2,2-dimethyl-4-(4-methoxy-phenoxy) butanoate and 2,2-dimethyl-4-azido butanoate: Two new pivaloate-ester-like protecting groups

Article abstract of DOI:10.1021/ol4008475

The title compounds were developed to extend the available orthogonalities within the class of protecting groups removed by assisted cleavage. The mild, complementary (oxidative vs reductive) reaction conditions for the removal, together with their pivalo

Full text of DOI:10.1021/ol4008475

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2270–2273
2,2-Dimethyl-4-(4-methoxy-phenoxy)
butanoate and 2,2-Dimethyl-4-azido
Butanoate: Two New Pivaloate-ester-like
Protecting Groups
Riccardo Castelli, Herman S. Overkleeft, Gijsbert A. van der Marel,* and
ꢀ
Jeroen D. C. Codee*
Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden,
The Netherlands
marel_g@chem.leidenuniv.nl; jcodee@chem.leidenuniv.nl
Received March 28, 2013
ABSTRACT
The title compounds were developed to extend the available orthogonalities within the class of protecting groups removed by assisted cleavage.
The mild, complementary (oxidative vs reductive) reaction conditions for the removal, together with their pivaloate-like character, were exploited,
in combination with a levulinoyl-ester functioning as a third orthogonal protecting group, in the assembly of a Streptococcus mutans
hexasaccharide built up from a oligorhamnose backbone featuring β-glucosyl appendages.
The success of oligosaccharide synthesis heavily relies
on the judicious choice of protecting groups to establish
the correct connectivity, tuning the reactivity of the
(mono)saccharide building blocks, and influencing the
stereochemical outcome of the associated glycosylation
reactions. The pivaloate stands among the ester-type
hydroxyl protecting groups for its strong neighboring
participation and ability to minimize the formation of
orthoester byproducts, along with the tolerance of an
ample range of reaction conditions.1 This stability is
paralleled by the forcing conditions required for its re-
moval. To circumvent this drawback, the pivaloate moiety
has been engineered by the connection through two
methylene units of a masked primary alcohol, as reported
by Crimmins,2 Trost,3 and Ensley.4 Upon intramolecular
lactonization (promoted by the ThorpeÀIngold effect of
the gem-disubstitution) the unprotected hydroxyl group is
released. While retaining the bulkiness adjacent to the
carboxylate, the overall orthogonality and stability of the
protecting group is translocated to the appending chain.5
To expand the orthogonalities of the aforementioned
precedents and to establish two mutually orthogonal
protecting groups, we considered making Kusumoto’s
4-azidobutyryl ester a pivalate derivative,6 thereby com-
plementing the (2-azidomethyl)-benzoate ester reported by
Sekine7 and Seeberger.8 In addition we used the p-methoxy
(3) Trost, B. M.; Hembre, E. J. Tetrahedron Lett. 1999, 40, 219.
(4) Yu, H.; Ensley, H. E. Tetrahedron Lett. 2003, 44, 9363.
(5) Crich, D.; Cai, F. Org. Lett. 2007, 9, 1613.
(6) Kusumoto, S.; Sakai, K.; Shiba, T. Bull. Chem. Soc. Jpn. 1986, 59,
1296.
(7) Wada, T.; Ohkubo, A.; Mochizuki, A.; Sekine, M. Tetrahedron
Lett. 2001, 42, 1069.
(8) Routenberg Love, K.; Andrade, R. B.; Seeberger, P. H. J. Org.
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: Hoboken, NJ, 1999. Pivaloyl orthoesters have
been observed. See for example: (a) Lemieux, R. U.; Morgan, A. R. Can. J.
Chem. 1965, 43, 2199. (b) Harreus, A.; Kunz, H. Liebigs Ann. Chem.
1986, 717. (c) Codee, J. D. C.; Van den Bos, L. J.; Litjens, R. E. J. N.;
Overkleeft, H. S.; Van Boom, J. H.; Van der Marel Org. Lett. 2003, 5,
1947.
(2) Crimmins, M. T.; Carroll, C. A.; Wells, A. J. Tetrahedron Lett.
1998, 39, 7005.
Chem. 2001, 66, 8165.
r
10.1021/ol4008475
Published on Web 04/22/2013
2013 American Chemical Society

