Formal synthesis of (+)-didemniserinolipid B

Article abstract of DOI:10.1016/j.tetlet.2011.10.117

The formal synthesis of (+)-didemniserinolipid B is achieved using Weinreb reaction, Yadav's chiral propargyl alcohol protocol and hydrolytic ketal formation as the key steps.

Full text of DOI:10.1016/j.tetlet.2011.10.117

Tetrahedron Letters 53 (2012) 45–47
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Tetrahedron Letters
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Formal synthesis of (+)-didemniserinolipid B
⇑
Bodugam Mahipal, Kundarapu Mallikarjun, Srivari Chandrasekhar
Organic Chemistry Division-I, Indian Institute of Chemical Technology-CSIR, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The formal synthesis of (+)-didemniserinolipid B is achieved using Weinreb reaction, Yadav’s chiral prop-
argyl alcohol protocol and hydrolytic ketal formation as the key steps.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 27 September 2011
Revised 17 October 2011
Accepted 19 October 2011
Available online 25 October 2011
Keywords:
D-Ribose
1,16-Hexadecanedial
b-Elimination
Weinreb reaction
Didemniserinolipid B
Marine waters have been an excellent source of new chemicals
with various bioactive compounds.1–3 The tunicate Didemnum sp.
is one of the most explored fauna under the sea. In 1999, Jiménez
and co-workers have isolated (+)-didemniserinolipid sulfate 1 hav-
ing intriguing central 6,8-dioxabicyclo-[3.2.1]-octane core with
two alkyl appendages, one ending in a 2-amino propane 1,3-diol
With this strategy at the back of our mind, the D-ribose was con-
verted to chiral allyl furanose derivative 8, following the literature
procedure.9 The oxidative osmylation of this derivative furnished
aldehyde 9 in 91% yield, which was then subjected to Julia olefin-
ation reaction with a known three carbon appendage 1010 to real-
ize 11 in a 92% yield, with 95:5 ratio of E/Z isomers. The
geometrical mixture of compound 11 in one-pot transformation
was subjected to selective hydrogenation of olefin, followed by
deacetylation to furnish alcohol 12 in an 84% yield (over two
steps). The primary alcohol functionality in 12 was transformed
to chloride 5 in an 87% yield by refluxing the substrate in CCl4 in
the presence of TPP and NaHCO3.The reductive opening of tetra-
hydrofurfuryl chloride 5 with LiNH2 in liquid NH3, following
Yadav’s Protocol11 resulted in 1-alkyn-5-ol 13, wherein the C5-OH
center has a wrong stereochemistry with respect to (+)-didemnis-
erinolipid B. The standard Mitsunobu operation was essential to
get the desired stereochemistry, which was performed using
ether and the other terminating as
a
,b-unsaturated ester.4 There
are good number of natural products both from marine and terres-
trial sources with 6,8-dioxabicyclo-[3.2.1]-octane core which have
shown biological properties ranging from insect sex-pheromones,
anti-malarials, to anticancer activities.5–7 Even though, (+)-didem-
niseinolipid 1 (Fig. 1) did not show activity in cancer cell lines,
there is no literature evidence of checking the activity of this class
of molecules for other indications. This may be attributed to the
non-availability of sufficient quantities of compounds for broad
screening. To address this limitation, we herein report the formal
synthesis of this natural product in a stereoselective fashion
involving easily accessible raw materials.
To date, three total and three formal syntheses of didemniserin-
olipid B (1) have been reported.8
The bicyclic-octane core 2 to be constructed through acid catal-
ysis which is proposed to disconnect between C12–C13 to the frag-
ments 3 and 4 and these two subunits can be stitched by Weinreb
OH
12
10
O
29 O
13
31
30
H
9
RO
13
8
O
NH2
reaction. The D-ribose was chosen as a key starting material for
bringing the desired chiral centers in the fragment 3 via 5. The
fragment 4 can be obtained from 6 and 7 (Scheme 1).
