Synthesis of chiral 1,2,3-triols via organocatalyzed α-hydroxylation of protected β-hydroxyaldehydes

Article abstract of DOI:10.1016/j.tetlet.2011.12.078

Protected 1,2,3-triols were prepared by organocatalytic α-hydroxylation of β-hydroxyaldehydes followed by in situ reduction. All diastereoisomers were obtained with correct yields and good to excellent de. The absolute configurations of the new asymmetric

Full text of DOI:10.1016/j.tetlet.2011.12.078

Tetrahedron Letters 53 (2012) 1085–1088
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of chiral 1,2,3-triols via organocatalyzed
a
-hydroxylation of protected
b-hydroxyaldehydes
⇑
Olivier Colin, Philippe Hermange, Christine Thomassigny, Christine Greck
ILV-UMR CNRS 8180, Université de Versailles-St-Quentin en Yvelines, 45, Avenue des Etats-Unis, 78035 Versailles Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Protected 1,2,3-triols were prepared by organocatalytic a-hydroxylation of b-hydroxyaldehydes followed
Received 28 November 2011
Revised 16 December 2011
Accepted 19 December 2011
Available online 29 December 2011
by in situ reduction. All diastereoisomers were obtained with correct yields and good to excellent de. The
absolute configurations of the new asymmetric centers were confirmed by derivatization into the corre-
sponding epoxide.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hydroxylation
Organocatalysis
Enantioselectivity
Hydroxyaldehydes
1,2,3-Triols
1,2,3-Triols are important building blocks in organic synthesis,
as proved by the occurrence of this pattern in numerous bioactive
molecules. A relevant approach to such derivatives is the creation
of one of the C–O bonds to obtain a configurationally controlled
carbon atom, independently from the other chiral centers of the
proline-type catalysts (meaning a catalyst bearing a Brønsted acid
functionality) allows oxygen to become electrophilic, and lead to
the
a-oxygenated products. For other catalysts which give preferen-
tially
a-aminated products, additives are necessary to reverse the
selectivity.13 The catalytic cycle has been well studied, and would
be in favor of an oxazolidinone species, precursor of an enamine-
key intermediate which would react with nitrosobenzene.1a Using
proline as the catalyst, McQuade14 demonstrated in 2009 that the
introduction of the additive 1-(2-(dimethylamino)ethyl)-3-phe-
nylurea 1 in nonpolar solvents induced drastic increase of the kinet-
ics without modification of the enantiomeric excesses (ee). This
effect was explained by the existence of hydrogen bonds between
the urea and the oxazolidinone intermediate, promoting the enam-
ine formation with proline (rate limiting step).
reactant. In this context, the organocatalyzed
a-hydroxylation of
carbonyls followed by an in situ reduction is a promising possibil-
ity, already well described as a good solution to the synthesis of
1,2-diols.1
Sometime after the description of the use of nitrosobenzene in
the presence of silyl or metal enolates leading, respectively, to the
formation of the C–O link (aminoxylation reaction) or the C–N link
(oxyamination reaction) depending on the reaction’s conditions,2
Hayashi,3 Mac Millan,4 and Zhong5 independently published the
reaction of
a
-aminoxylation of aldehydes catalyzed by proline. The
Exploring the scope of organocatalytic a-heterofunctionaliza-
method is now well-used and can be noticed in many total synthe-
tion of carbonyl compounds,15 the formation of chiral 2-hydra-
zino-1,3-diols in good yields and diastereoisomeric excesses (de)
was described recently by our team.15c We now extended the con-
cept to the preparation of 1,2,3-triols via an organocatalyzed
hydroxylation reaction of chiral b-hydroxyaldehydes. Indeed, the
reaction of nitrosobenzene with such aldehydes in the presence
of proline and 1 should lead to the corresponding 1,2,3-triols after
in situ reduction using sodium borohydride in ethanol.
