A general, highly anti-stereoselective aldolization method via camphor-derived boryl enolates

Article abstract of DOI:10.1021/jo9520147

Camphor-derived chiral boryl enolates are highly reactive and highly anti-stereoselective enolate synthon systems in aldol addition reactions promoted by a TiCl₄ or SnCl₄ cocatalyst. More significantly, this high-yield reaction exhibits remarkable generality with respect to the aldehyde nature, as illustrated by the rapid and anti-stereoselective aldolizations with the simple saturated and unsaturated aliphatic aldehydes, and aromatic aldehydes at temperatures as low as -90°C. The enhanced reaction generality and anti stereoselectivity of camphor-derived boryl enolates suggests the importance of the nature of chiral auxiliary architecture in determining the aldol bond construction process. Final nondestructive camphor-based auxiliary removal via hydroperoxide-mediated hydrolysis affords enantiomerically pure anti-β-hydroxy-α-methyl aldol products.

Full text of DOI:10.1021/jo9520147

2038
J . Org. Chem. 1996, 61, 2038-2043
A Gen er a l, High ly An ti-Ster eoselective Ald oliza tion Meth od via
Ca m p h or -Der ived Bor yl En ola tes
Ying-Chuan Wang, An-Wei Hung, Chii-Shin Chang, and Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing University, Taichung, Taiwan 400, Republic of China
Received November 14, 1995X
Camphor-derived chiral boryl enolates are highly reactive and highly anti-stereoselective enolate
synthon systems in aldol addition reactions promoted by a TiCl4 or SnCl4 cocatalyst. More
significantly, this high-yield reaction exhibits remarkable generality with respect to the aldehyde
nature, as illustrated by the rapid and anti-stereoselective aldolizations with the simple saturated
and unsaturated aliphatic aldehydes, and aromatic aldehydes at temperatures as low as -90 °C.
The enhanced reaction generality and anti stereoselectivity of camphor-derived boryl enolates
suggests the importance of the nature of chiral auxiliary architecture in determining the aldol
bond construction process. Final nondestructive camphor-based auxiliary removal via hydroper-
oxide-mediated hydrolysis affords enantiomerically pure anti-â-hydroxy-R-methyl aldol products.
In tr od u ction
the importance of the problem. Over the last decade,
progress in the development of promising chiral metal
enolate systems for achieving the high levels of facial
selection in the preparation of anti aldol addition prod-
ucts has been slow, despite the significant utility that
metal-assisted aldol bond construction processes would
enjoy in the asymmetric synthesis of syn aldols.2-5
Recently, Heathcock repotrted that E enolate 1 derived
fromthe chiral silyloxy ketone afforded useful levels of
asymmetric induction (typically >95:5) upon reaction
with saturated aldehydes7 however, the general ap-
plicability of aldol additions involving enolate 1 is limited,
and the source of chirality inherent in the silyloxy ketone
is not recoverable and recyclable. Later Heathcock and
co-workers made the crucial discovery that dibutylboryl
triflate-mediated aldolizations of Z enolate derived from
the Evans chiral imide gave mainly the anti aldols.
However, only the R-substituted aldehydes were highly
stereoselective (90:10 to 95:5).6a In contrast to the
hindered aldehydes, simple aliphatic (saturated or un-
saturated) and aromatic aldehydes were somewhat less
stereoselective.6 Helmchen and Oppolzer have also made
parallel observations with silyl ketene acetals.8ab In the
extensive survey of the valine-derived chiral imide eno-
lates, it has been shown by Heathcock et al. that further
increase in the steric requirements of the enolate ligand
substituent (R′) diminished anti selection (cf. 2 and 3,
Scheme 1).6a We contended that this limited anti/syn
selectivity was not due to insufficient orientation control
of the enolate ligand but to insufficient facial discrimina-
tion of the aldehyde carbonyl by the chiral auxiliary
architecture. A recent study from this laboratory sug-
gests that the chiral camphor-based oxazolidinones,
which are excellent auxiliaries for the metal-assisted
aldol reactions of acetate5b,c and propionate5a imide
enolates with aldehydes, might also be effective in anti-
stereoselective aldolizations. Quite recently, Oppolzer
has reported an efficient asymmetric synthesis of anti
While great strides in asymmetric induction has been
made in the development of chiral enolate synthon
systems and metal-assisted aldol type reactions,1,2 control
of the facial selectivity in the aldol additions of chiral
enolates represents an attractive challenge. The tre-
mendous impact of metal Lewis acid nature3-5 and
stoichiometry6 in reversing π-facial selection illustrates
X Abstract published in Advance ACS Abstracts, February 15, 1996.
(1) For some recent general reviews, see: (a) Heathcock, C. H. In
Comprehensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon
Press: Oxford, 1991; Vol. II, Ch. 1.6. (b) Braun, M. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 24. (c) Masamune, S.; Choy, W.; Petersen, J .
S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1. (d) Heathcock,
C. H. Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press: New
York, 1984; Vol. 3, part B, p 111. (e) Evans, D. A.; Nelson, J . V.; Taber,
T. R. Topics Stereochem. 1982, 13, 1.
(2) For related catalytic aldol type reactions, see: (a) Mikami, K.;
Matsukawa, S. J . Am. Chem. Soc. 1994, 116, 4077. (b) Bach, T. Angew.
Chem., Int. Ed. Engl. 1994, 33, 417. (c) Kobayashi, S.; Uchiro, H.;
Shiina, I.; Mukaiyama, T. Tetrahedron 1993, 49, 1761. (d) Deloux, L.;
Srebnik, M. Chem, Rev. 1993, 93, 763. (e) Parmee, E. R.; Hong, Y.;
Tempkin, O.; Masamune, S. Tetrahedron Lett. 1992, 33, 1729. (f) Corey,
E. J .; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907. (g)
Lohray, B. B.; Bhushan, V. Angew. Chem., Int. Ed. Engl. 1992, 31,
729. (h) Wallbaum, S.; Martens, J . Tetrahedron: Asymmetry 1992, 3,
1475. (i) Parmee, E. R.; Tempkin, O.; Masamune, S.; Atsushi, A. J .
Am. Chem. Soc. 1991, 113, 9365.
(3) (a) Evans, D. A.; Vogel, E.; Nelson, J . V. J . Am. Chem. Soc. 1979,
101, 6120. (b) Evans, D. A.; Nelson, J . V.; Vogel, E.; Taber, T. R. J .
Am. Chem. Soc. 1981, 103, 3099 and references cited therein. (c) Evans,
D. A.; Bartrol, J .; Shih, T. L. J . Am. Chem. Soc. 1981, 103, 2127. (d)
Heathcock, C. H.; Arseniyadis, S. Tetrahedron Lett. 1985, 26, 6009.
