In- or In(I)-employed tailoring of the stereogenic centers in the Reformatsky-type reactions of simple ketones, a-alkoxy ketones, and β-keto esters

Article abstract of DOI:10.1021/jo051659w

Comprehensive studies were carried out on efficient In- or In(I)-based diastereoselective Reformatsky-type reactions of simple ketones, α-alkoxy ketones, and β-keto esters. High anti selectivity was established in the addition of the branched α-halo ester

Full text of DOI:10.1021/jo051659w

In- or In(I)-Employed Tailoring of the Stereogenic Centers in the
Reformatsky-Type Reactions of Simple Ketones, r-Alkoxy Ketones,
and â-Keto Esters
Srinivasarao Arulananda Babu, Makoto Yasuda, Ikuya Shibata, and Akio Baba*
Department of Applied Chemistry and Handai Frontier Research Center, Graduate School of Engineering,
Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received August 7, 2005
Comprehensive studies were carried out on efficient In- or In(I)-based diastereoselective Refor-
matsky-type reactions of simple ketones, R-alkoxy ketones, and â-keto esters. High anti selectivity
was established in the addition of the branched R-halo ester derivatives to simple ketones using
indium metal under THF-refluxing conditions. The stereochemistry undoubtedly indicated that
the involvement of a cyclic transition state, formed from the ketone and stereochemically preferred
transient E-enolate derived from the branched R-halo ester. Next, with the view of tailoring high
degree of stereoselection, the concept of chelation-controlled addition of indium enolates was
envisioned. In this line, marvelously syn selective additions to R-alkoxy ketones and â-keto esters
were established. Interestingly, these diastereoselective additions to R-alkoxy ketones and â-keto
esters require either In(I)X or In-InCl3 systems in toluene under ultrasonication, while very poor
efficiency and diastereoselectivity were obtained using indium metal or THF as solvent. The
stereochemistry of key products was unambiguously determined by the single-crystal X-ray structure
analyses. On the basis of the observed astonishing diastereoselectivities due to strong chelation
plausibly, a low-valent RIn(I)-type transient spices could be projected as very reactive spices in
the Reformatsky-type reactions.
Introduction
however, some of these reagents must be freshly pre-
pared.3
Discovering remarkable stereoselectivity in the C-C
bond formation has been the prime objective of organic
chemists. Organometallic reactions are among the supe-
rior processes for the stereoselective bond formations, and
Reformatsky-type reactions are one of the cornerstones.1
Many processes have been developed using zinc.2 For very
high efficiency, new methods have been reported, e.g.,
Rieke-Zn,3a Zn-Cu couple,3b Zn/Ag-graphite;3c utilizing
other metals such as Cd,3d Ni,3e Ce,3f Mg,3g,h and indium;4a-f
Despite these recent developments, two significant
themes still remain to be explored in the Reformatsky-
type reactions of ketones:2 (a) an efficient diastereo-
selective addition of the branched R-halo ester derivatives
to simple ketones (Scheme 1, eq 1) and (b) chelation-
controlled stereoselective addition of R-halo esters to
R-alkoxy ketones and â-keto esters (Scheme 1, eqs 2 and
3).
(2) For recent reviews on Reformatsky reactions, see: (a) Fu¨rstner.
A. Synthesis 1989, 571. (b) Rathke, M. W.; Weipert, P. In Comprehen-
sive Organic Synthesis; Trost, B. M., Fleming, I., Eds; New York, 1991;
Vol. 2, p 277. (c) Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60,
9325. (d) Orsini, F.; Sello, G. Curr. Org. Synth. 2004, 1, 111.
* To whom correspondence should be addressed. Tel: +81-6-6879-
7384. Fax: +81-6-6879-7387.
(1) Reformatsky, S. Chem. Ber. 1887, 20, 1210.
10.1021/jo051659w CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/10/2005
10408
J. Org. Chem. 2005, 70, 10408-10419

In- or In(I)-Employed Reformatsky-Type Reactions
SCHEME 1. Cyclic and Chelation-Controlled Transition States
The former type of stereoselection should own to a
usual six-membered cyclic transition state that would
result from a transient indium enolate. There have been
a few examples with only moderate diastereoselectivity
in the case of addition of the branched R-halo ester
derivatives to simple ketones. This is probably because
the conditions to achieve the additions to ketones are too
severe to control the stereoselectivity in contrast to the
facile additions to aldehydes. In addition, the difference
in the rigid steric demand between the two substituents
on the carbonyl carbon of simple ketones importantly
decides the degree of stereoselection. This difference is
much lower in the case of ketones than aldehydes. In fact,
a survey of the existing examples on the addition of the
branched R-halo esters to simple ketones revealed the
difficulty in achieving good diastereoselectivity,5,6 e.g., Zn
dust/I2 (anti/syn 3:2),6 Et2Zn/RhCl(PPh3)3 (anti/syn 1:1),5a
and low-valent tantalum (ds 17:13).5b
For the latter type of chelation-controlled stereoselec-
tion, importantly, both of strong coordination acceptance
and high nucleophilicity are required for the Refor-
matsky-type metal enolates. Both of these unique char-
acteristics are more essential in the case of â-keto esters
than the case of R-alkoxy ketones because of the larger
ring size during the chelation and the low electrophilicity
of the carbonyl moiety (Scheme 1, eqs 2 and 3).
Taking an impetus from the recently advancing selec-
tive reactions based on indium,4,7 we envisioned the
indium-based tailoring of the stereogenic centers in the
Reformatsky-type additions.8 We have recently delin-
eated our preliminary studies on the stereoselective
addition of branched R-halo ester derivatives to simple
ketones.9 Next, we also aimed the tailoring of the ste-
reogenic centers through chelation-controlled protocol.
Herein, we report the comprehensive studies on three
types of the tailoring of the stereogenic centers in the
Reformatsky-type reactions of simple ketones, R-alkoxy
ketones and â-keto esters as shown in Scheme 1, where
the different selections of indium species and solvents
are essential. Low-valent indium enolates generated from
(3) (a) Rieke, R. D.; Uhm, S. J. Synthesis 1975, 452. (b) Santaniello,
E.; Manzocchi, A. Synthesis 1977, 698. (c) Csuk, R.; Fu¨rstner, A.;
Weidmann, H. J. Chem. Soc., Chem Commun. 1986, 775. (d) Burkhardt,
E.; Rieke, R. D. J. Org. Chem. 1985, 50, 416. (e) Inaba, S.-I.; Rieke, R.
D. Tetrahedron Lett. 1985, 26, 155. (f) Imamoto, T.; Kusumoto, T.;
Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M.
J. Org. Chem. 1984, 49, 3904. (g) Moriwake, T. J. Org. Chem. 1966,
31, 983. (h) Borno, A.; Bigley, D. B. J. Chem. Soc., Perkin Trans. 2
1983, 1311. (i) Paresh, J. D.; Shelton, D. R.; Little, R. D. Org. Lett.
2003, 5, 3615. (j) Shibata, I.; Suwa, T.; Sakakibara, H.; Baba, A. Org.
Lett. 2002, 4, 301 and references therein.
(4) For reviews on indium reagents, see: (a) Cintas, P. Synlett 1995,
1087. (b) Podlech, J.; Maier, T. C. Synthesis 2003, 633. (c) Nair, V.;
Ros, S.; Jayan, C. N.; Pillai, B.; S. Tetrahedron 2004, 60, 1959. (d)
Araki, S.; Hirashita, T. Main Group Metals Org. Synth. 2004, 1, 323.
(e) Chan, T. H.; Li, C.-J.; Lee, M. C.; Wei, Z. Y. Can. J. Chem. 1994,
72, 1181. (f) Loh, T.-P. Sci. Synth. 2004, 7, 413. (g) Babu, S. A. Synlett
2002, 531. (h) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Curr.
Org. Chem. 2003, 7, 1661. (i) Babu, G.; Perumal, P. T. Aldrichim. Acta
2000, 33, 16. (j) Chauhan, K. K.; Frost, C. G. J. Chem. Soc., Perkin
Trans. 1 2000, 3015. (k) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347.
(l). Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 1149. (m) Peppe, C.
Curr. Org. Synth. 2004, 1, 227.
(7) For some recent papers, see: (a) Yasuda, M.; Yamasaki, S.;
Onishi, Y.; Baba, A. J. Am. Chem. Soc. 2004, 126, 7186. (b) Loh, T.-P.;
Yin, Z.; Song, H.-S.; Tan, K.-L. Tetrahedron Lett. 2003, 44, 911. (c) Yi,
X.-H.; Meng, Y.; Li, C.-J. J. Chem. Soc, Chem. Commun. 1998, 449.
(d) Hirashita, T.; Kamei, T.; Satake, M.; Horie, T.; Shimizu, H.; Araki,
S. Org. Biomol. Chem. 2003, 1, 3799. (d) Babu, S. A.; Yasuda, M.;
Shibata, I., Baba, A. Synlett 2004, 1223. (e) Paquette, L., A. Synthesis
2003, 765. (f) Kumar, S. Kaur, P. Tetrahedron Lett. 2004, 45, 3413.
(g) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune,
Y. J. Org. Chem. 2005, 70, 3464. (h) Khan, F. A.; Dash, J. E. J. Org.
Chem. 2004, 2692.
(8) For early works dealing with nondiastereoselective Reformatsky-
type reactions, see: (a) Chao, L.-C.; Rieke, R. D. J. Org. Chem. 1975,
40, 2253. (b) Nair, V.; Jayan, C. N.; Ros, S. Tetrahedron 2001, 57, 9453.
(c) Araki, S.; Ito, H.; Butsugan, Y. Synth. Commun. 1988, 18, 453. (d)
Araki, S.; Katsumura, N.; Kawasaki, K.-I.; Butsugan, Y. J. Chem. Soc.,
Perkin Trans. 1 1991, 499. (e) Schick, H.; Ludwig, R.; Schwarz, K.-H.;
Kleiner, K.; Kunath, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 1191.
(f) Araki, S.; Katsumura, N.; Kawasaki, K.; Butsugan, Y. J. Chem. Soc.,
Perkin Trans. 1 1991, 499. (g) Yi, X.-H.; Meng, Y.; Li, C.-J. Tetrahedron
Lett. 1997, 38, 4731.
(5) (a) Kanai, K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2,
2549, and references therein. (b) Aoyagi, Y.; Tanaka, W.; Ohta, A. J.
Chem. Soc, Chem. Commun. 1994, 1225. (c) Delaunay, J.; Orliac-Le
Moing, A.; Simonet, J. Tetrahedron 1988, 44, 7089. (d) Canceill, J.;
Basselier, J. J.; Jacques, J. Bull. Soc. Chim. Fr. 1967, 1024.
(6) Ross, N. A.; Bartsch, R. A. J. Org. Chem. 2003, 68, 360 and
references therein.
(9) Preliminary report: Babu, S. A.; Yasuda, M.; Shibata, I.; Baba,
A. Org. Lett. 2004, 6, 4475.
J. Org. Chem, Vol. 70, No. 25, 2005 10409

