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Enantioselective Protonation of Enolates and Enols.

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REVIEWS
Enantioselective Protonation of Enolates and Enols
Charles Fehr”
In memory of Wolfgang Oppolzer
tiveness of enantioselective protonation
results from the fact that after reaction,
the chiral proton donor is regenerated in
its original protonated form by an extractive workup. Enantioselective protonation has been applied to the synthesis of amino acids, antiinflammatory
agents (2-arylpropanoic acids), and fra-
Enantioselective protonation, until recently a largely overlooked reaction,
has, in the last five years, developed into
a field of intense research activity. The
progress achieved parallels or complements that obtained in the understanding of enolate structures and reactivities.
The conceptual simplicity and attrac-
1. Introduction
Conceptually, enantioselective protonation is extremely simple. Because a prochiral enolate has two enantiotopic faces, the
transfer of a proton from a chiral, nonracemic proton source to
the enolate will be kinetically favored either from the top or
bottom face, thus affording the carbonyl compound enriched
with either the ( R )or ( S )enantiomer (Scheme I).[’] The impor-
x*
l -
R3
R‘
R’
)=.=O
R2
H@
R3M
grance compounds such as (S)-a-damascone, for which its industrial feasibility has been demonstrated.
Keywords: asymmetric syntheses * enols
lithium compounds protonations
-
deprotonation of the parent carbonyl compound or directly
from a synthetic operation such as nucleophilic addition to a
ketene[3’ or an e n ~ n e , [ is
~ ]“quenched’ with the chiral proton
donor to afford the enantiomerically enriched carbonyl compound. On addition of water, the chiral reagent is reprotonated
and recovered by simple extraction!
Enantioselective protonation can also be performed on
enols. In this case (M = H ; Scheme 1) the chiral reagent (X*H
or X t e ) is not consumed. Therefore, in
principle, these tautomerizations require only
catalytic amounts of the chiral reagent. Still
another possible variant is the protonation of
a complex formed between the enolate and
R2 (R)
the chiral ligand with an achiral proton
source.15]These three reaction types are closely interrelated, and because of possible reversible proton exchange reactions between
the various reaction partners, it is often diffiH
R3
cult to unambiguously differentiate between
(S)
them.
Rl)413
7-4
H
I
X*
Scheme 1 Enolate generation and enantioselective protonation
tance of enolates as intermediates in synthesis, the recent advances achieved in the regio- and stereoselective generation of
enolates with the desired counterion, and the increased knowledge of their structure and reactivity[*] make their protonation
a very attractive method for obtaining enantiomerically pure
carbonyl compounds. Indeed, the enolate, obtained either by
2. What Has Refrained Chemists from Exploring
Enantioselective Protonations?
[*I
0
Dr. C. Fehr
Firrnenich SA. Corporate Research Division
P. 0. Box 239. CH-1211 Geneva 8 (Switzerland)
Fax: Int. code +(22)780-3436
r-mail : charles.fehr(i firmenich.ch
A n p r . Chrm. 1121.Ed. End. 1996, 3s. 2566-2587
In spite of the potential synthetic power of enantioselective
protonation, this subject has not attracted great interest until
recently.r61This is probably due to the following reasons:
Proton exchange reactions between electronegative atoms are
considered to be among the most rapid, often diffusion-controlled reactions,[’] and thus it is difficult to discriminate efficiently between two diastereomeric transition states. There-
VCH Verlugsgesellschafi mbH, D-69451 Weinheim. 1996
0570-0833/9613522-2S67$15.00+ ,2510
2567
REVIEWS
0
0
C. Fehr
fore, the chiral reagent should be only weakly acidic. In addition, 0-protonation of enolates leads reversibly to enols,
which may be transformed into ketones without enantiofacial
discrimination, or may act as an undesired proton source for
C-protonation. The risk can be minimized by using an excess
of a chiral proton source and by applying reaction conditions
that allow complete C-protonation (for example appropriate
temperature range).
Enantioselective protonations are kinetically controlled reactions. Under thermodynamic control racemic products are
obtained. To prevent concomitant or subsequent racemization in the polar protic medium the choice of a chiral proton
donor of appropriate acidity is essential and short reaction
times enhance the chances of success. Evidently, this does not
apply to bulky systems, where racemization is difficult.
Quenching the reaction mixture with Me,SiC1 prior to hydrolysis is often recommended for following the progress of
the reaction (see Sections 3 and 4).
E- and 2-enolates exhibit different enantiofacial selectivities,
because the two diastereomeric transition states for the protonation of the E-enolate are different from those for the
Z-enolate. This is schematically represented with a chelate
model (Scheme 2), in which both the enolate 0 and C(2)
atoms are involved in the transition state. Accordingly, the
four possible transition state structures are diastereomeric, as
evidenced by the relative positioning of the substitutents. It is
0
0
thus important to minimize the amount of that enolate isomer which leads to lower, possibly reversed asymmetric induction.
The preferred trajectory for the C-protonation of enolates is
a vertical approach of the “proton” to the plane defined by
the enolate x-system, with a preferential colinear arrangement between donor atom, proton, and acceptor atom
(Scheme 1). More precise information concerning transition
state structures is, however, still lacking. As will be discussed
in Section 3, solvation, aggregation, and complexation phenomena also often dramatically influence the outcome of the
reaction. Efficient chiral proton donors or chiral ligands generally have electron-rich groups capable of undergoing chelation (see Section 3.2).
The first synthetically useful example of enolate protonation
that afforded a maximum enantiomeric excess of 70 % was
reported in 1978 by L. Duhamel and J.-C. Plaquevent.[’] Prior
to this study only scattered publications had appeared, describing for the most part only very weak inductions.[’l This
early period was reviewed in detail by Duhamel et al. in
1984.[6“1
In recent years, intense research activity has concentrated on
the general scope of enantioselective protonation. Due to the
vast structural diversity of chiral reagents investigated, it seems
judicious to subdivide the foIIowing section, after a presentation
of Duhamel’s work, into substrate structural classes.
3. Enantioselective Protonation of Enolates
3.1. The Pioneering Work of the Duhamel Group
...
@
41
:
M
I
2-enolate
E-enolate
Scheme 2. Two diastereomeric enolates: four diastereomeric transition states. The
gray circles represent the largest substituents.
The first in-depth study on the “deracemization” of amino
acid derivatives by enantioselective protonation of the corresponding anions was carried out by L. Duhamel and J.-C.
Plaquevent,[’] who proposed the commercially available (R,R)di-0,O’-pivaloyltartaric acid (( -)-2a) to be the chiral reagent of
choice. Thus, deprotonation of racemic methyl N-benzylidenephenylglycinate (( i)-la) with lithium diisopropylamide
(LDA) and protonation of the resulting enolate with excess
(-)-2a gives (S)-la with 50%ee (Scheme 3; Table 1, entry 1).
The size of the acyl group of the chiral acid is very critical, as
replacement of the tert-butyl groups by methyl or triethylmethyl
groups almost completely destroys the enantiofacial selectivity
of the chiral reagent (Table 1, entries 2 and 3). A wide range of
Charles Fehr, born in Zurich, Switzerland, in 1946, studied chemistry at the ETH in Zurich.
He completed his doctoral thesis in 1974 under the direction of Dr. Theodor Petrzilka for work
conducted in the group of Prof. Albert Eschenmoser. From 1974 to 1977 he conductedpostdoctoral research at the University of Geneva with Prof. Wolfgang Oppolzer and at the Johns
Hopkins University, Baltimore, with Prof. Gary H. Posner. In 1978 he joined the Corporate
Research Division of Firmenich SA and in 1990 he received the Ruzicka Prize.
2568
Angew. Chem. l n t . Ed. Engl. 1996, 35,2566-2587
REVIEWS
Enantioselective Protonation
OMe
Q
Q
R
R
R=H
Q
The deracemization of a variety of a-amino acid derivatives
with (-)-2a as the chiral proton donor predictably afforded the
(S)-esters as the major enantiomers (34-70% ee).[' A model
based on minimal steric interactions between (-)-2a and the
enolate-amine complex was proposed.["' However, the deconjugation -protonation sequence shown in Scheme 4 led to the
R
(+)-la
(S)-la
R = OMe (*)-lb
(S)-lb
- phy -
OMe
-70
(-)-2a
LDA
+ 35°C
-70°C
Ph
Ph
R'= fBu
(-)pa
R'= Me
(-)-2b
R'= CEt3
(-)-2C
H$ycoR
ROC0
H
COOH
Scheme 3. Deracemizdtion of amino acid derivatives
Ph
+ PhYN
42:58
Ph
34% ee
Tdble 1. Deracemization of amino acid derivatives.
Entry
Substrate Base
1
2
3
4
5
6
7
8
9
10
11
[a] LTMP
T['C]
LDA
-70
LDA
-70
LDA
-70
LDA
-70
LDA
-105
LiNEt,
-70
LTMP [a] - 70
lbl
- 70
Ibl
- 70
[bl
- 70
lbl
- 70
=
Scheme 4. Formation of a vinylglycine ester by deconjugation and enantioselective
protonation.
H-Donor
Product
ee[%] Yield ["A]
(-)-2a
(S)-la
(S)-la
(S)-la
(S)-lb
(S)-lb
(S)-la
(S)-la
(S)-la
(R)-la
(S)-La
(S)-la
50
(-)-Zb
(-)-ZC
( - )-2a
(-)-Za
( - )-Za
( - )-Za
( - )-Za
( )-2a
( f)-za
meso-2a
+
85
3
5
57
70
28
22
70
5
39
24
70
95
(R)-vinylglycine ester (34% ee)." '1 This reversal of the sense
of induction can be rationalized by the altered configuration of
the ester enolate.
Finally, (R,R)-di-0,O'-pivaloyltartaricacid (( - )-2a) was also
successfully used for the preparation of (S)-benzoin with
80 % ee (see Section 5 ) .["I
3.2. Protonation of Open-Chain Ketone Enolates
Lithium 2,2,6,6-tetramethyIp1peridide.[b] (R)-LiN(Et)CH(Me)Ph.
aldimino esters was investigated and shown to afford selectivities of 24-70 % ee.[', lo,
Aldimino groups possessing electron-donating groups have a beneficial effect, whilst lowering
the temperature increases both the yield and the enantioselectivity (entries 4 and 5 ) .
The French group has also demonstrated the crucial role that
the secondary amine, which is liberated after metalation, plays
in the proton transfer. Whereas the combination LDA/( -)-2a
affords (S)-1 with 50%ee (entry l), a much weaker induction
results when the deprotonation is performed with LiNEt, or
with lithium 2,2,6,6-tetramethylpiperidide (LTMP) (entries 6
and 7). It is therefore not surprising that the combination of
(-)-2a with a chirdl amine leads to a substantially improved
selectivity of 70%ee (entry 8). In line with this example of
double stereodifferentiation, the mismatched pair (entry 9) produces almost racemic product, and protonation with either
racemic (*)-2a (entry 10) or achiral meso-2a (entry 1 1 ) also
gives significant induction.110, The same results are obtained
by deprotonation of the ester with lithium bis(trimethylsily1)amide (LHMDS) and subsequent addition of the appropriate
amine.[13' Apparently, the disilazane does not form a strong
complex with the enolate and therefore does not actively participate in the p r o t ~ n a t i o n . ~Is]' ~It
, is not yet established whether
the importance of amine ligands rests exclusively on the formation of an enolate-amine complex['61or whether an ammonium
tartrate formed in situ acts as a proton transfer agent.
Angew. Chem. In1 Ed. Engi. 1996.35, 2566-2587
In our laboratory, enantioselective protonation of openchain enolates is under development and has been applied to
the synthesis of fragrance compounds of high enantiomeric
purity["] (for example 3-MgCl + (S)-cc-damascone ((S)-4),
Scheme 5).[20,"1 In contrast to the amino- and hydroxyl-substituted enolates discussed above, ketone enolate 3-MgCl has no
internal chelation sites. Thus, both its formation and protonation were anticipated to be more difficult to achieve in a stereocontrolled manner.
