Palladium-Catalyzed Decarbonylative Dehydration for the Synthesis of α-Vinyl Carbonyl Compounds and Total Synthesis of (-)-Aspewentins A, B, and C

Article abstract of DOI:10.1002/anie.201505161

The direct α-vinylation of carbonyl compounds to form a quaternary stereocenter is a challenging transformation. It was discovered that δ-oxocarboxylic acids can serve as masked vinyl compounds and be unveiled by palladium-catalyzed decarbonylative dehydr

Full text of DOI:10.1002/anie.201505161

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International Edition: DOI: 10.1002/anie.201505161
German Edition: DOI: 10.1002/ange.201505161
Natural Products Very Important Paper
Palladium-Catalyzed Decarbonylative Dehydration for the Synthesis of
a-Vinyl Carbonyl Compounds and Total Synthesis of (À)-
Aspewentins A, B, and C**
Yiyang Liu, Scott C. Virgil, Robert H. Grubbs,* and Brian M. Stoltz*
Abstract: The direct a-vinylation of carbonyl compounds to
form a quaternary stereocenter is a challenging transformation.
It was discovered that d-oxocarboxylic acids can serve as
masked vinyl compounds and be unveiled by palladium-
catalyzed decarbonylative dehydration. The carboxylic acids
are readily available through enantioselective acrylate addition
or asymmetric allylic alkylation. A variety of a-vinyl quater-
nary carbonyl compounds are obtained in good yields, and an
application in the first enantioselective total synthesis of (À)-
aspewentins A, B, and C is demonstrated.
A
n all-carbon quaternary center bearing an ethylene
substituent is a common structural motif in many natural
products (Figure 1).[1] An important approach to the con-
struction of this unit is the a-vinylation of carbonyl com-
pounds, and two general methods have been developed. One
is the direct coupling of an enolate nucleophile with a vinyl
electrophile such as an alkenyl ether,[2] vinyl bromide,[3] or
acetylene itself.[4,5] Although this approach can be extended to
alkenylations as well, and asymmetric versions are
known,[3a,c,4c] the scope of the enolate nucleophile is generally
limited to 1,3-dicarbonyl compounds[4] or those with only one
enolizable position.[2,3,5b] A second tactic involves addition of
the enolate nucleophile to a vinyl surrogate such as vinyl
sulfoxide,[6] (phenylseleno)acetaldehyde,[7] or ethylene
oxide,[8] followed by elimination. However, there are few
reports of stereoselective additions that form the quaternary
stereocenter,[9] and none are catalytic or enantioselective.
Because of these constraints, even the simplest 2-methyl-2-
vinylcyclohexanone (7) is not known as a single enantiomer in
the literature.
Figure 1. Natural products with ethylene substituents.
We envisioned an alternative approach to access a-vinyl
carbonyl compounds, by employing a decarboxylative elim-
ination of d-oxocarboxylic acids (Scheme 1). These acids may
be prepared by numerous methods, including addition of an
enolate nucleophile to an acrylate acceptor[10] and palladium-
catalyzed allylic alkylation.[11] Importantly, these two methods
allow the enantioselective construction of the requisite
quaternary stereocenter.
[*] Y. Liu, Dr. S. C. Virgil, Prof. R. H. Grubbs, Prof. B. M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, Division of Chemistry and Chemical Engi-
neering, California Institute of Technology
1200 E. California Blvd, MC 101-20, Pasadena, CA 91125 (USA)
E-mail: rhg@caltech.edu
stoltz@caltech.edu
[**] We wish to thank the Resnick Sustainability Institute at Caltech
(graduate fellowship to Y.L.), NIH (R01M080269 to B.M.S.,
5R01M031332-27 to R.H.G.), the Gordon and Betty Moore Foun-
dation, the Caltech Center for Catalysis and Chemical Synthesis, and
Caltech for financial support. Dr. David VanderVelde is acknowl-
edged for assistance with NMR spectroscopy. Dr. Mona Shahgholi
and Naseem Torian are acknowledged for assistance with high-
resolution mass spectrometry. We would like to thank Prof.
Richmond Sarpong of UC Berkeley for helpful discussions.
Scheme 1. Decarboxylative approach to vinylation.
