A Catalytic Asymmetric Ene Reaction for Direct Preparation of α-Hydroxy 1,4-Diketones as Intermediates in Natural Product Synthesis

Article abstract of DOI:10.1055/s-0037-1610748

Asymmetric access to α-hydroxy-1,4-diketones has been achieved by direct ene coupling of silyl enol ethers with glyoxal electrophiles, mediated by a chiral N, N ′-dioxide-nickel(II) complex catalyst. Successful union of a polyketide silyl enol ether with an α-quaternary glyoxal, generated by dioxirane oxidation of an α-diazo ketone, models a proposed C ₅ -C ₆ disconnection of the polyketide and spirocyclic imine domains of the marine natural product, portimine.

Full text of DOI:10.1055/s-0037-1610748

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
en
Synlett
H. R. Aitken et al.
Letter
A Catalytic Asymmetric Ene Reaction for Direct Preparation of
-Hydroxy 1,4-Diketones as Intermediates in Natural Product

Synthesis
Harry R. M. Aitken
O
O
α-hydroxy
Margaret A. Brimble*
0
0
0
0-
0
0
0
2-7
0
8
6-4
0
9
6
1
,4-diketone
Daniel P. Furkert*
0
0
0
0-
0
0
0
1-6
2
8
6-9
1
0
5
O
OH
OPG
BzO
O
TBSO
TBSO
School of Chemical Sciences and Maurice Wilkins Centre for
Molecular Biodiversity, The University of Auckland, 23 Symonds
St, Auckland 1010, New Zealand
d.furkert@auckland.ac.nz
m.brimble@auckland.ac.nz
(S)
N
O
N
O
O
O
BzO
NH
HN
Ni2+
PG = TMS
or TBS
35–71% (brsm)
dr 14:1 to 19:1
5
examples
Received: 16.12.2019
Accepted after revision: 18.01.2020
Published online: 19.02.2020
OH
O
O
H
H
N
O
O
DOI: 10.1055/s-0037-1610748; Art ID: st-2019-d0676-l
Me2N
O
Abstract Asymmetric access to -hydroxy-1,4-diketones has been
achieved by direct ene coupling of silyl enol ethers with glyoxal electro-
philes, mediated by a chiral N,N′-dioxide–nickel(II) complex catalyst.
Successful union of a polyketide silyl enol ether with an -quaternary
glyoxal, generated by dioxirane oxidation of an -diazo ketone, models
a proposed C –C disconnection of the polyketide and spirocyclic imine
H
O
HO
O
O
portimine (1)
O
alanolide (2)
O
O
O
O
H
H
H
H
H
O
5
6
O
O
domains of the marine natural product, portimine.
O
NH
H
H
O
Key words ene reaction, glyoxal, N,N′-dioxide–nickel(II) complex, nat-
ural product synthesis, Leighton crotylation, portimine
HO
O
O
tirandamycin A (4)
ineleganolide (3)
Figure 1 Natural products containing an -hydroxy-1,4-diketone motif
A wide variety of bioactive natural products contain
functionality derived from the -hydroxy-1,4-diketone
moiety (Figure 1). Examples include the caspase activator
enol ether 5 and glyoxal 6, a plausible model system for the
C5–C6 disconnection of the spirocyclic imine algal metabo-
lite, portimine.
1
2
portimine, the antileukemia agent ineleganolide, and the
3
antibiotic tirandamycin A. Despite the importance of -hy-
The synthesis of the methyl ketone coupling fragment 5
started from ester 9 (Scheme 2) prepared in one step from
droxy-1,4-diketones as potential intermediates in the syn-
thesis of these compounds, there are currently no broadly
applicable methods for the direct stereoselective prepara-
tion of complex examples of this challenging fragment.4
In 2011, the Feng group reported a novel asymmetric
N,N′-dioxide–nickel(II) complex for the Mukaiyama aldol
reaction of acetophenone-derived silyl enol ethers with
7
commercially available ethyl levulinate. Following DIBAL
reduction of ester 9, the crude aldehyde was subjected to
second-generation Leighton crotylation conditions using
8
the in situ generated chiral silicon complex 14, to afford al-
cohol 10 as a single diastereoisomer in excellent yield and
enantioselectivity (82%, 94% ee). While the standard aque-
ous acidic workup procedure for ligand recovery proved un-
suitable for the sensitive acetal functionality, simple gradi-
ent elution of the crude reaction mixture facilitated excel-
lent recovery (≤90%) of the recyclable diaminophenol ligand
derived from 14 by chromatography. In order to prepare
alkyne 5, alcohol 10 was protected as the TBS ether, fol-
lowed by oxidation and then homologation with the Ohira–
Bestmann reagent to give 13.9 Treatment of 13 with Am-
berlyst 15 sulfonic acid resin then liberated the free ketone
5 in good yield, for use in the key fragment coupling.
