Simple organic molecules as catalysts for enantioselective synthesis of amines and alcohols

Article abstract of DOI:10.1038/nature11844

The discovery of catalysts that can be used to synthesize complex organic compounds by enantioselective transformations is central to advances in the life sciences; for this reason, many chemists aim to discover catalysts that allow for preparation of chi

Full text of DOI:10.1038/nature11844

LETTER
doi:10.1038/nature11844
Simple organic molecules as catalysts for
enantioselective synthesis of amines and alcohols
Daniel L. Silverio1, Sebastian Torker1, Tatiana Pilyugina1, Erika M. Vieira1, Marc L. Snapper1, Fredrik Haeffner1 & Amir H. Hoveyda1
The discovery of catalysts that can be used to synthesize complex including the need for toxic tin-based reagents22, scarce metal salts23,
organic compounds by enantioselective transformations is central and moderate selectivities22 complicate these notable advances.
to advances in the life sciences1; for this reason, many chemists aim
Deliberations regarding catalyst design, alongside consideration of
to discover catalysts that allow for preparation of chiral molecules
as predominantly one mirror-image isomer2. The ideal catalyst
should not contain precious elements3 and should bring reactions
to completion in a few hours through operationally simple proce-
dures. Here we introduce a set of small organic molecules that can
catalyse reactions of unsaturated organoboron reagents with imi-
nes and carbonyls; the products of the reactions are enantiomerically
pure amines and alcohols, which might serve as intermediates in the
preparation of biologically active molecules. A distinguishing feature
of this catalyst class is the presence of a ‘key’ proton embedded within
their structure. Catalysts are derived from the abundant amino acid
valine and are prepared in large quantities in four steps with inex-
pensive reagents. Reactions are scalable, do not demand stringent
conditions, and can be performed with as little as 0.25 mole per cent
catalyst in less than six hours at room temperature to generate pro-
ducts in more than 85 per cent yield and $97:3 enantiomeric ratio.
The efficiency, selectivity and operational simplicity of the transfor-
mationsandtherangeofboron-basedreagentsareexpectedtorender
this advance important for future progress in syntheses of aminesand
alcohols, which are useful in chemistry, biology and medicine.
Many biologically active molecules contain nitrogen-substituted
carbon stereogenic centres. Routes for efficient preparation of enan-
tiomerically enriched homoallylic amines are therefore of considerable
consequence4. Anti-cancer agents aza-epothilones A–D5 (Fig. 1a), leu-
conicine A and B6, natural products that can reverse multi-drug
resistance, and immunosuppressant FR2352227 are among entities
the synthesis of which might involve homoallylic amines. Enan-
tioselective addition of an allyl group to an aldimine has thus been
the subject of substantial scrutiny4. Catalytic protocols have been
introduced forpreparing homoallylic amines and derivatives withhigh
enantioselectivity; nevertheless, all lack several important attributes.
Some demand the intermediacy of allylindiums8, prepared in situ from
allyl halides and the costly metal9,10; others entail the use of a rare
element11. Moreover, the following drawbacks are encountered fre-
quently: difficult-to-accessorexpensiveligands12, highcatalyst loadings
(for example, $10mol%)8–10,12,13, long reaction times (for example,
.8 h)8–11,13–16 exceedingly low temperatures (for example, –50 uC or
lower)15,17, narrow substrate range9,15,16,18, and the need for allyltin11 or
moisture-sensitive reagents13.
the mechanistic attributes of different extant approaches to catalytic
enantioselective allyl additions, led us to opt for metal-free pathways;
several factors led to such a conclusion. Most allylmetal reagents are
sensitive to oxygen and moisture24; their use entails vigilantly con-
trolled conditions. Furthermore, transformations with p-allylmetal
complexes are usually either not diastereoselective9,17 or one possible
isomer remains inaccessible13,23 regardless of whether the E or Z allylic
reagent is employed. Although strategies involving stoichiometric
quantities of enantiomerically pure substrates offer stereoselective
alternatives, the transformations suffer from similar limitations (see
the Supplementary Information for bibliography).
There is one metal-free catalytic method for enantioselective addi-
tions of allylboron reagents to imines13; reactions, however, proceed
less readily and demand higher catalyst amounts and longer reaction
times than when allylmetal species are involved (Fig. 1c); additionally,
moisture-sensitive allylboron derivatives are required (v, Fig. 1c), and
similar to transformations with crotylmetal reagents, only one product
diastereomer can be prepared13. Reactions with metal-containing sys-
tems are probably more efficient because of swift ligand exchange
leading to fast catalyst regeneration (Fig. 1b): the swap between a
homoallyl metal-amide (ii) and an allyl reagent (iii) to re-form the
active complex i can occur rapidly. In contrast, allylboron vi needs to
be re-assembled after each cycle (Fig. 1c): the enantiomerically
enriched vii must first be converted to diol iv by protolytic removal
of the boron and product moieties; the diol then reacts with allylboron
v to regenerate vi. Mechanistic studies indicate that it is indeed the
regeneration of the diol iv that hampers reaction rate25. Thus, to ensure
re-formation of vi, a more reactive but moisture sensitive allylboron
(v) was prepared and used.
