Efficient microwave-assisted synthesis of hydroxymethyl ketones using NHC organocatalysts

Article abstract of DOI:10.1016/j.tet.2016.10.023

Hydroxymethyl ketones are useful auxiliaries in organic synthesis and are also found in several medicinal agents. N-Heterocyclic carbenes (NHCs) have been used in the literature in order to introduce the hydroxymethyl group into aromatic aldehydes in good yields, but they are not that successful for aliphatic aldehydes. In the present work, the use of microwave irradiation has been efficiently incorporated into this organocatalytic synthesis of aromatic, but more importantly of aliphatic hydroxymethyl ketones that can be used as precursors for medicinally interesting compounds.

Full text of DOI:10.1016/j.tet.2016.10.023

Accepted Manuscript
Efficient microwave-assisted synthesis of hydroxymethyl ketones using NHC
organocatalysts
Aikaterini Nikolaou, George Kokotos, Victoria Magrioti
PII:
S0040-4020(16)31045-6
10.1016/j.tet.2016.10.023
TET 28164
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 July 2016
Revised Date: 29 September 2016
Accepted Date: 10 October 2016
Please cite this article as: Nikolaou A, Kokotos G, Magrioti V, Efficient microwave-assisted synthesis of
hydroxymethyl ketones using NHC organocatalysts, Tetrahedron (2016), doi: 10.1016/j.tet.2016.10.023.
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Efficient microwave-assisted synthesis of
hydroxymethyl ketones using NHC
organocatalysts
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Aikaterini Nikolaou, George Kokotos, and Victoria Magrioti*
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens,
Panepistimiopolis, Athens 15771, Greece

1
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Tetrahedron
journal homepage: www.elsevier.com
Efficient microwave-assisted synthesis of hydroxymethyl ketones using NHC
organocatalysts
Aikaterini Nikolaou, George Kokotos and Victoria Magrioti
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Hydroxymethyl ketones are useful auxiliaries in organic synthesis and are also found in several
medicinal agents. N-Heterocyclic carbenes (NHCs) have been used in the literature in order to
introduce the hydroxymethyl group into aromatic aldehydes in good yields, but they are not that
successful for aliphatic aldehydes. In the present work, the use of microwave irradiation has
been efficiently incorporated into this organocatalytic synthesis of aromatic, but more
importantly of aliphatic hydroxymethyl ketones that can be used as precursors for medicinally
interesting compounds.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Green Chemistry; N-Heterocyclic Carbenes;
Hydroxymethyl ketones; Microwave irradiation;
Organocatalysis
———
Corresponding author. Tel.: +30-210-727-4497; fax: +30-210-727-4761; e-mail: vmagriot@chem.uoa.gr

2
Tetrahedron
1. Introduction
aliphatic hydroxymethyl ketones, the method had to be somehow
ACCEPTED MANUSCRIPT
modified in order to afford the aliphatic hydroxymethyl ketones
successfully.
Hydroxymethyl ketones are valuable intermediates as they can
be found in some pharmaceutical agents, but they can also be
used as useful building blocks for the synthesis of numerous
compounds of synthetic or pharmaceutical interest. For instance,
the α-hydroxymethyl ketone functionality can be found in
antidepressants, HIV-protease inhibitors, selective inhibitors of
amyloid-β protein production, agents for the treatment of
Alzheimer’s disease, antitumor antibiotics and antifungal
agents.1-5 Furthermore, several natural products that present
various pharmaceutical properties contain the hydroxymethyl
ketone motif.6-13
At first, the commercially available (1, 2)26 or easy to
synthesize (3)26,35 NHCs (Scheme 1) were used and catalyst 3
turned out to be the most efficient out of the three. As a
consequence, catalyst 3 was used in a series of reactions under
different experimental conditions, which aimed to optimize the
yield. Heptanal was used as starting material since aliphatic
substrates were the main scope of this study.
