(+)-Sorangicin A synthetic studies. Construction of the C(1-15) and C(16-29) subtargets

Article abstract of DOI:10.1021/ol051119l

(Chemical Equation Presented) Effective stereocontrolled syntheses of subtargets (-)-2 and (-)-4, comprising respectively the C(16-29) and C(1-15) tetrahydropyran and dihydropyran moieties of the potent antibiotic (+)-sorangicin A (1), have been achieved. The cornerstone for the synthesis of (-)-2 involved an aldol tactic exploiting 1,4-induction, followed in turn by an acid-mediated cyclization/ketalization and hydrosilane reduction promoted by TMSOTf, while construction of (-)-4 entailed a stereoselective conjugate addition/α-oxygenation sequence.

Full text of DOI:10.1021/ol051119l

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3099-3102
(
+
)-Sorangicin A Synthetic Studies.
Construction of the C(1 15) and
C(16 29) Subtargets
−
−
Amos B. Smith, III,* Richard J. Fox, and John A. Vanecko
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 May 13, 2005
ABSTRACT
Effective stereocontrolled syntheses of subtargets (
dihydropyran moieties of the potent antibiotic (
an aldol tactic exploiting 1,4-induction, followed in turn by an acid-mediated cyclization/ketalization and hydrosilane reduction promoted by
TMSOTf, while construction of ( )-4 entailed a stereoselective conjugate addition/ -oxygenation sequence.
−)-2 and (
−)-4, comprising respectively the C(16
−29) and C(1
−15) tetrahydropyran and
+
)-sorangicin A (1), have been achieved. The cornerstone for the synthesis of (−)-2 involved
−
r
In 1985, the laboratories of Ho¨fle and Reichenbach reported
the isolation and structural determination of the sorangicins,
a new class of macrolide natural products produced by
Sorangium cellulosum.1 Importantly, (+)-sorangicin A, the
most potent congener, demonstrated extraordinary antibiotic
activity against a broad panel of both Gram-positive and
Gram-negative bacteria, displaying average MIC values of
10 ng/mL and 10 µg/mL, respectively. Subsequent mecha-
nistic examination revealed that the selective biological
response induced by the sorangicins in prokaryotic cells
arises from the inhibition of RNA polymerase in both
Escherichia coli and Staphylococcus aureus.2
both the novel architecture, including the signature dioxa-
bicyclo[3.2.1]octane moiety, the cis,cis,trans-trienoate, and
the 31-membered macrolide ring, and the significant biologi-
cal properties. In this Letter, we disclose our overall synthetic
strategy (Scheme 1), in conjunction with effective, stereo-
controlled assemblies of subtargets 2 and 4, comprising
respectively the C(16-29) and C(1-15) fragments of
(+)-sorangicin A. A viable approach to the signature element,
the C(30)-C(38) dioxabicyclo[3.2.1]-octane subtarget
(-)-3, was previously reported from this laboratory.4
A central tenet of our synthetic analysis of sorangicin A
(1), taking into careful consideration the reported significant
instability of the natural product to a variety of reagents (e.g.,
fluoride ion, DDQ, and the dissolving metal sodium amal-
gam),5 entailed development of a viable protecting group
The sorangicin class of natural products and, in particular,
sorangicin A (1) comprise timely synthetic targets3 given
(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.
(2) Irschik, H.; Jansen, R.; Gerth, K.; Ho¨fle, G.; Reichenbach, H.
J. Antibiot. 1987, 40, 7.
(3) For other synthetic approaches, see: Schinzer, D.; Schulz, C.; Krug,
O. Synlett 2004, 15, 2689.
(4) Smith, A. B., III; Fox, R. J. Org. Lett. 2004, 6, 1477.
(5) Schummer, D.; Irschik, H.; Ho¨fle, G. Liebigs Ann. Chem. 1993, 293.
10.1021/ol051119l CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/10/2005

