A new bromo trienyne: Synthesis of all-E, conjugated tetra-, penta-, and hexaenes common to oxo polyene macrolide antibiotics

Full text of DOI:10.1021/jo981107w

6092
J . Org. Chem. 1998, 63, 6092-6093
A New Br om o Tr ien yn e: Syn th esis of a ll-E,
Con ju ga ted Tetr a -, P en ta -, a n d Hexa en es
Com m on to Oxo P olyen e Ma cr olid e
An tibiotics
F igu r e 1.
Sch em e 1. P r ep a r a tion of Br om o Tr ien yn e 2
Bruce H. Lipshutz,* Brett Ullman, Craig Lindsley,
Sabina Pecchi, D. J . Buzard, and David Dickson
Department of Chemistry, University of California,
Santa Barbara, California 93106
Received J une 10, 1998
In a recent report from these laboratories,1 a new “linch-
pin” 1 was disclosed that allows for rapid construction of
the all-E oxopolyene network characteristic of many polyene
macrolide antifungal agents (Figure 1).2 This methodology
relies on an initial Pd(0) coupling, where 1 serves as the
nucleophilic partner. The acetylenic terminus can be regio-
and stereoselectively hydrozirconated, and while introduc-
tion of an acyl moiety could be accomplished in the presence
of Me2AlCl,3 a second Pd(0)-catalyzed vinyl-vinyl coupling
was not realized due to the highly deactivated, conjugated
vinylic zirconocene.4 This limitation encouraged us to
pursue a second-generation reagent that would make avail-
able not only all-E oxo tetra- and oxo pentaenes but also
the oxo hexaene framework as well. We now describe a
redesigned tetraene equivalent 2, which provides synthetic
opportunities not available to 1.
Sch em e 2
Bromo trienyne 2 is prepared via E-bromo dienal 4 and
the ylide derived from 5 utilizing a standard Wittig protocol
(Scheme 1). Known precursor potassium salt 3 (mp > 350
°C) is obtained from inexpensive pyridine‚sulfur trioxide
complex.5 Conversion of 3 to bromo dienal 4,6 reported to
proceed using Br2/PPh3 in CH2Cl2, in our hands affords low
yields of desired product. Attempts to modify conditions
(e.g., changing the solvent to 1,2-dichloroethane, adding
Bu4N+X-, various concentrations, and temperatures) or
conversion to other leaving groups (e.g., the triflate deriva-
tive of 3) were not productive. In time, we found that use
of NBS/PPh3 led to a good isolated yield of 4 (74%; 68:32
E/Z, separable by chromatography). The corresponding
iodide6 could likewise be prepared using NIS/PPh3 (76%; 1:1
E/Z). Treatment of phosphonium bromide 57 with NaN-
(TMS)2 in THF8 followed by aldehyde (E)-4 (mp 66-68 °C)
affords tetraene equivalent 2 in 86% yield as an g85:15
mixture of E,E,E to E,E,Z isomers.
reflects maintenance of stereochemical integrity, as ex-
pected.9 These initial products could be desilylated to 7 and
either hydrozirconated and then transmetalated to alumi-
num with Me2AlCl3 or carboaluminated directly to the
corresponding vinylalane 8.10 Subsequent exposure to a
chloroformate (or acid chloride) affords the desired conju-
gated polyene esters 9 (or ketones). Representative ex-
amples are illustrated as well in Table 1. Particularly
noteworthy cases include (1) the entire polyene section of
the mycoticins11 (entry 2) and (2) the alarm pheromone
navenone C (entry 4).12
The overall stereochemical outcome of these reactions, as
noted previously,1 is such that essentially all-E products are
obtained notwithstanding the g85:15 mix of polyenynes 7
formed from the vinyl-vinyl cross-coupling/desilylation. The
enhancement results not from eventual isomerization but
rather a kinetic resolution based on the greater reactivity
of the E- vs Z-vinylalane intermediate 8 toward the elec-
trophile.
The vinyl bromide portion of 2 represents a polarity
inversion relative to stannyl dienyne 1 and, hence, could be
coupled with vinyl- and dienylzinc reagents 6 (n ) 1, 2;
Scheme 2). Nucleophilic partners appear to tolerate TIPS-
protected alcohols, substituted styryl residues, and divalent
sulfur (Table 1). Yields tend to be uniformly good, and the
ratio of E:Z products associated with the newly formed bond
* To whom correspondence should be addressed. Phone: (805) 893-2521.
Fax: (805) 893-8265. E-mail: Lipshutz@chem.ucsb.edu.
(1) Lipshutz, B. H.; Lindsley, C. J . Am. Chem. Soc. 1997, 119, 4555.
(2) Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021. Omura, S.; Tanaka,
H. In Macrolide Antibiotics: Chemistry, Biology, and Practice; Omura, S.,
Ed.; Academic Press: New York, 1984; pp 351-404.
(3) Carr, D.; Schwartz, J . J . Am. Chem. Soc. 1979, 101, 3521.
(4) Negishi, E.; Owczarczyk, Z. Tetrahedron Lett. 1991, 46, 6683.
(5) Becher, J . Org. Synth. 1979, 59, 79.
(6) Soullez, D.; Ple, G.; Duhamel, L.; Duhamel, P. J . Chem. Soc., Chem.
Commun. 1995, 563. For a very recent report describing an improved route
to 4, see: Vicart, N.; Castet-Caillabet, D.; Ramondenc, Y.; Ple, G.; Duhamel,
L. Synlett 1998, 411.
(7) Corey, E. J .; Ruden, R. A. Tetrahedron Lett. 1973, 1495.
(8) Reitz, A. B.; Nortey, S. O.; J ordan, A. D.; Mutter, M. S.; Maryanoff,
B. E. J . Org. Chem. 1986, 51, 3302.
(9) Hegedus, L. S. In Transiton Metals in the Synthesis of Complex
Organic Molecules; University Science Books: Mill Valley, CA, 1994. Stille,
J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813.
(10) Okukado, N.; Negishi, E. Tetrahedron Lett. 1978, 2357.
(11) Wasserman, H. H.; Van Verth, J . E.; McCaustland, D. J .; Borowitz,
I. J .; Kamber, B. J . J . Am. Chem. Soc. 1967, 89, 1535. Poss, C. S.;
Rychnovsky, S. D.; Schreiber, S. L. J . Am. Chem. Soc. 1993, 115, 3360.
(12) Sleeper, H. L.; Fenical, W. J . Am. Chem. Soc. 1977, 99, 2367.
S0022-3263(98)01107-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/07/1998

