Diastereoselective reduction of chiral N-tosyl-2-benzoyl-1,3-oxazine derived from (1R)-(+)-camphor

Article abstract of DOI:10.3987/COM-10-12016

The stereochemistry of reduction of chiral N-tosyl-2-benzoyl-1,3-oxazine prepared by condensation of 1,3-amino alcohol derived from (1R)-(+)-camphor with phenylglyoxal was investigated using various reducing agents. Based on X-ray crystallography, 2-benzoyl group in 1,3-oxazine ring was situated in the axial position. High diastereoselectivity observed in the hydride reduction can be explained by a chelate model where N-tosyl oxygen atom takes part in chelation rather than ring oxygen atom. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-12016

HETEROCYCLES, Vol. 81, No. 10, 2010
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HETEROCYCLES, Vol. 81, No. 10, 2010, pp. 2351 - 2359. © The Japan Institute of Heterocyclic Chemistry
Received, 12th July, 2010, Accepted, 24th August, 2010, Published online, 25th August, 2010
DOI: 10.3987/COM-10-12016
DIASTEREOSELECTIVE REDUCTION OF CHIRAL
N-TOSYL-2-BENZOYL-1,3-OXAZINE DERIVED FROM
(1R)-(+)-CAMPHOR
Kwang-Youn Ko1* and Hoseop Yun2
1Department of Chemistry and Division of Energy Systems Research, Ajou
2
University, Suwon, 443-749, Korea
E-mail: kyko@ajou.ac.kr, hsyun@ajou.ac.kr
Abstract
–
The
stereochemistry
of
reduction
of
chiral
N-tosyl-2-benzoyl-1,3-oxazine prepared by condensation of 1,3-amino alcohol
derived from (1R)-(+)-camphor with phenylglyoxal was investigated using
various reducing agents. Based on X-ray crystallography, 2-benzoyl group in
1,3-oxazine ring was situated in the axial position. High diastereoselectivity
observed in the hydride reduction can be explained by a chelate model where
N-tosyl oxygen atom takes part in chelation rather than ring oxygen atom.
The diastereoselective addition of nucleophilic reagents to ketones having a chiral auxiliary is a useful
method for obtaining optically active alcohols.1 Chiral auxiliaries used for this purpose include
enantiomerically pure amino alcohols derived from norephedrine,2 (+)-pulegone3 or amino acids,4
3-hydroxythiols derived from (+)-pulegone,5 (-)-myrtenal6 or (1R)-(+)-camphor,7 and 1,3-diols.8 We
previously reported highly diastereoselective reduction of chiral N-tosyl-1,3-oxazines 1 derived from
D-glucose.9 In this case, the high diastereoselectivity observed in the reduction with chelating reducing
agents such as L-Selectride® (lithium tri-sec-butylborohydride) has been explained by invoking a Cram’s
chelate model, where the ring oxygen and the carbonyl oxygen take part in the chelation with metal cation.
On the contrary, non-chelating agents such as diisobutylaluminum hydride (DIBAL-H) and n-Bu4NBH4
have been suggested to react according to a Felkin-Anh model.9

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HETEROCYCLES, Vol. 81, No. 10, 2010
Me
Me
Ts
Ph
N
O
O
O
RO
NHR
OH
OR
OMe
1
2
(1R)-(+)-Camphor has been used as a starting material for the preparation of various chiral auxiliaries or
chiral catalysts.10 Chiral auxiliaries derived from camphor are known to have good crystallinity, giving
some advantages in purification of product. However, 3-amino alcohols 2 which can be easily derived
from camphor have not yet been used as chiral auxiliary for asymmetric reduction. As an extension of our
previous work,9 we wish to report a highly diastereoselective reduction of camphor-based oxazine and
determination of absolute configuration of newly formed stereocenter by single crystal X-ray diffraction.