In the search for an efficient chiral protonating agent we were
guided by the following criteria.[6b.201 Ideally, the chiral reagent
should be only weakly acidic to allow better discrimination between transition states. It should also contain electron-rich
groups capable of coordinating or chelating, which may enhance conformational rigidity in the transition state. Optimally,
the transferred proton should be located near the stereogenic
center (within the "chiral environment"). Finally, to be synthetically useful, the protonating agent should be readily accessible
in both enantiomeric forms and be easily recuperable. These
criteria are satisfied with the ephedrine derivatives (+)-ti and
(-)-6, and (+)-7-H and (-)-7-H (Scheme 5 ) . In imidazolidinone 6 an N H bond is confined in a rigid cyclic system, and 7-H
(and the corresponding alkoxide) can attain conformational
rigidity through chelation. It should be added that (+)-6 and
(-)-6 are commercially available (Merck), and that both enantiomers of 7-H are readily accessible by treatment of enantiomerically pure ephedrine with acetone under conditions of
catalytic hydrogenation.['''
2569
REVIEWS
C. Fehr
1
OMgCl4gand
+
3-MgCI ( E : Z - 9 : 1)
5
(W
(9-4
(+)-6
3 -MgCI
Mod-(
;;;z:eoLii
16% Pe ( R )
70% ee (8
(-)-7-H
79% ee (8
3 -MgCI.(-)-’I-Li
(-)-7-H
84% ee
3 -MgCI-(-)-7-Li
tBuOH
62% ee (S)
Ph
(-)-7.H. M=H
(-)-7-H
(-)-7~H
(S)
(-)-~-LI.M=Li
Scheme 5. Generation of a ketone enolate by C-C bond formation and enantioselective protonation of a Mg-enolate with or without a Li-alkoxide ligand. Proton
sources: (+)-6, (-)-7-H, and tBuOH.
either the methyl ester or the ketene) gave (S)-4 with 70% ee.1z61
LiOtBu proved to be a superior ligand (79%ee), and the best
results were obtained with the chiral Li-alkoxide ( -)-7-Li
(84%ee).[”] If the formation of a chiral complex between Mgenolate and Li-alkoxide is a prerequisite for high enantioselectivity,[’*] then protonation of a chiral complex with an achiral
proton source should also lead to asymmetric induction. Indeed,
protonation of the same chiral enolate complex with tBuOH
affords (S)-4 with 62Y0ee. In view of the complexity of the
described reaction (see Section 8) and the lack of structural information about the complexes involved we consider it premature to propose a transition state model.
During further investigations it was found that protonation
of the ligand-free, E-enriched enolate 3-Li ( E : Z 9 98:2)[291
with (-)-7-H afforded (S)-4 with excellent enantioselectivity
(95 % ee; Scheme 6) .I3’] Likewise, protonation of E-rich enolate
9 ( E : Z = 97:3), obtained from the reaction of nBuLi with
ketene 5, produced ketone (S)-10 with 96Y0ee. For the first
time, a marked difference in the the protonation rates of E- and
Z-enolates was noticed and exploited to further improve the
enantioselectivity. Thus, when enolate 9 ( E : Z = 97:3) was
treated with 0.95 equivalents of (-)-7-H and the unreacted enolate was quenched as an enol silyl ether ( E : Z = 1 :I),
ketone
(S)-10 was generated with an enantiomeric ratio of >99:
We have recently succeeded in generating the Z-enolate (Z)-9,
which displays the same enantiofacial preference on protonation with (-)-7-H but with a dramatically decreased enantiofacia1 discrimination of 40% ee (Scheme 7).f321This result convincingly illustrates the statement made in Section 2 (Scheme 2):
For transition state considerations, the global enolate structure
For the synthesis of (S)-cr-damascone ((S)-4)J2O8
2 1 1 the required enolate cannot be generated by deprotonation of the
parent ketone because of preferential deprotonation in the side
chain. However, the enolate 3-MgCI is directly proOSiMe,
OLi
duced as a 9:l mixture of E- and Z-isomers by C-C
bond formation through a Grignard reaction with
MeLi
(-)-7-H
either the ester e n ~ l a t e [ ~or
~ . the
~ ~ ]ketene 5
(q-4
(Scheme 5).1251 It should be emphasized that this
8 ( E : Z= 98 : 2)
3-Li
(95% ee)
reaction of the ester enolate also produces one
equivalent of lithium alkoxide, which can profound01i
0
ly alter the subsequent protonation step. Addition
to ketenes generally takes place from the least hindered side, affording with good selectivity the enolate in which the oxygen atom is oriented towards
the larger group.[31When the required ketenes are
5
9(€:2=97:3)
(S)-10 (96% ee)
stable and readily accessible, they are the best pre1) (-)-7-H (0.95equiv.)
cursors to alkoxide-free enolates, which can be com2) Me,SiCI
plexed subsequently.
The protonations performed on enolates 3-MgCl
0
OSiMe,
and 3-MgCI .MeOLi revealed that modification of
the ligand sphere of the enolate only slightly influenced proton delivery from urea ( + ) - 6 , affording
consistent enantiofacial discriminations ranging be11 ( E : Z = 1 : 1 )
(S)-lO(298% ee)
tween 50 and 60 YOee. A transition state model in
Scheme 6. Enantioselective protonation of Li-enolates.
which the enolate complexes the carbonyl group of
( + ) - 6 was proposed to rationalize the observed abOLi
0
solute configuration.[6b1In sharp contrast, protonation with (-)-N-isopropylephedrine
(( - )-7-H)
proved to be highly sensitive to the exact nature of
the enolate : whereas alkoxide-free enolate afforded
(0-9
(a-9
(R)-a-damascone as the major enantiomer (1 6 YOee),
Scheme 7. Dependence of enantiofacial discrimination on enolate configuration.
the LiOMe-complexed Mg-enolate (prepared from
-
~
1
2570
Angew. Chem. h t . Ed. Engl. 1996. 35, 2566-2587
REVIEWS
Enantioselective Protonation
has to be taken into account, and thus the relative positioning
of all four substituents of the enolate double bond.[331
Enantioselective protonation was also used as the key step in
the synthesis of (S)-y-damascone (Scheme 8). The synthetic
0
13
OMe
90% ee
(S)-y-damascone
12-MgCI. MeOLi
I
(49% ee)
1) Me3SiCl
2) MeLi
OLi
1 ) (-)-7-Li/
(-)-7-H
-
(S,5)-14
Scheme 9. Synthesis of a musk odorant by enantioselective protonation.
Table 2. Enantioselective protonation of Sm-enolates.
(S)-y-darnascone
(75% ee)
y4
0
+ 1-
R2
2 Srn12/HMPAP
THF
0
12-Li
Scheme 8 Synthesis of (S)-y-damascone by enantioselective protonation
R
Keno"
G
Rz
2
36 - 79%* R
I+
Ph
route for racemic y-damascone proceeds via the prochiral EPh
enolate 12-MgCI.MeOLi.[341Its protonation with (-)-7-H, fol.,06H
lowed by alumina-catalyzed isomerization of one double bond,
produces (S)-y-damascone with a 3 : 1 ratio of enantiomers. In15 O Y oPh
H
16
terestingly, protonation of the Li-enolate 12-Li by addition to
( - )-7-H proceeds with low enantioselectivity in the early stages
Entry
R'
R2
de [YO]
ee 19/01
of the reaction (roughly 35 YOee after addition of SO YO)and with
Ph
Et
increased selectivity towards the end of addition (final value
Ph
Me
49 % ee). Thus, the production of chiral Li-alkoxide during the
PhCMe,
Me
process increases the selectivity of the proton transfer. An optinBuCMe,
Me
p-ClC,H,
rPr
mum ee value of 75 YOis obtained by addition of the Li-enolate
PhCH,
Et
to a 2: 1 mixture of Li-alkoxide (-)-7-Li and amino alcohol
PhCH,
iPr
2,6-C1,C6H,
Me
( -)-7-H.13'' The complexity of this reaction is further demonstrated by the nonlinear relationship between enantiomeric
purity of chiral reagent and reaction product (100Y0ee
(reagent) + 75 % ee (product); 50 YOee (reagent) + 50 YOee
[a] With 16 as proton source. [b] The assignment reported in ref. [39b] ( ( E )and ( S ) )
(product)).
is probably incorrect (according to IUPAC priority rules),
Enantioselective protonation using (-)-7-H or its enantiomer is not resiricted to damascone-like enolates. In a recent
enantioselective synthesis of the more relevant enantiomer of
The enolate configurations reflect, with one exception (enthe important tetralin musk odorant ( k)-14[3h1
the required
try 8), preferential nucleophilic attack of the allylsainarium spechiral building block was prepared in 90 YOee by chelation-concies from the least hindered side. The striking similarity between
trolled deprotonation of enone 13 and enantioselective protonaenolate de values and ketone ee values led the authors to specution of the Z-enolate (Scheme 9).[371
late that with pure Z-enolates selectivitiesapproaching 100% ee
The Sm1,-mediated allylation of ketenes with allyl iodide and
would result, and analogously, the corresponding pure E-enolhexamethylphorphoric triamide (HMPA) in THF,13'] believed
ates would undergo protonation with high, but opposite enantiofacial selectivity. If this were the case, the chiral recognition
to proceed via an allylsamarium species, has been demonstrated
by Takeuchi and co-workers to afford diastereoselectively Smwould be solely accomplished by the OSmI, and allyl subenolates, which can be then protonated enantiosele~tively.[~~~stituents, regardless of R' and R2.1331
Until the authors confirm
their hypothesis by separate protonation of E- and Z-isomeric
The most efficient chiral proton donor proved to be the C,-symenolates, an alternative explanation seems more likely. High
metric diol 15; methoxy alcohol 16 gave slightly inferior results
selectivity in the enolate-forming step could be due to the
(Table 2). Both reagents are prepared from (S)-mandelic acid.
A n p v . Cliem. Int. Ed. Engl. 1996, 35, 2566-2587
2571
REVIEWS
C. Fehr
strong steric (and electronic) control exercised by the structurally different R' and R2 groups, and these substituents would also
allow better enantiofacial discrimination in the protonation
step.[401The same methodology was also applied to benzylation/protonation, affording benzyl ketones in lower yield but
with satisfactory enantioselectivity (Scheme 10).[39a1
PhCHzBr
Ar.f*40+
1) Srn121HMPA
~
2)
R
15
14 - 43%
68% ee
c\
&
F
%
,A
r
87% ee
88% ee (R)
Ar, R: Ph, Me
90% ee (R)
Ar, R: Ph, Et
Ar. R: pCI-Ph, /Pr 61% ee (S)
Scheme 10. Benzyl ketones prepared by enantioselective protonation of Smenolates.
-
&Ph
MeLj
3.3. Protonation of Cyclic Ketone EnoIates
Based on the criteria that had led to the design of urea 6 and
amino alcohol 7 as chiral proton
Rebek et al. prepared the chiral lactam 18, starting from Kemp's triacid (17)
(Section 3.4) .[421 Similarily, Yamamoto et al. have elaborated
the chiral imide-2-oxazoline system 19 to serve as a proton
by enantioselective protonation with
-
OLi BuOLi
&Ph
__t
b " " \ P h
PhS
A
Takeuchi's tetradentate reagent is very promising, as it proved
efficient with structurally diverse enolates. However, this ketone
synthesis appears to be limited to allylic and benzylic systems,
the reaction requires two equivalents of SmI,, and its success
critically depends on the correct relative proportions of the chiral reagent, Sml,, and HMPA. Finally, the same group reported
the generation of (R)-benzoin (91 %ee) by protonation of the
corresponding Sm-enediolate with q ~ i n i d i n e . ~Presumably,
~"
these protonations are governed by complexation of the tetradentate diol 15 with the highly oxophilic and coordinatively
unsaturated Sm-enolates.
78% ee
96% ee
Scheme 11. Cycloalkanones prepared
imide 19.
0
w,
NH.HC'
20a R = H
20b R = LBuCH2CH2
20~1443
+
70% ee
ZOb144] + 69% ee
(~)-211461 + 79% ee
Ph
~21~
--f ~ 1
97% ee
0
,T,
MC02Me
(R)-21 (92% ee)
F&
22
'
Scheme 12. (S)-2-Benzylcyclohexanone prepared by enantioselective protonation
with 20a, 20b, (R)-21, and 22 as proton donors.
