An efficient, second-generation synthesis of the signature dioxabicyclo[3.2.1]octane core of (+)-sorangicin a and elaboration of the (Z,Z, E)-triene acid system

Article abstract of DOI:10.1021/ol802942j

An efficient, second-generation synthesis of the signature dioxabicyclo[3.2.1]octane core of (+)-sorangicin A (1), in conjunction with an effective, stereocontrolled protocol to arrive at the requisite (Z,Z,E)-triene acid system has been developed. Highli

Full text of DOI:10.1021/ol802942j

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1099-1102
An Efficient, Second-Generation
Synthesis of the Signature
Dioxabicyclo[3.2.1]octane Core of
(+)-Sorangicin A and Elaboration of the
(Z,Z,E)-Triene Acid System
Amos B. Smith, III* and Shuzhi Dong
Department of Chemistry, Laboratory for Research on the Structure of Matter, and
Monell Chemical Senses Center, UniVersity of PennsylVania, Philadelphia,
PennsylVania 19104
smithab@sas.upenn.edu
Received December 22, 2008
ABSTRACT
An efficient, second-generation synthesis of the signature dioxabicyclo[3.2.1]octane core of (+)-sorangicin A (1), in conjunction with an effective,
stereocontrolled protocol to arrive at the requisite (Z,Z,E)-triene acid system has been developed. Highlights of the core construction entail
a three-component union, a KHMDS-promoted epoxide ring formation-ring opening cascade, a Takai olefination, and a chemoselective Sharpless
dihydroxylation. Assembly of the triene acid system was then achieved via Stille cross-coupling with the ethyl ester of (Z,Z)-5-tributylstannyl-
2,4-pentadienoic acid, followed by mild hydrolysis preserving the triene configuration.
The sorangicins comprise a family of architecturally complex
macrolide antibiotics isolated from a fermentation broth of
the myxobacteria Sorangium cellulosum (strain So ce 12).1
The most potent and prevalent congener, (+)-sorangicin A
(1), was found to be highly effective against a spectrum of
both Gram-positive (MIC 0.01-0.3 µg/mL) and Gram-
negative bacteria (MIC 3-25 µg/mL). Subsequent studies
revealed that (+)-sorangicin A (1) inhibits bacterial RNA-
polymerase in both E. coli and S. aureus, while not affecting
eukaryotic cells.2
The structure of (+)-sorangicin A (1; Scheme 1),3
endowed with a highly unsaturated 31-membered macrolac-
tone, a rare (Z,Z,E)-trienoate linkage, and the signature
dioxabicyclo[3.2.1]octane, in conjunction with the important
biological properties, has engendered considerable interest
(2) Irschik, H.; Jansen, R.; Gerth, K.; Ho¨fle, G.; Reichenbach, H. J.
Antibiot. 1987, 40, 7.
(1) (a) Jansen, R.; Wray, V.; Irschik, H.; Reichenbach, H.; Ho¨fle, G.
Tetrahedron Lett. 1985, 26, 6031. (b) Jansen, R.; Irschik, H.; Reichenbach,
H.; Schomburg, D.; Wray, V.; Ho¨fle, G. Liebigs Ann. Chem. 1989, 111.
(3) The stereocenter at C(10) in (+)-sorangicin A, as confirmed by R.
Jansen (Helmholtz Center for Infection Research, Braunschweig, Germany)
is S, not R as depicted in ref 4b. We thank R. Jansen for this clarification.
10.1021/ol802942j CCC: $40.75
Published on Web 01/30/2009
2009 American Chemical Society

