Diels-Alder Reactions of α-Amido Acrylates with N-Cbz-1,2-dihydropyridine and Cyclopentadiene

Article abstract of DOI:10.1021/acs.joc.6b01684

Thermal Diels-Alder reactions of α-amido acrylates with N-Cbz-1,2-dihydropyridine and cyclopentadiene have been explored to investigate the factors influencing the endo/exo selectivity. For the dihydropyridine, steric factors allowed the diastereoselectivity to be modulated to favor either endo- or exo-ester adducts. For cyclopentadiene, the endo-ester adducts were favored regardless of steric perturbation, although catalysis by bulky Lewis acids increased the proportion of exo-ester adducts in some cases. These Lewis acids were incompatible with the dihydropyridine diene as they induced its decomposition.

Full text of DOI:10.1021/acs.joc.6b01684

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Note
Diels-Alder reactions of alpha-amido acrylates with
N-Cbz-1,2-dihydropyridine and cyclopentadiene
Hossay Abas, Christopher S. Frampton, and Alan Christopher Spivey
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01684 • Publication Date (Web): 14 Sep 2016
Downloaded from http://pubs.acs.org on September 16, 2016
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The Journal of Organic Chemistry
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Diels-Alder reactions of α-amido acrylates with N-Cbz-1,2-dihydropyridine and cyclopentadiene
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Hossay Abas,[1] Christopher S. Frampton[2] and Alan C. Spivey[1]*
[1]Department of Chemistry, Imperial College London, South Kensington, SW7 2AZ, United Kingdom
a.c.spivey@imperial.ac.uk
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[2]Wolfson Centre for Materials Processing, Brunel University, Kingston Lane, Uxbridge, UB8 3PH, United Kingdom
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ABSTRACT | Thermal Diels-Alder reactions of α-amido acrylates with N-Cbz-1,2-dihydropyridine and cyclopentadiene have
been explored to investigate the factors influencing the endo/exo selectivity.
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O
N
O
O
O
Cbz
N
R'
OR
RO
N
R
OR
Cbz
R'
100 °C
neat
80 °C
neat
R'
N
O
N
O
R''
R''
When R is big;
Endo
-ester favoured
endo-ester favoured
When R' or R'' is big;
exo-ester favoured
irrespective of size of
R, R' or R''
For the dihydropyridine, steric factors allowed the diastereoselectivity to be modulated to favor either endo- or exo-ester adducts.
For cyclopentadiene, the endo-ester adducts were favored regardless of steric perturbation, although catalysis by bulky Lewis acids
increased the proportion of exo-ester adducts in some cases. These Lewis acids were incompatible with the dihydropyridine diene
as they induced its decomposition.
Since its discovery in 1928, the Diels-Alder (DA) reaction has fundamentally changed the landscape of organic synthesis.1 It allows
for the rapid generation of molecular complexity and has served as a pivotal transformation in many complex natural product
syntheses.2 Our focus here is on DA reactions of N-carbalkoxy-1,2-dihydropyridines, which are frequently employed for the
synthesis of isoquinuclidines.3 This azabicyclo[2.2.2]octane unit is a common structural motif in many natural product classes,
notably iboga4 and related catharanthus5 alkaloids (Figure 1).
Figure 1. Examples of iboga and catharanthus alkaloids having the isoquinuclidine core, and our target isoquinuclidine-
based α-helix mimetic.
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In our efforts towards the synthesis of 5-residue, multi-face α-helix mimetics based on an isoquinuclidine core (Figure 1),6 we
envisaged that an attractive, convergent strategy by which to access this skeleton would be via reaction of dienophile 1 with N-Cbz-
1,2-dihydropyridine (Figure 2).
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Figure 2. The DA reaction between tri-substituted alkene 1 and N-Cbz-1,2-dihydropyridine.
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NMR studies and a single crystal X-ray structure determination (see SI) on the major product 2 revealed that this DA reaction
afforded exclusively the undesired exo-ester isomer 2. Looking to understand this selectivity, we were surprised to find only limited
literature precedent for the use of α-amido acrylates, or β-substituted derivatives thereof in DA reactions. Published reports are
limited to cyclic compounds in which the nitrogen is constrained as a lactam,7,8 part of a quinolone,9 or part of an oxazine-2,4-
dione.10 Consequently, we decided to probe the reactivity of acyclic α-amido acrylates as dienophiles in DA reactions to determine
the factors influencing their endo/exo selectivity. In particular, we wanted to investigate the influence of steric and electronic
factors in controlling this diastereoselection. To this end, we prepared an array of β-unsubstituted-α-amido acrylates as test
dienophiles. These substrates were chosen for three reasons: firstly, to preclude alkene isomerization,11 secondly, because only two
diastereoisomeric products can form, and thirdly, because they show increased reactivity compared to β-substituted congeners. The
α-amido acrylates were reacted with both N-Cbz-1,2-dihydropyridine and cyclopentadiene to allow an assessment of the role of the
nitrogen substituent in the former dienophiles.12
The α-amido acrylates were synthesized in two steps starting from commercially available methyl malonyl chloride or mono-tert-
butyl malonate via amide bond formation followed by Mannich condensation-elimination (Scheme 1).13
Scheme 1. Method of synthesis of α-amido acrylates 4.
Rapid polymerization was observed upon attempted isolation of some α-amido methylacrylates containing a secondary amide (e.g.
where R’ = Me or Ph and R’’ = H), whereas no polymerization was apparent with tertiary amides. Presumably the secondary
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amides are both sufficiently nucleophilic and sterically unencumbered to allow for anionic polymerization via a 1,4-addition
pathway. By contrast, introducing 2,2-dimethyl substitution, or bulky groups on the aryl ring of the secondary amide, inhibits
polymerization allowing the dienophiles to be stored at room temperature for weeks without noticeable decomposition.
1,2-Dihydropyridines typically require heating to achieve efficient DA reactions, particularly given that they are unstable in the
presence of many Lewis acids,14 and so thermal DA reactions with N-Cbz-1,2-dihydropyridine were investigated first (Table 1).
Table 1. Diels-Alder reactions between N-Cbz-1-2-dihydropyridine and α-amido acrylates 4a-h.a
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Entry
Dienophile
drb
Endo : Exo
Reaction Time
Combined
Isolated Yield
1
62 : 38
3 d
68%
a
O
O
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3
4
58 : 42
69 : 31
24 : 76
7 d
50%
86%
58%
Et
MeO
N
Et
4b
6.5 h
16 h
5
20 : 80
2.5 h
66%c
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7
8
78 : 22
94 : 6
7 dd
6 dd
5 d
37%
48%
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No
reaction
aReaction conditions unless otherwise specified: dienophile (1 eq.), N-Cbz-1,2-dihydropyridine (1.5-2.5 eq.), neat, sealed tube, under Ar, 100 °C. bEndo/exo ratios were
determined by VT 1D and 2D NMR analysis and nOe experiments (see SI). cNeat for 2 h at 100 °C, then added dry toluene (0.5M) and heated at 100 °C for 30 mins. dUnreacted
dienophile remaining.
Overall, the dr of DA reactions of 1,2-dihydropryidines with α-amido acrylates appear to be dominated by the relative size of the
substituents on the ester and amide. When the size of the groups on the ester and amide are both moderate, such as in dienophiles
4a and 4b, there is a slight preference for formation of the endo-ester isomer (entries 1 & 2). This intrinsic selectivity may reflect
greater secondary orbital interactions between the ester and the diene due to the lower LUMO energy of an ester as compared to an
amide. However, once the amide contains a large substituent, such as the 2,6-diisopropylphenyl group, the formation of the exo-
ester becomes significantly more favored (entries 4 & 5). Presumably, the bulky aryl amide group sterically clashes with the N-Cbz
group in the endo-ester TS thus favoring the exo-ester-TS (Figure 3).
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Figure 3. Proposed rationale for selectivity.
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Diphenyl-substituted amide 4c (entry 3) showed similar levels of endo-ester selectivity as amides 4a and 4b, indicating that the two
aryl rings do not impose significant steric hindrance. The reactivity of the dienophiles increases significantly when an alkyl group is
replaced by an aryl group in the amide, presumably as the result of lowering of the LUMO energy (cf. reaction times for e.g. entries
2 vs. 1 vs. 3). Replacing the methyl ester with a tert-butyl ester tipped the dr in favor of the endo-ester isomer (e.g. 4f → 4g, entries
6 and 7) and led to the highest endo-ester selectivities. This is consistent with the findings of Krow et al. who noted a greater
preference for endo isoquinuclidine DA adducts when bulkier groups were present in simple acrylate esters.3a The gem-dimethyl
substituted dienophile 4h was found to be unreactive under the thermal DA conditions (entry 8).
To exclude the possibility that retro-DA re-addition could be occurring, which would invalidate a TS-based rationalization of the
selectivity trends, a mixture of the DA-adducts endo-5e and exo-5e was heated in the presence of the diene at 100 °C for 5 days. No
equilibration was observed, indicating that the initially observed exo/endo ratios reflect kinetic control. This is in agreement with
previous studies.15
From a synthetic perspective, the ability to predictably promote either exo or endo product formation by appropriate choice of ester
and amide substituents is attractive. Although the exo-ester configuration favored for the di-ortho-substituted diaryl amides 4d and
4e (cf. 1, Figure 2) is not useful for our α-helix mimetic targets, the endo-ester configuration strongly favored for the tert-butyl
esters 4f and 4g is potentially valuable for entry to the iboga alkaloids (Figure 1).4
For comparison, we next investigated the corresponding DA reactions of cyclopentadiene as the diene (Table 2).
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Table 2. DA reactions between cyclopentadiene and α-amido acrylates.a
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Entry
Dienophile
drb
Endo : Exo
Reaction Time
Yield
1
80 : 20
78 : 22
70 : 30
84 : 16
5 h
86%
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24 h
80 mins
16 h
45%
90%
58%
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76 : 24
2.5 h
90%c
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83 : 17
81 : 19
48 h
24 h
5 d
55%
67%
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No reaction
aReaction conditions unless otherwise specified: dienophile (1 eq.), cyclopentadiene (5 eq.), neat, sealed tube, under Ar, 80 °C. Reactions were stopped once all the dienophile was
consumed. bEndo/exo ratios were determined by VT 1D and 2D NMR analysis and nOe experiments (see SI). cNeat for 2 h at 80 °C, then added dry toluene (0.5M) and heated at
80 °C for a further 30 mins.
By contrast to the DA reactions of 1,2-dihydropyridine, the diastereoelectivities obtained from reactions of cyclopentadiene do not
appear to be influenced strongly by the steric demand of the amide and ester groups of the dienophile: all substrates afford the
endo-ester with fairly high levels of selectivity (entries 1-7). As expected on account of strain-relief, cyclopentadiene is more
reactive than 1,2-dihydropyridine as evidenced by shorter reaction times, although the gem-dimethyl substituted dienophile 4h was
still unreactive (entry 8). The good levels of exo/endo selectivity and insensitivity towards steric congestion displayed in these
reactions make them attractive for the synthesis of otherwise difficult to obtain exo-amide cyclopentadiene DA adducts.1b,16
DA adducts endo-6e and exo-6e were heated in the presence of cyclopentadiene at 100 °C for 48 h; there was no observed
epimerization after 24 h although after 48 h traces could be detected (<5%). Given that all but one of the DA reactions (entry 6, 48
h) were complete within 24 h, the observed exo/endo ratios were concluded to be those of kinetic control.
