Gold(I)-Mediated Cycloisomerization/Cycloaddition Enables Bioinspired Syntheses of Neonectrolides B-E and Analogues

Article abstract of DOI:10.1021/jacs.9b06355

Development of a synthetic route to the oxaphenalenone (OP) natural products neonectrolides B-E is described. The synthesis relies on gold-catalyzed 6-endo-dig hydroarylation of an unusual enynol substrate as well as a one-pot Rieche formylation/cyclization/deprotection sequence to efficiently construct the tricyclic oxaphenalenone framework in the form of a masked ortho-quinone methide (o-QM). A tandem cycloisomerization/[4 + 2] cycloaddition strategy was employed to quickly construct molecules resembling the neonectrolides. The tricyclic OP natural product SF226 could be converted to corymbiferan lactone E and a related masked o-QM. Our study culminates with the application of the tandem reaction sequence to syntheses of neonectrolides B-E as well as previously unreported exo-diastereomers.

Full text of DOI:10.1021/jacs.9b06355

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Article
Gold(I)-Mediated Cycloisomerization/Cycloaddition Enables
Bioinspired Syntheses of Neonectrolides B-E and Analogs
Thomas Jaye Purgett, Matthew W. Dyer, Bryce Bickel, James McNeely, and John A. Porco
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06355 • Publication Date (Web): 30 Aug 2019
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Gold(I)-Mediated Cycloisomerization/Cycloaddition Enables
Bioinspired Syntheses of Neonectrolides B-E and Analogs
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Thomas J. Purgett, Matthew W. Dyer, Bryce Bickel, James McNeely, and John A. Porco, Jr.*
Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue,
Boston, Massachusetts 02215, United States
KEYWORDS: Oxaphenalenone, [4+2] cycloaddition, gold catalysis, ortho-quinone methide
ABSTRACT: Development of a synthetic route to the oxaphenalenone (OP) natural products neonectrolides B-E is described. The
synthesis relies on gold-catalyzed 6-endo-dig hydroarylation of an unusual enynol substrate as well as a one-pot Rieche formyla-
tion/cyclization/deprotection sequence to efficiently construct the tricyclic oxaphenalenone framework in the form of a masked ortho-
quinone methide (o-QM). A tandem cycloisomerization/[4+2] cycloaddition strategy was employed to quickly construct molecules
resembling the neonectrolides. The tricyclic OP natural product SF226 could be converted to corymbiferan lactone E and a related
masked o-QM. Our study culminates with the application of the tandem reaction sequence to syntheses of neonectrolides B-E as well
as previously unreported exo-diastereomers.
INTRODUCTION
Scheme 1. A) Proposed biosyntheses of 1-5. B) Retrosynthetic
analysis for 2 and 3
Oxaphenalenones are a diverse yet largely unstudied class of
natural products from fungi and plants bearing a characteristic
oxidized, fused tricyclic core.1 Despite their compelling struc-
tures and biological properties, reports on the syntheses of oxa-
phenalenone (OP) natural products and derivatives remain
scarce.2,3 We first became interested in the spiroketal natural
product neonectrolide A (1)4 and the ketal-containing ne-
onectrolides B-E (2-5)5 (Figure 1), compounds isolated in 2012
and 2015, respectively, by Che and coworkers. While conge-
ners 1-5 show moderate anticancer activity, a patent indicates
activity of 1 as a Gram-negative and -positive antibacterial
agent.6 The scarce quantities of the isolated cycloadducts, how-
ever, have clearly impeded more detailed systematic evaluation
of their biological activities.
Figure 1. Structures of neonectrolides A-E (1-5) and biosyn-
thetic precursor corymbiferan lactone E (6)
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Scheme 2. Synthesis of o-QM precursor 24 and SF226 (25) via Au (I)-catalyzed hydroarylation and interrupted Rieche
formylation
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The natural product corymibiferan lactone E (6), an apparent
biosynthetic precursor,5 was also coisolated with 1-5 (Scheme
1A).4,5 Along these lines, the neonectrolides likely arise from
diastereoselective [4+2] cycloaddition between ortho-quinone
methide (o-QM) 7, derived from oxidation of 6, and the chiral
dihydrofuran partners (9-11) that may originate from modifica-
tion of the putative biosynthetic precursor 3-dehydroxy-4-O-ac-
etylcephasporolide C (8, Scheme 1A).5,7 We considered that by
first building the tricyclic core of 6, we could readily access ne-
onectrolide congeners 1-5 via o-QM formation followed by
[4+2] cycloaddition. Furthermore, rapid formation of the tricy-
clic OP ring system would allow for a convergent and modular
synthesis, thereby providing a platform for construction of ne-
onectrolide analogs, as well as enabling evaluation of the pro-
posed biosyntheses of 1-5.
phenylacetate derivative 18 through crossed-Claisen condensa-
tion.
