Stereoselective Synthesis of Enantiopure Amino Compounds, via Mitsunobu Azidation of (2S,Rs)-1-(p-Tolylsulfinyl)butan-2-ol

Article abstract of DOI:10.1039/a801562g

Azidation of (2S,R_s)-1-(p-tolysulfinyl)butan-2-ol under Mitsunobu conditions is the key step for a highly stereoselective preparation of enantiomerically pure amino compounds via chiral sulfoxide chemistry.

Full text of DOI:10.1039/a801562g

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666 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 666±667$
Stereoselective Synthesis of Enantiopure Amino
Compounds, via Mitsunobu Azidation of
(2S,RS)-1-(p-Tolylsulfinyl)butan-2-ol$
Pierfrancesco Bravo,*a Giancarlo Cavicchio,*b Marcello Crucianelli,a
Andrea Poggiali,a Alessandro Volonterioa and Matteo Zandaa
aCentro di Studio sulle Sostanze Organiche Naturali, Dipartimento di Chimica del Politecnico,
C.N.R., via Mancinelli 7, I-20131 Milano, Italy,
bIngegneria Chimica e Materiali, Coppito, Dipartimento di Chimica, Universita di L'Aquila, Via
Vetoio, I-67010 Coppito, Italy,
Azidation of (2S,RS)-1±(p-tolysulfinyl)butan-2-ol under Mitsunobu conditions is the key step for a highly stereoselec-
tive preparation of enantiomerically pure amino compounds via chiral sulfoxide chemistry.
The stereocontrolled synthesis and the reactivity of chiral
amines are topics of great interest in modern organic
chemistry,1 owing to the remarkable biological properties
connected with this class of molecule. Our recent atten-
tion towards the development of new stereocontrolled
approaches to chiral amines led us to investigate the
azidation of ¯uorosubstituted b-sul®nyl alcohols under
Mitsunobu conditions2 as a new tool for preparing enantio-
merically pure b-¯uoro a-amino acids.3 Since, to our knowl-
edge, no reports dealing with Mitsunobu-type reactions of
¯uorine-free b-sul®nyl alcohols are extant in the literature, a
further aim of this study was to investigate the compatibility
of the stereogenic sul®nyl group with the Mitsunobu
conditions, to extend this methodology to the synthesis of
¯uorine-free chiral amines. In this paper we describe
the Mitsunobu azidation of enantiopure (2S,RS)-1-( p-tolyl-
sul®nyl)butan-2-ol 1, and the transformation of the resulting
azide (2R,RS)-2 into several amino compounds (4±7)
(Scheme 1).
with HN3±PPh3±DEAD (method B, 57%). As expected the
desired product (2R,RS)-2 was formed with clean inversion
of con®guration at C-2, as a single diastereoisomer, isolated
in pure form by ¯ash chromatography on silica gel.
The b-sul®nyl azide (2R,RS)-2 can be considered as a
versatile synthetic intermediate. In fact its sul®nyl and
azide moieties were submitted to several chemoselective
elaborations, as described in Scheme 1. Oxidation of
(2R,RS)-2 to the corresponding b-tosylazide (R)-3 was
achieved by reaction with m-chloroperbenzoic acid
(m-CPBA) at 0 8C (96%). Furthermore, the azide function
of (2R,RS)-2 could be reduced to amine by treatment with
HS[CH2]3SH±triethylamine,6 providing the b-sul®nyl amine
(2R,RS)-4 in almost quantitative yield, without a€ecting the
stereogenic sul®nyl centre.
The amino group of (2R,RS)-4 was subsequently protected
upon treatment with DCC±benzoic acid (72%). The sul®nyl
group of the resulting N-benzoyl derivative (2R,RS)-5 was
deoxygenated with NaI±tri¯uoroacetic anhydride (TFAA),
according to the Oae±Drabowicz protocol,7 which delivered
the N-benzoyl b-( p-tolylthio)amine (R)-6 in 83% yield.
