Asymmetric synthesis of ceramide sphingolipid based on (2S,3S,4S)-3,4- dihydroxy-5-(hydroxymethyl)pyrrolidine lactam

Article abstract of DOI:10.1016/j.tetlet.2010.06.001

A facile approach to the versatile chiral building block 2 was developed based on glutamic acid, whereby a new method for asymmetric synthesis of sex pheromone 1 was explored from cheap glutamic acid.

Full text of DOI:10.1016/j.tetlet.2010.06.001

Tetrahedron Letters 51 (2010) 4317–4319
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of ceramide sphingolipid based on (2S,3S,4S)-
3,4-dihydroxy-5-(hydroxymethyl)pyrrolidine lactam
a,
Wen-Feng Huang a, Qian-Ru Li a, Lu-Men Chao a, Xin-Sheng Lei b, , Bang-Guo Wei
*
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile approach to the versatile chiral building block 2 was developed based on glutamic acid, whereby
a new method for asymmetric synthesis of sex pheromone 1 was explored from cheap glutamic acid.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 31 March 2010
Revised 2 June 2010
Accepted 2 June 2010
Available online 15 June 2010
Keywords:
Pheromone
Sphingolipid
Ceramide
Lactam
Asymmetric synthesis
The skeleton of either pyrrolidine lactam 2 or its fragment 3
(see Fig. 1) is one common structural unit found in drugs, drug can-
didates, and numerous bioactive natural products including sphin-
golipids or ceramides, which possess diverse bioactivities such as
controlling cell growth, maturity, survival, and death as well as
inhibiting or activating certain enzymes, and lead to promising
efficacies for the control of cancer and other cell proliferation.1
Therefore, the chiral lactam 2 might be a potentially attractive
building block for the natural products. Recently, ceramide sphin-
golipid 1, a sex pheromone of hair crab, has been isolated by Fuse-
tani and co-workers from the urine of the female hair crab defined
as the species Erimacrus isenbeckii, which elicits pre-copulatory
behavior in the male ones.2 Additionally the relative analogues
have been confirmed to exhibit cytotoxicity against tumors cells
in mice or inhibition against phospholipase A2.3 These natural
products have become the synthetic targets of many chemists
due to their biological activities and intriguing structures, and sev-
eral approaches to the total synthesis of the crab sex pheromone 1
or its analogues have been reported.4 Among these approaches, the
most challenging work is the construction of optically active sphin-
gosine unit bearing three chiral centers. In the recent years, we
have been devoted to exploring some multifunctional building
blocks and utilizing them in the asymmetric synthesis of some nat-
ural products including bioactive piperidine alkaloids, depsipep-
tides, and ceramides.5 Herein, we describe a concise method for
OH
OH
H
N
OH
H
OH
OH
N
OH
5 epi-Swainsonine
4 Hyacinthacine A1
HO
OH
NH2 OH
TBSO
OMe
OH
OTBS
O
N
OH
O
Boc
3
2
R O
O3
R1
N
H
R2
OH
OH
R1 = (CH2)16CHMe2
1 Cerebroside sphingolipid
R2 = (CH2)8Me; R3 = H
R1 = (CH2)19Me; R2 = (CH)9CHMe2
OH
O
2 Agelasphin-9b
HO
R3 =
HO
OH
* Corresponding authors. Tel./fax: +86 21 54237757 (B.-G.W.).
E-mail address: bgwei1974@fudan.edu.cn (B.-G. Wei).
Figure 1. Examples of the natural products containing lactam 2 or its fragment 3
unit.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.001

4318
W.-F. Huang et al. / Tetrahedron Letters 51 (2010) 4317–4319
the preparation of the lactam 2 based on the glutamic acid and its
utility in the total synthesis of the crab sex pheromone 1.