Salvatella et al. have proposed that electrostatic rather than secondary orbital interactions are responsible for the high endo
selectivity in the DA reaction between cyclopentadiene and acrolein.17 They hypothesized that given the greater electronegativity of
carbon relative to hydrogen, the δ+ charge on the hydrogen atom of the cyclopentadiene methylene facing the dienophile
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experiences a coulombic repulsion as it approaches the δ+ charge on the carbonyl carbon thereby destabilizing the exo-TS. In our
reactions, the lesser δ+ charge on the amide carbonyl carbon as compared to on the ester carbonyl might therefore be expected to
give rise to less repulsion and so favor the endo-ester TS, as observed (Figure 4).
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Figure 4. Proposed rationale for endo-ester selectivity
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Finally, we investigated whether Lewis acids could be used to perturb the endo/exo selectivity of the cyclopentadiene adducts. The
effects of three Lewis acids were explored: Et2AlCl, one of the most frequently utilized Lewis acid in DA reactions;18 B(C6F5)3, a
bulky Lewis acid capable of overriding the typically observed endo selectivity in DA reactions of α,β-enals,19 and TBSOTf, which
has been reported to activate acrylamides but not acrylates in DA reactions with cyclopentadiene.20 Although selective activation of
the amide over the ester, or vice versa, in an α-amido acrylate was anticipated to be challenging, it was expected that this would be
most feasible for sterically and/or electronically differentiated examples. Consequently, each of the three Lewis acids was reacted
with the 2,6-iso-propylphenyl amide/methyl ester dienophile 4e and the diethyl amide/tert-butyl ester dienophile 4f (Table 3).
Table 3. DA reactions between α-amido acrylates 4e and 4f and cyclopentadiene in the presence of Lewis acids.
Entry
Dienophile
Lewis Acid
dr
Endo : Exo
Reaction
Time
Yield
1a
2
3
-
76 : 24
77 : 23
76 : 24
71 : 29
83 : 17
88 : 12
52 : 48
50 : 50
2.5 h
30 mins
30 mins
30 mins
48 h
2 h
30 mins
2.5 h
90%
77%
88%
75%
55%
66%
67%
52%
Et2AlCl
B(C6F5)3
TBSOTf
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Et2AlCl
B(C6F5)3
TBSOTf
4
5b
6
7
8
Reaction conditions unless otherwise specified: dienophile (1 eq.), cyclopentadiene (10 eq.), Lewis acid (1 eq.), under Ar, RT, CH2Cl2 (0.1M). aSame reaction as Table 2, entry 5.
bSame reaction as Table 2, entry 6.
The reactions of the 2,6-diisopropylphenyl amide/methyl ester dienophile 4e in the presence of 1 equivalent of each of the three
Lewis acids resulted in only minor deviations from the endo/exo ratio that was observed for the uncatalysed reaction (entries 1-4).
The Lewis acid catalyzed reactions were however significantly faster (2.5 h → 30 min), suggesting that these Lewis acids are likely
either bridging between or at least equally activating the carbonyl groups of the 1,3-dicarbonyl moiety. It would appear therefore
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that for dienophile 4e, the bulky aryl amide and methyl ester carbonyls have balanced affinities for the Lewis acids (possibly the
higher intrinsic bacisity of the amide is counterbalanced by steric factors). By contrast, the drs of reactions of the diethyl
amide/tert-butyl ester dienophile 4f were more strongly affected: Et2AlCl slightly increased the endo-ester ratio (entry 6), whereas
B(C6F5)3 markedly increased the amount of the exo-ester formed (entry 7), and TBSOTf similarly increased the amount of the exo-
ester (entry 8). It would appear therefore that for dienophile 4f the alkyl amide carbonyl displays stronger affinity than the tert-butyl
ester carbonyl for the two most bulky Lewis acids (presumably because the bulky tert-butyl group limits co-ordination to the ester
carbonyl). Finally, TMSOTf was briefly explored as a non-bulky trialkyl silyl triflate, but it was found to be incompatible with our
reaction conditions.
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In conclusion, we have explored the use of α-amido acrylates as dienophiles in DA reactions with N-Cbz-1,2-dihydropyridine and
cyclopentadiene. We found that the endo/exo selectivity in the DA reactions with the dihydropyridine is strongly influenced by
steric factors, allowing access to good levels of selectivity favoring either isomer. By contrast, when cyclpentadiene is used as the
diene, the endo/exo selectivity is relatively unaffected by steric factors and electronic factors favor the endo-ester product. Lewis
acid catalysis of the reactions is not possible for the dihydropyridine cases due to decomposition of these dienes, but for the
cyclopentadiene cases, significant rate accelerations are achieved and increased proportions of exo-ester products can be formed by
using bulky Lewis acids [e.g. B(C6F5)3 and TBSOTf] in conjunction with α-amido acrylates designed to allow coordination
preferentially to the amide carbonyl rather than the ester carbonyl (e.g. acrylate 4f). As the result of the trends revealed in this work,
we anticipate that α-amido acrylates could find wide utility in the stereocontrolled synthesis of isoquinuclidine-containing natural
and unnatural products.
EXPERIMENTAL SECTION
N-Cbz-1,2-dihydropyridine.21 Pyridine (6 mL, 74.2 mmol) in MeOH (90 mL) was treated with NaBH4 (2.81 g, 74.2 mmol). The
reaction mixture was cooled to -78 °C before carefully adding benzylchloroformate (10.4 mL, 74.2 mmol) over a 1 h period via a
dropping funnel. The reaction mixture was stirred at -78 °C for 2 h, poured into ice-water (a gas presumed to be H2 was evolved)
and extracted with CH3Cl (4 × 50 mL). The combined organic phases were dried over MgSO4 and concentrated under reduced
pressure to give the crude material as an off-white oil. FC (flash chromatography) purification (n-hexane:Et2O 20:1 → 5:1) afforded
the 1,2-dihydropyridine as a pale yellow oil (5.49 g, 34%). 1H NMR (CDCl3, 400 MHz): δ 7.50 – 7.30 (m, 5H), 6.87 – 6.62 (m, 1H),
5.90 – 5.77 (m, 1H), 5.58 – 5.41 (m, 1H), 5.28 – 5.09 (m, 3H), 4.40 (br s, 2H). 13C NMR (CDCl3, 101 MHz,): δ 149.8, 136.0,
128.6, 128.3, 128.1, 125.6, 121.9, 119.2, 105.0, 67.8, 43.6. IR (neat): ν = 3385, 3036, 2924, 2854, 1696, 1497, 1453, 1417, 1310,
1219, 1154, 1118, 1047, 1024, 735, 696. HRMS (Cl+): m/z calcd. for C13H14NO2 216.1025 [M+H]+, found 216.1019.
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Methyl 2-((2-isobutoxy-6-isobutylphenyl)carbamoyl)-5-(4-methoxyphenyl)pent-2-enoate (1). A solution of α-amidoester 3d (180
mg, 0.56 mmol) in CH2Cl2 (1.5 mL) in a round bottom flask was cooled to 0 °C in an ice bath. To the cooled solution, was added
TiCl4 by syringe (1M solution in CH2Cl2, 0.62 mL, 0.62 mmol) drop-wise over 10 mins. The resulting mixture was stirred with
cooling for 30 mins at 0 °C, then 3-(4-methoxyphenyl)propanal (101 mg, 0.62 mmol) was added (diluted in 1.5 mL CH2Cl2) by
syringe. The reaction mixture was stirred for 10 mins at 0 °C after which anhydrous pyridine (0.09 mL, 1.12 mmol) was then added
drop-wise (caution: exothermic). The reaction was allowed to warm gradually to RT and stirred for 4 h under N2. The reaction
mixture was poured over ice and extracted with EtOAc (× 3). The organic solution was then washed with brine, dried over MgSO4
and concentrated to dryness. The crude residue was purified by FC (n-hexane:EtOAc 7.1 → 8:3) to afford a mixture of Z:E isomers
in a 29:71 ratio (199 mg, 76%). Z-Isomer: methyl (Z)-2-((2-isobutoxy-6-isobutylphenyl)carbamoyl)-5-(4-methoxyphenyl)pent-2-
enoate: 1H NMR (CDCl3, 400 MHz): δ 9.03 (s, 1H), 7.64 (t, J = 7.1 Hz, 1H), 7.18 – 7.09 (m, 3H), 6.88 – 6.82 (m, 2H), 6.80 (dd, J =
7.8, 1.1 Hz, 1H), 6.74 (dd, J = 8.3, 1.2 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.71 (d, J = 6.3 Hz, 2H), 2.92 – 2.74 (m, 4H), 2.46 (d, J
= 7.2 Hz, 2H), 2.11 – 1.97 [m, 1H), 1.92 – 1.78 (m, 1H), 0.98 (d, J = 6.8 Hz, 6H), 0.87 (d, J = 6.6 Hz, 6H). 13C NMR (CDCl3, 101
MHz): δ 168.0, 162.9, 161.9, 158.1, 154.6, 154.2, 154.1, 153.2, 140.1, 132.9, 129.5, 129.3, 128.7, 127.5, 127.3, 126.9, 122.2, 122.2,
114.0, 113.8, 109.6, 74.8, 74.6, 55.3, 55.2, 52.4, 52.2, 41.3, 41.2, 34.0, 33.9, 32.8, 31.9, 29.3, 29.2, 28.4, 28.3, 22.6, 19.3, 19.2. E-
Isomer: methyl (E)-2-((2-isobutoxy-6-isobutylphenyl)carbamoyl)-5-(4-methoxyphenyl)pent-2-enoate: 1H NMR (CDCl3, 400 MHz):
δ 7.99 (s, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.19 – 7.08 (m, 3H), 6.87 – 6.69 (m, 4H), 3.82 (s, 3H), 3.75 (s, 3H), 3.70 (d, J = 6.6 Hz,
2H), 3.00 (q, J = 7.6 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 2.48 (d, J = 7.2 Hz, 2H), 2.06 – 1.92 (m, 1H), 1.91 – 1.77 (m, 1H), 0.94 (d, J
= 6.7 Hz, 6H), 0.87 (d, J = 6.6 Hz, 6H). 13C NMR (CDCl3, 101 MHz): δ 162.9, 158.0, 154.2, 153.2, 140.3, 132.7, 129.5, 128.7,
127.5, 122.2, 114.0, 113.8, 109.6, 74.8, 55.2, 52.4, 41.2, 33.9, 31.9, 29.2, 28.3, 22.6, 19.3, 19.2. HRMS (ES) (of E:Z mixture): m/z
calcd. for C28H38NO5 468.2750 [M+H]+, found 468.2744.
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Methyl 3-(methyl(phenyl)amino)-3-oxopropanoate (3a).22 To a solution of methyl 3-chloro-3-oxopropanoate (0.5 mL, 4.52 mmol)
in dry CH2Cl2 (23 mL) at 0 °C under N2 was added N-methylaniline (0.44 mL, 4.11 mmol) after which a suspension resulted. Et3N
(0.69 mL, 4.93 mmol) was then added and after initial white fumes, a clear yellow solution formed. The reaction was allowed to
warm up to RT and stirred for 2 h under N2. The reaction mixture was concentrated, diluted in EtOAc and then sequentially washed
with 1M HCl solution, sat. NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated under reduced pressure
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to provide α-amido-ester 3a as an orange oil (840 mg, 99 %). H NMR (400 MHz, CDCl3): δ 7.46 – 7.31 (m, 3H), 7.25 – 7.19 (m,
2H), 3.67 (s, 3H), 3.30 (s, 3H), 3.22 (s, 2H). 13C NMR (CDCl3, 101 MHz): δ 168.2, 165.9, 143.5, 130.0, 128.3, 127.3, 52.3, 41.3,
37.5.
Methyl 3-(diethylamino)-3-oxopropanoate (3b).23 To a solution of methyl 3-chloro-3-oxopropanoate (0.7 mL, 6.53 mmol) in dry
CH2Cl2 (32 mL) at 0 °C under N2 was added diethylamine (1.35 mL, 13.05 mmol). The reaction was allowed to warm up to RT and
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stirred for 3 h. The reaction mixture was further diluted in CH2Cl2 and then sequentially washed with 1M HCl solution, sat.
NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated under reduced pressure to provide α-amido-ester
3b as an orange oil (1.03 g, 91 %). 1H NMR (CDCl3, 400 MHz): 3.75 (s, 3H), 3.44 (s, 2H), 3.40 (q, J = 7.4 Hz, 2H), 3.30 (q, J = 7.2
Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 168.3, 165.1, 52.4, 42.7, 41.1, 40.3, 14.2,
12.8.
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Methyl 3-(diphenylamino)-3-oxopropanoate (3c).24 To a solution of methyl 3-chloro-3-oxopropanoate (0.90 mL, 8.40 mmol) in dry
CH2Cl2 (35 mL) at 0 °C under N2 was added diphenylamine (1.18 g, 7.0 mmol) and then Et3N (1.17 mL, 8.40 mmol). The reaction
mixture was slowly allowed to warm up to RT and stirred for 2 h. The reaction mixture was further diluted in CH2Cl2 and then
sequentially washed with 1M HCl solution, sat. NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated
under reduced pressure, and the residue was recrystallized using n-hexane:Et2O 1:2 to provide α-amido-ester 3c as a pale yellow
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powder (820 mg, 43%). H NMR (CDCl3, 400 MHz): δ 7.52 – 7.14 (m, 10H), 3.70 (s, 3H), 3.41 (s, 2H). 13C NMR (CDCl3, 101
MHz): δ 168.0, 166.0, 142.4, 130.0, 129.0, 128.7, 128.4, 126.5, 126.3, 52.4, 42.5. HRMS (ES): m/z calcd. for C16H16NO3 270.1130
[M+H]+, found 270.1143.
Methyl 3-((2-isobutoxy-6-isobutylphenyl)amino)-3-oxopropanoate (3d). To a solution of methyl 3-chloro-3-oxopropionate (0.14
mL, 1.24 mmol) in dry CH2Cl2 (7 mL) was added Et3N (0.20 mL, 1.42 mmol) and the solution was cooled to 0 °C. To this was
added drop-wise a solution of di-ortho-substituted aniline25 (274 mg, 1.24 mmol) in dry CH2Cl2 (3 mL). The reaction mixture was
stirred at 0 °C for 30 mins. The solution was washed with a sat. NH4Cl solution and extracted with CH2Cl2 (× 2). The organics were
combined, washed with brine and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue purified
by FC (n-hexane:EtOAc 4.1 → 7:3) to afford α-amido ester 3d as a yellow oil (181 mg, 45%). 1H NMR (CDCl3, 400 MHz): δ 8.30
(br s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.79 (dd, J = 8.0, 1.3 Hz, 1H), 6.74 (dd, J = 8.2, 1.3 Hz, 1H), 3.81 (s, 3H), 3.71 (d, J = 6.3 Hz,
2H), 3.51 (s, 2H), 2.45 (d, J = 7.2 Hz, 2H), 2.14 – 2.00 (m, 1H), 1.91 – 1.77 (m, 1H), 1.00 (d, J = 6.7 Hz, 6H), 0.88 (d, J = 6.8 Hz,
6H). 13C NMR (CDCl3, 101 MHz): δ 127.7, 122.2, 109.6, 74.6, 52.5, 41.4, 41.2, 29.3, 28.4, 22.6, 19.2. IR (neat): ν = 3272, 2952,
2868, 1742, 1655, 1531, 1460, 1439, 1348, 1304, 1273, 1226, 1200, 1142, 1058, 727, 767. HRMS (ES): m/z calcd. for C18H28NO4
322.2018 [M+H]+, found 322.2000.
Methyl 3-((2,6-diisopropylphenyl)amino)-3-oxopropanoate (3e). To a solution of methyl 3-chloro-3-oxopropanoate (0.68 mL, 6.40
mmol) in dry CH2Cl2 (26 mL) at 0 °C under N2 was added 2,6-diisopropylaniline (1.0 mL, 5.3 mmol) and then Et3N (0.89 mL,
6.4 mmol). The reaction mixture was slowly allowed to warm up to RT and stirred for 3 h. The reaction mixture was further diluted
in CH2Cl2 and then sequentially washed with 1M HCl solution, sat. NaHCO3 solution and brine, and dried over MgSO4. The
solvent was evaporated under reduced pressure, and the residue purified by FC (n-hexane:Et2O 4.1 → 7:3) to provide α-amido-ester
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3e as a fluffy white solid (1.27 g, 86%). MP = 110 – 113 °C. 1H NMR (CDCl3, 400 MHz): δ 8.49 (br. s, 1H), 7.34 – 7.28 (m, 1H),
7.23 – 7.16 (m, 2H), 3.83 (s, 3H), 3.56 (s, 2H), 3.04 (hept, J = 6.9 Hz, 2H), 1.20 [d, J = 6.9 Hz, 12H). 13C NMR (CDCl3, 101 MHz):
δ 170.6, 164.2, 145.9, 130.8, 128.5, 123.5, 52.7, 40.8, 28.9, 23.6. IR (neat): ν = 3235, 2966, 1751, 1648, 1529, 1437, 1337, 1277,
1255, 1155, 796, 745, 709. HRMS (ES): m/z calcd. for C16H24NO3 278.1756 [M+H]+, found 278.1762.
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tert-Butyl 3-(diethylamino)-3-oxopropanoate (3f).26 To a solution of DMAP (159 mg, 1.30 mmol) and diethylamine (0.67 mL, 6.49
mmol) in dry CH2Cl2 (26 mL) was added 3-(tert-butoxy)-3-oxopropanoic acid (1 mL, 6.49 mmol). The reaction mixture was stirred
under N2 for 2 h. The reaction mixture was then diluted further in CH2Cl2 and washed with 1M HCL solution, brine (× 2) and dried
over MgSO4. The organic solution was then concentrated under reduced pressure to provide α-amido-ester 3f as a colourless oil
(1.21 g, 87%), with no purification necessary. 1H NMR (CDCl3, 400 MHz): δ 3.39 (q, J = 7.1 Hz, 2H), 3.33 (s, 2H), 3.28 (q, J = 7.1
Hz, 2H), 1.47 (s, 9H), 1.18 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 167.1, 165.6, 81.8, 42.5,
40.1, 28.0, 14.2, 12.8.
tert-Butyl 3-(methyl(phenyl)amino)-3-oxopropanoate (3g).22 To a solution of DMAP (159 mg, 1.30 mmol) and N-methylaniline
(0.70 mL, 6.49 mmol) in dry CH2Cl2 (26 mL) was added 3-(tert-butoxy)-3-oxopropanoic acid (1 mL, 6.49 mmol). The reaction
mixture was stirred under N2 for 2 h. The reaction mixture was then diluted further in CH2Cl2 and washed with 1M HCL solution,
brine (× 2) and dried over MgSO4. The organic solution was concentrated under reduced pressure to provide α-amido-ester 3g as a
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dark orange oil (1.50 g, 93%), with no purification necessary. H NMR (CDCl3, 400 MHz): δ 7.45 – 7.38 (m, 2H), 7.38 – 7.32 (m,
1H), 7.25 – 7.21 (m, 2H), 3.30 (s, 3H), 3.12 (s, 2H), 1.42 (s, 9H). 13C NMR (CDCl3, 101 MHz): δ 167.0, 166.5, 143.7, 129.9, 128.2,
127.3, 81.6, 42.7, 37.4, 28.0. IR (neat): ν = 2980, 2936, 1720, 1634, 1478, 1460, 1393, 1368, 131257, 1155, 1117, 850, 734, 701.
Methyl 3-oxo-3-(phenylamino)propanoate (3h).27 To a solution of methyl 3-chloro-3-oxopropanoate (0.5 mL, 4.52 mmol) in dry
CH2Cl2 (30 mL) at 0 °C under N2 was added aniline (0.41 mL, 4.52 mmol) after which a suspension resulted. Et3N (0.73 mL, 5.2
mmol) was then added and after initial white fumes were observed, a clear yellow solution formed. The reaction was stirred at 0 °C
for 2 h under N2. The reaction mixture was concentrated under reduced pressure, diluted in EtOAc and then sequentially washed
with 1M HCl solution, sat. NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated under reduced
pressure, and the residue purified by FC (n-hexane:EtOAc 4:1 → 3:2) to afford α-amido-ester 3h as a yellow semi-solid (865 mg,
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99 %). H NMR (CDCl3, 400 MHz): δ 9.16 (br s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 7.8 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H),
3.81 (s, 3H), 3.49 (s, 2H). 13C NMR (CDCl3, 101 MHz): δ 170.5, 162.7, 137.4, 129.0, 124.6, 120.1, 52.7, 41.3.
Methyl 2-(methyl(phenyl)carbamoyl)acrylate (4a). To a solution of methyl 3-(methyl(phenyl)amino)-3-oxopropanoate (3a, 150 mg,
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0.752 mmol), p-formaldehyde (65 mg, 2.17 mmol) and CF3COONH2 Pr2 salt (156 mg, 0.72 mmol) in dry THF (7 mL) was added
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TFA (6 µL, 0.07 mmol). The reaction mixture was then heated at 60 °C under N2 for 18 h. The reaction mixture was diluted with
EtOAc and washed with sat. NH4Cl solution (× 2), brine and dried over MgSO4. The solvent was evaporated under reduced
pressure, and the residue purified by FC (n-hexane:EtOAc 1:1) to give α-amido-acrylate 4a as a pale yellow oil (115 mg, 73%). 1H
NMR (CDCl3, 400 MHz): δ 7.33 (t, J = 7.5 Hz, 2H), 7.30 – 7.20 (m, 1H), 7.13 (d, J = 7.7 Hz, 2H), 6.21 (s, 1H), 5.85 (s, 1H), 3.60
(s, 3H), 3.40 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 166.4, 164.3, 143.3, 138.6, 130.3, 129.4, 127.6, 127.2, 52.1, 37.3. IR (neat): ν
= 1725, 1648, 1595, 1496, 1435, 1377, 1264, 1201, 1160, 1112, 772, 699. HRMS (ES): m/z calcd. for C12H14NO3 220.0974
[M+H]+, found 220.0968.
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Methyl 2-(diethylcarbamoyl)acrylate (4b). To a solution of methyl 3-(diethylamino)-3-oxopropanoate (3b, 400 mg, 2.31 mmol), p-
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formaldehyde (208 mg, 6.93 mmol) and CF3COONH2 Pr2 salt (497 mg, 2.31 mmol) in dry THF (20 mL) was added TFA (18 µL,
0.23 mmol). The reaction mixture was then heated at 60 °C under N2 for 18 h. The reaction mixture was diluted with EtOAc and
washed with sat. NH4Cl solution (× 2), brine and dried over MgSO4. The solvent was evaporated under reduced pressure, and the
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residue purified by FC (EtOAc:n-hexane 3:2 → 4:1) to give α-amido-acrylate 4b as a pale yellow oil (248 mg, 58%). H NMR
(CDCl3, 400 MHz): δ 6.41 (d, J = 0.8 Hz, 1H), 5.83 (d, J = 0.8 Hz, 1H), 3.79 (s, 3H), 3.46 (q, J = 7.1 Hz, 2H), 3.23 (q, J = 7.2 Hz,
2H), 1.18 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 166.3, 164.4, 138.4, 127.8, 52.5, 42.9, 39.0,
13.8, 12.6. IR (neat): ν = 1723, 1618, 1486, 1460, 1440, 1326, 1264, 1201, 1173, 1122. HRMS (ES): m/z calcd. for C12H14NO3
220.0974 [M+H]+, found 220.0968.
