Divergent synthesis of D-erythro-sphingosine, L-threo-sphingosine, and their regioisomers

Article abstract of DOI:10.1021/jo0268254

Starting from a vinyl epoxide, a divergent synthesis of four sphingosine isomers is described. The remaining four isomers can easily be synthesized using the same methodology. Although numerous syntheses of sphingosine have been published, this is the first general route leading to all eight isomers in this important compound class. The synthetic strategy relies on regioselective opening of a vinyl epoxide and a vinylaziridine in the allylic position.

Full text of DOI:10.1021/jo0268254

Development of such a route would be a great simplifica-
tion for studies on structure-activity relationships of
these pharmacologically active derivatives. We recently
developed a strategy leading to all eight possible isomers
of a given 1,2-amino alcohol starting from a readily
synthesized substrate.4,5 In the present paper, this route
is applied to the synthesis of sphingosine (1) and its
diastereo- and regioisomers (2-4, Figure 1). The synthetic
strategy is depicted in Scheme 1 and starts from vinyl
epoxide 5. Ring opening of 5 with a nitrogen nucleophile
can be performed either with inversion or retention of
stereochemistry, giving anti- and syn-amino alcohols 6
and 7, respectively. Ring closure of 6 to the corresponding
vinylaziridine 8 and subsequent ring opening with an
oxygen nucleophile, either with inversion or retention,
would then give anti- and syn-amino alcohols 9 and 10,
all reactions taking place regioselectively at the allylic
position. If desired, the remaining set of enantiomeric
sphingosine isomers (ent-1 to ent-4) can simply be
obtained by starting from ent-5 (Figure 1).4,5
Diver gen t Syn th esis of
D-er yth r o-Sp h in gosin e, L-th r eo-Sp h in gosin e,
a n d Th eir Regioisom er s
Berit Olofsson and Peter Somfai*
Department of Chemistry, Organic Chemistry, Royal
Institute of Technology, S-100 44 Stockholm, Sweden
somfai@kth.se
Received December 9, 2002
Abstr a ct: Starting from a vinyl epoxide, a divergent syn-
thesis of four sphingosine isomers is described. The remain-
ing four isomers can easily be synthesized using the same
methodology. Although numerous syntheses of sphingosine
have been published, this is the first general route leading
to all eight isomers in this important compound class. The
synthetic strategy relies on regioselective opening of a vinyl
epoxide and a vinylaziridine in the allylic position.
Syn th esis of Vin yl Ep oxid e 5. We envisaged the
synthesis to begin with commercially available tetrade-
canol, which could be transformed into 5 in four steps
(Scheme 2). A Swern/Wittig procedure would give un-
saturated ester 11, which is reduced to dienol 12.
Asymmetric epoxidation of this species is the key step of
the synthesis, as the enantioselectivity obtained will be
preserved throughout the remaining transformations
leading to 6, 7, 9, and 10. The reaction has previously
been attempted with Sharpless asymmetric epoxidation,
which led to decomposition.6 Instead, the epoxidation can
be accomplished using Shi’s catalyst 13, although this
would give rise to two regioisomeric vinyl epoxides (5 and
5′).7
Due to the lipid chain present throughout the reaction
scheme, solubility problems were often encountered at
low temperatures. Thus, diene ester 11 was formed in
poor yield and E/Z selectivity using the Swern/Wittig
protocol. Instead, oxidation was successfully conducted
with IBX at room temperaturefollowed by a modified
Horner-Emmons reaction using triethyl phosphonocro-
tonate and LiOH in refluxing THF.8 With this procedure,
11 was formed in quantitative crude yield and good E/Z
selectivity. In our experience, diene esters such as 11 are
unstable on silica, and reduction with DIBAL was
performed on the crude product. Hence, dienol 12 could
be isolated in 59% yield from tetradecanol. Benzylation
of 12 proved more difficult than expected, as the reaction
stopped before completion under standard conditions. As
E,E-hexadienol could be benzylated in 98% yield, the lipid
chain might be the origin of these problems.5 Extended
reaction time, increased temperature, excess reagents or
slow addition of 12 to avoid micelle formation all resulted
Glycosphingolipids are common membrane components
of all eucaryotic cells. The backbone of sphingolipids
consists of long-chain aliphatic 2-amino-1,3-diols, of
which D-erythro-sphingosine is the most common (1,
Figure 1). Recently, it has been shown that glycosphin-
gosines, as well as sphingosine itself, are important in
such diverse biological phenomena as cell-cell recogni-
tion and signaling within and between cells.1 Numerous
structurally related sphingoid base structures are present
in nature, which has led to an immense interest of this
compound class in medical research.
