A concise asymmetric route to chiral α-aminoxy acids

Article abstract of DOI:10.1055/s-0029-1218306

An efficient three-step method has been developed for enantioselective synthesis of chiral α-aminoxy acids from, aldehydes. In this method, chiral propargylic alcohols are obtained by asymmetric addition of terminal alkynes to aldehydes. The hydroxyl grou

Full text of DOI:10.1055/s-0029-1218306

LETTER
3159
A Concise Asymmetric Route to Chiral a-Aminoxy Acids
A
symmetric Route
i
to Chi
a
ral
a
-Amin
o
oxy
A
cids -Wei Chang,a Dan-Wei Zhang,*a Fei Chen,b Ze-Min Dong,b Dan Yang*a,b
a
Department of Chemistry, Fudan University, Shanghai 200433, P. R. of China
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax +86(21)65643575; E-mail: yangdan@hku.hk
b
Received 21 August 2009
general coupling reagent is routine for peptide synthesis.
Retrosynthetic analysis (Scheme 1) indicates that the car-
boxylic acid group can be generated from many functional
groups (such as C≡C triple bond by oxidative cleavage),
Abstract: An efficient three-step method has been developed for
enantioselective synthesis of chiral a-aminoxy acids from alde-
hydes. In this method, chiral propargylic alcohols are obtained by
asymmetric addition of terminal alkynes to aldehydes. The hydrox-
yl group then converted to aminoxy group via Mitsunobu reaction and the phthalimidooxy group can be formed from a hy-
and oxidative cleavage of the internal carbon–carbon triple bond
droxy group by Mitsunobu reaction accompanied with in-
version of the chiral center on the a-carbon.7 Additionally,
produce the carboxylic acid group. This represents a convenient ap-
proach to the general asymmetric synthesis of a-aminoxy acids with
chiral secondary propargylic alcohols, which can be syn-
the advantages of substantial overall yields (37–73%) and high
thesized in high optical purity from aldehydes and termi-
enantioselectivities (81–99% ee).
nal alkynes, are therefore selected as the key intermediate
Key words: a-aminoxy acid, asymmetric synthesis, Mitsunobu
to construct a-phthalimidooxyl carboxylic acids.8
reaction, aldehydes, alkynes
Carreira et al. have reported the enantioselective addition
of terminal alkynes to a wide range of aldehydes catalyzed
by N-methylephedrine (NME).8a–8e Following this meth-
a-Aminoxy acids are the basic building blocks of a-ami-
noxy peptides, a special kind of foldamers,1 which can
fold into various well-defined three-dimensional
structures2 and serve interesting functions.3,4 In order to
explore their potential in bioactivity, it is desirable to se-
cure an abundant source of chiral a-aminoxy acids that
have various side chains. However, up to this date, most
of the a-aminoxy acids incorporated in a-aminoxy pep-
tides have been restricted to preparation from the chiral
pool, for example, a-amino acids and natural a-hydroxy
acids.5 Consequently, the choice of side chains, which is
crucial to the folding and biological activities of peptides,6
has been extremely limited. Here we report a general
asymmetric approach towards the synthesis of chiral a-
aminoxy acids.
od, we employed different kinds of aldehydes, which are
a determinant of the side chains of target a-phthalim-
idooxyl carboxylic acids. Three alkynes 6, 7, and 8 were
also involved to examine their efficiency in this route. The
results are summarized in Table 1. Secondary aliphatic al-
dehydes 1–3 gave reasonably satisfactory results upon re-
actions with any of the three alkynes 6–8 (entries 1–7; 54–
88% yield). To prevent self-condensation, primary alde-
hyde 4 needed to be added by means of a syringe pump for
2 hours,8a and a yield of 51% was obtained by this proce-
dure (entry 8). For tertiary aldehyde 5 with a bulky group
on the a-position, excess amounts of catalyst (1.6 equiv)
and high reaction temperature (100 °C) were required (en-
try 9, 57% yield).8b For the three alkynes 6–8, propargylic
acetate 6 reacted with secondary aliphatic aldehydes in
good yield in the presence of a stoichiometric amount of
NME/Zn(OTf)2/Et3N (entries 1–3, 5, and 6; 72–88%
yield). Compared with propargylic acetate 6, trimethylsi-
lyl acetylene 8 showed lower reactivity (entry 7 vs. entry
5). Trimethyl(2-methylbut-3-yn-2-yloxy)silane (7) react-