Fuji et al.[441used various salts of chiral piperazine derivatives
as proton donors. A maximum selectivity of 70 YOee was obtained for the reaction of (S)-2-benzylcyclohexanone with 20a
in Et,O/CH,CI, at -90 "C. Replacement of one amine proton
by an alkyl group (as in 20b) still led to significant inductions
(32-69 % ee), but dialkylated piperazines were totally ineffective. The enantiofacial differentiation showed a strong dependence on the nature of the ammonium salt, the solvent, and the
temperature. For unspecified reasons, protonations could be
effected with only 0.6 equivalents of the ammonium salt.r45]
Matsumoto and Ohta[461found that quite high enantioselectivities were achieved for the same substrate when the enolate
was protonated at - 100 "C with an excess of an a-hydroxy
ester, ideally (R)-21. The enantiomeric hydroxy ester (S)-21 of
higher enantiomeric purity (96 % ee) was used in related systems
(Scheme 13).
Most recently, Kosugi et
reported that 2-sulfinyl alcohol 22 (Scheme 12) is a powerful chiral protonating agent. The
0
17
18
19
source.1431h i d e 19 and its enantiomer can be prepared from 17
and (1R,2S)-2-amino-1,2-diphenylethanoland its enantiomer,
respectively, in four efficient steps. Imide 19 has been used to
protonate structurally simple cyclic enolates (Scheme 11) with
high enantioselectivity.
The low-temperature protonation ( 5 -78 "C) of a structurally related cyclic enolate, generated (together with LiOtBu!)
from the reaction of the corresponding enol acetate with MeLi,
has been studied by three Japanese groups (Scheme 12).
2572
n = O . RxCH2Ph
34%ee
= 1. R = CHzPh
82% ee
fl
n=l. R-Me
f l = 1,
R ==Ally1
57% ee
72% ee
Scheme 13. Cycloalkanones prepared by enantioselective protonation with (S)-21
as the proton donor.
Angew. Chem. In!. Ed. Engl. 1996, 35,2566-2587
REVIEWS
Enantioselective Protonation
excellent enantiofacial discrimination is most likely due to the
ability of the hydroxy sulfoxide to coordinate to the lithium
enolate. Presumably, electronic effects also influence the enantiofacial selection.
3.4. Protonation of Enolate/Chiral Amine Complexes
The pioneering work on the protonation of an enolate/chiral
amine complex by Duhamel et a1.[”* 12,131 using an achiral
proton donor (- 24 YOee) was discussed in Section 3.1. Inspired
by these results, Hogeveen and Zwartt4*] deprotonated the
racemic ketone ( + _ ) - 2 3(Scheme 14) with four equivalents
(_+)-23
/
furnished (S)-26 with 87% ee.[’*]Thus, protonation occurs
from the Re face and alkylation from the Si face of the lithium
enolate. Perhaps the amine shields one enolate face, and alkylation occurs from the opposite side,[”] whereas the protonation
takes place within the framework of the complex. Such an explanation would be compatible with Vedejs’s discovery that an
enantioselective “internal proton return” from a complexed chiral amine to the enolate can be achieved by addition of a Lewis
3.5. Protonation of Amide, Ester, and Thioester Enolates
The enantioselective protonation of amide enolates has been
541 Deprotonation of the
investigated by the Vedejs
racemic naproxen amide ( + ) - 2 8 with two equivalents of sBuLi
afforded a yellow enolate, which was shown by silylation to
consist of a 14: 1 mixture of E- and Z-isomers. Treatment of this
solution with two equivalents of triamine 29b generated the
wine-red complex 30 (a 1 : 1 :1 complex of enolate, amine, and
lithium amide; Scheme 16). Protonation of this complex with
(-)-23
(48% ee)
Scheme 14. Protonation (with H,O) of a complex composed of a lithium enolate
and a chiral amine.
of lithium (S,S)-bis(1-phenylethy1)amide between - 90 and
- 75 “C and quenched the enolate/chiral amine complex with
water. Ketone ( - ) - 2 3 of unknown absolute configuration was
obtained with 48 YOee. Unfortunately, it was not verified
whether the deprotonation had been complete (for example by
silylation), and therefore the observed induction could also be
the result of enantioselective deprotonation by kinetic resoluti0n.1~~1
Yasukata and Koga[”] reported on the very efficient protonaOf a
between an
lithium
a chiral secondary amine, and LiBr with AcOH (Scheme 1 5 ) .
Tetralone (S)-26 was thus obtained with 91 % ee. Interestingly,
enantioselective methylation of the analogous nor-methyl complex, using excess Me1 under almost identical conditions, also
A
30 ( E :Z= 14 : 1)
(+)-28
(2 equiv.)
29
BF,-OEt2 (2 equiv.)
-78
--+
-23°C
(rn-28
R’ = Me
29a
R’ = CH2CH2NMez 29b
68% ee
77% ee
Scheme 16. Enantioselective protonation of a complex composed of an amide
enolate and a chiral amine by BF,-induced internal proton return.
protic acids gave (R)-28with at best 6 % ee (CF,CO,H). However, in the presence of BF;OEt,, the N H acidity of the amine
ligand is increased, and the proton is transferred
within “a specific, highly chirotopic environment”
OLi.R*RNH.LiBr
to produce amide (R)-28 with 77%ee (internal
proton ret~rn)!’~] Treatment of the ligand-free
enolate with a 1 :1 mixture of 29b and BF,.OEt,
leads
to only weak induction (25 % ee), thus fur(88%)
25
(S)-26
ther demonstrating the importance of proper com91% ee
plexation. Nevertheless, the exact nature of the
NMe,
(= R*RNH)
actual proton donor remains to be determined.
24
Moderate success was achieved in applications to
other
2-arylpropionamides (50-60 YOee).
OSiMe,
OLi-R*RNH-LiBr
More recently, Vedejs et al.[541have achieved
1) MeLi-LiBr
Me1
(S)-26
very high enantioselectivities by external protona2) 24
tol~enet45~C
tion of lithium enolates of P,y-unsdturated amides
87% ee
(66%)
with
commercially available N-methylaniline 31.
27
Using
the Same amide
as before, and an
Scheme 15. Comparison of enantioselective protonation and enantioselective alkylation of an
enolateichiral amine complex.
excess of sBuLi (1.75 equiv) to ensure complete
-
Angem. Chem. Inr. Ed. Engl. 1996.35. 2566-2587
2573
C. Fehr
REVIEWS
deprotonation, the resulting enolate was protonated by addition
of diamine 31 (2equiv), which delivered its proton while the
reaction mixture warmed from -78 to O T , to yield (R)-28
(Scheme 17). Although there is no prior complexation step, a
(*)-28
Hiinig et al.[l4,5 5 1 have extensively studied the enantioselective protonation of cyclic ester enolates of type 34 derived from
mandelic acid (Scheme 19). Of the multitude of proton donors
tested, the most efficient bifunctional reagents (45-54 % ee) are
listed.[14a,b1
sBuLi
(I .75 equiv.)
reagent
ph
(*)-33a
*
(2 equiv.)
(>go%)
A
(S)-33a
45-54% ee
34a
reagents:
(rn-28
97% ee
Scheme 11. External, enantloselective protonation of an amide enolate.
35
precomplexation of the enolate with lithiated aniline may be
envisaged, due to the excess sBuLi.
Since the pK, of the aniline is lower than that of amide 28 by
only two to three orders of magnitude, the effective acidities of
proton donor and acceptor are well-matched. However, if the
pK, values are too similar, incomplete proton transfer would
result and the risk of product racemization would be augmented. Reversible deprotonation was indeed observed with the
slightly more acidic amide 32. Whereas the usual protonation of
-78
36
37
CHZPh
Scheme 19. Enantioselective protonation of a dioxofanone enolate.
Protonation of the oxathiolanone enolate 38 revealed a strong
dependence on the precise reaction conditions; oxathiolanone
(S)-39 was obtained with a maximum ee value of 77 YO.
Interestingly, a very pronounced solvent effect was observed when
enolate 38 was protonated with (R)-pantolactone (35): the
highest selectivity (72% ee) was achieved in Et,O/THF (9/l)
(Scheme 20) !
With tartrate 36 as the chiral proton source, a dramatic salt
effect was noticed: the ee of (S)-39 increases from 39% (no
LiCI) to 77% in the presence of excess LiCl, but only when the
LiCl is already present during the deprotonation of (&)-39with
LHMDS.114'1The generation of an ate complex with two equivalents of Ti(OiPr), is also beneficial, as shown by the protonation of 38 with diamine 37. However, other Lewis acids led to
decreased enantioselectivities and sodium or potassium enol-
+ -25OC : 95% ee
-78 +
0°C : 85% ee
-78 + +20"C : 16% ee
the corresponding enolate between - 78 and -25 "C and subsequent addition of aqueous NH,Cl solution afforded (R)-32with
95YOee, quenching of the reaction mixture at 0 or 20 "C led to
diminished ee values of 85 and l6%, respectively.
The enantioselective protonation with aniline 31 was successfully extended to various amide dienolates (Scheme 18). With
the exception of the 8-unbranched enolate (R' = H), all examples gave consistently high ee values (95-97 YO).In two cases,
competing y-protonation also gave rise to significant amounts
of the a,B-unsaturated isomers.
38
35, THF
+
RJ$oNp
l rz
R
R', R2 = (CHz),;
97% ee (>go"/')
R', R2 =
R3 = H
(CH2)3; R3 = H
95% ee
R', R2 =
CH3; R3 = H
97% ee (>go%)
R', R3 =
CH3, R2 = H
95% ee
R'
=
H;R2, R3 = CH,
Scheme 18. Enantioselective protonation of amide dienolates
2574
(18%)
(60%)
53% ee ( ~ 9 0 % )
(66%)
44% ee
35, Et20/THF, 911
72% ee
35, Et20
27% ee
36, THF
39% ee
36, THF, LiCl(2 equiv.)
67% ee
77% Be
36, THF, LiCl (5 equiv.)
(30%)
(9-39
37, THF
40% ee
37, THF, Ti(ORr), (2 equiv.) 67% ee
Scheme 20. Enantioselective protonation of an
oxathiolanone enolate.
Angrw. Chem. In[. Ed. Engl. 1996,35,2566-2581
REVIEWS
Enantioselective Protonation
ates of 33a proved unsuitable for enantioselective protonation
( 53 o/o ee with 35) .[14c1
Hiinig's study shows that an understanding of the underlying
chemistry is extremely difficult and that it is still premature to
establish any guidelines for the protonation of enolates 34a and
38.[561Indeed, all described effects are only strongly pronounced
in conjunction with specific chiral reagents. Likewise, structually related lactone enolates such as I and IT show totally unpredictable enantiofacial selectivities.['4d1
1 -phenylethylamines (41) produce a complete selectivity change
(43%ee ( R ) with (S)-41, 2%ee with (R)-41). The best result
(76% ee ( R ) )was obtained with piperidine 42, and the combination 42/TFA furnished (S)-39 with 39%ee. These results
demonstrate that the amines are incorporated into the transition
state. Whether a rapidly formed ammonium species is the effective proton donor was not discussed, and protonation with a
preformed ammonium carboxylate was not tested.
Rebek and c o - w o r k e r ~ reasoned
[~~~
that higher selectivities
should be achieved in the protonation 34a + 33a (Scheme 22)
Ph
I
H+
COOEt
OH
60% ee (R)
I1
20% ee (R)
(i)-33a- e
34a-e
Ph
12% ee (R)
34% ee (R)
Surprisingly, the protonation of the lithium endates is insensitive to the presence or absence of secondary amines, although
deuterium incorporation strongly depends on the nature of the
amine present (see Section
The noncovalent interactions between substrate and reagents
can lead, via highly varied aggregates, to a multitude of
diastereomeric transition states, which account for the generally
modest protonation selectivities. For this reason Hiinig's group
has extended its study to the stereoselective protonation of a
monomeric, chiral boron enolate, in which the chiral ligands are
covalently bound to boron.[551This enolate was prepared by
treatment of the lithium enolate 38 with (-)-B-chlorodiisopinocampheylborane (40) (Scheme 21).
a
R=Ph
O%ee
9%ee (R)
b
R=Me
c
R=CHzPh 50% ee (S)
d
R=iPr
76% ee (S)
e
R=tBu
9l%ee
(s)
8).[14a3cl
1 ) additive
(R)- or (S)-39
2) HX
(+)-39
1
H
40
(941
42
Additive
HX
-
AcOH
54
(R)
(Rj41
AcOH
2
(R)
42
AcOH 76
(Rj
42
TFA
(s)
ee Confiq.
