Divergent synthesis and chemical reactivity of bicyclic lactone fragments of complex rearranged spongian diterpenes

Article abstract of DOI:10.1021/ja207727h

The synthesis and direct comparison of the chemical reactivity of the two highly oxidized bicyclic lactone fragments found in rearranged spongian diterpenes (8-substituted 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one and 6-substituted 7-acetoxy-2,8-dioxabicyclo[3.3.0]octan-3-one) are reported. Details of the first synthesis of the 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3- one ring system, including an examination of several possibilities for the key bridging cyclization reaction, are described. In addition, the first synthesis of 7-acetoxy-2,8-dioxabicyclo[3.3.0]octanones containing quaternary carbon substituents at C6 is disclosed. Aspects of the chemical reactivity and Golgi-modifying properties of these bicyclic lactone analogs of rearranged spongian diterpenes are also reported. Under both acidic and basic conditions, 8-substituted 2,7-dioxabicyclo[3.2.1]octanones are converted to 6-substituted-2,8-dioxabicyclo[3.3.0]octanones. Moreover, these dioxabicyclic lactones react with primary amines and lysine side chains of lysozyme to form substituted pyrroles, a conjugation that could be responsible for the unique biological properties of these compounds. These studies demonstrate that acetoxylation adjacent to the lactone carbonyl group, in either the bridged or fused series, is required to produce fragmented Golgi membranes in the pericentriolar region that is characteristic of macfarlandin E.

Full text of DOI:10.1021/ja207727h

ARTICLE
pubs.acs.org/JACS
Divergent Synthesis and Chemical Reactivity of Bicyclic Lactone
Fragments of Complex Rearranged Spongian Diterpenes
Martin J. Schnermann,† Christopher M. Beaudry,†,§ Nathan E. Genung,† Stephen M. Canham,†
Nicholas L. Untiedt,† Breanne D. W. Karanikolas,‡ Christine S€utterlin,‡ and Larry E. Overman*,†
†Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, United States
‡Department of Developmental and Cell Biology, 2011 Biological Sciences III, University of California, Irvine, California 92697-2300,
United States
S Supporting Information
b
ABSTRACT: The synthesis and direct comparison of the chemical
reactivity of the two highly oxidized bicyclic lactone fragments found
in rearranged spongian diterpenes (8-substituted 6-acetoxy-2,7-
dioxabicyclo[3.2.1]octan-3-one and 6-substituted 7-acetoxy-2,8-
dioxabicyclo[3.3.0]octan-3-one) are reported. Details of the first
synthesis of the 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring
system, including an examination of several possibilities for the key
bridging cyclization reaction, are described. In addition, the first
synthesis of 7-acetoxy-2,8-dioxabicyclo[3.3.0]octanones containing
quaternary carbon substituents at C6 is disclosed. Aspects of the chemical reactivity and Golgi-modifying properties of these bicyclic
lactone analogs of rearranged spongian diterpenes are also reported. Under both acidic and basic conditions, 8-substituted 2,7-
dioxabicyclo[3.2.1]octanones are converted to 6-substituted-2,8-dioxabicyclo[3.3.0]octanones. Moreover, these dioxabicyclic
lactones react with primary amines and lysine side chains of lysozyme to form substituted pyrroles, a conjugation that could be
responsible for the unique biological properties of these compounds. These studies demonstrate that acetoxylation adjacent to the
lactone carbonyl group, in either the bridged or fused series, is required to produce fragmented Golgi membranes in the
pericentriolar region that is characteristic of macfarlandin E.
’ INTRODUCTION
found in shahamin K (2),7 and more complex dioxabicyclic
lactone fragments. The 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-
3-one subunit is particularly rare; at the onset of our studies, it
was known only in the diterpene macfarlandin E (4)2,8 and 13
additional rearranged spongian diterpenes such as aplyviolene
(3),8 chromodorolide A (5),4a shahamin I (6),9 and norrlandin
(7)10 (Figure 1B). The isomeric 7-acetoxy(or hydroxy)-2,8-
dioxabicyclo[3.3.0]octan-3-one fragment is somewhat more
abundant in rearranged spongian diterpenes,11 as exemplified
by dendrillolide A (8),12 norrisolide (9),13 cheloviolenes
A (10) and B (11),14 and omriolide A (12)15 (Figure 1C).
The substituted dioxabicyclo[3.3.0]octanone ring system of
these diterpenes has been the subject of limited synthetic
efforts,16 highlighted by two total syntheses of norrisolide.17,18
Last year we disclosed the first synthesis of the 4,6-diacetoxy-
2,7-dioxabicylo[3.2.1]octan-3-one moiety of MacE and evidence
obtained by evaluation of related diterpenes and various analogs
that the entire oxygenated subunit—including both acetoxy
substituents—is required to elicit the MacE Golgi phenotype.6
Additionally, we showed that t-Bu-MacE (13) and its deacetoxy
congener 14 are converted to substituted pyrroles such as 15 and
16 in the presence of primary amines under mild conditions
Skeletal rearrangement and oxidation of spongian diterpene
precursors of general structure 1 (Figure 1A) provides a structu-
rally diverse group of marine-derived natural products referred to
as rearranged spongian diterpenes.1 These natural products are
isolated from sponges and dorid nudibranchs, the latter of which
are believed to acquire these diterpenes from sponge sources as a
chemical defense mechanism.1 Among the most structurally
complex of the rearranged spongian diterpenes is a structurally
unique group that contains a polycyclic hydrocarbon fragment
joined to an oxidized lactone unit (Figure 1). The biological
activity of this group of spongian-derived diterpenes has
been characterized to only a limited extent. Antimicrobial,2À4
cytotoxic,4 and nematocidal4 activities have been reported, and
norrisolide (9) has been shown to induce irreversible fragmenta-
tion and delocalization of Golgi membranes throughout the
cytosol in human cell lines.5 In addition, we reported in 2010 that
macfarlandin E (4, MacE) and a simplified analog 13 (t-Bu-MacE,
see eq 1) induce a novel Golgi organization phenotype that is
characterized by small, pericentriolar Golgi fragments and block-
age of protein transport from the Golgi to the plasma membrane.6
A central feature of the group of rearranged spongian natural
products depicted in Figure 1 is the presence of highly oxyge-
nated and hydrophobic subunits. The oxygenated fragment is
structurally diverse and includes monocyclic variants, such as that
Received: August 24, 2011
Published: October 11, 2011
r
2011 American Chemical Society
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Figure 1. Representative rearranged spongian diterpene natural products containing lactone fragments.