1
OEt
5
O
1, R = SO3Na, (+)-Didemniserinolipid B
2, R = H, precursor of (+)-Didemniserinolipid B as HCl salt
⇑
Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
Figure 1. Structure of didemniseinolipid B.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.117

46
B. Mahipal et al. / Tetrahedron Letters 53 (2012) 45–47
O
O
OBn
MOMO
O
Cl
O
D-ribose
5
O
O
OBn
3
2
1
1, 16-hexadecane diol
N
OBn
OH
Br
14
OMe
O
13
6
O
N
4
Boc
O
N
Boc
7
Scheme 1. Retrosynthetic analysis of (+)-didemniserinolipid B.
O
b
O
O
O
BnO
Cl
S
N
N
ref. 9
O
a
N
AcO
AcO
D-ribose
10
N
Ph
O
c
O
O
O
9
8
O
O
O
O
O
OBn
AcO
O
OBn
d
HO
OBn
12
5
O
O
O
11 E/Z = 95::5
O
O
O
O
O
O
f
e
g
OBn
HO
OBn
OBn
HO
14
MOMO
13
3
Scheme 2. Reagents and conditions: (a) OsO4, 2,6-lutidine, NaIO4, 1,4-dioxane/H2O (7:3), rt, 8 h, 91%; (b) KHMDS, THF, ꢀ78 °C, 1.5 h, 92%; (c) (i) H2, 10% Pd/C, NaHCO3, EtOAc,
1.5 h, (ii) LiOHꢁ5H2O, THF/H2O, (8:2), 0 °C to rt, 4 h, 84% (over two steps); (d) CCl4, PPh3, NaHCO3, reflux, 48 h, 87%; (e) Li, Liq NH3, Fe(NO3)3, ꢀ40 °C, 2 h, 86%; (f) (i) PPh3, DEAD,
p-NO2–C6H4–COOH, THF, 0 °C to rt, 12 h, (ii) K2CO3, MeOH, 0 °C, 30 min, 87% (over two steps); (g) MOM-Cl, DIPEA, CH2Cl2, 0 °C to rt, 6 h, 91%.
PPh3, p-nitrobenzoic acid, and DEAD followed by the hydrolysis
a
b
1,16-hexadecane diol
O
with K2CO3 in MeOH to generate compound 14 with the three –
OH groups in required orientation along with terminal acetylenic
functionality for further alkylation. For operational comfort, the
free ꢀOH group in 14 was protected as its OMOM ether 3 in a
91% yield (Scheme 2).
The other fragment 4 was synthesized in a more straight fash-
ion from 1,6-hexadecanediol via benzyloxy bromide 6 (Scheme 3).
The known serinol derivative 712 was alkylated with bromide 6
using the conditions of NaH, TBAI, and THF as a solvent to realize
the serinolipid part 15 in a 53% yield. The debenzylation of 15 with
20% Pd(OH)2 in EtOH and oxidation with BAIB and TEMPO
uneventfully gave acid 16. The acid 16 under the classical condi-
tions (DCC, DMAP, and Et3N in CH2Cl2) was activated as Weinreb
amide 4 in a 92% yield.
With the key fragments 3 and 4 on hand in substantial quanti-
ties, lithiated 3 was added onto Weinreb amide 4 in THF at ꢀ78 °C
to give the coupled product 17 in an 85% yield. Exhaustive hydro-
genation and debenzylation of 17 with 20% Pd(OH)2 in EtOH pro-
duced 18 in a 91% yield. The controlled oxidation of 18 with
Dess–Martin periodinane and Wittig homologation with ethyl tri-
ethyl phosphonoacetate in the presence of LiCl and DIPEA, resulted
OBn
O
Br
14
6
O
OBn
Boc
c
OH
14
O
14
O
N
15
N
16
Boc
Boc
O
N
O
d
14
O
OMe
N
4
Scheme 3. Reagents and conditions: (a) (i) NaH, BnBr, THF:DMF (9:1), 0 °C to rt,
12 h; (ii) CBr4, PPh3, CH2Cl2, 0 °C to rt, 45 min, 78% (over two steps); (b) 7, NaH,
TBAI, THF, 0 °C to rt, 12 h, 53%; (c) (i) 20% Pd(OH)2, EtOH, rt, 3 h, (ii) BAIB, TEMPO,
CH3CN/H2O (1:1), 0 °C to rt, 1 h, 81% (over two steps); (d) DCC, DMAP, Et3N,
CH3ONHCH3ꢁHCl, CH2Cl2, 0 °C to rt, 4 h, 92%.
