A formal synthesis of (+)-didemniserinolipid B employing a Pd-mediated 6-endo selective alkynediol cycloisomerization

Article abstract of DOI:10.1016/j.tetlet.2008.10.137

Herein, we describe a concise assembly of central 6,8-dioxabicyclo[3,2,1]octane core of didemniserinolipid by employing a Pd-mediated alkynediol cycloisomerization and a formal total synthesis of didemniserinolipid B.

Full text of DOI:10.1016/j.tetlet.2008.10.137

Tetrahedron Letters 50 (2009) 271–273
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A formal synthesis of (+)-didemniserinolipid B employing a
Pd-mediated 6-endo selective alkynediol cycloisomerization
*
C. V. Ramana , Boddeti Induvadana
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we describe a concise assembly of central 6,8-dioxabicyclo[3,2,1]octane core of didemniserino-
lipid by employing a Pd-mediated alkynediol cycloisomerization and a formal total synthesis of didem-
niserinolipid B.
Received 5 September 2008
Revised 20 October 2008
Accepted 29 October 2008
Available online 5 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Didemniserinolipid
Bridged bicyclic ketal
Alkynol cycloisomerization
Zipper reaction
Yamaguchi oxirane–alkyne coupling
The construction of bridged bicyclic ketal units through cyclo-
isomerization of alkynediols1 has gained attention recently due
to the isolation of several new natural products integrated with
bridged bicyclic ketal units and the diverse biological activities
documented for them.2–4 Various metals like palladium, silver,
gold, platinum, and iridium have been explored as catalysts for
the alkynediol cycloisomerization reaction.1,5 The key issue of the
cycloisomerization reactions is the mode of cyclization, that is,
exo-dig versus endo-dig.6 Recently, we reported a systematic
investigation dealing with the influence of electronic and steric
factors over alkynol cycloisomerization reactions mediated by
the Pd[CH3CN]2Cl2 complex. This study has revealed that the
nucleophile prefer selectively the b-carbon of alkyne with respect
to the –I group. Based on these findings, herein we document an
exclusive 6-endo cyclization of an
x-alkyne-1,2,3-triol forming
the central 6,8-dioxabicyclo[3,2,1]octane core of didemniserinoli-
pids and a formal synthesis of didemniserinolipid B (1).
Didemniserinolipids A–C were isolated from the methanol
extract of marine tunicate Didemnum sp., by González et al. in
1999 as the first examples of serinolipids with a unique 6,8-dioxa-
bicyclo[3,2,1]octane core.7 Subsequent to the isolation of
cyclodidemniserinol trisulfate, a related serinolipid with promising
HIV-integrase inhibition by Faulkner and co-workers,8 these
serinolipids have attracted considerable synthetic interest.9,10
The assigned constitution and the relative stereochemistry of
the didemniserinolipid B has been cross-checked by chemical
* Corresponding author. Tel.: +91 20 25902577; fax: +91 20 25902629.
E-mail address: vr.chepuri@ncl.res.in (C. V. Ramana).
Figure 1. Structure of didemniserinolipid and key retrosynthetic disconnections.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.137

272
C. V. Ramana, B. Induvadana / Tetrahedron Letters 50 (2009) 271–273
synthesis providing its absolute stereochemistry (1, Fig. 1) and a
revision in the constitution, by Ley and co-workers.9 Recently,
Burke and co-workers reported the second total synthesis of 1
employing an indigenous ‘intermolecular ketalization followed
by ring-closing metathesis’ (K/RCM) strategy.10
tive 8 was identified as the starting point for the synthesis of epox-
ide 6 after stereochemical comparison. An alkyne zipper reaction12
of a suitable propargyl alcohol for accessing 7 was planned.
