Catalytic synthesis of β3-amino acid derivatives from α-amino acids

Article abstract of DOI:10.1002/anie.200705310

(Chemical Equation Presented) α goes to β! The catalytic ring-expansive carbonylation of oxazolines, easily derived from α-amino acids, to yield β-amino acid derivatives is described. The catalyst is [HCo(CO)₄]; high yields are observed for mos

Full text of DOI:10.1002/anie.200705310

Angewandte
Chemie
DOI: 10.1002/anie.200705310
b-Amino Acids
Catalytic Synthesis of b3-Amino Acid Derivatives from a-Amino
Acids**
Christopher M. Byrne, Tamara L. Church, John W. Kramer, and Geoffrey W. Coates*
The synthesis of b-amino acids and their derivatives has
garnered considerable interest over the past decades.[1] These
one-carbon homologues of a-amino acids are vital compo-
nents of several pharmaceutics[1c,d,2] and have important roles
in medicinal chemistry[2a] and biochemistry.[3] Pioneering
[4]
workby Seebach et al.
and Gellman et al.[5] has revealed
that incorporating b-amino acids into peptide chains induces
new secondary and tertiary structures and leads to biological
activity in select cases. Central to all of these applications is
the use of stereochemically pure b-amino acids, and recently
reported enantioselective routes include Mannich reactions,[6]
Kowalsky rearrangements,[7] radical reactions,[8] isoxazoline
intermediates,[9] organocatalysis,[10] and enzymatic hydrolysis
of b-lactams.[11] The use of transition-metal catalysis shows
promise for the generation of enantiomerically pure b-amino
acid derivatives[12] and current research focuses on asymmet-
ric hydrogenation reactions using Rh catalysts.[13] Classic
synthetic methods such as the Arndt–Eistert protocol work
well for the b3-amino acids, but the hazardous nature of
diazomethane and high cost of silver render it undesirable for
large-scale synthesis.[1]
Given our previous workon the carbonylation of hetero-
cycles,[14] we were interested in two reports from Jia and co-
workers[15] on the catalytic carbonylation of 2-oxazolines to
give 2-oxazin-6-ones, which are precursors to b-amino acids.
The system featured benzyl tetracarbonylcobalt(I) as the
catalyst, and although 2-phenyl-2-oxazoline was converted
cleanly to oxazinone (19 turnovers in 48 h), 4- and 5-
substituted oxazolines were quite challenging (< 10 turnovers
in 48 h). We believed that our Lewis acid based carbonylation
catalysts could effect this transformation quickly and effi-
ciently. Though these catalysts may improve the carbon-
ylation step, the benefit of this method is the ease and
generality of substrate synthesis (Scheme 1). There are many
synthetic pathways to oxazolines;[16] we focused on those
using b-amino alcohols due to their commercial availability
and accessibility by a-amino acid reduction. The overall
synthetic pathway, shown in Scheme 1, begins with a bio-
Scheme 1. Synthetic pathway from a-amino acids to b-amino acids via
oxazoline carbonylation.
renewable, stereochemically rich resource and yields enan-
tiomerically pure b-amino acids.
We began investigating catalysts of the form [Lewis
acid]+[Co(CO)4]À, which demonstrate good activity for
epoxide, aziridine, and b-lactone carbonylation.[14,17] Though
these complexes showed poor activity for oxazoline carbon-
ylation, we continued to pursue an active catalyst system for
this transformation. Related workby Murai and co-workers
on the carbonylation of epoxides,[18a] oxetanes,[18b] and ben-
zylic esters[18c] using HSiR3/[Co2(CO)8] systems led to the
selection of [Ph3SiCo(CO)4] (1) as a candidate. The complex
is readily synthesized by the addition of two equivalents of
Ph3SiH to a hexanes solution of [Co2(CO)8].[17,19]
Our initial experiments focused on the carbonylation of a
representative substrate, 4-ethyl-2-phenyl-2-oxazoline, which
proceeded smoothly in 75% yield using 1 in tetrahydropyran
(THP) [Eq. (1)]. We examined the effect of a tert-butyl group
[*] Dr. C. M. Byrne, Dr. T. L. Church, J. W. Kramer, Prof. Dr. G. W. Coates
Department of Chemistry and Chemical Biology
Cornell University
Baker Laboratory, Ithaca, NY 14853-1301 (USA)
Fax: ( +1)607-255-4137
E-mail: gc39@cornell.edu
in the 4-position of the aromatic ring and found that the
presence of this substituent increased the yield to 94% using
the same conditions. Although this change in reactivity is
significant, we discovered that the reaction medium had a
greater effect on the yield of oxazinone.
