Enantioselective total synthesis of (-)-dactylolide

Article abstract of DOI:10.1021/ol053092b

The enantioselective total synthesis of (-)-dactylolide is reported. The absolute stereochemistry of the tetrahydropyran was established by catalytic asymmetric Jacobsen hetero-Diels-Alder reaction. The remote C19 stereocenter was introduced by a sequence

Full text of DOI:10.1021/ol053092b

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1117-1120
Enantioselective Total Synthesis of
)-Dactylolide
(−
Ignace Louis, Natasha L. Hungerford, Edward J. Humphries, and
Malcolm D. McLeod*
School of Chemistry, F11, The UniVersity of Sydney, NSW 2006, Australia
m.mcleod@chem.usyd.edu.au
Received December 21, 2005
ABSTRACT
The enantioselective total synthesis of (
catalytic asymmetric Jacobsen hetero-Diels
Grignard addition and Ireland Claisen rearrangement.
−)-dactylolide is reported. The absolute stereochemistry of the tetrahydropyran was established by
−Alder reaction. The remote C19 stereocenter was introduced by a sequence of chelation-controlled
−
In 2001, Riccio and co-workers1 reported the isolation of
dactylolide 1 (Figure 1) from a marine sponge belonging to
relative stereochemistry at the aldehyde-bearing C19-stereo-
center was not reported on isolation. The complete relative
stereochemistry was assigned by Smith2 in the first total
synthesis of (+)-dactylolide 1 in studies that were also
directed toward the total synthesis of the structurally related
and more potent natural product (-)-zampanolide 2.3,4 Since
this first report there have been four other total syntheses of
dactylolide disclosed by the groups of Hoye, Jennings,
Floreancig, and Keck.5
Key aspects of the retrosynthetic analysis applied in this
study are outlined in Scheme 1. The final stages of the
synthesis involve the convergent coupling of acid 3 and
tetrahydropyran fragment 4 using a sequence of Mitsunobu
esterification followed by Grubbs’ ring-closing metathesis
(RCM) to form the lactone ring, which could then be
elaborated to (-)-dactylolide 1 by global deprotection and
oxidation. The key tetrahydropyran fragment 4, containing
the remote C19 stereocenter, was to be obtained from
Figure 1. (+)-Dactylolide 1 and (-)-zampanolide 2.
the genus Dactylospongia found off the coast of Vanuatu. It
exhibited cytotoxicity against L1210 and SK-OV-3 tumor
cell lines, with 63% and 40% inhibition, respectively, at 3.2
µg mL-1.1 Structurally, dactylolide 1 posesses an unsaturated
18-membered lactone ring containing a 2,6-cis-substituted
tetrahydropyran and an aldehyde side chain. However, the
(2) (a) Smith, A. B., III; Safonov, I. G. Org. Lett. 2002, 4, 635. (b) Smith,
A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2002, 124,
11102.
(3) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535.
(4) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc.
2001, 123, 12426.
(5) (a) Hoye, T. R.; Hu, M. J. Am. Chem. Soc. 2003, 125, 9576. (b)
Ding, F.; Jennings, M. P. Org. Lett. 2005, 7, 2321. (c) Aubele, D. L.; Wan,
S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485. (d) Sanchez,
C. C.; Keck, G. E. Org. Lett. 2005, 7, 3053.
(1) Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.;
Gomez-Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775.
10.1021/ol053092b CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/14/2006

