Safety Catch Linker for Solid-Phase Synthesis
J . Org. Chem., Vol. 64, No. 10, 1999 3459
solution was syringed to a suspension of Merrifield resin (2 g,
2 mmol, 100 mol %) in anhydrous DMF (10 mL) and the
mixture shaken under argon for 12 h at 25 °C. The resin was
filtered, washed, and dried under vacuum to give the resin-
Resin 7f: loading ) 0.61 mmol/g (97%); IR 1725 (b), 3445,
3368 cm-1. Found: N, 0.8; S, 4.2.
Resin 7g: loading ) 0.25 mmol/g (94%); IR 1720 (b), 3445,
3368 cm-1. Found: N, 0.4; S, 1.7.
bound aldehydes 5a ,d ,f: IR 1697 cm-1
.
Gen er a l P r oced u r e for Dith ia n e Dep r otection of 7a -g
Usin g P er iod ic Acid (8a -g). A solution of periodic acid (68
µL, 0.3 mmol, 300 mol %) in anhydrous THF (1 mL) was added
dropwise to a suspension of the Fmoc-â-alanine loaded resin
7a -g (100 mg, ∼0.1 mmol, 100 mol %) in anhydrous THF (0.5
mL), and the mixture was gently stirred at room temperature.
The dithiane 13C NMR signals were virtually lost after 1 h.
The resin was filtered, washed, and dried under vacuum to
give the resin-bound dithiane-deprotected benzoin 8a -g.
Resin 8a : Fmoc analysis 0.65 mmol/g; IR 1695 cm-1; δC
171.5, 156.5, 144.0, 141.2, 133.7, 130.3, 128.7, 127.6, 127.0,
125.3, 121.1, 115.2, 77.9, 70.3, 66.8, 47.2, 36.5, 34.8. Found:
N, 1.0; S, 0.7 (83%, i.e., 0.54 mmol/g of 8a ).
Resin -Bou n d Ben za ld eh yd e 5b. Same procedure as for
5a except a mixture of phenol (3 × 70 mol %) and 3-hydroxy-
benzaldehyde (3 × 30 mol %) was used: IR 1697 cm-1
.
Resin -Bou n d Ben za ld eh yd e 5c,e. Same procedure as for
5a except 3-hydroxy-5-methoxybenzaldehyde32 (300 mol %)
was used: IR 1700 cm-1
.
Resin -Bou n d Ben za ld eh yd e 5g. Same procedure as for
5a except bromomethyl Tentagel resin (100 mol %) was used:
IR ) 1697 cm-1
.
Resin -Bou n d Dith ia n e-P r otected Ben zoin 6a . To a
stirred solution of 2-phenyl-1,3-dithiane (0.78 g, 4 mmol, 400
mol %) in anhydrous THF (4 mL) under argon at -78 °C was
added n-butyllithium (1.76 mL, 3.5 mmol, 350 mol %), and
stirring was continued for 10 min at 0 °C. This solution was
transferred via a cannula to a suspension of aldehyde resin
5a (1.0 g, ∼1 mmol, 100 mol %) cooled to 0 °C in THF (6 mL),
and the mixture was gently stirred at 0 °C. The aldehyde IR
peak was completely lost after stirring for 1 h. The resin
suspension was quenched with dilute 1 N HCl (5 mL), and
the resin was filtered, washed, and dried under vacuum to give
the resin-bound dithiane-protected benzoin 6a : loading ) 0.80
mmol/g (99%); IR 3583, 3445 (b) cm-1; δC 138.8, 137.5, 130.7,
128.1, 127.5, 126.0, 115.3, 113,9, 80.9, 69.7, 66.3, 27.2, 27.0,
24.7. Anal. Calcd: S, 5.18 Found: S, 5.1.
Resin 8b: Fmoc analysis 0.26 mmol/g; IR 1696 cm-1; δC
143.9, 141.2, 133.7, 127.6, 127.0, 125.2, 120.8, 119.9, 114.8,
77.9, 69.8, 66.8, 47.2, 36.9, 34.3. Found: N, 0.4; S, 0.2 (87%,
i.e., 0.21 mmol/g of 8a ).