(e) Abdel-Magid, A.; Lendon, N. P.; Drake, S. E.; Ivan, L. J . Am. Chem
Soc. 1986, 108, 4595. (f) Hsiao, C.-N.; Liu, L.; Miller, M. J . J . Org.
Chem. 1987, 52, 2201. (g) Oppolzer, W.; Blagg, J .; Rodriguez, I.;
Walther, E. J . Am. Chem. Soc. 1990, 112, 2767.
(4) (a) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J . Am.
Chem. Soc. 1991, 113, 1047. (b) Siegel, C.; Thornton, E. R. J . Am.
Chem. Soc. 1989, 111, 5722. (c) Nerz-Stormes, M.; Thornton, E. R. J .
Org. Chem. 1991, 56, 2489. (d) Siegel, C.; Thornton, E. R. Tetrahedron
Lett. 1986, 27, 457. (e) Reetz, M. T.; Kesseler, K.; Schmidtberger, S.;
Wenderoth, B.; Steinbach, R. Angew. Chem., Int. Ed. Engl. 1983, 22,
989. (f) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556, and
references cited therein.
(5) (a) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Hung, T.-Y. J .
Am. Chem. Soc. 1993, 115, 2613. (b) Yan, T.-H.; Hung, A.-W.; Lee,
H.-C.; Chang, C.-S. J . Org. Chem. 1994, 59, 8187. (c) Yan, T.-H.; Hung,
A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J . Org. Chem. 1995, 60,
3301. (d) Yan, T.-H.; Lee, H.-C.; Tan, C.-W. Tetrahedron Lett. 1993,
34, 3559. (e) Yan, T.-H.; Chu, V.-V.; Lin, T.-C.; Tseng, W.-H.; Cheng,
T.-W. Tetrahedron Lett. 1991, 32, 5563.
(6) (a) Walker, M. A.; Heathcock, C. H. J . Org. Chem. 1991, 56, 5747.
(b) Danda, H.; Hansen, M. M.; Heathcock, C. H. J . Org. Chem. 1990,
55, 173. (c) Heathcock, C. H. Aldrichim. Acta 1990, 23, 99-111, and
references cited therein.
aldols from bornanesultam-derived boryl enolates,9
a
(7) Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heath-
cock, C. H. J . Org. Chem. 1991, 56, 2499.
(8) (a) Oppolzer, W.; Marco-Contelles, J . Helv. Chim. Acta. 1986,
69, 1699. (b) Helmchen, G.; Leikauf, U.; Taufer-Knopfel, I. Angew.
Chem., Int. Ed. Engl. 1985, 24, 874. (c) Meyers, A. I.; Yamamoto, Y.
Tetrahedron 1984, 40, 2309. (d) Matsumoto, T.; Tanaka, I.; Fukui, K.
Bull. Chem. Soc. J pn. 1971, 44, 3378.
(9) Oppolzer, W.; Lienard, P. Tetrahedron Lett. 1993, 34, 4321.
0022-3263/96/1961-2038$12.00/0 © 1996 American Chemical Society

Anti-Stereoselective Aldolizations via Boryl Enolates
J . Org. Chem., Vol. 61, No. 6, 1996 2039
Sch em e 1
Sch em e 2
result that also indicates that the camphor-derived boryl
imide enolate may exhibit reaction generality and high
anti stereoselectivity. We wish to report herein a general
and highly anti-stereoselective aldolization method via
camphor-derived imide enolates, with the discovery that
the nature of the chiral auxiliary architecture may play
an influencing role in determining the aldol bond con-
struction process.
nation of TiCl4 and camphor-based boryl enolate to effect
a high level of anti stereocontrol, we established its
generality with respect to the aldehyde nature. Using a
standard protocol, a series of representative aldehydes
were reacted to give aldol adducts 7a -g (Scheme 2). We
were pleased to observe that the absence of the R-methyl
substitution does not appear to exert any influence on
either the yield or the selectivity of the reaction (Table
1, entries 2, 3; 99:1). In addition, the presence of
conjugation in an aldehyde molecule does not alter the
reaction anti selectivity. For example, highly anti stereo-
selective aldolization of simple unsaturated aldehydes
(crotonaldehyde and trans-2-hexenal) may be realized
(entries 4, 5; 99:1). However, aromatic aldehydes do pose
a problem. Thus, benzaldehyde and 2-furaldehyde were
somewhat less steroselective (entries 6, 8; ∼78:22).
Switching the cocatalyst to SnCl4 led to higher reaction
anti stereoselectivity (entries 7, 9; ∼88:12). In an effort
to further enhance aldol anti selection for aromatic
aldehydes, we turned our attention to a redesign of the
boryl enolate. In this regard, our previous observations
with respect to the effect of the boryl geometry (cyclic vs
acyclic) in influencing the reaction stereoselectivity
prompted us to examine 9-BBN imide enolate 6b.5b,c It
was felt that the enhanced Lewis acid character promoted
by the rigid skeletal geometry of 9-BBN11 should increase
the binding forces between the boron and the two
Resu lts a n d Discu ssion
Boryl triflate (LnBOTf)3,5-7 and titanium tetrachloride
(TiCl4)4a,5a,d have proven to be excellent metal catalysts
of choice in the aldolizations of imide enolates with
aldehydes. Earlier work in our laboratories also indicates
that camphor-based oxazolidinones, which are excellent
chiral auxiliaries to effect the syn facial selectivity switch
of propionate imide enolates5a and the enantioselective
aldol type reactions of acetate imide enolate,5b,c might also
be effective in asymmetric synthesis of anti aldols. In
the preliminary study we sought to establish the feasibil-
ity of TiCl4 as a cocatalyst to effect high levels of anti
selectivity in the aldol addition reactions of camphor-
derived dibutylboryl enolate 6a with isobutyraldehyde.
Previously reported camphor-based oxazolidinone 4 was
treated successively with NaH and the propionyl chloride
to afford imide 5 (Scheme 1).5 Dibutylboryl enolate 6a
was generated by the standard procedure.3,5 Treatment
of enolate 6a with TiCl4 (0.6 equiv, -90 °C, 5 min) and
isobutyraldehyde led within 20 min to aldol 7a in good
yield. The crude aldol adduct showed a single set of
peaks in the high-field NMR spectrum suggestive of
complete asymmetric induction. Assignment of the threo
1
configuration is based on the H NMR vicinal coupling
using the well-established fact that J threo (7-9 Hz) >
J erythro (3-6 Hz),10 and the absolute stereochemical as-
signments of the anti aldol 7a was made via nondestruc-
tive removal of the chiral auxiliary and correlation of the
resultant â-hydroxy-R-methyl carboxylic acid 9a .6a,8a,b
Having established the feasibility of the use of a combi-
(10) (a) House, H. O.; Crumrine, D. S.; Olmstead, H. D. J . Am. Chem.
