O ganoca aly ic Enan ioselec i e α‑Ni ogena ion o α,α-
Disubs i u ed Aldehydes in he Absence o a Sol en
Alejand o To eg osa-Chinillach, Asie Ca al-Menoyo, En ique Gómez-Bengoa,*and Ra ael Chinchilla*
Ci e This: J. O g. Chem. 2022, 87, 14507−14513
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sı Suppo ing In o ma ion
ABSTRACT: A highly e icien enan ioselec i e α-ni ogena ion
me hod o α,α-disubs i u ed aldehydes wi h azodica boxyla es
p omo ed by a chi al ca bama e-monop o ec ed cyclohexa-1,2-
diamine as o ganoca alys has been de eloped. The p ocess was
ca ied ou wi hou any sol en , and he co esponding α,α-
disubs i u ed α-ni ogena ed aldehydes we e ob ained wi h
excellen yields and enan ioselec i i ies up o 99% ee. The
sus ainabili y o he p ocedu e was es ablished h ough he
calcula ion o g een me ics, such as EcoScale and E- ac o . In
addi ion, heo e ical calcula ions ha e been used o jus i y he
ob ained enan ioselec i i y sense.
■INTRODUCTION
Enan ioen iched α-ni ogena ed aldehydes a e impo an
building blocks in chemical syn hesis, wi h many applica ions
in medicinal chemis y and he pha maceu ical indus y.
1−5
The aldehyde unc ionali y can be ans o med in o a ious
unc ional g oups, leading o subs i u ed chi al amines in
na u al p oduc s and bioac i e subs ances.
6
Pa icula ly
in e es ing is he syn hesis o qua e na y α-amino aldehydes
as hey can be ans o med in o qua e na y α-amino acids,
which a e building blocks o cons uc ing pep idomime ics o
aluable as pha maceu icals.
7−11
An example o he la e is α-
a yl−α-alkyl α-amino acid de i a i es, which ha e shown
s ong inhibi o y e ec s on aldose educ ases, a po en ial a ge
o ea ing a ious diabe es- ela ed diseases.
12
Al hough no oo ex ensi ely explo ed, o ganoca alysis has
been ound as a di ec and con enien me hod o he
asymme ic syn hesis o qua e na y α-amino aldehydes
h ough he conjuga e addi ion eac ion o α,α-disubs i u ed
aldehydes wi h azodica boxyla es as he elec ophilic ni ogen
sou ce. Chi al amine-con aining species, sui able o gene a e an
enamine nucleophile and, a he same ime, coo dina e wi h
he elec ophile o ge a close ansi ion s a e, ha e been used
as o ganoca alys s (Figu e 1).
Thus, L-p oline (1) has been he pionee ing and mainly
employed o ganoca alys in his eac ion.
13−18
In addi ion, he
seconda y amine in L-p oline has also been he enamine-
o ming moie y in he case o he L-p oline-de i ed e azole 2,
employed in he syn hesis o cell adhesion inhibi o BIRT-
377
19
o p olinamide-de i ed hiou ea 3.
20
Mo eo e , chi al
p ima y amines ha e also been used as o ganoca alys s o his
enamine-d i en ans o ma ion, as is he case o he amino
acids 3-(1-naph hyl) alanine hyd ochlo ide (4)
21
and L-β- e -
bu yl aspa a e (5).
22
O he o ganoca alys s con aining
p ima y amines ha e been naph hyle hanamine 6,
23
chi al
benzoisoquinoline-1,3-dione 7,
24
and 9-amino-(9-deoxy)-epi-
quinine (8), alone
25−27
o combined wi h (−)-campho sul-
onic acid as a chi al coun e anion
28
o e en magne ically
suppo ed.