ses.6 Other oxygen donors are also efficient for the organocatalyzed
asymmetric
a-oxidation of aldehydes, namely N-sulfonyloxaziri-
dine,7 TEMPO,8 benzoyl peroxide,9 o-quinone,10 and molecular oxy-
gen.11 Nevertheless, the use of nitrosobenzene remains the most
studied case,1a where the effect of the structure of the catalyst or
addition of an acid in the reaction medium has been shown to mod-
ify significantly the result of the reaction (aminoxylation or oxyam-
ination).12 The greater selectivity observed for the oxygen atom has
been explained by the stronger basicity of the nitrogen atom. Indeed,
N-protonation of the nitrosobenzene in the transition state by
First, racemic 3-tert-butyldimethylsilyloxybutanal 2 was se-
lected as model to optimize the reaction conditions (Scheme 1).
The reaction was run at 0 °C, in the presence of DL-proline and 5%
of urea 1 until coloration changes from blue to yellow. Then, the
reaction mixture was transferred to a suspension of sodium borohy-
dride (4 equiv) in ethanol and stirred 30 min at 0 °C. After treatment,
⇑
Corresponding author. Tel.: +33 (0) 139254474; fax: +33 (0) 139254452.
E-mail address: greck@chimie.uvsq.fr (C. Greck).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.078

1086
O. Colin et al. / Tetrahedron Letters 53 (2012) 1085–1088
1) PhNO
Pro (x mol %)
1 (5 mol %)
OTBS
2) NaBH4
2) NaBH4
OTBS
OTBS
OH
L-Pro
D-Pro
CHO
OH
ONHPh
3
OTBS
CHO
ONHPh
(2S,3S)-4
OTBS
1) PhNO, 1
2) NaBH4
2
CH3CN, 0 °C
(S)-2
OH
O
ONHPh
(2R,3S)-5
N
COOH
N
H
N
H
N
H
OTBS
L-Pro
1
2) NaBH4
2) NaBH4
OH
Scheme 1. Organocatalyzed aminoxylation of 2.
L-Pro
D-Pro
OTBS
ONHPh
1) PhNO, 1
(2S,3R)-5
CHO
purification by column chromatography on silica gel allowed to ob-
tain 3 as a mixture of diastereoisomers.16
OTBS
CH3CN, 0 °C
(R)-2
OH
The results are summarized in Table 1. Applying McQuade’s
conditions,14 that is, 5 mol % of 1 and proline in ethyl acetate at
0 °C with a 3/1 ratio of 2/PhNO for 3 h gave the desired triol in a
poor yield (10% related to nitrosobenzene, entry 1). Changing the
solvent to acetonitrile (entry 2) increased the yield to 56% in the
same time. For comparison, the same reaction in the absence of
urea was not finished after 24 h, proving the importance of this
catalyst. Then, increasing the amount of DL-proline to 10 and
20 mol% improved the yield, respectively, to 54% and 67% (entries
3 and 4). With this catalyst loading, acetonitrile remained the best
solvent among all other tested (entries 5 and 6). Finally, lowering
the quantity of 2 (entries 7–9) and/or increasing the amount of
PhNO (entries 8 and 9) to modify the 2/PhNO ratio gave 29% as best
yield based on the aldehyde. From all theses results, it was decided
to use the conditions described in entry 4 for the next experiments.
The two enantiomers of the hydroxyaldehyde, namely (S)-2 and
(R)-2 were then aminoxylated separately under these conditions
(ratio 2/PhNO 3/1; 20 mol % Pro; 5 mol % 1; MeCN; 3 h at rt then
reduction) (Scheme 2, Table 2). Depending on the configuration
of the proline used as the catalyst, we obtained the expected 3-
tert-butyldimethylsilyloxy-2-(phenylaminoxy) butanols as syn- or
anti-stereomers, respectively 4 and 5.16 The diastereoisomeric ratio
was measured by UPLC (compared to the stoichiometric mixture of
ONHPh
(2R,3R)-4
Scheme 2. Asymmetric aminoxylation of (S)- and (R)-2.
