2-Naphthylmethoxymethyl as a Mildly Introducible and Oxidatively Removable Benzyloxymethyl-Type Protecting Group

Article abstract of DOI:10.1021/acs.orglett.5b01408

2-Naphthylmethoxymethyl (NAPOM) was developed for the protection of various hydroxy (including phenolic hydroxy and carboxy) and mercapto groups. The NAPOM group can be introduced in extremely mild conditions (naphthylmethoxymethyl chloride, 2,6-lutidine, room temperature) without concomitant acyl migration in a 1,2-diol system. Furthermore, selective removal of NAPOM in the presence of naphthylmethyl (NAP) and p-methoxybenzyl (PMB) groups and, conversely, that of PMB in the presence of NAPOM were realized. These results, as well as its easy handling and compatibility with various solvents, show that NAPOM is a novel and useful choice as a protecting group.

Full text of DOI:10.1021/acs.orglett.5b01408

Letter
pubs.acs.org/OrgLett
2‑Naphthylmethoxymethyl as a Mildly Introducible and Oxidatively
Removable Benzyloxymethyl-Type Protecting Group
Takuya Sato, Tohru Oishi, and Kohei Torikai*
Department of Chemistry, Faculty and Graduate School of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka
812-8581, Japan
S
* Supporting Information
ABSTRACT: 2-Naphthylmethoxymethyl (NAPOM) was developed
for the protection of various hydroxy (including phenolic hydroxy
and carboxy) and mercapto groups. The NAPOM group can be
introduced in extremely mild conditions (naphthylmethoxymethyl
chloride, 2,6-lutidine, room temperature) without concomitant acyl
migration in a 1,2-diol system. Furthermore, selective removal of
NAPOM in the presence of naphthylmethyl (NAP) and p-
methoxybenzyl (PMB) groups and, conversely, that of PMB in the
presence of NAPOM were realized. These results, as well as its easy
handling and compatibility with various solvents, show that NAPOM
is a novel and useful choice as a protecting group.
Furthermore, even DIPEA sometimes causes side reactions
such as acyl migration in 1,2-diol systems.
rotecting groups are still playing important roles in the
Psynthesis of complex molecules, despite the recent negative
campaign against using them stating that they increase the E-
factor and the number of steps. Even in current studies of
multistep synthesis, the selection of appropriate protecting
groups is sometimes critical. The Benzyl (Bn) group and its
substituted analogs form one of the main families of protective
groups in synthetic organic chemistry.1 They have been widely
used because of their clean and mild cleavage in reductive
conditions (e.g., H2, Pd/C). Among these, the p-methoxybenzyl
(PMB) and 2-naphthylmethyl (NAP) groups have been
developed, which enable the selective cleavage in the presence
of Bn groups by oxidative removal (e.g., with DDQ or CAN).1
In contrast to the mildness of deprotection, the introduction
of Bn groups suffers from the harsh basic (e.g., NaH, BnBr,
DMF; diisopropylethyl amine (DIPEA), BnBr, neat, 150 °C)2
or acidic (e.g., BnOC(NH)CCl3, TfOH)3 conditions it
requires4 as well as from the procedure’s moisture sensitivity
that prevents operation at a small scale or by beginners and
nonspecialists. When a substrate is acid or base sensitive,
another choice is the benzyloxymethyl (BOM) family, since it
allows using a weaker base such as DIPEA for the
introduction.1 Hence, in multistep syntheses, sensitive alcohols
requiring oxidative deprotection at a later stage have been
protected as p-methoxybenzyloxymethyl (PMBOM) ethers.1
However, PMBOMCl, which is the most commonly used
reagent for introducing the PMBOM group, is known to be
labile (storable for less than 3 days at −20 °C),5 requiring its
fresh preparation. In addition, preparation of PMBOMCl also
requires a reaction at low temperature (generally −78 °C) that
releases sulfur-containing byproducts, which can act as a
catalytic poison to transition metals used for hydrogenolysis.6
To solve the problems above, we here report the develop-
ment of the 2-naphthylmethoxymethyl (NAPOM) group as a
new member of the BOM family, which can be introduced
under mild conditions and removed under oxidative conditions.
