Organocatalytic syn-aldol reactions of hydroxy ketones with (S)-isoserinal: Asymmetric synthesis of 6-deoxy-1,5-iminohexitols and related compounds

Article abstract of DOI:10.1002/ejoc.201201413

An improved and convenient preparation of protected (S)-isoserinal on a large scale is reported. This key intermediate was reacted through organocatalyzed aldol reaction or Wittig based chain extension and functionalization to give enantiopure 1,5,6-trideoxy-1,5-imino-hexitols such as 10a (L-manno) and 10b (D-gluco). These two compounds are of interest as glycosidase inhibitors. The elaborated organocatalytic process includes diastereoselective syn aldol reaction of (S)-isoserinal hydrate and hydroxyacetone or 1-hydroxy-2-octanone and is promoted by various amino acid-based catalysts. Diastereoselectivities of up to 8:1 were achieved, thus establishing a new, efficient synthetic route to these important carbohydrate mimics. A novel protocol for the preparation of 1,5,6-trideoxy-1,5-imino-L- mannitol and 1,5,6-trideoxy-1,5-imino-D-glucitol is reported. The key steps include organocatalyzed syn-selective direct aldol reaction of hydroxyacetone and CBz-protected isoserinal hydrate, followed by reductive amination/ cyclization. Copyright

Full text of DOI:10.1002/ejoc.201201413

Job/Unit: O21413
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Date: 16-01-13 11:59:07
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201201413
Organocatalytic syn-Aldol Reactions of Hydroxy Ketones with (S)-Isoserinal:
Asymmetric Synthesis of 6-Deoxy-1,5-iminohexitols and Related Compounds
Cyril Nicolas,[a] Roman Pluta,[b] Monika Pasternak-Suder,[b] Olivier R. Martin,*[a] and
Jacek Mlynarski*[b]
Dedicated to Professor Marek Chmielewski on the occasion of his 70th birthday
Keywords: Synthetic methods / Asymmetric synthesis / Medicinal chemistry / Organocatalysis / Wittig reactions / Aldol
reactions / Carbohydrates / Iminosugars
An improved and convenient preparation of protected (S)-
isoserinal on a large scale is reported. This key intermediate
was reacted through organocatalyzed aldol reaction or Wittig
based chain extension and functionalization to give enantio-
cess includes diastereoselective syn aldol reaction of (S)-iso-
serinal hydrate and hydroxyacetone or 1-hydroxy-2-oct-
anone and is promoted by various amino acid-based cata-
lysts. Diastereoselectivities of up to 8:1 were achieved, thus
establishing a new, efficient synthetic route to these impor-
tant carbohydrate mimics.
pure 1,5,6-trideoxy-1,5-imino-hexitols such as 10a (
L-manno)
and 10b ( -gluco). These two compounds are of interest as
D
glycosidase inhibitors. The elaborated organocatalytic pro-
often been overcome by removal of the C–O at the anom-
eric position (i.e., in 1-deoxy iminosugars such as DNJ) or
by replacement of the exocyclic oxygen by a methylene
group to form iminosugar C-glycosides.[3,4]
Major efforts have been dedicated to the synthesis of
both types of compound. Most strategies, however, proceed
through classical synthetic sequences from sugars involving
such reactions as intramolecular reductive aminations, ad-
ditions to imines or glycosylamines followed by intramolec-
ular nucleophilic substitutions, etc.
In our work, we have, for example, developed efficient
synthetic routes to 1-C-alkyl iminopentitols from pen-
toses;[5] 1-C-alkyl-substituted imino alditols, having an α-d-
xylo configuration, are indeed extremely potent inhibitors
of β-glucocerebrosidase (GCase) and behave as pharmaco-
logical chaperones of mutant GCase, thus showing poten-
tial as therapeutic agents for Gaucher disease.[6]
The preparation of these small organic molecules usually
require time-consuming reaction sequences and typically re-
sult in low overall yields and extensive protecting group ma-
Introduction
Since their discovery in the 1960’s, iminosugars have pro-
gressively made their way to become a topic of major inter-
est in bioorganic, medicinal, and pharmaceutical chemis-
try.[1] These polyfunctional molecules in which the endo-
cyclic oxygen of the sugar has been replaced by nitrogen
are important carbohydrate mimics and display remarkable
inhibitory activity towards a diverse range of carbohydrate-
active enzymes and/or act as chaperones of mutant glyco-
sidases.[2] Two iminosugar derivatives have already been
marketed as drugs for the treatment of Type I Gaucher dis-
ease and Type 2 diabetes, namely N-hydroxyethyl-1-deoxy-
nojirimycin (N-hydroxyethyl-DNJ or Glyset) and N-butyl-
DNJ (Zavesca).
However, one of the major drawbacks of free imino-
sugars is the lack of stability of the corresponding glycos-
ides under hydrolysis conditions. This instability, which is
caused by the lability of the simple N,O-acetal function, has
[a] Institut de Chimie Organique et Analytique, UMR CNRS nipulations. In addition, the configuration is controlled by
7311, Université d’Orléans,
the structure of the starting sugar moiety and therefore can-
not be easily modified.
BP 6759, 45067 Orléans cedex 2
Fax: +33-2-38417281
E-mail: olivier.martin@univ-orleans.fr
[b] Faculty of Chemistry, Jagiellonian University,
Ingardena 3, 30-060 Krakow, Poland
Fax: +48-12-6340515
On the other hand, recent progress in the area of de novo
synthesis of carbohydrates and of carbohydrate mimetics
have provided a way to achieve greater stereodiversity and
have significantly reduced the number of synthetic steps by
using, for example, elegant organocatalytic-mediated pro-
cesses.[7,8]
E-mail: jacek.mlynarski@gmail.com
Homepage: www.jacekmlynarski.pl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201413.
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FULL PAPER
Scheme 1. Retrosynthetic analysis of the target 1-alkyl-substituted iminosugar.
Interestingly, Majewski et al. have recently published a groups also needed to be chosen for the reaction sequence
protocol for the synthesis of 1-deoxy-l-idonojirimycin (l- leading to imino sugars. The Cbz-protected (S)-isoserinal
DIJ) and related iminoalditols through proline-catalyzed acetonide 1 (Scheme 2) was thought to fit these require-
syn-aldol reactions of Cbz-protected (S)-isoserinal aceton- ments, but, in spite of its high potential, few syntheses have
ide with 2-tert-butyl-2-methyl-1,3-dioxan-5-one.[9] The been reported.[9,15] All the methods are based on the use of
asymmetric organocatalytic reactions of cyclic dioxanone enantiopure derivatives of natural compounds as starting
were then followed by hydrogenolysis under acidic condi- materials, i.e., the chiral pool and are intrinsically diastereo-
tions to give the corresponding 1,5-dideoxy-1,5-imino-hex- selective.
itols in good yields. Of note was the moderate to surpris-
The most attractive method was described by Majewski
ingly high syn diastereoselectivity for the aldol products et al. (Scheme 2). In brief, isoserine hydrochloride was syn-
reached by using LiCl as an additive (dr = 5:1 and 95:5).[9] thesized in 62% yield from l-malic acid through a short
Based on these results, it could be envisaged that imino- sequence of reactions involving a Curtius rearrangement
pentitols carrying various “R” substituents at C-1 could be without isolating the intermediates.[16] Following the
reached by a related concise and stereocontrolled synthesis Schmidt procedure,[15a–15b] the amino acid hydrochloride 2
starting from isoserinal 1 (Scheme 1). A major question in was then protected and, after diisobutylaluminum hydride
this plan was the regio- and stereoselectivity of the reaction (DIBAL-H) mediated reduction, the Cbz-protected (S)-iso-
involving an unsymmetrical hydroxy ketone. Whereas or- serinal acetonide 1 was obtained in 23% overall yield, indi-
ganocatalytic aldol reaction of hydroxyacetone leading to cating that it forms readily as a stable hydrate.[9] When we
carbohydrates has been briefly examined,[10] such a reaction tried the reaction on modest scales (up to 2 g), we were
for various R-substituted ketones is unknown. In general, not able to make the DIBAL-H reduction work properly.
