)-6:other 6
THF
Toluene traces
THF traces
Toluene 76%
79%
4:1
2c
3c
4c
n.d.
n.d.
9:1
aIsolated yield. bDiastereomeric ratio determined by 1H NMR analysis
c
of the product mixture. Reaction conditions: ketone (0.5 mmol), 11
(0.5 mmol), 18 (20 mol%) in dry solvent (1.5 mL) under argon at -20
°C for 12 h.
4 | J. Name., 2012, 00, 1-3
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aldolases, which employ zinc ion to form an active enolate.22 part B).16 An attempt to synthetize
ARTICLE
4
was also made and
The role of two zinc species is to provide both a zinc to form resulted in an improvement of final product yield from 55% to
the requisite enolate and a second zinc to function as a Lewis 85% (Scheme 3, part C). High diastereoselectivity of products
acid to coordinate the aldehyde (S)-11. In such scenario the and is an outcome of a thermodynamic control obtain in
3
4
surrounding chiral ligand effect the asymmetric aldol addition acidic environment which accelerate formation of an isomer
of zinc-enolate to the aldehyde both coordinated to zinc with aliphatic substituent in more preferred equatorial
atoms.21 Similar observations were described in our previous position (β-isomer). Unfortunately, this protocol failed in the
work and the present results are in good agreement with case of synthesis of
2 which required additional oxidation of
those published before.19,23
furan ring before reductive amination due to sensitivity of
furan ring to reduction conditions. Various oxidation methods
were investigated leading to mixtures of products from which
we were unable to isolate desired product with reasonable
yield. Starting from
pipecolic ester 19 in 83% yield (Scheme 3, part A) and,
moreover, it was easily scaled up (826 mg of ).Modification of
the procedure was caused by the sensitivity of unprotected
compound for acidic condition of reductive amination, in
5 the slightly modified protocol provided
5
5
which it undergoes elimination reaction. Less acidic conditions
were introduce to the synthesis of 19, nevertheless this result
in decrease of final product diastereoselectivity (α/β anomers
ratio 1:3.4). What is more, hydrolysis of the sterically hindered
ester 19 turned out to be a more puzzling issue. Attempts
using known methods failed in this case due to steric
hindrance of the phenol moiety or because of sensitivity of the
sugar-like region toward harsh conditions. Finally, we managed
to remove the 2,6-di-tert-butyl-4-methoxyphenol ester by
treatment with excess sodium hydride and in situ generation
of sodium hydroxide through addition of H2O to the reaction
mixture. Compound
yield after 3 steps from compounds (S)-11 and
structure of was unambiguously determined by comparison
of the NMR of its hydrochloride spectra with the data reported
1
was obtained in 98% yield (45% overall
7). The
1
in the literature, because there are no spectra of
literature.6a
1 as such in
Conclusions
Scheme
2 Proposed model of observed stereochemistry
In conclusion, we have reported a short and facile synthesis of
iminosugars and pipecolic acid based on the
explanation
3
,
4
1
Having decided the core of our strategy, we needed to select a
convenient protocol for the preparation of iminosugars and
pipecolic acid derivatives from aldol precursors. The
diastereoselective aldol reaction of aldehyde (S)-11 with
various donors promoted both by tertiary amines and
Zn/Prophenol complexes. The synthetic approach developed
for aromatic ketones and pyruvates activation in aldol
reactions is a useful extension. In addition previously reported
results have been significantly improved. The present
methodology provides a concise and direct entry into the field
of polyhydroxylated piperidines and iminosugars, in a simple
and efficient way. In particular, it provides a new and short
method of synthesis of 1-C-alkyl-1,5-iminopentitols, which are
corresponding adducts
chromatography were transformed into iminosugars
and pipecolic ester 19 in a three step sequence (Scheme 3).
