On the macrocyclization of the erythromycin core: Preorganization is not required

Article abstract of DOI:10.1002/anie.201007309

Free of bias: Preorganization is not a requirement for the efficient cyclization of the erythromycin core, as has always been assumed. This finding has enabled Ci-H oxidative cyclization or Yamaguchi macrocyclization to form stereochemically modified eryt

Full text of DOI:10.1002/anie.201007309

Communications
DOI: 10.1002/anie.201007309
Natural Product Synthesis
On the Macrocyclization of the Erythromycin Core: Preorganization is
Not Required**
Erik M. Stang and M. Christina White*
The erythromycins, discovered and isolated in the early 1950s,
are the best-known members of the clinically important
macrolide class of antibiotics.[1] The 14-membered macro-
lactone core imbedded in these natural products has inspired
new synthetic methods for the construction of large ring
lactones, beginning with the landmark synthesis of erythro-
nolide B by the Corey group in 1978.[2] During these studies, a
single acetonide protecting group was utilized at the C-3/C-5
position. Similarly, this protecting group was used by the
Masamune group years later for the synthesis of 6-deoxyer-
ythronolide B (6-dEB).[3] While no rationale was given for the
use of this acetonide at the time, its function was revealed
during the historic synthesis of erythromycin A in 1981 by
Woodward et al. In three consecutive reports, the Woodward
group extensively explored the conformational requirements
for efficient acylation-based macrolactonization of erythro-
mycin A seco acid derivatives. In particular, cyclic protecting
groups were placed at various positions to serve as biasing
elements, that is, artificial structural features intended to aid
macrocyclic ring closure through substrate preorganization.[4]
The results from this study led the Woodward group to
conclude that “certain structural features such as … cyclic
protecting groups at C-3/C-5 and C-9/C-11 are required for
efficient lactonization” and that “these structural require-
ments probably arise from conformation requirements for
lactonization.” This conclusion—that preorganization is
analogues that are not readily accessible with the biasing
elements in place. Overall these findings require revision of
the 30-year-old dogma that preorganization is mandatory for
achieving macrocyclization of the erythromycins.
Inspired by the Woodward report, synthetic endeavors by
the research groups of Stork, Nakata, Yonemitsu, Danishef-
sky, Kochetkov, Hoffmann, Evans, Woerpel, Nelson, and us
have reduced the conformational space available to the seco
acid backbones of the erythronolide series (that is, 6-dEB,
erythronolide B, and erythronolide A) through the use of six-
membered-ring protecting groups on C-3/C-5 and C-9/C-11
(Scheme 1).[5,6] In addition to scaffolds with cyclic protecting
required for efficient cyclization—has become
a well-
accepted doctrine that has influenced the planning of all
ensuing erythromycin syntheses (see below). We now report
for the first time that conformational restraining elements are
in fact not required for attaining efficient lactonization of the
erythromycin core structure, 6-deoxyerythronolide B (6-
dEB). Moreover, we demonstrate that the removal of biasing
elements allows for more stereochemical flexibility in the
cyclization of 6-dEB, thus enabling access to stereochemical
Scheme 1. Cyclic biasing elements in erythromycin’s synthetic history.
PG=protecting group.
groups, other types of biasing elements (for example, hetero-
cycles, olefins) have been employed in similar positions to
rigidify the hydroxy acid backbone.[7,8] In a particularly
notable example, Paterson and Rawson validated this
approach by using two olefinic rigidifying elements in place
of cyclic protecting groups.[9] Furthermore, Martin and co-
workers demonstrated that steric bulk at C-5 (a desosamine
sugar appendage) coupled to a C-9/C-11 cyclic acetal could
enable cyclization.[10] The steadfast application of one[3] or
more structural biasing elements in erythromycinꢀs synthetic
history demonstrates the resonating impact of Woodwardꢀs
cyclization studies.
