Copper-promoted enantioselective Reformatsky-type reaction with ketones

Article abstract of DOI:10.1016/j.tetasy.2010.04.058

Controlled living polymerization of a broad range of monomers is a radical process known as ATRP (atom transfer radical polymerization) and is mediated by a variety of metals. A complex of copper has been found to be the most efficient catalyst, with a co

Full text of DOI:10.1016/j.tetasy.2010.04.058

Tetrahedron: Asymmetry 21 (2010) 1503–1506
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Copper-promoted enantioselective Reformatsky-type reaction with ketones
*
Fides Benfatti, Pier Giorgio Cozzi
ALMA MATER STUDIORUM, Dipartimento di Chimica ‘G. Ciamician’, Via Selmi 2, 40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Controlled living polymerization of a broad range of monomers is a radical process known as ATRP (atom
transfer radical polymerization) and is mediated by a variety of metals. A complex of copper has been
found to be the most efficient catalyst, with a copper(I)/copper(II) catalytic cycle. The radical, enantiose-
lective catalytic Reformatsky reaction mediated by Me2Zn can be efficiently promoted by copper(I) com-
plexes avoiding the use of other promoters such as air and oxidant, giving more reproducible and
affordable conditions. The CuCN-mediated enantioselective addition of ethyliodoacetate to functional-
ized ketones is described in this paper.
Received 2 March 2010
Accepted 28 April 2010
Available online 31 May 2010
Dedicated to Professor Henri B. Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
ducible, was sometimes capricious and failure of the reactions
was occasionally observed. The presence of radical inhibitors in
The classical Reformatsky reaction,1 which consists of the zinc-
induced formation of b-hydroxyalkanoates from -halo carbonyl
aged solvents was presumably responsible for the failure. In addi-
tion, the admission of air was not easily controlled in large-scale
reactions. Therefore, we wanted to pursue a more controlled and
easy way to induce radical formation and promote our stereoselec-
tive Reformatsky reaction. Controlled living polymerization of
monomers known as ATRP (atom transfer radical polymerization)
is a radical-mediated process.8 ATPR has had a tremendous impact
on synthesis, and it has been successfully mediated by a variety of
a
compounds with aldehydes or ketones, was introduced more than
115 years ago. More comprehensively, Reformatsky-type reac-
tions2 are those resulting from metal insertion (Zn or Sm, Ti, Co,
In, and Fe) into carbon–halogen bonds, activated by carbonyls or
carbonyl-related groups in a vicinal or vinylogous position, and
subsequent reaction of the resulting enolate with a variety of elec-
trophiles. The reaction is typically heterogeneous, and normally re-
quires activation of the metal in a low oxidation state. However,
making the Reformatsky reaction homogeneous has enabled the
design of a catalytic enantioselective transformation.
Me Zn
2
O
+
MeOOZnMe
2
In this context, the homogeneous Reformatsky reaction based
on the use of Me2Zn or Et2Zn coupled with a catalytic amount of
nickel or rhodium salts has been recently reported.3 In the homo-
geneous version of the Reformatsky reactions, Me2Zn or Et2Zn is
able to reduce the nickel or rhodium salts, favoring the formation
of the corresponding enolates that are rapidly trasmetalated by
R2Zn (R = Me, Et) to the zinc enolate. Recently, we4 and Feringa5
have described catalytic enantioselective Reformatsky reactions
of Me2Zn and iodoacetate, with ketones, aldehydes, and imines,
in the presence of a catalytic amount of ClMn(salen) (20 mol %),
N-methylephedrine (20–30 mol %), and 3,3’-trimethylsilylBINOL
(20 mol %) derivatives as the chiral catalysts. During these studies,
we have suggested that a radical cycle,6 (Fig. 1) established by the
admission of air, or by oxidants, was responsible for effective gen-
eration of the Reformatsky reagent, by formation of methyl radical,
and confirmed by EPR studies.7 However, admission of air or oxi-
dants in the reaction mixture, although in our hands quite repro-
O
Me
OEt
I
O
OEt
MeI
Me2Zn
1
O
Me
O
OEt
OEt
I
ZnMe
* Corresponding author. Tel.: +30 051 2099511; fax: +39 051 2099456.
