Versatile Construction of 6-Substituted cis-2,8-Dioxabicyclo[3.3.0]octan-3-ones: Short Enantioselective Total Syntheses of Cheloviolenes A and B and Dendrillolide C

Article abstract of DOI:10.1021/jacs.7b04265

A short enantioselective synthesis of 6-substituted cis-2,8-dioxabicyclo[3.3.0]octan-3-ones is described. The pivotal step is coupling of a tertiary radical generated directly from a tertiary alcohol with a 3-chloro-5-alkoxybutenolide. This strategy is ap

Full text of DOI:10.1021/jacs.7b04265

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Communication
Versatile Construction of 6-Substituted cis-2,8-
Dioxabicyclo[3.3.0]octan-3-ones. Short Enantioselective Total
Syntheses of Cheloviolenes A and B and Dendrillolide C
Yuriy Slutskyy, Christopher R. Jamison, Peng Zhao, Juyeol Lee, Young Ho Rhee, and Larry E. Overman
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 17 May 2017
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Versatile Construction of 6-Substituted cis-2,8-Dioxabicyclo[3.3.0]octan-3-ones. Short En-
antioselective Total Syntheses of Cheloviolenes A and B and Dendrillolide C
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Yuriy Slutskyy, †, ζ Christopher R. Jamison,†, ζ Peng Zhao, † Juyeol Lee, † Young Ho Rhee,‡ Larry E. Overman †,*
†Department of Chemistry, University of California, Irvine, California 92697-2025
‡Department of Chemistry, Pohang University of Science and Technology, Hyoja-dong San 31, Pohang, Kyungbook, Republic of Ko-
rea 790-784
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RECEIVED DATE
Supporting Information Placeholder
The biological activity of rearranged spongian diterpenoids of
marine origin remains largely unexplored.8,11 The unique effects
on the structure of the Golgi apparatus induced by norrisolide (3),
macfarlandin E (10), and structurally simplified racemic analogs
containing a cisꢀ2,8ꢀdioxabicyclo[3.3.0]octanꢀ3ꢀone (11) or 2,7ꢀ
dioxabicyclo[3.2.1]octanꢀ3ꢀone ring (12) are of most signifiꢀ
cance.12,13 The consequences of exposing the Golgi to norrisolide
(3), or macfarlandin E (10) and dioxabicyclo[3.3.0]octanones 11–
12, are remarkably different. Although both natural products
block protein transport from the Golgi to the plasma membrane,
norrisolide (3) induces irreversible fragmentation and delocalizaꢀ
tion of Golgi membranes throughout the cytosol in human cell
lines, whereas macfarlandin E (10) and analogs 11–12 (R = OAc)
induce an irreversible Golgi organization phenotype that is charꢀ
acterized by the formation of small fragments that remain in the
pericentriolar region. In addition, we have shown that macfarꢀ
landin E and analogs 11–12 react with primary amines, including
lysine side chains of the enzyme lysozyme, to form pyrroles, a
conjugation that potentially could be important for the observed
effects of these agents on the Golgi.13b
ABSTRACT: A short enantioselective synthesis of 6ꢀsubstituted
cisꢀ2,8ꢀdioxabicyclo[3.3.0]octanꢀ3ꢀones is described. The pivotal
step is coupling of a tertiary radical generated directly from a
tertiary alcohol with a 3ꢀchloroꢀ5ꢀalkoxybutenolide. This strategy
is applied towards scalable 14–15 step syntheses of three rearꢀ
ranged spongian diterpenoids, cheloviolenes A and B and dendrilꢀ
lolide C.
