Article Type: Full Paper ‡

AcceptedETH Article †

This article isThis article by protected copyright. All rightsreserved. 10.1002/hlca.201700182 doi: differences to citethisaslead article between the of thisversion and Version Record.Please copyediting, paginationbeen throughthe andproofreadingtypesetting, process,may which This article acceptedhas been for publication andundergone fullpeer review but hasnot T ETH am yrldn Eaie ih Relevance with Enamines Pyrrolidine Zürich, Laboratorium Zürich, für a Zürich, Laboratorium Zürich, für E-mail: Rig ra

Husch, ru ofrainl Analysis orous Conformational [email protected]; [email protected]; †

Dieter Dieter Organo Seeb Organische Chemie, Chemie, Organische Zürich, ach, Physikalische Chemie, Chemie, Physikalische Switzerland ∗ , ‡

Switzerland Al catalysis bert bert [email protected]

K. Vladimir-Pr

Beck,

Vladimir-Pr

‡

and el Markus o g-W el eg o g-W

2, Reiher

eg of 8093

3, to

8093 Zürich, Zürich, ∗

, †

carbonyl carbonyl tion myriad intermediates. has The In This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. Accepted Article tr Catalytic

2 become become reaction reaction – of and pr pronounced Michael stable at enamines. determined preferences in which tions whic method structure be differences energy by through tions o 36

oving of duction Michael Michael meaningful conclusions. conclusions. meaningful is agreemen elaboration elaboration It comp

substituen stereoselectivity requires requires stereoselectivity

presen of of has been suggested suggested been has we for

a pyrrolidine a large numba large distinct conformational conformational distinct of the reactions reactions additions

ounds pl validated

The aldehyde- alde W additions. additions. thermodynamic- ayground t ted stability e with

found

of hydes

preferred preferred in and and the ts a computational protocol

eur odtosta f require conditions that Scheme of the in enamines enamines against against er

tw that and pyrrolidine-deriv differences differences the and

av een een in h, of for for

pyrrolidine conformers. conformers. that ailable ketone-deriv in an 2psto. by A 2-position. ena

chiral ketones Most Most the diin must addition, explicitly explicitly one 1 for illustration 1 for appropriate co

is further ntioselective ntioselective the

ofres necessita conformers

n

achiev enamine enamine

of trol ex prominen preferences preferences secondary amines amines secondary origin origin

the perimental perimental with hypothesis.

theoretical correlated coupled coupled correlated ed ed Our deriv Abstract ed enamine isomers isomers enamine

of nitroolefins nitroolefins

enamines. enamines. by conformational sampling sampling conformational are are enamines enamines tl protocol is based on density density based on is protocol

that regio- regio- ativ organocatalytic organocatalytic chemistryi y all thermodynamic thermodynamic , of

not av

no s- pur ow data,

warran the es or cis cis

readily readily The

in means complete complete means and and/or p

for v

enamine and oses. enamines. enamines. te

estigation can, can, The but

computationally computationally to

e

are are substituted stereoselectivity stereoselectivity a a lucidation lucidation ts s- form form illustrate illustrate and high regio- regio-

cluster

h transferable transferable sufficien tr ow cause cleav cause ans

conformers conformers rather rather formation from the from formation ever, accuracy accuracy s γ

W of conformers are are conformers -nitro-carbonyl -nitro-carbonyl compounds and theor e

of t the

is

not that assess assess accuracy.

than

inevitable or th stereoselectivity stereoselectivity

y. to elementary elementary e

functional functional theory age in of conformational conformational feasible feasible be be chronological chronological p origin origin other other The kinetic kinetic in

yrrolidines

Michael Michael the nv this proposal proposal this

explained explained general, general, of

olving enamine enamine olving results results electronic intermediates The of similarly similarly to t calcula- calcula- yp co regio- regio-

small arriv precursor steps steps addi es ntrol dis

are are 1

b of in in

y collec- collec- with with e - - - a

collection collection absolute of sented. groups of Michael Scheme This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

one one

Accepted selected Article of and/or and/or 1: The additions additions

configuration th

of further of Li pyrrolidine e

st st authors authors (DS). examples examples stereogenic of pyrrolidine to examples see see examples nitroolefins nitroolefins

deriv op are posite posite from a from ce ativ In n deriv

ters ma es to in with peculiar peculiar with

th the ativ ny personal personal are catalytic e

first first cases, cases,

es

sh one that that

own,

sixteen pages pages sixteen sh the randomly randomly o have been used successfully successfully used been have or and wn authors authors

stoichiometric structures, structures,

throu acceptors acceptors

collected collected

g

used used in h o Ref. Ref. [36]. u containing additional functional containingfunctional additional t other than nitroolefins than other pyrrolidine this applications. applications. pile pa of per. F per.

references references deriv for for or ena Some Some a most most a a ti n v tioselectiv in es formulae a folder a with are recen pre

an e t - -

called called ena ketones Scheme pr of topicity aldehyde alde other than or basic presence a matter to o enamines in This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. xazines, ocess ocess the polymer-bound polymer-bound the Accepted Article γ in There This ntiomeric ntiomeric hydes -nitro-carbonyl -nitro-carbonyl tram

pyrrolidine ring pyrrolidine catalytic catalytic or syn whether whether with hydrocarb 2: 2: lk is re

38 of or o

-configuration. with is

induced by induced and and v l

nitr in

e i.e (2+2)- and (4+2)-cycloadducts. (4+2)-cycloadducts. and (2+2)- i.e

e a (

an cu ketone rs Si ketones (see Scheme Scheme (see ketones both s oeis (see oolefins nitroolefins occur occur nitroolefins up a tructural remarkable difference difference remarkable la

ketones ionic / l the

cycle Si r w step p

as )-Coupling

yrrolidine-t

comp on cases, cases, Michael α

-carbonyl carb -carbonyl first first liquid, ( side chains the cf re has

units of

46 . acidadditives). . verses: verses: ou

but

re b

so n low

same same 43 addition addition ported ported by ds een

-called -called the yp

of of

er in up observed. observed.

ni it e protic, aprotic, polar polar aprotic, protic, part γ

1.4 2

( on catalyst, -nitro-aldehydes -nitro-aldehydes is on S tr ). on

on a [ a oolefins with with oolefins domino )-form )-form b acid

occurs occurs 45,46 te pyrrolidine the -induction by the -induction by

e of Yamada

mixing mixing t and lk w

Scheme

, , een ic Stoichiometric reactions reactions Stoichiometric

lk 39,40 39,40 45 In

aqueous aqueous of in a in

-1.4]- -1.4]- the sequences sequences the overall the

the the of and in et catalytic 2-substituted pyrrolidines, 2-substituted The

1), a a 1), a ball mill, a ball reactions reactions al. pr β alde lead and hydrolysis w ocess ocess -nitroolefin carb -nitroolefin in orkup. re mo hydes

of stereogenic γ versal or 1969 to ntoktns respectiv -nitro-ketones, pr i or

e with

reactions,

t ocess ocess of non in a in cyclobutanes y

16,22,37,38

41

and in alde (see Scheme Scheme (see of

-polar solvents, with acidic, acidic, solvents, -polar with stoichiometric alde micr of

stoichiometric fashion, fashion, stoichiometric enantioselectivity the trigonal trigonal the

hydes ( these cycloadducts cycloadducts these

of R h center ow

34,44 34,44

on ydes e

preformed preformed / a R couple couple v

and 37 e e-assisted,

or

and and [ a )-coupling in

and/or and/or with with 1), 1), the 2-position 2-position the

to of ce

with

reactions reactions as as ketones: ketones: gi n pyrrolidine lk ters el ve acceptor an , , be

y, 42 di

ul 45 45 relativ

rise hydro

tw of of in

leads leads -1.4]- -1.4]- in with with with so- so- the the the een ter- ter-

of no no to e

s -

t the face for topical stitue supposed more Si aldehyde-deriv or interpreted Hence, intermediates. thermodynamic conditions should equilibrium slow too leading pr eventuallylead possible higher the substituted (for tivities re carb tr notableeffect ketone proline-ester This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. w oolefins oolefins under

ported ported constitutions ratio oduct -face -face Acceptedeen Article Due According Besides on stable n the the ts without without reacts reacts is to to reasons. (cf. a freely a rotating (cf. topicity to

the the to op

enamine rotamers rotamers enamine repulsion repulsion allow for allowfor the the as

en arrangemen and be be

ed to is observ resulting from from resulting

eislciey (e Sc (see regioselectively pr re in for coupling with for control the sterically to te niey determined entirely then (di-/trisubstituted (di-/trisubstituted

-amide-deriv cataly oducts. F oducts. enamine enamine versal terpretation. terpretation. re

differen versals

ap Curtin ed by Curtin both, the both, s p

the of of is in t roa

smaller by

pr additions enantioselectivity of t for or is

R-group ch – oduct a stereoisomers stereoisomers – more substituted higher the 2-substituted pyrrolidines: Hammett Hammett must the ed group), group), Hammett preferred conformations conformations preferred 5 aldeh CH be be by a nitroolefin. nitroolefin. a by

ketone-deriv

enamines enamines ena the

formation, but 3 (“flat”) presen consi be be - α stable than the s- the stable than double double ydes ntioselectivit -carbonyl -carbonyl on of ni well heme principle, a fast equilibrium dered. unsymmetrical unsymmetrical the pyrrolidine ring the s- the ring pyrrolidine the versus ketones versus kinetics tr t than

oolefin. oolefin. case, h case, with acrylonitrile, acrylic with displaced displaced would not affect the affect not would bond) theof bond) by ed so

be 3). Most Most 3).

enamine enamine 19

ht the that tw carb th an y

14b Note that the latter term term latter the that Note een een ow

e It instead implies a implies instead

re activation sp

Barb on

and ever, ever, versal and is to 3 alde

hbiie carb -hybridized

atom atom cis speculated speculated as (s that one R in of is enamines ketones, - hydes e

it cis s nitroolefin additions nitroolefin 10 10 the form form

-face -face

side” - w of

cis and /s thermodynamic thermodynamic free free as

the - ketones) ketones) numerous numerous tr and duct argued argued (see Scheme Scheme (see . would because because 14a pr

ans Alexakis Alexakis such

in regioselectivity that “the that predominan o energies energies tr

of

esters, and The The ketones, there there ketones, v ans

), ol

intermediates on

as become become v configurations configurations did did ed.

ht equilibration that ratio. Instead, Instead, the ratio.

regioselectivity regioselectivity conformation conformation an 2-butanone, 2-butanone, atom with atom 14 14 authors

10,14,19

do equilibrium be- be- equilibrium of not sp argued argued 2), 2), control by control es the t 2 meth the

- or role role

commen CH ,

not so

h α

who reactions preferred preferred is regioselec- regioselec- -carbonyl -carbonyl

av -group -group its of ht can that yl another that the the that refer that the the that e e - stable (E/Z), (E/Z), vi of to sub- sub- been been pre- ha h t n the

a yl ni on is is v s to to is

e - -

it cycle catalytic in ysis class chemists. ganic Scheme side chain(s) pyrrolidine of is reactions Scheme also the follo spect ( sp that briefly coupling the i.e. nitroolefins, with mation. suggesting phenomena, double b tuted b This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. ii een y tempting tempting v hm rte than rather them,

onding ) the the ) Accepted, Article ol

resulting 16,17,22,59 Since Since Before

58 ws discussed discussed v ( of i to es

) the s ) there there discussed the the

2 the the chiral compounds, see, see, compounds, electrophilic electrophilic 4. – s- the 4,6,9,11 i

nv turning transition state state transition general cis – substituen 62

olving to 2 a was seminal seminal - approach approach tr

and E/Z-e enamine enamine difference – ond ans enamines, enamines, in (see Scheme Scheme (see prop 13,15,17 They in terms

a ba

3. With 3).

to

view 14b,19 14b,19 enamine so ose renewed quilibr attack pological pological ck work by

are – t to ma 20,24,25,27 tr

from a to on

the ajectories ajectories e.g., Refs. [55 Refs. e.g., (S in of assume assume the treated treated of and ny the pyrrolidine ring, any pyrrolidine mainly atio cheme

the higher models models of the

from from A same same differen

2 burst the the nitro group nitro the

Stork lexakis structures structures n – rule, rule, which k –

, etone ) F 4). 32

stabil

22,63 observ nitroolefin nitroolefin in diinl interactions additional

an 3). 3). stability (i

in , A

of of

1 d text t

aldehyde whi ’

substituen structures

ea it interest the or enamines h enamines are – and Besides Besides and ed y 57]. Triggered 57]. li

bo

of some some z of

ch the ch the trigonal ed

identical one oks, oks,

B

Barb enamines, enamines, th ) of

occurs occurs transition-state (S most stable stable most

e and the the of deri the explicit explicit the relev

in and cheme and of

as enamines enamines in

enamines enamines av ts our

the the

v a ’ enamines because because enamines R pro e b e ati

corresp stereochemical outcome outcome stereochemical ce

an from from the hr are there (

2-substituted 2-substituted iii groups groups ves, ves, nters by on incoming electrophile, electrophile, such incoming the een t solid 4) work

