Diastereo- and enantioselective direct catalytic aldol reaction of 2-hydroxyacetophenones with aldehydes promoted by a heteropolymetallic complex: Catalytic asymmetric synthesis of anti-1,2-diols

Article abstract of DOI:10.1021/jo0162538

An anti-selective direct catalytic asymmetric aldol reaction of 2-hydroxyacetophenones with aldehydes is described. The reaction is catalyzed by a heteropolymetallic complex to afford anti-α,β-dihydroxy ketones as the major diastereomer with excellent enantioselectivity. The use of 2-hydroxyacetophenones bearing electron-donating groups at the phenyl moiety enabled efficient transformation of the aldol products (α,β-dihydroxy ketones) into the corresponding α,β-dihydroxy ester derivatives via Baeyer-Villiger oxidation. A plausible reaction mechanism is also discussed based on the stereochemistry of the products.

Full text of DOI:10.1021/jo0162538

2556
J . Org. Chem. 2002, 67, 2556-2565
Dia ster eo- a n d En a n tioselective Dir ect Ca ta lytic Ald ol Rea ction of
2-Hyd r oxya cetop h en on es w ith Ald eh yd es P r om oted by a
Heter op olym eta llic Com p lex: Ca ta lytic Asym m etr ic Syn th esis of
a n ti-1,2-Diols
Naoki Yoshikawa, Takeyuki Suzuki, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, J apan
mshibasa@mol.f.u-tokyo.ac.jp
Received October 31, 2001
An anti-selective direct catalytic asymmetric aldol reaction of 2-hydroxyacetophenones with
aldehydes is described. The reaction is catalyzed by a heteropolymetallic complex to afford anti-
R,â-dihydroxy ketones as the major diastereomer with excellent enantioselectivity. The use of
2-hydroxyacetophenones bearing electron-donating groups at the phenyl moiety enabled efficient
transformation of the aldol products (R,â-dihydroxy ketones) into the corresponding R,â-dihydroxy
ester derivatives via Baeyer-Villiger oxidation. A plausible reaction mechanism is also discussed
based on the stereochemistry of the products.
In tr od u ction
transformed into a series of carbohydrates. In artificial
catalysis by a small molecule, Kobayashi et al. utilized
chiral tin(II) Lewis acids for diastereo- and enantiose-
lective Mukaiyama-type aldol reactions of ketene silyl
acetals derived from O-protected R-hydroxy esters to
obtain syn-R,â-dihydroxy ester derivatives in a highly
stereoselective manner.5 Some drawbacks remain, how-
ever, when using this method, such as the necessity for
protection of the R-hydroxyl group and preparation of the
ketene silyl acetals from esters.
In 1997, we reported a successful example of a direct
catalytic asymmetric aldol reaction of unmodified ke-
tones, for which the preformation of enol ethers was no
longer needed.6 Since that time, we7-10 and others11-15
have reported several new types of catalytic asymmetric
A wide range of important compounds in organic
chemistry comprise the optically active 1,2-diol unit. This
unit occurs in many natural products as represented by
sugars and also has an important role as a chiral ligand
in asymmetric catalysis, attracting a great deal of atten-
tion from chemists. Accordingly, extensive efforts have
been made to develop a general synthetic tool to stereo-
selectively produce 1,2-diols. Among the many methods
reported to date, the catalytic asymmetric dihydroxyla-
tion (AD) of olefins, which was developed by Sharpless
et al., is widely accepted as reliable, with high levels of
diastereo- and enantioselectivity. Whereas a variety of
syn-diols are prepared in a highly enantioselective man-
ner from trans-olefins,1 anti-diols are less accessible due
to the moderate selectivity obtained in the dihydroxyla-
tion of cis-olefins.2 The development of a general method
for the catalytic asymmetric synthesis of anti-diols,
therefore, requires a different approach.3,4
(5) Kobayashi, S.; Kawasuji, T. Synlett 1993, 911-913.
(6) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1871-1873.
(7) Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1998, 39,
5561-5564.
The aldol reaction of R-hydroxy ketones with aldehydes
might enable an efficient synthesis of 1,2-diols, because
this process constructs vicinal hydroxyl groups by con-
trolling the two stereogenic centers to form a C-C bond
simultaneously. In practice, aldolases catalyze aldol
reactions in vivo between dihydroxyacetone phosphate
(DHAP) and aldehydes3 to produce 1,2-diols, which are
(8) Yoshikawa, N.; Yamada, Y. M. A.; Das, J .; Sasai, H.; Shibasaki,
M. J . Am. Chem. Soc. 1999, 121, 4168-4178.
(9) Yoshikawa, N.; Shibasaki, M. Tetrahedron 2001, 57, 2569-2579.
(10) Suzuki, T.; Yamagiwa, N.; Matsuo, Y.; Sakamoto, S.; Yamagu-
chi, K.; Shibasaki, M.; Noyori, R. Tetrahedron Lett. 2001, 42, 4669-
4671.
(11) Aldolase catalytic antibodies were reported. See: (a) Sinha, S.
C.; Sun, J .; Miller, G.; Barbas, C. F., III; Lerner, R. A. Org. Lett. 1999,
1, 1623-1626. (b) Zhong, G.; Lerner, R. A.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 1999, 38, 3738-3741 and references therein.
(12) For direct aldol reactions promoted by Zn catalysts, see: (a)
Trost, B. M.; Ito, H. J . Am. Chem. Soc. 2000, 122, 12003-12004. (b)
Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497-2500.
(13) For amino acids catalyzed direct aldol reactions, see: (a) List,
B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573-575. (b) Sakthivel,
K.; Notz, W.; Bui, T.; Barbas, C. F., III. J . Am. Chem. Soc. 2001, 123,
5260-5267 and references therein.
(14) For direct aldol reactions promoted by diamine-protonic acid
catalysts, see: Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001,
1245-1248.
(15) Catalytic asymmetric cyclocondensations between acyl halide
and aldehyde have been reported. See: (a) Nelson, S. G.; Peelen, T.
J .; Wan, Z. J . Am. Chem. Soc. 1999, 121, 9742-9743. Another group
has reported a rhodium-catalyzed enantioselective reductive aldol
reaction. See: (b) Taylor, S. J .; Duffey, M. O.; Morken, J . P. J . Am.
Chem. Soc. 2000, 122, 4528-4529.
(1) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483-2547.
(2) Wang, L.; Sharpless, K. B. J . Am. Chem. Soc. 1992, 114, 7568-
7570.
(3) For the catalytic asymmetric synthesis of syn- or anti-1,2-diols
by aldolases, see: (a) Bednarski, M. D.; Simon, E. S.; Bischofberger,
N.; Fessner, W.-D.; Kim. M.-J .; Lees, W.; Saito, T.; Waldmann, H.;
Whitesides, G. M. J . Am. Chem. Soc. 1989, 111, 627-635. (b) Fessner,
W.-D.; Sinerius, G.; Schneider, A.; Dreyer, M.; Schulz, G. E.; Badia,
J .; Aguilar, J . Angew. Chem., Int. Ed. Engl. 1991, 30, 555-558.
(4) For the catalytic asymmetric synthesis of syn- or anti-1,2-diols
by catalytic antibodies, see: (a) List, B.; Shabat, D.; Barbas, C. F., III;
Lerner, R. A. Chem. Eur. J . 1998, 4, 881-885. (b) Hoffmann, T.; Zhong,
G.; List, B.; Shabat, D.; Anderson, J .; Gramatikova, S.; Lerner, R. A.;
Barbas, C. F., III. J . Am. Chem. Soc. 1998, 120, 2768-2779.
10.1021/jo0162538 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/19/2002

Asymmetric Synthesis of anti-1,2-Diols
J . Org. Chem., Vol. 67, No. 8, 2002 2557
Ch a r t 1
aldol reactions. List et al. recently reported that (S)-
proline is an effective catalyst for the asymmetric direct
aldol reaction of hydroxyacetone,16 affording the corre-
sponding anti-R,â-dihydroxy ketones in moderate yield
with excellent enantioselectivity. Although this system
was applicable to R-substituted aldehydes, only one
example had been reported for an R-unsubstituted alde-
hyde. At the same time, we attempted to extend the
direct enantioselective aldol reaction of methyl ketones
to a diastereoselective variant using ethyl ketones9 and
hydroxy ketones as a substrate.17-19 Consequently, our
investigations resulted in the development of diastereo-
selective direct asymmetric aldol reactions of 2-hydroxy-
acetophenone with aldehydes,17,18 where either anti- or
syn-1,2-diols were obtained by choosing the appropriate
catalyst. Whereas a heteropolymetallic catalyst8 that is
based on La, Li, and K afforded anti-1,2-diols,17 a Zn-
Zn-linked-BINOL complex afforded 1,2-diols in a highly
syn-selective manner,17,18 with excellent enantioselectiv-
ity. In the present article, the use of the heteropolyme-
tallic catalyst for anti-selective direct aldol reactions of
2-hydroxyacetophenones is described. We examined a
series of 2-hydroxyacetophenones bearing substituent-
(s) on the phenyl group as a substrate for the aldol
reaction and found a consistent relationship between the
reaction rate and the electron density of the aryl group
in 2-hydroxyacetophenones. Moreover, the determination
of the absolute and relative configuration of the aldol
products provided a clue to the reaction mechanism.
to afford the products in good yield with good enantio-
meric excess. For example, the reaction of hexanal (1b)
with 2a at -20 °C gave the anti- and syn-aldol products
(anti-3b and syn-3b) in 79% combined yield with a
diastereomeric ratio of 1 to 1 after 18 h. The enantiomeric
excess of the anti-isomer (anti-3b) was determined to be
79%, and that of the syn-isomer (syn-3b) to be 56% by
HPLC analysis. The formation of the desirable anti-
diastereomer (anti-3b) was dominant (74:26) when the
reaction was performed at a lower temperature (-50 °C),
and the enantioselectivity also improved to 93% ee (anti).
Resu lts a n d Discu ssion
Op tim iza tion of Rea ction Con d ition s. In 1999, we
reported a direct enantioselective aldol reaction of methyl
ketones that was catalyzed by a complex prepared from
LLB (LaLi3tris(binaphthoxide)),20,21 KHMDS (potassium
bis(trimethylsilyl)amide), and H2O, and the catalyst was
referred to as a “heteropolymetallic catalyst” (Chart 1).8
We also reported that R,R-disubstituted aldehydes are
the most suitable substrates.
