Highly stereocontrolled access to a tetrahydroxy long chain base using anti-selective additions

Article abstract of DOI:10.1039/a902386k

Complete diastereostereoselection was attained for the addition of acetylide and benzyloxymethyl anions to a chiral aldehyde and an imine derived from meso-tartaric acid, leading to a facile synthesis of (2S,3S,4R,5R,6Z)-2-amino-1,3,4,5-tetrahydroxyoctadecene as its pentaacetyl derivative in enantiomerically pure form.

Full text of DOI:10.1039/a902386k

Highly stereocontrolled access to a tetrahydroxy long chain base using
anti-selective additions
Makoto Shimizu,* Manabu Kawamoto and Yasuki Niwa
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan.
E-mail: mshimizu@chem.mie-u.ac.jp
Received (in Cambridge, UK) 25th March 1999, Accepted 12th May 1999
Complete diastereostereoselection was attained for the
addition of acetylide and benzyloxymethyl anions to a chiral
aldehyde and an imine derived from meso-tartaric acid,
leading to a facile synthesis of (2S,3S,4R,5R,6Z)-2-amino-
1,3,4,5-tetrahydroxyoctadecene as its pentaacetyl derivative
in enantiomerically pure form.
formation (cat. TsOH, EtOH) and acetonization (cat. TsOH,
2,2-dimethoxypropane, benzene, 94% yield for two steps)
followed by reduction (LiAlH4, THF, 84%) and bis-acylation
(n-butyryl chloride, Et3N, CH2Cl2, 75%). The dibutyrate 3 was
treated with Lipase Amano PS in phosphate buffer–acetone at
room temperature for 5 h to give the mono-ester 4 in 93% yield
with > 99% ee.9 The protection of the hydroxy functionality
with an ethoxyethyl group (cat. PPTS, ethyl vinyl ether,
CH2Cl2) was followed by hydrolysis of the ester moiety
(K2CO3, MeOH). The benzyl etherification of the resulting
ethoxyethyl ether (KHMDS, BnBr, THF) and hydrolysis of the
ethoxyethyl group (cat. PPTS, PrOH) gave the alcohol, which
was oxidized using the Swern oxidation to give the aldehyde 5
in enantiomerically pure form in 66% overall yield from the
mono-ester 4.†
Increasing interest in the field of cerebrosides prompted us to
investigate an easy access to this class of compounds in a highly
stereocontrolled fashion.1 In conjunction with the amino
polyols which recently have attracted the interest of chemists,
several 2-amino-1,3,4,5-tetrahydroxyoctadecene derivatives
have been found in bovine spinal cords and human brains as
well as in green and red algae.2 Among them, (2S,3S,4R,5R,6Z)-
2-amino-1,3,4,5-tetrahydroxyoctadecene 1, the long-chain base
As shown in Table 1, the anti-selective addition of acetylide
to aldehyde 5 was conducted with triisopropoxytitanium
acetylide 7 as described earlier7,10 to give the desired adduct
anti-8 in 98% yield as single diastereomer (entry 1),‡ whereas
modest syn-selectivity was observed with halomagnesium,
lithium, or dichlorocerium acetylide (entries 2–5).
NH2 OH
1 R = H
C11H23
HOH2C
RO
O
OH OH
HO
HO
2 R =
OH
The anti-propargyl alcohol anti-8 was then transformed into
the imine 13 possessing the functionalities necessary for the
synthesis of tetrahydroxy-LCB 1 via the following sequences:
protection of the hydroxy group with TBDMS (TBDMSCl,
imidazole, DMF, 9: 95%); partial reduction of the triple bond
O
O
O
O
OR1
OR2
OBn
H
3 R1 = R2 = COPr
4 R1 = COPr, R2 = H
5 X = O
6 X = NBn
X
C11H23
X
O
O
(LCB) part of a new cerebroside 2, was isolated from the latex
of Eupohorbia characias L and its structure has been eluci-
dated.3 The biological importance of such cerebrosides, espe-
cially the imparted bioactivities, makes this compound a useful
target for synthesis. To the best of our knowledge, however,
only two approaches to tetrahydroxy-LCB 1 have been
reported; one starting from d-mannose4a and the other from d-
glutamic acid.4b There still appear to be important problems of
stereocontrol,5 and we focused on the topic of stereocontrol in
the addition of nucleophiles to chiral aldehydes and imines to
find a solution to these problems. We have recently reported that
complete anti-stereocontrol has been attained in an addition of
nucleophiles to the chiral aldehyde derived from l-serine,
leading to a short synthesis of (2S,3S,4R)-phytosphingosine,6
while syn-selective addition of nucleophiles has also been
successfully used for the synthesis of deoxybiotin.7 In these
studies, a non-chelation- or chelation-type transition state was
thought to be crucial for such complete anti- or syn-stereoselec-
tion, respectively.5–7 For the synthesis of tetrahydroxy-LCB 1,
the anti-stereocontrolled construction of the contiguous asym-
metric carbons is likely to be difficult, as can be seen from its
structure. Here we describe a new stereocontrolled approach to
tetrahydroxy-LCB 1 using a tandem anti-selective addition of
nucleophiles to the chiral aldehyde 5 and the imine 6 derived
from meso-tartaric acid.
BnO
C11H23
R
OTBDMS
O
OTBDMS
O
9
10 R = OBn, X = H2
11 R = OH, X = H2
12 R = H, X = O
13 R = H, X = NBn
under the Lindlar conditions [H2, Pd/BaSO4, quinoline, MeOH,
10: 99%, (Z : E = > 99+ < 1)]; removal of the benzyl protecting
group (Ca, liq. NH3, 11, 86%); Swern oxidation of the hydroxy
group (oxalyl chloride, DMSO, Et3N, CH2Cl2, 12: 93%);
benzylimination (BnNH2, Et2O, 13: 100%).
Table 1 Addition of dodecylacetylide to aldehyde 5
C11H23
[M]
7
C11H23
C11H23
+
5
O
O
THF
BnO
BnO
OH
OH
O
O
anti-8
syn-8
Entry
[M]
T/°C
Yield (%)a
anti+synb
1
2
3
4
5
Ti(OPri)3
MgBr
MgCl
Li
278–0
278–0
250–0
278–0
278–rt
98
43
66
43
48
> 99+ < 1
40+60
24+76
27+73
23+77
The chiral aldehyde 58 was prepared in good overall yield in
enantiomerically pure form starting from meso-tartaric acid
using lipase-mediated desymmetrization as a crucial step. meso-
Tartaric acid was converted into dibutyrate 3 via diethyl ester
CeCl2
a Isolated yields. b Determined by 1H and 13C NMR analyses.
Chem. Commun., 1999, 1151–1152
1151

