Rigidi ied Bis(sul onyl)e hylenes as E ec i e Michael Accep o s o
Asymme ic Ca alysis: Applica ion o he Enan ioselec i e Syn hesis
o Qua e na y Hydan oins
Lei e Villaescusa, Ike He nández, Lau a Azcune, Ainhoa Rudi, JoséM. Me ce o, Ai o Landa,*
Mikel Oia bide,*and Claudio Palomo*
Ci e This: J. O g. Chem. 2023, 88, 972−987
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sı Suppo ing In o ma ion
ABSTRACT: The ca aly ic, enan io- and dias e eoselec i e addi ion o
hydan oin su oga es II o “ igidi ied” inylidene bis(sul one) eagen s is
de eloped, hus o e coming he inabili y o commonly employed β-
subs i u ed inylic sul ones o eac . Adduc s a e ans o med in
enan ioen iched 5,5-disubs i u ed hydan oins h ough hyd olysis and
educ i e desul onyla ion p ocesses p o iding new s uc u es o
e en ual bioassays. Densi y unc ional heo y s udies ha a ionalize
he obse ed eac i i y and s e eoselec i i y ends a e also p o ided.
■INTRODUCTION
Hydan oins a e widesp ead he e ocyclic sca olds wi hin
biologically ac i e compounds,
1
and consequen ly, hei
chemical syn hesis has aised conside able cu en in e es .
2
In pa icula , 5,5-disubs i u ed (qua e na y) hydan oin s uc-
u al subuni s a e ound in ma ke ed d ugs
3
and p omising
clinical candida es o he ea men o pso iasis
4
as well as
selec i e and ogen ecep o modula o s.
5
Compounds possess-
ing α-qua e na y hydan oin uni s also include new po en
inhibi o s o agg ecanase ADAMTS-5 (in ol ed in ca ilage
deg ada ion du ing os eoa h i is
6
) and inhibi o s o he
decap enylphospho-β-D- ibo u anose 2-oxidase (Dp E1), use-
ul as an imycobac e ial inhibi o s.
7
Howe e , he numbe o
s e eoselec i e syn he ic app oaches o qua e na y hydan oins,
and mo e speci ically me hods in ol ing di ec and selec i e C-
unc ionaliza ion o p e o med hydan oins, is s ill sca ce.
8
Recen ly, ou labo a o y has in oduced sul u -subs i u ed
dihyd oimidazol-4-ones o gene al s uc u es Iand II as use ul
hydan oin su oga es amenable o base-p omo ed C−H
unc ionaliza ion (Figu e 1a). Mo e speci ically, in he p esence
o a chi al B øns ed base/H-bonding (BB/HB) bi unc ional
ca alys , hey can eac smoo hly wi h ac i e elec ophiles, o
example, ni oole ins, enones, and aldehydes, a o ding he α-
addi ion adduc s in high yields and e y high enan ioselec i i y
o mos cases. The esul ing adduc s may deli e he
co esponding 5,5-disubs i u ed hydan oins o ela ed α-
modi ied α-amino acid de i a i es wi h p ese ed con igu a ion
ia hyd oly ic p o ocols.
9
In o de o expand his echnology on o a b oade ange o
α,α-disubs i u ed hydan oins and α-amino acid de i a i es, we
en isioned inyl sul ones as an a ac i e ca ego y o
Recei ed: Oc obe 6, 2022
Published: Janua y 11, 2023
Figu e 1. Enan ioselec i e syn hesis o qua e na y hydan oins om
empla es I/II and he new ex ension using sul onyl elec ophiles.
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elec ophilic eac ion pa ne s. Sul ones a e ecognized as
e sa ile in e media es in syn hesis.
10,11
Fo ins ance, hey may
be ans o med in o he pa en alkanes h ough educ i e
desul onyla ion o be u he elabo a ed ia well-es ablished α-
ca banion chemis y. Howe e , p elimina y expe imen s using
simple sul onyl (A) and β-subs i u ed bis(sul onyl)e hylene
(B) eagen s (Figu e 1b) in conjunc ion wi h su oga es I/II
and sui able BB/HB ca alys s led o he eco e y o un eac ed
ma e ials mainly. This obse a ion is asc ibable o he ela i ely
low eac i i y o α,β-unsa u a ed sul onyl sys ems, pa icula ly
he β-subs i u ed ones ( ide in a). He e, we p esen
bis(sul onyl)e hylenes C(Figu e 2) as compe en Michael
accep o s in ca aly ic enan ioselec i e eac ions o which
common acyclic congene s Ba e no . Mo e speci ically, he
addi ion eac ion o N-acyl su oga es II o Cin he p esence
o sui able BB/HB ca alys s p oceeded smoo hly a oom
empe a u e, a o ding he Michael eac ion adduc s as
essen ially single dias e eome s in gene ally good yields and
e y high enan ioselec i i y (Figu e 1c). This inding allows us
o signi ican ly b oaden he ange o 5,5-disubs i u ed
hydan oin s uc u es a ailable in op ically pu e o m o
e en ual biological ac i i y sc eening p og ams.
Ou selec ion o Cas a po en ially mo e eac i e Michael
accep o sul onyl sys em was ou ed on p e ious inspi a ional
obse a ions om he li e a u e. On he one hand, lowe
eac i i y o acyclic e sus cyclic bis-sul onyl alkanes as
nucleophiles in iminium-media ed ca aly ic addi ion eac ions
has been epo ed by ou g oup and o he s (Figu e 2a).
12
Simila ly, he lowe Michael accep o eac i i y o (acyclic)
alkyliden malona es e sus (cyclic) alkyliden Meld um’s acids,
which co ela es wi h he lowe ca bon acidi y o malonic
es e s e sus Meld um’s acid, is well ecognized in he
li e a u e.
13
In addi ion, May has epo ed
14
ha , based on
kine ic da a, a yl-subs i u ed cyclic bis(sul ones) a e app ox-
ima ely 1 o de o magni ude mo e elec ophilic han hei
acyclic coun e pa s. Se e al a emp s o a ionalize heo e -
ically hese acidi y and eac i i y ends when compa ing
ac ylic e sus cyclic ( igidi ied) sys ems a e known.
15
Wi h
hese p eceden s in mind, we hypo hesized ha gi en he
luxional na u e o he ou C−S bonds in he acyclic bis-
sul onyl sys em B, i s low eac i i y may be asc ibed o he
un a o able ela i e o ien a ion o he S�O dipoles o one
SO2Ph g oup ela i e o he o he and he wo a yl ings
ela i e o one ano he as a esul o s e ic epulsions. In sha p
con as , he igid s uc u e o C would keep he S�O g oups
well aligned o ca alys coo dina ion while he πa yl and
ole in sys ems would s and pe ec ly coplana , ul ima ely
leading o highly o de ed and compac ansi ion s uc u es.
■RESULTS AND DISCUSSION
Assessmen o P onucleophile Reac i i y T ends
Using β-Unsubs i u ed E hylene Bis(sul one) 1a. Since
he i s o ganoca aly ic conjuga e addi ion o inyl bis-
(sul one) 1a epo ed by Mosseand Alexakis in 2005,
16
he
implemen a ion o enan ioselec i e ca aly ic C−C bond-
o ming me hods in ol ing inylic sul ones, and inylidene
bis(sul ones) in pa icula , has p og essed une enly. Reagen
1a exhibi s high eac i i y (E=−7.50 on he May scale)
14
and
has been o en employed as an elec ophilic eac ion pa ne
unde a ious ca aly ic ac i a ion app oaches. Howe e , he
s e ically mo e conges ed β-subs i u ed congene s, o example,
1b, ha e been used less o en
17
because o hei ela i ely lowe
elec ophilici y (≈1 uni lowe E alues we e epo ed)
14
and
he appea ance o e o-Knoe enagel side eac ion.
