A modified procedure for the deprotection of methoxymethyl ether

Article abstract of DOI:10.1016/S0040-4039(99)02200-5

A new modified procedure using a combination of catechol boron bromide with acetic acid was developed to deprotect methoxymethyl group to form 1,3- diols and 1,3-aminoalcohols. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02200-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 819–822
A modified procedure for the deprotection of methoxymethyl
ether
Chengzhi Yu, Bin Liu and Longqin Hu ∗
Department of Pharmaceutical Chemistry, College of Pharmacy, Rutgers, The State University of New Jersey,
160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA
Received 28 October 1999; revised 22 November 1999; accepted 22 November 1999
Abstract
A new modified procedure using a combination of catechol boron bromide with acetic acid was developed to
deprotect methoxymethyl group to form 1,3-diols and 1,3-aminoalcohols. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: methoxymethyl ether; catechol boron bromide; deprotection; formyl acetal.
Alkoxymethyl ethers are widely used to protect hydroxyl groups in organic synthesis. They are easily
introduced under very mild conditions and are quite stable even in the presence of strong acids and bases.
Methoxymethyl ether (MOM) group is the most robust of the alkoxymethyl ethers and plays a pivotal
role in protecting group chemistry. A variety of conditions are available for MOM cleavage;1 however,
there are often problems deprotecting MOM due to the unique structural features and functionalities in
the substrate. One such problem is the formation of cyclic formyl acetals when a nucleophilic hydroxy
or amino group is nearby.2
During our study of anticancer prodrug cyclophosphamides, we wanted to prepare 1,3-aminoalcohol
2 by removing the MOM protecting group in 1. A number of common conditions were attempted but
failed to afford the desired product 2. Instead, compound 33 was found to be the major product after flash
silica gel column chromatography. The conditions we tried include: (a) catechol boron bromide (CBB),
CH2Cl2, −78°C→0°C, 2 h, 87%; (b) HCl, MeOH, 0°C→rt, 30 min, complex; (c) (CH3)3SiBr, CH2Cl2,
0°C, 1.5 h, 67%; (d) PhSH, BF3·OEt2, CH2Cl2, 1 h, 61%; (e) TsOH·2H2O, toluene, reflux, 45 min, 55%
(yields given are for compound 3 only). The difficulty in obtaining the 1,3-aminoalcohol 2 prompted
us to develop a new procedure to cleave MOM protected 1,3-aminoalcohols or mono-MOM protected
1,3-diols.
∗
Corresponding author. Tel: (732) 445-5291; fax: (732) 445-6312; e-mail: longhu@rci.rutgers.edu (L. Hu)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02200-5
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Under common deprotection conditions, the formation of 3 could be the result of a facile acetal–acetal
exchange process where the primary amino group at the β position relative to the MOM ether was
nucleophilic and could attack the methylene electrophilic carbon forming the entropically-favored six-
membered ring. Similar examples reported in the literature showed that this could also occur when
cleaving MOM groups with nearby hydroxyl groups.2
To our knowledge, the only method that can circumvent this problem is using (i-PrS)2BBr in
methanol.4 Deprotection with (i-PrS)2BBr affords 1,2 and 1,3-diols without forming the formyl acetals
in a single step. Catechol boron halides, particularly the bromide, are similar to (i-PrS)2BBr and have
been shown to be more effective in cleaving MOM ethers in recent reports.5 They are also more selective
in multifunctional substrates. According to our experimental results, treatment of 1 using catechol boron
bromide gave compound 3 with the highest yield (87%). Therefore, it was reasonable for us to focus on
this reagent and explore further the conditions needed to effect the desired deprotection and at the same
time convert the cyclic formyl acetal to the desired product.
From the literature, we found a procedure using hydrogen bromide in acetic acid to cleave benzyl-
oxycarbonyl (Cbz) protecting group while concurrently hydrolyzing the formyl acetal functionality in
compound 4 to produce the erythro-γ-hydroxynorvaline 5.6 We reasoned that if acetic acid was added
to a mixture of 1 and excess catechol boron bromide, hydrogen bromide would be formed quickly (as
depicted below), due to the affinity of electrophilic boron(III) species for acetate anion. In this instance,
the reactive hydrogen bromide might cleave the formyl acetal in 3 to produce the desired product 2.
Based upon this hypothesis, we reinvestigated the deprotection of 1 and found that the deprotection
worked very well using the following one-pot procedure: (i) a solution of substrate 1 (1.0 g, 4.2 mmol)
in dry methylene chloride (25 mL) was cooled down to −78°C and treated with catechol boron bromide
(2.5 equiv., 2.1 g) in methylene chloride (25 mL); (ii) the reaction proceeded for 2 h at −78°C and was
allowed to warm up to −20°C before glacial acetic acid (5 equiv., 1.2 mL) was added. The reaction
mixture was stirred at ambient temperature for an additional 5 h; (iii) chloroform (100 mL) and 3N
aqueous sodium hydroxide (50 mL) were added to quench the reaction, the organic phase was washed
with 3N aqueous sodium hydroxide (3×30 mL) until the aqueous phase became colorless and clear. The
organic phase was then washed with brine and dried over anhydrous magnesium sulfate. After removal of
organic solvents under vacuum, the crude product was purified by flash silica gel column chromatography
(chloroform saturated with ammonium hydroxide: methanol, 9:1→8:1) to give 2 (0.63 g, 77%) as a
colorless oil, whose structure was confirmed by 1H NMR, IR and high resolution FAB-MS.7 Using thin
layer chromatography to monitor the reaction process, we clearly observed that 3 was formed in step (i)
and then disappeared quickly in step (ii) with the concomitant appearance of the more polar compound 2.