previous work with unprotected α-hydroxyacetone and non- Instead, a mixture of aldehyde, primary alcohol and signifi-
chiral aldehydes have shown that under organocatalytic cant amounts of unreacted methyl ester was formed.[17]
conditions, the reactions at the more substituted carbon are Therefore, by analogy with the work reported by Roush and
favored, resulting in diols with various configurations,[11,12] Dondoni,[17] it occurred to us that 1 could be obtained
whereas examples with longer chains are rare[11h] and, as more conveniently by a reduction/oxidation sequence. In
such, the regioselectivity is difficult to predict.[13,14]
addition, a more friendly procedure along with significantly
In this article we report an improved method for the syn- better overall yield was developed by using mostly known
thesis of the required starting material, (R)- or (S)-isoseri- transformations; the new, highly reproducible conditions
nal 1, the synthesis of reference compounds of known con- are set out in Scheme 3. Although it is only reported for
figuration by an alternative procedure, the results of our the preparation of (S)-1, it is also applicable to multigram
investigations on the organocatalyzed aldol reaction of two synthesis of (R)-1.
different hydroxy ketones with 1, and the synthesis of two
iminosugars of type I (Scheme 1, R = Me).
As reported by Majewski et al., l-malic acid was con-
verted into its isopropylidene derivative 3 by reacting with
p-toluenesulfonic acid (pTSA) and an excess of 2,2-dimeth-
oxypropane (DMP) at room temperature (Scheme 3).[9]
Compound 3 was isolated (87%) in a reasonably pure form
(Ͼ94% by 1H NMR spectroscopic analysis) by selective
precipitation (Et2O/hexane). Subsequent, Curtius re-
arrangement of 3 was carried out with diphenylphosphoryl
azide (DPPA) and triethylamine in toluene.[18] The reactive
isocyanate intermediate was not isolated but instead
Results and Discussion
Preparation of (R)- or (S)-Isoserinal on Large Scale
Having decided the core of our strategy, we needed to
select a convenient protocol for the preparation of (R)- or
(S)-isoserinal on a large scale. Suitable isoserinal protecting
Scheme 2. Synthesis of isoserinal from l-malic acid.
2
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Asymmetric 6-Deoxy-1,5-iminohexitols
Scheme 3. Improved preparation of Cbz-protected isoserinal acetonide (S)-1.
trapped with benzyl alcohol to provide the benzyloxycar- (Ͼ99%).[21] It should be noted that no other oxidant was
bonylamino derivative 4 directly in a very safe manner on satisfactory [2-iodoxybenzoic acid (IBX), 2,2,6,6-tetra-
a large scale (65%, 17.2 g). After reaction with catalytic methylpiperidine-1-oxyl (TEMPO), Corey–Suggs, Pfitzner–
pTSA in methanol (leading to 5) and acetonide formation Moffatt, Swern conditions].
using excess DMP in the presence of boron trifluoride
etherate, protected l-isoserine methyl ester 6 was produced
in 82% yield in two steps. It is noteworthy that the addition
Synthesis of Reference Compounds
of 7ϫ 1.5 equiv. of DMP gave better results than the ad-
dition of 10.5 equiv. in one portion[19]
To identify the diols resulting from the aldol reaction
Compound 6 was then reduced to provide 7. However, (compounds 8a–d, Scheme 4), we started our investigation
neither lithium aluminum hydride (LiAlH4) nor sodium with the synthesis of all isomers using an alternative and
borohydride (NaBH4) delivered 7 in good yields. Instead, reliable protocol. For this purpose, we chose dihydrox-
degradation and cleavage of the Cbz group or incomplete ylation of the corresponding enones; thus, (S)-1 was reacted
reaction was observed. Overall, the best reagent was by a Wittig chain extension to give unsaturated ketone 9 as
Ca(BH4)2 generated in situ, a fairly reactive hydride ob- a mixture of cis and trans isomers [(Z)-9 (12%) and (E)-9
tained from NaBH4 and CaCl2,[20] which gave 7 in 98% (58%); Scheme 4]. After separation of the isomers, com-
yield. Finally, oxidation was achieved easily using Dess– pound (E)-9 was converted into the syn diol 8a (90%,
Martin periodinane to obtain (S)-1 in quantitative yield dr Ͼ95%) by Sharpless asymmetric dihydroxylation using
(45% over six steps) and excellent enantiomeric purity AD-MIX-α and methanesulfonamide in a mixture of
Scheme 4. Synthesis of reference diols by Wittig chain extension and functionalization.
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tBuOH/H2O (1:1).[22] In the mismatched case, a 1:1 mixture are far more convenient and reliable substrates for organo-
of syn diol derivatives 8a and 8b (90%) was provided by catalytic synthesis of carbohydrates.[8] In general, the syn-
treatment of (E)-9 with AD-MIX-β under the same condi- thesis of diols from unprotected hydroxyacetone is rarely
tions.
attempted and is still a demanding methodology.[8b]
From (Z)-9, anti diols 8c and 8d (85%) were also formed
by nonselective dihydroxylation using osmium tetroxide
(OsO4) and N-methylmorpholine N-oxide (NMO) in a 9:3:2
mixture of tBuOH/THF/H2O (Scheme 4). The configura-
tion of 8a and 8b was confirmed by cyclization to give pi-
peridine triols 10a and 10b (Scheme 5). Having all four ref-
erence compounds 8a–d in hand, investigation of the
organocatalytic aldol reaction of hydroxy ketones was
started.
Table 1. Direct catalytic aldol reaction of hydroxyacetone with iso-
serinal hydrate 11.[a]
Organocatalytic Aldol Reactions
According to previously published data and based on
NMR analysis of the prepared compounds, we assumed
that aldehyde substrate 1 exists in equilibrium with the
stable hydrate 11 (Scheme 5).[9] With this compound in
hand, we first examined a direct aldol reaction of hy-
droxyacetone with 11 catalyzed by 20 mol-% (S)- and (R)-
proline in dimethyl sulfoxide (DMSO; Scheme 5). In both
cases, organocatalytic reactions resulted in unselective for-
mation of both syn-aldols 8a and 8b (Table 1, entries 1 and
2). The proline catalyst strictly controlled the formation of
the stereogenic center from the aldehyde function, whereas
the second stereogenic center was formed unselectively,
probably due to unselective formation of both (E)- and (Z)-
enamine from hydroxyacetone. This observation is similar
to a previously published example in which protected (R)-
glyceraldehyde was reported to react with hydroxyacetone
with only moderate 1,2-asymmetric induction. Deoxyfruc-
tose and deoxytagatose formation was observed by List
with moderate diastereoselectivities of only 2:1 when pro-
line was used as a catalyst.[10] This is, however, in contrast
to results published by Majewski for the highly syn-selective
proline-catalyzed reaction of 2-tert-butyl-2-methyl-1,3-di-
Entry Catalyst
Solvent
Yield (%)[b]
syn
syn/anti[c]
1
2
(S)-proline DMSO
(R)-proline DMSO
35
38
64
8b
8a
8b
8a
8b
8b
8b
8b
8b
–
8a
8a
8a
8a
1:1
1:1
4:1
4:1
4:1
3.5:1
3:1
2.5:1
2.1:1
–
5:1
8:1
3
4
5
6
7
8
9
10
11
12
13
14
12
DMSO
DMSO
DMSO
DMSO
DMF
THF
CH2Cl2
DMF
toluene
toluene
DMSO
DMF
ent-12
12
67
39[d]
48
12[e]
12
56
55
18
trace
52
45
32
15
12
12
13
14
15
16
8:1
7:1
16
[a] Reaction conditions: hydroxyacetone (3.8 mmol), aldehyde
(0.76 mmol), catalyst (20 mol-%), solvent (1 mL), r.t, 20 h. [b] Iso-
lated yield. [c] Diastereoselectivity was determined by 1H NMR
analysis of the reaction mixture, but both isomers were also sepa-
rated by column chromatography. [d] The reaction was performed
oxan-5-one. This is not surprising because cyclic ketones at 4 °C. [e] 10 mol-% catalyst was used.
