Study of the Cross-Metathesis Reaction of α-Hydroxy β,γ-Unsaturated Amides towards a Rapid and Flexible Total Synthesis of Symbioramide and its Isomer

Article abstract of DOI:10.1055/s-0036-1588579

The reactivity of novel α-hydroxy β,γ-unsaturated amides in cross-metathesis reactions was extensively studied and used to perform a short total synthesis of symbioramide and its isomer from l -serine methyl ester.

Full text of DOI:10.1055/s-0036-1588579

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
A. Gratais, S. Bouzbouz
Letter
Synlett
Study of the Cross-Metathesis Reaction of α-Hydroxy
β,γ-Unsaturated Amides towards a Rapid and Flexible Total
Synthesis of Symbioramide and its Isomer
Alexandre Gratais
Samir Bouzbouz*
Methodologic Challenge
Synthetic Challenge
O
O
screening of
ruthenium catalysts
O
R2
HN
C14H29
CNRS, INSA, Université de Rouen, COBRA UMR 6014,
76183 Mont Saint Aignan Cedex, France
samir.bouzbouz@univ-rouen.fr
HN
HN
OH
CH2Cl2, 25 °C
with or without
additive Lewis acid
OH
MeO2C
R1
OH
MeO2C
R1
C14H29
6 examples
22–54% yield
OH OH
total and rapid synthesis of symbioramide
9 steps from chiral serine methyl ester
R1 = Bn, Ph, CH(CH3)2, CH2CH(CH3)2, CH2CO2Me, CH2OTBDPS
2 = C14H29, C12H21, C9H19, C4H9, CH2SiMe3
R
Received: 20.07.2017
Accepted after revision: 04.09.2017
Published online: 12.10.2017
In 1988, symbioramide was isolated from the dinofla-
gellate Symbiodium sp. by Kobayashi et al.2 This marine nat-
ural product was found to exhibit antileukemic activity in
L-1210 cell lines and an increase in sarcoplasmic reticulum
Ca2+-ATPase activity.3 The antileukemic activity of symbior-
amide and its isomers within the L-1210 cells was evaluat-
ed revealing that unnatural stereoisomers have shown cell-
kill ratios between 70% and 88%, while natural symbiora-
mide led to only 31% cell kill.3
DOI: 10.1055/s-0036-1588579; Art ID: st-2017-d0570-l
Abstract The reactivity of novel α-hydroxy β,γ-unsaturated amides
in cross-metathesis reactions was extensively studied and used to
perform a short total synthesis of symbioramide and its isomer from
L-serine methyl ester.
Key words γ-silyl butenamides, cross-metathesis, hydroxyamide, syn-
thesis, symbioramide
Based on that assessment, the importance of developing
a flexible synthesis for both symbioramide and its stereo-
isomers, especially unreported isomers, in a rapid and ef-
fective manner is an important challenge. Previously, five
syntheses have been reported,3–7 all following a convergent
strategy. Different methodologies have been used for con-
trolling stereogenic centers including the use of chiral syn-
thons,3,4 Sharpless asymmetric epoxidation,5 chemo-enzy-
matic resolution,6 and asymmetric hydrogenation.7 Recent-
ly, the formal synthesis of symbioramide was reported
using an asymmetric organocatalytic and sigmatropic rear-
rangement approach to produce α-hydroxy-(E)-β,γ-unsatu-
rated esters.8
Over the past two decades, the olefin metathesis reac-
tion has contributed greatly in the development of new
methodologies and synthesis strategies. Based on our own
experience on the preparation of γ-silyl butenamides A,1 we
assumed that such substrates can be processed to furnish
hydroxyamide-functionalized substrates B in order to study
their reactivity in a cross-metathesis reaction. This ap-
proach could then be applied to the synthesis of symbio-
ramide (Scheme 1).
