new allyl group acceptors for palladium catalyzed removal of allylic protections and transacylation...

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Pergamon 0040-4039(95)01 147-1 Tetrahedron Letters, Vol. 36, No. 32, pp. 5741-5744, 1995 ElsevierScienceLid Printed in Great Britain 0040-4039/95 $9.50+0.00 New Allyi Group Acceptors for Palladium Catalyzed Removal of Allylic Protections and Transacylation of Allyi Carbamates. Mich~le Dessolin a, Marie-George Guillereza, Nathalie Thieriet a, Frant~ois Guib6 a* and Albert Loffet b alnstitut de Chimie Mol~culaired' Orsay, Laboratoiredes R6actions Organiques S61ectives, associ6 au CNRS, BiR.420, Universit6Paris-Sud, 91405 Orsay (France) bpropeptide, BP 12,91710, Vert-le-Petit(France). Key words: allylic protecting groups, palladium catalysis, transacylation, phenyltrihydrosilane, N-methyI-N-(trimethylsilyl)trifluoroacetamide. Abstract: Allyl carboxylates, carbamates and phenoxides may be cleaved or transacylated in the presence of palladium catalyst and either phenyltrihydrosilane or N-methyl-N-(trimethylsilyl)- trifluoroacetamide. These reactions are totally compatible with the presence of Boc and, as far as phenyltrihydrosilane is concerned, Fmoc protections. Allyl carboxylates, phenoxides, phosphates or phosphonates, and allyl carbonates or carbamates are rapidly cleaved in the presence of soluble palladium catalyst (typically Pd(PPh3)4) and a nucleophile acting as an allyl group scavenger, to regenerate the free unprotected function ! (eqs 1 and 2). Such catalytic x-allyl Pd catalyst (1) ZH + Nu / "6" Z ~ Nu,I~ Z = RCO 2, ArO, (RO)2P(O)O Y -CO2 ~ Y = RO, R2N ibid YH + CO 2 + Nu "~'~ (2) palladium methodology is of special interest for peptide synthesis because the deprotection conditions are usually mild enough to be compatible with the presence of the acid labile t-Bu, Boc protections and the base labile Fro, Fmoc protections, provided in the latter case that a nucleophilic allyl group acceptor of sufficiently low basicity is used 2. A variety of nucleophilic species has been used for intercepting the intermediate 7t-allyl complexes, which includes carbon nucleophiles, heteronucleophiles (amines, thiols, carboxylates...) and hydride donors 5741

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Pergamon

0040-4039(95)01 147-1

Tetrahedron Letters, Vol. 36, No. 32, pp. 5741-5744, 1995 Elsevier Science Lid

Printed in Great Britain 0040-4039/95 $9.50+0.00

New Allyi Group Acceptors for Palladium Catalyzed Removal of Allylic Protections and Transacylation of Allyi Carbamates.

Mich~le Dessolin a, Marie-George Guillerez a, Nathalie Thieriet a, Frant~ois Guib6 a* and Albert Loffet b

alnstitut de Chimie Mol~culaire d' Orsay, Laboratoire des R6actions Organiques S61ectives, associ6 au CNRS, BiR.420, Universit6 Paris-Sud, 91405 Orsay (France)

bpropeptide, BP 12,91710, Vert-le-Petit (France).

Key words: allylic protecting groups, palladium catalysis, transacylation, phenyltrihydrosilane, N-methyI-N-(trimethylsilyl)trifluoroacetamide.

Abstract: Allyl carboxylates, carbamates and phenoxides may be cleaved or transacylated in the presence of palladium catalyst and either phenyltrihydrosilane or N-methyl-N-(trimethylsilyl)- trifluoroacetamide. These reactions are totally compatible with the presence of Boc and, as far as phenyltrihydrosilane is concerned, Fmoc protections.

Allyl carboxylates, phenoxides, phosphates or phosphonates, and allyl carbonates or carbamates are

rapidly cleaved in the presence of soluble palladium catalyst (typically Pd(PPh3)4) and a nucleophile acting as

an allyl group scavenger, to regenerate the free unprotected function ! (eqs 1 and 2). Such catalytic x-allyl

Pd catalyst (1) ZH + Nu / " 6 "

Z ~ Nu,I~

Z = RCO 2, ArO, (RO)2P(O)O

Y -CO2 ~

Y = RO, R2N

ibid

YH + CO 2 + Nu " ~ ' ~ (2)

palladium methodology is of special interest for peptide synthesis because the deprotection conditions are

usually mild enough to be compatible with the presence of the acid labile t-Bu, Boc protections and the base

labile Fro, Fmoc protections, provided in the latter case that a nucleophilic allyl group acceptor of sufficiently

low basicity is used 2.