phenol-ether (PMP) as a masked nucleophile, because the
oxidative conditions required to cleave the 4-methoxyphe-
nol ether are well tolerated by azides and the reducing
agents that transform an azide into the parent amine
generally leave the PMP group unscathed.
The synthesis of the 2,2-dimethyl-4-(4-methoxy-phenoxy)-
butanoate ester (MPDMB) precursors is straightforward.
Alkylation of ethyl isobutyrate with bromide 1,9 followed
by saponification, affords the crystalline acid 2 in good
yield (Scheme 1). This compound is converted to the
corresponding chloride 3 by treatment with a slight excess
of oxalyl chloride in DCM at reflux, and reagent 3 can be
used without purification.
demands protection of the required building blocks with
two distinct participating groups.13 We envisaged acces-
sing 7, a dimeric form of the S. mutans type e trisaccharide
repeating unit, employing MPDMB-functionalized build-
ing block 9 and AzDMB-functionalized 10 and 11, the
latter equipped with an O3-Levulinoyl ester to introduce
the branching and complete the set of orthogonalities.
With glucose building block 8 bearing an AzDMB group,
β-linked branching could be introduced selectively in a
multiple (2-fold) glycosylation fashion, and we projected
cleavage of the AzDMB esters concomitantly with the
benzyl-type protecting groups in the ultimate hydrogeno-
lysis event. Target 7 could be equipped with a suitably
protected amino-pentyl moiety 12 at the reducing end for
potential further elaboration.
Scheme 1. Synthesis of the Protecting Group Precursors
Scheme 2. Target Identification and Retrosynthesis
The synthesis of the azido-functionalized counterpart
(2,2-dimethyl-4-azido butanoate, AzDMB) is performed
by reacting ethyl 2,2-dimethyl-4-chloro butanoate 410 with
sodium azide. Following saponification, the correspond-
ing acyl chloride 6 was generated with an excess of oxalyl
chloride in DCM at reflux, in analogy to acyl chloride 3.
We decided to engage the obtained pivaloate derivatives
in the assembly of an oligosaccharide, as the synthetic
operations and protecting group manipulations involved
represent an ideal setting to assess their properties. As an
exemplary target, we identified the (polymeric) backbone
of alternating (R1f2)- and (R1f3)-linked rhamnose units
that constitute the group-specific polysaccharide antigens
of Lancefield group A, C, and E streptococci, the serotype-
specific antigen of Streptococcus mutans and Streptococcus
sobrinus (Scheme 2).11 The capsular polysaccharide of
S. mutans12 features additional glucose residues on this
backbone located at the O2 of the (1f3)- linked rhamnose.
Inthecaseof S. mutans, serotypeetheglucosyl appendages
are β-linked. The generation of the pattern of alternating
1,2- and 1,3-trans rhamnosidic linkages in a linear fashion
The preparation of the monosaccharide building blocks
is depicted in Scheme 3. Thioglycosides 9 and 10 were ob-
tained by reacting the sodium alkoxide of rhamnose
thioglycoside 1314 with acyl chlorides 3 and 6, respectively,
in THF. The branching, central rhamnose unit 11 was
obtained by first protecting the equatorial hydroxyl group
of 14,14 by means of Bu2SnO-mediated regioselective
alkylation with PMBCl, followed by reaction of the axial
hydroxyl with 6, to furnish the AzDMB-ester. PMB-ether
cleavage was performed under acidic conditions (with
p-thiocresol as a cation scavenger)15 and was followed by
(9) Schultz, D. M.; Prescher, J. A.; Kidd, S.; Marona-Lewicka, D.;
Nichols, D. E.; Monte, A. Bioorg. Med. Chem. 2008, 16, 6242.
(10) Kuwahara, M.; Kawano, Y.; Kajino, M.; Ashida, Y.; Miyake,
A. Chem. Pharm. Bull. 1997, 45, 1447.
(11) Shibata, Y.; Yamashita, Y.; Ozaki, K.; Yoshio Nakano, Y.;
Koga, T. Infect. Immun. 2002, 70, 2891.
(12) Linzer, R.; Reddy, M. S.; Levin, M. J. In Molecular microbiology
and immunology of Streptococcus mutans; Hamada, S., Michalek, S. M.,
Kiyono, H., Menaker, L., McGhee, J. R., Eds.; Elsevier Science Publishers:
Amsterdam, The Netherlands, 1986; pp 29À38.
(13) For convergent approaches towards related structures, see: (a)
Bedini, E.; Barone, G.; Unverzagt, C.; Parrilli, M. Carbohydr. Res. 2004,
€€
339, 393. (b) Hoog, C.; Rotondo, A.; Johnston, B. D.; Pinto, M.
Carbohydr. Res. 2002, 337, 2023. (c) Mulard, L. A.; Clement, M.-J.;
Imberty, A.; Delepierre, M. Eur. J. Org. Chem. 2002, 2486.
(14) Rajput, V. K.; Mukhopadhyay, B. J. Org. Chem. 2008, 73, 6924.
(15) Using anisole as a scavenger led to isolation of the product in
lower yield (48%), due to the expulsion of the p-thiocresyl moiety from
the anomeric center. We excluded the use of DDQ. See: Crich, D.;
Vinogradova, O. J. Org. Chem. 2007, 72, 3581.
Org. Lett., Vol. 15, No. 9, 2013
2271

