A route to 1,2-diols by enantioselective organocatalytic α-oxidation with molecular oxygen

Article abstract of DOI:10.1016/j.tetlet.2006.04.133

A route to 1,2-diols by the direct organocatalytic enantioselective α-oxidation of aldehydes using molecular oxygen is presented. Protected commercially available chiral pyrrolidines catalyze the asymmetric α-oxidation of aldehydes with singlet molecular oxygen with high enantioselectivity to furnish the corresponding diols after in situ reduction in high yield with up to 98% ee. Electrophilic singlet molecular oxygen was photo or chemically generated ('dark' ¹O₂).

Full text of DOI:10.1016/j.tetlet.2006.04.133

Tetrahedron Letters 47 (2006) 4659–4663
A route to 1,2-diols by enantioselective organocatalytic
a-oxidation with molecular oxygen
*
´
´
Ismail Ibrahem, Gui-Ling Zhao, Henrik Sunden and Armando Cordova
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 27 March 2006; revised 18 April 2006; accepted 26 April 2006
Available online 18 May 2006
Abstract—A route to 1,2-diols by the direct organocatalytic enantioselective a-oxidation of aldehydes using molecular oxygen is
presented. Protected commercially available chiral pyrrolidines catalyze the asymmetric a-oxidation of aldehydes with singlet mole-
cular oxygen with high enantioselectivity to furnish the corresponding diols after in situ reduction in high yield with up to 98% ee.
1
Electrophilic singlet molecular oxygen was photo or chemically generated (‘dark’ O2).
ꢀ 2006 Elsevier Ltd. All rights reserved.
Optically active 1,2-diols are common in numerous
important natural products and synthetic pharmaceuti-
cals.1 This has led to the development of diastereoselec-
tive and enantioselective routes for their synthesis,
among them, the Sharpless asymmetric dihydroxylation
of olefins with osmium tetraoxide is one of the most
often used.2 Moreover, several indirect methods exist
for their preparation.3 Enzymatic resolution has also
been employed as a key step for their synthesis.4 Most
of these preparations, however, require multiple manip-
ulations, and no direct method from the corresponding
aldehyde is available. For these reasons, the develop-
ment of new methodologies for the direct catalytic enan-
tioselective a-hydroxylation of aldehydes has become an
intriguing target in organic synthesis. In this context,
Momiyama and Yamamoto have reported an excellent
catalytic asymmetric nitroso-aldol reaction between pre-
formed tin enolates and nitrosobenzene in the presence
of a catalytic amount of a BINAP–AgOTf complex.5
Organocatalysis is a rapidly developing area of research
in organic chemistry.6 Most recently, amino acids and
their derivatives were reported to catalyze a-oxidation
reactions with nitrosobenzene as the oxygen source to
give a-aminoxylated aldehydes and ketones.7 Further-
more, we recently demonstrated that amino acids cata-
lyze the biomimetic, asymmetric, aerobic a-oxidation
of aldehydes with moderate enantioselectivity.8
Molecular oxygen or air is considered a ‘green oxidant’
and is used in modern oxidation methods.9,10 Molecular
oxygen can be transferred between its more reactive sin-
glet state (1O2) and its non-excited triplet state (3O2).11
In this context, chemists have utilized photo or chemi-
1
cally generated molecular O2 as an oxygen source for
several synthetic transformations.12 Based on our re-
search interest in the development of organocatalytic
asymmetric reactions13 and our previous research expe-
rience in catalytic C–O bond formation with alde-
hydes,7h,8 we envisioned a ‘green’ oxidation route for
the asymmetric construction of 1,2-diols based on chiral
amine-catalyzed enantioselective a-oxygenation of alde-
1
hydes with O2 followed by in situ reduction of the cor-
responding a-hydroxyaldehyde. We envisioned that the
employment of a bulky chiral pyrrolidine derivative as
the catalyst would enable shielding of one of the faces
of the catalytically generated chiral enamine and conse-
quently give high levels of asymmetric induction
(Scheme 1).
Herein, we report a simple route to 1,2-diols by
direct organocatalytic enantioselective a-oxidation of
Ar
Ar
N
OR
H
1a: R = H;
Ar = Ph
1b: R = TMS, Ar = Ph
1c: R = TMS, Ar = 2-Naphthyl
1d: R = TMS, Ar = 3,5-CF3-C6H3
*
Corresponding author. Tel.: +46 8 162479; fax: +46 8 154908; e-mail
addresses: acordova@organ.su.se; acordova1a@netscape.net
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.133

4660
I. Ibrahem et al. / Tetrahedron Letters 47 (2006) 4659–4663
we decided to continue our study and investigate the
H2O
1O2
N
possibility of utilizing TMS protected diarylprolinols
(1b–d)15 as the catalysts (Table 1).