Our Work: Methodologic Challenge Cross-Metathesis of α-Hydroxyamides
Before attempting the total synthesis of symbioramide
and its stereoisomers, we decided to study the behavior of
chiral unsaturated hydroxyamides B towards ruthenium-
catalyzed metathesis. A range of substrates was synthesized
from the corresponding chiral allysilanes 2–61 by
dihydroxylation (OsO4, NMO) followed by treatment with
concentrated H2SO4 in diethyl ether to provide α-hydroxy-
amides 7–11 (Scheme 2). Despite the good yields (61–81%),
no significant diastereoselectivities were observed (d.r. =
1:1). However, both diastereoisomers were easily separable
by column chromatography. Sharpless asymmetric dihy-
droxylation was examined but did not lead to satisfying re-
sults (40% yield and d.e. = 1.3:1 for both AD-mix α and β).
O
O
O
R3
olefin
1R2RN
1R2RN
1R2RN
catalyst
OH
OH
SiMe3
B
A
synthesized
in our group
metathesis reaction
O
C14H29
HN
OH
C14H29
hydroxyamide moiety
OH OH
symbioramide 1
Scheme 1 α-Hydroxyamide moiety present in symbioramide
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
A. Gratais, S. Bouzbouz
Letter
Synlett
ented active intermediate D that produces the desired
cross-metathesis product. The proposed mechanism is
illustrated in Scheme 3.
O
R
O
R
1) OsO4 (cat.), NMO
acetone/H2O, r.t., 3 h
SiMe3
HN
HN
2) H2SO4, Et2O, r.t., 2 h
61–81%
OH
MeO2C
MeO2C
2–6
7–11
d.r. = 1:1 separable
O
O
R*
R
R = Bn (2), (78%, 7); Ph (3), (71%, 8); i-Pr (4), (74%, 9);
i-Bu (5), (81%, 10); CH2CO2Me (6), (61%, 11).
R*
OH
Ru
OH
Scheme 2 Synthesis of α-hydroxy β,γ-unsaturated amides
[2+2]
unreactive
complex
O
O
H
R
Ru
O
We first examined the reactivity of the 2′R and 2′S iso-
mers of compound 7 in the cross-metathesis reaction with
1-hexadecene that corresponds to the alkyl-chain length of
the natural product. Both diastereoisomers showed the
same reactivity (Table 1, entries 1 and 2), and we decided to
perform this study with the mixture of diastereoisomers.
For the key step, several conventional ruthenium-based
first-generation9,10 and second-generation11,12 catalysts
were screened for this cross-metathesis reaction in CH2Cl2
(Figure 1).
reactive
complex
Ru
R*
R*
Ru
R*
O
C
OH
D
OH
Ru
O
R*
[2+2]
R
O
OH
O
R
Ru
R
Ru
OH
OH
Scheme 3 Proposed catalytic process
To avoid the formation of the five-membered-ring-
deactivated chelate, the addition of a Lewis acid was consid-
ered. The synergistic effect of a Lewis acid in cross-meta-
thesis reactions involving carbonylated substrates has al-
ready been reported.16 Several cross-metathesis reactions
between unsaturated amide 7 and 1-hexadecene were test-
ed in the presence of stoichiometric amounts of Lewis acid,
but none of them resulted in an increase in yield (Table 1,
entries 10–13), and, in the case of Ti(Oi-Pr)4 and Zn(NTf2)2,
a significant reduction in yield was observed (Table 1,
entries 8 and 9). Accordingly, different types of olefin part-
ners (type I and type II) were then examined in this cross-
metathesis reaction involving α-hydroxyamide 7. A small
increase in yield was observed using 1-hexene and allyl-
trimethylsilane (Table 1, entries 14–17). In the case of N,N-
dimethylacrylamide, none of the substrates gave the de-
sired substituted olefin (Table 1, entry 18). These results
support our mechanistic hypothesis involving oriented and
sequestrated intermediates. We note that α-hydroxy-β,γ-
unsaturated amides present type II olefin behavior accord-
ing to the Grubbs olefin classification.17 The nature of the R1
group was next investigated to see the impact on reactivity.
