A concise asymmetric total synthesis of (+)-brevisamide

Article abstract of DOI:10.1021/ol201283n

A new protecting-group-free synthesis of the marine monocyclic ether (+)-brevisamide is reported. The enantioselective synthesis utilizes a key asymmetric Henry reaction and an Achmatowicz rearrangement for the formation of the tetrahydropyran ring. A pen

Full text of DOI:10.1021/ol201283n

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3636–3639
A Concise Asymmetric Total Synthesis of
(þ)-Brevisamide
Aaron T. Herrmann, Steven R. Martinez, and Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara,
Santa Barbara, California 93106, United States
zakarian@chem.ucsb.edu
Received May 12, 2011
ABSTRACT
A new protecting-group-free synthesis of the marine monocyclic ether (þ)-brevisamide is reported. The enantioselective synthesis utilizes a key
asymmetric Henry reaction and an Achmatowicz rearrangement for the formation of the tetrahydropyran ring. A penultimate Stille cross-coupling
allows for an efficient installation of the conjugated (E,E)-diene side chain ultimately delivering (þ)-brevisamide.
The art and science of natural producttotal synthesis has
become increasingly more associated with the various
priniciples of the “economies” of synthesis.1,2 Evaluation
of protecting group use serves as one metric of synthetic
efficiency and can provide a framework for developing a
synthesis plan. Among various classes of natural products
prepared by total synthesis without the use of protecting
groups, examples featuring polyketides or cyclic ethers
are scarce.2,3 Herein, we report a concise, enantioselective,
protecting-group-free total synthesis of the diversely func-
tionalized cyclic ether natural product brevisamide.
Brevisamide is a metabolite from Karenia brevis com-
prised of a complex functionalized tetrahydropyran core
containing a conjugated 3,4-dimethylhepta-2,4-dienal and
acetylated terminal amine subunits. The tetrahydropyran
ring also contains methyl and hydroxyl substituents. Bre-
visamide has been a target of total synthesis for multiple
research groups since its recent isolation by Wright and co-
workers.4 By completion of the first total synthesis, the
groups of Satake, Tachibana, and Wright provided conclu-
sive evidence for the absolute and relative stereochemistry
of brevisamide.5 Their synthesis is characterized by a step-
wise construction of the pyran ring followed by a Suzukiꢀ
Miyaura coupling to assemble the dienal fragment. This
synthesis required 21 steps in the longest linear sequence,
28 steps total, with an overall yield of 2.0%. In a subse-
quent paper, Satakeand co-workersimproved their overall
synthetic yield to 8.6%.5c Lindsley and co-workers com-
pleted the second total synthesis using a different route
in which the tetrahydropyran ring was formed by a
reductive cyclization with samarium(II) iodide.6 A Hor-
nerꢀWadsworthꢀEmmons reaction was recruited to in-
stall the diene fragment. This synthesis was accomplished
in 18 steps (longest linear sequence, 21 total) and 6.3%
overall yield. Shortly after Lindsley’s synthesis, Ghosh and
co-workers described an alternative route using an asym-
metric hetero-DielsꢀAlder reaction to form the tetrahy-
dropyran ring of brevisamide. This synthesis provided bre-
visamide in higher enantiopurity than the prior two and
required 23 steps total with the longest linear sequence of
19 steps and a ca. 1.5% overall yield from commercially
available starting materials.7 The last reported total synth-
esis of brevisamide is described by Panek and Lee. A [4 þ 2]
(1) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc.
Chem. Res. 2008, 41, 40–49.
(2) Hoffmann, R. W. Synthesis 2006, 21, 3531–3541.
(3) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193–205.
(4) Satake, M; Bourdelais, A. J.; Van Wagoner, R. M.; Baden, D. G.;
Wright, J. L. C. Org. Lett. 2008, 10, 3465–3468.
(5) (a) Kuranaga, T.; Shirai, T.; Baden, D. G.; Wright, J. L. C.;
Satake, M.; Tachibana, K. Org. Lett. 2009, 11, 217–220. (b) Van
Wagoner, R. M.; Satake, M.; Bourdelais, A. J.; Baden, D. G.; Wright,
J. L. C. J. Nat. Prod. 2010, 73, 1177–1179. (c) Tsutsumi, R.; Kuranaga,
T.; Wright, J. L. C.; Baden, D. G.; Ito, E.; Satake, M.; Tachibana, K.
Tetrahedron 2010, 66, 6775–6782. (d) Shirai, T.; Kuranaga, T.; Wright,
J. L. C.; Baden, D. G.; Satake, M.; Tachibana, K. Tetrahedron Lett.
2010, 51, 1394–1396.
(6) Fadeyi, O. O.; Lindsley, C. W. Org. Lett. 2009, 11, 3950–3952.
(7) Ghosh, A. K.; Li, J. Org. Lett. 2009, 11, 4164–4167.
r
10.1021/ol201283n
Published on Web 06/16/2011
2011 American Chemical Society

