to fish4 and invertebrates,5 inhibition of bacterial growth,
and lysis of mammalian erythrocytes.6 However, the bio-
logical mechanism of 1 has not been revealed due to the
difficulty of obtaining molecular probes derived from
natural sources. Therefore, elucidation of the mechanism
using an artificially synthesized molecular probe is highly
desirable. Due to the unprecedented structure and inter-
esting biological activity of 1, along with other CSLs
(2-5),7 these compounds have been the subject of much
attention from synthetic chemists.8 In 2009, Carreira
accomplished an elegant first total synthesis of chlorosul-
folipid 2.9 After this, total syntheses of 1-3 have been
achieved by two groups: racemic 1 and optically pure 3 by
Vanderwal2,10 and optically active 2 by Yoshimitsu and
Tanaka.11 In this report, we describe an asymmetric total
synthesis of danicalipin A (1) and explore the biological
activity of 1 and its enantiomer toward brine shrimp.
For the total synthesis of 1, although a ring-opening
reaction of a cis-epoxide bya chloridewould be expectedto
beeffective for the construction ofsyn-chlorohydrin atC13
and C14, Carreira first reported that epoxide ring-opening
using substrates containing intramolecular chlorides re-
sulted in an undesired product of diastereomers due to the
generation of intramolecular chloronium ions (Figure 2,
eq 1).9a Vanderwal also observed the similar phenom-
enon.2 To avoid this side reaction, an epoxide ring-
opening reaction using a substrate without chloride may
be employed at an early stage of the total synthesis.
Meanwhile, to synthesize the dichloride at C15 and C16
with anti configuration, anti-addition of a molecular chlo-
rine equivalent to an E-olefin was considered. However,
because a previous study by Yoshimitsu and Tanaka
indicated that the addition produced a syn-adduct along
with the anti-adducts,11a improvement of the selectivity of
the anti-addition reaction was concluded to be important
Figure 2. Previous synthetic problems to overcome.
Scheme 1. Retrosynthetic Analysis of Danicalipin A
(4) (a) Reich, K.; Spiegelstein, M. Isr. J. Zool. 1964, 13, 141. (b)
Leeper, D. A.; Porter, K. G. Arch. Hydrobiol. 1995, 134, 207–222.
(5) (a) Boxhorn, J. E.; Holen, D. A.; Boraas, M. E. Hydrobiologia
1998, 387/388, 283–287. (b) Boenigk, J.; Stadler, P. J. Plankton Res.
2004, 26, 1507–1514.
(6) (a) Hansen, J. A. Physiol. Plant. 1973, 29, 234–238. (b) Halevy, S.;
Saliternik, R.; Avivi, L. Int. J. Biochem. 1971, 2, 185–192. (c) Magazanik,
A.; Halevy, S. Experientia 1973, 15, 310–311.
(7) (a) Ciminiello, P.; Fattorusso, E.; Forino, M. J. Org. Chem. 2001,
66, 578–582. (b) Chen, J. L.; Proteau, P. J.; Roberts, M. A.; Gerwick,
W. H.; Slate, D. L.; Lee, R. H. J. Nat. Prod. 1994, 57, 524–527. (c)
Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.; Forino, M.; Magno,
S.; Di Meglio, P.; Ianaro, A.; Poletti, R. J. Am. Chem. Soc. 2002, 124,
13114–13120. (d) Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.;
Forino, M.; Magno, S.; Di Meglio, P.; Ianaro, A.; Poletti, R. Tetra-
hedron 2004, 60, 7093–7098. (e) Pereira, A. R.; Byrum, T.; Shibuya,
G. M.; Vanderwal, C. D.; Gerwick, W. H. J. Nat. Prod. 2010, 73, 279–
283.
(8) Denton, R. M.; Tang, X.; Przeslak, A. Org. Lett. 2010, 12, 4678–
4681.
(9) (a) Nilewski, C.; Geisser, R. W.; Carreira, E. M. Nature 2009, 457,
573–576. (b) Nilewski, C.; Geisser, R. W.; Ebert, M.-O.; Carreira, E. M.
J. Am. Chem. Soc. 2009, 131, 15866–15876.
(10) (a) Bedke, D. K.; Shibuya, G. M.; Pereira, A.; Gerwick, W. H.;
Vanderwal, C. D. J. Am. Chem. Soc. 2010, 132, 2542–2543. (b) Kanady,
J. S.; Nguyen, J. D.; Ziller, J. W.; Vanderwal, C. D. J. Org. Chem. 2009,
74, 2175–2178. (c) Shibuya, G. M.; Kanady, J. S.; Vanderwal, C. D. J.
Am. Chem. Soc. 2008, 130, 12514–12518. (d) Bedke, D. K.; Vanderwal,
C. D. Nat. Prod. Rep. 2011, 28, 15–25.
(11) (a) Yoshimitsu, T.; Fukumoto, N.; Nakatani, R.; Kojima, N.;
Tanaka, T. J. Org. Chem. 2010, 75, 5425–5437. (b) Yoshimitsu, T.;
Fukumoto, N.; Tanaka, T. J. Org. Chem. 2009, 74, 696–702.
(Figure 2, eq 2). With these considerations in mind, the fol-
lowing retrosynthetic analysis of 1 was planned (Scheme 1).
As mentioned above, 1 was expected to be obtained from
E-olefin 6 by anti-addition of the molecular chlorine
equivalent, which would be derived from aldehyde 7 and
phosphonium salt 8 by Wittig olefination. We envisioned
that aldehyde 7 would be accessed by R-chlorination with
aldehyde 9, as reported by Jørgensen,12 which would be
synthesized from the known cis-epoxide 10.
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