The cisꢀ2,8ꢀdioxabicyclo[3.3.0]octanꢀ3ꢀone (1) ring system is
found in nearly 100 natural products (Figure 1).1 In a subset of
these, the dioxabicyclic ring is isolated and joined at Cꢀ6 to a
hydrocarbon fragment of nine or fourteen carbons. The fungal
sesquiterpenoid 2 is an example of the former group,2 whereas
diterpenoids 3–8 exemplify the larger group that were isolated
from marine sponges or nudibranchs.3 Norrisolide (3) was the first
of these natural products to be described.4 In the more common
members of this group, the dioxabicyclo[3.3.0]octanꢀ3ꢀone fragꢀ
ment is attached to a quaternary carbon of the hydrocarbon unit,
for example diterpenoids 4–8. Two distinct structural subtypes
that differ in whether the hydrocarbon fragment resides on the
concave or convex face of the cisꢀ2,8ꢀdioxabicyclo[3.3.0]octanꢀ3ꢀ
one fragment, exemplified respectively by dendrillolide A (5)5
and cheloviolene A (6),6 are observed.7 The relative configuraꢀ
tions of norrisolide (3), macfarlandin C (4) and cheloviolene A (6)
are known by virtue of singleꢀcrystal Xꢀray analyses.4,6,8 The abꢀ
solute configuration of norrisolide (3) was established by Theꢀ
dorakis’ inaugural total synthesis,9 whereas that of rearranged
spongian diterpenoids 4–8 and structurally related natural prodꢀ
ucts has not been established. They are suggested to be as depictꢀ
ed in Figure 1 by virtue of their presumed biosynthesis from preꢀ
cursors having a spongian skeleton (9).3,10
O
O
AcO
O
H
OAc
R
O
H
O
O
tꢀBu
H
tꢀBu
O
O
O
OAc
R
OAc
12 (R = H or OAc)
H
macfarlandin E (10)
11 (R = H or OAc)
As analogs 11 and 12 appear to form identical 1,4ꢀdialdehyde
intermediates upon acetate cleavage, and structures harboring the
cisꢀ2,8ꢀdioxabicyclo[3.3.0]octanꢀ3ꢀone ring of the former are
expected to be more readily available by chemical synthesis, our
studies in this area have focused recently on developing a short
and
versatile
route
to
6ꢀsubstituted
cisꢀ2,8ꢀ
dioxabicyclo[3.3.0]octanꢀ3ꢀones. The sequence outlined in
Scheme 1, whose pivotal step would be the coupling of a tertiary
radical generated from a carboxylic acid or alcohol precursor
with a 5ꢀalkoxybutenolide (13), could potentially access a wide
variety of dioxabicyclooctanones 14 in 5 steps, representing a
significant improvement on an earlier synthesis of 11 (R = H) that
required 14 steps.13b Moreover, the sequence proposed in Scheme
1 could provide products 14 in enantiopure form, as both enantiꢀ
omers of several 5ꢀalkoxybutenolides are commercially availaꢀ
ble.14 We report herein the successful development of the strategy
adumbrated in Scheme 1 and illustrate its utility by notably short
and enantioselective total syntheses of the rearranged spongian
diterpenoids 6–8.
Scheme 1. General Route to 6-Substituted cis-2,8-
Dioxabicyclo[3.3.0]octan-3-ones (14).
Figure
1.
Terpenoids
containing
isolated
cisꢀ2,8ꢀ
dioxabicyclo[3.3.0]octanꢀ3ꢀone fragments and the presumed bioꢀ
synthetic precursor 9 of the marine diterpenoids 3–8.
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We chose 1ꢀmethylcyclohexanol (15) as the starting material to
Our application of this chemistry to accomplish a short total
explore the proposed approach in the alcohol series.15 Our initial
aim was to develop a oneꢀpot sequence for directly transforming a
tertiary alcohol to a coupled product. We eventually found that
exposure of alcohol 15 to 1 equiv of oxalyl chloride at room temꢀ
perature in DME, followed by adding water and 3 equiv of
K2HPO4 generated the potassium hemioxalate intermediate 16.16
Addition of 1 equiv of 5ꢀmethoxybutenolide 17,17 followed by
photoredoxꢀcatalyzed coupling as described previously16 provided
20 as a single stereoisomer in 58% yield. Using the analogous
menthyloxy butenolide 18,18 coupled product 21 was again generꢀ
ated as a single stereoisomer in 60% yield. As we had previously
observed high yields in the coupling of a tertiary radical with an
αꢀchlorocyclopentenone,19 we turned to examine chlorobutenolide
19 as the radical acceptor. In this case, addition of the tertiary
radical to the more activated acceptor was significantly more effiꢀ
cient. Following the initial fragment coupling, simply adding 10
equiv of triꢀnꢀbutylamine to the reaction mixture and allowing the
subsequent photocatalytic dechlorination to proceed for 4 h gave
21 in 80% yield from alcohol 15.20 The coupled product 21 could
be transformed in 49% yield over four steps to the 6ꢀsubstituted
cisꢀ2,8ꢀdioxabicyclo[3.3.0]octanꢀ3ꢀone 24 by way of isolated
intermediates 22 and 23.