It is also easy-to-handle without requiring special attention to
moisture and air.
First, as mentioned in the literature,7 2-naphthylmethoxy-
methyl chloride (NAPOMCl) was successfully prepared from
2-naphthylmethyl alcohol and paraformaldehyde catalyzed by
gaseous HCl and could be stored in the presence of CaCl2
(neutral drying agent) for more than a year at −20 °C without
decomposition.8 We then examined protection and depro-
tection of various alcohols as shown in Table 1. Introduction of
the NAPOM group was successfully achieved by treatment of
primary (1a), secondary (2a), and tertiary (3a) alcohols, a
carboxylic acid 4a, a phenol 5a, and even a thiol 6a with
NAPOMCl in the presence of DIPEA and CaCl29 in CH2Cl2 at
rt (entries 1−6). Although the use of excess reagent (3 equiv of
NAPOMCl and 6 equiv of DIPEA) and a prolonged reaction
time (32.5 h) were required for the protection of the tertiary
alcohol 3a (entry 3), it is noteworthy that all the reactions
proceeded at rt in satisfactory yields (>90%). Thus, as a second
step, removal of the NAPOM group from 1a−6a was
conducted with DDQ in an 18:1 mixture of CH2Cl2 and
phosphate buffered water (pH 7.0) at rt. Compounds (1a−5a)
were obtained in yields of 88−100%. Removal of the NAPOM
group from 6b also proceeded smoothly to give 6c in a yield of
94%.10 These results indicate that the NAPOM group has
Received: May 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01408
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Organic Letters
Letter
Table 1. Introduction and Removal of NAPOM Groups onto
Hydroxy Groups
Table 2. Compatibility with Solvents
introduction
removal
reaction time/h
a
solvent
reaction time/h
yield/%
yield/%
c
hexane
toluene
MTBE
CH2Cl2
AcOEt
THF
50
15.5
109
39
77
93
83
97
92
85
78
82
72
15
87
c
11.5
86
c
109
99
b
2
17
91
c
50
97
c
109
109
109
109
109
25
c
CH3CN
DMF
17.5
98
c
109
109
31
c
DMSO
63
a
b
3 equiv of NAPOMCl and 6 equiv of DIPEA were used. 1.5 equiv of
c
DDQ were used. 2.5 equiv of DDQ were used.
been reported to date. First, the introduction of the NAPOM
group onto monoacetylated diol 7 was attempted under the
conventional conditions using DIPEA (entry 1 of Table 3).
Table 3. Introduction and Removal of NAPOM Group on
Sensitive Alcohols
a
b
Isolated yields, after silica gel column chromatography. NAPOMCl
(1.8 to 3 equiv), DIPEA (4 to 6 equiv), CaCl2 (100 wt %), CH2Cl2
c
(subs. concn 0.1 M), rt, 6.5 to 32.5 h. DDQ (1.5 equiv), CH2Cl2/
d
phosphate buffered water (pH 7.0) = 18/1, rt, 2 to 3.5 h. Purified by
e
recrystallization. DDQ (2.0 equiv), CH2Cl2/pH 7.0 buffer, rt, 22.5 h.
potential as a novel oxidatively removable member of the BOM
protective groups.
To further investigate the usability of the NAPOM group, its
compatibility with a number of solvents was examined. The
results for the protection of 3a and the deprotection of 3b,
conducted in various solvents, in the absence of CaCl2 and
exposed to air, are shown in Table 2. For the introduction of
the NAPOM group, in all the solvents tested, the reactions
proceeded in moderate (77% in hexane, 78% in CH3CN, 72%
in DMSO, 82% in DMF, 83% in methyl-tert-butyl ether
(MTBE), and 85% in THF) to excellent (92% in AcOEt, 93%
in toluene, and 97% in CH2Cl2) yields. For the deprotection
with DDQ, the reaction also accepted many solvents such as
CH2Cl2 (91%), AcOEt (97%), hexane (87%), toluene (86%),
CH3CN (98%), and MTBE (99%), although relatively polar
solvents were less favored (25% in THF, 31% in DMF, and
63% in DMSO). The reaction’s compatibility with atmospheric
moisture, air, and a broad choice of solvents could be favorable
not only in academic but also in industrial contexts.