General synthetic methods reported in the literature for the
preparation of hydroxymethyl ketones include mostly oxidation
or hydrolysis reactions.5,14-21 More recently, several
organocatalytic methods have been published on the α-
hydroxylation of carbonyl compounds.22-26
N-Heterocyclic carbenes (NHCs) have been demonstrated to
be efficient synthetic tools as organocatalysts in various
reactions,27,28 such as benzoin reactions, the Stetter reaction and
nucleophilic substitution reactions, etc., due to simple reaction
handling, environmental friendliness, low cost and toxicity
compared to transition-metal catalysts; and the fact that new
synthetic strategies are made possible.29 In particular, the
inversion of the classical reactivity known as umpolung opens up
new synthetic pathways. On the other hand, microwave (MW)
irradiation is considered to be a more green mode of activation
than conventional heating and provides several advantages,30-33
such as significant acceleration as a result of the more efficient
energy transfer to the reaction mixture combined with pressure
effects, higher yields under milder reaction conditions and higher
product purities. Interestingly enough, the application of
microwave technology has not been widely used in
organocatalytic reactions, even though prolonged reaction time
and heat is used in several cases. In our effort to synthesize
hydroxymethyl ketones we decided to use NHCs combined with
MW irradiation, as they both seemed promising, in a reaction that
involves the formation of a new C-C bond.
Scheme 1. N-Heterocyclic carbenes used as organocatalysts
in this study.
In the literature26,36,37 the corresponding experimental
conditions mentioned heating at 60 οC for 24 h and several ratios
of aldehyde:paraformaldehyde:catalyst:base, e.g. 1 mol:2 mol:10
mol%:20 mol%, using various catalysts including structures 1-4.
To study this method, the reaction was tested using a ratio of
aldehyde:paraformaldehyde:catalyst:base
1
mol:2 mol:20
mol%:20 mol% via the conventional heating method (ꢀ), but all
three catalysts (1-3) afforded the product in low yields, despite
the prolonged reaction times (Table 1, Entries 2, 4, 5).
Changes in the molar ratio (Table 1, Entry 3) and also use of
microwave irradiation (MW) were studied (Table 1, Entries 10-
18) in order to both optimize the yield and minimize the reaction
time. Indeed, the new conditions, and especially the use of
microwaves, which has never been mentioned in the literature for
such a reaction, significantly improved the synthesis of the
hydroxymethyl ketones.
After having these promising results with the use of MW
irradiation, catalyst 4 was synthesized and examined in the new
MW methodology, as it was reported to give higher yields in the
2. Results and Discussion
conventional
heating
procedure.26
The
ratio
of
In the present work, a microwave-assisted method catalyzed
by NHCs was studied to introduce the hydroxymethyl group in
aliphatic and aromatic aldehydes. Recently, Kuhl and Glorius
described a strategy based on the NHC catalyzed umpolung
reactivity of aromatic aldehydes reacting with paraformaldehyde
aldehyde:paraformaldehyde:catalyst:base was also slightly
changed when compared to the reported 1 mol:3 mol:10
mol%:20 mol% while incorporating microwave irradiation, and
as it turned out catalyst 4 was even more efficient (Table 1,
Entries 19-20).
26
using several NHC precursors including compounds 1-4
(Scheme 1) by the formation of the Breslow-intermediate, a
mechanism recently confirmed by Berkessel et al.34 In that
synthetic study, only few examples of the use of an aliphatic
aldehyde were described and only afforded the hydroxymethyl
ketone in low yields. Since our target was the synthesis of such
It is essential to point out that using the same molar ratio of
the reagents, a yield of 7% in 24 h and 10% in 48 h of 60 °C
conventional heating, turned into a yield of 58% in just 1 h and at
100 °C with MW irradiation (Table 1, Entries 8, 9, 20).
Table 1. Synthesis of 1-hydroxyoctan-2-one.
