Stereoselective synthesis of trans-olefins by the copper-mediated SN2′ reaction of vinyl oxazines with Grignard reagents. Asymmetric synthesis of d-threo-sphingosines

Article abstract of DOI:10.1016/j.tetlet.2007.01.145

The S_N2′ reaction of 6-vinyl-5,6-dihydro-4H-[1,3]oxazines with Grignard reagents in the presence of CuCN was studied, and high trans selectivity for the formation of double bond was observed with a variety of RMgX. The S_N2′ reaction,

Full text of DOI:10.1016/j.tetlet.2007.01.145

Tetrahedron Letters 48 (2007) 2345–2348
Stereoselective synthesis of trans-olefins by the copper-
mediated SN20 reaction of vinyl oxazines with Grignard
reagents. Asymmetric synthesis of D-threo-sphingosines
Om V. Singh and Hyunsoo Han*
Department of Chemistry, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA
Received 29 November 2006; revised 22 January 2007; accepted 25 January 2007
Available online 30 January 2007
Abstract—The SN20 reaction of 6-vinyl-5,6-dihydro-4H-[1,3]oxazines with Grignard reagents in the presence of CuCN was studied,
and high trans selectivity for the formation of double bond was observed with a variety of RMgX. The SN20 reaction, coupled with
regioselective asymmetric aminohydroxylation reaction, provided a highly efficient route for the asymmetric synthesis of D-threo-N-
acetylsphingosine.
ꢀ 2007 Elsevier Ltd. All rights reserved.
2-Vinyloxiranes,1
5-vinyloxazolines/oxazolidinones,2
Ac
N
E
and 2-vinylaziridines3 are versatile synthetic intermedi-
ates in organic synthesis, and have been extensively
studied. These compounds have been shown to undergo
a variety of different reactions, depending upon their
structures, the nature of reagents used, and reaction
conditions. For example, 2-vinyloxiranes react with al-
base
E+
I
R1
R2
N
O
N
O
a
b
R1
R1
III
R2
R2
:Nu- via SN2
II
:Nu- via SN2'
MLm
NH
e
d
1f
c
:Nu-
kyl lithiums in the presence of BF3ÆOEt2 or Grignard
Ac
Ac
R1
Ac
reagents1k to give the SN2 products, whereas their reac-
tions with organocopper reagents afford the SN20 prod-
ucts.1i Also known is that 2-vinyloxiranes and 5-
vinyloxazolines/oxazolidinones can react with transition
metal complexes to form transition metal–p-allyl inter-
mediates, which in turn react with nucleophiles to fur-
nish ‘branched’ and ‘linear’ products.1d,j,2
Nu
MLn
NH Nu
NH
:Nu-
R1
g
R1
f
R2
VI
R2
R2
IV
V
π-allyl complex
Figure 1. Potential reactions of the 6-vinyl-5,6-dihydro-4H-[1,3]oxa-
zines I.
We recently reported a convenient route for the asym-
metric synthesis of 6-vinyl-5,6-dihydro-4H-[1,3]oxazines
I.4 By comparing the structures of I, 2-vinyloxiranes,
and 5-vinyloxazolines/oxazolidinones, it was noticed
that they all shared two common structural features,
the terminal vinyl group and the good leaving ability
at the allylic position, and thus should exhibit similar
reactivity patterns (reaction paths c–g, Fig. 1). In addi-
tion, after deprotonation by a base, I can react with
an electrophile to give a higher homolog (reaction path
a in Fig. 1).5 Compound I may also undergo a formal
[3,3]-rearrangement to N-acetyl protected piperidine
derivatives under appropriate reaction conditions (reac-
tion path b in Fig. 1).6 Despite such synthetic versatility,
the chemistry of the vinyl oxazine I has not been ex-
plored much to date. In this Letter, we report the novel
SN20 reaction of vinyl oxazines I with Grignard reagents
in the presence of CuCN, which proceeds with high
trans selectivity for double bond formation.7 Also re-
ported is an efficient asymmetric synthesis of D-threo-
N-acetyl-sphingosine, which utilizes the developed SN20
reaction and regioselective asymmetric aminohydroxyl-
ation reaction8 to stereoselectively introduce the requisite
Keywords: Sphingosine; Regioselective asymmetric aminohydroxyl-
ation; Oxazine; SN20 Reaction; Grignard reagents.
