Asymmetric synthesis of 1,2-amino alcohols using tert-butanesulfinimines as chiral auxiliary

Article abstract of DOI:10.1055/s-2004-836070

Facile and highly stereoselective synthesis of 1,2-amino alcohols has been achieved by the addition of [(dimethylphenyl-silyl)methyl] magnesium chloride to the tert-butanesulfinimines, followed by Fleming-Tamao oxidation of the silicon moiety.

Full text of DOI:10.1055/s-2004-836070

304
LETTER
Asymmetric Synthesis of 1,2-Amino Alcohols Using tert-Butanesulfinimines as
Chiral Auxiliary
A
symmetric Syn
h
a
Amino
A
lc
n
ohols g Hong Ko, Doo Young Jung, Min Kyun Kim, Yong Hae Kim*
Center for Molecular Design and Synthesis, Department of Chemistry, School of Molecular Science (BK-21), Korea Advanced Institute of
Science and Technology, 373-1, Guseong Dong, Yuseong Gu, Taejon, 305-701, Korea
Fax +82(42)8695818; E-mail: kimyh@kaist.ac.kr
Received 1 October 2004
ated in situ from a-amido sulfones.14 Here, we report an
Abstract: Facile and highly stereoselective synthesis of 1,2-amino
extension of our strategy to the synthesis of chiral amino
alcohols has been achieved by the addition of [(dimethylphenyl-
alcohols by the reaction of tert-butanesulfinimines13 with
silyl)methyl] magnesium chloride to the tert-butanesulfinimines,
[(dimethylphenylsilyl)methyl] magnesium chloride.15
followed by Fleming–Tamao oxidation of the silicon moiety.
Key words: amino alcohol, enantioselective synthesis, tert-butane- The synthesis of 1,2-amino alcohols has been achieved
sulfinimine, Grignard reagents, nucleophilic addition
via nucleophilic addition of [(dimethylphenylsilyl)meth-
yl] magnesium chloride to tert-butanesulfinimines fol-
lowed by appropriate functional group transformation and
Fleming–Tamao oxidation (Scheme 1).16
The 1,2-amino alcohol unit has been found in a number of
bioactive natural products1 such as alkaloids,2a–c amino
sugars,2d enzyme inhibitors,2e,3a–c and antibiotics.3d,e Also,
they are frequently employed in asymmetric synthesis as
chiral auxiliaries or chiral catalysts.4 Thus, the develop-
ment of new methods for general, facile and selective
preparations of amino alcohols remains an important goal
in synthetic organic chemistry.5 Many methods to synthe-
size amino alcohols and their derivatives, especially ami-
no acids, have been developed.5–8 Among the numerous
synthetic methods, there are only a few methods typically
employed to prepare chiral amino alcohols.9,10 Nucleo-
philic cleavage of epoxides with nitrogen nucleophiles
gives the amino alcohols.7a,b,9 However, low regioselec-
tivity can be problematic. Reduction of a-amino acid de-
rivatives affords the amino alcohols.10 However, a-amino
acids which are available as substrates are fairly limited.
Although several methods have been developed for chiral
1,2-amino alcohols, including asymmetric amino-
hydroxylation11 and nucleophilic additions to imines,12
most methods have narrow scope. The Ellman group re-
ported the synthesis of chiral 1,2-amino alcohols by using
tert-butanesulfinimines containing an a-alkoxy or a-silyl-
oxy substituent.13 Although this synthesis was highly dia-
stereoselective due to the tert-butanesulfinyl chiral
auxiliary, this method could only apply to aldehydes bear-
ing a-alkoxy or a-silyloxy substituents. After an extensive
survey of methods for preparing 1,2-amino alcohols, it oc-
curred to us that the direct condensation of imines derived
from various aldehydes with hydroxymethyl nucleophiles
would provide the most general and efficient way to syn-
thesize various chiral 1,2-amino alcohols. In the test of
this concept, we have reported that facile preparation of
racemic 1,2-amino alcohols was achieved by the reaction
of benzyloxymethyllithium with imines which are gener-
O
S
O
S
N
t-Bu
HN
t-Bu
(PhMe2Si)CH2MgCl
+
SiMe2Ph
R
H
R
1
2
NH2
OH
R
Functional group transformation
Fleming–Tamao oxidation
Scheme 1
[(Dimethylphenylsilyl)methyl] magnesium chloride (1)
was selected as a nucleophile due to the fact that dimeth-
ylphenylsilyl group is stable under various reaction condi-
tions and can be easily converted to a hydroxyl group by
Fleming–Tamao oxidation.16 In the initial stage of this
reaction, [(dimethylphenylsilyl)methyl] magnesium chlo-
ride was prepared in THF and reacted with sulfinimine
2a17 under various conditions (Table 1). Under the opti-
mized reaction condition, [(dimethylphenylsilyl)methyl]
magnesium chloride condensed with 1a in good yield and
excellent diastereoselectivity. Firstly, to test the effect of
solvents, 2a and 3 equivalents of [(dimethylphenyl-
silyl)methyl] magnesium chloride (1.0 M, THF) were
reacted in various solvents. THF turned out to be the best
solvent (entry 1–4, Table 1), while relatively non-polar
solvents such as diethyl ether, toluene and dichloro-
methane were not good. This may reflect the importance
of aggregation state of [(dimethylphenylsilyl)methyl]
magnesium chloride in the reaction. The amount of 1 was
crucial to obtain high diastereoselectivity. If more than 3
equivalents of 1 were employed, significant decrease of
diastereoselectivity was observed even at low tempera-
tures (entry 5–7, Table 1). When the reaction was carried
out at low temperature, the reaction required longer reac-
tion times at 0 °C (entry 7) or no reaction was observed at
SYNLETT 2005, No. 2, pp 0304–0308
0
1.
