Beyond Chemoselectivity: Catalytic Site-Selective Aldolization of Diketones and Exploitation for Enantioselective Alzheimer's Drug Candidate Synthesis

Article abstract of DOI:10.1002/chem.201602900

Site selectivity, differentiating instances of the same functional group type on one substrate, represents a forward-looking theme within chemistry: reduced dependence on protection/deprotection protocols for increased overall yield and step-efficiency. Despite these potential benefits and the expanded tactical advantages afforded to synthetic design, site selectivity remains elusive and especially so for ketone-based substrates. Herein, site-selective intermolecular mono-aldolization has been demonstrated for an array of prochiral 4-keto-substituted cyclohexanones with concomitant regio-, diastereo-, and enantiocontrol. Importantly, the aldol products allow rapid access to molecularly complex ketolactones or keto-1,3-diols, respectively containing three and four stereogenic centers. The reaction conditions are of immediate practical value and general enough to be applicable to other reaction types. These findings are applied in the first enantioselective, formal, synthesis of a leading Alzheimer's research drug, a γ-secretase modulator (GSM), in the highest known yield.

Full text of DOI:10.1002/chem.201602900

DOI: 10.1002/chem.201602900
Full Paper
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Diketone Site Selectivity
Beyond Chemoselectivity: Catalytic Site-Selective Aldolization of
Diketones and Exploitation for Enantioselective Alzheimer’s Drug
Candidate Synthesis
Thomas C. Nugent,* Foad Tehrani Najafian, Hussein Ali El Damrany Hussein, and
Ishtiaq Hussain[a]
Abstract: Site selectivity, differentiating instances of the
same functional group type on one substrate, represents
a forward-looking theme within chemistry: reduced depend-
ence on protection/deprotection protocols for increased
overall yield and step-efficiency. Despite these potential ben-
efits and the expanded tactical advantages afforded to syn-
thetic design, site selectivity remains elusive and especially
so for ketone-based substrates. Herein, site-selective inter-
molecular mono-aldolization has been demonstrated for an
array of prochiral 4-keto-substituted cyclohexanones with
concomitant regio-, diastereo-, and enantiocontrol. Impor-
tantly, the aldol products allow rapid access to molecularly
complex ketolactones or keto-1,3-diols, respectively contain-
ing three and four stereogenic centers. The reaction condi-
tions are of immediate practical value and general enough
to be applicable to other reaction types. These findings are
applied in the first enantioselective, formal, synthesis of
a leading Alzheimer’s research drug, a g-secretase modulator
(GSM), in the highest known yield.
Introduction
Differentiation of the same functional group type on one mol-
ecule is a challenge of site-selective transformations,[1] a subca-
tegory of regioselectivity. Mild reagents sometimes achieve site
selectivity when recognizable steric or electronic dissimilarities
prevail, but when subtle differences exist the product out-
comes are nonselective. The latter issue is the focus of this
study, and catalyst design can be pivotal in addressing this
challenge. The most successful applications of site selectivity
have been demonstrated for polyol substrates, and elegant
natural product examples have been demonstrated in the
name of expedited drug discovery.[2,3] In parallel, a smaller
subset of polyols, for example, meso-diols, require desymmetri-
zation to differentiate their alcohol moieties.[4,5]
Figure 1. Left: diketone starting materials of prior site selectivity or desym-
metrization studies; right: natural product applications. Blue-labeled atoms
are electrophilic and red-labeled atoms are nucleophilic.
