Proline-catalyzed α-aminooxylation of β-amino aldehydes: Access to enantiomerically pure syn - And anti -3-Amino-3-aryl-1,2-alkanediols

Article abstract of DOI:10.1055/s-0034-1379735

A new synthetic method for enantioselective synthesis of syn or anti-3-amino-3-aryl-1,2-alkanediols via proline catalyzed α-aminooxylation of β-amino aldehydes are described. This methodology is successfully applied to a concise and protecting group-free asymmetric synthesis of (-)-cytoxazone, (+)-epi-cytoxazone and formal synthesis of N-thiolated 2-oxazolidinone.

Full text of DOI:10.1055/s-0034-1379735

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 355–358
letter
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V. Venkataramasubramanian et al.
Letter
Synlett
Proline-Catalyzed α-Aminooxylation of β-Amino Aldehydes:
Access to Enantiomerically Pure syn- and anti-3-Amino-3-aryl-
1,2-alkanediols
i) L-proline (20 mol%),
PhNO (1.2 equiv),
MeCN, –10 °C, 15 h
V. Venkataramasubramanian
I. N. Chaithanya Kiran
Arumugam Sudalai*
cytoxazone epimers
(Ar = 4-anisyl)
NHBoc
NHBoc
OH
Ar
Ar
OH
O
and
then
NaBH4, MeOH,
0 °C, 15 min
ii) Cu(OAc)2·2H2O,
MeOH, 16 h
N-thilated
2-oxazolidinones
(Ar = Ph)
Chemical Engineering and Process Development Division,
National Chemical Laboratory, Pashan Road, Pune 411008,
India
Ar = Ph, 4-anisyl Ar = 2-ClC6H4, 4-tolyl,
(syn & anti)
1-naphthyl, 2-furfuryl
a.sudalai@ncl.res.in
(anti)
Received: 13.10.2014
Accepted after revision: 18.11.2014
Published online: 09.01.2015
ketones,6e amines,6f or carboxylic acids;6g (iv) reduction of
dihydroisooxazoles with LiAlH4;6h (v) diastereoselective hy-
droxylation of β-amino enolates with oxaziridine;6i (vi)
Sharpless ADH of C=C bond with subsequent stereoselective
N3 substitution.6j Despite the efforts devoted to the synthe-
sis of enantiopure 3-aryl-3-amino-1,2-alkanediols 1, there
are no broad-scope, organocatalytic, and high-stereoselec-
tivity routes established for preparing such compounds.
DOI: 10.1055/s-0034-1379735; Art ID: st-2014-b0858-l
Abstract A new synthetic method for enantioselective synthesis of syn
or anti-3-amino-3-aryl-1,2-alkanediols via proline catalyzed α-aminoox-
ylation of β-amino aldehydes are described. This methodology is suc-
cessfully applied to a concise and protecting group-free asymmetric
synthesis of (–)-cytoxazone, (+)-epi-cytoxazone and formal synthesis of
N-thiolated 2-oxazolidinone.
O
O
Key words amino aldehydes, asymmetric synthesis, catalysis, diaste-
reoselectivity, enantioselectivity, natural product
MeS
Ph
HN
NH2
N
O
O
Ar
OH
OH
OH
syn/anti-arylaminodiols (1)
MeO
(–)-cytoxazone (2)
and its 2-epimer (3)
N3
N-thiolated
2-oxazolidinone (4)
The enantiopure syn/anti-3-amino-3-aryl-1,2-alkanedi-
ols 1 are subunits often found in many natural products and
drugs (2–4, Figure 1), in particular as a central moiety of
nonproteinogenic amino acids and amino polyols.1 They are
also proven to be valuable ‘building blocks’ for the synthesis
of various bioactive molecules such as HIV protease inhibi-
tors,2 glycosphingolipids,3 polyhydroxylated nitrogen het-
erocycles4 or α-hydroxy β-amino acids.5 As a consequence
of the biological importance of amino diols, numerous syn-
thetic strategies6 have been developed for this important
class of molecules, mostly starting from chiral-pool materi-
als. The reported methods thus mainly comprise of: (i) ad-
dition of Grignard reagents onto imines6a and nitrones;6b (ii)
coupling reaction of α-amino aldehydes with aliphatic alde-
hydes6c or boronic acids, amines with (R)-hydroxy alde-
hydes;6d (iii) stereoselective ring opening of epoxides with
Figure 1 Structure of bioactive molecules containing amino diols
In this note, we describe a ‘one-pot’ procedure for ob-
taining chiral amino diols 1 using proline-catalyzed α-ami-
nooxylation of β-amino aldehydes 6a–f (Scheme 1).