N-Tosylamino alcohol 3, a camphor-derived chiral auxiliary used for the present study was prepared
according to Scheme 1. Thus, ketopinic acid derived from (+)-camphor was converted to known amino
alcohol 2.11 Subsequent tosylation with p-TsCl gave 3 as a crystalline solid. Finally, condensation with
phenylglyoxal in acidic condition gave a mixture of two phenyl ketones 4 in a ratio of 4 : 1, as judged by
1H-NMR spectrum. Major product could be isolated in a pure form by recrystallization from EtOH.
Me
Me
Me
Me
Me
Me
Ref. 11
p-TsCl, K2CO3
NH2
OH
NHTs
OH
EtOAc, H2O, 60%
CO H
O
2
2
3
ketopinic acid
PhCOCHO
NTs
NTs
O
6.52 ppm
+
2
H
O
O
Ph
p-TsOH, benzene, 80%
H
4.94 ppm
4e
O
4a
Ph
Scheme 1. Preparation of 2-Benzoyl-1,3-oxazines 4
Then, we studied reduction of phenyl ketone 4a using several reducing agents, as shown in Table 1
(Scheme 2).

HETEROCYCLES, Vol. 81, No. 10, 2010
2353
NTs
NTs
NTs
O
separation of
major product
O
2
H
H
O
O
+
Ph
H
O
O
Ph
4e
Ph
4a
4a
NTs
NTs
[H]
(see Table 1)
2
H
O
H
H
O
+
OH
H
HO
Ph
Ph
(S)-5
(R)-5
Scheme 2. Diastereoselective reduction of 2-benzoyl-1,3-oxazine 4a
Table 1. Diastereoselectivity in the reduction of 2-benzoyl-1,3-oxazine 4aa
Entry
Reagent
Solvent
Temp. Time (h)
(oC)
de (%)b,c
1
NaBH4
KBH4
EtOH
EtOH
THF
0
18
18
1
40
30
72(68d)
98(98d)
98
2
0
3a
3b
4a
4b
5a
5b
6a
6b
6c
7a
7b
7c
8a
8b
8c
8d
9
LiAlH4
-70
-70
-70
-70
-70
-70
-70
-70
-70
-70
-70
-70
-70
-70
-70
-70
20
LiAlH4
Et2O
1
L-Selectride®
L-Selectride®
LiAlH(O-t-Bu)3
LiAlH(O-t-Bu)3
LiEt3BH
Et2O
1
toluene
THF
1
90(87d)
10
10
1
70
Et2O
98
THF
8
LiEt3BH
Et2O
1
64
LiEt3BH
toluene
THF
1
70(30d, -60e)
66(-50e)
95(10e)
96(14f)
10
NaEt3BH
1
NaEt3BH
Et2O
1
NaEt3BH
toluene
THF
1
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
n-Bu4NBH4
1
Et2O
1
-81
toluene
CH2Cl2
CH2Cl2
1
40
1
53
10
10
a. Determined by 1H NMR on the crude products.
b. Minus sign indicates formation of (S)-isomer as the major product.
c. The number in parenthesis is the de in the presence of crown ether. The molar ratio of 4a, reagent,
and crown ether = 1 : 3 : 5.
d. In the presence of 12-Crown-4.
e. In the presence of 15-Crown-5.
f. In the presence of 18-Crown-6.

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HETEROCYCLES, Vol. 81, No. 10, 2010
1
Diastereoselectivity could be easily determined by H-NMR spectroscopy. For example, in entry 1, C-2
proton of the major product appeared as a doublet at δ 5.40 (J = 3.7 Hz) and that of the minor one
appeared as a doublet at δ 5.54 (J = 9.1 Hz).
Either alcohol (R)-5 or (S)-5 (see below for the determination of the absolute configuration) was obtained
as the major product, depending on the nature of reducing agents and solvents. Generally, all the
chelating reducing agents used in the present case gave the (R)-5 as the major product (entries 1~7).
