Total synthesis of elaiolide using a copper(l)-promoted stille cyclodimerization reaction

Article abstract of DOI:10.1021/ol990004c

(equation presented) Elaiolide (2) The 16-membered macrodiolide elaiolide (2) has been prepared in 20 steps from the ketone (S)-8 in 9.3% overall yield with a diastereoselectivity of 76%. Key steps included the copper(l) thiophene-2-carboxylate promoted c

Full text of DOI:10.1021/ol990004c

ORGANIC
LETTERS
1999
Vol. 1, No. 1
19-22
Total Synthesis of Elaiolide Using a
Copper(I)-Promoted Stille
Cyclodimerization Reaction
Ian Paterson,* Henry-Georges Lombart, and Charlotte Allerton
UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K.
ip100@cus.cam.ac.uk
Received March 9, 1999
ABSTRACT
The 16-membered macrodiolide elaiolide (2) has been prepared in 20 steps from the ketone (S)-8 in 9.3% overall yield with a diastereoselectivity
of 76%. Key steps included the copper(I) thiophene-2-carboxylate promoted cyclodimerization of the vinyl stannane 3 to give the C -symmetric
2
macrocycle 16 in 80% yield and the two-directional aldol coupling of the macrocyclic diketone 17 with aldehyde 5. Most of the stereocenters
in the macrocyclic precursor 3 were constructed using boron aldol methodology developed in this laboratory.
Elaiophylin (1), first isolated from cultures of Streptomyces
melanosporus by Arcamone et al.1a and shortly thereafter
from a related microorganism by Arai,1b is a 16-membered
macrolide which displays antimicrobial activity against
several strains of Gram-positive bacteria.2a-c Elaiophylin also
has anthelmintic activity against Trichonomonas Vaginalis,3a
as well as inhibitory activity against K+-dependent adenosine
triphosphatases.2d The C2-symmetric macrodiolide structure
was determined by chemical degradation3a-c and spectro-
scopic methods,3d with the full absolute configuration being
elucidated by X-ray crystallographic analysis.3e,f Elaiophylin
belongs to a family of structurally related compounds, all
having similar stereochemistry in the secoacid moiety. These
include several other 16- and 18-membered monomeric
macrolides, in particular the bafilomycins and concanamy-
cins.4 The elaiophylin aglycon elaiolide (2) has been obtained
through acidic deglycosylation of 1.5
Previous synthetic efforts6 directed toward elaiophylin (1)
have constructed the macrodiolide core by a conventional
esterification/lactonization strategy. This has generally been
followed by a double aldol coupling between a macrocyclic
dialdehyde and an ethyl ketone to form the C9-C10 bond,
which was employed in the total synthesis by Kinoshita et
al.6a,b In the same manner, various aglycon derivatives6c-h
(1) (a) Arcamone, F. M.; Bertazzoli, C.; Ghione, M.; Scotti, T. G. G.
Microbiol. 1959, 7, 207. (b) Azalomycin B, as reported by Arai, is identical
with elaiophylin: Arai, M. J. Antibiot., Ser. A 1960, 13, 46, 51.
(2) (a) Hammann, P.; Kretzschmar, G. Tetrahedron 1990, 46, 5603. (b)
Hammann, P.; Kretzschmar, G.; Seibert, G, J. Antibiot. 1990, 43, 1431. (c)
Liu, C.-M.; Jensen, L.; Westley, J. W.; Siegel, D. J. Antibiot. 1993, 46,
350. (d) Drose, S.; Bindseil, K. U.; Bowman, E. J.; Siebers, A.; Zeek, A.;
Altendorf, K. Biochemistry 1993, 32, 3902.
(3) (a) Takahashi, S.; Arai, M.; Ohki, E. Chem. Pharm. Bull. 1967, 15,
1651. (b) Takahashi, S.; Kurabayashi, M.; Ohki, E. Chem. Pharm. Bull.
1967, 15, 1657. (c) Takahashi, S.; Ohki, E. Chem. Pharm. Bull. 1967, 15,
1726. (d) Kaiser, H.; Keller-Schierlein, W. HelV. Chim. Acta 1981, 64, 407.
(e) Neupert-Laves, K.; Dobler, M. HelV. Chim. Acta 1982, 65, 262. (f) Ley,
S. V.; Neuhaus, D.; Williams, D. J. Tetrahedron Lett. 1982, 23, 1207.
(4) Omura, S. In Macrolide Antibiotics: Chemistry, Biology and Practice;
Omura, S., Ed.; Academic Press: New York, 1984; pp 510-546.
(5) Bindseil, K. U.; Zeeck, A. J. Org. Chem. 1993, 58, 5487.
10.1021/ol990004c CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/17/1999