O
O
HO
OH
Usually the optically active building block 2 could be obtained
through (R)-pyroglutamic acid6 derived from the natural glutamic
acid as the chiral source,7 or directly through the self-condensation
of glutamic acid derivative in high temperature and low pressure,8
and these approaches required many steps or inconvenience, and
led to an unsatisfied overall yield despite its robust chemistry. Con-
sidering step-efficiency, condition-mildness, and overall yield, we
started to explore a short approach to 2 from the cheap glutamic
acid (Scheme 1). Initially, (R)-glutamic acid was conveniently con-
verted to its derivative 7 in 57% yield according to the known
method.9 Next, protection of compound 7 as its TBS ether (TBSCl,
imidazole) gave the compound 8 in 97% yield. Upon hydrogenation
(10% Pd/C, MeOH) of compound 8 to remove the protective group
(Cbz) of the amino, spontaneously intramolecular cyclization and
subsequent amidation with Boc2O in ‘one pot’ resulted in the
known lactam 9 in 69% yield.6c,10 Treatment of compound 9 with
LDA/PhSeBr in tetrahydrofuran at ꢀ78 °C followed by elimination
a
b
OTBS
OTBS
O
N
O
N
Boc
Boc
11
2
O
O
O
O
d
O
c
H
N
OTBS
O
BocN
O
O
NHBoc
13
12
O
OH
C11H23
C11H23
e
O
OH
BocN
O
NH2
OH
15
14
11
of the resulting phenylselenyl derivative with H2O2 smoothly
Scheme 2. The synthetic route of the compound 15. Reagents and conditions: (a)
DMP, TsOH, acetone, rt, overnight, 96%; (b) (i) LiOH, THF/H2O (v/v = 3/1), rt, 1 h, (ii)
NH(OMe)MeꢂHCl, HOBt, EDC, i-Pr2NEt, DCM, 0 °C to rt, 12 h, two steps 67%; (c) (i)
TBAF, THF, rt, 3 h, (ii) DMP, BF3ꢂEt2O, DCM, rt, 4 h, two steps 63%, (iii) DIBAL-H, DCM,
ꢀ78 °C, 3 h, 69%; (d) (i) n-C10H21PPPh3Br, n-BuLi, THF, 0 °C to rt, 4 h, 71%, (ii) 10% Pd/
C, H2, MeOH, rt, overnight, 86%; (e) (i) CF3COOH, rt, 5 h, (ii) AcOH–H2O (v/v = 4/1),
45 °C, 12 h, 62%.
gave the alkene 10 in 71% yield. Then the alkene 10 was oxidized
with K2Os2O2(OH)4/NMO in t-BuOH/H2O to give the dihydroxyla-
tive compound 2 as the single isomer {½a D25
ꢁ
+10.8 (c 0.8, CHCl3);
lit.6c the enantiomer ½a 2D0
ꢀ10.6 (c 0.84, CHCl3)} in 65% yield. The
ꢁ
spectroscopic and physical data of the lactam 2 were identical with
the reported data.6c,12
Encouraged by the convenient method for preparation of build-
ing block 2, we then started to investigate the challenging synthe-
sis of sphingosine unit based on the lactam 2 (Scheme 2).
Protection of the two hydroxyl groups of 2 with 2,2-dimethoxypro-
pane (DMP) afforded the compound 11 in 96% yield. Treatment of
compound 11 with LiOH in THF/H2O gave the corresponding car-
boxylic acid as a colorless foam without further purification due
to its dehydrative reversion to lactam 11.13 Then immediate con-
densation of the crude carboxylic acid with N,O-dimethylhydroxyl-
amine hydrochloride in the presence of HOBt and EDC afforded the
desired product 12 in 67% overall yield. Next, 12 deprotected with
TBAF in tetrahydrofuran, followed by protection (DMP, BF3ꢂEt2O)14
and reduction with DIBAL-H15 generated the aldehyde 13 in 43%
overall yield (three steps).
ence of n-BuLi to afford the E and Z mixture of the olefin in 71%
combined yield. Hydrogenation (10% Pd/C, MeOH) of the olefin
mixture and removal of the protective groups (CF3COOH, AcOH/
H2O) afforded the desired compound 15 in 53% overall yield.