The above analysis led us to conclude that a pathway must be con-
ceived such that the catalyst is reproduced rapidly but without a sen-
sitive allylboron and the benefit of the favourable kinetics available to
metal-containing intermediates. Accordingly, we drafted the blueprint
outlined in Fig. 1d. A substituted aminophenol (A) offered an attract-
ive possibility; such molecules are structurally modular and syn-
thesized by dependable manipulations; chiral allylboron B would be
generated by reaction with the relatively robust (pinacolato)allylboron
1a. At this juncture, several challenges become evident: (1) the boron
centre, bearing a comparatively electron-donating amine ligand,
Readily obtainable catalysts for efficient, sustainable and practical would have to be rendered sufficiently Lewis acidic to bind readily
enantioselective additions to ketones are equally sought after. Isatins with the substrate. (2) The stereogenic centre resides at a conforma-
are carbonyl-containing entities that can be converted to enantiomeri- tionally mobile arm of the catalyst; high enantioselectivity would
cally enriched 3-hydroxy-2-oxindoles found within alkaloids of sub- demand strong differentiation between the diastereotopic faces of
stantial biological consequence19. Examples are proteasome inhibitors the coordinated imine. (3) A mechanism for quick catalyst regenera-
TMC-95A–D with ample potential in the treatment of cancer and tion would have to be identified. We considered that a solution could
immune disorders20, and interleukin 6 inhibitor and anti-osteoporosis involve an internal hydrogen bond, bridging the catalyst’s amide car-
agent madindoline A (Fig. 1a); proper configuration of the tertiary bonyl and boron-bound nitrogen (Fig. 1d). Such electrostatic attrac-
hydroxyl unit is needed for high activity21. A few reports concentrate tion would increase the boron centre Lewis acidity to facilitate
on catalytic enantioselective allyl additions to isatins; limitations substrate binding (RE) and C–C bond formation (RF) and rigidify
1Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA.
2 1 6
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LETTER RESEARCH
R
HO
O
O
OH
O
Br
a
N
HO
Et
Me
Me
OH
N
H
O
HN
Me
Me
Me
I
O
O
N
H
H
N
H
Br
Me
S
N
N
Me
N
H
R = COMe: Convolutamydine A
R = CH2Cl: Convolutamydine B
R = CH2OH: Convolutamydine E
Me
Me
O
Aza-epothilone A
Leuconicine B
Madindoline A
CO2Me
n-Bu
O
Reassembled
after every cycle
b
c
Metal-based,
more active than M1–allyl (iii)
15 mol%
Oi-Pr
Ph
Ph
B
Oi-Pr
i-PrO
(chiral ligand)M
v
B
O
OH
O
i
OH
OH
vi
Ph
M1
GPN
HN
Ph
Ph
i-PrOH
NPG
H
Facile
ligand exchange
H
Ph
R
iv
R
Ph
M(ligand)
O
Oi-Pr O
GPN
H
B
N
B(Oi-Pr)3
N
Ph
i-PrOH
O
Ph
M1
R
OH
slow
R
H
iii
ii
Ph
Remove B, regenerate chiral diol
Facile product release and catalyst regeneration
vii
Ph
G
d
Intramolecular H-bonding
L
N
1. Increase B Lewis acidity
a. Facilitate substrate binding
b. Facilitate allyl transfer
S
H
O
OH
A
O
O
2. Promote stereoselectivity
B
O
H
N
B
L
O
B
O
H
O
Me
1a
B
L
MeO
B
O
O
H
N
B
O
G
G
G
L
C
S
N
B
S
S
H
O
O
O
B
O
O
3
H
O
3
Me
O
1
O
1
D
B
OMe
O
PG
N
3
Efficient
B–allyl bond
formation
and
O
O
1
R
H
B
1a
catalyst
regeneration
L
O
H
N
B
L
O
H
N
B
L
O
H
N
B
G
G
G
S
S
S
3
PG
O
OMe
O
N
O
1
N
MeOH
1
H
1
PG
PG
3
G
F
E
R
N
R
3
R
Intramolecular protonation/product release
Net α addition
Figure 1
|
The significanceof homoallylic amines and alcohols illustrated by before each cycle. d, A boron-based small-molecule catalyst might be designed
three approaches to their catalytic enantioselective synthesis.
such that electrostatic forces caused by amine protonation lead to fast reaction
rates and high enantioselectivities. Catalytic cycles deliver net a addition (C1–
B R C1–C) resulting from two c-selective processes (GRB and DRF). Facile
catalyst regeneration may occur through allylation of G via H. PG, protecting
a, Representative biologically active natural products synthesized via chiral
homoallylic amines and 3-hydroxy-2-oxindoles. b, With a metal-containing
catalyst, high rates are achieved through facile ligand exchange; catalytic allyl
addition is shown. c, In a metal-free system, the catalyst must be reassembled group.
and generation of the parent amines24,26. Such protocols tolerate many
the catalystNsubstrate complex E, engendering high enantioselectivity.