Table 2
Hydroxylation of (S)- and (R)-2
Entry
Substrate
Catalyst
Product
Yield (%)
Syn/antia
1
2
3
4
(S)-2
(S)-2
(R)-2
(R)-2
(2S,3S)-4
(2R,3S)-5
(2S,3R)-5
(2R,3R)-4
76
75
70
62
97/3
4/96
2/98
97/3
L
-Pro
-Pro
-Pro
-Pro
D
L
D
a
Measured by UPLC.
into the corresponding epoxides (Scheme 3). A three-step sequence
starting with the hydrogenolysis of the N–O bond followed by a
selective sulfonylation of the primary alcohol and a cyclization of
6 under basic treatment gave the epoxide 7 from 4,17 with concor-
dant analytical data of the literature.18 The unknown 8 was ob-
tained with the same sequence from (2R,3S)-5.19
We extended the method using the long-chained 9 and the pro-
tected diol 10 as substrates (Table 3, Scheme 4). In all cases, the
same conditions than previously described were used. We first ap-
plied racemic proline, and the obtained equimolar mixture of epi-
mers at position 2 was used for NMR data and UPLC references. The
hexadecanal 9, prepared in five steps from palmitic acid, was re-
4/5). From (S)-2, the use of L-proline as the catalyst led to the amin-
oxylated syn product (2S,3S)-4 with the excellent diastereoiso-
meric ratio of 97/3 and good yields (76%) (entry 1). The use of
the D-catalyst gave access to the anti (2R,3S)-5 with a similar ratio
(4/96) and yield (entry 2). Correspondingly, (R)-2 is the precursor
of the two stereoisomers (2S,3R)-5 or (2R,3R)-4 with identical ste-
reochemical results (dr 2/98 and 97/3; entries 3 and 4). Thus, the
possibility to obtain each diastereoisomer and enantiomer by this
method has been demonstrated.
acted in the presence of either L- or D-proline. In both cases, pro-
tected triols 11 and 12, respectively, were obtained in good
yields and excellent diastereoisomeric ratios (entries 1 and 2).
Then, the (S)-3,4-O-isopropylidenebutanal 10 in the presence of
two antipods of the catalyst led, respectively, to the anti 13 (entry
The absolute configuration of the newly formed stereocenter
was proved by derivatization of the triols (2S,3S)-4 and (2R,3S)-5
Table 1
Optimization of the reaction of hydroxylation of 2
Entry
Solvent
Pro (mol %)
2 (equiv)
PhNO (equiv)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
EtOAc
MeCN
MeCN
MeCN
DMSO
DCM
MeCN
MeCN
MeCN
5
5
3
3
3
3
3
3
1.5
1
1
1
1
1
1
1
1
1
1.2
1.5
3
3
4
3
1
70
3
3
10
56
54
67
41
8
37
17b
29b
10
20
20
20
20
20
20
15
a
Isolated yield based on PhNO.
Isolated yield based on 2.
b

O. Colin et al. / Tetrahedron Letters 53 (2012) 1085–1088
1087
OTBS
OTBS
1) H2, Pd/C, MeOH
NaH, Et2O
(2S,3S)-4
OTs
O
2) TsCl, Et3N, CH2Cl2
OH
6
7
OTBS
1) H2, Pd/C, MeOH
(2R,3S)-5
O
2) TsCl, Et3N, CH2Cl2
3) NaH, Et2O
8
Scheme 3. Derivatization into epoxides 7 and 8.
Table 3
Hydroxylation of compounds 9 and 10
Entry
1
Substrate
Cat⁄
Product
OTBS
Yield (%)
68
Syn/antia
OTBS
CHO
1/99
99/1
L-Pro
OH
OH
9
14
14
11
12
ONHPh
OTBS
OTBS
CHO
2
3
83
30
D-Pro
9
14
14
ONHPh
Me2
Me2
C
C
O
O
O
O
O
1/99
L-Pro
CHO
CHO
10
10
OH
ONHPh
13
Me2
C
Me2
C
O
O
O
4
84
90/10
D-Pro
OH
ONHPh
14
a
Measured by UPLC.