E-mail address: piergiorgio.cozzi@unibo.it (P.G. Cozzi).
Figure 1. Catalytic cycle for the Reformatsky reaction mediated by Me2Zn.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.058

1504
F. Benfatti, P. G. Cozzi / Tetrahedron: Asymmetry 21 (2010) 1503–1506
Table 2
metals, capable of establishing a redox radical cycle (Ti, Mo, Re, Fe,
Ru, Os, Rh, Co, and Ni).9 Among all of the metals tested in the pro-
cess, complexes of copper has been found to be the most efficient
catalyst, established by a copper(I)/copper(II) catalytic cycle.10
Therefore, we reasoned to use copper(I) or (II) salts in establishing
the radical cycle in a stereoselective Reformatsky reaction with ke-
tones, and herein we report our findings.
Reformatsky reaction promoted by CuCN
Entrya
Ligand
Solvent
eeb (%)
1
2
3
4
5
6
7
2
2
2
2
Et2O
THF
84(R)
80
CH2Cl2
tBuOMe
Toluene
THF/Et2O
THF/Et2O
49
86
78
50
2
c
d
2. Results and discussion
52
Influence of solvents and chiral ligands.
a
The aldol stereoselective reaction to ketones still represents a
considerable synthetic endeavor and few methods for the catalytic
addition of enolate or an enolate equivalent to ketones are
described.
All the reactions were performed using 0.2 mmol of acetophenone in 5 mL of a
mixture THF/Et2O. Copper salts (15 mol %) were added as a solid before the addition
of Me2Zn and ligand. All the reactions were stopped after completion, checked by
TLC.
b
The enantiomeric excess was determined by chiral GC analysis.
The reaction was performed with (1S,2R)-N-methylephedrine.
The reaction was performed with (1S,2R)-N,N-dibutylnorephedrine.
c
d
OH
*
O
CuX , x mol%
Me2Zn, 2 equiv.
OEt
OEt
O
+
I
Furthermore, we noticed that CuCN was not completely soluble
in the reaction mixture. Therefore, in order to increase the effi-
ciency of the process we considered adding phosphines to CuCN,
and the amount of the salt was reduced to 15 mol %.12 Different
electron-rich or electron-poor phosphines, monodentate, or biden-
tate phosphines were examined in the process, and the ees ob-
tained at À25 °C, in the presence of 25 mol % of pyrrolidinyl
norephedrine as the chiral ligand, are reported in Table 3.
Ph
OH
N
O
20 mol%
2 equiv.
1 equiv
Me
THF/Et2O, Temp.
In particular, functionalized a-chloro or -bromo ketones repre-
sent difficult electrophiles for quite reactive enolates, and side
reactions, elimination, or the formation of the corresponding epox-
Table 3
Reformatsky reaction promoted by CuCN
ide can take place during the reaction. On the other hand,
a-chloro
Entrya
Phosphine
Conversion
eeb (%)
ketones and aldehydes are useful synthetic intermediates, and
were only recently investigated. As a-chloro ketones gave poor re-
1
2
3
PPh2CH2PPh2
PPh2(CH2)2PPh2
PPh2(CH2)3PPh2
(pFPh)3P
(2,4,6-MeOPh)3P
PPh2(CH2)2PPh2
(S)-TolBINAP
(S)-TolBINAP
(S,R)-JOSIPHOS
PCy3
<10
50
95
—
sults11 in the Mn(Salen)-promoted, as well as in the N-methyl-
ephedrine-catalyzed, enantioselective Reformatsky reaction, we
wanted to find different activation modes in order to enhance
the reactivity of our radical aldol reaction at low temperature,
86
66
—
70
55
66
0
68
53
43
4
5
<10
95
95
95
95
95
95
6c
7
allowing the employment of the sensitive
a-halo ketones. Given
8d
9
the radical properties of our catalytic Reformatsky reaction, we
have investigated, in a model reaction, the enantioselective addi-
tion of iodoacetate to acetophenone mediated by ZnMe2 in the
presence of N-pyrrolidinyl norephedrine 2 as a chiral ligand. Differ-
ent copper salts were employed in order to promote the reaction
through a radical cycle initiated by the presence of copper salts.
