Stereoselective synthesis of the butyrolactone and the oxazoline/furan fragment of leupyrrin A1

Article abstract of DOI:10.1021/ol401110x

Stereoselective syntheses of the Northern and the Southern fragments 2 and 3 of leupyrrin A₁ are reported. The convergent preparation of 2 is highlighted by a zirconocene-mediated one-pot cyclization-regioselective opening of an advanced diyne

Full text of DOI:10.1021/ol401110x

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Stereoselective Synthesis of the
Butyrolactone and the Oxazoline/Furan
Fragment of Leupyrrin A1
Thomas Debnar,† Tongtong Wang,‡ and Dirk Menche*
University of Bonn, Kekule-Intitute of Organic Chemistry and Biochemistry,
Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany
dirk.menche@uni-bonn.de
Received April 22, 2013
ABSTRACT
Stereoselective syntheses of the Northern and the Southern fragments 2 and 3 of leupyrrin A1 are reported. The convergent preparation of 2 is
highlighted by a zirconocene-mediated one-pot cyclizationꢀregioselective opening of an advanced diyne while the route to 3 involves a Krische
allylation and a one-pot Sharpless dihydroxylationꢀcyclization. Comparison of the spectroscopic data with those reported for the natural product
supports a relative stereochemical assignment within these heterocycles.
During the past decades, myxobacteria have proven to
be a particularly rich source of structurally novel and
diverse natural products with a broad range of biological
activities.1 The family of the leupyrrins was isolated as one
of the main groups of secondary metabolites from
Sorangium cellulosum, strains So ce705 and So ce690.2
They demonstrate potent biological activities against var-
ious fungi and eukaryotic cells.2 As shown in Scheme 1 for
the main metabolite leupyrrin A1 (1, Figure 1), their
singular architectures are highlighted by a number of
structurally unusual motifs, including an unusually sub-
stituted γ-butyrolactone ring together with a pyrrole and
an oxazoline ring which are embedded in a nonsymmetric
macrodiolide corestructure.1 The sidechain incorporatesa
unique unsymmetrically substituted furan ring with two
alkyliden groups, one of them directly appending the chiral
macrocyclic oxazoline. The potent biological properties
and natural scarcity, coupled with their unique and in-
triguing molecular architectures, render the leupyrrins
attractive synthetic targets. A synthesis is however severely
hampered by the lack of full stereochemical knowledge, as
merely one of the seven stereogenic centers (C-30) has been
rigorously assigned and only relative configurations have
beententativelyproposedwithinthebutyrolactone and the
oxazoline fragments by conformational NMR studies.2a
As a prelude to devising a first total synthesis of the
leupyrrins to unambiguously assign the stereochemistry
and enhance the supply for biological evaluation, we
report efficient syntheses of the Northern and the Southern
fragments 2 and 3. The concise routes proceed with high
† Contributed to synthesis of 2 and 3, including initial synthesis of 15a.
‡ Contributed to synthesis of 6 and large-scale synthesis of 15a.
€
(1) For reviews, see: (a) Reichenbach, H.; Hofle, G. In Drug Dis-
covery from Nature; Grabley, S., Thiericke, R., Eds.; Springer-Verlag:
Berlin, 1999; pp 149ꢀ179. (b) Menche, D. Nat. Prod. Rep. 2008, 25,
€
905–918. (c) Weissman, K. J.; Muller, R. Nat. Prod. Rep. 2010, 27, 1276–
1295.
€
€
(2) (a) Muller, R.; Bode, H. B.; Wenzel, S.; Hofle, G.; Irschik, H.;
Reichenbach, H. J. Nat. Prod. 2003, 66, 1203–1206. (b) Bode, H. B.;
€
€
Wenzel, S. C.; Irschik, H.; Hofle, G.; Muller, R. Angew. Chem., Int. Ed.
2004, 43, 4163–4167. (c) Kopp, M.; Irschik, H.; Gemperlein, K.; Buntin,
€
K.; Meiser, P.; Weissman, K. J.; Bode, H. B.; Muller, R. Mol. BioSyst.
2011, 7, 1549–1563.
r
10.1021/ol401110x
XXXX American Chemical Society