In contrast to these achievements with polyol substrates,
little is known about controlling the reaction outcome at one
of two electronically disconnected ketone functional groups
within a 1,n-diketone where nꢀ4. These substrates are the
focus of this study and, to our knowledge, only four systematic
studies have detailed site selectivity or desymmetrization with
high enantioselectivity (Figure 1). It is informative that half of
those investigations resulted in tactical advantages that per-
mitted the shortest known syntheses of two natural products
(Figure 1, right panel). Two of those four studies, by the
groups of Niemeyer and Kroutil, employed enzymes and inti-
mated how to reduce[6] or reductively aminate[7] one carbonyl
unit, specifically a methyl ketone. The remaining two studies,
both by List and co-workers,[8] were chemical based and dem-
onstrated how to perform intramolecular reactions, again with
methyl ketones (Figure 1). For all four studies, excellent selec-
tivities were reported. We are additionally aware of a single ex-
ample of double intermolecular site-selective aldolization of
a methyl ketone within a diketone (not shown).[9] Finally, it is
important to note the intramolecular aldol studies of the
Hajos–Parrish–Eder–Sauer–Wiechert triketones. These trike-
tones (not shown) and analogs thereof have been studied and
[a] Prof. T. C. Nugent, F. T. Najafian, H. A. E. D. Hussein, I. Hussain
Department of Life Sciences and Chemistry, Jacobs University Bremen
Campus Ring 1, 28759 Bremen (Germany)
E-mail: t.nugent@jacobs-university.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201602900.
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reviewed elsewhere,[10–13] and all conclusions made herein take
those findings into account.
the same reaction conditions and times, to produce remarka-
bly similar aldol product yields of each. Nevertheless, when
starting materials are not used in excess, clearer reactivity
trends can sometimes be noted for particular amine catalysts.
For example, Hayashi’s aldol studies of tert-butyldiphenylsily-
loxy (TBDPSO) 4-hydroxyproline catalyst 2 (Figure 2) revealed
a large difference in reactivity for 2-butanone and cyclohexa-
none.[19] In summary, despite long-held knowledge of cyclohex-
anone enamine formation and reactivity trends, it is remark-
able that those differences have never been demonstrated
within a multiketonic substrate, let alone exploited for synthet-
ic advantage. This manuscript details the first inroads toward
that goal.
General guidance on how to broaden or improve ketone
site selectivity is not apparent from the small number of stud-
ies (Figure 1) within this emerging field; and catalyst loadings
can be prohibitively high. Furthermore, many challenges
remain open to investigation; for example, whether methyl ke-
tones can be preserved (remain unreacted) while another type
of ketone carbonyl undergoes a transformation. A useful entry
point into that question is Stork’s 1963 observation that stoi-
chiometric pyrrolidine enamine formation is more rapid for cy-
clohexanone than for acyclic ketones.[14] Those results are in
general agreement with the last fifteen years of modern enam-
ine-based organocatalysis observations.[10,11,13,15] For example,
List et al. demonstrated rather early that l-proline (1; Figure 2)
produced the aldol products of cyclohexanone faster than
those of acetone.[16] However, these trends can also be inter-
rupted. For example, it has been repeatedly shown that 2-bu-
tanone and cyclohexanone react with p-nitrobenzaldehyde by
way of l-proline[17] or various prolinamide[18] catalysts, under
Results and Discussion
We speculated that 4-keto-substituted cyclohexanones 6–9
(Figure 3) could serve as prototypes to establish broader
knowledge in this area and envisioned that chiral amine cata-
lysts would permit high aldol site selectivity. This would be
possible if the intermediary enamines would have dramatically
different enamine equilibria with the available, and competing,
ketone carbonyl moieties.[20] Over the course of this study we
show that this was possible and demonstrated: i) the first reac-
tions in which unhindered methyl ketones remain unreacted,
ii) the first comprehensive chemical study to show that inter-
molecular ketone site selectivity is possible, and iii) the benefi-
cial application of this procedure in the highest yielding syn-
thesis reported to date of a recently described frontline Alz-
heimer’s drug candidate (see Scheme 2).[21,22,23]
Figure 2. Catalysts examined during this study.
Diketone 6 is a compelling starting point because it merges
2-butanone and cyclohexanone into one diketone substrate.
Its reaction with p-nitrobenzaldehyde under TBDPSO-4-hydrox-
yproline (2) catalysis can yield up to twenty-one possible prod-
ucts (Figure 4, left panel). However, only two products of type
D, specifically from cyclohexanone carbonyl attack, were
noted: 11 a (major) and 12a (minor; Figure 4, right panel). Two
regioisomeric intermolecular aldol products of the methyl
Figure 3. Diketones investigated.
