Asymmetric Allylation and Reduction on an Ephedrine-Derived Template: Stereoselective Synthesis of α-Hydroxy Acids and Derivatives

Full text of DOI:10.1021/jo9722820

4120
J . Org. Chem. 1998, 63, 4120-4124
R-alkyl R-allyl hydroxy acids, but these do not employ
Asym m etr ic Allyla tion a n d Red u ction on
R-keto acids as starting materials.
a n Ep h ed r in e-Der ived Tem p la te:
Ster eoselective Syn th esis of r-Hyd r oxy
Acid s a n d Der iva tives
Our interest in chiral amino alcohol-based hemiacetals
of R-keto acids as pecursors to R-hydroxy acids8 led us to
investigate (1R,2S)-ephedrine as a chiral controller in
such systems. Acylation of (1R,2S)-ephedrine hydrochlo-
ride with aliphatic R-keto acid chlorides generates the
corresponding hemiacetals 1b-e in 65-71% yield. Hemi-
acetal 1a is obtained by ester hydrolysis in the amido
ester obtained by bis-acylation of ephedrine with ben-
zoylformyl chloride (Scheme 1). The absolute configu-
ration of the hemiacetal stereocenter was established as
S by X-ray crystallographic analysis9 of 1d and 1e and
Sunil V. Pansare,* R. Gnana Ravi, and Rajendra P. J ain
Division of Organic Chemistry (Synthesis),
National Chemical Laboratory, Pune 411 008, India
Received December 16, 1997
The asymmetric synthesis of R-hydroxy acids continues
to be an area of active interest due to their utility as
chiral building blocks.1 Among the several synthetic
approaches to R-hydroxy acids, the stereoselective addi-
tion of carbon nucleophiles to chiral R-keto acid deriva-
tives has been extensively investigated.2 We describe
here a stereoselective synthesis of R-alkyl R-allyl R-hy-
droxy amides, R-alkyl R-hydroxy acids, and R-H R-hy-
droxy acids. The procedure involves prefunctionalization
of the precursor R-keto acid by intramolecular hemiac-
etalization followed by (a) stereoselective allylation or (b)
dehydration and hydrogenation of the chiral hemiacetal.
Stereoselective allylation of ketones has been a chal-
lenging task, and an efficient method has been described
only recently.3 Similarly, the development of an efficient
procedure for asymmetric allylation of R-keto acid deriva-
tives has been difficult, although their stereoselective
reactions with other carbon nucleophiles are well estab-
lished.2 Stereoselective carbonyl ene reactions have been
examined mainly with glyoxylates and, in a few in-
stances, with pyruvates.4 Menthyl esters of R-keto acids
have been allylated5 with low diastereoselectivity, whereas
the diastereoselectivity for allylation of proline-derived
R-keto amides is not uniformly high and the allylated
intermediates have been converted to R-hydroxy ketones
and not R-hydroxy acids.6 Enzymatic resolution7a of a
few R-allyl R-hydroxy esters and allylation of dioxolanone
enolates7b,c have been examined as alternative routes to
1
by analogy in the H NMR spectra of 1a -e.
Initial experiments were conducted with 1a (R ) Ph).
Contrary to expectation, 1a proved to be unreactive
toward a variety of carbon nucleophiles. Thus, treatment
of 1a with several alkyl Grignard reagents at ambient
temperature or with MeLi or MeTiCl3 at lower temper-
ature did not generate any carbonyl addition products.
The lack of reactivity of 1a with alkylmetal reagents is
in contrast to the facile reactions of lactols with carbon
nucleophiles10 and may be explained by formation of a
stable metal chelate involving the amide oxygen and the
hemiacetal alkoxide. Although the alkyl analogues 1b-e
were also unreactive toward Grignard reagents, all
hemiacetals proved to be excellent substrates for allyla-
tion (Scheme 2).
Treatment of 1d with allyltrimethylsilane/TiCl4 at 0
°C generated a 1/2.5 mixture of the allylated product 2d
and the elimination product 3d . As expected, the elimi-
nation process could be subdued by lowering the reaction
temperature. Although the reaction was prohibitively
slow at -78 °C, 1a -e could be allylated with allyltri-
methylsilane/TiCl4 at -40 °C to produce 2a -e as single
diastereomers in 67-92% yield.11 Small amounts (<5%)
of the elimination products 3b-e were also obtained
(Scheme 2). The olefins 3c and 3d have been assigned
the Z geometry on the basis of the chemical shift of the
olefinic methine proton (δ 6.12 in 3c) as compared to the
upfield shift12 in the E isomer (δ 5.75), which was
obtained by irradiation of 3c at 254 nm.
