Total synthesis of (+)-prelaureatin and (+)-laurallene

Article abstract of DOI:10.1021/ja0007197

The first total syntheses of (+)-prelaureatin and (+)-laurallene are described. An asymmetric glycolate aldol addition was followed by a ring- closing metathesis to close the eight-membered ring allowing construction of the oxocene core of (+)-prelaureati

Full text of DOI:10.1021/ja0007197

J. Am. Chem. Soc. 2000, 122, 5473-5476
5473
Total Synthesis of (+)-Prelaureatin and (+)-Laurallene
Michael T. Crimmins* and Elie A. Tabet
Contribution from the Venable and Kenan Laboratories of Chemistry, The UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
ReceiVed February 28, 2000
Abstract: The first total syntheses of (+)-prelaureatin and (+)-laurallene are described. An asymmetric glycolate
aldol addition was followed by a ring-closing metathesis to close the eight-membered ring allowing construction
of the oxocene core of (+)-prelaureatin and (+)-laurallene in seven synthetic steps from (R)-benzylglycidyl
ether.
The Laurencia red algae, particularly Laurencia nipponica,
and its predators contribute a stunning diversity of medium ring
ether metabolites to the C15 acetogenins.1 Many of these C15
nonterpenoids are halogenated and further decorated with a
variety of substituents including enyne side chains or bromoal-
lenes. Two basic structural types of halogenated eight medium
ring ethers have been isolated from Laurencia sp. (Figure 1).
The lauthisan structural type contains a cis R,R′-disubstituted
oxocene and the R configuration at carbons 6 and 7 while the
laurenan subclass possesses the S configuration at C6 and C7
enforcing a trans R,R′-disubstitution pattern at the ether oxygen.
Biosynthetic studies on the Laurencia cyclic ether metabolites
have demonstrated that lactoperoxidase (LPO) directly trans-
forms 3E,6R,7R-laurediol into deacetyllaurencin2 and 3Z,6S,7S-
laurediol into prelaureatin 1 through a bromo cationic cyclization
(Figure 2).3 Deacetyllaurencin is further transformed to laure-
fucin4 and laurexanyne5 by a second bromo cation cyclization
Figure 1. Medium ring ether natural products.
or to laurencin6 by acetylation. Prelaureatin 17 has been shown
to be the biogenetic precursor8 of several members of the
for the construction of medium ring ethers has resulted from
the synthetic efforts toward laurencin.16 The laurenan structural
subclass has received substantially less attention,17 presumably
because of the added challenge of constructing the oxocene with
the appropriate S configuration at carbons 6 and 7 dictating a
trans R,R′-disubstitution pattern at the ether oxygen.1
Recent reports from our laboratories described an asymmetric
aldol-ring closing metathesis strategy12 for the construction of
the oxocene core of laurencin and a second-generation synthesis
of laurencin based on an asymmetric alkylation-ring-closing
laurenan structural subclass such as laureatin 2, isolaureatin 3,9
and laurallene 4 (Figure 3).10 Laureatin 2 and isolaureatin 3
display significant larvacidal activity (IC50 ) 0.06 and 0.50 ppm,
respectively) in mosquitos.11
The lauthisan class has been the subject of substantial
synthetic effort culminating in several syntheses of the repre-
sentative member laurencin.12-15 A wealth of new strategies
(1) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155-198. Faulkner, D. J.
Nat. Prod. Rep. 1998, 15, 113-158. Faulkner, D. J. Nat. Prod. Rep. 1997,
14, 259-302. Faulkner, D. J. Nat. Prod. Rep. 1996, 13, 75-125 and earlier
reviews in the same series.
(11) Watanabe, K.; Umeda, K.; Miyakado, M. Agric. Biol. Chem. 1989,
53, 2513-2515.
(2) Fukuzawa, A.; Aye M.; Murai, A. Chem. Lett. 1990, 1579-1580.
Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193-4205.
(3) Fukuzawa, A.; Aye, M.; Nakamura, M.; Tamura, M.; Murai, A. Chem.
Lett. 1990, 1287-1290. Kurosawa, E.; Fukuzawa, A.; Irie, T. Tetrahedron
Lett. 1972, 2121-2124.
(12) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653-
5660.
(13) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029-2032.
(14) Masamune, T.; Matsue, H.; Murase, H. Bull. Chem. Soc. Jpn. 1979,
52, 127-134. Masamune, T.; Murase, H.; Matsue, H.; Murai, A. Bull. Chem.
Soc. Jpn. 1979, 52, 135-141. Bratz, M.; Bullock, W. H.; Overman, L. E.;
Takemoto, T. J. Am. Chem. Soc. 1995, 117, 5958-5966. Mujica, M. T.;
Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Synlett 1996, 983-984.
Kru¨ger, J.; Hoffman, R. W. J. Am. Chem. Soc. 1997, 119, 7499-7504.
Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A. J. Org. Chem.
1998, 63, 9728-9738.
(4) Furusaki, A.; Kurosawa, E.; Fukuzawa, A.; Irie, T. Tetrahedron Lett.
1973, 4579-4582.
(5) Fukuzawa, A.; Aye, M.; Nakamura, M.; Tamura, M.; Murai, A.
Tetrahedron Lett. 1990, 31, 4895-4898.
(6) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965, 1091-
1099.
(7) Fukuzawa, A.; Takasugi, Y.; Murai, A. Tetrahedron Lett. 1991, 32,
5597-5598.
(8) Ishihara, J.; Shimada, Y.; Kanoh, N.; Takasugi, Y.; Fukuzawa, A.;
Murai, A. Tetrahedron 1997, 53, 8371-8382.
(9) Irie, T.; Izawa, M.; Kurosawa, E. Tetrahedron Lett. 1968, 2091-
2096. Irie, T.; Izawa, M.; Kurosawa, E. Tetrahedron Lett. 1968, 2735-
2738. Irie, T.; Izawa, M.; Kurosawa, E. Tetrahedron 1970, 26, 851-870.
(10) Fukuzawa, A.; Kurosawa, E. Tetrahedron Lett. 1979, 2797-2800.
(15) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall, J. G.;
Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483-7498. Tsushima, K.;
Murai, A. Tetrahedron Lett. 1992, 33, 4345-4348.
(16) Alvarez, E.; Candenas, M.-L.; Pe´rez, R.; Ravelo, J. L.; Martin, J.
D. Chem. ReV. 1995, 95, 1953-1980.
(17) Edwards, S. D.; Lewis, T.; Taylor, R. J. K. Tetrahedron Lett. 1999,
40, 4267-4270.
10.1021/ja0007197 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/26/2000