5
simple aryl glyoxal derivatives (Scheme 1, A) achieving
good yields and high enantioselectivity. Recent theoretical
studies on N,N′-dioxide–metal complex catalysis by Su and
co-workers suggested that aliphatic enol ethers may react
6
via an ene-type mechanism. We became interested in in-
vestigating these reactions with a view to extending N,N′-
dioxide-nickel(II) complex catalysis to the asymmetric
union of complex, aliphatic substrates that serve as plausi-
ble intermediates in natural product synthesis. Specifically,
we report herein our investigation into the coupling of silyl
,10
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2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
H. R. Aitken et al.
Letter
A Feng (2011)
lyzed oxidation using periodate as the stoichiometric oxi-
dant.13 The resultant benzoate ester 21 then smoothly un-
derwent conversion into diazoketone 22. Addition of a solu-
tion of DMDO (69 mM in acetone) to 22 successfully
Ni(II)
N,N'-dioxide
complex (X)
O
OH
OTMS
Ar
O
Ar
O
Ar
Ar
O
6
5–95%
O
9
0–95% ee
14,15
resulted in rapid conversion into the desired glyoxal 6.
B This work
Notably, alternative efforts to prepare glyoxals 6 or 20 by a
number of -ketone oxidation strategies proved unsuccess-
ful, with other processes leading to rapid degradation, or a
complex mixture of byproducts (Scheme 3).1
O
O
O
OH
TBSO
TBSO
O
5
6
6–20
BzO
6
BzO
5
O
7
O
O
BnO
C Proposed application to portimine
(c)
(a)
(b)
ene reaction
O
O
O
O
O
NHBoc
34%
TBSO
OH
(3 steps)
6
BnO
H
15
16
17
5
N
BzO
O
O H
O
O
O
N2
O
5
8
HO
(d,e)
(f)
HO
O
portimine (1)
alkyne addition
BnO
BnO
BnO
18
19
20
Scheme 1 (A) Feng’s nickel(II)-catalyzed aldol reaction; (B) this work;
C) proposed application towards portimine.
(
(g) 88%
O
N2
O
O
O
HO
(d,e)
1%
(
f)
9
O
O
quant.
(
2 steps)
(
a,b)
HO
(c)
O
O
BzO
BzO
BzO
EtO
21
22
6
8
2%
97%
(
2 steps)
(94% ee)
O
10
9
X
O
O
O
[oxidation]
O
X = OH, Br, H
R = Bn, Bz
O
O
N
TBSO
TBSO
(d)
0%
Si
N
O
RO
RO
tBu
9
12
Scheme 3 Synthesis of glyoxal 6. Reagents and conditions: (a) MeI, NaH
60% w/w in mineral oil), THF, 3 h, reflux; (b) KOH, BnBr, toluene, 13 h,
Dean–Stark reflux; (c) KOH, MeOH/H O (2:1), 16 h, reflux; (d) (COCl) ,
11
14
(
2
2
O
DMF, CH Cl , 3 h, rt; (e) TMSCHN (2 M in hexane), MeCN, 16 h, rt; (f)
dimethyldioxirane (69 mM in acetone), 2 min, rt; (g) NaIO , RuCl ∙xH O,
4 3 2
2
2
2
O
O
TBSO
TBSO
(
e–g)
(d)
75%
EtOAc/H O (2:1), 3 h, rt.
2
8
4%
(
3 steps)
Initial investigation of the proposed ene reaction fo-
cused on the union of glyoxal 6 and ketone 12, readily pre-
pared by deprotection of acetal 11 (Scheme 4).
H
1
3
5
Scheme 2 Synthesis of methyl ketones 5 and 12. Reagents and condi-
tions: (a) DIBAL (1 M in hexane), CH Cl , 2 h, –78 °C; (b) 14, THF, 2 h,
rt to 0 °C, then TBAF (1 M in THF), Et O; (c) TBSOTf, 2,6-lutidine, CH Cl ,
min, 0 °C; (d) Amberlyst-15, acetone/CH Cl (1:1), 15 h–20 h, rt; (e)
-BBN dimer, THF, 3.5 h, rt, then NaOH (aq, 3 M), H O (30% aq); (f)
2
2
2
2
2
PGO
R2
5
9
2 2
2
2
R1
SO ·py, DMSO, i-Pr NEt, CH Cl , 5 min, 0 °C; (g) K CO , Ohira–Bestmann
3
2
2
2
2
3
OPG OH
reagent, MeOH, 1 h, rt.