In conclusion, we have achieved the formal synthesis of didem-
niserinolipid B in a complete stereocontrolled manner using easily
in
a,b-unsaturated ester 19 with all the desired functionalities and
accessible chemicals. D-Ribose and D-serine have been successfully
carbon length. The exposure of 19 to 2 N HCl in EtOH provided the
desired molecule 2 in a 75% yield (Scheme 4), 13 whose NMR-spec-
troscopic data matched with those reported for didemniserinolipid
B and can be converted to 1 using the literature procedure.8
utilized as the chiral sources for the desired stereochemistry via
Weinreb reaction, Yadav’s chiral propargyl alcohol protocol and
hydrolytic ketal formation as the key steps for this marine natural
product.

B. Mahipal et al. / Tetrahedron Letters 53 (2012) 45–47
47
O
O
O
O
a
O
b
14
O
14
3
4
O
O
O
O
MOMO
N
N
MOMO
17
Boc
Boc
18
OH
O
OBn
O
O
O
14
c
O
d
MOMO
ref. 8
N
2
O
1
Boc
19
OEt
Scheme 4. Reagents and conditions: (a) n-BuLi, THF, ꢀ78 to 0 °C, 1.5 h, 85%; (b) 20% Pd(OH)2, EtOH, rt, 5 h, 91%; (c) (i) DMP, CH2Cl2, NaHCO3, 0 °C to rt, 3 h, (ii)
triethylphosphoacetate, LiCl, DIPEA, CH3CN, 0 °C to rt, 3 h, 90% (over two steps); (d) 2 N HCl, EtOH, 70 °C, 8 h, 75%.
CHCl3); IR (KBr): vmax 2915, 1744, 1449, 1372, 1219, 1078, 863, 772 cmꢀ1 1H
;
Acknowledgment
NMR (300 MHz, CDCl3): d 7.40–7.24 (m, 5H), 5.65–5.45 (m, 2H), 4.52 (s, 2H),
4.46 (dd, J = 4.6, 7.0 Hz, 1H), 4.38 (dd, J = 4.6, 7.0 Hz, 1H), 4.26 (dd, J = 6.2,
14.0 Hz, 1H), 4.14–4.05 (m, 2H), 3.97 (dd, J = 6.2, 10.1 Hz, 1H), 3.50 (t, J = 6.2 Hz,
2H), 2.39–2.30 (m, 4H), 2.09 (s, 3H), 1.53 (s, 3H), 1.33 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 170.6, 138.3, 130.0, 128.2, 127.5, 127.4, 114.4, 83.9, 83.8,
83.7, 81.7, 81.5, 72.7, 69.7, 64.3, 36.5, 33.0, 27.2, 25.4, 20.7; MS (ESI): m/z 413
(100) [M+Na]+.
B.M. and K.M. thank the Council of Scientific and Industrial Re-
search-New Delhi for the award of research fellowships.
References and notes
(4S,5R)-4-((R)-6-(Benzyloxy)-1-(methoxymethoxy)hexyl)-5-ethynyl-2,2-dimethyl-
1,3-dioxolane (3): Rf = 0.50 (25% EtOAc in hexanes); ½a D30
ꢂ
= +67 (c 0.5, CHCl3); IR
1. (a) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086; (b)
Yuan, G.; Wahlqvist, M. L.; He, G.; Yang, M.; Li, D. Asia Pacific J. Clin. Nutr. 2006,
15, 143; (c) Terracciano, S.; Aquino, M.; Rodriquez, M.; Monti, M. C.; Casapullo,
A.; Riccio, R.; Gomez-Paloma, L. Curr. Med. Chem. 2006, 13, 1947.
2. (a) Bhadury, P.; Mohammad, B. T.; Wright, P. C. J. Ind. Microbiol. Biotechnol.
2006, 33, 325; (b) Souza, M. V. N. D. The Scientific World 2006, 6, 847.
3. (a) McDougald, D.; Rice, S. A.; Kjelleberg, S. BIOforum Europe 2006, 10, 25; (b)
Sehgal, R.; Sharma, C.; Nandave, M.; Ojha, S. K. Pharma Rev. 2006, 4, 143; (c)
Arias, H. R. Mar. Drugs 2006, 4, 37; For the reviews of Marine Natural Products,
see (d) Faulkner, D. J. Nat. Prod. Rep 2001, 18, 1; (e) Blunt, J. W.; Copp, B. R.; Hu,
W. P.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2009, 26,
170.