39
18
Scheme 22 Enantioselective protonation of dioxolanone enolates wlth 18
with a chiral reagent, in which the proton is "buried within an
asymmetric environment". For this purpose, they prepared chiral lactam 18, in which the N H group is shielded by a naphthyl
group, as evident in the 'H NMR spectrum. Protonation of 34a,
initially reported to be highly enantio~elective,[~'~
led to irreproducible results which were subsequently withdrawn. Apparently, 18 is not acidic enough to protonate the weakly basic enolate
Ma. However, the alkyl-substituted enolates 34b-e were successfully protonated with selectivities ranging between 9 and
91 % ee (Scheme 22), depending on the size of the R substituent.
A chelated eight-membered ring transition structure in which
the larger R group preferentially remains outside the cavity was
proposed to rationalize the observed absolute configurations.
In our laboratory, the enantioselective protonation of ketone
enolates (Section 3.2.) was extended to ester and thioester enolates derived from a-cyclogeranates, whose enantiomers are pivotal, versatile building blocks for the synthesis of fragrances and
pharmaceuticals (Scheme 23) .[581 When the racemic methyl es-
Scheme 21. Protonation of a chiral boron enolate
Whereas protonation of the boron enolate with AcOH a t
70 "C leads to an enrichment of (R)-39 (54 YOee), protonation
with the less nucleophilic trifluoroacetic acid (TFA) favors the
formation of the ( S )enantiomer (32% ee). It is assumed that the
binding of the AcOH carbonyl group by the boron atom allows
the proton to be transferred internally in an eight-membered,
cyclic transition state. In contrast, TFA predominantly delivers
its proton without prior complexation from the opposite face of
the enolate. The outcome of the protonation is strongly influenced by the presence of excess primary or secondary amines.
For instance. in conjunction with AcOH, the enantiomeric
-
Angels. CJiern. Int. Ed Engl. 1996, 35, 2566-2587
-
(+)-43a- d
44a d (2)
(q-43a- d
a
X=OMe
36% ee
b
X=OPh
77% ee
C
X =SPh
99% ee
X = S-2-Naphth
99% ee
d
Scheme 23. Enantioselective protonation of a-cyclogeranates and x-thiocyclogeranates. 2-Naphth = 2-naphthyl.
2575
C. Fehr
REVIEWS
ter 43a was deprotonated with nBuLi at - 78 "C and the resulting enolate 44a ( Z :E = 19: 1) protonated with (-)-N-isopropylephedrine (( -)-7-H) at low temperature (- 100 + - 10 "C),
ester (S)-43a was produced with a selectivity of only 36Y0ee.
This marked difference to the protonation of related ketone enolates (>90%ee) led us to assume that the low enantiofacial
differentiation was due to insufficient structural differentiation
of the substituents at C(l) of the enolate (OLi vs. OMe) and an
overly rapid protonation of 44a due to the high pK, of 43a. In
line with our expectations, protonation of the phenyl ester enolate is more selective (77 YOee), and the thioester enolates 44c and
44d afford the respective (S)-thioesters with an unprecedented
enantioselectivity of > 200: 1. Likewise, protonation with the
enantiomeric amino alcohol (+ )-7-H affords (R)-43c with
99 % ee.[581
It should be added that esters 43b-d were deprotonated at
- 100 "C because the corresponding enolates ( 2 98 % 2 ) are
unstable, decomposing above - 80 "C to give
ketene
5 and LiSPh. The reverse reaction, the
)O
enantioselective thiol addition to 5 in the presence of stoichiometric or catalytic amounts of
5
( -)-7-H,[591 is discussed in Section 4.
In view of the importance of y-cyclogeranates 47 in the perfume industry and as synthetic intermediates, we also applied enantioselective protonation to the enolates 46a and 46b (Scheme 24).[351Here, deproto-
a-
Y
S
P
h
-1 00°C
-1 00(-)-7-H
+ -1 0°C
fOLi
Y
S
P
+
h
35 :65
60%
49
48
Scheme 25. Enantloselective protonation of a thioester enolate.
R2
[
0
fast, irrev.
+ T*
t
,*0
fast, irrev.
R2
Scheme 26. Principle of catalytic enantioselective protonation involving transient
enolates.
One attractive strategy for rendering a stoichiometric process
catalytic without altering the reagent/enolate molar ratio consists of slowly generating the enolate (for example by addition of
Ye to a ketene, Scheme 26) under conditions that allow rapid,
irreversible protonation of the transient species.
The rate of regeneration of the catalyst, and thus
of the enolate, can be adjusted by the delivery of
+ 45a. b
the external protonating agent YH. Obviously, for
such a scheme to be feasible, the proton exchange
between YH and X*@must be fast and complete,
45a, b
46% b (0
(S)-47a,b
and Y" must be more nucleophilic than the chiral
a X = OMe LDA
(3 equiv.)
(+)-7-H(3.3 equiv.)
50% ee; 33 : 67
reagent. Because the added species YH may also
act
as an undesired proton source for the enolate,
b X = SPh nBuLi (2 equiv.)
(+)-7-H(2.7 equiv.)
96% ee; 43 : 57
its
concentration
in the reaction medium should be
b X = SPh LDA (3 equiv.)
(+)-7-H (4 equiv.) 96 - 97% ee; 55 : 45
kept as low as possible.[611
b X = SPh LDA (1.5 equiv.)
(+)-7-H (2 equiv.)
94% ee; 55 : 45
This concept has been realized in our laboratory
Scheme 24. Enantioselective protonation of y-cyclogeranates and 7-thiocyclogeranates.
for the synthesis of thioester (S)-43c by addition of thiophenol to ketene 5 in the presence of
(-)-7- Li (Scheme 27).[591As discussed in Section 3.5, thionation of the p-cyclogeranates 45a and 45b with nBuLi or LDA
ester (S)-43 is obtained with 99 % ee by protonation of enolate
generates, in a highly selective manner, the E-enolates, and the
44c at -1OO"C, using (-)-7-H as the chiral proton donor
use of the dextrorotatory amino alcohol (+)-7-H provides ( S ) (Scheme 27, top line). At temperatures above -80°C the enol47a and (S)-47b. As observed with the a-cyclogeranate series
ate eliminates PhSLi to give ketene 5. In order to favor the
(Scheme23), methyl ester enolate 46a is a much poorer subaddition reaction, the presence of a protic species is necessary.
strate for protonation (50% ee) than the thioester enolate 46b
Thus, slow addition of equimolar amounts of (-)-7-H to a
(94-97%ee). Although neither the amine nor excess LDA afsolution of ketene 5 and PhSLi in THF at - 55 "C afforded
fect the enantioselectivity, they influence the regioselectivity of
(S)-43c with 95 YOee.
protonation (47a,b: 45a,b). The same protocol was also applied
For the extension of this reaction to a catalytic process, the
to enolate 49 of undetermined configuration to afford thioester
continually added thiol serves as both nucleophile and proton
(R)-50 with 55% ee (Scheme 25).[601
source in the presence of catalytic amounts of (-)-7-Li. The rate
of introduction of PhSH has to be kept low (addition over 3-4h
4. Catalytic Enantioselective Protonation of Enolates
at -27 "C) to prevent accumulation ([PhSH] 5 [( -)-7-Li]) and
to
minimize the risk of enolate protonation by PhSH. As shown
4.1. Processes Involving Transient Enolates
in Scheme 27, very high enantioselectivities have been achieved
with as little as 2-5 mol% (-)-7-Li. Of the other thiols
Up to this point we have considered preformed enolates,
tested, 4-chlorothiophenol, which is more acidic than PhSH,
which have been submitted to at least equimolar amounts of a
proved the most efficient (97Y0ee with 1 equiv (-)-7-Li;
chiral proton donor X*H according to Scheme 26 (top line).
2576
Angen. Chem. Int. Ed. Engl. 1996. 35, 2566-2581
48
REVIEWS
Enantioselective Protonation
1
(-)-7-H
(S)-43c (84 -87%)
LPh
Q
i<
(-)-7-ti
5
(-)-7-Li (100 rnol "A)
-550~ + 95% ee
(-)-7-Li
( 5 rnol%)
-27°C
+ 89% ee
(-)-7-h
(2 rnol%)
-27%
+ 77% ee
leading to competing transition states, which undergo proton
transfers at different rates. This and related work have been
extensively reviewed by Scharf and ~ o - w o r k e r s in
[ ~their
~ ~ article on the isoinversion principle[641and will not be discussed
further here.
Pracejus et al.[651have also extended their work on reaction
sequences consisting of a thiol Michael addition and enantioselective protonation in the presence of a catalytic amount of a
chiral amine. A prerequisite for achieving significant inductions
(20-54Yoee) is the use of a /&N,N-dialkylamino alcohol. The
addition of phenylmethanethiol to methyl 2-phthalimidoacrylate with 5 mol O/' quinidine as catalyst furnishes the (R)-cysteine
ester with 54%ee (Scheme 29). Recently, the closely related
quinidine-catalyzed addition of thiophenol to 2-phenyfacrylates
has also been reported (45-51 %ee).r661
Scheme 27. Catalytic enantioselective addition-protonation of a thiophenol to a
ketene.
9oY0ee with 0.05 equiv (-)-7-Li), whereas aliphatic thiols and
alcohols were inefficient (10-40Yoee).
It should be added that the presence of free thiol in the reaction medium has a deleterious effect. A reaction solution containing ketene 5, thiophenol, and 20 mol% (-)-7-Li afforded
racemic thioester 43c! However, this restriction does not apply
to the related enantioselective additions of alcohols to ketenes,
which were studied by Pracejus et a1.[621
as early as the 1960s, in
which the alcohol (MeOH, EtOH) serves as solvent (Scheme 28).
I
phJ
qoMe
~ : ; I o \ % )
+
+
PhCHZSH
NPhth
toluene, 0°C
PhAS
"*"?
0
OMe
NPhth
(R) (54% ee)
Scheme 29. Catalytic enantioselective sequence: Michael addition followed by protonation. Nphth = phthalimido.
4.2. Preformed Enolates
In catalytic, enantioselective protonations of preformed enolates, the concentration of the enolate exceeds that of the chiral
catalyst. Formally, an external, achiral proton donor ZH selectively reprotonates X*@(Scheme 30), whilst the enolate is unaffected!6 71
-1 10°C
0
OMe
UZH
X*H
"
'
O
a
74% ee
Scheme 28. Catalytic enantioselective addition-protonation of methanol to a
ketene.
They found that the nucleophilic species in the low-temperature
reaction ( < - 50 " C ) consists of a 1 : 1 aggregate of the alcohol
and the chiral tertiary amine; the uncatalyzed addition was negligible. A slow, rate-determining addition step is followed by a
fast, selectivity-determining proton transfer from the postulated
ammonium ion to the enolate. Among the hundreds of experiments performed with the most diverse amine catalysts under
different reaction conditions, the most successful case in terms
of asymmetric induction (74% ee) is shown in Scheme 28. In his
work, Pracejus put special emphasis on the temperature dependence of the stereoselectivity. Thus, in the above example, a
reaction temperature of - 70 "C (instead of - 1 10 " C ) leads to
almost racernic ester ( < 5 % eel. The complexity of the reaction
is due to the existence of rapidly interconverting conformers
Anger{. C k n i fnt. Ed Engl. 19%.
31,2566-2587
20
Scheme 30. Formal reaction scheme for the catalytic enantioselective protonalion
of preformed enolates.