(eq 1). This latter finding suggests a functional role for the
oxygenated ring system of MacE, formation of a protein-bound
pyrrole species, which could be responsible for the unique
biological properties of these compounds.
’ RESULTS AND DISCUSSION
Enantioselective Synthesis of t-Bu-MacE. As an appropriate
initial target for developing a chemical synthesis of the 4,6-
diacetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system, we
chose t-Bu-MacE (13) which possesses a tert-butyl group in
place of the hydroazulene subunit of MacE. Our synthetic
approach to t-Bu-MacE was based on the prospect that kineti-
cally controlled cyclization of dialdehyde acid 17 would not
form the desired dioxabicyclo[3.2.1]octanone but rather the 2,8-
dioxabicyclo[3.3.0]octan-3-one isomer 19 (eq 2). Moreover, we
anticipated, and later established experimentally (see below),
that the fused isomer also would be favored thermodynamically.
Bolstering our expectation that direct cyclization of 17 was
unlikely to generate the 2,7-dioxabicyclo[3.2.1]octan-3-one ring
system is the conversion outlined in eq 3. In this example, even
the enforced 1,3-diaxial proximity of the carboxyl nucleophile
and the distal aldehyde of precursor 20 did not result in forming
the bridged dioxabicyclo product, but rather fused isomer 21.19
Although both MacE and norrisolide have pronounced effects
on the structure and function of the Golgi, their phenotypes are
different: MacE causes the conversion of the Golgi ribbon into
membrane fragments that remain in the pericentriolar region,
whereas norrisolide induces fragmentation and dispersal of
Golgi membranes throughout the cytoplasm.5,6 In addition, the
structureÀactivity relationships reported to date for these two
rearranged spongian natural products are quite distinct: the hydro-
phobic fragment is suggested to be essential for norrisolide’s
activity,5 whereas the full 4,6-diacetoxy-2,7-dioxabicylo[3.2.1]-
octan-3-one subunit, and not the hydroazulene fragment, is
believed to be essential for eliciting the MacE-Golgi phenotype.6
This article reports the synthesis of simplified analogs of the
oxygenated subunits of MacE (4) and dendrillolide A (8) and a
survey of their chemical reactivity and Golgi-modifying properties.
We find that both 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-ones
and 7-acetoxy-2,8-dioxabicyclo[3.3.0]octan-3-ones react under
mildconditionswith benzylamine or lysinesidechainsof lysozyme
to form substituted pyrrole products. Moreover, we show that the
presence ofacetoxysubstitution adjacent tothe lactone carbonyl in
either the bridged or fused dioxabicyclooctanone ring system
induces a nearly identical Golgi organization phenotype and
greater reactivity with lysine side chains.
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Scheme 1. Retrosynthetic Analysis of t-Bu-MacE
Scheme 3. Synthesis of Tricarbonyl Intermediate 24
Scheme 2. Synthesis of Enantiopure Cyclopentenone 26
tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF)
were less successful. After consumption of the starting materials
at 0 °C, addition of a slight molar excess of water to the reaction
mixture and allowing the reaction to warm to room temperature
prior to aqueous workup delivered the enone product in
reproducibly good yield. If this step was omitted, conjugate
addition product 31 was obtained in 30À60% yield.26 We
speculate that the trimethylsilyl group is only partially transferred
in the initial 1,4-addition; addition of water and warming to room
temperature is believed to transform any enoxysilane intermedi-
ate to the corresponding ketone, allowing enolate equilibration
and β-elimination to take place. Cyclopentenone 26 was then
obtained in high yield by cleavage of the butane diacetal group
with aqueous trifluoroacetic acid and methylation of the resulting
carboxylic acid.27
In five steps, enone 26 was elaborated in good overall yield to
tricarbonyl intermediate 24 (Scheme 3). The tert-butyl substi-
tuent was first incorporated by stereoselective addition of the
cuprate reagent generated from tert-butyllithium and CuCN (2:1
molar ratio) in the presence of tert-butyldimethylsilyl chloride
(TBSCl) to provide exclusively trans-substituted cyclopentenyl
silyl ether 32.28 At this stage, we needed to transform the methyl
ester to an acetyl group without cleaving the enoxysilane. A two-
step sequence, proceeding via methyl enol ether intermediate 33,
was eventually developed. Although methylenation of 32 with
the Tebbe reagent29 proceeded sluggishly, resulting in incom-
plete conversion, the Takai methylenation conditions developed
by Rainer and co-workers produced methyl enol ether 33 in
nearly quantitative yield.30 After examining several conditions for
hydrolyzing the methyl enol ether, the use of 1.5 equiv of oxalic
acid in aqueous i-PrOH at 0 °C was identified as particularly
effective in achieving the conversion to methyl ketone 25 with
minimal cleavage of the enoxysilane. We ascribe this rare, if not
unprecedented, selective acidic cleavage of a methyl enol ether in
the presence of a silyl enol ether to steric shielding of protonation
of the cyclopentenyl double bond by the two bulky trans-
oriented substituents.31 In our initial efforts, we cleaved the
double bond of 25 by reaction with OsO4 and NaIO4, followed
by addition of trimethylsilyldiazomethane32 to the crude product
mixture to provide tricarbonyl product 24 in useful, albeit
variable, yields (55À84%).6 To improve the reproducibility of
this conversion and avoid the undesirable use of TMSCHN2, an
The analysis that guided our initial synthesis of t-Bu-MacE
(13) is summarized in Scheme 1. Late stage BaeyerÀVilliger
oxidation was anticipated to form the C6-acetoxy substituent
from an acetyl precursor.17,20 It was anticipated initially that the
C4 acetate could be installed at a late stage as well. Bridged-
bicyclic intermediate 22 was seen arising from the cyclic acetal
23, wherein X is a leaving group. Acyclic tricarbonyl intermediate
24 was seen resulting from oxidative cleavage of cyclopentylox-
ysilane 25, which in turn would arise from facial-selective
conjugate addition of a tert-butylcuprate to cyclopentenone 26
in the presence of a silyl electrophile.
