Facile transformation of 2-azetidinones to unsaturated ketones: Application to the formal synthesis of sphingosine and phytosphingosine

Article abstract of DOI:10.1016/S0040-4039(02)02444-9

2-Azetidinones were smoothly transformed to unsaturated ketones through the ring opening of activated 2-azetidinone by phosphonate stabilized carbanion and subsequent Horner-Wadsworth-Emmons olefination of the resulting β-ketophosphonates with aldehydes.

Full text of DOI:10.1016/S0040-4039(02)02444-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9641–9644
Facile transformation of 2-azetidinones to unsaturated ketones:
application to the formal synthesis of sphingosine and
phytosphingosine
Hyeon Kyu Lee,* Eun-Kyung Kim and Chwang Siek Pak*
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yusung, Taejon 305-606,
South Korea
Received 30 April 2002; revised 9 October 2002; accepted 24 October 2002
Abstract—2-Azetidinones were smoothly transformed to unsaturated ketones through the ring opening of activated 2-azetidinone
by phosphonate stabilized carbanion and subsequent Horner–Wadsworth–Emmons olefination of the resulting b-ketophospho-
nates with aldehydes. A formal synthesis of L-erythro-sphingosine and D-lyxo-phytosphingosine from readily available 2-azetidi-
none was established utilizing this methodology. © 2002 Elsevier Science Ltd. All rights reserved.
Since the discovery of penicillin in 1928, 2-azetidinone
(b-lactam) skeleton is well known as the key structural
element of the most widely employed class of antibacte-
rial agents, the b-lactam antibiotics.1 As a consequence,
diverse methods for practical and stereoselective ring
formation of 2-azetidinone have been developed.2 With
plenty of methods for the synthesis of 2-azetidinone
available, applications of 2-azetidinones as efficient chi-
ral synthons for other classes of molecules have been
subjected to many investigations.3 For example, trans-
formations of 2-azetidinones to nonproteogenic amino
acids and peptides3d and ring expansion of 2-azetidi-
nones by internal or external nucleophiles to 2-
pyrrolidinones3c were reported.
Among the efforts in this area, recently we have
reported a new synthetic methodology for 2-piper-
idones which could be used as versatile intermediates for
the preparation of various piperidine and indolizidine
alkaloids from readily accessible 2-azetidinones.4
Scheme 1. Reagents and conditions: (a) CH3P(O)(OMe)2 (2 equiv.), nBuLi (2 equiv.), THF, −78°C, 30 min; (b) R4CHO,
base/solvent (see Tables 1 and 2).
Keywords: 2-azetidinone; ring-opening; Horner–Wadsworth–Emmons reaction; sphingosine; phytosphingosine.
* Corresponding authors. Tel.: +82-42-860-7016; fax: +82-42-861-0307.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02444-9

9642
H. K. Lee et al. / Tetrahedron Letters 43 (2002) 9641–9644
Table 1.
Entry
R4CHO
Base
Solvent
Temp.
Yields (%)
1
2
3
4
5
6
7
8
4-Cl-PhCHO
4-Cl-PhCHO
4-Cl-PhCHO
4-Cl-PhCHO
4-Cl-PhCHO
4-Cl-PhCHO
4-Cl-PhCHO
4-Cl-PhCHO
CH3CH2CHO
CH3CH2CHO
CH3CH2CHO
CH3CH2CHO
CH3CH2CHO
CH3CH2CHO
t-BuOK
K2CO3
NaH
THF
EtOH
THF
MeCN
DMF
THF
−78°Cꢀrt
rt
0°Cꢀrt
rt
0°Cꢀrt
0°Cꢀrt
−78°Cꢀrt
rt
rt
rt
rt
rt
69 (3a-1)
57
45
30
29
Trace
Trace
Trace
89 (3a-4)
80
Cs2CO3
NaOMe
Triton B
n-BuLi
DBU/LiCl
K2CO3
K2CO3
Cs2CO3
Cs2CO3
NaH
THF
MeCN
EtOH
MeCN
MeCN
EtOH
THF
9
10
11
12
13
14
78
50
Trace
Trace
0°Cꢀrt
−78°Cꢀrt
t-BuOK
THF
Reaction conditions: 2a (1 equiv.), base (1.2ꢀ2.0 equiv.), 18 h.
