Evaluation of enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl) methanol for catalytic asymmetric addition of organozinc reagents to aldehydes

Article abstract of DOI:10.1021/jo701943x

(Chemical Equation Presented) A facile and practical approach to preparation of enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)-methanol was developed from cheap and easily available L-(+)-methionine. Synthetic highlights include the three-step, one-pot construction of the chiral azetidine ring and the development of an improved one-step procedure for the synthesis of the key intermediate L-2-amino-4-bromobutanoic acid. Enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol was evaluated for catalytic asymmetric addition of organozinc reagents to aldehydes. The asymmetric ethylation, methylation, arylation, and alkynylation of aldehydes achieved enantioselectivity of up to 98.4%, 94.1%, 99.0%, and 84,6% ee, respectively, in the presence of a catalytic amount of chiral N-(ferrocenylmethyl)azetidin-2- yl(diphenyl)methanol. Our results demonstrated further that the four-membered heterocycle-based backbone was a good potential chiral unit for the catalytic asymmetric induction reaction, and the hindrance of the bulky ferrocenyl group, compared to a phenyl group, played an important role in the enantioselectivities. A possible transition for the catalytic asymmetric addition has been proposed on the basis of the crystal structure of the chiral ligand 3b including two HOAc molecules and previous studies.

Full text of DOI:10.1021/jo701943x

Evaluation of Enantiopure
N-(Ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol for Catalytic
Asymmetric Addition of Organozinc Reagents to Aldehydes
Min-Can Wang,* Qing-Jian Zhang, Wen-Xian Zhao, Xiao-Dan Wang, Xue Ding,
Tao-Tao Jing, and Mao-Ping Song
Department of Chemistry and Henan Key Laboratory of Chemical Biology and Organic Chemistry,
Zhengzhou UniVersity, Zhengzhou, Henan 450052, P. R. China
wangmincan@zzu.edu.cn
ReceiVed September 10, 2007
A facile and practical approach to preparation of enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)-
methanol was developed from cheap and easily available L-(+)-methionine. Synthetic highlights include
the three-step, one-pot construction of the chiral azetidine ring and the development of an improved
one-step procedure for the synthesis of the key intermediate L-2-amino-4-bromobutanoic acid. Enantiopure
N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol was evaluated for catalytic asymmetric addition of
organozinc reagents to aldehydes. The asymmetric ethylation, methylation, arylation, and alkynylation
of aldehydes achieved enantioselectivity of up to 98.4%, 94.1%, 99.0%, and 84.6% ee, respectively, in
the presence of a catalytic amount of chiral N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol. Our
results demonstrated further that the four-membered heterocycle-based backbone was a good potential
chiral unit for the catalytic asymmetric induction reaction, and the hindrance of the bulky ferrocenyl
group, compared to a phenyl group, played an important role in the enantioselectivities. A possible transition
for the catalytic asymmetric addition has been proposed on the basis of the crystal structure of the chiral
ligand 3b including two HOAc molecules and previous studies.
Introduction
Oguni and Omi on the reaction of diethylzinc with benzaldehyde
in the presence of a catalytic amount of (S)-leucinol producing
an addition product with moderate enantioselectivity (49% ee)
in 1984,1 the asymmetric addition of these reagents to prochiral
carbonyl compounds has been studied extensively, and various
chiral ligands have been synthesized to induce asymmetry in
The carbon-carbon bond-forming reaction is one of the most
useful operations for the construction of complex natural and
unnatural organic molecules. Addition of organometallic re-
agents to carbonyl compounds is among the most fundamental
reaction for this purpose, and its enantioselective transformation,
producing a C-C bond and a chiral alcohol center simulta-
neously, is particularly important. Among various organometallic
compounds, organozinc reagents such as diethylzinc, diphe-
nylzinc, and alkynylzinc serve as excellent nucleophiles in the
presence of chiral ligands because of their good tolerance of
various functionalities, including esters, amides, nitro groups,
and nitriles. Moreover, this variation of organozinc species
allows for high synthetic versatility. Since the initial report of
(1) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823.
(2) Reviews on enantioselective organozinc additions to aldehydes: (a)
Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49. (b)
Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833. (c) Pu, L.; Yu, H.-B. Chem.
ReV. 2001, 101, 757. (d) Seebach, D.; Beck, A. K.; Heckel, A. Angew.
Chem. Int. Ed. 2001, 40, 92. (e) Walsh, P. Acc. Chem. Res. 2003, 36, 739.
(f) Li, Z.-B.; Pu, L. Tetrahedron 2003, 59, 9873. (g) Zhu, H.-J.; Jiang,
J.-X.; Ren, J.; Yan, Y.-M.; Pittman, C. U. Curr. Org. Synth. 2005, 2, 547.
(h) Hatano, M.; Miyamoto, T.; Ishihara, K. Curr. Org. Chem. 2007, 11,
127.
10.1021/jo701943x CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/07/2007
168
J. Org. Chem. 2008, 73, 168-176

N-(Ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol
this reaction, including amino alcohols (N,O-ligands), diols
(O,O-ligands), diamines (N,N-ligands), and so on.2 However,
to the best of our knowledge, there is no report on a general
ligand for asymmetric addition of various organozinc reagents
to the prochiral aldehydes with high enantioselectivities, prob-
ably due to differences of reactivity of organozinc species
(methylzinc < ethylzinc < phenylzinc < alkynylzinc). The
development of new chiral ligands plays a key role for
overcoming this limitation, because subtle changes in confor-
mational, steric, and/or electronic properties of the chiral ligands
can often result in dramatic variation of the enantioselectivity
and reactivity.
FIGURE 1. Structure of some chiral nitrogen heterocycles containing
a â-amino alcohol moiety.
In recent years,3-7 we have been exploring the use of chiral
ferrocene-based ligands in catalytic asymmetric synthesis
because of their planar chirality, rigid bulkiness, ease of
derivatization, and stability. Chiral copper complexes of N,P-
ferrocenyl ligands with central and planar chirality as efficient
catalyst have been applied to the enantioselective addition of
diethylzinc to the N-diphenylphosphinoylimines,3 and the ap-
plication for highly enantioselective 1,4-conjugate addition of
diethylzinc to chalcones has also been demonstrated.4 Chiral
ferrocenylamidophosphine ligand for copper-catalyzed asym-
metric addition of diethylzinc to imines has been evaluated,5
and it is only one example that can afford highly enantioselective
addition of diethylzinc to the CdN bond of the different types
of imines such as N-sulfonylimines and N-phosphinoylimines.
A series of chiral ferrocenylaziridino alcohols have been
synthesized and applied to catalytic asymmetric addition of
diethylzinc to aldehydes, and in the best case, enantioselectivities
of up to 99% ee were obtained.6 Evaluation of chiral ferroce-
nylpyrrolidino alcohols for catalytic asymmetric addition of
diethylzinc to aldehydes has been reported.7 Moreover, in our
previous investigation,6c,d we discovered that the replacement
of the phenyl group on the nitrogen atom of three-membered
heterocycle-based skeleton with a ferrocenyl unit led to a
dramatic increase in the enantioselectivity from 49% ee to 92.7%
ee when used as the catalyst in the addition of diethylzinc to
benzaldehyde in the presence of 5 mol % of chiral ligands 1b
(Figure 1). Similar phenomena were also observed in the
presence of 5 mol % of chiral ligands 2b (Figure 1). More
interestingly, four-membered heterocycle containing a â-amino
alcohol moiety as a chiral ligand for catalytic asymmetric
addition of diethylzinc to benzaldehyde afforded the best
enantioselectivity when R was a phenyl group (Figure 1). In
order to examine the generality of these findings or observations,
we decided to synthesize enantiopure N-(ferrocenylmethyl)-
azetidin-2-yl(diphenyl)methanol 3b (Figure 1, R ) Fc) and
evaluated its application in catalytic asymmetric addition of
organozinc reagents to aldehydes.
Among chiral nitrogen heterocycle, azetidines seem to be the
least well studied to date, in terms of both synthetic methods
and applications. This is also the case for chiral 2-substituted
azetidines, as compared with the corresponding aziridines and
pyrrolidines. The main reason for the lack of progress may be
the difficult access to those strained heterocycles from acyclic
derivatives, especially in enantiomerically pure form. The
alternative method for the synthesis of the targeted molecule is
to carry out one-step alkylation of enantiomeric pure (S)-
azetidine-2-carbxylic acid,11 but the (S)-azetidine-2-carboxylic
acid is commercially available in milligram quantities only and
is very expensive. Therefore, it seems highly desirable to find
a simple, efficient, economical protocol for asymmetric con-
struction of the chiral four-membered ring from cheap and easily
available compounds.
More recently, we have reported in a preliminary com-
munication the facile and practical approach to preparation of
enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)metha-
nol from commercially available L-2-amino-4-bromobutanoic
acid and its application in catalytic asymmetric ethylation and
arylation of arylaldehydes.12 In this paper, we present the
extension of this study, including (1) starting from much cheaper
L-(+)-methionine (in our eyes, L-2-amino-4-bromobutanoic acid
is very expensive)13 to prepare and purify enantiopure N-(fer-
rocenylmethyl)azetidin-2-yl(diphenyl)methanol. (2) Highly enan-
tioselective addition of various organozinc reagents such as
dimethylzinc, diethylzinc, diphenylzinc, and alkynylzinc to
aldehydes was assessed. (3) A possible transition state for the
organic species addition reaction is proposed.
Results and Discussion
Synthesis of Chiral Ligand. The preparation of azetidino
alcohol 3b is shown in Scheme 1. Starting from the source of
chirality L-(+)-methionine, the synthetic route consists of eight
steps but only requires four “pots”. The L-homoserine 5 was
prepared readily on a large-scale from L-methionine 4 through
(3) Wang, M.-C.; Liu, L.-T.; Hua, Y.-Z.; Zhang, J.-S.; Shi, Y.-Y.; Wang,
D.-K. Tetrahedron: Asymmetry 2005, 16, 2531.
(4) Liu, L.-T.; Wang, M.-C.; Zhao, W.-X.; Zhou, Y.-L.; Wang, X.-D.
Tetrahedron: Asymmetry 2006, 17, 136.
(5) (a) Wang, M.-C.; Xu, C.-L.; Zou, Y.-X.; Liu, H.-M.; Wang, D.-K.
Tetrahedron Lett. 2005, 46, 5413. (b) Wang, M.-C.; Xu, C.-L.; Cheng, F.;
Ding, X. Tetrahedron 2006, 62, 12220.
(6) (a) Wang, M.-C.; Hou, X.-H.; Chi, C.-X.; Tang, M.-S. Tetrahedron:
Asymmetry 2006, 17, 2126. (b) Wang, M.-C.; Hou, X.-H.; Xu, C.-L.; Liu,
L.-T.; Li, G.-L.; Wang, D.-K. Synthesis 2005, 3620. (c) Wang, M.-C.; Wang,
D.-K.; Zhu, Y.; Liu, L.-T.; Guo, Y.-F. Tetrahedron: Asymmetry 2004, 15,
1289. (d) Wang, M.-C.; Liu, L.-T.; Zhang, J.-S.; Shi, Y.-Y.; Wang, D.-K.
Tetrahedron: Asymmetry 2004, 15, 3853. (e) Wang, M.-C.; Wang, D.-K.;
Lou, J.-P.; Hua, Y.-Z. Chin. J. Chem. 2004, 22, 512.
(8) Bulman Page, P. C.; Allin, S. M.; Maddocks, S. J.; Elsegood, M. R.
J. J. Chem. Soc. Perkin Trans. 1 2002, 36, 2827.
(9) Yang, X.; Shen, J.; Da, C.; Wang, R.; Choi, M. C. K.; Yang, L.;
Wong, K.-Y. Tetrahedron: Asymmetry 1999, 10, 133.
(10) Hermsen, P. J.; Cremers, J. G. O.; Thijs, L.; Zwanenburg, B.
Tetrahedron Lett. 2001, 42, 4243.
(11) Behnen, W.; Mehler, T.; Martens, J. Tetrahedron: Asymmetry 1993,
4, 1413.
(12) Wang, M.-C.; Wang, X.-D.; Ding, X.; Jing, T.-T. Synlett 2006, 3443.
(13) L-2-Amino-4-bromobutanoic acid hydrobromide is commercially
available in 1 g quantities only, 1 g ) 916 RMB; L-(+)-methionine, 1 kg
) 3380 RMB (1 g ) 3.38 RMB). Prices were taken from Aldrich, 2007-
2008.
(7) Xu, C.-L.; Wang, M.-C.; Hou, X.-H.; Liu, H.-M.; Wang, D.-K. Chin.
J. Chem. 2005, 23, 1443.
J. Org. Chem, Vol. 73, No. 1, 2008 169

Wang et al.
SCHEME 1. Synthesis of Chiral Compound 3b
TABLE 1. Properties of Hydrogen Bonds for Compound 3b
Including Two HOAc Molecules (Å and deg)
SCHEME 2. Synthesis of Chiral Compound 6
D-H···A
d(D-H)
d(H···A)
d(D···A)
(D-H···A)
O(5)-H‚‚‚O(3)
O(1)-H‚‚‚O(2)
N(1)-H‚‚‚O(3)
0.82
0.87(6)
0.89(5)
1.83
1.88(6)
1.88(5)
2.643(6)
2.734(5)
2.731(4)
168.2
171(5)
159(4)
S-methylation with methyl iodide followed by hydrolysis
according to literature procedure.14
SCHEME 3. Asymmetric Addition of Diethylzinc to
Benzaldehyde
L-2-Amino-4-bromobutanoic acid 6, the key intermediate in
this synthesis, was obtained in two steps by ring opening of
(S)-homoserine lactone hydrochloride 9, which was prepared
from L-homoserine 5 using the method reported by Koch
(Scheme 2).14a To shorten synthetic route, we developed an
improved and convenient one-step procedure for the direct
conversion of L-homoserine 5 into L-2-amino-4-bromobutanoic
acid 6 in the presence of AcOH saturated with HBr in 85%
yield.
The treatment of 6 with methanol saturated with dry HCl
afforded methyl L-2-amino-4-bromobutanoate 7 in 89% yield.15
Construction of the four-membered ring heterocycle from
acyclic compound is a key step in this synthesis. We developed
a simple three-step, one-pot protocol for the efficient conversion
of methyl L-2-amino-4-bromobutanoate 7 to methyl (S)-N-
(ferrocenylmethyl)azetidine-2-carboxylate 8 involving condensa-
tion, reduction, and cyclization.12 Ferrocenecarboxaldehyde was
first condensed with compound 7 in MeOH in the presence of
Et3N and then reduced by NaBH4, to give the desired methyl
(S)-N-(ferrocenylmethyl)azetidine-2-carboxylate 8, which was
cyclized in situ. The treatment of 8 with PhMgBr afforded the
corresponding chiral ferrocenyl â-amino alcohol 3b (87%). The
single-crystal growth of 3b was performed in a mixture of
hexane/ethyl acetate/acetic acid (2:1:0.3) at room temperature,
and orange red crystals containing two AcOH molecules were
obtained.
The subtle distortion of the four-membered ring unit showed
that an azetidine ring was a slightly more flexible framework
than an aziridine ring. The N(1)-C(12)-C(13), C(12)-C(13)-
C(14), N(1)-C(14)-C(13), C(12)-N(1)-C(14) bond angles
are 90.3°, 88.7°, 88.8°, and 89.7°, respectively. The nitrogen
atom in the azetidine ring has a trigonal-pyramidal structure
with 315.4° for the sum of the three bond angles [C(12)-N(1)-
C(14), 89.7°; C(12)-N(1)-C(11), 113.4°; C(11)-N(1)-C(14),
113.3°]. H+ is at the apex of the trigonal-pyramidal structure.
The single-crystal structure is formed by the intermolecular
hydrogen bonds between compound 3b and HOAc, and proper-
ties of the hydrogen bonds are summarized in Table 1.
Asymmetric Addition of Diethylzinc to Benzaldehyde.
Since the initial report of Oguni and Omi on the reaction of
diethylzinc with benzaldehyde in the presence of a catalytic
amount of (S)-leucinol with moderate enantioselectivity (49%
ee) in 1984,1 the asymmetric addition of diethylzinc to aldehydes
has been studied extensively, and products with excellent
enantiomeric excesses have been achieved with all types of
substrates.2a-c,g Due to the adequate reactivity of diethylzinc
(vs dimethylzinc and diphenylzinc) and the sensitivity of the
reaction to changes in the ligand structure, the enantioselective
reaction of diethylzinc with benzaldehyde has also become a
classical test to examine whether or not the designed chiral
ligands induce high enantioselectivities. In order to examine
the catalytic behavior of the chiral ligand 3b, the asymmetric
addition of diethylzinc to benzaldehyde has been investigated
in toluene in 0-20 °C in the presence of 3% ligand 3b (Scheme
3). The reactions using 3b as catalyst afforded 1-phenylpropanol
(S-configuration) in excellent yields (97%) with outstanding
enantiomeric excesses (98.4% ee).
The N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol 3b
containing two AcOH molecules was further characterized by
X-ray diffraction.16 The X-ray structure analysis revealed that
the N-ferrocenylmethyl group on the nitrogen atom of the
heterocycle is positioned anti to the diphenylhydroxymethyl
group on the heterocycle (see Supporting Information). The four-
membered N1, C12, C13, C14 ring moiety is almost a planar
structure, with the sum of the four bond angles being 357.5°.
(14) (a) Koch, T.; Buchardt, O. Synthesis 1993, 6, 1065. (b) Boyle, P.
H.; Davis, A. P.; Dempsey, K. J.; Hosken, G. D. Tetrahedron: Asymmetry
1995, 6, 2819.
(15) Jost, K.; Rudinger, J. Collect. Czech. Chem. Commun. 1967, 32,
2485.
(16) Crystallographic data for the structure reported in this paper have
been deposited with the Cambridge Crystallographic Data Center as
supplementary publication no. CCDC-648759. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road,
CAMBRIDGE CB2 1EZ, UK [fax: (+44) 1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk], or see the Supporting Information.
Recently, Zwanenburg et al. reported the same type of chiral
ligand 3a (R ) Ph) for the addition of diethylzinc to benzal-
dehyde with good enantioselectivities (88% ee) in the presence
of 20 mol % 3a.10 A comparison of our results (98.4% ee, 3
mol % 3b) with those (88% ee, 20 mol % 3a) of Zwanenburg
et al. demonstrates that the replacement of the phenyl group on
the nitrogen atom of the azetidine-based skeleton by a ferrocenyl
170 J. Org. Chem., Vol. 73, No. 1, 2008

N-(Ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol
face of benzaldehyde was attacked by nucleophile, affording
the corresponding addition product with the S absolute config-
uration.
As was mentioned above, for the same type of chiral ligands,
four-membered heterocycle-based ligands afforded higher enan-
tioselectivity than three-membered heterocycle-based ligands in
the asymmetric addition of diethylzinc to benzaldehyde. The
only difference between them was the ring area of the aziridine
and azetidine ring. Three-membered heterocycle-based ligands
possess a slightly more rigid ring backbone and more sterical
congestion than four-membered heterocycle-based ligands,
because the aziridine ring has the smaller ring area. The totally
rigid and sterically congested transition state 10 led to the
presence of the nonbonded repulsion between the phenyl ring
of benzaldehyde and the hydrogen atom on the aziridine ring,6a
which was responsible for the slightly lower enantioselectivity
compared to the azetidine case. Instead, in transition state 11,
the nonbonded repulsion between the phenyl ring of benzalde-
hyde and the hydrogen atom on the aziridine ring was avoided
due to the slightly less rigid (subtle distortion of azetidine ring
architecture) and less sterically congested (a great increase in
the area of azetidine ring) ring.
Asymmetric Addition of Dimethylzinc to Aldehydes.
Encouraged by the above result, we focused our attention on
the asymmetric addition of dimethylzinc to aldehydes. Due to
the lower reactivity of dimethylzinc than diethylzinc,19 asym-
metric addition of dimethylzinc to aldehydes has attracted much
less attention than the corresponding diethylzinc addition.
However, in recent years, the enantioselective addition of
dimethylzinc to aldehydes has received special attention in the
presence of catalytic amounts of chiral ligands,20 because the
asymmetric addition of dimethylzinc to aldehydes allows the
synthesis of the chiral 1-hydroxyethyl moiety that is widespread
in the structure of natural products and drug compounds.21 In
addition, the corresponding addition products are also useful
chiral intermediates for the preparation of chiral ligands for
enantioselective synthesis.22 The lack of reactivity of dimeth-
ylzinc combined with the importance of addition products in
synthesis prompted us to examine the catalytic efficiency of
the chiral ligand 3b in the asymmetric addition of dimethylzinc
to aldehydes.
FIGURE 2. Possible transition states.
unit leads to a remarkable improvement in the enantioselectivity
when used as the catalyst in the addition of diethylzinc to
benzaldehyde. These results also suggest that the hindrance of
the ferrocenyl group, compared to a phenyl group, plays an
important role in the enantioselectivities. The outstanding
enantioselectivity of the chiral ligand 3b, as compared with 3a
(R ) Ph), gives further support to the generality of the advantage
of the replacement of the phenyl group on the nitrogen atom of
a heterocycle-based skeleton by a ferrocenyl unit.
Compared with the same type of chiral three-membered
heterocycle-based ligand, (2S)-1-(ferrocenylmethyl)aziridin-2-
yl(diphenyl)methanol 1b (Figure 1, R ) Fc, 92.7% ee)6c,d and
five-membered heterocycle-based (ferrocenylmethyl)pyrrolidin-
2-yl(diphenyl)methanol 2b (Figure 1, R ) Fc, 90.8% ee)7 and
(2S)-1-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol 3b af-
forded the best asymmetric induction (98.4% ee). Similar
phenomena were also observed in the three-,8 four-,10 or five-
membered9 heterocycle-based â-amino alcohols with a N-
substituted benzyl unit (Figure 1, R ) Ph). Shi and co-workers
gave also the similar results for the asymmetric addition of
diethylzinc to arylaldehydes in the chiral C2-symmetric disub-
stituted backbone of three-, four-, or five-membered rings.17
The X-ray structures of the noncomplexed ligands did not
provide direct information about the structure of the catalytically
active metal complex, but they did help with the understanding
of the reaction mechanism and the effect of free ligands on
reaction enantioselectivity. A comparison of the three-membered
heterocycle-based structure 1b6c with the four-membered struc-
ture 3b (see Supporting Information) showed that they exhibit
certain similarities with respect to rigidity, configuration, and
conformation. The S absolute configuration of addition product
for the asymmetric addition of diethylzinc to benzaldehyde, the
same as the addition of diethylzinc to benzaldehyde catalyzed
by 1b,6c,d was noted. On the basis of this observation and a
great number of previous theoretical studies on the mechanism
of this reaction18 combined with our previous results,6a we
proposed a possible transition state, 11 (Figure 2), which was
similar to 10,6a for the asymmetric addition of diethylzinc to
benzaldehyde catalyzed by 3b. In the transition state 11, the se
At the outset of our study, we examined a reaction of
dimethylzinc with benzaldehyde under the same conditions as
diethylzinc addition. In the presence of 3 mol % 3b, there was
(19) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc.
1989, 111, 4028.
(20) For enantioselective addition of Me2Zn, see: (a) Blay, G.; Ferna´ndez,
I.; Herna´ndez-Olmos, V.; Marco-Aleixandre, A.; Pedro, J. R. Tetrahe-
dron: Asymmetry 2005, 16, 1953. (b) Cozzi, P. G.; Kotrusz, P. J. Am. Chem.