Scheme 1
have been synthesized, including a derivative originally
obtained from the acidic methanolysis of elaiophylin.6c,d
Recently, an elegant synthesis of elaiolide (2) was reported
by Evans and Fitch,6h in which a high level of diastereo-
selectivity was achieved in the C9-C10 aldol coupling step
described previously. As part of our studies in macrolide
synthesis,7 we devised an alternative strategy to synthesize
elaiolide (2) which did not rely on a conventional macro-
lactonization step to construct the 16-membered ring.
We envisaged8 a novel cyclodimerization process, involv-
ing a Stille cross-coupling reaction of vinylstannane 3, to
form the C3-C4/C3′-C4′ bonds while simultaneously con-
structing the macrocyclic core (Scheme 1). A double aldol
coupling between the macrocyclic methyl ketone 4 and
aldehyde 5 would then be required to form the C12-C13/
C12′-C13′ bonds. A further aldol disconnection at C8-C9 in
the monomeric unit 3 leads to ethyl ketone 6 and aldehyde
7. We now report a novel synthesis of elaiolide based on
this cyclodimerization strategy, which further demonstrates
the use of our chiral ketone methodology for the controlled
introduction of key stereocenters.
Scheme 2
tion/ester hydrolysis, and finally oxidative cleavage. The
aldehyde 5 was prepared from the propyl ketone (S)-109 and
acetaldehyde in a similar fashion, where the â-hydroxyl
group in intermediate 11 was protected as a diethylisoprop-
ylsilyl (DEIPS)6b ether, in 86% overall yield.
Using our standard conditions, a boron-mediated anti aldol
reaction between the lactate-derived ethyl ketone (S)-89 and
acetaldehyde proceeded with high diastereoselectivity (>97%
ds) to give adduct 9 in 95% yield (Scheme 2). The â-hydroxy
ketone 9 was then converted into aldehyde 7 in 84% yield,
via a three-step sequence of PMB protection, ketone reduc-
As shown in Scheme 3, the C5-C12 fragment 12 of
Scheme 3
(6) (a) Toshima, K.; Tatsuta, K.; Kinoshita, M. Tetrahedron Lett. 1986,
27, 4741. (b) Toshima, K.; Tatsuta, K.; Kinoshita, M. Bull. Chem. Soc.
Jpn. 1988, 61, 2369. (c) Seebach, D.; Chow, H.-F.; Jackson, R. F. W.;
Lawson, K.; Sutter, M. A.; Thaisrivongs, S.; Zimmermann, J. J. Am. Chem.
Soc. 1985, 107, 5292. (d) Seebach, D.; Chow, H.-F.; Jackson, R. F. W.;
Sutter, M. A.; Thaisrivongs, S.; Zimmermann, J. Liebigs Ann. Chem. 1986,
1281. (e) Wakamatsu, T.; Nakamura, H.; Nara, E.; Ban, Y. Tetrahedron
Lett. 1986, 27, 3895. (f) Wakamatsu, T.; Yamada, S.; Nakamura, H.; Ban,
Y. Heterocycles 1987, 25, 43. (g) Formal total synthesis of elaiophylin:
Nakamura, H.; Arata, K.; Wakamatsu, T.; Ban, Y.; Shibasaki, M. Chem.
Pharm. Bull. 1990, 38, 2435. (h) Evans, D. A.; Fitch, D. M. J. Org. Chem.
1997, 62, 454. (i) Ziegler, F. E.; Tung, J. S. J. Org. Chem. 1991, 56, 6530.
(7) For reviews on macrolide synthesis, see: (a) Paterson, I.; Mansuri,
M. M. Tetrahedron 1985, 41, 3569. (b) Masamune, S.; McCarthy, P. A. In
Macrolide Antibiotics: Chemistry, Biology and Practice; Omura, S., Ed.;
Academic Press: New York, 1984; pp 127-198.
elaiolide was prepared from the ethyl ketone (S)-6,10 which
has been used extensively as a dipropionate building block
for the expedient synthesis of a range of polypropionate
natural products.11 Using our standard conditions,10 a boron-
(8) For a model study for this cyclodimerization strategy, see: Paterson,
I.; Man, J. Tetrahedron Lett. 1997, 38, 695.
(9) Paterson, I.; Wallace, D.; Cowden, C. Synthesis 1998, 639.
20
Org. Lett., Vol. 1, No. 1, 1999