29
These men ioned o ganoca alys s 1−8only a o ded good
enan ioselec i i ies s a ing om α-alkyl−α-a yl aldehydes. In
addi ion, as is usual, an o ganic sol en is always p esen . Thus,
en i onmen ally un iendly halogena ed media
13,15,20,24,25,28
o
highly ola ile and lammable
22,23
o oxic
14,16−19,21
sol en s
ha e been employed. As he sol en is one o he key elemen s
o naming a chemical p ocess as sus ainable, we ha e aken
se iously in o conside a ion he apho ism “ he bes sol en is
no sol en ”
30−34
and ha e de eloped a highly e icien and
g eene enan ioselec i e sol en - ee α-amina ion o α,α-
disubs i u ed aldehydes wi h azodica boxyla es, using a simple
mono-N-Boc-p o ec ed cyclohexa-1,2-diamine 9
35
as a chi al
o ganoca alys .
■RESULTS AND DISCUSSION
The conjuga e addi ion eac ion be ween 2-phenylp opanal
(10a) and diisop opyI azodica boxyla e (DIAD, 11a), in he
p esence o he monoca bama e de i ed om (1R,2R)-
cyclohexa-1,2-diamine 9
35
as an o ganoca alys (20 mol%),
was chosen as a model eac ion o op imize he eac ion
Recei ed: Augus 11, 2022
Published: Oc obe 25, 2022
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condi ions (see Table 1). Ini ially, we we e in e es ed in he
beha io o o ganoca alys 9in con en ional, sol en -p esen
eac ion condi ions. Thus, he eac ion o 10a (2 equi ) wi h
11a o ganoca alyzed by 9(20 mol%) in se e al o ganic
sol en s a oom empe a u e o 48 h a o ded he α-
ni ogena ed α,α-disubs i u ed aldehyde 12aa in up o 71% ee
(Table 1, en ies 1−6). The absolu e s e eochemis y o 12aa
was de e mined acco ding o he o de o elu ion o he
co esponding enan iome s in chi al HPLC epo ed in he
li e a u e (see he Suppo ing In o ma ion).
Howe e , when he same eac ion was ca ied ou unde
sol en - ee condi ions, he eac ion was comple ed in 24 h,
obse ing simila enan ioselec i i y o 12aa o he one
ob ained when he bes sol en was used (Table 1, compa e
en y 7 wi h en ies 5 and 6). In addi ion, when he mola a io
o he eagen s was modi ied and 1.2 equi o 11a we e used
unde sol en - ee condi ions, he con e sion emained
unal e ed in 24 h, and he enan ioselec i i y o 12aa inc eased
sligh ly o 75% (Table 1, en y 8). This change in he mola
a io is impo an as he usual excess o he mos expensi e o
no comme cially a ailable aldehyde is a oided. The e o e, as
sol en - ee condi ions esul ed in a supe io me hodology, we
u he op imize his en i onmen ally iendlie p ocedu e.
We explo ed i he p esence o addi i es was bene icial o
he eac ion. The addi ion o an o ganic base such as 1,4-
diazabicyclo[2.2.2]oc ane (DABCO, 10 mol%) ga e ull
con e sion in only 8 h, al hough i was disas ous o he
enan ioselec i i y, ob aining 12aa as a acemic mix u e (Table
1, en y 9). Howe e , he use o acids as addi i es (10 mol%)
also ga e ull con e sions in 8 h while keeping he
enan ioselec i i y (Table 1, en ies 10−14), wi h he bes ee
(83%) being achie ed using he economic ace ic acid as an
addi i e (Table 1, en y 14). Lowe ing he loading o he
o ganoca alys 9down o 10 mol% diminished he
enan ioselec i i y sligh ly o 12aa (Table 1, en y 15), while
keeping he loading o 9in 20 mol% and inc easing he loading
o he acid addi i e up o 20 mol% aised he enan ioselec i i y
o 12aa (87%) (Table 1, en y 16). A u he inc ease in he
amoun o ace ic acid up o 30 mol% was de imen al o he
enan ioselec i i y (Table 1, en y 17).
Using hese condi ions, we employed di- e -bu yl azodi-
ca boxyla e (11b) as a bulkie elec ophilic ni ogen sou ce,
al hough he co esponding ni ogena ed aldehyde 12ab was
ob ained in lowe enan ioselec i i y (Table 1, en y 18). The
use o die hyl azodica boxyla e (DEAD) was disca ded because
i is comme cially a ailable in solu ion due o i s explosi e
po en ial.
