The 9-xanthenylmethyl group: A novel photocleavable protecting group for amines

Article abstract of DOI:10.1016/S0040-4039(01)01370-3

The 9-xanthenylmethyl group has been investigated as a photocleavable protecting group for amines. Several amines, including two amino acids, were protected in good to very good yield. Irradiation of the protected substrates in neutral solution regenerated the starting amines in good to excellent yield.

Full text of DOI:10.1016/S0040-4039(01)01370-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6645–6647
The 9-xanthenylmethyl group: a novel photocleavable protecting
group for amines
Hong Du and Mary K. Boyd*
Department of Chemistry, Loyola University Chicago, Chicago, IL 60626, USA
Received 11 July 2001; accepted 25 July 2001
Abstract—The 9-xanthenylmethyl group has been investigated as a photocleavable protecting group for amines. Several amines,
including two amino acids, were protected in good to very good yield. Irradiation of the protected substrates in neutral solution
regenerated the starting amines in good to excellent yield. © 2001 Elsevier Science Ltd. All rights reserved.
Photolabile protecting groups have led to recent
advances in areas and technologies as varied as organic
synthesis,1 photolabile calcium chelators,2 photoactive
precursors of neurotransmitters3 and time-resolved
studies in disciplines ranging from cell biology4,5 to
X-ray crystallography.6 Photoremovable protecting
groups are also key to the novel techniques of light-
directed synthesis, whereby the preparation of large
arrays consisting of thousands of biopolymer sequences
can be accomplished.7 To advance this new technique,
several photodeprotecting groups for alcohols have
been developed.8–11 However, there is still a need to
develop a viable photocleavable protecting group for
amines. Photoremovable protecting groups currently in
use for amines employ carbamate chemistry, notably
with nitrobenzyl moieties.12 However, limitations of the
o-nitrobenzylic system include complications due to the
production of a nitrosocarbonyl byproduct, and the
necessity for an acid or other scavenger in order to
achieve high yields for deprotection.13,14 More recently,
dimethoxybenzoin carbamate has been developed as a
photolabile protecting group for secondary amines.15–17
It offers the advantage over nitrobenzyl carbamates of
the formation of an inert byproduct, but it is not
effective for primary amines or amino acids. Other
substituted benzoins have also been investigated.18
substrates containing the 9-xanthenyl backbone have
been studied previously in our research group, and we
have developed the 9-phenylxanthyl (pixyl) and 9-
phenylthioxanthyl (S-pixyl) photocleavable protecting
groups for primary alcohols.8,9 These studies suggested
to us that we consider the 9-xanthenylmethyl moiety as
a potential photolabile protecting group for amines.
In order to investigate the 9-xanthenylmethyl moiety as
a potential photolabile protecting group for amines,
five primary amines, 4a–e (Table 1) were chosen as test
substrates. Amines 4a–c were protected by reaction
with 9-xanthenylmethyl phenylcarbonate 3a to yield
carbamates 5a–c, respectively, while substrates 4d–e
were reacted with 9-xanthenylmethyl p-nitrophenylcar-
bonate 3b to yield 5d–e (Scheme 1). Each of the deriva-
tives was isolated as a pure white crystalline solid
following column chromatography with an eluant of
hexane:ethyl acetate. Compounds 5a–e were character-
1
ized by melting point, H and 13C NMR and FT-IR.20
The yields for formation of the protected amines are
shown in Table 1.
Table 1. Amine protection and deprotection yields
Substrates
Protection yieldsa Deprotection yieldsb
4a cyclohexylamine
4b benzylamine
4c phenethylamine
4d phenylalanine
81
68
77
62
90
72
79
52
65
One literature report noted that the 9-xanthenylmethyl
group served as a base-sensitive protecting group for
amines.19 This group was very stable to trifluoroacetic
acid and catalytic hydrogenolysis, both common ther-
mal deprotection conditions for other protecting groups
in peptide synthesis. The photochemical properties of
4e glycine benzyl ester 84
a Isolated yield after column chromatography (hexane:ethyl acetate
on silica).
b Photolysis conditions: 300 nm, 5°C. Deprotection yields for 5a–c
were analyzed by GC. Deprotection yields for 5d and 5e were
analyzed by HPLC.
* Corresponding author. Tel.: 773-508-3174; fax: 773-508-3086;
e-mail: mboyd@luc.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01370-3

