A convergent total synthesis of (±)-γ-rubromycin

Article abstract of DOI:10.1021/ja1115524

An expeditious convergent total synthesis affords (±)-γ- rubromycin (1) in 4.4% overall yield. The longest linear sequence is 12 steps from commercial starting materials. The effort highlights a remarkable late-stage oxidative [3 + 2] cycloaddition for co

Full text of DOI:10.1021/ja1115524

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A Convergent Total Synthesis of (()-γ-Rubromycin
Kun-Liang Wu, Eduardo V. Mercado,† and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106-9510, United States
S Supporting Information
b
ABSTRACT: An expeditious convergent total synthesis
affords (()-γ-rubromycin (1) in 4.4% overall yield. The
longest linear sequence is 12 steps from commercial starting
materials. The effort highlights a remarkable late-stage
oxidative [3 þ 2] cycloaddition for construction of the
spiroketal, a regioselective carbonyl methylenation, a boron
tribromide promoted deprotection, ortho- to para- naphtho-
quinone spiroketal rearrangement, and a tautomerization
sequence.
Figure 1. Selected members of the rubromycin family.
he rubromycins represent a small growing family of natural
products (1ꢀ4) comprised of a densely oxygenated naph-
T
Scheme 1. Synthetic Analysis of γ-Rubromycin (1)
thoquinone moiety linked with an isocoumarin fragment
(Figure 1).1 Other structurally related compounds include the
griseorhodins, DK-7814, purpuromycin, and heliquinomycin.2
These natural products have been shown to display a broad
spectrum of assorted bioactivities.3 In the rubromycin series,
studies have revealed that γ-rubromycin (1) and β-rubromycin
(3), which are conjoined through an optically active [5,6]-
aryloxy spiroketal, all manifest strong inhibition of human
telomerase (IC50 g 3 μM). In contrast, R-rubromycin (4),
which is missing the [5,6]-aryloxy spiroketal, appears inactive
(IC50 > 200 μM). This contrasting profile of biological activity
led Hayashi to propose the [5,6]-spiroketal moiety as the motif
responsible for telomerase inhibition.4
Accordingly, the rubromycins and the related structures have
attracted intensive synthetic interests over the past several
decades,5 culminating first in the total synthesis of the aglycone
of (()-heliquinomycin by Danishefsky in 20016 and, more
recently, in a total and a formal synthesis of (()-γ-rubromycin
(1) by Kita7 and Brimble,8 respectively. However, to the best of
our knowledge the [5,6]-spiroketal core has never been installed
at a late stage with the fully intact naphthoquinone and iso-
coumarin subunits. The problem surrounding thermodynamic
ketalization of the fully elaborated core structure was initially
recognized by Kozlowoski5e and later substantiated and named
by Reissig9 as the “Negative Mesomeric & Inductive effects” (M&I
effects). The cause principally stems from the electron-withdraw-
ing nature of the isocoumarin moiety, which dramatically
diminishes the nucleophilicity of the corresponding phenol
moiety.
highly functionalized coupling partners was largely untested.
Herein, we report its application for a concise synthesis of
γ-rubromycin (1). The strategy provides convergent synthetic
access to all members of the rubromycin family. The general
synthetic analysis is depicted in Scheme 1. We aimed to assemble
the entire [5,6]-spiroketal core through a late-stage [3 þ 2]
cycloaddition between the fully mature naphthoquinone 5 and
the methylenated chroman 6. The naphthoquinone 5 would
originate from R-tetralone 7, whereas the chroman 6 could be
prepared from Reissig benzaldehyde 8 by sequential Heck,
HornerꢀWadsworthꢀEmmons, and Petasis reactions.
Our synthesis begins with the preparation of the naphthoqui-
none 5, a compound first synthesized by Thomson.11 In our
initial approach, the R-tetralone 712 was prepared in three steps
from commercially available 1,2,4-trimethoxybenzene. Further
application of oxidative procedures resulted in the corresponding
Our laboratory recently disclosed a facile method for oxidative
[3 þ 2] cycloadditions between β-diketones and exocyclic enol
ethers as a means for fashioning [5,6]-spiroketal frameworks, and
we described for the first time a facile rearrangement between
ortho- and para-quinone spiroketals.10 However, its tolerance of
Received: December 22, 2010
Published: March 31, 2011
r
2011 American Chemical Society
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Scheme 2. Synthesis of Naphthoquinone5 fromR-Tetralone 7
Scheme 4. Conclusion of the Total Synthesis of (()-γ-Ru-
bromycin (1)
(a) LiHMDS (2.4 equiv), THF, ꢀ78 °C, then NBS (2.06 equiv); DBU
(1.23 equiv), ꢀ78 °C to rt, 78% yield. (b) CAN (2.14 equiv), MeCN/
H2O, 0 °C, 60% yield. (c) NaN3 (1.46 equiv), THF/H2O, rt. (d) CsCO3
(1.5 equiv) PhCH3/MeOH, rt, 65% yield for 2 steps. (e) KOH (21.4
equiv), MeOH/H2O, 84% yield.
Scheme 3. Preparation of Methylenated Isocoumarin 6
corresponding E-unsaturated ester, which succumbs to catalytic
hydrogenation to afford the saturated ester 12 in 87% overall
yield. Subsequent acid-promoted lactonization provides the
dihydrocoumarin 13 in 82% yield. The aldehyde in this material
undergoes a HornerꢀWadsworthꢀEmmons reaction with
