Enantioselective synthesis of the core of banyaside, suomilide, and spumigin HKVV

Article abstract of DOI:10.1002/anie.200803655

Concise: The first synthesis of the unique azabicyclononane core found in the aeruginosin class of serine protease inhibitors is described. The route is characterized by its efficiency (eight steps) and sets the stage for subsequent introduction of the gl

Full text of DOI:10.1002/anie.200803655

Communications
DOI: 10.1002/anie.200803655
Natural Products
Enantioselective Synthesis of the Core of Banyaside, Suomilide, and
Spumigin HKVV**
Corinna S. Schindler, Corey R. J. Stephenson, and Erick M. Carreira*
Dedicated to Professor Duilio Arigoni on the occasion of his 80th birthday
Banyaside A (3) and B (4), suomilide (1), and spumigin
HKVV (2)[1] are novel natural products belonging to the
aeruginosin family of serine protease inhibitors (Scheme 1).[2]
As indicated in Scheme 2, the synthesis of the tricyclic
core I relies on a strategy involving a late-stage regioselective
olefin hydroxylation of II. Preparation of this key intermedi-
ate would necessitate the development of a series of reactions
ꢀ
stemming from III formally involving C N bond formation (a
ꢀ
in Scheme 2) and cleavage of the C O bond (b in Scheme 2).
As described below, the preparation of the oxabicyclic
norbornene presented an opportunity to establish a tandem
catalytic sequence.
Scheme 2. Retrosynthetic analysis of the azabicyclononane core.
Scheme 1. Azabicyclononane members of the aeruginosin family.
The synthesis commenced with the enantioselective
Diels–Alder reaction[3] of furan and bromoacrolein[4] leading
to aldehyde 6, employing Coreyꢀs oxazaborolidine catalyst
(Scheme 3). The sensitive exo-Diels–Alder adduct is allowed
to react in situ with the lithium enolate derived from ethyl
acetate to afford a mixture of aldol adducts 7a and 7b (63%
yield, d.r. 1.6:1, e.r. 87:13). It is important to note that the
enantioselective Diels–Alder reaction employing the oxaza-
borolidinone catalyst 3-methyl-substituted derivative of 9,
derived from N-tosyl (aS,bR)-b-methyltryptophan, is
reported to proceed with greater than 98% yield
(92% ee).[5] As a consequence of the subsequent step involv-
The tricyclic azabicyclononane core common to these is
densely functionalized with six stereogenic centers and
incorporates glycosyl as well as peptide side-chains at its
periphery. The biological activity along with the sheer
complexity of the structure renders these notable as targets
for synthesis studies. Herein we report a rapid enantioselec-
tive synthesis of the fully functionalized azabicyclononane
(Abn) core common to the banyasides, suomilide, and
spumigin HKVV. Key to the strategy is the implementation
of a tandem catalytic sequence along with a series of novel,
mechanistically intriguing transformations.
[*] C. S. Schindler, Dr. C. R. J. Stephenson, Prof. Dr. E. M. Carreira
Laboratorium für Organische Chemie, ETH Zürich, HCI H335
Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland)
Fax: (+41)44-632-1328
E-mail: carreira@org.chem.ethz.ch
[**] This work was supported by a grant from the Swiss National Science
Foundation. C.S.S. thanks the Roche Research Foundation for a
predoctoral fellowship. We are grateful to Dr. W. Bernd Schweizer for
the X-ray crystallographic analysis of compounds 7a and 18.
Scheme 3. a) 5 mol% 9 (see Scheme 4), CH2Cl2, furan, ꢀ788C;
b) LDA, EtOAc, ꢀ788C, 63%, d.r. 1.6:1; c) KOtBu, THF, ꢀ658C!
ꢀ458C, 75% (brsm, 39% conv.). LDA=lithium diisopropylamide,
brsm=based on recovered startingmaterial.
Supportinginformation for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803655.
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Chemie
ing conversion to 8, the generation of diastereomers in the
aldol addition is inconsequential. Indeed, treatment of the
diastereomeric mixture of bromohydrins 7a/7b with KOtBu
(below ꢀ458C) afforded E-a,b-unsaturated ester 8 in 75%
yield. This transformation likely proceeds through an inter-
mediate epoxy ester, which subsequently undergoes elimina-
tion to give 8. It is worth noting that the rates of conversion of
the b-hydroxy-g-bromo esters to product 8 were markedly
different for each of the diastereomers with 7b as the faster-
reacting component. Thus, when the reaction was stopped at
