Synthesis of chiral unsaturated aminolactones using Pd-catalyzed allylic amination

Article abstract of DOI:10.1016/j.tetasy.2010.09.003

Stereoselective synthesis of (5R,6R)- and (5S,6S)-5-benzylamino-6-(tert- butyldimethylsilanyloxymethyl)-5,6-dihydropyran-2-ones starting from d-glucal and furanaldehyde, respectively, is described. The synthesis relies on a Sharpless asymmetric dihydroxylation, an Achmatowicz reaction, and a stereoselective Pd-catalyzed allylic amination as the key steps.

Full text of DOI:10.1016/j.tetasy.2010.09.003

Tetrahedron: Asymmetry 21 (2010) 2367–2371
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of chiral unsaturated aminolactones using Pd-catalyzed
allylic amination
Annukka Kallinen a, Jan Tois a, Rainer Sjöholm b, Robert Franzén a,
⇑
a Department of Chemistry and Biotechnology, Tampere University of Technology, Korkeakoulunkatu 8, 33720 Tampere, Finland
b Department of Natural Sciences, Åbo Akademi University, Piispankatu 10, 20500 Turku, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2010
Accepted 16 September 2010
Available online 20 October 2010
Stereoselective synthesis of (5R,6R)- and (5S,6S)-5-benzylamino-6-(tert-butyldimethylsilanyloxymeth-
yl)-5,6-dihydropyran-2-ones starting from D-glucal and furanaldehyde, respectively, is described. The
synthesis relies on a Sharpless asymmetric dihydroxylation, an Achmatowicz reaction, and a stereoselec-
tive Pd-catalyzed allylic amination as the key steps.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
The amino functionality, often encountered in natural products
and active pharmaceutical ingredients, represents one of the most
An
a
,b-unsaturated d-lactone is a common motif represented in
highly pursued functionalities in organic chemistry.8 One feasible
method for introducing an amino functionality into hex-2-enopyr-
anosides, considered as masked d-lactones, is the Tsuji–Trost type
Pd-catalyzed allylic substitution with nitrogen nucleophiles.9–16 To
date, the compatibility of this reaction has been demonstrated
with secondary amine9–14 and azide15,16 nucleophiles, utilizing
acetates or carbonates as leaving groups. However, primary amines
have been reported to give a complex mixture of products under
these conditions.9–11 The reactions reported earlier use enantiome-
rically pure hex-2-enopyranosides as starting materials and yield
amino or azido product with retention of configuration.9–16
Inspired by the on-going research on the asymmetric substitu-
tions in our group, we decided to investigate the usefulness of this
reaction for the preparation of a chiral 5,6-dihydropyran-2-one
with an amino functionality at the allylic position (Scheme 1). Ret-
rosynthetically, the target aminolactones 1 and 2 were recognized
to be available from hex-2-enopyranoside carbonate A by Pd-cata-
lyzed asymmetric allylic amination, followed by oxidative depro-
tection to a lactone. Compound A, on the other hand, could be
prepared from hemiacetal B after protection of the anomeric
hydroxyl group followed by a Luche reduction17 of the enone car-
bonyl and a subsequent acylation of the alcohol.15 The hemiacetal
B in turn could be prepared from the chiral diol (R)-3 or (S)-3 via an
Achmatowicz rearrangement.18
various natural products exhibiting antibiotic,1 immunosuppres-
sive,2 and antitumor activities.3–5 Over the last 10 years, these
kinds of natural products, such as asperlin, pironetin, and obolac-
tone (Fig. 1), have emerged as new potential lead compounds for
antitumor drugs,3 and consequently extensive studies toward the
synthesis of these natural products have been carried out.6 Impor-
tantly, in many cases, the
a,b-unsaturated d-lactone moiety has
been found to be crucial for the bioactivity and therefore, the syn-
thesis of this fragment and its derivatives has become a topic of
great interest.5,7
O
O
O
O
O
O
O
O
O
(+)-asperlin
O
OH
OMe
O
H
obolactone
a,b-unsaturated d-lactone moiety.
