Catalytic Asymmetric Cycloadditions between Aldehydes and Enolizable Anhydrides: Cis-Selective Dihydroisocoumarin Formation

Article abstract of DOI:10.1021/acs.joc.8b02332

In the presence of a trityl-substituted cinchona alkaloid-based catalyst, homophthalic, aryl succinic, and glutaconic anhydride derivatives reacted with aromatic and aliphatic aldehydes to produce cis-lactones in up to 90:10 dr and 99% ee. A DFT study has shown how the catalyst is uniquely able to bring about the opposite sense of diastereocontrol to that usually observed.

Full text of DOI:10.1021/acs.joc.8b02332

Subscriber access provided by Kaohsiung Medical University
Note
Catalytic asymmetric cycloadditions between aldehydes and
enolizable anhydrides: cis-selective dihydroisocoumarin formation
Maria Luisa Aiello, Umar Farid, Cristina Trujillo, Brendan Twamley, and Stephen J. Connon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02332 • Publication Date (Web): 21 Nov 2018
Downloaded from http://pubs.acs.org on November 21, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Catalytic asymmetric cycloadditions between aldehydes and
enolizable anhydrides: cis-selective dihydroisocoumarin formation
Maria Luisa Aiello, Umar Farid, Cristina Trujillo, Brendan Twamley and Stephen J. Connon*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Trinity Biomedical Sciences Institute, School of Chemistry, The University of Dublin, Trinity College, Dublin 2, Ireland
Supporting Information Placeholder
In the presence of a trityl-substituted cinchona alkaloid-based catalyst, homophthalic-, aryl succinic- and glutaconic anhydride de-
rivatives reacted with aromatic and aliphatic aldehydes to produce cis-lactones in up to 90:10 dr and 99% ee. A DFT study has
shown how the catalyst is uniquely able to bring about the opposite sense of diastereocontrol to that usually observed.
The reaction between enolizable cyclic anhydrides and aldehydes
1,2,3,4,5
to form carboxy lactones is over a century old,
however a
catalytic asymmetric variant of the process was not reported until
6
2012. Since, the family of electrophiles amenable to these enanti-
oselective reactions with anhydrides has been extended to include
7
8
9
activated ketones, Michael acceptors and imines.
In the first such asymmetric reaction, homophthalic anhydride
(1) was shown – in the presence of a bifunctional squaramide-
10
based cinchona alkaloid catalyst 3 – to undergo cycloaddition
with a range of aldehydes 2 to form trans-3,4-dihydroisocourmain
(a structural unit present in numerous natural and synthetic mole-
11
cules of medicinal and biological importance ) products of general
type 4a,b with excellent enantiocontrol and good-excellent dia-
stereoselectivity favoring the formation of the trans-stereoisomer
(Figure 1A). A short time later a-aryl succinic anhydrides 5 were
reported to participate; providing access to arylated analogues of
trans-paraconic acids 6a,b with similar efficiency and stereo-
,
12 13
chemical outcomes. Calculations indicate that these reactions
involve the catalyst deprotonating the anhydride and organizing
the face-selective encounter between the squaramide-bound eno-
late and the ammonium ion-bound aldehyde in the stereocenter-
14
forming step (i.e. 7, Figure 1A).
15
In 2011, Yeung and co-workers reported an enantioselective
approach to the synthesis of trans-3,4-dihydroisocoumarins such
as 9a via an elegant bromocyclization of a styrenyl carboxylic
acid 8 promoted by thiocarbamate substituted cinchona alkaloid-
Figure 1. Organocatalytic formation of dihydroisocoumarins
derived catalyst 10 in excellent ee. These can be elaborated to cis-
16
derivatives via SN2 substitution. The competing formation of 9b
and the requirements for a) very low temperatures, b) onward
manipulation of the product to give a cis-diastereomer and c) the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 14
presence of the styrenyl unit, make the development of a direct, b-branched (i.e. product 33 – XRD structure shown in inset) and
1
2
3
4
5
6
7
8
broad-scope catalytic approach to cis-dihydroisocoumarins (espe-
cially in view of recent interest in these species following the
isolation of the eurotuimide family of anti-fouling and antibacteri-
a-branched (i.e. 34-37) aldehydes could be efficiently synthesized
with good to high cis-diastereocontrol and excellent to outstand-
ing levels of enantiomeric excess, with the latter class of substrate
providing products with ³ 80:20 dr and 98-99% ee. Cinnamalde-
hyde proved a more difficult substrate from a diastereocontrol
standpoint, yet 38 was still formed with high ee.
17
al natural products ) an attractive goal.
Herein we report the first such methodology involving the
efficient cis-selective asymmetric cycloaddition of enolizable
anhydrides and both aromatic and aliphatic aldehydes using a
trityl-substituted squaramide catalyst; which controls the stereo-
center forming event in an unusual and unexpected fashion.
Table 1. Catalyst evaluation
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Our study began with a catalyst screen (Table 1). As sub-
strates we chose the aliphatic hydrocinnamaldehyde 14 and
homophthalic anhydride 1 under the conditions used in previous
studies (0.1 M, MTBE, -15 °C). Crude reaction mixtures were
esterified in situ to prevent retro-cycloaddition and facilitate anal-
ysis of the resulting esters by CSP-HPLC. The prototype
18
(thio)urea-based cinchona alkaloid catalyst systems 16 and 17
promoted the reaction with poor-moderate enantio- and diastere-
ocontrol, favoring the trans-stereoisomer 15a (entries 1-2). Sul-
fonamide-substituted analogues (18-20, entries 3-5) – regardless
of their steric/electronic characteristics – fared little better, alt-
hough their use did provide 15b in higher (albeit unsatisfactory)
ee than 15a. Attention therefore returned to the squaramide-
substituted alkaloid family of catalysts utilized in the original
study. Specifically, we set out to vary the steric demand of the N-
alkyl (i.e. non alkaloid-bound) substituent as much as possible, to
probe
its
influence
on
diasterocontrol.
The
3,5-
bis(trifluoromethyl)phenyl substituted materials 21 and 22 per-
formed as expected: leading to the generation of both 15a and 15b
in excellent ee, but with 2:1 or 3:1 product ratios respectively,
favoring the undesired 15a. Interestingly, 21, which is devoid of
the C-2 phenyl unit at the catalyst’s quinoline moiety, promoted
the formation of greater levels of 15a than its substituted variant
15b, and so this (often beneficial) structural modification was not
19
considered in all subsequent catalyst designs.
entry
cat.
T
yield
(%)a
15a:15b a
ee15a
(%)b
ee15b
(%)b
Analogues of 21 in which the squaramide’s aromatic ring has
(h)
been exchanged for
a
benzyl- (i.e. 23), D- or L-
phenylglycinepyrrolidinamide (i.e. 24 and 25) or triethylmethyl
(i.e. 26) substituent failed to perturb the levels of trans-
diastereocontrol to an appreciable extent (entries 8-11). While the
incorporation of a very large tricyclohexylmethyl (i.e. 27) group
led to the formation of a greater proportion of 15b, enantioselec-
tivity was poor (entry 12). The hindered, C-2 symmetric catalyst
28 also catalyzed the cycloaddition slowly with ca. 1:1 dr, but this
reaction provided almost racemic 15b (entry 13). Gratifyingly, the
use of the N-trityl catalyst 29 led to a remarkable reversal of the
trend; affording predominantly the cis-15b in 90% ee, with the
minor trans-diastereomer also formed with excellent enantiocon-
trol (entry 14). Extending the reach of the trityl group through the
installation of p-methyl moieties did not lead to further improve-
ment (entry 15). A subsequent solvent and temperature screen
identified THF as a superior medium; allowing the formation of
15b with 71:29 dr and 99% ee (Table 1 entry 16)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16d
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
29
120
120
180
168
144
48
79
91
84
65
60
99
94
82
52
74
89
94
50
97
85
99
54:46
60:40
55:45
58:42
66:34
67:33
75:25
76:24
80:20
65:35
71:29
52:48
56:44
28:72
24:76
29:71
20
60
42
10
18
99
90
94
92
76
92
12
51
91
0
0
0
47
47
51
99
98
70
16
14
34
5
24
96
144
144
48
120
192
33
3
90
80
99
48
48
92
aCombined yield of both diasteromers determined by H NMR spectros-
copy using 4-iodoanisole as an internal standard. bDetermined by 1H NMR
spectroscopy. cDetermined by CSP-HPLC. dTHF solvent
1
With a catalyst and conditions leading to diastereo- and highly
enantioselective formation of cis-dihydroisocoumarins in hand,
we next wished to evaluate the substrate scope. A range of ali-
phatic aldehydes were evaluated as substrates for the process (Ta-
ble 2). Lactones derived from straight chain- (i.e. products 31-32),
Use of aldehydes incorporating non-conjugated olefin (i.e.
product 39) and Michael acceptor functionality were well tolerated
by the catalyst – no competing Tamura cycloaddition8 chemistry
was observed during the formation of 40. The only disappointing
ACS Paragon Plus Environment

Page 3 of 14
The Journal of Organic Chemistry
result occurred when an aldehyde incorporating a H-bond donat- from electron-neutral (i.e. 42), electron-deficient (i.e. 43-47) elec-
1
2
3
4
5
6
ing Boc-protected amine was utilized: in this case compound 41
was formed with a considerably lower ee of 81%.
tron rich (i.e. 48), hindered (i.e. 49) and heterocyclic (i.e. 50-51)
aromatic aldehydes could be isolated with moderate diastereocon-
trol and good-excellent ee.
Table 2. Substrate scope: aliphatic aldehydes
Scheme 1. Use of bromohomophthalic anhydride
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The process is not restricted to homophthalic anhydride (1). A
bromo-derivative (52, Scheme 1) could be reacted with the
branched aldehyde 53 to yield cis-54 in high dr and 98% ee. Grati-
fyingly, other enolizable anhydrides were also compatible: use of
the p-nitrophenyl succinic anhydride 55 in the presence of 53 pro-
vided 50% yield of the very sterically congested lactone 56 with
similar stereocontrol.
Scheme 2. Use of an enolizable succinic anhydride
Scheme 3. Use of a glutaconic anhydride derivative
Table 3. Substrate scope: aromatic aldehydes
A glutaconic anhydride derivative 5712 could also be utilized
(Scheme 3). This reacted with 53 to generate the densely func-
tionalized, highly malleable cis-ester derivative 58 in moderate
isolated yield but excellent ee. This is the first time this anhydride
class has been shown to react with aldehydes in an enantioselec-
tive process. Likewise, employment of a,a-diphenyl aldehyde 59
provided the corresponding lactone 60 in high isolated yield and
98% ee. This reaction was noteworthy in that the parent acid was
formed as a single diastereomer, however a dr of 90:10 cis:trans
was observed after esterification, despite careful experimentation
and very mild conditions. This was not observed in any other
20
case.
In order to rationalize both the stereochemical outcome of the
process and the key contribution of the catalyst’s trityl unit, we
carried out density functional theory (DFT) calculations on the
reaction between 1 and 53 catalyzed by 29 (Figure 2). These were
revealing – the catalyst deprotonates and binds the anhydride,
directing the same face of the enolate towards the ammonium ion-
bound aldehyde as seen before (i.e. 7), however it does so in a
very distinct fashion – via binding of the neutral (as drawn) car-
bonyl oxygen atom with the squaramide group. Further insight
into this curious binding mode was provided by QTAIM theory
(Figure 2, right): the unexpected binding mode is stabilized by
Aromatic aldehydes were substrates which were shown earlier
to be exceptionally well suited to the trans-selective cycloaddition
reaction.6 As expected, these were more difficult to coax into
forming cis-dihydroisocoumarins (Table 3), however, catalyst 29
still promoted cis-selective cycloaddition in all cases involving a
wide variety of functionalities. Esterified cycloadducts stemming
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 14
(THF), CH2Cl2 and Et2O were obtained by using Pure Solv
attractive interactions between the catalyst’s o- and m-trityl pro-
tons and two of the enolate’s oxygen atoms, thereby explaining
why the trityl-substituted catalyst alone was capable of bringing
about the formation of predominantly cis-products (for further
discussion see the ESI). This gave us a salutary lesson regarding
simplistic thinking in catalyst design: what was intended to be a
repulsive steric interaction in fact influenced enolate binding by
attractive means.
1
2
3
4
5
6
7
MD4EN Solvent Purification System. Methanol (MeOH) was
dried over activated 3Å molecular sieves. Commercially available
anhydrous t-butyl methyl ether (MTBE), 1,4-dioxane, 2-
methyltetrahydrofuran (2-MeTHF), 1,2-dimethoxyethane, diiso-
propyl ether were used. Analytical CSP-HPLC was performed on
Daicel Chiralpak, AD, AD-H, IA, OD, OD-H, OJ-H (4.6 mm x 25
cm) and using ACQUITY UPC2, Trefoil CEL1, CEL2, 2.5μm
(3.0 x 150 mm).
8
9
Procedure for the synthesis of catalyst 29. Synthesized accord-
ing to the literature procedure as a white solid (3.85 g, 91%).13
M.p. 156-158°C, 1H NMR (400 MHz, DMSO-d6): d = 8.61 (d, J =
4.5 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.56-7.46 (bs, 1H), 7.38
(dd, J = 2.3, 9.2 Hz, 1H), 7.20-7.09 (m, 9H), 7.07-6.91 (m, 6H),
6.55 (bs, 1H), 6.39 (bs, 1H), 5.91-5.71 (m, 2H), 5.06-4.96 (m,
2H), 3.90 (s, 3H), 3.69 (bs, 1H), 3.34-3.12 (m, 2H), 2.67-2.46 (m,
3H), 2.31-2.21 (m, 1H), 1.70-1.58 (m, 1H), 1.55-1.40 (m, 3H),
0.74-0.57 (m, 1H).
Procedure for the synthesis of compound 1.6 A 50 mL round-
bottomed flask containing a magnetic stirring bar was charged
with homophthalic acid (2.00 g, 11.1 mmol). Acetic anhydride (25
mL) was added, the flask was fitted with a condenser and the
reaction mixture was heated at 80 °C for 2 h. The excess acetic
anhydride was removed in vacuo and the solid obtained was tritu-
rated with Et2O (10 mL), filtered and dried to obtain homophthal-
ic anhydride (1) as an off white solid (1.50 g, 85%). M.p. 141-142
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. DFT-based stereochemical insight
In conclusion, we have developed the first enantioselective
cycloaddition reaction between aldehydes and enolizable anhy-
drides which is cis-selective. Diastereocontrol up to 90:10 dr and
enantiomeric excesses up to 99% are possible. The process is of
broad scope: aliphatic aldehydes are superior substrates to aro-
matic analogues, however both are accepted by the catalyst.
Homophthalic-, aryl succinic- and glutaconic anhydride deriva-
tives are also compatible. DFT calculations have shown that the
unique ability of 29 is due in part to an ability of the trityl aro-
matic protons to undergo attractive interactions with the catalyst-
bound anhydride conjugate base.
