Stereochemical elucidation of streptorubin B

Article abstract of DOI:10.1021/ja109164t

Streptorubin B is a structurally remarkable mem-ber of the prodiginine group of antibiotics produced by several actinobacteria, including the model organism Streptomyces coelicolor A3(2). Transannular strain within the pyrrolophane structure of this molecule causes restricted rotation that gives rise to the possibility of (diastereomeric) atropisomers. Neither the relative nor the absolute stereochemistry of streptorubin B is known. NOESY NMR experiments were used to define the relative stereochemistry of the major atropisomer of streptorubin BHCl in solution as anti. We exploited this finding together with our knowledge of streptorubin B biosynthesis in S. coelicolor to determine the absolute stereochemistry of the anti atropisomer. 2-Undecylpyrrole stereoselectively labeled with deuterium at C-4′ was synthesized and fed to a mutant of S. coelicolor, which was unable to produce streptorubin B because it was blocked in 2-undecylpyrrole biosynthesis, and in which the genes responsible for the last two steps of streptorubin B biosynthesis were overexpressed. ¹H and ²H NMR analysis of the stereoselectively deuterium-labeled streptorubin BHCl produced by this mutasynthesis strategy allowed us to assign the absolute stereochemistry of the major (anti) atropisomer as 7′S. HPLC analyses of streptorubin B isolated from S. coelicolor on a homochiral stationary phase and comparisons with streptorubin B derived from an enantioselective synthesis showed that the natural product consists of an approximately 88:7:5 mixture of the (7′S, anti), (7′S, syn), and (7′R, anti) stereoisomers.

Full text of DOI:10.1021/ja109164t

ARTICLE
pubs.acs.org/JACS
Stereochemical Elucidation of Streptorubin B
Stuart W. Haynes, Paulina K. Sydor, Christophe Corre, Lijiang Song, and Gregory L. Challis*
Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K.
S Supporting Information
b
ABSTRACT: Streptorubin B is a structurally remarkable mem-
ber of the prodiginine group of antibiotics produced by several
actinobacteria, including the model organism Streptomyces coeli-
color A3(2). Transannular strain within the pyrrolophane struc-
ture of this molecule causes restricted rotation that gives rise to
the possibility of (diastereomeric) atropisomers. Neither the
relative nor the absolute stereochemistry of streptorubin B is
known. NOESY NMR experiments were used to define the
relative stereochemistry of the major atropisomer of streptorubin
B HCl in solution as anti. We exploited this finding together with our knowledge of streptorubin B biosynthesis in S. coelicolor to
3
determine the absolute stereochemistry of the anti atropisomer. 2-Undecylpyrrole stereoselectively labeled with deuterium at C-40
was synthesized and fed to a mutant of S. coelicolor, which was unable to produce streptorubin B because it was blocked in
2-undecylpyrrole biosynthesis, and in which the genes responsible for the last two steps of streptorubin B biosynthesis were
1
2
overexpressed. H and H NMR analysis of the stereoselectively deuterium-labeled streptorubin B HCl produced by this
3
mutasynthesis strategy allowed us to assign the absolute stereochemistry of the major (anti) atropisomer as 70S. HPLC analyses of
streptorubin B isolated from S. coelicolor on a homochiral stationary phase and comparisons with streptorubin B derived from an
enantioselective synthesis showed that the natural product consists of an approximately 88:7:5 mixture of the (70S, anti), (70S, syn),
and (70R, anti) stereoisomers.