Babu et al.
TABLE 1. Optimization of Indium-Based
Diastereoselective Reformatsky-Type Reaction of 5a
with 6aa
SCHEME 2. Reaction Mechanism for the
Formation of Anti-Adducts from Simple Ketones
entry In or InXn time (h) methodb yield (%) (anti/syn)
1
2
3
4
5
6
7
8c
9
In
2.5
1.0
B
A
B
B
B
C
A
C
A
A
A
98 (75:25)
99 (84:16)
99 (76:24)
84 (84:16)
67 (68:32)
NR
In
InCl
InBr
InI
8.0
3.5
9.0
In
1.0
InCl2
Zn/I2
In
2.0
NR
nating groups slightly altered the diastereoselectivities.
The reactions with the R-halo ester derivative 6c having
a long carbon chain, also afforded the products 7ac and
7dc with high diastereoselectivities (entries 2 and 8). It
can be noted that compared to the existing methods, the
indium-based reagents behaved in a distinctive manner
with respect to the diastereoselectivity on the addition
of branched R-halo esters with simple ketones.
Stereochemistry. We have isolated both the major
and minor isomers of â-hydroxy esters in pure form in
some cases. The esterification of major isomers 7ca1 and
7ga1 was carried out according to the literature method11,12
to furnish the suitable crystalline for the single-crystal
X-ray structure analyses (see the Supporting Information
for the X-ray structures and data for the esters 7caB and
7gaB). The X-ray analyses unequivocally revealed the
formation of anti isomers as the major products in the
above reactions.
40 min
2.0
13 (50:50)
65 (88:12)d
NRe
10
11
In
InBr
2.0
2.0
NRd
a 5a (1 mmol), 6a (1.8 mmol), indium powder or In(I)X (1.2
mmol), and THF (2 mL) were used unless otherwise specified.
b Method A: The reaction mixture was dipped into a preheated
bath at reflux temperature. Method B: The reaction mixture was
gradually heated to reflux for an appropriate period. Method C:
Ultrasonication (38 kHz, 120 W) was employed at room temper-
ature. c Zn (1.8 mmol) and I2 (0.2 mmol) in 1,4-dioxane (2.5 mL)
were subjected to ultrasonication.6,10a d Reaction was carried out
in toluene at reflux. e Reaction was carried out in toluene at 70-
75 °C.
R-iodo esters plausibly act as a key intermediate in these
stereoselective reactions.
Results and Discussion
Mechanism. The predominant formation of anti iso-
mers can be rationalized by a cyclic model of an E-enolate
and a ketone as shown in Scheme 2. In this model, one
of the two substituents on the carbonyl carbon must be
located at the axial position in the six-membered cyclic
transition state; of course, it is not hydrogen in contrast
to aldehydes. In Scheme 2, the methyl moiety of ac-
etophenone is the case. This hypothesis is also supported
by the fact that isopropylphenyl ketone gave a rather
lower selectivity (Table 2, entries 9-11). These ideas
strongly indicate that a stable and rigid chair form of
cyclic model is hardly constructed, and so few reports
have achieved the selective addition to ketones in con-
trast to aldehydes. Thus, the higher selectivity obtained
by the indium system is noteworthy.
Type II. Chelation-Controlled Additions to R-
Alkoxy Ketones and â-Keto Esters. Despite only a
small stereogenic difference between methyl and meth-
oxymethyl groups on the carbonyl moiety of methoxy-
acetone 5k, considerable diastereoselectivity was ob-
tained using InBr (77/23) or InCl (72/28) as shown in
Scheme 3.10c This result could not be rationalized only
by the cyclic model shown in Scheme 2. In addition, the
fact that indium metal apparently showed less ability
than indium(I) halide indicates involvement of an alter-
native mechanism to the reaction of R-alkoxy ketones.
A plausible involvement of a chelated-transition state
(chelated-cyclic transition state) as noted in our previous
Sn(II) system is strongly envisioned.13,14 Along this line,
Type I. Reactions of Branched R-Halo Esters with
Simple Ketones. In an initial experiment, to a mixture
of acetophenone (5a) and ethyl-2-bromopropionate (6a)
in dry THF was added indium metal powder at room
temperature, and the resulting mixture was heated to
reflux to afford the product 7aa5,6 in 98% yield with the
diastereoselectivity of 75:25 (anti/syn) (Table 1, entry 1).
Although both of indium metal and indium(I) halide
system have satisfied effect, the former is rather advan-
tageous in terms of a short reaction period. We further
found that dipping the flask containing all the substrates,
indium metal, and dry THF solvent into a preheated bath
(66-69 °C) gave the product (99% yield) with higher
selectivity of 84:16 (anti/syn) (entry 2). Indium dichloride
gave no product, and either the zinc system or indium
metal was not efficient using low intensiity ultrasonica-
tion (38 kHz, 120 W) in our investigation (entries 6-8).10a
Toluene solvent gave poor results under similar condi-
tions (entries 10 and 11), and a moderate yield was
obtained even under harsh conditions (entry 9). Employ-
ing other solvents such as MeCN, DMF, and the systems
of MeCH(Cl)COOEt or RX/NaI in DMF/rt were ineffec-
tive.4
The generality of this important stereoselective reac-
tion was demonstrated with a variety of ketones as
summarized in Table 2. Electron-withdrawing and -do-
(10) (a) Reported yield for this reaction is 99% (ds 3:2) using HIU
(20 kHz, 600 W, 13 mm tip diameter at a power level of 7); see ref 6.
(b) In some of the cases, InBr was employed. The results are
comparable with indium metal as noted in our preliminary studies;
see ref 9. (c) The reactions were carried out using method A.
(11) Yasuda, M.; Hirata, K.; Nishino, M.; Yamamoto, A.; Baba, A.
J. Am. Chem. Soc. 2002, 124, 13442.
(12) Vedejs, E.; Daugulis, O. J. Org. Chem. 1996, 61, 5702.
10410 J. Org. Chem., Vol. 70, No. 25, 2005

In- or In(I)-Employed Reformatsky-Type Reactions
TABLE 2. Indium-Based Diastereoselective Reformatsky-Type Reaction of Ketones 5 with 6a
a 5 (1 mmol), 6 (1.6-1.8 mmol), indium powder, or In(I)X (1.2 mmol) were used in refluxing dry THF (2 mL). b See the footnote in Table
1. c 5 (1 mmol), 6 (2 mmol), and indium powder (2 mmol) were used. d Only the major isomers (anti) are drawn.
SCHEME 3. Reaction of Ketone 5k with 6aa
esters with R-halo ester (1,5-chelated model, Scheme 1),
and R-alkoxy ketone with branched R-halo ester.
Primarily, we examined on the additions to R-alkoxy
ketones under the optimized conditions for the simple
ketones in the above section (Table 3). However, neither
indium metal nor InCl system gave positive results
(13) Yasuda, M.; Okamoto, K.; Sako, T.; Baba, A. Chem. Commun.
2001, 157 and references therein.
(14) For selective reactions under the chelation-controlled conditions,
see: (a) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462. (b) Reetz, M. T.
Angew. Chem. Int. Ed. Engl. 1994, 23, 556. For the chelation-controlled
aldol-type additions to R-alkoxy aldehydes using enol silanes, see: (c)
Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron 1984, 40, 4327. (d)
Reetz, M. T.; Raguse, B.; Marth, C. F.; Hugel, H. M.; Bach, T.; Fox, D.
N. A. Tetrahedron 1992, 48, 5731. (e) Reetz, M. T.; Fox, D. N. A.
Tetrahedron Lett. 1993, 34, 1119.
a 7ka was isolated as inseparable diastereomers; the stereo-
chemistry was not determined.
we envisaged three types of reactions: R-alkoxy ketones
with R-halo ester (1,4-chelated model, Scheme 1), â-keto
J. Org. Chem, Vol. 70, No. 25, 2005 10411