We first examined the reaction of aldehydes with
2-hydroxyacetophenone (2a ) using 10 mol % of the
heteropolymetallic catalyst (eq 1). In contrast to the
previous case, the reaction of R,R-disubstituted or R-mono-
substituted aldehydes with 2a afforded the aldol products
with poor yield and poor enantiomeric excess. R-Unsub-
stituted aldehydes, however, which gave less satisfactory
results in the previous system, reacted rapidly with 2a
Because the anti-isomer (anti-3b) slightly decomposed
during purification by silica gel column chromatography,
the crude mixture of the aldol products (crude 3b) was
treated with 2,2-dimethoxypropane in the presence of a
catalytic amount of p-toluenesulfonic acid to form the
corresponding acetonides (4b) before isolation of the
products. The diastereomeric acetonides were separable
by silica gel column chromatography. The conditions for
aldol reactions were eventually optimized to afford the
acetonides (4b) in 84% overall yield (based on the
aldehyde used) with 94% ee (anti) and 84% ee (syn) (anti:
syn ) 74:26, entry 3 in Table 1).22 The relative and
absolute configuration of syn-isomers (syn-3) was re-
vealed by conversion to the acetonides (syn-4) and
comparison with authentic samples obtained after Sharp-
less AD followed by acetonide formation.23 Determination
of the relative and absolute configuration of the anti-
isomers was performed after epimerization of the ac-
etonides (anti-4) obtained from the anti-aldol products
(anti-3).23
(16) Notz, W.; List, B. J . Am. Chem. Soc. 2000, 122, 7386-7387.
(17) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima,
T.; Suzuki, T.; Shibasaki, M. J . Am. Chem. Soc. 2001, 123, 2466-2467.
(18) Kumagai, N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.;
Shibasaki, M. Org. Lett. 2001, 3, 1539-1542.
(19) Trost et al. have independently reported the direct aldol reaction
of hydroxy ketones with various aldehydes using a chiral semi-crown
Zn complex, and syn-1,2-diols were accessible by means of this reaction.
See: Trost, B. M.; Ito, H.; Silcoff, E. R. J . Am. Chem. Soc. 2001, 123,
3367-3368.
(20) For reviews of heterobimetallic multifunctional catalysts de-
veloped in our group, see: (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1236-1256. (b) Shibasaki, M.; Sasai,
H.; Arai, T.; Iida, T. Pure Appl. Chem. 1998, 70, 1027-1034. (c)
Shibasaki, M.; Iida, T.; Yamada, Y. M. A. J . Synth. Org. Chem. J pn.
1998, 56, 344-356. (d) Shibasaki, M. Chemtracts-Org. Chem. 1999,
12, 979-998. (e) Shibasaki, M. Enantiomer 1999, 4, 513-527. (f)
Shibasaki, M.; Yamada, K.-i.; Yoshikawa, N. In Lewis Acids in Organic
Synthesis; Yamamoto, H., Ed.; Wiley-VCH: Weinheim, 2000; Vol. 2,
Chapter 20.
Th e Ald ol Rea ction s of 2-Hyd r oxya cetop h en on e
(2a ) w ith Ald eh yd es 1a -e. According to the optimized
procedure, the aldol reactions of several R-unsubstituted
aldehydes (1a -e) with 2-hydroxyacetophenone (2a ) were
examined using 10 mol % of the heteropolymetallic
catalyst at -50 °C (Table 1). All the substrates tested
afforded the corresponding anti-R,â-dihydroxy ketones
(anti-3) as the major diastereomer in a highly enanti-
oselective manner. Aldehyde 1a reacted with 2a to
produce a better diastereomeric ratio (anti:syn ) 84:16),
(21) LLB is now commercially available as a solution in THF from
Fluka.
(22) The diastereomeric ratio was determined by 1H NMR of the
crude mixture of the diols.

2558 J . Org. Chem., Vol. 67, No. 8, 2002
Yoshikawa et al.
Ta ble 1. Ald ol Rea ction of 2-Hyd r oxya cetop h en on e (2a ) w ith Ald eh yd es 1a -e P r om oted by 10 m ol % of a
Heter op olym eta llic Ca ta lyst
entry
aldehyde (R)
C6H5(CH2)3 (1a )
diol
time (h)
yielda (%)
drb (anti:syn)
eec (anti/syn)
1
3a
3a
3b
3c
3d
3e
24
40
24
28
24
24
84
78
84
90
86
89
84:16
78:22
74:26
72:28
65:35
69:31
95/74
92/70
94/84
94/83
90/83
95/87
2d
3
1a
n-C5H11 (1b)
(E)-CH3(CH2)4CHdCH(CH2)2 (1c)
i-Bu (1d )
4
5
6
C6H5(CH2)2 (1e)
a
b
Isolated yield of acetonides 4 (see the main text). Determined by 1H NMR of the crude mixture of aldol products (diols). c Ee of
d
acetonide 4 (see the main text). Catalyst (5 mol %), -40 °C.
with an enantiomeric excess of the major diastereomer
of 95% (entry 1). The anti-adduct was obtained in 92%
ee even with a reduced amount of the catalyst (5 mol %)
(entry 2). Aldehyde 1c, which bears a C-C double bond,
was also a suitable substrate for this system to afford
the products in 90% yield (anti:syn ) 72:28) with 94% ee
(anti) (entry 4). This result indicates that the present
catalytic system tolerates substrates bearing C-C double
bonds, which is a functional group that can be used as a
scaffold for further manipulation of the aldol products,
whereas this is not the case in the Sharpless AD.
Although a substitution at the â- or γ-position of the
aldehydes produced lower diastereoselectivity, the enan-
tioselectivity was maintained at high levels (>90%; anti)
(entries 5 and 6).
to an ester moiety by Baeyer-Villiger oxidation would
fulfill this purpose. As a preliminary experiment, we
treated acetonide 4b with m-chloroperoxybenzoic acid (m-
CPBA) in the presence of phosphate buffer, and the
reaction proceeded with a rapid, regioselective rearrange-
ment of the alkyl group to produce benzoate ester 6 in
91% yield. We next attempted to obtain a phenyl ester,
instead of the benzoate, by changing the regioselectivity
in the Baeyer-Villiger oxidation. To achieve the rear-
rangement of the phenyl moiety, another protecting
group for the diol moiety was pursued, and carbonate
5b18 was synthesized from diol anti-3b and subjected to
Baeyer-Villiger oxidation using m-CPBA. The reaction
was, however, very sluggish and messy. The use of
another oxidant such as bis(trimethylsilyl) peroxide
(BTSP)24 was also ineffective.
The disappointing results prompted us to modify the
phenyl moiety in 2-hydroxyacetophenone as a substrate
for the aldol reaction, because an electron-rich aryl group
might undergo a facile rearrangement during Baeyer-
Villiger oxidation. Thus, a series of substituted 2-hy-
droxyacetophenones were prepared, and the effects of the
electron density of the aryl group were investigated in
aldol reactions at -40 °C (Table 2). The use of ketones
possessing a methoxy group on the phenyl group (2b-
d ) decelerated the aldol reaction (entries 1-3), and much
slower reaction rates were observed when 2-hydroxy-2′,5′-
dimethoxyacetophenone (2e) was used. In contrast, the
aldol reaction of 2-hydroxy-2′-methylacetophenone (2f)
proceeded at a reasonable rate to afford the diols (3k ) in
90% yield, albeit with lower selectivity (anti:syn ) 77:
23, anti ) 84% ee) (Table 2, entry 6). On the other hand,
excellent enantioselectivity was obtained in the reaction
of 2-hydroxy-4′-methylacetophenone (2g) with aldehyde
1a (yield 90%, anti:syn ) 83:17, anti ) 97% ee) (entry
7). The reaction is essentially completed within a shorter
time (13 h), as shown in entry 8. These results illustrate
the dependency of the reaction rate on the electron
density of the aryl group of the ketone (2). The decreased
reaction rates observed for methoxy-substituted hydroxy-
acetophenones 2b-e are probably due to the resulting
lower acidity of the R-proton of the ketone.
Tr a n sfor m a tion s of Ald ol P r od u cts 3. To demon-
strate the synthetic utility of the present aldol reaction,
we attempted to convert the aldol products (R,â-dihydroxy
ketones 3) into synthetically more versatile compounds.
The conversion of the ketone moiety in the aldol products
(23) The relative and absolute configuration of the aldol products
was determined according to the following procedures:
(24) (a) Go¨ttlich, R.; Yamakoshi, K.; Sasai, H.; Shibasaki, M. Synlett
1997, 971-973. (b) Suzuki, M.; Takada, H.; Noyori, R. J . Org. Chem.
1982, 47, 902. (c) Matsubara, S.; Takai, K.; Nozaki, H. Bull. Chem.
Soc. J pn. 1983, 56, 2029. See also 8.
For 3c and 3i, see Supporting Information.

Asymmetric Synthesis of anti-1,2-Diols
J . Org. Chem., Vol. 67, No. 8, 2002 2559
Ta ble 2. Ald ol Rea ction of Su bstitu ted 2-Hyd r oxya cetop h en on es (2b-g) P r om oted by 10 m ol % of a Heter op olym eta llic
Ca ta lyst
entry
aldehyde (R)
C6H5(CH2)3 (1a )
1a
1a
(E)-CH3(CH2)4CHdCH(CH2)2 (1c)
C6H5(CH2)3 (1a )
1a
1a
ketone (R′)
diol
time (h)
yielda (%)
dra (anti:syn)
eeb (anti/syn)
1
2
3
4c
5
6
7
8
9
2-MeO (2b)
3-MeO (2c)
4-MeO (2d )
2d
2,5-(MeO)2 (2e)
2-Me (2f)
4-Me (2g)
2g
3f
3g
3h
3i
3j
3k
3l
35
35
35
13
35
35
35
13
12
69
82
50
76d
42g
90
90
96
96
76:24
77:23
81:19
67:33e
74:26
77:23
83:17
82:18
75:25
95/74
95/83
98/79
93/91f
80/41
84/57
97/85
96/83
96/89
1a
3l
3m
n-C5H11 (1b)
2g
a
b
Determined by 1H NMR of the crude mixture of aldol products (diols). Ee of acetonide 4 (see the main text). c The reaction was
carried out at -30 °C. Isolated yield of diols. e The ratio calculated based on isolated diols. f The ee of anti-3i was determined at the
stage of the diol. Isolated yield of acetonides 4 (see the main text).
d
g
Sch em e 1. Ba eyer -Villiger Oxid a tion sa
F igu r e 1. Stereochemical course of the direct aldol reaction
of methyl ketones (top) and hydroxy ketones (bottom).
Rea ction Mech a n ism . Examination of the stereo-
chemistry of the aldol products (3) revealed that the
configuration at the â-position of the major diastereomer
(anti-3, bottom of Figure 1) is opposite to that of previ-
a
ously reported aldol products from acetophenone (top of
Figure 1).25 Moreover, an identical configuration (R) was
expressed at the R-position both of anti- and of syn-
products for all direct aldol reactions examined (eq 1 or
bottom of Figure 1), suggesting that the aldehyde attacks
the Re-face of the (Z)-enolate for the formation of both
diastereomers.
Reagents and conditions: (a) m-CPBA (2 mol equiv), NaH2PO4
(2.5 mol equiv), 1,2-dichloroethane, rt, 3.5 h; (b) m-CPBA (4 mol
equiv), NaH2PO4 (6 mol equiv), 1,2-dichloroethane, 50 °C, 5 h; (c)
m-CPBA (8 mol equiv), NaH2PO4 (10 mol equiv), 1,2-dichloro-
ethane, 40 °C, 2.5 h; (d) SnCl4 (1 mol equiv), N,N-bis(p-toluene-
sulfonyl)cyclohexane-1,2-diamine (1 mol equiv), bis(trimethylsilyl)
peroxide (4 mol equiv), CH2Cl2, MS 4A, -20 °C, 50 min.
