Chirality transfer from guanidinium ylides to 3-alkenyl (or 3-alkynyl) aziridine-2-carboxylates and application to the syntheses of (2R,3S)-3-hydroxyleucinate and D-erythro-sphingosine

Article abstract of DOI:10.1021/jo051495j

Reaction of chiral guanidinium ylides with α,β-unsaturated aldehydes gives 3-(α,β-unsaturated) aziridine-2-carboxylates in high diastereo- and enantioselectivities (up to 93% diastereomeric excess and 98% enantiomeric excess). 3-(1-Methylvinyl)- and 3-[(E)-pentadec-1-enyl]aziridine-2- carboxylates were successfully employed to prepare (2R,3S)-3-hydroxyleucinate and D-erythro-sphingosine, respectively.

Full text of DOI:10.1021/jo051495j

Chirality Transfer from Guanidinium Ylides to 3-Alkenyl
(or 3-Alkynyl) Aziridine-2-carboxylates and Application to the
Syntheses of (2R,3S)-3-Hydroxyleucinate and
D-erythro-Sphingosine
Wannaporn Disadee and Tsutomu Ishikawa*
Graduate School of Pharmaceutical Sciences, Chiba University, Inage, Chiba 263-8522, Japan
benti@p.chiba-u.ac.jp
Received July 19, 2005
Reaction of chiral guanidinium ylides with R,â-unsaturated aldehydes gives 3-(R,â-unsaturated)
aziridine-2-carboxylates in high diastereo- and enantioselectivities (up to 93% diastereomeric excess
and 98% enantiomeric excess). 3-(1-Methylvinyl)- and 3-[(E)-pentadec-1-enyl]aziridine-2-carboxylates
were successfully employed to prepare (2R,3S)-3-hydroxyleucinate and D-erythro-sphingosine,
respectively.
Introduction
ceramide (4). R-Amino-â-hydroxy acid units can be de-
rived from the corresponding aziridine-2-carboxylates7 by
a stereoselective ring-opening reaction.8 We recently
reported new asymmetric synthesis of 3-arylaziridine-2-
carboxylates from chiral guanidinium ylides and aryl
(and heterocyclic) aldehydes.9 Alkenyl (or alkynyl) aziri-
dines have also been increasingly found as useful inter-
mediates in organic synthesis;10 however, there are not
so many general methods for their enantioselective
preparation.11 We applied the guanidinium ylide chem-
istry to the reaction with R,â-unsaturated aldehydes and,
then, examined the ring-opening reaction of aziridines
formed, focusing on the preparation of R-amino-â-hydroxy
acid derivatives. In this paper, we present the effective
chirality transfer from guanidinium salts 5 (or ent-5) to
3-alkenyl (or 3-alkynyl) aziridine-2-carboxylates 7 (or
ent-7) in the reactions with R,â-unsaturated aldehydes
6 and the syntheses of (2R,3S)-3-hydroxyleucinate 1 and
D-erythro-sphingosine (3) from 3-(1-methylvinyl)- and
R-Amino-â-hydroxy acid is not only an important
component of numerous peptide antibiotics or endogenous
substances but also a key synthon in their synthesis.
Thus, 3-hydroxyleucine appears in telomycin,1 azinothri-
cin,2 and lysobacin,3 and its (2R,3S)-derivative 1 has been
used as a key compound in the enantioselective synthe-
sis4 of (+)-lactacystin5 (2). D-erythro-Sphingosine
[(2S,3R,4E)-2-aminooctadec-4-en-1,3-diol]6 (3) appears in
(1) Sheehan, J. C.; Maeda, K.; Sen, A. K.; Stock, J. A. J. Am. Chem.
Soc. 1962, 80, 1303-1305.
(2) Maehr, H.; Liu, C.-M.; Palleroni, N. J.; Smallheer, J.; Todan, L.;
Williams, T. H.; Blount, J. F. J. Antibiot. 1986, 39, 17-21.
(3) Tymiak, A. A.; Mclormick, T. J.; Unger, S. E. J. Org. Chem. 1989,
54, 1149-1157.
(4) (a) Sunazuka, T.; Nagamitsu, T.; Matsuzaki, K.; Tanaka, H.;
Omura, S.; Smith, A. B. J. Am. Chem. Soc. 1993, 115, 5302. Nagamitsu,
T.; Sunazuka, T.; Tanaka, H.; Omura, S.; Sprengeler, P. A.; Smith, A.
B. J. Am. Chem. Soc. 1996, 118, 3584-3590. (b) Panek, J. K.; Masse,
C. E. Angew. Chem., Int. Ed. 1999, 38, 1093-1095. (c) Soucy, F.;
Grenier, L.; Behnke, M. L.; Destree, A. T.; McCormack, T. A.; Adams,
J.; Plamondon, L. J. Am. Chem. Soc. 1999, 121, 9967-9976. For
different approaches to (+)-lactacystin (2) without going through the
hydroxyleucinate 1, see: Corey, E. J.; Reichard, G. A. J. Am. Chem.
Soc. 1992, 114, 10677-10678. Baldwin, J. E.; Russell, A. T. J. Am.
Chem. Soc. 1993, 115, 2139-2140. Chida, N.; Takeoka, J.; Tsutsumi,
N.; Ogawa, S. J. Chem. Soc., Chem. Commun. 1995, 793-794;
Donohoe, T. J.; Sintim, H. O.; Sisangia, L.; Ace, K. W.; Guyo, P. M.;
Cowley, A.; Harling, J. D. Chem.-Eur. J. 2005, ASAP.
(7) For reviews on aziridine syntheses, see: Tanner, D. Angew.
Chem., Int. Ed. Engl. 1994, 33, 599-619. Li, A.-H.; Dai, L.-X.;
Aggarwal, V. K. Chem. Rev. 1997, 97, 2341-2372. Osborn, H. M. I.;
Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693-1715. Atkinson,
R. S. Tetrahedron 1999, 55, 1519-1559. Mitchinson, A.; Nadin, A. J.
Chem. Soc., Perkin Trans. 1 2000, 2862-2892. Chemla, F.; Ferreira,
F. Curr. Org. Chem. 2002, 6, 539-570. Cardillo, G.; Gentilucci, L.;
Tolomelli, A. Aldrichimica Acta 2003, 36, 39-50.
(8) For recent review on the ring-opening reaction of aziridines,
see: Hu, X. E. Tetrahedron 2004, 60, 2701-2743.
(9) Hada, K.; Watanabe, T.; Isobe, T.; Ishikawa, T. J. Am. Chem.
Soc. 2001, 123, 7705-7706.
(5) Omura, S.; Fujimoto, T.; Otaguro, K.; Matsuzaki, K.; Moriguchi,
R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113-116. Omura, S.;
Matsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita, S.;
Nakagawa, A. J. Antibiot. 1991, 44, 117-118.
(6) Merck Index, 13th ed. 2001, p1560, Merck & Co., Inc. Whitehouse
Station, NJ.
10.1021/jo051495j CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/20/2005
J. Org. Chem. 2005, 70, 9399-9406
9399

Disadee and Ishikawa
TABLE 1. Reaction of (R,R)-Guanidinium Bromide 5 with Methacrolein (6a) under Various Conditions Followed by
Treatment with SiO2
yield (%) of 7b
entry
basea/solvent
temp (°C)
time (d)
cis (ee)c
trans (ee)c
total
cis/trans
8 (%)
1
2
3
4
5
6
7
TMG/none
TMG/THF
TMG/THF
TMG/THF
TMG/PhMe
TMG/PhMe
NaH/DMF
25
0
25
50
0
25
-10
1
62 (84)
79 (87)
76 (89)
64 (89)
80 (86)
75 (88)
39 (86)
9 (81)
13
14 (81)
26 (82)
12
12 (83)
25 (85)
71
92
90
90
92
87
64
87/13
86/14
84/16
71/29
87/13
86/14
61/39
100
93
7
3
1.5
7
3
2
93
100
100
93
78
a TMG ) 1.5 Meq; NaH ) 2.0 Meq. b Isolated yield. c Determined by a chiral HPLC and data without parenthesis means no measurement
of ee.
[(E)-pentadec-1-enyl]aziridine-2-carboxylates, respec-
tively, obtained in the asymmetric aziridinations.
as base under various conditions, followed by treatment
with silica gel (SiO2). As shown in Table 1, desired
vinylaziridines 7a were obtained as a diastereomeric
mixture in 64-92% combined yields with a range of 81-
89% enantiomeric excess (ee) together with a chiral urea
8, recyclable to the starting guanidinum salt 5. Inspection
of coupling constant (J ) 7.1 Hz) between 2-H (δ 2.35)
1
and 3-H (δ 2.31) in the H NMR spectrum of the major
diastereoisomer indicated that cis-aziridine was prefer-
entially formed (22-74% diastereomeric excess (de)). We
already observed, in the aziridination using aryl alde-
hydes, that the diastereoselectivity of aziridine products
is dependent upon the electronic character of substituent
on aryl aldehydes used. In general, major isomers are
trans derivatives in the cases of aldehydes carrying an
electron-donating group, whereas cis ones mainly ob-
served with aldehydes either carrying an electron-
withdrawing group or without substituent.12 Thus, cis-
rich diastereoselectivity in the reaction of 5 and 6a can
be reasonably accepted as an example of the latter cases.