(KBr): v ;
max 3285, 2987, 2857, 1453, 1371, 1225, 1099, 918, 864, 738, 698 cmꢀ1
1H NMR (300 MHz, CDCl3): d 7.39–7.23 (m, 5H), 4.95 (d, J = 6.8 Hz, 1H), 4.71–
4.59 (m, 2H), 4.50 (s, 2H), 4.07–3.83 (m, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.41 (s, 3H),
2.47 (d, J = 1.8 Hz, 1H), 1.73–1.21 (m, 14H), 13C NMR (75 MHz, CDCl3): d 138.5,
128.3, 127.6, 127.5, 110.8, 96.8, 81.3, 79.9, 76.6, 75.6, 72.8, 70.3, 67.1, 55.8,
31.6, 29.6, 27.7, 26.2, 26.09, 24.8; MS (ESI): m/z 399 (100) [M+Na]+.
(S)-tert-Butyl-4-((16-(benzyloxy)hexadecyloxy)methyl)-2,2-dimethyloxazolidine-
3-carboxylate (15): Rf = 0.50 (10% EtOAc in hexanes);
CHCl3); IR (KBr): vmax 2926, 2854, 1700, 1458, 1388, 1262, 1102, 845,
½ ꢂ = +4.0 (c = 0.5,
a 3D0
735 cmꢀ1 1H NMR (300 MHz CDCl3): d 7.37–7.22 (m, 5H), 4.50 (s, 2H), 4.15–
;
3.85 (m, 3H), 3.66–3.20 (m, 6H), 1.71–1.06 (m, 43H); 13C NMR (75 MHz,
CDCl3): d 163.6, 138.7, 128.3, 127.5, 127.4, 93.6, 79.9, 72.8, 71.3, 70.5, 69.2,
65.6, 56.3, 29.8–29.3 (CH2 ꢃ 11), 28.4, 27.4, 26.7, 26.1, 24.4, 23.0; MS (ESI): m/z
584 (100) [M+Na]+.
4. González, N.; Rodríguez, J.; Jiménez, C. J. Org. Chem. 1999, 64, 5705.
5. Silverstein, R. M.; Brownlee, R. G.; Bellas, T. E.; Wood, D. L.; Browne, L. E. Science
1968, 159, 889.
(S)-tert-Butyl-4-((18-((4R,5S)-5-((R)-6-(benzyloxy)-1-(methoxymethoxy)hexyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-16-oxooctadec-17-ynyloxy)methyl)-2,2-dimeth-
6. Armstrong, R. W.; Beau, J. M.; Cheon, S. H.; Christ, W. J.; Fujioka, H.; Ham, W. H.;
Hawkins, L. D.; Jin, H.; Kang, S. H.; Kishi, Y.; Martinelli, M. J.; McWhorter, W. W.;
Mizuno, M.; Nakata, M.; Stutz, A. E.; Talamas, F. X.; Taniguchi, M.; Tino, J. A.;
Ueda, K.; Uenishi, J.; White, J. B.; Yogana, M. J. Am. Chem. Soc. 1989, 111, 7530.
7. (a) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.; Semones, M. A.;
Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647; (b) Wagner, C.; Anke, H.; Sterner, O. J.
Nat. Prod. 1998, 61, 501.
8. For total synthesis, see: (a) Kiyota, H.; Dixon, D. J.; Luscombe, C. K.; Hettstedt,
S.; Ley, S. V. Org. Lett. 2002, 4, 3223; (b) Marvin, C. C.; Voight, E. A.; Burke, S. D.
