Total synthesis of marinomycin A using salicylate as a molecular switch to mediate dimerization

Article abstract of DOI:10.1038/nchem.1330

Antibiotics play a significant role in human health because of their ability to treat life-threatening bacterial infections. The growing problems with antibiotic resistance have made the development of new antibiotics a World Health Organization priority. Marinomycin A is a member of a new class of bis-salicylate-containing polyene macrodiolides, which have potent antibiotic activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Herein, we describe a triply convergent synthesis of this agent using the salicylate as a novel molecular switch for the chemoselective construction of the macrodiolide. This strategy raises new questions regarding the biosynthetic role of the salicylate and its potential impact on the mechanism of action of these types of agents. For instance, in contrast to penicillin, which enhances the electrophilicity of the cyclic amide through ring strain, salicylates reduce the electrophilicity of the aryl ester through an intramolecular resonance-assisted hydrogen bond to provide an amide surrogate.

Full text of DOI:10.1038/nchem.1330

ARTICLES
PUBLISHED ONLINE: 1 JULY 2012 | DOI: 10.1038/NCHEM.1330
Total synthesis of marinomycin A using salicylate
as a molecular switch to mediate dimerization
P. Andrew Evans1 , Mu-Hua Huang1, Michael J. Lawler2 and Sergio Maroto1
*
Antibiotics play a significant role in human health because of their ability to treat life-threatening bacterial infections. The
growing problems with antibiotic resistance have made the development of new antibiotics a World Health Organization
priority. Marinomycin A is a member of a new class of bis-salicylate-containing polyene macrodiolides, which have potent
antibiotic activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium.
Herein, we describe a triply convergent synthesis of this agent using the salicylate as a novel molecular switch for the
chemoselective construction of the macrodiolide. This strategy raises new questions regarding the biosynthetic role of the
salicylate and its potential impact on the mechanism of action of these types of agents. For instance, in contrast to
penicillin, which enhances the electrophilicity of the cyclic amide through ring strain, salicylates reduce the electrophilicity
of the aryl ester through an intramolecular resonance-assisted hydrogen bond to provide an amide surrogate.
he problems associated with widespread antibiotic resistance1 hydrogen bond (RAHB) and resonance deactivation, respectively12.
have driven the development of new classes of agents with Hence, the salicylate can modulate the conformation and reactivity
T
novel modes of action2 since the discovery of penicillin by of the ester in a manner analogous to that of an amide, thereby
Fleming3 in 1928. Polyketide macrolides have proven to be impor- raising a number of intriguing questions with respect to the biosyn-
tant leads in this regard, because access to their biosynthetic thesis and mechanism of action of salicylate-containing natural pro-
machinery provides the ability to manipulate the pathways that ducts. We envisioned that this dichotomy in reactivity would provide
assemble these agents to readily access a series of analogues the basis for a unique strategy for the chemoselective construction of
for structure–activity relationship studies (SAR)4,5. For instance, a biologically important macrodiolide, namely marinomycin A.
the biosynthesis of a polyketide chain involves the repeated
Marinomycins A–C (1–3, Fig. 1c) were isolated by Fenical and
novel marine actinomycete,
decarboxylative condensation of small carboxylic acids catalysed co-workers13 in 2006 from
a
by polyketide synthases (PKS), followed by specifically programmed Marinispora strain CNQ-140, which was cultured from a sediment
reduction and dehydration steps6,7. The macrolactone is prepared sample collected deep off the coast of La Jolla in California.