) the ) posals. posals. the the

lead lead between i and relativ is nv ond adopt as of discussions discussions often often

state, has

coupling coupling estigated estigated ad less hindered

heter

se the on i reactiv to these these tr ng v If veral monographs monographs veral

ajectories ajectories e the en put

formation,

enamine enamine topicity an

most most 64 we pyrrolidineand ocycle ocycle t ucinl groups functional assumed assumed

– forward s- of t

66 e observ w one ma of intermediates

tr by mo o pyramidality of reactiv the ans reactants, must ke

(S class class generations generations dern of these these anti A ed centerstrigonal with cheme

the of implicitly when when implicitly their or

in

relative stabil- stabil- relative

the and

e s pr -face -face

organocatal- organocatal-

198 a trisubsti- trisubsti- a isomers, assumptions assumptions of remarkable - oducts cis

the ab

catalysis

reac n 1), B 1,

umerous umerous as as with out on

confor- confor- 47 on corre

50,51 50,51 of of for for ti

C the then then

the o this

the the 10,14 10,14 or (see n re all all b s in - it it

e

- -

considered considered tor. pro as arrangemen Scheme 6.2 Refs. and/or tr Scheme This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. oolefins. oolefins. Accepted Article in . p

49 49 v

osals,

in C [2, [2, Thus, , , Ref. Ref. [54]. more more 4: 3: 6, of

2,3,6,13,17

a Schematic Schematic as The 10, Reg ts

de reactiv syn just just (

C 14,

i pending pending o enamine enamine ) ) s e substituen – The

another large large another of 20, l 20,27 e e ctiv a than the than tr

26, regioselectivities regioselectivities – substituen ajectories ajectories 32 e on ih the with

disregarding disregarding 28, pyrrolidine-catalyzed pyrrolidine-catalyzed the solven the t

with

29,

one one substituen

39, t

of the

trisubs in with only only with

enamine-nitroolefin coupling coupling enamine-nitroolefin

52, 2-position 2-position nitro t, the are a functional group group functional a

53], t i fc ht ir group nitro a that fact tuted t,

in group

as . for a a

t suggested suggested w

coupling coupling range of o discussions discussions double double

the geminal geminal ae b have pyrrolidine ring. ring. pyrrolidine of b

60:40 60:40 of ond in een substituents. unsymmetrical a

and on B’

is i

nv to teproiie ig may ring pyrrolidine the for a proline for derivativ

references, references, assumed assumed 95:5. 95:5. ok with is ed

in anti 48 po 14

ma

to Interactions, suc F or see also also see or ketones

( ny A be be H-bond H-bond

examples, see see examples, , ,

me more B ) ) chanistic Section Section and with e. stable accep- accep-

syn syn ni b h e -

higher formed ( prop-1- the b according pyrrolidine i future of nalize fo other regioselectivity allow will this results v ture series assembled ences. Michael out interest the spite well Alexakis and nitrogen This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. 5 eled cus the Accepted), Article N(1) W In

ab reactions reactions and

as as

this this e

on 2

by origin the hand, substituted

ov respective reactions, reactions, respective – en nv generated generated from the from 4,6,9 theoretical conformational conformational theoretical the styrenyl ( styrenyl , , e) additions atom, substituen integers, atoms atoms integers, -2- estigations. Barb to theoretical theoretical

– substituen mo

15,17 the yl i we establish establish we al nv

of s as

( 54,64,67 us idated against against idated explicitly t of 2 – estigation the

of

20,24,25,27 same k same ), of , , enamines qualitativ scheme presented presented scheme

a to and i Michael

α 6 enamines, enamines, in

ts nv prop-1-en-1- series series -carbonyl test the test groups. ) enamine intermediates which

–

work, ts by olving 69 ter groups did their

etone,

stereo- stereo- (see Scheme Scheme (see

oain ar rotation l ihn the within – ow a of 32 of

71 71 e additions additions i we presen we

er which sound sound

enamines enamines me enamines enamines

e have we rpsdcnomtoa preferences conformational proposed for for which case case greek 2- A

carb Enamines Enamines and lexakis chanistic discussions discussions chanistic yl butanone,

is th ( on ound

3 C(2) C(2) in regioselectivity regioselectivity analyses analyses

), 5). 5). e out t

oretical nv a atom but-2-en-2-yl but-2-en-2-yl (

to ’ by Scheme and we discuss free energies energies deriv free discuss we as

refer refer olving detailed conformational analysis analysis conformational detailed the correlated coupled coupled correlated W n gradually gradually of letters. letters.

substituen with o nu

e t

the 2,6,10,14,20,26,28,29,40,52,53 2,6,10,14,20,26,28,29,40,52,53 whi

la Barb c N ap

with state- with l the substituen the basis basis b e – to ch 5:

enamines enamines p el op C-b sco ear h ieaue the literature, the Atoms within the pyrrolidine ring are ring pyrrolidine the within Atoms

The as w the h pe pe on iles as

rather than rather ’ ts for further for i

ncreasi to of

proposals proposals N(1) is d

atoms atoms 4 of are sh by primed by ,

the surprising

), 64,65,67 64,65,67 be be th o

of deriv wn buten-1-

is

-the aw substituen ng based based cluster data. stereo

within the pyrrolidine the within foundational to the ts are ed reactivity -art meth -art react react me on

on 4 from (see Scheme Scheme (see integers, integers, of. Still, of.

on co the origin the en

chanistic discussions. discussions. chanistic size size brough and the detailed detailed the because because ed

ntrol

-2- pre conformational conformational ts

regioselectively regioselectively

from from of sec. sec.

4’ yl , - chosen are are chosen

2004 68 of o the

of t On ds ( work

on forward and a systematically

4’ n organocatalytic organocatalytic ex amines. amines. electronic electronic (as (as ucleophilicit are N(1) N(1) the ), N(1) are both are both N(1)

of 3). 3). perimen part part

atoms atoms cyclohexen

me w stereo- stereo-

and

scarce scarce Th one one e vinyl enamines enamines and

c of

to h p lf for left e On prefer- prefer- a whic on C(2) C(2)

oi within within tal hand, hand, struc- n ratio- ratio- C(2) nted isms isms the and and the ( y

de

W 1 , la as

yl yl 70 ), ), h e - - -

includes generic enamines enamines generic includes models) comprises comprises approximations models) evaluating standard for protocol Gibbs free Ne elective Ov Computational greek case substituen the pyrrolidinering Atoms within letter. referred Scheme stitue structure ditions The ta on ( substituen This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. d n ), the pyrrolidine ring ring pyrrolidine the Accepted vertheless, Article er ts

pyrrolidine with with pyrrolidine and the last last the n of

t 2,6,10,14,20,26,28,29,40,53

stoichiometric 5: organocatalytic organocatalytic names, e.g., e.g., names, to (ihnl(rmtysllx)ehl ( (diphenyl)(trimethylsilyloxy)methyl is

ts with a black a with ts letters. Lewis Lewis

a by of v ea decades, decades, ailable. the blue primed ch s

tructures of proiie ring pyrrolidine 1a

an these standard models (e.g., (e.g., models standard these

66 66 theoretical chemistry and . . and

reactions reactions itgradC2 substituen C(2) integer and e Note that that Note metho

substituen and for N(1) N(1) for ih ipeaihtc side simple aliphatic with

as also derivatives, also integers, integers,

intermediates

6e can

to dology is are we and

t k one

and eep

is be successfully analyzed analyzed successfully be refer refer

mty ( methyl C(2) perhaps perhaps are

of atoms atoms the the the

energies energies la to of has

which calculations feasible, feasible, calculations substituen b the the catalytic e eled few few

groups. ) within the N(1) N(1) the within the matured a appr ),

were

specific compounds compounds specific most by enamines enamines in et ts chains (series (series chains oximate electronic electronic oximate blue the h ( ts yl R Michael re where where

( to common common 2

Hence, Hence, ported ported ) with a black l black a with ) b gas a integers, atoms atoms integers, ), pro for whi for phase, phase, ih the with stage where where stage N(1) N(1) substituen additions in whi our our y ( pyl catalyst catalyst ( the a ch a crystallo a ch ch ( , substituen or series series

c by literature mo b necessarily necessarily ipii solvation implicit structure structure meth ), ( , their their methoxymethyl ( ts dels ow ma in wit c d

of , Me, Et, Et, Me, ,

by blue byl , , er Michael h ny

( at in compounds compounds

ts e case case

join ). ena the

hand. (

as 5,16,17,66 R grap entails t

1 ntios- sub reac Latin Latin C(2) ) are ) ow ad od, od, Pr)

hic hic 72 er er - -

- - - -

free free of to Considering accoun on (e.g., qua functionals a for work results well (RMSD<0.05 l lected cluster functionals of theory turbation with structures PBE-D3, to uncertain This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. ow the

Accepted protocol applied, the the Article Refs. relativ arri est est The W ntum

as energy these these e were obtained obtained were discussion discussion non

functionals, M06-2X/def2-TZVPP functionals, effect

v t largest absolute absolute largest (MAD<0.1 kcal (MAD<0.1 ro calculated calculated singles doubles doubles singles

for for

e 86 calculation calculation

ot 78 ties. e chemical calculations calculations chemical – -interacting at electronic 95 i

density nv

or wi mean conformational conformational meaningful conclusions. of PBE0

of the for further discussion. further for

estigated estigated

73 solvation, t a polar SCS Å) h –

those obtained with 75 conformational conformational of

square square (SCS-MP2) and -D3, gas

the functionals M2 were -MP2 careful A of ih M06 with

-phase Gibbs free energies, energies, free Gibbs -phase

molecules, molecules, M06-2X/def2-TZVPP Gibbs free energies energies free Gibbs energies

79 79 salsrcua and structural small en p deviation (MAD in erturbativ mo vironmen deviation (RMS deviation hs work. this and ∆ G flexibili l − uncertain sol

1 81 choice empl betw -2X/def2-TZVPP M06- ,

and v A<. kcal LAD<0.2 which

flexibili . structures. rigid-rotor W t e ty,

oy triples theory (DF-LCCSD(T0)-F12b). (DF-LCCSD(T0)-F12b). theory triples 2X een sp on e of

ed.

in necessitates necessitates see see On t

the 80 describ an

y ty W -comp enamine conformers conformers enamine th

) with with ) and

in ass e the D) with D) explicitly correlated density-fitting local coupled coupled local correlated density-fitting explicitly 83 the e of

– optimized stru optimized

computational computational compare compare

solution, solution, harmonic-oscillator harmonic-oscillator

ociated ociated reactan LAD, optimized On energetic differences differences energetic

relativ

ed Supporting Supporting one one one mo

the other other the wav G and

the the n ga res the t hand, hand, l

− res s e efunctions efunctions ts with , , scaled second-order second-order scaled