16c
In his
s udy, bo h bis(sul onyl)ole ins 1a and 1b along wi h ela ed
eagen 2displaying a igidi ied skele on we e es ed in
ca aly ic addi ions o hydan oin su oga es I/II.
The s udy was ini ia ed by e alua ing he addi ion eac ion
o a ious dihyd oimidazol-4-ones 3and 4 o bis(sul onyl)-
e hylene 1a using ep esen a i e bi unc ional BB/HB ca alys s
such as squa amide C1,Scheme 2. To ou deligh , he eac ion
o N-benzoyl dihyd oimidazol-4-one 3a in he p esence o 10
mol % C1 in dichlo ome hane as he sol en a 0 °C p oceeded
o almos comple ion wi hin 24 h o a o d p oduc 10a in 88%
ee. Su p isingly, he N-ace yl analogue 4a esul ed comple ely
un eac i e unde he same condi ions. Di e ences in ca bon
acidi y may be in oked o a ionalize his huge di e ence in he
eac i i y o N-phenyl e sus N-ace yl analogue. In a i s
es ima e, he pKa alues acco ding o G zybowski’s p edic ion
ool
18
o 3a and 4a in DMSO a e 15 and 16, espec i ely. In
i s u n, he “ au ome ic” 8 eac ed o a signi ican 80%
con e sion bu p oduced essen ially a acemic ma e ial. These
esul s indica ed ha he p esen ca aly ic eac ion sys em is
qui e sensi i e in e ms o bo h eac i i y and selec i i y o
Figu e 2. Tunning Nuc/Elec eac i i y by subs a e igidi ica ion.
Scheme 1. Vinylidene Bis(sul ones) and P onucleophilic
He e ocycles Employed in This S udy
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inny s uc u al a ia ions on he subs a e he e ocycle. Fo
compa a i e pu poses, he eac ion using azlac one 9 was also
ca ied ou , which led o ull con e sion wi h he o ma ion o
adduc 13 in 58% ee. Thus, he ela i ely highe eac i i y o
azlac ones in his ype o ca aly ic addi ions
19
was co obo-
a ed.
A e his b ie subs a e sc eening, se e al o he ca alys s
C2−C6 wi h a ying s uc u e and unc ionali y we e
e alua ed o he model eac ion be ween 1a and 3a. As he
esul s in Table 1 show, ca alys C2, which has been de eloped
in ou g oup and p esen s an addi ional amide NH a ailable o
engaging in H-bonding in e ac ions,
9,20
a o ded an inc eased
98% ee (en y 2 s 1). Takemo o’s ca alys C6
21
(en y 6) and
he ela ed u ea and hiou ea ca alys s C3
22
and C4
23
(en ies
3 and 4) did also p omo e he eac ion, al hough nei he yields
no enan ioselec i i ies we e imp o ed. Finally, he u eidoa-
minal C5, which also has an addi ional NH g oup and
demons a ed highly ac i e and selec i e ca alys s o a ious
eac ions,
24
ailed o p omo e his eac ion e ec i ely (en y
5).
Wi h C2 selec ed as an op imal ca alys , he scope o he
eac ion was b ie ly explo ed. As he esul s in Scheme 3a
show, he eac ion o 1a wi h 3bea ing simple alkyl o allyl
subs i uen s a C5 p oceeded sa is ac o ily gi ing ise o
p oduc s 10b−ein ee’s in be ween 93 and 98% and gene ally
high yields (adduc 10b was an excep ion). The eac ions
leading o adduc s 10 and 10g also wo ked well, a o ding he
espec i e p oduc in 91%/98% yield and 92%/96% ee, hus
showing ha subs a es bea ing hioe he and es e unc ions
a e well ole a ed. Howe e , as da a in Scheme 3b show,
phenyl-subs i u ed bis(sul onyl)e hene 1b was no eac i e
enough, and only ma ginal con e sion was a ained a e
p olonged ime a oom empe a u e.
Ca aly ic Addi ion Reac ions Using Rigidi ied β-
Subs i u ed E hylene Bis(sul one) 2. P omp ed by his
esul , ou a en ion u ned o he igidi ied eagen s C.
P epa a ion o 2-benzylidene-2H-benzo[d][1,3]di hiole
1,1,3,3- e aoxides 2a and 2b in one s ep om benzodi hiole
e oxide was epo ed by May in 75 and 77% yields,
espec i ely. Following a sligh ly modi ied h ee-s ep sequence
om comme cially a ailable o-benzenedi hiol (Scheme 1), he
emaining compounds 2c− we e ob ained in an o e all 31−
53% yield.
25
Wi h eagen 2a a hand, i s beha io as a Michael
accep o in he abo e ca aly ic eac ions was in es iga ed
(Scheme 4). G a i yingly, he eac ion o 2a wi h 3a in he
p esence o 10 mol % C1 p oceeded o almos comple ion a e
Scheme 2. E alua ion as Se e al P onucleophiles agains he
Ca aly ic Addi ion Reac ion o Bis(sul one) 1a
Table 1. Ca alys Sc eening o he Addi ion o 1a o 3a
En y Ca alys Time (h)
a
Con . (%)
b
ee (%)
c
1C1 24 95 88
2C2 24 75 98
4C3 48 82 75
5C4 48 68 67
6C5 24 63 29
7C6 24 88 18
a
Reac ion condi ions: 3a (0.1 mmol), 1a (0.12 mmol), and ca alys
(10 mol %) in CH2Cl2(1.0 mL).
b
Con e sion de e mined by 1H
NMR.
c
ee de e mined by HPLC.
Scheme 3. (a) Scope o He e ocycles 3 Sui able o he
Ca aly ic Addi ion o 1a and (b) he A enua ed Reac i i y
o Accep o 1b
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24 h a 0 °C, om which 60% o adduc 15aa o 91% ee could
be isola ed. Once again, ca alys C2 impa ed almos pe ec
s e eoinduc ion p o iding a single enan iome o 15aa in 79%
yield a e 48 h a he same empe a u e. The N-acyl analogues
4−6and he “ au ome ic” dihyd oimidazol-4-one 8 we e less
e icien p onucleophiles agains he new eagen 2a (Scheme
4). No su p isingly, he N-benzyl analogue 7a was also o ally
un eac i e unde he p esen ca aly ic condi ions.
Encou aged by he good eac i i y p o ile showed by eagen
2a, he emaining analogues 2b−2 we e also e alua ed in
combina ion wi h a a ie y o p onucleophiles 3(Table 2). In
he i s se o eac ions in he p esence o C2,2a was
submi ed o he eac ion wi h alkyl- and allyl-subs i u ed
dihyd oimidazolones 3c,3d, and 3e which led o he
co esponding adduc s 15ca,15da, and 15ea as single
dias e eome in high yields and enan ioselec i i ies o 96, 92,
and 95%, espec i ely. The hioe he - and me hyl es e -bea ing
subs a es 3 and 3g also led o he addi ion o adduc s 15 a
and 15ga in high yield and dias e eoselec i i y, al hough he
la e was ob ained wi h sligh ly diminished enan ioselec i i y
unless eac ion empe a u e was dec eased o −20 °C. The
eac ion o unsa u a ed es e -bea ing 3h o a o d 15ha
p oceeded exceedingly (91% ee), demons a ing ha he
p esen ca aly ic conjuga e addi ion eac ions may p oceed
chemoselec i ely in he p esence o addi ional Michael
accep o uni s in he subs a e. Then, se e al a yl-subs i u ed
accep o s 2we e sc eened. p-Me hoxyphenyl-subs i u ed
accep o 2b was equally compe en o gi e ise o 15ab in a
highly selec i e manne . Simila ly, he p-chlo ophenyl-sub-
s i u ed analogue 2c eac ed o comple ion wi hin 2 days
ega dless o he empe a u e wi h he dihyd oimidazolones 3a,
3b, and 3e, a o ding p oduc s 15ac,15bc, and 15ec in good
yields and excellen enan iocon ol. The eac ions wi h 1-
naph hyl and 2-naph hyl-bea ing inyl sul ones 2g and 2h did
also wo k sa is ac o ily o p oduce compounds 15ge and 15ah
in good yields and high s e eoselec i i y. In e es ingly, 15ah
p esen ed spli signals in 1H NMR, which we e assigned o he
exis ence o o ame ic isome s. Tha is why his compound was
cha ac e ized as he co esponding hydan oin de i a i e a e
hyd oly ically emo ing bo h he N-benzoyl and benzyl hio
g oups (see he Suppo ing In o ma ion o de ails). On he
o he hand, bis(sul ones) 2d− , bea ing a he e oa yl β-
subs i uen , we e also ole a ed. The u yl and py idyl
de i a i es 15ad and 15a we e ob ained in good yields and
e y high s e eoselec i i y. The hiophenyl-subs i u ed adduc s
15ae and 15ge we e isola ed wi h somewha educed yields
and, in he la e case, diminished selec i i y oo. Finally, he
me hod is applicable a a la ge scale wi hou any signi ican
a ia ion in yields o selec i i ies. Fo ins ance, in eac ions
ca ied ou a a 4 mmol scale, 2.18 g (77%) and 2.43 g (82%)
o adduc s 15aa and 15ac, espec i ely, we e ob ained in bo h
cases wi h almos pe ec enan ioselec i i y o 99% ee (see he
Suppo ing In o ma ion o de ails).