Soc. 1973, 95, 3310. (b) Kleschick, W. A.; Buse, C. T.; Heathcock, C.
H. J . Am. Chem. Soc. 1977, 99, 247-248. (c) Heathcock, C. H.; Buse,
C. T.; Kleschick, W. A.; Pirrung, M. C.; J ohn, J . E.; Lampe, J . J . Org.
Chem. 1980, 45, 1066-1081.

2040 J . Org. Chem., Vol. 61, No. 6, 1996
Wang et al.
Ta ble 1. An ti-Ster eoselective Ald ol Ad d ition s of Di-n -bu tylbor yl En ola te 6a w ith Rep r esen ta tive Ald eh yd es
entry
electrophile
cocatalyst
anti:syna 7:8
yieldb (%)
[R]25 c deg (c, CHCl3)
mp, °C
D
1
2
3
4
5
6
7
8
9
Me2CHCHO
EtCHO
n-PrCHO
MeCHdCHCHO
n-PrCHdCHCHO
PhCHO
PhCHO
(2-furyl)-CHO
(2-furyl)-CHO
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
SnCl4
TiCl4
SnCl4
99:1d
99:1d
99:1d
99:1d
99:1d
78:22
88:12
78:22
87:13
90
85
90
91
85
89
86
88
85
+68.8 (1.0)
+46.2 (0.9)
+46.1 (1.1)
+35.5 (1.8)
+26.2 (3.6)
-5.4 (2.1)
-
158-159
78-79
93-94
81-82
-
159-160
-
+13.5 (2.6)
-
105-106
-
a
Ratios determined by 300-MHz 1H NMR. b Combined isolated yield of all diastereomers. c Optical rotation of purified anti diastereomers
d
7. None of the syn diastereomers could be detected by 1H NMR.
Ta ble 2. An ti-Ster eoselective Ald ol Ad d ition s of 9-BBN En ola te 6b w ith Rep r esen ta tive Ald eh yd es
9
entry
electrophile
cocatalyst
anti:syna 7:8
yieldb (%)
[R]25D, deg (g/100 mL)c
[R]25D, deg (lit. ref)
1
2
3
4
Me2CHCHO
EtCHO
n-PrCHO
TiCl4
TiCl4
TiCl4
TiCl4
99:1d
99:1d
99:1d
99:1d
86
85
86
84
-17.6 (0.49)
-6.4 (0.68)
-5.4 (0.44)
+11.6 (0.42)e
-6.2 (0.91)f
+14.8 (2.8)
-54.3 (0.34)
-
-15.3 (8a); -14.3 (7)
-5.9 (8a)
-5.0 (8a)
MeCHdCHCHO
-
-5.0 (8a)
5
6
7
8
9
n-PrCHdCHCHO
PhCHO
PhCHO
(2-furyl)-CHO
(2-furyl)-CHO
TiCl4
TiCl4
SnCl4
TiCl4
SnCl4
99:1d
88:12
96:4
88:12
94:6
84
89
86
88
84
-
-49.0 (8a); -17.5 (7)
-
-
-
-36.6 (0.10)
-
a
b
Ratios determined by 300-MHz 1H NMR. Combined isolated yield of all diastereomers. c All rotations were measured in CHCl3.
None of the syn diastereomers could be detected by 1H NMR. e Hydrogenation of the anti aldol 9d afforded the saturated anti aldol
d
which proved to be identical in all respects with those of 9c. f Hydrogenation of the anti aldol 9d followed by hydroperoxide-assisted
hydrolysis.
carbonyl oxygen atoms, thereby resulting in “transition
state compression” which appears to enhance the π-facial
stereoselection. As expected, the aldol addition reactions
from 9-BBN imide enolate 6b exhibited high anti stereo-
selection in the presence of a cocatalyst TiCl4. More
significantly, in the aldolizations of aromatic aldehydes,
dramatic enhancement in anti selectivity was noted when
the tin chloride (SnCl4) was employed as a cocatalyst
(Table 2, entries 7, 9; g94:6). These comparative experi-
ments highlight the contribution to aldol diastereo-
selectivity due to the nature of boryl triflates.5bc,12
The results in Table 1 and 2 clearly demonstrate that
camphor-derived oxazolidinone serves as an excellent
chiral auxiliary for asymmetric synthesis of anti aldols.
It is noteworthy that the TiCl4-assisted aldol addition
reactions of camphor-based boryl imide enolates 6a and
6b are highly anti-selective. These results are in marked
contrast to those of Heathcock and co-wokers who
observed that TiCl4 was syn-selective in the aldolizations
of the valine- and tert-leucine-derived boryl enolates 2
and 3.6a In view of the observations of Heathcock with
respect to the limited steric contribution to aldol anti
stereoselection due to the appended side chain in 2 and
3,6a it was felt that some property of the camphor-based
auxiliary is important to the observed excellent anti
stereoselectivity of the aldolizations of 6a and 6b. Given
the reasonable postulate that in the presence of a
cocatalyst the aldolization proceeds via open transition
states,6,13 syn and anti aldols are derived from the open
transition states E and T, respectively (Scheme 3). A
reasonable explanation of the high levels of anti stereo-
selection achieved with camphor-based boryl enolates
derives from consideration of the relative stability of E
and T. In the aldol transition state represented by E,
the large group R projects toward the ring methylene
(-CH2CH2-), encountering a severe nonbonded interaction.
Such a nonbonded interaction is between the small
hydrogen atom and ring methylene in transition state
T. On this basis, the latter would be favored. The
presence of steric repulsion between the methyl group
and the bulky group OTiCl4 further destabilize transition
state E , thereby precluding formation of syn aldols 8.
While further mechanistic work is clearly required, the
implication from the above data is that the chiral
auxiliary architecture plays an important role in influ-
encing the aldol anti stereoselectivity.
Con clu sion s
The preceding studies highlight the improved face-
shielding capability of camphor-based boryl enolates
which exhibit remarkable reaction generality and high
levels of anti stereoselectivity in the aldol bond construc-
tion process. In addition, this work exemplifies once
more the general applicability of camphor-derived chiral
oxazolidinone as a practical chiral auxiliary for asym-
(13) The stereochemical outcome of metal-mediated aldol and related
reactions has previously been interpreted employing the open transi-
tion state, see: (a) Oare, D.; Heathcock, C. H. Topics in Stereochemistry;
Eliel, E. L., Wilen, S. H., Eds.; J ohn Wiley and Sons: New York, 1991;
Vol. 20, pp 161-165. (b) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J .
