A one-pot C-H insertion/olefination sequence for the formation of α-alkylidene-γ-butyrolactones

Article abstract of DOI:10.1021/ol501092m

A one-pot C-H insertion/olefination sequence for the conversion of α-diazo-α-(dialkoxyphosphoryl)acetates into α-alkylidene- γ-butyrolactones is reported. The key C-H insertion process is achieved using a catalytic amount of a dirhodium carboxylate cataly

Full text of DOI:10.1021/ol501092m

Letter
pubs.acs.org/OrgLett
A One-Pot C−H Insertion/Olefination Sequence for the Formation of
α‑Alkylidene-γ-butyrolactones
Matthew G. Lloyd, Richard J. K. Taylor,* and William P. Unsworth*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, U.K.
S
* Supporting Information
ABSTRACT: A one-pot C−H insertion/olefination sequence for the conversion of α-diazo-α-(dialkoxyphosphoryl)acetates into
α-alkylidene-γ-butyrolactones is reported. The key C−H insertion process is achieved using a catalytic amount of a dirhodium
carboxylate catalyst, using operationally simple conditions. The size and electronic properties of the attached substituents were
found to influence the regio- and diastereoselectivity of the process. The utility of the process is demonstrated by the synthesis of
a known Staphylococcus aureus (MRSA) virulence inhibitor.
good overall yields, from phosphonates (6) derived from γ-
hydroxy unsaturated carbonyl compounds.5 This reaction is
initiated by deprotonation and intramolecular Michael addition,
to generate an intermediate anion (7). An aldehyde may then
be added directly to the reaction mixture, resulting in Horner−
Wadsworth−Emmons-type (HWE) olefination (Scheme 1),
furnishing product 8. We subsequently showed3c,d that acylated
phosphoranes, prepared in situ by the reaction of functionalized
alcohols (9) with Bestmann’s ylide,6 react similarly, thus
incorporating an additional synthetic step into the telescoped
sequence (Scheme 1).
α-Alkylidene-γ-butyrolactones are found in a vast number of
important bioactive natural products; remarkably, approx-
imately 3% of all known natural products contain this structural
motif (e.g., 1−5, Figure 1).1
Both procedures are relatively simple to perform exper-
imentally and give good yields of the desired products.
However, a notable drawback of both methods is that three
functional groups (an alcohol, an alkene, and a carbonyl group)
are necessary for the desired reactions to take place, which
reduces the generality of the methodology in cases where the
starting material synthesis is not trivial. The strategy reported
herein is based on an efficient rhodium-catalyzed C−H
activation process,7 which is used in place of the Michael
addition in the TIMO sequence. Using this method, the
starting material synthesis is simplified dramatically, so that
simple, unfunctionalized alcohol derivatives (10) may be used
as precursors to α-alkylidene-γ-butyrolactones. In addition,
Michael acceptors are no longer required, thus increasing the
generality of the process.
Figure 1. α-Alkylidene-γ-butyrolactone natural products.
A number of methods for the synthesis of α-alkylidene-γ-
butyrolactones have been reported,1,2 most commonly
involving initial lactone formation followed by methylenation,
e.g. via aldol-type processes. However, many of the reported
procedures are either impractical or low yielding due to
problems handling the relatively sensitive products and/or the
length of the synthetic routes. Previous work in our own
laboratory3 aimed to redress this via the application of
telescoped reaction processes.4 We first reported a telescoped
intramolecular Michael/olefination (TIMO)3 sequence which
enabled the construction of α-alkylidene-γ-butyrolactones, in
To the best of our knowledge, only three examples
(contained in a single report)8 of the rhodium-catalyzed C−
H insertion of α-diazo-α-(dialkoxyphosphoryl)acetates9 are
known and these reactions were reported to furnish mixtures
Received: April 15, 2014
Published: May 2, 2014
© 2014 American Chemical Society
2772
dx.doi.org/10.1021/ol501092m | Org. Lett. 2014, 16, 2772−2775