1 G se pect pect we effects application electronic ).

at pectively) pectively) is so structures exhibited structures veral

clearly l refer refer 298.15 298.15 , , Hence, Hence, ct these approximations, these approximations, we compared compared we Information requires requires to ures ures hand, methodology methodology

of density SCS-MP2 SCS-MP2 to calculated a polar polar a meth K the and energies im approximation). F approximation). all from from

based based we of found when found t p

w the re orta

functionals o various Supporting Supporting o ds studied the the studied s

DF and steps: steps: ults ults optimized optimized structures structures optimized en n fr subset a for

calculation calculation on with these with densit Mø the -LCCSD(T0)-F12b -LCCSD(T0)-F12b t is vironmen

es 7, 84, [74, Refs. isolated-molecule isolated-molecule and presen

82 l

hence hence ler approximations lowest mean as as mean lowest on The

Out of the the of Out densit other -Plesset -Plesset

we

and

av I (PBE,

n assessmen ted a or may erage erage form t im greemen of

how details details

on perativ

in of Gi refer

ation ation 76,77 the this this the p 85]. 85]. bbs bbs the the to er se y y

e t t - - -

tt nryt elc oa nryo mlclr irsae hc ilb suitable electronically a and be conformers will all which for similar microstates ground- very “molecular” are electronic contributions of the nuclear energy chosen if have total approximation we a expression, replace this to in energy that state Note one. yields sum their conformer of energy electronic the where weight Boltzmann conformer its a of conformers by occurrence the relative of The diversity K. the 298.15 at illustrates conformations equilibrium 1 of in Figure variety present pyrrolidine a other. adopt each with with can aldehyde equilibrium 1) in Scheme or are in which ketone shown ones a the of as such reaction (e.g., derivatives the in formed intermediates Enamine enamines pyrrolidine of diversity Conformational discussion and Results for used solvent [14]). common Ref. a e.g., is which (see, solvent a as chloroform for opted We data. experimental of this in investigated ones the as such environments work. chemical and solvents of range wide interesting a over be may formation molecules as solvent cases, (such with certain solvent interactions in a specific with While solute a bonds). of hydrogen interactions of model specific solvation any implicit for an account that not Note does polarity). solvent’s a solvation with dielectric Implicit correlates a by (which model. characterized constant continuum solvation dielectric isotropic implicit an an as solvent of the means represent models by molecule solute a of structure This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. Accepted Article 34,39–44 k B steBlzanconstant, Boltzmann the is ecalculated We 93,96 hyaelkl fn motnei hnmn hc r encountered are which phenomena in importance no of likely are they G sol p i , sotie yadding by obtained is ∆ G solv p i ihteS1 model SM12 the with i nisgon tt.All state. ground its in = N P h ubro conformers, of number the j N exp =1 11 exp  −  k ∆ E B − i T G k  E B solv j T  97 to , p hc a te oawd range wide a to fitted was which i G ausaenraie uhthat such normalized are values gas natemdnmccycle. thermodynamic a in T h eprtr,and temperature, the i Michael a equantified be may additions (1) E i

excited states states excited This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. Accepted Article

Cumulative Boltzmann weights 0 0 0 0 1 0 ...... 2 2 4 6 8 0 0

are 1a 4

1b

9 of

significantly 1c

24 1d 20

2a 4

2b 11

2c higher

25 2d

20 3a

4 3b energy.

10 3c

3d 23

4a 20

4b 4

4c 13

4d 24

4’a 18

4’b 9

4’c 24 4

’ 48 d

5a 45

5b 17

5c 43

5d 81

6e 69 252

to all other other all and en in detected dielectric constan when fashion systematic W substituen larger C(2) in stereoselectivity populated rings are (pyrrolidine arrangemen kcal — kcal [kcal the Figure This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. optimized structures optimized to a dielectric con dielectric a e vironmen

AcceptedW Article illustrate illustrate green, green, conformers. conformers. When The

s- e mo accoun mo

mol exploring exploring tr

compared compared 1:

l ans l − molecules molecules − (RMSD (RMSD

conformational conformational − 1 0 1 Nu we ). ts 1 ). in . t t t, ],

and 6

are conformers), we conformers),

can equilibrium equilibrium where

around around mb 35,93,98 ≤

in refer refer The

the N(1) substituents. A N(1) complex reactions reactions complex ∆

er so in optimized structures optimized g be t. Ea E < E remaining intervals for for intervals remaining

i

1a ti Wti this Within of v in – small, small, to Michael next tw n 102 e a dark a the ch en ch

order order

energy uum , , conformers conformers een een pu r

i 2a 1 of but N(1)-C( se ck . degrees degrees 2

, ,

we section section oeue emb molecules (0 optimized optimized ered ered try

w to — 3a neglect neglect green color marks the marks green color to as . ag ubro stable of number large a additions 05

al il only will yello ifrne be differences

, , is observed observed wa reduce reduce in

model, model, colored according and α < of ys

for for ) how a how (as (as outlined, t

w, w p b

freedom, freedom, the

i refer refer ond o 4a isolated structures structures isolated

ea 1 large numb large

< discuss isolated structures structures discuss isolated the differen of ta

. hard ch

2 conformational conformational

can adopt four four adopt can ed selection selection (s isolated k to 0 ≤ computational effort which effort computational to e com . - d hs or conformational these four

59). 59).

∆ cis cis the tw ly ed ∆ be be either by either E E any een E < E t pound pound

ways). and e.g., in < < are colored are er nry difference energy Ma a dielectric con dielectric a enamine conformers conformers enamine of

molecules molecules effect effect 0.08 Å). 0.08 Å).

1 s- of to in ny

. tr relev 8 l and rotatable

their ow theoretical studies theoretical Refs. weighi ans — All di and and optimized conformers conformers est-energy est-energy on conformations conformations

versity an four four cu

orange, ) ) optimized the

and t [74, m Because Because as as ng

relativ (dielectric (dielectric conformers conformers ulativ

follows:

bonds bonds conformers conformers ih the with which quickly which around around 103]). in

ti ∆ whi the e n e conformer conformer E > E (e.g., ov (e.g., electronic energy uum Boltzmann Boltzmann the ch

in is structures structures following 0 (e.g., (e.g., degrees degrees hc ifr by differ which the constan the

Boltzma

with ta es 1 may effects effects . structures can can structures

0 . k on C(4)-C(3) b C(4)-C(3) 8 pecially pecially are es C(2) C(2) er < — be the

200 for p signif (∆ in an red (all t ∆ of emerges emerges r tw

sections. to o of weigh E < < E em of E origin of of origin

nn freedom een ceed and infinite

a polar polar a zero) relev accoun b

icantly = w

edded N(1) eigh s ts the in 6e ond 0 - ∆ 0 an in

cis for for . b

. of 6 6 E ). 0 a

e t t t

substituen sterically and tion. a (see also ferred examine electrophile C( the anti on Qualitativ selectivit Facial Origin also in for This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. the synclinal- α Accepted Articlethe electrophile electronic energy differences energy electronic )=C(

) )

the the It is

molecular molecular assumption assumption

strongly w β Supporting Supporting the as of ) e t

exo exo

explanations explanations is enantioselectivity from the from suggested basis basis on located should located whichlead shields which the C(2) C(2) the which the ( to sc preferred preferred atto function partition y the . In -

that that of ex Information). Information).

tr

op

the the 44,66,69 44,66,69 t o oduction). oduction).

w ), enamine posite side side posite one one o for the for a

side side suggestions suggestions ov synclinal- of ht the that er the of the or stereo the double bond from from double bond substituen by As

other. other. t of of w plane C(2) C(2) endo illustrated in including all other other including all ti plane this o

co one

as

osbe mo possible ntrol Michael Michael

to enamine conformation conformation enamine to

substituen ( The t preferred sc defined defined

why one one why is in - end oae. Acrigy te addition the Accordingly, located. term term

organocatalytic organocatalytic in is Figure o called called des ), by th additions

t “

or e

the

anti syn preferably adopts adopts preferably of N(1)-C( side for the for

conformational conformational

an

- 2, “

-addition. -addition. addition”

anti an

th

of

modes modes e electrophile electrophile

ti the α - C(2) C(2) Michael addition”. periplanar ( periplanar

)=C( (e.g., (e.g., s plane

denotes denotes β may su If ) ) the b degrees degrees the ecin are reactions on - stitue

cis defined defined be be In addition ( addition which the which

ap sc sc

an or hs work, this togy pre strongly -exo -exo - n ) conforma- conforma- ) endo s addition of addition t of

- can freedom tr by position position an

syn N(1)- N(1)- or of adopt adopt based C(2) s

, , ap the the see see w or e - -

hncnieig lcrnc nrydfeecs H differences. energy electronic considering when ergy by stability ilar ines Steric preference down Figure (∆ for electrophile adopts a tion bonding ∆ may substituen C(5)-N(1)-C(2). and up structural This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted Article defined

or 0.7 > > an the

(N(1) (N(1) contributions of be be

) which would )

0). 0). down down –

the C(2) C(2) the enamine 2: sh 1.3 pyramidalized. substituen partners. Illustration Illustration quasi-equatorial quasi-equatorial

ielding ielding t as features features = for the for

kcal are located located are conformation. conformation. will

2 (∆ the , , 4 mol E in be stereoelectronically stereoelectronically be

, , shortest distance distance shortest substituen The addition ( addition

64 a of 4’ t = of in

− lead lead , ,

on one face The sign The 1 the the 0.0 down

or

of down less the C(2) atom atom C(2) the on

the In – 5 pyrrolidine ring. pyrrolidine to

0.6 0.6 ),

gas op position The this work, this either stable than the stable than

t conformation with the N(1) N(1) the conformation with

ap syn/anti

(positiv conformational conformational conformation conformation posite sides sides posite kcal

phase leads leads phase of

of conformations are are f conformations up

the enamine the ∆

mol syn conformation conformation of

(∆ indicates indicates ). the e) we −

or

are located located are

1 f < or ) av nitrogen the atom from

of employ anti

as away 17,54,64,66 17,54,64,66 0) ored. ored.

is this plane. plane. The nitrogen this atom to ap

degrees the

the the

in

whether the pyramidalization whether the an addition or would or addition conformers. conformers.

from In

an dou is

adtoa destabilization (on additional ap ow Dunitz’ one one av the contrast, on The The pyrrolidine

ever, up of ored ored conformers. conformers. b the in

le it

freedom freedom conformation conformation which the C(3) atom atom C(3) the which conformation, conformation, a

bond. bond.

(negati substituen ov the d same side side same e er The The fi

anti nition

sc sc ( -endo -endo ve). -exo -exo ap consideration consideration

not -addition would -addition

The The plane spanned plane F

, , ri t of or

sc of

ng may ng in lead and If in the conformers conformers

sc the - the which the ketone-deriv end

- quasi-axial quasi-axial

syn exo sc to pyramidalization o in N(1) N(1) ln spanned plane -endo -endo , any

-addition either

is sc conformers conformers these enamines enamines these of

and - in ex

all free free all average by pronounced pronounced C(3) atom C(3) substituen

are be be conformers conformers o t ed the C(2) the its , h adopt position position e

up favored

of direc enam- enam- three of , , and sim- the by en are an b y t - - - -

The the interactions at C(4)-H migh the situ and substituen vibrational differences. slightly 6e of conclude conformation H C(3’) cases. the butions, detected. be can conformations enamines and, structures crystallographic because ∆ sc This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. ow G

- , the the ,

Acceptedone Article endo

Schmid Schmid solv solv conformation conformation a structure similar similar structure a

hence, hence, ever, NMR non t b

face face be be In · ond

(∆

f sc · -co conformations conformations no av

all · that, a result

a high a -exo -exo (N(1) (N(1) t G π study ored

v are et

effects effects of gauche also adopts adopts also our The alen sol sol in sc cases al. the (least teractions. in -endo -endo position

=

results agree agree results ov

. t li = preference

60 intramolecular of ena suggested suggested general, general, of 6.0 smaller than kely

1.1 er enamine

and (N(1) (N(1) 1 the Our Our

effect example sterical shielding) shielding) sterical the insufficien – ntioselectivity conformers become less less become conformers or 2.1

and

C(2) it

the is to

a 3 ap

60 n clearly clearly = is is the ),

kcal a

6e

of

sc

more for the the for ht the that double double b l sc Figure 3 Figure observ position 1 y no of well with the well with substituen facial

- , , si

-exo ketone-deriv endo t w the

s 2

mol pronounced electronic energy differences be differences energy electronic pronounced as conformational conformational

When thermal including all , , suggests suggests neatos w interactions stable (by f 3 peoiaey encountered predominately av ed. conformation conformation sc most stable most

−

selectivity , , is conformations are are conformations

(by 1 ored sc ond 4 - presen

). exo ex , , Th is -exo

t 4’ kcal 0.8 clearly of

eietly observ perimentally by the C(2) C(2) the by

These These

e ed that the conflicting conflicting the that ov conformer increases increases conformer , ,

available ap or conformation conformation 6e ts 1.6 enamines enamines er kcal

mol

stable than the other other the stable than

the

a visualization a 5 conformation conformation ca ere and sampling. sampling. ), r p kcal ap es in n the barriers for rotations about the about rotations barriers for the mol re − evaluated not

the ults ults may 1 sc , , similar structurally f

ex e sc

(see - rred − solely be be solely endo mo substituen further further perimental perimental 1 -

) with end re

l when considering electronic electronic considering when

− is ported crystallographic crystallographic ported also the according according

1 o

position (by 2.8 (byposition

) preferred preferred

, , ed corrections corrections than is, un in be considered considered be and of theoretical results reported reported results theoretical destabilized when considering when destabilized up terms terms

bran in for for attributed h

t non ow on this

data. F data.