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Table 2 Addition of nucleophiles to imine 6
O
O
Nucleophile
Nu
Nu
6
+
BnO
BnO
O
O
NHBn
NHBn
anti-14
syn-14
Entry
Nucleophile
Solvent
T/°C
Additive (equiv)
Yield (%)a
anti+synb
1
2
3
4
5
6
7
8
Li-dithianide
Li-dithianide
LiC·CTMS
LiC·CTMS
2-FurylLi
2-FurylLi
TMSCN
LiCH2OBnc
THF
THF
THF
THF
THF
THF
CH2Cl2
THF
250–rt
250–0
278–rt
278–0
278–rt
278–rt
278–rt
278–0
none
BF3•Et2O (4.0)
none
BF3•Et2O (4.0)
none
BF3•Et2O (4.0)
BF3•Et2O (4.0)
BF3•Et2O (4.0)
33
78
17
55
16
34
48
78
< 1+ > 99
> 99+ < 1
< 1+ > 99
> 99+ < 1
< 1+ > 99
> 99+ < 1
88+12
> 99+ < 1
a Isolated yields. b Determined by HPLC analysis (Merck Hibar Column). c Preparation of this anion, see ref. 12.
was stirred at 278 °C for 30 min. A solution of ClTi(OPri)3 (1.0 M in n-
hexane, 7.8 ml, 7.76 mmol) was added to the mixture at 278 °C and it was
allowed to stand at 260 °C for 1 h. A solution of 5 (647 mg, 2.58 mmol) in
THF (35 ml) was added to the resulting mixture at 278 °C, and the mixture
was stirred at that temperature for 2 h. After usual work-up, the crude oil
was purified by flash silica gel chromatography to give the propargyl
alcohol anti-8 (1.09 g, 98%) as a colorless oil.
§ To a solution of SnCl2 (214 mg, 1.15 mmol) in THF (2 ml) was added a
solution of LiBr (100 mg, 1.15 mmol) in THF (2 ml) and the mixture was
stirred at room temperature for 30 min. A solution of BnOCH2Cl (180 mg,
1.15 mmol) in THF (2 ml) was added to the resulting mixture, to which was
added BuLi (1.68 M in n-hexane, 2.74 ml, 4.61 mmol) at 278 °C, and
stirred for 1 h at that temperature. BF3•Et2O (164 mg, 1.152 mmol) was
added to the mixture and after 10 min a solution of 13 prepared in situ from
12 (131 mg, 0.288 mmol) and BnNH2 (32.4 mg, 0.302 mmol) in THF (2 ml)
was added at 278 °C, and the whole mixture was gradually warmed to 0 °C.
After usual work-up, the crude oil was purified on preoperative TLC to give
15 (60.7 mg, 32%) as a colorless oil.
For the introduction of a hydroxymethyl moiety into the
imine 13, three types of nucleophiles were investigated for the
addition reaction in terms of diastereoselectivity, in which the
imine 6 was used as a model substrate, and Table 2 summarizes
the results.
As shown in Table 2, lithium dithianide in THF added to the
imine 6 to give syn-14 (Nu = 1,3-dithiane) as the sole product,
whereas reversal of the diastereoselectivity was observed in the
same reaction conducted in the presence of an excess BF3•Et2O,
giving anti-14 stereospecifically (entries 1 and 2).7 Similar
trends of reversal of the diastereoselectivity were observed in
the cases with the lithium acetylide and 2-furyllithium (entries
3–6). TMSCN in the presence of BF3•Et2O11 also effected the
predominant formation of the anti-adduct anti-14 (Nu = CN)
(entry 7). For the preparation of tetrahydroxy-LCB, the use of a
hydroxymethyl anion equivalent was more preferable in terms
of functional group manipulation and, therefore, benzyloxy-
methyllithium12 was used for the addition in the presence of
BF3•Et2O to give anti-14 (Nu = BnOCH2) as the sole product
in good yield (entry 8). This high selectivity is most probably
explained in terms of non-chelation (for anti-adduct) and
