Enantioselective Intermolecular [2+2] Photocycloaddition Reaction of Cyclic Enones and Its Application in a Synthesis of (-)-Grandisol

Article abstract of DOI:10.1021/jacs.8b01011

The intermolecular [2+2] photocycloaddition of typical cyclic α,β-unsaturated enones, such as 2-cyclohexenone, with olefins was performed in moderate to good yields (42-82%) and with high enantioselectivity (82%-96% ee). An unusual substitution pattern at the chiral oxazaborolidine-AlBr₃ Lewis acid complex that promotes the reaction was found to be crucial for the success of the reaction. The method was applied to the enantioselective synthesis of the monoterpene (-)-grandisol, which could be accomplished in six steps and with an overall yield of 13% starting from 3-methyl-2-cyclohexenone.

Full text of DOI:10.1021/jacs.8b01011

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Communication
Enantioselective Intermolecular [2+2] Photocycloaddition Reaction
of Cyclic Enones and its Application in a Synthesis of (-)-Grandisol
Saner Poplata, and Thorsten Bach
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 19 Feb 2018
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Enantioselective Intermolecular [2+2] Photocycloaddition Reaction
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of Cyclic Enones and its Application in a Synthesis of (−)-Grandisol
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Saner Poplata and Thorsten Bach*
Department Chemie and Catalysis Research Center (CRC), Technische Universität München, Lichtenbergstrasse 4,
85747 Garching, Germany
Supporting Information Placeholder
ketone carbonyl group but does not remove any undesired
constitutional isomers. Most severely, there is up to this date
no way to access the cyclobutane products of a typical inter-
ABSTRACT: The intermolecular [2+2] photocycloaddition of
typical cyclic α,β-unsaturated enones, such as 2-cyclo-
hexenone, with olefins was performed in moderate to good
molecular enone [2+2] photocycloaddition reaction in an
yields (42-82%) and with high enantioselectivity (82%-96%
enantioselective fashion.6,7 Indirect methods which rely on
ee). An unusual substitution pattern at the chiral oxazoborol-
diastereoselective reactions require a major synthetic effort
idine-AlBr3 Lewis acid complex that promotes the reaction
involving multi-step sequences.8 Recently developed proto-
was found to be crucial for the success of the reaction. The
cols for enantioselective intermolecular [2+2] photocycload-
method was applied to the enantioselective synthesis of the
dition reactions9 are not applicable to unfunctionalized cy-
monoterpene (−)-grandisol which could be accomplished in
six steps and with an overall yield of 13% starting from 3-
methyl-2-cyclohexenone.
clic enones, such as 2-cyclohexenone (1a). We have now
found a way to prepare cyclobutanes such as 2a from enones
with high enantioselectivity and our results are disclosed in
this communication.
Although the intramolecular [2+2] photocycloaddition reac-
tion of cyclic enones had been discovered as early as 1908,1 it
was not before the 1960s that the first intermolecular variants
of this reaction were reported.2 Over the last 40 years, the
reaction has been employed as a key step in literally hun-
dreds of natural product synthesis3 and it represents one of
the most powerful transformations of organic chemistry.4
Typically, the reaction is induced by direct excitation of an
enone, such as 2-cyclohexenone (1a), the triplet state (T1) of
which is populated by rapid intersystem crossing (ISC) from
the first excited singlet state (S1). The former state is long-
lived and can be captured by a photochemically inactive
Figure 1. UV/Vis spectra of 2-cyclohexenone (1a) in the
absence () and in the presence of 20 equivalents of
either EtAlCl2 (− − −) or BCl3 (- - -) (c = 0.5 mM in CH2Cl2)
alkene to generate a cyclobutane. A representative reaction is
the addition of isobutene which was employed in Corey’s
landmark synthesis of racemic caryophyllene (Scheme 1).5
Scheme 1. Corey’s Landmark Synthesis of Racemic
Caryophyllene with an Intermolecular [2+2] Photocy-
cloaddition Reaction of 2-Cyclohexenone (1a) as the
Key step
In preliminary work we studied the UV/Vis properties of 2-
cyclohexenone (1a) upon treatment with Lewis acids (Figure
1). In line with previous observations,10,11 the strong ππ* ab-
sorption of the parent compound at λ = 224 nm (ε = 13400
1
1
M− cm− ) was shifted bathochromically and was recorded at