Finally, N-benzoyl sec-butylamine (S)-7 was obtained by
reductive desulfenylation of (R)-6, with Raney-Ni in ethanol
at 60 8C (94%). Since the enantiomeric compound (R)-7,
The starting b-sul®nyl alcohol (2S,RS)-1 was stereoselec-
tively prepared by reduction with diisobutylaluminium
hydride (DIBAH) of the corresponding (R)-1-( p-tolyl-
sul®nyl)butan-2-one.4 Transformation of (2S,RS)-1 into the
b-sul®nyl azide (2R,RS)-2 was accomplished by treatment
with NaN3±PPh3±CBr4 (method A, 76%)5 or, alternatively,
having [a]20
described in the literature,8 polarimetric analysis of our
sample, having [a]20
D
21.5 (c 1.15, CH2Cl2), has been previously
D
‡24.7 (c 1.12, CH2Cl2), allowed
us to con®rm both its (S)-con®guration, as well as the
enantiomeric purity of all the precursor compounds 2±6,
represented in the Scheme 1.
In conclusion, we have reported a synthetically useful
protocol for the synthesis of enantiomerically pure amino
compounds from b-sul®nyl alcohols, which uses azidation
under Mitsunobu conditions as the key step. This method
features both high overall yields and stereoselectivity, and
could therefore be successfully exploited for the preparation
of many other biologically interesting, enantiopure amino
compounds.
Experimental
General Procedure.ÐThe instrumentation and general exper-
imental and analytical procedures were recently described in detail.9
Scheme 1 Reagents, conditions and yields: i Method A: NaN3,
Ph3P, CBr4 (76%); Method B: HN3, Ph3P, DEAD (57%);
ii, m-CPBA, 0 8C (96%); iii, HS[CH2]3SH±NEt3 (97%);
iv, PhCO2H±DCC (72%); v, (CF3CO)2O±NaI (83%);
Raney-Ni±H2, 60 8C (94%)
The ꢀ-sul®nyl alcohol (2S,RS)-1 was prepared according to
a
literature procedure.4
ꢀ-Sul®nyl Azide (2R,RS)-2.ÐMethod A. To a stirred solution of
(2S,RS)-1 (1.22 g, 5.75 mmol) in DMF (50 ml) cooled at 0 8C were
added NaN3 (5.61 g, 86.3 mmol), Ph3P (5.53 g, 17.3 mmol) and
®nally CBr4 (5.74 g 17.3 mmol). The mixture was stirred at r.t. for
4 h, then water and diethyl ether were added and the phases were
separated. The organic phase was repeatedly washed with water in
order to remove DMF, then dried over anhydrous Na2SO4, ®ltered
and the solvent removed at reduced pressure. The crude mixture
was submitted to ¯ash chromatography (FC) (1:1 n-hexane±ethyl
*To receive any correspondence (e-mail: bravo@dept.chem.poli-
mi.it).
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

View Article Online
J. CHEM. RESEARCH (S), 1998 667
acetate), which a€orded 1.02 g of the desired azide (2R,RS)-2 (76%),
as a yellowish oil.
ꢁ
max/cm1 (KBr) 3303, 1634, 1530, 1029 (Found: C, 68.0; H, 7.1;
N, 4.9, C18H21NO2S requires C, 68.4; H, 6.7; N, 4.5%).
Method B. A solution of (2S,RS)-1 (212 mg, 1 mmol) and Ph3P
(524 mg, 2 mmol) in anhydrous benzene (11 mL) and HN3 (4.0 mL
of 1.0 M solution in anhydrous benzene, 4 mmol) was cooled with
an ice±water bath under nitrogen. To the stirred solution DEAD
(0.63 ml, 4 mmol) diluted with the same solvent (5 mL) was added
dropwise. The bath was removed and, after ca. 15 min, TLC control
revealed that all (2S,RS)-1 had been consumed. The reaction
mixture was ®ltered, the solvent was removed in vacuo, and ®nally
the crude was puri®ed ®rst by FC on silica gel, then on neutral
alumina (4:6 n-hexane±ethyl acetate), providing 135 mg of the
desired azide (2R,RS)-2 (57%).
