Asymmetric synthesis of the fully elaborated pyrrolidinone core of oxazolomycin A

Article abstract of DOI:10.1021/ol302541j

The asymmetric synthesis of the key pyrrolidinone core, including a highly elaborated exocyclic carbon chain, of the γ-lactam β-lactone antibiotic oxazolomycin A is described. Principal features include the Birch reduction of an aromatic pyrrole nucleus, a late stage RuO₄ catalyzed pyrrolidine oxidation, and a highly diastereoselective organocerium addition to an aldehyde.

Full text of DOI:10.1021/ol302541j

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Asymmetric Synthesis of the Fully
Elaborated Pyrrolidinone Core of
Oxazolomycin A
Timothy J. Donohoe,*,† Timothy J. C. O’Riordan,†,§ Manuel Peifer,†
Christopher R. Jones,† and Timothy J. Miles‡
Chemistry Research Laboratory, Department of Chemistry, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, U.K., and Medicines Research Centre,
GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
timothy.donohoe@chem.ox.ac.uk
Received September 14, 2012
ABSTRACT
The asymmetric synthesis of the key pyrrolidinone core, including a highly elaborated exocyclic carbon chain, of the γ-lactam β-lactone antibiotic
oxazolomycin A is described. Principal features include the Birch reduction of an aromatic pyrrole nucleus, a late stage RuO4 catalyzed pyrrolidine
oxidation, and a highly diastereoselective organocerium addition to an aldehyde.
First isolated in 1985 by Uemura et al.1 from Strepto-
myces species, oxazolomycin A 1 is the parent compound
of a class of spiro γ-lactam β-lactone ring containing
antibiotics2 that have been shown to exhibit wide ranging
antibacterial and antiviral activities.3 Due to its structural
complexity and potent biological activity, oxazolomycin A
has attracted considerable attention from the chemistry
community. Syntheses of the diene and triene fragments, in
addition to a large number of studies focusing on models
of the pyrrolidinone core, void of the exocyclic carbon
chain, have been described.4 The sole total synthesis of
oxazolomycin A was reported in 2011 by Hatakeyama et
al. in 34 linear steps, utilizing a Conia-ene type cyclization
to construct the central γ-lactam ring.5 Elsewhere, the
groups of Kende in 1990 and Hatakeyama in 2007 have
(4) (a) Andrews, M. D.; Brewster, A. G.; Moloney, M. G. Synlett
1996, 612. (b) Henaff, N.; Whiting, A. Org. Lett. 1999, 1, 1137. (c)
Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2000, 2, 1987. (d) Wang, Z.;
Moloney, M. G. Tetrahedron Lett. 2002, 43, 9629. (e) Bulger, P. G.;
Moloney, M. G.; Trippier, P. C. Org. Biomol. Chem. 2003, 1, 3726. (f)
Moloney, M. G.; Yaqoob, M. Synlett 2004, 1631. (g) Mohaptra, D. K.;
Mondal, D.; Gonnade, R. G.; Chorghade, M. S.; Gurjar, M. K. Tetra-
hedron Lett. 2006, 47, 6031. (h) Bennett, N. J.; Prodger, J. C.; Pattenden,
G. Tetrahedron 2007, 63, 6216. (i) Yamada, T.; Sakaguchi, K.; Shinada,
T.; Ohfune, Y.; Soloshonok, V. A. Tetrahedron: Asymmetry 2008, 19,
2789. (j) Webb, M. R.; Addie, M. S.; Crawforth, C. M.; Dale, J. W.;
Franci, X.; Pizzonero, M.; Donald, C.; Taylor, R. J. K. Tetrahedron
2008, 64, 4778. (k) Mondal, D.; Bera, S. Synthesis 2010, 3301. (l) Bastin,
R.; Dale, J. W.; Edwards, M. G.; Papillon, J. P. N.; Webb, M. R.; Taylor,
R. J. K. Tetrahedron 2011, 67, 10026.
(5) Eto, K.; Yoshino, M.; Takahashi, K.; Ishihara, J.; Hatakeyama,
S. Org. Lett. 2011, 13, 5398.
(6) (a) Kende, A. S.; Kawamura, K.; DeVita, R. J. J. Am. Chem.
Soc. 1990, 112, 4070. (b) Onyango, E. O.; Tsurumoto, J.; Imai, N.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem., Int. Ed.
2007, 46, 6703.
† University of Oxford.
‡ GlaxoSmithKline.
§ Author to whom correspondence regarding X-ray crystallography should
be addressed.
(1) Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemura, D.;
Katayama, C.; Iwadare, S.; Shizuri, Y.; Mitomo, R.; Nakano, F.;
Matsuzaki, A. Tetrahedron Lett. 1985, 26, 1073.
(2) Moloney, M. G.; Trippier, P. C.; Yaqoob, M.; Wang, Z. Curr.
Drug Discovery Technol. 2004, 1, 181.
(3) (a) Kawai, S.; Kawabata, G.; Kobayashi, A.; Kawazu, K. Agric.
€
Biol. Chem. 1989, 53, 1127. (b) Tonew, E.; Tonew, M.; Grafe, U.; Zoepel,
P. Acta Virol. 1992, 36, 166.
r
10.1021/ol302541j
XXXX American Chemical Society