1
°C (lit.,6 m.p. 143-144 °C); H NMR (400 MHz, DMSO-d6): d =
8.05 (d, J = 7.9 Hz, 1H), 7.75 (app. t, 1H), 7.52 (app. t, 1H), 7.44
(d, J = 7.8 Hz, 1H), 4.28 (s, 2H).
(E)-Ethyl-7-oxohept-2-enoate (S1). Synthesized according to the
procedure developed by Singleton et al.[22] To an aqueous solution
of glutaraldehyde (15 mL, 166 mmol, 25% w/v in water) in
CH2Cl2 (3 mL) was added a solution of (carboethoxymeth-
ylene)triphenylphosphorane (5.78 g, 16.6 mmol) in CH2Cl2 (5
mL). The corresponding reaction mixture was allowed to stir at
room temperature for 12 h, after which time EtOAc (30 mL) was
added. The resulting solution was washed with water (20 mL) and
then concentrated under reduced pressure. The crude product
obtained was then purified by flash column chromatography elut-
ing with 80:20 hexanes:EtOAc to furnish (E)-S1 as a colourless
oil (1.24 g, 44%).1H NMR (400 MHz, CDCl3): δ = 9.79-9.74 (t, J
= 1.3 Hz, 1H), 6.93 (dt, J = 6.8, 15.7 Hz, 1H), 5.85 (d, J = 15.7
Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.50 (dt, J = 1.3, 13.2 Hz, 2H),
2.33-2.21 (m, 2H), 1.89-1.77 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H);
HRMS (ESI) m/z: [M - H]- Calcd. for C9H13O3 169.0867; Found
169.0865.
EXPERIMENTAL SECTION
General information. Proton Nuclear Magnetic Resonance
(NMR) spectra was recorded on Bruker DPX 400 MHz spectrom-
eter using CDCl3, DMSO-d6 or D2O as solvents and referenced
relative to residual CHCl3 (δ = 7.26 ppm) DMSO (δ = 2.50 ppm)
or H2O (δ = 4.79 ppm). Chemical shifts are reported in ppm and
coupling constants (J) in Hertz. Carbon NMR spectra were rec-
orded on the same instruments (100 MHz) with total proton de-
coupling. Fluorine NMR spectra were recorded on the Bruker
DPX400 machine (376.5 and 202 MHz respectively). HSQC,
HMBC, NOE and ROESY NMR experiments were used to aid
assignment of NMR peaks when required. All melting points are
uncorrected. Infrared spectra were obtained using neat samples on
a Perkin Elmer Spectrum 100 FT-IR spectrometer equipped with
a universal ATR sampling accessory. ESI mass spectra were ac-
quired using a Waters Micromass LCT- time of flight mass spec-
trometer (TOF), interfaced to a Waters 2690 HPLC. APCI exper-
iments were carried out on a Bruker microTOF-Q III spectrometer
interfaced to a Dionex UltiMate 3000 LC or direct insertion
probe. The instrument was operated in positive or negative mode
as required. Flash chromatography was carried out using silica
gel, particle size 0.04-0.063 mm. TLC analysis was performed on
precoated 60F254 slides, and visualized by UV irradiation or
KMnO4 staining. Optical rotation measurements were made on a
Rudolph Research Analytical Autopol IV instrument and are
quoted in units of 10-1 deg cm2 g-1. Anhydrous tetrahydrofuran
tert-butyl (2-aminoethyl)carbamate (S2). Synthesized according
to the procedure developed by Guenter et al.[23] A 500 mL round-
bottomed flask containing a magnetic stirring bar was charged
with a solution of ethylenediamine (5.6 mL, 83.3 mmol) in
CH2Cl2 (25 mL). A solution of di-tert-butyl dicarbonate (3.05 g,
14.0 mmol) in CH2Cl2 (200 mL) was then added dropwise over 3
h. The volatiles were removed in vacuo and the resulting oil was
dissolved in a saturated aqueous solution of Na2CO3 (300 mL)
and extracted with CH2Cl2 (2 x 150 mL). The combined organic
phases were dried over anhydrous MgSO4 and concentrated under
1
reduced pressure to afford S2 as colourless oil (1.59 g, 71%). H
NMR (400 MHz, CDCl3): δ = 4.90 (bs, 1H), 3.13 (m, 2H), 2.76
(m, 2H), 1.41 (s, 9H), 1.22 (bs, 2H); HRMS (APCI) m/z: [M +
H]+ Calcd for C7H17N2O2 161.1284; Found 161.1289.
ACS Paragon Plus Environment

Page 5 of 14
The Journal of Organic Chemistry
(1 equiv.) was added via syringe. The reaction was allowed to stir
tert-butyl (3-oxopropyl)carbamate (S3). Synthesized according to
the procedure developed by Fujisawa et al.[24] An oven-dried 50
mL round-bottomed flask containing a magnetic stirring bar under
an argon atmosphere, was charged with a solution of DMSO (3
mL, 32.3 mmol) in CH2Cl2 (57 mL), followed by oxalyl chloride
(1.4 mL, 16.1 mmol) at -78 °C. The resultant mixture was stirred
for 15 min and a solution of S2 (1.71 g, 10.7 mmol) in CH2Cl2 (50
mL) was added dropwise. After 1 hour, triethylamine (7.5 mL,
53.8 mmol) was added at -78 °C and the corresponding solution
was allowed to stir at room temperature for 30 min. The reaction
mixture was then quenched with a 10% aqueous solution of HCl
(100 mL) and extracted with EtOAc (2 × 50 mL). The combined
organic phases were washed with a saturated aqueous solution of
NaHCO3, then brine, dried over anhydrous MgSO4 and concen-
trated under reduced pressure. The crude product was purified by
flash column chromatography eluting with 70:30 hexanes:EtOAc,
to afford S3 as a yellow oil (1.50 g, 81%). TLC (hexanes:EtOAc
at -15 °C and for a time indicated in the relative Table. The yield
and diastereomeric ratio of the carboxylic acids were determined
by 1H NMR spectroscopic analysis using p-iodoanisole (0.5
equiv.) as an internal standard. The reaction was then diluted with
EtOAc (10 mL) and extracted with a 10% aqueous solution of
NaHCO3 (15 mL). The combined aqueous phases were acidified
with an aqueous solution of HCl (2.0 N, 5 mL) and the mixture
was then extracted with EtOAc (3 x 15 mL). The combined organ-
ic extracts were dried over anhydrous MgSO4 and the solvent was
removed under reduced pressure to furnish the diastereomeric
mixture of carboxylic acids. To a solution of the carboxylic acid
products in dry THF (0.1 M) were added via syringe anhydrous
MeOH (750 μL, 18.5 mmol) followed by trimethylsilyldiazome-
thane (2.0 M solution in diethyl ether, 150 μL, 0.300 mmol) and
the reaction was allowed to stir for 20 min. The solvent was then
evaporated in vacuo and the crude mixture of diastereomeric es-
ters was purified by flash column chromatography, to isolated
both diastereomers – the enantiomeric excesses of which were
determined by CSP-HPLC.
General procedure C for the racemic synthesis of kavalac-
tones derivatives (Scheme 3). An oven-dried 10 mL round-
bottomed flask containing a magnetic stirring bar under an argon
atmosphere was charged with phenyl glutaconic anhydride (57,
46.3 mg, 0.246 mmol) and anhydrous THF (2.5 mL, 0.1 M). The
relevant aldehyde (1 equiv.) was then added to the reaction fol-
lowed by equal amounts of catalyst 18 (14.2 mg, 0.0246 mmol -
10 mol%) and its pseudoenantiomer catalyst epi-18 (14.2 mg,
0.0246 mmol - 10 mol%) and the resulting mixture was allowed
to stir for 20 h at room temperature. The corresponding solution
of carboxylic acids in dry THF (2.5 mL, 0.1 M) was then cooled
to -15 °C and anhydrous iPrOH (94 µL, 1.23 mmol), followed by
trimethylsilyldiazomethane (2.0 M solution in diethyl ether, 150
µL, 0.300 mmol) were added via syringe. The reaction was al-
lowed to stir for 20 min at -15 °C, after which time the solvent
was removed in vacuo. The resultant crude mixture of diastereo-
meric esters was then purified by flash column chromatography to
furnish both diastereomers.
General procedure D for the enantioselective synthesis of ka-
valactones (Scheme 3) An oven-dried 10 mL round-bottomed
flask containing a magnetic stirring bar under an argon atmos-
phere was charged with phenyl glutaconic anhydride (57, 46.3
mg, 0.246 mmol), catalyst 29 (8.13 mg, 0.0123 mmol - 5 mol%)
and anhydrous THF (0.1 M). The resulting mixture was cooled to
-15 °C and the relevant aldehyde (1 equiv.) was added via syringe.
The reaction was allowed to stir at -15 °C and for a time indicated
in the relative Table. The yield and diastereomeric ratio of the
carboxylic acids were determined by 1H NMR spectroscopic anal-
ysis using p-iodoanisole (0.5 equiv.) as an internal standard. The
reaction was then diluted with EtOAc (10 mL) and extracted with
a 10% aqueous solution of NaHCO3 (15 mL). The combined
aqueous phases were acidified with an aqueous solution of HCl
(2.0 N, 5 mL) and the mixture was then extracted with EtOAc (3 x
15 mL). The combined organic extracts were dried over anhy-
drous MgSO4 and the solvent was removed under reduced pres-
sure to furnish the diastereomeric mixture of carboxylic acids. To
a solution of the corresponding carboxylic acids in dry THF (0.1
M) cooled to -15 °C, anhydrous iPrOH (94 µL, 1.23 mmol), fol-
lowed by trimethylsilyldiazomethane (2.0 M solution in diethyl
ether, 150 µL, 0.300 mmol) were added via syringe and the reac-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
8:2, v/v): Rf = 0.42; H NMR (400 MHz, CDCl3): δ = 9.79 (s,
1H), 4.73 (bs, 1H), 3.48-3.32 (m, 2H), 3.75-3.60 (m, 2H), 1.42 (s,
9H); HRMS (APCI) m/z: [M + Na]+ Calcd. for C8H15NO3Na
196.0944; Found 196.0936.
Bromoisochroman-1,3-dione (52). Synthesized according to the
literature procedure as an off white solid (800 mg, 85%).[25]. M.p.
176-177 °C (lit.[25] 171-173 °C); 1H NMR (400 MHz, CDCl3): δ =
8.13 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 2.0, 8.3 Hz, 1H), 7.41 (d, J
= 8.3 Hz, 1H), 4.23 (s, 2H).
3-(4-Nitrophenyl)dihydrofuran-2,5-dione (55). Synthesized ac-
cording to the literature procedure as a white solid (1.20 g,
68%).12 M.p. 66-68 °C; 1H NMR (400 MHz, DMSO-d6): δ = 8.22
(d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 4.84 (dd, J = 8.3,
10.2 Hz, 1H), 3.44 (dd, J = 10.2, 18.3 Hz, 1H), 3.32 (dd, J = 8.3,
18.3 Hz, 1H).
Phenyl-2H-pyran-2,6(3H)-dione (57). Synthesized according to
the literature procedure as a white solid (118 mg, 51%).8 M.p.
195-197 °C (lit.[8] m.p. 193-195 °C); 1H NMR (400 MHz, DMSO-
d6): δ = 7.79 (d, J = 6.7 Hz, 2H), 7.55-7.41 (m, 3H), 6.78 (s, 1H),
4.15 (s, 2H).
General procedure A for the racemic synthesis of dihydroiso-
coumarins and γ-butyrolactones (Table 1 entry 16, Tables 2 and
3). An oven-dried 10 mL round-bottomed flask containing a mag-
netic stirring bar under an argon atmosphere was charged with the
relevant anhydride (1 equiv.) and anhydrous THF (2.5 mL, 0.1
M). The relevant aldehyde (1 equiv.) followed by N,N-
diisopropylethylamine (8.6 µL, 0.0492 mmol - 20 mol%) were
then added via syringe and the resulting mixture was allowed to
stir for 20 h at room temperature. To the corresponding solution
of carboxylic acids in THF (2.5 mL, 0.1 M), were added via sy-
ringe anhydrous MeOH (750 µL, 18.5 mmol), followed by trime-
thylsilyldiazomethane (2.0 M solution in diethyl ether, 150 µL,
0.300 mmol) and the reaction was allowed to stir for 30 min at
room temperature. The solvent was then removed in vacuo and
the crude mixture of diastereomeric esters was purified by flash
column chromatography to afford both diastereomers.
General procedure B for the enantioselective synthesis of di-
hydroisocoumarins and γ-butyrolactones (Table 1 entry 16,
Tables 2 and 3). An oven-dried 10 mL round-bottomed flask con-
taining a magnetic stirring bar under an argon atmosphere was
charged with the relevant anhydride (1.0 equiv.), catalyst 29 (8.13
mg, 0.0123 mmol - 5 mol%) and anhydrous THF (0.1 M). The
resulting mixture was cooled to -15 °C and the relevant aldehyde
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
tion was allowed to stir for 20 minutes. The solvent was then
1012, 790, 685, 705; HRMS (APCI) m/z: [M + H]+ Calcd. for
1
2
3
4
5
6
7
8
evaporated under reduced pressure and the crude mixture of dia-
stereomeric esters was purified by flash column chromatography
to furnish both diastereomers. The enantiomeric excesses of the
products were determined by CSP-HPLC using the conditions
indicated for each case.
C18H25O4 305.1747; Found 305.1760.
*[α]%$& refers to a mixture of cis-31:trans-31 in a 79:21 ratio
Methyl-3-benzyl-1-oxoisochromane-4-carboxylate (cis-32, trans-
32). Prepared according to general procedure B, using freshly
distilled phenylacetaldehyde (27.4 µL, 0.246 mmol) and
homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction
was stirred for 48 h to furnish a diastereomeric mixture of car-
boxylic acids in a 87:13 ratio (cis:trans). After esterification and
purification by flash column chromatography, eluting with 80:20
hexanes:EtOAc, cis-32 and trans-32 were isolated combined as a
white solid (67.1 mg, 92%). CSP-HPLC analysis: Chiralcel IA
(4.6 mm x 25 cm), n-hexane/IPA: 90/10, 1.0 mL min-1, RT, UV
detection at 254 nm, retention times: cis-32 40.3 min (minor
enantiomer) and 48.0 min (major enantiomer); trans-32 15.4 min
(major enantiomer) and 21.6 min (minor enantiomer). M.p. 68-70
°C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.41, [α]%$& = -4.5 (c =
0.04, CHCl3);*cis-32: 1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J
= 6.5 Hz, 1H), 7.56 (app. t, 1H), 7.49 (app. t, 1H), 7.45-7.36 (m,
5H), 7.35 (d, J = 6.9 Hz, 1H), 4.81 (ddd, J = 2.9, 6.7, 7.8 Hz,
1H), 3.84 (d, J = 2.9 Hz, 1H), 3.73 (s, 3H), 3.30 (dd, J = 6.7, 14.2
Hz, 1H), 3.16 (dd, J = 7.8, 14.2 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3): δ = 169.2, 164.6, 136.7, 135.8, 133.7, 130.7,
129.5, 129.1, 128.8, 127.4, 127.2, 125.4, 79.7, 52.7, 46.7, 38.9;
trans-32: 1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 6.4 Hz,
1H), 7.64 (app. t, 1H), 7.49 (app. t, 1H), 7.45-7.36 (m, 5H), 7.17
(d, J = 6.3 Hz, 1H), 5.22-5.17 (m, 1H), 3.86 (d, J = 5.2 Hz, 1H),
3.72 (s, 3H), 3.17 (dd, J = 6.3, 14.1 Hz, 1H), 2.89 (dd, J = 7.8,
14.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ = 170.4,
163.5, 135.5, 135.2, 134.3, 130.5, 129.5, 128.87, 128.82, 127.9,
127.3, 124.7, 79.4, 52.8, 46.5, 39.6; IR (neat): 3030, 2952, 1724,
1658, 1453, 1434, 1376, 1261, 1158, 1119, 1030, 979, 738, 698;
HRMS (ESI) m/z: [M + Na]+ Calcd. for C18H16O4Na 319.0940;
Found 319.0945.