(-)-pironetin
2. Results and discussion
Figure 1. Natural products containing the
The synthesis of aminolactone 1 began by the preparation of
diol (R)-3 from the commercially available
D
-glucal 4 by the meth-
od reported by Babu and Balasubramanian.19
D-Glucal 4 was
treated with InCl3ꢀ3H2O in CH3CN to give the diol (R)-3 in 76% yield
in a single step (Scheme 2). The enantiomer (S)-3, needed for
⇑
Corresponding author.
E-mail address: robert.franzen@tut.fi (R. Franzén).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.09.003

2368
A. Kallinen et al. / Tetrahedron: Asymmetry 21 (2010) 2367–2371
3
OP2
2
4
O
OH
OH
OH
5
O
O
O
O
1
O
HN
HN
MeO
MeO
O
O
O
O
6
OP1
OP1
O
O
OP1
A
A
(R)-3
(S)-3
1
B
B
OP2
O
OH
OH
OH
O
O
O
OP1
OP1
OP1
2
Scheme 1. Retrosynthetic analysis for the aminolactones 1 and 2.
OH
OH
OH
HO
HO
O
InCl3·3H2O
CH3CN, RT
O
(R)-3, 76%
4
PhCOCl, Et2N, DMAP, 73%
TMS
OH
OR
OR
O
1M HCl
O
TMSCH2MgCl
dry Et2O
O
O
O
AD-mix-β, t-BuOH/H2O (3/2)
º
DCM, 0 C -> RT
Et2O
º
T = 0
C
(S)-8, R = COPh
5
6, quantitative
(S)-3, R = H, 80%
7
Et3N, MeOH, H2O (1/4/5), 81%
D-glucal 4 and (S)-3 from furanaldehyde 5.
Scheme 2. The preparation of the chiral furan diols (R)-3 from
aminolactone 2, was readily prepared by the method reported by
Harris et al. starting from a furanaldehyde 5 (Scheme 2).20 Alde-
hyde 5 was first reacted with a Grignard reagent prepared from
(chloromethyl)trimethylsilane and magnesium to yield b-hydrox-
ysilane 6 in quantitative yield. The Peterson olefination of b-
hydroxysilane 6 with 1 M HCl gave a vinylfuran intermediate 7,
which was used directly as an ether solution in a Sharpless asym-
metric dihydroxylation reaction.21 Diol (S)-3 was obtained in 80%
yield over three steps. The enantiomeric purity of (S)-3 was im-
proved by converting the diol to a dibenzoate, which was recrystal-
lized, followed by hydrolysis to yield (S)-3.
With diol (R)-3 in hand, the primary hydroxyl group was selec-
tively protected with TBSCl to give (R)-9 in 86% yield (Scheme 3).
The ee of (R)-9 was confirmed to be 99% by converting the alcohol
OH
OH
OTBS
OH
O
O
TBSCl, TEA, DMAP
O
Ethyl vinyl ether, PPTS
DCM, RT
NBS, NaOAc, NaHCO3
THF/H2O (4/1)
OTBS
º
-
C > RT
DCM, T = 0
HO
O
(2R)-10, 88%
(R)-9,86%
(R)-3
O
OH
O
O
O
ClCOOMe, Py, DMAP
NaBH4, CeCl3·7H2O
MeOH, RT
OTBS
OTBS
OTBS
EEO
O
EEO
O
EEO
O
º
º
C
-
DCM, -78
C
> 0
(2R)-12, 82%
(2R)-13, 66%
(2R)-11, 82%
H
N
H
N
PhCH2NH2, π3-(C3H5PdCl)2, PPh3
CrO3, H2SO4, H2O
OTBS
OTBS
O
O
EEO
O
º
C
CH3CN, T = 40
º
acetone, T = 0 C
(5S,6S)-1, 26%
(2S)-14, 71%
Scheme 3. Synthesis of aminolactone 1 from (R)-3.

A. Kallinen et al. / Tetrahedron: Asymmetry 21 (2010) 2367–2371
2369
to a Mosher ester and comparing the integrals of the methoxy
signal of the different diastereomers. Next, the TBS-protected furan
diol (R)-9 was subjected to an Achmatowicz rearrangement18 using
NBS in aqueous THF to afford hemiacetal (2R)-10 as a mixture of
two diastereomers in 88% yield. The hemiacetal was protected
with ethyl vinyl ether to give (2R)-11 as a mixture of four diaste-
reomers in 82% yield. Although the ethoxyethyl acetal protection
complicated the NMR spectra interpretation, it was found suitable
for selective removal in the presence of TBS-protection. Methyl and
isopropyl acetals were found to be impossible to remove selec-
tively.22 The protected pyranone was reduced under Luche condi-
tions17 at room temperature to give alcohol (2R)-12 as a complex
mixture of diastereomers in 82% yield. Alcohol (2R)-12 was then
acylated with methyl chloroformate to give carbonate (2R)-13 as
a mixture of diastereomers in 70% yield. The carbonate (2S)-13
was prepared analogously from (S)-3 in 35% yield (over five steps).
