Total synthesis of (+)-dactylolide.

Article abstract of DOI:10.1021/ol017271e

[reaction: see text] The total synthesis of the new cytotoxic marine macrolide (+)-dactylolide (1) has been achieved in nine steps from known vinyl bromide (-)-AB. In addition, (+)-zampanolide (2) has been converted to (+)-dactylolide (1) via thermolysis.

Full text of DOI:10.1021/ol017271e

ORGANIC
LETTERS
2002
Vol. 4, No. 4
635-637
Total Synthesis of (+)-Dactylolide
Amos B. Smith, III,* and Igor G. Safonov
Department of Chemistry, Monell Chemical Senses Center,
and Laboratory for Research on the Structure of Matter,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received December 19, 2001
ABSTRACT
The total synthesis of the new cytotoxic marine macrolide (+)-dactylolide (1) has been achieved in nine steps from known vinyl bromide
(−)-AB. In addition, (+)-zampanolide (2) has been converted to (+)-dactylolide (1) via thermolysis.
In 2001 Riccio and co-workers reported the isolation, partial
structure elucidation, and biological activity of (+)-dactylo-
lide (1), a new cytotoxic metabolite from the Vanuatu sponge
Dactylospongia sp.1 Extensive spectroscopic analysis re-
vealed structure 1 (Figure 1), the major architectural elements
undefined stereogenicity at C(19). The absolute stereochem-
istry remained undetermined. The cytotoxic activity of (+)-1
(63% inhibition of L1210 and 40% inhibition of SK-OV-3
tumor cell lines at 3.2 µg/mL),1 although modest in com-
parison to potent cytotoxic agents such as the spongistatins2
and phorboxazoles,3 nevertheless is remarkable in view of
the rather simple structure.
Our interest in the total synthesis of (+)-dactylolide
originated from the close structural similarity of 1 to the
cytotoxic macrolide (-)-zampanolide (2), isolated in 1996
from the Okinawan sponge Fasciospongia rimosa.4 Recently
we disclosed the first total synthesis and stereochemical
assignment of the nonnaturally occurring antipode of zam-
panolide, (+)-2.5 Herein, we report the total synthesis and
complete relative and absolute stereochemical assignments
of (+)-dactylolide (1). In addition, we have achieved the
conversion of (+)-2 to (+)-1.
Figure 1. (+)-Dactylolide (1) and (-)-zampanolide (2), two
metabolites emanating from taxonomically different marine sponges.
Our synthetic analysis of (+)-dactylolide (1), outlined in
Scheme 1, reveals strategic bond disconnections similar to
(2) (a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M.
R.; Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58, 1302. (b)
Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R. J. Chem.
Soc., Chem. Commun. 1993, 1166.
(3) (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
(b) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am.
Chem. Soc. 1996, 118, 9422.
of which include a highly unsaturated but otherwise sparsely
functionalized 20-membered macrolactone; a 2,6-disubsti-
tuted tetrahydropyran, with relative cis stereochemistry
assigned between C(11) and C(15) stereogenic centers; and
(4) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535.
(5) Smith, A. B., III; Safonov I. G.; Corbett, R. M. J. Am. Chem. Soc.
2001, 123, 12426.
(1) Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.;
Gomez-Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775.
10.1021/ol017271e CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/31/2002