’ INTRODUCTION
they proposed that the structure 6 should be revised to 2, i.e., that
the carbocyclic undecylprodigiosin derivatives isolated from the
four different actinomycetes are all the same compound, namely,
streptorubin B. In 2005, F€urstner and co-workers reignited the
controversy surrounding the structure of the carbocyclic unde-
cylprodigiosin derivative produced by S. coelicolor. They com-
pleted a total synthesis of structure 6 and, by comparison with the
NMR data reported by Floss and co-workers, concluded that this
is identical to the carbocyclic undecylprodigiosin derivative
produced by S. coelicolor.11 However, in the course of biosyn-
thetic studies, we recently isolated the carbocyclic undecylpro-
digiosin derivative produced by S. coelicolor and showed
conclusively by an extensive array of 1D and 2D NMR experi-
ments that this compound is 2.12 Thus, to summarize, there is no
convincing evidence that compound 6 is a natural product,
whereas 2 has been unambiguously identified as the carbo-
cyclic undecylprodigiosin derivative produced by two different
actinomycetes.3,12
The prodiginines are a structurally remarkable group of
4-methoxypyrrolyldipyrromethene antibiotics produced by a
wide variety of bacteria, in particular Streptomyces and related
actinobacteria.1 Members of this family include undecylprodi-
giosin (1) and its cyclic derivatives streptorubin B (2) and
metacycloprodigiosin (3) as well as the cometabolites prodi-
giosin R1 (4) and roseophilin (5), which appear to derive from
a common precursor (Figure 1).2-6 There has been much
recent interest in the prodiginines arising from the broad range
of biological activities displayed by these antibiotics.1 In parti-
cular, GX-15-070, a synthetic analogue of metacycloprodigiosin
and streptorubin B, is currently in phase 1 and 2 oncology
trials.7
There has been confusion in the literature regarding the
structure of streptorubin B 2. Gerber and co-workers reported
the isolation of a prodiginine pigment from two Streptomyces
species in 1975, to which they assigned the structure 6 (Figure 1;
a regioisomer of streptorubin B).8 Three years later, the structure
of this pigment was revised by Gerber to 2, although the reasons
for this are not clear.9 In 1985, Floss and co-workers reported the
isolation of a carbocyclic derivative of 1 to which they also
tentatively assigned the structure 6.10 Subsequently, Laatsch and
co-workers isolated a carbocyclic prodiginine pigment from an
unidentified actinomycete, which they convincingly identified as
2 on the basis of extensive NMR data.3 As suggested by Gerber,
Laatsch and co-workers recognized that the pyrrolophane
structure of streptorubin B 2 possesses considerable conforma-
tional stability.3 This causes one of the protons attached to C-40
to sit directly within the anisotropy cone of pyrrole C, resulting in
a remarkable chemical shift of -1.54 ppm for this proton in the
1H NMR spectrum of 2. The other proton attached to C-40 lies
Received: October 12, 2010
Published: December 17, 2010
r
2010 American Chemical Society
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ARTICLE
/BQNL-serine, S-adenosyl-L-methionine, and malonyl-CoA,
whereas 8 is assembled from one unit of acetyl-CoA, six units
of malonyl-CoA, and a unit of glycine.14,15 Both pathways involve
the first-discovered examples of polyketide chain termination
catalyzed by R-oxamine synthase domains within polyketide
synthases15 (a fact which was overlooked in a recent review of
the subject of chain-release mechanisms in polyketide bio-
synthesis16). The condensation of 7 and 8 to form 1 is catalyzed
by the putative ATP-dependent multienzyme RedH, and 1
undergoes oxidative cyclization catalyzed by the Rieske oxyge-
nase-like enzyme RedG to form 2 (Figure 3).17,18 Mutants in
which MBC biosynthetic genes are deleted do not produce
prodiginines and thus accumulate 8.13 Prodiginine production
is restored in such mutants by feeding them with synthetic MBC,
and analogues of 1 can be produced by “mutasynthesis” (feeding
the mutants with chemically synthesized analogues of MBC).13,17
Similarly, mutants lacking 2-undecylpyrrole biosynthetic genes
cannot produce prodiginines, and the production of both 1 and
streptorubin B 2 can be restored by feeding the mutants with
synthetic 8.12
Here we report the elucidation of the relative stereochem-
istry of the major solution configuration of the hydrochloride
salt of streptorubin B 2 using nuclear Overhauser effect
spectroscopy (NOESY) NMR experiments. We also report
the exploitation of the remarkable chemical shift difference
between the diastereotopic protons attached to C-40 of 2 to
assign the absolute stereochemistry of the major isomer via
mutasynthetic production of 2 stereoselectively deuterium-
1
2
labeled at C-40 coupled with H and H NMR analysis. The
deuterium-labeled 2 was produced by stereoselective synthesis
of deuterium-labeled 8, which was then fed to mutants of S.