With carbonates (2R)-13 and (2S)-13 in hand, they were sub-
jected to a Tsuji–Trost type asymmetric allylic amination, using
benzylamine as a nucleophile. Triphenylphosphine (12 mol %) was
ysis gave a major peak at 15.3 min for aminolactone 1 and at
18.2 min for aminolactone 2. The enantiomeric excesses for the
compounds 1 and 2 were >95% and >97.6%, respectively, according
to HPLC analysis. The specific rotation for aminolactone 1 was
measured to be ½a D20
ꢁ
¼ ꢂ35:2 and for aminolactone 2 ½a D20
¼
ꢁ
þ38:1 (c 1.0, CH3OH). To determine the configuration at carbon 5
of the aminolactones 1 and 2, the coupling constants for protons
H-4, H-5, and H-6 were measured by NMR. The coupling constants
obtained were 3.4 Hz for J (H-4, H-5) and 7.1 Hz for J (H-5, H-6),
which correspond well to the values reported in the literature for
5-substituted 5,6-dihydropyran-2-ones having a trans-configura-
tion.20,23 This indicated the configuration of the aminolactones to
be (5S,6S)-1 and (5R,6R)-2.
3. Conclusion
We have successfully prepared novel chiral aminolactone frag-
ments starting from D-glucal and furanaldehyde using a Tsuji–Trost
complexed with palladium, utilizing p
3-(C3H5PdCl)2 (4 mol %) as a
type Pd-catalyzed allylic amination as the key step. In contrast to
the earlier reported results,9,10 the substitution of the carbonate
by primary amine was shown to give 3-amino-hex-4-enopyrano-
sides with good yield. Furthermore, it was noticed that the
asymmetric induction of the allylic amination took place intramo-
lecularly, furnishing the target aminolactones with high
stereoselectivity (de 100%, ee 95–97%). The amination was
found to result in a trans-configuration, which is usually not seen
in 5-substituted 5,6-dihydropyranones isolated from natural
Pd-source, and used as a catalyst in the reaction. No attempts to re-
duce the amount of ligand or catalyst were made. Three fractions of
aminated products were isolated during the purification. The struc-
tures of these compounds were assigned on the basis of their 1H-,
13C-, and 1H,1H-COSY NMR and HRMS spectroscopic analysis.
According to the COSY experiments, the first two fractions con-
tained the mixtures of different diastereomers of the wanted
aminopyranoside 14 (63% and 8%), while the third fraction con-
tained the putative SN20 side product 15 (14%) (Fig. 2). The chemical
shift of the anomeric carbon was d 91.8 ppm for the first two frac-
tions, compared to 96.2 ppm for the third fraction. This is in accor-
dance with the values given in the literature for 2,3-unsaturated and
3,4-unsaturated enopyranoses.10,15 The allylic amination gave (2S)-
14 in 71% and (2R)-14 in 77% yields.
sources.1,3,24 Further investigations of these chiral
a,b-unsaturated
aminolactones as building blocks and aminated carbohydrate
mimetics are currently in progress in our laboratory.
4. Experimental
4.1. General
Melting points were determined on a Stuart SMP10 melting
point apparatus and are uncorrected. 1H (300 MHz) and 13C
(75 MHz) spectra were recorded on a Varian Mercury 300 spec-
trometer; chemical shifts are reported relative to internal tetra-
methylsilane (d 0.0 ppm). High resolution mass spectra were
acquired with Micromass LCT instrument. High pressure liquid
chromatography (HPLC) was performed using a CHIRALPAKÒ IC
column with the indicated solvent system and flow rate, the UV
detector was set to 220 nm. Optical rotations were measured with
a PerkinElmer 341 polarimeter using methanol as a solvent. Thin
layer chromatography (TLC) was carried out on plates coated with
silica gel (60 F-254), and column chromatography on Silica gel 60.
