Dialkoxycarbenes in (4 + 1) Cycloadditions: Application to the Synthesis of Carotol

Article abstract of DOI:10.1021/acs.orglett.6b02023

Dialkoxycarbenes are more reactive than NHCs and participate in many reactions including a formal (4 + 1) cycloaddition with electron-deficient dienes. We have learned to control the relative stereochemistry of the newly created chiral carbons in this pro

Full text of DOI:10.1021/acs.orglett.6b02023

Letter
pubs.acs.org/OrgLett
Dialkoxycarbenes in (4 + 1) Cycloadditions: Application to the
Synthesis of Carotol
Machhindra Gund, Martin Dery,† Valerie Amzallag, and Claude Spino*
́
́
́ ́ ́
Universite de Sherbrooke, Departement de Chimie, 2500 Boul. Universite, Sherbrooke, QC J1K 2R1, Canada
S
* Supporting Information
ABSTRACT: Dialkoxycarbenes are more reactive than NHCs
and participate in many reactions including a formal (4 + 1)
cycloaddition with electron-deficient dienes. We have learned
to control the relative stereochemistry of the newly created
chiral carbons in this process and now report that, combined
with a chiral auxiliary, it has been used successfully in a short
and efficient synthesis of the sesquiterpene carotol.
ialkoxycarbenes1 (DACs) are the more reactive counter-
Dparts of the better known N-heterocyclic carbenes
(NHCs)2 and acyclic diaminocarbenes (ADCs).3 Dialkoxycar-
benes participate as nucleophilic species in reactions with
carbonyls, alkenes, alkynes,1 isocyanates,4 and vinyl isocya-
nates.5 We have ourselves described their reaction with
electron-deficient dienes to give (4 + 1) cycloadducts.6 The
reaction takes place via a concerted (4 + 1) cycloaddition or a
concerted cyclopropanation/vinylcyclopropane rearrangement,
depending on the substrate structure.
Scheme 1. Retrosynthetic Analysis for Carotol
Dialkoxycarbenes can be generated easily using Warkentin’s
oxadiazoline method, but despite this fact, relatively few
applications of DACs to the synthesis of natural products
have been reported.7 We wish to report a short and efficient
synthesis of carotol and thus showcase the convenience of
oxadiazolines as DAC precursors and the effectiveness of the (4
+ 1) cycloaddition between DACs and dienes to construct
natural products.
generate a 5−5 cis-fused ring system 3 having the C2−C5
relative stereochemistry as shown.6 If the tether had been four
or five atoms long, the C2−C5 stereochemistry of the
corresponding oxabicyclic cycloadducts would have been the
opposite of that shown for product 3. For many synthetic
targets, the length of the tether is of little consequence after the
cyclic acetal has been opened. The three-atom tether supplies
the right number of carbons to efficiently complete the
syntheses of members of this family of sesquiterpenes.
(+)-Carotol (1) is a daucane-type sesquiterpene found in the
seeds and roots of many plants of the Apiaceae (carrots) and
Zingiberaceae (ginger) families.8 Controversy existed around its
9
̌
structure for a while, but it was eventually proven by Sorm in
1959.10 It has strong larvicidal11 and antimicrobial12 activities
and acts as a potent olfactive attractant to the black bean aphid
(Aphis fabae).13
First, the carbene precursor 8a was prepared starting from 3-
butyn-1-ol (4), which was subjected to Negishi’s carboalumi-
nation protocol to give vinyl iodide 5 (Scheme 2). The latter
was efficiently coupled to methyl vinyl ketone via a Heck
reaction to give diene 6 as a single E,E geometrical isomer.