In continuation of our work on the α-functionalization
of aldehydes using organocatalysis,7 we envisioned that
one-pot synthesis of amino diol 1a directly from imine 5a
could be realized via its Mannich reaction with MeCHO8 fol-
lowed by α-aminooxylation of the resulting β-amino alde-
hyde 6a, formed in situ, with PhNO in a sequential fashion
under proline catalysis. Thus, we have chosen 5a as a model
substrate and performed this sequential reaction under
i) L-proline (20 mol%),
PhNO (1.2 equiv),
MeCN, –10 °C, 15 h
NBoc
NHBoc
NHBoc
L-Proline,
MeCHO,
OH
O
OH
then
NaBH4, MeOH,
0 °C,15 min
ii) Cu(OAc)2⋅2H2O,
MeOH, 16 h
MeCN,
0 °C, 3 h
6a
yield 55%
98% ee
1a
5a
50% yield
93% ee
Scheme 1 α-aminooxylation of β-amino aldehydes
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 355–358

356
V. Venkataramasubramanian et al.
Letter
Synlett
various reaction parameters, which included the variation
of solvents (MeCN, DMSO) and temperature (0 °C to –15 °C).
Unfortunately, the reaction gave only 12% of the desired
product 1a, and the rest being complex mixtures. The low
yield was due to the formation of several side products by
the reaction of PhNO with byproducts formed in the Man-
nich reaction. We then thought to carry out this reaction in
two steps of firstly isolating β-amino aldehyde 6a followed
by its α-aminooxylation process. The pure β-amino alde-
hyde was thus prepared8 and subjected to α-aminooxyl-
ation [L-proline, PhNO, then NaBH4, Cu(OAc)2·2H2O, MeCN,
–20 °C] to yield amino diol 1a in 50% yield and 93% enantio-
meric excess (Table 1, entry 2). We became interested in
improving the yield of 1a by optimizing the aminooxylation
conditions such as solvent and temperatures. It was then
found that MeCN was the best solvent (68% yield; 93% ee)
for the reaction while other solvents (DMSO, CHCl3, CH2Cl2,
THF) gave the product 1a in low yields (17–55%). The opti-
mum temperature for this reaction was found to be –10 °C.
To determine the scope and generality of the reaction, a
variety of other aromatic β-amino aldehydes were subject-
ed to α-aminooxylation. In every case, the reaction pro-
ceeded smoothly to give yields of anti-3-aryl-3-amino-1,2-
diols 118–22 ranging from 55–68% with excellent enantiose-
lectivity. For instance, aryl substrates having electron-rich
(Table 1, entry 10) or electron-deficient (Table 1, entry 12)
substituents on the aromatic ring including 1-naphthyl ring
system (Table 1, entry 13) and heteroaryl (Table 1, entry 14)
gave the desired anti-3-amino-3-aryl-1,2-diols in good
yields. The absolute configuration of the newly generated
chiral center was assigned on the basis of the previously es-
tablished configuration of α-aminoxylation of aldehydes.9
The anti stereochemistry in anti-3-amino-3-aryl-1,2-diol
1c has been unambiguously proven from X-ray crystallo-
graphic analysis (see Supporting Information).
Table 1 L-Proline-Catalyzed α-Aminooxylation of β-Amino Aldehydes:
Optimization Studies and Substrate Scopea
Entry
6a–f Ar
Solvent
Time
(°C)
Time
(h)
Yield of ee of
(%)b,c
1a–f (%)d
1
2
6a Ph
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
25
20
0.5
22
18
15
0.5
1
30
50
68
53
55
17
30
40
16
65
63
60
62
58
92
93
6a Ph
3
6a Ph
–10
0
93
4
6a Ph
90
5
6a Ph
25
93
6
6a Ph
25
n.d.e
90
7
6a Ph
CHCl3
CH2Cl2
THF
25
24
20
24
18
18
18
18
18
8
6a Ph
25
91
9
6a Ph
25
n.d.e
92
10
11
12
13
14
6b 4-anisyl
6c 4-tolyl
6d 2-ClC6H4
6e 1-naphthyl
6f 2-furfuryl
MeCN
MeCN
MeCN
MeCN
MeCN
–10
–10
–10
–10
–10
95
>99
92
90
a Reaction conditions: (i) β-amino aldehyde (4 mmol), PhNO (4.8 mmol),
L-proline (0.8 mmol), solvent (15 mL), temp (°C), time (h), then NaBH4 (8
mmol), MeOH (10 mL), 0 °C, 20 min; (ii) Cu(OAc)2 (0.6 mmol), MeOH (15
mL), 25 °C, 16 h.
b The dr was determined to be >99% for all the substrates based on 1HNMR
analysis.
c Isolated yield after column chromatographic purification.
d The ee was determined from HPLC analysis and by comparing with the re-
ported14 specific rotation value [α]D25 +42.90 (c 1.4, CHCl3) for its antipode.
e n.d. = not determined as the yield was very low.
