L-valinol and L-phenylalaninol-derived 2-imidazolidinones as chiral auxiliaries in asymmetric aldol reactions

Article abstract of DOI:10.1016/S0040-4039(99)02325-4

The chiral N-propionyl-2-imidazolidinones were synthesized in three steps from L-valinol and L-phenylalaninol and the aldol reaction of their boron enolate with aldehydes proceeded with high diastereoselectivity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02325-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1505–1508
L-Valinol and L-phenylalaninol-derived 2-imidazolidinones as
chiral auxiliaries in asymmetric aldol reactions
∗
Taek Hyeon Kim and Gue-Jae Lee
Faculty of Applied Chemistry, Chonnam National University, Kwangju 500-757, South Korea
Received 29 November 1999; accepted 10 December 1999
Abstract
The chiral N-propionyl-2-imidazolidinones were synthesized in three steps from L-valinol and L-phenylalaninol
and the aldol reaction of their boron enolate with aldehydes proceeded with high diastereoselectivity. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: chiral N-propionyl-2-imidazolidinones; asymmetric aldol reaction; L-valinol; L-phenylalaninol.
The asymmetric aldol reaction has become a major tool for the asymmetric C–C bond construction.1
Among the developments of highly stereoregulated aldol reactions, the use of the Evans’ α-amino acid-
derived oxazolidinones 1 as the chiral auxiliaries is one of the most straightforward and efficient strategies
2
3
in organic synthesis. In connection with our effort to prepare various 2-imidazolidinones, we have
previously developed interesting 2-imidazolidinones 2a and 2b from L-valine and L-phenylalanine, which
combine structural features of similar oxazolidinones 1a and 1b.3a This letter reports the utility of 2 as
the chiral auxiliaries in highly diastereoselective aldol reactions, which is proven to be efficient for boron
enolates.
Evans’ 2-oxazolidinone methodology in aldol reactions has some limitations suffering from nu-
cleophilic ring opening of the oxazolidinone ring in the sterically congested aldol adduct such
4
as α,α-disubstituted β-hydroxycabonyl units to lead to the corresponding oxazinedione. The 2-
imidazolidinone, (4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidinone, was reported to be a successful chi-
5
ral auxiliary avoiding such a nucleophilic ring opening in aldol reactions. Therefore, we expected the
6
related 2-imidazolidinone 2 to have the similar resistance to nucleophilic ring opening. In addition, the
compound 2, which is closely related to 1, has been used with the hope that the phenyl chromophore
present in the 2-imidazolidinone ring could facilitate reaction monitoring and product isolation.
∗
Corresponding author. Tel: +82 62 530 1891; fax: +82 62 530 1889; e-mail: thkim@chonnam.chonnam.ac.kr
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02325-4
tetl 16253

1
506
In general, 2-imidazolidinones are prepared from the cyclization of the corresponding 1,2-diamines
7
8
with phosgene or its derivatives. This reaction, however, causes the side reaction such as polymeri-
zation, and an access to an appropriate range of optically pure diamines is restricted. As a result, the
diversity of the synthetically useful 2-imidazolidinones has remained severely limited.
Scheme 1.
1
8
However, the 2-imidazolidinones 2a (mp: 80–82°C, [α]
−26.9 (c 0.85, CHCl )) and 2b (mp:
D
3
1
8
1
15–117°C, [α]D −43.3 (c 0.55, CHCl )) were easily prepared in two simple steps (addition to
3
3
a
isocyanate, and cyclization) starting from readily available L-valinol and L-phenylalaninol, respectively
(Scheme 1). We chose the N-propionyl derivatives for examination of the auxiliary in aldol reactions.
Thus, acylation of 2-imidazolidinones 2 with 4.0 equiv. of propionyl chloride under 2.0 equiv. of t-BuOK
1
8
at room temperature furnished the N-propionyl-2-imidazolidinones in high yield (6a: 89%, [α]
+35.1
D
1
8
10
(
c 1.2, CHCl ), 6b: 91%, [α]
+37.7 (c 1.9, CHCl )). Aldol reaction of 6 with a representative
3
D
3
series of aldehydes (1.2 equiv.) was initially examined. The Z-enolate of 6 was generated upon treatment
with n-Bu BOTf (1.1 equiv.) followed by diisopropylethylamine (1.2 equiv.) in CH Cl in an ice bath.
