Enantioselective Organocatalytic Synthesis of Bicyclic Resorcinols via an Intramolecular Friedel?Crafts-Type 1,4-Addition: Access to Cannabidiol Analogues

Article abstract of DOI:10.1002/adsc.202100647

The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel–Crafts-type 1,4-addition using a J?rgensen-Hayashi-like organocatalyst with a large silyl protecting group, and show that heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols were obtained with excellent enantioselectivities (up to 94%). To show the utility of these constructs, and as part of a wider project involving the synthesis of cannabinoid-like compounds, the resorcinol formed was used to generate both ‘normal’ and ‘abnormal’ cannabidiol (CBD) derivatives which were shown to have anticonvulsant activity. (Figure presented.).

Full text of DOI:10.1002/adsc.202100647

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100647
Enantioselective Organocatalytic Synthesis of Bicyclic Resorcinols
via an Intramolecular FriedelÀ Crafts-Type 1,4-Addition: Access
to Cannabidiol Analogues
Laura A. Bryant,a Kenneth Shankland,b Hannah E. Straker,c Callum D. Johnston,a
Nicholas R. Lees,a and Alexander J. A. Cobba,*
a
Department of Chemistry, King’s College London, 7 Trinity Street, London SE1 1DB, UK
E-mail: andre.cobb@kcl.ac.uk
School of Chemistry, Food and Pharmacy (SCFP), University of Reading, Whiteknights, Reading, Berks RG6 6AD, UK
GW Pharmaceuticals, Kent Science Park, Sittingbourne, Kent ME9 8AG, UK
b
c
Manuscript received: May 26, 2021; Revised manuscript received: July 7, 2021;
Version of record online: July 12, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100647
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Abstract: The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a
highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel–Crafts-type
1,4-addition using a Jørgensen-Hayashi-like organocatalyst with a large silyl protecting group, and show that
heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols
were obtained with excellent enantioselectivities (up to 94%). To show the utility of these constructs, and as
part of a wider project involving the synthesis of cannabinoid-like compounds, the resorcinol formed was used
to generate both ‘normal’ and ‘abnormal’ cannabidiol (CBD) derivatives which were shown to have
anticonvulsant activity.
Keywords: organocatalysis; resorcinols; Michael addition; cannabinoids
Introduction
The resorcinol unit is a constituent of many natural
products, in particular the flavanoids, isoflavanoids,
and stilbenes (e.g. flemistrictin F 1, and angelichalcone
2, Figure 1), as well as most of the cannabinoids (e.g.
3–5).[1] The latter class, which originate from Cannabis
sativa L.,[2] has received a great deal of attention, not
just because of the recreational uses of the main
psychoactive component, Δ9-THC 4, but also due to
the incredible medicinal properties of cannabidiol
(CBD) 5 which in recent years has come to some
prominence.[3] This has been demonstrated with the
recent FDA approval in June 2018 of Epidiolex®, an
oral CBD solution indicated for the treatment of
Lennox-Gastaut syndrome or Dravet syndrome – two
difficult-to-treat forms of childhood onset epilepsy.[4]
Figure 1. Typical natural products containing the resorcinol
unit.
The success of this compound has driven us to find
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new ways of accessing analogues with improved
pharmacological profiles,[5] with our current focus
being on modifications to the alkyl chain in CBD.
In that respect, we believed we could exploit the
nucleophilic properties of the resorcinol unit to
facilitate an intramolecular FriedelÀ Crafts-type reac-
tion so as to generate conjunctive analogues of CBD.
We expected to achieve this via intramolecular 1,4-
conjugate addition, ultimately leading to an SN2’
Table 1. Catalyst screening for the FriedelÀ Crafts-type 1,4-
addition.
