Total synthesis of isoroquefortine E and phenylahistin

Article abstract of DOI:10.1016/j.tetlet.2009.09.074

Isoroquefortine E and phenylahistin were synthesized using the Horner-Wadsworth-Emmons reaction as the key step to build the dehydroamino acid moiety. The syntheses provided the materials for the biological studies of the roquefortine-phenylahistin molecu

Full text of DOI:10.1016/j.tetlet.2009.09.074

Tetrahedron Letters 50 (2009) 6755–6757
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of isoroquefortine E and phenylahistin
*
Ning Shangguan, Madeleine M. Joullié
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Isoroquefortine E and phenylahistin were synthesized using the Horner–Wadsworth–Emmons reaction
as the key step to build the dehydroamino acid moiety. The syntheses provided the materials for the bio-
logical studies of the roquefortine–phenylahistin molecules.
Received 1 September 2009
Accepted 14 September 2009
Available online 25 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Roquefortine E
Phenylahistin
Dehydroamino acid
Horner–Wadsworth–Emmons reaction
Roquefortine E (1), a natural product isolated from an Austra-
lian strain of Gymnoascus reessii Baranetzki, by Capon and co-work-
ers in 2005, is the first roquefortine to be isolated from a fungus
other than Penicillium.1 It combines the main structural features
of two classes of natural products: the cyclized isoprenylated tryp-
tophan of the roquefortine C (2) and the isoprenylated dehydrohis-
Capon reported that roquefortine E should have the E configura-
tion by comparing the 1H and 13C NMR data of roquefortine E to
that of roquefortine C and isoroquefortine C. However, the authors
failed to convert roquefortine E to isoroquefortine E by the treat-
ment with UV light, under the conditions used for the conversion
of roquefortine C to isoroquefortine C. A synthesis of roquefortine
E and isoroquefortine E should confirm the E/Z configuration of
roquefortine E and also provide enough material for further biolog-
ical studies. Therefore, we began the syntheses of both 1 and 3. The
synthesis of aldehyde 9 started from the conversion of amino acid
(ꢀ)-serine (4) to TBS-protected methyl ester 5. Following Baran’s
protocol, a controlled prenyl magnesium chloride addition, thio-
urea 7 formation, oxidation–elimination, and TBS deprotection
converted 6 to imidazole 8.5 Aldehyde 9 was obtained by the oxi-
dation of alcohol 8 with manganese dioxide (Scheme 1).
tidine of the phenylahistin (3).2,3 Both roquefortine
C and
phenylahistin were reported to have potent biological activities;
phenylahistin showed strong binding affinity toward microtubules
and potent growth inhibition of various cancer cell lines.3b Roque-
fortine E (1), however, only showed weak cytotoxic activity to
mammalian cells.1 The structure and biological activity relation-
ship among these compounds is still unknown. Phenylahistin has
a Z dehydroamino acid moiety, while roquefortine C contains an
E structure. Isoroquefortine C, the Z isomer of roquefortine C, does
not show any significant biological activity. Roquefortine C (2) and
phenylahistin (3) have already been synthesized but no total syn-
thesis of roquefortine E (1) has been reported yet4 (Fig. 1).
Due to the instabilities of Boc, mesyl, and tosyl-protecting
groups on the free nitrogen of imidazole 9, we chose ortho-nitro-
benzyl (ONB) as the protecting group.6 After LDA treatment of
Figure 1. Roquefortine E, roquefortine C and phenylahistin.
* Corresponding author. Tel.: +1 215 898 3158; fax: +1 215 573 9711.
E-mail address: mjoullie@sas.upenn.edu (M.M. Joullié).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.074

6756
N. Shangguan, M. M. Joullié / Tetrahedron Letters 50 (2009) 6755–6757
Scheme 1. Synthesis of aldehyde 9.
Scheme 2. Synthesis of amine 15.
Scheme 3. The elimination approach.
Scheme 4. Synthesis of phenylahistin and isoroquefortine E.

