Divergent Enantioselective Synthesis of (Nor)illudalane Sesquiterpenes via Pd0-Catalyzed Asymmetric C(sp3)-H Activation

Article abstract of DOI:10.1021/acs.orglett.8b04086

A divergent enantioselective synthesis of (nor)illudalane sesquiterpenes was designed by using a Pd⁰-catalyzed asymmetric C(sp³)-H arylation as a key step to control the isolated, highly symmetric quaternary stereocenter of the targe

Full text of DOI:10.1021/acs.orglett.8b04086

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Divergent Enantioselective Synthesis of (Nor)illudalane
Sesquiterpenes via Pd0‑Catalyzed Asymmetric C(sp3)−H Activation
‡
Romain Melot,†,§ Marcus V. Craveiro,†,§ Thomas Burgi, and Olivier Baudoin*,†
̈
†University of Basel, Department of Chemistry, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
‡Department of Physical Chemistry, University of Geneva, 30 Quai Ernest-Ansermet, 1211 Geneva 4, Switzerland
S
* Supporting Information
ABSTRACT: A divergent enantioselective synthesis of (nor)-
illudalane sesquiterpenes was designed by using a Pd0-
catalyzed asymmetric C(sp3)−H arylation as a key step to
control the isolated, highly symmetric quaternary stereocenter
of the target molecules. A matched combination of chiral
substrate and catalyst proved optimal to reach good levels of
stereoselectivity. This approach enabled the synthesis of three
(nor)illudalanes, including (S)-deliquinone and (S)-russuja-
ponol F, which are synthesized for the first time in enantioenriched form.
igher fungi are sources of diverse bioactive illudalane and
norilludalane sesquiterpenes such as the fused benzo-
for the enantioselective synthesis of these natural products.4
Indeed, despite a deceptively simple structure, only two
enantioselective syntheses of puraquinonic acid have been
reported and none for deliquinone, russujaponol F, or other
(nor)illudalanes of this type.5,6 The first synthesis of (S)-
puraquinonic acid by Clive and co-workers featured 31 steps
and showcased the difficulty of controlling the isolated
quaternary stereocenter by classic chiral auxiliary-based
approaches.5a,b It also established the absolute configuration
of natural puraquinonic acid as (R). The number of steps was
greatly improved in a more recent synthesis of (R)-
puraquinonic acid by Gleason and co-workers.5c The
quaternary stereocenter was installed at an early stage of the
synthesis by diastereoselective alkylations from an in-house
chiral auxiliary.7 Subsequently, the indane system was
efficiently constructed by enyne metathesis and Diels−Alder
cycloaddition. The chiral auxiliary was removed in the last
steps of the synthesis prior to the oxidization of the benzene
ring to the benzoquinone. This strategy resulted in a much
shorter and efficient enantioselective synthesis −12 steps, 20%
overall yield from the chiral auxiliary, or 15 steps, 14% from
(S)-valinol.
H
quinones puraquinonic acid (1)1 and deliquinone (2)2 and the
indane russujaponol F (3)3 (Scheme 1, top). In particular, the
Scheme 1. (Nor)illudalane Targets Featuring a Highly
Symmetric Quaternary Stereocenter and Retrosynthetic
Analysis
Previous work from our group8 led us to consider an
alternative and, in principle, more divergent approach to
(nor)illudalane sesquiterpenes 1−3 by means of Pd0-catalyzed
enantioselective C(sp3)−H activation (Scheme 1, bottom).9,10
Benzoquinone- and benzene-fused cyclopentanes 1−3 would
arise from the same indane precursor 4, which should be easily
accessible from the less substituted intermediate 5 through
aromatic Claisen rearrangement.5a,b,6 Indane 5 would be
obtained by Pd0-catalyzed enantioselective C(sp3)−H arylation
from a structurally simple aryl bromide 6. In this step, the
former was shown to induce the differentiation of HL-60 cells.1
In addition to a densely functionalized 6-membered ring, the
most striking common structural feature of compounds 1−3 is
certainly the presence of a single, highly symmetric quaternary
stereocenter, which arises from the presence of different
substituents three (3) or four (1 and 2) carbons away. Despite
very low specific rotations, compounds 1−3 have been
reported to occur as single enantiomers with the (R) (1 and
2) or (S) (3) absolute configuration.1−3 The presence of this
isolated quaternary stereocenter represents a major challenge
Received: December 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04086
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
chiral catalyst would achieve the desymmetrization of the two
methyl groups in 6 and generate the quaternary stereocenter at
the adjacent position. We previously reported the enantiose-
lective synthesis of indanes by Pd0-catalyzed C(sp3)−H
arylation in the presence of a chiral phosphine.11 In this
case, two isopropyl groups were desymmetrized to generate a
quaternary stereocenter two carbons away from the cleaved
C−H bond. Besides, the desymmetrization of gem-dimethyl
groups on a tetrasubstituted carbon was reported by our group
in the context of indoline synthesis, through the use of a
catalytic chiral phosphate.12 The enantioselectivity was good
but lower than the one achieved with compounds bearing
trisubstituted carbons.13 In addition, in both precedents the
more substituted linker between Pd and the cleaved C−H
bond favored the intramolecular C−H activation step by
Thorpe−Ingold-type effects. Hence, we anticipated that the
enantioselective C−H arylation of substrate 6 would be
challenging both because of the lack of conformational bias
and the presence of the adjacent quaternary carbon. On the
other hand, this new route would allow introduction of the
quaternary stereocenter at a later stage compared to previous
syntheses and would be more enantiodivergent, i.e., more
flexible to access the desired (R) or (S) enantiomer of
(nor)illudalanes 1−3. Herein, we report the implementation of
this C(sp3)−H activation-based strategy14 for the enantiose-
lective synthesis of compounds 1−3 with the (S) absolute
configuration.