We next turned our attention to the challenging introduction
of the NAPOM group onto sensitive substrates. 1,2-Diols are
known to give irregular results during protection and
deprotection. Of these, monoacylated 1,2-diols are notorious
for undergoing acyl migration under both acidic and basic
conditions. To the best of our knowledge, clean introduction of
the BOM and MOM group onto 2-acetoxy-1-ols has never
a
Inseparable. Yield was calculated from 1H NMR spectrum of the
mixture.
Despite the mild basicity and temperature, acyl migration
occurred to give a mixture of the desired product 8a (47%) and
the migrated product 8b (19%) as expected.11 After
considerable experimentation,12 we finally found that the
treatment of 7 with NAPOMCl in the presence of 2,6-lutidine
and TBAI at rt (entry 2) furnished the desired compound 8a in
good yield (89%), with little migration product 8b (3%). The
method using 2,6-lutidine was also effective for the protection
of 9 (giving 10a in 75% yield, entry 3), an alcohol possessing a
highly reactive benzyl chloride moiety, while a conventional
mild method using Ag2O and alkyl halides was difficult to apply.
Another task was the deprotection of the mono-NAPOM
protected diol 11 (entry 4). Attempted deprotection of 11 with
B
DOI: 10.1021/acs.orglett.5b01408
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DDQ in pH. 7.0 buffer resulted in the formation of the cyclic
acetal 12b as the main product (51%) with concomitant
formation of the desired diol 12a (27%). In order to accelerate
the in situ acidic hydrolysis of 12b to 12a, we examined the
reaction in nonbuffered water (entry 5). Although TLC
revealed the presence of more 12a than in the previous
experiment, the reaction was incomplete with remaining 12b.
However, addition of MeOH, which might act as a mediator of
H+ between the CH2Cl2 and H2O phases, proved to be a
solution to this problem, affording the desired diol 12a in 90%
yield.
ASSOCIATED CONTENT
* Supporting Information
Synthetic procedures, spectral data, and H and 13C NMR
charts of new compounds. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b01408.
■
S
1
AUTHOR INFORMATION
■
Corresponding Author
* E-mail: torikai@chem.kyushu-univ.jp.
Notes
Having established the mild introduction and robust removal
methods, the characteristics and conditions of selective removal
of NAPOM were investigated (Scheme 1). In acidic media, the
The authors declare the following competing financial
interest(s): A patent, regarding NAPOMCl-utilization for the
protection of alcohols and thiols, is pending (Kyushu
University. Japanese Patent Application No. 2014-206408,
October 7, 2014).
a
Scheme 1. Selective Removal
ACKNOWLEDGMENTS
■
We are grateful to Koji Kosaka, Ryosuke Iryo, and Takuya
Kubo in our laboratory for their preliminary experimentation.
We thank Mr. Nicholas Shillingford, who teaches on the Front
Researcher Program (Graduate School of Sciences, Kyushu
University), for his proofreading. This work was financially
supported by the Grant-in-Aid for Young Scientists (B) (No.
15K21210 to K.T.) from JSPS and the grant from Wako Pure
Chemical Industries (to K.T.), accompanied by the Wako
Award in Synthetic Organic Chemistry, Japan.
REFERENCES
■
a
1:1 (mol/mol) mixture of substrates was used. For each entry,
(1) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; John Wiley & Sons: NJ, 2007.
(2) Gathirwa, J. W.; Maki, T. Tetrahedron 2012, 68, 370−375.
(3) Iversen, T.; Bundle, K. R. J. Chem. Soc., Chem. Commun. 1981,
1240−1241.
(4) Many Lewis acids are also used.
(5) Kozikowski, A. P.; Wu, J.-P. Tetrahedron Lett. 1987, 28, 5125−
5128.
(6) PMBOMCl was prepared by the treatment of PMBOCH2SMe
with SO2Cl2 at −78 °C; see: Benneche, T.; Strande, P.; Undheim, K.
Synthesis 1983, 762−763. Subsequent hydrogenolytic deprotections of
freshly prepared PMBOM ethers often resulted in failure, probably
because a traceless amount of sulfur-containing species was
contaminated.