from the fully processed acyclic polyketide, which is bound to the Although these agents have significant antimicrobial and anticancer
acyl carrier protein (ACP) by a thioester, through a thioesterase- activity, (þ)-marinomycin A (1) is the most potent and the major
domain-mediated transesterification and concomitant cyclization constituent of the fermentation. For instance, it has a minimum
with a specific hydroxyl group present in the polyketide backbone. inhibitory concentration (MIC90) of 0.13 mM against both methicil-
Although this process is now relatively well understood for alicyc- lin-resistant Staphlococcus aureus (MRSA)14 and vancomycin-
lic macrolides8,9, our studies suggest that the biosynthesis of salicylate resistant Enterococcus faecium (VREF)15, which is similar in
macrolides10 may be complicated by the existence of an intramolecu- potency to vancomycin. Marinomycin A (1) also exhibits significant
lar hydrogen bond between the ortho-phenol and the carboxylate anticancer activity against the National Cancer Institute’s panel of 60
(Fig. 1a), which modulates the reactivity of the ester to nucleophilic cell lines (LC50 ¼ 0.4–2.7 mM), with excellent selectivity against six of
acyl substitution either through the functionalization of the phenol the eight melanoma cell lines and particular potency for the SK-MEL-
or disruption of the intramolecular hydrogen bond11. Moreover, 5 melanoma cell line (LC50 ¼ 5.0 nM). Furthermore, in contrast to
this has important implications for the conformation and hydrolytic the other well-known polyene antibiotics (such as nystatin and
stability of these agents. For example, a comparison of the infrared amphotericin B)16, these macrodiolide dimers are devoid of signifi-
stretch of the ester carbonyl of salicylates A–C illustrates a significant cant antifungal activity, which suggests that they have a potentially
shift to a lower wavenumber for phenol A (Dn ¼ 68 cm21) and new mechanism of action rather than forming pores within the
phenoxide B (Dn ¼ 35 cm21) compared to the methyl aryl ether C cell membrane. Structurally, marinomycin A (1) is a unique
(Fig. 1b). Density functional theory (DFT) calculations further polyene-polyol macrodiolide, which has an unusual 44-membered
support the infrared trend, in which the carbonyl bond lengths macrocycle with C2-symmetry. The monomer consists of a 2-
(C¼O) for phenol A (1.24 Å) and phenoxide B (1.25 Å) are slightly hydroxy-6-alkenyl-benzoic acid with conjugated tetraene-penta-
longer than that of the corresponding methyl aryl ether C (1.21 Å). hydroxy polyketide chains containing a syn-1,3-diol as well as an
Furthermore, salicylate A has a relatively planar arrangement of anti,anti-1,3,5-triol separated by an E-alkene. Synthetic approaches
O(1)¼C(2)–C(3)¼C(4) (f ¼ 5.38), whereas phenoxide B and to marinomycin A–C are further complicated by their known
methyl aryl salicylate C are distorted out of plane (O(1)¼C(2)– sensitivity to light-mediated isomerization of the styrenyl alkenes,
C(3)¼C(4); f ¼ 27.28 and 59.98, respectively). The reduction in which provides an additional challenge for their efficient and
electrophilicity for phenol A and phenoxide B is consistent with elec- selective construction17,18. Nevertheless, the identification of new
tronic communication through an intramolecular resonance-assisted classes of antibiotics is critical given the problems with antibiotic
1Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK, 2Department of Chemistry, Indiana University, Bloomington, Indiana 47405,
USA. e-mail: Andrew.Evans@liverpool.ac.uk
*
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1
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1330
ARTICLES
a
R
R
O
R
R
TE
OH
P
P
O
O
O
H
O
HO
HO
HO
O
S
S
O
O
H
TE
SH
OH
ACP
O
O
TE
ACP
ACP
Activation?
Acyl transfer
Cyclization
c
b
IRνmax (C=O)
OH
O
9
4
4
4
HO
5
O
H
NaO
MeO
8
3
3
3
5
5
OH OH
OH
9'
O
2
2
2
O
O
OH
OH OH
O
OMe
O
OMe
O
OMe
8'
1
1
1
OH
A
B
C
1,661 cm–1
1,694 cm–1
1,729 cm–1
HO
Δν = 33 cm–1
Δν = 35 cm–1
Marinomycin A (1; trans Δ8,9, trans Δ8',9'
Marinomycin B (2; cis Δ8,9, cis Δ8',9'
Marinomycin C (3; trans Δ8,9, cis Δ8',9'
)
)
)
Deactivation
d
TBSO
OMOM
OH
O
O
Ester
formation
HO
O
MOMO
OH OH
OH
O
O
O
O
OH
OH OH
4
5
+
OH
Ester
O
O
formation
MeO
MeO
O
HO
Cross
metathesis
Olefination
Marinomycin A (1)
P
O
6
Figure 1 | Proposed role of salicylate as a molecular switch for macrolide construction and synthetic plan for marinomycin A. a, Proposed mechanism for
salicylate-type macrolactonization involving an ACP thioester and thioesterase. b, Infrared data illustrating deactivation of the ortho-carboxylate for the phenol
and sodium phenoxide versus the methyl aryl ether. c, Structure of marinomycin A–C (1–3). d, Retrosynthetic analysis: triply convergent coupling and
dimerization strategy. ACP, acyl carrier protein; TE, thioesterase; P, functionalization or hydrogen bond; IR, infrared spectrum; nmax, maximum absorption;
MOM, methoxymethyl; TBS, tert-butyldimethylsilyl.
resistance, which provides the impetus to develop a practical synthesis 7 with the lithium anion of 1,3-dithiane 8, followed by in situ
of this agent to facilitate detailed SAR studies and elucidate the mech- protection of the resulting secondary alkoxide with methoxymethyl
anism of action.
chloride furnished the monosubstituted dithiane in quantitative yield.
