New organocatalysts derived from tartaric and glyceric acids for direct aldol reactions

Article abstract of DOI:10.1016/j.tetasy.2012.08.008

The synthesis of several new pyrrolidine based asymmetric organocatalysts derived from tartaric, glyceric acids and a pyrrolidine moiety is described with a study of their application in the development of an enantioselective aldol protocol. The influence

Full text of DOI:10.1016/j.tetasy.2012.08.008

Tetrahedron: Asymmetry 23 (2012) 1262–1271
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Tetrahedron: Asymmetry
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New organocatalysts derived from tartaric and glyceric acids for direct
aldol reactions
Christopher D. Maycock a,b, M. Rita Ventura a,
⇑
a Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Apartado 127, 2780-901 Oeiras, Portugal
b Faculdade de Ciências da Universidade de Lisboa, Departamento de Química e Bioquímica, 1749-016 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2012
Accepted 14 August 2012
The synthesis of several new pyrrolidine based asymmetric organocatalysts derived from tartaric, gly-
ceric acids and a pyrrolidine moiety is described with a study of their application in the development
of an enantioselective aldol protocol. The influence of different proton donor groups, such as a primary
hydroxyl or a carboxylic acid group, or their absence, on the efficiency of the organocatalyst was studied.
The configuration of the tartrate derived catalysts and the presence of the rigid butane-2,3-diacetal were
found to have a strong influence on the stereoselective outcome of the aldol reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
such as the configuration of an additional stereogenic centre or the
presence of a hydroxyl or amino group at the b-position relative to
The aldol reaction is one of the most important carbon–carbon
bond-forming reactions in organic synthesis, and since the work of
List and Barbas et al., L-proline and its structural derivatives have
the amide nitrogen, than on amide acidities.
We considered that although several simple proline derived
compounds have been shown to be excellent organocatalysts,3
the addition of extra chirality and suitably positioned participating
functional groups can also create new effective organocatalysts
been extensively evaluated for their use in the organocatalysed
asymmetric variant of this reaction.1,2 The high enantioselectivity
of proline mediated reactions can be attributed to their capacity
to promote the formation of highly organised transition states with
extensive hydrogen bonding networks. Proline is regarded as a
bifunctional catalyst, since it not only acts as an enamine catalyst
but also brings along its own Brønsted acid cocatalyst.2 Moreover
in some organocatalysed transformations, an acid additive is often
needed.1,10 The pKa value of proline is essential to the enamine
mechanism of class I aldolase enzymes and the same has been
found for proline catalysed aldol reactions.4 In some examples,
an acid is not needed,5 but generally in these cases the catalyst is
designed to induce high enantioselectivities by controlling the
geometry of the enamine and through efficient face shielding.
(Fig. 1). (S)-Binam-L-prolinamides, in combination with benzoic
acid, have recently been reported as catalysts for the aldol reac-
tions between cycloalkyl, alkyl and
a-functionalised ketones and
aldehydes under solvent-free reaction conditions.10 In these stud-
ies, 10 mol % of catalyst required 5 mol % of benzoic acid.
L-Proline amide organocatalysts derived from tartaric acid have
already been described (Fig. 2).9 The most important features
recognised for the efficiency of these organocatalysts in the direct
aldol reaction between 4-nitrobenzaldehyde and several ketones,
with ee’s ranging from 93% to >99%, were the electron-withdraw-
ing ester groups and the presence of a free hydroxyl group in the
catalyst structure. Rotational isomers are possible in this linear
structure and this aspect could complicate the transition state con-
formations and intramolecular interactions. Tartaric and glyceric
acids can be easily converted into their rigid and stereo-defined
bis-acetals having, in the case of the bifunctional tartaric acid
derivatives, the possibility of remote acidic (protonating) or hydro-
gen bonding functional groups. This rigidity combined with a
pyrrolidine ring could provide a structure with catalytic activity
via enamine and/or iminium intermediates. The chiral bis-acetal
provides additional stereocenters, which have been shown to
induce enhanced stereoselectivity in several reactions.7,8 The selec-
tive desymmetrisation of the carboxyl groups of 8 allows the
formation of difunctional molecules in enantiomerically pure form.
The presence of this rigid moiety in the organocatalyst structure
2. Results and discussion
A study on the acidities of proline amide derivatives in DMSO
and their influence on the stereoselectivity was recently reported.6
An increase in amide acidity can contribute to an enhancement of
enantioselectivity, this effect results from the formation of stronger
hydrogen bonding and a tighter transition state. However, when
the acidity of the amide varies within a relatively narrow scale,
the enantioselectivity seems to depend more on structural features
⇑
Corresponding author.
E-mail address: rventura@itqb.unl.pt (M. Rita Ventura).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.08.008

C. D. Maycock, M. Rita Ventura / Tetrahedron: Asymmetry 23 (2012) 1262–1271
1263
OH
OH
O
O
O
O
CO2H
NH
O
O
MeO
MeO
MeO
MeO
MeO
MeO
H
N
H
N
N
N
N
H
H
O
O
H
O
O
2
3
1
O
O
H
O
H
N
O
O
CO2H
NH
MeO
MeO
O
O
MeO
MeO
N
O
N
H
N
N
H
OMe
H
O
O
OH
4
6
5
O
O
NH
MeO
MeO
N
H
7
Figure 1. New organocatalysts from L- and D-tartaric acid and glyceric acid.
Tempo/BAIB reagent combination in 84% yield. Removal of the
O
Cbz group afforded catalyst 2 (Scheme 1).
R1
Starting from the D
-tartrate derivative 1512,13 and following the
R2
same synthetic strategy described in Scheme 1, amine 16 was ob-
tained in excellent overall yield (49%). Coupling with Cbz-proline
produced amide 17, a diastereoisomer of 12, in 88% yield, which
after removal of the protecting groups afforded catalyst 3. Cleavage
of the silyl group and oxidation of the free alcohol with Tempo/
BAIB furnished the corresponding carboxylic acid in 96% yield. Fi-
nally, hydrogenolysis of the CBz group afforded catalyst 4 in 93%
yield (Scheme 2).
N
H
N
OH
H
R1=R2=Ph, c-C6H11, CO2Et
Figure 2. Gong’s catalysts.9
The cis-catalyst 5, was prepared from dithioester 18,12 obtained
from 8, as was described for the dimethyl tartrate 8.14 Oxidation of
18 by treatment with LDA in THF at ꢀ78 °C followed by the addi-
tion of 1 equiv of iodine afforded 19 in 82% yield (Scheme 3). Per-
haps due to the presence of sulfur, the hydrogenation of the double
bond to afford the cis-product was not successful. Reduction of the
dithioester to afford the primary diol was attempted, however this
reaction afforded a complex mixture.
should confer more organised and less spatially flexible transition
states during the catalytic cycle, and thus favour the stereoselec-
tive outcome of the aldol reaction.
These rigid tartrate structures were coupled to a proline to form
seven candidate catalysts 1–6 (Fig. 1), which were screened for dia-
stereo- and enantioselectivity in aldol reactions with aromatic alde-
hydes. The analogous glycerate 7 was also prepared and screened.
The presence of a proton donor, such as a hydroxyl or a carboxylic
acid on the tartrate derivatives, and their absence, as in glycerate
catalyst 7 and cyclised catalyst 6, also provided an opportunity to
determine the importance of appended acidic groups.
Catalysts 1 and 2 were obtained from dimethyl (2R,3R,5R,6R)-
dimethoxy-2,3-dimethyl-1,4-dioxane-5,6-dicarboxylate 8, which
was easily obtained from tartaric acid.11,12 These compounds were
stable and the reactions involved in their synthesis afforded high
yields.
