Stepwise approach for sterically hindered Csp3-Csp3 bond formation by dehydrogenative: O -alkylation and Lewis acid-catalyzed [1,3]-rearrangement towards the arylalkylcyclopentane skeleton of sesquiterpenes

Article abstract of DOI:10.1039/d0cc01017k

A stepwise dehydrogenative cross-coupling method was developed for the formation of sterically hindered C_sp³-C_sp³ bonds. Intramolecular dehydrogenative O-alkylation of a β-ketoester by 2,3-dichloro-5,6-dicyano-p-benzoquinone to form an oxolane followed by Lewis acid-catalyzed [1,3]-rearrangement furnished the sesquiterpene arylmethylcyclopentane skeleton. The formal syntheses of herbertane-type β-herbertenol, cuparane-type enokipodins A and B were also achieved.

Full text of DOI:10.1039/d0cc01017k

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Stepwise approach for sterically hindered
Csp –Csp bond formation by dehydrogenative
3
3
Cite this:DOI: 10.1039/d0cc01017k
O-alkylation and Lewis acid-catalyzed
[1,3]-rearrangement towards the arylalkylcyclopentane
skeleton of sesquiterpenes†
Received 8th February 2020,
Accepted 20th February 2020
DOI: 10.1039/d0cc01017k
Ban Fujitani, Kengo Hanaya, Takeshi Sugai
and Shuhei Higashibayashi
*
rsc.li/chemcomm
A stepwise dehydrogenative cross-coupling method was developed for
the formation of sterically hindered Csp –Csp bonds. Intramolecular
3
3
dehydrogenative O-alkylation of a b-ketoester by 2,3-dichloro-5,6-
dicyano-p-benzoquinone to form an oxolane followed by Lewis
acid-catalyzed [1,3]-rearrangement furnished the sesquiterpene
arylmethylcyclopentane skeleton. The formal syntheses of herbertane-
type b-herbertenol, cuparane-type enokipodins A and B were also
achieved.
The dehydrogenative C–C bond-forming cross-coupling reaction
between two C–H bonds under oxidative conditions is an attractive
approach for the construction of organic frameworks since pre-
functionalization of C–H bonds of the substrates is not required.
While numerous useful dehydrogenative reactions have been
developed to date,1 there are still problems to be overcome. One
of these is the difficulty of forming sterically hindered Csp3–Csp3
bonds such as those with quaternary carbons. For Csp3–Csp3 bond
formation with a quaternary aryltrialkylcarbon, only three metal-
catalyzed methods to synthesize b-aromatic a-amino acids,2a
b-arylethylamines,2b and acylimidazoles3 have been reported by
You et al. and Ohshima et al., respectively. However, the moderate
yields under harsh conditions at high temperatures (80–150 1C) are
not satisfactory. To overcome this problem, we propose a stepwise
approach consisting of dehydrogenative O-alkylation of carbonyl
compounds with aryldialkylmethanes4 and subsequent acid-
catalyzed [1,3]-O-to-C-rearrangement5 to furnish the sterically
hindered Csp3–Csp3 bond with a quaternary carbon under mild
conditions (Scheme 1A). Formation of the less hindered Csp3–O
bond is kinetically favored through the nucleophilic attack of the
carbonyl oxygen on the oxidatively generated carbocation to give
an enol ether. The thermodynamically more stable Csp3–Csp3
bond is then formed through [1,3]-rearrangement under acidic
Scheme 1 (A) Stepwise dehydrogenative cross-coupling approach for
sterically hindered Csp3–Csp3 bonds consisting of dehydrogenative
O-alkylation of b-ketoesters with aryldialkylmethanes and acid-catalyzed
[1,3]-rearrangement. (B) Skeletons of cuparane-, herbertane-, laurane-
type sesquiterpenes possessing sterically hindered Csp3–Csp3 bonds with
quaternary carbons. (C) Intramolecular dehydrogenative O-alkylation and
acid-catalyzed [1,3]-rearrangement to arylmethylcyclopentanones.
conditions. As a proof of concept, cuparane-, herbertane-, and
laurane-type sesquiterpenes having a quaternary aryltrialkylcarbon
structure on a cyclopentane ring were chosen as synthetic targets
(Scheme 1B), since a variety of their derivatives have been produced
through biosynthesis.6,7 Their broad useful biological activities
Department of Pharmaceutical Sciences, Faculty of Pharmacy,
Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
E-mail: higashibayashi-sh@pha.keio.ac.jp
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0cc01017k
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Table 1 Dehydrogenative O-alkylation to oxolanes 2
have been reported such as antimicrobial, cytotoxic and neuro-
trophic properties.7 In this paper, we report the synthesis of
arylmethylcyclopentanones by stepwise Csp3–Csp3 bond for-
mation through intramolecular dehydrogenative O-alkylation
of a b-ketoester by 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ) to give oxolane intermediates and subsequent Lewis-
acid catalyzed [1,3]-rearrangement of the oxolanes. The formal
syntheses of herbertane-type b-herbertenol6b and cuparane-type
enokipodins A and B7d are also described.