Babu et al.
TABLE 3. Reactions of r-Halo Ester with r-Alkoxy Ketone under the Established Conditionsa
entry
8a (mmol)
R-halo ester (mmol)
metal source (mmol)
solventb
conditions (h)
yield (%) (syn/anti)
1
0.5
0.5
1.0
0.5
0.5
0.5
5.0
10.0
0.5
10 (1.0)
10 (1.0)
10 (1.6)
10 (1.0)
10 (1.0)
10 (1.0)
9 (5.5)
In (1.0)
InCl (1.0)
In (1.1)
InCl (1.0)
SmI2 (0.6)
SmI2 (0.6)
Zn (6.0)
Zn (16.0)
InCl (1.0)
THF
reflux (2)
reflux (2)
US (1.5)
99 (50:50)
50 (50:50)
32 (56:46)
<5
2
THF
3
THF
THF
toluene
THF
benzene-Et2O
Et2O
toluene
4
US (2)
5c
6c
7
US (2)/0-10 °C
-78 °C to rt (2.5)
reflux
35 °C (1)
US (2)
<5
<5
40 (31:69)
32 (48:52)
99 (98:2)
8d
9
9 (12.0)
10 (1.0)
a US ) ultrasonication (38 kHz, 120 W) at room temperature. b THF (1.5 mL), toluene (1.5 mL), benzene-Et2O (5:1, 12 mL), Et2O (45
mL). c SmI2 0.1 M THF solution was used. d Me3SiCl (0.15 mL) was used for the activation of zinc in ether.
TABLE 4. Optimization of Reaction Conditions: Chelation-Controlled Addition of Indium Enolates to r-Alkoxy
Ketonesa
In system
entry
R-halo ester
In or InX
InXm (mmol)
conditions (h)
11a yield (%) (syn/anti)
1
2
10
10
10
10
10
10
10
10
9
In
110 °C (1)
US (2)
95 (50:50)
18 (90:10)
99 (98:2)b
91 (98:2)
94 (98:2)
99 (98:2)
99 (98:2)
99 (98:2)
<5
In
3
InCl
InBr
InI
In
In
In
InBr
In
In
US (2)
4
US (2)
5
US (2)
6
InCl3 (1)
InCl3 (0.35)
InBr3 (1)
US (2)
7
US (2)
8
US (1.5)
US (1.5)
US (1.5)
US (1.5)
9
10
11
10
10
InCl3 (1)
InCl2 (0.5)
<5c
80 (98:2)
a Reactions were carried out using 8a (0.5 mmol), R-halo ester (1 mmol), and indium powder or InX (1.0 mmol) in dry toluene (1.5 mL)
under ultrasonication (US; 38 kHz, 120 W) at room temperature unless otherwise specified. b Benzene solvent was used. c THF solvent
was used.
(entries 1 and 2). THF refluxing gave high yields but
suffered from no selectivities. Other solvents such as 1,4-
dioxane and DMF were ineffective. Representative other
metallic reagents for Reformatsky-type reactions such as
zinc13,15 and samarium(II) iodide16 gave low yields or low
diasteroselectivities (entries 5-8). Fortunately, we suc-
ceeded in optimizing the chelation-controlled addition to
8a using indium(I) halide in dry toluene at ambient
temperature under ultrasonication (Table 3, entry 9, and
Table 4, entries 3 and 4).
The change of solvent into a nonpolar solvent such as
toluene is very much essential, and benzene also acted
as an effective solvent (entry 4, Table 4). Surprisingly,
the reactivity order of indium metal and In(I)X was
completely changed in contrast to the reaction with
simple ketones (see Table 1). The use of indium powder
at room temperature gave only low yield (18%, entry 2),
and heating at 110 °C resulted in losing diastereoselec-
tivity (entry 1). Employing ethyl bromoacetate instead
of ethyl iodoacetate was ineffective (entry 9).
Although indium metal powder did not afford a satis-
factory result, strikingly the combined use of indium
metal with InCl3 or InBr3 afforded the “syn” isomer 11a
in excellent yields under the same conditions employed
for In(I)X system (entries 6-8).17 THF solvent again
completely disturbed the addition in this combined
system (entry 10), perhaps because of the strong coordi-
nation of THF to an active species. It is notable that the
use of InCl2 instead of InCl3 also afforded 11a with
excellent diastereoselectivity (>98:2, entry 11). This
interesting result does not indicate that InCl3 acts as a
simple Lewis acid. We believe that the in situ formation
of In(I)X occurs by the disproportionation between indium
metal and InX3 or InX2 under the experimental condi-
tions.4m,17
(17) Although the reaction occurs without InCl3 (Table 4, entry 2),
addition promoted the reaction very effectively in toluene. (b) Interest-
ing results were obtained. However, at this stage we believe the
disproportionation occurs between indium and InCl3; see: Cotton, F.
A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M. Advanced Inorganic
Chemistry; Wiley: New York, 1999; p 203.
(15) Picotin, G.; Miginiac, P. J. Org. Chem. 1987, 52, 4796.
(16) SmI2-mediated Reformatsky-type reactions: (a) Orsini, F.;
Lucci, E. M. Tetrahedron Lett. 2005, 46, 1909 and references therein.
(b) Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P.-J. Acc. Chem.
Res. 1991, 113, 8036.
10412 J. Org. Chem., Vol. 70, No. 25, 2005

In- or In(I)-Employed Reformatsky-Type Reactions
TABLE 5. Chelation-Controlled Addition of Indium Enolates to Various r-Alkoxy Ketones in Toluenea
a Reactions were carried out using alkoxy ketone 8 (0.5 mmol) or iodo ester 10 (1 mmol) in dry toluene (1.5 mL) under US (38 kHz, 120
W) at room temperature unless otherwise specified. b THF solvent was used. c 8e (1 mmol) and 10 (2 mmol) were used.
SCHEME 4. Mechanism of Chelation-Controlled Addition to r-Alkoxy Ketones
Under the optimized conditions, a variety of R-alkoxy
ketones 8 and iodo ester 10 were treated to afford the
corresponding “syn” isomers 11 exclusively as sum-
marized in the Table 5. When the substitution at 2-posi-
tion of alkoxy ketone 8 which would crucially direct the
chelation-controlled stereochemistry was changed from
phenyl to methyl moiety, no decrease in the selectivity
was observed (entries 6, 7 vs 8, 9). 2-Methoxycyclohex-
anone 8f gave a lower selectivity perhaps because of ring
strain (entry 10). The observed very high diastereoselec-
tion seems to be explainable through a usual chelation-
controlled mechanism (path “a”) as shown in Scheme 4.
No effect of the bulkiness of R2, however, suggestively
indicates an alternative model like chelated-cyclic transi-
tion state (path “b”).11,18
Next, we were very much interested to widen up the
addition to â-keto esters (Scheme 1, eq 3). To the best of
our knowledge, there exist no reports on the chelation-
controlled diastereoselective Reformatsky-type reactions
of â-keto esters.2 Both In(I)X and In-InX3 systems could
be again applied to this reaction to afford “syn” products
13 selectively. Optimizations of reaction conditions as
well as the results using a variety of â-keto esters are
summarized in Table 6.
ultrasonication was most effective to give 89% yield with
>98% of syn-selectivity (entry 4), while InCl gave also a
satisfactory yield of 73% with >98% selectivity (entry 1).
Employing indium powder, zinc, SmI2, or THF solvent
did not promote the addition (entries 5-8).19a A limitation
is that no reaction was observed with ketone 12d bearing
tert-butyl moiety because of its steric hindrance. Decreas-
ing of the reactivity and selectivity is observed in alkyl
ketone 12e. Reduction of product 13a was carried out to
afford the corresponding triol 13aB as a colorless solid.19b
Single-crystal X-ray structure analysis of the triol 13aB
(see the Supporting Information for the ORTEP struc-
ture) unambiguously revealed the stereochemistry of
products in these reactions. Further, because of a loser
1,5-chelation compared with the 1,4-chelation for R-alkoxy
ketone, the chelated-cyclic transition state model is again
plausible for the observed high diastereoselectivities
(Scheme 5, path b).11,18
In the above reactions, we have shown the facile
stereoselective construction of two stereogenic centers;
next, we aimed to tailor three stereogenic centers. A
combination of both the type-I and type-II reaction model
that is a chelated cyclic transition state would cleanly
complete the stereoselective construction of subsequent
three stereogenic centers. In an exemplar reaction, we
A nonpolar solvent such as toluene is again the choice.
The combined use of indium metal and InCl3 under
(19) (a) Even refluxing the reaction mixture in THF was not effective
in this case. (b) Reduction was carried out in THF with an excess of
LiAlH4 (6 mmol) for 1 mmol of substrate at room temperature.
(18) Sato, K.; Kira, M.; Sakurai, H. J. Am. Chem. Soc. 1989, 111,
6429.
J. Org. Chem, Vol. 70, No. 25, 2005 10413

Babu et al.
TABLE 6. Concept of Chelation-Controlled Addition of Indium Enolates to â-Keto Esters in Toluenea
a Reactions were carried out using 12 (0.5 mmol) and 10 in dry toluene (1.5 mL) under US (38 kHz, 120 W) at room temperature unless
otherwise specified. b InBr3 was used. c 12 (1.0 mmol) was used. d THF solvent was used. e 12a (2 mmol). Benzene-ether (5:1) mixture
solvent used. f SmI2 0.1 M solution of THF was added.
SCHEME 5. Mechanism of Chelation-Controlled Addition to â-Keto Esters
SCHEME 6. Reaction of 8d with 6a
observed that two kinds of independent active species (in
THF-d8) at 2.08 ppm (species A) and 1.85 ppm (species
B) are forming in the reaction of ethyl iodoacetate (10)
with In(I)I or indium metal.22,23 Only the latter species
B was found to immediately react with benzaldehyde in
THF solution as already noted.9 The active species B is
believed to react fast with simple ketones in THF solution
as already discussed. In the nonpolar solvents such as
attempted the addition of branched R-halo ester 6a to
R-alkoxy ketone 8d as shown in Scheme 6. However, in
this stage a mixture of four isomers was produced in
>95% combined yield.20 The establishment of control over
three stereogenic centers is under investigation.
(21) For the H1 NMR spectra see ref 9 and the Supporting Informa-
tion therein.
(22) Similar results have been discussed by Chan et al. for the
generation of allyl- or allenylindiums from indium metal and allyl- or
propargyl bromide, respectively, in DMF solution, see: (a) Chan, T.
H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228. (b) Miao, W.; Chung,
L., W.; Wu, Y.-D.; Chan, T., H. J. Am. Chem. Soc. 2004, 126, 13326.
Araki et al. reported the formation of allyl-In(III)I2 from allyl iodide
and In(I)I in THF solution; see: (c) Araki, S.; Ito, H.; Katsumura, N.;
Butsugan, Y. J. Organomet. Chem. 1989, 369, 291.
Active Species Involved in the Reformatsky-Type
Reactions. In our previous 1H NMR studies,9,21 we
(20) The complete isolation of isomers and the determination of
isomeric ratio is under investigation on the stereoselective construction
of three subsequent stereogenic centers.
(23) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831.
10414 J. Org. Chem., Vol. 70, No. 25, 2005