The reduction of bis-acetal 8 with lithium aluminium hydride
afforded the corresponding diol (98%), which was monosilylated
in 89% yield.12 Tosylation of the free hydroxyl group afforded 9
and substitution of the resulting tosyl group with sodium azide
furnished azide 10 quantitatively. Amine 11 was obtained in 88%
yield by catalytic hydrogenation of azide 10 with hydrogen and
Pd/C, and immediately coupled with carboxybenzyl protected pro-
line, using EDC, HOBt and triethylamine in dichloromethane, to af-
ford proline amide 13 in excellent yield (90%). Hydrolysis of the
silyl group with TBAF in THF, followed by hydrogenolysis of the
Cbz amine protecting group afforded catalyst 1 in excellent yield.
In order to obtain catalyst 2, the primary hydroxyl group was effi-
ciently oxidised into the corresponding carboxylic acid with the
Isomerisation to cis-dithioester 21 was performed via the for-
mation of the enolate and reprotonation with methanol, to afford
an inseparable mixture of 1.6:1 cis/trans isomers 21:18 (Scheme 4).
Interestingly, sodium borohydride was able to selectively reduce
the trans-isomer to the corresponding diol, and after a facile chro-
matographic separation, the pure cis-dithioester 21 was obtained.
The trans-diol was recycled for the synthesis of organocatalysts 1
and 2 (Scheme 1). However, all attempts to reduce 21 with lithium
aluminium hydride and DIBAL-H were unsuccessful, and complex
mixtures were obtained. Transesterification with isopropanol and
titanium tetraisopropoxide afforded the corresponding diisopropyl
ester 22 in 82% yield (Scheme 5). This reaction took 10 days at
100 °C and required 2 equiv of titanium tetraisopropoxide; if less
time was allowed then one of the two possible monoisopropyl es-
ters was also recovered. Compared with the method to obtain the
corresponding dimethyl meso-tartrate from 8,14 one more step is
required. However this step avoids the 5d hydrogenation at very
high pressure (80 bar) with high catalyst loading (20% of Rh-
Al2O3). Isomerisation of 21 with DBU was studied in CDCl3 and
we demonstrated that enolate was formed because it was deuter-
ated by H/D exchange from the solvent to afford the trans-deuter-
ated isomer 20 (Scheme 4).

1264
C. D. Maycock, M. Rita Ventura / Tetrahedron: Asymmetry 23 (2012) 1262–1271
O
OTBDMS
N3
O
OTBDMS
OTs
O
CO2Me
CO2Me
MeO
MeO
MeO
MeO
MeO
MeO
d
a-c
74%
99%
O
O
O
10
8
9
OTBDMS
O
O
O
OTBDMS
NH2
g
MeO
MeO
MeO
H
N
f
e
85%
90%
88%
N
MeO
O
Cbz
O
12
11
OH
OH
O
O
O
O
MeO
MeO
MeO
h
H
N
H
N
91%
N
N
MeO
H
Cbz
1
13
O
O
i, 84%
O
O
O
CO2H
NH
CO2H
NH
MeO
MeO
MeO
MeO
h
97%
N
N
O
H
Cbz
O
O
2
14
Scheme 1. (a) LiAlH4, THF, 0 °C/rt, 98%. (b) (1) NaH, THF, rt; (2) TBDMSCl, 89%. (c) TsCl, pyr, DMAP, 0 °C/rt, 85%. (d) NaN3, DMF, 70 °C. (e) H2, Pd/C 10%, AcOEt/EtOH, 50 psi. (f)
-Pro-Cbz, HOBt, EDC, Et3N, CH2Cl2, 0 °C/rt. (g) TBAF, THF, rt. (h) H2, Pd/C 10%, MeOH, 50 psi. (i) BAIB/Tempo, CH2Cl2/H2O.
L
OTBDMS
O
CO2Me
CO2Me
O
O
O
OTBDMS
NH2
MeO
MeO
MeO
MeO
MeO
MeO
H
N
a - e
49%
f
N
88%
O
O
Cbz
O
16
15
17
g, h
87%
g, i, h 87%
OH
O
O
O
O
CO2H
NH
MeO
MeO
MeO
MeO
H
N
N
N
H
O
H
O
4
3
Scheme 2. (a) LiAlH4, THF, 0 °C/rt, 81%. (b) (1) NaH, THF, rt; (2) TBDMSCl, 85%. (c) TsCl, pyr, DMAP, 0 °C/rt, 80%. (d) NaN3, DMF, 70 °C, 99%. (e) H2, 10%, AcOEt/EtOH, 50 psi, 90%.
(f) -Pro-Cbz, HOBt, EDC, Et3N, CH2Cl2, 0 °C/rt. (g) TBAF, THF, rt, 97%. (h) H2, Pd/C 10%, MeOH, 50 psi and 93%. (i) BAIB/Tempo, CH2Cl2/H2O, rt, 96%.
L
Reduction of 22 with lithium aluminium hydride afforded the
even after heating the reaction mixture for several days. Fortu-
cis-diol in excellent yield (96%, Scheme 5). Treatment of the cis-diol
with TBDMSCl and NaH, in THF and pentane15,16 afforded the axial
silyl ether with high selectivity (60% yield). Without the use of pen-
tane as the co-solvent, a lower selectivity of 5:1 was obtained,
although the yield was higher. Attempts to silylate the equatorial
hydroxyl group with TBDMSCl and imidazole in THF were unsuc-
cessful,15,17 and the silylated product of alcohol 28 was obtained
as the major product.
nately, the Mitsunobu reaction with hydrazoic acid on the mono
alcohol rapidly afforded the desired azide 23 in very good yield
(84%). The final steps afforded the expected products in excellent
yields and the new compound 5 was obtained (Scheme 5). In order
to prepare the corresponding carboxylic acid, the oxidation of the
primary hydroxyl group of CBz protected 5 with TEMPO/BAIB
was attempted; however a complex mixture was obtained. Organ-
ocatalyst 7 was readily prepared from glyceric acid methyl ester8
as described in Scheme 6.
The synthesis of 5 used the same sequence of steps as for the
synthesis of 1; however the treatment of the corresponding tosy-
lated cis-analogue of 9 with sodium azide did not afford azide 23,
Finally, organocatalyst 6 was prepared from the bicyclic prod-
uct15 28 with all of the steps being straightforward (Scheme 7).

C. D. Maycock, M. Rita Ventura / Tetrahedron: Asymmetry 23 (2012) 1262–1271
1265
O
O
MeO
MeO
O
COSEt
COSEt
O
COSEt
COSEt
OH
OH
b
MeO
MeO
MeO
MeO
a
X
82%
O
O
19
18
c
d
X
O
O
COSEt
COSEt
MeO
MeO
X
O
O
CHO
CHO
MeO
MeO
Scheme 3. (a) (1) LDA, ꢀ78 °C; (2) I2. (b) LiAlH4, THF, rt/NaBH4, MeOH, rt. (c) Rh/C 5%, MeOH, H2 80 atm. (d) DIBAL-H, THF, ꢀ78 °C.
O
COSEt
COSEt
O
O
COSEt
COSEt
MeO
MeO
MeO
MeO
a
b
21
+
trans diol
+
18
98%
O
c
quant.
18
21
1.6:1
D
O
COSEt
COSEt
MeO
MeO
O
D
20
Scheme 4. (a) (1) LDA, THF, ꢀ78 °C; (2) MeOH. (b) NaBH4, MeOH, 0 °C/rt. (c) DBU, CDCl3, rt, 48 h.
