of 12
Palladium-Catalyzed Decarbonylative Dehydration for the
Synthesis of
α
-Vinyl Carbonyl Compounds and Total Synthesis
of (−)-Aspewentin A, B, and C
Yiyang Liu
a
,
Scott C. Virgil
a
,
Robert H. Grubbs
a,*
, and
Brian M. Stoltz
a,*
a
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E.
California Blvd, MC 101-20, Pasadena, CA 91125 (USA)
Abstract
The direct
α
-vinylation of carbonyl compounds that forms a quaternary stereocenter is a
challenging transformation. We discovered that
δ
-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
α
-vinyl quaternary carbonyl compounds are obtained in good yields, and
an application in the first enantioselective total synthesis of (−)-aspewentin A, B, and C is
demonstrated.
Keywords
α
-vinyl carbonyl compounds; decarbonylative dehydration; palladium catalysis; quaternary
stereocenters
An all-carbon quaternary center bearing an ethylene substituent is a common structural
motif in many natural products (see Figure 1).
[
1
]
An important approach to the construction
of this unit is the
α
-vinylation of carbonyl compounds, 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,3c
,
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. Due to these constraints, even the simplest 2-
methyl-2-vinylcyclohexanone (
7
) is not known as a single enantiomer in the literature.
We envisioned an alternative approach to access
α
-vinyl carbonyl compounds, by
employing a decarboxylative elimination of
δ
-oxocarboxylic acids (Scheme 1). These acids
Fax: (+1) 626-395-8436, stoltz@caltech.edu, rhg@caltech.edu.
HHS Public Access
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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 for the enantioselective construction of the requisite quaternary stereocenter.
Recently, we reported on the palladium-catalyzed decarbonylative dehydration of fatty acids
to form terminal olefins.
[
12
]
Due to the importance of
α
-vinyl carbonyl compounds and the
challenges in their preparation, we became interested in applying our decarbonylative
dehydration chemistry as an alternative strategy to
α
-vinylation. Since the carboxylic acid,
which bears a quaternary center two atoms away from the reactive carboxyl 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 g 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 carboxylic acid
8a
and subjected it to
modified palladium-catalyzed decarbonylative dehydration conditions, when slightly higher
loadings of catalyst, ligand, and additive were employed (Scheme 2). We were pleased to
isolate vinyl cyclopentanone
9a
in 67% yield.
[
13
]
This result demonstrated that steric bulk at
the quaternary center does not significantly retard the reaction, but proximal functionality
(e.g. the ketone) could alter the reaction pathway.
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
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, which can be prepared via palladium-catalyzed allylic
alkylation,
[
11
]
also underwent decarbonylative dehydration smoothly to provide the
corresponding 2-allyl-2-vinyl-substituted cyclohexanones
9d
and
9e
(entries 4 and 5), the
latter in 92% ee from enantioenriched acid
8e
. It is worth noting that double bond
isomerization in the allyl moiety is negligible for
9d
and does not occur at all for
9e
. Acylic
keto acid
8f
is converted to acyclic ketone
9f
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
α
-vinyl ester
9g
, lactam
9h
, and aldehyde
9i
can all be prepared in good
yields. More complex scaffolds such as acid
8j
, obtained by oxidative cleavage of
testosterone,
[
14
]
also undergo the reaction to provide vinylated tricycle
9j
(entry 11). While
the reaction can be carried out in the absence of a solvent at a fairly large scale (5 mmol,
entries 1–7), we found that for smaller scale synthesis it is more convenient to use
N
-
methylpyrrolidinone (NMP) as solvent along with slightly modified 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 natural
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product isolated from
Aspergillus wentii
.
[
16
,
17
]
This terpenoid contains an
α
-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
δ
-oxocarboxylic acid
11
, which might be obtained by elaboration of allyl
ketone
12
.
[
18
]
The quaternary stereocenter would be set by palladium-catalyzed
enantioselective allylic alkylation of tricyclic ketone
13
, which could be constructed from
known aryl bromide
14
.
[
19
]
We commenced our total synthesis by copper-catalyzed coupling of a Grignard reagent
derived from aryl bromide
14
with ethyl 4-iodobutyrate (Scheme 4).
[
20
]
α
-Methylation of
the coupled product produces ester
15
, which was saponified and then cyclized to form
tricyclic ketone
13
. The ketone was converted to the corresponding allyl enol carbonate (
16
),
and subjected to palladium-catalyzed enantioselective decarboxylative allylic alkylation to
afford allyl ketone
12
in nearly quantitative yield and 94% ee. Interestingly, the allylic
alkylation reaction proceeds efficiently with low palladium catalyst loading, employing a
new catalytic protocol recently developed by our group.