H
R
To our delight, TMS protection of diphenylprolinol 1a
had a remarkable effect on the reactivity and enantio-
selectivity of the reaction. That is, the organocatalyst
1b catalyzed the asymmetric formation of 3a in 43%
yield with 90% ee within 5 h. Increasing, the bulk of
the aryl groups on the catalyst 1 from phenyl to 2-naph-
thyl (catalyst 1c) slightly increased the enantioselectivity
of the reaction and diol 4a was isolated in moderate
yield with 92% ee. The chiral diarylprolinol 1d was the
most efficient catalyst and gave diol 4a in 50% yield with
70% ee. The order of asymmetric induction by the pro-
tected diaryprolinols was as follows 1c > 1b > 1d. Cata-
lyst 1b was selected for further studies, since it gave a
high asymmetric induction and can be prepared from
commercially available 1a in one-step. Thus, the chiral
amine 1b catalyzed asymmetric a-oxidation of heptanal
2b with molecular oxygen was investigated in different
solvents (Table 2). The solvent screen was performed
at low conversion (<50%, 0.5–2.5 h), since ice had to
be added manually in order to maintain the desired
temperature.
O
H
R
+
-
N
O
O
N
H
H
R
H+
H2O
H2O, H+
OH
O
O
O
HO
H
H
R
R
Scheme 1. Direct organocatalytic asymmetric a-oxidations of alde-
hydes with 1O2.
aldehydes with molecular oxygen, which after in situ
reduction provides the corresponding diols with up to
98% ee.
We initially decided to investigate the commercially
available diphenyl-2-pyrrolidinemethanol (1a, diphenyl-
prolinol), which has been developed by Corey and co-
workers, as a catalyst.14
The protected diphenylprolinol 1b catalyzed the reaction
with moderate to high enantioselectivity under all the
conditions tested. For instance, the reactions in CHCl3
and MeOH gave 1,2-diol 4b with 80 and 81% ee’s, respec-
tively, after in situ reduction of 3b. Aubry, Alsters and
co-workers have reported an excellent way of chemically
generating singlet molecular oxygen (‘dark’ 1O2) by using
La(NO2) · 6H2O as the catalyst and H2O2.16 Hence, the
organocatalytic a-oxygenation reactions were also per-
formed with ‘dark’ 1O2 and catalyst 1b (10 mol %) to give
the corresponding diol 4b in 23% and 26% yields with
80% and 72% ee, respectively (entries 2 and 4). These
results represent the first direct catalytic asymmetric
reactions with ‘dark’ 1O2. We next performed the organo-
catalytic asymmetric a-oxidation of aldehydes with a set
of different aldehydes 2 (Table 3).17
Hence, 3-phenylpropionaldehyde 2a (0.5 mmol) was
added to a scintillation vial containing CHCl3 (2 mL),
1a (10 mol %) and tetraphenylporphine (TPP)
(1 mol %) at 0 ꢁC. A continuous flow of O2 or air was
bubbled through the vial and the reaction exposed to
visible light from two 250 W high-pressure sodium
lamps (Table 1, entry 1). After 4 h of stirring and main-
taining the temperature at 0 ꢁC, the light was switched
off and the reaction diluted with MeOH (2 mL) followed
by in situ reduction of the a-hydroxy aldehyde 3a with
excess NaBH4 to give the crude diol 4a, which was puri-
fied by silica-gel column chromatography. Diacetylation
of the pure diol 4a gave the corresponding diacetate in
trace amounts with 24% ee. Thus, the reaction exhibited
poor reactivity and low enantioselectivity. Nevertheless,
The protected diphenyl prolinol 1b catalyzed a-oxygen-
ation reactions were efficient and highly enantioselective
and furnished aldehydes 4a–f in high yields with 74–98%
Table 1. Catalyst screen
O
O
1
NaBH4
(10 mol%)
HO
HO
1O2
H
H
OH
+
R
R
R
4a
TPP (1 mol%)
MeOH
2a: R = PhCH2
3a
CHCl3, 0 °C
Entry
Catalyst
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
1a
1b
1c
1d
4
5
5
4
Trace
43
38
24
90
92
70
50
a Isolated yield of pure diacetylated 4a.
b Ee as determined by chiral-phase HPLC analyses.

