Synthesis of γ-amino esters via Mn-mediated radical addition to chiral γ-hydrazonoesters

Article abstract of DOI:10.1021/ol802932v

Highly stereoselective Mn-mediated couplings of alkyl iodides with chiral N-acylhydrazones bearing ester functionality afford a series of γ-hydrazino esters, including γ-substituted, α,γ-disubstituted, and α,α,γ-trisubstituted examples. In contrast to prior work with chiral N-acylhydrazones, high stereoselectivity was observed even in the absence of Lewis acid. Microwave-assisted acylation with trifluoroacetic anhydride and reductive N-N bond cleavage provided the γ-amino ester functionality in a synthetically useful N-TFA-protected form.

Full text of DOI:10.1021/ol802932v

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1095-1098
Synthesis of γ-Amino Esters via
Mn-Mediated Radical Addition to Chiral
γ-Hydrazonoesters
Gregory K. Friestad* and Koushik Banerjee
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242
gregory-friestad@uiowa.edu
Received December 19, 2008
ABSTRACT
Highly stereoselective Mn-mediated couplings of alkyl iodides with chiral N-acylhydrazones bearing ester functionality afford a series of
γ-hydrazino esters, including γ-substituted, r,γ-disubstituted, and r,r,γ-trisubstituted examples. In contrast to prior work with chiral
N-acylhydrazones, high stereoselectivity was observed even in the absence of Lewis acid. Microwave-assisted acylation with trifluoroacetic
anhydride and reductive N-N bond cleavage provided the γ-amino ester functionality in a synthetically useful N-TFA-protected form.
In contrast to R- and ꢀ-amino acids, general synthetic
methods to supply γ-amino acids are comparatively under-
developed.1 Interest in biologically important γ-amino acids
is expanding along with discoveries of their roles as agonists
and antagonists of receptors for the neurotransmitter γ-ami-
nobutyric acid (GABA) (Figure 1), of their presence as
substructures in unusual peptide natural products,2 and of
Figure 1. Structures of GABA and substituted γ-amino acids.
the conformational constraints they impart to peptides.3
General C-C bond construction routes to γ-substituted
γ-amino acids typically involve homologation of R-amino
acids.4 Alternatives to this strategy assume greater importance
when uncommon γ-substituents are present or when there
are substitutions at the R and ꢀ carbons, but few C-C bond
construction approaches take this into account in a general
way.5
Our interest in γ-amino acids originated because two
unique examples, tubuvaline and tubuphenylalanine (Figure
2), are prominently featured in the tubulysins, a series of
extraordinarily potent tubulin-active cytotoxins.6 We previ-
ously reported novel routes to these R-substituted γ-amino
acids exploiting free radical addition7 to chiral N-acylhy-
drazones,8,9 in which silyl ethers at the C-termini of 1 and
2 were later oxidized to carboxylic acid functionality.10 The
Mn-mediated radical addition conditions we developed for
this purpose exhibited excellent chemoselectivity and func-
tional group tolerance,11 and we began to question whether
the efficiency and generality of this approach to γ-amino
acids could be augmented if the C-terminus were to be
already in the carboxylic acid oxidation state. Here we report
the results of our test of this hypothesis, revealing that
γ-hydrazonoesters are indeed excellent radical acceptors in
Mn-mediated coupling with alkyl iodides.
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Kauffman, C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2007, 9, 1525–
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10.1021/ol802932v CCC: $40.75
Published on Web 02/06/2009
2009 American Chemical Society