Guided by these considerations, we initiated the synthesis of t-
Bu-MacE by targeting cyclopentenone 26. Attempts to access
enone 26 from known cyclopentanone 2721 were unsuccessful,
as regioselective installation of the double bond proved proble-
matic under a variety of conditions (Scheme 2).22 Consequently,
enantiopure cyclopentenone 29, which is readily available in four
steps from cyclopentadiene, was used as the Michael acceptor.23
The union of silyl ketene acetal 2824 and enone 29 to afford
cyclopentenone 30 was realized in good yield in dry DMF in the
presence of lithium acetate.25 Earlier attempts to promote this
reaction with Lewis acids (SnCl4 or TiCl4 in CH2Cl2) or
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Scheme 4. Formation of Tetrahydrofuryl Cyclization
Precursors
Table 1. Cyclization Reactions To Form 22
Entry
1
R
Conditions
DEAD, PPh3,
Yield 22a
OH (35)
0%
CH2Cl2
2
3
4
OH (35)
OMe (37)
F (39)
0.2 equiv of CSA,
CHCl3, rt, 12 h
1.2 equiv of BF3•OEt2,
CH2Cl2, 0 °C, 1 h
2 equiv of SnCl2,
DMF, rt, 18 h
54%
66%
71%
a Yield reported as conversion from methyl ester precursor (34, 36, and
38, respectively).
À78 °C in CH2Cl2. Saponification of this product with 1.5 equiv
of 1 N NaOH in MeOH at room temperature provided
carboxylic acid 39.
With cyclization substrates 35, 37, and 39 in hand, their
transformation to 2,7-dioxabicyclo[3.2.1]octan-3-one 22 was stu-
died (Table 1). Mitsunobu conditions failed to promote cycliza-
tion of hemiacetal 35 (entry 1); however, in the presence of 1
equiv of camphorsulfonic acid (CSA) in chloroform, lactol 35 was
converted at room temperature to dioxabicyclooctanone 22 in
54% overall yield from ester precursor 34 (entry 2). In a similar
fashion, methoxy acetal 37 was transformed in the presence of 1
equiv of BF3•Et2O to dioxabicyclooctanone 22 in 66% yield (entry
3). Anomeric fluoride 39 cyclized with slightly enhanced efficiency
when exposed to 2 equiv of SnCl2 in DMF at room temperature,
generating bicyclic lactone 22 in 71% yield (entry 4).34
With several complementary methods for accomplishing the
critical bridging lactonization reaction identified, all that remained
was installing the additional oxygen functionality of t-Bu-MacE.
The C6 acetoxy substituent was readily introduced by reaction of
dioxabicyclooctanone 22 with 4 equiv of trifluoroperacetic acid at
room temperature,35 providing the tert-butyl analogof aplyviolene,
6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one (14), in 88% yield.
We had hoped that the enhanced acidity of lactones relative to
esters would allow the remaining acetoxy substituent to be
incorporated at this stage.36 However, all attempts to directly
introduce a hydroxyl substituent adjacent to the lactone carbonyl
group were unsuccessful. For example, enolization of 14 with 1À2
equiv of LDA or KHMDS, followed by oxidation (Davis
oxaziridine37 or O2), silylation, or acylation resulted in either
recovered starting material or extensive decomposition.38
alternate sequence was developed. In this improved procedure,
enoxysilane 25 was oxidized with OsO4 (0.05 equiv) and
N-methylmorpholine-N-oxide (NMO, 2.0 equiv), followed by
cleavage of the resulting α-hydroxyketone with 1.3 equiv of
methanolic Pb(OAc)4, a sequence that reproducibly delivered
tricarbonyl intermediate 24 in 95% yield.