Table 1. Optimization of Reaction Conditions
We first searched for the most selective substrate/catalyst
combination and prepared model substrates 7a−k lacking the
5′-methyl group of the target molecules (Table 1). The effect
of R1 and R2 groups on the yield and enantioselectivity was
studied with various ligands that were previously employed in
enantioselective C(sp3)−H activation reactions by our group
and others (Table S1).15 Bulky chiral NHCs [NHC = N-
heterocyclic carbene] developed by Kundig and co-work-
̈
ers13a,d were the only tested ligands that provided good yields
and significant enantioselectivities for methyl ester 7a (entry
1). The tested chiral phosphorus ligands including binepines,11
phosphoramidites,16 and phosphonites17 provided low yields
and enantioselectivities. Increasing the bulk of the phenol
substituent provided a minor improvement (entry 2), which
was not judged sufficient in light of the expected cleavage
issues at a later stage of the synthesis. Replacing the methyl
ester with a nitrile (entry 3) or a tert-butyl ester (entry 4) led
to decreased yields and enantioselectivities. We then prepared
more bulky amide substrates (entries 5−7), which indeed
provided better enantioselectivities. However, attempts at
hydrolyzing the amide group on products 8e−g were
successful only for the least enantioenriched morpholinamide
8g. Testing other chiral NHCs in the reaction of 7g failed to
improve the enantioselectivity (Table S2). As a consequence,
we considered employing chiral proline-derived substrates,
which would both be cleavable and provide a cheap source of
additional chirality. The L-proline-derived amide 7h indeed
furnished a promising diastereoselectivity of 83:17 (entry 8).
Optimizing the ester substituent (entries 10 and 12) led to a
further improvement of the diastereoselectivity for isopropyl
ester 7i (entry 10). The D-proline-derived amide 7k provided a
lower dr than its enantiomer 7i in combination with L1,
indicative of matched−mismatched effects (entry 14). To
further dissect the stereochemical induction by the substrate vs
the ligand, we tested achiral NHCs, and the most efficient one
turned out to be IBioxMe4 (L2), developed by Glorius and co-
a
b
Based on GC/MS analysis. Yield of isolated product 8 in
c
parentheses. Determined by HPLC on a chiral stationary phase.
workers.18 This ligand provided lower levels of diastereose-
lectivity with 7i (66:34, entry 11) and 7k (36:64, entry 15)
than the combination of 7i and L1 (87:13, entry 10). A similar
outcome was observed for substrates 7h and 7j (entries 8, 9
and 12, 13). Moreover, combining 7k and L1 led to a 63:37
ratio in favor of the same major diastereoisomer as from 7i.
These results show that (1) the chiral ligand is able to override
the induction by the chiral substrate (entries 14 and 15) and
(2) L-prolinamide substrate 7i and ligand L1 afford a matched
combination. We failed to further increase the stereoselectivity
by modifying the substrate, ligand, or reaction conditions.
However, motivated by the excellent yield achieved in this
step, we planned to perform a recrystallization at a later stage
of the synthesis to improve the enantiopurity while preserving
a good overall yield for the target molecules. To maximize the
efficiency of the crystallization, we chose the double stereo-
induction system (7i) providing an 87:13 dr against the best
cleavable single induction system (7g) providing an 80:20 er.