Recently, we reported on the palladium-catalyzed decar-
bonylative dehydration of fatty acids to form terminal
olefins.[12] Because of the importance of a-vinyl carbonyl
compounds and the challenges in their preparation, we
Supporting information for this article (including experimental
details) is available on the WWW under http://dx.doi.org/10.1002/
anie.201505161.
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Table 1: Decarbonylative dehydration of d-oxocarboxylic acids (8).
became interested in applying our decarbonylative dehydra-
tion chemistry as an alternative strategy to a-vinylation. Since
the carboxylic acid, which bears a quaternary center two
atoms away from the reactive carboxy group, is more
hindered than a simple fatty acid, we expected that the
reaction conditions would need to be tuned for this particular
class of substrates. Additionally, from a practical standpoint,
our previous studies were typically conducted on 5 grams of
the fatty acid substrate without solvent, under vacuum
distillation conditions. Thus, a smaller-scale alternative for
implementation on laboratory scale and in the context of
multistep organic synthesis would need to be developed.
At the outset of our investigation, we prepared the
carboxylic acid 8a and subjected it to modified palladium-
catalyzed decarbonylative dehydration conditions, where
slightly higher loadings of catalyst, ligand, and additive were
employed (Scheme 2). We were pleased to isolate the vinyl
cyclopentanone 9a in 67% yield.[13] This result demonstrated
that the steric bulk at the quaternary center does not
significantly retard the reaction, but proximal functionality
(e.g. the ketone) could alter the reaction pathway.
Entry[a] d-Oxocarboxylic acid
Product
Yield and ee
1
67%
60%
92% ee
2
3
66%
4
54%[b]
69%
92% ee
5
6
75%
Scheme 2. Decarbonylative dehydration of the d-oxocarboxylic acid 8a.
Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
7
50%
51%
8[c]
With this exciting initial result in hand, we proceeded to
investigate the scope of the reaction (Table 1). First, we
synthesized (R)-3-(1-methyl-2-oxocyclohexyl)propanoic acid
(8b) by an enantioselective d’Angelo Michael addition,[10] and
subjected it to decarbonylative dehydration (entry 2). We
were delighted to obtain the desired product, (R)-2-methyl-2-
vinylcyclohexanone (ent-7), in 60% yield and 92% ee.
Likewise, 2-ethyl-2-vinylcyclohexanone (9c) was prepared
in a similar fashion. Carboxylic acids bearing allyl or 2-
methallyl substituents were prepared by palladium-catalyzed
allylic alkylation,[11] and they undergo decarbonylative dehy-
dration smoothly to provide the corresponding 2-allyl-2-vinyl-
substituted cyclohexanones 9d and 9e (entries 4 and 5),
respectively, with the latter in 92% ee from the enantioen-
riched acid 8e. It is worth noting that double-bond isomer-
ization in the allyl moiety is negligible for 9d and does not
occur at all for 9e. The acyclic keto acid 8 f is converted into
the acyclic ketone 9 f in good yield (entry 6). Aside from keto
acid substrates, we examined acids bearing other types of
carbonyl functionalities (entries 7–10), and found that the a-
vinyl ester 9g, lactam 9h, and aldehyde 9i can all be prepared
in good yields. More complex scaffolds such as 8j, obtained by
oxidative cleavage of testosterone,[14] also undergo the
reaction to provide the vinylated tricycle 9j (entry 11).
While the reaction can be carried out in the absence of
a solvent on a fairly large scale (5 mmol, entries 1–7), we
9[c]
57%
77%
10[c]
11[c]
41%
[a] 5 mmol scale. [b] Isolated as a 95:5 mixture of desired product and
internal olefin isomer. [c] Reaction conditions: 0.5 mmol substrate
(1 equiv), benzoic anhydride (1.2 equiv), [PdCl2(nbd)] (1 mol%), Xant-
phos (1.2 mol%), NMP (0.25 mL), 1 atm N2, 1328C, 3 h. nbd=2,5-
norbornadiene.
found that for smaller scale synthesis it is more convenient to
use N-methylpyrrolidinone (NMP) as a solvent along with
slightly modified reaction conditions (entries 8–11).[15]
To further demonstrate the utility of our decarbonylative
dehydration approach to vinylation, we embarked on a total
synthesis of aspewentin B (1, Figure 1), a norditerpene nat-
ural product isolated from Aspergillus wentii.[16,17] This
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terpenoid contains an a-vinyl quaternary cyclohexanone
scaffold, and is therefore ideally suited for our chemistry.