2
2
2
Treatment of the enolate with the appropriate aldehydes provided the desired aldol adducts 7–12 in good
1
1
yields (Scheme 2). The syn/anti relative stereochemistry of aldol adducts may be assigned on the basis
1
12
0
0
of H NMR vicinal coupling constants. For the compounds 7–12, the J(2 ,3 ) values were in the range
of 2.1–3.3 Hz, consistent with the syn stereochemistry. The absolute stereochemistry of the aldol product
was confirmed by NaOH hydrolysis of 10 to furnish the enantiomer of the known carboxylic acid 13
along with the chiral auxiliary which could be recycled (Scheme 3).2d The results summarized in Table 1
illustrate the excellent diastereofacial selection in these reactions. This was the expected stereochemistry
and shows that 2 gives the same aldol product as the corresponding Evans’ N-acyl oxazolidinone. From
the observed diastereoselectivities, we propose that this reaction should be complete via a kinetic Z-boron
enolate generation and the similar coordinated transition state model between boron enolate and aldehyde
2
,13
as in Evans’ system.
Scheme 2.
In conclusion, we have successfully shown that the reagent 2a and 2b are highly diastereoselective
chiral enolate equivalents for the aldol reactions. Also, we have developed the direct synthetic route

1
507
Scheme 3.
Table 1
Aldol reaction of N-propionyl-2-imidazolidinones 6
of N-acyl-2-imidazolidinones in three steps from chiral 1,2-aminoalcohols.14 The extension to other
asymmetric reaction will be reported in due course.15
Acknowledgements
This work was supported by the Korea Research Foundation (Brain Korea 21 Project for a Small
Research Group). Spectroscopic analyses were performed in the Korea Basic Science Institute.
References
1
. For references, see: (a) Kim, B.-M.; Williams, S. F.; Masamune, S. Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2 (Heathcock, C. H., Ed.), Chapter 1.7. (b) Heathcock, C. H. Modern Synthetic
Methods; Schefford, R., Ed.; VCH: New York, 1992; p. 1. (c) Denmark, S. E.; Stavenger, R. A.; Wong, K.-T.; Su, X. J. Am.
Chem. Soc. 1999, 121, 4982–4991.
2
. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem Soc. 1981, 103, 2127–2129. (b) Evans, D. A.; Takacs, J. M.; McGee,
L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure Appl. Chem. 1981, 53, 1109–1127. (c) Evans, D. A.; Nelson, J. V.; Taber,
T. R. Top. Stereochem. 1982, 13, 1–115. (d) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83–91. (e) Ager, D. J.; Prakash,
I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3–12.
3
4
. (a) Kim, T. H.; Lee, G.-J. J. Org. Chem. 1999, 64, 2941–2943. (b) Kim, T. H.; Lee, G.-J.; Cha, M.-H. Synth. Commun. 1999,
2
9, 2753–2758.
. (a) Kende, A. S.; Kawamura, K.; Orwat, M. J. Tetrahedron Lett. 1989, 30, 5821–5824. (b) Mulzer, J.; Speck, T. Tetrahedron
Lett. 1995, 36, 7643–7646. (c) Heathcock, C. H.; Pirrrung, M. C.; Young, S. D.; Hagen, J. P.; Jarui, E. T.; Badertscher, D.;
Marki, H.-P.; Montgomery, S. H. J. Am. Chem. Soc. 1984, 106, 8161–8174.
5
6
. Drewes, S. E.; Malissar, D. G. S.; Roos, G. H. P. Chem. Ber. 1993, 126, 2663–2673
. To lower the reactivity of the carbonyl group in 2-oxazolidinone, 2-imidazolidinone 2 was used in the asymmetric synthesis
of difluorocyclopropanes through the Michael addition of lithium enolate of 2; see: Taguchi, T.; Shibuya, A.; Sasaki, H.;
Endo, J.-i.; Morikawa, T.; Shiro, M. Tetrahedron: Asymmetry 1994, 5, 1423–1426.
7
8
. (a) Maclaren, J. A. Aust. J. Chem. 1977, 30, 455–457. (b) Kim, J.-M.; Wilson, T. E.; Norman, T. H.; Schultz, P. G.
Tetrahedron Lett. 1996, 37, 5309–5312.
. Leung, M.; Lai, J.; Lau, K.; Yu, H.; Hsiao, H. J. Org. Chem. 1996, 61, 4175–4179.

1
1
508
9
. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993, 58, 3568–3571.