coelicolor blocked in 2-undecylpyrrole biosynthesis. HPLC
comparisons of natural streptorubin B with chemically synthe-
sized (70S)-, (70R)-, and (70RS)-streptorubin B on a homochiral
stationary phase showed that 2 isolated from S. coelicolor
consists of the (70S, anti), (70S), and (70R, syn) isomers in an
approximately 88:7:5 ratio.
Figure 1. Structures of some of the prodiginine alkaloids 1-5 produced
by actinomycetes and the incorrect structure 6 originally proposed for
streptorubin B (2).
’ RESULTS AND DISCUSSION
Relative Stereochemistry of the Major Diastereomer of
Streptorubin B HCl in Solution. NOESY NMR analysis of
Figure 2. Structures of the anti and syn atropisomeric diastereomers of
streptorubin B that arise from restricted rotation about the C-10;C-2C
and C-70;C-4C bonds.
3
streptorubin B HCl (9) purified from S. coelicolor M511 estab-
3
lished the relative stereochemical relationship of C-100 and the
n-butyl group attached to C-70 in the major species present in
solution (Figure 4). Correlations between the protons attached
to C-70 and C-100 and those attached to C-80 and C-3C indicated
that C-100 and the n-butyl group attached to C-70 have an anti
stereochemical relationship. The presence of a signal at -1.48
ppm in the 1H NMR spectrum of 9 having ∼5% of the intensity
of the signal at -1.54 ppm indicated that a second, minor
diastereomer (presumably the syn diastereomer) is also present.
The NOESY data also established that the relative stereochem-
ical relationship between the proton with a chemical shift of
-1.54 ppm attached to C-40 and the C-70 stereocenter is pro-R, S
in the major diastereomer.
outside the anisotropy cone, and as a result, it has a “typical”
methylene chemical shift of 1.16 ppm. The conformational
stability of the streptorubin B pyrrolophane implies some intrigu-
ing stereochemical features. Thus, in addition to the conven-
tional stereocenter at C-70, restricted rotation about the C-70;
C-4C and C-10;C-2C bonds arising from the strained ansa-
bridged 10-membered carbocycle in 2 results in an axial stereo-
chemical element. As a consequence, streptorubin B has the
potential to exist as atropisomeric diastereomers in which the
n-butyl group attached to C-70 is either syn or anti to rings A and
B (Figure 2). However, these stereochemical features have not
been investigated further, and both the relative and absolute
stereochemistry of streptorubin B remain unknown.
The configurations of the C-5C;C-100, C-100;C-2B, and
C-5B;C-2A bonds were likewise deduced from the NOESY
data. Correlations between the protons attached to C-70 and
C-100, those attached to C-100 and the methoxy group at C-3B,
and those attached to C-4B and C-3A indicated that the C-5C;
C-100, C-100;C-2B and C-5B;C-2A bonds all have the Z or
Undecylprodigiosin 1 and streptorubin B 2 are biosynthesized
in S. coelicolor from the common intermediates 4-methoxy-2,20-
bipyrrole-5-carboxaldehyde (MBC, 7) and 2-undecylpyrrole
(8).12,13 MBC is assembled from one unit each of L-proline,
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ARTICLE
Figure 3. Pathway for the biosynthesis of undecylprodigiosin (1) and streptorubin B (2) in S. coelicolor A3(2). RedH catalyzes the condensation of
2-undecylpyrrole (8) and 4-methoxy-2,20-bipyrrole-5-carboxaldehyde (MBC, 7) to form 1, which undergoes oxidative carbocyclization catalyzed by
RedG to form 2.
of (4R)-12 with the hydrochloride salt of dimethylamine and
trimethylaluminum afforded hydroxyamide 16,24 which upon
treatment with tosyl chloride and pyridine gave the (4S)-γ-
butyrolactone (4S)-12. (40S)-10 was synthesized from this
lactone using chemistry identical to that used for the synthesis
of (40R)-10 from (4R)-12.