annulation approach utilizing a (Z)-crotylsilane was used
as a strategic basis for the synthesis. This route provided
brevisamide in a 0.8% overall yield in 30 total steps, with
the longest linear sequence of 27 steps from commercially
available starting materials.8 Since this latest completed
total synthesis, two formal syntheses have been accom-
plished by the groups of Smith and Sabitha.9
Scheme 2. Synthesis of Aldehyde 5
In devising our own approach, we became intrigued
by the challenge of developing a concise, enantioselective,
and protecting-group-free construction of the diversely
functionalized tetrahydropyran ring in brevisamide. A
synthesis plan based on the combination of a catalytic
asymmetric Henry reaction and an Achmatowicz re-
arrangement,10 outlined in Scheme 1, proved to be success-
ful in meeting this challenge. The final operation in the
synthesis was envisioned to employ a Stille-cross-coupling
reaction to install the conjugated (E,E)-dieneal.
procedure developed by Wan and co-workers.13 This
method has been reported to provide products in high
enantioselectivity, under practical reaction conditions at
room temperature and within reasonable reaction times.
The method employs a catalytic system derived from read-
ily available Cu(OAc)2 H2O and ligand 9 in ethanol as the
3
solvent. Much to our delight, when 5 was exposed to these
conditions, the product 4 was isolated with a 99% ee. Ex-
tended reaction timesresultedinaccumulation of thenitro-
alkene 4a as a byproduct resulting from dehydration of
the initially formed nitro-alcohol 4 (Scheme 3). To mini-
mizethis problem, the reaction was terminatedafter 40 h at
room temperature and the products were separated to
provide the requisite Henry addition product 4 (57% yield,
99% ee), the starting material (33% yield), and the ni-
troalkene 4a (10% yield). The starting material was then
resubmitted to the reaction conditions to afford 4 in a 69%
combined yield and 99% ee after one recycle.
Scheme 1. Synthesis Plan for Brevisamide (1)
Scheme 3. Asymmetric Henry Reaction
The synthesis of the aldehyde 5, shown in Scheme 2,
begins from commercially available ethyl 3-(furan-2-yl)-
propionate 6, which was treated with LiAlH4 to afford the
corresponding primary alcohol. After oxidation, the resul-
tant aldehyde was immediately submitted to the Cor-
eyꢀFuchs reaction yielding dibromoalkene 7,11 which
was treated with n-butyllithium and iodomethane to form
the desired alkyne 8, along with a furan methylation
byproduct. Addition of DMPU prior to the addition of
iodomethane resulted in the isolation of only the desired
methylated alkyne 8 in high yield. Aldehyde 5 was pre-
pared directly from 8 by a VilsmeierꢀHaack reaction in
90% yield.12
After the development of the enantioselective Henry reac-
tion, the synthesis was advanced as illustrated in Scheme 4.
The nitro group in 4 was reduced to the corresponding
amine with LiAlH4 under carefully controlled reaction
conditions. Lithium aluminum hydride was preferred to
other commonly used reagents for reduction of nitro com-
poundssuchasH2 and Pd/C, Raney-Nickel, and SmI2, due
to incompatibility of these reagents with the alkyne group
present in the substrate.13,14 After assessment of a variety
of reaction conditions, it was determined that a drop-
wise addition of a solution of the nitro compound 4 into
a precooled solution of LiAlH4 in THF (ꢀ15 °C) limited
the retro-Henry process leading to the formation of an
With aldehyde 5 in hand, the key enantioselective Henry
reaction was investigated. Although a variety of methods
are available for this transformation, we focused on a
(8) Lee, J.; Panek, J. S. Org. Lett. 2009, 11, 4390–4393.
(9) (a) Smith, A. B., III; Kutsumura, N.; Potuzak, J. Tetrahedron
Lett. 2011, 52, 2117–2119. (b) Sabitha, G.; Nayak, S.; Bhikshapathi, M.;
Yadav, J. S. Org. Lett. 2011, 13, 382–385.
(10) Achmatowicz, O.; Bukowski, P.; Szechner, B.; Zwierzchowska,
Z.; Zamojski, A. Tetrahedron 1971, 27, 1973–1996.
(11) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769–3772.
(12) Vilsmeier, A.; Haack, A. Ber. 1927, 60, 119–122.
(13) (a) Jin, W.; Li, X.; Huang, Y.; Wu, F.; Wan, B. Chem.;Eur. J.
2010, 16, 8259–8261. (b) Smith, M. B.; March, J. March’s Advanced
Organic Chemistry, 6th ed.; John Wiley & Sons: Hoboken, NJ, 2007;
pp 1815ꢀ1823.
(14) Kende, A. S.; Mendoza, J. S. Tetrahedron Lett. 1991, 32, 1699–
1702.
Org. Lett., Vol. 13, No. 14, 2011
3637