O
CO2iPr
CO2iPr
O
N3
MeO
MeO
MeO
MeO
e
a
b-d
21
48%
82%
99%
O
O
OTBDMS
23
22
O
Cbz
O
O
NH2
MeO
MeO
O
MeO
N
g, h
f
N
H
81%
97%
MeO
OTBDMS
O
24
OTBDMS
25
O
H
MeO
MeO
O
N
N
H
O
OH
5
Scheme 5. (a) Ti(OiPr)4 (2 eq), iPrOH, 10 °C, 10 days, 82%. (b) LiAlH4, THF, 70 °C, 96%. (c) (1) NaH, THF, pentane, rt; (2) TBDPSCl, rt, 60%. (d) HN3, PPh3, DIAD, THF, 0 °C, 84%. (e)
H2, Pd/C 10%, AcOEt/EtOH, 50 psi. (f) -Pro-Cbz, HOBt, EDC, Et3N, CH2Cl2, 0 °C/rt. (g) TBAF, THF, rt, 98%. (h) H2, Pd/C 10%, MeOH, 50 psi, 99%.
L
The scope and limitations of catalysts 1–7 were then examined
in the aldol reaction of several substituted aromatic aldehydes
with acetone, cyclopentanone and cyclohexanone (Tables 1–3).
Analysis of Tables 1–3, allowed us to conclude that the best
results were obtained with cyclic ketones, with ee’s of up to 91%
(Table 2, entry 5, Table 3, entry 8) and dr of up to 3:97 (Table 2,
entry 11). We believe that the amide NH participated in the tran-
sition state, establishing a hydrogen bond with the aldehyde,9
and that the reaction proceeded through an enamine intermediate.
In Figure 3, a proposed transition state for the aldol reaction be-
tween cyclohexanone and 2-nitrobenzaldehyde catalysed by 3 is
shown. In general, 2-nitrobenzaldehyde afforded higher enantiose-
lectivities than 4-nitrobenzaldehyde, and this may be explained by
the formation of a hydrogen bond between the alcohol (or carbox-
ylic acid) group of the catalyst and the nitro group at the ortho-
position. With 4-nitrobenzaldehyde, the formation of the

1266
C. D. Maycock, M. Rita Ventura / Tetrahedron: Asymmetry 23 (2012) 1262–1271
O
H
N
O
CO2Me
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
NH2
a-d
e, f
N
H
85%
92%
O
O
26
27
7
Scheme 6. (a) LiAlH4, THF, 97%. (b) TsCl, Pyr, DMAP, 95%. (c) NaN3, DMF, 70 °C, 93%. (d) H2, Pd/C 10%, AcOEt/EtOH, 50 psi, 99%. (e)
L-Pro-CBz, HOBt, EDC, Et3N, CH2Cl2, 93%. (f)
H2, Pd/C 10%, MeOH, 50 psi, 99%.
O
O
O
O
H
O
O
d, e
N
a-c
O
O
N
H
O
O
HO
H2N
82%
78%
OMe
OMe
OMe
6
28
29
Scheme 7. (a) TsCl, pyr, DMAP, 0 °C/rt, 87%. (b) NaN3, DMF, 70 °C, 90%. (c) H2, Pd/C 10%, AcOEt/EtOH, 50 psi, 99%. (d) L-Pro-CBz, HOBt, EDC, Et3N, CH2Cl2, 0 °C/rt, 83%. (e) H2,
Pd/C 10%, MeOH, 50 psi, 99%.
Table 1
Aldol reaction of various 2- and 4-substituted benzaldehydes with acetone catalysed by pyrrolidines 1–7
O
OH
O
O
0.1eq Cat.
+
H
r.t.
R
R
Entry
Catalyst
R
Time (h)
Yield (%)
eea (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
1
2
3
4
5
6
7
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
48
48
106
24
48
26
48
48
48
106
48
10
76
8
48
25
—
69
30
21
—
61
40
42
74
39
21
43
43
55
55
66b
19
70
19
80
64
53
42
9
10
11
12
13
14
48
26
48
a
Determined by HPLC on a chiralpak AD-H column. Entries 1–7: flow 0.8 mL/min, k = 254 nm, iPrOH/hexane = 1:9, tR (major) = 20.5 min (R), tR (minor) = 21.7 min (S).18
Entries 8–14: flow 0.8 mL/min, k = 254 nm, iPrOH/hexane = 0.5:9.5, tR (major) = 33.0 min (R), tR (minor) = 34.7 min (S).19
b
The elimination product was obtained.
corresponding hydrogen bond is very unlikely. The rigid acetal
structure constrains the positions of the substituents at the tartrate
carbons 2 and 3 since no rotation around the bond between these
two carbons is allowed, and the conformation of the six membered
ring of the acetal also imposes strong limitations on the position of
the hydroxymethyl and the prolinamidemethyl groups.
Catalyst 1 afforded very good enantioselectivities in the aldol
reactions of cyclohexanone with 2-nitrobenzaldehyde (ee 89%, Ta-
ble 2, entry 8), and of cyclopentanone with the same aldehyde (ee
91% for the anti-isomer, Table 3, entry 8). Catalyst 5, with a cis-ori-
entation of the hydroxyl group and the amide bond of proline, was
not generally a better catalyst than the trans one, however it was a
very efficient catalyst for the aldol reaction between cyclohexa-
none and 4-nitrobenzaldehyde, affording 81% of a mixture of syn-
and anti-diastereoisomers with an ee of 91% for the anti-isomer
(Table 2, entry 5).
In general, catalysts 1, 3 and 6 were the best ones for the aldol
reactions with cyclopentanone with each aldehyde tested (Table 3).
Catalysts 6 and 7 did not possess an extra proton donor group nor
an additional stereogenic centre, however compound 7 was a very
good catalyst for the reaction between 4-nitrobenzaldehyde and
cyclopentanone (82% yield, ee 81% for the syn-isomer, Table 3, en-
try 7), and also for the same reaction employing 2-nitrobenzalde-
hyde (Table 3, entry 14). This same catalyst afforded exclusively
the elimination product in the aldol reaction between acetone
and 4-nitrobenzaldehyde (66% yield, Table 1, entry 7).
Some aldehydes were better substrates than others, 2-nitro-
benzaldehyde afforded the best results, followed by 4-nitrobenzal-
dehyde. The addition of additives had different effects, acetic acid
improved the yields of most of the reactions catalysed by 1 and
3. The addition of TFA did not cause any significant improvements,
while the use of DMSO as a co-solvent, which improves the yield of

C. D. Maycock, M. Rita Ventura / Tetrahedron: Asymmetry 23 (2012) 1262–1271
1267
Table 2
Aldol reaction of various 2- and 4-substituted benzaldehydes with cyclohexanone catalysed by pyrrolidines 1–7
O
OH
O
O
0.1eq Cat.
+
H
r.t.
R
R
Entry
Catalyst
R
Time (h)
Yield (%)
dra (syn:anti %)
eeb (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
1
2
3
4
5
6
7
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
48
43
90
20
48
22
48
44
43
90
48
48
72
48
49
51
49
25
81
42
44
51
43
40
76
54
38
53
37:63
14:86
23:77
29:71
31:67
42:58
43:57
18:82
13:87
10:90
3:97
22/54
10/46
5/84
29/65
11/91
11/58
28/34
—/89
77/27
—/87
—/79
10/37
84/26
72/85
9
10
11
12
13
14
37:63
36:54
28:72
a
Determined from the crude 1H NMR spectrum.
