Catalytic asymmetric propargyl- and allylboration of hydrazonoesters: a metal-free approach to sterically encumbered chiral α-amino acid derivatives

Article abstract of DOI:10.1039/c8cc07908k

A new asymmetric catalytic propargyl- and allylboration of hydrazonoesters is reported. The reactions utilize allenyl- and allylboronic acids in the presence of the inexpensive parent BINOL catalyst. The reactions can be performed under mild conditions (0 °C) without any metal catalyst or other additives affording sterically encumbered chiral α-amino acids. This is the first metal-free method for the asymmetric propargyl- and allylboration of hydrazonoesters.

Full text of DOI:10.1039/c8cc07908k

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Catalytic asymmetric propargyl- and allylboration
of hydrazonoesters: a metal-free approach to
sterically encumbered chiral a-amino acid
derivatives†
Cite this: Chem. Commun., 2018,
54, 12852
Received 3rd October 2018,
Accepted 24th October 2018
a
Sybrand J. T. Jonker, ‡a Colin Diner, ‡a Goran Schulz,
Hiroaki Iwamoto,a
¨
DOI: 10.1039/c8cc07908k
a
Lars Erikssonb and Kalman J. Szabo
*
´
´
´
rsc.li/chemcomm
A new asymmetric catalytic propargyl- and allylboration of hydrazono-
esters is reported. The reactions utilize allenyl- and allylboronic acids in
the presence of the inexpensive parent BINOL catalyst. The reactions
can be performed under mild conditions (0 8C) without any metal
catalyst or other additives affording sterically encumbered chiral
a-amino acids. This is the first metal-free method for the asymmetric
propargyl- and allylboration of hydrazonoesters.
Unnatural a-amino acids represent a very important class of
bioactive compounds in life sciences. As a consequence, there
has been great interest in developing new methodologies for
their synthesis, in particular for the synthesis of chiral a-amino
acids.1 However, finding efficient methods for the enantio- and
diastereoselective de novo formation of stereocenters in amino
acid products is still a challenging task.2 One strategy towards
this goal is the enantioselective addition of organoboron
species3 to a-iminoesters (Fig. 1). The highly selective allyl-4 and
Fig. 1 Asymmetric propargyl- and allylboration of iminoesters for the
synthesis of a-amino acid derivatives.
Recently, we have published several studies on the application
propargylboration5 of ketones and imines has been demonstrated of allyl-11 and allenylboronic12 acids for asymmetric allyl-6a,b and
in many recent studies.6 However, the allyl- and propargylboration propargylations12 under metal-free conditions using BINOL-
of iminoesters for the direct synthesis of a-amino acids is less based organocatalysts. These methods take advantage of the
developed. Kobayashi and co-workers7 have shown that Zn-catalyzed unusually compact cyclic transition states provided by allylboron
allylboration of hydrazonoesters can be used for the asymmetric reagents that enable high levels of enantio- and diastereoselec-
synthesis of allylated a-amino acids (Fig. 1a). Subsequently, an tivity. In addition, the high reactivity of allyl- and allenylboronic
In-catalyzed variant of this reaction was reported.8 Recently, acids allows coupling of densely substituted organoboron species
Pyne and co-workers9 demonstrated that N-tert-butylsulfinyl opening a new route for the synthesis of sterically encumbered
imines undergo In-catalyzed couplings with allenylboron species chiral a-amino acids. Here we present the first report on asym-
(Fig. 1b). This reaction proceeds with high stereoselectivity affording metric synthesis and catalysis using metal-free allyl- and propargyl-
propargylated a-amino acids. Related methods can also be used for boration of hydrazone substrates.
the synthesis of racemic a-amino acids.10
Beyond its obvious environmental impact, developing metal-
free allyl- and propargylborations has important implications
regarding the stereochemical model of this class of reactions.