6646
H. Du, M. K. Boyd / Tetrahedron Letters 42 (2001) 6645–6647
H
COOH
H
CH2OH
Acknowledgements
LiAlH4
THF
O
O
Acknowledgement is made to the donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for the support of this research.
1
2
O
X
OCCl
pyridine, CH2Cl2
References
O
O
X
H
CH2OCO
H
CH2OC NHR
1. Organic Photochemistry; Pillai, V. N. R.; Padwa, A.,
Eds.; Marcel Dekker: New York, 1987; Vol. 9, pp. 225–
323.
2. Ellis-Davies, G. C. R.; Kaplan, J. H. J. Org. Chem. 1988,
53, 1966–1969.
RNH2
(4a-e)
i, ii, iii
O
O
3a-b
5a-e
3. Wilcox, M.; Viola, R. W.; Johnson, K. W.; Billington, A.
P.; Carpenter, B. K.; McCray, J. A.; Guzidowski, A. P.;
Hess, G. P. J. Org. Chem. 1990, 55, 1585–1589.
4. Adams, S. R.; Kao, J. P. Y.; Tsien, R. Y. J. Am. Chem.
Soc. 1989, 111, 7957–7968.
5. Trentham, D. R. J. Am. Chem. Soc. 1988, 110, 7170–
7177.
6. Schlichting, I.; Rapp, G.; John, J.; Wittinghoffer, A.; Pai,
E. F.; Goody, R. S. Proc. Natl. Acad. Sci. USA 1989, 86,
7687–7690.
Scheme 1. 3a: X=H, 3b: X=NO2. 5a–c: i=DMF, 5d: ii=
Na2CO3/THF, 5e: iii=TEA/THF.
Photochemical deprotection was accomplished by irra-
diation of 5a–e in neutral aqueous acetonitrile using
low pressure 300 nm mercury lamps and quartz photol-
ysis tubes in a Rayonet photolysis chamber. Analysis of
the photolysis solution by GC or HPLC showed recov-
ery of the substrate amines. Parallel dark reactions were
conducted for all experiments and demonstrated that
there was no thermal reaction under the photolysis
conditions.
7. Fodor, S. P. A.; Read, J. L.; Pirrung, M. C.; Stryer, L.;
Lu, A. T.; Solas, D. Science 1991, 251, 767–773.
8. Misetic, A.; Boyd, M. K. Tetrahedron Lett. 1998, 39,
1653–1656.
9. Coleman, M. P.; Boyd, M. K. Tetrahedron Lett. 1999, 40,
7911–7915.
10. Pirrung, M. C.; Bradley, J. C. J. Org. Chem. 1995, 60,
1116–1117.
11. Pirrung, M. C.; Lee, Y. R. J. Org. Chem. 1993, 58,
6961–6963.
12. Green, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley: New York, 1999; pp.
545–547.
13. Holmes, C. P.; Kiangsoontra, B. Pept.: Chem., Struct.
Biol., Proc. Am. Pept. Sup., 13th. 1994, 110.
14. Amit, B.; Zehavi, U.; Patchornik, A. J. Org. Chem. 1974,
39, 192–196.
15. Cameron, J. F.; Willson, C. G.; Frechet, J. M. J. J.
Chem. Soc., Chem. Commun. 1995, 923–924.
16. Pirrung, M. C.; Huang, C.-Y. Tetrahedron Lett. 1995, 36,
5883–5884.
17. Papageorgiou, G.; Corrie, J. E. T. Tetrahedron 1997, 53,
3917–3932.
18. Cameron, J. F.; Willson, C. G.; Frechet, J. M. J. J.
Chem. Soc., Perkin Trans. 1 1997, 2429–2442.
19. Carpino, L. A.; Wu, A. C. US Patent 446 021 05, 1989;
Chem. Abstr. 1991, 115, 183967.
20. The following synthesis is representative for 5a–c: 9-Xan-
thylmethyl phenylcarbonate 3a19 (0.32 mmol, 0.11 g) was
dissolved in 1.5 mL DMF at 50°C. Cyclohexylamine
(0.35 mmol, 0.040 mL) was dissolved in 0.5 mL DMF,
and added to the 9-xanthylmethyl phenylcarbonate solu-
tion. The reaction mixture was stirred overnight at 50°C.
Ethyl ether (10 mL) and water (10 mL) were added to the
reaction mixture. The aqueous layer was washed with
ether (2×10 mL). The combined organic layers were dried
over MgSO4, filtered and the solvent was evaporated in
vacuo to give a white solid. Recrystallization from hex-
ane:ethyl acetate (95:5) gave 0.078 g (72%). Mp 135–
Experiments were conducted in order to determine both
the best possible solvent system and irradiation time to
optimize the deprotection yield. When the solvent sys-
tem was varied from 10:90 to 50:50 water:acetonitrile,
an optimum deprotection yield for amine recovery was
obtained using
a
solvent system of 40:60
water:acetonitrile for substrates 5a–c. A solvent system
of 50:50 water:acetonitrile was used for substrates 5d
and 5e. Higher percentages of water resulted in solubil-
ity problems for some of the substrates. Reaction con-
ditions were also optimized by varying times of
irradiation. Optimum deprotection times varied from
80 to 150 min. Longer irradiation times resulted in
decreased deprotection yields due to secondary pho-
toreactions. The deprotection yields are summarized in
Table 1. Very good to excellent yields were obtained for
5a–c, demonstrating the utility of the 9-phenylxan-
thenyl carbamate moiety as a photolabile protecting
group for primary amines. However, lower yields were
obtained for 5d and 5e. We were unable to obtain
higher yields for the deprotection due to a secondary
photochemical reaction between the amines and xan-
thone, a byproduct of the irradiation. This secondary
reaction was particularly problematic for the selected
amino acid substrates. In addition, both substrates 5d
and 5e contain g-benzylic hydrogens, which may be
abstracted by the carbonate carbonyl resulting in addi-
tional side reactions. Higher yields may be expected
with other amino acid substrates.
In summary, the 9-xanthenylmethyl moiety is a useful
photoremovable protecting group for selected primary
amines.

