Total Synthesis of (-)-Chromodorolide B

Article abstract of DOI:10.1021/jacs.6b00541

The first total synthesis of a chromodorolide diterpenoid is described. The synthesis features a bimolecular radical addition/cyclization/fragmentation cascade that unites butenolide and trans-hydrindane fragments while fashioning two C-C bonds and stereoselectively forming three of the ten contiguous stereocenters of chromodorolide B.

Full text of DOI:10.1021/jacs.6b00541

Communication
pubs.acs.org/JACS
Total Synthesis of (−)-Chromodorolide B
Daniel J. Tao, Yuriy Slutskyy, and Larry E. Overman*
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, United States
S
* Supporting Information
analogues are of most interest for their potential effects on the
Golgi apparatus.5c We report herein the first total synthesis of a
ABSTRACT: The first total synthesis of a chromodor-
olide diterpenoid is described. The synthesis features a
chromodorolide, (−)-chromodorolide B (1), by a concise
bimolecular radical addition/cyclization/fragmentation
cascade that unites butenolide and trans-hydrindane
fragments while fashioning two C−C bonds and stereo-
selectively forming three of the ten contiguous stereo-
centers of chromodorolide B.
sequence that features a bimolecular radical addition/
cyclization/fragmentation (ACF) cascade.
We envisaged that the chromodorolides containing distinc-
tive dioxatricyclic fragments of both fused (1, 2, 3) and bridged
(4, 5) motifs could be accessible from a common tetracyclic
acid 9 (Scheme 1). In this analysis, the substituents at C-15 and
C-16 of acid 9 would be differentiated to allow selective
lactonization to construct either dioxatricyclic fragment.
Further simplification of acid 9 leads to intermediate 10 having
the C12 hydrocarbon and the highly oxidized fragment joined at
a vinylic carbon of the hydrophobic fragment.6 On the basis of
our recent experience showing that fragment couplings of
hromodorolides A−E (1−5), which contain 10 con-
C
tiguous stereocenters, are among the most structurally
complex members of the rearranged spongian diterpenoids
(Figure 1).1,2 They have been isolated from nudibranches in
Scheme 1
Figure 1. Chromodorolides and three structurally related rearranged
spongian diterpenoids that also contain 6-acetoxy-2,7-dioxabicyclo-
[3.2.1]octan-3-one (red) and 7-acetoxy-2,8-dioxabicyclo[3.3.0]octan-
3-one (blue) fragments.
the genus Chromodoris and the encrusting sponges on which
these nudibranches potentially feed. The 6-acetoxy-2,7-
dioxabicyclo[3.2.1]octan-3-one and 7-acetoxy-2,8-dioxabicyclo-
[3.3.0]octan-3-one rings embedded in the chromodorolides are
distinctive features of many rearranged spongian diterpenes
such as norrisolide (6),3 norrlandin (7),4 and aplyviolene (8).5
In the chromodorolides, these dioxabicyclic rings are appended
to an additional oxygenated cyclopentane ring. Although
modest in vitro antitumor, nematocidal, and antimicrobial
activities have been reported,1b,c,e the chromodorolides and
Received: January 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b00541
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
nucleophilic tertiary radicals with alkenes can be high
yielding,5b we envisioned a cascade sequence in which
trisubstituted carbon radical B, generated by visible-light
photoredox fragmentation of the N-acyloxyphthalimide sub-
stituent of intermediate 12,7 would couple with (R)-4-
methoxybutenolide (11)8 to generate α-acyloxy-radical inter-
mediate A, which was hoped would undergo intramolecular 5-
exo cyclization from a conformation such as A′ depicted in
Scheme 1 that minimizes destabilizing allylic A1,3 interactions.
