Angewandte
Chemie
formed into an N-phthalimido-protected amino acid ester.
Disappointingly, 13b proved inert under the optimal DKR
conditions.
We therefore rendered the OPCB protecting group
strategy more amenable to organocatalytic DKR through
the design of a novel class of tetrachloroisopropoxycarbonyl
(TCIC)-substituted azlactones (e.g. (rac)-15, Scheme 2c). The
chlorine atoms both improve the electrophilicity of the
azlactone and also augment steric bulk at the point of
attachment to the heterocycle to ensure high diastereocon-
trol. The exchange of the pyrrolidinamide for an isopropy-
lester is also a key modification. The ester enhances the
electrophilicity of the substrate further, and facilitates phtha-
limide formation by ring-closure after DKR has taken place.
Gratifyingly, the reaction of the TCIC-substituted ala-
nine-derived azlactone (rac)-15 with a range of C- and N-
protected serines (11 and 16–18) led to the formation of the
N-phthalimido amino acid esters 19–22 in good to excellent
yields and excellent to outstanding diastereocontrol (Sche-
me 2c). After DKR had taken place, the addition of a catalytic
loading of DABCO ensured the clean and efficient one-pot
phthalimide formation. It is noteworthy that esters which are
cleavable under very different conditions are tolerated (i.e.
methyl, benzyl, and p-nitrobenzoyl[16] variants) as are both
Boc and Cbz protection of the amino functionality. Larger
protecting groups bring about very high levels of diastereo-
control.
From a mechanistic standpoint (Scheme 2d), it is clear
that the catalytic addition of the alcohol to (rac)-15 leads to
the ring-opened adduct 15a, which was identified by 1H NMR
spectroscopic analysis. In the absence of DABCO some ring
closure (presumably catalyzed by 3b) occurs, however
addition of the second amine catalyst leads to complete ring
closure to the phthalimide 15b. Here the requirement for the
isopropylester moiety is apparent: when analogues of (rac)-15
incorporating simpler methyl or ethyl esters were used, the
methanol or ethanol (respectively) liberated during phthali-
mide-formation, catalyzed by 3b, competed effectively with
the protected serine for 15, thus leading to the formation of
some phthalimide methyl or ethyl ester products (i.e. 15b,
R = H or Me). Use of an isopropylester results in the
liberation of isopropyl alcohol, which is too hindered to
participate in azlactone alcoholysis, thus leading to products
derived from the addition of 11 and 16–18 to 15 only.
We were next keen to explore the scope of the method-
ology. Accordingly, we reacted 17 with a range of amino-acid-
derived TCIC-substituted azlactones of the general structure
23 in the presence of 3b, followed by one-pot DABCO-
mediated ring closure as before (Scheme 3). This sequence
allowed the synthesis of the phenylalanine- and valine-
derived O-acyl serines 24 and 25 in good to excellent yield
and with excellent diastereocontrol.[17] Interestingly, in the
case of the more hindered valine-derived 25, ring closure to
form the phthalimide was the slower reaction. The process
was also applied to the synthesis of analogues derived from
abiotic amino acids and a-ethyl- and a-n-butyl-substituted
analogues (26 and 27, respectively) could be prepared with
excellent stereochemical fidelity, as could the p-fluoropheny-
lalanine (an important artificial amino acid chemical
Scheme 3. Substrate scope: Natural/unnatural amino acid derivatives.
Boc=tert-butoxycarbonyl, PNB=para-nitrobenzyl.
probe)[18] derivative 28. A protected serine ester derivative
of the expensive[19] cystathionine g-lyase inhibitor l-propargyl
glycine was also synthesized (29),[20] however diastereocontrol
and product yields were lower (albeit still appreciable) than
was the case with 24–28. It is noteworthy that the major
diastereomer of 29 could be readily separated from the minor
by flash chromatography in an overall yield 53%.
To demonstrate the potential of these materials to serve as
precursors to dipeptides, 26 was first treated with trifluoro-
acetic acid to cleave the Boc group (Scheme 4). Removal of
Scheme 4. Boc removal for 26 followed by O!N acyl transfer.
DMAP=4-(N,N-dimethylamino)pyridine, TFA=trifluoroacetic acid.
the volatiles in vacuo and basic workup allowed a subsequent
and clean DMAP-mediated[21] O!N acyl transfer reaction to
occur to yield 30 (which is orthogonally protected at the C-
and N-termini) in excellent yield.
We wished to confirm that the products were demonstra-
bly orthogonally protected. The azlactone 31 was prepared
and exposed to benzyl alcohol in the presence of the catalyst
3b at ꢁ308C (Scheme 5). This reaction resulted in the
formation of 32 in near quantitative yield and 98% enantio-
meric excess. It is noteworthy that product enantiomeric
excess is higher than would be expected by using the
azlactone 1. The phthalimide ester 32 could be selectively
deprotected. Exposure to hydrogenolysis conditions afforded
the acid 33 in 99% yield, while treatment with ethylene
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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