RESULTS AND DISCUSSION
Our synthesis began with self-condensation of dimethyl 1,3-
acetonedicarboxylate (19), followed by Fischer esterification of
the resulting phenylacetic acid (Scheme 2).13,15 We elected to
first prepare the bis-TBS protected phenylacetate derivative
20.16 Crossed-Claisen condensation of 2017 with freshly pre-
pared 2-butynoyl chloride18 cleanly afforded the tetrasubsti-
tuted enynol 21 in excellent yield19 as a single stereoisomer17
1
and enol tautomer as indicated by H chemical shift (CDCl3,
12.6 ppm) of the enynol hydroxyl proton.15,20 Computational
studies (DFT, B3LYP/6-31G**) indicate that the enynol moiety
is distorted from the aryl ring plane by approximately 66°
(Scheme 2). Enynol 21 was then treated with catalytic
[(SPhos)AuNCMe]SbF6 to induce 6-endo-dig hydroarylation,21
cleanly furnishing the desired naphthoate 22. As noted by both
Barriault22 and Banwell,23 we found that bulky phosphino
gold(I) salts performed particularly well in the hydroarylation
to furnish the desired product 22 in high yield with low catalyst
loading. During our efforts to study the scope of this transfor-
mation, we noticed that enynol substrates such as 26 (a 3.5:1
mixture of enol:keto tautomers in CDCl3) lacking an activated,
electron-rich aromatic ring alternately afforded 4-pyrone prod-
ucts via enol isomerization followed by nucleophilic attack of
Our retrosynthetic analysis for neonectrolide congeners 2 and
3 is shown in Scheme 1B. We sought to emulate the biosyn-
thetically proposed inverse-electron demand Diels-Alder
(IEDDA) cycloaddition8 of 7 to assemble the neonectrolide
scaffold which after methylation may provide the desired natu-
ral products 2-5. As this key biosynthetic step may be non-en-
zymatic,9 we anticipated that use of chiral cycloaddition part-
ners 10 and 11 may provide access to both 2 and 5 or 3 and 4,
respectively, with facial selectivity of the pivotal endo-cycload-
dition with o-QM 12 dictating the formation of either diastere-
omeric natural product. Cycloaddition partner 10 may be de-
rived from chiral alkynol 1310 which may be prepared by union
of the known alkynol 1411 and butanolide 15,12 the latter pre-
pared in three steps from L-glutamic acid. Compound 11, the
4’-epimer of 10 (neonectrolide numbering), may be prepared in
an identical fashion from D-glutamic acid, thereby allowing ac-
cess to both congeners 3 and 4. In order to access the tricyclic
oxaphenalenone framework of the neonectrolides, we envi-
sioned that dehydration of isochromanone-lactol precursor 16
may provide o-QM 12. We considered that formylation fol-
lowed by subsequent annulation could form the lactol ring of
16,13 while the naphthol moiety may be installed by metal-cat-
alyzed hydroarylation of enynol 17,14 readily accessible from
Scheme 3. Rearrangement of enynol 26 to 4-pyrone 27
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the ester carbonyl onto the enynol triple bond (Scheme 3).24 No-
Scheme 5. Conversion of 24 to corymbiferone C (32)
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tably, the 4-pyrone 27 bears resemblance to the fungal natural
product betulinan C (28).25 While treatment of 26 with TFA af-
forded 27 in decreased yield (19%), exposure of 21 to Brønsted
acid led only to cleavage of the silyl ether protecting groups.