As a prelude to examining the pivotal bridging reaction, acyclic
intermediate 24 was transformed to several potential tetrahy-
drofuryl cyclization precursors (Scheme 4). Cleavage of the silyl
ether by reaction of 24 with 1.5 equiv of TBAF provided
tetrahydrofuryl lactol 34 in moderate yield, which upon careful
saponification with 1.5 equiv of NaOH at 0 °C gave the crude
carboxylic acid 35 in sufficient purity for subsequent cyclization
studies. Attempts to access intermediate 35 more expeditiously
from cyclopentenyl precursor 25 by sequential reaction with
OsO4/NaIO4 and TBAF were unsuccessful, providing only
complex mixtures of products. Reaction of tricarbonyl inter-
mediate 24 with 1.6 equiv of camphorsulfonic acid (CSA) and
trimethylorthoformate in methanol at room temperature gener-
ated diacetal 36 as a 1:1 mixture of separable methoxy anomers in
65% yield. The α epimer of 36 could be converted to the β
epimer by equilibration in methanol in the presence of cam-
phorsulfonic acid, allowing the β-36 to be obtained in 66%
overall yield from acyclic precursor 24 after two recycles.
Subsequent saponification of the ester and selective cleavage of
the dimethyl acetal with aqueous HCl at 0 °C yielded crude
tetrahydrofuryl ketoacid 37. As glycosyl fluorides are used
extensively as glycosyl donors because of their stability and the
mild, orthogonal methods available for their activation,33 hemi-
acetal 34 was transformed to anomeric fluoride 38 by reaction
with 1.6 equiv of diethylaminosulfur trifluoride (DAST) at
As a result of our inability to selectively oxidize bicyclic lactone
14, we turned to examine introduction of the α-acetoxy
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Scheme 5. Completion of the Synthesis of t-Bu-MacE (13)
Scheme 6. Synthesis of 2,8-Dioxabicyclo[3.3.0]octanones 46
and 49
substituent prior to forming the dioxabicyclo[3.2.1]octanone
ring system. Hydroxylation of the sodium enolate of the
β-methoxy epimer of tetrahydrofuryl acetal 36 with oxaziridine
4039 proceeded smoothly to generate α-hydroxy ester 41 as a
single stereoisomer (Scheme 5). The stereoselectivity of this
oxidation is rationalized by orientation of the enolate away from
the tetrahydrofuran ring and delivery of the electrophile to the
face opposite the tert-butyl group. As the hydroxyl substituent of
41 has the opposite relative configuration to the corresponding
acetate of MacE, it was inverted by oxidation with DessÀMartin
reagent40 and subsequent stereoselective reduction of the ketone
product with sodium borohydride at À78 °C. This sequence
provided alcohol 42 in 88% overall yield. Saponification of
the ester and acidic hydrolysis of the ketal, followed by exhaustive
acylation and anhydride methanolysis, yielded α-acetoxycar-
boxylic acid 43. We were delighted to find that tetrahydrofuryl
acetal 43, when exposed to 1.1 equiv of BF3•OEt2 at 0 °C, gave
rise to 2,7-dioxabicyclo[3.2.1]octan-3-one 44 in 71% overall
yield from tetrahydrofuran 42. BaeyerÀVilliger oxidation of this
product with trifluoroperacetic acid then provided t-Bu-MacE
(13) in 90% yield.41 The synthetic sequence outlined in
Schemes 2À5 allowed 0.5 g of t-Bu-MacE to be synthesized,
enabling the chemical reactivity and biological profile of this
compound to be studied in detail.
1
were initially secured by H NMR NOE analysis and subse-
quently confirmed by single crystal X-ray diffraction.42
Analog 49, which possesses an acetoxy group adjacent to the
lactone carbonyl, was also prepared. The enolate of bicyclic
lactone 45 was generated with NaHMDS in THF at À78 °C and
hydroxylated to afford 47 (Scheme 6). Subsequent acetylation of
the secondary alcohol gave acetate 48 in low (unoptimized)
yield over two steps.43 The methoxy acetal functional group
of 48 was hydrolyzed with dilute HCl, followed by acetylation
of the hemiacetal product with acetic anhydride and pyridine, to
provide an inseparable mixture of 4,7-diacetoxy-2,8-dioxa-
bicyclo[3.3.0]octan-3-one 49 and an uncharacterized aldehyde
byproduct. Pure dioxabicyclo[3.3.0]octanone 49 was obtained in
modest yield from this crude product mixture by sodium chlorite
oxidation,44 which allowed for easy removal of carboxylic acid
impurities by chromatography. Of note, the syntheses summar-
ized in Scheme 6 are the first of 7-acetoxy-2,8-dioxabicyclo-
[3.3.0]octan-3-ones possessing a quaternary-carbon substituent
at C6, a structural feature found in many rearranged spongian
diterpene natural products (see Figure 1).