Org. Chem. 1990, 55, 481. (c) Murata, S.; Suzuki, M.; Noyori, R.
Tetrahedron 1988, 44, 4259. (d) Denmark, S. E.; Henke, B. R.; Weber,
E. J . Am. Chem. Soc. 1987, 109, 2512. (e) Reetz, M. T.; Sauerwald, M.
J . Org. Chem. 1984, 50, 2292. (f) Dubois, J . E.; Axiotis, G.; Ber-
tounesque, E. Tetrahedron Lett. 1984, 25, 4655. (g) Seebach, D.;
Golinski, J . Helv. Chim. Acta 1981, 64, 1413. (h) Mulzer, J .; Bruntrup,
G.; Finke, J .; Zippel, M.; J . Am. Chem. Soc. 1979, 101, 7723.
(11) The rigid 9-BBN moiety had proven to be less sensitive to steric
factors than of dialkylboryl in hydroboration reactions, see: Smith,
K.; Pelter, A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8, Chapter 3, p
703.
(12) For examples of the reaction stereoselectivity switch by boryl
geometry (n-Bu2B-OTf vs 9-BBN-OTf), see: (a) Inoue, T.; Uchimaru,
T.; Mukaiyama, T. Chem. Lett. 1977, 153. (b) Hirama, M.; Garvey, D.
S.; Lu, D.-L.; Masamune, S. Tetrahedron Lett. 1979, 3937.

Anti-Stereoselective Aldolizations via Boryl Enolates
J . Org. Chem., Vol. 61, No. 6, 1996 2041
N-P r op ion yl-(1S,5R,7R)-10,10-d im eth yl-3-oxo-2-a za -4-
oxa tr icyclo[6.2.1.01,5]d eca n e (5). To a solution of sodium
hydride (1.8 g, 75 mmol) in 200 mL of anhydrous THF at 0 °C
was added a solution of (9.05 g, 50 mmol) of oxazolidinone 4
in 100 mL of dry THF. The mixture was stirred at 0 °C for 30
min, allowed to warm to room temperature for an additional
5 h, and then recooled to 0 °C. To the above solution was added
via cannula a solution of 5.2 mL (60 mmol) of propionyl
chloride in 30 mL of dry THF. The resulting solution was
stirred at 0 °C for 1 h and 25 °C for 2 h. The reaction mixture
was recooled to 0 °C and quenched with 2 N HCl (15 mL).
Following removal of the THF in vacuo on the rotary evapora-
tor, the residue was diluted with 300 mL of dichloromethane
and 50 mL of water. The organic extract was washed succes-
sively with saturated aqueous sodium bicarbonate and brine,
dried (MgSO4), and concentrated in vacuo to yield 5 (11.6 g,
98%) as a viscous oil, which was used without purification. A
small portion was purified by flash chromatography on silica
gel for analysis: Rf 0.35 (30% hexane/dichloromethane); IR
Sch em e 3
(neat) 2968, 1786, 1710 cm-1 1H NMR (300-MHz, CDCl3) δ
;
4.20 (dd, J ) 7.8, 4.8 Hz, 1H), 3.20-1.21 (m, 9H), 1.13 (t, J )
10.8 Hz, 3H), 1.11 and 0.99 (2s, 6H); 13C NMR (75.5 MHz,
CDCl3) δ 175.1, 154.8, 84.4, 71.9, 47.9, 42.1, 34.4, 29.7, 25.7,
25.5, 21.3, 18.9, 8.1; [R]25 +58.4° (c 13, CH2Cl2); high-
D
resolution MS m/ e Calcd for C13H19NO3: 237.1365. Found:
237.1365. Anal. Calcd for C13H19NO3: C, 65.85; H, 8.07; N,
5.91. Found: C, 65.63; H, 8.03; N, 5.92.
Gen er a l P r oced u r e for th e Ald ol Typ e Rea ction s of
Bor yl En ola tes 6a a n d 6b. Di-n-butylboryl triflate (1 M in
CH2Cl2, 0.55 mL) was added dropwise to a stirred solution of
the N-propionyloxazolidinone 5 (0.5 mmol) in 2.5 mL of
dichloromethane at 0 °C. After stirring at 0 °C for 10 min,
0.6 mmol of diisopropylethylamine (0.5 M in CH2Cl2, 1.2 mL)
was added dropwise. After allowing 30 min for complete
enolization, the resulting enolate solution was cooled to -90
°C, and 0.3 mmol of TiCl4 or SnCl4 (1 M in CH2Cl2, 0.3 mL)
was added dropwise. To the above solution was added 0.6
mmol of freshly distilled aldehyde (0.3 M in CH2Cl2, 2 mL).
The reaction mixture was stirred at -90 to -78 °C for 20 min
and quenched with aqueous phosphate buffer (pH ) 7, 4 mL).
In the case of 9-BBN enolate 6b, the reaction mixture was
quenched at 0 °C. The aqueous layer was extracted with two
portions of CH2Cl2 . The combined organic extracts (16 mL)
were cooled to 0 °C and treated with a mixture of 4 mL of
methanol and 2 mL of 28% H2O2. After stirring at 0 °C for 20
min, the organic layer was separated and washed successively
with saturated aqueous NH4Cl (4 mL), aqueous NaOH (1 N,
3 mL), and brine. The organic extract was dried (MgSO4) and
concentrated in vacuo. The residue was subjected to NMR
analysis and purification by flash chromatography or recrys-
tallization.
metric aldol type reactions.5 Of particular note is the
enhanced reactivity14 and diastereoselectivty promoted
by TiCl4 and SnCl4 in camphor-based boryl enolate aldol
bond constructions. Significantly, high yields of optically
pure anti aldols are easily obtained either by recrystal-
lization or flash chromatography. The high incidence of
crystallinity associated with the camphor-derived auxil-
iary is of great practical advantage (Table 1). Finally,
the nondestructive chiral auxiliary removal together with
the aforementioned advantages and the remarkable ease
of preparation of 4 make camphor-derived boryl imide
enolates attractive choices for the asymmetric synthesis
of anti aldol products.