We examined various amino acid derivatives including
phenylglycine, leucine, valine, and methyl aspartate, and all
substrates tested gave similar yields in the range of 43–45%
(Table 1, entries 19–22).
P(Cy)3
Cl
Cl
Mes
N
P(Cy)3
Ru
N
Mes
Ru
O
Cl
Cl
Cl
Ru
P(Cy)3
Cl
P(Cy)3
G(I)
HG(I)
G(II)
Mes
N
N
Mes
Cl
Cl
Ru
O
HG(II)
Figure 1 Ruthenium-based metathesis catalysts
It appeared that, with the exception of Grubbs first-
generation catalyst G(I) (entry 7), all catalysts gave similar
yields in the range of 43–49% (Table 1, entries 3–6). Increas-
ing the temperature did not lead to higher yields. We decid-
ed to use the Hoveyda–Grubbs second-generation HG(II)
catalyst, which proved to be the most efficient at room tem-
perature, for subsequent reactions. In some cases, we were
able to characterize α-ketoamides as side products, respon-
sible in some part for the moderate yields of the desired
cross-metathesis products. These α-ketoamides are the
result of allylic isomerization caused by the ruthenium
hydride complex formed during the catalytic cycle.13 In ad-
dition, the observed low yields could be due to possible
carbene sequestration. In the case of β,γ-unsaturated esters
or amides, the formation of stable five-membered ring che-
lates between the ruthenium carbene and the carbonyl
function C has been reported by several groups.14 This
sequestrated metallacyclobutane was unreactive towards
[2+2] cycloaddition by deactivation of the catalyst.15 A four-
membered ring chelate could also occur leading to an ori-
We then used this cross-metathesis methodology to
achieve the total synthesis of symbioramide and its iso-
mers. The synthetic sequence began with the preparation
of the chiral allylsilane 23 (Scheme 4) from L-serine methyl
ester hydrochloride. The aminoester was transformed to
the corresponding tert-butyldiphenylsilyl (TBDPS) deriva-
tive 22 (98%) by a standard protection procedure. The chiral
γ-trimethylsilylprop-2-enamide 2318 was obtained in 84%
yield by a one-pot process. Firstly, cross-metathesis be-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
A. Gratais, S. Bouzbouz
Letter
Synlett
tween acryloyl chloride and allyltrimethylsilane was car-
ried out, followed by the addition of O-protected amino-
ester 22. The construction of the α-hydroxyamide 24 was
achieved in two steps from precursor 23 following the
methodology described above (OsO4/NMO, H2SO4). Com-
pound 24 was obtained in a 74% yield as a separable mix-
ture of diastereoisomers (d.r. = 1:1). Treatment of the mix-
ture with 1-hexadecene (1.5 equiv) and second-generation
Hoveyda–Grubbs catalyst (5 mol% in CH2Cl2) afforded the
disubstituted unsaturated amide 2518 in 47% yield. Protec-
tion of 25, followed by ester reduction of 26 (NaBH4 in
THF/MeOH) gave a mixture of the corresponding diastereo-
isomers 27 and 28 that were easily separated by silica gel
chromatography (Scheme 4).
Swern oxidation of 27 under standard conditions led to
the corresponding aldehyde, which was not isolated be-
cause of its propensity to epimerize during workup. In-
stead, the aldehyde was directly treated with a large excess
of pentadecylmagnesium bromide (7 equiv). Under these
conditions, no diastereoselectivity was observed. The crude
mixture was treated with TBAF (3 equiv) in THF leading,
after preparative TLC, to symbioramide 1 and its C-3 epimer
Table 1 Screening of Reaction Parameters
O
catalyst (x mol%),
CH2Cl2, 25 °C
O
R2
HN
HN
OH
R2
(1.5 equiv)
OH
MeO2C
R1
7–11
MeO2C
R1
12–21
Entry
Amide (R1)
Olefin (R2)
Catalyst
x mol%
Additive L.A.