0. General procedure for the preparation of the N-propionyl-2-imidazolidinones 6: To a stirred solution 2-imidazolidinone 2
(0.5 mmol, 100 M%) in THF (7 mL) under nitrogen at 0°C was added t-BuOK (0.11 g, 1.0 mmol, 200 M%) and propionyl
chloride (0.21 mL, 2.0 mmol, 400 M%) dropwise for 5 min with a syringe. The reaction mixture was stirred for 10 min,
added to water (20 mL), and extracted with ether (30 mL×2). The organic layer was dried, filtered, evaporated, and purified
−1
1
by flash column chromatography to give 6. Compound 6a: IR (CDCl , cm ) 1687, 1587; H NMR (300 MHz, CDCl )
3
3
7
.56–7.15 (5H, m), 4.45–4.40 (1H, m), 3.89 (1H, t, J=9.3), 3.55 (1H, dd, J=9.3, 2.3), 3.13–2.89 (2H, m), 2.43 (1H, m,
1
3
J=6.8, 3.9), 1.19 (3H, t, J=7.2). 0.96 (3H, d, J=6.9), 0.84 (3H, d, J=6.9); C NMR (75 MHz, CDCl
1
4
3
) 174.6, 153.1, 138.7,
) 7.41–7.10 (10H, m),
1
29.0, 124.4, 119.1, 54.7, 43.2, 29.6, 28.9, 18.1, 14.6, 8.9. Compound 6b: H NMR (300 MHz, CDCl
3
.72–4.64 (1H, m), 3.84 (1H, t, J=9.3), 3.53 (1H, dd, J=9.3, 1.8), 3.30 (1H, dd, J=13.2, 3.3). 3.13–2.94 (2H, m), 2.77 (1H,
13
dd, J=13.2, 9.3), 1.19 (3H, t, J=7.2); C NMR (75 MHz, CDCl
24.7, 119.5, 51.9, 46.7, 38.9, 29.8, 9.0.
3
) 174.8, 152.8, 139.0, 136.4, 129.7, 129.2, 129.0, 127.3,
1
1
1. General procedure of the aldol reactions: To a stirred solution of the N-acyl-2-imidazolidinone 6 (0.3 mmol, 100 M%)
in dichloromethane (4 mL) under nitrogen at 0°C was added dibutylboron triflate (0.33 mL, 0.33 mmol, 110 M%) and
diisopropylethylamine (0.36 mmol, 120 M%) dropwise for 5 min with a syringe. The reaction mixture was stirred for 60
min, cooled to −78°C, and the appropriate aldehyde (0.36 mmol, 120 M%) was added. After 60 min at −78°C, the reaction
temperature was allowed to rise to 0°C and maintained at this temperature for 60 min. The reaction mixture was quenched
with aqueous pH 7 phosphate buffer (2 mL), MeOH (3 mL), and 28% H
removed. The aqueous layer was extracted with dichloromethane (30 mL) and the organic layer was washed with water,
dried, and evaporated. The crude product was purified by flash chromatography to give 7–12. Compound 7: IR (CDCl
2 2
O (2 mL). After 60 min at 0°C methanol was
3
,
−1
1
cm ) 3485, 1728, 1671; H NMR (300 MHz, CDCl
3
) 7.54–7.15 (10H, m), 5.13 (1H, d, J=3.3), 4.44–4.39 (1H, m), 4.27
(
1H, dq, J=7.2, 3.3), 3.83 (1H, t, J=9.3), 3.53 (1H, dd, J=9.3, 2.7), 2.39 (1H, m, J=6.9, 3.9), 1.21 (3H, d, J=6.9), 0.96 (3H,
13
3
d, J=6.9), 0.85 (3H, d, J=7.2); C NMR (75 MHz, CDCl ) 178.0, 152.4, 141.5, 138.4, 129.1, 128.1, 127.1, 126.1, 124.7,
1
−
1
1
19.4, 73.3, 54.7, 44.4, 43.2, 29.0, 18.0, 14.7, 11.1. Compound 8: IR (CDCl
3
, cm ) 3501, 1732, 1677; H NMR (300 MHz,
CDCl
3
) 7.56–7.15 (5H, m), 4.51–4.46 (1H, m), 4.18 (1H, dq, J=6.6, 2.4), 3.92 (1H, t, J=9.3), 3.90 (1H, dq, J=7.2, 2.4), 3.57
(
1H, dd, J=9.3, 2.7), 2.45–2.35 (1H, m), 1.30 (3H, d, J=7.2), 1.18 (3H, d, J=6.6), 0.97 (3H, d, J=6.9), 0.86 (3H, d, J=6.9);
13
C NMR (75 MHz, CDCl
Compound 9: IR (CDCl
, cm 1) 3509, 1731, 1664; H NMR (300 MHz, CDCl
.15 (1H, dq, J=6.6, 2.1), 3.93 (1H, t, J=9.3), 3.58–3.51 (1H+1H, m), 2.40 (1H, m, J=7.2, 3.9), 1.73 (1H, m, J=6.9, 2.1),
3
) 178.4, 152.6, 138.4, 129.1, 124.7, 119.4, 67.4, 54.5, 43.2, 43.1, 28.9, 19.4, 18.0, 14.6, 10.8.
