Concise enantiospecific total synthesis of tubingensin A

Article abstract of DOI:10.1021/ja501142e

We report the enantiospecific total synthesis of (+)-tubingensin A. Our synthesis features an aryne cyclization to efficiently introduce the vicinal quaternary stereocenters of the natural product and proceeds in only nine steps (longest linear sequence) from known compounds.

Full text of DOI:10.1021/ja501142e

Communication
pubs.acs.org/JACS
Concise Enantiospecific Total Synthesis of Tubingensin A
Adam E. Goetz,† Amanda L. Silberstein,† Michael A. Corsello, and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
experiments,9 their use in the assembly of sterically congested
linkages is limited.10 Furthermore, to our knowledge, arynes
have not previously been employed for the introduction of
vicinal quaternary stereocenters. In this Communication, we
report the use of a late-stage carbazolyne cyclization to
efficiently construct the tubingensin A framework. Our
approach not only demonstrates that arynes can be used for
the assembly of challenging molecular scaffolds but also
provides (+)-1 in just nine steps (longest linear sequence)
from known compounds.
ABSTRACT: We report the enantiospecific total syn-
thesis of (+)-tubingensin A. Our synthesis features an
aryne cyclization to efficiently introduce the vicinal
quaternary stereocenters of the natural product and
proceeds in only nine steps (longest linear sequence)
from known compounds.
arbazole-containing natural products have long provided a
C
fruitful area for scientific discovery.1 The complex alkaloid
tubingensin A (1)2 and its structural isomer tubingensin B (2)3
are members of this class that were isolated from the fungus
Aspergillus tubingensis by Gloer and co-workers in 1989 (Figure
1). Compounds 1 and 2 are both postulated to arise
Our retrosynthetic analysis for the synthesis of tubingensin A
(1) is shown in Scheme 1. It was envisioned that the natural
Scheme 1
Figure 1. Tubingensin A (1) and related family members 2 and 3.
biosynthetically from the indole diterpenoid anominine (3)4
and have been shown to display antiviral, anticancer, and
insecticidal activity.2,3 Structurally, tubingensin A (1) possesses
a disubstituted carbazole that is fused to a densely function-
alized cis-decalin framework.5 Moreover, the decalin core
contains four contiguous stereocenters, two of which are
vicinal quaternary centers. With regard to synthetic efforts
toward tubingensin A (1), Bonjoch and co-workers reported an
approach to assemble the natural product’s scaffold,6 and Li and
Nicolaou recently completed an elegant bio-inspired total
synthesis of 1 that proceeds in 23 linear steps from a cyclohexyl
precursor.4a
Given our interest in assembling congested scaffolds using
heterocyclic aryne intermediates,7,8 we questioned if the vicinal
quaternary stereocenters of tubingensin A (1) could be
introduced using aryne cyclization methodology. Although
arynes have been used in an array of interesting trapping
product would arise by late-stage reduction of ketone 4. This
intermediate could be constructed through a key carbazolyne11
cyclization (see transition structure 5). If successful, this
transformation would fashion the challenging vicinal quaternary
stereocenters and provide the cis-decalin framework of the
natural product. Ketone 6, the precursor to potential
carbazolyne cyclization substrates, would ultimately arise from
the coupling of two simple fragments, cyclohexyl derivative 7
and carbazole triflate 8.
The key coupling partners were prepared in a straightforward
manner (Figure 2). Commercially available hydroxycarbazole 9
was brominated using a known procedure.12 Subsequent O-
triflation and N-protection afforded 8 in 61% yield over three
Received: February 4, 2014
Published: February 14, 2014
© 2014 American Chemical Society
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Scheme 3
Figure 2. Synthesis of carbazole and cyclohexyl fragments.
steps. The synthesis of cyclohexyl fragment 7 began from
commercially available (+)-dihydrocarvone (10), which was
elaborated to enone 11 using a known three-step procedure.13
Vinyl cuprate addition and trapping of the resulting enolate
furnished silyl enol ether 7 as a single diastereomer.14
With cyclohexyl fragment 7 and carbazole triflate 8 in hand,
we pursued their coupling and the ensuing carbazolyne
cyclization (Scheme 2). Treatment of 7 with 9-BBN15 led to
enone 13 with LiHMDS and Eschenmoser’s salt led to C20
alkylation.23 Exposure of the crude adduct to mCPBA furnished
enone 16.24 Addition of prenylcuprate23 provided 17 as an
inconsequential mixture of diastereomers. Unfortunately,
attempts to effect the carbazolyne cyclization of substrate 17
were unsuccessful. Analysis of the major product suggested that
a skeletal rearrangement had occurred, rather than the desired
formation of 18.
Scheme 2
To identify the skeletal rearrangement product, we prepared
the simpler C20 methylated substrate 19 and exposed it to
aryne cyclization conditions (Scheme 4). The major product
Scheme 4
chemoselective hydroboration of the terminal olefin. Sub-
sequent Pd-catalyzed cross-coupling16 with 8 proceeded
smoothly to generate coupled product 12. Addition of TBAF
to the reaction mixture then delivered ketone 6. The highly
optimized conversion of 7 and 8 to 6 in one pot17 provides a