The enantio- and diastereoselectivity can be rational-
ized by considering models depicted in Figure 2. Because
the majority (97.5% for 3l) of the product bears (RR)-
hydroxyl group, the shielding of the Si-face of the enolate
by the catalyst should be almost perfect. The configura-
tion of the â-position, meanwhile, would depend on a
direction in which the enolate-LLB complex approaches
the aldehyde, namely the differentiation of the enantio-
face of the aldehyde (a vs b in Figure 2).
The aldol products (anti-3h , anti-3i, and anti-3l) with
electron-donating substituents on the aryl group were
transformed into the corresponding cyclic carbonates (5h ,
5i, and 5l) in 86 to 91% yield by treatment with
triphosgene. Baeyer-Villiger oxidation of carbonate 5h
proceeded with a smooth, clean rearrangement of the aryl
group (Scheme 1), as we expected. In addition, the same
type of reaction with carbonate 5l, derived from anti-3l,
cleanly produced the corresponding aryl ester (9) in 85%
yield (Scheme 1). Furthermore, carbonate 5i, which has
a C-C double bond, also underwent a chemoselective
rearrangement of the aryl group by utilizing BTSP as
an oxidant to afford ester 10 in 78% yield.
(25) Note that the aldol products in ref 8 were obtained using (R)-
catalyst, whereas the catalyst described in this article possesses the
(S)-configuration. We extrapolated in this article the absolute config-
uration of the product for (S)-LLB for consistency.

2560 J . Org. Chem., Vol. 67, No. 8, 2002
Yoshikawa et al.
F igu r e 2. Postulated intermediates for the formation of anti-diol (a ), syn-diol (b), and â-hydroxy ketone (c).
Sch em e 2. P ostu la ted Ca ta lytic Cycle
metal over that of the aldehyde can be explained by the
possible capability of the ketone to form a stable complex
with Lewis acids such as a lanthanum ion. Avoiding the
resulting sterically crowded lanthanide center, the alde-
hyde subsequently coordinates to the lithium metal and
is then attacked by the enolate, affording an alkoxide-
LLB complex (IV) via intermediate III (see also Figure
2). In this intermediate (III), proper orientation of the
enolate in the cavity of the catalyst permits the Re-face
of the enolate to be selectively exposed to the electrophilic
attack of the aldehyde coordinating to the lithium. The
resulting alkoxide-LLB complex (IV in Scheme 2) is then
protonated by H2O to produce the dihydroxy ketone, and
the catalyst (I) is regenerated.
All the steps should be reversible in principle so that
prolonged reaction time may decrease the enantiomeric
or diastereomeric excess of the product through a retro-
aldol reaction or epimerization at the R-position.26 Nev-
ertheless, the time-course of the present aldol reaction
indicates that either the enantiomeric or diastereomeric
ratio of the aldol product was maintained almost constant
during at least 49 h (eq 2). Hence, the stereochemistry
of the products is likely to be kinetically controlled under
the reaction conditions.
Previously, some kinetic studies and other experimen-
tal results led us to propose that the direct aldol reaction
of acetophenone is promoted by the synergistic functions
of the heteropolymetallic catalyst, wherein the lantha-
num ion acts as a Lewis acid to activate the aldehyde,
and the KOH functions as a Brønsted base to generate
an enolate from the ketone.8 On the basis of the previ-
ously proposed mechanism and the above-described ster-
eochemistry of the products (3), we postulated the
following catalytic cycle (Scheme 2) for the present
system. First, 2-hydroxyacetophenone coordinates to the
lanthanum metal of the catalyst (I) in a bidentate fashion
and is deprotonated by KOH at the R-position. The
resulting potassium enolate then forms a chelate complex
(II) with the lanthanum metal of LLB. The priority of
the ketone for the coordination to the lanthanide center
The use of other ketones as substrates was investigated
to obtain supporting evidence for the bidentate interac-
(26) A deterioration in the enantiopurity of aldol adducts was
observed in
a direct aldol reaction promoted by a calcium-based
catalyst. See ref 10.

Asymmetric Synthesis of anti-1,2-Diols
J . Org. Chem., Vol. 67, No. 8, 2002 2561
benzophenone ketyl. Dichloromethane was distilled from CaH2.
m-Chloroperoxybenzoic acid (m-CPBA) was dissolved in chloro-
form and then washed with phosphate buffer (pH 7.5) before
recrystallization from chloroform, unless otherwise noted. (S)-
BINOL was dried at 45 °C for 3 h under reduced pressure
before use. Aldehydes were distilled before use. 2-Hydroxy-
acetophenones were recrystallized before use. Acetophenones
as a starting material for the preparation of 2-hydroxy-
acetophenones were purchased and used without further
purification.
Gen er a l P r oced u r e for Sin gle-step P r ep a r a tion of
2-Hyd r oxya cetop h en on es (2a -g) (On ly Ap p lica ble to
Sm a ll-Sca le Syn th esis).29 A mixture of acetophenone or
substituted acetophenone (8.32 mmol), trifluoroacetic acid
(1.27 mL, 16.6 mmol), acetonitrile (42 mL), H2O (8.3 mL), and
(bis(trifluoroacetoxy)iodo)benzene (7.16 g, 16.6 mmol) was
heated to reflux until the starting ketone was consumed (1-5
h) based on TLC. After cooling to room temperature, acetoni-
trile was evaporated, and CH2Cl2 and H2O were added. The
aqueous layer was separated and extracted with CH2Cl2 twice.
The combined organic layers were washed with saturated
aqueous solution of NaHCO3 and brine and dried over anhy-
drous Na2SO4. The solvent was removed under reduced
pressure, and the residue was purified by flash silica gel
column chromatography to afford the R-hydroxylated ac-
etophenone in 30-50% yield, which was recrystallized before
use.
tion between the 2-hydroxyacetophenones (2) and the
catalyst. Ketones 11 and 12 are expected to be much less
effective for generating a chelate complex, compared with
2-hydroxyacetophenones (2). The aldol reaction of either
11 or 12 with aldehyde 1a under the optimized conditions
(catalyst: 10 mol %, -40 °C) did not give aldol products
even after a prolonged reaction time (66 h). On the basis
of these results, the presence of the hydroxyl group in
the ketones (2) seems to be essential for the present
system.27
The formation of an enolate would be facilitated by a
strong interaction between the ketone and the catalyst
through a bidentate coordination with the hydroxyl and
carbonyl group of 2, and the chelate complex (vide supra)
could be formed only from (Z)-enolate. The present
catalytic system, therefore, seems to require the partici-
pation of the (Z)-enolates rather than the (E)-enolates.28
Con clu sion s. We achieved an anti- and enantioselec-
tive direct aldol reaction of R-unsubstituted aldehydes
with 2-hydroxyacetophenones, which is promoted by a
heteropolymetallic catalyst. The method allows for direct
access to anti-R,â-dihydroxy ketones with excellent enan-
tioselectivity from aldehydes and hydroxy ketones, which
are commonly available materials in organic synthesis.
Although the diastereoselectivity remains to be improved,
the system described is one of the most effective methods
of catalytic asymmetric synthesis of anti-1,2-diols so far
reported.2-4,16,17 Hence, synthesis of 1,2-diols by means
of a direct aldol reaction is a new, efficient, and direct
approach, together with the already-established syn-
selective variants.1,3,4,17-19 The direct aldol reaction of
R-hydroxy esters instead of ketones, however, has not yet
been achieved and is currently being investigated, be-
cause that process would preclude the necessity of using
the Baeyer-Villiger oxidation step to obtain synthetically
versatile compounds.
2-Hydr oxy-2′-m eth oxyacetoph en on e (2b). Colorless solid;
mp 83 °C; IR (KBr) ν 3441, 1661 cm-1; 1H NMR (CDCl3) δ 8.05
(dd, J ) 7.8, 1.8 Hz, 1H), 7.55 (ddd, J ) 8.2, 7.1, 1.8 Hz, 1H),
7.06 (ddd, J ) 7.8, 7.1, 0.8 Hz, 1H), 7.00 (d, J ) 8.2 Hz, 1H),
4.76 (d, J ) 4.8 Hz, 2H), 3.94 (s, 3H), 3.74 (t, J ) 4.8 Hz, 1H);
13C NMR (CDCl3) δ 199.1, 160.2, 135.3, 131.0, 123.0, 120.9,
111.7, 70.0, 55.5; LRMS (EI) m/z 166 (M+), 135 (ArCtO+, base
peak). Anal. Calcd for C9H10O3: C, 65.05; H, 6.07. Found: C,
64.83; H, 6.05.
2-Hydr oxy-3′-m eth oxyacetoph en on e (2c). Colorless solid;
mp 50 °C; IR (KBr) ν 3501, 1681 cm-1 1H NMR (CDCl3) δ
;
7.47-7.45 (m, 2H), 7.40 (t, J ) 8.0 Hz, 1H), 7.16 (ddd, J )
8.0, 2.6, 0.9 Hz, 1H), 4.85 (d, J ) 4.6 Hz, 2H), 3.86 (s, 3H),
3.49 (t, J ) 4.6 Hz, 1H); 13C NMR (CDCl3) δ 198.3, 160.0, 134.7,
130.0, 120.7, 120.1, 112.1, 65.5, 55.5; LRMS (EI) m/z 166 (M+),
135 (ArCtO+, base peak). Anal. Calcd for C9H10O3: C, 65.05;
H, 6.07. Found: C, 64.91; H, 6.11.
2-Hyd r oxy-4′-m eth oxya cetop h en on e (2d ). Pale yellow
1
solid; mp 106-107 °C; IR (KBr) ν 3387, 1682 cm-1; H NMR
(CDCl3) δ 7.91-7.89 (m, 2H), 6.98-6.96 (m, 2H), 4.82 (s, 2H),
3.88 (s, 3H), 3.52 (brs, 1H); 13C NMR (CDCl3) δ 196.7, 164.4,
130.0, 126.4, 114.2, 65.0, 55.5; LRMS (EI) m/z 166 (M+), 135
(ArCtO+, base peak). Anal. Calcd for C9H10O3: C, 65.05; H,
6.07. Found: C, 64.90; H, 6.07.
Exp er im en ta l Section
2-Hyd r oxy-2′,5′-d im eth oxya cetop h en on e (2e). Pale yel-
In str u m en ts a n d Ma ter ia ls. NMR spectra were recorded
at 500 MHz for 1H NMR and 125.65 MHz for 13C NMR.
