Stereoselective synthesis of 2-amino-1,3,5-hexane triols using l-proline catalyzed aldol reaction

Article abstract of DOI:10.1016/j.tetasy.2006.02.013

An efficient synthesis of the 2-amino-1,3,5-hexane triol pattern has been achieved by a diastereoselective aldol reaction of an amino aldehyde with acetone catalyzed by l-proline.

Full text of DOI:10.1016/j.tetasy.2006.02.013

Tetrahedron: Asymmetry 17 (2006) 763–766
Stereoselective synthesis of 2-amino-1,3,5-hexane triols using
L-proline catalyzed aldol reaction
Indresh Kumar and C. V. Rode*
Homogenous Catalysis Division, National Chemical Laboratory, Dr. Homi Baba Road, Pune 411008, India
Received 21 December 2005; revised 10 February 2006; accepted 10 February 2006
Available online 15 March 2006
Abstract—An efficient synthesis of the 2-amino-1,3,5-hexane triol pattern has been achieved by a diastereoselective aldol reaction of
an amino aldehyde with acetone catalyzed by L-proline.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
occurs naturally and is significantly more effective than
2 in inhibiting the breast tumor cell line (Fig. 1).7 Amino
polyols are also important synthetic precursors for var-
ious nitrogenated heterocycles, accessible through cycli-
zation of an activated hydroxyl group (Fig. 2).
The aldol reaction is an important and concise method
for C–C bond formation, because of the importance of
b-hydroxyl carbonyl compounds in organic chemistry.
Over the past half decade, rapid progress has been made
in the development of asymmetric aldol reactions using
‘preformed and stereo defined stable enolates’1 and
‘in situ generated labile enalote synthons’.2 In part, the
efficiency and applicability of amino acids, especially
proline catalyzed aldol reactions, have been established
recently.3 Highly efficient syntheses of carbohydrates
and polyhydroxy amino acids can be achieved in one
to two steps by using L-proline catalyzed aldol reaction
of suitably protected ketones or a-oxyaldehydes with
different aldehydes.4 However this catalytic reaction still
requires investigation in order to achieve its application
in natural product synthesis.
R'
OH
3R
R"
2S
HO
5
OBn
HN
1a R'=H, R''=OH
1b R'=OH, R"=H
O
1
OH
R'
R"
C13H27
2S
HO
C13H27
HO
3R
R
R
HN
HN
O
O
Stereoselective synthesis of amino polyols or poly
hydroxy amino acids have been the focus of major inter-
est because of their occurrence in the complex nucleo-
side antibiotics that exhibit a variety of biological
activities.5 For example, sphingolipids are widely dis-
tributed in mammalian membranes, and all have most
commonly (2S,3R,4E)-2-amino-4-ene-1,3-diol 2 defined
as a ‘sphingoid base’ backbone. The anticancer activity
of sphingosine 2 and other sphingolipids, particularly
against colon cancer lines has been established recently.6
The sphingoid base with 5-hydroxy-(3E)-sphingenine 3
2
3a R'=H, R''=OH
3b R'=OH, R"=H
Figure 1.
OH OH
OH
OH OH
NH
OH
HO
HO
HO
OH
NH
OH
N
*
Corresponding author. Tel.: +91 20 25902349; fax: +91 20
25893260; e-mail addresses: cv.rode@ncl.res.in; rode@dalton.ncl.
res.in
fagomine
swainsonine
nojirimycin
Figure 2.
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.013