As planned, our synthesis started with the Wittig reaction of the
arabinose diacetonide 8 (prepared in 3 steps from D
-mannitol)13
As outlined in Figure 1, our synthesis of the bridged bicyclic ke-
tal core relied upon the palladium mediated cycloisomerization of
and 4-carbon ylide generated from the known phosphonium salt
914 (Scheme 1) to afford E/Z mixture of 10. The hydrogenation of
10 with Raney Ni proceeded by acetonide hydrolysis using PPTS
in MeOH resulted in diol 12. Diol 12 was transformed into oxirane
6 by selective primary OH tosylation using TsCl, Bu2SnO, and tri-
ethylamine in dichloromethane followed by cyclization using
K2CO3 in methanol.15 The requisite C17-alkynol 7 was prepared
from commercially available propargyl alcohol THP ether 14 by a
sequence of 4 steps (Scheme 1b). Thus, the alkylation of 14 with
n-tetradecyl bromide followed by deprotection of the THP group
gave the substituted propargyl alcohol 16. After considerable
experimentation, the acetylenic zipper reaction of 16 could be
the
x-alkyne-1,2,3-triol 5. Though several possibilities exist, the
major concern is the competitive 5-exo-dig versus 6-endo-dig
mode of addition of the central hydroxyl group, the latter being
anticipated from our observations. The synthesis of 2, an advanced
intermediate reported in Burke’s total synthesis of didemniserin-
olipid B was planned by etherification of the 3 with the
unit 4 followed by a two carbon Wittig homologation at C(3).
The synthesis of the key -alkyne-1,2,3-triol 5 was intended
through the coupling of epoxide 6 and C17-alkynol 7 following
the Yamaguchi protocol.11 The easily available
-arabinose deriva-
D-serinol
x
D
Scheme 1. Synthesis of coupling partners (a) epoxide 6 and (b) alkynol 7.
Scheme 2. Key Pd-mediated cycloisomerization of the
x-alkyne-1,2,3-triol 5 and the formal synthesis of didemniserinolipid B (1).

C. V. Ramana, B. Induvadana / Tetrahedron Letters 50 (2009) 271–273
273
effected successfully with Li/t-BuOK16 in 1,3-diaminopropane as
solvent at rt. The resulting alkynol 17 was protected as its TBS
ether to procure the key coupling fragment 7.
2. For recent reviews on synthesis of bridged bicyclic ketals see: (a) Mori, K.
Tetrahedron 1989, 45, 3233–3298; (b) Kotsuki, H. Synlett 1991, 97–106; (c)
Francke, W.; Schröder, W. Curr. Org. Chem. 1999, 3, 407–443; (d) Jun, J.-G.
Synlett 2003, 1759–1777; (e) Kiyota, H. Top. Heterocycl. Chem. 2006, 5, 65–95.
3. Recent reviews: (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2003, 20, 1–48; (b) Blunt, J. W.; Copp, B. R.; Hu, W.
–P.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2008, 25, 35–
94.
4. For representative total synthesis employing alkynediol cycloisomerizations
see: (a) Trost, B. M.; Horne, D. B.; Woltering, M. J. Angew. Chem., Int. Ed. 2003,
42, 5987–5990; (b) Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46,
7664–7666.
5. (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285–2309; (b) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079–3159; (c) Muzart, J.
Tetrahedron 2005, 61, 5955–6008; (d) Hintermann, L.; Labonne, A. Synthesis
2007, 1121–1150; (e) Larrosa, I.; Romea, P.; Urpí, F. Tetrahedron 2008, 64,
2683–2723.
6. (a) Nakamura, H.; Ohtaka, M.; Yamamoto, Y. Tetrahedron Lett. 2002, 43, 7631–
7633; (b) Gabriele, B.; Salerno, G.; Fazio, A.; Pittelli, R. Tetrahedron 2003, 59,
6251–6259; (c) Ramana, C. V.; Mallik, R.; Gonnade, R. G. Tetrahedron 2008, 64,
219–233 and Refs. 5d,e.
After having an easy access to epoxide 6 and alkyne 7, we next
focused our efforts on the synthesis of key cycloisomerization sub-
strate 5. The coupling of 6 with lithiated alkyne 7 in the presence of
BF3ꢀEt2O delivered alkynol 18 in excellent yields (Scheme 2).11 Fi-
nally, the deprotection of acetonide and the TBS protecting groups
of 18 gave tetrol 5.17 The next concern was the key cycloisomeriza-
tion of 5. The treatment of 5 with Pd[CH3CN]2Cl2 (10 mol %) in ace-
tonitrile at room temperature under an argon atmosphere for 2 h
gave exclusively 19 in 70% yield. The structure of 19 was estab-
lished on the basis of spectral and analytical data.18 The presence
of a 6,8-dioxabicyclo[3,2,1]octane moiety in 19 was supported by
the existence of three characteristic methine signals in the 13C
NMR spectrum at 66.3, 77.9, and 82.4 ppm corresponding to
C(8)–C(10) and a quaternary signal corresponding to ketal carbon
at 109.5 ppm which are in agreement with the data reported for
similar derivatives.