In- or In(I)-Employed Reformatsky-Type Reactions
SCHEME 7. Formation of Low-Valent RIn(I)-Type Species in the Reformatsky Reactions
toluene and benzene, the generation of similar species
would be expected. In fact, when the mixture of InCl and
10 in benzene-d6 was subjected to ultrasonication for 45
min, two broad peaks appeared around δ 2.65 (less
intensive) and δ 2.59 (more intensive).24a Both the new
peaks disappeared smoothly by the addition of either
benzaldehyde or R-alkoxy ketone 8a (see the Supporting
Information for the spectra). Similarly, an easy genera-
tion of the active species was monitored in the combined
system of In-InCl3 in benzene-d6.24b In contrast, the
appearance of the new peaks corresponding to the active
species was very slow in the case of indium metal in
benzene-d6. Perhaps this is the reason indium metal
could not promote the reaction in toluene under mild
conditions.25 Since using THF solvent a complete loss
chelation control was observed (Table 3), the active
species is plausibly a low valent RIn(I)-type rather than
RIn(III)X2. In toluene, the low-valent indium species has
a high coordination acceptance that can play an impor-
tant role for both activation of ketones and directing for
a high diastereoselective addition without the distur-
bance of the coordination by the solvent.
result, we accomplished that involvement of transient but
discrete RIn-type organoindium intermediates in the
Reformatsky-type reactions. Interestingly, the establish-
ment of control over two stereogenic center is accounted
here, and stereoselective construction of three stereogenic
centers would be a challenging target, investigations are
under progress in this line.
Experimental Section
General Methods. Ultrasonication was carried out using
ultrasonic cleaner (38 kHz, 120 W). Melting points are uncor-
rected. IR spectra were recorded as thin films or KBr pellets.
1H and 13C NMR spectra were recorded on 270 or 400 (270/
67.9 or 400/100 MHz) spectrometers, respectively, with TMS
as internal or external standard. Column chromatography was
performed on silica gel (100-200 mesh). Reactions were
carried out either under ultrasonication (bath temperature
about 10-25 °C, ice was added time to time to the ultrasoni-
cation water bath) or at reflux temperature under an inert
atmosphere. Solutions were dried with anhydrous magnesium
sulfate. Reagents were added to the reaction flask through a
syringe. Analytical thin-layer chromatography (TLC) was
performed on silica plates, and components were visualized
by observation under iodine or UV light. Yields were deter-
mined from 1H NMR spectra using internal standards or after
isolation in column chromatography. Ratios of diastereomers
From these results and discussions, the formation of
RIn(I)-type transient species could be conjectured as
1
given in the Scheme 7. From the H NMR spectra it is
1
were determined from H NMR of crude reaction mixture.
believed that the facile transformation from RIn(III)X2
to RIn(I) is taking place in toluene (see Supporting
Information). The other low reactive species could be
RIn(III)X2-type which perhaps cannot be involved in the
chelation process. The facile reaction with indium metal
would proceed only in THF solution.
Materials. Toluene/benzene/Et2O/THF were distilled from
sodium and benzophenone. All starting ketones, R-halo esters,
indium powder (100 mesh), and In(I)X used in this work are
commercially purchased. InI and InBr are available in beads
form and used either as beads or particularly, after grinding
under an inert atmosphere in the cases of reactions under
ultrasonication. InCl is available in powder form. SmI2 (0.1
M solution in THF), Zn powder, InCl3, InCl2, and InBr3 were
commercially purchased.
Ethyl 3-Hydroxy-2-methyl-3-phenylbutyrate (7aa).
Column chromatographic purification afforded a mixture of
diastereomers; see references 5 and 6 for spectral data.
Ethyl 3-Hydroxy-2-ethyl-3-phenylbutyrate (7ab).5c Col-
umn chromatographic purification afforded a mixture of anti/
syn diastereomers as colorless thick oil: IR (neat) 3502, 3482,
1708, 1376, 1187 cm-1; 1H NMR (270 MHz, CDCl3) 7.49-7.17
(m, 5 H), 4.25 (q, J ) 7.3 Hz, 2 H),* 3.98 (s, 1 H), 3.95-3.81
(m, 2 H,), 2.80 (dd, J1 ) 10.3, J2 ) 4.9 Hz, 1 H), 2.66 (dd, J1 )
11.3, J2 ) 3.80 Hz, 1 H),* 1.96-1.67 (m, 2 H), 1.52 (s, 3 H),*
1.49 (s, 3 H), 1.32 (t, J ) 7.0 Hz, 3 H),* 0.95 (t, J ) 7.3 Hz, 3
H), 0.89 (t, J ) 7.0 Hz, 3 H), 0.75 (t, J ) 7.3 Hz, 3 H);* 13C
NMR (100 MHz, CDCl3) 176.8,* 176.2, 147. 6, 145.3,* 128.0,*
127.9, 126.7, 126.6,* 124.8,* 124.7, 74.9, 74.4,* 60.7,* 60.2,
57.5,* 56.8, 30.1,* 27.1, 20.8,* 20.4, 14.3,* 13.8, 12.3, 12.1;*
MS (EI) m/z 236 (M+, 2), 191 (2), 116 (42), 105 (24), 101 (20);
HRMS (EI) calcd for C14H20O3 236.1412, found m/z 236.1420,
236.1418 (M+). Asterisk corresponds to the minor (syn) isomer.
In conclusion, an exceedingly important highly dias-
tereoselective C-C bond formation synthetic protocol was
established, via In- or In(I)-based Reformatsky-type
reactions of simple ketones, R-alkoxy ketones and â-keto
esters. We have demonstrated that indium-based re-
agents exhibit a distinctive diastereoselective pattern for
the Reformatsky-type reactions of ketones. The predomi-
nant formations of “anti” isomers, noticeably suggest the
participation of the transient “E enolates” in the transi-
tion state of the reaction in the case of branched R-halo
esters. Diastereoselective tailoring of the stereogenic
centers in the chelation-controlled addition of indium
enolates to R-alkoxy ketones and â-keto esters was
established. In this line, excellent “syn” selective products
were obtained using In(I)X or In-InCl3 systems in
toluene. Based on the astonishing diastereoselectivities
and taking the chelation as the key point in the present
(24) (a) A similar trend was observed in THF as noted in ref 9. (b)
Noticeably, treatment of ethyl iodoacetate and indium and InCl3 also
afforded a similar type of spectra and species (see the Supporting
Information for the spectra).
(25) Treatment of indium metal with ethyl iodoacetate in benzene-
d6 afforded two new peaks; however, very slow consumption of ethyl
iodoacetate was noted and the rate of consumption of ethyl iodoacetate
was very high and fast in the cases of In-InCl3 as well as InCl systems.
See the Supporting Information for the spectra.
(2S*,3S*)-Ethyl
3-Hydroxy-2-undecanyl-3-phenyl-
butyrate (7ac1). Repetitive silica gel column purification
afforded anti (major) isomer in pure form. 7ac1: isolated as a
colorless thick oil which solidified on standing; mp 46-48 °C;
IR (neat) 3502, 3019, 2927, 1700, 1214 cm-1 1H NMR (270
;
MHz, CDCl3) 7.43-7.18 (m, 5 H), 3.97 (s, 1 H), 3.91-3.79 (m,
2 H), 2.85 (dd, J1 ) 11.00, J2 ) 3.80 Hz, 1 H), 1.80-1.61 (m,
J. Org. Chem, Vol. 70, No. 25, 2005 10415