Scheme 5. Asymmetric synthesis of iminosugars by direct aldol reaction of hydroxyacetone.
4
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Asymmetric 6-Deoxy-1,5-iminohexitols
Scheme 6. Organocatalytic aldol reaction of isoserinal hydrate with 1-hydroxy-oct-2-one.
Our previous studies[23] have shown that the direct aldol imino alditols 10a and 10b. This involved acidic deprotec-
reaction using the same hydroxyacetone donor can be ef- tion of the isopropylidene moiety with hydrogenolysis of
ficiently and more selectively promoted by C2-symmetrical the CBz group followed by highly stereoselective, intramo-
(S)-proline-based amides 12. We tested this possibility and lecular reductive amination (Scheme 5). Detailed analysis of
found that the aldol reaction promoted by 20 mol-% 12 the spectroscopic data for 10a and 10b established the con-
afforded syn-diol 8b in good yield (64%) and good syn/anti figuration of the cyclic iminosugars and confirmed the ab-
diastereoselectivity (4:1, Table 1, entry 3). Moreover, appli- solute configuration of compounds 8a and 8b. Spectro-
cation of enantiomeric (R)-proline-based catalyst ent-12 re- scopic data for both 1,5,6-trideoxy-iminohexitols 10a (e.g.,
sulted in the formation of the syn-configured diastereoiso- 1,5,6-trideoxy-1,5-imino-l-mannitol) and 10b (e.g., 1,5,6-
meric structure 8a with the same diastereoselectivity. Thus, trideoxy-1,5-imino-d-glucitol) have been previously pub-
the application of enantiomeric proline-based catalysts 12 lished.[24] Cyclization to iminosugars from unstable precur-
can give convenient access to both of the desired imi- sors 17a and 17b under analogous conditions unfortunately
nosugar precursors 8a and 8b with good stereoselectivity resulted in the formation of complex mixtures, probably due
(Scheme 5).
to unselective formation of derivatives.
Interestingly, DMSO was the solvent of choice for the
Although the origin of the syn-diastereoselectivity of the
12-reaction catalyzed by 12 (Table 1, entries 3–9). Notably, aldol reaction of hydroxyacetone with aldehydes promoted
the presence of 20 mol-% of the catalyst at room temp. was by proline-based organocatalysts may be difficult to explain
necessary to afford the reaction products from the highly in the light of previous mechanistic studies,[25] it can be ra-
demanding hydroxyacetone donor (entries 3–6). To explore tionalized by assuming that the reaction involves an active
further organocatalytic reactions of hydroxyacetone with 11 aldehyde hydrate. Such an observation was previously re-
we compared the efficiency of the elaborated catalytic sys- ported for the same isoserinal aldehyde hydrate[9] and for
tem with other syn-selective organocatalysts selected from chloral hydrate.[26] The existence of both compounds (alde-
studies reported previously on the asymmetric reaction of hyde and hydrate) in the reaction mixture, as confirmed by
hydroxyacetone.[11] From among the amino acid-catalysts 1H NMR spectroscopic analysis of the starting material,
used (13–16), the best results were observed for leucine- makes a stereochemistry model highly elusive and difficult
based catalyst 15[11g] and O-t-Bu-threonine 16.[11h] In both to predict.
cases, the aldol reaction afforded syn-diols 8a with good
diastereoselectivity, albeit in lower yield (Table 1, entries 12
and 13). Further careful optimization of the reaction condi-
tions did not improve the reaction yield or stereoselectivity.
Conclusions
The optimal protocol with prolinamide catalysts 12 was
An improved, convenient preparation of an enantiomer-
then expanded to the aldol reaction of some other hydroxy ically pure isoserinal derivative on a large scale is reported.
ketones. Although all tested conditions failed when α- The (S)-enantiomer was engaged in a Wittig-based chain
hydroxyacetophenone was used as a substrate, application extension and dihydroxylation sequence to prepare stereo-
of a ketone with an R-alkyl group was more promising. 1- chemically homogeneous 1,6-dideoxy-6-aminohexulose de-
Hydroxy-2-octanone underwent the direct aldol reaction to rivatives, two of which were converted into 1,5,6-trideoxy-
afford predominantly syn-17a with ent-12 as a catalyst, in 1,5-iminohexitols 10a and 10b; these compounds are of
43% yield (Scheme 6). Again, application of (S)-proline- interest as glycosidase inhibitors. A novel and original or-
based catalyst 12 delivered syn-17b in similar yield and ganocatalytic syn-selective aldol reaction of (S)-isoserinal
stereoselectivity. It is important to mention that compounds hydrate 11 and hydroxy-acetone or 1-hydroxy-2-octanone
17a and 17b were found to be unstable. This unwelcome promoted by various amino acid-based catalysts was also
tendency resulted in rapid decomposition of the com- developed and diastereoselectivities of up to 8:1 were
pounds even during NMR experiments; for this reason, achieved; these aldol products could be stereochemically
1
only H NMR spectra were recorded for these compounds. characterized by comparison with the products obtained by
To complete the synthesis of 1-C-methyl-substituted using the Wittig approach. Enantiopure imino alditols 10a
iminopentitols from 8a and 8b, both precursors were iso- and 10b could thus also be prepared by the syn selective
lated and subsequently converted into the corresponding direct aldol reaction as the key step. Although compounds
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pressure of argon (argon line) and a mineral oil bubbler (outlet
needle). The system was closed with rubber septa, flame-dried and
flushed with argon (2ϫ7 min) and glassware was allowed to cool
to room temp. (25 °C, 2ϫ10 min). Through the open neck and
under a gentle flow of argon, the flask was then charged with 3[9]
(16.5 g, 94.8 mmol, 1.0 equiv.), the neck was sealed with a glass
stopper and anhydrous toluene (150 mL) was added by using a sy-
ringe (left neck). The dropping funnel was charged with triethyl-
amine (Et3N) by using a syringe (10.6 g, 104.3 mmol, 14.5 mL,
1.1 equiv.) and subsequently added to the stirred reaction mixture
dropwise (6 min), followed by diphenyl phosphoryl azide (DPPA)
(26.1 g, 94.8 mmol, 20.4 mL, 1.0 equiv.) over 10 min. Once the ad-
ditions were completed, the funnel was rinsed with anhydrous tolu-
ene (20 mL) and replaced by a glass stopper. The flow of argon
was stopped, water circulation in the reflux condenser started, and
the colorless reaction mixture was heated gradually to 85–90 °C.
The reaction mixture became dark-brown as gas evolution occurred
(6–7 bubbles per second at 85 °C, mineral oil bubbler). When gas
evolution had ceased (15–30 min), an argon-filled balloon was con-
nected to the reaction set-up through a syringe needle, a purge was
carried out, and the bubbler removed. Stirring was continued at the
same temperature for an additional 1 h, after which time anhydrous
benzyl alcohol (10.3 g, 94.8 mmol, 9.8 mL, 1.0 equiv.) was added
by using a syringe (1 min). The reflux condenser was rinsed with
anhydrous toluene (20 mL) and heating was continued for 19 h.