7. González, N.; Rodríguez, J.; Jiménez, C. J. Org. Chem. 1999, 64, 5705–5707.
8. Mitchell, S. S.; Rhodes, D.; Bushman, F. D.; Faulkner, D. J. Org. Lett. 2000, 2,
1605–1607.
9. Kiyota, H.; Dixon, D. J.; Luscombe, C. K.; Hettstedt, S.; Ley, S. V. Org. Lett. 2002, 4,
3223–3226.
After executing the synthesis of the central bicyclic core with
the requisite stereochemical information, the remaining portion
of the synthesis required installation of a serinol unit followed by
two carbon elongations at the C(3) end. Simple protective-group
manipulations and mesylation proceeded smoothly to give the
key intermediate 3 in 69% yield, over four steps from diol 19. The
serinol fragment 4 was synthesized according to the reported pro-
cedures.19 By optimizing the conditions reported by Burke and co-
workers, the coupling of 3 and 4 was carried out successfully by the
slow addition of mesylate 3 to a solution of serinol 4 and NaH in
DMSO maintaining the internal temperature at 0 °C. The coupling
product 23 was obtained in 65% yield. Removal of the benzyl ethers
in 23 under hydrogenolysis followed by selective 1°-OH oxidation
of resulting diol 24 with Dess–Martin periodinane (DMP) and two
carbon Wittig homologation completed the synthesis of 2 (Scheme
2). The spectral and analytical data of compound 2 were in agree-
ment with the data reported by Burke and co-workers.20
10. (a) Marvin, C. C.; Voight, E. A.; Burke, S. D. Org. Lett. 2007, 9, 5357–5359; (b)
Marvin, C. C.; Voight, E. A.; Suh, J. M.; Paradise, C. L.; Burke, S. D. J. Org. Chem., in
press. doi:10.1021/jo801666t.
11. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
12. Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891–892.
13. English, J. J.; Griswold, J. P. H. J. Am. Chem. Soc. 1948, 70, 1390–1392.
14. Arndt, S.; Emde, U.; Baurle, S.; Friedrich, T.; Grubert, L.; Koert, U. Chem. Eur. J.
2001, 7, 993–1005.
15. Spectral data of epoxide 6: colorless oil. ½a D25
ꢁ
+4.5 (c 1.2, CHCl3). IR (CHCl3):
m
2937, 2861, 1455, 1371, 1217, 1099, 876, 756, 698 cmꢂ1
.
1H NMR (200 MHz,
CDCl3): d 1.33 (s, 6H), 1.33–1.43 (m, 4H), 1.50–1.65 (m, 4H), 2.58 (dd, J = 2.6,
5.1 Hz, 1H), 2.75 (dd, J = 3.9, 5.1 Hz, 1H), 2.88 (ddd, J = 2.6, 3.9, 6.3 Hz, 1H), 3.22
(dd, J = 6.3, 7.8 Hz, 1H), 3.40 (t, J = 6.5 Hz, 2H), 3.89 (br dt, J = 4.7, 7.8 Hz, 1H),
4.43 (s, 2H), 7.18–7.27 (m, 5H) ppm. 13C NMR (50 MHz, CDCl3): d 25.6 (t), 26.1
(t), 26.6 (q), 27.2 (q), 29.5 (t), 33.1 (t), 45.1 (t), 51.6 (d), 70.2 (t), 72.7 (t), 79.6
(d), 81.1 (d), 109.0 (s), 127.4 (d), 127.5 (d, 2C), 128.2 (d, 2C), 138.6 (s) ppm.ESI-
MS: m/z 343.3 (100%, [M+Na]+). Anal. Calcd for C19H28O4: C, 71.22; H, 8.81.