Submitting alcohol 6 to a catalytic amount of camphorsulfonic
We are aware of only one synthesis of (+)-carotol in very low
yield from (+)-daucene by Levisalles and co-workers in 1972.14
Approaches to the daucane skeleton have been reported,
however.15
The diastereocontrol exerted over the C2−C5 relative
stereochemistry by the length of the tether connecting the
carbene to the diene in intermediate 2 is a key feature of our
strategy (Scheme 1). When the tether is composed of three
atoms, the formal (4 + 1) cycloaddition of carbene 2 will
Received: July 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02023
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Preparation of the DAC Precursors 8a and 8b
Scheme 4. Synthesis and Alkynylation of Ketones 15
was best achieved with Amberlyst-15 resin and gave good yields
of the corresponding keto alcohols ( )-15 or (−)-15. In the
latter case, the commercial chiral auxiliary (alcohol) could be
recovered in 89% yield and reused. A very small amount of
epimerization occurred, but the C2 epimer could easily be
separated from (−)-15. Keto alcohol (−)-15 had been made by
Srikrishna and co-workers in eight steps from (+)-limonene.16
We have made it in seven steps from 3-butyn-1-ol.
acid and Warkentin’s oxadiazoline 7a gave an excellent yield of
the DAC precursor 8a.
Heating a toluene solution of oxadiazoline 8a to reflux
temperature afforded an 84% yield of an expected 93:7 mixture
of oxabicyclo[3.3.0]octenes 10a and 10b, which are easily
separable by normal column chromatography (Scheme 3).
Scheme 3. Key (4 + 1) Cycloadditions
The optical rotation of (−)-15 was compared with the one
obtained by Srikrishna, and we thus could infer that the major
diastereomer formed in the formal (4 + 1) cycloaddition was
compound 11.17 The absolute stereochemistry of natural
(+)-carotol was established in 1964.18 In addition, the minor
diastereomer 12 was also transformed into the corresponding
diastereomer of 14b (not shown), and X-ray diffraction analysis
of a single crystal confirmed the assignation. The mechanism of
the reaction proceeds via the formation of a cyclopropane,6
which is the stereodetermining step, followed by rearrange-
ment. Following our model,6 we believe that the average of
conformers A and B, lacking the steric interaction between the
R group and the rest of the molecule, is favored over the
average of conformers C and D, in which the R group is
directed toward the forming ring (conformation D), leading to
the preferred formation of 11 (Figure 1).
We then completed the synthesis of carotol using racemic
alcohol 15. We tried to add sp3- or sp2-hybridized carbon
nucleophiles to ketone 15, but all of our efforts were in vain
(Scheme 4).19 Only alkynylmetals successfully added to this
rather hindered ketone. We tried several different ones and
reaction conditions and opted for the cerium derivative of TBS-
protected 2-methylbut-3-yn-2-ol (16).20 The TBS protecting
group also helps avoid inopportune hydrogenolysis of the
adjacent C−O bond during the subsequent hydrogenation of
the triple bond. This was best accomplished with Pd on
alumina to give compound 18 in excellent yield.
Their relative stereochemistries were assigned by NOESY
experiments (see the Supporting Information). Then the chiral
alcohol corresponding to structure 9 was transformed into the
corresponding oxadiazoline 7b following Warkentin’s proce-
dure (Scheme 2; see the Supporting Information for details).
The exchange of acetate in 7b for alcohol 6 was efficient, and
the resulting chiral carbene precursor 8b underwent the formal
(4 + 1) cycloaddition with success in 74% yield (Scheme 3).
The C2−C5 relative stereochemistry was unaffected by the
chirality of the auxiliary, remaining >93:7. After separation, a
55% yield of optically pure oxabicycle 11 was isolated from a
70:30 ratio of diastereomers 11 and 12 in the crude mixture.
Converting the methyl ketone in 10a or 11 to the isopropyl
unit in 13a or 13b, respectively, was uneventful: the missing
carbon was added using the Petasis reagent, and both double
bonds were hydrogenated over platinum oxide (Scheme 4).