*
Corresponding author. Tel.: +1 210 458 4958; fax: +1 210 458 7428;
e-mail: hyunsoo.han@utsa.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.145

2346
O. V. Singh, H. Han / Tetrahedron Letters 48 (2007) 2345–2348
trans double bond and vicinal aminoalcohol functional-
ities, respectively.
four step reaction sequence of regioselective asymmetric
aminohydroxylation, PMB-protection, DIBAL reduc-
tion, and vinylation.4 Alcohol 2 was obtained as a 5:1
mixture of 3 and its C3 epimer. Treatment of 2 with
mesyl chloride in the presence of excess triethylamine
at 0 ꢁC directly afforded oxazine 4.
As shown in Figure 2, the vinyl oxazines may exist in
two conformers I and I0. Assuming that the reaction
of the vinyl oxazines with soft nucleophiles proceeds
through SN20 mechanism, conformer I should lead to
trans double bond formation, while cis double bond for-
mation is expected from conformer I0. Due to steric
repulsion between the terminal @CH2 group and R2 in
conformer I0, conformer I would be more stable and
thus more abundant in the equilibrium. Furthermore,
attack of a soft nucleophile on conformer I0 would be
kinetically less favorable due to the steric hindrance be-
tween the R2 and the incoming nucleophile. Therefore,
trans selectivity is anticipated from the reaction between
the vinyl oxazines and soft nucleophiles such as Grig-
nard reagents in the presence of CuCN.
As a proof of our approach, the reaction of oxazine 4
with dodecylmagnesium bromide in the presence of
20 mol % (relative to the amount of the Grignard
reagent used) CuCN was attempted. Gratifyingly, the
reaction proceeded well to provide the protected
D-threo-C18-sphingosine 7a in a good yield and with a
high trans:cis selectivity (ꢀ10:1) (Table 1, entry 1).9
CuCN was found to be crucial for the reaction, since
no reaction was observed in the absence of CuCN.
Next, it was reasoned that the stereochemistry at the
allylic position (C6 of the oxazine ring) might also influ-
ence on the stereochemical outcome of the reaction.
Thus, the optically pure vinyl oxazines 5 and 6 were pre-
pared from alcohol 3, which was obtained from 2 by col-
umn separation (Scheme 1). Refluxing 3 in the presence
of a catalytic amount of p-toluenesulfonic acid in tolu-
ene furnished vinyl oxazine 5 with retention of the con-
figuration at C6.4 On the other hand, treatment of 3 with
mesyl chloride and excess Et3N generated vinyl oxazine
6 with the inverted C6 configuration.4 When vinyl oxa-
zines 5 and 6 were subjected to the above reaction con-
ditions, indeed, they showed different trans:cis
selectivities in the formation of the protected D-threo-
C18-sphingosine product, with 5 being more trans selec-
tive (>15:1) than 6 (ꢀ8:1) (Table 1, entries 2–3).
Scheme 1 describes the asymmetric synthesis of vinyl
oxazines 4–6, which commenced with achiral a,b-unsat-
urated ester 1. Compound 1 was converted to the com-
mon synthetic precursor 2 for vinyl oxazines 4–6
according to the literature procedure, which included a
N
O
N
O
R1
R1
:Nu-
R2
R2
I'
I
:Nu-
Ac
R1
Ac
R1
NH
NH
The different trans selectivities of two C6 epimeric vinyl
oxazines 5 and 6 in the SN20 reactions may be rational-
ized by considering the equilibriums between conform-
ers VII and VII0 for 6, and between conformers VIII
and VIII0 for 5 (Fig. 3). Due to steric repulsion caused
by the endo terminal @CH2 group, conformers VII
and VIII will be more stable than conformers VII0 and
Nu
R2
trans-isomer
R2
cis-isomer
Nu
Figure 2. Cis and trans selectivities of the SN20 reaction.