Nonchelating agents such as DIBAL-H and n-Bu4NBH4 also gave the (R)-isomer albeit in rather poor
selectivity, except for the entry 8b. High selectivity (>98%) favoring the (R)-alcohol was observed when
LiAlH4, L-Selectride® or LiAlH(O-t-Bu)3 was used as reducing agents (entries 3b, 4a, 5b).
Next, we undertook the cleavage of oxazines 5 to determine the absolute configuration of the newly
formed carbinol carbon and thereby the approaching preference of the nucleophile to the carbonyl faces:
alcohol 5 obtained from L-Selectride® reduction (entry 4b) was converted to diol 6, [α]D20 -35.5 (c 1.01,
EtOH) using acidic hydrolysis followed by NaBH3CN reduction of the resulting 2-hydroxyaldehyde
intermediate (Scheme 3).12
NTs
NTs
H
HO
5% HCl, H2O-MeOH;
NaBH3CN, 86%
H
OH
Ph
H
H
H
O
O
HO
HO
+
+
Ph
OH
Ph
(S)-6
(R)-6
H
HO
Ph
(S)-5
(R)-5
Scheme 3. Preparation of diol 6 by acidic hydrolysis of oxazine ring followed by reduction
20
Since (R)-6 is known to be levorotatory ([α]D -39.7 (c 4.33, EtOH)),13 we can conclude that the
carbinol carbon has (R)-configuration. The formation of (R)-isomer can be explained by invoking a
similar chelate model as in the case of ketone 1 where ring oxygen atom takes part in chelation, assuming
that benzoyl group is situated equatorially.9 However, chemical shift for C-2 proton of major phenyl
ketone 4 appeared downfield relative to that in the minor one (6.52 vs. 4.94 ppm), which may imply that
benzoyl group is situated in an axial position rather than in an equatorial one.14 To unambiguously
determine the absolute configuration of C-2 on 4a and carbinol carbon of 5, we resorted to single crystal
X-ray crystallography of 4a and 5.15 Figure 1 and 2 show an ORTEP drawing of ketone 4a16 and the
major product 517 of LiAlH4 reduction, respectively. Figure 1 clearly shows the axial orientation of the
1
benzoyl group in 4a,18 as suspected based on the H NMR data. The oxazine ring has a chair
conformation, which is in contrast to the boat conformation of the similar N-tosyl-2-vinyl-1,3-oxazine
ring.19 Figure 2 shows the (R)-configuration of carbinol carbon, which agrees with the optical rotation
data.

HETEROCYCLES, Vol. 81, No. 10, 2010
2355
Figure 1. A view of 4a. Vibrational ellipsoids Figure 2. A view of (R)-5. Vibrational ellipsoids
are drawn at the 30% probability level.
Hydrogen atoms are omitted for clarity.
are drawn at the 30% probability level.
Hydrogen atoms except H14 are omitted for
clarity.
We can consider three conformations I~III that may result in the (R)-configuration, as shown in Scheme
4.1
Ph
H
O
Ts
Ph
Ts
H
N
Ph
O
N
Ph
H
Ph
O
O
H
O
TsN
O
N
O
Met
O
Met
NTs
O
O S O
Ar
H
O
Dipolar Model V
Felkin-Anh Model I
Felkin-Anh Model II
Chelate Model IV
Chelate Model III
Scheme 4. Stereochemical models
Felkin-Anh polar model I where N-tosyl group is located perpendicular to the carbonyl group, appears to
be unfavorable due to the steric reason. Another Felkin-Anh model II and the chelate model III can
predict the correct stereochemistry. Model II is in accord with the X-ray structure of ketone 4, which
shows that the carbonyl group, situated inside the oxazine ring is nearly perpendicular to the α-C-O
bond.20 The chelate model III where the sulfonyl oxygen, not the ring oxygen as in model IV takes part
in chelation can also explain the formation of (R)-alcohol.21
To see the effect of crown ether on the chelation, we performed the reduction in the presence of crown
ethers.9 Little decrease in selectivity in the presence of crown ether was observed in the LiAlH4 and
L-Selectride® reductions (entries 3a, 3b, 4b). This fact may be explained by assuming that Felkin-Anh
model II is operating or chelation in model III is rather strong as not to be disturbed by crown ether.