Chemical shifts in CDCl3 were reported downfield from TMS
low solid; mp 100-101 °C; IR (KBr) ν 3492, 1654 cm-1 1H
;
NMR (CDCl3) δ 7.56 (d, J ) 3.2 Hz, 1H), 7.12 (dd, J ) 8.9, 3.2
Hz, 1H), 6.94 (d, J ) 8.9 Hz, 1H), 4.76 (d, J ) 4.7 Hz, 2H),
3.90 (s, 3H), 3.81 (s, 3H), 3.71 (t, J ) 4.7 Hz, 1H); 13C NMR
(CDCl3) δ 198.9, 154.9, 153.7, 123.2, 122.6, 113.6, 70.0, 56.0;
LRMS (EI) m/z 196 (M+), 165 (ArCtO+, base peak). Anal.
Calcd for C10H12O4: C, 61.22; H, 6.16. Found: C, 60.99; H,
6.35.
1
() 0) or in the scale relative to CHCl3 (7.26 ppm) for H NMR.
Chemical shifts in C6D6 were reported in the scale relative to
C6H6 (7.15 ppm) for 1H NMR. For 13C NMR, chemical shifts
were reported in the scale relative to CHCl3 (77.0 ppm for 13C
NMR) or C6H6 (128.0 ppm for 13C NMR) as an internal
reference. Column chromatography was performed with silica
gel Merck 60 (230-400 mesh ASTM). The HPLC analysis was
performed using UV at 254 nm. Reactions were carried out in
dry solvents under an argon atmosphere, unless otherwise
stated. Tetrahydrofuran (THF) was distilled from sodium
2-Hyd r oxy-2′-m eth yla cetop h en on e (2f). Colorless solid;
mp 32-33 °C; IR (KBr) ν 3449, 1685 cm-1; 1H NMR (CDCl3) δ
7.62 (d, J ) 7.8 Hz, 1H), 7.45 (dt, J ) 7.5, 0.9 Hz, 1H), 7.32-
7.28 (m, 2H), 4.76 (d, J ) 4.6 Hz, 2H), 3.60 (t, J ) 4.6 Hz,
1H), 2.59 (s, 3H); 13C NMR (CDCl3) δ 200.9, 139.7, 133.0, 132.8,
132.4, 128.4, 126.0, 66.5, 21.6; LRMS (EI) m/z 150 (M+), 119
(ArCtO+, base peak). Anal. Calcd for C9H10O2: C, 71.98; H,
6.71. Found: C, 71.82; H, 6.83.
(27) Evans et al. reported a Mukaiyama-type aldol reaction cata-
lyzed by a copper complex, in which catalyst-substrate chelation
proved to be essential. See: Evans, D. A.; Kozlowski, M. C.; Murry, J .
A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J . J . Am.
Chem. Soc. 1999, 121, 669-685.
(28) Analogous arguments appeared in the literature describing the
diastereoselective aldol reactions of R-alkoxy esters. See: Heathcock,
C. H.; Pirrung, M. C.; Young, S. D.; Hagen, J . P.; J arvi, E. T.;
Badertscher, U.; Ma¨rki, H.-P.; Montgomery, S. H. J . Am. Chem. Soc.
1984, 106, 8161-8174. See also ref 5.
2-Hyd r oxy-4′-m eth yla cetop h eon e (2g). Pale yellow solid;
mp 83 °C; IR (KBr) ν 3434, 1682 cm-1 1H NMR (CDCl3) δ
;
7.83-7.81 (m, 2H), 7.31-7.29 (m, 2H), 4.85 (s, 2H), 3.51 (brs,
(29) Moriarty, R. M.; Berglund, B. A.; Penmasta, R. Tetrahedron
Lett. 1992, 33, 6065-6068.

2562 J . Org. Chem., Vol. 67, No. 8, 2002
Yoshikawa et al.
1H), 2.43 (s, 3H); 13C NMR (CDCl3) δ 197.9, 145.3, 130.9, 129.6,
127.8, 65.3, 21.8; LRMS (EI) m/z 150 (M+), 119 (ArCtO+, base
peak). Anal. Calcd for C9H10O2: C, 71.98; H, 6.71. Found: C,
71.82; H, 6.83.
Gen er a l P r oced u r e for Ca ta lytic Asym m etr ic Ald ol
Rea ction P r om oted by (S)-Heter op olym eta llic Com p lex
(GP 1). To a stirred solution of potassium bis(trimethylsilyl)-
amide (KHMDS) in toluene (0.027 mmol, 54 µL, 0.5 M) was
added a solution of H2O in THF (0.06 mmol, 60 µL, 1.0 M) at
0 °C. After stirring for 15 min a solution of LaLi3tris((S)-
binaphthoxide) ((S)-LLB) in THF (0.03 mmol, 300 µL, 0.1 M)
was added, and the stirring was continued at 0 °C for 30 min.
The resulting solution was cooled to temperature indicated in
Table 1 or 2, and a solution of 2 (0.6 mmol) in THF (2 mL for
2a ; 3 mL for 2b-g) and 1 (0.3 mmol) were added successively.
The stirring was continued until the reaction was quenched
by addition of 1 M HCl (2 mL). The mixture was extracted
with ethyl acetate (×3), and the combined organic layers were
washed with brine and dried over Na2SO4. Evaporation of
solvent gave a crude mixture of the aldol products. The
chemical yield and diastereomeric ratio of all aldol products
except for anti-3i were determined by measuring the 1H NMR
of the crude material after addition of 0.3 mmol of anisole,
1,3-dimethoxybenzene, or N,N-dimethylformamide as an in-
ternal standard, unless otherwise stated. The products except
for 3i were converted into the corresponding acetonides (4)
before isolation. Diols (anti- and syn-) 3i were isolated by flash
silica gel column chromatography.
Gen er a l P r oced u r e for th e Con ver sion of th e Ald ol
P r od u cts to th e Cor r esp on d in g Aceton id es. The crude
mixture of the aldol product obtained according to the general
procedure (GP1; starting aldehyde: 0.3 mmol) was treated
with p-toluenesulfonic acid monohydrate (10 mg) in N,N-
dimethylformamide/2,2-dimethoxypropane (1.5 mL/1.5 mL) at
room temperature for 2 h. Saturated aqueous solution of
NaHCO3 (2 mL), H2O and ether were added to the mixture,
and the aqueous layer was separated and extracted with ether
(×2). The combined organic layers were washed with H2O and
brine (×2) and then dried over Na2SO4. The solvent was
removed under reduced pressure, and the resulting residue
was purified by flash silica gel column chromatography to
afford the acetonides (4). The diastereomers were separated
at this stage. The enantiomeric excess of the acetonides (4a -
g) was determined by HPLC. Acetonides 4a -e were reported
in ref 17. HRMS data of 4a -e are provided below.
Rep r esen ta tive P r oced u r e for La r ge-Sca le P r ep a r a -
tion of 2-Hyd r oxya cetop h en on es. Several hydroxy ketones
were prepared in large scale. Because the above-mentioned
procedure requires a large amount of (bis(trifluoroacetoxy)-
iodo)benzene, we recommend the following procedure for a
large-scale preparation. To a stirred solution of diisopropyl-
amine (25.1 mL, 0.179 mol) in THF (358 mL), a hexane
solution of n-BuLi (101 mL, 0.158 mol, 1.56 M) was added over
10 min at 0 °C. The resulting solution was stirred for 30 min
at 0 °C, and a solution of 4′-methylacetophenone (20 g, 0.149
mol) in THF (14.9 mL) was then added over 10 min at -78
°C. After stirring for 1 h, chlorotrimethylsilane (32.2 mL, 0.253
mol) was added via syringe over 5 min at -78 °C. The cooling
bath was removed, and the reaction mixture was stirred at
room temperature for 1 h. The mixture was poured into a
stirred, ice-cooled mixture of saturated aqueous solution of
NaHCO3 (300 mL) and ether (300 mL), and the aqueous layer
was separated and extracted with ether (200 mL). The
combined organic layers were washed with saturated aqueous
solution of NaHCO3 (200 mL), H2O (200 mL), and brine (150
mL) and then dried over Na2SO4. The solvent was removed
under reduced pressure, and the residue was dissolved in CH2-
Cl2 (700 mL). Solid NaHCO3 (31.3 g, 0.373 mol) and m-CPBA
(0.179 mol, >65%, commercial reagent was used as served)
were added to the solution at -50 °C, and the resulting
suspension was stirred at -50 °C for 3.5 h and then diluted
with ethyl acetate (1.1 L). The mixture was washed with 10%
aqueous solution of Na2S2O3 (300 mL), saturated aqueous
solution of NaHCO3 (200 mL × 2), and brine and then dried
over Na2SO4. The solvent and other volatile materials were
removed under reduced pressure, and the resulting residue
was dissolved in MeOH (500 mL). After aqueous solution of
NH4F (200 mL, 1 M) was added, the resulting mixture was
stirred at room temperature for 15 min. Evaporation of MeOH
was followed by the addition of ethyl acetate (1 L), and the
mixture was washed with H2O (twice) and brine and then dried
over Na2SO4. After evaporation of the solvents, recrystalliza-
tion (from ether/hexane) of the crude material yielded analyti-
cally pure 2-hydroxy-4′-methylacetophenone (8.0 g) as pale
yellow crystals. The rest was recovered by concentration of the
filtrate followed by column chromatography to afford 3.6 g of
the desired hydroxy ketone (52% combined yield). Several
2-hydroxyacetophenones were prepared according to similar
procedures in yields around 50%. Yields are not optimized.
(2R,3R)-2,3-Dih ydr oxy-2,3-O-isopr opyliden e-1,6-diph en -
yl-1-h exa n on e (a n ti-4a fr om a n ti-3a ). HRMS (EI) calcd for
C
21H24O3 (M+) 324.1725, found 324.1708.
(2R,3S)-2,3-Dih ydr oxy-2,3-O-isopr opyliden e-1,6-diph en -
yl-1-h exa n on e (syn -4a fr om syn -3a ). HRMS (EI) calcd for
C
21H24O3 (M+) 324.1725, found 324.1724.
(2R,3R)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-p h en yl-
1-octa n on e (a n ti-4b fr om a n ti-3b). HRMS (EI) calcd for
P r epar ation of LaLi3tr is((S)-bin aph th oxide) ((S)-LLB).
A 200 mL flask equipped with a three-way tap was charged
with solid La(O-i-Pr)3 (4.61 g, 14.57 mmol) in a glovebox.
Addition of dry THF (72.8 mL) via syringe under argon
atmosphere gave a 0.2 M solution of La(O-i-Pr)3 (NOTE: we
recommend that the solution is prepared immediately before
use; otherwise it must be stored below -20 °C under argon
atmosphere. The decomposition of La(O-i-Pr)3 was sometimes
observed at higher temperatures in THF). A separate 100 mL
flask was charged with (S)-BINOL (6.78 g, 24 mmol), equipped
with a three-way tap and a magnetic stirrer, and heated at
45 °C under reduced pressure for 2 h. After the BINOL was
dissolved in dry THF (21 mL) under argon, the solution of La-
(O-i-Pr)3 (40.0 mL, 8 mmol) was added at 0 °C, and the
resulting pale yellow solution was stirred at room temperature
for 30 min. The solvent was removed under reduced pressure
at room temperature by using a vacuum pump, and the
resulting residue was further dried at the same temperature
under reduced pressure for 1 h. The residue was dissolved in
dry THF (65.7 mL), and a solution of n-BuLi in hexanes (14.3
mL, 24 mmol, 1.68 M) was added at 0 °C. Stirring for another
12 h at room temperature gave a pale yellow solution of (S)-
LLB (0.1 M), which can be stored at room temperature under
argon atmosphere for at least 6 months without loss of activity.