Soc. 2006, 128, 4940. (c) Garcia-Delgado, N.; Fontes, M.; Perica´s, M. A.;
Riera, A.; Verdaguer, X. Tetrahedron: Asymmetry 2004, 15, 2085. (d)
Sprout, C. M.; Richmond, M. L.; Seto, C. T. J. Org. Chem. 2004, 69, 6666.
(e) Cozzi, P. G.; Locatelli, M. Lett. Org. Chem. 2004, 1, 208. (f) A unique
example for Me2Zn addition to ketones: Garcia, C.; LaRochelle, L. K.;
Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970. (g) Addition of Me2Zn
to ketoesters: Wieland, L. C.; Deng, H.; Snapper, M. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2005, 127, 15453. (h) Sokeirik, Y. S.; Mori, H.; Omote,
M.; Sato, K.; Tarui, A.; Kumadaki, I.; Ando, A. Org. Lett. 2007, 9, 1927.
(i) Hatano, M.; Miyamoto, T.; Ishihara, K. Synlett. 2006, 1762.
(21) Examples of the total synthesis of natural products having a chiral
methylcarbinol moiety: (a) Cohen, F.; Overman, L. E. J. Am. Chem. Soc.
2006, 128, 2604. (b) Scott, M. S.; Luckhurst, C. A.; Dixon, D. J. Org. Lett.
2005, 7, 5813. (c) Jones, G. B.; Guzel, M.; Chapman, J. Tetrahedron:
Asymmetry 1998, 9, 901. (f) Sabitha, G.; Reddy, C.; Yadaf, J. S. Tetrahedron
Lett. 2006, 47, 4513.
(17) (a) Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999, 10, 1673.
(b) Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999, 10, 1109. (c) Shi,
M.; Jiang, J.-K.; Feng, Y.-S. Tetrahedron: Asymmetry 2000, 11, 4923.
(18) (a) Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327.
(b) Yamakawa, M.; Noyori, R. Organometallics 1999, 18, 128. (c) Goldfuss,
B.; Houk, K. N. J. Org. Chem. 1998, 63, 8998. (d) Goldfuss, B.;
Steigelmann, M.; Khan, S. I.; Houk, K. N. J. Org. Chem. 2000, 65, 77. (e)
Goldfuss, B.; Steigelmann, M.; Rominger, F. Eur. J. Org. Chem. 2000,
1785. (f) Goldfuss, B.; Steigelmann, M. J. Mol. Modell. 2000, 6, 166. (g)
Vazquez, J.; Pericas, M. A.; Maseras, F.; Lledos, A. J. Org. Chem. 2000,
65, 7303. (h) Brandt, P.; Hedberg, C.; Lawonn, K.; Pinho, P.; Andersson,
P. G. Chem. Eur. J. 1999, 5, 1692. (i) Kozlowski, M. C.; Dixon, S. L.;
Panda, M.; Lauri, G. J. Am. Chem. Soc. 2003, 125, 6614.
(22) Corey, E. J.; Helal, C. J. Angew. Chem.; Int. Ed. Engl. 1989, 37,
1986.
J. Org. Chem, Vol. 73, No. 1, 2008 171

Wang et al.
TABLE 2. Asymmetric Addition of Dimethylzinc to Aldehyde
Catalyzed by 3ba
rable with the best literature values hitherto reported for the
asymmetric addition of dimethylzinc to aldehydes.
Asymmetric Aryl Transfer to Aldehydes. Recently, the
enantioselective arylation of aldehydes has received special
attention in the presence of catalytic amounts of chiral ligands,
because the arylation products of this reaction are chiral
diarylmethanols,23,24 some of which are key intermediates for
the preparation of pharmacologically and biologically important
compounds.25 In this context, the asymmetric arylation of
aldehydes using arylboronic acids as aryl resources,24 in
comparison with Ph2Zn or Ph2Zn-Et2Zn as aryl resources,23
becomes an attractive method for the preparation of diaryl-
methanols in high enantioselectivity. This new protocol allows
the easy preparation of several substituted arylzinc reagents and
therefore the synthesis of a wide range of substituted chiral
diarylmethanols. In addition, phenylboronic acids offer a cheaper
alternative to the expensive diphenyl zinc, and the background
reaction23b generated by use of Ph2Zn itself as aryl resource is
avoided. More interestingly, another feature of this methodology
is that both enantiomers of a given diarylmethanol can be easily
prepared in excellent yields and high enantiomeric excesses with
the same catalyst, just by the appropriate choice of both reaction
partners: arylboronic acid and aldehyde. Unfortunately, ligands
that effectively catalyze the asymmetric arylation of aldehydes
using arylboronic acids as aryl resource with high ee values
are relatively rare. In order to examine the catalytic efficiency
of chiral ligand 3b, the asymmetric aryl transfer to aldehydes
was tested.
3b
temp time yield ee
entry
Ar
(mol %) (°C) (h) (%)b (%)c confignd
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
C6H5
3
3
5
10
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
0
30
30
30
10
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
72 trace
48 83
48 90
48 90
120 79
48 97
48 95
48 93
48 97
48 99
48 93
48 99
48 82
48 98
48 95
48 94
48 93
48 97
48 97
48 81
48 64
S
S
S
S
S
S
80.2
84.8
85.0
74.2
92.3
84.3
73.6
93.6
90.5
82.3
93.0
89.1
80.2
90.2
77.8
90.5
91.5
94.1
93.8
71.6
p-MeC6H4
m-MeC6H4
o-MeC6H4
p-MeOC6H4
S
S
S
S
S
S
S
S
S
S
S
S
S
S
10 m-MeOC6H4
11 o-MeOC6H4
12 m-PhOC6H4
13 p-Me2NC6H4
14 o-ClC6H4
15 m-ClC6H4
16 p-ClC6H4
17 m-BrC6H4
18 p-BrC6H4
19 3,4-OCH2OC6H3
20 ferrocenyl
21 PhCH2CH2CHO
a The mol ratio of Me2Zn:aldehyde was 2:1. b Isolated yields. c Deter-
mined by HPLC using chiral columns: Chiralcel OD or OB, respectively.
In all cases, the product chromatograms were compared against a known
racemic mixture. d Absolute configuration assigned by comparison with
known elution order from Chiralcel OD or OB columns according to the
literature and considering the similarity in the stereochemical reaction
pathway (Figure 3).
The asymmetric phenylation of 4-tolualdehyde was tested
(Table 3, entries 1-5). The phenylzinc reagent was prepared
in situ by heating a mixture of diethylzinc and phenylboronic
almost no reaction after 72 h at 0 °C. At room temperature
(30 °C), the reaction afforded the desired addition product in
83% yield with 80.2% ee. Increasing the amount of ligand from
3 to 5 mol % led to a further improvement in catalytic activity
and reaction enantioselectivity (Table 2, entry 3 vs 2), and
further addition of 10 mol % ligand did not benefit the
enantioselectivity and the yield of the products (Table 2, entries
4 vs 3). Thus, 5 mol % chiral ligand and 30 °C were selected
as the best reaction conditions in toluene.
(23) For enantioselective addition of Ph2Zn, see: (a) Dosa, P. I.; Ruble,
J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444. (b) Huang, W.-S.; Pu, L. J.
Org. Chem. 1999, 64, 4222. (c) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org.
Chem. 1999, 64, 7940. (d) Huang, W.-S.; Pu, L. Tetrahedron Lett. 2000,
41, 145. (e) Ko, D.-H.; Kim, K. H.; Ha, D.-C. Org. Lett. 2002, 4, 3759. (f)
Bolm, C.; Muniz, K. Chem. Commun. 1999, 1295. (g) Bolm, C.;
Kessilgraber, M.; Hermanns, N.; Hildebrand, J. P.; Raabe, G. Angew. Chem.,
Int. Ed. 2001, 40, 1488. (h) Bolm, C.; Hermanns, N.; Hildebrand, J. P.;
Muniz, K. Angew. Chem., Int. Ed. 2000, 39, 3465. (i) Hermanns, N.;
Dahmen, S.; Bolm, C.; Brase, S. Angew. Chem., Int. Ed. 2002, 41, 3692.