N -[(2 R ,3 R )-3 -H y d r o x y -2 ,4 -d i m e t h y l p e n t a n o y l ]-
(1S,5R,7R)-10,10-d im eth yl-3-th ioxo-2-a za -4-oxa tr icyclo-
[6.2.1.01,5]d eca n e (7a ). As described above, 5 (118 mg, 0.5
mmol) and isobutyraldehyde (44 mg, 0.6 mmol) afforded a
Exp er im en ta l Section
Gen er al. Diisopropylethylamine and dichloromethane were
dried by distillation under N2 from calcium hydride. Sodium
hydride (80% dispersion in mineral oil), Bu2B-OTf (1 M in
CH2Cl2), 9-BBN-OTf (0.5 M in hexane), TiCl4 (1 M in CH2Cl2)
and SnCl4 (1 M in CH2Cl2) were purchased from Aldrich
Chemical Co. All aldehydes were freshly distilled prior to use.
Unless otherwise noted, all nonaqueous reactions were carried
out under a dry nitrogen atmosphere with oven-dried glass-
ware. Flash chromatography was done on E. Merck silica gel
60 (230-400 mesh).15 Melting points (Pyrex capillary) are
uncorrected. Concentrations for rotation data are given as
g/100 mL of solvent. Diastereomeric excesses (de) were
determined by 300-MHz 1H NMR. All NMR spectra were
measured in CDCl3 solution. Chemical shifts are expressed
in ppm downfield from internal tetramethylsilane; coupling
constants are expressed in hertz.
1
crude reaction mixture. Analysis [300-MHz H NMR integra-
tion of the C-2 and/or C-3 methine protons (CHOH and
CH3CHCdO)] of the unpurified product indicated the presence
of a single aldol adduct. Purification by recrystallization
(CH2Cl2/hexane) gave 139 mg (90%) of 7a as a white solid: mp
158-159 °C; IR (KBr) 3516, 2980, 1770, 1714, 1456, 1392, 1080
1
cm-1; H NMR (300 MHz, CDCl3) δ 4.24 (dd, J ) 8.4, 4.2 Hz,
1H), 3.99 (quintet, J ) 7.2 Hz, 1H), 3.42 (m, 1H), 2.99-1.19
(m with d at 2.93, J ) 10.5 Hz, 9H), 1.16 (d, J ) 7.2 Hz, 3H),
1,14 and 1.04 (2s, 6H), 0.99 and 0.94 (2d, J ) 6.9 Hz, 6H); 13
C
NMR (75.5 MHz, CDCl3) δ 178.6, 155.8, 84.6, 79.7, 72.7, 48.3,
42.2, 41.1, 34.5, 30.3, 25.9, 25.5, 21.5, 19.8, 18.9, 15.2, 15.1;
[R]25 +68.8° (c 1.0, CHCl3); high-resolution MS m/ e calcd for
D
C17H27NO4: 309.1941. Found: 309.1942. Anal. Calcd for
C17H27NO4: C, 65.99; H, 8.80; N, 4.53. Found: C, 65.79; H,
8.69; N, 4.51.
(14) While complete conversion to aldol adducts 7 occurred within
20 min at -90 to -70 °C, the corresponding aldol addition of valine-
based enolate 2 with Lewis acid-precomplexed aldehyde required 4 h
at -78 °C. This differential reactivity is important to the high-yield
anti-stereoselective aldolization of boryl enolate 6.
N-[(2R,3R)-3-Hyd r oxy-2-m eth ylp en ta n oyl]-(1S,5R,7R)-
10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo[6.2.1.01,5]-
d eca n e (7b). As described above, 5 (118 mg, 0.5 mmol) and
n-propionaldehyde (35 mg, 0.6 mmol) afforded a crude reaction
1
(15) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
mixture. Analysis [300-MHz H NMR integration of the C-2

2042 J . Org. Chem., Vol. 61, No. 6, 1996
Wang et al.
and/or C-3 methine protons (CHOH and CH3CHCdO)] of the
unpurified product indicated the presence of a single aldol
adduct. Purification by flash chromatography (silica gel, 15%
ethyl acetate/hexane, Rf 0.35) yielded 126 mg (85%) of 7b as a
white solid: mp 78-79 °C; IR (KBr) 3532, 2944, 1785, 1710,
1464, 1377,1305, 1077 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.25
(dd, J ) 8.4, 4.5 Hz, 1H), 3.88 (quintet, J ) 7.2 Hz, 1H), 3.55
(m, 1H), 3.01-1.20 (m with d at 2.78, J ) 9.6 Hz, 10H), 1.18
(d, J ) 7.2 Hz, 3H), 1.16 and 1.05 (2s, 6H), 1.02 (t, J ) 7.5 Hz,
3H); 13C NMR (75.5 MHz, CDCl3) δ 178.3, 155.7, 84.6, 76.3,
72.7, 48.4, 43.5, 42.3, 34.6, 27.9, 26.0, 25.7, 21.6, 19.0, 15.0,
9.7; [R]25D +46.2° (c 0.9, CHCl3); high-resolution MS m/ e calcd
for C17H27NO4: 295.1784. Found: 295.1778. Anal. Calcd for
C16H25NO4: C, 65.06; H, 8.53; N, 4.74. Found: C, 64.87; H,
8.45; N, 4.94.
