Investigations on the [2,3]-Wittig Rearrangement of Chiral 4-Aminopropargyloxy Acetates to Novel α-Hydroxy-γ-amino Acids Containing an Allene Unit

Article abstract of DOI:10.1055/s-0034-1380740

The [2,3]-Wittig rearrangement of propargyloxy acetates bearing a propargylic stereocenter opposite to the oxyacetic acid moiety gives α-hydroxy-γ-amino acids containing an allene unit under high stereocontrol. The resulting product displays a novel type of γ-amino acid with a potentially intriguing biological profile.

Full text of DOI:10.1055/s-0034-1380740

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2015, 26, 1702–1704
1702
letter
Synlett
N. Griebenow et al.
Letter
Investigations on the [2,3]-Wittig Rearrangement of Chiral
-Aminopropargyloxy Acetates to Novel α-Hydroxy-γ-amino
4
Acids Containing an Allene Unit
Nils Griebenow*a
Florimond Cumineb
Alicia M. Dilmacc
LDA
•
H
O
CO2t-Bu
H
a
Boc N
Boc N
CO t-Bu
Bayer HealthCare Pharmaceuticals AG, Global Drug Discovery,
Medicinal Chemistry, Aprather Weg 18a, 42113 Wuppertal, Germany
nils.griebenow@bayer.com
–70 °C, 3 d
14%
*
2
OH
b
c
University of Strathclyde, University of Strathclyde,
2
95 Cathedral Street, Glasgow G1 1XL, UK
Institute of Organic Chemistry, Karlsruhe Institute of Technology
KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
(
Received: 02.04.2015
Accepted after revision: 14.04.2015
Published online: 11.05.2015
Herein, we describe the results of our investigations to-
wards the [2,3]-Wittig rearrangement of propargyloxy ace-
tates derived from amino acid derivatives (Scheme 2). Such
a rearrangement will provide access to novel α-hydroxy-
γ-amino acids incorporating an allene unit.
DOI: 10.1055/s-0034-1380740; Art ID: st-2015-d0236-l
Abstract The [2,3]-Wittig rearrangement of propargyloxy acetates
bearing a propargylic stereocenter opposite to the oxyacetic acid moi-
ety gives α-hydroxy-γ-amino acids containing an allene unit under high
stereocontrol. The resulting product displays a novel type of γ-amino
acid with a potentially intriguing biological profile.
R2
R2
R2 R2
•
LDA
H
O
CO2t-Bu
H
Boc N
Boc N
CO2t-Bu
Key words Wittig rearrangement, propargyloxy acetates, γ-amino ac-
*
ids, allenes
R1
R1
OH
Scheme 2 Projected [2,3]-Wittig rearrangement of propargyloxy ace-
Previously, we reported on the synthesis of 4-amino-al-
tates
lyloxy acetates 1 and their stereoselective [2,3]-Wittig rear-
rangement to form novel α-hydroxy-γ-amino acids 2–4,
which display γ-turn geometric features (Scheme 1).1
Notwithstanding the novel mechanistic aspects of the
rearrangement, such allenic amino acids would also be of
interest regarding their potential biological profile. Allenic
2
H
Boc N
a)
H
O
CO2t-Bu
Boc N
CO2t-Bu
amino acids are described as irreversible enzyme inhibitors
of GABA-transaminase as well as bacterial ornithine decar-
boxylase. It is supposed that the allenic unit, as a key ele-
ment, is covalently bound to the active site of the enzyme
to block its function.3
+
R
1
R
R
OH
OH
2
,4
H
The [2,3]-Wittig rearrangement of propargyloxy ace-
Boc N
CO2t-Bu
+
Yield of 2
Ratio
2/3/4
5
R
tates was first reported by Marshall et al. Rearrangement
(
isolated, %)
3
of the enantiomerically enriched propargyloxy acetate (ee =
Me
Bn
i-Bu
i-Pr
78
76
90:9:1
87:10:3
91:6:3
92:4:4
90%) yielded the allenyl alcohol with complete chirality
66
transfer (Scheme 3).
53
H
In this work, we became interested in whether a prop-
argylic stereocenter opposite to the oxyacetic acid moiety
can also provide high stereocontrol. The synthesis of a suit-
able model system is outlined in Scheme 4. By analogy with
Boc N
CO2t-Bu
R
OH
4
Scheme 1 Reagents and conditions: (a) LDA, THF, –78 °C, 1 h, TMEDA,
35 °C, 2 d.
6
the work of Chung et al., propargylic alcohol 9 was built up
–
in four steps. Initially, aminoalcohol was Boc protected to
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1702–1704