The reaction mixture was cooled and then transferred (in air) to a
500 mL flask and the solvent was removed by rotary evaporation
(45 °C, 40 Torr). The residue was dissolved in dichloromethane
(200 mL), transferred to a 1 L separatory funnel, washed with
water (200 mL), and the aqueous phase was extracted with dichlo-
romethane (2ϫ 150 mL). The combined organic phases were
washed with saturated aqueous NaHCO3 (2ϫ 100mL), dried with
magnesium sulfate (MgSO4), filtered through a cotton plug, and
the solvent was evaporated under reduced pressure (28 °C,
200 Torr). The crude product was purified by column chromatog-
raphy to afford benzyl carbamate 4 as a pale-yellow oil (17.2 g,
65%). Rf = 0.14 (SiO2; PE/EtOAc, 4:1). [α]2D0 –3.4 (c = 1.13,
CHCl3). 1H NMR (400 MHz, CDCl3/TMS): δ = 7.42–7.28 (m, 5
H), 5.24–5.02 (m, 3 H), 4.47 (t, J = 4.7 Hz, 1 H), 3.68 (ddd, J =
14.5, 6.0, 5.2 Hz, 1 H), 3.58 (ddd, J = 14.5, 6.3, 5.2 Hz, 1 H), 1.55
(s, 3 H), 1.53 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
171.5, 156.4, 136.3, 128.6, 128.3, 111.4, 73.5, 67.2, 41.6, 27.1,
17a and 17b, which result from the aldol reaction with the
long-chain ketone, were found to be unstable, this approach
is more flexible than the synthesis from sugars, which are
substrates of predefined configuration, and opens a new
synthetic route to these important carbohydrate mimics.
The synthesis of differently substituted iminopentitols of
distinct configurations by the use of (R)-isoserinal and/or
various 1-hydroxy-2-alkanones is in progress and will be re-
ported in due course.
Experimental Section
General Remarks: Unless otherwise stated, all reagents were pur-
chased from commercial sources and used as received. THF (99.9%
GC) with 2,6-di-tert-butyl-4-methylphenol (250 mg/L) as stabilizer
was purchased from Sigma–Aldrich Chemical Co., Inc. and puri-
fied by passage through a column containing activated alumina
under nitrogen pressure (Dry Solvent Station GT S100, GlassTech-
nology, Geneva, CH). Petroleum ether (PE) had a boiling range of
40–65 °C.
NMR spectra were recorded at 298 K with a Bruker Avance
400 MHz spectrometer equipped with a PABBO BBO probe. The
structures were assigned with the aid of 1H NMR, 13C NMR, Dis-
tortionless Enhancement by Polarization Transfer (DEPT), Corre-
lation Spectroscopy (COSY), Heteronuclear Multiple Quantum
Coherence (HMQC), Heteronuclear Multiple-bond Correlation
(HMBC) and Nuclear Overhauser Effect Spectroscopy (NOESY).
1H NMR (400 MHz) chemical shift values are listed in parts per
million (ppm) downfield from TMS as the internal standard. Data
are reported as follows: chemical shift (ppm on the δ scale), multi-
plicity (s = singlet, d = doublet, dd = doublet of doublet, ddd =
doublet of doublet of doublet, td = triplet of doublet, t = triplet
and m = multiplet), coupling constant J (Hz), and integration. 13
C
NMR (100 MHz) chemical shifts are given in ppm relative to TMS
as the internal standard. Mass determinations were carried out
with an AB Sciex triple quadrupole mass spectrometer. High-reso-
lution mass spectra were recorded with a MaXis ESI qTOF ultra-
high-resolution mass spectrometer (FR2708, Orléans). Infrared
spectra were recorded with a Thermo Scientific Nicolet IS10 FTIR
spectrometer using diamond ATR golden gate sampling and are
reported in wave numbers (cm–1). Melting points were measured in
open capillary tubes with a Buchi melting point apparatus. Specific
optical rotations were measured with a Perkin–Elmer 341 polarime-
ter in a thermostatted (20 °C) 1 dm long cell with high-pressure
sodium lamp and are reported as follows: [α]λT [solvent, c (g/
100 mL)]. Analytical thin-layer chromatography (TLC) was per-
formed with Merck Silica Gel 60 F254 precoated plates. Visualiza-
tion of the developed chromatogram was performed under ultravio-
let light (254 nm) and on staining by immersion in aqueous, acidic
ceric ammonium molybdate (CAM; 470 mL H2O, 28 mL H2SO4,
24 g ammonium molybdate, 0.5 g cerium ammonium nitrate) fol-
lowed by heating on a hot plate. Flash chromatography was per-
formed in air on Silica Gel 60 (230–400 mesh) with petroleum ether
(bp 40–65 °C) and ethyl acetate as eluents, unless otherwise stated.
Organic solutions were concentrated under reduced pressure with
a Buchi rotary evaporator.
25.9 ppm. IR (film): ν = 3341, 2993, 1788, 1709, 1521, 1455, 1383,
˜
1232, 1132, 1062, 992, 901, 734, 698 cm–1. HRMS (ESI): m/z calcd.
for C14H17NNaO5 [M + Na]+ 302.09989; found 302.10003.
Methyl (S)-3-(Benzyloxycarbonylamino)-2-hydroxypropanoate (5):
A
1-L round-bottomed flask was charged with 4 (17.0 g,
60.9 mmol, 1 equiv.) and equipped with a magnetic stir bar and
with a rubber septum pierced by two needles, one needle being
connected to an argon inlet. Through the open neck, the flask was
then charged with p-toluenesulfonic acid monohydrate (0.289 g,
1.52 mmol, 0.025 equiv.) and methanol (600 mL). The neck was
capped and the outlet needle removed. The yellowish reaction mix-
ture was then stirred at room temp. (25 °C) until no starting mate-
rial was present (TLC). When the reaction was complete (24–48 h),
the crude mixture was evaporated under reduced pressure (27 °C,
40 Torr) and the residue was dissolved in ethyl acetate (200 mL).
The organic solution was transferred to a 500 mL separatory funnel
and washed with aq. NaHCO3 (4.6 g/L, 200 mL). The layers were
separated and the aqueous phase was extracted with ethyl acetate
(3ϫ 150 mL). The combined organic phases were dried with
MgSO4, filtered through a cotton plug, and the solvent was evapo-
rated under reduced pressure by rotary evaporation (30 °C,
Benzyl
(S)-[(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)methyl]carb-
amate (4): A 500-mL three-necked round-bottomed flask was
equipped with a magnetic stir bar, a 50-mL pressure-equalizing
dropping funnel and reflux condenser fitted at the top by a rubber
septum pierced by two needles connected respectively to a positive
6
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Pages: 11
Asymmetric 6-Deoxy-1,5-iminohexitols
40 Torr). The corresponding hydroxypropanoate 5 was obtained as
a pale-yellow oil that solidified upon cold storage (m.p. 41–43 °C)
to form a white rock-solid (15.1 g, 96%, crude yield). Rf = 0.31
(SiO2; PE/EtOAc, 1:1). [α]2D0 +19.8 (c = 1.42, MeOH); m.p. 41–
43 °C. 1H NMR (400 MHz, CDCl3/TMS): δ = 7.42–7.27 (m, 5 H),
5.17 (br. s, 1 H), 5.10 (s, 2 H), 4.29 (br. s, 1 H), 3.78 (s, 3 H), 3.64–
3.49 (m, 2 H), 3.22 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 173.3, 156.7, 136.3, 128.4, 128.0, 127.9, 70.0, 66.8, 52.5,
(25 °C) and further stirred at 25 °C for 18 h. The white precipitate
was then filtered under vacuum through a pad of Celite 545 and
the solids remaining in the reaction flask were transferred to the
Celite pad by scraping with a spatula and washing with THF
(20 mL). The resulting filtrate was transferred to a 1-L separatory
funnel and washed with brine (350 mL). The layers were separated
and the aqueous phase was extracted with EtOAc (3ϫ 200 mL).