Resin 8c: Fmoc analysis 0.61 mmol/g; IR 1696 cm-1; δC
171.5, 156.8, 144.0, 141.2, 136.3, 136.2, 128.7, 127.6, 127.0,
125.3, 119.9, 107.6, 101.9, 78.0, 70.0, 66.8, 55.3, 47.2, 36.9, 34.8.
Found: N, 0.9; S, 0.9 (78%, i.e., 0.51 mmol/g of 8a ).
R esin 8d : Fmoc analysis 0.50 mmol/g; IR 1682 cm-1; δC
171.8, 164.3, 156.1, 143.9, 141.2, 134.9, 127.6, 127.0, 125.3,
120.9, 14.0, 77.6, 70.0, 66.0, 55.4, 47.2, 37.0, 34.9. Found: N,
1.1; S, 0.4 (90%, i.e., 0.56 mmol/g of 8a ).
Resin 8e: Fmoc analysis 0.58 mmol/g; IR 1682 cm-1; δC
171.5, 156.5, 143.9, 141.2, 131.2, 127.6, 127.0, 119.9, 113.9,
107.5, 77.7, 70.1, 66.8, 55.4, 47.2, 36.5, 34.8. Found: N, 0.8;
S, 0.8 (76%, i.e., 0.40 mmol/g of 8a ).
Resin -Bou n d Dith ian e-P r otected Ben zoin s 6b,c,g. Same
procedure as for 6a except aldehyde resins 5b, 5c, and 5g (100
mol %) were used, respectively.
Resin 6b: loading ) 0.27 mmol/g. Found: S, 1.7.
Resin 8f: Fmoc analysis 0.66 mmol/g; IR 1715 cm-1
;
Resin 6c: loading ) 0.81 mmol/g (103%); IR 3583, 3445 (b)
δC162.0, 156.3, 143.9, 141.2, 127.6, 127.0, 125.1, 119.9, 115.9,
115.1, 77.6, 70.0, 66.8, 47.2, 36.8, 34.6. Found: N, 0.9; S, 0.9
(78%, i.e., 0.50 mmol/g of 8a ).
cm-1. Calcd: S, 5.1. Found: S, 5.3.
Resin 6g: loading ) 0.29 mmol/g (100%); IR 3514 (b) cm-1
Calcd: S, 1.9. Found: S, 1.9.
.
Resin 8g: Fmoc analysis 0.26 mmol/g; IR 1697 cm-1; δC
193.3, 170.9, 158.8, 155.9, 143.5, 140.7, 134.0, 133.7, 133.3,
129.7, 128.3, 127.1, 126.5, 124.7, 120.7, 119.4, 115.0, 114.5,
77.3, 69.0, 66.9, 63.0, 46.6, 36.4, 34.3. Found: N, 0.4; S, 0.5
(69%, i.e., 0.18 mmol/g of 8a ).
Resin -Bou n d Dith ia n e-P r otected Ben zoin 6d ,e. Same
procedure as for 6a except 2-(4-dimethoxyphenyl)-1,3-dithiane28
(0.30 g, 1.5 mmol, 300 mol %) and aldehyde resin 5d or 5e
(100 mol %) were used.
Resin 6d : loading ) 0.81 mmol/g (103%); IR 3583, 3445
Subjecting 8a ,g to the same deprotecting conditions yielded
a further 5-10% reduction in S content.
(b) cm-1. Calcd: S, 5.1. Found: S, 5.2.
Resin 6e: loading ) 0.78 mmol/g (101%); IR 3584, 3445 (b)
cm-1. Calcd: S, 4.9. Found: S, 5.0.
Gen er a l P r oced u r e for Dith ia n e Dep r otection of 7a
Usin g Meth yl Tr ifla te. Methyl triflate (136 µL, 0.96 mmol,
1000 mol %) was added dropwise to a suspension of the Fmoc-
â-alanine loaded resin 8a (120 mg, ∼0.1 mmol, 100 mol %) in
anhydrous DCM (1 mL), and the mixture was gently stirred
at room temperature. The dithiane 13C NMR signals were
virtually lost after 20 min. The resin was filtered, washed, and
dried under vacuum to give the resin-bound dithiane-depro-
tected benzoin 8a . Found: N, 1.0; S, 0.9 (79%, i.e., 0.54 mmol/g
of 8a ). Subjecting 8a to the same deprotecting conditions
yielded a further 5-10% reduction in S content.
