Synthesis of threo-β-aminoalcohols from aminoaldehydes via chelation-controlled additions. Total synthesis of l-threo sphingosine and safingol

Article abstract of DOI:10.1016/j.tetlet.2012.05.153

Chelation-controlled addition of organocuprates to N-carbamoyl aminoaldehydes, prepared from functionalized amino acids, generated predominately the threo-β-amino alcohol derivatives through chelation with the carbamoyl moiety. The carbamate group is a stronger chelating group than other potentially good chelators, for example ethers, esters, thioethers, and gives good diastereoselectivity with cuprates. Thus addition of lithium divinylcuprate to the aldehyde generated from the serine derivative 25 in the presence of extra copper for chelation afforded the threo compound 26 in 83% yield. Cross-metathesis and cleavage of the protecting groups furnished l-threo sphingosine 21. In addition the lyso-sphingolipid protein kinase C inhibitor, safingol, 22, was prepared from commercially available O-benzyl N-BOC serine 28 in six steps and 56% overall yield by this method.

Full text of DOI:10.1016/j.tetlet.2012.05.153

Tetrahedron Letters 53 (2012) 4216–4220
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of threo-b-aminoalcohols from aminoaldehydes via
chelation-controlled additions. Total synthesis of L-threo sphingosine and
safingol
⇑
Michael E. Jung , Sung Wook Yi
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90064, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Chelation-controlled addition of organocuprates to N-carbamoyl aminoaldehydes, prepared from func-
tionalized amino acids, generated predominately the threo-b-amino alcohol derivatives through chelation
with the carbamoyl moiety. The carbamate group is a stronger chelating group than other potentially good
chelators, for example ethers, esters, thioethers, and gives good diastereoselectivity with cuprates. Thus
addition of lithium divinylcuprate to the aldehyde generated from the serine derivative 25 in the presence
of extra copper for chelation afforded the threo compound 26 in 83% yield. Cross-metathesis and cleavage
of the protecting groups furnished L-threo sphingosine 21. In addition the lyso-sphingolipid protein kinase
C inhibitor, safingol, 22, was prepared from commercially available O-benzyl N-BOC serine 28 in six steps
and 56% overall yield by this method.
Received 17 May 2012
Revised 29 May 2012
Accepted 30 May 2012
Available online 8 June 2012
Keywords:
Diastereoselective addition
Chelation-controlled addition
Total synthesis
Ó 2012 Published by Elsevier Ltd.
Threo-b-aminoalcohols
Introduction
iPr
N
Vicinal amino alcohols are an important class of compounds
having significant biological and chemical properties. In addition
to peptides and sugars, a number of naturally occurring com-
pounds that exhibit interesting biological properties, including
ritonavir 1, bestatin 2, AI-77-B 3, anisomycin 4, and pseudo-ephed-
rine 5 (Fig. 1), all have a syn-vicinal amino alcohol moiety.1,2 More-
over many compounds possessing a threo-amino alcohol moiety
have been designed for a variety of scientific purposes.3 Recently,
numerous catalytic reactions have been developed using amino
alcohols as catalysts or ligands for catalysis.4 Therefore, finding a
good stereospecific method to these amino alcohols would facili-
tate their preparation.1 Among other approaches, strategies that
S
N
O
Me
S
N
HN
iPr
O
O
OH HN
O
HN
1
HO
OAc
utilize a
-amino aldehydes might offer certain advantages,5 namely
OH
H
many natural amino acids are commercially available and these
starting materials already have one chiral center, which conceiv-
ably could be instrumental in directing the stereochemical out-
come of subsequent transformations. Consequently, expensive
chiral catalysts might not be required for these approaches. Fig-
ure 2 shows the two opposite approaches that follow different
addition models. Pathway (a) would give the anti b-amino alcohols
by the Felkin–Anh model6 while pathway (b) would provide the
syn b-amino alcohols by the chelation-controlled cyclic Cram mod-
el.7 There have been some studies in which N,N-diprotected
N
COOH
iPr
N
H
NH2
O
2
OMe
Me
4
OH
O
O
OH
OH NH2
H
H
N
COOH
O
OH
NHMe
iPr
3
5
⇑
Corresponding author. Tel.: +1 310 825 7954; fax: +1 310 206 3722.
E-mail address: jung@chem.ucla.edu (M.E. Jung).
Figure 1. Threo vicinal amino alcohol containing compounds.
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.05.153