Feeding 2-undecylpyrrole 8 to a redL mutant of S. coelicolor
M511 (blocked in 2-undecylpyrrole biosynthesis) restores
production of undecylprodigiosin 1 and streptorubin B 2.12
However, the amount of 2 relative to 1 produced in the
experiment is low, making it difficult to purify sufficient 2 for
NMR spectroscopic analysis. Thus, we investigated the effect of
expressing additional copies of the genes encoding the enzymes
Figure 4. Key correlations observed in the NOESY NMR spectrum of
streptorubin B HCl (9) isolated from S. coelicolor M511 that establish
3
that catalyze condensation of MBC 7 and 2-undecylpyrrole 8 to
the relative stereochemistry of the major isomer in solution.
form undecylprodigiosin 1 (RedH)17 and the oxidative carbo-
cyclization of undecylprodigisin 1 to afford streptorubin B 2
(RedG)18 in trans under the control of the strong constitutive
ermE* promoter in S. coelicolor M511. Expression of redG alone
did not significantly affect the 1/2 ratio. In contrast, expression
of redHG resulted in a significant increase in the amount of 2
produced relative to the amount of 1 produced, provid-
ing further evidence for the formation of a RedH-RedG
complex.18 Similarly, overexpression of redHG in the redL
mutant of S. coelicolor M51112 to create S. coelicolor W116
resulted in significantly higher production levels of 2 relative to
1 upon feeding with 8, facilitating the isolation of sufficient
quantities of 2 from the experiment for NMR spectroscopic
analysis.
S-cis configurations. These configurations place the three
nitrogen atoms in streptorubin B HCl in close proximity, and
3
as a consequence, strong repulsion between the protons
attached to each of these atoms would be expected. We
hypothesized that this repulsion is overcome by coordination
of the chloride ion by the three protons (Figure 4). This
supposition, along with our relative stereochemical assignments
for streptorubin B HCl 9, were confirmed by subsequent X-ray
3
crystallographic analysis of synthetic (70R)-streptorubin
B HCl.19
3
Mutasynthesis of Streptorubin B Stereoselectively Deu-
terium-Labeled at C-40. Our mutasynthesis approach for
elucidation of the absolute stereochemistry of streptorubin B
2 required 2-undecylpyrrole 8 stereoselectively deuterium-
labeled at C-40. [40-2H](40R)-2-undecylpyrrole [(40R)-10]
was synthesized from the known epoxy ester 1120 in six steps
(Scheme 1). Regiospecific opening of the epoxide in 11 with the
cuprate derived from n-hexyllithium and copper cyanide
yielded (4R)-γ-butyrolactone (4R)-12,21 which upon treat-
ment with excess trimethylsilyl iodide followed by methanol
afforded iodo ester (4S)-13.22 The stereochemical purity of the
iodo ester was confirmed by converting it back to (4R)-12 using
aqueous sodium hydroxide and then performing HPLC analysis
on a homochiral stationary phase (see the Supporting In-
formation). Reaction of (4S)-13 with sodium borodeuteride
gave the deuterated ester 14, which was assumed to result
predominantly from SN2 displacement of iodide with deuteride
and, as a consequence, to be enriched in the 4R enantiomer.23
Hydrolysis of (4R)-14 yielded the corresponding acid (4R)-15,
which was converted to (40R)-10 using a previously reported
procedure.12
LC-MS analyses of mycelia extracts of S. coelicolor W116 to
which (40S)-10 or (40R)-10 had been separately fed indicated
that 2 bearing a single deuterium label was produced in both
cases. The deuterium-labeled 2 afforded by each of these experi-
ments was purified from the extracts by a combination of alumina
chromatography and semipreparative HPLC.