O
Ac
MsCl
Et3N
Table 1. SN20 Reactions of vinyl oxazines 4–6 with Grignard reagents
in the presence of CuCN in ethyl ether at 0 ꢁC
OEt
NH OH
3
ref 4
O
PMPO
0 oC to rt
85%
1
Ac
2
RMgBr
20 mol% CuCN
Et2O, 0 oC
OPMB
NH
OMe
4-6
cis-isomer
column
separation
PMPO
7a-e
Entry Oxazines Product R=
+
R
OPMB
Ac
Yields Trans:cisa
(%)
N
O
NH OH
3
PMPO
PMPO
1
2
3
4
5
6
7
8
4
6
5
5
5
5
5
5
7a
7a
7a
7b
7c
7d
7e
—
–(CH2)11CH3 82
–(CH2)11CH3 80
–(CH2)11CH3 85
ꢀ10:1
8:1
3
4
OPMB
OPMB
MsCl, Et3N,
0 oC to rt, 85%
>15:1
>15:1
>15:1
>15:1
>15:1
–CH2CH3
50
p
–(CH2)4CH3 80
–(CH2)9CH3 82
–(CH2)13CH3 82
N
O
N
O
NRb
PMPO
PMPO
–CH(CH3)2
6
6
a The ratio of trans:cis was determined by the 1H NMR of the reaction
mixture.
b NR: no reaction.
5
6
OPMB
OPMB
Scheme 1. Asymmetric synthesis of vinyl oxazines 4–6.

O. V. Singh, H. Han / Tetrahedron Letters 48 (2007) 2345–2348
2347
C11H23MgBr in the presence of 20 mol % CuCN pro-
duced 7a. Deprotection of both PMP- and PMB-groups
by ceric ammonium nitrate (CAN)14 in acetonitrile–
water (4:1) provided D-threo-N-acetyl-C18-sphingosine
(8), whose structure was confirmed by converting it to
triacetate 9 and comparing with the corresponding
known compound.15 Finally, it is worthwhile mention-
ing that given the fact that the C3 stereochemistry of
sphingosines can be easily controlled,16 the correspond-
ing L-erythro-N-acetyl-C18-sphingosine should be syn-
thesized by applying the same synthetic route.
6:
O
O
N
N
H
OPMP
H
H
OPMP
H
H
H
OPMB
VII
VII'
Nu:
OPMB
H
H
5:
N
N
O
O
H
H
PMPO
PMPO
H
H
VIII
H
H
H
Nu:
H
PMBO
PMBO
VIII'
In conclusion, we have demonstrated that the reaction
of the vinyl oxazines with Grignard reagents in the pres-
ence of CuCN proceeded via the SN20 mechanism, and
excellent trans selectivity for the formation of double
bond was observed. Also described was that the devel-
oped SN20 reaction, combined with the regioselective
asymmetric aminohydroxylation reaction of olefins,
could provide an efficient and convenient asymmetric
route for the synthesis of sphingosine derivatives. Stud-
ies toward other possible reactions of the vinyl oxazines
are currently under progress in our laboratory, and will
be reported in due course.
cis-isomer
trans-isomer
Figure 3. A plausible explanation for the trans selectivity of the SN20
reaction of the vinyl oxazines 5 and 6.
VIII0. Such steric hindrance will be particularly severe in
conformer VIII0, where both PMPOCH2- and PMBO-
groups are in close proximity to the endo terminal
@CH2 group. This will shift the equilibrium for 5 to-
ward conformer VIII more relative to the equilibrium
for 6. Moreover, approach of the nucleophile to con-
formers VII0 and VIII0 for the SN20 reaction would be
severely retarded due to the steric hindrance between
the incoming nucleophile and the oxazine ring, and the
up-stereochemistry of both PMPOCH2- and PMBO-
groups in conformer VIII0 would further disfavor such
approach of the nucleophile. Therefore, 5 should be
more trans selective than 6.