0
2.
2
0
0
5
Advanced online publication: 10.12.2004
DOI: 10.1055/s-2004-836070; Art ID: U27404ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Synthesis of 1,2-Amino Alcohols
305
Table 1 Reaction of 1 with 2a under Various Conditionsa
O
S
O
S
O
S
(PhMe2Si)CH2MgCl
1
HN
t-Bu
HN
t-Bu
N
t-Bu
+
SiMe2Ph
SiMe2Ph
Ph
Ph
Ph
H
3a (SR,R)
3a (SR,S)
2a
Entry
Equiv (1)
Solvent
Temp (°C)
Time (h)
48
Yield (%)b
R:Sc
75:25
90:10
84:16
97:3
–
1
2
3
3
Et2O
25
25
25
25
–15
25
0
77
63
54
80
–
CH2Cl2
Toluene
THF
48
3
5
48
4
3
40
5
3
THF
168
24
6
5
THF
74
66
75
75
–
93:7
93:7
99:1
98:2
–
7
10
2
THF
72
8d
9
THF
25
25
25
72
2
THF
72
10
1
THF
72
a Compound 2a was prepared according to ref.17 and the configuration was SR.
b Isolated yields.
c Determined by HPLC analysis with DAICEL AS-H column.
d Concentration of 1 was 0.5 M.
–15 °C (entry 5). In the optimized reaction conditions, 2 in minor S-product. In cases where more than two equiv-
equivalents of Grignard reagent were reacted with 2a at alents of Grignard reagents were employed, however, the
room temperature and the concentration of Grignard re- reagents can attack the sulfinimine intermolecularly to re-
agent was 0.5 M (entry 8, Table 1). Dilution of Grignard sult in diminished diastereoselectivity. As predicted by
reagent to 0.5 M was beneficial to the stereoselectivity of this model, when we employed only one equivalent of 1
the reaction (entry 9, Table 1). This might be attributed to in the reaction, we failed in obtaining 3a. In this case, one
the fact that by lowering the concentration, it became equivalent of 1 coordinated to 2a and no 1 was available
more feasible to employ exactly 2.0 equivalents of Grig- to react with 2a, so no product formation was observed.
nard reagent in the reaction. When we employed only 1 Thus, in the optimized condition, the use of two equiva-
equivalent of 1, the reaction did not proceed at all (entry lents of 1 is promising. To further prove the transition
10, Table 1).
state in Scheme 2, experiments using one equivalent of
Lewis acid activator and one equivalent of Grignard
reagents are now underway.
To explain the trend observed above, the six-membered
ring transition state model suggested by Ellman13 was em-
ployed. In his mechanistic study, Ellman proposed that the
reaction underwent a six-membered ring transition state
with chair conformation and in the case where an activator
was employed, he suggested that the activator coordinated
to the nitrogen atom of sulfinimine and occupied the axial
position to activate the reaction. In our cases, the [(di-
methylphenylsilyl)methyl] magnesium chloride is a rela-
tively weak nucleophile compared to conventional
Grignard or alkyllithium reagents due to a-anion stabiliz-
ing effect of silicon. Thus, in the present reaction, one
more equivalent of 1 is needed as an activator. Therefore,
two molecules of 1 are required in the transition state. The
intramolecular attack of [(dimethylphenylsilyl)methyl]
magnesium chloride, which gives major R-product is
much faster than the intermolecular attack that may result
Intermolecular nucleophilic addition
(S)-Product
(PhMe2Si)CH2MgCl
H
Intramolecular nucleophilic
addition
(R)-Product
S
Ph
N
Mg
SiMe2Ph
O
Mg
(PhMe2Si)CH2
Activator
Scheme 2 Plausible mechanism
Synlett 2005, No. 2, 304–308 © Thieme Stuttgart · New York