Continuing our investigation on the utilization of 2-aze-
tidinones as chiral synthons to other classes of
molecules, we report herein the facile transformation of
2-azetidinones to unsaturated ketones through ring
opening of activated 2-azetidinone by phosphonate sta-
bilized carbanion and subsequent Horner–Wadsworth–
Emmons olefination of the resulting b-ketophospho-
nates with aldehydes and its application to the formal
synthesis of sphingosine and phytosphingosine.
lithiated dimethyl methylphosphonate was treated to
3,4-disubstituted N-Boc-2-azetidinones 1, d-N-Boc-
amino-b-ketophosphonates 2 were smoothly obtained
as a sole product with good yields (Scheme 1).6
With d-N-Boc-amino-b-ketophosphonates 2 in our
hands, we tried to optimize HWE olefination with
different aldehydes by varying base and solvent.7 As
shown in Table 1 the HWE olefination of 2a with
aliphatic and aromatic aldehydes was revealed to be
highly dependent on the reaction condition of base and
solvent combination. In the HWE reaction of 2a with
aromatic aldehyde of 4-chlorobenzaldehyde, t-BuOK–
It was reported that nucleophilic ring opening of N-
Boc-2-azetidinones with simple alkyl or aryl carbanion
from Grignard or organocuprate reagent produced b-
amino ketone and b-amino carbinol.5 However, when
Table 2.
Entry
2
R4CHO
Conditiona
Yields of 3 (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
4-Cl-PhCHO
A
A
A
B
A
B
A
B
A
B
A
B
69 (3a-1)
52 (3a-2)
66 (3a-3)
89 (3a-4)
53 (3b-1)
53 (3b-2)
63 (3c-1)
45 (3c-2)
56 (3d-1)
68 (3d-2)
56 (3e-1)
64 (3e-2)
5-Cl-2-NO2-PhCHO
trans-PhCHꢀCHCHO
CH3CH2CHO
4-Cl-PhCHO
CH3CH2CHO
4-Cl-PhCHO
PhCH2CH2CHO
4-Cl-PhCHO
CH3CH2CHO
4-Cl-PhCHO
9
10
11
12
CH3CH2CHO
a Reaction conditions: (A: t-BuOK/THF, −78°Cꢀrt; B: K2CO3/EtOH, rt, 18 h).

H. K. Lee et al. / Tetrahedron Letters 43 (2002) 9641–9644
9643
Figure 1.
Scheme 2. Reagents and conditions: (a) CH3P(O)(OMe)2 (2 equiv.), nBuLi (2 equiv.), THF, −78°C, 30 min; (b) CH3(CH2)11CHO
(2 equiv.), K2CO3 (1.8 equiv.), EtOH, rt, 4 h; (c) H2, Pd/C, EtOAc; (d) Ref. 9.
THF system was the choice of the reaction condition
(Table 1, entry 1). On the contrary HWE reaction of 2a
with aliphatic aldehyde of propionaldehyde gave no
desired product 3a–4 (R4=Et) under the same reaction
conditions, but we could obtain unsaturated ketone
3a–4 (R4=Et) in the presence of K2CO3 in EtOH
solvent in 89% yield (Table 1, entries 9 and 14).
1a4,9 produced E-(2R,3R)-1-(TBDPS-oxy)-2-(N-Boc-
amino)-3-(TBDMS-oxy)-4-oxo-octadeca-5-ene
under the presence of K2CO3 in EtOH solvent in 78%
(4)11
yield. Hydrogenation of 4 cleanly afforded saturated
ketone 5.11 Since transformation of ent-5 to
D-erythro-
L-lyxo-phytosphingosine was already
sphingosine and
reported,9 our synthesis of 5 constitutes formal synthe-
sis of -erythro-sphingosine and -lyxo-phytosphin-
gosine (Scheme 2).