OR
2) NaBH4
2) NaBH4
N
R'
R'
OH
OH
N
O
O
H
O
L-Pro
ONHPh
OR
Ph
O
H
O
Me2C
11,13
1) PhNO, 1
CHO
R'
OR
CH3CN, 0 °C
Figure 1. Proposed transition state with
L
-proline and 10.
D-Pro
9-10
hindrance is probably lower with nitrosobenzene than with
azodicarboxylates.
ONHPh
12,14
In conclusion, we prepared the four protected butan-1,2,3-triols
in good yields and de up to 96% by the use of organocatalysis in the
presence of proline and urea. The process is applicable to more
functionalized structures, and the excesses observed made of this
method a very respectable proposal for the obtention of chiral
triols.
Scheme 4. General asymmetric aminoxylation.
3) or syn 14 (entry 4). The low yield for 13 could be explained by
the unstability of the product on silica gel during the column chro-
matography. In a similar way than observed during the a-hydraz-
ination of this substrate,15c a significant difference of de between
Acknowledgment
13 (98%) and 14 (80%) was observed.
A model for the transition state for the
a-aminoxylation reac-
We particularly thank E. Galmiche for UPLC-mass studies.
References and notes
tion of b-hydroxyaldehyde could be proposed. The use of proline
as the catalyst would favor the approach of the nitrosobenzene
on the same face than the carboxylic acid function. In the case of
L
-proline and the substrate 10, the transition state favored could
explain excellent de and match effect (Fig. 1). Mismatch effect is
observed with the -proline. However the mismatch effect in the
hydroxylation procedure is much lower compared to the amina-
tion reaction where -proline gave no selectivity, because the steric
1. Reviews: (a) Vilaivan, T.; Bhanthumnavin, W. Molecules 2010, 15, 917–958. and
references therein; (b) de Figueiredo, R. M.; Christmann, M. Eur J. Org. Chem.
2007, 2575–2600.
2. Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038–6039.
3. Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44,
8293–8296.
D
D

1088
O. Colin et al. / Tetrahedron Letters 53 (2012) 1085–1088
4. Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003,
125, 10808–10809.
5. Zhong, G. Angew. Chem. 2003, 115, 4379–4382.
Compound 4: 1H NMR (300 MHz, CDCl3) d (ppm): 7.30–7.25 (m, 2H), 7.01–6.98
(m, 3H), 4.19 (m, 1H), 3.89 (d, 2H), 3.72 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H), 0.89 (s,
9H), 0.10 (d, J = 2.6 Hz, 3H), 0.09 (d, J = 2.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
(ppm): 148.5, 129.2, 122.6, 115.0, 86.2, 68.5, 62.3, 26.0, 19.1, 18.2, ꢁ4.5, ꢁ4.7;
SM-HR-ES(+) m/z C16H30O3NSi M+H+; calcd 312.1995, found 312.1998.
6. For recent examples, see: (a) Yadav, J. S.; Subba Reddy, U. V.; Subba Reddy, B. V.
Tetrahedron Lett. 2009, 50, 5984–5986; (b) Sawant, R. T.; Waghmode, S. B.
Tetrahedron 2009, 65, 1599–1602; (c) Chandrasekhar, S.; Mahipal, B.; Kavitha,
M. J. Org. Chem. 2009, 74, 9531–9534; (d) Jha, V.; Kondekar, N. B.; Kumar, P. Org.
Lett. 2010, 12, 2762–2765; (e) Subba Reddy, B. V.; Phaneendra Reddy, B.;
Pandurangam, T.; Yadav, J. S. Tetrahedron Lett. 2011, 52, 2306–2308.
7. Tong, S.-T.; Brimble, M. A.; Barker, D. Tetrahedron 2009, 65, 4801–4807.
8. Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124–4125.
