Total synthesis of (+)-sorangicin A

Article abstract of DOI:10.1021/ja906115a

(Chemical Equation Presented) The final synthetic challenges associated with (+)-sorangicin A have been overcome, thus leading to the first total synthesis of this complex macrolide antibiotic. Highlights of the highly convergent synthesis include two Jul

Full text of DOI:10.1021/ja906115a

Published on Web 08/11/2009
Total Synthesis of (+)-Sorangicin A
Amos B. Smith, III,* Shuzhi Dong, Jehrod B. Brenneman, and Richard J. Fox
Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
Received July 22, 2009; E-mail: smithab@sas.upenn.edu
Myxobacteria Sorangium cellulosum is a rich source of secondary
metabolites possessing important biological profiles. Perhaps most
notable, the epothilone class of natural products, analogues of which
are currently in clinical use for the treatment of solid tumors resistant
to alternative treatments (i.e., Taxol), were isolated by Ho¨fle and
co-workers in 1996 from the S. cellulosum strain So ce 90.1 Earlier
(1985), the same research group reported the isolation of members
of another family of architecturally complex macrolides from the
strain So ce 12, termed the sorangicins.2 Importantly, (+)-sorangicin
A (1), the most potent and prevalent congener, demonstrated
remarkable antibiotic activity against a broad spectrum of both
Gram-positive [minimum inhibitory concentration (MIC) 0.01-0.3
µg/mL] and Gram-negative bacteria (MIC 3-25 µg/mL). The
mechanism of action was subsequently determined to entail
inhibition of RNA polymerase in both Escherichia coli and
Staphylococcus aureus without affecting eukaryotic cells.3
Elegant cross-resistance studies by the Jansen and Darst groups
on (+)-sorangicin A and rifampicin, the latter a clinically used
ansamycin antibiotic, also revealed that although both bind the
same ꢀ-subunit pocket of RNA polymerase, (+)-sorangicin A
displays an advantageous profile against rifampicin-resistant
microbial mutants, a result proposed to arise from increased
conformational flexibility, leading to better adaption to muta-
tional changes in the binding pocket.4
only in a simple model system.11c The total synthesis of 1 has thus
remained an elusive goal. Herein, we describe the development of
chemistry that addresses the synthetic challenges associated with
1, that in turn has led to the first total synthesis of this intriguing
natural product.
Scheme 1
Although scalable routes to access bicyclic aldehyde (-)-2,11a,c
tetrahydropyran (-)-3,11b,12 and dihydropyran (-)-10-epi-611b,13
had been developed by our research group, the stereogenicity at
C(10) in (-)-10-epi-6 required revision because of some confusion
relating to this stereogenic center.5 Toward this end, we outline in
Scheme 2 the requisite inversion of the C(10) stereogenic center.
Global desilylation of (-)-10-epi-6 followed by chemoselective
silylation14 furnished allylic alcohol (-)-7. Initial attempts to invert
the C(10) center with Mitsunobu methods failed because of the
predominance of an SN2′ pathway, which is favored by the steric
nature of the C(1)-C(8) side chain. Recourse was thus made to a
Ley oxidation15/Luche reduction16 sequence, which generated the
desired allylic alcohol (+)-8 as a single diastereomer. The high
selectivity can be attributed to the same bulky side chain. Formal
transposition of the TBS group followed by standard protocols to
introduce the sulfone unit furnished fragment (+)-10 in good yield
(46% over eight steps).
The structure of (+)-sorangicin A (1, Scheme 1)5 comprises a
signature dioxabicyclo[3.2.1]octane skeleton in conjunction with a
rare (Z,Z,E)-trienoate linkage, both inscribed within a highly
unsaturated 31-membered macrolactone ring. The initial structural
assignment was based on extensive one- and two-dimensional NMR
experiments along with high-resolution mass spectrometry.2 Con-
firmation of both the connectivity and absolute configurations of
the 15 stereogenic centers was subsequently secured by X-ray
analysis.6 The structural features, in particular the (Z,Z,E)-trienoate
linkage affixed to the bicyclic ether core, provide the major source
of the reported instability of the natural product toward a variety
of reagents (e.g., fluoride ion, DDQ, and the dissolving metal
sodium amalgam),7 thus presenting a serious challenge to the current
state of the art in organic synthesis. In addition, two polar structural
elements, the C(1) carboxyl group and the C(21, 22, 25)-triol moiety
of (+)-sorangicin A associate via a hydrogen bond to generate a
hydrophilic region of this amphiphilic natural product. This
interaction is particularly sensitive to the solvent and pH environ-
Scheme 2
1
ments, thereby leading to a significant dependence of the H and
13C NMR spectra on the exact experimental variants.6
Not surprisingly, the intricate architecture of 1, in conjunction
with the important biological properties, has stimulated considerable
interest within the synthetic community. Indeed, significant progress
has been registered by the Schinzer,8 Crimmins,9 and Lee10
laboratories in addition to ours.11 Although successful preparations
of mono- and bicyclic subtargets have been described, assembly
of the highly sensitive (Z,Z,E)-trienoate linkage has been reported
With all of the major subtargets in hand, we were set to achieve
their union. Toward this end, we envisaged construction of both
the C(29)-C(30) and C(15)-C(16) trans double bonds via
Julia-Kociénski olefinations, followed in turn by Stille union of 4
and macrolactonization to complete the overall carbon skeleton.