As expected from the previous results,9 TMG was found
to be a more effective base than NaH not only for
conversion but also for selectivity (entries 1-6 vs entry
7). Although the solvent-free reaction was operative
(entry 1), the copresence of a limited amount of tetra-
hydrofuran (THF) or toluene as solvent led to better
isolated yield (entries 2-6).
Results and Discussion
Asymmetric Aziridination. According to our previ-
ous report,9 reaction of (R,R)-guanidinium salt 5 with
methacrolein (6a) was examined using either 1,1,3,3-
tetramethylguanidine (TMG) or sodium hydride (NaH)
(10) Application of alkenylaziridines in organic synthesis, see:
Ahman, J.; Somfai, P.; Tanner, D. J. Chem. Soc., Chem. Commun.
1994, 2785-2786. Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875-
4886. Fujii, N.; Nakai, K.; Tamamura, H.; Otaka, A.; Mimura, N.;
Miwa, Y.; Taga, T.; Yamamoto, Y.; Ibuka, T. J. Chem. Soc., Perkin
Trans. 1 1995, 1359-1371. Coldham, I.; Collis, A. J.; Mould, R. J.;
Rathmell, R. E. J. Chem. Soc., Perkin Trans. 1 1995, 2739-2745.
Hudlicky, T.; Tian, X.; Koenigsberger, K.; Maurya, R.; Rouden, J.; Fan,
B. J. Am. Chem. Soc. 1996, 118, 10752-10765. Ahman, J.; Jarevang,
T.; Somfai, P. J. Org. Chem. 1996, 61, 8148-8159. Lindstroem, U. M.;
Somfai, P. J. Am. Chem. Soc. 1997, 119, 8385-8386. Ibuka, T.;
Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.; Miwa, Y.; Taga, T.;
Nakai, K.; Tamamura, H.; Fujii, N.; Yamamoto, Y. J. Org. Chem. 1997,
62, 999-1015. Vogel, C. Synthesis 1997, 497-505. Toda, A.; Aoyama,
H.; Mimura, N.; Ohno, H.; Fujii, N.; Ibuka, T. J. Org. Chem. 1998, 63,
7053-7061. McCoull, W.; Davis, F. A. Synthesis 2000, 1347-1365.
Lindstroem, U. M.; Somfai, P. Chem.-Eur. J. 2001, 7, 94-98.
(11) Knight, J. G.; Muldowney, M. P. Synlett 1995, 949-951. Li,
A.-H.; Dai, L.-X.; Hou, X.-L.; Chen, M.-B. J. Org. Chem. 1996, 61,
4641-4648. Cantrill, A. A.; Jarvis, A. N.; Osborn, H. M. I.; Ouadi, A.;
Sweeney, J. B. Synlett 1996, 847-849. Ohno, H.; Ando, K.; Hamaguchi,
H.; Takeoka, Y.; Tanaka, T. J. Am. Chem. Soc. 2002, 124, 15255-
15266. Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Synlett
2003, 1985-1988. Morton, D.; Pearson, D.; Field, R. A.; Stockman, R.
A. Org. Lett. 2004, 6, 2377-2380.
On the basis of our previous works,9 the stereogenic
center of the major enantiomers in cis-aziridines was
expected to be of the (2S,3S) configuration when (R,R)-
guanidinium bromide 5 is used as a chiral source. The
expected absolute stereochemistry could be confirmed by
chemical correlation of the cis-aziridine c-7a to tert-butyl
N-Boc-(-)-leucinate (9), which was independently derived
from (S)-(+)-leucine (10) {[R]24D -8.5 (CHCl3) from c-7a;
[R]24 -9.8 (CHCl3) from 10} (Scheme 1).
D
Scope and limitations of this asymmetric aziridination
were investigated by varying the substituents on the R
and â positions of unsaturated aldehydes, using enan-
(12) Haga, T.; Ishikawa, T. Tetrahedron 2005, 61, 2857-2869.
9400 J. Org. Chem., Vol. 70, No. 23, 2005

Chirality Transfer from Guanidinium Ylides
TABLE 2. Asymmetric Aziridination Using (S,S)-Guanidinium Bromide ent-5 and Various r,â-Unsaturated Aldehydes 6
in the Presence of TMG
yield (%) of ent-7a
entry
6
cis (ee)b
trans (ee)b
total
cis/trans
ent-8 (%)
1
6a
6b
6c
6d
6e
6f
6g
6h
6i
80 (89)
31 (58)
46 (95)
4
12 (82)
31
41 (97)
<1
18
60 (65)
42 (92)
2
10 (87)
26
48 (98)
92
62
87
<5
51
82
51
30
42
44
70
87/13
50/50
53/47
>80/20
65/35
27/73
18/82
93 /7
92
2
94
3
quant.
89
4
5
33 (99)
22 (75)
9 (93)
28 (98)
32 (91)
18
94
6
91
7
91
8
90
9
76/24
41/59
31/69
94
10
6j
6k
94
11c
22 (91)
63
a Isolated yield. b Determined by chiral HPLC and data without parenthesis means no measurement of ee. c Ac2O was used in the
second step, instead of SiO2.12
SCHEME 1. Chemical Correlation between
tert-Butyl
cis isomers (entries 1, 5, and 8), whereas in the cinna-
maldehyde series trans-aziridines were obtained as major
isomers (entries 6 and 7), as expected from the result in
the previous achiral version.9 It was found that this
aziridination was applicable to alkynyl aldehydes (entries
10 and 11). High ee was also observed in 3-phenylprop-
2-ynal (6k).
cis-1-Benzyl-3-isopropenylaziridine-2-carboxylate
(c-7a) and (S)-(+)-Leucine (10)a
Preparation of t-Butyl (2R,3S)-3-Hydroxyleuci-
t
nate (1: R ) Bu). For the formal synthesis of (+)-
a Reagents and conditions: (a) H2, 5% Pd(OH)2/C, Boc2O, MeOH,
room temperature (rt), 12 h (94%); (b) Boc2O, 1 N NaOH, tBuOH,
rt, 15 h; (c) N,N-dimethylformamide di-tert-butyl acetal, benzene,
rt, 21 h followed by 50 °C, 6 h (52% in 2 steps).
lactacystin (2) conversion of tert-butyl cis-(2R,3R)-3-(1-
methylvinyl)aziridine-2-carboxylate (c-ent-7a, 89% ee,
entry 1 in Table 2) to (2R,3S)-3-hydroxyleucinate 1 (R )
tBu) was examined (Scheme 2). Treatment of c-ent-7a
with p-toluenesulfonic acid monohydrate (TsOH‚H2O)
smoothly afforded R-amino-â-hydroxy ester 11 in 93%
yield as a single product. The stereochemistry was
determined after conversion to the corresponding oxazo-
lidinone 12 by reaction with carbonyldiimidazole (Im2-
CO), in which a racemic ring-opened product rac-11 was
used as a starting material. In general, the coupling
constant between 4-H and 5-H is ∼9-10 Hz in cis-
oxazolidinone systems, whereas ∼4-6 Hz in trans sys-
tems.14 The small coupling constant (J4,5 ) 5.2 Hz)
observed in 12 indicates that the hydroxyl-inserted
product 11 has threo stereochemistry. This deduction was
supported by nuclear overhauser effect (NOE) enhance-
ment (13.6%) between these protons observed in the
corresponding cis-oxazolidinone derivative 13 (J4,5 ) 8.6
Hz) derived from the trans-aziridines. Thus, the ring-
tiomeric (S,S)-guanidinium salt ent-5 as a chiral source
for the asymmetric induction of (2R)-aziridines ent-7
(Table 2). The conditions of entry 3 in Table 1 were
chosen as a standard condition for further aziridination
reactions. Aziridines were generally formed in good to
moderate yields with high ee; however, conversion and
selectivity were strongly influenced by the substituent
introduced.13 Thus, no diastereoselectivity was observed
in the cases of vinyl and â-alkylvinyl aldehydes (entries
2 and 3). Interestingly, cis- and trans-3-[(E)-pentadec-1-
enyl]aziridines 7c, possible synthetic precursors for D-
erythro-sphingosine (3), were smoothly produced from
(E)-hexadec-2-enal (6c) not only in high combined yield
but also with high ee (entry 3). The reaction was greatly
retarded when R,â-dialkylvinyl aldehyde was used (entry
4). Introduction of a substituent at the position like
methacrolein (6a) led to the preferential production of
(14) For the basic discussion on the coupling constant, see: Foglia,
T. A.; Swern, D. J. Org. Chem. 1969, 34, 1680-1684. Williams, T. M.;
Crumbie, R.; Mosher, H. S. J. Org. Chem. 1985, 50, 91-97. Cardillo,
G.; Orena, M.; Sandri, S. J. Org. Chem. 1986, 51, 713-717.