(j) Rudolph, J.; Bolm, C.; Norrby, P.-O. J. Am. Chem. Soc. 2005, 127,
1548. (k) Fontes, M.; Verdaguer, X.; Sola´, L.; Perica´s, M. A.; Riera, A. J.
Org. Chem. 2004, 69, 2532. (l) Hatano, M.; Miyamoto, T.; Ishihara, K.
AdV. Synth. Catal. 2005, 347, 1561. (m) Hatano, M.; Miyamoto, T.; Ishihara,
K. J. Org. Chem. 2006, 71, 6474.
(24) (a) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850. (b)
Rudolph, J.; Hermanns, N.; Bolm, C. J. Org. Chem. 2004, 69, 3997. (c)
Rudolph, J.; Schmidt, F.; Bolm, C. Synthesis 2005, 840. (d) Ozcubukcu,
S.; Schmidt, F.; Bolm, C. Org. Lett. 2005, 7, 1407. (e) Park, J. K.; Lee, H.
G.; Bolm, C.; Kim, B. M. Chem. Eur. J. 2005, 11, 945. (f) Rudolph, J.;
Loumann, M.; Bolm, C.; Dahmen, S. AdV. Synth. Catal. 2005, 347, 1361.
(g) Wu, X.; Liu, X.; Zhao, G. Tetrahedron: Asymmetry 2005, 16, 2299.
(h) Liu, X.; Wu, X.; Chai, Z.; Wu, Y.; Zhao, G.; Zhu, S. J. Org. Chem.
2005, 70, 7432. (i) Zhao, G.; Li, X.-G.; Wang, X.-R. Tetrahedron:
Asymmetry 2001, 12, 399. (j) Ji, J.-X.; Wu, J.; Au-Yeung, T. T.-L.; Yip,
C.-W.; Haynes, R. K.; Chan, A. S. C. J. Org. Chem. 2005, 70, 1093. (k)
Braga, A. L.; Lu¨dtke, D. S.; Vargas, F.; Paixa˜o, M. W. Chem. Commun.
2005, 2512. (l) Braga, A. L.; Lu¨dtke, D. S.; Schneider, P. H.; Vargas, F.;
Schneider, A.; Wessjohann, L. A.; Paixa˜o, M. W. Tetrahedron Lett. 2005,
46, 7827. (m) Wu, P.-Y.; Wu, H.-L.; Uang, B.-J. J. Org. Chem. 2006, 71,
833. (n) Dahmen, S.; Lormann, M. Org. Lett. 2005, 7, 4597. (o) Ito, K.;
Tomita, Y.; Katsuki, T. Tetrahedron Lett. 2005, 46, 6083.
The asymmetric addition of dimethylzinc to a variety of
aldehydes was next examined under the best reaction conditions,
and the results are presented in Table 2 (entries 6-21). As can
be seen from Table 2, good to excellent enantioselectivities
could be achieved for various aromatic aldehydes, including
ortho-, para-, and meta-substituted benzaldehydes (Table 2,
entries 6-18), heliotropin (Table 2, entry 19), and ferrocen-
ecarboxaldehyde (Table 2, entry 20). The presence of electron-
donating or electron-withdrawing substituents on the aromatic
ring is also compatible with these reaction conditions, but the
electronic effects of substituents on the reaction enantioselec-
tivity were observed. For example, aromatic aldehydes with
electron-donating group were methylated with higher enanti-
oselectivities than with electron-withdrawing group. o-Methyl-
and o-methoxy-substituted benzaldehydes afforded lower enan-
tioselectivities than other meta- and para-substituted benzalde-
hydes with donating group, probably due to steric effects of
the ortho substituents. The chiral ligand 3b was also tested with
aliphatic aldehyde. It was found that this catalyst gave also good
enantioselectivity for the addition of dimethylzinc to 3-phenyl-
propionaldehyde (Table 1, entry 19). These results are compa-
(25) For selected active pharmaceutical ingredients, see: (a) Meguro,
K.; Aizawa, M.; Sohda, T.; Kawarnatsu, Y.; Nagaoka, A. Chem. Pharm.
Bull. 1985, 33, 3787. (b) Toda, F.; Tanaka, K.; Roshiro, K. Tetrahedron:
Asymmetry 1991, 2, 873. (c) Stanchev, S.; Rakovska, R.; Berova, N.;
Snatzke, G. Tetrahedron: Asymmetry 1995, 6, 138. (d) Casy, A. F.; Drake,
A. F.; Ganellin, C. R.; Merce, A. D.; Upton, C. Chirality 1992, 4, 356. (e)
Torrens, A.; Castrillo, J. A.; Claparols, A.; Redondo, J. Synlett 1999, 765.
172 J. Org. Chem., Vol. 73, No. 1, 2008

N-(Ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol
TABLE 3. Asymmetric Arylation of Arylaldehydes Catalyzed by
3ba
TABLE 4. Enantioselective Preparation of (R)- and
(S)-Diarylmethanols Catalyzed by 3ba
1
temp yield ee
yield
(%)b
ee
entry
Ar
Ar′
C6H5
(mol %) (°C) (%)b (%)c confignd
entry
Ar
Ar′
(%)c
confignd
1
2
3
4
5
6
7
8
9
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
m-PhOC6H4
10
10
10
5
0
96 89.0
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
R
1
2
3
4
5
6
7
8
9
p-MeC6H4
p-MeOC6H4
p-MeC6H4
p-ClC6H4
p-MeOC6H4
p-ClC6H4
p-MeC6H4
o-MeC6H4
p-MeOC6H4
o-MeC6H4
p-ClC6H4
p-MeOC6H4
p-MeC6H4
p-ClC6H4
p-MeC6H4
p-ClC6H4
p-MeOC6H4
o-MeC6H4
p-MeC6H4
o-MeC6H4
p-MeOC6H4
o-MeC6H4
p-ClC6H4
92
91
95
93
89
94
92
95
97
93
84
92
91.4
93.3
95.1
95.3
93.8
94.6
82.3
96.2
81.7
>99.0
59.2
95.0
R
S
R
S
R
S
R
S
R
S
R
S
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
-20 95 92.0
-40 71 88.5
-20 88 84.0
-20 96 92.1
-20 86 83.9
-20 99 87.1
-20 95 83.3
-20 94 93.9
-20 94 83.4
-20 98 90.8
-20 80 83.1
-20 97 85.7
-20 92 91.1
-20 99 88.2
-20 84 95.5
-20 88 95.7
-20 79 70.0
15
10
10
10
10
10
10
10
10
10
10
10
10
10
10 o-ClC6H4
10
11
12
11 m-ClC6H4
12 p-ClC6H4
13 m-BrC6H4
14 o-CF3C6H4
o-MeC6H4
a The mole ratio Ar′B(OH)2:Et2Zn:aldehyde was 1:3:1. b Isolated yields.
c Determined by HPLC using chiral columns: Chiralcel OD or OB or
Chiralpak AD, respectively. In all cases, the product chromatograms were
compared against a known racemic mixture. d Absolute configuration
assigned by considering the similarity in the stereochemical reaction pathway
(Figure 3).
15 3,4-OCH2OC6H3 C6H5
16 ferrocenyl
17 C6H5
18 C6H5
C6H5
o-MeC6H4
2-Naph
a The mol ratio of Ar′B(OH)2:Et2Zn:aldehyde was 1:3:1. b Isolated yields.
c Determined by HPLC using chiral columns: Chiralcel OD or OB or
Chiralpak AD, respectively. In all cases, the product chromatograms were
compared against a known racemic mixture. d Absolute configuration
assigned by comparison with known elution order from Chiralcel OD or
OB or Chiralpak AD columns according to the literature and considering
the similarity in the stereochemical reaction pathway (Figure 3).
benzaldehyde gave the lower enantioselectivity (70.9% ee),
probably because of the steric effects of a bulky naphthalenyl
group.