2). Similarly, by using D-proline as catalyst for the aminoox-
ylation process, the corresponding (+)-epi-cytoxazone (3)16
was obtained in 35% overall yield and 95% enantiomeric ex-
cess.
O
The advantage of this strategy is that all the four stereo-
isomers of 3-amino-3-aryl-1,2-diols can be prepared by
choosing a suitable proline for Mannich as well as subse-
quent aminooxylation reactions. For instance, anti-amino
diols could be achieved using D- or L-proline for both the re-
actions, while syn-amino diols could be obtained using L-
and D-proline for both the reactions in that order.
HN
NHBoc
NaH
(2.2 equiv)
O
OH
dry THF,
3 h, 90%
OH
OH
MeO
MeO
1b
(–)-cytoxazone (2)
Scheme 2 Synthesis of (–)-cytoxazone (2)
A wide range of synthetic applications of this method is
readily envisaged and is amply illustrated in the short en-
antioselective synthesis of three bioactive molecules name-
ly (–)-cytoxazone (2; high cytokine modular activity
against Th2 cells),10 (+)-epi-cytoxazone (3; antiallergenic
activity),11 and N-thiolated 2-oxazolidinone (4; antibacteri-
al).12
The synthesis of (–)-cytoxazone (2) was readily
achieved from β-amino aldehyde 6b via anti-amino diols
(where Ar = 4-anisyl) 1b followed by NaH-mediated selec-
tive cyclization of secondary alcohol13,15 with tert-butyloxy
carbonyl in 90% yield and 93% enantiomeric excess (Scheme
Additionally, a formal enantioselective synthesis of N-
thiolated 2-oxazolidinone 4 was achieved in a similar fash-
ion from β-amino aldehyde 6a. Then 6a was subjected to
α-aminooxylation
[D-proline,
PhNO, then NaBH4,
Cu(OAc)2·2H2O, MeCN, –10 °C) to provide the syn-amino
diol 1g (59% yield and 93% ee),17 followed by NaH-mediated
intramolecular cyclization of 1b with tert-butyloxy carbon-
yl selectively to give oxazolidinone, which was readily
transformed into the corresponding azide 9 via (i) mesyla-
tion (MsCl, Et3N, 0 °C, 1 h) of oxazolidinone 7 and (ii) treat-
ment of mesylate 8 with an azide anion (NaN3, DMF, 60 °C,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 355–358

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V. Venkataramasubramanian et al.
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i) PhNO (1.2 equiv),
D-proline (20 mol%),
MeCN, –15 °C, 18 h;
then
NaBH4 (2.5 equiv),
MeOH, 0 °C, 15 min
O
O
NHBoc
HN
NaH
(2.2 equiv)
NHBoc
Ph
OH
Ph
Ph
O
OH
1g
dry THF,
3 h, 88%
ii) Cu(OAc)2, MeOH,
25 °C, 16 h,
R
6a
7, R = OH
59% for two steps
8, R = OMs
9, R = N3
Scheme 3 Formal synthesis of N-thiolated 2-oxazolidinone 4
12 h, 81%; Scheme 3). The conversion of azide 9 into N-thio-
lated 2-oxazolidinone 4 has already been reported in the
literature.12
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In conclusion, we have developed a simple D- or L-pro-
line-catalyzed procedure to obtain syn- or anti-3-amino-3-
aryl-1,2-diols, respectively, in a single step directly from β-
amino aldehydes, and the potential application of this reac-
tion has been demonstrated by achieving a short, protec-
tion-group-free enantioselective synthesis of three import-
ant drugs such as (–)-cytoxazone, (+)-epi-cytoxazone, and
N-thiolated 2-oxazolidinone in good yields and very high
enantiomeric excess. We strongly believe that this strategy
will find applications in the field of asymmetric synthesis of
bioactive molecules owing to the flexible nature of the syn-
thesis and the ready availability of proline catalysts in both
enantiomeric forms.