The flask containing the LLB was also shielded from light
during storage.
C
16H21O3 (M+ - CH3) 261.1491, found 261.1489.
(2R,3S)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-p h en yl-
1-octa n on e (syn -4b fr om syn -3b). HRMS (EI) calcd for
C
16H21O3 (M+ - CH3) 261.1491, found 261.1490.
(2R,3R,6E)-2,3-Dih ydr oxy-2,3-O-isopr opyliden e-1-ph en -
yl-6-d od ecen -1-on e (a n ti-4c fr om a n ti-3c). HRMS (EI)
calcd for C21H30O3 (M+) 330.2195, found 330.2196.
(2R,3S,6E)-2,3-Dih ydr oxy-2,3-O-isopr opyliden e-1-ph en -
yl-6-d od ecen -1-on e (syn -4c fr om syn -3c). HRMS (EI) calcd
for C21H30O3 (M+) 330.2195, found 330.2194.
(2R,3R)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-5-m eth yl-
1-p h en yl-1-h exa n on e (a n ti-4d fr om a n ti-3d ). HRMS (EI)
calcd for C16H22O3 (M+) 262.1569, found 262.1575.
(2R,3S)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-5-m eth yl-
1-p h en yl-1-h exa n on e (syn -4d fr om syn -3d ). HRMS (EI)
calcd for C16H22O3 (M+) 262.1569, found 262.1568.
(2R,3R)-2,3-Dih ydr oxy-2,3-O-isopr opyliden e-1,5-diph en -
yl-1-p en ta n on e (a n ti-4e fr om a n ti-3e). HRMS (EI) calcd
for C20H22O3 (M+) 310.1569, found 310.1583.
(2R,3S)-2,3-Dih ydr oxy-2,3-O-isopr opyliden e-1,5-diph en -
yl-1-p en ta n on e (syn -4e fr om syn -3e). HRMS (EI) calcd for
C
20H22O3 (M+) 310.1569, found 310.1579.
(2R,3R)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(2-m eth -
oxyp h en yl)-6-p h en yl-1-h exa n on e (a n ti-4f fr om a n ti-3f).
95% ee; colorless oil; IR (neat) ν 1682, 1089 cm-1; [R]D26 +60.2

Asymmetric Synthesis of anti-1,2-Diols
J . Org. Chem., Vol. 67, No. 8, 2002 2563
1
(c 0.88, CHCl3); H NMR (CDCl3) δ 7.80 (dd, J ) 7.5, 1.9 Hz,
panol 9/1 (v/v), flow: 0.5 mL/min, tR 23.4 min (minor) and 25.5
min (major).
1H), 7.50 (ddd, J ) 8.1, 7.3, 1.9 Hz, 1H), 7.21-7.18 (m, 2H),
7.14-7.11 (m, 1H), 7.05-7.03 (m, 3H), 6.93 (d, J ) 8.1 Hz,
1H), 5.57 (d, J ) 6.9 Hz, 1H), 4.48 (ddd, J ) 9.9, 6.9, 3.1 Hz,
1H), 3.82 (s, 3H), 2.53 (ddd, J ) 13.5, 8.5, 6.4 Hz, 1H), 2.47
(ddd, J ) 13.5, 8.4, 6.5 Hz, 1H), 1.87-1.78 (m, 1H), 1.62 (s,
3H), 1.59-1.50 (m, 1H), 1.46-1.38 (m, 1H), 1.42 (s, 3H), 1.34-
1.27 (m, 1H); 13C NMR (CDCl3) δ 197.2, 158.3, 142.0, 134.2,
131.0, 128.1, 126.6, 125.6, 121.1, 111.6, 109.4, 82.6, 77.8, 55.4,
35.3, 30.6, 28.1, 27.2, 25.6; LRMS (EI) m/z 354 (M+), 91 (Bn+,
base peak); HRMS (EI) calcd for C22H26O4 (M+) 354.1831, found
354.1831; HPLC, column: DAICEL CHIRALPAK AS, eluent:
hexane/2-propanol 9/1 (v/v), flow: 1.0 mL/min, tR 5.4 min
(minor) and 17.8 min (major).
(2R,3S)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(4-m eth -
oxyp h en yl)-6-p h en yl-1-h exa n on e (syn -4h fr om syn -3h ).
79% ee; colorless oil; IR (neat) ν 1678, 1260 cm-1; [R]D26 -26.9
(c 0.49, CHCl3); 1H NMR (CDCl3) δ 8.06-8.04 (m, 2H), 7.27-
7.24 (m, 3H), 7.18-7.15 (m, 3H), 6.95-6.93 (m, 2H), 4.67 (d,
J ) 7.2 Hz, 1H), 4.49-4.45 (m, 1H), 3.88 (s, 3H), 2.70-2.64
(m, 2H), 1.86-1.80 (m, 1H), 1.76-1.70 (m, 2H), 1.65-1.55 (m,
1H), 1.49 (s, 3H), 1.36 (s, 3H); 13C NMR (CDCl3) δ 195.6, 163.9,
142.1, 131.7, 128.7, 128.4, 128.3, 125.7, 113.8, 110.2, 81.9, 77.7,
55.5, 35.7, 33.0, 27.5, 26.1; LRMS (EI) m/z 354 (M+), 339 (M+
- CH3); HRMS (EI) calcd for C22H26O4 (M+) 354.1831, found
354.1834; HPLC, column: DAICEL CHIRALPAK AS, eluent:
hexane/2-propanol 9/1 (v/v), flow: 0.5 mL/min, tR 10.7 min
(minor) and 14.4 min (major).
(2R,3R,6E)-2,3-Dih ydr oxy-1-(4-m eth oxyph en yl)-6-dode-
cen -1-on e (a n ti-3i). This diol was isolated from the crude
mixture of the aldol reaction by flash silica gel column
chromatography. The enantiomeric excess was determined to
be 93% by HPLC. Colorless solid; mp 75-77 °C; IR (KBr) 3426,
3302, 1679, 1605 cm-1; [R]D26 +18.0 (c 0.6, CHCl3); 1H NMR
(CDCl3) δ 7.95-7.93 (m, 2H), 6.98-6.96 (m, 2H), 5.27 (dt, J )
14.5, 6.2 Hz, 1H), 5.19 (dt, J ) 14.5, 6.1 Hz, 1H), 5.16 (t, J )
3.3 Hz, 1H), 3.95-3.90 (m, 2H), 3.88 (s, 3H), 2.41 (br-s, 1H),
2.12-2.06 (m, 1H), 1.96-1.88 (m, 1H), 1.86-1.81 (m, 2H),
1.49-1.42 (m, 1H), 1.28-1.11 (m, 7H), 0.85 (t, J ) 7.1 Hz, 3H);
13C NMR (CDCl3) δ 198.0, 164.7, 131.6, 131.3, 129.1, 127.1,
114.4, 77.5, 73.2, 55.8, 32.6, 31.6, 30.9, 29.3, 28.6, 22.7, 14.2;
LRMS (EI) m/z 320 (M+), 135 (ArCtO+, base peak); HRMS
(EI) calcd for C19H28O4 (M+) 320.1988, found 320.1981; HPLC,
column: DAICEL CHIRALPAK AD, eluent: hexane/2-pro-
panol 9/1 (v/v), flow: 1.0 mL/min, tR 12.0 min (minor) and 13.7
min (major).
(2R,3S,6E)-2,3-Dih yd r oxy-1-(4-m eth oxyp h en yl)-6-d od e-
cen -1-on e (syn -3i). This diol was isolated from the crude
mixture of the aldol reaction by flash silica gel column
chromatography. Colorless solid; mp 55-56 °C; IR (KBr) 3409,
1677, 1599, 1258 cm-1; [R]D26 -8.9 (c 0.9, CHCl3); 1H NMR
(CDCl3) δ 7.89-7.87 (m, 2H), 6.97-6.95 (m, 2H), 5.50 (dt, J )
14.8, 6.2 Hz, 1H), 5.43 (dt, J ) 14.8, 6.2 Hz, 1H), 4.94 (br-s,
1H), 4.00 (d, J ) 4.2 Hz, 1H), 3.96-3.93 (m, 1H), 3.88 (s, 3H),
2.25-2.12 (m, 2H), 2.03-1.86 (m, 1H), 1.98 (q, J ) 6.8 Hz,
2H), 1.78 (q, J ) 7.0 Hz, 2H), 1.36-1.22 (m, 6H), 0.87 (t, J )
6.8 Hz, 3H); 13C NMR (CDCl3) δ 198.3, 164.2, 131.6, 131.0,
129.1, 126.4, 114.1, 74.8, 72.6, 55.5, 34.4, 32.5, 31.4, 29.2, 28.8,
22.5, 14.0; LRMS (EI) m/z 320 (M+), 135 (ArCtO+, base peak);
HRMS (EI) calcd for C19H28O4 (M+) 320.1988, found 320.1979.
The enantiomeric excess was determined to be 91% by HPLC
after conversion to the corresponding acetonide; HPLC, col-
umn: DAICEL CHIRALPAK AD, eluent: hexane/2-propanol
98/2 (v/v), flow: 0.3 mL/min, tR 21.8 min (major) and 24.5 min
(minor).
(2R,3R)-1-(2,5-Dim eth oxyp h en yl)-2,3-d ih yd r oxy-2,3-O-
isop r op ylid en e-6-p h en yl-1-h exa n on e (a n ti-4j fr om a n ti-
3j). 80% ee; colorless oil; IR (neat) ν 1683 cm-1; [R]D26 +33.6 (c
1.5, CHCl3); 1H NMR (CDCl3) δ 7.37 (d, J ) 3.1 Hz, 1H), 7.21-
7.18 (m, 2H), 7.14-7.11 (m, 1H), 7.07 (dd, J ) 8.9, 3.1 Hz,
1H), 7.05-7.03 (m, 3H), 6.87 (d, J ) 8.9 Hz, 1H), 5.60 (d, J )
7.0 Hz, 1H), 4.48 (ddd, J ) 9.9, 7.0, 3.2 Hz, 1H), 3.80 (s, 3H),
3.78 (s, 3H), 2.53 (ddd, J ) 13.5, 8.3, 6.4 Hz, 1H), 2.48 (ddd, J
) 13.5, 8.4, 6.6 Hz, 1H), 1.87-1.78 (m, 1H), 1.62 (s, 3H), 1.60-
1.50 (m, 1H), 1.43-1.27 (m, 2H), 1.42 (s, 3H); 13C NMR (CDCl3)
δ 196.8, 153.7, 153.0, 142.0, 128.3, 128.1, 126.7, 125.6, 121.3,
114.0, 113.2, 109.4, 82.6, 77.9, 55.9, 55.8, 35.4, 30.6, 28.2, 27.6,
25.6; LRMS (EI) m/z 384 (M+), 165 (ArCtO+, base peak);
HRMS (EI) calcd for C23H28O5 (M+) 384.1937, found 384.1918;
HPLC, column: DAICEL CHIRALCEL OD, eluent: hexane/
2-propanol 9/1 (v/v), flow: 1.0 mL/min, tR 9.5 min (minor) and
26.1 min (major).