9 to known enone (-)-8,9 followed in turn by R-oxygenation
and Pd-catalyzed tin hydride reduction of the kinetic enol
triflate derived from the C(11) ketone. Stereo- and regio-
selectivity in these transformations would derive from
substrate control.
Scheme 1
With this overview in mind, we began construction of 2,
exploiting the Petasis-Ferrier union/rearrangement. Sily-
lation of known â-hydroxy acid (+)-67c (Scheme 2), followed
by condensation with aldehyde (+)-7,8 promoted by
TMSOTf,10 afforded dioxanone (+)-10.
Scheme 2
scenario. Fortunately, Ho¨fle had demonstrated the potential
utility of an acetonide for the C(21,22) diol system, in
particular with removal by TFA treatment.6 With this
information in mind, we envisioned disconnections at the
macrocyclic lactone, the C(38)-C(39) σ-bond, and both the
C(15-16) and C(29-30) trans-disubstituted olefins to reveal
subtargets 2, (-)-3,4 and 4.
Recognition of the 2,6-cis-disubstituted tetrahydropyran
in 2 initially suggested the powerful Petasis-Ferrier union/
rearrangement7 tactic developed in our laboratory exploiting
known â-hydroxy acid (+)-67c and aldehyde (+)-7.8 This
strategy, however, was not without significant risk: first,
the Petasis-Ferrier rearrangement had not been explored
with an R-oxygenated aldehyde; second, to the best of our
knowledge, there are no examples of selective reductions of
a C(4) carbonyl to the corresponding axial alcohol in a
2,3,6-cis-cis-trisubstituted tetrahydropyranone (cf. 5).
For aldehyde 4, our synthetic plan (Scheme 1) called for
a conjugate addition of a cuprate derived from vinyl bromide
Petasis-Tebbe methylenation11 and in turn exposure of
the derived enol ether to Me2AlCl to trigger the Petasis-
Ferrier rearrangement furnished tetrahydropyranone (+)-5
both in good yield and as a single diastereomer.12 Impor-
tantly, this transformation comprises the first example of the
use of an R-oxygenated aldehyde in a Petasis-Ferrier union/
rearrangement sequence.13 However, despite the clear success
of the Petasis-Ferrier union/rearrangement tactic, selective
reduction of the derived ketone (+)-5 to the requisite C(25)
axial alcohol proved unattainable. A wide variety of reduction
conditions including K- and L-selectride, NaBH4/CeCl3, CBS
employing both (R) and (S) enantiomers, and DIBAL-H
furnished at best a mixture (ca. 1:1) of the C(25) axial and
equatorial alcohols. Equally daunting, Mitsunobu inversion
of the undesired diastereomer resulted only in elimination.
A nearly identical observation, including Mitsunobu elimina-
tion, was recently reported by Funk and Cossey for an
analogous 2,3,6-cis-cis-trisubstituted tetrahydropyranone.14
We therefore turned to an aldol construction tactic between
methyl ketone (+)-14 and aldehyde (+)-16 (Scheme 3),
(6) Jansen, R.; Schummer, D.; Irschik, H.; Ho¨fle, G. Liebigs Ann. Chem.
1990, 975.
(7) (a) Ferrier, R. J.; Middleton, S. Chem. ReV. 1993, 93, 2779. (b) Petasis,
N. A.; Lu, S.-P. Tetrahedron Lett. 1996, 37, 141. For examples exploiting
the Petasis-Ferrier union/rearrangement tactic in natural product synthesis,
see: (c) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M.
J. Am. Chem. Soc. 2001, 123, 10942. (d) Smith, A. B., III; Verhoest, P. R.;
Minbiole, K. P.; Lim, J. J. Org. Lett. 1999, 1, 909. (e) Smith, A. B., III;
Minbiole, K. P.; Verhoest, P. R.; Beauchamp, T. J. Org. Lett. 1999, 1, 913.
(f) Smith, A. B., III; Sfouggatakis, C.; Gotchev, D. B.; Shirakami, S.; Bauer,
D.; Zhu, W.; Doughty, V. A. Org. Lett. 2004, 6, 3637. (f) Smith, A. B., III;
Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2002, 124, 11102.
(g) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc.
2001, 123, 12426. For more recent modifications, see: (h) O’Neil, K. E.;
Kingree, S. V.; Minbiole, K. P. C. Org. Lett. 2005, 7, 515.
(9) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60,
5998.
(10) Seebach, D.; Imwinkelried, R.; Stucky, G. HelV. Chim. Acta 1987,
70, 448.
(11) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(12) The stereochemistry in (+)-5 was established on the basis of NMR
nOe measurements observed between the C(23) and C(27) hydrogens.
(13) Although dioxanone formation and methylenation proceeded smoothly,
attempts to perform the rearrangement with an acetonide at C(21,22) led to
decomposition.
(8) Redlich, H.; Bruns, W.; Francke, W.; Schurig, V.; Payne, T. L.; Vite,
J. P. Tetrahedron 1987, 2029.
(14) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 12216.
3100
Org. Lett., Vol. 7, No. 14, 2005