C(36)-O bond would lead to a tetrahydropyran,8 sharing
the same 2,6-trans-relationship as 4, and thus potentially
available via a similar substrate-controlled stereoselective
conjugate addition of a Michael donor to a similar dihydro-
pyrone as employed to construct 4.7b
Scheme 1
Toward this end, dihydropyrone (-)-6 was readily pre-
pared in 86% yield (33:1 dr) via a hetero Diels-Alder (HDA)
reaction between the Danishefsky diene and aldehyde (-)-
8,9 catalyzed by the chromium(III)-Schiff base 9, the same
Jacobsen catalyst employed for our earlier synthesis of
dihydropyrone (-)-7 (Scheme 2).10
Scheme 2
within the synthetic and biomedical communities.4 Indeed,
significant progress toward the total synthesis of (+)-
sorangicin A has been recorded by the Schinzer5 and
Crimmins6 groups, in addition to our laboratory.7
From the outset, our synthetic analysis of (+)-sorangicin
A (1) called for disconnections at the macrocyclic lactone,
the C(38-39) σ-bond, and both the C(15-16) and C(29-30)
trans-disubstituted olefins to yield three advanced subtargets:
bicyclic ether (-)-2, tetrahydropyran (-)-3, and dihydro-
pyran 4 (Scheme 1).7 To construct the dioxabicyclo[3.2.1]oc-
tane core of (-)-2, our first-generation route featured an acid-
promoted intramolecular cascade of epoxide openings, the
first facilitated and controlled chemoselectively by a Co2(CO)6-
alkyne complex of bis-epoxide (+)-5 and the second medi-
ated by BF3•OEt2.7a Although effective, the route was not
highly efficient vis-a`-vis material advancement. We now
report a second-generation synthesis of (-)-2, in conjunction
with the development of an effective, highly stereocontrolled
protocol to elaborate the C(37-43) (Z,Z,E)-triene acid unit.
Attention next turned to the three-component union of
dihydropyrone (-)-6 with MeI and a suitable Michael donor,
the latter corresponding to a surrogate aldehyde. The
literature however is not rich with such examples, due
presumably to deactivation of the enone by the ring
oxygen.11,7b In fact, dihydropyrone (-)-6 proved to be a
reluctant Michael acceptor. For example, use of the cuprate
derived from BnOCH2SnBu3 displayed no reactivity. This
result may however be a donor problem, given the low
reactivity of this type of organometallic addend toward
Michael addition as observed by Fuchs et al.12
Reanalysis of the structure of (-)-2 led to the observation
that disconnection of the bicyclic ether fragment at the
We turned next to the commercially available ꢀ-bromosty-
rene (10) as a prospective nucleophile progenitor, with a view
(4) (a) Jansen, R.; Schummer, D.; Irschik, H.; Ho¨fle, G. Liebigs Ann.
Chem. 1990, 975. (b) Schummer, D.; Irschik, H.; Ho¨fle, G. Liebigs Ann.
Chem. 1993, 293. (c) Campbell, E. A.; Pavlova, O.; Zenkin, N.; Leon, F.;
Irschik, H.; Jansen, R.; Severinov, K.; Darst, S. A. EMBO J. 2005, 24,
674.
(8) A similar disconnection was elegantly employed by the Crimmins
laboratory in an efficient approach to (-)-18; see ref 6.
(9) Aldehyde (-)-8, although commercially available, was prepared in
two steps from L-gulonic acid γ-lactone; see: Hubschwerlen, C.; Specklin,
J.-L.; Higelin, J. Org. Synth. 1995, 72, 1.
(5) Schinzer, D.; Schulz, C.; Krug, O. Synlett 2004, 15, 2689.
(6) Crimmins, M. T.; Haley, M. W. Org. Lett. 2006, 8, 4223.
(7) (a) Smith, A. B., III; Fox, R. J. Org. Lett. 2004, 6, 1477. (b) Smith,
A. B., III; Fox, R. J.; Vanecko, J. A. Org. Lett. 2005, 7, 3099.
(10) Joly, G. D.; Jacobsen, E. N. Org. Lett. 2002, 4, 1795.
(11) Paterson, I.; Steven, A.; Luckhurst, C. A. Org. Biomol. Chem. 2004,
2, 3026
.
(12) Hutchinson, D. K.; Fuchs, P. L. J. Am. Chem. Soc. 1987, 109, 4930.
1100
Org. Lett., Vol. 11, No. 5, 2009

