Highly anti-selective dihydroxylation of 1,2-dialkyl substituted (Z)-allylic amines: stereoselective synthesis of a d-ribo-phytosphingosine derivative

Article abstract of DOI:10.1016/j.tetlet.2006.12.084

Protection of 1,2-dialkyl substituted (Z)-allylic amines with an N,N-diBoc group resulted in an opposite stereoselectivity in the OsO₄-catalyzed dihydroxylation reactions to that of N-Boc-(Z)-allylic amines. A higher anti selectivity (>10:1) wa

Full text of DOI:10.1016/j.tetlet.2006.12.084

Tetrahedron Letters 48 (2007) 1105–1108
Highly anti-selective dihydroxylation of 1,2-dialkyl substituted
(Z)-allylic amines: stereoselective synthesis of a
D-ribo-phytosphingosine derivative
Jongho Jeon, Moonyong Shin, Jae Won Yoo, Joon Seok Oh, Jae Gwang Bae,
Seung Hwan Jung and Young Gyu Kim*
Department of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
Received 7 November 2006; revised 10 December 2006; accepted 14 December 2006
Available online 8 January 2007
Abstract—Protection of 1,2-dialkyl substituted (Z)-allylic amines with an N,N-diBoc group resulted in an opposite stereoselectivity
4
in the OsO -catalyzed dihydroxylation reactions to that of N-Boc-(Z)-allylic amines. A higher anti selectivity (>10:1) was shown in
CH Cl . An efficient stereoselective synthesis of a tetraacetyl derivative of D-ribo-phytosphingosine was reported using the N,N-
2
2
diBoc-controlled dihydroxylation from Garner’s aldehyde.
Ó 2006 Elsevier Ltd. All rights reserved.
We have been interested in the stereoselective syntheses
of some biologically active compounds with a vicinal
amino dihydroxyl moiety (Fig. 1). In principle, they
could be efficiently prepared from the stereo-controlled
osmylation of the corresponding chiral allylic amines.1c
With the conjugated (E)-ester, the anti selectivity of about
12:1 was obtained, while the opposite syn selectivity of
>13:1 was observed with the conjugated (Z)-ester without
using any chiral auxiliaries. It is to be noted that the
stereoselective dihydroxylation reactions of allylic amines
have not been studied as much as those of allylic alco-
OsO -catalyzed dihydroxylations of chiral allylic amines
4
that are readily derived from one of the chirality pools,
a-amino acids.
2
hols. Often, the poor or inconsistent stereochemical
We have recently reported the efficient stereoselective syn-
theses of the a-hydroxyisostatine and (2R,3R,4S)-4,7-
results have been reported for acyclic allylic amino
derivatives with flexible conformation. In several cases,
1
a
2,3
diamino-2,3-dihydroxyheptanoic acid (DADHA) deriva-
tives by employing the N-diphenylmethylene-controlled
even the well-established Sharpless asymmetric dihydr-
oxylation reactions resulted in mixed results.
1
b
2e,4
OH
O
OH
O
H N
OH
OH
2
NH2 OH
NH2 OH
α-Hydroxyisostatine
R3
R2
(2R,3R,4S)-DADHA
NH2 R1
O
OH
O
OH
C14H29
HO
OH
HO
NH2 OH
NH2 OH
D-ribo-Phytosphingosine
Dihydroxyglutamic acid
Figure 1. Compounds with an amino dihydroxyl unit.
*
0
Corresponding author. Tel.: +82 2 880 8347; fax: +82 2 885 6989; e-mail: ygkim@snu.ac.kr
040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.084

