Synthesis of enantiopure syn-β-amino alcohols. A simple case of chelation-controlled additions of diethylzinc to α-(dibenzylamino) aldehydes

Article abstract of DOI:10.1021/jo960017t

Enantiomerically pure syn-2-amino alcohols 6 are prepared by addition of diethylzinc to chiral α-(dibenzylamino) aldehydes 4. The addition is highly stereoselective, leading to syn-2-(dibenzylamino) alcohols 5 with excellent diastereomeric excesses (76-98%). Debenzylation of 5 by hydrogenolysis on Pearlman's catalyst yields quantitatively the amino alcohols 6.

Full text of DOI:10.1021/jo960017t

4210
J . Org. Chem. 1996, 61, 4210-4213
Syn th esis of En a n tiop u r e syn -â-Am in o Alcoh ols. A Sim p le Ca se of
Ch ela tion -Con tr olled Ad d ition s of Dieth ylzin c to
r-(Diben zyla m in o) Ald eh yd es†
J ose´ M. Andre´s, Roberto Barrio, Mar´ıa A. Mart´ınez, Rafael Pedrosa,* and
Alfonso Pe´rez-Encabo
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/ n, 47011-Valladolid, Spain
Received J anuary 2, 1996X
Enantiomerically pure syn-2-amino alcohols 6 are prepared by addition of diethylzinc to chiral
R-(dibenzylamino) aldehydes 4. The addition is highly stereoselective, leading to syn-2-(dibenzyl-
amino) alcohols 5 with excellent diastereomeric excesses (76-98%). Debenzylation of 5 by
hydrogenolysis on Pearlman’s catalyst yields quantitatively the amino alcohols 6.
In tr od u ction
reactions proceed with modest diastereoselectivity. Quite
surprisingly, there are few precedents in the literature
on the reactivity of dialkylzincs toward R-(N,N-dibenzyl-
amino) aldehydes,11 probably as a consequence of the very
low reactivity of these organometallics.12 It is well known
that the nucleophilicity of diethylzinc is increased by
coordination to donor ligands, and this is the basis of the
catalyzed enantioselective additions to carbonyl com-
pounds.13
N-Protected amino aldehydes have been widely used
as chiral building blocks for a wide variety of compounds.1
Most of the reactions on this class of compounds are
directed to the synthesis of biologically important â-ami-
no alcohols, and it is well known that, contrary to
R-alkoxy derivatives, additions of organometallics to N,N-
dibenzylamino aldehydes lead to anti adducts.2
On the basis of a previous work on the enantioselective
ethylation of aldehydes,14 we decided to explore the
unreported reactivity of chiral R-(N,N-dibenzylamino)
aldehydes with diethylzinc without any additional re-
agent, in the hope that (a) the donor properties of the
dibenzylamino group present at the substrates might be
sufficient to enhance the reactivity of diethylzinc15 and
(b) the diastereoselection might be dictated by the ster-
eochemistry at the starting amino aldehyde.16
This behavior is explained on the basis of a nonchelated
transition state and has been confirmed thoroughly,3 but
“inducing the opposite diastereoselectivity in favour of
chelation control remains a challenge”.5 Only partial
success has been achieved by using a combination of less
sterically demanding protective groups on the nitrogen
or monoprotected aminoaldehydes4 and cuprates,2 man-
ganese reagents5 or chromium derivatives6 as nucleo-
philes; allyltin7 and allylsilanes8 in the presence of
different Lewis acids have also been used. On the other
hand, phenyl or vinyl additions on aluminoxy acetals
derived from R-amino esters lead to the chelation control
products.9
Resu lts a n d Discu ssion
Starting R-amino aldehydes 4a -f were prepared by
Swern oxidation17 of 2-(dibenzylamino) alcohols 3a -f
obtained by a modified reported procedure2 as sum-
marized in Scheme 1. To this end, natural R-amino acids
were reduced by sodium borohydride-boron trifluoride
in THF at reflux18 to 2-amino alcohols 1b-e, which after
treatment with benzyl bromide and potassium carbonate
in acetonitrile at reflux were transformed into 2-(diben-
zylamino) alcohols 3b-e in excellent yields.
Organozinc reagents have also been used as nucleo-
philes in diastereoselective additions to chiral amino
aldehydes, but always associated to Lewis acids2 or to
amino alcohols acting as a catalyst;10 in both cases, the
†Dedicated to Prof. William S. J ohnson. In Memoriam.