Enantioselective Synthesis of 7-Acetoxy-2,8-dioxabicy-
clo[3.3.0]octan-3-ones. Several intermediates prepared during
the synthesis of t-Bu-MacE provide potential access to related
structures in the 2,8-dioxabicyclo[3.3.0]octan-3-one series. We
demonstrated this chemistry with the α-methoxy epimer of
intermediate 36, thus allowing both epimers of acetal 36 to be
utilized (Scheme 6). Sequential ester saponification and ketal
hydrolysis cleanly provided tetrahydrofuran α-37 from acetal
precursor α-36. BaeyerÀVilliger oxidation of this intermediate
took place with concomitant cyclization to provide 7-methoxy-
2,8-dioxabicyclo[3.3.0]octanone 45 in 82% overall yield for the
three steps. Hydrolysis of 45 with dilute HCl yielded a mixture of
bicyclic lactols, which upon acetylation delivered crystalline
7-acetoxy-2,8-dioxabicyclo[3.3.0]octanone 46 as a single stereo-
isomer. The structure and relative configuration of this product
Chemical Reactivity of the 6-Acetoxy-2,7-dioxabicylo-
[3.2.1]octan-3-one and 7-Acetoxy-2,8-dioxabicylo[3.3.0]-
octan-3-one Ring Systems. Our expectation that the 2,7-
dioxabicyclo[3.2.1]octan-3-one ring system would be less stable
than the isomeric 2,8-dioxabicyclo[3.3.0]octan-3-one ring sys-
tem was readily confirmed by exposure of dioxabicyclo-
[3.2.1]octanone 14 to BF3•OEt2 in acetic acid at 0 °C to
generate dioxabicyclo[3.3.0]octanone isomer 46 as a 3.5:1
mixture of separable acetal epimers, favoring the β-acetoxy
isomer (Scheme 7).45 Alternatively, hydrolysis of 14 at room
temperature with 1 N HCl in THF gave a mixture of dioxa-
bicyclo[3.3.0]octanone lactol epimers 50,46 which upon acetyla-
tion provided the α epimer of dioxabicyclo[3.3.0]octanone 46
exclusively. This sample was identical to the material prepared by
the approach outlined in Scheme 6. In a similar fashion, acidic
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Scheme 7. Conversion of Bridged Dioxabicyclic Lactones 13
and 14 to Fused Isomers 46 and 49
Table 2. Half-life of Hydrolysis at pD 8.3
Compound
t1/2 (h)a
13
14
46
49
10.2
91.9
9.7
1.5
a Incubated at 37 °C in 50 mM phosphate buffer; disappearance of
substrate (5 mM) was monitored by 1H NMR.
stable than stereoisomer 50. Under the basic reaction conditions
(pH ∼14), the predominant aldehyde intermediates generated
from hydroxide opening of the lactone (or cleavage of the acetate
substituent) of precursor 14 would be expected to be 53 and 54
(eq 5). Base-promoted epimerization of the likely predominant
species, uncharged 54, would lead to the formation of the
observed product 51. The partial erosion of enantiomeric purity
observed in the conversion of 14 to 51 indicates that there is
some epimerization under these conditions of the central
methine carbon of intermediate 53.48
Scheme 8. Synthesis of 51 and Its Mosher Ester
To gain further insight into the reactivity of these dioxabicyclic
lactone ring systems, we examined the rate of hydrolysis of
compounds 13, 14, 46, and 49. The hydrolytic rate was measured
by NMR observation of the disappearance of the dioxabicyclic
ring system in a pD 8.3 phosphate buffer containing 10%
DMSO at 37 °C (Table 2). The presence of an acetoxy group
adjacent to the lactone carbonyl results in an enhanced hydrolysis
rate of both the substituted dioxabicyclo[3.2.1]octanone and
dioxabicyclo[3.3.0]octanone ring systems, with the latter ring
system hydrolyzing more rapidly than the former.
In our initial report, we demonstrated that the reaction of
substituted dioxabicyclo[3.2.1]octanones 13 and 14 with ben-
zylamine leads to substituted pyrroles.6 Specifically, we showed
that t-Bu-MacE (13) was converted to pyrrole 15 in a mixture
of perdeutero-benzylamine (2.5 equiv) and THF-d8 and that
dioxabicyclooctanone 14 is transformed to pyrrole 16 in high
yield in the presence of 5 equiv of benzylamine in DMSO and
water (eq 1). Under these conditions, fragmentation of these
precursors undoubtedly generates transient 1,4-dialdehyde inter-
mediates, 17, which undergo PaalÀKnorr pyrrole formation
(Scheme 9).6 In the case of the pyrrole derived from t-Bu-MacE
(13), the oxygen substituent of the acetic acid side chain is
exchanged for a benzylamino substituent, likely after formation
of the pyrrole by a gramine-type fragmentation/addition
pathway.
The conversion of t-Bu-MacE (13) and analog 14 to pyrrole
products was examined in CD3OD to gain insight into the initial
step of the pyrrole-forming process under protic conditions
(Scheme 10).49 NMR analysis of the reaction of 13, perdeu-
tero-benzylamine (5 equiv), and CD3OD at room temperature
indicated that pyrrole 57 was formed along with equimolar
quantities of acetic acid and methyl acetate.50 Similarly, when
14 was converted to 58 under identical conditions, methyl
acetate was observed.49 The formation of methyl acetate, as well
hydrolysis of t-Bu-MacE (13) provided a lactol intermediate,
which was identical to the product formed by acidic hydrolysis
of 48. Ensuing acetylation of this lactol intermediate gave
α-acetoxylactone 49 in 36% overall yield from t-Bu-MacE.
The transformation of the 2,7-dioxabicyclo[3.2.1]octan-3-one
ring system to fused bicyclic lactone products could also be
accomplished under basic conditions. In the presence of sodium
hydroxide at room temperature, dioxabicylo[3.2.1]octanone 14
yielded a single 2,8-dioxabicylo[3.3.0]octan-3-one lactol pro-
duct. However, in this case, 1H NMR NOE analysis showed that
the tert-butyl group of product 51 resides on the convex face of
the 2,8-dioxabicyclo[3.3.0]octanone ring system (Scheme 8).
