A short stereoselective synthesis of (+)-aza-galacto-fagomine (AGF)

Article abstract of DOI:10.1016/j.tet.2017.03.052

A catalytic asymmetric synthesis of (+)-aza-galacto-fagomine (AGF) – the most promising compound for the pharmacological chaperone therapy of Krabbe disease – was accomplished in six steps, in 14% overall yield. The synthesis hinges on the combination of

Full text of DOI:10.1016/j.tet.2017.03.052

Accepted Manuscript
A short stereoselective synthesis of (+)-aza-galacto-fagomine (AGF)
Jasna Marjanovic Trajkovic, Zorana Ferjancic, Radomir N. Saicic
PII:
S0040-4020(17)30302-2
10.1016/j.tet.2017.03.052
TET 28558
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 October 2016
Revised Date: 2 March 2017
Accepted Date: 20 March 2017
Please cite this article as: Trajkovic JM, Ferjancic Z, Saicic RN, A short stereoselective synthesis of (+)-
aza-galacto-fagomine (AGF), Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.052.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
A short stereoselective synthesis of (+)-aza-
galacto-fagomine (AGF)
Leave this area blank for abstract info.
Jasna Marjanovic Trajkovic, Zorana Ferjancic, and Radomir N. Saicic
Faculty of Chemistry, University of Belgrade, Studentski trg 16, POB 51, 11158 Belgrade 118, Serbia, and
Innovation Centre, Faculty of Chemistry, 11000 Belgrade, Serbia

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A Short stereoselective synthesis of (+)-aza-galacto-fagomine (AGF)
Jasna Marjanovic Trajkovicb , Zorana Ferjancica, and Radomir N. Saicica,
a Faculty of Chemistry, University of Belgrade, Studentski trg 16, POB 51, 11158 Belgrade 118, Serbia
b Innovation Centre, Faculty of Chemistry, 11000 Belgrade, Serbia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A catalytic asymmetric synthesis of (+)-aza-galacto-fagomine (AGF) – the most promising
compound for the pharmacological chaperone therapy of Krabbe disease – was accomplished in
six steps, in 14% overall yield. The synthesis hinges on the combination of organocatalyzed
aldolization and reductive hydrazination.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Aza-galactofagomine
Organocatalysis
Krabbe disease
Enantioselective synthesis
Azasugars
———
Corresponding author. Tel.: +381-11-333-6658; fax: ++381-11-328-2537; e-mail: zferjan@chem.bg.ac.rs
Corresponding author. Tel.: +381-11-328-2537; fax: +381-11-328-2537; e-mail: rsaicic@chem.bg.ac.rs

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Sugar processing enzymes play an important role, in both
homeostasis and pathological states. Their selective inhibition
could provide a basis for the treatment of various diseases, such
as diabetes, cancer, obesity, and viral (including HIV)
infections.1 Malfunction of lysosomal glycosphingolipid (GSL)
hydrolases that results in the accumulation of substrates in
lysosomes, is the cause of a particular class of diseases known
under the collective name “lysosomal storage disorders”.2 On the
contrary, Krabbe disease, which is also a consequence of the
deficiency of lysosomal β-galactocerebrosidase (GALC), does
not induce glycolipid precipitation, but leads to progressive
demyelination of the white mass in the central nervous system, as
well as in peripheral nerves, and neurodegeneration, usually with
a fatal outcome.3 The presumed agent for this destructive process
is psychosine, a cytotoxic galactosphingolipid which induces a
cascade of events leading to cell death.4 The enzyme replacement
therapy for Krabbe disease is hampered by the fact that GALC
does not cross the blood-brain barrier. In a number of cases, the
disease is not caused by the complete absence of GALC, but
rather by its structural modification, i. e. misfolding. The mutated
enzyme is not only less efficient, but it cannot leave
endoplasmatic reticulum. In such cases, a complex between a
small molecule and the protein could stabilize the correctly
folded enzyme, thus allowing it to reach lysosome and effect
there its glycolytic activity. This effect, known as the active site-
specific chaperone effect, provides a basis for the so called
pharmacological chaperone therapy (PCT): interestingly (and,
maybe, counterintuitively), at subinhibitory concentrations
glycosylase inhibitors act as enzyme-rectifying agents. Restoring
10% of the enzyme activity would be enough to prevent the
disease. Iminosugars are known to exert strong, yet selective
inhibitory activity on sugar-processing enzymes. 1-
Deoxygalacto-nojirimycin (DGJ) was shown to enhance α-
galactosidase A activity in patients with Fabry disease.5 Quite
recently, a similar approach was proposed for the treatment of
Krabbe disease.6 In a detailed study, a series of azasugars were
synthesized and tested for their potential as PCT agents. The
most active among them was aza-galacto-fagomine (AGF). This
compound was prepared in 16 steps from the commercially
Scheme 1
selective aldol transform into dihydroxyacetone and a properly
protected hydrazino-acetaldehyde 3.