H. Du, M. K. Boyd / Tetrahedron Letters 42 (2001) 6645–6647
6647
1
137°C IR: 3328 cm−1 (N-H), 1689 cm−1 (CꢀO). H NMR
(CDCl3) l 1.10–1.90 (m, 10H), 3.85 (m, 1H), 4.16 (d, 2H),
4.25 (t, 1H), 4.55 (d, 1H), 7.05–7.30 (m, 8H). 13C NMR
l 24.80, 25.44, 33.34, 49.81, 39.08, 69.55, 116.45, 121.67,
extraction with ethyl acetate (3×20 mL). The organic
layer was dried over MgSO4 and the solvent was removed
in vacuo. The remaining mixture was chromatographed
on silica gel to give 0.11 g (56%) white solid. Mp 141–
143°C (lit. mp 143–145°C).19 IR: 1716 cm−1 (CꢀO), 3328
123.13, 128.25, 129.27, 152.19, 155.29. 5b: mp 81–83°C.
(CꢀO), 3334 cm−1 (-NH-). 1H NMR
−1
1
cm−1 (OH), 3405 cm−1 (NH). H NMR (CDCl3) l 3.04–
IR: 1712 cm
(CDCl3) l 4.30 (m, 5H), 5.0 (s, 1H), 7.08–7.30 (m, 13H).
3.18 (m, 2H), 4.08–4.24 (m, 3H), 4.64 (dd, 1H), 5.10 (d,
1H), 7.01–7.32 (m, 13H). 13C NMR l 837.75, 38.95,
54.45, 70.08, 116.55, 121.28, 121.35, 123.22, 127.27,
128.40, 128.68, 129.29, 135.45, 152.17, 155.56, 175.77.
9-Xanthenylmethoxycarbonyl glycine benzyl ester 5e.
Glycine benzyl ester p-toluenesulfonate salt (0.21 g, 0.61
mmol) was dissolved in 6.0 mL THF, 400 ml triethyl
amine was added, and stirred until the solution turned to
clear. 9-Xanthylmethyl p-nitrophenylcarbonate 3b (0.23
g, 0.60 mmol) was dissolved in 6.0 mL freshly distilled
THF, and was added dropwise into the above solution.
The reaction mixture was stirred at room temperature
overnight, when TLC indicated no more 9-xanthylmethyl
p-nitrophenylcarbonate remained. The THF was evapo-
rated in vacuo, the remaining mixture was chro-
matographed on silica gel with 3:1 hexane:ethyl acetate to
13C NMR l 39.07, 45.02, 69.97, 116.51, 121.53, 123.17,
127.31, 127.36, 127.49, 128.31, 128.65, 129.23, 138.20,
−1
152.23, 156.16. 5c: mp 87–89°C. IR: 1710 cm
(CꢀO),
3328 cm −1 (-NH-). 1H NMR (CDCl3) l 2.78 (t, 2H), 3.40
(q, 2H), 4.22 (m, 3H), 4.72 (s, 1H), 7.08–7.30 (m, 13H).
13C NMR l 39.045 (CH), 69.737 (CH2), 36.132, 42.117
(CH2CH2), 116.48, 121.56, 123.14, 126.49, 128.29, 128.60,
128.77, 129.28, 138.71, 152.17, 156.02).
9-Xanthenylmethoxycarbonyl-
L
-phenylalanine 5d.
L-
Phenylalanine (0.08 g, 0.49 mmol) was dissolved in 4.0
mL aqueous Na2CO3, and stirred at room temperature
for 10 min. 9-Xanthylmethyl p-nitrophenylcarbonate 3b
(0.21 g, 0.55 mmol) was dissolved in 6.0 mL freshly
distilled THF, and was added dropwise into the L-phenyl-
alanine solution. The reaction mixture was stirred at
room temperature for 5.5 h when TLC indicated no more
9-xanthylmethyl p-nitrophenylcarbonate remained. The
THF was removed in vacuo. The reaction mixture was
poured into 20 mL H2O, and extracted with ether (2×20
mL). The aqueous layer was acidified with 6 M HCl to
pH 2, and kept in the refrigerator overnight followed by
1
give 0.20 g (85%) of a white solid. Mp 82.5–84.5°C. H
NMR l 3.94 (d, 2H), 4.16 (d, 2H), 4.26 (t, 1H), 5.16 (s,
1H), 5.25 (s, 1H), 7.00–7.34 (m, 13H). 13C NMR l 38.89,
42.70, 67.14, 70.13, 116.46, 121.38, 123.16, 128.31, 128.32,
128.49, 128.58, 129.29, 135.08, 152.10, 155.99, 169.76.