Acknowledgment
We thank CSIR, New Delhi for the award of a Senior Research Fellow-
ship. The authors are also thankful to Dr. V. V. Ranade, Chair, Chemical
Engineering and Process Development Division for his constant en-
couragement and support.
(7) (a) Kumar, B. S.; Venkataramasubramanian, V.; Sudalai, A. Org.
Lett. 2012, 14, 2468. (b) Kotkar, S. P.; Chavan, V. B.; Sudalai, A.
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6565.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379735.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(8) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List, B. Nature
(London, U.K.) 2008, 452, 453.
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(19) (2R,3R)-3-(tert-Butoxycarbonylamino)-3-(p-tolyl)-1,2-pro-
panediol (1c)
Yield 63%; colorless solid recrystallized from CHCl3; mp 126–
25
129 °C. [α]D –57.87 (c 2.7, CHCl3); 95% ee from chiral HPLC
analysis [Chiracel AD-H, n-hexane–i-PrOH (90:10), 0.5 mL min–1]:
tR = 21.6 min (97%) and 27.1 min (2%). IR (CHCl3): νmax = 727,
780, 815, 884, 1049, 1101, 1163, 1247, 1287, 1365, 1391, 1506,
(11) Hamersak, Z.; Sepac, D.; Ziher, D.; Sunjic, V. Synthesis 2003, 375.
(12) (a) Mishra, R. K.; Revell, K. D.; Coates, C. M.; Turos, E.; Dickeyb,
S.; Limb, D. V. Bioorg. Med. Chem. 2006, 16, 2081. (b) Steven, R.
W.; Hisao, I.; Marvin, J. M. Tetrahedron Lett. 1985, 26, 3891.
(13) Reddy, R. S.; Chouthaiwale, P. V.; Suryavanshi, G.; Chavan, V. B.;
Sudalai, A. Chem. Commun. 2010, 46, 5012.
1683, 2929, 2976, 3366 cm–1 1H NMR (200 MHz, CDCl3): δ =
.
1.42 (s, 9 H), 2.34 (s, 3 H), 2.82 (br s, 1 H), 3.31 (br s, 1 H), 3.51–
3.62 (m, 2 H), 3.78 (br s, 1 H), 4.59–4.66 (m, 1 H), 5.25 (d, J = 6.7
Hz, 1 H), 7.09–7.22 (m, 4 H). 13C NMR (50 MHz, CDCl3 + DMSO-
d6): δ = 20.5, 27.9, 56.4, 62.8, 73.2, 78.4, 127.0, 128.3, 135.9,
136.4, 155.0. ESI-HRMS: m/z calcd for C15H23NO4 [M + Na]+:
304.1519, found: 304.1514. Anal. Calcd for C15H23NO4: C, 64.04;
H, 8.24; N, 4.98. Found: C, 63.91; H, 8.12; N, 4.93.
(14) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int.
Ed. 2006, 45, 7230.
(15) Mishra, R. K.; Coates, C. M.; Revell, K. D.; Turos, E. Org. Lett. 2007,
9, 575.
(20) (2R,3R)-3-(tert-Butoxycarbonylamino)-3-(o-chlorophenyl)-
1,2-propanediol (1d)
25
(16) Kim, S.-G.; Park, T.-H. Tetrahedron: Asymmetry 2008, 19, 1626.
(17) As we have obtained the major diastereomer of >99% with
enantiopurity of 93%, we believe that the stereoinduction of
newly generated chiral center (C–O bond) is fully controlled by
the type of proline we used, irrespective of the stereocenter in
the substrate (Figure 2).
Yield 55%; colorless gum; [α]D –7.50 (c 0.32, CHCl3); 99% ee
from chiral HPLC analysis [Chiracel AS-H, n-hexane–i-PrOH
(95:05), 0.5 mL min–1]: tR = 25.9 min (0.5%) and 28.8 min
(99.5%). IR (CHCl3): νmax = 702, 704, 1036, 1164, 1264, 1367,
1393, 1498, 1694, 2928, 3420 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 1.43 (s, 9 H), 2.97 (br s, 1 H), 3.39 (br s, 1 H), 3.64–3.79 (m, 2
H), 3.98–3.99 (m, 1 H), 5.15–5.17 (m, 1 H), 5.55 (br s, 1 H), 7.19–
7.25 (m, 2 H), 7.27–7.42 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ
= 28.3, 54.1, 62.8, 72.2, 80.4, 127.1, 129.0, 130.1, 133.8, 136.6,
H
H
Ph
N
Ph
S
N
N
Ph
S
NHBoc
Ph
O
156.3. ESI-HRMS: m/z calcd for
C14H20ClNO4 [M +
Na]+:
N
324.0973; found: 324.0970. Anal. Calcd for C14H20ClNO4: C,
55.72; H, 6.68; N, 4.64. Found: C, 55.56; H, 6.48; N, 4.47.