We surveyed a collection of solvents diverse in dielectric
constant and donor ability, and the results are shown in
Table 1. The highest conversions to oxazinone were obtained
[**] We are grateful to the Department of Energy (DE-FG02-05ER15687)
for financial support. We thank Dr. E. B. Lobkovsky for X-ray
crystallographic assistance, J. M. Rowley for help with in situ IR
experiments, and NSERC Canada for financial support to T.L.C.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Solvent effect on oxazoline carbonylation using 1.[a]
oxazoline species.[17] Moreover, the absence of peaks repre-
senting either [HCo(CO)4] or H2 indicates that there is no
significant free [HCo(CO)4] present under these conditions.
Therefore, we conclude that the alcoholysis of 1 in the
presence of oxazoline generates an oxazolinium cobaltate
species (Scheme 2, A), which is similar to previously reported
trialkylammonium cobaltate salts.[23]
Entry
Solvent
Yield[b] [%]
1
2
3
4
5
toluene
1,4-dioxane
tetrahydrofuran
1,2-dimethoxyethane
tetrahydropyran
19
38
95
95
94
1
On the basis of the IR and H NMR data and the results
from the solvent-screening reactions,[17,24] we established a
standard set of conditions (54 atm CO, 808C, 6 h) and
examined the use of 1 and BnOH (1:1) as a catalyst system
for the carbonylation of oxazolines, which were derived from
an assortment of a-amino acids (Table 2). In general,
[a] All reactions were performed using 2 mol% 1, 1 mmol substrate,
60 atm CO, 2 mL solvent, 808C, 24 h. [b] Yield of oxazinone determined
by 1H NMR spectroscopy.
Table 2: Carbonylation of 4-substituted oxazolines using 1/BnOH.[a]
for carbonylations using tetrahydrofuran (THF), 1,2-di-
methoxyethane (DME), or THP, though reactions run in
THF or DME displayed a lackof reproducibility. Intrigued by
these results, we monitored a typical carbonylation reaction of
2-(4-tert-butylphenyl)-4-methyl-2-oxazoline (2a) in THP
using in situ IR spectroscopy. We observed an initiation
period before relatively clean consumption of oxazoline
occurred.[17] Previous workby Murai demonstrated that
HSiR3/[Co2(CO)8] systems are capable of ring-opening
THF[20] and, on the basis of his work, we hypothesized that
a similar reaction between THP and 1 might be generating an
alkylcobalt species. b-Hydride elimination from this species
would produce [HCo(CO)4], which could serve as the active
catalyst. We pursued the alcoholysis of the silicon–cobalt
bond as a reproducible route to [HCo(CO)4] by adding a
stoichiometric amount of methanol to a toluene solution of 1.
The carbonylation of 2a using 1/MeOH under standard
reaction conditions was monitored by in situ IR spectroscopy
and displayed a markedly higher reaction rate and no
induction period.[17]
The indication from these in situ IR reactions is that
[HCo(CO)4] is generated by the reaction of methanol and 1,
and is acting as the catalyst. However, direct observation of
the cobalt–hydride species was not possible by IR spectros-
copy due to overlap of the [HCo(CO)4] signals with those of
the instrument window. To observe [HCo(CO)4] directly, we
examined the reaction between benzyl alcohol and 1 by
1H NMR spectroscopy. In C6D6, the reaction between BnOH
and 1 did yield [HCo(CO)4] (d = À11.6 ppm),[21] albeit slowly
and with significant decomposition to H2 and a red cobalt
species.[22] To more closely emulate reaction conditions, we
performed the reaction in [D10]Et2O. The combination of 1
and BnOH immediately generated an equivalent of
[HCo(CO)4], which decomposed to H2 and [Co2(CO)8] over
the course of 16 h. Though the production of [HCo(CO)4] in
ether solvent is clean and efficient, instability is problematic.