5474 J. Am. Chem. Soc., Vol. 122, No. 23, 2000
Crimmins and Tabet
Scheme 1
Figure 2.
metric aldol reaction between 3-butenal21 and the chlorotitanium
enolate of the acyl oxazolidinethione22,23 (or oxazolidinone)
derived from acid 7 would serve to establish the C6 and C7
stereocenters of the oxocene core. Since the critical C6 and C7
stereogenic centers are set in the asymmetric aldol reaction,
simple exchange of the auxiliary chirality could in principle
allow entry into either the lauthisan or laurenan structural type.
The synthesis of the oxocene core 11 is illustrated in Scheme
1. The alcohol 8 was prepared in near quantitative yield by
treatment of (R)-benzylglycidyl ether with vinylmagnesium
bromide in the presence of a copper(I) catalyst.24 Alkylation of
the sodium alkoxide of alcohol 8 with the sodium salt of
bromoacetic acid provided the acid 7 in 93% yield. The acid 7
was converted to the mixed pivalic anhydride and treated in
situ with the lithium salt of (R)-4-benzyl-2-oxazolidinone to
produce 89% of the acyl oxazolidinone 9a. Alternately, the acid
7 was converted to its acid chloride and the acid chloride was
exposed to (R)-4-benzyl-2-oxazolidinethione and triethylamine
to give the acyl oxazolidinethione 9b. Exposure of 9a to titanium
tetrachloride and diisopropylethylamine followed by addition
of a dichloromethane solution of 3-butenal gave 65% of the
aldol adduct 6a accompanied by two minor diastereomers
(<10% combined yield). The oxazolidinethione 9b provided
the aldol adduct 6b with higher selectivity (>95:5) but
somewhat lower yield (57%). Protection of the secondary
hydroxyl of 6a as its tert-butyldimethylsilyl ether gave the diene
10 in excellent yield. The diene 10 was treated with the Grubbs
ruthenium catalyst25 resulting in smooth conversion to the ∆-4-
oxocene 11 in 95% yield with no detectable dimerization. While
Figure 3.
Figure 4. Retrosynthetic plan for prelaureatin.
metathesis approach.13 Here we disclose the total synthesis of
(+)-prelaureatin and (+)-laurallene demonstrating that both the
laurenan and lauthisan structural types are accessible through
similar strategies.
Prelaureatin 1 was isolated by Fukuzawa and Murai in 1991
from laurencia nipponica. Its structure was elucidated as 1 by
a combination of spectroscopic techniques and chemical trans-
formations.7 Retrosynthetically, prelaureatin 1 could be prepared
from the substituted oxocene 5 through selective modification
of the two substituents flanking the ether oxygen (see Figure
4). The eight-membered ring of the oxocene 5 would be
constructed from aldol adduct 6 by a ring-closing metathesis
reaction,18,19 exploiting the gauche effect20 of the C6 and C7
oxygen substituents to accelerate the ring closure. An asym-
(19) For other applications of ring-closing metathesis in the synthesis
of medium ring ethers see: Clark, J. S.; Hamelin, O. Angew. Chem. In.
Ed. 2000, 39, 372-374 and references therein.
(20) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley and Sons: New York, 1994; pp 609-610.
(21) Crimmins, M. T.; Kirincich, S. J.; Wells, A. J.; Choy, A. L. Synth.
Commun. 1998, 28, 3675-3679.
(22) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883-7884.
(23) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047-1049.
(24) Gravestock, M. B.; Knight, D. W.; Lovell, J. S.; Thornton, S. R. J.
Chem. Soc., Perkin Trans. 1 1994, 1661-1663. Takano, S.; Sekiguchi, Y.;
Sato, N.; Ogasawara, K. Synthesis 1987, 139-141.
(25) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(18) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446-452. Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 7324-
7325.