stereoselectivity and confirm the relative stereochemistry
within the heterocyclic moieties.
stereocenter should be derived from an enzymatic diester
hydrolysis catalyzed by PLE.4
As shown in Figure 1, these moieties may be discon-
nected from the natural product by an esterification, a
ring-closing metathesis, and an oxazoline formation. At
the beginning of our campaign the absolute configurations
within the heterocycles were arbitrarily assigned while
selection of the relative configurations was based on the
proposal in the isolation paper.2a Finally, a modular
synthetic route to set the stereogenic center at C-26 was
pursued by late-stage diversification (vide infra).
As shown in Scheme 1, the synthesis of 3 started from
known aldehyde 7,5 which was obtained in four steps from
methyl dimethyl malonate.4 Unfortunately, direct vinyla-
tion of 7 using different vinylating agents6 resulted in either
low conversion or poor diastereoselectivities. Instead,
allylation following the protocol developed by Krische7
afforded the homoallyl alcohol in good yield and excellent
diastereoselectivity whose configuration was confirmed by
Mosher ester analysis.8
Scheme 1. Synthesis of the Butyrolactone Fragment 3
Subsequent TES-protection of the free alcohol afforded
8, which was elaborated into 9 by ozonolysis, reduc-
tive workup, and subsequent elimination following the
Grieco protocol.9 Sharpless dihydroxylation10 using the
(DHQD)2AQN ligand resulted in clean formation of the
five-membered butyrolactone 10 as a single diastereomer
Figure 1. Synthetic approach to the Northern and Southern
fragments of leupyrrin A1 (1).
The synthesis of bis-alkylidene-substituted tetrahydro-
furan of 2 should be accomplished by a Zr-mediated
cyclization strategy, as recently developed in our group.3
The required diyne 4 with either configuration at C-26 was
to be synthesized from a stereodivergent alkyne addition
and subsequent etherification. The γ-butyrolactone 3, in
turn, was envisioned to arise from an esterification of
known acid 6 with fragment 5 whose anti-diol moiety
was planned to arise from an asymmetric allylation and
subsequent Sharpless’ dihydroxylation and the quaternary
(4) (a) Jones, J. H.; Thomas, D. W.; Thomas, R. M.; Wood, M. E.
€
Synth. Commun. 1986, 16, 1607–1610. (b) Luyten, M.; Muller, S.;
Herzog, B.; Keese, R. Helv. Chim. Acta 1987, 70, 1250–1254.
(5) Prantz, K.; Mulzer, J. Chem.;Eur. J. 2010, 16, 485–506.
(6) (a) Burke, S. D.; Armistead, D. M.; Schoenen, F. J.; Fevig, J. M.
Tetrahedron 1986, 42, 2787–2801. (b) Keck, G. E.; Andrus, M. B.;
Romer, D. R. J. Org. Chem. 1991, 56, 417–420. (c) Hirose, T.; Sunazuka,
T.; Tsuchiya, S.; Tanaka, T.; Kojima, Y.; Mori, R.; Iwatsuki, M.;
Omura, S. Chem.;Eur. J. 2008, 14, 8220–8238.
(7) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 14891–14899.
(8) Interestingly, use of the (S)-Cl,MeO-BIPHEP ligand enabled
access to the diastereomeric homoallylic alcohol in excellent diastereo-
selectivity, suggesting that substrate control is completely overridden by
the catalyst.
(3) Debnar, T.; Dreisigacker, S.; Menche, D. Chem. Commun. 2013,
49, 725–727.
B
Org. Lett., Vol. XX, No. XX, XXXX

in 88% yield without isolation of the intermediary diol due
to the basic reaction conditions employed.11 At this stage,
it became necessary to transform 10 into its more stable
TBS-congener 5 to secure reproducibly high yields for the
ensuing introduction of the methylene unit. To this end, 5
was oxidized to an aldehyde and treated with MeMgCl to
give a 1:1 diastereomeric mixture of the secondary alcohols
which were directly oxidized to methyl ketone 11. Next,
installation of the required methylene group was exam-
ined which proved to be troublesome. None of the stan-
dard methylenation methods, such as Wittig,12 Tebbe,13
Peterson,14 or Takai-Lombardo olefination15 resulted in
the formation of olefin 12, presumably due to steric
hindrance or inherent enolate formation under the basic
reaction conditions. Trapping of the enolate as the corre-
sponding vinyl triflate for a cross-coupling reaction also
remained unsuccessful. Finally, base-free conditions using
the Petasis reagent16 gave rise to 12, yet in only moderate
proved not feasible,20 a chromatographically separable
1:1 mixture of 15a and 15b was obtained from addition
of lithiated 14. Diastereomerically enriched 15b can be
directly obtained from this mixture following an oxidation/
reduction sequence. In detail, CBS-reduction21 using the
(R)-CBS oxazaborolidine afforded (26R)-configured 15b
in excellent yield and a preparatively useful diastereomeric
ratio of 6:1.22 Epimeric 15a, in turn, may be selectively
accessed by a Mitsunobu inversion from 15b.23
Scheme 2. Joint Synthesis of 15a and 15b by a Late Stage
Diversification Strategy
yields (30%). Deprotection of the TBS-group with HF py
3
and subsequent esterification with acid 617 proceeded
uneventfully to give the fully elaborated fragment 3.
We then turned our attention to the synthesis of
Northern fragment 2. As shown in Scheme 2, our route
started from known aldehyde 13, which was prepared in
seven steps following a route developed by McLeod
et al.18 Introduction of the alkyne,19 reduction of the ester
with LAH, and subsequent PMB-protection proceeded
smoothly giving 14 in 61% overall yield. Next, a modular
construction of the stereogenic center at C-26 was pursued.
While asymmetric alkyne addition to isovaleraldeyde
(9) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485–1486.
(10) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483–2547. (b) Becker, H.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 1996, 35, 448–451. (c) Zaitsev, A. B.; Adolfsson, H. Synthesis
2006, 1725–1756. (d) Takeda, Y.; Shi, J.; Oikawa, M.; Sasaki, M. Org.
Lett. 2008, 10, 1013–1016.
(11) It should be noted that the use of (DHQ)2AQN also resulted in
the formation of the C3ꢀC4 antidisubstitued butyrolactone as the only
diastereomer, assuming that, in this case, substrate control was stronger
than the influence of the catalyst.
(12) (a) Oikawa, Y.; Tanaka, T.; Horita, K.; Noda, I.; Nakajima, N.;
Kakusawa, N.; Hamada, T.; Yonemitsu, O. Chem. Pharm. Bull. 1987,
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50, 1212–1216.
Isomer 15a was then further homologated with tosylate
16 to access diyne 4. Efforts were directed to apply our key
Zr-mediated cyclization/regioselective opening sequence
to access the furan core of leupyrrin A1 (Scheme 3)
following a sequence previously developed in our group.3
To this end, 4 was subjected to a freshly prepared zirco-
nocene solution24 atꢀ78°C. The mixture was thenallowed
to warm to room temperature, and the reaction progress
was monitored by TLC. After conversion to zirconacyclo-
pentadiene 17 was complete, regioselective opening was
accomplished in situ by addition of 2.00 equiv of NBS at
ꢀ78 °C. Gratifyingly, bromide 18 was obtained as a single
regioisomer with the desired constitution in 88% yield, in
(14) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763–
4776.
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Chem. Soc. 1997, 119, 8738–8739.
(22) In contrast, asymmetric reduction of the ynone leading also
directly to (26S)-configured 15a failed, possibly due to steric shielding of
the re-face of the ketone by the bulky Boc-group.
€
(19) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett
(23) For a review on the Mitsunobo reaction, see: Swamy, K. C. K.;
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109, 2551–2651.
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C