(13) Low yields in some cases may be caused by dimerization of
starting aldehydes. See: Laitalainen, T.; Kuronen, P.; Hesso, A. Org.
Pre. Pro. Int. 1993, 25, 597-599.
J. Org. Chem, Vol. 70, No. 23, 2005 9401

Disadee and Ishikawa
SCHEME 2. Synthesis of
SCHEME 3. Ring-opening Reaction of the
(2R,3S)-3-Hydroxyleucinate 1 from tert-Butyl
cis-(2R,3R)-3-(1-Methylvinyl)aziridine-2-carboxylate
(c-ent-7a)a
trans-Aziridine t-ent-7ca
a Reagents and conditions: (a) TsOH‚H2O, THF/H2O, 25 °C, 30
min then 50 °C, 20 h (93%); (b) Im2CO, 35 °C, 2 days (90%); (c)
H2, 10% Pd/C, 25 °C, 9.5 h (91%).
a Reagents and conditions: (a) TsOH‚H2O, THF/H2O, 25 °C, 35
h [14, 71%; 15, 16% (cis:trans ) ca. 1:1)]; (b) AcOH, 25 °C, 2.5 h
(quant); (c) KOH, THF/MeOH, 0 °C, 15 min (14: 99%); (d) KOH,
EtOH/H2O, 2 °C, 0.5 h (14, 18%; 17, 52%); (e) Im2CO, CH2Cl2, 25
°C, 12 h (99%).
opening reaction should be controlled by SN2 type sub-
stitution leading to inversion at the C3 position.15 Cata-
lytic hydrogenation of 11 in the presence of 10% palladium
on carbon (Pd/C) smoothly gave (2R,3S)-3-hydroxyleuci-
nate 1.16 High retention of chirality in 1 (87% ee)
supported the stereoselective ring-opening reaction of
c-ent-7a with TsOH.
In literatures (2R,3S)-3-hydroxyleucine derivatives 1
had been prepared in 48-65% overall yields using aldol-
type reaction (92% ee),17 epoxidation (97% ee),4a dihy-
droxylation (87% ee),4b and aminohydroxylation (70%
ee)4c as key step under asymmetric conditions. In our
synthetic method 1 can be prepared in 68% overall yield
with 87% ee from the guanidinium salt 5.
Synthesis of D-erythro-Sphingosine (3). (a) From
the trans-aziridine t-ent-7c. Next, we examined the
enantioselective synthesis18 of D-erythro-sphingosine (3)
from both trans-(2R,3S)- t-ent-7c and cis-(2R,3R)-3-[(E)-
pentadec-1-enyl]aziridine-2-carboxylates c-ent-7c ob-
tained in entry 3 in Table 2. At first the ring-opening
reactions of the former t-ent-7c (97% ee) were examined
(Scheme 3). To directly introduce a hydroxyl function into
the aziridine skeleton, reaction with TsOH was tried
under the same condition as in Scheme 2. Although a
desired R-amino-â-hydroxy ester 14 was obtained in 71%
yield with good de, a regioisomerically ring-opened
product, â-amino-R-hydroxy ester 15, was also produced
in 16% yield without diastereoselectivity. Therefore,
acetic acid (AcOH) was used as an alternative nucleophile
for the ring-opening reaction, and an acetoxy-inserted
product 16 was quantitatively afforded as a single
diastereoisomer. R-Amino-â-hydroxy ester 14 was ob-
tained in 99% yield when 16 was subjected to metha-
nolysis (KOH, THF/MeOH), whereas conventional alka-
line hydrolysis (KOH, EtOH/H2O) afforded 14 only in low
yield (18%); instead, a conjugated dehydration product
17 was mainly produced (52%). The erythro stereochem-
istry of the ring-opened R-amino-â-hydroxy ester 14 was
determined by NOE enhancement (15%) and coupling
constant (J ) 9.2 Hz) between 4-H (δ 3.95) and 5-H
(δ 4.93) of the corresponding 2-oxazolidinone 18.14
Johnson et al.19 reported the total synthesis of L-
erythro-sphingosine from the corresponding enantiomeric
methyl ester of 18 derived from enzymatically prepared
cyanohydrin derivative. Although this means that the
synthesis of natural D-erythro-sphingosine could be for-
mally achieved in this stage, we independently developed
our own route. After protection of the hydroxyl group of
R-amino-â-hydroxy ester 14 with triisopropylsilyl (TIPS)
function the silyl ether 19 was treated with lithium
aluminum hydride. An intended reduced product 20 was
obtained in 82% yield, but concomitant removal of the
TIPS function was also observed as diol 21 was formed
in 18% yield. After conversion of 20 to oxazolidinone 22,
selective debenzylation was carried out under Birch
reduction conditions19 to give an N-deprotected oxazoli-
dinone 23 in high yields. Successively, removal of the
TIPS function of 23 with fluoride ion followed by alkaline
hydrolysis quantitatively afforded D-erythro-sphingosine
(3), which was fully characterized as a crystalline tri-
acetate 24, melting point (mp) 100-102 °C, [R]D24 -13.0
(CHCl3).20 Thus, 3 was synthesized in 62% overall yield
(15) We have observed that the ring-opening reaction of 3-arylaziri-
dine-2-carboxylates is greatly dependent upon the nature of substituent
on the aryl group. These results will be reported elsewhere in the near
future.
(16) The threo stereochemistry of 1 was further confirmed by 1H
NMR examination (J4,5 ) 6.0 Hz) after cyclization to an oxazolidin-
thione using diimidazolethiocarbonyl (Im2CS).
(17) Corey, E. J.; Lee, D.-H. Choi, S. Tetrahedron Lett. 1992, 33,
6735-6738.
(18) For reviews of the synthesis of sphingosine, see: Byun, H.-S.;
Bittman, R. In Phospholipids Handbook; Cevc, G., Ed.; Dekker: New
York, 1993; pp 97-140. Koskinen, P. M.; Koskinen, A. M. P. Synthesis
1998, 1075-1091. Curfman, C.; Liotta, D. Methods Enzymol. 1999,
311, 391-440. Koskinen, P. M.; Koskinen, A. M. P. Methods Enzymol.
1999, 311, 458-479. Jung, K.-H.; Schmidt, R. R. In Lipid Synthesis
and Manufacture; Gunstone, F. D., Ed.; Sheffield Academic: Schefield
UK, 1999; pp 208-249.
(19) Johnson, D. V.; Felfer, U.; Griengl, H. Tetrahedron 2000, 56,
781-790.
(20) Data of triacetate derived from sphingosine, see: Findeis, M.
A.; Whitesides, G. M. J. Org. Chem. 1987, 52, 2838-2848.
9402 J. Org. Chem., Vol. 70, No. 23, 2005

Chirality Transfer from Guanidinium Ylides
SCHEME 4. Synthesis of D-erythro-Sphingosine (3)
SCHEME 6. Synthesis of D-erythro-Sphingosine (3)
from the cis-Aziridine c-ent-7ca
from the Ring-Opened Product 14a
a Reagents and conditions: (a) TIPSOTf, NEt3, CH2Cl2, 2 °C,
30 min (95%); (b) LiAlH4, THF, 25 °C, 10 min (20, 82%; 21, 18%);
(c) Im2CO, CH2Cl2, 25 °C, 12 h (97%); (d) Li, liq NH3, Et2O, -70
°C, 5 min (89%); (e) TBAF, THF, rt, 1.5 h; (f) 2 N NaOH aq, EtOH,
80 °C, 2.5 h; (g) Ac2O, pyridine, DMAP, CH2Cl2, rt, 3 h (24, 93%
from 23)
a Reagents and conditions: (a) AcOH, CH2Cl2, 0 °C, 3 d (62%);
(b) KOH, THF/MeOH, 0 °C, 15 min (93%); (c) TsOH‚H2O, THF/
H2O (1:1), 25 °C, 35 h (77%); (d) Im2CO, CH2Cl2, rt, 12 h (93%);
(e) Boc2O, 45 °C, 4 h (95%); (f) MsCl, NEt3, CH2Cl2, 0 °C, 30 min
(96%); (g) LiBH4, THF, 50 °C, 2 d (73%); (h) TIPSOTf, NEt3,
CH2Cl2, 2 °C, 30 min (97%); (i) Li, liq NH3, Et2O, -72 °C, 5 min
(78%); (j) TBAF, THF, rt, 1.5 h (70%); (k) 2 N NaOH aq, EtOH, 80
°C, 2.5 h (quant)
SCHEME 5. Trial for Direct Conversion of the
cis-Aziridine c-ent-7c to cis-Oxazolidinone 18a
7c to AcOH without solvent at room temperature. The
acetoxy-inserted product 26 was obtained when the
reaction was carried out in dichloromethane, even in
moderate yield (62%), and subsequent methanolysis
afforded the R-amino-â-hydroxy ester 27 (58% in two
steps). A small coupling constant (J ) 5.6 Hz) between
4-H and 5-H of the corresponding oxazolidine derivative
25 indicates that the ring-opened product 27 with a threo
stereochemistry is, as expected, formed by inversion at
the C3 position of an aziridine skeleton.14 After introduc-
tion of t-butoxycarbonyl (Boc) group to the nitrogen atom
of 27, treatment with methanesulfonyl choloride led to
an intramolecular cyclization22 with stereochemical in-
version at the C3 position, resulting in the production of
cis-oxazolidinone 18 in high yield, which was identical
with the sample obtained in Scheme 3.
a Reagents and conditions: (a) ClCO2Me, MeCN, 80 °C, 7 h (18,
25%; 25, 8%)
with high optical purity (∼97% ee), starting from the
trans-aziridine t-ent-7c through eight steps.