ed with 2-ethylbutanal (2) to afford (S)-11 with a yield of
61% (entry 4), even in the presence of a catalytic amount
of NME/Zn(OTf)2/Et3N.8b The result is comparable to the
stoichiometric reaction using propargylic acetate 6 as a
nucleophile (entry 3; 72% yield). This method, in accor-
dance with atomic economics, is more suitable for large-
scale preparation of target compounds. Aldehydes 4 and
5, which contain a silyloxyl group, also reacted smoothly
with alkyne 7, though excess amounts of NME/Zn(OTf)2/
Et3N must be used (entries 8 and 9). The absolute config-
urations of the products were established according to the
literatures.8a–e
O
O
FGI
FGI
N
O
N
O
R2
*
*
COOH
R1
R1
O
O
O
HO
R1
asymmetric addition
R2
H
R2
*
+
R1
H
Scheme 1 Retrosynthetic analysis of a-aminoxy acids
a-Phthalimidooxyl carboxylic acids are building blocks
for synthesizing a-aminoxy peptides. Hydrazinolysis of
the phthaloyl group affords the aminoxy group,5a the sub-
sequent coupling of which with carboxylic acid group by
SYNLETT 2009, No. 10, pp 3159–3162
x
x
.x
x
.2
0
0
9
With the key intermediates of chiral propargylic alcohols
being ready, we proceeded with the downstream steps of
Advanced online publication: 23.10.2009
DOI: 10.1055/s-0029-1218306; Art ID: W13209ST
© Georg Thieme Verlag Stuttgart · New York

3160
X.-W. Chang et al.
LETTER
functional group interconversion, wherein the phthalim- for synthetic purposes and few reports can be found on
idooxy group was introduced through a Mitsunobu reac- their applications to an extensive degree.
tion.7 The configuration of compounds 9–14 is inverted in
this step via an SN2 mechanism. High yields in the range
of 83–97% were obtained for 9–14 (Scheme 2). The enan-
To avoid decomposition of other functional groups, espe-
cially the phthalimidooxy group which is sensitive to
acidic or basic conditions, mild oxidation conditions were
tiomeric purities of the products determined by chiral
chosen. A method employing sodium periodate as an oxi-
HPLC method showed that the ee values of 16–21 were
dant in the presence of a catalytic amount of RuO2 has
between 81% and 99%. The yields of (R)-18 and (R)-21
were calculated after deprotection of the OTMS group.
For compound 15, the conversion was reduced dramati-
cally because of steric hindrance; no product was found
even after overnight reaction. Thus far, we have complet-
ed two important steps, whereby a-phthalimidooxyl
alkynes 16–21 can be prepared in good yields with high to
excellent enantioselectivities.
been reported successfully for a variety of alkynes.9a–9c In
experimenting with this oxidation method, we found that
the solvent significantly affected the reaction rate. For ex-
ample, oxidation in the MeCN–CCl4–H2O solvent system
was very slow. However, when the solvent was changed
to MeCN–H2O (3:2), the reaction was accelerated dramat-
ically. All substrates could be transformed to their corre-
sponding carboxylic acids in 2 hours in almost
Although several strategies have previously been estab- quantitative yields (85–97%). The sensitive phthalim-
lished on the basis of oxidation of the internal C≡C triple idooxyl group was tolerant to these mild conditions. In ad-
bond,9 most of them are deemed not sufficiently efficient dition, the two carboxylic acids produced had different
solubility in water, which greatly facilitated purification.
Table 1 Asymmetric Addition of Terminal Alkynes to Aldehydes
O
N-methyl ephedrine
HO
R1
R2
+
R2
*
R1
1–5
H
Zn(OTf)2, Et3N
toluene
6–8
9–15
Entry
R1
1
R2
NME/Zn(OTf)2/Et3Na Product
Yield (%)
HO
1
2
(–) 1.2:1.1:1.2
(+) 1.2:1.1:1.2
(S)-9
(R)-9
79
88
*
CH2OAc 6
OAc
HO
3
CH2OAc 6
(+) 1.2:1.1:1.2
(–) 0.22:0.2:0.5
(R)-10
(S)-11
72
61
OAc
2
HO
HO
4b
OTMS
OTMS
OAc
2
7
*
5
6
(–) 1.2:1.1:1.2
(+) 1.2:1.1:1.2
(S)-12
(R)-12
86
81
CH2OAc 6
TMS 8
3
3
HO
TMS
7
(–) 1.2:1.1:1.2
(S)-13
54
3
4
5
HO
OTBDPS
3
8c
9d
(–) 2.1:2.0:2.1
(–) 1.6:1.5:1.6
(S)-14
(S)-15
51
57
OTMS
OTMS
OTMS
3
7
OTBDPS
HO
OTBDPS
OTMS
7
OTBDPS
a Chirality of N-methylephedrine (NME) used and equivalent ratio of NME/Zn(OTf)2/Et3N to its aldehyde substrate are indicated.
b Reaction was carried out at 60 °C.
c Aldehyde was added dropwise via a syringe pump for 2 h.
d Reaction was carried out at 100 °C.