To further approximate carbonylation conditions, the reaction
of BnOH and 1 was repeated in the presence of oxazoline 2h,
as this substrate is slower to react under typical carbonylation
conditions (vide infra). The 1H NMR spectrum of this
combination is consistent with the formation of Ph3SiOBn
and a new oxazoline-derived product. The downfield shift of
the oxazoline resonances and the presence of a broad singlet
near d = 12 ppm indicate the presence of a protonated
Entry
Oxazoline (R)
mol% 1
Yield[b] [%]
1
2
3
4
5
6
7
2a (Me)
2b (Et)
2c (iBu)
2d (CH2Ph)
2e (CH2OSiMe2tBu)
2 f (iPr)
1
3
3
3
3
97
99
99
99
99
99
86
5
10
2g (Ph)
[a] All reactions were performed using [1]/[BnOH]=1, [2]=0.5m in
DME, 54 atm CO, 808C, 6 h. [b] Yield of oxazinone determined by
1H NMR spectroscopy; yields of isolated, analytically pure compounds
are ca. 90% of spectroscopic yields.
reactivity declined with increasing steric bulkat the 4-
position. The 4-methyl- (2a, entry 1) and 4-ethyl-substituted
oxazolines (2b, entry 2) required 1 and 3 mol% of the catalyst
system, respectively. Attempted carbonylation of 2b using
lower CO pressure (6.8 atm) gave roughly an 80% yield of
oxazinone and about 11% yield of an E/Z mixture of 4-tert-
butyl-N-(1-methylpropenyl)benzamide.[17]
Oxazolines
derived from leucine (2c, entry 3), phenylalanine (2d,
entry 4), and serine (2e, entry 5) were all carbonylated
cleanly to the corresponding oxazinones using 3 mol% 1/
BnOH. Larger substituents at the 4-position, such as isopro-
pyl (2 f, entry 6) or phenyl groups (2g, entry 7) required more
catalyst, but were still carbonylated in high yield.
The catalytic carbonylation of oxazolines is applicable to
the synthesis of a range of racemic 4-substituted oxazinones,
which complements exciting recent workby Berkessel et al.
on the kinetic resolution of oxazinones using thiourea-based
organocatalysts.[25] However, we sought to establish this route
as a direct approach to stereopure oxazinones and therefore
enantiopure b-amino acids. To this end, we synthesized
oxazolines bearing 4R-ethyl ((R)-2b), 4S-isobutyl ((S)-2c),
4S-isopropyl ((S)-2 f), and 4R-phenyl ((R)-2g) substituents
(Table 3). The retention of configuration at the 4-position was
demonstrated by derivatization of the racemic and enantio-
pure
oxazinones
with
(S)-(À)-a-methylbenzylamine
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Table 3: Carbonylation of enantiopure oxazolines using 1/BnOH.[a]
than for the racemic substrate (43% vs. 50%), the reaction
Oxazoline[b]
Oxazinone[c]
mol% 1
ee[d] [%]
produced (S)-3h cleanly. Derivatization of these oxazinones
gave products similar to the 4-substituted derivatives. Char-
acterization of the enantiopure b-benzamido alkanamide
(S,S)-4h using NMR spectroscopy and x-ray crystallogra-
phy[17] supports the inversion of configuration at the 5-
position of the oxazoline ring.
Drawing upon the mechanistic implications of the NMR
studies, the carbonylation results, and the mechanisms of
other carbonylation reactions, we propose a catalytic cycle for
Entry
1
3
>99
2
3
4
3
5
>99
>99
>99
the carbonylation of oxazolines using
1 and BnOH
(Scheme 2). The results of the NMR experiments indicate
that the generation of an oxazolinium cobaltate ion pair A is
facile in ether solvent.
10
[a] All reactions were performed using [1]/[BnOH]=1, [2]=0.5m in
DME, 54 atm CO, 808C, 6 h. [b] Ar=4-tBuC6H4; >99% ee, determined
by chiral HPLC. [c] Isolated and spectroscopic yields comparable to
those of the racemic substrates (Table 2). [d] Determined by 1H NMR
spectroscopy of (S)-(À)-a-methylbenzylamine derivatives; see Support-
ing Information.