The conversion of the reaction was measured by 1H NMR and the
enantiomeric excess obtained in the model reaction was taken as
an efficiency of the new activation mode. As shown in Table 1,
among all the different copper salts investigated CuCN gave the
best ee% when the reaction was operated at À25 °C. In preliminary
experiments copper salts were used at 30 mol %. The reaction con-
ditions were further optimized, taking into consideration different
solvents and norephedrine derivatives (Table 2).
10
11e
(Ph3P)3CuF(MeOH)2
Influence of copper ligands.
a
All the reactions were performed using 0.2 mmol of acetophenone in tBuOMe
(0.04 M). Copper salts (15 mol %) were mixed with the phosphine and stirred for
0.5 h at rt in 1 mL of DCM; then the solvent was removed under vacuum, tBuOMe
was added followed by Me2Zn and ligand. The mixture was cooled to À25 °C and
finally iodoacetate and acetophenone were added. The reaction mixtures were
stirred at À25 °C for 3 h and then the reactions were quenched. The conversion was
determined by 1H NMR spectroscopy.
b
The enantiomeric excess was determined by chiral GC analysis.
The reaction was performed in the absence of ligand 2.
The reaction was performed in the absence of pyrrolidinylnorephedrine.
The reaction was performed with the phosphine copper complex (Ph3P)3CuF-
c
d
e
(MeOH)2.
Table 1
Copper-mediated catalytic enantioselective Reformatsky reaction
Copper phosphines induce the initiation of the radical process
responsible for the generation of the Reformatsky reagent.
Although dppe (entry 2) was giving the highest enantiomeric ex-
cess in the reaction, the reactivity with acetophenone, and in gen-
eral other ketones, was quite modest. A good compromise between
yield and enantiomeric excess was obtained employing the dppp
phosphine (entry 3), the most efficient phosphine additive. In most
cases, the low ee obtained for some phosphines showed that the
background reaction was quite fast. Monodentate phosphines
were, in general, not suitable, probably due to the formation of
polymeric insoluble complexes.12 On the other hand, the employ-
ment of optically active phosphines (Table 3, entry 8) without
the admission of the aminoalcohol ligand gave no enantiomeric ex-
cess. The copper–phosphine complexes are prepared in CH2Cl2 and,
Entrya
Temp (°C)
Cu salt
X (mol %)
eeb (%)
1
2
3
4
5
6
7
8
0
À25
À25
À25
0
0
0
0
CuCN
CuCN
CuCN
CuCN
CuI
CuBr
CuPF6
CuO
100
100
50
78(R)
82(R)
78(R)
79(R)
62(R)
60(R)
33(R)
60(R)
30
100
100
100
100
a
All the reactions were performed using 0.2 mmol of acetophenone in 5 mL of a
mixture THF/Et2O. Copper salts were added as solid before the addition of Me2Zn
and ligand. All the reactions were stopped after completion, checked by TLC.
b
The enantiomeric excess was determined by chiral GC analysis. The absolute
configuration of the product was established by the elution order.4a,4b

F. Benfatti, P. G. Cozzi / Tetrahedron: Asymmetry 21 (2010) 1503–1506
1505
rapidly, complete dissolution of the copper salt occurs. As we have
found that the background reaction was faster in CH2Cl2 (Table 2,
entry 3), in order to improve ees, we have introduced tBuOMe as
the reaction solvent, performing the reaction in tBuOMe/CH2Cl2
4:1. This solvent mixture gave the best compromise between reac-
tivity and enantioselectivity of the reaction. The reaction, opti-
mized with acetophenone, was tested with different substrates
(À25 °C). The reaction is particularly efficient with
a
-halo ketones,
which are rather challenging substrates for enolate chemistry. We
have gained more knowledge about the possibility of initiating the
radical catalytic cycle of our enantioselective Reformatsky reaction
by the use of metals and additives, and we hope to solve the problems
related to the employment of chiral iodoesters in the near future.