(b) From the cis-aziridine c-ent-7c. Application of
the above reaction scheme to the synthesis of D-erythro-
sphingosine (3) from the corresponding cis-aziridine
c-ent-7c requests stereochemical inversion at the C3
position of a ring-opened product because of the undes-
ired production of threo-(2R,3S)-amino alcohol by SN2-
type ring-opening reaction of the cis-aziridine. As men-
tioned above, cis-oxazolidinone 18 can be a possible
precursor for D-erythro-sphingosine (3) according to the
synthetic method by Johnson et al.19 Therefore, we follow
their route for comparison with our modified route shown
in Scheme 4. Recently Lee et al.21 reported direct conver-
sion of a cis-aziridine system to a cis-oxazolidinone. Thus,
reaction of c-ent-7c with methyl chloroformate, in which
double inversion processes should occur as a main
reaction path, was attempted (Scheme 5); however, a 3:1
mixture of cis-18 and trans-oxazolidinones 25 was formed
in low yields (33%). These situations made us examine a
stepwise procedure as an alternative approach (see,
Scheme 6).
According to the method of Johnson,19 the ester func-
tion was reduced with lithium borohydride to afford the
corresponding alcohol 29 in 73% yield with partial
recovery of the starting 18 (20%). After protection of the
alcoholic function of 29 with TIPSOTf, selective removal
of the benzyl group of 30 was effected under Birch
reduction conditions to give an N-deprotected oxazolidi-
none 31. Treatment of 31 with fluoride anion followed
by alkaline hydrolysis completed the alternative synthe-
sis of D-erythro-sphingosine (3) from the cis-aziridine
c-ent-7c (95% ee) in 27% overall yield without loss of
enantiopurity through eight steps. Thus, it was found
that the modified route (Schemes 3 and 4) is practically
superior to the reported route.
Although treatment of c-ent-7c (95% ee) with TsOH‚
H2O gave a desired R-amino-â-hydroxy ester 27 and a
regioisomeric â-amino-R-hydroxy ester (not shown) in 77
and 11% yields, respectively, similar to the trans isomer
(see Scheme 3), a ring-opened product 26 was unexpect-
edly produced in low yield (<50%) on exposure of c-ent-
Key strategies for the construction of a chiral amino
alcohol unit in the reported syntheses of D-erythro-
(21) Shim, T. B.; Kang, S. H.; Lee, K. S.; Lee, W. K. J. Org. Chem.
2003, 68, 104-108.
(22) Agami, C.; Couty, F.; Hamon, L.; Venier, O. Tetrahedron Lett.
1993, 34, 4509-4512.
J. Org. Chem, Vol. 70, No. 23, 2005 9403

Disadee and Ishikawa
sphingosine (3) can be classified into five-types of reac-
tions except the ring-opening of aziridines:23 C-C bond
formation,19,24 the ring-opening of epoxides with a nitro-
gen nucleophile,25 displacement of alcohols or halides
with a nitrogen nucleophile,20,26 reduction of aminoke-
tone,27 and modification of natural chiral sources includ-
ing phytosphingosine.28 Among those major accesses are
the C-C bond formation and the displacement methods.
As for aziridine-participating synthesis only one approach
had been reported, in which cis-(2R,3R)-N-toluenesulfin-
ylaziridine derivative, an activated aziridine,29 prepared
by aldol-type reaction of the sulfinylimine derived from
(+)-menthyl-(R)-p-toluenesulfinate with bromoacetate,30
was used. Thus, our approach offers the second report of
this kind and the unique example of the use of unacti-
vated aziridine29 as well as the first access from trans-
aziridine with high effectivity (62%).31
Conclusions
In conclusion, reaction of chiral guanidinium ylides
with R,â-unsaturated aldehydes successfully gave a
variety of R,â-unsaturated aziridine-2-carboxylates in
good to moderate yields and chirality of the guanidinium
ylides was effectively transferred to the 2 and 3 positions
of aziridine products (up to 93% de and 98% ee). The
formed R,â-unsaturated aziridines are easily converted
into R-amino-â-hydroxy esters synthetic precursors. Thus,
(2R,3S)-3-hydroxyleucinate was enantioselectively pre-
pared from (2R,3R)-3-isopropenylaziridine-2-carboxylate
obtained using methacrolein as aldehyde substrate. In
addition, D-erythro-sphingosine was synthesized in good
overall yield with high optical purity starting from both
trans-(2R,3S)- and cis-(2R,3R)-3-[(E)-pentadec-1-enyl]-
aziridine-2-carboxylates.
(23) Davis, F. A.; Reddy, G. V. Tetrahedron Lett.1996, 37, 4349-
4352.
(24) Tkaczuk, P.; Thornton, E. R. J. Org. Chem. 1981, 46, 4393-
4398. Julina, R.; Herzig, T.; Bernet, B.; Vasella, A. Helv. Chem. Acta
1986, 69, 368-373. Ito, Y.; Sawamura, M.; Hayashi, T. Tetrahedron
Lett. 1988, 29, 239-240. Herold, P. Helv. Chem. Acta 1988, 71, 354-
362. Radunz, H.-E.; Devant, R. M.; Elermann, V. Ann. 1988, 1103-
1105. Garner, P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988, 53,
4395-4398. Nimkar, S.; Menaldino, D.; Merrill, A. H.; Liotta, D.
Tetrahedron Lett. 1988, 29, 3037-3040. Dondoni, A.; Fantin, G.;
Fogagnolo, M.; Pedrini, P. J. Org. Chem. 1990, 53, 1439-1446. Groth,
U.; Scho¨llkopf, U.; Tiller, T. Tetrahedron 1991, 47, 2835-2842.
Solladie-Cavallo, A.; Koessler, J. L. J. Org. Chem. 1994, 59, 3240-
3242. Spanu, P.; Rassu, G.; Pinna, L.; Battistini, L.; Casiraghi, G.
Tetrahedron: Asymmetry 1997, 8, 3237-3243. Hertweck, C.; Boland,
W. J. Org. Chem. 1999, 64, 4426-4430. Suzuki, H.; Mori, M.;
Shibakami, M. Synlett 2003, 2163-2166.
Experimental Section
General Procedure for Aziridine Formation (Tables
1 and 2). (A) TMG/SiO2 (or Ac2O) System. To a solution of
5 (or ent-5) (100 mg) and 6 (3 equiv) in an appropriate solvent
(0.1 mL) was added TMG (1.5 equiv) at 25 °C under argon,
and the whole was stirred at the same temperature for 3 days.
After dilution with CHCl3 (2 mL) either the mixture was added
into a suspension of SiO2 (3 g) in CHCl3 (10 mL) and stirred
for 2 days or the mixture was stirred with Ac2O (3 equiv) for
30 min. In the former case after removal of the SiO2 through
a Celite pad, the filtrate was concentrated, whereas the
reaction mixture was directly concentrated in the latter case.
The residue obtained was purified by column chromatography
to give 7 and 8.
(B) NaH/SiO2 System. A suspension of 5 (or ent-5) (100
mg) and NaH (2.0 equiv) in DMF (0.5 mL) was stirred at -10
°C for 30 min (the mixture turned yellow) under argon. To
the mixture was added 6 (3.0 equiv) and the whole was stirred
at the same temperature for 2 days. The same workup as above
gave 7 and 8.
(25) Bernet, B.; Vasella, A. Tetrahedron Lett. 1983, 24, 5491-5494.
Shibuya, H.; Kawashima, K.; Ikeda, M.; Kitagawa, I. Tetrahedron Lett.
1989, 30, 7205-7208. Olofsson, B.; Somfai, P. J. Org. Chem. 2003,
68, 2514-2517. Raghavan S.; Rajender, A. J. Org. Chem. 2003, 68,
7094-7079. Torssell, S.; Somfai, P. Org. Biomol. Chem. 2004, 2, 1643-
1646.
