Chiral diazaborolidine-mediated enantioselective aldol reactions of phenylthioacetate esters

Article abstract of DOI:10.1016/S0040-4039(00)00302-6

Methodology is described for the enantioselective conversion of achiral aldehydes by anti-selective aldol reaction to chiral β-hydroxy-α-phenylthio esters and aldehydes. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00302-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2769–2772
Chiral diazaborolidine-mediated enantioselective aldol reactions
of phenylthioacetate esters
E. J. Corey ∗ and Soongyu Choi
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA
Received 18 January 2000; accepted 16 February 2000
Abstract
Methodology is described for the enantioselective conversion of achiral aldehydes by anti-selective aldol reaction
to chiral β-hydroxy-α-phenylthio esters and aldehydes. © 2000 Elsevier Science Ltd. All rights reserved.
The chiral diazaborolidine 1 is an exceedingly useful reagent for a number of boron enolate-mediated
enantioselective reactions, including anti- and syn-selective aldol reactions of esters with aldehydes1 and
enantioselective Ireland–Claisen rearrangements.2 Reported herein is the extension of this methodology
to the enantioselective synthesis of β-hydroxy-α-phenylthio esters and aldehydes, versatile intermediates
which have received limited attention thus far.3,4
The reaction of the boron reagent 1 (R,R-form) with phenylthioacetate esters (2) and diisopropyl-
ethylamine in CH2Cl2 at −78°C produced the (Z)-boron enolate (OBR*2 and SPh trans). The aldol
reactions between the (Z)-enolate and four different aldehydes at −78°C afforded anti-β-hydroxy-α-
phenylthio esters 3, with efficient recovery of the chiral ligand. As listed in Table 1, isolated yields,
diastereoselectivities and enantioselectivities were generally good and comparable to those of the t-butyl
bromoacetate.1b
The stereochemistry of the aldol products 3 was established by 1H NMR NOE analysis (Fig. 1) of the
corresponding 1,3-dioxane derivatives 5, which were prepared by lithium aluminum hydride reduction
(ether, 0°C, 1 h) and subsequent ketalization of the diols 4 (2,2-dimethoxypropane, cat. p-toluenesulfonic
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00302-6
tetl 16582

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Table 1
Reactions of 1, phenylthioacetate esters and aldehydes
acid, acetone, 23°C). In the case of 5a from 3a (R=t-Bu, R1=C6H5), the coupling constant between H-4
and H-5 of the major diastereomer was 10.8 Hz (a typical value for vicinal diaxial hydrogens of a 1,3-
dioxane) and that of the minor diastereomer was 2.3 Hz (typical of the cis stereorelationship of H-4 and
H-5).4b,5
Fig. 1. Selected NOE enhancements of 1,3-dioxane 5a
The major diastereomer of the aldol product 3 was confirmed to be the anti aldol diastereomer through
NOE measurements (Fig. 1) as well as from coupling constant data. The absolute configuration of the
hydroxy group in β-hydroxy-α-phenylthio ester 3a was established by conversion to the corresponding
diol 8 and comparison of the specific rotation with literature values. To arrive at the β-hydroxy ester
6a, the aldol product 3a (R=t-Bu, R1=Ph: 90.3% ee) was treated with tributyltin hydride and a catalytic
amount of azobis-isobutyronitrile (AIBN) in benzene at reflux for 30 min (96% yield). The resulting
(3R)-3-hydroxy-3-phenyl-propionate (6a), which had previously been prepared from tributyltin hydride
reduction of (2S,3S)-t-butyl 2-bromo-3-hydroxy-3-phenylpropionate,1b was identical with the known
compound; (for 6a: [α]23 +39.0 (c 1.24, CHCl3)). Methyl 3-hydroxy-3-phenyl-2-thiophenoxypropionate
D