The first reported enolate protonation using catalytic
amounts of a chiral reagent is a special case, because the most
acidic proton of the product ketone (S)-48 (at C(2)) serves to
protonate (-)-7-Li or, more likely, the mixed aggregate 3Li,( -)-7-Li (Scheme 31) .r301Whereas protonation of enolate
3-Li with an equimolar quantity of amino alcohol (-)-7-H
affords ketone (S)-48 with 95 YOee, as little as 0.3 equivalents of (-)-7-H also suffice for highly enantioselective protonation. The a-damascone isomer (S)-48 and subsequently (S)-4
are produced efficiently with 93 YOee and 86 % yield.[681This
autocatalytic cycle is based on subtle kinetic differences in the
proton transfer reactions between chiral reagents, enolate, and
non-inducing proton donor.r69]When the quantity of (-)-7-H
2577
REVIEWS
C. Fehr
0.8 equiv phenyl-2-propanone) for a total
amount of 1.05 equiv nBuLi are used, and the
reaction mixture is quenched with Me,SiCI,
(S)-10 is obtained with 98%ee!g3'' Under
3-Li
(S)-a-damascone (S)-4
these conditions, onIy (E)-9, which allows a
(-)(-H
(-)-7-Li
better enantiofacial discrimination, is protonated (see also Section 3.2.). Interestingly,
this experiment also revealed that deprotonaOSiMe3
ai
OSiMe3
tion of phenyl-2-propanone is kinetically
Me,SiCI+
controlled, as the (2)-silyl enol ether was
formed exclusively.
In contrast to the simplified reaction in
8
( 9-49
(s)-50
Scheme 30, which implies a rapid proton
1 equiv. of (-)-7-H 3 95% ee
transfer between ZH and X*', the proton
0.3 equiv. of (-)-7-H --3 93% ee
exchanges between (-)-7-Li and phenyl-2Scheme 31. "Autocatalytic" enantioselective protonation of 3-Li.
propanone are slow, incomplete (in other
words reversible), and unselective (mixture of
E- and Z-enolates). However, protonation
is reduced to less than about 0.2 equivalents, the reaction rate
of enolate (E)-9 by phenyl-2-propanone is rapid, irreversible,
and selectivity are significantly decreased.
and selective, affording the (Z)-silyl ether (Z)-51 after silylation
This case is, of course, very particular, because the product
(Scheme 33). Therefore, phenyl-2-propanone certainly furnishes
ketone (S)-48 is rapidly and exclusively deprotonated at C(2).
An analogous autocatalytic reaction is not possible with enolate
9, as the acidity of the C(2) protons of (S)-10 is substantially
weaker. To circumvent this problem. phenyl-2-propanone has
been successfully used as an external, achiral proton donor
(Scheme 32).[701Thus, protonation of 9 ( E : Z = 97:3), readily
7
1
t
w
*
1% (-50%. 5 rnin)
(-)-7-H
40% (-20°C. 1 h)
(1.05 equiv.)
5
-100
-i
-70°C
(-)-70H
Ph
~
(fOL
(9-9
A
9 ( E : Z = 97 : 3)
0
(9-10
0
( - ) - 7 - ~ (equiv.)
P
h
A (equiv.)
1.1
-
0.2
0.85
0.1
0.95
85% ee
0.8. then MeBSiCl 98% ee
0.2
96% ee (90%)
94% ee (94%)
1) -5O"C, 5 rnin, 2) Me3SiCl 96%
1) -50°C. 15 min, 2) MesSiCI 1OO0/o
Scheme 33. Proton exchange reactions between phenyl-2-propanone and (-)-7-Li
and (E)-9.
Scheme 32. Catalytic enantioselective protonation of 9
obtained from ketene 5 and nBuLi, with equimolar amounts of
(-)-7-H affords the butyl ketone (S)-10 with 96% ee, and the
catalytic enantioselective protonation with 0.2 equivalents of
(-)-7-H, followed by the addition of 0.85 equivalents of
phenyl-2-propanone furnishes (S)-10 also with high enantioselectivity (94% ee). With 0.1 equivalents of (-)-7-H the selectivity decreases to 85 YOee.
We have succeeded in further improving the attained selectivity by exploiting the observed rate difference between protonation of (E)-9 and (Z)-9 (Section 3.2.). When slightly less than
one equivalent of the proton donor (0.2equiv (-)-7-H,
2578
its proton directly to enolate (E)-9 or to a chiral enolate complex
formed from (E)-9 and ( -)-7-Li.[7'1 The catalytic conditions
were also extended to the preparation of thioesters of high enantiomeric purity (Scheme 34).f351
Very recently, Yamamoto et al.[721have reported that enolate
52 can be enantioselectively protonated at - 78 "C by sequential
addition of (S,S)-imide 19 (0.1 equiv) and succinimide (1 equiv)
(Scheme 35). The selectivity (83 O/O ee) approaches that obtained
with stoichiometric quantities of 19 (87 O h ee, see Section 3.3.).
With phenol 54, as little as 0.01 equivalents of chiral imide 19
were required to achieve 81 OO/ ee. The reaction is believed to
follow the general mechanism shown in Scheme 30."31
Angew. Chem. lnr. Ed Engi. 1996. 35, 2566-2587
REVIEWS
Enantioselective Protonation
Ph
0
nEuLi
&sph
(-1-7-H
&SPh
&S' Ph
P
h
P
LDA
.
SPh
e
O
L
i
(1.5 equiv.)
-78°C
OK
(S)-43C
(-)-7-H (2.0 equiv.); PhCh2COCH3 (-)
(-)-7-H (0.5 equiv.); PhChZCOCH3 (1.55 equiv.)
(-)-7-H (0.2 equiv.); PhChzCOCHS (1.85 equiv.)
S
THF
i
-100 + -10°C
(+)-43c
E
Ph+OK
OH
(1.5 equiv.)
-1 00°C
0
Ph
Ph+
99% ee
98% ee
81% ee
-
-70°C
(fast)
tBuoC0
H
F
U
CCQH
0
1) 15 min
7
-";
S P h + 45b
(ca. 1 : 1)
P h J L
0
PhJ
P
h
g OH
OH
0
58 (>75%)
(-1
(-)-7-H (2.0 equiv.); PhChzCOCH3
(-)-7-H (0.5equiv.); PhChzCOCH3 (1.5 equiv.)
* 2) air
f
57
94% ee
88% ee
Scheme 34. Enantioselective protonatlon of thioester enolates with substoichiometric amounts of
( - )-7-H
OSiMen
0
olj
59
MeLi
Scheme 36. Enantioselective tautomerization of an enediol
2) achiral
prot. donor
Ph
52
1) 19 (1.1 equiv.);
(rn-53
2)
-
87% ee
0
83% ee
n
0
19
4LH
1)19 (0.1 equiv.);
mu
(5)-55 (82%)
80% ee
ee
2)
54
90%
1)19 (0.01 equiv.); 2)
54
81% ee
The most important contribution to the enantioselective protonation of dienols is attributed to Pete and co-workers. In a
series of publications[741they have demonstrated that n,B-unsaturated esters and lactones can be enantioselectively deconjugated by irradiation at 254 nm in the presence of a chiral catalyst
(Scheme 37). This reaction involves an intramolecular y-hydro-
54
Scheme 31. Enantloselectwe protonation with catalytic amounts of 19.
5. Enantioselective Tautomerization of Enols
In this section the reactions proceeding via enol intermediates
are reviewed. Since enols and enolates are often rapidly interconverting, enol tautomerizations are closely related to the previously discussed enolate protonations.
As a borderline case, Duhamel's protonation of enediolate 56
has to be cited (Scheme 36).[18' In the presence of (R,R)-diO,O'-pivaloyltartaric acid (( -)-2a) at - 70"C, enediol 57 is
rapidly formed. Its tautomerization, however, is much slower,
and quenching of the reaction mixture after less than 1 h affords
essentially benzil ( 5 8 ) , which is formed by autoxidation of enediol 57 during workup. In contrast, when the reaction is
allowed to continue for 15 h, (S)-benzoin ((S)-55)is obtained
in high yield (80%) with 8OY0ee. As 57 is certainly in equilibrium with its monoanion 59, we suggest 59 as the reactive
intermediate. The fact that large excesses of chiral diacid
(-)-2a are deleterious to the process may also be rationalized
by an unfavorable shift of the equilibrium between 57
and 59.
Angrw. C'him. hi. Ed EngI. 1996, 35, 2566-2587
A
ti
hv
Scheme 37. Enantioselective photodeconjugation of an aJ-unsaturated ester.
gen abstraction of the allylic hydrogen from the singlet excited
state (B + C; Norrish typeII).[751The transient dienol species
C, which is in equilibrium with ester B (thermal 1,5 H-shift).
then undergoes a base-catalyzed tautomerization. With catalytic amounts (0.1-0.15 equiv) of chiral 8-amino alcohols, this
rate-determining, irreversible C-protonation affords enantiomerically enriched esters with fair to excellent ee values
(Scheme 38). Essential to this photodeconjugation is that the
dienol is maintained at a low steady-state concentration
([C] < [X*H]) and that the reaction product D is more inert
than A to the photochemical conditions. For good results,
2579
REVIEWS
C. Fehr
n
0
CH&N
-40°C
60
I
h
64 ( n = 0)
65 (n = 1 )
0
OH
62
(+)-cinchonins
63
Catalyst
R*
62a
62 b
62c
62d
62e
62f
H
Me
H
Me
Me
Me
H
iPr
H
CHEtz
CHiPr?
H
H
rBu
Me
iPr
CHzPh
2
63b
63c
(+)-cinchonine
(-kinchonidine
R2
(-)-cinchonidine
&(%I
R3
Method
H
A
A
A
31
6
7
C
70
A
62
8
5
Me
H
H
H
H
H
C
C
B
B
B
C
A
<5
89
81
41
37
78
70
65
47
56
68
61
76
75
(S) 40
( R ) 66
rigorously moisture-free, apolar solvents such as n-heptane and
CHzC1, had to be used, and the optimal temperature was determined to be approximately - 55 oC.[74a3
761
Amino alcohols that have a secondary NH group were found
to be more efficient inductors. The size of the N-alkyl substituents is extremely critical; 62d, 63b, and 63c (RZ=
iPr, PhCH,) gave the best results (70-91 YOee). Either decreasing or increasing the size of the amine substituent led to diminished enantioselectivities. (+)-Cinchonine and (-)-cinchonidine gave modest, opposite inductions. With bornane 63b,
various other esters of type A have been deconjugated with
43-77 %ee. In general, better results were
A
obtained with y-disubstituted esters.r74c1
Pite et al. propose that the enantioselective
OMHI
protonation of the dienol proceeds by the formation of a complex of type E.[741The hydrogen bonding between the enolic proton and
the nitrogen atom increases the electron denE
sity on C(2) and allows a more or less concerted proton transfer via a nine-membered cyclic transition state.
An alternative reaction course involving the intermediacy of an
enolate/ammonium ion pair was considered unlikely in view of
the analogous phenol/tertiary amine complexes in apolar solvents, in which the OH bond is not cleaved.
These enantioselective tautomerizations are not restricted to
dienols. Aryl enols 66 and 67 have been generated by Norrish
type11 photoeliminations from 64 and 65 in acetonitrile
( A > 290 nm) and tautomerized in the presence of p-amino alcohols (Scheme 39) .I7'] Enol66 was shown to be stable under the
irradiation conditions (1. = 337 nm) in the absence of amino
alcohol catalysts, but it tautomerized in the dark with as little as
1 mol YO(-)-ephedrine (62a) (68: 45 Yoee). One disadvantage of
this interesting method is that prolonged irradiation times lead,
d..
2580
(R)-68 ( n = 0 ) : 26% ee
( 4 - 2 6 (n = 1) : 89% ee (40%)
Scheme 39. Enantioselective tautomerization of aryl enols.
80
Scheme 38. Structural requirements of the chiral catalyst in the enantioselective
photodeconjugation of ester 60.A : 0.1 equiv catalyst, -78"C, B: 0.15 equiv catalyst, -55°C; C: 0.1 equiv catalyst, -40°C (or -5OT).
7.j
66 (n = 0)
67 (n = 1 )
Yieldl%l
through Norrish type I
fission, to competing
cleavage reactions and
product racemization.
