2-(Prenyloxymethyl)benzoyl (POMB) as a new temporary protecting group for alcohols

Article abstract of DOI:10.1016/j.tetlet.2005.02.008

The 2-(prenyloxymethyl)benzoyl (POMB) group was introduced in high yields to hydroxyl functions using the crystalline reagent, 2-(prenyloxymethyl)benzoic acid, in the presence of dicyclohexylcarbodiimide (DCC) and 4- dimethylaminopyridine (DMAP). 2-(Prenyloxymethyl)benzoic acid is readily available, in two steps, from phthalide in 65% overall yield. The POMB group can be cleaved, in two steps, by treatment with 2,3-dichloro-5,6-dicyanoquinone (DDQ) followed by intramolecular lactonisation of the resulting hydroxy ester induced by a catalytic amount of Yb(OTf)₃·H₂O. The reaction conditions are compatible with the presence of a number of protecting groups such as isopropylidene, benzyl, acetyl, chloroacetyl, benzoyl, levulinoyl, Fmoc and Boc groups.

Full text of DOI:10.1016/j.tetlet.2005.02.008

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2299–2301
2-(Prenyloxymethyl)benzoyl (POMB) as a new
temporary protecting group for alcohols
*
`
Jean-Michel Vatele
´
Laboratoire de Chimie Organique 1, UMR 5181 CNRS, Universite Claude Bernard, ESCPE, 43 Boulevard du 11 Novembre 1918,
69622 Villeurbanne, France
Received 1 December 2004; revised 31 January 2005; accepted 1 February 2005
Abstract—The 2-(prenyloxymethyl)benzoyl (POMB) group was introduced in high yields to hydroxyl functions using the crystalline
reagent, 2-(prenyloxymethyl)benzoic acid, in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine
(DMAP). 2-(Prenyloxymethyl)benzoic acid is readily available, in two steps, from phthalide in 65% overall yield. The POMB group
can be cleaved, in two steps, by treatment with 2,3-dichloro-5,6-dicyanoquinone (DDQ) followed by intramolecular lactonisation of
the resulting hydroxy ester induced by a catalytic amount of Yb(OTf)3ÆH2O. The reaction conditions are compatible with the pres-
ence of a number of protecting groups such as isopropylidene, benzyl, acetyl, chloroacetyl, benzoyl, levulinoyl, Fmoc and Boc
groups.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The hydroxyl groupis one of the most important func-
tional groups present in the natural products. Although
over 150 hydroxyl protecting groups have been re-
ported, few have found wide applications.1 Novel hy-
droxyl protection and new cleavage techniques for
existing protecting groups are thus required as molecu-
lar targets increase in complexity and new fields such
as supported-oligosaccharide synthesis emerge.2 Among
the new principle developed for the deprotection of alco-
hols is the assisted cleavage. These classes of protecting
groups contains an auxiliary group, that initially exists
in a chemically stable form and can be converted to a
reactive nucleophile that facilitates the deprotection
via an intramolecular reaction.3 Ester protecting groups
designed in this way can be used to liberate hydroxyl
groups under mild conditions that usually do not affect
common esters such as acetates or benzoates.4 Among
esters, which have been designed according to this prin-
ciple are the O-substituted 2-(hydroxymethyl)benzoyl
groups: 2-(isopropyl or methylthiomethoxymethyl)benz-
oyl (respectively PTMT5 and MTMT6) and 2-(chloro-
acetoxymethyl)benzoyl (CAMB).7
The deblocking process of these protecting groups in-
volves the unmasking of the hydroxyl auxiliary function
(Hg(ClO4)2, base, THF–H2O for the PTMT and MTMT
groups; thiourea at 50 ꢁC for 24–48 h for the CAMB
group) followed by base-catalysed lactonisation with
formation of the deblocked alcohol and phthalide.5–7
The main drawbacks of these 2-substituted benzoates
are: (1) for PTMT and MTMT groups, the high cost
and toxicity of the Hg(II) salt used for the deprotection
and for the MTMT group, the MTM deprotection step
is for some substrates very sluggish;5 (2) for the CAMB
group, the deprotection of the chloroacetoxy group
using thiourea is rather slow necessitating prolonged
heating, which may cause side reactions8 or incomplete
deprotection.7
In relation with an ongoing project aimed at developing
the uses of the prenyl group in the protection of alcohol
and amine functions,9,10 we report, in this letter, a new
hydroxyl protecting group, a new derivative of the 2-
(hydroxymethyl)benzoyl groupnamely 2-(rpenyloxy-
methyl)benzoyl (POMB) group, which can be selectively
removed under mild conditions by the couple DDQ/
Yb(OTf)3 (Scheme 1).