Acknowledgements
Financial support from National Institute of Health
(GM 08194) and The Welch Foundation (AX-1534) is
gratefully recognized.
Now with the right C6 stereochemistry and reaction
conditions established, the generality of the SN20 reac-
tion was examined with vinyl oxazine 5 and Grignard re-
agents with different chain length (C2–C14) in the
presence of 20 mol % CuCN. As shown in Table 1, all
linear chain Grignard reagents produced the corre-
sponding protected D-threo-sphingosines (7a–e)10 with
excellent trans selectivities and good reaction yields (en-
tries 3–7). However, a branched Grignard reagent failed
to react (entry 8), and PhMgBr and vinyl-MgBr did not
react under the conditions. Use of other cuprate
reagents such as Gilman’s and higher-order cuprates,
which contain branched alkyl groups, also proved to
be fruitless.11
References and notes
1. (a) Restorp, P.; Somfai, P. Eur. J. Org. Chem. 2005, 3946–
3951; (b) Smith, A. B.; Pitram, S. M.; Boldi, A. M.; Gaunt,
M. J.; Sfouggatakis, C.; Moser, W. H. J. Am. Chem. Soc.
2003, 125, 14435–14445; (c) Equey, O.; Vrancken, E.;
Alexakis, A. Eur. J. Org. Chem. 2004, 2151–2159; (d)
Trost, B. M.; Jiang, C. J. Am. Chem. Soc. 2001, 123,
12907–12908; (e) Bertozzi, F.; Crotti, P.; Macchia, F.;
Pineschi, M.; Feringa, B. L. Angew. Chem., Int. Ed. 2001,
40, 930–932; (f) Alexakis, A.; Vrancken, E.; Mangeney, P.;
Chemla, F. J. Chem. Soc., Perkin Trans. 1 2000, 3352–
3353; (g) Lipschutz, B. H.; Woo, K.; Gross, T.; Buzard, D.
J.; Tirado, R. Synlett 1997, 477–478; (h) Jung, M. E.;
D’Amico, D. C. J. Am. Chem. Soc. 1995, 117, 7379–7388;
For a review: (i) Marshall, J. A. Chem. Rev. 1989, 89,
1503–1511; (j) Tsuji, J.; Kataoka, H.; Kobayashi, Y.
Tetrahedron Lett. 1981, 22, 2575–2578; (k) Herr, R. W.;
Johnson, C. R. J. Am. Chem. Soc. 1970, 92, 4979–4981.
2. (a) Cook, G. R.; Saraswathiamma, M. Tetrahedron Lett.
2005, 46, 6491–6494; (b) Cook, G. R.; Yu, H.; Sankara-
narayanan, S.; Shanker, P. S. J. Am. Chem. Soc. 2003, 125,
5115–5120; (c) Cook, G. R.; Pararajasingham, K. Tetra-
hedron Lett. 2002, 43, 9027–9029; (d) Oishi, S.; Niida, A.;
Kamano, T.; Odagaki, Y.; Tamamura, H.; Otaka, A.;
Hamanaka, H.; Fujii, N. Org. Lett. 2002, 4, 1055–1058; (e)
Otaka, A.; Katagiri, F.; Kinoshita, T.; Odagaki, Y.; Oishi,
S.; Tamamura, H.; Hamanaka, N.; Fujii, N. J. Org. Chem.
2002, 67, 6152–6161.
The developed SN20 reaction can be easily applied to the
asymmetric synthesis of sphingosines, which are ubiqui-
tous membrane constituents of eukaryotic cells and have
been reported to exhibit a variety of structural and reg-
ulatory functions.12,13 Scheme 2 describes the asymmet-
ric synthesis of D-threo-N-acetyl-C18-sphingosine (8).