1
[Eq. (2)]. The difference in H NMR chemical shifts of the
diastereomers allowed for the determination of diastereo-
meric excess, and therefore, enantiomeric purity of the
oxazinone.[17] In all cases, the oxazinones retained the
absolute configuration of the oxazoline precursor.[26] The x-
ray crystal structure of (R,S)-4 f displays retention at the 4-
position, as the N-(S)-a-methylbenzyl center allows the
absolute configuration to be assigned.[17]
In addition to 4-substituted oxazolines, we attempted the
carbonylation of 2-(4-tert-butylphenyl)-5-methyl-2-oxazoline,
2h [Eq. (3)]. This substrate suffered from lower activity, and
required 10 mol% catalyst to achieve only 50% conver-
sion.[27] This reduced reactivity, also observed by Jia,[15a] is
likely due to the sterics at the 5-position, as the isomeric 4-
methyl derivative was cleanly carbonylated in high conver-
sion using only 1 mol% catalyst (Table 2, entry 1). Despite
the lower conversion to oxazinone for this substrate, we
examined the carbonylation of the 5R-methyl derivative, (R)-
2h, with 10 mol% catalyst. Though yield was slightly lower
Scheme 2. Proposed catalytic cycle for oxazoline carbonylation using
1/BnOH system (Ar=4-tBuC6H4).
Nucleophilic attackby the [Co(CO) ]À at the 5-position
4
inverts this center and creates B, a b-amido alkylcobalt
species. Migratory insertion and uptake of CO, which are
well-documented,[28] produce the acyl–cobalt species C. There
is precedent for the ring closing of b-amido acids to give 2-
oxazin-6-ones,[29] and C should exhibit analogous reactivity,
resulting in the ion pair D. Ring closing through the nitrogen
atom to give a b-lactam should be energetically unfavorable;
no b-lactam product is observed under any conditions. The
cycle is completed by proton transfer from D to oxazoline,
regenerating A with extrusion of oxazinone. On the basis of
preliminary in situ IR kinetic studies, ring closing is rate
limiting for 4-substituted oxazolines, whereas ring opening is
rate limiting for 5-substituted oxazolines. The 4-tert-butyl
group on the aryl ring may facilitate either the protonation
step (generation of A) or the ring-closing step (generation of
D) or both by creating a more electron-rich substrate.
We have described a synthetic transformation for the
generation of both racemic and enantiopure 4- and 5-
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Communications
62, 5831 – 5854; c) E. Forró, T. Paal, G. Tasnadi, F. Fulop, Adv.
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[12] For a review, see: J. A. Ma, Angew. Chem. 2003, 115, 4426 – 4435;
Angew. Chem. Int. Ed. 2003, 42, 4290 – 4299.
substituted 2-aryl-2-oxazin-6-ones via the carbonylation of
oxazolines using a silylcobalt precatalyst. The oxazinones are
labile compounds that can be ring opened by nucleophiles
such as amines and alcohols, or hydrolyzed directly to yield b-
amino acids. In addition, this workdemonstrates a new
methodology for the generation of [HCo(CO)4] in a con-
trolled manner that is applicable to other areas of carbon-
ylation chemistry. Given the ease of catalyst and substrate
synthesis and the wealth of commercially available a-amino
acids, the carbonylative ring expansion of oxazolines is a
significant contribution to the synthesis of stereopure b-
amino acid derivatives.
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Received: November 19, 2007
Revised: January 25, 2008
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Published online: April 11, 2008
Keywords: amino acids · carbonylation · cobalt ·
.
insertion reactions · ring expansion
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its assignment has changed due to the change in priority from
oxygen to carbon.
[27] Carbonylation of 2h using 5 mol% 1/BnOH for 6 h yielded 37%
oxazinone 3h. Longer reaction time (24 h) and higher catalyst
loading (10 mol%) left no signs of either oxazoline 2h or
oxazinone 3h, but gave exclusively 2-(4-tert-butylphenyl)-4-
ethyl-2-oxazalone. For details, see C. M. Byrne, Ph.D. thesis,
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