A rapid synthesis of 4-oxazolidinones: Total synthesis of synoxazolidinones A and B

Article abstract of DOI:10.1002/anie.201402310

A five-step total synthesis of the marine natural product synoxazolidinone A was achieved through a diastereoselective imine acylation/cyclization cascade. Synoxazolidinone B and a series of analogues were also prepared to explore the potential of these 4-oxazolidinone natural products as antimicrobial agents. These studies confirmed the importance of the chlorine substituent for antimicrobial activity and revealed simplified dichloro derivatives that are equally potent against several bacterial strains. Synthetic synoxazolidinones: A five-step total synthesis of the marine natural product synoxazolidinone A was achieved through a diastereoselective imine acylation/cyclization cascade. Synoxazolidinone B and a series of analogues were also prepared to explore the potential of these 4-oxazolidinones as antimicrobial agents. The results revealed simplified dichloro derivatives that are equally potent against several bacterial strains.

Full text of DOI:10.1002/anie.201402310

Angewandte
Chemie
DOI: 10.1002/anie.201402310
Natural Product Synthesis
A Rapid Synthesis of 4-Oxazolidinones: Total Synthesis of
Synoxazolidinones A and B**
Nataliia V. Shymanska, Il Hwan An, and Joshua G. Pierce*
Abstract: A five-step total synthesis of the marine natural
product synoxazolidinone A was achieved through a diastereo-
selective imine acylation/cyclization cascade. Synoxazolid-
inone B and a series of analogues were also prepared to
explore the potential of these 4-oxazolidinone natural products
as antimicrobial agents. These studies confirmed the impor-
tance of the chlorine substituent for antimicrobial activity and
revealed simplified dichloro derivatives that are equally potent
against several bacterial strains.
substitution pattern.[6] Interestingly, although rare in natural
products, oxazolidinones (particularly 2-oxazolidinones) have
a rich history in medicinal chemistry as highlighted by
successful synthetic drugs such as linezolid.[7] A synthetic
approach to these bioactive scaffolds would thus not only
serve the synthesis of this class of natural products but also
enable the synthesis of heterocyclic libraries.
Inspired by the proposed biosynthetic route,[5] we envi-
sioned an imine acylation/cyclization cascade that would
construct the core 4-oxazolidinone ring while stereoselec-
tively controlling the alkene geometry and the aminal center
in the process (Scheme 1b).[8,9] The acylation of imines to
generate iminium ions and subsequent trapping with
T
he continued emergence of multidrug-resistant bacteria
highlights the pressing need for the development of novel
antimicrobial agents.[1] Compounds that display antimicrobial
activity and bear novel structural features are compelling
targets for synthesis and serve as a platform for antibiotic
development.[2–4] Synoxazolidinones A (1) and B (2) are
recently discovered natural products isolated from the sub-
arctic ascidian Synoicum pulmonaria, collected off the
Norwegian coast (Figure 1).[5] The synoxazolidinones contain
an unusual 4-oxazoldinone heterocycle bearing an exocyclic
conjugated aromatic moiety. To our knowledge, an oxazolid-
inone is present in only one other class of natural products
(the lipoxazolidinones; 3, Figure 1), albeit with an alternate
Scheme 1. Potential addition pathways for acyliminium intermediate 4.
appended nucleophiles has provided rapid access to a variety
of heterocyclic scaffolds.[10] Furthermore, intermolecular
addition of phenylpyruvic acids to imines has been reported
to prepare the biologically active but undesired 3-hydroxy-
1,5-dihydro-2H-pyrrol-2-ones (5, Scheme 1a) through an
addition/cyclization/dehydration sequence.[11] Unlike these
previously developed methods, the proposed reaction
requires the formation of an activated enolizable a-keto
carboxylic acid, subsequent reaction with an enolizable a-
chloroimine[12] to generate an acyliminium ion, and finally
cyclization through the oxygen atom (as opposed to the
carbon atom) of the enol to generate 4-oxazolidinone 6.