(Table 4), and in particular with
eral moderate enantiomeric excesses ranging from 56% to 72% ee
were obtained with -halo ketones. The reaction gave moderate
yields of the desired products. The absolute configuration of the
products was assigned by analogy with the results obtained with
acetophenone (attack of the Reformatsky reagent on the Re
face).4a,c
a-chloro or bromo ketones. In gen-
4. Experimental
a
4.1. General methods
1H NMR spectra were recorded on Varian 200 MHz, Varian
300 MHz spectrometers. Chemical shifts are reported in ppm from
tetramethylsilane with the solvent resonance as the internal stan-
dard (deuterochloroform: d 7.27 ppm). Data are reported as follows:
chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet,
Table 4
Additon of iodoacetate to
a-haloketones promoted by CuCN–dppp complex, in the
q = quartet, br = broad, m = multiplet), coupling constants (Hz). 13
C
presence of N-pyrrolidinyl norephedrine
NMR spectra were recorded on a Varian 50 MHz, Varian 75 MHz,
or Varian 100 MHz spectrometers with complete proton decoupling.
Chemical shifts are reported in ppm from tetramethylsilane with the
solvent as the internal standard (deuterochloroform: d 77.0 ppm).
Mass spectra were performed at an ionizing voltage of 70 eV. Chro-
matographic purification was done with 240–400 mesh silica gel.
Analytical gas chromatography (GC) was performed on a Hewlett–
Packard HP 6890 gas chromatograph with a flame ionization detec-
tor and split mode capillary injection system, using a Crosslinked 5%
PH ME Siloxane (30 m) column or a Megadex5 chiral (25 m) column.
Analytical high performance liquid chromatography (HPLC) was
performed on a HP 1090 liquid chromatograph equipped with a var-
iable wavelength UV detector (deuterium lamp 190–600 nm), using
Daicel Chiralcel™ OD column (0.46 cm I.D. Â 25 cm) (Daicel Inc.),
Daicel Chiralcel™ IC column (0.46 cm I.D. Â 25 cm) (Daicel Inc.);
HPLC grade isopropanol and n-hexane were used as the eluting
solvents.
All reactions were carried out under a nitrogen atmosphere in
flame-dried glassware using standard inert techniques for intro-
ducing reagents and solvents.
Me2Zn 2 M in toluene was purchased by Fluka. Anhydrous Et2O,
THF, CH2Cl2, toluene, and tBuOMe were purchased by Fluka. All ke-
tones were commercially available and carefully purified by crys-
tallization or distillation before use.
Ph2P
CuCN 15 mol%
PPh2 15 mol%
O
O
O
R2 R1
*
+ Me2Zn +
2eq.
R1
R2
EtO
2eq.
EtO
OH
T, time,
Ph
OH
25%
I
N
tBuOMe:DCM
4:1
Entrya
Ketone
Time (h)
Yieldb
eec (%)
1
2
3
4
5
6
7
8
9
pFPhCOCH2Br
pClPhCOCH2Cl
pClPhCOCH2Br
PhCOCH2Br
PhCOCH2Cl
PhCOCH2CH2Cl
oClPhCH3
20
20
48
48
48
20
20
48
14
90
66
99
50
50
50
40
55
30
59(R)
72
56(R)
69
68(R)
50(S)
72
PhCH2CH2COCH3
CyclopropylCOCH3
32
76
a
b
c
All the reactions were performed on a 0.2 mmol scale as described in Table 3.
Isolated yield after chromatographic purification.
The enantiomeric excess was determined by chiral GC/HPLC analysis.