Supporting Information). Information). Supporting in sc ap 5d ched ev

inclusion inclusion a -co to t - exo w for for

of er,

16

conformers. conformers. conformation conformation o compounds sc our v the – and also encoun also alen

18 conformers conformers 6e or C(2) C(2) -exo -exo

conformers conformers to

analysis. analysis. for which the which for

kcal aldeh coun reduced due t steric steric shielding tw solvation intramolecular of oiin F position. een substituen thermal and

to ter-in mol yde-deriv structure

favorable 35,99,104,105 35,99,104,105 the The density in in − tered W energy energy of 1 co tuitiv three three

C(2)- C(2)- most most ) e C(2) C(2) an

and can can n 6e ts

tri- tri- or

for for

ap ed ed

in in in 66 64 64 . .

e

comparison comparison et of conformers dispersive teractions et and actions the interactions tures, ring pyrrolidine contribution sure the description interactions gradien This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted al., stable ones. the all the al., Article C(2) substituen C(2) These analyses analyses These the N(1) reduced reduced

of the the our

t be dispersive dispersive

s sc tw

interactions sc in analysis analysis as and of to -exo een (colored (colored as the -exo -exo density to substituen proposed proposed

dispersion dispersion

ap

’dis th

we in them. them. ofre displa conformer

conformer conformer e l or the ow co persiv interactionenergy. re only only p

ts sc gradien ntacts rather than ntacts rather est-energy est-energy in oi veal are

- green). green). ap n between hra we Whereas endo t In e’, e’, ts

by visualized visualized interactions are considerably considerably are , , the smaller

non sc

to we t Y

migh -

the conformers. ang end s -co

ap

The note may the conformer. conformer. v o ys t origin

alen

conformer, conformer, , , and in be be the

C(2) C(2) and

the cannot cannot the

ta ti notion this that size size be considered considered be in t preferred

interactions co non the

most extended isosurfaces isosurfaces extended most sc as

of of sc -w

substituen sma -

-co the the exo a -endo underlying underlying or pr H qua k v the ll ovide ow

alen ers.

higher stability higher e conformers. conformers.

isosurfaces betw isosurfaces for for r. ever, interactions n

conformer

titativ 106 In t 6e interactions as evidence evidence t

be and accord

While

do a rather rather a the because because tw electronic electronic e es een

the

measure measure

analysis analysis Out Out not

with the with

indicating indicating we for the for the pyrrolidine ring ring pyrrolidine be the

een of insensitiv of necessarily necessarily for of tw refer refer C(2) C(2)

structure structure

aoal C(4)-H favorable ass the three three the

een een th the pyrrolidine ring and and ring pyrrolidine the also th

statemen hypothesis hypothesis ociated ociated a

to re t sc the less dispersiv less substituen

e re leads leads e -exo -exo some some

intermediates intermediates C(2) C(2) vealed qualitativ mo reflect a pro a reflect with example example ts conformers conformers d to non-co in

e by by a s a substituen l

the . t significan disp Instead, ·

· Schmid e and Schmid Schmid

e · pecific pecific

mea- mea-

π other other v s ersi in

alen truc- truc- the the in ter- ter- per per out out - v in

e t t t

— the blue interactions, dispersive values and s 3: Figure This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. ( r Accepted red, silicium Article ) Supporting Supporting Information.

ap regions emerged emerged regions = = of

conformers conformers 0

. sign( 5 revealing the intramolecular interactions intramolecular revealing 5 the Isosurfaces Isosurfaces λ — 2 ) yello ρ ( r of )

, of in -0.05 ranging from 6e w, and the

th . hydrogen hydrogen

blue would indicate strongly The e

analysis. reduced Elemen

surfaces surfaces — t color d

wh e The n are si ite. ite. t to y co definitions for for definitions

colored colored 0.05 0.05 Red indicates a.u. steric gradien de:

Nitrogen Nitrogen t on

in s a a ( the attractiv r ) blue

— s of

( l blue, r densi ow - ), green

est e λ

2 interactions, -energy -energy , , carb ty - red and functional theory for for theory functional on scale according according scale

ρ

— ( sc r clashes, clashes, ) gre - are ex but but o y, oxygen ,

gi sc no v green green - suc end en

to to in in o h ,

an nitrogen their of ization which repulsiv ring. Furthermore,the and C(2) C(2)-C( by The 0.04 Å axial is is all for or preference but The increases (e.g., 0.2 kcal most for energies, steering Stereoelectronic This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

lo observ also absolute absolute pyramidalization Accepted destabilized Article 5d 5 the the In The

◦ quasi-axial down down angle )

substituen hydrogen hydrogen , , which ad The leads leads enamines low bu e closer closer α effects interactions dition the ) ) comp with betw

t

conformation remains remains conformation angle

o the for enamine intermediates intermediates enamine decreases decreases energy energy to

down down ed we already already we the the to mol ou een by to

atoms. atoms. of t

the hydrogen hydrogen

ex would nds. nds.

(at most by most (at is

−

up

th

these these ov conformation conformation p r down conformer size size 1 lctd Additionally located. C(3)-C(2)-C( ep

erimen C(2) C(2) e

for for erall small ring ring ring flattens (for (for flattens ring betw o others, e.g., for ulsiv The The increase increase of atoms (see (see atoms contributions 1a

noted conformation the atoms atoms are een

e tally substituen lcrnc nry differences energy electronic

pu vicinal interactions and electrophilic addition. addition. electrophilic s N(1) of ck 0.4 kcal 0.4

be circles (green the C(2) C(2) the previously .

60,64,66 60,64,66

the

energetic differences be differences energetic ering, the α of the 3a tw ) the een 0.15 een are, are, ). steric steric quasi-axial al Figure Figure 4).

and preferred preferred

li wa t

are In

kely pyrrolidine 1a Schmid Schmid in 6e increases increases ys hence, hence,

mo C2 substituen C(2) substituen

. the general, , , , be

exceeds exceeds 68

shielding shielding conformers conformers not steric steric on 4’a l mi

− – tw in W 1 0.30

nimized by a nimized by ). Figure Figure een av arran , , up e systematic systematic hydrogen hydrogen et tutrly flexible structurally

or erage erage sp A

for for

the conformers conformers repulsion al. which Å

ri t eculated the 5c the

g for for ng ng and preference

60 emen

se preference preference . 4) C(2) C(2) differ differ tetrahedral by

is

an tw suggested suggested veral compounds, compounds, veral with N(1) N(1) with ∆ vicinal are, are,

atom is, atom preferred preferred ts een G atta t 6 ov after after

s (e.g., ◦ 68 sol sol

is ) widened widened considerably considerably er be however,

substituen

similar similar ht the that up than in ck

When When hardly hardly the tw o the for

quasi-axial quasi-axial

from the from com inclusion inclusion the for and een een to ht the that h ov

angle angle substituen ow in 1.2 kcal series series enough enough p

er the C(3)-C(2)-C( down ever, considering considering the

a deviates deviates small small to wideni

t ri the

down

pyramidalizations down so of C2 substituents C(2) and

in

e.g., e.g., of of

down face face n

up up on the 109 conformers. conformers. hydrogen hydrogen

with to thermal in enamines: enamines: ng vicinal vicinal ts mo

conformation conformation

conformation conformation conformation conformation conformation conformation av ◦

2a on se av from from

pyramidal- 1

of l (on erage erage conformers. conformers. − – the veral cases cases veral oid strong oid , , which the electronic 1 the 5 α

2d angle. )

display for for effects a ∆

quasi- quasi- atoms v C(3)- , , down down only only G erage erage 5d 4’b The gas ). ).

,

a C(2) C(2) a as enamines, interpreted a indicate would which ring Overall, a only small fraction Å) ( than with of ex in horizontal dotted dash blue energy electronic circles Figure This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. | ∆ the the

Accepted perimentally Article 6e | re

in < < quasi-axial quasi-axial , , conformers conformers ported by ported

aldehyde-deriv

corresponding corresponding ˚ 4: —

one 0 Pyramidalization [A] conjunction conjunction ∆ substituen . -0.30 -0.20 -0.10 Dunitz pyramidalization Dunitz 10 0.00 0.10 0.20 0.30 0.40

is down but for but

face face

in ) This Å). included included

1a such a observ

1b of position position Seebach conformers, conformers, with with lines are lines t relativ t

the 1c

w with in ed o

amines. amines. 1d for the for observation ed

differen double bond enamines an wa ∆

2a

a e stereoelectronic preference preference stereoelectronic by of

et

y

< 2b exo to quasi-axial quasi-axial the gi that the that

Brown

al. the ex v 2c color color . F 0. t en of

N(1) conformation which

perimental reference reference value perimental

66 reasons: reasons: 2d the

for a for

is in is exhibits a epcie l respective 3a o this for or ∆ et squares squares

structures display structures

3b substituen

al. for similar is [Å] for for all [Å] 6e anti

∆ position position

g sterically sterically 3c oo , , (

i of

3d

60 -additions are favored are -additions ) F ) d d comp

—

0.00 0.00 4a ∆ agreemen % % or ow

up 4b t <

conformers conformers of

molecules molecules ound est-energy conformers conformers est-energy of (∆ Å and and a Å

4c the N(1) N(1) the 0. shielded conformers), where where conformers), the

F enamines

4d > > is for for based based or

t

4’ 0) not structures are hardly are structures with an a

syn ketone-deriv

4’ are

∆ the for b with bulky C(2) C(2) bulky with up from from of

4’ adtos Or results could Our -additions. substituen

the of c t on pyrrolid (>0.20 ∆ conformation conformation w 4

’ 0.41 0.41 d

o case case a crystallographic crystallographic analysis. a measured measured lowpyramidalization (0.04

an 5a to across across

5b eetohlcadto b electrophilic addition three times times three Å which Å Å). Å). ed for

i 5c ne t enamines, enamines, th (maximally ∆

5d molecules 64

e deriv the E E color color

for for

Remarkably, 6e su of whole [kcal are are

the pyrami bstituen 6e ativ more .

enc encoun 66 pyrrolidine 0 0 0 1 1 2 2 2 3 3 es mol conformer ......

with 0 0 4 8 2 6 0 4 8 2 6 Auxiliary Auxiliary (colored 7% o series series

frequen des ts dalized − − 1

1 ∆ E [kcal mol ] ( tered tered none none suc ]. less 4a

the the b

of of )) )) A h y e t s

exist the s the s and s- bond compounds. patterns. be of enantioselectivity for former s- the that mo ditions The Stabilit work. which equilibrium anism preference are bulky This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. - - cis trans the

Acceptedtw Article de former former

strongly W Todefini enamine double double enamine

een 150 configuration configuration

has has C(2) substituents. C(2) conformers conformers e

of enamine double double enamine optimized optimized of is y arrangemen tr

◦ the the electrophilic theaddition

C( ans not not determin

or

differences differences

for for aldehyde-deriv case case cis β

ti be

pyramidalized )=C( electrophile electrophile In vely been considered considered been to anti conformer conformer tw hs set this the and een only α be stable stable ed

elucidate elucidate -additions. of is -()C2 ( )-N(1)-C(2) ts C(2) C(2)

tw b the the

∆ -

bey by the exhibit ond differ differ een aldehydes een

b 130 < be ond ond s of pr ed ( addition 0

- is

ii in tw substituen cis structures, structures, oducts formed formed oducts and and

in more the in ) )

arrangemen whi enamines enamines

in relativ een

the the 17,54,64,66 the These molecules molecules These the direction direction the ( their their in one − origin - theoretical 180 ch 60

sco φ

latter latter s- stable for stable conformation with is e fr all for ) ◦ in cis cis ∆

◦ pe pe

to t < < and

enamine preferred preferred detail and and detail

(see (see of > the in φ to of we detected detected we t and the ktns Figure ketones.

case. According According case.