(2R,3S)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(2-m eth -
oxyp h en yl)-6-p h en yl-1-h exa n on e (syn -4f fr om syn -3f).
74% ee; colorless oil; IR (neat) ν 1686, 1246 cm-1; [R]D26 -15.3
1
(c 0.90, CHCl3); H NMR (CDCl3) δ 7.51 (dd, J ) 7.4, 1.8 Hz,
1H), 7.45 (ddd, J ) 8.3, 7.3, 1.8 Hz, 1H), 7.27-7.24 (m, 2H),
7.19-7.12 (m, 3H), 7.00 (ddd, J ) 7.4, 7.3, 0.8 Hz, 1H), 6.92
(d, J ) 8.3 Hz, 1H), 4.91 (d, J ) 6.7 Hz, 1H), 4.26-4.22 (m,
1H), 3.80 (s, 3H), 2.64-2.60 (m, 2H), 1.86-1.76 (m, 1H), 1.73-
1.61 (m, 3H), 1.45 (s, 3H), 1.33 (s, 3H); 13C NMR (CDCl3) δ
201.6, 157.9, 142.0, 133.4, 130.1, 128.4, 128.2, 127.5, 125.7,
120.8, 111.5, 110.2, 84.7, 78.3, 55.5, 35.6, 33.3, 27.5, 27.2, 26.1;
LRMS (EI) m/z 354 (M+), 339 (M+ - CH3), 296 (base peak), 91
(Bn+); HRMS (EI) calcd for C22H26O4 (M+) 354.1831, found
354.1830; HPLC, column: DAICEL CHIRALCEL OD, elu-
ent: hexane/2-propanol 9/1 (v/v), flow: 1.0 mL/min, tR 7.6 min
(minor) and 10.4 min (major).
(2R,3R)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(3-m eth -
oxyp h en yl)-6-p h en yl-1-h exa n on e (a n ti-4g fr om a n ti-3g).
95% ee; colorless solid; mp 62-64 °C; IR (KBr) ν 1695 cm-1
;
[R]2D6 +30.8 (c 1.4, CHCl3); H NMR (CDCl3) δ 7.46-7.45 (m,
2H), 7.39-7.35 (m, 1H), 7.21-7.17 (m, 2H), 7.15-7.11 (m, 2H),
7.03-7.01 (m, 2H), 5.47 (d, J ) 7.0 Hz, 1H), 4.53 (ddd, J )
10.2, 6.9, 3.1 Hz, 1H), 3.84 (s, 3H), 2.48 (t, J ) 7.6 Hz, 2H),
1.84-1.74 (m, 1H), 1.64 (s, 3H), 1.60-1.51 (m, 1H), 1.46-1.34
(m, 1H), 1.44 (s, 3H), 1.27-1.19 (m, 1H); 13C NMR (CDCl3) δ
195.7, 159.9, 141.8, 137.4, 129.7, 128.2, 128.1, 125.6, 120.7,
119.9, 112.5, 109.8, 80.0, 77.9, 55.4, 35.3, 30.4, 27.8, 27.3, 25.6;
LRMS (EI) m/z 354 (M+), 91 (Bn+, base peak); HRMS (EI) calcd
for C22H26O4 (M+) 354.1831, found 354.1829; HPLC, column:
DAICEL CHIRALPAK AS, eluent: hexane/2-propanol 9/1 (v/
v), flow: 1.0 mL/min, tR 6.6 min (minor) and 16.7 min (major).
1
(2R,3S)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(3-m eth -
oxyp h en yl)-6-p h en yl-1-h exa n on e (syn -4g fr om syn -3g).
83% ee; colorless oil; IR (neat) ν 1686, 1256 cm-1; [R]D26 -30.2
(c 0.81, CHCl3); 1H NMR (CDCl3) δ 7.64-7.62 (m, 1H), 7.56-
7.54 (m, 1H), 7.39-7.36 (m, 1H), 7.27-7.24 (m, 2H), 7.18-
7.12 (m, 4H), 4.71 (d, J ) 7.1 Hz, 1H), 4.48-4.44 (m, 1H), 3.86
(s, 3H), 2.67-2.64 (m, 2H), 1.87-1.79 (m, 1H), 1.76-1.67 (m,
3H), 1.50 (s, 3H), 1.37 (s, 3H); 13C NMR (CDCl3) δ 197.1, 159.7,
142.0, 136.9, 129.5, 128.4, 128.3, 125.7, 122.0, 113.3, 110.4,
82.0, 77.7, 55.4, 35.7, 33.0, 27.5, 27.3, 26.1; LRMS (EI) m/z
354 (M+, base paek), 339 (M+ - CH3); HRMS (EI) calcd for
C
22H26O4 (M+) 354.1831, found 354.1831; HPLC, column:
DAICEL CHIRALCEL OD, eluent: hexane/2-propanol 9/1 (v/
v), flow: 0.5 mL/min, tR 10.8 min (major) and 12.0 min (minor).
(2R,3R)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(4-m eth -
oxyp h en yl)-6-p h en yl-1-h exa n on e (a n ti-4h fr om a n ti-3h ).
98% ee; colorless solid; mp 58 °C; IR (neat) ν 1686 cm-1; [R
27
D
]
+42.7 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.93-7.90 (m,
2H), 7.21-7.17 (m, 2H), 7.14-7.10 (m, 1H), 7.04-7.02 (m, 2H),
6.95-6.93 (m, 2H), 5.44 (d, J ) 7.0 Hz, 1H), 4.52 (ddd, J )
10.2, 7.0, 3.1 Hz, 1H), 3.89 (s, 3H), 2.48 (t, J ) 7.6 Hz, 2H),
1.83-1.74 (m, 1H), 1.64 (s, 3H), 1.59-1.50 (m, 1H), 1.45-1.37
(m, 1H), 1.44 (s, 3H), 1.26-1.20 (m, 1H); 13C NMR (CDCl3) δ
194.1, 163.7, 141.9, 130.6, 129.1, 128.2, 128.1, 125.6, 113.9,
109.7, 79.9, 77.9, 55.5, 35.3, 30.5, 27.8, 27.4, 25.5; LRMS (EI)
m/z 354 (M+), 339 (M+ - CH3), 296 (base paek); HRMS (EI)
calcd for C22H26O4 (M+) 354.1831, found 354.1846; HPLC,
column: DAICEL CHIRALCEL OD, eluent: hexane/2-pro-
(2R,3S)-1-(2,5-Dim eth oxyp h en yl)-2,3-Dih yd r oxy-2,3-O-
isop r op ylid en e-6-p h en yl-1-h exa n on e (syn -4j fr om syn -3j).
41% ee; colorless oil; IR (neat) ν 1685, 1226 cm-1; [R]D26 -10.2
(c 0.82, CHCl3); 1H NMR (CDCl3) δ 7.27-7.24 (m, 2H), 7.18-

2564 J . Org. Chem., Vol. 67, No. 8, 2002
Yoshikawa et al.
7.12 (m, 3H), 7.08 (d, J ) 2.9 Hz, 1H), 7.01 (dd, J ) 8.9, 2.9
Hz, 1H), 6.86 (d, J ) 8.9 Hz, 1H), 4.96 (d, J ) 6.5 Hz, 1H),
4.25-4.21 (m, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 2.64-2.61 (m,
2H), 1.85-1.76 (m, 1H), 1.71-1.63 (m, 3H), 1.46 (s, 3H), 1.36
(s, 3H); 13C NMR (CDCl3) δ 201.1, 153.6, 152.4, 142.1, 128.4,
127.7, 125.7, 119.8, 114.2, 113.1, 110.3, 84.7, 78.4, 56.1, 55.8,
35.6, 33.3, 27.5, 27.2, 26.2; LRMS (EI) m/z 384 (M+), 165 (ArCt
O+, base peak); HRMS (EI) calcd for C23H28O5 (M+) 384.1937,
found 384.1932; HPLC, column: DAICEL CHIRALCEL OD,
eluent: hexane/2-propanol 9/1 (v/v), flow: 1.0 mL/min, tR 8.1
min (minor) and 9.7 min (major).
Hz, 1H), 2.40 (s, 3H), 1.63 (s, 3H), 1.46-1.32 (m, 2H), 1.43 (s,
3H), 1.25-1.09 (m, 6H), 0.78 (t, J ) 7.1 Hz, 3H); 13C NMR
(CDCl3) δ 195.4, 144.3, 133.6, 129.4, 128.3, 109.6, 80.0, 78.1,
31.4, 30.9, 27.4, 25.8, 25.5, 22.4, 21.6, 13.8; LRMS (EI) m/z
290 (M+), 275 (M+ - CH3), 171 (M+ - ArCdO, base peak),
119 (ArCtO+); HRMS (EI) calcd for C17H23O3 (M+ - CH3)
275.1647, found 275.1648; HPLC, column: DAICEL CHIRAL-
CEL OD, eluent: hexane/2-propanol 98/2 (v/v), flow: 1.0 mL/
min, tR 6.1 min (minor) and 8.8 min (major).
(2R,3S)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(4-m eth -
ylp h en yl)-1-octa n on e (syn -4m fr om syn -3m ). 89% ee; color-
less oil; IR (neat) ν 2932, 1685, 1607 cm-1; [R]D24 -34.6 (c 0.55,
CHCl3); 1H NMR (CDCl3) δ 7.96-7.95 (m, 2H), 7.28-7.26 (m,
2H), 4.72 (d, J ) 7.0 Hz, 1H), 4.45-4.41 (m, 1H), 2.42 (s, 3H),
1.70-1.62 (m, 2H), 1.52-1.46 (m, 1H), 1.50 (s, 3H), 1.38-1.25
(m, 5H), 1.37 (s, 3H), 0.89-0.86 (m, 3H); 13C NMR (CDCl3) δ
197.0, 144.6, 133.3, 129.4, 129.2, 110.2, 82.0, 78.0, 33.6, 31.8,
27.3, 26.1, 25.5, 22.5, 21.7, 14.0; LRMS (EI) m/z 290 (M+), 275
(M+ - CH3), 171 (M+ - ArCdO), 119 (ArCtO+, base peak);
HRMS (EI) calcd for C18H27O3 (M+ + H) 291.1960, found
291.1963; HPLC, column: DAICEL CHIRALPAK AS, eluent:
hexane/2-propanol 199/1 (v/v), flow: 0.3 mL/min, tR 16.4 min
(minor) and 20.0 min (major).
(2R,3R)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(2-m eth -
ylp h en yl)-6-p h en yl-1-h exa n on e (a n ti-4k fr om a n ti-3k ).