reaction with commercially available terpene
6
(Scheme 1).[6] However, the organocatalytic transfor-
mation of resorcinols in particular is a challenging and
rare feat. To the best of our knowledge, only a few
examples capable of exploiting this motif in such a
way exist, including Yoshida and Takao’s intramolecu-
lar FriedelÀ Crafts-type construction of spiroindane
derivatives,[6b] and Nicolaou’s intramolecular α-aryla-
tion of aldehydes using organo-SOMO catalysis.[6c,7]
Results and Discussion
In order to test our hypothesis, we accessed (E)-6-(3,5-
dimethoxyphenyl)hex-2-enal 7a in a 4-step synthesis
from 3,5-dimethoxybenzyl bromide (see supporting
information). A variety of catalysts were screened
(Table 1) including primary amine I (Entry 1), a
bifunctional thiourea II (Entry 2), – a system with
which we have much experience, a selection of chiral
phosphoric acids III (Entry 3) and a range of secon-
dary amines IV–X (Entries 4–10). Interestingly, the
cinchona alkaloid derived primary amine I, used by
Takao and co-workers in the only other successful
organocatalytic resorcinol derived FriedelÀ Crafts proc-
ess known to date,[6b] gave very poor selectivity
(entry 9). Pleasingly, however the variously silylated
Jørgensen-Hayashi type catalysts[8] did give the desired
cyclized product. Although the unoptimized yields for
these systems were low, we found that the selectivities
Entry
Catalyst
Time, d[a]
Yield[b]
ee (%)[c,d]
1
2
3
4
5
6
7
8
I
II
1
69
–
–
15
29
–
–
–
68
58
26
9
–
–
72
81
–
–
–
nr
nr
1
IIIa-c
IV
V
VI
VII
VIII
IX
X
1
nr
nr
nr
7
1
7
9
À 68
À 43
92
10
11e
V
[a] Complete consumption of starting material as indicated by
NMR.
[b] Isolated yield over two steps.
[c] Determined by chiral HPLC using a Chiralcel OD column
(see supporting information).
[d] Absolute structure was determined by X-ray crystallography
of the corresponding (1S)-camphorsulfonyl derivative (com-
pound 8aa in supporting information). Other compounds
assigned by analogy
[e] Performed with no co-catalyst.
Scheme 1. Concept: Intramolecular asymmetric organocatalytic
FriedelÀ Crafts alkylation towards the generation of new CBD
derivatives.
were very encouraging. As described by Hayashi,
Seebach and co-workers, the bulkier protecting group
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led to higher selectivity in such 1,4-additions,[9] the yield was to vary the temperature (entries 10–11),
although interestingly the non-trifluoromethyl system where intriguingly not only did the yield and reaction
VI and VIII did not work at all (Entry 3). In contrast, rate improve with increased temperature, but the
the MacMillan catalysts IX and X gave better yields enantioselectivity remained the same, even at the
°
but poorer enantioselectivities.
optimal conditions of 50 C (entry 11).
We also found that removal of the co-catalyst led to
To expand the scope of this reaction, we explored
much improved selectivity (entry 11). This was con- the use of various substrates (Table 3). Compounds
firmed insomuch that a screen of additives including varied from the nature of the saturated ring to the
acid co-catalysts and bases did not significantly substitution of the resorcinol. Heterocyclic compounds
improve the reaction (see supporting information for worked well, including oxygen and various N-substi-
complete study), leading us to conclude that such tuted systems. All gave excellent enantioselectivities,
additives might be catalyzing the non-enantioselective including 8c and 8d, which can open the door to
background process.
constrained δ-amino acids which are of potential use
In view of this, and because of its superior within foldamer systems.[10] Interestingly, catechol 8k
selectivity, we decided our best option was to optimize whilst suffering from poorer conversion gave a
the yield of the conditions described in entry 10. To reasonable enantioselectivity. Substrates containing
begin with, we performed a solvent screen (Table 2)
which showed that chlorinated solvents worked best
with our reaction, with chloroform being optimal and
Table 3. Scope of the FriedelÀ Crafts-type 1,4-addition.[a,b]
giving improved yield and further improved enantiose-
lectivity (96%, entry 2). Fascinatingly, in other sol-
vents, both of these variables suffered - with toluene,
THF and ether giving no reactivity whatsoever (en-
tries 4 and 5). Pleasingly however, modulation of
concentration (Table 2, entries 7–9) showed that yield
could be further improved with no detriment to the
excellent enantioselectivity, whilst at the same time
improving reaction time. Our last attempt to improve
Table 2. Further optimization for the FriedelÀ Crafts-type 1,4-
addition.
