Efficient stereoselective synthesis of α-hydroxy aldehydes with (R)-piperidin-3-ol as a new chiral auxiliary

Full text of DOI:10.1021/jo000201l

2484
J . Org. Chem. 2001, 66, 2484-2486
Sch em e 1
Efficien t Ster eoselective Syn th esis of
r-Hyd r oxy Ald eh yd es w ith
(R)-P ip er id in -3-ol a s a New Ch ir a l
Au xilia r y
In-Young Choi, Hyung Goo Lee, and Kyoo-Hyun Chung*
Department of Chemistry, Inha University,
Inchon 402-751, Korea
kyoohyun@inha.ac.kr
Ta ble 1. Rea ction s of 2 w ith Or ga n om eta llic Rea gen ts
entrya
RM
3
4
yield, %c
Received February 14, 2000 (Revised Manuscript Received
October 20, 2000)
1
2
3
4
5
6
7b
8
9
MeMgBr
EtMgBr
VinylMgBr
iPrMgBr
nBuMgCl
MeLi
MeLi
MeLi+CeCl3
nBuLi
93
98
98
98
77
40
28
69
39
7
2
2
84
85
84
Chiral R-hydroxy carbonyl compounds have been used
as chiral synthons in the preparation of many natural
products.1 They can be prepared efficiently by stereose-
lective addition of organometallics to a chiral ketone
possessing two heteroatoms in the neighborhood of the
carbonyl group.2-5 For example, the reaction of 2-benzoyl-
1,3-oxathianes or perhydro-2-benzoyl-1,3-oxazines with
organometallics results in a high degree of asymmetric
induction that was attributed to the chelation control.2,3
Here, the ring oxygen atom chelates much more
effectively than the ring sulfur or nitrogen atom with the
metals of Grignard reagents as well as other organome-
tallics. However, there have been some reports that the
sulfur or the nitrogen atom can be involved in the
chelation.4,5 In this paper, we describe the excellent
diastereoselectivity observed in the reaction of Grignard
reagents with the chiral 2-acyl-1,3-oxazolidine which can
be prepared from commercially available (R)-piperidin-
3-ol,6 and propose a chelation model with the nitrogen
atom instead of the oxygen atom.
The condensation of phenylglyoxal monohydrate and
(R)-piperidin-3-ol (1) in the presence of molecular sieves
(4 Å) gave (5R,7R)-7-benzoyl-6-oxa-1-azabicyclo[3.2.1]-
octane (2) in 85% yield. Only a trace amount of the C-7
epimer of compound 2 was detected by 1H NMR, probably
because of severe steric hindrance between the benzoyl
group and H-3a (Scheme 1).7
Without further purification, the reactions of keto
oxazolidine 2 with organometallic reagents were carried
out at -78 °C in THF to give carbinols 3 and 4. The
reaction yields and diastereomeric excesses were deter-
mined by the integration of the H-7 peak on their 1H
2
82
23
60
72
31
61
NAd
83
82
62
NAd
a
The molar ratio of RM to the ketone was 3. The reaction was
run in THF at -78 °C, and the ratio was determined by the
b
integration of H-7 peak. The reaction was run in THF-HMPA.
c Isolated yield of a mixture of 5 and 6. A mixture of 5e and 6e
d
was partially decomposed during isolation.
NMR spectra, and the configuration of the major product
was assigned by comparing optical rotation values of the
mixture of R-hydroxy aldehydes 5 and 6 prepared by the
hydrolysis of a mixture of carbinols 3 and 4 with the
known values.2,5 The reactions proceeded to near comple-
tion, and chiral auxiliary 1 was recovered in over 80%
yield (Scheme 2).
As shown in Table 1, the addition of the Grignard
reagents to benzoyl oxazolidine 2 generally proceeded
with high diastereoselectivity giving S-carbinol 3, while
organolithium reagents gave R-carbinol 4 as a major
product with lower stereoselection. The selectivity with
MeLi was enhanced slightly by addition of HMPA to the
reaction solvent (entry 7), whereas reversed diastereo-
selectivity was observed with the addition of CeCl3 (entry
8).
