Synthesis of microcin SF608 through nucleophilic opening of an oxabicyclo[2.2.1]heptane

Article abstract of DOI:10.1021/ol1017189

The total synthesis of Microcin SF608 is reported. Access to the octahydroindole core structure of Microcin SF608 relies on the TMSOTf/NEt ₃-mediated opening of an oxabicyclic ring system. Additional highlights of the synthetic strategy that is reported include a highly regioselective epoxide reduction and photolytic excision of a 3° alcohol.

Full text of DOI:10.1021/ol1017189

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3950-3953
Synthesis of Microcin SF608 through
Nucleophilic Opening of an
Oxabicyclo[2.2.1]heptane
Stefan Diethelm, Corinna S. Schindler, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH-Ho¨nggerberg,
HCI, H335, CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received July 23, 2010
ABSTRACT
The total synthesis of Microcin SF608 is reported. Access to the octahydroindole core structure of Microcin SF608 relies on the TMSOTf/
NEt3-mediated opening of an oxabicyclic ring system. Additional highlights of the synthetic strategy that is reported include a highly regioselective
epoxide reduction and photolytic excision of a 3° alcohol.
Microcin SF608 (1)1,2 is a member of the Aeruginosin family
of serine protease inhibitors. On the basis of their core
structure, these biologically active natural products are
differentiated into two distinct subclasses: the Aeruginosin
and Dysinosin members, including Microcin SF608 (1) with
a carboxy hydroxyoctahydroindole (Choi) core,3 and those
that share an azabicyclononane (Abn) core. Microcin SF608
was first isolated from the cyanobacterium Microcystis sp.
in 1999 and was shown to selectively inhibit the serine
protease trypsin over chymotrypsin (IC50 0.5 and >20 µg
mL-1, respectively).1
semble the Choi core common to the Aeruginosin members
of this family of serine protease inhibitors.
As outlined in Scheme 1, the total synthesis of Microcin
SF608 relies on a key TMSOTf-mediated nucleophilic
opening of oxabicyclic diol 2. Systems such as 2 were
previously found to undergo rapid TMSOTf-mediated open-
ing of the oxabicyclic framework by attack of an internal
nucleophile and thereby give access to highly functionalized
hydroindole structures.4 Substrate 2 was to be obtained by
regioselective hydroxylation and amination of the oxabicyclo-
[2.2.1]heptene building block 3, the synthesis for which had
been previously documented in the enantioselective synthesis
of the azabicyclononane core of the Abn subclass of the
Aeruginosin protease inhibitors.5 The successful implementa-
tion of the versatile and easily accessible intermediate 3 in
the synthesis of Microcin SF608 would allow the preparation
Herein we report the total synthesis of Microcin SF608
relying on the TMSOTf-mediated nucleophilic opening of
an oxabicyclo[2.2.1]heptane building block to rapidly as-
(1) Banker, R.; Carmeli, S. Tetrahedron 1999, 55, 10835
.
(2) For a previous synthesis of 1, see: Valls, N.; Vallribera, M.; Lope´z-
(4) Schindler, C. S.; Diethelm, S.; Carreira, E. M. Angew. Chem., Int.
Ed. 2009, 48, 6296.
Canet, M.; Bonjoch, J. J. Org. Chem. 2002, 67, 4945
.
(3) For a recent review covering Aeruginosin serine protease inhibitors,
(5) Schindler, C. S.; Stephenson, C. R. J.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2008, 47, 8852.
see: Del Valle, J. R.; Hanessian, S. Angew. Chem., Int. Ed. 2008, 47, 1202.
10.1021/ol1017189  2010 American Chemical Society
Published on Web 08/12/2010