I. Ibrahem et al. / Tetrahedron Letters 47 (2006) 4659–4663
4661
Table 2. Solvent screen
O
O
1b
NaBH4
MeOH
(10 mol%)
HO
HO
H
1O2
H
OH
+
R
R
3b
R
4b
solvent, 0-4 °C
2b: R = n-pent
Entry
Solvent
Conditions
Time (h)
Yielda (%)
eeb
1
2
3
4
5
6
7
8
CHCl3
CHCl3
MeOH
MeOH
CCl4
DMF
DMSO
t-BuOH–H2O
A
B
A
B
A
A
A
A
2
20
0.5
20
1.1
2.5
1
28
23
10
26
15
43
34
12
80
80
81
72
76
67
54
70
1
O
9
A
1
6
57
S
O
A: The singlet oxygen was generated by TPP (1 mol %) and two 250-W high-pressure sodium lamps in CHCl3. B: The singlet oxygen was catalytically
generated from H2O2 by LaIII according to Ref. 16 in MeOH (1 mL) at room temperature.
a Isolated yield of pure diacetylated 4b.
b Ee as determined by chiral-phase GC analyses.
Table 3. Chiral amine 1b catalyzed asymmetric a-oxidations of aldehydes 2 with 1O2
O
O
1b
NaBH4
MeOH
(20 mol%)
HO
HO
1O2
H
H
OH
+
R
R
4
R
3
TPP (1 mol%)
2
0 °C, 6h
Entry
Aldehyde
R
Prod.
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
2a
2a
2b
2c
2d
2e
2f
Bn
Bn
n-Pent
4-NO2C6H4CH2
4-ClC6H4CH2
4-BrC6H4CH2
n-Butyl
4a
4a
4b
4c
4d
4e
4f
70
50c
67
64
71
68
76
87
90c
75
98
98
98
74
a Isolated yield of pure diacetylated 4a.
b Ee as determined by chiral-phase HPLC or GC analyses.
c 10 mol % catalyst.
ee. In particular, the reactions with aldehydes 2c–e pro-
ceed with excellent enantioselectivity and gave the corre-
sponding aldehydes 4c–e with 98% ee. The dependence
of the enantioselectivity of the reaction was also investi-
gated as a function of the optical purity of the catalyst
1b (Fig. 1). No non-linear effects were observed. The
absolute stereochemistry of the 1,2-diols 4 was (2S) as
established by comparison with literature and chiral-
phase HPLC analysis.3a,7,8 Based on the absolute stereo-
chemistry of the (2S)-1,2-diols, we propose intermediate
I to account for the stereochemical outcome of the pro-
tected diarylprolinol 1b–d catalyzed a-oxidation reac-
tion of aldehydes with molecular oxygen. The high
enantioselectivity of the a-oxygenation reaction can be
explained by an efficient shielding of the Si-face of the
chiral enamine and stabilization of the trans-configura-
tion of the chiral enamine. Thus, the chiral enamine at-
Ar
Ar
OSiR3
N
1O2
H
R
I
The remarkable change of reactivity by TMS protection
of the diarylprolinol 1a was explained by prevention of
aminal formation with the substrate or product and
the increased hydrophobicity of the corresponding
diarylprolinol 1b, which improves the rate of enamine
formation with aldehydes 2. The organocatalytic a-oxi-
dations with ‘dark’ 1O2 confirmed that this was the elec-
trophile and not 3O2. Furthermore, no product was
observed in the amine 1 catalyzed a-oxidation reactions
with molecular oxygen without addition of TPP
sensitizer.
1
tacks the O2 from its Re-face.

4662
I. Ibrahem et al. / Tetrahedron Letters 47 (2006) 4659–4663
100
90
80
70
60
50
40
30
20
10
0
0
10
20
30
40
50
60
70
80
90
100
Catalyst 1b Ee (%)
Figure 1. Relationship between the enantiomeric excess of (S)-1b and that of the newly formed aldiol 4b (j).
Reinhold, U. Liebigs Ann. 1996, 11; (h) Janey, J. M. J.
Angew. Chem., Int. Ed. 2005, 44, 2492.
4. Burkart, M. D.; Zhang, Z.; Hung, S.-C.; Wong, C.-H.
J. Am. Chem. Soc. 1997, 119, 11743.
5. Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003,
125, 6038.
6. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001,
40, 3726; (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138; (c) Marigo, M.; Jørgensen, K. A.
Chem. Commun. 2006. Adv. Article.
7. (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247; (b)
Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2003, 125, 10808; (c) Hayashi,
Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron
Lett. 2003, 44, 8293; (d) Hayashi, Y.; Yamaguchi, J.;
Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293; (e)
Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Angew.