0. of explain the the explain the < ketone-deriv in C(2) Figure 5). 5). Figure Tefc ht multiple that fact The the 60 facial selectivity comp s-

i of n organocatalytic organocatalytic ketone-derived enamines ketone-derived

nitrogen v p ◦ adopt the C(2) C(2) the

ov tr ) estigations resen enamine double b double enamine and and s- substituen ans er ounds not the t preferentially a t

only the only ed work w pyrrolidineenamines. In r ena o

pyramidalizations pyramidalizations t other. addition, enamines: enamines: stable 1 ans 5 su to –

so ntioselectivity t presen 6 our bstitue

and qua

( and ih their with one one far. far. res |

φ ofrainl preferences conformational It will | n arrangemen conformational analysis, analysis, conformational

pect pect ond

tifi ts < < must stoichiometric stoichiometric has n

conformers conformers stable stable all t 120 e φ

whi be be down down d (s b

to by the dihedral angle is differen investigate - and ◦ een various cis cis the the either either )

ch p ch and whi conformers conformers s sp conformation conformation

or - ts th su tr

the arrangemen

ans ch

oi s- t eculated e bject bject of

arrangments with s n tr between substitution substitution Michael the i ts

ans s - conformers conformers re tr

the t ∆ ans of versal ow differen

double double ) )

for for future future > > me

if 10,14,19 10,14,19 ard

con- con- 0 130 130 one one and t all ad the the ch- of of

of of in in in a

t - -

s The the with 0.2 (see ferences kcal 0.4 s re is s by = illustrate the which fall the where circles) enamines (colored dine Figure This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. - - - also also found veals tr tr cis

Accepted4.5 Article – Schmid group ans ans F respective conformer. conformer. respective

0.8 inclusion inclusion or conformation conformation kcal

5: 6e Conformers Conformers ht the that conformers conformers kcal mo Dihedral exception exception φ , , in of

we mol et (yellow

l the s- − mo also also the

1 of al. in ob

− tr

l vibrational, thermal, vibrational, more the 1 results ans

−

s 60,61 , category category er

1 ∆ ) angle be angle for structures structures similar very for numbers) numbers) by ve hn s than of with

G crystallographic structure structure crystallographic conformers. conformers.

Supporting Information).Supporting s stable than who who

0.5 a sol sol 5a clear preference preference clear

for for = = aldehyde-

The and kcal “s re - tw 4.9 tr - ported ported 6e cis ans in een

4d area area kcal

this context. this mo are conformers”,

Th

conformers conformers C( (s deri l −

− ht the that - e - not mol 1 β cis tr

the

60 and t )=C( v ans on w ed readily ◦ − for for conformers conformers o

color color 1 < s av

). solvation corrections leads leads corrections solvation α N(1) N(1) is s- - This φ erage. s )-N(1)-C(2) ( )-N(1)-C(2) tr

by tr

the ans for for < - enc ans tr to

ans s- su 60 transferable transferable 0.2 of

area ketone- o 6e conformers conformers

is Hence, Hence, ◦ bstituen

conformers conformers des cis

– 6e

when is

conformation conformation 0.3 0.3 in in

.

| co

the pyramidalizationthe Dunitz Conformers Conformers

solution. solution. φ 66 excellen | | kcal l deri o

<

φ u conformational analysis no Our ts red considering considering se ) )

120 v ( [ v to mo ed purple purple of ◦ 1 eral (∆ ] t for all for other pyrrolidine other

◦

and

4a

l enam agreemen − E is ketone- The 1 is

are

= colored colored are

clearly more 3 to to ) are ) 4.0 s i more electronic electronic conformers conformers nes a stabilization

indicate conformers gi - tr kcal v stable than deri ( ans t en

with on

blue 2 f stable av , , v

as mo

ed average conformation 4 ored ored

, , the an to l enamines energy − 4’ of indicate enamines. enamines.

1 inset ∆ , , (∆ , ov

results p ∆

and

[Å] [Å] yrroli- yrroli- s- er of E only only G cis the the gas dif- dif- to =

of 5

w ).

)

migh because is t ∆ culated it exist and Figure Effect the enantioselectivity for tioselectivity stoichiometric conformations. detected studies which mational be difference energy electronic This stability a can from originate electivity and ( the (e.g., This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. w < <

unlikely that the most stable most the that unlikely G is Acceptedeen Article

Figure 6 gas,min gas,min 6.1 barriers electrophile electrophile

differen ∆ calculated calculated t is across across

2c G h 6 ∆ kcal

of av in from from the sol sol initial , , G presen analysis).

e presumed presumed e cnomtoa sampling. conformational 2d and and gas,min gas,min agreemen sh t for rotations for the

mo ill , , subsets subsets o u ws

4d Michael ∆ 59 structures are are structures ts from only from

l strat to −

series series – G

l , , and 5d 62,69 ow 1 ∆ the high the neither that must gas ,

or

33,35,62,93,98 G t est-energy est-energy

see see 16,17 16,17 es with

of

a gas differ differ 5c ∆

Additional

of enamine double double enamine

the down down again again additions are additionsare inevitable

be determined determined be G al also the ab

) also preferentially adopt the s the also adopt preferentially ) be

enamines. enamines. cannot gas

dehyde- dehyde- one se optimized conformers. tw at out

conformation conformation – een een veral are that that often often s- most by 0.4 by most 100,107 tw s

th een een cis cis - Supporting Information). Information). Supporting larger larger conformer conformer cis cis be be s i e n no other theoretical other - and N(1)-C( – created created v cis and 109 and s estigations Additionally, rationalized solely solely rationalized distinct - cis

and b on

ketone-deriv Our Our s s- whenev ond. ena difference difference - the the and trans trans and s- kcal α based will will ntioselectivity results results b )

tr s preferences preferences

wa ans a in - er ond conformer, conformer, conformers conformers because because tr be be mol sc

y

ans on to we

a large a -exo in conformers calculated calculated conformers to ed found without found are the the

− investigations are

the s the available the transition state state transition the

1 lutae how illustrate conformers conformers enamines enamines

also also ( conformation conformation on readily 3c the the me - for s for numb tr the cnomtoa ruet. The conformational arguments. nor ). - ans respectiv for for cis chanism in The Ntrly the Naturally, ex

ex -

agreemen ea and eietly observ perimentally

cis passed passed conformation. conformation. er magnitu perimental perimental in ch compound chcompound (without (without

ht also that or conformational conformational re s s of ∆ s versal el - of su

- tr cis G conformers conformers at y. -

ans ch tr organocatalytic organocatalytic gas t ro ans ∆ from the from with as de as of

G

extensive is of enamines om

data. data. those the addition of of addition the

re gas differences

well of

conformations the the affected ported ported small temperature

( e A ∆ may ∆ xp dditionally E as G Here, exists. exists. whole whole re ena sampling erimen ed , gas,min

ported ported confor- confor- s be be

∆ alone. alone. enan - ntios- when trans G be- one one and cal- cal- set set ga ). tal tal It s

- -

, ,

in se > enamines (e.g., exists conformers numerous when obtained of tures when 1.2 enamines (see, the cis in the binations the s green lines formers, whole set and Figure This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. - the ab cis verely

Acceptedkcal 4 Article Refs. Refs. kcal ring pyrrolidine ring pyrrolidine and pr and out e.g., e.g.,

on randomly randomly oduct oduct recen

6: s the [60, [60, 66]. mo 1 kcal 1 affect the affect s mo - with of ∆ tr 1d - t l s ans tr − G literature. literature. of

l − ans p , , 1 - the gas 1 the cis . oten differen Figure 6 additionally 6 Figure 4’d ).

selecting selecting conformers conformers

mol

o the for conformers conformers The and In

Boltzmann

, , substituen ti conclusions — in summary, subjecti in − a 5d l 1 s-

the the

t the

deviations deviations l

ow energy energy 91,111,112 ). ). o structures for subsets subsets tr isomerization isomerization ans s s-nry s- est-energy

down - The down cis cis which feature which t

whi conformers where where conformers

weigh surface. While the random the While surface. d

and

W of analysis analysis of conformation, conformation, ch feature ch prefer prefer conformation) easily surpass surpass easily conformation) of theoretical e the

s

therefore therefore ∆ ts - tr wt few with

G

cis co of ans located conformers: conformers: located the of vely gas the in ntains s and

the

this adoption from from conformers conformers C(2) the - cis choosing seemingly seemingly choosing

ad respective respective

in C(2) C(2) s - red red vocate vocate a tr and the width width the v conformers conformers case case ∆ estiga ans spread spread G areas s gas,exp substituen of

substituen would lines blue conformers, - for for tr the whichare tion conformers. ans

110 110 of

an of (calculated (calculated s with s

selection selection which has which

black lines blacklines — ∆ (e.g., (e.g., the - conformers calculated calculated conformers

have extensive conformational conformational extensive tr G

ans 2.0 ∆ t gas t

c red im

G all in in

sh kcal 1a erroneously

gas p the conformation conformation whi the minim ortan ow

), only

areas areas from all from large from from ch could ch

— mo also

∆ sc sc

t G whole set leads leads

-exo -exo -exo -exo l is um conformers conformers − gas — l 1 ow proportional proportional b spreads spreads

een

in

possible possible in l energy est-energy est-energy position and position ow position to be be

a by sho ma illus a spread spread a est-energy range

obtained obtained from the from at ny wn of can least tr struc sam- sam- may con- con- com- com- cases cases

and and ated ated that that of b to to s

e - - -

ines ines 4’ kcal the tuted 2-position all stable, more ture. stable ity leading is It the for k and The tones Origin 0.1 of after reactions. pling This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. etones thermodynamically thermodynamically more

the w Acceptedslightly Article kcal enamine enamine The difference between difference stoichiometric higher substituted higher as enamines enamines with with mol

sampling sampling to As population population double double sp than than

most most 2,6,10,14,20,26,28,29,39,52,53 2,6,10,14,20,26,28,29,39,52,53 elimi to smallest smallest − mo

ex 4 eculated 1 of the the regioselectivity. ) decreases decreases with by the than pected, pected, l 1-buten-2- − regioselectivity i u both but n 1 nate bond) and bond)

im . with termediates at

has a The

p unsymmetrical unsymmetrical ketone, least –

according according 10,14,19 10,14,19 orta this additional this been carried carried been d the l the the Michael numb when considering considering when and and

enamines

n ol 0.4 t smr are isomers

t w compound compound

ow α which 4’ ht the that 2-butanone: 2-butanone: o conformers conformers

kcal -carbonyl carb -carbonyl which maywhich

er

enols enols er (l

stable than to additions of pyrrolidine of additions ow of substituted double substituted ( (see Scheme Scheme (see their mol W with the with

corresponds corresponds conformers conformers er u. When out. of e

− and enamine s ih the with in begin begin

sti 1 ubstituted ubstituted -uaoe (2E)-2-buten-2- 2-butanone: Boltzmann .

may

l significantly ll The The N(1) N(1) The form form

∆ Michael Michael unnecessary unnecessary higher higher G

our 2-butanone 2-butanone on an

ga

be selected, e.g., based based e.g., selected, be preference preference ) This 3). higher higher substituted can can in s atom to

selecting selecting

in , enamine enamine discussion discussion

which the double bond the which but a ratio a reaction a double double substituted substituted be reduced reduced be weigh substituen

enamines enamines reacts regioselectively regioselectively reacts additions additions 4’ uncertain populated populated b ) regioselectivit (i.a., (i.a., for for the enamines enamines of ts, bond). bond). with of

ond 3:1 3:1 4’

∆ conformers conformers the a l a of ts

in G double bonds. bonds. double increases increases by with in are more stable pyrrolidines

gas t then

In c y

equilibrium equilibrium regioselect ow up hloroform).

in double double contrast in is deriv ol of equili 4’ er

to y predicted predicted comprise comprise studies studies on a on is

unsymmetrical unsymmetrical

are preferred s

by 55% btttd double bond ubstituted to ed has which constitute 99.9%

b is Boltzmann criterion, Boltzmann brium. brium. 0.6 1.7 from unsymmetrical from ond i ev higher

v substituted in to ( The

2,10,14,26,28,29,39,52,53 it of – 5d at organ the 1.1 1.1 en kcal y 4

with organocatalytic organocatalytic (2

with ). ro (∆

b (higher (higher substi- preference -buten-2-ol) -buten-2-ol)

kcal W

om een substit ex

E mol ov e an the

ocatalytic- ocatalytic- pectation, pectation,

assembled assembled er = tempera mo observ error −

1 enam in 1.2 stabil-

l − more more uted the the 1

– k for for

in < 1.3 e- e- ed is is -

-

h according enamines face Curtin represen differences ity. of stitutional analysis conformational extensive erences attributed stoichiometric Based Conclusions reaction and tional pr reactions elementary form. the with chloroform. This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. ow ovides ovides Accepted Article enamines enamines The vr do ever,

