Thioallenoates in catalytic enantioselective [2+2]-cycloadditions with unactivated alkenes

Article abstract of DOI:10.1016/j.tet.2019.04.028

The application of thioallenoates to catalytic enantioselective [2+2]-cycloadditions with unactivated alkenes is reported. In many cases, the thioallenoates examined exhibit superior reactivity and selectivity compared to the allenic esters generally used in these cycloadditions.

Full text of DOI:10.1016/j.tet.2019.04.028

Accepted Manuscript
Thioallenoates in catalytic enantioselective [2+2]-cycloadditions with unactivated
alkenes
Michael L. Conner, Johannes M. Wiest, M. Kevin Brown
PII:
S0040-4020(19)30430-2
https://doi.org/10.1016/j.tet.2019.04.028
TET 30273
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 December 2018
Revised Date: 8 April 2019
Accepted Date: 11 April 2019
Please cite this article as: Conner ML, Wiest JM, Brown MK, Thioallenoates in catalytic enantioselective
[2+2]-cycloadditions with unactivated alkenes, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.04.028.
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Thioallenoates in Catalytic Enantioselective
[2+2]-Cycloadditions with Unactivated
Alkenes
Leave this area blank for abstract info.
Michael L. Conner, Johannes M. Wiest and M. Kevin Brown*
Indiana University, Department of Chemistry, 800 E. Kirkwood Ave. Bloomington, IN 47405

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Thioallenoates in Catalytic Enantioselective [2+2]-Cycloadditions with Unactivated
Alkenes
a
Michael L. Conner, Johannes M. Wiest, and M. Kevin Brown
a Indiana University, Department of Chemistry, 800 E. Kirkwood Ave. Bloomington, IN 47405
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The application of thioallenoates to catalytic enantioselective [2+2]-cycloadditions with
unactivated alkenes is reported. In many cases, the thioallenoates examined exhibit superior
reactivity and selectivity compared to the alkoxy analogs generally used in these cycloadditions.
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
Cycloaddition
Enantioselective
Lewis-Acid
Allenes
Cyclobutane
———
Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron
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1. Introduction
propargyl bromide, which upon generation of the Grignard
reagent and quench with carbon dioxide provided carboxylic acid
6 in 51% yield. Esterification with trifluoroethanol assisted by
DCC and DMAP furnishes the allenoate in 20% yield after in situ
isomerization to the allene. The low yield in this reaction is due
to the poor nucleophilicity of 2,2,2-trifluoroethanol, the high
volatility of 1, and the requirement of sequential purification by
column chromatography and distillation. Due to the difficulties
with the synthesis, preparation on gram scale was never achieved.
In light of this limitation, we set out to identify an allenoate that
offers similar reactivity to trifluoroethyl allenoate 1, yet is easier
to prepare. Herein, we report a solution to this problem through
the synthesis and use of thioallenoates (Scheme 2B).
The synthesis of cyclobutane containing molecules through
[2+2]-cycloadditions has seen wide application in chemical
synthesis.1 This can be attributed to the presence of the
cyclobutane ring structure in a large number of biologically
relevant molecules, the availability of alkene precursors for
[2+2]-cycloadditions, and the rapid molecular complexity built in
a single step. Thus, the development of catalytic enantioselective
[2+2]-cycloaddition to access cyclobutanes has seen significant
developments in recent years.2 Impressive advances have been
made in intermolecular enantioselective [2+2] cycloadditions by
photochemical activation,3 reactions of highly polarized π-
components,2a and radical anion/cation processes initiated by
photocatalysts;4 however, all involve stepwise mechanisms and
thus activated alkenes are required in nearly every case to
stabilize charged/radical intermediates (Scheme 1A).3c
Enantioselective [2+2] cycloadditions with unactivated alkenes
are significantly more rare. In one instance, Ishihara reported the
enantioselective [2+2] cycloaddition with 1,1’- and trisubstituted
unactiavted alkenes.5 In a more recent study, Bach and
coworkers reported photochemical [2+2] cycloaddition between
cyclohexenone derivatives and unactivated alkenes.3c Despite
these
advances,
generally
effective
approaches for
enantioselective [2+2] cycloadditions with unactivated alkenes
are lacking. Therefore, our lab initiated a program towards
addressing this challenge through the use of allenoates (Scheme
1B).6,7,8 Our mechanistic rationale for development of these
reactions is that the cycloadditions are likely concerted,
asynchronous processes and thus highly polar or radical
intermediates do not need to be supported. Thus, a wide range of
unactivated alkenes can engage in these reactions. 8a-c
3. Results and Discussion
Using cyclopentene as a test system, initial investigations of
different allenic esters were performed (Table 1).9 Whereas
improved reaction enantioselectivity was obtained with benzyl
allenoate 7, a dramatic decrease in overall reaction yield was
observed (Table 1, compare entries 1 and 2). The use of the more
reactive phenyl allenoate
8 showed similar reactivity to
trifluoroethyl allenoate 1; however, decreased diastereo- and
enantioselectivities were obtained (Table 1, compare entries 1
and 3). We next examined thiobenzyl allenoate 9 in the reaction
as it proved to be uniquely effective in obtaining high
enantioselectivities with aryl alkenes in a recent report from this
lab.6d To our delight, a similar yield and high enantioselectivity
was obtained from the cycloaddition with 9 compared to
trifluoroethyl allenoate 1 (Table 1, compare entries 1 and 4).
Furthermore, the desired cycloadduct was obtained as a single
alkene isomer marking a drastic improvement in reaction
diastereoselectivity. As demonstrated in our previous report, the
alkene isomers of products are of opposite absolute
2. Background
Driven by the motivations described above, in 2015 we
reported the first catalytic enantioselective [2+2] cycloaddition of
allenoates and unactivated alkenes promoted by N-protonated
oxazaborolidene catalysts (generated in situ by protonation of 3
with HNTf2) (Scheme 2A).6a To achieve sufficient reactivity
across a range of alkenes, the use of trifluoroethyl allenoate was
required (Scheme 2A).6a However, the synthesis of this allene is
challenging and thus represents a significant limitation in the
utility of this method. The optimized route to 1 starts from

3
configuration.6a Therefore, formation of the product as a single
alkene isomer is particularly important.