We envisioned that the macrodiolide could be prepared by The lithium anion of the dithiane20 was preformed and treated with
sequential formation of the ester groups using the aforementioned (R)-(–)-epichlorohydrin 9 to initiate ring opening/closure, followed
salicylate switch to modulate the reactivity of the esters (Fig. 1d). by treatment of the terminal epoxide with vinyl magnesium
A potential problem with this strategy lies in the opportunity for bromide in the presence of copper iodide to afford the homoallylic
competitive intramolecular cyclization of the dimeric seco-acid to alcohol 10 in 77% yield (2 steps). Protection of the homoallylic
provide the macrolide. For example, the attempted double Suzuki alcohol 10 as the methoxymethyl ether and removal of the dithiane
dimerization to form the macrodiolide favours intramolecular with iodine buffered with sodium hydrogen carbonate furnished
cyclization to provide the macrolide17. We envisioned that a acyclic ketone 11 in 75% overall yield (2 steps). Stereoselective
syn-1,3-dioxane would provide a conformational lock19 to enforce reduction of 11 using samarium diiodide under Keck conditions21
the linear chain conformation of the monomer and thereby suppress furnished the secondary alcohol (diastereoselectivity ≥ 19:1 by
their intramolecular cyclization. The monomeric seco-acid would in NMR), which was protected as the tert-butyldimethylsilyl ether in
turn be readily derived from a triply convergent assembly of the 88% overall yield (two steps) to complete the synthesis of the
protected anti,anti-1,3,5-triol 4 with the syn-1,3-dioxane 5 followed differentially protected anti,anti-1,3,5-triol 4.
by homologation and coupling with the dienyl phosphonate 6 using
cross metathesis and olefination reactions.
Figure 2b outlines the five-step sequence used for the construc-
tion of the 1,3-dioxane fragment 5 from commercially available 1-
O-methyl-2-deoxy-D-ribose 12. Iodination of the primary alcohol
in 12 followed by protection of the secondary alcohol with a triethy-
Results and discussion
The differentially protected anti,anti-1,3,5-triol 4 was prepared in silyl group furnished the iodofuranoside 13 in 73% yield. Vasella
51% overall yield using the six-step sequence outlined in Fig. 2a. fragmentation22 of the primary alkyl iodide 13 with zinc powder
Regioselective ring opening of enantiomerically enriched epoxide afforded the corresponding aldehyde, which was immediately
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1330
ARTICLES
a
1. i. n-BuLi, 8
ii. 7, then MOM-Cl
THF, −78 to 0 ºC
1. MOM-Cl, i-Pr2EtN
1. SmI2, THF
CH3OH, RT
O
OMOM
TBSO
OMOM
OH
S
S
CH2Cl2, –5 ºC
O
O
+
+
S
S
2. i. n-BuLi, then 9
ii. CH2=CHMgBr
CuI, THF
2. I2, sat. NaHCO3
CH3CN, –5 ºC
75% (2 steps)
2. TBS-Cl
imidazole
DMF, RT
Cl
MOMO
MOMO
MOMO
7
8
9
10
4
11
−78 ºC to RT
77% (2 steps)
88% (2 steps)
b
c
1. I2, Ph3P, imidazole
THF, 0 ºC to RT
1. Zn, H2O
THF, 80 ºC
Cat. Bi(NO3)3·5H2O
CH3CHO
O
O
OMe
OMe
OTES
O
O
O
O
HO
I
TESO
2. TES-Cl, pyridine
CH2Cl2, 0 ºC
CH2Cl2, 0 ºC to RT
88%
2. Ph3P=CHCOCH3
toluene, 110 ºC
HO
12
13
5
14
77% (2 steps)
73% (2 steps)
1. n-BuLi, (i-Pr)2NEt
n-Bu3SnH
O
O
O
O
17, Pd2(dba)3,
1. PBr3
THF, 0 ºC to RT
CH2Cl2, 0 ºC
Ph3As, LiCl
MeO
MeO
OHC
O
O
NMe2
HO
SnBu3
HO
P
DMF, 80 ºC
94%
2. P(OCH3)3
toluene
110 ºC
2. NaBH4
THF/H2O (4:1), 0 ºC
O
15
16
18
6
33% (2 steps)
O
O
64% (2 steps)
TfO
O
17
Figure 2 | Synthesis of fragments 4, 5 and 6. a, Preparation of differentially protected anti,anti-1,3,5-triol 4. b, Preparation of the syn-1,3-dioxane 5. c,
Preparation of dienyl phosphonate 6. THF, tetrahydrofuran; RT, room temperature; DMF, N,N-dimethylformamide; TES, triethylsilyl; Pd2(dba)3,
tris(dibenzylidineacetone)dipalladium(0).