(CH2O)n
Catalyst
(mol%)
10
DIPEA
Entry
Method
Catalyst
Solvent
Τ/oC
t/h
Yield(%)
(eq)
2
(mol%)
20
1
2
3
ꢀ
ꢀ
ꢀ
1
1
1
THF
THF
THF
60
60
60
48
24
48
4
2
20
20
20
16
2
50
50

3
4
ꢀ
2
3
4
4
4
4
1
2
3
3
3
3
3
3
3
4
4
2
2
2
2
3
3
2
2
2
2
2
2
3
1
2
2
3
20
20
THF
60
48
96
48
48
24
48
1
-
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5
ꢀ
20
20
20
10
10
20
20
20
20
20
20
20
20
10
20
10
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
THF
THF
DMF
THF
THF
-
60
10
22
24
7
6
ꢀ
60
7
ꢀ
120
60
8
ꢀ
9
ꢀ
60
10
19
4
10
11
12
13
14
15
16
17
18
19
20
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
120
120
120
120
100
100
120
120
120
100
100
-
1
-
1
28
36
36
36
28
27
30
40
58
DMF
DMF
THF
-
1
1
1
1
DMF
DMF
THF
THF
1
1
1
1
Table 2. Synthesis of 1-hydroxy-3-phenylbutan-2-one.
(CH2O)n
Catalyst
Yield
(%)
31
Entry
Method
Catalyst
Solvent
Τ/oC
t/h
(eq)
2
(mol%)
20
1
2
3
4
MW
MW
MW
ꢀ
3
4
4
4
DMF
DMF
THF
THF
120
120
100
60
1
2
20
1
38
3
10
1
63
3
10
24
18
In order to study the application of this methodology on
different aliphatic aldehydes, several reaction conditions were
tested on 2-phenylpropanal, an aliphatic aldehyde that has a
secondary carbon atom next to the carbonyl moiety (Table 2).
aminoaldehydes 21, 23, 25 and 29. It should be noted that even
though several experiments (Chiral HPLC and NMR analysis of
Mosher esters and amides) were conducted to find out whether
the final products 22, 24 and 26 where optically pure, the results
were inconclusive. Finally, the N-Boc protected α-
aminoaldehydes yielded the corresponding hydroxymethyl
ketones in higher yields than the N-Cbz protected α-amino
aldehyde.
Once again, it was obvious that the microwave assisted
reaction conditions, optimized for heptanal, yielded the desired
product in far better yield (Table 2, Entry 3) than the
corresponding conventional heating reaction conditions (Table 2,
Entry 4).
Using the most efficient reagent ratios and conditions with
microwave irradiation, the hydroxymethyl ketones shown in
Table 3 were successfully synthesized. When compared to the
Table 3. Hydroxymethyl ketones synthesized by the
microwave-assisted method using catalyst 4.
previously reported26 yield of 57% after 24
h heating,
hydroxymethyl ketone 12 was synthesized using our MW
methodology in a slightly higher yield, but in the significantly
shorter time of just one hour.
Entry
Reactant
Product
Yield (%)
58
1
We have to report that, interestingly enough, this methodology
did not work as well for aromatic substrates such as compounds
15 and 17. On the other hand, this green method worked better
for p-anisaldehyde 19 yielding hydroxymethyl ketone 20 in 45%,
while the classic heating method yielded it in just 32%.
6
5
2
3
63
42
8
7
9
Furthermore, this method was used in order to synthesize
optically active hydroxymethyl ketones 22, 24, 26 and 30,
starting from the corresponding N-protected α- or β-
10

4
Tetrahedron
used without further purification. All the products gave
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satisfactory elemental analysis results.
4
59
4.2. General procedure for the microwave-assisted synthesis of
hydroxymethylketones from the corresponding aldehydes
11
13
12
14
5
6
55
45
To a solution of the aldehyde (1 mmol) in dry THF (0.29 mL)
in the appropriate MW vial was added paraformaldehyde (3
mmol, 90 mg), catalyst
4
(0.1 mmol, 37 mg) and
diisopropylethylamine (0.2 mmol, 26 mg, 35 ꢁL). The vial was
flushed with argon and then inserted in the MW apparatus for 1
h, under stirring at 100 C (max temperature) and at 50 Watts
15
17
16
18
o
(max energy). After 1 h, the solvent was evaporated under
reduced pressure, H2O (15 mL) and CH2Cl2 (15 mL) were added
to the mixture and the layers separated. The aqueous layer was
extracted twice with CH2Cl2 (15 mL) and the combined organic
layers were dried over Na2SO4. The solvent was evaporated
under reduced pressure and the final product obtained after flash
column chromatography using the appropriate eluent.