Figure 4. Left: twenty-one possible first generation products; right: only two stereoisomers of product type D are detected (11 a and 12a).
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ketone are also possible: E and F (Figure 4, left panel), but no
evidence of their formation was detected. Although intramo-
lecular aldol cyclization may occur (e.g., product types A and C
are Baldwin favored),[24,25] control experiments, without the al-
dehyde, ruled out this possibility by returning only the starting
diketone (6). In that light, it is interesting to note that a closely
related compound does undergo intramolecular cyclization in
the presence of catalyst 2, namely, the corresponding aldehy-
dic cyclohexanone (not shown), which replaces the methyl
ketone of 6 with an aldehyde moiety.[26] In conclusion, the for-
mation of 11 a (87% yield, 99% ee) represents a highly site-se-
lective differentiation of diketone 6 with concomitant diaster-
eo- and enantiocontrol.
To preserve the a-keto labile stereogenic centers of aldol
products 11,[27] they were worked up by organic solvent extrac-
tion from water and dried under high vacuum. Their diastereo-
1
meric ratios were assessed by H NMR spectroscopy (Table 1)
and the crude aldol products oxidized or reduced to respec-
tively give previously unknown, but stable and fully character-
izable, ketolactones (13, three stereogenic centers; Scheme 1)
or keto-1,3-diols (14, not shown), which were identified as
their keto-acetonide analogues (15, four stereogenic centers;
Scheme 1). Products 13 and 15 were isolated after column
chromatography as single diastereoisomers and the overall
yields of each diastereoisomer, calculated from the aldehyde
limiting reagent used for the aldol reactions with diketones (6-
9), were good to excellent, given that these yields respectively
reflect two or three reaction steps (Scheme 1 and Figures 5
and 6). Conversion of aldol products 11 into 13 or 15 consti-
tuted a second, albeit predictable, level of site selectivity
based, respectively, on well-established Baeyer–Villiger migra-
tory aptitudes[28] and the known proclivity of NaB(OAc)3H to
chemoselectively reduce b-hydroxyketones selectively over ke-
tones.[29,30,31]
Figure 5. Ketolactone products (Scheme 1) with two-step overall yields from
the corresponding aldehyde limiting reagent reacted with diketones (6, 7, or
9). Each product represents a single diastereomerically pure compound after
column chromatography.
Figure 6. Keto-acetonide products (Scheme 1) with three-step overall yields
from the corresponding aldehyde limiting reagent reacted with diketones
(6–9). Each product represents a single diastereomerically pure compound
after column chromatography.
Screening and catalyst optimization of the aldol reactions
were guided by the fact that the O-protected serine,[32] threo-
nine,[33] and 4-hydroxyproline[34] catalyst frameworks had been
previously reported for the aldol desymmetrization of 4-meth-
ylcyclohexanone.[35] The reactions of catalysts 3–5 (5.0 mol%;
Figure 2) with diketone 6 and p-nitrobenzaldehyde were in-
complete, except for 5, and resulted in mediocre diastereose-
lectivities (2:1 to 3.5:1) at the remote g stereogenic center. To
our knowledge, a silyl protected 4-hydroxyproline,[34a] such as
TBDPSO-4-hydroxyproline 2 (Figure 2), has never been exam-
ined as a catalyst for the desymmetrization of 4-substituted cy-
clohexanones. It was thus gratifying to find that catalyst 2 pro-
vided aldol product 11 a with greater than 24:1 diastereoselec-
tivity at the remote stereogenic center. This high remote
Scheme 1. Ketone site selectivity and overview of: aldol, ketolactone, and
keto-acetonide products.
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lyst loadings (10 mol%). Trials examining this aldehyde were
not further pursued.