M. E. Jung, S. W. Yi / Tetrahedron Letters 53 (2012) 4216–4220
4217
Table 1
Nuc
Optimization of the chelation controlled addition
R"2N
R"2N
Felkin-Anh
addition
a
OH
O
R
anti
NHBoc
H
NHBoc
CH3 TrS
NHBoc
CH3
R"2N
conditions
H
TrS
TrS
+
b
R
Nuc
O
OH
12a
OH
12b
chelated
addition
11
OH
R
Entry
Nucleophiles
MeLi
MeMgBr
Me2CuMgBr
Me2CuLi
Me2CuLi
MeCu
Solvents
Temp
h
12a:12b
syn
1
2
3
4
5
6
Et2O
À78 °C
0 °C
À40 °C
À40 °C
À40 °C
À40 °C
1
2
5
3
3
3
1:1
2:1
7:3
N.R.
12a only
N.R.
Et2O/tol
Et2O/tol
THF
Et2O
Et2O
Figure 2. Syn and anti additions to a-aminoaldehyde derivatives.
a
-amino aldehydes,8 Garner’s aldehydes,9 and monoprotected
a-
amino aldehydes10 are used as electrophiles to synthesize either
anti-amino alcohols or syn-amino alcohols. However, these studies
were limited to only simple amino aldehydes and often suffered
from poor selectivities and low yields. To the best of our knowl-
edge, amino aldehydes derived from cysteine, glutamic acid, aspar-
tic acid, threonine, and tyrosine have never been studied for the
chelation-controlled addition to produce b amino alcohols stereo-
specifically. Herein, we report the highly stereoselective chela-
tion-controlled addition of nucleophiles to amino aldehydes that
provide syn-b-amino alcohols with synthetically useful functional-
ized alkyl side chains.
epimerization.10,11 As shown in Table 1, although addition of meth-
yllithium gave no selectivity (entry 1), we were able to obtain the
two, diastereomeric products12 that were easily separable by flash
column chromatography. Addition of methylmagnesium bromide
(entry 2) gave a slight excess (2:1) of the desired syn compound,
and the addition of bromomagnesium dimethylcuprate improved
the selectivity (7:3) but was not satisfactory. Lithium dimethyl-
cuprate in THF (entry 4) gave no reaction. Therefore the result of
alkylation using lithium dimethylcuprate in diethyl ether (entry
5) was somewhat unexpected. We observed complete diastereose-
lectivity and did not see any of the other diastereomer in this case.
We believe that the bulky nature of the trityl protected thiol blocks
the other side of the aldehyde and at the low reaction temperature,
the reaction gives only the desired syn-amino alcohol product.
Methyl copper (I) was not reactive at all under the same conditions
(entry 6). With the optimal conditions for the chelation-controlled
alkylation established, we applied this method to the synthesis of
Results and discussion
For one of our medicinal chemistry projects, we designed the
peptidomimetic compound 6 (Cbz-LPAT⁄) that mimics the sorting
signal of Sortase A from Staphylococcus aureus (Fig. 3). Previously3
we reported the synthesis of the protected thiol-containing threo-
nine analogue 8 from L-threonine 7. Because of the demand for lar-
ger quantities of 6 for use in other sorting signal mimics, we
designed a new synthetic route that could improve the synthesis
but required the addition of a methyl group to a protected alde-
hyde derived from cysteine 9 in a stereospecific manner to afford
the desired syn-configuration 10. Although we could find no prec-
edent for clean addition of alkyl groups to a protected cysteine
aldehyde, we envisioned a bulky thio-protecting group enhancing
the diastereoselectivity of the reaction while shielding the sulfur
from any undesired chelation. Therefore, we chose the acid-labile
tert-butoxycarbonyl (Boc) and triphenylmethyl (trityl, Tr) groups
as the N- and S-protecting groups, respectively, for the protected
cysteine aldehyde in our study of the alkylation. The N-Boc, S-Tr
protected cysteine aldehydes were prepared from the correspond-
ing readily available protected acid by borane reduction followed
by oxidation using freshly prepared Dess–Martin periodinane.
The sequence was chosen over other possible routes, for example,
DIBAL reduction of the Weinreb amide, because of its practicality
and mild conditions, which are known to give minimal
17, the intermediate for the threonine modifier 6, from (D)-N-Boc
S-trityl cysteine 13 (Scheme 1). Borane reduction of the carboxylic
acid of 13 afforded the primary alcohol 14 in 96% yield. The alcohol
14 was then oxidized with Dess–Martin periodinane in the pres-
ence of sodium bicarbonate to give the aldehyde 15. In order to
avoid any epimerization, the crude aldehyde 15 was subjected to
the crucial alkylation using the optimized conditions of Table 1.
The secondary alcohol 16 was isolated in 92% yield for the two
steps. Deprotection of the N-Boc group of 16 was effected by treat-
ing 16 with 50% TFA solution in dichloromethane to yield the thre-
onine modifier 17 in 85% yield. Therefore, the new modifier 17 was
prepared in four steps from the protected amino acid in 75% overall
yield. This improved procedure provided a sufficient amount of 17
for preparing 6 as well as other sorting signal mimics.
Inspired by the excellent selectivity and yields of this cysteine
case, we decided to screen other amino aldehydes that are derived
from functionalized amino acids such as serine, threonine, aspartic
Me
OTBDPS
S-TBDPS
Me
OH
9 steps
Me
OH
SH
O
H
N
H2N
H2N
COOH
N
N
H
CBZNH
iPr
8
7
O
Me
O
Me
P3NH
OP1
S-P2
6 Cbz-LPAT*
COOH
SH
H2N
9
10
Figure 3. Proposed preparation of the new threonine modifier 10.