Methyl-1-oxo-3-((E)-styryl)isochromane-4-carboxylate (15a, 15b).
Prepared according to general procedure B, using freshly distilled
hydrocinnamaldehyde (14, 32.0 µL, 0.246 mmol) and homoph-
thalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was
stirred for 33 h to give a diastereomeric mixture of carboxylic
acids in a 71:29 ratio (cis:trans). After esterification and purifica-
tion by flash column chromatography, eluting with 80:20 hex-
anes:EtOAc, cis-15b and trans-15a were isolated combined as a
pale yellow oil (74.0 mg, 99%). CSP-HPLC analysis: Chiralcel
OJ-H (4.6 mm x 25 cm), hexane/IPA: 70/30, 0.3 mL min-1, RT,
UV detection at 254 nm, retention times: cis-15b 70.4 min (major
enantiomer) and 105.9 min (minor enantiomer); trans-15a 60.6
min (major enantiomer) and 79.2 min (minor enantiomer). Spec-
tral data for this compound were consistent with those in the litera-
ture.6 TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.34; cis-15b: 1H NMR
(400 MHz, CDCl3): δ = 8.15 (d, J = 7.9 Hz, 1H), 7.56 (app. t, 1H),
7.48 (app. t, 1H), 7.32-7.24 (m, 2H), 7.25-7.14 (m, 4H), 4.60-4.52
(m, 1H), 3.83 (d, J = 3.2 Hz, 1H), 3.67 (s, 3H), 3.05-2.90 (m, 1H),
2.90-2.83 (m, 1H), 2.31-2.18 (m, 1H), 2.14-2.02 (m, 1H); trans-
15a: 1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 7.7 Hz, 1H),
7.57 (app. t, 1H), 7.47 (app. t, 1H), 7.32-7.24 (m, 3H), 7.25-7.14
(m, 3H), 4.90-4.82 (m, 1H), 3.92 (d, J = 6.8 Hz, 1H), 3.76 (s, 3H),
3.05-2.90 (m, 1H), 2.83-2.75 (m, 1H), 2.15-2.01 (m, 1H), 1.99-
1.84 (m, 1H); HRMS (APCI) m/z: [M + H] + Calcd. for C19H19O4
311.1277; Found 311.1284.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl-3-heptyl-1-oxoisochromane-4-carboxylate (cis-31, trans-
31). Prepared according to general procedure B, using freshly
distilled octanal (38.4 µL, 0.246 mmol) and homophthalic anhy-
dride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 18 h
to give a diastereomeric mixture of carboxylic acids in a 76:24
ratio (cis:trans). After esterification and purification by flash col-
umn chromatography, eluting with 90:10 hexanes:EtOAc, cis-31
and trans-31 were isolated combined as a white solid (70.4 mg,
94%). CSP-HPLC analysis: Chiralcel IA (4.6 mm x 25 cm), hex-
ane/IPA: 98/2, 0.5 mL min-1, RT, UV detection at 221 nm, reten-
tion times: cis-31 48.4 min (minor enantiomer) and 62.1 min (ma-
jor enantiomer); trans-31 33.4 min (minor enantiomer) and 35.6
min (major enantiomer). M.p. 50-55 ºC; TLC (hexanes/EtOAc, 8:2
*[α]%$& refers to a mixture of cis-32:trans-32 in a 84:16 ratio
Methyl-3-isopropyl-1-oxoisochromane-4-carboxylate
(cis-33,
trans-33). Prepared according to general procedure B, using
freshly distilled isovaleraldehyde (26.9 µL, 0.246 mmol) and
homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction
was stirred for 18 h to give a diastereomeric mixture of carbox-
ylic acids in a 78:22 ratio (cis:trans). After esterification and
purification by flash column chromatography, eluting with 80:20
hexanes:EtOAc, cis-33 and trans-33 were isolated combined as
a white solid (58.7 mg, 91%). CSP-HPLC analysis: Chiralcel
ODH (4.6 mm x 25 cm), n-hexane/IPA: 95/5, 1.0 mL min-1, RT,
UV detection at 221 nm, retention times: cis-33 16.8 min; trans-
33 11.2 min. M.p. 95-97 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf
v/v): Rf = 0.61; [α]%$& = -3.2 (c = 0.05, CHCl3);*cis-31: H NMR
1
(400 MHz, CDCl3): δ = 8.17 (d, J = 7.8 Hz, 1H), 7.61 (app. t,
1H), 7.50 (app. t, 1H), 7.32 (d, J = 7.4 Hz, 1H), 4.63-4.59 (m,
1H), 3.88 (d, J = 3.2 Hz, 1H), 3.69 (s, 3H), 1.92-1.82 (m, 1H),
1.84-1.73 (m, 1H), 1.66-1.61 (m, 1H), 1.52-1.47 (m, 1H), 1.47-
1.32 (m, 8H), 0.92-0.86 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ = 169.3, 164.8, 136.8, 133.7, 130.7, 129.0, 127.2, 125.5,
78.7, 52.6, 47.9, 32.8, 31.73, 29.2, 29.04, 25.2, 22.7, 14.1; trans-
= 0.27; [α]%$& = -6.3 (c = 0.04, CHCl3);* cis-33: H NMR (400
1
MHz, CDCl3): δ = 8.17 (d, J = 7.8 Hz, 1H), 7.59 (app. t, 1H),
7.51 (app. t, 1H), 7.33 (d, J = 7.4 Hz, 1H), 4.72 (ddd, J = 3.3,
4.5, 9.2 Hz, 1H), 3.83 (d, J = 3.3 Hz, 1H), 3.70 (s, 3H), 2.10-
2.01 (m, 1H), 1.88 (ddd, J = 5.9, 9.2, 14.6 Hz, 1H), 1.58 (ddd, J
= 4.5, 8.4, 14.6 Hz, 1H), 1.01 (d, J = 6.6 Hz, 3H), 0.98 (d, J =
6.6 Hz, 3H);13C{1H} NMR (100 MHz, CDCl3): 169.3, 164.8,
136.8, 133.7, 130.7, 129.0, 127.2, 125.4, 76.8, 52.6, 48.3, 41.5,
24.1, 22.9, 21.9; trans-33: 1H NMR (400 MHz, CDCl3): δ = 8.15
(d, J = 7.4 Hz, 1H), 7.63-7.59 (m, 1H), 7.49-7.45 (m, 1H), 7.24
(d, J = 7.3 Hz, 1H), 4.96 (ddd, J = 4.5, 6.1, 9.2 Hz, 1H), 3.87 (d,
J = 6.1 Hz, 1H,), 3.80 (s, 3H), 2.01-1.94 (m, 1H), 1.85 (ddd, J =
5.9, 9.2, 14.6 Hz, 1H), 1.55 (ddd, J = 4.5, 8.4, 14.6 Hz, 1H),
1
31: H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 8.0 Hz, 1H),
7.58 (app. t, 1H), 7.48 (app. t, 1H), 7.23 (d, J 7.4 Hz, 1H), 4.63
(ddd, J = 3.8, 6.5, 12.5 Hz, 1H), 3.92 (d, J = 6.5 Hz, 1H), 3.81 (s,
3H), 1.83-1.74 (m, 1H), 1.66-1.61 (m, 2H), 1.52-1.47 (m, 1H),
1.47-1.32 (m, 8H), 0.92-0.86 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ = 170.7, 163.9, 135.9, 134.0, 130.5, 128.6, 127.3, 124.7,
79.1, 52.7, 48.4, 33.7, 31.7, 29.1, 29.08, 25.0, 22.6, 14.0; IR
(neat): 3133, 3025, 1730, 1680, 1580, 1467, 1156, 1125, 1096,
ACS Paragon Plus Environment

Page 7 of 14
The Journal of Organic Chemistry
7.6 Hz, 1H), 4.90-4.84 (m, 1H), 4.14 (d, J = 6.7 Hz, 1H), 3.80 (s,
0.97 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13C{1H}
1
2
3
4
5
6
7
3H), 1.90-1.77 (m, 3H), 1.70-1.59 (m, 1H), 1.55-1.42 (m, 1H),
0.94-0.88 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ = 170.9,
164.2, 137.2, 134.0, 130.4, 128.6, 127.2, 125.6, 80.7, 52.7, 46.2,
43.2, 21.9, 20.9, 11.2, 10.8; IR (neat): 2963, 2878, 1724, 1604,
1458, 1264,1226, 1158, 1110, 1085, 997, 717, 691; HRMS (ESI)
m/z: [M + Na]+ Calcd. for C16H20O4Na 299.1259; Found
299.1279.
NMR (100 MHz, CDCl3): δ = 170.7, 163.8, 135.8, 134.1, 130.4,
128.7, 127.4, 124.7, 77.4, 52.8, 48.8, 42.8, 24.2, 23.1, 21.5; IR
(neat): 2956, 1719, 1605, 1459, 1311, 1264, 1163, 1113, 1087,
993, 948, 827, 711, 606, 567; HRMS (APCI) m/z: [M + H]+
Calcd. for C15H19O4 263.1277; Found 263.1273.
*[α]%$& refers to cis-33 which was isolated after trituration of the
diastereomeric mixture with isopropanol
*[α]%$& refers to a mixture of cis-35:trans-35 in a 90:10 ratio.
Methyl-3-isopropyl-1-oxoisochromane-4-carboxylate
(cis-34,
8
trans-34). Prepared according to general procedure B, using fresh-
ly distilled isobutyraldehyde (22.4 µL, 0.246 mmol) and homoph-
thalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was
stirred for 18 h to give a diastereomeric mixture of carboxylic
acids in a 84:16 ratio (cis:trans). After esterification and purifica-
tion by flash column chromatography, eluting with 85:15 hex-
anes:EtAOc, cis-34 and trans-34 were isolated combined as a
white solid (54.9 mg, 90%). CSP-HPLC analysis: Chiralcel ODH
(4.6 mm x 25 cm), n-hexane/IPA: 85/15, 0.5 mL min-1, RT, UV
detection at 221 nm, retention times: cis-34 20.3 (minor enantio-
mer) and 21.8 min (major enantiomer); trans-34 15.2 min (major
enantiomer) and 17.2 (minor enantiomer). M.p. 69-72 °C; TLC
(hexanes/EtOAc, 8:2 v/v): Rf = 0.26; [α]%$& = -5.1 (c = 0.05,
CHCl3);* cis-34: 1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 7.5
Hz, 1H), 7.56 (app. t, 1H), 7.50 (app. t, 1H), 7.31 (d, J = 7.5 Hz,
1H), 4.15 (dd, J = 3.0, 9.9 Hz, 1H), 4.01 (d, J = 3.0 Hz, 1H), 3.65
(s, 3H), 2.13-2.03 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 1.10 (d, J =
6.8 Hz, 3H); 13C{1H} (100 MHz, CDCl3): 169.4, 164.9, 137.1,
133.7, 130.7, 129.0, 127.3, 125.6, 84.4, 52.6, 46.2, 31.1, 18.5,
19.4; trans-34: 1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 7.8
Hz, 1H), 7.58 (app. t, 1H), 7.48 (app. t, 1H), 7.21 (d, J = 7.4 Hz,
1H), 4.64-4.60 (m, 1H), 4.04 (d, J = 6.4 Hz, 1H), 3.77 (s, 3H),
1.88-1.77 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ = 169.5, 165.6, 136.1, 134.1,
130.3, 128.6, 127.3, 125.6, 83.9, 52.8, 46.3, 30.9, 19.3, 17.2; IR
(neat): 2973, 1718, 1604, 1436, 1263, 1210, 1168, 1109, 1084,
Methyl-3-cyclohexyl-1-oxoisochroman-4-carboxylate
(cis-36
9
trans-36). Prepared according to general procedure B, using fresh-
ly distilled cyclohexanecarboxyaldehyde (29.8 µL, 0.246 mmol)
and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reac-
tion was stirred for 24 h to give a diastereomeric mixture of car-
boxylic acids in a 80:20 ratio (cis:trans). After esterification and
purification by flash column chromatography, eluting with 90:10
hexanes:EtOAc, cis-36 and trans-36 were isolated combined as a
pale yellow oil (67.4 mg, 95%). Spectral data for this compound
were consistent with those in the literature.6 CSP-HPLC analysis:
Chiralcel ODH (4.6 mm x 25 cm), n-hexane/IPA: 60/40, 1.0 mL
min-1, RT, UV detection at 254 nm, retention times: cis-36 59.5
min (minor enantiomer) and 65.1 min (major enantiomer); trans-
36 51.8 min (major enantiomer) and 62.3 min (minor enantiomer).
cis-36: 1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 7.6 Hz, 1H),
7.58 (app. t, 1H), 7.50 (app. t, 1H), 7.33 (d, J = 7.6 Hz, 1H), 4.26
(dd, J = 3.0, 9.9 Hz, 1H), 4.03 (d, J = 3.0 Hz, 1H), 3.69 (s, 3H),
2.41-2.23 (m, 1H), 2.03-1.08 (m, 8H), 1.08-0.95 (m, 2H); trans-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
36: H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 7.9 Hz, 1H),
7.58 (app. t, 1H), 7.46 (app. t, 1H), 7.22 (d, J = 7.6 Hz, 1H), 4.66
(m, 1H), 4.06 (d, J = 5.7 Hz, 1H), 3.77 (s, 3H), 1.97-1.88 (m, 1H),
1.87-1.08 (m, 10 H); HRMS (APCI) m/z: [M- H]- Calcd. for
C17H19O4 287.1288; Found 287.1277.
(3R,4R)-Methyl-3-benzhydryl-1-oxoisochromane-4-carboxylate
(cis-37, trans-37). Prepared according to general procedure B,
using freshly distilled diphenylacetaldehyde (43.6 µL, 0.246
mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol).