presented syntheses of neooxazolomycin 2, the γ-lactone
congener of 1.6
The resulting diester was reduced to furnish diol 8 with the
required all-carbon quaternary center, and subsequent
enzymatic desymmetrization10 produced the monoacetate
in good yield and excellent ee (>98% ee).11
In order to control facial selectivity in the key olefin
hydroboration, the remaining alcohol was protected as a
bulky tert-butyldiphenyl silyl ether. The acetate group,
however, proved to be labile under the hydroboration
conditions and was thus exchanged for a MOM group to
afford pyrroline 9 in 79% yield over two steps. Treatment
We have previously reported applications of the partial
Birch reduction of substituted aromatic pyrroles7 to the
synthesis of complex natural products.8 With a view to
extending the utility of this methodology, we targeted an
asymmetric synthesis of the γ-lactam β-lactone core of
oxazolomycin A, including an elaborated exocyclic carbon
chain primed for a future total synthesis.
of the olefin in 9 with BH3 THF, followed by an oxidative
3
workup with trimethylamine N-oxide,12 gave the desired
hydroxy pyrrolidine 10 with excellent regioselectivity and
good diastereoselectivity (8:1), resulting from addition to
the less hindered face to set the C-2 methyl stereocenter.
Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of Pyrrolidine Core 12
Given that the labile β-lactone ring would need to be
constructed in the final step of any subsequent synthesis
of 1, a protected hydroxy acid would be taken through
the sequence (Scheme 1). Similar to Hatakeyama,5,6b the
central diene fragment would be introduced via a NozakiÀ
HiyamaÀKishi reaction with aldehyde 3. A unique late-
stage introduction of the lactam carbonyl group onto 4
would avoid complications from potential epimerization
at the C-2 methyl stereocenter,4a while chelation-con-
trolled addition to aldehyde 4 would install the exocyclic
side chain. Finally, pyrroline 5 could be accessed via
desymmetrization of the achiral diol arising from partial
Birch reduction of pyrrole 6.
Oxidation of alcohol 10 was effected using Dess-Martin
periodinane to give the corresponding ketone. Unfortu-
nately the opportunity to install the complete side chain at
this stage, via the addition to the ketone of an R-oxyanion,
proved unsuccessful.13 As a result, we pursued an alter-
native strategy to generate an R-hydroxy-aldehyde that
The synthesis began by N-Boc protecting commercially
available pyrrole 6 and subjecting this to a partial Birch
reduction, quenched with iodomethyl pivalate 7 (Scheme 2).9
(10) Donohoe, T. J.; Rigby, C. L.; Thomas, R. E.; Nieuwenhuys,
W. F.; Bhatti, F. L.; Cowley, A. R.; Bhalay, G.; Linney, I. D. J. Org.
Chem. 2006, 71, 6298.
(11) The enantiomeric excess of this reaction was determined by
HPLC analysis of a derivative of 9; see the Supporting Information
for details, and the absolute configuration by analogy with ref 10.
(12) Kabalka, G. W.; Hedgecock, H. C., Jr. J. Org. Chem. 1975, 40,
1776.
(13) Including metallated allylic ethers: (a) Evans, D. A.; Andrews,
G. C.; Buckwalter, B. J. Am. Chem. Soc. 1974, 96, 5560. LiCH2O-
CH2OCH3: (b) Johnson, C. R.; Medich, J. R.; Danheiser, R. L.;
Romines, K. R.; Koyama, H.; Gee, S. K. Org. Synth. 1993, 71, 133.
(7) Donohoe, T. J.; Guyo, P. M.; Beddoes, R. L.; Helliwell, M.
J. Chem. Soc., Perkin Trans. 1 1998, 667.
(8) (a) Donohoe, T. J.; Sisangia, L.; Sintim, H. O.; Harding, J. D.
Angew. Chem., Int. Ed. 2004, 43, 2293. (b) Donohoe, T. J.; Chiu, J. Y. K.;
Thomas, R. E. Org. Lett. 2007, 9, 421.
(9) Schieweck, F.; Altenbach, H.-J. J. Chem. Soc., Perkin Trans. 1
2001, 3409.
B
Org. Lett., Vol. XX, No. XX, XXXX