As an initial test of the proposed reaction, phenylpyruvic
acid (7) was treated with various activating agents and imine 8
to explore the feasibility and addition chemoselectivity of this
process (Scheme 2). Coupling agents such as DCC or cyanuric
chloride provided the undesired carbon addition product 9
exclusively in up to 57% yield. We cannot rule out an
intermolecular imine addition process analogous to that
reported;[11] however, that mechanism appears unlikely
under the conditions employed. By contrast, the acid chloride
generated from oxalyl chloride/DMF provided the desired 4-
oxazolidinone 10 as the major product from the reaction
mixture (24–40% yield of isolated product).[13] As well as the
acid chloride, PyBOP/Hunigꢀs base also proved effective for
preparing the 4-oxazolidinone products in 20–30% yield
(Scheme 2). The complete switch in selectivity is striking and
is possibly accounted for by an electrocyclization mechanism
Figure 1. Natural products containing 4-Oxazolidinone.
[*] N. V. Shymanska, I. H. An, Prof. J. G. Pierce
Department of Chemistry, North Carolina State University
2620 Yarbrough Drive, Raleigh NC 27695 (USA)
E-mail: jgpierce@ncsu.edu
Homepage: http://www.ncsu.edu/chemistry/jgp
[**] We thank North Carolina State University for start-up funds and the
NCSU Department of Chemistry for generous support. We also
thank Prof. Christian Melander and Dr. Roberta Melander for helpful
discussions and assistance with initial MIC assays. Mass spec-
trometry data were obtained at the NCSU Mass Spectroscopy
Facility.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402310.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
by treatment with 2,4-dimethoxybenzyl amine (13) and
MgSO4, and the crude imine was directly subjected to the
aforementioned acylation/cyclization cascade with acid chlo-
ride 14 to provide the fully functionalized synoxazolidinone B
scaffold in 30% yield over two steps. Subsequent deprotec-
tion provided compound 2 in 77% yield after preparative
reverse-phase chromatography (20% over four steps) and the
1H and 13C NMR spectroscopy data are in agreement with the
isolation report.[5]
Scheme 2. Imine acylation/enol addition chemoselectivity. DMB=2,4-
dimethoxybenzyl, DCC=N,N’-dicyclohexylcarbodiimide, DMAP=4-
dimethylaminopyridine, THF=tetrahydrofuran, DMF=N,N-dimethyl-
formamide, PyBOP=benzotriazol-1-yloxytripyrrolidinophosphonium
hexafluorophosphate, DIPEA=N,N-diisopropylethylamine.
In parallel to the efforts to construct synoxazolidinone B
(2), we explored the installation of the secondary chlorine
substituent present in synoxazolidinone A (1). To determine
the potential of employing an imine acylation/cyclization
cascade analogous to that employed for the deschloro
product 2, we required access to a-chloro aldehyde 16 (Sche-
me 3B).[12] Although the chlorination of aldehydes is a well-
established reaction, with several elegant catalytic asymmet-
ric approaches,[16] it became apparent that a protected gua-
nidine moiety in close proximity to the reacting aldehyde
significantly complicated this reaction. All attempts at
catalytic chlorination proved unsuccessful, with no reactivity
observed. To overcome these difficulties, we employed
stoichiometric proline to promote efficient chlorination of
aldehyde 12, thereby producing compound 16 in 60%
yield.[17] With this aldehyde in hand, we carried out the
imine formation/acylation/cyclization cascade to provide
compound 17 in 40% yield and d.r. 4:1 favoring the desired
diastereomer.[18] Significant efforts were made to improve this
diastereoselectivity; however, no conditions provided
a higher quantity of the desired product upon isolation. The
presence of the dimethoxybenzyl group was essential to
obtaining diastereoselectivity, with many substrates and
conditions yielding a 1:1 mixture of diastereomers. With the
natural product skeleton complete, removal of both the
dimethoxybenzyl and Boc protecting groups was achieved
with TFA (408C, 48 h) to yield synoxazolidinone A (1) as
a 4:1 mixture of diastereomers in 88% yield (19% over 5
steps). No erosion of the diastereomeric ratio during the
deprotection reactions was detected, even upon prolonged
(rather than a 5-endo enol addition) in which the equilibrium
of keto/enol tautomers, influenced by pH value and other
factors, would dictate reaction selectivity.[14] The mass balance
