Total Synthesis of Sphingofungin F Based on Chiral Tricyclic Iminolactone

Article abstract of DOI:10.1021/jo100183d

A new, efficient synthesis of sphingofungin F has been accomplished with 10.4% overall yield in 15 steps. The salient features of the synthesis are the utilization of methyl tricyclic iminolactone 3 for the asymmetric aldol reaction as a key step to intro

Full text of DOI:10.1021/jo100183d

pubs.acs.org/joc
centers, was first isolated from the fermentation broth of
Total Synthesis of Sphingofungin F Based on Chiral
Tricyclic Iminolactone
Paecilomyces variotii by a Merck group in 1992.2 It exhibits
inhibitory effects toward serine palmitoyl transferase (SPT),
which induces apoptosis in both yeast and mammalian cells
by blocking the sphingosine biosynthesis pathway.3 Due to
its structural novelty and biological activity, the synthesis of
sphingofungin F has attracted considerable attention to
synthetic chemists.4 The first asymmetric synthesis of sphingo-
fugin F was achieved by Kobayashi using SnII-catalyzed
Feng-Feng Gan, Shao-Bo Yang, Yong-Chun Luo,
Wan-Bang Yang, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, College
of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, PRC
€
asymmetric aldol reaction of Schollkopf’s bislactam in 1997
with 6.5% overall yield in 24 steps.4a After that, Trost4c,f and
Lin4e accomplished the total synthesis of sphingofungin F
using palladium-catalyzed asymmetric allylic alkylation
reaction and Lewis acid-catalyzed intramolecular epoxide-
opening with an N-nucleophile as key steps with the yield of
17.0% in 15 steps and 3.7% in 22 steps, respectively. Then,
Ham4g and Li4h reported the synthesis of sphingofungin F in
15 and 17 steps, with an overall yield of 6.0% and 7.7%.
Recently, Wang and Lin reported a flexible common ap-
proach for the total synthesis of sphingofungin E and F with
efficient use of both diastereomers of the Baylis-Hillman
adduct in a stereoconvergent manner on the basis of their
previous report with the yield about 4.0% in 27 steps.4i
Among these, the strategies are all more than 15 steps, and
only the route described by Trost gives overall yield higher
than 10%.
xupf@lzu.edu.cn
Received February 8, 2010
A new, efficient synthesis of sphingofungin F has been
accomplished with 10.4% overall yield in 15 steps. The
salient features of the synthesis are the utilization of
methyl tricyclic iminolactone 3 for the asymmetric aldol
reaction as a key step to introduce two desired stereogenic
centers, one-pot reaction for the synthesis of ω-hydroxy-
ketone from ε-caprolactone, and an effective one-step
deprotection strategy to remove all protecting groups
using 0.2 N HCl.
Chiral tricyclic iminolactone,5,6 a useful chiral auxiliary
for the preparation of amino acids, especially β-hydroxy-R-
amino acids, has been reported by our group recently.6g On
the basis of this method, a new efficient strategy for the total
synthesis of sphingofungin F is described herein. In this
strategy, chiral methyl tricyclic iminolactone 3 was used as
an alanine equivalent for the asymmetric aldol reaction to
introduce the two desired stereogenic centers.
As shown in our retrosynthetic analysis (Scheme 1), sphingo-
fungin F can be divided into two parts: methyl tricyclic imino-
lactone and polyhydroxyl long chain aldehyde 2. The latter can
be obtained by the coupling reaction of long chain lipid 4 and
polyhydroxyl trans-olefin 5.
Sphingosines are important second messengers and regu-
latory molecules in the cell-signaling transduction path-
way with inhibition to protein kinase C (PKC).1 One of
the derivatives, sphingofungin F, bearing a C20 straight
carbon chain with E-olefin and four contiguous asymmetric
The first stage of the synthesis involved the preparation of
the compound 4 (Scheme 2). According to our reported
method,7 1-hydroxydodecan-6-one (7) was synthesized by
a convenient one-pot reaction from ε-caprolactone (6) and
n-hexyl Grignard reagent in 87% yield. Then the carbonyl
group was protected with catechol to afford the compound 8
(1) (a) Hannun, Y. A.; Loomis, C. R.; Merrill, A. H.; Bell, R. M. J. Biol.