Finally, we lowe ed he eac ion empe a u e. Thus, when
he eac ion was ca ied ou a −10 °C, he ee obse ed o
12aa aised sligh ly (Table 1, en y 19), inc easing o 94%
when wo king a −20 °C (Table 1, en y 20). A lowe eac ion
empe a u e (−30 °C) did no inc ease he enan ioselec i i y
(Table 1, en y 21). Diminishing he ca alys loading o 10 mol
% a −20 °C ga e only 70% ee o 12aa (Table 1, en y 22).
This change in enan ioselec i i y wi h ca alys loading has been
p e iously obse ed when using his o ganoca alys in o he
enan ioselec i e eac ions.
25
This could sugges ha when he
ca alys concen a ion eaches a ce ain alue, o he species
(e en combined wi h he coca alys ), such as agg ega es, could
also be p esen , modi ying he enan ioselec i i y o he p ocess
upwa d. Mo eo e , in he absence o o ganoca alys 9and in
he p esence o 20 mol% o AcOH as a coca alys , almos no
eac ion was obse ed (Table 1, en y 23). In he absence o a
backg ound eac ion, enan ioselec i i y should no a y wi h
ca alys loading unless some o he p ocesses, such as desc ibed
abo e, a e occu ing.
Once he op imized eac ion condi ions we e es ablished [9
(20 mol%), AcOH (20 mol%), 11a (1.2 equi ), sol en - ee,
−20 °C, 24 h], we p oceeded o ex end he applica ion o his
o ganoca aly ic me hodology o o he α,α-disubs i u ed
aldehydes 10 (see Table 2). Thus, we explo ed a se ies o α-
a yla ed p opanals 10b−k, bea ing di e en subs i uen s on he
a oma ic ing (Table 2, en ies 2−11).
In all cases, high isola ed yields and high enan ioselec i i ies
o he co esponding α-amina ed aldehydes 12ba-ja we e
ob ained, al hough in he case o he 4-ni o-con aining
aldehyde 10k, he co esponding adduc 12ka was ob ained
in a lowe 77% ee (Table 2, en y 11). In addi ion, a 2-naph hyl
in he aldehyde 10l ga e he co esponding adduc 12la in an
80% ee (Table 2, en y 12). Mo eo e , changing he α-me hyl
in he aldehyde 10a by e hyl (10m) allowed us o ob ain he
co esponding inal ni ogena ed aldehyde 12ma in 97% ee
(Table 2, en y 13). Fu he mo e, when 1,2,3,4- e ahyd o-
naph halene-1-ca baldehyde (10n) was employed as he
s a ing aldehyde, he inal adduc 12na was ob ained in a
90% ee (Table 2, en y 14).
When using an α-benzyla ed-α-me hyl aldehyde, such as
cyclamen aldehyde (10o), he eac ion ga e he co esponding
ni ogena ed adduc 12oa wi h an enan ioselec i i y o 89%
(Table 2, en y 15). In e es ingly, when se e al α,α-dialkyla ed
aldehydes 10p−swe e used as s a ing ma e ials, he inal
adduc s 12pa-sa we e ob ained wi h excellen yields and
enan ioselec i i ies anging om 82 o 95% (Table 2, en ies
16−19). These high enan ioselec ions a e ema kable as low o
Figu e 1. O ganoca alys s 1−8employed p e iously in he
enan ioselec i e addi ion o α,α-disubs i u ed aldehydes o azodica -
boxyla es and o ganoca alys 9used in his s udy.
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qui e mode a e enan ioselec i i ies ha e been ob ained om
α,α-dialkyla ed aldehydes using o he o ganoca alys s and
sol en -including eac ion condi ions.
13,15,20−25,28
These las
esul s demons a ed he unusual applicabili y o his me hod-
ology o all kinds o s a ing disubs i u ed aldehydes.
