On the Asymmetric Induction in Proline-Catalyzed Aldol Reactions: Reagent-Controlled Addition Reactions of 2,2-Dimethyl-1,3-dioxane-5-one to Acyclic Chiral α-Branched Aldehydes

Article abstract of DOI:10.1002/ejoc.201701073

Reagent stereocontrol in the proline-catalyzed aldol reaction of 2,2-dimethyl-1,3-dioxane-5-one 1 with chiral aldehydes has been investigated. Synthetically useful levels of diastereoselectivity could be achieved in reactions with acyclic chiral α-oxy and α-amino aldehydes in both matched and mismatched cases. By using this reaction as a key step, two medicinally relevant azasugars, 1-deoxy-galactonojirimycin (9) and 2,5-dideoxy-2,5-imino-d-altritol (10), were efficiently synthesized.

Full text of DOI:10.1002/ejoc.201701073

A Journal of
Accepted Article
Title: On the asymmetric induction in proline-catalyzed aldol reactions:
Reagent-controlled additions of 2,2-dimethyl-1,3-dioxane-5-one
to acyclic chiral α-branched aldehydes
Authors: Zorana Ferjancic, Radomir N Saicic, Jasna Marjanovic
Trajkovic, and Vesna Milanovic
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701073
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701073
Supported by

10.1002/ejoc.201701073
European Journal of Organic Chemistry
FULL PAPER
On the asymmetric induction in proline-catalyzed aldol reactions:
Reagent-controlled additions of 2,2-dimethyl-1,3-dioxane-5-one to
acyclic chiral α-branched aldehydes
Jasna Marjanovic Trajkovic,[a] Vesna Milanovic,[b] Zorana Ferjancic*[b] and Radomir N. Saicic*[b, c]
Abstract: Reagent stereocontrol in the proline-catalyzed aldol
reaction of 2,2-dimethyl-1,3-dioxane-5-one 1 with chiral aldehydes
with the results of Cordova5c and several other groups.9
However, Enders and coworkers reported that in the addition of
dioxanone 1 to a cyclic chiral α-substituted aldehyde, i. e.
has
been
investigated.
Synthetically
useful
levels
of
diastereoselectivity could be achieved in reactions with acyclic chiral
α-oxy and α-amino aldehydes in both matched and mismatched
cases. Using this reaction as a key step, two medicinally relevant
azasugars, namely 1-deoxy-galactonojirimycin (DGJ) (9) and 2,5-
dideoxy-2,5-imino-D-altritol (DIA) (10), have been efficiently
synthesized.
Garner’s aldehyde, (S)-aldehyde and (S)-proline were a
matched pair, whereas the use of (R)-proline with (S)-Garner’s
aldehyde resulted in poor yield, but high stereoselectivity.5b In
addition, Houk et al. also reported that inherent selectivities of
aldehyde and proline could reinforce each other, but in this study
acyclic (R)-azido aldehyde and (S)-proline constituted the
matched pair.10 These inconsistencies prompted us to
investigate more closely the double asymmetric induction in the
proline-promoted aldol reactions of dioxanone 1 and chiral α-
branched aldehydes. We were also interested to find out
whether acyclic nature of chiral α-substituted aldehydes could
play a decisive role in the stereochemical outcome of these
reactions (i. e. allow for reagent controlled stereochemistry).
Introduction
Over the past two decades, organocatalytic aldol reactions
emerged as a convenient and complementary method to the
asymmetric aldol reactions of preformed enolates and their
equivalents, due to mild reaction conditions which avoid use of
strong bases and chiral auxiliaries.1 Enamine-based
organocatalytic aldol additions, which use proline as an
inexpensive and readily available chiral catalyst, serve as a
Results and Discussion
good illustration of usefulness of this methodology. Conveniently, (R)- and (S)-proline-promoted aldol additions of dioxanone 1 to
stereocenters with either absolute configuration can be formed
chiral aldehydes were performed with 30 mol % of catalyst, in
DMF as a solvent at 4 °C (Table 1). In each reaction, self-
condensation of dioxanone 1 was detected in small extent, so
we used it in excess. We evaluated a diverse set of chiral α-
branched aldehydes 2a-i with hetero (N or O), or carbon atom in
the α-position. It is known that proline-catalyzed aldol reactions
are anti-selective,11 which could be rationalized by the Houk-List
model, through the formation of an intermolecular hydrogen
bond between the enamine intermediate and the aldehyde.12
The minor product of these anti-selective aldolizations should be
simply by using R or S enantiomer of catalyst.2 Among various
ketones one can use as donor component for proline catalyzed
3
cross-aldol additions, 2,2-dimethyl-1,3-dioxane-5-one
(dioxanone) occupies prominent position
1
a
as
a
dihydroxyacetone (DHA) equivalent and a very useful C3
building block for asymmetric synthesis.4,5 Indeed, tactical
combination of organocatalyzed aldol reaction of dioxanone 1
and reductive amination recently allowed us to synthesize
optically pure iminosugars which possess common natural
iminosugar’s frameworks, i. e. members of piperidine,6
pyrrolizidine7 and indolizidine8 series. In one of these asymmetric
syntheses, we used a chiral α-substituted acceptor.7 Aldol
addition of dioxanone 1 to chiral acyclic α-amino aldehyde 2a,
promoted with (R)-proline, proceeded in good yield and with
synthetically useful diastereoselectivity.7 In addition, when (S)-
proline was used as organocatalyst, the reaction also proceeded
smoothly and with excellent diasteroselectivity, in agreement
syn aldol (not the other anti isomer), as predicted by Houk and
12a
coworkers by computational methods.10,
Interestingly, in all
examples except one, we found that aldol mixtures are
composed of two anti aldols; minor quantities of syn aldol(s)
were observed only in few, mostly mismatched, cases. Anti
aldols 3a-i and 4a-i were obtained in moderate to good yields
(45-77%), after chromatographic purifications on silica gel.
Aldol addition of dioxanone 1 to chiral acyclic α-oxy or α-amino
aldehydes 2a-e (entries 1-5) furnished anti aldols 3a-e and 4a-e.
The reaction proceeded with good diastereoselectivity,
irrespective of the proline enantiomer used as a catalyst,
suggesting synthetically useful level of reagent control in both
matched and mismatched cases. However, substituting Boc
(entry 5) for Cbz (entry 4) as the NH protecting group in
aldehyde resulted in diminished diastereoselectivity. In reactions
with α-NH substitued aldehydes (entries 1, 4 and 5), the
corresponding aldols with 3,5-syn arrangement of substituents
assumed 5-membered cyclic, hemiaminal forms 5, 7 and 8; this
property considerably facilitated chromatographic separation of
[a]
[b]
Innovation Centre, Faculty of Chemistry
Studentski trg 16, POB 51, 11158 Belgrade 118, Serbia
University of Belgrade – Faculty of Chemistry
Studentski trg 16, POB 51, 11158 Belgrade 118, Serbia
E-mail: zferjan@chem.bg.ac.rs; rsaicic@chem.bg.ac.rs
[c]
Serbian Academy of Sciences and Arts
Knez Mihailova 35, 11 000 Belgrade, Serbia
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
the
diastereomeric
adducts
(Figure
1).13
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701073
European Journal of Organic Chemistry
FULL PAPER
Table 1. The proline-catalyzed aldol reaction of dioxanone 1 with various chiral α-branched aldehydes 2a-i.
anti/anti[b]
entry
1[c]
R
catalyst
time
yield (%)[a]
major product
3/4
S
R
12 h
12 h
70
77
3a→5[d]
6/1
4a
1/10
S
R
48 h
48 h
53
57
3b
12/1
1/13
2
3
4
5
4b→6[d]
S
R
48 h
48 h
47
45
3c
4c
10/1
1/10
S
R
48 h
48 h
55
55
3d
10/1
1/7
4d→7[d]
S
R
48 h
48 h
70
72
3e→8[d]
3/1
1/4
4e
S
R
7 days
7 days
50
55
3f[h]
4f
7/1[e]
0/10
6
7
S
R
8 days
8 days
57
50
3g[h]
4g[h]
7/1
1/2
S
R
48 h
48 h
50
52
3h
4h
5/2[f]
8
6/100[g]
S
R
48 h
48 h
50
38
3i[h]
4i
25/1
n. d.
9
[a] Overall yield of isolated aldols. [b] Determined by 1H NMR of the crude reaction mixture. [c] Reaction performed with 20 mol % of catalyst, at room
temperature. [d] Aldol adduct assumed cyclic hemiaminal form (see Figure 1.). [e] Syn aldol was obtained in 21% yield. [f] Syn aldol was obtained in 7% yield. [g]
Trace of syn aldol was obtained. [h] mixture of anti aldols could not be separated by coloumn chromatography. n. d. = not determined.