Yield: (%)[b] ee (%)[c]
°
Entry Solvent
(conc, M)
T, C
t
1
2
3
4
5
6
7
8
CH2Cl2 (0.2) rt
CH2Cl2 (0.2) rt
MeOH (0.2) rt
7 d 26
6 d 35
2 d 38
92
96
47
–
THF (0.2)
Et2O (0.2)
MeCN (0.2)
rt
rt
rt
nr
nr
6 d
–
–
6
–
69
86
96
95
94
94
CHCl3 (0.05) rt
2 d 31
3 d 48
2 d 31
2 d 50
7 h 68
CHCl3 (0.5)
CHCl3 (1.0)
CHCl3 (0.5)
CHCl3 (0.5)
rt
rt
40
50
9
10
11
[a] Complete consumption of starting material as indicated by
NMR.
[b] Isolated yield over two steps.
[c] Determined by chiral HPLC using a Chiralcel OD column
(see supporting information).
[a] Isolated yield over two synthetic steps.
[b] Determined by chiral HPLC (see Supporting Information).
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electron-withdrawing substituents, unfortunately, failed also attracted widespread medical attention because of
to convert (see supporting information). However, their interesting pharmacological properties including
post-cyclization modification to introduce these is analgesic, antiemetic and as an appetite stimulant.[12–14]
possible as demonstrated in compound 14 discussed Since the discovery and characterization of the CB1
vide infra.
and CB2 receptors and the human endocannabinoid
Based on the observed stereochemical outcome system in the early 90s, the pursuit for small molecules
(determined by X-ray crystallographic analysis of the capable of modulating these systems has accelerated
corresponding camphorsulfonyl system of compound astonishingly.[15–17] Interestingly, although it is known
8a – see supporting information), we propose the that CBD itself does not interact with this system, its
transition state shown in figure 2, whereby the bulky clearly beneficial pharmacological properties have in
silyl group of the expected E-iminium ion blocks the turn established a need for creating new, useful and
approach of the resorcinol nucleophile from the re- easily accessible routes to enantiopure unnatural
face. Cyclization via SNAr thus leads to the (S)- analogues.
tetrahydronaphthalene system reported.
In our first synthesis, removal of the primary
We then demonstrated the utility of our resorcinol alcohol of 8a by simple mesylation and treatment with
systems by using the Friedel–Crafts type 1,4-addition lithium aluminium hydride gave deoxygenated system
in the synthesis of a CBD derivative, one of the major 9 in 97% overall yield. Subsequent O-demethylation
°
cannabinoids found in cannabis both in its ‘normal’ with boron tribromide at 0 C afforded deprotected
and ‘abnormal’ forms (Scheme 2). The medicinal chiral resorcinol 10 in 99% yield. This was then
utility of cannabinoids has led to the development of reacted with cis-isolimonenol 6 in either one of two
multiple cannabinoid-derived medications such as conditions. The first was in the presence of boron
Nabilone and Sativex.[11] Cannabinoid analogues have trifluoride diethyl etherate - conditions first used by
Petrzilka, Haefliger and Sikemeier[18] to access abnor-
mal CBD derivative 11. The second set of conditions,
however, allowed access to the normal CBD analogue,
through the use of a substoichiometric quantity of
PTSA. Not only did we obtain the desired target 12,
but also the abnormal derivative 11 and a small
quantity of what is speculated to be the bis-limonene
system 13 identified by LC-MS. Exclusive access to
the ‘normal’ system, however, was achieved through
bromination of chiral bicyclic system 9, to give us the
arylbromide system 14 upon demethylation. Coupling
with the same terpene gave the ‘normal’ regioisomer
of the bromo-CBD compound 15 in 31% yield. The
Figure 2. Proposed transition state for the FriedelÀ Crafts type
1,4-addition. The diarylsilylether substituent blocks one face of
the electrophilic centre.
Scheme 2. Synthesis of ‘normal’ and ‘abnormal’ isomers of cannabidiol.
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°
complete, the solution was cooled to 0 C and reduced using
NaBH4 (1.5 equiv.) and MeOH (0.2 M). After 20 min the
reaction was quenched with saturated NH4Cl and distilled water.
The solution was diluted with EtOAc and extracted three times.
The combined organic layers were washed with brine and dried
over MgSO4. The crude mixture was purified using silica gel on
column chromatography.
structure and absolute configuration of this was also
unambiguously determined by X-ray crystallographic
analysis (using a molybdenum X-ray source, Figure 3)
owing to the known configuration of the limonene
(1S,4R), and further confirmed the previously assigned
absolute stereochemistry. Additionally, not only did
this system allow us to obtain more crystalline material
for XRD, but it also has two further clear advantages –
first of course, that only the ‘normal’ regioisomer is
obtained, and second that the aryl bromide can be
derivatized to further systems via aryl coupling
methodologies.
(S)-2-(6,8-Dimethoxy-1,2,3,4-Tetrahydronaph-
thalen-1-yl)Ethan-1-ol (8a)
Yield: 1.19 g, 68% (yellow oil). Purified using column
conditions: Hex/EtOAc, 3:1. 1H NMR (400 MHz, CDCl3) δ
6.30 (d, J=2.31, 1H, ArH), 6.24 (d, J=2.25, 1H, ArH), 3.81 (s,
3H, OMe), 3.77 (s, 3H, OMe), 3.73–3.62 (m, 2H, CH2), 3.11–
3.08 (m, 1H, CH), 2.80–2.66 (m, 2H, CH2), 1.88–1.63 (m, 7H,
3×CH2 and OH); 13C NMR (101 MHz, CDCl3) δ 158.45 (Ar),
Conclusion
In conclusion, we have developed a highly enantiose-
lective organocatalytic method for the synthesis of 158.00 (Ar), 138.75 (Ar), 122.28 (Ar), 104.88 (Ar), 96.33 (Ar),
61.81 (CH2OH), 55.52 (OMe), 55.38 (OMe), 38.61
(CH2CH2OH), 29.70 (Cy), 27.53 (Cy), 27.40 (Cy), 18.14 (Cy).
[α]D20 +28.0 (c 0.06, CH3OH) IR (diamond) υ 3357, 3285,
2992, 2939, 2916, 2865, 2837, 1605, 1591,1067, 822 cmÀ 1;
HRMS (EI) Exact mass calculated for C14H20O3 [M+H]+
237.1491; Found 237.1490; HPLC analysis: Daicel Chiralpak
OD, hexane/iso-propanol=99:1, flow rate=0.8 mL/min, λ=
210 nm
bicyclic resorcinols. Such transformations are rare, but
we have exploited the nucleophilic character of the
resorcinol towards an organocatalytic intramolecular
FriedelÀ Crafts type 1,4-addition. The key features of
this reaction are that it requires a catalyst with a bulky
silyl protecting group and can tolerate high temper-
atures. Furthermore, we have applied our reaction to
the synthesis of cannabidiol analogues, a class of
compound our group has had a long-term interest in
owing to their biological character and with the aim of
developing new therapies towards the treatment of
epilepsy and other conditions. The cannabinoid com-
pounds within this report have been shown to have
promising anticonvulsant activity and this will be the
subject of a future communication elsewhere.
(R)-2-(5,7-Dimethoxychroman-4-yl)Ethan-1-ol (8b)
Yield: 0.073 g, 51% (orange solid). Purified using column
1
conditions: Hex/EtOAc, 65:35. H NMR (400 MHz, CDCl3) δ
6.06 (d, 1H, J=2.4 Hz, ArH), 6.03 (d, 1H, J=2.4 Hz, ArH),
4.27–4.22 (m, 2H, CH2), 4.17–4.11 (m, 1H, CHH), 3.80 (s, 3H,
OMe), 3.75–3.66 (m, 5H, OMe and CH2OH), 3.10–3.05 (m,
1H, CH), 2.04–1.86 (m, 3H, 2×CH and OH), 1.80 (qd, 1H, J=
14.0 and 2.3 Hz, CH), 1.75–1.67 (m, 1H, CH), 1.60 (s, 1H, OH)
ppm; 13C NMR (101 MHz, CDCl3) δ 159.60 (Ar), 158.46 (Ar),
155.55 (Ar), 107.15 (Ar), 93.77 (Ar), 91.42 (Ar), 62.29 (Cy),
61.11 (CH2OH), 55.71 (OMe), 55.42 (OMe), 38.90
(CH2CH2OH), 26.72 (Cy), 24.30 (Cy). [α]D20 +50.5 (c 0.2,
Experimental Section
General procedure for the organocatalytic cyclization of
resorcinols.