The stereoselectivity observed with the Grignard re-
agents can be rationalized on the basis of a chelation
model.2,3,8 Magnesium cation preferentially chelates be-
tween the carbonyl oxygen and the nitrogen atom to the
ether oxygen atom in 1,3-oxazolidine ring. These results
are comparable with those of 2-benzoyl-1,3-oxazolidine,
derived from (2-pyrrolidinyl)methanol,5 but are different
from those of perhydro-2-benzoyl-1,3-oxazine.2e,3
In the reaction of perhydro-2-benzoyl-1,3-oxazine with
organometallics, the facial selectivity was explained by
the chelation of the metal between the carbonyl oxygen
and the ether oxygen.2,3 The preference of the oxygen to
the nitrogen was proposed by the effective alignment,
based on the orbital geometry.3 The lone pair electrons
of the nitrogen are not aligned with those of the carbonyl
oxygen. However, the electrons of the nitrogen at the
bridgehead in compound 2 are aligned with the carbonyl
oxygen such that chelation with the nitrogen becomes
(1) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in Enantio-
selective Syntheses; J ohn Wiley & Sons: New York, 1997.
(2) Mukaiyama, T.; Sakito, Y.; Asami, M. Chem. Lett. 1978, 1253-
1256. (b) Morris-Natschke, S.; Eliel, E. L. J . Am. Chem. Soc. 1984,
106, 2937-2942. (c) Lynch, J . E.; Eliel, E. L. J . Am. Chem. Soc. 1984,
106, 2943-2948. (d) Ko. K. Y.; Eliel, E. L. J . Org. Chem. 1986, 51,
5353-5362. (e) He, X.-C.; Eliel, E. L. Tetrahedron 1987, 43, 4979-
4987.
(3) Choi, I.-Y.; Son, J .-Y.; Chung, K.-H. Bull. Korean Chem. Soc.
1999, 20, 484-486.
(4) Utimoto, K.; Nakamura, A.; Matsubara, S. J . Am. Chem. Soc.
1990, 112, 8189-8190.
(5) Ukaji, Y.; Yamamoto, K.; Fukui, M.; Fujisawa, T. Tetrahedron
Lett. 1991, 32, 2919-2922.
(6) Purchased from Aldrich Chem. Co. For synthesis see; Olsen, R.
K.; Bhat, K. L.; Wardle, R. B.; Hennen, W. J .; Kini, G. D. J . Org. Chem.
1985, 50, 896-899. For resolution see; Hammer, C. F.; Weber, J . D.
Tetrahedron 1981, 37, 2173-2180.
(7) Sainsbury, M. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R.; Rees, C. W.; Scriven. E. F. V., Ed.; Pergamon: London,
U.K., 1996; Vol. 6, pp 306-310.
(8) Paddon-Row, M. N.; Rondan, N. G.; Houk, K. N. J . Am. Chem.
Soc. 1982, 104, 7162-7166.
10.1021/jo000201l CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/02/2001

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2485
Sch em e 2
F igu r e 1. Directionality of the lone pair electrons of nitrogen and carbonyl oxygen atoms in (a) perhydro-2-benzoyl-1,3-oxazine
and (b) 2-benzoyl-1,3-oxazolidine.
Sch em e 3a
more effective (Figure 1). As a result, re face attack is
predominant in case of compound 2.