1. isobutene
1
1
O
λ = 260 nm (ε = 9670 M− cm− ) with EtAlCl2 and at λ = 266
hν (λ > 280 nm)
O
H
H
1 1
nm (ε = 13080 M− cm− ) with the stronger Lewis acid BCl3. In
5 °C (C5H12
)
2. Al2O3 (Et2O)
both cases, there is still a detectable absorption of the com-
1
1
plex at λ = 330 nm where the weak (ε = 70 M− cm− ) nπ*
absorption of uncomplexed 2-cyclohexenone is located. Since
it was expected that the AlBr3-based oxazaborolidine Lewis
acids12 would exert an event stronger bathochromic shift
than BCl3, it seemed possible to selectively excite the com-
plex of cyclohexenone with a chiral Lewis acid but not the
uncomplexed substrate. In this scenario, enantioselective
35-45%
H
H
1a
rac-2a
rac-caryophyllene
Although the olefin is commonly used in excess, the reaction
is not perfectly chemo- and regioselective and an extensive
purification is required to obtain product rac-2a in yields of
35-45%. The treatment with basic alumina facilitates the
epimerization of the stereogenic center in α-position to the
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intermolecular [2+2] photocycloaddition to an alkene should
The 2,3,4-trifluorophenyl derivative 3c gave already a
much improved yield and enantioselectivity (entry 3) com-
pared to 3b. The performance was further improved when
employing a 2,4,6-trifluorophenyl group as Ar’ (entry 4). The
last entry of the table (entry 5) illustrates that also the aryl
group Ar’ has a subtle influence on the enantioselectivity but
not on the regio- and chemoselectivity. Indeed, apart from
the high enantioselectivity, it is notable that the yield of the
[2+2] photocycloaddition significantly increased compared to
the racemic reaction (see Supporting Information) which
delivered a yield of only 51% for product rac-2b.
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be possible as previously found for intramolecular reac-
tions.10,13 However, several questions remained open, e.g.
whether the lifetime of the complex would be sufficiently
long to allow for enantioface differentiation before dissocia-
tion and whether previously used Lewis acids would provide
a reasonable enantioselectivity. It was also unclear whether
the photoexcited cyclohexenone would lead to a destruction
of the Lewis acid and whether the known side reactions of
intermolecular [2+2] photocycloaddition reactions would be
enhanced. Initial results with the previously used13b Lewis
acid 3a seemed to confirm the worst concerns (Table 1, entry
1). The enantioselectivity in the reaction of 1a with 2-
ethylbut-1-ene under typical conditions was disappointingly
low and the Lewis acid seemed unstable under the reaction
conditions. Variation of Ar’ showed that the insufficient
performance was not associated with this substituent but
rather with the aryl group Ar (entry 2). Gratifyingly, an ex-
tensive screening of oxazaborolidines14 with different sub-
stituents Ar delivered Lewis acids with which the selectivity
issues could be smoothly overcome. The superior substituent
was a 2,3-dimethylphenyl group which was incorporated for
example in Lewis acids 3c-3e.
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Lewis acid 3d evolved from the optimization studies as the
optimal choice to promote an enantioselective intermolecu-
lar [2+2] photocycloaddition of cyclic enones 1. The Lewis
acid was prepared in situ by addition of AlBr3 to the respec-
tive oxazaborolidine and it was applied to a variety of
enone/olefin combinations (Table 2). The reason for the high
catalyst loading of 50 mol% is the racemic background reac-
tion which can only be suppressed if the catalyst concentra-
tion is high.10b
Table 2. Enantioselective Intermolecular [2+2] Pho-
tocycloaddition of Cyclic Enones (1) and Various
Terminal Olefins to Bicyclic Products 2a
Table 1. Enantioselective Intermolecular [2+2] Photo-
cycloaddition of 2-Cyclohexenone (1a) and 2-Methyl-
1-butene Mediated by Chiral Lewis Acids 3
entry
1
Ar
Ar’
cat. yielda (%) eeb (%)
3a
3b
3c
3d
3e
27
29
56
73
65
18
30
88
90
66
2
3
4
5
a
The crude product was purified by chromatography on
a
Reactions were performed at a concentration of c = 20 mM
silica gel (eluent: pentane/Et2O = 4/1). The material was
dissolved in CH2Cl2 and successively treated with basic alu-
mina and dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate. Filtra-
tion through a short pad of silica and solvent removal deliv-
ered pure compound 2b. The enantiomeric excess was
determined by chiral GLC analysis.