N-[(2R,3S)-3-H yd r oxy-2-m et h yl-3-p h en ylp r op ion yl]-
(1S ,5R ,7R )-10,10-d im e t h yl-3-oxo-2-a za -4-oxa t r icyclo-
[6.2.1.01,5]d eca n e (7f). As described above, 5 (118 mg, 0.5
mmol) and benzaldehyde (62 mg, 0.6 mmol) afforded a crude
1
reaction mixture. Diastereomer analysis [300-MHz H NMR
integration of the C-2 and/or C-3 methine protons (CH(OH)-
C6H5 and CH3CHCdO)] of the unpurified adduct revealed the
presence of two aldols 7f and 8f. The ratio of 7f vs 8f was a
function of the boryl enolate and cocatalyst, varying from 78:
22 to 88:12 to 88:12 to 96:4 on switching from 6a /TiCl4 to 6a /
SnCl4 to 6b/TiCl4 to 6b/SnCl4 in CH2Cl2. Purification by
recrystallization (CH2Cl2/hexane) provided 153 mg (89%) of 7f
as a colorless, crystalline solid: mp 159-160 °C; IR (KBr) 3504,
2976, 1778, 1682, 1456, 1384 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.45-7.21 (m, 5H), 4.70 (t, J ) 8.1 Hz, 1H), 4.37 (quintet, J
) 7.2 Hz, 1H), 4.24 (dd, J ) 8.4, 4.2 Hz, 1H), 3.49 (d, J ) 8.4
Hz, 1H), 3.02-1.21 (m, 7H), 1.09 (d, J ) 7.2 Hz, 3H), 1.05 and
0.90 (2s, 6H); 13C NMR (75.5 MHz, CDCl3) δ 178.1, 155.6,
142.4, 128.5, 127.8, 126.6, 84.6, 77.5, 72.7, 48.4, 44.8, 42.3, 34.6,
N-[(2R,3R)-3-Hyd r oxy-2-m eth ylh exa n oyl]-(1S, 5R, 7R)-
10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo[6.2.1.01,5]-
d eca n e (7c). As described above, 5 (118 mg, 0.5 mmol) and
n-butylaldehyde (44 mg, 0.6 mmol) afforded a crude reaction
26.0. 25.8, 21.4, 18.7, 15.2; [R]25 -5.4° (c 2.1, CHCl3); high-
1
mixture. Analysis [300-MHz H NMR integration of the C-2
D
resolution MS m/ e calcd for C20H25NO4: 343.1784. Found:
343.1789. Anal. Calcd for C20H25NO4: C, 69.95; H, 7.33; N,
4.08. Found: C, 69.76; H, 7.28; N, 4.06. 8f:5a mp 43-44 °C;
and/or C-3 methine protons (CHOH and CH3CHCdO)] of the
unpurified product indicated the presence of a single aldol
adduct. Purification by recrystallization (CH2Cl2/hexane) gave
139 mg (90%) of 7c as a white solid: mp 93-94 °C; IR (KBr)
IR (KBr) 3468, 2972, 1784, 1694, 1488 cm-1 1H NMR (300
;
3524, 2968, 2884, 1780, 1696, 1416, 1380, 1234, 1180 cm-1
;
MHz, CDCl3) δ 7.46-7.20 (m, 5H), 5.15 (t, J ) 3.6 Hz, 1H),
4.23 (dq, J ) 7.2, 4.2 Hz, 1H), 4.22 (dd, J ) 7.8, 4.5 Hz, 1H),
3.04 (d, J ) 3 Hz, 1H), 2.98-1.18 (m, 7H), 1.13, (d, J ) 6.9
Hz, 3H), 1.026 and 0.878 (2s, 6H); 13C NMR (75.5 MHz, CDCl3)
δ 177.9, 154.7, 141.5, 128.1, 127.5, 127.4, 84.4, 73.6, 72.4, 48.1,
1H NMR (300 MHz, CDCl3) δ 4.25 (dd, J ) 8.1, 4.2 Hz, 1H),
3.87 (quintet, J ) 7.2, 1H), 3.63 (m, 1H), 3.01-1.21 (m with d
at 2.76, J ) 9.6 Hz, 12H), 1.18 (d, J ) 7.2 Hz, 3H), 1.15 and
1.04 (2s, 6H), 0.94 (t, J ) 6.9 Hz, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 178.3, 155.7, 84.6, 74.6, 72.7, 48.4, 43.9, 42.3, 37.4,
44.9, 42.3, 34.6, 25.8, 25.7, 21.3, 18.8, 11.4; [R]25 +44.2° (c
D
34.6, 26.0, 25.7, 21.6, 19.0, 18.5, 14.9, 13.9; [R]25 +46.1° (c
2.4, CHCl3); high-resolution MS m/ e calcd for C20H25NO4:
343.1784. Found: 343.1789. Anal. calcd for C20H25NO4: C,
70.00; H, 7.34; N, 4.08. Found: C, 69.97; H, 7.28; N, 4.05.
N-[(2R,3S)-3-(2-F u r yl)-3-h yd r oxy-2-m eth ylp r op ion yl]-
(1S ,5R ,7R )-10,10-d im e t h yl-3-oxo-2-a za -4-oxa t r icyclo-
[6.2.1.01,5]d eca n e (7g). As described above, 5 (118 mg, 0.5
mmol) and 2-furaldehyde (58 mg, 0.6 mmol) afforded a crude
D
1.1, CHCl3); high-resolution MS m/ e calcd for C17H27NO4:
309.1941. Found: 309.1938. Anal. Calcd for C17H27NO4: C,
65.99; H, 8.80; N, 4.53. Found: C, 65.82; H, 8.71; N, 4.63.
N-[(2R,3R)-3-Hydr oxy-2-m eth yl-4-h exen oyl]-(1S,5R,7R)-
10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo[6.2.1.01,5]-
d eca n e (7d ). As described above, 5 (118 mg, 0.5 mmol) and
crotonaldehyde (43 mg, 0.6 mmol) gave a crude reaction
1
reaction mixture. Diastereomer analysis [300-MHz H NMR
1
integration of the C-2 and/or C-3 methine protons (CH(OH)-
furyl and CH3CHCdO)] of the unpurified adduct revealed the
presence of two aldols 7g and 8g. The ratio of 7g vs 8g was
a function boryl enolate and cocatalyst, varying from 78:22 to
88:12 to 88:12 to 94:6 on switching from 6a /TiCl4 to 6a /SnCl4
to 6b/TiCl4 to 6b/SnCl4 in CH2Cl2. Purification by recrystal-
lization (CH2Cl2/hexane) afforded 147 mg (88%) of 7g as a
colorless, crystalline solid: mp 105-106 °C; IR (KBr) 3502,
3010, 2968, 1752, 1713, 1506, 1455, 1378. 1306 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.38 (m, 1H), 6.34-6.32 (m, 2H), 4.73 (t,
J ) 8.4 Hz, 1H), 4.40 (quintet, J ) 7.2 Hz, 1H), 4.26 (dd, J )
8.1, 4.2 Hz, 1H), 3.58 (d, J ) 8.4 Hz, 1H), 3.01-1.20 (m, 7H),
1.14 (d, J ) 7.2 Hz, 3H), 1.10 and 1.01 (2s, 6H); 13C NMR (75.5
MHz, CDCl3) δ 177.6, 155.5, 154.9, 142.2, 110.2, 107.3, 84.6,
72.6, 71,0, 48.4, 42.7, 42.3, 34.6, 26.0. 25.8, 21.4, 18.8, 14.8;
mixture. Analysis [300-MHz H NMR integration of the C-2
and/or C-3 methine protons (CHOH and CH3CHCdO)] of the
unpurified product indicated the presence of essentially a
single aldol adduct. Purification by flash chromatography
(silica gel, 15% ethyl acetate/hexane, Rf 0.3) provided 140 mg
(91%) of 7d as a white solid: mp 81-82 °C; IR (KBr) 3496,
2974, 1791, 1710, 1458, 1383, 1077, 1014 cm-1; 1H NMR (300
MHz, CDCl3) δ 5.74 (ddq, J ) 15.6, 6.3, 0.6 Hz, 1H), 5.45 (ddq,
J ) 15.6, 6.9, 1.5 Hz, 1H), 4.25 (dd, J ) 8.4, 4.2 Hz, 1H), 4.10
(m, 1H), 3.94 (quintet, J ) 7.2 Hz, 1H, 3.02-1.20 (m with d at
1.72, J ) 6.0 Hz, 11H), 1.15 (d, J ) 7.2 Hz, 1H), 1.14 and 1.04
(2s, 6H); 13C NMR (75.5 MHz, CDCl3) δ 177.7, 155.3, 131.6,
128.2, 84.3, 75.5, 72.5, 48.2, 43.6, 42.1, 34.4, 25.8, 25.6, 21.2,
18.6, 17.4, 14.6; [R]25 +35.5° (c 1.8, CHCl3); high-resolution
D
MS m/ e calcd for C17H25NO4: 307.1784. Found: 307.1781.