The cascade would then be terminated by β-fragmentation of
the adjacent C−X (X = halide) bond to deliver the desired
coupled product 10.9 Essential for success of this proposed
sequence would be correctly setting the C-12 and C-13
stereocenters in the union of the two fragments to form
intermediate A. The desired configuration at C-13 was
anticipated from the radical addition to the butenolide
occurring preferentially from the face opposite the methoxy
substituent.10 Unclear at the outset was from which face radical
intermediate B would couple, as few C−C bond-forming
reactions of 2,2-dimethyl-1,3-dioxolane trisubstituted radicals
have been described and preferences for both syn and anti
addition have been reported.11 In an exploratory model study,
we confirmed that radical coupling at such a carbon would
preferentially occur from the desired face syn to the vicinal
substituent.12 Further simplification of intermediate 12 leads to
two readily available precursors: (S,S)-trimethylhydrindanone
133 and (R,R)-tartaric acid derived acetonide 14.
natively can be prepared in 98% ee on a large scale in two steps
from 2-methylcyclopentane-1,3-dione.15 Selective ketalization
of 15, stereoselective 1,2-reduction of the enone, and
methoxycarbonylation provided β-allylic carbonate 16 in 94%
overall yield. Palladium-catalyzed reductive transposition of the
allylic carbonate then gave trans-hydrindene ketal 17 in 77%
yield.16 Cyclopropanation of trisubstituted alkene 17 with
diethylzinc and chloroiodomethane,17 followed by acidic
workup, produced ketone 18. Subjection of cyclopropane 18
to hydrogenolysis conditions, followed by oxidation of the
resulting secondary alcohol, delivered trans-hydrindanone 13 in
88% yield over two steps. The seven-step sequence summarized
in Scheme 2 provides (S,S)-13 of high enantiomeric purity
(98% ee) on multigram scales in 59% overall yield from
enedione 15.
In six subsequent steps, hydrindanone 13 was elaborated to
radical coupling precursor 24. This sequence began by
conversion of ketone 13 to known vinyl iodide 19.3 The
other fragment, sensitive aldehyde 20, is accessible in three
steps from acetonide 14.12 A variety of standard conditions
were examined for the Nozaki−Hiyama−Kishi coupling of
iodide 19 with aldehyde 20;18 however, only low yields (<20%)
and modest diastereoselectivities (3:1) were observed. In
contrast, in the presence of (R)-sulfonamide ligand 21
introduced by Kishi,19 allylic alcohol 22 was obtained in 66%
yield as a single alcohol epimer. Saponification of the ester and
subsequent esterification with N-hydroxyphthalimide provided
crystalline ester 23 in 69% yield, whose structure was confirmed
by single-crystal X-ray analysis.20a Exposure of this intermediate
to thionyl chloride and pyridine at −45 °C in diethyl ether
mediated suprafacial allylic transposition21 to give crystalline
allylic chloride 2420b in 62% yield.
Although several enantioselective routes to trans-hydrinda-
none 13 have been reported,3,13 a readily scalable, efficient
synthesis had not been described. During our investigations,
such a route was developed (Scheme 2). This sequence began
with commercially available (S)-enedione 15,14 which alter-
We then examined the key ACF cascade that ideally would
set two new C−C bonds and four stereocenters of 1 in a single
step. Initial experiments employed conditions previously used
in the coupling of tertiary radicals with (R)-methoxybutenolide
11 (Scheme 3, entry 1).7b,10 Two products arising from the
ACF cascade sequence, 25 and 26, were isolated.22,23 Detailed
analysis of their NMR spectra showed that these products were
epimeric at C-8. Particularly diagnostic were 1H NOE
correlations between the C-8, C-17, and C-14 methine
hydrogens.12 Confirmation of the structures of these epimers
was obtained by eventual conversion of cascade product 25 to
(−)-chromodorolide B (vide infra). The third predominant
product retained the alkylidene chlorohydrindane fragment of
Scheme 2
1
precursor 24 and showed H NOE data consistent with a cis
relationship of the allylic hydrogen at C-17 and the
benzyloxymethyl substituent. Products 25−27 all arose from
coupling of the dioxolane radical with the chiral butenolide syn
to the vicinal hydrophobic fragment, with 27 resulting from
premature trapping of the α-acyl radical intermediate. ACF
product 25 derives from the 5-exo cyclization occurring in the
