Enantioselective Synthesis of β-Dibenzylamino Alcohols via a Dynamic Kinetic Resolution of α-Halo Acids

Full text of DOI:10.1021/jo9712714

J . Org. Chem. 1998, 63, 3117-3119
3117
Sch em e 1
En a n tioselective Syn th esis of
â-Diben zyla m in o Alcoh ols via a Dyn a m ic
Kin etic Resolu tion of r-Ha lo Acid s
J eff A. O’Meara, Nizar Gardee, Manfred J ung,
Robert N. Ben, and Tony Durst*,†
Ottawa-Carleton Chemistry Institute, Department of
Chemistry, University of Ottawa, Ottawa, Canada K1N 6N5
Sch em e 2
Received J uly 14, 1997; (Revised Manuscript Received March
9, 1998 )
Chiral, nonracemic â-amino alcohols are the key pre-
cursors to the synthetically important R-amino aldehydes.
Particularly valuable are the â-dibenzylamino alcohols
since these are readily oxidized to R-dibenzylamino
aldehydes, also known as Reetz aldehydes. The latter
compounds have been shown to be configurationally quite
stable and to react with organometallics with high
diastereoselectivity (Scheme 1).1 The relative stereo-
chemistry of the new â-amino alcohols thus generated is
predicted on the basis of nonchelation-controlled addition
of the organometallic to the aldehyde carbonyl group.1,2
Reetz aldehydes are usually prepared from R-amino
acids via N,N-dibenzylation, reduction with LiAlH4, and
subsequent oxidation. This is an efficient route to
nonracemic compounds when the precursor R-amino acid
is available in enatiomerically pure form as is the case
with the natural R-amino acids. With side chains not
found in the natural R-amino acids, the additional steps
required to prepare such compounds make the access to
compounds such as 1 and 2 a somewhat lengthy and
inefficient procedure.
We have recently reported that the reaction of (R)-
pantolactone esters of racemic R-bromo acids 4 with
primary amines in THF at room temperature affords
R-amino esters in a highly diastereomeric manner in
greater than 50% yield.3 The greater than 50% yield of
one diastereomer was attributed to a dynamic kinetic
resolution process in which the (R,R) isomer of 4 reacted
more quickly with the amine than the (S,R) isomer and
the released bromide or the added iodide served to
isomerize the slower to the faster reacting isomer.
When these conditions were applied to the reaction of
4, R ) CH2alkyl, or aryl, with dibenzylamine in THF
containing 20 mol % of tetra-n-butylammonium iodide,
the (S,R)-R-amino esters 5 were obtained with good to
excellent de’s (77-98%) and in acceptable yields (60-
85%) (Scheme 2). The products 5 were subsequently
reduced with LiAlH4 to give the enantiomerically en-
riched â-dibenzylamino alcohols 1 without loss of stere-
ochemical integrity4 (Table 1). The 500 MHz proton
NMR showed the diastereotopic benzylic hydrogens as
Ta ble 1. P r ep a r a tion of r-Diben zyla m in o Alcoh ols via
th e Sequ en ce 4, 5, 3a
compound 5
R
yield (%)
de (%)a
compound 3, yield (%)
C2H5
Ph
pBrC6H4
Ph(CH2)2
C6H11(CH2)2
66
70
76
56
82
86
>98
>98
82
76
87
76
76
78
88
a
Determined by 500 MHz NMR integration of the signals of
the pantolactone methine hydrogen of the two diastereomers.
an AB quartet (J AB ) 13-14 Hz), with one doublet
typically near δ ) 3.3 and the other near δ ) 3.8. The
oxidation of these alcohols to the Reetz aldehydes 2 has
been described.1,5
We have also investigated the use of tert-butyl (4S)-
1-methyl-2-oxoimidazolidine-4-carboxylate as the chiral
auxiliary in the above process.6 This compound had been
shown to be superior to (R)-pantolactone as an auxiliary
in the dynamic kinetic resolution process. For example,
reaction of the diastereomeric mixture of 6 (R ) C2H5)
with benzylamine afforded excellent yields of the ami-
noimide 7 in essentially enatiomerically pure form.
