J. Xu et al. / Tetrahedron Letters 61 (2020) 151709
3
Fig. 3. HPLC traces recorded during irradiation of 2f.
Scheme 3. Possible photodeprotection mechanism.
with protection yield of 59% and deprotection yield of 65%. Partic-
ularly, a certern amount of water (1 equivalent) has been added
into the reaction mixture for every 15 min, to inhibit the thermal
effects during the illumination, and to avoid side reaction of the
amino aldehyde caused by excessive water.
1c was protected by Nppd to obtain 2c, and the process of
deprotection was detected by UV spectrophotometer (Fig. 2). A
new absorption peak appeared at the wavelength of 265 nm in
the photolysis reaction and would increase gradually with the
reaction time prolonging. This peak was the characteristic peak
of 1c [22], indicating that the original compound 1c could be
released rapidly at a constant speed from its protected compound
2c under UV at 365 nm.
reaction will not proceed without the presence of a certain amount
of water. On this basis, a possible photodeprotection mechanism
(Scheme 3) according to that of Npp [9] was infered herein. The
photorelease of Nppd from the aldehyde’s protected product (ac-
etal) via a property-labile semiacetal formed from the acetal by a
b-elimination mechanism. The semiacetal was decomposed imme-
diately andyields were lower than the actual values due to their
volatility. These aldehydes need to be processed by derivation after
the deprotection to eliminate the volatility. For example, if 1a
released from 2a after the deprotection is unprocessed by deriva-
tion, the releasing yield will fall to 13%.
Results of Nppd’s application are illustrated in Table 1, which
show that the Nppd can protect aldehydes with relatively high pro-
tection and deprotection yields. The protection yields on the aro-
matic aldehydes (1a, 1b, 1c, 1d, 1e), the unsaturated aldehyde
(1f), the amino aldehyde protected by Fmoc (1h), and the aliphatic
aldehyde (1g) were 64%, 47%, 78%, 39%, 83%, 70%, 73%, and 59%,
respectively. In addition, their deprotection yields were 71%, 83%,
96%, 87%, 86%, 75%, 65%, and 74%. Amino aldehydes are widely
used to synthesize medicine and can be served as precursors of
synthetic antimicrobial drugs penicillin [19] or anticancer drug
[20], and they also play an important role in synthesizing pseu-
dopeptide. In the meanwhile, the amino groups or aldehyde groups
of amino aldehydes are usually protected when they are used
because of their chemical instability [21]. In this study, the amino
aldehyde protected by Fmoc (1h) can be protected by the Nppd,
Reversed-phase HPLC was used to investigate the photodepro-
tection progress of protected aldehydes. For example, 2f (0.02 M
in CH3CN) was investigated during irradiation at 365 nm (Fig. 3).
The analysis was performed on Agilent 1100 apparatus equipped
with a Agela Venusil ASB C18 column (5
l
m, 4.6 mm  250 mm)
over a 10–70% gradient of acetonitrile: water with 0.1% TFA using
a gradient elution in 30 min and flow rate of 1 mL/min. The wave-
length for the detector was set at 220 nm, and the injection volume
was 10
lL. Before irradiation, a peak with a retention time of
31.0 min, corresponding to 2f, was observed. During irradiation,
this peak gradually disappeared, and a new peak (retention time
21.2 min, corresponding to 1f) appeared instead, proving that 2f
released aldehyde under photoirradiation.
The performance of Nppd and Npeg in protecting efficiency,
protecting selectivity, and deprotecting efficiency was compared
(Table 4). The results shown in Table 2 indicated that Nppd’s pro-
tecting efficiency for the carbonyls was lower than that of Npeg.
Npeg formed five-membered cyclic acetals, which were easy to
obtain, but the aldehyde group cannot be selectively protected
by Npeg, and the releasing speed of aldehydes from the Nppd
acetal is faster than that from the Npeg acetal. The deprotecting
yield of Nppd (65%–96%) is nearly the same with Npeg (31%–
90%). However, the reaction time for Nppd was only approximately
Table 4
Comparative protecting efficiency of Nppd and Npeg.
Protecting
group
Protection yield for
Protection yield for
Nppd
Npeg
0
96
78
97
.
Fig. 2. UV spectra of 2c.