Scheme 4. Ini ial Assessmen o Reagen 2a as a Michael
Accep o in Ca alysis
Table 2. Scope o he Reac ion be ween Hydan oin
Su oga e 3 and Accep o 2 in he P esence o Ca alys C2
a
a
Reac ions conduc ed on a 0.1 mmol scale in 1 mL o CH2Cl2; mol
a io o 3/2/C2 1:1.2:0.1. Yield o isola ed p oduc a e column
ch oma og aphy. ee’s de e mined by HPLC analysis using a chi al
s a iona y phase.
b
Reac ion un a a 4 mmol scale using 5 mol % C2
as a ca alys .
c
Ob ained as a mix u e o o ame s.
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Ha ing es ablished 2as a compe en Michael accep o
eagen o he enan iocon e gen ans o ma ions in ol ing
chi al acemic p onucleophiles 3, he likelihood o he pa en
unsubs i u ed dihyd oimidazolone 21 pa icipa ing in such
enan ioselec i e ans o ma ions was assessed nex (Scheme
5). I could be an icipa ed ha a majo di icul y would be
associa ed wi h he con igu a ional in eg i y o he Cα
s e eocen e in he p oduc 22 in he p esence o he basic
ca alys . Acco dingly, eac ions we e ca ied ou in c yogenic
condi ions. As he esul s in Scheme 5 show, i was deligh ing
o obse e ha e en a −25 °C, he eac ion o 21 wi h
bis(sul one) 2a in he p esence o 10 mol % C2 p oceeded o
a o d p oduc 22a as a single dias e eome in easonably good
yield (61, 70% con .) and 95% ee. Simila ly, he eac ion wi h
p-chlo ophenyl de i a i e 2b a o ded p oduc 22b in 74%
yield and 88% ee. A his poin , i is impo an o no e ha
p oduc 22 did no epime ize du ing column ch oma og aphy
pu i ica ions on silica gel.
Then, some possibili ies o u he chemical elabo a ion o
enan ioen iched adduc s we e explo ed, pa icula ly he
hyd olysis o he he e ocyclic ing and he educ i e
elimina ion o he sul onyl moie y (Scheme 6). Fo example,
ea men o 10a wi h 6 M HCl in 1,4-dioxane a 65 °C led o
hydan oin 23 in 73% yield. Desul onyla ion
26
o 23 wi h Mg/
TMSCl/1,2-dib omoe hane in me hanol a oom empe a u e
a o ded, unexpec edly and selec i ely, he monodesul onyla-
ion p oduc 24 in 51% yield. This case o selec i e
monodesul onyla ion o a bis-sul onyla ed adduc is ele an
because he al e na i e and di ec ou e o he monosul onyl
de i a i e h ough ca aly ic addi ion o he dihyd oimidazolone
3a o phenylsul onyle hene did no wo k e en a 70 °C
o e nigh . Acidic hyd olysis a 80 °C (ba h empe a u e) o
adduc s 15aa and 15ac ga e ise o N-benzoyl hydan oins 25a
and 25b in good yields.
27
An X- ay c ys al s uc u e analysis o
25b allowed us o es ablish i s absolu e and ela i e
con igu a ions.
28
The con igu a ion o he emaining adduc s
was assigned assuming a uni o m eac ion mechanism. Double
desul onyla ion o 25a unde he abo e condi ions yielded he
5,5-disubs i u ed hydan oin 26 in 67% yield o e he wo s eps
om 15aa. On he o he hand, emo ing he N-benzoyl g oup
om 15aa could be ca ied ou by ea men wi h TFA a 40
Scheme 5. Enan io- and Dias e eoselec i e Addi ion o 5-
Unsubs i u ed Dihyd oimidazol-4-One 21 o Accep o s 2
Scheme 6. Chemical Elabo a ion o Adduc s in o Hydan oins and De i a i es The eo
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976
°C, leading o 27 in essen ially quan i a i e yield. Wi h he NH
de i a i e 27 in hand, hyd olysis led o hydan oin 32a;
al e na i ely, a ious alkyl and allyl g oups could be ins alled a
ni ogen ia s anda d N-alkyla ion p o ocols leading o 28−31
and hus o e coming he inabili y o N-alkyl dihyd oimidazol-
4-ones (e.g., 7a,Scheme 4) o pa icipa e in he abo e ca aly ic
addi ion eac ion. Submission o he N-alkyl de i a i es 28−30
o acid hyd olysis led o N-alkyl hydan oins 32b−d.
Su p isingly, hyd olysis o adduc 31 ollowed a di e gen
pa hway and a o ded bicyclic iso hiou ea 33, p obably h ough
a chlo ide anion-p omo ed S-debenzyla ion/in amolecula S-
alkyla ion cascade. De e mina ion o he enan iome ic pu i y o
p oduc 32c (98% ee) se ed o p o e ha he ull sequence,
including N-dep o ec ion, N-alkyla ion, and inal hyd olysis,
p oceeded wi h p ese ed s e eochemis y.
Theo e ical Ra ionaliza ion o he Obse ed Reac-
i i y T ends and S e eoselec i i y. A heo e ical analysis
was unde aken in o de o unde s and (a) he huge di e ences
in eac i i y be ween he N-benzoyl he e ocycle 3and he N-
ace yl analogue 4obse ed expe imen ally and (b) he
s e eoselec i i y and sense o chi al induc ion in he abo e
ca aly ic eac ions. To asce ain whe he he highe eac i i y
o 3a e sus 4a was a ibu able, as hypo hesized abo e, o
di e ences in he ca bon acidi ies among hese wo
p onucleophiles, we i s calcula ed he pKa alues o 3a and
4a using he Jagua pKamodule
29
as implemen ed in he
Sch odinge 2021-01
30
p og am sui e. In bo h wa e and
DMSO as a sol en , he calcula ed pKao 3a is smalle han
ha o 4a, 11.56 e sus 12.51 in wa e and 19.71 e sus 21.15
in DMSO, espec i ely. These di e ences a e in ag eemen
wi h ou ini ial g oss es ima es ( ide sup a) and co ela e well
wi h he obse ed eac i i y end. Subsequen ly, he ene gy
ba ie was calcula ed o he dep o ona ion s ep o bo h 3a
and 4a by he ac ion o ca alys C2. In his s ep, a p o on om
he α-posi ion o ei he subs a e is ans e ed o he ca alys
quinuclidine ni ogen ia TS1 leading o complexes C2−H·
3aenola e and C2−H·4aenola e, wi h ene gy ba ie s o 13.03 and
16.95 kcal/mol, espec i ely (Figu e 3). The di e ence
Figu e 3. Ca alys − eac an complex, eac ion TS1 o he eac an dep o ona ion, and p o ona ed ca alys −enola e complex co esponding o he
p o on ans e s ep o bo h 3a and 4a. Ene gies in kcal/mol.