Sphingosine and its isomers have been targets of
synthetic interest for decades. Most asymmetric synthe-
ses rely on the chiral pool, although some publications
make use of asymmetric reactions to create the two
stereocenters.2 Divergent syntheses are rare, though
Hudlicky recently presented an elegant synthesis of
sphingosine and its diastereomers.3
To the best of our knowledge, no divergent route from
a common starting material toward all possible regio- and
stereoisomers of sphingosine has been documented.
* To whom correspondence should be addressed. Tel: +46-8-
7906960. Fax: +46-8-7912333.
(1) (a) Karlsson, K.-A. Trends Pharm. Sci. 1991, 12, 265-272. (b)
Liscowitch, M.; Lavie, Y. Trends. Glycosci. Glycothechn. 1990, 2, 470-
485. (c) Hannun, Y.; Bell, R. M. Science 1989, 243, 500-507.
(2) (a) Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998, 1075-
1091. (b) Trost, B. M.; Lee, C. B. J . Am. Chem. Soc. 1998, 120, 6818-
6819. (c) Chung, S.-K.; Lee, J .-M. Tetrahedron: Asymmetry 1999, 10,
1441-1444. (d) Hertweck, C.; Boland, W. J . Org. Chem. 1999, 64,
4426-4430. (e) Khiar, N.; Singh, K.; Garcia, M.; MartinLomas, M.
Tetrahedron Lett. 1999, 40, 5779-5782. (f) Nakamura, T.; Shiozaki,
M. Tetrahedron Lett. 1999, 40, 9063-9064. (g) Takikawa, H.; Nozawa,
D.; Kayo, A.; Muto, S.; Mori, K. J . Chem. Soc., Perkin Trans. 1 1999,
2467-2477. (h) Corey, E. J .; Choi, S. Tetrahedron Lett. 2000, 41, 2765-
2768. (i) Fernandes, R. A.; Kumar, P. Eur. J . Org. Chem. 2000, 3447-
3449. (j) Martin, C.; Prunck, W.; Bortolussi, M.; Bloch, R. Tetrahedron:
Asymmetry 2000, 11, 1585-1592. (k) Chun, J .; Li, G.; Byun, H.-S.;
Bittman, R. Tetrahedron Lett. 2002, 43, 375-377.
(4) Olofsson, B.; Khamrai, U.; Somfai, P. Org. Lett. 2000, 2, 4087-
4089.
(5) Olofsson, B.; Somfai, P. J . Org. Chem. 2002, 67, 8574-8583.
(6) Bernet, B.; Vasella, A. Tetrahedron Lett. 1983, 24, 5491-5494.
(7) (a) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J . Org.
Chem. 1998, 63, 2948-2953. (b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang,
J .-R.; Shi, Y. J . Am. Chem. Soc. 1997, 119, 11224-11235.
(8) Takacs, J . M.; J aber, M. R.; Clement, F.; Walters, C. J . Org.
Chem. 1998, 63, 6757-6760.
(3) (a) Nugent, T. C.; Hudlicky, T. J . Org. Chem. 1998, 63, 510-
520. (b) Shultz, M. D.; Kiessling, L. L. Abstracts of Papers. 222nd ACS
National Meeting, Chicago, IL, Aug 26-30, 2001; American Chemical
Society: Washington, DC, 2001; ORGN-055. (c) Lee, J .-M.; Lim, H.-
S.; Chung, S.-K. Tetrahedron: Asymmetry 2002, 13, 343-347.