The reaction was stirred for 48 hours to give a diastereomeric
mixture of carboxylic acids in a 87:13 ratio (cis:trans). After es-
terification, the crude mixture was purified by flash column chro-
matography to give 37 (a chromatographically inseparable mix-
ture of diastereomers with retention of dr) as a white solid (78.1
mg, 85%). Full characterisation of cis-37 was made possible by
trituration of the diastereomeric mixture with IPA in which trans-
37 is completely soluble. Full characterisation of trans-37 was
complicated due to the partial solubility of cis-37 in IPA. CSP-
HPLC analysis: ACQUITY UPC2, Trefoil AMY1, 2.5µm (3.0 x
+
983, 768, 714, 642; HRMS (APCI) m/z: [M + H] Calcd. for
C14H17O4 249.1121; Found 249.1122.
*[α]%$& refers to a mixture of cis-34:trans-34 in a 84:16 ratio
Methyl-1-oxo-3-(pentan-3-yl)isochromane-4-carboxylate (cis-35,
trans-35). Prepared according to general procedure B, using fresh-
ly distilled 2-ethylbutyraldehyde (30.3 µL, 0.246 mmol) and
homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction
was stirred for 6 days to give a diastereomeric mixture of carbox-
ylic acids in a 88:12 ratio (cis:trans). After esterification and puri-
fication by flash column chromatography, eluting with 95:5 hex-
anes:EtOAc, cis-35 and trans-35 were isolated combined as a
white solid (61.2 mg, 90%). CSP-HPLC analysis: ACQUITY
UPC2, Trefoil AMY1, 2.5µm (3.0 x 150mm). ABPR: 1500 (psi).
A (CO2) = 97%/B (Ethanol/ACN/IPA 1:1:1, v:v:v) = 3%, 1.2 mL
min-1, 30 °C, UV detection at 254 nm, retention times: cis-35 2.05
min; trans-35 2.02 min. M.p. 45-47 °C; TLC (hexanes/EtOAc, 8:2
150mm). ABPR: 1500 (psi).
A (CO2) = 97%/B (Etha-
nol/ACN/IPA 1:1:1, v:v:v) = 3%, 1.2 mL min-1, 30 °C, UV detec-
tion at 254 nm, cis-37 3.38 min (minor enantiomer) and 3.58 min
(major enantiomer); trans-37 3.69 min (major enantiomer) and
3.85 min (minor enantiomer). M.p. 174-176. ºC; TLC (hex-
anes:EtOAc, 8/2 v/v): Rf = 0.67; [α]20D = -2.9 (c = 0.04, CHCl3);*
cis-37: 1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 7.7 Hz, 1H),
7.56 (app. t, 1H), 7.50 (app. t, 1H), 7.43-7.38 (m, 2H), 7.38-7.25
(m, 8H), 7.22 (t, J =7.3 Hz, 1H,), 5.39 (dd, J = 2.4, 10.9 Hz, 1H),
4.59 (d, J = 10.9 Hz, 1H), 3.75 (d, J = 2.4 Hz, 1H), 3.66 (s, 3H);
13C{1H} (100 MHz, CDCl3): δ = 168.9, 164.4, 140.2, 140.1,
136.9, 133.7, 130.7, 129.1, 129.0, 128.6 (C x 2), 128.1, 127.6,
127.5, 126.8, 125.3, 79.9, 53.6, 52.4, 45.8; IR (neat): 3029, 1734,
1724, 1600, 1494, 1452, 1251, 1221, 1157, 1107, 1085, 996, 973,
v/v): Rf = 0.64; [α]%$& = -3.9 (c = 0.04, CHCl3);* cis-35: H NMR
1
(400 MHz, CDCl3): δ = 8.16 (d, J = 7.7 Hz, 1H), 7.58 (app. t, 1H),
7.50 (app. t, 1H), 7.34 (d, J = 7.7 Hz, 1H), 4.45 (dd, J = 2.9, 9.8
Hz, 1H), 4.01 (d, J = 2.9 Hz, 1H), 3.68 (s, 3H), 1.90-1.77 (m, 3H),
1.70-1.59 (m, 1H), 1.55-1.42 (m, 1H), 0.94-0.88 (m, 6H);
13C{1H} NMR (100 MHz, CDCl3): δ = 169.5, 165.0, 137.2,
133.6, 130.7, 129.0, 127.3, 125.6, 80.6, 52.6, 46.1, 41.7, 20.0,
19.7, 9.8, 9.6; trans-35: 1H NMR (400 MHz, CDCl3): δ = 8.14 (d,
J = 5.8 Hz, 1H), 7.61 (app. t, 1H), 7.50 (app. t, 1H), 7.23 (d, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
749, 695, 592; HRMS (APCI) m/z: [M + H]+ Calcd. for C24H21O4
1H), 5.85-5.74 (m, 1H), 5.09 (dd, J = 1.6, 17.3 Hz, 1H), 5.03 (dd,
1
2
3
4
5
6
7
8
373.1434; Found 373.1434.
J = 1.6 Hz, 1H), 4.95 (ddd, J = 4.0, 6.6 Hz, 1H), 3.94 (d, J = 6.6
Hz, 1H), 3.81 (s, 3H), 2.43-2.20 (m, 2H), 1.96-1.82 (m, 1H), 1.77-
1.64 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ = 170.6,
163.8, 136.6, 135.8, 134.1, 130.5, 128.7, 126.6, 124.6, 116.0,
78.3, 52.8, 48.4, 32.9, 29.1; IR (neat): 2951, 1720, 1640, 1604,
1458, 1435, 1240, 1159, 1116, 1086, 1030, 996, 916, 768, 709.
HRMS (APCI) m/z: [M + H]+ Calcd. for C15H17O4 261.1121;
Found 261.1116.
*[α]%$& refers to cis-37 which was isolated after trituration of the
diastereomeric mixture with isopropanol
Methyl-1-oxo-3-((E)-styryl)isochromane-4-carboxylate
(cis-38,
trans-38). Prepared according to general procedure B, using fresh-
ly distilled cinnamaldehyde (31.0 µL, 0.246 mmol) and homoph-
thalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was
stirred for 18 h to give a diastereomeric mixture of carboxylic
acids in a 63:37 ratio (cis:trans). After esterification and purifica-
tion by flash column chromatography, eluting with 80:20 hex-
anes:EtOAc, cis-38 and trans-38 were isolated combined as a pale
yellow oil (57.6 mg, 76%). CSP-HPLC analysis: ACQUITY
UPC2, Trefoil AMY1, 2.5µm (3.0 x 150mm). ABPR: 1500 (psi).
A (CO2) = 97%/B (Ethanol/ACN/IPA 1:1:1, v:v:v) = 3%, 1.2 mL
min-1, 30 °C, UV detection at 254 nm, retention times: cis-38 3.0
min (minor enantiomer) and 3.3 min (major enantiomer); trans-38
3.4 min (major enantiomer) and 3.7 min (minor enantiomer). TLC
(hexanes/EtOAc, 8:2 v/v): Rf = 0.42; [α]%$& = -6.0 (c = 0.03,
CHCl3);*cis-38: 1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 7.7
Hz, 1H,), 7.63 (app. t, 1H), 7.54 (app. t, 1H), 7.44 (d, J = 7.9 Hz,
2H), 7.42-7.29 (m, 4H), 6.91 (d, J = 16.0 Hz, 1H), 6.38 (dd, J =
6.1, 16.0 Hz, 1H), 5.36 (ddd, J = 1.4, 3.5, 6.1 Hz, 1H,), 4.08 (d, J
= 3.5 Hz, 1H), 3.68 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ = 168.9, 164.3, 136.3, 135.7, 134.0, 133.9, 130.8, 129.2, 128.7,
128.5, 127.55, 126.88, 125.2, 123.1, 78.4, 52.6, 48.9; trans-38: 1H
NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.9 Hz, 1H), 7.63 (app.
t, 1H), 7.51 (app. t, 1H), 7.40 (d, J = 7.4 Hz, 2H), 7.42-7.29 (m,
4H), 6.79 (d, J = 15.9 Hz, 1H), 6.20 (dd, J = 6.8, 15.9 Hz, 1H),
5.60-5.54 (m, 1H), 4.11 (d, J = 6.3 Hz, 1H), 3.80 (s, 3H).
13C{1H} (100 MHz, CDCl3): δ = 170.1, 163.7, 135.5, 135.4,
135.2, 134.3, 130.5 128.9, 128.69, 128.6, 127.51, 126.85, 124.7,
123.9, 79.4, 52.9, 49.1; IR (neat): 2954, 1732, 1713, 1606, 1439,
1311, 1266, 1230, 1164, 1154, 1117, 710, 690, 607; HRMS
(APCI) m/z: [M + Na]+ Calcd. for C19H16O4Na 331.0940; Found
331.0943.
*[α]%$& refers to a mixture of cis-39: trans-39 in a 74:26 ratio
Methyl-3-((E)-6-ethoxy-6-oxohex-4-en-1-yl)-1-oxoisochromane-4-
carboxylate (cis-40, trans-40). Prepared according to general
procedure B, using aldehyde S1 (42.0 mg, 0.246 mmol) and
homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction
was stirred for 18 h to give a diastereomeric mixture of carboxylic
acids in a 73:27 ratio (cis:trans). After esterification and purifica-
tion by flash column chromatography, eluting with 85:15 hex-
anes:EtOAc, cis-40 and trans-40 were isolated combined as a pale
yellow oil (71.6 mg, 84%). CSP-HPLC analysis: Chiralcel IA (4.6
mm x 25 cm), hexane/IPA: 90/10, 1.0 mL min-1, RT, UV detec-
tion at 221 nm, retention times: cis-40 42.9 min; trans-40 20.9
min (minor enantiomer) and 23.5 min (major enantiomer).TLC
(hexanes/EtOAc, 8:2 v/v): Rf = 0.16, [α]%$& = -3.4 (c = 0.01,
CHCl3);* cis-40: 1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 7.1
Hz, 1H), 7.56 (app. t, 1H), 7.49 (app. t, 1H), 7.29 (d, J = 7.8 Hz,
1H), 6.96-6.88 (m, 1H), 5.84 (d, J = 15.5 Hz, 1H), 4.67-4.55 (m,
1H), 4.18 (q, J = 7.1 Hz, 2H), 3.84 (d, J = 2.8 Hz, 1H), 3.66 (s,
3H), 2.29-2.25 (m, 2H), 1.92-1.89 (m, 2H), 1.76-1.64 (m, 2H),
1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ =
169.1, 165.5, 164.5, 147.8, 136.6, 133.8, 130.8, 129.1, 127.5,
125.4, 122.1, 78.3, 60.2, 52.6, 47.9, 32.2, 31.6, 23.8, 14.3; trans-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
40: H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 7.8 Hz, 1H),
7.54 (app. t, 1H), 7.48 (app. t, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.96-
6.88 (m, 1H), 5.78 (d, J = 14.5 Hz, 1H), 4.97-4.84 (m, 1H), 4.17
(q, J = 7.1 Hz, 2H), 3.89 (d, J = 6.9 Hz, 1H), 3.79 (s, 3H), 2.24-
2.22 (m, 2H) 1.87-1.82 (m, 2H), 1.76-1.64 (m, 2H), 1.27 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 170.5,
166.5, 163.7, 147.7, 135.8, 134.2, 130.6, 128.8, 127.2, 124.5,
122.1, 78.6, 60.2, 52.8, 48.5, 33.0, 31.4, 23.4, 14.2; IR (neat):
2953, 1717, 1652, 1459, 1367, 1265, 1159, 1032, 976, 706, 625;
HRMS (ESI) m/z: [M + Na]+ Calcd. for C19H22O6Na 369.1308;
Found 369.1309.
*[α]%$& refers to a mixture of cis-38:trans-38 in a 66:34 ratio
Methyl-3-(but-3-en-1-yl)-1-oxoisochromane-4-carboxylate (cis-
39, trans-39). Prepared according to general procedure B, using
freshly distilled 4-pentenal (26.0 µL, 0.246 mmol) and homoph-
thalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was
stirred for 18 h to give a diastereomeric mixture of carboxylic
acids in a 74:26 ratio (cis:trans). After esterification and purifica-
tion by flash column chromatography, eluting with 85:15 hex-
anes:EtOAc, cis-39 and trans-39 were isolated combined as a pale
yellow oil (61.4 mg, 96%). CSP-HPLC analysis: Chiralcel IA (4.6
mm x 25 cm), n-hexane/IPA: 90/10, 1.0 mL min-1, RT, UV detec-
tion at 254 nm, retention times: cis-39 8.4 min (minor enantiomer)
and 13.4 min (major enantiomer).); trans-39 9.2 min (major enan-
tiomer) and 10.7 min (minor enantiomer). TLC (hexanes/EtOAc,
*[α]%$& refers to a mixture of cis-40: trans-40 in a 73:27 ratio
Methyl-3-(2-((tert-butoxycarbonyl)amino)ethyl)-1-
oxoisochromane-4-carboxylate (cis-41, trans-41). Prepared ac-
cording to general procedure B, using aldehyde S2 (42.6 mg,
0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246
mmol). The reaction was stirred for 24 h to give a diastereomeric
mixture of carboxylic acids in a 70:30 ratio (cis:trans). After es-
terification and purification by flash column chromatography,
eluting with 70:30 hexanes:EtOAc, cis-41 and trans-41 were iso-
lated combined as a pale yellow oil (64.4 mg, 75%). CSP-HPLC
analysis: Chiralcel ODH (4.6 mm x 25 cm), hexane/IPA: 98/2, 0.5
mL min-1, RT, UV detection at 254 nm, retention times: cis-41
364.7 min; trans-41 220.1 min (minor enantiomer) and 190.1 min
(major enantiomer). TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.17;
8:2 v/v): Rf = 0.47; [α]%$& = -5.9 (c = 0.07, CHCl3);* cis-39: H
1
NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 7.3 Hz, 1H), 7.59 (app.
t, 1H), 7.50 (app. t, 1H), 7.32 (d, J = 8.3 Hz, 1H), 5.90-5.76 (m,
1H), 5.12 (dd, J = 1.5, 17.1 Hz, 1H), 5.04 (dd, J = 1.5, 10.1 Hz,
1H), 4.68 (ddd, J = 3.3, 4.8, 8.7 Hz, 1H), 3.87 (d, J = 3.3 Hz, 1H),
3.69 (s, 3H), 2.49-2.25 (m, 2H), 2.13-1.97 (m, 1H), 1.95-1.81 (m,
1H). 13C{1H} NMR100 MHz, CDCl3): δ = 169.2, 164.7, 136.7,
133.7, 130.7, 129.0, 127.3, 125.4, 116.1, 77.7, 52.6, 47.8, 31.8,
29.2; trans-39: 1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 7.6
Hz, 1H), 7.61 (app. t, 1H), 7.49 (app. t, 1H), 7.24 (d, J = 7.9 Hz,
[α]%$& = -4.4 (c =0.02, CHCl3);* cis-41: H NMR (400 MHz,
1
CDCl3): δ = 8.17 (d, J = 7.8 Hz, 1H), 7.61 (app. t, 1H), 7.51 (app.
t, 1H), 7.34 (d, J = 7.4 Hz, 1H), 4.88-4.77 (bs, 1H), 4.76-4.68 (m,
1H), 3.95 (d, J = 3.5 Hz, 1H), 3.69 (s, 3H), 3.48-3.33 (m, 2H),
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
(47.9 mg, 54%, 92% ee). CSP-HPLC analysis: Chiralcel IA (4.6
2.12-2.03 (m, 2H), 1.44 (s, 9H); 13C{1H} NMR (100 MHz,
mm x 25 cm), n-hexane/IPA: 95/5, 0.5 mL min-1, RT, UV detec-
tion at 221 nm, retention times: 87.1 min (minor enantiomer) and
91.2 min (major enantiomer). M.p. 135-137 °C; TLC (hex-
anes/EtOAc, 8:2 v/v): Rf = 0.35; [α]%$& = -7.6 (c = 0.03, CHCl3); 1H
NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 7.8 Hz, 1H), 7.65 (app.
t, 1H), 7.60-7.54 (m, 3H), 7.39 (m, 3H), 5.75 (d, J = 3.6 Hz, 1H),
4.14 (d, J = 3.6 Hz, 1H), 3.49 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ = 168.4, 164.1, 136.0, 135.2, 134.1, 131.8, 131.0,
129.4, 127.4, 127.3, 125.1, 122.8, 78.7, 52.5, 50.3; IR (neat):
3061, 3018, 2952, 1725, 1601, 1490, 1258, 1009, 822, 736, 692;
HRMS (ESI) m/z: [M - H]- Calcd. for C17H12O4Br 358.9924;
Found 358.9920.