To
a
solution
of
(R)-α,α-Bis[3,5-bis
(trifluoromethyl)phenyl]-2-pyrrolidinemethanol tert-butyldime-
thylsilyl ether (0.2 equiv.) in CHCl3 (0.5 M) in a sealed tube
was added the α,β-unsaturated aldehyde (1 equiv.). The mixture
°
CH2Cl2). m.p: 82.1–83.1 C. HRMS (ES-Tof) Exact mass
calculated for C13H18O4 [M+H]+ 239.1283, Found 239.1272
IR (Diamond) υ 3387, 3303, 2982, 2958, 1269, 1612, 1588,
1051, 818, 810, 789 cmÀ 1; HRMS (ES-Tof) Exact mass
calculated for C13H18O4 [M+H]+ 239.1283, Found 239.1272
HPLC analysis: Daicel Chiralpak OD, hexane/iso-propanol=
99:1, flow rate=1.0 mL/min, λ=210 nm
°
was heated to 50 C and stirred until consumption of starting
which was monitored by NMR. Once the reaction was
tert-Butyl (S)-4-(2-Hydroxyethyl)-5,7-Dimethoxy-
3,4-Dihydroquinoline-1(2H)-Carboxylate (8c)
Yield: 0.17 g, 77% (pale yellow oil). Purified using column
1
conditions: Hex/EtOAc, 75:25. H NMR (400 MHz, CDCl3) δ
7.01 (d, 1H, J=2.0 Hz, ArH), 6.23 (d, 1H, J=2.4 Hz, ArH),
3.81 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.73–3.60 (m, 3H, CH
and CH2), 3.53–3.47 (m, 1H, CH), 3.32–3.30 (m, 1H, CH), 2.32
(m, 1H, OH), 1.95–1.89 (m, 1H, CH), 1.87–1.78 (m, 1H, CH),
1.73–1.67 (m, 2H, CH2), 1.52 (s, 9H, 3×CH3) ppm; 13C NMR
(101 MHz, CDCl3) δ 158.37 (Ar), 156.87 (Ar), 154.10 (C=O),
139.35 (Ar), 114.65 (Ar), 101.59 (Ar), 94.25 (Ar), 80.97
Figure 3. X-ray crystal structure of compound 15 (CCDC no:
1881707).
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(C(CH3)3), 61.17 (Cy), 55.86 (OMe), 55.53 (OMe), 42.17
(CH2OH), 36.13 (Cy), 28.58 (CH3), 28.48 (CH2CH2OH), 26.02
Benzyl (S)-4-(2-Hydroxyethyl)-5,6,7-Trimethoxy-
3,4-Dihydroquinoline-1(2H)-Carboxylate (8f)
20
(Cy). [α]D À 24.0 (c 0.2, CH2Cl2) HRMS (ES-Tof) IR (Dia-
mond) υ 3512, 2938, 1689, 1609, 1204, 825, 744 cmÀ 1 Exact
mass calculated for C18H27NO5 [M+H]+ 338.1967, Found
338.1967 HPLC analysis: Daicel Chiralpak OD, hexane/iso-
propanol=96.5:3.5 flow rate=1.0 mL/min, λ=210 nm
Yield: 0.16 g, 46% (dark yellow oil). Purified using column
1
conditions: Hex/EtOAc, 55:45. H NMR (400 MHz, CDCl3) δ
7.41–7.31 (m, 5H, ArH), 7.20 (s, 1H, ArH), 5.32 (d, 1H, J=
12.4 Hz, CH), 5.18 (d, 1H, AB system, 12.4 Hz, CH) 3.89 (s,
3H, OMe), 3.82–3.72 (m, 8H, 2×OMe and CH2), 3.65–3.61 (m,
1H, CH), 3.50–3.44 (m, 1H, CH), 3.31–3.26 (m, 1H, CH), 2.57
(s, 1H, OH), 2.02–1.96 (m, 1H, CH), 1.91–1.82 (m, 1H, CH),
1.74 (ddt, 1H, J=14.51, 10.8 and 14.3 Hz, CH), 1.66–1.58 (m.