10.1021/jo0268254 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/15/2003
2514
J . Org. Chem. 2003, 68, 2514-2517

F IGURE 1. All possible regio- and stereoisomers of sphingosine.
SCHEME 1. Syn th etic Str a tegy to
Ben zyl-P r otected Sp h in gosin e (9) a n d Th r ee
Isom er s (6, 7, a n d 10)
Syn th esis of a n ti-Am in o Alcoh ol 6. Ring-opening
of vinyl epoxide 5 was performed using our previously
developed aminolysis protocol.5 In this method, the
epoxide is heated in ammonium hydroxide to 125 °C for
1 h, which gives a diastereospecific and regioselective
opening in the allylic position. As noted in the reactions
discussed above, the reactivity of 5 was diminished
compared to similar substrates lacking a lipid chain.
When 5 was heated in ammonium hydroxide, 170 °C for
1 h was required for formation of amino alcohol 6. At
these rather severe conditions, an unidentified byproduct
was formed along with 6. As we suspected solubility
problems to be the reason for the low reactivity, a number
of cosolvents were investigated. DMF, THF, and DMSO
all resulted in a lowering of the required reaction tem-
perature; furthermore, the byproduct formation was sup-
pressed. THF was the cosolvent of choice, giving anti-
amino alcohol 6 in 98% yield in a completely regioselec-
tive reaction (>20:1).
Vinyl epoxide 5′ was also subjected to aminolysis in
ammonium hydroxide. Surprisingly, this compound was
even less reactive than 5, which might be explained by
the lipid chain being in closer proximity to the allylic
position than in 5. This finding caused us to investigate
if a mixture of vinyl epoxides 5 and 5′ could be used in
the aminolysis reaction. If conditions could be found
where only 5 reacts, separation of 5 and 5′ with subse-
quent loss of material could be avoided. Gratifyingly,
the reaction was completely selective toward formation
of 6 in NH4OH/THF at 110 °C for 3 h, which means that
vinyl epoxides 5 and 5′ need not be separated before
aminolysis.
in no improvement. Other procedures were scanned; both
Ag2O/BnBr9 and benzyl trichlorotriacetimidate/triflic
acid10 gave a complex mixture of products. Gratifyingly,
addition of Bu4NI to the original protocol gave benzylated
diene 14 in 95% yield.11
Shi’s epoxidation works well on protected dienols,
epoxidizing the most electron rich double bond in good
selectivity. We have previously used this reaction on
benzyl-protected E,E-hexadienol, which differs from diene
14 only by the length of the carbon chain (CH3 instead
of C13H27)
5 That epoxidation resulted in a 4:1 mixture of
regioisomers, favoring reaction at the 4,5-double bond.
Due to that result, we were doubtful if 5, which was
expected to be the minor isomer, could be formed in
synthetically useful yields with this method.
Syn th esis of syn -Am in o Alcoh ol 7. Pd(0)-catalyzed
ring-opening of vinyl epoxide 5 in the presence of tosyl
isocyanate gave oxazolidinone 15 in 75% yield with
retention of configuration (Scheme 3).5,13 Detosylation of
15 was performed by titration with sodium naphthalide
at -78 °C,14 and N-H oxazolidinone 16 could be isolated
in 88% yield. Basic hydrolysis of 16 resulted in syn-amino
alcohol 7 in nearly quantitative yield.
With diene 14 at hand, Shi’s epoxidation was per-
formed.7 Surprisingly, epoxides 5 and 5′ were formed in
1:1 ratio, i.e., in far better selectivity than expected (es
90-95%). Again, the difference in reaction outcome could
be due to the lipid chain, which might be shielding the
4,5-double bond. To get the reaction to completion,
stoichiometric amounts of the catalyst were needed. The
catalyst is believed to undergo Baeyer-Villiger oxidation
in the presence of Oxone, and Shi recently described a
method using hydrogen peroxide instead of Oxone to
avoid this.12 However, when used on 14 these conditions
failed to give any reaction. Vinyl epoxides are known to
be unstable on silica,7 and separation of epoxides 5 and
5′ was possible only at the expense of decreased yield.