84% ee; colorless oil; IR (neat) ν 1697 cm-1; [R]D22 +29.6 (c 2.3,
CHCl3); 1H NMR (CDCl3) δ 7.59-7.57 (m, 1H), 7.42-7.38 (m,
1H), 7.28-7.20 (m, 4H), 7.16-7.13 (m, 1H), 7.06-7.04 (m, 2H),
5.31 (d, J ) 6.9 Hz, 1H), 4.44 (ddd, J ) 9.9, 6.9, 3.2 Hz, 1H),
2.53 (t, J ) 7.3 Hz, 2H), 2.47 (s, 3H), 1.87-1.78 (m, 1H), 1.59-
1.40 (m, 2H), 1.56 (s, 3H), 1.42 (s, 3H), 1.34-1.27 (m, 1H); 13
C
NMR (CDCl3) δ 200.3, 141.8, 138.8, 136.4, 132.1, 131.6, 128.4,
128.3, 128.2, 125.7, 125.5, 109.8, 81.0, 78.2, 35.4, 30.2, 28.8,
27.1, 25.5, 21.0; LRMS (EI) m/z 338 (M+), 323 (M+ - CH3), 91
(Bn+, base peak); HRMS (EI) calcd for C22H26O3 (M+) 338.1882,
found 338.1869; HPLC, column: DAICEL CHIRALCEL OD,
eluent: hexane/2-propanol 9/1 (v/v), flow: 1.0 mL/min, tR 7.2
min (major) and 8.3 min (minor).
(4S ,5R )-4-Be n zoyl-2,2-d im e t h yl-5-p e n t yl-1,3-d ioxo-
la n e (6). To a solution of acetonide 4b (13.2 mg, 0.048 mmol)
in 1,2-dichloroethane (0.5 mL) were added anhydrous NaH2-
PO4 (14.3 mg, 0.119 mmol) and m-CPBA (16.5 mg, 0.096
mmol). The mixture was stirred at room temperature for 4 h
and poured into a mixture of ether and H2O. The organic phase
was separated, washed with an aqueous solution of Na2S2O3,
saturated aqueous solution of NaHCO3, H2O and brine, and
dried over Na2SO4. After evaporation of solvent, the resulting
residue was purified by flash silica gel column chromatography
to afford ester 6 (12.7 mg, 91% yield) as a colorless oil; 94%
ee; IR (neat) ν 1728 cm-1; [R]D27 -74.8 (c 0.49, CH2Cl2); 1H
NMR (C6D6) δ 8.18-8.16 (m, 2H), 7.09-7.05 (m, 1H), 7.02-
6.99 (m, 2H), 6.62 (d, J ) 3.1 Hz, 1H), 3.90 (ddd, J ) 8.0, 5.1,
3.1 Hz, 1H), 1.85-1.78 (m, 1H), 1.61-1.54 (m, 1H), 1.53 (s,
3H), 1.45-1.35 (m, 1H), 1.30 (s, 3H), 1.26-1.09 (m, 5H), 0.78
(t, J ) 6.9 Hz, 3H); 13C NMR (C6D6) δ 165.5, 133.1, 130.8,
129.9, 128.7, 111.0, 95.4, 80.2, 32.0, 29.0, 28.7, 26.1, 25.9, 22.8,
14.1; LRMS (EI) m/z 277 (M+ - CH3), 171 (M+ - C6H5CO),
(2R,3S)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(2-m eth -
ylp h en yl)-6-p h en yl-1-h exa n on e (syn -4k fr om syn -3k ). 57%
ee; colorless oil; IR (neat) ν 1686 cm-1; [R]D23 -16.7 (c 0.29,
CHCl3); 1H NMR (CDCl3) δ 7.66-7.64 (m, 1H), 7.40-7.37 (m,
1H), 7.27-7.24 (m, 4H), 7.19-7.13 (m, 3H), 4.65 (d, J ) 7.2
Hz, 1H), 4.33-4.29 (m, 1H), 2.65-2.61 (m, 2H), 2.45 (s, 3H),
1.86-1.76 (m, 1H), 1.72-1.65 (m, 3H), 1.46 (s, 3H), 1.30 (s,
3H); 13C NMR (CDCl3) δ 202.0, 142.0, 138.3, 136.4, 131.7,
131.5, 129.3, 128.4, 128.3, 125.8, 125.4, 110.4, 83.5, 78.1, 35.6,
33.2, 27.4, 27.2, 26.0, 20.8; LRMS (EI) m/z 338 (M+), 323 (M+
- CH3), 91 (Bn+, base peak); HRMS (EI) calcd for C22H26O3
(M+) 338.1882, found 338.1880; HPLC, column: DAICEL
CHIRALPAK AS, eluent: hexane/2-propanol 9/1 (v/v), flow:
1.0 mL/min, tR 7.6 min (minor) and 9.4 min (major).
(2R,3R)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(4-m eth -
ylp h en yl)-6-p h en yl-1-h exa n on e (a n ti-4l fr om a n ti-3l).
97% ee; colorless solid; mp 63-65 °C; IR (KBr) ν 1691, 1088
cm-1; [R]2D4 +48.6 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.83-7.81
(m, 2H), 7.28-7.26 (m, 2H), 7.21-7.17 (m, 2H), 7.14-7.11 (m,
1H), 7.03-7.01 (m, 2H), 5.47 (d, J ) 6.9 Hz, 1H), 4.53 (ddd, J
) 10.1, 6.9, 3.1 Hz, 1H), 2.48 (t, J ) 7.5 Hz, 2H), 2.43 (s, 3H),
1.83-1.73 (m, 1H), 1.64 (s, 3H), 1.59-1.50 (m, 1H), 1.45-1.37
(m, 1H), 1.44 (s, 3H), 1.26-1.19 (m, 1H); 13C NMR (CDCl3) δ
195.3, 144.3, 141.9, 133.6, 129.4, 128.3, 128.2, 128.1, 125.6,
109.7, 79.9, 77.8, 35.3, 30.5, 27.8, 27.3, 25.5, 21.6; LRMS (EI)
m/z 338 (M+), 91 (Bn+, base peak); HRMS (EI) calcd for
105 (ArCO+, base peak); HRMS (EI) calcd for C16H21O4 (M+
CH3) 277.1440, found 277.1439.
-
(2R,3R)-2,3-Ca r bon yld ioxy-1-p h en yl-1-octa n on e (5b).
Colorless solid; IR (KBr) ν 1793, 1685 cm-1; 1H NMR (CDCl3)
δ 7.91 (d, J ) 7.2 Hz, 2H), 7.68 (t, J ) 7.1 Hz, 1H), 7.54 (dd,
J ) 7.2, 7.1 Hz, 2H), 6.02 (d, J ) 7.7 Hz, 1H), 5.03 (ddd, J )
10.2, 7.7, 2.6 Hz, 1H), 1.54-1.42 (m, 2H), 1.35-1.23 (m, 2H),
1.21-1.10 (m, 4H), 0.79 (t, J ) 6.5 Hz, 3H); 13C NMR (CDCl3)
δ 191.6, 153.8, 134.8, 134.6, 129.4, 128.2, 79.1, 77.9, 30.9, 30.3,
25.2, 22.2, 13.7; LRMS (EI) m/z 262 (M+), 105 (PhCO+, base
peak); HRMS (EI) calcd for C15H18O4 (M+) 262.1205, found
262.1210.
C
22H26O3 (M+) 338.1882, found 338.1878; HPLC, column:
DAICEL CHIRALCEL OD, eluent: hexane/2-propanol 9/1 (v/
v), flow: 1.0 mL/min, tR 6.2 min (minor) and 8.0 min (major).
(2R,3S)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(4-m eth -
ylp h en yl)-6-p h en yl-1-h exa n on e (syn -4l fr om syn -3l). 85%
ee; colorless oil; IR (neat) ν 1684 cm-1; [R]D26 -31.5 (c 0.56,
CHCl3); 1H NMR (CDCl3) δ 7.95-7.93 (m, 2H), 7.27-7.24 (m,
4H), 7.18-7.15 (m, 3H), 4.70 (d, J ) 7.0 Hz, 1H), 4.48-4.44
(m, 1H), 2.67-2.63 (m, 2H), 2.42 (s, 3H), 1.89-1.79 (m, 1H),
1.76-1.67 (m, 3H), 1.49 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3)
δ 196.9, 144.5, 142.0, 133.2, 129.4, 129.2, 128.4, 128.3, 125.7,
110.3, 82.0, 77.7, 35.7, 33.0, 27.5, 27.3, 26.1, 21.7; LRMS (EI)
m/z 338 (M+), 323 (M+ - CH3), 91 (Bn+, base peak); HRMS
(EI) calcd for C22H26O3 (M+) 338.1882, found 338.1879; HPLC,
column: DAICEL CHIRALPAK AS, eluent: hexane/2-pro-
panol 98/2 (v/v), flow: 1.0 mL/min, tR 5.4 min (minor) and 7.6
min (major).
(2R,3R)-2,3-Car bon yldioxy-1-(4-m eth oxyph en yl)-6-ph en -
yl-1-h exa n on e (5h ). The crude mixture of aldol products (3h ),
which was obtained according to GP1, was dissolved in 0.9
mL of dry CH2Cl2, and the solution was cooled to -20 °C.
Pyridine (97 µL, 1.2 mmol) and a solution of triphosgene (356
mg, 1.2 mmol) in CH2Cl2 (1.2 mL) were added, and the
resulting mixture was stirred at the same temperature for 2
h. The reaction mixture was poured into a mixture of saturated
aqueous NaHCO3 solution and ether, and the organic phase
was washed with 1 M HCl and with brine and dried over Na2-
SO4. The solvent was evaporated, and the residue was purified
by flash silica gel column chromatography (hexane/ethyl
acetate 8/1 f 4/1) to afford 65 mg of carbonate 5h (86% yield
from the diol) as a colorless solid. The yield is not optimized;
mp 101-103 °C; IR (KBr) ν 1805, 1685 cm-1; [R]D27 +36.9 (c
1.6, CHCl3); 1H NMR (CDCl3) δ 7.86-7.84 (m, 2H), 7.22-7.18
(m, 2H), 7.16-7.12 (m, 1H), 7.01-6.97 (m, 4H), 5.93 (d, J )
8.1 Hz, 1H), 4.98 (ddd, J ) 10.0, 8.1, 3.0 Hz, 1H), 2.52 (ddd, J
) 13.2, 8.3, 6.3 Hz, 1H), 2.47 (ddd, J ) 13.2, 8.4, 6.3 Hz, 1H),
(2R,3R)-2,3-Dih yd r oxy-2,3-O-isop r op ylid en e-1-(4-m eth -
ylp h en yl)-1-octa n on e (a n ti-4m fr om a n ti-3m ). 96% ee;
colorless oil; IR (neat) ν 2934, 1694, 1607 cm-1; [R]D24 +56.3 (c
2.6, CHCl3); 1H NMR (CDCl3) δ 7.84-7.82 (m, 2H), 7.27-7.25
(m, 2H), 5.45 (d, J ) 6.9 Hz, 1H), 4.51 (ddd, J ) 10.2, 6.9, 3.1
1.88-1.77 (m, 1H), 1.63-1.50 (m, 2H), 1.40-1.34 (m, 1H); 13
C

Asymmetric Synthesis of anti-1,2-Diols
J . Org. Chem., Vol. 67, No. 8, 2002 2565
NMR (CDCl3) δ 189.6, 164.8, 153.9, 141.0, 130.6, 128.3, 128.2,
127.5, 125.9, 114.6, 78.9, 77.6, 55.7, 34.9, 29.8, 27.2; LRMS
(EI) m/z 340 (M+), 135 (ArCtO+, base peak); HRMS (EI) calcd
for C20H20O5 (M+) 340.1311, found 340.1311.