Previously, others13 and our group9,10,11 have shown dioxanone
414 to be a convenient synthetic equivalent of a dihydroxyacetone
enolate in proline-catalyzed enantioselective aldol additions.15 As
the acceptor component we chose hydrazinoaldehyde 7, whose
three-step preparation from the commercially available
hydrazinoethanol (5) was described earlier (Scheme 2).16 It is of
note that the oxidation step (i. e. 6 → 7) must be performed with
freshly prepared Dess-Martin periodinane17 (DMP); the use of
commercial DMP gives rise to impurities in aldehyde 7 that are
difficult to remove and which affect the optical rotation of the
intermediates and the final product. The key aldol reaction was
performed in aqueous DMSO,18 at 4 °C, to afford the aldol
adduct 8 as a single diastereoisomer (98% ee, determined by
chiral HPLC, see Supplementary material), in 53% yield
(comparable results were obtained in DMF as a solvent: 50%
yield). Catalytic hydrogenation of aldol 8 in pure ethanol resulted
in the removal of the Cbz protecting group (55%); subsequent
treatment with NaCNBH3 in the presence of AcOH then gave the
cyclic product of reductive hydrazination (9; 35%). However, we
found that these two operations could be better accomplished as a
one-pot procedure, by performing the catalytic hydrogenation of
8 in methanol/AcOH (40% yield for the deprotection/cyclization
tandem). Interestingly, palladium catalyst should be added in
three portions, as this protocol gives cyclic product 9 of superior
purity; addition of Pd/C in a single portion results in side
reactions and contamination of product with impurities.
Treatment of compound 9 with methanolic HCl effected
available 2,3-O-isopropylidene-D-ribofuranose. Chemoenzymatic
synthesis of AGF was also described (8 steps, 4% overall yield).7
Further studies of AGF would require an efficient method of
preparation. Several syntheses of diastereoisomeric azafagomine
and the derivatives thereof were reported;8 however, the results
of these studies are not directly applicable to the synthesis of
AGF. Herein we describe an enantioselective synthesis of AGF
that may provide a ready access to this compound.
2. Results and discussion
For some time, we have explored a tactical combination of
organocatalyzed aldolization with reductive amination, for the
efficient
construction
of
polyhydroxylated
alkaloids
(iminosugars). In this way, optically pure members of
pyrrolidine, piperidine,9 pyrrolizidine10 and indolizidine11 series
were prepared. We envisaged that a similar approach could be
applied to the synthesis of AGF, as outlined in retrosynthetic
format (Scheme 1). The piperazine ring in 1 could be formed by
“reductive hydrazination” – an analogy of reductive amination
applied to hydrazino ketone 2 (whereas intermolecular reductive
hydrazinations have been reported recently, we are aware of only
a single example of the intramolecular reaction in the literature,
so far).12 Compound 2 could be further disconnected by an anti-
Scheme 2
deprotection and provided the target compound – AGF (1;
97%) whose physical properties are in agreement with the

3
literature data.6,7 The three-step conversion of aldol 8 into AGF
(1) could be effected as a one-pot operation, in 60% yield;
2-Benzyl
1-tert-butyl
1-(2-oxoethyl)hydrazine-1,2-
ACCEPTED MANUSCRIPT
dicarboxylate (7)16
however, although no visible impurities could have been
observed in the NMR spectra, the values for optical rotation were
low, indicating the presence of trace impurities with strong
levorotatory power. Thus, for the AGF to be analytically pure,
compound 9 should be purified prior to deprotection.