[*] E. M. Stang, Prof. M. C. White
Department of Chemistry, Roger Adams Laboratory
University of Illinois
Urbana, IL 61801 (USA)
Fax: (+1)217-244-8024
E-mail: white@scs.illinois.edu
Homepage: http://www.scs.illinois.edu/white
[**] We thank Prof. Paul Hergenrother for helpful discussions. Financial
support was provided by the NIH/NIGMS (grant no. GM076153)
and kind gifts were received from Eli Lilly, Bristol–Myers Squibb,
Pfizer, and Amgen. E.M.S is the recipient of a Bristol-Myers Squibb
graduate fellowship, R. C. Fuson graduate fellowship, and a Pfizer
graduate fellowship.
ꢀ
We recently reported a late-stage C H oxidation strategy
for the total synthesis of 6-deoxyerythronolide B (6-dEB), by
ꢀ
using a palladium(II)/bis(sulfoxide) (1) catalyzed C H oxi-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007309.
dative macrolactonization reaction.[6,11] As a part of our
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Angew. Chem. Int. Ed. 2011, 50, 2094 –2097

synthetic planning, we also chose to employ traditional cyclic
protecting groups at C-9/C-11 and C-3/C-5 (2) to facilitate
macrocyclic ring closure (see Scheme 3). In the presence of
these biasing elements, the 14-membered macrolide product
was formed in 34% yield (45% recovered starting material
(rSM); 56% yield after recycling twice) and with > 40:1 d.r. in
favor of the natural C-13 diastereomer 3 (Scheme 3). Based
on the Hammond postulate, we attributed the inability to
form the unnatural C-13 diastereomer under the chelate-
ꢀ
controlled C H oxidative macrolactonization conditions to
the large difference in the ground-state product energies
between the C-13 diastereomers (the natural C-13 diastereo-
mer was calculated to be 3 kcalmolꢀ1 more stable than the
C-13 epimer). Similarly, while an acylation-based Yamaguchi
cyclization of 5 provided the natural macrolide 3 in high yield,
the unnatural C-13 diastereomer (4) could not be formed.
Upon revisiting the studies of Woodward et al., in which
the positioning of cyclic protecting groups had been opti-
mized for the natural erythromycin structure, we questioned
whether the biasing elements were in fact hampering the
cyclization of stereochemical analogues. In this vein, we
recognized the absence of a key control experiment: the
attempted cyclization of a substrate completely devoid of
biasing elements. Surprisingly, this experiment has remained
unreported in the literature, despite over 30 years of eryth-
romycin syntheses. We therefore set out to test the well-
accepted idea that preorganization is necessary for cyclization
of the erythromycin structure.
Scheme 2. Synthesis of hydroxy acid 8 and alkenoic acid 9. Conditions:
a) 1m HCl (aq), 70% yield; b) Me3OBF4, proton sponge, 62% yield;
c) 1 (10 mol%), benzoquinone (2.0 equiv), p-NO2BzOH (1.5 equiv),
458C, 72 h, 1.2:1 d.r., 59% yield; d) LiOOH (aq); e) K2CO3, MeOH,
89% (2 steps); f) LiOOH (aq), 99% yield. Bn=benzyl, Bz=benzoyl,
PMP=p-methoxyphenyl.
ꢀ
auxiliary with LiOOH provided the C H oxidative cycliza-
tion substrate 9 in 99% yield. Intermolecular palladium(II)/
ꢀ
bis(sulfoxide) (1) catalyzed C H oxidation provided the C-13
oxidized products as diastereomeric allylic p-nitrobenzoates
in 59% yield (1.2:1 d.r.). Hydrolysis of the chiral auxiliary
with LiOOH and methanolysis of the p-nitrobenzoates
furnished the unbiased seco acid 8 in 89% yield (over
6-Deoxyerythronolide B, the aglycone precursor to the
erythromycins, serves as the archetypical core of the poly-
ketide macrolide antibiotics. In nature, a seco acid bearing
unadorned hydroxy groups at C-3, C-5, and C-11 and a ketone
functionality at C-9 is cyclized to form 6-dEB, which is then
hydroxylated at the C-6- and C-12-positions through enzy-
ꢀ
2 steps, 1.2:1 d.r.). Notably, C H oxidation greatly aided
these studies by circumventing de novo syntheses of both
epimeric Yamaguchi precursors 8.[6,16,17]
To evaluate if preorganization is needed for efficient
macrolactonization of erythromycin precursors we attempted
ꢀ
matic C H functionalization to form erythronolides B and A,
a
traditional acylation-based macrolactonization with
respectively. In addition to practical considerations of elim-
inating the formation of unwanted ring sizes,[12] the introduc-
tion of protecting groups was deemed necessary to prevent
preorganization through 1,3-hydrogen bonding.[13] Polypropi-
onate molecules typically adopt conformations that minimize
syn-pentane interactions, and thus will have inherent preor-
ganization that may aid cyclization.[14] However, in attempts
to minimize artificial bias (bias not present in the native
polypropionate structure), we selected methyl ether protect-
ing groups for this study because of their inability to induce
electrostatic preorganization while maintaining similar steric
properties as the free hydroxy groups of the natural substrate.