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
(1) For recent reviews see: (a) J urczak, J .; Golebiowski, A. Chem.
Rev. 1989, 89, 149. (b) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991,
30, 1531. (c) Reetz, M. T. Organometallic compounds for selective C-C
bond formation and for molecular recognition. In Stereocontrolled
Organic Synthesis; Trost, B. M., Ed.; Blackwell Science Pub.: Oxford,
1994; p 97.
An alternative route was used to prepare 3a and 3f;
N,N-dibenzylalaninol was obtained from alanine methyl
(10) Soai, K.; Takahashi, K. J . Chem. Soc., Perkin Trans. 1 1994,
1257.
(11) Recently, a reaction of epoxy aldehydes with diethylzinc has
been reported: Urabe, H.; Evin, O. O.; Sato, F. J . Org. Chem. 1995,
60, 2660.
(12) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J . Am. Chem.
Soc. 1989, 111, 4028.
(13) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49.
(2) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1141.
(3) (a) Heneghan, M.; Procter, G. Synlett 1992, 489. (b) Golebiowski,
A.; J urczak, J . Synlett 1993, 241. (c) Hormuth, S.; Reissig, H. U.;
Dorsch, D. Angew. Chem., Int. Ed. Engl. 1993, 32, 1449.
(4) (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J . Org.
Chem. 1990, 55, 1439. (b) Dondoni, A.; Perrone, D.; Semola, T.
Synthesis 1995, 181.
(5) Reetz, M. T.; Ro¨lfing, K.; Griebenow, N. Tetrahedron Lett. 1994,
35, 1969.
(6) Ciapetti, P.; Taddei, M.; Ulivi, P. Tetrahedron Lett. 1994, 35,
3183.
(7) (a) Kiyooka, S.; Suzuki, K.; Shirouchi, M.; Kaneko, Y.; Tanimori,
S. Tetrahedron Lett. 1993, 34, 5729. (b) Marshall, J . A.; Seletsky, B.
M.; Coan, P. S. J . Org. Chem. 1994, 59, 5139.
(8) J urczak, J .; Prokopowicz, P.; Golebiowski, A. Tetrahedron Lett.
1993, 34, 7107.
(14) Andre´s, J . M.; Mart´ınez, M. A.; Pedrosa R.; Pe´rez-Encabo, A.
Tetrahedron: Asymmetry 1994, 5, 67.
(15) Boersma, J . In Comprehensive Organometallic Chemistry;
Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon Press: New
York, 1982; Chapter 16.
(16) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni,
N.; Hayashi, M.; Kaneo, T.; Matsuda, Y. J . Organomet. Chem. 1990,
382, 19.
(17) Thaisrivongs, S.; Pals, D. T.; Kati, W. M.; Turner, S. R.;
Thomasco, L. M.; Watt, W. J . Med. Chem. 1986, 29, 2080.
(18) Meyers, A. I.; Elworthy, T. R. J . Org. Chem. 1992, 57, 4732.
(9) Polt, R.; Peterson, M. A.; De Young, L. J . Org. Chem. 1992, 57,
5469.
S0022-3263(96)00017-5 CCC: $12.00 © 1996 American Chemical Society

Synthesis of Enantiopure syn-â-Amino Alcohols
J . Org. Chem., Vol. 61, No. 13, 1996 4211
Ta ble 1. Ster eoselective Ad d ition of Et2Zn to
Sch em e 1
N,N-Diben zyla m in o Ald eh yd es 4a -f
entry
aldehyde
time (h) yielda (%)
5
syn/antib
1
2
3
4
5
6
7
8
4a
4b
4c
4c
4d
16
36
24
24
17
19
15
24
95
64
62
48c
70
65
68
70
5a
5b
5c
5c
5d
5e
88:12
>99:<1
92:8
92:8
90:10
>99:<1
>99:<1
95:5
4e
ent-4e
4f
ent-5e
5f
a
Numbers reflect the combined yield of diastereomers after
purification by flash chromatography. Determined by 1H-NMR
b
analysis of the crude of reactions. c This reaction was carried out
with 1 equiv of Et2Zn, and in the final mixture 25% of 4c was
recovered unchanged.
