Rhodium-catalyzed Reformatsky-type reaction for asymmetric synthesis of difluoro-β-lactams using menthyl group as a chiral auxiliary

Article abstract of DOI:10.1016/j.tetlet.2008.04.101

We developed a new methodology for the asymmetric Reformatsky-type reaction of (-)-menthyl bromodifluoroacetate (2) with imine in the presence of RhCl(PPh₃)₃. Ester 2 with the cost-effective chiral auxiliary gave (S)-difluoro-β-lacta

Full text of DOI:10.1016/j.tetlet.2008.04.101

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3839–3843
Rhodium-catalyzed Reformatsky-type reaction
for asymmetric synthesis of difluoro-b-lactams
using menthyl group as a chiral auxiliary
Atsushi Tarui, Daiki Ozaki, Naoko Nakajima, Yuto Yokota, Yasser S. Sokeirik,
Kazuyuki Sato, Masaaki Omote, Itsumaro Kumadaki, Akira Ando *
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
Received 27 February 2008; revised 14 April 2008; accepted 17 April 2008
Available online 22 April 2008
Abstract
We developed a new methodology for the asymmetric Reformatsky-type reaction of (ꢀ)-menthyl bromodifluoroacetate (2) with imine
in the presence of RhCl(PPh3)3. Ester 2 with the cost-effective chiral auxiliary gave (S)-difluoro-b-lactams in moderate to good yields and
high diastereoselectivities through spontaneous removal of the auxiliary.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Fluorine; Rhodium; Difluoro-b-lactam; Imine; Diethylzinc; Chiral auxiliary; Reformatsky-type reaction
Fluorine compounds have attracted much attention in
Boc
Ph
Boc
Ph
OH
H
OH
H
NH
NH
the field of bioactive materials as medicines. The bioactivity
of the fluorine compounds is usually affected by the posi-
tion or configuration of fluorine atoms or groups.1 So,
the developments of their regio- or stereoselective introduc-
tion to organic molecules have been strongly desired. On
the other hand, gem-difluoromethylene compounds are
one of the most attractive compounds among the bioactive
fluorine compounds.2 Especially, difluoromethylene analog
of b-amino acids are interesting in the bioactivity, and they
have been synthesized by several methods.3 For example,
enzyme inhibitors for HIV protease, a-chymotrypsin, and
rennin, which have a,a-difluoro-b-amino acid unit in their
molecules, were synthesized.4
O
O
O
O
2'
2'
OH
OH
O
O
F F
OH
HO
BzO
HO
BzO
O
O
AcO
Docetaxel
AcO
2',2'-Difluoro analog of docetaxel
Fig. 1. Anticancer taxoid docetaxel and 20,20-difluoro analog of docetaxel.
difluorinated analog of docetaxel, an anticancer taxoid,
and its activity was compared with docetaxel (Fig. 1).6
Here, it was necessary to provide a chiral difluoro-b-
amino acid unit to synthesize the compound, which was
performed by ring-opening esterification of taxane alcohol
with chiral difluoro-b-lactam.7 However, there are only few
reports on the asymmetric synthesis of difluoro-b-lactams
and/or difluoro-b-amino acids.8 The asymmetric Refor-
matsky reaction have been carried out mainly using dia-
stereoselective methods. On the other hand, although
asymmetric Reformatsky reactions using chiral ligands
have also been reported, they were applied only to carbonyl
The Reformatsky reaction have been used frequently to
prepare difluoro-b-amino acids and/or difluoro-b-lactams
unit of many bioactive compounds in one step.5 One exam-
ple using Reformatsky reaction is Soga’s synthesis of 20,20-
*
Corresponding author. Tel.: +81 72 866 3140; fax: +81 72 850 7020.
E-mail address: aando@phram.setstnsn.ac.jp (A. Ando).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.101