Unfortunately the reaction of 6 with dibenzylamine was
quite slow and thus the desired adduct 8 was not
obtained directly from 6 but was best prepared via
N-benzylation of 7 with K2CO3 and benzyl bromide.
Fortunately, the two-step sequence was efficient and gave
8 from 6 in approximately 70% yield. The chiral auxil-
iary was removed by treatment with sodium methoxide
in methanol to yield the ester 9 which is a suitable
precursor to 1 and 2. In the earlier publication6 we had
shown that compounds of the type 6 (R ) CH2alkyl, aryl)
react with benzylamine to give 7 in good chemical yield
(60-85%) and excellent enantiomeric purity (>98% ee).
The conversion of these derivatives of 7 into 9, and
eventually the dibenzylamino aldehydes, should be analo-
gous to that described above (Scheme 3).
† Fax (613) 562 5800 ex 6072. e-mail: tdurst@oreo.chem.uottawa.ca.
(1) For an excellent review, see: Reetz, M. T. Angew. Chem., Int.
Ed. Engl. 1991, 30, 1531.
(2) (a) Hanessian, S.; Devasthale, P. V. Tetrahedron Lett. 1996, 37,
987. (b) For use of these aldeydes in hetero Diels-Alder reactions: (i)
Grieco, P. Moher, E. D. Tetrahedron Lett. 1993, 34, 5567. (ii) J ucak,
J .; Golebiowski, A.; Raczko, J . J . Org. Chem. 1989, 54, 2496. Midland,
M. M.; Afonso, M. M. J . Am. Chem Soc. 1989, 111, 4368.
(3) Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett. 1993, 34, 4473.
The absolute stereochemistry at the R-carbon of the
major isomer is (S) when (R)-pantolactone is used and
(R) when the imidazolidinone is used as the chiral
auxiliary. Thus these auxiliaries, when used in conjunc-
(5) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1141. (b) Reetz, M. T.; Drewes, M. W.; Harms, K.; Reif,
W. Tetrahedron Lett. 1988, 29, 3295.
(6) O’Meara, J .; Durst, T. Tetrahedron Lett. 1995, 35, 2559. See
also: correction (Tetrahedron Lett. 1995, 35, 5096).
(4) The enantiomeric purity of several of the alcohols
4 was
determined by 500 MHz analysis of the Mosher esters [Dale, J .; Dull,
D. L.; Mosher, H. S. J . Org. Chem. 1969, 34, 2543]. The results were
as expected on the basis of the de of the precursor ester 5.
S0022-3263(97)01271-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/17/1998

3118 J . Org. Chem., Vol. 63, No. 9, 1998
Notes
CDCl3) δ 0.95 (t, J ) 7 Hz, 3H), 1.13 (s, 3H), 1.20 (s, 3H), 1.76-
1.83 (m, 2H), 3.33-3.36 (m, 1H), 3.78 (AB, J ) 14.0 Hz, 4H),
4.06-4.08 (m, 2H), 5.47 and 5.45 (2 s, 14:1 ratio, 1H) 7.2-7.3
(m, 10 H); 13C NMR δ 10.9, 20.2 22.9, 23.0 40.4, 54.2, 62.2, 74.8,
76.2, 127.0 (2X), 128.2, 128.5, 128.8, 139.6, 171.6, 172.3. Anal.
Calcd for C24H29NO4: C, 72.88; H, 7.39. Found: C, 72.92; H,
7.32.