All the reagents used were purchased from Sigma Aldrich and used
without purification. Compounds 3 and 6–10 were prepared
according to the known literature procedures and the spectro-
scopic and physical data were consistent with those previously
reported.19,20,25
NH
OTBS
EEO
O
(2S)-14, 71%
O
[PdLn]+
O
O
OTBS
OTBS
EEO
O
EEO
O
(2R)-13
HN
OTBS
EEO
O
4.1.1. 2-(tert-Butyldimethylsilanyloxymethyl)-6-(10-ethoxy-
ethoxy)-6H-pyran-3-one (2R)-11 and (2S)-11
(2S)-15, 14%
Figure 2. The two possible routes in the allylic amination.
To a stirred solution of (2R)-10 (1.50 g, 5.80 mmol) in DCM
(12 ml) was added ethyl vinyl ether (0.58 ml, 6.06 mmol) at rt.
After the addition of PPTS (102 mg, 0.41 mmol), the reaction mix-
ture was stirred for 4 h at rt, after which saturated NaHCO3
(10 ml) and DCM were added. The organic layer was separated
and the water phase was extracted with DCM (3 ꢃ 10 ml). The
combined organic phases were washed with brine and dried over
Na2SO4. After concentration, the crude product was purified by
silica gel column chromatography (EtOAc/Hex 1/10) to give
Finally, the EEO-acetal protection was removed and the result-
ing hemiacetal was oxidized to an aminolactone in one pot. Amino-
lactones 1 and 2 were obtained in 26% and 39% yields over two
steps. To our surprise, the NMR-spectra of the aminolactones did
not show any double peaks arising from the two diastereomers,
which suggested the amination had proceeded diastereoselectively
with intramolecular induction of asymmetry. The chiral HPLC anal-

2370
A. Kallinen et al. / Tetrahedron: Asymmetry 21 (2010) 2367–2371
compound (2R)-11 as a mixture of four diastereomers (1.58 g) in
82% yield.
O
4
3
2
O
7
O 8
5
2''
1''
4
3
2
5
O
7
8
6
2''
1''
OTBS
1'
O
O
O
1
Si
6
O
1'
O
O
O
1
2'
2'
9
1H NMR (300 MHz, CDCl3): d = 6.25–5.90 (m, 1H, H4), 5.89–5.73
(m, 1H, H5), 5.39–5.21 (m, 1H, H6), 5.21–5.10 (m, 1H, H3), 5.09–
4.85 (m, 1H, H10), 4.03–3.89 (m, 1H, H2), 3.78 (s, 3H, H8), 3.77–
3.71 (m, 2H, H7), 3.56–3.42 (m, 2H, H100), 1.42–1.30 (d, J = 5.4 Hz,
3H, H20), 1.27–1.14 (t, J = 7.0 Hz, 3H, H200), 0.88 (s, 9H), 0.04 (s,
6H); 13C NMR (75 MHz, CDCl3): d = 155.5 (2 ꢃ C), 133.9, 131.8,
131.2, 129.2, 129.1, 128.7, 128.3, 126.7, 126.2, 126.0, 99.7, 98.8,
94.4, 91.6, 89.8, 69.8, 69.7, 69.3, 69.1, 63.5, 63.0 (2 ꢃ C), 61.9,
55.3 (2 ꢃ C), 55.2 (2 ꢃ C), 55.0, 26.2 (4 ꢃ C), 21.6, 21.2, 18.8, 18.7,
15.6, 15.5, ꢂ5.1 (5 ꢃ C). HRMS (ES+) calcd for C18H34O7NaSi
[M+Na]+ 413.1972, found 413.1966.