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Thioallenoate 9 can be prepared by a straightforward sequence
involving Wittig olefination of in situ generated ketene (Scheme
3).9 Importantly, the reaction can be performed on multigram
scale and the product is easily purified and isolated. The
thioallenoate was also found to be stable for months when stored
at -20 °C.
With optimized conditions in hand, we investigated the scope
of the reaction with a range of unactivated alkenes. Cyclic
unactivated alkenes underwent cycloaddition in high
enantioselectivity, with more strained alkenes (e.g., cyclooctene
vs. cyclohexene) proceeding in higher overall yield. (Scheme 4,
products 12, 16, 18). Cycloaddition of cis-4-octene provided
cycloadduct 20 in 67% yield, >20:1 E/Z, and 93:7 er. Notably,
the alkene geometry is conserved to provide only the syn-
substituted cyclobutane suggesting the reaction is concerted in
accordance with our previous reports.6 In addition, reaction with
an asymmetric alkene resulted in formation of 22 with improved
regioselectivity as compared to reaction with the trifluoroethyl
allenoate 1 (compare with product 21).
While the thioallenoate was superior in many instances when
compared to allenic esters, there are several cases in which yield
and/or selectivity suffered (Scheme 4). For example, reaction
with terminal alkenes resulted in poor yields (compare products
23 and 24). In addition, reaction of trisubstituted alkenes resulted
in lower selectivity and yield compared to the benzyl allenoate
(compare products 25 and 26).6c At this time, justification for the
divergence in selectivity and yield with these two examples is
unclear.
Desymmetrization of TIPS protected alcohol 27 with
thioallenoate 9 by [2+2]-cycloaddition was also investigated for
the potential to set multiple stereocenters (eq (1)). [3.2.0]
bicycloheptane 28 was obtained as
a single observable
stereoisomer in 51% yield and 94:6 er. The cycloaddition likely
proceeds through a transition state in which the sterically
demanding protected alcohol is oriented away from the bond
formation site thus setting the remote stereocenter.

4
Tetrahedron
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The utility of the thioallenoates was extended to reaction of the
γ, γ-dimethyl derivative 30 (Scheme 5).
The requisite
thioallenoate was prepared by Wittig olefination of in situ
generated dimethylketene in 60% yield on multigram scale.
Enantioselective cycloaddition with the catalyst derived from
oxazaborolidine 3 resulted in formation of product 32 as a 1:1
mixture of alkene isomers; albeit, the E-isomer was formed in
high enantioselectivity.
Interestingly, use of the
oxazaborolidinium catalyst derived from 33, which bears 3,5-
(CF3)2C6H3 groups instead of Ph-groups on the catalyst backbone,
resulted in an improved selectivity for formation of the E-isomer.
The reaction could be extended to other alkenes with mixed
results. While cyclopentene and cis-4-octene worked to provide
products 34 and 35 in good enantioselectivity, control of alkene
geometry was poor. In addition, reaction of 1-hexene resulted in
poor enantioselectivity (product 36). Finally, it should also be
noted that use of the corresponding benzylester allenoate resulted
in low yields, thus further highlighting the increased reactivity
with the thioallenoate.
4. Summary
In summary, the utility of thioallenoate in [2+2]
cycloadditions is presented. In many cases, reactions with the
thioallenoate offers superior selectivity compared to reactions
with alkoxy analogs.
In addition, the synthesis of the
thioallenoate is straightforward and can be performed on gram
scale, which significantly increases the synthetic utility of these
reactions.
5. Experimental section
1H NMR and 13C NMR spectra were recorded at room
temperature using a Varian I400 (1H NMR at 400 MHz, 13C
NMR at 100 MHz, 19F at 375 MHz), Varian VXR400 (1H NMR
at 400 MHz, 13C NMR at 100 MHz), Varian I500 (1H NMR at
500 MHz and 13C NMR at 125 MHz) and Varian I600 (1H NMR
at 600 MHz and 13C NMR at 150MHz). Chemical shifts are
reported in ppm from tetramethylsilane with the respective
solvent resonance as the internal standard (1H NMR CHCl3: δ
7.26 ppm 13C NMR CDCl3: δ 77.2 ppm). Data is reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, p = pentet, br = broad, m = multiplet),
coupling constants (Hz) and integration. Infrared spectra (IR)
were obtained on a Bruker Tensor II FTIR Spectrometer (ATR
sampling technique) and recorded in wavenumbers (cm-1). Bands
are characterized as broad (br), strong (s), medium (m), and weak

5
(w). Melting points were obtained on a Thomas Hoover capillary
melting point apparatus without correction. High Resolution
Mass Spectrometry (HRMS) analysis was obtained using
Electron Impact Ionization (EI), Chemical Ionization (CI) or
Electrospray Ionization (ESI) and reported as m/z (relative
intensity). GC-MS data was acquired using an Agilent 6890N
Gas Chromatograph and 5973 Inert Mass Selective Detector. ESI
was acquired using a Waters/Micromass LCT Classic (ESI-TOF).