Noteworthy is the fact that both R and S enantiomers of a
given product can be readily prepared in high yields with
excellent enantioselectivivities in the presence of the identical
catalyst, only by the reverse combination of both reaction
partners (arylboronic acid and aromatic aldehydes). But the so
far assessed substrate scope seems to be rather limited. Usually,
phenyl transfer to aromatic aldehydes (substituted benzalde-
hydes) or aryl transfer to benzaldehyde has been investigated,
affording arylphenylmethanols. To the best of our knowledge,
only one example has been just reported about the synthesis of
diarylmethanols with two differently substituted aryl groups by
organozinc reagents.26
acid in hexanes to 60 °C for 12 h. We first investigated the
effect of reaction temperature on enantioselectivity in the
presence of 10 mol % of the chiral ligand 3b. Decreasing the
reaction temperature from 0 °C to -20 °C led to an increase in
the enatioselectivity from 89.0% to 92.0% (Table 3, entries 1
and 2). We attempted to decrease the reaction temperature
further in order to have better enantioselectivity, but a big
decrease in both yield and enantioselectivity was observed when
the reaction was performed at -40 °C (Table 3, entry 3). Then,
we examined the effects of the chiral ligand loading on
enantioselectivity. Lowering the ligand amount from 10% to
5% led to a decrease in both yield and enantioselectivity at
-20 °C (Table 3, entry 4 vs 1). Increasing the ligand loading
from 10% to 15% did not result in an improvement of yield
and enantioselectivity (Table 3, entries 2 and 5). These reaction
conditions were tested on other arylaldehydes in the presence
of the ligand 3b (Table 3, entries 6-16). As can be seen from
Table 1, good to excellent enantioselectivities could be achieved
for various aromatic aldehydes containing ortho-, para-, and
meta-substituents on the benzene ring. The presence of electron-
donating or electron-withdrawing substituents on the aromatic
ring also furnished the corresponding products in good to
outstanding levels of enantioselectivity. The best asymmetric
induction (as high as 95.5% ee) was found by using a ferrocenyl
aldehyde as the substrate (Table 3, entry 16).
In order to examine the applicability of the approach to more
functionalized diarylmethanols, a series of reverse combinations
of the reaction of arylaldehydes with arylboronic acid were
tested, and the results are summarized in Table 4. As seen in
Table 4, just by the appropriate choice of both reaction partners,
in most cases, both the enantiomers of a given diarylmethanol
can be easily obtained in excellent yields with high to outstand-
ing enantioselectivivities by means of the same catalyst 3b
(Table 4, entries 1-12). Probably due to the steric effects of
the ortho substituent and the withdrawing-electronic effect of
the substrate, the reaction of o-methylphenylboronic acid with
p-chlorobenzaldehyde afforded the corresponding product with
a moderate ee value (Table 4, entry 11).
Asymmetric Addition of Alkynylzinc to Arylaldehydes.
The asymmetric addition of alkynylzinc to aldehydes is par-
ticularly useful, because the resulting chiral secondary propar-
gylic alcohols are important precursors to many organic
molecules, including natural products and pharmaceutical
In order to examine if different aryl groups could be
transferred to benzaldehyde with the same level of enantiose-
lectivity, the aryl transfer reaction of some substituted phenyl-
boronic acids with benzaldehyde was investigated (Table 3,
entries 17 and 18). (R)-o-Methylphenylphenylmethanol with
excellent enantioselectivity of up to 95.7% ee was obtained when
o-methylphenylboronic acid was used as the aryl transfer reagent
(Table 3, entry 17). The asymmetric naphthalenyl transfer to
(26) Schmidt, F.; Rudolph, J.; Bolm, C. AdV. Synth. Catal. 2007, 349,
703.
J. Org. Chem, Vol. 73, No. 1, 2008 173

Wang et al.
compounds.27 In addition, the acetylene and hydroxyl functions
of the propargylic alcohol products can be used to construct
very diverse molecular structures. In the past few years,28 great
progresses have been made on asymmetric alknylzinc additions
to aldehydes in the presence of either stoichiometric or catalytic
quantities of chiral ligands including N-methylephedrine,29
BINOL and its derivatives,30 â-hydroxy amides,31 and other
amino alcohol compounds.32 The above results of highly
enantioselective methylation, ethylation, and arylation of alde-
hydes inspired us to test the asymmetric addition of alkynylzinc
to aldehydes in the presence of (2S)-1-(ferrocenylmethyl)-
azetidin-2-yl(diphenyl)methanol 3b in order to achieve highly
enantiopure propargylic alcohols.
In an initial screening, asymmetric addition of alkynylzinc
to benzaldehyde was tested in order to explore optimal reaction
conditions (Table 5, entries 1-12). The alkynylzinc reagent was
formed in situ by deprotonation of phenylacetylene with
dialkylzinc at room temperature. In the presence of catalytic
amounts of chiral ligand 3b (10 mol %), asymmetric addition
of alkynylzinc to benzaldehyde afforded the corresponding
propargylic alcohol in good yield with 56.8% ee at -10 °C.
Recently, Dahmen reported that the additive DiMPEG [dimethox-
ypoly(ethylene glycol)] could improve the enantioselectivity of
the reaction. To our delight, addition of 2.5 mol % DiMPEG
2000 to the catalytic system led to an increase in the enanti-
oselectivity from 56.8 to 70.4% ee. Upon further increasing the
TABLE 5. Asymmetric Addition of Alkynylzinc to Benzaldehyde
Catalyzed by 3ba
DiMPEG
3b
temp yield
ee
entry
ZnR2
(mol %) (mol %) (°C) (%)b (%)c confignd
1
2
3
4
5
6
7
8
9
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Me2Zn
0
2.5
5
10
10
10
10
10
10
10
10
10
5
-10
-10
-10
-10
-10
-20
15
83
81
86
81
82
79
92
89
20
79
87
97
56.8
70.4
74.5
84.6
80.8
77.4
65.5
74.8
33.2
78.4
80.5
61.2
R
R
R
R
R
R
R
R
R
R
R
R
10
15
10
10
10
10
10
10
10
0
-40
-10
-10
-20
10
11
12
20
10
a The mol ratio of phenylacetylene:Et2Zn:benzaldehyde was 2:2:1.
b Isolated yields. c Determined by HPLC using a Chiralcel OD column. The
product chromatograms were compared against a known racemic mixture.
d Absolute configuration assigned by known elution order from a Chiralcel
OD column according to the literature.32f
TABLE 6. Asymmetric Addition of Alkynylzinc to Arylaldehydes
Catalyzed by 3ba
(27) For selected examples, see: (a) Fox, M. E.; Li, C.; Marino, J. P.,
Jr.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 5467. (b) Trost, B. M.;
Krische, M. J. J. Am. Chem. Soc. 1999, 121, 6131. (c) Tan, L.; Chen, C.-
Y.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Angew. Chem. Int. Ed.
1999, 38, 711. (d) Modern Acetylene Chemistry; Stang, P. J., Diederich,
F., Eds.; VCH: Weinheim, 1995. (e) Marshall, J. A.; Wang, X. J. J. Org.
Chem. 1992, 57, 1242. (f) Myers, A. G.; Zheng, B. J. Am. Chem. Soc.
1996, 118, 4492. (g) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1994,
116, 6457. (h) Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116,
3151.
(28) For reviews, see: (a) Frantz, D. E.; Fa¨ssler, R.; Tomooka, C. S.;
Carreira, E. M. Acc. Chem. Res. 2000, 33, 373. (b) Pu, L. Tetrahedron
2003, 59, 9873.
(29) (a) Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D. E.; Carreira, E. M.
Org. Lett. 2000, 2, 4233. (b) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J.
Am. Chem. Soc. 2000, 122, 1806. (c) Bode, J. W.; Carreira, E. M. J. Am.
Chem. Soc. 2001, 123, 3611. (d) Anand, N. K.; Carreira, E. M. J. Am.
Chem. Soc. 2001, 123, 9687. (e) Boyall, D.; Frantz, D. E.; Carreira, E. M.
Org. Lett. 2002, 4, 2605.
(30) (a) Xu, M.-H.; Pu, L. Org. Lett. 2002, 4, 4555. (b) Moore, D.; Huang,
W.-S.; Xu, M.-H.; Pu, L. Tetrahedron Lett. 2002, 43, 8831. (c) Moore, D.;
Pu, L. Org. Lett. 2002, 4, 1855. (d) Gao, G.; Moore, D.; Xie, R. G.; Pu, L.