Alternatively, enols 66
and 67 have also been
generated by Pd-cdtaof appropriate
lyzed
cleavage reactions
precur-
&'
f
-
/
Q)y0A
66
I
67
son (Scheme 40) and ke(CH,)"
tonized in the presence of
n = 0.1
chirai b-amino akohok
Scheme 40. Pd-catalyzed generation of
(max. 64% ee).L7'1 The
enols.
intermediacy of enol species remains, however, speculative, and the possibility of the
C-protonation of a Pd-enolate cannot be excluded. Also worthy
of mention are a related enol tautomerization catalyzed by
[Rh-(S)-BINAP]@ (BINAP = 2,2'-bis(diphenylphosphanyl)I ,l'-binaphthyl) affording 2-phenylpropanol with 18 % ee,r791
and a Cu'-alkoxide-catalyzed decarboxylation of methylphenylmalonates (max. 36% ee).r801
6. Enantioselective Protonation of Enol Ethers,
Ketene Acetals, and Enol Esters
6.1. SnC1,-Complexed Binaphthol as a New Chiral Proton
Donor
Yamamoto et al.r811have found that the complex between
(R)-binaphthol and SnCI,, (R)-69, generated in situ is highly
effective for the enantioselective protonation of 2-aryl enol
ethers but less suitable for the protonation of 2-alkyl enol ethers
(Scheme 41). This reaction was also successfully applied to
ketene bis(trialkylsily1) acetals, affording 2-aryl esters with
60-95 YOee (Scheme 42). Ketene acetals with different substituents R2 and R3 usually exist as mixtures of ( E ) and ( Z )
isomers and undergo protonation with lower induction. The
authors propose a transition state model based on minimum
steric interactions, which accounts for the fact that the highest
enantiofacial discriminations are observed with small R' groups
(methyl). In one case it was ascertained that the protonation did
not occur via a tin enolate, but the question of a concerted or
Angew. Chem. In[. Ed. Engl. 1996, 35, 2566-2587
REVIEWS
Enantioselective Protonation
mandelate with or without ZnCI, o r LiC1 additives at -78 "C
led to (S)-33a with generally low selectivities (1 3 -50 YOee).[ssl
In conclusion, the polymer-supported chiral reagent leads to a
substantially improved asymmetric induction and offers the advantage of simple recovery of the reagent by filtration without
loss of activity.
OSiMealBu
tf
R = Ar 85-96% ee
>95%
42% ee
R=Me
Scheme 41. Enantioselective protonation of enol ethers. rt
=
room temperature.
OR2
R1#
OR3
f
*
(469
R1-
COOMe
toluene I-78°C + r l
Ar
2) M e O H lMe3SiCI
60 - 95% ee
>95%
Scheme 42. Enantioselective protonation ofketene acetdls. rt
6.3. Enzyme-Mediated Hydrolysis of Enol Esters
=
room temperature.
stepwise[821mechanism was not clarified.183]It should also be
noted that in this process the chiral reagent is transformed into
the monosilylated binaphthol derivative.
Enzymatic ester hydrolyses are known to generally proceed
by acylation of the enzyme, followed by hydrolysis of the acylated species. When this hydrolysis method is applied to prochiral
enol esters, concomitant acyl group cleavage and C-protonation
of the liberated enols by the enzyme is expected to give enantiomerically enriched products. With this reasoning, Ohta et
al.["l have thoroughly investigated the hydrolysis of a series of
a-substituted cycloalkanone enol esters. After extensive screening, the yeast Pichia farinosa IAM4682 was found to be the
most efficient in terms of reactivity and selectivity. Generally,
when the reaction was performed with a large excess of Pichia
farinosa, high ee values were obtained with a variety of substrates (Scheme 44). For example, 78 mg of enol acetate
6.2. A Polymer-Supported Chiral Proton Donor
The enantioselective protonation of ketene acetal70 (see also
Section 3.5) has been achieved with excellent enantioselectivity
(94% ee) when the proton donor (R)-mandelic acid (71) was
bound to a polymeric resin (-72, Scheme 43).[841Most intrigu0
n
95%
70
71
(9-33a (94% ee)
-25
+20
26
18
Scheme 43. Enantloselective protonation of a ketene acetal using a polymer-supported chirdl proton donor. @ -CH,CI = Merrifield resin.
ingly, this protonation is highly temperature dependent: when
the temperature deviates only slightly from -40 "C, a surprisingly large decrease in enantioselectivity results. In application
of the isoinversion principle[63*641 Verducci et al. attribute these
changes to a two-step mechanism involving the preliminary formation of rapidly interconverting diastereomeric complexes.
However, it can be verified readily that the selectivity of 94% ee
obtained at -40 "C does not fit the Eyring plot.[761Therefore,
these results cannot be explained solely by a change in dominance of enthalpy and entropy in the partial steps.
In a previous investigation the same group found that protonation of' 70 with (R)-pantolactone (35) and with (R)-methyl
Angew. Chrm.In!. Ed. Engl. 1996, 35,2566-2587
R1
R2
eel%l
1 M e M e
1
Et
Me
1
Ph
Me
1
Et
Pr
1
Et
All
1
Et
CH7Ph
90
92
71
86
78
3 M e G
67
5
7
Et
Me
7
Ph
10
10
Me
Ph
Me
Me
Me
Me
Me
84
89
95(R)
96(R)
<2
11
Yield1%1
79
18
71
78
57
75
71
83
67
59
38
25
Scheme 44. Enzyme-mediated enantioselective hydrolysis of enoi esters. The yeast
strain P.farinosa is used in large excess. For enol esters with n = 7 the induction is
opposite to that with other ring sizes although the configuration is the same.
(Scheme 44; n = I , R' = R2 = Me) and 14 g of grown, centrifuged cells in phosphate buffer (pH 6.5) at 30°C furnished
(S)-2-methylcyclohexanone with 90 % ee. Reducing the weight
of the cells to 2.7 g slowed down the reaction rate and favored
nonspecific reactions catalyzed by other enzymes of the cell
(41 %ee). The possibility of racemization due to prolonged reaction times at 30 "C (24 h instead of 3 h) should also be taken
into consideration.
The large amount of yeast cells necessary for this process and
the severe emulsion problems encountered during the extraction
prompted the Japanese group to develop a procedure that
would be more amenable to large-scale preparations.[871As hydrolysis with immobilized cells resulted in only very poor conversions, a new system ("interface bioreactor") was tested, in
2581
REVIEWS
C. Fehr
which the microorganism was grown on a hydrophilic polysaccharide layer (agar plate). For the desired hydrolysis a solution
of the substrate enol ester in an apolar solvent was added, and
the reaction proceeded at the interface between the entrapped
cells and solvent. In this way, the microorganisms are protected
against toxic compounds, the freshly grown cells can be used
directly in organic solvents, and the recovery of the product is
greatly facilitated. Thus, with 50 mL of isooctane as the solvent,
500 mg of enol ester (n = I , R' = Et, R2 = CH,Ph) was hydrolyzed with 21 g of wet cells (on a surface of 638 cm2) to
afford, after 24 h at 25 "C, (R)-2-benzylcyclohexanone in 66%
yield with 84-87 % ee.
6.4. Antibody-Catalyzed Protonation of Enol Ethers
Whereas active enzymes are found by screening, catalytic antibodies (or abzymes) are raised against rationally designed antigens (haptens) that mimic the transition state of the planned
reaction.[881The first encouraging result-the enantioselective
protonation of an enol ester affording (R)-2-methylcyclohexanone with 42 YOee-was achieved by an antibody elicited
against a hapten possessing a phosphonate moiety.[891For the
acid-catalyzed protonation of enol ethers 73, 74, and 76, the
scientists at the Scripps Research Institute selected cationic
haptens such as 78 and structurally related ammonium spec i e ~ , ' ~ with
' ~ the assumption that the antibodies generated
would contain a carboxylate group in the combining site for
reasons of electrostatic complementarity. This functional group
may either stabilize the transition state or assist the desired
C-protonation. In view of the similarity between the hapten and
the pyramidalized transition state for the proton transfer, a
good binding affinity of the activated substrate to the antibody
was expected (Scheme 45).
Indeed, monoclonal antibody 14D9 (from 23 antibodies
raised against 78) showed excellent activity for both rate enhancement and enantioselectivity in the hydrolysis of 73 (kc=,/
k,,,,, = 2500; 96Yoee) and to a lesser degree 74 (kcat/
k,,,,, = 290; 93 % ee).[90a1Interestingly, the E- and Z-enol
ethers afford the same enantiomer. The reaction was performed
in a cyanide buffer (pH 6) at 25 "C for several days (< 50%
conversion). Under these conditions the formed aldehyde 75 is
protected from racemization by conversion into the corresponding cyanohydrin diastereomers. However, an estimated loss in
enantiomeric purity of approximately 1.5 YOee (hydrolysis of 73)
and about 5 % ee (hydrolysis of 74) is attributed to the noncatalyzed background reaction.
The same abzyme hydrolyzes 76 with a rate enhancement
(k,,,/k,,,,,) of 104.f90b1
When a catalytic amount of antibody
14D9 (400 mg, ca. 2.7 pmol; ca. 0.15 mol%) is used, hydrolysis
of 76 (500 mg, 1.83 mmol) proceeds to 80% conversion in 5h
giving ketone 77 with 89-91 Yore. After separation of the low
molecular weight compounds 76 and 77 by dialysis, 77 is obtained after recrystallization in 60-65 YOyield (86 % ee), and the
antibody is recycled with roughly 5 '/O loss of activity. The background reaction is considered to have eroded the ee by about
10%. If larger amounts of abzyme had been used, it could have
been proved that the antibody-catalyzed hydrolysis is indeed
100 YOenantioselective.
Very recently,[911a rate acceleration of 65 000 and an enantiofacial discrimination greater than 200: 1 was measured for the
14D9-catalyzed hydrolysis of 2-enol ether 79 (Scheme 46). In
1409
80% a m v . )
79 [65000]
11
12 steps
OM8
I
Ar
(~50%
conv.)
74 [290]
73 [2500]
75
96% ee (from 73)
93% ee (from 74)
Me0
60 - 65%
(80% mnv.)
Ar
80 [5000]
(-)-am
ultistriatin
0
Ar
77 (86-91% ee)
76 [lOOOO]
.n,v.
hapten:
78
Ar
Scheme 45. Antibody-catalyzed enantioselective protonation of enol ethers. The
rate enhancements k,,,ik,,,,, are given in square brackets.
2582
("(
Scheme 46. Antibody-catalyzed enantioselective protonation of an enol ether. The
rate enhancements k,,,ik,,,,, are given in square brackets.
preparative
scale:
81 (95% ee)
analogy to the reaction of Z- and E-en01 ethers 73 and 74,
catalysis is much more effective with 79 than with 80 ( k J
k,,,,, = 5000). On a preparative scale, with 180 mg of 79 and
0.23 mol% partially purified 34D9, 81 was isolated after 80%
conversion in 87 'YOyield and with 95 YOee. Ketone 81 was used
as a chiral building block for the synthesis of the insect aggregation pheromone ( -)-a-multistriatin.
Based on recent mechanistic investigations, Reymond, Lerner, et aLfg2]arrived at the conclusion that the assumed carboxylate function in the antibody active site is not within binding
distance of the transient tetragonal carbon undergoing protonation. but it more likely interacts with the electron-deficient carbon bearing the methoxy group. Indeed, hydrolysis of both 76
and the regioisomeric enol ether 82 is significantly catalyzed by
Angen. Chem. Inr. Ed. Enzl. 1996,35,2566-2587
Enantioselective Protonation
REVIEWS
MeoTr
14D9. Therefore, the initially proposed structural similarity between the hapten and the
transition state does not fully account for the
82
observed
From inhibition experiments of the hydrolysis of 73 in the presence of
hapten analogs, the orientation of the enol ether at the transition state relative to the hapten was deduced, and the importance of hydrophobic binding interactions between enol ether
substituents and the antibody for pyramidalization of the proton-accepting carbon atom was
7. Enantioselective Protonation of a Phosphane
Oxide Carbanion
Recently, Vedejs and G a r ~ i a - R i v a s were
~ ~ ~ ]able to deracemize phosphane oxide 83 by enantioselective protonation of the
corresponding carbanion 84 (Scheme 47), thus confirming that
benzylic carbanions stabilized by a P=O substituent are either
planar or invert rapidly.