cooled to -25 oC. Oxazaborolidine 1 (0.25 M in PhMe, 0.53 mL,
ACCEPTED MANUSCRIPT
0.13 mmol, 0.53 equiv,) was added and allowed to stir for 30
minutes. Cyclohexene (130 µL, 1.25 mmol, 5.00 equiv) was
added followed quickly by the allenoate (38.0 µL, 0.25 mmol,
1.00 equiv) and the reaction was allowed to warm to room
temperature. After 16 hours, the reaction was quenched with 100
µL Et3N and the solution was concentrated. The resulting brown
residue was purified directly by silica gel chromatography (1 -
2% EtOAc:hexanes) to yield 40.5 mg (59% yield, >20:1 E/Z) of
the title compound as a yellow oil. IR (film): 3029 (w), 2926
(m), 2851 (m), 1672 (s), 1638 (s), 1567 (m), 1495 (m), 1453 (m),
1413 (m), 1332 (m), 1276 (m), 1156 (m), 1035 (s), 825 (s), 744
(s), 699 (s) cm-1. 1H NMR (600 MHz, CDCl3) δ 7.33 – 7.27 (m,
4H), 7.25 – 7.21 (m, 1H), 5.99 (app q, J = 2.1 Hz, 1H), 4.20 –
4.13 (m, 2H), 3.12 – 3.04 (m, 2H), 2.82 – 2.77 (m, 1H), 2.44 (app
ddq, J = 13.1, 8.4, 4.9, 4.2 Hz, 1H), 1.96 – 1.89 (m, 1H), 1.71
(app dq, J = 13.4, 4.3 Hz, 1H), 1.58 – 1.50 (m, 2H), 1.48 – 1.40
(m, 1H), 1.38 – 1.29 (m, 1H), 1.28 – 1.19 (m, 1H), 1.19 – 1.09
(m, 1H). 13C NMR (125 MHz, CDCl3) δ 188.2, 167.7, 138.2,
129.0, 128.7, 127.2, 118.1, 43.0, 40.3, 33.0, 29.9, 28.9, 24.3,
22.5, 21.8. HRMS (EI): Calcd for C17H20O1S1 [M]+: 272.1229,
Optical rotations were measured on
a Perkin-Elmer 241
polarimeter at 589 nm wavelength (sodium D-line) using a
standard 10 cm cell (1 mL). Specific rotations, [α]D20, are
reported in degree mL/(gꢀdm) at the specific temperature.
Concentrations (c) are given in grams per 100 mL of the specific
solvent. Unless otherwise noted, all reactions have been carried
out with distilled and degassed solvents under an atmosphere of
dry N2 in oven- (135 oC) and flame-dried glassware with standard
vacuum-line techniques. Dichloromethane, diethyl ether and
tetrahydrofuran were purified under a positive pressure of dry
argon by passage through two columns of activated alumina.
Toluene was purified under a positive pressure of dry argon by
passage through columns of activated alumina and Q5 (Grubbs
apparatus). All work-up and purification procedures were carried
out with reagent grade solvents (purchased from Sigma-Aldrich)
in air. Standard column chromatography techniques using
ZEOprep 60/40-63 ꢁm silica gel were used for purification.
20
Found: 272.1234. Optical Rotation: [α]D -33.4 (c = 1.00,
CHCl3) for an enantiomerically enriched sample of 94:6 er. The
enantiomeric purity was established by HPLC analysis using a
chiral column (Lux 3u Cellulose-4 column, 22 °C, 0.25 mL/min,
99:1 hexanes:isopropanol, 254 nm, tmajor = 30.955 min, tminor
34.093 min). See supporting information part B for HPLC
chromatograms.
=
General Procedure for [2+2] cycloaddition (unless otherwise
stated). HNTf2 (14.0 mg, 0.05 mmol, 0.20 equiv) was added to a
flame dried screw cap test tube in an argon filled glovebox,
capped with a septum and removed from the glovebox. CH2Cl2
S-benzyl
(E)-2-((1S,8S)-bicyclo[6.2.0]decan-9-
o
(0.50 mL) was added and the reaction mixture cooled to -78 C.
ylidene)ethanethioate [18]: Prepared according to the general
procedure utilizing cyclooctene as the alkene component.
Purification by silica gel chromatography (hexanes – 2%
EtOAc:hexanes gradient) provided 67.6 mg (90% yield, 20:1
E/Z) of the title compound as a pale yellow oil. IR (film): 3029
(w), 2918 (s), 2850 (m), 1672 (s), 1638 (s), 1495 (w), 1461 (m),
1454 (w), 1407 (w), 1334 (w), 1160 (w), 1136 (w), 1038 (s), 916
(w), 825 (m), 762 (w), 741 (w), 700 (m), 565 (w), 470 (w) cm-1.
1H NMR (600 MHz, CDCl3) δ 7.33 – 7.27 (m, 4H), 7.25 – 7.21
(m, 1H), 5.98 (q, J = 2.3 Hz, 1H), 4.16 (s, 2H), 3.33 – 3.27 (m,
1H), 3.02 – 2.95 (m, 1H), 2.66 (dddd, J = 18.4, 5.9, 3.7, 2.5 Hz,
1H), 2.48 (app qdd, J = 9.0, 5.6, 2.0 Hz, 1H), 1.79 – 1.43 (m,
8H), 1.38 – 1.23 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 188.2,
169.5, 138.2, 129.0, 128.7, 127.2, 118.8, 48.3, 40.0, 36.9, 32.9,
30.3, 29.9, 29.3, 26.3, 25.9, 25.8. HRMS (EI): Calcd for
C19H24O1S1 [M]+: 300.1542, Found: 300.1535. Optical Rotation:
Oxazaborolidine 3 or 34 (0.25 M in PhMe, 0.25 mL, 0.06 mmol,
0.25 equiv) was added and allowed to stir for 30 minutes. The
alkene (1.25 mmol, 5.00 equiv) was added, followed quickly by
the allenoate (38.0 µL, 0.25 mmol, 1.00 equiv) and the reaction
was allowed to warm to room temperature. After 16 hours, the
reaction was quenched with 100 µL Et3N and the solution was
concentrated. The resulting residue was purified directly by silica
gel chromatography.
S-benzyl
(E)-2-((1S,5S)-bicyclo[3.2.0]heptan-6-
ylidene)ethanethioate [12] Prepared according to the general
procedure utilizing cyclopentene as the alkene component.
