Formal synthesis of (+)-sorangicin A

Article abstract of DOI:10.1021/ol201920j

The formal synthesis of (+)-sorangicin A was completed by two independent routes. Both approaches feature a cross metathesis reaction to form the C29-C30 bond to arrive at the bicyclic ether/tetrahydropyran fragment. Formation of the C15-C16 olefin to uni

Full text of DOI:10.1021/ol201920j

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4712–4715
Formal Synthesis of (þ)-Sorangicin A
Michael T. Crimmins,* Matthew W. Haley, and Elizabeth A. O’Bryan
Kenan, Caudill, Venable, and Murray Laboratories of Chemistry, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
crimmins@email.unc.edu
Received July 15, 2011
ABSTRACT
The formal synthesis of (þ)-sorangicin A was completed by two independent routes. Both approaches feature a cross metathesis reaction to form
the C29ꢀC30 bond to arrive at the bicyclic ether/tetrahydropyran fragment. Formation of the C15ꢀC16 olefin to unite the dihydropyran fragment
with the rest of the molecule was achieved by either a cross metathesis reaction or a JuliaꢀKocienski olefination.
(þ)-Sorangicin A (1) was isolated in 1985 from the
Herein we describe two approaches toward C1ꢀC38
fragment 2, an advanced intermediate in Smith’s total
synthesis of (þ)-sorangicin A (1). Our synthetic approach
involved the preparation of three orthogonally differen-
tiated core fragments: bicyclic ether 3, tetrahydropyran 4,
and dihydropyran 5 or 6, which would allow us to inves-
tigate a variety of coupling strategies (Scheme 1).
Our initial retrosynthetic plan involved the use of a cross
metathesis reaction to form both the C29ꢀC30 and
C15ꢀC16 olefins; however, a low yield for the second
cross metathesis reaction prompted investigation of a
JuliaꢀKocienski olefination, also used in Smith’s synth-
esis, to form the C15ꢀC16 bond.
€
gliding bacterium Sorangium cellulosum by Hofle and
Reichenbach.1 It exhibits potent antibiotic activity against
both Gram-positive (MIC 0.01ꢀ0.1 μg/mL) and Gram-
negative bacteria (MIC 3ꢀ30 μg/mL) through inhibition of
RNA polymerase in vivo.2 Sorangicin A is comprised of
several synthetically challenging structural features includ-
ing the C30ꢀC37 signature bicyclic ether, C21ꢀC29 tetra-
substituted tetrahydropyran, and C1ꢀC15 trisubstituted
dihydropyran, all of which are embedded in a 31-membered
lactone. Additionally, the macrocyclic skeleton is highly
unsaturated featuring a unique and highly sensitive (Z,Z,E)-
trienoate linkage to which the instability of the natural
product toward several reagents has been attributed.3 The
potent antibiotic activity and complex structure of (þ)-
sorangicin A have prompted several synthetic approaches4
culminating in a total synthesis by the Smith group.5
Scheme 1. Synthetic Approach toward (þ)-Sorangicin A (1)
€
(1) Jansen, R.; Wray, V.; Irschik, H.; Reichenbach, H.; Hofle, G.
Tetrahedron Lett. 1985, 26, 6031.
(2) Irschik, H.; Jansen, R.; Gerth, K.; Hofle, G.; Reichenbach, H. J.
€
Antibiot. 1987, 40, 7.
(3) Schummer, D.; Irschik, H.; Hofle, G. Liebigs Ann. Chem. 1993,
293.
€
(4) (a) Schinzer, D.; Schulz, C.; Krug, O. Synlett 2004, 2689–2692. (b)
Park, S. H.; Lee, H. W. Bull. Korean Chem. Soc. 2008, 29, 1661. (c)
Srihari, P.; Kumaraswamy, B.; Yadav, J. S. Tetrahedron 2009, 65, 6304.
(d) Mohapatra, D. K.; Das, P. P.; Pattanayak, M. R.; Yadav, J. S.
Chem.;Eur. J. 2010, 16, 2072.
(5) (a) Smith, A. B., III; Dong, S.; Brenneman, J. B.; Fox, R. J. J. Am.
Chem. Soc. 2009, 131, 12109. (b) Smith, A. B., III; Fox, R. J. Org. Lett.
2004, 6, 1477–1480. (c) Smith, A. B., III; Fox, R. J.; Vanecko, J. A. Org.
Lett. 2005, 7, 3099. (d) Smith, A. B., III; Dong, S. Org. Lett. 2009, 11,
1099.
r
10.1021/ol201920j
Published on Web 08/11/2011
2011 American Chemical Society