Time (h)
Yield (%)a
Product
Screening of the ruthenium catalyst
1
2
3
4
5
6
7
Bn (2′S)
Bn (2′R)
Bn
C
14H29
HG(II)
HG(II)
HG(II)
HG(II)
G(II)
5
5
none
none
none
none
none
none
none
24
24
24
24
24
24
24
43
44
48
49
43
45
30
12
12
12
12
12
12
12
C14H29
C14H29
C14H29
C14H29
C14H29
C14H29
5
Bn
10
5
Bn
Bn
HG(I)
G(I)
5
Bn
5
Screening of the Lewis acid
8
9
Bn
Bn
Bn
Bn
Bn
Bn
C14H29
C14H29
C14H29
C14H29
C14H29
C14H29
HG(II)
HG(II)
HG(II)
HG(II)
HG(II)
HG(II)
5
5
5
5
5
5
Ti(Oi-Pr)4
16
16
16
16
16
16
22
25
45
45
46
49
12
12
12
12
12
12
Zn(NTf2)2
10
11
12
13
Cu(OTf)·C6H6
RuCl3
B(OPh)3
C6H4O2BCl
Effect of group R2 on reactivity
14
15
16
17
18
Bn
Bn
Bn
Bn
Bn
C
12H25
HG(II)
HG(II)
HG(II)
HG(II)
HG(II)
5
5
5
5
5
none
none
none
none
none
24
24
24
24
24
45
45
53
54
0
13
14
15
16
17
C9H19
C4H9
CH2SiMe3
CO2NMe2
Effect of group R1 on reactivity
19
20
21
22
Ph
C14H29
C14H29
C14H29
C14H29
HG(II)
HG(II)
HG(II)
HG(II)
5
5
5
5
none
none
none
none
16
16
16
16
43
44
43
45
18
19
20
21
CH2CH(CH3)2
i-Pr
CH2CO2Me
a Yield of isolated pure product.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
A. Gratais, S. Bouzbouz
Letter
Synlett
29 in a global yield of 29% (Scheme 5). Spectroscopic data
(IR, MS, 1H NMR, and 13C NMR) were found to be identical to
those previously reported for symbioramide.
However, for confirmation, we transformed symbio-
ramide 1 into its triacetate 1a (Scheme 6). The 1H NMR and
13C NMR spectra of compound 1a are identical to the spec-
tra described by the Sugai group.6
In summary, the present work illustrates a novel route
for the synthesis of α-hydroxy-β,γ-unsaturated amides
from chiral allylsilanes. Those new substrates can be readily
converted into functionalized compounds by cross-meta-
thesis leading to a range of disubstituted olefins. This meth-
odology is applicable to the synthesis of natural products
containg the α-hydroxyamide moiety such as sphingosines
or ceramides.
The same final steps could be applied to synthetize the
two other diastereoisomers from alcohol 28.
Acknowledgment
O
O
1) HG(II) (2.5 mol%)
CH2Cl2, r.t., 4 h
SiMe3
Cl
HN
This work has been partially supported by the CNRS, Region Haute
Normandie, European Fund for Regional Development (35476), and
Labex SynOrg (ANR-11-LABX-0029).
+
NH2
23
MeO2C
2) NMM,
SiMe3
OTBDPS
MeO2C
22
OTBDPS
1) OsO4, NMO
acetone/H2O, r.t.
84%
Supporting Information
2) H2SO4, Et2O, r.t.
74%
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588579.
O
O
C14H29
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
C14H29
HG(II) (5 mol%)
HN
HN
O
OH
OH
24 d.r. = 1:1
CH2Cl2, r.t., 24 h
47%
MeO2C
MeO2C
25
separable
References and Notes
OTBDPS
OTBDPS
(1) Bouzbouz, S. Synlett 2011, 1888.