Purification by silica gel chromatography (2% EtOAc:hexanes)
to yield 40.7 mg (63% yield, >20:1 E/Z) of the title compound as
a bright yellow oil. IR (film): 3029 (s), 2854 (w), 1672 (s), 1638
(s), 1495 (m), 1454 (m), 1403 (m), 1337 (m), 1161 (m), 1035 (s),
752 (s), 701 (s) cm-1. 1H NMR (500 MHz, CDCl3) δ 7.38 – 7.21
(m, 5H), 5.96 – 5.93 (m, 1H), 4.17 (s, 2H), 3.42 – 3.35 (m, 1H),
3.26 (app ddt, J = 19.4, 9.0, 2.5 Hz, 1H), 2.96 – 2.89 (m, 1H),
2.65 – 2.58 (m, 1H), 1.86 – 1.52 (m, 6H). 13C NMR (100 MHz,
CDCl3) δ 188.1, 169.5, 138.1, 129.0, 128.7, 127.2, 120.0, 49.0,
38.2, 36.2, 33.3, 32.9, 32.7, 24.7. HRMS (CI): Calcd for
C16H18O1S1 [M]+: 258.1073, Found: 258.1084. Optical Rotation:
20
[α]D -33.5 (c = 1.00, CHCl3) for an enantiomerically enriched
sample of 98:2 er. The enantiomeric purity was established by
HPLC analysis using a chiral column (Lux 3u Cellulose-4
column, 22 °C, 0.25 mL/min, 99:1 hexanes:isopropanol, 254 nm,
tmajor = 34.240 min, tminor = 37.805 min). See supporting
information part B for HPLC chromatograms.
S-benzyl
(E)-2-((2S,3S)-2,3-
[20]: Prepared
dipropylcyclobutylidene)ethanethioate
according to the general procedure utilizing cis-4-octene as the
alkene component. Purification by silica gel chromatography
(hexanes – 2% EtOAc:hexanes gradient) provided 50.7 mg (67%
yield, >20:1 dr, >20:1 E/Z) of the title compound as a pale yellow
liquid. IR (film): 3086 (w), 3062 (w), 3029 (w), 2955(s), 2926
(s), 2870 (s), 1674 (s), 1639 (s), 1495 (m), 1454 (m), 1410 (w),
1378 (w), 1334 (w), 1162 (w), 1118 (w), 1071 (w), 1036 (s), 919
(w), 828 (m), 786 (m), 736 (m), 699 (s), 565 (w), 471 (w) cm-1.
1H NMR (500 MHz, CDCl3) δ 7.35 – 7.27 (m, 4H), 7.25 – 7.21
(m, 1H), 5.98 (q, J = 2.2 Hz, 1H), 4.16 (s, 2H), 3.16 (app ddt, J =
17.5, 8.6, 1.6 Hz, 1H), 3.05 (app dtdd, J = 9.2, 7.5, 3.4, 1.7 Hz,
1H), 2.73 (app ddt, J = 17.6, 5.6, 2.9 Hz, 1H), 2.50 – 2.40 (m,
20
[α]D +67.0 (c = 1.00, CHCl3) for an enantiomerically enriched
sample of 94:6 er. The enantiomeric purity was established by
HPLC analysis using a chiral column (Lux 3u Cellulose-4
column, 22 °C, 0.25 mL/min, 99:1 hexanes:isopropanol, 254 nm,
tminor = 29.496 min, tmajor = 30.606 min). See supporting
information part B for HPLC chromatograms.
S-benzyl
(E)-2-((1S,6S)-bicyclo[4.2.0]octan-7-
ylidene)ethanethioate [16]: HNTf2 (35.1 mg, 0.125 mmol, 0.50
equiv) was added to a flame dried screw cap test tube in an argon
filled glovebox, capped with a septum and removed from the
glovebox. CH2Cl2 (1.25 mL) was added and the reaction mixture

6
Tetrahedron
ACCEPTED MANUSCRIPT
1H), 1.54 – 1.40 (m, 3H), 1.40 – 1.16 (m, 5H), 0.92 (td, J = 7.2,
provided 58.0 mg (51% yield, >20:1 dr, >20:1 E/Z) of the title
3.4 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 188.2, 168.8,
138.2, 129.0, 128.7, 127.2, 118.7, 47.6, 38.7, 34.6, 32.9, 32.2,
30.1, 21.4, 20.8, 14.3, 14.3. HRMS (EI): Calcd for C19H26O1S1
compound as a yellow oil. IR (film): 2942 (m), 2864 (m), 1674
(m), 1641 (m), 1495 (w), 1463 (w), 1389 (w), 1276 (m), 1261
(m), 1113 (m), 1035 (m), 882 (w), 764 (s), 750 (s), 700 (w) cm-1.
1H NMR (500 MHz, CDCl3) δ 7.35 – 7.27 (m, 4H), 7.25 – 7.21
(m, 1H), 5.98 – 5.92 (m, 1H), 4.16 (s, 2H), 3.74 – 3.66 (m, 2H),
3.44 – 3.33 (m, 1H), 3.26 (dddd, J = 19.4, 9.0, 2.4 Hz, 1H), 2.99
– 2.86 (m, 1H), 2.68 (dddd, J = 19.4, 4.3, 2.5 Hz, 1H), 2.48 –
2.33 (m, 1H), 1.76 (ddd, J = 25.0, 12.7, 5.9 Hz, 2H), 1.56 – 1.39
(m, 2H), 1.10 – 1.00 (m, 21H). 13C NMR (125 MHz, CDCl3) δ
188.1, 169.4, 138.2, 129.0, 128.7, 127.2, 120.2, 66.4, 49.1, 41.4,
38.7, 36.4, 36.3, 35.8, 32.9, 18.2, 12.1. HRMS (EI): Calcd for
C26H40O2S1Si1 [M]+: 444.2513, Found: 444.2522. Optical
Rotation: [α]D20 +15.9 (c = 1.00, CHCl3) for an enantiomerically
enriched sample of 94:6 er. The enantiomeric purity was
established by HPLC analysis using a chiral column (Lux 3u
[M]+: 302.1699, Found: 302.1696. Optical Rotation: [α]D -7.7
20
(c = 1.00, CHCl3) for an enantiomerically enriched sample of
93:7 er. The enantiomeric purity was established by HPLC
analysis using a chiral column (Lux 3u Cellulose-1 column, 22
°C, 0.25 mL/min, 99:1 hexanes:isopropanol, 254 nm, tminor
24.454 min, tmajor = 31.649 min). See supporting information part
B for HPLC chromatograms.