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3m (Table 1, entry 6) was transformed into diol 8 to verify its absolute configuration {7: (n-Bu)3SnH,
AIBN, toluene, 90% yield, [α]23 +45.9 (c 0.41, CHCl3); 8: LAH, ether, 0°C, 87% yield, [α]23 +54.9 (c
D
D
0.59, CHCl3)}.
The synthesis of β-hydroxy-α-phenylthio aldehydes 9 from anti aldol adducts 3 was demonstrated
as follows.7 Treatment of esters 3 with t-butyl-dimethylsilyl trifluoromethanesulfonate in CH2Cl2 led
quantitatively to the silyl ethers 10. Reduction of the silyl ether 10 (diisobutylaluminum hydride, −78°C,
toluene) followed by pyridinium dichromate oxidation8 (molecular sieve 4 Å, 23°C, CH2Cl2) furnished
the aldehydes 9.9
In summary, the transformations described above provide a new route to a variety of chiral inter-
mediates which are useful in synthesis. The following procedure is illustrative of the enantio- and
diastereoslective aldol step.
(3S,2S)-(−)-t-Butyl 3-hydroxy-3-phenyl-2-thiophenoxypropionate (3a) (R1=Ph, R=t-Bu); the diaza-
borolidine 1R (1.0 equiv.) prepared from the (R,R)-(+)-bis-3,5-di(trifluoromethyl)benzene-sulfonamide
(320 mg, 0.419 mmol) and 0.5 M BBr3 in CH2Cl2 (1.68 mL, 0.838 mmol),1a was dissolved in CH2Cl2 (8
mL) at 23°C and cooled to −78°C. The solution was treated with t-butyl thiophenoxyacetate (94.0 mg,
0.419 mmol) and diisopropylethylamine (108.3 mg, 0.838 mmol) at −78°C. The reaction mixture was
stirred for 5 h at −78°C and then treated with benzaldehyde (40.0 mg, 0.377 mmol) in dichloromethane
(3 mL). After stirring for an additional 30 min, the reaction was quenched with MeOH (3 mL) and water
(8 mL) at −78°C. The aqueous layer was extracted with dichloromethane (3×10 mL). The collected
organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford the
crude product. Final purification of the crude product by silica gel chromatography gave the alcohol
23
D
3a (120.2 mg, 97% yield, anti:syn=98:2, anti 90% ee, syn 43% ee). anti Product: [α] −76.8 (c 1.76,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39−7.24 (m, 10H), 5.01 (dd, J=6.7, 6.5 Hz, 1H), 3.88 (d, J=6.7
Hz, 1H), 3.54 (d, J=6.5 Hz, 1H), 1.29 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 170.9, 140.7, 133.6, 133.1,
128.9, 128.4, 128.1, 127.9, 126.7, 82.5, 74.4, 58.2, 27.8; FTIR (thin film, cm−1) 3475, 3458, 2977, 1724,
1368; Rf=0.33 (17% ethyl acetate in hexane). syn Product: 1H NMR (500 MHz, CDCl3) δ 7.46–7.25 (m,
10H), 4.98 (d, J=7.5 Hz, 1H), 3.76 (d, J=7.5 Hz, 1H), 3.47 (s, 1H), 1.23 (s, 9H); 13C NMR (100 MHz,