N-Benzoyl p-Tolylthioamine (R)-6.ÐTo a mixture of N-benzoyl
ꢀ-sul®nyl amine (2R,RS)-5 (107 mg, 0.32 mmol) and NaI (145 mg,
0.97 mmol) in acetone (2 ml) at 20 8C,
a solution of TFAA
(0.23 ml, 1.62 mmol) in acetone (1 ml) was added dropwise. The
mixture immediately became dark green. After 5 min at 20 8C
(TLC monitoring) the reaction was quenched with a saturated aqu-
eous sodium sul®te solution, then a saturated aqueous NaHCO3 sol-
ution was added until neutral pH was reached. The mixture was
allowed to warm at room temperature, then the mixture was
extracted with ethyl acetate, the collected organic phases were dried
over anhydrous sodium sulfate and ®ltered and the solvent was
removed in vacuo. FC (n-hexane±ethyl acetate 7:3) provided the
desired N-benzoyl amine (R)-6 (80 mg, 83%).
20
(2R,RS)-2: Rf (6:4 n-hexane±ethyl acetate) 0.31; [a]D ‡140.4
(c 0.88, CHCl3); dH (CDCl3) 7.56 (2 H, d, J 8.1 Hz), 7.36 (2 H, d,
J 8.1 Hz), 3.6±3.4 (1 H, m), 3.08 (1 H, dd, J 13.1 and 7.0 Hz), 2.84
(1 H, dd, J 13.1 and 6.3 Hz), 2.42 (3 H, s), 2.0±1.5 (2 H, m), and
1.01 (3 H, t, J 7.3 Hz); dC (CDCl3) 142.0, 139.9, 130.2, 124.1, 61.0,
58.3, 27.3, 21.5, 10.1 (Found: C, 55.3; H, 6.8; N, 17.4. C11H15N3OS
requires C, 55.7; H, 6.4; N, 17.7%).
(R)-6. Rf 0.45 (7:3 n-hexane±ethyl acetate); dH (CDCl3) 7.59 (2 H,
m), 7.52±7.29 (5 H, m), 7.06 (2 H, d, J 7.8 Hz), 6.12 (1 H, brd,
J 8.1 Hz), 4.30 (1 H, m), 3.21 (2 H, br signal), 2.28 (3 H, s),
1.88±1.58 (2 H, m), 0.96 (3 H, t, J 7.3 Hz); m/z (EI, 70 eV) 299
‡
1
(M , 68%), 178 (46), 105 (100), 77 (67). FT IR ꢁmax/cm (KBr)
3308, 1639, 1535, 1490 (Found: C, 71.2; H, 7.2; N, 4.6. C18H21NOS
requires C,72.2; H, 7.1; N, 4.7%).
ꢀ-Tosyl Azide (R)-3.ÐTo a solution of sul®nyl azide (2R,RS)-2
(44 mg, 0.18 mmol) in CH2Cl2 (2 ml), cooled at 0 8C, a solution of
commercial m-CPBA (57±86%) (84 mg, 0.27±0.41 mmol) in CH2Cl2
(3 ml) was added dropwise. After 1 h at 0 8C (TLC monitoring) the
reaction mixture was washed with aqueous 10% sodium sul®te,
then with saturated aqueous NaHCO3, ®nally with brine. The aqu-
eous phases were washed with CH2Cl2, the collected organic phases
were dried over anhydrous sodium sulfate, ®ltered and the solvent
was removed in vacuo. FC of the crude (n-hexane±ethyl acetate 8:2)
provided pure (R)-3 as a yellowish oil (45 mg, 96%).