When a mixture of vinyl epoxides 5 and 5′ were used
in this reaction sequence, the oxazolidinones could easily
be separated after detosylation, without loss in yield. This
renders separation of 5 and 5′ redundant, as both amino
alcohols 6 and 7 can be isolated in high yields without
interference of products corresponding to 5′.
(9) Bouzide, A.; Sauve´, G. Tetrahedron Lett. 1997, 38, 5945-5948.
(10) Fleming, I.; Lawrence, N. J . J . Chem. Soc., Perkin Trans. 1
1998, 17, 2679-2686.
(11) Kulkarni, B. A.; Sankaranarayanan, A.; Subbaraman, A. S.;
Chattopadhyay, S. Tetrahedron: Asymmetry 1999, 10, 1571-1577.
(12) Suhu, L.; Shi, Y. Tetrahedron 2001, 57, 5213-5218.
(13) Trost, B. M.; Sudhakar, A. R. J . Am. Chem. Soc. 1987, 109,
3792-3794.
(14) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J . Org.
Chem. 1989, 54, 1548-1562.
J . Org. Chem, Vol. 68, No. 6, 2003 2515

SCHEME 2. Syn th esis of Vin yl Ep oxid e 5
SCHEME 3. Rin g Op en in g of 5 w ith Reten tion of
Con figu r a tion
and gratifyingly also with complete regioselectivity
(>20:1). The latter can be rationalized by the stabilizing
effect of the vinyl group on the transition state, thus
favoring attack of the carbonyl oxygen at the allylic
position. Hydroxy amide 19 was hydrolyzed in 5% aque-
ous H2SO4, giving syn-amino alcohol 10 in good yield.
The synthesis was completed by removal of the ben-
zyl group from amino alcohols 6, 7, 9, and 10. This was
performed by means of sodium in liquid ammonia, giving
sphingosine isomers 3, 4, 1, and 2, respectively, in
excellent yields. Analysis data of isomers 1 and 2 were
in good agreement with literature data.16
SCHEME 4. F or m a tion a n d Rin g Op en in g of
Vin yla zir id in e 8
Deter m in ation of Relative Ster eoch em istr y. Amino
alcohols 6, 9, and 10 were converted to the corresponding
oxazolidinones. The ring protons (H4,H5) of these com-
pounds have coupling constants (J H4,H5) that are larger
for cis than trans configuration.17 When anti-amino
alcohols 6 and 9 were converted into oxazolidinones 20
and 21, the coupling constants of the ring protons were
8.2 and 8.4 Hz, respectively, which is consistent with the
cis configuration. Oxazolidinone 16 (Scheme 3), which
shows the relative configuration of syn-amino alcohol 7,
had a ring coupling constant of 6.8 Hz, confirming the
trans configuration. Finally, syn-amino alcohol 10 was
transformed to oxazolidinone 22, which had a coupling
constant of 6.8 Hz, in agreement with the trans config-
uration.
To conclude,the synthesis of four isomers of sphin-
gosine has been detailed, starting from vinyl epoxide 5.
The remaining four isomers are easily obtained with the
same methodology starting from ent-5. The synthetic
strategy focused on regioselective opening of vinyl epoxide
5 and vinylaziridine 8 in the allylic position. The syn-
thesis exemplifies the potential of our recently reported
synthetic route leading to all isomers of a given vic-amino
alcohol.
SCHEME 5. Rin g Op en in g of 8 w ith Reten tion of
Con figu r a tion
Syn th esis of Bn -P r otected D-er yth r o-Sp h in gosin e
9. The two remaining amino alcohols 9 and 10 are
regioisomers of 6 and 7. We envisaged the synthesis of 9
and 10 by regioselective ring opening of N-H vinylaziri-
dine 8, which can be obtained from anti-amino alcohol 6
by ring closure under Mitsunobu conditions (Scheme 4).15
As vinylaziridines are unstable on silica, crude 8 was
used in the following reactions. When aziridine 8 was
treated with trifluoroacetic acid, anti-amino alcohol 9 was
formed with complete diastereo- and regioselectivity
(>20:1) in 62% yield from 6.