Deprotection with acidic ion exchange resin was followed by
5
and 6b−c isolated by column
3
and
4
−
intramolecular imine formation and reduction of the newly
created C=N bond that could be done in a single flask by
hydrogenolysis in the presence of palladium on carbon in
acidic environment. This approach was successfully exploited
known as potent glycosidase inhibitors, especially for
glucocerebrosidase.24
β-
for the synthesis of 3 in quantitative yield, a much better result
than with our previously reported methodology (Scheme 2,
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O
H
O
OH
O
H
1. NaH, 15 min
2. H2O, 4h
1. DOWEX 50WX8, 60h
2. H2 Pd/C, 12h
N
N
OAr
OAr
OH
(R)
A
CbzN
(S)
MeOH
THF
O
O
HO
HO
(R)
OH
OH
5
1
19
98%
82%
β
only
α β
/
1/3.4
OH
O
H
N
1. DOWEX 50WX8, 24h
2. H2 Pd/C, HCl, 12h
(S)
•HCl
B
CbzN
(S)
(S)
O
OH
MeOH
HO
OH
(S)
OH
6b
3
99%
β
only
H
N
OH
O
1. DOWEX 50WX8, 12h
2. H2 Pd/C, HCl, 60h
(S)
(S)
C
CbzN
(S)
HO
OH
(S)
MeOH
O
OH
OH
6c
4
85%
β
only
Scheme 3 Cyclisation of aldol products to give desired iminosugar and pipecolic acid derivatives.
anhydrous magnesium sulfate (MgSO4). Reaction products
were purified by normal phase flash chromatography, in air,
using silica gel 60 (230–400 mesh) with n-hexane and ethyl
acetate (EA) as eluents, unless otherwise stated.
Hydroxyketones, such as (2-hydroxyacetyl)furane 817 and 1-
hydroxy-2-octanone 926 were synthesized using previously
published protocols. The synthesis of 2,6-di-tert-butyl-4-
Experimental section
General remarks
Infrared (IR) spectra were recorded with a Fourier transform
infrared (FT-IR) spectrometer and are reported in wave
numbers (cm–1). 1H NMR (600 MHz and 300 MHz) chemical
shift values are listed in parts per million (ppm) downfield from
TMS as the internal standard or relative to the corresponding
nondeuterated solvent. Data are reported as follows: chemical
methoxyphenyl pyruvate
7 was carried out using a method
reported by Morin et al.27 Aldehyde 11 was prepared
according to a procedure described by J. Mlynarski and O. R.
Martin.16
shift (ppm on the
δ scale), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, dd = doublet of doublet, m = multiplet),
coupling constant J (Hz), and integration. br meaning broaden.
13C NMR (151 MHz and 75 MHz) chemical shifts are given in
ppm relative to the corresponding nondeuterated solvent or
TMS as the internal standard. High resolution mass spectra
(HRMS) were recorded with an electrospray ionization time-of-
flight (ESI-TOF) mass spectrometer. Specific optical rotations
were measured with a digital polarimeter in a thermostated
General Method for the Aldol Reactions Catalyzed by Tertiary
Amines (GP A). The related hydroxyketones 8−10 or 2,6-di-
tert-butyl-pyruvate
7 (0.5 mmol, 1.0 equiv.) and isoserinal (S)-
11 (0.5 mmol, 1.0 equiv.) were dissolved in MTBE (1.0 ml) and
the tertiary amine catalyst was added (0.2 equiv.). The
reaction mixture was then stirred at rt (ca. 20 °C) for an
appropriate time (12 h to 12 d). The solvent was evaporated
and the residue was purified by column chromatography to get
mixture of products as oil. The main diastereomers were
sometimes isolated and used in further reactions.
