Stereoselective and Catalytic Synthesis of anti-β-Alkoxy-α-azido Carboxylic Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b03255

Direct addition of a chiral N-azidoacetyl thiazolidinethione to a variety of dialkyl acetals catalyzed by a commercially available and structurally simple nickel(II) complex gives access in good yields and a highly stereocontrolled manner to anti-β-alkoxy-α-azido carboxylic derivatives which, in turn, can be easily converted into a wide array of enantiomerically pure compounds.

Full text of DOI:10.1021/acs.orglett.7b03255

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Stereoselective and Catalytic Synthesis of anti-β-Alkoxy-α-azido
Carboxylic Derivatives
́ ̀ ̀
Javier Fernandez-Valparis, Pedro Romea,* Fel
ix Urpí,*,† and Merce Font-Bardia‡
†
,†
†Seccio
Barcelona (IBUB), Universitat de Barcelona, Carrer Martí i Franques
‡Unitat de Difraccio
de RX (CCiTUB), Universitat de Barcelona, Carrer Sole
́
de Química Organ
̀
ica, Departament de Química Inorgan
̀
ica i Organ
1-11, 08028 Barcelona, Catalonia, Spain
i Sabarís 1-3, 08028 Barcelona, Catalonia, Spain
̀
ica and Institut de Biomedicina de la Universitat de
́
́
́
*
S Supporting Information
ABSTRACT: Direct addition of a chiral N-azidoacetyl thiazolidine-
thione to a variety of dialkyl acetals catalyzed by a commercially
available and structurally simple nickel(II) complex gives access in
good yields and a highly stereocontrolled manner to anti-β-alkoxy-α-
azido carboxylic derivatives which, in turn, can be easily converted
into a wide array of enantiomerically pure compounds.
anti-β-Hydroxytyrosine derivatives are key structural motifs in a
pressure and long reaction time required (100 atm for 4 days)
have thwarted further applications. Alternative aldol-based
approaches might seem much more promising, but their scope
variety of biologically active compounds, ranging from
1
structurally simple 3-acyltetramic acids to much more complex
2
7
vancomycin antibiotics or cyclodepsipeptides such as stellato-
is still very limited. Maruoka reported the enantioselective
3
lides (Figure 1).
synthesis of anti-α-amino-β-hydroxy acids through aldol
reactions from a glycinate Schiff base catalyzed by a chiral
quaternary ammonium salt, but aromatic aldehydes turned out to
8
be unsuitable substrates. More recently, Kumagai and Shibasaki
have described a highly diastereoselective and enantioselective
catalytic aldol reaction of α-azido 7-azaindolinylacetamide, but
9
this is restricted to ortho-substituted aromatic aldehydes. In the
face of this lack of experimentally simple and broad ranging
synthetic methods, we envisaged that the direct addition of chiral
N-glycyl thiazolidinethiones to dialkyl acetals catalyzed by
nickel(II) complexes might afford anti-β-alkoxy-α-amino
10,11
carboxylic derivatives.
Herein, we report that (Me P) NiCl
3 2 2
triggers the stereocontrolled addition of a chiral N-2-azidoacetyl
thiazolidinethione (NPG: N in Scheme 1) to aromatic and
3
12
propargylic dialkyl acetals to give anti-β-alkoxy-α-azido adducts
which, in turn, can be easily converted into a plethora of
enantiomerically pure intermediates.
Exploratory experiments indicated that most of the amino
protecting groups (NPG: Boc, Fmoc, Z, and Bz in Scheme 1)
were unsuitable for our purposes. Only nickel(II)-catalyzed
addition of phthaloyl and azido derivatives 1 and 2, respectively,
Figure 1. anti-β-Hydroxytyrosine fragments in natural products.
13
in Scheme 2, to the dimethyl acetal of p-anisaldehyde (a) gave
the desired adducts in good yields. Unfortunately, and despite
our efforts, we did not succeed in exerting proper stereocontrol
over the configuration of the β-stereocenter from 1, and adduct
a was isolated as a 67:33 diastereomeric mixture in an overall
yield of 89% (Scheme 2). In contrast, N-2-azidoacetyl-4-
isopropyl-1,3-thiazolidine-2-thione 2 gave adduct 4a as a 96:4
mixture of diastereomers with a 60% yield (Scheme 2).
It should therefore come as no surprise that their synthesis has
attracted much attention, but despite considerable effort, that
goal has remained elusive. Lipton reported a single example of a
highly enantioselective and diastereoselective synthesis of anti-β-
methoxytyrosine through asymmetric aziridination of the TBS-
3
protected methyl p-coumarate followed by ring opening in
4
methanol. In turn, Hamada found that α-amino-β-aryl-β-keto
esters can be hydrogenated through dynamic kinetic resolution
in the presence of a chiral iridium catalyst to give the
corresponding anti-α-amino-β-hydroxy acids as a single diaster-
Received: October 18, 2017
5
,6
eomer with excellent enantiocontrol; however, the high
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03255
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Direct and Catalyzed Addition of N-(2-
Azaacetyl)thiazolidinethiones to Dialkyl Acetals
73:27 and improved again to 82:18 when we passed from 4-OMe
to 3-OMe and 2-OMe acetals, respectively (compare 4a−c in
Scheme 3). In accordance with such a trend, piperonal and 4-
NMe dimethyl acetals, d and e, respectively, also furnished the
2
anti adducts 4d and 4e in high diastereomeric ratios and yields
(
Scheme 3). The less activated tolyl and phenyl acetals, f and g,
respectively, afforded the anti adducts with a progressively poorer