Figu e 4. S uc u es pa icipa ing in s eps 2 and 3 o he eac ion. In he i s ow, he ansi ion s a e TS2 o he C−C o ma ion s ep, wi h he
co esponding in e media es, and in he hi d ow, TS3 o he hi d s ep co esponding o he p o on ans e om p o ona ed C2 o he inal
p oduc 15aa.
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be ween bo h ene gy ba ie s (3.92 kcal/mol) is app eciable
and may jus i y he signi ican eac i i y di e ence obse ed
expe imen ally o bo h subs a es.
In an a emp o unde s and he s e eoselec i i y o he
eac ion, we ha e analyzed he C−C o ma ion s ep, which will
dic a e bo h he p oduc ela i e and absolu e con igu a ion.
Fou di e en ansi ion s a es we e loca ed (see Suppo ing
In o ma ion o calcula ions de ails) ha co espond o
di e en o ien a ions o eac an s, ou o which TS2 was he
lowes in ene gy (Figu e 4). In his ansi ion s a e, each
squa amide NH g oup o he ca alys in e ac s wi h he enola e
om 3a in acco dance wi h he so-called Papai model. In
compa ison, ansi ion s a e TS2-B (see Suppo ing In o ma-
ion), which would lead o he co esponding enan iome ic
p oduc , is 4.40 kcal/mol highe in ene gy. The ene gy
di e ence could be a ibu ed o he addi ional H-bond o med
be ween he p o ona ed quinuclidine moie y o he ca alys
and he enola e oxygen in TS2. The emaining wo ansi ion
s a es TS2-C and TS2-D a e 5.9 and 9.3 kcal/mol highe in
ene gy han TS2 and p esen a single H-bond in e ac ion
be ween he enola e oxygen and he ca alys (see Suppo ing
In o ma ion o de ails).
In he las s ep o he ca aly ic cycle, he p o on will be
ans e ed back om he p o ona ed ca alys o he o med
Michael adduc deli e ing p oduc 15aa ia TS3. In TS3, he
p oduc −ca alys in e ac ion in ol ing he dihyd oimidazoli-
none and he squa amide moie ies, espec i ely, changes, and
now he squa amide wo NH g oups in e ac wi h one o he
dihyd oimidazolinone ca bonyls only. This new a angemen
o he H-bonds causes his ansi ion s a e o be a ound 15
kcal/mol highe in ene gy. No e hough ha he inal p o on
ans e o he anionic eac ion adduc migh also occu ia
o he al e na i e mechanisms. Figu e 5 shows collec i ely he
a ious eac ion elemen a y s eps o he lowes in he ene gy
pa hway om eac an s 3a and 2a in he p esence o ca alys
C2.
■CONCLUSIONS
In conclusion, he ca aly ic asymme ic conjuga e addi ion o
hydan oin su oga es o inyl sul ones has been de eloped
using a seconda y amide-bea ing e ia y amine/squa amide
bi unc ional ca alys . N-Benzoyl 2-(benzyl hio)-1,5-dihyd o-
4H-imidazole-4-ones, o example, 3, a e able o ac as
hydan oin su oga es and eac wi h inyl bis(sul one) 1a
smoo hly o p o ide he co esponding adduc s in good yield
and s e eoselec i i y. In con as , he β-subs i u ed inyl
bis(sul ones), such as 1b, p o ed o be comple ely un eac i e
unde he abo e ca aly ic condi ions. This p oblem could be
ci cum en ed by employing he “ igidi ied” β-subs i u ed inyl
sul ones 2ins ead. Ul e io acid hyd olysis o he he e ocycle
sys em in adduc s combined wi h a desul onyla ion p ocess
allowed o access a a ie y o 5-subs i u ed hydan oins,
including he 5,5-disubs i u ed qua e na y ones, in essen ially
op ically pu e o m o e en ual applica ions in medicinal
chemis y. The sui abili y o “ igidi ied” β-subs i u ed inyl
sul ones 2as Michael accep o s in o he un ela ed ca aly ic
addi ion eac ions may be o eseen.
■EXPERIMENTAL SECTION
Gene al In o ma ion. All nonaqueous eac ions we e pe o med
unde an ine a mosphe e using o en-d ied glasswa e and we e
magne ically s i ed. Fo eac ions ha equi e hea ing, an oil ba h was
used. Yields e e o ch oma og aphically pu i ied samples unless
o he wise s a ed. We o ganic laye s we e d ied o e MgSO4, and
sol en s we e e apo a ed unde educed p essu e. Fo ace sol en
emo al, a acuum pump (≈0.5 mmHg) was applied. Column
ch oma og aphy was pe o med on ROCC 60 silica gel 40−63 μm as
he s a iona y phase and a sui able mix u e o sol en s ( ypically
hexane: e hyl ace a e) as he eluen . Op ical o a ions we e eco ded
using a Jasco P-2000 pola ime e . Mel ing poin s we e de e mined in
open capilla ies in a S ua SHP3 mel ing poin appa a us. 1H NMR
and 13C NMR spec a we e eco ded a 300 o 500 MHz and 75 o
126 MHz, espec i ely. The chemical shi s a e epo ed in ppm
ela i e o CDCl3(δ= 7.26) and CD2Cl2(δ= 5.32) o 1H NMR and
ela i e o he cen al esonances o CDCl3(δ= 77.2) and CD2Cl2(δ
= 53.8) o 13C NMR. Peaks a e labeled as single (s), b oad single
(bs), double (d), iple ( ), qua e (q), double double (dd), double
iple (d ), double o double o iple s (dd ), qua e s o double s
(qd), o mul iple (m). Coupling cons an s (J) a e epo ed in He z
(Hz). Mass spec a we e eco ded on an ESI-ion ap mass
spec ome e (Agilen 1100 se ies LC/MSD, SL model) and a
UPLC−DAD−QTOF, ul a-high-pe o mance liquid ch oma og a-
phy−mass spec ome e . Enan iome ic (ee) alues we e de e mined
by HPLC pe o med on Wa e s 600-E (equipped wi h a 2998
pho odiode a ay UV de ec o ) employing Daicel Chi alpack columns
(IA, IB, IC, and IF). In a ed spec a we e measu ed employing a
B uke ALPHA-P compac FT-IR spec ome e . The X- ay di ac ion
analysis was conduc ed by he Gene al Resea ch Se ice (SGIke ) o
UPV/EHU.
All eagen s we e pu chased om comme cial supplie s and used
wi hou u he pu i ica ion, unless o he wise s a ed. Subs a es 1a,1b,
3a,3b,3c,3d,3 ,4a,5a,6a,7a,8, and 9we e syn hesized acco ding
o he epo ed p ocedu es (see he Suppo ing In o ma ion o
de ails). T ie hylamine was pu i ied by dis illa ion. Dichlo ome hane
and ace oni ile we e d ied o e CaH2, and DMF was d ied o e
molecula sie es. Analy ical eagen -g ade MeOH and oluene we e
used wi hou u he d ying.
Gene al P ocedu e o he Ca aly ic Addi ion o Hydan oin
Su oga es 3 o 1a. In a 5 mL es ube, he co esponding
p onucleophile (0.1 mmol, 1 equi ) was dissol ed in CH2Cl2(1 mL)
a oom empe a u e, and a e cooling he solu ion down o 0 °C, he
co esponding inylic sul one (37 mg, 0.12 mmol, 1.2 equi ) and
ca alys C2 (8 mg, 0.01 mmol, 10 mol %) we e added. The mix u e
was s i ed a 0 °C un il he eac ion was inished as moni o ed by 1H
NMR. The c ude p oduc was di ec ly submi ed o silica gel lash
column ch oma og aphy (eluen : hexane/e hyl ace a e, om 3:1 o
1:1).