Babu et al.
2 H), 1.48 (s, 3 H), 1.20-1.40 (m, 20 H), 0.88 (t, J ) 7.0 Hz, 3
H), 0.89 (t, J ) 7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3) 176.4,
147.5, 127.9, 126.7, 124.7, 74.9, 60.3, 55.1, 31.9, 29.7, 29.6, 29.6,
29.5, 29.5, 29.4, 29.3, 27.9, 27.3, 27.2, 22.7, 14.1, 13.8; MS (EI)
m/z 376 (M+, 0.64), 257 (11), 256 (64), 213 (15), 157 (22), 121
(100), 105 (48), 101 (74), 77 (21); HRMS (EI) calcd for C24H40O3
376.2977, found m/z 376.2971 (M+). The minor isomer could
not be isolated.
240 (4.8), 209 (1.1), 183 (1.7), 160 (1.2), 139 (100), 112 (0.6),
91 (1.1), 75 (2.5); HRMS (EI) calcd for C20H20BrClO4 438.0233,
found m/z 438.0227 (M+).
(2R*,3S*)-Ethyl 3-(4-bromophenyl)-3-hydroxy-2-meth-
ylbutyrate (7ca2): syn (minor) isomer, isolated as a colorless
thick oil; IR (neat) 3502, 2981, 1712, 1484, 1191 cm-1; 1H NMR
(270 MHz, CDCl3) 7.45 (d, J ) 8.4 Hz, 2 H), 7.29 (d, J ) 8.4
Hz, 2 H), 4.27-4.18 (m, 2 H), 3.99 (s, 1 H), 2.77 (q, J ) 7.3
Hz, 1 H), 1.53 (s, 3 H), 1.31 (t, J ) 7.3 Hz, 3 H), 0.94 (d, J )
7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3) 177.1, 144.2, 131.2,
126.8, 120.6, 74.1, 61.0, 49.0, 29.8, 14.1, 12.7; MS (EI) m/z 302
(M+ + 2, 2), 300 (M+, 2), 201 (78), 200 (10), 199 (80), 185 (33),
183 (34), 102 (100), 74 (46), 57 (6), 56 (8); HRMS (EI) calcd for
C13H17BrO3 300.0361, found m/z 300.0369 (M+).
Ethyl 3-(4-Bromophenyl)-3-hydroxy-2-ethylbutyrate
(7cb). Column chromatographic purification afforded a mix-
ture of anti/syn diastereomers as a colorless thick oil: IR (neat)
3490, 2973, 1708, 1484, 1187 cm-1; 1H NMR (400 MHz, CDCl3)
7.46-7.27 (m, 2 H), 7.32-7.27 (m, 2 H), 4.26 (q, 2 H),* 4.02 (s,
1 H), 3.90 (q, J ) 7.3 Hz, 2 H), 2.75 (dd, J1 ) 10.0, J2 ) 5.4
Hz, 1 H), 2.60 (dd, J1 ) 11.3, J2 ) 3.5 Hz, 1 H),* 1.94-1.79
(m, 2 H), 1.49 (s, 3 H),* 1.44 (s, 3 H), 1.32 (t, J ) 7.0 Hz, 3
H),* 0.95 (t, J ) 7.0 Hz, 3 H), 0.95 (t, J ) 7.3 Hz, 3 H), 0.75 (t,
J ) 7.3 Hz, 3 H);* 13C NMR (100 MHz, CDCl3) 176.6,* 176.1,
146.8, 144.5,* 131.1,* 131.0, 126.7,* 126.7, 120.6, 120.6,* 74.7,
74.3,* 60.9,* 60.5, 57.2,* 56.4, 30.1,* 27.2, 20.8,* 20.4, 14.3,*
13.9, 12.2, 12.0;* MS (EI) m/z 316 (M+ + 2, 2), 314 (M+, 1),
301 (4), 300 (1), 299 (4), 201 (43), 199 (45), 185 (29), 183 (30),
157 (7), 116 (100), 101 (35), 88 (14); HRMS (EI) calcd for C14H19-
BrO3 314.0518, found m/z 314.0534, 314.0514 (M+). Asterisk
corresponds to the minor isomer.
Ethyl 3-(4-Methylphenyl)-3-hydroxy-2-methylbutyrate
(7da).26 Column chromatographic purification afforded a
mixture of anti/syn diastereomers as a colorless thick oil: IR
(neat) 3498, 2985, 1712, 1457, 1191 cm-1; 1H NMR (270 MHz,
CDCl3) 7.31 (d, J ) 8.4 Hz, 2 H), 7.11 (d, J ) 8.4 Hz, 2 H),
4.23-4.16 (m, 2 H),* 4.04 (s, 1 H), 3.92 (q, J ) 7.3 Hz, 2 H),
2.98 (q, J ) 7.3 Hz, 1 H), 2.80 (q, J ) 7.3 Hz, 1 H),* 2.33 (s, 3
H),* 2.31 (s, 3 H), 1.54 (s, 3 H),* 1.43 (s, 3 H,), 1.31 (d, J ) 7.3
Hz, 3 H), 0.99 (t, J ) 7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
176.7, 144.6, 136.2, 128.6, 124.5, 74.5, 60.4, 48.4, 26.8, 20.8,
13.8, 12.3; MS (EI) m/z 236 (M+, 1), 191 (2), 136 (10), 135 (100),
119 (20), 102 (5), 91 (14), 65 (4); HRMS (EI) calcd for C14H20O3
236.1412, found m/z 236.1410, 236.1419 (M+). Asterisk corre-
sponds to the minor isomer.
Ethyl 3-(4-Chlorophenyl)-3-hydroxy-2-methylbutyrate
(7ba).26 Column chromatographic purification afforded a
mixture of anti/syn diastereomers as a colorless thick oil: IR
(neat) 3490, 2985, 1712, 1492, 1191 cm-1; 1H NMR (270 MHz,
CDCl3) 7.39-7.26 (m, 4 H), 4.27-4.21 (m, 2 H),* 4.15 (s, 1 H),*
4.00 (s, 1 H), 3.93 (q, J ) 7.3 Hz, 2 H), 2.96 (q, J ) 7.3 Hz, 1
H), 2.78 (q, J ) 7.3 Hz, 1 H),* 1.54 (s, 3 H),* 1.43 (s, 3 H), 1.33
(d, J ) 7.3 Hz, 3 H), 1.30 (t, J ) 7.3 Hz, 3 H),* 1.00 (t, J ) 7.3
Hz, 3 H), 0.97 (d, J ) 7.3 Hz, 3 H);* 13C NMR (100 MHz,
CDCl3) 177.1,* 176.6, 146. 2, 143.6,* 132.5, 128.2,* 128.1,
126.4,* 126.2, 74.4, 74.0,* 61.0,* 60.6, 49.1,* 48.2, 29.8,* 26.8,
14.1,* 13.8, 12.6,* 12.3; MS (EI) m/z 256 (M+, 1), 157 (18), 155
(54), 154 (25), 141 (32), 139 (100), 113 (14), 102 (39), 75 (19);
HRMS (EI) calcd for C13H17ClO3 256.0866, found m/z 256.0843,
256.0844 (M+). Asterisk corresponds to the minor (syn) isomer.
Ethyl 3-(4-Bromophenyl)-3-hydroxy-2-methylbutyrate
(7ca).26 Repetitive silica gel column chromatography (three
times) afforded both the isomers 7ca1 and 7ca2 in pure form.
(2S*,3S*)-Ethyl 3-(4-bromophenyl)-3-hydroxy-2-methyl-
butyrate (7ca1): anti (major) isomer, isolated as a colorless
thick oil; IR (neat) 3490, 2981, 1712, 1484, 1191 cm-1 1H
;
NMR: (270 MHz, CDCl3) 7.43 (d, J ) 8.4 Hz, 2 H), 7.28 (d, J
) 8.4 Hz, 2 H), 4.14 (s, 1 H), 3.93 (q, J ) 7.3 Hz, 2 H), 2.95 (q,
J ) 7.3 Hz, 1 H), 1.42 (s, 3 H), 1.33 (d, J ) 7.3 Hz, 3 H), 1.00
(t, J ) 7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3) 176.6, 146.7,
131.1, 126.6, 120.7, 74.2, 60.7, 48.2, 26.8, 13.8, 12.3; MS (EI)
m/z 302 (M+ + 2, 2), 300 (M+, 2), 201 (91), 199 (92), 185 (21),
183 (22), 102 (100), 74 (44); HRMS (EI) calcd for C13H17BrO3
300.0361, found m/z 300.0375 (M+).
Preparation of Ester Derivative, 4-Chlorobenzoic
acid-1-(4-bromophenyl)-2-ethoxycarbonyl-1-methyl-
propyl ester (7caB) from Major Isomer 7ca1. The esteri-
fication was performed according to the literature.11,12 A flask
was charged with dry dichloromethane (10 mL) and 7ca1 (1.0
mmol) under a nitrogen atmosphere at room temperature. To
this solution were sequentially added MgBr2 (2.0 mmol), Et3N
(3.0 mmol), and 4-chlorobenzoic acid anhydride (2.0 mmol).
After the mixture was stirred for 15 h, water (10 mL) was
added. The water phase was extracted with ethyl acetate, and
the organic layer was dried over MgSO4. The solvent was
distilled off under reduced pressure. Column chromatographic
purification (hexane/AcOEt, 3/1) of the resultant residue on
silica gel gave the product 7caB in 65% yield. Recrystallization
from hexane/ether gave the suitable crystals for X-ray struc-
ture analysis. See the Supporting Information for the X-ray
structure data of product 7caB.
Ethyl
3-Hydroxy-2-undecanyl-3-(4-methylphenyl)-
butyrate (7dc). Repetitive silica gel column chromatography
(three times) purification afforded both isomers 7dc1 and 7dc2
in pure form. (2S*,3S*)-Ethyl 3-hydroxy-2-undecanyl-3-(4-
methylphenyl)butyrate (7dc1): anti (major) isomer, isolated
as a colorless thick oil and solidified on standing; mp 47-49
°C; IR (neat) 3502, 2927, 2854, 1708, 1187 cm-1; 1H NMR (270
MHz, CDCl3) 7.29 (d, J ) 8.4 Hz, 2 H), 7.10 (d, J ) 8.4 Hz, 2
H), 3.88 (s, 1 H), 3.87 (q, J ) 7.3 Hz, 2 H), 2.83 (dd, J1 ) 11.0,
J2 ) 3.8 Hz, 1 H), 2.30 (s, 3 H), 1.90-1.65 (m, 2 H), 1.46 (s, 3
H), 1.40-1.10 (m, 20 H), 0.91 (t, J ) 7.0 Hz, 3 H), 0.88 (t, J )
7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3) 176.4, 144.6, 136.2,
128.5, 124.6, 74.8, 60.2, 55.1, 31.9, 29.6, 29.6, 29.5, 29.5, 29.4,
29.3, 27.9, 27.3, 27.2, 22.7, 21.0, 14.1, 13.8; MS (EI) m/z 390
(M+, 0.4), 256 (10), 235 (14), 135 (100), 134 (8), 119 (31), 115
(5), 101 (24); HRMS (EI) calcd for C25H42O3 390.3134, found
m/z 390.3130 (M+).
Spectral data for the ester 7caB are as follows. The
compound was isolated as a colorless solid and repetitively
recrystallized from hexane/ether (35 mg of compound in a
solution of 1.5 mL diethyl ether and ∼1 mL hexane was
subjected to ultrasonication until a clear (diethyl ether can be
used if needed more) solution was obtained, which was allowed
to stand at rt for ∼1 day to afford the crystals): mp 93-95
°C; IR (Neat) 2985, 1724, 1592, 1488, 1272, 1191 cm-1 1H
;
NMR (270 MHz, CDCl3) 7.98 (d, J ) 8.4 Hz, 2 H), 7.46 (d, J )
8.4 Hz, 2 H), 7.41 (d, J ) 8.4 Hz, 2 H), 7.23 (d, J ) 8.4 Hz, 2
H), 4.18 (q, J ) 7.0 Hz, 2 H), 3.09 (q, J ) 7.3 Hz, 1 H), 2.08 (s,
3 H), 1.28 (t, J ) 7.0 Hz, 3 H), 1.03 (d, J ) 7.3 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) 173.2, 163.5, 141.6, 139.5, 131.5,
131.1, 129.3, 128.7, 127.0, 121.8, 84.7, 60.8, 51.3, 18.6, 14.2,
12.4; MS (EI) m/z 440 (M++2, 0.3), 438 (M+, 0.2), 337 (1.7),
(2R*,3S*)-Ethyl 3-hydroxy-2-undecanyl-3-(4-methyl-
phenyl)butyrate (7dc2): syn (minor) isomer, isolated as a
colorless thick oil; IR (neat) 3525, 2954, 2854, 1708, 1492, 1187
1
cm-1; H NMR (270 MHz, CDCl3) 7.31 (d, J ) 8.0 Hz, 2 H),
7.14 (d, J ) 8.0 Hz, 2 H), 4.24 (q, J ) 7.3 Hz, 2 H), 3.72 (s, 1
H), 2.71 (dd, J1 ) 11.0, J2 ) 3.8 Hz, 1 H), 2.34 (s, 3 H), 1.70-
1.60 (m, 2 H), 1.49 (s, 3 H), 1.32 (t, J ) 7.0 Hz, 3 H), 1.20-
1.00 (m, 20 H), 0.88 (t, J ) 7.0 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) 176.9, 144.4, 136.1, 128.8, 124.7, 74.4, 60.7, 55.7, 31.9,
30.4, 29.6, 29.6, 29.5, 29.3, 29.2, 27.6, 27.5, 22.7, 21.0, 14.3,
(26) Balsamo, A.; Barili, P., L.; Crotti, P.; Ferretti, M.; Macchia, B.;
Macchia, F. J. Chem. Soc., Perkin Trans. 1 1974, 2548.
10416 J. Org. Chem., Vol. 70, No. 25, 2005