Communications
J . Org. Chem., Vol. 63, No. 18, 1998 6093
Ta ble 1. Cou p lin g Rea ction s of Lin ch p in 2
a
b
Fully characterized by spectral and HRMS data. Isolated, chromatographically purified material. c Yield refers to silylated alkyne
prior to treatment with K2CO3 in EtOH.
Sch em e 3. Cou p lin g Rea ction s of 2 In itia lly a t th e
Alk yn e Ter m in u s
Sch em e 4. Syn th esis of th e Oxo Hexa en e P or tion of
th e Der m osta tin s
Instead of an initial Pd(0)-catalyzed coupling at the vinyl
bromide terminus of 2, the protocol could be inverted,
whereby the alkyne is desilylated and then carboalumi-
nated (Scheme 3). Quenching with ethyl chloroformate, or
methyl chloroformate, leads to bromotetraenes 10 and 11,
respectively. Subsequent coupling of 10 arrives at aryl-
substituted tetraenoate 12, while 11 is converted to oxopen-
taene 13.
rived vinylalane acylations to afford highly (light, acid,
base, heat, oxygen, etc.) sensitive polyenes. Further re-
finements, alternative organometallic chemistry, and ad-
ditional applications (e.g., to the preparation of capped
polyacetylenes)14 are in progress and will be reported in
due course.
Another application of this approach, where 2 is effectively
equivalent to an all-E 1,8-octatetraenyl monocation/mono-
anion (cf. Figure 1), to the oxohexaene portion of the
dermostatins13 is shown in Scheme 4. For this case, target
14 could be constructed in short order in 56% overall yield.
In summary, a very short sequence has been developed
for fabricating all-E, conjugated oxopolyene networks
that constitute key subsections of important natural prod-
ucts. The route relies on a newly fashioned trienyne 2
that participates in both vinyl-vinyl couplings and de-
Ack n ow led gm en t. We warmly thank the NIH (GM
40287) for continued support of our programs and Prof.
Duhamel (Rouen) for helpful comments regarding the
preparation of 4.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic data for all new compounds (45 pages).
J O981107W
(14) Nonlinear Optical Materials: Theory and Modeling; Karna, S. P.,
Yeates, A. T., Eds.; ACS Symposium Series 628; American Chemical
Society: Washington, DC, 1996.
(13) Rychnovsky, S. D.; Richardson, T.; Rodgers, B. N. J . Org. Chem.
1997, 62, 2925.