We also ca ied ou he syn hesis o compound 12qa unde
he op imal eac ion condi ions, bu using 20 mol% o p oline
(1) as a commonly used o ganoca alys , achie ing an
enan ioselec i i y o 59% ee. In addi ion, he use o 20 mol%
o chi al naph hyle hanamine 6ga e 12aa in 63% ee and
quinine-de i ed amine 8a o ded 71% ee. These enan iose-
lec ions a e no iceably highe han hose epo ed o simila
adduc s om 10q o o he dialkyla ed aldehydes when using
hese ca alys s unde con en ional sol en -including eac ion
condi ions.
15,23,25
To e alua e he “g eenness” o ou p o ocol, we calcula e he
EcoScale and E- ac o o he eac ions, leading o adduc s 12
(see Table S1 in he Suppo ing In o ma ion). Thus, he
ob ained EcoScale
36
alues anged om 63 o 72, which
means, acco ding o he es ablished de ini ions, ha he
eac ion condi ions canno be anked as “excellen ” (EcoScale
> 75) bu can be si ua ed in he uppe pa o “accep able”
(EcoScale > 50). No “inadequa e” eac ion condi ions we e
obse ed (EcoScale < 50). Expec edly, he EcoScale alues
om his sol en - ee me hodology a e highe han he
calcula ed o p e iously epo ed sol en -including eac ion
condi ions (see Table S1 in he Suppo ing In o ma ion). In
addi ion, he E- ac o
37
o he p epa a ion o all compounds
12 was ini ially calcula ed excluding pu i ica ion ma e ials (no
wo kup is employed), gi ing alues in he ange 0.27−0.47
(see Table S1 in he Suppo ing In o ma ion). Howe e , mo e
ealis ic alues (244−346) we e ob ained when conside ing he
pu i ica ion by column ch oma og aphy, a me hod p esen in
all p e iously epo ed p ocedu es, which also include wo kup.
We also p o ed he easy scalabili y o his sol en - ee
p ocess by ca ying ou he conjuga e addi ion o aldehyde 10a
wi h 11a unde he condi ions o Table 2 bu on a 3 mmol
scale o 10a. This scaled-up eac ion allowed us o isola e 0.96
g (95% yield) o he adduc 12aa in a 93% enan ioselec i i y,
which a e almos iden ical esul s o hose ob ained when
wo king on a 0.2 mmol scale (Table 2, en y 1).
The syn he ic use ulness o hese enan ioen iched ni o-
gena ed adduc s 12 was exempli ied by p epa ing he
hyd azide-con aining oxazolidin-2-one 13 in a 92% yield a e
educ ion o aldehyde 12aa, ob ained in he scaled-up eac ion
(93% ee), and u he cycliza ion (Scheme 1). The subsequen
eac ion o 13 wi h me hyl b omoace a e in he p esence o
cesium ca bona e, and addi ional ea men wi h his base, ga e
he (R)-oxazolidinone 14 in a 90% yield and he expec ed 93%
ee.
To ge u he insigh in o he beha io o o ganoca alys 9
when leading o he obse ed sense o enan ioselec i i y, we
pe o med DFT heo e ical calcula ions (see he Suppo ing
In o ma ion) on subs a es 10a and 11a. Thus, he ini ial
enamine o med be ween aldehyde 10a and ca alys 9can
adop wo di e en con igu a ions, and he mos s able one
Table 1. Enan ioselec i e O ganoca aly ic α-Amina ion o Aldehyde 10a wi h Azodica boxyla es: Op imiza ion Expe imen s
en y R 9 (mol %) 10a/11 mola a io addi i e (mol %)
a
sol en T(°C) (h) % con .