Subjection of 22 to Rieche formylation conditions (SnCl4, di-
chloromethyl methyl ether)26 triggered an interrupted formyla-
tion/cyclization/deprotection sequence, presumably via oxo-
carbenium intermediate 23, to provide the isochromanone-ace-
tal 24, a candidate o-QM precursor.27 Ionic reduction of 24 was
cleanly accomplished using trifluoroacetic acid (TFA) and tri-
ethylsilane (Et3SiH) to provide the tricyclic oxaphenalenone
natural product SF226 (25).28
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We then studied the ability of 24 to serve as a suitable o-QM
precursor diene in model inverse demand [4+2] cycloadditions.
(Scheme 4). We found that treatment of 24 with TFA in 1,2-
dichloroethane followed by addition of indene cleanly afforded
the formal exo-[4+2] cycloadduct 29 (5:1 dr).29 We also evalu-
ated the ability of 24 to react with dienophiles in inverse-elec-
tron-demand fashion under Lewis acidic conditions, first sur-
veying reactivity with simple enol ethers such as 2,3-dihydro-
furan and 2,3-dihydropyran. We observed that PtCl4 success-
fully catalyzed the formation of cycloadducts 30 and 31, albeit
in moderate yield and diastereoselectivity.30
[4+2] cycloaddition have recently been employed for rapid con-
struction of natural products and natural product-like mole-
cules.34,35 In particular the De Brabander and Rodríguez groups
have developed elegant approaches to the structurally-related
spiroketal natural product berkelic acid36,37 utilizing tandem 5-
exo-dig cycloisomerization/o-QM formation/[4+2] cycloaddi-
tions via isochroman acetal35a,c or ortho-alkynylbenzaldehyde35b
Scheme 4. Initial reactions with o-QM precursor 24
intermediates, respectively. To the best of our knowledge, how-
ever, these two examples represent the only applications of this
Table 1. Catalyst screen for one-pot cycloisomerization/cy-
cloaddition with 24 and 36
As several oxaphenalenone natural products (cf. 32-34,
Scheme 5) which bear a para-quinone methide (p-QM) func-
tionality have been isolated,31 we also considered whether 24
could be converted into a stable and isolable QM derivative
(Scheme 5). Gratifyingly, exposure of 24 to catalytic camphor-
sulfonic acid (CSA) in the presence of 3Å molecular sieves led
to precipitation of the insoluble quinone methide 35 which
could be isolated by filtration.32 However, this compound
proved to be unstable in solution, likely a consequence of its
vinylogous acid functionality. Nonetheless, O-methylation of
the isolated compound 35 afforded the p-QM natural product
corymbiferone C (33) in 21% yield after preparative HPLC pu-
rification (32).31a
In order to achieve a more efficient and selective cycloaddi-
tion, as well as mitigate the isolation and purification of unsta-
ble and reactive quinone methide and dihydrofuran reaction
partners, we next evaluated a one pot cycloisomerization/cy-
cloaddition process33 for construction of the neonectrolide core.
Tandem processes involving alkynol cycloisomerization and
powerful methodology in natural product total synthesis. Fur-
thermore, tandem reactions involving in situ generation and cy-
cloaddition of a 2,3-dihydrofuran partner have not been applied
in such a context.
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We first studied the proposed cycloisomerization/cycloaddi-
Scheme 7. Evaluation of alkynol scope in the tandem re-
action with masked o-QM 24
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tion cascade with 4-phenyl-3-butynol (36) as the alkynol reac-
tion partner. We evaluated a range of -acidic metals to induce
alkynol cycloisomerization38 as well as o-QM formation from
24 via loss of methanol (Table 1). Gratifyingly, use of Pt(II),
Pd(II), Ag(I), Au(III), and Au(I) catalysts all led to formation
of the desired cycloadduct as an inseparable mixture of diastere-
omers (entries 1-5), significantly favoring the endo-cycload-
duct, the latter defined with respect to the dihydrofuran oxygen..