Table 1. Reaction conditions and diastereomeric ratios (11/12) for the
aldol reaction depicted in Scheme 1.[a]
Of importance, diketone substrates 7 and 9 may be more
prone than diketone 6 to undergo intramolecular aldol reac-
tions because each of them has three Baldwin favored intra-
molecular aldol ring closure possibilities (as opposed to two
for diketone 6), and furthermore, 9 contains a more electro-
philic p-trifluoromethyl phenylketone carbonyl moiety as com-
pared to a methyl ketone. Despite these increased alternative
possibilities, both 7 and 9 maintain high selectivity for the cy-
clohexanone carbonyl (Table 1, entries 9 and 12; Figure 5, 13h
and 13i; Figure 6, 15h and 15i). Finally, we studied benzyl di-
ketone 8 because a related proline catalyst was shown to have
a very similar propensity for enamine formation with either cy-
clohexanone or methyl benzyl ketone.[20] Again, the cyclohexa-
none carbonyl was the only site of attack (see Table 1, en-
tries 10 and 11; Figure 6, keto-acetonide 15j), presumably due
to its lack of steric congestion as compared to the enamine of
the benzyl ketone moiety. Attempts to convert the aldol prod-
uct 11 j of benzyl diketone 8 into a ketolactone resulted in low
yields due to competitive, albeit nonselective, Baeyer–Villiger
migration of the benzylic carbonyl substituent versus the de-
sired secondary carbon carbonyl substituent.
Entry
Diketone
R
t [h][b]
Aldol products 11/12
d.r.[c]
12:1
6:1
19:1
>24:1
>24:1
13:1
3.3:1
10:1
1
6
6
6
6
6
6
6
6
7
8
8
9
4-NO2
4-NO2
3-NO2
2-NO2
2,6-Cl2
4-CN
30
80
30
38
30
36
28
30
34
13
23
44
11 a/12a
11 a/12a
11 b/12b
11 c/12c
11 d/12d
11 e/12e
11 f/12 f
11 g/12g
11 h/12h
11 j/12j
2[d]
3[e]
4
5
6
7[e]
8
4-Br
4-CF3
4-NO2
4-NO2
4-NO2
4-CF3
9
17:1
10[f,g,h]
11[f,g,i]
12[h,j]
6.3:1
8.2:1
>24:1
11 j/12j
11 i/12i
[a] Conditions (unless otherwise stated): aldehyde (0.50 or 0.75 mmol), di-
ketone (1.5 equiv), water (3.0 equiv), catalyst 2 (2.0 mol%), 258C; aldol
products are stereochemically labile and further reacted without purifica-
tion, no yield data; [b] t corresponds to aldehyde consumption (1H NMR
spectroscopy) of 95Æ2%; [c] from 1H NMR spectra of crude anti-11/syn-
12 (a and b’ carbons); [d] 50 mol% l-proline used as catalyst; [e] t corre-
sponds to aldehyde consumption (1H NMR spectroscopy) of 91Æ2%;
[f] T=358C; [g] 8.0 equivalents of H2O; [h] catalyst 2 (4.0 mol%); [i] cata-
lyst 2 (2.0 mol%) added at t=0 and 9 h; total catalyst loading=4 mol%;
[j] diketone
(4.5 equiv), 258C.
9 is the limiting reagent; aldehyde (2.0 equiv), H2O
X-ray crystallographic analysis and circular dichroism (CD)
spectroscopy (see the Supporting Information, section 5) of
keto-acetonide 15i provided the relative and absolute stereo-
chemistry for that product and, by extension, for all depicted
aldol products (Figures 5 and 6). The transition state depicted
in Figure 7 shows a likely scenario for the formation of aldol
11 i through the reaction of diketone 9 with p-trifluoromethyl
benzaldehyde, which in turn was elaborated into keto-aceto-
nide 15i.
center diastereoselectivity was noted for all aldol products
formed in this study. The use of l-proline provided the same
high remote center diastereoselectivity, but required
a 50 mol% catalyst loading and an 80 h reaction time (Table 1,
entry 2). The result with l-proline offers the possibility of im-
provement by the ball-milling technique reported by Bolm and
co-workers,[35a] although this method was not pursued here.