B
DOI: 10.1021/acs.orglett.8b04086
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a
Scheme 2. Divergent Synthesis of (S)-Puraquinonic Acid, (S)-Deliquinone, and (S)-Russujaponol
a
Reagents and conditions: (a) Br2, AlBr3, CH2Cl2, 0 °C; (b) HI aq, reflux; (c) K2CO3, MeI, acetone, reflux; (d) N-bromosuccinimide, AIBN, CCl4,
reflux; (e) i-PrCO2Me, LDA, THF, 0 °C, then aryl bromide, 0 → 20 °C; (f) LiOH aq, THF/MeOH, 80 °C; (g) (COCl)2, DMF cat., CH2Cl2, 20
°C, then L-Pro-Oi-Pr; (h) [Pd(cinnamyl)Cl]2 (5 mol %), L1 (10 mol %), CsOPiv, Cs2CO3, mesitylene, 160 °C; (i) HBr aq, AcOH, reflux, then
recrystallization from CHCl3/C6H12 3:1; (j) KHCO3, MeI, DMF, 40 °C, then NaH, allyl bromide; (k) PhNEt2, 200 °C; (l) OsO4 (5 mol %),
NaIO4, AcOEt/H2O, 20 °C; (m) NaBH4, MeOH, 0 °C; (n) LiOH aq, dioxane, reflux; (o) 13 (10 mol %), Oxone, CF3CH2OH/H2O, 20 °C; (p)
LiAlH4, THF, 0 → 20 °C; (q) Tf2O, pyridine, CH2Cl2, 0 → 20 °C; (r) [Pd2dba3·CHCl3] (2.5 mol %), XPhos (5 mol %), DABCO·2AlMe3, THF,
b
reflux. DABCO = 1,4-diazabicyclo[2.2.2]octane; XPhos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl. Measured by HPLC on a chiral
stationary phase using the racemic compound as reference.
The common intermediate 4, containing the required
additional methyl group on the benzene ring, was then
synthesized as described in Scheme 2. Perbromination and
selective debromination19 of commercially available phenol 9
(31 CHF/100 g), followed by phenoxide methylation, afforded
aryl bromide 10 on a 50 g scale. Selective radical
bromination20 and enolate alkylation generated 6a, which
was converted to the L-proline-derived C−H activation
precursor (S)-6b in two additional steps. Application of the
optimized reaction conditions employing chiral NHC L1
furnished indane 11 in good yield (87%) and with a slightly
diminished dr compared to 8i lacking the 5′-methyl group
(85:15 instead of 87:13). Next, the concomitant prolinamide
hydrolysis and methyl ether cleavage were performed with
hydrobromic acid in refluxing acetic acid. Slow crystallization
from chloroform and cyclohexane provided a greatly improved
er of 96:4 for the solid isolated from the mother liquor (57%
yield). This ratio was measured after the next step (j) against a
racemic sample, which was prepared through a similar
synthetic sequence using achiral NHC L2 as the ligand.15
The configuration of the major enantiomer of 12 was
determined to be (S) by vibrational circular dichroism
(VCD, Figures S1−S5) and NOESY NMR (Figure S6)
analysis of derivatives. To our dismay, and despite numerous
efforts, none of the compounds of the whole synthetic
sequence or derivatives thereof provided crystals suitable for
Xray diffraction analysis. From 12, sequential selective
alkylations of the carboxylic acid and the phenol and aromatic
Claisen rearrangement6b led to the common intermediate 4 in
66% yield over three steps and good overall yield from phenol
9 (15.6% over 11 steps).
Compound 4 was first converted to (S)-puraquinonic acid 1.
Lemieux−Johnson oxidation21 and reduction of the resulting
aldehyde furnished primary alcohol 14. Previous work by
Kraus hinted that the ester hydrolysis should be performed
prior to the phenol oxidation.6b Indeed, after standard
hydrolysis with lithium hydroxide, the phenol oxidation was
performed under mild conditions using the catalytic hyper-
valent iodine reagent reported by Yakura and Konishi22 to give
(S)-puraquinonic acid in 82% yield over two steps and 9.6%
overall yield over 15 steps from 9. (S)-Deliquinone 2 was
obtained in a similar way by Johnson−Lemieux oxidation,
reduction of the aldehyde and ester groups with LiAlH4, and
phenol oxidation, hence leading to the first enantioselective
synthesis of this molecule with an overall yield of 9.7% over 14
steps. Finally, (S)-russujaponol F (3) was synthesized in four
steps from 4 starting with triflation and Pd0-catalyzed cross-
coupling with the air-stable DABCO-trimethylaluminum
complex introduced by Woodward and co-workers,23 which
furnished indane 15 in 85% yield. Lemieux−Johnson oxidation
and ester reduction completed the synthesis of (S)-3 in 15
steps, 11.6% overall yield from phenol 9. Of note, the racemic
natural products were also synthesized according to a similar
pathway involving the C−H activation of 6a in the presence of
achiral NHC L2.15 This sequence avoiding the formation of
prolinamide 6b led to racemic targets 1−3 in two steps fewer
(12 overall for 2 and 13 for 1 and 3).