in both the acid chloride and PyBOP reactions is high, with
the remainder of the material being lost through activated-
acid dimerization. Although the yields for this process are
modest, the readily available starting materials, straightfor-
ward isolation, and one-step protocol allow ample material to
be prepared through this approach. Furthermore, the carbon
addition products, 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones
(9), are commonly found in nature and possess a wide range
of biological activities.[15] The imine acylation/enol addition
provides a mild method to generate these heterocycles and
provides compatibility with alkyl substituents that is not
possible with current methods.[11]
With a route to the core heterocycle in hand, we turned
our attention to the incorporation of the functional groups
required for the synoxazolidinones. Being the simplest
member of the family, synoxazolidinone B (2) was initially
targeted for synthesis (Scheme 3A). The treatment of 4-
aminobutanol (11) with N,N’-bis(tert-butoxycarbonyl)-S-
methylisothiourea provided a Boc-protected guanidine alco-
hol that was oxidized under Swern conditions to yield
aldehyde 12 in 88% yield over the two steps. Conversion of
the aldehyde to the requisite benzylimine was accomplished
Scheme 3. A) Synthesis of synoxazolidinone B (2) and B) diastereoselective synthesis of synoxazolidinone A (1). DMB=2,4-dimethoxybenzyl,
NCS=N-chloro succinimide, DMSO=dimethylsulfoxide, TFA=trifluoroacetic acid, Boc=tert-butoxycarbonyl.
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Table 1: Antimicrobial activity of the natural products and their ana-
logues.
heating. The diastereomers of the fully deprotected natural
product proved difficult to separate without the use of HPLC,
but fortunately, the partially deprotected product 18 (TFA/
CH2Cl2, RT, 2 h) was readily separable by reverse phase
chromatography. As with compound 2, the NMR data is in
full agreement with the reported data.[5]
As well as the two natural products, we prepared a small
panel of compounds (19–22) to explore the impact of deleting
the guanidine moiety, making the aryl ring electron deficient
(21–24), or installing an additional chlorine substituent
(20, 22, 25) in order to define an initial structure–activity
relationship (SAR) for this class of compounds (Figure 2). All
of the analogues were produced without modification to our
method, thereby highlighting the straightforward nature of
this approach for generating an array of 4-oxazolidinone
MIC [mgmLÀ1
Compound
]
S. Aureus[a]
MRSA[b]
A. baumannii[c]
1
2
10
19
20
21
22
12.5
30
>100
>100
50
20
30
>100
>100
60
100
>100
>100
>100
>100
100
>100
10
>100
20
80
23
60
40
80
24
25
>100
12.5
1
>100
20
1
1
100
>100
50
>100
>100
2
vancomycin
linezolid
tetracycline
0.5
0.25
[a] ATCC 29213. [b] ATCC 33591. [c] ATCC 19606. MIC=minimum
inhibitory concentration, MRSA=methicillin-resistant Staphylococcus
aureus.
a gram-negative bacterium that is resistant to many com-
monly employed antibiotics. These dichloro derivatives are
particularly straightforward to prepare and provide a starting
point for further improving the potency of these natural-
product analogues and/or generating probe molecules to
study the interaction of these electrophilic natural products
with proteins.[21]
In conclusion, we have developed a rapid and diastero-
selective synthesis for the synoxazolidinone family of natural
products. Through these efforts, we have gained insight into
the chemistry of these unusual heterocycles and provided new
lead compounds for antimicrobial development. Efforts to
increase the potency and selectivity of this class of compounds
are underway, as well as studies aimed at identifying their
intracellular targets.
Received: February 11, 2014
Revised: March 6, 2014
Published online: && &&, &&&&
Figure 2. Analogues of synoxazolidinones A and B.
Keywords: antimicrobial agents · heterocycles ·
natural products · stereoselectivity · total synthesis
.
products. It should be noted that the dichloro compounds
(20, 22, 25) arise from chlorination of the crude imine (excess
NCS) since purified dichloro aldehydes do not undergo our
dehydration/acylation/cyclization cascade reaction.[19]
[1] Infectious Diseases Society of America (IDSA), Clin. Infect. Dis.
2011, 52, S397 – S428.
[2] J. W. H. Li, J. C. Vederas, Science 2009, 325, 161 – 165.