7
8
32
45
20
22
24
19
21
23
4.2.1. 1-Hydroxyoctan-2-one3 8 (6)
9
51
48
Yield 58% (146 mg); Yellow oil; Flash column
o
chromatography eluent: petroleum ether (b.p. 40-60 C) / ethyl
acetate 9/1 to 7/3; δH (200 MHz, CDCl3) 4.21 (2H, s, CH2OH),
3.05 (1H, s, OH), 2.38 (2H, t, J 8.0 Hz, CH2), 1.80-1.50 (2H, m,
CH2), 1.40-1.10 (6H, m, CH2), 0.85 (3H, t, J 6.0 Hz, CH3); δC (50
MHz, CDCl3) 209.9, 68.0, 38.3, 31.4, 28.7, 23.6, 22.3, 13.9; m/z
(ESI) (%) 145.3 [(M+H)+, 52].
10
O
OH
11
12
30
NHCbz
4.2.2. 1-Hydroxy-3-phenylbutan-2-one2 6 (8)
25
27
26
18a
Yield 63% (182 mg); Yellow oil; Flash column
chromatography eluent: petroleum ether (b.p. 40-60 C) / ethyl
o
28
acetate 9/1 to 7/3; δH (200 MHz, CDCl3) 7.50-7.00 (5H, m,
arom), 4.20 (2H, s, CH2OH), 3.77 (1H, q, J 4.0 Hz, CH), 2.88
(1H, s, OH), 1.48 (3H, d, J 4.0 Hz, CH3); δC (50 MHz, CDCl3)
210.0, 139.3, 129.1, 127.7, 127.6, 66.8, 49.1, 17.1; m/z (ESI) (%)
165.2 [(M+H)+, 48].
13
50
29
30
aThe low yield is due to the volatility of both starting material
and product.
4.2.3. (Z)-1-Hydroxynonadec-10-en-2-one (10)
Yield 42% (210 mg); White solid; mp. 35-38 οC; Flash
column chromatography eluent: petroleum ether (b.p. 40-60 oC) /
ethyl acetate 9/1; Rf (20% AcOEt/PE) 0.48; vmax(KBr) 3400,
2922, 1722, 1463, 1406, 1378, 1075 cm-1; δH (200 MHz, CDCl3)
5.50-5.20 (2H, m, CH), 4.20 (2H, s, CH2OH), 3.20 (1H, s, OH),
2.36 (2H, t, J 6.0 Hz, CH2CH2CO), 2.10-1.80 (4H, m,
2xCH2CH), 1.70-1.40 (2H, m, CH2), 1.40-1.00 (20H, m, CH2),
0.84 (3H, t, J 6.0 Hz, CH3); δC (50 MHz, CDCl3) 209.8, 129.9,
129.5, 68.0, 38.3, 31.8, 29.7, 29.6, 29.4, 29.3, 29.2, 29.1, 29.0,
27.1, 27.0, 25.5, 23.6, 22.6, 14.0; m/z (ESI) (%) 295.4 [(M-H)-,
100]; HRMS (EI): MH-, found 295.2649. C19H36O2 requires
295.2643.
3. Conclusion
To conclude, a new microwave-assisted method has been
developed, which allows the synthesis of both aliphatic and
aromatic hydroxymethyl ketones via NHC organocatalysis
starting from the corresponding aldehydes. In this method,
thiazolium catalyst 4 proved to be the most efficient and the
optimal conditions were 1 mol:3 mol:10 mol%:20 mol% of
aldehyde:paraformaldehyde:catalyst:base in THF at 100 °C for 1
h. It is important to note that by using this procedure, one can
synthesize aliphatic hydroxymethyl ketones in good yields,
something not reported in the past.