[
21
]
Only 2.7 mg Pd(OAc)
2
is
needed for a reaction of 1.42 g starting material (
16
) to deliver 1.25 g allyl ketone product
(
12
). Hydroboration/oxidation of the terminal olefin of
12
, followed by further oxidation,
delivers carboxylic acid
11
in 73% yield.
[
18
]
Gratifyingly, palladium-catalyzed
decarbonylative dehydration
[
22
]
furnishes
α
-vinyl ketone
17
in 93% yield.
[
23
]
Removal of
the
O
-methyl group provides (−)-aspewentin B (
1
) in 78% yield.
[
24
]
Thus, (−)-aspewentin B
(
1
) was synthesized in 9 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 (−)-aspewentin A (
18
) in 85% yield.
[
25
]
Oxidation of the phenol in
18
affords (−)-aspewentin C (
19
) in 13% yield and (+)-10-
epi
-
aspewentin C (
20
) in 7% yield, over 2 steps.
[
26
]
In summary, we have developed a new approach to access
α
-vinyl quaternary carbonyl
compounds via palladium-catalyzed decarbonylative dehydration of
δ
-oxocarboxylic acids.
A variety of acids with different scaffolds and functional groups can be transformed into the
corresponding
α
-vinyl carbonyl compounds without erosion of the stereointegrity of the
neighboring quaternary center. We have also applied the method to the first enantioselective
total synthesis of (−)-aspewentin A, B, and C. Further applications of this transformation in
natural product synthesis are currently ongoing in our lab and will be reported in due course.
Experimental Section
See Supporting Information for experimental details.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgements
The authors wish to thank the Resnick Sustainability Institute at Caltech (graduate fellowship to Y.L.), NIH
(R01GM080269 to B.M.S., 5R01GM031332-27 to R.H.G.), the Gordon and Betty Moore Foundation, the Caltech
Liu et al.
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Center for Catalysis and Chemical Synthesis, and Caltech for financial support. Dr. David VanderVelde is
acknowledged for NMR spectroscopy assistance. Dr. Mona Shahgholi and Naseem Torian are acknowledged for
high-resolution mass spectrometry assistance. We would like to thank Prof. Richmond Sarpong of UC Berkeley for
helpful discussions.
References
1. a) Bernauer K, Englert G, Vetter W, Weiss E. Helv. Chim. Acta. 1969; 52:1886–1905.b) Moore RE,
Cheuk C, Patterson GML. J Am. Chem. Soc. 1984; 106:6456–6457.c) Masuda T, Masuda K,
Shiragami S, Jitoe A, Nakatani N. Tetrahedron. 1992; 48:6787–6792.d) Rubal JJ, Moreno-Dorado
FJ, Guerra FM, Jorge ZD, Saouf A, Akssira M, Mellouki F, Romero-Garrido R, Massanet GM.
Phytochemistry. 2007; 68:2480–2486. [PubMed: 17669447]
2. Nishimoto Y, Ueda H, Yasuda M, Baba A. Angew. Chem. Int. Ed. 2012; 51:8073–8076.
3. a) Chieffi A, Kamikawa K, Åhman J, Fox JM, Buchwald SL. Org. Lett. 2001; 3:1897–1900.
[PubMed: 11405739] b) Huang J, Bunel E, Faul MM. Org. Lett. 2007; 9:4343–4346. [PubMed:
17887766] c) Taylor AM, Altman RA, Buchwald SL. J Am. Chem. Soc. 2009; 131:9900–9901.
[PubMed: 19580273]
4. a) Nakamura M, Endo K, Nakamura E. Org. Lett. 2005; 7:3279–3281. [PubMed: 16018640] b)
Endo K, Hatakeyama T, Nakamura M, Nakamura E. J Am. Chem. Soc. 2007; 129:5264–5271.
[PubMed: 17388598] c) Fujimoto T, Endo K, Tsuji H, Nakamura M, Nakamura E. J Am. Chem.
Soc. 2008; 130:4492–4496. [PubMed: 18331035]
5. a) Yamaguchi M, Tsukagoshi T, Arisawa M. J Am. Chem. Soc. 1999; 121:4074–4075.b) Arisawa
M, Miyagawa C, Yoshimura S, Kido Y, Yamaguchi M. Chem. Lett. 2001:1080–1081.
6. Tanikaga R, Sugihara H, Tanaka K, Kaji A. Synthesis. 1977:299–301.
7. a) Kowalski CJ, Dung J-S. J Am. Chem. Soc. 1980; 102:7950–7951.b) Clive DLJ, Russell CG, Suri
SC. J Org. Chem. 1982; 41:1632–1641.
