Towards the total synthesis of FD-838: Modular enantioselective assembly of the core

Article abstract of DOI:10.1039/b716445a

A rapid assembly of the tetracyclic core of FD-838, featuring a catalytic asymmetric Stetter reaction, is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b716445a

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Towards the total synthesis of FD-838: modular enantioselective
assembly of the core{
Arturo Orellana{ and Tomislav Rovis*
Received (in Cambridge, UK) 25th October 2007, Accepted 22nd November 2007
First published as an Advance Article on the web 4th December 2007
DOI: 10.1039/b716445a
A rapid assembly of the tetracyclic core of FD-838, featuring a
catalytic asymmetric Stetter reaction, is described.
The antibiotic FD-8381a (Fig. 1) belongs to a family of natural
products that share a densely functionalized spirofuranone-lactam
core. Minor structural modifications of the substituents around
Scheme 1 General synthesis plan for FD-838 and the spirofuranone-
this core result in markedly different biological activity profiles.
For example, azaspirene1b is a potent anti-angiogenic agent,
synerazol1c is an antifungal antibiotic, and cephalimysin A1d is
cytotoxic towards p388 and HL-60 cells. Not surprisingly, these
natural products have attracted attention from the synthetic
community in recent years.2
lactam family of natural products.
1,3-propanediol under basic conditions generates the expected
alcohol.5 A number of oxidation methods were screened, and
although aldehyde 3 could be observed in crude reaction mixtures,
attempts to isolate it resulted in its decomposition. We speculate
that this material decomposes via a b-elimination process, releasing
an oxymaleimide leaving group. Gratifyingly, Dess–Martin
oxidation, followed by a careful work-up and purification
procedure, provides aldehyde 3 in good yield. The analogous
PMB-protected maleimide 4 can also be prepared using this
protocol.
Intrigued by the densely functionalized spirocyclic core of these
natural products and by their diverse biological activities, we
initiated a synthesis program with FD-838 as our primary target.
Central to our synthesis plan was the rapid construction of the
spirobicyclic core common to all these natural products using the
catalytic asymmetric Stetter reaction3 recently developed in our
laboratory (Scheme 1).4 This functionalized core would serve as a
platform for a modular synthesis of FD-838 and should also prove
useful in the synthesis of other congeners of this family.
With access to aldehydes 3 and 4, we evaluated the key catalytic
asymmetric Stetter reaction under a variety of conditions. We were
delighted to find that the use of aminoindanol derived precatalyst
A under the optimized conditions6 resulted in formation of the
desired product in excellent yield and enantiomeric excess
(Scheme 3).
To test the viability of the proposed Stetter reaction, we
undertook the synthesis of an aldehyde bearing an N-benzyl
substituted maleimide (Scheme 2). Dibromination and elimination
provides the bromomaleimide, and addition–elimination of
Conversion of spirocyclic compound 5 into a Michael acceptor
is achieved using a two-step process. Generation of the triethylsilyl
enol ether 7 proceeds efficiently under soft enolization conditions.
Oxidation of 7 to furanone 8 is achieved through a hydride
abstraction using the trityl cation in the presence of a hindered
base.7
Fig. 1 Selected spirofuranone-lactam natural products.
Department of Chemistry, Colorado State University, Fort Collins, CO,
USA. E-mail: rovis@lamar.colostate.edu; Fax: +1 970-491-1801;
Tel: +1 970-491-7208
{ Electronic supplementary information (ESI) available: Experimental
details and characterization of 2, 3, 5, 7, 8, 9 and 10. See DOI: 10.1039/
b716445a
{ Current address: Department of Chemistry, York University, 4700
Keele Street, Toronto, ON, Canada M3J 1P3. E-mail: aorellan@yorku.ca;
Fax: +1 416-736-5936; Tel: +1 416-736-5246 x 70760
Scheme 2 Synthesis of substrates for the Stetter reaction.
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730 | Chem. Commun., 2008, 730–732

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Scheme 5 Barbier-type alkylation of tricycle 9.
report on the synthesis of FD-838 and other congeners of this
family in due course.
Financial support has been provided by the National Institute
of General Medical Sciences (GM72586). We thank Eli Lilly and
Boehringer-Ingelheim for unrestricted support, and Donald
Gauthier (Merck Research Laboratories) for a generous gift of
aminoindanol. T. R. is a fellow of the Alfred P. Sloan Foundation
and thanks the Monfort Family Foundation for a Monfort
Professorship.
Scheme 3 Key catalytic asymmetric Stetter reaction.
Next our attention turned to the installation of the pendant
furan ring. This is carried out by treating furanone 8 with a strong
Lewis acid in the presence of methylfuran.8 This reaction is
thought to proceed via formation of a resonance-stabilized
oxocarbenium ion which is trapped by furan, followed by
rearomatization. Notably, this reaction fails completely in DCM
and nitromethane, which leads us to speculate that the
oxocarbenium ion formed is stabilized by reversible addition of
acetonitrile to form the corresponding nitrilium ion9 until trapping
by furan can occur. The stereochemistry of the trapping event may
be rationalized by considering model B, Scheme 4. The bottom
face of the oxocarbenium ion is shielded by the proximal carbonyl
on the succinimide ring while the top face has the methylene.10
With tricyclic compound 9 as a platform, we have begun to
explore end-game strategies for the synthesis of FD-838. The
Barbier-type alkylation of succinimides reported by Farcas and
Namy seemed well-suited for this task.11 Indeed, treatment of
compound 9 with samarium diiodide in the presence of benzyl
bromide provides hemiaminal 10 in 33% unoptimized yield as a
single regioisomer (Scheme 5).12 The illustrated stereochemistry is
likely inconsequential since the hemiaminal may undergo facile
ring-opening.
Notes and references
1 (a) K. Mizoue, T. Okazaki, K. Hanada, T. Amamoto, M. Yamagashi
and S. Omura, Eur. Pat. Appl. EP 216607, J. P. Appl. 205278, 1987;
Chem. Abstr., 1987, 107, 132627x; (b) Y. Asami, H. Kakeya, R. Onose,
A. Yoshida, H. Matsuzaki and H. Osada, Org. Lett., 2002, 4, 2845; (c)
O. Ando, H. Satake, M. Nakajina, A. Sato, T. Nakamura, T. Kinoshita,
K. Furuya and T. Haneishi, J. Antibiot., 1991, 44, 382; (d) T. Yamada,
E. Imai, K. Nakatuji, A. Numata and R. Tanaka, Tetrahedron Lett.,
2007, 48, 6294.
2 Reported syntheses: (a) Y. Hayashi, M. Shoji, J. Yamaguchi, K. Sato,
S. Yamaguchi, T. Mukaiyama, K. Sakai, Y. Asami, H. Kakeya and
H. Osada, J. Am. Chem. Soc., 2002, 124, 12078; (b) Y. Hayashi,
M. Shoji, S. Yamaguchi, T. Mukaiyama, J. Yamaguchi, H. Kakeya and
H. Osada, Org. Lett., 2003, 5, 2287; (c) S. Aoki, T. Oi, K. Shimizu,
R. Shiraki, K. Takao and K. Tadano, Heterocycles, 2004, 62, 161; (d)
S. Aoki, T. Oi, K. Shimizu, R. Shiraki, K. Takao and K. Tadano, Bull.
Chem. Soc. Jpn., 2004, 77, 1703; (e) Y. Hayashi, M. Shoji,
T. Mukaiyama, H. Gotoh, S. Yamaguchi, M. Nakata, H. Kakeya
and H. Osada, J. Org. Chem., 2005, 70, 5643. Synthetic Studies: (f) Z. Su
and C. Tamm, Tetrahedron, 1995, 51, 11177; (g) J. M. Mitchell and
N. S. Finney, Org. Biomol. Chem., 2005, 3, 4274. Biosynthetic studies:
(h) Y. Igarashi, Y. Yabuta, A. Sekine, K. Fujii, K. Harada, T. Oikawa,
M. Sato, T. Furumai and T. Oki, J. Antibiot., 2004, 57, 748.
In conclusion, we have constructed the spirobicyclic core of FD-
838 using a high yielding and highly enantioselective catalytic
Stetter reaction. In addition, we have developed a protocol for the
installation of the furan ring and alkylation of the succinimide
ring. We continue to study these advanced intermediates and will
3 (a) H. Stetter and H. Kuhlmann, Organic Reactions, ed. L. A. Paquette,
Wiley, New York, 1991, vol. 40, p. 407; (b) H. Stetter and H. Kuhlmann,
Chem. Ber., 1976, 109, 2890; (c) H. Stetter, Angew. Chem., Int. Ed. Engl.,
1976, 15, 639.