Scheme 3. Zr-Mediated Oxidative Cyclization of 4 Leading to
the Furan Core of the Leupyrrins
Figure 2. Selected NMR data determined for the Southern (a)
and Northern fragment (b).
agreement with our previously developed mechanistic
proposal based on a remote coordination in such type of
oxidative ring cleavages.3 The following halogenꢀlithium
exchange was then initiated by reaction with t-BuLi and
addition of Me2SO4 leading to the formation of the
targeted C-18 methyl-substituted diene 2.25
Importantly, the NMR data of both synthetic fragments
were closely related to those reported for the natural
product.2 As exemplarily shown for 5 in Figure 2a, all
butyrolactone moieties displayed similar sets of NOE
correlations as those reported for natural leupyrrin A1,
i.e. from H-4 to both Me-2 and from H-3 to both H-22 and
Me-5. In a similar fashion, also synthetic 2 resided in a
closely related conformation to that reported for natural 1,
as indicated by a similar set of coupling constants
(Figure 2b).26 These data confirm both the constitution
and relative configuration within these segments of the
stereoselective allylation and dihydroxylation to install the
C3/C4 stereocenters with high selectivity, while syn-
thesis of 2 relied on a one-pot zirconocene-mediated
diyne cyclizationꢀregioselective opening, which proceeds
with excellent and predictable regioselectivities. Notably,
this presents one of the most advanced applications of
Zr-mediated oxidative cyclization in complex target syn-
thesis. Importantly, the stereogenic center at C-26 may be
set with either configuration by a late stage diversification
strategy adding considerable flexibility to the route. The
close spectroscopic similarity of these fragments with the
data reported for the natural products supports the assign-
ment of the relative configuration as shown. With this
stereochemical confirmation in hand efforts can now be
directed toward the development of a modular synthetic
strategy to enable a first total synthesis of the leupyrrins.
€
natural product as originally proposed by the Muller
Acknowledgment. Generous financial support by the
Deutsche Forschungsgemeinschaft (SFB 813), the Fond
der Chemischen Industrie (stipend to T.D.), and the
Chinese Scholarship Council(stipend toT.W.) isgratefully
acknowledged.
group.2
In summary, we have devised efficient stereoselec-
tive syntheses of the fully functionalized Northern and
Southern fragments 2 and 3 of the leupyrrins. Preparation
of the highly substituted butyrolactone 3 was based on a
Supporting Information Available. Experimental de-
tails, spectral data, and copies of NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(25) Diene 2 was obtained as a 4:1 mixture of 2 and the corresponding
diene which was formed by hydrolysis of lithiated 18. See Supporting
Information for further details.
(26) A characteristic NOE correlation from H-14 to H-26 was also
observed, which has not been mentioned in the isolation manuscript.
This may suggest the configuration at C-26 of 2 could be opposite to that
in the natural product.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX