Enantio- and diastereoselective synthesis of anti-α-bromo-α-fluoro-β-hydroxycarboxylates

Article abstract of DOI:10.1055/s-1998-1677

Reaction of aldehydes with bromofluoroketene silyl acetal 1 in the presence of 20 mol% chiral Lewis acid 2 proceeds with enantio-and diastereoselectivities at -20°C to afford optically active anti-α-bromo-α-fluoro-β-hydroxy esters 3a-f (up to 89:11 anti:s

Full text of DOI:10.1055/s-1998-1677

April 1998
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437
Enantio- and Diastereoselective Synthesis of anti-α-Bromo-α-fluoro-β-hydroxycarboxylates
Katsuhiko Iseki*, Yoshichika Kuroki and Yoshiro Kobayashi
MEC Laboratory, Daikin Industries, Ltd., Miyukigaoka, Tsukuba, Ibaraki 305, Japan
Fax: +81-298-58-5082, E-mail: iseki@mec.daikin.co.jp
Received 9 January 1998
Abstract: Reaction of aldehydes with bromofluoroketene silyl acetal 1
in the presence of 20 mol% chiral Lewis acid 2 proceeds with enantio-
and diastereoselectivities at -20°C to afford optically active anti-α-
bromo-α-fluoro-β-hydroxy esters 3a-f (up to 89:11 anti:syn, up to 93%
ee).
The synthesis of chiral fluoroorganic compounds is important in the
biological and medicinal chemistry fields in view of the influence of
1
fluorine’s unique properties on biological activity. Fluorine, due to its
high electronegativity, has a considerable electronic effect on its
neighboring groups in a molecule. Thus, the introduction of fluorine
into bioactive compounds frequently leads to the discovery of novel and
potent biochemical tools and medicinal agents which are chiral in many
2
cases.
The asymmetric Mukaiyama-aldol addition of
a
bromofluoroketene silyl acetal to carbonyl compounds to provide
optically active α-bromo-α-fluoro-β-hydroxy esters is a valuable
synthetic method since the products must be versatile intermediates for
the synthesis of various useful chiral fluorinated molecules.
Recently, we successfully isolated bromofluoroketene ethyl
trimethylsilyl acetal (1) and explored its application to asymmetric
Mukaiyama-aldol reactions. The reaction of various aldehydes with
Table 1, entries 1-4, the aldol additions at -78°C and higher
temperatures (-45 to -10°C) afforded the products, both anti- and syn-
aldols 3a, having opposite signs of optical rotation. While the anti-and
syn-isomers obtained at -78°C show dextrorotation (entry 1), those at -
45, -20 and -10°C are levorotatory (entries 2-4). It is very noteworthy
that the reactions carried out at -78 and -20°C provides the (+)- and (-)-
anti-α-bromo-α-fluoro-β-hydroxy esters 3a, respectively, with
significant enantioselectivities (98% ee and 91% ee). On the other hand,
the syn-isomers obtained at -45, -20 and -10°C showed opposite optical
rotation to that at -78°C (entry 1) although the degrees of
enantioselectivity were modest (entries 2-4).
3
acetal 1 in the presence of Masamune’s catalyst 2 at -78°C affords the
corresponding optically active α-bromo-α-fluoro-β-hydroxy esters 3
with high enantioselectivities. However, the reaction is not
diastereoselective (anti/syn). In this paper, we disclose the enantio- and
diastereoselective aldol reaction of acetal 1 mediated by a chiral catalyst
2 to stereoselectively provide optically active anti-aldols 3.
We next examined the aldol reaction of various aldehydes at -20°C
under the conditions used in Table 1, entry 3. As shown in Table 2, the
chemical yields were rather good. The anti stereoselectivity was
observed except for benzaldehyde. The highest anti/syn ratio was
obtained with butanal (89/11, entry 1). The anti-aldol products showed
opposite signs of optical rotation to those obtained at -78°C in all cases
7
although benzaldehyde gave a very low enantioselectivity. The anti-
From the results summarized in Table 1, the anti/syn ratio of the aldol
aldol 3b obtained from butanal showed the highest optical yield (93%
4
3a obtained through treatment of isovaleraldehyde with acetal 1 under
ee, entry 1).
5
the influence of 20 mol% of catalyst 2 was found to depend on the
reaction temperature. The reaction was carried out by the addition of the
aldehyde to a solution of acetal 1 and catalyst 2 in EtNO over 3 h at the
2
specified temperature, followed by stirring at the same temperature for 1
3
h prior to quenching. As with our previous work, the reaction at -78°C
resulted in a nearly 1:1 mixture of anti- and syn-aldols 3a (Table 1,
6
entry 1). The reaction at -45°C also gave a similar anti/syn ratio (entry
2). On the contrary, anti diastereoselection was observed at -20 and -
10°C (entries 3 and 4), and the aldol addition at -20°C provided aldol 3a
with an anti/syn ratio of 89/11. However, the addition of acetal 1 to a
mixture of the aldehyde and catalyst 2 at -20°C completely lost all anti
stereoselection (anti/syn = 39/61), and the chemical yield was also low
(entry 6).
More interestingly, elevating the reaction temperature has a significant
influence on the enantiofacial selection of the aldehyde. As shown in

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The reason is not yet clear why the anti selectivity is obtained at -20°C
and elevation of the reaction temperature causes a reversal of the
enantiofacial selection, although some transition state models can be
considered (Scheme 1). In the aldol reaction mediated by the catalyst 2,
the bromofluoroketene silyl acetal 1 preferentially reacts on the si face
of the aldehydes at -78°C and the fluorine-free dimethylketene methyl
5a,b
trimethylsilyl acetal
also shows the same enantiofacial selection,
suggesting that the catalyst 2 plays the role of a Lewis acid and the
reaction with 1 proceeds via the extended open transition states A and B.
The anti- and syn-aldols are given through transition states A and B,
respectively. On the contrary, the reaction with acetal 1 in the presence
of the catalyst 2 at -20°C preferentially proceeds with re facial
8
enantioselection. We propose the cyclic chair transition states C and D
leading to the reversal of the enantioselectivity when transmetallation to
9
19
a boron enolate rapidly occurs. As shown in the Figure, the F NMR
of a 1:1 mixture of acetal 1 and catalyst 2 in C D NO at -78 and -20°C
2
5
2
10
may suggest the formation of the boron enolate. The anti selectivity
may be caused by the predominant formation of the (E)-boron enolate
and/or by its higher reactivity than the (Z)-isomer. From the (E)-boron
enolate, the corresponding anti-aldol 3 should be obtained via the cyclic
transition state C. However, a cyclic chair transition state (E)
coordinated by the Lewis acid 2 is also a probable model leading to the
11-13
anti-product.
enantioselectivities of the syn- and anti-aldols 3a were determined to be
31% ee and 91% ee, respectively, by HPLC analysis using a chiral
column (Chiralcel OD-H, Daicel Chemical Industries, Ltd.). syn-3a: a
26
colorless oil; [α]
-7.7° (c 0.7, CHCl ); IR (neat) 3467, 2960, 1749,
3
D
-1
1
1265, 1171, 1046, 666 cm ; H NMR (200 MHz, CDCl ) δ 0.92 (d, J =
3
6.5 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H), 1.19-1.30 (m, 1H), 1.36 (t, J = 7.2
Figure
Hz, 3H), 1.58-2.02 (m, 2H), 2.55-2.62 (m, 1H), 4.02-4.20 (m, 1H), 4.29-
19
4.43 (m, 2H); F NMR (188 MHz, CDCl , CFCl ) δ -129.86 (d, J =
3
3
+
+
A representative experimental procedure is given by the Lewis acid 2
catalyzed reaction of isovaleraldehyde with acetal 1 (Table 1, entry 3):
15.2 Hz, 1F); MS (FAB) m/z 273 [M+1 ], 271 [M+1 ]; HRMS (FAB)
+
Calcd for C H BrFO [MH ] 271.0345. Found 271.0356. anti-3a: a
9
17
26
3
A 1 M THF solution of the BH •THF complex (200 µl, 0.2 mmol) was
3
colorless oil; [α]
-26.2° (c 0.9, CHCl ); IR (neat) 3468, 2959, 1751,
D 3
-1
1
added dropwise to a solution of (1S,2S,5R)-2-isopropyl-5-methyl-1-(N-
1300, 1262, 1047, 867 cm ; H NMR (200 MHz, CDCl ) δ 0.99 (d, J =
3
4'-toluenesulfonamido)cyclohexanecarboxylic acid (71 mg, 0.2 mmol)
6.2 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.48-2.25
(m, 4H), 4.12-4.32 (m, 1H), 4.39 (q, J = 7.2 Hz, 2H); F NMR (188
19
in EtNO (3 ml) at ambient temperature under an argon atmosphere.
2
The solution was allowed to warm to 45°C, stirred for 1 h and then
cooled to -20°C. The bromofluoroketene silyl acetal 1 (E/Z: 62/38, 308
mg, 1.2 mmol) was added. A solution of isovaleraldehyde (107 µl, 1.0
MHz, CDCl , CFCl ) δ -137.67 (d, J = 20.5 Hz, 1F); MS (FAB) m/z 273
3
3
+
+
+
[M+1 ], 271 [M+1 ]; HRMS (FAB) Calcd for C H BrFO [MH ]
9
17
3
271.0345. Found 271.0336.
mmol) in EtNO (2 ml) was then added using a syringe pump over a 3 h
2
period at -20°C; the resulting solution was stirred at the same
temperature for an additional hour, quenched with a saturated aqueous
References and Notes
(1) For reviews see: (a) Welch, J. T. Tetrahedron 1987, 43, 3123.
(b) Bravo, P.; Resnati, G. Tetrahedron: Asymm. 1990, 1, 661.
(c) Resnati, G. Tetrahedron 1993, 49, 9385.
NaHCO solution and extracted with ether. The combined extracts were
3
washed with brine, dried over anhydrous MgSO , and concentrated in
4
vacuo after filtration. The oily residue was dissolved in a mixture of 2 N
HCl (2 ml) and THF (10 ml) and stirred at ambient temperature for 1 h.
The mixture was extracted with ether. The combined extracts were
(2) (a) Biomedical Aspects of Fluorine Chemistry; Filler, R.;
Kobayashi, Y. Eds.; Kodansha Ltd. and Elsevier Biomedical
Press: Tokyo and Amsterdam, 1982. (b) Biomedical Frontiers of
Fluorine Chemistry; Ojima, I.; McCarthy, J. R.; Welch, J. T. Eds.;
American Chemical Society: Washington, D. C., 1996.
washed with a saturated aqueous NaHCO solution and brine, dried
3
with anhydrous MgSO and filtered. After evaporation of the solvent,
4
the residual crude product was purified by column chromatography with
n-hexane-EtOAc as the eluent on silica gel to afford the syn-aldol (25
mg, 9% yield) and the anti-aldol (210 mg, 78% yield). The
(3) Iseki, K.; Kuroki, Y.; Kobayashi, Y. Tetrahedron Lett. 1997, 38,
7209.