1H NMR (300 MHz, CDCl3): d = 6.92–6.78 (m, 1H ꢃ 4, H5),
6.15–6.07 (m, 1H ꢃ 4, H4), 5.65–5.57 (m, 1H ꢃ 4, H6), 5.22–
4.92 (4 ꢃ q, J = 5.3 Hz, 1H ꢃ 4, H10), 4.57–4.51 (m, 1H, H2),
4.48–4.42 (m, 1H, H2), 4.22–4.15 (m, 1H, H2), 4.12–3.90 (m,
1H + 2H ꢃ 4, H2 and H7), 3.87–3.75 (m, 2H, H100), 3.75–3.62 (m,
2H, H100), 3.62–3.46 (m, 2H ꢃ 2, H100), 1.46–1.36 (4 ꢃ d,
J = 5.3 Hz, 3H ꢃ 4, H20), 1.28–1.17 (4 ꢃ t, J = 7.0 Hz, 3H ꢃ 4, H200),
0.88 (s, 9H, H9), 0.87 (s, 9H, H9), 0.86 (2 ꢃ s, 9H ꢃ 2, H9),
0.07–0.03 (m, 6H ꢃ 4, H8); 13C NMR (75 MHz, CDCl3): d = 195.2,
195.0, 194.7, 148.4, 147.0, 145.0, 144.3, 129.2, 128.8, 128.5,
128.2, 100.3, 100.1, 99.3, 98.4, 91.4, 90.9, 90.3, 88.6, 80.7
(2 ꢃ C), 76.9, 76.5, 63.9, 63.8, 63.5, 63.4, 63.2, 62.9, 62.1, 61.9,
26.2 (4 ꢃ C), 21.4 (2 ꢃ C), 21.2, 21.0, 18.7, 18.6, 15.7, 15.6, 15.5,
15.4, ꢂ5.0 (6 ꢃ C), ꢂ7.7; HRMS (ES+) calcd for C16H30O5NaSi
[M+Na]+ 353.1760, found 353.1750.
Compound (2S)-13 was prepared using (2S)-12 (2.11 g,
6.35 mmol) as a starting material, yield 1.64 g (66%). The (2R)-13
and (2S)-13 are enantiomeric mixtures of diastereomers and gave
the same NMR spectra. HRMS (ES+) calcd for
C18H34O7NaSi
[M+Na]+ 413.1972, found 413.1984.
Compound (2S)-11 was prepared the same way using (2S)-10
(2.3 g, 8.9 mmol) as a starting material, with a yield of 2.44 g (82%)
ofa mixtureoffourdiastereomers. The(2R)-11and (2S)-11are enan-
tiomeric mixtures of four diastereomers, while the NMR data for
(2S)-11 were the same as for (2R)-11. HRMS (ES+) calcd for
4.1.4. Benzyl-[2-(tert-butyldimethylsilanyloxymethyl)-6-(1-
ethoxyethoxy)-3,6-dihydro-2H-pyran-3-yl]-amine (2R)-14 and
(2S)-14
Allylpalladium(II) chloride dimer (15 mg, 0.04 mmol) and PPh3
(32 mg, 0.12 mmol) were weighed into a two-necked flask fitted with
a reflux condenser, and the systemwas filled with argon. Next, CH3CN
(13 ml) was added to the reaction flask and the solution was stirred
for 20 min at rt. Carbonate (2R)-13 (0.40 g, 1.02 mmol), dissolved in
CH3CN (2 ml), was added to the reaction flask and allowed to stir
for 20 min. Finally, benzylamine (0.34 ml, 3.06 mmol) was added to
the reaction mixture, after which the reaction flask was placed in an
oil-bath and the temperaturewas adjusted to 50 °C. After the reaction
was complete (TLC), the solution was cooled down to rt and saturated
aqueous NH4Cl (10 ml) was added. The organic layer was separated
and the water phase was extracted with EtOAc (3 ꢃ 10 ml). The com-
bined organic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to give a residue which was
purified with column chromatography (EtOAc/Hex, 1/4). Purification
gave a mixture of different diastereomers of (2S)-14 (0.309 g, 71%)
and a minor amount of SN20 side product (2S)-15 (14%).
C
16H30O5NaSi [M+Na]+ 353.1760, found 353.1752.
4.1.2. 2-(tert-Butyl-dimethylsilanyloxymethyl)-6-(1-ethoxy-
ethoxy)-3,6-dihydro-2H-pyran-3-ol (2R)-12 and (2S)-12
Ketone (2R)-11 (1.74 g, 5.26 mmol) was added to a solution of
CeCl3ꢀ7H2O in MeOH (0.4 M, 13 ml, 5.26 mmol) and stirred for
30 min at rt. To this solution, NaBH4 (0.20 g, 5.26 mmol) was
added over 5 min. After completion of the reaction (monitored
by TLC), the reaction was quenched by adding water (10 ml)
and diluted with Et2O (20 ml). The organic layer was separated
and the water phase was extracted with Et2O (3 ꢃ 10 ml). The
combined organic layers were washed with brine (2 ꢃ 5 ml),
dried over NasSO4, and concentrated to dryness. Concentrated
product (2R)-12 (1.44 g, 82%) was used without purification in
the next step.