In- or In(I)-Employed Reformatsky-Type Reactions
14.1; MS (EI) m/z 390 (M+, 0.7), 256 (12), 211 (3), 157 (6), 135
(100), 119 (47), 101 (27), 88 (27); HRMS (EI) calcd for C25H42O3
390.3134, found m/z 390.3139 (M+).
Ethyl 3-Hydroxy-2-isopropyl-3-phenylbutyrate (7ea).
Column chromatographic purification afforded a mixture of
diastereomers; see ref 6 for spectral data.
3 H), 4.27 (m, 2 H),* 4.14 (s, 1 H), 4.00 (s, 1 H),* 3.79 (q, J )
7.3 Hz, 2 H), 2.94 (dd, J1 ) 10.5, J2 ) 4.6 Hz, 1 H), 2.79 (dd,
J1 ) 11.6, J2 ) 3.5 Hz, 1 H),* 2.02-1.80 (m, 2 H), 1.60 (s, 3
H),* 1.56 (s, 3 H), 1.31 (t, J ) 7.3 Hz, 3 H),* 1.24 (t, J ) 7.0
Hz, 3 H),* 0.97 (t, J ) 7.3 Hz, 3 H,), 0.76 (t, J ) 7.3 Hz, 3 H);
13C NMR (100 MHz, CDCl3) 176.2, 145.0, 133.0, 132.3, 128.1,*
128.2, 127.8,* 127.7, 127.3, 125.9, 125.7, 123.8,* 123.4, 123.2,
123.0,* 75.1, 74.7,* 60.8,* 60.3, 57.2,* 56.5, 30.2,* 27.1, 21.0,*
20.5, 14.3,* 13.7, 12.4, 12.1*; MS (EI) m/z 286 (M+, 6), 172
(13), 171 (100), 155 (28), 141 (3), 127 (25), 116 (6), 101 (6), 73
(4); HRMS (EI) calcd for C18H22O3 286.1569, found m/z
286.1567 (M+).* Asterisk corresponds to the minor isomer.
Ethyl 3-(3-Bromophenyl)-3-hydroxy-2-methylbutyrate
(7ha). Column chromatographic purification afforded a mix-
ture of anti/syn diastereomers as a colorless thick oil: IR (neat)
3498, 2981, 1712, 1457, 1191 cm-1; 1H NMR (270 MHz, CDCl3)
7.62-7.59 (m, 1 H), 7.39-7.15 (m, 3 H), 4.28-4.18 (m, 2 H),*
4.15 (s, 1 H), 4.01 (s, 1 H,), 4.00-3.84 (m, 2 H), 2.96 (q, J )
7.0 Hz, 1 H), 2.79 (q, J ) 7.0 Hz, 2 H),* 1.54 (s, 3 H),* 1.43 (s,
3 H), 1.35-1.26 (m, 3 H), 1.00 (t, J ) 7.3 Hz, 3 H), 0.96 (d, J
) 7.0 Hz, 3 H);* 13C NMR (100 MHz, CDCl3) 177.0,* 176.5,
150.1, 147.5,* 129.8, 129.7,* 129.7,* 129.6, 128.2,* 128.1,
123.5,* 123.4, 123.5,* 123.4, 74.4, 74.0,* 61.0,* 60.6, 49.0,*
48.2, 29.8,* 26.8, 14.1,* 13.8, 12.7,* 12.3; MS (EI) m/z 302 (M+
+ 2, 3), 300 (M+, 3), 202 (4), 201 (41), 199 (41), 185 (16), 183
(17), 102 (100), 74 (39), 56 (9); HRMS (EI) calcd for C13H17-
BrO3 300.0361, found m/z 300.0370, 300.0361 (M+). Asterisk
corresponds to the minor isomer.
Ethyl
3-Hydroxy-2-methyl-3-naphth-2-ylbutyrate
(7ga).5d Repetitive column chromatography purification (three
times) afforded anti (major) isomer 7ga1 in ∼80% of total yield.
The syn (minor) isomer 7ga2 was isolated in ∼5% yield and
the rest as a mixture of diastereomers. (2S*,3S*)-Ethyl
3-hydroxy-2-methyl-3-naphth-2-ylbutyrate (7ga1): anti
(major) isomer, isolated as a colorless thick oil; IR (neat) 3490,
2981, 1708, 1454, 1373, 1184 cm-1; 1H NMR (270 MHz, CDCl3)
7.91 (s, 1 H), 7.82-7.78 (m, 3 H), 7.56-7.44 (m, 3 H), 4.26 (s,
1 H), 3.85 (q, J ) 7.3 Hz, 2 H), 3.14 (q, J ) 7.0 Hz, 1 H), 1.54
(s, 3 H), 1.38 (d, J ) 7.0 Hz, 3 H), 0.87 (t, J ) 7.3 Hz, 3 H); 13
C
NMR (100 MHz, CDCl3) 176.7, 145.0, 133.0, 132.3, 128.1,
127.7, 127.3, 125.9, 125.7, 123.4, 123.3, 74.8, 60.5, 48.3, 26.7,
13.7, 12.4; MS (EI) m/z 272 (M+, 1), 254 (1), 172 (4), 171 (33),
170 (58), 155 (100), 127 (89), 57 (14); HRMS (EI) calcd for
C17H20O3 272.1412, found m/z 272.1427 (M+).
Preparation of Ester Derivative 4-Chlorobenzoic acid-
2-ethoxycarbonyl-1-methyl-1-naphthalen-2-ylpropyl Es-
ter (7gaB) from Major Isomer 7ga1. The esterification was
performed according to the literature method.11,12 A flask was
charged with dry dichloromethane (10 mL) and 7ga1 (1.0
mmol) under a nitrogen atmosphere at room temperature. To
this solution were sequentially added MgBr2 (2.0 mmol), Et3N
(3.0 mmol), and 4-chlorobenzoic acid anhydride (2.0 mmol).
After the mixture was stirred for 15 h, water (10 mL) was
added. The water phase was extracted with ethyl acetate, and
the organic layer was dried over MgSO4. The solvent was
distilled off under reduced pressure. Column chromatographic
purification (hexane/AcOEt, 3/1) of the resultant residue on
silica gel gave the esterified product 7gaB in 65% yield.
Recrystallization from hexane/ether gave the suitable crystals
for X-ray analysis. See the Supporting Information for the
X-ray structure data.
Ethyl 3-(9H-Fluoren-2-yl)-3-hydroxy-2-methylbutyrate
(7ia): (2S*,3S*)-Ethyl 3-(9H-Fluoren-2-yl)-3-hydroxy-2-
methylbutyrate (7ia1). Column chromatographic purification
afforded a pale yellow thick oil, which solidified as a viscous
solid later on: IR (deposit from CHCl3) 3494, 3016, 1704, 1214,
1
1191 cm-1; H NMR (400 MHz, CDCl3) 7.75 (d, J ) 7.6 Hz, 1
H), 7.71 (d, J ) 7.6 Hz, 1 H), 7.65 (s, 1 H), 7.53 (d, J ) 7.6 Hz,
1 H), 7.42-7.25 (m, 3 H) 4.18 (s, 1 H,), 3.90 (q, J ) 7.0 Hz, 2
H), 3.90 (s, 2 H), 3.06 (q, J ) 7.0 Hz, 1 H), 1.50 (s, 3 H,), 1.35
(d, J ) 7.0 Hz, 3 H), 0.94 (t, J ) 7.0 Hz, 3 H); 13C NMR (100
MHz, CDCl3) 176.8, 146.4, 143.4, 143.1, 141.4, 140.2, 126.7,
126.5, 125.0, 123.4, 121.5, 119.8, 119.3, 74.9, 60.5, 48.6, 36.9,
27.0, 13.8, 12.5; MS (EI) m/z 310 (M+, 0.4), 292 (1), 209 (22),
208 (65), 194 (15), 193 (100), 179 (1.5), 165 (88), 164 (12), 163
(16), 139 (6); HRMS (EI) calcd for C20H22O3 310.1569, found
m/z 310.1565 (M+). (2R*,3S*)-Ethyl 3-(9H-Fluoren-2-yl)-3-
hydroxy-2-methylbutyrate (7ia2). Isolated as a pale yellow
thick oil, solidified as a viscous solid later on: IR (deposit from
7gaB. isolated as a colorless solid. Repetitive recrystalliza-
tion from hexane/ether was carried out (∼35 mg of compound
in a solution of ∼1.5 mL diethyl ether and ∼1 mL hexane was
subjected to ultrasonication until a clear (diethyl ether can be
used if needed more) solution was obtained, which was allowed
to stand at rt for ∼1 day to afford the crystals): mp 117-115
°C; IR (KBr) 3000, 1720, 1592, 1384, 1272, 1176, 1091 cm-1
;
1H NMR (270 MHz, CDCl3) 8.01 (d, J ) 8.1 Hz, 2 H), 7.84-
7.81 (m, 4 H), 7.50-7.24 (m, 5 H), 4.21 (m, 2 H), 3.26 (q, J )
7.0 Hz, 1 H), 2.22 (s, 3 H), 1.27 (t, J ) 7.3 Hz, 3 H), 1.02 (d, J
) 7.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) 173.6, 163.5, 139.7,
139.4, 132.6, 132.6, 131.1, 129.5, 128.6, 128.4, 128.3, 127.5,
126.3, 126.2, 124.7, 122.8, 85.4, 60.7, 51.2, 18.4, 14.2, 12.5; MS
(EI) m/z 411 (M+ + 1, 1), 410 (M+, 6), 254 (18), 239 (5), 225
(3), 209 (6), 208 (2), 181 (12), 165 (10), 152 (5), 139 (100), 113
(3); HRMS (EI) calcd for C24H23ClO4 410.1285, found m/z
410.1268 (M+).
CHCl3) 3517, 3016, 1708, 1214 cm-1 1H NMR (270 MHz,
;
CDCl3) 7.78-7.67 (m, 2 H), 7.67 (s, 1 H), 7.53 (d, J ) 7.0 Hz,
1 H), 7.43-7.25 (m, 3 H), 4.23-4.16 (m, 2 H), 4.01 (s, 1 H,),
3.90 (s, 2 H), 2.90 (q, J ) 7.3 Hz, 1 H), 1.66 (s, 3 H), 1.32 (t, J
) 7.0 Hz, 3 H), 0.99 (d, J ) 7.0 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) 177.4, 143.8, 143.4, 143.2, 141.4, 140.2, 126.7, 126.5,
125.0, 123.4, 121.6, 119.7, 119.4, 74.6, 60.9, 49.4, 37.0, 30.1,
14.2, 12.8; MS (EI) m/z 310 (M+, 1), 292 (2), 209 (31), 208 (63),
194 (15), 193 (100), 166 (16), 165 (85), 163 (17), 115 (5), 83 (9);
HRMS (EI) calcd for C20H22O3 310.1569, found m/z 310.1593
(M+).
(2R*,3S*)-Ethyl
3-hydroxy-2-methyl-3-naphth-2-yl-
butyrate (7ga2): syn (minor) isomer, isolated as a colorless
thick oil; IR (neat) 3502, 1712, 1488, 1191 cm-1; 1H NMR (270
MHz, CDCl3) 7.99 (s, 1 H), 7.87-7.79 (m, 3 H), 7.49-7.24 (m,
3 H), 4.30-4.14 (m, 2 H), 4.11 (s, 1 H), 2.96 (q, J ) 7.3 Hz, 1
H), 1.64 (s, 3 H), 1.31 (t, J ) 7.3 Hz, 3 H), 0.97 (d, J ) 7.3 Hz,
3 H); 13C NMR (100 MHz, CDCl3) 177.4, 142.3, 133.1, 132.2,
128.2, 127.8, 127.4, 126.0, 125.7, 123.8, 123.1, 74.5, 60.9, 49.0,
30.0, 14.2, 12.8; MS (EI) m/z 272 (M+, 1), 171 (31), 155 (100),
141 (2), 127 (81), 126 (13), 102 (4), 101 (5), 57 (15); HRMS
(EI) calcd for C17H20O3 272.1412, found m/z 272.1415 (M+).
Ethyl 3-(9H-Fluoren-2-yl)-3-hydroxy-2-ethylbutyrate
(7ib): (2S*,3S*)-Ethyl 3-(9H-Fluoren-2-yl)-3-hydroxy-2-
ethylbutyrate (7ib1). Column chromatographic purification
afforded a pale yellow thick oil, which solidified as a viscous
solid: IR (deposit from CHCl3) 3490, 2973, 1708, 1461, 1191
1
cm-1; H NMR (270 MHz, CDCl3) 7.76 (d, J ) 7.0 Hz, 1 H),
7.70 (d, J ) 7.0 Hz, 1 H), 7.63 (s, 1 H), 7.53 (d, J ) 7.0 Hz, 1
H), 7.42-7.23 (m, 3 H), 4.05 (s, 1 H), 3.85 (q, J ) 7. 0 Hz, 2
H), 3.87 (s, 2 H,), 2.87 (dd, J1 ) 10.3, J2 ) 4.9 Hz, 1 H), 1.96-
1.86 (m, 2 H), 1.53 (s, 3 H), 0.96 (t, J ) 7.3 Hz, 3 H), 0.87 (t,
J ) 7.0 Hz, 3 H); 13C NMR (67.9 MHz, CDCl3) 176.3, 146.5,
143.4, 143.1, 141.4, 140.3, 126.7, 126.5, 125.0, 123.5, 121.4,
119.8, 119.3, 75.1, 60.3, 56.9, 36.9, 27.4, 20.6, 13.9, 12.4; MS
(EI) m/z 324 (M+, 0.4), 209 (22), 208 (64), 194 (15), 193 (100),
Ethyl 3-Hydroxy-2-ethyl-3-naphth-2-ylbutyrate (7gb).
Column chromatographic purification afforded a mixture of
anti/syn diastereomers as a colorless thick oil: IR (neat) 3494,
3058, 2973, 1704, 1461, 1022 cm-1; 1H NMR (270 MHz, CDCl3)
7.99 (s,1 H),* 7.90 (s. 1 H), 7.86-7.62 (m, 3 H), 7.53-7.39 (m,
J. Org. Chem, Vol. 70, No. 25, 2005 10417

Babu et al.
179 (2), 165 (89), 164 (10), 163 (16), 139 (6); HRMS (EI) calcd
forded a colorless solid: mp 42-44 °C; IR (KBr) 3417, 1708,
1
for C21H24O3 324.1725, found m/z 324.1702 (M+).
1492, 975 cm-1; H NMR (400 MHz, CDCl3) 7.46-7.32 (m, 2
H), 7.25-7.12 (m, 8 H), 4.49 (s, 1 H), 4.31 (s, 1 H), 4.00 (q, J
) 7.3 Hz, 2 H), 3.43-3.32 (m, 1 H), 3.22-3.11 (m, 1 H), 3.12
(d, J ) 16.0 Hz, 1 H), 3.03 (d, J ) 16.0 Hz, 1 H), 1.11 (t, J )
7.3 Hz, 3 H), 1.09 (t, J ) 7.3 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) 172.9, 143.6, 137.4, 128.6, 127.5, 127.4, 127.2, 126.9,
125.9, 87.4, 77.0, 65.1, 60.5, 41.2, 15.0, 13.9; MS (CI) m/z 329
(M+ + 1, 3), 311 (66), 284 (19), 283 (100), 237 (2), 195 (2), 193
(6); HRMS (CI) calcd for C20H25O4 329.1753, found m/z
329.1735 (M+ + 1).
(2R*,3S*)-Ethyl 3-(9H-Fluoren-2-yl)-3-hydroxy-2-eth-
ylbutyrate (7ib2). Column chromatographic purification af-
forded a pale yellow oil, solidified as a viscous solid later on:
IR (deposit from CHCl3) 3517, 3019, 1704, 1214, 1191 cm-1
;
1H NMR (270 MHz, CDCl3) 7.78-7.37 (m, 2 H), 7.68 (s, 1 H),
7.53 (d, J ) 7.0 Hz, 1 H), 7.43-7.25 (m, 3 H), 4.24 (q, J ) 7.3
Hz, 2 H), 3.90 (s, 2 H), 3.89 (s, 1 H), 2.72 (dd, J1 ) 11.3, J2 )
3.8 Hz, 1 H), 1.78-1.58 (m, 2 H), 1.58 (s, 3 H), 1.33 (t, J ) 7.3
Hz, 3 H), 0.76 (t, J ) 7.3 Hz, 3 H); 13C NMR: (100 MHz, CDCl3)
176.9, 146.1, 143.4, 143.2, 141.4, 140.2, 126.7, 126.5, 125.0,
123.4, 121.6, 119.8, 119.4, 74.3, 60.8, 57.7, 37.0, 30.4, 21.0, 14.4,
12.2; MS (EI) m/z 324 (M+, 0.3), 209 (21), 208 (67), 194 (16),
193 (100), 166 (14), 165 (85), 163 (17), 115 (4), 97 (5); HRMS
(EI) calcd for C21H24O3 324.1725, found m/z 324.1711 (M+).
(3S*,4R*)-Ethyl 3-Hydroxy-3,4-diphenyl-4-methoxy-
butanoate (11d). Column chromatographic purification af-
forded a colorless solid: mp 94-96 °C; IR (KBr) 3495, 1712,
1203, 748, 702 cm-1 1H NMR (400 MHz, CDCl3) 7.31-7.06
;
(m, 10 H), 4.51 (s, 1 H), 4.23 (s, 1 H), 4.02 (q, J ) 7.3 Hz, 2 H),
3.17 (s, 3 H), 3.07 (s, 2 H), 1.12 (t, J ) 7.3 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) 172.8, 143.2, 136.5, 128.7, 127.6, 127.5,
127.3, 126.9, 125.8, 89.4, 77.1, 60.6, 57.4, 41.5, 13.9; MS (CI)
m/z 315 (M+ + 1, 67), 297 (100), 283 (52), 269 (3), 237 (10);
HRMS (CI) calcd for C19H23O4 315.1596, found m/z 315.1584,
315.1624 (M+ + 1). Anal. Calcd for C19H22O4: C, 72.59; H, 7.05.
Found: C, 72.51; H, 7.06. The stereochemistry of the products
was established on the basis of similarity in the spectral data
and the X-ray structure analysis reported by us.13
(3S*,2S*)-Ethyl
3-Hydroxy-4-methoxy-2-methyl-3-
phenylbutyrate (7ja1). Column chromatographic purification
afforded the major anti isomer in pure form as a colorless thick
oil: IR (neat) 3482, 2981, 2888, 1712, 1450, 1191, 767 cm-1
;
1H NMR (400 MHz, CDCl3) 7.50-7.45 (m, 2 H), 7.37-7.24 (m,
3 H), 4.26 (s, 1 H), 4.19 (q, J ) 7.4 Hz, 2 H), 3.63 (d, J ) 10.0
Hz, 1 H), 3.51 (d, J ) 10.0 Hz, 1 H), 3.32 (s, 3 H), 2.93 (q, J )
7.2 Hz, 1 H), 1.30 (t, J ) 7.4 Hz, 3 H), 0.94 (d, J ) 7.3 Hz, 3
H); 13C NMR (67.9 MHz, CDCl3) 176.6, 141.8, 128.1, 127.0,
125.1, 80.1, 76.5, 60.7, 59.3, 45.6, 14.1, 12.7; MS (CI) m/z 253
(M+ + 1, 12), 237 (2), 236 (17), 235 (100), 207 (5), 175 (1), 151
(3), 103 (1); HRMS (CI) calcd for C14H21O4 253.1440, found m/z
253.1439 (M+ + 1). The minor isomer was isolated as a mixture
with the major isomer.
(3S*,4R*)-Ethyl 3-Hydroxy-3-phenyl-4-methoxypen-
tanoate (11e). Column chromatographic purification afforded
a colorless thick oil: IR (neat) 3482, 1712, 1450, 1033, 701
cm-1; 1H NMR (400 MHz, CDCl3) 7.49-7.22 (m, 5 H), 4.44 (s,
1 H), 4.03 (q, J ) 7.3 Hz, 2 H), 3.43 (q, J ) 6.4 Hz, 1 H), 3.09
(s, 3 H), 3.06 (d, J ) 16.0 Hz, 1 H), 2.83 (d, J ) 16.0 Hz, 1 H),
1.11 (t, J ) 7.3 Hz, 3 H), 0.95 (d, J ) 6.4 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) 173.0, 143.6, 128.1, 127.0, 125.4, 83.0, 77.3,
60.5, 57.2, 42.8, 14.0, 12.1; MS (CI) m/z 253 (M+ + 1, 3), 236
(13), 235 (100), 207 (3), 193 (4), 161 (3), 105 (3); HRMS (CI)
calcd for C14H21O4 253.1362, found m/z 253.1445 (M+ + 1).
Ethyl 2-[(1S*,2S*)-1-Hydroxy-2-methoxycyclohexyl]-
acetate (11f). Column chromatographic purification afforded
a colorless thick oil (data for major isomer): IR (neat) 3494,
1728, 1450, 1327, 1103 cm-1; 1H NMR (270 MHz, CDCl3) 4.15
(q, J ) 7.3 Hz, 2 H), 3.34 (s, 3 H), 3.24 (s, 1 H), 3.05 (dd, J )
10.5, 4.2 Hz, 1 H), 2.59 (d, J ) 14.2 Hz, 1 H), 2.43 (d, J ) 14.2
Hz, 1 H), 1.85-1.25 (m, 8 H), 1.28 (t, J ) 7.3 Hz, 3 H); 13C
NMR (67.9 MHz, CDCl3) 172.1, 82.9, 72.5, 60.3, 56.5, 44.0,
36.1, 25.2, 23.6, 20.8, 14.2; MS (EI) m/z 216 (M+, 29), 198 (27),
184 (45), 170 (13), 143 (36), 138 (27), 97 (53), 84 (100); HRMS
(EI) calcd for C11H20O4 216.1362, found m/z 216.1366, 216.1375
(M+).
(2S*,3S*)-3-Hydroxy-2-ethyl-3-phenylpentanedioic Acid
5-Ethyl Ester 1-Methyl Ester (13a). Column chromato-
graphic purification afforded a colorless thick oil: IR (neat)
3482, 2969, 1727, 1446 cm-1; 1H NMR (400 MHz, CDCl3) 7.41-
7.21 (m, 5 H), 4.59 (s, 1 H), 3.96 (double q, 2 H), 3.57 (s, 3 H),
3.27 (d, J ) 16.0 Hz, 1 H), 2.81 (d, J ) 16.0 Hz, 1 H), 2.67 (dd,
J ) 12.0, 3.2 Hz, 1 H), 1.76-1.68 (m, 1 H), 1.54-1.47 (m, 1
H), 1.04 (t, J ) 7.0 Hz, 3 H), 0.79 (t, J ) 7.6 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) 174.3, 172.2, 143.8, 128.0, 127.1,
125.1, 75.4, 60.5, 58.7, 51.4, 42.7, 20.4, 13.7, 12.2; MS (CI) m/z
295 (M+ + 1, 87), 278 (17), 277 (100), 245 (31), 231 (5), 207
(4), 193 (9), 103 (2); HRMS (CI) calcd for C16H23O5 295.1546,
found m/z 295.1559 (M+ + 1).
Ethyl 3-Hydroxy-4-methoxy-2,3-dimethylbutyrate (7ka).
Isolated as a mixture of diastereomers as a colorless oil: IR
(neat) 3508, 2981, 2888, 1731, 1461, 1373, 1191 cm-1; 1H NMR
(270 MHz, CDCl3) 4.20-4.11 (m, 2 H), 3.52 (s, 1 H), 3.63, 3.58
(s, 3 H), 3.33-3.24 (m, 2 H), 2.73-2.63 (m, 1 H), 1.31-1.25
(m), 1.22, 1.15 (s, 3 H), 1.21-1.17 (m, 3 H); 13C NMR (100 MHz,
CDCl3) 176.1, 175.6,* 79.1, 72.8, 72.5,* 60.4, 60.4,* 59.2, 45.6,*
44.8, 22.9,* 21.1, 14.1, 12.3,* 11.8; MS (CI) m/z 191 (M++1,
82), 174 (9), 173 (100), 145 (25), 113 (11), 103 (4), 99 (4); HRMS
(CI) calcd for C9H19O4 191.1283, found m/z 191.1286, (M+
1). Asterisk corresponds to the minor isomer.
+
(3S*,4R*)-Ethyl 3-Hydroxy-3,4-diphenyl-4-isopropoxy-
butanoate (11a). Column chromatographic purification af-
forded a colorless solid: mp 77-79 °C; IR (KBr) 3417, 1700,
1454, 852, 698 cm-1 1H NMR (270 MHz, CDCl3) 7.38-7.36
;
(m, 2 H), 7.26-7.19 (m, 8 H), 4.44 (s, 1 H), 4.37 (s, 1 H), 3.98
(q, J ) 7.3 Hz, 2 H), 3.34-3.25 (m, 1 H), 3.14 (d, J ) 16.0 Hz,
1 H), 2.94 (d, J ) 16.0 Hz, 1 H), 1.09 (t, J ) 7.3 Hz, 3 H), 1.02
(d, J ) 6.5 Hz, 3 H), 0.89 (d, J ) 6.5 Hz, 3 H); 13C NMR (67.9
MHz, CDCl3) 172.9, 144.0, 138.2, 128.7, 127.4, 127.3, 127.1,
126.8, 126.1, 84.8, 77.5, 70.0, 60.5, 40.6, 23.2, 20.5, 14.0; MS
(CI) m/z 343 (M+ + 1, 3), 325 (20), 284 (19), 283 (100), 255 (2),
195 (2), 193 (3); HRMS (CI) calcd for C21H27O4 343.1909, found
m/z 343.1905 (M+ + 1). Anal. Calcd for C21H26O4: C, 73.66; H,
7.65. Found: C, 73.18; H, 7.62.
(3S*,4R*)-Ethyl 3-Hydroxy-3,4-diphenyl-4-isobutyl-
oxybutanoate (11b). Column chromatographic purification
afforded a colorless thick oil: IR (neat) 3495, 1712, 1454 cm-1
;
1H NMR (270 MHz, CDCl3) 7.38-7.35 (m, 2 H), 7.27-7.13 (m,
8 H), 4.41 (s, 1 H), 4.29 (s, 1 H), 3.98 (q, J ) 7.3 Hz, 2 H), 3.17
(d, J ) 16.0 Hz, 1 H), 3.07 (dd, J1 ) 8.8, J2 ) 6.5 Hz, 1 H),
2.97 (d, J ) 16.0 Hz, 1 H), 2.83 (dd, J1 ) 8.8, J2 ) 6.5 Hz, 1
H), 1.82-1.72 (m, 1 H), 1.09 (t, J ) 7.3 Hz, 3 H), 0.81 (d, J )
8.8 Hz, 3 H), 0.81 (d, J ) 8.8 Hz, 3 H); 13C NMR (67.9 MHz,
CDCl3) 172.8, 143.8, 137.3, 128.7, 127.5, 127.4, 127.2, 126.9,
126.0, 87.8, 76.6, 60.5, 40.6, 28.6, 19.4, 19.4, 13.9; MS (CI) m/z
357 (M+ + 1, 1), 339 (30), 283 (100), 237 (4), 197 (1), 193 (5),
163 (2); HRMS (CI) calcd for C22H29O4 357.2066, found m/z
357.2057 (M+ + 1).
(2R*,3S*)-2-Ethyl-3-phenylpentane-1,3,5-triol (13aB).
Column chromatographic purification afforded a colorless
solid:, mp 94-96 °C; IR (KBr) 3467, 3432, 3401, 1627 cm-1
;
1H NMR (400 MHz, CDCl3) 7.36-7.30 (m, 5 H), 4.97 (s, 1 H),
4.15 (d, J ) 11.6 Hz, 1 H), 3.78-3.71 (m, 2 H), 3.49-3.44 (m,
1 H), 3.31 (s, 1 H), 2.56-2.48 (m, 2 H), 2.05-2.00 (m, 1 H),
1.71-1.66 (m, 1 H), 1.41-1.18 (m, 1 H), 1.17-1.08 (m, 1 H),
0.81 (t, J ) 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) 144.3,
128.0, 126.5, 125.5, 82.5, 61.0, 60.3, 50.5, 40.6, 18.2, 12.5; MS
(CI) m/z 225 (M+ + 1, 6), 189 (33), 177 (100), 159 (17), 151
(13), 105 (17); HRMS (CI) calcd for C13H21O3 225.1491, found
(3S*,4R*)-Ethyl
3-Hydroxy-3,4-diphenyl-4-ethoxy-
butanoate (11c). Column chromatographic purification af-
10418 J. Org. Chem., Vol. 70, No. 25, 2005