stereocontrol, whereas the deactivated 4-chloro dimethyl acetal
(
h) required 20 mol % of (Me P) NiCl to obtain 4h with a
3 2 2
meager 15% yield (Scheme 3). Finally, the alkyl group R did not
have any effect on these reactions. Indeed, the allyl and benzyl
acetals, i and j, respectively, gave the corresponding anti adducts
4
i and 4j with diastereoselectivities and yields close to those for
14
the dimethyl acetal a (Scheme 3).
Scheme 2. Preliminary Results
Thiazolidinethiones are renowned among the chiral auxiliaries
15
for their ease of removal; therefore, 4a was smoothly converted
into the enantiomerically pure alcohol 5, ester 6, and keto ester 7
under mild conditions (Scheme 4). Furthermore, treatment of 4a
with (S)-α-methylbenzylamine afforded amide 8, whose X-ray
analysis permitted us to establish the anti configuration of 4. In
turn, a parallel reaction with 1 equiv of methyl leucinate
hydrochloride gave the dipeptide 9 with a 96% yield in a
straightforward manner (Scheme 4).
Aiming to expand the scope of this transformation, we then
focused our attention on other acetals. Since Schreiber reported
that cobalt-derived propargylic acetals easily undergo S 1-like
N
16,17
reactions,
we envisaged that their use might provide access to
Following comprehensive optimization, we found that the
direct reaction of 2 with the acetal a (1.1 equiv) using 5 mol % of
commercially available (Me P) NiCl , 1.5 equiv of TESOTf, and
a much larger range of compounds. Thus, we were pleased to
observe that model cobalt phenylpropargylaldehyde diethyl
acetal (k) participated in a highly stereoselective reaction with 2.
Indeed, its direct addition to 2 using 10 mol % of (Me P) NiCl ,
2.2 equiv of TESOTf, and 1.5 equiv of 2,6-lutidine provided
diastereomerically pure 10k with 73% yield (Scheme 5). These
conditions were further applied to a number of acetals k−t
possessing a wide array of functional groups to obtain 10k−t as
single diastereomers in high yields, with the exception of 10m,
from the simple propargylaldehyde diethyl acetal (Scheme 5). All
together, these results show that the addition of 2 catalyzed by a
3
2
2
2,6-lutidine for 15 h at −20 °C led to a 96:4 diastereomeric
mixture from which the pure anti adduct 4a was isolated in 85%
yield (Scheme 3). Once the synthesis of such a β-methoxytyr-
osine precursor had been completed, we next applied the above-
mentioned conditions to a variety of dimethyl acetals from
aromatic aldehydes. As shown in Scheme 3, the methoxy-
substituted acetals a−c revealed the dramatic influence of the
electronic character of the aryl group on the outcome of these
additions. Indeed, the diastereomeric ratio dropped from 96:4 to
3
2
2
18
Scheme 3. Diastereoselective and Nickel(II)-Catalyzed Addition of (S)-N-2-Azidoacetyl-4-isopropyl-1,3-thiazolidine-2-thione (2)
to Dialkyl Acetals of Aromatic Aldehydes
a
b
1
0 mol % of (Me P) NiCl . 20 mol % of (Me P) NiCl .
3 2 2 3 2 2
B
DOI: 10.1021/acs.orglett.7b03255
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Removal of the Chiral Auxiliary
Scheme 5. Diastereoselective and Nickel(II)-Catalyzed Addition of (S)-N-2-Azidoacetyl-4-isopropyl-1,3-thiazolidine-2-thione (2)
to Diethyl Acetals of Propargylic Aldehydes
Scheme 6. Conversion of Adducts 10 into Enantiomerically Pure Compounds
C
DOI: 10.1021/acs.orglett.7b03255
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Organic Letters
Letter
nickel(II) complex to properly activated acetals provides a totally
stereocontrolled access to highly functionalized anti-β-alkoxy-α-
azido carboxylic derivatives.
ACKNOWLEDGMENTS
■
́
Financial support from the Spanish Ministerio de Economia y
Competitividad (Grant No. CTQ2015-65759) and the General-
itat de Catalunya (2014SGR586) as well as a doctorate
studentship to J.F.-V. (APIF−IBUB) are acknowledged.
Importantly, the resulting adducts 10 can be transformed into
a variety of advanced intermediates. As shown in Scheme 6,
appropriate manipulation of adduct 10k produced the Boc-
protected amino alcohol 11 in a 48% overall yield. This can then
be hydrogenated to the alkyl 12 or Z-alkenyl derivative 13 in
excellent yields. Unfortunately, the obtention of the E-counter-
part 14 was much more troublesome. Attempts to reduce the
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stereocontrol. In turn, the resultant adducts can be converted
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straightforward manner.
(
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*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03255.
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AUTHOR INFORMATION
■
Corresponding Authors
(
̈
19) (a) Trost, B. M.; Ball, Z. T.; Joge, T. J. Am. Chem. Soc. 2002, 124,
*
E-mail: pedro.romea@ub.edu.
E-mail: felix.urpi@ub.edu.
7922. (b) Trost, B. M.; Hung, C.-I. J. Am. Chem. Soc. 2015, 137, 15940.
(20) Olefin Metathesis. Theory and Practice; Grela, K., Ed.; John Wiley &
Sons: Hoboken, 2014.
*
ORCID
(
21) (a) Blanco-Urgoiti, J.; Anorbe, L.; Perez-Serrano, L.; Dominguez,
G.; Perez-Castells, J. Chem. Soc. Rev. 2004, 33, 32. (b) Simeonov, S. P.;
Nunes, J. P. M.; Guerra, K.; Kurteva, V. B.; Afonso, C. A. M. Chem. Rev.
Pedro Romea: 0000-0002-0259-9155
Felix Urpí: 0000-0003-4289-6506
̀
Notes
2
016, 116, 5744.
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b03255
Org. Lett. XXXX, XXX, XXX−XXX