Organic Letters
Letter
Scheme 1. One-Pot C−H Insertion/Olefination Compared
with Previous Michael Addition Methodology
Table 1. Optimization of Rhodium-Catalyzed C−H Insertion
of Diazophosphonates 10a and 10b
Rh(II)
catalyst
catalyst loading
[mol %]
DCM
(mL/mmol)
yield
(%)
entry sub.
a
1
10a
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
Rh2(esp)2
Rh2(esp)2
Rh2(OAc)4
Rh2(oct)4
Rh2(tpa)4
Rh2(oct)4
Rh2(oct)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
5
5
20
20
20
20
20
20
200
20
20
20
20
20
64
a
2
57
a
3
5
74
a
4
5
66
a
5
5
59
a
6
2
70
ac
,
7
2
30
77
71
87
80
89
b
b
b
b
b
8
5
9
2
10
11
12
10
5
2
a
Heated at 45 °C in a round-bottom flask fitted with reflux condenser
b
and argon balloon for 20 h. Heated at 45 °C in an oven-dried sealable
tube flushed with argon for 20 h. A 51% yield of the product of water
c
insertion [4-methoxyphenethyl 2-(diethoxyphosphoryl)-2-hydroxy-
acetate (15)] was also isolated in this instance.
oven-dried sealable tube at 45 °C for 20 h with 2 mol % of
Rh2(oct)4 in DCM at a concentration of 20 mL/mmol afforded
lactone 11b in the highest isolated yield (89%, entry 12).
With optimized C−H insertion conditions in hand, attention
switched to performing the HWE olefination. As the only
byproduct of the cyclization is nitrogen gas, it was expected that
this step could be performed in the same reaction vessel
without workup or purification. This was achieved by cooling
the crude reaction mixture and directly adding KOBu-t (1.2−
1.5 equiv), followed by paraformaldehyde (2 equiv). In some
cases a solvent switch (DCM to THF) was made prior to the
HWE reaction. Scoping studies were performed on a range of
α-diazo-α-(dialkoxyphosphoryl)acetates 10a−10l (which were
synthesized as described in Scheme 2) to generate α-
methylene-γ-butyrolactones 12a−12l (Table 2).
The two-step, one-pot telescoped sequence works well using
benzylic substrates 10a−10c; cyclization using the optimized
C−H insertion conditions followed by treatment with KOBu-t
(1.2 equiv), then paraformaldehyde (2 equiv), resulted in the
formation of α-methylene-γ-butyrolactones 12a−12c in good
overall yield (Table 2, entries 1−4). The use of more than 1
equiv of base is noteworthy, as related HWE reactions are
known to proceed better with substoichiometric amounts of
base.3,15 Compound 10d reacted smoothly (entries 5−6),
demonstrating that insertion into sterically hindered tertiary
C−H bonds is viable. There is also scope for the construction
of lactones with a high level diastereocontrol; the reaction of
dibenzyl substrate 10e resulted in the formation of lactone 12e
as a single trans-diastereoisomer in excellent overall yield (entry
7). Furthermore, remarkable levels of regiocontrol have been
demonstrated; the C−H insertion reaction of unsymmetrical
dibenzyl substrate 10f took place exclusively α- to the 4-MeO−
C6H4 group,16 clearly highlighting the strong proclivity of such
rhodium(II) carbenoids to insert into electron-rich C−H bonds
of β- and γ-lactones in moderate/low yield. Related α-diazo-α-
(dialkoxyphosphoryl)acetamides are also known to react
similarly, but in this case there is a stronger bias toward
formation of the β-lactam C−H insertion product.8,10 Note that
the HWE reactions of the C−H insertion products were not
examined in any of these reports. A desire to avoid β-lactone
formation directed our decision to use substrates 10a and 10b
to test the key C−H insertion reaction; rhodium(II) carbenoids
are highly electrophilic and typically insert preferentially into
electron-rich C−H bonds,7 and thus it was expected that the
use of benzylic substrates would expedite the desired γ-lactone
formation. The requisite substrates were made in two steps
from alcohols 13a and 13b via coupling with diethyl
phosphonoacetic acid (DEPAA) using propyl phosphonic
anhydride (T3P)11 and N,N-diisopropylethylamine (DIPEA),
followed by a Regitz diazo-transfer reaction (Scheme 2).12
Scheme 2. Formation of Diazophosphonates 10a and 10b
Pleasingly, both substrates reacted with 5 mol % of Rh2(esp)2
in DCM at 45 °C to generate γ-lactones 11a and 11b as single
regio- and diastereoisomers (Table 1, entries 1−2). The
structural assignment of compound 11a is supported by X-ray
crystallography (see Supporting Information).13,14 Additional
optimization experiments (entries 3−12) examined the catalyst
choice and its loading, the reaction concentration, and the
reaction vessel, revealing that heating the substrate 10b in an
2773
dx.doi.org/10.1021/ol501092m | Org. Lett. 2014, 16, 2772−2775