(S)-1-Benzoyl-5-benzyl-2-(benzyl hio)-5-(2,2-bis(phenylsul onyl)-
e hyl)-1,5-dihyd o-4H-imidazole-4-one (10a). The i le compound
was p epa ed om 1-benzoyl-5-benzyl-2-(benzyl hio)-1,5-dihyd o-
4H-imidazole-4-one (40 mg, 0.1 mmol) acco ding o he gene al
Figu e 5. Reac ion p o ile. Rela i e Gibbs ee ene gy alues in kcal
mol−1calcula ed wi h O ca 5 (see Suppo ing In o ma ion o mo e
de ails).
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p ocedu e. Silica gel lash column ch oma og aphy (eluen : hexane/
e hyl ace a e, om 3:1 o 1:1). Whi e oam. Yield: 67 mg, 95%. [α]D
20
+ 47.0 (c= 1, 98% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ
8.15−6.94 (m, 25H), 5.67 (dd, J= 6.1, 3.0 Hz, 1H), 4.20 (d, J= 13.3
Hz, 1H), 4.04 (d, J= 13.3 Hz, 1H), 3.54 (d, J= 13.6 Hz, 1H), 3.33
(dd, J= 16.6, 3.0 Hz, 1H), 3.22 (d, J= 13.8 Hz, 1H), 3.19−3.11 (m,
1H). 13C{1H} NMR (75 MHz, CDCl3): δ186.2, 185.0, 168.2, 138.0,
137.0, 134.9, 134.7, 134.4, 134.0, 133.1, 132.1, 130.3, 130.2, 130.0,
129.8, 129.3, 129.1, 128.9, 128.78, 128.76, 128.6, 128.0, 127.7, 77.9,
73.2, 41.2, 39.7, 31.6. HRMS (ESI) m/z: [M + H]+calcd o
C38H33N2O6S3, 709.1501; ound, 709.1506. IR (cm−1): 3062, 3056,
2940, 1725, 1600. The ee alue was de e mined by HPLC analysis
(Daicel Chi alpak IC, hexane/isop opanol 30:70), low a e: 0.5 mL/
min, e en ion imes: 43.8 min (majo ) and 52.0 min (mino ).
(S)-1-Benzoyl-2-(benzyl hio)-5-(2,2-bis(phenylsul onyl)e hyl)-5-
me hyl-1,5-dihyd o-4H-imidazole-4-one (10b). The i le compound
was p epa ed om 1-benzoyl-2-(benzyl hio)-5-me hyl-1,5-dihyd o-
4H-imidazole-4-one (32 mg, 0.1 mmol) acco ding o he gene al
p ocedu e. Silica gel lash column ch oma og aphy (eluen : hexane/
e hyl ace a e, om 3:1 o 1:1). Yellow oam. Yield: 23 mg, 36%.
(con . 55%). [α]D
20 −3.3 (c= 1, 97% ee, CH2Cl2). 1H NMR (300
MHz, CDCl3): δ8.14−8.05 (m, 2H), 8.02−7.93 (m, 2H), 7.75−7.36
(m, 12H), 7.24 (m, 4H), 5.56 (dd, J= 5.8, 3.1 Hz, 1H), 4.47−4.34
(m, 2H), 3.19 (dd, J= 16.5, 3.1 Hz, 1H), 2.99 (dd, J= 16.5, 5.8 Hz,
1H), 1.57 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ186.9, 183.9,
168.0, 138.2, 136.8, 134.9, 134.61, 134.56, 133.3, 133.2, 130.4, 130.0,
129.29, 129.26, 129.1, 128.9, 128.8, 128.1, 77.3, 68.1, 39.6, 31.5, 22.4.
HRMS (ESI) m/z: [M + H]+calcd o C32H29N2O6S3, 633.1182;
ound, 633.1192. IR (cm−1): 3062, 2931, 1728, 1681. The ee alue
was de e mined by HPLC analysis (Daicel Chi alpak IA, hexane/
isop opanol 30:70), low a e: 0.5 mL/min, e en ion imes: 32.8 min
(majo ) and 39.7 min (mino ).
(S)-1-Benzoyl-2-(benzyl hio)-5-(2,2-bis(phenylsul onyl)e hyl)-5-
e hyl-1,5-dihyd o-4H-imidazole-4-one (10c). The i le compound
was p epa ed om 1-benzoyl-2-(benzyl hio)-5-e hyl-1,5-dihyd o-4H-
imidazole-4-one (34 mg, 0.1 mmol) acco ding o he gene al
p ocedu e. Silica gel lash column ch oma og aphy (eluen : hexane/
e hyl ace a e, om 3:1 o 1:1). Whi e oam. Yield: 62 mg, 96%. [α]D
20
+ 19.7 (c= 1, 93% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ
8.11−8.03 (m, 2H), 7.98−7.92 (m, 2H), 7.74−7.63 (m, 2H), 7.62−
7.52 (m, 8H), 7.48−7.35 (m, 2H), 7.23 (m, 4H), 5.56 (dd, J= 6.0,
2.9 Hz, 1H), 4.39 (s, 2H), 3.13 (dd, J= 16.6, 3.0 Hz, 1H), 3.00 (dd, J
= 16.6, 6.0 Hz, 1H), 2.27 (dq, J= 14.5, 7.3 Hz, 1H), 1.82 (dq, J=
14.4, 7.3 Hz, 1H), 0.72 ( , J= 7.3 Hz, 3H). 13C{1H} NMR (75 MHz,
CDCl3): δ186.3, 184.8, 167.9, 138.2, 136.9, 134.8, 134.7, 134.6,
133.3, 133.2, 130.3, 130.1, 129.29, 129.26, 129.1, 128.92, 128.85,
128.1, 77.4, 72.8, 39.7, 31.4, 28.9, 8.2. HRMS (ESI) m/z: [M + H]+
calcd o C33H31N2O6S3, 647.1344; ound, 647.1340. IR (cm−1):
3062, 2971, 2934, 1726, 1682. The ee alue was de e mined by HPLC
analysis (Daicel Chi alpak IF, hexane/isop opanol 30:70), low a e:
0.5 mL/min, e en ion imes: 44.9 min (majo ) and 97.4 min
(mino ).
(S)-1-Benzoyl-2-(benzyl hio)-5-(2,2-bis(phenylsul onyl)e hyl)-5-
isobu yl-1,5-dihyd o-4H-imidazole-4-one (10d). The i le com-
pound was p epa ed om 1-benzoyl-2-(benzyl hio)-5-isobu yl-1,5-
dihyd o-4H-imidazole-4-one (37 mg, 0.1 mmol) acco ding o he
gene al p ocedu e. Silica gel lash column ch oma og aphy (eluen :
hexane/e hyl ace a e, om 3:1 o 1:1). Whi e oam. Yield: 56 mg,
83%. [α]D
20 + 11.5 (c= 1, 97% ee, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ8.16−8.04 (m, 2H), 8.04−7.93 (m, 2H), 7.75−7.39 (m,
12H), 7.23 (s, 4H), 5.51 (dd, J= 5.9, 2.9 Hz, 1H), 4.39 (s, 2H), 3.14
(dd, J= 16.6, 2.9 Hz, 1H), 2.95 (dd, J= 16.6, 5.9 Hz, 1H), 2.10 (dd, J
= 14.2, 4.9 Hz, 1H), 1.53 (dd, J= 14.1, 7.8 Hz, 1H), 1.39 (dq, J=
19.4, 6.5 Hz, 1H), 0.75 (dd, J= 7.3, 6.6 Hz, 6H). 13C{1H} NMR (75
MHz, CDCl3): δ186.5, 184.4, 167.9, 138.3, 137.2, 134.8, 134.7,
134.6, 133.3, 133.1, 130.2, 130.1, 129.3, 129.2, 129.1, 128.81, 128.76,
128.7, 128.0, 77.5, 71.5, 43.0, 39.6, 32.8, 24.9, 23.8, 22.8. HRMS
(ESI) m/z: [M + H]+calcd Fo C35H35N2O6S3, 675.1657; ound,
675.1650. IR (cm−1): 3062, 2958, 2916, 1728, 1682. The ee alue was
de e mined by HPLC analysis (Daicel Chi alpak IF, hexane/
isop opanol 30:70), low a e: 0.5 mL/min, e en ion imes: 44.2
min (majo ) and 86.0 min (mino ).