In order to prepare acid 20 for the total synthesis of sex phero-
mone 1, we again selected
D
-glutamic acid 6 as a starting material
O
Ref 5b
a
c
D-Glutamic acid
HO
OMe
OTBS
6
16
The unpurified aldehyde 13 was directly subjected to the Wittig
reaction with decanetriphenylphosphonium bromide in the pres-
O
O
b
MeO
OH
MeO
O
O
8
8
OTBS
OTBS
NHCbz
17
18
a
b
O
D-Glutamic acid
Ref 9
O
O
OH
e, 15
d
6
HO
MeO
OTBS
19
7
17
ref
17
OH
20
HO
NHCbz
c
OTBS
O
O
N
O
OH
O
OTBS
Boc
8
9
N
H
OH
OH
HO
OH
OTBS
d
e
OTBS
O
N
O
N
Boc
1 Cerebroside sphingolipid
Boc
10
Scheme 3. The synthesis of the Cerebroside sphingolipid 1. Reagents and condi-
tions: (a) (i) (COCl)2, DMSO, TEA, DCM, ꢀ78 °C, 4 h, 85%, (ii)
BnOCH2(CH2)5CH2PPh3Br, n-BuLi, THF, rt, 3 h, 81%, (iii) 10% Pd/C–20% Pd(OH)2/C,
MeOH, overnight, 95%; (b) (i) (COCl)2, DMSO, TEA, DCM, ꢀ78 °C, 4 h, 95%; (c) (i)
Me2CH(CH2)7CH2PPh3Br, n-BuLi, THF, 0 °C, 3 h, 85%, (ii) 10% Pd/C, MeOH, rt, 4 h,
92%; (d) (i) TBAF, THF, rt, 4 h, (ii) LiOH, THF–H2O (v/v = 3/1), rt, 6 h, two steps 53%;
(e) (i) [1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride] (WSCI),
HOBt, DCM, rt, 24 h, (ii) TBAF, THF, rt, 6 h, two steps 46%.
2
Scheme 1. The synthetic route of the important lactam 2. Reagents and conditions:
(a) (i) MeOH, SOCl2, ꢀ20 °C to rt, 2 h, (ii) CbzCl, Na2CO3–NaHCO3, 1,4-dioxione/H2O
(v/v = 1/1), 0 °C to rt, overnight, (iii) NaBH4, MeOH, THF, 0 °C, 2 h, three steps 57%;
(b) TBSCl, imidazole, DMAP, DMF, rt, overnight, 97%; (c) 10% Pd/C, H2, TEA, Boc2O, rt,
48 h, 69%; (d) (i) LDA, THF, PhSeBr, ꢀ78 °C, 6 h, (ii) H2O2, DCM, rt, 2 h, two steps
71%; (e) K2Os2O2(OH)4, NMO, t-BuOH/H2O (v/v = 3/1), rt, overnight, 65%.

W.-F. Huang et al. / Tetrahedron Letters 51 (2010) 4317–4319
4319
4. (a) Asai, N.; Fusetani, N.; Matsunaga, S. J. Nat. Prod. 2001, 64, 1210; (b) Masuda,
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for the preparation of the important intermediate 16 by our own
method (Scheme 3).5b
Oxidization of alcohol 16 with DMSO/(COCl)2 at ꢀ78 °C pro-
vided the unpurified aldehyde, which was directly subjected to
the Wittig reaction and hydrogenation to afford alcohol 17 in
65% yield. Similarly, the alcohol 17 was easily converted to the
compound 19 according to the above Wittig reaction conditions
in 74% yield. Deprotection and hydrolysis of the compound 19 gave
the corresponding acid 20 in 53% yield. By the known method4a the
condensation of the acid 20 with the amino of the compound 15 in
the presence of [1-(3-dimethylaminopropyl)-3-ethylcarbodimide
hydrochloride] (WSCI)4a and HOBt followed by the removal of
the protective group afforded the sex pheromone 1 {½a D25
ꢁ
+12.3 (c
0.13, CHCl3–MeOH, 1:1); lit.4c
½
a 2D2
+12.5 (c 0.16, CHCl3–MeOH,
ꢁ
1:1); lit.4b
½
a 2D8
+14 (c 0.70, CHCl3–MeOH, 1:1)} in 46% overall yield.
ꢁ
The spectroscopic and physical data of the synthetic sex phero-
mone 1 were identical with the reported data.4,16 Thus, a new
method for the asymmetric synthesis of sex pheromone 1 was
established based on the glutamic acid as the starting material.