Anal. Calcd for C17H25NO4: C, 66.43; H, 8.20; N, 4.56.
Found: C, 66.36; H, 8.24; N, 4.58.
[R]25 +13.5° (c 2.6, CHCl3); high-resolution MS m/ e calcd for
D
C18H23NO5: 333.1576. Found: 333.1574. Anal. calcd for
C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C, 64.89; H,
7.11; N, 4.23. 8g: IR (neat) 3512, 3008, 2964, 1750, 1710,
N-[(2R, 3R)-3-Hydr oxy-2-m eth yl-4-octen oyl]-(1S,5R,7R)-
10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo[6.2.1.01,5]-
d eca n e (7e). As described above, 5 (118 mg, 0.5 mmol) and
(E)-2-hexenal (59 mg, 0.6 mmol) gave a crude reaction mixture.
Analysis [300-MHz 1H NMR integration of the C-2 and/or C-3
methine protons (CHOH and CH3CHCdO)] of the unpurified
product indicated the presence of essentially a single aldol
adduct. Purification by flash chromatography (silica gel, 15%
ethyl acetate/hexane, Rf 0.3) provided 142 mg (85%) of 7e as
a colorless oil: IR (neat) 3502, 2968, 1785, 1713, 1464, 1383,
1179, 1080 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.65 (ddt, J )
15.0, 6.6, 0.6 Hz, 1H), 5.45 (ddt, J ) 15.6, 6.9, 1.2 Hz, 1H),
4.25 (dd, J ) 8.4, 4.2 Hz, 1H), 4.03 (m, 1H), 3.86 (quintet, J )
7.2 Hz, 1H), 2.94-1.13 (m, 12H), 1.07 (d, J ) 7.2 Hz, 3H), 1.07
and 0.97 (2s, 6H), 0.83 (t, J ) 7.2 Hz, 3H); 13C NMR (75.5
MHz, CDCl3) δ 177.9, 155.6, 133.8, 130.5, 84.6, 75.9, 72.7, 48.4,
43.9, 42.3, 34.6, 34.2, 25.9, 25.8, 22.1, 21.5, 18.9, 14.8, 13.6;
1
1503, 1451, 1379 cm-1; H NMR (300 MHz, CDCl3) δ 7.30 (t,
J ) 1.4 Hz, 1H), 6.32-6.22 (m, 2H), 5.06 (d, J ) 5.4 Hz, 1H),
4.28 (dq, J ) 6.6, 5.4 Hz, 1H), 4.18 (dd, J ) 8.1, 4.2 Hz, 1H),
3.01-1.16 (m with d at 1.21, J ) 6.9 Hz, 11H), 0.97 and 0.91
(2s, 6H); 13C NMR (75.5 MHz, CDCl3) δ 177.4, 154.8, 154.7,
142.2, 110.2, 106.7, 84.4, 72.3, 68.5, 48.1, 43.0, 42.2, 34.5, 25.7,
25.6, 21.1, 18.7, 12.5; [R]25 +44.9° (c 4.4, CHCl3); high-
D
resolution MS m/ e calcd for C18H23NO5: 333.1576. Found:
333.1574. Anal. Calcd for C18H23NO5: C, 64.85; H, 6.95; N,
4.20. Found: C, 64.89; H, 7.11; N, 4.23.
Gen er a l P r oced u r e for th e Hyd r op er oxid e-Assisted
Sa p on ifica tion r-Meth yl-â-h yd r oxy Ca r boxylic a cid 9. To
a solution of aldol adduct 7 (1 equiv) in THF/H2O (3:1, 0.16
M) at 0 °C was added a solution of LiOH (6 equiv) in 10 equiv
of 28% H2O2. The resulting mixture was stirred at 0 °C for
0.5-3 h and treated with a solution of 12 equiv of Na2SO3 in
H2O. Following removal of the THF in vacuo on the rotary
evaporator, the aqueous residue was diluted with H2O and
extracted with three portions of CH2Cl2. The combined CH2Cl2
[R]25 +26.2° (c 3.6, CHCl3); high-resolution MS m/ e calcd for
D
C19H29NO4: 335.2097. Found: 335.2094. Anal. Calcd for
C19H29NO4: C, 68.03; H, 8.71; N, 4.18. Found: C, 67.85; H,
8.64; N, 4.17.

Anti-Stereoselective Aldolizations via Boryl Enolates
J . Org. Chem., Vol. 61, No. 6, 1996 2043
extracts were dried (MgSO4) and evaporated in vacuo to give
recovered auxiliary 5 (>95%). The aqueous phase was acidi-
fied with 3 N HCl and extracted with three portions of ether.
The combined organic extracts were dried (MgSO4) and
concentrated in vacuo to afford pure R-methyl-â-hydroxy
carboxylic acid 9. In the case of 9b, the acid was treated with
a solution of CH2N2 (excess) in ether at 0 °C. After the reaction
mixture was stirred at 0 °C for 1 h, it was concentrated in
vacuo to yield the esterification product of 9b.
6.6, 1.2 Hz, 3H), 1.16 (d, J ) 7.5 Hz, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 180.3. 130.7, 129.9, 74.8, 45.5, 17.6, 13.9; [R]25
D
+11.6° (c 0.42, CHCl3); observed [R]25 values for the hydro-
D
genation (Raney-nickel) product of 9d : [R]25 -6.1° (c 0.91,
D
CHCl3); lit.8a [R]25 -5.0° (c 0.2, CHCl3); high-resolution MS
D
m/ e calcd for C7H12O3: 144.0786. Found: 144.0781.