(S)-5-Allyl-1-benzoyl-2-(benzyl hio)-5-(2,2-bis(phenylsul onyl)-
e hyl)-1,5-dihyd o-4H-imidazole-4-one (10e). The i le compound
was p epa ed om 5-allyl-1-benzoyl-2-(benzyl hio)-1,5-dihyd o-4H-
imidazole-4-one (35 mg, 0.1 mmol) acco ding o he gene al
p ocedu e. Silica gel lash column ch oma og aphy (eluen : hexane/
e hyl ace a e, om 3:1 o 1:1). Whi e oam. Yield: 56 mg, 85%. [α]D
20
+ 27.3 (c= 1, 98% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ
8.12−7.15 (m, 20H), 5.56 (dd, J= 6.0, 3.0 Hz, 1H), 5.44 (m, 1H),
5.19−5.04 (m, 2H), 4.36 (s, 2H), 3.21 (dd, J= 16.6, 3.1 Hz, 1H),
3.05 (dd, J= 10.8, 5.8 Hz, 1H), 3.02−2.95 (m, 1H), 2.57 (dd , J=
13.9, 5.4, 1.4 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ186.1,
184.9, 168.2, 138.3, 137.1, 135.1, 134.9, 133.5, 133.3, 130.6, 130.3,
130.2, 129.5, 129.3, 129.2, 129.0, 129.0, 128.8, 128.3, 121.9, 77.7,
71.8, 39.9, 39.6, 31.3. HRMS (ESI) m/z: [M + H]+calcd o
C34H31N2O6S3, 659.1344; ound, 659.1346. IR (cm−1): 3061, 2923,
1728, 1683. The ee alue was de e mined by HPLC analysis (Daicel
Chi alpak IC, hexane/isop opanol 30:70), low a e: 0.5 mL/min,
e en ion imes: 34.6 min (majo ) and 42.5 min (mino ).
(S)-1-Benzoyl-2-(benzyl hio)-5-(2,2-bis(phenylsul onyl)e hyl)-5-
(2-(me hyl hio)e hyl)-1,5-dihyd o-4H-imidazole-4-one (10 ). The
i le compound was p epa ed om 1-benzoyl-2-(benzyl hio)-5-(2-
(me hyl hio)e hyl)-1,5-dihyd o-4H-imidazole-4-one (38 mg, 0.1
mmol) acco ding o he gene al p ocedu e. Silica gel lash column
ch oma og aphy (eluen : hexane/e hyl ace a e, om 3:1 o 1:1).
Whi e oam. Yield: 63 mg, 91%. [α]D
20 + 19.7 (c= 1, 92% ee, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ8.18−8.06 (m, 2H), 8.05−7.95 (m,
2H), 7.85−7.38 (m, 12H), 7.25 (m, 4H), 5.57 (dd, J= 5.9, 3.0 Hz,
1H), 4.41 (s, 2H), 3.16 (dd, J= 16.6, 3.0 Hz, 1H), 3.00 (dd, J= 16.6,
5.9 Hz, 1H), 2.51 (ddd, J= 14.0, 9.2, 5.4 Hz, 1H), 2.30−2.14 (m,
2H), 2.07 (ddd, J= 8.0, 5.6, 2.4 Hz, 1H), 2.02 (s, 3H). 13C{1H} NMR
(75 MHz, CDCl3): δ185.7, 184.7, 168.0, 138.1, 136.9, 135.0, 134.7,
134.6, 133.3, 133.1, 130.3, 130.1, 129.4, 129.3, 129.2, 129.0, 128.90,
128.86, 128.2, 77.3, 71.4, 39.7, 34.3, 31.7, 28.4, 15.6. HRMS (ESI) m/
z: [M + H]+calcd o C34H33N2O6S4, 693.1221; ound, 693.1227. IR
(cm−1): 3060, 2928, 2849, 1727, 1681. The ee alue was de e mined
by HPLC analysis (Daicel Chi alpak IF, hexane/isop opanol 30:70),
low a e: 0.5 mL/min, e en ion imes: 58.9 min (majo ) and 114.1
min (mino ).
Me hyl (S)-2-(1-Benzoyl-2-(benzyl hio)-5-(2,2- bis(phenylsul o-
nyl)e hyl)-4-oxo-4,5-dihyd o-1H-imidazole-5-yl)ace a e (10g). The
i le compound was p epa ed om me hyl 2-(1-benzoyl-2-(benzyl h-
io)-4-oxo-4,5-dihyd o-1H-imidazole-5-yl)ace a e (38 mg, 0.1 mmol)
acco ding o he gene al p ocedu e. Silica gel lash column
ch oma og aphy (eluen : hexane/e hyl ace a e, om 3:1 o 1:1).
Yellow oam. Yield: 68 mg, 98%. [α]D
20 −17.9 (c= 1, 96% ee,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ8.12−7.98 (m, 4H), 7.96−
7.88 (m, 1H), 7.77−7.37 (m, 12H), 7.24−7.22 (m, 3H), 5.50 (dd, J=
4.8, 3.3 Hz, 1H), 4.53 (d, J= 13.3 Hz, 1H), 4.34 (d, J= 13.3 Hz, 1H),
3.64 (s, 3H), 3.39 (d, J= 17.9 Hz, 1H), 3.31 (dd, J= 16.6, 3.3 Hz,
1H), 3.11 (d, J= 17.8 Hz, 1H), 2.88 (dd, J= 16.6, 4.8 Hz, 1H).
13C{1H} NMR (75 MHz, CDCl3): δ185.4, 184.7, 169.8, 168.2, 137.9,
136.6, 135.1, 135.0, 134.71, 134.65, 133.22, 133.16, 130.6, 130.1,
129.9, 129.4, 129.3, 129.2, 129.1, 128.9, 128.8, 128.1, 77.1, 68.3, 52.3,
39.8, 36.6, 31.6. HRMS (ESI) m/z: [M + H]+calcd o
C34H31N2O8S3, 691.1237; ound, 691.1240. IR (cm−1): 3063, 2951,
1731, 1680. The ee alue was de e mined by HPLC analysis (Daicel
Chi alpak IC, hexane/isop opanol 30:70), low a e: 0.5 mL/min,
e en ion imes: 47.5 min (mino ) and 67.6 min (majo ).
Gene al P ocedu e o he Ca aly ic Addi ion o Su oga es
3 o 2. In a 5 mL es ube, he co esponding dihyd oimidazole-5-
one (0.1 mmol) was dissol ed in 1 mL o CH2Cl2a oom
empe a u e. Then, he eac ion was cooled down o 0 °C, and he
inyl sul one (1.2 equi , 0.12 mmol) and 10 mol % o C2 (8 mg, 0.01
mmol) we e added. Once he addi ion was comple ed, he mix u e
was s i ed a 0 °C un il he eac ion was inished as moni o ed by
NMR. The c ude was pu i ied di ec ly by silica gel lash column
ch oma og aphy (eluen : hexane/e hyl ace a e, om 3:1 o 1:1).