[3] a) C. T. Walsh, T. A. Wencewicz, J. Antibiot. 2013, 1 – 16;
b) K. M. G. OꢀConnell, J. T. Hodgkinson, H. F. Sore, M. Welch,
G. P. C. Salmond, D. R. Spring, Angew. Chem. 2013, 125, 10904 –
10932; Angew. Chem. Int. Ed. 2013, 52, 10706 – 10733; c) T.
Bçttcher, M. Pitscheider, S. A. Sieber, Angew. Chem. 2010, 122,
2740 – 2759; Angew. Chem. Int. Ed. 2010, 49, 2680 – 2698.
[4] D. J. Newman, G. M. Cragg, J. Nat. Prod. 2007, 70, 461 – 477.
[5] a) M. Tadesse, M. B. Strøm, J. Svenson, M. Jaspars, B. F. Milne,
V. Tørfoss, J. H. Andersen, E. Hansen, K. Stensvꢁg, T. Haug,
Org. Lett. 2010, 12, 4752 – 4755; b) M. Tadesse, J. Svenson, M.
Jaspars, M. B. Strøm, M. H. Abdelrahman, J. H. Andersen, E.
Hansen, P. E. Kristiansen, K. Stensvꢁg, T. Haug, Tetrahedron
With synoxazolidinone A (1) and B (2) and their ana-
logues in hand, we explored the antimicrobial activity of these
compounds against several bacterial strains. The activities of
compounds 1 and 2 are in line with those reported for the
isolated natural products against both sensitive and resistant
gram-positive bacteria S. Aureus (Table 1).[5,20] Deletion of
the guanidine moiety on monochloro derivatives was detri-
mental to the antimicrobial activity (19, 21); however, the
installation of an additional chloride or an electron-with-
drawing group on the aryl ring was generally beneficial. In
particular, compounds 22 and 25 displayed comparable activ-
ity to that of 1 and increased activity against A. baumannii,
ˇ
Lett. 2011, 52, 1804 – 1806; c) K. H. Hopmann, J. Sebestꢂk, J.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Novotnꢃ, W. Stensen, M. Urbanovꢃ, J. Svenson, J. S. Svendsen, P.
Frontier, ChemCatChem 2011, 3, 1531 – 1548; K. K. S. Sai, M. J.
OꢀConnor, D. A. Klumpp, Tetrahedron Lett. 2011, 52, 2195 –
2198.
ˇ
Bour, K. Ruud, J. Org. Chem. 2012, 77, 858 – 869.
[6] V. R. Macherla, J. Liu, M. Sunga, D. J. White, J. Grodberg, S.
Teisan, K. S. Lam, B. C. M. Potts, J. Nat. Prod. 2007, 70, 1454 –
1457.
[7] M. R. Barbachyn, C. W. Ford, Angew. Chem. 2003, 115, 2056 –
2070; Angew. Chem. Int. Ed. 2003, 42, 2010 – 2023.
[15] For example: C. Intaraudom, N. Boonyuen, R. Suvannakad, P.
Rachtawee, P. Pittayakhajonwut, Tetrahedron Lett. 2013, 54,
744 – 748.
[16] For an example: M. P. Brochu, S. P. Brown, D. W. C. MacMillan,
J. Am. Chem. Soc. 2004, 126, 4108 – 4109. For a review: S. France,
A. Weatherwax, T. Lectka, Eur. J. Org. Chem. 2005, 475 – 479.
[17] The most successful asymmetric chlorination we have achieved
provides aldehyde 16 in 56% ee (2 equiv proline amide, 2 equiv
NCS, dioxane, 08C); however, the crude product can not be
successfully carried forward and all attempts at aldehyde
purification provided racemic product in low yield. New catalyst
development, a multistep work-around, or a substrate lacking
the guanidine functionality would likely be required to over-
come these obstacles.
[18] The diastereomeric ratio ranges from 5:1 to 2.5:1 depending on
the batch of acid chloride and conditions employed; 4:1 is the
most commonly observed diastereoselectivity. The 1H NMR
spectra for the two diastereomers are significantly different
(chemical shifts and coupling constants) for both the protected
and deprotected 1, thus allowing straightforward assignment of
the isolated diastereomers (see compound 17 in the Supporting
Information).