Chem. 1986, 261, 12604–12612. (b) Hannun, Y. A. Science 1989, 243, 500–
506. (b) Nugent, T. C.; Hudlicky, T. J. Org. Chem. 1998, 63, 510–520. (c)
Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima, M.; Hanada, K. J. Am.
Chem. Soc. 1998, 120, 908–919. (d) Mandala, S. M.; Harris, G. H. Methods
Enzymol. 2000, 311, 335–382. (e) Pruett, S. T.; Bushnev, A.; Hagedorn, K.;
Adiga, M.; Haynes, C. A.; Sullards, M. C.; Liotta, D. C.; Merrill, A. H., Jr.
J. Lipid Res. 2008, 49, 1621–39.
(2) Horn, W. S.; Smith, J. L.; Bills, G. F.; Raghoobar, S. L.; Helms, G. L.;
Kurtz, M. B.; Marrinan, J. A.; Frommer, B. R.; Thornton, R. A.; Mandala,
S. M. J. Antibiot. 1992, 45, 1692–1996.
(5) For the preparation of chiral tricyclic iminolactone, see: (a) Xu, P. F.;
Chen, Y. S.; Lin, S. I.; Lu, T. J. J. Org. Chem. 2002, 67, 2309–2314. (b) Xu,
P. F.; Lu, T. J. J. Org. Chem. 2003, 68, 658–661.
(3) Zweerink, M. M.; Edison, A. M.; Well, G. B.; Pinto, W.; Lester, R. L.
J. Biol. Chem. 1992, 267, 25032–25038.
(6) For the application of chiral tricyclic iminolactone, see: (a) Li, S.; Hui,
X. P.; Yang, S. B.; Jia, Z. J.; Xu, P. F.; Lu, T. J. Tetrahedron: Asymmetry
2005, 16, 1729–1731. (b) Xu, P. F.; Li, S.; Lu, T. J.; Wu, C. C.; Fan, B. T.;
Golfis, G. J. Org. Chem. 2006, 71, 4364–4373. (c) Wang, P. F.; Gao, P.; Xu,
P. F. Synlett 2006, 7, 1095–1099. (d) Zhang, H. H.; Hu, X. Q.; Wang, X.; Luo,
Y. C.; Xu, P. F. J. Org. Chem. 2008, 73, 3634–3637. (e) Wang, H. F.; Ma,
G. H.; Yang, S. B.; Han, R. G.; Xu, P. F. Tetrahedron: Asymmetry 2008, 19,
1630–1635. (f) Huang, Y.; Li, Q.; Liu, T. L.; Xu, P. F. J. Org. Chem. 2009, 74,
1252–1258. (g) Li, Q.; Yang, S. B.; Zhang, Z. H.; Li, L.; Xu, P. F. J. Org.
Chem. 2009, 74, 1627–1631.
(4) For total synthesis of sphingofungin F, see: (a) Kobayashi, S.;
Matsumura, M.; Furuta, T.; Hayashi, T.; Iwamoto, S. Synlett. 1997, 301–
303. (b) Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima, M.; Hanada, K.
J. Am. Chem. Soc. 1998, 120, 908–919. (c) Trost, B. M.; Lee, C. B. J. Am.
Chem. Soc. 1998, 120, 6818–6819. (d) Kobayashi, S.; Furuta, T. Tetrahedron
1998, 54, 10275–10294. (e) Liu, D. G.; Wang, B.; Lin, G. Q. J. Org. Chem.
2000, 65, 9114–9119. (f) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123,
12191–12201. (g) Lee, K. Y.; Oh, C. Y.; Ham, W. H. Org. Lett. 2002, 4, 4403–
4405. (h) Li, M.; Wu, A. Synlett 2006, 18, 2985–2988. (i) Wang, B.; Lin, G. Q.
Eur. J. Org. Chem. 2009, 5038–5046.