A variety of nucleophilic species has been used for intercepting the intermediate 7t-allyl complexes,

which includes carbon nucleophiles, heteronucleophiles (amines, thiols, carboxylates...) and hydride donors

5741

5742

(HCO2H, Bu3SnH, NaBH4) I-3. We report here our preliminary results on the use of two new allyl group

scavengers, the hydride donor phenyltrihydrosilane -PhSiH3- 1 , and N-methyl-N-(trimethylsilyl)trifluoro-

acetamide CF3CON(S iMe3)CH3 2. 4 Our choice of 1 was guided by an earlier report by Keinan and

Greenspoon on the fast palladium catalyzed hydrosilylolysis of allylic esters by this reagent 5 while that of 2 is

the result of a large screening of silylated nucleophiles 6. Both of them appear to be very promising, especially

1 which, albeit somewhat slower in rate, presents a scope of utilization similar to that of tributyltin hydride 7

without the inconvenients often associated with use of tin compounds ( toxicity, elimination of by-products).

We have thus observed (eqs 3 and 4) that allyl carboxylates, carbonates and carbamates are cleaved to

silyl derivatives within 5 to 15 min. in dichloromethane and at room temperature in the presence of Pd(PPh3)4

(0.02 molar equiv.) and of 1 (2 molar equiv.) or 2 (1.2 to 2 molar equiv.). The silyl derivatives may, in turn,

be instantaneously hydrolysed upon exposure to water (eqs 3 and 4). Infrared analyses showed that allyl

carbonates are directly converted to silyl alkoxides, while decarboxylation occurs only during the hydrolytic

treatment in the case of carbamates (eq. 4). Aryl allyl ethers are also deprotected by the palladium/1 system

(reaction time 20 to 40 min.), but not by the palladium/2 system (ca 20% cleavage after 24 hours).

Pd (PPh3)4cal. , 1 or 2 H20

Z " " ' @ -- Z-[Si] " ZH (3) . Nu.-'--~ - [Sil-O-[Sil

Z = RCO 2 or (with 1 only) ArO

Nu = H or CF3-CO-(CH3)N

Y-CO2 ~

Y = RO H20 RO-[Sil ~ ROH ~ - CO2 - [Si]-O-[Si]

ibid (4)

H20 RR'N-CO2-[Si ] _--- RR'NH

Y = RR'N - [Si]-O-[Si] - C02

Our results 8, a good part of them dealing with aminoacids derivatives, are reported in the Table. In all

cases except those related to the application of the Pd/2 system to Fmoc aminoacid derivatives (see below),

direct analyses of the crude reaction mixtures (NMR, TLC) showed complete and selective removal of allylic

protections. Competi t ive decarboxylative rearrangement of allylcarbamates to allylamines l was never

encountered, even with the sensitive 1 allyloxycarbonyl (Alloc) derivative of morpholine 8. Blank experiments

showed that Fmoc derivatives of aminoacids are perfectly stable in 1M CH2C12 or DMF solution of 1, and

with 2, loss of Fmoc group occurs only to a very small extent ( 2% after 24hrs as determined by HPLC). In

accordance with these observations, the palladium catalyzed deprotections of 4, 10 and 13 were found to be

5743

TABLE

Allylic substrate Deprotected product Isolated* yield

P d / l Pd /2

~ / C H 2 C O 2 All

( 3 )

Fmoc-Asp(OAll)-OMe ( 4 )

[ ~ r ~ CH2CO2H quaat b quant b

Fmoc-Asp-OMe 74%~ _ a

Boc-Asp(OAll)-OMe ( 5 ) Boc-Asp-OMe 95% b 98% b

Boc-Ser(Alloc)OMe ( 6 ) Boc-Ser-OMe 92% c 96% c

M e - ~ - C H 2 - N H - A I I o c ( 7 ) M ¢ ' - ~ -CH2-NH2 >95%e >95%e

Or'N- AUoc (8) O~N H quant f quant f

Boc-Lys(Alloc)-OMe ( 9 ) Boc-Lys-OMe 74% c 82%

Fmoc-Lys(Alloc )-OMe (10) Fmoc-Lys-OMe 88% e 85% c

---OAll (1 1) ~ ) - - O H qu antf

Boc-Tyr(AU)-OMe ( l 2) Boc-Tyr-OMe 77% c _ g

Fmoc-Tyr(All)-OMe (13) Fmoc-Tyr-OMe 75% c _ g

a: unless otherwise specified; b: isolated through conventional successive basic and aqueous work-up; c: flash chromatography;

d: paxtial loss of Fmoc group (see the text ); e: precipitated as its hydrochloride salt; f: not isolated; yield based on gas chro- matography analysis after proper calibration; g: the Pd/2 system is not efficient for deprotection aryl allyl ethers (see the text).

5744

totally se lect ive towards Al loc removal with 1, but, surprisingly, some loss of Fmoc group (ca 10-15%) was

exper ienced in the deprotec t ion of 4 and 10 with 2.