synthesis of (+)ꢀcheloviolene A is summarized in Scheme 4. The
synthesis began with the known cyclopentene nitrile 29,26 which
is accessible from (+)ꢀfenchone as a single alkene regioisomer in
three steps by a sequence we optimized to provide 29 on ~10 g
scale.27 Reduction of 29 with (iꢀBu)2AlH and Wittig elaboration
of the resulting aldehyde provided dienyl nitrile 30 in 87% yield
over two steps. The trisubstituted double bond of this intermediate
was regioselectively epoxidized upon reaction with mꢀ
chloroperbenzoic acid (m-CPBA) at –10 °C to give an 8:1 mixture
of stereoisomers from which epoxide 31 was isolated in 81%
yield after chromatographic purification. Deprotonation of 31
with lithium 2,2,6,6ꢀtetramethylpiperidide (LiTMP) induced steꢀ
reospecific Stork epoxy/nitrile cyclization, to form cisꢀ
perhydrazulene alcohol 32 in 85% yield.28 To our knowledge, this
is the first example of forming a sevenꢀmembered ring in this
way.29 After examining several alternatives, the elaboration of the
nitrile to an exocyclic methylene was best realized in a classical
fashion. First, global reduction with concomitant Eschweilerꢀ
Clarke methylation yielded tertiary amine 33. After treatment with
mꢀCPBA, the resulting amine oxide underwent clean Cope elimiꢀ
nation when heated in DMF at 120 °C to yield alcohol 34 in 70%
yield over the two steps. This sixꢀstep sequence provided convenꢀ
ient access to cisꢀperhydrazulene alcohol 34 on gramꢀscale.
Our early survey of conditions for carrying out the pivotal couꢀ
pling reaction of the tertiary radical derived from alcohol 34 and
butenolides 17 and 19 indicated that ethereal solvents (THF or
DME) were optimal. In addition, these exploratory investigations
showed that a significant competing reaction was reduction of the
initially generated tertiary radical. Thus, the yield of the coupled
product was enhanced when the concentration of the reaction was
increased from 0.05 M to 0.6 M in THF. Under optimal condiꢀ
tions, the oneꢀstep generation of the potassium hemioxalate salt
from 34 and the photoredox catalyzed coupling of the derived
radical with 1 equiv of butenolide 19 was highly efficient, providꢀ
ing product 35 in 76% yield after addition of triꢀnꢀbutylamine.
Elaboration of coupled product 35 to (+)ꢀcheloviolene A (6)
began with alkylation of the lactone enolate with methyl bromoꢀ
acetate to deliver ester 36 as a single stereoisomer. Reduction of
36 with 2.2 equiv of (iꢀBu)2AlH in toluene at –78 °C gave rise to
an inconsequential mixture of dioxabicyclo[3.3.0]octane lactol
epimers 37. The crude mixture of lactols was oxidized to the corꢀ
responding lactone 38 upon treatment with PCC. Finally, subjectꢀ
ing dioxabicyclooctanone 38 to dilute HCl provided (+)ꢀ
cheloviolene A (6) in 79% overall yield from ester 36. Synthetic
crystalline 6 exhibits a different optical rotation from the one
reported in literature, synthetic: [α]D22 +53 (c 0.11, CHCl3), literaꢀ
ture: [α]D +4.5 (c 0.11, CHCl3).11 However, the spectroscopic data
and the melting point for synthetic 6 compared well with those
reported for the natural product isolated from the New Zealand
sponge Chelonaplysilla violacea, leaving little doubt as to their
identity.6,27,30
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Scheme 2. Optimization of the Fragment Coupling Step and
Elaboration of the Coupled Product to the 6-Substituted cis-
2,8-Dioxabicyclo[3.3.0]octan-3-one 24.