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HETEROCYCLES, Vol. 81, No. 10, 2010
However, decrease in selectivity in THF which is a better solvating solvent than ether (entry 3a vs. 3b, 5a
vs. 5b, 6a vs. 6b, and 7a vs. 7b) may support that the chelate model is more important. In contrast, in the
case of LiEt3BH and NaEt3BH reduction the presence of crown ether dramatically affected the degree
and/or direction of selectivity. For example, the diastereoselectivity of LiEt3BH reduction in toluene
changed from 70% de to 30% in the presence of 12-crown-4 (entry 6c). Surprisingly, the use of
15-crown-5, which is known to complex with sodium cation more efficiently than lithium cation resulted
in the opposite stereochemistry (entry 6c).22 Similar trend was also observed in the NaEt3BH reduction
(entry 7). Compared with the LiEt3BH reduction the selectivity in the NaEt3BH reduction was better,
decreasing in a larger extent in the presence of crown ether. This result is expected in that sodium chelate
is less tight than lithium chelate, thus being disturbed more easily by crown ether. However, the reason
for the better selectivity of less tight sodium chelate is not clear. In DIBAL-H reduction, the
stereochemistry of reduction was moderate, except for the reduction in ether solvent, which gave the
opposite stereochemistry to LiAlH4 reduction. This formation of (S)-carbinol can be explained by
invoking the dipolar model V where the ring oxygen atom is anti to the carbonyl group. However, the
reason why ether solvent behaves differently in the DIBAL-H reduction remains to be answered.
In summary, axial phenyl ketone 4a derived from a new camphor-based chiral auxiliary 3 was found to be
reduced with chelating reducing agents in high diastereoselectivity. In the present case, the
stereochemistry of this reduction could be explained by invoking a chelate model III where tosyl oxygen
takes part in chelation. Participation of tosyl oxygen atom in chelation is in sharp contrast with the case of
ketone 1 where ring oxygen atom takes part in chelation. This study shows that ketones 1 and 4a which
are similar in structures can react with reducing agents in different stereochemical sense.
EXPERIMENTAL
IR spectra were recorded with a Nicolet Magna FT-IR spectrophotometer 550. NMR spectra were
recorded on Varian Gemini 400 spectrometer in CDCl3 with tetramethylsilane (TMS) as internal standard.
Melting points were determined on a Buchi and are uncorrected. Optical rotations were measured on a
Jasco DIP-370 digital polarimeter. Elemental analyses were performed by Eager 200 CHNS CE
Instrument. Liquid Column chromatography was performed over silica gel (Merck, silica gel 60, 70-230
mesh). Analytical TLC was performed on precoated Merck glass plates (silica gel 60 F254) and
compounds were visualized under UV light or by dipping in an ethanol solution of phosphomolybdic acid,
followed by heating. Dry THF was distilled over sodium benzophenone ketyl under nitrogen atmosphere.
