C-H functionalization logic enables synthesis of (+)-hongoquercin A and related compounds

Article abstract of DOI:10.1002/anie.201303838

The specifics: A synthesis of the sesquiterpenoid antibiotic (+)-hongoquercin A using sequential site-specific C-H methylation and oxidation reactions is described. A key advancement toward this goal was the development of a ligand-accelerated C-H methylation reaction, and enabled the generation of a library of eight structurally diverse analogues. Copyright

Full text of DOI:10.1002/anie.201303838

Angewandte
Chemie
DOI: 10.1002/anie.201303838
Synthesis Design
À
C H Functionalization Logic Enables Synthesis of
(
+)-Hongoquercin A and Related Compounds**
Brandon R. Rosen, Leah R. Simke, Peter S. Thuy-Boun, Darryl D. Dixon, Jin-Quan Yu,* and
Phil S. Baran*
Advances in the strategy and methodology of CÀH function-
alization have begun to alter the way organic chemists
[1]
approach the synthesis of arenes. Given the widespread
occurrence, versatility, and accessibility of benzoic acids, one
of our groups (J.-Q.Y.) has developed a diverse suite of
[2]
reactions for their functionalization. The expansive reaction
scope, robust operational procedures, and high chemoselec-
tivity have already contributed to the application of these
[
3]
methods in total synthesis. Although CÀH functionalization
reactions in the context of drug analogue syntheses have been
[
4]
reported, there are few examples using CÀH functionaliza-
[5]
tion in the divergent functionalization of natural product
[6]
cores. The structure of (+)-hongoquercin A (1, Figure 1A),
[7]
a sesquiterpenoid antibiotic of fungal origin, inspired our
groups to pursue a strategically unique pathway which
required the invention of a ligand-accelerated reaction for
CÀH alkylation (Figure 1B). Herein, a synthesis of 1 is
reported in which the benzoic acid moiety of core structure 3
serves to direct two sequential site-selective CÀH function-
alization events (methylation and oxidation). The successful
employment of this logic in the context of a synthesis of 1, as
well as the preparation of eight analogues by functionaliza-
tion of the intermediate 3, demonstrates the feasibility of such
CÀH disconnections in the retrosynthetic analysis of complex
molecules.
With the above CÀH disconnection strategy in mind, it
was envisioned that 1 could arise from sequential CÀH
activation reactions of the sites ortho to the carboxylic acid,
thus leading to 3. In the forward sense, the conversion of 3
into 2 would require the development of a ligand-accelerated
CÀH methylation reaction, and oxygenation of 2 might be
accomplished using a palladium-catalyzed hydroxylation
(
Figure 1a). The core structure 3 could be easily accessed
from (+)-chromazonarol (4, previously prepared on gram
scale in six steps from (+)-sclareolide) by formation of the
[8]
Figure 1. a) CÀH disconnection approach to (+)-1. b) Development of
a ligand-accelerated CÀH methylation. [a] Yields were determined by
NMR analysis of the crude reaction mixture with CH Br as an internal
standard. Yields given within parentheses refer to yields of products
isolated from reactions run on a 0.1 mmol scale. For detailed reaction
procedures, see the Supporting Information. [b] Yields within parenthe-
ses refer to reactions in which Boc-Phe-OH was omitted. Boc=tert-
butoxycarbonyl, THF=tetrahydrofuran.
2
2
[*] B. R. Rosen, L. R. Simke, P. S. Thuy-Boun, Dr. D. D. Dixon,
Prof. Dr. J.-Q. Yu, Prof. Dr. P. S. Baran
Department of Chemistry, The Scripps Research Institute
1
0550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: pbaran@scripps.edu
**] Financial support for this work was provided by LEO Pharma, NSF
CCI Center for Selective C-H Functionalization, CHE-1205646 and
a predoctoral fellowship to B.R.R.), and US EPA STAR Fellowship
Assistance Agreement no. FP917296-01-01, P.S.T.-B.). We are
[
(
corresponding aryl triflate and hydroxycarbonylation. Most
importantly, 3 would serve as the central intermediate from
which numerous analogues could be prepared using the
plethora of CÀH functionalization reactions available.
(
grateful to Prof. A. Rheingold and Dr. C. E. Moore (UCSD) for X-ray
crystallographic analysis and Dr. D.-H. Huang and Dr. L. Pasternack
for assistance with NMR spectroscopy.
A prerequisite of this plan was the development of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303838.
a ligand-accelerated CÀH methylation reaction. After sub-
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stantial optimization, the use of MeBF K in the presence of
3
catalytic Pd(OAc) with the amino-acid-derived ligand Boc-
2
Phe-OH provided optimal results with m-toluic acid (Fig-
ure 1b, entry 1). Omission of either Boc-Phe-OH or 1,4-
benzoquinone resulted in diminished conversion (entries 2
and 6), while other methyl sources, solvents, and bases also
gave inferior results (entries 3–5 and 7). These conditions
were then applied to several other commercially available
benzoic acids, thus providing the alkylated products (A–D) in
[
9]
satisfying yields. In most cases, monoalkylation resulted in
the major product (ca. 6:1–15:1), but the reaction of p-anisic
acid gave predominantly bisalkylation with low conversion.
