COMMUNICATIONS
purity (94% and 99% ee), high diastereomeric ratio
(93:7 and 95:5), and in good yields (65% and 56%).
On the other hand, the introduction of a benzyl group
at the α-position of 4l or a phenyl group at the ring
nitrogen of 4m turned out detrimental for the
enantioselectivity of the corresponding spiro-hetero-
cycles 7l (55% ee) and 7m (49% ee), arguably due to
steric reasons. In light of these results, other bulkier
groups were not investigated. In the case of N-
unsubstituted Δ2-pyrrolin-4-ones 5a–l (Scheme 5), on
average, higher yields with lower diastereoselectivities
of the isolated products 8 were obtained compared to
the N-Me substituted analogues 7, while still retaining
high enantioselectivity (up to >99%). Interestingly, in
this series, the ortho-hydroxy substituted heterocycle
5c gave the expected product 8c with unchanged
reactivity and only a slightly diminished ee value of
94%. The absolute configuration of the major stereo-
isomer of products 7a and 8a was determined by
single crystal X-ray analysis of the corresponding
acetoxy derivatives 10 and 9a, respectively
(Scheme 6). Consequently, the determined absolute
configuration (5S,6R,9S) of the product 10 and
(5R,6S,9R) of the product 9a was tentatively assigned
to all the major diastereomers of compounds 7a–m
and 8a–l, respectively.
Table 1. Optimization of the reaction conditions.
Entry[a] Solvent
Yield[%] dr
ee[%]
1
2
3
4
5
6
7
8
1,4-dioxane
toluene
Et2O
1,2-dimetoxyethane 85
CHCl3
EtOAc
THF
CH2Cl2
PhCF3
acetone
MeOH
MeCN
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
72
75
88
94:6
96
71
82
93
79
84
81
73
48
51
14
95:5
95:5
95:5
93:7
94:6
94:6
93:7
94:6
93:7
93:7
89:11 12
93:7 95
64:36 88
88:12 81
93:7
95:5
75
69
72
76
82
86
77
69
65
59
63
82
84
82
86
9
10
11
12
13[b]
14[c]
15[d]
16[e]
17[f]
18[f,g]
19[f,h]
92
99
90:10 99
95:5 99
Analysis of the crystal structure revealed the
pseudo-enantiomeric relationship between 7a and 8a.
According to the observed configuration and DFT
calculation studies by Grayson[24] a plausible transition
state leading to the products 7a and 8a was postulated
(Scheme 6). It is assumed that the catalyst IVb
activates the electrophile 4a or 5a through hydrogen
bonds provided by the protonated tertiary amine group.
This activation proceeds irrespectively of the config-
uration or N-substitution of the starting alkene. In a
similar manner, the mercaptoacetaldehyde nucleophile
6 is activated by the squaramide moiety through
hydrogen bonding. The nucleophilic attack/Michael
addition proceeds on the Re face of the E-alkene 4a or
[a] Pyrrol-4-one 4a (0.1 mmol), 1,4-dithiane-2,5-diol (6)
(0.07 mmol), catalyst IVb (10 mol%), solvent (1 mL),
1
°
25 C, 24 h; conversion and dr determined by H-NMR
(DMSO); ee determined by HPLC.
[b] Catalyst IVb (5 mol%).
[c] Catalyst IVb (1 mol%).
[d]
°
12 C.
[e]
°
50 C.
[f] 1,4-Dithiane-2,5-diol (6) (0.15 mmol) used.
[g] 2 h reaction time.
[h] 48 h reaction time.
electron donating and electron withdrawing substitu- on the Si face of the Z-alkene 5a. The following
ents on the phenyl ring of the arylidene moiety of the intramolecular spirocyclization/aldol reaction yields
N-substituted Δ2-pyrrolin-4-ones 4a–m was evaluated. the observed spirocyclic products 7a and 8a
The results are presented in Scheme 4. In most cases, (Scheme 6). Gratifyingly, the catalyst of choice IVb
the products were isolated with excellent enantioselec- can accommodate both the E- or the Z-configured
tivities (up to >99% ee), high diastereoselectivities arylidene-Δ2-pyrrolin-4-ones furnishing products in
(up to 91:9 dr), and typical yields between 55% and high enantioselectivity. Furthermore, the configuration
72%. Product 7b, with the dimethylamino group, was of the exocyclic C=C bond of 4 and 5 in conjunction
obtained with a slightly lower ee (89%), presumably with catalyst IVb dictates the absolute configuration of
due to the possible competing interference of the basic the spirocyclic products 7 and 8, a very simple
group with the organocatalyst (hydrogen bonding/ concept, though seldom applied in organocatalyzed
deprotonation). The reaction with the ortho-OMe transformations.
substituted Δ2-pyrrolin-4-one 4d proceeded sluggishly
The synthetic utility of the discovered transforma-
(yield <5%, t=3 days) with the undetermined enan- tions 4a!7a and 5a!8a was demonstrated by
tioselectivity, due to a complex mixture of products. performing these reactions on a gram scale. The
Heteroaryl-substituted Δ2-pyrrolin-4-ones 4j and 4k reactions proceeded smoothly, yielding products with
furnished products 7j and 7k in high enantiomeric unchanged stereoselectivity (99% ee). Alcohols 7 and
Adv. Synth. Catal. 2019, 361, 1–10
5
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