Turnover could be facilitated by acceleration of product release
through intramolecular protonation in F, affording the desired pro-
duct and chiral intermediate G, which could then react to regenerate
the catalytically active B through a structure such as H (Fig. 1). As will
be detailed below, the facility with which H can be accessed is central to
the high turnover rates achieved; the intermediacy of H has stereo-
chemical consequences that are among the hallmarks of the present
system. We further noted a significant implication of the projected
mechanistic scenario: once the boron-based catalyst (B) is generated
(that is, after the first cycle), subsequent cycles would deliver net a
commonly used functional groups and do not require strongly reduc-
tive conditions (for example, diisobutylaluminium hydride13 required
in Fig. 1c), or costly metal salts (for example, SmI2; refs 18, 27) and/or
alkyllithium reagents10.
When imine 3a and allylboron 1a are subjected to 3.0 mol% amino
alcohol 2a (Fig. 2, Table 1, entry 1), 2.5 mol% NaOt-Bu and 2.5 equiv.
of MeOH, 71% conversion to homoallylamide 4a is observed in four
hours (with an enantiomeric ratio, e.r., of 74.5:25.5). With Schiff
base 2b or amide 2c (Table 1, entries 2–3), there is minimal trans-
formation. Placement of a sizeable t-butyl unit adjacent to the phenol
addition of an allyl unit (C1–BRC1–C) resulting from two c-selective group in 2d (Table 1, entry 4), incorporated with the idea of discourag-
processes (that is, GRB and DRF; Fig. 1d).
ing dimerization of two or more amino alcohols in solution, led to
improved efficiency (.98% conversion); the superior enantioselec-
tivity (91:9 e.r.) reflects a substantially more facile process initiated
by the chiral catalyst, because control experiments indicate that allyl
addition proceeds with reasonable efficiency in its absence (70% con-
version, 75 min, 22 uC). Lower e.r. and diminished reactivity is fur-
nished by less Lewis basic ethyl ester 2e (Table 1, entry 5). With
We first probed the ability of aminophenols 2a–2h (Table 1, Fig. 2)
to serve as catalyst precursors for reactions involving commercially
available (pinacolato)allylboron 1a and N-phosphinoylimine 3a
(Fig. 2). The choice of the N-activating group, despite its ostensible
non-optimal atom economy, was for several reasons. The derived
imines, aryl- or alkyl-containing, can be prepared efficiently; such
entities are relatively robust and generate products that are easy to dialkylamides 2f and 2g (Table 1, entries 6 and 7) additions proceed
purify owing to their strong tendency to be crystalline (chromato- to completion readily, affording the desired amide in approximately
graphy avoided). There are inexpensive and efficient mildly acidic 96:4 e.r. Reaction with 2h (Table 1, entry 8) is more selective (98:2 e.r.)
methods for removal of the phosphorous-based protecting group but requires the exorbitantly expensive t-Leu residue. Lastly, similar
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RESEARCH LETTER
The representative transformation:
3.0 mol%
Table 1
Entry number
|
Examination of various amino alcohols
R1
Amino alcohol;
(mol%)
Time (h);
T (uC)
Conversion (%)*
Enantiomeric
G
ratio{
N
H
G
O
OH
1
2
3
4
5
6
7
8
2a; 3.0
2b; 3.0
2c; 3.0
2d; 3.0
2e; 3.0
2f; 3.0
2g; 3.0
2h; 3.0
4.0; 22
4.0; 22
4.0; 22
4.0; 22
4.0; 22
4.0; 22
4.0; 22
4.0; 22
71
,2
,10
.98
47
.98
.98
97
74.5:2.5
ND
ND
91:9
80:20
96:4
NPOPh2
NHPOPh2
2.5 mol% NaOt-Bu
Ph
Ph
3a
4a
O
B
O
1a
2.5 equiv. MeOH, toluene
Representative catalyst precursors used in screening studies:
i-Pr i-Pr i-Pr
96.5:3.5
98:2
O
The representative transformation is shown in Fig. 2. Reactions were carried out in toluene under an
atmosphere of nitrogen gas. ND, not determined.
NHn-Bu
NHn-Bu
NHn-Bu
N
H
OH
N
N
H
OH
* Conversion to the desired product as measured by analysis of 400 MHz 1H NMR spectra of unpurified
mixtures versus an internal standard of 9-methylanthracene; the variance of values is estimated to be
,62%.
O
O
O
OH
2a
i-Pr
2b
i-Pr
2c
i-Pr
{ Enantiomeric ratios were determined by HPLC analysis; the variance of values is estimated to be
,62%. See Supplementary Information for details.
NHn-Bu
OEt
N
N
H
OH
N
H
OH
N
H
O
O
O
OH
t-Bu
2d
t-Bu
2e
t-Bu
t-Bu
2f
and other cheap materials. Purification of 2g, indefinitely stable to air
and moisture, entails routine filtration without the need for costly chro-
matography procedures. Enantioselective additions are scalable, as the
case in Fig. 4a illustrates; reaction work-up is no more than solvent
evaporation (analytically pure homoallylamide is obtained by tritura-
tion)—distillation or silica gel chromatography is, again, not needed.
Such a simple and cost effective product isolation procedure (no need
for expensive chromatography solvents) is largely due to the diphenyl-
phosphinoyl unit, more than compensating for its perceived lack of
atom economy.