The dehydrogenative O-alkylation of ketones with arylmethanes
to form enol ethers has not been reported, whereas some redox
reactions of benzoquinones4 are known. First, the intramolecular
dehydrogenative O-alkylation of b-ketoester 1a (keto/enol = 10/1)
with a 4-methoxyphenyl group was screened, using DDQ, Ph3CBF4,
PhI(OAc)2, PhI(OCOCF3)2, FeCl3/tBuOOtBu, Mn(OAc)3, and
(NH4)2[Ce(NO3)6] as oxidants (Scheme 2).8 Desired oxolane 2a was
obtained only when DDQ was used. Under conditions using 1.5 eq.
DDQ in CH2Cl2 at room temperature for 6 h, 74% yield (E/Z = 13/1)
of 2a was achieved with 7% recovery of 1a. Using 3.0 eq. DDQ, 1a
was completely consumed and the yield of 2a was increased up to
87%. While dehydrogenative a-benzylation of 1,3-dicarbonyl com-
pounds with the partial arylmethane structure by FeCl2/tBuOOtBu,
Cu(ClO4)2/bathophenanthroline/tBuOOCOPh, and DDQ has been
reported,9 3a was not observed in our screenings.
With the oxolane 2a in hand, we attempted the [1,3]-
rearrangement of 2a to cyclopentanone 3a in the presence of
an acid (Scheme 2 and Table S1 in ESI†).10 The desired 3a was
formed from (E)-2a by various acids such as TfOH, BF3ÁOEt2,
BiCl3, and Me3SiOTf at room temperature for 6–18 h, and the
best 94% yield was obtained with 100 mol% Sc(OTf)3 for 13 h.
Since 3a was a mixture of keto and enol forms (keto/enol =
2.3/1) as well as the diastereomers of the keto forms (dr = 1.3/1)
as judged by 1H NMR, the structure was fully identified only
after conversion to a ketone by dealkoxycarboxylation (see
ESI†). The amount of Sc(OTf)3 could be reduced to 30 mol%
with a similar yield (86%) for 6 h. (Z)-2a also afforded 3a in 87%
yield under the same conditions.
a
b
E/Z ratio was determined by 1H NMR. Combined yield of both
c
isomers. 24 h.
The reactions will proceed through a benzylic cationic
intermediate (Scheme S1 in ESI†). At 1st reaction, DDQ oxida-
tion of 1a generates an intermediate cation and kinetically
favored nucleophilic attack of oxygen of the carbonyl group
affords the oxolane 2a. At 2nd reaction, the intermediate cation
is generated by acid and the nucleophilic attack of the enolate
gives the thermodynamically favored 3a.
With the successful development of the stepwise method
from 1a with a 4-methoxyphenyl group to 3a through the oxolane
2a, we investigated the applicability to the substrates 1 with
other substituted phenyl groups. The results of dehydrogenative
O-alkylation to oxolanes by 1.5 eq. DDQ in CH2Cl2 at room
temperature are shown in Table 1. In contrast to the high yield of
2a, the yields of 2b and 2c with 2- and 3-methoxy groups were 0%
and a trace amount, and 1b and 1c were recovered in 95% and
73% yields, respectively. The reaction of 1d with electron-
donating 4-acetoamido group and 1e with electron-rich benzo-
furyl group afforded 2d in 60% and 2e in 34% yield with the
recovery of 1d in 18% and 1e in 48%, respectively. The reaction
proceeded with substrates 1f and 1g with 2,4- and 3,4-dimethoxy
groups, giving 2f and 2g in 38% and 85% yields. Only a trace
Scheme 2 Intramolecular dehydrogenative O-alkylation to an oxolane 2a and Lewis acid-catalyzed [1,3]-rearrangement to cyclopentanone 3a.