Methyl 2-(diphenylcarbamoyl)acrylate (4c). To a solution of methyl 3-(diphenylamino)-3-oxopropanoate (3c, 800 mg, 2.97 mmol),
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p-formaldehyde (268 mg, 8.91 mmol) and CF3COONH2 Pr2 salt (640 mg, 2.97 mmol) in dry THF (20 mL) was added TFA (23 µL,
0.29 mmol). The reaction mixture was heated at 60 °C under N2 for 20 h. The reaction mixture was then concentrated under
reduced pressure and the resulting residue purified by FC (Et2O:n-hexane 7:3) to give α-amido-acrylate 4c as a pale yellow oil (780
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mg, 93%). H NMR (CDCl3, 400 MHz): δ 7.44 – 7.06 (m, 10H), 6.31 (s, 1H), 6.09 (s, 1H), 3.60 (s, 3H). 13C NMR (CDCl3, 101
MHz): δ 166.2, 164.2, 142.2, 139.3, 131.2, 129.2 (br), 128.8 (br), 127.5 (br), 126.5 (br), 52.2. IR (neat): ν = 1727, 1662, 1593,
1490, 1399, 1351, 1266, 1201, 1132, 974, 760. HRMS (ES): m/z calcd. for C17H16NO3 282.1130 [M+H]+, found 282.1142.
Methyl 2-((2-isobutoxy-6-isobutylphenyl)carbamoyl)acrylate (4d). To
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isobutylphenyl)amino)-3-oxopropanoate (3d, 65 mg, 0.20 mmol), p-formaldehyde (18 mg, 0.61 mmol) and CF3COONH2 Pr2 salt
(44 mg, 0.20 mmol) in dry THF (2 mL) was added TFA (2 µL, 0.02 mmol). The reaction mixture was heated at 60 °C under N2 for
18 h. The reaction mixture was then concentrated under reduced pressure and the resulting residue purified by FC (Et2O:n-hexane
1:1) to give α-amido-acrylate 4d a coloulress oil (33 mg, 50%), which was used immediately in the next step. 1H NMR (CDCl3, 400
MHz): δ 9.57 (s, 1H), 7.21 (d, J = 1.6 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 6.83 (d, J = 1.6 Hz, 1H), 6.80 (dd, J = 7.8, 1.3 Hz, 1H), 6.75
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(dd, J = 8.2, 1.3 Hz, 1H), 3.89 (s, 3H), 3.71 (d, J = 6.3 Hz, 2H), 2.48 (d, J = 7.2 Hz, 2H), 2.04 (dh, J = 13.2, 6.5 Hz, 1H), 1.85 (dh, J
= 13.6, 6.8 Hz, 1H), 0.97 (d, J = 6.7 Hz, 6H), 0.87 (d, J = 6.6 Hz, 6H). 13C NMR (CDCl3, 101 MHz): δ 166.9, 160.7, 154.1, 140.0,
138.7, 132.8, 127.4, 124.2, 122.1, 109.7, 74.6, 52.7, 41.3, 29.3, 28.4, 22.6, 19.2. IR (neat): ν = 3310, 2953, 2868, 1745, 1733, 1666,
1581, 1516, 1508, 1460, 1266, 1053, 776, 734. HRMS (ES): m/z calcd. for C19H28NO4 334.2018 [M+H]+, found 334.2028.
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Methyl 2-((2,6-diisopropylphenyl)carbamoyl)acrylate (4e). To a solution of methyl 3-((2,6-diisopropylphenyl)amino)-3-
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oxopropanoate (3e, 800 mg, 2.88 mmol), p-formaldehyde (260 mg, 8.65 mmol) and CF3COONH2 Pr2 salt (620 mg, 2.88 mmol) in
dry THF (20 mL) was added TFA (23 µL, 0.29 mmol). The reaction mixture was then heated at 60 °C under N2 for 16 h. The
reaction mixture was then concentrated under reduced pressure and the resulting residue purified by FC (n-hexane:Et2O 7:3 → 3:7)
to give α-amido-acrylate 4e as an off-white fluffy solid (505 mg, 61%). MP = 97 – 98 °C. 1H NMR (CDCl3, 400 MHz): δ 9.66 (s,
1H), 7.33 – 7.26 (m, 2H), 7.23 – 7.17 (m, 2H), 6.90 (d, J = 1.8 Hz, 1H), 3.92 (s, 3H), 3.05 (hept, J = 6.9 Hz, 2H), 1.20 [d, J = 6.9
Hz, 12H). 13C NMR (CDCl3, 101 MHz): δ 167.2, 161.3, 145.8, 139.7, 132.3, 131.2, 128.2, 123.4, 52.8, 28.9, 23.6. IR (neat): ν =
3235, 2966, 1751, 1648, 1529, 1437, 1338, 1255, 1214, 1155, 745, 709. HRMS (ES): m/z calcd. for C17H24NO3 290.1756 [M+H]+,
found 290.1758.
tert-Butyl 2-(diethylcarbamoyl)acrylate (4f). To a solution of the tert-butyl 3-(diethylamino)-3-oxopropanoate (3f, 1.2 g, 5.58
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mmol), p-formaldehyde (503 mg, 16.7 mmol) and CF3COONH2 Pr2 salt (1.2 g, 5.58 mmol) in dry THF (28 mL) was added TFA
(43 µL, 0.56 mmol). The reaction mixture was heated at 60 °C under N2 for 16 h. The reaction mixture was then concentrated under
reduced pressure and the resulting residue purified by FC (n-hexane:Et2O 3:2) to give α-amido-acrylate 4f as a yellow oil (558 mg,
44%). 1H NMR (CDCl3, 400 MHz): δ 6.31 (d, 1H, J = 0.8 Hz), 5.76 (d, 1H, J = 0.8 Hz), 3.45 (q, J = 7.2 Hz, 2H), 3.21 (q, J = 7.1
Hz, 2H), 1.49 (s, 9H), 1.17 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 166.7, 162.9, 140.3, 126.7,
82.1, 42.6, 38.7, 28.0, 13.9, 12.4. IR (neat): ν = 2977, 2931, 1722, 1640, 1460, 1368, 1258, 1158, 1118, 851. HRMS (ES): m/z
calcd. for C12H22NO3 228.1600 [M+H]+, found 228.1602.
tert-Butyl 2-(methyl(phenyl)carbamoyl)acrylate (4g). To a solution of tert-butyl 3-(methyl(phenyl)amino)-3-oxopropanoate (3g,
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1.29 g, 5.98 mmol), p-formaldehyde (540 mg, 17.95 mmol) and CF3COONH2 Pr2 salt (1.29 g, 5.58 mmol) in dry THF (30 mL) was
added TFA (46 µL, 0.56 mmol). The reaction mixture was heated at 60 °C under N2 for 40 h. The reaction mixture was then
concentrated under reduced pressure and the resulting residue purified by FC (n-hexane:Et2O 4:1 → 3:2) to give α-amido-acrylate
4g as a yellow oil (873 mg, 56%). 1H NMR (CDCl3, 400 MHz): δ 7.36 – 7.13 (m, 5H), 6.14 (s, 1H), 5.83 (s, 1H), 3.39 (s, 3H), 1.32
(s, 9H). 13C NMR (CDCl3, 101 MHz): δ 162.6, 143.4, 140.7, 129.2, 129.2, 127.2, 127.2, 81.8, 37.2, 27.9, 27.8. IR (neat): ν = 2976,
1715, 1650, 1595, 1496, 1394, 1368, 1272, 1257, 1149, 1110, 849, 768, 699. HRMS (ES): m/z calcd. for C15H20NO3 262.1443
[M+H]+, found 262.1447.
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Methyl 3-methyl-2-(phenylcarbamoyl)but-2-enoate (4h). A solution of methyl 3-oxo-3-(phenylamino)propanoate (150 mg, 0.77
mmol) in CH2Cl2 (4 mL) in a round bottom flask was cooled to 0 °C in an ice bath. To the cooled solution, was added TiCl4 by
syringe (1M solution in CH2Cl2, 0.85 mL, 0.85 mmol) drop-wise over 10 mins. The resulting mixture was stirred with cooling for
30 mins at 0 °C, after which acetone (0.063 mL, 0.85 mmol) was added. The reaction mixture was stirred for 10 mins at 0 °C before
drop-wise addition of anhydrous pyridine (0.13 mL, 1.55 mmol) (caution: very exothermic). The reaction was allowed to warm
gradually to RT overnight and then poured over ice and extracted with EtOAc (× 3). The organic solution was then washed with
brine, dried over MgSO4 and concentrated to dryness. The crude residue was purified by FC (n-hexane:EtOAc 4:1 → 3:2) to give
the tetra-substituted alkene 4h as a white solid (137 mg, 76%). MP = 137 – 142 °C. 1H NMR (CDCl3, 400 MHz): δ 7.73 (br s, 1H),
7.58 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 3.78 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H). 13C NMR (CDCl3,
101 MHz): δ 166.1, 164.6, 155.1, 137.8, 129.1, 127.0, 124.5, 119.9, 52.0, 24.1, 22.6. IR (neat): ν = 3240, 1715, 1652, 1547, 1444,
1331, 1258, 1217, 1062, 762. HRMS (ES): m/z calcd. for C13H16NO3 234.1130 [M+H]+, found 234.1127.
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General procedure for DA reactions between α-amido acrylates and N-Cbz-1,2-dihydropyridine (GP1): N-Cbz-1,2-dihydropyridine
(1.5-2.5 eq.) and α-amido acrylate (1 eq.) were transferred to a Biotage® microwave vial containing a Teflon-coated magnetic stirrer
bar which was subsequently thoroughly purged with Ar prior to sealing. The reaction was then heated at 100 °C until consumption
of the dienophile was observed by TLC analysis. The reaction mixture was directly loaded onto a Si gel column and purified by FC
to afford the DA adducts.
2-Benzyl 6-methyl (1R*,4S*,6S*)-6-((2-isobutoxy-6-isobutylphenyl)carbamoyl)-5-(4-methoxyphenethyl)-2-azabicyclo[2.2.2]oct-7-
ene-2,6-dicarboxylate (2). According to GP1, N-Cbz-1,2-dihydropyridine (133 mg, 0.62 mmol) and methyl 2-((2-isobutoxy-6-
isobutylphenyl)carbamoyl)-5-(4-methoxyphenyl)pent-2-enoate (1, 145 mg, 0.31 mmol; as a 29:71 mixture of Z:E isomers) were
heated for 4 d. FC purification (n-hexane:EtOAc 4:1 → 3:2) afforded exo-ester 2 exclusively (108 mg, 51%). MP = 39 – 40 °C. 1H
NMR & 13C NMR: complex even at 398 K due to atropisomerism – see SI. HRMS (ES): m/z calcd. for C41H51N2O7 683.3696,
found 683.3671. IR (neat): ν = 3387, 2954, 2928, 2868, 1740, 1693, 1584, 1512, 1457, 1416, 1366, 1335, 1245, 1179, 1115, 1054,
748. A single crystal X-ray structure determination was performed on this compound to confirm its structure – see SI and CIF file.