=
S-benzyl
(E)-2-((2S,3R)-3-isopropyl-2-
methylcyclobutylidene)ethanethioate [22]: Prepared according
to the general procedure utilizing cis-4-methyl-2-pentene as the
alkene component. Purification by silica gel chromatography
(hexanes – 2% EtOAc:hexanes gradient) provided 40.1 mg (58%
yield, 5:1 E/Z, 10:1 rr) of the title compound as an inseparable
mixture of isomers. IR (film): 3062 (w), 3029 (w), 2957 (m),
2929 (m), 2870 (w), 1674 (s), 1634 (s), 1454 (m), 1416 (w), 1335
Cellulose-1
column,
22
°C,
0.5
mL/min,
99:1
hexanes:isopropanol, 254 nm, tminor = 10.348 min, tmajor = 10.822
min). See supporting information part
chromatograms.
B
for HPLC
(w), 1160 (w), 1038 (s), 827 (m), 751 (w), 700 (m) cm-1. H
1
NMR (500 MHz, CDCl3) δ 7.40 – 7.18 (m, 5H), 6.18 – 6.08 (m,
1H), 4.18 (s, 2H), 3.16 (ddd, J = 17.4, 8.3, 2.4 Hz, 1H), 2.77 –
2.70 (m, 1H), 2.69 – 2.54 (m, 2H), 1.95 – 1.82 (m, 1H), 1.12 (d, J
= 6.8 Hz, 3H), 1.05 – 0.98 (m, 3H), 0.91 (d, J = 6.4 Hz, 3H).13C
NMR (125 MHz, CDCl3) δ 188.2, 167.5, 138.2, 129.0, 129.0,
129.0, 128.7, 127.2, 119.4, 55.5, 40.3, 33.0, 29.3, 27.3, 21.8,
21.6, 16.0.HRMS (EI): Calcd for C17H22O1S1 [M]+: 274.1386,
S-(4-chlorobenzyl)
dimethylbicyclo[6.2.0]decan-9-ylidene)ethanethioate
2-((1R,8S)-10,10-
[35]:
HNTf2 (14.0 mg, 0.05 mmol, 0.20 equiv) was added to a flame
dried round bottom flask in an argon filled glovebox, capped
with a septum, and removed from the glovebox. CH2Cl2 (0.50
mL, 0.50 M) was added and the reaction mixture was cooled to -
78 oC. Oxazaborolidine 3 (0.25 M in PhMe, 250 µL, 0.06 mmol,
0.25 equiv) was added and allowed to stir for 30 minutes.
Cyclooctene (160 µL, 1.25 mmol, 5.00 equiv) was added,
followed quickly by S-(4-chlorobenzyl) 4-methylpenta-2,3-
dienethioate 32 (63.0 mg, 0.25 mmol, 1.00 equiv) and the
reaction was allowed to warm to room temperature. After 16
hours, the reaction was quenched with 100 µL Et3N and the
solution was concentrated. Purification by silica gel
chromatography (hexanes – 2% Et2O:hexanes gradient) provided
82.4 mg (93% yield, ~1:1 E/Z mixture of alkene isomers) of the
title compound as a pale yellow oil. For characterization, small
amounts of the respective E-isomer were separated. E-isomer:
IR (film): 2918 (br, m), 2850 (m), 1672 (s), 1636 (s), 1490 (m),
1460 (w), 1443 (w), 1339 (w), 1261 (w), 1242 (w), 1092 (m),
1066 (s), 1066 (s), 980 (w), 813 (s), 738 (m), 678 (w), 641 (w),
552 (w), 509 (w cm-1. 1H NMR (500 MHz, CDCl3) δ 7.26 – 7.11
(m, 4H), 5.87 – 5.77 (m, 1H), 4.07 (d, J = 14.5 Hz, 1H), 4.01 (d,
J = 13.4 Hz, 1H), 3.27 (t, J = 10.0 Hz, 1H), 2.07 – 1.92 (m, 2H),
1.76 – 1.41 (m, 6H), 1.42 – 1.33 (m, 1H), 1.31 – 1.08 (m, 4H),
1.04 (s, 3H), 1.00 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 187.3,
179.8, 137.0, 133.0, 130.3, 128.8, 116.6, 48.4, 46.13, 45.4, 32.3,
31.21, 29.2, 28.1, 27.9, 26.1, 25.7, 22.5, 22.1. HRMS (ESI):
Calcd for C21H27O1Cl1S1Na1 [M+Na]+: 385.1369, Found:
385.1369. The enantiomeric purity was established by HPLC
analysis using a chiral column. E-isomer: (Lux 3u Cellulose-2
column, 22 °C, 0.25 mL/min, 400:1 hexanes:isopropanol, 254
nm, tminor = 30.711 min, tmajor = 34.576 min): 96:4 er. Z-isomer:
(Lux 3u Cellulose-2 0.25mL/min, 400:1 hexanes:isopropanol,
254 nm, tmajor = 36.894 min, tminor = 41.498 min): 86:14 er.
Absolute stereochemistry only tentatively assigned. See
supporting information part B for HPLC chromatograms.
20
Found: 274.1384. Optical Rotation: [α]D -26.7 (c = 1.00,
CHCl3) for an enantiomerically enriched sample of 94:6 er. The
enantiomeric purity was established by HPLC analysis using a
chiral column (Lux 3u Cellulose-1 column, 22 °C, 0.25 mL/min,
400:1 hexanes:isopropanol, 254 nm, tminor = 38.095 min, tmajor
=
56.180 min). See supporting information part B for HPLC
chromatograms.