[19] N. De Kimpe, R. Verhe, L. De Buyck, H. Hasma, N. Schamp,
Tetrahedron 1976, 32, 2457 – 2466. For detailed procedures and
yields, see the Supporting Information.
[20] The compounds tested herein are racemic; although the
numbers reported are within the error of those reported in
Ref. [5] for enantiomerically enriched compounds, we do not
currently have accesses to purified enantiomers of the natural
products for a direct comparison of the impact of stereochem-
istry on activity. These efforts are underway.
[8] For singular examples of similar 4-oxazolidinone synthesis, see:
a) W. R. Roush, A. P. Essenfeld, J. S. Warmus, B. B. Brown,
Tetrahedron Lett. 1989, 30, 7305 – 7308; b) Y. S. Laxmi, D. S.
Iyengar, J. Chem. Soc. Perkin Trans. 1 1995, 3043 – 3045.
[9] P.-L. Shao, X.-Y. Chen, S. Ye, Angew. Chem. 2010, 122, 8590 –
8594; Angew. Chem. Int. Ed. 2010, 49, 8412 – 8416.
[10] a) W. P. Unsworth, G. Coulthard, C. Kitsiou, R. J. K. Taylor, J.
Org. Chem. 2014, 79, 1368 – 1376; b) W. P. Unsworth, C. Kitsiou,
R. J. K. Taylor, Org. Lett. 2012, 15, 258 – 261; c) W. P. Unsworth,
K. A. Gallagher, M. Jean, J. P. Schmidt, L. J. Diorazio, R. J. K.
Taylor, Org. Lett. 2012, 15, 262 – 265; d) O. Sieck, M. Ehwald,
J. R. Liebscher, Eur. J. Org. Chem. 2005, 663 – 672; e) K. T.
Wanner, U. Weber, Synthesis 1994, 387 – 390.
[11] a) S. V. Ryabukhin, D. M. Panov, A. S. Plaskon, O. O. Grygor-
enko, ACS Comb. Sci. 2012, 14, 631 – 635; b) Y. I. Sakhno, S. V.
Shishkina, O. V. Shishkin, V. I. Musatov, E. V. Vashchenko, S. M.
Desenko, V. A. Chebanov, Mol. Diversity 2010, 14, 523 – 531.
[12] For preparation and reaction of a-chloro aldimines, see: G. R.
Stanton, M. Gçllꢄ, R. M. Platoff, C. E. Rich, P. J. Carroll, P. J.
Walsh, Adv. Synth. Catal. 2013, 355, 757 – 764 and references
therein. For a recent example of intermolecular Cl-controlled
aldehyde addition, see: W. J. Chung, J. S. Carlson, D. K. Bedke,
C. D. Vanderwal, Angew. Chem. 2013, 125, 10236 – 10239;
Angew. Chem. Int. Ed. 2013, 52, 10052 – 10055.
[13] Reverse phase purification was required for these substrates and
yields of isolated product were significantly lower than expected
1
by inspection of crude H NMR or LC–MS analysis; however,
isolated, purified products were stable to long-term storage.
[14] For a discussion of related Nazarov-type cyclizations of enols to
enones: W. A. Batson, D. Sethumadhavan, M. A. Tius, Org. Lett.
2005, 7, 2771 – 2774. Also see: T. Vaidya, R. Eisenberg, A. J.
[21] For a discussion of the value of electrophilic natural product
scaffolds: a) M. Gersch, J. Kreuzer, S. A. Sieber, Nat. Prod. Rep.
2012, 29, 659 – 682; b) A. W. Puri, M. Bogyo, Biochemistry 2013,
52, 5985 – 5996.
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Natural Product Synthesis
Synthetic synoxazolidinones: A five-step
total synthesis of the marine natural
product synoxazolidinone A was achieved
through a diastereoselective imine acyla-
tion/cyclization cascade. Synoxazolid-
inone B and a series of analogues were
also prepared to explore the potential of
these 4-oxazolidinones as antimicrobial
agents. The results revealed simplified
dichloro derivatives that are equally
potent against several bacterial strains.
N. V. Shymanska, I. H. An,
J. G. Pierce*
&&&& — &&&&
A Rapid Synthesis of 4-Oxazolidinones:
Total Synthesis of Synoxazolidinones A
and B
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!