Highly stereoselective addition to alkoxy or hydroxy ketones using an α-stannyl ester-stannous chloride system in a chelation-controlled manner

Article abstract of DOI:10.1039/b008493j

The reaction of an α-stannyl ester with α-alkoxy or hydroxy ketones in the presence of SnCl₂ gave aldol-type products with high selectivity in a chelation-controlled manner.

Full text of DOI:10.1039/b008493j

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Highly stereoselective addition to alkoxy or hydroxy ketones using an
a-stannyl ester–stannous chloride system in a chelation-controlled manner
Makoto Yasuda, Keishi Okamoto, Toshifumi Sako and Akio Baba*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka
565-0871, Japan. E-mail: baba@ap.chem.eng.osaka-u.ac.jp
Received (in Cambridge, UK) 20th October 2000, Accepted 21st November 2000
First published as an Advance Article on the web 4th January 2001
The reaction of an a-stannyl ester with a-alkoxy or hydroxy
ketones in the presence of SnCl2 gave aldol-type products
with high selectivity in a chelation-controlled manner.
However, the use of TiCl4 as an additive gave a complicated
mixture with a small amount of the aldol-type product which
was confirmed in a crude reaction mixture by NMR (entry 1). In
the presence of BF3·OEt2 almost no reaction took place and the
starting ketone was recovered (entry 2). Recently, we have
reported a carbonyl addition system using a-stannyl ester or
tributylallylic stannane with SnCl2 in which transmetallation
occurs to generate an active species.7 This activation method-
ology successfully attained the stereoselective reaction of 4 with
1 in the presence of SnCl2 to give the product in 40% yield with
excellent selectivity (entry 3). Changing the solvent from
CH2Cl2 to MeCN improved the yield while retaining high
selectivity (86% yield, > 99+1, entry 4).†
Stereoselective C–C bond formation is undoubtedly important
for organic syntheses. Since the transition state of the reaction
concerned demands a rigid structure for a selective reaction,
chelation of a substrate bearing coordinative sites to a metal
center often has a significant effect on the stereoselectivity. A
number of selective reactions under chelation-controlled condi-
tions have been reported for carbonyl addition by carbon
nucleophiles.1 Reetz has developed chelation-controlled aldol-
type addition to a-alkoxy aldehydes using enol silane in the
presence of Lewis acids.2 However, chelation-controlled addi-
tion of a metal enolate or its equivalent to a-alkoxy ketones is
scarcely known in spite of the fascinating structure of the
products which would be tertiary alcohols bearing a stereocon-
trolled O-substituent. This is probably because the reaction
conditions required to achieve the addition to ketones, which are
much less reactive than aldehydes, would be too severe to
control the selectivity. In this communication, we report a
highly diastereoselective addition of an ester enolate equivalent
to a-alkoxy or hydroxy ketones using an a-stannyl ester–
stannous chloride system in a chelation-controlled manner.
In the initial trials, we obtained moderate selectivities of
diastereomers 2 and 3 in the reactions of a-alkoxy ketone 1 with
a lithium enolate3 or zinc enolate equivalent4 [eqns. (1) and (2)].
These results prompted us to develop a novel system having
high chelation ability.
The relative configuration of the stereochemistry of 2 was
unambiguously determined by its X-ray analysis and the
ORTEP drawing is shown in Fig. 1.‡ It corresponds to the
product which is formed by chelation-controlled alkylation.
(1)
(2)
Fig. 1 Molecular structure of 2.
Although the reaction mechanism is now not clear, we
assume that the active species is chlorinated stannous ester 5
which is generated by transmetallation between 4 and SnCl2
(Scheme 1). The metal center has high Lewis acidity and thus
high chelation ability to alkoxy ketone. The carbonyl addition
proceeds via transition states which direct the selective addition
by chelation. In fact, a transmetallation was confirmed by the
following experiment. A mixture of a-stannyl ester 4 and SnCl2
in MeCN at room temp. gave 71% yield of Bu3SnCl which was
confirmed by 119Sn NMR. A lower yield (16%) of Bu3SnCl was
observed when CH2Cl2 was used as a solvent. This significant
solvent effect on the transmetallation accounts for the difference
in yields in entries 3 and 4 (Table 1). Unfortunately, the signal
A stannyl nucleophile is often used for stereoselective
organic synthesis.5 Keck has reported chelation-controlled
addition of allylic stannanes in the presence of TiCl4.6 We
examined the reaction of a-stannyl ester 4 in the presence of
metal halides, and the results are summarized in Table 1.
Table 1 Reaction of a-stannyl ester 4 with 1a
Scheme 1 Plausible path of chelation-controlled addition.
DOI: 10.1039/b008493j
Chem. Commun., 2001, 157–158
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157

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corresponding to the generated nucleophilic tin(II) species was
not detected probably because of its broadening in 119Sn
NMR.
(4)
Various alkoxy ketones were investigated and the results are
shown in Table 2. The reaction with the a-ethoxy ketone 6 also
gave the aldol product 7 in high selectivity and yield (entry 2).
Even isopropoxy ketone 8, which has a bulky substituent, was
also subjected to this reaction system to afford 9 exclusively
(entry 3). The reaction with 2-methoxypropiophenone 10
provided the selective aldol-reaction in > 95+5 selectivity
(entry 4). When the cyclic substrate 12 was used, 13 was
selectively formed in a 92+8 ratio (entry 5). The relative
configuration of the cyclic product 13 was determined by NOE
experiment. The increased intensity at the carbonyl methylene
protons was observed by irradiating the axial proton bonded to
the methoxy-substituted carbon.
In conclusion, we have shown a highly diastereoselective
addition of an alkoxycarbonylmethyl group to a-alkoxy or
hydroxy ketones, controlled by the chelation effect, using an a-
stannyl ester–SnCl2 system. The transmetallation between the
a-stannyl ester and SnCl2 generates an active species which has
high Lewis acidity to form a chelate. Further investigation of the
scope and limitations of the methodology, and the reaction
mechanism is now under way.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture, of the Japanese Government.
The chelation-controlled reaction using hydroxy carbonyl
compounds without protection is a challenging problem
because organometals for chelates are readily affected or
quenched by the protic sites. Actually, the reaction with a-
hydroxy ketone 14 performed under Reformatsky reaction
conditions or using a lithium enolate according to the proce-
dures employed in eqns. (1) or (2) did not effectively proceed
and a significant amount of the starting ketone was recovered.
Surprisingly, the stannyl ester–SnCl2 system can provide high
yield and high selectivity of 15 even with the use of hydroxy
ketones 14 [eqn. (3)].8 Other additives, TiCl4 and BF3·OEt2 for
the reaction of 4 with 14 gave the recovered ketone 14 and low
yields (9 and 26%) of 15, respectively. The reaction with
2-hydroxypropiophenone 16 also gave the product 17 in high
selectivity [eqn. (4)].9 These results show the strong advantage
of our system which tolerates protic conditions.
Notes and references
† Representative experimental procedure for the synthesis of 2: to a mixture
of SnCl2 (1.2 mmol) and a-alkoxy ketones 1 (1.0 mmol) in MeCN (1 mL)
was added an a-stannyl ester 4 (1.2 mmol) under nitrogen. The solution was
stirred for 3 h at ambient temperature. The reaction mixture was poured into
the mixed solvent of Et2O (30 mL) and aq. NH4F (15%; 15 mL) with
vigorous stirring for 10 min. The precipitating Bu3SnF was filtered off. The
filtrate was extracted with Et2O (30 mL 3 2), dried (MgSO4) and