N-Benzoyl sec-Butylamine (S)-7.ÐTo a stirred solution of the
thioamine (R)-6 (72 mg, 0.24 mmol) in absolute ethanol (5.0 ml)
Raney-Ni (ca. 0.4 g) was added and the slurry was vigorously
stirred for 3 h at 80 8C under a hydrogen atmosphere. The Raney-
Ni was removed by ®ltration on a Celite pad and the solvent was
removed under reduced pressure. FC (n-hexane±ethyl acetate 4:1 to
7.3) provided the desired N-benzoyl amine (S)-7 (40 mg, 94%) as a
white solid.
(R)-3. Rf 0.35 (4:1 n-hexane±ethyl acetate); [a]D20+40.1 (c 0.33,
CHCl3); dH (CDCl3) 7.83 (2 H, d, J ˆ 8.4 Hz), 7.37 (2 H, d, J
8.4 Hz), 3.87±3.78 (1 H, m), 3.26 (1 H, dd, J 14.5 and 8.2 Hz), 3.16
(1 H, dd, J 14.5 and 4.0 Hz), 2.47 (3 H, s), 1.8±1.5 (2 H, m), and
1.00 (3 H, t, J 7.3 Hz); dC (CDCl3) 145.8, 137.3, 130.7, 128.7, 60.5,
(S)-7. Rf 0.40 (75:25 n-hexane±ethyl acetate); [a]D ‡24.7 (c 1.12,
20
CH2Cl2); in the literature the enantiomer (R)-7 is reported to have
20
[a]D
21.5 (c 1.15, CH2Cl2)8; dH (CDCl3) 7.81±7.78 (2 H, m),
7.52±7.36 (3 H, m), 6.10 (1 H, br signal), 4.20±4.03 (1 H, m), 1.57
(2 H, dq, J ca. 7.3 Hz both), 1.22 (3 H, d, J 6.8 Hz), 0.96 (3 H, t,
J 7.3 Hz); dC (CDCl3) 166.9, 135.0, 131.2, 128.4, 126.8, 47.0, 29.7,
20.5, 10.4.
1
59.3, 28.7, 22.4, 10.6; FT IR ꢁmax/cm (KBr) 2972, 2121, 2070,
‡
1598, 1319, 1303, 1146; m/z (EI, 70 eV) 226 (M ‡1 C2H5, 18),
‡
211 (M
requires C, 52.2; H, 6.0; N, 16.6%).
N3) (Found: C, 52.5; H, 6.4; N, 16.4. C11H15N3O2S
Received, 24th February 1998; Accepted, 16th July 1998
Paper E/8/01562G
ꢀ-Sul®nyl Amine (2R,RS)-4.ÐTo a solution of azide (2R,RS)-2
(200 mg, 0.84 mmol) in methanol (5 mL) at r.t. under nitrogen were
added propane-1,3-dithiol (847 ꢂL, 8.44 mmol) and triethylamine
(1.17 mL, 8.44 mmol). After ca 4 h (TLC monitoring) the mixture
was submitted to prolonged evaporation in vacuo, then the residue
was puri®ed by FC (ethyl acetate±isopropanol 95:5 to 5:95). The
desired amine (2R,RS)-4 was obtained as a yellowish oil (172 mg,
97%).
References
1 (a) J. Klein, in The Chemistry of Double-Bonded Functional
Groups: Supplement A, ed. S. Patai, Wiley, Chichester, 1989, Vol.
2, Part 1, ch. 10; (b) Methods of Organic Chemistry (Houben-
Weyl): Stereoselective Synthesis, eds. G. Helmchen, R. W.
Ho€mann, J. Mulzer and E. Schaumann, Georg Thieme, Verlag:
Stuttgart, 1995, Vol. E 21b.