4218
M. E. Jung, S. W. Yi / Tetrahedron Letters 53 (2012) 4216–4220
COOH
STr
CH2OH
STr
CHO
BH3-THF
THF, 0 C
96%
DMP
NaHCO3
CH2Cl2
STr
BocNH
BocNH
BocNH
15
13
14
Me
BocNH
OH
STr
Me
OH
STr
Me2CuLi
Et2O
92% 2 steps
TFA
CH2Cl2
85%
6 Cbz-LPAT*
TFA-H2N
16
17 4 steps, 75% overall yield
Scheme 1. Improved method for synthesis of 6.
acid, glutamic acid, and tyrosine. Although chelation-controlled
addition of metallated nucleophiles to protected -aminoalde-
of the addition. The large TIPS ether also gave the desired syn-com-
pound with excellent selectivity (entry 4). A benzyl ether was a
good protecting group for the aldehydes derived from serine (entry
5), threonine (entry 8), and tyrosine (entry 11). The tert-butyl es-
ters of aspartate and glutamate (entries 9 and 10) were also shown
to improve selectivity. It is noteworthy that the tert-butyl ethers of
the aldehydes derived from homoserine (entry 6) and even bis-
homoserine (entry 7) both gave excellent selectivity.
a
hydes derived from less functionalized amino acids or cyclic deriv-
atives such as Garner’s aldehyde is well known,10,13 analogous
additions to functionalized systems where additional chelating
groups are present has not been reported. The results of the initial
screening studies were quite good as shown in Table 2.
All of the primary alcohols were prepared by reduction of the
corresponding acids with the borane-THF complex. As shown, both
Boc and Cbz groups were suitable for the N-protecting groups. For
the alcohol protection, a tert-butyl ether (entries 2, 3, 6, and 7)
proved to be an excellent choice for increasing the syn-selectivity
After the good results obtained with lithium dimethylcuprate,
we wanted to see if other nucleophiles could be utilized. As shown
in Table 3, adding longer alkyl groups, butyl and hexyl, to the pro-
tected cysteine (entries 1 and 3) and serine (entries 2 and 4) alde-
hydes presented no problems for the selectivity. We wanted to
extend our methodology to unsaturated nucleophiles, since alkenyl
groups are synthetically quite useful and versatile. However, our
initial attempts at adding alkenyl nucleophiles to the protected
aldehydes were problematic. The addition of vinyl-magnesium
bromide (entry 5) to the Boc and benzyl protected serine aldehyde
gave only a 60:40 mixture of the syn- and anti-compounds. Addi-
tion of bromomagnesium divinylcuprate (entry 6) had essentially
no effect on the selectivity. Addition of vinylmagnesium chloride
(entry 7) and chloromagnesium divinylcuprate (entry 8) improved
the selectivity slightly. We believed that the poor selectivity came
from weaker chelation and therefore decided to add a chelating
agent before adding the nucleophiles. Since we postulated that
the lithium dialkylcuprates chelated the aldehydes well (Tables 2
and 3, entries 1–4), we decided to add one equiv of lithium
dialkylcuprate to chelate the aldehydes before the addition of the
alkenyl nucleophiles. One equivalent of lithium dimethylcuprate
followed by the addition of excess chloromagnesium divinylcup-
rate (entry 9) gave a much better selectivity and allowed us to iso-
late 62% of the desired syn-product. Since transferring the
Table 2
Reaction of lithium dimethylcuprate with amino aldehydes
Entry
P
R
Yield (%)
(% de)
1
2
3
4
5
6
7
8
Boc
Cbz
Boc
Boc
Boc
Cbz
Cbz
Boc
Cbz
Cbz
Boc
CH2STr
CH2OtBu
CH2OtBu
CH2OTIPS
92
87
88
91
88
82
85
90
83
90
85
P99
P95
P95
P95
P95
P95
P95
P95
P90
P95
P95
CH2OBn
(CH2)2OtBu
(CH2)3OtBu
(R) MeCHOBn
CH2CO2tBu
(CH2)2CO2tBu
CH2-4-(OBn)C6H4
9
10
11
Table 3
Reactions of various amino aldehydes with other nucleophiles
Entry
Nucleophiles
R
Solvent
Temp/hours
Yield (%)
syn/anti
1
2
3
4
5
6
7
8
nBu2CuLi
nBu2CuLi
nHex2CuLi
nHex2CuLi
VinylMgBr
(Vinyl)2MgBr
VinylMgCl
(Vinyl)2MgCl
Me2CuLi (1 equiv)/ (Vinyl)2MgCl
Me2CuLi(1 equiv)/ CuI+VinylMgCl
Bu2CuLi (1 equiv)/ CuI+VinylMgCl
Me2CuLi (1 equiv)/ CuI+VinylMgCl
Bu2CuLi (1 equiv)/ CuI+VinylMgCl
CH2STr
CH2OBn
CH2STr
Et2O/hexanes
Et2O/hexanes
Et2O/hexanes
Et2O/hexanes
Et2O/THF
Et2O/THF
Et2O/THF
Et2O/THF
Et2O/THF
Et2O/THF
Et2O/THF
Et2O/THF
Et2O/THF
À78 °C to À40 °C/ 4 h
À78 °C to À40 °C/ 4 h
À78 °C to À40 °C/ 5 h
À40 °C/ 5 h
88
83
91
86
n/c
n/c
n/c
n/c
62
69
80
72
83
P98/2
P95/5
P95/5
P95/5
60/40
63/37
65/35
67/33
76/24
78/22
85:15
80:20
89:11
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OTIPS
CH2OTIPS
À78 °C to 0 °C/ 1 h
À78 °C to 0 °C/ 1 h
À78 °C to 0 °C/ 1 h
À78 °C to 0 °C/ 1 h
À78 °C to 0 °C/ 1 h
À78 °C to 0 °C/ 1 h
À78 °C to 0 °C/ 1 h
À78 °C to 0 °C/ 1 h
À78 °C to 0 °C/ 2 h
9
10
11
12
13