0
0
II
%
phzpy
Ph
I
toluene
-7aac
~~
(+)-83
84
-7aoc
1
85
pounds of high enantiomeric purity. The importance of this
“young” reaction is now being confirmed by a growing number of applications in the syntheses of antiinflammatory
agents,[53’54- 661 pheromone^[^^.^^^ and fragrance^.^"] However, currently, no generally applicable reagent is known and
each chiral proton donor is only specific for a particular type of
substrate under well-defined reaction conditions.
The complexity of enolate protonation stems from the fact
that the reaction partners are not simple monomolecular entities, but a multitude of interconvertible aggregates of differing
reactivity. During protonation the changing composition of the
reaction mixture further complicates the process. The effects of
the crucial role of solvent,[’4C1and
amines and lithium
the nonlinearity between chiral induction and the enantiomeric
composition of the reagent[351 are typical phenomena of
changes in the supramolecular structure of the reaction species.
The participation of amines and lithium amides was first
demonstrated by Duhamel’s group[”. 1 2 , 1 3 1 (see Section 3.1),
who showed that the enantiofacial selectivity of protonation is
strongly dependent on the chiral or achiral lithium amide employed. Protonation of an enolate/chiral amine complex[51with
an achiral proton source also afforded enantiomerically enriched product.[”. 1 2 * 4 8 1
Hiinig et a1.i14a,c1demonstrated that amines interact or interfere during protonation, as incomplete deuteration was observed when ( i ) - 3 3 a was deprotonated with LDA and the enolate/HN(iPr), complex was submitted to deuteration with
[Dl36 (Scheme 48). However, the amine has no effect on the
>:I+
LDA
(+)-33a
COOiPr
H+
a X=CN’
b X = PO(0Et)Z
c X=NHPh
OD
0% ee
47% ee
81 - 83% ee
(24% ee in THF)
Scheme 47 Enantioselective protonation of a phosphane oxide carbanion
For the protonation of carbanion 84, the camphor-derived
chiral proton donors 85b and 85c gave satisfactory enantiofacial
discriminations of 47 and 81 -83 YOee, respectively. Interestingly, the chiral di- and triamines 29a and 29b, which efficiently
promote enolate protonation (see Section 3.51, were ineffective
for anion 84 (0-29 YOee). In this reaction, where the least acidic
camphor derivative 8% gives the highest induction, the formation of transient mixed-aggregate species of defined but unknown structure appears to be crucial.[941 With the strongly
coordinating solvent THF, the reaction course is markedly
changed and a selectivity of only 24 YOee results.
[D]36:
([D]:[HI
36 :
=
55% ee
41 59)
45% ee
Scheme 48. D/H-scrambling in the enantioselective deuteration of an enolate/secondary amine complex.
8. Summary and Outlook
enantioselectivity and does not necessarily participate in the
transition state. Complete deuteration and a selectivity of
57 YOee could be attained by substituting LDA for LHMDS in
the deprotonation step. The absence of an amine effect during
deuteration in the presence of the less basic HMDS was already
noticed by Duhamel et al.[’31 Likewise, we have observed that
the site selectivity for protonation of dienolates is improved in
the presence of LDA and HN(iPr),, although the amine has
little effect on the enantioselectivity (see Schemes
25,[35’
and 26‘6011.
In recent years enantioselective protonation has become a
field of intense research, and numerous procedures have been
developed allowing direct and efficient access to carbonyl com-
In contrast, the groups of V e d e j ~ [ and
~ ~ ] Koga[”] demonstrated that chiral amine ligands can efficiently control the enantiofacial proton delivery to the enolate. The “internal proton
return”[531 from the 1 : 1 : 1 complex 30, which consists of an
Angru. fficm. h i . Ed. Engi. 1996, 35, 2566-2587
2583
REVIEWS
C. Fehr
enolate, a chiral amine,
of the intermediacy of hybride enol/enolate structures (for exand a chiral lithium amide,
ample 87 in Scheme 50) was obtained from the enantioselective
ketonization of isolated enol86 in the presence of chiral lithium
back to the enolate has
=M ~ )
been achieved by increasalkoxide (-)-7-Li, which afforded the same @)-ketone 48 as
that obtained by enolate protonation. The lower ee value (60 %)
ing the acidity of the NH
(R = H,
group with BF;OEt, (see
is presumably due to concurrent nonenantioface-discriminating
25 R = M e
Section 3.5). A very improtonation.[”’] Complex 87, which is probably further aggre27 R = H
pressive example of “extergated with chiral or achiral ligands, may ultimately transfer the
proton with the participation of the N atom, via a nine-memnal” protonation of a complex composed of an enolate, a tetradentate chiral amine, and
bered ring transition state, in which a more or less colinear
LiBr with AcOH was recently reported by Yasukata and
arrangement is attained for N-H-C.
Koga.[”] Interestingly, protonation of the
chiral enolate complex 25 and methylation of
the chiral enolate complex 27 take place with
opposite enantiotopicity, thus giving the
same product (see Section 3.3). In view of
(-)-7-Li
Vedejs’s results, it may be assumed that the
proton is transferred internally from the chiral ligand to one enolate face, whereas the
methylation of a structurally and conformationally related complex proceeds from the
(-)-7-H
3-Li
opposite fa~e.1’~.
961
87
The presence Of LiBr in
is
Scheme 50. Comparison of enol and enolate protonation.
for the success of the aforementioned reaction. Added lithium halides, lithium alkoxides, and lithium amides are known to profoundly affect enolate
In view of the related deprotonations of ketones, often involvaggregation and to favor deaggregation of enolate tetramers F
ing two lithium amide molecules in an optimal eight-membered
and dimers G , leading to monomeric, mixed aggregates H
cyclic transition s t r u ~ t u r e , an
f ~ analogous
~ ~ * ~ ~ general model for
(Scheme 49).12a*97~981
In addition, oligomeric cyclic enolate
enolate protonations can be formulated by inspection of the
structures are disfavored for sterically hindered systems.[97a1
more highly aggregated structures J and K : Formal disconnection of the inner bond in the ladder structures J and
K would lead to complex L,[’o’l which then would
E
S
S
undergo C-protonation via the eight-membered ring
/E
transition state M.
s-u-x*
-
I
I
LiX
I I
y
.
Li.
I
S
F
E
E
S
I
H.
,Li
‘0‘
=
enolate, S
= solvent,
X
:
’Li
0
,I
H
= ligand
L
It therefore seems reasonable to assume that efficient enantioselective protonation reactions proceed by the formation of
monomeric enolate complexes of type I, J, or K (X* = bi- (or
poly-) dentate chiral ligand, X = achiral ligand), which are followed immediately by irreversible C-protonation.16b* In these
complexes the chiral information necessary for the subsequent
irreversible proton transfer is still intact. Some support in favor
2584
*/
H
G
Scheme 49. Structures ofenolate aggregates. E
(halide, Roe, R,Ne).
S
-
Li- X*(W
‘?*(X,
M
At least two examples can be cited in which protonation indicates the participation of two or more chiral reagent molecules,
namely Vedejs’s internal protonations of 1:1:1 complexes 30
consisting of an enofate, a chiral amine, and a chiral lithium
amidefS3](Scheme 51, see Section 3 3 , and the protonation of
enolate 12-Li with a 1 :2 mixture of the amino alcohol (-)-7-H
and the corresponding lithium alkoxide ( -)-7-Lic3’] (see Section 3.2). The outcome of this reaction is not significantly
changed when the enolate is first complexed with the lithium
alkoxide and then protonated by the amino alcohol. Nevertheless, it is essential that (-)-7-Li is present at the beginning of the
protonation. Consistent with these facts, a nonlinear relationship between the enantiomeric purity of the chiral reagent and
the enantiomeric excess of the reaction product was found. Possibly (-)-7-Li not only affects the structure of the interacting
species but also lowers its
Angew. Chem. I n l . Ed. Engl. 1996,35,2 5 6 6 2 5 8 1
Enantioselective Protonation
REVIEWS
M
M
30
=H
(-)-7-H
Li
(-)-7-Li
=
Scheme 51. Representation of complex 30 and structural formulas of the chiral
compounds 12-Li, ( - )-7-H, and (-)-7-Li.
In analogy to the tetrameric structure 88 (simplified representation) of crystalline lithium e ~ h e d r a t e , [ ”it~ ~is tempting to
speculate on analogous 3: 1 mixed aggregates N for enolate protonations promoted by amino alcohols. In solution and in the
presence of a proton donor, a multitude of partially disconnected species such as 0 would be expected to be in equilibrium with
each other.
88
Recent stability evaluations of eight-membered ring aggregates‘”] as well as fascinating X-ray structures of “partially
deprotonated” mixed aggregates (with Li- and H-binding),1104]
give some credibility to the above mechanistic considerations
and also highlight the complexity of proton transfer reactions.
Certainly the application of new spectroscopic and computational methods will lead to a better understanding of the dynamic behavior of interacting aggregates and open the door to the
development of tailor-made reagents and catalysts in the area of
enolate protonation.
After this review had been written two relevant articles appeared: the efficient enantioselective protonation of Mg-enolates
of 2-alkyltetralones with 1,l’-binaphthalene-8,8’-diol-derivedcarbamates has been reportedt10s1and a review article on enantioand diastereoselective protonation has been published.[106]
I would like to thank my colleagues, in particular Dr. R . L.
Snowden, Dr. B. Winter, Dr. K Rautenstrauch, and Dr. B.
Maurer, for valuable suggestions and critical proofreading of the
manuscript.
Received: November 21, 1995 [A140IE]
German version: Angew. Chem. 1996, 108, 2726-2748
Angen. Chem. Int. Ed. En$ 1996, 35, 2566-2587
[l] In the special cases of enolates or dienolates with C, symmetry, protonation
can also be viewed as an enantiotopic group differentiation. For an example
of enantioselective protonation of a dicarboxylate with C, symmetry, see K.
Fuji, M. Node, S. Terada, M. Murata, H. Nagasawa, J. Am. Chem. SOC.1985,
107, 6404.
[2] Leading references: a) D. Seebach, Angew. Chem. 1988. 100, 1685; Angen..
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[3] T. T. Tidwell, Ketenes, Wiley, New York, 1995; Ace. Chem. Res. 1990,23,273;
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[4] B. H. Lipshutz, S. Sengupta, Org. React. 1992, 41, 135: M. P. Cooke, Jr.,
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[5] Chiral amine ligands: P. J. Cox, N. S . Simpkins, Tetrahedron: Asymmetry
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[6] Reviews: a) L. Duhamel, P. Duhamel, J.-C. Launay, J.-C. Plaquevent, Bull.
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1121 L. Duhamel, J.-C. Plaquevent, Tetrahedron Lett. 1980, 21, 2521.
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[14] a) U. Gerlach, S. Hiinig, Angew. Chem. 1987,YY, 1323; Angew. Chem. Int. Ed.
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[18] L. Duhamei, J.-C. Launay, Tetrahedron Lett. 1983, 24, 4209.
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[22] R. J. Adamski, S. Numajiri, US 3860651 1%9 [Chem. Abstr. 1975, 82,
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1231 a) C. Fehr, J. Galindo, J. Org. Chem. 1988,53, 1828; b) R. Haner, T. Laube,
D. Seebach, J. Am. Chem. Soc. 1985, 107, 5396.
[24] The electrophilic nature of ester enolates may be due to charge delocalization.
It is also possible that loss of LiOMe allows the Grignard reaction to proceed
via a ketene[23b] or ketenoid species.
1251 F. Naef, R. Decorzant, Tetrahedron 1986, 42, 3245.
[26] Protonation with (R,R)-di-O,U-pivaloyltartaric acid [8] or with (R)-pantolactone[l4] provides (S)-4 with 8 and 25%ee. respectively.