764
I. Kumar, C. V. Rode / Tetrahedron: Asymmetry 17 (2006) 763–766
The significance of the 2-amino-1,3,5-triol 1 unit relies
upon the fact that it is wide spread in natural products
and synthetic drugs.
stereomeric purity is over 90%. The formation of
(R)-benzyl 4-((R)-1-hydroxy-3-oxobutyl)-2,2-dimethyl
oxazolidine-3-carboxylate 6 can be explained through
the Houk–List model11 for L-proline catalyzed aldol
reactions (Fig. 3).
2. Results and discussion
As a part of our ongoing programme8 on L-proline
catalyzed asymmetric aldol reactions towards the devel-
opment of new procedures for the synthesis of natu-
ral products, we have been pursuing a simple and
straightforward route to the synthesis of 2-Cbz-amino-
1,3,5-hexane triol pattern 1, in which the stereogenic
integrity at C-5 was altered using different reduction
conditions. The key features of our proposed route
involves: (1) the highly diastereoselective aldol reaction
catalyzed by L-proline; (2) diastereoselective reduction
of 3-hydroxy ketone 6 using different reaction condi-
tions; (3) all reaction materials are readily available, thus
making this method practical.
O
O
N
H
N
H
O
O
O
O
O
H
H
O
N
N
Cbz
Cbz
(a) Favored
(b) Disfavored
Figure 3.
Our next aim was to propagate the existing stereocentres
created in the diastereoselective aldol reaction through
successive highly diastereoselective transformations.
The b-hydroxyl ketone 6 obtained was diastereoselec-
tively reduced to 3,5-syn-diol 7a (dr = 95:5) using Et2-
B(OMe)/NaBH4 in dry THF/MeOH at À78 °C with
combined 89% yield12 and similarly 3,5-anti-diol 7b
(dr = 20:80) was obtained in 82% combined yield using
NaBH (OAc)3/acetic acid/CH3CN at room tempera-
ture,13 respectively (Scheme 2).
The first diastereo- and enantioselective organocatalytic
aldol reaction of amino aldehyde 4 with dioxanone was
reported by Enders et al.9a Furthermore the proline cata-
lyzed diastereoselective aldol reaction of several amino
aldehydes with different ketones has also been studied
recently.9b In our study, (S)-3-(benzyloxy-carbonyl)-4-
formyl-2,2-dimethyloxazolidine 4 was easily obtained
through the reported procedure from L-serine.10 Amino
aldehyde 4 was subjected to the aldol reaction in ace-
tone/DMSO at 20 °C for 50 h using 20 mol % L-proline
as a catalyst, to afford b-hydroxy ketone 6 in 85% yield
(Scheme 1). The minor diastereoisomer was not detected
The diastereomeric ratio of the stereoselective reduction
was determined by weighing separately, after purifica-
tion, by column chromatography.
The 2-amino-1,3,5-triol 1 pattern was achieved by
deprotection of acetonide (Scheme 3). To this end, 7a
was treated with p-TSA/MeOH at room temperature
1
by H and 13C NMR analysis, implying that its dia-
O
OH
O
L-proline
(20 mol%)
O
OH OH
O
H
OH
OH
O
+
Cbz
N
DMSO, 20 oC,
50 hr
N
p-TSA, MeOH,
rt, 2 hr, 95%
O
HO
Cbz
N
HN
Cbz
Cbz
5
6
4
85% yield
>90% de
7a
1a
Scheme 1.
Scheme 3.
OH OH
OH OH
O
+
O
N
N
Cbz
Cbz
O
OH
a
b
7b
7a
O
N
OH OH
OH OH
Cbz
O
O
+
6
N
N
Cbz
Cbz
7a
7b
Scheme 2. Reagents and conditions: (a) Et2B(OMe)/NaBH4, dry THF/MeOH, À78 °C, 5 h, 89% (dr, 7a/7b 95:5); (b) NaBH (OAc)3/acetic acid/
CH3CN, rt, 4 h, 82% (dr, 7a/7b 20:80).