b
%ee
c
1iP 20 2/1 PhMe 25 48 89 52
2iP 20 2/1 CH2Cl225 48 93 54
3iP 20 2/1 DMF/H2O
d
25 48 100 57
4iP 20 2/1 THF 25 48 57 60
5iP 20 2/1 TBME 25 48 73 71
6iP 20 2/1 E 2O 25 48 51 71
7iP 20 2/1 25 24 100 69
8iP 20 1/1.2 25 24 100 75
9iP 20 1/1.2 DABCO (10) 25 8 100 0
10 iP 20 1/1.2 HDA (10) 25 8 100 77
11 iP 20 1/1.2 PhCO2H (10) 25 8 100 71
12 iP 20 1/1.2 3,4-DMBA (10) 25 8 100 73
13 iP 20 1/1.2 NBA (10) 25 8 100 81
14 iP 20 1/1.2 AcOH (10) 25 8 100 83
15 iP 10 1/1.2 AcOH (10) 25 8 100 81
16 iP 20 1/1.2 AcOH (20) 25 8 100 87
17 iP 20 1/1.2 AcOH (30) 25 8 100 76
18 Bu 20 1/1.2 AcOH (20) 25 8 100 (98) 84
19 iP 20 1/1.2 AcOH (20) −10 24 100 88
20 iP 20 1/1.2 AcOH (20) −20 24 100 (99) 94
21 iP 20 1/1.2 AcOH (20) −30 24 100 89
22 iP 10 1/1.2 AcOH (20) −20 24 100 70
23 iP 1/1.2 AcOH (20) −20 24 3
a
Abb e ia ions: DABCO: 1,4-diazabicyclo[2.2.2]oc ane; 3,4-DMBA: 3,4-dime hoxybenzoic acid; HDA: hexanodioic acid; NBA: 4-ni obenzoic
acid; TBME: e -bu yl me hyl e he .
b
De e mined by 1H NMR om he emaining aldehyde; isola ed yield a e lash ch oma og aphy in
pa en hesis.
c
Enan ioselec i i ies and absolu e s e eochemis y de e mined by chi al HPLC on he eac ion c ude.
d
2:1 ( / ).
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co esponds o he phenyl g oup ans o he NH moie y (A-E
isome , Figu e 2). The A-Zenamine was ound o be 1.4 kcal/
mol highe in ene gy, a o ding a p edic ed 10:1 E/Zenamine
a io. This di e ence is signi ican bu no enough o disca d
he pa icipa ion o bo h enamines in he eac ion (see below).
F om his ini ial poin , he nucleophilic a ack on he
azodica boxyla e looks qui e s aigh o wa d o compu e.
Howe e , as p e iously desc ibed by ou g oups in ela ed
eac ions,
35
he calcula ions showed a complex mix u e o
possible con o ma ions and eac ing aces o he wo
subs a es. Fo example, jus o indica e some o he a ying
ac o s, he enamine can adop di e en con o ma ions, ha is,
A(Eand Z) o B(Eand Z) (Figu e 2). The app oach be ween
he enamine and azodica boxyla e can p oceed h ough
dias e eome ic endo (C) o exo (D) ansi ion s a es, and
bo h he nucleophile and elec ophile p esen wo eac ing Si
and Re aces. In he case o he azodica boxyla e, hese aces do
no gene a e a new s e eogenic cen e bu s ill s ongly a ec
he app oach’s selec i i y o he enamine. Meanwhile, he wo
aces o he enamine lead o he Rand Senan iome s o
p oduc 12aa a e o ming he co esponding dias e eoselec-
i e ansi ion s a es.