N. Shangguan, M. M. Joullié / Tetrahedron Letters 50 (2009) 6755–6757
6757
Boc-protected glycine methyl ester, the resulting enolate was
Supplementary data
added to aldehyde 12 to afford a mixture of diastereomeric aldol
addition products (14). Zinc chloride addition was necessary to
make the polar dianion enolate of 13 soluble in THF. Subsequent
zinc bromide treatment removed the Boc group to afford amine
157 (Scheme 2).
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.074.
References and notes
Acid 168 was coupled with amine 15 under standard conditions
to form compound 17, the precursor for the elimination reaction.
Unfortunately, all efforts to dehydrate compound 17 were unsuc-
cessful (Scheme 3).
1. Clark, B.; Capon, R. J.; Lacey, E.; Tennant, S.; Gill, J. H. J. Nat. Prod. 2005, 68, 1661.
2. Ohmomo, S.; Sato, T.; Utagawa, T.; Abe, M. Agric. Biol. Chem. 1975, 39, 1333.
3. (a) Kanoh, K.; Kohno, S.; Asari, T.; Harada, T.; Katada, J.; Muramatsu, M.;
Kawashima, H.; Sekiya, H.; Uno, I. Bioorg. Med. Chem. Lett. 1997, 7, 2847; (b)
Kanoh, K.; Kohno, S.; Katada, J.; Takahashi, J.; Uno, I. J. Antibiot. 1999, 52, 134.
4. (a) Shangguan, N.; Hehre, W. J.; Ohlinger, W. S.; Beavers, M. P.; Joullié, M. M. J.
Am. Chem. Soc. 2008, 130, 6281; (b) Hayashi, Y.; Orikasa, S.; Tanaka, K.; Kanoh,
K.; Kiso, Y. J. Org. Chem. 2000, 65, 8402; (c) Couladouros, E. A.; Magos, A. D. Mol.
Diversity 2005, 9, 99.
5. Baran, P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem., Int. Ed. 2005, 44, 3714.
6. Schiavi, B. M.; Richard, D. J.; Joullié, M. M. J. Org. Chem. 2002, 67, 620.
7. Nigam, S. C.; Mann, A.; Taddei, M.; Wermuth, C. G. Synth. Commun. 1989, 19,
3139.
The Horner–Wadsworth–Emmons (HWE) reaction is an estab-
lished method to construct the carbon–carbon double bond of
the dehydroamino acid moiety.9 The known phosphonate 194c
was coupled with aldehyde 9 to give compound 20, which was
deprotected and cyclized to give (ꢀ)-phenylahistin. Aldehyde 12
and other protected imidazoyl aldehydes failed to give good yields
in this HWE reaction. Phosphonate 216 was coupled with aldehyde
9 under standard HWE conditions to give product 22. Subsequent
treatment with TMSI and triethyl amine afforded isoroquefortine
E (23) as the final product10 (Scheme 4).
In conclusion, a concise total synthesis of isoroquefortine E and
phenylahistin was completed and will allow the structure–activity
relationship of roquefortines and phenylahistin to be investigated.
The synthesis and evaluation of the biological activities of the
analogs of roquefortines and phenylahistin will be reported in
due course.
8. Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953.
9. Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.; Mangold, R.;
Meyer, R.; Riedl, B. Synthesis 1992, 487.
10. Selected data. Compound 22: 1H NMR (CDCl3): d 11.19 (1H, br), 8.02 (1H, s), 7.54
(1H, s), 7.39 (1H, d, J = 7.9 Hz), 7.26 (1H, t, J = 7.4 Hz), 7.21 (1H, d, J = 7.5 Hz),
7.10 (1H, d, J = 7.5 Hz), 6.92 (1H, s), 6.19 (1H, s), 6.13 (1H, dd, J = 17.5, 10.6 Hz),
5.87 (1H, dd, J = 17.4, 10.8 Hz), 5.09 (4H, m), 3.80 (3H, s), 1.54 (9H, s), 1.50 (9H,
s), 1.48 (3H, s), 1.45 (3H, s), 1.06 (3H, s), 0.98 (3H, s); 13C NMR (CDCl3): d 171.5,
165.8, 155.3, 154.0, 152.4, 147.4, 142.9, 142.8, 137.0, 133.8, 128.6, 125.6, 124.9,
123.7, 120.2, 118.8, 115.2, 114.6, 110.9, 82.7, 81.8, 79.1, 61.9, 61.8, 52.4, 40.4,
39.5, 28.6, 28.5, 28.4, 27.9, 22.9, 22.3; HRMS (ESI) m/z calcd for C20H23N4O2
(M+H)+: 690.3796, found (M+H)+: 690.3867; IR (cmꢀ1): 3282 (w, br), 2978 (m),
1716 (s), 1480 (m), 1368 (m), 1164 (m), 734 (w); ½a D22
ꢁ
+49 (c 0.65, CHCl3).
Isoroquefortine E (23): 1H NMR (CDCl3): d 11.85 (1H, br), 9.18 (1H, br), 7.51 (1H,
s), 7.16 (1H, J = 7.5 Hz), 7.08 (1H, t, J = 7.6 Hz), 6.93 (1H, s), 6.74 (1H, t,
J = 7.5 Hz), 6.57 (1H, d, J = 7.7 Hz), 6.02 (1H, dd, J = 17.5, 10.5 Hz), 5.99 (1H, dd,
J = 17.4, 10.8 Hz), 5.65 (1H, s), 5.21 (1H, dd, J = 10.5, 0.7 Hz), 5.17 (1H, dd,
J = 17.4, 0.6 Hz), 5.12 (1H, dd, J = 10.8, 1.1 Hz), 5.09 (1H, dd, J = 17.4, 1.1 Hz),
4.94 (1H, s), 4.10 (1H, dd, J = 11.5, 5.8 Hz), 2.60 (1H, dd, J = 12.3, 5.8 Hz), 2.47
(1H, dd, J = 11.6, 12.0 Hz), 1.50 (6H, s), 1.14 (3H, s), 1.03 (3H, s); 13C NMR
(CDCl3): d 165.5, 158.7, 150.4, 144.6, 143.6, 136.6, 132.4, 132.3, 128.9, 128.9,
125.6, 125.2, 118.8, 114.4, 113.3, 108.9, 105.4, 78.1, 61.6, 59.1, 40.9, 37.5, 37.2,
28.0, 27.9, 23.0, 22.5; HRMS (ESI) m/z calcd for C27H32N5O2 (M+H)+: 458.2485,
found (M+H)+: 458.2556; IR (cmꢀ1): 3234 (w, br), 2971 (m), 1661 (s), 1436 (s),
Acknowledgments
We thank NIH (CA-40081) and NSF (0515443) for financial sup-
port. Financial support for the departmental instrumentation was
provided by the National Institutes of Health (IS10RR23444-1).
We thank Dr. George T. Furst and Dr. Rakesh Kohli of the University
of Pennsylvania Spectroscopic Service Center for assistance in
securing and interpreting high-field NMR spectra and mass spec-
tra, respectively.
1215 (m), 918 (w), 733 (w); ½a D24
ꢀ233 (c 0.50, CHCl3).
ꢁ