Sch em e 3
Com p ou n d 5 (R ) P h (CH2)2): obtained in 56% yield as a
1
slightly yellowish oil; IR (film) 1795, 1766 cm-1; H NMR (200
MHz, CDCl3) δ 1.12 (s, 3H), 1.21 (s, 3H), 2.77-2.81 (m, 4H),
3.50 (t, J ) 7.7 Hz, 1H), 3.97 and 3.67 (2 d, J ) 13.8 Hz, 4H),
4.03 (s, 2H), 5.46 and 5.48 (2 s, 10:1 ratio, 1H), 7.07-7.39 (m,
15H); 13C NMR δ 20.4, 23.0, 31.7, 32.4, 40.1, 54.4, 60.2, 75.0,
76.2, 126.0, 127.1, 128.3, 129.0, 139.4, 171.4, 172.3; HRMS calcd
for C30H33NO4 471.2417, found 471.2409.
Com p ou n d 4 (R ) P h ): obtained as a single isomer, mp 83-
84 °C, in 70% yield; IR (KBr) 1794, 1748 cm-1 1H NMR (200
;
MHz, CDCl3) δ 0.95 (s, 3H), 1.27 (s, 3H), 3.78 (AB, J ) 13.6 Hz,
4H), 4.05 (s, 2H), 4.70 (s, 1H), 5.60 (s,1H), 7.2-7.4 (m, 15H);
13C NMR δ 19.6, 22.0.7, 39.6, 53.7, 65.2, 74.7, 75.9, 127.7, 128.0,
128.2, 128.3, 128.4, 128.7, 135.9, 138.9, 170.5, 171.7. Anal.
Calcd for C28H29NO4: C, 75.82; H, 65.9. Found: C, 75.42, H
6.58.
tion with racemic R-halo acids, can provide a variety of
â-dibenzylamino alcohols 1 and the derived Reetz alde-
hydes 2 in either enantiomeric form.
Com p ou n d 4 (R ) p-Br C6H4): beige solid, mp 145-146 °C;
yield 76%; IR (KBr) 1792, 1745 cm-1; 1H NMR (200 MHz, CDCl3)
δ 0.99 (s, 3H), 1.18 (s, 3H), 3.81 (AB, J ) 13.9 Hz, 4H), 4.05 (s,
2H), 4.66 (s, 1H), 5.54 (s, 1H), 7.2-7.35 (m, 12H), 7.46-7.48 (m,
2H); 13C NMR δ 20.1, 23.0, 40.1, 54.0, 64.9, 75.2, 76.2, 122.2,
127.2, 128.4, 128.9, 130.4, 131.6, 135.3, 138.9, 170.4, 171.9.
Anal. Calcd for C28H28BrNO4: C, 64.36; H, 5.41; N, 2.68.
Found: C, 64.35; H, 5.59; N, 2.43.
Com p ou n d 4 (R ) C6H11(CH2)2). This compound was
obtained in about 70% yield as a pale yellowish oil; it was
contaminated with about 5% of the R,â-unsaturated ester
resulting from HBr elimination. These two materials were not
separable by silica gel chromatography. The mixture was not
further characterized except to determine the diastereomer ratio
in the usual manner (SR:RR ) 10:1). The material was reduced
as is, and the reduction product was characterized.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of th e (R)-
P a n tola cton e Ester s 4. P r oced u r e A. A solution of the
appropriate acid chloride, commercially available or prepared
via the procedure of Harpp et al.,7 in dry THF was added to a
solution of THF containing (R)-pantolactone (1.0 equiv) and
triethylamine (2.1 equiv) at 0 °C. The reaction mixture was
stirred for 1 h and then diluted with water. Usual workup and
silica gel chromatography afforded the desired esters 4.
P r oced u r e B. The appropriate R-halo acid (1.0 equiv), DCC
(1.0 equiv), and DMAP (0.1 equiv) were dissolved in dry CH2Cl2
and stirred under nitrogen until TLC indicated that the starting
alcohol had been consumed.8 The mixture was filtered, and the
filtrate was washed three times with water and once with 10%
HCl. The crude product was purified via silica gel chromatog-
raphy.
Red u ction of th e r-Diben zyla m in o ester s 4 to r-Diben -
zyla m in o Alcoh ols 3. Gen er a l P r oced u r e. The R-dibenzyl-
amino-(R)-pantolactone ester (1 equiv) was dissolved in dry THF
to make approximately a 0.1 M solution. To this was added 4
equiv of powdered LiAlH4 over a period of about 30 min. The
reaction mixture was stirred at room temperature for 16 h and
quenched carefully with a sodium potassium tartrate solution.