Following ex ensi e calcula ions o all possibili ies, s uc u e
A-Ewas ound o be he mos eac i e enamine, whe e wo
main ac o s a ec he elec ophile’s app oach. Fi s , he Re
ace (uppe ace in A-E ep esen a ion), which leads o he
mino Senan iome o he p oduc , is less s e ically conges ed,
as compu ed by he di e ence be ween TS2 and TS4 (Figu e
3). Meanwhile, an in amolecula hyd ogen bond can be
o med be ween he ca bama e NH o he ca alys and one o
he ca bonyl g oups in he azodica boxyla e. This H-bond is
easie o c ea e and s onge in he lowe Si ace o he enamine
(TS1 s TS3). Thus, wo opposi e ac o s a e compe ing, wi h
he s e ic one a o ing he Re app oach and he H-bond
leading o he Si ace ac i a ion. The compu ed ene gies o he
mos p e e ed s uc u es (TS1−TS4) show he s onge
s abilizing e ec o he H-bond, which ou compe es he s e ic
des abiliza ion, making TS1-E he lowes ansi ion s a e in
ene gy and explaining he o ma ion o he expe imen al R
majo enan iome . Rela ed ansi ion s a es we e ound o he
mino Zenamines, bu hei ac i a ion ene gies a e a leas 2.0
kcal/mol highe , indica ing ha hey do no pa icipa e in he
eac ion. I is wo h no ing ha , in he absence o he
in e molecula H-bond be ween he elec ophile and enamine,
a weake in amolecula H-bond o ms be ween he NH o he
enamine and he ca bonyl g oup o he ca bama e, bo h in he
ca alys . Finally, he calcula ions we e epea ed wi h aldehyde
10p, con aining me hyl and e hyl subs i uen s, and he esul s
we e almos iden ical o he p e ious ones, ein o cing he
ag eemen be ween calcula ions and expe imen s (see Figu e
S106 in he Suppo ing In o ma ion).
■CONCLUSIONS
α,α-Disubs i u ed aldehydes ha e been enan ioselec i ely α-
ni ogena ed employing diisop opyl azodica boxyla e as he
elec ophilic ni ogen sou ce and a simple chi al mono-N-Boc-
p o ec ed cyclohexa-1,2-diamine as he o ganoca alys unde
Table 2. Enan ioselec i e O ganoca aly ic α-Amina ion o
α,α-Disubs i u ed Aldehydes 10 unde Sol en -F ee
Condi ions
a
a
Reac ions we e ca ied ou by mixing 10 (0.2 mmol), 11a (0.24
mmol), ca alys 9(0.04 mmol), and AcOH (0.04 mmol).
b
Isola ed
yield a e lash ch oma og aphy.
c
De e mined by chi al HPLC on he
eac ion c ude (see he Suppo ing In o ma ion).
d
Absolu e s e eo-
chemis y o known compounds was de e mined acco ding o he
elu ion o de o he co esponding enan iome s (chi al HPLC) in he
li e a u e (see he Suppo ing In o ma ion). Absolu e s e eochemis y
o unknown compounds was assigned by analogy.
Scheme 1. P epa a ion o Enan ioen iched Oxazolidinone
14 om α-Ni ogena ed Aldehyde 12aa
Figu e 2. Compu a ional models o he nucleophilic E-enamine (A,B)
and he endo (C) and exo (D) ansi ion s a es.
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sol en - ee condi ions, he p esence o ace ic acid as an
addi i e imp o ing he esul s. Con a y o o he epo ed
me hodologies, high yields and enan ioselec i i ies we e
ob ained om alkyl-α-a yl aldehydes and hei α,α-dialkyla ed
coun e pa s. The ob ained adduc s can be ans o med in o
aluable compounds, such as enan ioen iched oxazolidine-2-
ones. Theo e ical calcula ions con i med he bi unc ional
beha io o he employed o ganoca alys , esponsible o he
o ma ion o he nucleophilic enamine and he ac i a ion o he
elec ophilic azodica boxyla e h ough he c ea ion o an
in e molecula hyd ogen bond wi h he NH o he ca bama e.
The s abilizing e ec o he H-bond is also esponsible o he
enan ioselec i e o ma ion o he majo Risome . This
p ocedu e is e icien , easily scalable, and en i onmen ally
con enien o he enan ioselec i e p epa a ion o syn he ically
use ul α,α-disubs i u ed α-ni ogena ed aldehydes.
■EXPERIMENTAL SECTION
Gene al P ocedu e o he O ganoca aly ic Enan ioselec-
i e α-Ni ogena ion. A glass ial (ø 16 mm) was cha ged wi h 9
(8.6 mg, 0.04 mmol, 0.2 equi ), ace ic acid (2.3 μL, 0.04 mmol, 0.2
equi ), aldehyde 10 (0.2 mmol, 1 equi ), and azodica boxyla e 11
(0.24 mmol, 1.2 equi ). The mix u e was gen ly s i ed a −20 °C
unde an a gon a mosphe e o 24 h. A e his ime, he eac ion
c ude was pu i ied by column ch oma og aphy [silica gel, hexanes/
e hyl ace a e (85/15, / )] o a o d he p oduc 12. All cha ac e -
iza ion da a o compounds 12 a e a ailable in he Suppo ing
In o ma ion.
Scaled-Up Syn hesis o 12aa. A glass ial (ø 16 mm) was
cha ged wi h 9(0.6 mmol, 129 mg), ace ic acid (0.6 mmol, 36 mg,
34.5 μL), aldehyde 10a (3 mmol, 402 mg, 0.40 mL), and
azodica boxyla e 11a (3.6 mmol, 727 mg, 0.73 mL). The mix u e
was gen ly s i ed a −20 °C unde an a gon a mosphe e o 24 h.
A e his ime, he eac ion c ude was pu i ied by column
ch oma og aphy [silica gel, hexanes/e hyl ace a e (85/15, / )] o
a o d p oduc 12aa (0.95 g, 95%, 93% ee).
■ASSOCIATED CONTENT
*
sı Suppo ing In o ma ion
The Suppo ing In o ma ion is a ailable ee o cha ge a
h ps://pubs.acs.o g/doi/10.1021/acs.joc.2c01919.
Ma e ials, me hods, expe imen al p ocedu es, cha ac e -
iza ion da a, 1H NMR and 13C NMR spec a, HPLC
Figu e 3. Compu ed ansi ion s a es o he eac ion be ween he enamine om 9and 10a and 11a. Ene gies a e gi en in kcal/mol (see he
Suppo ing In o ma ion).
The Jou nal o O ganic Chemis y pubs.acs.o g/joc A icle
h ps://doi.o g/10.1021/acs.joc.2c01919
J. O g. Chem. 2022, 87, 14507−14513
14511
ch oma og ams, calcula ion o sus ainabili y me ics, and
compu a ional da a (PDF)
■AUTHOR INFORMATION
Co esponding Au ho s
En ique Gómez-Bengoa −Depa men o O ganic Chemis y
I, Uni e si y o he Basque Coun y UPV/EHU, Donos ia-
San Sebas ián 20018, Spain; o cid.o g/0000-0002-8753-
3760; Email: [email p o ec ed]
Ra ael Chinchilla −Depa men o O ganic Chemis y and
Ins i u e o O ganic Syn hesis (ISO), Uni e si y o Alican e,
Alican e 03080, Spain; o cid.o g/0000-0002-9894-1671;
Email: [email p o ec ed]
Au ho s
Alejand o To eg osa-Chinillach −Depa men o O ganic
Chemis y and Ins i u e o O ganic Syn hesis (ISO),
Uni e si y o Alican e, Alican e 03080, Spain; o cid.o g/
0000-0002-4416-9559
Asie Ca al-Menoyo −Depa men o O ganic Chemis y I,
Uni e si y o he Basque Coun y UPV/EHU, Donos ia-San
Sebas ián 20018, Spain
Comple e con ac in o ma ion is a ailable a :
h ps://pubs.acs.o g/10.1021/acs.joc.2c01919
Au ho Con ibu ions
The manusc ip was w i en h ough he con ibu ions o all
au ho s. All au ho s ha e gi en app o al o he inal e sion o
he manusc ip .
No es
The au ho s decla e no compe ing inancial in e es .
■ACKNOWLEDGMENTS
This wo k was unded by he Spanish Minis y o Economy,
Indus y and Compe i i eness (PGC2018-096616-B-I00), he
Spanish Minis y o Science and Inno a ion (PID2019-
110008GB-I00), and he Uni e si y o Alican e (VIGROB-
173). We also hank SGIke (UPV/EHU) o p o iding
human and compu a ional esou ces.
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