M. E. Jung, S. W. Yi / Tetrahedron Letters 53 (2012) 4216–4220
4219
silyl protected serinol 25 (Scheme 2). Oxidation to the aldehyde
followed by the chelation-controlled vinylation gave the desired
threo amino alcohol 26 in 83% yield. Cross-metathesis reaction
with 1-pentadecene using the Hoveyda–Grubbs second generation
catalyst16 afforded the E-alkene 27 in 80% yield. Final two-step re-
moval of the protecting groups provided L-threo-sphingosine 21 in
only 8 steps and in 44% overall yield. Additionally, safingol, 22, a
lysosphingolipid protein kinase C inhibitor,14b,17 was obtained by
palladium-catalyzed hydrogenation of
96% yield.
L-threo-sphingosine 21 in
Furthermore, a shorter synthesis of safingol 22 was also accom-
plished. Commercial N-BOC serine benzyl ether 28 was converted
in three steps, via alcohol 29, to the amino alcohol 30 (Scheme 3).
Cross-metathesis of 30 with 1-pentadecene, hydrogenation, and N-
BOC deprotection afforded safingol 22 in only six steps and 56%
overall yield.
Conclusion
In summary, the chelation-controlled addition of an organocup-
rate species to various protected
afford highly functional syn-b-amino alcohols diastereoselectively.
The bulky protecting groups on the -amino aldehydes directed
a-amino aldehydes was shown to
Scheme 2. Synthesis of threo-sphingosine 21 and safingol 22.
a
the addition to give the corresponding b-amino alcohols with very
high syn-selectivity. Using this new protocol, we synthesized three
targets: the new threonine modifier for a structural study of Sor-
tase A, L-threo-sphingosine, and safingol. Further applications of
this protocol in synthetic organic chemistry are underway and will
be reported in due course.
BocNH
BnO
COOH BH3-THF
BocNH
CH2OH
THF, 0
91%
C
BnO
29
28
1) DMP, CH2Cl2
2) (1 eq) Bu2CuLi;
BocNH
BnO
C13H27
Hoveyda-Grubbs
2nd gen catalyst
CH2Cl2, 21 C
16 h, 84%
Acknowledgments
OH
4 eq CuI, 7.5 eq
vinylMgCl, Et2O
-78 to 4 C
We thank Dr. John Greaves at the University of California Irvine
Mass Spectrometry Facility for his help in obtaining the HRMS
data.
30
80% (2 steps)
NHBoc
Pd/C
H2 (g)
MeOH
96%
NHBoc
BnO
C13H27
HO
C13H27
Supplementary data
OH
31
OH
32
Supplementary data (proton and carbon NMR data for all new
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.153.
HCl (g)
NH2
1,4-dioxane
95%
HO
C13H27
OH
22
References and notes
Scheme 3. Alternative synthesis of Safingol 22.
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