(26) Schlosser, M.; Obayashi, M. Chem. Lett. 1985, 1715-1718.
Ohashi, K.; Yamagiwa, Y.; Kamikawa, T.; Kates, M. Tetrahedron Lett.
1988, 29, 1185-1188. Nicolaou, K. C.; Caulfield, T.; Kataoka, H.;
Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 7910-7912. Takano, S.;
Iwabuchi, Y.; Ogasawara, K. J. Chem. Soc. Chem. Commun. 1991,
820-821. Yadav, J. S.; Vidyanand, D.; Rajagopal, D. Tetrahedron Lett.
1993, 34, 1191-1194. Somfai, P.; Olsson, R. Tetrahedron 1993, 49,
6645-6650. Hudlicky, T.; Nugent, T.; Griffith, W. J. Org. Chem. 1994,
59, 7944-7946. Kobayashi, S.; Hayashi, T.; Kawasuji, T.; Kobayashi,
S.; Furuta, T. Tetrahedron Lett. 1994, 35, 9573-9576. Bettelli, E.;
Chinzari, P.; Andrea, P. D.; Passacantilli, P.; Piancatelli, G.; Topai, A.
Korean J. Med. Chem. 1996, 6, 339-343. Li, Y.-L.; Wu, Y.-L. Ann. 1996,
2079-2082. Tuch, A.; Saniere, M.; Le Merrer, Y.; Depezay, J.-C.
Tetrahedron Asymmetry 1996, 7, 897-906. He, L.; Byun, H.-S.;
Bittman, R. J. Org. Chem. 2000, 65, 7627-7633. Corey, E. J.; Choi, S.
Tetrahedron Lett. 2000, 41, 2765-2768. Nakamura, T.; Shiozaki, M.
Tetrahedron 2001, 57, 9087-9092. Lee, H. K.; Kim, E.-K.; Pak, C. S.
Tetrahedron Lett. 2002, 43, 9641-9644. Kang, S. H.; Hwang, Y. S.;
Lee, H. S. Bull. Korean Chem. Soc. 2002, 23, 1195-1197. Milne, J. E.;
Jarowicki, K.; Kocienski, P. J.; Alonso, J. Chem. Commun. 2002, 426-
427. Lu, X.; Bittman, R. Tetrahedron Lett. 2005, 46, 1873-1875.
(27) Boutin, R. H.; Rapopport, H. J. Org. Chem. 1986, 51, 5320-
5327. Koskinen, A. M. P.; Krische, M. J. Synlett 1990, 665-666.
Hoffman, R. V.; Tao, J. Tetrahedron Lett. 1998, 39, 3953-3956. Khiar,
N.; Singh, K.; Garcia, M.; Martin-Lomas, M. Tetrahedron Lett. 1999,
40, 5779-5782. Chun, J.; Li, G.; Byun, H.-S.; Bittman, R. Tetrahedron
Lett. 2002, 43, 375-377.
(28) Murakami, T.; Minamikawa, H.; Hato, M. Tetrahedron Lett.
1994, 35, 745-748. Murakami, T.; Hato, M. J. Chem. Soc., Perkin
Trans. 1. 1996, 823-827. van den Berg, R. J. B. H. N.; Korevaar, C.
G. N.; van der Marel, G. A.; Overkleeft, H. S.; Boom, J. H. Tetrahedron
Lett. 2002, 43, 8409-8412. van den Berg, R. J. B. H. N.; Korevaar, C.
G. N.; Overkleeft, H. S.; van der Marel, G. A.; Boom, J. H. J. Org.
Chem. 2004, 69, 5699-5704.
(29) Discrimination between activated and unactivated (or nonac-
tivated) is dependent upon a substituent on the nitrogen atom of
aziridine systems and the former is used in the cases of electron-
attractive group such as an acyl group; see, McCoull, W.; Davis, F. A.
Synthesis 2000, 1347-1365.
t-Butyl 1-Benzyl-3-isopropenylaziridine-2-carboxylate
(Entry 1 in Table 2). (2R,3R)-cis-Derivative c-ent-7a. A
colorless needles, mp 65-66 °C; chiral high-performance liquid
chromatography (HPLC) [CHIRALCEL OD-H, n-hexane/2-
propanol ) 800:1, flow rate ) 0.5 mL/min, detection wave-
length ) 215 nm, tR (major) ) 36.7 min, tR (minor) ) 46.3 min],
89% ee; [R]20 +51.1 (c 2.0, CHCl3); IR (ATR) υmax 1732 cm-1
;
D
1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.70 (s, 3H), 2.31
(d, J ) 7.1 Hz, 1H), 2.35 (d, J ) 7.1 Hz, 1H), 3.38 (d, J ) 13.7
Hz, 1H), 3.88 (d, J ) 13.7 Hz, 1H), 4.92 (br s, 1H), 5.10 (br s,
1H), 7.23-7.27 (m, 1H), 7.32 (dif. dd, J ) 7.6, 7.1 Hz, 2H),
7.40 (dif. d, J ) 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
20.7, 28.0, 45.4, 48.8, 63.4, 80.9, 113.4, 127.0, 127.9, 128.2,
138.1, 138.3, 167.4; high-resolution fast-atom bombardment
mass spectroscopy (HRFABMS) m/z 274.1792 (calcd for C17H24-
NO2: 274.1807). (2R,3S)-trans-Derivative t-ent-7a. A pale-
yellow oil; chiral HPLC [CHIRALCEL OD-H, n-hexane/2-
propanol ) 800:1, flow rate ) 0.5 mL/min, detection wavelength
) 215 nm, tR (minor) ) 15.7 min, tR (major) ) 23.8 min], 82%
1
ee; [R]22 +59.4 (c 0.8, CHCl3); IR (ATR) νmax 1720 cm-1; H
D
NMR (400 MHz, CDCl3) (invertomer ratio ) ca. 10:1) δmajor
1.39 (s, 9H), 1.64 (s, 3H), 2.65 (d, J ) 2.3 Hz, 1H), 2.77 (d, J
) 2.3 Hz, 1H), 3.96 (d, J ) 14.1 Hz, 1H), 4.09 (d, J ) 14.1 Hz,
(30) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Portonovo, P. S.
Tetrahedron Lett. 1993, 34, 6229-6232; Davis, F. A.; Zhou, P.; Reddy,
G. V. J. Org. Chem. 1994, 59, 3243-3245; Davis, F. A.; Reddy, G. V.;
Liu, H. J. Am. Chem. Soc. 1995, 117, 3651-3652.
(31) The aziridine-participating synthesis of (()-sphingosine had
been reported, see: Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C.
Tetrahedron Lett., 1986, 42, 917-922.
9404 J. Org. Chem., Vol. 70, No. 23, 2005

Chirality Transfer from Guanidinium Ylides
1H), 4.91 (br s, 1H), 5.05 (br s, 1H), 7.23 (t, J ) 7.1 Hz, 1H),
7.30 (dd, J ) 7.7, 7.1 Hz, 2H), 7.35 (dif. d, J ) 7.0 Hz, 2H);
δminor 2.33 (br s, 1H), 3.01 (br s, 1H), 3.45 (br d, J ) 13.6 Hz,
1H), 3.79 (br d, J ) 13.6 Hz, 1H), 4.97 (br s, 1H), 5.21 (br s,
1H), 7.23-7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δmajor 18.2,
28.0, 41.4, 50.5, 54.6, 81.5, 113.1, 126.7, 127.9, 128.1, 139.5,
142.2), 168.2; HRFABMS m/z 274.1816 (calcd for C17H24NO2:
274.1807).
114.4, 128.1, 128.4, 128.9, 135.0, 140.5, 157.2, 168.4; HR-
FABMS m/z 318.1701 (calcd for C18
H24NO4: 318.1705).
t-Butyl (2R,3S)-3-Hydroxyleucinate (1). A mixture of 11
(124 mg, 0.424 mmol) and 10% Pd/C (93 mg) in EtOH (10 mL)
was stirred at 25 °C for 9.5 h under hydrogen. Conventional
workup followed by column chromatography (SiO2, AcOEt)
afforded 1 as a pale-yellow oil (78 mg, 91%): [R]23 -11.2 (c
D
1.4, CHCl3); IR (film) νmax 3371, 1728 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.96 (d, J ) 6.8 Hz, 3H), 1.01 (d, J ) 6.8 Hz, 3H),
1.48 (s, 9H), 1.68-1.79 (m, 1H), 2.06 (br s, 3H), 3.39-3.43 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 17.6, 19.5, 28.0, 30.8, 56.4,
77.1, 81.5, 173.8; FABMS m/z: 204 (48), 148 (100).