Total Synthesis of (+)-Prelaureatin and (+)-Laurallen
J. Am. Chem. Soc., Vol. 122, No. 23, 2000 5475
Scheme 2
Scheme 3
Scheme 4
there have been observations that a trans relationship of the
substituents flanking the ether oxygen can adversely affect the
rate of ring-closing metathesis reactions of eight- and nine-
membered ethers,26 the gauche effect of the C6 and C7 oxygens
apparently has an overriding effect in this case. With the
successful execution of the ring-closing metathesis, the laurenan
oxocene core, complete with the required stereochemistry and
the trans R,R′-disubstituted ether linkage, had been rapidly
assembled in just six synthetic steps.
Initial attempts to extend the C6 and C12 side chains focused
on a one-carbon extension at C5 (see Scheme 2). To this end,
the chiral auxiliary was reductively removed with lithium
borohydride to produce the primary alcohol 12. The primary
alcohol 12 was oxidized to the aldehyde under Swern27
conditions and the unstable aldehyde was immediately exposed
to methoxymethylenetriphenylphosphorane to give a modest
yield of the vinyl ether 13 contaminated with varying amounts
of the unsaturated aldehyde 14. Ratios of 13:14 varied from
6:1 to 8:1 and storage of vinyl ether 13 led to slow conversion
to the aldehyde 14. Since removal of the C13 benzyl ether was
required prior to introduction of the enyne moiety, the benzyl
ether of 13 was cleaved by treatment with sodium in ammonia
at -78 °C. The resultant alcohol 15 was exposed to aqueous
mercuric acetate to effect hydrolysis of the vinyl ether. While
aldehyde 16 was produced, the yield (37%) for the last two
steps was low and competitive elimination to produce an
unsaturated aldehyde was once again observed.
in the production of aldehyde 16, it was decided to pursue the
extension of the C12 side chain prior to the attachment of the
C5 enyne.
Reduction of the oxazolidinone 6a or the oxazolidinethione
6b followed by protection of the C5 and C7 hydroxyls as their
tert-butyldimethylsilyl ethers afforded the diene 20 (see Scheme
4). The diene 20 was treated with the Grubbs ruthenium
catalyst25 resulting in smooth conversion to the ∆-4-oxocene
21 in 2 h in 95% yield. Modification of the C12 substituent
required removal of the benzyl ether at C13. Treatment of benzyl
ether 21 with sodium in THF and ammonia afforded the alcohol
22 in 95% yield. Oxidation of the alcohol 22 under Swern27
conditions followed by addition of ethylmagnesium bromide
provided the secondary alcohol with only modest stereocontrol
(1.1:1 in favor of the desired isomer 24) in 90% overall yield.
This and other13 examples indicate that chelation control is
apparently limited in R-alkoxyaldehydes where the chelating
ether oxygen resides in a medium ring, probably because of
reduced Lewis basicity of the ether oxygen. Attempted use of
diethylzinc in the presence of chiral catalysts to control the
stereochemistry at C13 was not effective.28 However, oxidation
of the mixture of secondary alcohols 23 and 24 to the
corresponding ethyl ketone followed by Felkin-Anh reduction
Other methods for one carbon extension were also investi-
gated with little success (see Scheme 3). Conversion of alcohol
12 to the mesylate 17 proceeded readily, but attempts to displace
the mesylate (or triflate) with iodide or cyanide ion were
unsuccessful presumably because of the adverse inductive effect
of the adjacent ring oxygen and the steric effect of the adjacent
TBS ether. Direct conversion of the alcohol 12 to iodide 19
also proceeded in low yield. Because of the difficulty with the
one-carbon extension at C5 and the problems with â-elimination
(26) Linderman, R. J.; Siedlecki, J.; O’Neill, S. A.; Sun, H. J. Am. Chem.
Soc. 1997, 119, 6919-6920. Clark, J. S.; Kettle, J. G. Tetrahedron Lett.
1997, 38, 127-130. Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38,
123-126.
(27) Swern, D.; Mancuso, A. J.; Huang, S.-L. J. Org. Chem 1978, 43,
2480-2482.
(28) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M. Tetrahedron
1994, 50, 4363-4384.