mediated anti aldol reaction between (S)-6 and aldehyde 7
proceeded with high diastereoselectivity (>97% ds) to give
adduct 13 in 96% yield. This was followed by an anti
reduction12 using tetramethylammonium triacetoxyboro-
hydride, which afforded, after hydroxyl protection, a 92%
yield of acetonide 12 with a similar level of diastereoselec-
tivity. In this way, the anti-syn-anti-syn C5-C11 stereopentad
was efficiently established.
Isomerization of this mixture was achieved under mild
conditions using basic alumina or Ti(OiPr)422 to provide the
desired C3 regioisomer 3 in 78% yield (6.5:1) or 68% yield
(9.6:1) from 15, respectively.
In our earlier model study,8 a Cu(I)-promoted Stille cross-
coupling23 reaction was successfully used to prepare a
truncated version of the macrocyclic core of elaiolide (2),
where the two (E)-alkenes precluded cyclization to form an
eight-membered ring. The key cyclodimerization reaction
was performed on the vinylstannane 3 with copper(I)
thiophene-2-carboxylate (CuTC), a new Cu(I) reagent in-
troduced by Allred and Liebeskind24 to promote rapid Stille
cross-coupling reactions under mild conditions in the absence
of Pd catalysis. Thus, treatment of a 0.01 M solution of
monomer 3, in N-methylpyrrolidinone with CuTC (10 equiv)
at room temperature for 15 min, produced the required 16-
membered macrocycle 16 as a white crystalline solid in 80%
yield (88% based on the C7 regioisomer), accompanied by
traces of other macrocycles (Scheme 5). The reaction led to
The synthesis of the cyclodimerization substrate 3 (Scheme
4) began with the conversion of the benzyl ether functionality
Scheme 4
Scheme 5
to the (E)-alkenyl iodide 14 in 80% overall yield. This was
achieved via a three-step sequence of Raney nickel selective
deprotection,13 Swern oxidation,14 and Takai olefination.15
The Takai reaction was performed with CHI3 and CrCl2 in
THF-dioxane (1:1) and produced a 20:1 ratio of E to Z
isomers. Acetonide hydrolysis followed by a Pd(0)-catalyzed
iodine-tin exchange,16 using (Me3Sn)2 in the presence of
Li2CO3, then gave the desired vinylstannane 15 in 77% yield.
Esterification17,18 of diol 15 with (E)-3-iodopropenoic acid,19
using DCC and DMAP in CH2Cl2 at -20 °C, then provided
an inseparable 1:5 mixture20 of 3 and its C9 regioisomer.21
clean formation of 16 without the isolation of the open-chain
intermediate, suggesting the occurrence of a rapid Cu(I)-
mediated cyclization without competing oligomerization. In
contrast, under more concentrated reaction conditions (c 0.2
M), the monomer 3 was converted into a mixture of three
major macrocycles. Here, the desired dimer 16 was obtained
in 42% yield, along with 34% of the C7 macrotrimer and
13% of the C9 macrotrimer.25
(10) (a) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
30, 7121. (b) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister,
M. A. J. Am. Chem. Soc. 1994, 116, 11287.
(11) Reviews: (a) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
(b) Paterson, I. Pure Appl. Chem. 1992, 64, 1821.
(12) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(13) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(14) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(15) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(16) (a) Azizian, H.; Eaborn, C.; Pidcock, A. J. Organomet. Chem. 1981,
215, 49. (b) Barrett, A. G. M.; Boys, M. L.; Boehm, T. L. J. Org. Chem.
1996, 61, 685. (c) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan,
K.-S.; Faron, K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray.
C. K. J. Org. Chem. 1986, 51, 277.
(17) Steric hindrance at the C7 position when C9 is protected prevents
direct esterification, and an esterification on the diol 15 is thus required.
(18) (a) Boyce, R. J.; Pattenden, G. Tetrahedron Lett. 1996, 37, 3501.
(b) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.
(c) Hofle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed. Engl.
1978, 17, 569.
(19) (E)-3-Iodopropenoic acid was prepared via a modification of a
procedure described by: Zoller, T.; Ugen, D. Tetrahedron Lett. 1998, 39,
6719. See the Supporting Information for details.
1
(20) Determined by 500 MHz H NMR of the crude reaction mixture.
(21) Under these kinetic conditions, reaction at the C9-OH was greatly
preferred over that at the presumably more hindered C7-OH.
(22) Seebach, D.; Hungerbu¨hler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zu¨ger, M. Synthesis 1982, 138.
(23) Reviews: (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508. (b) Mitchell, T. N. Synthesis 1992, 803. (c) Farina, V. Pure Appl.
Chem. 1996, 68, 73.
(24) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748.
(25) The structures of these macrocycles were confirmed by FAB MS.
Org. Lett., Vol. 1, No. 1, 1999
21