Freshly prepared Dess-Martin’s periodinane (3.00 g, 7.07
mmol) was added to a solution of alcohol 6 (0.95 g, 3.06 mmol)
in water-saturated dichloromethane (28.0 mL) and the reaction
mixture was stirred at room temperature for 1 h. The reaction
mixture was diluted with dichloromethane, washed with 10%
Na2S2O3 (2 × 50 mL), sat. aq. NaHCO3 (2 × 50 mL) and brine
(50 mL), dried over anh. MgSO4, filtered and concentrated under
reduced pressure. Purification of the residue by dry-flash
chromatography (SiO2; eluent: petroleum ether/EtOAc = 7/3)
afforded aldehyde 7 (0.80 g, 85 %) as a pale yellow viscous oil.
1H NMR (500 MHz, CDCl3; at room temperature the compound
exists as a mixture of rotamers21): δH 9.66 (bs, 1H), 7.35 (s, 5H),
7.02 (bs, NH, 1H; minor rotamer) and 6.91 (bs, NH, 1H; major
rotamer), 5.16 (s, 2H), 4.33 (bs, 2H; major rotamer), and 4.24
(bs, 2H, minor rotamer), 1.45 (s, 9H; minor rotamer) and 1.39 (s,
9H; major rotamer); 13C NMR (126 MHz, CDCl3): δC 197.9
(CH), 156.2 and 155.7 (C), 155.0 and 154.6 (C), 135.5 and 135.4
(C), 128.6 and 128.5 (CH), 128.4 and 128.3 (CH), 128.2 and
128.2 (CH), 83.1 and 82.5 (C), 67.8 and 67.7 (CH2), 61.2 and
59.5 (CH2), 28.0 and 27.9 (3 × CH3); IR (ATR) vmax 3302, 2979,
2935, 1714, 1501, 1371, 1259, 1154, 1067, 756 cm-1; HRMS
(ESI) for C15H20N2NaO5 [M+Na]+ calculated: 331.1264; found:
331.1270.
3. Conclusions
To summarize, the catalytic asymmetric synthesis of (+)-aza-
galacto-fagomine (AGF, 1) was accomplished in 6 steps from the
commercially available alcohol 5, in 14% overall yield, which
makes this compound readily accessible for further medical
research.
4. Experimental section
4.1. General experimental
All chromatographic separations were performed on silica gel,
10–18, 60
Å
(dry-flash), 100–200, 60Å (column
chromatography), ICN Biomedicals, 60 (0.063-0.200 mm)
(column chromatography), and ion exchange column
chromatography (acidic resin DOWEX 50WX8-100). Standard
techniques were used for the purification of reagents and
solvents.19 Petroleum ether (PE) refers to the fraction boiling at
70–72 °C. 1H NMR spectra were recorded at 500 MHz, 13C NMR
at 126 MHz. Chemical shifts are expressed in ppm (δ) using
TMS as the internal standard. IR spectra were recorded on a FT
instrument, and are expressed in cm–1. Mass spectra were
obtained on TOF LC/MS instrument. Melting points are
uncorrected.
2-Benzyl 1-tert-butyl 1-((R)-2-((R)-2,2-dimethyl-5-oxo-1,3-
dioxan-4-yl)-2-hydroxyethyl)hydrazine-1,2-dicarboxylate (8)
Aldehyde 7 (800 mg, 2.59 mmol) was added to a solution of
D
-proline (90.0 mg, 0.78 mmol, 30 mol %) in DMSO (9.0 mL).