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This result suggests that the formyl acetal formed during the Lewis acid-catalyzed deprotection of MOM
can be completely hydrolyzed by enhancing the acidity of the medium through the addition of acetic acid
and excess CBB. It is believed that acetic acid reacted with CBB to produce hydrogen bromide, which is
the reagent responsible for the eventual cleavage of cyclic formyl acetal intermediates.
To demonstrate the capability of our new procedure, we compared the two conditions (CBB/CH2Cl2,
−78°C→0°C versus CBB/CH2Cl2 followed by HOAc, −78°C→rt) in the deprotection of compounds 6
and 9. It was found that CBB deprotection of 6 gave cyclic formal acetal 7 in 25% yield and 1,3-diol
8 in 74% yield while our modified procedure using CBB followed by the addition of acetic acid gave
compound 8 as the only product in 96% yield after isolation. Similarly, CBB deprotection of 9 gave a
mixture of 10 (28%) and 11 (71%) while CBB followed by acetic acid afforded compound 11 as the only
product in 91% yield after isolation.8 The difference between these parallel experiments indicates that
our modified procedure is better than CBB alone in deprotecting MOM groups when there is another
nucleophilic functional group situated nearby.
In conclusion, the combination of catechol boron bromide with acetic acid effectively cleaves MOM
groups, especially in cases where a neighboring hydroxy or amino group might prevent the formation of
the desired product using commonly available procedures. Our one-pot procedure presented here is mild
and convenient and should be useful in the synthesis of complex natural products.
Acknowledgements
We gratefully acknowledge the financial support of grant DAMD 17-98-1-8544 from the US Army
Department of Defense Prostate Cancer Research Program. We thank Dr. Larry Russon (OU Mass Spec.
Lab.) for providing MS spectral analysis. Part of this work was done at the University of Oklahoma
College of Pharmacy.
References
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed., Wiley-Interscience: New York, 1999; Chapter
2, pp. 29–33.
2. Barot, B. C.; Pinnick, H. W. J. Org. Chem. 1981, 46, 2981–2983.
3. Selected physical and spectral data for compound 3: IR (neat): ν/cm−1 3200, 2870, 1575, 1485, 1405, 1360, 1300, 1250,
1080, 1000, 920, 750, 675; 1H NMR (300 MHz, CDCl3): δ/ppm 8.22–8.20 (m, 2H), 7.70–7.65 (m, 2H), 5.00–4.95 (m, 1H),
4.61 (d, J=6.8 Hz, 1H), 4.50 (d, J=6.8 Hz, 1H), 3.40–3.10 (m, 2H), 2.10–1.85 (m, 2H); MS (FAB, 3NBA): m/z 209.0 (MH+,
3.8).

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4. Corey, E. J.; Hua, D. H.; Seitz, S. P. Tetrahedron Lett. 1984, 25, 3–6.
5. (a) Paquette, L. A.; Gao, Z.; Ni, Z.; Smith, G. F. Tetrahedron Lett. 1997, 38, 1271–1274; (b) Boeckman, R. K.; Potenza, J. C.
Tetrahedron Lett. 1985, 26, 1411–1414.
6. (a) Harding, K. E.; Marman, T. H.; Nam, D.-H. Tetrahedron Lett. 1988, 29, 1627–1630; (b) Bodanszky, M.; Vigneaud, V. Du
J. Am. Chem. Soc. 1959, 81, 5688–5691.
7. Selected physical and spectral data for compound 2: mp (CHCl3–MeOH): 126–127.5°C; IR (KBr): ν/cm−1 3330, 3260, 3100,
2880, 2850, 1575, 1490, 1400, 1330, 1300, 1275, 1085, 1075, 1050, 1000, 935, 810, 730, 680; 1H NMR (300 MHz, CDCl3):
δ/ppm 8.13 (dd, J=2.0, 6.9 Hz, 2H), 7.52–7.47 (m, 2H), 5.03 (dd, J=2.7, 8.7 Hz, 1H), 3.12–3.06 (m, 1H), 3.07–2.92 (m, 1H),
1.99–1.81 (m, 1H), 1.67–1.41 (m, 1H); MS (FAB, 3NBA): m/z 197.1 (MH+, 30.5), 181.0 (M−OH, 1.8); HR FAB-MS: calcd
for C9H13N2O3 (M+1) 197.0926, found 197.0939.
8. Yields were not optimized.