could then be used to introduce the carbon chain. To this
end, addition of allylmagnesium bromide to the less hin-
dered face of the ketone afforded homoallylic alcohol 11 in
70% yield to set the C-3 stereocenter with very good
diastereocontrol (10:1 dr). X-ray crystallographic analysis
confirmed the relative configuration of the major diaster-
eoisomer (see Scheme 2).14 Isomerization of the terminal
olefin employing a [Ru]ÀH species generated in situ from
Grubbs’ second generation catalyst15 gave the allylic alco-
hol, and ozonolysis of this internal olefin provided the
desired R-hydroxy-aldehyde 12 in excellent yield.
diastereoisomer (Scheme 4). To confirm that the addition
had occurred from the required Si-face of 12 acetonide 18
was prepared and subsequent NOE analysis confirmed the
correct configuration at C-4.
Scheme 4. Chelation Control for the Synthesis of Diol 17
Next we prepared a nucleophile that would enable the
carbon skeleton of the side chain to be installed onto
aldehyde 12. Hence we embarked on the synthesis of
bromide 13 that possesses the C-6 methyl stereocenter
and an alkene unit acting as a masked carbonyl group
(Scheme 3). Phase transfer conditions16 with benzyl alco-
hol enabled monosubstitution of dibromide 14, which was
then subjected to the asymmetric allylic alkylation proto-
col developed by Feringa et al. to produce olefin 15 as a
single enantiomer.17 Cross metathesis of 15 with 3,3-
dimethyl-1-butene afforded exclusively the E-isomer of
the disubstituted olefin. Finally, bromination of the pri-
mary alcohol resulting from benzyl ether deprotection
gave the desired bromide 13 in 82% yield over two steps.
Conversion of the newly formed secondary alcohol 17
into its corresponding methyl ether was accomplished in
78% yield using Meerwein’s reagent and proton sponge
(Scheme 5). Ozonolysis of the pendant olefin, followed by
reduction of the ozonide and protection of the resulting
primary alcohol furnished acetate 19. Oxidation and N-
functionalization was smoothly effected using catalytic
RuO4 followed by dilute TFA in the presence of a cation
scavenger (to selectively remove the N-Boc over O-MOM
protecting group) and then N-methylation to afford 20.
Next, a higher concentration of TFA cleaved the O-MOM
group, and a two-step oxidation protocol then yielded
carboxylic acid21in99% yield overtwo steps. A derivative
of 21 lacking the pyrrolidinone N-methyl group 22 proved
suitable for X-ray crystallographic analysis,18 providing
confirmation of the desired stereochemistry at all five
stereogenic centers as well as the site of O-methylation
(see Scheme 5). Considering a future total synthesis of
oxazolomycin A, we decided to test the viability of a late-
stage β-lactonization. To this end, deprotection of the silyl
ether in 21 followed by lactonization of the resulting
hydroxy-acid furnished the γ-lactam β-lactone core 23 in
64% yield over two steps. As suspected, this β-lactone
proved to be extremely labile; hence carboxylic acid 21
required a suitable protecting group for the remainder of
the sequence.
Scheme 3. Synthesis of Bromide 13
With enantiopure bromide 13 in hand, attention turned
to the union of the exocyclic carbon chain and aldehyde 12.
At length it was found that chelation-controlled addition
of an organocerium species derived from bromide 13
provided the desired diol 17 in the best yield and as a single
(14) CCDC 894648 contains the supplementary crystallographic
data for compound 11; see the Supporting Information for further
details.
(15) (a) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.;
Nishida, A. J. Org. Chem. 2006, 71, 4255. For a recent review, see: (b)
Donohoe, T. J.; O’Riordan, T. J. C.; Rosa, C. P. Angew. Chem., Int. Ed.
2009, 48, 1014.
At length, it was found that the bulky di-tert-butyl-
methylsilyl ester of 21, prepared in 91% yield from
DTBMS triflate,19 was stable to the proceeding O-acetate
(16) Kottirsch, G.; Koch, G.; Feifel, R.; Neumann, U. J. Med. Chem.
2002, 45, 2289.
(17) (a) van Zijl, A. W.; Lopez, F.; Minnaard, A. L.; Feringa, B. L.
ꢀ
ꢀ
J. Org. Chem. 2007, 72, 2558. (b) van Zijl, A. W.; Szymanski, W.; Lopez,
(18) CCDC 894647 contains the supplementary crystallographic
data for compound 22; see the Supporting Information for all of the
details.
(19) Bhide, R. S.; Levison, B. S.; Sharma, R. B.; Ghosh, S.; Salomon,
R. G. Tetrahedron Lett. 1986, 27, 671.
F.; Minnaard, A. L.; Feringa, B. L. J. Org. Chem. 2008, 73, 6994. The
enantiomeric excess of this reaction was determined by HPLC analysis
of a derivative of 15 (see the Supporting Information for details), and the
absolute configuration has been determined previously by Feringa and
co-workers; see ref 17a.
Org. Lett., Vol. XX, No. XX, XXXX
C