Steglich esterification with levulinic acid to produce 11.
Glucose building block 8 was accessed by reacting thioglu-
coside 1716 with sodium hydride and chloride 6.
hydroxyl group to cyclize and liberated product 19.21 The
so-obtained acceptor was reacted with 11 at low tempera-
ture to give disaccharide 20. Subsequent deprotection of
the levulinoyl ester in 20 proceeded rapidly22 without any
detectable migration of the AzDMB group. After further
rhamnosylation of 21 with 9, trisaccharide 22was obtained
in excellent yield.
Scheme 3. Building Block Preparation
Scheme 4. Rhamnan Synthesis
We commenced (Scheme 4) assembly of the target struc-
ture 7 by condensing 9 and 12 by exposure to NIS/
TMSOTf in DCM.17 The reaction occurred rapidly and
in consistently high yield employing a slight excess of 12 at
0 °C. The absence of any byproduct deriving from poten-
tial electrophilic attack on the electron-rich 4-methoxy-
phenoxy moieties demonstrated the compatibility of the
MPDMB with the glycosylation conditions employed.18
We next investigated cleavage of the MPDMB group. To
this end, cerium ammonium nitrate (CAN) was added in
the form of an aqueous solution to a chilled solution of 18
in acetone. Twofold single-electron oxidation, followed by
ipso-substitution by water, proceeded rapidly.19 However,
the unveiled primary alcohol did not spontaneously attack
the carbonyl function of the ester to extrude the secondary
alcohol and liberate the lactone. In line with the conditions
reported by Ensley,4 we exposed the crude20 alcohol to a
stoichiometric amount of DBU in methanol, to induce the
At this stage we explored the key mutual orthogonality
of the two protecting groups (Scheme 5). Treatment of an
acetone solution of 22 with aqueous CAN was followed
(after workup) by the addition of DBU in methanol. The
two combined steps furnished compound 23 in 80% yield,
demonstrating the compatibility of the AzDMB group
with both oxidative and basic conditions employed. Cleav-
age of the AzDMB ester from 22 was performed by
Staudinger reduction of the azide group with PMe3 in
THF/water. To drive the overall process of AzDMB
deprotection to completion at an acceptable rate, it was
found necessary to add a catalytic amount of aqueous
KOH, to speed up the hydrolysis of the intermediate
imino-phosphorane. The liberated primary amine un-
eventfully engaged in the intramolecular 2,2-dimethyl
γ-butyrolactam formation to release the deprotected sec-
ondary alcohol.23,24
(16) Chayajarus, K.; Chambers, D. J.; Chughtai, M. J.; Fairbanks,
A. J. Org. Lett. 2004, 6, 3797.
(17) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H. Tetra-
(21) The Rf for the primary alcohol and the deprotected secondary
alcohol are the same. Monitoring the reaction by 1H NMR (0.03 M in
CD3OD) showed full conversion in less than 1 h.
hedron Lett. 1990, 31, 1331.
(18) (a) Panchadhayee, R.; Misra, A. K. Tetrahedron: Asymmetry
2010, 21, 2142. (b) Clausen, M. H.; Madsen, R. Chem.;Eur. J. 2003, 9,
3821. In a related experiment, we were able to selectively hydrolize the
thioglycoside moiety of 9 with NBS in wet acetone. See Supporting
Information.
(19) Jacob, P.; Callery, P. S.; Shulgin, A. T.; Castagnoli, N. J. Org.
Chem. 1976, 41, 3627.
(20) Washing with an aqueous, basic solution containing 2 equiv of
cysteine during the workup, the generated 1,4-benzoquinone byproduct
is converted into hydrophilic species, simplifying the chromatographic
purification in the subsequent step. Crescenzi, O.; Prota, G.; Schultz, T.;
Wolfram, L. J. Tetrahedron 1988, 44, 6447.
(22) Hanashima, S.; Castagner, B.; Esposito, D.; Nokami, T.;
Seeberger, P. H. Org. Lett. 2007, 9, 1777.
(23) More basic conditions employed during the Staudinger reduc-
tion of azide groups have also been reported: Arungundram, S.; Al-
Mafraji, K.; Asong, J.; Leach, F. E., III; Amster, I. J.; Venot, A.;
Turnbull, J. E.; Boons, G.-J. J. Am. Chem. Soc. 2009, 131, 17394.
(24) Cleavage of the AzDMB group could also be effected employing
exc. NaBH4/cat. NiCl2 in EtOH. However these cleavage conditions
gave varying poorly reproducible outcomes, which seemed to depend on
the cosolvent (Et2O or ethyl acetate) used to solubilize the substrate. The
reproducibility of the homogeneous PMe3/cat. KOH system discour-
aged further investigations along this line.
2272
Org. Lett., Vol. 15, No. 9, 2013