Confirmation that this product resulted from epimerization of
the carbon bearing the tert-butyl substituent, and not the methine
hydrogens of the ring junction, was obtained by conversion of 51
to the R and S Mosher esters 52. Enhanced Mosher analysis
established that 52 possesses the 1R,5R,6S,7R absolute config-
uration with a slightly eroded enantiomeric purity of 78% ee.47
The formation of product 51 from dioxabicyclo[3.2.1]-
octanone precursor 14 requires further comment. Certainly
isomer 51 having the tert-butyl group on the convex face of the
cis-dioxabicyclo[3.3.0]octanone ring system should be more
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Scheme 9. Mechanistic Outline for Pyrrole Formation from
13 and 14
Scheme 11. Conversion of Dioxabicyclo[3.3.0]octanones 46
to Pyrroles 59 and 60
Scheme 12. Regioselectivity of Initial Nucleophilic Attack on
Bicyclic Lactones 14 and 46 Leading to 1,4-Dialdehyde
Intermediates
Scheme 10. In Situ Observation of the Formation of 57 and
58 and Reaction Byproducts
as the exclusive formation of the carboxylates 57 and 58,
demonstrates that fragmentation of the 6-acetoxy-2,7-dioxa-
bicyclo[3.2.1]octanones 13 and 14 is initiated by initial reaction
of the protic solvent at the anomeric acetoxy substituent.
Pyrroles are also formed from the reaction of 7-acetoxy-2,8-
dioxabicyclo[3.3.0]octan-3-ones with primary amines. For ex-
ample, 7-acetoxydioxabicyclo[3.3.0]octanone 46 was converted
to pyrrole carboxylic acid 59 when exposed at room temperature
to 2 equiv of benzylamine in DMSO/H2O (Scheme 11). When
this reaction was conducted in methanol, pyrrole methyl ester 60
was observed as the major product. The formation of methyl
ester 60 suggests, in contrast to bridged dioxabicyclo[3.2.1]-
octanone compounds 13 and 14, that fragmentation in this series
is initiated by reaction of the protic solvent at the lactone
carbonyl group.
The divergence in fragmentation pathways of the two isomeric
bicyclic lactone ring systems (summarized in Scheme 12) is
consistent with the reactivity of related simple lactones. Although
six-membered lactones are typically more reactive than their five-
membered ring counterparts,51 oxabicyclo[3.2.1]octanone 62 is
saponified at a dramatically reduced rate (Figure 2).52 The
reduced rate of saponification of lactone 62 is readily ascribed
to developing destabilizing syn-pentane interactions during axial
Figure 2. Saponification rates of select lactones.53
approach of hydroxide to the lactone carbonyl group. Similar
destabilizing interactions would be involved in the tetrahedral
intermediate generated from the addition of nucleophiles to the
lactone carbonyl of 6-acetoxy-2,7-dioxabicyclo[3.2.1]octanones 14.
To ascertain whether the oxygenated bicyclic lactones would
react with lysine residues of proteins under biologically relevant
conditions, we examined the reactivity of these molecules with
hen egg white lysozyme (HEWL).53 In initial experiments, we
found that dioxabicyclo[3.2.1]octanones 13 and 14 converted
lysine residues of HEWL to pyrrole adducts at room temperature
in pH 7 phosphate buffer (Figure 3 and Table 3, entries 1 and 3).
Analog 14 provided the pyrrole-3-acetic acid modification (+164
mu), whereas t-Bu-MacE (13) led to the pyrrole-3-hydroxyacetic
acid adduct (+180 mu) resulting from solvolytic incorporation of
a hydroxyl substituent at the heterobenzylic site (Figure 3).
The reaction of dioxabicyclo[3.3.0]octanones 46 and 49 with
HEWL at pH 7 and 8 was also examined. As expected, 6-acetoxy-
2,7-dioxabicyclo[3.2.1]octan-3-ones and isomeric 7-acetoxy-
2,8-dioxabicyclo[3.3.0]octan-3-ones provided identical pyrrole
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ARTICLE
Figure 3. Modification of lysozyme under the conditions shown with
13 and 14 to form lysine adducts (a) and the distribution of alkylated
products obtained from 14 (b) and 13 (c). The ESI-MS spectra were
reconstructed from charge ladders.
Table 3. Modification of HEWL by Dioxabicyclolactones 13,
Figure 4. NRK cells were treated with control (DMSO), MacE (4) at
20 μg/mL, 49 at 40 μg/mL, or 46 at 80 μg/mL for 1 h at 37 °C. MacE
and 49 are shown at the minimal active concentration, and 46 is shown at
the maximal concentration tested. Cells were fixed and stained with an
antibody to the Golgi resident protein mannosidase II (green) and the
DNA dye Hoechst 33342 (blue). Area demarcated by the white square is
enlarged in the insets to show detail of Golgi organization following each
treatment. Scale bar is 10 μm.
14, 46, and 49a
Unmod.
(%)
+1
+2
+3
+4
Entry
Substrate
pH
(%)
(%)
(%)
(%)
1
2
3
4
5
6
7
8b
13
13
14
14
46
46
49
49
7
8
7
8
7
8
7
8
9
0
54
14
12
47
35
48
47
4
33
49
0
4
32
0
0
5
0
0
0
0
0
7
88
43
61
7
indistinguishable from that of MacE or t-Bu-MacE (13), with the
conversion of the Golgi ribbon into small fragments that remained
localized adjacent to the centrosome (Figure 4). By contrast,
7-acetoxy-2,8-dioxabicyclo[3.3.0]octanone 46, which lacks an
acetoxy substituent adjacent to the lactone carbonyl group, did
not affect the Golgi structure at concentrations of up to 80 μg/mL.
As 6-acetoxy-2,7-dioxabicyclo[3.2.1]octanone 14 also did not
impact the Golgi structure,6 these findings indicate that the
formation of pericentrosomal Golgi fragments characteristic of
MacE depends on the presence of oxygenation adjacent to the
lactone carbonyl group, in either the substituted dioxabicyclo-
[3.2.1]octanone or dioxabicyclo[3.3.0]octanone ring systems.