3840
A. Tarui et al. / Tetrahedron Letters 49 (2008) 3839–3843
compounds and did not give high ee even by the use of the
stoichiometric amount of ligand. Recently, Knochel and
co-workers reported an asymmetric Reformatsky reaction
using DAIB to give a high ee, but the reaction required
nearly stoichiometric amount of expensive DAIB.9 Honda
and his co-workers reported a novel Reformatsky reaction
of non-fluorinated bromoacetate using Wilkinson catalyst
and diethylzinc (Honda’s Reformatsky reaction).10 We
applied their method to the reaction of ethyl bromodifluo-
roacetate with imines and obtained difluoro-b-lactams in
good yields.11 Further, we have developed an asymmetric
Reformatsky reaction of ethyl bromodifluoroacetate (1)
with chiral imines to give difluoro-b-lactams in a good
diastereoselectivity. On the other hand, Qurion and his
co-workers reported a similar asymmetric Reformatsky
reaction with imine using activated zinc,8a,12 while we used
diethylzinc.11b However, removal of the expensive chiral
auxiliary from the product had remained as a problem.
To solve this problem, we designed a new strategy for the
asymmetric Reformatsky-type reaction of imine using bro-
modifluoroacetate of a chiral alcohol. Herein, we would
like to report our new results for asymmetric synthesis of
difluoro-b-lactams based on the above strategy.
As the chiral auxiliary, we selected natural chiral alco-
hols of easy availability, such as menthol. Tomioka et al.
have showed high asymmetric induction of menthyl acetate
on Mannich reaction.13 However, the application of men-
thyl bromoacetate to Reformatsky reaction did not show
high de even in the presence of amino alcohol ligands.14
Generally, the reaction of bromodifluoroacetate with imi-
nes led to addition, followed by internal cyclization, to give
difluoro-b-lactams.5a Based on these results, we planned
asymmetric Reformatsky-type reaction using (ꢀ)-menthyl
group as chiral auxiliary expecting the construction of
difluoro-b-lactam skeleton through spontaneous removal
of chiral auxiliary.
First, some bromodifluoroacetates (2–4) with chiral aux-
iliaries on the ester moiety were synthesized by transesteri-
fication of 1 with chiral natural alcohols (Scheme 1).15
Next, we examined the reaction of the chiral bromo-
difluoroacetates with imine (5a) by the previous reaction
condition that was used on the reaction of ethyl bromo-
difluoroacetate with chiral imines to give chiral difluoro-
b-lactams.11b The results are shown in Table 1.
Chiral alcohol
O
O
KOt-Bu
R*
Br
Br
O
O
hexane
F F
F F
1
2: R = (−)-menthyl, 80%
3: R = (+)-menthyl, 74%
4: R = (+)-isomenthyl, 49%
Scheme 1. Transesterification of ethyl bromodifluoroacetate with chiral
alcohols.
Table 1
Effect of chiral auxiliaries on the formation of difluoro-b-lactam
RhCl(PPh3)3
PMB
PMB
O
PMB
NH O
O
Et2Zn
N
*
R
N
R*
+
Ph
+
F
O
THF, -10 °C
BrCF2
O
Ph
Ph
H
F
F
F
2-4
5a
6a
7a
Entry
Chiral bromodifluoroacetate
Time (h)
Yield (%)
ee of 6a (%)16
6a
7a
1
2
71
0
92
BrCF2COO
2
2
3
1
3
83
79
58
0
0
91a
22a
91
BrCF2COO
3
BrCF2COO
4
4b
19
11c
BrCF2COO
2
a
Enantiomer of the product obtained by 2.
The reaction was carried out in the absence of Rh catalyst.
The diastereomixture was obtained (6:1).
b
c