promoted lactonization. The introduction of the amine at C-2
of the Choi core was effected by azidation of lactone 4.6
The corresponding enolate of 4 was generated by slow
addition of the substrate to a dilute (0.02 M) solution of
LiHMDS in CH2Cl2 at -78 °C, and it was allowed to react
at -50 °C with a number of different sulfonyl azides (e.g.,
PhSO2N3, p-NO2-C6H4SO2N3, PhCH2SO2N3, camphor sul-
fonyl azide, and 2,4,6-triisopropylbenzenesulfonyl azide).
Among these, trisyl azide 5 proved superior and led to the
formation of desired azidolactone 6 in 58% yield as a
mixture of diastereomers (1.2:1 6/C-2-epi-6 as determined
Scheme 1. Retrosynthetic Strategy
1
by H NMR spectroscopic analysis), favoring the desired
stereoisomer at C-2. These could be separated by chro-
matography on silica gel. The configuration of 6 was
confirmed by X-ray crystallographic analysis of derivative
7,7 formed by treatment of lactone 6 with 1-phenethyl
amine as shown in Figure 1.
of both polycyclic core structures, the Choi as well as the
Abn core, found in the Aeruginosin family of natural
products.
The synthesis of an appropriate precursor that would
enable the installation of the C-6 hydroxyl group found in
the Choi core commences with the diastereoselective epoxi-
dation of 3 employing m-CPBA in CH2Cl2 to form the
desired epoxide in 93% yield (Scheme 2). The intermediate
epoxide was further converted into lactone 4 in 78% overall
yield upon enoate reduction with H2/Pd followed by K2CO3-
Figure 1. ORTEP representation of the X-ray crystal structure of
derivative 7.
Scheme 2
The azidolactone in 6 was opened smoothly in 94% yield
upon treatment with O-TBDPS-protected 4-aminobutanol,
which serves as a synthetic precursor for the agmatine side
chain of the natural product. The azide was reduced under
hydrogenolytic conditions and the resulting amine protected
in 88% yield as the corresponding Cbz-carbamate 8 upon
treatment with CbzCl.
Key to the installation of the C-6 hydroxy group of the
Choi core common to the Aeruginosin family of natural
products is the regioselective reduction of the epoxide moiety
in 8. We decided to investigate the use of low-valent Ti
reagents, relying on the hypothesis that regioselectivity might
be observed because of the pendant side chain at C-3a in
proximity to C-7, the desired site of attack. In this respect,
titanocene(III)chloride (Cp2TiCl) was investigated as reagent
in the presence of 1,4-cyclohexadiene8 in THF, according
(6) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am.
Chem. Soc. 1990, 112, 4011.
(7) CCDC 785240 contains the supplementary crystallographic data for
compound 7. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(8) Water can be used instead of 1,4-cyclohexadiene, affording the
product in slightly lower yield.
(9) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116,
986.
Org. Lett., Vol. 12, No. 17, 2010
3951

to a procedure reported by RajanBabu and Nugent.9 Under
these conditions, 8 afforded the desired alcohol 9 selectively
with only trace amounts (<5%) of the corresponding regio-
isomer being formed.10
achieve removal of the 3° alcohol at C-3a (natural product
numbering system). The standard, known methods that
have been documented to effect deoxygenation of tertiary
alcohols (Et3SiH/TFA or BF3·Et2O, Barton-McCombie,
SmI2, NaBH3CN/ZnI2) proved unsuccessful on this sub-
strate. However, the hydroxyl group could be easily
excised employing a mild photocleavage protocol reported
by Saito and co-workers.14 Functionalization of the tertiary
alcohol as a m-CF3-substituted benzoate proceeded in 91%
yield to afford 10, which was immediately subjected to
UV irradiation in the presence of N-methylcarbazole and
1,4-cyclohexadiene to yield the desired product 11 in 68%
yield. It is especially noteworthy that 3° alcohols had been
previously found to be poor substrates under these sets
of conditions, as a consequence of the formation of
products arising from disproportionation.14
Recently, a computational study based on density func-
tional methods by Daasbjerg, Gansa¨uer, and Grimme de-
scribes the structure of ClCp2Ti·oxirane complexes.11 The
investigators suggest that the reactions of the complexed
epoxides proceed through early transition states with the spin
density mostly located on the Ti center. Although N-H’s
are typically not hydrogen donors in free-radical reactions,
the recent work by Wood, Renaud, and Newcomb12 has
underscored the ability of alcohols as well as water to serve
as donors when complexed to Lewis acids. It has also been
noted that proton donors, such as water, can serve as
reductants in the presence of Ti(III).13 Prior to the results
we describe above, however, carbamates had not been shown
to serve as hydrogen donors. We hypothesize that the
surprising selectivity in the reductive opening of the epoxide
arises from H-transfer at the C-7 carbon center by the N-H
of the neighboring carbamate coordinated to titanium as
shown in Scheme 3.
With a route to oxabicycle 11 secured, attention was
focused on the key step, involving TMSOTf-mediated
nucleophilic opening, to assemble the highly functionalized
carboxy octahydroindole core of Microcin SF608 (Schemes
4 and 5). Preceeding studies had revealed that oxabicyclic
Scheme 4. Cyclization Modes of the TMSOTf/NEt3-Mediated
Nucleophilic Opening of Oxabicyclo[2.2.1]heptenes
Scheme 3. Proposed Mechanism of Epoxide Reduction
With a route to the selective formation of diol 9 secured,
attention was focused on protocols to effectively deoxygenate
the C-3a OH in 9. The secondary alcohol in 9 was selectively
converted into the corresponding acetate in 99% yield
(Scheme 2), and several procedures were evaluated to
systems can undergo TMSOTf-mediated nucleophilic open-
ing in either of two modes (A versus B in Scheme 4) to
give rise to perhydroquinoline (mode A) or perhydroindole
(mode B) products, respectively. Depending on the position
of the amine or amide functional group in the side chain of
the oxabicyclic substrate, the reaction can be tuned to form
either product selectively. In the case of two competing
amide substituents for 5- vs 6-ring formation, an intrinsic
preference of these systems to form the corresponding
(10) 9 was obtained as a 3:1 mixture of diastereomers at C-2.
(11) (a) Gansa¨uer, A.; Lauterbach, T.; Narayan, S. Angew. Chem., Int.
Ed. 2003, 42, 5556. (b) Daasbjerg, K.; Svith, H.; Grimme, S.; Gerenkamp,
M.; Mu¨ck-Lichtenfeld, C.; Gansa¨uer, A.; Barchuk, A.; Keller, F. Angew.
Chem., Int. Ed. 2006, 45, 2041. (c) Gansa¨uer, A.; Barchuk, A.; Keller, F.;
Schmitt, M.; Grimme, S.; Gerenkamp, M.; Mu¨ck-Lichtenfeld, C.; Daasbjerg,
K.; Svith, H. J. Am. Chem. Soc. 2007, 129, 1359.
(12) (a) Spiegel, D. A.; Wiber, K. B.; Schacherer, L. N.; Medeiros, M. R.;
Wood, J. L. J. Am. Chem. Soc. 2005, 127, 12513. (b) Pozzi, D.; Scanlan,
E. M.; Renaud, P. J. Am. Chem. Soc. 2005, 127, 14204. (c) Jin, J.; Newcomb,
M. J. Org. Chem. 2007, 72, 5098.
(13) Cuerva, J. M.; Campan˜a, A. G.; Justicia, J.; Rosales, A.; Oller-
Lo´pez, J. L.; Robles, R.; Ca´rdenas, D. J.; Bun˜uel, E.; Oltra, J. E. Angew.
Chem., Int. Ed. 2006, 45, 5522.
(14) Saito, I.; Ikehira, H.; Kasatani, R.; Watanabe, M.; Matsuura, T.
J. Am. Chem. Soc. 1986, 108, 3115.
3952
Org. Lett., Vol. 12, No. 17, 2010