2-Benzyl 6-methyl (1R*,4R*,6R*)-6-(methyl(phenyl)carbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (endo-5a) & 2-
benzyl 6-methyl (1R*,4R*,6S*)-6-(methyl(phenyl)carbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (exo-5a). According
to GP1, N-Cbz-1,2-dihydropyridine (135 mg, 0.63 mmol) and methyl 2-(methyl(phenyl)carbamoyl)acrylate (4a, 55 mg, 0.25
mmol) were heated for 3 d. FC purification (Et2O: n-hexane 1:1 → 4:1) afforded a mixture of diastereoisomers endo-5a:exo-5a in a
62:38 ratio (74 mg, 68%). Isolated endo-5a, white solid. MP = 83-85 °C. 1H NMR (DMSO-d6, 400 MHz, 398K): δ 7.43 – 7.22 (m,
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10H), 6.39 – 6.24 (m, 2H), 5.23 (dd, J = 5.8, 1.5 Hz, 1H), 5.19 – 5.06 (AB, m, 2H), 3.42 (s, 3H), 3.33 (d, J = 9.7 Hz, 1H), 3.11 (s,
3H), 2.88 (dt, J = 9.9, 2.7 Hz, 1H), 2.84 – 2.74 (m, 2H), 1.49 (dt, J = 13.2, 2.9 Hz, 1H). 13C NMR (DMSO-d6, 101 MHz, 398K): δ
170.2, 167.1, 154.1, 142.6, 136.5, 133.4, 130.5, 128.4, 127.7, 127.6, 127.0, 126.9, 126.8, 65.5, 59.1, 51.1, 49.2, 45.2, 33.1, 29.6. IR
(neat): ν =1737, 1680, 1652, 1638, 1496, 1441, 1417, 1405, 1247, 1215, 1130, 1122, 990, 732. HRMS (ES): m/z calcd. for
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C25H27N2O5 435.1920 [M+H]+, found 435.1928. Isolated exo-5a, off-white semisolid. H NMR (DMSO-d6, 400 MHz, 378K): δ
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7.43 – 7.25 (m, 8H), 7.16 – 7.10 (m, 2H), 6.51 (ddd, J = 7.7, 5.9, 1.5 Hz, 1H), 6.33 (ddd, J = 7.8, 6.5, 1.2 Hz, 1H), 5.15 (dd, J = 6.0,
1.2 Hz, 1H), 5.08 – 4.96 (AB, m, 2H), 3.47 (s, 3H), 3.18 – 3.08 (m, 1H), 3.07 (s, 3H), 2.86 – 2.75 (m, 2H), 2.16 (d, J = 13.1 Hz,
1H), 1.62 (dt, J = 13.0, 2.7 Hz, 1H). 13C NMR (DMSO-d6, 101 MHz, 378K): δ 170.5, 168.7, 153.6, 141.7, 136.5, 132.5, 131.9,
128.5, 127.7, 127.1, 127.1, 126.8, 124.3, 65.5, 60.2, 51.5, 51.0, 44.7, 37.8, 32.9, 29.6. IR (neat): ν = 1739, 1696, 1650, 1593, 1496,
1411, 1363, 1335, 1294, 1276, 1114. HRMS (ES): m/z calcd. for C25H27N2O5 435.1920 [M+H]+, found 435.1924.
2-Benzyl 6-methyl (1R*,4R*,6R*)-6-(diethylcarbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (endo-5b) & 2-benzyl 6-
methyl (1R*,4R*,6S*)-6-(diethylcarbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (exo-5b). According to GP1, N-Cbz-
1,2-dihydropyridine (350 mg, 1.63 mmol) and methyl 2-(diethylcarbamoyl)acrylate (4b, 100 mg, 0.54 mmol) were heated for 7 d.
FC purification (n-hexane:EtOAc 4:1 → 2:3) afforded a mixture of diastereoisomers endo-5b:exo-5b in a 58:42 ratio (120 mg,
50%). Isolated endo-5b, colourless paste. 1H NMR (DMSO-d6, 400 MHz, 378K): δ 7.45 – 7.25 (m, 5H), 6.48 – 6.36 (m, 2H), 5.22
– 5.18 (m, 1H), 5.11 – 4.97 (AB, m, 2H), 3.64 (s, 3H), 3.40 – 3.09 (m, 5H), 2.91 – 2.82 (m, 2H), 1.76 (br s, 1H), 1.06 – 0.92 (m,
6H). 13C NMR (DMSO-d6, 101 MHz, 398K): δ 171.3, 166.0, 154.0, 136.7, 134.1, 130.6, 127.7, 127.0, 126.8, 65.4, 58.5, 51.6, 49.0,
45.3, 32.6, 29.8, 11.81. IR (neat): ν = 2978, 2957, 1731, 1699, 1638, 1417, 1293, 1245, 1211, 1114, 736, 699. HRMS (ES): m/z
calcd. for C22H29N2O5 401.2076 [M+H]+, found 401.2082. Exo-5b not fully separated from endo-5b, pale yellow paste.
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Distinguishable peaks only: H NMR (DMSO-d6, 400 MHz, 378K): δ 6.51 – 6.45 (m, 1H), 6.33 – 6.25 (m, 1H), 5.14 (dd, J = 6.0,
0.8 Hz, 1H), 3.52 (s, 3H), 1.45 (dt, J = 12.8, 2.7 Hz, 1H), 1.32 – 1.19 (m, 1H). Distinguishable peaks only: 13C NMR (DMSO-d6,
101 MHz, 378K): δ 171.5, 168.1, 153.7, 136.6, 132.9, 131.5, 127.7, 127.1, 65.6, 59.9, 51.8, 51.0, 30.3, 29.6, 21.3, 13.1.
2-Benzyl 6-methyl (1R*,4R*,6R*)-6-(diphenylcarbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (endo-5c) & 2-benzyl 6-
methyl (1R*,4R*,6S*)-6-(diphenylcarbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (exo-5c). According to GP1, N-Cbz-
1,2-dihydropyridine (467 mg, 2.17 mmol) and methyl 2-(diphenylcarbamoyl)acrylate (4c, 305 mg, 1.09 mmol) were heated for 6.5
h. FC purification (n-hexane:Et2O 3:2 → 3:7) afforded a mixture of diastereoisomers endo-5c:exo-5c in a 69:31 ratio (465 mg,
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86%). Isolated endo-5c, white solid. MP = 140 – 141 °C. H NMR (DMSO-d6, 500 MHz, 398K): δ 7.45 – 7.20 (m, 15H), 6.37 –
6.30 (m, 1H), 6.30 – 6.24 (m, 1H), 5.33 (d, J = 5.3 Hz, 1H), 5.23 – 5.10 (AB, app q, 2H, J = 15.5 Hz), 3.41 (s, 3H), 3.39 – 3.33 (m,
1H), 2.93 (dt, J = 9.9, 2.6 Hz, 1H), 2.88 – 2.78 (m, 2H), 1.50 – 1.43 (dt, 1H, J = 16.5, 3.5 Hz). 13C NMR (DMSO-d6, 126 MHz,
398K) δ 169.7, 167.8, 154.4, 142.3, 136.4, 133.3, 130.6, 128.3, 128.0, 127.6, 127.0, 126.8, 126.6, 65.7, 59.8, 51.1, 49.6, 45.2, 33.4,
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29.6. IR (neat): ν = 2948, 1719, 1693, 1654, 1491, 1417, 1333, 1275, 1258, 1104, 768, 752, 706. HRMS (ES): m/z calcd. for
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398K): δ 7.43 – 7.18 (m, 15H), 6.52 (ddd, J = 7.7, 5.9, 1.5 Hz, 1H), 6.39 (ddd, J = 7.9, 6.5, 1.2 Hz, 1H), 5.21 (dd, J = 5.9, 1.2 Hz,
1H), 5.03 (AB, app. q, J = 12.7 Hz, 2H), 3.51 (s, 3H), 3.10 (d, J = 10.0 Hz, 1H), 2.84 – 2.76 (m, 2H), 2.00 (dd, J = 13.2, 2.9 Hz,
1H), 1.82 (dt, J = 13.2, 2.6 Hz, 1H). 13C NMR (DMSO-d6, 101 MHz, 398K): δ 171.2, 170.0, 154.6, 142.6, 137.6, 133.3, 129.4,
129.3, 129.1, 128.7, 128.1, 128.0, 127.8, 66.6, 62.0, 52.5, 52.4, 34.1, 30.8. IR (neat): ν = 2952, 1740, 1695, 1661, 1491, 1410, 1333,
1292, 1274, 1212, 1107, 753, 693. HRMS (ES): m/z calcd. for C30H29N2O5 497.2076 [M+H]+, found 497.2069.
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2-Benzyl 6-methyl (1R*,4R*,6R*)-6-((2-isobutoxy-6-isobutylphenyl)carbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate
(endo-5d) & 2-benzyl 6-methyl (1R*,4R*,6S*)-6-((2-isobutoxy-6-isobutylphenyl)carbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-
dicarboxylate (exo-5d). According to GP1, N-Cbz-1,2-dihydropyridine (50 mg, 0.23 mmol) and methyl 2-((2-isobutoxy-6-
isobutylphenyl)carbamoyl)acrylate (4d, 30 mg, 0.09 mmol) were heated for 16 h. FC purification (n-hexane:Et2O 7:3 → 1:1)
afforded an inseparable mixture of diastereoisomers endo-5d:exo-5d in a 24:76 ratio28 (29 mg, 58%;): colourless oil. Endo-5d:exo-
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5d mixture: H NMR (DMSO-d6, 400 MHz, 398K): δ 8.18 (br s, 0.76H), 8.03 (br s, 0.24H), 7.41 – 7.23 (m, 5H), 7.19 – 7.05 (m,
1H), 6.86 – 6.72 (m, 2H), 6.54 – 6.37 (m, 2H), 5.47 – 5.36 (m, 1H), 5.18 – 5.04 (m, 2H), 3.72 – 3.59 (m, 5H), 3.35 – 3.22 (m, 1H),
3.02 – 2.90 (m, 2H), 2.82 – 2.69 (m, 1H), 2.45 – 1.95 (m, 4H), 1.92 – 1.77 (m, 1H), 1.02 – 0.95 (m, 6H), 0.84 (m, 6H). 13C NMR
(DMSO-d6, 101 MHz, 398K): δ 171.7, 170.6, 169.9, 166.9, 154.4, 153.8, 139.9, 136.5, 133.5, 131.0, 130.0, 127.5, 127.5, 126.9,
126.9, 126.6, 126.5, 126.4, 126.4, 124.4, 120.9, 109.7, 109.7, 74.3, 65.7, 65.5, 60.6, 51.7, 51.5, 49.7, 49.2, 46.9, 45.5, 31.0, 30.2,
29.9, 29.7, 29.6, 27.3, 27.2, 27.1, 27.0, 21.7, 21.6, 21.6, 18.3, 18.2. IR (neat): ν = 2955, 2932, 2876, 1736, 1699, 1585, 1499, 1459,
1414, 1248, 1112, 1055, 749, 698. HRMS (ES): m/z calcd. for C32H41N2O6 549.2965 [M+H]+, found 549.2982, ꢀ = 3.1 ppm.
Methyl (1R*,4S*,6S*)-6-((2-isobutoxy-6-isobutylphenyl)carbamoyl)-2-isobutyl-2-azabicyclo[2.2.2]octane-6-carboxylate (exo-5dx).
To a solution of a mixture of N-Cbz-alkenes endo-5d:exo-5d in a 24:76 ratio (23.8 mg, 0.043 mmol, ) in MeOH (1 mL) was added
NH3 (7N soln. in MeOH, 31 µL, 0.22 mmol), isobutyraldehyde (12 µL, 0.13 mmol) and Pd/C (10% wt., 9 mg, 0.0086 mmol) after
which the reaction mixture was subjected to a H2 atmosphere for 18 h. The reaction was concentrated to dryness and the residue
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was then purified by FC (n-hexane:Et2O 7:3) to afford the N-alkylated quinucidine exo-5dx as a yellow oil (11.3 mg, 56%). H
NMR (CDCl3, 400 MHz): δ 11.22 (s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 6.72 (dd, J = 15.6, 7.9 Hz, 2H), 3.73 (s, 3H), 3.71 – 3.62 (m,
2H), 3.29 (t, J = 2.5 Hz, 1H), 3.24 – 3.17 (m, 1H), 2.96 – 2.86 (m, 1H), 2.64 (dd, J = 11.5, 4.1 Hz, 1H), 2.49 (dd, J = 13.5, 7.0 Hz,
1H), 2.39 (dd, J = 13.4, 7.5 Hz, 1H), 2.32 – 2.24 (m, 1H), 2.18 (t, J = 11.0 Hz, 1H), 2.13 – 2.00 (m, 2H), 2.00 – 1.84 (m, 3H), 1.83
– 1.68 (m, 1H), 1.55 (d, J = 9.1 Hz, 2H), 1.40 – 1.30 (m, 1H), 1.03 (t, J = 6.6 Hz, 6H), 0.92 – 0.83 (m, 9H), 0.74 (d, J = 6.5 Hz,
3H). 13C NMR (CDCl3, 101 MHz): δ 172.8, 172.6, 154.6, 141.0, 127.0, 123.8, 122.3, 109.4, 74.6, 64.5, 57.4, 55.5, 54.2, 52.4, 41.5,
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31.8, 29.4, 28.5, 26.1, 25.8, 23.3, 22.8, 22.5, 21.3, 20.0, 19.5, 19.4, 18.1. HRMS (ES): m/z calcd. for C28H45N2O4 473.3379
[M+H]+, found 473.3398.