Retrosynthetically, we envisioned that the vinyl group could
be formed by decarbonylative dehydration of the d-oxocar-
boxylic acid 11, which might be obtained by elaboration of the
allyl ketone 12 (Scheme 3).[18] The quaternary stereocenter
would be set by palladium-catalyzed enantioselective allylic
alkylation of the tricyclic ketone 13, which could be con-
structed from the known aryl bromide 14.[19]
Scheme 3. Retrosynthetic analysis of (À)-aspewentin B.
We commenced our total synthesis by copper-catalyzed
coupling of a Grignard reagent derived from 14 with ethyl 4-
iodobutyrate (Scheme 4).[20] a-Methylation of the coupled
product produces the ester 15, which was saponified and then
cyclized to form the tricyclic ketone 13. The ketone was
converted into the corresponding allyl enol carbonate (16),
which was then subjected to palladium-catalyzed enantiose-
lective decarboxylative allylic alkylation to afford the allyl
ketone 12 in nearly quantitative yield and 94% ee. Interest-
ingly, the allylic alkylation reaction proceeds efficiently with
a low palladium catalyst loading, employing a new catalytic
protocol recently developed by our group.[21] Only 2.7 mg of
Pd(OAc)2 is needed for a reaction of 1.42 grams of starting
material (16) to deliver 1.25 grams of allyl ketone product
(12). Hydroboration/oxidation of the terminal olefin of 12,
and further oxidation, delivers 11 in 73% yield.[18] Gratify-
ingly, palladium-catalyzed decarbonylative dehydration[22]
furnishes the a-vinyl ketone 17 in 93% yield.[23] Removal of
the O-methyl group provides (À)-aspewentin B (1) in 78%
yield.[24] Thus, (À)-aspewentin B (1) was synthesized in nine
steps and 25% overall yield from known starting materials.
With 1 in hand, two other natural products of the aspewentin
family can also be accessed. Reduction of the ketone moiety
of 1 furnishes (À)-aspewentin A (18) in 85% yield.[25]
Oxidation of the phenol in 18 affords (À)-aspewentin C (19)
in 13% yield and (+)-10-epi-aspewentin C (20) in 7% yield,
over two steps.[26]
Scheme 4. Total synthesis of (À)-aspewentin A, B, and C. cap=capro-
lactamate, DCE=1,2-dichloroethane, DIBAL-H=diisobutylaluminum
hydride, HMDS=hexamethyldisilazide, LDA=lithium diisopropyla-
mide, MTBE=methyl tert-butyl ether, NMP=N-methylpyrrolidone,
PHOX=phosphinooxazoline, TFA=trifluoroacetic acid, THF=tetrahy-
drofuran.
method to the first enantioselective total synthesis of (À)-
aspewentins A, B, and C. Further applications of this trans-
formation in natural product synthesis are currently ongoing
in our lab and will be reported in due course.
Keywords: enantioselectivity · natural products · olefination ·
palladium · total synthesis
In summary, we have developed a new approach to access
a-vinyl quaternary carbonyl compounds by palladium-cata-
lyzed decarbonylative dehydration of d-oxocarboxylic acids.
A variety of acids with different scaffolds and functional
groups can be transformed into the corresponding a-vinyl
carbonyl compounds without erosion of the stereointegrity of
the neighboring quaternary center. We have also applied the
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11800–11803
Angew. Chem. 2015, 127, 11966–11969
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[22] Decarbonylative dehydration of 11 using Ac2O under standard
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[23] An alternative route from the allyl ketone 12 to vinyl ketone 17
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unsuccessful, likely a result of the steric bulk at the adjacent
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[24] Spectroscopic data (1H and 13C NMR) and exact mass of the
synthetic compound matches those of natural (+)-aspewentin B.
The optical rotation, however, is significantly different (synthetic
25
compound: [a]D À90.5 (c 0.20, MeOH, 98% ee); natural
20
product: [a]D + 23.3 (c 0.20, MeOH)). HPLC analysis showed
the synthetic compound to be of 98% ee. Based on the
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[15] The small-scale reactions were performed under 1 atm N2 (no
distillation). Acetic anhydride was found to be unsuitable under
such conditions, while benzoic anhydride proved to be optimal.
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[17] While the natural product has (+) stereochemistry, we synthe-
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(S)-tBuPHOX ligand.
Received: June 6, 2015
Published online: July 29, 2015
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