Initial efforts were focused on the synthesis of tetrahy-
dropyran (THP) 4 (Scheme 2). We envisioned that this
fragment could be prepared via an acid-catalyzed epoxide-
opening cascade, similar to our previously reported route
used for the preparation of bicyclic ether 3.6 To begin, a
cross metathesis reaction7 between known aldehyde 78 and
diacetate 8 was performed with Grubbs’ second generation
catalyst (G2) to deliver cross metathesis adduct 9 in 67%
yield. Subsequent Brown asymmetric allylation9 of alde-
hyde 9 with (þ)-Ipc2B-allyl gaverise todiol 10in 86% yield
after basic workup. Allylic alcohol 10 was employed in a
Sharpless asymmetric epoxidation reaction,10 which upon
acidic workup of the intermediate epoxy alcohol initiated
the epoxide opening/cyclization to arrive at the cyclic
ether. Finally, protection of the diol as the bis-triethylsilyl
(TES) ether delivered THP 4 in 62% yield over the two-
step sequence.
generated in situ from C16ꢀC20 vinyl iodide 12 underwent
a FelkinꢀAnh controlled addition to the aldehyde to
introduce the C21 stereocenter as an 8:1 mixture of separ-
able diastereomers. Subsequent conversion of the 1,2-diol
to the acetonide by a two-step sequence afforded dihydro-
pyran 13 in 66% yield over the four steps.
The cross metathesis reaction between bicyclic ether 11
and THP fragment 13 was accomplished in 40% yield,
69% basedon recovered bicyclic ether 11, upon addition of
THP 13 dropwise over several hours to a solution of
bicyclic ether 11 and Grubbs’ second generation catalyst.
Removal of the TIPS protecting group, followed by Lin-
dlar reduction of the alkyne,13 and subsequent adjustment
of the C25 and C37 protecting groups provided terminal
olefin 16 in 55% yield over the six-step sequence.
Having developed an efficient route toward bicyclic
ether THP/fragment 16, synthesis and incorporation of
the dihydropyran (DHP) fragment was next explored. The
synthesis of the dihydropyran fragment commenced with a
Wittig, reduction, oxidation sequence of aldehyde 17,5c
available in two steps via a Myers alkylation,14 reduction
sequence, to provide trisubstituted olefin 19 in 92% yield
over the three steps (Scheme 4). Exposure ofaldehyde 19to
a Brown alkyoxy-allylation15 delivered differentially pro-
tected syn-1,2-diol 20 in 96% yield. Upon treatment of the
allylation adduct with acrolein diethyl acetal,16 an inter-
mediate diene was obtained, which underwent ring closing
metathesis in the presence of Grubbs’ second generation
catalyst (G2) to generate mixed acetal 21 as an inconse-
quential 1:1 mixture of diastereomers in 72% yield over
Scheme 2. Synthesis of Tetrahydropyran 4
two steps.17 Treatment of the mixed acetal with BF3 OEt2
3
in the presence of allyl-trimethylsilane effected a Sakurai
reaction to deliver allylated product 5 in 92% yield as a
single diastereomer.18 Introduction of the desired oxida-
tion state at C1 was achieved by a four-step sequence5c
involving cleavage of the PMB ether under oxidative
conditions, DessꢀMartin oxidation,19 Pinnick oxida-
tion,20 and finally ester formation21 to afford C1ꢀC15
dihydropyran 22 in 57% yield. The MOM ether was
exchanged for a TBS ether via a two-step sequence to give
rise to dihydropyran 23 in 93% yield.
With a route toward both THP 4 and bicyclic ether 3,
cross metathesis to form the C29ꢀC30 bond was explored.
The desired cross metathesis substrate, bicyclic ether 11,
was prepared by a three-step sequence of acylation, ozo-
nolysis, and methylenation11 from previously prepared
bicyclic ether 36 in 85% yield (Scheme 3). Elaboration of
THP 4 to incorporate the C16ꢀC20 fragment was also
carried out prior to the key cross metathesis reaction.
Toward this end, selective cleavage and oxidation of the
primary TES ether was realized upon subjection of THP 4
to modified Swern conditions.12 The vinyl zinc species
With both cross metathesis partners in hand, bicyclic
ether/THP fragment 16 and DHP 23 were exposed to
HoveydaꢀGrubbs’ second generation catalyst (HG2).
Scheme 3. Cross Metathesis To Form Bicyclic Ether/THP Fragment 16
Org. Lett., Vol. 13, No. 17, 2011
4713