9
10.1021/ja906115a CCC: $40.75  2009 American Chemical Society
J. AM. CHEM. SOC. 2009, 131, 12109–12111 12109

C O M M U N I C A T I O N S
Scheme 4
However, the first Julia-Kociénski olefination raised an unexpected
challenge. Through the use of conditions developed by the Jacobsen
group (LiHMDS in DMF/HMPA),17 E-olefin (-)-11 was obtained,
albeit in low yield (24%), along with substantial recovery of the
two coupling partners (-)-2 (36%) and (-)-3 (63%, Scheme 3).
Switching the base counterion to Na+ increased the yield (40%),
but the E/Z selectivity (3.6:1) decreased. Use of the traditional
E-selective conditions (KHMDS in DME)18 provided the highest
yield (54%) but the lowest E/Z selectivity (2.0:1). Neither Barbier
conditions19 nor the corresponding benzothiazole sulfone (BT-
sulfone) improved the situation. In the end, the most reliable
conditions proved to be use of t-BuLi in aprotic polar solvents
(DMF/HMPA), which on a 300 mg scale furnished the E-configured
product in 39% yield. Several recycles permitted the advance of
material to (-)-11 in upward of 65% yield.
Scheme 3
nation suffered extensive E/Z isomerization upon purification. A
solution to this issue entailed the use of an alternative linker, stannyl
dienoate 5,23 which proved to be surprisingly stable under standard
laboratory conditions. Again in a model system, we demonstrated
the effective use of 5 in a Stille union employing excess
Ph2PO2NBu4 (6 equiv) to suppress the E/Z isomerization.11c With
(+)-16, however, an even larger excess of Ph2PO2NBu4 (12 equiv)
was required for delivery of geometrically pure (Z,Z,E)-trienoate
(+)-17 in good yield (88%). Equally important, the subsequent
hydrolysis of trienoate (+)-17 with LiOH in aqueous THF furnished
the corresponding trienoacid 18 without noticeable geometric
isomerism (Scheme 4). However, acid 18 did prove to be extremely
unstable and was therefore employed in the next step without full
characterization.
In the transformations leading up to the critical macrocyclization,
we fully anticipated the possibility of significant isomerization
during activation of the trienoacid. This indeed proved to be the
case! However, a careful survey revealed two sets of mild conditions
that delivered the desired (Z,Z,E)-configured macrolactone (+)-19
as the major product (Scheme 5): (1) the Yonemitsu modification
of the Yamaguchi conditions24 involving direct introduction at room
temperature of DMAP at the outset without preformation of the
mixed anhydride and (2) the Evans-modified Mukaiyama protocol25
The second Julia-Kociénski olefination involving sulfone (-)-
12 [obtained from (-)-11] and aldehyde (-)-13 [derived from
(-)-10-epi-6] also proved problematic. In this case, the E/Z-
selectivity trend was reversed, with the best selectivity obtained
employing KHMDS in DME. Interestingly, no selectivity was
observed with LiHMDS in DMF/HMPA (Scheme 3). In addition,
both sets of conditions suffered from low conversion. At this point,
we surmised that the low efficiency in both olefinations might arise
from the nature of the sulfone fragments [i.e., (-)-3 and (-)-12)],
that is, from difficulty with the initial deprotonation and/or
intramolecular coordination of the resulting metalated species. To
test these ideas, we reversed the coupling partners, preparing
aldehyde (-)-15 from (-)-11 in two steps (Scheme 4) and sulfone
(+)-10 as outlined in Scheme 2. Gratifyingly, under the conditions
of KHMDS in DME, the union proceeded with both complete
conversion and excellent stereocontrol to provide E-olefin (+)-16
in 86% yield after desilylation,20 with this product having the correct
stereogenicity at C(10).21
Scheme 5
Having installed both the C(29)-C(30) and C(15)-C(16) trans
olefins with high stereoprecision, all that remained to complete the
synthesis of 1 was construction of the C(38)-C(39) and C(43)-O
σ bonds followed by global deprotection. Initially, we envisioned
that the labile (Z,Z,E)-trienoate moiety could be introduced in a
protected form comprising a dienyne that would mask the
C(39)-C(40) Z-olefin as an alkyne. Although the dienyne moiety
could be introduced into a simple model bicyclic vinyl iodide by
employing known alkynyl stannane 4,22 subsequent semihydroge-
9
12110 J. AM. CHEM. SOC. VOL. 131, NO. 34, 2009

C O M M U N I C A T I O N S
employing NaHCO3 and 20 at room temperature. Notwithstanding
our initial success in solving the challenging macrolactonization,
(+)-19 was contaminated with minor amounts of other geometric
isomers, which proved difficult to separate. The problem appears
to lie with the reversibility of a Michael addition of DMAP or iodide
to the activated trienoacid during the lactonization process. Another
issue associated with Mukaiyama reagent 20 is halogen exchange
to give 21, which is known to be nonreactive as an activating agent
for carboxylic acid coupling.26 To address these issues, we adopted
the modified Mukaiyama reagent 22,27 which possesses a non-
nucleophilic counterion (i.e., tetrafluoroborate), thus mitigating the
undesired Michael addition as well as the inactivation pathway.