TBSO
OMOM
NaH, DME
TBSO
OMOM
O
O
TBSO
OMOM
O
O
Cat. Hoveyda-Grubbs II
EtO2CCH2P(O)(OEt)2
MOMO
4
R1
+
O
CH2Cl2, 40 ºC
80%
0 ºC to RT
R2
63% 20a / 20% 20b
MOMO
MOMO
19
O
O
O
1. n-BuLi, p-MeOC6H4SH,
0 ºC, to RT
2. m-CPBA, −78 ºC to RT
R1 = CO2Et, R2 = H
20a
20b
1 = H, R2 = CO2Et
5
R
50% 20a / 38% 20b
(2 steps)
O
O
MeO
MeO
O
1. DIBAL-H, CH2Cl2, −78 ºC
2. TPAP, NMO, 4Å MS, CH2Cl2, RT
3. 6, NaHMDS, THF, −78 ºC
P
TBSO
OMOM
O
O
O
6
O
88% (3 steps)
MOMO
O
O
21
Figure 3 | Synthesis of differentially protected monomer 21. Monomer 21 was prepared by a five-step sequence involving cross metathesis of fragments 4
and 5 to afford ketone 19, chain elongation and subsequent coupling of the resulting aldehyde with phosphonate 6. DME, 1,2-dimethoxyethane; m-CPBA,
3-chloroperbenzoic acid; RT, room temperature; DIBAL-H, diisobutylaluminium hydride; TPAP, tetrapropylammonium perruthenate; NMO, N-methylmorpholine
N-oxide; MS, molecular sieves; NaHMDS, sodium hexamethyldisilazide.
subjected to a Wittig olefination to provide the a,b-unsaturated phosphite furnished the dienyl phosphonate in 64% overall yield
ketone 14 in 77% overall yield (E/Z ≥ 19:1). The synthesis of the (two steps).
syn-1,3-dioxane 5 was completed in a highly stereoselective
Figure 3 outlines the fragment coupling sequence to provide
manner (diastereoselectivity ≥ 19:1) from the d-triethylsilyloxy the monomeric precursor to demonstrate the dimerization strategy.
a,b-unsaturated ketone 14, using a novel bismuth-mediated two-com- Cross metathesis26 of the olefins, 4 and 5, with Hoveyda–GrubbsII cat-
ponent hemiacetal/oxa-conjugate addition reaction with acetaldehyde23. alyst furnished 19 in 80% yield, favouring the E-isomer (E/Z ≥ 19:1).
The dienyl phosphonate 6 was prepared from Zincke aldehyde Although the Horner–Wadsworth–Emmons homologation of methyl
15 using the five-step sequence outlined in Fig. 2c. Stannylation24 ketone 19 provided the a,b-unsaturated esters 20a/20b with modest
and reduction of the conjugated aldehyde in 15 furnished the dienyl selectivity (E/Z ¼ 3:1), the isomers were readily separable by
stannane 16 with ≥19:1 E/Z selectivity. Stille cross-coupling of the column chromatographyand the Z-isomer 20b recycled by the follow-
dienyl stannane 16 with the known aryl triflate 1725 provided ing two-step sequence27. Treatment of the a,b-unsaturated ester 20b
dienyl salicylate 18 in 94% yield. Finally, bromination of primary with the anion of 4-methoxybenzenethiol followed by the oxidation
alcohol 18 followed by an Arbuzov reaction with trimethyl of the resulting sulfide to the sulfoxide and syn-elimination, furnished
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1330
ARTICLES
max = 1,655 cm–1
ν
max = 1,732 cm–1
ν
1. TBAF, NH4F
THF, RT
TBSO
OMOM
O
O
OH OMOM
O
O
O
OH
OTMSE
2. NaHMDS
TMSE-OH
THF, 0 ºC
MOMO
O
O
MOMO
O
21
22
81% (2 steps)
22, NaHMDS, then 21
THF, 0 ºC
82%
OMOM
HO
O
O
MOMO
OTBS
O
O
OMOM
O
O
MOMO
TMSEO2C
23
OH
Figure 4 | Salicylate molecular switch-mediated dimerization. Dimeric ester 23 was prepared by coupling electrophilic monomer 21 with the dianion
of deactivated monomer 22. TBAF, tetrabutylammonium fluoride; RT, room temperature; TMSE-OH, 2-(trimethylsilyl)ethanol; NaHMDS, sodium
bis(trimethylsilyl)amide.