4 (a) M. S. Kerr, J. Read de Alaniz and T. Rovis, J. Am. Chem. Soc.,
2002, 124, 10298; (b) M. S. Kerr and T. Rovis, Synlett, 2003, 1934; (c)
M. S. Kerr and T. Rovis, J. Am. Chem. Soc., 2004, 126, 8876; (d) J. Read
de Alaniz and T. Rovis, J. Am. Chem. Soc., 2005, 127, 6284; (e)
N. T. Reynolds and T. Rovis, Tetrahedron, 2005, 61, 6368; (f) Q. Liu
and T. Rovis, J. Am. Chem. Soc., 2006, 128, 2552; (g) J. L. Moore,
M. S. Kerr and T. Rovis, Tetrahedron, 2006, 62, 11477; (h) Q. Liu and
T. Rovis, Org. Process Res. Dev., 2007, 11, 598.
5 M. J. Sahoo, S. B. Mhaske and N. P. Argade, Synthesis, 2003, 346.
6 Larger scale reactions proceed with lower catalyst loading.
Representative experimental procedure for the catalytic asymmetric
Stetter reaction: to a cooled (0 uC) suspension of triazolium carbene
precatalyst A (10 mol%, 73 mg, 0.16 mmol) in toluene (12 mL) under Ar
is added via a cannula a freshly prepared, cooled (0 uC) solution of
KHMDS (10 mol%, 32 mg in toluene). After this mixture has been
stirred for 10 minutes, a cooled (0 uC) solution of aldehyde 3 (409 mg,
1.58 mmol) in toluene (12 mL) is added via a cannula. Consumption of
the aldehyde is monitored by TLC and once the reaction is deemed
complete the mixture is filtered through a pad of silica gel to remove the
solids. The filtrate is concentrated and the crude product purified by
flash column chromatography (1 : 1 EtOAc : Hex) to give spirocycle 5
(279 mg, 1.07 mmol, 68% yield) as a pale yellow solid. 1H NMR
(CDCl3, 400 MHz): d 2.61–2.72 (ddd, 1 H, J = 8.5, 8.5, 18.5 Hz), 2.70–
2.75 (d, 1 H, J = 18.1 Hz), 2.76–2.84 (ddd, 1 H, J = 18.5, 7.9, 4.5 Hz),
Scheme 4 Synthesis of tricycle 9.
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2.91–2.96 (d, 1 H, J = 18.1 Hz), 4.37–4.44 (ddd, 1 H, J = 9.0, 8.5,
4.5 Hz), 4.62–4.69 (ddd, 1 H, J = 7.9, 8.5, 9.0 Hz), 4.66 (s, 2 H), 7.25–
7.31 (m, 5 H). 13C NMR (CDCl3, 100 MHz) d 35.7, 38.2, 42.9, 66.1,
82.3, 128.3, 128.6, 129.0, 135.0, 172.8, 174.0, 210.2. HRMS: [M + H]+
calculated: 260.0917, found: 260.0915.
7 (a) M. E. Jung, Y.-G. Pan, M. W. Rathke, D. F. Sullivan and
R. P. Woodbury, J. Org. Chem., 1977, 42, 3961; (b) I. Fleming and
I. Paterson, Synthesis, 1979, 736.
747; (c) A. Marra, J. Esnault, A. Veyrieres and P. Sinay¨, J. Am. Chem.
Soc., 1992, 114, 6354.
10 Stereochemistry was assigned on the basis of extensive NOE
experiments on an analogue bearing a vinyl group in place of
the furan. Further support for this assignment was provided by a
partially solved crystal structure of compound 10 (a fully
solved structure proved unattainable presumably due to crystal
twinning).
8 M. A. Grundl, A. Kaster, E. D. Beaulieu and D. Trauner, Org. Lett.,
2006, 8, 5429.
11 S. Farcas and J.-L. Namy, Tetrahedron Lett., 2001, 42,
879.
9 (a) J.-R. Pougny and P. Sinay¨, Tetrahedron Lett., 1976, 17, 4073; (b)
A. J. Ratcliffe and B. Fraser-Reid, J. Chem. Soc., Perkin Trans. 1, 1990,
12 Observed by-products invariably involved dihydrofuran ring opening. In
no case did we observe formation of regioisomers.
732 | Chem. Commun., 2008, 730–732
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