N-Tosyl amino alcohol 3
To a well stirred mixture of amine 2 (1.80 g, 10.6 mmol) in EtOAc (35 mL) and water (20 mL) was added

HETEROCYCLES, Vol. 81, No. 10, 2010
2357
K2CO3 ( 1.47 g, 10.6 mmol) followed by p-TsCl ( 2.20 g, 11. 7 mmol) at 0 oC. The reaction mixture was
o
stirred at 0 C for 30 min and then at rt for 10 h. Then, the organic layer was separated and the aqueous
layer was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed successively
with brine (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude
yellowish product (3.30 g). Trituration in EtOAc (10 mL) gave 3 (2.00 g, 60%) as a white solid. 3: mp
20
195-197 oC; [α]D -4.3 (c 1.00, CHCl3); IR (KBr) νmax 3445 (OH), 3225, 2956, 1475, 1321, 1160;
1H-NMR (400 MHz, CDCl3): δ 7.77 (2H, d, J = 8.3 Hz), 7.32 (2H, d, J = 8.0 Hz), 5.29 (1H, s, J = 8.0 Hz,
NH), 4.04, 3.46 (2H, ABq, J = 12 Hz), 3.22 (1H, dd, J = 10, 4.6 Hz), 2.44 (s, 3H), 1.68-1.52 (5H, m),
1.35-1.20 (2H, m), 1.00 (3H, s), 0.88 (3H, s); 13C-NMR (100 MHz, CDCl3): δ143.5, 136.6, 129.8, 129.2,
61.7, 59.2, 53.3, 47.0, 46.0, 39.5, 32.0, 26.4, 21.5, 21.0, 20.6; Anal. Calcd for C11H25NO3S: C, 63.12; H,
7.81; N, 4.33; S, 9.91. Found: C, 62.51; H, 7.90; N, 4,29; S, 9.54.
Phenyl ketone 4a
A solution of 3 (970 mg, 3.00 mmol) and phenylglyoxal hydrate (790 mg, 5.89 mmol) in benzene (50
mL) was refluxed for 20 h in the presence of p-TsOH (75 mg). The reaction mixture was diluted with
EtOAc (50 mL) and water (20 mL). The organic layer was separated and washed successively with brine
(2 x 10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude residue, which was
purified by recrystallization from EtOH to afford 4a (660 mg, 50%). 4a: mp 181-182 oC; [α]D20 -65.1 (c
1
0.98, CHCl3); IR (KBr) νmax 3447 (OH), 3225, 1640 (C=O), 1329, 1160, 715; H-NMR (400 MHz,
CDCl3): δ 8.14 (2H, d, J = 8.1 Hz), 7.73 (2H, d, J = 8.1 Hz), 7.65-7.45 (3H, m), 7.31 (2H, s), 6.52 (1H, s),
4.16 (1H, dd, J = 8.1, 4.6 Hz), 3.78, 3.38 (2H, ABq, J = 13 Hz), 2.44 (s, 3H), 2.25-2.13 (1H, m),
1.78-1.62 (4H, m), 1.40-1.09 (2H, m), 0.98 (3H, s), 0.83 (3H, s); 13C-NMR (100 MHz, CDCl3): δ 195.2,
143.2, 139.6, 134.1, 133.8, 129.3, 129.2, 128.6, 127.3, 84.9, 63.5, 59.4, 47.2, 46.5, 45.5, 35.6, 30.9, 26.6,
21.6, 21.4, 20.2; Anal. Calcd for C25H29NO4S: C, 68.23; H, 6.66; N, 3.19; S, 7.29. Found: C, 68.16; H,
6.68; N, 3.16; S, 6.91.
Reduction of phenyl ketone 4a
An example: A solution of 4a (0.50 g, 1.18 mmol) in dry ether (20 mL) was treated with a solution (2.0
mL) of 1 M LiAlH4 in ether under nitrogen atmosphere at -70 oC. After stirring for 1 h, the reaction
mixture was quenched with NH4Cl aq. and extracted with EtOAc (20 mL). The organic layer was
separated and washed successively with brine (2 x 10 mL), dried over anhydrous Na2SO4 and
concentrated in vacuo to give a crude residue 5 (0.45 g, 90%), whose 1H-NMR spectrum showed that the
diastereoselective excess was 98%. Recrystallization from EtOH gave 5 as a single diastereomer. 5: mp

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HETEROCYCLES, Vol. 81, No. 10, 2010
20
1
172-173 oC; [α]D -93.1 (c 1.02, CHCl3); IR (KBr) νmax 3487 (OH), 1160, 1057, 975; H-NMR (400
MHz, CDCl3): δ 7.71 (2H, d, J = 8.3 Hz), 7.51-7.23 (7H, m), 5.66 (1H, d, J = 3.7 Hz), 5.40 (1H, d, J = 3.7
Hz), 4.40, 3.61 (2H, ABq, J = 12 Hz), 4.15 (1H, dd, J = 8.1, 5.1 Hz), 2.40 (s, 3H), 2.08-1.98 (2H, m),
1.70-1.08 (5H, m), 0.77 (3H, s), 0.76 (3H, s); 13C-NMR (100 MHz, CDCl3): δ 143.2, 140.2, 140.1, 129.4,
128.3, 127.6, 127.0, 125.9, 86.0, 79.0, 62.8, 60.3, 46.9 46.3, 45.2, 35.8, 31.7, 26.5, 21.5, 20.7, 20.3.