O
O
N
R1
R2
(S)
O
Ni
O
O
HN
NH
O
O
N
Synthesis of glyoxal 6 proceeded from -butyrolactone
15, Scheme 3). Initially, dimethylation was followed by a
(
ring-opening protection sequence to generate carboxylic
1
1,12
acid 18 in moderate yield.
Surprisingly, attempts to con-
Scheme 4 Favored facial approach for glyoxal ene reaction, as pro-
posed by Feng4
vert carboxylic acid 18 into glyoxal 20 met with failure, due
to cleavage of the benzyl ether during preparation of the
corresponding acid chloride. To circumvent this issue, the
sensitive benzyl ether was submitted to ruthenium-cata-
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
Synlett
H. R. Aitken et al.
Letter
In order to carry out the ene reaction (Table 1), ketone
2 was converted into the corresponding TMS enol ether,
the efficiency of the ene coupling was most likely limited by
its decomposition under the reaction conditions. To test
this possibility, the reaction sequence was performed with
3 equivalents of glyoxal 6, added in three portions over 3 h,
which afforded -hydroxy-1,4-diketone 7 in an improved
yield of 32% (71% based on recovered starting material; Ta-
ble 1, entry 5). In the ene coupling, only minimal concomi-
tant desilylation of intermediate silyl enol ether was ob-
served prior to the reaction workup, suggesting that im-
proved yields could be achieved using an even larger excess
of glyoxal.
1
which was directly used without further purification, for
21
reaction with freshly prepared crude glyoxal 6. This mix-
ture was treated with the N,N′-dioxide–nickel(II) complex
derived from ligand 23, to afford small quantities of aldol
product 25, together with large amounts of recovered ke-
tone 12 (Table 1, entry 1). Notably however, the reaction
appeared to proceed with good stereoselectivity (dr = 11:1),
as determined by comparison of the relative integral of the
1
newly formed epimeric hydroxyl proton in the H NMR
spectrum.
The absolute stereochemistries of the -hydroxy-1,4-
diketone adducts were determined by analogy with the
model proposed by the Feng group for related ene and aldol
transformations. In this model a nucleophile undergoes ad-
dition to a facially discriminated, activated glyoxal–nickel
When the more hindered TBS enol ether derivative was
employed, coupling proceeded cleanly, affording the ene
enol silane product 24. Stirring this compound in wet chlo-
roform overnight resulted in clean cleavage of the enol si-
lane, leading to the isolation of -hydroxy-1,4-diketone 25
in 29% yield from ketone 12 (14:1 dr, Table 1, entry 2). How-
ever, when the reaction sequence was repeated using the
more stable TIPS enol ether derivative of 12, only 19% of -
hydroxy-1,4-diketone 25 was isolated, with competing de-
composition of glyoxal 6 observed after prolonged reaction
times (Table 1, entry 3).
4
complex. Accordingly, the newly formed stereocenter of
hydroxy dione 7 exists in the S configuration (Scheme 4).
In conclusion, an asymmetric ene reaction catalyzed by
Feng’s N,N′-dioxide–nickel(II) complex has been applied to
the union of ketone 5 and glyoxal 6, to model to the C –C
5
6
disconnection of portimine.21 The reaction cleanly afforded
the challenging -hydroxy-1,4-diketone motif with excel-
lent stereocontrol over three steps from ketone 5. This
transformation is the first application of N,N′-dioxide–nick-
el(II) catalysis to a target-directed synthetic sequence and
Similar results were obtained using the TBS enol ether
of the portimine polyketide fragment 5 (Table 1, entry 4).
Due to the inherent instability of glyoxal 6, it appeared that
Table 1 Optimization of the N,N′-Dioxide–Nickel(II) Complex Catalyzed Ene Reactiona
O
O
OPG OH
O
OH
PG-OTf
Et N
3
R
O
R
O
N
O
N
O
BzO
(S)
(S)
O
O
O
OPG
6
NH
HN
R
1
R
CH2Cl2
10 °C, 1 h
catalyst 23 (11 mol%)
Ni(BF4)2 (10 mol%)
CH2Cl2
23
wet
CHCl3
–
BzO
BzO
25 or 7
30 °C, 24 h
2 or 5
24
Entry
Ketone
PG
TMS
Product
Yield (%)b and dr
Recovered SM
1
2
O
OH
21 (11:1)
29 (14:1)
–c
O
TBSO
O
TBS
TIPS
TBS
(S)
17
TBSO
3d
4
19 (14:1)
44
48
12
BzO
25
O
OH
12 (>19:1)
O
TBSO
O
TBSO
(S)
5e
TBS
32 (>19:1)
55
5
BzO
7
a
Reactions were performed on ketone 5 or 13 (25 mg) with glyoxal 6 (1.3 equiv) unless otherwise noted. Intermediate silanes were not purified before use.