−
1
3
3
) 7.55–7.15 (5H, m), 4.50–4.45 (1H, m),
4
1
1
3
.28 (3H, d, J=7.2), 1.03 (3H, d, J=6.6), 0.97 (3H, d, J=7.2), 0.89 (3H, d, J=6.9), 0.86 (3H, d, J=6.9); C NMR (75 MHz,
) 179.0, 152.4, 138.4, 129.1, 124.7, 119.5, 76.6, 54.5, 43.1, 39.4, 30.5, 28.8, 19.5, 18.9, 18.0, 14.6, 10.6. Compound
CDCl
0: IR (CDCl
1H, m), 4.25 (1H, dq, J=7.2, 3.3), 3.78 (1H, t, J=9.0), 3.51 (1H, dd, J=9.6, 1.8), 3.24 (1H, dd, J=13.2, 3.0), 2.80 (1H, dd,
3
−1
1
1
(
3
, cm ) 3483, 1732, 1676; H NMR (300 MHz, CDCl ) 7.42–7.14 (15H, m), 5.14 (1H, d, J=3.3), 4.70–4.63
3
13
3
J=13.2, 9.0), 1.24 (3H, d, J=7.2); C NMR (75 MHz, CDCl ) 177.6, 151.9, 141.5, 138.4, 135.8, 129.4, 129.0, 128.8, 127.1,
1
−1
1
26.1, 124.8, 119.5, 73.7, 51.6, 46.4, 44.5, 38.5, 10.8. Compound 11: IR (CDCl
3
, cm ) 3502, 1731, 1675; H NMR (300
MHz, CDCl
3
) 7.39–7.15 (10H, m), 4.77–4.70 (1H, m), 4.19 (1H, dq, J=6.3, 2.4), 3.94–3.86 (1H+1H, m), 3.56 (1H, dd,
1
3
J=9.6, 2.1), 3.25 (1H, dd, J=13.2, 3.3), 2.81 (1H, dd, J=13.2, 9.0), 1.32 (3H, d, J=7.2), 1.20 (3H, d, J=6.3); C NMR (75
MHz, CDCl ) 177.9, 152.2, 138.4, 135.8, 129.4, 129.0, 128.8, 127.2, 124.8, 119.6, 67.8, 51.5, 46.4, 43.2, 38.5, 19.5, 10.6.
Compound 12: IR (CDCl
3
−1
1
3
, cm ) 3500, 1732, 1670; H NMR (300 MHz, CDCl
3
) 7.39–7.12 (10H, m), 4.76–4.69 (1H, m),
4
1
1
.12 (1H, dq, J=7.2, 2.1), 3.89 (1H, t, J=8.4), 3.57–3.53 (1H+1H, m), 3.23 (1H, dd, J=13.5, 3.3), 2.82 (1H, dd, J=13.5, 9.0),
.75 (1H, m, J=6.6, 2.1), 1.30 (3H, d, J=7.2), 1.04 (3H, d, J=6.6), 0.89 (3H, d, J=6.6); C NMR (75 MHz, CDCl ) 178.7,
3
1
3
51.9, 138.4, 135.8, 129.4, 129.0, 128.8, 127.2, 124.7, 119.6, 76.8, 51.5, 46.4, 39.5, 38.5, 30.6, 19.5, 18.9, 10.2.
1
1
2. For the H NMR vicinal coupling constant using the well-established fact that Janti (4–7 Hz)>Jsyn (2–4 Hz); see: (a)
Kleschick, W. A.; Buse, C. T.; Heathcock, C. H. J. Am. Chem. Soc. 1977, 99, 247–248. (b) Oppolzer, W.; Blagg, J.;
Rodriguez, I.; Walther, E. J. Am. Chem. Soc. 1990, 112, 2767–2772.
1
1
3. Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990, 55, 173–181.
4. Prasad and co-workers reported that compound 6 was also prepared from the ring opening of chiral 1,2-aminoalcohol-
derived oxazoline with aniline followed by cyclization of the resulting N-acylated 1,2-diamine with phosgene. This method,
however, has some limitations in the diversity of 6; see: Konigsberger, K.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron:
Asymmetry 1997, 8, 2347–2354.
15. For the use of 2 as a chiral auxiliary so far; see Refs. 6 and 14.