1106
J. Jeon et al. / Tetrahedron Letters 48 (2007) 1105–1108
For an efficient stereoselective synthesis of D-ribo-phyto-
sphingosine (Fig. 1), the N-diphenylmethylene-con-
trolled dihydroxylation reactions were also applied to
the corresponding allylic amino derivatives but showed
much lower stereoselectivities of <3:1 for the undesired
syn diastereomer. Through a model study, however,
we have found that the highly anti-selective dihydroxyl-
ations of 1,2-dialkyl substituted (Z)-allylic amines are
possible by simply changing the N-protecting group
and the reaction conditions and wish to report the
results as follows.
when the alcohol is protected with an acetyl group (en-
try 5). We have also examined the dihydroxylations of
the N,N-dibenzyl protected derivatives of the model ole-
fin (not shown). They showed the good anti selectivity of
about 8:1, but a significant amount of unknown byprod-
ucts were produced to cause low yields of the desired
diol products. The dihydroxylation reaction rates of
2
e,8
the N,N-dibenzyl derivatives were slow, too.
The observed anti selectivity of the N,N-diBoc protected
(Z)-allylic amines can be explained by a transition state
of an H-eclipsed conformation in Figure 2 as suggested
9
a
For the model study, the propyl substituted (Z)-allylic
by Kishi and co-workers in their monensin synthesis.
amines were prepared from Garner’s aldehyde (2) using
It has been reported that the N-outside conformation
is favored with the 1,2-dialkyl substituted N-Boc-(Z)-
allylic amine to give the syn diol as a major product.
+
a commercially available phosphonium salt (Ph P -
3
ꢀ
5
BuBr ) according to the protocol shown in Scheme 1
(
R = C H ). The diBoc and dibenzyl groups were cho-
The N-outside conformation would reduce the 1,3-
allylic (A ) strain between the N-Boc group (P = H)
3
7
1
,3
sen as the N-protecting group because they are easily
introduced and the monoBoc N-protecting group is
known to give the syn selectivity with the similar (Z)-
allylic amino derivatives. In addition, the bulky diBoc
or dibenzyl protecting group resulted in the high anti
selectivity in the cyclic allylic amines. The diastereo-
selective osmylation results of the N,N-diBoc protected
model compounds in some different solvents are shown
and the alkyl (R) group although there is some increase
1
,2
in the 1,2-allylic (A ) strain between the N-Boc group
and the vinylic hydrogen atom. With the N,N-diBoc
5
1
,2
protected (Z)-allylic amines, however, the A strain
between the bulky N,N-diBoc group (P = Boc) and the
vinylic hydrogen atom would be so severe that the H-
eclipsed conformation is preferred to give anti diol as
3
a
6
9
in Table 1. All entries show a consistent anti selectivity
a major product. The H-eclipsed conformation at the
and the better results are obtained in less polar solvents
transition state can also explain the higher anti selectiv-
ity with the smaller acetyl group (Table 1, entries 4 and
7
(
entries 3 and 4). The best result is observed in CH Cl
2
2
5
).
With the above results in hand, the N,N-diBoc con-
trolled dihydroxylation reaction of (Z)-allylic amines
was applied to an efficient stereoselective synthesis of
D-ribo-phytosphingosine. D-ribo-Phytosphingosine is a
key component of glycosphingolipids that are widely
distributed in plants, fungi, marine organisms, and
mammalian tissues. In addition to its structural role in
membranes, it is shown to possess some important bio-
o
Ph PCH RBr, KHMDS, -78 C
NBoc
NBoc
CHO
3
2
O
O
R
82-85%
3
(a: R=Pr
b: R=C14H29
)
2
NHBoc
) Dowex 50Wx4-100 (H+ form)
) Ac O, TEA, DMAP, 4a,b 90-95%
1
PO
R
2
4 (a: P=Ac, R=Pr
b: P=Ac, R=C14H
c: P=Boc, R=Pr)
logical activities such as induction of apoptosis in some
2
or Boc O, TEA, DMAP, 4c 52%, 5c 47%
29
10a
2
cancer cells
cell.
and a heat stress response of the yeast
1
0b
Because of its biological importance as well as
NBoc2
its scarcity in nature, considerable efforts for the synthe-
sis of phytosphingsine, its stereoisomers, and its homo-
Boc O, TEA
2
5
(a: P=Ac, R=Pr
b: P=Ac, R=C14H29
c: P=Boc, R=Pr)
4
a,b
PO
R
DMAP, 96-97%
11
logues have been devoted to date. Among them,
there have been a few synthetic reports for D-ribo-phyto-
Scheme 1. Preparation of N,N-diBoc olefins 5.
OsO4
H
Boc
H
Boc
N
P N
Table 1. Dihydroxylations of model compounds, 5a and 5c (R = Pr)
A1,2
H
P
H
H
H
NBoc2
NBoc
2
A1,3
AcO
R
NBoc2
cat. OsO4
R
vinylic
PO
R
PO
R
PO
R
+
AcO
OsO4
NMO,
solvent
HO OH
anti
HO OH
syn
N-outside conformer
H-eclipsed conformer
A1,2
5
a,c (R = Pr)
A1,3
a
Entry
P
Solvent
anti:syn
Yield (%)
P
Boc
1
2
3
4
5
Boc (5c)
Boc (5c)
Boc (5c)
Boc (5c)
Ac (5a)
1
THF–H
i-PrOH
Toluene
DCM
2
O (2:1)
3.3:1
4.0:1
6.3:1
10:1
20:1
52
82
84
83
P
Boc
N
N
AcO
R
AcO
R
HO
anti (P = Boc)
Figure 2. Probable transition states of the (Z)-allylic amines.
OH
HO
OH
b
DCM
78
syn (P = H)
a
Determined by H NMR.
Isolated yield of diacetates after acetylation of the diols.
b