Synlett 2009, No. 10, 3159–3162 © Thieme Stuttgart · New York

LETTER
Asymmetric Route to Chiral a-Aminoxy Acids
3161
HO
R1
PhthNO
N-hydroxy phthalimide
Ph3P, DIAD, THF, 0 °C
R2
R2
*
*
R1
9−14
16−21
yield (%) ee (%)
yield (%) ee (%)
97
88
(88)
(89)
R2 = CH2OAc,
R1
=
R2 = CH2OAc,
CH2OAc,
R1
=
(R)-16
(S)-16
(R)-19
(S)-19
93
83
(94)
(81)
92
(94)
(97)
(R)-20
96
(93)
(S)-17
(R)-18
TMS
87a
(R)-21
84a
(>99)
OTBDPS
OH
OH
a two steps yield involved Mitsunobu reaction and deprotection of tertiary OTMS group
Scheme 2 Results of Mitsunobu reaction of propargylic alcohols 9–14
step, while the S-forms were obtained from (+)-N-methyl-
ephedrine (Table 2).
Table 2 Oxidative Cleavage of Internal C≡C Triple Bonds
NaIO4
PhthNO
R1
PhthNO
COOH
RuO2
*
R2
By using this synthetic route, chiral a-aminoxy acids were
obtained from secondary aldehydes and alkyne 6 in three
steps in good overall yields (63–73%). Moderate yields
(50% in three steps) were achievable under catalytic con-
ditions with alkyne 7 as a nucleophile. In comparison, pri-
mary aldehyde 4 showed relatively lower reactivity as a
result of competitive self-condensation in the first step
(37% overall yield). Tertiary aldehyde 5 proved to be a
poor substrate because the propargylic alcohol derived
from it could not undergo Mitsunobu reaction.
*
R1
MeCN–H2O (3:2)
16–21
22–25
Entry
1
Substrate Product
Yield (%)
(R)-16
(R)-22
93
PhthNO
COOH
COOH
COOH
*
*
*
2
3
(S)-16
(S)-17
PhthNO
(S)-22
(S)-23
85
97
In conclusion, a-phthalimidooxyl carboxylic acids can be
efficiently constructed in a three-step strategy involving
asymmetric addition of terminal alkynes to aldehydes,
Mitsunobu reaction, and mild oxidation.10 This approach
typically allows good yields (37–73% in three steps) and
high ee values (up to 99% ee). It is the first general method
for the asymmetric synthesis of a-phthalimidooxyl car-
boxylic acids in a concise route, whereby the abundant
supply of diverse side-chain species for peptidomimetic
studies can be achieved in an efficient and reliable man-
ner.
4
5
(R)-18
(R)-19
(R)-23
(R)-24
94
91
PhthNO
6
(R)-20
(R)-24
95
Supporting Information for this article is available online at
7
8
(S)-19
(S)-24
(R)-25
94
86
http://www.thieme-connect.com/ejournals/toc/synlett.
PhthNO
COOH
(R)-21
Acknowledgment
3
TBDPSO
This work was supported by Fudan University, The National Natu-
ral Science Foundation of China (project no. 20202001), Fok Ying
Tung Education Foundation (project no. 94023), The Hong Kong
Research Grants Council (HKU7654/06M), and HKU-Fudan Joint
Laboratory on Molecular Design and Synthesis. D.-W. Z. thanks
Fudan University for the conferment of the Century Star Award.
The carboxylic acid byproducts could be washed away by
water and required no column purification.
The absolute configurations of compounds 22–25 were
determined by comparing their CD spectra with that of the
authentic compound (R)-3-methyl-2-phthalimidooxy-
butyric acid [(R)-22], which was prepared from L-valine
as previously reported5a (see Figure S1 in Supporting In-
formation). Thus, the R-form of 22–25 were afforded by
employing (–)-N-methylephedrine as a ligand in the first
References and Notes
(1) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Hill,
D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. Rev. 2001, 101, 3893. (c) Seebach, D.; Beck, A. K.;
Bierbaum, D. J. Chem. Biodiversity 2004, 1, 1111.