1
2
3
4
5
6
7
8
CDCl3): δ = 169.2, 164.5, 156.1, 136.7, 133.8, 130.7, 129.1,
127.4, 125.2, 77.2, 67.9, 52.6, 47.7, 36.9, 33.1, 28.3; trans-41: 1H
NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 6.2 Hz), 7.63 (app. t,
1H), 7.49 (app. t, 1H), 7.27 (d, J 8.0 Hz, 1H), 5.04-4.96 (m, 1H),
4.88-4.77 (bs, 1H), 3.96 (d, J = 5.6 Hz, 1H), 3.82 (s, 3H), 3.48-
3.33 (m, 2H), 1.92-1.89 (m, 1H), 1.84-1.77 (m, 1H), 1.45 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3): δ = 170.3, 163.5, 155.9,
135.7, 134.3, 130.5, 128.8, 127.4, 124.4, 79.5, 77.2, 52.8, 48.2,
36.7, 30.1, 28.3; IR (neat): 3383, 2976, 1705, 1609, 1516, 1458,
1366, 1241, 1161, 1086, 1031, 994, 734, 605; HRMS (ESI) m/z:
[M- H]- Calcd. for C18H22NO6 348.1447; Found 348.1450.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*[α]%$& refers to a mixture of cis-41: trans-41 in a 84:16 ratio
Methyl 1-oxo-3-phenylisochroman-4-carboxylate (cis-42). Pre-
pared according to general procedure B, using freshly distilled
benzaldehyde (25.0 μL, 0.246 mmol) and homophthalic anhydride
(1, 39.9 mg, 0.246 mmol). The reaction was allowed to stir for 5
days to give a diastereomeric mixture of carboxylic acids in a
61:39 ratio (cis:trans). After esterification and purification by
flash column chromatography, eluting with 80:20 hexanes:EtOAc,
the diastereomer cis-42 was isolated as a white solid (37.5 mg,
54%, 92% ee). CSP-HPLC analysis: Chiralcel IA (4.6 mm x 25
cm), n-hexane/IPA: 90/10, 1.0 mL min-1, RT, UV detection at 221
nm, retention times: 17.6 min (minor enantiomer) and 22.3 min
(major enantiomer). M.p. 115-117 °C; TLC (hexanes/EtOAc, 8:2
Methyl-3-(4-bromophenyl)-1-oxoisochromane-4-carboxylate
(trans-43)6
Prepared according to general procedure B, using recrystallised
p-bromobenzaldehyde (45.5 mg, 0.246 mmol) and homophthalic
anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for
22 h to give a diastereomeric mixture of carboxylic acids in a
60:40 ratio (cis:trans). After esterification and purification by
flash column chromatography, eluting with 85:15 hex-
anes:EtOAc, the diastereomer trans-43 was isolated as a white
solid (31.7 mg, 36%, 74% ee). CSP-HPLC analysis. Chiralcel IA
(4.6 mm x 25 cm), hexane/IPA: 95/5, 0.5 mL min-1, RT, UV
detection at 254 nm, retention times: 70.0 min (minor enantio-
mer) and 80.7 min (major enantiomer). M.p. 137-138 °C (lit.,6
v/v): Rf = 0.41; [α]%$& = -4.3 (c = 0.02, CHCl3); H NMR (400
1
1
m.p. 138-140 °C); TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.38; H
MHz, CDCl3): δ = 8.24 (d, J = 7.8 Hz, 1H), 7.63 (app. t, 1H), 7.56
(app. t, 1H), 7.52-7.48 (m, 2H), 7.44 (app. t, 2H), 7.42-7.36 (m,
2H), 5.78 (d, J = 3.7 Hz, 1H), 4.14 (d, J = 3.7 Hz, 1H), 3.50 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 168.6, 164.4, 136.3,
136.2, 134.0, 131.0, 129.3, 128.7, 128.6, 127.3, 125.6, 125.3,
79.4, 52.3, 50.7; IR (neat): 2955, 1721, 1601, 1454, 1431, 1244,
1080, 997, 782, 701; HRMS (APCI) m/z: [M - H]- Calcd. for
C17H13O4 281.0819; Found 281.0811.
Methyl 1-oxo-3-phenylisochroman-4-carboxylate (trans-42)6
Prepared according to general procedure B, using freshly distilled
benzaldehyde (25 μL, 0.246 mmol) and homophthalic anhydride
(1, 39.9 mg, 0.246 mmol). The reaction was allowed to stir for 5
days to give a diastereomeric mixture of carboxylic acids in a
61:39 ratio (cis:trans). After esterification and purification by
flash column chromatography, eluting with 80:20 hexanes:EtOAc,
the diastereomer trans-42 was isolated as a white solid (24.3 mg,
35%, 64% ee). CSP-HPLC analysis. Chiralcel IA (4.6 mm x 25
cm), hexane/IPA: 90/10, 1.0 mL min-1, RT, UV detection at 254
nm, retention times: trans-42 17.0 min (minor enantiomer) and
19.5 min (major enantiomer). M.p. 118-120 °C; TLC (hex-
anes/EtOAc, 8:2 v/v): Rf = 0.38. (lit.,6 m.p. 129-132 °C); 1H NMR
(400 MHz, CDCl3): δ = 8.19 (d, J = 8.0 Hz, 1H), 7.60 (app. t,
1H), 7.49 (app. t, 1H), 7.44-7.30 (m, 5H), 7.20 (d, J = 8.0 Hz,
1H), 5.86 (d, J = 8.3 Hz, 1H), 4.34 (d, J = 8.3 Hz, 1H), 3.69 (s,
3H).
NMR(400 MHz, CDCl3): δ = 8.17 (d, J = 7.9 Hz, 1H), 7.61 (app.
t, J = 7.9 Hz, 1H), 7.55-7.45 (m, 3H), 7.28 (d, J = 8.5 Hz, 2H),
7.19 (d, J = 7.5 Hz, 1H), 5.80 (d, J = 8.5 Hz, 1H), 4.28 (d, J = 8.5
Hz, 1H), 3.71 (s, 3H).
Methyl 3-(4-chlorophenyl)-1-oxoisochroman-4-carboxylate (cis-
44). Prepared according to general procedure B, using recrystal-
lised 4-chlorobenzaldehyde (34.6 mg, 0.246 mmol) and homoph-
thalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was
stirred for 36 h to give a diastereomeric mixture of carboxylic
acids in a 59:41 ratio (cis:trans). After esterification and purifica-
tion by flash column chromatography, eluting with 80:20 hex-
anes:EtOAc, the diastereomer cis-44 was isolated as white solid
(42.1 mg, 54%, 85% ee) CSP-HPLC analysis: Chiralcel IA (4.6
mm x 25 cm), n-hexane/IPA: 90/10, 1.0 mL min-1, RT, UV detec-
tion at 221 nm, retention times: 21.3 min (minor enantiomer) and
22.8 min (major enantiomer). M.p. 65-68 °C; TLC (hex-
anes/EtOAc, 8:2 v/v): Rf = 0.70; [α]20D = -11.6 (c = 0.03, CHCl3);
1H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 7.8 Hz, 1H), 7.60
(app. t, 1H), 7.56 (app. t, 1H), 7.45-7.36 (m, 5H), 5.74 (d, J = 3.4
Hz, 1H), 4.12 (d, J = 3.4 Hz, 1H), 3.46 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ = 168.4, 164.1, 136.0, 134.7, 134.6, 134.2,
131.0, 129.4, 128.9, 127.4, 127.0, 125.1, 78.6, 52.5, 50.4; IR
(neat): 2953, 2926, 2862, 1736, 1709, 1602, 1459, 1261, 1001,
+
826, 740; HRMS (ESI) m/z: [M + H] Calcd. for C17H14O4Cl
317.0580; Found: 317.0568.
Methyl-3-(4-bromophenyl)-1-oxoisochromane-4-carboxylate (cis-
43). Prepared according to general procedure B, using recrystal-
lised p-bromobenzaldehyde (45.5 mg, 0.246 mmol) and homoph-
thalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was
stirred for 22 h to give a diastereomeric mixture of carboxylic
acids in a 60:40 ratio (cis:trans). After esterification and purifica-
tion by flash column chromatography, eluting with 85:15 hex-
anes:EtOAc, the diastereomer cis-43 was isolated as a white solid
Methyl 3-(4-chlorophenyl)-1-oxoisochroman-4-carboxylate
(trans-44)6
Prepared according to general procedure B, using recrystallised
4-chlorobenzaldehyde (34.6 mg, 0.246 mmol) and homophthalic
anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for
36 h to give a diastereomeric mixture of carboxylic acids in a
59:41 ratio (cis:trans). After esterification and purification by
flash column chromatography eluting with 80:20 hexanes:EtOAc,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
the diastereomer trans-44 was isolated as a white solid (29.6 mg, of carboxylic acids in a 59:41 ratio (cis:trans). After esterification
1
2
3
4
5
6
7
8
38%, 78% ee). CSP-HPLC analysis Chiralcel IA (4.6 mm x 25
cm), hexane/IPA: 90/10, 1.0 mL min-1, RT, UV detection at 254
nm, retention times: 20.2 min (minor enantiomer) and 23.0 min
(major enantiomer). M.p. 71-73 °C (lit.,6 m.p. 70-72 °C); TLC
(hexanes/EtOAc, 8:2 v/v): Rf = 0.6; 1H NMR (400 MHz, CDCl3):
d = 8.18 (d, J = 7.7 Hz, 1H), 7.61 (app. t, J = 7.7 Hz, 1H), 7.50
(app. t, J = 7.7 Hz, 1H), 7.39-7.29 (m, 4H), 7.19 (d, J = 7.7 Hz,
1H), 5.82 (d, J = 8.7 Hz, 1H), 4.30 (d, J = 8.7 Hz, 1H), 3.71 (s,
3H).
and purification by flash column chromatography, eluting with
70:30 hexanes:EtOAc, the diastereomer cis-46 was isolated as a
white solid (46.0 mg, 55%, 94% ee). CSP-HPLC analysis: Chiral-
cel IA (4.6 mm x 25 cm), hexane/IPA: 90/10, 1.0 mL min-1, RT,
UV detection at 254 nm, retention times: 33.8 min (major enanti-
omer) 55.7 min (minor enantiomer). M.p. 144-146 °C; TLC (hex-
anes/EtOAc, 8:2 v/v): Rf = 0.31; [α]20D = -10.4 (c = 0.04, CHCl3);
1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 7.8 Hz, 1H), 8.13
(d, J = 8.3 Hz, 2H), 7.67 (app. t, 1H), 7.66- 7.53 (m, 3H), 7.38 (d,
J = 7.0 Hz, 1H), 5.82 (d, J = 3.5 Hz, 1H), 4.17 (d, J = 3.5 Hz, 1H),
3.93 (s, 3H), 3.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ =
168.3, 166.6, 164.1, 141.2, 136.0, 134.4, 131.1, 130.5, 129.9,
129.5, 127.4, 125.7, 125.1, 78.8, 52.5, 52.3, 50.3; IR (neat): 3016,
2162, 2030, 1748, 1611, 1428, 1280, 1250, 1193, 1072, 921, 870,
742, 642; HRMS (APCI) m/z: [M + Na]+ Calcd. for C19H16O6Na
363.0839; Found: 363.0839.
9
Methyl 3-(3-bromophenyl)-1-oxoisochromane-4-carboxylate (cis-
45). Prepared according to general procedure B, using freshly
distilled 3-bromobenzaldehyde (28.7 µL, 0.246 mmol) and
homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction
was stirred for 40 h to give a diastereomeric mixture of carboxylic
acids in a 55:45 ratio (cis:trans). After esterification and purifica-
tion by flash column chromatography, eluting with 85:15 hex-
anes:EtOAc, the diastereomer cis-45 was isolated as a white solid
(39.1 mg, 44%, 88% ee). CSP-HPLC analysis: Chiralcel IA (4.6
mm x 25 cm), n-hexane/IPA: 95/5, 1.0 mL min-1, RT, UV detec-
tion at 221 nm, retention times: 58.7 min (minor enantiomer) and
78.6 min (major enantiomer). M.p. 92-94 °C; TLC (hex-
anes/EtOAc, 8/2 v/v): Rf = 0.50; [α]%$& = -5.9 (c = 0.03, CHCl3);
1H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 7.9 Hz, 1H), 7.67-
7.59 (m, 2H), 7.56-7.49 (m, 2H), 7.42-7.32 (m, 2H) 7.30-7.26 (m,
1H), 5.73 (d, J = 3.7 Hz, 1H), 4.12 (d, J = 3.7 Hz, 1H), 3.47 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 168.4, 164.0, 138.4,
135.9, 134.2, 131.9, 131.1, 130.2, 129.4, 128.8, 127.4, 125.1,
124.3, 122.8, 78.4, 52.5, 50.4; IR (neat): 2947, 1722, 1601, 1458,
1358, 1286, 1261, 1225, 1112, 1085, 1056, 996, 971, 989, 787,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 3-(4-(methoxycarbonyl)phenyl)-1-oxoisochromane-4-
carboxylate (trans-46)
Prepared according to general procedure B, using recrystallised
methyl 4-formylbenzoate (40.4 mg, 0.246 mmol) and homoph-
thalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was
stirred for 48 h to give a diastereomeric mixture of carboxylic
acids in a 59:41 ratio (cis:trans). After esterification and purifica-
tion by flash column chromatography, eluting with 70:30 hex-
anes:EtOAc, the diastereomer trans-46 was isolated as a white
solid (31.8 mg, 38%, 83% ee). CSP-HPLC analysis. Chiralcel IA
(4.6 mm x 25 cm), hexane/IPA: 90/10, 1.0 mL min-1, RT, UV
detection at 254 nm, retention times: 32.2 min (minor enantiomer)
and 37.9 min (major enantiomer). M.p. 156-158°C, TLC (hex-
anes/EtOAc, 8:2 v/v): Rf = 0.32, [α]20D= + 6.3 (c = 0.04 CHCl3);
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 7.9 Hz, 1H), 8.06
(d, J = 8.2 Hz, 2H), 7.64 (app. t, J = 7.9 Hz, 1H), 7.57-7.45 (m,
3H), 7.22 (d, J = 7.9 Hz, 1H), 5.95 (d, J = 8.2 Hz, 1H), 4.35 (d, J
= 8.2 Hz, 1H), 3.94 (s, 3H), 3.73 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ = 169.8, 166.5, 163.7, 141.4, 135.7, 134.7, 130.8,
130.7, 130.0, 129.0, 126.8, 126.7, 124.4, 80.0, 52.8, 52.3, 50.6; IR
(neat): 3010, 2158, 2029, 1735, 1020, 1609, 1425, 1280, 1250,
1184, 1279, 1107, 1056, 1018, 921, 869, 736, 641; HRMS
(APCI): m/z: [M + Na]+ Calcd. for C19H16O6Na 363.0839; Found:
363.0835.