306
C. H. Ko et al.
LETTER
To broaden the utility of this reaction, several different protect amines 4a–f. The compounds 4a–f were treated
sulfinimines, derived from benzaldehydes of different under Fleming–Tamao oxidation condition16a (KBr–
electronic property and cyclohexane carboxaldehyde, HOOAc, NaOAc–HAcOH) to give amino alcohols 5a–f20
were treated with 1. Sulfinimines 2b–f were prepared in good yield (Table 3).
from commercially available (R)-tert-butanesulfinamide
Table 3 Conversion to Amino Alcohols 6a–fa,b
and various aldehydes.17 The sulfinimines 2b–f had an R-
configuration and were determined to have high enan-
O
tiopurity (>99%). Sulfinimine 2b derived from electron
S
NHBoc
SiMe2Ph
NHBoc
OH
HN
t-Bu
i, ii
iii
deficient p-bromobenzaldehyde underwent smooth reac-
tion to give R-3b in excellent yield and stereoselectivity
(entry 1, Table 2). When highly electronically rich sulfin-
imine 2c was employed, due to the high electron donating
ability of para-OMe group, the sulfinimine became less
susceptible to the nucleophilic attack and the reaction be-
came sluggish. However, with 5 equivalents of 1, com-
plete conversion of 3c was achieved after longer reaction
time to give R-3c in 70% yield and 95:5 diastereoselectiv-
ity (entry 2). But with mildly electron rich sulfinimine 3d,
the reaction proceeded smoothly to give the product in
high yield and excellent diastereoselectivity. Other sulfin-
imines 2e and 2f also condensed with 1 in good yield and
excellent diastereoselectivity (entry 4, 5). Due to the elec-
tron donating character of cyclohexyl and cinnamyl sub-
strate, however, the yields were lower than the cases with
neutral and electron deficient aromatic sulfinimine cases.
Importantly, no 1,4-addition product was observed in the
reaction of 118 and 2e.
To convert the adduct 3a–f22 to the corresponding amino
alcohols, removal of sulfinyl group and oxidation of sili-
con atom to the hydroxyl group remained. It was found
out that sulfinyl group had to be removed prior to the
oxidation. Due to the acidic and oxidative nature of
Fleming–Tamao oxidation, sulfinyl group was found to
interfere with oxidation reactions to give many side
products. Thus, the sulfinyl group was removed under 4
M HCl–dioxane condition and treated with (Boc)2O to
SiMe2Ph
R
R
R
5a–f
6a–f
3a–f
Entry
Product
6a
R
Yield (%)c
1
2
3
4
5
6
Ph
73
75
70
71
59
65
6b
p-BrPh
p-MeOPh
p-MePh
Cinnamyl
c-Hex
6c
6d
6e
6f
a Reagents and conditions: i) 4 N HCl–1,4-dioxane–MeOH (1:1:1),
25 °C, 1 h; ii) (Boc)2O (1.5 equiv), Et3N–MeOH (1:1); (iii) KBr (1.5
equiv), HOOAc (5 equiv), NaOAc (1.5 equiv), HOAc, 0–25 °C, 12 h.
b Compounds 6a–f were assigned to be R by comparison with the
known compounds.
c Isolated yields.
In conclusion, highly stereoselective and efficient synthe-
sis of chiral 1,2-amino alcohols has been achieved by
addition of [(dimethylphenylsilyl)methyl] magnesium
chloride to various sulfinimines derived from aldehydes.
In addition, since sulfinimines can be prepared from
numerous aldehydes, the scope of chiral 1,2-amino alco-
hols is diverse.
Table 2 Reaction of 1 with Various Sulfinimines 2b–fa
O
S
O
S
O
S
(PhMe2Si)CH2MgCl
HN
t-Bu
N
t-Bu
HN
t-Bu
1
SiMe2Ph
SiMe Ph
+
2
R
R
H
R
THF, 25 °C
3b–f (SR,S)
3b–f (SR,R)
2b–f
Entry
Product
3b
R
Equiv (1)
Time (h)
12
Yield (%)b
R:Sc
1
p-BrPh
2
5
2
2
2
88
70
79
69
65
95.5:4.5
95:5
2d
3
3c
p-MeOPh
p-MePh
Cinnamyl
c-Hex
168
48
3d
98.3:1.7
95:5
4
3e
48
5
3f
48
99:1
a Compounds 2b–f were prepared according to ref.17 and the configurations were SR.
b Isolated yields.
c Determined by HPLC analysis with DAICEL AS-H column.21
d Concentration of 1 was 1.0 M. Except for entry 2, the concentration of 1 was 0.5 M.