50% conversion, the re-isolated material consisted exclu-
sively of alcohol 7a.[6]
Oxazaborolidines have been shown to serve as catalysts in
a variety of processes including cycloadditions as well as
carbonyl addition reactions.[7] We were thus intrigued by the
possibility of merging the Diels–Alder cycloaddition and a
Mukaiyama aldol reaction to directly afford bromohydrin
adducts. In this experiment, furan and bromoacrolein are
allowed to react in the presence of 5 mol% oxazaborolidine 9
in CH2Cl2 at ꢀ788C; upon consumption of the educts, the silyl
ketene acetal 10 was added as a solution in THF (Scheme 4).
The application of such tandem-catalysis protocol led to the
formation of 7a in 67% yield and improved diastereoselec-
tivity (d.r. 5:1, e.r. 86:14).
catalysts were screened to effect the aziridination reaction,
and best results were observed using the protocol developed
by Du Bois and Espino.[10] We were able to cleanly effect
opening of the aziridine with o-nitrobenzenesulfonamide to
afford the desired product 12 in 75% yield. Deprotection of
12 with K2CO3/PhSH gave amine 13 (91%). Although 13
could be taken forward through the sequence to the desired
target, it was readily protected upon treatment with benzal-
dehyde and NaBH3CN to afford 14.
The critical point had been reached in the synthesis that
demanded the identification of a process that would effect the
conversion of 14 into the tricyclic azabicyclononane 19
(Scheme 5). Attention was focused on a two-step sequence
Scheme 5. a) I2, NaHCO3, THF, H2O, 238C, 73% (13!15); b) N-
iodophthalimide, hn, CH2Cl2, 89% (14!17), 63% (13!16);
c) 4.0 equiv SmI2, THF, 0!238C, 82% (17!19), 62% (16!18).
involving a haloamination of the oxabicyclonorbornene and a
fragmentation to realize the desired Abn framework. Treat-
ment of amine 14 with I2/NaHCO3 in THF[11] led to exclusive
formation of exo-iodide 15, as expected from the addition
proceeding in an anti fashion. Surprisingly, however, the
reaction of 14 with either NISor N-iodophthalimide[12]
resulted in exclusive formation of the endo-iodide 17 within
10 min in 89% yield, consistent with a formal syn-addition
across the olefin. Although the mechanism of this unusual
transformation is unclear at present, we have made some
observations that would need to be reconciled with any
mechanistic proposal. Firstly, the syn-iodoamination reaction
proceeds slower and affords considerable quantities of the
exo-adduct when conducted in the dark under otherwise
identical conditions. Secondly, in a series of 1H NMR
spectroscopic experiments, we observed that at short reaction
times (60 s) a mixture of starting material 14 and NISin
CD2Cl2 leads to the transient formation of an intermediate in
which the olefin is intact. As the reaction proceeded to
completion this intermediate disappears, giving the syn-
iodoamination product 16 and merely traces of N-Bn-15.
Analysis of the spectroscopic data is consistent with a
tentative assignment of the intermediate as the N-iodo
derivative of 14. Importantly, we were able to show that the
unprotected primary amine 13 could be subjected to the same
Scheme 4. a) 9 (5 mol%), CH2Cl2, furan, ꢀ788C; b) 10, THF, ꢀ788C,
67%, d.r. 5:1; c) KOtBu, THF, ꢀ65!ꢀ458C, 75% (brsm, 39% conv.);
d) 1. Cl3CC(O)NCO, CH2Cl2, 238C; 2. Al2O3, CH2Cl2, 238C, 95%; e) 1.
[Rh2esp2] (5 mol%), PhI(OAc)2, MgO, CH2Cl2, reflux; 2. NsNH2, NaH,
DMF, 238C, 75%; f) PhSH, K2CO3, CH3CN, 238C, 91%; g) PhCHO,
NaBH3CN, AcOH, MeOH, 0!238C, 92%. Esp=Espino ligand,[10]
Ns=o-nitrobenzenesulfonyl.
With a route to the key bicyclic ester secured, we
envisioned the introduction of both the oxazolidinone
moiety and C(3)-nitrogen atom using a one-pot sequence
consisting of an intramolecular enoate aziridination and ring-
opening. Despite literature precedence[8] which indicated a
preference for the aziridine opening at the internal position to
afford the 1,3-oxazinan-2-one, we anticipated that the activa-
tion by the ester group would bias the system to yield the
desired oxazolidin-2-one.
The allylic alcohol 8 was readily converted to carbamate
11 upon reaction with trichloroacetyl isocyanate followed by
treatment with activated basic alumina.[9] A number of RhII
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8853