Yield reported over three steps from starting ketone.
Treatment with wet CHCl was not performed.
3
Ene reaction performed for 40 h.
b
c
d
e
Glyoxal 6 (3 equiv) was added in three portions over 3 h.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
Synlett
H. R. Aitken et al.
Letter
represents a significant increase in substrate scope for that
methodology.
sample gave the following data. IR (film): 2972, 1716, 1452,
–1 1
1

7
316, 1274, 1113, 1026, 712 cm . H NMR (400 MHz, CDCl ):
= 9.20 (s, 1 H), 7.91–7.86 (m, 2 H), 7.59–7.52 (m, 1 H), 7.47–
3
.40 (m, 2 H), 4.36 (t, J = 6.1 Hz, 2 H), 2.31 (t, J = 6.1 Hz, 2 H),
13
Funding Information
1.35 (s, 6 H). C NMR (100 MHz, CDCl
33.3, 129.7, 129.6, 128.6, 61.5, 44.3, 37.8, 24.0. HRMS (ESI):
3
):  = 202.3, 188.7, 166.4,
1
+
The University of Auckland provided a Doctoral Scholarship to HA.
This work was also supported by the Royal Society of New Zealand
m/z [M + Na] calcd for C14H16NaO : 271.0941; found: 271.0935.
4
(16) Wu, F.; Mandadapu, V.; Day, A. I. Tetrahedron 2013, 69, 9957.
(17) Kornblum, N.; Frazier, H. W. J. Am. Chem. Soc. 1966, 88, 865.
(Marsden Found, Grant No. UOA1422).
R
o
y
a
lS
o
c
i
ety of
N
e
w
Z
e
a
l
a
n
d
(1
4
2
2)U
n
i
v
ersity of
A
u
c
k
l
a
n
d
()
(18) Mitschka, R.; Oehldrich, J.; Takahashi, K.; Cook, J. M.; Weiss, U.;
Silverton, J. V. Tetrahedron 1981, 37, 4521.
(19) Kotha, S. S.; Sekar, G. Tetrahedron Lett. 2015, 56, 6323.
Supporting Information
(
20) Zhu, Y.-P.; Jia, F.-C.; Liu, M.-C.; Wu, A.-X. Org. Lett. 2012, 14,
414.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610748.
4
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orti
n
g Inform ati
o
n
(
21) To a solution of ketone 5 (40 mg, 0.142 mmol) in dichlorometh-
ane (1 mL) at –10 °C triethylamine (97 L, 0.71 mmol) was
added, followed by tert-butyldimethylsilyl trifluoromethanesul-
fonate (65 L, 0.28 mmol). After 1 h the reaction was quenched
with saturated aqueous sodium hydrogen carbonate (2 mL) and
extracted with dichloromethane (3 × 3 mL). The combined
organic layers were dried over sodium sulfate, filtered, concen-
trated, then dissolved in petroleum ether (10 mL), filtered
through a plug of cotton wool and concentrated again, to give
the crude silyl enol ether. To a solution of diamine-N-dioxide
References and Notes
(1) Selwood, A. I.; Wilkins, A. L.; Munday, R.; Shi, F.; Rhodes, L. L.;
Holland, P. T. Tetrahedron Lett. 2013, 54, 4705.
(2) Duh, C.-Y.; Wang, S.-K.; Chia, M.-C.; Chiang, M. Y. Tetrahedron
Lett. 1999, 40, 6033.
(3) Meyer, C. E. J. Antibiot. 1971, 24, 3.
(
4) Some methods for asymmetric synthesis of simple derivatives
have been reported: (a) Moles, F. J. N.; Guillena, G.; Nájera, C.
Synlett 2015, 26, 656. (b) Alberg, D. G.; Poulsen, T. B.; Bertelsen,
S.; Christensen, K. L.; Birkler, R. D.; Johannsen, M.; Jørgensen, K.
A. Bioorg. Med. Chem. Lett. 2009, 19, 3888. (c) Guo, L.; Plietker, B.
Angew. Chem. Int. Ed. 2019, 58, 8346. (d) Richter, C.; Krumey, M.;
Klaue, K.; Mahrwald, R. Eur. J. Org. Chem. 2016, 5309.