desired orientation as depicted in intermediate A′ (Scheme 1),
whereas epimer 26 arises from the cyclization taking place from
the alternate face of the alkylidene double bond. The fourth
product 28 is tentatively assigned as the C12 epimer of 27,24
which would arise from radical addition to the butenolide
occurring from the face of the 1,3-dioxolane anti to the vicinal
hydrophobic fragment.12
A number of experiments were conducted to minimize the
formation of byproduct 27 arising from premature quenching
of the coupled radical.12 Removal of i-Pr2EtN, which was
expected to minimize amine-mediated reduction of intermedi-
B
DOI: 10.1021/jacs.6b00541
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 3
ate A to its corresponding enolate,7b reduced formation of
byproduct 27 (entry 2). However, as intermediate A can also be
quenched by hydrogen-atom transfer from the Hantzsch
ester,7b this pathway also needed attenuation. Employing 4,4-
dideuterio Hantzsch ester in the absence of i-Pr2EtN (entry 3),
which was expected to minimize hydrogen-atom transfer to the
initially generated coupled radical, significantly decreased the
formation of product 27, increasing the combined yield of ACF
products 25 and 26 to a 70% yield. Attempts thus far to
improve the ratio of epimeric products 25/26 have been less
successful.12 This ratio was slightly improved in reactions
conducted in acetonitrile (entry 4), allowing product 25 to be
oxidized to carboxylic acid 30, which upon exposure to 4 M
HCl in THF at room temperature underwent acetonide
deprotection and lactonization to form lactol 31. Exhaustive
acetylation of this triol gave (−)-chromodorolide B (1), [α]D =
−66.8 (c = 0.12, CH2Cl2), in 49% overall yield from
1
intermediate 29. This product showed H and 13C NMR data
and optical rotation in close accord to those reported for a
natural sample.1b,c In addition, synthetic 1 provided single
crystals, which allowed the structure of chromodorolide B to be
unambiguously confirmed by X-ray analysis.20c
In summary, the enantioselective total synthesis of
(−)-chromodorolide B (1) was completed in 21 steps and
1.2% overall yield from commercially available enedione 15. An
unprecedented photoredox radical cascade reaction allowed
butenolide and trans-hydrindane fragments to be combined
while forming two C−C bonds and stereoselectively creating
three of the ten contiguous stereocenters of 1. As with almost
all first total syntheses of a unique and structurally complex
natural product, several aspects of the synthetic route can be
improved upon. Toward this end, our current efforts focus on
discovering the origins of diastereoselectivity of both Csp3−
Csp3 bond-forming steps in the radical cascade and improving
the diastereoselectivity of the 5-exo cyclization step.
1
formed in 28% yield (by H NMR with internal standard) and
isolated in 27% yield.
As summarized in Scheme 4, cascade product 25 was readily
transformed to (−)-chromodorolide B (1). Reduction of the
Scheme 4
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b00541.
■
S
Experimental details; NMR data (PDF)
Crystallographic data for 1 (CIF)
Crystallographic data for 23 (CIF)
Crystallographic data for 24 (CIF)
Crystallographic data for S4 (CIF)
AUTHOR INFORMATION
Corresponding Author
*leoverma@uci.edu
■
lactone carbonyl of 25 with (i-Bu)2AlH at −78 °C and in situ
acetylation with Ac2O and DMAP afforded the acetoxy acetal as
a single epimer at C-15. H NOE correlations between the C-
1
Notes
The authors declare no competing financial interest.
17 and C-15 methine hydrogens revealed that the acetoxy
group was oriented α.25 Following removal of the benzyl
protecting group, the trisubstituted double bond was hydro-
genated selectively (dr >20:1) from the face opposite the
angular methyl group to yield product 29 in 68% overall yield
from 25. Without purifying subsequent intermediates, 29 was
ACKNOWLEDGMENTS
■
Financial support was provided by the National Institute of
General Medical Sciences by Research Grant R01GM098601
and a graduate fellowship award to Y.S. (1F31GM113494).
C
DOI: 10.1021/jacs.6b00541
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Journal of the American Chemical Society
Communication
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NMR and mass spectra were determined at UC Irvine using
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D
DOI: 10.1021/jacs.6b00541
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX