Re-visiting the diastereoselectivity of organocatalytic conjugate addition of 2-trimethylsiloxyfuran to trans-crotonaldehyde

Article abstract of DOI:10.1016/j.tetlet.2021.153056

We describe the re-assignment of configuration previously ascribed to product diastereomers resultant from imidazolidinone-catalyzed conjugate addition of 2-trimethylsiloxyfuran to trans-crotonaldehyde. A modified procedure that uses a diphenylprolinol catalyst was subsequently developed to selectively provide the ‘syn’ diastereomeric product in high enantiomeric excess on decagram scales.

Full text of DOI:10.1016/j.tetlet.2021.153056

Tetrahedron Letters 72 (2021) 153056
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Re-visiting the diastereoselectivity of organocatalytic conjugate addition
of 2-trimethylsiloxyfuran to trans-crotonaldehyde
⇑
Liubo Li, Anton El Khoury, Brennan O. Clement, Patrick G. Harran
Department of Chemistry and Biochemistry, University of CaliforniaÀLos Angeles, 607 Charles E. Young Drive East, Los Angeles, CA 90095-1569, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the re-assignment of configuration previously ascribed to product diastereomers resultant
from imidazolidinone-catalyzed conjugate addition of 2-trimethylsiloxyfuran to trans-crotonaldehyde.
A modified procedure that uses a diphenylprolinol catalyst was subsequently developed to selectively
provide the ‘syn’ diastereomeric product in high enantiomeric excess on decagram scales.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 18 February 2021
Revised 25 March 2021
Accepted 30 March 2021
Available online 6 April 2021
Keywords:
Mukaiyama-Michael reaction
Butenolide
The catalyzed conjugate addition of 2-siloxyfurans to Michael
acceptors is a valuable method to prepare -substituted buteno-
We synthesized racemic 1 using a procedure developed by
Yadav and co-workers for the addition of 2-trimethylsiloxyfuran
to enones [6]. Stirring 2-trimethylsiloxyfuran with crotonalde-
c
lides – a structural motif commonly observed in natural products
and synthetic drug substances [1]. Studies by Brown and co-work-
ers [2] demonstrated that chiral imidazolidinones could catalyze
asymmetric conjugate addition of siloxyfurans to enal acceptors.
Following that report, additional organocatalysts were shown
effective for the transformation [3]. As part of studies aimed at syn-
thesizing the pro-apoptotic natural product portimine [4], we
required scalable access to the (3S, 5R) enantiomer of butenolide
2
hyde in the presence of catalytic I gave (±)-1 with exquisite
stereocontrol (76%, dr > 20:1). When that material was reduced
under Luche conditions and the incipient alcohol treated with
NaH (THF, rt), one isomer of bicyclic tetrahydropyran 3 was iso-
lated, albeit in low yield. J-couplings and NOE data (see ESI for
details) obtained for 3 supported the stereochemistry drawn in
Scheme 1, thereby implying precursor (±)-1 was ‘anti’ (as
drawn). Further support for this assignment came from hydro-
genating (±)-1, oxidizing the product under Pinnick conditions
and coupling the resultant acid with 2-oxazolidone to afford
imide (±)-4. NMR spectral data for (±)-4 were identical to those
reported by Katsuki [5a].
1
2
, a ‘syn’ diastereomer resultant from adding 2(5H)-furanone (or
-trimethylsiloxyfuran) to trans-crotonaldehyde (Fig. 1A).
Of the known syntheses of 1 [3a-c], only Brown and co-workers
reported [2] isolating the molecule in high diastereomeric and
enantiomeric excess. In our hands, however, imidazolidinone cat-
alyzed addition of 2-trimethylsiloxyfuran to trans-crotonaldehyde
gave two isomeric butenolides in a ratio of ~2:1. Moreover, data
originally reported for those products were inconsistent with that
expected when using trans-crotonaldehyde. Instead, it appeared to
reflect products derived from using 4-methyl-2-pentenal in the
Having identified the anti diastereoisomer of 1, we confirmed
the identity of the syn diastereomer through regioselective
Wacker–Tsuji oxidation [7] of (3S, 5S)-c-butyrolactone 5 [8] to
1
afford aldehyde 6. The H NMR spectrum of 6 was identical to that
obtained by hydrogenating the minor isomer of 1 obtained from
the Brown catalysis (Table 1, entry 1). Thus, the 2:1 mixture of
isomers generated using the Brown procedure favors the
anti-diastereomer, not the syn as reported. Our assignments
are in agreement with those made by Yanai and co-workers [3a]
and contrary to those made by Luo and co-workers. The major
diastereomer isolated by Luo is syn, not anti as reported [3b].
Confident in our relative stereochemical assignments, we next
sought to optimize the catalytic asymmetric synthesis of (3S,
5R)-1. We screened diastereoselectivity in the addition of 2-
trimethylsiloxyfuran to trans-crotonaldehyde using several
1
reaction [9]. Adding to this puzzle was the fact that H NMR data
for isomers 1 prepared by others were conflicting (Fig. 1B) [3a-c].
Lastly, related reactions of 2(5H)-furanone derivatives with (E)-b-
methyl Michael acceptors gave mainly anti diastereomers [3a,5]
or were non-selective [3b,3c]. For our own studies to progress,
we needed to clarify these findings and develop an efficient,
selective and scalable synthesis of (3S, 5R)-1.
⇑
Corresponding author.
E-mail address: harran@chem.ucla.edu (P.G. Harran).
https://doi.org/10.1016/j.tetlet.2021.153056
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0