Enantiopure 3ꢀchloroꢀ5ꢀalkoxybutenolide 19 was available by
the sequence outlined in Scheme 3.21 Palladiumꢀcatalyzed enantiꢀ
oselective hydroalkoxylation of Dꢀmentholꢀderived allene 26 with
allylic alcohol 25 by the general method of Rhee22 delivered aceꢀ
1
tal 27 in 99% yield as a single detectable diastereomer (by H
NMR analysis). Using the HoveydaꢀGrubbs secondꢀgeneration
catalyst, ringꢀclosing metathesis of 27 gave dihydrofuran 28 in
excellent yield on gramꢀscale.23 Allylic oxidation of 28 to yield
the corresponding butenolide not surprisingly was extremely chalꢀ
lenging. Under the best conditions defined to date,24 butenolide 19
was formed in 32% yield. The opposite enantiomer of butenolide
19 was readily accessible on gramꢀscale by the same sequence,
The key coupling step of an identical sequence to synthesize
the diastereomeric tetracyclic product 8 is summarized in Scheme
5. The slightly lower yield in the fragment coupling step (68%)
likely reflects a slight miss match in the addition of the tertiary
radical generated from alcohol 34 to butenolide 39. The relative
configuration of synthetic 8 was confirmed by singleꢀcrystal Xꢀ
ray analysis.27 Structure 8 originally had been assigned erroneousꢀ
ly to a diterpenoid isolated from a Chelonaplysilla sp. sponge
found in Palau and referred to as chelonoplysin B. This Palaun
marine isolate was shown later to be identical to cheloviolene A
(6).6b 1H and 13C NMR data for synthetic 8 were nearly identical
to those reported for cheloviolene B, which had been isolated
together with cheviolene A (6) and assigned on the basis of NMR
data to be the lactol epimer of 6. This original assignment is incorꢀ
rect and the structure of cheloviolene B should be revised to 8.
starting from
Lꢀmenthol and utilizing the R,R enantiomer of the
Trost ligand.25
Scheme 3. Synthesis of Enantiopure 3-Chloro-5-
Alkoxybutenolide 19.
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Scheme 4. Short Total Synthesis of (+)-Cheloviolene A (6) from (+)-Fenchone-Derived Cyclopentene Nitrile 29.
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10
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16
17
18
19
20
The synthesis of dendrillolide C (7) and its interconversion
equimolar amounts is the pivotal step of this synthetic strategy.
This sequence was exemplified by short syntheses of (+)ꢀ
cheloviolenes A and B and (+)ꢀdendrillolide C, which estabꢀ
lished the absolute configuration of these diterpenoid natural
products and corrected the structural assignment for chelovioꢀ
lene B. This rapid and versatile construction of the 6ꢀ
substituted-cisꢀ2,8ꢀdioxabicyclo[3.3.0]octanꢀ3ꢀones should aid
in future studies of biological activity of molecules harboring
this ring system.