Compound (2S)-12 was prepared using the reaction conditions
described above using (2S)-11 (2.44 g, 7.38 mmol) as a starting
material. Crude product (2S)-12 (2.15 g, 87%) was used directly in
the next step.
4
8
5
HN
3
2''
1''
4.1.3. Methyl 2-(tert-butyldimethylsilanyloxymethyl)-6-(10-
ethoxy-ethoxy)-3,6-dihydro-2H-pyran-3-yl carbonate (2R)-13
and (2S)-13
6
OTBS
1'
O
O
O
1
2
7
2'
Alcohol (2R)-12 (1.40 g, 4.20 mmol) was dissolved in DCM
(30 ml) under an argon atmosphere and the solution was cooled
to ꢂ78 °C in a dry-ice/acetone bath. To this solution, pyridine
(1.02 ml, 12.6 mmol) and DMAP (0.10 g, 0.82 mmol) were added.
Methyl chloroformate (0.65 ml, 8.41 mmol) was added dropwise
to the solution over 10 min. After 3 h, the reaction mixture was al-
lowed to warm up to 0 °C overnight. After the reaction was com-
plete (TLC), saturated aqueous NaHCO3 was added and the DCM
layer was separated. The water phase was extracted with EtOAc
(3 ꢃ 20 ml) and the organic phases were washed with 10% CuSO4
solution. The combined organic phases were dried over Na2SO4,
concentrated and purified by column chromatography (EtOAc/
Hex 1/6) to give (2R)-13 (1.15 g) in 70% yield as a complex mixture
of diastereomers.
Major diastereomers (2S)-14 1H NMR (300 MHz, CDCl3):
d = 7.40–7.19 (m, 5H, Ar), 6.29–5.94 (m, 1H, H4), 5.90–5.67 (m, 1H,
H5), 5.33–5.14 (m, 1H, H6), 5.10–4.84 (m, 1H, H10), 3.99–3.36 (m,
7H, H8, H7, H2 and H100), 3.26–3.10 (m, 1H, H3); 1.37 (d, J = 5.3 Hz,
3H, H20), 1.21 (t, J = 7.0 Hz, 3H, H200), 0.89 (s, 9H), 0.07 (2 ꢃ s, 6H);
13C NMR (75 MHz, CDCl3): d = 140.7 (2 ꢃ C), 132.4, 132.3, 128.7,
128.4, 127.3 (2 ꢃ C), 126.2, 125.9, 99.5, 98.7, 91.7, 90.0, 71.9
(2 ꢃ C), 64.6, 64.5, 63.4, 61.9, 52.0 (2 ꢃ C), 50.8 , 50.7, 26.3 (2 ꢃ C),
26.2 (2 ꢃ C), 21.7, 21.3, 18.8, 18.7, 15.6, 15.5, -5.0 (3 ꢃ C); HRMS
(ES+) calcd for C23H40NO4Si [M+] 422.2727, found 422.2728.
Minor diastereomers (2S)-14 1H NMR (300 MHz, CDCl3): d = 7.37–
7.20 (m, 5H, Ar), 6.09–6.01 (m, 1H, H4), 5.85–5.67 (m, 1H, H5), 5.32–
5.23 (m, 1H, H6), 5.09–4.84 (m, 1H, H10), 3.93–3.44 (m, 7H, H8, H7,

A. Kallinen et al. / Tetrahedron: Asymmetry 21 (2010) 2367–2371
2371
H2and H100), 3.26–3.17(m, 1H, H3), 1.36(d, J = 5.3 Hz, 3H, H20), 1.20 (t,
J = 7.0 Hz, 3H, H200); 13C NMR (75 MHz, CDCl3): d = 140.6 (2 ꢃ C),
130.4, 130.0, 128.7, 128.5 (2 ꢃ C), 128.0, 127.3 (2 ꢃ C), 99.6, 98.1,
91.8, 91.2, 76.7, 76.4, 64.5, 64.4, 63.2, 61.5, 51.4, 51.2, 51.1, 50.9,
26.2 (2 ꢃ C), 21.6, 21.4, 18.6, 15.7, 15.5, -5.0 (3 ꢃ C); HRMS (ES+) calcd
for C23H40NO4Si [M+] 422.2727, found 422.2719.