in CH2Cl2 solution. Work-up included treatment with basic
alumina in CH2Cl2 (see Table 1). The purified material was
treated with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate to
remove olefinic impurities. The reaction remained incom-
b
c
b
plete and the yield is based on enone conversion.
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The Lewis acid catalyzed process enabled an enantioselec-
and the reduction of the acid to the alcohol proceeded une-
ventfully and delivered (−)-grandisol in 96% ee. Starting from
3-methyl-2-cyclohexenone, the synthesis proceeded in only
six steps with an overall yield of 13% and thus represents a
concise route to the enantiopure natural product.
1
2
3
4
tive access to cyclobutane 2a which was obtained in higher
yield than racemic compound rac-2a (Scheme 1). It is known
that the levorotatory enantiomer ([α]D20 = −152.8 at c = 1.4 in
CHCl3) ent-2a exhibits the (1R,6R)-configuration at the two
stereogenic centers of the bicyclo[4.2.0]octane skeleton.15
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20
Product 2a was dextrorotatory ([α]D = +162.6 at c = 1.4 in
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7
8
9
CH2Cl2) proving unambiguously its absolute configuration as
(1S,6S). The absolute configuration of the other products 2
was assigned in analogy and matches our model for the en-
antioface differentiation (vide infra). Product yields were
moderate to good (42-82%) and the enantioselectivity was
consistently high (82%-96% ee). Olefinic substrates were
restricted to ethylene (products 2h, 2i, 2l, 2m, 2o, 2p) and to
symmetric 1,1-disubstituted olefins in order to avoid the
formation of cis/trans-diastereoisomers.16 Oxygen and chlo-
rine substituents were tolerated (products 2e, 2f, 2g, 2n) and
several cyclobutanes were prepared which had previously
been employed in racemic form as starting material for natu-
ral product total syntheses.5,17 Enone substitution was varied
at the β-position (products 2l, 2m, 2n, 2p) and within the
six-membered ring of 2-cyclohexenone (products 2i, 2j, 2k,
2m, 2n). Five-membered substrates reacted with high enan-
tioselectivity (products 2h, 2o) but the reaction was slower
than the reaction of the respective 2-cyclohexenones.
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Figure 2. Suggested structure of 1:1 enone/Lewis acid
complexes 1a·3a and 1a·3d and of putative 1,4-diradical
intermediate 9
Mechanistic considerations concerning the enantioselec-
tive intermolecular [2+2] photocycloaddition, which go be-
yond previously established facts,10 must account for the
improved performance of Lewis acid 3d compared to 3a. So
far only intramolecular Lewis acid-catalyzed [2+2] photocy-
cloaddition reactions had been studied with substrates (di-
hydropyridones, β-alkoxyenones) which bear a tethered
olefin in β- or γ-position. Assuming a reaction on the triplet
hypersurface21 the first bond formation step in these cases
occurs rapidly in the β-position. Intermolecular trapping of
photoexcited enones, such 2-cyclohexenone (1a), in a Lewis
acid complex is likely slower and it occurs with high prefer-
ence in α-position (vide infra). The former fact, possibly in
combination with the reactive T1 state of 1a, could be respon-
sible for hydrogen abstraction22 in complex 1a·3a thus lead-
ing to a decomposition of the catalyst. In complex 1a·3d the
methyl groups are oriented differently (e.g. as shown in Fig-
ure 2) and not only escape hydrogen abstraction but also
lead to an improved enantioface differentiation in α-position.