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set of conditions to give 16 with a small decrease in overall
yield.
ꢀ
Attempts to achieve cleavage of the C7 O bond by
treatment of the compounds 15, N-Bn-15, 16, or 17 with tBuLi
or Li-naphthalide led to intractable mixtures of products.
ꢀ
Interestingly, undesired C N bond cleavage was favored in
the reaction of 15 and 16 with Zn in AcOH. However,
[13]
treatment of endo-iodide 17 with 4 equivalents SmI2
in
THF at 08C and subsequent warming to ambient temperature
resulted in isolation of the desired alkene 19 in 82% yield. By
contrast, the corresponding exo-iodide 15 was found to be
unreactive under these reaction conditions. Thus, the combi-
nation of the fortuitous syn-iodoamination and the subse-
quent cleavage provides access to the core tricyclic ring
system.
Figure 1. Ortep representation of 20 (probability ellipsoids at 50%).
The completion of the synthesis required the regioselec-
tive hydration of the newly generated alkene in 19. Initially
hydroboration and epoxidation conditions were investigated.
However, the olefin proved to be unreactive with the standard
reagents (i.e. mCPBA, BH3·SMe2, 9-BBN). Application of the
Mn-catalyzed hydration initially developed by Mukaiyama
and Isayama[14] and studied by us[15] resulted in the formation
of the desired diol 20 as a single regio- and diastereoisomer in
75% yield (Scheme 6). It is important to note that the
presence of the axial hydroxy group in 19 was crucial for the
success of this reaction, as the acylated congener failed to
react.
substituted oxanorbornene; 2) a Rh-catalyzed aziridination
reaction; 3) an unusual syn-iodoamination which proved
ꢀ
critical for 4) a subsequent oxanorbornene C O cleavage;
and 5) a Mn-catalyzed olefin hydration, which permits
installation of the hydroxy group. The route we have
described is characterized by its efficiency (eight steps via
13 or ten steps via 14 starting from bromoacrolein 5) and sets
the stage for subsequent introduction of the glycosyl and
peptidyl side-chains that differentiate the members of the
aeruginosin family of natural products.
Received: July 26, 2008
Published online: October 15, 2008
Keywords: asymmetric synthesis · iodoamination ·
.
natural products · tandem catalysis · total synthesis
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6.7577(2), b = 21.6919(6), c = 8.4629(3) Š, V= 1237.93(7) Š3,
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subsequently
confirmed
by
X-ray
crystallography
(Figure 1).[16] Hydrogenolysis of the N-benzyl amine was
accomplished with Pd/C under standard conditions, complet-
ing the synthesis of the core of banyaside, suomilide, and
spumigin HKVV 21 in 98% yield. It is interesting to note that
the unprotected secondary amine 18 was also a substrate for
the olefin hydration reaction (59%), thus providing a route to
the core 21 without protecting groups.
1calcd = 1.562 Mgmꢀ3
, T= 298 K, reflections collected: 4803,
independent reflections 2812 (R(int) = 0.0660), R(all) = 0.0940,
wR(gt) = 0.1975.
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In conclusion the first synthesis of the unique azabicyclo-
nonane core found in the aeruginosin class of serine protease
inhibitors is described. The salient features of the route
include: 1) a tandem catalysis sequence to provide access to a
ꢀ
[8] For an excellent overview on Rh-catalyzed C H amination, see:
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Angewandte
Chemie
[9] The use of the more typical K2CO3/MeOH conditions resulted in
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of oxazolidinone products.
[10] C. G. Espino, K. W. Fiori, M. Kim, J. Du Bois, J. Am. Chem. Soc.
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separated by column chromatography.
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[12] When using NISas iodinating agent, complete removal of the
succinimide byproduct was difficult. This was circumvented
through the use of N-iodophthalimide. For preparation of this
reagent, see: L. Hadjiarapoglou, S. Spyroudis, A. Varvoglis,
Synthesis 1983, 207.
[13] G. A. Molander, P. R. Eastwood, J. Org. Chem. 1995, 60, 8382.
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[16] Crystallographic data for 18: C19H24N2O6, M = 376.41, ortho-
rhombic, space group P212121, a = 6.5399(2), b = 8.0975(3), c =
34.228(2) Š, V= 1812.59(12) Š3, 1calcd = 1.379 Mgmꢀ3
,
T=
203 K, reflections collected: 2553, independent reflections 2535
(R(int) = 0.0556), R(all) = 0.0689, wR(gt) = 0.1499.
CCDC 695727 (7a) and 695726 695727 (18) contain the supple-
mentary 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.
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