DMSO-aided o-iodoxybenzoic acid (IBX) oxidation of Fmoc-protected amino alcohols

Article abstract of DOI:10.1080/00397910701555469

A fast and highly convenient procedure for the formation of Fmoc-protected amino aldehydes from the corresponding alcohols using 1.1 equiv. of IBX in the presence of dimethylsulfoxide (DMSO) is discussed. This procedure leads to the clean synthesis of Fmo

Full text of DOI:10.1080/00397910701555469

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DMSO‐Aided o‐Iodoxybenzoic Acid (IBX)
Oxidation of Fmoc‐Protected Amino Alcohols
a
a
Jack J. Chen & Vince Aduda
a
Wyeth Research, Pearl River, NY, USA
Published online: 05 Oct 2007.
To cite this article: Jack J. Chen & Vince Aduda (2007) DMSO‐Aided o‐Iodoxybenzoic Acid (IBX) Oxidation
of Fmoc‐Protected Amino Alcohols, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:20, 3493-3499, DOI: 10.1080/00397910701555469
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Synthetic Communications , 37: 3493–3499, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701555469
DMSO-Aided o-Iodoxybenzoic Acid (IBX)
Oxidation of Fmoc-Protected Amino
Alcohols
Jack J. Chen and Vince Aduda
Wyeth Research, Pearl River, NY, USA
Abstract: A fast and highly convenient procedure for the formation of Fmoc-protected
amino aldehydes from the corresponding alcohols using 1.1 equiv. of IBX in the
presence of dimethylsulfoxide (DMSO) is discussed. This procedure leads to the
clean synthesis of Fmoc-amino aldehydes in excellent yields with less than 1% epimer-
ization and with no chromatography required for purification.
Keywords: amino alcohol, amino aldehyde, periodinane oxidation
o-Iodoxybenzoic acid (IBX, 1) was first reported in 1893 by Hartmann and
[
1]
Meyer. Because of its poor solubility in virtually all common organic
solvents, its mild oxidation ability was hardly noticed until 1994 when
Frigerio and Santagostino reported the successful IBX oxidation of alcohols
[
2–4]
in DMSO.
synthesis of Dess–Martin periodinane (DMP, 2), a derivative that is more
Prior to this application, IBX was primarily employed in the
[5]
soluble in common organic solvents.
Received in the USA February 23, 2007
Address correspondence to Jack J. Chen, Wyeth Research, 401 N. Middleton Road,
Pearl River, NY 10965, USA. E-mail: chenj24@wyeth.com
3
493

3
494
J. J. Chen and V. Aduda
Our interest in IBX as an oxidant stemmed from our attempts to prepare
Fmoc-protected amino as building blocks for synthesis of peptidomimetics.
These aldehydes have been mainly obtained via (1) reduction of esters of
Weinreb amides or (2) Swern or Dess–Martin periodinane (DMP) oxidation
[6,7]
of the corresponding alcohols.
The reduction and Swern oxidation
[8]
approaches suffer from harsh reducing agents, loss of Fmoc protection,
foul-smelling by-products, and tedious chromatographic purification. The
DMP method involves the use of the expensive oxidant. Finney and More
recently reported that at elevated temperatures, a suspension of IBX (in most
organic solvents) heterogeneously oxidizes alcohols to the corresponding
[9,10]
aldehydes with no purification required beyond filtration.
(Caution! IBX
has been reported to explode on impact or heating above 2008C). Unfortunately,
according to our findings, this procedure does not work for most Fmoc-
protected amino alcohols, especially the a-branched and stereohindered ones.
In the belief that IBX could be an economical and convenient choice for
our purpose, we decided to investigate alternative reaction conditions. We
have found first that IBX-mediated oxidation is air sensitive. The aldehyde
product is partially oxidized to the carboxylic acid when the reaction is
carried out in air, which compromises the yield and complicates purification.
Second, the oxidation can be dramatically accelerated with the addition of
DMSO. In the presence of DMSO, a suspension of IBX in EtOAc at 808C
rapidly and cleanly oxidizes Fmoc-protected amino alcohols to the corre-
sponding aldehydes in excellent yields mostly within 1 h (Scheme 1). The
workup process is simple, and no chromatographic purification is required.
This finding prompted us to further investigate the amount of DMSO
required for the reaction using the oxidation of Fmoc-L-Asp (OtBu)-ol (3f)
as a model reaction. Our experiments suggested the following: (1) DMSO
alone is not a good solvent. The reactions are too slow even with 10 equiv.
of the oxidant, while at elevated temperatures the starting material is
rapidly consumed but unfortunately leads to unisolable products, (2) For
IBX to completely oxidize Fmoc-L-Asp(OtBu)-ol (3f) to the corresponding
aldehyde (4f), at least 2.2 equiv. of DMSO had to be present. No reaction
was observed with 1.1 equiv. or less.
This optimized method was then applied to the oxidation of a series of
Fmoc-protected amino alcohols listed in Table 1, all in good yield. It is note-
worthy that among the nine alcohols investigated, only the unbranched Fmoc-
glycinol (3a, entry 1) was converted to the aldehyde (4a) in the absence of
Scheme 1.