Notably, despite our previous success employing PtCl4 as cata-
lyst for direct o-QM formation and cycloaddition, no reaction
was observed when this catalyst was used in the tandem process
(entry 6). This observation may be attributed to the “hard”
Lewis acidic character of Pt (IV) and inability of this catalyst to
serve as a suitable π-acid. Furthermore, treatment of 24 with a
cationic gold (I) catalyst and 2,3-dihydrofuran did not afford
cycloaddition products. However, addition of CSA (20 mol%)
allowed the reaction to proceed, implicating the necessity for a
Brønsted acid catalyst in the process. We considered that the
alkynol reaction partner may be interacting with the cationic
Au(I) catalyst to form a  complex, thereby generating a Lewis
acid-activated Brønsted acid (LBA) which may significantly
enhance the acidity of the pendant alcohol. However, addition
of benzenebutanol to the mixture of 24/2,3-dihydrofuran/Au(I)
catalyst did not grant reactivity.15,39,40
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Scheme 6. Proposed mechanism for Au(I)-mediated cy-
cloisomerization/cycloaddition
We next explored a small set of electronically and sterically
distinct substrates to evaluate the scope of the tandem process
for the synthesis of neonectrolide analogs (Scheme 7). Reaction
of 24 with alkynol 36 at 0 °C with 2 mol% of catalyst enabled
formation of 37 in high diastereoselectivity (>20:1 dr), thereby
generating two rings and three stereocenters in a single reaction.
While both electron-rich and electron-poor aryl alkynols pro-
vided the corresponding cycloadducts in good yield as nearly
single diastereomers (40, 41), diastereoselectivity was found to
drop dramatically when alkyl alkynol substrates were employed
(cf. 42 and 43). It is worth noting that the majority of tandem
alkynol cycloisomerization/cycloadditions have been con-
ducted with aryl-substituted reaction partners which typically
afford products as single diastereomers.34 As expected, con-
ducting the reaction with the parent alkynol (R = H) afforded
cycloadduct 29.
Based on our experimental findings, a proposed mechanism
for the tandem cycloisomerization/cycloaddition between phe-
nyl alkynol 36 and isochromanone acetal 24 is shown in
Scheme 6. Gold(I)-catalyzed hydroalkoxylation of 36 may gen-
erate the aurated dihydrofuran 38A, an intermediate which may
also serve as a Brønsted acid39,40 to induce formation of the pro-
tonated o-QM 38 via loss of methanol along with the vinyl gold
species 38B. Protonated o-QM 39 or 12 bearing a vinylogous
acid moiety may also serve as competent Brønsted acids in the
process. Protodeauration of 38B may then generate reaction
partners 12 and dihydrofuran 38C and regenerate the Au(I) cat-
alyst. Final [4+2] cycloaddition of 12 and 38C may then afford
the observed major cycloadduct 37.34d, 35a
As the chiral methyl group of partners 9-11 may be responsi-
ble for directing the approach of the dihydrofuran reaction part-
ner in the biosynthesis of the neonectrolides,4,5 we sought to
probe the effect of this component’s introduction on the dia-
stereofacial selectivity in the [4+2] cycloaddition. As antici-
pated, conducting the tandem reaction with chiral alkynol 44
provided the endo-anti cycloadduct 45 as the major product
(Scheme 8A). Notably, the minor cycloadduct generated in this
reaction was derived from endo cycloaddition from the opposite
face of the o-QM (endo-syn approach).15 The observed facial
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synthesizing the chiral, γ-butyrolactone-containing alkynol ep-
selectivity in the reaction likely arises from a simple steric bias
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for the in situ-generated dihydrofuran to approach the o-QM
anti to the methyl substituent.
imers 13 and 46. Alkylation of 14 was readily achieved by use
of epoxide 47 or ent-47 on a multigram scale, which was fol-
lowed by one-pot silyl deprotection and lactonization under
acidic conditions to yield the desired alkynols 13 and 46
(Scheme 9A).10
Transition state calculations (PBEh-3C/SMD(THF),DLPNO-
CCSD(T)/CBS/CPCM(THF))15 were performed to compare
both stepwise and concerted asynchronous reaction pathways to
form the four possible stereoisomers of cycloadduct 45.41, 42
These calculations (cf. Table SQ1-SQ2) are consistent with the
experimentally observed product distribution. Schemes 8B and
8C show a comparison of concerted vs. stepwise transition
states leading to anti-endo adduct 45. The computations indi-
cate that concerted and stepwise pathways are highly competi-
tive for each stereoisomer; however, the endo isomers prefer to
form via a stepwise mechanism, whereas the exo isomers appear
to prefer a concerted, asynchronous transition state. Interest-
ingly, we also noticed that the most energetically favorable tran-
We also developed a three-step sequence to access corymbif-
eran lactone E (6), the likely biosynthetic precursor of 1-5, from
SF226 (25) (Scheme 9B). While direct methylation of 24 or 25
proved to be unselective, 25 could be converted regioselectively
to the silyl ether 48. Methylation was achieved with Meerwein’s
salt, which was followed by desilylation to afford 6 in excellent
yield. Exposure of 6 to silver (I) oxide in a 1:1 mixture of THF
and methanol cleanly oxidized 6 to install the isochromanone-
acetal functionality of the masked o-QM 49.43
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To our surprise, however, treatment of 49 and 13 with
[(SPhos)AuNCMe]SbF6 did not lead to the formation of any de-
tectable cycloaddition products. We suspected that exogenous
Brønsted acid may be needed to promote o-QM formation from
49. Indeed, conducting the transformation in the presence of 10
mol% of CSA enabled the reaction to proceed (Scheme 9C).