The specific rotations of the synthetic products 1−3 were
found to be +1.4, +0.9 ,and +2.1, respectively. The reported
specific rotations of the natural products in the same solvents
are −2.2 for (R)-1,5a,b −0.5 for (R)-2,2 and +1.3 for (S)-3.3
Hence, our values are consistent with (S) enantiomers for the
three final products. This assignment was confirmed by the
C
DOI: 10.1021/acs.orglett.8b04086
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above-mentioned VCD and NMR analyses.15 Hence, we have
synthesized natural russujaponol F (3) and the antipodes of
natural puraquinonic acid (1) and deliquinone (2).
In conclusion, a divergent enantioselective synthesis of
(nor)illudalane sesquiterpenes was designed by using a Pd0-
catalyzed asymmetric C(sp3)−H arylation as the key step. This
first application of such reaction in natural product synthesis
demonstrates its great potential to construct isolated
quaternary stereocenters in complex molecules.
(10) For recent reviews on catalytic enantioselective methods to
construct quaternary stereocenters, see: (a) Quasdorf, K. W.;
Overman, L. E. Nature 2014, 516, 181. (b) Zeng, X.-P.; Cao, Z.-Y.;
Wang, Y.-H.; Zhou, F.; Zhou, J. Chem. Rev. 2016, 116, 7330.
(11) (a) Martin, N.; Pierre, C.; Davi, M.; Jazzar, R.; Baudoin, O.
Chem. - Eur. J. 2012, 18, 4480. (b) Holstein, P. M.; Vogler, M.; Larini,
P.; Pilet, G.; Clot, E.; Baudoin, O. ACS Catal. 2015, 5, 4300.
(12) (b) Yang, L.; Melot, R.; Neuburger, M.; Baudoin, O. Chem. Sci.
2017, 8, 1344.
(13) See also: (a) Nakanishi, M.; Katayev, D.; Besnard, C.; Kundig,
̈
E. P. Angew. Chem., Int. Ed. 2011, 50, 7438. (b) Anas, S.; Cordi, A.;
Kagan, H. B. Chem. Commun. 2011, 47, 11483. (c) Saget, T.;
Lemouzy, S. J.; Cramer, N. Angew. Chem., Int. Ed. 2012, 51, 2238.
ASSOCIATED CONTENT
* Supporting Information
■
S
(d) Larionov, E.; Nakanishi, M.; Katayev, D.; Besnard, C.; Ku
P. Chem. Sci. 2013, 4, 1995.
̈
ndig, E.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04086.
(14) (a) Dailler, D.; Danoun, G.; Baudoin, O. Top. Organomet.
Chem. 2015, 56, 133. (b) Brady, P. B.; Bhat, V. Eur. J. Org. Chem.
2017, 2017, 5179.
(15) See the Supporting Information for details.
(16) (a) Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2012, 51,
12842. (b) Pedroni, J.; Cramer, N. Angew. Chem., Int. Ed. 2015, 54,
11826. For a review, see: (c) Pedroni, J.; Cramer, N. Chem. Commun.
2015, 51, 17647.
(17) Pedroni, J.; Boghi, M.; Saget, T.; Cramer, N. Angew. Chem., Int.
Ed. 2014, 53, 9064.
(18) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am.
Chem. Soc. 2004, 126, 15195.
(19) Gore, M. P.; Gould, S. J.; Weller, D. D. J. Org. Chem. 1991, 56,
2289.
(20) Hirano, Y.; Tokudome, K.; Takikawa, H.; Suzuki, K. Synlett
2017, 28, 214.
(21) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J.
Org. Chem. 1956, 21, 478.
Supplementary tables and figures; procedural and
spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: olivier.baudoin@unibas.ch.
ORCID
Thomas Burgi: 0000-0003-0906-082X
̈
Olivier Baudoin: 0000-0002-0847-8493
Author Contributions
§R.M. and M.V.C. contributed equally.
Notes
(22) Yakura, T.; Konishi, T. Synlett 2007, 2007, 765.
(23) Cooper, T.; Novak, A.; Humphreys, L. D.; Walker, M. D.;
Woodward, S. Adv. Synth. Catal. 2006, 348, 686.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the University of Basel
■
̀
and Fundaca
̧
o
̃
de Amparo a Pesquisa do Estado de Sao
̃
Paulo,
Brazil (FAPESP - process 2016/22636-2). We thank A. Huber,
̈
University of Basel, for preparative work, Dr. D. Haussinger,
University of Basel, for assistance with NMR experiments, S.
Mittelheisser, Dr. H. Nadig, and Dr. M. Pfeffer, University of
̈
Basel, for MS analyses, and Prof. Dr. E. P. Kundig, University
of Geneva, for a gift of chiral NHC ligand.
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Org. Lett. XXXX, XXX, XXX−XXX