Asymme ic syn hesis o dibenzo[b,d]azepines by
Cu-ca alyzed educ i e o bo yla i e cycliza ion†
Pa icia Rod ´
ıguez-Salamanca,
a
Roc´
ıo Ma ´
ın-de la Calle,
a
Ve ´
onica Rod ´
ıguez,
b
Ped o Me ino,
c
Rosa io Fe n´
andez, *
b
Jos´
e M. Lassale a *
a
and Valen ´
ın Ho nillos *
ab
A coppe -ca alyzed asymme ic in amolecula educ i e cycliza ion o he syn hesis o dibenzo[b,d]
azepines is desc ibed. Use o 20- inyl-bia yl-2-imines as subs a es and in si u o med [Cu
I
/(Ph-BPE)] as
he ca alys enables he syn hesis o 7-membe ed b idged bia ylamines con aining bo h cen al and axial
s e eogenic elemen s in high yields (up o 98%) and wi h excellen dias e eo- and enan ioselec i i ies
(>20 : 1 d. ., up o 99% ee). Mo eo e , he same ca alys was ound o acili a e a ela ed bo yla i e
cycliza ion o affo d e sa ile bo onic es e de i a i es. Bo h eac ions p oceed unde mild condi ions ( )
and a e applicable o a a ie y o subs i u ed a oma ic and he e ocyclic de i a i es.
In oduc ion
The asymme ic syn hesis o bia yl a opisome s has e ol ed
in o a s imula ing esea ch eld in o ganic syn hesis owing o
he ubiqui ous occu ence o his s uc u al mo i in a a ie y o
na u al p oduc s and bioac i e subs ances, and o hei wide-
anging u ili ies in ca alys design and ma e ial science.
1
Mos
o hese compounds comp ise con o me s wi h es ic ed o a-
ion a ound a single bond whose congu a ional s abili y is
gene ally de e mined by he numbe and size o he subs i u-
en s a he o ho posi ions ela i e o he s e eogenic axis. A less
common class o bia yl a opisome s consis o hose whe e he
bia yl uni is inco po a ed in o a cyclic sys em, wi h he ypical
o ho,o ho0subs i uen s being eplaced by a b idge (Fig. 1).
2
In hese sys ems, he congu a ional s abili y di ec ly
co ela es wi h he ing size: in 5- and 6-membe ed ings he
o a ion a ound he s e eogenic axis is usually no hinde ed, bu
7-membe ed b idged bia yls exhibi a highe congu a ional
s abili y owing o con o ma ional easons and can be oen
esol ed as a opisome s. Addi ionally, he in oduc ion o sp
2
hyb idized a oms inc eases he igidi y in he b idging cycle,
and he e o e he congu a ional s abili y,
3
while he p esence
o s e eogenic cen e s in he b idge is known o impose
a specic congu a ion on he bia yl axis by a cen al o axial
chi ali y elay e en .
4
No ably, hese p ope ies ha e been
ecen ly exploi ed o he cons uc ion o a unidi ec ional o a y
molecula mo o based on he o ma ion o bia yl s uc u es
ea u ing a se en-membe ed lac one b idge.
5
The mos dis inc i e class o b idged bia yls p esen ing his
elay phenomenon comp ises chi al dibenzoazepines. These 7-
membe ed cyclic b idged bia yl amines and ela ed analogues
ha e ecei ed conside able a en ion due o hei p esence in
se e al na u al subs ances and d ugs. Selec ed examples shown
in Fig. 2 include e y h i aeine B (A), a dime ic E y h ina alkaloid
isola ed om E. a iega e,
6
dipep ide LY-411575 (B) which has
demons a ed effec i i y as g-sec e ase inhibi o o he ea -
men o melanoma and Alzheime 's disease,
7
RO4929097 (C),
ano he po en and selec i e g-sec e ase which a ge s No ch
signaling in umo cells,
8
indolobenzoazepinone D, a ubulin
polyme iza ion inhibi o exhibi ing an ip oli e a i e ac i i ies
in a a ie y o cance cell lines,
9
and paullones E, a amily o
cy o oxic compounds which efficien ly inhibi cyclin-dependen
kinases (CDKs).