to achieving olefin cleavage at a later stage to access the
C(30) aldehyde. Application of the Noyori three-component
prostaglandin coupling protocol,13 involving Li halogen
exchange of the bromine in 10 with t-BuLi at -78 °C,14
followed in turn by addition of Me2Zn, warming to 0 °C to
furnish a mixed zincate, and then addition of dihydropyrone
(-)-6 at -78 °C effectively led to conjugate addition.15
Although forcing conditions (ca. 10 equiv of MeI and HMPA
at -40 °C) were required to quench the resultant enolate
(11), a single diastereomer (+)-12 was obtained in modest
yield (51%), along with the formation of a significant amount
of R,R′-bismethylated product (+)-13 (20%). This result is
not without precedent. Alexakis et al. observed unusual
reactivity of a Zn-methyl group with an enolate similar to
11 upon trapping with allyl bromide.16 We reasoned that
during the slow enolate capture process 11, possessing the
Zn-methyl group, is sufficiently basic in the presence of
excess HMPA to deprotonate (+)-12, and in turn lead via
methylation to (+)-13. Lowering the alkylation temperature
from -40 to -60 °C only led to longer reaction times and
an increase of (+)-13 (38%). Higher temperature (-20 °C)
however did have a beneficial effect on the yield of (+)-12;
the same trend was observed by Alexakis et al. In the end,
we discovered that the reactivity of the zinc enolate (11)
could be successfully down-regulated by addition of
CuI•PBu3 just prior to the addition of MeI, which led to a
slower, but more selective reaction to furnish (+)-12 in 73%
yield. Confirmation of the requisite 2,3,6-trans-cis-config-
uration was obtained by NOESY studies (Scheme 2).
Final elaboration to (-)-2 began with L-Selectride reduc-
tion of (+)-12 to furnish (-)-14 as a single diastereomer
(Scheme 3); confirmation of the requisite configuration at
C(33) was again achieved by NOESY correlations. The
acetonide moiety was then removed with aqueous acetic acid
to furnish triol (-)-15.
Scheme 3
situation. A less elegant, two-step protocol was thus explored.
The primary hydroxyl of (-)-15 was first selectively sulfo-
nylated with triisopropylbenzenesulfonyl chloride (TrisylCl)
employing pyridine/CH2Cl2 (2:3) as solvent at room tem-
perature.18 Under these conditions, sulfonylation of the
secondary hydroxyl was suppressed; in addition, the resultant
sulfonate (-)-20 proved stable to purification and handling.
The primary sulfonate was then treated with 1 equiv of
KHMDS to furnish bicyclic ether (-)-18 in high yield,
possessing spectral data in complete accord with the data
reported by the Crimmins laboratory.6 Bicycle (-)-18,
comprising the signature dioxabicyclo[3.2.1]octane core of
(+)-sorangicin A (1), was thus available in 6 steps and 35%
overall yield from (-)-8.
With (-)-15 in hand, we turned to the critical task of
generating the two-atom bridge. Triol (-)-15 was treated
with KHMDS (1 equiv), followed by slow addition of the
bulky N-triisopropylbenzenesulfonylimidazole (TrisIm; 1
equiv) to effect regioselective sulfonylation of the least
hindered hydroxyl. In analogy with the work of Crimmins
et al.,6 treatment of the resultant trisylate (16) with an
additional 2 equiv of KHMDS then promoted a reaction
cascade involving epoxide ring formation, followed by ring
opening to generate the bridged bicycle.17 Although this
“one-pot” protocol delivered the desired product (-)-18, the
yield was disappointing (ca. 33%), due to oversulfonylation
to form (-)-19 (ca. 36%). Lower reaction temperatures or
the use of potassium tert-butoxide did not improve the
To arrive at (-)-2 (Scheme 4), (-)-18 was oxidized
employing Parikh-Doering conditions,19 and the resultant
sensitive aldehyde 21 immediately subjected to Takai ole-
fination without purification.20 Initial experiments on small
scale employing THF as solvent afforded an E/Z diastere-
omeric mixture (3.2:1); the olefin configurations were
assigned, respectively, based on 1H NMR coupling constants
(13) Suzuki, M.; Morita, Y.; Koyano, H.; Koga, M.; Noyori, R.
Tetrahedron 1990, 46, 4809.
(14) It is critical to add ꢀ-bromostyrene to t-BuLi; the inverse addition
led to low conversion.
(15) Commercial ꢀ-bromostyrene is a trans/cis mixture (ca. 9:1);
interestingly only one geometric product was observed. This result could
be attributed to unproductive 1,4-addition of the cis-isomer, cf.: Fu¨rstner,
A.; Grela, K.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 2000, 122,
11799.
(18) Kojima, N.; Maezaki, N.; Tominaga, H.; Asai, M.; Yanai, M.;
Tanaka, T. Chem. Eur. J. 2003, 9, 4980.
(16) Rathgeb, X.; March, S.; Alexakis, A. J. Org. Chem. 2006, 71, 5737.
(17) Dounay, A. B.; Florence, G. J.; Saito, A.; Forsyth, C. J. Tetrahedron
2002, 58, 1865.
(19) Parikh, J.; Doering, W. V. E. J. Am. Chem. Soc. 1967, 89, 5505.
(20) Takai, K. R.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
Org. Lett., Vol. 11, No. 5, 2009
1101