Synlett 2005, No. 2, 304–308 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of 1,2-Amino Alcohols
307
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This work was financially supported by grant No. R11-1999-056-
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(18) Experimental Procedure for Preparation of [(Dimethyl-
phenylsilyl)methyl] Magnesium Chloride (1):
Under an argon atmosphere, a suspension of magnesium
turnings (0.14 g, 5.83 mmol) in refluxing THF (2 mL) was
activated by addition of catalytic amounts of 1,2-dibromo-
ethane.Then,(chloromethyl)dimethylphenylsilane(902.1mL,
5 mmol) was added at such a rate as to maintain a gentle
reflux. After the addition was complete, the solution became
transparent and grayish. To this solution, additional THF
was added to adjust the concentration to be 0.5 M or 1.0 M
and the mixture was refluxed for 2 h to give THF solutions
of 1. The concentration of THF solution of 1 was determined
by the method of Orgura et al.23
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(19) Representative Experimental Procedure for the Addi-
tion of 1 to tert-Butanesulfinimines (Table 1, Entry 8):
tert-Butanesulfinimine 2a, prepared according to the known
procedure,13 was dissolved in THF and charged with argon.
To this solution, [(dimethylphenylsilyl)methyl] magnesium
chloride (0.5 M THF), prepared as above, was added
dropwise and stirring was continued for 72 h. After TLC
analysis indicated the completion of the reaction, the
reaction mixture was diluted with Et2O and quenched with
sat. NH4Cl aq solution. The organic layer was separated and
the aqueous layer was further extracted with Et2O 3 times.
The combined organic layer was dried over anhyd MgSO4
and the solvent was evaporated under reduced pressure. The
crude product 3a was purified by flash column
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chromatography using EtOAc–n-hexane = 1:6 as eluents.
The product was obtained in 75% yield. To determine
diastereoselectivity, 3a was converted to 5a by procedures
described below and analyzed with HPLC using racemic 5a,
prepared independently as a standard. HPLC conditions:
DAICEL AS-H column, 2-propanol–n-hexane = 1:99, 0.5
mL/min flow rate, retention time (major = 12.86 min,
minor = 14.90 min). Determination of absolute
configuration of major isomer was achieved by HPLC
analysis of amino alcohol 6a using both S- and R-6a
synthesized independently from the commercially available
enantiopure phenyl glycine methyl ester [HPLC conditions:
DAICEL OD-H column, 2-propanol–n-hexane = 5:95, 0.5
mL/min flow rate, tR (R) = 15.72 min, tR (S) = 18.99 min,
synthetic 6a 15.81 min]. 1H NMR (300 MHz, CDCl3): d =
–0.02 (s, 3 H), 0.15 (s, 3 H), 1.12 (s, 9 H), 1.42 (m, 2 H), 3.33
(s, 1 H), 4.52 (t, 1 H), 7.23 (m, 5 H), 7.31 (m, 3 H), 7.41 (m,
2 H). 13C NMR (75 MHz, CDCl3): d = –3.440, –2.249,
22.457, 27.935, 55.172, 56.384, 127.408, 127.618, 128.002,
128.899, 129.190, 133.694, 138.259, 143.481. HRMS (EI):
Anal. Calcd for C20H29NOSSi: 359.1739. Found: 359.1742.
(20) Representative Experimental Procedure for Removal of
Sulfinyl Group and Protection as Boc-carbamate
(Preparation of 5b):
(9) Caron, M.; Carlier, P. R.; Sharpless, K. B. J. Org. Chem.
1985, 53, 5185.
(10) Wuts, P. G.; Pruitt, L. E. Synthesis 1989, 622.
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Ed. Engl. 1996, 35, 451. (b) Reiser, O. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1308.
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1998, 120, 431. (b) Sigman, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 1998, 120, 4901.
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2001, 66, 8772. (b) Ellman, J. A.; Owens, T. D.; Tang, T. P.
Acc. Chem. Res. 2002, 35, 984.
Compound 3b was dissolved in 1 mL of MeOH at 25 °C. To
this solution, 1 mL of 1,4-dioxane and 1 mL of 4 M aq HCl
solution was added. The resulting mixture was stirred for 1
h at that temperature. After TLC analysis indicated the
(14) Jung, D. Y.; Ko, C.; Kim, Y. H. Synlett 2004, 1315.