FMOC-Proctected Amino Alchohols
3495
Table 1. IBX Fmoc-amino alcohol oxidation
Yield
a
Entry
1
Alcohol
Aldehyde
No DMSO DMSO (%)
3.5 h
1 h
1 h
100
92
3
a
4a
4b
2
Incomplete
after
3
b
2
4 h
3
4
No reaction
(6 h)
1 h
1 h
98
88
3
c
4c
4d
4e
Incomplete
after
3
3
d
e
2
4 h
5
6
Incomplete
after
1 h
90
96
2
4 h
No reaction 1.25 h
(
6 h)
3
f
4f
7
8
No reaction
6 h)
1 h
95
(
3
3
g
4g
4h
Incomplete
after
1 h
2 h
92
91
h
2
4 h
9
No reaction
3
i
4i (6 h)
a
Yield after workup. The purity is acceptable for further applications.
[
10]
DMSO, as reported by Finney and More.
aldehydes are recorded in Table 2.
To scrutinize the racemization level of this chemistry, we reduced two
The physical data of the
[
6]
pairs of racemization-prone aldehydes (4d, 4e, 4f, and 4g) to the corre-
sponding amino alcohols (Scheme 2). The alcohols were then analyzed on
chiral HPLC to deduce the %ee level of the original aldehydes. The exper-
imental results suggested that the four Fmoc-amino aldehydes examined in

3
496
J. J. Chen and V. Aduda
Table 2. Physical constants of Fmoc-amino aldehydes
LCMS [M þ H] ꢀþ
2
0
Entry
Aldehyde
calc.
Found MP (8C) [a ] (c 0.1, CHCl3)
D
1
282.3
282.1 124–126
296.1 153–154
þ0.0
4
a
2
3
296.3
310.4
þ40.6
4
b
310.1
99–101
þ38.2
þ46.0
4
c
4
5
6
372.4
372.4
396.4
372.1 135–137
372.1 135–137
4
d
251.2
þ2.4
4
e
396.1
396.1
Oil
Oil
4
f
7
396.4
22.6
4
g
8
9
367.4
410.5
368.1
410.1
Oil
Oil
þ31.8
þ29.4
4
h
4
i
Scheme 2.

FMOC-Proctected Amino Alchohols
3497
Table 3. Racemization analysis
Entry
Aldehyde
Alcohol
ee (%)
1
2
3
4
Fmoc-L-Phe-H (4d)
Fmoc-D-Phe-H (4e)
Fmoc-L-Phe-ol (3d)
Fmoc-D-Phe-ol (3e)
100
100
99.5
99.6
Fmoc-L-Asp(OtBu)-H (4f)
Fmoc-D-Asp(OtBu)-H (4g)
Fmoc-L-Asp(OtBu)-ol (3f)
Fmoc-D-Asp(OtBu)-ol (3g)
this study have insignificant or no racemization (Table 3). Chiral HPLC
analysis condition: Chiralcel OD column, 25–55% H O/CH CN (0.1%
2
3
HCO H) in 30 min, 1 ml/min, l ¼ 220 nm. ee (%) data were determined
2
by individual injections and co-injections of the enantiomeric sample pairs.
In conclusion, the method discussed in this report provides a fast and
highly convenient procedure for the synthesis of the widely used Fmoc-
protected amino aldehydes using IBX (1) in the presence of DMSO.
TYPICAL EXPERIMENTAL PROCEDURES
Fmoc-L-Asp(OtBu)-al (4f)
Commercially available Fmoc-Asp(OtBu)-ol (3f) (397 mg, 1.00 mmol, 1.0
equiv.) was dissolved in anhydrous ethyl acetate (10.0 mL). IBX (308 mg,
1
.1 equiv.) was added to form a suspension. The mixture was stirred briskly
and refluxed at 808C under argon. DMSO (172 mg, 157 mL, 2.2 mmol, 2.2
equiv.) was added via a syringe. After 1 h 15 min, thin-layer chromatography
(TLC) analysis showed clean, complete consumption of the amino alcohol and
formation of the amino aldehyde. The insoluble o-iodobenzoic acid (IBA) by-
product was filtered off, and the filtrate was washed with three portions
(20 ml) of 10% Na S O –saturated aqueous NaHCO solution (1:1). This
was followed by H O (10 ml) and brine (10 ml). The aqueous washings
2 2 3 3
2
were then back-extracted with EtOAc (40 ml). The organic layers were
combined, washed with brine, dried over anhydrous Na SO , and concentrated
in vacuo to yield the aldehyde 4f as a pale yellow oil (379 mg, 96% yield).
2
4
This product can be used without further purification.
Reduction of Fmoc-L-Asp(OtBu)-al (4f) to the Corresponding
Alcohol (3f)
Fmoc-L-Asp(OtBu)-al (198 mg, 0.5 mmol) was dissolved in 1,2-dimethox-
yethane (15 ml) and cooled to 2208C. A solution of NaBH4 (38 mg,
1.0 mmol) in water (5 ml) was added. The reaction was stirred for 1 h at
ambient temperature. The mixture was diluted with EtOAc (20 ml) and