* To whom correspondence should be addressed. Tel./Fax: 091-212-
335153. E-mail: pansare@ems.ncl.res.in.
(1) (a) Hanessian, S. Total Synthesis of Natural Products: The
Chiron Approach; Pergamon Press: New York, 1983; Chapter 2. (b)
Seuring, B.; Seebach, D. Helv. Chim. Acta 1977, 60, 1175-1181.
(2) (a) Akiyama, T.; Ishikawa, K.; Ozaki, S. Synlett 1994, 275-276.
(b) Kim, Y. H.; Byun, I. S.; Choi, J . Y. Tetrahedron: Asymmetry 1995,
6, 1025-1026. (c) Basavaiah, D.; Pandiaraju, S.; Bakthadoss, M.;
Muthukumaran, K. Tetrahedron: Asymmetry 1996, 7, 997-1000. (d)
Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C. J .
Am. Chem. Soc. 1997, 119, 7893-7894.
Liberation of the hydroxy acids from the ephedrine
template13 in 2 proved to be challenging. The benzylic
C-O bond is resistant to cleavage under a variety of
(8) For a stereodivergent reduction of prolinol based hemiacetals of
R-keto acids see: Pansare, S. V.; Ravi, R. G. Tetrahedron Lett. 1995,
36, 5959-5962.
(9) Hemiacetal 1d : colorless, orthorhombic crystals; space group
P212121; unit cell parameters, a ) 8.083(2) Å, b ) 9.135(4) Å, c )
40.635(5) Å; R ) 90°, â ) 90°, γ ) 90°; Z ) 8, R (I > 2σ(I)) ) 0.0495,
GOF ) 1.119. Hemiacetal 1e: colorless, orthorhombic crystals; space
group P212121; unit cell parameters, a ) 8.256(5) Å, b ) 9.522(2) Å,
c ) 18.836(4) Å; R ) 90°, â ) 90°, γ ) 90°; Z ) 4, R (I > 2σ(I)) )
0.0365, GOF ) 1.071.
(3) Tietze, L. F.; Schiemann, K.; Wegner, C. J . Am. Chem. Soc. 1995,
117, 5851-5852.
(4) Asymmetric ene reactions of glyoxylates: a) Whitesell, J . K.;
Bhattacharya, A.; Buchanan, C. M.; Chen, H. H.; Deyo, D.; J ames, D.;
Liu, C.-L.; Minton, M. A. Tetrahedron 1986, 42, 2993-3001. (b)
Mikami, K. Pure Appl. Chem. 1996, 68, 639 and references therein.
Ene reactions of pyruvates: (c) Whitesell, J . K.; Nabona, K.; Deyo, D.
J . Org. Chem. 1989, 54, 2258-2260. (d) Gladysz, J . A.; Yu, Y. S. Chem.
Commun. 1978, 599-600. (e) Spencer, H. K.; Hill, R. K. J . Org. Chem.
1975, 40, 217-220.
(10) (a) Tomooka, K.; Okinaga, T.; Suzuki, K. Tsuchihashi, G.
Tetrahedron Lett. 1989, 30, 1563-1566. (b) Tomooka, K.; Okinaga, T.;
Suzuki, K. Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 6335-6338.
(c) Tomooka, K.; Matsuzawa, K.; Suzuki, K.; Tsuchihashi, G. Tetra-
hedron Lett. 1987, 28, 6339-6342.
(5) Ojima, I.; Miyazawa, Y.; Kumagai, M. Chem. Commun. 1976,
927-928.
(6) (a) Waldmann, H. Synlett 1990, 627-628. (b) Soai, K.; Ishizaki,
M. J . Org. Chem. 1986, 51, 3290-3295.
(7) (a) Moorlag, H.; Kellogg, R. M.; Kloosterman, M.; Kaptein, B.;
Kamphuis, J .; Schoemaker, H. E. J . Org. Chem. 1990, 55, 5878-5881.
(b) Fra´ter, Gy.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron Lett. 1981, 22,
4221-4224. (c) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984,
40, 1313-1324.