Next, dioxanone 4 (900 mg, 6.92 mmol) and water (206.0 ꢀL,
11.44 mmol) were added to the flask and the mixture was
vigorously stirred for 48 h at 4 °C. The reaction mixture was
diluted with EtOAc and washed with water (50 mL). The
aqueous phase was back-extracted with EtOAc (2 × 50 mL). The
combined organic extract was dried over anh. MgSO4, filtered
and concentrated under reduced pressure. Purification of the
crude product by column chromatography (SiO2; eluent:
petroleum ether/acetone = 8/2) afforded the title aldol 8 (604.0
2-Benzyl 1-tert-butyl 1-(2-hydroxyethyl)hydrazine-1,2-
dicarboxylate (6)16
A solution of (Boc)2O (2.87 g, 13.15 mmol) in dry ethanol
(8.0 mL) was added dropwise to a cold (0 °C) solution of N-2-
hydroxyethylhydrazine 5 (1.00 g, 13.14 mmol) in dry ethanol
(10.0 mL). After 30 min, cooling bath was removed and the
reaction mixture was stirred for 24 h at room temperature. The
solvent was removed under reduced pressure and the residue was
further used without purification.
20
mg, 53%) as a pale yellow, viscous oil. [α]D +70.0 (c 1.00,
CHCl3); 1H NMR (500 MHz, DMSO-d6, 65 °C) δH 9.15 (bs, NH,
1H), 7.38-7.32 (m, 5H), 5.12 (s, 2H), 4.39 (s, 1H), 4.26 (dd, J
16.7, 1.2 Hz, 1H), 4.06 (td, J 6.5, 3.0 Hz, 1H), 3.93 (d, J 16.7 Hz,
1H), 3.55 (bs, 2H), 3.15 (bs, OH, 1H), 1.41 (s, 6H), 1.37 (s, 9H);
13C NMR (126 MHz, DMSO-d6, 65 °C) δC 206.9 (C), 155.7 (C),
154.5 (C), 136.2 (C), 128.0 (CH), 127.6 (CH), 127.3 (CH), 99.6
(C), 79.9 (C), 76.2 (CH), 67.5 (CH), 66.5 (CH2), 65.8 (CH2), 51.8
(CH2), 27.5 (3 × CH3), 24.3 (CH3), 22.8 (CH3); IR (ATR) vmax
3306, 2984, 2938, 1743, 1714, 1374, 1224, 1158, 1086, 859, 754
cm-1; HRMS (ESI) for C21H30KN2O8 [M+K]+ calculated:
477.1634; found: 477.1635. The optical purity of compound 8
was determined by chiral HPLC as >98% ee (See the
Supplementary material for details, page S12).
A solution of the crude product from the previous experiment
(2.30 g, 13.05 mmol) in CH2Cl2 (13.6 mL) was added to a
solution of NaOH (0.57 g, 14.25 mmol) in water (13.6 mL), at 0
°C, followed by a dropwise addition of benzyl chloroformate
(1.86 mL, 2.23 g, 13.07 mmol). After 10 min, cooling bath was
removed and the reaction mixture was stirred for 24 h at room
temperature. The organic layer was washed with water and 20%
citric acid aq. solution, dried over anh. MgSO4, filtered and
concentrated under reduced pressure. Purification of the residue
by dry-flash chromatography (SiO2; eluent: petroleum
ether/EtOAc = 8/2) afforded the title alcohol 6 (3.26 g, 80 %) as
1
a white solid. mp 58-59 °C; H NMR (500 MHz, DMSO-d6, 65
°C):20 δH 9.21 (bs, 1H), 7.40-7.30 (m, 5H), 5.11 (s, 2H), 4.29 (t, J
5.6 Hz, 1H), 3.50 (q, J 6.3 Hz, 2H), 3.40 (bs, 2H), 1.37 (s, 9H);
13C NMR (126 MHz, DMSO-d6, 65 °C): δC 155.8 (C), 154.5 (C),
136.3 (C), 128.0 (CH), 127.6 (CH), 127.4 (CH), 79.8 (C), 65.8
(CH2), 57.9 (CH2), 51.7 (CH2), 27.6 (3 × CH3); IR (ATR) vmax
3362, 3198, 3009, 2980, 2886, 1716, 1422, 1364, 1288, 1138,
1061, 737 cm-1; HRMS (ESI) for C15H22N2NaO5 [M+Na]+
calculated: 333.1421; found: 333.1422.