The resultant solution was stirred for 16 h and then extracted
several times with ethyl acetate. The crude product was purified
by silica gel chromatography using hexane:ethyl acetate (3:1)
as eluent.
Com p ou n d 4 (R ) P h ): prepared in 72% yield via method
B; colorless solid, mp 143-144 °C; IR (film) 1800, 1762 cm-1
;
1H NMR (200 MHz, CDCl3) δ 0.88, 1.10, 1.15, 1.23 (4 s, total
6H) 3.98, 4.05 (2 s, 2H), 5.34, 5.36 (2 s, 1H), 5.48, 5.51 (both s,
1H) 7-25-7.60 (m,5H). Anal. Calcd for C14H15BrO4: C, 51.40;
H 4.62. Found: C, 51.61; H, 4.70.
Com p ou n d 4 (R ) p-Br C6H4): obtained as a yellowish oil
in 76% yield via method A; IR (film) 1782, 1740 cm-1; 1H NMR
(200 MHz CDCl3) δ 1.20 and 1.23 (2 s, 6H) 3.92 (s, 2H), 5.23,
5.27 (both s, 1H), 5.32, 5.37 (both s, 1H), 7.24-7-53 (m, 4H);
HRMS calcd for m/z C14H14Br2O4 325.0022, found 325.0048.
Com p ou n d 4 (R ) C6H11(CH2)2, Br ) I): prepared via
(S)-2-(N,N-Diben zyla m in o)bu ta n e: yield 76%; [R]23
)
D
42.6° (CH2Cl2, c ) 1.16); IR (film) 3434 cm-1 13C NMR δ 11.8,
;
method A in 82% yield; colorless oil; IR (film) 1782, 1740 cm-1
;
17.9, 53.2, 60.5, 60.7, 127.2, 128.5, 129.1, 139.4. Anal. Calcd
for C18H23NO: C, 80.23; H, 8.62; N, 5.20. Found: C, 79>84; H,
8.86; N, 4.89.
1H NMR (200 MHz) δ 0.75 (m, 2H), 1.06, 1.08, 1.13, 1.14 (all s,
total 6H), 1.03-1.36 (m, 6H), 1.55 (m, 5H), 1.82-1.97 (m, 2H),
3.93 (s, 2H), 4.21, 4.32 (2 t, J ) 7.6 Hz, 2H), 5.24, 5.28 (2,s, 1H);
MS (CI) m/z (relative intensity) 409 (100, M + 1).
(S)-2-(N,N-Diben zyla m in o)-4-p h en ylbu ta n ol: yield 76%.
[R]23 ) -28.2° (c ) 1.08, CH2Cl2); IR (film) 3611, 3440 cm-1
;
D
Compounds 4 (R ) C2H5 and Ph(CH2)2), see ref 3.
1H NMR (500 MHz) δ 1.52-1.60 (m, 1H), 1.98-2.07 (m, 1H),
2.43-2.50 (m, 1H), 2.62-2.68 (m, 1H), 2.78-2.82 (m, 1H), 3.05
(bs, 1H), 3.34 (d, J ) 13.2 Hz, 2H), 3.46 (dd, J ) 10.5, 10.3 Hz,
1H), 3.57 (dd, J ) 10.5, 4.9 Hz, 2H), 3.77 (d, J ) 13.2 Hz, 2H),
7.13-7.30 (m 15 H); 13C NMR δ 27.1, 33.2, 53.1, 58.1, 60.6, 126.0,
127.1, 128.3, 128.4, 128.5, 129.0, 139.1, 141.7. Anal. Calcd for
P r ep a r a tion of r-Diben zyla m in o Der iva tives 5. Gen -
er a l P r oced u r e. (R)-Pantolactone esters 4 (1.0 equiv), Bu4N+
I- or Hex4N+ I- (0.2 equiv), triethylamine (2.0 equiv), and
dibenzylamine (1.05 equiv) were dissolved in sufficient dry THF
to form approximately a 0.2 M solution of the R-halo ester. The
mixture was stirred at approximately 20 °C until TLC indicated
the absence of starting halo ester, diluted with ether and washed
with water. The aqueous phase was re-extracted with ether.