The combined organic phases were then dried with anhydrous
Na2SO4, filtered through a cotton plug, and the solvent was evapo-
rated under reduced pressure by rotary evaporation (30 °C,
44.2 ppm. IR (neat): ν = 3359, 2953, 1700, 1527, 1453, 1215, 1116,
˜
1059, 980, 775, 738, 697 cm–1. HRMS (ESI): m/z calcd. for
C12H15NNaO5 [M
+
Na]+ 276.08424; found 276.08443. 50 Torr). The residue was dissolved in EtOAc (20 mL) and filtered
C12H15NO5 (253.25): calcd. C 56.91, H 5.97, N 5.53; found C
57.23, H 6.07, N 5.49.
through a short pad of silica gel (5.0 cm heightϫ5.0 cm width, i.e.,
ca. 35 g of silica). The material remaining in the flask was washed
with EtOAc and the solution was passed over the silica gel (2ϫ
100 mL of ethyl acetate). The combined organic layers were evapo-
rated under reduced pressure to give 7 (6.3 g, 98%). Rf = 0.41
(SiO2; PE/EtOAc, 1:1). [α]2D0 –12.5 (c = 1.3, CHCl3). 1H NMR
(400 MHz, CDCl3/TMS, 300 mm): δ (equilibrium mixture of rota-
mers) = 7.41–7.27 (m, 5 H), 5.14 (br. s, 0.11 H) and 5.11 (br. s, 2
H), 4.28–4.17 (m, 1 H), 3.79 (br. d, J = 11.7 Hz, 1 H), 3.75–3.55
(m, 2 H), 3.39 (t, J = 9.6 Hz, 1 H), 2.27 (br. s, 1 H), 1.63 (s, 3 H),
1.54 (s, 3 H) and 1.50 (br. s, 0.5 H) ppm. 13C NMR (100 MHz,
CDCl3/TMS, 300 mm): δ (major rotamer) = 152.4, 136.6, 128.6,
128.1, 127.9, 94.5, 74.5, 66.7, 62.4, 46.5, 26.2, 24.4; δ (minor rot-
amer) = 153.0, 136.3, 93.9, 74.3, 67.4, 47.3, 27.3, 25.5 ppm. IR
3-Benzyl 5-Methyl (S)-2,2-Dimethyl-1,3-oxazolidine-3,5-dicarboxyl-
ate (6): An oven-dried 250-mL round-bottomed flask equipped
with a magnetic stir bar, a rubber septum and an inlet of argon
(rubber septum fitted with an argon-filled balloon through a sy-
ringe needle) was charged with 5 (7.22 g, 28.5 mmol, 1.0 equiv.) and
anhydrous acetone (108 mL). 2,2-Dimethoxypropane (4.45 g,
42.8 mmol, 5.24 mL, 1.5 equiv.) and boron trifluoride etherate
(BF3·Et2O, 0.243 g, 217 μL, 1.7 mmol, 0.06 equiv.) were added by
using a syringe over periods of 10 and 60 seconds, respectively, and
the resulting dark-yellow solution was stirred at room temp.
(26 °C); 2,2-dimethoxypropane (DMP, 1.5 equiv.) was added a 1 h
intervals until TLC analysis indicated the reaction was complete
(ca. 6.5 h; 10.5 equiv. DMP added). The brown reaction mixture
was then treated with Et3N (99.5%; 578 μL, 0.433 g, 4.28 mmol,
0.15 equiv.) and the solvent was removed by rotary evaporation
(26 °C, 60 Torr then 35 °C, 60 Torr). The residual yellow syrup was
partitioned between diethyl ether (100 mL) and saturated aq.
NaHCO3 solution (200 mL) and transferred to a 500 mL separa-
tory funnel. The organic layer was separated and the aqueous
phase was extracted with diethyl ether (2ϫ 100 mL). The combined
organic phases were dried with anhydrous Na2SO4, filtered through
a cotton plug, and the solvent was evaporated under reduced pres-
sure (rotary evaporation, 26 °C, 200 Torr). The crude product was
purified by column chromatography to provide pure oxazolidine
methyl ester 6 as a yellow-colored oil (7.1 g, 85%). Rf = 0.45 (SiO2;
PE/EtOAc, 4:1). [α]2D0 +14.5 (c = 1.1, MeOH). 1H NMR (400 MHz,
CDCl3/TMS): δ = 7.40–7.27 (m, 5 H), 5.12 (br. s, 2 H), 4.63 (t, J
= 7.3 Hz, 1 H), 4.00–3.87 (m, 1 H), 3.77 (s, 3 H), 3.78–3.65 (m, 1
H), 1.66 (s, 3 H), 1.56 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3/
TMS): δ = 170.3, 152.1, 136.4, 128.6, 128.2, 128.0, 95.7, 72.6, 66.8,
(film): ν = 3347, 2982, 2938, 2884, 1694, 1409, 1352, 1255, 1213,
˜
1150, 1092, 1057, 978, 903, 868, 764, 737, 698 cm–1. HRMS (ESI):
m/z calcd. for C14H19NO4Na [M + Na]+ 288.12063; found
288.12093. C14H19NO4 (265.31): calcd. C 63.38, H 7.22, N 5.28;
found C 63.44, H 7.36, N 5.21.
Benzyl (S)-5-Formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1):
A 250-mL flask equipped with a magnetic stir bar was charged
with 7 (5.84 g, 22.0 mmol, 1 equiv.) under an argon atmosphere
and fitted with a rubber septum connected to an argon-filled bal-
loon through a syringe needle. Anhydrous CH2Cl2 (100 mL) was
added by using
a syringe followed by solid Dess–Martin
periodinane (11.20 g, 26.4 mmol, 1.2 equiv.) by temporarily opened
flask and the reaction mixture was stirred at room temp. (25 °C)
for 18 h. The solvent was then removed under reduced pressure
(rotary evaporation, 25 °C, 100 Torr) and the white precipitate was
suspended in ice-cold Et2O (100 mL). The resulting suspension was
filtered through a membrane filter, the precipitate washed with ice-
cold Et2O (2ϫ 25 mL) and the filtrate was transferred to a 500-
mL separatory funnel. The organic phase was then washed with
saturated aq. NaHCO3 (2ϫ 50 mL), dried with anhydrous Na2SO4
(15 g) and filtered through a glass funnel fitted with a cotton plug.
