Direct and practical Gilman-Speeter synthesis of 3,4-trisubstituted β-lactams via the Thorpe-Ingold effect

Article abstract of DOI:10.1016/j.tetlet.2020.152375

A highly efficient Gilman-Speeter synthesis of 3,4-trisubstituted β-lactams possessing a 4-aryl substituent is described, employing a direct, uncatalyzed Mannich reaction between TMS imines and TMS ketene acetals. The process avoids cryogenic conditions, making it more amenable to process-scale use than related methods for β-lactam synthesis. A Gilman-Speeter diastereoselective version using a sulfinyl imine and leading to homochiral sulfinyl β-aminoester is also presented.

Full text of DOI:10.1016/j.tetlet.2020.152375

Tetrahedron Letters 61 (2020) 152375
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct and practical Gilman-Speeter synthesis of 3,4-trisubstituted
b-lactams via the Thorpe-Ingold effect
⇑
Maria Panagiotou, Vasileios Demos, Plato Α. Magriotis
Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, University of Patras, Rio 26504, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient Gilman-Speeter synthesis of 3,4-trisubstituted b-lactams possessing a 4-aryl sub-
stituent is described, employing a direct, uncatalyzed Mannich reaction between TMS imines and TMS
ketene acetals. The process avoids cryogenic conditions, making it more amenable to process-scale use
than related methods for b-lactam synthesis. A Gilman-Speeter diastereoselective version using a sulfinyl
imine and leading to homochiral sulfinyl b-aminoester is also presented.
Received 15 April 2020
Revised 7 August 2020
Accepted 16 August 2020
Available online 27 August 2020
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
b-Lactam
Gilman-Speeter
Mannich
b-Aminoester
N-Sulfinyl
Thorpe-Ingold effect
Introduction
lithium enolates [8], we reasoned that trimethylsil;yl ketene acet-
als might be productive partners in this Gilman-Speeter process
The azetidin-2-one (b-lactam) ring provides unique opportuni-
ties for the design and synthesis of new derivatives with unprece-
dented biological profiles. During the last two decades medicinal
chemists convincingly demonstrated that structural modifications
of monocyclic b-lactams (monobactams) is an effective procedure
for the discovery of new and important pharmacological properties
different from antibacterial activity [1]. In fact, new b-lactam com-
pounds have been shown to inhibit a wide range of enzymes [2].
The recent discovery that b-lactams can potentially serve as the
basis for treatments for neurological disorders including amy-
otrophic lateral sclerosis (ALS)-also known as Lou Gehrig’s disease
[3], increases the need for scalable synthetic methods for this hete-
rocycle [4]. The use of b-lactams as useful reactive intermediates
leading to biologically active compounds also inspired this work
[5]. In connection with our preliminary studies aimed at a novel
total synthesis of Ecteinascidin-743 via substituted 1-azetines
[6], we became interested in more efficient routes to related b-lac-
tams [7].
[9]. It was also thaught that the in situ production of one equivalent
of trimethylsilyloxy lithium upon formation of the TMS-imine,
would obviate the need for catalysis [10].
In practice, when a solution of benzaldehyde in THF was treated
with a solution of lithium hexamethyldisilazide in THF at 0 °C, fol-
lowed by stirring at ambient temperature for 0.5 h, addition of
TMS-ketene acetal 1 and heating at THF reflux for 1.5 h, b-lactam
2 was produced as a white solid in 92% yield after extractive isola-
tion and recrystallization (Scheme 1, Ar = Ph, 2a, Table 1, entry 1).
Although the acid-catalyzed silyl ketene acetal additions to
imine-type compounds have been studied in detail [11], none of
these methods provides a b-lactam directly thus requiring an extra
cyclization step [10]. On the other hand, the direct addition of eno-
lates to N-trimethysilyl imines requires costly cryogenic cooling
[8], as opposed to the approach presented herein that avoids cryo-
genic conditions, making it more amenable to process-scale use
than related methods for b-lactam formation. It has been found
that the reaction proceeds also at ambient temperature, but it
takes at least 36 h to complete [12], rendering these reaction con-
ditions unacceptable. In fact, in one experiment in which the TMS-
imine of 4-fluorobenzaldehyde was treated with 1 at ambient
temperature for 40 h, the corresponding b-aminoester was isolated
in good yield suggesting that cyclization to b-lactam is much faster
at refluxing THF leading to an excellent yield of b-lactam 2c
(Table 1, entry 3).
Results
Mindful of the pioneering work of Hart on the application of N-
trimethylsilyl imines to the synthesis of b-lactams employing
⇑
Corresponding author.
E-mail address: pmagriotis@upatras.gr (Plato Α. Magriotis).
https://doi.org/10.1016/j.tetlet.2020.152375
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
M. Panagiotou et al. / Tetrahedron Letters 61 (2020) 152375
on developing a potential, direct and diastereoselective synthesis
of sulfinyl b-lactams using homochiral sulfinimines [13], based
on the following premise described in Scheme 2.
Actually, when sulfinimine 3 was treated with TMS-ketene
acetal 1 in DMF at 70 °C for 24 h, the corresponding b-amino ester
5 was isolated in 18% yield and 66% de as shown in Scheme 3.
This modest uncatalyzed process is interesting given that both
Lewis acid-mediated and Lewis base-catalyzed corresponding
Mannich reactions have been described [14].
Scheme 1. Synthesis of b-lactam 2 from arylaldehyde and TMS-ketene acetal 1.
Assignment of the stereochemistry for the major diastereomer
was made as previously established by Kawecki.14a In fact, the
major diastereomer is the same as the major product from both
the Lewis acid-mediated and Lewis base-catalyzed reactions [15].
To further explore the scope of this b-lactam synthesis, trisub-
stituted TMS ketene acetals 1a–c were prepared in order to deter-
mine its stereoselectivity (cis/trans ratios) [10a,16]. Unfortunately,
however, none of these provided the desired b-lactam product 6
upon reaction with benzaldehyde TMS imine in THF (Scheme 4).
At this point, the Thorpe-Ingold or gem-dimethyl effect came to
mind as a likely explanation of these disparate results [17]. The lat-
ter effect (gem-Disubstitution effect) refers to the greater facility of
synthesis of small or even larger rings that have gem-substitution
over the less substituted cases [18]. To prove this possibility, tetra-
substituted ketene acetal 1d was synthesized and reacted with
benzaldehde TMS imine [19]. To our satisfaction, b-lactam 7 was
obtained in 80% yield, suggesting the full operation of the
Thorpe-Ingold effect, as suspected, in this Gilman-Speeter b-lactam
synthesis (Scheme 5).
Scheme 2. Projected diastereoselective synthesis of sulfinyl b-lactams employing
homochiral sulfinimines.
Scheme 3. Diastereoselective synthesis of b-aminoester 5.
The diastereoselectivity of formation of 1d was very high as
reported [19], and the major E isomer led to b-lactam 7 possessing
cis phenyl and methyl groups as determined by its NOESY 2D-NMR
spectrum [20].
Conclusion
In conclusion, we have developed a highly efficient and practi-
Scheme 4. Failed b-lactam synthesis with trisubstituted ketene acetals 1a–c.
cal synthesis of unprotected 3,4-Trisubstituted b-lactams amen-
able
to
process-scale
employment.
Furthermore,
a
diastereoselective Gilman-Speeter reaction of ketene acetal 1 with
sulfinimine 3 has been discovered giving rise to useful sulfinyl b-
aminoesters. Work is in progress toward the establishment of a
catalytic diastereoselective synthesis of sulfinyl b-lactams of type
4 which have been reported to potentially possess very interesting
and intriguing biological activities [21].
Scheme 5. Gilman-Speeter b-lactam synthesis with tetrasubstituted ketene acetal
1d.
Declaration of Competing Interest
Prior to our success employing N-TMS imines and establishing
an efficient and convenient as well as economical method not
requiring cryogenic cooling, we had been focusing our attention
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Table 1
Data for the one-pot synthesis of b-lactams, see Scheme 1.
Entry (2)
Ar
M.P (oC).
Lit. M.P.(oC)1
Yield (%)
1 (a)
2 (b)
3 (c)
4 (d)
Phenyl
104–105
103–104
102–103
96–97
104–105
102–103
92
90
88
83
4-Methoxyphenyl
4-Fluorophenyl
4-Ethoxy-3-methoxyphenyl
2-Furyl
5 (e)
6 (f)
7 (g)
2-Bromophenyl
2-Thienyl
100–101
127–128
114–115
99–101
75
85
80
113–115
1. a J. Org. Chem. 1983, 48, 289–294, b Chem. Pharm. Bull. 1993, 41, 1933–1938, e Tetrahedron 1988, 44, 4157–4172, g J. Chem. Soc. Perkin Transl. 1988, 945–948.

M. Panagiotou et al. / Tetrahedron Letters 61 (2020) 152375
3
[11] (a) C. Gennari, I. Venturini, G. Gilson, G. Schimperna, Tetrahedron Lett. 28
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Acknowledgment
(b) G. Guanti, E. Narisano, L. Banfi, Tetrahedron Lett. 28 (1987) 4331 and 4335.
[12] For the ambient temperature reaction of TMS imines with tris
(trimethylsilyloxy)ethane resulting mainly in cis-b-lactams, see: P. Vu, R.A.
Holton, PCT Int. Appl. WO (2006) 6135656A2, 2006; Chem. Abstr. 146 (2007)
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Many thanks are due to the Stavros Niarchos Foundation (SNF)
for their generous donation of a chiral HPLC equipment.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152375.
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