Syn t h esis of Bn -P r ot ect ed L-th r eo-Sp h in gosin e
10. Ring-opening of aziridine 8 with retention of config-
uration would yield syn-amino alcohol 10. Our synthetic
strategy focused on an SNi rearrangement of N-acetyl-
aziridine 17 into oxazoline 18, followed by hydrolysis to
10 (Scheme 5).4 Acetylation of 8 proceeded in nearly
quantitative yield, and N-acetylaziridine 17 was used as
crude product in the subsequent reaction, as it was
unstable to standard purification. Rearrangement of 17
was performed with BF3‚OEt2 followed by in situ hy-
drolysis of 18 to hydroxy amide 19, which was isolated
in 43% yield from 6. The rearrangement proceeded, as
expected, with complete diastereoselectivity (dr >20:1)
Exp er im en ta l Section
This section contains synthesis procedures for formation of
compounds 1, 6-9, 15, and 19. For general experimental details,
see the Supporting Information.
D-er yth r o-Sp h in gosin e (1). NH3 (2 mL) was distilled over
Na and transferred to a vessel containing Na (excess) at -78
°C. Amino alcohol 9 (3.3 mg, 8.5 µmol) in Et2O (0.5 mL) was
added, and the mixture was stirred at -78 °C for 3 h, quenched
by addition of Et2O and saturated NH4Cl, and stirred at room
temperature for 2 h. Extrelut workup yielded amino diol 1 as a
(16) (a) Boutin, R. H.; Rapoport, H. J . Org. Chem. 1986, 51, 5320-
5327. (b) Solladie´-Cavallo, A.; Koessler, J . L. J . Org. Chem. 1994, 59,
3240-3242. (c) Lee, J .-M.; H.-S.; Chung, S.-K. Tetrahedron: Asymmetry
2002, 13, 343-347.
(17) Barrett, A. G. M.; Seefeld, M. A.; White, A. J . P. J . Org. Chem.
1996, 61, 2677-2685.
(15) Olofsson, B.; Wijtmans, R.; Somfai, P. Tetrahedron 2002, 58,
5979-5982.
2516 J . Org. Chem., Vol. 68, No. 6, 2003

white, waxy solid in 92% yield (2.3 mg, 7.8 µmol): mp 73-75
°C; 1H NMR (400 MHz, CDCl3) δ 5.77 (dt, 1H, J ) 15.4, 6.7 Hz),
5.48 (dd, 1H, J ) 15.4, 7.2 Hz), 4.04 (br t, 1H, J ) 6.4 Hz), 3.69
(dd, 1H, J ) 10.9, 4.7 Hz), 3.62 (dd, 1H, J ) 10.9, 6.0 Hz), 2.87
(dt, 1H, J ) 6.0, 4.7 Hz), 2.06 (q, 2H, J ) 6.9 Hz), 1.64 (br s,
4H), 1.37 (m, 2H), 1.26 (m, 20H), 0.88 (t, 3H, J ) 6.8 Hz); 13C
NMR (125 MHz, CDCl3) δ 134.9, 129.3, 75.7, 64.4, 56.2, 32.3,
31.9, 29.7, 29.7, 29.7, 29.7, 29.6, 29.5, 29.4, 29.2, 29.2, 22.7, 14.1;
[R]D -6.2 (c 0.21, CH2Cl2).