(4R,4aS,8aR)-tert-Butyl
dimethyltetrahydro-1H-[1,3]dioxino[5,4-c]pyridazine-2(3H)-
carboxylate (9)
4-hydroxy-6,6-
10% Pd/C (4.4 mg, 0.004 mmol, 7.5 mol %) was added to a
solution of aldol 8 (23.1 mg, 0.053 mmol) in a solvent mixture
methanol/acetic acid (3.7 mL, v/v= 7/1), and the reaction mixture
was stirred at room temperature under a hydrogen atmosphere
(20 at). After 2 h a second portion of Pd/C (8.8 mg, 0.008 mmol,

4
Tetrahedron
ACCEPTED MANUSCRIPT
15 mol %) was added, and after 24 h a third portion of Pd/C
4683-4696; (c) Kolter, T.; Sandhoff, K. Angew. Chem.
Int. Ed. 1999, 38, 1532-1568.
(4.4 mg, 0.004 mmol, 7.5 mol %) was added. The total time of
the reaction was 48 h. The mixture was filtered through celite and
concentrated under reduced pressure. Purification of the residue
by column chromatography (SiO2; eluent: petroleum
ether/EtOAc = 1/2) afforded the title compound (9) (6.0 mg,
3. Suzuki, K.; Suzuki, Y.; Suzuki, K. In The Metabolic and
Molecular Bases of Inherited Diseases. S. Scriver, A. L.
Beaudet, W. S. Sly, D. Valle, Eds., McGraw Hill, New
York, 7th edition, 1995; pp 2671-2692.
20
40%) as a white solid. mp 180-181 °C; [α]D +50.9 (c 1.20,
MeOH); 1H NMR (500 MHz, DMSO-d6, 65 °C) δH 4.59 (d, J 5.7
Hz, 1H), 4.23 (d, J 11.4 Hz, 1H), 4.07-4.00 (m, 2H), 3.81 (dd, J
12.2, 5.2 Hz, 1H), 3.60 (dd, J 12.3, 1.6 Hz, 1H), 3.49-3.42 (m,
1H), 2.90 (t, J 11.7 Hz, 1H), 2.54-2.50 (m, 1H), 1.41 (s, 3H),
1.40 (s, 9H), 1.35 (s, 3H); 13C NMR (126 MHz, DMSO-d6, 65
°C) δC 154.4 (C), 97.9 (C), 78.5 (C), 66.5 (CH), 65.8 (CH), 61.3
(CH2), 51.3 (CH), 45.0 (CH2), 28.9 (CH3), 27.8 (3 x CH3), 18.5
(CH3); IR (ATR) vmax 3417, 3250, 2983, 2973, 1695, 1502, 1385,
1177, 1066, 993, 853 cm-1; HRMS (ESI) for C13H24N2NaO5
[M+Na]+ calculated: 311.1577; found: 311.1584.
4. (a) Miyatake, T.; Suzuki, K. Biochem. Biophys. Res.
Commun. 1972, 48, 538-543; (b) Svennerholm, L.;
Vanier, M. T.; Mansson, J. E. J. Lipid Res. 1980, 21, 53-
64; (c) Giri, S.; Khan, M.; Rattan, R.; Singh, I.; Singh, A.
K. J. Lipid Res. 2006, 47, 1478-1492.
5. (a) Fan, J.-Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nature
Med. 1999, 5, 112-115; (b) Asano, N.; Ishii, S.; Kizu,H.;
Ikeda, K.; Yasuda, K.; Kato, A.; Martin, O. R.; Fan, J.-Q.
Eur. J. Biochem. 2000, 267, 4179-4186.
6. Hill, C. H.; Viuff, A. H.; Spratley, S. J.; Salamone, S.;
Christensen, S. H.; Read, R. J.; Moriarty, N. W.;
Jensen,H.; Deane, J. E. Chem. Sci. 2015, 6, 3075-3086.