Chem., Int. Ed. 2004, 43, 1112; (f) Hayashi, Y.; Yama-
guchi, J.; Sumiya, T.; Hibino, K.; Shoji, M. J. Org. Chem.
In summary, we report a simple route to 1,2-diols by
organocatalytic enantioselective a-oxidation with
molecular oxygen. Protected diaryl prolinols catalyzed
the reaction with excellent enantioselectivity and the
corresponding 1,2-diols were isolated in high yields with
up to 98% ee. The electrophile was photo or chemically
1
generated O2. In fact, the organocatalytic transforma-
tions represent the first examples of direct catalytic
asymmetric reactions with ‘dark’ 1O2. The methodology
presented herein demonstrates that commercially avail-
able non-toxic catalysts can catalyze highly enantioselec-
tive a-oxidations of aldehydes with the ‘green oxidant’
molecular oxygen.
Acknowledgements
´
´
´
2004, 69, 5966; (g) Bøgevig, A.; Sunden, H.; Cordova, A.
We gratefully acknowledge the Swedish National
Research Council, The Swedish Research Council
for Environment, Agricultural Sciences and Spatial
Planning and Carl-Trygger Foundation for financial
support.
Angew. Chem., Int. Ed. 2004, 43, 1109; (h) Cordova, A.;
Sunden, H.; Bøgevig, A.; Johansson, M.; Himo, F. Chem.
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Eur. J. 2004, 10, 3673.
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8. Cordova, A.; Sunden, H.; Engqvist, M.; Ibrahem, I.;
Casas, J. J. Am. Chem. Soc. 2004, 126, 8914.
9. Eissen, M.; Metzger, J. O.; Schmidt, E.; Schneidewind, U.
Angew. Chem., Int. Ed. 2002, 41, 414.
10. Ba¨ckvall, J.-E. Modern Oxidation Methods; Wiley-VCH:
Weinheim, 2004.
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photo-oxygenations see: (b) Prein, M.; Adam, W. Angew.
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Chem. Rev. 1994, 94, 2483.
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naga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.;
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Lohray, B. B.; Enders, D. Helv. Chim. Acta 1989, 72, 980;
(d) Asami, M.; Mukaiyama, T. Chem. Lett. 1983, 93; (e)
Heitz, M. P.; Gellibert, F.; Mioskowski, C. Tetrahedron
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C. Tetrahedron Lett. 1994, 35, 3309; (g) Enders, D.;
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Angew. Chem., Int. Ed. 2005, 44, 4877, and references
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I. Ibrahem et al. / Tetrahedron Letters 47 (2006) 4659–4663
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15. (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgen-
sen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794; (b)
Marigo, M.; Fielenbach, D.; Braunton, A.; Kjaersgaard,
A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44,
or HPLC analyses. (2S)-3-Phenyl-propane-1,2-diol 4a:
1H NMR (300 MHz, CDCl3): d = 1.85 (br s, 2H, OH),
2.78 (m, 2H, PhCH2CH), 3.54 (m, 1H, CH2OH), 3.70 (m,
1H, CH2OH), 3.95 (m, 1H, CHOH), 7.24 (m, 3H, ArH),
7.33 (m, 2H, ArH); 13C NMR (300 MHz, CDCl3): 40.0,
66.3, 73.3, 126.9, 128.9, 129.6, 137.9; HPLC (Daicel
Chiralpak AD, hexanes/i-PrOH = 98:2, flow rate
0.5 mL/min, k = 242 nm): major isomer: tR = 53.08 min;
minor isomer: tR = 47.61 min; [a]D À29.0 (c 1.2, EtOH),
lit. (À35.4 (c 1.00, EtOH)) (Sone, H.; Shibata, T.; Fujita,
T.; Ojika, M.; Yamada, K. J. Am. Chem. Soc. 1996, 118,
1874.).
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3703; (c) Franzen, J.; Marigo, M.; Fielenbach, D.;
Wabnitz, T. C.; Kjaersgaard, A.; Jørgensen, K. A. J.
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Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2006, 47, 99;
(e) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212; (f) Chi, Y. G.; Gellman, S.