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amount of 2h was formed in the reaction of 1h with a 2,5-dimethoxy temperature, 2a, 2f, and 2g were converted to 3a, 3f, and 3g, in
group. In the case of 1i with an unsubstituted phenyl group, 2i was 86%, 84%, and 78% yields, respectively. Oxolanes 2d, 2e, 2i, 2j,
obtained in 25% yield for 24 h. The reaction of 1j with a weaker and 2k were converted to 3d, 3e, 3i, 3j and 3k in 78%, 85%,
electron-donating 4-methyl group compared to the methoxy group 94%, 88%, and 83% yield at 40 or 80 1C, respectively. 3l, 3m,
afforded 2j in 35% yield for 24 h. The substrates 1i and 1j were and 3n were also obtained in 82%, 86%, and 75% yields.
recovered in 49% and 38% yields, respectively. The reaction of 1k Concerning the reactivity, the oxolanes with less electron-rich aryl
with naphthyl group gave 2k in better 61% yield. Judging from these groups stabilizing the intermediate cation showed lower reactivity,
results, the reaction using DDQ as the oxidant is sensitive to the requiring higher temperature and/or longer reaction time.
oxidation potential and the steric hindrance of the substituents, and
On the basis of the stepwise conversion from 1 to cyclo-
the electron-rich aryl group stabilizing the intermediate cation is pentanones 3 through oxolanes 2, the one-pot conversion from
necessary to afford the desired oxolane 2 in high yield. Next, the 1 to 3 without isolation of 2 was also attempted. Using 1l as the
reaction was applied to the conversion from 1l, 1m, and 1n to the substrate, which afforded high yields for both reactions, the
corresponding oxolanes, which can be used as the synthetic pre- reaction to 3l in one-pot was carried out by two methods: (A)
cursors for b-herbertenol,12a enokipodins A and B,12b respectively. addition of DDQ and Sc(OTf)3 at the beginning; (B) stepwise
The desired 2l, 2m, and 2n were obtained in 88%, 39%, and 45% addition of DDQ and Sc(OTf)3 (Scheme 3). In method (A), DDQ
yields, respectively. 1m with 2,5-dimethoxy and 4-methyl groups and and Sc(OTf)3 were added at the start of the reaction. On thin
1n with 3-methoxy and 4-methyl groups showed similar reactivities layer chromatography (TLC), formation of 2l and 3l was
as 2j with a 4-methyl group rather than 2h with 2,5-dimethoxy observed. After 8 h, 2l disappeared on TLC and 3l was obtained
groups or 2c with a 3-methoxy group.
in 52% yield with 19% recovery of 1l. In method (B), Sc(OTf)3
Next, Sc(OTf)3-catalyzed [1,3]-rearrangement from the was added after the confirmation by TLC of the conversion from 1l
obtained (E)-2 to 3 was investigated (Table 2). In all entries, to 2l in 6 h. In 2 h after the addition of Sc(OTf)3, 2l disappeared and
the desired cyclopentanones 3 were obtained in good yields. 3l was obtained in 64% yield. In each method, the yields were
Under conditions using 30 mol% Sc(OTf)3 in CH2Cl2 at room slightly lower than the 72% yield for the stepwise method.
In method A, the consumption of 1l was slower than that without
Sc(OTf)3, suggesting that the coordination of the Lewis acid to
Table 2 [1,3]-Rearrangement from oxolanes 2 to cyclopentanones 3
1l lowers the oxidation potential and suppresses the oxidation
by DDQ. In both methods, the hydrobenzoquinone of DDQ
generated in situ is suspected to cause side reactions during the
[1,3]-rearrangement resulting in the slightly lower yields of 3l.
To explore the applicability of our developed method to
catalytic enantioselective syntheses, we investigated the asym-
metric induction on the [1,3]-rearrangement step (Scheme 4).
Using an asymmetric Cu(II) catalyst (S,S)-4 with a (S,S)-tBu-BOX
ligand,11 (2S)-3l was formed with 19.1% ee (see ESI†). Although
the enantiomeric excess was not practical, the applicability of
Scheme 3 One-pot conversion by (A) addition of DDQ and Sc(OTf) from
the beginning and (B) stepwise addition of DDQ and Sc(OTf)3.
Scheme 4 [1,3]-Rearrangement of 2l to 3l using an asymmetric Cu
catalyst (S,S)-4.
a
b
c
d
e
6 h. 2 h. 24 h. 40 1C. 80 1C.
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Scheme 5 Formal syntheses of (Æ)-b-herbertenol, (Æ)-enokipodins A and B.
2 (a) K. Li, Q. Wu, J. Lan and J. You, Nat. Commun., 2015, 6, 8404;
(b) M. Tan, K. Li, J. Yin and J. You, Chem. Commun., 2018, 54, 1221.