4.2. Optimized procedure for copper-promoted catalytic
Reformatsky-type reaction with ketones
a
-Halo ketones are important synthetic intermediates for the
preparation of fungicides,13 and recently a key intermediate for
the synthesis of a series of optically active triazole antifungal
agents, such as voriconazole, ravuconazole, TAK-187, and RO-
009481515, was obtained through a diastereoselective Reformat-
sky reaction.14 In particular, the metal–halogen exchange reaction
In a flame-dried, 25 mL, two-necked round-bottomed flask, CuCN
(15 mol %, 3 mg) and dppp (1,2-bis(diphenylphosphino) propane,
15 mol %, 12 mg) were dissolved in anhydrous DCM (1 mL) and stir-
red at rt for 30 min under nitrogen. Then, the solvent was removed
under vacuum and replaced with tBuOMe (5 mL); the mixture was
cooled to À25 °C and Me2Zn (2 equiv, 0.2 mL of 2 M solution in tolu-
ene) was added followed by N-pyrrolidinyl norephedrine (25 mol %,
10 mg) and immediately by ketone (1 equiv, 0.2 mmol) and ethyl
of chiral
der the catalysis of Ni(acac)2 allowed the asymmetric zinc-Refor-
matsky reaction with -halo acetophenone. With other aromatic
ketones, the procedure gave in general less interesting results com-
pared with the methodologies recently described by us and by
Feringa. For aliphatic ketones different results depending on the
ketone investigated were obtained. While quite interesting results
were achieved with cyclopropyl methyl ketone, an unbranched ke-
tone (Table 4, entry 8) gave lower enantiomeric excess.
a-bromopropionyl-2-oxazolidinones with diethyl zinc un-
a
iodoacetate (2 equiv, 48 lL) added at once. The reaction mixture
was stirred at À25 °C for the specified time, then the reaction was
quenched with HCl 1 M and the reaction mixture was diluted with
Et2O. The phases were separated, and the aqueous phase was ex-
tracted with Et2O. The organic phase was collected, dried over
Na2SO4 and evaporated under reduced pressure to give the crude
product, which was purified by chromatography on silica gel.
3. Conclusion
4.3. Analytical data for Reformatsky-type products
In conclusion, we have presented here a new method for the cata-
lytic enantioselective Reformatsky reaction based on the employ-
ment of CuCN as a promoter in the presence of phosphines. The
stereoselective Reformatsky reaction takes place at low temperature
Analytical data for compounds in Table 4, entries 2 and 4 can
be found in Adv. Synth. Catal. 2008, 350, 975–978 (Ref. 4c), for

1506
F. Benfatti, P. G. Cozzi / Tetrahedron: Asymmetry 21 (2010) 1503–1506
compounds in entries 7 and 8 in Angew. Chem. Int. Ed. 2006, 45,
2951–2954 (Ref. 4a).
4.57 (1H, s, OH), 7.28–7.45 (4H, m); 13C NMR (CDCl3, 50 MHz) d:
13.9, 39.6, 45.6, 45.8, 60.9, 74.3, 124.8 (2C), 127.3, 128.4 (2C),
143.7, 172.4; GC–MS: 238 (1), 193 (80), 169 (25), 147 (22), 105
(100), 91 (14), 77 (30); Chiral HPLC analysis OD: isocratic 99:1
(hexane/i-PrOH) for 9 min flow 0.5 mL/min, then gradient to 9:1
in 30 min flow 0.5 mL/min; tm = 16.3 min; TM = 18.1 min.
4.3.1. Ethyl 4-bromo-3-(4-fluorophenyl)-3-hydroxybutanoate
(Table 4, entry 1)
Yellow oil;
[
a
]
D = À14.0 (c 2.00, CHCl3); 1H NMR (CDCl3,
300 MHz) d: 1.18 (3H, t, J = 7.2 Hz), 3.00 (1H, d, J = 16.5 Hz), 3.15
(1H, d, J = 16.5 Hz), 3.53 (1H, d, J = 10.5 Hz), 3.61 (1H, d,
J = 10.5 Hz), 4.04 (2H, q, J = 7.2 Hz), 4.60 (1H, s, OH), 7.03 (2H, dd,
J = 1.5, 8.7 Hz), 7.42 (2H, dd, J = 1.5, 8.6 Hz); 13C NMR (CDCl3,
75 MHz) d: 13.9, 42.4, 42.8, 61.2, 73.7, 115.3 (2C, JC–Fortho = 85.2 Hz),
Acknowledgment
The European commission through the project Fp7-
201431(CATAFLU.OR), PRIN, and Bologna University is acknowl-
edged for financial support.