Thompson’s phosphonate 14 to afford the unsaturated triester
15 as a 6:1 mixture of E/Z isomers.18 Interestingly, the dihy-
drocoumarin carbonyl in compound 15 undergoes selective
methylenation upon treatment with the Petasis reagent to cleanly
afford the exocyclic enol ether 16 as an 8:1 mixture of E/Z
isomers.19 Further treatment of the silyl enol ether of compound
16 with tert-butyl ammonium fluoride (TBAF) causes sequential
deprotection and cyclization to furnish the desired methylenated
isocoumarin 6 in 94% yield.
Having successfully prepared both the naphthoquinone 5 and
the isocoumarin 6, we were eager to implement the key bond-
forming reaction (Scheme 4). Coupling of 5 and 6 in the
presence of CAN in THF at room temperature affords a
nonequilibrating10b separable 1:2 mixture of regioisomers in
58% combined yield (o-naphthoquinone spiroketal 17 and
p-naphthoquinone spiroketal 18, respectively). From a synthetic
perspective, the [3 þ 2] oxidative cycloaddition fashions the
most challenging aspect of the framework of γ-rubromycin (1) in
a single step. Given the success of this unprecedented strategy,
we next investigated the individual deprotection of each of the
valence tautomers. Gratifyingly, exposure of the p-naphthoqui-
none spiroketal 18 to an excess of boron tribromide (BBr3) in
CH2Cl2 (ꢀ78 to ꢀ20 °C) expectedly provides synthetic (()-γ-
rubromycin (1), in a respectable 61% yield. This material is
indistinguishable from an authentic natural sample (1H NMR,
IR, TLC).19
(a) Pd(OAc)2, PPh3, methyl acrylate (1.9 equiv), LiCl, NEt3 (1.81
equiv), DMF, 80 °C, 93% yield. (b) H2 (1 atm), Pd/C, EtOAc, 94%
yield. (c) p-TsOH (cat.), PhMe, reflux, 82% yield. (d) 14 (1.03 equiv),
LiHMDS (1.0 equiv), THF, ꢀ78 °C, then 13 (1.0 equiv), 60% yield,
E/Z = 6/1. (e) CpTiMe2 (2.19 equiv), PhMe, 70 °C, 72% yield, E/Z =
8/1. (f) TBAF (1.03 equiv), THF, ꢀ78 °C, 94% yield.
naphthoquinone 5, but in a manner not easily scaled.13,10d
Hence, we turned our attention toward exploration of an
alternative route (Scheme 2). Functionalization of the R-tetra-
lone 7 using Nicolaou’s sequential bromination method provided
the desired bromophenol intermediate,14 which was then sub-
jected to cerium ammonium nitrate (CAN) oxidation to provide
the bromonaphthoquinone 9 in 47% overall yield from 7.15
According to an unusual leaving group effect, previously de-
scribed by Anufriev16 and subsequently utilized by Brimble,8 the
vinyl bromide 9 was reformulated into its azide 10 for subsequent
displacement. The azide 10 was then subjected to methanol in
cesium carbonate thereby resulting in the regioselective forma-
tion of the methyl ether 11 in a 65% yield. Subsequent saponi-
fication of the vinylogous ester with potassium hydroxide affords
the desired naphthoquinone 5 in 84% yield. The naphthoqui-
none 5 displays a β-diketone of sorts ready for examination in the
key oxidative [3 þ 2] cycloaddition.
We next considered the application of protic conditions with
the o-naphthoquinone ketal 17, as previously used by Kita to
catalyze a similar rearrangement for a simplified albeit related
system.7 To our surprise, all attempts to induce rearrangement
on 17 with acid were unsuccessful and they resulted in un-
changed starting material. Upon subjection of compound 17 to
an excess of BBr3 in CH2Cl2 (ꢀ78 to ꢀ20 °C), however, the
o-napthoquinone spiroketal 17 cleanly provides γ-rubromycin
(1) in greater than 50% yield. Although the exact timing of
demethylation(s) within this sequence remains unclear, this
The preparation of the other coupling partner, the fully elabo-
rated isocoumarin 6, was much more challenging (Scheme 3).7
After considering several new strategies, we decided to begin with
Reissig’s aldehyde 8, which was prepared in four steps and 42%
overall yield from vanillin according to literature protocol.17
Heck reaction of its aryl iodide with methyl acrylate affords the
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COMMUNICATION
Scheme 5. tris-Deprotection/ortho- to para-Naphthoqui-
none Spiroketal Rearrangement/Tautomerization
formative role at UCSB. E.V.M. greatly appreciates support
provided by the ACS Division of Organic Chemistry (SURF)
and the Pfizer-La Jolla (AIR Diversity Research Fellowship)
administered by Indrawan McAlpine and Ron Lewis (II), as well
as the Ronald E. McNair Scholars Program at UCSB.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures,
b
structural proofs, and full spectral data for all new compounds
are provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
pettus@chem.ucsb.edu
Notes
†Undergraduate research participant, UCSB.
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’ ACKNOWLEDGMENT
T.R.R.P. is very grateful that the early efforts were supported
by a National Science Foundation Early Career Award
(0135031), and subsequent research efforts have been supported
by a National Science Foundation award (0806356). K.-L.W. is
appreciative of a dissertation fellowship granted by the University
of California Tobacco-Related Disease Research Program
(TRDRP) as well as for departmental support provided as a B.
R. Baker Fellowship for excellence in biologically related chem-
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