Bond formation occurs from the Si face and establishes the
first stereogenic center at the future carbon atom C1 of the
bicyclo[4.2.0]octane skeleton. Circumstantial evidence for
the intermediacy of 1,4-diradicals such as 9 stems from the
observation that olefinic products are formed as minor impu-
rities in the reactions with 1,1-disubstituted alkenes. They
arise likely from hydrogen abstraction which is a side reac-
tion competing with C-C bond formation. Synthetically, the
occurrence of the by-products is a minor issue as they can be
removed by treating the crude reaction mixture with dime-
thyl 1,2,4,5-tetrazine-3,6-dicarboxylate23 (see Tables 1 and 2).
Scheme 2. Enantioselective Total Synthesis of (−)-
Grandisol (8)
In order to showcase the synthetic utility of the enantiose-
lective intermolecular [2+2] photocycloaddition reaction we
performed a total synthesis of (−)-grandisol. Grandisol is a
component of the aggregation pheromone of the cotton boll
weevil (Anthonomus grandis) and has received a lot of atten-
tion by the synthetic community.18 Although many syntheses
exist and some of them provided enantiomerically enriched
product,19 there is no synthesis which features an enantiose-
lective [2+2] photocycloaddition as the key step. Our synthe-
sis follows a known bond set19f and commenced with photo-
cycloadditon product 2l. The introduction of the olefinic
double bond was accomplished by the catalytic Saegusa
oxidation protocol reported by Stahl and co-workers.20 Addi-
tion of methyl lithium to enone 4 produced tertiary alcohol 5
the enantiopurity of which could be nicely increased by re-
crystallization. Oxidative cleavage of the double bond and
further oxidation to keto acid 6 was performed with sodium
periodate and RuCl3 as the catalyst. Olefination to product 7
The improved regioselectivity of the Lewis-acid catalyzed
intermolecular [2+2] photocycloaddition is associated with
the above-mentioned preference of α-attack which in turn is
evidenced by the exclusive formation of head-to-tail photo-
cycloaddition products. No head-to-head products were
identified in the crude product mixture while they are
formed in notable amounts in the course of racemic [2+2]
photocycloaddition reactions. It appears as if the Lewis acid
increases the polarity of the excited state which is opposite to
the ground state polarity.4 In the ground state the β-position
of an enone is electrophilic while in the excited state the α-
positon is electrophilic. In a simplistic picture this polarity
reversal is due to the ππ* character of the triplet state with
the half-filled π orbital lacking electron density in α-position.
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I.; Akiyama, N.; Tsutsumi, K.; Nishiyama, Y.; Kakiuchi, K. Highly
In summary, the substitution pattern of the oxazaboroli-
dine was found to have a strong influence on the outcome of
the enantioselective intermolecular [2+2] photocycloaddition
of enones which was mediated by an oxazaborolidine-AlBr3
complex. Catalyst 3d evolved as the catalyst of choice ena-
bling high enantioface differentation (82%-96% ee) and good
chemoselectivity. Studies are ongoing to reveal its mode of
action and to detect potential reaction intermediates.
Tetrahedron 2013, 69, 782-790. For additional references, see ref.19.
(9) (a) Du, J.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P. Science 2014,
344, 392-396. (b) Maturi, M. M.; Bach, T. Angew. Chem. Int. Ed. 2014,
53, 7661-7664. (c) Blum, T. R.; Miller, Z. D.; Bates, D. M.; Guzei, I. A.;
Yoon, T. P. Science 2016, 354, 1391-1395. (d) Tröster, A.; Alonso, R.;
Bauer, A.; Bach, T. J. Am. Chem. Soc. 2016, 138, 7808-7811. (e) Huang,
X.; Quinn, T. R.; Harms, K.; Webster, R. D.; Zhang, L.; Wiest, O.;
Meggers, E. J. Am. Chem. Soc. 2017, 139, 9120-9123. (f) Miller, Z. D.;
Lee, B. J.; Yoon, T. P. Angew. Chem. Int. Ed. 2017, 56, 11891-11895.