26.1, 18.5, -5.1 (2xC); HRMS (ES+) calcd for C19H30NO3Si [M+]
348.1995, found 348.1992; HPLC (iPrOH/Hex 2/8, flow rate
1.0 ml/min) t = 15.3 min; mp 90–91 °C; ½a D20
¼ ꢂ35:2 (c 1.0, MeOH).
ꢁ
Compound (5R,6R)-2 was prepared the same way using (2R)-14
as the starting material (332 mg, 0.78 mmol). Purification gave
(5R,6R)-2 (107 mg) in 39% yield as an off-white solid. 1H NMR
(300 MHz, CDCl3): d = 7.37–7.23 (m, 5H, Ar), 6.84 (dd, J = 9.9,
3.3 Hz, 1H, H4), 5.97 (dd, J = 9.9, 1.8 Hz, 1H, H3), 4.37 (ddd, J = 7.1,
5.2, 3.7 Hz, 1H, H6), 3.94 (dd, J = 11.1, 3.7 Hz, 1H, H7) 3.90 (A,
JAB = 13.1 Hz, 1H, H8), 3.89 (B, JAB = 13.1 Hz, 1H, H8), 3.81 (dd,
J = 11.0, 5.3 Hz, 1H, H7), 3.67 (ddd, J = 7.1, 3.4, 1.8 Hz, 1H, H5),
0.86 (s, 9H), 0.06 (2 ꢃ s, 6H); 13C NMR (75 MHz, CDCl3): d = 163.2,
147.4, 139.7, 128.9, 128.4, 127.7, 120.6, 81.6, 63.1, 51.2, 50.5,
26.1, 18.5, ꢂ5.1 (2 ꢃ C); HRMS (ES+) calcd for C19H30NO3Si [M+]
348.1995, found 348.1988; HPLC (iPrOH/Hex 2/8, flow rate
8
4
5
HN
2''
1''
3
6
OTBS
1'
O
O
O
1
2
7
2'
(2S)-15 1H NMR (300 MHz, CDCl3): d = 7.38–7.19 (m, 5H, Ar),
5.90–5.87 (m, 2H, H3 and H4), 5.08 (q, J = 5.3 Hz, 1H, H10), 5.03
(d, J = 3.0 Hz, 1H, H6), 4.24–4.15 (m, 1H, NH), 3.94 (s, 2H, H8),
3.80–3.47 (m, 5H, H100, H2 and H7), 3.25 (q, J = 3.0 Hz, 1H, H5),
1.40 (d, J = 5.3 Hz, 3H, H20), 1.21 (t, J = 7.0 Hz, 3H, H200), 0.90 (s,
9H), 0.06 (2 ꢃ s, 6H); 13C NMR (75 MHz, CDCl3): d = 141.5, 129.1,
128.6, 128.5, 127.3, 127.0, 98.1, 96.2, 75.2, 66.0, 61.6, 52.9, 51.2,
26.2, 21.3, 18.7, 15.8, -5.0 (2 ꢃ C); HRMS (ES+) calcd for C23H40NO4-
Si [M+] 422.2727, found 422.2734.
1.0 ml/min) t = 18.2 min; mp 90–91 °C; ½a D20
¼ þ38:1 (c 1.0, MeOH).
ꢁ
Acknowledgments
We thank Mrs. Päivi Joensuu (University of Oulu) for analyzing
the HRMS data and Dr. Arto Liljeblad (University of Turku) for his
assistance in measuring the optical rotation data.
References
(2R)-14 was prepared by the method described above using
(2S)-13 (0.40 g, 1.02 mmol) as a starting material. Purification
yielded the diastereomers of (2R)-14 (0.332 g, 77%) and a minor
amount of SN20 side product (2R)-15 (13%). The (2R)-14 and (2S)-
14 are enantiomeric mixtures of several diastereomers and gave
the same NMR spectra. Major diastereomers of (2R)-14 HRMS
(ES+) calcd for C23H40NO4Si [M+] 422.2727, found 422.2735. Minor
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diastereomers of (2R)-14 HRMS (ES+) calcd for
[M+] 422.2727, found 422.2720. (2R)-15 HRMS (ES+) calcd for
23H40NO4Si [M+] 422.2727, found 422.2726.