evaporated. Recrystallisation (hexane–benzene, 9+1) of the resultant
residue gave the pure product 2.
‡ Crystal data for 2: C19H22O4, M = 314.38, monoclinic, a = 12.14(10),
b = 5.9(1), c = 23.99(8) Å, V = 3741.0(9) Å3, T = 300 K, space group
P21/n (no. 14), Z = 4, m(Mo-Ka) = 0.9 cm21, 4075 reflections measured,
3894 unique (Rint = 0.032) which were used in all calculations. The final
agreement factors were R = 0.051, Rw = 0.090. CCDC 182/1866.
1 M. T. Reetz, Acc. Chem. Res., 1993, 26, 462; M. T. Reetz, Angew. Chem.,
Int. Ed. Engl., 1994, 23, 556; X. Chen, E. R. Hortelano, E. L. Eliel and
S. V. Frye, J. Am. Chem. Soc., 1992, 114, 1778.
2 M. T. Reetz, K. Kesseler and A. Jung, Tetrahedron, 1984, 40, 4327; M. T.
Reetz, B. Raguse, C. F. Marth, H. M. Hugel, T. Bach and D. N. A. Fox,
Tetrahedron, 1992, 48, 5731; M. T. Reetz and D. N. A. Fox, Tetrahedron
Lett., 1993, 34, 1119.
(3)
3 A flask was charged with MeCO2Et (1.25 mmol) and dried THF (1 mL)
under nitrogen and was cooled to 278 °C. A 2.0 M solution of lithium
diisopropylamide (from Aldrich) in THF–heptane–EtPh (0.63 mL) was
added and the mixture was stirred for 20 min keeping it at 278 °C. To the
mixture was added 1 (1.0 mmol). After 3 h of stirring at 278 °C, the
reaction mixture was quenched with 10 mL of aq. NH4Cl, and extracted
with Et2O.
Table 2 Chelation-controlled reaction of a-stannyl ester 4 with alkoxy
a
ketones in the presence of SnCl2
4 A flask was charged with Zn powder (6.0 mmol) and dried benzene–Et2O
(5+1, 2 mL) under nitrogen. A solution of ethyl 2-bromoacetate (5.5
mmol), 1 (5.0 mmol) in benzene–Et2O (5+1, 5 mL) was slowly added
over a period of 30 min to the mixture at 80 °C. Additional solvent (5 mL)
was introduced and the reaction mixture was stirred for 2 h at 80 °C.
5 M. Pereyre, J.-P. Quintard and A. Rahm, Tin in Organic Synthesis,
Butterworth & Co., London, 1987.
6 G. E. Keck and E. P. Boden, Tetrahedron Lett., 1984, 25, 265; G. E. Keck
and E. P. Boden, Tetrahedron Lett., 1984, 25, 1879; G. E. Keck and D. E.
Abbott, Tetrahedron Lett., 1984, 25, 1883.
7 M. Yasuda, Y. Sugawa, A. Yamamoto, I. Shibata and A. Baba,
Tetrahedron Lett., 1996, 37, 5951; M. Yasuda, M. Tsuchida and A. Baba,
Chem. Commun., 1998, 563; M. Yasuda, Y. Matsukawa, K. Okamoto, T.
Sako, N. Kitahara and A. Baba, Chem. Commun., 2000, 2149.
8 The stereochemistry of the product 15 was determined by the following
transformation: the methoxy-hydroxy ester 2 was converted by Fujita’s
method using AlBr3–EtSH–CH2Cl2 at rt for 3 h to a dihydroxy ester
whose NMR spectrum shows excellent agreement with the product 15
(yield of 15, 26%, recovery of 2, 68%). M. Node, K. Nishide, M. Sai, K.
Ichikawa, K. Fuji and E. Fujita, Chem. Lett., 1979, 97; M. Node, K.
Nishide, M. Sai and E. Fujita, Tetrahedron Lett., 1978, 52, 5211.
9 The reaction was carried out using 4 (3.6 mmol), 16 (1.0 mmol), and
SnCl2 (3.0 mmol).
158
Chem. Commun., 2001, 157–158