When organolithium reagents were employed, the
opposite si face attack was observed. The chelation with
the nitrogen may not be stronger, because lithium is
smaller than magnesium. So steric hindrance becomes
the larger factor in the control of diastereoselectivity. In
the presence of HMPA, the chelation becomes less
effective, while the steric bulkiness has more effect (entry
7). When cerium is added with the lithium reagent,
a
Conditions: (i) MeMgBr or MeLi, (ii) silica gel, (iii) NaClO2,
chelation with nitrogen becomes more effective, because
cerium is larger than lithium (entry 8). While compounds
5a -d and 6a -d were quite stable to isolate, 5e and 6e
cannot be isolated (entries 5 and 9). In the reaction with
DIBAL or NaBH4, the corresponding carbinols were too
labile to be isolated, unlike the reaction of perhydro-1,3-
oxazines.
In addition to phenylglyoxal, tert-butylglyoxal was
employed.9 The condensation of tert-butylglyoxal with
(R)-piperidin-3-ol gave ketooxazolidine 7 which was used
in the addition reaction with MeMgBr or MeLi. Since the
resulting carbinol was unstable, it was hydrolyzed to
2-hydroxy-2,3,3-trimethylbutanal which was identified by
1H NMR. The hydroxy aldehyde was also slightly un-
stable and converted to methyl 2-tert-butyldimethylsil-
yloxy-2,3,3-trimethylbutanoate (8) by the sequence: oxida-
tion,4c methyl ester formation,10 and protection of the
2-methyl-2-butene, (iv) Me3SiCH2N2, (v) TBDMSCl, imidazole.
hydroxy moiety11 (Scheme 3). The diastereoselectivity in
the addition reaction could be determined by measuring
the enantiomeric ratio of silyl ester 8 using a chiral GC.
Like phenylglyoxal, the selectivity with MeMgBr was
opposite to that with MeLi.
In conclusion, the addition reaction of bridged 2-acyl-
1,3-oxazolidine, prepared from (R)-piperidin-3-ol, with
Grignard reagents proceeded with high diastereoselec-
tivity to give nearly optically pure R-hydroxy aldehydes.
The selectivity can be attributed to a chelation model
involving the nitrogen and carbonyl oxygen atoms. Thus,
chiral piperidin-3-ol has been demonstrated to be an
efficient chiral auxiliary for the preparation of R-hydroxy
carbonyl compounds in the present study.12
(10) Giuliano, R. M.; J ordan, A. D., J r.; Gauthier, A. D.; Hoogsteen,
K. J . Org. Chem. 1993, 58, 4979-4988.
(11) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190-6191.
(9) Fuson R. C.; Gray H.; Guoza, J . J . J . Am. Chem. Soc. 1939, 61,
1937-1940.

2486 J . Org. Chem., Vol. 66, No. 7, 2001
Notes
Since [R] value of the mixture of 5a and 6a was +190°, and that
of (S)-2-hydroxy-2-phenylpropanal was +244°,2a carbinol 3a
having S chirality at the benzylic position was predominant,
resulting from re face attack. The ratio of the peak intensities
at 4.81 and 4.77 ppm (H-7) was 93:7. Therefore, the diastereo-
selectivity was 93:7 in favor of 3a . The diastereoselectivity was
also confirmed by a chiral GC with methyl 2-hydroxy-2-phenyl-
propanoate (methyl atrolactate),2a derived from a mixture of 5a
and 6a . The same calculations were done for other reactions.
7-(2,2-Dim eth yl-1-oxo)p r op yl-6-oxa -1-a za bicyclo[3.2.1]-
octa n e (7). The condensation adduct was subjected to a short
columm on alumina to give a yellow oil (58.3%); 1H NMR δ 1.17
(s, 9H), 1.41-1.55 (m, 2H), 1.77-1.97 (m, 2H), 2.73-2.98 (m,
4H), 4.33-4.37 (m, 1H), 5.30 (s, 1H); 13C NMR δ 17.7, 24.3, 27.7,
40.6, 51.3, 54.3, 70.5, 89.9, 207.7. HRMS-EI (m/z): M+ calcd for
Exp er im en ta l Section
All chemicals were reagent grade (Aldrich Chemical Co.) and
were used as purchased without further purification. 1H NMR
spectra were recorded at 250 and 300 MHz (75 MHz for 13C
NMR).