steps. Thioether formation via a Mitsunobu reaction,24 and
oxidation of the derived sulfide to the sulfone completed
construction of (-)-2. Sulfone (-)-2 was thus prepared in
17 steps (longest linear sequence) from commercially avail-
able starting materials; the overall yield was 17%.
Scheme 3
Scheme 4
calling upon 1,4-stereoinduction15 to install the C(25) hy-
droxyl prior to pyran ring formation.
Ketone (+)-14 and aldehyde (+)-16 proved readily ac-
cessible as outlined in Scheme 3. Notable here was the two-
step construction of (+)-13 via DIBAL reduction of lactone
(+)-12,16 followed by exposure of the resulting lactol to
trimethylsilyldiazomethane.17
For the aldol, treatment of the boron enolate derived from
(+)-14 with aldehyde (+)-16 furnished a separable mixture
(ca. 3.4:1) of C(25) diastereomers (Scheme 4).15 Removal
of the TES group in 17a and 17b, accompanied by cycliz-
ation and methyl ketal formation,18 furnished mixed methyl
ketals (+)-18 and (+)-19 in excellent yield. Although the
aldol diastereoselectivity proved only modest, this route held
considerable appeal since the minor diastereomer could be
completely converted in excellent yield to (+)-18 via
oxidation and reduction of (+)-19.18
Continuing with construction of 2, Et3SiH reduction
promoted by TMSOTf and MOM protection of the C(25)
hydroxyl afforded tetrahydropyran (+)-20 in excellent yield
as a single diastereomer.19
Hydrozirconation/iodination,20 followed by Suzuki-
Miyaura coupling21 with alkyl boronate 21,22 next furnished
olefin (+)-22 as a single E-isomer possessing the full carbon
skeleton of subtarget 2. Removal of the benzyl groups
employing dissolving metal conditions, followed in turn by
conversion of the resulting diol to the acetonide, and selective
removal of the tert-butyldiphenylsilyl (BPS) group with
hydroxide23 led to alcohol (+)-23 in 59% yield for the three
We next turned to construction of aldehyde 4, beginning
with enone (-)-8, exploiting a conjugate addition/R-
oxygenation sequence (Scheme 5). Synthesis of the requisite
vinyl bromide (-)-9 entailed a Myers alkylation25 between
(+)-24 and 25 (Scheme 5) to furnish amide (+)-26, both in
excellent yield and with high diastereoselectivity (>20:1).26
Reduction to the aldehyde,25,27 followed by Corey-Fuchs
homologation28 and hydrozirconation/bromination20 led to
vinyl bromide (-)-9 as a single stereoisomer.
(15) For a similar example proceeding with 1,4-anti selectivity, see:
Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein, S. P.; McAtee,
L. F. J. Am. Chem. Soc. 2002, 124, 5661.
(16) Marshall, J. A.; Seletsky, J. A.; Boris, M.; Luke, G. P. J. Org. Chem.
1994, 59, 3413.
(17) Myers, A. G.; Goldberg, S. D. Angew. Chem., Int. Ed. 2000, 29,
2732 and references therein.
(18) For selectivity precedent, see: Heathcock, C. H.; McLaughlin, M.;
Medina, J.; Hubbs, J. L.; Wallace, G. A.; Scott, R.; Claffey, M. M.; Hayes,
C. J.; Ott, G. R. J. Am. Chem. Soc. 2003, 125, 12844.
(19) The stereochemistry of (+)-20 was verified upon semi-hydrogenation
to afford material identical to that prepared through the Petasis-Ferrier
rearrangement sequence.
Enone (-)-89 (Scheme 5) was readily prepared enantio-
selectively via cyclocondensation between the Danishefsky
(24) Mitsunobu, O. Synthesis 1981, 1.
(20) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
97, 679.
(21) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(22) Alkyl boronate 21 was prepared from 1,3-propanediol; see Sup-
porting Information.
(23) Shekhani, M. S.; Khan, K. M.; Mahwood, K.; Shah, P. M.; Malik,
S. Tetrahedron Lett. 1990, 1669.
(25) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(26) Iodide 25 was prepared in two steps from 1,5-pentanediol; see
Supporting Information.
(27) The absolute stereochemistry of the aldehyde was verifed via
chemical correlation; see Supporting Information.
(28) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
Org. Lett., Vol. 7, No. 14, 2005
3101