Hydrolysis of the acetal in racemic 14a or optically pure 14b
The primary alcohol was oxidized with IBX, and the resulting
aldehyde underwent a Wittig olefination to give product 19
(Scheme 5). After deprotection, the tertiary alcohol was
submitted to Martin’s sulfurane reagent to give the elimination
product 20 with the terminal double bond as the major
B
DOI: 10.1021/acs.orglett.6b02023
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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AUTHOR INFORMATION
■
Corresponding Author
* Claude.Spino@USherbrooke.ca
Present Address
†M.D.: Paraza Pharma, 7171 Rue Frederick-Banting, Montreal,
QC H4S 1Z9, Canada.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Universite
́
de Sherbrooke and the Natural
Sciences and Engineering Research Council for financial
support.
Figure 1. Suggested model for the diastereoselectivity.
REFERENCES
■
(1) For a review of dialkoxycarbenes, see: Warkentin, J. Acc. Chem.
Res. 2009, 42, 205−212.
Scheme 5. Completion of the Synthesis of Carotol
(2) For reviews of the use of NHCs as reagents and catalysts, see:
(a) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42,
4906−4917. (b) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int.
Ed. 2004, 43, 5130−5135. Also see: (c) Legault, M. C. B.; McKay, C.
S.; Moran, J.; Lafreniere, M. A.; Pezacki, J. P. Tetrahedron Lett. 2012,
53, 5663−5666.
(3) Boyarskiy, V. P.; Luzyanin, K. V.; Kukushkin, V. Y. Coord. Chem.
Rev. 2012, 256, 2029−2056.
(4) Rigby, J. H.; Brouet, J.-C.; Burke, P. J.; Rohach, S.; Sidique, S.;
Heeg, M. J. Org. Lett. 2006, 8, 3121−3123.
(5) Rigby, J. H.; Cavezza, A.; Ahmed, G. J. Am. Chem. Soc. 1996, 118,
12848−12849.
(6) (a) Beaumier, F.; Dupuis, M.; Spino, C.; Legault, C. Y. J. Am.
Chem. Soc. 2012, 134, 5938−5953. (b) Boisvert, L.; Beaumier, F.;
Spino, C. Org. Lett. 2007, 9, 5361−5363. (c) Spino, C.; Rezaei, H.;
Dupont-Gaudet, K.; Bel
9927.
́
anger, F. J. Am. Chem. Soc. 2004, 126, 9926−
product. A ring-closing metathesis21 gave pure racemic carotol
in 69% yield from the mixture of alkene isomers (the corrected
yield of the desired RCM product is 86%). Since we have in
hand optically pure (−)-15, we have also achieved a formal
synthesis of (+)-carotol. The synthesis has a total of 14 steps
from the structurally very simple 3-butyn-1-ol, a global yield of
5.6% (counting the nonracemic route), and an average of 82%
yield per step.
With this short synthesis of carotol, we have demonstrated
the power of DACs as partners in (4 + 1) cycloadditions. It is
noteworthy that an all-carbon quaternary center was thus created
with control over its relative and absolute stereochemistry.
Ketone 15 is a central fragment for many terpenoids of this
type.15
(7) (a) Rigby, J. H.; Cavezza, A.; Heeg, M. J. J. Am. Chem. Soc. 1998,
120, 3664−3670. For the use of a dialkylthiocarbene in synthesis, see:
(b) Rigby, J. H.; Dong, W. Org. Lett. 2000, 2, 1673−1675. For a
synthetic approach to indole alkaloids using dimethoxycarbene, see:
(c) Rigby, J. H.; Burke, P. J. Heterocycles 2006, 67, 643−653.
(8) (a) Williams, C. A.; Harborne, J. B. Phytochemistry 1972, 11,
1981−1987. (b) Ghisalberti, E. L. Phytochemistry 1994, 37, 597−623.
(9) (a) Platzer, N.; Goasdoue, N.; Davoust, D. Magn. Reson. Chem.
1987, 25, 311−319. (b) Zalkow, L. H.; Eisenbraun, E. J.; Shoolery, J.