t-Butyl 1-Benzyl-3-(pentadec-1-enyl)aziridine-2-car-
boxylate (Entry 3 in Table 2). (2R,3R)-cis-Derivative
c-ent-7c. Colorless needles, mp 45-46 °C; chiral HPLC
[CHIRALCEL OD-H, n-hexane/2-propanol ) 1000:1, flow rate
) 0.5 mL/ min, detection wavelength ) 215 nm, tR (major) )
t-Butyl (2R,3R,4E)-2-Benzylamino-3-acetoxyoctadec-
4-enoate (16). A mixture of t-ent-7c (222 mg, 0.50 mmol) and
AcOH (0.6 mL, 10.5 mmol) was stirred at 25 °C for 2.5 h and
concentrated. The residue was purified by column chromatog-
raphy (SiO2, n-hexane/AcOEt ) from 20:1 to 10:1) to afford
33.8 min, tR (minor) ) 40.3 min], 95% ee; [R]23 -5.3 (c 1.5,
D
CHCl3); IR (KBr) υmax 1728 cm-1; 1H NMR (500 MHz, CDCl3)
δ 0.88 (t, J ) 7.0 Hz, 3H), 1.25-1.35 (br, 22H), 1.46 (s, 9H),
2.03 (br dt, J ) 7.0, 7.0 Hz, 2H), 2.29 (d, J ) 6.7 Hz, 1H), 2.36
(dd, J ) 8.2, 6.7 Hz, 1H), 3.63 (d, J ) 14.7 Hz, 1H), 3.66 (d, J
) 14.7 Hz, 1H), 5.46 (dd, J ) 15.6, 8.2 Hz, 1H), 5.80 (dt, J )
15.6, 7.0 Hz, 1H), 7.22-7.25 (m, 1H), 7.31 (t, J ) 7.6 Hz, 2H),
7.35 (d, J ) 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 14.1,
22.7, 28.2, 29.1, 29.3, 29.5, 29.59, 29.64, 29.7, 31.9, 32.4, 45.1,
47.4, 63.1, 81.2, 124.9, 126.9, 127.6, 128.2, 136.0, 138.1, 168.2;
HRFABMS m/z 442.3663 (calcd for C29H48NO2: 442.3685).
(2R,3S)-trans-Derivative t-ent-7c. A pale-yellow oil; chiral
HPLC [CHIRALCEL OD-H, n-hexane/2-propanol ) 250:1, flow
rate ) 0.5 mL/min; detection wavelength ) 215 nm, tR (major)
) 13.4 min, tR (minor) ) 18.0 min], 97% ee; [R]23D -6.6 (c 2.7,
16 as a pale-yellow oil (252 mg, quant); [R]23 -6.2 (c 2.5,
D
1
CHCl3); IR (film) υmax 3332, 1735 cm-1; H NMR (400 MHz,
CDCl3) δ 0.88 (t, J ) 7.0 Hz, 3H), 1.25-1.36 (br, 22H), 1.46 (s,
9H), 2.00-2.05 (m, 2H), 2.03 (s, 3H), 3.35 (d, J ) 5.1 Hz, 1H),
3.70 (d, J ) 13.4 Hz, 1H), 3.88 (d, J ) 13.4 Hz, 1H), 5.40 (dd,
J ) 7.7, 5.1 Hz, 1H), 5.46 (br dd, J ) 15.0, 7.7 Hz, 1H), 5.76
(dt, J ) 15.0, 7.0 Hz, 1H), 7.22-7.35 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 14.1, 21.2, 22.7, 28.1, 28.8, 29.1, 29.3, 29.4,
29.55, 29.62, 29.635, 29.643, 29.7, 31.9, 32.3, 52.2, 64.1, 75.4,
81.6, 124.3, 127.0, 128.2, 128.3, 136.7, 139.7, 169.7, 171.0;
HRFABMS m/z 502.3897 (calcd for C31H52NO4: 502.3896).
1
CHCl3); IR (film) υmax 1720 cm-1; H NMR (400 MHz, CDCl3)
t-Butyl (2R,3R,4E)-2-Benzylamino-3-hydroxyoctadec-
4-enoate (14). A solution of 16 (388 mg, 0.77 mmol) in THF
(29 mL) was stirred with a solution of KOH in MeOH
(prepared from KOH 1.023 g in MeOH 2.1 mL) (0.86 mL, 6.29
mmol) at 0 °C for 15 min. Conventional workup followed by
column chromatography (NH-SiO2, n-hexane/AcOEt ) from
10:1 to 5:1) afforded 14 as a pale-yellow oil (351 mg, 99%);
(invertomer ratio ) ca. 10:9) δmajor 0.88 (t, J ) 7.0 Hz, 3H),
1.22-1.34 (br, 22H), 1.38 (s, 9H), 2.02 (dt, J ) 7.0, 7.0 Hz,
2H), 2.56 (d, J ) 2.6 Hz, 1H), 2.72 (dd, J ) 7.3, 2.6 Hz, 1H),
3.94 (d, J ) 13.9 Hz, 1H), 4.13 (d, J ) 13.9 Hz, 1H), 5.20 (dd,
J ) 15.4, 7.3 Hz, 1H), 5.80 (dt, J ) 15.4, 7.0 Hz, 1H), 7.20-
7.36 (m, 5H); δminor 0.88 (t, J ) 7.0 Hz, 3H), 1.22-1.34 (br,
22H), 1.46 (s, 9H), 2.07 (dt, J ) 7.0, 7.0 Hz, 2H), 2.20 (d, J )
2.8 Hz, 1H), 3.00 (dd, J ) 8.8, 2.8 Hz, 1H), 3.65 (d, J ) 14.3
Hz, 1H), 3.84 (d, J ) 14.3 Hz, 1H), 5.41 (dd, J ) 15.6, 8.8 Hz,
1H), 5.92 (dt, J ) 15.6, 7.0 Hz, 1H), 7.20-7.36 (m, 5H); 13C
NMR (100 MHz, CDCl3) (a mixture of invertomers) δ 14.0,
22.6, 27.8, 27.9, 28.86, 28.90, 28.96, 29.01, 29.2, 29.35, 29.36,
29.46, 29.53, 29.54, 29.6, 31.8, 32.2, 32.5, 42.7, 45.38, 45.40,
47.7, 54.3, 55.5, 80.9, 81.1, 122.00, 122.01, 126.5, 126.6, 127.4,
127.8, 127.9, 128.0, 134.5, 138.9, 139.0, 139.3, 167.9, 169.5;
HRFABMS m/z 442.3663 (calcd for C29H48NO2: 442.3685).
[R]23 +21.1 (c 3.0, CHCl3); IR (film) υmax 3448, 3317, 1728
D
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.88 (t, J ) 7.0 Hz, 3H),
1.24-1.32 (m, 22H), 1.46 (s, 9H), 1.99 (br dt, J ) 7.0, 7.0 Hz,
2H), 3.29 (br s, 1H), 3.37 (d, J ) 4.8 Hz, 1H), 3.63 (d, J ) 12.6
Hz, 1H), 3.90 (d, J ) 12.6 Hz, 1H), 4.30 (br dd, J ) 6.4, 4.8
Hz, 1H), 5.30 (ddt, J ) 15.4, 6.4, 1.1 Hz, 1H), 5.71 (dtd, J )
15.4, 7.0, 1.1 Hz, 1H), 7.24-7.33 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 14.1, 22.6, 28.1, 29.0, 29.1, 29.3, 29.4, 29.5, 29.59,
29.60, 29.62, 31.9, 32.2, 52.7, 65.3, 71.5, 81.6, 127.2, 127.3,
128.3, 128.4, 133.7, 139.5, 171.5; HRFABMS m/z 460.3785
(calcd for C29H50NO3: 460.3791).
t-Butyl (2R,3S)-2-Benzylamino-3-hydroxy-4-methylpent-
4-enoate (11). A solution of c-ent-7a (145 mg, 0.529 mmol)
in THF (2 mL) containing TsOH H2O (107 mg, 0.563 mmol)
was stirred at 25 °C for 30 min and then at 50 °C for 20 h.