The protecting agent, 2-(prenyloxymethyl)benzoic
acid (POMBOH) 1 was easily prepared according
to the procedure developed for the synthesis of
MTMTOH.6 After saponification of the phthalide by
Keywords: DDQ; Prenyl ethers; Protecting groups; Ytterbium triflate.
*
Tel.: +33 472431151; fax: +33 472431214; e-mail: vatele@univ-
lyon1.fr
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.008

`
J.-M. Vatele / Tetrahedron Letters 46 (2005) 2299–2301
2300
a
Table 1. Deprotection of POMbenzoates 2–11 with DDQ/Yb(OTf)3
CO2H
O
1
R2
, DCC, DMAP cat.
O
Entry
1
Substrate
Yield (%)
92
H
R2
R1
O
OH
H
O
R1
1. DDQ, CH2Cl2-H2O
2. Yb(OTf)3 cat., CH2Cl2
OPOMB
Scheme 1.
2
OPOMB
O
tetra-N-butylammonium hydroxide, the resulting oily
ammonium salt was dissolved in DMF and successively
treated with NaH and prenyl bromide to afford pure
POMBOH 1 in 65% yield, after acidification and recrys-
tallisation in hexane (Scheme 2).11
O
O
2
3
4
5
6
7
86
60
79
75
87
90
O
O
3
O
O
O
OPOMB
Ph
CO2NBu4
NBu4OH
O
OH
O
OMe
OBz
H2O
4
1. NaH,
DMF
Br
OPOMB
O
2. HCl
OAc
CO2H
AcO
OMe
OAc
O
5
1 (65 %)
OPOMB
O
Scheme 2.
OBn
POMBO
OMe
OBn
Diversely functionalised alcohols were esterified with
POMBOH in CH2Cl2 at room temperature, in the
presence of DCC and DMAP,12 to furnish POMB
esters 2–11 in excellent yields (90–97%).13,14 We next
examined the deprotection of the POMB group on
the 2-substituted benzoates 2–11 with DDQ in
CH2Cl2–H2O, which cleaved the prenyl ether group
followed by lactonisation of the resulting hydroxy ester
with Yb(OTf)3ÆH2O15 (Table 1).16 It is noteworthy that
for substrates 3–5 and 8–10, only 2 mol% of the cata-
lyst (10 mol% for the other substrates) was necessary
for the lactonisation to proceed at room temperature
and at a reasonable rate (3 h).
6
OPOMB
O
7
POMBO
OR
R = ClAc 8
R = Lev 9
R = Fmoc 10
8
9
88
91
As seen in Table 1, the reaction conditions for the POM
group cleavage are compatible with a number of pro-
tecting groups such as isopropylidene, benzyl, acetyl,
benzoyl, Boc groups (entries 2, 3, 4, 5, 10) but not with
the benzylidene group, which was partially cleaved by
Yb(OTf)3 (entry 3). In the presence of Yb(OTf)3, methyl
2,3,4-tri-O-acetyl-a-D-glucopyranoside, resulting from
the cleavage of the POMB groupof 5, was partially
transformed to methyl 2,3,6-tri-O-acetyl-a-D-glucopyr-
anoside obtained in 8% yield, via acetyl migration from
4-to-6 position (entry 4).17 Temporary protecting groups
such as ClAc, Lev and Fmoc groups, which are used in
the orthogonal sets of protecting groups in carbohydrate
chemistry,18 were left unscathed (entries 7–9).
BocNH CO2Me
OPOMB
10
85
H
11
a For the deprenylation step, 1.5 equiv of DDQ was used for all sub-
strates except for the di-POMB derivative 6 (3 equiv) and the reac-
tion time was 6 h.
Considering these attributes, the 2-(prenyloxymethyl)-
benzoyl groupmay find valuable and versatile use in
synthetic organic chemistry.
References and notes
In conclusion, the 2-(prenyloxymethyl)benzoyl group
has been developed as a new protection for alcohols,
which can be installed in high yield and cleaved selec-
tively in the presence of other alcohol protecting groups.
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons: New
York, 1999; Chapter 2.

`
J.-M. Vatele / Tetrahedron Letters 46 (2005) 2299–2301
2301
2. (a) Osborn, H. M. I.; Khan, T. H. Tetrahedron 1999, 55,
1807–1850; (b) Roussel, F.; Knerr, L.; Grathwihl, M.;
Schmidt, R. R. Org. Lett. 2000, 2, 3043–3044; (c)
Palmacci, E. R.; Hewitt, M. C.; Seeberger, P. H. Angew.
Chem., Int. Ed. 2001, 40, 4433–4437.
13. All new compounds gave satisfactory physical and ana-
lytical data.