Congruent with the pathway in Fig. 1d, and confirmed by the reac-
tion with d2-1a (Fig. 4b), the overall transformation takes place with
net a selectivity (d2-4o; 95% a)27. Homoallylic amide 4o can be used
in enantioselective synthesis of anti-cancer agents aza-epothilones
(Fig. 1a)5. The ability to convert the C–B of an allylboron entity to a
C–C bond, while generating a N-substituted stereogenic centre, has
i-Pr
NMe2
NMe2
N
N
H
OH
H
O
O
OH
t-Bu
2g
t-Bu
2h
Figure 2
|
Chiral amino alcohols as candidates for catalyst precursors. Top,
the representative transformation; bottom, the representative catalyst
precursors. Table 1 reports the results. The lack of activity shown by catalysts
derived from 2b and 2c is consistent with the mechanistic scenario outlined in
Fig. 1d, as the requisite chiral allylboron species D cannot be generated. Also
consistent is the low activity and enantioselectivity by ester-containing
2e, underscoring the pivotal role of the catalyst’s Lewis basic C terminus in
establishing a hydrogen bond.
efficiency and enantioselectivity is attained when organic amines are
used as base (for example, 1,8-diazabicycloundec-7-ene, dbu).
A wide array of imines undergoes allyl additions with 3.0 mol% of
amino alcohol 2g and 1.5 equiv. of allylboron 1a within six hours at
ambient temperature (Table 2). Homoallylamides, including those
that bear heterocyclic moieties, such as a furyl or a pyridyl unit (entries
11 and 12, Table 2), are isolated often in .85% yield and $97:3 e.r. As
the syntheses of 4m and 4n illustrate (Fig. 3), use of 2-substituted
allylboron reagents results in equally efficient and enantioselective
processes. The method can be extended to additions with alkenyl-,
alkynyl- and alkyl-substituted aldimines (Table 3).
Stereochemical models, supported by computational studies (Sup-
plementary Information), are presented in Fig. 3. Association of the
N-phosphinoylimine with the boron centre and allyl addition takes
place as depicted (IRII); the allyl and the i-Pr groups of the catalyst in
IIIbringaboutsteric repulsion. The proposedscenarioassigns anaddi-
tional role to hydrogen-bonding: a three-pronged association involv-
ing the catalyst’s amine and amide carbonyl and the phosphinoyl unit
is established; reactions with N-aryl imines, which lack an appro-
priate hydrogen-bond acceptor, engender minimal enantioselectivity.
Other observations support the hypothesis regarding the function
of electrostatic interactions (Fig. 1d). Kinetic studies point to the
C–C bond forming step as rate determining, with imines bearing
electron-donating groups reacting at a slower pace (Supplementary
Information). There is ,2% conversion without MeOH. Further-
more, treatment of a solution of 2g with one equivalent of NaOt-Bu
results in rapid and complete phenol deprotonation. The addition of
five equivalents of MeOH does not lead to major changes; when two
equivalents of allylboron 1a are introduced, allowing for Lewis acid
activation of the alcohol additive (Fig. 1d), the phenol is regenerated
immediately(.98%). The aboveobservationssupport thenotion that,
overall, the mixture is a buffered acidic solution.
`
critical implications vis-a-vis its utility in stereoselective synthesis.
With allylboron S-9 or its enantiomer R-9, accessed in 94:6 e.r. by a
Cu-catalysed protocol28, homoallylamides 10 and 11 are obtained in
84% and 93% yield, 84:16 and 83:17 diastereomeric ratio (d.r.), respec-
tively, and 95:5 e.r. (for the major diastereomer); reaction with allyl-
boron 1228, bearing a quaternary carbon stereogenic centre (95:5 e.r.),
delivers 13 in 70% yield (pure diastereomer), 89:11 d.r. and 95:5 e.r.
(major isomer) (Fig. 4c). Alternative diastereomeric products can be
synthesized through the use of the other enantiomer of a chiral allyl-
boron (10 versus 11, Fig. 4c). There is complete a selectivity in all
instances. The route charted in Fig. 1d implies that a net c-selective
addition should result from the initial catalytic cycle (that is, boron-
based catalyst B first generated by ligand exchange); that none of the
homoallylamine from overall c-addition is detected suggests that the
catalyst is derived from a minute fraction of the amino alcohol, or B is
initially formed by a pathway to be elucidated. Reaction with sterically
demanding 12, for reasons that remain to be determined, proceeds
more readily when performed with Zn(Ot-Bu)2.
The reversal in the stereochemical identities in the reactions shown
in Fig. 4c, ascertained through X-ray crystallography, supports the
suggested general mechanism and the pivotal allyl exchange step lead-
ing to rapid catalyst regeneration. As initially put forth in Fig. 1d,
stereoselective formation of 13 begins with product release by intra-
molecular proton transfer (Fig. 4d), leading to the formation of VI,
wherein the boron centre is stabilized by chelation with the Lewis basic
amide group. Subsequent reaction with MeOH yields VII (Fig. 4d)
Stereoselective generation of chiral allylboron species IX can proceed
via VIII (Fig. 4d), involving a synclinal (cyclic) transition state4; other-
wise, the corresponding Z isomer of IX or a mixture of the two would
be formed and the reverse diastereoselectivity or little stereochemical
preference would be observed. Selective formation of 13 would take
place through transition complex X.