(20 °C) 1 dm long cell with high-pressure sodium lamp and are
T
reported as follow: [
α
]
D
[solvent, c (g/100 mL)]. Reactions
were controlled using analytical thin-layer chromatographies
(TLC) using Merck Silica Gel 60 F254 precoated plates. All
reagents and solvents were purified and dried according to
common methods.25 All organic solutions were dried over
General Method for the Aldol Reactions Catalyzed by Zinc
Complexes (GP B). The Zinc/Prophenol catalyst was prepared
as described in the literature.23 A solution of 18 (0.2
M in dry
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THF, 0.5 mL, 0.2 equiv.) was added to a mixture of compound hydroxyoctan-2-one
8−10 or pyruvate
9
and (S)-Isoserinal 11 were reacted with
7
(0.5 mmol, 1.0 equiv.) and (S)-11 (0.5 catalyst (R,R)-18. Column chromatography (n-hexane:EA 7:3)
mmol, 1.0 equiv.) in dry THF (1 mL) at -20 °C. The reaction was performed on the crude mixture to give related aldol
mixture was then stirred for 12 h in case of ketones 8−10 or 60 compound as colorless oil (160 mg, 79%) as a mixture of
h for pyruvate
HCl (1 , 0.2 mL) was performed. Stirring was pursued for 5 separated (n-hexane:EA 4:1) and characterized. Rf 0.45 (n-
min at 20 °C and the reaction mixture was poured in a mixture hexane:EA 7:3). H NMR (600 MHz, CDCl3):
7 at the same temperature and addition of aq. diastereomers. The main diastereomer (100 mg, 50%) was
M
1
δ
7.41–7.29 (m, 5
of EA (25 mL) and H2O (25 mL). The aqueous phase was H), 5.12 (s, 2 H), 4.37 (s, 1 H), 4.19 (t d, J = 7.7, 6.4 Hz, 1 H),
discarded and the organic phase was washed successively with 3.98 (t, J = 8.3 Hz, 1 H), 3.84 (s, 1 H), 3.78 (d, J = 3.8 Hz, 1 H),
H2O (25 mL), saturated aq. NH4Cl (25 mL), H2O (25 mL) and 3.61–3.53 (m, 1 H), 2.60 (ddd, J = 17.1, 8.2, 6.7 Hz, 1 H), 2.52
brine (25 mL). The Organic phase was dried (MgSO4), filtered (ddd, J = 17.1, 8.1, 6.9 Hz, 1 H), 2.21 (d, J = 9.7 Hz, 1 H), 1.74–
over a cotton plug and concentrated under vacuum to afford a 1.47 (m, 8 H), 1.37–1.23 (m, 6 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm.
residue. The crude product was purified through column 13C NMR (151 MHz, CDCl3):
δ 210.2, 152.6, 136.7, 128.7, 128.2,
chromatography to give related aldol compound as a mixture 94.6, 76.2, 74.3, 72.7, 66.8, 48.3, 37.9, 31.6, 28.9, 23.6, 23.4,
of diastereomers. The main stereoisomer was isolated to carry 22.6, 14.1 ppm.
further cyclization reactions.
Benzyl-(S)-5-((1R,2R)-1,2-dihydroxy-3-oxobutyl)-2,2-
dimethyloxazolidine-3-carboxylate 6c.16 Following GP B,
hydroxyacetone 10 and (S)-Isoserinal 11 were reacted with
Benzyl-(S)-5-((R)-4-(2,6-di-tert-butyl-4-methoxyphenoxy)-
1-hydroxy-3,4-dioxobutyl)-2,2-dimethyloxazolidine-3-
carboxylate 5. Following GP B, 2,6-di-tert-butyl-4- catalyst (S,S)-18. Column chromatography (n-hexane:EA 1:1)
methoxyphenyl pyruvate and (S)-Isoserinal 11 were reacted was performed on the crude mixture to give related aldol
7
with catalyst (R,R)-18. Column chromatography (n-hexane:EA compound as white solid (128 mg, 72%) as a mixture of
5:2) was performed on the crude mixture to give related aldol diastereomers. The main isomer (85 mg, 48%) was separated
adduct (158 mg, 56%, yellow oil) as a 1:6 (syn : anti) mixture of (n-hexane:EA 1:1) and characterized. Rf 0.41 (n-hexane:EA 1:1).
diastereomers. The main diastereomer (130 mg, 46%) was M.p. 107
separated (n-hexane:EA 4:1) and characterized. Rf 0.52 (n- 5.13 (s, 2 H), 4.38 (d, J = 1.2 Hz, 1 H), 4.27–4.12 (m, 1 H), 4.00
hexane:EA 4:1). 1H NMR (600 MHz, Acetone-d6):
7.47–7.24 (d, J = 6.8 Hz, 1 H), 3.89–3.75 (m, 1 H), 3.56 (dd, J = 10.6, 8.0
(m, 5 H), 6.90 (s, 2 H), 5.11 (s, 2 H), 4.52 (d, J = 4.5 Hz, 1 H), Hz, 1 H), 2.30 (s, 3 H), 1.63 (s, 3 H), 1.53 (s, 3 H) ppm. 13C NMR
4.36–4.26 (m, 1 H), 4.13 (dd, J = 14.2, 6.7 Hz, 1 H), 3.89–3.73 (75 MHz, CDCl3): 207.7, 128.8, 128.2, 128.1, 76.7, 74.3, 72.7,
− δ 7.35 (s, 5 H),
109 °C. 1H NMR (300 MHz, CDCl3):
δ
δ
(m, 4 H), 3.60–3.45 (m, 1 H), 3.24 (dd, J = 17.1, 3.5 Hz, 1 H), 66.8, 48.1, 26.9, 25.3 ppm.