3
498
J. J. Chen and V. Aduda
washed with 1N NaOH (30 ml), 1N HCl (30 ml), and brine (30 ml). The organic
layers were dried over Na SO and concentrated in vacuo. The residue was
2
4
purified by flash-column chromatography to yield 3f as a white solid
140 mg, yield 70%).
(
Data
Data for 4f
1
H NMR (300 MHz, CDCl ) d 1.47 (s, 9H), 2.70 (dd, J ¼ 4.8, 17.2 Hz, 1H), 2.88
3
(
(
(
dd, J ¼ 4.8, 17.2, Hz, 1H), 4.16 (t, J ¼ 7.0 Hz, 1H), 4.36 (m, 3H), 5.81
d, J ¼ 8.1 Hz, 1H), 7.22–7.36 (m, 4H), 7.51 (d, J ¼ 7.3 Hz, 2H), 7.69
13
d, J ¼ 7.3 Hz, 2H), 9.68 (s, 1H). C NMR (75 MHz, CDCl ) d 197.7, 169.2,
3
1
55.1, 142.6, 140.3, 126.8, 126.1, 124.0, 119.0, 81.2, 66.2, 55.5, 46.1, 34.7, 27.0.
Data for 3f
1
H NMR (300 MHz, CDCl ) d 1.47 (s, 9H), 2.42 (m, 1H), 2.58 (m, 2H), 3.75
3
(
(
m, 2H), 4.09 (m, 1H), 4.22 (m, 1H), 4.45 (m, 2H), 5.69 (m, 1H), 7.29–7.41
1
3
m, 5H), 7.61 (d, J ¼ 7.2 Hz, 2H), 7.79 (d, J ¼ 7.2, 2H). C NMR (75 MHz,
CDCl ) d 171.5, 156.8, 144.3, 141.7, 128.1, 127.5, 125.5, 120.4, 81.8, 67.3,
3
6
4.6, 50.5, 47.6, 37.7, 28.5.
ACKNOWLEDGMENT
The authors are grateful to Arthur Grieb for chiral HPLC analysis.
REFERENCES
1
2
3
. Hartmann, C.; Meyer, V. Ueber jodobenzoesaure[J]. Chem. Ber. 1893, 26,
727–1732.
1
. Frigerio, M.; Santagostino, M. A mild oxidizing reagent for alcohols and 1,2-diols:
o-iodoxybenzoic acid (IBX) in DMSO. Tetrahedron Lett. 1994, 35, 8019–8022.
. Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. Oxidation of alcohols
with o-iodoxybenzoic acid in DMSO: A new insight into an old hypervalent
iodine reagent. J. Org. Chem. 1995, 60, 7272–7276.
4
. De Munari, S.; Frigerio, M.; Santagostino, M. Hypervalent iodine oxidants:
structure and kinetics of the reactive intermediates in the oxidation of alcohols
and 1,2-diols by o-iodoxybenzoic acid and dess-martin periodinane. A compara-
tive H-NMR study. J. Org. Chem. 1996, 61, 9272–9279.
. Dess, D. B.; Martin, J. C. Readily accessible 12-I-5 oxidant for the conversion of
1
5
primary and secondary alcohols to aldehydes and ketones. J. Org. Chem. 1983, 48,
4
155–4156.

FMOC-Proctected Amino Alchohols
3499
6. Fehrentz, J.-A.; Pothion, C.; Califano, J.-C.; Leffet, A.; Martinez, J. Synthesis of
chiral N-protected a-amino aldehydes by reduction of N-protected N-carboxy-
anhydrides (UNCAs). Tetrahedron Lett. 1994, 35, 9031–0934 and the references
therein.
7
. Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman, B. A.; Kwon, S.
Synthesis of highly epimerizable N-protected a-amino aldehydes of high enantio-
meric excess. Tetrahedron Lett. 2000, 41, 1359–1362.
8
. Wen, J. J.; Crews, C. M. Synthesis of 9-fluorenylmethoxycarbonyl-protected
amino aldehydes. Tetrahedron Asymmetry. 1998, 9, 1855–1858.
. More, J. D.; Finney, N. S. A Simple and advantageous protocol for the oxidation of
alcohols with o-iodoxybenzoic acid (IBX). Org. Lett. 2002, 4, 3001–3003.
9
1
1
0. Plumb, J. B.; Harper, D. J. 2-Iodoxybenzoic acid. Chem. Eng. News 1990, 68, 3.
1. Rodriguez, M.; Linares, M.; Doulut, S.; Heitz, A.; Martinez, J. A facile synthesis of
chiral N-protected b-amino alcohols. Tetrahedron Lett. 1991, 32, 923–926.