Resin -Bou n d Dith ia n e-P r otected Ben zoin 6f. Same
procedure as for 6a except 2-(3-trifluoromethylphenyl)-1,3-
dithiane and aldehyde resin 5f (100 mol %) were used: loading
) 0.78 mmol/g (101%); IR 3582, 3445 (b) cm-1. Calcd: S, 4.9.
Found: S, 5.0.
Gen er a l F m oc-P r otected â-Ala n in e Loa d in g P r oce-
d u r e (7a -g). Diisopropylcarbodiimide (94 µL, 0.6 mmol, 300
mol %) followed by diisopropylethylamine (104 µL, 0.6 mmol,
300 mol %) was syringed into a solution of dithiane-protected
benzoin resin 6a -g (200 mg, ∼0.2 mmol, 100 mol %), Fmoc-
protected â-alanine (168 mg, 0.6 mmol. 300 mol %), (dimethyl-
amino)pyridine (10 mg), and HOBt (10 mg) in anhydrous DMF
(2 mL) under argon at room temperature, and the mixture was
gently stirred for 5 h. The resin was filtered, washed, and dried
under vacuum to give the resin-bound Fmoc-protected amino
acid 7a -g. Loading was determined by Fmoc analysis of
7a -g.
Gen er a l P h otolysis P r oced u r e (9a -g). Dithiane-depro-
tected resin 8a -g (20 mg) and Fmoc-serine (internal standard,
3 mg) in 3:1 distilled THF/MeOH (12 mL) in a quartz test tube
was purged with a stream of nitrogen gas for 10 min. The
suspension was UV irradiated for 2 h with constant N2
bubbling to yield the benzofuranyl resin 9a -g and Fmoc-
protected â-alanine in solution. Twenty-five microliters of
solution was removed at various time intervals and analyzed
by HPLC using UV detection at 254 nm. A 1H NMR spectrum
of the cleaved Fmoc-protected â-alanine was identical to an
authentic sample.
Resin 7a : loading ) 0.62 mmol/g (95%); IR 1725 (b), 3445,
3368 cm-1; δC 170.2, 156.3, 143.9, 141.2, 136.9, 130.7, 128.2,
127.6, 127.0, 125.0, 119.9, 115.3, 114.5, 80.6, 69.7, 66.6, 47.2,
36.5, 35.0, 27.2, 24.6. Found: N, 1.1. S, 4.1.
Resin 9a : Fmoc analysis 0.13 mmol/g; δC 47.2, 27.2, 24.7.
Resin 9b: Fmoc analysis 0.09 mmol/g.
Resin 9c: Fmoc analysis 0.18 mmol/g.
Resin 9d : Fmoc analysis 0.41 mmol/g.
Resin 7b: loading ) 0.24 mmol/g (100%); IR 1725 (b) cm-1
Found: N, 0.4; S, 1.5.
.
Resin 7c: loading ) 0.62 mmol/g (97%); IR 1728 (b), 3445,
3368 cm-1. Found: N, 0.9; S, 4.6.
Resin 9e: Fmoc analysis 0.13 mmol/g.
Resin 7d : loading ) 0.59 mmol/g (92%); IR 1726 (b), 3445,
3368 cm-1. Found: N, 0.9; S, 4.1.
Resin 9f: Fmoc analysis 0.20 mmol/g.
Resin 9 g: Fmoc analysis 0.07 mmol/g.
Resin 7e: loading ) 0.51 mmol/g (81%); IR 1724 (b), 3445,
Gen er a l P r oced u r e for Ben zoyla tin g Resin 6a (12h ,i).
To a suspension of resin 6a (200 mg, ∼0.15 mmol) in
3368 cm-1. Found: N, 0.8; S, 4.2.