2
0
4
0
38
28
19
7
13
0
12
43
a Conditions: 50 μM substrate, 10 μM lysozyme, 50 mM K2HPO4 buffer
incubated at 22 °C for 20 h. Product distributions were determined from
ESI-MS analyses. With 13 and 49, the addition of +180 mu was observed
per modification, and with 14 and 46, +164 mu was observed. b In
addition +5 (7%).
adducts: 14 and 46 (+164 mu), 13 and 49 (+180 mu).54 t-Bu-
MacE (13) and 49, which possess an acetoxy substituent adjacent
to the lactone carbonyl group, modified lysozyme to a greater
extent than the corresponding desacetoxy congeners 14 and 46.
Subjecting the modified lysozymes to trypsin digestion, followed
by standard MALDI-MS-MS peptide sequencing, revealed that
the two most surface-accessible lysines (K-33 and K-97) were the
predominant sites of covalent modification.55
Effects of 6-Acetoxy-2,7-dioxabicylo[3.2.1]octan-3-ones
and 7-Acetoxy-2,8-dioxabicylo[3.3.0]octan-3-ones on Golgi
Organization. Synthetic access to 2,8-dioxabicyclo[3.3.0]octan-
3-ones 46 and 49 allowed us to compare the Golgi-modifying
properties of these structures with those of isomers in the 2,7-
dioxabicyclo[3.2.1]octan-3-one series. Normal Rat Kidney
(NRK) cells grown on coverslips were incubated with analogs
46 and 49 for 60 min at 37 °C, followed by examination of the
Golgi for the MacE-induced reorganization phenotype by im-
munofluorescence analysis with antibodies to the known Golgi
resident protein, mannosidase-II.56 The 4,7-diacetoxy-2,8-
dioxabicyclo[3.3.0]octanone 49 produced a Golgi phenotype
’ CONCLUSIONS
The synthesis and initial comparison of the chemical reactivity
of two highly oxidized bicyclic lactone fragments found in
rearranged spongian diterpenes — 8-substituted 6-acetoxy-2,7-
dioxabicyclo[3.2.1]octan-3-one and 6-substituted 7-acetoxy-2,8-
dioxabicyclo[3.3.0]octan-3-one — are reported. The syntheses
of t-Bu-MacE (13) and congener 14 are the first syntheses of the
8-substituted 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring
system found in rearranged spongian diterpenes such as macfar-
landin E (4) and aplyviolene (3). A late-stage intermediate, 36,
was diverted to provide the first synthetic entry to isomeric
structures (46 and 49) in the 7-acetoxy-2,8-dioxabicyclo-
[3.3.0]octan-3-one series.
Access to these highly oxidized bicyclic lactones allowed the
chemical reactivity and Golgi-modifying activity of these ring
systems to be studied. Under both acidic and basic conditions,
8-substituted 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-ones are
converted to 6-substituted 7-acetoxy-2,8-dioxabicyclo[3.3.0]-
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Journal of the American Chemical Society
ARTICLE
octan-3-one products. Both dioxabicyclooctan-3-one ring sys-
tems are found to react readily with primary amines to form
pyrrole products. Of particular significance, lysine side chains of
hen egg white lysozyme are converted under physiologically
relevant conditions to substituted pyrroles upon exposure to
dioxabicyclic lactones 13, 14, 46, and 49. The presence of an
acetoxy substituent adjacent to the lactone carbonyl group, in
either the bridged or fused dioxabicyclooctanone series, increases
the extent of the lysine to pyrrole conversion and is essential for
induction of the macfarlandin E Golgi phenotype. These investi-
gations provide a basis for future studies aimed at identifying the
biological target(s) of these Golgi-modifying natural products, as
well as initial insight into the reactivity of the family of structurally
distinctive rearranged spongian diterpenes depicted in Figure 1.
Chavasiri, W.; Kokpol, U.; Kotze, A.; Garson, M. J. Marine Drugs 2004,
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Dumdei, E.; Andersen, R. J. J. Nat. Prod. 1991, 54, 993. (b) Total
synthesis: Lebsack, A. D.; Overman, L. E.; Valentekovich, R. J. J. Am.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and co-
b
pies of 1H and 13C NMR spectra of new compounds; CIF files for
compounds 46 and 51. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
leoverma@uci.edu
(16) Select preparative approaches: (a) Corey, E. J.; Su, W. G. J. Am.
Chem. Soc. 1987, 109, 7534. (b) Petit, R.; Furstoss, R. Synthesis
1995, 1517. (c) Corey, E. J.; Letavic, M. A. J. Am. Chem. Soc. 1995,
117, 9616. (d) Weisser, R.; Yue, W.; Reiser, O. Org. Lett. 2005, 7, 5353.
(17) Brady, T. P.; Kim, S. H.; Wen, K.; Theodorakis, E. A. Angew.
Chem., Int. Ed. 2004, 43, 739.
(18) Granger, K. E. Norrisolide: Convergent Total Synthesis and
Preliminary Biological Investigation. Ph.D. Thesis, Boston College,
Boston, MA, 2009.
Present Addresses
§Department of Chemistry, 153 Gilbert Hall, Oregon State
University, Corvallis, OR 97331.
’ ACKNOWLEDGMENT
(19) (a) Arnꢀo, M.; Gonzꢀalez, M. A.; Zaragozꢀa, R. J J. Org. Chem.