Org. Lett. 2002, 4, 4143. (e) Li, Z.-B.; Pu, L. Org. Lett. 2004, 6, 1065. (f)
Li, X.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am. Chem. Soc. 2002, 124,
12636. (g) Lu, G.; Li, X.; Chen, G.; Chan, W. L.; Chan, A. S. C.
Tetrahedron: Asymmetry 2003, 14, 449. (h) Zhou, Y.; Wang, R.; Xu, Z.;
Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org. Lett. 2004, 6, 4147. (i) Takita,
R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
13760.
(31) (a) Xu, Z.; Wang, R.; Xu, J.; Da, C.-S.; Yan, W.-J.; Chen, C. Angew.
Chem., Int. Ed. 2003, 42, 5747. (b) Xu, Z.; Chen, C.; Xu, J.; Miao, M.;
Yan, W.; Wang, R. Org. Lett. 2004, 6, 1193. (c) Zhou, Y.-F.; Wang, R.;
Xu, Z.-Q.; Yan, W.-J.; Liu, L.; Gao, Y.-F.; Da, C.-S. Tetrahedron:
Asymmetry 2004, 15, 589. (d) Fang, T.; Du, D.-M.; Lu, S.-F.; Xu, J. Org.
Lett. 2005, 7, 2081.
(32) (a) Kang, Y.-F.; Liu, L.; Wang, R.; Yan, W.-J.; Zhou, Y.-F.
Tetrahedron: Asymmetry 2004, 15, 3155. (b) Kang, Y.-F.; Wang, R.; Liu,
L.; Da, C.-S.; Yan, W.-J.; Xu, Z.-Q. Tetrahedron Lett. 2005, 46, 863. (c)
Lu, G.; Li, X.; Zhou, Z.; Chan, W. L.; Chan, A. S. C. Tetrahedron:
Asymmetry 2001, 12, 2147. (d) Kamble, R. M.; Singh, V. K. Tetrahedron
Lett. 2003, 44, 5347. (e) Pizzuti, M. G.; Superch, S. Tetrahedron:
Asymmetry 2005, 16, 2263. (f) Watts, C. C.; Thoniyot, P.; Hirayama, L.
C.; Tomano, T.; Singaram, B. Tetrahedron: Asymmetry 2005, 16, 1829.
(g) Li, M.; Zhu, X.-Z.; Yuan, K.; Cao, B.-X.; Hou, X.-L. Tetrahedron:
Asymmetry 2004, 15, 219. (h) Koyuncu, H.; Dogan, O¨ . Org. Lett. 2007, 9,
3477.
yield
(%)b
ee
entry
Ar
(%)c
confignd
1
2
3
4
5
6
7
8
9
C6H4
81
89
88
82
90
87
82
88
91
85
84.6
74.5
77.3
76.3
84.3
77.3
75.2
75.4
74.1
70.8
R
R
R
R
R
R
R
R
R
R
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
m-PhOC6H4
p-MeC6H4
o-ClC6H4
m-ClC6H4
p-ClC6H4
3,4-OCH2OC6H 3
10
a The mole ratio of phenylacetylene:Et2Zn:benzaldehyde was 2:2:1.
b Isolated yields. c Determined by HPLC using a Chiralcel OD column.
In all cases, the product chromatograms were compared against a
known racemic mixture. d Absolute configuration assigned by known
elution order from a Chiralcel OD column according to the literature and
considering the similarity in the stereochemical reaction pathway
(Figure 3).32f
additive amounts to 5 and 10 mol %, the enantioselectivity rose
to 74.4 and 84.6% ee. However, a decrease in chemical yield
and enantioselectivity was observed when additive loading was
15 mol %. We also investigated the effect of reaction temper-
ature on enantioselectivity in the presence of 10 mol % of the
chiral ligand 3b and 10 mol % DiMPEG 2000. The highest ee
(84.6%) was observed when the reaction was carried out at
-10 °C.
Under the optimized reaction condition (Table 5, entry 4),
we examined the scope of the reaction using a variety of
aromatic aldehyde substrates, and the results are summarized
in Table 6. In all cases, chiral ligand 3b proved to be effective,
and the corresponding propargylic alcohols were produced in
good yields (82-91%) and high enantioselectivities (70.8-
84.6%). Chiral ligand 3b is comparable to the existing amino
alcohol ligands for alkynyl addition using a terminal alkyne and
174 J. Org. Chem., Vol. 73, No. 1, 2008

N-(Ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol
diethylzinc in the presence of chiral ligands,32 although the
maximum asymmetric induction obtained was 84.3% ee.
Synthesis of Methyl L-2-Amino-4-bromobutanoate hydro-
chloride 7. l-2-Amino-4-bromobutanoic acid hydrobromide 6 (4.2
g, 15.6 mmol) was suspended in methanol (120 mL), dry HCl was
passed through for 2 h at such a rate that the temperature of the
reaction mixture was maintained at 35-40 °C. The solution was
evaporated to dryness, the residue was dissolved in methanol, and
the solution was again evaporated to dryness; the same procedure
was repeated once more, the residual oil was dried in vacuo over
sodium hydroxide, and the resulting crystals were triturated with
ether, collected, and washed with ether. Recrystallization of the
product from C2H5OH-Et2O gave methyl L-2-amino-4-bromobu-
tanoate hydrochloride 7 (3.3 g, 89%). Mp 100.3-102.1 °C [lit.15
mp 98-99 °C]. [R]D20 ) +29.1 (c 0.83, CH3OH).
Synthesis of Methyl (S)-N-(Ferrocenylmethyl)azetidine-2-
carboxylate 8. Methyl l-2-amino-4-bromobutanoate hydrochloride
7 (2.4 g, 10.3 mmol) was dissolved in 14 mL of anhydrous methanol
and cooled to 0 °C. Triethylamine (1.7 mL, 11.9 mmol) was added,
and the reaction was stirred for 10 min. Ferrocenecarboxaldehyde
(2.2 g, 10.3 mmol) was added, the reaction mixture was stirred for
5 h, and the reaction was monitored by TLC. Sodium borohydride
(0.4 g) was added portionwise to the reaction mixture over a period
of 1 h. After stirring for 24 h, methanol was evaporated under the
reduced pressure at 40 °C. The resulting residue was carefully
neutralized with 3% HCl to pH ) 7-8 and extracted three times
with 3 × 20 mL portions of EtOAc. The combined ether extract
was washed with brine, dried over Na2SO4, and evaporated under
the reduced pressure. The resulting residue was purified by
preparative TLC with petroleum (60-90 °C)/EtOAc (3:1) as
developing solvent to give 8 in 67% yield (2.2 g). [R]2D0 -97 (c
0.84, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 2.09-2.16 (m, 1H),
2.27-2.36 (m, 1H), 2.92-2.98 (m, 1H), 3.26 (t, J ) 6.8 Hz, 1H),
3.48, 3.54 (dd, J ) 12.8 Hz, each 1H), 3.66 (s, 3H), 3.70 (d, J )
8.4 Hz, 1H), 4.11 (s, 7H), 4.14 (s, 2H). 13C NMR (100 MHz,
CDCl3): δ 21.6, 49.7, 51.8, 56.4, 63.3, 68.15, 68.18, 68.4, 69.5,
69.6, 81.7, 173.0. IR (KBr pellet): 3092, 3007, 2950, 2842, 1742,
1436, 1400, 1340, 1229, 1201, 1104, 1037, 1001, 819. HRMS
(ESI): calcd for C16H19FeNO2 M+ 313.0765, found 313.0767; (M
+ Na)+ 336.0663, found 336.0655.