The full substrate scope and mechanism of this transforma-
tion will be the subject of a separate report.
With a reliable set of reaction conditions for CÀH
alkylation in hand, the preparation of 3 was pursued. As
shown in Scheme 1, treatment of 4 with Tf O resulted in the
2
corresponding aryl triflate, which underwent hydroxycarbo-
nylation using Pd(OAc) , dppf, and KOAc under 1 atm of CO
2
10]
[
to give 3 (gram-scale), which was characterized by X-ray
crystallographic analysis. Gratifyingly, the reaction of 3 under
our optimized methylation conditions afforded the carboxylic
acid 2 in 45% yield, along with the bisalkylated product 5 in
1
5% yield and 32% of recovered 3. Interestingly, omission of
either Boc-Phe-OH or 1,4-benzoquinone from this reaction
had much more dramatic effects than with m-toluic acid, as
conversion fell below 10%. Prolonged reaction times or
higher temperatures resulted in an increase in the amount of 5
formed, thus diminishing the isolated yield of 2 and compli-
cating purification.
Scheme 1. Synthesis of (+)-Hongoquercin A (1). Reagents and condi-
tions: a) Tf O, pyridine, CH Cl , 08C, 3 h; 91%. b) CO (1 atm),
mol% Pd(OAc) , 20 mol% dppf, KOAc, DMSO, 608C, 16 h; 80%.
At this stage, all that remained to complete the synthesis
2
2
2
[2j]
5
of 1 was the hydroxylation of 2. Exposing 2 to 1 atm of O in
2
2
c) MeBF K, 10 mol% Pd(OAc) , 20 mol% Boc-Phe-OH, Ag CO ,
3
2
2
3
the presence of Pd(OAc) and KOAc in DMA at 1158C
2
Li CO , 5 mol% 1,4-benzoquinone, tBuOH, 908C, 12 h; 45% 2, 15%
2
3
resulted in only recovered starting material. Increasing the
5
1
1
, 32% 3. d) O (10 atm), 10 mol% Pd(OAc) , KOAc, DMA, 1158C,
2
2
pressure of O to 10 atm resulted in approximately 15–20%
2
5 h; ca. 15%. e) i. (COCl) , cat. DMF, CH Cl , 5 h; ii. C F NH , PhMe,
2
2
2
6
5
2
yield of isolated 1 along with substrate decomposition.
0 mol% DMAP, 1208C, 12 h; 76%. f) MeBF K, 10 mol% Pd(OAc) ,
3
2
Unfortunately, an extensive survey of reaction conditions
Ag CO , Li CO , 50 mol% 1,4-benzoquinone, THF, 1208C, 24 h; 60%.
2
3
2
3
(
e.g., solvent, temperature, base, etc.) did not improve the
g) PhI(OAc)
2
, 10 mol% Pd(OAc) , NaOAc, Ac O, DCE, 808C, 24 h;
2
2
[
11]
54%. h) BF ·OEt , MeOH, 1058C, 48 h, then 6m NaOH, THF, 808C,
3 2
yield. These results are likely due to a combination of steric
factors and catalyst instability in the relatively harsh oxidation
conditions, thus highlighting a significant limitation in Csp
oxidation.
2
h; 71%. DCE=1,2-dichloroethane, DMA=N,N-dimethylacetamide,
DMAP=4-(N,N-dimethylamino)pyridine, DMF=N,N-dimethylform-
amide, DMSO=dimethylsulfoxide, dppf=1,1’-bis(diphenylphosphino)-
ferrocene, Tf=trifluoromethanesulfonyl.
2
ÀH
Although this ultimate oxidation proved challenging, it
was reasoned that converting the carboxylic acid of 3 into
a suitable amide would improve the CÀH functionalization
reactions, possibly overcoming any difficulties that thwarted
worthy that under widely used acidic conditions for acet-
[6a,12]
[12b,13]
initial experiments.
For example, electron-deficient aryl
oxylation (e.g. AcOH/Ac O, 1008C),
decomposition of 6
2
amides have been shown to be powerful directing groups for
many transformations where benzoic acids have failed and
occurred, and these weakly basic conditions were necessary to
obtain 7.
[
12a]
can be readily cleaved using a variety of methods.