(15.8 Hz vs 8 Hz).21 The observed low E/Z selectivity was
unexpected given that R-alkoxy-aldehydes in general exhibit
near complete (E)-selectivity.22 Larger-scale reactions also
proved problematic, furnishing the vinyl iodides in signifi-
cantly lower yield. Recourse to a mixture of dioxane/THF
(4:1; v/v) as solvent system,23 although not significantly
improving the selectivity, did improve the scale-up issue to
furnish (-)-22 and (-)-23 in 52 and 16%, respectively, on
half gram reaction scale.
trile)-dichloropalladium(II) as catalyst in DMF, along with
excess Ph2PO2NBu4 (6 equiv) as a tin scavenger26 to suppress
Z/E isomerization. Under these conditions, (+)-25 was
produced in 96% yield as a single isomer (>20:1). Correla-
tions derived from NOESY studies, as well as coupling
constants, confirmed the desired (Z,Z,E)-configuration of (+)-
25 (Scheme 5). Hydrolysis of trienoate (+)-25 was then
achieved with LiOH in aqueous THF to furnish acid (+)-26
in 81% yield, with complete preservation of the olefin
configuration.
Scheme 4
Scheme 5
In summary, an effective, scalable route to (-)-2 possess-
ing the C(30-38) signature core of (+)-sorangicin A (1) has
been achieved in 10 steps from (-)-8. In addition, an
effective protocol has been developed for prospective
elaboration of the C(37-43) (Z,Z,E)-triene acid functionality,
required for any successful (+)-sorangicin A (1) endgame.
Progress toward the total synthesis of (+)-sorangicin A (1)
will be reported in due course.
Required at this stage was differentiation of the two olefins
present in (-)-22 to access aldehyde (-)-2. We reasoned
that the electron-withdrawing and -donating biases, respec-
tively, of the iodide and phenyl substituents would permit
chemoselective functionalization of the more electron-rich
olefin. Gratifyingly, Sharpless dihydroxylation of (-)-22 at
room temperature proceeded only at the styrene moiety to
generate the corresponding diol,24 which upon reaction with
NaIO4 employing buffered conditions furnished (-)-2 identi-
cal in all respects to material prepared previously in our
laboratory.7a
Having achieved an effective, second-generation synthesis
of (-)-2, we turned next to explore possible tactics to
construct the sensitive (Z,Z,E)-triene acid fragment. Vinyl
iodide (-)-22 was selected as a model system. Stille cross-
coupling with known (Z,Z)-dienoate 24 led to (+)-25
(Scheme 5).25 Best results were obtained using bis(benzoni-
Acknowledgment. Support was provided by the National
Institutes of Health through Grant No. GM-29028. We thank
Drs. George Furst (University of Pennsylvania) and Rakesh
Kohli (University of Pennsylvania) for assistance in obtaining
NMR spectra and high-resolution mass spectra, respectively,
and Dr. Kallol Basu (Schering-Plough Corporation) for the
insightful discussions.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Z-Vinyl iodide (-)-23 could be useful for the synthesis of (+)-
Sorangicin A1.
OL802942J
(22) Kende, A. S.; DeVita, R. J. Tetrahedron Lett. 1990, 31, 307.
(23) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(24) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(25) Franci, X.; Martina, S. L. X.; McGrady, J. E.; Webb, M. R.; Donald,
C.; Taylor, R. J. K. Tetrahedron Lett. 2003, 44, 7735.
(26) Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1997,
119, 12376.
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