Determined by HPLC on a chiralpak AD-H column. Entries 1–7: flow 0.8 mL/min, k = 254 nm, iPrOH/hexane = 1:9, syn isomers: tR = 23.8 min, tR = 26.7 min, anti isomers: tR
b
(minor) = 29.3 min (2S,10R) tR (major) = 39.7 min (2R,10S).18,20 Entries 8–14: flow 1 mL/min, k = 254 nm, iPrOH/hexane = 0.5:9.5, syn isomers: tR (major) = 29.7 min, tR
(minor) = 30.9 min, anti isomers: tR (major) = 51.2 min (2S,10R), tR (minor) = 55.6 min (2R,10S).18,20
Table 3
Aldol reaction of various 2- and 4-substituted benzaldehydes with cyclopentanone catalysed by pyrrolidines 1–7
O
OH
O
O
0.1eq Cat.
r.t.
+
H
R
R
Entry
Catalyst
R
Time (h)
Yield (%)
dra (syn:anti %)
eeb (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
1
2
3
4
5
6
7
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
46
46
46
46
48
46
46
47
46
47
47
48
48
46
58
36
47
36
41
21
82
19
40
10
10
37
17
48
61:39
70:30
66:34
70:30
52:48
63:37
61:39
75:25
76:24
74:26
55:45
77:23
78:22
67:33
54/61
10/41
43/80
14/28
34/13
1/0.3
49/81
70/91
26/46
61/85
9/16
9
10
11
12
13
14
10/37
2/18
63/85
a
Determined from the crude 1H NMR spectrum.
Determined by HPLC on a chiralpak AD-H column. Entries 1–7: flow 0.8 mL/min, k = 254 nm, iPrOH/hexane = 1:9, syn isomers: tR (major) = 18.2 min, tR (minor) = 23.5 min,
b
anti isomers: tR (minor) = 30.3 min (2S,10R), tR (major) = 31.7 min (2R,10S).20 Entries 8–14: flow 1 mL/min, k = 254 nm, iPrOH/hexane = 0.5:9.5, syn isomers: tR
(major) = 11.7 min, tR (minor) = 20.1 min, anti isomers: tR (major) = 26.6 min, tR (minor) = 29.2 min.21–23
-proline catalysed aldol reactions,24 also did not have any effect
H
L
O
O
with our organocatalysts. Performing the reactions at lower tem-
peratures, that is, ꢀ20 °C, with catalyst 2, reduced the yield and
ee of the aldol reaction between acetone and 2- and 4-
nitrobenzaldehyde.
N
O
O
MeO
N
3. Conclusion
H
O
N
O
OH
MeO
We can conclude that the configuration of the tartrate has a rel-
evant influence on the stereochemistry of the aldol reaction and
the presence of the proton donor group was also important for
the stereocontrol. None of the catalysts were generally applicable
Figure 3. Proposed transition state for the aldol reaction of 2-nitrobenzaldehyde
with cyclohexanone catalysed by 3.

1268
C. D. Maycock, M. Rita Ventura / Tetrahedron: Asymmetry 23 (2012) 1262–1271
but they were very good catalysts for particular aldol reactions
although highly dependent on the substrate structure, both the
aldehyde and the ketone. We think that this is a consequence of
the conformational rigidity conferred by the chiral dioxane acetal.
This could be an important feature for the development of new
selective organocatalysts requiring precise tuning of the configura-
tion of the substituents on tartrate, the choice of the proton donor
group and the configuration of the proline, the latter of which was
not studied herein. Future work involving detailed theoretical
studies of the possible transition states for the reactions presented,
and the application of these new organocatalysts in other reactions
is currently in progress.
sium sulfate and the solvents were evaporated under reduced
pressure to give compound 10 as a light yellow oil, (1.8 g, 99%).
½
a 2D0
ꢁ
¼ ꢀ45:5 (c 1.4, CH2Cl2). 1H NMR (CDCl3): d 3.86–3.79 (1H,
m), 3.66–3.60 (3H, m), 3.40–3.39 (2H, m), 3.54–3.49 (1H, m),
3.30 (3H, s), 3.26 (3H, s), 1.32 (3H, s), 1.27 (3H, s), 0.88 (9H, s),
0.06 (3H, s), 0.05 (3H, s). 13C NMR (CDCl3): d 98.7, 71.4, 69.7,
63.7, 50.9, 47.9, 25.8, 18.2, 17.5, 17.4, ꢀ5.45, 5.47. FT-IR (film):
2098 cmꢀ1. Anal. Calcd for C16H33N3O5Si: C 51.17, H 8.86, N
11.19. Found: C 50.90, H 8.56, N 10.99.
4.4. (2R,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethyl-2-amino-
methyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-dioxane 11
4. Experimental
4.1. General
Azide 10 (1.2 g, 3.18 mmol) in AcOEt/EtOH (10 mL/10 mL) was
hydrogenated at 50 psi in the presence of a catalytic amount of
Pd/C 10% (0.25 equiv). After 3 h, the reaction mixture was filtered,
the solvent was evaporated and the residue dried under vacuum to
afford amine 11 as a viscous colourless oil (1.0 g, 88%). This mate-
rial was sufficiently pure to proceed with the next step.
1H NMR spectra were obtained at 400 MHz in CDCl3, DMSO-d6
or D2O with chemical shift values (d) in ppm downfield from tetra-
methylsilane in the case of CDCl3, and 13C NMR spectra were ob-
tained at 100.61 MHz in CDCl3, DMSO-d6 or D2O. Assignments
are supported by 2D correlation NMR studies. Medium pressure
preparative column chromatography: silica gel Merck 60 H. Ana-
lytical TLC: Aluminium-backed silica gel Merck 60 F254. Specific
½
a 2D0
ꢁ
¼ ꢀ98:1 (c 0.80, CH2Cl2). 1H NMR (CDCl3): d 3.70–3.59 (3H,
m), 3.20 (6H, s), 2.88–2.72 (2H, m), 1.32 (3H, s), 1.30 (3H, s), 0.88
(9H, s), 0.06 (6H, s). 13C NMR (CDCl3): d 98.6, 98.4, 72.3, 70.6,
63.7, 47.8, 47.7, 42.7, 25.8, 18.2, 17.6, 17.5, ꢀ5.44, ꢀ5.47. FT-IR
(film): 3690, 1265 cmꢀ1. HR-MS: Calcd for C16H36O5NSi [M++H]:
350.2357. Found: 350.2365.
rotations (½a 2D0
ꢁ
) were measured using an automatic polarimeter.
Reagents and solvents were purified and dried according to the lit-
erature.25 All reactions were carried out under an inert atmosphere
(argon), except when the solvents were undried. The enantiomeric
excesses were determined by HPLC on a Waters 600E/U6K instru-
ment using a Daicel Chiralpack AD-H column.