However, in the process the γ-butyrolactone moiety unexpect-
edly underwent elimination to afford the alkenoic acids 50 and
51 as major products. Notably, the same products were obtained
in comparable yield and diastereoselectivity when epimeric al-
kynol 46 was used in the process. The outcome of these reac-
tions reinforced that a stepwise mechanism was operative (cf.
Scheme 8C).42bAs detailed in Scheme 9D, dihydrofuran 10 may
undergo conjugate addition to the reactive, protonated o-QM 52
generating oxonium intermediate 53. Computational studies in-
dicate that the lactone carbonyl of this intermediate may partic-
ipate in a hydrogen bond with the phenolic proton of the OP
ring system, while also placing the requisite oxocarbenium moi-
ety within suitable proximity for ring closure.15 We believe that
subsequent cyclization to afford the benzyopyran functionality
may be accompanied by intramolecular proton transfer and
deprotonation by the camphorsulfonate anion leading to anti
elimination affording the observed endo-anti alkenoic acid cy-
cloadduct 50 as the major product. In further support of a step-
wise process, cycloisomerization of 46 was conducted in the
presence of tetracyanoethylene (TCNE) to afford dihydrofuran
54 (Scheme 10). This result is consistent with the ability of di-
hydrofurans to undergo formal [2+2] cycloaddition with suita-
ble electrophiles such as TCNE44 and dimethyl acetylenedicar-
boxylate (DMAD)45 through proposed zwitterionic intermedi-
ates similar to 55.
Scheme 8. (A) Tandem reaction with chiral alkynol 44 (B)
Optimized concerted, asynchronous endo-anti transition
state leading to cycloadduct 45 (C) Rate-limiting, stepwise
transition state leading to 45
2.051
2.681
Based on recent work reported by Xu and coworkers, we also
attempted the cycloisomerization/[4+2] cycloaddition between
49 and 13 in the presence of [(SPhos)AuNCMe]SbF6 and
Sc(OTf)3.46 We were pleased to find that the use of Sc(OTf)3 as
Lewis acid led to the formation of neonectrolides C and D (3
and 4) as well as the exo-diasteromer 56, with the endo-anti and
exo-anti cycloadducts comprising the majority of the product
mixture as determined by analysis of the crude reaction mixture
(3:56:4 = 5:3:1). Comparable results were observed with al-
kynol 46 as reaction partner to afford neonectrolides B and E (2
and 5) as well as the exo-anti diastereomer 57, again in a 5:3:1
ratio, favoring the anti-cycloadducts (Scheme 11A). While they
remain unisolated, we believe that neonectrolide stereoisomers
1.992
sition states are stabilized by π-stacking and electrostatic/hydro-
gen bonding interactions between the aryl moiety of the dihy-
drofuran partner with the oxaphenalenone ring system (cf.
Scheme 8C, Figure SZ1).
Encouraged by our experimental results, we next focused on
the construction of the natural products neonectrolides 2-5 by
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Scheme 9. (A) Syntheses of chiral butyrolactone-containing cycloaddition partners 13 and 46 (B) Synthesis of corymbiferan
lactone E (6) and the derived isochromanone-acetal 49 (C) Synthesis of alkenoic acids 50 and 51 (D) Mechanistic rationale for
formation of elimination product 50 (E) Relevant conformer of adduct 53 leading to 50.