The combined organic fractions were dried, and the solvent was
evaporated. The crude product was examined by 500 MHz 1H
NMR to determine the diastereomer ratio. Purification was done
via silica gel chromatography using hexane:ethyl acetate mix-
tures as eluents.
C
24H27NO: C, 83.42; H, 7.89; N, 4.06. Found: C, 83.08; H, 7.74;
N, 4.24.
(S)-2-(N,N-Diben zyla m in o)-2-p h en yleth a n ol: yield 89%;
[R]17 ) +17.3° (c ) 1.8, CH2Cl2); IR (film) 3459 cm-1; 1H NMR
D
(500 MHz) δ 2.98 (bs, 1H), 3.13 (d, J ) 13.2 Hz, 2H), 3.60 (dd,
J ) 10.6, 5.3 Hz, 1H), 3.90-3.94 (m, 3H) 4.12 (t, J ) 10.6 Hz,
1H) 7.22-7-42 (m, 15H); 13C NMR δ 53.6, 60.5, 63.1, 128.1,
128.4, 128.6, 129.0, 129.3, 135.0, 139.1. Anal. Calcd for C22H23
-
Com p ou n d 5 (R ) C2H5): obtained in 66% yield as a
NO: C, 83.24; H, 7.32; N, 4.41. Found: C, 83.19; H, 7.14, N,
4.72.
yellowish oil; IR (film) 1782, 1740 cm-1 1H NMR (200 MHz,
;
(S)-2-(N,N-Dib en zyla m in o)-2(4-b r om op h en yl)et h a n ol:
yield 64%; white solid mp ) 104-105 °C; [R]23 ) +168° (c )
D
(7) Harpp, D. W.; Black, C. J .; Gleason, J . G.; Smith, R. A. J . Org.
Chem. 1975, 40, 3420.
(8) Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 4475.
1.0, CH2Cl2); IR (KBr) 3468 cm-1; 1H NMR (500 MHz) δ 3.13 (d,
J ) 13.5 Hz, 2H), 3.60 (dd, J ) 10.5, 5.3 Hz, 1H), 3.88-3.91 (m,

Notes
J . Org. Chem., Vol. 63, No. 9, 1998 3119
3H), 4.08 (t, J ) 10.6 Hz), 7.13,(m, 2H), 7.23-7.38 (m, 10H),
7.51-7.55 (m, 2H); 13C NMR δ 53.5, 60.4, 62.5, 122.0, 127.4,
128.6, 128.9, 130.8, 131.5, 134.2, 138.8. Anal. Calcd for
bromide (0.47 g, 2.75 mmol), potassium carbonate (0.76 g, 7.5
mmol), and Bu4N+ I- (0.1 g) were added. The reaction mixture
was stirred for 48 h and then diluted with 75 mL of ether and
washed with water. The crude product was purified by silica
gel chromatography to afford 1.0 g, 86%, of 8 as a colorless oil:
IR (film) 1739, 1697 cm-1; 1H NMR (500 MHz) δ 0.98 (t, 7.3 Hz,
3H), 1.55 (s, 9H), 1.71 (m, 2H), 2.79 (s, 3H), 3.29 (dd, J ) 9.6,
4.7 Hz, 1H), 3.60 (t, J ) 9.6 Hz, 1H), 3.87 (AB quartet, J ) 14.5
Hz, 4H), 4.62, (dd, J ) 10.3, 4.7 Hz, 1H), 4.72 (t, J ) 7.6 Hz,
1H), 7.17-7.41 (m, 10H); MS (CI) m/z (relative intensity) 466
(M + 1, 55), 410 (11), 238 (100), 91 (100).