14. Typical procedure for the introduction of the POMB group.
To a cooled (0 ꢁC) mixture of N-(tert-butyloxycarbonyl)-
L-serine methyl ester (0.33 g, 1.5 mmol) and 2-(prenyl-
oxymethyl)benzoic acid (0.397 g, 1.2 equiv) in CH2Cl2
(6 mL) were successively added DCC (0.403 g, 1.3 equiv)
and DMAP (0.03 g, 0.15 equiv). After stirring overnight at
room temperature, the precipitate of urea was filtered and
the filtrate evaporated. Flash chromatography of the
residue on silica gel (ether–petroleum ether, 1:2) afford the
desired compound 11 in 95% yield, obtained as an oil,
which crystallised on standing (63–64 ꢁC). IR (KBr) 1740,
1710 cmÀ1. 1H NMR: 1.45 (s, 9H, t-Bu), 1.65 (s, 3H, Me),
1.75 (s, 3H, Me), 3.78 (s, 3H, OMe), 4.05 (d, 2H, J =
6.85 Hz, CH2–C@C), 4.6 (d, 2H, J = 3.45 Hz, CH2OCO),
4.67 (m, 1H, CH–CO2Me), 4.76 (m, 1H, J = 14.4 Hz,
CHaAr), 4.91 (d, 1H, J = 14.2 Hz, CHbAr), 5.41 (br t, 1H,
J = 6.85 Hz, CH@CMe2), 5.74 (d, 1H, J = 7.95 Hz, NH),
7.33 (td, 1H, J = 1.2 and 7.9 Hz, Ar), 7.52 (td, 1H, J = 1.2
and 7.8 Hz, Ar), 7.61 (d, 1H, J = 7.3 Hz, Ar), 7.88 (d, 1H,
J = 7.4 Hz, Ar). 13C NMR: 18.1, 27.7, 28.3 (3C), 52.8,
53.0, 65.0, 65.9, 69.9, 80.3, 121.1, 127.2, 127.8, 128.3,
130.8, 132.6, 137.0, 141.1, 155.4, 166.7, 170.5. Anal. Calcd
for C22H31NO7: C, 62.69; H, 7.41; N, 3.32; O, 26.57.
Found: C, 62.63; H, 7.53; N, 3.37; O, 26.47.
3. Patek, M. Int. J. Pept. Protein Res. 1993, 42, 97–
117.
4. Well-known chloracetyl (ClAc) and levulinoyl (Lev) esters
are deprotected by ꢀassisted cleavageꢁ mechanism. For the
deprotection of ClAc esters: Van Boeckel, C. A. A.; Beetz,
T. Tetrahedron Lett. 1983, 24, 3775–3778, and references
cited therein; For the deprotection of Lev esters: Koeners,
H. J.; Verhoeven, J.; Van Boom, J. H. Tetrahedron Lett.
1980, 21, 381–382.
5. Brown, J. M.; Christodoulou, C.; Jones, S. S.; Modak, A.
S.; Reese, C. B.; Sibanda, S.; Ubasawa, A. J. Chem. Soc.,
Perkin Trans. 1 1989, 1735–1750.
6. Brown, J. M.; Christodoulou, C.; Reese, C. B.; Sindona,
G. J. Chem. Soc., Perkin Trans. 1 1984, 1785–1790.
7. Ziegler, T.; Pantkowski, G. Liebigs Ann. Chem. 1994, 659–
664.
8. Smith, A. B., III; Hale, K. J.; Vaccaro, H. A.; Rivero, R.
A. J. Am. Chem. Soc. 1991, 113, 2112–2122.
9. (a) We have shown that O-prenyl ethers could be cleaved
chemoselectively by I2 in CH2Cl2 and DDQ in CH2Cl2–
`
H2O. Vatele, J.-M. Synlett 2001, 1989–1991; (b) Vatele, J.-
M. Synlett 2002, 507–509; (c) Vatele, J.-M. Tetrahedron
`
`
15. In our knowledge, it is the first example of the use of
Yb(OTf)3 as a lactonisation agent.
2002, 58, 5689–5698.
10. (a) We recently developed a two-step procedure for the
16. Typical procedure for the cleavage of the POMB group. To
a stirred solution of the 6-O-POMB diacetone galactose 3
(0.24 g, 0.52 mmol) in a mixture CH2Cl2–H2O (9:1, 6 mL)
was added DDQ (0.177 g, 1.5 equiv). After stirring the
reaction mixture for 6 h at room temperature, sodium
bicarbonate in powder was added and the stirring was
continued for 10 min. The yellow phase was separated
from the black gum, which was washed twice with
CH2Cl2.The combined phases were concentrated to a
volume of about 5 mL, filtered through a pad of silica gel
(7 g) and eluted with ether–petroleum ether, 3:1. The
resulting mixture, which is composed mainly of the
hydroxy ester, was dried under vacuum and dissolved in
CH2Cl2 (3 mL) and Yb(OTf)3ÆH2O (6.2 mg, 0.02 equiv)
was added. After stirring for 3 h at room temperature, two
drops of saturated NaHCO3 solution was added and the
stirring was continued for 5 min. After evaporation of the
reaction mixture, the residue was purified by flash
chromatography on silica gel (ether–petroleum ether,
3:1) to give diacetone galactose as an oil (0.116 g, 86%).