Sch em e 3
Sch em e 2
Ta ble 2. Ch em ica l Sh ifts a n d Cou p lin g Con sta n ts for
4-H a n d 5-H in Oxa zolid in on es 7
oxazolidinone
δ4-H (ppm)
δ5-H (ppm)
J 4,5 (Hz)
trans-7a
trans-7b
trans-7d
cis-7d
trans-7e
ent-trans-7e
trans-7f
3.59
3.19
3.67
3.97
4.51
4.51
3.39
4.04
4.21
4.24
4.58
4.27
4.27
4.18
6.3
5.0
5.3
7.3
6.9
6.9
5.1
After separation by flash chromatography20 syn-5a -f
and anti-5a ,c,d were debenzylated to the final â-amino
alcohols syn-6a -f and anti-6a ,c,d by hydrogenolysis21 on
Pearlman’s catalyst in excellent chemical yields.
Assignment of the absolute stereochemistry of amino
alcohols 6 was made by 1H NMR spectroscopy and by
comparison of the specific rotations of their derivatives.
Thus, the amino alcohols syn-6a -f and ent-syn-6e were
transformed into the oxazolidinones trans-7a -f and ent-
trans-7e and anti-6d into cis-7d , respectively, by treat-
ment with a solution of phosgene in toluene.22 The signs
and values of the specific rotation for compounds trans-
7a -d are coincident with those previously described,23
whereas the vicinal coupling constants between the ring
protons in trans oxazolidinones (5.0-6.3 Hz) are smaller24
than in cis-7d (7.3 Hz) (Scheme 3 and Table 2).
ester by sequential dibenzylation with benzyl bromide
in the presence of potassium carbonate and lithium
aluminum hydride reduction in boiling THF, whereas 3f
was prepared in the same way by LAH reduction of
methyl N,N-dibenzylserinate where the hydroxyl group
was previously protected as its MEM derivative by
reaction with MEMCl in the presence of N,N-diisopro-
pylethylamine.19
Treatment of the N,N-dibenzylamino aldehydes 4a -f
with 2 equiv of Et2Zn in toluene at 0 °C gave, after hy-
drolysis, the corresponding syn amino alcohols 5a -f in
good chemical yields and excellent stereoselectivity
(Scheme 2 and Table 1). The degree of stereoselection
was moderately affected by the size of the substituent at
the stereogenic center in the R-amino aldehyde. The mo-
lar ratio of reagents does not modify the stereoselectivity
but decreases the chemical yield as shown in the reac-
tion of 4c with 1.1 equiv of Et2Zn (entry 4 in Table 1).
The sense and degree of stereoselection are not affected
by the presence of an additional donor heteroatom in the
dibenzylamino aldehyde 4f (entry 8 in Table 1).
The stereochemistry of oxazolidinone 7e (J 4,5 ) 6.9 Hz)
was deduced through NOE experiments; an Overhauser
effect of 17% was measured for the 4-H proton upon
irradiation of the CH2 of the ethyl group at C-5, confirm-
(20) See the Experimental Section.
(21) Yoshida, K.; Nakajima, S.; Wakamatsu, T.; Ban, Y.; Shibasaki,
M. Heterocycles 1988, 27, 1167.
(22) Sibi, M. P.; Rutherford, D.; Sharma, R. J . Chem. Soc., Perkin
Trans 1 1994, 1675.
(23) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Tetrahedron
Lett. 1987, 28, 6331.
(19) Corey, E. J .; Gras, J . L.; Ulrich, P. Tetrahedron Lett. 1976, 11,
809.
(24) Lin, J . T.; Yamazaki, T.; Kitazume, T. J . Org. Chem. 1987, 52,
3211.

4212 J . Org. Chem., Vol. 61, No. 13, 1996
Andre´s et al.
1
CHCl3); IR (film) 3420 cm-1; H NMR δ 0.93 (t, 3H, J ) 7.3
Hz), 1.00 (d, 3H, J ) 6.7 Hz), 1.14 (m, 1H), 1.54 (m, 1H), 2.55
(dq, 1H, J 1 ) 6.7 Hz, J 2 ) 2.7 Hz), 3.30 (d, 2H, J ) 13.6 Hz),
3.41 (m, 1H); 3.82 (d, 2H, J ) 13.6 Hz), 7.20-7.40 (m, 10H);
13C NMR δ 7.9, 9.9, 26.4, 53.1, 57.9, 71.8, 127.1,128.4, 128.9,
138.8.