Organic Letters
Letter
underwent cyclization and olefination in in excellent overall
yield but resulted in the formation of a 1.45:1 mixture of the
desired product 12g and its regioisomer 16, in which C−H
insertion has taken place on one of the methyl groups (entry
9). The partial formation of lactone 16 was somewhat
surprising given the stereoelectronic bias for insertion into
electron-rich C−H bonds, but this is likely to be a result of
reduced steric hindrance in the C−H insertion step. Until this
point, the formation of lactones 12a−g all involved electroni-
cally favorable C−H insertion into benzylic C−H bonds (vide
supra). Pleasingly, this assistance to the cyclization is by no
means essential; substrates 10h−10j, which are derived from
simple aliphatic alcohols, were all compatible with the two-step
sequence, affording lactones 12h−12j in comparable yields to
those of the preceding benzylic substrates (entries 10−12).
Crucially, there was no evidence for the formation of β- or δ-
lactone products in any of these reactions. Finally, the reaction
of cyclopentyl substrate 10k generated spirocyclic lactone 12k
in very good overall yield (entry 13).
Table 2. One-Pot C−H Insertion/Olefination Sequence for
the Formation of α-Methylene-γ-butyrolactones
α-Alkylidene-γ-butyrolactones may also be accessed using the
same procedure (Table 3). A range of aromatic aldehydes can
Table 3. One-Pot C−H Insertion/Olefination Sequence for
the Formation of α-Alkylidene-γ-butyrolactones
entry
R
product
E:Z
yield (%)
a
1
2
3
4
5
6
7
Ph
12l
1:1
65
ab
,
4-NO2-C6H4
2-F-C6H4
12m
12n
12o
12p
12q
12r
1:1.3
1:1.5
1:1
69
91
61
56
39
67
a
a
4-Ph-C6H4
3,4-OCH2O-C6H3
CH3
ac
,
1:1.2
a
a
1.2:1
1:3.7
n-butyl
a
(i) 2 mol % Rh2(oct)4, DCM, 45 °C, 20 h; (ii) THF; (iii) 1.2 equiv of
b
KOBu-t, 0 to −78 °C; (iv) 2 equiv of RCHO, −78 °C to rt. HWE at
0 °C. HWE at reflux.
c
be used instead of paraformaldehyde in the telescoped two-
step, one-pot procedure. The olefination proceeds smoothly at
rt when electron-neutral and -deficient benzaldehyde deriva-
tives are used (entries 1−4), but the reaction required heating
at reflux when electron-rich piperonal was used (entry 5). In all
cases the desired lactones 12l−12p were obtained in good to
excellent overall yield. Aliphatic aldehydes are also compatible,
as evidenced by the formation of lactones 12q−12r (entries 6−
7).
This method would appear to have great potential in target
synthesis, and as a simple demonstration, the synthesis of
lactone 17 was completed (Scheme 3). This was the most
potent compound found in a recent study of Staphylococcus
aureus (MRSA) virulence inhibitors.17 Along with other related
α-alkylidene-γ-butyrolactones, it works by binding covalently to
the cysteine residues of several binding proteins involved in α-
hemolysin expression and, thus, represents a highly promising
treatment of antibiotic-resistant S. aureus strains. The synthesis
commenced by the conversion of commercially available acid
18 into ketone 19 via its Weinreb amide. Subsequent reduction
and conversion into the α-diazo-α-(dialkoxyphosphoryl)acetate
a
(i) 2 mol % Rh2(oct)4, DCM, 45 °C, 20 h; (ii) 1.2 equiv of KOBu-t, 0
b
to −78 °C; (iii) 2 equiv of (CH2O)n, −78 to 0 °C. Solvent switched
from DCM to THF before the HWE. HWE was done with 1.5 equiv
of KOBu-t and was warmed to rt.
c
(entry 8). This furnished lactone 12f in good overall yield,
albeit without the high level of diastereocontrol observed
during the formation of its analogue 12e. Substrate 10g
2774
dx.doi.org/10.1021/ol501092m | Org. Lett. 2014, 16, 2772−2775

