Tetrachlorophthaloyl as a versatile amine protecting group

Full text of DOI:10.1021/jo951943v

432
J . Org. Chem. 1996, 61, 432-433
between these protected donors when NIS/TESOTf12 is
used as promoter, as both react to completion within
minutes.
Tetr a ch lor op h th a loyl a s a Ver sa tile Am in e
P r otectin g Gr ou p
J ohn S. Debenham and Bert Fraser-Reid*
Paul M. Gross Chemical Laboratory,
Department of Chemistry, Duke University,
Durham, North Carolina 27708
Received November 2, 1995
We reported recently that the pent-4-enoyl and tetra-
chlorophthaloyl (TCP)1 groups serve as protecting devices
for amine functionalities that can be removed orthogo-
nally and chemoselectively.2 TCP belongs to the class of
cyclic imidic protecting groups including the parent
phthaloyl,3 maloyl,4 and dithiosuccinoyl5 that have served
synthetic organic chemists well,6 and hence, we have
invested additional effort in examining its potential. In
this paper, we report that the TCP group offers a wealth
of advantages in synthetic manipulations where a pri-
mary amine must be carried in protected form. Of special
importance is the survival of carboxylate esters during
TCP cleavage. Our examples are chosen mainly from the
carbohydrate domain in view of the current high interest
in glycoproteins7 and amino glycans.8
The TCP group has been found to be stable to a wide
range of reagents normally used in standard oligosac-
charide transformations (vide infra)2,9 which therefore
makes it possible to install this inexpensive protecting
device at the outset of a major synthesis with confidence
about its survival prospects.10 That TCP is able to
exercise neighboring group participation in spite of being
deactivated is demonstrated in eqs i-iii, and the proce-
dure for direct N-linkage of amino acid residues devel-
oped in our laboratory11 is effectively applied to 8, leading
to high yields of 9 as a single diastereomer (eq iv). Thus,
Phth and TCP are comparable from the standpoints of
ease of installation3a and stereodirecting properties.
Furthermore, there is no substantial reactivity difference
It is with respect to the conditions for its removal that
the attractiveness of the TCP group is accentuated.
Hindsgaul and co-workers have shown that cleavage of
the parent phthalimide function can be achieved with
ethylenediamine.13 However, the reagent must be used
literally as cosolvent at temperatures of 80-100 °C up
to 20 h, conditions so harsh that amino acids may be
racemized and other base sensitive functionalities af-
fected.
(1) The use of TCP group for amine protection in oligosaccharide
synthesis was first reported (J . S. Debenham and B. Fraser-Reid) at
the XVIIth International Carbohydrate Symposium, Ottawa, Canada,
J uly 1994, paper B1.38, and subsequently (J . S. Debenham and B.
Fraser-Reid) at the 209th National Meeting of the American Chemical
Society, Anaheim, CA, April 1995, paper CARB 008.
(2) Debenham, J . S.; Madsen, R.; Roberts, C.; Fraser-Reid, B. J . Am.
Chem. Soc., 1995, 117, 3302-3303.
(3) (a) Lemieux, R.; Takeda, T.; Chung, B. In Synthetic Methods for
Carbohydrates; El Khadem, H. S., Ed.; ACS Symposium Series:
Washington, DC, 1976; Vol. 39, pp 90-115. (b) Ing, H.; Manske, R. J .
Chem. Soc. 1926, 2348-2351.
(4) Zehavi, U. J . Org. Chem. 1977, 42, 2819-2821.
(5) (a) Barney, G.; Merrifield, R. B. J . Am. Chem. Soc. 1977, 99,
7363-7365. (b) Meinjohanns, E.; Meldal, M.; Paulsen, H.; Bock, K. J .
Chem. Soc., Perkin Trans. 1 1995, 405-415.
(6) For example; see the chapters on protection of amino groups in
the most extensive of two recent source books: (a) Protecting Groups;
Kocienski, P. J ., Ed.; Thieme:Stuttgart, 1994; Chapter 6. (b) Protecting
Groups in Organic Synthesis, 2nd ed.; Greene, T. W., Wuts, P. G. M.,
Eds.; J ohn Wiley & Sons, Inc.: New York, 1991; Chapter 7.
(7) Garg, H. G.; von dem Bruch, K.; Kunz, H. Advances in Carbo-
hydrate Chemistry and Biochemistry; Horton, D., Ed.; Academic Press,
Inc.: San Diego, 1994; Vol. 50, pp 277-310.
(8) Kjelle´n, L.; Lindahl, U., Annu. Rev. Biochem. 1991, 60, 443-
475. Hassell, J ohn R.; Kimura, J ames H; Hascall, Vincent C. Annu.
Rev. Biochem. 1986, 55, 539-567.