with cheloviolene B (8) is summarized in Scheme 5. Reaction of
8 with 2.5 equiv of MsCl and excess Et3N in toluene at 90 °C
21
22
23
24
25
26
27
28
29
30
31
32
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1
provided (+)ꢀdendrillolide C (7) in 77% yield. H NMR data of
synthetic 7 were indistinguishable from that reported for the
diterpenoid isolated from the sponge Dendrilla sp. collected in
Palau.27,31 As the relative configuration of the stereogenic carꢀ
bons that join the two rings of cheloviolene B (8) are opposite to
that found in diterpenoids 4–6 and are opposite to that of the Cꢀ
8 and Cꢀ14 stereocenters of a spongian precursor, Faulkner had
suggested that structure 8 might arise by hydration of the enol
ether functionality of dendrillolide C (7).11 To test this hypotheꢀ
sis, synthetic dendrillolide C (7) was treated with various aqueꢀ
ous acids. Although it was stable to 2 M HCl in 1:1 THF/H2O at
room temperatuere, at 40 °C a 1.2:1 mixture of cheloviolene B
(8) and furan 41 was formed. 32
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization data, and CIF files
for Xꢀray structures of compounds 8 and 39. This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 5. Total Syntheses of (+)-Cheloviolene B (8) and (+)-
Dendrillolide C (7), and Stereoselective Hydration of Den-
drillolide C to Form Cheloviolene B.
AUTHOR INFORMATION
Corresponding Author
leoverma@uci.edu
Author Contributions
ζY.S. and C.R.J. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by the NSF (CHE1265964) and
by a graduate fellowship award to YS (1F31GM113494). J.L.’s
research at UC Irvine was supported by the National Research
Foundation of Korea (NRFꢀ2015R1A2A1A15056116). We
thank Dr. Michelle R. Garnsey and Kyle B. Schenthal for their
initial contributions to the project, and Materia for a gift of
HoveydaꢀGrubbs secondꢀgeneration olefin metathesis catalyst.
NMR and mass spectra were obtained at UC Irvine using inꢀ
strumentation acquired with the assistance of NSF and NIH
Shared Instrumentation grants.
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(30) The NMR spectra of (+)ꢀcheloviolene A isolated from Che-
lonaplysilla sp.,11 show the presence of several impurities
which we attribute to the discrepancy in the measured optiꢀ
cal rotations.
9
10
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12
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(31) Sullivan, B.; Faulkner, D. J. J. Org. Chem. 1984, 49, 3204–
3206.
(32) Protonation of the enol ether occurred (to the limits of deꢀ
tection by NMR) exclusively from the concave face of the
bicyclic enol ether. If this event is stereochemistry deterꢀ
mining, developing torsional interactions rather than steric
effects dictate the stereochemical outcome.33
(33) Houk, K. N.; PaddonꢀRow, M. N.; Rondan, N. G.; Wu, Y.ꢀ
D.; Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.;
Loncharich, R. J. Science 1986, 231, 1108–1117.
(15) The development of this chemistry with tertiary carboxylic
acid precursors will be described in a future publication.
(16) Nawrat, C. C.; Jamison, C. R.; Slutskyy, Y.; MacMillan, D.
W. C.; Overman, L. E. J. Am. Chem. Soc. 2015, 137,
11270−11273.
(17) (a) Feringa, B. L.; De Jong, J. C. J. Org. Chem. 1988, 53,
1125−1127. (b) Enantiopure samples of (R)ꢀ and (S)ꢀ
enantiomers can be purchased from Accel Pharmtech.
(18) (a) Moradei, O. M.; Paquette, L. A. Org. Synth. 2003, 80,
66−74. (b) Enantiopure samples of (R)ꢀ and (S)ꢀenantiomers
can be purchased from Proactive Molecular Research.
(19) Schnermann, M. J.; Overman L. E. Angew. Chem., Int. Ed.
2012, 51, 9576−9580.
(20) Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.; Steꢀ
phenson, C. R. J. Nat. Chem. 2012, 4, 854–859.
(21) Direct chlorination of 5ꢀalkoxybutenolides failed as a result
of the sensitive allylic acetal functionality leading to deꢀ
composition and racemization of the desired product.
(22) Lim, W.; Kim, J.; Rhee, Y. H. J. Am. Chem. Soc. 2014, 136,
13618–13621.
(23) Gatti, M.; Drinkel E.; Wu, L.; Pusteria, I.; Gaggia, F.;
Dorta, R. J. Am. Chem. Soc. 2010, 132, 15179–15181.
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