Synlett 2005, No. 2, 304–308 © Thieme Stuttgart · New York

308
C. H. Ko et al.
LETTER
complete consumption of 3b, the solvents and HCl were
removed by evaporation under reduced pressure. The crude
4b was not purified and directly dissolved in mixed solvents
of 1 mL of MeOH and 1 mL of Et3N, followed by addition
of 1.5 equiv of (Boc)2O. After 1 h, the solvent was removed
and the crude 5b was dissolved in CH2Cl2 and washed with
Brine, sat. NH4Cl aq solution and brine successively. The
resulting 5b was purified by column chromatography
(eluent: EtOAc–n-hexane = 1:8) to give 5b in quantitative
yield. 1H NMR (300 MHz, CDCl3): d = 0.17 (s, 3 H), 0.22 (s,
3 H), 1.23 (m, 2 H), 1.25 (s, 9 H), 4.66 (m, 2 H), 7.05 (d, 2
H), 7.40 (m, 8 H). 13C NMR (75 MHz, CDCl3): d = –3.100,
–2.680, 25.430, 28.299, 51.864, 79.384, 120.666, 127.790,
127.849, 129.0182, 129.236, 131.430, 133.384, 144.214,
154.497. HRMS (EI): Anal. Calcd (433.1073) for
more CO2 gas evolution was detected. The organic layer was
dried over anhyd MgSO4 and the solvent was evaporated
under reduced pressure. The resulting crude 5a was purified
by column chromatography (eluent: EtOAc–n-hexane =
1:2). The spectral data of obtained 5a matched exactly with
known compounds. 1H NMR (300 MHz, CDCl3): d = 1.40
(s, 9 H), 2.39 (s, 1 H), 3.80 (m, 2 H), 4.74 (s, 1 H), 5.30 (s, 1
H), 7.32 (m, 5 H). 13C NMR (75 MHz, CDCl3): d = 28.280,
57.079, 66,688, 79.902, 126.525, 127.632, 128.686,
139.621, 156.016.
(22) HPLC Analysis of 3b–f and Determination of Absolute
Configuration. HPLC Conditions:
Compound 3b: DAICEL AS-H column, 2-propanol–n-
hexane = 1:99, 0.5 mL/min flow rate, tR (R) = 14.08 min, tR
(S) = 17.44 min. Compound 3c: DAICEL AS-H column, 2-
propanol–n-hexane = 1:99, 0.5 mL/min flow rate, tR (R) =
19.89 min, tR (S) = 23.11 min. Compound 3d: DAICEL
AS-H column, 2-propanol–n-hexane = 1:99, 0.5 mL/min
flow rate, tR (R) = 13.65 min, tR (S) = 15.89 min. Compound
3e: DAICEL AS-H column, 2-propanol–n-hexane = 1:99,
0.5 mL/min flow rate, tR (R) = 14.77 min, tR (S) = 17.01 min.
Compound 3f: DAICEL AS-H column, 2-propanol–n-
hexane = 1:99, 0.5 mL/min flow rate, tR (R) = 6.23 min, tR
(S) = 8.15 min. Determination of absolute configurations:
3b–f were tentatively assigned as (SR, R) in analogy with
3a.19 The absolute stereochemistry of 3a–f and amino
alcohols 6a–f were determined by comparisons with known
compounds.
C21H28BrNO2Si: C, 70.13; H, 8.24; N, 4.09; Si, 8.20; Br,
18.39. Found: 433.1124. HPLC (DAICEL AS-H column, 2-
propanol–n-hexane = 1:99, 0.5 mL/min flow rate)
tR(minor) = 16.15 min, (major) = 20.22 min.
(21) Representative Experimental Procedure for Fleming
Oxidation (Table 3, Entry 1): HOAc (1 mL), NaOAc
(0.032 g, 0.39 mmol), and KBr (0.045 g, 0.38 mmol) were
added to 5a, and the mixture was stirred until the salts were
dissolved. The solution was cooled to 0 °C and HOOAc
(1.59 mL, 30% in HOAc) was added dropwise with
exclusion of light. After the mixture was stirred for 3 h at
25 °C, TLC analysis indicated the completion of the
reaction. The mixture was diluted with Et2O and poured into
a cooled solution of Na2S2O3 (30 mL, 10%). The organic
layer was washed with sat. aq solution of NaHCO3 until no
(23) Aso, Y.; Yamashita, H.; Otsubo, T.; Orgura, F. J. Org.
Chem. 1989, 54, 5627.
Synlett 2005, No. 2, 304–308 © Thieme Stuttgart · New York