(>20:1 dr).20 This Fmoc protected amine 26 is primed for
conjunction withinthomycin, the triene-oxazole portion of
oxazolomycin A. Subsequent global protecting group
removal and β-lactonization would complete a synthesis
of the natural product.
Scheme 5. Synthesis of the γ-Lactam β-Lactone Core 23
Scheme 6. Elaborating the Side Chain in the Synthesis of (R)-26
The pyrrolidinone core 26 of oxazolomycin A, including
a fully elaborated exocyclic carbon chain, has been synthe-
sized in 28 linear steps from commercially available pyrrole 6.
This advanced oxazolomycin A intermediate has been
created as a single diastereoisomer and a single enantio-
mer. Work is currently underway in our laboratories to
establish a concise preparation of inthomycin; its appli-
cation to the total synthesis of oxazolomycin A 1 will then
follow.
cleavage (Scheme 6). It is also worth noting that this silyl
group was compatible with our β-lactonization protocol.
Next, a Swern oxidation of the resulting primary alcohol
afforded aldehyde 24 in 72% yield. The central diene
component was successfully installed using a NozakiÀ
HiyamaÀKishi reaction,5,6b with vinyl iodide 25,5 to pro-
duce vinyl alcohol 26 as a 1:1 mixture of epimers. Finally,
oxidation to the C-7 ketone using Dess-Martin period-
inane, followed by diastereoselective reduction employing
Acknowledgment. We are grateful to GlaxoSmithKline
(T.J.C.), SNF (M.P.), and St. John’s College Oxford (C.R.
J.) for providing financial support and Matthew Tatton
(University of Oxford) for help with X-ray crystallo-
graphic analysis.
BH3 SMe2 in the presence of (S)-(À)-2-methyl-CBS-
3
oxazaborolidine at À30 °C, afforded the target vinyl alcohol
(7R)-26 in 96% yield and with excellent diastereoselectivity
Supporting Information Available. Experimental pro-
cedures and spectral data of new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(20) Absolute configuration of the C-7 alcohol after CBS reduction
could not be unequivocally proven by analytical means; however, the
desired diastereomeric outcome is supported by literature precedent for
CBS reduction of alkyl-vinyl ketones. See: Corey, E. J.; Helal, C. J.
Angew. Chem., Int. Ed. 1998, 37, 1986 and references cited therein.
The authors declare no competing financial interest.
D
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