(2S,3R)-2-(N,N-Dib en zyla m in o)-3-p en t a n ol (a n ti-5a ):
hexane/EtOAc 10/1; 11% yield; colorless oil; [R]23 ) +48.2 (c
D
1, CHCl3); IR (film) 3320 cm-1; 1H NMR δ 0.87 (t, 3H, J ) 7.4
Hz), 1.11 (d, 3H, J ) 6.8 Hz), 1.30 (m, 1H); 1.77 (m, 2H), 2.71
(m, 1H), 3.47 (d, 2H, J ) 13.8 Hz), 3.52 (m, 1H), 3.76 (d, 2H,
J ) 13.8 Hz), 7.15-7.40 (m, 10H); 13C NMR δ 8.5, 10.2, 27.1,
54.6, 56.9, 75.0, 126.8, 128.1, 128.6, 140.0.
F igu r e 1.
ing the cis relationship of these substituents and thus
the trans relative stereochemistry for 4-H and 5-H.
Finally, the identity of the minor diastereomers anti-
5a and anti-5c obtained by us was established by
comparison of their physical and spectroscopic properties
with those obtained as major components in the reactions
of 4a and 4c with ethylmagnesium bromide as described
by Reetz.2
This unprecedent syn selectivity for the addition to
dibenzylamino aldehydes can be explained by ethylation
from the less hindered si face of the carbonyl group in a
Cram chelate complex (Figure 1). Moreover, the efficient
alkylation observed for the compounds described here is
in contrast with the low reactivity of diethylzinc with
aldehydes and can be attributed to the well-known
“ligand acceleration” promoted by the amino group13
present in R-(dibenzylamino) aldehydes. Nevertheless,
the nature of the reaction intermediate probably was
rather complex, and the ethylzinc alkoxide formed in the
reaction is likely to be involved in the reactive species.
In summary, diethylzinc shows a very high syn selec-
tivity in reactions with chiral R-(dibenzylamino) alde-
hydes, and the reactions described here are complemen-
tary and constitute an alternative to the use of other
organometallics described in the literature.
(3S ,4S )-4-(N ,N -Dib e n zyla m in o)-5-m e t h yl-3-h e xa n ol
(syn -5b): hexane/EtOAc 15/1; 64% yield; colorless oil; [R]23
D
) +12.5 (c 1, CHCl3); IR (film) 3380 cm-1; H NMR δ 0.93 (t,
1
3H, J ) 7.3 Hz), 1.03 (d, 3H, J ) 7.0 Hz), 1.06 (d, 3H, J ) 7.0
Hz), 1.11 (m, 1H), 1.58 (m, 1H), 2.25 (m, 1H), 2.33 (dd, 1H, J 1
) 9.3 Hz, J 2 ) 2.1 Hz), 3.43 (d, 2H, J ) 13.0 Hz), 3.67 (m,
1H), 3.92 (d, 2H, J ) 13.0 Hz), 4.50 (br s, 1H), 7.20-7.40 (m,
10H); 13C NMR δ 10.1, 19.1, 23.9, 24.6, 27.9, 53.8, 65.3, 68.2,
127.1, 128.3, 129.1, 138.9 .
(3S,4S)-4-(N,N-Dib en zyla m in o)-6-m et h yl-3-h ep t a n ol
(syn -5c): hexane/EtOAc 15/1; 57% yield; colorless oil; [R]23
)
D
+34.3 (c 1, CHCl3); IR (film) 3440 cm-1 1H NMR δ 0.92 (t,
;
3H, J ) 7.3 Hz), 0.94 (d, 6H, J ) 6.4 Hz), 1.18 (m, 2H), 1.57
(m, 2H), 1.70 (m, 1H), 2.48 (m, 1H), 3.38 (m, 1H), 3.41 (d, 2H,
J ) 13.4 Hz), 3.85 (d, 2H, J ) 13.4 Hz), 4.55 (br s, 1H), 7.20-
7.40 (m, 10H); 13C NMR δ 10.2, 22.9, 23.4, 26.6, 35.6, 53.7,
60.4, 72.3, 127.1, 128.4, 128.9, 139.1.
(3R,4S)-4-(N,N-Dib en zyla m in o)-6-m et h yl-3-h ep t a n ol
(a n ti-5c): hexane/EtOAc 15/1; 5% yield; colorless oil; [R]23
)
D
+15.7 (c 1, CHCl3); IR (film) 3420 cm-1; H NMR δ: 0.72 (d,
3H, J ) 6.5 Hz), 0.91 (d, 3H, J ) 6.6 Hz), 0.94 (t, 3H, J ) 7.3
Hz), 1.15-1.65 (m, 4H), 1.76 (m, 1H), 2.10 (br s, 1H), 2.72 (dt,
1H, J 1 ) 7.0 Hz, J 2 ) 3.6 Hz), 3.63 (d, 2H, J ) 13.6 Hz), 3.65
(m, 1H), 3.68 (d, 2H, J ) 13.6 Hz), 7.20-7.40 (m, 10H); 13C
NMR δ 11.1, 22.7, 23.1, 24.7, 27.6, 34.4, 55.0, 58.1, 72.2, 126.9,
128.2, 129.0, 140.2.