W h e n allyl ca rbamates 7-10 were reacted with Pd/PhSiH3 in the presence of acetic anhydr ide or di-

ter t -buty l d i ca r bona t e ( (Boc)20) , a rapid ( ins tantaneous with A c 2 0 , 15 to 30 min wi th ( B o c ) 2 0 ) and total

t ransacyla t ion 9 was obse rved (eq.5). Similar results were obta ined by reacting these ca rbamates , still in a one

Pd°/ 1 ( 2 equiv.) / Ac20 or ( Boc)20 R N H C O R ' RNHCO2AII ~ (5)

or I'd°/ 2 (1,1 equiv.) , 10 min; then Ac20 or ( Boc)20 (R '=CH 3, Ot-Bu)

pot p rocedure but this t ime sequent ia l ly , with the Pd/2 sys tem (eq. 5). We are cur rent ly inves t iga t ing other

appl ica t ions o f such t ransacyla t ion processes , especial ly with regard to direct fo rmat ion of pept ide bonds

be tween Na-Al loc aminoac id der ivat ives and various acyl-act ivated aminoacid components .

Notes and references.

I. 2.

4.

5. 6.

7. 8.

9.

Merzouk, A.; Guib~, F.; Loffet, A. Tetrahedron Lett. 1992, 33,477-480 and references therein. a) Ciommer, M.; Kunz, H. Synlett.. 1991. 593-595; b) Kates, S. A.: Daniels, S. B.; Albericio, F. Anal. Biochem. 1993, 212. 303-310; c) Lloyd-Williams, P.; Merzouk, A.; Guib~, F.; Aibericio, F.: Giralt, E. Tetrahedron Lett. 1994, 35, 4437- 4440. Most recently proposed reagents include a) N-trimethylsilylated secondary amines (ref 1); b) acetic acid/N-methylmorpho- line (ref. 2-b); c) thiosalicylic acid (Genii, J. P.; Blart, E.; Savignac, M.; Lemeune, S.; Lemaire- Audoire, S.: Bernard, J. M. Synlett, 1993, 680-682); d) trimethylsilyl azide/tetrabutylammonium fluoride (Shapiro, G.; Buechler, D. Tetrahedron Lett. 1994, 35, 5421-5424): e) sodium borohydride ( Beugelmans. R.; Bourdet, S.; Bigot, A. ; Zhu, J. Tetrahedron Lett. 1994, 35, 4349). Both reagents are commercially available. Phenyltrihydrosilane may also be readily prepared by LiAIH4 reduction of the inexpensive trichlorophenylsilane: Vebergall, W. H. J. Am, Chem. Soc. 1950, 72, 4702-4704. Keinan, E.; Greenspoon, N. Isr. J. Chem., 1984, 24, 82-87. Besides N,N-dialkyI-N-trimethylsilylamines l, were included in this screening hexamethyidisilazane, 1-(trimethylsilyl)imi- dazole. N.O-bis(trimethylsilyl)hydroxylamine, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)carbamate, ethoxytrimethylsilane, (ethylthio)trimethylsilane, ethyl trimethylsilylacetate. 3-trimethylsilyl-2-oxazolidinone, N-(trimethylsilyl)acetamide and N-methyl-N-(trimethylsilyl)acetamide. These compounds were tested with respect to their efficiency as allyl group scavengers and their compatibility with Fmoc protecting groups. Dangles, O.; Guib~. F.; Balavoine, G.; Lavielte, S.; Marquet, A. J. Org. Chem. 1987.52, 4984-4993. Reactions were usually carried on a 1 mmolar scale of allyl substrate in 2-4 mL of CH2CI 2, in preference under inert (Arg, N2) atmosphere. After hydrolysis of the silylaled primary products, the deprotected compounds were isolated by conven- ventional extractive work-up and/or chromatography. Efficient transacylation of allyl carbamates has already been achieved by use of the reagents combination Pd cat/ Bu3SnH/acylating agent (Roos, E. C.; Bernab6, P.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1991.32.6633-6636; Roos, E. C.; Beroab& P.; Hiemstra, H.; Speckamp, W. N.; Kaptein, B.; Boesten. W. H. J. J. Org. Chem. 1995. 60, 1733) and by use of the reagents combination Pd cat/NaBl-14/acylating agent ( Beugelmans, R.; Neuville, L.; Bois-Choussy, M; Chastener. J.;Zhu, J. Tetrahedron Lett. 1995, 36, 3129-3133). Benzyi carbamates have been transacylated to tert-butyl carbamates by use of Pd(OAc)2/Et3SiH//BocOBoc: Sakaitani, M.; Hori, K.; Ohfune, Y. Tetrahedron Lett. 1988, 29, 2983-2984; this last reaction is unlikely to involve ;t-allyl palladium intermediates (see Roos et at., J. Org. Chem., cited above).

(Received in France 18 Apri l 1995; accepted 21 June 1995)