1
703
Synlett
N. Griebenow et al.
Letter
Considering that the rearrangement proceeds via a five-
O
OH
O
membered transition state, it is likely that allyloxy acetates
react more readily than propargyloxy acetates because of a
less strained transition state. Hence, we speculated that
geminal dimethylation at the propargylic ether moiety will
facilitate the rearrangement of 9.8 According to these con-
siderations, we synthesized disubstituted propargyloxy ac-
etate 12 starting from the dibromo compound 8, as outline
in Scheme 6. Olefin 8 was transferred to the lithium
acetylide by treatment with n-butyllithium, followed by
quenching with acetone. The resulting propargylic alcohol
11 was then reacted with tert-butyl bromoacetate to give
ether 12.
H
a)
•
O
OH
,9
OH
Scheme 3 Reagents and conditions: (a) LDA, THF, –78 °C, 1 h, –20 °C,
8 h; 48%, ds = 91%, ee = 90%.
1
give 6, followed by conversion into aldehyde 7 through
Swern oxidation. Elongation to the propargyl alcohol was
performed by following the Corey–Fuchs protocol.7 Final
etherification yielded the desired propargyloxy acetate 10.
CO2t-Bu
H
H2N
Boc
N
O
OH
OH
a
b
H
OH
H
Boc
N
5
6
a
b
Boc
N
8
H
H
H
H
11
12
Boc
Boc
N
Boc
N
Br
O
c
d
Br
Scheme 6 Reagents and conditions: (a) n-BuLi,, THF, –78 °C, 1 h, ace-
tone –40 °C, 12 h (54%); (b) BrCH CO t-Bu, aq KOH (8.9 M), toluene,
r.t., 4 h (43%).
7
8
2
2
H
OH
H
O
CO2t-Bu
N
Boc N
Ether 12 was successfully rearranged to a single isomer
e
1
3 by carrying out the reaction with LDA at –78 to –70 °C
1
0
9
10
for three days in 14% isolated yield. Other conditions
failed, as outlined in Scheme 7. By analogy with our previ-
ous work, we propose the R-configuration at the C-2 car-
Scheme 4 Reagents and conditions: (a) Boc O, CH Cl , r.t., 12 h (99%);
b) oxalyl chloride, DMSO, Et N, CH Cl , –78 °C, 1.5 h (quant.); (c) Zn,
PPh , CBr , CH Cl , r.t., 24 h (61%); (d) n-BuLi, paraformaldehyde, THF,
1
2
2
2
(
3 2 2
bon atom of 13.
3
4
2
2
–
4
78 °C to r.t., 2 h (29%); (e) BrCH CO t-Bu, aq KOH (8.9 M), toluene, r.t.,
h (89%).
2 2
a, b or c
•
H
O
CO2t-Bu
H
In a first attempt to rearrange propargyloxy acetate 10,
2
Boc N
Boc N
CO2t-Bu
we used the same reaction conditions that were successful
for allyloxy acetates 1. However, treatment with LDA at
12
R
R
OH
13
–
78 °C and addition of TMEDA at –35 °C yielded only de-
Scheme 7 Attempts to rearrange 12 (R = i-Bu). Reaction conditions:
(
(
a) LDA, THF, –78 °C, 1 h, TMEDA, –35 °C, 12 h, decomposition;
b) LDA, THF, –78 °C, 1 h, –35 °C, 12 h, decomposition; (c) LDA, THF,
composition. Without TMEDA, the rearrangement also
failed. Below –70 °C no reaction was observed, whereas
above –35 °C the reaction proceeded with decomposition
–
78 °C, 1 h, –70 °C, 3 d (14%, ds > 95:5).
(Scheme 5).
In summary, we have been able to perform the [2,3]-
a, b or c
Wittig rearrangement with propargyloxy acetates bearing a
propargylic stereocenter opposite to the oxyacetic acid
moiety under high stereocontrol. The resulting product dis-
plays a novel type of γ-amino acid with a potentially in-
triguing biological profile. Further investigations on the re-
action with bases other than LDA will be reported in due
course.
•
H
O
CO2t-Bu
H
Boc N
Boc N
CO2t-Bu
*
9
R
R
OH
Scheme 5 Attempts to rearrange 9 (R = i-Bu). Reaction conditions:
a) LDA, THF, –78 °C, 1 h, TMEDA, –35 °C, 12 h, decomposition; (b) LDA,
THF, –78 °C, 1 h, –35 °C, 12 h, decomposition; (c) LDA, THF, –78 °C,
h, –70 °C, 3 d, no reaction.
(
1
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1702–1704