Similarly, aldehyde 2b with β-NH substituent (entry 2) gave
corresponding adduct which also exists as an equilibrium
mixture of two forms - aldol 4b and hemiaminal 6.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701073
European Journal of Organic Chemistry
FULL PAPER
have pronounced negative effect on the level of asymmetric
induction in the mismatched combination of aldehyde/catalyst,
although examples with high diastereoselectivities were also
9
reported.5c,
Previous quantum mechanical calculations
predicted that transition states involving syn-enamine are higher
in energy than the ones involving anti-enamine and the former
was not further considered as stereochemically relevant
pathway.10 However, major components of aldol mixtures that
we obtained were two anti aldols (see all entries in Table 1
except entry 6). This fact indicates that transition state involving
syn-enamine (TS C, Scheme 1) is not so high in energy as it
was computed and should be reconsidered as a possible
stereochemical pathway. Additionally, in all examples with
acyclic substrates the combinations of (S)-configured aldehydes
and (R)-proline constitute matched pairs, the finding that is in
agreement with the observations of other researchers.5c, 9, 10 On
the other hand, with cyclic aldehydes it is not easy to anticipate
which combination of substrate and catalyst would constitute the
matched double asymmetric pair (e. g. compare entries 8 and 9
in Table 1).
.
Figure 1. The hemiaminals 5, 6, 7 and 8.
Chiral α-methyl branched aldehydes (entries 6, 7) can also
participate in aldol reactions with dioxanone. Proper matching of
aldehyde and catalyst is more important in these cases,
particularly with sterically demanding OTBS group in β-position
of aldehyde 2f (entry 6; mismatched reaction with (S)-proline
gave mixture of two anti and one syn aldols in ratio 7/1/6).
Although these additions were slower and required prolonged
reaction times, the obtained diastereoselectivities in the matched
cases were good and preparatively useful.
a)
A
B
O
O
With cyclic chiral α-oxy aldehyde 2h (entry 8) reaction also
proceeded smoothly with both catalysts, but with different levels
of diastereoselection. Whereas the matched double asymmetric
combination of (S)-aldehyde and (R)-proline selectively gave the
expected anti aldol 4h, the diastereoselectivity in the
mismatched reaction was not satisfactory from a synthetic point
of view, as a mixture of three diastereoisomers was obtained.
However, contrary to the previous example, cyclic (S)-α-amino
aldehyde 2i constitutes matched pair with (S)-proline (entry 9),
N
O
N
O
O
H
H
R'
X
O
syn
aldol
R'
R
H
X
3
H
R''
H
R''
H
R
O
C
N
O
H
O
the result that is in accordance with the work of Enders.5b
A
4
R'
X
mismatched combination of (S)-aldehyde 2i and (R)-catalyst led
to a complex mixture of diastereoisomers.
Attempts to perform reactions with chiral α-thio aldehydes were
unsuccessful: although reactions were fast and conversions of
the starting materials were complete, the obtained aldols were
unstable and decomposed upon workup and purification.
H
H
R''
R
b)
E
D
O
O
From these results, it is evident that proline-catalyzed aldol
additons of dioxanone 1 to acyclic chiral α-alkoxy and α-amino
branched aldehydes proceed with good reagent control, offering
synthetically acceptable diastereoselectivities in both matched
and mismatched cases. Proposed transition states for the (S)-
and (R)- proline catalyzed aldol reaction, rationalized by the
Houk-List model,12 are given in Scheme 1. With acyclic substrate,
attacks of anti-enamine derived from (S)-proline (TS A) or (R)-
proline (TS D) could readily occur at both faces of the aldehyde
(TS A and TS D are energetically preferred over more crowded
TS B and TS E). The enantioselectivity exerted by the anti-
enamines override the intrinsic diastereofacial preference of the
conformationally unrestricted chiral acyclic substrate. As the
intrinsic diastereofacial bias of the cyclic, conformationally
constrained aldehydes increase, it becomes more difficult for the
aldehyde to fit well in the both proposed transition states A and
D. Incorporation of the α-substituent in a cyclic structure can
N
N
O
O
O
H
H
R'
R
syn
aldol
O
4
R'
X
H
H
H
H
R''
R''
X
R
Scheme 1. Proposed transition states (Houk-List model) for the proline-
catalyzed aldol reaction. a) transition states with (S)-proline; b) transition
states with (R)-proline.
The synthetic applicability of these reactions is illustrated by
short syntheses of medicinally important compounds, namely 1-
deoxy-galactonojirimycin (DGJ) (9)14 and 2,5-dideoxy-2,5-imino-
D-altritol (DIA) (10)15 (Figure 2).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701073
European Journal of Organic Chemistry
FULL PAPER
H
HO
OH
N
HO
HO
OH
N
HO
OH
H
OH
10
9
Scheme 3. Synthesis of 2,5-dideoxy-2,5-imino-D-altritol (DIA) (10) from
hemiaminal 7.
Figure 2. 1-Deoxy-galactonojirimycin (DGJ) (9) and 2,5-dideoxy-2,5-imino-D-
altritol (DIA) (10).
To summarize, stereochemical outcome of proline-catalyzed
aldol addition of dioxanone 1 to acyclic chiral α-alkoxy and α-
amino branched aldehydes is under reagent control, with good
level of diastereoselectivity, synthetically useful in both the
matched and the mismatched cases. To the contrary, with cyclic
aldehydes high degree of reagent control in mismatched cases
is not granted: in these reactions it is not easy to predict the
level of diastereoselectivity, nor the matching combination.
Among various biologically important iminosugars,16 these two
have attracted our attention due to their powerful inhibition of
human
lysosomal
hydrolase
-
α-galactosidase
A.17
Malfunctioning of this enzyme results in progressive
accumulation of globotriaosylceramide and related α-galactosyl
terminating glycosphingolipids, primarily in lysosomes of the
vascular system. This syndrome is known as Fabry’s disease - a
relatively rare X-linked human genetic disorder,18 where the
mutated α-galactosidase A has defects in its tertiary structure
and is retained in the endoplasmatic reticulum by quality control.
In subinhibitory doses, competitive inhibitors like DGJ stabilize,
otherwise unstable, misfolded α-galactosidase A; in this way,
DGJ exerts the chaperon-effect on α-galactosidase A, allows for
its lysosomal trafficking and significantly improves the enzyme
activity.19 The therapeutic potential of DGJ (9) is reflected by the
fact that it has been approved for the treatment of Fabry’s
disease in the EU in patients with amenable mutations.20 In
addition, recently it was reported that DIA (10) exhibits the
active-site-specific-chaperon activity towards mutated α-
galactosidase A, thus leading to enhancement of the enzyme
activity in Fabry lymphoblasts.15a
Exposure of aldol 4b (Table 1, entry 2) to hydrogen in the
presence of Pd/C, resulted in the amino group deprotection
followed by stereoselective reductive amination, providing cyclic
amine 11 in 74% yield, as a single diastereoisomer (Scheme 2).
Simultaneous acid-catalyzed removal of the acetonide and TBS
protecting groups under acidic conditions afforded DGJ (9) in
good yield (86%). Thus obtained synthetic DGJ (9) showed
spectral data (1H and 13C NMR) and optical rotation that closely
matched those previously reported.21
Using this reaction as
a key step, two pharmacological
chaperones for the treatment of Fabry’s disease, namely 1-
deoxy-galactonojirimycin (DGJ) (9) and 2,5-dideoxy-2,5-imino-D-
altritol (DIA) (10), were efficiently synthesized.
Experimental Section
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.22 Petroleum ether (PE) refers to the fraction boiling at 70–72 °C.
NMR spectra were recorded on Bruker Avance III 500 (1H NMR 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
Nicolet 6700 FT instrument, and are expressed in cm–1. Mass spectra
were obtained on Agilent technologies 6210 TOF LC/MS instrument (LC:
series 1200). Melting points were determined on
a Electrothermal
apparatus and are uncorrected. Optical rotation was determined on a
Rudolph Research Analytical AUTOPOL IV Automatic Polarimeter.
General experimental procedure for direct asymmetric aldol
reactions catalyzed by (S)- or (R)-proline: A catalytic amount of (S)- or
(R)-proline (30 mol%) was added to a vial containing aldehyde 2a-i and
dioxanone 1 in DMF. After vigorous stirring at 4 oC (the reaction time
indicated in Table 1), the reaction mixture was diluted with EtOAc and
washed with water. The aqueous phase was back‐extracted with EtOAc.
The combined organic extract was dried over anh. MgSO4, filtered and
concentrated under reduced pressure. The crude residue was purified by
silica gel column or dry-flash chromatography to furnished pure aldol
product.
Scheme 2. Synthesis of 1-deoxy-galactonojirimycin (DGJ) (9) from aldol 4b.