The hydrogenolysis was effected in two stages. A first cycle
of hydrogenolysis in a THF/t-BuOH/H2O solvent mixture
reduced the Cbz-group and the two AzDMB esters to
liberate the primary amine functions and some of the
alcohol functions. The resulting partially deprotected ma-
terial was redissolved in water, and 4 equiv of HCl were
added to neutralize the generated primary amines, fol-
lowed by a second hydrogenolysis round. After removal of
the catalyst, the addition of an excess of triethylamine to
the filtrate (to neutralize the acid, which is potentially
harmful to rhamnosidic linkages) finally triggered the
cyclization to 2,2- dimethyl-γ-butyrolactam, thereby fur-
nishing the fully deprotected compound 27.
Scheme 5. Selective Cleavage and Completion of the Synthesis
Insummary, wehavedeveloped two structurally related,
pivaloate-like protecting groups that are cleaved under
mild, mutually orthogonal reaction conditions that make
them a self-contained orthogonal set. Complementary
with a third temporary protecting group, we established
their performances in the linear synthesis of a complex
oligosaccharide sequence, representing two repeating units
of the S. mutans type e antigen.
Scheme 6. Global Deprotection
Continuing the synthesis from 23, rhamnosylation with
thioglycoside 10 furnished the bis-AzDMB protected tet-
rasaccharide 25, from which both esters were selectively
cleaved employing an excess of PMe3 and a catalytic
amount of KOH to give 26. We finally took on the double
glucosylation of tetrarhamnoside 26.25 With a modest
excess of donor 8 (2.8 equiv) at 0 °C, hexasaccharide 7
was obtained in 55% yield. Lowering the temperature
to À25 °C had a detrimental effect, while employing a
larger excess (4.5 equiv) of 8 at 0 °C raised the yield of 7 to a
more satisfactory 69%.
Acknowledgment. This work was supported by The
Netherlands Organization for Scientific Research (NWO).
Final deprotection of 7 could be effected via a hydro-
genolysis event, in which all the benzyl groups, the benzyl-
carbamate, and the AzDMB esters were removed (Scheme 6).
Supporting Information Available. Experimental pro-
cedures and analytical data for all the new compounds are
given in the Supporting Information. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(25) To test the reactivity profile of 8 we set a scouting reaction with
19 as the model acceptor. Under the promotion of NIS/TMSOTf at 0 °C
we obtained the corresponding disaccharide with complete β-selectivity
in 85% yield. See Supporting Information for details.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
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