[27] Likewise, use of the enantiomeric reagent (+)-7-H affords (R)-4 with 84% ee.
The enantiofacial discrimination with pure E-enolate is expected to be even
higher. This synthetic scheme can be used to prepare (S)-a-damascone((S)-4)
with excellent enantiomeric purity (99% ee after recrystallization) and in an
improved yield of 55% starting from ketene 5: C. Fehr, 0. Guntern, Helv.
Chim. Acta 1992, 75, 1023.
I281 The analogous Li-enolate/Li-alkoxide complex shows lower enantiofacial discrimination (65 % e e ) , and the MgC1-enolate/MgCl-alkoxidecomplex is ineffective (10% ee).
[29] Addition of allyl-Li to ketene 5 gives a mixture of E-and 2-enolates (3-Li,
E: Z = 2:l).
[30] C. Fehr, J. Galindo, Angew. Chem. 1994, 106. 1967; Angew. Chem. Int. Ed.
Engl. 1994, 33, 1888.
131) C. Fehr, J. Galindo, presented at the New Swiss Chemical Society (Berne,
Switzerland, October 21, 1994).
2585
REVIEWS
[32] C. Fehr, J. Galindo, unpublished results.
[33] If E- and 2-enolates would give rise to equally high, but opposite induction,
the enantiofacial selectivity would be determined entirely by the substituents
at C( 1) of the enolate, since the substituents at C(2) are nondiscriminating (see
Scheme 7). See also L. Duhamel, P. Duhamel, C . R . Acad. Sci. I1 1995, 320,
689.
[34] C. Fehr, J. Galindo. J. Org. Chem. 1988, 53, 1828.
[35] C Fehr, J. Galindo, Helv. Chim. Acta 1995, 78, 539.
[36] C. Fehr, J. Galindo, R. Haubrichs, R. Perret, Helv. Chim. Actn 1989, 72, 1537.
[37] C. Fehr, F. Delay; €‘-A. Blanc, N. Chaptal-Gradoz (Firmenich). EP Appl.
664286 1994 [Chem. Ahstr. 1995, 123. 169 37881
[3X] D. P. Curran, M. J. Totleben, J Am. Chem. SOC.1992, 114. 6050.
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A. Ohira. N . Miyoshi, H. Mashio, Y Ohgo. Tetrahedron. Asymmelrv 1994,5,
1763.
[40] The importance of the substituents R’ and R Z is acknowledged in one example (Table 2, entry 9). in which only a fair enantioselectivity (48 % ee) is
measured from the protonation of a pure Z-enolate. In this case it appears
that the rigid planar phenyl group is not sterically demanding enough in the
direction orthogonal to the enolate plane.
[41] S. Takeuchi, N . Miyoshi. K. Hirata. H. Hayashida, Y. Ohgo. Bull. Chem. SOC.
Jpn. 1992.65, 2001.
[42] D. Potin, K Williams, J. Rebek, Jr.. Angew. Chem. 1990, 102, 1485; Angew.
Chem. Int. Ed. Engl. 1990. 29, 1420.
[43] A. Yanagisawa, T. Kuribayashi, T. Kikuchi, H. Yamamoto, Angew. Chem.
1994, 106, 129; Angen. Chem. In/. Ed. Engl. 1994. 33, 107.
[44] K. Fuji, K. Tanaka, H. Miyamoto. Tetrahedron: Asymmetry 1993. 4, 247.
I451 It IS possible that the piperazine forms a complex with unreacted enolate.
Protonation of this complex during the hydrolytic workup may also occur
enantioselectively.
I461 K Matsumoto, H. Ohta, Tetrahedron Lett. 1991. 32, 4729.
[47] H Kosugi, K. Hoshino, H. Uda, Phosphorous, Sulfur Silicon Relut. Elem.
1994, 95-96. 401.
[48] H Hogeveen, L. Zwart, Tetrahedron Lett. 1982, 23, 105.
1491 In this case silylation would have permitted the recovery of highly enantioenrrched (-)-23.
[SO] T. Yasukata. K. Koga, Tetrahedroo: Asymmetry 1993. 4, 35.
[51] M. Murakatd, M. Nakajima, K. Koga, J. Chem. SOC.Chem. Commun. 1990,
1657.
[52] For analogous diastereoface-selective alkylations see K. A. Durkln, D. Liottd. J Am. Chem. SOC.1990,112,8162; L. A. Castonguay. J. W. Guiles, A. K.
Rappe, A. I. Meyers, J. Org. Chem 1992, 57. 3819.
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Chem. Int. Ed. Engf. 1993, 32, 398.
[56] Protonation of 34a with (R,R)-di-0.0‘-pivaloyltartaric acid [S] afforded ( R ) .
33a with 5%ee; protonation of 38 with ephedrine derivatives[20] gave fair
enan tioselectivities (20- 36 % ee).
[57] J. Rebek, Jr., Chemlracts Org. Chem. 1989. 2, 337; Angew. Chem. 1990, 102.
206; Angew. Chem. In/. Ed. Engl. 1990, 29, 245
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Chem. Int. Ed. Engl. 1993.32.1042, b) J. A. Marshall, Chemtracts Org. Chem.
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[59] C. Fehr, I. Stempf, J. Galindo. Angew. Chem. 1993,105.1093; Angew. Chem.
Int. Ed. EngI. 1993, 32, 1044; ref. [58b].
[60] C . Fehr, N. Chaptal-Gradoz, unpublished results. The absolute configuration
of the aromatic musk odorant (S,S)-14was determined by chemical correlation with (R)-50.
[61] Alternatively, Y o can also be preformed. On addition of an external proton
donor ZH, unreactive Ze would be formed.
[62] H. Pracejus, Liebigs Ann. Chem. 1960,634,9; H. Pracejus, G. Kohl, h i d . 1969,
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[65] H. Pracejus, F.-W. Wilcke, K. Hanemann, J Prakt. Chem. 1977. 319. 219.
[661 A. Kumar, R. V. Salunkhe. R. A. Rane, S . Y. Dike, J. Chem. SOC.Chem.
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[671 This reaction type may also proceed by 0-protonation either by X*H or ZH.
followed by enantioselective tautomerization of the en01 or by protonation of
an enolate/chiral ligand complex (see Section 8).
[68] The formation of enolate 49 was proved by isolation of the corresponding silyl
enol ether 50. Under acidic conditions both 48 and 50 are converted into
(S)-a-damascone ((S)-4).
[69] (S)-48 does not protonate 3-Li enantioselectively in the absence of (-)-7-H.
[70] Various CH-, OH-, and SH-acidic compounds (p-ketoesters, phenols. thiophenol, carboxylic acids, and rac-48),all of which are more acidic than (Sl-10
by several orders of magnitude. were tested and shown to be effective.
2586
C. Fehr
1711 See ref 1671. As the catalytic enantioselective reaction (Scheme 32) is even
more rapid (2 min at - 50 “C), protonation of an enolateichiral ligand complex seems more probable.
[72] A. Yanagisawa. T. Kikuchl, T. Watanabe, T. Kuribayashi, H. Yamamoto.
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[73] The small but significant gain in enantioselectivity under catalytic conditions
(0.1 equiv 19 in the presence of 54 rather than 1 equiv 19) reflects a more
complex scenario, in which 54 (or its anion) is involved in the transition state.
It would be interesting to verify that this difference is not due to a modified
workup procedure (which includes treatment with Me,SiCI)
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[911 S. C Sinha, E. Keinan, J Am. Chem. SOC.1995, 117, 3653.
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1 1 264.
[93] E. Vedejs, J. A. Garcia-Rivas. J Org. Chem. 1994, 59, 6517.
[94] Whereas 85a and 85b are carbon acids. 8% is believed to transfer the aniline
NH proton.
[95] Possibly, y-protonation involves a [1.5] H-shift of the s-cis dienol. In the
presence of amines, the enoi/enolate equilibrium is shifted towards the enolate, thus suppressing y-protonation.
[96] For the alternative possibility of an anti protonation of an enol or enolate
(unti-S,Z’ reaction), see V. R. Bodepudi, W. J. LeNoble, J. Org. Chem. 1994,
59, 3265.
[97] a) F. E. Romesberg, D. B. Collum, J Am. Chem. Soe. 1994,116,9187; b) F. E.
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[98] P. Cauhere, Chem. Rev. 1993, 93, 2317.
[99] For the importance of monomeric enolates as reactive species, see
A. Abbotto. A. Streitwieser, J. Am. Chem. Soc. 1995, 117, 6358; F. AbuHasanayn, M. Stratakis, A. Streitwieser, J. Org. Chem 1995. 60, 4688;
for enantioselective hydroxylations of monomeric enolate species, see R. D.
Bach. J. L. Andrts, F. A. Davis, J. Org. Chem. 1992, 5 7 , 613; Y. Wei, R.
Bakthavatchalam. X.-M. Jin, C. K. Murphy, F. A. Davis, Tetrahedron Letl.
1993, 34, 371 5.
[loo] C. Fehr, J. Galindo, unpublished results.
[lo1j Recently, the stability of ladder structures for lithium enolate/lithium amide
mixed aggregates in solution was questioned, and six- or eight-membered ring
Angew. Chem. Int. Ed. Engl. 1996, 35, 2566-2587
Enantioselective Protonation
REVIEWS
structures (obtained by formal removal of the inner “rungs”) were favored [97a]. For disassembly of lithium amide ladder structures by insertion
of THF molecules, see W. Clegg, L. Horsburgh, E M. Mackenzie, R. E. Mulvey, 1 Chem. Sor. Chem. Commun. 1995,2011.
[I021 The comparison of pK, values is often problematic, as these values are determined under conditions that differ from those prevailing in enolate protonations; see E. M. Arnett, K. D. Moe, J . Am. Chem. SOC.1991, ff3,7288.It
should also be stressed that proton donors that are seemingly too weak can
protonate an enolate under kinetically controlled conditions to completion, if
deprotonation of the resulting carbonyl compound is prohibited.
[lo31 M. A. Nichols, A. T. McPhail, E. M. Arnett, J. Am. Chem. SOC.1991,113,
6222.
[lo41 C.Lamhert, F. Hampel, P. von R. Schleyer, Angew. Chem. 1992,104, 1242;
Angew. Chern. hit. Ed. Engi. 1992,31,1209; C. Lambert, P. von R. Schleyer,
U. Pieper, D. Stalke, ibid. 1992,f04, 78; and 1992,3f, 77; M.C. Etter, G.
Ranawake, .
l
Am. Chem. SOC.1992,ff4,4430.
[lo51 K. Fuji, T. Kawabata, A. Kuroda, J. Org. Chem. 1995,60,1914.
[lo61 S. Hiinig, h u b e n - Weyl, Methods of Organic Chemistry, Vol. E2fd(Eds.: G .
Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart,
1995, 3851.
EVENTS
GDCh
Fachgruppe Medizinische Chemie
International Symposium
How Rational Can Drug Design Be?
Frankfurt am Main/Germany, February 7,1997
A Report about Novel Combinations of
Rational Design and Screening Techniques
H. Kessler, Munchen/D
Rational Drug Design: The Holy Grail
J. G. Topliss, Michigan/USA
The Discovery and Optimization of Potent NonPeptidic Matrix-Metalloprotease Inhibitors
H. Kluender, West Haven/USA
Current Issues in De Novo Design
C. W. Murray, Macclesfield/GB
3D-QSAR: What Can We Learn from the
Obtained Correlations?
G. Klebe, Marburg/D
Design of Pharmacokinetic Properties
D. A. Smith, Sandwich/GB
Molecular Pharmacological and Modelling
Approaches in the Design of Agonists and
Antagonists of G-Protein-Coupled Receptors
M. A. Cascieri, Rahway/USA
Structure-Based Drug Design: Which
Information Can Really Be Obtained from
Structures?
H. Kogler, Frankfurt am Main/D
Design of New Peptide Mimetics of both
Continous and Non-Continous Peptide,
Epitopes and their Pharmacological Profiles
D. C. Howell, Cambridge/GB
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P.Muller, Biberach/D
Further Information
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Anpew. Chern. Int. Ed. Ennl. 1996,35,256&2587
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enolate, protonation, enol, enantioselectivity
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