(5R,7R)-7-Ben zoyl-6-oxa -1-a za bicyclo[3.2.1]octa n e (2). A
mixture of (R)-piperidin-3-ol (0.140 g, 1.38 mmol), phenylglyoxal
monohydrate (0.185 g, 1.38 mmol), and molecular seives (4 Å)
in dry CH2Cl2 (30 mL) was refluxed overnight. After cooling,
the reaction mixture was washed with water, dried over Na2-
SO4, filtered, and concentrated in vacuo. The residue was
purified by recrystallization with CH2Cl2 and n-hexane to give
ketooxazolidine 2 (0.256 g, 85%) as a yellow solid: mp 128-129
°C; 1H NMR δ 1.53-1.69 (m, 2H), 1.89-2.24 (m, 2H), 2.97-3.18
(m, 3H), 3.18-3.31(m, 1H), 4.44-4.50 (m, 1H), 5.85 (s, 1H),
7.44-7.68 (m,3H), 8.00-8.13 (m, 2H); 13C NMR (CDCl3) δ 20.8,
30.5, 54.3, 57.8, 73.6, 94.6, 128.9, 129.4, 133.6, 135.4, 194.3. Anal.
Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.83;
H, 7.08; N, 6.38.
Gen er a l P r oced u r e for th e Gr ign a r d Rea ction u sin g
MeMgBr . To a solution of ketone 2 (0.020 g, 0.092 mmol) in
dry THF (1 mL) at -78 °C under N2 was added dropwise 3.0 M
methylmagnesium bromide in ether (0.01 mL, 0.27 mmol). After
stirring for 1 h, the reaction was quenched with saturated NH4-
Cl solution at -78 °C and allowed to warm to room temperature,
and ethyl acetate (5 mL) and brine (5 mL) were added. The
organic layer was separated, and the aqueous layer was further
extracted with ethyl acetate (5 mL) twice. The combined organic
layer was washed with brine, dried over Na2SO4, and concen-
trated to give a mixture of oily carbinols 3a and 4a (0.018 g,
84%). A mixture of 3a and 4a ; 1H NMR δ 1.39-1.53 (m, 2H),
1.61 (s, 3H), 1.78-2.11(m, 2H), 2.29-2.36 (m, 1H), 2.80-3.00
(m, 3H), 3.63-3.79 (m. 1H), 4.08-4.11 (m, 1H), 4.81 and 4.77
(s, 1H), 7.19-7.58 (m, 5H). In the case of other compounds, the
chemical shift of H-7 is described.
C
11H19NO2, 197.1416; found, 197.1415.
Met h yl 2-ter t-Bu t yld im et h ylsilyloxy-2,3,3-t r im et h yl-
bu ta n oa te (8). 2-Hydroxy-2,3,3-trimethylbutanal (93.8 mg, 0.72
mmol, 79%) was prepared from 7 (180 mg. 0.91 mmol) by
organometallic reaction and hydrolysis; 1H NMR δ 0.94 (s, 9H),
1.20 (s, 3H), 9.71 (s, 1H). To a solution of the aldehyde and
2-methyl-2-butene (2.5 mL) in acetone (8 mL) was added a
freshly prepared solution (8 mL) of KH2PO4 (910 mg) and
NaClO2 (810 mg) in H2O (15 mL) dropwise. The mixture was
stirred at room temperature for 45 min and then concentrated
to remove acetone. To this residue was added 5% aqueous Na2-
CO3. The basic water layer was extracted with ethyl ether (15
mL × 3) and then acidified with 5% HCl until pH 1. The water
layer was saturated with brine and extracted with ethyl ether
(15 mL × 3). The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated to give an oil (90 mg, 0.62
mmol, 86%) which was identified by 1H NMR as 2-hydroxy-2,3,3-
1
trimethylbutanoic acid; H NMR δ 1.00 (s, 9H), 1.40 (s, 3H).