I. Kumar, C. V. Rode / Tetrahedron: Asymmetry 17 (2006) 763–766
765
for 2 h to afford the 1a amino triol unit as a white solid
in 95% yield. In the same manner, 7b was transformed to
1b. All the new compounds were fully characterized by
spectroscopic means.
209.3. LC–MS (ESI-TOF): m/z calcd for C17H23NO5
[M+H]+ 321.15, found [M+H]+ 321.48.
4.3. (R)-Benzyl 4-((1R,3R)-1,3-dihydroxybutyl)-2,2-di-
methyloxazolidine-3-carboxylate 7a
3. Conclusion
To a stirred solution of b-hydroxy ketone 6 (321 mg,
1 mmol) in dry THF (8 ml) and anhydrous methanol
(2 ml) at À78 °C under argon, was added dropwise Et2-
B(OMe) (1.1 mmol). The solution was stirred for
20 min and then NaBH4 (42 mg, 1.1 mmol) was added.
The resulting mixture was stirred further for 5 h at the
same temperature. The reaction was quenched with
1 ml of acetic acid. The reaction was warmed to rt and
solvent was removed in vacuo. The crude mass was ta-
ken in EtOAc (25 ml) and stirred with saturated NaH-
CO3 (8 ml) for 2 h. The organic layer was separated,
washed with brine and dried over Na2SO4 after which
it was concentrated under reduced pressure. The residue
was purified by flash column chromatography eluting
with (15% EtOAc/5% acetone/pet. ether) to give 7a
(272 mg, Rf = 0.35, syn) TLC (15% EtOAc/5% ace-
tone/pet ether) and 7b, in combined 85% yield. Com-
pound 7a: [a]D = À13.2 (c 1, CHCl3), FT-IR (cmÀ1):
In conclusion, we have described L-proline catalyzed
highly diastereoselective aldol reaction of acetone with
a-amino aldehyde 4. The potential of this reaction has
been further demonstrated in the synthesis of the versa-
tile 2-Cbz-amino-1,3,5-hexane triol pattern. Further
studies in the direction of the synthesis of sphingolipids
analogues using the same strategy is currently underway
and will be reported in due course.
4. Experimental
4.1. General methods
All reagents were used as supplied. The reactions involv-
ing hygroscopic reagents were carried out, under argon,
using oven-dried glassware. THF was distilled from
sodium-benzophenone ketyl prior to use. Reactions
were followed by TLC using 0.25 mm Merck silica gel
plates (60F-254). Optical rotation values were measured
using JASCO P-1020 digital polarimeter using Na light.
IR spectra were recorded on a Perkin–Elmer FT-IR 16
PC spectrometer. The NMR spectra were recorded on
a Bruker system (200 MHz for 1H and 75 MHz for
13C). The chemical shifts are reported using the d (delta)
1
3423, 1698, 1413, 1362, 1089, 757. H NMR (200 MHz
CDCl3): d 1.15 (d, J = 7 Hz 3H), 1.3–1.6 (m, 8H), 2.4–
2.8 (br s, 2H, OH), 3.75–4.20 (m, 5H), 5.13 (s, 2H),
7.33 (s, 5H). 13C NMR (75 MHz, CDCl3): d 23.4, 24.3,
26.3, 40.4, 61.1, 62.3, 64.6, 67.5, 69.1, 94.4, 128.0,
128.1, 128.4, 135.6, 154.5. LC–MS (ESI-TOF): m/z calcd
for C17H25NO5 [M+H]+ 323.17, found [M+H]+ 323.18.
4.4. (R)-Benzyl 4-((1R,3S)-1,3-dihydroxybutyl)-2,2-di-
methyloxazolidine-3-carboxylate 7b
scale for H and 13C spectra. Choices of deuterated sol-
1
vents (CDCl3, D2O) are indicated below. LC–MS were
recorded using electrospray ionization technique. All
organic extracts were dried over sodium sulfate and con-
centrated under aspirator vacuum at room temperature.
Column chromatography was performed using (100–200
and 230–400 mesh) silica gel obtained from M/s Spectro-