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2-Benzyl 6-methyl (1R*,4R*,6R*)-6-((2,6-diisopropylphenyl)carbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (endo-5e)
& 2-benzyl 6-methyl (1R*,4R*,6S*)-6-((2,6-diisopropylphenyl)carbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (exo-
5e). According to GP1, N-Cbz-1,2-dihydropyridine (349 mg, 1.62 mmol) and methyl 2-((2,6-diisopropylphenyl)carbamoyl)acrylate
(4e, 276 mg, 0.96 mmol) were heated for 2 h, after which dry toluene (0.2 mL) was added to aid solubility and the mixture heated at
100 °C for a further 30 mins. FC purification (n-hexane:Et2O 7:3 → 3:7) afforded a mixture of diastereoisomers endo-5e:exo-5e in
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a 20:80 ratio (319 mg, 66%): Isolated endo-5e, colourless paste. H NMR (DMSO-d6, 400 MHz, 398K): δ 8.64 (br s, 1H), 7.42 –
7.08 (m, 10H), 6.48 (dd, J = 4.4, 3.2 Hz, 2H), 5.50 (dd, J = 4.2, 2.9 Hz, 1H), 5.12 – 5.05 (m, 2H), 3.70 (s, 3H), 3.28 (dd, J = 10.1,
2.1 Hz, 1H), 3.07 – 2.92 (m, 4H), 2.55 (dd, J = 13.6, 2.5 Hz, 1H), 2.15 (dt, J = 13.6, 3.1 Hz, 1H), 1.10 (app. dd, J = 6.9, 5.3 Hz,
12H). 13C NMR (DMSO-d6, 101 MHz, 398K): δ 170.2, 166.8, 154.9, 145.9, 145.8, 136.2, 134.5, 131.6, 130.8, 127.6, 127.2, 126.9,
126.8, 126.6, 126.5, 125.8, 122.2, 122.1, 122.0, 65.7, 60.1, 51.5, 49.4, 46.4, 30.51, 29.7, 27.1, 22.7, 22.6. IR (neat): ν = 3371, 2961,
1731, 1695, 1682, 1506, 1496, 1456, 1417, 1334, 1249, 1203, 1120. HRMS (ES): m/z calcd. for C30H37N2O5 505.2702 [M+H]+,
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found 505.2706. Isolated exo-5e, colourless paste. H NMR (DMSO-d6, 400 MHz, 398K): δ 8.72 (br s, 1H), 7.43 – 7.29 (m, 5H),
7.26 – 7.19 (m, 1H), 7.15 – 7.07 (m, 2H), 6.58 – 6.39 (m, 2H), 5.47 (dd, J = 5.7, 1.5 Hz, 1H), 5.15 – 5.05 (AB, m, 2H), 3.62 (s, 3H),
3.34 – 3.26 (m, 1H), 3.06 – 2.97 (m, 2H), 2.97 – 2.90 (m, 2H), 2.69 (dd, J = 13.5, 2.5 Hz, 1H), 2.03 (dt, J = 13.5, 2.9 Hz, 1H), 1.11
(dd, J = 14.1, 6.9 Hz, 12H). 13C NMR (DMSO-d6, 101 MHz, 398K): δ 170.5, 167.7, 153.8, 145.9, 136.6, 133.7, 131.7, 130.9, 127.6,
126.9, 126.8, 126.6, 122.2, 122.0, 65.4, 60.7, 51.3, 49.4, 45.7, 31.1, 29.7, 26.9, 22.6, 22.5. IR (neat): ν = 3323, 2961, 1737, 1692,
1680, 1498, 1415, 1336, 1245, 1114. HRMS (ES): m/z calcd. for C30H37N2O5 505.2702 [M+H]+, found 505.2727.
2-Benzyl 6-(tert-butyl) (1R*,4R*,6R*)-6-(diethylcarbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (endo-5f) & 2-benzyl
6-(tert-butyl) (1R*,4R*,6S*)-6-(diethylcarbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (endo-5f). According to GP1,
N-Cbz-1,2-dihydropyridine (568 mg, 2.64 mmol) and tert-butyl 2-(diethylcarbamoyl)acrylate (4f, 300 mg, 1.31 mmol) were heated
for 7 days. FC purification (n-hexane:EtOAc 4:1 → 2:3) afforded a mixture of diastereoisomers endo-5f:exo-5f in a 78:22 ratio
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(219 mg, 37%): Isolated endo-5f, colourless paste. H NMR (DMSO-d6, 400 MHz, 398K): δ 7.42 – 7.24 (m, 5H), 6.44 – 6.34 (m,
2H), 5.26 – 5.12 (dd, J = 3.2, 3.6 Hz, 1H), 5.11 – 5.00 (AB, m, 2H), 3.42 – 3.14 (m, 5H), 2.89 – 2.82 (m, 2H), 2.49 – 2.44 (m, 1H),
1.82 (br d, J = 12.7 Hz, 1H), 1.40 (s, 9H), 1.06 (app. t, J = 7.0 Hz, 6H). 13C NMR (DMSO-d6, 101 MHz, 398K): δ 169.4, 166.6,
154.0, 136.7, 133.5, 130.6, 127.5, 126.8, 126.6, 81.0, 65.3, 59.3, 49.3, 45.5, 32.3, 29.9, 26.9, 11.7. IR (neat): ν = 2972, 2936, 1698,
1638, 1411, 1367, 1332, 1294, 1273, 1250, 1157, 1114, 761, 698. HRMS (ES): m/z calcd. for C25H35N2O5 443.2546 [M+H]+, found
443.2551. Exo-5f not fully separated from endo-5f, pale yellow paste. Distinguishable peaks only: 1H NMR (DMSO-d6, 400 MHz,
398K): δ 6.50 (ddd, J = 7.9, 5.9, 1.6 Hz, 1H), 6.30 – 6.24 (m, 1H), 3.15 – 3.04 (m, 2H), 2.95 (dt, J = 10.1, 2.7 Hz, 1H), 1.37 (s, 9H).
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Distinguishable peaks only: 13C NMR (DMSO-d6, 101 MHz, 398K): δ 134.0, 132.3, 130.8, 127.4, 126.8, 126.3, 65.4, 51.1, 45.1,
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2-Benzyl 6-(tert-butyl) (1R*,4R*,6R*)-6-(methyl(phenyl)carbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (endo-5g) &
2-benzyl 6-(tert-butyl) (1R*,4R*,6S*)-6-(methyl(phenyl)carbamoyl)-2-azabicyclo[2.2.2]oct-7-ene-2,6-dicarboxylate (exo-5g).
According to GP1, N-Cbz-1,2-dihydropyridine (393 mg, 1.83 mmol) and tert-butyl 2-(diethylcarbamoyl)acrylate (4g, 321 mg, 1.23
mmol) were heated for 6 days. FC purification (n-hexane:Et2O 1:1 → 3:7) afforded a mixture of diastereoiosmers endo-5g:exo-5g
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in a 94:6 ratio (280 mg, 48%): Isolated endo-5g, colourless paste. H NMR (DMSO-d6, 400 MHz, 398K): δ 7.44 – 7.13 (m, 10H),
6.44 – 6.34 (m, 2H), 5.35 – 5.28 (m, 1H), 5.15 – 5.05 (AB, m, 2H), 3.27 – 3.15 (m, 4H), 2.92 – 2.85 (m, 1H), 2.85 – 2.81 (m, 1H),
2.67 (br. d, J = 13.0 Hz, 1H), 1.63 (dt, J = 13.2, 2.9 Hz, 1H), 1.41 (s, 9H). 13C NMR (DMSO-d6, 101 MHz, 398K): δ 169.0, 167.5,
154.0, 144.0, 136.5, 133.4, 130.5, 128.2, 127.5, 126.9, 126.6, 126.5, 126.0, 81.2, 65.5, 60.0, 49.0, 45.32, 38.3, 32.5, 29.8, 27.0. IR
(neat): ν = 2976, 2936, 1694, 1600, 1495, 1443, 1413, 1367, 1272, 1251, 1153, 1110, 1085, 733, 697. HRMS (ES): m/z calcd. for
C28H33N2O5 477.2389 [M+H]+, found 477.2379. Isolated exo-5g, pale yellow paste. 1H NMR (DMSO-d6, 398K, 400 MHz): δ 7.39
– 7.26 (m, 8H), 7.19 – 7.12 (m, 2H), 6.48 (ddd, J = 7.9, 5.8, 1.5 Hz, 1H), 6.31 (ddd, J = 7.9, 6.5, 1.2 Hz, 1H), 5.25 (dd, J = 5.8, 1.2
Hz, 1H), 5.11 – 4.99 (m, 2H), 3.26 – 3.22 (m, 1H), 3.11 (s, 3H), 2.92 (dt, J = 10.1, 2.7 Hz, 1H), 2.85 – 2.80 (m, 1H), 2.41 (dd, J =
12.9, 3.0 Hz, 1H), 1.66 (dt, J = 13.0, 2.7 Hz, 1H), 1.41 (s, 9H). 13C NMR (DMSO-d6, 101 MHz, 398K): δ 168.9, 168.8, 153.8,
143.0, 136.2, 132.9, 131.5, 128.1, 127.4, 126.8, 126.6, 126.2, 125.9, 81.5, 65.4, 61.0, 51.1, 44.8, 37.0, 32.2, 29.7, 26.7. HRMS
(ES): m/z calcd. for C28H33N2O5 477.2389 [M+H]+, found 477.2386.
General procedure for DA reactions between α-amido acrylates and cyclopentadiene (GP2): Cyclopentadiene (5 eq.) and α-amido
acrylate (1 eq.) were transferred to a Biotage® microwave vial containing a Teflon-coated magnetic stirrer bar which was
subsequently thoroughly purged with Ar prior to sealing. The reaction was then heated at 80 °C until consumption of the dienophile
was observed by TLC analysis. The reaction mixture was directly loaded onto a Si gel column and purified by FC to afford the DA
adducts.