Methyl 3-(4-cyanophenyl)-1-oxoisochromane-4-carboxylate (cis-
47). Prepared according to general procedure B, using recrystal-
lised 4-cyanobenzaldehyde (32.3 mg, 0.246 mmol) and homoph-
thalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was
stirred for 48h to give a diastereomeric mixture of carboxylic acids
in a 58:42 ratio (cis:trans). After esterification and purification by
flash column chromatography eluting with 75:25 hexanes:EtOAc,
the diastereomer cis-47 was isolated as a white solid (78.4 mg,
51%, 89% ee). CSP-HPLC analysis: ACQUITY UPC2, Trefoil
AMY1, 2.5µm (3.0 x 150mm). ABPR: 1500 (psi). A (CO2) =
97%/B (Ethanol/IPA 1:1, v:v) = 3%, 1.2 mL min-1, 30 °C, UV
detection at 254 nm, retention times: 3.5 min (major enantiomer)
and 3.6 min (minor enantiomer). M.p. 126-128 °C; TLC (hex-
anes/EtOAc, 8:2 v/v): Rf = 0.25; [α]20D = -1.7 (c = 0.14, CHCl3);
1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 7.7 Hz, 1H), 7.74 (d,
J = 8.1 Hz, 2H), 7.68-7.61 (m, 3H), 7.56 (app. t, 1H), 7.39 (d, J =
7.6, 1H), 5.82 (d, J = 3.6 Hz, 1H), 4.16 (d, J = 3.6 Hz, 1H), 3.45
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 168.1, 163.6,
141.3, 135.7, 134.3, 132.5, 131.1, 129.6, 127.5, 126.5, 124.9,
+
717, 689, 638, 584; HRMS (APCI) m/z: [M + Na] Calcd. for
C17H13BrO4Na 382.9888; Found: 382.9889.
Methyl 3-(3-bromophenyl)-1-oxoisochromane-4-carboxylate
(trans-45)
Prepared according to general procedure B, using freshly distilled
3- bromobenzaldehyde (28.7 µL, 0.246 mmol) and homophthalic
anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for
40 h to give a diastereomeric mixture of carboxylic acids in a
55:45 ratio (cis:trans). After esterification and purification by
flash column chromatography, eluting with 85:15 hexanes:EtOAc,
the diastereomer trans-45 was isolated as a white solid (35.3 mg,
39%, 72% ee). CSP-HPLC analysis. Chiralcel IA (4.6 mm x 25
cm), hexane/IPA: 90/10, 1.0 mL min-1, RT, UV detection at 254
nm, retention times: 16.7 min (minor enantiomer) and 18.8 min
(major enantiomer). M.p. 100-105°C; TLC (hexanes/EtOAc, 8/2
v/v): Rf = 0.46; [α]%$& = +8.8 (c = 0.05, CHCl3); H NMR (400
1
MHz, CDCl3): δ = 8.21 (d, J = 7.9 Hz, 1 H), 7.64 (app. t, J = 7.9
Hz, 1H), 7.59 (s, 1H), 7.55-7.52 (m, 1H), 7.51-7.49 (m, 1H), 7.36-
7.31 (m, 1H), 7.28-7.20 (m, 2H), 5.83 (d, J = 8.7 Hz, 1H), 4.32 (d,
J = 8.7 Hz, 1H), 3.74 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ = 169.8, 163.7, 138.8, 135.8, 134.6, 132.3, 130.7, 130.3, 129.9,
129.0, 126.7, 125.4, 124.3, 122.8, 79.7, 52.8, 50.7. IR (neat)/cm-1:
2940, 1720, 1601, 1455, 1348, 1285, 1260, 1235, 1112, 1075,
1054, 995, 971, 989, 783, 713, 687, 584; HRMS (APCI) m/z: [M
+ H]+ Calcd. for C17H14BrO4 360.9888; Found: 360.9887.
Methyl
3-(4-(methoxycarbonyl)phenyl)-1-oxoisochromane-4-
carboxylate (cis-46). Prepared according to general procedure B,
using recrystallised methyl 4-formylbenzoate (40.4 mg, 0.246
mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol).
The reaction was stirred for 48 h to give a diastereomeric mixture
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
Chiralpak IA (4.6 mm x 25 cm), hexane/IPA: 97/3, 1.0 mL min-1,
118.3, 112.7, 78.2, 52.5, 49.9; IR (neat): 2922, 2231, 1742, 1609,
1
2
3
4
5
6
7
8
1458, 1356, 1275, 1164, 1080, 1064, 971, 816, 704, 557; HRMS
(ESI) m/z: [M - H]- Calcd. for C18H12NO4 306.0771; Found:
306.0784.
Methyl 3-(4-cyanophenyl)-1-oxoisochromane-4-carboxylate
(trans-47)
RT, UV detection at 254 nm, retention times: 26.5 min (minor
enantiomer) and 29.3 min (major enantiomer). M.p. 80-82 °C,
(lit.,6 m.p. 82-84 °C); TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.57;
1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.8 Hz, 1H), 7.60
(app. t, 1H), 7.49 (app. t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.6 Hz,
2H), 7.19 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 5.77 (d, J
= 9.0 Hz, 1H), 4.34 (d, J = 9.0 Hz, 1H), 3.80 (s, 3H), 3.69 (s, 3H).
Methyl 1-oxo-3-(o-tolyl) isochromane-4-carboxylate (cis-49).
Prepared according to general procedure B, using freshly distilled
2-methylbenzaldehyde (28.4 µL, 0.246 mmol) and homophthalic
anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for
4 days to give a diastereomeric mixture of carboxylic acids in a
67:33 ratio (cis:trans). After esterification and purification by
flash column chromatography eluting with 85:15 hexanes: EtOAc,
the diastereomer cis-49 was isolated as a white solid (42.3 mg,
58%, 95% ee). CSP-HPLC analysis: ACQUITY UPC2, Trefoil
AMY1, 2.5µm (3.0 x 150mm). ABPR: 1500 (psi). A (CO2) =
99%/B (Ethanol/ACN/IPA 1:1:1, v:v:v) = 1%, 1.2 mL min-1, 30
°C, UV detection at 212 nm, retention times: 3.2 min (minor en-
antiomer) and 3.4 min (major enantiomer). M.p. 108-110 °C; TLC
Prepared according to general procedure B, using recrystallised 4-
cyanobenzaldehyde ( 32.3 mg, 0.246 mmol) and homophthalic
anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for
48h to give a diastereomeric mixture of carboxylic acids in a
58:42 ratio (cis:trans). After esterification and purification by
flash column chromatography, eluting with 75:25 hexanes:EtOAc,
the diastereomer trans-47 was isolated as yellow oil (67.6 mg,
42%, 60% ee). CSP-HPLC analysis. ACQUITY UPC2, Trefoil
CEL2, 2.5µm (3.0 x 150mm). ABPR: 1500 (psi). A (CO2) =
97%/B (Ethanol/ACN 1:1, v:v) = 3%, 1.2 mL min-1, 30 °C, UV
detection at 254 nm, retention times: 3.1 min (minor enantiomer)
and 3.4 min (major enantiomer). TLC (hexanes/EtOAc, 8:2 v/v):
Rf = 0.23, [α]20D = +19.1 (c = 0.05, CHCl3); 1H NMR (400 MHz,
CDCl3): δ = 8.21 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H),
7.65 (app. t, J = 7.9 Hz, 1H), 7.58.7.51 (m, 3H), 7.22 (d, J = 7.7
Hz, 1H), 5.94 ( d, J = 8.5 Hz, 1H), 4.32 (d, J = 8.5 Hz, 1H), 3.76
(s, 3H);13C{1H} NMR (100 MHz, CDCl3): δ = 169.6, 163.4,
141.7, 135.4, 134.7, 132.6, 130.8, 129.2, 127.6, 126.7, 124.2,
118.2, 113.2, 78.6, 52.9, 50.5; IR (neat): 2921, 2215, 1730, 1609,
1454, 1356, 1272, 1167, 1078, 1061, 956, 811, 701, 557; HRMS
(ESI): m/z: [M - H]- Calcd. for C18H12NO4 306.0771; Found:
306.0767.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(hexanes/EtOAc, 8:2 v/v): Rf = 0.38; [α]20 = -15.0 (c = 0.04,
D
1
CHCl3); H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 7.7 Hz,
1H), 7.64-7.60 (m, 2H), 7.55 (app. t, 1H), 7.35 (d, J = 7.3 Hz,
1H) 7.28-7.26 (m, 2H), 7.23-7.20 (m, 1H), 5.93 (d, J = 3.5 Hz,
1H), 4.01 (d, J = 3.5 Hz, 1H), 3.44 (s, 3H), 2.36 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ = 168.7, 164.7, 136.4, 134.2, 133.9,
133.5, 131.0, 130.6, 129.3, 128.6, 127.3, 126.4, 125.9, 125.4,
76.9, 52.3, 48.6, 19.1; IR (neat): 3071, 3024, 2952, 2929, 2844,
1718, 1602, 1457, 1250, 1003, 915, 736; HRMS (ESI) m/z: [M++
Na] Calcd. for C18H16O4Na 319.0940; Found 319.0932.
Methyl 1-oxo-3-(o-tolyl) isochromane-4-carboxylate (trans-49)6
Prepared according to general procedure B, using freshly distilled
2-methylbenzaldehyde (28.4 µL, 0.246 mmol) and homophthalic
anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for
4 days to give a diastereomeric mixture of carboxylic acids in a
67:33 ratio (cis:trans). After esterification and purification by
flash column chromatography eluting with 85:15 hexanes:EtOAc,
the diastereomer trans-49 was isolated as a white solid (20.4 mg,
28%, 82% ee). CSP-HPLC analysis. Chiralcel ODH (4.6 mm x
25 cm), hexane/IPA: 83/17, 0.5 mL min-1, RT, UV detection at
254 nm, retention times: 22.3 min (minor enantiomer) and 35.6
min (major enantiomer). M.p. 109-110 °C, (lit.,6 114-116 °C);
TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.41; 1H NMR (400 MHz,
CDCl3): δ = 8.20 (d, J = 7.7 Hz, 1H), 7.62 (app. t, 1H), 7.51 (app.
t, 1 H), 7.31 (d, J = 7.7 Hz, 1H) 7.28-7.13 (m, 4H), 6.08 (d, J =
8.7 Hz, 1H), 4.48 (d, J = 8.7 Hz, 1H), 3.68 (s, 3H), 2.45 (s, 3H).
Methyl 3-(4-methoxyphenyl)-1-oxoisochroman-4-carboxylate (cis-
48). Prepared according to general procedure B, using freshly
distilled 4-methoxybenzaldehyde (30 µL, 0.246 mmol) and
homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction
was allowed to stir for 48 h to give a diastereomeric mixture of
carboxylic acids in a 58:42 ratio (cis:trans). After esterification
and purification by flash column chromatography eluting with
85:15 hexanes:EtOAc, the diastereomer cis-48 was isolated as a
white solid (26.9 mg, 35%, 94% ee). CSP-HPLC analysis: Chi-
ralpak IA (4.6 mm x 25 cm), n-hexane/IPA: 97/3, 1.0 mL min-1,
RT, UV detection at 254 nm, retention times: 110.8 min (minor
enantiomer) and 124.4 min (major enantiomer). M.p. 75-77 °C;
TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.52; [α]20D= -7.1 (c = 0.04,
1
CHCl3); H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 7.8 Hz,
1H), 7.61 (app. t, 1H), 7.53 (app. t, 1H), 7.40-7.34 (m, 3H), 6.93
(d, J = 8.6 Hz, 2H), 5.72 (d, J = 3.6, 1H), 4.01 (d, J = 3.6 Hz,
1H), 3.83 (s, 3H), 3.48 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ = 168.8, 164.6, 159.7, 136.4, 133.9, 130.9, 129.2,
128.2, 127.3, 126.9, 125.3, 113.9, 79.2, 55.3, 52.4, 50.8; IR (neat):
3012, 2959, 2930, 2834, 1710, 1604, 1518, 1248, 990, 734;
HRMS (ESI) m/z: [M + Na] + Calcd. for C18H16O5Na 335.0895;
Found 335.0888.
Methyl 1-oxo-3-(thiophen-2-yl)isochroman-4-carboxylate (cis-
50). Prepared according to general procedure B, using freshly
distilled 2-thiophenecarboxaldehyde (23 µL, 0.246 mmol) and
homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction
was allowed to stir for 6 days to give a diastereomeric mixture of
carboxylic acids in a 56:44 ratio (cis:trans). After esterification
and purification by flash column chromatography, eluting with
75:25 hexanes:EtOAc, the diastereomer cis-50 was isolated as a
brown solid (35.5 mg, 50%, 86% ee). CSP-HPLC analysis: Chi-
ralpak IA (4.6 mm x 25 cm), hexane/IPA: 97/3, 1.0 mL min-1, RT,
UV detection at 221 nm, retention times: 21.8 min (minor enanti-
omer) and 25.8 min (major enantiomer). M.p. 110-112 °C; TLC
Methyl
3-(4-methoxyphenyl)-1-oxoisochroman-4-carboxylate
(trans-48)6
Prepared according to general procedure B, using freshly distilled
4-methoxybenzaldehyde (30.0 µL, 0.246 mmol) and homophthal-
ic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was allowed
to stir for 48 h to give a diastereomeric mixture of carboxylic
acids in a 58:42 (cis:trans) ratio. After esterification and purifica-
tion by flash column chromatography eluting with 85:15 hex-
anes:EtOAc, the diastereomer trans-48 was isolated and purified
as a white solid (23.1 mg, 30%, 40% ee). CSP-HPLC analysis.