chem India Ltd. Room temperature is referred to as rt.
To a stirred solution of NaBH(OAc)3 (1.899 g, 9 mmol)
(freshly prepared) in dry CH3CN (6 ml) and glacial ace-
tic acid (3 ml), was added b-hydroxy ketone 6 (321 mg,
1 mmol) in CH3CN dropwise. The combined reaction
mixture was stirred for a further 4 h at rt. The solvent
was removed in vacuo. Similar workup procedure and
flash column chromatography gave 7b (212 mg, Rf =
0.28, anti) TLC (15% EtOAc/5% acetone/pet. ether)
and 7a in combined 82% yield. Compound 7b:
[a]D = À9.7 (c 1, CHCl3), FT-IR (cmÀ1): 3423, 1698,
4.2. (R)-Benzyl 4-((R)-1-hydroxy-3-oxobutyl)-2,2-di-
methyloxazolidine-3-carboxylate 6
1
To a stirred solution of amino aldehyde 4 (263 mg,
1 mmol) in 10 ml acetone and 2 ml DMSO at 20 °C,
L-proline (23 mg, 20 mol %) was added. The reaction
mixture was stirred further for 50 h at the same temper-
ature, followed by TLC. The reaction mixture was
reduced in vacuo. The resulting residue was taken in
EtOAc (30 ml) and stirred with 10% NaHCO3 solution
(10 ml). The organic layer was separated, washed with
brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The crude residue was purified
by column chromatography, eluting with (20% EtOAc/
pet. ether) to give a slightly yellow oil 6 (272 mg, 85%
yield): [a]D = +5.7 (c 1, CHCl3); TLC (20% EtOAc/
1413, 1362, 1089, 757. H NMR (200 MHz, CDCl3): d
1.14 (d, J = 7 Hz 3H), 1.3–1.7 (m, 8H), 2.6–3.0 (br s,
2H, OH), 3.75–4.20 (m, 5H), 5.14 (s, 2H), 7.34 (s, 5H).
13C NMR (75 MHz, CDCl3): d 23.4, 24.3, 26.3, 40.4,
61.1, 62.3, 64.6, 67.5, 69.1, 94.4, 128.0, 128.1, 128.4,
135.6, 154.5. LC–MS (ESI-TOF): m/z calcd for
C17H25NO5 [M+H]+ 323.17, found [M+H]+ 323.20.
4.5. Benzyl (2R,3R,5R)-1,3,5-trihydroxyhexan-
2-ylcarbamate 1a
To a solution of 7a (200 mg, 0.62 mmol) in MeOH
(8 ml) at rt, was added p-TSA (catalytic amount) and
the mixture was further stirred for 2 h. Small amount
of solid K2CO3 was added and the solvent was removed
in vacuo. The residue was dissolved in diethyl ether and
the precipitated material was filtered. Organic solvent
was dried over Na2SO4 and concentrated to gave a white
1
pet. ether), Rf = 0.32; H NMR (200 MHz, CDCl3): d
1.54 (s, 6H), 2.14 (s, 3H), 2.40–2.65 (m, 2H), 3.80–4.15
(m, 4H), 5.15 (s, 2H), 7.35 (s, 5H). 13C NMR
(75 MHz, CDCl3): d 24.2, 26.7, 30.7, 45.9, 61.0, 64.8,
67.4, 68.7, 94.3, 127.9, 128.1, 128.4, 135.8, 154.2,

766
I. Kumar, C. V. Rode / Tetrahedron: Asymmetry 17 (2006) 763–766
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(c 0.5, MeOH), FT-IR (cmÀ1): 3452, 3317, 2958,
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3.45–3.70 (m. 3H), 3.8–4.0 (m, 2H), 5.05 (s, 2H), 7.29
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In the similar way, 7b was converted into 1b: [a]D =
+6.6 (c 0.5, MeOH), FT-IR (cmÀ1): 3452, 3317, 2958,
2884, 1686, 1470, 1238, 1049. 1H NMR (200 MHz,
CDCl3/D2O): d 1.13 (m, 3H), 1.58 (m, 2H), 3.45–3.70
(m, 3H), 3.8–4.0 (m, 2H), 5.05 (s, 2H), 7.29 (s, 5H).
13C NMR (75 MHz, CDCl3): d 25.9, 40.5, 60.7, 61.8,
63.5, 66.2, 68.8, 128.2, 128.5, 128.8, 135.4, 155.1. LC–
MS (ESI-TOF): m/z calcd for C14H21NO5 [M+H]+
283.14, found [M+H]+ 284.17.
Acknowledgements
Indresh Kumar thanks CSIR, New Delhi, for a research
fellowship.
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