and Hu¨nig’s base) to afford peptide 13 in 77% yield.16
Deoxygenation of the 2° alcohol at C-5 was achieved relying
on the previously described photochemical conditions to give
rise to 14.
Scheme 5
To complete the total synthesis of Microcin SF608,
protected 1° alcohol 14 was transformed into the desired
guanidine. Removal of the silyl group using TASF afforded
the corresponding free 1° alcohol. Subsequent conversion
of the alcohol into the corresponding mesylate proceeded
smoothly and was immediately followed by standard nu-
cleophilic substitution with NaN3 and acetate deprotection
to yield the desired azide 15 in 57% yield over 4 steps. The
final installation of the guanidine subunit relied on reduction
of the azide using Staudinger conditions followed by reaction
with di-Cbz-trifluoromethanesulfonyl guanidine 16 to yield
the desired di-N-Cbz protected guanidine in 85%.17 Final
overall hydrogenolytic deprotection afforded the natural
product Microcin SF608 1 in 87% yield. The spectroscopic
data of the synthetic material (1H and 13C NMR, MS, optical
rotation) matched that which has been previously docu-
mented.1,2
In conclusion, we have demonstrated the utility of a
TMSOTf-mediated nucleophilic opening of oxabicyclic ring
systems for the total synthesis of Microcin SF608. Thus,
treatment of 11 with TMSOTf/NEt3 produces the core
structure of the natural product and establishes that an amine
can effectively compete with an amide in the ring-opening
event. Additional salient features of the route include: a
highly regioselective Ti(III)-mediated epoxide reduction to
install the C-6 hydroxyl group and smooth photocleavage
of a 3° alcohol. Starting with allylic alcohol 3 as a common,
versatile, and easily accessible oxabicyclic building block,
it is now possible to synthetically access both polycyclic Choi
and Abn core structures of the Aeruginosin family of natural
products.
hydroquinolines was observed (cyclization mode A in
Scheme 4). However, the case of a competing amine- vs
amide-substituent had not yet been examined in our earlier
work. Nevertheless, a free 1° amine at C-2 was expected to
override the system’s inherent preference to form perhyd-
roquinoline derivatives as a consequence of the enhanced
nucleophilicity of the 1° amine compared to the correspond-
ing C-1 amide.
Acknowledgment. This work was supported by a grant
from the Swiss National Science Foundation (NF5/2-
7723408) and partial support through the ETH. S.D. thanks
Novartis for a masters fellowship and for a predoctoral
fellowship. 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 deriva-
tive 7.
Generation of the amine from 11 by hydrogenolytic
cleavage of the N-Cbz group and subsequent exposure to
the reaction conditions established for the nucleophilic
opening of oxabicyclic systems (TMSOTf/NEt3) resulted in
formation of the desired octahydroindole core, obtained as
the corresponding bis(trimethylsilyl)ether in 81% yield
(Scheme 5). Removal of the TMS groups proceeded smoothly
using H2SiF6/NEt3 to afford the desired product in 81%
yield.15 The resulting hindered 2° amine was then coupled
to acid 12 using standard peptide coupling protocols (HATU
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL1017189
(16) 13 was obtained as a 2:1 mixture of diastereomers at C-2′.
(17) (a) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J. Org.
Chem. 1998, 63, 3804. (b) Feichtinger, K.; Sings, H. L.; Baker, T. J.;
Matthews, K.; Goodman, M. J. Org. Chem. 1998, 63, 8432.
(15) Newton, R. F.; Kelly, D. R.; Roberts, S. M. Tetrahedron Lett. 1979,
41, 3981.
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