Synlett 2009, No. 10, 3159–3162 © Thieme Stuttgart · New York

3162
X.-W. Chang et al.
LETTER
(2) Li, X.; Yang, D. Chem. Commun. 2006, 3367; and
references cited therein.
product was purified by flash chromatography to give (S)-4-
hydroxy-5-methylhex-2-ynyl acetate [(S)-9]8d as a colorless
oil in 79% yield (539 mg); [a]D20 –1.1 (c 4.0, CHCl3). 1H
NMR (300 MHz, CDCl3): d = 4.72 (d, J = 1.7 Hz, 2 H), 4.21
(br s, 1 H), 2.43 (br s, 1 H), 2.10 (s, 3 H), 1.94–1.83 (m, 1 H),
1.01 (d, J = 6.7 Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H). 13C NMR
(125 MHz, CDCl3): d = 170.3, 86.6, 79.1, 67.5, 52.3, 34.2,
20.6, 17.9, 17.3.
(3) (a) Yang, D.; Qu, J.; Li, W.; Zhang, Y.-H.; Ren, Y.; Wang,
D.-P.; Wu, Y.-D. J. Am. Chem. Soc. 2002, 124, 12410.
(b) Yang, D.; Li, X.; Yao, S.; Wu, Y.-D. Chem. Eur. J. 2005,
11, 3005. (c) Li, X.; Shen, B.; Yao, X.-Q.; Yang, D. J. Am.
Chem. Soc. 2007, 129, 7264.
(4) Yang, D.; Li, X.; Fan, Y.-F.; Zhang, D.-W. J. Am. Chem.
Soc. 2005, 127, 7996.
Mitsunobu Reaction of Propargylic Alcohol:
(5) (a) Yang, D.; Li, B.; Ng, F.-F.; Yan, Y.-L.; Qu, J.; Wu,
Y.-D. J. Org. Chem. 2001, 66, 7303. (b) Lee, M.-R.; Lee, J.;
Baek, B.-H.; Shin, I. Synlett 2003, 325. (c) Shin, I.; Lee, M.-
R.; Lee, J.; Jung, M.; Lee, W.; Yoon, J. J. Org. Chem. 2000,
65, 7667.
(6) (a) Yang, D.; Zhang, Y.-H.; Li, B.; Zhang, D.-W.; Chan,
J. C.-Y.; Zhu, N.-Y.; Luo, S.-W.; Wu, Y.-D. J. Am. Chem.
Soc. 2004, 126, 6956. (b) Martinek, T. A.; Fülöp, F. Eur. J.
Biochem. 2003, 270, 3657; and references cited therein.
(7) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Ahn, C.; Correia,
R.; DeShong, P. J. Org. Chem. 2002, 67, 1751.
(8) (a) Boyall, D.; López, F.; Sasaki, H.; Frantz, D.; Carreira,
E. M. Org. Lett. 2000, 2, 4233. (b) Anand, N. K.; Carreira,
E. M. J. Am. Chem. Soc. 2001, 123, 9687. (c) Frantz, D. E.;
Fässler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806. (d) El-Sayed, E.; Anand, N. K.; Carreira, E. M. Org.
Lett. 2001, 3, 3017. (e) Boyall, D.; Frantz, D. E.; Carreira,
E. M. Org. Lett. 2002, 4, 2605; and references cited therein .
For related reviews, see: (f) Pu, L.; Yu, H.-B. Chem. Rev.
2001, 101, 757. (g) Cozzi, P. G.; Hilgraf, R.; Zimmermann,
N. Eur. J. Org. Chem. 2004, 4095.
(9) For selected examples, see: (a) Merino, P.; Franco, S.;
Merchan, F. L.; Tejero, T. J. Org. Chem. 1998, 63, 5627.
(b) Griffith, W. P.; Shoair, A. G.; Suriaatmaja, M. Synth.
Commun. 2000, 30, 3091. (c) Yang, D.; Chen, F.; Dong,
Z.-M.; Zhang, D.-W. J. Org. Chem. 2004, 69, 2221.