Scheme 6
The macrodiolide 16 was converted into the bis(methyl
ketone) 17 by a three-step sequence of TES protection, PMB
deprotection, and Dess-Martin oxidation26 in 56% overall
yield (Scheme 6). The final key step of the synthesis of
elaiolide required a double aldol coupling between the
macrocyclic diketone 17 and the chiral aldehyde 5. Obtaining
a high level of Felkin-Anh selectivity from the aldehyde
component in this reaction was crucial in order to set up the
13,14-syn relationship.27 The diketone 17 was enolized with
LiHMDS at -78 °C for 1 h, followed by addition of an
excess of aldehyde 5. This led to isolation of the desired
adduct 18 in 75% yield along with 15% of a mixture of
diastereoisomers. We attribute the good diastereoselectivity
of this two directional extension (ca. 90% ds for each side)
to matching of Felkin-Anh control from the aldehyde with
the facial bias of the macrocyclic enolate. Finally, global
deprotection28 using HF‚pyridine-THF-H2O6h was ac-
companied by concomitant cyclization to form the bis-
(hemiacetal), leading to isolation of elaiolide (2) in 80%
yield. The H NMR data of the product corresponded well
with that of material obtained by acid hydrolysis of elaio-
phylin.29 All spectral data (1H and 13C NMR, IR, MS, [R]D)
obtained from the synthetic material were in agreement with
reported values.5,6h
1
In summary, a novel total synthesis of elaiolide (2) has
been completed using the copper(I)-mediated cyclodimer-
ization, 2 × 3 f 16. This route demonstrates the power of
the Liebeskind modification of the Stille cross-coupling
reaction in the synthesis of structurally complex macrocycles.
Acknowledgment. We thank the EPSRC (Grant No.
L41646) and Pfizer Central Research for support and Robert
Davies (Cambridge) and Dr. Mark Gardner (Pfizer) for
helpful discussions.
Supporting Information Available: Text giving experi-
mental procedures and tables and figures giving complete
spectroscopic data for key compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(26) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(27) Originally this aldol was attempted using Mukaiyama conditions,
involving treatment of the ketone 17 with TMSCl-Et3N and LiHMDS to
form the silyl enol ether and then addition of 5 and BF3 etherate. These
conditions (Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.;
Roush, W. R. Angew. Chem., Int. Ed., in press) provided a 7:1 ratio in
favor of the desired aldol in model studies, producing hemiacetal 19 on
deprotection. In contrast, with diketone 17 only recovered starting ketone
and aldehyde were isolated.
OL990004C
(28) Using TASF, only 35% of elaiolide was obtained, accompanied by
an eliminated compound which was also formed in the degradation of
elaiophylin: Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.;
Coffey, C. D.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(29) (a) Elaiophylin, kindly provided by Professor S. V. Ley, was
degraded according to the procedure described by Zeeck.5 (b) See the
1
Supporting Information for tabulated H and 13C NMR data for elaiolide
with comparative data previously reported.
22
Org. Lett., Vol. 1, No. 1, 1999