Asymmetric routes in the reaction of cyclic ketene ortho ester with aldehydes involving the use of chiral Lewis acid

Article abstract of DOI:10.1039/b107454g

Enantio- and diastereoselective synthesis of threo 2 and erythro 3 was accomplished by the conversion of 1 with aldehydes promoted by chiral borane 10; enantioselctivities range from 45-95% ee, while diastereoselectivities vary from 4.3-49:1 with 8 differ

Full text of DOI:10.1039/b107454g

Asymmetric routes in the reaction of cyclic ketene ortho ester with
aldehydes involving the use of chiral Lewis acid
Chan-Mo Yu,* Jae-Young Lee, Kwangwoo Chun, In-Kyung Choi and Suk-Ku Kang
Department of Chemistry and BK-21 School of Molecular Science, Sungkyunkwan University, Suwon
440-746, Korea. E-mail: cmyu@chem.skku.ac.kr
Received (in Cambridge, UK) 16th August 2001, Accepted 6th November 2001
First published as an Advance Article on the web 26th November 2001
Enantio- and diastereoselective synthesis of threo 2 and
erythro 3 was accomplished by the conversion of 1 with
aldehydes promoted by chiral borane 10; enantioselctivities
range from 45–95% ee, while diastereoselectivities vary from
4.3–49+1 with 8 different aldehydes.
process. Although the exact mechanistic aspects of this
transformation have not been rigorously elucidated, the follow-
ing pathway could be a probable stereochemical route on the
basis of product population. We reasoned that if 5 could be a
stereochemical model, then it might be possible to control facial
selectivity by a chiral catalyst in a predictable fashion.
Preliminary investigations for the stereochemical transforma-
tion of 1 with aldehyde indicated that the conversion to the
corresponding 2 could not be satisfied with a variety of chiral
Lewis acids including BINOL–Ti(IV), and bisoxazoline com-
plexes with Cu, Sc, Zn mainly due to a lack of reactivity.6
However, bisoxazoline–Sn(OTf)2 complex 67 and chiral borane
78 could be a chiral promoter for the enantioselective conver-
sion. Initial attempts to convert 1 to 2 with benzaldehyde in the
presence of 6 (20 mol%) at 220 °C in CH2Cl2 were met with
limited success, providing moderate enantioselectivity with
poor diastereoselectivity (47% yield, 76% ee, 2+1 dr). A survey
of modifications of ligands provided no significant advantages
in terms of reactivity and stereoselectivity. On the other hand,
reaction of 1 with benzaldehyde in the presence of 7 occurred
readily at 278 °C; this chiral Lewis acid was generally superior
and chosen for systematic studies.
The availability of efficient synthetic methods for achieving
absolute stereocontrol via a catalytic process in the construction
of acyclic systems is of considerable current interest in synthetic
chemistry.1 During the past decades, substantial progress has
been made, and as a result, many enantioselective synthetic
routes have been extensively explored.2 Nonetheless, only a few
methods exist to establish all stereoisomers selectively, despite
their plentiful synthetic potential.3 Recently we have disclosed
novel synthetic methods for the synthesis of both diastereomers
2 and 3 in high levels of stereoselectivity from the ketene ortho
ester 1 with an aldehyde mediated by a Lewis acid catalyst
(Scheme 1). This highly stereocontrolled transformation for the
synthesis of 2 involves the diastereoselective generation of a
carbon–carbon bond to form 4 and introduction of ester
functionality from hydrolysis of the ortho ester intermediate 4.4
A reversal of diastereoselectivity to obtain 3 was realized by an
epimerization of intermediate 4 under basic conditions.5
The general feature of this transformation is the synthesis of
highly functionalized compounds from simple starting materi-
als in high diastereoselectivity. The characteristic feature of this
chemical transformation process has encouraged us to carry out
further investigation concerning absolute stereoselection to
establish all four stereoisomers. This research led to the
discovery of efficient enantioselective routes in forming threo 2
and erythro 3 with high levels of diastereoselectivity and
moderate to excellent enantioselectivity. In the course of this
study, the absolute configuration of the major component was
unambiguously established by comparison with a synthetic
sample.
Reaction of 1 (RA = Et) with benzaldehyde in the presence of
20 mol% of 7 for 24 h afforded 2 and 3 in 57% isolated yield in
a ratio of 72+28 with 77% ee. The lack of diastereoselectivity
was attributed to acidic media in the reaction mixture causing
epimerization of reaction intermediate 4 for long reaction times.
Thus, diastereoselectivity was enhanced by the use of 1 eq. of 7
within 2 h, providing 78% yield in 91+9 dr with 83% ee (278
°C for 2 h in CH2Cl2). After surveying numerous modifications
of N-sulfonylamino acids, the remarkable observation has been
made that the use of 10 as a chiral promoter led to the best
results in terms of chemical yields and stereoselectivities
(PhCHO, 95% yield, 2+3 = 97+3, 93% ee): (a) chiral Lewis
acid 10 was prepared from the reaction of 8 with 99 at 23 °C for
2 h;10 (Scheme 2) (b) reaction at 278 °C for 30 min in CH2Cl2
were the optimal conditions, while with longer reaction times,
especially more than 2 h, diminished diastereoselectivity was
observed; (c) R1 = Et in 1 was generally superior to others such
as Me and Pri in terms of chemical availability and efficacy. It
is worthy of note that efficient recovery of the chiral ligand 8
was made after work up procedure.
From the mechanistic perspective, major functions for the
stereoselectivity are immediately discernable in the catalytic
Under optimal conditions, the reaction was performed by the
addition of 1 (R1 = Et) to a solution of benzaldehyde and 10 in
CH2Cl2 at 278 °C. After stirring for 30 min, the reaction
mixture was quenched with 2 N aqueous HCl followed by work
up and silica gel chromatography to afford threo 2a with erythro
3a in a ratio of 97+3 as judged by 500 MHz 1H NMR of crude
products. With the notion that this protocol might lead to a
general and efficient method for the synthesis of multifunctional
Scheme 1
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Chem. Commun., 2001, 2698–2699
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b107454g

Table 2 Diastereo- and enantioselective synthesis of 3a
Yield
(%)
Entry
RCHO
Product dr (3+2)
Ee (%)
1
2
3
4
5
6
7
8
Ph
4-Br-Ph
CH3
PhCH2
PhCH2CH2
C6H13
PhCHNCH
Me2CH
a
b
c
d
e
f
95+5
96+4
91+9
94+6
98+2
95+5
91+9
93+7
92
95
90
86
91
81
71
48
88
73
75
81
88
74
68
53
g
h
a Conditions for analysis of diastereo- and enatioselectivities were identical
with Table 1.
Scheme 2 Reagents and conditions: i, 10, 278 °C, 30 min, CH2Cl2; ii, 10,
278 °C , 2 h, CH2Cl2, then DBU, pyridine, 278 °C–23 °C, 24 h.
substances, we set out to determine the scope of reaction with
various aldehydes. Indeed, the method is successful with a
variety of aldehydes and affords products of high diaster-
eomeric purity with moderate to good enantioselectivies as
summarized in Table 1. The ee values were determined by 500
1
MHz H NMR of the corresponding (+)-MTPA ester and/or
HPLC or GC analysis using a chiral column as indicated in
Table 1.
Fig. 1 Determination of absolute configuration.
Table 1 Diastereo- and enantioselective synthesis of 2a
Generous financial support by grants from the Center for
Molecular Design and Synthesis (CMDS: KOSEF SRC) at
KAIST and the Ministry of Science and Technology through the
National Research Laboratory program is gratefully acknowl-
edged.
Yield
Entry
RCHO
Product dr (2+3)b
Ee (%)c
(%)d
1
2
3
4
5
6
7
8
Ph
4-Br-Ph
CH3
PhCH2
PhCH2CH2
C6H13
PhCHNCH
Me2CH
a
b
c
d
e
f
97+3
95+5
92+8
95+5
94+4
92+8
81+19
88+12
93
95
91
88
90
84
74
45
95
88
78
77
83
77
79
61
Notes and references
† It is important to report that the higher temperature especially over 50 °C
for the epimerization of intermediate 4 resulted in seriously diminished
chemical yields.
‡ Evans aldol product 11 (9+1 dr)11 was converted to 12 by 3 steps [i,
LiAlH4, 278 °C–0 °C, THF; ii, MeC(OMe)2Me, pTsOH (5 mol%),
CH2Cl2; iii, 9-BBN, 0–23 °C THF, then NaOH, H2O, 40% overall].
Compound 3a was also transformed to 12 [i, LiAlH4, 278 °C–0 °C, THF;
iii, MeC(OMe)2Me, pTsOH (5 mol%), CH2Cl2, 67% overall]. Both
synthetic 12 from 11 and 3a has not only the same specific rotation sign but
also the identical NMR spectra of (+)-MTPA ester derivatives.
g
h
a Reactions were carried out in CH2Cl2 at 278 °C for 30 min.b Diaster-
eomeric ratio was determined by the analysis of 500 MHz 1H NMR spectra
of crude products (all entries) and by GC analysis using HP21 (Hewlett-
Packard, cross linked methyl siloxane, 25 m 3 0.32 mm 3 0.52 mm, entries
3, 4, 6, 8).c Ees were determined by preparation of (+)-MTPA ester
derivatives, analysis by 500 MHz 1H NMR spectra (entries 1,2,3,4,8) and by
HPLC analysis using chiral column (Chiracel OD-H, 3–5% PriOH in
hexanes, entries 1,2,5,7) and by GC (FID, Chiral Dex-30, G-TA, gamma-
cyclodextrin Trifluoroacetyl, 30 m 3 0.32 mm, entries 3,6,8).d Yields refer
to isolated and purified products.
1 For general discussions, see: (a) A. H. Hoveyda, D. A. Evans and G. C.
Fu, Chem. Rev., 1993, 93, 1307; (b) D. J. Ager and M. B. East,
Asymmetric Synthetic Methodology, CRC Press, New York, 1996.
2 For examples, see: (a) Catalytic Asymmetric Synthesis, ed. I. Ojima,