S-Benzyl
(S,Z)-2-(3,3-dimethyl-2-(2-
((triisopropylsilyl)oxy)ethyl)cyclobutylidene)ethanethioate
[26]: Prepared according to the general procedure utilizing
triisopropyl((4-methylpent-3-en-1-yl)oxy)silane as the alkene
component. Purification by silica gel chromatography (hexanes –
2% Et2O:hexanes gradient) provided 78.0 mg (70% yield, 1:1
Z/E, mixture of alkene isomers) of the title compound as a
colorless oil. For characterization, small amounts of the
respective isomers were separated. Z-isomer: IR (film): 2942
(s), 2865 (s), 1738 (m) 1678 (s), 1647 (m), 1071 (m), 1033 (m),
883 (m), 682 (m) cm-1 1H NMR (600 MHz, CDCl3) δ 7.36 – 7.19
(m, 5H), 5.98 (q, J = 2.1 Hz, 1H), 4.14 (s, 2H), 3.84 – 3.72 (m,
1H), 3.72 – 3.64 (m, 1H), 3.01 (ddt, J = 8.5, 5.6, 2.8 Hz, 1H),
2.57 – 2.51 (m, 1H), 2.35 (ddd, J = 16.3, 3.0, 1.7 Hz, 1H), 2.21 –
2.06 (m, 1H), 1.88 – 1.78 (m, 1H), 1.19 (s, 3H), 1.13 (s, 3H),
1.08 (d, J = 5.3 Hz, 21H). 13C NMR (125 MHz, CDCl3) δ 187.0,
164.7, 138.2, 129.0, 128.7, 127.2, 120.7, 62.8, 52.4, 44.6, 35.3,
33.1, 32.5, 29.9, 23.9, 18.2, 12.2. HRMS (APCI): Calcd for
C26H43O2S1Si1 [M]+: 447.2748, Found: 447.2747. Optical
20
Rotation: [α]D +1.6 (c = 0.64, CHCl3) for an enantiomerically
enriched sample of 87:13 er. The enantiomeric purity was
established by HPLC analysis of the respective deprotected
bicyclic thioester, see the supporting information part A for
details.
The reaction was repeated using oxazaborolidine 34 under
otherwise unchanged conditions. The isolated yield was 84.2 mg
(95% yield, ~4:1 E/Z) and the corresponding er was 98:2 for the
major E-isomer and 81:19 for the minor Z-isomer. Absolute
stereochemistry only tentatively assigned. See supporting
information part B for HPLC chromatograms.
S-benzyl
(E)-2-((1S,3R,5S)-3-
(((triisopropylsilyl)oxy)methyl)bicyclo[3.2.0]heptan-6-
ylidene)ethanethioate [28]: Prepared according to the general
procedure
utilizing
(cyclopent-3-en-1-
ylmethoxy)triisopropylsilane as the alkene component.
Purification by silica gel chromatography (2% EtOAc:hexanes)
S-(4-chlorobenzyl)
dimethylbicyclo[3.2.0]heptan-6-ylidene)ethanethioate
2-((1R,5S)-7,7-
[36]:

7
HNTf2 (14.0 mg, 0.05 mmol, 0.20 equiv) was added to a flame
dried round bottom flask in an argon filled glovebox, capped
with a septum, and removed from the glovebox. CH2Cl2 (0.50
mL, 0.50 M) was added and the reaction mixture cooled to -78
oC. Oxazaborolidine 3 (0.25 M in PhMe, 250 µL, 0.06 mmol,
0.25 equiv) was added and allowed to stir for 30 minutes.
Cyclopentene (114 µL, 1.25 mmol, 5.00 equiv) was added
Et2O:hexanes) provided 73.9 mg (81% yield, ~1:3 E/Z,
ACCEPTED MANUSCRIPT
inseparable mixture of alkene isomers) of the title compound as a
colorless oil. IR (film): 2955 (m), 2928 (m), 1674 (m), 1635 (m),
1490 (m), 1092 (m), 1030 (s), 1015 (m), 831 (m), 793 (m), 507
(m) cm-1. H NMR (600 MHz, CDCl3) Z-Isomer: δ 7.40 – 7.00
1
(m, 4H), 5.89 (d, J = 2.1 Hz, 1H), 4.11 (d, J = 14.0 Hz, 1H), 4.07
(d, J = 14.0 Hz, 1H), 3.00 – 2.67 (m, 1H), 2.16 (ddd, J = 9.7, 8.2,
6.8 Hz, 1H), 1.60 – 1.22 (m, 8H), 1.30 (s, 3H), 1.26 (s, 3H), 0.96
– 0.86 (m, 6H). 13C NMR (125 MHz, CDCl3) Z-Isomer: δ
186.3, 177.2, 137.0, 133.0, 130.3, 128.8, 118.7, 47.5, 44.6, 42.6,
32.6, 32.1, 28.2, 27.3, 22.4, 21.7, 20.5, 14.6, 14.3. HRMS (EI):
Calcd for C21H29Cl1O1S1 [M]+: 364.1622, Found: 364.1624. The
enantiomeric purity was established by HPLC analysis using a
chiral column. E-isomer: (Lux 3u Cellulose-1 column followed
by Lux 3u Amylose 2 column, 22 °C, 0.5 mL/min, 99:1
hexane:isopropanol, 254 nm, tmajor = 25.089 min, tminor = 27.090
min): 91:9 er. Z-isomer: (Lux 3u Cellulose-1 column followed
by Lux 3u Amylose 2 column, 22 °C, 0.5 mL/min, 99:1
hexane:isopropanol, 254 nm, tmajor = 23.950 min, tminor = 24.571
min): 74:26 er. Absolute stereochemistry only tentatively
followed quickly by
a solution of S-(4-chlorobenzyl) 4-
methylpenta-2,3-dienethioate (32) (63.0 mg, 0.25 mmol, 1.00
equiv) in PhMe (0.20 mL) and the reaction was allowed to warm
to room temperature. After 16 hours, the reaction was quenched
with 100 µL Et3N and the solution was concentrated. Purification
by silica gel chromatography (1% Et2O:hexanes) provided 59.4
mg (74% yield, 1:1 E/Z, mixture of alkene isomers) of the title
compound as a colorless oil. Small amounts of the isomers were
separable for analytical characterization. Z-Isomer: IR (film):
2944 (m), 1672 (s), 1635 (m), 1490 (m), 1085 (m), 1042 (m),
1027 (s), 1004 (m), 789 (m), 743 (m) cm-1. 1H NMR (600 MHz,
CDCl3) 7.32 – 7.16 (m, 4H), 5.81 (d, J = 1.9 Hz, 1H), 4.08 (s,
2H), 3.29 (app. td, J ≈ 7.2, 1.7 Hz, 1H), 2.41 (app. t, J ≈ 7.7 Hz,
1H), 1.86 – 1.64 (m, 3H), 1.59 – 1.39 (m, 3H), 1.34 (s, 3H), 1.13
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 187.2, 179.7, 137.0,
133.0, 130.3, 128.8, 117.1, 47.6, 47.5, 43.3, 32.3, 30.9, 30.9,
28.2, 27.0, 19.1. HRMS (EI): Calcd for C18H21Cl1O1S1 [M]+:
assigned. See supporting information part
B for HPLC
chromatograms. The reaction was repeated using
oxazaborolidine 34 under otherwise unchanged conditions. The
isolated yield was 79.4 mg (87% yield, ~1:1 E/Z) and the
corresponding er was 95:5 for the E-isomer and 71:29 for the Z-
isomer. Absolute stereochemistry only tentatively assigned. See
supporting information part B for HPLC chromatograms.