Generation of this remote stereogenic center in high diastereo-
meric ratio was the pivotal stereochemical element allowing
access to the later discussed Alzheimer’s research drugs (see
below, Scheme 2).
Further investigation of this system demonstrated that aro-
matic aldehydes, present as the limiting reagents and under
chiral amine catalysis (2.0 mol% of 2), could site selectively de-
symmetrize a diverse set of achiral 4-keto-substituted cyclohex-
anones 6–8 (1.5 equiv). In doing so, cyclohexanone-substituted
aldol products 11 and 12 were produced (Scheme 1, Table 1),
mostly in diastereomeric ratios (anti-11/syn-12, a and b’ car-
bons) of greater than 10:1 and with high enantioselectivities
(96–99% ee), as observed in the final products 13 and 15. De-
tails of the reactions involving diketone 9 are given in the dis-
cussion of the Alzheimer’s drug synthesis.
Figure 7. Proposed transition state for aldol 11 i.
In brief summary, most of the aldol reactions were per-
formed with diketone 6 to unequivocally demonstrate that
a non-hindered methyl ketone repeatedly showed no reactivi-
ty. It is clear that methyl-ketones act as if they are protected
under these mild reaction conditions. These results comple-
ment the earlier findings, all of which required the reaction of
a methyl ketone within diketone substrates (Figure 1).
Regarding the structural breadth of the aldehyde electro-
philes, steric effects can restrict the addition of ortho-substitut-
ed benzaldehydes but here they are well tolerated, as shown
by the addition of 2-nitrobenzaldehyde and 2,6-dichlorobenzal-
dehyde, respectively forming ketolactones 13c and 13d
(Figure 5). Finally, from an electronic point of view, high-yield-
ing substrates are those that incorporate aromatic substituents
with either inductive or resonance-based electron-withdrawing
effects. Benzaldehyde itself provided a low aldol yield under
extended reaction times of four days, even with elevated cata-
Early onset Alzheimer’s disease is marked by proteolysis
events initiated by b-secretase but refined multiple times by g-
secretase.[36] The most frequent outcome is amyloid beta (Ab)
peptide formation in the range of 37–43 amino acid resi-
dues.[37] In the Alzheimer’s patient, this manifests itself as neu-
rotoxic Ab42 peptide brain deposition, otherwise known, in one
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Scheme 2. The first enantioselective synthesis of piperidine 20 and formal synthesis of Alzheimer’s drug candidates 21 and 22.
typical form, as extracellular senile plaque. At present, no
drugs are known for the treatment of Alzheimer’s disease, but
leading drugs currently under investigation are g-secretase
modulators (GSMs).[21] GSMs were explicitly developed for re-
ducing Ab42 peptide formation, and include the investigational
drug examples synthesized by GlaxoSmithKline (21)[23,38] and
Merck, Sharp & Dohme (22; Scheme 2).[22] Both companies
leveraged one advanced enantiopure piperidine building block
(20) to produce well over 100 drug candidates.[22,23,39] Of those,
the most often and very recently cited representative, with
potent Ab42 peptide-lowering effects, is the piperidine-based
amino acid 22.[21,37,40,41]
All syntheses of these Alzheimer’s drugs proceed through
enantiopure cis-piperidine 20. Our route to 20 was envisioned
through lactone 13i because we could repeatedly obtain ex-
ceptionally high overall yield (91%) and enantioselectivity
(98% ee) from diketone 9 and p-trifluoromethyl benzaldehyde
(Scheme 2). The reaction is robust, regardless of the scale of
the reaction, which varied from 1 to 15 mmol. To obtain these
results, we modified our general procedure as follows. Dike-
tone 9 became the limiting reagent (1.0 equiv) in the presence
of excess p-trifluoromethyl benzaldehyde (2.0 equiv) and water
(4.5 equiv). After 44 h, the ring-substituted aldol products 11 i
and 12i formed in an anti-(a,b’)/syn-(a,b’) ratio of greater than
24:1 (Scheme 2; 12i not shown). Extractive workup gave 11 i/
12i in high crude yield and purity (ꢀ95%). This material could
be used without further purification in the next reaction step.