4.2.4. 1-Cyclohexyl-2-hydroxyethan-1-one2 6 (12)
4. Experimental
Yield 57% (143 mg); Yellow oil; Flash column
chromatography eluent: petroleum ether (b.p. 40-60 C) / ethyl
o
4.1. General
acetate 8/2 to 7/3; δH (200 MHz, CDCl3) 4.26 (2H, s, CH2OH),
3.38 (1H, s, OH), 2.50-2.20 (1H, m, CH), 2.00-1.50 (4H, m,
CH2), 1.50-1.10 (6H, m, CH2); δC (50 MHz, CDCl3) 212.7, 66.4,
47.0, 28.8, 25.8, 25.4; m/z (ESI) (%) 143.3 [(M+H)+, 57].
Melting points were determined on a Buchi 530 apparatus and
are uncorrected. Nuclear magnetic resonance spectra were
obtained on a Varian Mercury spectrometer (1H NMR recorded at
200 MHz, 13C NMR recorded at 50 MHz) and were recorded in
chloroform (CDCl3), using the CHCl3 residual peak as the 1H
internal reference (7.27 ppm); and the central peak of CDCl3 at
77.0 ppm for 13C NMR. Thin layer chromatography (TLC) plates
(silica gel 60 F254) and silica gel 60 (230-400 mesh) for flash
column chromatography were purchased from Merck.
Visualization of spots was effected with UV light and/or
phosphomolybdic acid, in EtOH stain. Tetrahydrofuran and DMF
were dried by standard procedures and stored over molecular
sieves. All other solvents and chemicals were reagent grade and
4.2.5. 1-Hydroxy-6-phenylhexan-2-one3 9 (14)
Yield 55% (150 mg); Yellow oil; Flash column
o
chromatography eluent: petroleum ether (b.p. 40-60 C) / ethyl
acetate 9/1 to 7/3; δH (200 MHz, CDCl3) 7.50-7.00 (5H, m,
arom), 4.21 (2H, s, CH2OH), 3.16 (1H, s, OH), 2.62 (2H, t, J 6.0
Hz, CH2), 2.41 (2H, t, J 6.0 Hz, CH2), 1.90-1.50 (4H, m, CH2); δC
(50 MHz, CDCl3) 209.6, 141.8, 128.3, 125.8, 68.0, 38.1, 35.5,
30.8, 23.2; m/z (ESI) (%) 193.2 [(M+H)+, 51].

5
4.2.6. 2-Hydroxy-1-phenylethan-1-one4 0 (16)
Yield 18% (55 mg); Yellow oil; Flash column
ACCEPTED MANUSCRIPT
o
Yield 45% (110 mg); White solid; mp. 83-85 οC (lit mp 84-85
chromatography eluent: petroleum ether (b.p. 40-60 C) / ethyl
acetate 8/2 to 6/4; δH (200 MHz, CDCl3) 4.20 (2H, s, CH2OH),
3.23 (1H, s, OH), 2.39 (2H, q, J 8.0 Hz, CH2CH3), 1.07 (3H, t, J
8.0 Hz, CH3); δC (50 MHz, CDCl3) 210.3, 67.6, 31.5, 7.4; m/z
(ESI) (%) 87.2 [(M-H)-, 100].
οC40); Flash column chromatography eluent: petroleum ether (b.p.
o
40-60 C) / ethyl acetate 9/1 to 7/3; δH (200 MHz, CDCl3) 7.91
(2H, d, J 8.0 Hz, arom), 7.80-7.20 (3H, m, arom), 4.87 (2H, s,
CH2OH), 3.52 (1H, s, OH); δC (50 MHz, CDCl3) 198.4, 134.3,
128.9, 127.6, 65.4; m/z (ESI) (%) 135.0 [(M-H)-, 45].