3 T. Tanaka, K. Hashiguchi, T. Tanaka, R. Yazaki and T. Ohshima, ACS
Catal., 2018, 8, 8430.
4 For benzoquinones’ redox reactions with arylmethanes to form
hydroquinones’ ethers, see the following references; (a) G. Song,
Z. Zheng, Y. Wang and X. Yu, Org. Lett., 2016, 18, 6002;
(b) M. A. Hossain, K. Akiyama, K. Goto and K. Sugiura, Chemistry-
Select, 2016, 1, 3784; (c) Y. Ando, T. Matsumoto and K. Suzuki,
Synlett, 2017, 1040; (d) G. A. Shevchenko, B. Oppelaar and B. List,
Angew. Chem., Int. Ed., 2018, 57, 10756.
this method to catalytic enantioselective synthesis was demon-
strated in principle.
Finally, 3l and 3m were further derivatized to reported
synthetic intermediates 512a and 612b for b-herbertenol, enokipodins
A and B, respectively (Scheme 5). Methylation of 3l by K2CO3 and
MeI in acetone afforded the intermediate 5 stereoselectively in 73%
yield. Decarboxylation of 3m by LiCl in wet DMSO gave the inter-
mediate 6 in 97% yield. Thus, the formal syntheses of b-herbertenol,
enokipodins A and B were achieved.
5 Reviews; (a) S. J. Meek and J. P. A. Harrity, Tetrahedron, 2007, 63, 3081;
(b) C. G. Nasveschuk and T. Rovis, Org. Biomol. Chem., 2008, 6, 240.
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8 Oxolane formation through a nucleophilic attack of a carbonyl
group to a cation generated by the other methods than oxidative
dehydrogenation of a CH bond; (a) K. Ohkata, T. Sakai, Y. Kudo and
T. Hanafusa, J. Org. Chem., 1978, 43, 3070; (b) H. Arimoto,
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In summary, we succeeded in developing a stepwise dehydro-
genative cross-coupling method for the sterically hindered Csp3–Csp3
bond formation consisting of intramolecular dehydrogenative
O-alkylation of b-ketoesters 1 by DDQ to oxolanes 2 and [1,3]-
rearrangement of 2 by Sc(OTf)3 to arylcyclopentanones 3. Using an
asymmetric Cu catalyst, asymmetric induction in the [1,3]-
rearrangement step was demonstrated. Formal syntheses of
b-herbertenol, enokipodins A and B were also accomplished by
the derivatization of 3. Although the method still has a limitation
on the oxidation potentials of the aryl groups owing to the oxidizing
ability of DDQ, the approach was proven to be effective for the
construction of sterically hindered Csp3–Csp3 bonds with quaternary
carbons. This method is expected to be applicable for the con-
struction of other skeletons. The developed dehydrogenative
O-alkylation of carbonyl compounds also would be attractive for
syntheses of oxolane derivatives. This approach is a safer method to
form sterically hindered Csp3–Csp3 bonds between 1,3-dicarbonyl
compounds and arylmethanes compared to the metal-catalyzed
insertion into the C–H bond of arylmethanes of a carbene gene-
rated from potentially explosive diazocarbonyl compounds.12a
9 Dehydrogenative C–C bond formation between arylalkylmethane and
1,3-dicarbonyl compounds: (a) Z. Li, L. Cao and C.-J. Li, Angew. Chem.,
Int. Ed., 2007, 46, 6505; (b) N. Borduas and D. A. Powell, J. Org. Chem.,
2008, 73, 7822; (c) D. Ramesh, U. Ramulu, S. Rajaram, P. Prabhakar
and Y. Venkateswarlu, Tetrahedron Lett., 2010, 51, 4898.
10 Lewis acid-catalyzed [1,3]-rearrangement of benzyl enol ethers;
¨
(a) A. Gansauer, D. Fielenbach and C. Stock, Adv. Synth. Catal.,
Conflicts of interest
¨
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D. Geich-Gimbel, Adv. Synth. Catal., 2003, 345, 1017.
11 D. A. Evans, D. M. Barnes, J. S. Johnson, T. Lectka, P. Matt, S. J.
Miller, J. A. Murry, R. D. Norcross, E. A. Shaughnessy and K. R.
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There are no conflicts to declare.
Notes and references
1 Reviews; (a) S. A. Girard, T. Knauber and C.-J. Li, Angew. Chem., Int. Ed.,
2014, 53, 74; (b) R. Narayan, K. Matcha and A. P. Antonchick,
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