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979
(S)-1-Benzoyl-5-benzyl-2-(benzyl hio)-5-((R)-phenyl(1,1,3,3- e -
aoxido-2H-benzo[d][1,3]di hiol-2-yl)me hyl)-1,5-dihyd o-4H-imi-
dazole-4-one (15aa). The i le compound was p epa ed om 1-
benzoyl-5-benzyl-2-(benzyl hio)-1,5-dihyd o-4H-imidazole-4-one (40
mg, 0.1 mmol) and 2-benzylidene-2H-benzo[d][1,3]di hiole 1,1,3,3-
e aoxide (37 mg, 0.12 mmol, 1.2 equi ) acco ding o he gene al
p ocedu e. Silica gel lash column ch oma og aphy (eluen : hexane/
e hyl ace a e, om 3:1 o 1:1). Whi e oam. Yield: 56 mg, 79%. [α]D
20
+ 35.1 (c= 1, 99% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ
8.19−7.77 (m, 6H), 7.65−7.29 (m, 8H), 7.25−7.15 (m, 8H), 6.95−
6.89 (m, 2H), 6.32 (d, J= 9.7 Hz, 1H), 5.21 (d, J= 9.8 Hz, 1H), 4.30
(d, J= 13.2 Hz, 1H), 4.08 (d, J= 13.2 Hz, 1H), 3.92 (d, J= 12.9 Hz,
1H), 3.77 (d, J= 12.9 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ
186.7, 185.2, 167.3, 137.9, 136.5, 135.2, 135.0, 134.4, 133.8, 133.1,
132.8, 132.62, 132.55, 130.9, 130.0, 129.5, 129.2, 128.7, 128.64,
128.56, 128.4, 128.23, 128.18, 128.0, 127.6, 123.0, 122.2, 77.7, 73.9,
46.6, 41.9, 40.0. HRMS (ESI) m/z: [M + H]+calcd o
C38H31N2O6S3, 707.1344; ound, 707.1339. IR (cm−1): 3060, 3025,
2968, 1697, 1652. The ee alue was de e mined by HPLC analysis
(Daicel Chi alpak IA, hexane/isop opanol 30:70), low a e: 0.5 mL/
min, e en ion imes: 37.0 min (mino ) and 55.5 min (majo ).
(S)-1-Benzoyl-2-(benzyl hio)-5-e hyl-5-((R)-phenyl(1,1,3,3- e -
aoxido-2H-benzo[d][1,3]di hiol-2-yl)me hyl)-1,5-dihyd o-4H-imi-
dazole-4-one (15ca). The i le compound was p epa ed om 1-
benzoyl-2-(benzyl hio)-5-e hyl-1,5-dihyd o-4H-imidazole-4-one (34
mg, 0.1 mmol) and 2-benzylidene-2H-benzo[d][1,3]di hiole 1,1,3,3-
e aoxide (37 mg, 0.12 mmol, 1.2 equi ) acco ding o he gene al
p ocedu e. Silica gel lash column ch oma og aphy (eluen : hexane/
e hyl ace a e, om 3:1 o 1:1). Whi e solid, mp: 115−120 °C. Yield:
50 mg, 78%. [α]D
20 + 24.1 (c= 1, 96% ee, CH2Cl2). 1H NMR (300
MHz, CDCl3): δ8.16−8.02 (m, 1H), 8.00−7.69 (m, 4H), 7.51−7.04
(m, 14H), 6.15 (d, J= 9.4 Hz, 1H), 4.95 (d, J= 9.4 Hz, 1H), 4.27 (d,
J= 13.4 Hz, 1H), 4.11 (d, J= 13.4 Hz, 1H), 2.95−2.77 (m, 2H), 0.76
( , J= 7.2 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ186.9, 184.8,
166.9, 138.0, 136.7, 135.2, 135.0, 134.6, 133.12, 133.07, 132.6, 131.3,
129.5, 129.3, 128.92, 128.86, 128.7, 128.5, 128.4, 128.1, 127.9, 123.0,
122.2, 77.8, 73.9, 46.4, 39.7, 30.0, 8.7. HRMS (ESI) m/z: [M + H]+
calcd o C33H29N2O6S3, 645.1182; ound, 645.1192. IR (cm−1):
3083, 3022, 2850, 1724, 1681. The ee alue was de e mined by HPLC
analysis (Daicel Chi alpak IC, hexane/isop opanol 30:70), low a e:
0.5 mL/min, e en ion imes: 38.1 min (mino ) and 55.8 min
(majo ).
(S)-1-Benzoyl-2-(benzyl hio)-5-isobu yl-5-((R)-phenyl-(1,1,3,3-
e aoxido-2H-benzo[d][1,3]di hiol-2-yl)me hyl)-1,5-dihyd o-4H-
imidazole-4-one (15da). The i le compound was p epa ed om 1-
benzoyl-2-(benzyl hio)-5-isobu yl-1,5-dihyd o-4H-imidazole-4-one
(37 mg, 0.1 mmol) and 2-benzylidene-2H-benzo[d][1,3]di hiole
1,1,3,3- e aoxide (37 mg, 0.12 mmol, 1.2 equi ) acco ding o he
gene al p ocedu e. Silica gel lash column ch oma og aphy (eluen :
hexane/e hyl ace a e, om 3:1 o 1:1). Whi e solid, mp 213−217 °C.
Yield: 65 mg, 97%. [α]D
20 + 14.3 (c= 1, 92% ee, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ8.19−8.06 (m, 1H), 7.97−7.73 (m, 3H),
7.52−7.21 (m, 13H), 7.13 (m, 2H), 6.13 (d, J= 9.0 Hz, 1H), 5.00 (d,
J= 9.0 Hz, 1H), 4.28 (d, J= 13.3 Hz, 1H), 4.09 (d, J= 13.4 Hz, 1H),
2.85 (dd, J= 13.9, 4.7 Hz, 1H), 2.76 (dd, J= 13.9, 7.2 Hz, 1H), 1.42
(d , J= 11.5, 6.7 Hz, 1H), 0.95 (d, J= 6.6 Hz, 3H), 0.88 (d, J= 6.6
Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ187.2, 184.7, 167.0,
138.2, 136.8, 135.1, 135.0, 134.6, 133.3, 133.0, 132.9, 130.7, 129.6,
129.4, 128.78, 128.75, 128.6, 128.5, 128.3, 128.1, 123.0, 122.3, 76.3,
73.9, 47.7, 44.3, 39.8, 25.8, 24.4, 23.2. HRMS (ESI) m/z: [M + H]+
calcd o C35H33N2O6S3, 673.1501; ound, 673.1492. IR (cm−1):
2982, 2868, 1720, 1683. The ee alue was de e mined by HPLC
analysis (Daicel Chi alpak IC, hexane/isop opanol 30:70), low a e:
0.5 mL/min, e en ion imes: 29.4 min (mino ) and 75.1 min
(majo ).