20
320.0996, Found: 320.0999. Optical Rotation: [α]D +36.8 (c =
2.30, CHCl3) for an enantiomerically enriched sample of 66:34
er. The enantiomeric purity was established by HPLC analysis
using a chiral column (Lux 3u Cellulose-1 column, 22 °C, 0.5
mL/min, 99:1 hexanes:isopropanol, 254 nm, tminor = 8.477 min,
tmajor = 9.571 min). E-Isomer: IR (film): 2951 (m), 1673 (s),
S-(4-chlorobenzyl)
(S,E)-2-(3-butyl-2,2-
dimethylcyclobutylidene)ethanethioate [38]: HNTf2 (14.0 mg,
0.05 mmol, 0.20 equiv) was added to a flame dried round bottom
flask in an argon filled glovebox, capped with a septum, and
removed from the glovebox. CH2Cl2 (0.50 mL, 0.50 M) was
added and the reaction mixture cooled to -78 oC. Oxazaborolidine
3 (0.25 M in PhMe, 250 µL, 0.06 mmol, 0.25 equiv) was added
and allowed to stir for 30 minutes. 1-hexene (313 µL, 2.50 mmol,
10.0 equiv) was added followed quickly by a solution of S-(4-
chlorobenzyl) 4-methylpenta-2,3-dienethioate (32) (63.0 mg,
0.25 mmol, 1.00 equiv) in PhMe (0.20 mL) and the reaction was
allowed to warm to room temperature. After 48 hours, the
reaction was quenched with 100 µL Et3N and the solution was
concentrated. Purification by silica gel chromatography (1%
Et2O:hexanes) provided 73.9 mg (81% yield, >20:1 E/Z) of the
title compound as a colorless oil. IR (film): 2956 (s), 2942 (s),
2864 (w), 1675 (s), 1640 (s), 1492 (m), 1114 (m), 1036 (s), 883
1
1637 (m), 1491 (m), 1491 (w), 1039 (s), 798 (w) cm-1. H NMR
(600 MHz, CDCl3) δ 7.29 – 7.19 (m, 4H), 5.86 (d, J = 2.4 Hz,
1H), 4.13 (d, J = 14.0 Hz, 1H), 4.07 (d, J = 14.0 Hz, 1H), 3.75
(ddd, J = 8.7, 5.2, 2.0 Hz, 1H), 2.44 (app. t, J ≈ 7.2 Hz, 1H), 2.11
– 2.00 (m, 1H), 1.85 – 1.69 (m, 2H), 1.59 – 1.43 (m, 3H), 1.21 (s,
3H), 0.96 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 186.0, 178.4,
136.9, 133.0, 130.3, 128.8, 118.3, 47.4, 45.5, 44.8, 32.5, 32.0,
28.1, 27.8, 26.6, 18.1. HRMS (EI): Calcd for C18H21Cl1O1S1
20
[M]+: 320.0996, Found: 320.0997. Optical Rotation: [α]D
−190.4 (c = 2.18, CHCl3) for an enantiomerically enriched
sample of 89:11 er. The enantiomeric purity was established by
HPLC analysis using a chiral column (Lux 3u Cellulose-4
column, 22 °C, 0.5 mL/min, 99:1 hexanes:isopropanol, 254 nm,
tmajor = 8.913 min, tminor = 9.535 min). Absolute stereochemistry
only tentatively assigned. See supporting information part B for
(m) cm-1. H NMR (600 MHz, CDCl3) δ 7.26 – 7.22 (m, 4H),
1
HPLC chromatograms.
The reaction was repeated using
5.91 (app. t, J ≈ 2.4 Hz, 1H), 4.10 (s, 2H), 3.25 (ddd, J = 17.9,
8.6, 2.2 Hz, 1H), 2.65 (ddd, J = 17.9, 7.7, 2.6 Hz, 1H), 2.04 (app.
tdd, J ≈ 9.0, 7.7, 6.1 Hz, 1H), 1.50 (app. ddt, J ≈ 13.1, 9.6, 5.8
Hz, 1H), 1.37 – 1.19 (m, 5H), 1.18 (s, 3H), 1.09 (s, 3H), 0.89 (t, J
= 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 188.2, 173.5,
137.0, 133.0, 130.4, 128.8, 116.9, 47.2, 42.7, 37.0, 32.2, 30.6,
30.2, 27.5, 22.9, 21.3, 14.2. HRMS (APCI): Calcd for
C19H26Cl1O1S1 20[M+H]+: 337.1387, Found: 337.1390. Optical
Rotation: [α]D +9.0 (c = 1.00, CHCl3) for an enantiomerically
enriched sample of 69:31 er. The enantiomeric purity was
established by HPLC analysis using a chiral column (Chiralpak
IA-PG024 column, 22 °C, 0.3 mL/min, 99:1 hexane:isopropanol,
254 nm, tmajor = 15.876 min, tminor = 16.613 min). Absolute
stereochemistry only tentatively assigned. See supporting
information part B for HPLC chromatograms. The reaction was
repeated using oxazaborolidine 34 under otherwise unchanged
conditions. The isolated yield was 39.5 mg (47% yield of pure E-
isomer, ~4:1 E/Z isomeric mixture from crude NMR) and the
corresponding er was 67:33 for the E-isomer. Absolute
stereochemistry only tentatively assigned. See supporting
information part B for HPLC chromatograms.
oxazaborolidine 34 under otherwise unchanged conditions. The
isolated yield was 55.4 mg (69% yield, ~2:1 E/Z) and the
corresponding er was 94:6 for the major E-isomer and 77:23 for
the minor Z-isomer. Absolute stereochemistry only tentatively
assigned. See supporting information part
chromatograms.