Thus, the trans selective SN20 reaction of oxazine 5 with
Ac
C
12H25MgBr,
CAN,
MeCN-H2O
NH
CuCN, 0 oC
PMPO
(CH2)12CH3
5
85%
83%
7a
OPMB
Ac
Ac
NH
NH
3
Ac2O
AcO
(CH2)12CH3
HO
(CH2)12CH3
DMAP
99%
3. (a) Cantrill, A. A.; Jarvis, A. N.; Osborn, H. M. I.; Ouadi,
A.; Sweeney, J. B. Synlett 1996, 847–849; (b) Tammura,
H.; Yamashita, M.; Nakajima, Y.; Sakano, K.; Otaka, A.;
9
8
OAc
OH
Scheme 2. Asymmetric synthesis of D-threo-N-acetylsphingosine (8).

2348
O. V. Singh, H. Han / Tetrahedron Letters 48 (2007) 2345–2348
Ohno, H.; Ibuka, T.; Fujii, N. J. Chem. Soc., Perkin
115.64, 114.69, 113.80, 76.69, 70.06, 66.86, 55.69, 55.15,
Trans. 1 1999, 2983–2996, and references cited therein; For
a review: (c) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247–
258.
52.30, 34.29, 23.18, 22.25, 13.49. Compound 7c: mp = 40–
25
41 ꢁC; ½aꢁD ꢂ59.7 (c 1.3, CH2Cl2); 1H NMR (500 MHz,
CDCl3): d 7.18 (d, 2H, J = 8.5 Hz), 6.82–6.80 (m, 6H),
5.87 (d, 1H, J = 8.7 Hz), 5.73 (dt, 1H, J = 6.5, 15.4 Hz),
5.41 (dd, 1H, J = 8.5, 15.6 Hz), 4.53 (d, 1H, J = 12 Hz),
4.32–4.25 (m, 2H), 4.13 (dd, 1H, J = 3.0, 8.5 Hz), 3.97–
3.90 (m, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 2.11–2.04 (m, 2H),
1.99 (s, 3H), 1.40–1.35 (m, 2H), 1.32–1.25 (m, 6H), 0.89 (t,
3H, J = 6.8 Hz); 13C NMR (75 MHz, CDCl3): d 169.80,
159.32, 154.10, 152.83, 136.00, 130.35, 129.46, 126.68,
115.69, 114.72, 113.83, 76.77, 70.09, 66.89, 55.72, 55.20,
52.33, 32.27, 31.64, 29.12, 28.79, 23.23, 22.55, 13.98.
4. Singh, O. V.; Kampf, D. J.; Han, H. Tetrahedron Lett.
2004, 45, 7239–7242.
5. (a) Toshimitsu, A.; Terao, K.; Uemura, S. J. Org. Chem.
1987, 52, 2018–2026; (b) Adickes, H. W.; Politzer, I. R.;
Meyers, A. I. J. Am. Chem. Soc. 1969, 91, 2155–2156.
6. (a) Wang, C.-L. J.; Calabresse, J. C. J. Org. Chem. 1991,
56, 4341–4343; (b) Overman, L. E. Angew. Chem., Int. Ed.
Engl. 1984, 23, 579–586; (c) Knapp, S.; Patel, D. V.
Tetrahedron Lett. 1982, 23, 3539–3542.
25
7. For a review of SN20 reactions: Kar, A.; Argade, N. P.
Synthesis 2005, 2995–3022.