The solvent was evaporated by rotary evaporation (100 Torr, 25 °C)
to give a residue that was dissolved in EtOAc (20 mL) and filtered
through a short pad of silica gel (5.0 cm heightϫ5.0 cm width of
dry silica, i.e., ca. 35 g of silica). The flask was washed further with
EtOAc and the solution was passed through the silica gel
(2ϫ100 mL of ethyl acetate). The combined organic layers were
then evaporated under reduced pressure (30 °C, 60 Torr) to afford
pure 1 as a colorless oil in quantitative yield. Rf = 0.31 and 0.66
(SiO2, PE/EtOAc, 1:1). [α]2D0 –7.7 (c = 1.23, CHCl3); 4.5 h after
addition of 2 equiv. of Et3N: [α]2D0 –24.9 (c = 1.20, CHCl3) {ref[9]
[α]2D4 –25 (C, HCl3, c 1.15, 2 equiv. of Et3N)}. 1H NMR (400 MHz,
CDCl3/TMS): δ (equilibrium mixture of aldehyde and hydrate) =
9.74 (d, J = 1.1 Hz, 0.64 H), 7.43–7.29 (m, 5 H), 5.12 (s, 2 H), 4.97
(br. s, 0.23 H), 4.43 (ddd, J = 7.6, 6.4, 1.2 Hz, 0.67 H), 4.12 (ddd,
J = 8.8, 6.7, 3.8 Hz, 0.43 H), 3.85–3.79 (m, 0.77 H), 3.73 (dd, J =
10.5, 6.4 Hz, 1 H), 3.64 (br. d, J = 6.4 Hz, 0.18 H), 3.53–3.35 (m,
0.29 H), 1.89 (s, 0.37 H), 1.62 (s, 2.6 H), 1.57 (s, 2.2 H), 1.55 (s, 2.1
52.6, 47.7, 25.8, 24.9 ppm. IR (film): ν = 2986, 2953, 2894, 1761,
˜
1740, 1703, 1439, 1407, 1353, 1300, 1257, 1212, 1147, 1115, 1068,
1028, 866, 765, 736, 698 cm–1. HRMS (ESI): m/z calcd. for
C15H19NNaO5 [M
+
Na]+ 316.11554; found 316.11576.
C15H19NO5 (293.32): calcd. C 61.42, H 6.53, N 4.78; found C
61.43, H 6.57, N 4.83.
Benzyl (S)-5-Hydroxymethyl-2,2-dimethyl-1,3-oxazolidine-3-carb-
oxylate (7): An oven-dried 500 mL, two-necked, round-bottomed
flask equipped with a magnetic stir bar and a 100-mL pressure-
equalizing dropping funnel fitted with a rubber septum connected
to a steady flow of argon was charged with powdered activated
CaCl2 (3.97 g, 35.8 mmol, 1.5 equiv.) and NaBH4 (2.71 g,
71.5 mmol, 3.0 equiv.). The neck was sealed with a glass stopper,
the reaction set-up was cooled to ca. 0 °C through application of
an external ice-water bath and anhydrous THF (100 mL) was
added by using a syringe. The white suspension was then stirred
for 15 min and a solution of 6 (7.0 g, 23.8 mmol, 1 equiv.) in abso-
lute ethanol (80 mL) was added dropwise over 1 h. The dropping
funnel was rinsed with additional absolute EtOH (10 mL), the reac-
tion mixture was warmed slowly (ca. 2 h) to ambient temperature
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O21413
/KAP1
Date: 16-01-13 11:59:07
Pages: 11
O. R. Martin, J. Mlynarski et al.
FULL PAPER
H) ppm. 13C NMR (100 MHz, CDCl3/TMS): δ = 200.2, 152.4,
136.2, 128.7, 128.6, 128.3, 128.2, 128.1, 95.6, 78.3, 67.1, 66.8, 46.7,
solution of osmium tertoxide in tert-butyl alcohol (0.034 mL,
0.0034 mmol, 1 mol-%) and the solution was stirred vigorously at
25 °C. After 24 h, the reaction was quenched by the addition of
40% aq. NaHSO4 (10 mL) and the mixture was extracted with
EtOAc (3ϫ 25 mL). The combined organic phases were dried
45.6, 26.1, 25.0, 24.5 ppm. IR (film): ν = 3401, 2981, 2938, 2897,
˜
1701, 1407, 1379, 1254, 1213, 1060, 868, 748, 697 cm–1. HRMS
(ESI): m/z calcd. for C14H17NNaO4 [M + Na]+ 286.104979; found
286.105020; calcd. for C14H19NNaO5 [M
304.115543; found 304.115604. C14H19NO5 (281.31): calcd. C orated under reduced pressure. The residue was purified by column
+ H2O +
Na]+ (Na2SO4), filtered through a cotton plug, and the solvent was evap-
59.78, H 6.81, N 4.98; found C 59.66, H 6.81, N 4.69.
chromatography (SiO2; PE/EtOAc, 1:1) to afford 8 (0.097 g, 85%)
as a 1:1 mixture of diastereoisomers 8c and 8d.
The enantiomeric purity (Ͼ99%) was determined by HPLC analy-
sis of the alcohols (S)-7 and (R)-7, obtained by reduction of the
aldehydes (S)-1 and (R)-1. CSP-HPLC {chiralpak AD-H,
DAICEL; hexane/2-propanol, 90:10; 1 mLmin–1; 21 °C, λ = 208
nm; Rt = 10.5 [(S)-7], 11.8 min [(R)-7]}. To an ice-cold solution of
aldehyde 1 (0.031 g, 0.117 mmol, 1 equiv.) in a 1:1 mixture of THF/
iPrOH (1 mL), was added solid NaBH4 (13.3 mg, 0.351 mmol,
3 equiv.). The mixture was stirred for 30 min at this temperature,
then acetone (0.02 mL) was added and the reaction mixture was
concentrated to dryness under reduced pressure. The residue was
partitioned between H2O (10 mL) and EtOAc (10 mL) and the
phases were separated. The aqueous phase was extracted with
EtOAc (3ϫ 10 mL) and the combined organic phases were dried
with anhydrous Na2SO4 and concentrated by rotary evaporation.
The residue was purified by flash chromatography over silica gel
(PE/EtOAc, 3:2) to give pure alcohol 7 (27.5 mg, 88%) as a color-
less oil. The same procedure was performed with ent-1.
Benzyl (5S)-5-[(1S,2R)-1,2-Dihydroxy-3-oxobutyl]-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate (8c): [α]2D0 –53.1 (c = 1.11, CHCl3). 1H
NMR (600 MHz, CDCl3/TMS): δ = 7.38–7.29 (m, 5 H), 5.12 (s, 2
H), 4.38 (ddd, J = 10.5, 6.4, 3.8 Hz, 1 H), 4.13 (dd, J = 7.6, 6.2 Hz,
1 H), 3.75 (s, 1 H), 3.58 (d, J = 5.6 Hz, 1 H), 3.50 (m, 2 H), 2.83
(s, 1 H), 2.38 (s, 3 H), 1.64 (s, 3 H), 1.55 (s, 3 H) ppm. 13C NMR
(150 MHz, CDCl3/TMS): δ (mixture of rotamers) = 209.7, 152.6,
152.2, 136.4, 128.5, 128.0, 127.8, 94.4, 93.9, 77.4, 73.9, 73.7, 71.7,
67.3, 66.6, 47.5, 46.8, 27.9, 25.9, 24.4 ppm. MS (ESI): m/z = 360.0
[M + Na]+.
Benzyl (5S)-5-[(1R,2S)-1,2-Dihydroxy-3-oxobutyl]-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate (8d): [α]2D0 +13.5 (c = 1.09, CHCl3). 1H
NMR (600 MHz, CDCl3/TMS): δ = 7.38–7.29 (m, 5 H), 5.11 (s, 2
H), 4.22 (s, 1 H), 4.18 (dt, J = 8.9, 6.6 Hz, 1 H), 3.93 (t, J = 5.6 Hz,
1 H), 3.88–3.78 (br. m, 2 H), 3.52 (t, J = 9.0 Hz, 1 H), 2.91 (s, 1
H), 2.30 (s, 3 H), 1.57 (s, 3 H), 1.46 (s, 3 H) ppm. 13C NMR
(150 MHz, CDCl3/TMS): δ (mixture of rotamers) = 206.8, 152.8,
152.3, 136.4, 128.5, 128.0, 127.9, 94.6, 78.0, 72.9, 72.8, 72.5, 67.2,
66.68, 48.3, 47.4, 27.0, 26.7, 25.9, 25.2, 24.1 ppm. MS (ESI): m/z =
360.0 [M + Na]+.