One of the main reasons for using Zn or In catalysis (Fig. 1a
and b) in allyl- and propargylborations is that replacing the
boron atom with a different metal can make the reagent more
reactive or enable a stronger interaction with a chiral element
(ligand or coordinating moiety on electrophiles) to achieve
efficient stereoinduction. The flip side of this strategy is that the
interaction distance between the metal atom and the Lewis-base
a Department of Organic Chemistry, Stockholm University, SE-106 91 Stockholm,
Sweden. E-mail: kalman.j.szabo@su.se
b Department of Materials and Environmental Chemistry, Stockholm University,
SE-106 91 Stockholm, Sweden
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and compound characterization data are given. CCDC 1850578. For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8cc07908k
‡ These authors contributed equally to this work.
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(nitrogen or oxygen center) will be longer13 than that with the yield (25%, entry 6). We did not observe product formation (4a)
original boron reagent. DFT calculations on the allylboration of in the absence of BINOL catalysts (entry 7). Under these conditions
imines and ketones indicate short (1.5–1.7 Å) C–O and C–N (0 1C), 2 was practically insoluble in toluene. At room temperature,
bonds in the TS.14 A compact TS is beneficial for stereo- racemic 4a was formed with 68% yield without BINOL catalysts
selectivity because it capitalizes steric repulsions between the (entry 8). In previous studies, we have noticed15 that hydrazones
interacting substituents in the competing TS structures. Here, have a poor solubility in toluene, and therefore the racemic
we report our new method for a highly selective metal-free allylboration reactions were conducted in DMSO as a solvent.15
propargyl- and allylboration reaction affording a-amino acids These studies also indicated that only benzoyl hydrazones (such
with one or two new stereocenters (Fig. 1c).
as 2) reacted with allylboronic acids, while other hydrazones
After optimization of the reaction conditions, we observed did not give any coupling product.15
that benzoyl hydrazone 2 reacted with allenylboronic acid 3a in
With the above optimization results in hand, we studied the
the presence of BINOL 1a (10 mol%) to afford the propargylated synthetic scope of the reaction (Table 2). First, we studied
a-amino acid 4a with high enantioselectivity (e.r. 96 : 4) and in the effects of replacement of 3a with other tetrasubstituted
good yield (79%) when the reaction was conducted in toluene at allenylboronic acids (entries 1–5) and replacement of 1a with its
0 1C (Table 1, entry 1). The reaction proceeds smoothly with a enantiomer. As expected, when (R)-BINOL (entry 2) was employed
sterically encumbered (tetrasubstituted) allenylboronic acid instead of (S)-BINOL 1a (entry 1), 4b was formed, which is the
derivative (3a) without any metal catalyst or additive. Deviation enantiomeric form of 4a. The yield and selectivity were nearly
from the above optimal conditions led to either lower selectivity identical in the two reactions, confirming that our method is
or yield (entries 2–8) for the formation of 4b. When the reaction suitable for the efficient synthesis of both enantiomers of the
time of 48 hours was decreased to 24 hours, product 4a was propargylated a-amino acids. Trimethyl substituted allenylboronic
obtained in a lower yield without any significant change in the acid 3b reacted with a bit lower selectivity (e.r. 92 : 8) than 3a
enantioselectivity (entry 2). Application of a larger amount (entry 3). The replacement of the terminal methyl groups with
(20 mol%) of the BINOL (1a) catalyst did not alter the yield or a cyclohexyl ring (3c) did not alter the enantioselectivity
the selectivity (entry 3). At room temperature, the enantio- (c.f. entries 4 and 1). Likewise, the replacement of the butyl
selectivity (e.r. 88 : 12) was significantly lower than that at substituent on the borylated carbon of 3a, such as in 3d–e,
0 1C (e.r. 96 : 4, entry 4). In our previous studies on asymmetric allowed for highly selective reactions to the corresponding
allyl- and propargylborations, we observed that the addition a-amino acid derivatives 4d–e (entries 5 and 6).