undesired primary alcohol. The reaction was then heated
to reflux, which delivered the primary amine in opti-
mized yields. The primary amine was then chemoselec-
tively acetylated with acetic anhydride in ethyl acetateꢀ
methanol (4:1), giving amide 10 in 67% yield over the two
steps.
Similar outcomes were observed with the samarium-based
reagent. Reduction with sodium borohydride under stan-
dard conditions in methanol produced the undesired axial
alcohol exclusively. On the other hand, reduction with
NaBH4 in aqueous THF substantially increased the frac-
tion of the desired equatorial alcohol, giving a 1:1 mixture
of separable products in 85% isolated yield.17 The under-
sired isomer could be separated and recycled through an
additional oxidationꢀreduction sequence.
Scheme 4. Synthesis of the Tetrahydropyran Core
Installation of vinyl iodide proceeded in high regioselec-
tivity and yield employing the silylcupration-iododesylila-
tion protocol.18,19 Silylcupration took place with complete
stereoselectivity and high regioselectivity (∼13:1). Subse-
quent iododesilyation with N-iodosuccinimide (NIS) in
hexafluoroisopropanol (HFIP) successfully delivered the
(E)-iodoalkene 3 in high yield and with complete retention
of the double bond geometry.18,20
Scheme 5. Completetion of Brevisamide (1) Synthesis
According to our synthesis plan, acetamide 10 was now
properly functionalized for the ensuing key Achmatowicz
rearrangement. Furan 10 underwent oxidative ring expan-
sion in the presence of NBS to form the cyclic hemiketal,
which was then treated with BF3 OEt2 and Et3SiH to pro-
3
duce intermediate 11 in a satisfactory 54% yield.15 Instal-
lation of the methyl group was achieved by conjugate
addition of lithium dimethylcuprate directly to enone 11
(81% yield, 8:1 dr).16
Known vinyltin reagent 2 (prepared by hydrostannyla-
tion of 2-butyn-1-ol)21 was used in a Stille cross-coupling
reaction with 3 to forge the conjugated diene (Scheme 5).
Sasaki and co-workers previously reported a similar Stille
Our next goalwas reduction of12under thermodynamic
conditions to generate the more stable diastereomer 13
that has the desired configuration at the newly generated
stereocenter. Our initial attempts centered on various ver-
sions of the MeerweinꢀPondorfꢀVerley (MPV) reaction
using Al(OPr-i)3 and Sm(OPr-i)3 reagents. With the alu-
minum-based reagent, the desired diastereomer 13 was
formed exclusively at high temepratures (100 °C), however,
at low yields. An unidentified byproduct was formed in
significant quantitites apparently resulting from reactivity
of the acetamide. At lower temperatures (75 °C), an equi-
molar mixture of diastereomeric alcohols was produced.
(17) Oguchi, T.; Watanabe, K.; Ohkubo, K.; Abe, H.; Katoh, T.
Chem.;Eur. J. 2009, 15, 2826–2845.
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Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003, 125,
7822–7824. (e) Cha, J. Y.; Burnett, G. L., IV; Huang, Y.; Davidson, J. B.;
Pettus, T. R. R. J. Org. Chem. 2011, 76, 1361–1371. (f) Parker, K. A.;
Denton, R. W. Tetrahedron Lett. 2011, 52, 2115–2116. (g) Xie, Q.;
Denton, R.; Parker, K. A. Org. Lett. 2008, 10, 5345–5348. For a
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(19) (a) Fleming, I.; Roessler, F. J. Chem. Soc., Chem. Commun.
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Tetrahedron Lett. 1985, 38, 4629–4632. (e) Archibald, S. C.; Barden,
D. J.; Bazin, J. F. Y.; Fleming, I.; Foster, C. F.; Mandal, A. K.; Mandal,
A. K.; Parker, D.; Takaki, K.; Ware, A. C.; Williams, A. R. B.; Zwicky,
A. B. Org. Biomol. Chem. 2004, 2, 1051–1064.
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Org. Lett., Vol. 13, No. 14, 2011

coupling in the total synthesis of brevenal.20 In our work,
copper(I) thiophene-2-carboxylate was replaced with the
copper(I) bromide dimethylsulfide complex (CuBr•DMS)
without any detrimental effect on the Pd2(dba)3/Ph3As-
catalyzed cross-coupling process, furnishing 14 in 78%
yield. Completion of the synthesis was achieved with a
chemoselective oxidation of the allylic alcohol using TEM-
PO in the presence of PhI(OAc)2 in CH2Cl2 at room
temperature, yielding (þ)-brevisamide (1) in 90% yield.7
In summary, the total synthesis of (þ)-brevisamide
(1) has been completed in 16 steps (longest linear sequence)
and an overall yield of 2.5% starting from the commercially
availableethyl3-(furan-2-yl)propionate6. Thestrategywas
developed based on a notion of concise enantioselective
assembly of the properly functionalized tetrahydropyran
ring without the use of protecting groups. A catalytic
asymmetric Henry reaction and then an Achmatowicz
rearrangement were enlisted to successfully achieve this
goal.
Acknowledgment. This work was supported by Eli
Lilly, Amgen, and the National Institutes of Health,
National Institute of General Medical Sciences (R01
GM077379). We thank Nicholas D. C. Tappin (EPFL,
Lausanne, Switzerland) and Craig Stivala (UC Santa
Barbara) for performing preliminary experiments.
Dr. Hongjun Zhou (UC Santa Barbara) is thanked for
continued assistance with NMR spectroscopy.
Supporting Information Available. General experimen-
1
tal procedures, characterization data, and copies of H
and 13C NMR spectra for compounds 1ꢀ14. This materi-
al is available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 14, 2011
3639