1
(2S,3S)-2-(N,N-Dib en zyla m in o)-1-p h en yl-3-p en t a n ol
(syn -5d ): hexane/EtOAc 8/1; 63%; colorless oil; [R]23D ) +25.0
Exp er im en ta l Section
1
(c 1, CHCl3); IR (film) 3400 cm-1; H NMR δ 0.81 (t, 3H, J )
7.3 Hz), 1.06 (m, 1H), 1.46 (m, 1H), 2.65 (dd, 1H, J 1 ) 14.3
Hz, J 2 ) 6.0 Hz), 2.88 (m, 1H), 3.07 (dd, 1H, J 1 ) 14.3 Hz, J 2
) 6.5 Hz), 3.35 (d, 2H, J ) 13.2 Hz), 3.52 (m, 1H), 3.89 (d, 2H,
J ) 13.2 Hz), 4.47 (s, 1H), 7.10-7.40 (m, 15H); 13C NMR δ
9.7, 26.8, 32.2, 53.7, 63.3, 71.3, 126.1, 127.1, 128.3, 128.4, 128.9,
129.0, 138.7, 140.4.
Gen er a l P r oced u r es. Optical rotations were measured on
a digital polarimeter in a 1-dm cell. 1H-NMR and 13C-NMR
were taken at 300 and 75 MHz, respectively, in CDCl3, and
chemical shifts are given in ppm relative to TMS as internal
standard. Only the most significant IR signals are given, and
microanalyses have been done at the Department of Inorganic
Chemistry. Chromatographic separations was done by flash
chromatography using 240-400 mesh silica gel.
The starting R-(dibenzylamino) aldehydes were prepared by
a modified described method.2 Diethylzinc (1 M solution in
hexanes) is commercially available. All the reactions were
carried out in oven-dried glassware under argon atmosphere.
Solvents were distilled prior to use: toluene and THF from
benzophenone ketyl, CH2Cl2 from CaH2, and methanol from
magnesium turnings.
Alk yla tion of Am in o Ald eh yd es 4 w ith Et2Zn . Gen er a l
Meth od . A 50 mL oven-dried flask equipped with a septum
and a magnetic stirrer and purged with argon was charged
with the corresponding N,N-dibenzylamino aldehyde (2 mmol)
in 8 mL of anhydrous toluene. The solution was cooled to 0
°C (ice bath), and 4 mL of a 1 M solution of diethylzinc in
hexane (4 mmol, 2 equiv) was injected through the septum.
The mixture was stirred at that temperature until the reaction
was finished (TLC) and then quenched with 40 mL of an
aqueous saturated solution of ammonium chloride. The
organic layer was separated, and the aqueous phase was
extracted with diethyl ether (3 × 20 mL). The combined
organic layers were washed with brine and dried over anhy-
drous Na2SO4. The solvents were eliminated on a Rotavapor,
and the residue was purified by flash chromatography (silica
gel, hexane/ethyl acetate).
(2S,3R)-2-(N,N-Dib en zyla m in o)-1-p h en yl-3-p en t a n ol
(a n ti-5d ): hexane/EtOAc 8/1; 7% yield; colorless oil; [R]23
)
D
+20.1 (c 1, CHCl3); IR (film) 3420 cm-1 1H NMR δ 0.88 (t,
;
3H, J ) 7.3 Hz), 1.37 (m, 1H), 1.68 (m, 1H), 1.90 (br s, 1H),
2.80 (dd, 1H, J 1 ) 12.7 Hz, J 2 ) 5.8 Hz), 3.05 (m, 2H), 3.60
(m, 1H), 3.65 (d, 2H, J ) 13.8 Hz), 3.77 (d, 2H, J ) 13.8 Hz),
7.10-7.40 (m, 15H); 13C NMR δ 10.9, 27.6, 31.9, 55.0, 63.0,
73.2, 125.9, 126.9, 128.2, 128.3, 128.7, 129.3, 139.7, 140.6.