(11) All crude products were analyzed for isomer composition by 200
MHz 1H NMR and/or 13C NMR.
(12) The stereochemical assignment is based on the reported trend
in chemical shifts for the olefinic methine protons in (E) and (Z)-
benzylidenecamphor derivatives, see: Kossanyi, J .; Furth, B.; Morizur,
J . P. Tetrahedron 1970, 26, 395-409.
S0022-3263(97)02282-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/15/1998

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4121
Sch em e 1
F igu r e 1. Stereoselective allylation of hemiacetals 1.
Sch em e 4
Sch em e 2
Sch em e 3
isopropyl group, and undergoes decomposition. Conver-
sion of 4d to 5d was not examined since 5d is achiral.
The configuration of the allylated product 2, with
respect to the hemiacetals 1 (Figure 1), is strongly
suggestive of an SN1-like mechanism16 for the allylation
process. The stereoselectivity of the allylation may be
due to a stereoelectronic effect.17 Considering a pseu-
doequatorial orientation of the phenyl group in the
hemiacetal derived oxocarbenium ion, axial attack of the
allylsilane would generate the product with the observed
stereochemistry (Figure 1). Thus, the origin of stereo-
control in the allylation of oxocarbenium ions in the
ephedrine template is similar to that proposed for the
stereoselective addition of nucleophiles to chiral iminium
ions17a and chiral imines17b in morpholin-2-one templates
employed in the asymmetric synthesis of R-amino acids.
Hemiacetals 1 can also be employed in a stereoselective
synthesis of R-H R-hydroxy acids by conversion to the
elimination products 3, which are admirable precursors
of R-hydroxy acids. Dehydration of 1c-e with trifluoro-
acetic acid in refluxing dichloromethane (78 h) affords
the olefins 3c-e in 92-98% yield. 1b is inert under
these conditions but affords 3b in low yield (25%, 34%
recovery of 1b) by treatment with catalytic sulfuric acid
in dichloromethane (0 °C, 20 min).18 Hydrogenation of
3b-e (H2, Pd/C, 50 psi) generates 6b-e as single
diastereomers11 in quantitative yield (Scheme 4).
hydrogenolytic conditions and is also inert under mild
ether cleavage conditions (NBS/CCl4, followed by NaOH).
However, treatment of 2b-e with Na in liquid NH3 at
-78 °C cleanly generates the hydroxy amides 4b-e in
85-95% yield.14 Presumably, the intermediate benzylic
anion derived from 2 undergoes facile â-elimination of
the N-acyl moiety at low temperature. Amides 4b and
4c were hydrogenated in quantitative yield (H2, Pd/C, 1
atm) and hydrolyzed (3 M H2SO4, 120 °C) to the free
R-alkyl R-hydroxy acids (Scheme 3).
Thus, 5b and 5c were obtained with the R configura-
tion15 (Scheme 3), which is assigned by comparison of the
sign of the optical rotation with literature values.15 The
enantiomeric excess (>95%) of the R-alkyl R-hydroxy
acids is based on the obtainment of precursors 2 as single
diastereomers by H and 13C NMR (epimerization of the
newly generated stereocenter during conversion of 2 to
4 and 4 to 5 is unlikely) and was confirmed by H NMR
analysis of the corresponding Mosher ester of 5b. The
R configuration establishes that the allylsilane adds to
the re face of an oxocarbenium ion derived from 1. The
hydrogenation product of amide 4e is resistant to hy-
drolysis, presumably due to steric hindrance by the
1
1
Alternatively, 1 can be reduced to 6 directly19 (TiCl4/
Et3SiH, CH2Cl2, -40 °C), but with low stereoselectivity
(16) (a) Denmark, S. E.; Almstead, N. G.; J . Am. Chem. Soc. 1991,
113, 8089-8110. (b) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.;
Yamamoto, H.; Bartlett, P. A.; Heathcock, C. H. J . Org. Chem. 1990,
55, 6107-6115.
(17) (a) Chiral glycine derivatives: Vigneron J . P.; Kagan, H.;
Horeau, A. Tetrahedron Lett. 1968, 5681-5683. Sinclair, P. J .; Zhai,
D.; Reibenspies, J .; Williams, R. M. J . Am. Chem. Soc. 1986, 108,
1103-1104. Williams, R. M. Aldrichim. Acta 1992, 25, 11-25. (b)
Chiral morpholin-2-ones derived from phenylglycinol: Cox, G. G.;
Harwood, L. M. Tetrahedron: Asymmetry 1994, 9, 1669-1672.