of 3a-3d to the corresponding aldehydes 4a-4d,14 and
condensation with N-aminooxazolidinone 515 provided chiral
γ-hydrazonoesters 6a-6d. Isolation of small quantities of
aldehydes 4b14a and 4c14c in pure form was best avoided
due to their volatility, and yields of 6b and 6c are reported
over four-step and two-step sequences, respectively, without
purification of intermediates. Specifically, the ester 3b was
obtained from the corresponding N-acyloxazolidinone (a
known Evans allylation product,16 not shown) by successive
treatment with LiOOH and CH2N2, followed by oxidation
and condensation as shown in Scheme 1 to furnish 6b in
43% overall yield for the four steps.
Figure 2. Precursors of tubuvaline and tubuphenylalanine, in which
the C-termini required oxidation (ref 10).
Scheme 1
The study began with series of 4-pentenoate esters 3a-3d
(Scheme 1) which were either commercially available or
were known compounds prepared via modifications of
published methods.12 Lemieux-Johnson oxidation employ-
ing the Jin protocol13 oxidatively cleaved alkene functionality
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4048.
With several γ-hydrazonoesters in hand, prototypical
isopropyl radical additions were examined using the Mn-
mediated photolysis conditions. With InCl3 as the Lewis acid,
coupling of isopropyl iodide and hydrazone 6a (Table 1,
entry 1) afforded a quantitative yield of 7a in very high
diastereomeric purity.
Next, several hydrazones bearing varied substitution at the
R-position of the γ-hydrazonoester were employed for
addition of 2-iodopropane (Table 1, entries 2-4). Smooth
Mn-mediated radical addition occurred with R-methyl, R,R-
dimethyl, and R-benzyloxy-substituted γ-hydrazonoesters, all
providing the isopropyl adducts with consistently high
diastereoselectivities and excellent yields (91-98%). This
small group of substrates 7a-7d offers a brief scan of both
steric and electronic effects, and within this group the
reaction efficiency and selectivity appear to be largely
independent of substitution at the R-position.
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Analysis of the diastereomer ratios recorded in Table 1
called for a standard containing both diastereomers, so the
Mn-mediated addition was attempted in the absence of InCl3.
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Org. Lett., Vol. 11, No. 5, 2009

The purpose of the InCl3 in these reactions is 2-fold: the
chelation of bidentate N-acylhydrazones with the Lewis acid
(a) activates the CdN bond toward radical addition by
lowering its LUMO energy and (b) assists in discriminating
the re and si faces at the prochiral imino carbon by restricting
rotamer populations.8,9 Thus, Mn-mediated radical additions
in the absence of InCl3 would be expected to furnish low
diastereoselectivity. Surprisingly, the selectivity was only
slightly diminished (dr 91:9) for isopropyl addition to 6a
(Table 1, entry 5); the yield was modest, as expected. For
hydrazone 6d, the diminished selectivity in the absence of
InCl3 was also observed, and the yield was maintained at a
synthetically useful level (entry 6).
Figure 3.
Affects of InCl3 on 1H and 13C chemical shifts of
γ-hydrazonoester 6a.
and primary iodides (Table 2). Both isopropyl and sec-butyl
groups added more efficiently in the presence of InCl3, as
previously observed in Table 1. Analysis of diastereomerism
in the sec-butyl addition, where an additional new stereo-
center is formed, has not yet been addressed.
Table 1. Mn-Mediated Addition of i-PrI to γ-Hydrazonoestersa
Previously, we have shown that the Mn-mediated pho-
tolysis conditions enable challenging radical additions of
primary iodides.9-11 This class of radical precursor generally
gives low yields or mixtures of products in Et3B- or tin-
mediated additions. When primary iodides were subjected
to coupling with γ-hydrazonoester 6a, the desired adducts
were obtained in moderate yields (33-66%, Table 2, entries
3-8) and excellent diastereoselectivity. Silyl ether and
alcohol functionality were accommodated. Upon repeating
these reactions under In-free conditions, there was no clear
trend of diminished yields, in contrast to the observations
with secondary iodides. Interestingly, the additions of
homologous alcohols (entries 5 and 6) showed opposite
effects of the InCl3 on the yield. In most cases, the additions
of primary iodides showed an erosion of diastereoselectivity
when carried out in the absence of InCl3.
entry
γ-hydrazonoester
InCl3
yield
drb
1
2
3
4
5
6
6a
6b
6c
6d
6a
6d
2.2 equiv
2.2 equiv
2.2 equiv
2.2 equiv
0 equiv
>99%
98%
96%
96%
32%
75%
94:6
95:5
99:1
90:10c
91:9
0 equiv
85:15c
a Conditions: InCl3 (2.2 equiv) and γ-hydrazonoester in CH2Cl2 (0.02
M), 2 h, then Mn2(CO)10 (1.1 equiv) and alkyl iodide (8 equiv), irradiation
(300 nm, Pyrex) for 18 h at ca. 35 °C under Ar. b Ratio by GC and GC-MS
unless noted. c Ratio by HPLC (Chirex 3014; 6% i-PrOH, 0.5% HCO2H,
hexane).
The presence of a Lewis basic ester could potentially alter
the normal two-point binding of InCl3 by N-acylhydra-
zones,8,9 and this consideration prompted NMR experiments
to substantiate the chelation model with substrates of this
new type. Admixture of γ-hydrazonoester 6a with InCl3 in
17
CD2Cl2 caused the characteristic H-CdN absorbance of
the γ-hydrazonoester to shift from 8.04 to 7.74 ppm (Figure
3), an upfield shift precedented in similar cases.18 Downfield
shifts were observed for the R- and ꢀ-protons, as well as
those of the oxazolidinone. Similar downfield shifts were
noted throughout the 13C NMR spectra, and of particular note,
the carbons of the oxazolidinone CdO and the hydrazone
CdN exhibited downfield shifts of 8 and 5 ppm in the
complex compared to the starting γ-hydrazonoester. In
contrast, the CdO carbon of the ester showed minimal
change (<1 ppm). This suggests that the InCl3 is chelated
by the imino nitrogen and the oxazolidinone carbonyl in the
usual way, without significant interference by the ester
function.
The reaction of 3-chloropropyl iodide with γ-hydrazo-
noester 6a in the presence of InCl3 afforded a mixture of
alkyl chloride 13 in quantities which were dependent on the
duration of photolysis. Acyclic chloropropyl adduct 13 was
the major product when the irradiation time was 15 h (Table
2, entry 7). A longer irradiation time of 65 h afforded
pyrrolidine 14 (dr >98:2) as a major product (eq 1),
presumably via a radical addition followed by in situ SN2-
type polar cyclization. Such radical-polar crossover reactions
have attracted considerable interest.9,19 Interestingly, in this
instance, operation in the absence of InCl3 seems to be
advantageous for the polar cyclization stage; under In-free
conditions, pyrrolidine 14 was the exclusive isolated product,
even without extended reaction time (Table 2, entry 8).
Lastly, removal of chiral auxiliary from the γ-hydrazi-
noester was examined. Our preferred general method in-
A range of iodides were next examined in reactions with
and without InCl3, starting with a comparison of secondary
(17) See Supporting Information for details.
(18) Lin, C. H. Synth. React. Inorg. Met.-Org. Chem. 1993, 23, 1097–
1106.
Org. Lett., Vol. 11, No. 5, 2009
1097