Scheme 1
Scheme 2
Dess-Martin oxidation10 of the derived primary alcohol then
furnished (-)-3 (57% yield, three steps), substrate for the
Horner-Emmons macrocyclization.6 Exposure of (-)-3 to
1 equiv of NaHMDS at -78 °C with subsequent warming
to 0 °C led to macrocycle (-)-8 in 72% yield.
those employed to advantage in our successful synthesis of
(+)-zampanolide (2).5 Assuming that the two natural prod-
ucts are related biosynthetically, we envisioned 1 to possess
the same C(19) relative stereochemistry. Thus, disconnection
of the macrocycle at the C(2-3) olefin gives rise to the
Horner-Emmons macrocyclization6 substrate 3. Scission at
the C(1-2) acyl phosphonate linkage and a higher order
cuprate7 coupling transform at C(17-18) further simplifies
3 to epoxide 4, diethylphosphonoacetic acid (5), and vinyl
bromide (-)-AB, the latter arising from fragments (+)-A
and (-)-B in our zampanolide program.5
The synthesis of dactylolide (1) began with union of the
higher order cuprate,7 derived from vinyl bromide (-)-AB,
and epoxide 4;8 alcohol (-)-6 was obtained in an unopti-
mized yield of 40% (Scheme 2). Acylation with com-
mercially available 5, employing the Steglich conditions,9
followed by selective desilylation (HF‚Pyr) at C(3) and
With sufficient quantities of (-)-8 in hand, the synthesis
of (+)-dactylolide (1) was completed in a straightforward
fashion (Scheme 3). Unmasking the C(7) hydroxyl (TBAF),
followed by Dess-Martin oxidation,10 furnished ketone
(+)-9 in 50% overall yield for the two steps. Oxidative
removal of the PMB ether (DDQ)11 then gave the penultimate
C(20) alcohol, which upon oxidation with Dess-Martin
periodinane10 afforded (+)-1 as the sole product (69% yield,
1
two steps), with spectral data [e.g., H (500 and 600 MHz)
and HSQC (600 MHz) NMR and HRMS] corresponding to
those derived from the natural material.12
Completion of the total synthesis of (+)-1 provided an
interesting observation: vinyl bromide (-)-AB gives rise
(6) Aristoff, P. A. J. Org. Chem. 1981, 46, 1954. Nicolaou, K. C.; Seitz,
S. P.; Pavia, M. R. J. Am. Chem. Soc. 1982, 104, 2030.
(7) (a) Lipshutz, B. H.; Kozlowski, J. A.; Parker, D. A.; Nguyen, S. L.;
McCarthy, K. E. J. Organomet. Chem. 1985, 285, 437. (b) Smith, A. B.,
III; Friestad, G. K.; Duan, J. J.-W.; Barbosa, J.; Hull, K. G.; Iwashima, M.;
Qiu, Y.; Spoors, P. G.; Bertounesque, E.; Salvatore, B. A. J. Org. Chem.
1998, 63, 7596.
(8) Prepared in one step from (S)-(-)-glycidol. For further details, see
the Supporting Information.
(9) Neisis, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.
(10) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(11) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.
(12) (a) The 125 MHz 13C NMR data for synthetic (+)-1 revealed small
shifts (∆δ ) (0.1-0.9 ppm) for most carbon signals relative to the
corresponding signals reported for natural (+)-1; the 1H (500 and 600 MHz)
NMR spectra were identical. (b) Optical rotation data for natural (+)-1 )
+30.0° (c 1.0, MeOH); optical rotation for synthetic (+)-1 ) +235° (c
0.52, MeOH).
636
Org. Lett., Vol. 4, No. 4, 2002

Scheme 3
Scheme 4
for 105 min cleanly furnished (+)-1 and 10, as evidenced
by the 1H NMR of the crude reaction mixture. Interestingly,
upon standing in deuterated chloroform at room temperature
both to natural (+)-dactylolide (1) and to the nonnaturally
occurring antipode of zampanolide, (+)-2. Thus, assuming
the published chiroptic data for the two natural products are
accurate, the macrocyclic domain of natural zampanolide is
enantiomeric with that of natural dactylolide!
This observation in turn led us to address another issue,
the origin of dactylolide in relation to zampanolide. Although
(+)-1 and (-)-2 were isolated from two taxonomically
different, geographically widely separated sponge species,
the structural similarity of the two metabolites would seem
to imply that both may arise from genetically related
symbiotic microorganisms. That is, (+)-dactylolide may
either be a biosynthetic precursor of (+)-zampanolide (if the
latter does exist in nature?) or perhaps comprise a degradation
product thereof.
To address the latter chemical issue, we speculated that
exposure of (+)-zampanolide (2) to an organic base or to
thermolysis would lead to elimination of the side chain by
cleavage of the C(20)-N bond, presumably via a pseudo
retro-ene reaction, to afford (+)-1 and hexa-2(Z),4(E)-dienoic
acid amide (10). Interestingly, all attempts to promote the
base-induced fragmentation of (+)-zampanolide (2) either
with triethylamine (Et3N) or 1,8-diazobicyclo[5.4.0]undec-
7-ene (DBU) at room temperature or with sodium bis(tri-
methylsilyl)amide (NaHMDS) at -78 °C met with failure
(Scheme 4). We next turned to thermolysis of (+)-2.
Pleasingly, heating (+)-zampanolide in benzene at 85 °C
1
there was no indication (i.e., H NMR) of reformation of
zampanolide. Chromatographic purification of the reaction
mixture furnished (+)-dactylolide (1), which displayed
spectral and physical data identical in all respects to those
of (+)-1, prepared from vinyl bromide (-)-AB (e.g., 500
1
MHz H NMR, 125 MHz 13C NMR, HRMS, and optical
rotation).
In summary, an efficient total synthesis of (+)-dactylolide
(1) has been achieved in nine linear steps from the known
vinyl bromide (-)-AB. The synthesis permits assignment
of the relative and absolute stereochemistry in (+)-1 as 11R,
15R, and 19R. In addition, facile thermolysis of (+)-
zampanolide (2) to (+)-1 has been achieved.
Acknowledgment. Support was provided by the National
Institutes of Health (National Cancer Institute) through Grant
1
CA-19033. We thank Professor Raffaele Riccio for the H
and HSQC NMR spectra of natural (+)-1.
Supporting Information Available: Spectroscopic data
for compounds 1, 3, 4, and 6-9 as well as complete
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL017271E
Org. Lett., Vol. 4, No. 4, 2002
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