of aliphatic alcohols, such as EtOH, led to an increase in
To our delight, even allylboronic acids, such as 3f–g, can be
enantioselectivity.6a,b,12 However, the addition of only 2 equiv. employed in this asymmetric functionalization of hydrazono-
of EtOH to the reaction mixture led to a major decrease in ester 2. Under the same conditions, geranylboronic acid11 3f
enantioselectivity from an e.r. of 96 : 4 (entry 1) to 50 : 50 (entry 5). gave a-amino acid 4g in good selectivity (e.r. 92 : 8) and yield
This drastic change in selectivity is a clear indication of the (71%). As 3f is a g-disubstituted allylboronic acid, two adjacent
mechanistic differences for the allylboration of hydrazones stereocenters were formed, one of which being quaternary
(such as 2) and other species, such as ketones and imines. In (entry 7). The selective formation of quaternary all carbon stereo-
the allylation- and propargylation of imines and ketones with centers in acyclic molecules is still considered a challenge in
allyl- and propargylboronic acids, substituted BINOLs, in parti- organic synthesis.16 An important requirement in modern drug
cular bromo-BINOL 1b, always outperformed the parent BINOL development is finding synthetic routes to all stereoisomeric
1a in regards to enantioselectivity. However, the enantioselec- forms of the potentially bioactive compounds with two or multiple
tivity with bromo-BINOL 1b (e.r. 64 : 36, entry 6) was much stereocenters.17 We have found that all four stereoisomeric
lower than that with BINOL 1a (e.r. 96 : 4, entry 1). In addition, a-amino acids 4g–j can be synthesized in good selectivity/yield
the application of 1b instead of 1a led to a major decrease in using this method. Application of (R)-BINOL leads to the
selective formation of 4h, which is the enantiomer of 4g. An
epimer of 4g, compound 4i, can be prepared from nerylboronic
acid11 3g (which is the stereoisomer of 3f). a-Amino acid 4j
Table 1 Variation of reaction conditions for the propargylboration of
hydrazone 2
(enantiomer of 4i and epimer of 4g and 4h) can be prepared by
allylboration of hydrazonoester 2 with nerylboronic acid 3g in
the presence of catalytic amounts of (R)-BINOL (entry 10). The
reactions can be easily scaled up. A 10-fold scale-up of the
reaction of 2 with 3a afforded 4a with practically the same yield
and selectivity, like the reaction on a 0.1 mmol scale (entry 1).
We were not able to obtain crystals of products 4a–j, which
would be suitable for X-ray structure determination, and there-
Entry Catalyst
Additive
t (h) T (1C) Yield (%) e.r.
1
2
3
4
5
6
7
8
10 mol% 1a None
10 mol% 1a None
20 mol% 1a None
10 mol% 1a None
10 mol% 1a 2 equiv. EtOH 48
10 mol% 1b None
No catalyst
No catalyst
48
24
48
24
0
0
0
r.t.
0
0
0
79
67
78
83
52
25
0
96 : 4
95 : 5
97 : 3
88 : 12 fore the absolute configurations were determined by analysis of
the corresponding Mosher amides (see the ESI†).18 A similar
50 : 50
64 : 36
N/A
48
48
24
method was used for determining the absolute configuration of the
None
None
r.t.
68
50 : 50 amino substituted stereocenter in 4g. The relative configuration of
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Table 2 Catalytic asymmetric allylboration and propargylboration of
hydrazonoester 2 using various boronic acidsa
Yieldb
t (h) (%)
Entry Boronic acid
1
Product
e.r.
79
75c
48
96 : 4
2d
3e
3a
48
48
81
66
96 : 4
92 : 8
Fig. 2 Proposed stereoinduction model for the asymmetric propargylation
of hydrazonoester 2 with BINOL ester 5.