chelation transition states (for syn-adduct).
¶ The spectral properties are identical with the reported data (ref. 4).
1 Y. Hannun and R. M. Bell, Science, 1989, 243; C. Djerassi and W. K.
Lam, Acc. Chem. Res., 1991, 24, 69; A. Olivera and S. Spiegel, Nature,
1993, 365, 557.
2 H. S. Garg, M. Sharma, D. S. Bhakuni, B. N. Paramanik and A. K. Bose,
Tetrahedron Lett., 1992, 33, 1641; C. B. Rao and C. Satyanarayana,
Indian J. Chem., Sect. B, 1994, 33B, 97.
3 G. Falsone, F. Cateni, F. Katusian, H. Wagner, O. Seligmann, G.
Pellizer and F. Asaro, Z. Naturforsch, Teil B: Chem. Sci., 1993, 48,
1121; G. Falsone, F. Cateni, G. Visintin, V. Lucchini, H. Wagner and O.
Seligmann, Farmaco, 1994, 49, 167.
4 (a) Y.-L. Li and Y.-L. Wu, Tetrahedron Lett., 1995, 36, 3875; (b) H.
Yoda, T. Oguchi and K. Takabe, Tetrahedron: Asymmetry, 1996, 7,
2113.
Thus, addition of benzyloxymethyllithium to the imine 13
was conducted as in the case with 6 in the presence of BF3•Et2O
to give, as expected, the desired anti-adduct 15 exclusively in
AcHN
OAc
BnHN
O
AcO
C11H23
BnO
C11H23
OTBDMS
OAc OAc
O
5 For reviews, see, J. Jurczak and A. Golebiowski, Chem. Rev., 1989, 89,
149; Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon, Oxford, 1991, vol. 1 and references cited therein; A.
Dondoni and D. Perrone, Aldrichim. Acta, 1997, 30, 35.
6 M. Shimizu, I. Wakioka and T. Fujisawa, Tetrahedron Lett., 1997, 38,
6027.
32% yield.§ Dep1r5otection of the benzyl gr1o6up was carried out
with Na-NH3, and subsequent hydrolysis with TFA followed by
acetylation gave the pentaacetyl derivative 16 of tetrahydroxy-
LCB 1 in 11% overall yield from 15.¶
In conclusion, the present synthesis using a tandem anti-
addition reaction to the chiral aldehyde and the imine realizes a
rapid access to biologically important molecules in a highly
stereocontrolled fashion. Since the level of the diaster-
eoselectivity attained on the addition of nucleophiles to a-
hydroxy aldehyde and imine was extremely high, this procedure
may be applied to the syntheses of a variety of amino polyols of
biological importance in a stereocontrolled manner.
7 T. Fujisawa, M. Nagai, Y. Koike and M. Shimizu, J. Org. Chem., 1994,
59, 5865.
8 A. Dondoni and P. Merino, Synthesis, 1992, 196; P. Munier, A.
Krusinski, D. Picq and D. Anker, Tetrahedron, 1995, 51, 1229.
9 For lipase-mediated kinetic resolution of this kind of diol, see, M. Pottie,
V. der Eycken and M. Vandewalle, Tetrahedron: Asymmetry, 1991, 2,
329; H. J. Bestmann and L. Bauriegel, Tetrahedron Lett., 1995, 36,
853.
10 F. Tabusa, T. Yamada, K. Suzuki and T. Mukaiyama, Chem. Lett., 1984,
405.
11 D. A. Evans, G. L. Carroll and L. K. Truesdale, J. Org. Chem., 1974, 39,
914 and references cited therein.
12 E. J. Corey and T. M. Eckrich, Tetrahedron Lett., 1983, 24, 3163; W. C.
Still, J. Am. Chem. Soc., 1978, 100, 1481.
Notes and references
† The enantiomeric purity was determined by HPLC using a chiral
stationary column (Daicel OJ).
‡ To a solution of tridecyne (1.63 g, 647 mmol) in 70 ml of THF was added
BuLi (1.68 M in n-hexane, 4.62 ml, 7.76 mmol) at 278 °C, and the mixture
Communication 9/02386K
1152
Chem. Commun., 1999, 1151–1152
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