[a] À54 (c 2.5, CHCl3) (Lit.19 [a] À55 (c 3.5, CHCl3)).
Spectroscopic data are in accordance with those of an
authentic sample.
`
selective cleavage of prenyl carbamates: Vatele, J.-M.
`
Tetrahedron Lett. 2003, 46, 9127–9129; (b) Vatele, J.-M.
Tetrahedron 2004, 60, 4251–4260.
11. Preparation of 2-(prenyloxymethyl)benzoic acid 1 from
phthalide. A mixture of phthalide (4 g, 0.0298 mol) and
tetra-N-butylammonium hydroxide in water (40% w/v,
20 mL, 0.031 mol) was heated at reflux for 90 min. The
clear solution was cooled down, extracted with CH2Cl2
(3 · 40 mL) and the combined organic phases were
washed with water (10 mL). The organic phase was dried
(Na2SO4) and concentrated. The oily residue was dried
under high vacuum at room temperature. To a solution
of the ammonium salt (11.73 g) in DMF (40 mL), cooled
to 0 ꢁC, was added by portions NaH (60% dispersion in
mineral oil, 3.6 g, 3 equiv). The reaction mixture was
allowed to warm upto room temperature and stirred for
1 h. The reaction mixture was cooled (0 ꢁC) and prenyl
bromide (4.2 mL, 1.2 equiv) was added dropwise. The
mixture was stirred at room temperature for 4 h, cooled
(0 ꢁC) and MeOH was carefully added followed by H2O
(140 mL). The solution was extracted with ether
(3 · 40 mL). To the well-stirred aqueous phase, cooled
to 0 ꢁC, was added dropwise 2 N HCl solution until pH 2
and the resulting suspension was extracted with ether
(2 · 125 mL).The combined organic phases were dried
(Na2SO4) and concentrated. Crystallisation of the residue
in hexane gave 1 (4.3 g; 65% yield) as colourless crystals,
17. (a) The propensity of the 4-O-acetyl groupof methyl 2,3,4-
tri-O-acetyl-a-D-glucopyranoside to migrate in 6 position
under acidic and basic conditions is well precedented. In
acid medium: Li, X.; Ohtake, H.; Takahashi, H.; Ikegami,
S. Tetrahedron 2001, 57, 4283–4295; (b) Horrobin, T.;
Tran, C. H.; Crout, D. J. Chem. Soc., Perkin Trans. 1
1998, 1069–1080; In the presence of bases: (c) Albert, R.;
mp90–92 ꢁC. IR (KBr): 1680 cmÀ1
.
1H NMR: 1.70 (s,
3H, Me), 1.78 (s, 3H, Me), 4.13 (d, 2H, J = 6.95 Hz,
CH2–CH@C), 4.91 (s, 2H, CH2Ar), 5.46 (br t, 1H,
J = 7 Hz, CH@CMe2), 7.4 (t, 1H, J = 7.9 Hz, Ar), 7.58 (t,
1H, J = 7.8 Hz, Ar), 7.68 (d, 1H, J = 8 Hz, Ar), 8.09 (d,
1H, J = 7.8 Hz, Ar), 9.7 (br s, 1H, CO2H). 13C NMR:
18.1, 25.9, 67.4, 70.2, 120.8, 127.6, 127.7, 128.21, 131.7,
133.2, 137.7, 141.3, 172.2. Anal. Calcd for C13H16O3: C,
70.89; H, 7.32; O, 21.79. Found: C, 70.64; H, 7.17; O,
21.99.
Dax, K.; Stutz, A. E.; Weidmann, H. J. Carbohydr. Chem.
¨
1983, 279–292; (d) Xu, J.; Guo, Z. Carbohydr. Res. 2002,
337, 87–91.
18. See for recent examples of the uses of these protecting
groups in oligosaccharide synthesis. For Lev and ClAc:
Wong, C.-H.; Ye, X.-S.; Zhang, Z. J. Am. Chem. Soc.
1998, 120, 7137–7138; For the Fmoc group: Zhu, T.;
Boons, G.-J. Tetrahedron: Asymmetry 2000, 11, 199–205;
Roussel, F.; Takhi, M.; Schmidt, R. R. J. Org. Chem.
2001, 66, 8540–8548.
12. (a) Weises, B.; Steglich, W. Angew. Chem., Int. Ed. 1978,
17, 522–524; (b) Hassner, A.; Alexanian, V. Tetrahedron
Lett. 1978, 4475–4478.
19. Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 318–325.