OMOM
OMOM
MOMO
HO
MOM-Cl
i-Pr2NEt
O
O
MOMO
O
O
MOMO
OTBS
OTBS
O
O
O
O
OMOM
O
O
OMOM
O
O
CH2Cl2, 0 ºC
94%
MOMO
TMSEO2C
MOMO
TMSEO2C
24
23
OMOM
OH
1. TBAF, NH4F, THF, RT
2. 2-bromo-1-ethylpyridinium
34% (2 steps)
tetrafluoroborate
NaHCO3, CH2Cl2, RT
OMOM
O
OH
O
MgBr2
n-BuSH
MOMO
HO
O
O
O
MOMO
OH OH
OH
O
O
O
O
O
OMOM
O
O
OH
OH OH
CH3NO2
Et2O, RT
OMOM
OH
61%
MOMO
HO
25
Marinomycin A (1)
Figure 5 | Completion of the total synthesis of marinomycin A. The C2-symmetrical macrodiolide 25 was prepared by a three-step sequence involving
protection of the deactivated phenols in dimer 23, selective cleavage of the silyl ether, and a modified Mukaiyama macrolactonization. Final deprotection
afforded the natural product, marinomycin A.
20a/20b in 84% overall yield and with 1.3:1 E/Z selectivity. This with 2-(trimethylsilyl)ethanol, to provide the deactivated
enabled the preparation of a,b-unsaturated ester 20a in 76% monomer 22 in 81% overall yield. The differentiation in reactivity
overall yield after recycling the Z-isomer 20b twice. Reduction of is evident from a comparison of the infrared stretch for the two
the a,b-unsaturated ester 20a with diisobutylaluminium hydride, esters (Dn ¼ 77 cm21), which provided the impetus to test the
followed by oxidation of the allylic alcohol with tetrapropylammo- hypothesis for the phenoxide as outlined earlier. Gratifyingly,
nium perruthenate (TPAP)28, afforded the a,b-unsaturated alde- treatment of electrophilic monomer 21 with the dianion of the deac-
hyde, which was subjected to fragment coupling with dienyl tivated monomer 22 furnished the dimeric ester 23 in 82% overall
phosphonate 6 to provide the differentially protected monomer yield. Interestingly, the removal of the tert-butyldimethylsilyl
21 in 88% overall yield for three steps, with ≥19:1 E/Z geometry.
group from 21 provided the corresponding secondary alcohol,
In accord with our hypothesis, we envisioned that the salicylate which undergoes base-mediated decomposition under analogous
would attenuate the reactivity of the esters and thereby facilitate the conditions. This is in sharp contrast to the deactivated ester 22,
transesterification of 21 with 22 to provide dimeric ester 23 (Fig. 4). which is stable to strong base, confirming the necessity to deactivate
In practice, the salicylate esters were differentiated via a two-step the salicylate ester of the pronucleophile for acylation.
sequence, which involved the removal of the tert-butyldimethylsilyl
Figure 5 outlines the completion of the total synthesis of (þ)-mar-
ether in 21 with ammonium fluoride buffered tetrabutylammonium inomycin A (1). Protection of the deactivated phenols in the dimeric
fluoride and transesterification of the salicylic acid acetonide29 ester 23 as methoxymethyl ethers furnished the bis-MOM aryl ether
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1330
ARTICLES
9. Akey, D. L. et al. Structural basis for macrolactonization by the pikromycin
thioesterase. Nature Chem. Biol. 2, 537–542 (2006).
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as a methyl salicylate esterase and implicate it in plant innate immunity.