(21) (2R,3R)-3-(tert-Butoxycarbonylamino)-3-(1-naphthyl)-1,2-
propanediol (1e)
H
H
O
O
BocHN
O
O
O
L-proline
anti-amino diol
D-proline
syn-amino diol
25
Yield 62%; colorless gum; [α]D –13.00 (c 0.2, CHCl3); 92% ee
from chiral HPLC analysis [Chiracel AD-H, n-hexane–i-PrOH
(90:10), 0.5 mL min–1]: tR = 12.55 min (3.92%) and 21.64 min
(96.1%). IR (CHCl3): νmax = 774, 1019, 1038, 1121, 1159, 1351,
Figure 2
1408, 1499, 1687, 2921, 2991, 3382 cm–1 1H NMR (400 MHz,
.
(18) General Experimental Procedure for the Preparation of 3-
Amino-1,2-alkane Diols 1a–f
CDCl3): δ = 1.44 (s, 9 H), 2.66 (br s, 1 H), 3.48 (br s, 1 H), 3.76–
3.86 (dd, J = 12.0, 29.3 Hz, 2 H), 4.10–4.12 (m, 1 H), 5.14 (d, J =
8.1 Hz, 1 H), 5.53–5.57 (m, 1 H), 7.48–7.57 (m, 4 H), 7.81 (d, J =
To a stirred precooled (–10 °C) MeCN (25 mL) solution of β-
amino aldehydes 6a–f (17 mmol) and nitrosobenzene (13.6
mmol) was added L-proline (0.039 g, 20 mol%). The reaction
mixture was allowed to stir at the same temperature for 20 h
followed by the addition of MeOH (10 mL) and NaBH4 (25
mmol) to the reaction mixture, which was stirred for further 10
min. After addition of phosphate buffer, the resulting mixture
was extracted with EtOAc (3 × 30 mL), the combined organic
phases were dried over anhydrous Na2SO4 and concentrated to
give the crude aminooxy alcohol, which was directly taken up
for the next step without purification. To a MeOH (25 mL) solu-
tion of the above crude aminooxy alcohol was added
Cu(OAc)2·H2O (2.6 mmol) at 25 °C, and the reaction mixture was
allowed to stir for 10 h at that temperature. After addition of
phosphate buffer, the resulting mixture was extracted with
CHCl3 (3 × 30 mL), and the combined organic phases were dried
over anhydrous Na2SO4 and concentrated to give the crude
product, which was then purified by column chromatography
over silica gel using PE–EtOAc to give 3-amino-1,2-alkane diols
1a–f.
8.1 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 8.06 (d, J = 8.3 Hz, 1 H). 13
C
NMR (100 MHz, CDCl3): δ = 28.3, 51.7, 62.9, 72.9, 80.6, 122.9,
123.9, 125.3, 125.9, 126.8, 128.8, 129.1, 131.8, 134.2, 134.7,
156.8. ESI-HRMS: m/z calcd for C18H23NO4 [M + Na]+: 340.1519;
found: 340.1515. Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N,
4.41. Found: C, 67.93; H, 7.12; N, 4.31.
(22) (2R,3S)-3-(tert-Butoxycarbonylamino)-3-(furfuryl)-1,2-pro-
panediol (1f)
25
Yield 58%; colorless gum; [α]D –44.32 (c 0.46, CHCl3); 90% ee.
IR (CHCl3): νmax = 784, 1089, 1066, 1178, 1263, 1398, 1469,
1508, 1699, 2824, 2841, 3384, 3421 cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 1.44 (s, 9 H), 2.95 (br s, 2 H), 3.67 (s, 2 H), 3.81 (br s,
1 H), 4.76–4.79 (m, 1 H), 5.29 (br s, 1 H), 6.32–6.34 (m, 2 H),
7.37 (br s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 28.3, 50.7, 62.8,
73.1, 80.6, 108.1, 110.5, 142.2, 151.7, 156.2. ESI-HRMS: m/z
calcd for C12H19NO5 [M + Na]+: 280.1169; found: 280.1177. Anal.
Calcd for C12H19NO5: C, 56.02; H, 7.44; N, 5.44. Found: C, 56.07;
H, 7.36; N, 5.32.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 355–358

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