Transformation of aldol 11 i into lactone 13i required the
cyclic ketone’s secondary-carbon substituent to undergo
Baeyer–Villiger migration while the acyclic ketone’s aromatic
substituent remained unreacted. These two types of substitu-
ents have similar migratory aptitudes, but we were confident
that this aromatic ring would not migrate because Baeyer–Vil-
liger rearrangements with strongly electron-withdrawing para-
substituents on the aromatic ring, to our knowledge, have no
published precedent when using meta-chloroperbenzoic acid
(mCPBA). Our results bear out that conclusion, with a 91%
overall yield of lactone 13i from diketone 9, as one diastereo-
merically pure compound after column chromatography
(Scheme 2). This is an uncommon demonstration of an elec-
tronic effect dictating Baeyer–Villiger migratory aptitude.[28]
Ammonolysis of 13i quantitatively provided the ring-
opened primary amide, whose concomitantly liberated diol
preferred to collapse onto the aromatic ketone resulting in the
six-membered lactol 16 (Scheme 2). Lactol 16 resisted high
level purification, which may reflect diastereomeric lactol inter-
conversions (see the Supporting Information, section 6). This
prompted us to use this nearly pure crude product as such.
The next reaction, a catalytic ruthenium (0.50 mol%)-based oxi-
dative cleavage, occurred under mildly acidic aqueous biphasic
conditions. These conditions advantageously promoted in situ
lactol hydrolysis, temporarily freeing the vicinal diol whose oxi-
dative cleavage produced an aldehyde that was readily oxi-
dized to the desired carboxylic acid 17 in the presence of cata-
lytic perruthenate. Thus, in one pot, lactol 16 was converted
into carboxylic acid 17. The isolated overall yield of 17 from
lactone 13i was 92%. Treatment of 17 with ethereal trimethyl-
silyl diazomethane gave the methyl ester 18 in 82% yield
(Scheme 2).
We initially sought to convert methyl ester 18 into piperi-
dine 20 by Hofmann rearrangement, but otherwise reliable
modern reagents for doing so, PhI(CF3CO2)2 or PhI(OAc)2,[43]
[42]
provided intractable product mixtures. This is perhaps unsur-
prising, given the number, type, and proximity of the present
spectator functional groups. By contrast, the combination of
1.2 equivalents of lead tetraacetate in near-boiling tert-butanol
proved efficient for isocyanate formation,[44] affording the tert-
butoxycarbonyl (boc)-protected amine 19 in high yield after in
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lution of the diketone (6–8; 1.12 mmol, 1.5 equiv) and the alde-
hyde (0.75 mmol, 1.0 equiv). Upon dissolution, water (40.5 mL,
3.0 equiv) was added. This mixture was stirred at room tempera-
ture in a closed reaction vessel until an aldehyde conversion of
situ solvent trapping. Deprotection of carbamate 19 proceed-
ed satisfactorily in a one-spot to one-spot transformation
(monitored by TLC) with trifluoroacetic acid (25 equiv). Hydro-
genation (2.0 mol% Pd/C, 10 bar H2) exclusively from the less
hindered face of the resulting crude cyclic imine (not shown)
provided the desired cis-piperidine 20 at the expense of the
undesired trans diastereoisomer. This synthesis constitutes the
first enantioselective synthesis of cis-piperidine 20 and by ex-
tension, the first (formal) enantioselective synthesis of g-secre-
tase modulators 21 and 22 (Scheme 2). The latter is sometimes
referred to in the neuroscience literature as GSM-1.[40]
1
ꢀ95% could be confirmed by H NMR spectroscopy (see the Sup-
porting Information for the exact reaction times with individual
compounds; note that extension of the indicated reaction times is
often detrimental due to decreased diastereoselectivity from a-
keto epimerization). The reaction was worked up by repeated ex-
traction with CH2Cl2 or EtOAc (6ꢁ10 mL). The combined extracts
were dried (Na2SO4), filtered, and concentrated under reduced
pressure (T<308C). The crude residue was then exposed to high
vacuum for 2–4 h before treatment in the next reaction step to
form 13 or 15. Full experimental details are provided in the Sup-
porting Information.[47]
The present synthesis constitutes a seven-step high-yielding
transformation of diketone 9 into cis-piperidine 20, occurring
in an overall yield of 58%. A 36% overall yield of cis-piperidine
20 is noted when starting from 1,1-ethylenedioxy-4-cyclohexa-
none, the commercial starting material required for the synthe- Acknowledgements
sis of diketone 9 (see the Supporting Information, section 2).