Absolute and Relative Stereochemical Assignment of
1
2
Streptorubin B. H and H NMR spectroscopic analysis of
deuterium-labeled streptorubin B HCl (17) isolated from the
3
mutasynthesis experiment using (40S)-10 indicated that ∼70% of
the deuterium label occupied the endo position at C-40 (with the
deuterium atom sitting directly above the π electrons of ring C)
and ∼30% of the deuterium label was in the exo position (see the
Supporting Information). In contrast, 17 isolated from the
mutasynthesis experiment with (40R)-10 contained ∼30% label
in the endo position and ∼70% label in the exo position of C-40
(see the Supporting Information). Our discovery that anti-
streptorubin B HCl is the major diastereomer in solution
3
[40-2H](40S)-2-undecylpyrrole [(40S)-10] was synthesized
from γ-butyrolactone (4R)-12 in seven steps (Scheme 2). Reaction
coupled with the finding that the proton with a chemical shift
of -1.54 ppm attached to C-40 and the C-70 stereocenter in this
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Scheme 1. Synthesis of [40-2H](40R)-2-Undecylpyrrole [(40R)-10]
Scheme 2. Synthesis of [40-2H](40S)-2-Undecylpyrrole [(40S)-10]
Scheme 3. Relative and Absolute Stereochemistry Assigned
to the Stereoselectively Deuterium-Labeled Streptorubin B
Derivatives 17 Produced by Mutasynthesis
major anti diastereomer (as indicated by the 1H NMR spectroscopic
analysis of 17). Thus, we analyzed streptorubin B HCl 9
3
isolated from S. coelicolor using HPLC on a homochiral sta-
tionary phase, monitoring the absorbance at 470 nm (the λmax
for the free base of the 4-methoxypyrrolyldipyrromethene core
structure of streptorubin B, which was produced from the
hydrochloride salt under the HPLC conditions) (Figure 5).
Comparisons with authentic standards of (70R)-, (70S)-, and
(70RS)-streptorubin B19 identified the compound with a reten-
tion time of ∼9.5 min as (70S, anti)-streptorubin B and the
compound with a retention time of ∼34.5 min as (70R, anti)-
streptorubin B (Figure 5). The compound with a retention time
of ∼13.5 min was also found in the synthetic sample of (70S)-
streptorubin B. We hypothesized that this is (70S, syn)-streptor-
ubin B, which can be derived from (70S, anti)-streptorubin B by
rotation about the C-10;C-2C and C-4C;C-70 bonds. To test
this hypothesis, we collected the compound with a retention
time of ∼9.5 min and reanalyzed it using HPLC both imme-
diately and after allowing the compound to stand for 7 days at
room temperature. While none of the compound with a
retention time of ∼13.5 min was detected in the sample that
was reanalyzed immediately after collection, this compound
was detected in the sample that was reanalyzed after 7 days.
These findings are consistent with the hypothesis that the
compound with a retention time of ∼13.5 min is (70S, syn)-
streptorubin B and that it results from (70S, anti)-streptorubin B
via slow rotation about the C-10;C-2C and C-4C ; C-70
bonds.25 This hypothesis was corroborated by the findings of
Thomson and co-workers,19 who showed that in the synthesis
of streptorubin B, the syn diastereomer is initially formed but
isomerizes to the anti diastereomer upon standing. Thus, the
stereoselective rather than stereospecific labeling of streptor-
ubin B in the mutasynthesis experiments results from the fact
that natural streptorubin B contains small amounts of (70 R,
anti)-streptorubin B and (70 S, syn)-streptorubin B in addition
to (70 S, anti)-streptorubin B as well as from some erosion of
stereochemical purity during the predominantly SN2 displace-
ment of iodide with deuteride in (4S)-13 and (4R)-13.26
diastereomer have a pro-R, S relative stereochemical relationship
allowed us to use the results of the deuterium labeling experi-
ments to assign the absolute stereochemistry of C-70 as S in the
predominant enantiomer of streptorubin B produced by S.
coelicolor (Scheme 3).