3.21–3.14 (m, 1 H), 1.54 (s, 3 H), 1.48 (s, 3 H), 1.29 (s, 18 H) General procedure for the preparation of iminosugars 3, 4
ppm. 13C NMR (75 MHz, Acetone-d6):
δ
192.7, 162.8, 158.1, and compound 19 (GP C). Aldol products 5, 6a−c (100 mg)
144.3, 129.5, 128.9, 112.7, 78.0, 69.0, 67.6, 67.0, 55.7, 48.5, were dissolved in MeOH (10 mL) and resin DOWEX 50W×4 (H+
44.3, 36.4, 32.0 ppm. IR (ATR): 3338, 2961, 2929, 2871, 1751, form) (200 mg, 2 mass equiv.) was added. The suspension was
1592, 1418, 1170, 1062 cm-1. [ꢀ]ꢁꢂꢃ + 0.5 (c 1.00, CHCl3). HRMS stirred for a given reaction time (12
60 h, as followed by TLC
(ESI): m/z [M + Na+] found 592.2871, C32H43NNaO8 requires analysis, n-hexane:EA 1:1) and the resin was filtered over a
ν
−
592.2886.
Benzyl-(S)-5-((1R,2R)-3-(furan-2-yl)-1,2-dihydroxy-3-
cotton plug. It was washed with MeOH and the solution was
concentrated under reduced pressure. The precipitate was
oxopropyl)-2,2-dimethyloxazolidine
-3-carboxylate
6a. dissolved in MeOH (10 mL) and aq. HCl (1M, 0.5 mL only for
Following GP B, hydroxyacetylfurane
8 and (S)-11 were reacted ketones 6a−c) was added, followed by Pd/C (1.9 equiv.). The
with catalyst (R,R)-18. Column chromatography (DCM:MTBE:n- reaction mixture was then stirred under hydrogen atmosphere
hexane 5:1:2) was performed on the crude mixture to give (H2-filled balloon) (12 60 h). The suspension was filtered over
−
related aldol compound as yellow oil (179 mg, 92%) as a celite and the cake washed with MeOH (50 mL). The solution
mixture of diastereomers. The main diastereomer (115 mg, was evaporated in vacuo. The residue was purified by column
60%) was separated (n-hexane:EA 1:1) and characterized. Rf chromatography on silica gel to get the desired product as
0.49 (n-hexane:EA 1:1). 1H NMR (600 MHz, Acetone-d6):
(d, J = 1.0 Hz, 1 H), 7.44 (d, J = 3.6 Hz, 1 H), 7.41–7.28 (m, 5 H),
δ
7.89 yellow oil or white solid (82
−99%).
2,6-di-tert-Butyl-4-methoxyphenyl-(4R,5S)-4,5-
6.71 (dd, J = 3.6, 1.7 Hz, 1 H), 5.12 (s, 2 H), 5.04–4.97 (m, 1 H), dihydroxypiperidine-2-carboxylate 19. The titled product was
4.38 (dd, J = 14.1, 7.1 Hz, 1 H), 4.15 (m, 2 H), 3.86–3.78 (m, 1 obtained according to a scaled-up procedure of GP C, using
H), 3.59 (t, J = 8.6 Hz, 1 H), 1.62 (s, 3 H), 1.51 (s, 3 H) ppm. 13C compound
NMR (151 MHz, Acetone-66):
138.3, 129.4, 128.8, 128.6, 119.8, 113.4, 94.8, 75.4, 75.2, 74.6, reaction mixture was stirred successively for 60 h and 12 h.