Our Our automated automated of The co - the on facial selectivity Hammett of ts kinetics. kinetics. mp l a suitable a qua ap ow

the the with

ex origin to isomers). isomers). a suitable a to of proac enamine lex es er The

perimental perimental

which could which

our thermodynamic thermodynamic

intermediates intermediates

small C(2) substituted it enamines enamines Michael not approac y

h regioselectivity regioselectivity analysis. A small C(2) C(2) small A analysis.

principle of of sterically suggests suggests

the

W double double b our of basis basis e

the ntum h

additions findings,

examined whether conformational conformational whether examined of regioselectivity regioselectivity

( 113 series series rationalize the rationalize A

114

double b double s Michael

for further for lexakis ubstituen

me an of shield to

chemical chemical to ond control

chanism accurate accurate Mi pr of hold true. must the origin the ovide a

b teC2 substituen C(2) the by c

of enamines, enamines, ’ of hael ond additions additions and one

ts a

p theoretical in hrfr h therefore yrrolidin

prefere protocol protocol systematically composed series series composed systematically additions additions is, (including all transition transition all (including

face pre can can protocol that protocol Barb

complete complete ex

in substituen

perimentally perimentally -equilibria therefore therefore of most cases, cases, most this this as of has regio- regio- and ntially adopt e

the the ’ of proposals). proposals).

b av enamines enamines is

in me een sufficien and e

an enamine differen a chanistic studies studies chanistic t

only i attributed attributed

g differen s endeav co in able ov the observ

nvincing t. erned

t preferences preferences stereoselectivity stereoselectivity an be explained explained be accuracy.

to

an t thermodynamically more more thermodynamically In conformations. This conformations. In

double double b to or t antiperiplanar contrast

Michael origin antiperiplanar hs work, this ed reliably states), states),

ydsic structural distinct by that that to stereo- stereo- picture picture a steric shielding shielding steric

exist requires requires ht may that because because ond of Gi acceptors acceptors for which this study study which thisfor

to resolve free free resolve by v enamines en and from from of that that i across across e presented we in the underlying the nv the conforma- conforma- the catalytic catalytic conformation,

conformation conformation a systematic systematic a estigating the regioselectiv- regioselectiv- assume assume an h the the series yp has enamine enamine protocol protocol (25 incom- othe energy energy of stable been been pref- pref- con

one and the the s an all all is, is, - -

of their l a with ines Our other. double ichiometric for in C(2) C(2) the by addition C(2) across op of are comparison the the ring pyrrolidine in pyrrolid the within ring. steering popular Another electrophile. ing This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved. the equilibrium. the

Accepted posite Article conclusions pyrrolidine ring. Additionally, the pyrrolidine ring ring pyrrolidine the Additionally, ring. pyrrolidine C(2) strongly pyramidalized. strongly The W stereoelectronic stereoelectronic in

substituen isomers substituents, one face one substituents, e direction direction W C2 substituen C(2)

ilsrtd the illustrated the our bond configuration ow e of the the of cncnimta pyrrolidine can that confirm substituen ieto. u results Our direction.

whole series series whole er series. series. conformational analysis analysis conformational and to

substituted (s with

dr down - electrophiles electrophiles ts catalytic catalytic cis of The and a

a higher Similarly,the preferentially adopt a the wn i t reasons. reasons. or ne

the the

in up conformations. conformations. from theoretical i theoretical from

substituen C(2) C(2) of s- im ring. ring.

t, of

closer closer tr the while conformation conformation portance portance 2

ans double double reactions reactions enamines, enamines, -s substituted ubstituen of

substituen which pr Aldehyde-deriv

) ) the up pr if oducts formed from

regioselectivit k t

could oximity

eto b one in Conformations Conformations are,

ond of enamine explanation explanation is a may re n appropriate appropriate mo but

e All t based based veals, h veals,

-d synclinal- are on t

is in be be whi

enamines enamines double double pyrrolidine nv for for

eri stabilized by a widening a stabilized by de down to

be determined determined be comparison comparison estigations estigations the interpreted such interpreted that

v ed of chp on bond bond ed t ow y w the the

enamin

av conformation conformation bond. bond. o must conforma enamines exo exo enamine double double enamine selectivi facial the for ever,

oi erage erage differen preferentially adopt a preferentially adopt conformational sampling sampling conformational is n electrophile electrophile ts sterically sterically enamines enamines conformation. conformation. h enamines enamines t th av of to h ow es t a ow flattened h organocatalytic organocatalytic reactions. e a e the t by the by ti t is

erm

ard a ard are this may o reasons: reasons: ever,

n differen a tetrahedral and o

l pyramidalized pyramidalized and

dynamically

shield addition be be is with preferences preferences

preference preference arrangemen bond also also populated

are not anti

pyramidalized

Michael Molecules Molecules F of t small C(2) substituents small C(2) ed origin or the the strongly in

-additions are favored are -additions and ty

molecules from from

is up is down

angle case case

further angle a more more stable than

preferred preferred for for

of the pyrrolidine the of because because for the for conformations conformations t acceptors acceptors

in an stereo pyramidalized of with anti for the for the

conformation conformation betw the which brings brings which electrophilic electrophilic significantly also with

away

-additions -additions less direction direction reliabilit e enamines enamines

con- A l ov enamine enamine een e

ctronic ctronic in enam in er bu bulky bulky sto- sto- from from the the

the the the lky lky in y - -

References lidine considering ology, examination The Sup This A conformers Michael elucidation formational This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted Articlec Supporting Supporting following files are kn work ring, ring, porting Information Information porting to E Ketones Unmodified L 1954 musz and F or i nd o Nitros s additions t

wledgemen , w e M B.; B.; to r ko arrangemen of allof , , of as differen s sampling sampling i 76 , acrylonitrile acrylonitrile c the vicz, vicz, D.; D.; supported h In P tyrene. a , , e 2029 o

formation formation possible intermediates, intermediates, possible origin l j

S a J. A J. requires of a t e r

dd li k the ofrain, arrangemen conformations, – e i is 2030. , available free free available i Synlett Synlett v ts

t mandatory for the mandatory for A. , New i of P

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co a a see see

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t z stereoselectivity stereoselectivity

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t will li t of

by i P d of of o C(2) C(2)

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n c c organocatalytic organocatalytic e y t

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h of Ketones. Ketones. t Stork, G.; Terrell, R.; G.; Stork, M , for for the e a in the 2423 x l i y c e future work. future h z n e a e

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n of all all n e

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This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted Article Asymmetric Induction Asymmetric Yamada, (a) Mi ysis Cobb, P T Addition 34 Mi 4332; Nitroolefins oselective W (a) Chem. lysts D 2343. Deriv Conjugate Addition A hedr I 10 I: et a l u

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edr A. e , Eur. J. J. Eur. Lett. D.; D.; Prolinamides Prolinamides , a

Addition

– and – Conjugate Conjugate J. A.; A.; J. l S. rln eiaie: Impr Derivatives: Proline 4236; 428; on: of é Mi J.; Li, H.; H.; Li, J.; ,

J.; J.; ang,

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of B.; B.; D. to as y 18

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1447. 1447. o D. e e

Chem. Chem.

Highly s Asymmetric - Keto-Enamine. Keto-Enamine.

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4,4-Disubstituted-Cyclohexenone. 4,4-Disubstituted-Cyclohexenone. A.; Gold, A.; . N E.; and mm ub A. Chalcones. Eur. J. Or J. Eur. by s

t for for the e

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m α l Ch S Means Means B.; J. , Aldehydes Aldehydes n , , , . N Y.;

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ll - Chem. Chem. h 84 P T e nthesis u. J. Eur. Ena e

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2007 edr e S. and i i

a Arenesulfonamide. Arenesulfonamide. t P t c Organocatalytic Organocatalytic with Amino Amino with i , 2006 h Acid

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T Nitro- Nitro- l chael c C s y et A a t with with e a s e t t cid cid t t r r a r – s a- a- a e , , , , i – I l

c - - - - :

This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted Article Aldehyde Asymmetric Direct Catalytic B So Chem. for Praktisc (a) 2006 Diastereo- and Proline Y Aldehydes Deriv A.; Alexakis, Ketones and Aldehydes (a) for V Taming B 2004 Nitrostyrenes Organocatalytic ric Mase, 1509 an, e e i s t t hn Mi a a th B A – n n

, , , ativ Z. l um l 1521. e c c c a e 6 17

o o hael r N.; N.; x -Y.; Niu, -Y.; Enan , , r r e h Na a a t t r es 2527 , , c. k , , y , Donors Donors vollständig diastereo- vollständig 3288 J. M.; M.; J. J.

and i

to a k

S. s Th as Reaction Reaction 2006 k k ed ,; , ‘Cli Nitroolefins. Nitroolefins. tioselectiv A.;

– for for the T Organocatalysts Organocatalysts S J.; J.; M.; Aldehyde Donors. Donors. Aldehyde ayumanav

2530. – Enan oma i 3293. c n Y. , , g

S to A B h, 12 S c -N.; -N.; Chemistry’: s hw

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k of Mi b , t r e e a

h nthesis

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Ketones Ketones W z K. c s y . Bernardinelli, A.; Mi i an, v e

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e Nitrostyrene. II r e Highly Adv.Synth. Catal. c , i O. l

, , I hael R; T R.;

K.; – W. , H. C. F. F. C. Mi

Reactions 9625. 9625. e e of D

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B.; B.; -L.; W -L.; for the for Mi chael Reactions: Reactions: chael Malonates Malonates i Addition

to a Quaternary Carb Quaternary Or

Th m c Nitroolefins. Nitroolefins. E und ana Class Class hael i n g. Seebac ayumanavan, C n a u, e Lett. a Asymmetric Asymmetric n k -C

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F.; F.; y g. s t -Y.; -Y.; of h, t and e Versatile a n G. i Lett. 2001 l l c

Cyclic ti e y 2004

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D t , Nitro e The Zhao, B selektiv i α

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2002 e on r

s 3 , , . Tanak R.; A g. c b W Water.

y t Mi , , 34 Use Use a - s Ketones Ketones mm Lett. Olefins.

Co 3737 y s a A Y. Organocatalysts Organocatalysts

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F. F. r F.; F.; e r – ah

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h Y. B D 1117 2, l e i a on: a c i

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r 2004 Asymmetry a Bi

e Ketones Ketones A t des -Additionen. ga –

l s

Co dd 1119. 1119.

p Or R A n II yrrolidine yrrolidine o Enam- e i s mbining g. I t , , c y a Highly Highly , J. J. i a

mm c o 2004

t L C. t n a i ett. A s o and and and l of y n e m. m. β F s t s , t - - - -

: . This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted Article 1983 (Methoxymethyl)pyrrolidin"Prolinolmethylether" und Blarer, Aryl-2 Cyclohexanon aus ins cepted Organocatalyzed (a) 13860 The D 891 lectiv Syu, 1406 Addition S a - (SMP) E Ber. (M ti B (2S)-2-[(Phenylsulfinyl)methyl]pyrrolidine-Catalyzed i v nd l o n a e ethoxymethyl)pyrrolidin n g r – lyirne Alkylierungen

Diarylprolinol P e s e h, 897. – l r 1983 , , r e S. a ena und, – 1413. s ,

1 11 t

, -Nitroäth 13874. K. Mi -e.; -e.; D.; o Me S.

r 6 S. S. N.; N.; n of chael Addition a

, , tioselektiv , , J.; J.; - Pioneer Pioneer

chanism B. Kao, K

3086 11 Cyclohexanone Cyclohexanone K o

J.; J.;

S 6 m S.; l i , a Seebach, Seebach, n yl)cyclohexanonen. – i tt 2250 s

T. g 3096. a Mi Johansen, h, , Silyl Silyl Seebach, r T; Lin, -T.; Auxiliary. Auxiliary. Revisited s M. P chael Additionchael e k Alkylierungen a – .;

des , 2260. Kaur, A.; A.; Kaur, K.; K.; A und Et of D. D. s y R- (R)-

h mm

Ketones Ketones and dur e T. W. B

Asymme

rs D. D. and Synthesis Prolinylmethyläther e K.; K.; : e c n A

T t Cyclopentanone Cyclopentanone h o r h i S A α en Revised. c und

o New New i -(Methoxycarbonyl)zimtsäure-methylester.

s n P of ud, to Helv. S y

g o trisc Years mm y

h, Nitroolefins Nitroolefins u der Aldehydes Aldehydes n

(S)-Enamins aus Cyclohexanon und 2- 2- und Cyclohexanon aus (S)-Enamins 1996 l P t s M.; T h e he e Chim. Acta Chim. Enamine aus aus Enamine y .; n, e t p s

r

After. After. . . H H.; P. Sharma, i i

e Helv. , , s s I Mi

s c 1996 of h h w c i e

i k to hael

t O a h to hm Acta Chim.