This overall yield improves the best previously reported syn-
thesis of cis-piperidine 20,[22,23] which required resolution with
l-(+)-mandelic acid and gave 25% overall yield.[23]
This work was generously supported by the Deutsche For-
schungsgemeinschaft (award no. NU235/6-1) and by Jacobs
University Bremen. We are very thankful for low- and high-res-
olution mass spectrometry measurements provided by Profes-
sor Dr. Nikolai Kuhnert. The authors thank Prof. Dr. Jens Beck-
mann (University of Bremen) for X-ray analysis of keto-aceto-
nide 15i. We thank Professor Dr. Heiko Ihmels (University
Siegen) for initial CD discussions. We thank Dr. Richard Friary
for insightful comments regarding style and conciseness.
Conclusion
In summary, mild amine catalysis enabled the regio-, dia-
stereo-, and enantioselective differentiation of a diverse set of
cyclohexanone-based diketones (6–9) during aldol reactions.
The present method has accordingly established new chemical
territory for further exploration by offering previously unreal-
ized site selectivity for diketone substrates. Importantly, the
aldol products reported herein allow fast entry to high-density
chiral compounds including ketolactones (13) and keto-aceto-
nides (15) under practical reaction conditions. These achieve-
ments embody a forward-looking theme within chemistry, re-
duced dependence on protection/deprotection protocols, and
opportunities to extend this method to other electrophiles,
such as nitroso compounds, and other diketones, such as 3-
keto-substituted cyclobutanones, likely exist. Of further signifi-
cance, the product features of rich functional group diversity
combined with a remote stereogenic center may expand tacti-
cal application possibilities for more step-efficient approaches
to complex biomolecules. A first-generation example of this is
our formal synthesis of Alzheimer’s g-secretase modulator drug
candidates in the highest yielding synthesis reported to date.
It is also clear that new doors have been opened for drug-dis-
covery opportunities within Alzheimer’s drug discovery re-
search. Moreover, we propose that unraveling ketolactones 13
into intermediates based on a central chiral methine unit, like
that found in keto ester amide 18, may be a logical starting
point for the preparation of artificial chiral cavities, as used in
supramolecular host–guest chemistry,[45] or for generating, by
dendritic extension, chiral tertiary macromolecules reminiscent
of protein environments.[46]
Keywords: Alzheimer’s disease
· diketones · enamines ·
enantioselective aldol · gamma-secretase modulator · site
selectivity
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Received: June 17, 2016
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 8
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FULL PAPER
Let your enamines play: Ketone site se-
lectivity for cyclohexanone-based dike-
tones has been firmly established and
permits a high yielding synthesis of a g-
secretase modulator (GSM). The ach-
ievements embody a forward-looking
theme within chemistry; reduced de-
pendence on protection/deprotection
protocols for increased step efficiency in
biomolecule synthesis.
&
Diketone Site Selectivity
T. C. Nugent,* F. T. Najafian,
H. A. E. D. Hussein, I. Hussain
&& – &&
Beyond Chemoselectivity: Catalytic
Site-Selective Aldolization of
Diketones and Exploitation for
Enantioselective Alzheimer’s Drug
Candidate Synthesis
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Chem. Eur. J. 2016, 22, 1 – 8
www.chemeurj.org
8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!