Compound 7d: mp = 49–50 ꢁC; ½aꢁD ꢂ46.89 (c 1.22,
CH2Cl2); 1H NMR (500 MHz, CDCl3): d 7.18 (d, 2H,
J = 8.9 Hz), 6.82–6.81 (m, 6H), 5.85 (d, 1H, J = 8.7 Hz),
5.73 (dt, 1H, J = 6.0, 15.5 Hz), 5.41 (dd, 1H, J = 8.1,
15.6 Hz), 4.53 (d, 1H, J = 11.3 Hz), 4.31–4.25 (m, 2H),
4.13 (dd, 1H, J = 3.0, 8.0 Hz), 3.97–3.90 (m, 2H), 3.78 (s,
3H), 3.76 (s, 3H), 2.07 (q, 2H, J = 7.2 Hz), 1.99 (s, 3H),
1.41–1.35 (m, 2H), 1.26 (s, 16H), 0.88 (t, 3H, J = 6.8 Hz);
13C NMR (75 MHz, CDCl3): d 169.97, 159.17, 153.88,
152.63, 136.24, 130.16, 129.53, 129.40, 126.39, 115.49,
114.54, 113.72, 69.93, 66.57, 55.67, 55.19, 52.18, 32.34,
31.90, 29.64, 29.48, 29.35, 29.17, 23.36, 22.67, 14.11.
8. (a) Han, H.; Cho, C. W.; Janda, K. D. Chem. Eur. J. 1999,
5, 1565–1569; see, for other similar approaches: (b)
Morgan, A. J.; Masse, C. E.; Panek, J. S. Org. Lett.
1999, 1, 1949–1952; (c) Chuang, C.-C.; Vassar, V.; Ma, Z.;
Geney, R.; Ojima, I. Chirality 2002, 14, 151–162; For
initial studies: (d) Li, G.; Chang, H.-T.; Sharpless, K. B.
Angew. Chem., Int. Ed. 1996, 35, 451–454; (e) Rudolph, J.;
Sennhenn, P. C.; Vlaar, C. P.; Sharpless, K. B. Angew.
Chem., Int. Ed. 1996, 35, 2810–2813; (f) Bruncko, M.;
Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int. Ed.
1997, 36, 1483–1486.
25
Compound 7e: mp = 67–68 ꢁC; ½aꢁD ꢂ40.5 (c 1.2,
9. General procedure for the copper-mediated SN20 reaction of
vinyl oxazine with Grignard reagents: A flame dried two-
necked flask was charged with cuprous cyanide (8.5 mg,
0.1 mmol) and dry ether (10 mL) under nitrogen atmo-
sphere. The reaction flask was cooled to 0 ꢁC in ice–salt
mixture and a solution of Grignard reagent in ether (1 M,
0.5 mL, 0.5 mmol) was added dropwise. After stirring for
10 min, a solution of vinyl oxazine (79 mg, 0.2 mmol) in
ether was added dropwise through cannula for 10 min.
The reaction mixture was stirred for an additional hour,
and then brought to room temperature and stirred for
another 1 h. After the complete disappearance of the
starting material on TLC, the brownish reaction mixture
was quenched with saturated ammonium chloride,
extracted with ethyl ether (3 · 20 mL), washed with water,
and dried over anhydrous sodium sulfate. The solvents
were removed in vacuo and the residue was purified by
flash column chromatography on silica gel (ethyl acetate–
hexane, 3:1) to afford the respective protected N-acetyl-
sphingosines 7a–e.
CH2Cl2); 1H NMR (500 MHz, CDCl3): d 7.18 (d, 2H,
J = 8.2 Hz), 6.82–6.81 (m, 6H), 5.84 (d, 1H, J = 8.5 Hz),
5.73 (dt, 1H, J = 6.7, 15.5 Hz), 5.41 (dd, 1H, J = 7.6,
15.6 Hz), 4.53 (d, 1H, J = 11.0 Hz), 4.31–4.25 (m, 2H),
4.13 (dd, 1H, J = 3.0, 7.5 Hz), 3.97–3.90 (m, 2H), 3.78 (s,
3H), 3.77 (s, 3H), 2.07 (q, 2H, J = 7.4 Hz), 1.99 (s, 3H),
1.41–1.35 (m, 2H), 1.26 (s, 24H), 0.88 (t, 3H, J = 6.5 Hz);
13C NMR (75 MHz, CDCl3): d 169.81, 159.35, 154.12,
152.84, 136.07, 130.37, 129.49, 126.67, 115.70, 114.75,
113.86, 76.79, 70.12, 66.91, 55.75, 55.23, 52.34, 32.32,
31.92, 29.69, 29.50, 29.22, 23.28, 22.67, 14.03.