10
The asymme ic syn hesis o axially chi al 7-membe ed
b idged bia yl amines has adi ionally elied on chi al
Fig. 1 Configu a ional s abili y o acyclic and b idged bia yls.
a
Ins i u o In es igaciones Qu´
ımicas (CSIC-US), C/Am´
e ico Vespucio, 49, 41092 Se illa,
Spain. E-mail: [email protected]
b
Depa amen o de Qu´
ımica O g´
anica, Uni e sidad de Se illa, C/P o . Ga c´
ıa Gonz´
alez,
1, 41012 Se illa, Spain
c
Ins i u o de Biocompu aci´
on y F´
ısica de Sis emas Complejos (BIFI), Uni e sidad de
Za agoza, 50009 Za agoza, Spain
†Elec onic supplemen a y in o ma ion (ESI) a ailable: Expe imen al p o ocols,
cha ac e iza ion da a. CCDC 2095490–2095492. Fo ESI and c ys allog aphic
da a in CIF o o he elec onic o ma see DOI: 10.1039/d1sc04980a
Ci e his: Chem. Sci.,2021,12,15291
All publica ion cha ges o his a icle
ha e been paid o by he Royal Socie y
o Chemis y
Recei ed 8 h Sep embe 2021
Accep ed 8 h No embe 2021
DOI: 10.1039/d1sc04980a
sc.li/chemical-science
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auxilia ies o s a ing ma e ials om he chi al pool, gene ally
equi ing mul is ep p ocedu es.
3,11
The con ol o bo h cen al
and axial chi ali y elemen s in he mos in e es ing dibenzo[b,d]
azepine de i a i es cons i u es a challenge: o da e, only
a hand ul o me hods ha e been desc ibed o hei ca aly ic
asymme ic syn hesis (Scheme 1).
Axially chi al dibenzoazepinones wi h amide b idges ha e
been p epa ed by desymme iza ion ia Pd-ca alyzed C–H a y-
la ion
12
(Scheme 1A) and, e y ecen ly, by a cyclo-
ca bopallada ion-ca bonyla ion cascade eac ion using
alcohols o anilines as nucleophiles
13
(Scheme 1B). To ou
knowledge, he au ome iza ion o me as able enamines
p omo ed by a chi al phospho ic acid ca alys appea s as he
only ca aly ic me hod epo ed o ob ain axially chi al dibenzo
[b,d]azepines (Scheme 1C).
14,15
Hence, he de elopmen o
a modula and s aigh o wa d ca aly ic enan ioselec i e
me hod, p o iding access o hese s uc u al mo i s emains as
a desi able goal.
Resul s and discussion
Inspi ed by he wo k o Buchwald
16
and Yun
17
on Cu-ca alyzed
cycliza ions using aldimines as elec ophiles, we en isioned
ha Schiffbases om o ho- inyl, o ho0-amino bia yls could
also be sui able subs a es o pe o m educ i e o bo yla i e
cycliza ions o he cons uc ion o axially chi al dibenzo[b,d]
azepine de i a i es ea u ing a s e eogenic axis and wo
con iguous s e eogenic cen e s (Scheme 1D).
P elimina y s udies we e pe o med wi h compound 1Aa,
eadily ob ained by condensa ion o 20- inyl-biphenyl-2-amine
wi h benzaldehyde, as a model subs a e (Table 1). Using
Cu(OAc)
2
as he p eca alys , me hyldie hoxysilane (DEMS) as
he hyd ide sou ce and anhyd ous TBME : THF (95 : 5) mix u e
as he sol en a oom empe a u e, ep esen a i es o
comme cially a ailable chi al biphosphine ligands L1–L6 we e
es ed o he syn hesis o he desi ed azepine 2Aa. Poo eac-
i i ies we e obse ed wi h BINAP L1, SEGPHOS L2, DUPHOS L3
o he JOSIPHOS ep esen a i e L4 (en ies 1–4), while mode a e
ca aly ic ac i i y and enan ioselec i i y we e obse ed wi h MeO-
Fig. 2 Selec ed bioac i e dibenzoazepines and ela ed analogues.
Scheme 1 Ca aly ic asymme ic syn hesis o axially chi al 7-
membe ed cyclic b idged bia yl amines.
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SEGPHOS L5 (en y 5).Finally, (R,R)-Ph-BPE L6 p o ed o be he
ligand o choice, affo ding op imal esul s in e ms o eac i i y,
dias e eo- and enan ioselec i i y (99% yield, >20 : 1 d. ., 99% ee,
en y 6).
Wi h he op imized condi ions es ablished, we examined he
subs a e scope o he 20- inyl-biphenyl-2-imine p ecu so s o
explo e he gene ali y o his asymme ic educ i e cycliza ion.
Subs a es wi h elec on- ich me hyl and me hoxy subs i uen s
on he aldimine a yl ing we e ans o med in o he co e-
sponding dibenzoazepines 2Ab–ein high yields and excellen
enan ioselec i i ies. The s e ic effec o placing subs i uen s on
he o ho posi ion o he ing has a negligible effec on eac i i y
and enan ioselec i i y as demons a ed o he syn hesis o 2Ab,
2A and 2Ai. Elec on-decien subs i uen s on he phenyl ing
o he aldimine we e also ole a ed. Thus, uo ina ed subs a es
u nished he co esponding dibenzoazepines 2Ah and 2Ai wi h
excellen selec i i ies. Howe e , he enan ioselec i i y d ops
when a CF
3
g oup is loca ed a he pa a posi ion o he phenyl
ing (2Am). Impo an ly, p oduc s bea ing halide (2A ,2Ag,2Aj
and 2Ak), es e (2Al) and ni ile (2An) unc ionali ies we e also
Scheme 2 Subs a e scope. Reac ions pe o med on 0.2 mmol scale o a 36 h pe iod a . Yields o isola ed p oduc a e ch oma og aphy. A
single dias e eome was obse ed by
1
H NMR in he c ude eac ion mix u es. Ee's we e de e mined by HPLC on chi al s a iona y phases.
a
Reac ion pe o med on 2 mmol (566 mg) scale.
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ob ained in good o high yields (66–99%) and mode a e o high
enan ioselec i i ies (up o 92%), p o iding syn he ically use ul
unc ionali ies o u he ans o ma ions. Mo eo e , he
me hod also ole a es a a ie y o he e ocyclic subs a es,
leading o u an (2Ap), N-me hyl py ole (2Aq), hiophene (2A ),
py idine (2A ) and used he e ocyclic de i a i es (benzo u an
2As,N-me hylindole 2A and hianaph hene 2Au) in good yields
and excellen enan ioselec i i ies. The S
a
,6S,7Rabsolu e
congu a ion o p oduc s 2Ag, and 2Aj was de e mined by X- ay
diff ac ion analysis,
18
while ha o o he p oduc s 2was
assigned by analogy. Mo eo e , he cen al o axial chi ali y
elay phenomenon was con med by a dihed al angle o 39
be ween he wo a yl g oups in bo h compounds. I should be
no ed ha he cis-dias e eome s we e exclusi ely o med in all
cases. Bia yls deco a ed wi h se e al elec on-dona ing o
wi hd awing g oups (e.g. Me, OMe, o F) we e also sui able
subs a es o his ans o ma ion, affo ding he desi ed p od-
uc s in mode a e o good yields wi h high enan ioselec i i ies
(2Ba–2Ea,94–99% ee).
We nex explo ed he kine ic esolu ion (KR) o a isubs i-
u ed, hence congu a ionally s able, bia ylimine 1Fa ia Cu-
ca alyzed hyd ocup a ion/cycliza ion ollowed by educ ion o
he un eac ed, enan ioen iched imine (Scheme 3). The eac ion
s opped a 50% con e sion, despi e he p esence o a la ge
excess (2 equi .) o silane. In his way, dibenzoazepine 2Fa could
be ob ained in high enan ioselec i i y unde he p e iously
op imized condi ions, while he enan ioen iched s a ing
ma e ial was ans o med in o amine (S)-3Fa, ob ained in nea ly
enan iopu e o m (>99% ee) ae LiAlH
4
educ ion (s¼98). The
bia yl-2-amine 3Fa, ea u ing only axial chi ali y, shows an
appealing s uc u e wi h po en ial applica ions in asymme ic
ca alysis. Reasoning ha subs a es 1should o m e y simila
o ganocoppe in e media es ae inse ion o he inyl g oup
in o L*Cu–Bpin ca alys s, we decided o explo e also he Cu-
ca alyzed enan ioselec i e bo yla i e cycliza ion o he same
subs a es 1as an al e na i e app oach o axially chi al dibenzo
[b,d]azepines, in his case deco a ed wi h a bo yl g oup ha
should be use ul o u he de i a iza ion o bioconjuga ion
(Scheme 4). Using again 1A as a model subs a e in he eac ion
wi h bis(pinacola o)dibo on [B
2
(pin)
2
], he ca alys o med by
combina ion o [Cu(MeCN)
4
]PF
6
wi h biphosphine L2,KO Bu as
he base, iP OH as he p o on sou ce and anhyd ous THF as he
sol en we e iden ied as he bes condi ions, leading o he
bo yla ed axially chi al dibenzoazepine (S
a
,6S,7R)-4Aa in 85%
yield wi h excellen egio-, dias e eo- and enan ioselec i i y
(>20 : 1 d. . 98% ee). Single c ys al X- ay analysis o his
compound
18
con med he assigned absolu e congu a ion.
Bo yla i e cycliza ion o o he 20- inyl-biphenyl-2-imines p o-
ceeded efficien ly unde he same condi ions o affo d p oduc s
4wi h excellen enan iocon ol (>20 : 1 d. ., 92–98% ee). Again,
elec on- ich and -decien subs i uen s as well as o ho-
subs i u ion in he phenyl ing we e ole a ed. The eac ion also
accep s he e oa enes as illus a ed o compound 4A .
To explo e he syn he ic po en ial o he me hodology, g am-
scale syn hesis and de i a iza ions we e pe o med. Asymme ic
in amolecula educ i e cycliza ion o 1Aa on a 2 mmol scale
affo ded he desi ed p oduc 2Aa in 93% yield and 98% ee
(Scheme 2). As shown in Scheme 5, deme hyla ion o 2Ae
Scheme 3 Kine ic esolu ion o ac-1Fa. Reac ion pe o med on
0.2 mmol scale o a 36 h pe iod a . Yields o isola ed p oduc a e
ch oma og aphy. Ee's we e de e mined by HPLC on chi al s a iona y
phases.
Table 1 Sc eening o ligands and op imiza ion o he eac ion
En y
a
Ligand Con .
b
(%) ee
c
(%)
1L1,(S)-BINAP <5 nd
2L2,(R)-DTBM-SEGPHOS <10 nd
3L3,(S,S)-Me-DUPHOS <20 nd
4L4,(R)-(S)-JOSIPHOS <20 nd
5L5,(R)-MeO-BIPHEP 42 77
6
d
L6,(R,R)-Ph-BPE 99 (99 yield) 99
a
Reac ions pe o med on 0.2 mmol scale.
b
Es ima ed by
1
H-NMR
spec oscopy.
c
De e mined by HPLC on chi al s a iona y phases.
d
A
single dias e eome was obse ed by
1
H NMR in he c ude eac ion
mix u e.