1H, CH) ppm; 13C NMR (101 MHz, CDCl3) δ 154.90 (C=O),
151.43 (Ar), 150.02 (Ar), 138.02 (Ar), 136.37 (Ar), 132.96
(Ar), 128.73 (Ar),128.39 (Ar), 128.27 (Ar), 119.51 (Ar), 104.44
(Ar), 67.75 (CH2Ph), 61.45 (OMe), 61.04 (OMe), 60.88
(CH2OH), 55.96 (OMe), 42.25 (Cy), 35.91 (CH2CH2OH), 28.31
(9H-Fluoren-9-yl)Methyl (S)-4-(2-Hydroxyethyl)-
5,7-Dimethoxy-3,4-Dihydroquinoline-1(2H)-Car-
boxylate (8d)
Yield: 0.28 g, 69% (white solid). Purified using column
1
conditions: Hex/EtOAc, 55:45. H NMR (400 MHz, CDCl3) δ
7.77 (d, 2H, J=7.6 Hz, ArH), 7.55 (t, 2H, J=6.8 Hz, ArH),
7.40 (td, 2H, J=3.3 and 7.5 Hz, ArH), 7.32–7.28 (m, 2H, ArH),
7.01 (s, 1H, ArH), 6.27 (d, 1H, J=2.4 Hz, ArH), 4.61–4.51 (m,
2H, CH2), 4.28 (t, 1H, J=6.7 Hz, ArH), 3.83 (s, 3H, OMe),
3.74 (s, 3H, OMe), 3.70–3.61 (m, 3H, CH and CH2), 3.52–3.46
(m, 1H, CH), 3.36–3.30 (m, 1H, CH), 2.27 (s, 1H, OH), 1.93–
1.82 (m, 2H, CH2), 1.72–1.59 (m, 2H, CH2). 13C NMR
(101 MHz, CDCl3) δ 158.62 (Ar), 156.95 (Ar), 154.93 (8-C),
144.02 and 143.97 (2×rotamer Ar), 141.53 (Ar), 138.78 (Ar),
127.89 and 127.88 (2×rotamer Ar), 127.24 and 127.22 (2×
rotamer Ar) 125.15 (2×rotamer Ar), 120.15 (Ar), 115.01 (Ar),
101.54 (Ar), 94.85 (Ar), 67.64 (OCH2CH), 61.13 (CH2OH),
55.54 (OMe), 55.55 (OMe), 47.45 (CH(Fmoc)), 42.25 (Cy),
36.11 (CH2CH2OH), 28.37 (Cy), 25.92 (Cy). [α]D20 +6.5 (c 0.2,
20
(Cy), 26.78 (Cy). [α]D À 14.5 (c 0.2, CH2Cl2). [M+H]+
402.1917, Found 402.1908 IR (Diamond) υ 3480, 3011, 2941,
2866, 2827, 1696, 1685, 1207, 833 cmÀ 1 HRMS (EI) Exact
mass calculated for C22H27NO6 HPLC analysis: Daicel Chir-
alpak OD, hexane/iso-propanol=96:4, flow rate=1.0 mL/min,
λ=210 nm
(S)-2-(5,7-Dimethoxy-1-Tosyl-
1,2,3,4-Tetrahydroquinolin-4-yl)Ethan-1-ol (8g)
Yield: 0.055 g, 45% (pale yellow oil). Purified using column
1
conditions: Pentane/Et2O, 9:1. H NMR (400 MHz, CDCl3) δ
7.49 (d, 2H, J=8.4 Hz, ArH), 7.19 (m, 3H, ArH), 6.28 (d, J=
2.3 Hz, ArH), 3.94–3.89 (m, 1H, CH), 3.83 (s, 3H, OMe), 3.78
(s, 3H, OMe), 3.54 (td, 1H, J=12.4 and 5.12 Hz, CH), 3.25–
3.12 (m, 2H, CH2), 3.08–3.02 (m, 1H, CH), 2.42 (s, 3 H, CH3),
2.07 (s, 1H, OH), 1.75–1.60 (m, 2H, CH2), 1.27–1.22 (m, 1H,
CH), 0.80 (ddt, 1H, J=13.7, 8.4 and 5.0 Hz, CH) ppm; 13C
NMR (101 MHz, CDCl3) δ 158.75 (Ar), 157.27 (Ar), 143.88
(Ar), 137.69 (Ar), 135.58 (Ar), 129.62 (Ar), 127.27 (Ar),
114.82 (Ar), 101.20 (Ar), 95.61 (Ar), 60.72 (CH2OH), 55.87
(OMe), 55.65 (OMe), 43.44 (Cy), 36.61 (CH2CH2OH), 27.22
°
CH2Cl2) m.p: 50.5–51.0 C. IR (Diamond) υ 3457, 3001, 2968,