Several key features of the catalytic system are outlined in Fig. 4. The
chiral amino alcohol has the low molecular weight of 306.4g mol21
;
it can be prepared on a multi-gram scale by an uncomplicated four-step
The catalytic strategy can be applied to carbonyl-containing sub-
sequence involving valine, inexpensively available as either enantiomer, strates, entities that do not readily lend themselves to chiral auxiliary
2 1 8
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LETTER RESEARCH
Table 2
imines
|
Catalytic enantioselective allyl additions to aryl-substituted Table 3
|
Catalytic enantioselective allyl additions to alkenyl-,
alkynyl- and alkyl-substituted imines
3.0 mol% 2g
2.5 mol% NaOt-Bu
3.0–6.0 mol% 2g
2.5–8.5 mol% NaOt-Bu
NPOPh2
NHPOPh2
NPOPh2
NHPOPh2
Ar
Ar
G
G
1.5 equiv. 1a,
2.5 equiv. MeOH, toluene, 22 °C
1.5 equiv. 1a,
2.5 equiv. MeOH, toluene, 22 °C, 4.0 h
3
4
5–8
Entry number
Ar
Time (h)
Conversion (%)*; Enantiomeric
Entry
G
2g (mol%);
Conversion (%)*; Enantiomeric
yield (%){
ratio{
number
NaOt-Bu (mol%)
Yield (%){
ratio{
1
2
3
4
5
6
7
8
9
Ph; 3a
o-FC6H4; 3b
4.0
4.0
4.0
6.0
4.0
6.0
4.0
4.0
4.0
4.0
6.0
4.0
.98; 95
.98; 91
.98; 86
.98; 91
.98; 95
.98; 91
.98; 93
.98; 92
.98; 98
95; 93
96.5:3.5
98:2
97.5:2.5
93.5:6.5
98:2
97:3
98:2
98:2
96.5:3.5
92:8
1
2
3.0; 2.5
3.0; 2.5
.98; 84
.99:1
5a
5b
o-BrC6H4; 3c
o-MeC6H4; 3d
m-BrC6H4; 3e
p-BrC6H4; 3f
p-CF3C6H4; 3g
p-MeO2CC6H4; 3h
p-MeOC6H4; 3i
p-(n-Bu)2C6H4; 3j
2-furyl; 3k
.98; 95
.98; 98
.98; 96
.99:1
.99:1
98:2
NO2
3
4
3.0; 2.5
3.0; 2.5
5c
MeO
10
11
12
.98; 93
90; 75
98:2
98:2
5d
Br
3-pyridyl; 3l
5
6
7
2.5; 2.5
3.0; 2.5
6.0; 5.0
.98; 96
.98; 95
66; 50
98:2
88:12
.99:1
n-Pr
6
7
Reactions were carried out in toluene under an atmosphere of nitrogen gas.
* Conversion to the desired product as measured by analysis of 400 MHz 1H NMR spectra of unpurified
mixtures versus an internal standard of 9-methylanthracene; the variance of values is estimated to be
,62%.
Ph
Ph
8a
8b
{ Yield of isolated product after purification; the variance of values is estimated to be 62%.
{ Enantiomeric ratios were determined by HPLC analysis; the variance of values is estimated to be
,62%. See Supplementary Information for details.
8
9
6.0; 5.0
6.0; 8.5
70; 51
90; 71
.99:1
i-Pr
97.5:2.5
8c
approaches. The catalyst derived from 2g promotes efficient enantio-
selective reactions with isatins, potential precursors to tertiary alcohols
used in drug development19. With 0.5–2.0 mol% 2g and 1.5 equiv. of
the allylboron reagent, addition to N-protected isatins is complete at
22 uC within two hours (Fig. 5a); homoallylic alcohols are obtained in
84–98% yield and 91.5:8.5–98.5:1.5 e.r. As the syntheses of 15a and
15b exemplify, enantioselective allyl addition/amide deprotection can
be carried out in a single vessel easily and with exceptional efficiency.
Homoallyl carbinol 15a is applicable to the synthesis of madindoline
A29 and 15b is a potential intermediate en route to different convolu-
tamydines (Fig. 3a)30. A stereochemical model similar to that offered
for additions to imines applies (XI and XII, Fig. 5b). Allyl addition to
acetophenoneunder the same conditionsproceedswith high efficiency
(3.0 mol% 2g, .98% conversion in 4.0 h) but in 70:30 e.r., consistent
with the proposed mechanistic model.
Reactions were carried out in toluene under an atmosphere of nitrogen gas.
* Conversion to the desired product as measured by analysis of 400 MHz 1H NMR spectra of unpurified
mixtures versus an internal standard of 9-methylanthracene; the variance of values is estimated to be
,62%.
{ Yield of isolated product after purification; the variance of values is estimated to be 62%.
{ Enantiomeric ratios were determined by HPLC analysis; the variance of values is estimated to be
,62%. See Supplementary Information for details.