Aldol reactions with aldehyde 2a
Compound 5. The above general procedure was followed using 436 mg
of dioxanone 1 (3.35 mmol), 676 mg of aldehyde 2a7 (2.30 mmol), and
50 mg of (S)-proline (0.44 mmol) and 5.2 mL of DMF. Purification of the
crude residue by column chromatography (SiO2; petroleum ether/ethyl
acetate = 6:4) afforded aminal 5 (575 mg, 59%) as white crystals,
followed by diastereoisomeric aldol 4a (97 mg, 10%).Data for 5: m.p. 99–
101 °C. [α]D20 +5.4 (c = 1.00, CHCl3); 1H NMR (500 MHz, DMSO-d6, 338
K) δ 7.41–7.29 (m, 5 H), 5.85 (s, 1 H), 5.10 (dd, J = 12.5, 8.0 Hz, 2 H),
Similarly, reductive amination of hemiaminal 7 (Table 1, entry 4
and Figure 1), followed by acidic removal of the both protecting
groups furnished 2,5-dideoxy-2,5-imino-D-altritol (DIA) (10) in
high yield (Scheme 3). Again, the obtained synthetic iminosugar
10 has spectroscopic and physical data fully consistent with
those previously reported.15a
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701073
European Journal of Organic Chemistry
FULL PAPER
4.61 (br. d, J = 7.5 Hz, 1 H), 4.35–4.15 (m, 1 H), 4.11–4.04 (m, 1 H), 4.05
(q, J = 7.0 Hz, 2 H), 3.78 (d, J = 4.5 Hz, 1 H), 3.76 (d, J = 12.0 Hz, 1 H),
3.63 (td, J = 7.7, 2.7 Hz, 1 H), 2.37–2.22 (m, 2H), 2.20–2.09 (m, 1 H),
2.04–1.96 (m, 1 H), 1.38 (s, 3 H), 1.27 (s, 3 H), 1.18 (t, J = 7.1 Hz, 3 H);
13C NMR (126 MHz, DMSO-d6, 338 K) δ 172.4 (C), 153.3 (C), 136.4 (C),
127.9 (CH),127.4 (CH), 127.4 (CH), 98.4 (C), 86.6 (C), 75.5 (CH2), 71.0
(CH), 65.7 (CH2), 64.9 (CH), 61.6 (CH), 59.3 (CH2), 28.7 (CH2), 26.1
(CH2), 25.9 (CH3), 20.9 (CH3), 13.7 (CH3); IR (ATR) v 3435, 2928, 1730,
1702, 1453, 1413, 1378, 1337, 1220, 1078 cm-1; HRMS (ESI) for
C21H29NNa O8 [M + Na]+ calculated 446.1785; found 446.1783.
1464, 1422, 1381, 1356, 1255, 1225, 1105, 1083, 836, 779, 756 cm-1;
HRMS (ESI) for C23H37NNaO7Si [M+Na]+ calculated: 490.2232; found:
490.2224. Data for 6: 1H NMR (500 MHz, CDCl3) δ 7.32 – 7.25 (m, 5H),
4.63 (d, J = 8.4 Hz, 1H), 4.38 (dt, J = 9.0, 2.2 Hz, 1H), 4.27 (dd, J = 17.4,
1.4 Hz, 1H), 4.11 (dd, J = 8.9, 1.2 Hz, 1H), 4.03 (d, J = 17.4 Hz, 1H), 3.26
(d, J = 2.3, 1H), 2.06 – 1.96 (m, J = 7.2, 1.6 Hz, 1H), 1.43 (s, 3H), 1.40 (s,
3H), 0.84 (s, 9H), 0.71 (d, J = 7.0 Hz, 3H), 0.03 (s, 3H), -0.25 (s, 3H); 13
C
NMR (126 MHz, CDCl3) δ 212.4 (C), 144.2 (C), 128.0 (2xCH), 127.2 (CH),
127.1 (2xCH), 101.0 (C), 77.0 (CH), 73.4 (CH), 68.1 (CH), 66.4 (CH2),
40.8 (CH), 25.8 (3xCH3), 23.8 (CH3), 23.7 (CH3), 18.1 (C), 9.4 (CH3), -4.7
(CH3), -5.2 (CH3).
Compound 4a. The above general procedure was followed using 800
mg of dioxanone 1 (6.15 mmol), 1.10 g of aldehyde 2a7 (3.72 mmol), 85
mg of (R)-proline (0.74 mmol) and 8.4 mL of DMF. Purification of the
crude residue by dry-flash chromatography (SiO2; petroleum ether/ethyl
acetate = 6:4) afforded aldol 4a (1.10 g, 70%) as a yellow oil and aminal
Aldol reactions with aldehyde 2c
Compound 3c. The above general procedure was followed using 140
mg of dioxanone 1 (1.08 mmol), 100 mg of commercially available
aldehyde 2c (0.53 mmol), 18 mg of (S)-proline (0.16 mmol) and 1.3 mL of
DMF. Purification of the crude residue by column chromatography (SiO2;
petroleum ether/ethyl acetate = 9:1) afforded aldol 3c (72 mg, 43%) as
colorless viscous oil and aldol 4c (7 mg, 4%). Data for 3c: [α]D20 -108.8 (c
0.99, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.40 (dd, J = 6.0, 1.5 Hz, 1H),
4.26 (dd, J = 17.2, 1.4 Hz, 1H), 4.08 (qd, J = 6.3, 4.8 Hz, 1H), 4.00 (d, J =
17.3 Hz, 1H), 3.74 (dd, J = 6.0, 4.8 Hz, 1H), 2.83 (bs, 1H), 1.46 (s, 3H),
1.43 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 210.0 (C), 100.9 (C), 74.8 (CH), 73.5
(CH), 68.9 (CH), 66.9 (CH2), 25.8 (3xCH3), 23.8 (CH3), 23.6 (CH3), 19.2
(CH3), 18.0 (C), -4.5 (CH3), -4.80 (CH3); IR (ATR) v 3434, 2955, 2933,
2892, 2858, 1792, 1734, 1467, 1382, 1256, 1224, 1095, 835, 778 cm-1;
HRMS (ESI) for C15H30NaO5Si [M+Na]+ calculated: 341.1755; found:
341.1741.
20
5 (110 mg, 7%). Data for aldol 4a: [α]D +87.0 (c = 1.27, CHCl3).; 1H
NMR (500 MHz, DMSO-d6) δ 7.40–7.27 (m, 5 H), 6.64 (d, J = 9.5 Hz, 1
H), 5.04 (d, J = 6.5 Hz, 1 H), 5.00 (dd, J = 23.5, 12.5 Hz, 2 H) 4.27 (dd, J
= 17.2, 1.1 Hz, 1 H), 4.17 (dd, J = 6.5, 1.0 Hz, 1 H), 4.05–3.99 (m, 3 H),
3.80–3.68 (m, 2 H), 2.26 (br. t, J = 7.7 Hz, 2 H), 1.70 (dd, J = 14.8, 7.3
Hz, 2 H), 1.31 (s, 3 H), 1.26 (s, 3 H), 1.16 (t, J = 7.1 Hz, 3 H); 13C NMR
(126 MHz, DMSO-d6) δ 208.3 (C), 172.6 (C), 156.0 (C), 137.2 (C), 128.3
(CH), 127.7 (CH), 127.6 (CH), 100.5 (C), 74.5 (CH), 69.5 (CH), 66.4
(CH2), 65.2 (CH2), 59.7 (CH2), 50.8 (CH), 30.4 (CH2), 27.1 (CH2), 23.9
(CH3), 22.9 (CH3), 14.1 (CH3); IR (ATR) v 3500, 3439, 3377, 3089, 3064,
3034, 2986, 2939, 2904, 1730, 1713, 1519, 1451, 1417, 1380, 1332,
1257, 1179, 1092, 1044, 949, 863 cm-1; HRMS (ESI) for C21H29NO8 [M +
H]+ calculated 424.1966; found 424.1961.
Aldol reactions with aldehyde 2b
Compound 4c. The above general procedure was followed using 140
mg of dioxanone 1 (1.08 mmol), 100 mg of commercially available
aldehyde 2c (0.53 mmol), 18 mg of (R)-proline (0.16 mmol) and 1.3 mL
of DMF. Purification of the crude residue by column chromatography
(SiO2; petroleum ether/ethyl acetate = 9:1) afforded aldol 4c (69 mg,
41%) as colorless film and aldol 3c (7 mg, 4%). Data for 4c: [α]D20 +73.6
(c 0.99, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.31 – 4.26 (m, 2H), 4.14
(qd, J = 6.4, 4.0 Hz, 1H), 4.05 (d, J = 16.8 Hz, 1H), 3.70 (t, J = 4.9 Hz,
1H), 2.98 (bs, 1H), 1.48 (s, 3H), 1.45 (s, 3H), 1.21 (d, J = 6.3 Hz, 3H),
0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
209.0 (C), 100.6 (C), 74.8 (CH), 74.7 (CH), 67.4 (CH), 67.1 (CH2), 25.8
(3xCH3), 24.6 (CH3), 23.6 (CH3), 20.4 (CH3), 18.0 (C), -3.9 (CH3), -4.7
(CH3); IR (ATR) v 3439, 2955, 2933, 2891, 2858, 1737, 1467, 1380,
1255, 1224, 1088, 1008, 901, 835, 778 cm-1 HRMS (ESI) for
C15H30NaO5Si [M+Na]+ calculated: 341.1755; found: 341.1756.
