BURTOLOSO GROUP MEETING

Ketene Chemistry:
From Discovery to Total Synthesis

Evandro de Azevedo Rocha

March 1st, 2019
 Burtoloso Group Meeting- Ketene Chemistry

Content
.1. A brief history of ketene
2. Ketene reactivity .
.3. Ketene preparation
4. Ketene in synthesis .
.5. Application in total synthesis 2
 Burtoloso Group Meeting- Ketene Chemistry

1. A brief of history

Edgar Wedekind Hermann Staudinger Ludwig Wolff

1901 1905 1902

Tidwell, T. T. (2005). The first century of ketenes (1905–2005): the birth of a versatile family of reactive
3
intermediates. Angewandte Chemie International Edition, 44(36), 5778-5785 .
 Burtoloso Group Meeting- Ketene Chemistry

2. Structure and Reactivity

Frontier orbitals Resonance structure Spectroscopy data

Ketene: 2200-2100 cm-1

Alkenes: 1680 cm-1
IR Alkynes: 2200 cm-1
Allenes: 1960-1950 cm-1
Carbonyl: 1760-1665 cm-1

δCα=203-178 ppm
RMN-13C
δCβ=48-33 ppm
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Tidwell TT. Ketenes. 2nd ed. Hoboken, NJ: Wiley Interscience; 2006
 Burtoloso Group Meeting- Ketene Chemistry

2. Structure and Reactivity

Structure

Electronic and
Properties steric effects
Not Isolable Isolable

Substituents

5
Nguyen MT, Ha T, More O’Ferrall RA. J Org Chem. 1990;55:3251–3256.
 Burtoloso Group Meeting- Ketene Chemistry

2. Structure and Reactivity

Table 1. Comparative calculated stabilization energies (Kcal.mol-1) for ketenes
RCH=C=O for the isodesmic reactions

R ∆E(MP2)
H 3.9
Li 30.1 ∆E + Estável
MgH 23.2
AlH2 20.1
SiH3 11.5 ∆E - Estável
NH2 -9.3
OH -14.5
F -16.9
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Boyd RJ, Edgecombe KE. J Am Chem Soc. 1988;110:4182–4186
 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation

. a. Ketenes by Eliminations from Carboxylic Acid

. b. Ketene by Oxidative, Reductive
. c. Ketene by Wolff Rearrangement
. d. Ketene from Metal Carbene Complexes
.e. Ketenes from other sources 7
 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes by Eliminations from Carboxylic Acid

Great Pharmaceutical Importance

a. Kumar K, Kaur S, Ishar MPS. Synlett. 1999;8:1237–1238; b. Lang RW, Hansen H-J. Helv Chim Acta. 1980;63:438–455; c. Yamagami T, Hatsuda M, Utsugi M,
Kobayashi R, Moritani Y. Eur J Org Chem. 2013;33:7467–7470; d. Yamagami T, Moriyama N, Kyuhara M, et al. Org Proc Res Dev. 2014;18:437–445; e. Larsen 8
RD, Corley EG, Davis P, Reider PJ, Grabowski EJJ. J Am Chem Soc. 1989;111:7650–7651.
 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes by eliminations from carboxylic acid

77%

Ester which was

used as na
intermediate for
the synthesis of
lyngbyaloside B

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Yadav JS, Haldar A, Maity T. Eur J Org Chem. 2013;15:3076–3085;
 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes by eliminations from carboxylic acid

69%

This method was used in the acylation of a variety of resin bound peptides

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.
Chandra K, Roy TK, Naoum JN, Gilon C, Gerber RB, Friedler A. Org Biomol Chem. 2014;12:1879–1884
 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes by oxidative and reductive

Reductive

Hydrogenation of palmitic acid using Ni/ZrO2 catalyst at 250°C proceeds through formation
of ketene as an adsorbed intermediate, ans this then reduced to the aldehyde.

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Peng B, Zhao C, Kasakov S, Foraita S, Lercher JA. Chem Eur J. 2013;19:4732–4741 .
 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes by oxidative and reductive

Oxidative

Ketenes have been prepared for oxidation of acetic acid on a gold surface supported on
(TiO)2 which has been shown to involve formation of the gold ketenylidene specie.
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a. Green IX, Tang W, Neurock M, Yates JT. Faraday Discuss. 2013;162:247–265; b. Green IX, Tang W, Neurock M, Yates JT. Acc Chem Res. 2014;47:805–815;
 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes by Wolff rearrangement

Thermal Wolff

55%

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Vidal A, Marin-Luna M, Alajarin M. Eur J Org Chem. 2014;4:878–886.
 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes by Wolff rearrangement

Photochemical Wolff

83%
Allen AD, Fedorov AV, Fu N, Kobayashi S, Tidwell TT, Vukovic S, Badal MdMR, Mishima M. Can J Chem. in press.

Metal-catalyzed Wolff

80-91%

Sudrik, S.G. et al. Org. Lett.2003, 2355

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 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes from metal carbene complexes

78%

Hegedus, L. S. et al. J. Am. Chem. Soc. 1996, 7873

93%
Wang, J. et al. J. Am. Chem. Soc. 2011, 4330

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 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes by others methods

Peng, Z.; McLuckey, S. A. Int. J. Mass Spectrometry 2015, 391, 17–23.

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 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes by others methods

75%

Fosfotriesterase is a dimeric and binuclear

metalloenzyme derived from the bacterium
Brevudimonas diminuta. This enzyme has a
unique ability to catalyze a hydrolytic selection
in the P-O, P-S, P-CN and P-F options in a wide
variety of organophosphates.