2g, reaction of benzyl amide 14c or p-methoxybenzyl amide 14d
with commercially available (pinacolato)allenylboron 19 is complete
within four hours at ambient temperature, affording allenyl carbinols
20a and 20b in 98:2 and 96:4 e.r. and 91% and 90% yield, respectively
(Fig. 5c). Similar to the reaction with 14d, addition to silylamide 14a
can be performed on the gram scale in a standard fume hood with
0.25 mol% 2g and 1.05 equiv. of 19; C–C bond formation is complete
within two minutes and the silyl group is removed through mild acidic
workup to afford 21, which can be isolated in high purity without
chromatography, in 90% overall yield and .99:1 e.r. The enantiose-
Another readily accessible organoboron reagent may be used in the
present set of catalytic transformations: in the presence of 0.5 mol% lective synthesis of a-hydroxy alcohol 22 further demonstrates utility;
2.5 mol% 2g
NPOPh2
Ph2OPHN
R
2.5 mol% NaO t-Bu
R
1.5 equiv.
3a
B(pin)
4m (R = Me): >98% conv.,
96% yield, 97.5:2.5 e.r.
4n (R = Ph): >98% conv.,
98% yield, 97.5:2.5 e.r.
1b R = Me
1c R = Ph
2.5 equiv. MeOH, toluene,
22 °C, 4.0–6.0 h
‡
‡
t-Bu
t-Bu
t-Bu
t-Bu
L3B–OMe
L3B–OMe
L3B–OMe
L3B–OMe
O
O
B
R
O
O
R
R
R
major
isomer
minor
isomer
S
R
B
B
N
B
N
H
N
P
N
H
N
P
N
H
H
NMe2
H
H
NMe2
N
N
H
Me2N
O
Me2N
O
P
P
Ph
Ph
H
O
Ph
Ph
O
O
O
O
O
Ph
Ph
Ph
Ph
I
II
III
IV
repulsion
Figure 3
|
Efficient and enantioselective catalytic allyl additions to
differentiation by enforcing an organized transition structure, and facilitate
bond formation by minimizing electron–electron repulsion caused by the
aldimines. Aryl-, alkenyl-, alkynyl- and alkylimines can be used to generate
homoallylic amides with high efficiency and enantioselectivity (Tables 2 and 3). converging heteroatoms (see text for discussion). This model is supported by
Top, use of 2-substituted allylboron reagents results in equally efficient and
enantioselective processes. Bottom, mechanistic models account for the
observed enantioselectivity and involve hydrogen-bonding interactions that
bring the reaction components together, promote high enantiotopic face
the X-ray crystal structures of 2g and its HCl salt, which contain a proton-
bridge connecting the amine and carbonyl units (see Supplementary
Information).
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RESEARCH LETTER
a
c
i-Pr
NHPOPh2
NMe2
(pin)B
1.0 mol%
(10 mg)
N
H
OH
6.0 mol% 2g
3a
Ph
Ph
O
H
H
5.0 mol% NaOt-Bu, 2.5 equiv. MeOH,
2g (306.4 g mol–1
)
toluene, 18 h, 22 °C
t-Bu
S-9 Ph
94:6 e.r.
10
NPOPh2
NHPOPh2
84% yield 84:16 d.r.,
1.0 mol% NaOH
>98% α, 95:5 e.r.
R
Ph
Ph
1.3 equiv. 1a, 1.5 equiv. MeOH,
3a
1.0 gram
4a >98% conv, 92% yield
NHPOPh2
toluene, 22 °C, 2.0 h
97:3 e.r.
(pin)B
H
6.0 mol% 2g
3a
3a
Ph
H
5.0 mol% NaOt-Bu, 2.5 equiv. MeOH,
toluene, 18 h, 22 °C
R-9 Ph
94:6 e.r.
Ph
11
93% yield 83:17 d.r.,
>98% α, 96:4 e.r.
b
NHPOPh2
NPOPh2
(pin)B
NHPOPh2
(pin)B
6.0 mol% 2g
3.0 mol %2f
S
Me
Ph
S
D
Me
Cy
D
D
N
Me
Me Cy
N
Me
D
20 mol% NaO t-Bu,
2.5 equiv. MeOH,
toluene, 6.0 h, 22 °C
2.5 mol% Zn(Ot-Bu)2, 2.5 equiv. MeOH,
Me
d2-4o
12
95:5 e.r.
13
toluene, 18 h, 22 °C
3m
d2-1a
86% yield, 95% α,
95.5:4.5 e.r.