(2R,3R)-2-Meth yl-3-h yd r oxy-(E)-4-octen oic a cid (9e):
IR (neat) 3494, 2972, 1716, 1464, 972 cm-1; 1H NMR (300 MHz,
CDCl3) δ 5.76 (ddt, J ) 15.3, 6.9, 0.3 Hz, 1H), 5.43 (ddt, J )
15.3, 7.2, 0.3 Hz, 1H), 4.91 (bs, 2H), 4.18 (dd, J ) 7.5, 7.2 Hz,
1H), 2.55 (quintet, J ) 7.2 Hz, 1H), 2.03 (dt, J ) 6.9, 6.6 Hz,
2H), 1.41 (sextet, J ) 7.2, 2H), 1.17 (d, J ) 7.2 Hz, 3H), 0.90
(t, J ) 7.2 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ 180.8. 135.0,
(2R,3R)-2,4-Dim eth yl-3-h yd r oxyp en ta n oic a cid (9a ): IR
(neat) 3472, 3364, 2964, 1700, 1458, 1374 cm-1; 1H NMR (300
MHz, CDCl3) δ 5.10 (bs, 2H), 3.44 (dd, J ) 7.2, 6.6 Hz, 1H),
2.69 (quintet, J ) 7.2 Hz, 1H), 1.80 (octet, J ) 6.6 Hz, 1H),
1.25 (d, J ) 7.2 Hz, 3H), 0.99 and 0.94 (2d, J ) 6.6 Hz, 6H);
13C NMR (75.5 MHz, CDCl3) δ 181.3, 78.0, 42.7, 30.5, 19.7,
15.9, 14.7; [R]25 -17.6° (c 0.49, CHCl3); lit.8a [R]25 -15.3° (c
129.5, 74.8, 45.5, 34.2, 22.1, 13.9, 13.5; [R]25 +14.8° (c 2.8,
D
CHCl3); high-resolution MS m/ e calcd for C9H16O3: 172.1100.
Found: 172.1101. Anal. Calcd for C9H16O3: C, 62.81; H, 9.37.
Found: C, 62.79; H, 9.31.
D
D
1.2, CHCl3); lit.7 [R]25 -14.3° (c 1.0, CHCl3); high-resolution
D
MS m/ e calcd for C7H14O3: 146.0943. Found: 146.0947.
(2R,3R)-2-Met h yl-3-h yd r oxyp en t a n oic a cid (9b ): IR
(neat) 3456, 2940, 1712, 1464, 1264, 1090 cm-1; 1H NMR (300
MHz, CDCl3) d 6.58 (bs, 2H), 3.65 (m, 1H), 2.58 (quintet, J )
7.2 Hz, 1H), 1.72-1.41 (m, 2H), 1.23 (d, J ) 7.2 Hz, 3H), 0.99
(t, J ) 7.5 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ 180.7, 74.6,
44.8, 27.2, 14.1, 9.6; [R]25 -6.4° (c 0.68, CHCl3); lit.8a [R]25
(2R,3S)-2-Met h yl-3-h yd r oxy-3-p h en ylp r op a n oic a cid
(9f): mp 101-102 °C; IR (neat) 3488, 3028, 2980, 2620, 1686,
1
1554, 1454 cm-1; H NMR δ (300 MHz, CDCl3) δ 7.41-7.31
(m, 5H), 4.71 (d, J ) 8.7 Hz, 1H), 2.86 (dq, J ) 8.7, 7.2 Hz,
1H), 1.03 (d, J ) 7.2 Hz, 3H); 13C (75.5 MHz, CDCl3) δ 180.3,
141.1, 128.7, 128.4, 126.8, 76.3, 46.9, 14.3; [R]25D -53.4° (c 0.34
CHCl3); lit.8a [R]25 -49.0° (c 0.44, CHCl3); lit.7 [R]25 -17.5°
D
D
D
D
-5.0° (c 0.2, CHCl3); observed [R]25D values for the methyl ester
(c 2.3, CHCl3); lit.8d [R]25 -19.7° (c 0.094, EtOH); high-
D
derived from 9b: [R]25D -7.3° (c 0.43, CHCl3); lit.6b [R]25D -7.9°
resolution MS m/ e calcd for C10H12O3: 180.0787. Found:
180.0790.
(c 0.52, CHCl3); lit.8c [R]25 -9.9° (c 0.28, CHCl3); high-
D
resolution MS m/ e calcd for C6H12O3: 132.0787. Found:
132.0789.
(2R,3S)-2-Meth yl-3-h yd r oxy-3-(2-fu r yl)p r op a n oic a cid
(9g): IR (neat) 3452, 3020, 2936, 1726, 1466, 1012, 908 cm-1
;
(2R,3R)-2-Meth yl-3-h ydr oxyh exan oic acid (9c): IR (neat)
3488, 3308, 2968, 2736, 2696, 2572, 1716, 1456 cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.67 (bs, 2H), 3.71 (m, 1H), 2.56 (quintet,
J ) 7.2 Hz, 1H), 1.61-1.36 (m, 4H), 1.24 (d, J ) 7.2 Hz, 3H),
0.95 (t, J ) 7.2 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ 180.9,
1H NMR δ (300 MHz, CDCl3) δ 7.41 (bs, 1H), 6.33 (m, 2H),
4.80 (d, J ) 8.7 Hz, 1H), 3.06 (quintet, J ) 7.2 Hz, 1H), 1.11
(d, J ) 7.2 Hz, 3H); 13C (75.5 MHz, CDCl3) δ 180.1, 153.5,
142.6, 110.2, 108.0, 69.5, 44.7, 14.0; [R]25D -36.6° (c 0.1 CHCl3);
high-resolution MS m/ e calcd for C8H10O4: 170.0580.
Found: 170.0585. Anal. Calcd for C8H10O4: C, 56.50; H, 5.93.
Found: C, 56.72; H, 5.91.
73.0, 45.2, 36.6, 18.6, 14.1, 13.9; [R]25 -5.4° (c 0.44, CHCl3);
D
lit.8a [R]25D -5.0° (c 0.2, CHCl3); high-resolution MS m/ e calcd
for C7H14O3: 146.0943. Found: 146.0951.
(2R,3R)-2-Meth yl-3-h yd r oxy-(E)-4-h exen oic a cid (9d ):
Ack n ow led gm en t. Support from the National Sci-
ence Council of the Republic of China (NSC 85-2113-
M-005-003) is gratefully acknowledged.
IR (neat) 3544, 2986, 1722, 1464, 1263, 969 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 5.76 (ddq, J ) 14.7, 6.6, 0.3 Hz, 1H), 5.43
(ddq, J ) 14.7, 7.5, 1.2 Hz, 1H), 4.91 (bs, 2H), 4.16 (dd, J )
7.8, 7.5 Hz, 1H), 2.55 (quintet, J ) 7.5 Hz, 1H), 1.73 (dd, J )
J O9520147