(7) Yang, S. B.; Gan, F. F.; Chen, G. J.; Xu, P. F. Synlett 2008, 16, 2532–
2534.
DOI: 10.1021/jo100183d
r
Published on Web 03/23/2010
J. Org. Chem. 2010, 75, 2737–2740 2737
2010 American Chemical Society

Gan et al.
JOCNote
SCHEME 1. Retrosynthetic Analysis
SCHEME 4. Synthesis of Intermediate 2 and Its Aldol Reaction
SCHEME 2. Synthesis of Intermediate 4
(two steps).11 Fortunately, an excellent (E)-selectivity was
observed while the corresponding (Z)-isomer was not
detected. Reduction of the ester 12 with DIBAL-H provided
the alcohol 13 in 95% yield. Then the hydroxy group was
replaced with iodine to afford the iodide 5 in 87% yield.
With two intermediates in hand, our attention focused on
the coupling of 4 and 5 (Scheme 4). Various bases (LDA,
BuLi, t-BuLi), additives (HMPA, DMPU), and tempera-
tures (-78, -40 °C) were used in the attempts. As a result, the
desired product 14 was prepared successfully using BuLi as
base at -78 °C in 78% yield. Deprotection of the silyl ether
14 gave the alcohol 15 in 83% yield, and removal of the
phenylsulfonyl group with Na/Hg alloy in anhydrous methanol
afforded the compound 16 in 90% yield.12 Then Swern
oxidation of 16 furnished the crude aldehyde 2 in 93% yield.
Soon afterward, asymmetric aldol reaction of compounds 2
and 3 to give the desired aldol adduct6g proved to be
troublesome under a variety of conditions (Scheme 4).
Initially, LiCl and LDA wre employed, and only a trace
amount of the aldol product was obtained. To improve the
SCHEME 3. Synthesis of Intermediate 5
yield, other Lewis acids (Et2AlCl, BF3 Et2O) and bases
3
in 95% yield. Direct iodination of the alcohol 8 with PPh3/I2/
imidazole followed by sulfonylation with PhSO2Na pro-
duced the sulfone 4 in satisfactory yield (88%, two steps).8
Next, the stage was set for the synthesis of intermediate 5
starting from known diol 9 (Scheme 3), which could be
prepared from L-(þ)-tartaric acid in three steps according
to the reported procedure.9 Compound 10 was obtained
from compound 9 by monosilylation (TBDPSCl, NaH,
90%). Swern oxidation of 10 gave a crude aldehyde,10 which
was subjected to Wittig reaction with the ylide 11 in refluxing
THF to give R,β-unsaturated ester 12 in 88% yield
(KHMDS, NaHMDS, LHMDS) were tested, and finally,
the desired product 17 was provided in 65% yield with
dr =3:1 (17:170) when BF3 Et2O and KHMDS were used.
3
Since there is no observable NOE signal between the methyl
group and the hydrogen adjacent to the ester moiety, it can
be assumed that the methyl group is in the equatorial
position. (Scheme 4).
With compound 17 in hand, our focus then shifted to the
final hydrolysis to remove the chiral auxiliary and protecting
groups, which proved to be particularly challenging. A wide
variety of reaction conditions (acids, temperatures, and
solvents) were examined, and some of the representative
results are shown in Table 1. First, according to the previous
work in our laboratory,6g the condition of 6 N HCl at 80 °C
was examined (entry 1). The reaction proved to be complicated,
(8) Lange, G. L.; Gottardo, C. Synth. Commun. 1990, 20, 1473–1479.
(9) (a) Houston, T. A.; Wilkinson, B. L.; Blanchfield, J. T. Org. Lett.
2004, 6, 679–681. (b) Kobayashi, Y.; Kokubo, Y.; Aisaka, T.; Saigo, K.
Tetrahedron: Asymmetry 2008, 19, 2536–2541.
(10) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2481.
(11) Bergel’son, L. D.; Vaver, V. A.; Barsukov, L. I.; Shemyakin, M. M.