Scheme 5
Scheme 6
diene and aldehyde 27,29 catalyzed by chromium(III) com-
plex 28.30 Both the yield and enantioselectivity proved
excellent (ca. 98%; 20:1 er).
Pleasingly, treatment of the higher-order cuprate derived
from (-)-9 with enone (-)-8 (Scheme 6), in the presence
of chlorotriethylsilane, led to enol ether (+)-29 as a single
diastereomer. Chemo- and stereoselective C(10) oxidation
of (+)-29 employing the Rubottom protocol,31 followed by
conversion of the derived R-TES ether to the R-TBS ether,
next furnished (-)-30 in 46% yield for the three steps.32,33
Kinetic enolate formation (LDA/HMPA), followed in turn
by formation of the enol triflate with Comin’s reagent
[N-(5-chloro-2-pyridyl)triflimide]34 and palladium-catalyzed
reduction,35 led to diene (-)-31. A two-step oxidation36 and
tert-butyl ester formation,37 after removal of the PMB
protecting group, next furnished (-)-32. Elaboration of
aldehyde (-)-4 was then achieved by chemoselective
removal of the primary TBS group and Dess-Martin
oxidation.38 Overall, the synthesis of (-)-4 entailed a longest
linear sequence of 19 steps and proceeded in 5% overall
yield.
In summary, syntheses of advanced intermediates (-)-2
and (-)-4, comprising respectively the C(16-29) and
C(1-15) backbone of sorangicin A (1), have been achieved
in 17 and 19 steps. The cornerstone of the synthetic strategy
for (-)-2 entailed an aldol tactic, followed in turn by an
acid-mediated cyclization/ketalization and hydrosilane reduc-
tion, whereas (-)-4 arose via a highly stereoselective
conjugate addition/R-oxygenation sequence. Studies to com-
plete the total synthesis of (+)-sorangicin A (1) will be
reported in due course.
(29) Aldehyde 27 was prepared in two steps from 1,3-propanediol; see
Supporting Information.
(30) (a) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1999, 38, 2398. (b) Gademann, K.; Chavez, D. E.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2002, 41, 3059.
(31) RuBottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 49, 4319.
(32) Conversion of the corresponding TBS-enol ether to (-)-30 or the
enol acetate to the R-hydroxy ketone were significantly less efficient.
(33) (a) The absolute stereochemistry of C(10) was verified via Mosher
ester analysis; see Supporting Information. (b) The observed J value of 8.3
Hz between the C(9) and C(10) hydrogens of (-)-30 verified the relative
stereochemistry. For the conformation of substituted tetrahydropyranones,
see: (c) Goodwin, T. E.; Crowder, M.; White, R. B.; Swanson, J. S.
J. Org. Chem. 1983, 48, 376.
(34) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(35) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033.
(36) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
Acknowledgment. Support was provided by the National
Institutes of Health through Grant GM-29028 and an Eli Lilly
and Dissertation Graduate Fellowship to R.J.F.
Supporting Information Available: Spectroscopic and
analytical data for all new compounds and selected experi-
mental procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
(37) Mathias, L. J. Synthesis 1979, 561.
(38) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
OL051119L
3102
Org. Lett., Vol. 7, No. 14, 2005