previous models on the propargylboration of ketones, we
suggest that esterification of allenylboronic acid 3a leads to
the formation of boronic ester 5. Previously, we have performed
NMR studies, which indicated that the B(OH)2 functionality
in allylboronic acids undergoes diesterification with BINOL
derivatives.6a In addition, our DFT modeling studies on the
asymmetric allylboration of imines with allylboronic acids have
shown14b that the formation of BINOL esters (such as 5) leads to
a considerable increase in the Lewis acidity of the boron atom,
and thus an acceleration of the reactions. The steric inter-
actions at the TS are dependent on which face of prochiral 2 is
attacked by chiral species 5. In the case of the Si-face attack
(TS1), the C30–H bond of (S)-BINOL 1a and the COOEt moiety
are in close proximity. This (or any other) clash is absent in the
Re-face arrangement (TS2), which leads to the favored product
4a. Indeed, 4a was formed in high selectivity (e.r. 96 : 4) in the
above reaction (Table 1, entry 1). As mentioned above, 2 has a
very poor solubility in toluene at 0 1C, which may explain why
racemic propargylboration in the absence of BINOL did not
occur (Table 1, entry 7). The poor performance of bromo-BINOL
1b (Table 1, entry 6) is probably due to possible clashes even in
a TS2-like transition state, for example by the (long) C3–Br bond
and the NHCOPh group of 2. Accordingly, when bromo-BINOL
1b is applied as a catalyst, the C30–Br bond is supposed to clash
with the COOEt moiety in a TS1-type of transition state, while
the C3–Br bond and the NHCOPh group would clash in TS2
rendering both transition states sterically hindered. The rela-
tively low yield (25%) in the case of application of bromo-BINOL
1b (Table 1, entry 6) indicates a slow reaction, which is probably
the consequence of the relatively high activation barrier raised
by both the TS1- and TS2-types of transition states.
4
5
24
72
63
66
96 : 4
95 : 5
6
48
56
96 : 4
92 : 8
(97 : 3 dr)
7
48
48
71
78
92 : 8
(97 : 3 dr)
8d
3f
92 : 8
(98 : 2 dr)
9
48
48
81
75
92 : 8
(98 : 2 dr)
10d
3g
a
Unless otherwise stated, 2 (0.1 mmol), 3 (0.12 mmol) and 1a
(0.01 mmol, 10 mol%) were reacted in toluene at 0 1C in the presence
b
c
of molecular sieves (3 Å) MS. Isolated yields. 1 mmol of 2 was applied.
A simplified stereoinduction model is presented for the
allylboration reaction of 2 and 3f in the presence of (S)-BINOL
1a in Fig. 3. In the case of the Re-face approach (TS3), there is
no major clash between the COOEt moiety of 2 and the C30–H
d
(R)-BINOL (10 mol%) was used as a catalyst instead of (S)-BINOL 1a.
e
The reaction temperature was ꢀ10 1C.
the stereocenters was determined by derivatization of 4h (see bond of (S)-BINOL ester 6. The relative stereochemistry of the
the ESI†), which gave a crystalline product suitable for X-ray newly formed stereocenters is controlled by the E-configuration
analysis.
of the COOEt and NHCOPh functionalities along the CQN
A stereoinduction model for the propargylborylation reac- bond of 2. A proposed mechanism for the catalytic cycle for
tion is given in Fig. 2. For simplicity, we selected the reaction of propargylboration of 2 with 3a in the presence of BINOL 1a is
2 with 3a in the presence of 1a in this model. Similarly to our presented in the ESI.†
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propargyl- and allylboration of hydrazonoester 2 can be per-
formed in very high selectivity in the presence of inexpensive
BINOL. The reaction results in a-amino acids with high enantio-
selectivity and in generally good yields. The reactions can be
performed without the application of metal catalysts, which is
probably beneficial for the very high selectivity. In fact, this study
presents the first metal-free asymmetric propargyl- and allylbora-
tion of hydrazones. In this reaction densely substituted allenyl-
and allylboronic acids can be employed opening a new route to
asymmetric synthesis of sterically encumbered a-amino acids.
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We are grateful to Mr Erik Ulriksson Ardehed for performing
some of the experiments. Support from the Swedish Research
Council is greatly appreciated. An ERASMUS stipend for G. S. is
gratefully acknowledged. H. I. thanks the Japan Society for the
Promotion of Science (JSPS) for financial support. A generous
gift of B2(OH)4 from Allychem is highly appreciated.
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There are no conflicts to declare.
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