8. Nozoye T, Shibanuma Y, Nakai T, Hatori Y. Chem. Pharm. Bull. 1988; 36:4980–4985.
9. a) Meyers AI, Hanreich R, Wanner KT. J Am. Chem. Soc. 1985; 107:7776–7778.b) Kawashima H,
Kaneko Y, Sakai M, Kobayashi Y. Chem. – Eur. J. 2014; 20:272–278. [PubMed: 24273103]
10. Pfau M, Revial G, Guingant A, d’Angelo J. J Am. Chem. Soc. 1985; 107:273–274.
11. Mohr JT, Behenna DC, Harned AM, Stoltz BM. Angew. Chem. Int. Ed. 2005; 44:6924–6927.
12. Liu Y, Kim KE, Herbert MB, Fedorov A, Grubbs RH, Stoltz BM. Adv. Synth. Catal. 2014;
356:130–136. [PubMed: 24772061]
13. Cyclic lactone
10
was also isolated in 20% yield as the major byproduct. Byproducts of this type
are observed in cases where cyclic ketones possess an enolizable position.
14. de Avellar IGJ, Vierhapper FW. Tetrahedron. 2000; 56:9957–9965.
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.
16. Miao F-P, Liang X-R, Liu X-H, Ji N-Y. J Nat. Prod. 2014; 77:429–432. [PubMed: 24499164]
17. While the natural product has (+)-stereochemistry, we synthesized the (−)-enantiomer due to the
ready availability of the (
S
)-
t
-BuPHOX ligand.
18. The enantioselective Michael addition does not work for 1-tetralone substrates. For details, see:
d’Angelo J, Desmaële D, Dumas F, Guingant A. Tetrahedron Asymmetry. 1992; 3:459–505.
19. Allergan, Inc. Patent. WO2005/58301 A1. 2005.
Liu et al.
Page 4
Angew Chem Int Ed Engl
. Author manuscript; available in PMC 2016 September 28.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript
20. Brown ML, Eidam HA, Paige M, Jones PJ, Patel MK. Bioorg. Med. Chem. 2009; 17:7056–7063.
[PubMed: 19747831]
21. Stoltz BM, et al. Manuscript accepted by Adv. Synth. Catal.
22. Decarbonylative dehydration of
11
using Ac
2
O under standard vacuum distillation conditions
results in no conversion; the reaction mixture solidifies upon distillation of AcOH.
23. An alternative route from allyl ketone
12
to vinyl ketone
17
involves isomerization of the double
bond to the internal position followed by ethenolysis. While the isomerization (i.e.
12
SI-17
)
proceeded smoothly using the protocol developed by Nishida ( Arisawa M, Terada Y, Nakagawa
M, Nishida A. Angew. Chem. Int. Ed. 2002; 41:4732–4734. ) to afford internal olefin
SI-17
,
attempts at ethenolysis of the resulting internal olefin were unsuccessful, likely due to steric bulk
at the adjacent quaternary center. See Supporting Information for details.
24. Spectroscopic data (
1
H and
13
C NMR) and exact mass of the synthetic compound matches those of
natural (+)-aspewentin B. Optical rotation, however, is significantly different (synthetic
compound: [
α
]
D
25
−90.5 (
c
0.20, MeOH, 98% ee); natural product: [
α
]
D
20
+23.3 (
c
0.20,
MeOH)). HPLC analysis showed the synthetic compound to be of 98% ee. Based on the
stereoselectivity of the Pd-PHOX catalyst in previous examples, we reasoned that the absolute
configuration of our synthetic compound is opposite to that of the natural product, and thus the
sign of optical rotation is correct. The difference in magnitude may arise from the possibility that
the natural product contains an impurity, or that the natural product is a scalemic mixture (i.e. not
enantiopure). For a review on non-enantiopure natural products, see: Finefield JM, Sherman DH,
Kreitman M, Williams RM. Angew. Chem. Int. Ed. 2012; 51:4802–4836. Another possibility is
that the isolated natural product contained a small amount of impurity that had a large effect on
optical rotation.
25. Quandt G, Höfner G, Wanner KT. Bioorg. Med. Chem. 2013; 21:3363–3378. [PubMed:
23598250]
26. Carlsen PN, Mann TJ, Hoveyda AH, Frontier AJ. Angew. Chem. Int. Ed. 2014; 53:9334–9338.
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Figure 1.
Natural products with ethylene substituents.
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Scheme 1.
Decarboxylative approach to vinylation.
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Scheme 2.
Decarbonylative dehydration of
δ
-oxocarboxylic acid
8a
.
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Scheme 3.
Retrosynthetic analysis of (−)-aspewentin B.
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Scheme 4.
Total synthesis of (−)-aspewentin A, B, and C.
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Table 1
Decarbonylative dehydration of
δ
-oxocarboxylic acids.
[a]
5 mmol scale.
[b]
Isolated as a 95:5 mixture of desired product and internal olefin isomer.
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[c]
Condition: 0.5 mmol substrate (1 equiv), benzoic anhydride (1.2 equiv), PdCl
2
(nbd) (1 mol%), Xantphos (1.2 mol%), NMP (0.25 mL), 1 atm
N
2
, 132 °C, 3 h.
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