70% yield 89:11 d.r.,
>98% α, 95:5 e.r.
t-Bu
d
t-Bu
t-Bu
L3B–OMe
L3B–OMe
L3B–OMe
O
O
Ph
O
B
B
N
N
B
N
P
Cy
Ph
N
Me2N
Me2N
(pin)B
Cy Me
12
H
MeOH
OMe
O
H
O
O
O
Me2N
Me
Ph
NHPOPh2
Me Cy 13
t-Bu
V
VI
VII
Ph
Efficient and
stereospecific
B–allyl bond
formation and
catalyst
‡
t-Bu
‡
t-Bu
NPOPh2
L3B–OMe
L3B–OMe
L3B–OMe
3a
regeneration
Ph
“synclinal”
O
O
O
Ph
B
B
N
B
N
N
N
P
E
Cy
B
Cy
Ph
Me2N
Me2N
O
*
Me2N
*(pin) group
omitted for
clarity
MeO–B(pin)
O
Cy
H
H
H
O
O
Me
Me
O
Me
Me
Ph
X
VIII
IX
Figure 4
|
Practical, scalable and highly a-selective catalytic enantioselective reversal of stereochemistry at the B-substituted carbon. d, The stereochemical
allyl additions to imines. a, A practical catalytic protocol. Amino alcohol 2g is outcome with substituted allylboron reagents support the proposed mechanism
prepared in multi-gram quantities inexpensively by simple procedures; and shed light on the efficient and stereoselective allyl transfer phase of the
additions are easily performed on gram scale. Key points: 2g is prepared in four catalytic cycle (catalyst regeneration/product release). Facile allyl transfer and
steps in 73% yield (,5 g scale from inexpensive materials, with no catalyst regeneration is pivotal to high catalyst efficiency. Hydrogen-bonding in
chromatography, and isindefinitely air-stableat22uC;the reaction isperformed VII stimulates enhanced Lewis acidity at the chiral catalyst’s boron centre,
in a common fume hood with commercial (undistilled/unpurified) allylboron,
NaOH, MeOH, without aqueous extraction or silica gel chromatography.
favouring donation by the p bond of the organoboron reagent 12 (see
VIII), facilitating stereoselective generation of IX. Conversions and
b, Deuterium-labelling experimentssupport thepreferencefor higha selectivity. diastereomeric ratios were measured byanalysis of400 MHz 1H NMR spectra of
Shown is synthesis of a fragment of aza-epothilone A. c, Various attributes of the unpurified mixtures; the variance of values estimated to be ,62%. Yields
chiral catalyst allow access to homoallylamides with an additional tertiary or
quaternary carbon stereogenic centre with high a-, diastereo- and
enantioselectivity. Shown are reactions with a-substituted allylborons, with
correspond to isolated and purified products (62%). Enantiomeric ratios were
determined by HPLC analysis (62%). See Supplementary Information for
experimental details and spectroscopic analyses.
Figure 5
|
Catalytic
a
b
i-Pr
0.5 mol%
enantioselective additions to isatins
and reactions with an allenylboron
reagent. a, Catalytic enantioselective
allyl additions to isatins afford
t-Bu
t-Bu
NMe2
N
H
OH
O
O
R
O
O
O
HO
t-Bu
2g
R
B
B
major
isomer
N
H
N
H
O
0.5 mol% NaOt-Bu
Me2N
Me2N
homoallylic alcohols. b, A
O
O
N
H
O
O
N
1.5 equiv. allylboron, 2.5 equiv. MeOH,
toluene, 22 °C, 1.5 h; p-TsOH, 22 °C
O
O
stereochemical model proposed to
account for the enantioselectivities.
c, Broad applicability is illustrated by
enantioselective allene additions to
isatins, performed with commercially
available organoboron reagent 19. All
reactions were carried out in toluene
under an atmosphere of nitrogen gas.
Conversions measured by analysis of
400 MHz 1H NMR spectra of
unpurified mixtures; the variance of
values estimated to be ,62%. Yields
correspond to isolated and purified
products (62%). Enantiomeric ratios
were determined by HPLC analysis
(62%). See Supplementary
TBS
N
N
Bn
Bn
XI
XII
14a
15a
94% yield, 98:2 e.r.
Br
Br
2.0 mol% 2g,
2.0 mol% NaOt-Bu
c
G
O
HO
O
HO
0.5 mol% 2g,
0.5 mol% NaO t-Bu
G
•
O
O
N
O
O
1.5 equiv. 1a, 2.5 equiv. MeOH,
N
•
Br
Br
N
N
P
1.4 equiv.
H
SEM
toluene, 22 °C, 2.0 h;
MgBr2•Et2O, 22 °C
P
(pin)B
19
14b
15b
14c G = OMe, P = Bn
14d G = H, P = PMB
(performed on gram scale)
20a 91% yield, 98:2 e.r.
20b 90% yield, 96:4 e.r.
2.0 equiv. MeOH, toluene,
22 °C, 1.0 h and 4.0 h
86% yield, 91.5:8.5 e.r.
Me
HO
HO
HO
Me
O
HO
•
0.25 mol% 2g,
0.4 mol% NaOt-Bu
MeO
O
O
O
O
O
N
N
N
•
Bn
N
N
H
TBS
Bn
1.05 equiv.
TBS
(pin)B
19
16
17
18
14a
21 90% yield, >99:1 e.r.
2.0 equiv. MeOH, toluene,
96% yield, 98:2 e.r.
91% yield, 98.5:1.5 e.r.
98% yield, 95:5 e.r.