Izv. Akad. Nauk. SSSR. Khim. 1966, 3, 506–511.
(12) Satoh, T.; Oguro, K.; Shishikura, J.; Kanetaka, N.; Okada, R.;
Yamakawa, K. Bull. Chem. Soc. Jpn. 1993, 66, 2339–2347.
2738 J. Org. Chem. Vol. 75, No. 8, 2010

Gan et al.
JOCNote
TABLE 1. Hydrolysis of Compound 17
mixture was allowed to warm to rt and stirred for 6 h. The
reaction was quenched with 1 N HCl solution (100 mL), and the
mixture was stirred for another 2 h. The solvent was evaporated,
and the residue was diluted with H2O (100 mL) followed by
extraction with CH2Cl2. The organic layer was washed with
saturated NaHCO3 solution and brine, respectively, and then
dried over anhydrous Na2SO4 and concentrated. The residue
was purified by flash column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate =5:1) to afford 7 (1.4 g,
87%) as a white solid: mp 37-38 °C; IR (KBr) 3214, 2928, 2854,
1
1700, 1465, 1416, 1375, 1241, 1054, 725 cm-1; H NMR (400
entrya
acid
temp (°C)
solvent
H2O
H2O
H2O
H2O
yieldb (%)
MHz, CDCl3) δ 3.65 (t, J = 6.6 Hz, 2H), 2.43-2.37 (m, 4H),
1.64-1.54 (m, 7H), 1.40-1.28 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 211.6, 62.4, 42.8, 42.5, 32.3,
31.5, 28.8, 25.3, 23.7, 23.4, 22.4, 13.9; ESIMS for C12H25O2 m/z
201 [M þ H]þ.
1
2
3
4
5
6
6 N HCl
6 N HCl
12 N HCl
CF3COOH
CH3COOH
0.2 N HCl
80
0
0
0
reflux
reflux
reflux
reflux
reflux
trace
trace
66
H2O
H2O/EtOHc
2-Hexyl-2-[(7E,9S,10S)-5-phenylsulfonyl-9,10-isopropylide-
nedioxy-11-tert-butyldiphenylsilyloxy-7-hendecene]benzo[1,3]-
dioxole (14). To a stirred solution of 4 (666 mg, 1.6 mmol) in dry
THF (50 mL) was added BuLi (1.26 mL, 1.52 M in THF, 1.92
mmol) at -78 °C under argon atmosphere slowly, and the
mixture was stirred for 15 min. Then a solution of compound
5 (1.01 g, 1.92 mmol) in THF (10 mL) was trickled slowly down
the side of the tube. After 1 h, the reaction was quenched with
saturated NH4Cl solution (1.0 mL), and the mixture was
allowed to warm to rt. The resulting solution was concentrated,
and the residue was purified by flash column chromatography
on silica gel (eluent: petroleum ether/ethyl acetate = 8:1) to
aGeneral reaction conditions: concentration 0.2 M in solvents. bIso-
lated yield. cH2O/EtOH (v/v = 1:1).