Scheme 4. Formal Synthesis of C1ꢀC38 Fragment 2 via a Cross Metathesis Approach
This key bond forming reaction was complicated by the
fact that both cross metathesis partners are Type I olefins;7
thus a statistical mixture of cross metathesis adduct 24 and
the C16ꢀC37 fragment 16 and DHP 23 homodimers was
expected; however, only a 16% yield of the desired cross
metathesis adduct was obtained. Despite the low yield for
this key reaction, intermediate 24 was advanced through a
three-step sequence to arrive at C1ꢀC38 fragment 2 in
31% yield.22
In light of the low yield obtained for the cross metathesis
reaction to unite the DHP fragment with the rest of the
molecule, we decided to turn our attention toward the
JuliaꢀKocienski olefination used by Smith to form the
C15ꢀC16 bond.5a To prepare the bicyclic ether/THP and
dihydropyran fragments necessary for the Julia olefina-
tion, we needed to modify our protecting group strategy
and investigate an alternative cross metathesis/vinyl addi-
tion sequence.
previously prepared bicyclic ether 36 was protected as
the PMB-ether, which upon oxidative cleavage by the
JohnsonꢀLemieux protocol23 and methylene Wittig olefi-
nation delivered bicyclic ether 25 (Scheme 5). To our
delight, upon dropwise addition of THP 4 to a solution
of bicyclic ether 25 and Grubbs’ second generation catalyst
(G2), cross metathesis adduct 26 was obtained in 77%
yield as a single detectable E isomer. Exposure of TES
ether 26 to modified Swern conditions allowed for the
selective oxidation of the C21 alcohol to generate an
intermediate aldehyde, which, upon treatment with the
vinyl zinc species formed from vinyl iodide 27, afforded
bicyclic ether/THP fragment 28 in 64% yield (two steps).
To arrive at C1ꢀC38 fragment 2, several protecting
group manipulations were necessary. Toward this end,
all of the silyl protecting groups from vinyl addition
product 28 were removed with TBAF to reveal an inter-
mediate tetraol. The tetraol was subjected to CSA in neat
dimethoxypropane to effect acetonide formation, where-
upon the C16 and C25 alcohols were protected as TBS and
Attention was first turned toward synthesis of the
modified bicyclic ether/THP fragment. Toward this end,
Scheme 5. Cross Metathesis To Form Bicyclic Ether/THP Fragment 31
4714
Org. Lett., Vol. 13, No. 17, 2011