TBDPSCl, imidazole
CH2Cl2, r.t., 97%
(2) (a) Kobayashi, J.; Ishibashi, M.; Nakamura, H.; Hirata, Y.;
Yamasu, T.; Sasaki, T.; Ohizumi, Y. Experientia 1988, 44, 800.
(b) Kobayashi, J. J. Nat. Prod. 1989, 52, 225.
(3) (a) Nakagawa, M.; Yoshida, J.; Hino, T. Chem. Lett. 1990, 1407.
(b) Yoshida, J.; Nakagawa, M.; Seki, H.; Hino, T. J. Chem. Soc.,
Perkin Trans. 1 1992, 343.
(4) Azuma, H.; Takao, R.; Niiro, H.; Shikata, K.; Tamagaki, S.;
Tachibana, T.; Ogino, K. J. Org. Chem. 2003, 68, 2790.
(5) Mori, K.; Uenishi, K. Liebigs Ann. Chem. 1994, 41.
(6) Takanami, T.; Tokoro, H.; Kato, D.; Nishiyama, S.; Sugai, T. Tetra-
hedron Lett. 2005, 46, 3291.
C14H29
HN
O
OTBDPS
C14H29
27
HN
OH OTBDPS
1) NaBH4
OTBDPS
+
MeO2C
THF/MeOH, r.t.
68% for both isomers
O
OTBDPS
C14H29
2) separation
26
HN
OTBDPS
28
OH OTBDPS
Scheme 4 Synthesis of alcohols 27 and 28
(7) Prevost, S.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V.
Adv. Synth. Catal. 2011, 353, 3213.
O
(8) Hess, L. C.; Posner, G. H. Org. Lett. 2010, 12, 2120.
(9) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. (b) Schwab, P.; Grubbs, R. H.;
Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100. (c) Belderrain, T. R.;
Grubbs, R. H. Organometallics 1997, 16, 4001.
HN
n = 13
OH
1. (COCl)2, DMSO, Et3N,
–78 °C
2. C15H31MgBr, THF, 0 °C
3. TBAF, THF, r.t
n = 14
O
OH OH
symbioramide 1
(10) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A.
H. J. Am. Chem. Soc. 1999, 121, 791. (b) Harrity, J. P. A.; Visser, M.
S.; Gleason, J. D.; Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119,
1488. (c) Harrity, J. P. A.; La, D. S.; Cefalo, D. R.; Visser, M. S.;
Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 2343.
(11) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1,
1751. (c) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H.
J. Am. Chem. Soc. 2000, 122, 3783.
HN
+
n = 13
O
3 steps
29% for two symbioramide
OR
HN
OH
OH OR
separable
n = 13
(–)-27
R = TBDPS
n = 14
OH OH
(–)-29
Scheme 5 Synthesis of symbioramide 1 and isomer 29
(12) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168. (b) Gessler, S.; Randl, S.; Blechert, S.
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5, 3548.
O
O
HN
HN
pyridine, DMAP
n = 13
n = 13
OH
OAc
Ac2O, CH2Cl2
81%
n = 14
n = 14
OH OH
OAc OAc
1
1a
Scheme 6 Synthesis of triacetate symbioramide 1a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
A. Gratais, S. Bouzbouz
Letter
Synlett
(14) (a) Fürstner, A.; Thiel, O. R.; Lehmann, C. W. Organometallics
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1.0, CHCl3). IR (neat): ν = 2953, 2858, 1747, 1661, 1627, 1504,
1428, 1248, 1111, 847, 701 cm–1.1H NMR (300 MHz, CDCl3): δ =
7.63–7.58 (m, 4 H), 7.43–7.35 (m, 6 H), 6.95 (dt, J = 15.1, 8.8 Hz,
1 H), 6.29 (d, J = 8.2 Hz, 1 H), 5.67 (d, J = 15.1 Hz, 1 H), 4.81 (dt,
J = 8.1, 2.9 Hz, 1 H), 4.04 (ddd, J = 57.0, 10.2, 3.0 Hz, 2 H), 3.74 (s,
3 H), 1.72 (d, J = 8.8 Hz, 2 H), 1.04 (s, 9 H), 0.06 (s, 9 H). 13C NMR
(75 MHz, CDCl3): δ = 170.6, 165.1, 143.0, 135.0, 134.9, 132.5,
132.3, 129.4, 129.4, 127.3, 120.8, 64.1, 53.7, 51.6, 26.2, 23.7,
18.8, –2.3. HRMS (ESI+): m/z calcd for C27H40NO4Si2 [M + H]+:
498.2496; found: 498.2500.