4.2.7. Methyl 4-(2-hydroxyacetyl)benzoate2 6 (18)
Yield 32% (110 mg); White solid; mp. 154-156 οC; Flash
column chromatography eluent: CH2Cl2 / MeOH 98/2; δH (200
MHz, CDCl3) 8.16 (2H, d, J 8.0 Hz, arom), 7.98 (2H, d, J 8.0 Hz,
arom), 4.92 (2H, s, CH2OH), 3.96 (3H, s, OCH3), 3.42 (1H, s,
OH); δC (50 MHz, CDCl3) 214.5, 168.1, 130.4, 130.1, 128.2,
127.6, 65.8, 52.6; m/z (ESI) (%) 195.1 [(M+H)+, 55].
4.2.13. Methyl (R)-2-((bi-tert-
butoxycarbonyl)amino)-5-hydroxy-4-oxopentanoate
(30)
ο
20
Yield 50% (180 mg); Yellow solid; mp. 108-110 C; [α]D
-
69.4 (c 1, CHCl3). Flash column chromatography eluent:
petroleum ether (b.p. 40-60 oC) / ethyl acetate 8/2 to 6/4; Rf (50%
AcOEt/PE) 0.52; vmax(KBr) 3472, 2973, 1744, 1727, 1707, 1480,
1458, 1369, 1100, 1037, 1021 cm-1; δH (200 MHz, CDCl3) 5.60-
5.40 (1H, m, CH), 4.42-4.14 (2H, m, CH2OH), 3.66 (3H, s,
OCH3), 3.38 (1H, dd, J 18.0, 8.0 Hz, CHH), 3.04 (1H, s, OH),
2.59 (1H, dd, J 18.0, 6.0 Hz, CHH), 1.45 (18H, s, Boc); δC (50
MHz, CDCl3) 206.2, 170.3, 151.6, 83.7, 68.2, 54.09, 52.6, 39.3,
27.8; m/z (ESI) (%) 360.3 [(M-H)-, 100]; HRMS (EI): MH-,
found 360.1656. C16H27NO8 requires 360.1664.
4.2.8. 2-Hydroxy-1-(4-methoxyphenyl)ethan-1-one4 1
(20)
Yield 45% (130 mg); Yellow solid; mp. 95-97 οC (lit mp 98.5-
100.5 οC41); Flash column chromatography eluent: petroleum
ether (b.p. 40-60 C) / ethyl acetate 9/1 to 7/3; δH (200 MHz,
o
CDCl3) 7.89 (2H, d, J 8.0 Hz, arom), 6.96 (2H, d, J 8.0 Hz,
arom), 4.81 (2H, s, CH2OH), 3.87 (3H, s, OCH3), 3.51 (1H, s,
OH); δC (50 MHz, CDCl3) 196.7, 164.3, 132.2, 130.0, 114.1,
64.9, 55.5; m/z (ESI) (%) 167.3 [(M+H)+, 70].
References and notes
4.2.9. tert-Butyl (4-hydroxy-3-oxo-1-phenylbutan-2-
1.
2.
Adam, W.; Lazarus, M.; Saha-Möller, C. R.; Schreier, P.
Acc. Chem. Res. 1999, 32, 837-845.
Wallace, O. B.; Smith, D. W.; Deshpande, M. S.; Polson,
C.; Felsenstein, K. M. Bioorg. Med. Chem. Lett. 2003, 13,
1203-1206.
yl)carbamate (22)
ο
20
Yield 51% (270 mg); Yellow solid; mp. 96-98 C; [α]D -1.2
(c 0.5, CHCl3). Flash column chromatography eluent: petroleum
ether (b.p. 40-60 oC) / ethyl acetate 8/2 to 6/4; Rf (50%
AcOEt/PE) 0.58; vmax(KBr) 3446, 3366, 2967, 2929, 1727, 1680,
1515, 1171 cm-1; δH (200 MHz, CDCl3) 7.50-7.00 (5H, m, arom),
5.12 (1H, d, J 7.4 Hz, NH), 5.30-4.90 (1H, m, CH), 4.27 (1H, d, J
20.0 Hz, CHHOH), 4.11 (1H, d, J 20.0 Hz, CHHOH), 3.40-2.60
(3H, m, OH, CH2Ph), 1.38 (9H, s, C(CH3)3); δC (50 MHz, CDCl3)
209.4, 155.2, 135.6, 129.0, 128.8, 127.2, 80.3, 67.2, 57.8, 37.4,
28.1; m/z (ESI) (%) 280.0 [(M+H)+, 100]; HRMS (EI): MH-,
found 278.1390. C15H21NO4 requires 278.1398.