Dihydroxylation of (E)-9: To
a solution of (E)-9 (0.152 g,
0.50 mmol, 1 equiv.) in a mixture of tBuOH/H2O (1:1, 5 mL) was
added methylsulfonamide (0.048 g, 0.50 mmol, 1 equiv.) and AD-
mix-β (0.750 g, 1.50 g/mmol, 1 equiv.) and the solution was stirred
vigorously at room temp. (ca. 25 °C). After 24 h, the reaction was
quenched by the addition of 40% aq. NaHSO4 (10 mL) and the
mixture was extracted with EtOAc (3ϫ 25 mL). The combined or-
ganic phases were dried (Na2SO4), filtered through a cotton plug,
and the solvent was evaporated under reduced pressure. The resi-
due was purified by column chromatography (SiO2, PE/EtOAc, 1:1)
to afford 8 (0.151 g, 90%) as a 1:1 mixture of diastereoisomers 8a
and 8b.
Benzyl (5R)-2,2-Dimethyl-5-[(1E)-3-oxobut-1-en-1-yl]-1,3-oxazolid-
ine-3-carboxylate [(E)-9] and Benzyl (5R)-2,2-Dimethyl-5-[(1Z)-3-
oxobut-1-en-1-yl]-1,3-oxazolidine-3-carboxylate [(Z)-9]: To a solu-
tion of 1 (0.790 g, 3.0 mmol, 1 equiv.) in anhydrous dichlorometh-
ane (20 mL) was added slowly a solution of 1-(triphenylphosphor-
anylidene)-2-propanone (1.150 g, 3.60 mmol, 1.2 equiv.) in anhy-
drous dichloromethane (8 mL) and the reaction mixture was stirred
at 25 °C for 3 h. The solvent was then evaporated and the residue
was purified by column chromatography over silica gel (PE/Et2O,
3:1) to afford (E)-9 (0.527 g, 58%) and (Z)-9 (0.110 g, 12%).
Benzyl (5S)-5-[(1R,2R)-1,2-Dihydroxy-3-oxobutyl]-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate (8a): [α]2D0 –24.9 (c = 1.07, CHCl3). 1H
NMR (400 MHz, CDCl3/TMS): δ = 7.44–7.28 (m, 5 H), 5.13 (s, 2
H), 4.39 (d, J = 2.8 Hz, 1 H), 4.20 (td, J = 7.8, 6.3 Hz, 1 H), 4.00
(t, J = 8.3 Hz, 1 H), 3.90–3.80 (br. m, 1 H), 3.72 (d, J = 3.9 Hz, 1
H), 3.56 (dd, J = 10.5, 8.1 Hz, 1 H), 2.31 (s, 3 H), 2.20 (d, J =
9.6 Hz, 1 H), 1.64 (s, 3 H), 1.54 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3/TMS): δ = 207.7, 152.4, 136.4, 128.5, 128.0, 127.9, 94.3,
76.6, 74.1, 72.5, 66.6, 48.0, 26.4, 25.2, 24.4 ppm. HRMS (ESI): m/z
Compound (E)-9: [α]2D0 –17 (c = 1.21, CHCl3); Rf = 0.27 (SiO2; PE/
1
Et2O, 1:1). H NMR (400 MHz, CDCl3/TMS): δ = 7.43–7.27 (m,
5 H), 6.71 (dd, J = 16.0, 5.4 Hz, 1 H), 6.34 (d, J = 16.0 Hz, 1 H),
5.12 (s, 2 H), 4.75–4.60 (m, 1 H), 4.00–3.80 (m, 1 H), 3.37–3.21 (m,
1 H), 2.27 (s, 3 H), 1.65 (s, 3 H), 1.58 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3/TMS): δ (mixture of rotamers) = 197.6, 152.5,
151.8, 141.5, 136.3, 135.9, 131.4, 128.4, 127.9, 127.7, 94.5, 93.9,
72.9, 72.7, 67.2, 66.5, 50.6, 49.8, 27.3, 27.0, 25.9, 25.4, 24.3 ppm.
calcd. for C17H23NNaO6 [M
360.141812.
+
Na]+ 360.141758; found
IR (film): ν = 2984, 2939, 2882, 1700, 1680, 1636, 1407, 1352, 1253,
˜
Benzyl (5S)-5-[(1S,2S)-1,2-Dihydroxy-3-oxobutyl]-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate (8b): [α]2D0 +11.2 (c = 1.04, CHCl3). 1H
NMR (600 MHz, CDCl3/TMS): δ = 7.39–7.21 (m, 5 H), 5.19–5.07
(br. m, 2 H), 4.30 (dt, J = 9.0, 6.2 Hz, 1 H), 4.11–4.08 (br. m, 1 H),
4.05–3.98 (br. m, 1 H), 3.88–3.74 (br. m, 1 H), 3.74–3.67 (s, 1 H),
3.47–3.35 (br. m, 1 H), 2.69 (s, 1 H), 2.29 (s, 3 H), 1.65 (s, 3 H),
1.45 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ (mixture of
rotamers) = 207.1, 152.7, 152.1, 136.4, 136.1, 128.5, 128.1, 127.9,
94.8, 94.2, 77.4, 75.0, 74.6, 72.4, 67.4, 66.7, 47.7, 46.9, 27.2, 26.1,
25.7, 25.4, 24.3 ppm. HRMS (ESI): m/z calcd. for C17H23NNaO6
[M + Na]+ 360.141759; found 360.141694.
1214, 1084, 1048, 977, 907, 877, 735, 698 cm–1. HRMS (ESI): m/z
calcd. for C17H22NNaO4 [M + Na]+ 326.13628; found 326.13682.
Compound (Z)-9: [α]2D0 –180 (c = 1.29, CHCl3); Rf = 0.46 (SiO2; PE/
1
Et2O, 1:1). H NMR (400 MHz, CDCl3/TMS): δ = 7.41–7.26 (m,
5 H), 6.27 (d, J = 11.5 Hz, 1 H), 6.15 (dd, J = 11.5, 6.4 Hz, 1 H),
5.42–5.32 (m, 1 H), 5.11 (s, 2 H), 4.16–4.07 (m, 1 H), 3.19–3.05 (m,
1 H), 2.23 (s, 3 H), 1.64 (s, 3 H), 1.54 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3/TMS): δ (mixture of rotamers) = 198.1, 152.1,
144.5, 144.1, 136.5, 128.4, 128.2, 127.9, 127.8, 94.1, 93.7, 71.9, 71.5,
67.0, 66.4, 50.2, 49.2, 31.0, 27.2, 26.1, 25.3, 24.2 ppm. IR (film): ν
˜
Dihydroxylation of (Z)-9: To
0.34 mmol, 1 equiv.) in a mixture of tBuOH/THF/H2O (9:3:2,
5 mL) was added NMO (0.047 g, 0.40 mmol, 1.18 equiv.) and a
a solution of (Z)-9 (0.103 g, = 2961, 2899, 1698, 1623, 1407, 1353, 1257, 1214, 1182, 1087, 1046,
1015, 875, 789, 698 cm–1. HRMS (ESI): m/z calcd. for
C17H22NNaO4 [M + Na]+ 326.13628; found 326.13625.
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21413
/KAP1
Date: 16-01-13 11:59:07
Pages: 11
Asymmetric 6-Deoxy-1,5-iminohexitols
Aldol Reaction with Hydroxyacetone: To a solution of 1 (200 mg,
1,5,6-Trideoxy-1,5-imino-D-glucitol (10b): The reaction was carried
0.76 mmol, 1 equiv.) in DMSO (1 mL) were added catalyst (20 mol- out using the same procedure as for 11a; compound 8b (40 mg,
%) and hydroxyacetone (260 μL, 3.8 mmol, 5 equiv.) and the solu-
tion was stirred at room temperature. After 24 h, the reaction mix-
ture was quenched by the addition of saturated aq. NH4Cl (5 mL),
diluted with EtOAc (30 mL) and the organic phase was washed
with water (4ϫ 10 mL). The organic phase was subsequently dried
with Na2SO4, filtered through a cotton plug and the solvent was
evaporated under reduced pressure. The crude product was purified
by column chromatography (SiO2; PE/EtOAc, 1:1) to afford a mix-
ture of diastereoisomers, which were separated by a second column
chromatography over silica gel (PE/EtOAc, 1:1).