Wiley-VCH, New York, 2000; (b) Comprehensive Asymmetric Cataly-
sis I–III, eds. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer-
Verlag, Berlin, 1999; (c) Lewis Acids in Organic Synthesis Vol. 1, 2, ed.
H. Yamamoto, Wiley-VCH, Weinheim, 2000.
3 For examples, the aldol processes, see: (a) R. Mahrwald, Chem. Rev.,
1999, 99, 1095–1120; (b) S. G. Nelson, Tetrahedron: Asymmetry, 1998,
9, 357–389.
4 (a) C.-M. Yu, H.-S. Choi, J.-K. Lee and S.-K. Yoon, J. Org. Chem.,
1997, 62, 6687–6689; (b) C.-M. Yu, W.-H. Jung, H.-S. Choi, J. Lee and
J.-K. Lee, Tetrahedron Lett., 1995, 36, 8255–8258.
5 C.-M. Yu, J. Lee, K. Chun, J. Lee and Y. Lee, J. Chem. Soc., Perkin
Trans 1, 2000, 3622–3626.
6 General discussion, see: J. Seyden-Penne, Chiral Auxiliaries and
Ligands in Asymmetric Synthesis, John Wiley & Sons, New York,
1995.
7 Reviews, see: (a) A. K. Ghosh, P. Mathinanan and J. Cappiello,
Tetrahedron: Asymmetry, 1998, 9, 1–45; (b) A. Pfaltz, Acc. Chem. Res.,
1993, 26, 339–345.
8 K. Ishihara and H. Yanamoto, in Advances in Catalytic Process, ed. M.
P. Doyle, JAI, Greenwich, 1995, pp. 29–59.
With our research scope of the asymmetric synthesis of threo
2, we turned our attention next to examine possibility of this
approach for a reversal of diastereoselectivity.5 Under optimal
conditions, the reaction was performed by addition of 1 to 10
and benzaldehyde in CH2Cl2 at 278 °C. After 2 h at 278 °C,
freshly distilled pyridine (20 eq.) and DBU (10 eq.) was added
during which time a white precipitate was formed. After stirring
for 30 min at 278 °C, the cooling bath was removed and the
temperature was allowed to rise to 23 °C for 24 h.† After
cooling to 0 °C, the reaction mixture was quenched with 2 N
aqueous HCl in EtOH followed by work up and silica gel
chromatography to afford erythro 3a along with threo 2a in a
ratio of 95+5 as judged by 500 MHz NMR of crude products
with virtually identical enantiomeric purity compared to that of
2a in Table 1. In addition, parallel experiments were performed
with a variety of aldehydes and the results are summarized in
Table 2.
Absolute configuration of 3a was unambiguously established
by a comparison of synthetic samples as illustrated in Fig. 1.‡
In summary, this paper describes methodologies for the
enantioselective and diastereoselective synthesis of 2 and 3 in a
general and efficient way as a result of the present investigation
because of the simplicity of the reaction and the ready
availability and efficient recovery of the chiral ligand, and also,
absolute configurations of products were unambiguously con-
firmed by the experiments.
9 Compound 9 was prepared according to the established procedure and
used for next operation without further purification, see: H. C. Brown,
N. Ravindran and S. U. Kulkarni, J. Org. Chem., 1980, 45, 384–389.
10 M. Kinugasa, T. Harada, T. Egusa, K. Fujita and A. Oku, Bull. Chem.
Soc. Jpn., 1996, 69, 3639–3650.
11 D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981, 103,
2127–2128.
Chem. Commun., 2001, 2698–2699
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