H. Org. Lett. 2005, 7, 4253.
16. Nardello, V.; Barbillat, J.; Marko, J.; Witte, P. T.; Alsters,
P. L.; Aubry, J.-M. Chem. Eur. J. 2003, 9, 435, Typical
experimental procedure for the direct catalytic a-oxidation
of aldehydes with ‘dark’ 1O2. To a scintillation vial
containing a catalytic amount of 1b (10 mol %), heptanal
2b (0.5 mmol), La(NO2)3Æ6H2O (4 mol %), NaOH (5M,
5 mL) in CHCl3 or MeOH (1 mL) was added H2O2
(4.8 mmol) at room temperature. After 16 h of vigorous
stirring, the reaction was quenched by in situ reduction
with NaBH4 at 0 ꢁC to afford the corresponding optically
active crude diol 4. The pure diol 4 was obtained by silica-
gel column chromatoghraphy (toluene/EtOAc mixtures).
Next, the diol 4 was converted to the corresponding
diacetylated product and the enantiomeric excess was
determined by chiral-phase GC analyses.
17. Typical experimental procedure for the direct catalytic
a-oxidation of aldehydes with molecular oxygen. To a
scintillation vial containing tetraphenylporphine (TPP)
(1 mol %) and a catalytic amount of 1b (20 mol %) in
CHCl3 (2 mL) was added aldehyde 2 (0.5 mmol). The
reaction was initiated and performed by bubbling a
continuous flow of molecular oxygen for 6 h in the
presence of visible light from two 250-W high-pressure
sodium lamps at 0 ꢁC. The reaction was quenched by
in situ reduction with NaBH4 at 0 ꢁC to afford the
corresponding optically active crude diol 4. The pure diol
4 was obtained by silica-gel column chromatography
(toluene/EtOAc mixtures). Next, the diol 4 was converted
to the corresponding diacetylated product and the
enantiomeric excess was determined by chiral-phase GC
(2S)-3-Phenyl-propane-1,2-diol diacetate: 1H NMR
(400 MHz, CDCl3): d = 2.02 (s, 3H), 2.07 (s, 3H), 2.93
(m, 2H), 4.02 (dd, J = 6.3, 12.1 Hz, 1H), 4.23 (dd, J = 3.5,
11.8 Hz, 1H), 5.28 (m, 1H), 7.19–7.31 (m, 5H); 13C NMR
(100 MHz, CDCl3); d = 21.0, 21.3, 37.3, 64.5, 72.3, 127.1,
128.8, 129.5, 136.5, 170.6, 171.0; Chiral-phase HPLC
(Daicel Chiralpak AS, isohexanes/i-PrOH 99.5:0.5, flow
rate 0.5 mL/min, k = 254 nm): major isomer: tR
31.02 min; minor isomer: tR = 35.82 min.
=
(2S)-Heptane-1,2-diol diacetate: 1H NMR (400 MHz,
CDCl3): d = 0.77 (m, 3H), 1.20 (m, 6H), 1.46 (m, 2H),
1.94 (s, 3H), 1.96 (s, 3H), 4.00 (dd, J = 6.8, 11.9 Hz, 1H),
4.11 (dd, J = 3.3, 11.9 Hz, 1H), 4.92–4.97 (m, 1H); 13C
NMR (100 MHz, CDCl3): d = 14.0, 20.6, 21.0, 22.3, 24.7,
30.5, 31.4, 65.0, 71.5, 170.5, 171.0; Chiral-phase GC:
(CP-Chirasil-Dex CB); Tinj = 250 ꢁC, Tdet = 275 ꢁC,
flow = 1.8 mL/min, Ti = 80 ꢁC (9 min), up to 120 ꢁC
(6 min) rate 20 ꢁC/min, Tf = 200 ꢁC, rate 80 ꢁC/min
(5 min), retention times, tmaj = 17.1 min, tmin = 16.9 min.
(2S)-3-(4-Nitrophenyl)-propane-1,2-diol diacetate: 1H
NMR (400 MHz, CDCl3): d = 2.00 (s, 3H), 2.07 (s, 3H),
2.88–3.01 (m, 2H), 4.03 (dd, J = 5.8, 11.9 Hz, 1H), 4.24
(dd, J = 3.7, 11.9 Hz, 1H), 5.25–5.31 (m, 1H), 7.37 (d,
J = 8.7 Hz, 2H), 8.15 (d, J = 8.7 Hz, 2H); 13C NMR
(100 MHz, CDCl3); d = 20.9, 21.1, 37.1, 64.3, 71.4, 124.0,
130.4, 144.4, 147.3, 170.3, 171.0; Chiral-phase HPLC
(Daicel Chiralpak ODH, isohexanes/i-PrOH 98.0:2.0, flow
rate 0.5 mL minÀ1
39.6 min; minor isomer: tR = 46.1 min.
, k = 254 nm): major isomer: tR =