(hexanes/EtOAc, 8:2 v/v): Rf = 0.35, [α]20 = -3.2 (c = 0.01,
D
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 14
1
CHCl3); H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 7.9 Hz,
1H), 7.62 (app. t, 1H), 7.54 (app. t, 1H), 7.41 (d, J = 7.9 Hz, 1H),
7.35 (dd, J = 1.2, 5.1 Hz, 1H), 7.16 (d, J = 1.2, 3.7 Hz, 1H), 7.03
(dd, J = 3.7, 5.1 Hz, 1H), 6.00 (d, J = 3.6 Hz, 1H), 4.20 (d, J = 3.6
Hz, 1H), 3.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ =
168.6, 163.9, 138.4, 135.9, 134.1, 131.1, 129.4, 127.4, 126.8,
126.1, 125.6, 125.0, 52.7, 50.7, 30.9; IR (neat): 3104, 3011, 2951,
2925, 1727, 1703, 1605, 1459, 1431, 1359, 1332, 1226, 1081,
943, 714; HRMS (APCI) m/z: [M + H] + Calcd. for C15H13O4S
enantiomer) and 32.8 min (minor enantiomer). TLC (hex-
anes/EtOAc, 8/2 v/v): Rf = 0.30; [α]20D = +0.3 (c = 0.04, CHCl3);
1H NMR (400 MHz, CDCl3): δ = 8.52 (d, J = 4.4 Hz, 1H), 8.13
(d, 1H, J = 7.8 Hz), 7.69 (app. t, 1H), 7.57 (app. t, 1H), 7.53 (d,
1H, J = 7.9 Hz), 7.43 (app. t, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.23-
7.17 (m, 1H), 6.13 (d, J = 4.5 Hz, 1H), 4.89 (d, J = 4.5 Hz, 1H),
3.80 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 170.6,
163.6, 156.3, 149.0, 137.1, 135.2, 134.2, 130.2, 128.6, 128.3,
124.6, 123.2, 121.3, 79.9, 52.8, 47.0; IR (neat): 2969, 1715, 1601,
1455, 1425, 1289,1253, 1119, 1004, 862, 824, 733, 723; HRMS
(ESI): m/z: [M - H]- Calcd. for C16H12NO4 282.0766; Found
282.0760.
1
2
3
4
5
6
7
8
289.0529; Found: 289.0518.
Methyl 1-oxo-3-(thiophen-2-yl)isochroman-4-carboxylate (trans-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
50)6
Prepared according to general procedure B, freshly distilled 2-
Methyl 7-bromo-1-oxo-3-(pentan-3-yl)isochromane-4-carboxylate
(cis-54). Prepared according to general procedure B, using freshly
distilled 2-ethylbutaraldehyde (53, 30.4 µL, 0.246 mmol) and
anhydride 52 (59.3 mg, 0.246 mmol). The reaction was stirred for
9 days to give a diastereomeric mixture of carboxylic acids in a
84:16 ratio (cis:trans). After esterification, the diastereomer cis-54
was isolated and purified by flash column chromatography, elut-
ing with 90:10 hexanes:EtOAc to give cis-54 as a white solid
(62.0 mg, 71%, 99% ee). CSP-HPLC analysis: Chiralcel IA (4.6
mm x 25 cm), hexane/IPA: 90/10, 1.0 mL min-1, RT, UV detection
at 254 nm, retention times: 14.5 min (major enantiomer). M.p. 72-
75 °C, TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.67; [α]20D = -1.9 (c =
thiophenecarboxaldehyde (23 µL, 0.246 mmol) and homophthalic
anhydride (1, 39.9 mg, 0.246 mmol).The reaction was allowed to
stir for 5 days to give a diastereomeric mixture of carboxylic acids
in a 56:44 ratio (cis:trans). After esterification and purification by
flash column chromatography, eluting with 75:25 hexanes:EtOAc,
the diastereomer trans-50 was isolated as a white solid (26.2 mg,
37%, 57% ee). CSP-HPLC analysis. Chiralpak IA (4.6 mm x 25
cm), hexane/IPA: 90/10, 1.0 mL min-1, RT, UV detection at 254
nm, retention times: 30.3 min (minor enantiomer) and 32.9 min
(major enantiomer). M.p. 110-112 °C (lit.,6 126-128 °C); TLC
(hexanes/EtOAc, 8:2 v/v): Rf = 0.36. 1H NMR (400 MHz, CDCl3):
δ = 8.16 (d, J = 7.9 Hz, 1H), 7.63 (app. t, 1H), 7.51 (app. t, 1H),
7.33-7.21 (m, 2H), 7.09-7.01 (m, 1H), 6.96-6.89 (m, 1H), 6.19 (d,
J = 6.1 Hz, 1H), 4.35 (d, J = 6.1 Hz, 1H), 3.75 (s, 3H).
Methyl 1-oxo-3-(pyridin-2-yl)isochromane-4-carboxylate (cis-51).
Prepared according to general procedure B, using freshly distilled
pyridin-2 carboxaldehyde (23.5 µL, 0.246 mmol) and homoph-
thalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was
stirred for 4 days to give a diastereomeric mixture of carboxylic
acids in a 61:39 ratio (cis:trans). After esterification and purifica-
tion by flash column chromatography, eluting with 70:30 hex-
anes:EtOAc, the diastereomer cis-51 was isolated as a thick yel-
low oil (40.4 mg, 58%, 80% ee). CSP-HPLC analysis: Chiralcel
OJ-H (4.6 mm x 25 cm), hexane/IPA: 90/10, 1.0 mL min-1, RT,
UV detection at 221 nm, retention times: 52.0 min (major enanti-
omer) and 78.3 min (minor enantiomer). TLC (hexanes/EtOAc,
8:2 v/v): Rf = 0.20; [α]20D= -1.14 (c = 0.03, CHCl3); 1H NMR (400
MHz, CDCl3): δ = 8.62 (d, J = 4.8 Hz, 1H), 8.24 (d, J = 7.7 Hz,
1H), 7.86-7.78 (m, 2H), 7.65 (app. t, 1H), 7.55 (app. t, 1H), 7.48
(d, J = 7.7 Hz, 1H), 7.30 (m, 1H), 5.84 (d, J = 3.6 Hz, 1H), 4.63
(d, J = 3.6 Hz, 1H), 3.44 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ = 168.8, 164.0, 156.0, 149.0, 137.0, 136.4, 134.2,
130.9, 129.2, 127.9, 125.1, 123.2, 120.7, 79.6, 52.3, 47.9; IR
(neat): 2968, 1715, 1601, 1453, 1420, 1287,1253, 1119, 1002,
862, 824, 731, 720; HRMS (ESI) m/z: [M - H]- Calcd. for
C16H12NO4 282.0766; Found 282.0769.
1
0.03, CHCl3); H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 2.1
Hz, 1H), 7.70 (dd, J = 2.1, 8.1 Hz, 1 H), 7.23 (d, J = 8.1 Hz, 1H),
4.42 (dd, J = 2.9, 9.8 Hz, 1H), 3.97 (d, J = 2.9, 1H), 3.69 (s, 3H),
1.89-1.79 (m, 2H), 1.67-1.57 (m, 1H), 1.55-1.41 (m, 2H), 0.98-
0.86 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ = 168.9,
163.7, 136.6, 135.9, 133.5, 128.8, 127.3, 122.9, 80.7, 52.7, 45.6,
41.6, 21.8, 20.8, 9.8, 9.6; IR (neat): 2959, 2888, 1716, 1601, 1468,
1414, 1255, 1227, 1166, 1130, 987, 907, 767, 638; HRMS (APCI)
m/z: [M + Na]+ Calcd. for C16H19BrO4Na 377.0358; Found
377.0361.
Methyl 3-(4-nitrophenyl)-5-oxo-2-(pentan-3-yl)tetrahydrofuran-3-
carboxylate (cis-56). Prepared according to general procedure B,
using freshly distilled 2-ethylbutyraldehyde (53, 30.3 µL, 0.246
mmol) and anhydride 56 (54.4 mg, 0.246 mmol). The reaction was
stirred for 13 days to give a diastereomeric mixture of carboxylic
acids in a 87:13 ratio (cis:trans). After esterification, the diastere-
omer cis-56 was isolated and purified by flash column chromatog-
raphy, eluting with 75:25 hexanes:EtOAc, to give cis-56 as a yellow
oil (43.7 mg, 53%, 95% ee). CSP-HPLC analysis: ACQUITY
UPC2, Trefoil CEL2, 2.5µm (3.0 x 150mm). ABPR: 1500 (psi). A
(CO2) = 97%/B (Ethanol/ACN 1:1, v:v) = 3%, 1.2 mL min-1, 30 °C,
UV detection at 254 nm, retention times: 3.3 min (minor enantio-
mer) and 3.8 min (major enantiomer); TLC (hexanes/EtOAc, 8:2
v/v): Rf = 0.69; [α]20D = +5.0 (c = 0.01, CHCl3); 1H NMR (400 MHz,
CDCl3): δ = 8.27 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 5.06
(d, J = 3.4 Hz, 1H), 3.81 (s, 3H), 3.59 (d, J = 17.1 Hz, 1H), 2.72 (d,
J = 17.1 Hz, 1H), 1.84-1.76 (m, 1H), 1.55-1.46 (m, 2H), 1.47-1.41
(m, 2H), 1.02-0.93 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ =
172.8, 171.0, 147.4, 127.2, 124.3, 85.9, 57.9, 53,3, 42.8, 41.6, 23.1,
20.6, 11.2, 11.0; IR (neat): 2962, 2922, 1786, 1722, 1600, 1512,
1409, 1512, 1347, 1233, 1206, 1185, 1012, 949, 853, 798, 703;
HRMS (APCI) m/z: [M + H]+ Calcd. for C17H22NO6 336.1441;
Found: 336.1438.
Methyl 1-oxo-3-(pyridin-2-yl)isochromane-4-carboxylate (trans-
51). Prepared according to general procedure B, freshly distilled
pyridin-2 carboxaldehyde (385, 23.5 µL, 0.246 mmol) and
homophthalic anhydride (147, 39.9 mg, 0.246 mmol). The reac-
tion was stirred for 4 days to give a diastereomeric mixture of
carboxylic acids in a 61:39 ratio (cis:trans). After esterification
and purification by flash column chromatography, eluting with
70:30 hexanes:EtOAc, the diastereomer trans-51 was isolated as
a thick yellow oil (22.3 mg, 32%, 25% ee). CSP-HPLC analysis.
Chiralcel IA (4.6 mm x 25 cm), hexane/IPA: 90/10, 1.0 mL min-
1, RT, UV detection at 254 nm, retention times: 26.3 min (major
Methyl 6-oxo-2-(pentan-3-yl)-4-phenyl-3,6-dihydro-2H-pyran-3-
carboxylate (cis-58). Prepared according to general procedure D,
using freshly distilled 2-ethylbutyraldehyde (53, 30.3 µL, 0.246
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
2
For earlier related work by Perkin see: (a) Perkin, W. H. On the
Hydride of Aceto-Salicyl. J. Chem. Soc. 1868, 21, 181; (b) Perkin,
W. H. On the Formation of Coumarin and of Cinnamic and of other
Analogue Acids from the Aromatic Aldehydes. J. Chem. Soc. 1877,
31, 388.
(a) Erdmann, H.; Kirchhoff, R. Disubstituirte Naphtaline aus den
isomeren Chlorphenylparaconsäuren. Justus Liebigs Ann. Chem.
1888, 247, 366; (b) Erdmann, H.; Schwechten, E. Ueber gechlorte
Abkömmlinge des Benzaldehyds. Justus Liebigs Ann. Chem. 1890,
260, 53; (c) Fuson, R. C. Naphthalene and the Centroid Structure. J.
Am. Chem. Soc. 1924, 46, 2779; (d) Shoesmith J. B.; Guthrie, A.
The Synthesis of 1-Phenanthrol. J. Chem. Soc. 1928, 2332; (e)
Jones, J. B.; Pinder, A. R. Some Synthetical Investigations in Iso-
coumarin Chemistry. J. Chem. Soc. 1958, 2612.
For early work on the imine-based reaction (different mechanism):
(a) Castagnoli, N. Condensation of Succinic Anhydride with N-
Benzylidene-N-Methylmine. Stereoselective Synthesis of trans- and
cis-1-Methyl-4-Carboxy-5-Phenyl-2-Pyrrolidinone. J. Org. Chem.
1969, 34, 3187; (b) Cushman, M.; Gentry J.; Dekow, F. W. Conden-
sation of Imines with Homophthalic Anhydrides. A Convergent Syn-
thesis of cis- and trans-13-Methyltetrahydroprotoberberines. J. Org.
Chem. 1977, 42, 1111; (c) Haimova, M. A.; Mollov, N. M.; Ivanova,
S. C.; Dimitrova A. I.; Ognyanov, V. I. A Highly Stereoselective
Synthesis of 3,4-Dihydro-1(2H)-Isoquinlinones and 8-Oxoberbines
from Homophthalic Anhydrides and Azomethines. Tetrahedron,
1977, 33, 331.
mmol). The reaction was stirred for 72 hours to give a diastereo-
1
2
3
4
5
6
7
8
meric mixture of carboxylic acids in a 95:5 ratio (cis:trans). After
esterification and purification by flash column chromatography,
eluting with 80:20 hexanes:EtOAc, cis-58 was isolated as a white
solid (41.6 mg, 56%, 89% ee). CSP-HPLC analysis: Chiralcel
OD (4.6 mm x 25 cm), hexane/IPA: 90/10, 0.3 mL min-1, RT, UV
detection at 254 nm, retention times: 52.7 min (enantiomer) and
55.8 (major enantiomer). M.p. 132-134 °C; TLC (hexanes/EtOAc,
8:2 v/v): Rf = 0.5; [α]$%& = -3.6 (c = 0.04, CHCl3); 1H NMR (400
MHz, CDCl3): δ = 7.63-7.54 (m, 2H), 7.48-7.44 (m, 3H), 6.55 (s,
1H), 4.44 (dd, J = 3.1, 9.1 Hz, 1H), 3.93 (d, J = 3.1 Hz, 1H), 3.73
(s, 3H), 1.84-1.69 (m, 3H), 1.70-1.62 (m, 1H), 1.53-1.44 (m, 1H),
0.98-0.94 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ = 168.7,
165.0, 152.1, 134.9, 130.9, 129.2, 126.1, 116.8, 79.9, 52.9, 45.2,
41.7, 20.2, 19.7, 9.9, 9.6; IR (neat): 3086, 2965, 2877, 1721, 1696,
1624, 1446, 1353, 1269, 1245, 1086, 1012, 990, 893, 777, 689,
602, 576; HRMS (APCI) m/z: [M + H]+ Calcd. for C18H23O4:
303.1590; Found: 303.1598.
3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
Methyl
2-benzhydryl-6-oxo-4-phenyl-3,6-dihydro-2H-pyran-3-
carboxylate (cis-60) Prepared according to general procedure D,
using freshly distilled diphenylacetaldehyde (59, 43.6 µL, 0.246
mmol). The reaction was stirred for 2 days furnishing only the
diastereomer cis-60. Upon esterification, the reaction gave a dia-
stereomeric mixture of esters in a 90:10 ratio (cis:trans). The ma-
jor diastereomer cis-60 was then isolated by flash column chroma-
tography, eluting with 95:5 hexanes:EtOAc, as a white solid (83.3
mg, 85%, 99% ee). CSP-HPLC analysis: ACQUITY UPC2, Tre-
foil AMY1, 2.5µm (3.0 x 150mm). ABPR: 1500 (psi). A (CO2) =
97%/B (Ethanol/CAN/IPA 1:1:1, v:v) = 3%, 1.2 mL min-1, 30 °C,
UV detection at 254 nm, retention times: 2.9 min. M.p. 142-144
°C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.67; [α]%$& = -2.8 (c =
5
6
7
González-López, M.; Shaw, J. T. Cyclic Anhydrides in Formal
Cycloadditions and Multicomponent Reactions. Chem. Rev. 2009,
109, 164.