(1S,2S)-1-(N,N-Diben zylam in o)-1-ph en yl-2-bu tan ol (syn -
5e): hexane/EtOAc 15/1; 65% yield; colorless solid; mp 85-86
°C (from hexane); [R]23 ) +151.5 (c 1, CHCl3); IR (KBr) 3420
D
cm-1; H NMR δ 0.86 (t, 3H, J )7.3 Hz), 1.04 (m, 1H), 1.26
1
(m, 1H), 3.02 (d, 2H, J ) 13.3 Hz), 3.49 (d, J ) 10.3 Hz), 3.96
(d, 2H, J ) 13.3 Hz), 4.15 (m, 1H), 4.50 (br s, 1H), 7.15 (m
15H); 13C NMR δ 10.0, 26.7, 53.5, 67.1, 69.0, 127.2, 127.8,
128.2, 128.5, 129.0, 129.9, 134.1, 138.6. Anal. Calcd for
C24H27NO: C, 83.44; H, 7.88; N, 4.05. Found: C, 83.20; H,
7.74; N, 4.21.
(1R,2R)-1-(N,N-Diben zylam in o)-1-ph en yl-2-bu tan ol (syn -
en t-5e): 68% yield; white solid; mp 85-86 °C (from hexane);
[R]23 ) -151.3 (c 1, CHCl3).
D
(2S,3S)-2-(N,N-Diben zyla m in o)-1-[(2-m eth oxyeth oxy)-
m eth oxy]-3-p en ta n ol (syn -5f): hexane/EtOAc 5/1; 67% yield;
colorless oil; [R]23 ) +58.3 (c 1, CHCl3); IR (film) 3420 cm-1
;
D
1H NMR δ 0.90 (t, 3H, J ) 7.4 Hz), 1.20 (m, 1H), 1.57 (m, 1H),
2.69 (m, 1H), 3.43 (s, 3H), 3.56 (d, 2H, J ) 13.2 Hz), 3.60 (m,
3H), 3.77 (m, 4H), 3.96 (d, 2H, J ) 13.2 Hz), 4.25 (br s, 1H),
(2S,3S)-2-(N,N-Diben zylam in o)-3-pen tan ol (syn -5a): hex-
ane/EtOAc 10/1; 84% yield; colorless oil; [R]23 ) +70.5 (c 1,
D

Synthesis of Enantiopure syn-â-Amino Alcohols
J . Org. Chem., Vol. 61, No. 13, 1996 4213
4.75 (s, 2H), 7.20-7.40 (m, 10H); 13C NMR δ 9.8, 26.5, 54.2,
58.9, 61.2, 64.2, 67.0, 68.3, 71.6, 95.4, 127.0, 128.2, 129.0, 138.8.
(2 S ,3 R )-2 -(N ,N -D i b e n z y l a m i n o )-1 -((2 -m e t h o x y -
eth oxy) m eth oxy)-3-p en ta n ol (a n ti-5f): hexane/EtOAc 5/1;
3% yield; colorless oil; IR (film) 3400 cm-1; 1H NMR δ 0.86 (t,
3H, J ) 7.4 Hz), 1.32 (m, 1H), 1.85 (m, 1H), 2.65 (br s, 1H),
2.74 (dt, J 1 ) 7.4 Hz, J 2 ) 4.9 Hz), 3.41 (s, 3H), 3.58 (m, 4H),
3.75 (m, 3H), 3.86 (d, 2H, J ) 13.8 Hz), 3.96 (m, 2H), 4.75 (s,
2H), 7.10-7.35 (m, 10H); 13C NMR δ 10.0, 27.4, 55.2, 59.0,
60.1, 65.3, 67.2, 71.7, 72.7, 95.7, 126.9, 128.2, 128.8, 139.8.
Gen er a l Meth od for th e Hyd r ogen olysis of N,N-Diben -
zyla m in o Alcoh ols 5.21 To a solution of the appropriate N,N-
dibenzylamino alcohol 5 (1.0 mmol) in 10 mL of dry methanol
was added 50 mg of 20% Pd(OH)2-C in one portion. The
mixture was stirred under 1 atm of hydrogen, and the reaction
was monitored by TLC analysis. After completion of the
reaction, the catalyst was removed by filtration through Celite
and washed with 20 mL of methanol. The solvent was
evaporated under reduced pressure to afford the pure product.