(3R,4S,5R)-3-(hydroxymethyl)piperazine-4,5-diol
galacto-fagomine) (1)
(aza-
7. Jensen, H. H.; Bols, M. J. Chem. Soc. Perkin Trans. 1,
2001, 905–909.
A solution of compound 9 (21.0 mg, 0.07 mmol) in a solvent
mixture methanol/3M HCl (3.6 mL, v/v= 1/1) was stirred at room
temperature for 24 h. After the volatiles were removed under
reduced pressure, the residue was purified by ion exchange
column chromatography (acidic resin DOWEX 50WX8-100) to
give (+)-aza-galacto-fagomine (AGF, 1) (10.5 mg, 97%) as a
8. (a) Bols, M.; Hazell,R. G.; Thomsen, I. B. Chem. Eur. J.,
1994, 3, 940-947; (b) Sivertsen, A. C.; Gasior, M.;
Bjerring, M.; Hansen, S. U.; Lopez, O. L.; Nielsen, N. C.;
Bols, M. Eur. J. Org. Chem. 2007, 1735-1742; (c)
Moreno-Clavijo, E.; Carmona, A. T.; Moreno-Vargas, A.
J.; Rodriguez-Carvajal, M. A.; Robina, I. Bioorg. Med.
Chem. 2010, 18, 4648-4660; (d) Alves, M. J.; Costa, F.
T.; Duarte, V. C. M.; Fortes, A. G.; Martins,J. A.;
Micaelo, N. M. J. Org. Chem. 2011, 76, 9584-9592; (e)
Mendes, R.; Duarte, V. C. M.; Fortes, A. G.; Alves, M. J.
Carbohydr. Res. 2014, 395, 52-57.
20
20
colorless film. [α]D +10.4 (c 1.00, H2O), [lit.7 [α]D +11.9 (c
1.00, H2O)]; [lit.6 [α]D20 +9.0 (c 1.00, H2O)]; 1H NMR (500 MHz,
D2O) δH 4.02-3.99 (m, 1H), 3.79 (ddd, J 11.0, 5.2, 3.0 Hz, 1H),
3.64 (d, J 6.3 Hz, 2H), 2.96-2.87 (m, 2H), 2.81 (dd, J 12.6, 11.1
Hz, 1H); 13C NMR (126 MHz, D2O) δC 64.9 (CH), 63.7 (CH),
58.1 (CH), 57.6 (CH2), 43.5 (CH2); IR (ATR) vmax 3274, 2932,
1570, 1413, 1102, 1029, 817, 657 cm-1; HRMS (ESI) for
C5H13N2O3 [M+H]+ calculated: 149.0921; found: 149.0924.
9. Marjanovic, J.; Ferjancic, Z.; Saicic, R. N. Tetrahedron,
2015, 71, 6784-6789.
10. Marjanovic, J.; Divjakovic, V.; Matovic, R.; Ferjancic,
5. Acknowledgments
Z.; Saicic, R. N. Eur. J. Org. Chem. 2013, 5555-5560.
This work was supported by the Serbian Ministry of
Education, Science and Technological Development (Project No.
172027) and by the Serbian Academy of Sciences and Arts
11. Trajkovic, M.; Balanac, V.; Ferjancic, Z.; Saicic, R. N.
RSC Adv. 2014, 4, 53722-53724.
12. Intermolecular reactions: (a) Kawase, Y.; Yamagishi, T.;
Kato, J.-y.; Kutsuma, T.; Kataoka, T.; Iwakuma, T.;
Yokomatsu, T. Synthesis, 2014, 46, 455-464; (b)
Sugawara, A.; Kubo, M.; Nakashima, T.; Hirose, T.;
Tsunoda, N.; Yahagi, K.; Asami, Y.; Yamada, T.;
Shiomi, K.; Takahashi, Y.; Omura, S.; Sunazuka, T.
Tetrahedron, 2015, 71, 2149-2157; (c) Shestakov, A. N.;
Kuznetsov, M. A. Chem. Commun. 2016, 52, 2398-2400;
Intramolecular reactions: (d) Carabateas, P. M.; Surrey,
A. R.; Harris, L. S. J. Med. Chem. 1964, 7, 293-297.
(Project No. F193)
.
6. Supplementary Material
1
Supplementary material available (copies of H and 13C NMR
spectra for all compounds).
7. References and notes
1. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W.
J. Tetrahedron: Asymmetry, 2000, 11, 1645-1680; (b)
Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R.
J.; Nash, R. J. Phytochemistry, 2001, 56, 265-295; (c)
Compain, P.; Martin, O. R. Iminosugars: From Synthesis
to Therapeutic Applications, Eds.; Wiley: Chichester,
2007; (d) Winchester, B. G. Tetrahedron: Asymmetry,
2009, 20, 645-651; (e) Nash, R. J.; Kato,A.; Yu,C.-Y.;
Fleet, G. W. J. Future Med. Chem. 2011, 3, 1513-1521.
13. For the first examples of organocatalyzed aldol reactions
with dioxanone, see: (a) Suri, J. T.; Ramachary, D. B.;
Barbas III , C. F. Org. Lett. 2005, 7, 1383-1385. (b)
Enders, D.; Grondal, C. Angew. Chem. Int. Ed. 2005, 44,
1210-1212. (c) Ibrahem, I.; Cordova, A. Tetrahedron
Lett. 2005, 46, 3363-3367.
14. For selected examples on organocatalyzed aldolizations
with dioxanone, see: (a) Calderon, F.; Doyaguez, E. G.;
Fernandez-Mayoralas, A. J. Org. Chem. 2006, 71, 6258-
6261; (b) Calderon, F.; Doyaguez, E. G.; Cheong,
Fernandez- A. Mayoralas, P. H.-Y.; Houk, K. N. J. Org.
Chem. 2008, 73, 7916-7920; (c) Palyam, N.; Majewski,
2. (a) For a recent overview of the topic, see a series of
articles in Nature Outlook: Lysosomal Storage Disorders,
Nature 2016, 537, Issue 7621, S143-S165; (b) Butters, T.
D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100,

5
M. J. Org. Chem. 2009, 74, 4390-4392; (d) Palyam, N.;
Niewczas, I.; Majewski, M. Synlett, 2012, 2367-2370; (e)
Miura, D.; Fujimoto, T.; Tsutsui, A.; Michinami, T.
Synlett, 2013, 1501-1504; (f) Dibello, E.; Brovetto, M.;
Seoane, G.; Gamenara, D. Tetrahedron Lett. 2013, 54,
5895-5897; A pertinent review article: (g) Enders, D.;
Narine, A. A. J. Org. Chem. 2008, 73, 7857-7870.
16. Cerea, P.; Giannini, C.; Dall’Angelo, S.; Licandro, E.;
ACCEPTED MANUSCRIPT
Maiorana, S.; Marchelli, R. Tetrahedron, 2007, 63, 4108-
4199.
17. D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113,
7277-7278.
18. Ibrahem, I.; Zou, W.; Xu, Y.; Cordova, A. Adv. Synth.
Catal. 2006, 348, 211-222.
15. For selected review articles on enamine organocatalysis,
see: (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
2004, 43, 5138-5175; (b) Notz, W.; Tanaka, F.; Barbas
III, C. F. Acc. Chem. Res. 2004, 37, 580; (c) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007,
107, 5471-5569; (d) Geary, L. M.; Hultin, P. G.
Tetrahedron: Asymmetry, 2009, 20, 131-173; (e) Heravi,
M. M.; Asadi, S. Tetrahedron: Asymmetry, 2012, 23,
1431-1465; (f) Bisai,V.; Bisai, A.; Singh, V. K.
Tetrahedron, 2012, 68, 4541-4580.
19. Armarego, W. L. F.; Chai, C. L. L. Purification of
Laboratory Chemicals, Elsevier, Oxford, 6th edition,
2009.
20. There is no perfect matching of J values for coupled
protons because multiplets are somewhat deformed due to
the existence of rotamers.
21. Aldehyde 7 decomposes on heating, so NMR spectra
could not be recorded at elevated temperature.