J. Jeon et al. / Tetrahedron Letters 48 (2007) 1105–1108
1107
Boc N
AcO
OAc
R
OAc
anti (>20:1)
R = C14H29
AcHN
AcO
OAc
R
2
i) OsO , NMO
i) HCl in MeOH
4
5
4
b
b
ii) Ac O, TEA
ii) Ac O, TEA
2
2
OAc
1anti
R = C14
DMAP, 77%
DMAP, 79%
6
H
29
BocHN
AcO
OAc
AcHN
AcO
OAc
R
i) OsO , NMO
i) HCl in MeOH
4
R
ii) Ac O, TEA
ii) Ac O, TEA
2
2
OAc
OAc
1syn
R = C14H29
DMAP, 91%
DMAP, 77%
7
syn (5-7.5:1)
R = C14H29
Scheme 2. Synthesis of the tetraacetyl derivatives of D-ribo- and L-arabino-phytosphingosine.
sphingosine employing the OsO -catalyzed dihydroxyla-
amine 4b was subjected to the same dihydroxylation
conditions. Although the syn selectivity of the dihydr-
oxylation reactions of 4b was lower (5 ꢁ 7.5:1), the
major isomer obtained after derivatization to the
tetraacetyl derivative, 1syn, matched the minor isomer
4
tions of the corresponding (Z)-allylic amines. However,
the facial selectivities employing the osmylation reac-
tions showed the mixed results ranging from 2.9:1 to
2
c,4d,12
1
:2.4 of an anti:syn ratio.
Even the asymmetric
2
c
dihydroxylation reagent, AD-mix-b, gave the selectivity
derived from 5b in every aspect.
4
b
of less than 5:1 for the desired anti isomer.
In summary, we have found through a model study that
In our synthetic effort for D-ribo-phytosphingosine, the
required key intermediate 5b (R = C H ), N,N-diBoc
the anti-selective OsO -catalyzed dihydroxylations of
4
1,2-dialkyl substituted (Z)-allylic amines could be
achieved consistently via their N,N-diBoc derivatives.
The best selectivity of 20:1 for the anti isomer was
obtained with the O-acetyl group in CH Cl as a reaction
1
4
29
(
Z)-allylic amine, was obtained in an overall 73% yield
from Garner’s aldehyde (2) (Scheme 1). Here, the multi
gram quantity of 2 was prepared from L-serine in a
2
2
7
8% yield over four steps according to the literature
solvent. It is a great improvement over the previously re-
ported results that showed inconsistent selectivities, and
better than the well-known asymmetric dihydroxylation
reactions employing AD-mix-b. The selectivity observed
in the present study was rationalized with the H-eclipsed
conformation at the transition state. These results are
interesting in that the opposite syn selectivity has been
known with 1,2-dialkyl substituted N-Boc-(Z)-allylic
amines. The addition of one more Boc group to the
allylic nitrogen atom shifted the favored transition state
from the N-outside conformation to the H-eclipsed
conformation. Thus, the dihydroxylation results in the
present study are complementary to the syn selectivity
shown with the N-Boc protected (Z)-allylic amines,
but is better in terms of the degree of asymmetric
induction.
1
3
procedure.
The alkyl substituted (Z)-olefin 3b
(
R = C H ) was obtained as a major isomer in a
14 29
1
6:1 ratio [(Z)/(E)] under the salt-free conditions using
+
ꢀ
the phosphonium salt, Ph P C H Br , which was
prepared by heating C H Br with Ph P under reflux
of xylene. The acetonide group of 3b was selectively
3
15 31
1
5
31
3
4
b
removed under weakly acidic conditions and the
following acetylation of the primary alcohol produced
N-Boc-O-Ac (Z)-allylic amine 4b. Further conversion
of 4b into N,N-diBoc protected 5b required excess
amount of Boc anhydride (ca. 10 equiv) because the
reaction was sluggish. The minor E-olefin of 3b was
separable by column chromatography at the stage of
either 3b or 4b.
The dihydroxylation reaction of 5b was conducted using
catalytic amount of OsO and 2.5 equiv of N-methyl-
As an application of the N,N-diBoc-controlled dihydr-
oxylation reactions, an efficient stereoselective synthesis
of the tetraacetyl derivative of D-ribo-phytosphingosine
was realized in eight steps over a 45% overall yield from
Garner’s aldehyde with more than a 20:1 ratio. The con-
sistent anti selectivity reported here should be useful in
predicting the stereochemical outcome of the dihydroxy-
lation products of 1,2-dialkyl substituted (Z)-allylic
amines, in particular, phytosphingosine homologues,
both natural and unnatural.
4
morpholine N-oxide (NMO) in DCM at room tempera-
ture (Scheme 2). After quenching the reaction with aq
Na SO , the crude diol products were acetylated to give
2
3
a diastereomeric mixture of triacetates 6 that was sepa-
1
rable on H NMR and whose ratio was more than
2
0:1 for the desired anti isomer, 6anti. The relative ste-
reochemistry at the new stereogenic centers of 6anti
was confirmed by converting 6 to the known tetraacetyl
1
13
derivative 1anti. The H and C NMR spectra of the
major isomer (1anti) were in excellent agreement with
those reported in the literature.2c,14 Thus, the major iso-
mer of 6, 6anti, should have the same relative stereo-
chemistry as that of D-ribo-phytosphingosine.
Meanwhile, it was expected, as discussed in Figure 2,
that the other diastereomer with the L-arabino configu-
ration, 1syn, could be obtained when N-Boc-(Z)-allylic
Acknowledgements
This work was financially supported by KOSEF
through the Research Center for Energy Conversion
and by the Agency for Defense Development of Korea.

