Approach to the Synthesis of Briarane Diterpenes through a Dianionic Claisen Rearrangement and Ring-Closing Metathesis

Article abstract of DOI:10.1021/acs.orglett.7b01806

The synthesis of the briarane-brianthein A core has been accomplished utilizing an extension of the dianionic Ireland-Claisen rearrangement to establish the C1 quaternary carbon and the adjacent C10 ring juncture stereocenters. Two sequential ring-closing metathesis reactions were exploited to construct the 6-10 trans fused ring system.

Full text of DOI:10.1021/acs.orglett.7b01806

Letter
pubs.acs.org/OrgLett
Approach to the Synthesis of Briarane Diterpenes through a
Dianionic Claisen Rearrangement and Ring-Closing Metathesis
Michael T. Crimmins,* Yan Zhang,† and Philip S. Williams‡
Kenan, Caudill, Venable, and Murray Laboratories of Chemistry University of North Carolina at Chapel Hill, Chapel Hill, North
Carolina 27599, United States
S
* Supporting Information
ABSTRACT: The synthesis of the briarane−brianthein A core has been accomplished utilizing an extension of the dianionic
Ireland−Claisen rearrangement to establish the C1 quaternary carbon and the adjacent C10 ring juncture stereocenters. Two
sequential ring-closing metathesis reactions were exploited to construct the 6−10 trans fused ring system.
Scheme 1. Proposed Retrosynthesis of Brianthein A
he briarane diterpenes are a class of highly oxygenated
Tmarine metabolites that contain a modified cembranoid
skeleton.1 In the context of a broader program directed toward
the synthesis of marine natural products,2,3 we were attracted to
the briaranes because of their unique structural features and
intrigued by the relative lack of activity reported toward their
synthesis.4−9 Examination of the core carbocyclic structure of
the briaranes reveals a trans-fused 6,10 carbon skeleton with an
angular methyl group completing the substitution of a
quaternary carbon at the ring fusion. The quaternary carbon
center at the ring fusion and the 10-membered carbocyclic ring
were of particular interest due to the paucity of general
methods available for their construction.10,11 Reported herein is
an approach to the construction of the briarane skeleton
focused toward the synthesis of brianthein A.
Of the multitude of briaranes that have been isolated and
identified, brianthein A was chosen as an initial target because
its carbocyclic skeleton possessed a relatively low level of
oxygenation for a briarane but retained the interesting 6,10-
fused carbocycle and the ring juncture quaternary stereocenter.
The biological profile of brianthein was also of interest since it
has been shown to reverse multidrug resistance (MDR) in
human carcinoma cell lines, KB-C2, overexpressing P-
glycoprotein.12
Our retrosynthetic plan for the synthesis of brianthein A (1)
is illustrated in Scheme 1. Strategically, we anticipated
appending the butenolide at a late stage to a core 6,10-
carbocycle 2 that contained the remaining structural features of
the molecule. The 6,10 bicycle 2 would be constructed by two
sequential ring-closing metathesis (RCM) reactions. RCM of
triene 4 would provide a cyclohexene which would be modified
to triene 3, the substrate for the RCM closure of the
cyclodecene. The required ring fusion stereochemistry,
including the quaternary carbon center, would be set by a
dianionic Ireland−Claisen rearrangement of hydroxy ester 5,
which could be prepared through a diastereoselective
thiazolidinethione mediated aldol addition.
We recently reported the development of the pivotal
dianionic Ireland−Claisen rearrangement,13 a modification of
the classic Ireland−Claisen rearrangement of an allylic ester
enolate that was initially disclosed by Kurth and co-work-
ers.14,15
The Kurth method was extended to the construction of
quaternary carbon centers by combining our thiazolidinethione
mediated propionate aldol reaction16 with the dianionic
Ireland−Claisen rearrangement as shown in Scheme 2. The
“Evans” syn propionate aldol adduct of N-propionylthiazolidi-
nethione 6 proceeded in high yield and diastereoselectivity to
give the aldol adducts 7. Nucleophilic displacement of the chiral
Received: June 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01806
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Letter
imidazole with catalytic DMAP afforded ester 5 in 88% yield,
poised for the dianionic Ireland−Claisen rearrangement. The
hydroxyester 5 was treated under the optimized conditions
from the dianionic Ireland−Claisen studies and the resultant
acid was esterified with diazomethane to provide ester 16 as the
only detectable isomer (500 MHz NMR) in 72% yield. This
reaction successfully established the two contiguous stereo-
centers that would constitute the ring juncture for the briarane
core, including the quaternary carbon C1.