The resulting mixture was stirred vigorously at 40 °C for 2.5
h. After cooling to room temperature, ethyl acetate and H2O
were added, and the organic layer was washed with saturated
aqueous Na2S2O3 solution. The combined aqueous layers were
extracted with ethyl acetate (twice) and washed with saturated
aqueous NaHCO3 solution, 1 M HCl, H2O, and brine. After
the organic layers were dried over Na2SO4, the solvent was
removed under reduced pressure, and the resulting residue
was purified by flash silica gel column chromatography (hex-
ane/ethyl acetate 3/1) to afford ester 9 (20 mg, 85%) as a
colorless solid. 97% ee; mp 104-105 °C; IR (KBr) ν 1825, 1780
cm-1; [R]D29 -18.6 (c 0.64, CHCl3); 1H NMR (CDCl3) δ 7.32-
7.28 (m, 2H), 7.24-7.15 (m, 5H), 6.86-6.84 (m, 2H), 5.23 (d,
J ) 8.1 Hz, 1H), 4.95-4.91 (m, 1H), 2.76-2.66 (m, 2H), 2.37
(2R,3R,6E)-2,3-Ca r bon yld ioxy-1-(4-m eth oxyp h en yl)-6-
d od ecen -1-on e (5i). To a stirred solution of diol anti-3i (34
mg, 0.106 mmol) in CH2Cl2 (0.3 mL), were added pyridine (21.5
µL, 0.265 µL) and a solution of triphosgene (79 mg, 0.265
mmol) in CH2Cl2 (0.5 mL) at -20 °C. After stirring at the same
temperature for 2 h, the reaction mixture was quenched by
addition of saturated aqueous solution of NaHCO3 and diluted
with ethyl acetate. The aqueous layer was separated and
extracted with ethyl acetate (×2), and the combined organic
layers were washed with 1 M HCl and brine and then dried
over Na2SO4. The solvent was evaporated under reduced
pressure, and the resulting residue was purified by flash silica
gel column chromatography (hexane/ethyl acetate 4/1) to afford
carbonate 5i (33 mg, y. 90%) as a colorless oil; IR (neat) ν 1807,
(s, 3H), 2.05-1.95 (m, 1H), 1.87-1.75 (m, 3H);
13C NMR
(CDCl3) δ 164.8, 153.2, 147.2, 140.7, 136.6, 130.2, 130.2, 128.6,
126.2, 120.5, 78.5, 75.9, 35.1, 29.5, 27.0, 20.9; LRMS (EI) m/z
340 (M+), 108 (HO+C6H4OCH3); HRMS (EI) calcd for C20H20O5
(M+) 340.1311, found 340.1323.
28
1
1601, 1174 cm-1; [R]D +13.5 (c 1.5, CHCl3); H NMR (CDCl3)
δ 7.90-7.88 (m, 2H), 7.01-6.99 (m, 2H), 5.95 (d, J ) 8.1 Hz,
1H), 5.40-5.34 (m, 1H), 5.21-5.15 (m, 1H), 5.01 (ddd, J ) 10.8,
8.1, 2.8 Hz, 1H), 3.90 (s, 3H), 2.18-2.10 (m, 1H), 2.05-1.97
(m, 1H), 1.93-1.88 (m, 2H), 1.63-1.54 (m, 1H), 1.39-1.18 (m,
7H), 0.86 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 189.7, 164.8,
153.9, 133.0, 130.7, 127.5, 126.8, 114.6, 78.2, 77.5, 55.7, 32.4,
31.3, 30.1, 29.0, 28.3, 22.4, 14.0; LRMS (EI) m/z 346 (M+), 135
(ArCtO+, base peak); HRMS (EI) calcd for C20H26O5 (M+)
346.1780, found 346.1777.
4-Meth oxyph en yl (2R,3R,6E)-2,3-Car bon yldioxy-6-dode-
cen oa te (10). Molecular sieves 4A (80 mg) was placed in a
test tube and heated at 180 °C under reduced pressure for 12
h. After cooling to room temperature, trans-N,N-bis(p-tolu-
enesulfonyl)-1,2-cyclohexanediamine (35 mg, 0.0828 mmol) and
CH2Cl2 (500 µL) were added under argon. After cooling to -20
°C, a solution of SnCl4 (82.8 µL, 0.0828 mmol, 1 M in CH2Cl2)
and bis(trimethylsilyl) peroxide (53 µL, 0.249 mmol) were
added via syringe. After stirring for 5 min, ketone 5i (28.7 mg,
0.0828 mmol) in CH2Cl2 (700 µL) was added, and the resulting
mixture was stirred at -20 °C for 50 min. The reaction was
quenched by addition of saturated aqueous NaHCO3 solution
and diluted with ethyl acetate. The aqueous layer was
separated and extracted with ethyl acetate (twice), and the
combined organic layers were washed with H2O and brine and
then dried over Na2SO4. The solvent was removed under
reduced pressure, and the resulting residue was purified by
flash silica gel column chromatography (hexane/ethyl acetate
6/1) to afford ester 10 (23.5 mg, yield 78%) as a colorless solid;
(2R,3R)-2,3-Ca r bon yld ioxy-1-(4-m eth ylp h en yl)-6-p h en -
yl-1-h exa n on e (5l). This compound was prepared according
to a procedure similar to that for 5h . Yield 91% (from diol);
colorless solid; mp 137-139 °C; IR (KBr) ν 1802, 1690 cm-1
;
[R]2D8 +43.1 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.77-7.75 (d, J
) 8.0 Hz, 2H), 7.32 (d, J ) 8.0 Hz, 2H), 7.21-7.18 (m, 2H),
7.16-7.12 (m, 1H), 4.98 (ddd, J ) 9.7, 8.1, 3.0 Hz, 1H), 2.55-
2.43 (m, 2H), 2.46 (s, 3H), 1.87-1.79 (m, 1H), 1.63-1.49 (m,
3H), 1.40-1.32 (m, 1H); 13C NMR (CDCl3) δ 190.9, 153.7, 146.1,
140.9, 132.2, 130.0, 128.4, 128.3, 128.2, 126.0, 78.8, 77.8, 34.9,
29.8, 27.1, 21.8; LRMS (EI) m/z 324 (M+), 91 (Bn+, base peak);
HRMS (EI) calcd for C20H20O4 (M+) 324.1362, found 324.1348.
4-Meth oxyp h en yl (2R,3R)-2,3-Ca r bon yld ioxy-6-p h en -
ylh exa n oa te (8). To a stirred solution of ketone 5h (23 mg,
0.0676 mmol) in 1,2-dichloroethane (0.5 mL), were added
anhydrous NaH2PO4 (48.6 mg, 0.405 mmol) and m-CPBA (46.6
mg, 0.270 mmol). The resulting mixture was stirred vigorously
at 50 °C for 5 h. After cooling to room temperature, the reaction
mixture was diluted with ether, washed with saturated
aqueous Na2S2O3 solution, saturated aqueous NaHCO3 solu-
tion, H2O, and brine, and then dried over Na2SO4. The solvent
was removed under reduced pressure, and the resulting
residue was purified by flash silica gel column chromatography
(hexane/ether 1/1) to afford ester 8 (21 mg, 87%) as a colorless
mp 61-63 °C; IR (KBr) ν 2924, 1833, 1768, 1508, 1083 cm-1
;
[R]2D4 -13.7 (c 1.0, CHCl3); H NMR (CDCl3) δ 7.06-7.03 (m,
2H), 6.92-6.90 (m, 2H), 5.56-5.50 (m, 1H), 5.39-5.33 (m, 1H),
5.24 (d, J ) 8.2 Hz, 1H), 4.97 (dt, J ) 8.2, 4.8 Hz, 1H), 3.81 (s,
3H), 2.36-2.28 (m, 1H), 2.25-2.17 (m, 1H), 2.02-1.97 (m, 2H),
1.91-1.81 (m, 2H), 1.38-1.22 (m, 6H), 0.89 (t, J ) 6.9 Hz, 3H);
13C NMR (CDCl3) δ 165.0, 157.9, 153.2, 143.0, 133.5, 126.7,
121.7, 114.7, 77.8, 75.9, 55.6, 32.4, 31.4, 29.9, 29.0, 28.3, 22.5,
14.0; LRMS (EI) m/z 362 (M+), 124 (HO+C6H4OCH3, base
peak); HRMS (EI) calcd for C20H26O6 (M+) 362.1729, found
362.1719.
1
Ack n ow led gm en t. We thank Mr. Naoya Kumagai,
Mr. Shigeki Matsunaga, and Dr. Takashi Ohshima for
fruitful discussions and the generous gift of several
substrates. This study was financially supported by
CREST and RFTF. Naoki Yoshikawa thanks the J apan
Society for the Promotion of Science (J SPS) for a
research fellowship.
solid; 98% ee; mp 92-93 °C; IR (KBr) ν 1826, 1774 cm-1; [R
29
D
]
-20.6 (c 0.94, CHCl3); 1H NMR (CDCl3) δ 7.32-7.28 (m,
2H), 7.24-7.21 (m, 1H), 7.18-7.14 (m, 2H), 6.89 (s, 4H), 5.22
(d, J ) 8.2 Hz, 1H), 4.93 (ddd, J ) 9.3, 8.2, 3.9 Hz, 1H), 3.82
(s, 3H), 2.76-2.66 (m, 2H), 2.05-1.95 (m, 1H), 1.87-1.73 (m,
3H); 13C NMR (CDCl3) δ 164.9, 157.9, 153.2, 142.9, 140.7,
128.6, 128.4, 126.2, 121.7, 114.7, 78.5, 75.9, 55.6, 35.1, 29.5,
27.0; LRMS (EI) m/z 356 (M+), 124 (HO+C6H4OCH3, base
peak); HRMS (EI) calcd for C20H20O6 (M+) 356.1260, found
356.1265.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
spectra for all new compounds. The procedure for the deter-
mination of the relative and absolute configuration of 3c and
3i. This material is available free of charge via the Internet
at http://pubs.acs.org.
4-Meth ylp h en yl (2R,3R)-2,3-Ca r bon yld ioxy-6-p h en yl-
h exa n oa te (9). To a stirred solution of ketone 5l (22 mg, 0.068
mmol) in 1,2-dichloroethane (0.5 mL), were added anhydrous
NaH2PO4 (81 mg, 0.68 mmol) and m-CPBA (94 mg, 0.54 mmol).
J O0162538