2 (a) O. Mitsunobu, Synthesis, 1981, 1; (b) D. L. Hughes, Organic
Reactions, 1992, Vol. 42, ch. 2; (c) E. Fabiano, B. T. Golding and
M. M. Sadeghi, Synthesis, 1987, 190.
3 P. Bravo, G. Cavicchio, M. Crucianelli, A. Poggiali and
M. Zanda, Tetrahedron: Asymmetry, 1997, 8, 2811.
4 (a) G. Solladie, C. Greck, G. Demailly and A. Solladie-Cavallo,
Tetrahedron Lett., 1982, 23, 5047; (b) G. Solladie, G. Dmailly and
C. Greck, Tetrahedron Lett., 1985, 26, 435.
5 (a) I. Yamamoto, M. Sekine and T. Hata, J. Chem. Soc., Perkin
Trans. 1, 1980, 306; (b) S. Shuto, S. Ono, Y. Hase, N. Kamiyama,
H. Takada, K. Yamashita and A. Matsuda, J. Org. Chem., 1996,
61, 915.
20
(2R,RS)-4. Rf 0.30 (5:95 ethyl acetate±isopropanol); [a]D ‡166.5
(c 1.02, CHCl3); dH (CDCl3) 7.56 (2 H, d, J 8.0 Hz), 7.33 (2 H, d, J
8.0 Hz), 3.24 (1 H, m), 2.88 (1 H, dd, J 8.3 and 13.2 Hz), 2.73 (1 H,
dd, J 4.2 and 13.2 Hz), 2.41 (3 H, s), 1.71 (2 H, s), 1.61 (1 H, m),
‡
1.47 (1 H, m), 0.95 (3 H, t, J 7.3 Hz); m/z (EI, 70 eV) 212 (M ‡1,
1
85), 148 (46), 91 (25), 72 (100); FT IR ꢁmax/cm (KBr) 3365 (br),
3270, 1597, 1495, 1459, 1399, 1087, 1034.
N-Benzoyl ꢀ-sul®nyl amine (2R,RS)-5.ÐA mixture of ꢀ-sul®nyl
amine (2R,RS)-4 (130 mg, 0.62 mmol), benzoic acid (144 mg,
1.18 mmol), DCC (243 mg, 1.18 mmol) and p-dimethylaminopyri-
dine (13 mg, 0.11 mmol) in CH2Cl2 (6 ml) was stirred at r.t. for
90 min (TLC monitoring). The mixture was diluted with 10 ml of
diethyl ether, ®ltered, and the solvent was removed in vacuo. FC
(n-hexane±ethyl acetate 1:1) provided the desired N-benzoyl amine
(2R,RS)-5 as a white solid (202 mg, 72%).
(2R,RS)-5. Rf 0.30 (1:1 n-hexane±ethyl acetate); mp 151.5±
6 H. Bayley, D. N. Standring and J. R. Knowles, Tetrahedron
Lett., 1978, 19, 3633.
7 J. Drabowicz and S. Oae, Synthesis, 1977, 404.
8 (a) F. Foubelo and M. Yus, Tetrahedron Lett., 1994, 35, 4831;
(b) F. Foubelo and M. Yus, Tetrahedron: Asymmetry, 1996, 7
2911.
20
153.0 8C (ethyl acetate); [a]D ‡79.1 (c 0.61, CHCl3); dH (CDCl3)
7.82 (2 H, d, J 8.0 Hz), 7.58 (2 H, d, J 8.0 Hz), 7.50±7.27 (5 H, m),
7.23 (1 H, br d, J 7.4 Hz), 4.32 (1 H, m), 3.23 (1 H, dd, J 8.7 and
13.4 Hz), 3.12 (1 H, dd, J 4.8 and 13.4 Hz), 2.40 (3 H, s), 1.94±1.50
(2 H, m), 0.92 (3 H, t, J 7.3 Hz); dC (CDCl3) 167.4, 141.8, 140.3,
134.2, 131.5, 130.1, 128.4, 127.1, 124.2, 61.9, 48.3, 27.8, 21.4, 10.2;
9 A. Volonterio, M. Zanda, P. Bravo, G. Gronza, G. Cavicchio
and M. Crucianelli, J. Org. Chem., 1997, 62, 8031.
‡
m/z (EI, 70 eV) 316 (M ‡1, 10), 176 (100), 105 (70), 77 (32); FT IR