(2S,3S)-2-Am in o-3-p en ta n ol (syn -6a ): 92% yield; colorless
solid; mp 67-68 °C (from hexane); [R]23D ) -15.9 (c 0.34, CH3-
OH); IR (film) 3380 cm-1; 1H NMR δ 0.98 (t, 3H, J ) 7.4 Hz),
1.10 (d, 3H, J ) 6.4 Hz) ; 1.37 (m, 1H), 1.57 (m, 1H), 2.56 (br
s, 3H), 2.77 (m, 1H), 3.13 (ddd, 1H, J 1 ) 8.1 Hz, J 2 ) 6.6 Hz,
J 3 ) 3.5 Hz); 13C NMR δ 9.9, 20.0, 26.5, 50.7, 76.6. Anal. Calcd
for C5H13NO: C, 58.21; H, 12.70; N, 13.58. Found: C, 58.06;
H, 12.89; N, 13.42.
C8H19NO: C, 66.16; H, 13.19; N, 9.64. Found: C, 66.35; H,
13.28; N, 9.47.
(2S,3S)-2-Am in o-1-ph en yl-3-pen tan ol (syn -6d): 86% yield;
colorless oil; [R]23 ) -72.5 (c 2, CHCl3); IR (film) 3340 cm-1
;
D
1H NMR δ 1.01 (t, 3H, J ) 7.3 Hz), 1.55 (m, 2H), 2.31 (br s,
3H), 2.51 (m, 1H), 2.92 (m, 2H), 3.32 (m, 1H), 7.15-7.35 (m,
5H); 13C NMR δ 10.1, 27.0, 40.4, 56.2, 74.4, 126.2, 128.4, 129.1,
138.8. Anal. Calcd for C11H17NO: C, 73.70; H, 9.56; N, 7.81.
Found: C, 73.54; H, 9.66; N, 7.68.
(2S,3R)-2-Am in o-1-p h en yl-3-p en t a n ol (a n ti-6d ): 80%
yield; colorless solid; mp 103-104 °C (from hexane); [R]23
)
D
-39.0 (c 1, CHCl3); IR (KBr) 3420 cm-1 1H NMR δ 1.05 (t,
;
3H, J ) 7.4 Hz), 1.56 (m, 2H), 1.85 (br s, 3H), 2.45 (dd, 1H, J 1
) 13.5 Hz, J 2 ) 10.5 Hz), 2.89 (dd, 1H, J 1 ) 13.5 Hz, J 2 ) 3.4
Hz), 3.07 (m, 1H), 3.51 (m, 1H), 7.20-7.40 (m, 5H); 13C NMR
δ 10.6, 25.3, 37.6, 56.4, 75.3, 126.2, 128.5, 129.1, 139.3. Anal.
Calcd for C11H17NO: C, 73.70; H, 9.56; N, 7.81. Found: C,
73.59; H, 9.72; N, 7.60.
(1S,2S)-1-Am in o-1-p h en yl-2-bu ta n ol (syn -6e): 85% yield;
colorless solid; mp 80-81 °C (from hexane); [R]23 ) +31.2 (c
D
1, CHCl3); IR (KBr) 3320, 3260 cm-1; 1H NMR δ 0.93 (t, 3H, J
) 7.3 Hz), 1.33 (m, 2H), 2.87 (br s, 3H), 3.55 (m, 1H), 3.68 (d,
1H, J ) 7.9 Hz), 7.20-7.40 (m, 5H); 13C NMR δ: 10.1, 26.3,
61.0, 76.5, 127.1, 127.3, 128.4, 142.8. Anal. Calcd for C10H15
-
NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 71.72; H: 9.48; N,
8.18.
(1R,2R)-1-Am in o-1-p h en yl-2-bu ta n ol (syn -en t-6e): 94%
(2S,3R)-2-Am in o-3-p en ta n ol (a n ti-6a ): 91% yield; color-
yield; white solid; mp 80-81 °C (from hexane); [R]23 ) -32.9
D
1
less oil; [R]23 ) +14.0 (c 1, CHCl3); IR (film) 3380 cm-1; H
D
(c 1.1, CHCl3). Anal. Calcd for C10H15NO: C, 72.69; H, 9.15;
N, 8.48. Found: C, 72.49; H, 8.95; N, 8.41.
NMR δ 0.98 (t, 3H, J ) 7.4 Hz), 1.04 (d, 3H, J ) 6.6 Hz), 1.42
(m, 2H), 2.91 (br s, 3H), 3.01 (dq, 1H, J 1 ) 6.6 Hz, J 2 ) 3.2
Hz), 3.44 (m, 1H); 13C NMR δ 10.5, 16.1, 25.4, 50.2, 75.4. Anal.