C
22H22BrNO: C, 66.67; H, 5.61; N, 3.53. Found: C, 66.71; H,
5.64; N, 3.46.
(S)-2-(N,N-Diben zylam in o)-4-cycloh exylbu tan ol: yield 76%,
based on crude 4; [R]23 ) -15.6° (c ) 1.06, CH2Cl2); IR 3468
D
cm-1; H NMR (500 MHz, CDCl3) δ 0.97 (m, 2H) 1.17 (m, 6H),
1
1.57 (bs), 1.54-1.69 (m, 5H), 2.72 (t, J ) 4.5 Hz, 2H), 3.16 (m,
1H), 3.39 (d, J ) 13.2 Hz, 2H), 3.47 (dd, J ) 10.2, 4.5 Hz, 1 H),
3.80 (d, J ) 13.2 Hz, 2H), 7.21-7.31 (m, 10 H); 13C NMR δ 21.9,
126.3, 26.4, 33.1, 33.5, 34.7, 37.7, 53.2, 59.2, 60.8, 127.2, 128.5,
129.1, 139.4. Anal. Calcd for C24H31NO: C, 81.85; H, 9.26.
Found: C, 81.64; H, 9.38.
Meth yl (R)-2-(N,N-Diben zyla m in o)bu ta n oa te, (9). Com-
pound 8 (2 mmol) was allowed to react with 1 equiv of a 2.4 M
solution of NaOCH3 in methanol at room temperature until TLC
indicated the absence of 8 (approximately 3 h). The reaction
mixture was neutralized with a 1% HCl solution, and the
methanol was removed under reduced pressure. The remaining
aqueous phase was extracted with ether. Further workup
afforded a crude product. Purification by silica gel chromatog-
P r ep a r a tion of 7. The diastereomeric mixture 66 was
subjected to the kinetic dynamic resolution conditions described
above but using benzylamine as nucleophile. 7: yield 92%; mp
) 88-90 °C; [R]23 ) -19.5° (c ) 2.6, CH3OH); IR (KBr) 3425,
D
1
1738, 1677 cm-1; H NMR (500 MHz, CDCl3) δ 0.96 (t, J ) 7.5
Hz, 3H), 1.48 (s, 9H), 1.40-1.70 (m, 2H), 2,85 (s, 3H), 3.28 (dd,
J ) 9.7, 4.0 Hz, 1H), 3.64 (t, J ) 9.9 Hz, 1H), 3.67 (AB, J ) 12.4
Hz, 2H), 4.53 (dd, J ) 10.3, 4.0 Hz, 1H), 4.57 (dd, J ) 7.2, 5.4
Hz, 1H), 7.29, (m, 5H); 13C NMR δ 10.3, 26.7, 27.9, 30.6, 46.7,
52.0, 53.2, 60.7, 82.9, 126.9, 128.3, 128.5, 140.1, 153.7, 168.8,
176.4. Anal. Calcd for C20 H29N3O4: C, 63.98; H, 7.99. Found:
C, 64.16, H 7.84.
raphy afforded 9 as a colorless oil in 94% yield: [R]23 ) +51.5°
D
(c )1.1, CH2Cl2); IR (film) 1728 cm-1; 1H NMR (500 MHz) δ 0.91
(s, 3H), 1.76 (m, 2H), 3.24 (t, J ) 7.8 Hz, 1H), 3.72 (AB quartet,
J ) 13.8 Hz, 4H), 3.75 (s, 3H), 7.35 (m, 10H); 13C NMR δ 11.6,
23.4, 51.6, 55.1, 63.1, 127.5, 128.8, 129.3, 129.4, 140.3, 174.1;
HRMS calcd for m/z C19H23NO2 297.1735, found 297.1740.
P r ep a r a tion of 8 via Ben zyla tion of 7. Compound 7 (0.93
g, 2.5 mmol) was dissolved in 10 mL of dry THF, and benzyl
J O9712714