(10) (a) Brimioulle, R.; Bach, T. Science 2013, 342, 840-843. (b)
Brimioulle, R.; Bauer, A.; Bach, T. J. Am. Chem. Soc. 2015, 137, 5170-
5176.
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ASSOCIATED CONTENT
9
Supporting Information
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(11) For pioneering work on Lewis acid catalysis in [2+2] photocy-
cloaddition reactions, see: (a) Lewis, F. D.; Howard, D. K.; Oxman, J.
D. J. Am. Chem. Soc. 1983, 105, 3344-3345. (b) Lewis, F. D.; Barancyk,
S. V. J. Am. Chem. Soc. 1989, 111, 8653-8661.
(12) Review: Corey, E. J. Angew. Chem. Int. Ed. 2009, 48, 2100-2117.
(13) (a) Guo, H.; Herdtweck, E.; Bach, T. Angew. Chem. Int. Ed.
2010, 49, 7782-7785. (b) Brimioulle, R.; Bach, T. Angew. Chem. Int.
Ed. 2014, 53, 12921-12924.
The Supporting Information is available free of charge on the
ACS Publications website at http://pubs.acs.org.
Experimental procedures, analytical data and NMR spectra
for all new compounds, GLC traces of products.
AUTHOR INFORMATION
Corresponding Author
thorsten.bach@ch.tum.de
Notes
(14) More than 50 different chiral oxazaborolidines were prepared
and tested in combination with different Lewis acids.
(15) (a) Liu, D.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
8160-8161. (b) Shen, R.; Corey, E. J. Org. Lett. 2007, 9, 1057-1059.
(16) Other olefins (4,4-dimethylpentene, cyclopentene) reacted
also with high ee but the reactions suffered from lower selectivity.
(17) Examples: (a) Takeda, K.; Shimono, Y.; Yoshii, E. J. Am. Chem.
Soc. 1983, 105, 563-568. (b) El-Hachach, N.; Fischbach, M.; Gerke, R.;
Fitjer, L. Tetrahedron 1999, 55, 6119-6128. (c) Ishii, S.; Zhao, S.; Mehta,
G.; Knors, C. J.; Helquist, P. J. Org. Chem. 2001, 66, 3449-3458.
(18) For a review on previous photochemical approaches to gran-
disol, see ref.3c.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support by the European Research Council under
the European Union’s Horizon 2020 research and innovation
programme (grant agreement No 665951 − ELICOS) is grate-
fully acknowledged. We thank O. Ackermann and J. Kuder-
mann for their help with the HPLC and GLC analyses.
(19) Syntheses of (+)- and (−)-grandisol (excluding formal total
syntheses): (a) Hobbs, P. D.; Magnus, P. D. J. Am. Chem. Soc. 1976,
98, 4594-4600. (b) Mori, K. Tetrahedron 1978, 34, 915-920. (c) Jones,
J. B.; Finch, M. A. W.; Jakovac, I. J. Can. J. Chem. 1982, 60, 2007-2011.
(d) Meyers, A. I.; Fleming, S. A. J. Am. Chem. Soc. 1986, 108, 306-307.
(e) Demuth, M.; Palomer, A.; Sluma, H.-D.; Dey, A. K.; Krüger, C.;
Tsay, Y.-H. Angew. Chem. Int. Ed. 1986, 25, 1117-1119. (f) Silverstein, R.
M.; Webster, F. X. J. Org. Chem. 1986, 51, 5226-5231. (g) Mori, K.;
Miyake, M. Tetrahedron 1987, 43, 2229-2239. (h) Mori, K.; Nagano, E.
Liebigs Ann. Chem. 1991, 341-344. (i) Hoffmann, N.; Scharf, H.-D.
Liebigs Ann. Chem. 1991, 1273-1277. (j) Mori, K.; Fukamatsu, K. Liebigs
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Tetrahedron Lett. 1993, 34, 7455-7458. (l) Martín, T.; Rodríguez, C.
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Langer, K.; Mattay, J. J. Org. Chem. 1995, 60, 7256-7266. (n) Alibés,
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