5) Zhao, J.; Zheng, K.; Yang, Y.; Shi, J.; Lin, L.; Liu, X.; Feng, X. Synlett
(8.7 mg, 0.015 mmol) in dichloromethane (1 mL) at 30 °C, nickel
tetrafluoroborate hexahydrate (4.8 mg, 0.014 mmol) was added,
the mixture was stirred vigorously for 30 min, and then concen-
trated and dried in vacuo for 5 h. A solution of freshly prepared
crude glyoxal (6, ca. 0.142 mmol) and the previously prepared
silyl enol ether in dichloromethane (1 mL) was then added, and
the mixture warmed to 30 °C. After 2 h, further glyoxal 6 (ca.
(
0
.142 mmol) in dichloromethane (0.5 mL) was added dropwise,
followed after a further 2 h by another solution of glyoxal 6 (ca.
.142 mmol) in dichloromethane (0.5 mL). The reaction was
2011, 903.
(
(
6) Wang, J.; Su, Z.; Yang, N.; Hu, C. J. Org. Chem. 2016, 81, 6444.
7) Wanner, M. J.; Boots, R. N. A.; Eradus, B.; Gelder, R. D.; van Maar-
seveen, J. H.; Hiemstra, H. Org. Lett. 2009, 11, 2579.
0
then stirred for 18 h and quenched with aqueous citric acid (0.5
M, 3 mL), stirred for 30 min, and then extracted with dichloro-
methane (3 × 3 mL). The combined organic layers were washed
with brine (6 mL), dried over sodium sulfate, filtered, and con-
centrated. The resultant oil was allowed to stand in chloroform
for 14 h, then concentrated in vacuo. Chromatography (petro-
leum ether/ethyl acetate, 15:1) afforded (7, 24 mg, 32%) as a col-
orless oil and returned starting material ketone (5, 22 mg, 55%);
(8) Suen, L. M.; Steigerwald, M. L.; Leighton, J. L. Chem. Sci. 2013, 4,
2
413.
9) Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
21.
(
5
(10) Ohira, S. Synth. Commun. 1989, 19, 561.
(11) Jägel, J.; Schmauder, A.; Binanzer, M.; Maier, M. E. Tetrahedron
2
007, 63, 13006.
12) Wilson, Z. E.; Hubert, J. G.; Brimble, M. A. Eur. J. Org. Chem. 2011,
938.
13) Schuda, P. F.; Cichowicz, M. B.; Heimann, M. R. Tetrahedron Lett.
983, 24, 2.
14) Ihmels, H.; Maggini, M.; Prato, M.; Scorrano, G. Tetrahedron Lett.
991, 32, 6215.
2
0
[
]D 2.2 (c 2.4, CHCl ). IR (film): 3480, 2958, 2857, 1716, 1275,
3
(
(
(
(
–1 1
1
8
4
3
113, 1027, 837, 776, 713 cm . H NMR (400 MHz, CDCl ):  =
3
3
.01–7.97 (m, 2 H), 7.59–7.53 (m, 1 H), 7.46–7.40 (m, 2 H),
.90–4.83 (m, 1 H), 4.39–4.27 (m, 2 H), 3.71–3.67 (m, 1 H),
.60–3.56 (m, 1 H), 2.65–2.57 (m, 2 H), 2.58–2.36 (m, 2 H), 2.28
1
(ddd, J = 16.6, 5.8, 2.6 Hz, 1 H), 2.23–1.98 (m, 3 H), 1.95 (dd, J =
1
3.0, 2.6 Hz, 1 H), 1.80–1.62 (m, 3 H), 1.33 (s, 3 H), 1.33 (s, 3 H),
15) Preparation of Glyoxal (6)
13
0.96 (d, J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 6 H). C NMR (100
To stirred diazoketone 22 (104 mg, 0.400 mmol), dimethyldiox-
irane (69 mM in acetone, 6.7 mL, 0.466 mmol) was added rap-
idly. The mixture was vigorously stirred for 2 min, then concen-
trated under a stream of nitrogen. The resultant crude oil was
used in the next step without further purification. An analytical
MHz, CDCl ):  = 214.4, 209.4, 166.7, 133.2, 130.3, 129.7, 128.5,
3
83.9, 73.4, 70.6, 69.2, 61.9, 46.0, 45.8, 40.2, 38.3, 37.9, 26.9, 26.0,
+
25.4, 24.6, 21.9, 18.2, 14.4, –4.1, –4.4. HRMS (ESI): m/z [M + H]
calcd for C30H46NaO Si: 553.2956; found: 553.2957.
6
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D