127.2 (2C, J meta = 33.9 Hz), 138.3, 162.3 (JC–F = 983.1 Hz), 172.1;
C–F
GC–MS: 219 (20), 217 (20), 211 (85), 165 (15), 123 (100), 109
(31), 95 (20), 83 (7), 75 (8); Chiral GC: 3 °C/min ramp from
100 °C to 200 °C, tm = 26.1 min, TM = 26.3 min.
References
1. (a) Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325–9374; (b) Babu, S.
A.; Yasuda, M.; Shibata, I.; Baba, A. J. Org. Chem. 2005, 70, 10408–10419; (c)
Cozzi, P. G. Angew. Chem., Int. Ed. 2007, 46, 2568–2571.
2. (a) Ferstner, A. Synthesia 1989, 571–590; (b) Ferstner, A. In Organozinc Reagents;
Knochel, P., Jones, P., Eds.; Oxford University Press: New York, 1999; pp 287–
305; (c) Nakamura, E. In Organometallics in Synthesis: A Manual; Schlosser, M.,
Ed.; Wiley: New York, 2002; pp 579–664.
3. (a) Adrian, J. C., Jr.; Snapper, M. L. J. Org. Chem. 2003, 68, 2143–2150; (b) Kanai,
K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2, 2549–2551; (c) Kanai, K.;
Wakabayashi, H.; Honda, T. Heterocycles 2002, 58, 47–51; (d) Sato, K.; Tarui, A.;
Kita, T.; Ishida, Y.; Nakamura, H. T.; Omote, M.; Ando, A.; Umadaki, I. K.
Tetrahedron Lett. 2004, 45, 5735–5737.
4. (a) Cozzi, P. G. Angew. Chem., Int. Ed. 2006, 45, 2951–2954; (b) Cozzi, P. G. Adv.
Synth. Catal. 2006, 348, 2075–2079; (c) Cozzi, P. G.; Mignogna, A.; Vicennati, P.
Adv. Synth. Catal. 2008, 350, 975–978; (d) Cozzi, P. G.; Mignogna, A.; Zoli, L. Pure
Appl. Chem. 2008, 80, 891–901; (e) Cozzi, P. G.; Benfatti, F.; Guiteras Capdevila,
M.; Mignogna, A. Chem. Commun. 2008, 3317–3318; (f) Benfatti, F.; Yilmaz, S.;
Cozzi, P. G. Adv. Synth. Catal. 2009, 351, 1763–1767.
5. (a) Fernandez-Ibanez, M. A.; Macia, B.; Minnaard, A. J.; Feringa, B. L. Angew.
Chem., Int. Ed. 2008, 47, 1317–1319; (b) Fernandez-Ibanez, M. A.; Macia, B.;
Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2008, 2571–2573; (c) Fernandez-
Ibanez, M. A.; Macia, B.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2008, 10, 4041–
4044.
6. Bertrand, M.; Feray, S.; Gastaldi, S. Comptes Rendus Chim. 2002, 623–638.
7. Mileo, E.; Benfatti, F.; Cozzi, P. G.; Lucarini, M. Chem. Commun. 2009, 469–470.
8. Pintauer, T.; Matyaszewski, K. Chem. Soc. Rev. 2008, 37, 1087–1097.
9. Matyaszewski, K.; Xia, J. Chem. Rev. 2001, 101, 2921–2990.
10. (a) Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T. Eur. J. Inorg. Chem. 2009, 563–
571; (b) Pintauer, T.; Eckenhoff, W. T.; Ricardo, C.; Balili, M. N. C.; Biernesser, A.
B.; Noonan, S. T.; Taylor, M. T. Chem. Eur. J. 2009, 15, 38–41.