(18) Extended reaction times lead to the exclusive formation of a
dimeric product that probably arises from reaction of the enol ether
in 3b with the oxocarbenium ion derived from 1b.
(13) The alkylation of an ephedrine-based glycolic acid derivative
has been briefly described. However, removal of the ephedrine portion
was not investigated due to potential difficulties; see: Ludwig, J . W.;
Newcomb, M.; Bergbreiter, D. E. Tetrahedron Lett. 1986, 27, 2731-
2734.
(14) Dissolving metal reduction of 2a generated
a mixture of
products arising from cleavage of both the benzylic C-O bonds and
other side reactions. Other methods for regioselective cleavage of 2a
are being examined.
(15) (a) Ohta, H.; Kimura, Y.; Sugano, Y.; Sugai, T. Tetrahedron
1989, 45, 5469-5476. (b) Lynch, J . E.; Eliel, E. L. J . Am. Chem. Soc.
1984, 106, 2943-2948.
(19) Nishiyama, Y.; Tujino, T.; Yamano, T.; Hayashishita, M.; Itoh,
K. Chem. Lett. 1997, 165-166.

4122 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
Ta ble 1. Allyla tion , Deh yd r a tion , a n d Red u ction of
Mor p h olin on es 1-3, a n d 6 a n d Hyd r olysis of Am id es 4
a n d 7 to Acid s 5 a n d 8
plates were used for TLC. Silica gel for column chroma-
tography was 60-120 or 230-400 mesh. All melting
points are uncorrected. 1H NMR and 13C NMR spectra
were recorded on Bruker MSL-300 or Bruker AC-200
instruments. Coupling constants (J ) are given in Hz.
Optical rotations were measured at the sodium D line on
a J ASCO-181 digital polarimeter at ambient tempera-
ture. Elemental analyses were performed by the Mi-
croanalysis facility at NCL, Pune.
% yield
% ee
2a
3a,b
4
5
6a
7
8
5
8c
b
c
d
e
75
80
83
92
25
96
92
98
85
84
89
96
55
50
96
95
99
99
50
68
59
51
>95c
>95d
87
88
72
92c
92c
96e
aSingle diastereomers by 1H NMR. bObtained by acid-catalyzed
Gen er a l P r oced u r e for th e P r ep a r a tion of Hem i-
a ceta ls 1b-e. To a suspension of the sodium salt of the
R-keto acid in CH2Cl2 or to the neat R-keto acid was
added Cl2CHOMe at ambient temperature, and the
mixture was stirred for 20 min. The resulting suspension
or solution was heated at 50-55 °C for 30 min, after
which time it was cooled to ambient temperature and
diluted with anhydrous CH2Cl2, and the solution was
added to a suspension of (1R,2S)-ephedrine hydrochlo-
ride, triethylamine, and DMAP in anhydrous CH2Cl2
dropwise with cooling (ice bath). The mixture was then
stirred at ambient temperature for 6 h. The reaction
mixture was diluted with CH2Cl2 and the solution
washed with 5% HCl, saturated aqueous sodium bicar-
bonate, and brine, dried (Na2SO4), and concentrated to
provide the crude product, which was purified by flash
chromatography on silica gel.
c
dehydration of 1. Based on 1H NMR analysis of Mosher esters.
e
dBased on the de of 2. HPLC analysis of Mosher ester.
(88% yield of 6b, ds ) 5/1). The stereochemistry of the
new stereocenter in 6e is assigned as S by NOE mea-
surements, which indicated a cis relationship of the
hydrogens at C2, C5, and C6 in the morpholinone ring.
Dissolving metal reduction (Na/NH3, 20 s) of morpholi-
nones 6 yields the R-hydroxy amides 720 (51-68%). It is
noteworthy that this reduction is extremely rapid at -78
°C, and prolonged reaction times (>30 s) result in
significantly lower yields of 7. Hydrolysis of 7c-e (1 M
H2SO4, reflux) generates the R-hydroxy acids 8c-e21 (72-
1
88% yield, 92-96% ee by H NMR or HPLC analysis of
Mosher derivatives of the methyl esters) with the S
configuration, which confirms the stereochemistry of 6.
The high stereoselectivity for hydrogenation emphasizes
the strong, intrinsic stereochemical bias for reagent
approach in the ephedrine-derived template (Scheme 4).