2943, 2866, 2827, 1700, 1696, 1608, 1492, 1002, 726 cmÀ 1
HRMS (EI) Exact mass calculated for C28H29NO5 [M+H]+
460.2124, Found 460.2118 HPLC analysis: Daicel Chiralpak
AD-H, hexane/iso-propanol=92.5:7.5, flow rate=1.0 mL/min,
λ=210 nm
Benzyl (S)-4-(2-hHydroxyethyl)-5,7-Dimethoxy-
3,4-Dihydroquinoline-1(2H)-Carboxylate (8e)
20
(Cy), 25.71 (Cy), 21.62 (ArCH3). [α]D +66.0 (c 0.2, CH2Cl2),
Yield: 0.26 g, 78% (pale yellow oil). Purified using column
conditions: Hex/EtOAc, 7:3. 1H NMR (400 MHz, CDCl3) δ
7.41–7.30 (m, 5H, ArH), 7.01 (s, 1H, ArH), 6.24 (d, 1H, J=
2.3 Hz, ArH), 5.29 (d, AB system, 1H, J=12.4 9-CH), 5.20 (d,
AB system, 1H, J=12.4 Hz, 9-CH), 3.85–3.72 (m, 5H, OMe
and CH2), 3.68 (s, 3H, OMe), 3.65–3.57 (m, 1H, CH), 3.53–
3.46 (m, 1H, CH), 3.36–3.30 (m, 1H, CH), 2.32–3.27 (m, 1H,
OH), 1.98–1.92 (m, 1H, CH), 1.90–1.80 (m, 1H, CH), 1.76–
1.66 (m, 2H, CH2) ppm; 13C NMR (101 MHz, CDCl3) δ 158.50
(Ar), 156.90 (Ar), 154.88 (C=O), 138.71 (Ar), 136.40 (Ar),
128.70 (Ar), 128.32 (Ar), 128.24 (Ar), 114.79 (Ar),101.16 (Ar),
94.82 (Ar), 67.72 (CH2Ph), 61.10 (CH2OH), 55.89 (OMe),
55.42 (OMe), 42.36 (Cy), 36.01 (CH2CH2OH), 28.27 (Cy),
IR (Diamond) υ 3557, 3386, 2941, 2882, 1607, 1585, 1127,
1120, 669 cmÀ 1. HRMS (ES-Tof) Exact mass calculated for
C20H25 NO5S [M+H]+ 392.1532, Found 392.1531 HPLC
analysis: Daicel Chiralpak OD, hexane/iso-propanol=95.5:4.5,
flow rate=1.0 mL/min, λ=210 nm. Amended conditions of
hexane/iso-propanol 95:5 were used for the racemic sample.
(S)-1-(4-(2-Hydroxyethyl)-5,7-Dimethoxy-
3,4-Dihydroquinolin-1(2H)-yl)Ethan-1-One (8h)
Yield: 0.14 g, 54% (yellow oil). Purified using column
conditions: Hex/EtOAc, gradient, 75:25 to 9:1. 1H NMR
(400 MHz, CDCl3) δ 6.42–6.32 (m, 2H, ArH), 4.14–3.96 (m,
1H, CH), 3.84 (s, 3H, OMe), 2.78 (s, 3H, OMe), 3.63–3.57 (m,
1H, CH), 3.50–3.35 (m, 2H, 2×CH), 2.21 (s, 3H, CH3), 2.05–
1.96 (m, 1H, CH), 1.93–1.81 (m, 1H, CH), 1.72 (ddt, 1H, J=
14.2, 8.7 and 5.8 Hz, CH), 1.64–1.56 (m, 1H, CH). 13C NMR
(101 MHz, CDCl3) δ 170.35 (C=O), 158.69 (Ar), 157.26 (Ar),
140.19 (Ar), 103.02 (Ar), 95.52 (Ar), 61.20 (CH2OH), 55.98
(OMe), 55.61 (OMe), 41.85 (Cy), 36.21 (CH2CH2OH), 29.11
20
25.91 (Cy). [α]D À 21.0 (c 0.2, CH2Cl2). IR (Diamond) υ 3417,
2943, 2844, 1696, 1607, 1587, 1206, 826, 697 cmÀ 1 HRMS
(ES-Tof) Exact mass calculated for C21H25NO5 [M+H]+
372.1811, Found 372.1816 HPLC analysis: Daicel Chiralpak
OD, hexane/iso-propanol=94:6, flow rate=1.0 mL/min, λ=
210 nm
20
(Cy), 26.39 (Cy), 23.54 (C(O)CH3). [α]D À 105.0 (c 0.2,