(performed on
gram scale)
22 °C, 2.0 min;
HO
R
Br
aq. HCl, MeOH, 22 °C
HO
O
O
HO
OH
O
N
H
O3, MeOH,
–78 °C, 5.0 min;
15b
O
Information for details. TBS,
t-butyldimethylsilyl; Bn, benzyl;
PMB, p-methoxybenzyl; SEM,
Me
N
Br
15a
H
>98% allene addition:
<2% propargyl addition
product in all cases
Me
N
NaBH4, –78 22 °C,
20 min
R = COMe: convolutamydine A
R = CH2Cl: convolutamydine B
R = CH2OH: convolutamydine E
n-Bu
H
O
22 89% yield
(>99:1 e.r.)
madindoline A
2-(trimethylsilyl)ethoxymethyl.
2 2 0
| N A T U R E | V O L 4 9 4 | 1 4 F E B R U A R Y 2 0 1 3
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LETTER RESEARCH
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homoallylic amines through reactions of (pinacolato)allylborons with aryl-,
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the enantiomerically pure diol, not easily accessed by an alterna-
tive protocol, can serve as precursor to various derivatives. All allene
additions proceed with complete a selectivity (,2% of propargyl
products detected).
The ease of accessing the present class of catalysts, the importance of
aminesandalcohols to the preparation of biologically activemolecules,
as well as the simplicity, economy and selectivity with which the cata-
lytic transformations proceed, foreshadow a lasting impact on future
efforts in catalyst development and chemical synthesis. Development
of other efficient and enantioselective C–C bond forming reactions
promoted by the present catalyst class is in progress.
METHODS SUMMARY
Preparation of catalyst solution. Aminophenol 2g (15.0mg, 0.049mmol) is
weighed out into a 4 ml vial to which is added 263ml of a solution of sodium
hydroxide (1.95 mg, 0.049mmol) in reagent grade methanol (a 111mg NaOH
pellet (Fisher) is dissolved in 15 ml solvent). After removal of solvent, 0.5 ml of
technical grade anhydrous toluene is added and concentrated in vacuo to remove
residual methanol and water. The resulting white solid is dried at 0.5 torr for
30 min and the vial sealed with a cap containing a Teflon septum. Toluene
(1.0 ml) is added to yield a suspension.
Gram-scale procedure for allyl addition. A round-bottom flask (50 ml, not flame
dried, equipped with a magnetic stirring bar) is charged with imine 3a (1.0 g,
3.3 mmol) and subjected to 0.5 torr for 30 min, purged with dry nitrogen and
sealed with a rubber septum. Toluene (30 ml) is added, followed by allylboronic
acid pinacol ester 1a (800 ml, 4.26 mmol, 1.3 equiv.) from a septum-sealed bottle
(Frontier Scientific, used as received) and methanol (200 ml, 4.92 mmol) from a
septum-sealed bottle (Acros, 99.9% ExtraDry, used as received). A suspension of
the catalyst containing aminophenol 2g (10.1 mg, 0.033mmol) and sodium
hydroxide (1.31 mg, 0.033mmol, 0.01 equiv.) in 0.67 ml toluene is added through
a syringe to the mixture. After two hours, the solvent is evaporated and the residue
is taken up in 30 ml technical grade mixed hexanes. The suspension is subjected to
sonication for two minutes, filtered and washed four times with 3 ml hexanes. The
product is dried at 0.5 torr and obtained in 92% yield (1.04 g, 3.01 mmol, e.r.
97.5:2.5). Elemental analysis for C22H22NOP: calculated; C, 76.06; H, 6.38;
N, 4.03. Found: C, 75.77; H, 6.43; N 3.98.
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Received 28 August; accepted 17 December 2012.
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Supplementary Information is available in the online version of the paper.
Acknowledgements This research was supported by the US National Institutes of
Health, Institute of General Medical Sciences (grant GM-57212). S.T. was a Swiss
National Science Foundation Postdoctoral Fellow; E.M.V. was an AstraZeneca Graduate
Fellow. We thank B. Li for assistance in securing X-ray structures, S. J. Meek,
S. J. Malcolmson and K. L. Tan for discussions, Boston College for providing access to
computational facilities and Frontier Scientific for gifts of various organoboron
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Author Contributions D.L.S. and T.P. were involved in the discovery, design and
development of the catalysts; D.L.S., S.T. and T.P. worked on applications to
enantioselective additions to imines; D.L.S. and E.M.V. developed the enantioselective
allyl and allene additions to isatins, respectively; D.L.S., S.T., T.P. and F.H. carried out
mechanistic and computational studies. A.H.H. conceived, designed and directed the
investigations and wrote the manuscript with revisions provided by D.L.S. and E.M.V.
This work is part of a collaborative programme between A.H.H. and M.L.S. involving the
development of amino acid-derived chiral catalysts.
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perfluoroalkylsulfones: highly efficient catalysts for enantioselective In-mediated
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complexes: selective allylation of sulfonimines with allyl stannane and allyl
trifluoroborate. J. Org. Chem. 72, 4689–4697 (2007).
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper. Correspondence
and requests for materials should be addressed to A.H.H. (amir.hoveyda@bc.edu).
12. Wada, R. et al. Catalytic enantioselective allylation of ketoimines. J. Am. Chem. Soc.
128, 7687–7691 (2006).
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