enhanced N-acylhydrazine acylation is an important practical
advance, extending the Mn-mediated coupling to chiral
amines which bear ester functionality.
Table 2. Mn-Mediated Addition of Various Iodides to 6aa
Scheme 2
In summary, we have developed a new entry to γ-amino
acids via Mn-mediated coupling of alkyl iodides and γ-hy-
drazinoesters. This study exhibits additional elements of
novelty in surprisingly high diastereomer ratios in the absence
of InCl3, NMR evidence regarding Lewis acid binding to
γ-N-acylhydrazonoesters, facile radical-polar crossover an-
nulation in the absence of InCl3, and a new microwave-
enhanced procedure for release of N-TFA-protected amines
from the hydrazines formed in Mn-mediated radical addition.
a Conditions: see Table 1. Data in parentheses are for reactions without
InCl3. b Isolated yield. c Ratios by GC-MS or HPLC (Chiralcel OD-H;
i-PrOH/hexane). d Due to complications from the additional stereocenter
in the s-Bu group, the dr was not determined. e Irradiated for 15 h.
f Compound 13 was not observed in chloropropyl addition without InCl3.
g For the structure of 14, see eq 1.
Acknowledgment. We thank NSF (CHE-0749850) for
generous support of our radical addition methodology
program, and we thank Dr. J.-C. Marie´ (University of Iowa,
current affiliation Broad Institute, Cambridge, MA) for some
initial observations which suggested this work.
volves acylation with trifluoroacetic anhydride (TFAA) to
activate the N-N bond toward SmI2-mediated reductive
cleavage.20 Hydrazines of the N-aminooxazolidinone type
are somewhat recalcitrant toward acylation, which often
requires sequential treatment with n-BuLi and TFAA.
However, such conditions are incompatible with the ester
functionality of 7a. An effective alternative procedure was
discovered; this entailed trifluoroacetylation under microwave
irradiation21 in the presence of Et3N and DMAP (Scheme
2). The N-TFA derivative of 7a obtained in this manner was
exposed to SmI2, smoothly furnishing known γ-aminoester
15 and proof of absolute configuration.22,23 This microwave-
Supporting Information Available: Preparative details
and characterization data for 6-15. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL802932V
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