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56 and 57 represent “anticipated” natural products that likely
significant formation of exo-anti isomer 56. A representative
exist in Nature.47,48
conformer from a conformational search15 for one diastereomer
The product distribution in the latter process may be ex-
plained by the ability of Sc(OTf)3 to promote acetal exchange
as suggested by Xu and coworkers.46 We observed that the
mixed acetal 58 could be isolated as roughly a 1:1 mixture of
inseparable diastereomers when the experiment was conducted
in a stepwise fashion (Scheme 11B). Exposure of isolated 58 to
Au(I) catalysis afforded a 2:1:1 mixture of products (3:56:4)
similar to that obtained in the one-pot transformation. In terms
of reaction mechanism, treatment of 58 with cationic Au(I) may
form the tethered dihydrofuran intermediate 59 after alkyne ac-
tivation by the Au(I) catalyst. Formation of the requisite o-QM
may proceed by elimination of the dihydrofuran, generating the
two reaction partners, o-QM 7 and dihydrofuran 11. Subsequent
[4+2] cycloaddition provides the observed products 3, 4, and
56.46 It is worth noting that the butyrolactone carbonyl of 58 and
59 may interact with the phenolic proton of the tethered oxa-
phenalenone scaffold, as previously described in the formation
of cycloadducts 50 and 51 (Scheme 9D/9E). We believe that
this hydrogen-bonding interaction may orient the dihydrofuran
partner in an exo-cycloaddition geometry, thereby leading to the
Scheme 10. Au(I)-catalyzed cycloisomerization of 49 in
the presence of TCNE
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Scheme 11. Syntheses of neonectrolides 2-5 and exo-diastereomers 56 and 57 via Au(I)/Sc(III) catalysis
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of 58 is shown in Scheme 11B (inset). Similar results were also
achieved when employing alkynol 46.15 Furthermore, reaction
between 49 and 60 under synergistic Au(I)/Sc(III) conditions
led to the isolation of endo-cycloadduct 61 as nearly a single
diastereomer, underscoring the significance of the hydrogen-
bonding lactone moiety present in 13 and 46 to access exo-cy-
cloadducts 56 and 57.
products to be synthesized in over three decades. We have uti-
lized gold-catalyzed hydroarylation of an enynol substrate and
an interrupted Rieche formylation sequence to efficiently con-
struct the oxaphenalenone framework in the form of a masked
o-quinone methide. Access to this core structure has enabled
synthesis of the isolatable p-quinone methide natural product
corymbiferone C31a as well as the natural product SF226 (25).28
Our convergent and bioinspired approach to the neonectrolides
has also provided access to natural product analogs via gold(I)-
mediated alkynol cycloisomerization/o-QM cycloaddition and
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
In conclusion, we have described the first total syntheses of
neonectrolides B-E (2-5), the first oxaphenalenone natural
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China, Sun, A. Application of Neonectrolide A in Preparing Antibac-
has led to further understanding of substrate-controlled induc-
tion of diastereoselectivity in such processes. Additionally, we
have demonstrated the power of 5-endo-dig cycloisomeriza-
tion/[4+2] cycloaddition pathways for the efficient and concise
construction of natural products 2-5. Our synthetic route is
highly flexible and scalable, allowing for preparation of multi-
gram amounts of oxaphenalenone core structure 24 in a single
campaign. Finally, syntheses of 2-5 support their postulated bi-
osynthetic origins while highlighting the power of biomimetic
synthetic design not only in the efficient execution of total syn-
theses, but in the production of “anticipated” natural prod-
ucts.47,48 Efforts in our laboratory to develop catalytic, enanti-
oselective cycloisomerization/cycloaddition processes49 to-
wards oxaphenalenone natural products including ne-
onectrolide A (1)50 as well as biological studies of this underex-
plored class of natural products are currently in progress and
will be reported in due course.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Corresponding Author
*porco@bu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Institutes of Health (NIH) (R35 GM
118173) and Boston University (BU) for financial support. We
gratefully acknowledge Prof. Yongsheng Che (Beijing Institute of
Pharmacology and Toxicology) for providing natural samples of
neonectrolides B and C. We thank the National Science Foundation
(NSF) for support of NMR (CHE-0619339) and MS (CHE-
0443618) facilities at BU. Dr. Martin Himmelbauer, Dr. Adam
Scharf, and Mr. Adam Zahara (Boston University) are acknowl-
edged for helpful discussions. We thank Dr. Kyle Reichl (Boston
University) for assistance with computation.
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31
32
33
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35
36
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41
42
43
44
45
46
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49
50
51
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53
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56
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60
11
ACS Paragon Plus Environment