(7) Stefan, E.; Taylor, R. E. Org. Lett. 2012, 14, 3490−3493. In this
paper, NAPOM ether was prepared but immediately converted to the
corresponding NAP ether, via an original rearrangement reaction. The
usage of NAPOM as a protecting group has never been reported.
(8) NAPOMCl is storable at 4 °C for several months (1-month-
storage at 4 °C caused 13% decrease of NAPOMCl), although it
decomposed at rt (t1/2 at rt is ca. 10 days).
compounds whose protecting groups remained untouched are
highlighted in red.
NAPOM group was found to be more stable than the
triisopropylsilyl (TIPS) group, which allows the CSA-mediated
selective removal of TIPS (13) in the presence of NAPOM
ether 1b (quantitative recovery) (Scheme 1A).13 The difference
in stability in acidic conditions also allows the selective removal
of NAPOM (1b) in the presence of NAP (14, 96% recovery)
by treatment with CBr4 in refluxing MeOH (Scheme 1B).14 On
the other hand, selective removal of PMB (15) in the presence
of the NAPOM group (1b, quantitative recovery) was readily
achieved via treatment with CAN (Scheme 1C).15,16 In
contrast, the opposite selectivity appeared when a mixture of
NAPOM- and PMB-protected compounds (1b and 15) were
subjected to hydrogenolysis; i.e., the NAPOM group was
selectively cleaved in the presence of PMB (94% recovery), by
treatment with Pd/C under a hydrogen atmosphere (1 atm)
(Scheme 1D).17
In this paper, we have reported the development of
NAPOM, a novel group of the BOM family, for the protection
of hydroxy groups.18 The advantages of the NAPOM group, i.e.
(i) storability of NAPOMCl, (ii) mild introduction using 2,6-
lutidine without triggering acyl migration, (iii) selective removal
in the presence of NAP and PMB, (iv) compatibility with
removal conditions for PMB and PMBOM, and (v) easy
handling without the need for protection from atmospheric
moisture and air, will facilitate organic syntheses (e.g.,
carbohydrates) by suggesting novel routes to the target
molecules. The total synthesis of natural products using the
NAPOM group is underway in our laboratory.
(9) Addition of CaCl2, as a neutral drying agent, is not absolutely
necessary but effectively decreases the amount of NAPOMCl required
for completing the reaction, probably by removing the moisture that
destroys the NAPOMCl.
(10) Although the generated thiol 6a automatically dimerized,
forming a disulfide bond to give 6c, reductions of alkyl disulfides to
thiols are known in the literature (for example using LiCl, NaBH4,
THF). See: Rajaram, S.; Chary, K. P.; Iyengar, D. S. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 2001, 40B, 622−624.
(11) The reaction was not clean, leading to a poor mass balance.
(12) For example, use of DMAP as a base caused acyl migration.
(13) Although the NAPOM group was more stable in acidic
conditions than TBDPS, attempted removal of TBDPS with complete
recovery of NAPOM failed. Treatment of a 1:1 mixture of the
C
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NAPOM and TBDPS ethers with CSA (1 equiv) in MeOH/THF
(5:1) for 4 h resulted in the recovery of the NAPOM ether in 68%
yield with full consumption of TBDPS ether.
(14) Lee, A. S.-Y.; Hu, Y.-J.; Chu, S.-F. Tetrahedron 2001, 57, 2121−
2126. The NAPOM group was as stable as the PMB group in protic
acids (data not shown).
(15) For the selective removal of the PMB group in the presence of
the NAP group, see: Wright, J. A.; Yu, J.; Spencer, J. B. Tetrahedron
Lett. 2001, 42, 4033−4036.
(16) In addition, as expected, NAPOM could be selectively removed
in the presence of the BOM group (91% recovery) with DDQ (1.5
equiv) at rt, but conditions to remove BOM in the presence of
NAPOM have not yet been identified.
(17) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63, 4172−
4173.
(18) Patent pending (Kyushu University. Japanese Patent Applica-
tion No. 2014-206408, October 7, 2014).
D
DOI: 10.1021/acs.orglett.5b01408
Org. Lett. XXXX, XXX, XXX−XXX