Methyl (1R*,2R*,4R*)-2-(methyl(phenyl)carbamoyl)bicycle-[2.2.1]hept-5-ene-2-carboxylate (endo-6a) & methyl (1R*,2S*,4R*)-2-
(methyl(phenyl)carbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (exo-6a). According to GP2, cyclopentadiene (0.38 mL, 4.56
mmol) and methyl 2-(methyl(phenyl)carbamoyl)acrylate (4a, 200 mg, 0.91 mmol) were heated for 5 h. FC purification (Et2O: n-
hexane 1:1 → 3:2) afforded a mixture of diastereoisomers endo-6a:exo-6a in a 80:20 ratio (222 mg, 86%): Isolated endo-6a,
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yellow solid. MP = 61-63 °C. H NMR (DMSO-d6, 373K, 400 MHz): δ 7.41 – 7.34 (m, 2H), 7.32 – 7.25 (m, 1H), 7.21 – 7.13 (m,
2H), 6.19 (dd, J = 5.6, 3.0 Hz, 1H), 5.73 (dd, J = 5.7, 2.9 Hz, 1H), 3.47 (s, 3H), 3.43 – 3.39 (m, 1H), 3.16 (s, 3H), 2.88 – 2.82 (m,
1H), 1.98 (dd, J = 12.0, 3.6 Hz, 1H), 1.71 (dd, J = 11.9, 3.0 Hz, 1H), 1.60 (dt, J = 8.5, 1.6 Hz, 1H), 1.43 – 1.37 (m, 1H). 13C NMR
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(DMSO-d6, 101 MHz, 398K): δ 170.6, 170.3, 142.6, 139.5, 131.7, 128.4, 127.7, 126.8, 58.7, 51.4, 51.1, 49.3, 41.5, 38.3, 35.8. IR
(neat): ν = 2974, 1737, 1648, 1595, 1496, 1357, 1251, 1231, 1116, 1057, 705. HRMS (ES): m/z calcd. for C17H20NO3 286.1443
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[M+H]+, found 286.1468. Exo-6a not fully separated from endo-6a, colourless oil. Distinguishable peaks only: H NMR (DMSO-
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d6, 400 MHz, 373K): δ 3.65 (s, 3H), 3.12 (s, 3H), 2.95 – 2.88 (m, 3H), 2.81 – 2.73 (m, 1H), 2.04 (dd, J = 12.0, 2.8 Hz, 1H), 1.88
(dd, J = 12.0, 3.6 Hz, 1H), 1.49 (d, J = 8.8 Hz, 1H), 1.27 – 1.21 (m, 1H). Distinguishable peaks only: 13C NMR (DMSO-d6, 101
MHz, 373K): δ 172.9, 168.1, 137.6, 134.1, 128.5, 127.5, 126.8, 60.5, 51.5, 49.9, 46.6, 40.9, 38.4, 37.2, 30.0. From trace amounts of
exo-6a isolated: HRMS (ES): m/z calcd. for C17H20NO3 286.1443 [M+H]+, found 286.1457.
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Methyl (1R*,2R*,4R*)-2-(diethylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (endo-6b)
& methyl (1R*,2S*,4R*)-2-
(diethylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (exo-6b). According to GP2, cyclopentadiene (0.23 mL, 2.8 mmol) and
methyl 2-(diethylcarbamoyl)acrylate (4b, 102 mg, 0.55 mmol) were heated for 24 h. FC purification (Et2O: n-hexane 3:2) afforded
a mixture of diastereoisomers endo-6b:exo-6b in a 78:22 ratio (62 mg, 45%). Isolated endo-6b, colourless paste. 1H NMR (DMSO-
d6, 400 MHz): δ 6.29 (dd, J = 5.6, 2.9 Hz, 1H), 5.82 (dd, J = 5.7, 2.9 Hz, 1H), 3.57 (s, 3H), 3.46 – 3.41 (m, 1H), 3.39 – 3.31 (m,
1H), 3.30 – 3.20 (m, 1H), 3.18 – 3.05 (m, 2H), 2.92 – 2.79 (m, 1H), 2.13 – 1.97 (m, 1H), 1.70 (dd, J = 11.8, 3.4 Hz, 1H), 1.42 –
1.36 (m, 2H), 0.98 (t, J = 7.0 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H). 13C NMR (DMSO-d6, 101 MHz): δ 172.7, 169.7, 140.9, 132.6, 59.1,
52.6, 51.7, 50.4, 42.2, 40.5, 36.1, 13.4, 12.6. IR (neat): ν = 2974, 2941, 1733, 1642, 1456, 1432, 1274, 1251, 1236, 1116, 1059, 711.
HRMS (ES): m/z calcd. for C14H22NO3 252.1600 [M+H]+, found 252.1594. Exo-6b not fully separated from endo-6b, colourless
oil. Distinguishable peaks only: 1H NMR (DMSO-d6, 400 MHz): δ 6.14 (dd, J = 5.6, 3.0 Hz, 1H), 6.11 – 6.03 (m, 1H), 3.66 (s, 3H),
2.35 – 2.24 (m, 1H), 1.51 (d, J = 8.6 Hz, 1H), 1.31 – 1.26 (m, 1H). Distinguishable peaks only: 13C NMR (DMSO-d6, 101 MHz,) δ
174.6, 168.3, 138.0, 135.9, 61.0, 53.0, 51.0, 47.0, 37.6, 13.7, 12.4.
Methyl (1R*,2R*,4R*)-2-(diphenylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (endo-6c) & methyl (1R*,2S*,4R*)-2-
(diphenylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (exo-6c). According to GP2, cyclopentadiene (0.30 mL, 3.56 mmol)
and methyl 2-(diphenylcarbamoyl)acrylate (4c, 200 mg, 0.71 mmol) were heated for 80 mins. FC purification (n-hexane:Et2O 7:3
→ 3:7) afforded a mixture of diastereoisomers endo-6c:exo-6c in a 70:30 ratio (221 mg, 90%). Isolated endo-6c, colourless paste.
1H NMR (DMSO-d6, 400 MHz): δ 7.46 – 7.16 (m, 10H), 6.16 (dd, J = 5.6, 2.9 Hz, 1H), 5.68 (dd, J = 5.7, 2.9 Hz, 1H), 3.43 (s, 3H),
3.39 – 3.36 (m, 1H), 2.90 – 2.78 (m, 1H), 2.18 (dd, J = 12.0, 3.6 Hz, 1H), 1.64 (d, J = 8.3 Hz, 1H), 1.47 (dd, J = 11.9, 2.8 Hz, 1H),
1.43 – 1.37 (m, 1H). 13C NMR (DMSO-d6, 101 MHz): δ 171.7, 171.0, 140.7, 132.5, 129.5, 127.9, 59.7, 52.8, 52.4, 50.5, 42.59,
37.1. IR (neat): ν = 2980, 2948, 1743, 1714, 1663, 1491, 1333, 1298, 1273, 1255, 1232, 1154, 1116, 756, 700. HRMS (ES): m/z
calcd. for C22H22NO3 348.1600 [M+H]+, found 348.1606. Exo-6c not fully separated from endo-6c, colourless paste.
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Distinguishable peaks only: H NMR (DMSO-d6, 400 MHz): δ 6.36 (dd, J = 5.6, 2.8 Hz, 1H), 6.27 (dd, J = 5.6, 2.9 Hz, 1H), 3.69
(s, 3H), 2.80 – 2.70 (m, 2H), 1.72 (dd, J = 12.1, 3.5 Hz, 1H). Distinguishable peaks only: 13C NMR (DMSO-d6, 101 MHz): δ 173.8,
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169.2, 139.3, 134.5, 61.7, 52.9, 48.2, 41.8, 38.6. From trace amounts of exo-6c isolated: HRMS (ES): m/z calcd. for C22H22NO3
348.1600 [M+H]+, found 348.1591.
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Methyl (1R*,2R*,4R*)-2-((2-isobutoxy-6-isobutylphenyl)carb-amoyl)bicycle[2.2.1]hept-5-ene-2-carboxylate (endo-6d) & methyl
(1R*,2S*,4R*)-2-((2-isobutoxy-6-isobutylphenyl)-carbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (exo-6d). According to GP2,
cyclopentadiene (0.10 mL, 1.19 mmol) and methyl 2-((2-isobutoxy-6-isobutylphenyl)carbamoyl)acrylate (4d, 30 mg, 0.09 mmol)
were heated for 14 h. FC purification (n-hexane:Et2O 9:1 → 4:1) afforded a mixture of diastereoisomers endo-6d:exo-6d in a 84:16
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ratio (28 mg, 58%). Isolated endo-6d, white solid. MP = 62.0 °C. H NMR (DMSO-d6, 400 MHz): δ 8.76 (s, 1H), 7.14 (t, J = 7.9
Hz, 1H), 6.82 (dd, J = 8.3, 1.2 Hz, 1H), 6.73 (dd, J = 7.7, 1.2 Hz, 1H), 6.29 (dd, J = 5.6, 2.9 Hz, 1H), 5.99 (dd, J = 5.6, 2.8 Hz, 1H),
3.65 (d, J = 6.4 Hz, 2H), 3.62 (s, 3H), 3.59 – 3.54 (m, 1H), 2.93 – 2.81 (m, 1H), 2.36 (dd, J = 12.3, 3.7 Hz, 1H), 2.33 – 2.23 (m,
2H), 2.00 – 1.86 (m, 2H), 1.82 – 1.68 (m, 1H), 1.50 (d, J = 8.4 Hz, 1H), 1.46 – 1.38 (m, 1H), 0.95 (dd, J = 6.6, 2.2 Hz, 6H), 0.80
(dd, J = 6.5, 3.9 Hz, 6H). 13C NMR (DMSO-d6, 101 MHz): δ 172.3, 169.3, 155.4, 141.0, 140.4, 133.9, 127.7, 125.2, 122.1, 110.0,
74.4, 62.0, 52.6, 49.5, 48.9, 28.6, 28.4, 23.0, 22.9, 19.5. IR (neat): ν = 3364, 2955, 2928, 2868, 1732, 1762, 1586, 1498, 1461, 1276,
1260, 1054, 750. HRMS (ES): m/z calcd. for C24H34NO4 400.2488 [M+H]+, found 400.2477. Isolated exo-6d, white solid. MP =
100.3 °C. 1H NMR (DMSO-d6, 400 MHz): δ 8.65 (s, 1H), 7.12 (t, J = 7.9 Hz, 1H), 6.79 (dd, J = 8.5, 1.2 Hz, 1H), 6.76 – 6.69 (m,
1H), 6.27 – 6.09 (m, 2H), 3.70 (s, 3H), 3.68 – 3.58 (m, 3H), 2.85 (s, 1H), 2.28 – 2.21 (m, 2H), 2.17 (dd, J = 12.5, 3.5 Hz, 1H), 2.05
– 1.91 (m, 2H), 1.87 – 1.70 (m, 1H), 1.47 – 1.37 (m, 2H), 0.96 (dd, J = 9.0, 6.6 Hz, 6H), 0.79 (dd, J = 6.4, 1.8 Hz, 6H). 13C NMR
(DMSO-d6, 101 MHz): δ 173.7, 167.9, 155.3, 141.0, 139.1, 134.6, 127.5, 125.2, 121.9, 110.0, 74.6, 62.2, 52.9, 49.3, 48.9, 41.9,
35.7, 28.3, 28.2, 23.0, 19.7. IR (neat): ν = 3332, 2955, 2928, 2868, 1733, 1704, 1500, 1462, 1276, 1261, 1056, 750. HRMS (ES):
m/z calcd. for C24H34NO4 400.2488 [M+H]+, found 400.2497.
Methyl (1R*,2R*,4R*)-2-((2,6-diisopropylphenyl)carbamoyl)-bicycle[2.2.1]hept-5-ene-2-carboxylate (endo-6e)
&
methyl
(1R*,2S*,4R*)-2-((2,6-diisopropylphenyl)carbamoyl)bicyclo[2.2.1]-hept-5-ene-2-carboxylate (exo-6e). According to GP2,
cyclopentadiene (0.20 mL, 2.40 mmol) and methyl 2-((2,6-diisopropylphenyl)carbamoyl)acrylate (4e, 139 mg, 0.48 mmol) were
heated for 2 h, after which dry toluene (0.2 mL) was added to aid solubility and the mixture heated at 80 °C for a further 30 mins.
FC purification (n-hexane:Et2O 4:1 → 3:2) afforded a mixture of diastereoisomers endo-6e:exo-6e in a 76:24 ratio (153 mg, 90%).