amino alcohol 9 as a white solid in 62% yield (1.7 mg, 4.4 µmol)
from amino alcohol 6: mp 73-74 °C; 1H NMR (400 MHz, CDCl3)
δ 7.38-7.27 (m, 5H), 5.73 (dtd, 1H, J ) 15.4, 6.8, 0.9 Hz), 5.43
(ddt, 1H, J ) 15.4, 6.9, 1.4 Hz), 4.52 (s, 2H), 4.04 (br t, 1H, J )
6.0 Hz), 3.55 (dd, 1H, J ) 9.3, 4.7 Hz), 3.50 (dd, 1H, J ) 9.3, 6.5
Hz), 3.03 (dt, 1H, J ) 6.5, 5.1 Hz), 2.04 (app q, 1H, J ) 6.8 Hz),
1.55 (br s, 3H), 1.25 (m, 22H), 0.88 (t, 3H, J ) 6.8 Hz); 13C
NMR (125 MHz, CDCl3) δ 138.0, 134.3, 128.9, 128.5, 127.7, 127.7,
74.8, 73.5, 72.5, 54.8, 32.4, 31.9, 29.7, 29.7, 29.7, 29.7, 29.6, 29.5,
29.4, 29.2, 29.2, 22.7, 14.1; IR (neat) 3423, 2916, 2849 cm-1; [R]D
+4.2 (c 0.12, CH2Cl2); HRMS (FAB+) exact mass calcd for
(2S,3S,4E)-3-Am in o-1-ben zyloxyocta d ec-4-en -2-ol (6). Vi-
nyl epoxide 5 (64.0 mg, 0.172 mmol) in THF (1 mL) and
NH4OH (25%, 1 mL) was heated to 130 °C for 2 h in a sealed
tube. Extrelut workup followed by a short silica plug afforded
anti-amino alcohol 6 as a low melting solid in 98% yield (65.7
mg, 0.168 mmol): 1H NMR (400 MHz, CDCl3) δ 7.35-7.26 (m,
5H), 5.58 (dt, 1H, J ) 15.4, 6.6 Hz), 5.43 (dd, 1H, J ) 15.4, 7.3
Hz), 4.53 (s, 2H), 3.74 (dt, 1H, J ) 5.6, 4.7 Hz), 3.51 (d, 2H, J )
5.6 Hz), 3.42 (dd, 1H, J ) 7.3, 4.7 Hz), 2.12 (br s, 3H), 2.00 (app
q, 1H, J ) 6.8 Hz), 1.32 (m, 2H), 1.26 (m, 20H), 0.88 (t, 3H, J )
6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 138.0, 132.8, 130.0, 128.3,
127.7, 127.6, 73.4, 72.9, 71.8, 56.0, 32.3, 31.9, 29.7, 29.6, 29.6,
29.6, 29.6, 29.5, 29.3, 29.2, 29.1, 22.6, 14.1; IR (neat) 3351, 2925,
2855 cm-1; [R]D +2.7 (c 0.86, CH2Cl2); HRMS (FAB+) exact mass
calcd for C25H44NO2 (M + H) 390.3372, found 390.3383.
(2S,3R,4E)-3-Am in o-1-ben zyloxyocta d ec-4-en -2-ol (7). A
solution of oxazolidinone 16 (17.4 mg, 41.9 µmol) in KOH (1 M,
EtOH/H2O 1:1) was refluxed for 3 h. Extrelut workup followed
by a short silica plug afforded syn-amino alcohol 7 as a white
solid in 95% yield (15.5 mg, 39.8 µmol): mp 47-48 °C; 1H
NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 5.59 (dt, 1H, J )
15.3, 6.7 Hz), 5.36 (dd, 1H, J ) 15.3, 7.5 Hz), 4.55 (AB-q, 2H, J
) 12.0 Hz), 3.58 (dd, 1H, J ) 9.2, 2.8 Hz), 3.53 (m, 1H), 3.46
(dd, 1H, J ) 9.2, 5.5 Hz), 3.34 (m, 1H), 2.19 (br s, 3H), 1.98
(app q, 1H, J ) 6.9 Hz), 1.30 (m, 2H), 1.26 (m, 20H), 0.88 (t, 3H,
J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 138.1, 133.0, 131.1,
128.4, 127.7, 127.7, 73.5, 73.4, 71.8, 58.5, 32.4, 31.9, 29.7, 29.7,
29.7, 29.7, 29.6, 29.6, 29.5, 29.4, 29.2, 22.7, 14.1; IR (neat) 3361,
2925, 2854 cm-1; [R]D +19.9 (c 1.07, CH2Cl2); HRMS (FAB+)
exact mass calcd for C25H44NO2 (M + H) 390.3372, found
390.3365.