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CDCl3) δ 170.0, 139.6, 133.3, 129.0, 128.3, 128.1, 127.1, 82.1, 72.9, 60.5, 27.6; Rf=0.35 (17% ethyl
acetate in hexane).10
References
1. (a) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976. (b) Corey, E. J.; Choi, S. Tetrahedron Lett. 1991, 32, 2857.
2. (a) Corey, E. J.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 1229. (b) Corey, E. J.; Lee, D.-H. J. Am. Chem. Soc. 1991, 113,
4026.
3. (a) Sato, T.; Okazaki, H.; Otera, J.; Nozaki, H. J. Am. Chem. Soc. 1988, 110, 5209. (b) Sato, T.; Otera, J.; Nozaki, H. J. Org.
Chem. 1990, 55, 6116.
4. (a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G.; Consolandi, E. J. Org. Chem. 1992, 57, 456. (b) Sugano, Y.; Naruto,
S. Chem. Pharm. Bull. 1988, 36, 4619. (b) Youn, J.-H.; Herrmann, R.; Ugi, I. Synthesis 1987, 159. (c) Poli, G.; Belvisi, L.;
Manzoni, L.; Scolastico, C. J. Org. Chem. 1993, 58, 3165. (d) Enders. D.; Schäfer, T. Piva, O.; Zamponi, A. Tetrahedron
1994, 50, 3349. (e) Chibale, K.; Warren, S. Tetrahedron Lett. 1994, 35, 3991.
5. Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1984, 753.
6. Kim, B. PhD dissertation, Department of Chemistry, M.I.T., Feb. 1988.
7. anti Aldol adduct 3 was separated from its syn diastereomer by flash chromatography on silica gel.
8. Furber, M.; Mander, L. N. J. Am. Chem. Soc. 1987, 109, 6389.
9. A small amount of the α-epimeric diastereomer was formed in this process. (a) R1=Ph, anti:syn=93:7; anti Aldehyde: [α]2D3
+82.2 (c 3.13, CHCl3); 1H NMR (500 MHz, CDCl3) δ 9.53 (d, J=5.7 Hz, 1H), 7.34–7.19 (m, 10H), 5.03 (d, J=7.0 Hz, 1H),
3.71 (dd, J=7.0, 5.7 Hz, 1H), 0.87 (s, 9H), 0.08 (s, 3H), −0.22 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 193.8, 141.0, 132.7,
132.1, 129.1, 128.5, 127.8, 126.9, 75.1, 66.6, 64.7, 25.7, 18.2, −4.5, −5.0; FTIR (thin film, cm−1) 2954, 2890, 1722, 1470;
LRMS (CI) for [C21H28SO2Si] m/e 390 (M+NH4+); Rf=0.47 (10% ethyl acetate in hexane). syn Aldehyde: 1H NMR (500
MHz, CDCl3) δ 9.50 (d, J=4.5 Hz, 1H), 7.42–7.2 (m, 10H), 5.20 (d, J=5.1 Hz, 1H), 3.71 (dd, J=5.1, 4.5 Hz, 1H), 0.91 (s,
9H), 0.08 (s, 3H), −0.14 (s, 3H). (b) R1=i-Pr, anti:syn=97:3; anti Aldehyde: [α]D23 +35.9 (c 0.56, CHCl3); 1H NMR (500
MHz, CDCl3), δ 9.47 (d, J=5.8 Hz, 1H), 7.39–7.25 (m, 5H), 4.02 (dd, J=5.8, 4.3 Hz, 1H), 3.59 (dd, J=4.7, 4.4, 4.3 Hz,
1H), 2.03 (qd, J=6.7, 4.7 Hz, 1H), 0.97 (d, J=6.7 Hz, 3H), 0.96 (d, J=6.7 Hz, 3H), 0.92 (s, 9H), 0.16 (s, 3H), 0.10 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 194.7, 132.6, 132.3, 129.3, 127.9, 77.8, 60.1, 33.5, 26.0, 18.4, 17.6, −3.9, −4.0; FTIR (thin
film, cm−1) 3061, 2959, 2886, 1718, 1583, 1470, 1440; LRMS (CI) for [C18H30SO2Si] m/e 356 (M+NH4+); Rf=0.49 (10%
ethyl acetate in hexane). syn Aldehyde: 1H NMR (500 MHz, CDCl3) δ 9.55 (d, J=4.4 Hz, 1H), 7.4–7.3 (m, 5H), 3.94 (dd,
J=4.9, 4.4 Hz, 1H), 3.7 (dd, J=6.8, 4.4 Hz, 1H), 1.83 (qd, J=6.8, 4.9 Hz, 1H), 1.0 (d, J=6.8 Hz, 3H), 0.95 (d, J=6.8 Hz,
3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.02 (s, 3H).
10. This research was assisted financially by a grant from the National Institutes of Health.