(9) Castro-Palomino, J . C.; Schmidt, R. R. Tetrahedron Lett. 1995,
36, 5343-5346.
(10) TCP is the cheapest of a group of deactivated phthalides,
including mononitro and mono- and dihalo. Additionally, many of the
TCP derivatives that we have prepared tend to crystallize readily, the
attendant advantages for large scale work being obvious.
(11) (a) Handlon, A. L.; Fraser-Reid, B. J . Am. Chem. Soc. 1993,
115, 3796-3797. (b) Ratcliffe, A. J .; Konradson, P.; Fraser-Reid, B. J .
Am. Chem. Soc. 1990, 112, 5665-5666.
We have found that the TCP group can be removed
with as little as 1.5 equiv of ethylenediamine for sensitive
substrates. However, in most cases, 2-4 equiv can be
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Communications
J . Org. Chem., Vol. 61, No. 2, 1996 433
safely used, under which conditions cleavage is completed
within reasonable periods of time. It is worth noting that
the cleavage byproduct is insoluble in many commonly
used solvents (CH2Cl2, DMF, DMSO, acetone, EtOAc,
MeOH, etc.) and is therefore conveniently removed by
filtration.14
carried out in the presence of MeOH complete trans-
esterification and significant racemization were observed.
The TCP group may also be placed on the acceptor
molecule as illustrated with 11 (eq v) forming the
differentially protected chitobiose derivative 12. The
latter compound has been used to demonstrate an
advantage of TCP in the chemoselective cleavage leading
to product 13 in 64% yield.
The survival of esters under the conditions for TCP
cleavage was of primary interest to us. The C4-OAc
group in 14 (eq vi) is hindered, and hence, its presence
in product 15 might have been fortuitous. Indeed, when
triacetate 2a was treated under comparable conditions,
product 16 (eq vii) was obtained in only 30% yield. An
increase in yield to 54% was experienced with MeCN/
THF/EtOH (2:1:1), indicating that a change in solvent
can have a salutary effect. However, exploration of this
promising possibility was rendered less urgent by the
experiment in eq viii which showed that benzoate esters
in 3 survived the cleavage conditions very well. Thus,
the yield of 82% over two steps for 17 was most encour-
aging.
In cases where the synthetic plan requires that an
ester be preserved, the susceptibility of the TCP group
to bases as mild as ethylenediamine is advantageous.
However, for the opposite selectivity, it is worthwhile to
note that where ready removal of an ester is desired,
chloroacetyl groups can be utilized. Thus, chloroacetyl
esters can be removed efficiently with thiourea in the
presence of a TCP group as exemplified in eq x.
In view of the importance of benzyl protecting groups
in oligosaccharide synthesis, note should be taken of eq
xi, which shows that acidic-benzylation15 can be carried
out on suitable TCP derivatives in quantitative yield.16
However, as is obvious from eq xi, there may be a
decrease in reactivity for TCP acceptors as compared to
the Phth counterpart.17
Reasons for our emphasis on ester survival are appar-
ent in eq ix. With respect to the glycosyl serine 4
prepared in eq ii, treatment with ethylenediamine in a
solvent of MeCN/THF/EtOH (2:1:1) followed by acetyla-
tion provided the N-acetylated glycopeptide 18 without
racemization or transesterification. The importance of
solvent should be noted, because when the reaction was
(12) Fraser-Reid, B.; Udodong, U.; Wu, Z.; Ottosson, H.; Merritt, J .
R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett. 1992, 927-942.
(13) Kanie, O.; Crawley, S. C.; Palcic, M. M.; Hindsgaul, O. Carbo-
hydr. Res. 1993, 243, 139-164.
(14) It is worth noting that the ethylenediamine-based cleavage
product’s lack of solubility makes it difficult to positively characterize.
(15) Wessel, H.-P.; Iverson, T; Bundle, D. R. J . Chem. Soc., Perkin
Trans. 1 1985, 2247-2250.
(16) It should be noted that the TCP group is unstable to the strongly
basic conditions necessary for standard NaH/BnBr benzylations.
(17) Whether this reactivity difference can be leveraged into an
armed/disarmed protocol for amino acceptors is currently being tested
in our laboratories.
Ack n ow led gm en t. This work was supported by
NIH grant GM-40171. We are indebted to Robert
Madsen and Sheryl Debenham for their assistance in
this work.
Su p p or tin g In for m a tion Ava ila ble: Listings of experi-
mental procedures for the preparation of all key compounds
with selected analytical data (8 pages).
J O951943V