9. (a) Vaismaa, M. J. P.; Yau, S. C.; Tomkinson, N. C. O. Tetrahedron Lett. 2009, 50,
3625–3627; (b) Gotoh, H.; Hayashi, Y. Chem. Commun. 2009, 3083–3085; (c)
Kano, T.; Mii, H.; Maruoka, K. J. Am. Chem. Soc. 2009, 131, 3450–3451.
10. Hernandez-Juan, F. A.; Cockfield, D. M.; Dixon, D. J. Tetrahedron Lett. 2007, 48,
1605–1608.
ACQUITY UPLC BEH C18 1.7
MeCN + 0.1% solution of HCOOH: rt (4) = 4.30 min; rt (5) = 4.35 min.
17. Compound 7: mixture of (2S,3S)-3-(tert-butyldimethylsilyloxy)-2-
(phenylaminooxy)butan-1-ol (125 mg, 0.4 mmol) and 10% Pd/C (25 mg,
lm 2.1 ꢂ 50 mm; 0.45 mL/min; T = 40 °C; gradient
A
4
20% w/w) in MeOH (4 mL) was hydrogenated for 16 h at atmospheric pressure
and the solvent was removed under reduced pressure. Ethyl acetate (10 mL)
was added to the residue, the mixture was filtered on celite and the filtrate was
evaporated under reduced pressure. Purification of the residue by column
chromatography on silica gel using pentane/EtOAc: 5:1 to pentane/EtOAc: 2:1
provided (2S,3S)-3-(tert-butyldimethylsilyloxy)butan-1,2-diol as a colorless oil
(81%, 72 mg) which was added to a solution of triethylamine (67 lL, 0.5 mmol)
11. (a) Córdova, A.; Sundén, H.; Engqvist, M.; Ibrahem, I.; Casas, J. J. Am. Chem. Soc.
2004, 126, 8914–8915; (b) Ibrahem, I.; Zhao, G.-L.; Sundén, H.; Córdova, A.
Tetrahedron Lett. 2006, 47, 4659–4663.
12. Mielgo, A.; Velilla, I.; Gómez-Bengoa, E.; Palomo, C. Chem. Eur. J. 2010, 16,
7496–7502. and references therein.
13. Lu, M.; Zhu, D.; Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G. J. Am. Chem. Soc. 2009,
131, 4562–4563.
14. Poe, S. L.; Bogdan, A. R.; Mason, B. P.; Steinbacher, J. L.; Opalka, S. M.; McQuade,
D. T. J. Org. Chem. 2009, 74, 1574–1580.
15. (a) Thomassigny, C.; Prim, D.; Greck, C. Tetrahedron Lett. 2006, 47, 1117–1119;
(b) Ait-Youcef, R.; Kalch, D.; Moreau, X.; Thomassigny, C.; Greck, C. Lett. Org.
Chem. 2009, 6, 377–380; (c) Ait-Youcef, R.; Sbargoud, K.; Moreau, X.; Greck, C.
Synlett 2009, 3007–3010; (d) Kalch, D.; Ait-Youcef, R.; Moreau, X.;
Thomassigny, C.; Greck, C. Tetrahedron: Asymmetry 2010, 21, 2302–2306.
and tosyl chloride (67 mg, 0.4 mmol) in dichloromethane (3 mL). The reaction
mixture was stirred for 16 h at room temperature and the solvent was
removed under reduced pressure. Purification of the residue by column
chromatography on silica gel using pentane/EtOAc: 10:1 to pentane/EtOAc: 5:1
provided compound 6 as a colorless oil (68 mg; 57%). 1H NMR (300 MHz,
CDCl3) d (ppm): 7.79 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 3.98–3.86 (m,
3H), 3.58–3.53 (m, 1H), 2.44 (s, 3H), 2.35 (bs, 1H), 1.15 (d, J = 6.4 Hz, 3H), 0.83
(s, 9H), 0.06 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3) d (ppm): 144.9,
132.6, 129.8 (2C), 128.0 (2C), 72.6, 70.1, 67.3, 25.7 (3C), 21.1, 19.8, 17.8, ꢁ4.3,
ꢁ5.1; HRMS (ESI) C17H30O5SSi M+Na+; calcd 397.1481, found 397.1486.