A. Tarui et al. / Tetrahedron Letters 49 (2008) 3839–3843
3841
Interestingly, the best result on diastereoselective addi-
tion of CF2COOR* group was brought about by 2 that
was synthesized from the most inexpensive (ꢀ)-menthol
to give difluoro-b-lactam (6a) through spontaneous
removal of the chiral auxiliary in 92% ee as shown in entry
1. Furthermore, (ꢀ)-menthol could be recovered from the
reaction mixture. The product of opposite configuration
was obtained using (+)-menthyl auxiliary (entry 2). On
the other hand, (+)-isomenthyl group was less effective
than (ꢀ)-menthyl group (entry 3). The results of entries
1–3 suggested that the configuration of the product was
governed by the configuration of the alkoxy carbon moiety
on the chiral auxiliary. The stereoselectivity seems to
depend on the total volume of chiral auxiliary: the more
widespread menthyl group works as the better auxiliary
in this reaction. As shown in entry 4, the reaction of (ꢀ)-
menthyl bromodifluoroacetate with 5a in the absence of
Rh catalyst for prolonged reaction time (19 h) gave 6a in
58% yield with 91% ee and non-cyclized product (7a) in
11% yield, which was obtained as the diastereo mixture
(6:1). In entries 1–3, 7a was not observed in 19F NMR at
all. Absence of the Rh catalyst did not affect the stereo-
selectivity, but the chemoselectivity was decreased. So, this
Rh catalyzed system provided high reactivity, chemoselec-
tivity, and stereoselectivity for the Reformatsky-type
reaction.
Next, the influence of the structures of various aldimines
(5a–g) on the reactivity and diastereoselectivity was exam-
ined. The results are shown in Table 2.
The high diastereoselectivities were achieved with aro-
matic imines as shown in entries 1–5. Sterically hindered
1-naphthyl group did not affect the stereoselectivity on
the asymmetric Reformatsky addition, though it lowered
the yield probably due to the steric hindrance (entry 2).
Table 2
Scope of the diastereoselective rhodium-catalyzed Reformatsky addition of 2 with 5a–g using diethylzinc17
R2
RhCl(PPh3)3
R2
R1
R2
O
NH
Et2Zn
O
N
N
+
R1
+
THF, -10 °C
R1
F
F
O
BrCF2COO
H
5a-g
F F
7a-g
2
6a-g
R2 = PMB or PMP
Entry
1
Imine 5
Time (h)
Yield of 6 (%)
ee (%)
92
PMB
N
2
71
5a
H
PMB
N
N
2
3
4
5
6
18
2
45
46
57
66
41
92
94
87
80
80
5b
5c
5d
5e
H
PMB
H
OMe
Cl
PMB
N
N
2
H
PMB
3
H
OMe
O
PMP
N
N
1
5f
H
PMP
7
0.5
14
Racemic
5g
H

3842
A. Tarui et al. / Tetrahedron Letters 49 (2008) 3839–3843
Zn
Et
O
RhCl(PPh3)3
Et2Zn
Zn
BrCF2COOR*
CF2COOR*
Et
F
R*O
9
F
2
8
Reformatsky-type
reagent
Scheme 2. The proposed formation of chiral zinc enolate (9).
The reactions of the imines bearing electron-withdrawing
group on aromatic rings showed slightly low stereoselectiv-
ities (entries 4 and 5). However, all aryl imines (5c–e) affor-
ded the desired products in moderate yields and high ee
(entries 3–5, 80–94% ee). Aliphatic imines (5f,g) also affor-
ded the desired product in low to moderate yields. The
stereoselectivity with cyclohexyl imine (5f) was 80% ee,
but isopropyl imine (5g) gave racemic product (6g); the vol-
ume on the side chain of imines might have an influence on
the stereoselectivity (entries 6 and 7). So, in order to check
the influence of the volume on the side chain of imines
upon the stereoselectivity, we tried to synthesize linear side
chain and tertiary side chain of imines. Unfortunately, it
was difficult to synthesize those imines, so we could not
check these influences. In all the cases where imines could
be synthesized, one diastereomer of the objective
difluoro-b-lactams was obtained in high stereoselectivity
(except in entry 7), and non-cyclized compounds (7) were
not observed even in 19F NMR at all.
The reaction mechanism is not clearly proved, but
Honda and co-workers reported that rhodium catalyst
acted as a catalyst for the formation of the Reformatsky-
type reagent.10a In our previous work, the reaction of ethyl
bromodifluoroacetate (1) with N-phenyl-imine by using
diethylzinc in the absence of Rh catalyst gave the product
in 60% yield, while the reaction time was much longer than
that in the presence of Rh catalyst. This result supported
Honda’s mechanism, and the Rh catalyst would only accel-
erate the formation of chiral zinc enolate (9) (Scheme 2).
The resulting chiral zinc enolate (9) added to imine dia-
stereoselectively followed by the spontaneous removal of
chiral auxiliary to give chiral difluoro-b-lactams (6) and
(ꢀ)-menthol. The study on the further mechanistic details
is in progress.
PMB
H
O
O
CAN
N
N
F
F
F
CH3CN - H2O
Ph
Ph
F
6a
10a
H2SO4
Et2O
Ph
N
Ph
Ph
N
HO
TfO
Tf2O, Pyr.
CH2Cl2
DBU
O
O
O
N
CH2Cl2
F
F
F
F
Ph
Ph
Ph
F
F
11a
12a
13a
Scheme 3. The determination of absolute configuration of 6a.
nes, followed by spontaneous elimination of the chiral aux-
iliary in good yields and high diastereoselectivity. This
highly diastereoselective Reformatsky reaction was
achieved using 2, which was derived from cost-effective
and readily available (ꢀ)-menthol as a chiral source. The
chiral difluoro-b-lactams themselves are expected not only
to have a potentially bio-activity, but also to be the syn-
thon for the chiral difluoroamino acids. Our new conve-
nient route for synthesizing the chiral difluoro-b-lactams
will be used in various areas.
References and notes
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Tetrahedron 1987, 43, 3207; (c) Resnti, G. Tetrahedron 1993, 49, 9385;
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Spanton, S. G.; Kohlbrenner, W. E.; Betebenner, D. A.; Kempf, D. J.;
Norbeck, D. W.; Plattner, J. J.; Erickson, J. W. J. Chem. Soc., Chem.
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Turner, S. R. J. Med. Chem. 1987, 30, 1837–1842.
Finally, the determination of the absolute configuration
of difluoro-b-lactam (6a) is described. The N-deprotection
of 6a was performed by oxidative cleavage with CAN to
give N-free difluoro-b-lactam (10a).18 On the other hand,
the (S)-difluoro-b-lactam (11a),11b obtained from chiral
imine, was also converted to 10a through compound 13a
via few steps (Scheme 3).8a Both the compounds show
the same retention time on chiral HPLC analysis. Thus,
the absolute configuration of 6a was decided to be (S) con-
figuration. We assume the configuration of other products
would be same as 6a.
5. (a) Taguchi, T.; Kitagawa, O.; Suda, Y.; Ohkawa, S.; Hashimoto, A.;
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Lett. 1992, 2, 1235–1238; (c) Tsukamoto, T.; Kitazume, T. J. Chem.
In conclusion, we have developed a new methodology
for the synthesis of chiral difluoro-b-lactams (6) by the
reaction of (ꢀ)-menthyl bromodifluoroacetate (2) with imi-