1108
J. Jeon et al. / Tetrahedron Letters 48 (2007) 1105–1108
diastereomers, D-ribo- and L-arabino–phytosphingosine,
References and notes
from each dihydroxylation product as described in the
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from the dihydroxylation products after the SiO column
separation was determined by converting separately into
the following cyclic compounds and comparing their
coupling constants. The small coupling constants of
7
2
4
–5 Hz as in 8syn are generally assigned to the trans
oxazolidinones [(a) Ref. 1a and references cited therein.
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(
1
1
as in 8anti are typically due to the diaxial relationship
between the two adjacent protons in six-membered rings
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[
Pretsch, E.; B u¨ hlmann, P.; Affolter, C.; Structure Deter-
mination of Organic Compounds, 3rd ed.; Springer: Berlin,
000; pp 161–198]. The sense of asymmetric induction
27
2c
23
2
14. 1anti: ½aꢂ þ 26:5 (c 0.84, CHCl
3
) [lit. ½aꢂD þ 26:2 (c 2.0,
D
2
D
8
2c
caused by the N,N-diBoc group was confirmed further by
stereoselective syntheses of the known derivatives of both
CHCl
3
)]; 1syn: ½aꢂ ꢀ 22:1 (c 0.74, CHCl
3
) [lit.
25
½aꢂ ꢀ 25:1 (c 1.5, CHCl
3
)].
D