1
704
Synlett
N. Griebenow et al.
Letter
Supporting Information
mmol, 1.33 mL) at –78 °C. The solution was stirred at –78 °C for
1
h followed by the dropwise addition of 12 (210 mg, 0.55
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380740.
mmol) dissolved in anhydrous THF (3 mL). The mixture was
stirred at 78 °C for 1 h and at –70 °C for 3 d. The mixture was
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
quenched with sat. aq NaHCO3 (5 mL). H O (2 mL) was added
2
and the mixture was extracted with Et O (3 ×). The combined
2
References and Notes
organic phases were washed with brine and sat. aq NaHCO3.
Subsequently, the organic phase was dried and concentrated.
(1) Reetz, M. T.; Griebenow, N.; Goddard, R. J. Chem. Soc., Chem.
1
13
The crude product was analyzed by H and C NMR spectros-
copy. The spectra showed only signals of 12 and 13. The corre-
sponding stereoisomer of 13 was not observed. Finally, the
Commun. 1995, 1605.
(2) Chilton, W. S.; Tsou, G.; Kirk, L.; Benedict, R. G. Tetrahedron Lett.
1968, 6283.
residue was purified on silica gel (Et O–pentane, 1:4 v/v). Yield:
2
(
(
3) Casara, P.; Jund, K.; Bey, P. Tetrahedron Lett. 1984, 25, 1891.
4) Hiemstra, H.; Fortgens, H. P.; Speckamp, W. N. Tetrahedron Lett.
2
1 mg (0.05 mmol, 14% based on recovered starting material).
1
H NMR (200 MHz, CDCl ): δ = 0.91 [d, J = 6.8 Hz, 3 H, CH -
3
2
1
984, 25, 3115.
5) Marshall, J. A.; Robinson, E. D.; Zapata, A. J. Org. Chem. 1989, 54,
854.
CH(CH ) ], 0.93 [d, J = 6.8 Hz, 3 H, CH -CH(CH ) ], 1.30–1.49 [m,
3
2
2
3 2
(
2
H, CH -CH(CH ) ], 1.44 [br s, 9 H, C(CH ) ], 1.48 [s, 9 H,
2 3 2 3 3
5
C(CH ) ], 1.59–1.67 [m, 1 H, CH CH(CH ) ], 1.71 and 1.72 [2 s,
3
3
2
3 2
(
(
(
6) Chung, J. Y. L.; Wasicak, J. T. Tetrahedron Lett. 1990, 31, 3957.
7) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
8) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans.
6
1
1
2
1
H, C=C=C(CH ) ], 3.54 (d, J = 7.6 Hz, 1 H, CHOH), 4.27–4.33 (m,
3 2
H, NHCH), 4.42 (d, J = 9.6 Hz, 1 H, NHCH), 4.46 (d, J = 7.6 Hz,
13
H, CHOH). C NMR (50 MHz, CDCl ): δ = 20.04, 20.36, 22.36,
3
1
915, 107, 1080.
9) Allinger, N. L.; Zalkow, V. J. Org. Chem. 1960, 25, 701.
of tert-Butyl (2R,4S)-4-[(tert-Butoxycar-
bonyl)amino]-2-hydroxy-6-methyl-3-(2-methylprop-1-en-
-ylidene)heptanoate (13): Under an atmosphere of argon,
2.83, 24.99, 28.09, 28.41, 43.97, 48.17, 71.12, 79.36, 81.99,
01.20, 104.57, 155.40, 172.58, 199.06. MS (EI): m/z (%) = 29
(
(
10) Synthesis
(17.25), 41 (27.93), 57 (100.00), 86 (59.50), 124 (11.85), 130
(
=
9
42.03), 136 (12.08), 226 (10.12), 253 (22.69); MS (CI, NH ): m/z
3
1
+
384 [M + H] . Anal. Calcd for C21H37NO (384.53): C, 65.77; H,
5
i-Pr NH (230 mg, 2.27 mmol) was dissolved in anhydrous
2
.72; N, 3.65. Found: C, 65.80; H, 9.66; N, 3.66.
THF (2 mL) and charged with n-BuLi (1.6 M in n-hexane, 2.16
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1702–1704