Organic Letters
Letter
5338. (d) Kitson, R. R. A.; McAllister, G. D.; Taylor, R. J. K.
Tetrahedron Lett. 2011, 52, 561.
Scheme 3. Synthesis of S. aureus Virulence Inhibitor 17
(4) For more recent examples of tandem/telescoped reaction
sequences, see: (a) Lubkoll, J.; Millemaggi, A.; Perry, A.; Taylor, R.
J. K. Tetrahedron 2010, 66, 6606. (b) Burns, A. R.; McAllister, G. D.;
Shanahan, S. E.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2010, 49, 5574.
(c) Unsworth, W. P.; Kitsiou, C.; Taylor, R. J. K. Org. Lett. 2013, 15,
258. (d) Osler, J. D.; Unsworth, W. P.; Taylor, R. J. K. Org. Biomol.
Chem. 2013, 11, 7587. (e) Unsworth, W. P.; Coulthard, G.; Kitsiou,
C.; Taylor, R. J. K. J. Org. Chem. 2014, 79, 1368.
(5) Burns, A. R.; Taylor, R. J. K. Synthesis 2011, 681.
(6) (a) Bestmann, H. J.; Sandmeier, D. Angew. Chem., Int. Ed. Engl.
1975, 14, 634. (b) Bestmann, H. J.; Sandmeier, D. Chem. Ber. 1980,
113, 274.
(7) (a) Evans, P. A. Modern Rhodium-Catalyzed Organic Reactions;
Wiley: New York, 2005. (b) Davies, H. M. L.; Beckwith, R. E. J. Chem.
Rev. 2003, 103, 2861. (c) Doyle, M. P. Chem. Rev. 1986, 86, 919.
(d) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911.
(8) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 19,
3798.
(9) For related cyclopropanation reactions, see: Callant, P.;
D’Haenens, L.; Vandewalle, M. Synth. Commun. 1984, 14 (2), 155.
(10) (a) Afonso, C. A. M.; Gomes, L. F. R.; Trindade, A. F.;
Candeias, N. R.; Gois, P. M. P.; Veiros, L. F. Synthesis 2009, 3519.
(b) Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M. Chem. Commun.
2005, 391. (c) Afonso, C. A. M.; Candeias, N. R.; Gois, P. M. P.;
Veiros, L. F.; Gois, P. M. P. J. Org. Chem. 2008, 73, 5926.
(11) Wissmann, H.; Kleiner, H. J. Angew. Chem., Int. Ed. 1980, 19,
133.
in the usual way furnished precursor 20. The synthesis was then
completed using the standard one-pot C−H insertion/HWE
protocol; the desired product 17 was isolated in 49% yield,
along with 19% of the regioisomeric lactone 21. The high level
of diastereoselectivity (all trans) is noteworthy, as the
corresponding cis-isomer was found to be a significantly less
potent inhibitor.17
Rhodium(II) carbenoids have therefore been used to convert
alcohol derivatives into a range of α-alkylidene-γ-butyro-
lactones, via a one-pot C−H insertion/olefination sequence
in good overall yields.18 The convenient starting material
synthesis and the mild, straightforward experimental conditions
should prove valuable in both academic and industrial research
settings.
(12) Regitz, M. Angew. Chem., Int. Ed. 1967, 6, 733.
(13) CCDC 980606 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
(14) The NMR data of compound 11a match those reported with
the exception of the H-3 resonance: 4.00−4.26 (5 H, m, H-3, 2 ×
CH2) [lit. 3.65 (dd, 3JHH = 6.5 Hz, 3JPH = 6.0 Hz, 1H, H-3)]. In view of
the fact that the X-ray structure of 11a was solved it seems likely that
there is an error in the previously reported data. Krawczyk, H.; Wasek,
K.; Kedzia, J.; Wojciechowski, J.; Wolf, W. M. Org. Biomol. Chem.
2008, 6, 308.
(15) This has been attributed to the instability of α-methylene-γ-
butyrolactones with respect to the base, but in this study, the use of 0.9
equiv of KOBu-t led to a lower overall yield in all cases.
(16) The assignment of regioisomer 12f is supported by HMBC
correlation data: H-7 to C-3, H-13 to C-11, H-11 to C-12, no
correlation between H-11 and C-6 (see Supporting Information).
(17) Kunzmann, M. H.; Bach, N. C.; Bauer, B.; Sieber, S. A. Chem.
Sci. 2014, 5, 1158.
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures, spectral data, and X-ray data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: richard.taylor@york.ac.uk.
*E-mail: william.unsworth@york.ac.uk.
Notes
The authors declare no competing financial interest.
(18) Efforts to develop an asymmetric variant of this reaction using
chiral rhodium(II) catalysts are ongoing and will be reported in due
course.
ACKNOWLEDGMENTS
■
The authors wish to thank Elsevier (M.G.L) and The
University of York (WPU) for funding, Mariantonietta
D’Acunto (visiting researcher, University of Salerno) for
performing related preliminary studies, and Dr A. C. Whitwood
(University of York) for X-ray crystallography.
REFERENCES
■
(1) For a recent review, see: Kitson, R. R. A.; Millemaggi, A.; Taylor,
R. J. K. Angew. Chem., Int. Ed. 2009, 48, 9426.
(2) (a) Kang, S.-K.; Kim, K.-J.; Hong, Y.-T. Angew. Chem., Int. Ed.
2002, 41, 1584. (b) Muller, S.; Murillo, R.; Castro, V.; Brecht, V.;
̈
Merfort, I. J. Nat. Prod. 2004, 67, 62. (c) Ramachandran, P. V.;
Pratihar, D. Org. Lett. 2007, 9, 2087 and references therein.
(3) (a) Edwards, M. G.; Kenworthy, M. N.; Kitson, R. R. A.; Perry,
A.; Scott, M. S.; Whitwood, A. C.; Taylor, R. J. K. Eur. J. Org. Chem.
2008, 4769. (b) Edwards, M. G.; Kenworthy, M. N.; Kitson, R. R. A.;
Scott, M. S.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2008, 47, 1935.
(c) Kitson, R. R. A.; Taylor, R. J. K.; Wood, J. L. Org. Lett. 2009, 11,
2775
dx.doi.org/10.1021/ol501092m | Org. Lett. 2014, 16, 2772−2775