Org. Lett. 2007, 9, 5357; (c) Marvin, C. C.; Voight, E. A.; Suh, J. M.; Paradise, C. L.;
Burke, S. D. J. Org. Chem. 2008, 73, 8452. for formal synthesis, see:; (d) Ramana,
C. V.; Induvadana, B. Tetrahedron Lett. 2009, 50, 271; (e) Prasad, K. R.; Gandi, V.
R. Synlett 2009, 2593; (f) Prasad, K. R.; Gandi, V. Tetrahedron:Asymmetry 2010,
21, 2848.
yloxazolidine-3-carboxylate (17): Rf = 0.40 (25% EtOAc in hexanes); ½a D27
ꢂ
= +42.0
(c 0.5, CHCl3); IR (KBr): mmax 2928, 2856, 2208, 1698, 1457, 1387, 1158, 1099,
1031, 859, 72, 1221 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.36–7.23 (m, 5H), 4.95
;
(d, J = 7.3 Hz, 1H), 4.77 (d, J = 6.1 Hz, 1H), 4.67 (d, J = 6.1 Hz, 1H), 4.49 (s, 2H),
4.10 (dd, J = 6.1, 8.5 Hz, 1H), 4.02–3.96 (m, 1H), 3.94–3.88 (m, 1H), 3.86–3.80
(m, 1H), 3.63–3.24 (m, 10H), 2.53 (t, J = 7.3 Hz, 2H), 1.70–1.20 (m, 55H); 13C
NMR (75 MHz, CDCl3): d 187.2, 156.4, 138.6, 128.3, 127.5, 127.4, 111.1, 96.7,
86.8, 85.5, 81.5, 77.1, 76.4, 72.8, 71.3, 70.2, 70.0, 69.3, 67.1, 56.4, 56.3, 55.8,
45.5, 31.8, 29.65–29.60 (CH2 ꢃ 11), 29.4, 29.3, 28.9, 28.4, 27.7, 26.2, 26.1, 24.8,
23.9, 23.1; MS (ESI): m/z 866 (100) [M+Na]+.
(E)-Ethyl-7-((1R,5S,7R)-5-(15-((R)-2-amino-3-hydroxy- propoxy)-pentadecyl)-2-
hydroxy-6,8-dioxa-bicyclo[3.2.1]-octan-7-yl)hept-2-enoate. Hydrochloride (2):
Rf = 0.30 (20% MeOH in CH2Cl2); ½a D27
ꢂ
= +26.2 (c 1.1, CHCl3); IR (KBr): mmax
9. Fürstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J.
Am. Chem. Soc. 2002, 124, 7061.
3348, 2923, 2851, 1718, 1655, 1467, 1241, 1045, 979, 772 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): d 6.97 (dt, J = 7.3, 15.6 Hz, 1H), 5.81 (d, J = 15.6 Hz, 1H), 4.52
(br s, 4H), 4.18 (q, J = 6.9, 14.8 Hz, 2H), 4.06 (s, 1H), 3.88 (dd, J = 5.0, 7.7 Hz, 1H),
3.84–3.79 (m, 1H), 3.72–3.54 (m, 4H), 3.50–3.40 (m, 3H), 2.21 (q, J = 6.9,
13.8 Hz, 2H), 2.11–1.88 (m, 1H), 1.85–1.73 (m, 1H), 1.72–1.60 (m, 2H), 1.57–
1.45 (m, 4H), 1.44–1.35 (m, 2H), 1.33–1.19 (m, 31H); 13C NMR (75 MHz,
CDCl3): d 166.6, 148.8, 121.4, 109.5, 82.3, 77.6, 71.8, 68.4, 66.1, 60.4, 60.0, 53.2,
37.4, 35.0, 32.0, 30.0, 29.8–29.3 (CH2 x 11), 27.7, 25.8, 25.0, 24.9, 22.9, 14.2; MS
(ESI): m/z 584 (100) [M+H]+.
10. Golden, J. E.; Aubé, J. Angew. Chem., Int. Ed. 2002, 41, 4316.
11. (a) Yadav, J. S.; Chander, M. C.; Joshi, B. V. Tetrahedron Lett. 1988, 29, 2737; (b)
Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron 1990, 46, 7033; (c)
Yadav, J. S.; Chander, M. C. Tetrahedron Lett. 1990, 31, 4349.
12. Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
13. Spectroscopic data for representative compounds: ((3aR, 4R,6S,6aS)-6-((E)-5-
(Benzyloxy)pent-2-enyl)-2,2-dimethyl-tetrahydrofuro[3,
4-d][1,3]dioxol-4-
yl)methyl acetate (11): Rf = 0.40 (20% EtOAc in hexanes); ½a D25
ꢂ
= +7.8 (c 0.8,