MOM ethers respectively,24 furnishing the fully protected
bicyclic ether/THP fragment 29 in 45% yield over the four-
step sequence. Introduction of the vinyl iodide moiety was
next pursued. Cleavage of the PMB ether was achieved
under oxidative conditions with DDQ, and the resultant
alcohol was oxidized under DessꢀMartin conditions. The
resultant intermediate aldehyde was immediately utilized
in a Takai olefination22,25 to give rise to a 4:1 ratio of
E/Z-vinyl iodides. The vinyl iodides were readily separated
by flash column chromatography to deliver E-vinyl iodide
30 in 28% yield over the three steps. Vinyl iodide 30 was
converted to aldehyde 31, required for the JuliaꢀKocienski
olefination, by a known two-step sequence in 68% yield.5
the previously employed route toward dihydropyran 23.
A Lewis acid mediated addition of acetaldehyde silyl ether
to mixed acetal 21 delivered aldehyde 6 in 82% yield as a
single diastereomer (Scheme 6).26 Aldehyde 6 was reduced
via a sodium borohydride reduction to give rise to the C15
alcohol. The MOM ether was cleaved from the resultant
alcohol under acidic conditions to reveal an intermediate
diol, which was converted to bis-TBS ether 32 in 83% yield
over the three-step sequence. Introduction of the desired
oxidation state at C1 was achieved via the previously used
sequence,5c in which PMB-ether 32 was converted to tert-
butyl ester 33 in four steps and 72% yield. Ester 33
corresponds to an intermediate from Smith’s synthesis;
thus a known three-step sequence was carried out to
selectively cleave the C15 TBS-ether and convert the
resultant alcohol to sulfone 34.5a Finally, sulfone 34
and aldehyde 31 were employed in a JuliaꢀKocienski
olefination,27 using the conditions described by Smith,5a
to give rise to C1ꢀC38 fragment 2 in 79% yield. Fragment
2 was spectroscopically identical to that reported by
Smith.5a
Scheme 6. JuliaꢀKocienski Olefination Approach to
Fragment 2
In summary, two routes toward the formal synthesis of
the C1ꢀC38 fragment of (þ)-sorangicin A (1) have been
completed. Both routes feature a cross metathesis reaction
to unite the bicyclic ether and THP fragments. Our initial
approach featured a second cross metathesis to append the
DHP fragment; however a low yield for this key reaction
prompted us to instead employ a JuliaꢀKocienski olefina-
tion to form the C15ꢀC16 bond.
Acknowledgment. Financial support from the National
Institute of General Medical Sciences (GM60567) is grate-
fully acknowledged.
Supporting Information Available. Experimental de-
tails and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
With the aldehyde coupling partner in hand, we turned
our attention to the synthesis of the C1ꢀC15 sulfone. This
was achieved in an efficient manner upon modification of
(17) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 3783.
(18) (a) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am.
Chem. Soc. 2000, 122, 168. (b) Krumper, J. R.; Salamant, W. A.;
Woerpel, K. A. Org. Lett. 2008, 10, 4907.
(19) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(20) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
(6) Crimmins, M. T.; Haley, M. W. Org. Lett. 2006, 8, 4223.
(7) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
(8) Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein, S. P.;
McAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661.
(9) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(10) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko,
S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(11) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654.
(12) Rodrıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetra-
´
hedron Lett. 1999, 40, 5161.
(21) Mathias, L. J. Synthesis 1979, 561.
(22) Takai, K.;Nitta, K.;Utimoto, K.J. Am. Chem. Soc. 1986, 108, 7408.
(23) Pappo, R.; Allen, J.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
(13) Lindlar, H. Helv. Chim. Acta 1952, 35, 446.
(14) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(15) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988,
110, 1535.
(24) Druais, V.; Hall, M. J.; Corsi, C.; Wendeborn, S. V.; Meyer, C.;
Cossy, J. Tetrahedron 2010, 66, 6358.
(25) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(26) Enev, V. S.; Kaehlig, H.; Mulzer, J. J. Am. Chem. Soc. 2001, 123,
10764.
ꢀ
(27) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26.
(16) Ahmed, A.; Hoegenauer, E. K.; Enev, V. S.; Hanbauer, M.;
€
Kaehlig, H.; Ohler, E.; Mulzer, J. J. Org. Chem. 2003, 68, 3026.
Org. Lett., Vol. 13, No. 17, 2011
4715