Cornaggia, C.; Manoni, F.; Torrente, E.; Tallon S.; Connon, S. J. A
Catalytic Asymmetric Reaction Involving Enolizable Anhydrides.
Org. Lett. 2012, 14, 1850.
(a) Cornaggia, C.; Gundala, S.; Manoni, F.; Gopalasetty N.; Connon,
S. J. Catalytic Formal Cycloadditions Between Anhydries and Ke-
tones: Excellent Enantio and Diastereocontrol, Controllable
Decaboxylation and the Formation of Adjacent Quaternary Stereo-
centres. Org. Biomol. Chem. 2016, 14, 3040; (b) Wu, J.-L.; Du, B.-
X; Zhang, Y.-C.; He, Y.-Y.; Wang, J.-Y.; Wu, P.; Shi, F. Diastereo-
and Enantioselective Construction of Dihydroisocoumarin-Based
Spirooxindole Frameworks via Organocatalytic Tandem Reactions.
Adv. Synth. Catal. 2016, 358, 2777.
(a) Manoni F.; Connon, S. J. Catalytic Asymmetric Tamura
Cycaloadditions. Angew. Chem. Int. Ed. 2014, 53, 2628; (b) Manoni,
F.; Farid, U.; Trujillo C.; Connon, S. J. Catalytic Asymmetric Tamu-
ra Cycloadditions Involving Nitroalkenes. Org. Biomol. Chem.
2017, 15, 1463; (c) Nath U.; Pan, S. C. Organocatalytic Asymmetric
Tamura Cycloadditions with α-Branched Nitroolefins: Synthesis of
Functionalized 1-Tetralones. J. Org. Chem. 2017, 82, 3262.
(a) Cronin, S. A.; Gutierrez Collar, A.; Gundala, S.; Cornaggia, C.;
Torrente, E.; Manoni, F.; Botte, A.; Twamley B.; Connon, S. J. The
First Catalytic Asymmetric Cycloadditions of Imines with an
Enolisable Anhydride. Org. Biomol. Chem., 2016, 14, 6955; (b)
Jarvis, C. L.; Hirschi, J. S.; Vetticatt M. J.; Seidel, D. Catalytic En-
antioselective Synthesis of Lactams Through Formal [4+2] Cy-
cloaddition of Imines with Homophthalic Anhydride. Angew. Chem.
Int. Ed. 2017, 56, 2670.
1
0.04, CHCl3); H NMR (400 MHz, CDCl3): δ = 7.49-7.45 (m,
8
9
2H), 7.44-7.39 (m, 5H), 7.38-7.35 (m, 4H), 7.35-7.29 (m, 3H),
7.21- 7.19 (m, 1H), 6.52 (s, 1H), 5.34 (dd, J = 1.4, 10.6 Hz, 1H),
4.39 (d, J = 10.6 Hz, 1H), 3.79 (d, J = 1.4 Hz, 1H), 3.64 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ = 168.1, 164.4, 152.3,
140.2, 139.9, 134.6, 130.9, 129.2, 129.1, 128.6, 128.3, 128.2,
127.5, 126.9, 126.3, 116.7, 79.7, 53.7, 52.8, 44.9; IR (neat): 3088,
2971, 2923, 1660, 1592, 1506, 1472, 1311, 1217, 1072, 998, 768,
642; HRMS (ESI) m/z: [M + Na]+ Calcd. for C26H22O4Na
421.1410; Found: 421.1407.
ASSOCIATED CONTENT
1H and 13C NMR spectra, analytical and crystallographic data.
Computational study.
10
11
An arylated analogue of a catalyst first introduced by Rawal et al.:
Malerich, J. P.; Hagihara K.; Rawal, V. H. Chiral Squaramide
Derivatives are Excellent Hydrogen Bond Donor Catalysts. J. Am.
Chem. Soc. 2008, 130, 14416.
AUTHOR INFORMATION
Cytotoxic/antiproliferative: (a) Wan, S.; Wu, F.; Rech, J. C.;
Green, M. E.; Balachandran, R.; Horne, W. S.; Day B. W.; Flore-
ancig, P. E. Total Synthesis and Biological Evaluation of Pederin,
Psymberin, and Highly Potent Analogs. J. Am. Chem. Soc. 2011,
133, 16668; Phytotoxic: (b) Enomoto M.; Kuwahara, S. Total Syn-
thesis of Bacilosarcins A and B. Angew. Chem. Int. Ed. 2009, 48,
1144; Antimicrobial: (c) Tabopda, T. K.; Fotso, G. W.; Ngoupayo,
J.; Mitaine-Offer, A. -C.; Ngadjui B. T.; Lacaille-Dubois, M.-A.
Antimicrobial Dihydroisocoumarins from Crassocephalum Biafrae.
Planta Med. 2009, 75, 1258; Antifungal: (d) Hussain, H.; Akhtar,
N.; Draeger, S.; Schulz, B.; Pescitelli, G.; Salvadori, P.; Antus, S.;
Kurtán T.; Krohn, K. New Bioactive 2,3-Epoxycyclohexenes and
Isocoumarins from the Endophytic Fungus Phomopsis sp. from
Laurus Azorica. Eur. J. Org. Chem. 2009, 749; Antiulcer: (e)
Shimojima, Y.; Shirai, T.; Baba, T.; Hayashi, H. 1H-2Benzopyran-
1-one Derivatives, Microbial Products with Pharmacological Ac-
tivity. Conversion into Orally Active Derivatives with Antiinflam-
matory and Antiulcer Activities. J. Med. Chem. 1985, 28, 3; anti-
Corresponding Author
* email connons@tcd.ie
ACKNOWLEDGMENT
Financial support from Science Foundation Ireland (12/IA/1645)
is gratefully acknowledged. We are grateful to ICHEC for the
provision of computational facilities and to Dr Goar Sánchez for
the AIM graphical outputs.
REFERENCES
1
Jayne, H. W; Jayne, H. W. Ueber das Phenyl-Butyrolacton und die
Phenyl-Paraconsäure. Justus Liebigs Ann. Chem. 1883, 216, 97.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 14
malarial/antiinflammatory: (f) Kongsaeree, P.; Prabpai, S.;
20 We were able to reduce the levels of epimerization with methyl
Sriubolmas, N.; Vongvein C.; Wiyakrutta, S. Antimalarial Dihy-
droisocoumarins Produced by Geotrichum sp., An Endophytic Fun-
gus of Crassocephalum Crepidioides. J. Nat. Prod. 2003, 66, 709;
(g) antioxidant: Nazir, N.; Koul, S.; Quirishi, M. A.; Najar M. A.;
Zargar, M. I. Evaluation of Antioxidant and Antimicrobial Activi-
ties of Bergenin and its Derivatives obtained by Chemoenzymatic
Syntheis. Eur. J. Med. Chem. 2011, 46, 2415; antiallergic: (h) Yo-
shikawa, M.; Uchida, E.; Chatan, N.; Kobayashi, H.; Naitoh, Y.;
Okuno, Y.; Matsuda, H.; Yamahara J.; Murakami, N. Thun-
berginols C, D and E, New Antiallergic and Antimicrobial Dihy-
droisocoumarins, and Thunberginols G 3’-O-Glucoside and (-)-
Hydrangenol-4’-O-Glucoside, New Dihydroisocoumarin Glyco-
sides, from Hydrangeae Dulcis Folium. Chem. Pharm. Bull. 1992,
40, 3352.
triflate (NEt3, -15 °C), which provided the methyl ester in 96:4 dr
and 98% ee, however isolated yield was reduced to 62%.
1
2
3
4
5
6
7
8
21 Spangler, R. J.; Kim, J. H.; Cava, M. P. Prolytic and Photochemical
Wolff Rearrangement of Diazoindanones. Synthesis of 2-
Carboalkoxybenzocyclobutenones. J. Org. Chem. 1977, 42, 1697.
22 Klimko, P. G.; Singleton, D. A. Extended Stereocontrol in Silyl
Group-Transfer Cyclizations: Control of Four Contiguous Chiral
Centers. Synthesis, 1994, 9, 979.
23
Becht, J.-M.; Meyer O.; Guenter, H. Enantioselective Syntheses of
(-)-(R)-Baclofen and Other GABA Analogues via Rhodium-
Catalyzed Conjugate Addition of Arylboronic Acids. Synthesis,
2003, 18, 2805.
9
24 Yokoyama, H.; Ejiri, H.; Miyazawa, M.; Yamaguchi, S.; Yoshiro,
H. Asymmetric synthesis of fagomine. Tetrahedron: Asymm. 2007,
18, 852.
25 Özcan, S.; Balci, M. The Chemistry of Homophthalic Acid : A New
Synthetic Strategy for Contruction of Substituted Isocoumarin and
Indol Skeletons. Tetrahedron, 2008, 64, 5531.
26 Bruker (2016). APEX3 v2016.9-0, Bruker AXS Inc., Madison, WI,
USA.
27 Bruker (2016). SADABS, Bruker AXS Inc., Madison, Wisconsin,
USA.
28 Sheldrick, G.M. SHELXT-Integrated Space-Group and Crystal
Structure Determination. Acta Cryst. 2015, A71, 3.
29 Sheldrick, G.M. Acta Cryst.A Short History of SHELX. 2008, A64,
112.
30 Dolomanov, O.V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. OLEX2: A Complete Structure Solution, Refine-
ment and Analysis Program. Appl. Cryst. 2009, 42, 339.
31 Becke, A. D. J. Chem. Phys. Density-Functional Thermochemistry.
III. The Role of Exact Exchange. 1993, 98, 5648.
32 Lee, C. T.; Yang, W. T.; Parr, R. G. Developement of the Colle-
Salvetti Correlation-Energy Formula into a Functional of the Elect-
ron Density. Phys. Rev. B 1988, 37, 785.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12
Manoni, F.; Cornaggia, C.; Murray, J.; Tallon, S.; Connon, S. J.
Catalytic, Enantio- and Diastereoselective Synthesis of γ-
Butyrolactones Incorporating Quaternary Stereocentres. Chem.
Commun. 2012, 48, 6502.
13 DKR of diarylsuccinic anhydrides has been reported: Claveau, R.;
Twamley, B.; Connon, S. J. Dynamic Kinetic Resolution of bis-
Arylsuccinic Anhydrides: Enantioselective Synthesis of Densely
Functionalised γ-Butyrolactones. Chem. Commun. 2018, 54, 3231.
14 Trujillo, C.; Rozas, I.; Botte A.; Connon, S. J. A DFT Mechanistic
Study of the Organocatalytic Asymmetric Reaction of Aldehydes
and Homophthalic Anhydride. Chem. Commun. 2017, 53, 8874.
15 Chen, J.; Zhou, L.; Tan, C. K.; Yeung, Y. -Y. An Enantioselective
Approach Toward 3,4-Dihydroisocoumarin Through the Bromocy-
clization of Styrene-Type Carboxylic Acids. J. Org. Chem. 2012, 77,
999.
16 Very recently the same authors were able to control the regioselec-
tivity of the racemic process using catalytic trifluoroacetic acid, giv-
ing 6-endo:5-exo ratios of up to 99:1. However, no regioselective
asymmetric variant was reported: Chena T.; Yeung, Y. -Y. Tri-
fluoroacetic Acid Catalyzed Highly Regioselective Bromocycliza-
tion of Styrene-Type Carboxylic Acids. Org. Biomol. Chem. 2016,
14, 4571.
17 (a) Chen, M.; Shao, C.-L.; Wang, K.-L.; Xu, Y.; She, Z. -G.; Wang,
C.-Y. Dihydroisocoumarin Derivatives with Antifouling Activities
from a Gorgonian-Derived Eurotium sp. Fungus.Tetrahedron 2014,
70, 9132; (b) Nakayama, A.; Sato, H.; Karanjit, S.; Hayashi, N.;
Oda, M.; Namba, K. Asymmetric Total Syntheses and Structure Re-
visions of Eurotiumide A and Eurotiumide B and their Evaluation as
Natural Florescent Probes. Eur. J. Org. Chem. 2018, 4013.
18 (a) Li, B. -J.; Jiang, L.; Liu, M.; Chen, Y. -C.; Ding L. -S.; Wu, Y.
Asymmetric Michael Addition of Arylthiols to α,β-Unsaturated Car-
bonyl Compounds Catalyzed by Bifunctional Organocatalysts. Syn-
lett 2005, 603; (b) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T.
Highly Enantioselective Conjugate Addition of Nitromethane to
Chalcones Using Bifunctional Cinchona Organocatalysts. Org. Lett.
2005, 7, 1967; (c) McCooey, S. H.; Connon, S. J. Urea and Thiourea
Substituted Cinchona Alkaloid Derivatives as Highly Efficient Bi-
functional Organcatalysts for the Asymmetric Addition of Malonates
to Nitroalkenes: Inversion of Configuration at C9 Dramatically Im-
proves Catalyst Performance. Angew. Chem. Int. Ed. 2005, 44,
6367. (d) Ye, J.; Dixon, D. J.; Hynes, P. S. Enantioselective Organo-
catalytic Michael Addition of Malonate Esters to Nitro Olefins Us-
ing Bifunctional Cinchonine Derivatives. Chem. Commun. 2005,
4481.
33 Frisch, M. J.; Pople, J. A.; Binkley, J. S. Self-Consistent Molecular
Orbital Methods 25. Supplimentry Functions for Gausian Basis Sets.
J. Chem. Phys. 1984, 80, 3265.
34 Ditchfield, R. Self-Consistent Perturbation Theory of Dimagnetism.
Mol. Phys. 1974, 27, 789.
35 Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Mont-
gomery, J., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J.
J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar,
S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi,
R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J.
V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Gaussian, Inc.: Walling-
ford CT, 2009.
36 Bader, R. F. W. Atoms in Molecules: A Quantum Theory. Claren-
don Press: Oxford, 1990.
37 Keith, T. A. AIMAll, TK Gristmill Software (aim.tkgristmill.com),
11.10.16; 2011.
19 Interestingly, we have recently shown that this unit plays a role in
the face-selective binding of the anhydride in the trans-selective
process, which may explain why it is detrimental from a diastere-
ocontrol perspective here see ref. 14.
Ann. Chem. 1883, 216, 97.
2
The process had earlier been discovered by Perkin, however using high reaction temperatures he observed only decarboxylated products: (a)
Perkin, W. H. J. Chem. Soc. 1868, 21, 181; (b) Perkin, W. H. J. Chem. Soc. 1877, 31, 388.
ACS Paragon Plus Environment