Conclusions
We described in this paper a facile and practical approach to
asymmetric preparation of the enantiopure N-(ferrocenylmethyl)-
azetidin-2-yl(diphenyl)methanol from cheap and easily available
L-(+)-methionine. In the key cyclization step, the three-step,
one-pot protocol for construction of the chiral azetidine ring
was developed. The enantioselective addition of organozinc
reagents to aldehydes was investigated in the presence of a
catalytic amount of the enantiopure N-(ferrocenylmethyl)-
azetidin-2-yl(diphenyl)methanol 3b. The asymmetric ethylation,
methylation, arylation, and alkynylation of aldehydes achieved
enantioselectivity of up to 98.4%, 94.1%, 99.0%, and 84.6%
ee, respectively. The results showed that the chiral ligand 3b
was a general catalyst for asymmetric addition of various
organozinc reagents such as methylzinc, ethylzinc, phenylzinc,
and alkynylzinc to the prochiral aldehydes with high enanti-
oselectivities. In addition, we demonstrated further that the four-
membered heterocycle-based backbone was a good potential
chiral unit for the catalytic asymmetric induction reaction, and
the hindrance of the bulky ferrocenyl group, compared to a
phenyl group, played an important role in the enantioselective
addition reactions. A possible transition state for the catalytic
asymmetric addition has been proposed on the basis of the
crystal structure of the chiral ligand 3b including two HOAc
molecules and previous studies. Further applications of the chiral
compound 3b for asymmetric synthesis are under investigation
in our laboratory.
Experimental Section
Synthesis of L-Homoserine 5. L-(+)-Methionine 4 (75 g, 0.5
mol) was suspended in H2O/MeOH (1400 mL/200 mL), and methyl
iodide (75 mL, 1.21 mol) was added. The resulting two-phase
system was stirred vigorously for 48 h. The volume of the solvent
was then reduced to one-third by evaporation, and simultaneously
excess methyl iodide was removed. Water was added to a total
volume of 1000 mL, and NaHCO3 (42 g, 0.5 mol) was added. This
solution was refluxed for 15 h and cooled, and the solvent was
evaporated under reduced pressure to yield thick syrup. This residue
was dissolved in a minimum quantity of water (140 mL), with
heating. Addition of acetone (270 mL) followed by ethanol (3000
mL) caused immediate precipitation of L-homoserine 5 as a white
solid (37 g, 62%). Mp 202-203 °C (dec) [lit.33 mp 203 °C (dec)].
[R]2D0 ) 8.2 (c 3.08, H2O) [lit.33 [R]D26 ) 8.0 (c 5, H2O)]. 1H NMR
(400 MHz, D2O): δ 1.79-1.87 (m, 1H), 1.92-2.01 (m, 1H), 3.54-
3.58 (m, 2H), 3.66 (dd, J ) 4.8 Hz, J ) 7.4 Hz, 1H).
Synthesis of N-(Ferrocenylmethyl)azetidin-2-yl(diphenyl)-
methanol 3b. A Grignard reagent was prepared in the usual way
from 68 mg (2.8 mmol) of magnesium and methyl iodide (0.18
mL, 2.8 mmol) in Et2O (6 mL). The solution was cooled to 0 °C
before addition of a solution of 8 (114 mg, 0.36 mmol) in Et2O (2
mL). The reaction mixture was stirred for 3 h at 0 °C and then was
heated to reflux for 5 h. The reaction was quenched with saturated
aqueous NH4Cl (10 mL) at 0 °C. The phases were separated, and
the aqueous phase was extracted with Et2O (3 × 10 mL). The
combined organic phases were washed with brine (10 mL) and dried
over Na2SO4, and after filtration the solvent was removed under
reduced pressure. The resulting residue was purified by preparative
TLC with hexane/EtOAc (3:1) as developing solvent to give 3b
(97 mg, 85%). Mp 122.7-123.9 °C. [R]2D0 -27.2 (c 0.36, CHCl3).
[R]2D0 -27.2 (c 0.32, in CHCl3). H NMR (400 MHz, CDCl3): δ
1
Synthesis of L-2-Amino-4-bromobutanoic Acid Hydrobromide
6. L-Homoserine 5 (1.6 g, 13.3 mmol) and AcOH (36 mL, saturated
with HBr) were placed in an autoclave, which was immersed in an
oil bath, and then the temperature was raised to 75-80 °C. After
stirring for 5 h, the temperature was gradually lowered to room
temperature overnight. The precipitate was collected by suction
filtration on a Bu¨chner funnel and was washed with Et2O.
Recrystallization of the product from C2H5OH-Et2O afforded L-2-
amino-4-bromobutanoic acid hydrobromide 6 (3.1 g, 85%). Mp
187-188 °C [lit.14 mp 188-190 °C]. [R]2D0 ) +11.8 (c 0.21,
1.87-2.09 (m, 1H), 1.92-2.03 (m, 1H), 2.81, 2.87 (dd, J ) 13.2
Hz, each 1H), 2.89-2.93 (m, 1H), 3.18 (t, J ) 6.0 Hz, 1H), 3.83-
4.05 (m, 9H), 4.27 (t, J ) 7.2 Hz, 1H), 5.20 (s, 1H), 7.18-7.61
(m, 10H). 13C NMR (100 MHz, CDCl3): δ 19.42, 49.44, 55.2, 67.6,
68.0, 68.4, 69.2, 70.9, 75.7, 82.9, 128.2, 126.0, 126.6, 126.7, 128.0,
128.2, 144.1, 147.2. IR (KBr pellet): 3418, 3086, 3030, 2963, 2926,
2841, 1632, 1600, 1490, 1447, 1383, 1319, 1232, 1163, 1038, 1105,
996, 814, 748, 701. MS (ESI): calcd for C27H27FeNO (M + H)+
438, found 438. HRMS (ESI): calcd for C27H27FeNO (M + H)+
438.1520, found 438.1521.
1
DMF) [lit.14 [R]D ) +11.8 (c 0.20, DMF)]. H NMR (400 MHz,
DMSO): δ 2.22-2.41 (m, 2H), 3.59-3.71 (m, 2H), 4.00 (d, J )
X-ray Crystallographic Study. An orange red crystal of
approximate dimensions 0.20 × 0.18 × 0.17 mm was mounted on
a glass fiber. Crystallographic data for 3b containing two HOAc
molecules were measured on a Rigaku RAXIS-IV imaging plate
area detector. The data were collected at 291(2) K using graphite-
5.6 Hz, 1H), 8.33 (s, 3 H), 8.57 (s, 1H).
(33) Handbook of Fine Chemicals and Laboratory Equipment; Aldrich
Chemical Co.: 2000-2001, p 905.
J. Org. Chem, Vol. 73, No. 1, 2008 175

Wang et al.
monochromated Mo KR (λ ) 0.710 73 Å), 1.71° < θ < 25.50°.
The structures were solved by a direct method and expanded by
using Fourier techniques. The non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were included but not refined. All
calculations were performed using the teXsan crystallographic
software package. Crystal data for 3b containing two HOAc
molecules: triclinic P1, a ) 7.4950 [15] Å, R ) 97.02 [3]°, b )
8.1766[16] Å, â ) 98.63 [3]°, c ) 12.237[2] Å, γ ) 109.63[3]°,
Acknowledgment. We are grateful to the National Natural
Sciences Foundation of China (NNSFC: 20672102), the
Ministry of Education of China for the financial supports.
Supporting Information Available: HPLC analysis details
for asymmetric methylation, arylation, and alkynylation of alde-
1
hydes, copies of the H spectra of compounds 5, 6, copies of the
V ) 686.3(2) Å3, formula unit C31H35FeNO5 with Z ) 1, Dcalcd
)
1H and 13C NMR spectra of compounds 8 and 3b, and X-ray data
of compound 3b containing two HOAc molecules in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1.349 g cm-3, F(000) ) 294, µ(Mo KR) ) 0.590 mm-1. Full-
matrix least-squares refinement on F2 based on 2381 independent
reflections (Rint ) 0.0000) converged with 352 parameters. Final
R indices [I > 2σ(I)]: R1 ) 0.0341, wR2 ) 0.0797; R indices (all
data): R1 ) 0.0381, wR2 ) 0.0824; GoF ) 1.015.
JO701943X
176 J. Org. Chem., Vol. 73, No. 1, 2008