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offe ed he co esponding phenol p oduc 5which can be used
as syn he ic handle o u he ans o ma ions. Mo eo e ,
uo escen labelling o 2Ag was accomplished ia Suzu-
kiMiyau a coupling p o iding py ene subs i u ed compound 6
wi h emi ing p ope ies o hei po en ial use in biological
s udies.
19
On he o he hand, oxida ion o 4Ah wi h sodium
pe bo a e led o chi al p ima y alcohol 7in high yield while
in amolecula Suzuki coupling o 4A affo ds cis- e ahy-
d odibenzoindenoazepine 8in 56% yield.
To assess he congu a ional s abili y o he bia yl axis o
p oduc s 2, we calcula ed he o a ion abou he axis o he
biphenyl moie y o compound 2Aa. The dibenzoazepine ing
can adop boa aand hal -chai bcon o ma ions (Scheme 6).
20
A
hi d con o ma ion can be loca ed bu a a conside able highe
ene gy.
21
The mos s able con o ma ion o 2Aa was ound o be
C1a, ma ching he X- ay s uc u es o analogs 2ag,2Aj and 4Aa.
Rema kably, no in e con e sion be ween C1a and C2a con o -
ma ions is possible due o s e ic easons. Thus, axial epime i-
za ion by biphenyl bond o a ion equi es a p e ious change
om a o bcon o ma ions. The in e con e sion o he S
a
-C1a/
S
a
-C1b and R
a
-C2a/R
a
-C2b con o me s ha e ee ene gy ba ie s
o 15.6 and 14.0 kcal mol
1
, espec i ely and he diffe ence
be ween ee ene gy o con o me s accoun s o he p e e ed
C1a and C2b con o ma ions in each case. The in e con e sion
be ween S
a
-C1b/R
a
-C2b con o ma ions in ol ing epime iza ion
has ee ene gy ba ie s o only 2, 6 and 8.1 kcal mol
1
. Those
alues clea ly show ha a as equilib ium is es ablished a
25 C (a ba ie o 15.6 kcal mol
1
co esponds, app oxima ely,
o a kine ic cons an o 22.4 s
1
wi h
1/2
o 0.031) and, conse-
quen ly, he obse ed popula ion o con o me s depends on
hei ela i e s abili y. The calcula ed ela i e ene gies o he
mos s able S
a
-C1a/R
a
-C2b con o me s co espond o a 2.4 kcal
diffe ence, co esponding o a 98 : 2 a io. Conside ing hese
alues and he assumed DFT expe imen al e o i is possible o
conclude ha , essen ially, only S
a
-C1a will be obse ed. Low
empe a u e
1
H-NMR expe imen s p o ided u he suppo o
his conclusion: a single se o peaks is obse ed a empe a-
u es as low as 60 C.
On he ligh o hese calcula ions, we specula ed on he
possibili y o eezing o shiing he con o ma ional equilib-
ium by in oducing a bulkie
Bu g oup ins ead o he Ph
g oup. In e es ingly, he calcula ion p edic s ha R
a
-C2b is he
lowes ene gy con o ma ion in his case (1.7 lowe han S
a
-C1a).
This esul can be a ionalized by he lowe impac o he s e ic
effec s in he S
a
-C1a con o me as a esul o he wo gauche
in e ac ions o he R g oup, while he e is only one in R
a
-C2b.In
o de o check whe he a shio he axial chi ali y could be
indeed expe imen ally achie ed, pi alaldehyde de i a i e 1Aw
was p epa ed and subjec ed o he educ i e cycliza ion p o ocol
o achie e p oduc 2Aw in 85% yield and 97% ee (Scheme 7).
The R
a
,6S,7Rcongu a ion is in his case en a i ely assigned
on he basis o he abo e calcula ions and he absence o a NOE
obse ed be ween H-7 and he Me g oup, clea ly obse ed o
2Aa (R ¼Ph) due o hei ela i e gauche disposi ion (suppo ed
Scheme 4 Coppe -ca alyzed bo yla i e cycliza ion. Reac ions pe -
o med on 0.2 mmol scale. Yields o isola ed p oduc a e ch oma-
og aphy. A single dias e eome (>20 : 1 d. .) was obse ed as
de e mined by
1
H NMR in he c ude eac ion mix u es. Ee's we e
de e mined by HPLC analysis.