and no product was obtained. Compared with the previous
molecules,6g aldol adduct 17 is more complex and its steric
hindrance is more prominent, which may increase the diffi-
culty of hydrolysis. When the temperature was increased to
reflux and even 12 N HCl was used (entries 2 and 3), any
desired hydrolyzed fragments could not be found. We had to
change the strategy using weaker acids (acetic acid and
trifluoroacetic acid) to remove the chiral auxiliary and
protecting groups one by one (entries 4 and 5), and then
some partly hydrolyzed fragments were obtained, especially
3-exo-hydroxycamphor. By analyzing the fragments, it was
found that the catechol group was the most difficult one to
remove. In this regard, when a mixture of 0.2 N HCl and
ethanol (v/v = 1:1) was used, all protecting groups were
removed smoothly. To our surprise, the hydrolytic molecule
we obtained was not the final desired product but its
corresponding lactone formed by an intramolecular cycliza-
tion. Thus, saponification of the crude lactone was carried
out with 1 N NaOH solution. Then, 1 N HCl and propylene
oxide were used for neutralization and removal of hydro-
chloride to afford the final desired product 1 in 66% yield
afford 14 (1.03 g, 78%) as a colorless oil: [R]20 -5 (c 1.5,
D
CHCl3); IR (KBr) 2952, 2931, 2859, 1486, 1303, 1239, 1144,
1109, 1084, 824, 737, 704, 506 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.84 (d, J=7.6 Hz, 2H), 7.68-7.61 (m, 5H), 7.53 (t,
J = 7.6 Hz, 2H), 7.42-7.34 (m, 6H), 6.73-6.68 (m, 4H),
5.64-5.54 (m, 1H), 5.44 (dd, J = 15.6, 6.8 Hz, 1H), 4.34 (dd,
J = 13.8, 6.6 Hz, 1H), 3.80-3.77 (m, 1H), 3.70-3.66 (m, 1H),
2.91 (br s, 1H), 2.55-2.50 (m, 1H), 2.36-2.25 (m, 1H),
1.83-1.75 (m, 4H), 1.56 (br s, 2H) 1.41-1.25 (m, 18H), 1.04
(s, 9H), 0.86 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
147.9, 138.0, 137.9, 135.6, 133.6, 133.2, 131.3, 131.2, 129.7 (2C),
129.4, 129.1, 129.0, 128.8 (2C), 127.7 (2C), 120.8, 120.1 (2C),
109.0, 107.9, 81.2 (2C), 78.2, 78.1, 77.2, 63.8 (2C), 62.8, 62.7,
37.8, 37.2, 31.6, 31.1, 30.8, 29.2, 27.3, 27.1, 26.9, 26.8, 26.6, 26.5,
22.6, 22.5, 22.4, 19.2, 14.0; HRMS (ESI) calcd for C49H68NO7S-
Si [M þ NH4]þ 842.4480, found 842.4489.
1
(two steps). The H and 13C NMR spectral data of 1 were
Aldol Adduct (17). To a solution of 3 (122 mg, 0.55 mmol) in
dry THF (2.0 mL) was added KHMDS (0.72 mL, 1 M in THF,
0.72 mmol) at -78 °C under argon atmosphere. The mixture was
found to be in good accord with the values reported for
sphingofungin F.4g
stirred for 30 min, and then a solution of BF3 Et2O (58 uL, 0.55
In summary, a new and efficient strategy for the total
synthesis of sphingofungin F has been accomplished in 15
steps with 10.4% overall yield. In this strategy, methyl
tricyclic iminolactone was used as a chiral template for the
asymmetric aldol reaction to introduce other two desired
stereogenic centers. Besides that, a convenient one-pot me-
thod for the synthesis of ω-hydroxy ketones and an effective
one-step deprotection strategy simplified the synthetic route
dramatically. It is also worth noticing that by simple modi-
fication of the tricyclic iminolactone or other structurally
related substances, other members of sphingofungin family
could be synthesized easily.
3
mmol) in THF (1.0 mL) was added. After 30 min, a solution of 2
(187 mg, 0.42 mmol) in THF (1.0 mL) was trickled slowly
down the side of the tube. After 2 h, saturated NH4Cl solution
(0.5 mL) was added, and the reaction was allowed to warm to rt.