pathway, allowing for the synthesis of compound 9 on a
multigram scale. Removal of the PMB protecting group with
DDQ provided alcohol 10 in 82% yield. Parikh-Doering
oxidation10 of the hydroxyl group then furnished the dicar-
bonyl compound, which was subjected to Wittig methylena-
tion of the carbonyl groups and silyl ether deprotection to
provide diene 11 in 58% yield. Oxidation of the primary
alcohol 11 provided the corresponding aldehyde in good
yield, which was used directly in the subsequent Grignard
addition (Scheme 3). It was envisaged that addition of
Scheme 1. Retrosynthetic Analysis
Scheme 3
aldehyde 5 by a judicious sequence of substrate-controlled
reactions including Grignard addition and Ireland-Claisen
rearrangement. The stereochemistry of aldehyde 5 would
itself be established by a Jacobsen catalytic asymmetric
hetero-Diels-Alder reaction. Herein, we report the successful
execution of this strategy for the efficient enantioselective
synthesis of (-)-dactylolide 1.
The synthesis of tetrahydropyran 4 began with the union
of triethylsilyl enol ether 6 and aldehyde 7 in the presence
of Jacobsen’s chiral tridentate chromium(III) catalyst 8
(Scheme 2).6,7 Careful workup of the resulting silyl enol ether
Scheme 2
isopropenyl Grignard to the aldehyde would proceed with
chelation control to favor formation of 12 with the (16S)-
configuration at the newly formed stereocenter.11 The Grig-
nard addition was best achieved by lithium-halogen ex-
change of 2-bromopropene with tert-butyllithium followed
by a transmetalation with magnesium bromide. Grignard
addition to the aldehyde provided allylic alcohol 12 in 63%
yield as an inseparable 86:14 mixture in favor of the desired
(6) Paterson, I.; Tudge, M. Tetrahedron 2003, 59, 6833.
(7) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 1999, 38, 2398.
(8) The enantiomeric excess was determined using chiral HPLC (Chiral-
cel AD-H, 5% isopropyl alcohol/hexane) by comparison with both enan-
tiomers of the tetrahydropyran 9.
(9) An attempted hetero-Diels-Alder reaction of TBS-protected analogue
of enol ether 6 and PMB-protected analogue of aldehyde 7 gave the
corresponding pyran in 77% yield but only 66% ee.
(10) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505.
(11) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem.
Soc. 2000, 122, 10033.
afforded the cis-tetrahydropyranone 9 in 82% yield and 99%
ee8,9 Via an endo-selective hetero-Diels-Alder cycloaddition
1118
Org. Lett., Vol. 8, No. 6, 2006

(16S)-diastereomer.12 The alcohol 12 was then esterified with
PMB protected glycolic acid 13 to give the glycolate ester
in 91% yield. At this stage, the two diastereomers resulting
from the preceding Grignard addition were easily separable
by HPLC to afford ester 14 (76%) as a single diastereomer.
The Ireland-Claisen [3,3] sigmatropic rearrangement13 of
ester 14 afforded polar carboxylic acid 15, which was not
isolated but immediately reduced to give the primary alcohol
16 (80%) as a single diastereomer. Protection of primary
alcohol 16 as the TBS ether and removal of the PMB group
provided alcohol 4 (74%). In this sequence, the (16S)-
configuration of the starting ester 1411 and the chelation-
controlled generation of the (Z)-ketene silyl acetal interme-
diate 1714 (see box, Scheme 3) leads ultimately, Via a
chairlike transition state, to the formation of tetrahydropyran
4 with the (19R,16E)-configuration depicted.15,16
Scheme 5
A concise synthesis of the C1-C9 coupling fragment,
trienoic acid 3, was completed from acrylate ester 18, as
shown in Scheme 4, with the trisubstituted Z-alkene estab-
Scheme 4
20,18 using the RCM protocol of Buchwald,19 afforded
lactone 19 in excellent yield (95%). Partial reduction of the
lactone 19 gave the corresponding lactol as a latent hydroxy-
aldehyde, and direct reaction of this intermediate with
stabilized ylide 21 afforded the desired (2E,4Z)-diene ester
22 in 86% yield (over two steps) after chromatographic
separation of the 94:6 2E/Z mixture. Oxidation of the
primary alcohol 22 with Dess-Martin periodinane20 afforded
the aldehyde, but its elaboration to trienol 23 with vinyl
Grignard reagent proved problematic due to the acidity of
the R-proton in the â,γ-unsaturated aldehyde, a finding also
reported by Jennings et al.5b In an attempt to reduce any
competing enolization of the aldehyde, advantage was taken
of the reduced basicity of organocerium reagents.21 Genera-
tion of the vinylcerium reagent Via transmetalation at
-78 °C and addition of the aldehyde gave the desired trienol
23 in 56% yield. Finally, protection of the allylic alcohol 23
as the TBS ether and hydrolysis of the methyl ester afforded
lished Via a six-membered lactone intermediate 19. Treatment
of the ester 1817 with Grubbs’ second-generation catalyst
(12) Assigned by analogy to the literature (ref 11). Confirmation of this
stereochemical assignment was obtained on the synthesis of pyran 4 (see
below, refs 15 and 16).
(13) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc.
1976, 98, 2868. (b) Martin-Castro, A. M. Chem ReV. 2004, 104, 2939.
(14) (a) Rozners, E.; Xu, Q. Org. Lett. 2003, 5, 3999. (b) Hong, J. H.;
Oh, C.-H.; Cho, J.-H. Tetrahedron 2003, 59, 6103. (c) Mulzer, J.; Mohr,
J.-T. J. Org. Chem. 1994, 59, 1160. (d) Burke, S. D.; Pacofsky, G. J.;
Piscopio, A. D. J. Org. Chem. 1992, 57, 2228. (e) Burke, S. D.; Pacofsky,
G. J. Tetrahedron Lett. 1986, 27, 445. (f) Burke, S. D.; Fobare, W. F.;
Pacofsky, G. J. J. Org. Chem. 1983, 48, 5221.
(17) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S.
P. J. Org. Chem. 2000, 65, 2204.
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(19) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 11253.
(15) The (19R)-configuration of the secondary alcohol 4 was confirmed
using the modified Mosher method: Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
(16) The (16E)-configuration of the alkene 16 was confirmed by the
presence of a strong 1H NMR NOESY cross-peak between the C16 alkene
proton and the C18 allylic protons.
(20) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(21) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.
Org. Lett., Vol. 8, No. 6, 2006
1119

the key C1-C9 trienoic acid 3. Notably, the stereochemistry
at C7 becomes trivial as it is oxidized in the ultimate
synthetic step to (-)-dactylolide 1. Overall, the synthesis of
the C1-C9 fragment 3 was achieved in seven steps and 33%
yield from ester 18.
In conclusion, an efficient synthesis of (-)-dactylolide 1
has been achieved in 21 steps from commercially available
but-3-en-1-ol. An expedient route to the C1-C9 trienoic acid
subunit 3 has been developed. Notably, the absolute con-
figuration of (-)-dactylolide 1 is ultimately derived from a
single chiral catalyst by application of the Jacobsen catalytic
asymmetric hetero-Diels-Alder reaction. The remote C19
stereocenter in fragment 4 is established by substrate control
in an efficient sequence involving chelation controlled
Grignard reaction and Ireland-Claisen rearrangement. Thus,
application of the enantiomeric Jacobsen hetero-Diels-Alder
catalyst ent-8 also allows for the synthesis of (+)-dactylolide
1. Using established methodology,5a (-)-dactylolide could
be readily elaborated to prepare quantities of (-)-zampano-
lide 2.
The final stage of the synthesis involved the coupling of
key subunits 3 and 4, with inversion of configuration at C19,
to form the macrocycle of (-)-dactylolide 1 (Scheme 5).
Mitsunobu esterification22 proceeded cleanly to provide the
ester 24 as a 1:1 mixture of diastereomers about the C7
stereocenter in 63% yield.23 Removal of the silyl ether
protecting groups under mildly acidic conditions afforded
the corresponding diol. This was subjected to ring-closing
metathesis mediated by Grubbs’ second-generation ruthenium
catalyst 2018,24 in degassed dichloromethane to afford
macrocyclic diols 25 with the (8E)-stereoisomer formed. The
final step in the total synthesis of (-)-dactylolide involved
the global oxidation of diols 25. The oxidation was success-
fully accomplished using Dess-Martin periodinane20 in the
presence of solid sodium bicarbonate to provide (-)-
dactylolide 1 in 71% yield. The spectroscopic data and
Acknowledgment. We thank the Australian Research
Council (A00104181) for support.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
spectra for 1, 3, 4, 9-12, 14, 16, 19, and 22-25. This
material is available free of charge via the Internet at
http://pubs.acs.org.
optical rotation for synthetic (-)-dactylolide 1 ([R]20
)
D
-169, c 0.42, MeOH) were in agreement with those
previously reported in the literature.2,5,25
OL053092B
(22) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380. (b) Mitsunobu, O. Synthesis 1981, 1.
(23) Inversion of the C19 configuration during the Mitsunobu esterifi-
cation was confirmed by the synthesis of (-)-dactylolide 1. By contrast,
for a route targeting the synthesis of (+)-zampanolide 2 containing a related
esterification at C19 that occurs with retention of configuration, see ref 2.
(24) This RCM reaction was inspired by the approach reported by Hoye
for a structurally related substrate (ref 5a). In the final stages of this work
a similar sequence of steps was applied to compound 24 by Jennings
(ref 5b).
(25) The sign but not the magnitude of the optical rotation is consistent
for all synthetically derived samples of dactylolide. For (-)-(11S,15S,19S)-
dactylolide: [R]20 ) -169 (c 0.42, MeOH), this work; [R]rt ) -128
D
D
(c 0.39, MeOH), ref 5a; [R]rt ) -136 (c 1.2, MeOH), ref 5b. For (+)-
D
(11R,15R,19R)-dactylolide: [R]D ) +235 (c 0.52, MeOH), ref 2; [R]rt
)
D
+163 (c 0.29, MeOH), ref 5c; [R]rt ) +134 (c 0.065, MeOH), ref 5d.
D
The optical rotation of naturally occurring dactylolide is reported as
[R]D ) +30 (c 0.29, MeOH), ref 1.
1120
Org. Lett., Vol. 8, No. 6, 2006