0.118 mmol) afforded 10b (7.5 mg, 43%). [α]2D0 +11 (c = 1.07, H2O).
1H NMR (600 MHz, D2O): δ = 3.49 (ddd, J = 10.9, 9.2, 5.2 Hz, 1
H), 3.27 (t, J = 9.2 Hz, 1 H), 3.06 (dd, J = 12.3, 5.2 Hz, 1 H), 3.00
(t, J = 9.4 Hz, 1 H), 2.52 (dq, J = 9.7, 6.4 Hz, 1 H), 2.45 (dd, J =
12.3, 10.9 Hz, 1 H), 1.14 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(150 MHz, D2O): δ = 78.1, 76.4, 71.0, 55.1, 48.7, 17.0 ppm. MS
(ESI): m/z = 148.1 [M + H]+.
Supporting Information (see footnote on the first page of this arti-
1
cle): Spectroscopic data (e.g., H and 13C NMR) of compounds 1,
3–11, 17 and chiral HPLC traces of 1.
Aldol Reaction with 1-Hydroxy-2-octanone: To a solution of 1
(200 mg, 0.76 mmol, 1 equiv.) in DMSO (1 mL) were added bis-
(prolinamide) (62 mg, 0.15 mmol, 20 mol-%) and 1-hydroxy-2-oc-
tanone (550 mg, 3.8 mmol, 5 equiv.). The solution was stirred at
room temp. for 24 h, then the reaction was quenched by addition
of saturated aq. NH4Cl (5 mL), diluted with EtOAc (30 mL) and
the organic phase was washed with water (4ϫ 10 mL). The organic
phase was dried with Na2SO4 and the solvents evaporated. The
product was purified by column chromatography (SiO2; PE/EtOAc,
7:3) to afford a mixture of diastereoisomers (dr measured by 1H
NMR analysis of the crude mixture), which were separated by col-
umn chromatography over silica gel (PE/EtOAc, 7:3).
Acknowledgments
The authors are grateful for financial support cofinanced by the
European Regional Development Fund (Foundation for Polish Sci-
ence, TEAM programme) and by the VML Foundation (Vaincre
les Maladies Lysosomales).
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Benzyl
(5S)-5-[(1R,2R)-1,2-Dihydroxy-3-oxononyl]-2,2-dimethyl-
1,3-oxazolidine-3-carboxylate (17a): [α]2D0 –20.0 (c = 1.02, CHCl3).
1H NMR (300 MHz, CDCl3/TMS): δ = 7.39–7.30 (m, 5 H), 5.13
(s, 2 H), 4.37 (s, 1 H), 4.19 (td, J = 7.8, 6.5 Hz, 1 H), 3.98 (d, J =
7.1 Hz, 1 H), 3.90–3.66 (m, 2 H), 3.56 (dd, J = 10.6, 7.9 Hz, 1 H),
2.60 (dt, J = 17.0, 7.4 Hz, 1 H), 2.51 (dt, J = 17.0, 7.4 Hz, 1 H),
2.27 (br. m, 1 H), 1.70–1.57 (m, 5 H), 1.53 (s, 3 H), 1.40–1.23 (m,
6 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. MS (ESI): m/z = 408.2 [M +
H]+.
Benzyl (5S)-5-[(1S,2S)-1,2-Dihydroxy-3-oxononyl]-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate (17b): [α]2D0 +9.5 (c = 1.03, CHCl3). 1H
NMR (300 MHz, CDCl3/TMS): δ = 7.41–7.28 (m, 5 H), 5.12 (s, 2
H), 4.30 (dt, J = 9.1, 6.2 Hz, 1 H), 4.11–4.05 (br. m, 1 H), 4.04–
3.96 (br. m, 1 H), 3.87–3.75 (br. m, 1 H), 3.73 (d, J = 4.3 Hz, 1 H),
3.40 (br. t, J = 9.0 Hz, 1 H), 2.70–2.44 (m, 3 H), 1.69–1.57 (m, 5
H), 1.54 (s, 3 H), 1.43–1.24 (m, 6 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm.
MS (ESI): m/z = 408.2 [M + H]+.
1,5,6-Trideoxy-1,5-imino-L-mannitol (10a): To a solution of com-
pound 8a (60 mg, 0.178 mmol) in methanol (2 mL) was added p-
toluenesulfonic acid (6.7 mg, 0.035 mmol, 20 mol-%) and the solu-
tion was stirred for 30 min at room temperature. 10% Palladium
on charcoal (20 mg) was then added and the reaction mixture was
stirred vigorously under a hydrogen atmosphere (1 bar). After 6 h,
1 m aq. HCl (0.4 mL) was added and stirring under hydrogen atmo-
sphere was continued for another 12 h. The reaction mixture was
filtered through a short pad of Celite and the solids were washed
with a mixture of methanol and water (4:1). The filtrate was con-
centrated under reduced pressure, then passed over a short pad of
ion exchange resin [Amberlite IRA-400(OH–)], washing with meth-
anol (50 mL). The residue was purified by column chromatography
(SiO2; CHCl3/CH3OH/H2O/aq. NH3, 50:50:19:1) to afford 10a
(14.5 mg, 55%). [α]2D0 +53 (c = 1.13, H2O). 1H NMR (400 MHz,
D2O): δ = 4.11 (ddd, J = 3.0, 2.9, 1.6 Hz, 1 H), 3.58 (dd, J = 9.6,
3.0 Hz, 1 H), 3.50 (dd, J = 9.6 Hz, 1 H), 3.15 (dd, J = 14.0, 2.9 Hz,
1 H), 2.97 (dd, J = 14.0, 1.6 Hz, 1 H), 2.79 (dq, J = 9.6, 6.5 Hz, 1
H), 1.30 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, D2O): δ
= 73.8, 72.6, 68.3, 56.0, 48.5, 16.3 ppm. HRMS (ESI): m/z calcd.
for C6H14NO3 [M + H]+ 148.0968; found 148.0969.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 16-01-13 11:59:07
Pages: 11
O. R. Martin, J. Mlynarski et al.
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Received: October 23, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21413
/KAP1
Date: 16-01-13 11:59:07
Pages: 11
Asymmetric 6-Deoxy-1,5-iminohexitols
Iminosugar Synthesis
A novel protocol for the preparation of
1,5,6-trideoxy-1,5-imino-l-mannitol and
1,5,6-trideoxy-1,5-imino-d-glucitol is re-
ported. The key steps include organocata-
lyzed syn-selective direct aldol reaction
of hydroxyacetone and CBz-protected iso-
serinal hydrate, followed by reductive
amination/cyclization.
C. Nicolas, R. Pluta, M. Pasternak-Suder,
O. R. Martin,* J. Mlynarski* ......... 1–11
Organocatalytic syn-Aldol Reactions of
Hydroxy Ketones with (S)-Isoserinal:
Asymmetric Synthesis of 6-Deoxy-1,5-
iminohexitols and Related Compounds
Keywords: Synthetic methods / Asymmetric
synthesis / Medicinal chemistry / Organo-
catalysis / Wittig reactions / Aldol reac-
tions / Carbohydrates / Iminosugars
Eur. J. Org. Chem. 0000, 0–0
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