The resulting solution was evaporated, and the residue was
purified by flash column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 6:1) to afford 17 (181.8 mg,
65%, dr = 3:1) as a colorless oil: [R]20D þ12.2 (c 4.3, CHCl3);
IR (KBr) 3404, 2928, 2857, 1749, 1626, 1486, 1456, 1375, 1239,
1064, 1043, 876, 736 cm-1 1H NMR (400 MHz, CDCl3) δ
;
6.76-6.70 (m, 4H), 5.86-5.79 (m, 1H), 5.34 (dd, J = 15.2, 8.4
Hz, 1H), 4.64 (s, 1H), 4.23 (t, J = 8.4 Hz, 1H), 3.79 (d, J = 8.4
Hz, 1H), 3.61 (d, J =10.4 Hz, 1H), 2.92 (d, J = 10.4 Hz, 1H),
2.20 (d, J = 4.4 Hz, 1H), 2.06-1.99 (m, 3H), 1.89-1.85 (m,
4H), 1.78-1.71 (m, 1H), 1.63 (s, 3H), 1.44-1.27 (m, 24H), 1.05
(s, 3H), 0.95 (s, 3H), 0.86 (t, J = 6.6 Hz, 3H), 0.78 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 181.3, 172.0, 148.0, 138.6, 125.3,
120.7, 120.6, 110.0, 107.9, 80.5, 80.1, 78.1, 70.5, 66.8, 52.9,
48.3, 48.0, 37.7 (2C), 32.3, 31.6, 29.4, 29.3, 29.0, 28.9, 28.8,
27.4, 26.6, 26.2, 23.9, 22.6 (2C), 22.5, 20.2, 19.4, 14.0, 10.3;
Experimental Section
1-Hydroxydodecan-6-one (7). A slurry of ε-caprolactone 6
(0.912 g, 8.0 mmol), HN(OMe)Me HCl (0.935 g, 9.6 mmol),
and NaOMe (108 mg, 2.0 mmol) in THF (100 mL) was stirred at
0 °C under argon atmosphere. n-HexMgBr (128 mL, 0.5 M in
THF, 64.0 mmol) was added slowly. After 2 h, the reaction
3
J. Org. Chem. Vol. 75, No. 8, 2010 2739

Gan et al.
JOCNote
HRMS (ESI) calcd for C40H60NO7 [M þ H]þ 666.4364, found
(m, 4H), 1.50 (s, 3H), 1.39-1.44 (m, 2H), 1.29-1.37 (m, 13H),
0.90 (t, J = 6.9 Hz, 3H); 13C NMR (150 MHz, CD3OD) δ
214.3, 175.3, 135.7, 130.2, 76.2, 75,7, 72.5, 66.7, 43.5 (2C),
33.4, 32.8, 30.2 (2C), 30.0 (2C), 24.9 (2C), 23.6, 21.8, 14.4;
HRMS (ESI) calcd for C21H39NO6 [M þ H]þ 402.2850, found
402.2853.
666.4376.
Sphingofungin F (1). To a solution of 17 (133 mg, 0.2 mmol) in
ethanol (0.5 mL) was added 0.2 N HCl (0.5 mL). The mixture
was stirred under reflux for 12 h. The solution was evaporated,
and the residue was treated with 1 N NaOH solution (2 mL).
The mixture was stirred at rt for 2 h and then neutralized with 1
N HCl solution. The solvent was evaporated, and the residue
was treated with propylene oxide. The resulting solution was
concentrated and the residue was purified by flash column
chromatography on silica gel (eluent: CHCl3/CH3OH/H2O =
20:5:1) to afford 1 (52.9 mg, 66%) as a white solid: mp 143-
Acknowledgment. We are grateful for the National Basic
Research Program of China (No. 2010CB833200), the Foun-
dation (20772051, 20972058) from NSFC, and the “111”
program from MOE of P. R. China.
145 °C (CH3OH-H2O); [R]20 þ2 (c 0.4, CH3OH); IR (KBr)
D
Supporting Information Available: Experimental proce-
dures, spectral data, comparison of the NMR data of synthetic
sphingofungin F with those reported for the natural product,
and copies of 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org
3405, 2927, 2855, 1713, 1628, 1462, 1409, 1373, 1055, 979, 578, 468
cm-1; 1H NMR (600 MHz, CD3OD) δ 5.78 (dt, J = 15.0, 7.2 Hz,
1H), 5.46 (dd, J = 15.0, 7.8 Hz, 1H), 4.12 (t, J = 7.5 Hz, 1H),
3.87 (br s, 1H), 3.68 (d, J = 7.2 Hz, 1H), 2.45 (t, J = 7.2 Hz, 2H),
2.44 (t, J = 7.2 Hz, 2H), 2.06 (q, J = 7.0 Hz, 2H), 1.53-1.57
2740 J. Org. Chem. Vol. 75, No. 8, 2010