1-Phenyl-1,2-ethanediol (6)
A solution of 5 (0.40 g, 0.91 mmol, derived from L-Selectride® reduction (entry 4b)) in MeOH (50 mL)
was treated with 5% HCl aq. (10 mL) and the whole mixture was refluxed for 3 h. After adjusting pH to
4~5 by adding Na2CO3, the reaction mixture was treated with NaBH3CN (60 mg, 0.95 mmol) and
refluxed for 30 min. Concentration in vacuo gave a yellow solid, which upon column chromatography
(hexanes:EtOAc = 2:1) yielded 6 (0.10 g, 79%) and 3 (0.25 g, 85%). Kugelrohr distillation (145~150 oC,
20
0.1 mmHg) of crude 6 gave a pure known diol 6. 6: [α]D -35.5 (c 1.01, EtOH) [lit.13 for (R)-isomer
20
1
[α]D -39.7 (c 4.33, EtOH)]; H-NMR (400 MHz, CDCl3): δ 7.36 (5H, s), 4.80 (1H, X part of ABX,
HOCH2CH-, J = 8.0, 3.5 Hz), 3.74, 3.65 (2H, AB part of ABX, HOCH2CH-, J = 11.4, 8.0, 3.5 Hz),
3.11-2.20 (2H, s).
ACKNOWLEDGEMENTS
The authors are grateful to Ajou University for use of its X-ray facilities. One of the authors (K-Y. Ko)
thanks Ajou University for providing a sabbatical leave during the year 2009.
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HETEROCYCLES, Vol. 81, No. 10, 2010
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axial proton due to small diamagnetic anisotropy of a C-C bond. See: ‘Stereochemistry of Organic
Compounds: Principles and Applications’, D. Nasipuri, Wiley, 1991. The equatorial nature of 1 (R =
Me) was determined by 1H NMR spectrum, where for the equatorial and axial 1, the proton between
oxygen and nitrogen resonates at δ 5.34 and 6.70, respectively.
15. Crude alcohol obtained from LiAlH4 reduction was purified by recrystallization from EtOH, yielding
adequate crystals for X-ray crystallography.
16. K.-Y. Ko and H. Yun, Acta Cryst., 2007, E63, o4712.
17. Further details of the crystal structure investigations may be obtained from the Cambridge
Crystallographic Data Centre (CCDC, 12 Union Road, Cambridge CB2 1EZ (UK); tel.:
(+44)1223-336-408, fax: (+44)1223-336-033, e-mail: deposit@ccdc.cam.ac.uk) on quoting the
depository number CCDC 672055.
18. The steric repulsion between gem-dimethyl group and phenyl group as well as the anomeric effect of
phenyl group may contribute to the formation of axial anomer. See: ‘Introduction to Stereochemistry
& Conformational Analysis’, E. Juaristi, Wiley-Interscience, 1991.
19. J. Lacoste, C. Soucy, F. D. Rochon, and L. Breau, Tetrahedron Lett., 1998, 39, 9121.
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parallel to π and π* orbitals of carbonyl. It is known that σ* C-O bond is a better acceptor than σ*
C-N bond. See: I. V. Alabugin and T. A. Zeidan, J. Am. Chem. Soc., 2002, 124, 3175.
21. As shown in Figure 1, the sulfonyl oxygen atoms are disposed into the direction of carbonyl group.
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