B for HPLC
S-(4-chlorobenzyl)
2-((3R,4S)-2,2-dimethyl-3,4-
dipropylcyclobutylidene)ethanethioate [37]: HNTf2 (14.0 mg,
0.05 mmol, 0.20 equiv) was added to a flame dried round bottom
flask in an argon filled glovebox, capped with a septum, and
removed from the glovebox. CH2Cl2 (0.50 mL, 0.50 M) was
added and the reaction mixture cooled to -78 oC. Oxazaborolidine
3 (0.25 M in PhMe, 250 µL, 0.06 mmol, 0.25 equiv) was added
and allowed to stir for 30 minutes. Cis-4-octene (195 µL, 1.25
mmol, 5.00 equiv) was added followed quickly by a solution of
S-(4-chlorobenzyl) 4-methylpenta-2,3-dienethioate (32) (63.0
mg, 0.25 mmol, 1.00 equiv) in PhMe (0.20 mL) and the reaction
was allowed to warm to room temperature. After 16 hours, the
reaction was quenched with 100 µL Et3N and the solution was
concentrated. Purification by silica gel chromatography (1%

8
Tetrahedron
ACCEPTED MANUSCRIPT
Supplementary Material
Photocycloaddition Reaction of Cyclic Enones and Its
Application in a Synthesis of (−)-Grandisol. J. Am. Chem. Soc.
2018, 140 (9), 3228–3231.
Du, J.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P. A Dual-
Supplementary material (1H NMR and 13C NMR) is available
for all compounds as well as additional experimental details.
4
Catalysis
Approach
to
Enantioselective
[2
+
2]
Acknowledgments
Photocycloadditions Using Visible Light. Science 2014, 344,
392–396.
5 Ishihara, K.; Nakano, K. Enantioselective [2 + 2] Cycloaddition
of Unactivated Alkenes with Α-Acyloxyacroleins Catalyzed by
Chiral Organoammonium Salts. J. Am. Chem. Soc. 2007, 129
(29), 8930–8931.
We thank Indiana University and the National Institutes of
Health (R01GM110131) for generous support of this work. The
Deutsche
Forschungsgemeinschaft
(WI
4933/1-2)
is
acknowledged for postdoctoral fellowship support to J.M.W.
This project was partially funded by the Vice Provost for
Research through the Research Equipment Fund and the NSF
(CHE1726633).
6
(a) Conner, M. L.; Xu, Y.; Brown, M. K. J. Am. Chem. Soc.
2015, 137 (10), 3482. (b) Xu, Y.; Hong, Y. J.; Tantillo, D. J.;
Brown, M. K. Org. Lett. 2017, 19 (14), 3703. (c) Wiest, J. M.;
Conner, M. L.; Brown, M. K. Angew. Chem. Int. Ed. 2018, 57
(17), 4647. (d) Wiest, J. M.; Conner, M. L.; Brown, M. K. J. Am.
Chem. Soc. 2018, 140 (46), 15943.
References and notes
7
For a chirality transfer [2+2] cycloaddition of an electron
deficient allene, see: Line, N. J.; Witherspoon, B. P.; Hancock, E.
N.; Brown, M. K. J. Am. Chem. Soc. 2017, 139 (41), 14392.
For early studies on the development of [2+2] Cycloadditions
1
8
(a) E. Lee-Ruff, G. Mladenova, Chem. Rev. 2003, 103, 1449.
(b) J. C. Namyslo, D. E. Kaufmann, Chem. Rev. 2003, 103,
1485. (c) N. Hoffmann Chem. Rev. 2008, 108, 1052. (d) T.
Bach; J. P. Hehn Angew. Chem., Int. Ed. 2011, 50, 1000. (e) T.
P. Yoon, ACS Catal. 2013, 3, 895.
between electron deficient allenes and alkenes, see: (a) Snider, B.
B.; Spindell, D. K. J. Org. Chem. 1980, 45 (25), 5017. (b)
Hoffmann, H.; Ismail, Z. M.; Weber, A. Tetrahedron Lett. 1981,
22 (21), 1953. (c) Snider, B. B.; Ron, E. J. Org. Chem. 1986, 51
(19), 3643. (d) Padwa, A.; Meske, M.; Murphree, S. S. J. Am.
Chem. Soc. 1995, 117, 7071. Padwa, A.; Lipka, H.; Watterson, S.
H.; Murphree, S. S. J. Org. Chem. 2003, 68 (16), 6238. (e) Jung,
M. E.; Murakami, M. Org. Lett. 2006, 8 (25), 5857. (f) Zhao, J.-
F.; Loh, T.-P. Angew. Chem. Int. Ed. 2009, 48 (39), 7232.
2 (a) Xu, Y.; Conner, M. L.; Brown, M. K. Angew. Chem. Int. Ed.
2015, 54 (41), 11918. (b) Poplata, S.; Tröster, A.; Zou, Y.-Q.;
Bach, T. Chem. Rev. 2016, 116 (17), 9748. (c) Wang, N.; Lu, P.
Org. Chem. Front. 2018, 5, 254.
3 (a)
Brimioulle, R.; Lenhart, D.; Maturi, M. M.; Bach, T.
9
Enantioselective Catalysis of Photochemical Reactions. Angew.
Chem. Int. Ed. Engl. 2015, 54 (13), 3872–3890. (b) Blum, T. R.;
Miller, Z. D.; Bates, D. M.; Guzei, I. A.; Yoon, T. P.
Enantioselective Photochemistry Through Lewis Acid-Catalyzed
Triplet Energy Transfer. Science 2016, 354 (6318), 1391–1395.
(c) Poplata, S.; Bach, T. Enantioselective Intermolecular [2+2]
For similar observations made in the development of
enantioselective [3+2] cycloadditions with N-acyl imines and
allenoates, see: Cowen, B. J.; Saunders, L. B.; Miller, S. J. J. Am.
Chem. Soc. 2009, 131 (17), 6105.