The results of the allylation and dehydration of 1,
conversion of 2 to the free R-alkyl R-hydroxy acids 5;
hydrogenation of 3 to 6, and subsequent conversion to
R-H R-hydroxy acids 8 have been summarized in Table
1.
(2S,5S,6R)-2,4,5-Tr im eth yl-2-h ydr oxy-6-ph en ylm or -
p h olin -3-on e (1b). Reaction of pyruvoyl chloride (pre-
pared from pyruvic acid (2.06 mL, 30 mmol) and Cl2-
CHOCH3 (3.2 mL, 35 mmol)) and (1R,2S)-ephedrine
hydrochloride (3 g, 15 mmol) in the presence of triethyl-
amine (8.4 mL, 60 mmol) and DMAP (183 mg, 1.5 mmol)
in CH2Cl2 (45 mL) afforded 4.03 g of crude product, which
on purification by flash chromatography on silica gel (3/7
petroleum ether/ethyl acetate) furnished 2.48 g (71%) of
1b. An analytical sample was obtained by crystallization
from ethyl acetate: mp 110 °C; IR (CHCl3) 3340, 3000,
2940, 1635, 1490, 1450, 1380, 1220, 1130, 1010, 940, 890,
In conclusion, we have demonstrated high stereoselec-
tivity in asymmetric carbon-carbon and carbon-hydro-
gen bond construction with chiral hemiacetals derived
from R-keto acids and ephedrine. The methodology has
been applied to the stereoselective synthesis of several
R-H R-hydroxy acids, R-alkyl R-hydroxy acids, and R-allyl
R-hydroxy amides, which are potential precursors of
R-substituted butyrolactams and lactones.22 Since (1S,2R)-
ephedrine is also commercially available, the enantio-
meric series of R-hydroxy acids should also be readily
available by this methodology. Current efforts focus on
the reactivity of 3 and acetals derived from 1.
1
750 cm-1; H NMR (300 MHz, CDCl3) δ 7.36-7.23 (m,
5H), 5.47 (d, 1H, J ) 2.9), 4.4 (br s, 1H), 3.43 (dq, 1H, J
) 2.9, 6.5), 2.99 (s, 3H), 1.69 (s, 3H), 0.93 (d, 3H, J )
6.5); 13C NMR (50.3 MHz, CDCl3) δ 168.7, 137.4, 128.1,
127.4, 125.6, 95.9, 71.2, 59.2, 33.5, 26.3, 11.9; MS (70 eV)
m/z 58 (100), 77 (12), 91 (8), 100 (28), 105 (71), 118 (32),
146 (2), 235 (<1, M+); [R]24 ) -107.4 (c 1.1, CHCl3).
D
Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95.
Found: C, 66.39; H, 7.43; N, 5.99.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Allyla tion of Hem ia c-
eta ls 1a -e to Mor p h olin on es 2a -e. To a solution of
1 in CH2Cl2 was added allyltrimethylsilane at -40 °C
followed by TiCl4, and the solution was stirred for 6-10
h at -40 °C (-20 °C for 1a ). Saturated aqueous NH4Cl
was added to the reaction mixture, and it was warmed
to ambient temperature. Water was added to dissolve
precipitated solids, and the solution was extracted with
CH2Cl2, dried (Na2SO4), and concentrated to furnish the
crude product, which was purified by flash chromatog-
raphy on silica gel.
Gen er a l Meth od s. All reactions requiring anhydrous
conditions were performed under a positive pressure of
argon using oven-dried glassware (120 °C) that was
cooled under argon. THF was distilled from sodium
benzophenone ketyl, and dichloromethane and triethyl-
amine were distilled from CaH2. Commercially available
titanium tetrachloride (TiCl4) was used as such. Petro-
leum ether refers to the fraction boiling in the range 60-
80 °C. Commercial precoated silica gel (Merck 60F-254)
(2R,5S,6R)-2,4,5-Tr im et h yl-6-p h en yl-2-(1-p r op e-
n yl)m or p h olin -3-on e (2b). Reaction of 1b (0.29 g, 1.2
mmol) and allyltrimethylsilane (1 mL, 6.3 mmol) in the
presence of TiCl4 (0.68 mL, 6.2 mmol) in CH2Cl2 (10 mL)
afforded 0.32 g of a gum, which on purification by flash
chromatography on silica gel (7/3 petroleum ether/ethyl
acetate) furnished 0.24 g (75%) of 2b as a gum: IR
(CHCl3) 3000, 1630, 1430, 1210, 750 cm-1; 1H NMR (200
(20) Dobashi, Y.; Nakamura, K.; Saeki, T.; Matsuo, M.; Hara, S.;
Dobashi, A. J . Org. Chem. 1991, 56, 3299-3305.