(2R,3S)-2-Ben zyloxym eth yl-3-p en ta d ec-1-(E)-en yla zir i-
d in e (8). To a solution of PPh3 (48 mg, 0.18 mmol) in THF (1
mL) at 0 °C was added DIAD (35 µL, 0.18 mmol). After 20 min,
amino alcohol 6 (50 mg, 0.13 mmol) in THF (1 mL) was added,
and the resultant mixture was refluxed for 17 h. The solvent
was evaporated at reduced pressure, and flash chromatography
on deactivated silica (10% Et3N during packing) (pentane/EtOAc
5:1 f 1:1) afforded a mixture of reduced DIAD and vinylaziridine
8 (80 mg),which was used without further purification: 1H NMR
(400 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 5.74 (dt, 1H, J ) 15.2,
6.9 Hz), 5.03 (dd, 1H, J ) 15.2, 8.1 Hz), 4.55 (AB-q, 2H, J )
11.9 Hz), 3.60 (dd, 1H, J ) 10.4, 4.4 Hz), 3.44 (dd, 1H, J ) 10.4,
5.8 Hz), 2.31 (dd, 1H, J ) 8.1, 2.5 Hz), 2.16 (m, 1H), 2.00 (q, 1H,
J ) 6.8 Hz), 1.57 (br s, 1H), 1.32 (m, 2H), 1.26 (m, 20H), 0.88 (t,
3H, J ) 6.8 Hz); 13C NMR (125 MHz, CDCl3) δ 138.2, 133.6,
129.4, 128.4, 127.8, 127.7, 73.1, 71.0, 37.8, 37.7, 32.4, 31.9, 29.7,
29.7, 29.7, 29.7, 29.6, 29.5, 29.4, 29.2, 28.2, 22.7, 14.1.
C
25H44NO2 (M + H) 390.3372, found 390.3377.
(4R,5S)-5-Ben zyloxym eth yl-4-pen tadec-1(E)-en yl-3-(tolu -
en e-4-su lfon yl)oxazolidin -2-on e (15). To a solution of (dba)3Pd2‚
CHCl3 (8.3 mg, 8.1 µmol) in THF (1 mL) was added distilled
P(OiPr)3 (20 µL, 81 µmol). The mixture was stirred for 20 min
at room temperature before addition of distilled TsNCO (25 µL,
0.161 mmol) and vinyl epoxide 5 (30.0 mg, 80.5 µmol) in THF (1
mL), and the resultant mixture was stirred at room temperature
for 90 min. Water was added, and the mixture was extracted
with Et2O. The organic phase was washed with brine, dried
(MgSO4), and concentrated. Flash chromatography (pentane/
EtOAc 10:1 f 8:1) afforded oxazolidinone 15 as a colorless oil
in 75% yield (33.0 mg, 60.3 µmol): 1H NMR (400 MHz, CDCl3)
δ 7.87 (d, 1H, J ) 8.4 Hz), 7.38-7.23 (m, 7H), 5.87 (dt, 1H, J )
15.2, 6.7 Hz), 5.41 (dd, 1H, J ) 15.2, 8.6 Hz), 4.77 (dd, 1H, J )
8.6, 3.8 Hz), 4.49 (AB-q, 2H, J ) 12.2 Hz), 4.22 (app q, 1H, J )
3.9 Hz), 3.58 (dd, 1H, J ) 10.9, 4.0 Hz), 3.55 (dd, 1H, J ) 10.9,
3.8 Hz), 2.41 (s, 3H), 2.06 (m, 2H), 1.37 (m, 2H), 1.27 (m, 20H),
0.88 (t, 3H, J ) 6.8 Hz); 13C NMR (125 MHz, CDCl3) δ 151.5,
145.1, 137.7, 137.2, 135.5, 129.4, 129.4, 128.5, 128.0, 127.7, 125.8,
79.0, 73.7, 68.7, 61.1, 32.0, 31.9, 29.7, 29.7, 29.7, 29.7, 29.6, 29.4,
29.3, 29.2, 28.6, 22.7, 21.6, 14.1; IR (neat) 2927, 2855, 1787, 1372
cm-1; [R]D +22.2 (c 3.00, CH2Cl2); HRMS (FAB+) exact mass
calcd for C33H48NO5S (M + H) 570.3253, found 570.3257.