Pleasingly, reagent 22 delivered macrolide (+)-19 in 85% yield
with minimum isomerization (ca. <4%).
through Grant GM-29028. We thank Drs. George Furst and
Rakesh Kohli (University of Pennsylvania) for assistance in
obtaining NMR spectra and high-resolution mass spectra,
respectively. We also thank Dr. Rolf Jansen (Helmholtz Center
for Infection Research, Braunschweig, Germany) for an authentic
sample of (+)-sorangicin A.
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for all transformations and new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) (a) Ho¨fle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
Reichenbach, H. Angew. Chem., Int. Ed. 1996, 35, 1567. (b) Gerth, K.;
Bedorf, N.; Ho¨fle, G.; Irschik, H.; Reichenbach, H. J. Antibiot. 1996, 49,
560.
Clearly aware that our late-stage intermediates were exceedingly
prone to isomerization and/or decomposition because of the delicate
(Z,Z,E)-trienoate moiety, we were now compelled to identify
conditions that were mild but still sufficiently potent to remove
the MOM, acetonide, and tert-butyl protecting groups. This task
proved to be nontrivial! We first took the lead of the Ho¨fle group,
who had employed TFA in aqueous THF at 85 °C to remove the
acetonide group in their synthesis of an extensive library of
sorangicin analogues.28 The product yields, however, were highly
substrate-dependent, varying from 20 to 70%. Application of these
conditions to the fully protected macrolide (+)-19 led only to
decomposition. We therefore initiated an extensive series of
deprotection studies on available individual fragments, which in
the end led to the observation that although the MOM and acetonide
groups could be removed under aqueous protic acidic conditions
(at 85 and 45 °C, respectively), hydrolysis of the tert-butyl ester
was far from efficient (only 50% conversion at 85 °C for 3 h). A
more efficient protocol for removing the tert-butyl group had to be
devised. Use of TFA in anhydrous CH2Cl2 led to destruction of
the trienoate moiety. In regard to Lewis acids, B-bromocatecholbo-
rane29 rapidly removed both the MOM and acetonide groups, but
removal of the tert-butyl group was quite slow. Initially, TMSOTf
was able to remove the MOM and tert-butyl moieties efficiently
on individual fragments, but with the fully protected macrolide (+)-
19, only decomposition occurred. Clearly TMSOTf was too reactive.
Eventually we learned that employing the milder TBSOTf reagent
(buffered with 2,6-lutidine) allowed the tert-butyl ester to be cleanly
transformed into the TBS ester without compromising the delicate
(Z,Z,E)-trienoate linkage. Without further purification, the TBS ester
was then treated with 4 N HCl in THF at room temperature for
24 h to produce (+)-sorangicin A (1) in 70% yield for the two
steps (Scheme 5). The totally synthetic 1 was identical in all respects
(e,g., 1H, 13C, HRMS, and HPLC-LRMS) to an authentic natural
sample provided by Dr. Jansen,30 including chiroptic properties
{[R]D19: +56 (c 0.06, MeOH); lit.6 [R]2D2 +60.9 (c 0.7, MeOH)}.
In summary, the first total synthesis of the structurally complex
macrolide (+)-sorangicin A (1) has been achieved in a highly
convergent fashion. Late stages of the synthetic venture featured
the use of two Julia-Kociénski olefinations to unite three complex
advanced fragments with high E-stereoselectivity. The final steps
of the synthesis then involved a modified Stille union and
Mukaiyama macrolactonization as well as Lewis and protic acid-
promoted deprotections employing carefully defined conditions
required to suppress E/Z isomerization and/or destruction of the
sensitive (Z,Z,E)-trienoate linkage.