(21) (a) Kim, M.-J .; Whitesides, G. M. J . Am. Chem. Soc. 1988, 110,
2959-2964. (b) Li, W.-R.; Ewing, W. R.; Harris, B. D.; J oullie´, M. M.
J . Am. Chem. Soc. 1990, 112, 7659-7672. (c) Chenault, H. K.; Kim,
M.-J .; Akiyama, A.; Miyazawa, T.; Simon, E. S.; Whitesides, G. M. J .
Org. Chem. 1987, 52, 2608-2611.
(22) (a) Chung, S.-K.; J eong, T.-H.; Kang, D.-H. Tetrahedron:
Asymmetry 1997, 8, 5-9. (b) Kitagawa, O.; Sato, T.; Taguchi, T. Chem.
Lett. 1991, 177-180.

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4123
Hz, CDCl3) δ 7.45-7.20 (m, 5H), 5.98-5.75 (m, 1H), 5.2
(d, 1H, J ) 2.7), 5.18-5.03 (m, 2H), 3.5 (dq, 1H, J ) 6.5,
2.7), 3.04 (s, 3H), 2.83 (dd, 1H, J ) 14.4, 5.9), 2.53 (dd,
1H, J ) 14.4, 8.7), 1.50 (s, 3H), 0.98 (d, 3H); 13C NMR
(75.5 MHz, CDCl3) δ 171.4, 137.7, 132.6, 127.8, 127.0,
125.1, 117.6, 78.8, 71.7, 58.7, 40.2, 33.2, 24.8, 12.1; MS
(70 eV) m/z 58 (53), 67 (22), 77 (19), 91 (27), 105 (18),
117 (40), 148 (100), 174 (6), 190 (27), 218 (69), 259 (8,
M+); HRMS (FAB+) for C16H22NO2 [M + H]+ calcd
The purified products decompose gradually at room
temperature. Storage at -20 °C under Ar is beneficial.
However, solutions in common solvents are stable at
ambient temperatures.
(5S,6R)-2-(2-P r op ylid en e)-4,5-d im eth yl-6-p h en yl-
m or p h olin e-3-on e (3e) was prepared from hemiacetal
1e (108 mg, 0.41 mmol) and trifluoroacetic acid (0.5 mL)
in anhydrous dichloromethane (8 mL). Purification of
the crude product by flash chromatography on silica gel
(7/3 petroleum ether/ethyl acetate) gave 99 mg (98%) of
3e as a pale yellow oil: IR (neat) 2922, 1660, 1626, 1449,
260.1651, found 260.1645; [R]24 ) -67.1 (c 2.1, CHCl3).
D
Gen er a l P r oced u r e for Dissolvin g Meta l Red u c-
tion of Mor p h olin on es 2b-2e to Am id es 4b-e. To
anhydrous liquid ammonia (distilled over sodium) was
added Na (10 equiv) at -78 °C and the mixture stirred
for 15 min. To the resulting blue solution was added a
solution of 2 (1 equiv) in anhydrous THF, and the mixture
was stirred for 2-3 min. Methanol (3 mL) was added
followed by water (3 mL), and the mixture was warmed
to ambient temperature and extracted with ethyl acetate
after removal of ammonia. The combined extracts were
dried over Na2SO4 and concentrated to provide the crude
product, which was purified by flash chromatography on
silica gel.
1
1378, 1291, 1174, 1067, 757 cm-1; H NMR (200 MHz,
CDCl3) δ 7.5-7.3 (m, 5H), 5.12 (d, J ) 2.5, 1H), 3.55 (dq,
J ) 2.5, 7, 1H), 3.05 (s, 3H), 2.25 (s, 3H), 1.9 (s, 3H), 0.95
(d, J ) 7, 3H); 13C NMR (50.3 MHz, CDCl3) δ 160.4, 138.2,
137.3, 128.1, 127.4, 126.3, 125.1, 76.5, 58.5, 33.0, 19.8,
11.6; MS (70 eV) m/z 56 (43), 67 (33), 77 (24), 82 (40), 91
(47), 96 (22), 105 (19), 110 (7), 118 (100), 128 (21), 140
(6), 146 (25), 154 (15), 228 (16), 245 (M+, 67); [R]23
-177.1 (c 0.7, CHCl3).