4.5. (2S)-N-Benzyloxycarbonylprolinyl-[(2R,3R,5R,6R)-3-tert-
butyldimethylsilyloxymethyl-2-aminomethyl-5,6-dimethoxy-
5,6-dimethyl-[1,4]-dioxane]-amide 12
To
a solution of N-benzyloxycarbonyl-L-proline (0.688 g,
4.2. (2R,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethyl-2-p-tol-
uenesulfonyloxymethyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-
dioxane 9
2.76 mmol) in dichloromethane (8 mL) was added 11, EDC
(0.635 g, 3.32 mmol), HOBt (0.448 g, 3.32 mmol) and Et3N
(0.46 mL, 3.32 mmol) at 0 °C. The reaction mixture was stirred at
room temperature for 2 h, after which water was added and the
aqueous layer was extracted with ethyl acetate (3 ꢂ 10 mL), dried
over anhydrous magnesium sulfate and concentrated. The residue
was purified through flash column chromatography on silica gel
with hexane-ethyl acetate (5:5) to afford 12 as a colourless viscous
To a solution of (2R,3R,5R,6R)-3-tert-butyldimethylsilyloxym-
ethyl-2-hydroxymethyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-diox-
ane (2.38 g, 6.8 mol) in pyridine (10 mL) at 0 °C, was added
p-toluenesulfonyl chloride (1.94 g, 10.2 mmol) and a catalytic
quantity of DMAP and the mixture was stirred for 20 h at rt. The
mixture was then washed with a solution NaHCO3 (sat) and
extracted with ethyl ether (3 ꢂ 10 mL). The combined organic
phases were dried over anhydrous magnesium sulfate, filtered,
and concentrated to afford a light yellow oil. The crude product
was subjected to flash column chromatography on silica gel (2/8
AcOEt/hexane) to afford the pure product 9 (2.8 g, 85%) as colour-
oil (1.44 g, 90%). ½a D20
ꢁ
¼ ꢀ109:8 (c 0.51, CH2Cl2). 1H NMR (CDCl3): d
7.57–7.44 (5H, m), 5.18 (1H, dd, J = 12.2 Hz, J = 2.0 Hz), 5.02 (1H,
dd, J = 18.9 Hz, J = 12.2 Hz), 3.90–3.88 (1H, m), 3.74–3.38 (6H, m),
3.30 (3H, s), 3.27 (3H, s), 3.09–3.01 (1H, m), 2.34–2.31 (1H, m),
1.98–1.88 (3H, m), 1.32 (3H, s), 1.30 (3H, s), 0.88 (9H, s), 0.06
(3H, s), 0.05 (3H, s). 13C NMR (CDCl3): d 171.5, 156.0, 136.0,
128.7, 128.1, 127.9, 98.6, 98.5, 71.0, 69.1, 67.4, 63.4, 60.8, 48.2,
47.1, 39.6, 28.7, 25.9, 24.4, 18.4, 17.6, 17.5, ꢀ5.2, ꢀ5.3. FT-IR (film):
1706, 1687 cmꢀ1. HR-MS: Calcd for C29H48O8N2SiNa [M++Na]:
603.3072. Found: 603.3069.
less oil. ½a 2D0
ꢁ
¼ ꢀ80:2 (c 0.56, CH2Cl2). 1H NMR (CDCl3): d 7.78 (2H,
d, J = 8.3 Hz), 7.31 (2H, d, J = 8.0 Hz), 4.39 (1H, dd, J = 10.8 Hz,
J = 2.4 Hz), 4.01 (1H, dd, J = 10.8 Hz, J = 7.6 Hz), 3.91–3.86 (1H, m),
3.60 (2H, d, J = 5.2 Hz), 3.54–3.49 (1H, m), 3.21 (3H, s), 3.18 (3H,
s), 2.44 (3H, s), 1.23 (3H, s), 1.20 (3H, s), 0.85 (9H, s), 0.039 (3H,
s), 0.027 (3H, s). 13C NMR (CDCl3): d 144.6, 133.2, 129.7, 128.0,
98.7, 98.5, 69.5, 69.4, 68.9, 63.3, 47.9, 47.8, 25.7, 21.6, 18.1, 17.4,
17.3, ꢀ5.52, ꢀ5.55. FT-IR (film): 2954, 2930, 1265 cmꢀ1. Anal.
Calcd for C23H40O8SSi: C 54.73, H 7.99, S 6.35. Found: C 54.40, H
7.69, S 6.30.
4.6. (2S)-N-Benzyloxycarbonylprolinyl-[(2R,3R,5R,6R)-3-hydr-
oxymethyl-2-aminomethyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-
dioxane]-amide 13
To a solution of compound 12 (0.914 g, 1.6 mmol) in THF (5 mL)
was added tetrabutylammonium fluoride 1 M in THF (0.49 mL,
1.9 mmol). The reaction mixture was stirred at room temperature
for 1 h, after which 5 mL of water was added. The mixture was then
extracted with ethyl acetate (3 ꢂ 10 mL), and the combined organ-
ic layers were dried over anhydrous magnesium sulfate. After re-
moval of solvent, the residue was purified by flash column
chromatography on silica gel (1/9 AcOEt/hexane) to afford the pure
4.3. (2R,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethyl-2-azido-
methyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-dioxane 10
To a solution of 9 (2.5 g, 4.9 mmol) in DMF (10 mL) was added
sodium azide (0.348 g, 5.4 mmol) at room temperature. The mix-
ture was stirred during 18 h at 70 °C, after which the mixture
was washed with water and extracted with ethyl acetate
(3 ꢂ 10 mL). The organic phase was dried over anhydrous magne-
product 13 (0.63 g, 86%) as a viscous colourless oil. ½a D20
¼ ꢀ85:4 (c
ꢁ
0.32, CH2Cl2). 1H NMR (CDCl3): d 7.35–7.10 (5H, m), 5.20–5.07 (1H,
m), 4.38–4.35 (1H, m), 3.78–3.43 (8H, m), 3.23 (3H, s), 3.20 (3H, s),

C. D. Maycock, M. Rita Ventura / Tetrahedron: Asymmetry 23 (2012) 1262–1271
1269
2.32–2.27 (1H, m), 2.04–1.91 (3H, m), 1.29 (6H, broad s). 13C NMR
4.10. (2S)-N-Benzyloxycarbonylprolinyl-[(2S,3S,5S,6S)-3-tert-
(CDCl3): d 169.1, 156.0, 136.3, 128.6, 128.2, 127.9, 98.7, 69.9, 67.8,
butyldimethylsilyloxymethyl-2-aminomethyl-5,6-dimethoxy-
5,6-dimethyl-[1,4]-dioxane]-amide 17
67.3, 62.3, 60.7, 47.9, 47.8, 47.0, 39.7, 28.7, 24.4, 17.5, 17.4. FT-IR
(film): 3440, 3264, 1701, 1681 cmꢀ1
. MS (ESI): m/z 405
[M+ꢀ2xOMe]. HR-MS: Calcd for C23H34O8N2Na [M++Na]:
Starting from amine 16 (0.556 g, 2.23 mmol) the same proce-
dure for obtaining 12 was followed and afforded 1.23 g (88%) of
489.2207. Found: 489.2217.
17 as a viscous oil. ½a D20
ꢁ
¼ þ30:4 (c 0.85, CH2Cl2). 1H NMR (CDCl3):
d 7.34 (5H, broad s), 5.18–5.09 (1H, m), 4.38–4.34 (1H, m), 3.74–
3.42 (7H, m), 3.25 (3H, s), 3.17 (3H, s), 3.15–3.10 (1H, m), 2.33–
2.31 (1H, m), 1.98–1.89 (3H, m), 1.28 (3H, s), 1.27 (3H, s), 0.89
(9H, s), 0.08 (3H, s), 0.07 (3H, s). 13C NMR (CDCl3): d 172.1, 136.3,
128.6, 128.2, 127.8, 98.6, 98.5, 70.9, 68.9, 67.2, 63.4, 60.7, 47.9,
47.6, 46.9, 39.9, 28.6, 25.8, 24.1, 18.2, 17.5, 17.4, ꢀ5.4, ꢀ5.3. FT-
IR (film): 1709, 1689 cmꢀ1. HR-MS: Calcd for C29H48O8N2SiNa
[M++Na]: 603.3072. Found: 603.3051.