In conclusion, sex pheromone 1 of the hair crab was synthesized
based on the readily available building block 2 derived from the
cheap starting material. Further application of this methodology
in the asymmetric synthesis of other ceramides and natural prod-
ucts, through the versatile chiral building block 2, is in progress
and to be published elsewhere.
10. Yoda, H.; Oguchi, T.; Takabe, K. T. Tetrahedron: Asymmetry 1996, 7, 2113.
11. (a) Clive, D. L. J. Tetrahedron 1978, 34, 1049; (b) Reich, H. J. Acc. Chem. Res. 1979,
12, 22; (c) Wei, B.-G.; Chen, J.; Huang, P.-Q. Tetrahedron 2006, 62, 190.
12. Physical data for synthetic building block 2. ½a D20
ꢁ
+10.8, (c 0.8, CHCl3), {lit.6c the
enantiomer ½a 2D0
ꢀ10.6 (c 0.84, CHCl3)}. IR 3440, 2956, 1775, 1368, 1286, 1154,
ꢁ
1093 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.58 (dd, J = 5.1, 3.3 Hz, 1H), 4.35 (d,
;
J = 4.8 Hz, 1H), 4.14–4.11 (m, 1H), 3.98 (dd, J = 10.8, 2.7 Hz, 1H), 3.83 (dd,
J = 11.1, 1.5 Hz, 1H), 3.33 (s, 1H), 3.08 (s, 1H), 1.54 (s, 9H), 0.85 (s, 9H), 0.03 (s,
3H), 0.01 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d 173.9, 149.6, 83.7, 71.5,
69.2, 64.6, 61.7, 27.9, 25.8, 18.1, ꢀ5.7, ꢀ5.6 ppm; MS (ESI): 384 (M+Na+);
HRESIMS calcd for [C16H31NO6Si+Na]+: 384.1820, found: 384.1835.
13. Smith, A. B., III; Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Duan, J. J.-W.; Hull,
K.-G.; Iwashima, M.; Qiu, Y.-P.; Spoors, P. G.; Salvatore, B. A. J. Am. Chem. Soc.
1999, 121, 10478.
14. Foss, F. W.; Snyder, A. H.; Davis, M. D.; Rouse, M.; Okusa, M. D.; Lynch, K. R.;
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Acknowledgments
15. Qi, X.-X.; Wang, X.-L.; Wang, L.-M.; Wang, Q.; Cheng, S.-X.; Suo, J.-S.; Chang, J.-
B. Eur. J. Med. Chem. 2005, 40, 805.
This work was financially supported by NSFC (20832005,
20702007) and the 973 program of China (2010CB912600).
16. Physical data for synthetic pheromone of hair crab 1. ½a D25
ꢁ
+12.3 (c 0.13, CHCl3–
+14 (c 0.70,
1H
MeOH, 1:1); {lit.4c
½
a 2D2
ꢁ
+12.5 (c 0.16, CHCl3–MeOH, 1:1); lit.4b a 2D8
½ ꢁ
CHCl3–MeOH, 1:1)}. IR (film): mmax 3379, 2915, 1642, 1472, 1084 cmꢀ1
;
References and notes
NMR (300 MHz, CDCl3–CD3OD, 1:1): d 4.12–4.07 (m, 1H), 4.02 (dd, J = 7.9,
3.8 Hz, 1H), 3.76 (dd, J = 11.4, 4.9 Hz, 1H), 3.70 (dd, J = 11.4, 4.9 Hz, 1H), 3.57–
3.49 (m, 2H), 1.73–1.60 (m, 2H), 1.56–1.08 (br m, 59H), 0.87–0.83 (m, 9H)
ppm; 13C NMR (75 MHz, CHCl3–MeOH, 1:1): d 176.21, 75.62, 72.68, 72.32,
61.34, 52.01, 51.92, 39.44, 34.83, 33.01, 32.31, 30.29, 30.17, 30.09, 30.03, 30.00,
29.95, 29.88, 29.72, 28.32, 27.83, 26.24, 25.62, 23.08, 22.82, 14.34, 13.72 ppm;
MS (ESI): 650.5 (M+Na+); HRMS(MALDI/DHB) calcd for (C38H77NO5+Na+):
650.5717, found: 650.5699.
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