Scheme 2. Dianionic Ireland−Claisen Rearrangement
Transformation of ester 16 to the briarane core would
require closure of the 6- and 10-membered rings19 by
sequential ring-closing metathesis reactions. The additional
olefinic functionality needed to construct the 6-membered ring
was incorporated as shown in Scheme 3. Protection of the C2-
free alcohol 16 as the TBS ether and reduction of the ester
afforded alcohol 17 in 90% yield. Swern oxidation18 of alcohol
17 provided the aldehyde, which was treated with allylmagne-
sium bromide to afford a 1:1 mixture of diastereomers 4S/4R in
84% yield. The S isomer could be recycled to the R
diastereomer (or conversely the R isomer could be recycled
to the S diastereomer) through an oxidation−reduction−
recycle process since the isomeric alcohols were readily
separable by chromatography. Attempts to set the C14
stereocenter in a more efficient manner with chiral allylating
agents were unsuccessful. Further investigations focused on
alcohol 4S with the natural S-stereochemistry at C14. Exposure
of 4S to the Grubbs second-generation catalyst20 in toluene at
110 °C provided the cyclohexene triol 18 in 80% yield for two
steps after removal of the silyl ethers. Selective protection of the
1,3-diol as the acetonide afforded the primary alcohol 19 which
was oxidized under Swern conditions.18 The resultant aldehyde
was treated with allylmagnesium bromide to produce an 86%
yield of a mixture of C8 alcohols 20 poised for the ring closure
to the 10-membered ring. When triene 20 was treated with
auxiliary under mild conditions with a variety of allylic alcohols
produced the allylic esters 8 necessary for the dianionic
Ireland−Claisen rearrangement study. The β-hydroxy allylic
esters 8 were exposed to excess base LiN(SiMe3)2 in toluene
with 4 equiv of THF and then warmed to room temperature.
Excellent diastereoselectivity (ranging from 6:1 to >20:1) was
observed.13
The application of the dianionic Claisen rearrangement to
the construction of the carbocyclic core of brianthein A is
presented here. The preparation of the hydroxyester 5 required
for the strategic rearrangement is shown in Scheme 3. The
requisite aldehyde 13, needed for the initial aldol addition, was
prepared from glycolyloxazolidinone 11. Diastereoselective
alkylation17 of the sodium enolate of glycolate 11 followed by
reductive removal of the auxiliary afforded primary alcohol 12
(77% overall). Alcohol 12 was oxidized to the aldehyde under
Swern conditions,18 and the aldehyde was used directly in an
aldol addition with the chlorotitanium enolate of thiazolidine-
thione 6 to deliver the aldol adduct 14 (91% yield, > 20:1 dr; 2
steps). Exposure of aldol 14 to alcohol 15 in the presence of
Scheme 3. Synthesis of the Cyclohexene Core of Brianthein A
B
DOI: 10.1021/acs.orglett.7b01806
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Letter
Grubbs second-generation catalyst in benzene at 80 °C no
closure to the 10-membered ring was observed (Scheme 4).
be successful. Consequently, preparation of the acetonide 3 was
pursued to investigate its behavior in an RCM reaction to form
the 10-membered ring.
The C14 R diastereomer 3 was prepared in an analogous
fashion to acetonide 20 (Scheme 5). Triene 4R readily formed
the cyclohexene 18 upon treatment with the Grubbs G2
catalyst followed by global desilylation. Exposure of triol 18 to
dimethoxypropane and p-TsOH selectively formed the C2−
C14 acetonide 19 in 89% yield. The stereochemistry of 19, and
therefore, the stereochemistry at C2, C10, C14, and C15 was
determined by X-ray analysis. Oxidation of the primary alcohol
under Swern conditions18 with subsequent addition of
allylmagnesium bromide to the resultant aldehyde delivered a
1:1 mixture of alcohols 3 in 84% yield. The alcohols were
separable and could be interconverted by oxidation reduction
(1, Swern; 2, DiBAl-H), and only one diastereomer was carried
forward for convenience of analysis. Upon conversion of the
secondary alcohol to its corresponding acetate, it was gratifying
to observe that exposure of the triene acetate to Grubbs G2
catalyst20 in degassed toluene at reflux for 15 min produced the
desired 6,10-fused bicyclic core structure 21 of brianthein A in
>90% yield.