After being cooled to 0 °C and made alkaline, conventional
workup afforded 11 as a pale-yellow oil (143 mg, 93%), which
was used in the next step without purification: [R]21D +45.0 (c
1.2, CHCl3); IR (film) νmax 3448, 3307, 1726 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.43 (s, 9H), 1.76 (s, 3H), 3.18 (d, J ) 8.1 Hz,
1H), 3.71 (d, J ) 13.0 Hz, 1H), 3.83 (d, J ) 13.0 Hz, 1H), 3.93
(d, J ) 8.1 Hz, 1H), 4.93 (m, 1H), 4.99 (m, 1H), 7.26-7.34 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 16.8, 28.0, 52.6, 64.6, 76.5,
82.0, 114.7, 127.3, 128.3, 128.5, 139.2, 143.5, 172.2; HRFABMS
m/z 292.1934 (calcd for C17H26NO3: 292.1913).
t-Butyl (1′E,4R,5R)-cis-3-Benzyl-2-oxo-5-(pentadec-1-
enyl)-1,3-oxazolidine-4-carboxylate (18). A mixture of 14
(301 mg, 0.66 mmol) and Im2CO (116 mg, 95% purity, 0.68
mmol) in CH2Cl2 (1.5 mL) was stirred at 25 °C for 12 h under
argon. After evaporation, the residue was purified by column
chromatography (SiO2, n-hexane/AcOEt ) from 10:1 to 5:1)
to afford 18 as colorless prisms, which were recrystallized from
n-hexane (315 mg, 99%); mp 52-53 °C; chiral HPLC [CHIRAL-
CEL OD-H; n-hexane/2-propanol ) 100: 1; flow rate ) 1.0 mL/
min; detection wavelength ) 254 nm; tR (minor) ) 18.6 min,
tR (major) ) 26.1 min], 92% ee; [R]25D +34.3 (c 3.3, CHCl3); IR
(film) υmax 1754, 1718 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.88
(t, J ) 7.0 Hz, 3H), 1.25-1.38 (br m, 22H), 1.44 (s, 9H), 2.04
(br dt, J ) 7.2, 7.2 Hz, 2H), 3.95 (d, J ) 9.2 Hz, 1H), 4.00 (d,
J ) 14.7 Hz, 1H), 4.93 (dd, J ) 9.2, 7.9 Hz, 1H), 4.94 (d, J )
14.7 Hz, 1H), 5.42 (ddt, J ) 15.6, 7.9, 1.5 Hz, 1H), 5.89 (dt, J
) 15.6, 7.0 Hz, 1H), 7.24, 7.24 (each br d, J ) 8.2 Hz, 1H),
7.30-7.37 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 14.1, 22.7,
28.0, 28.5, 29.1, 29.3, 29.4, 29.5, 29.605, 29.612, 29.63, 29.64,
31.9, 32.2, 47.3, 61.3, 76.0, 83.0, 122.0, 128.1, 128.6, 128.9,
135.2, 138.9, 157.6, 166.7; FABMS m/z 486 (MH+), 91 (100).
Anal. Calcd for C30H47NO4: C, 74.19; H, 9.75; N, 2.88. Found:
C, 74.25; H, 9.72; N, 2.91.
(dl)-tert-Butyl trans-3-Benzyl-5-isopropenyl-2-oxo-1,3-
oxazolidine-4-carboxylate (rac-12). A mixture of rac-11 (32
mg, 0.108 mmol) and Im2CO (22 mg, 95% purity, 0.129 mmol)
in CH2Cl2 (1 mL) was stirred at 35 °C for 3 days under argon.
After evaporation the residue was purified by column chro-
matography (SiO2, n-hexane/AcOEt ) from 10:1 to 4:1) to
afford the oxazolidinone rac-12 as a colorless oil (31 mg, 90%);
1
IR (film) νmax 1763, 1743 cm-1; H NMR (400 MHz, CDCl3) δ
1.48 (s, 9H), 1.61 (br s, 3H), 3.62 (d, J ) 5.1 Hz, 1H), 4.18 (d,
J ) 14.8 Hz, 1H), 4.78 (d, J ) 5.3 Hz, 1H), 4.95 (d, J ) 14.8
Hz, 1H), 4.96 (br s, 1H), 5.09 (br s, 1H), 7.23-7.37 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 16.5, 27.9, 47.1, 60.6, 78.7, 83.4,
t-Butyl
(2R,3R,4E)-2-Benzylamino-3-triisopropyl-
silanyloxyoctadec-4-enoate (19). A solution of 14 (436 mg,
0.95 mmol), TIPSOTf (0.26 mL, 0.97 mmol, 1.02 equiv), and
J. Org. Chem, Vol. 70, No. 23, 2005 9405

Disadee and Ishikawa
NEt3 (0.14 mL, 1.0 mmol) in CH2Cl2 (4.4 mL) was stirred at 2
°C for 30 min. Conventional workup followed by column
chromatography (SiO2, n-hexane/AcOEt ) from 10:1 to 4:1)
afforded 19 as a colorless oil (557 mg, 95%); [R]24D -1.5 (c 3.1,
min. After quickly quenched with phosphate buffer (prepared
from 0.5 M KH2PO4 and 0.5 M K2HPO4 in water, pH 6.8) (5
mL) the mixture was diluted with water (30 mL) and extracted
with AcOEt (50 mL). Conventional workup followed by column
chromatography (SiO2, n-hexane/AcOEt ) 3:1) afforded 23 as
1
CHCl3); IR (film) υmax 3333, 1736, 1725 cm-1; H NMR (500
a colorless oil (88 mg, 89%): [R]20 -13.3 (c 1.1, MeOH); IR
MHz, CDCl3) δ: 0.88 (t, J ) 7.0 Hz, 3H), 1.00-1.06 (m, 21H),
1.25-1.34 (m, 22H), 1.47 (s, 9H), 2.01 (br dt, J ) 6.7, 6.1 Hz,
2H), 3.29 (d, J ) 4.0 Hz, 1H), 3.69 (d, J ) 13.4 Hz, 1H), 3.91
(d, J ) 13.4 Hz, 1H), 4.50 (dd, J ) 7.3, 4.0 Hz, 1H), 5.52 (dd,
J ) 15.3, 7.3 Hz, 1H), 5.59 (dt, J ) 15.3, 6.1 Hz, 1H), 7.21-
7.24 (dd, J ) 7.0, 6.7 Hz, 1H), 7.28-7.33 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 12.4, 14.1, 18.0, 18.1, 22.7, 28.1, 29.0, 29.2,
29.3, 29.5), 29.58, 29.62, 29.64, 29.7, 31.9, 32.2, 52.2, 67.4, 76.0,
80.7, 126.7, 128.16, 128.20, 129.6, 133.1, 140.2, 171.3; HR-
FABMS m/z 616.5150 (calcd for C38H70NO3Si: 616.5125).
D
(film) υmax 3260, 1761 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.88
(t, J ) 7.0 Hz, 3H), 1.03-1.07 (m, 21H), 1.26-1.37 (m, 22H),
2.05 (br dt, J ) 6.8, 6.8 Hz, 2H), 3.79 (dt, J ) 8.6, 5.3 Hz, 1H),
4.08 (dd, J ) 7.9, 4.9 Hz, 1H), 4.30 (dd, J ) 8.8, 4.9 Hz, 1H),
4.43 (t, J ) 8.8 Hz, 1H), 4.95 (br s, 1H), 5.36 (br dd, J ) 15.6,
8.1 Hz, 1H), 5.73 (dt, J ) 15.6, 7.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 12.3, 14.1, 17.96, 18.02, 22.7, 28.9, 29.2, 29.3,
29.4, 29.57, 29.62, 29.64, 29.65, 31.9, 32.2, 57.2, 66.9, 75.8,
127.9, 136.2, 159.5; HRFABMS m/z 482.4045 (calcd for C28H56-
NO3Si: 482.4029).
Reduction of 19: (2S,3R,4E)-2-Benzylamino-3-triiso-
propylsilanyloxyoctadec-4-en-1-ol (20) and (2S,3R,4E)-
2-Benzylaminooctadec-4-en-1,3-diol (21). A mixture of 19
(325 mg, 0.53 mmol) and LiAlH4 (52 mg, 80% purity, 1.10
mmol) in THF (7 mL) was stirred at 25 °C for 10 min under
argon. Conventional workup followed by column chromatog-
raphy (NH-SiO2, n-hexane/AcOEt ) from 10:1 to 5:1) afforded
20 as a colorless oil (235 mg, 82%) and 21 as colorless plates
(37 mg, 18%), respectively. 20: [R]25D -12.7 (c 2.1, CHCl3); IR
(film) υmax 3448, 3324 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.88
(t, J ) 7.0 Hz, 3H), 1.00-1.11 (m, 21H), 1.26-1.35 (m, 22H),
2.03 (br dt, J ) 7.3, 7.0 Hz, 2H), 2.63 (ddd, J ) 5.5, 4.6, 4.6
Hz, 1H), 3.06 (br s, 1H), 3.61 (dd, J ) 10.7, 5.5 Hz, 1H), 3.66
(dd, J ) 10.7, 4.6 Hz, 1H), 3.81 (d, J ) 13.1 Hz, 1H), 3.88 (d,
J ) 13.1 Hz, 1H), 4.36 (dd, J ) 7.9, 4.6 Hz, 1H), 5.43 (br dd,
J ) 15.6, 7.9 Hz, 1H), 5.63 (dt, J ) 15.6, 7.0 Hz, 1H), 7.23-
7.32 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 12.5, 14.1, 18.06,
18.12, 22.7, 29.0, 29.2, 29.3, 29.5, 29.58, 29.64, 29.66, 29.67,
31.9, 32.2, 51.6, 59.9, 63.4, 74.9, 127.0, 128.1, 128.4, 130.4,
133.7, 140.3; HRFABMS m/z 546.4704 (calcd for C34H64NO2-
Si: 546.4706). 21: mp 45-47 °C; [R]22D -7.0 (c 0.5, CHCl3); IR
(KBr) υmax 3341 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J
) 7.0 Hz, 3H), 1.25-1.38 (m, 22H), 1.97 (br s, 3H), 2.04 (dt, J
) 7.0, 7.0 Hz, 2H), 2.67 (dt, J ) 4.8, 4.8 Hz, 1H), 3.70 (d, J )
4.8 Hz, 2H), 3.83 (d, J ) 13.2 Hz, 1H), 3.87 (d, J ) 13.2 Hz,
1H), 4.24 (dd, J ) 6.8, 4.8 Hz, 1H), 5.44 (ddt, J ) 15.4, 6.8,
1.5 Hz, 1H), 5.75 (dtd, J ) 15.4, 7.0, 0.9 Hz, 1H); 7.24-7.36
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 14.1, 22.7, 29.1, 29.2,
29.3, 29.5, 29.57, 29.62, 29.65, 29.66, 31.9, 32.3, 51.4, 60.5, 61.6,
72.5, 127.1, 128.1, 128.5, 129.3, 134.0, 139.9; HRFABMS m/z
390.3373 (calcd for C25H44NO2: 390.3372).
D-erythro-Sphingosine [(2S,3R,4E)-2-Aminooctadec-4-
ene-1,3-diol] (3). A mixture of 23 (127 mg, 0.26 mmol) and a
1.0 M solution of TBAF in THF, (0.3 mL, 0.30 mmol) was
stirred 25 °C for 1.5 h and concentrated. The residue was
dissolved in EtOH (2.1 mL) and then stirred with 2 N NaOH
aq (2.1 mL) at 80 °C for 2.5 h. Conventional workup afforded
3 (103 mg) as colorless solids, which was subjected to acety-
lation without further purification; 1H NMR (400 MHz, CDCl3)
δ 0.88 (t, J ) 7.0 Hz, 3H), 1.26-1.47 (m, 22H), 2.01 (dt, J )
6.8, 6.8 Hz, 2H), 2.86 (br dt, J ) 5.8, 4.7 Hz, 1H), 3.62 (dd, J
) 10.7, 5.8 Hz, 1H), 3.70 (dd, J ) 10.7, 4.7 Hz, 1H), 4.04 (dd,
J ) 6.6, 6.6 Hz, 1H), 5.48 (ddt, J ) 15.4, 7.1, 1.5 Hz, 1H), 5.72
(dtd, J ) 15.4, 7.0, 0.7 Hz, 1H). [ref 20: 1H NMR (CDCl3) δ
0.88 (t, J ) 7.0 Hz, 3H), 1.15-1.4 (m, 22H), 2.06 (q, J ) 7.0 Hz,
2H), 2.89 (m, 1H), 3.67 (m, 2H), 4.04 (t, J ) 6.3 Hz, 1H), 5.48
(dd, J ) 15.3, 7.1 Hz, 1H), 5.76 (dt, J ) 15.3, 6.7 Hz, 1H)].
D-erythro-Sphingosine Triacetate 24. A mixture of crude
3 (103 mg, 0.26 mmol), Ac2O (0.16 mL, 1.70 mmol), DMAP
(6.4 mg, 0.05 mmol), and pyridine (0.35 mL, 4.33 mmol) in
CH2Cl2 (3.5 mL) was stirred at 25 °C for 3 h. Conventional
workup followed by recrystallization from n-hexane/AcOEt
afforded 24 as a colorless solid (105 mg, 93%); mp 100-102
°C; [R]24D -13.0 (c 1.6, CHCl3); IR (KBr) υmax 3288, 1736 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J ) 7.0 Hz, 3H), 1.25-
1.36 (m, 22H), 1.99 (s, 3H), 2.07 (s, 3H), 2.07 (s, 3H), 2.01-
2.06 (m, 2H), 4.04 (dd, J ) 11.6, 3.8, Hz, 1H), 4.31 (dd, J )
11.6, 6.0 Hz, 1H), 4.43 (dddd, J ) 9.0, 6.0, 6.0, 3.8 Hz, 1H),
5.28 (dd, J ) 7.5, 6.0 Hz, 1H), 5.39 (ddt, J ) 15.3, 7.5, 1.1 Hz,
1H), 5.66 (d, J ) 9.0 Hz 1H), 5.79 (dt, J ) 15.3, 7.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 14.0, 20.7, 21.0, 22.6, 23.2, 28.8,
29.0, 29.2, 29.3, 29.46, 29.52, 29.536, 29.543, 29.6, 31.8, 32.2,
50.6, 62.5, 73.7, 124.1, 137.2, 169.7, 169.9, 170.8; HRFABMS
m/z 426.3208 (calcd for C24H44NO5: 426.3219). Anal. Calcd for
C24H43NO5: C, 67.73; H, 10.18; N, 3.29. Found: C, 67.99; H,
(1′R,2′E,4S)-3-Benzyl-4-(1-triisopropylsilanyloxyhexa-
dec-2-enyl)-1,3-oxazolidin-2-one (22). A mixture of 20 (233
mg, 0.43 mmol) and Im2CO (73 mg, 95% purity, 0.43 mmol)
in CH2Cl2 (1 mL) was stirred at 25 °C for 12 h. After
concentration the residue was purified by column chromatog-
raphy (SiO2, n-hexane/AcOEt ) from 10:1 to 5:1) to afford 22
as a colorless oil (237 mg, 97%): chiral HPLC [CHIRALCEL
OD-H, n-hexane/2-propanol ) 100: 1; flow rate ) 1.0 mL/ min;
detection wavelength ) 254 nm; tR (minor) ) 10.6 min, tR
10.37; N, 3.31. [ref 20 mp 101-102 °C; [R]25 -13.3 (c 1.4,
D
CHCl3); 1H NMR (CDCl3) δ 0.88 (t, J ) 7.0 Hz, 3H), 1.15-1.4
(m, 22H), 1.95-2.1 (m, 11H; Me peaks at 1.98, 2.06, 2.07), 4.04
(dd, J ) 11.5, 3.8, Hz, 1H), 4.30 (dd, J ) 11.5, 6.0 Hz, 1H),
4.38-4.48 (m, 1H), 5.28 (t, J ) 7.0 Hz, 1H), 5.38 (dd, J ) 15.0,
7.4, 1.1 Hz, 1H), 5.68 (d, J ) 9.0 Hz 1H; NH), 5.79 (dt, J )
15.0, 7.0 Hz, 1H); 13C NMR (CDCl3) δ 14.1, 20.8, 21.1, 22.7,
23.3, 28.9, 29.1, 29.3, 29.4, 29.6, 31.9, 32.3, 50.6, 62.5, 73.7,
124.0, 137.2, 169.6, 169.8, 170.7].
(major) ) 13.0 min], 92% ee; [R]25 -11.4 (c 2.4, CHCl3); IR
D
1
(film) υmax 1757 cm-1; H NMR (400 MHz, CDCl3) δ 0.88 (t, J
) 7.0 Hz, 3H), 1.02-1.13 (m, 21H), 1.22-1.36 (m, 22H), 2.01
(br dt, J ) 6.8, 6.8 Hz, 2H), 3.60 (ddd, J ) 9.0, 5.3, 2.8 Hz,
1H), 4.15 (d, J ) 15.2 Hz, 1H), 4.18 (dd, J ) 9.0, 8.8 Hz, 1H),
4.27 (dd, J ) 8.8, 5.3 Hz, 1H), 4.34 (dd, J ) 7.7, 2.6 Hz, 1H),
4.96 (d, J ) 15.2 Hz, 1H), 5.32 (br dd, J ) 15.6, 7.7 Hz, 1H),
5.66 (dt, J ) 15.6, 6.8 Hz, 1H), 7.28-7.37 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 12.5, 14.1, 18.02, 18.03, 22.7, 28.8, 29.2,
29.3, 29.4, 29.57, 29.62, 29.64, 29.65, 31.9, 32.2, 46.3, 59.1, 63.2,
73.1, 127.8, 127.9, 128.0, 128.7, 135.4, 136.0, 158.9; HRFABMS
m/z: 572.4515 (calcd for C35H62NO3Si: 572.4499).
(1′R,2′E,4S)-4-(1-Triisopropylsilanyloxyhexadec-2-enyl)-
1,3-oxazolidin-2-one (23). A solution of 22 (118 mg, 0.21
mmol) in Et2O (3.2 mL) was slowly added to a solution of Li
(60 mg, 8.7 mmol) in liquid ammonia (12 mL) at -70 °C under
argon and the whole was stirred at same temperature for 5
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research (14370717) from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: The spectral data
of aziridines in Tables 1 and 2 except entries 1 and 3 in Table
2 and Experimental procedures except for the preparation of
the leucinate (Scheme 2) and the synthesis of D-erythro-
sphingosine from trans-aziridine (Schemes 3 and 4). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO051495J
9406 J. Org. Chem., Vol. 70, No. 23, 2005