Angew. Chem. Chem. Angew. Nitroolefins. Nitroolefins. dur w , r dur

on M ga Nitro Nitro 1403 a ( Efficien S. -Additionen. Regio-, diastereo Regio-, -Additionen. S , i a Water. c H.; H.; c n ) ch l

h h - o s K.; Khullar, K.; 2 a k c – 1982 ω - e o a 1418. M l ω v -Nitrost t - β Al Seebac a A , -Nitrost t e

Ttaoe und -Tetralonen l

t k y K. dd Stereoselective Stereoselective h T , enes s

o et t

i 2011 xy for Highly for Synthesis t 65 . J S.; r i n. Ed. Int. ah o h, yrole. m

n , yrole

— S.; e edr e

. H D.; ø , n. 1637 t Generally h r

g 94 Mandal, Mandal, on y

zu e

Chem. Ber. l p n S , ,

2013 2015 – y 2010 s t a e 719 e rr 1654; 1654; y S n, r a Mi (S)-2- (S)-2- o e t u Chem. Chem. s

e o li

– h -2-(1 K. r chael , , , , s , , d S. 745; e i e , 45 i Ac- 66 54 o l

n

(b) (b) e s K Y A e k e , , , , , 1

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Accepted Article Mu Sc Acta Chim. Helv. des 1,2-Oxazine (b) Guo, Guo, Zhao, 2005 Catalyzed T plications Strohmann, J.; Stiller, O.; J. Bauer, (b) hydes Catalyzed by Maruok H.; Mii, T.; Kano, (a) A J. Pyridine I Krisc Pharmaceutic Hiroaki, 2013 the for Enamines s e h hw r ii

k a Seebac to m. , ai k T.; T.; e he, , , , a X. i yama, T.; Nitro H. 96 34 z d

er, hm So Chem. o Corresponding Corresponding -

Y. M. W; Y -W.; Conjugate Base Base Conjugate Catalysts G.; , , , , D.; Tak D.; F

in 799 962 Deri h, Asymmetric Direct Asymmetric Mi u W. J. K., Williams, Williams, K., J. H Asymmetric Olefins j

N-Oxides C. i al c D.; Sun, X.; Sparr, C.; Ebert, Ebert, C.; Sparr, Sun, X.; D.; o – – B.; Purkayastha, B.; N.; hael v a k 963. 852.

Silyl-Modified Silyl-Modified ang, y ed a and a , Benohoud, Benohoud, c.

s from Di from S.;

Addition h ano, 2012 2004 2-T Z.; Fine Fine i ,

Organocatalyzed Organocatalyzed

S Y. as as Organocatalytic Organocatalytic e M.; M.; k Y ri , ,

, , i Organ tylpyrrolidine. In u g 12 Catalyst Resting States States Resting Catalyst Chemic 95 phe e u

, M.; 6 c M.

Sustainable Sustainable , , Ori Reactions Reactions h , Y. nylprolin i 1064 9558 Marqués- Analogues Analogues T., Eds.; Eds.; Wiley-V T., , ocatalysis. ocatalysis.

Y; Li, -Y.; Y.; Y.; Mi a, yama, T. Highly T. yama, H al

ay chael for for K. –

– 1078; 1078; ashi, ashi, Industries K

9559. 9559. Use Be D o by ol t

Ló of Co i H. React s Silyl Ethers with Silyl r Catalysis: Catalysis: ck, . A J. u e in Ketones Ketones Y.; Y.; α pez, pez, of -L.; -L.; Chem. Chem. c k nv (c) (c) ,

t i Asymmetric Asymmetric α 2-T ,

A. ersions

M. m. -Diphenylprolinol A R H. i , 1st ed.; Dunn, ed.; 1st , o K.; K.; Song, Song, Seebach, Seebach, s e E.; Strohfeldt, K.; Christmann, K.; Strohfeldt, E.; n -O.; Chem. Soc. y A i ri her, s CH: mm u. J. Eur. tylpyrrolidine: tylpyrrolidine:

E of in Challenges Challenges to New New n Duschmalé, Duschmalé, —

Schweizer, X. e

a Cyclohexanone Cyclohexanone

M. Ho t Mi n β r a Survey. a - t i Q.; -Nitros

c D.; Sun, X.; Ebert, Ebert, X.; Sun, D.; Mi i bok c C o Stoichiometric Reactions Reactions Stoichiometric 2010

hael Nitro s B l chael

e a en, Sheng, Sheng, l e ss e n 2009 c

z , , J., P. Trimethylsilyl Ether. Trimethylsilyl t 2013; 2013; tyrenes. A of and o i W. 16

v y Addition dd J.; J.; Chiral Olefins Olefins e l Sy o Helv.

, , B.; B.; , ,

xy i Z. 12553 ( Practic tio nthesis S Wennemers, 13 with -H.; -H.; l ) pp Hii, a n - 1 H t Ci. Acta Chim. Chem. Be s i

,

and o Reactions. P 287 o Aromatic

of 3450 – n M m es y K. ck,

12558. 12558. rr Alde o and e of

– p n Lessons Lessons o o the for K. A. 316. M.

r g – li L o A , 3451; 3451; d

li ett. -O.; -O.; Ap l i W M., M., M.; M.; K. hy n d n H.

of of e e e .;

------; This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted Article tr Highly Organocatalyst: Cao, Organocatalysts. Nitroolefins 3204 and Enan S Aldehydes Co R 2013 New Ferrocenyl a for Pyrrolidine P 2010 p Alexakis, N.; Krause, Compounds. alysts (a) ta Asymmetric rido, D u oolefins. oolefins. ounds e e i ck e t l dd ntaining z r z Qu

e u , Vi – of D.; tioselectiv r y , , zz N. C. 3220. - , — n 19 35 i M

the n i

yl M; Broughton, M.; -L.; R. e to t Highly Highly o 2 ll , ,

a ss , ,

7696 o J.; Kuan, J.; Or Phosphonates Phosphonates Jose Jose r

to Nitro Enamine Enamine 667 d, , é Organocatalysts Organocatalysts D.; D.; in Y ,

Mi g. A.; A.;

u. . Or J. Eur. Nitroalkenes. Nitroalkenes. e Water S.; – , e – Lett. c

Gil, 7700. 695. dienes/N hael M. S

Organocatalytic Conjugate Conjugate Organocatalytic Efficien Synlett Synlett A t B e -C.; -C.; l

e n e

l M.; on x Addition t 2006

o

a Catalyzed Catalyzed a t H. , k , the A. M.; M.;

Sun, t g. i Moro, Moro, S.; as s

H. 2014 Enan -H.; Chou, -H.; itro

and , , ,

A.; A.; Organ Challenging Challenging Chem. Chem.

Chem. Chem. B.; B.; 8 Trans-Nitrostyrene. Marchal, M for Direct Asymmetric Michael Asymmetric Addition Direct for , , en X. Modular Catalysts Catalysts for Modular

2901 tioselectiv , , a M Reactions. Reactions. y L; T -L.; zz 25 Urones, Urones, n R. by Nov by ocatalyzed ocatalyzed a e a r Stereoselective , u. J. Eur. 2010 s n F.; F.; e –

293 t d and 2904.

i E.; a , ang, T. A.; A.; , – J.; J.; , , -Y.; -Y.; el 297. e M Mi

J. J.

Sy 201 A Aily Unfixed Axially Mi a New New 2009

C chael Y. l B r G. e nthetic

c o c Addition x o 0 Conjugate Addition Conjugate Chen, Chen,

o zz hael A New A ll a , P s k o , i , , Me 927

y T , i t Acceptors. Acceptors. P. s 15 rr I. , et Enamine Enamine Catalysis. ,

Addition

G.; chanism chanism Applications. Applications. o – r A. , , S.; S.; ah li G. K. N K. 936; 936; 9294

α d

of A B edr i -Functionalization A Class Class n García, P García, e m

e r Aldehydes Aldehydes b Belot, (b) - on o R – n i T n Biaryl-Based Biaryl-Based v a 9298. a via via h Chem. Chem. e a

r t of 2007 of l l i d i

- o o P i

P Cia Pyrrolidine Chiral u n n Cyclohexanone Cyclohexanone Simple Simple y r r e a e

rr o lli .; l Adv. Synth. Catal. Synth. Adv. , , a

of li

Approach o Eur. Eur.

, 63 n

Basab li as to Carbonyl Com- Com- Carbonyl S.; G.; a d Chem. Eur. , , m

i of

740 Vi 4+2 a n Filin i Quintard, Bifunctional Bifunctional J. e d Unmodified Unmodified n B of e e,

O yl -C 2009 – i Carbonyl Carbonyl f

r

T 747. 747. un ch P ga a T Sulfones Sulfones y .; mph o c p uk, uk, n to Gar- Gar- w t , , e o i

a o 15 c for A Ni r n J. A.; A.; a o Y d a t- t- r t , ,

s - - - - - . l This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted Article (a) (a) J. Leading quence Organocatalysis: E F 5678. of F 1965 K to Ramón, A 55 jugate Addition felder, Silyl Diphenylprolinol by the of Study tal T.; Uchimaru, S.; Tsuzuki, H.; Gotoh, istry Comp mun. alytic an, e nd l u

ll o , , 2- 2012 Nitroalkenes. Nitroalkenes. e n u Zhao, 8571 hn e X.; (4 s ga r

, , 2012 o 2007 s one E -Morph e 30 , , C. ,

D.; D.; , F.; F.; , , na

– D. D.

M. , , 18 R E.; Kisunzu, J. K.; Kisunzu, J. E.; 8574. n G. n 4280 , , A.; A.; J. J. t o , , tioselectiv E.;

, , Nitti, Nitti, d 734 -L.; Xu, Y.; Y.; Xu, -L.; 8 Sy 10226 r , , G olin í Recen

– g nthesis 1804 r – 4284. u Baeza, Baeza, Reactions Reactions e Molecules Molecules to Effects Effects F 735; 735; e b, yl)-1-Phen P An o z ercci noeSrcue ih Six Structures Tetracyclic Indole with l - .; A.; A.; – – e E t

10229. 10229. Asymmetric Aza- Asymmetric 1813; 1813; y

e P s (b) (b) Advances ,

c

of i Conjugate Conjugate t r L. A.; Chinchilla, R.; R.; Chinchilla, A.; of Silyl Silyl of a i a Library Sundén, Ether. Ether. c Fenster, cc

D h, R of 2017 (c) (c) e o C.; C.; ylprop e c ,

a k Aldehydes Aldehydes G.; Wennemers, c e H t r in Substituen , , i s ay S o Chem. Chem.