66.9, 48.8, 26.8, 24.8 ppm. IR (ATR): 3445, 2932, 1703, 1682, Compound 19 (yellow oil, 470 mg, 82%) was obtained as a
1411, 1355, 1068 cm-1. [ꢀ]ꢁꢂꢃ - 8.4 (c 1.00, CHCl3). HRMS (ESI): mixture of diastereomers (1:3.4
) after purification over
Na+] found 412.1367, C20H23NNaO7 requires column chromatography (CHCl3:MeOH 10:1). The main
stereoisomer 19 (360 mg, 63%) was isolated after
chromatography over silica gel (CHCl3:MeOH 20:1 to 15:1). β-
5
(860 mg, 1.5 mmol) dissolved in MeOH (50 mL),
δ
188.8, 153.2, 151.7, 148.4, resin DOWEX 50W×4 (H+ form) (1.6 g) and Pd/C (305 mg). The
ν
α,β
m/z [M
+
412.1372.
β-
Benzyl-(S)-5-((1R,2R)-1,2-dihydroxy-3-oxononyl)-2,2-
dimethyloxazolidine-3-carboxylate 6b.16 Following GP B, 1- 19. Rf 0.45 (CHCl3:MeOH 15:1). H NMR (600 MHz, MeOD-d4):
1
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δ
6.87 (d, J = 4.3 Hz, 2 H), 3.80–3.74 (m, 5 H), 3.69 (dd, J = 12.3, Hz, 1 H), 2.30 (dt, J = 13.6, 3.8 Hz, 1 H), 2.02 (td, J = 13.1, 11.6
2.9 Hz, 1 H), 3.12 (dd, J = 14.1, 2.6 Hz, 1 H), 2.78 (dd, J = 14.0, Hz, 1 H) ppm. 13C NMR (151 MHz, D2O):
172.8, 67.4, 64.6,
1.2 Hz, 1 H), 2.37–2.24 (m, 1 H), 1.92 (d, J = 1.0 Hz, 1 H), 1.33 57.5, 46.9, 28.2 ppm. IR (ATR): 3513, 3295, 2925, 2807, 2594,
(t, J = 2.0 Hz, 18 H) ppm. 13C NMR (151 MHz, MeOD-d4): 2529, 2446, 2190, 2134, 1737, 1397, 1203, 1065, 1021 cm-1.
δ
ν
δ
174.3, 158.0, 144.8, 144.7, 143.0, 112.7, 112.6, 70.9, 68.3, [ꢀ]ꢂꢁꢃ + 11.2 (c 1.00, 2
M
HCl). HRMS (ESI): m/z [M + H+] found
59.8, 55.7, 50.5, 36.5, 36.5, 32.9, 32.0, 31.9 ppm. IR (ATR):
3338, 2961, 2928, 2871, 1751, 1592, 1170, 1062 cm-1. [ꢀ]ꢁꢂꢃ
ν
+
162.0758 C6H12NO4 requires 162.0761; (ESI): m/z [M + Na+]
found 184.0575, C6H11NNaO4 requires 184.0586.
1.6 (c 1.00, MeOH). HRMS (ESI): m/z [M + H+] found 380.2430, 2R,4R,5S-dihydroxypipecolic acid hydrochloride (1•HCl).6a
C21H34NO5 requires 380.2432.
Compound
1
(34 mg, 0.34 mmol) was dissolved in D2O (1 mL)
, 0.5 mL) was added. The reaction mixture was
1-C-(1S)-1-n-Hexyl-1,5-dideoxy-1,5-imino-
L
-arabinitol
and aq. HCl (1M
hydrochloride 3. The titled product was obtained according to stirred for 5 min and concentrated under reduced pressure.