Compound 25: Allylic alcohol 24 (2.64 g, 6 mmol, 1.0 equiv) was
dissolved in dry CH2Cl2 (2 mL) with alkene (5.18 mL, 3.0 mmol,
3.0 equiv). Then HG(II) (94 mg, 2.5 mol%) was added, and the
reaction mixture was stirred at r.t. for 24 h. The solution was
concentrated under vacuum, and the residue was purified by
silica gel column chromatography purified by column chroma-
tography (CH2Cl2/EtOAc, 9:1). The product was obtained as a
mixture of diastereoisomers; only the major isomer is
described; colorless oil (1.79 g, 47%). Rf = 0.73 (CH2Cl2/EtOAc,
9:1). IR (neat): ν = 2924, 2954, 1751, 1659, 1520, 1112, 823, 701
cm–1.1H NMR (300 MHz, CDCl3): δ = 7.60–7.58 (m, 4 H), 7.43–
7.36 (m, 6 H), 7.09 (d, J = 8.2 Hz, 1 H), 5.95 (dt, J = 15.3, 6.6 Hz, 1
H), 5.57 (dd, J = 15.4, 7.6 Hz, 1 H), 4.68 (dt, J = 8.3, 2.4 Hz, 1 H),
4.54 (d, J = 7.6 Hz, 1 H), 4.01 (ddd, J = 13.2, 10.1, 2.6 Hz, 2 H),
3.75 (s, 3 H), 3.25 (br s, 1 H), 2.05 (dt, J = 8.7, 6.8 Hz, 2 H), 1.41–
1.26 (m, 24 H), 1.03 (s, 9 H), 0.88 (t, J = 6.6 Hz, 3 H). 13C NMR (75
MHz, CDCl3): δ = 172.3, 170.5, 137.0, 135.5, 135.5, 132.7, 132.6,
130.0, 127.9, 127.8, 127.1, 73.0, 64.2, 54.2, 52.5, 32.3, 32.0, 29.7,
29.7, 29.6, 29.5, 29.4, 29.3, 28.9, 26.7, 22.7, 19.3, 14.2. HRMS
(ESI+): m/z calcd for C38H60NO5Si [M+H]+: 638.4241; found:
638.4236.
(17) Chatterjee, A. K.; Choi, T.-L.; Sanders, D.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(18) Representative Experimental Procedure and Characteriza-
tion Data
Compound 23: Allyltrimethylsilane (6.7 mL, 42 mmol, 3.0
equiv) was dissolved in dry CH2Cl2 (20 mL), then acryloyl chlo-
ride (1.12 mL, 14 mmol, 1.0 equiv), and HG(II) (219 mg, 2.5
mol%) were added. The reaction mixture was stirred at r.t. for 4
h. The obtained solution was slowly added to a solution of O-
protected L-serine methyl ester 22 (5 g, 14 mmol, 1.0 equiv) in
CH2Cl2 (15 mL) at –20 °C. i-Pr2EtN (4.86 mL, 28 mmol, 2.0 equiv)
was then added to the solution and stirred for 1 h. After com-
pletion, the reaction was quenched with sat. aq NH4Cl solution
and extracted with EtOAc (2 × 30 mL). The combined organic
phases were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (cyclohexane/EtOAc, 8:2)
to give the corresponding product as a brown waxy solid 23
(5.84 g, 84%). Rf = 0.48 (cyclohexane/EtOAc, 8:2). [α]D25 +24.0 (c
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E