L
D
Having optimized base–solvent systems, we examined
the HWE reaction condition of 2 with different alde-
hydes. As shown in Table 2, HWE reaction with vari-
ous aliphatic and aromatic aldehydes proceeded
smoothly and afforded good yields of unsaturated
ketones. In all cases, only E isomers of unsaturated
ketones were obtained under the conditions.
In summary, we described facile transformation of 2-
azetidinones to unsaturated ketones through the addi-
tion of phosphonate stabilized carbanion to
2-azetidinone ring and Horner–Wadsworth–Emmons
olefination of the resulting b-ketophosphonates with
aldehydes. We also established an efficient formal syn-
thesis of
gosine from readily available 2-azetidinone from
-(+)-tartaric acid9,10 or Bose–Manhas b-lactam4 utiliz-
ing the present methodology.
L-erythro-sphingosine and D-lyxo-phytosphin-
With the established transformation process of 2-aetidi-
none to unsaturated ketone, we applied this methodol-
ogy to the formal synthesis of sphingosine and
phytosphingosine (Fig. 1). Sphingolipids are ubiquitous
membrane components of essentially all eukaryotic cells
and abundantly located in all plasma membranes as
well as in some intracellular organelles.8 Sphingosines
are liphophilic components of glycosphingolipids and
ceramides. Sphingosines and ceramides have been
shown to play a role in intracellular signaling pathway.
Phytosphingosines constitute the major base compo-
nent of higher plants, protozoa, yeast and fungi, and
have also been found in human kidney cerebrosides and
in some cancer cell-types. Because of the importance of
these compounds, even though a great number of
efforts have been devoted to the synthesis of chiral
sphingosines, still a lot of investigations are being pur-
sued to produce them more efficiently.8b,c
L
Acknowledgements
We thank the Ministry of Science and Technology of
Korea for financial support.
References
1. For some reviews on b-lactam antibiotics, see: (a) Chem-
istry and Biology of i-Lactam Antibiotics; Morin, R. B.;
Gorman, M., Eds.; Academic Press: New York, 1982;
Vol. 1–3; (b) Recent Advances in the Chemistry of i-Lac-
tam Antibiotics; Brown, A. G.; Roberts, S. M., Eds.; The
Royal Society of Chemistry, Burling House: London,
1984; (c) The Chemistry of i-Lactams; Page, M. I., Ed.;
Chapman and Hall: London, 1992.
HWE olefination of tridecanal with b-ketophosphonate
2a which is derived from (3R,4R)-N-Boc-2-azetidinone

9644
H. K. Lee et al. / Tetrahedron Letters 43 (2002) 9641–9644
9. Nakamura, T.; Shiozaki, M. Tetrahedron Lett. 1999, 40,
2. (a) Georg, G. I.; Rabikumar, V. T. In The Organic
9063.
Chemistry of i-Lactams; Georg, G. I., Ed.; VCH: New
York, 1992; p. 295; (b) Hart, D. J.; Ha, D. C. Chem. Rev.
1989, 89, 1447.
10. Barrett, A. G. M.; Sakadarat, S. J. Org. Chem. 1990, 55,
5110.
11. Within the limit of NMR detection, the absence of the
epimerized products of the 2a and 4 was confirmed.
Spectral data of compounds 4 and 5. Compound 4: [h]D25
3. (a) Ojima, I. In The Organic Chemistry of i-Lactams;
Georg, G. I., Ed.; VCH: New York, 1992; p. 197; (b)
Palomo, C.; Aizpurua, J. M.; Ganboa, I. In Enantioselec-
tive Synthesis of i-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997; p. 279; (c) Ha, D.-C.; Kang, S.;
Chung, C.-M.; Lim, H.-K. Tetrahedron Lett. 1998, 39,
7541; (d) Ojima, I. Acc. Chem. Res. 1995, 28, 383; (e)
Palomo, C.; Cossio, F. P.; Cuevas, C.; Odriozola, J. M.;
Ontoria, J. M. Tetrahedron Lett. 1992, 33, 4827; (f)
Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose, A. K.
Heterocycles 1988, 27, 1755.
1
−5.2 (c 2.9, CHCl3); H NMR (300 MHz, CDCl3) l 0.00
(s, 6H), 0.79 (s, 9H), 0.86 (t, J=6.7 Hz, 3H), 1.07 (s, 9H),
1.22–1.31 (m, 20H), 1.36 (s, 9H), 2.01 (dt, J=6.8, 6.8 Hz,
2H), 3.54 (dd, J=10.3, 6.3 Hz, 1H), 3.66 (dd, J=10.3, 5.3
Hz, 1H), 3.88–4.05 (m, 1H), 4.49 (d, J=4.7 Hz, 1H), 4.78
(d, J=8.9 Hz, 1H), 6.19 (d, J=15.7 Hz, 1H), 6.63 (dt,
J=15.7, 6.8 Hz, 1H), 7.28–7.42 (m, 6H), 7.58–7.62 (m,
4H). 13C NMR (125 MHz, CDCl3) l −5.58, −5.48, 14.12,
15.47, 18.20, 19.54, 19.61, 22.68, 25.83, 26.99, 27.89,
28.31, 29.18, 29.35, 29.40, 29.50, 29.64, 31.91, 32.51,
55.15, 61.34, 76.67, 79.08, 126.39, 127.52, 127.68, 129.78,
129.87, 132.94, 133.04, 135.89, 136.00, 148.23, 155.32,
198.04. MS m/z 766 (M+, 0.08), 652 (14), 591 (100), 492
(40), 415 (36%). Compound 5: [h]2D5 −3.9 (c 1.8, CHCl3);
1H NMR (300 MHz, CDCl3) l 0.00 (s, 6H), 0.83 (s, 9H),
0.86 (t, J=6.2 Hz, 3H), 1.08–1.24 (m, 33H), 1.37 (s, 9H),
2.08 (dt, J=17.5, 7.1 Hz, 1H), 2.22 (dt, J=17.5, 7.2 Hz,
1H), 3.61 (dd, J=10.0, 6.8 Hz, 1H), 3.69 (dd, J=10.0, 4.7
Hz, 1H), 4.00–4.09 (m, 1H), 4.32 (d, J=5.0 Hz, 1H), 4.75
(d, J=9.1 Hz, 1H), 7.31–7.39 (m, 6H), 7.58–7.63 (m, 4H).
13C NMR (125 MHz, CDCl3) l −5.59, −5.51, 14.12,
15.45, 18.28, 19.53, 19.64, 22.69, 22.74, 25.87, 27.04,
27.88, 28.29, 28.93, 29.35, 29.60, 29.66, 31.92, 34.28,
38.85, 54.56, 61.32, 78.05, 79.32, 127.59, 127.71, 129.83,
129.90, 132.97, 133.04, 135.87, 135.98, 155.26, 209.13.;
MS m/z 768 (M+, 2), 594 (100), 494 (43), 354 (52%).
4. Lee, H. K.; Chun, J. S.; Pak, C. S. Tetrahedron Lett.
2001, 42, 3483.
5. Palomo, C.; Aizpurus, J. M.; Garcia, J. M.; Iturburu, M.;
Odriozola, J. M. J. Org. Chem. 1994, 59, 5184.
6. For the nucleophilic ring opening of monosubstituted
2-azetidinone with carbanions, see: (a) Baldwin, J. E.;
Adlington, R. M.; Russel, A. T.; Smith, M. L. Tetra-
hedron 1995, 51, 4733; (b) Baldwin, J. E.; Adlington, R.
M.; Godfrey, C. R. A.; Gollins, D. W.; Smith, M. L.;
Russel, A. T. Synlett 1993, 51.
7. By now, only one example of HWE olefination of b-
ketophosphonates derived from amino acid with alde-
hyde was reported. Werner, R. M.; Williams, L. M.;
Davis, J. T. Tetrahedron Lett. 1998, 39, 9135.
8. (a) Kolter, T.; Sandhoff, K. Angew. Chem., Int. Ed. 1999,
38, 1532; (b) Koskinen, P. M.; Koskinen, A. M. P.
Synthesis 1998, 1075; (c) Bittman, R.; He, L.; Byun, H.-S.
J. Org. Chem. 2000, 65, 7618.