5476 J. Am. Chem. Soc., Vol. 122, No. 23, 2000
Crimmins and Tabet
Scheme 5
Scheme 6
with L-selectride15 gave excellent stereocontrol for the desired
Aldehyde 28 was also converted directly to a 3:1 mixture of
E and Z enynes 33 upon exposure to Wittig reagent 32 as
illustrated in Scheme 6. Removal of the alcohol and the
acetylene protecting groups as before afforded a 3:1 mixture of
E-prelaureatin 34 and prelaureatin 1. The E-enyne was treated
with tetrabromocyclohexadienone according to the procedure
described by Murai8 to produce laurallene 4 and its bromoallene
diastereomer 35 in 53% yield. The isomeric bromoallenes were
separated by HPLC to give pure (+)-laurallene 4 and the
bromoallene isomer 35. Synthetic (+)-laurallene illustrated
identical physical properties (1H NMR, 13C NMR, IR, [R]d) to
those reported for the natural product.10
The first total syntheses of (+)-prelaureatin, (+)-E-prelau-
reatin, and (+)-laurallene illustrate the efficiency and power of
the asymmetric aldol-ring closing metathesis strategy for the
construction of complex medium ring ethers. Both the lauthisan
structural class such as laurencin and the laurenan structural
class exemplified by laurallene and prelaureatin are accessible
through this versatile and efficient strategy. Further application
of the asymmetric aldol-ring closing metathesis strategy for
the construction of medium rings is in progress.
diastereomer 24 (>95:5 diastereoselectivity). Exposure of
29
alcohol 24 to trioctylphosphine and CBr4 cleanly effected
incorporation of the C13 bromide providing bromide 25 in 88%
yield.
With completion of the C12 side chain, attention turned once
again to extension of the C6 substituent (see Scheme 5). The
primary TBS ether was selectively removed (HF-pyr, pyridine,
THF) in preparation for a one-carbon extension at C5. Swern27
oxidation of 26 followed by methoxymethylenation proceeded
in good yield to give a mixture of the vinyl ethers 27 that were
immediately hydrolyzed to the aldehyde 28. Exposure of
aldehyde 28 to the ylide developed by Stork30 provided Z vinyl
iodide 29 in 70% yield. Due to the lability of the vinyl ethers
27 and the aldehyde 28, it was important to process the alcohol
26 to the vinyl halide 29 as quickly as possible. Rapid processing
led to reproducible, workable yields from 26 to 29. The vinyl
iodide 29 was converted to the enyne 30 in 87% yield through
a Sonogashira31 coupling with trimethylsilylacetylene. Removal
of the trimethylsilyl and tert-butyldimethylsilyl protecting groups
could be accomplished concomitantly with n-Bu4NF (THF, 0
°C) to give prelaureatin 1, but competing elimination of the
secondary bromide was observed. Better overall yields and
cleaner conversion was observed when the TBS ether was
removed with 5% HF (CH3CN, 0 °C) followed by removal of
the acetylenic TMS with n-Bu4NF (THF, -78 °C). Synthetic
Acknowledgment. This work was supported by a research
grant from the National Institutes of Health. Burroughs-
Wellcome and Bost Fellowships for E.A.T. are gratefully
acknowledged.
(+)-prelaureatin was spectroscopically identical (1H NMR, 13
NMR, IR, [R]d) with that reported for the natural material.7
C
Supporting Information Available: Spectral data and
experimental procedures for compounds 1, 4, 6a, 6b, 7, 9a, 9b,
20-31, 33, and 34 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(29) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345-4348.
(30) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
(31) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
12, 4467-4470.
JA0007197