A. Tarui et al. / Tetrahedron Letters 49 (2008) 3839–3843
3843
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16. In order to determine the optical purity of difluoro-b-lactam (6a), N-
deprotected difluoro-b-lactam (10a) was used as a standard for chiral
HPLC analysis. The deprotection of 6a was performed by oxidative
cleavage with CAN to give 10a in 70% yield, according to literature
18. Optical purities of difluoro-b-lactams (6a–e) obtained from
aromatic imines were determined by this methodology. On the
analysis of ee for 6f,g obtained from aliphatic imines, difluoro-b-
lactams were analyzed directly by chiral HPLC. Chiral HPLC: Daicel
Chiralcel OD-H column (4.6 mm£, 250 mm), isopropanol/hexane =
9:1, wavelength: 254 nm, flow rate: 0.8 mL/min, retention time:
18.9 min ((R)-10a), 38.9 min ((S)-10a).
PMB
Ph
H
O
O
CAN
N
N
F
F
CH3CN - H2O
*
*
6a
Ph
F
F
10a
17. Typical procedure is as follows: under an Ar atmosphere, 2 (938 mg,
3 mmol) was added to the solution of imine (5a, 225 mg, 1 mmol) and
RhCl(PPh3)3 (9 mg, 0.01 mmol) in THF (8 mL) at ꢀ10 °C, then the
mixture was stirred for 30 min. Then, 1.0 M Et2Zn in hexane (3 mL,
3 mmol) was slowly added to the mixture. The mixture was stirred for
2 h at the same temperature, and was quenched with saturated
aqueous NaHCO3. The mixture was filtered through Celite layer, and
the filtrate was extract with AcOEt. The extract was washed with
brine and dried over MgSO4. Concentration of the dried layer in
vacuo followed by flush chromatography on silica gel (AcOEt/
hexane = 2:8) gave the corresponding product (6a, 214 mg, 71%).
18. For removal of PMB or PMP group, see: (a) Wright, J. A.; Yu, J.;
Spencer, J. B. Tetrahedron Lett. 2001, 42, 4033–4036; (b) Buttero, P.
D.; Molteni, G.; Pilati, T. Tetrahedron 2005, 61, 2413–2419.
´
´
´