Thus,
Cleavage of the amide was accomplished using BF ·OEt
3
2
treating 3 with oxalyl chloride and catalytic DMFafforded the
corresponding acid chloride, which furnished amide 8 in 76%
yield when heated with C F NH in refluxing toluene.
in refluxing methanol, which also resulted in concomitant
[
14]
removal of the acetate group. Addition of NaOH to the
reaction mixture and subsequent acidic workup afforded the
target 1 in 71% yield. Synthetic 1 exhibited identical spectral
6
5
2
Gratifyingly, palladium-catalyzed methylation proceeded to
1
give 6 in 60% yield and set the stage for the final CÀH
properties to those reported by Roll and co-workers ( H and
1
3
[7a]
oxidation reaction. In the event, extensive exploration
C NMR spectroscopy, IR, m.p.).
The primary feature of the initial design was the ability of
revealed that exposure of 6 to catalytic Pd(OAc) in the
2
presence of stoichiometric PhI(OAc) , Ac O, and NaOAc
3 to serve as a point of divergence from which a multitude of
2
2
affords the acetoxylated amide 7 in 54% yield. It is note-
hongoquercin congeners could be fashioned. To this end,
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Scheme 2. Synthesis of analogues using CÀH functionalization. Reagents and conditions: a) CF CH CH BF K, 10 mol% Pd (OAc) , 20 mol% Boc-
3
2
2
3
2
Phe-OH, Ag CO , Li CO , 5 mol% 1,4-benzoquinone, tBuOH, 908C, 18 h; 52% 9, 35% 3. b) 10 mol% Pd(OAc) , KHCO , CH Br , 1408C, 48 h;
2
3
2
3
2
3
2
2
4
8%. c) O (1 atm), 10 mol% Pd(OAc) , KOAc, 1,4-benzoquinone, DMA, 1158C, 15 h; 38% 11, 43% 3. d) 1.05 equiv 3, 1 equiv styrene, 5 mol%
2 2
[
(Cp*RhCl ) ], AgOAc, DMF, 1208C, 24 h; 66%. e) O-benzoyl N-hydroxymorpholine, 10 mol% Pd(OAc) , AgOAc, CsF, DCE, 1308C, 24 h; 90%;
2
2
2
f) 4-trifluoromethylphenylboronic acid pinacol ester, 10 mol% Pd(OAc) , NaHCO , Ag CO , 1,4-benzoquinone, DMSO, H O, t-amyl alcohol,
2
3
2
3
2
1
008C, 24 h; 44%. g) CO (1 atm), 10 mol% Pd(OAc) , KH PO , AgOAc, TEMPO, DCE, 1008C, 24 h; 70%. Cp*=C Me , TEMPO=2,2,6,6-
2
2
4
5
5
tetramethylpiperidin-1-oxyl.
[
15]
a small library of analogues from the CÀH activation
arylamine 13 in 90% yield. A CÀH Suzuki-type coupling
with (p-CF )C H BPin afforded the biaryl product 14 in 44%
precursors 3 and 8 was targeted. As depicted in Scheme 2,
a range of ortho-CÀH functionalizations were executed on
3
6
4
[
16]
yield. The lower yield in this case was due to the fact that 14
was co-polar with 8, thus complicating purification, and
additional 14 was isolated alongside small amounts of 8.
Carbonylation under 1 atm of CO gave the phthalimide 15.
Interestingly, it was found that TEMPO was an essential
additive for this reaction, and only 8 was recovered in its
both 3 and 8. For instance, the reaction conditions employed
for methylation of 3 could also be applied to deliver the
trifluoropropylated acid 9. It is of note that no overalkylation
product was detected in the crude reaction mixture. Domino
CÀH alkylation/lactonization was accomplished using CH Br
2
2
[
2i]
[17]
and Pd(OAc) to give the lactone 10. Contrary to observa-
absence. It is notable that, although the yields for several of
2
tions with the methylated substrate 2, substrate 3 was oxidized
these reactions are modest, the only other isolable component
was recovered starting material, which could generally be
separated using standard chromatographic methods (flash
chromatography or preparative TLC). This limitation is one
that could likely be overcome with further optimization when
necessary, whereas for diversity-based and medicinal chemis-
try applications, we believe that the versatility of these
transformations outweighs this shortcoming. Furthermore,
these studies complement existing directed ortho-lithiation/
functionalization methodologies, which may not be as effec-
under 1 atm of O , and, although the conversion was modest
2
after 15 hours, no decomposition was observed, and the
[2j]
remaining starting material could be recovered. Carboxylic
acid 3 also proved to be an excellent substrate for rhodium-
catalyzed vinylation, as demonstrated by the CÀH Heck-type
[2g]
reaction with styrene to give olefin 12.
Given the enhanced reactivity of amide 8, we expected
that analogues otherwise difficult to access directly from 3
could also be prepared. Thus, reaction of 8 with a morpholine-
[
18]
derived amine in the presence of catalytic Pd(OAc) gave
tive at delivering such a broad range of products.
2
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The synthesis of (+)-hongoquercin A (1) reported herein
serves to highlight the utility of CÀH functionalization logic
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