Compound 3b. The above general procedure was followed using 50 mg
of dioxanone 1 (0.38 mmol), 32.8 mg of aldehyde 2b23 (0.10 mmol), 3.5
mg of (S)-proline (0.03 mmol) and 0.2 mL of DMF. Purification of the
crude residue by column chromatography (SiO2; petroleum ether/ethyl
acetate = 8:2) afforded aldol 3b (22 mg, 49%) as colorless film and aldol
20
4b (2 mg, 4%). Data for 3b: [α]D -50.7 (c 1.00, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.40 – 7.32 (m, 5H), 5.18 – 5.08 (m, 3H), 4.47 (d, J = 4.8
Hz, 1H), 4.32 (d, J = 16.9 Hz, 1H), 4.18 (q, J = 4.5 Hz, 1H), 4.01 (d, J =
16.9 Hz, 1H), 3.87 (dd, J = 8.8, 5.1 Hz, 1H), 3.63 (ddd, J = 14.0, 7.0, 4.6
Hz, 1H), 3.58 (d, J = 3.3 Hz, 1H), 3.27 (dt, J = 14.3, 4.9 Hz, 1H), 1.50 (s,
3H), 1.48 (s, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 210.1 (C), 157.3 (C), 136.6 (C), 128.8 (2xCH), 128.4 (CH),
128.4 (2xCH), 101.2 (C), 73.6 (CH), 72.5 (CH), 71.7 (CH), 67.3 (CH2),
67.2 (CH2), 43.6 (CH2), 26.0 (3xCH3), 24.3 (CH3), 23.7 (CH3), 18.2 (C), -
4.4 (CH3), -4.5 (CH3); IR (ATR) v 3445, 2988, 2962, 2932, 2891, 2857,
1729, 1518, 1465, 1380, 1255, 1225, 1091, 837, 779 cm-1; HRMS (ESI)
for C23H37NNaO7Si [M+Na]+ calculated: 490.2232; found: 490.2228.
Aldol reactions with aldehyde 2d
Compound 3d. The above general procedure was followed using 210
mg of dioxanone 1 (1.61 mmol), 145 mg of aldehyde 2d23 (0.43 mmol),
15 mg of (S)-proline (0.13 mmol) and 1.2 mL of DMF. Purification of the
crude residue by column chromatography (SiO2; toluene/ethyl acetate =
8:2) afforded aldol 3d (100 mg, 50%) as colorless oil and aminal 7 (10
Compound 4b. The above general procedure was followed using 50 mg
of dioxanone 1 (0.38 mmol), 32.8 mg of aldehyde 2b23 (0.10 mmol), 3.5
mg of (R)-proline (0.03 mmol) and 0.2 mL of DMF. Purification of the
crude residue by column chromatography (SiO2; petroleum ether/ethyl
acetate = 8:2) afforded aldol 4b (24 mg, 53%) as colorless film and aldol
20
mg, 5%). Data for 3d: [α]D -99.3 (c 0.73, CHCl3); 1H NMR (500 MHz,
20
3b (2 mg, 4%). Data for 4b: [α]D +33.4 (c 0.95, CHCl3); 1H NMR (500
CDCl3) δ1H NMR (500 MHz, CDCl3) δ 7.38 – 7.32 (m, 5H), 5.18 (d, J =
9.7 Hz, 1H), 5.12 (d, J = 12.2 Hz, 1H), 5.05 (d, J = 12.2 Hz, 1H), 4.29 (dd,
J = 12.8, 9.9 Hz, 1H), 4.17 (d, J = 9.0 Hz, 1H), 4.14 (d, J = 8.7 Hz, 1H),
4.08 – 3.99 (m, 2H), 3.71 – 3.67 (m, 2H), 3.50 (s, 1H), 1.39 (s, 3H), 1.33
(s, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.06 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 212.4 (C), 155.9 (C), 136.5 (C), 128.4 (2xCH), 128.1 (3xCH),
101.4 (C), 71.6 (CH), 68.5 (CH), 66.7 (CH2), 66.5 (CH2), 62.7 (CH2), 51.2
(CH), 25.8 (3xCH3), 23.3 (CH3), 23.1 (CH3), 18.2 (C), -5.5 (CH3), -5.5
(CH3); IR (ATR) v 3506, 3443, 3389, 2987, 2953, 2930, 2886, 2857,
MHz, CDCl3) δ 7.41 – 7.27 (m, 5H), 5.27 – 5.01 (m, 3H), 4.32 (d, J = 6.4
Hz, 1H), 4.28 (d, J = 17.6 Hz, 1H), 4.15 – 3.98 (m, 2H), 3.97 – 3.82 (m,
1H), 3.41 – 3.34 (m, 2H), 3.08 (d, J = 5.1 Hz, 1H), 1.48 (s, 3H), 1.39 (s,
3H), 0.86 (s, 9H), 0.10 (s, 3H), 0.05 (m, 3H); 13C NMR (126 MHz, CDCl3)
δ 209.5 (C), 156.4 (C), 136.4 (C), 128.5 (2xCH), 128.1 (CH), 128.0
(2xCH), 100.7 (C), 74.2 (CH), 71.6 (CH), 69.2 (CH), 67.2 (CH2), 66.6
(CH2), 44.0 (CH2), 26.6 (CH3), 25.6 (3xCH3), 20.3 (CH3), 18.0 (C), -4.7
(CH3), -5.0 (CH3); IR (ATR) v 3437, 2991, 2953, 2932, 2857, 1709, 1517,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701073
European Journal of Organic Chemistry
FULL PAPER
1728, 1506, 1466, 1380, 1255, 1223, 1096, 1041, 839, 778 cm-1; HRMS
(ESI) for C23H38NO7Si [M+H]+ calculated: 468.2412; found: 468.2422.
acetate = 9:1) afforded an inseparable mixture (10.9 mg, 29%) of aldols
3f and 4f, and diastereomeric syn aldol as a colorless film (7.7 mg, 21%).
Data for 3f: 1H NMR (500 MHz, CDCl3) δ 7.32 – 7.22 (m, 5H), 5.03 (d, J
= 4.0 Hz, 1H), 4.29 – 4.24 (m, 2H), 3.97 (d, J = 16.6 Hz, 1H), 3.88 – 3.83
(m, 1H), 3.70 (d, J = 3.0 Hz, 1H), 2.36 – 2.28 (m, 1H), 1.50 (s, 3H), 1.46
(s, 3H), 0.90 (s, 9H), 0.82 (d, J = 7.0 Hz, 3H), 0.06 (s, 3H), -0.20 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 209.1 (C), 142.8 (C), 128.0 (2xCH), 127.3
(CH), 127.2 (2xCH), 100.8 (C), 76.6 (CH), 76.5 (CH), 73.0 (CH), 67.6
(CH2), 43.1 (CH), 26.1 (3xCH3), 24.9 (CH3), 23.5 (CH3), 18.4 (C), 11.4
(CH3), -4.4 (CH3), -5.0 (CH3); IR (ATR) v 3498, 3063, 3030, 2932, 2889,
2857, 1744, 1466, 1380, 1252, 1224, 1160, 1092, 1066, 1042, 838, 778
cm-1 HRMS (ESI) for C22H36NaO5Si [M+Na]+ calculated: 431.2224; found:
431.2227.
Compound 7. The above general procedure was followed using 400 mg
of dioxanone 1 (3.07 mmol), 316 mg of aldehyde 2d23 (0.94 mmol), 32
mg of (R)-proline (0.28 mmol) and 2.6 mL of DMF. Purification of the
crude residue by column chromatography (SiO2; toluene/ethyl acetate =
8:2) afforded aminal 7 (210 mg, 48%) as a pale yellow viscous oil and
20
aldol 3d (31 mg, 7%). Data for 7: [α]D -37.7 (c 1.04, CHCl3); 1H NMR
(500 MHz, DMSO-d6, 338 K) δ 7.43 – 7.23 (m, 5H), 5.30 (bs, 1H), 5.15 –
5.03 (m, 2H), 4.43 (d, J = 7.0 Hz, 1H), 4.35 (dd, J = 11.9, 7.2 Hz, 1H),
4.30 – 4.10 (m, 1H), 4.10 – 3.97 (m, 1H), 3.83 (d, J = 4.7 Hz, 1H), 3.81 (d,
J = 12.3 Hz, 1H), 3.73 (dd, J = 10.3, 2.1 Hz, 1H), 3.63 – 3.55 (m, 1H),
1.39 (s, 3H), 1.28 (s, 3H), 0.86 (s, 9H), 0.01 (s, 3H), -0.01 (s, 3H); 13
C
20
NMR (126 MHz, DMSO-d6, 338 K) δ 153.2 (C), 136.4 (C), 127.9 (2xCH),
127.4 (CH), 127.3 (2xCH), 98.4 (C), 86.7 (C), 75.6 (CH), 68.1 (CH), 65.6
(CH2), 65.5 (CH2), 64.4 (CH), 59.7 (CH2), 25.8 (CH3), 25.4 (3xCH3), 21.1
(CH3), 17.6 (C), -5.8 (CH3), -5.9 (CH3); IR (ATR) v 3441, 2991, 2954,
2932, 2887, 2857, 1703, 1467, 1413, 1380, 1343, 1256, 1226, 1087,
1051, 838, 779 cm-1; HRMS (ESI) for C23H38NO7Si [M+H]+ calculated:
468.2412; found: 468.2419.
Data for syn aldol: [α]D -80.5 (c 1.02, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.32 – 7.22 (m, 5H), 5.03 (d, J = 4.0 Hz, 1H), 4.29 – 4.24 (m,
2H), 3.97 (d, J = 16.6 Hz, 1H), 3.88 – 3.83 (m, 1H), 3.70 (d, J = 3.0 Hz,
1H), 2.36 – 2.28 (m, 1H), 1.50 (s, 3H), 1.46 (s, 3H), 0.90 (s, 9H), 0.82 (d,
J = 7.0 Hz, 3H), 0.06 (s, 3H), -0.20 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
209.1 (C), 142.8 (C), 128.0 (2xCH), 127.3 (CH), 127.2 (2xCH), 100.8 (C),
76.6 (CH), 76.5 (CH), 73.0 (CH), 67.6 (CH2), 43.1 (CH), 26.1 (3xCH3),
24.9 (CH3), 23.5 (CH3), 18.4 (C), 11.4 (CH3), -4.4 (CH3), -5.0 (CH3); IR
(ATR) v 3498,3063, 3030, 2932, 2889, 2857, 1744, 1466, 1380, 1252,
1224, 1160, 1092, 1066, 1042, 838, 778 cm-1; HRMS (ESI) for
C22H36NaO5Si [M+Na]+ calculated: 431.2224; found: 431.2225.
Aldol reactions with aldehyde 2e
Compound 8. The above general procedure was followed using 30 mg
of dioxanone 1 (0.23 mmol), 25 mg of aldehyde 2e23 (0.08 mmol), 2.8 mg
of (S)-proline (0.024 mmol) and 0.2 mL of DMF. Purification of the crude
residue by column chromatography (SiO2; petroleum ether /ethyl acetate
= 9:1) afforded aminal 8 (19 mg, 53%) as colorless oil and aldol 4e (6 mg,
Compound 4f. The above general procedure was followed using 70 mg
of dioxanone 1 (0.58 mmol), 26 mg of crude aldehyde 2f23 (0.09 mmol),
3.1 mg of (R)-proline (0.027 mmol) and 0.1 mL of DMF. Purification of the
crude residue by column chromatography (SiO2; petroleum ether/ethyl
acetate = 9:1) afforded aldol 4f (20.8 mg, 55%) as colorless film. Data for
4f: [α]D20 +53.4 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.36 – 7.23
(m, 5H), 4.64 (d, J = 8.8 Hz, 1H), 4.16 – 4.09 (m, 2H), 3.94 (d, J = 17.3
Hz, 1H), 3.45 (dt, J = 8.7, 2.1 Hz, 1H), 2.95 (bs, 1H), 2.08 – 2.00 (m, 1H),
1.46 (s, 3H), 1.34 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H), 0.86 (s, 9H), 0.02 (s,
3H), -0.27 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 212.8 (C), 143.8 (C),
127.9 (2xCH), 127.1 (2xCH), 127.1 (CH), 100.9 (C), 76.7 (CH), 73.1 (CH),
69.7 (CH), 66.3 (CH2), 41.8 (CH), 25.8 (3xCH3), 23.7 (CH3), 23.5 (CH3),
18.1 (C), 9.1 (CH3), -4.6 (CH3), -5.0 (CH3); IR (ATR) v 3541, 3031, 2988,
2955, 2932, 2889, 1739, 1459, 1379, 1254, 1224, 1089, 1058, 870, 838,
776 cm-1; HRMS (ESI) for C22H36NaO5Si [M+Na]+ calculated: 431.2224;
found: 431.2230.
20
17%). Data for 8: [α]D +24.0 (c 1.04, CHCl3); 1H NMR (500 MHz,
DMSO-d6) δ 5.08 – 4.86 (m, 1H), 4.36 – 4.27 (m, 2H), 4.23 – 3.97 (m,
2H), 3.83 – 3.78(m, 2H), 3.72 (d, J = 10.0 Hz, 1H), 3.53 – 3.49 (m, 1H),
1.43 (s, 9H), 1.38 (s, 3H), 1.29 (s, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s,
3H); 13C NMR (126 MHz, DMSO) δ 152.4 (C), 98.5 (C), 86.8 (C), 78.8 (C),
75.6 (CH), 67.9 (CH2), 65.8 (CH), 64.4 (CH), 59.5 (CH2), 27.8 (3xCH3),
25.4 (4xCH3), 21.4 (CH3), 17.6 (C), -5.8 (CH3), -5.9 (CH3). IR (ATR) v
3449, 2955, 2932, 2887, 2858, 1698, 1469,1373, 1254, 1227, 1170,
1090, 1050, 839, 779 cm-1; HRMS (ESI) for C20H39NNaO7Si [M+Na]+
calculated: 456.2388; found: 456.2396.
Compound 4e. The above general procedure was followed using 30 mg
of dioxanone 1 (0.23 mmol), 25 mg of aldehyde 2e23 (0.08 mmol), 2.8 mg
of (R)-proline (0.024 mmol) and 0.2 mL of DMF. Purification of the crude
residue by column chromatography (SiO2; petroleum ether/ethyl acetate
= 9:1) afforded aldol 4e (20.4 mg, 57%) as colorless oil and aminal 8 (6
Aldol reactions with aldehyde 2g
20
mg, 15%). Data for 4e: [α]D +96.3 (c 1.03, CHCl3); 1H NMR (500 MHz,
Compound 3g. The above general procedure was followed using 43 mg
of dioxanone 1 (0.05 mmol), 8.7 mg of aldehyde 2g24 (0.036 mmol), 1.4
mg of (S)-proline (0.012 mmol) and 0.1 mL of DMF. Purification of the
crude residue by column chromatography (SiO2; petroleum ether/ethyl
acetate = 9:1) afforded an inseparable mixture (7.6 mg, 57%) of aldols 3g
and 4g as a colorless film. Data for main aldol 3g: 1H NMR (500 MHz,
CDCl3) δ 4.26 (dd, J = 17.4, 1.5 Hz, 1H), 4.12 (dd, J = 8.7, 1.5 Hz, 1H),
4.02 (d, J = 17.4 Hz, 1H), 3.81 – 3.79 (m, 1H), 3.47 (dd, J = 9.8, 5.2 Hz,
1H), 3.36 (dd, J = 9.7, 6.4 Hz, 1H), 3.06 (bs, 1H), 1.96 (qd, J = 7.1, 2.5
Hz, 1H), 1.75 – 1.66 (m, 1H), 1.52 (dd, J = 13.7, 6.9 Hz, 1H), 1.48 (s, 3H),
1.41 (s, 3H), 1.08 (dt, J = 13.7, 7.5 Hz, 1H), 0.90 (d, J = 4.4 Hz, 3H), 0.89
(d, J = 3.7 Hz, 3H) 0.89 (s, 9H), 0.03 (s, 6H). 13C NMR (126 MHz, CDCl3)
δ 213.2 (C), 101.0 (C), 73.1 (CH), 71.9 (CH), 68.4 (CH2), 66.4 (CH2),
37.1 (CH2), 32.9 (CH), 30.1 (CH), 26.0 (3xCH3), 23.7 (CH3), 23.6 (CH3),
18.3 (C), 17.6 (CH3), 12.9 (CH3), -5.4 (CH3), -5.4 (CH3); IR (ATR) v 3527,
2956, 2932, 2888, 2857, 1739, 1466, 1380, 1252, 1224, 1161, 1094, 838,
778 cm-1; HRMS (ESI) for C19H39O5Si [M+H]+ calculated: 375.2561;
found: 375.2556.
CDCl3) δ 4.94 (d, J = 9.8 Hz, 1H), 4.28 (dd, J = 17.5, 1.3 Hz, 1H), 4.15
(dd, J = 20.2, 9.0 Hz, 2H), 4.04 – 3.94 (m, 2H), 3.69 – 3.60 (m, 2H), 3.52
(bs, 1H), 1.42 (s, 3H), 1.41 (s, 9H), 1.39 (s, 3H), 0.87 (s, 9H), 0.05 (s,
6H); 13C NMR (126 MHz, CDCl3) δ 212.7 (C), 155.3 (C), 101.5 (C), 79.1
(C), 71.4 (CH), 68.6 (CH), 66.5 (CH2), 62.7 (CH2), 50.6 (CH), 28.3
(3xCH3), 25.8 (3xCH3), 23.3 (CH3), 23.2 (CH3), 18.2 (CH3), -5.4 (CH3), -
5.5 (CH3); IR (ATR) v 3519, 3450, 3387, 2955, 2932, 2887, 2858, 1720,
1500, 1469, 1385, 1370, 1254, 1225, 1170, 1098, 1044, 840, 779 cm-1;
HRMS (ESI) for C20H39NNaO7Si [M+Na]+ calculated: 456.2388; found:
456.2393.
Aldol reactions with aldehyde 2f
Compound 3f. The above general procedure was followed using 70 mg
of dioxanone 1 (0.58 mmol), 26 mg of crude aldehyde 2f23 (0.09 mmol),
3.1 mg of (S)-proline (0.027 mmol) and 0.1 mL of DMF. Purification of the
crude residue by column chromatography (SiO2; petroleum ether/ethyl
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701073
European Journal of Organic Chemistry
FULL PAPER
Compound 4g. The above general procedure was followed using 43 mg
of dioxanone 1 (0.05 mmol), 10.2 mg of aldehyde 2g24 (0.042 mmol), 1.4
mg of (R)-proline (0.012 mmol) and 0.1 mL of DMF. Purification of the
crude residue by column chromatography (SiO2; petroleum ether/ethyl
acetate = 9:1) afforded an inseparable mixture (7.8 mg, 50%) of aldols 4g
and 3g as a colorless film. Data for main aldol 4g: 1H NMR (500 MHz,
CDCl3) δ 4.27 (dd, J = 17.3, 1.5 Hz, 1H), 4.20 (dd, J = 7.8, 1.5 Hz, 1H),
4.02 (d, J = 17.3 Hz, 1H), 3.75 (dd, J = 7.8, 3.5 Hz, 1H), 3.54 (dd, J = 9.8,
5.0 Hz, 1H), 3.27 (dd, J = 9.8, 7.2 Hz, 1H), 3.14 (bs, 1H), 2.00 – 1.91 (m,
1H), 1.75 – 1.64 (m, 1H), 1.48 (s, 3H), 1.47 – 1.39 (m, 1H), 1.43 (s, 3H),
1.07 (ddd, J = 13.8, 9.9, 5.0 Hz, 1H), 1.02 (d, J = 6.9 Hz, 3H), 0.93 (d, J =
6.7 Hz, 3H), 0.90 (s, 9H), 0.04 (s, 6H). 13C NMR (126 MHz, CDCl3) δ
212.4 (C), 100.9 (C), 74.5 (CH), 73.6 (CH), 68.2 (CH2), 66.6 (CH2), 34.7
(CH2), 33.4 (CH), 32.0 (CH), 26.0 (3xCH3), 23.8 (CH3), 23.8 (CH3), 18.6
(CH3), 18.4 (C), 16.8 (CH3), -5.3 (CH3), -5.4 (CH3); IR (ATR) v 3528,
2956, 2932, 2888, 2858, 1739, 1466, 1380, 1253, 1224, 1162, 1094, 838,
777 cm-1; HRMS (ESI) for C19H39O5Si [M+H]+ calculated: 375.2561;
found: 375.2560.
(CH3), 22.9 (CH3); IR (ATR) v 3519, 2988, 2935, 2838, 1742, 1614, 1516,
1460, 1378, 1301, 1247, 1167, 1128, 1088, 1063, 1032, 862, 861 cm-1;
HRMS (ESI) for C19H26NaO7 [M+Na]+ calculated: 389.1571; found:
389.1574.
Aldol reaction with aldehyde 2i
Compound 3i. The above general procedure was followed using 280 mg
of dioxanone 1 (2.15 mmol), 97 mg of aldehyde 2i25 (0.45 mmol), 18.0
mg of (S)-proline (0.15 mmol) and 1.1 mL of DMF. Purification of the
crude residue by column chromatography (SiO2; petroleum ether/ethyl
acetate = 1:4) afforded an inseparable mixture (78 mg, 50%) of aldols 3i
20
and 4i as a colorless oil. Data for main aldol 3i: [α]D -121.0 (c 1.01,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.45 (d, J = 8.3 Hz, 1H), 4.35 –
4.27 (m, 2H), 4.14 (dd, J = 9.0, 1.3 Hz, 1H), 4.08 (d, J = 17.6 Hz, 1H),
3.21 (bs, 1H), 2.79 (ddd, J = 17.5, 10.7, 9.8 Hz, 1H), 2.36 (ddd, J = 17.5,
10.0, 2.1 Hz, 1H), 2.12 – 2.06 (m, 1H), 2.04 – 1.94 (m, 1H), 1.52 (s, 9H),
1.47 (s, 3H), 1.43 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 211.1 (C), 175.2
(C), 149.9 (C), 101.2 (C), 82.8 (C), 72.5 (CH), 70.4 (CH), 66.3 (CH2),
57.7 (CH), 32.4 (CH2), 28.0 (3xCH3), 23.6 (CH3), 23.3 (CH3), 17.4 (CH2);
IR (ATR) v 3428, 2981, 2936, 1785, 1751, 1390, 1317, 1254, 1223, 1162,
1026, 855 cm-1; HRMS (ESI) for C16H25NNaO7 [M+Na]+ calculated:
366.1523; found: 366.1529.
Aldol reaction with aldehyde 2h
Compound 3h. The above general procedure was followed using 160
mg of dioxanone 1 (0.92 mmol), 80 mg of crude aldehyde 2h23 (0.34
mmol), 12 mg of (S)-proline (0.10 mmol) and 0.7 mL of DMF. Purification
of the crude residue by column chromatography (SiO2; petroleum ether
/ethyl acetate = 6:4) afforded aldol 3h (39 mg, 31%) as a colorless film,
aldol 4h (15.3 mg, 12%) and diastereomeric syn aldol (7.9 mg, 7%) as a
Synthesis of 1-deoxy-galactonojirimycin (DGJ) (9)
Compound 11. A mixture of aldol 4b (69.0 mg, 0.15 mmol) and 10%
Pd/C (30.1 mg, 0.03 mmol) in ethanol (10.0 mL) was stirred for 2.5 h
under a hydrogen atmosphere (4.5 atm). The mixture was filtered and
concentrated under reduced pressure. Purification of the residue by
column chromatography (SiO2; ethyl acetate/methanol = 95/5) afforded
20
colorless film. Data for 3h: [α]D -106.9 (c 0.13, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.37 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.09 (d,
J = 7.8 Hz, 1H), 4.29 – 4.21 (m, 2H), 4.18 – 4.11 (m, 2H), 3.98 (d, J =
17.2 Hz, 1H), 3.80 (s, 3H), 3.01 (d, J = 4.6 Hz, 1H), 1.55 (s, 3H), 1.48 (s,
3H), 1.37 (s, 3H), 1.12 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 209.1 (C),
159.3 (C), 129.8 (C), 128.3 (2xCH), 113.6 (2xCH), 108.5 (C), 100.4 (C),
81.4 (CH), 78.8 (CH), 73.3 (CH), 70.7 (CH), 66.2 (CH2), 54.8 (CH3), 26.8
(CH3), 26.3 (CH3), 23.5 (CH3), 22.6 (CH3); IR (ATR) v 3466, 2988, 2928,
2854, 1741, 1614, 1515, 1461, 1377, 1247, 1168, 1063, 878, 831 cm-1;
HRMS (ESI) for C19H26NaO7 [M+Na]+ calculated: 389.1571; found:
389.1570.
20
amine 11 (34.6 mg, 74%) as a white crystals. m. p. 108-109 °C; [α]D
+75.0 (c 1.04, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.23 (d, J = 2.1 Hz,
1H), 4.10 (dd, J = 12.1, 2.3 Hz, 1H), 3.76 (dd, J = 12.1, 1.4 Hz, 1H), 3.73
– 3.67 (m, 1H), 3.37 (dd, J = 9.0, 3.3 Hz, 1H), 3.09 (dd, J = 13.7, 5.1 Hz,
1H), 2.48 (s, 1H), 2.43 (dd, J = 13.7, 10.5 Hz, 1H), 2.35 (s, 2H, OH+NH),
1.47 (s, 3H), 1.44 (s, 3H), 0.90 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13
C
NMR (126 MHz, CDCl3) δ 99.4 (C), 75.6 (CH), 71.0 (CH), 70.4 (CH), 64.2
(CH2), 51.8 (CH), 50.8 (CH2), 29.9 (CH3), 26.0 (3xCH3), 18.5 (CH3), 18.3
(C), -4.2 (CH3), -4.3 (CH3); IR (ATR) v 3439, 3320, 2995, 2955, 2931,
2883, 2856, 1456, 1405, 1378, 1244, 1195, 1124, 1096, 1064, 1038, 998,
948, 914, 888, 857, 834, 777 cm-1; HRMS (ESI) for C15H32NO4Si [M+H]+
calculated: 318.2095; found: 318.2092.