Scheme 4. Attempted RCM of C14 S isomer
Additionally, various combinations of protecting groups at C2,
C8, and C14 without cyclic constraints at C2−C14 (e.g., TBS,
Ac, as well as free OH groups) were explored for the C14 S
configuration 20, but none of the desired RCM product could
be detected with any of the protecting group combinations.
Analysis of the conformational preferences of the acetonides
20 and 3 (Figure 1) indicated that the conformations needed
With the core structure of the briaranes constructed, it
remained to invert the C14 stereocenter and append the
butenolide to complete the synthesis of brianthein A. Beginning
with the bicycle 21, deprotection of the acetonide under acidic
conditions resulted in partial cleavage of the acetate; however, a
60% yield of the hydroxyacetate 22 was achieved after two
recycles (Scheme 5). Oxidation of the p-methoxybenzyl ether
resulted in trapping by the neighboring free alcohol to afford
the p-methoxyphenyl acetal 23 as a single diastereomer (92%
brsm). Inversion of the free alcohol proceeded in an 8:1 dr via a
Dess−Martin oxidation21 to ketone 24 followed by a R-CBS
reduction to give the C14 S diastereomer 25.22
Figure 1. Conformations of acetonides 20 and 3.
for the two alkene chains to undergo ring closure were not
energetically favorable. In contrast, the unnatural R config-
uration of the C14 carbinol center provides a better
opportunity to restrict the entropy of the pendant alkene
chains and place them proximal for ring-closing metathesis to
Our end-game strategy involved conversion of the C8
carbinol to a carbonyl as a handle to incorporate the butenolide.
To that end, the C14 S diastereomer 25 was protected as the
TES ether, whereupon deprotection of the acetate with
potassium carbonate and methanol followed by Dess−Martin
Scheme 5. Completion of the Brianthein A Skeleton
C
DOI: 10.1021/acs.orglett.7b01806
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Letter
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oxidation smoothly delivered ketone 26 in 86% yield (two
steps). While selective deprotonation at the C7 position
(supported by deuterium quenching studies) with LHMDS
followed by oxidation of the enolate with the chiral
camphorsulfonyl oxaziridine23 afforded an α-hydroxyketone in
good yield, further elaboration to brianthein A through
standard butenolide synthesis strategies have been unsuccessful
to date.24
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In conclusion, we have demonstrated the utility of the
dianionic Ireland−Claisen rearrangement in the construction of
quaternary carbon stereocenters and applied this method to the
synthesis of the brianthein A core. Additionally, the synthesis of
the 10-membered ring via ring-closing metathesis was achieved
through the use of strategically engineered conformational
restraints.
(13) Crimmins, M. T.; Knight, J. D.; Williams, P. S.; Zhang, Y. Org.
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Org. Chem. 2001, 66, 894. Crimmins, M. T.; Chaudhary, K. Org. Lett.
2000, 2, 775.
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(18) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01806.
■
S
Experimental procedures and full characterization data
for all compounds (PDF)
(20) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
AUTHOR INFORMATION
■
(21) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(22) (a) Corey, E. J.; Bakshi, K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551−5553. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed.
1998, 37, 1986−2012.
(23) (a) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org. Synth.
1987, 66, 203. (b) Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal,
S.; Reddy, T. J. Org. Chem. 1988, 53, 2087.
Corresponding Author
*E-mail: crimmins@email.unc.edu.
ORCID
Michael T. Crimmins: 0000-0003-0313-6010
Present Addresses
†(Y.Z.) Idexx Laboratories, One Idexx Dr, Westbrook, ME
(24) Boukouvalas, J.; Loach, R. P. J. Org. Chem. 2008, 73, 8109 and
references cited therein.
04092.
‡(P.S.W.) BASF, 26 Davis Dr, Research Triangle Park, NC
27709.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the National Institute of General
Medical Sciences (GM60567) is gratefully acknowledged.
■
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D
DOI: 10.1021/acs.orglett.7b01806
Org. Lett. XXXX, XXX, XXX−XXX