4.7. (2S)-Prolinyl-[(2R,3R,5R,6R)-3-hydroxymethyl-2-amino-
methyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-dioxane]-amide 1
Alcohol 13 (0.63 g, 1.35 mmol) in MeOH (7 mL) was hydroge-
nated at 50 psi in the presence of a catalytic amount of Pd/C 10%
(0.25 equiv). After 3 h, the reaction mixture was filtered, the sol-
vent was evaporated and the residue dried under vacuum to afford
1 as a viscous colourless oil (0.430 g, 96%). ½a D20
¼ ꢀ157:3 (c 1.0,
ꢁ
CH2Cl2). 1H NMR (DMSO-d6): d 8.55 (1H, broad s), 4.12–5.07 (1H,
m), 3.55–3.48 (2H, m), 3.38–3.31 (3H, m), 3.10 (2H, broad s),
3.08 (3H, s), 3.07 (3H, s), 2.98–2.93 (1H, m), 2.23–2.18 (1H, m),
1.80–1.70 (3H, m), 1.12 (3H, s), 1.10 (3H, s). 13C NMR (DMSO-d6):
4.11. (2S)-Prolinyl-[(2S,3S,5S,6S)-3-hydroxymethyl-2-amino-
methyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-dioxane]-amide 3
Compound 17 (0.321 g, 0.561 mmol) after the removal of the
protecting groups following the same procedure for obtaining 1
d
168.5, 98.0, 97.9, 70.5, 68.3, 60.9, 58.7, 47.2, 47.1, 45.4,
39.0, 29.8, 23.7, 17.4, 17.39. FT-IR (film): 3388, 1677 cmꢀ1. HR-
MS: Calcd for C9H17O4N2Na [M+ꢀC6H11+Na]: 240.1086. Found:
240.1588.
afforded 0.160 g (87%,
2
steps) of
3
as
a
viscous oil.
½
a 2D0
ꢁ
¼ þ109:0 (c 0.3, CH2Cl2). 1H NMR (DMSO-d6): d 8.53 (1H,
broad s), 4.12–4.09 (1H, m), 3.66–3.62 (1H, m), 3.48–3.17 (7H,
m), 3.14 (6H, s), 2.26–2.23 (1H, m), 1.87–1.78 (3H, m), 1.19 (3H,
s), 1.18 (3H, s). 13C NMR (DMSO-d6): d 168.9, 98.0, 97.9, 70.5,
68.1, 60.9, 58.9, 47.3, 47.2, 45.6, 39.0, 29.9, 23.8, 17.4, 17.3. FT-
IR (film): 3353, 1658 cmꢀ1. MS (ESI): m/z 331 [M+ꢀH]. HR-MS:
Calcd for C9H17O4N2Na [M+ꢀC6H11+Na]: 240.1086. Found:
240.1321.
4.8. (2S)-N-Benzyloxycarbonylprolinyl-[(2R,3R,5R,6R)-3-hydr-
oxycarbonyl-2-aminomethyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-
dioxane]-amide 14
To compound 13 (0.63 g, 1.35 mmol) in dichloromethane (5 mL)
and water (2.5 mL) were added BAIB (1.08 g, 3.37 mmol) and Tem-
po (0.044 g, 0.83 mmol). The mixture was vigorously stirred at
room temperature for 3 h and then a 20% solution of Na2SO3
(5 mL) was added and the aqueous phase was extracted with ethyl
acetate (3 ꢂ 5 mL). The organic phase was then washed with sat.
aqueous NaHCO3 solution. The aqueous phase was washed with
ethyl ether and then acidified with HCl 10% to pH 3, and finally ex-
tracted with AcOEt (3 ꢂ 10 mL). The combined organic phases
were dried over anhydrous magnesium sulfate, filtered, and con-
centrated under reduced pressure to give the corresponding prod-
4.12. (2S)-N-Prolinyl-[(2S,3S,5S,6S)-3-hydroxycarbonyl-2-amino-
methyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-dioxane]-amide 4
Compound 17 (0.349 g, 0.61 mmol), following the same three
sequencing steps employed for obtaining catalyst 2, afforded
0.149 g (87%, 3 steps) of 4 as a viscous oil. ½a D20
¼ þ112:3 (c 0.26,
ꢁ
CH2Cl2). 1H NMR (D2O):
d 4.28–4.24 (1H, m), 3.87 (1H, d,
J = 10.3 Hz), 3.79–3.74 (1H, m), 3.45–3.43 (2H, m), 3.41–3.21 (2H,
m), 3.21 (3H, s), 3.18 (3H, s), 2.37–2.34 (1H, m), 2.00–1.94 (3H,
m), 1.25 (3H, s), 1.22 (3H, s). 13C NMR (D2O): d 174.6, 169.8, 99.1,
72.7, 68.2, 59.8, 47.9, 47.8, 46.4, 40.2, 29.8, 23.8, 16.8, 16.7. FT-IR
(film): 3434, 3246, 1674, 1607 cmꢀ1. MS (ESI): m/z 347 [M++H].
HR-MS: Calcd for C11H16O6N [M+ꢀC4H10NO]: 258.0978. Found:
258.1337.
uct 14 (0.560 g, 84%). ½a D20
ꢁ
¼ ꢀ84:2 (c 0.26, CH2Cl2). 1H NMR
(CDCl3): d 7.35 (5H, broad s), 5.22–5.09 (1H, m), 4.43–4.41 (1H,
m), 4.17–4.10 (1H, m), 3.91 (1H, broad s), 3.54–3.41 (4H, m),
3.23 (6H, s), 2.28–2.20 (1H, m), 2.03–1.92 (3H, m), 1.35 (6H, broad
s). 13C NMR (CDCl3): d 176.4, 170.1, 156.1, 136.1, 128.6, 128.2,
127.9, 99.1, 98.7, 69.7, 67.5, 67.2, 60.6, 48.3, 48.1, 47.1, 40.1,
28.8, 24.4, 17.3, 17.2. FT-IR (film): 3343, 1704, 1689 cmꢀ1. MS
(ESI): m/z 479 [M+ꢀH]. HR-MS: Calcd for C23H32O9N2Na [M++Na]:
503.2000. Found: 503.2008.
4.13. (2S,5R,6R)-2-Aminomethyl-5,6-dimethoxy-5,6-dimethyl-
[1,4]-dioxane 27
Compound 26 (2.07 g, 8.83 mmol), following the same
procedure to obtain compound 11, afforded 1.45 g of 27 (80% over-
4.9. (2S)-Prolinyl-[(2R,3R,5R,6R)-3-hydroxycarbonyl-2-amino-
methyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-dioxane]-amide 2
all yield for 4 steps) as a colourless oil. ½a D20
¼ ꢀ180:4 (c 0.36,
ꢁ
CH2Cl2). 1H NMR (CDCl3): d 3.91–3.85 (1H, m), 3.59 (1H, t,
J = 11.2 Hz), 3.45 (1H, dd, J = 11.2 Hz, J = 3.2 Hz), 3.30 (3H, s), 3.27
(3H, s), 2.76 (1H, dd, J = 13.0 Hz, J = 7.8 Hz), 2.68 (1H, dd,
J = 13.0 Hz, J = 4.0 Hz), 1.31 (3H, s), 1.30 (3H, s). 13C NMR (CDCl3):
d 98.9, 98.1, 69.0, 61.5, 48.0, 47.9, 42.9, 17.8, 17.5. FT-IR (film):
3384 cmꢀ1. HR-MS: Calcd for C9H20O4N [M++H]: 206.1387. Found:
206.1381.
Compound 14 (0.430 g, 0.89 mmol) in MeOH (6 mL) was hydro-
genated at 50 psi in the presence of a catalytic amount of Pd/C 10%
(0.25 equiv). After 3 h, the reaction mixture was filtered, the sol-
vent was evaporated and the residue dried under vacuum to afford
2 as a viscous colourless oil (0.310 g, 97%). ½a D20
¼ ꢀ131:1 (c 0.37,
ꢁ
CH2Cl2). 1H NMR (D2O):
d 4.30–4.27 (1H, m), 3.88 (1H, d,
J = 10.3 Hz), 3.77 (1H, ddd, J = 10.9 Hz, J = 7.6 Hz, J = 3.3 Hz),
3.36–3.24 (2H, m), 3.21 (4H, broad s), 3.18 (3H, s), 2.37–2.34
(1H, m), 2.00–1.92 (3H, m), 1.23 (3H, s), 1.25 (3H, s). 13C NMR
(D2O): d 174.7, 169.5, 99.1, 72.5, 68.2, 59.7, 47.8, 47.7, 46.4, 40.2,
29.7, 23.7, 16.8, 16.6. FT-IR (film): 3413, 1679, 1611 cmꢀ1. HR-
4.14. (2S)-Prolinyl-[(2S,5R,6R)-2-aminomethyl-5,6-dimethoxy-
5,6-dimethyl-[1,4]-dioxane]-amide 7
Amine 27 (0.507 g, 2.5 mmol), following the same reaction pro-
cedures to obtain 12 and 1, afforded 7 (0.656 g, 92% 2 steps) as a
MS: Calcd for
258.1285.
C
11H16O6N [M+ꢀC4H10NO]: 258.0978. Found:
colourless viscous oil. ½a D20
ꢁ
¼ ꢀ150:8 (c 0.80, CH2Cl2). 1H NMR

1270
C. D. Maycock, M. Rita Ventura / Tetrahedron: Asymmetry 23 (2012) 1262–1271
(CDCl3): d 7.97 (1H, broad s), 5.20–5.09 (2H, m), 3.97–3.92 (1H, m),
3.74 (1H, dd, J = 9.0 Hz, J = 5.0 Hz), 3.56 (1H, t, J = 11.2 Hz), 3.48–
3.37 (2H, m), 3.26 (3H, s), 3.24 (3H, s), 3.22–3.16 (1H, m), 3.03–
2.99 (1H, m), 2.93–2.89 (1H, m), 2.15–2.09 (1H, m), 1.95–1.89
(1H, m), 1.75–1.69 (2H, m), 1.30 (3H, s), 1.28 (3H, s). 13C NMR
(CDCl3): d 175.1, 99.1, 97.9, 66.5, 61.0, 60.6, 48.1, 48.0, 47.2, 39.2,
30.9, 26.1, 17.7, 17.5. FT-IR (film): 1733, 1686 cmꢀ1. MS (ESI): m/
z 302 [M+]. HR-MS: Calcd for C14H26O5N2K [M++K]: 341.1489.
Found: 341.2066.
(3H, s), 1.28 (3H, d, J = 6.6 Hz), 1.27 (3H, d, J = 2.9 Hz), 1.25 (3H,
d, J = 2.8 Hz), 1.21 (3H, J = 6.3 Hz). 13C NMR (CDCl3): d 168.5,
167.4, 100.6, 99.2, 69.2, 69.1, 68.5, 66.2, 50.3, 48.4, 21.8, 17.9,
17.6. FT-IR (film): 1739 cmꢀ1. Anal. Calcd for C16H28O8: C 55.16,
H 8.10. Found: C 54.79, H 8.23.
4.18. (2R,3S,5R,6R)-3-tert-Butyldimethylsilyloxymethyl-2-
azidomethyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-dioxane 23
To a solution of monoalcohol, derived from 22 after reduction to
the diol and monosylilation,15,16 (0.264 g, 0.75 mmol) in THF
(6 mL) at 0 °C were added triphenylphosphine (0.299 g, 1.1 mmol),
hydrazoic acid (1.6 M in benzene, 0.712 mL, 1.1 mmol) and DIAD
(0.220 mL, 1.1 mmol). The reaction mixture was then stirred at
rt. When all of the starting material had been consumed (TLC),
the solvent was evaporated and the residue was purified by med-
ium pressure column chromatography (2/8 AcOEt/hexane) to af-
4.15. (2S)-Prolinyl-[(1R,2S,4R,5R)-2-aminomethyl-4-methoxy-
4,5-dimethyl-3,6,8-trioxabicyclo[3.2.1]octane]-amide 6
From alcohol 28 (0.187 g, 0.922 mmol) catalyst 6 was obtained
as a colourless viscous oil (0.174 g, 64%, 5 steps) using the same
reaction sequence to obtain 1 and 7. ½a D20
¼ ꢀ103:7 (c 0.43, ace-
ꢁ
tone). 1H NMR (D2O): d 4.45 (1H, d, J = 5.3 Hz), 4.34–4.30 (1H,
m), 4.12 (1H, d, J = 7.9 Hz), 4.09–4.06 (1H, m), 3.78 (1H, d,
J = 7.7 Hz, J = 5.2 Hz), 3.44–3.31 (3H, m), 3.21 (3H, s), 2.11 (1H,
dd, J = 14.2 Hz, J = 8.2 Hz), 2.41–2.39 (1H, m), 2.02–1.92 (3H, m),
1.34 (3H, s), 1.24 (3H, s). 13C NMR (D2O): d 169.7, 106.6, 100.2,
75.5, 70.8, 64.1, 59.7, 48.1, 46.4, 39.2, 29.8, 23.7, 17.4, 17.3. FT-IR
ford azide 23 (0.237 g, 84%) as a colourless oil. ½a D20
¼ ꢀ26:1 (c
ꢁ
0.92, CH2Cl2). 1H NMR (CDCl3): d 4.34–4.30 (1H, m), 4.27 (1H, t,
H = 10.5 Hz), 3.60–3.54 (2H, m), 3.46 (1H, dd, J = 13.4 Hz,
J = 10.0 Hz), 3.34 (3H, s), 3.24 (3H, s), 3.19 (1H, dd, J = 13.4 Hz,
J = 2.5 Hz), 1.31 (3H, s), 1.27 (3H, s), 0.88 (9H, s), 0.06 (3H, s),
0.05 (3H, s). 13C NMR (CDCl3): d 99.7, 98.1, 73.0, 69.0, 61.8, 51.3,
49.3, 47.9, 25.8, 18.1, 18.0, 17.8, ꢀ5.4, ꢀ5.5. FT-IR (film):
2096 cmꢀ1. HR-MS: Calcd for C15H29O4N3SiNa [MꢀOMeꢀH+Na]+:
366.1825. Found: 366.1881.
(film): 1679 cmꢀ1
269.1501. Found: 269.1522.
.
HR-MS: Calcd for C13H21O4N2 [MꢀOMe]+:
4.16. (2R,3S,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-[1,4]-dioxane-
2,3-dicarbothioic acid di-S-ethyl ester 21
4.19. (2S)-N-Benzyloxycarbonylprolinyl-[(2R,3S,5R,6R)-3-tert-
butyldimethylsilyloxymethyl-2-aminomethyl-5,6-dimethoxy-
5,6-dimethyl-[1,4]-dioxane]-amide 25
To a solution of diisopropylamine (1.05 mL, 6.8 mmol) in THF
(5.3 mL) at 0 °C was slowly added BuLi (1.6 M in hexanes, 3.9 mL,
6.2 mmol). After 15 min, a solution of 188 (1 g, 2.8 mmol) in THF
(5 mL) was added at ꢀ78 °C. After 30 min at ꢀ78 °C, MeOH
(2.8 mL) was added. After 15 min, saturated aqueous NH4Cl solu-
tion (10 mL) was added and the aqueous layer extracted with
CH2Cl2 (3 ꢂ 8 mL). The organic phase was dried over anhydrous
MgSO4 and concentrated to afford a mixture of isomers 21 and
18 (1.6:1, 1 g, 99% yield) as a yellow oil. To a solution of this mix-
ture (1 g) in MeOH (8 mL) at 0 °C was added NaBH4 (0.171 g,
4.5 mmol) and the mixture was stirred at rt for 1 h. A saturated
aqueous NH4Cl solution (10 mL) was added and the aqueous layer
extracted with AcOEt (3 ꢂ 10 mL). The organic phase was dried
over anhydrous MgSO4 and concentrated. Purification by medium
pressure chromatography (3/7 AcOEt/hexane) afforded 21
(0.549 g) as a colourless oil and trans-diol6 (0.338 g) as white crys-
Azide 23 (0.213 g, 0.60 mmol) was converted into compound 25
(0.265 g, 80%, 2 steps, colourless viscous oil) following the same
procedure for obtaining compound 12 from azide 10.
½
a 2D0
ꢁ
¼ ꢀ77:1 (c 2.39, CH2Cl2). 1H NMR (CDCl3): d 7.33 (5H, broad
s), 5.15–5.07 (2H, m), 4.28–4.18 (2H, m), 3.62–3.32 (7H, m), 1.22
(6H, broad s), 2.12 (1H, broad s), 1.92–1.86 (3H, m), 1.25 (3H, s),
1.23 (3H, s), 0.89 (9H, s), 0.06 (3H, s), 0.05 (3H, s). 13C NMR (CDCl3):
d 171.5, 155.9, 136.3, 128.5, 128.0, 127.9, 127.8, 99.5, 98.1, 73.03,
67.2, 66.7, 62.2, 60.8, 49.3, 47.0, 39.4, 28.8, 25.9, 24.5, 18.3, 17.8,
ꢀ5.39, ꢀ5.4. FT-IR (film): 1711, 1689 cmꢀ1. HR-MS: Calcd for
C
29H48O8N2SiNa [M++Na]: 603.3072. Found: 603.3056.
tals. 21: ½a 2D0
ꢁ
¼ ꢀ82:4 (c 1.20, CH2Cl2). 1H NMR (CDCl3): d 4.72 (1H,
4.20. (2S)-Prolinyl-[(2R,3S,5R,6R)-3-hydroxymethyl-2-amino-
methyl-5,6-dimethoxy-5,6-dimethyl-[1,4]-dioxane]-amide 5
d, J = 4.2 Hz), 4.64 (1H, d, J = 4.2 Hz), 3.33 (3H, s), 3.24 (3H, s), 2.95–
2.85 (4H, m), 1.42 (3H, s), 1.36 (3H, s), 1.27 (6H, q, J = 7.4 Hz). 13C
NMR (CDCl3): d 198.3, 197.3, 101.4, 100.2, 75.6, 74.5, 50.0, 48.6,
22.8, 22.2, 18.2, 18.1, 14.45, 14.43. FT-IR (film): 1679 cmꢀ1. Anal.
Calcd for C14H24O6S2: C 47.71, H 6.86, N 11.19. Found: C 47.40, H
6.68.
Compound 25 (0.217 g, 0.37 mmol) was converted into catalyst
5 (0.123 g, 99%, colourless viscous oil) using the same procedure to
obtain 1. ½a 2D0
ꢁ
¼ ꢀ122:7 (c 0.30, CH2Cl2). 1H NMR (D2O): d 4.15–4.12
(1H, m), 3.86–3.83 (1H, m), 3.78–4.65 (3H, m), 3.47 (14.2 Hz,
J = 3.5 Hz), 3.26 (3H, s), 3.18 (3H, s), 3.16–3.13 (1H, m), 2.90–2.85
(2H, m), 2.11–2.08 (1H, m), 1.73–1.65 (3H, m), 1.27 (3H, s), 1.23
(3H, s). 13C NMR (D2O): d 176.9, 100.0, 98.9, 72.6, 67.2, 60.4, 60.1,
49.4, 47.7, 39.0, 30.5, 25.2, 17.3, 17.0. FT-IR (film): 3342,
4.17. (2R,3S,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-[1,4]-dioxane-
2,3-dicarboxylic acid diisopropyl ester 22
1668 cmꢀ1
.
HR-MS: Calcd for C9H17O4N2Na+ [M+ꢀC6H11+Na]:
To a solution of dithioester 21 (0.654 g, 1.8 mmol) in isopropa-
240.1086. Found: 240.1532.
nol (30 mL) in
a sealed tube was added Ti(OiPr)4 (1.1 mL,
3.6 mmol). The reaction mixture was stirred at 100 °C for 10 days.
After cooling, water (20 mL) was added and the aqueous layer was
extracted with AcOEt (3 ꢂ 8 mL). The organic phase was dried over
anhydrous MgSO4 and concentrated. Purification by medium pres-
sure chromatography (1/9–2/8 AcOEt/hexane) afforded 22
4.21. (5R,6R)-(S,S)-Diethyl 5,6-dimethoxy-5,6-dimethyl-5,6-
dihydro-1,4-dioxine-2,3-bis(carbothioate) 19
To a solution of diisopropylamine (1.14 mL, 8.2 mmol) in THF
(6.0 mL) at 0 °C was slowly added BuLi (1.6 M in hexanes,
4.26 mL, 6.8 mmol). After 15 min, a solution of 18 (1.2 g, 3.4 mmol)
in THF (5 mL) was added at ꢀ78 °C. After 30 min at ꢀ78 °C, I2
(0.531 g, 82%) as a colourless oil. ½a D20
¼ ꢀ90:1 (c 0.43, CH2Cl2).
ꢁ
1H NMR (CDCl3): d 5.10–5.01 (2H, m), 4.59 (1H, d, J = 4.0 Hz),
4.40 (1H, d, J = 4.0 Hz), 3.29 (3H, s), 3.21 (3H, s), 1.38 (3H, s), 1.33

C. D. Maycock, M. Rita Ventura / Tetrahedron: Asymmetry 23 (2012) 1262–1271
1271
(0.860 g, 3.4 mmol) was added. After 5 min, a saturated aqueous
References
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organic phase was dried with anhydrous MgSO4 and concentrated
to afford a residue which was purified by medium pressure column
chromatography (1/9 AcOEt/hexane) and afforded 19 (0.984 g,
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¼ ꢀ158:1 (c 1.0, CH2Cl2). 1H NMR
(CDCl3): d 3.39 (6H, s), 3.03–2.91 (4H, m), 1.55 (6H, s), 1.29 (6H,
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To a solution of 21 (0.020 g, 0.06 mmol) in CDCl3 (1.0 mL) in an
NMR tube was added one drop of DBU. After 48 h, 1H NMR analysis
showed complete deuterium exchange and isomerisation.
Saturated NH4Cl solution was added and the aqueous phase was
extracted with CH2Cl2 (3 ꢂ 5 mL). The organic phase was dried
over anhydrous MgSO4 and concentrated to afford a residue which
was purified by preparative TLC (3/7 AcOEt/hexane) and afforded
20 (0.021 g, 99%) as a colourless oil. ½a D20
¼ ꢀ35:8 (c 0.9, CH2Cl2).
ꢁ
1H NMR (CDCl3): d 3.32 (6H, s), 2.91 (4H, q, J = 7.4 Hz), 1.36 (6H,
s), 1.27 (6H, t, J = 7.4 Hz). 13C NMR (CDCl3): d 195.9, 99.6, 73.9 (t,
JCD = 22.2 Hz), 48.5, 22.9, 17.3, 14.2. m/z 354.5 (M+), 322.9
(M+ꢀOMe). HR-MS: Calcd for C14H22D2O6S2Na [M+Na]+:
377.1032. Found: 377.1031.
Acknowledgements
We thank Rita Lopes for her contribution to this work and Paula
Chicau for helping with HPLC analyses.
The NMR spectrometers are part of the National NMR Network
and were purchased in the framework of the National Programme
for Scientific Re-equipment, contract REDE/1517/RMN/2005, with
funds from POCI 2010 (FEDER) and Fundação para a Ciência e a
Tecnologia (FCT). This work was supported by the FCT grant
PEst-OE/EQB/LA0004/2011.
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