The observation that the labeling of streptorubin B in the
mutasynthesis experiments appears merely to be stereoselective
rather than stereospecific intrigued us. This could be explained
simply by partial racemization during conversion of the en-
antiomerically pure iodides (4S)-13 and (4R)-13 to the corre-
sponding deuterated esters (4R)-14 and (4S)-14, which may
have resulted from the displacement of iodide with deuteride
via an SN1 mechanism in addition to the predominant SN2
pathway. However, this observation could also result if the
natural product were a mixture of enantiomers and/or con-
tained syn-streptorubin B as a minor diastereomer alongside the
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Figure 5. Chromatograms from HPLC analyses on a homochiral stationary phase of streptorubin B isolated from S. coelicolor M511 (top trace), the
compound with a retention time of ∼9.5 min analyzed immediately after collection (middle trace), and that compound analyzed after it was allowed to
stand for 7 days at room temperature (bottom trace).
’ CONCLUSION
’ ASSOCIATED CONTENT
We have used a combination of NOESY NMR spectroscopy,
mutasynthesis of stereoselectively deuterium-labeled streptor-
ubin B derivatives, and HPLC analyses on a homochiral
stationary phase to show that natural streptorubin B isolated
from S. coelicolor M511 consists of a mixture of three stereo-
isomers, among which the (70S, anti) isomer predominates.
The (70S, syn) atropisomer, which is a minor component of the
mixture, can arise from the major stereoisomer by rotation
about the C-10;C-2C and C-4C;C-70 bonds. Intriguingly,
the (70R, anti) enantiomer of the major stereoisomer is also a
minor component of the mixture, indicating that the RedG-
catalyzed oxidative carbocyclization of undecylprodigiosin to
form streptorubin B18 proceeds with incomplete stereocontrol.
This could arise either from (1) the formation of a radical or
cation intermediate by stereospecific hydrogen/hydride ex-
traction at C-70 that can on occasion undergo rotation about
the C-60;C-70 bond prior to cyclization onto pyrrole ring C to
generate the minor 70R isomer or (2) as a result of incomplete
stereocontrol during oxidation at C-70 to generate stereoiso-
meric intermediates that undergo cyclization to form enantio-
meric products. Discrimination between these mechanistic
possibilities could be achieved by mutasynthesis experi-
ments using 2-undecylpyrrole that is stereospecifically labeled
at C-70.
S
Supporting Information. Experimental procedures, chro-
b
matograms from HPLC analyses of (4R)- and (4S)-12 on a homo-
1
2
chiral stationary phase, H and H NMR spectra for deuterium-
labeled 17 isolated from the mutasynthesis experiments, and
complete ref . This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
g.l.challis@warwick.ac.uk
’ ACKNOWLEDGMENT
We thank Regan Thomson for helpful discussions, sharing of
information prior to publication, and provision of samples of
synthetic (70R)-, (70S)-, and (70RS)-streptorubin B. Adam Clarke
is thanked for measuring 2H NMR spectra.
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Chem. 2003, 68, 1771–1779.
(25) (70R, syn)-streptorubin B (retention time ≈ 10 minutes) could
be detected in the samples of synthetic (70RS) and (70R)-streptorubin B
(see the Supporting Information). It was not detectable in the sample of
streptorubin B isolated from S. coelicolor because it constitutes only
∼0.5% of the mixture [the anti/syn ratio is ∼88:7 and only ∼5% of (70R,
anti)-streptorubin B is present in the natural product].
(26) This erosion of stereochemical purity could presumably be
overcome, in principle, by using a more reactive source of deuteride,
such as LiAlD4, which should promote the SN2 reaction and ensure that
a greater proportion of the displacement proceeds with inversion.
However, LiAlD4 would also reduce the ester in 13 to the corresponding
alkoxide, which would be expected to displace iodide in an intramolec-
ular reaction to form the corresponding tetrahydrofuran. Thus, a
different synthetic approach for the stereospecific deuterium-labeling
of 2-undecylpyrrole at C-40 would be required.
1798
dx.doi.org/10.1021/ja109164t |J. Am. Chem. Soc. 2011, 133, 1793–1798