April 1998
SYNLETT
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19
(4) The E/Z ratio was determined to be 62/38 by F NMR [CFCl ,
(8) In the case of the dimethylketene methyl trimethylsilyl acetal,
elevating the reaction temperature to -20°C does not cause
reversal of the enantiofacial selection although the degree of
enantioselectivity decreases.
3
CDCl ; 133.1 (s, 0.62F), 134.5 (s, 0.38F)]. The minor isomer was
confirmed to be the (Z)-acetal by the NOE between F and the
3
methylene proton of the ethoxy group.
(9) Kuwajima, I.; Kato, M.; Mori, A. Tetrahedron Lett. 1980, 21,
4291.
13
(10) The C NMR of a 1:1 mixture of dimethylketene methyl
trimethylsilyl acetal and Lewis acid 2 in C D NO at -78°C
2
5
2
showed almost the same spectrum as that at -20°C.
(11) Mikami et al. proposed the silatropic ene mechanism for the
asymmetric catalysis of aldol-type reactions with ketene silyl
acetals. See: (a) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc.
1994, 116, 4077. (b) Mikami, K.; Matsukawa, S.; Sawa, E.;
Harada, A.; Koga, N. Tetrahedron Lett. 1997, 38, 1951.
(5) Catalyst 2 was prepared by stirring a mixture of BH •THF and p-
3
toluenesulfonamide of the corresponding amino acid in EtNO at
2
45°C for 1 h. See: (a) Parmee, E. R.; Tempkin, O.; Masamune, S.
J. Am. Chem. Soc. 1991, 113, 9365. (b) Parmee, E. R.; Hong, Y.;
Tempkin, O.; Masamune, S. Tetrahedron Lett. 1992, 33, 1729.
(12) The aldol reaction catalyzed by a bidentate Lewis acid was
reported by Maruoka et al. See: Ooi, T.; Takahashi, M.; Maruoka,
K. J. Am. Chem. Soc. 1996, 118, 11307.
(6) Elevating the reaction temperature to -20°C and stirring for 2 h
after 1 h at -78°C did not affect the anti/syn ratio (53/47): anti-3a
[99% ee (+)]; syn-3a [99% ee (+)].
(13) Iseki, K.; Kuroki, Y.; Asada, D.; Takahashi, M.; Kishimoto, S.;
(7) The enantioselectivities of the anti-aldols obtained at -78°C are as
follows: 3b: 98% ee (+); 3c: 98% ee (+); 3d: 89% ee (+); 3e: 98%
ee (+); 3f: 97% ee (+); 3g: 90% ee (2R,3R). See ref. 3.
Kobayashi, Y. Tetrahedron 1997, 53, 10271.