In- or In(I)-Employed Reformatsky-Type Reactions
m/z 225.1497 (M+ + 1). See the Supporting Information for
the X-ray structure analysis and ORTEP diagram.
afforded a mixture of diastereomers as a colorless thick oil:
IR (neat) 3502, 2981, 1731, 1457, 1196 cm-1 1H NMR (400
;
(2S*,3S*)-3-Hydroxy-2-methyl-3-phenylpentanedioic
Acid Diethyl Ester (13b). Column chromatographic purifica-
tion afforded a colorless thick oil: IR (neat) 3482, 2981, 1727,
MHz, CDCl3) 4.20-4.11 (m, 4 H), 4.06 (s, 1 H),* 4.04 (s, 1 H),
2.78-2.72 (m, 1 H), 2.59 (s, 2 H), 2.51 (d, J ) 16.0 Hz, 1 H),*
1.30-1.17 (m, 12 H); 13C NMR (100 MHz, CDCl3) 175.4, 172.0,
71.8, 62.6,* 60.6, 60.6, 47.7, 43.9, 24.2,* 24.1, 21.8,* 14.1, 14.0,*
12.6; MS (CI) m/z 233 (M+ + 1, 100), 216 (3), 215 (28), 187 (8),
169 (34), 145 (7), 131 (8), 103 (2); HRMS (CI) calcd for C11H21O5
233.1389 found m/z 233.1401, 233.1379 (M+ + 1). Asterisk
corresponds to the minor isomer.
1450 cm-1 1H NMR (400 MHz, CDCl3) 7.42-7.21 (m, 5 H),
;
4.62 (s, 1 H), 4.08 (q, J ) 7.2 Hz, 2 H), 4.06-3.92 (double q, 2
H), 3.21 (d, J ) 16.0 Hz, 1 H), 2.92 (d, J ) 16.0 Hz, 1 H), 2.87
(q, J ) 7.6 Hz, 1 H), 1.18 (t, J ) 7.2 Hz, 3 H), 1.06 (t, J ) 7.6
Hz, 3 H), 1.04 (t, J ) 7.6 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
174.7, 172.1, 143.5, 128.0, 127.2, 125.3, 75.5, 60.6, 49.9, 43.4,
14.0, 13.9, 12.3; MS (CI) m/z 295 (M+ + 1, 21), 278 (17), 277
(100), 232 (9), 231 (60), 207 (7), 193 (10), 103 (2); HRMS (CI)
calcd for C16H23O5 295.1546, found m/z 295.1552 (M+ + 1).
(2S*,3S*)-3-Hydroxy-2-methyl-3-phenylpentanedioic
Acid 5-Ethyl Ester 1-Methyl Ester (13c). Column chro-
matographic purification afforded a colorless thick oil: IR
(neat) 3486, 2981, 1727, 1450 cm-1; 1H NMR (400 MHz, CDCl3)
7.41-7.22 (m, 5 H), 4.62 (s, 1 H), 3.97 (q, J ) 7.2 Hz, 2 H),
3.63 (s, 3 H), 3.20 (d, J ) 16.0 Hz, 1 H), 2.91 (d, J ) 16.0 Hz,
1 H), 2.88 (q, J ) 7.6 Hz, 1 H), 1.05 (t, J ) 7.2 Hz, 3 H), 1.05
(d, J ) 7.6 Hz, 3 H); 13C NMR (100 MHz, CDCl3) 175.0, 172.2,
143.5, 128.1, 127.2, 125.3, 75.5, 60.7, 51.7, 49.9, 43.4, 13.9, 12.3;
MS (CI) m/z 281 (M+ + 1, 36), 264 (26), 263 (100), 232 (5), 231
(33), 217 (9), 194 (4), 193 (35); HRMS (CI) calcd for C15H21O5
281.1389, found m/z 281.1379 (M+ + 1).
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan. Thanks are due to Mr. H. Moriguchi, Faculty of
Engineering, Osaka University, for assistance in obtain-
ing MS spectra.
Supporting Information Available: General experimen-
tal procedures, determination of relative stereochemistry of
key products, 1H NMR spectra of active species determination,
details of X-ray structure analyses, and 13C NMR spectra of
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(2S*,3S*)-3-Hydroxy-2,3-dimethylpentanedioic Acid Di-
ethyl Ester (13e). Column chromatographic purification
JO051659W
J. Org. Chem, Vol. 70, No. 25, 2005 10419