Sodium hydride (60% in oil, 10.9 mg, 0.3 mmol) under argon was washed twice
with pentane (2 mL). Then dry Et2O (1 mL) and compound
6 (68 mg,
0.18 mmol) in dry Et2O (1 mL) were added. The mixture was stirred for 16 h
at room temperature and filtered on celite. The filtrate was evaporated under
16. Typical procedure: To 25 mg of PhNO (0.2 mmol; 1 equiv) in MeCN (460
l
L)
reduced pressure to afford compound 7 as a colorless oil (24.2 mg; 66%). ½a D25
ꢃ
was added -proline (5 mg, 0.05 mmol, 0.2 equiv) and urea 1 (2 mg, 0.01 mmol,
L
+4.3 (c 0.30, CHCl3) (lit.18 a D25 +1.8 (c 1.1, CHCl3)); 1H NMR (300 MHz, CDCl3) d
½ ꢃ
0.05 equiv) at 0 °C. After stirring during 15 min, (R)-2 (139 mg, 0.7 mmol,
3 equiv) was added and the overall was stirred for 2 h. Then the reaction
mixture was poured on NaBH4 (35 mg, 0.9 mmol, 4 equiv) in EtOH (1.5 mL) and
stirred 30 min at 0 °C. The reaction mixture was neutralized with saturated
aqueous NaHCO3 (2 mL), and extracted with EtOAc (3 ꢀ 2 mL). The organic
layers were dried, concentrated for give an yellow oil which was purified by
silica gel chromatography (EtOAc/cyclohexane: 1:18 then 1:9) for give (2S,3R)-
5 (50 mg, 70%). 1H NMR (300 MHz, CDCl3) d (ppm): 7.29–7.23 (m, 2H), 7.02–
6.94 (m, 3H), 4.19 (m, 1H), 3.95 (d, J = 6.0 Hz, 2H), 3.72 (m, J = 6.0 Hz, 1H), 1.28
(d, J = 6.5 Hz, 3H), 0.91 (s, 9H), 0.11 (d, J = 2.0 Hz, 3H), 0.10 (d, J = 2.0 Hz, 3H);
13C NMR (75 MHz, CDCl3) d (ppm): 148.6, 129.2, 122.4, 114.8, 86.7, 69.4, 61.8,
(ppm): 3.56 (quin, J = 6.3 Hz, 1H), 2.96–2.92 (m, 1H), 2.77 (t, J = 4.6 Hz, 1H),
2.59–2.57 (m, 1H), 1.22 (d, J = 6.5 Hz, 3H), 0.91 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H);
13C NMR (75 MHz, CDCl3) d (ppm): 70.1, 56.6, 44.5, 25.8 (3C), 20.2, 18.2, ꢁ4.7,
ꢁ4.9.
18. Hatakeyama, S.; Sakurai, K.; Takano, S. Heterocycles 1986, 24, 633–636.
19. Compound 8. The same sequence than for the obtention of 7 from 4 was
applied to (2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(phenylaminooxy)butan-
1-ol 5, and afforded the compound 8 as a colorless oil (16.6 mg; 29% over
three steps). ½a D25
ꢃ
+52.3 (c 0.33, CHCl3). 1H NMR (300 MHz, CDCl3) d (ppm):
3.76–3.68 (m, 1H), 2.87–2.82 (m, 1H), 2.72–2.63 (m, 2H), 1.23 (d, J = 6.2 Hz,
3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz, CDCl3) d (ppm):
67.6, 55.6, 44.8, 25.7 (3C), 20.8, 18.1, ꢁ4.7, ꢁ4.9; SM-HR-ES(+) m/z C10H22O2Si
M+H+; calcd 203.1467, found 203.1467.
25.9, 20.8, 18.1, ꢁ4.4, ꢁ4.7; SM-HR-ES(+) m/z
C
16H30O3NSi M+H+; calcd
312.1995, found 312.2003.