11. (a) Lipshutz, B. H. Synlett 1990, 119–128; (b) Spino, C.;
Beaulieu, C.; Lafreniere, J. J. Org. Chem. 2000, 65, 7091–
7097.
12. For the biological activities of sphingosines: (a) Merrill, A.
H., Jr.; Sweeley, C. C. In Biochemistry of Lipids, Lipopro-
teins and Membranes; Vance, D. E., Vance, J. E., Eds.;
Elsevier Science B.V.: Amsterdam, 1996; Chapter 12, pp
309–339; (b) Kolter, T.; Sandhoff, K. Angew. Chem. Int.
Ed. 1999, 38, 1532–1568; (c) Hannun, Y. A. Sphingolipid-
Mediated Signal Transduction; R.G. Landes Company:
Austin, 1997.
25
10. Characterization data 7a: Mp = 62–63 ꢁC; ½aꢁD ꢂ44.5 (c
1
1.2, CHCl3); H NMR (500 MHz, CDCl3): d 7.18 (d, 2H,
J = 9.0 Hz), 6.82–6.81 (m, 6H), 5.86 (d, 1H, J = 8.6 Hz),
5.73 (dt, 1H, J = 7.0, 16.0 Hz), 5.41 (dd, 1H, J = 8.0,
15.6 Hz), 4.53 (d, 1H, J = 10.5 Hz), 4.31–4.25 (m, 2H),
4.13 (dd, 1H, J = 3.0, 8.0 Hz), 3.97–3.90 (m, 2H), 3.78 (s,
3H), 3.77 (s, 3H), 2.07 (q, 2H, J = 7.4 Hz), 1.99 (s, 3H),
1.44–1.35 (m, 2H), 1.26 (s, 20H), 0.88 (t, 3H, J = 6.7 Hz);
13C NMR (75 MHz, CDCl3): d 169.78, 159.29, 154.05,
152.78, 135.99, 130.29, 129.43, 126.60, 115.64, 114.67,
113.78, 70.04, 66.84, 55.67, 55.14, 52.28, 32.24, 31.84,
29.59, 29.42, 29.14, 23.15, 22.57, 13.93. Compound 7b:
13. For reviews on the synthesis of sphingosines: (a) Koski-
nen, P. M.; Koskinen, A. M. P. Synthesis 1998, 1075–
1091; (b) Vankar, Y. D.; Schmidt, R. R. Chem. Soc. Rev.
2000, 29, 201–216; For more recent syntheses: (c) Chaud-
hari, V. D.; Kumar, K. S. A.; Dhavale, D. D. Org. Lett.
2005, 7, 5805–5807; (d) Rai, A. N.; Basu, A. Org. Lett.
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25
1
½aꢁD ꢂ50.0 (c 1.3, CH2Cl2); H NMR (500 MHz, CDCl3):
d 7.18 (d, 2H, J = 9.0 Hz), 6.82–6.80 (m, 6H), 5.88 (d, 1H,
J = 8.8 Hz), 5.73 (dt, 1H, J = 6.4, 15.4 Hz), 5.42 (dd, 1H,
J = 7.6, 15.6 Hz), 4.54 (d, 1H, J = 11.5 Hz), 4.32–4.25 (m,
2H), 4.14 (dd, 1H, J = 3.0, 8.0 Hz), 3.97–3.91 (m, 2H),
3.77 (s, 3H), 3.76 (s, 3H), 2.08–2.04 (m, 2H), 1.99 (s, 3H),
1.42 (d hexate, 2H, J = 1.5, 7.0 Hz), 0.91 (t, 3H,
J = 7.0 Hz); 13C NMR (75 MHz, CDCl3): d 169.77,
159.29, 154.05, 152.78, 135.61, 130.29, 129.43, 126.88,
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