Found: C, 71.40; H, 8.93.
16. Abrams, S. R.; Shaw, A. C. Org. Synth. 1993, Coll. vol. 8, 146.
17. Spectral data of tetrol 5: white solid. ½a D25
ꢁ
ꢂ3.2 (c 0.5, MeOH). IR (Nujol):
m 3438,
2923, 1462, 1377, 1111, 1058, 737, 648 cmꢂ1
.
1H NMR (methanol-d4, 200
MHz): d 1.22 (m, 18H), 1.35–1.59 (m, 16H), 2.10–2.16 (m, 2H), 2.38 (ddt, J = 2.5,
5.8, 16.8 Hz, 1H), 2.54 (ddt, J = 2.5, 4.7, 16.9 Hz, 1H), 3.32 (dt, J = 1.6, 7.1 Hz,
1H), 3.48 (t, J = 6.6 Hz, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.70 (ddd, J = 4.7, 6.3,
10.5 Hz, 1H), 3.74–3.80 (m, 1H), 4.43 (s, 2H), 7.22–7.28 (m, 5H) ppm. 13C NMR
(methanol-d4, 50 MHz): d 19.1 (t), 21.5 (t), 24.3 (t), 26.0 (t), 26.1 (t), 26.5 (t),
29.3 (t), 29.4 (t), 29.5 (t), 29.8 (t), 29.9 (t), 30.0 (t, 6C), 32.7 (t), 33.7 (t), 62.8 (t),
70.5 (d), 70.8 (t), 71.6 (d), 73.3 (t), 74.3 (s), 76.4 (d), 83.0 (s), 128.0 (d), 128.1 (d,
2C), 128.7 (d, 2C), 138.6 (s) ppm. ESI-MS: m/z 555.4 (100%, [M+Na]+). Anal.
Calcd for C33H56O5: C, 74.39; H, 10.59. Found: C, 74.17; H, 10.44.
In conclusion, a formal synthesis of didemniserinolipid B is doc-
umented. Rapid accesses to the key carbon skeleton and a 6-endo-
selective Pd-mediated cycloisomerization protocol for the central
bicyclic core of the didemniserinolipids highlight the accomplished
synthesis.
Acknowledgments
18. Spectral data of bicyclic ketal 19: colorless syrup. ½a D25
ꢁ
+14.4 (c 1.0, CHCl3). IR
m .
(CHCl3):
3437, 2929, 1639, 1560, 1416, 1216, 757, 668 cmꢂ1 1H NMR (CDCl3,
We thank the Ministry of Science and Technology for funding
through the Department of Science and Technology under the
Green Chemistry Program (No. SR/S5/GC-20/2007). Financial sup-
port from CSIR (New Delhi) in the form of a research fellowship
to B.I. is gratefully acknowledged.
400 MHz): d 1.24–1.32 (m, 23H), 1.35–1.44 (m, 5H), 1.49–1.58 (m, 4H), 1.60–
1.69 (m, 6H), 1.77 (dt, J = 5.5, 12.3 Hz, 1H), 1.92–2.01 (m, 1H), 3.45 (t, J = 6.5 Hz,
2H), 3.57–3.59 (m, 1H), 3.62 (t, J = 6.8 Hz, 2H), 3.87 (dd, J = 5.3, 7.1 Hz, 1H), 4.04
(br s, 1H), 4.48 (s, 2H), 7.26–7.35 (m, 5H) ppm. 13C NMR (CDCl3, 100 MHz): d
22.9 (t), 25.0 (t), 25.3 (t), 25.7 (t), 26.0 (t, 2C), 26.1 (t), 29.4 (t), 29.5 (t), 29.6 (t,
6C), 29.8 (t), 30.1 (t), 32.9 (t), 35.2 (t), 37.5 (t), 63.0 (t), 66.3 (d), 70.3 (t), 72.9 (t),
77.9 (d), 82.4 (d), 109.5 (s), 127.5 (d), 127.6 (d, 2C), 128.3 (d, 2C), 138.6 (s) ppm.
ESI-MS: m/z 555.7 (100%, [M+Na]+). Anal. Calcd for C33H56O5: C, 74.39; H,
10.59. Found: C, 74.20; H, 10.46.
References and notes
19. (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361–2364; (b) Dondoni, A.;
Perrone, D. Org. Synth 2004, Coll. vol. 10, 320.
1. (a) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845–1853; (b) Scheffknecht, C.;
Peringer, P. J. Organomet. Chem. 1997, 535, 77–79; (c) Genin, E.; Antoniotti, S.;
20. Spectral data of compound 2: colorless oil. ½a D25
ꢁ
+24. 6 (c 0.5, CHCl3) lit a 2D5
½ ꢁ +37.6
ˇ
(c 0.98, CHCl3).10a IR (CHCl3):
m 3451, 2928, 1732, 1693, 1465, 1393, 1247,
Michelet, V.; Genet, J.-P. Angew. Chem., Int. Ed. 2005, 44, 4949–4953; (d)
ˇ
1046, 758, 667 cmꢂ1 1H NMR (400 MHz, CDCl3): d 1.24–1.70 (m, 54H), 1.78 (dt,
.
Antoniotti, S.; Genin, E.; Michelet, V.; Genet, J.-P. J. Am. Chem. Soc. 2005, 127,
J = 5.4, 12.4 Hz, 1H), 1.92–2.05 (m, 1H), 2.20 (q, J = 6.8 Hz, 2H), 2.30–2.44 (m,
1H), 3.26–3.60 (m, 5H), 3.60 (br s, 1H), 3.86–3.92 (m, 2H), 3.97–3.99 (m, 1H),
4.05 (br s, 1H), 4.11, 4.17 (2q, J = 7.2 Hz, 2H), 5.80 (br d, J = 15.6 Hz, 1H), 6.94
(dt, J = 7.0, 15.6 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): d 14.3 (q), 22.7 (t),
23.0 (t), 23.1, 24.4 (2q, 1C), 25.0 (t), 25.1 (t), 26.1 (t), 26.7, 27.5 (2q, 1C), 27.8 (t),
28.4, 28.5 (2q, 3C), 29.3 (t), 29.5 (t), 29.7 (t, 8C), 29.8 (t), 30.1 (t), 31.9 (t), 35.0
(t), 37.5 (t), 56.3, 56.5 (2d, 1C), 60.2 (t), 65.4, 65.7 (2t, 1C), 66.2 (d), 69.3, 70.0
(2t, 1C), 71.4 (t), 77.7 (d), 79.7, 80.2 (2s, 1C), 82.4 (d), 93.2, 93.7 (2s, 1C), 109.6
(s), 121.5 (d), 148.9 (d), 166.7 (s) ppm. ESI-MS: m/z 746.8 (100%, [M+Na]+).
Anal. Calcd for C41H73NO9: C, 68.01; H, 10.16; N, 1.93. Found: C, 67.90; H,
10.03; N, 1.72.
9976–9977; (e) Ramana, C. V.; Mallik, R.; Gonnade, R. G.; Gurjar, M. K.
Tetrahedron Lett. 2006, 47, 3649–3652; (f) Liu, B.; De Brabander, J. K. Org. Lett.
2006, 8, 4907–4910; (g) Oh, C. H.; Yi, H. J.; Lee, J. H. New J. Chem. 2007, 31, 835–
837; (h) Ramana, C. V.; Patel, P.; Gonnade, R. G. Tetrahedron Lett. 2007, 48,
4771–4774; (i) Messerle, B. A.; Vuong, K. Q. Organometallics 2007, 26, 3031–
3040; (j) Milroy, L.-G.; Zinzalla, G.; Prencipe, G.; Michel, P.; Ley, S. V.;
Gunaratnam, M.; Beltran, M.; Neidle, S. Angew. Chem., Int. Ed. 2007, 46, 2493–
2496; (k) Diéguez-Vázquez, A.; Tzschucke, C. C.; Wing, Y. L.; Ley, S. V. Angew.
Chem., Int. Ed. 2008, 47, 209–212; (l) Zhang, Y.; Xue, J.; Xin, Z.; Xie, Z.; Li, Y.
Synlett 2008, 940–944; (m) Santos, L. L.; Ruiz, V. R.; Sabater, M. J.; Corma, A.
Tetrahedron 2008, 64, 7902–7909.