C23H40NO4Si
C
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Academic Press: New York, 1990; chapter 13.
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10. Baer, H. H.; Hanna, Z. S. Can. J. Chem. 1980, 59, 889–906.
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M. Synlett 2006, 3049–3052.
4.1.5. 5-Benzylamino-6-(tert-butyldimethylsilanyloxymethyl)-
5,6-dihydropyran-2-one (5S,6S)-1 and (5R,6R)-2
To a cooled solution of (2S)-14 (309 mg, 0.73 mmol) in acetone
(20 ml) was added Jones’ reagent26 (2.6 M, 0.45 ml) over 15 min in
0 °C. After 2.5 h the reaction was quenched by adding iPrOH (5 ml)
and the solution was stirred for 10 min at rt. After this, the pH was
adjusted to neutral with saturated aqueous NaHCO3. The mixture
was filtered and the filtrate was concentrated to half the volume
under reduced pressure. The residue was dissolved in EtOAc, after
which the water phase was taken out and extracted with EtOAc.
The combined organic layers were washed with brine and dried
over Na2SO4. Concentration under reduced pressure gave the crude
product which was purified with column chromatography (EtOAc/
Hex 1/3). Purification gave a light yellow oil which crystallized
over time (5S,6S)-1 (68 mg) in 26% yield.
15. De Oliveira, R. N.; Cottier, L.; Sinou, D.; Srivastava, R. M. Tetrahedron 2005, 61,
8271–8281.
16. Guo, H.; O’Doherty, G. A. J. Org. Chem. 2008, 73, 5211–5220.
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20. Harris, J. M.; Keränen, M. D.; Nguyen, H.; Young, V. G.; O’Doherty, G. A.
Carbohydr. Res. 2000, 328, 17–36.
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2547.
22. Attempted hydrolysis of the isopropyl acetal with PPTS cleaved the TBS-group.
The lability of the TBS-group was rather surprising. The TBS-protected secondary
hydroxyl group is stable under these mild acidic conditions, see: Reichard, H. A.;
Rieger, J. C.; Micalizio, G. C. Angew. Chem., Int. Ed. 2008, 47, 7837–7840.
23. See Ref. 20.
4
8
5
HN
6
3
O
O
OTBS
2
1
O
O
1
2
7
3
4
O
O
TBSO
TBSO
6
5
1H NMR (300 MHz, CDCl3): d = 7.38–7.21 (m, 5H, Ar), 6.85 (dd,
J = 9.7, 3.4 Hz, 1H, H4), 5.97 (dd, J = 9.9, 1.7 Hz, 1H, H3), 4.37 (ddd,
J = 7.1, 5.2, 3.7 Hz, 1H, H6), 3.94 (dd, J = 11.0, 3.7 Hz, 1H, H7), 3.90
(A, JAB = 13.1 Hz, 1H, H8), 3.89 (B, JAB = 13.1 Hz, 1H, H8), 3.81 (dd,
J = 11.0, 5.3 Hz, 1H, H7), 3.68 (ddd, J = 7.1, 3.4, 1.8 Hz, 1H, H5),
0.86 (s, 9H), 0.06 (2 ꢃ s, 6H); 13C NMR (75 MHz, CDCl3): d = 163.2,
147.4, 139.7, 128.9, 128.4, 127.7, 120.5, 81.7, 63.1, 51.2, 50.4,
OTBS
OTBS
J (H-4,H-5) = 5.5 Hz
J (H-5,H-6) = 3.0 Hz
J (H-4,H-5) = 2.5 Hz
J (H-5,H-6) = 9.0 Hz
24. Blázquez, M. A.; Bermejo, A.; Zafra-Polo, M. C.; Cortes, D. Phytochem. Anal. 1999,
10, 161–170.
25. Albano, E.; Horton, D.; Tsuchiya, T. Carbohydr. Res. 1966, 2, 349.
26. Harding, K. E.; May, L. M.; Dick, K. F. J. Org. Chem. 1975, 40, 1664–1665.