20
Data for syn aldol: [α]D -101.9 (c 0.16, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.34 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.91 (d, J =
8.4 Hz, 1H), 4.28 (dd, J = 16.6, 1.3 Hz, 1H), 4.21 – 4.19 (m, 1H), 4.12 –
4.05 (m, 2H), 3.95 (d, J = 16.6 Hz, 1H), 3.80 (s, 3H), 2.88 (d, J = 8.2 Hz,
1H), 1.54 (s, 3H), 1.48 (s, 3H), 1.40 (s, 3H), 1.15 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 207.4 (C), 159.5 (C), 128.6 (C), 128.2 (2xCH), 113.7
(2xCH), 108.7 (C), 100.2 (C), 81.7 (CH), 78.7 (CH), 74.0 (CH), 68.2 (CH),
66.4 (CH2), 54.9 (CH3), 26.8 (CH3), 26.4 (CH3), 23.9 (CH3), 22.4 (CH3);
IR (ATR) v 3479, 2987, 2930, 1746, 1613, 1587, 1515, 1461, 1377, 1244,
1169, 1125, 1063, 888, 831 cm-1; HRMS (ESI) for C19H26Na O7 [M+Na]+
calculated: 389.1571; found: 389.1572.
Compound 9 (DGJ, 1-Deoxy-galactonojirimycin). A solution of amine
11 (17.0 mg, 0.05 mmol) in solvent mixture methanol/3M HCl (2.1 mL,
v/v= 2/1) was stirred at room temperature for 6 h. After the volatiles were
removed under reduced pressure, the residue was purified by ion
exchange chromatography (acidic resin DOWEX 50WX8-100), to give
compound 9 (7.5 mg, 86%) as a colorless viscous oil. [α]D20 +47.1 (c 0.75,
H2O); [lit.21a [α]D20 +54° (c 0.9, H2O); lit.21b [α]D20 +50.2° (c 1.02, H2O)];1H
NMR (500 MHz, D2O) δ 3.91 (dd, J = 3.2, 1.4 Hz, 1H), 3.66 (ddd, J =
10.7, 9.9, 5.3 Hz, 1H), 3.55 (dd, J = 11.2, 6.7 Hz, 1H), 3.51 (dd, J = 11.2,
6.7 Hz, 1H) 3.38 (dd, J = 9.7, 3.2 Hz, 1H), 3.03 (dd, J = 12.7, 5.3 Hz, 1H),
2.66 (td, J = 6.7, 1.4 Hz, 1H), 2.29 (dd, J = 12.7, 10.9 Hz, 1H); 13C NMR
(126 MHz, D2O) δ 75.2 (CH), 69.4 (CH), 68.3 (CH), 61.5 (CH2), 59.0 (CH),
49.2 (CH2); IR (ATR) v 3355, 2926, 1647, 1452, 1363, 1250, 1103, 1063,
941, 862, 814, 725 cm-1; HRMS (ESI) for C6H14NO4 [M+H]+ calculated:
164.0917; found: 164.0914.
Compound 4h. The above general procedure was followed using 160
mg of dioxanone 1 (0.92 mmol), 80 mg of crude aldehyde 2h23 (0.34
mmol), 12 mg of (R)-proline (0.10 mmol) and 0.7 mL of DMF. Purification
of the crude residue by column chromatography (SiO2; petroleum
ether/ethyl acetate = 6:4) afforded aldol 4h (55 mg, 49%) as a colorless
20
oil and aldol 3h (4.0 mg, 3%). Data for 4h: [α]D +71.0 (c 1.00, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.7 Hz,
2H), 5.08 (d, J = 8.8 Hz, 1H), 4.38 (dd, J = 8.3, 1.3 Hz, 1H), 4.13 (dd, J =
17.6, 1.4 Hz, 1H), 4.02 – 3.95 (m, 2H), 3.84 – 3.80 (m, 1H), 3.80 (s, 3H),
3.26 (d, J = 3.7 Hz, 1H), 1.54 (s, 3H), 1.53 (s, 3H), 1.44 (s, 3H), 1.32 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 211.0 (C), 159.2 (C), 128.9 (C), 127.8
(2xCH), 113.5 (2xCH), 108.3 (C), 101.0 (C), 80.4 (CH), 76.9 (CH), 72.3
(CH), 66.2 (CH), 66.0 (CH2), 54.8 (CH3), 26.7 (CH3), 26.4 (CH3), 23.0
Synthesis of 2,5-dideoxy-2,5-imino-D-altritol (DIA) (10)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701073
European Journal of Organic Chemistry
FULL PAPER
Compound 12. A mixture of aminal 7 (40.0 mg, 0.08 mmol) and 10%
Pd/C (19.0 mg, 0.02 mmol) in ethanol (8.0 mL) was stirred for 2 h under
1210-1212. c) I. Ibrahem, A. Cordova. Tetrahedron Lett. 2005, 46,
3363-3367.
a
hydrogen atmosphere (4.5 atm). The mixture was filtered and
concentrated under reduced pressure. Purification of the residue by
column chromatography (SiO2; dichloromethane/methanol 95/5)
[6]
[7]
[8]
[9]
J. Marjanovic, Z. Ferjancic, R. N. Saicic. Tetrahedron 2015, 71,
6784‐6789.
=
J. Marjanovic, V. Divjakovic, R. Matovic, Z. Ferjancic, R. N. Saicic. Eur.
J. Org. Chem. 2013, 5555-5560.
afforded amine 12 (22.5 mg, 83%) as a white crystals. m. p. 51-52 °C;
[α]D20 +29.0 (c 1.05, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.25 (t, J = 4.3
Hz, 1H), 4.02 (dd, J = 8.4, 4.8 Hz, 1H), 3.96 (dd, J = 12.1, 4.9 Hz, 1H),
3.85 – 3.78 (m, 2H), 3.64 (dd, J = 12.1, 5.0 Hz, 1H), 3.27 (dd, J = 9.0, 4.9
Hz, 1H), 3.13 (dt, J = 8.3, 3.5 Hz, 1H), 2.32 (bs, 2H, OH+NH), 1.46 (s,
3H), 1.43 (s, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 98.3 (C), 74.6 (CH), 70.7 (CH), 63.7 (CH), 62.0 (CH2),
61.5 (CH2), 53.6 (CH), 27.4 (CH3), 25.8 (3xCH3), 20.8 (CH3), 18.2 (C), -
5.6 (CH3), -5.6 (CH3); IR (ATR) v 3349, 3170, 2992, 2907, 2864, 1466,
1374, 1251, 1216, 1195, 1172, 1122, 1091, 1067, 1008, 976, 933, 856,
834, 777 cm-1; HRMS (ESI) for C15H32NO4Si [M+H]+ calculated:
318.2095; found: 318.2084.
M. Trajkovic, V. Balanac, Z. Ferjancic, R. N. Saicic. RSC Adv. 2014, 4,
53722-53724.
a) F. Calderon, E. G. Doyaguez, A. Fernandez-Mayoralas. J. Org.
Chem. 2006, 71, 6258-6261. b) M. Cieplak, M. Ceborska, P. Cmoch, S.
Jarosz. Tetrahedron: Asymmetry 2012, 23, 1213-1217.
[10] F. Calderon, E. G. Doyaguez, P. H.-Y.Cheong, A. Fernandez-
Mayoralas, K. N. Houk. J. Org. Chem. 2008, 73, 7916-7920.
[11] For an interesting syn-selective aldol addition of dioxanone to hydrated
form of aldehydes, see: N. Palyam, M. Majewski. J. Org. Chem. 2009,
74, 4390-4392.
[12] a) S. Bahmanyar, K. N. Houk, H. J. Martin, B. List. J. Am. Chem. Soc.
2003, 125, 2475-2479; b) L. Hoang, S. Bahmanyar, K. N. Houk, B. List.
J. Am. Chem. Soc. 2003, 125, 16-17; c) S. Bahmanyar, K. N. Houk, J.
Am. Chem. Soc. 2001, 123, 12911-12912.
Compound 10 (DIA, 2,5-dideoxy-2,5-imino-D-altritol). A solution of
amine 12 (21.0 mg, 0.07 mmol) in solvent mixture methanol/3M HCl (2.7
mL, v/v= 2/1) was stirred and heated to reflux for 2 h. After the volatiles
were removed under reduced pressure, the residue was purified by ion
exchange chromatography (acidic resin DOWEX 50WX8-100), to give
[13] The structure of compound 5 was determined by X-ray analysis (see ref.