We reasoned that the use of any other protecting group, albeit
potentially more synthetically useful, might inadvertently
enable cyclization through either steric or electronic preor-
ganization of the substrate.[15] Accordingly, we synthesized a
tetramethyl ether protected hydroxy acid 8 and alkenoic acid
9 as the unbiased cyclization precursors (Scheme 2).
unbiased hydroxy acids 8 (1.2:1 d.r., Scheme 3).[18,19] Strik-
ingly, both the natural and unnatural C-13 diastereomeric
hydroxy acids cyclized efficiently under standard Yamaguchi
macrolactonization conditions, to afford the 14-membered
macrolide products 10 and 11 in 70% yield (2:1 d.r.)! The ease
with which these hydroxy acids cyclized in the absence of
biasing elements is remarkable; matching the best yield
obtained from the original preorganization studies by Wood-
ward et al.[4] Despite decades of erythromycin syntheses, this
is the first reported case where precursors to any member of
the erythromycins have been cyclized successfully without the
use of biasing elements to aid in the formation of the 14-
membered macrolide.
ꢀ
The C H oxidative macrolactonization of unbiased
alkenoic acid (9!10/11) also proceeded in the absence of
biasing elements, with comparable yields (36% yield, 45%
recovered SM) to the analogue containing biasing elements
(2!3, Scheme 3). More importantly, in contrast to previous
results with cyclic protecting groups at C-9/C-11 and C-3/C-5,
the unnatural C-13 diastereomer 11 could be now be accessed
from this unbiased precursor (1:3.3 d.r. from 9 versus
1: > 40 d.r. from 2). On the basis of these results we may
The syntheses of both unbiased cyclization precursors 8
and 9 proceeded conveniently via a common intermediate,
terminal olefin 7. Global deprotection of a previously
synthesized bisacetal intermediate (6),[6] followed by perme-
thylation with Me3OBF4 furnished tetramethylated terminal
olefin 7 (Scheme 2). Straightforward removal of the chiral
ꢀ
conclude that Pd/bis(sulfoxide)-catalyzed C H oxidative
macrolactonizaton of erythromycin precursors also does not
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www.angewandte.org 2095

Communications
Scheme 3. Macrocyclization studies on biased and unbiased 6-dEB precursors.
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Tone, K. Horita, O. Yonemitsu, J. Org. Chem. 1990, 55, 7;
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A. S. Kim, R. Metternich, V. J. Novack, J. Am. Chem. Soc. 1998,
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2010, 122, 2645; Angew. Chem. Int. Ed. 2010, 49, 2591; for a
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[6] E. M. Stang, M. C. White, Nat. Chem. 2009, 1, 547.
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require biasing elements, although such elements can signifi-
cantly improve the diastereomeric outcome of the cyclization.
These results definitively demonstrate that artificial pre-
organization is not a requirement for the efficient cyclization
of erythromycinꢀs polypropionate core (6-dEB). In other
words, the inherent conformation of the linear polypropi-
onate structure is sufficient for facile macrolactonization.[20]
Significantly, we have shown that designed preorganization
has a dramatic impact on the cyclization outcome of
stereochemical analogues of the erythromycins. Removal of
artificial biasing elements allows for increased stereochemical
flexibility in the macrocyclization process. We anticipate that
empowered with the knowledge that preorganization is not a
requirement for cyclization, a broader evaluation of protect-
ing groups[15] will lead to the syntheses of stereochemically
modified and/or functional group deficient analogues of
erythromycin that may have been difficult or impossible to
generate under the former perceived constraints.