3.
4.
5.
6.
7.
Tanaka, T.; Kawase, M.; Tani, S. Bioorg. Med. Chem.
2004, 12, 501-505.
Hoyos, P.; Sinisterra, J. V.; Molinari, F.; Alcántara, A. R.;
De María, P. D. Acc. Chem. Res. 2010, 43, 288-299.
Calam, E.; Porté, S.; Fernández, M. R.; Farrés, J.; Parés,
X.; Biosca, J. A. Chem-Biol. Interact. 2013, 202, 195-203.
Chen, H.-D.; Yang, S.-P.; Wu, Y.; Dong, L.; Yue, J.-M.
Journal of Natural Products 2009, 72, 685-689.
Su, J.-H.; Tseng, S.-W.; Lu, M.-C.; Liu, L.-L.; Chou, Y.;
Sung, P.-J. Journal of Natural Products 2011, 74, 2005-
2009.
4.2.10. tert-Butyl (4-hydroxy-3-oxo-1-phenylbutan-
2-yl)carbamate (24)
ο
20
Yield 48% (160 mg); Yellow solid; mp. 96-98 C; [α]D +0.8
(c 1.0, CHCl3). Flash column chromatography eluent: petroleum
ether (b.p. 40-60 oC) / ethyl acetate 8/2 to 6/4; Rf (50%
AcOEt/PE) 0.58; vmax(KBr) 3446, 3366, 2967, 2929, 1727, 1680,
1515, 1171 cm-1; δH (200 MHz, CDCl3) 7.50-7.00 (5H, m, arom),
5.12 (1H, d, J 7.4 Hz, NH), 5.30-4.90 (1H, m, CH), 4.27 (1H, d, J
20.0 Hz, CHHOH), 4.11 (1H, d, J 20.0 Hz, CHHOH), 3.40-2.60
(3H, m, OH, CH2Ph), 1.38 (9H, s, C(CH3)3); δC (50 MHz, CDCl3)
209.4, 155.2, 135.6, 129.0, 128.8, 127.2, 80.3, 67.2, 57.8, 37.4,
28.1; m/z (ESI) (%) 280.0 [(M+H)+, 100]; HRMS (EI): MH-,
found 278.1393. C15H21NO4 requires 278.1398.
8.
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4.2.11. Benzyl (4-hydroxy-3-oxo-1-phenylbutan-2-
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Yield 30% (70 mg); Yellow solid; mp. 112-114 οC (lit
12.
13.
20
mp 76.5-77.5 οC42); [α]D -2.9 (c 1.0, CHCl3). Flash column
o
chromatography eluent: petroleum ether (b.p. 40-60 C) / ethyl
acetate 8/2 to 6/4; δH (200 MHz, CDCl3) 7.60-6.90 (10H, m,
arom), 5.48 (1H, d, J 8.0 Hz, NH), 5.04 (2H, s, OCH2Ph), 4.70-
4.50 (1H, m, CH), 4.30-4.00 (2H, m, CH2OH), 3.43-2.70 (3H, m,
OH, CH2Ph); δC (50 MHz, CDCl3) 208.9, 155.8, 135.9, 135.3,
129.0, 128.8, 128.5, 128.2, 128.0, 127.2, 67.2, 67.1, 57.4, 37.5;
m/z (ESI) (%) 331.1 [(M+NH4)+, 55, 314.2 [(M+H)+, 35].
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6
Tetrahedron
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