7). The stereochemistry of the newly formed stereocenters in
compounds 7 and 8 were determined by NOESY experiments. NOESY
spectrums for these compounds (with the relevant NOESY correlations
marked) are given in the Supporting information. Compound 6 is in
equilibrium with its acyclic form 4b, and the NOESY spectrum of this
mixture does not offer sufficient data for the determination of
20
compound 10 (10.3 mg, 95%) as a colorless viscous oil. [α]D +32.6 (c
1.03, H2O); [lit.15a [α]D +34.2 (c 0.83, H2O)]; 1H NMR (500 MHz, D2O) δ
20
4.08 (t, J = 4.1 Hz, 1H), 3.90 (dd, J = 8.5, 4.3 Hz, 1H), 3.69 (dd, J = 11.1,
6.7 Hz, 1H), 3.65 (dd, J = 11.7, 4.0 Hz, 1H), 3.57 – 3.52 (m, 2H), 3.26 –
3.19 (m, 1H), 3.04 (ddd, J = 8.8, 5.9, 4.0 Hz, 1H); 13C NMR (126 MHz,
D2O) δ 73.0 (CH), 71.4 (CH), 61.4 (CH2), 60.9 (CH), 59.9 (CH2), 59.3
(CH); IR (ATR) v 3448, 3338, 3274, 2945, 2920, 2889, 2695, 1428, 1396,
stereochemistry. Therefore, the indicated stereochemistry of
6 is
assigned by analogy with the related hemiaminals 5, 7 and 8 (i. e. two
OH groups are anti).
1333, 1298, 1232, 1148, 1112, 1051, 1014, 969, 927, 829, 776, 736 cm-
[14] For the recent synthesis of DGJ, see: a) J.-S. Kim, Y.-T. Lee, K.-H. Lee,
I.-S. Myeong, J.-C. Kang, C. Jung, S.-H. Park, W.-H. Ham. J. Org.
Chem. 2016, 81, 7432-7438. b) S. Chacko, R. Ramapanicker. J. Org.
Chem. 2015, 80, 4776-4782. c) S. F. Jenkinson, G. W. J. Fleet, R. J.
Nash, Y. Koike, I. Adachi, A. Yoshihara, K. Morimoto, K. Izumori, A.
Kato. Org. Lett. 2011, 13, 4064-4067. d) M. S. M. Timmer, E. M.
Dangerfield, J. M. H. Cheng, S. A. Gulab, B. L. Stocker. Tetrahedron
Lett. 2011, 52, 4803-4805. e) T. Wennekes, A. J. Meijer, A. K. Groen, R.
G. Boot, J. E. Groener, M. van Eijk, R. Ottenhoff, N. Bijl, K. Ghauharali,
H. Song, T. J. O’Shea, H. Liu, N. Yew, D. Copeland, R. J. van den Berg,
G. A. van der Marel, H. S. Overkleeft, J. M. Aerts. J. Med. Chem. 2010,
53, 689-698. f) T. H. Chan, Y. F. Chang, J. J. Hsu, W. C. Cheng. Eur. J.
Org. Chem. 2010, 5555-5559. g) M. Ruiz, T. M. Ruanova, O. Blanco, F.
Nunez, C. Pato, V. Ojea. J. Org. Chem. 2008, 73, 2240-2255. h) C.
Boucheron, P. Compain, O. R. Martin. Tetrahedron Lett. 2006, 47,
3081-3084. i) C. McDonnell, L. Cronin, J. L. O’Brie, P. V. Murphy, J.
Org. Chem. 2004, 69, 3565-3568. j) S. J. Pyun, K. Y. Lee, C. Y. Oh, W.
H. Ham. Heterocycles 2004, 62, 333-341.
1
;
HRMS (ESI) for C6H14NO4 [M+H]+ calculated: 164.0917; found:
164.0913.
Acknowledgements
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 (Project No.
F193).
Keywords: organocatalysis • aldol reaction • iminosugars •
Fabry’s disease • 1-deoxy-galactonojirimycin
[1]
[2]
R. Mahrwald (Ed.), Modern Aldol Reactions, Wiley-VCH, Weinheim,
2004.
[15] a) A. Kato, Y. Yamashita, S. Nakagawa, Y. Koike, I. Adachi, J.
Hollinshead, R. J. Nash, K. Ikeda, N. Asano. Bioorg. Med. Chem. 2010,
18, 3790-3794. b) C. Saotome, Y. Kanie, O. Kanie, C.-H. Wong. Bioorg.
Med. Chem. 2000, 8, 2249-2261. c) M. H. Fechter, A. E. Stutz.
Carbohydrate Res. 1999, 319, 55-62.
For selected review articles organocatalyzed aldol reactions, see: a) S.
Mukherjee, J. W. Yang, S. Hoffmann, B. List. Chem. Rev., 2007, 107,
5471-5569. b) S. G. Zlotin, A. S. Kucherenko, I. P. Beletskaya. Russ.
Chem. Rev. 2009, 78, 737-784. c) L. M. Geary, P. G. Hultin.
Tetrahedron: Asymmetry 2009, 20, 131-173. d) V. Bisai, A. Bisai, V. K.
Singh. Tetrahedron 2012, 68, 4541-4580. e) M. M. Heravi, S. Asadi.
Tetrahedron: Asymmetry 2012, 23, 1431-1465. f) E. Dibello, D.
Gamenara, G. Seoan. Curr. Organocatal. 2015, 2, 124-149.
a) D. Enders, M. Voith, S. J. Ince. Synthesis 2002, 1775–1779. b) D.
Enders, B. Bockstiegel. Synthesis 1989, 493-496.
[16] a) P. Compain and O. R. Martin (Ed.), Iminosugars: From Synthesis to
Therapeutic Applications. Chichester: Wiley; 2007; b) B. G. Winchester.
Tetrahedron Asymmetry. 2009, 20, 645-651. (c) R. J. Nash, A. Kato,
C.-Y. Yu, G. W. J. Fleet. Future Med Chem. 2011, 3, 1513-1521.
[17] a) For a recent overview of the topic, see a series of articles in Nature
Outlook Lysosomal storage disorders. Nature. 2016, 537(7621), S143-
S165. b) T. D. Butters R. A. Dwek, F. M. Platt. Chem Rev. 2000, 100,
4683-4696. c) T. Kolter, K. Sandhoff. Angew Chem Int Ed. 1999, 38,
1532-1568.
[3]
[4]
[5]
D. Enders, M. Voith, A. Lenzen. Angew. Chem. Int. Ed. 2005, 44, 1304-
1325.
a) J. T. Suri, D. B. Ramachary, C. F. Barbas. Org. Lett. 2005, 7, 1383-
1385. b) D. Enders, C. Grondal, Angew. Chem., Int. Ed. 2005, 44,
[18] R. J. Desnick, R. Brady, J. Barranger, A. J. Collins, D. P. Germain, M.
Goldman, G. Grabowski, S. Packman, W. R. Wilcox. Ann. Intern. Med.
2003, 138, 338–346.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701073
European Journal of Organic Chemistry
FULL PAPER
[19] J.-Q. Fan, S. Ishi, N. Asano, Y. Suzuki. Nat. Med. 1999, 5, 112-115.
[22] W. L. F. Armarego, C. L. L. Chai. Purification of Laboratory Chemicals,
6th edition, Elsevier, Oxford, 2009.
[20] a) R. Giugliani, S. Waldek, D. P. Germain, K. Nicholls, D. G. Bichet, J.
K. Simosky, A. C. Bragat, J. P. Castelli, E. R. Benjamin, P. F. Boudes.
Mol. Genet. Metab. 2013, 109, 86-92. b) A. Markham. Drugs 2016, 76,
1147-1152.
[23] For the preparation of aldehydes 2b, 2d, 2e, 2f and 2h, see Supporting
information.
[24] a) U. C. Dyer, J. A. Robinson, J. Chem. Soc. Perkin Trans. 1 1988, 53-
60; b) R. W. Hoffmann, U. Schopfer, G. Mller, T. Brand, Helv. Chim.
Acta 2002, 85, 4424-4441.
[21] a) F. R. Heiker, A. M. Schueller, Carbohydr. Res. 1990, 203, 314-318.
b) A. Kato, N. Kato, E. Kano, I. Adachi, K. Ikeda, L. Yu, T. Okamoto, Y.
Banba, H. Ouchi, H. Takahata, N. Asano, J. Med. Chem. 2005, 48,
2036-2044.
[25] M. Trajkovic, Z. Ferjancic, R. N. Saicic, Synthesis, 2013, 45, 389-395.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701073
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Organocatalysis*
Jasna Marjanovic Trajkovic, Vesna
Milanovic, Zorana Ferjancic* and
Radomir N. Saicic*
Page No. – Page No.
Proline-catalyzed aldol additions of 2,2-dimethyl-1,3-dioxane-5-one to chiral
aldehydes proceed under reagent stereocontrol (in both matched and mismatched
cases) when aldehyde α-oxy or α-amino substituents are acyclic. For cyclic
substituents, the stereochemical outcome of the aldolization in mismatched cases is
difficult to predict.
On the asymmetric induction in
proline-catalyzed aldol reactions:
Reagent-controlled additions of 2,2-
dimethyl-1,3-dioxane-5-one to acyclic
chiral α-branched aldehydes
Title
This article is protected by copyright. All rights reserved.