[8] J. Mulzer, H. M. Kirstein, J. Buschmann, C. Lehmann, P. Luger,
J. Am. Chem. Soc. 1991, 113, 910.
[9] I. Paterson, D. J. Rawson, Tetrahedron Lett. 1989, 30, 7463.
[10] a) P. J. Hergenrother, A. Hodgson, A. S. Judd, W. L. Lee, S. F.
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[11] K. F. Fraunhoffer, N. Prabagaran, L. E. Sirois, M. C. White,
J. Am. Chem. Soc. 2006, 128, 9032.
Received: November 20, 2010
Revised: December 31, 2010
Published online: January 27, 2011
[12] K. C. Nicolaou, E. J. Sorenson, Classics in Total Synthesis,
Weinheim, Wiley-VCH, 1996, p. 182.
[13] Hydrogen bonding in acyclic 1,3-diols may induce a solution
conformation analogous to that of acetonide protecting groups:
C. E. Anderson, D. K. Britt, S. Sangji, D. J. OꢀLeary, C. D.
Anderson, S. D. Rychnovsky, Org. Lett. 2005, 7, 5721.
ꢀ
Keywords: C H oxidation · cyclization · erythromycin ·
lactonization · natural products
.
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[14] R. W. Hoffmann, Angew. Chem. 2000, 112, 2134; Angew. Chem.
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C. H. Chen, J. Am. Chem. Soc. 1981, 103, 3213
[15] The use of sterically bulky cladinose and desosamine sugar
residues at the C-3 and C-5 hydroxy groups were thought to
reduce the conformational mobility along the C-1–C-8 subunit of
the backbone and facilitate cyclization of erythromycin B
precursors (Ref. [10b]). Given this, we anticipate the use of
larger, more removable protecting groups than methyl ethers
will not impede cyclizations.
ꢀ
[5] a) G. Stork, S. D. Rychnovsky, J. Am. Chem. Soc. 1987, 109,
1565; b) M. Nakata, M. Arai, K. Tomooka, N. Ohsawa, M
[16] Streamlining synthesis by late-stage C H oxidation: a) for the
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Synthesis 2006, 3531; f) R. W. Hoffmann in Elements of Synthesis
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[18] Although in the original studies by Woodward et al. (Ref. [4]),
acylation-based macrolactonization was effected by the Corey
method (Ref. [2]), nearly all subsequent studies have used the
Yamaguchi protocol (Refs. [5c,d,f–i,6]); J. Inanaga, K. Hirata, H.
Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem. Soc. Jpn. 1979, 52,
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[19] Allylic alcohol 5 (Scheme 3) gave a comparable macrolactoni-
zation yield to that of an analogous saturated alcohol under
identical Yamaguchi conditions (namely, 87% and 86%, respec-
tively, Ref. [5g]).
[20] It is clear that the polypropionate core of the erythromycins
(6-dEB) does not require artificial preorganization for macro-
cyclization. While we cannot exclude the possibility that
erythronolide B or A would require preorganization because
of the presence of a C-6 and/or C-12 hydroxy group(s), the fact
that linear precursors to erythronolide B, A, and 6-dEB have all
been cyclized under comparable Yamaguchi conditions using the
same cyclic biasing elements in the same positions, strongly
suggests that they will continue to behave in a very similar
manner to 6-dEB (see Ref. [5f,g,i]).
ꢀ
ples of late-stage C H hydroxylation and amination, see g) P. A.
Wender, M. K. Hilinski, A. V. W. Mayweg, Org. Lett. 2005, 7, 79;
h) A. Hinman, J. Du Bois, J. Am. Chem. Soc. 2003, 125, 11510;
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[17] For branched intermolecular allylic oxidations, see a) M. S.
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