(S)-5-Allyl-1-benzoyl-2-(benzyl hio)-5-((R)-phenyl(1,1,3,3- e -
aoxido-2H-benzo[d][1,3]di hiol-2-yl)me hyl)-1,5-dihyd o-4H-imi-
dazole-4-one (15ea). The i le compound was p epa ed om 5-allyl-
1-benzoyl-2-(benzyl hio)-1,5-dihyd o-4H-imidazole-4-one (35 mg,
0.1 mmol) and 2-benzylidene-2H-benzo[d][1,3]di hiole 1,1,3,3-
e aoxide (37 mg, 0.12 mmol, 1.2 equi ) acco ding o he gene al
p ocedu e. Silica gel lash column ch oma og aphy (eluen : hexane/
e hyl ace a e, om 3:1 o 1:1). Whi e solid, mp 225−228 °C. Yield:
52.5 mg, 80%. [α]D
20 + 54.9 (c= 1, 95% ee, CH2Cl2). 1H NMR (300
MHz, CDCl3): δ8.21−6.99 (m, 19H), 6.18 (d, J= 9.7 Hz, 1H), 5.43
(m, 1H), 5.23 (m, 1H), 5.12−4.95 (m, 2H), 4.26 (d, J= 13.4 Hz,
1H), 4.06 (d, J= 13.4 Hz, 1H), 3.68−3.49 (m, 2H). 13C{1H} NMR
(75 MHz, CDCl3): δ186.3, 184.8, 166.9, 142.7, 137.9, 136.5, 135.3,
135.22, 135.17, 135.1, 134.6, 133.8, 132.9, 132.8, 132.7, 132.6, 130.9,
130.0, 129.5, 129.3, 128.7, 128.6, 128.3, 128.0, 122.9, 122.4, 122.2,
122.1, 121.5, 76.3, 73.7, 46.0, 40.4, 39.5. HRMS (ESI) m/z: [M + H]+
calcd o C34H29N2O6S3, 657.1188; ound, 657.1179. IR (cm−1):
2978, 1714, 1694. The ee alue was de e mined by HPLC analysis
(Daicel Chi alpak IC, hexane/isop opanol 30:70), low a e: 0.5 mL/
min, e en ion imes: 49.0 min (mino ) and 57.9 min (majo ).
(S)-1-Benzoyl-2-(benzyl hio)-5-(2-(me hyl hio)e hyl)-5-((R)-
phenyl(1,1,3,3- e aoxido-2H-benzo[d][1,3]di hiol-2-yl)me hyl)-1,5-
dihyd o-4H-imidazole-4-one (15 a). The i le compound was
p epa ed om 1-benzoyl-2 (benzyl hio)-5-(2-(me hyl hio)e hyl)-1,5-
dihyd o-4H-imidazole-4-one (38 mg, 0.1 mmol) and 2-benzylidene-
2H-benzo[d][1,3]di hiole 1,1,3,3- e aoxide (37 mg, 0.12 mmol, 1.2
equi ) acco ding o he gene al p ocedu e. Silica gel lash column
ch oma og aphy (eluen : hexane/e hyl ace a e, om 3:1 o 1:1).
Whi e oam. Yield: 64 mg, 93%. [α]D
20 + 30.6 (c= 1, 96% ee, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ8.16−8.07 (m, 1H), 8.03−7.77 (m,
4H), 7.51−7.10 (m, 14H), 6.14 (d, J= 9.4 Hz, 1H), 4.99 (d, J= 9.5
Hz, 1H), 4.28 (d, J= 13.3 Hz, 1H), 4.12 (d, J= 13.4 Hz, 1H), 3.27−
3.09 (m, 2H), 2.37−2.14 (m, 2H), 2.12 (s, 3H). 13C{1H} NMR (75
MHz, CDCl3): δ186.3, 184.8, 167.0, 138.1, 136.7, 135.2, 135.0,
134.5, 133.3, 133.2, 132.5, 130.6, 129.7, 129.4, 129.0, 128.9, 128.8,
128.4, 128.2, 128.1, 123.1, 122.3, 76.2, 73.9, 46.7, 39.8, 35.5, 28.6,
15.4. HRMS (ESI) m/z: [M + H]+calcd o C34H31N2O6S4,
691.1065; ound, 691.1061. IR (cm−1): 3060, 3029, 2915, 1723, 1682.
The ee alue was de e mined by HPLC analysis (Daicel Chi alpak IC,
hexane/isop opanol 30:70), low a e: 0.5 mL/min, e en ion imes:
40.6 min (mino ) and 74.2 min (majo ).
Me hyl 2-((S)-1-benzoyl-2-(benzyl hio)-4-oxo-5-((R)-phenyl-
(1,1,3,3- e aoxido-2H-benzo[d][1,3]di hiol-2-yl)me hyl)-4,5-dihy-
d o-1H-imidazole-5-yl)ace a e (15ga). The i le compound was
p epa ed om me hyl 2-(1-benzoyl-2-(benzyl hio)-4-oxo-4,5-dihyd o-
1H-imidazole-5-yl)ace a e (38 mg, 0.1 mmol) and 2-benzylidene-2H-
benzo[d][1,3]di hiole 1,1,3,3- e aoxide (37 mg, 0.12 mmol, 1.2
equi ) acco ding o he gene al p ocedu e. Silica gel lash column
ch oma og aphy (eluen : hexane/e hyl ace a e, om 3:1 o 1:1).
Whi e oam. Yield: 62 mg, 91%. [α]D
20 −6.5 (c= 1, 84% ee, CH2Cl2)
(−20 °C). 1H NMR (300 MHz, CDCl3): δ8.16−8.08 (m, 1H),
7.98−7.78 (m, 3H), 7.54−7.26 (m, 9H), 7.25−7.04 (m, 6H), 5.94 (d,
J= 10.1 Hz, 1H), 5.11 (d, J= 10.1 Hz, 1H), 4.25−4.16 (m, 2H), 4.07
(d, J= 13.1 Hz, 1H), 3.89 (d, J= 16.6 Hz, 1H), 3.65 (s, 3H). 13C{1H}
NMR (75 MHz, CDCl3): δ185.6, 185.2, 169.7, 167.1, 138.1, 136.2,
135.4, 135.1, 134.2, 133.0, 132.91, 132.87, 129.8, 129.5, 129.3, 129.0,
128.8, 128.7, 128.6, 128.4, 128.1, 127.6, 123.0, 122.4, 73.5, 72.4, 52.3,
47.1, 40.1, 38.7. HRMS (ESI) m/z: [M + H]+calcd o
C34H29N2O8S3, 689.1086; ound, 689.1092. IR (cm−1): 2952, 2936,
1725, 1679. The ee alue was de e mined by HPLC analysis (Daicel
Chi alpak IC, hexane/isop opanol 30:70), low a e: 0.5 mL/min,
e en ion imes: 63.9 min (mino ) and 80.6 min (majo ).
Me hyl 2-(((S)-1-benzoyl-2-(benzyl hio)-4-oxo-5-((R)-phenyl-
(1,1,3,3- e aoxido-2H-benzo[d][1,3]di hiol-2-yl)me hyl)-4,5-dihy-
d o-1H-imidazole-5-yl)me hyl)ac yla e (15ha). The i le compound
was p epa ed om a sample o 3h con aining i s dialkyla ed analogue
3h′(mol a io o 3h/3h′2:1; 41 mg, 0.1 mmol) and 2-benzylidene-
2H-benzo[d][1,3]di hiole 1,1,3,3- e aoxide (37 mg, 0.12 mmol, 1.2
equi ) acco ding o he gene al p ocedu e. Silica gel lash column
ch oma og aphy (eluen : hexane/e hyl ace a e, om 3:1 o 1:1).
Whi e oam. Yield: 47 mg, 98%. [α]D
20 + 20.1 (c= 1, 91% ee, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ8.17−8.08 (m, 1H), 7.95−7.78 (m,
3H), 7.64−7.19 (m, 13H), 7.15−7.06 (m, 2H), 6.35 (d, J= 9.7 Hz,
1H), 6.25 (d, J= 1.4 Hz, 1H), 5.80 (d, J= 1.3 Hz, 1H), 5.14 (d, J=
9.7 Hz, 1H), 4.13 (q, J= 13.1 Hz, 2H), 4.04−3.90 (m, 2H), 3.65 (s,
3H). 13C{1H} NMR (75 MHz, CDCl3): δ185.6, 184.8, 167.0, 166.9,
The Jou nal o O ganic Chemis y pubs.acs.o g/joc A icle
h ps://doi.o g/10.1021/acs.joc.2c02403
J. O g. Chem. 2023, 88, 972−987
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basic condi ions (11 equi o NaOH 6 M, 20 °C, 2 h, 1,4-dioxane)
was unp ac ical because he occu ence o e o-Michael eac ion o a
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J. O g. Chem. 2023, 88, 972−987
987
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