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16. Matsumori, N., Yamaji, N., Matsuoka, S., Oishi, T. & Murata, M. Amphotericin
B covalent dimers forming sterol-dependent ion-permeable membrane
channels. J. Am. Chem. Soc. 124, 4180–4181 (2002).
17. Nicolaou, K. C. et al. Total synthesis of marinomycins A–C and of their
monomeric counterparts monomarinomycin A and iso-monomarinomycin A.
J. Am. Chem. Soc. 129, 1760–1768 (2007).
18. Amans, D., Bareille, L., Bellosta, V. & Cossy, J. Synthesis of the monomeric
counterpart of marinomycin A. J. Org. Chem. 74, 7665–7674 (2009).
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24 in 94% yield. Although the protection of the phenols formally acti-
vates both salicylate esters, we envisioned that the syn-1,3-dioxane
would enforce a linear conformation to promote the formation of
the macrodiolide rather than the macrolide19. Deprotection of the
tert-butyldimethylsilyloxy and (trimethylsilyl)ethoxy protecting
groups provided the seco-acid, which was subjected to macrolactoni-
zation using the modified Mukaiyama salt to furnish the 44-mem-
bered C2-symmetrical macrodiolide 25 in 34% yield (two steps)30.
Although there was no evidence of macrolide formation, the low
overall yield is attributed to a combination of complications with
the deprotection of the silyl protecting groups and the conversion of
the methoxymethyl aryl ether of seco-acid to the corresponding
monofluoromethyl phenyl ether. Global deprotection of macrodiolide
25 under carefully optimized reaction conditions furnished
marinomycin A (1) in 61% isolated yield after reverse-phase high-
performance liquid chromatography purification. Interestingly,
rapid hydrolysis of the aryl methoxymethyl ethers in 25 deactivates
the salicylate esters to hydrolysis in this challenging deprotection
sequence, which further illustrates the role of the resonance-assisted
hydrogen bond (RAHB) in this class of molecules. The spectro-
scopic data and optical rotation of synthetic marinomycin A (1)
were identical in all respects to the values reported for the natural
substance (1H/13C NMR, IR, [a]2D3 þ 168 (c 0.09, EtOH)
[lit.13 [a]D þ 180 (c 0.11, EtOH)]) by Fenical and co-workers13.
In summary, we describe a highly convergent asymmetric total
synthesis of (þ)-marinomycin A (1) using a triply convergent
18-step sequence (longest linear sequence) in 3.5% overall
yield. A key feature of the synthesis is the recognition of the role
that salicylate has in modulating the reactivity and conformation
via an intramolecular RAHB or the corresponding phenoxide; this
raises important new questions with regard to the biosynthesis,
conformation and biological activity of macrodiolides that contain
salicyclates. An additional feature of the synthesis is the ability to
utilize a syn-1,3-dioxane to facilitate a conformation-assisted
macrolactonization to preferentially afford the macrodiolide.
These observations have prompted biological studies to gain a
better understanding of the biosynthetic assembly of salicylate-
containing macrolide and macrodiolide natural products. Finally,
we believe that salicylates may have evolved as amide surrogates,
which may prove useful in bioorganic and medicinal chemistry.
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Methods
The reactions involving conjugated polyenes were carried out in the absence of light.
For experimental procedures and spectroscopic data of all new compounds, see
Supplementary Information.
Received 26 January 2012; accepted 12 March 2012;
published online 1 July 2012
Acknowledgements
References
The authors acknowledge the National Institutes of Health (GM54623) and the National
Science Foundation (CHE-0316689) for generous financial support, and the Royal Society
for a Wolfson Research Merit Award (to P.A.E.). The authors are also grateful to the EPSRC
National Mass Spectrometry Service Centre (Swansea, UK) for high-resolution
mass spectrometry. This Article is dedicated to Professor Robert H. Grubbs on the occasion
of his 70th birthday.
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Author contributions
P.A.E. managed the project, analysed data and prepared the manuscript with M-H.H.
and S.M. M.J.L. and M-H.H. devised the synthesis of the monomer and performed the
laboratory experiments. M-H.H. identified the significance of the salicylate molecular
switch and performed the laboratory work to complete the total synthesis of the natural
product. S.M. conducted key control experiments on the salicylates and identified the major
side product from the macrolactonization.
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Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at www.nature.com/
reprints. Correspondence and requests for materials should be addressed to P.A.E.
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