GP C using compound 6b. The reaction mixture was stirred Absolute ethanol (1 mL) was added to the residue, that
successively for 24 h and 12 h. Compound
mg, 99%) was obtained as a single diastereomer (
purification over column chromatography (DCM:MeOH 4:1). until water was removed. Later CD3OD (1 mL) was added to
3
(white solid, 64 resulted in precipitation of white solid. The solvent was
β
form) after removed under reduced pressure. This procedure was repeat
1
M.p. 140−147 °C H NMR (300 MHz, D2O): δ 4.12 (td, J = 3.0, the residue and the suspension was stirred for 5 min followed
1.5 Hz, 1 H), 3.61 (t, J = 9.7 Hz, 1 H), 3.52 (dd, J = 9.5, 3.0 Hz, 1 by solvent evaporation. The solid obtained was dried in vacuo
H), 3.25 (dd, J = 13.6, 3.1 Hz, 1 H), 3.08 (dd, J = 13.6, 1.4 Hz, 1 to provide product 1•HCl with 40 mg (96%). 1H NMR (600
H), 2.90 (ddd, J = 9.8, 8.8, 3.5 Hz, 1 H), 1.88 (ddd, J = 9.4, 7.6, MHz, D2O):
δ 4.14 (s, 1 H), 4.10–3.97 (m, 2 H), 3.50 (dd, J =
4.4 Hz, 1 H), 1.53 (ddd, J = 23.6, 12.3, 6.7 Hz, 1 H), 1.43–0.98 13.5, 3.8 Hz, 1 H), 3.24 (dd, J = 13.5, 1.8 Hz, 1 H), 2.35 (dt, J =
(m, 9 H), 0.73 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, 13.7, 4.1 Hz, 1H), 2.20–2.06 (m, 1 H) ppm. 13C NMR (151 MHz,
D2O/Acetone-d6):
δ
63.0, 59.8, 56.4, 50.2, 38.4, 21.3, 19.6, D2O):
3402, 3333, 3210, 3009,
δ 170.5, 66.6, 64.2, 55.4, 46.4, 27.4 ppm.
18.7, 15.0, 12.5, 3.9 ppm. IR (ATR):
ν
2953, 2925, 2855, 1529, 1100 cm-1. [ꢀ]ꢁꢂꢃ + 3.5 (c 1.00, MeOH).
HRMS (ESI): m/z [M + H+] found 218.1751, C11H24NO3 requires
218.1751.
Conflicts of interest
There are no conflicts to declare.
1,5,6-Trideoxy-1,5-imino-L
-mannitol 4.14 The titled product
was obtained according to GP C using compound 6c. The
reaction mixture was stirred successively for 12 h and 60 h.
Acknowledgements
Compound
single diastereomer (
chromatography (CHCl3:MeOH:H2O:NH3
4
(white solid, 37 mg, 85%) was obtained as a
form) after purification over column
50:50:19:1). M.p.
Financial support from the Polish National Science Centre
(MAESTRO Grant Nr. 2013/10/A/ST5/00233) is gratefully
acknowledged.
β
(aq.)
1
140−143 °C. H NMR (600 MHz, D2O): δ 3.97 (dd, J = 4.6, 2.9
Hz, 1 H), 3.51 (dd, J = 9.7, 3.3 Hz, 1 H), 3.29 (t, J = 9.6 Hz, 1 H),
2.92 (dd, J = 14.5, 2.7 Hz, 1 H), 2.71 (dd, J = 14.5, 1.6 Hz, 1 H),
2.44 (dd, J = 9.6, 6.4 Hz, 1 H), 1.16 (d, J = 6.4 Hz, 3 H) ppm. 13C
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Çꢀꢁꢂꢃ ꢄꢅ ꢄꢆꢇꢃꢆꢇꢈ ꢃꢆꢇꢉꢊ
Çh/ ꢀꢁꢂꢃ ꢄꢅꢆ
!ꢇꢈꢉꢉꢊꢋꢁꢄꢅ ꢇꢈꢌꢋ ꢊꢇꢄꢇ ꢍꢎ ꢄꢉꢄꢌꢍꢇꢏꢀꢂꢁꢇ ꢉꢍꢄꢊꢋꢈ ꢀꢁꢂ ꢐꢄꢂꢇꢋꢊꢁꢊꢍꢇꢊꢑꢊꢅꢋꢄꢒꢊ ꢂꢑꢐꢍꢑ ꢂꢐꢐꢄꢋꢄꢍꢌ ꢍꢎ ꢂ ꢃꢈꢁꢏꢒꢂꢋꢊꢓ ꢂ
ꢁꢂꢌꢀꢊ ꢍꢎ ꢈꢐꢁꢍꢔꢈꢕꢊꢋꢍꢌꢊꢇ ꢖꢄꢋ ꢗ{ꢘ ꢄꢇꢍꢇꢊꢁꢄꢌꢂꢑꢓ ꢎꢍꢑꢑꢍꢖꢊꢐ !ꢈ ꢅꢂꢋꢂꢑꢈꢋꢄꢅ ꢁꢊꢐꢏꢅꢋꢄꢒꢊ ꢄꢌꢋꢁꢂꢉꢍꢑꢊꢅꢏꢑꢂꢁ
ꢂꢉꢄꢌꢂꢋꢄꢍꢌ"