4.3.2. Ethyl 4-bromo-3-(4-chlorophenyl)-3-hydroxybutanoate
(Table 4, entry 3)
Yellow oil;
[a
]
D = À5.3 (c 1.75, CHCl3); 1H NMR (CDCl3,
300 MHz) d: 1.17 (3H, t, J = 7.2 Hz), 3.03 (1H, d, J = 16.2 Hz), 3.18
(1H, d, J = 16.2 Hz), 3.57 (1H, d, J = 10.8 Hz), 3.64 (1H, d,
J = 10.8 Hz), 4.09 (2H, q, J = 7.2 Hz), 4.62 (1H, s, OH), 7.28–7.45
(4H, m); 13C NMR (CDCl3, 50 MHz) d: 13.9, 42.1, 42.6, 61.2, 73.7,
126.8 (2C), 128.6 (2C), 134.7, 141.0, 172.1; GC–MS: 235 (22), 233
(20), 229 (34), 227 (85), 181 (18), 154 (8), 141 (42), 139 (100),
125 (18), 11 (16); Chiral HPLC analysis IC: isocratic 9:1 (hexane/
i-PrOH), flow 1.0 mL/min. TM = 13.6 min; tm = 14.7 min.
4.3.3. Ethyl 4-chloro-3-hydroxy-3-phenylbutanoate (Table 4,
entry 5)
Yellow oil;
[a
]
D = À14.2 (c 1.25, CHCl3); 1H NMR (CDCl3,
300 MHz) d: 1.14 (3H, t, J = 7.2 Hz), 3.05 (1H, d, J = 15.9 Hz), 3.17
(1H, d, J = 15.9 Hz), 3.69 (1H, d, J = 10.5 Hz), 3.77 (1H, d,
J = 10.5 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.58 (1H, s, OH), 7.28–7.51
(4H, m); 13C NMR (CDCl3, 50 MHz) d: 13.8, 41.8, 45.9, 52.9, 60.9,
74.6, 125.2 (2C), 127.8, 128.3 (2C), 142.4, 172.1; GC–MS: 224 (1),
193 (75), 155 (20), 147 (20), 105 (100), 91 (18), 77 (31); Chiral
GC: 5 °C/min ramp from 50 °C to 200 °C, tm = 25.4 min,
TM = 25.6 min.
11. Cozzi, P. G.; Mignogna, A.; Zoli, L. Synthesis 2007, 2746–2750.
12. Lin, Y.-Y.; Lai, S.-W.; Che, C.-M.; Fu, W.-F.; Zhou, Z.-Y.; Zhu, N. Inorg. Chem.
2005, 44, 1511–1524.
13. (a) Fromtling, R. A.; Castãner, J. Drugs Future 1997, 22, 326; (b) Naito, T.; Hata,
K.; Tsuruoka, A. Drugs Future 1996, 21, 20; (c) Tasaka, A.; Kitazaki, T.; Tamura,
N.; Tsuchimori, N.; Matsushita, Y.; Hayashi, R.; Okonogi, K.; Itoh, K. Chem.
Pharm. Bull. 1997, 45, 321; (d) Umeda, I.; Yamazaki, T.; Ichihara, S. Bioorg. Med.
Chem. Lett. 2003, 13, 191.
4.3.4. Ethyl 5-chloro-3-hydroxy-3-phenylpentanoate (Table 4,
entry 6)
Yellow oil;
[a
]
D = À7.3 (c 1.14, CHCl3); 1H NMR (CDCl3,
200 MHz) d: 1.23 (3H, t, J = 7.2 Hz), 2.08–2.22 (2H, m), 2.84 (1H,
d, J = 15.8 Hz), 2.98 (1H, d, J = 15.8 Hz), 3.17 (1H, dt, J = 6.2,
10.6 Hz), 3.61 (1H, dt, J = 5.6, 10.6 Hz), 4.05 (2H, q, J = 7.2 Hz),
14. Yu, L.-T.; Ho, M.-T.; Chang, C.-C.; Yang, T.-K. Tetrahedron: Asymmetry 2007, 18,
949–962.