J-based configuration analysis (JBCA),4 which was later
utilized in the stereochemical assignment of undecachloro-
sulfolipid (Mytilipin B),3b a cytotoxin that is structurally far
more complex than hexachlorosulfolipid. Okino and co-
workers also applied the Murata method to the elucidation
of the stereochemistry of danicalipin A (1).5 Besides such
progress in structural analysis, the recent development of a
synthetic means to install chlorine functionalities has allowed
synthetic chemists to gain access to this class of natural
compounds.6 In this context, avid research aimed at the
establishment of stereoselective routes to chlorosulfolipids
has culminated in the total synthesis of (()-hexachlorosul-
folipid by Carreira and co-workers7 and in the syntheses of
(()-danicalipin A (1)8 and (þ)-malhamensilipin A by
Vanderwal’s group,9 all of which have revealed the unique
reactivity of the chlorinated molecular architecture toward
chemical reactions.
Scheme 1. Retrosynthesis of (þ)-Danicalipin A
Our group has also been engaged in the synthesis of
natural chlorosulfolipid toxins and has developed a
method for the asymmetric construction of chlorinated
hydrocarbon motifs relevant to the polychlorosulfo-
lipids.10 Application of the method has allowed us to ac-
complish the asymmetric total synthesis of (þ)-hexachlo-
rosulfolipid.11 As part of our continuing efforts to establish
a chlorosulfolipid library that would enable us to pursue
structure-activity relationship studies of this new class of
natural toxins, we have initiated a research program to devise
an enantioselective access to the algal toxin (þ)-danicalipin A
(1). In the present study, we disclose a convergent asymmetric
total synthesis of (þ)-danicalipin A (1), in which two chlori-
nated fragments are stereoselectively joined by a 1,3-dipolar
coupling reaction, establishing a successful route to the
polychlorinated molecular architecture.
(þ)-Danicalipin A (1), isolated from the cellular and
flagellar membranes of the freshwater alga Ochromonas
danica, contains six chlorine atoms in its linear hydro-
carbon motif bearing two sulfates. The chemical synthesis of
this molecule in the racemic form was recently accomplished
by Vanderwal and co-workers, which features the sequen-
tial use of stereoselective chlorination of an unsaturated
hydrocarbon motif.8 Okino’s group also succeeded in the
isolation of natural (þ)-danicalipin A (1) from the cultured
chrysophyte O. danica (IAM CS-2) and confirmed its
absolute stereochemistry and toxicological properties.5
Our convergent synthesis of danicalipin A is retro-
synthetically outlined in Scheme 1. In our approach, target
compound 1 was dissected into two parts, i.e., C12-C22
fragment 4 and C1-C11 fragment 5. C12-C22 unit 4 was
prepared in an enantiomerically pure form from a dichlor-
ide readily obtainable from a chiral epoxide. C1-C11
fragment 5, a 1,3-dipolar precursor, would be connected
to fragment 4, giving rise to the whole hydrocarbon motif
bearing oxygen functionalities suitable for the stereoselec-
tive installation of two more chlorine atoms at a later stage.
C12-C22 fragment 4 was synthesized from known
chiral epoxy alcohol 6 with 80% ee, which was prepared
by the asymmetric epoxidation of commercially available
cis-2-nonene-1-ol (Scheme 2).12 Epoxy alcohol 6 was in-
itially protected as pivalate 7 (95%), which, by dichlorina-
tion with the chlorophosphonium reagent generated in situ
from NCS and triphenylphosphine, furnished dichloride 8
in 86% yield. DIBAL reduction of resultant dichloride 8
allowed the removal of the ester group, providing alcohol 9
in 94% yield. This compound 9 was then oxidized with
Dess-Martin periodinane to furnish unstable aldehyde i,
which was immediately reacted with vinylmagnesium
bromide at -78 to 0 °C in Et2O to deliver alcohol 10
stereoselectively. The facial selectivity observed for the
(4) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana,
K. J. Org. Chem. 1999, 64, 866–876.
(5) Kawahara, T.; Kumaki, Y.; Kamada, T.; Ishii, T.; Okino, T.
J. Org. Chem. 2009, 74, 6016–6024.
(6) (a) Shibuya, G. M.; Kanady, J. S.; Vanderwal, C. D. J. Am. Chem.
Soc. 2008, 130, 12514–12518. (b) Kanady, J. S.; Nguyen, J. D.; Ziller, J. W.;
Vanderwal, C. D. J. Org. Chem. 2009, 74, 2175–2178. For a review, see:
Bedke, D. K.; Vanderwal, C. D. Nat. Prod. Rep. 2011, 28, 15–25.
(7) (a) Nilewski, C.; Geisser, R. W.; Carreira, E. M. Nature 2009, 457,
573–576. For the related study, see:(b) Nilewski, C.; Geisser, R. W.;
Carreira, E. M. J. Am. Chem. Soc. 2009, 131, 15866–15876.
(8) (a) Bedke, D. K.; Shibuya, G, M.; Pereira, A. R.; Gerwick, W. H.;
Haines, T. H.; Vanderwal, C. D. J. Am. Chem. Soc. 2009, 131, 7570–7572.
(b) While this manuscript was under review, asymmetric total synthesis of
(þ)-danicalipin A was reported;Umezawa, T.; Shibata, M.; Kaneko, K.;
Okino, T.; Matsuda, F. Org. Lett. 2011, ASAP (DOI: 10.1021/ol102882a).
(9) Bedke, D. K.; Shibuya, G, M.; Pereira, A. R.; Gerwick, W. H.;
Vanderwal, C. D. J. Am. Chem. Soc. 2010, 132, 2542–2543.
(10) (a) Yoshimitsu, T.; Fukumoto, N.; Tanaka, T. J. Org. Chem. 2009,
74, 696–702. For the recent development of this method in catalysis, see:
(b) Denton, R. M.; Tang, X.; Przeslak, A. Org. Lett. 2010, 12, 4678–4681.
(11) Yoshimitsu, T.; Fukumoto, N.; Nakatani, R.; Kojima, N.;
Tanaka, T. J. Org. Chem. 2010, 75, 5425–5437.
1
vinylation (ds =1.7: 1 determined by H NMR analysis
of the crude mixture; for details, see Supporting Information)
can be rationalized by considering the Cornforth transition
(12) (a) Burke, C. P.; Shi, Y. Org. Lett. 2009, 11, 5150–5153.
€
(b) Kanerva, L. T.; Vanttinen, E. Tetrahedron: Asymmetry 1993, 4,
85–90. (c) Yu, L.; Wang, Z. J. Chem. Soc., Chem. Commun. 1993, 232–
234. The enantiomeric purity of this epoxide was determined by the
Mosher method. For details, see the Supporting Information.
Org. Lett., Vol. 13, No. 5, 2011
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