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Banzon A, Kuo JM, Miles BR, Fischer DR, Stang PJ, Raushel FM. Biochemistry. 1995;34:743–749;
 Burtoloso Group Meeting- Ketene Chemistry

3. Ketene preparation: Ketenes by others methods

71%

Robb, M. J.; Moore, J. S. J. Am. Chem. Soc. 2015, 137, 10946−10949 .

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 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Cycloadditons

The reaction proceeds through a [2 + 2] cycloaddition forming a cyclobutane, followed by a vinyl
ketene formation opening as an unobserved intermediate or followed by an intramolecular
electrocyclization

Smith LI, Hoehn HH. J Am Chem Soc. 1939;61:2619–2624. 19

Smith LI, Hoehn HH. J Am Chem Soc. 1941;63:1180–1181.
 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Cycloadditons

[2+2] Cycloaddition with Alkenes
Dichloroketene generated in situ by zinc dechlorination of trichloroacetyl chloride reacts by a
highly stereoselective [2+2] cycloaddition with the alkene giving the cyclobutanone which is
used in the synthesis of a variety of other polyclic products

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Surendra K, Rajendar G, Corey EJ. J Am Chem Soc. 2014;136:642–645.
 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Cycloadditons

[2+2] Cycloaddition with Imines
Vinylketene forms in 99% conversion from rhodium catalyzed reaction of diazo ester as
observed in NMR, and subsequent [2+2] cycloaddition with imine gives β-lactama

This work was extended to a one-pot multicomponent procedure involving two different
ketenes derived from diazo ketones

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Mandler MD, Truong PM, Zavalij PY, Doyle MP. Org Lett. 2014;16:740–743.
 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Nucleophilic Additions

Hydration of Ketene

86%

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 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Nucleophilic Additions

Esterification of ketene
Thermal generation of ketenes in the presence of alcohols senstitive to acid or base permits the
formation of esters under neutral conditions and is a valuable technique for use with such
substrates

Miyatake-Ondozabal H, Barrett AGM. Tetrahedron Lett. 2013;54:4817–4820.

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 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Nucleophilic Additions

Esterification of ketene
Alkyl(aryl)ketenes react with betaines prepared from sulfoxonium ylides with acetaldehyde by
nucleophilic attack on the ketene followed by a net [3+2] cycloaddition with displacement to
give trans γ-lactona

(60%, dr 83:17)
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Mondal M, Ho H-J, Peraino NJ, Gary MA, Wheeler KA, Kerrigan NJ. J Org Chem. 2013;78:4587–4593.
 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Nucleophilic Additions

Esterification of ketene
Alkyl(aryl)ketenes react with readily enolizable
aldehydes with catalysis by XXX to give
stereoselective formation of enol ester

99%, 97% ee

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a. Schaefer C, Fu GC. Angew Chem Int Ed. 2005;44:4606–4608;
 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Nucleophilic Additions

Amination of Ketene
Acylketene generation by dioxinone thermolysis with cyclization on a pendent amino group
together with na intramolecular Diels-Alder forms a large ring lactam.

Reber KP, Tilley SD, Carson CA, Sorensen EJ. J Org Chem. 2013;78:9584–9607.

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 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Nucleophilic Additions

Ketene Reactions with Carbon Nucleophiles
Phenylketene generated by photochemical Wolff rearrangement in the presence of na acid
anydride and na isocyanate gives a 3-component reaction forming acrylamide

Basso A, Banfi L, Garbarino S, Riva R. Angew Chem Int Ed. 2013;52:2096–2099; 27

Garbarino G, Banfi L, Riva R, Basso A. J Org Chem. 2014;79:3615–3622;
 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Nucleophilic Additions

Ketene Reactions with Carbon Nucleophiles

Excellent
Regiosselectivities
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Mohanan K, Presset M, Mailhol D, Coquerel Y, Rodriguez J. Chem Eur J. 2012;18: 9217–9220.
 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Nucleophilic Additions

Wittig reaction
Simplest a-vinylidene-7-butyrolactones triphenylphosphine derivatives in CHsCl, solution
react readily with gaxeous ketene to afford a-vinylidene-7-butyrolactones respectively in
high yields.

Buono, G. et al. Tetrahedron Lett. 1990, 4859

Wittig reagent was formed in solution reacts with methylketene also generated in situ to
give a ketene-Wittig reaction forming de product allene.

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Xu S, Zhu S, Shang J, Zhang J, Tang Y, Dou J. J Org Chem. 2014;79:3696–3703
 Burtoloso Group Meeting- Ketene Chemistry

4. Ketene in synthesis: Polymer Chemistry

Used for printing

submicrometer-scale
patterns for microcontact
printing

30
.
Aida, T. et al. J. Am. Chem. Soc. 2011, 2840
 Burtoloso Group Meeting- Ketene Chemistry

4. Application in total synthesis

Ginkgolide B

Active
biological
terpene lactons
present in
Ginkgo biloba
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Corey et al. J. Am. Chem. Soc. 1998, 649.
 Burtoloso Group Meeting- Ketene Chemistry

4. Application in total synthesis

Epicoccins derivative

Is a species of fungus, in
the phylum Ascomycota

32
.
Brase, S et al. Chem. Eur. J. 2016, 11624
 Burtoloso Group Meeting- Ketene Chemistry

4. Application in total synthesis

Macrocidin A

Represent a new family of plant pathogens

produced by Phoma macrostoma, a
microorganism parasitic to Canadian thistle
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Hoye, T. R. et al. J. Org. Chem. 2012, 7052.
 Burtoloso Group Meeting- Ketene Chemistry

4. Application in total synthesis

(+)-FR900482
Antitumor agent

34
.
Danheiser, R. L. et al. J. Org. Chem. 2011, 1852