Calcd for C5H13NO: C, 58.21; H, 12.70; N, 13.58. Found: C,
58.09; H, 12.83; N, 13.44.
(2S,3S)-2-Am in o-1-((2-m eth oxyeth oxy)m eth oxy)-3-p en -
ta n ol (syn -6f): 98% yield; colorless oil; [R]23 ) -3.2 (c 1,
D
CHCl3); IR (film) 3360 cm-1; H NMR δ 0.99 (t, 3H, J ) 7.4
1
Hz), 1.54 (m, 2H), 2.56 (br s, 3H), 2.93 (m, 1H), 3.40 (s, 3H),
3.47 (m, 1H), 3.57 (m, 3H), 3.70 (m, 3H), 4.74 (s, 2H); 13C NMR
δ 10.0, 26.8, 54.3, 58.9, 66.9, 70.1, 71.6, 72.2, 95.5. Anal. Calcd
for C9H21NO4: C, 52.15; H, 10.21; N, 6.76. Found: C, 52.36;
H, 10.38; N, 6.52.
(3S,4S)-3-Am in o-2-m eth yl-4-h exa n ol (syn -6b): 70% yield;
colorless oil; [R]23 ) -8.4 (c 0.7, CHCl3); IR (film) 3300 cm-1
;
D
1H NMR δ 0.87 (d, 3H, J ) 6.8 Hz), 0.98 (m, 6H), 1.40 (m,
1H), 1.55 (m, 1H), 1.83 (m, 1H), 2.46 (dd, 1H, J 1 ) 6.5 Hz, J 2
) 4.5 Hz), 2.73 (br s, 3H), 3.38 (ddd, 1H, J 1 ) 8.1 Hz, J 2 ) 6.5
Hz, J 3 ) 3.8 Hz); 13C NMR δ 10.0, 16.2, 20.4, 26.9, 29.0, 60.2,
72.4. Anal. Calcd for C7H17NO: C, 64.07; H, 13.06; N, 10.67.
Found: C, 63.92; H, 13.18; N, 10.49.
Ack n ow led gm en t. This work was supported by the
Spanish DGICYT (Project PB92-0262). M.A.M. thanks
to the University of Valladolid for a Predoctoral scholar-
ship.
(3S,4S)-4-Am in o-6-m eth yl-3-h eptan ol (syn -6c): 92% yield;
colorless oil; [R]23 ) -31.0 (c 1, CHCl3); IR (film) 3320 cm-1
;
D
1H NMR δ 0.90 (d, 3H, J ) 6.6 Hz), 0.94 (d, 3H, J ) 6.6 Hz),
0.98 (t, 3H, J ) 7.4 Hz), 1.25 (m, 2H), 1.42 (m, 1H), 1.56 (m,
1H), 1.73 (m, 1H), 2.36 (br s, 3H), 2.66 (m, 1H), 3.17 (ddd, 1H,
J 1 ) 8.2 Hz, J 2 ) 5.8 Hz, J 3 ) 3.9 Hz); 13C NMR δ 10.0, 21.5,
23.5, 24.5, 26.7, 43.2, 52.6, 75.1. Anal. Calcd for C8H19NO:
C, 66.16; H, 13.19; N, 9.64. Found: C, 66.28; H, 13.22; N, 9.51.
(3S,4R)-4-Am in o-6-m eth yl-3-h ep ta n ol (a n ti-6c): 60%
Su p p or tin g In for m a tion Ava ila ble: Copies of 13C NMR
spectra for compounds 5a -f and 6a -f, general experimental
procedures for the preparation of dibenzylamino alcohols 3a -
f, dibenzylamino aldehydes 4a -f, and oxazolidinones 7a -f,
as well as physical and spectroscopic data for these compounds
(25 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
yield; colorless oil; [R]23 ) -4.8 (c 0.8, CHCl3); IR (film) 3300
D
cm-1; 1H NMR δ 0.89 (d, 3H, J ) 6.6 Hz), 0.95 (d, 3H, J ) 6.6
Hz), 0.99 (t, 3H, J ) 7.3 Hz), 1.23 (m, 2H), 1.41 (m, 2H), 1.68
(m, 1H), 2.22 (br s, 3H), 2.88 (m, 1H), 3.41 (m, 1H); 13C NMR
δ 10.6, 21.5, 23.8, 24.4, 24.6, 40.8, 52.7, 75.8. Anal. Calcd for
J O960017T