N. J. Org. Chem. 1961, 26, 981−982. (c) Sykora, V.; Novotny, L.;
́
́
̌
Holub, M.; Herout, V.; Sorm, F. Collect. Czech. Chem. Commun. 1961,
̌
26, 788−802. (d) Sorm, F.; Urbanek, L. Collect. Czech. Chem. Commun.
̌
1948, 13, 49−58. (e) Sorm, F.; Urbanek, L. Collect. Czech. Chem.
̌
Commun. 1948, 13, 420−427. (f) Sykora, V.; Novotny, L.; Sorm, F.
́
́
Tetrahedron Lett. 1959, 1, 24−28. (g) Chiurdoglu, G.; Descamps, M.
Chem. Ind. 1959, 1377−1387.
(10) Chiurdoglu, G.; Descamps, M. Tetrahedron 1960, 8, 271−290.
(11) (a) Park, H.-M.; Park, I.-K. J. Asia-Pac. Entomol. 2012, 15, 631−
634. (b) Ho, J.-C. J. Chin. Chem. Soc. 2011, 58, 563−567.
(12) (a) Agnihotri, S.; Wakode, S.; Ali, M. J. Essent. Oil-Bear. Plants
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02023.
2011, 14, 417−422. (b) Alarcon, L. D.; Pena, A. E.; Gonzales de C, N.;
́
̃
Quintero, A.; Meza, M.; Usubillaga, A.; Velasco, J. Rev. Soc. Quim. Peru
2009, 75, 221−227. (c) Glisic, S. B.; Misic, D. R.; Stamenic, M. D.;
Zizovic, I. T.; Asanin, R. M.; Skala, D. U. Food Chem. 2007, 105, 346−
352.
̌
̌
̌
Characterization data and copies of NMR spectra for
new compounds and an ORTEP of compound 14b
(PDF)
(13) Lipok, J.; Jasicka-Misiak, I.; Wieczorek, P. P. Pestycydy 2005,
201−207.
C
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(14) (a) De Broissia, H.; Levisalles, J.; Rudler, H. Bull. Soc. Chim. Fr.
1972, 11, 4314−4318. (b) De Broissia, H.; Levisalles, J.; Rudler, H. J.
Chem. Soc., Chem. Commun. 1972, 855.
(15) For a review of approaches to this and other related carbon
skeletons, see: Foley, D. A.; Maguire, A. R. Tetrahedron 2010, 66,
1131−1175. Also see, for example: Bennett, N. B.; Stoltz, B. M. Chem.
- Eur. J. 2013, 19, 17745−17750.
(16) Srikrishna, A.; Nagaraju, G.; Ravi, G. Synlett 2010, 2010, 3015−
3018.
(17) The [α]D of their compound is −80.7 (c = 1.5, CHCl3). See:
Ravi, G. Ph.D. Thesis, Indian Institute of Science, July 2009; pp 163−
164. Ours are −85.9 (c = 1.5, CHCl3) for compound (−)-15 obtained
from the major isomer 11 and +83.4 (c = 1.5, CHCl3) for compound
(+)-15 obtained from the minor isomer 12.
(18) (a) Levisalles, J.; Rudler, H. Bull. Soc. Chim. Fr. 1964, 2020−
2021. (b) Levisalles, J.; Rudler, H. Bull. Soc. Chim. Fr. 1967, 2059−
2066.
(19) We were not the only ones to have trouble with similar ketones.
See: Wender, P. A.; Bi, F. C.; Brodney, M. A.; Gosselin, F. Org. Lett.
2001, 3, 2105−2108. However, allylmagnesium bromide was added to
a derivative (see ref 16).
(20) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392−4398.
(21) (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003; Vols. 1−3. (b) Fu, G. C.; Nguyen, S. T.;
Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856−9857.
D
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Org. Lett. XXXX, XXX, XXX−XXX