Scheme 5 De i a iza ion eac ions.
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by he compu a ional analysis o non-co alen in e ac ions,
NCI; see ESI†). As in he p eceden case, a single se o signals is
isible in he
1
H-NMR spec um upon cooling o 60 C, indi-
ca ing he absence o any signican amoun s o mino
con o me s.
Based on p e ious mechanis ic s udies by Buchwald
22
and
Ha wig
23
labo a o ies, we assume ha he hyd ocup a ion o
subs a es 1, gene a ing in e media e Ia (Scheme 8) is he
s e eode e mining s ep. Ensuing cis-selec i e cycliza ion o
affo d complex IIa should hen p oceed ia a well-o ganized
ansi ion s a e TS wi h he assis ance p o ided by
coo dina ion o he imine ni ogen. Then, he esul ing in e -
media e IIa eac s wi h he silane eagen o egene a e he CuH
ca alys . A simila model and ca aly ic cycle can be also
p oposed o he bo yla i e cycliza ion (X ¼Bpin).
Conclusions
We ha e success ully de eloped a s aigh o wa d app oach o
he enan ioselec i e syn hesis o dibenzo[b,d]azepines ea u ing
cen al and axial chi ali y elemen s by means o Cu-ca alyzed
asymme ic in amolecula educ i e o bo yla i e cycliza-
ions. Bo h eac ions p oceed wi h good yields and excellen
dias e eo- and enan ioselec i i ies unde mild condi ions.
Axially chi al bia yl-2-amines could also be ob ained in nea ly
pe ec enan ioselec i i y h ough a kine ic esolu ion p ocess.
Compu a ional wo k indica es ha he axial chi ali y is he -
modynamically con olled, and ha he sense o he axial
chi ali y depends on he na u e o he imine R g oup.
Da a a ailabili y
All expe imen al and compu a ional da a associa ed wi h his
s udy can be ound in he a icle o in he ESI.†
Au ho con ibu ions
R. F., J. M. L. and V. H. concei ed and supe ised he s udy. P.
R.-S., R. M. C. and V. R. pe o med he expe imen s and
analyzed he da a. V. H. and J. M. L. w o e he manusc ip . P. M.
pe o med he compu a ional s udies.
Scheme 6 Compu a ional analysis o he axial epime iza ion o
dibenzoazepines 2A (wb97xd/de 2 z p//wb97xd/de 2s p/cpcm ¼
diisop opyle he ). Rela i e ee ene gies a e gi en in b acke s
in kcal mol
1
. Da a o R ¼Ph in plain ex , da a o R ¼
Bu in i alics. Fo
de ails see he ESI.†
Scheme 7 Syn hesis o e -bu yl-subs i u ed dibenzoazepine 2Aw.
Scheme 8 Ca aly ic cycle and s e eochemical model.
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Conflic s o in e es
The e a e no conic s o decla e.
Acknowledgemen s
We hank he Spanish Minis e io de Ciencia e Inno aci´
on
(G an s PID2019-106358GB-C21, PID2019-106358GB-C22,
PID2019-104090RB-100, con ac s RYC-2017-22294 o V.H.
and BES-2017-081561 o P. R-S), Eu opean unding (ERDF),
Jun a de Andaluc´
ıa (G an s P18-FR-3531, P18-FR-644, US-
1262867, and US-1260906), and A agon Go e nmen (G upos
E34_20R). Compu a ional esou ces om he supe -compu e s
“Memen o”and “Cie zo”p o ided by BIFI-ZCAM (Uni e si y
o Za agoza, Spain) a e also acknowledged. We also hank D
F ancisco Jos´
e Fe n´
andez de C´
o do a o X- ay s uc u e de e -
mina ion o compounds 2Aj,2Ag and 4Aa.
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