To a solution of the R-hydroxy acid in THF (5 mL) and
methanol (2 mL) was added dropwise 2.0 M trimethylsilyldia-
zomethane (1.54 mL, 3.08 mmol) in hexane at room temperature.
After stirring for 2 h, the reaction mixture was concentrated in
vacuo. The residue oil was dissolved in DMF (2 mL), and
imidazole (147 mg, 2.15 mmol) and TBDMSCl (139 mg, 0.92
mmol) were added at room temperature. The mixture was stirred
overnight and then poured into water (20 mL). The aqueous
solution was extracted with ethyl ether (20 mL × 2). The
combined organic layer was washed with water, brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (methylene chloride) to
give an oil (136 mg, 80.5%): 1H NMR δ 0.00 (s, 6H), 0.82 (s,
9H), 0.87 (s, 9H), 1.27 (s, 3H); 13C NMR δ -6.97, 15.5, 18.1, 22.9,
23.2, 35.0, 49.8, 76.9, 175.0. HRMS-CI (m/z): MH+ calcd for
A mixture of 3b and 4b: 4.79 and 4.76 (s, 1H). A mixture of
3c and 4c: 4.86 and 4.84 (s, 1H). A mixture of 3d and 4d : 5.05
and 5.03 (s, 1H). A mixture of 3e and 4e: 4.78 and 4.77 (s, 1H).
Hyd r olysis of th e Mixtu r e of 3a a n d 4a .2,5 A mixture of
carbinols 3a and 4a (54 mg, 0.23 mmol), silica gel (5 g), and
CH2Cl2 (20 mL) was stirred for 2 h at room temperature. The
reaction mixture was subjected to column chromatography on
silica gel (elution with 20% ethyl acetate in n-hexane). After most
of hydroxy aldehydes 5a and 6a (30 mg, 87%) were eluted, the
chiral auxiliary, (R)-piperidin-3-ol (19 mg, 82%), was eluted with
MeOH. A mixture of 5a and 6a : [R]20 +190° (c 0.18, benzene,
D
lit.2a 5a ; [R]23 +244°).
D
A mixture of 5b and 6b; [R]20D+215° (c 0.18, benzene, lit.2a
C
14H30O3Si, 275.2043; found, 275.2046.
5b; [R]23 +239°).
D
Deter m in a tion of Dia ster eom er ic Excess Usin g ter t-
A mixture of 5c and 6c; [R]20 +100° (c 0.022, benzene, lit.2a
D
Bu tylglyoxa l. The de could be determined by measuring ee of
8 using a chiral GC. The enantiomeric ratio was 94:6 with
MeMgBr, while the ratio was 19:81 with MeLi.
5c; [R]23 +179°).
D
A mixture of 5d and 6d ; [R]20 +272° (c 0.50, benzene, lit.2a
D
5d ; [R]23 +310°).
D
Deter m in a tion of Ch ir a lity a t th e Ben zylic P osition ,
Dia ster eom er ic Excess, a n d th e Rea ction Yield . By com-
paring the [R] value of the mixture of 5 and 6 with the known
[R] value, the major component between 3 and 4 was determined.
Ack n ow led gm en t. We thank Korea Science and
Engineering Fund (NO. 97-03-01-01-5-L) for financial
support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compound 2, 7, 8, mixtures of 3a -e and 4a -e, and 13C NMR
spectra for compound 2, 7, and 8. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) Addition of Grignard reagents to the oxazolidine having the
methoxycarbonylmethyl moiety in the equatorial position at C-2
proceeded in much lower diastereoselection (Reddy, P. N.; Han. S.-S.;
Chung, K.-H. Bull. Korean Chem. Soc. 1998, 19, 617-618), presumably
because the side chain is involved in the chelation to some extent (Frye,
S. V.; Eliel, E. L. J . Am. Chem. Soc. 1988, 110, 484-489).
J O000201L