N-((1S,2S,3E)-1-Ben zyloxym eth yl-2-h yd r oxyh ep ta d ec-3-
en yl)a ceta m id e (19). To a solution of crude 17 (22 mg with
DIAD, <20 µmol 17) in THF (0.5 mL) at -25 °C was added
BF3‚OEt2 (13.5 µL, 0.11 mmol). After 1.5 h, full conversion into
the corresponding oxazoline was achieved, H2O (0.05 mL) was
added, and the resultant mixture was stirred at room tempera-
turefor 3 h. Aqueous NaOH (2 M) was added followed by Extrelut
workup. Flash chromatography (EtOAc) afforded syn-hydroxy
amide 19 as a white solid in 43% yield (3.8 mg, 8.8 µmol) from
amino alcohol 6: mp 100-102 °C; 1H NMR (400 MHz, CDCl3) δ
7.37-7.27 (m, 5H), 6.08 (br d, 1H, J ) 8.4 Hz), 5.71 (dt, 1H, J
) 15.5, 6.8 Hz), 5.41 (dd, 1H, J ) 15.5, 6.4 Hz), 4.51 (AB-q, 2H,
J ) 11.7 Hz), 4.39 (dd, 1H, J ) 6.4, 3.4 Hz), 4.02 (dq, 1H, J )
8.4, 3.7 Hz), 3.69 (dd, 1H, J ) 9.5, 3.4 Hz), 3.66 (dd, 1H, J )
9.5, 4.0 Hz), 2.01 (m, 2H), 2.0 (m, 3H), 1.57 (br s, 3H), 1.32 (m,
2H), 1.25 (m, 20H), 0.88 (t, 3H, J ) 6.9 Hz); 13C NMR (125 MHz,
CDCl3) δ 170.6, 137.4, 133.7, 128.7, 128.6, 128.0, 127.8, 73.7,
73.3, 71.4, 52.9, 32.3, 31.9, 29.7, 29.7, 29.7, 29.7, 29.6, 29.5, 29.4,
29.2, 29.1, 23.3, 22.7, 14.1; IR (neat) 3284, 2922, 2852, 1641 cm-1
;
[R]D -6.1 (c 0.25, CH2Cl2); HRMS (FAB+) exact mass calcd for
C
27H46NO3 (M + H) 432.3478, found 432.3477.
(2S,3R,4E)-2-Am in o-1-ben zyloxyocta d ec-4-en -3-ol (9). To
a solution of vinylaziridine 8 and reduced DIAD (molar ratio
1:1.4, 4.6 mg, 7.4 µmol 8) in CH2Cl2 (1 mL) and H2O (6.7 µL,
0.22 mmol) at 0 °C was added TFA (1.2 µL, 0.16 mmol). The
solution was stirred at room temperature for 90 min. NaOH (2
M) was added followed by Extrelut workup. KOH (1M, 1 mL,
EtOH/H2O 1:1) was added, and the mixture was refluxed for 30
min to hydrolyze the amide. Workup as above followed by flash
chromatography (EtOAc/MeOH 10:1 + 1% NH4OH) afforded
Ack n ow led gm en t. This work was supported finan-
cially by the Swedish Research Council.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and synthesis of 2-4, 5, 5′, 10-12, 14, 16,
17, and 20-22. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O0268254
J . Org. Chem, Vol. 68, No. 6, 2003 2517