(2) Jansen, R.; Wray, V.; Irschik, H.; Reichenbach, H.; Ho¨fle, G. Tetrahedron
Lett. 1985, 26, 6031.
(3) Irschik, H.; Jansen, R.; Gerth, K.; Ho¨fle, G.; Reichenbach, H. J. Antibiot.
1987, 40, 7.
(4) Campbell, E. A.; Pavlova, O.; Zenkin, N.; Leon, F.; Irschik, H.; Jansen,
R.; Severinov, K.; Darst, S. A. EMBO J. 2005, 24, 674, and references
cited therein.
(5) The stereocenter at C(10) in 1, as confirmed by Dr. R. Jansen (Helmholtz
Center for Infection Research, Braunschweig, Germany) is S (as originally
reported in ref 6) and not R (as depicted in ref 7). We thank Dr. Jansen for
this clarification.
(6) Jansen, R.; Irschik, H.; Reichenbach, H.; Schomburg, D.; Wray, V.; Ho¨fle,
G. Liebigs Ann. Chem. 1989, 111.
(7) Schummer, D.; Irschik, H.; Ho¨fle, G. Liebigs Ann. Chem. 1993, 293.
(8) Schinzer, D.; Schulz, C.; Krug, O. Synlett 2004, 15, 2689.
(9) Crimmins, M. T.; Haley, M. W. Org. Lett. 2006, 8, 4223.
(10) Park, S. H.; Lee, H. W. Bull. Korean Chem. Soc. 2008, 29, 1661.
(11) (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. (c) Smith, A. B.,
III.; Dong, S. Org. Lett. 2009, 11, 1099.
(12) Brenneman, J. B. University of Pennsylvania. Unpublished results.
(13) The clarification of the (+)-sorangicin A structure as S rather than R at
C(10) was achieved in 2008. At the beginning of this project, 10-epi-
sorangicin A was targeted, leading to the preparation of (-)-10-epi-6 in
2005.
(14) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 20, 99.
(15) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(16) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
(17) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772.
(18) Blakemore, P. R.; Cole, W. J.; Kociénski, P. J.; Morley, A. Synlett 1998,
26.
(19) Under Barbier conditions, LiHMDS was added to a mixture of sulfone
(-)-3 and aldehyde (-)-2 in 3:1 DMF/HMPA, leading to a <24% yield of
(-)-11 along with recovery of starting materials.
(20) For the first Julia-Kociénski olefination, we envisioned that reversal of
the coupling partners might be not without risk because of the proclivity
of ꢀ-elimination from the bicyclic sulfone derived from (-)-2.
(21) Earlier studies had led to the construction of (-)-10-epi-16.
(22) Rossi, R.; Bellina, F.; Catanese, A.; Mannina, L.; Valensin, D. Tetrahedron
2000, 56, 479.
(23) Franci, X.; Martina, S. L. X.; McGrady, J. E.; Webb, M. R.; Donald, C.;
Taylor, R. J. K. Tetrahedron Lett. 2003, 44, 7735. Stannyl dienoate 5 was
prepared in an analogous fashion according to procedures described therein.
(24) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989. (b) Hikota, M.; Sakurai, Y.; Horita, K.;
Yonemitsu, O. Tetrahedron Lett. 1990, 31, 6367.
(25) (a) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 5, 49. (b) Evans,
D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531.
(26) (a) Oh, S. H.; Cortez, G. S.; Romo, D. J. Org. Chem. 2005, 70, 2835. (b)
Bradlow, H. L.; Vanderwerf, C. A. J. Org. Chem. 1951, 16, 1143.
(27) Xu, J.-C.; Li, P. Tetrahedron 2000, 56, 8119. For the advantages of using
modified Mukaiyama reagents, see: Folmer, J. J.; Acero, C.; Thai, D. L.;
Rapoport, H. J. Org. Chem. 1998, 63, 8170.
(28) Jansen, R.; Schummer, D.; Irschik, H.; Ho¨fle, G. Liebigs Ann. Chem. 1990,
975.
(29) Boeckman, R. K., Jr.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.
(30) The NMR spectra of both the natural and synthetic samples are sensitive
to NMR experimental conditions. More specifically, in the 1H NMR spectra,
the resonances for protons of the C(1)-C(8) side chain depend on the pH
and solvent environments, most apparently for H(2), H(7), and H(44). In
the 13C NMR spectra, the chemical shifts and intensities for both C(1) and
C(2) vary significantly in different solvent and pH environments.
Acknowledgment. Support was provided by the National
Institutes of Health (National Institute of General Medical Sciences)
JA906115A
9
J. AM. CHEM. SOC. VOL. 131, NO. 34, 2009 12111