CH2Cl2). IR (Diamond) υ 3408, 2937, 2878, 2839, 1634, 1607,
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1048, 827 cmÀ 1 HRMS (EI) Exact mass calculated for
C15H21NO4 [M+H]+ 280.1549, Found 280.1546 HPLC analy-
sis: Daicel Chiralpak OD, hexane/iso-propanol=92.5:7.5, flow
rate=1.0 mL/min, λ=210 nm
(Ar), 100.95 (Ar), 63.5 (CH2OAr), 60.6 (CH2OH), 56.7 (OMe),
56.0 (OMe), 39.5 (CH2CH2OH), 29.9 (CHAr), 27.4
20
D
(CH2CH2OAr) ppm; [α]
+36.00 (c 0.1, CH2Cl2), IR
(diamond) υ 3443, 2989, 2956, 2862, 2833, 1619, 1054, 1449,
1371, 1262, 1218, 1054, 1034, 855 cmÀ 1 HRMS (EI) Exact
mass calculated for C13H18O4 [M+H]+ 239.1283, Found
239.1293
(S)-1-(4-(2-Hydroxyethyl)-5,7-Dimethoxy-
3,4-Dihydroquinolin-1(2H)-yl)-2-Methylpropan-
1-One (8i)
CCDC-1881707 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via https://
www.ccdc.cam.ac.uk/structures/
Yield: 0.18 g, 64% (Yellow solid). Purified using column
conditions: Hex/EtOAc, 2:3. 1H NMR (400 MHz, CDCl3) δ
6.34 (6.38–6.34 (m, 2H, ArH), 4.23–4.15 (m, 1H, CH), 3.85 (s,
3H, OMe), 3.79 (s, 3H, OMe), 3.61–3.56 (m, 1H, CH), 3.50–
3.43 (m, 1H, CH), 3.42–3.30 (m, 2H, 2×CH), 3.17 (sept, 1H,
J=6.7 Hz, CH(CH3)2), 2.24 (s, 1H, OH), 1.99–1.85 (m, 2H,
CH2), 1.74–1.58 (m, 2H, CH2), 1.25 (d, 3H, J=6.6 Hz, CH3),
1.01 (d, 3 H, J=6.6 Hz, CH3) ppm; 13C NMR (101 MHz,
CDCl3) δ 177.72 (C=O), 158.69 (Ar), 157.48 (Ar), 140.41 (Ar),
117.36 (Ar), 102.52 (Ar), 95.61 (Ar), 61.21 (CH2OH), 56.00
(OMe), 55.58 (OMe), 41.90 (Cy), 36.43 (CH2CH2OH), 31.48
Acknowledgements
We would like to acknowledge the support of GW Pharmaceut-
icals and the BBSRC for funding (to L.A.B, Grant No: BB/
L015714/2) and thank the Chemical Analysis Facility (CAF) at
the University of Reading for access to X-ray diffractometers.
(CH(CH3)2), 29.43 (Cy), 26.55 (Cy), 20.52 (CH3), 19.92 (CH3).
References
20
°
[α]D À 124.0 (c 0.1, MeOH), m.p: 60.2-62.3 C. HRMS (Es-
Tof) IR (Diamond) υ 3405, 2956, 2937, 2872, 1653, 1634,
1494, 1046, 821 cmÀ 1 Exact mass calculated for C17H25NO4 [M
+H]+ 308.1862, Found 308.1864 HPLC analysis: Daicel
Chiralpak AD-H, hexane/iso-propanol=92.5:7.5, flow rate=
1.0 mL/min, λ=210 nm
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Enantioselective Organocatalytic Synthesis of Bicyclic Resor-
cinols via an Intramolecular FriedelÀ Crafts-Type 1,4-
Addition: Access to Cannabidiol Analogues
Adv. Synth. Catal. 2021, 363, 1–9
L. A. Bryant, K. Shankland, H. E. Straker, C. D. Johnston,
N. R. Lees, A. J. A. Cobb*