Isolated endo-6e, white powder. MP = 140 - 142 °C. 1H NMR (DMSO-d6, 400 MHz): δ 9.20 (s, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.17
– 7.09 (m, 2H), 6.31 (dd, J = 5.7, 2.9 Hz, 1H), 6.02 (dd, J = 5.8, 2.9 Hz, 1H), 3.71 – 3.56 (m, 4H), 3.05 – 2.86 (m, 3H), 2.32 (dd, J
= 12.3, 3.6 Hz, 1H), 1.94 (dd, J = 12.2, 2.7 Hz, 1H), 1.52 – 1.42 (m, 1H), 1.43 – 1.33 (m, 1H), 1.24 – 0.94 (m, 12H). 13C NMR
(DMSO-d6, 101 MHz): δ 172.2, 169.9, 146.6, 140.3, 133.8, 133.1, 128.1, 123.2, 62.1, 52.5, 49.3, 49.0, 35.8, 28.3, 28.3, 23.9, 23.8,
23.7. IR (neat): ν = 3311, 2960, 2932, 2868, 1743, 1644, 1501, 1236, 1157, 735. HRMS (ES): m/z calcd. for C22H30NO3 356.2226
[M+H]+, found 356.2224. Isolated exo-6e, white powder. MP = 165 °C. 1H NMR (DMSO-d6, 400 MHz): δ 9.03 (s, 1H), 7.23 (t, J
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= 7.6 Hz, 1H), 7.15 – 7.06 (m, 2H), 6.30 (dd, J = 5.7, 3.0 Hz, 1H), 6.09 (dd, J = 5.5, 2.9 Hz, 1H), 3.71 (s, 3H), 3.67 – 3.61 (m, 1H),
3.08 – 2.95 (m, 1H), 2.93 – 2.82 (m, 2H), 2.20 (dd, J = 12.5, 3.7 Hz, 1H), 2.02 (d, J = 12.3 Hz, 1H), 1.50 – 1.42 (m, 2H), 1.21 –
0.96 (m, 12H). 13C NMR (DMSO-d6, 101 MHz): δ 173.8, 168.8, 146.8, 146.7, 139.6, 134.3, 133.1, 128.0, 123.2, 62.3, 52.8, 49.2,
49.1, 41.9, 35.7, 28.0, 24.0, 23.9. IR (neat): ν = 3300, 2957, 2928, 2868, 1738, 1639, 1504, 1236, 736. HRMS (ES): m/z calcd. for
C22H30NO3 356.2226 [M+H]+, found 356.2236.
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tert-Butyl (1R*,2R*,4R*)-2-(diethylcarbamoyl)bicycle[2.2.1]-hept-5-ene-2-carboxylate (endo-6f) & tert-butyl (1R*,2S*,4R*)-2-
(diethylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (exo-6f). According to GP2, cyclopentadiene (0.28 mL, 3.30 mmol) and
tert-butyl 2-(diethylcarbamoyl)acrylate (4f, 150 mg, 0.66 mmol) were heated for 48 h. FC purification (n-hexane:Et2O 4:1 → 2:3)
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(DMSO-d6, 400 MHz): δ 6.29 (dd, J = 5.7, 2.9 Hz, 1H), 5.85 (dd, J = 5.7, 2.9 Hz, 1H), 3.52 – 3.39 (m, 2H), 3.31 – 3.21 (m, 1H),
3.19 – 3.01 (m, 2H), 2.83 (br. s, 1H), 1.95 (dd, J = 11.6, 2.1 Hz, 1H), 1.67 (dd, J = 11.8, 3.6 Hz, 1H), 1.43 – 1.28 (m, 11H), 1.01
(dt, J = 17.9, 7.0 Hz, 6H). 13C NMR (DMSO-d6, 101 MHz): δ 171.0, 170.2, 140.6, 132.6, 81.0, 60.0, 51.85, 50.5, 42.3, 39.1, 35.6,
28.0, 13.6, 12.4. IR (neat): ν = 2976, 2948, 1718, 1635, 1458, 1423, 1367, 1280, 1257, 1139, 1116, 1100, 1052, 845, 709. HRMS
(ES): m/z calcd. for C17H28NO3 294.2069 [M+H]+, found 294.2065. Exo-6f not fully separated from endo-6f, white powder.
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Distinguishable peaks only: H NMR (DMSO-d6, 400 MHz): δ 6.16 – 6.10 (m, 1H), 6.09 – 6.02 (m, 1H). Distinguishable peaks
only: 13C NMR (DMSO-d6, 101 MHz): δ 81.4, 41.9, 37.2, 27.9, 13.9, 12.0. From trace amounts of exo-6f isolated: IR (neat): ν =
2976, 2944, 1718, 1636, 1458, 1421, 1367, 1280, 1257, 1139, 1117, 1099, 1053, 846, 709. HRMS (ES): m/z calcd. for C17H28NO3
294.2069 [M+H]+, found 294.2057.
tert-Butyl
(1R*,2R*,4R*)-2-(methyl(phenyl)carbamoyl)bicycle-[2.2.1]hept-5-ene-2-carboxylate
(endo-6g)
&
tert-butyl
(1R*,2S*,4R*)-2-(methyl(phenyl)carbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (exo-6g). According to GP2, cyclopentadiene
(0.42 mL, 4.94 mmol) and tert-butyl 2-(diethylcarbamoyl)acrylate (4g, 258 mg, 0.99 mmol) were heated for 24 h. FC purification
(n-hexane:Et2O 4:1 → 1:1) afforded a mixture of diastereoisomers endo-6g:exo-6g in a 81:19 ratio (217 mg, 67%). Isolated endo-
6g, off-white powder. MP = 132-136 °C. 1H NMR (DMSO-d6, 400 MHz): δ 7.39 (t, J = 7.7 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.24 –
7.18 (m, 2H), 6.40 – 6.20 (br. m, 1H), 5.85 (br. M, 1H), 3.44 – 3.38 (m, 1H), 3.14 (s, 3H), 2.87 (br. s, 1H), 2.09 – 1.81 (br. m, 1H),
1.50 – 1.33 (m, 11H). 13C NMR (DMSO-d6, 101 MHz) δ 171.3, 170.5, 140.6, 132.4, 129.4, 127.0, 81.3, 60.2, 52.0, 50.6, 42.6, 38.7,
35.7, 28.1. IR (neat): ν = 2976, 2932, 1731, 1660, 1494, 1366, 1257, 1154, 1115, 764. HRMS (ES): m/z calcd. for C20H26NO3
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(DMSO-d6, 400 MHz): δ 6.22 – 6.03 (m, 2H). Distinguishable peaks only: 13C NMR (DMSO-d6, 101 MHz): δ 172.8, 129.5, 81.6,
28.0. From trace amounts of exo-6g isolated: IR (neat): ν = 2981, 1721, 1658, 1494, 1367, 1247, 1154, 1075, 693. HRMS (ES): m/z
calcd. for C20H26NO3 328.1906 [M+H]+, found 328.1909.
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General procedure for DA reactions between α-amido acrylates 4e and 4f and cyclopentadiene in the presence of Et2AlCl: To a
solution of α-amido acrylate (4e or 4f, 1 eq.) in dry CH2Cl2 (0.1M) at 0 °C under Ar was added Et2AlCl (1 eq., 1M in hexane). The
reaction mixture was stirred at RT for 30 mins before cooling back down to 0 °C and adding cyclopentadiene (10 eq.), after which
the reaction mixture was stirred at RT until consumption of the dienophile was observed by TLC analysis. The reaction mixture was
then directly loaded onto a Si gel column and purified by FC to afford the DA adducts.
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General procedure for DA reactions between α-amido acrylates 4e and 4f and cyclopentadiene in the presence of B(C6F5)3: To a
solution B(C6F5)3 (1 eq.) and 4Å MS in dry CH2Cl2 at RT under Ar was added a solution of α-amido acrylate (4e or 4f, 1 eq.) in dry
CH2Cl2 (0.1M). The reaction mixture was stirred at RT for 30 mins before cooling back down to 0 °C and adding cyclopentadiene
(10 eq.), after which the reaction mixture was stirred at RT until consumption of the dienophile was observed by TLC analysis. The
reaction mixture was then directly loaded onto a Si gel column and purified by FC to afford the DA adducts.
General procedure for DA reactions between α-amido acrylates 4e and 4f and cyclopentadiene in the presence of TBSOTf: To a
solution of α-amido acrylate (4e or 4f, 1 eq.) in dry CH2Cl2 (0.1M) at 0 °C under Ar was added freshly distilled TBSOTf (1 eq.).
The reaction mixture was stirred at RT for 30 mins before cooling back down to 0 °C and adding cyclopentadiene (10 eq.), after
which the reaction mixture was stirred until consumption of the dienophile was observed by TLC analysis. The reaction mixture
was then directly loaded onto a Si gel column and purified by FC to afford the DA adducts.
SUPPORTING INFORMATION
1H and 13C NMR for all new compounds and the CIF file and crystallographic details for compound 2 can be found in the SI files.
REFERENCES
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Pergamon: New York, 1991; Vol. 5, pp 315−401. (b) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007. (c) Abele, S.; Funel, J-Alexix. Angew. Chem.,
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(11) In our hands tri-substituted dienophiles were found to isomerize at room temperature within a few hours of isolation.
(12) Initial control experiments with 1,3-cyclohexadiene revealed this did not react efficiently with some of the α-amido acrylates (e.g. dienophile 4a).
(13) Bugarin, A.; Jones, K. D.; Connell, B. T. Chem. Commun. 2010, 46, 1715–1717.
(14) In our hands, treatment of N-Cbz- and N-carboxyphenyl-1,2-dihydropyridines with various Lewis acids resulted in rapid formation of a complex
mixture of products, as evidenced by 1H NMR; cf. ref. 3b, but see also: Rawal, V, H.; Huang, Y.; Takenaka, N. Tetrahedron, 2002, 58, 8299-8305.
(15) The stereochemical outcomes for D-A reactions between dihydopyridines and acrolein, methyl acrylate and methyl vinyl ketone have been shown to be
of kinetic origin – see ref 3a.
(16) Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 1731-1733.
(17) Salvatella, L.; Mayoral, J, A.; Garcia, J, I. Acc. Chem. Res. 2000, 33, 658-664.
(18) M. Santelli, J. M. Pons, Lewis Acids and Selectivity in Organic Synthesis, CRC, Boca Raton, FL, 1995, pp. 267-328.
(19) Zhou, J.-H.; Jiang, B.; Meng, F.-F.; Xu, Y.-H.; Loh, T.-P. Org. Lett. 2015, 17, 4432–4435.
(20) Mathieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219–8226.
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(22) Bisai, A.; Adhikary, A.; Bhunia, S.; Kakde, B. N.; De, S.; Ghoush, S. Org. Lett. 2012, 14, 5864-5867.
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(24) Masaki, N.; Quentin, L.; Rueping, M. Chem. Commun. 2014. 50, 3619-3622.
(25) Bayly, A. R. Design and Synthesis of New Modulators of Liver Receptor Homologue – 1. Ph.D. Thesis, Imperial College London 2011.
(26) M-Hyn, K.; S-Hoon, C.; Y-Ju, L.; Jihye, L.; Keepyung, N.; B-Seon, J.; H-Geun, P.; S-Sup, J. Chem. Commun. 2009, 7, 782-784.
(27) Chu, G-H.; Gu, M.; Cassel, J. A.; Belanger, S.; Graczyk, T. M.; DeHaven, R. N.; C-James, N.; Koblish, M.; Little, P. J.; D-Hudkins, D. L.; Dolle, R. E.
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(28) The major diastereoisomer in this mixture was assigned as the exo-adduct following hydrogenation/reductive amination to give compound exo-5dx
which was amenable to nOe analysis.
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