, H.; H.; 22 V Asymmetric K.; K.; a Addition n E.; E.; en ashi, ashi, y of a

, , a of l e e

E 895. l and and Nitroolefins. Hill, γ e n

r -Lactams. -Lactams. r E t i Mi o i k S . Okamura, D.; Y.; Eur. J. J. Eur. t Seebac n n, , o ss e D.; D.;

a chael/Michael/Michael/Aldol

li S.;

ts H. m Maleimide. Maleimide. o E. of g Gómez, n,

, i

in P

n P L.; L.; Peptide-Catalyzed Stereoselective Stereoselective Peptide-Catalyzed Car Aldehydes Aldehydes Reiser, e

h, Organocatalyzed Conjugate Conjugate Organocatalyzed e s Ena .; 2014 r

i Beilstein Beilstein Journal

bo- bo- w c D. S à M i ay n t s A Theoretical and Theoretical A C.; C.; h tioselectiv , e , , and

O.; ah, N r M. Angew. Chem. Chem. Angew. 20 k T e

i G Aubé, Automated Three- J. et to

n t M.; , , H r A. u s Yamazaki, 17077 r Stereo

o , ah e ill Maleimides. Maleimides. C.

t

O P e Córdov e edr r n e a l o e

a r – Reactions Reactions c fi a , ce on Qu y 17088; 17088; G.; G.; n l d c of s nters. li

e . 1989 a a,

h Organic Chem- z d . Or J. n. Ed. Int. . Ameda, T.; a y

r A. P t d up i Reaction Reaction Chem. Chem.

a e o (d) Grünen- Grünen- (d) Ex

, , Chem. Chem.

s n l O as t e Catalyzed Catalyzed 45 g.

o A R Domino Domino r perimen- perimen-

r ga Chem. dditions dditions e , an , ,

2016 a 5667 n I. c Com- Com- Ac Con- Con- o t M.; M.; Eur. Eur. i c o Se Y.; Y.; a n – , , - t

s - - - -

This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted Article 3717 A Alza, E.; I e Poulsen, J. Eur. T Asymmetric Zhou, o electiv Aratak actions. (c) t E E C.; Palomo, (a) of Chen, Domino E t Š V n r r t ce e e nd n nd dd oa e a

c b v K s a l o nters. e d e m E l e e i mp e – s r k t e r r in a in t t nd k 3720 i e i h s s J; Sun, J.; o o a n e, . io . Ni, Qiao, Y.; Q.; o e, n , , y n a n D.; R.; Krüll, D.; , e v e e

d 2009 R t Catalytic, e S.; S.; Angew.Ed. Chem. Int. s / á s r P. H.; R. C i e

s Angew. Chem. Chem. Angew. I

s b , e .

in m E.; E.; in

, a T a t l D.; Grondal, D.;

P e mb o r c

O

i Hazelard, Hazelard,

Hüttl, Hüttl, i n r N t W W , , C p e i r i andem o P um l ga c e a 15 a a e i Jørgensen, Jørgensen, n u X. i t t o t

r t s r a r n e l o e , ,

Cascade Cascade oo á - s -L.; T -L.; l r o T M r , of I y o 11384 č

and

o c X. M. r s k l C

i a n andem e

t A e o

t s fi

C.; C.; J in a l v R

a . c go D.

n C t

B á l R. e

e B. a Chem. Chem. ang, in y s , – t a n. Ed. Int. A e action , l Diphenylprolinol Silyl Ether Silyl Diphenylprolinol V.; s a A. Diarylprolinol Diarylprolinol A. y 11 t C.; C.; tt in

a Ball-Mill. Highly t s a l K. z M.;

O d i y r

l

e m 389; 389; E y Mi e a t Y.; Li, Y.-X.; Li, G.-Y.; Sun, J. J. Sun, G.-Y.; Li, Y.-X.; Li, Y.; mm d

r h h L y s ffi e ga A. y a by i , e y n he/er Rato o the Reaction for chael/Henry o the for i Grondal, C.; C.; Grondal, u. J. Eur. s Hüttl, Hüttl,

p c

d . o Asymmetric Organocatalytic Asymmetric Organocatalytic n W. e P i

t e (f , e 2007 o t á 2007 Angew. C.; r

n r E c ) e and k

i c a c s n o M y t e P

Jensen, Jensen, v a a

n M P á S M. n i , , in l N ChemCatChem ChemCatChem , , c 2013 c , y t e Construction - L.; L.; i r e 46 S i r

t c 46 o

i

o i i Chem. Int. Ed. Chem. Int. h t up t of w c c s A r h a , , à e

, , oa a

e e s l K p s , , 1570 W R 4922 v e

y l , K. o

19 l

c e M á Raab mm e E k M. a r R t - z a L.; L.; e t A i t t i m , , v c e e n c e h –

– ss 10814 t d a e h r e A. e e e 1581; i 4925; 4925;

. c

s a o t r r e, i

O t . s P r o s Synlett Synlett e Highly n.

Di i t i :

l v Synthesis Synthesis r o y c Expanding e

ga G. á n

ckmeiss, ckmeiss, d rr A 2012 of – as ,

Natur s O

E.; E.; dd n o 10817.

d Hysi . Okano, Hayashi, Y.; (d) (e) Cao, (e) O Bicyclic Bicyclic

li r o P C a Catalyst a ga r d c i 2006 r o t ga a 2013 E i o , , M i n n n t o trol trol e m 4 n t n a e o Co n

e r

, , a . Sy l o o 2010 c s č o

y 2006 n G.; 1013 a t c of , , i Or l t An , , a n e t

a t nthesis i C. i 45 d a r c t of 24 o o g. Donslun a Skeletons. Skeletons. l by s Organocatalytic Organocatalytic y A v M t -L.; -L.; , , F l , , e , Lett. , , y t h – á in l 2010 l i 7876 839 i t e

e d , 1018. of c our

c

i 44 c

Domino e c M.; h S an t F h Zhou,

P of a i i 1 Qu v t y

– e , o

our e – Enantios- Complex Complex e Toma, , , d S l 842. 842. t 2007 567 -

7880; 7880;

e t

e I M A d, 861 a e s s n d Stere o

r dd Chem. Chem. t i

– e r t B. c l Y. i a up a o o – h 572. , , i

t l N c 863; 863; t S.; a -Y.; -Y.; of of e Re (b) (b) e i T.; T.; 9 l e Š d o e n- n- l , i n .;

------This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted Article F ders, Alder Is I.; Atodiresei, Derivatives. Cyclopenta[b]quinoline Communication. Communication. logical by Seebac Stereoselective Hoffmann, F CO when holds 52 Generating R.; to Bern A.; Alexakis, or Chem. The F Ed. our or or ochromenes ochromenes Nitroolefins Catalyzed Nitroolefins by

, , nitroolefines nitroolefines Diastereoselective

- Wennemers, 7228

2013 t p -Step -Step CH Unambiguous Specification Specification Unambiguous h D. r Sequence. Sequence. e o h, Rule Rule for n. Ed. Int.

b 3 A R

– l + + , , e D.; D.; 7232. 7232. e Sy m 52

Branched Domino Domino Branched / R. All only RCH=CH-Acc Si a nthesis , , t G W.; Herrmann, Herrmann, W.;

-Carb i -specification -specification 2977 via synthesis c o En 1982 C, — carrying additional carrying

one Synthesis Synthesis li H. s Helv. Helv. ActaChim. t ń C-Bond Forming The The ders, ders, e an

ar s – r stereogenic k on Peptide-Catalyzed Peptide-Catalyzed of e , , 2980. 2980. i dinelli, o Mi raoaayi Triple Organocatalytic ,

21 J. J. Polyfunctionalized c Quaternary Stereogenic Stereogenic Quaternary

h ; Thieme: ; Si c D. e , hael m

654 S Asymmetric 2012 and and y i

of c Chiral Diamine. Diamine. Chiral G. n Reaction: Reaction: a – -Addition t steric steric l 660. 660. wt OCH-CH with

h

Asymmetric W. Re , , of ce t e e s 44 the r i St n

s m

1981 The The ter topicity A.

Or heteroatoms, see Refs. [14b,22a] [14b,22a] see Refs. heteroatoms, , , Pr tgr, 1996. uttgart, of s courses courses 2107 and and

ocesses be ocesses g. Steric Course Course Steric

i Houb Stereoselect s of Op Asymmetric Organocatalytic Organocatalytic Asymmetric R Lett.

, , formed, formed, Sy Cyclohexene Derivatives. Cyclohexene

e – 64 (E)-Enamines (E)-Enamines

e 2113; / t n- nthesis preference en Si e , , of r Mi 1413 Ch 2 m

2011 -descriptors -descriptors -Weyl Metho -Weyl R Ce

Or ecin e: Seebac see: reactions acd/bCtlzd Hetero-Diels Cascade/Yb-Catalyzed c s

tw a

(h) (h) hael vs. vs. for for g. nters. n i n een een – i o v Lett. ,

of 1423. 1423. t of instance instance R- e Zeng, Zeng, 13 2

Addition

3-Substituted Hexahydro 3-Substituted t ,

Asymmetric Conjugate Conjugate 3 o CO Pr for for , Angew. Chem. Chem. Angew. -

D 3678 be used, see: see: used, be to ochiral 2003 i -CH may al s ()Ntolfn.A Topo- A (E)-Nitroolefins. X.; X.; ds ub dehydes – with

s 3681; 3681; of 2 Ni,

, , t - re of i Organic Chemistry: Organic R’ t 5 Ce verse OCH- Addition u

, , Q.;

α t Angew. Chem. Chem. Angew. + + Sy 2559 ntres. e -Hydro (g) (g) d h, and Andre and T vs. vs.

H ntheses

Raab n. Ed. Int. w

4 H with 2 D.; D.; Erdmann, Erdmann, o- – - CH C=CH-A e N ketones 2561; 2561; l Preliminary Preliminary Reactions Reactions Com m i xy t Prelog, e, 3 3 r c enamines enamines o vs. vs.

h ketones Angew. G.; En- En- G.; k e 2013 p e n, Kastl, Kastl, y, O.; O.; y, one t CH - o also also G.; G.; cc. 3H Int. Int. n N.; N.; V. V. n e , , 3

– s t - - - -

This article is protected by copyright. All rights reserved. This article is protected rights by All copyright. reserved.

Accepted Article acid. 206 P compare F 2363 Addition Bu W Catalyzed Mi W 7952 Addition Giorgi, A.; diastereoselectivity acetaldehyde W or d.r. with F Sulfonate, Binding-Affinity a form amide neighboring or or r ang, ang,

e o c ketones tyldiphenylsilyl Ether Ether tyldiphenylsilyl

t hael c m Lecture a o – – o r In n 2366. 7957. o up e J.; Li, J.; C; Y C.; a s

H-bonded complex complex H-bonded t Addition t DM a li e

Figure Figure and w of p be d n by and and nitroolefines. with

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a g Ketones and G.; n

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6, d b h nitrob of only v i Lou,

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t n group group e which is which e u z

r and es d e o B.; B.; n e

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u e L.; Guo, H.; W Guo, H.; L.; pr 5 Comin, c do J. A J. Unmodified Unmodified eng, s t ov NO e a urea a derivativ versity

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is - h Isosteres Isosteres n Chem. Chem. T en a e t J. J.

r

s

95:5, respectiv 95:5, 1, i discussed discussed (al Aldehydes Aldehydes

t p su fl form form Bifunctional y

ang, u An t rr peracid: peracid: o a ko c. r b e: o Eur. J. J. Eur. o ti li l

xy -Selectiv m e

1994 Kelly, — an W. d s e i

n Nitro, Nitro, a e t

in n h in: e T r E e - and a a et 22 in , , tram c

n value m n 2006 a p 11 c r el a the e Donadío, Donadío, t yl ah T. r i

n Organocatalyst Organocatalyst s . Or J. a n e y, e

and 6 -butanol -butanol u t Ketones Ketones Organocatalytic Organocatalytic l s R.; Kim, R.; e o Phosphate, Phosphonate, Phosphonate, Phosphate, , edr y i l e

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Accepted Article Compounds Compounds Amoun Be ular be 536 M Ethers. Diarylprolinol with H Seebac and Structures (a) tions. stituen Raab tural Br 172. Nitroolefinen Verlauf der Seebac 1203. Ions? ay ü own, tw ck, ll – Seebac ashi, ashi, with

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Accepted Article Ebert, Ebert, and See 1418. Electrostatic Potential, ture, 520. tum P J. S lysts. Houk, 10.02.2017). http://www.scripps.edu/baran/imagegrpm by presented ines, a For 10.02.2017). http://www.cup.lmu.de/o See ines. Bock, Acta Chim. Diarylprolinol Models i r mm, o Chem. Chem. pp the

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Accepted Article Perdew, Perdew, gas Perdew, chemistry. S Phys. Chem. Chem. Phys. Phys. Chem. Chem. Phys. and W 13 for A 2003 Scaling G Functionals Transiti Thermochemical mochemistry, Zhao, justable C.; Adamo, Elemen Parametrization tio G Simple. i d r r mm, e 5 i i l i

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Accepted Article T J. nen, P M B Revisited. nisms son, A 52 molecule T. Linderoth, N nistic P 2016 ligands N istry. of Zhang, 1250 chona eng, a a e r i u

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Accepted Article ities. ities. Me Cheong, cross-coupling. of Y Or J. sign Yang, Chem. electivity D nitroalkenes. (pyrrolidin-2-yl)-1 Arnó, SM12. M asymmetric P Chem. B Chem. Angew. Br ang, a a i conformational searc a own, J. n t l chanical I chanical r c il é e e r of , n g. ll Chem. Chem. , H; W H.; M. P i H.; M.; s

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Accepted Article Catalyst Bifunctional K Chem. Better in I P. Hubin, Chem. of Zhao, 6506. Yang, J So Chem. sis: B A N, Organocatalyst F B p nv o r oi m. e e ó

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Accepted49 "Downstream A.; Armstrong, J.; meth F S Article catalyzed Houk, Y.; Lam, 2010 electivities A discrete chosen N to H or i ll o a mm, Diarylprolinol-Silyl Ethers Diarylprolinol-Silyl , , t l e a a s 214 e m k

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