(d) Moriarty, R. M.; Penmasta, R.; Awasthi, A. K.; Prakash,
I. J. Org. Chem. 1988, 53, 6124.
Preparation of (R)-4-Phthalimidooxy-5-methylhex-2-
ynyl Acetate [(R)-16]
A solution of compound (S)-9 (85 mg, 0.50 mmol) in THF
(3 mL) was dropped to the mixture of N-hydroxyphthalimide
(90 mg, 0.55 mmol) and Ph3P (157 mg, 0.60 mmol) under
nitrogen atmosphere. Then, diisopropyl-azodicarboxylate
(0.116 mL, 0.55 mmol) was added at 0 °C. The mixture was
stirred to r.t. over 3 h, at the end of which the solvent was
removed. The resulting residue was purified by flash
chromatography to afford 97% yield (154 mg) of (R)-16 and
88% ee as determined in HPLC analysis (Chiralcel OD, 6%
i-PrOH in hexane, 0.8 mL/min, 254 nm), tR = 17.0(minor),
20.2 (major). [a]D20 +76.8 (c 1.0, CHCl3). 1H NMR (400
MHz, CDCl3): d = 7.86–7.83 (m, 2 H), 7.78–7.74 (m, 2 H),
4.90 (dt, J = 5.8, 1.7 Hz, 1 H), 4.64 (ABd, J = 15.6, 2.0 Hz,
2 H), 2.30–2.22 (m, 1 H), 2.02 (s, 3 H), 1.17 (d, J = 6.8 Hz,
3 H), 1.13 (d, J = 6.8 Hz, 3 H). 13C NMR (125 MHz, CDCl3):
d = 169.5, 163.2, 134.2, 128.7, 123.2, 83.3, 82.2, 81.2, 51.6,
31.5, 20.2, 18.2, 17.3. IR (CH2Cl2): 2965, 2940, 2875, 1787,
1735 cm–1. MS (EI, 20 eV): m/z (%) = 316 (1) [M+ + H], 153
(100). HRMS (EI): m/z calcd for C17H18NO5 [M+ + H]:
316.1185; found: 316.1185.
Oxidative Cleavage of Internal Triple Bond: Preparation
of (R)-3-Methyl-2-phthalimidooxy-butyric Acid [(R)-22]
To a solution of (R)-16 (58 mg, 0.18 mmol) in MeCN–H2O
(1.25 mL, 3:2) was added NaIO4 (315 mg, 1.47 mmol). After
NaIO4 was completely dissolved, RuO2·H2O (1 mg) was
added. The mixture was stirred vigorously at r.t. Upon
confirmation by TLC that most of the starting material
converted, Et2O and H2O were added to the flask. The
aqueous layer was extracted with Et2O, and the organic layer
was washed with H2O and concentrated. Then CH2Cl2 (100
mL) was added to the flask, and the organic layer was
washed with H2O, dried with anhyd Na2SO4, and
(10) Representative Procedure: Asymmetric Addition of
Terminal Alkyne 6 to Aldehyde 1
A flask was charged with Zn(OTf)2 (1.6 g, 4.4 mmol).
Vacuum (<0.5 mbar) was applied, and the flask was heated
to 125 °C overnight. The flask was cooled to r.t. The vacuum
was released and (–)-N-methylephedrine (859 mg, 4.8
mmol) was added. Vacuum (<0.5 mbar) was applied for 0.5
h and then released. To the flask were added toluene (8.0
mL) and Et3N (485 mg, 4.8 mmol). The resulting mixture
was stirred for 2 h at r.t. before propargylic acetate 6 (470
mg, 4.8 mmol) was added in one portion. After stirring for
15 min at r.t., isobutanal (1, 288 mg, 4.0 mmol) was added
in one portion. The reaction mixture was stirred at r.t.
overnight. The reaction was quenched with sat. NH4Cl aq
solution, followed by extraction with Et2O. The combined
ether extracts were washed with sat. NH4Cl aq solution and
brine, dried over Na2SO4, and concentrated. The crude
concentrated to give the product (R)-22 as an oil in 93%
yield (45 mg); [a]D27 +69.0 (c 1.0, CHCl3). 1H NMR (500
MHz, CDCl3): d = 7.88–7.86 (m, 2 H), 7.81–7.79 (m, 2 H),
4.59 (d, J = 5.0 Hz, 1 H), 2.47–2.42 (m, 1 H), 1.24 (d, J = 7.0
Hz, 3 H), 1.18 (d, J = 6.9 Hz, 3 H). 13C NMR (125 MHz,
CDCl3): d = 172.3, 163.6, 134.8, 128.5, 123.8, 90.4, 30.7,
18.2, 17.5. IR (CH2Cl2): 3088, 2966, 2927, 1791, 1735
cm–1. MS (EI, 20 eV): m/z (%) = 218 (1) [M+ – COOH], 160
(100). HRMS (EI): m/z calcd for C12H12NO3 [M+ – COOH]:
218.0817; found: 218.083.
Synlett 2009, No. 10, 3159–3162 © Thieme Stuttgart · New York