L. Li, A. El Khoury, B.O. Clement et al.
Tetrahedron Letters 72 (2021) 153056
Table 1
Optimization studies.
a
Entry
1c
Catalyst
Acid
Solvent
drb (syn:anti)
7
7
7
7
8a
8a
8a
8b
8c
9
DCA
DNBA
TfOH
TFA
DNBA
DNBA
TFA
TFA
TFA
TFA
TFA
CHCl
CHCl
CHCl
THF
3
3
3
1.0:2.1
1.0:3.3
1.0:5.2
2.5:1.0
2.5:1.0
3.0:1.0
4.0:1.0
4.0:1.0
4.3:1.0
5.0:1.0
5.5:1.0
8.5:1.0
d
2
3
e
4
f
5
2 2
CH Cl
f
6
THF
THF
THF
THF
THF
THF
f,g
7
f
8
f
9
g,h
1
1
1
0
1
2
g,i
9
9
g,j
TFA
THF
Fig. 1. A) Butenolide 1 maps cleanly onto a segment of portimine. B) Data for
isomers 1 synthesized by organocatalytic methods were missing and, in part,
conflicting; aas originally assigned; not reported.
a
Reagents and conditions: 2 (1.0 eq.), crotonaldehyde (3.0 eq.), cat. (20 mol%),
b
acid (20 mol%), H
2
O (2.0 eq.), solvent (0.1 M), À10 °C.
b
dr measured by 1H NMR.
c
2
DCA: dichloroacetic acid, reaction was performed with 5.0 eq. of H O in 0.5 M of
CHCl
3
at À78 °C.
d
DNBA: 2,4-dinitrobenzoic acid.
Parallel reactions were carried out at À10 °C and 50 °C. Both resulted in similar
selectivity.
e
f
(
3R, 5S)-1 was the major product.
g
h
i
2
crotonaldehyde (5.0 eq.), H O (3.0 eq.).
The reaction was left at À20 °C overnight after 1 h at À10 °C.
1
0 mol% of 9 and 13 mol% of TFA was used.
j
TFA (26 mol%), 2 was added over 7 h at À15 °C, er > 20:1, measured on a chiral
amine derivative by 1H NMR.
organocatalysts under varied conditions (see Table 1). Imidazolidi-
none catalyst 7 [2] in the presence of co-catalytic protic acids uni-
formly gave poor diastereoselectivities, although the major isomer
did switch from anti to syn when TFA in THF was used (Entry 4).
A set of hydroxyproline-derived catalysts 8a-c were then syn-
thesized and their performance were examined. Under the condi-
tions shown in Table 1, each formed syn-1 as the major
diastereomer, although selectivities were modest (Entries 5–9).
Improvements came when simpler diphenylprolinol catalyst 9
was employed. At À20 °C in THF, 20 mol% 9 and TFA catalyzed for-
mation of syn and anti 1 in a 5:1 ratio (Entry 10). Selectivity was
not diminished when the catalyst loading was reduced to 10 mol
%
(Entry 11). When siloxyfuran 2 was added slowly (7 h) to a stir-
red THF solution of crotonaldehyde containing catalyst 9 and TFA
at À15 °C, diastereoselectivity increased to 8.5:1 (Entry 12) [9].
This last procedure could be scaled to support our total synthe-
sis studies (Scheme 2). On 0.15 mol scale (0.1 M in THF), the reac-
tion was stirred at À15 °C for 1 h after the addition of 2 was
complete. The reaction was filtered through a pad of silica gel
and concentrated. The crude material was dissolved in MeOH
Scheme 1. Syntheses of syn and anti 1 by non-organocatalyzed means.a Reagents
and conditions: (a) trans-crotonaldehyde (0.7 eq.), I
À78 °C, 76%, dr > 20:1; (b) CeCl Á7H O (2.0 eq.), NaBH
°C, 60%; (c) NaH (2.0 eq.), THF (0.05 M), rt, 25%; (d) Pd(OH)
balloon), MeOH (0.3 M), rt; (e) NaClO (5.0 eq.), NaH PO (6.0 eq.), tBuOH:
O (1.5:1:1, 0.05 M), rt; (f) EDCIÁHCl (1.4 eq.), oxazolidinone (1.3 eq.),
Cl (0.1 M), rt; 20% from (±)-anti-1; (g) Pd(PhCN) Cl (7.5 mol
), tBuONO (20 mol%), O (balloon), tBuOH (0.05 M), rt, 51% brsm.
2
(7 mol%), Et
(2.0 eq.), MeOH (0.05 M),
/C (3 mol%), H
2
O (0.07 M),
and hydrogenated over Pd(OH)
2
/C to give
c-butyrolactone 6
3
2
4
(
12.9 g, 54%, dr = 8.5:1) following chromatography. Isolated 6
0
2
2
2
3
(
2
2
4
D 3
showed [a] = +30.8 (c = 0.1, CHCl ) and material synthesized pre-
viously from alkene 5 (Scheme 1) gave [
2
4
amylene:H
2
D
a] = +26.7 (c = 0.1,
DMAP (1.15 eq.), CH
2
2
2
2
CHCl ), confirming absolute stereochemistry as (3S, 5S). An enan-
3
%
2
2

L. Li, A. El Khoury, B.O. Clement et al.
Tetrahedron Letters 72 (2021) 153056
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Declaration of Competing Interest
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1
Funding provided by the D. J. & J. M. Cram Endowment, the
George Gregory Fellowship (fellowship to LL) and NSF equipment
grant CHE1048804.
trimethylsiloxyfuran and 4-methyl-2-pentenal gave
a
diastereomeric butenolides. The 1H NMR spectrum of the major isomeric
product (syn-10) corresponded to the major isomer reported by Luo (ref. 3b),
whereas the 1H NMR spectrum of the minor isomeric product (anti-10) matched
the data reported for syn-1 in ref 2
Appendix A. Supplementary data
Experimental procedures and spectral data can be found in ESI.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153056.
.
3