2003, 68, 1242. (b) Arnꢀo, M.; Gonzꢀalez, M. A.; Marin, M. L.; Zaragozꢀa,
R. J. Tetrahedron Lett. 2001, 42, 1669.
(20) Krow, G. R. Org. React. 1993, 43, 251.
(21) Díez, E.; Dixon, D. J.; Ley, S. V. Angew. Chem., Int. Ed. 2001,
40, 2906.
We gratefully acknowledge the late Professor John Faulkner,
Scripps Institution of Oceanography, for authentic macfarlandin
E. Professor Gregory Weiss, University of California, Irvine, is
acknowledged for helpful discussions and Issa Moody, University
of California, Irvine, for initial protein-labeling studies. We thank
Dr. Joe Ziller, University of California, Irvine, for the single-
crystal X-ray analyses and Dr. John Greaves, University of
California, Irvine, for mass spectrometric analyses. This research
was supported by the NIH Neurological Disorders & Stroke
Institute (Grant NS-12389), the NIH National Institutes of
General Medical Sciences (Grant GM-098601), and NIH post-
doctoral fellowships for M.J.S. (CA-138084) and C.M.B. (GM-
079937). B.D.W.K. was supported by a postdoctoral fellowship
from the UC Irvine Training Program in Cancer Biology (NCI
Grant 5 T32 CA009054-34). NMR spectra, mass spectra, and the
X-ray analyses were obtained at UC Irvine using instrumentation
acquired with the assistance of NSF and NIH Shared Instru-
mentation grants. Unrestricted funds from Amgen and Merck are
also gratefully acknowledged.
(22) (a) For an example of a similar functionalization, see ref 7b. (b)
IBX in DMSO/toluene generated regioisomeric enone products as a 1:1
mixture. Similarly, reaction conditions such as PhSCl in MeCN or LDA,
PhSSPh in THF provided unselective introduction of the sulfur unit.
(23) Tietze, L. F.; Stadler, C.; B€ohnke, N.; Brasche, G.; Grube, A.
Synlett 2007, 485.
(24) (a) Dixon, D. J.; Ley, S. V.; Rodriguez, F. Org. Lett. 2001,
3, 3753. (b) Ley, S. V.; Dixon, D. J.; Guy, R. T.; Rodriguez, F.; Sheppard,
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(26) The lithium enolate (generated with LiHMDS at À78 °C in
THF) of the butane-2,3-diacetal glycolic acid derivative (the precursor
to 28) also reacted with 29 to afford 30; however, competing formation
of aldol product i (∼1:1 with 30) significantly reduced the yield of 30.
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(50) Compound 57 was identified by NMR and mass spectroscopic
observation. Efforts to isolate 57 were complicated by the formation of
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fied by NMR and mass spectroscopic observation but could be isolated
in pure form. See Supporting Information for details.
(31) Steric shielding must be involved, as 1-(trimethylsiloxy)-
cyclopentene is a much stronger nucleophile than ethyl vinyl ether;
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(32) Diazomethane could be employed, but the yield was reduced by
10À20%.
(54) No products resulting from an acyl transfer reaction to HEWL
appeared to be formed by ESI-MS analysis, suggesting that initial
hydrolysis, and not protein side chain reactivity, provides the reactive
1,4-dialdehyde intermediate.
(33) (a) Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett. 1981; 10,
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Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 5630.
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known Golgi protein giantin, which led to nearly indistinguishable
staining patterns (see Supporting Information).
(34) The use of dry DMF was critical for efficient cyclization. For a
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Y.; Chen, J.; Liu, C.; Mong, K. T. Angew. Chem., Int. Ed. 2011, 50, 7315.
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(38) It is likely that the acetate was competitively enolized under
many ofthese conditions. Wewere able to generatethevinyltriflateofthe
ketone 22 in modest yield (∼35%) with KHMDS and the Comins
reagent in THF at À78 °C. Although the subsequent α-oxidation
reaction with KHMDS and the Davis oxaziridine in THF at À78 °C
provided the α-hydroxy lactone in a useful yield (∼60%), initial attempts
to selectively cleave the vinyl triflate were unsuccessful.
(39) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org. Synth.
1988, 66, 203.
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(41) The chemical structures of 13 and 30 were confirmed by X-ray
crystallography: CDCC 762682 and 762683.6
(42) Crystallographic data for this compound were deposited at the
Cambridge Crystallographic Data Centre: CCDC 839175.
(43) The low yield observed in this sequence is likely a result of the
sensitivity of the α-hydroxylated intermediate 47 to silica gel.
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37, 2091. (b) Kraus, G. K.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
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(45) That the acetal mixture reflected a thermodynamic ratio was
confirmed by individually exposing the separable acetal diastereomers of
46 to the reaction conditions (BF3•OEt2, AcOH, CH2Cl2, 0 °C) to
provide an identical 3.5:1 α:β mixture of diastereomers.
(46) The ratio of epimeric lactols was somewhat variable (between
1:1 and 3:1).
(47) Further confirmation was obtained by chromatographic separa-
tion of the major diastereomer of 52 (possessing the S-Mosher-ester) and
single crystal X-ray diffraction. Crystallographic data for this compound
were deposited at the Cambridge Crystallographic Data Centre: CCDC
839176.
(48) Longer reaction times do not afford fully equilibrated, racemic
51, as significant quantities of Cannizzaro product ii are formed. For
example, after 72 h in 1 N NaOH at room temperature 54% of ii is
isolated from the reaction mixture.
(49) The initial site of nucleophilic attack in protic conditions was
not established in ref 6 in which either aprotic (BnNH2, THF) or
aqueous (BnNH2, DMSO, H2O) conditions were used.
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