rare example of a silyl enol ether being employed as a ketone
protecting group in a complex setting.14,18 To control
regioselectivity of enolate formation in the forthcoming
carbazolyne cyclization,19 ketone 6 was oxidized to enone 13
using IBX and NMO.20 To our delight, exposure of enone 13
to NaNH2 and t-BuOH in THF8c,21 facilitated the desired
cyclization and afforded C20-epimeric products 14 and 15 in
44% combined yield (1:2.3 ratio). We hypothesize that 14
forms kinetically as the major product but is prone to
epimerization under the reaction conditions.22
obtained was analogous to that formed in the attempted
cyclization of 17. Interestingly, although the desired C11−C20
linkage was intact, a bond was unexpectedly formed between
the carbazole and C19. In addition, the C15−C16 and C19−
C20 linkages had been severed. 2D NMR analysis eventually
revealed the rearranged structure to be compound 20. We
propose that the desired enolate−carbazolyne intermediate
indeed undergoes cyclization, but the resulting anion cyclizes
onto C19, analogous to C−C aryne insertion reactions of 1,3-
dicarbonyls (see transition structure 21).10e,25 A subsequent
retro-Diels−Alder reaction, as shown in transition structure 22,
and protonation yield 20.
Having demonstrated the feasibility of the carbazolyne
cyclization, we next prepared a C20-substituted substrate to
test if the method could be used to forge the critical vicinal
quaternary stereocenters (Scheme 3). Sequential treatment of
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Journal of the American Chemical Society
Communication
Scheme 5
As the attempted cyclization indeed led to the desired C11−
C20 bond formation, we postulated that a modified substrate
might be more likely to undergo the desired transformation
without rearrangement. Specifically, we envisioned that a
substrate lacking the alkene in the six-membered ring could
not suffer from the retro [4+2] cycloaddition and would thus
not be prone to cyclohexyl ring fragmentation.26 Therefore, we
elected to prepare enol ether 26 (Scheme 5). In contrast to
enone substrates 13 and 17, the selectivity for C20 enolate
formation for the critical carbazolyne cyclization would be
dictated by the controlled formation of 26 as a single enol ether
isomer.
cyclization to efficiently introduce the vicinal quaternary
stereocenters of the natural product and proceeds in only
nine steps (longest linear sequence) from known compounds.
Further efforts to probe the use of arynes for the assembly of
challenging molecular scaffolds are currently underway in our
laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, compound characterization,
and crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
The design and synthesis of substrate 26 ultimately proved
fruitful and enabled an efficient enantiospecific total synthesis
of tubingensin A (1), which is summarized in Scheme 5.27 Vinyl
cuprate addition to enone 11, followed by trapping with Me2(i-
Pr)SiCl (DMIPSCl), gave enol ether 23. Next, a one-pot
hydroboration/Suzuki coupling (analogous to that described
previously) afforded the desired coupled product 24 in 64%
yield. Using the labile DMIPS enol ether, enone 25 was
generated via a two-step sequence.28 Subsequent cuprate
addition and trapping with TESCl supplied aryne cyclization
precursor 26. Fortuitously, in the key step, aryne cyclization
delivered the desired product 28 in 84% yield and established
the vicinal quaternary centers with complete diastereoselectiv-
ity. The structure of 28 was verified by X-ray crystallography.
Only two steps remained to complete the total synthesis: N-
deprotection and ketone reduction. The removal of the MOM
group of 28 provided ketone 4 smoothly. However, reduction
proved more challenging. An array of reducing agents were
examined, all of which gave the undesired C19 epimer as the
major product.29 The best conditions using Na/i-PrOH
delivered a 1:2 ratio of tubingensin A (1) and its C19 epimer.
It should be noted that oxidation of epi-1 gives 4, so the
undesired epimer can be readily recycled.30 Nonetheless,
synthetic (+)-1 was found to be identical to an authentic
sample in all respects.
AUTHOR INFORMATION
■
Corresponding Author
neilgarg@chem.ucla.edu
Author Contributions
†A.E.G. and A.L.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the NIH-NIGMS (R01
GM090007), Boehringer Ingelheim, DuPont, Eli Lilly,
Amgen, AstraZeneca, Roche, Bristol-Myers Squibb, the A. P.
Sloan Foundation, the Dreyfus Foundation, the S.T. Li
Foundation, UCLA, the NSF (M.A.C., DGE-1144087), the
ACS Division of Organic Chemistry (A.E.G.), UCLA DYF
program (A.E.G.), and the Foote Family (A.E.G. and A.L.S.)
for financial support. We thank Steven Loskot for experimental
assistance, the Garcia-Garibay laboratory (UCLA) for access to
instrumentation, Dr. Saeed Khan (UCLA) for X-ray analysis,
and Professor Gloer (University of Iowa) for an authentic
sample of tubingensin A. These studies were supported by
shared instrumentation grants from the NSF (CHE-1048804)
and the National Center for Research Resources
(S10RR025631).
In summary, we have achieved a concise enantiospecific total
synthesis of tubingensin A (1). Our synthesis features an aryne
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Communication
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