)
D
Gen er a l P r oced u r e for Red u ction of Alk ylid en -
em or p h olin on es 3 to Mor p h olin on es 6. A solution
of alkylidene morpholinones 3 in ethyl acetate was
shaken with 5% Pd/C in a Parr hydrogenator under 50
psi of hydrogen at room temperature for 1.5-2.5 h. The
catalyst was removed by filtration through a pad of
Celite, and the solvent was removed under reduced
pressure to give pure morpholinones 6 as colorless oils.
(2R)-2-Hyd r oxy-2-m eth ylp en t-4-en oic Acid N-m e-
th yla m id e (4b) was prepared from 2b (0.18 g, 0.7 mmol)
in THF (2 mL) and Na (0.16 g, 7 mmol) in ammonia (8
mL) to furnish 0.105 g of crude product, which on
purification by flash chromatography on silica gel (6/4
petroleum ether/ethyl acetate) furnished 85 mg (85%) of
product. IR (CHCl3) 3366, 3078, 2936, 1651, 1545, 1456,
(2S,5S,6R)-2-(2-P r opyl)-4,5-dim eth yl-6-ph en ylm or -
p h olin -3-on e (6e) was prepared from 3e (150 mg, 0.61
mmol) in ethyl acetate (15 mL) and Pd/C (5%, 30 mg):
reaction time 2.5 h; yield 150 mg (99%); IR (neat) 2966,
1
1412, 1369, 1240, 1165, 1070, 1033, 918 cm-1; H NMR
(200 MHz, CDCl3) δ 6.80 (br s, 1H), 5.88-5.65 (m, 1H),
5.25-5.10 (m, 2H), 2.81 (d, 3H, J ) 5), 2.7 (dd, 1H, J )
13.7, 6.0), 2.3 (dd, 1H, J ) 13.7, 8.7), 1.4 (s, 3H); 13C NMR
(75.5 MHz, CDCl3) δ 176, 132.7, 119.8, 74.9, 44.5, 26.0,
25.9; HRMS (FAB+) for C7H14NO2 [M + H]+ calcd
1
1735, 1648, 1451, 1253, 1151, 1042, 705 cm-1; H NMR
(300 MHz, CDCl3) δ 7.37-7.24 (m, 5H), 4.93 (d, J ) 2.8,
1H), 4.16 (d, J ) 2.4, 1H), 3.45 (dq, J ) 2.8, 6.4, 1H),
3.00 (s, 3H), 2.52 (dseptet, J ) 6.9, 2.4, 1H), 1.12 (d, J )
6.9, 3H), 0.96 (d, J ) 6.9, 3H), 0.92 (d, J ) 6.4, 3H); 13C
NMR (50 MHz, CDCl3) δ 168.7, 137.9, 128, 127.2, 125.1,
82, 75.7, 58.3, 33, 30.4, 19, 16.3, 12.8; MS (70 eV) m/z 58
(92), 69 (43), 77 (24), 84 (20), 91 (34), 98 (31), 105 (22),
113 (71), 118 (100), 126 (21), 132 (7), 141 (86), 148 (12),
205 (11), 247 (M+, 29); HRMS calcd for C15H21NO2
247.1573, found 247.1565; [R]24D ) -158.7 (c 1.8, CHCl3).
(S)-2-Hyd r oxy 3-m eth yl bu ta n oic a cid N-m eth yl-
a m id e (7e)20 was prepared from 6e (0.488 g, 1.98 mmol)
in THF (2 mL) and Na (0.453 g, 19.7 mmol) in ammonia
(40 mL). Purification by flash chromatography on silica
gel (ethyl acetate) furnished 0.132 g (51%) of 7e: IR
144.1025, found 144.1021; [R]25 ) +45.8 (c 0.6, CHCl3).
D
Gen er a l P r oced u r e for Hyd r ogen a tion of Am id es.
Amides 4b,c,e were dissolved in ethyl acetate and
hydrogenated over 5% Pd/C (5 wt %) at ambient tem-
perature and atmospheric pressure for 2-3 h. The
catalyst was removed by filtration through Celite. The
filtrate upon concentration furnished the hydrogenated
amides in quantitative yield. These were pure by 1H
NMR and were hydrolyzed to the acids without purifica-
tion.
(2R)-2-Hyd r oxy-2-m eth ylp en ta n oic Acid (5b). Hy-
drolysis (3 M H2SO4, 120 °C, 30 h) of the hydrogenation
product of 4b (0.04 g, 0.28 mmol) gave 0.02 g (55%) of
(CHCl3) 3365, 2958, 1632, 1577, 1409, 1021, 616 cm-1
;
-1
5b: IR (CHCl3) 3019, 2964, 1713,1216, 759, 669 cm
;
1H NMR (200 MHz, CDCl3) δ 6.59 (bs, 1H), 3.98 (bs, 1H),
2.96 (bs, 1H), 2.85 (d, J ) 4.9, 3H), 2.17 (dsept, J ) 3.1,
6.9, 1H), 1.02 (d, J ) 6.9, 3H), 0.84 (d, J ) 6.9, 3H). MS
(70 eV): m/z 55 (87), 58 (74), 60 (64), 73 (86), 83 (17), 89
1H NMR (200 MHz, CDCl3) δ 6.6 (br s, 1H), 1.9-1.1 (m,
4H), 1.47 (s, 3H), 0.93 (t, 3H, J ) 7.2); MS (70 eV) m/z
69 (20), 71 (12), 87 (100), 133 (1, M + 1); [R]24 ) -11.2
D
(c 0.4, CHCl3), ee >95% (based on de of 2b) (lit.15a [R]24
D
(100), 98 (3), 113 (11), 131(M+, 5); [R]25 ) -57.0 (c 2.6,
D
) +9.53 (c 2.1, CHCl3) for the S enantiomer, >95% ee).
Gen er a l P r oced u r e for Deh yd r a tion of Hem ia c-
eta ls 1 to Alk ylid en em or p h olin on es 3. A solution of
the hemiacetal 1 in dichloromethane was either treated
with concentrated sulfuric acid at 0 °C for 20 min or
heated to reflux with trifluoroacetic acid for 78 h. The
reaction mixture was then washed with saturated aque-
ous sodium bicarbonate solution followed by brine. The
organic layer was separated and dried over anhydrous
sodium sulfate. Concentration of the organic phase
under reduced pressure gave the crude product, which
was purified by column chromatography over silica gel.
CHCl3).
(2S)-2-Hyd r oxy-3-m eth ylbu ta n oic Acid (8e).21b 7e
(130 mg, 0.99 mmol) in 1 M H2SO4 (18 mL) was heated
to reflux for 36 h to yield 85 mg (72%) of 8e: IR 2967,
1
1728, 1467, 1215, 1136, 1028, 895, 759 cm-1; H NMR
(200 MHz, CDCl3) δ 5.8 (bs, 2H), 4.16 (d, J ) 3.4, 1H),
2.30-2.05 (m, 1H), 1.07 (d, J ) 6.9, 3H), 0.93 (d, J ) 6.9,
3H); MS (70 eV) m/z 55 (53), 58 (38), 73 (85), 76 (100), 87
(5), 102 (5), 118 (M+, 2). Ee of the methyl ester of 8e
(obtained by treatment with CH2N2): 96% (HPLC analy-
sis of the Mosher derivative with (S)-MTPA; Macherey-

4124 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
Nagel Nucleosil 5 C8 (reversed phase) column, 250 × 4
mm, acetonitrile/water 6/4, flow rate 1.2 mL/min; tR
(major) 3.81 min; tR (minor) 5.11 min).
ships to R.G.R. and R.P.J .) for financial support. This
is NCL Communication No: 6420.
Su p p or tin g In for m a tion Ava ila ble: Experimental meth-
ods and spectroscopic data with assignments for all compounds
(1-8) and copies of 1H and/or 13C NMR spectra for 1a , 2a -e,
3b-e, 4b,d ,e, 6b-e, and 7b-e (45 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Ack n ow led gm en t. We are grateful to Professor
Scott E. Denmark for valuable comments. We thank
Professor S. Kanemasa, Kyushu University, for HRMS
of some of the intermediates, the Department of Science
and Technology (Grant No. SP/S1/G-11/96), and the
Council of Scientific and Industrial Research (fellow-
J O9722820