Total synthesis of scytophycin C. 2. Coupling reaction of the C(1)-C(18) segment and the C(19)-C(31) segment, a key macrolactonization, and the crucial terminal amidation reaction

Article abstract of DOI:10.1021/ol0352299

[Equation presented] Stereoselective syntheses of the C(1)-C(18) segment (segment A) and the C(19)-C(31) segment (segment B) are described in the preceding paper. This paper reports the key coupling reaction of both segments, 22-membered lactonization, an

Full text of DOI:10.1021/ol0352299

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3583-3586
Total Synthesis of Scytophycin C. 2.
Coupling Reaction of the C(1) C(18)
Segment and the C(19) C(31) Segment,
−
−
a Key Macrolactonization, and the
Crucial Terminal Amidation Reaction
Ryoichi Nakamura, Keiji Tanino, and Masaaki Miyashita*
Graduate School of Science, DiVision of Chemistry, Hokkaido UniVersity,
Sapporo 060-0810, Japan
miyasita@sci.hokudai.ac.jp
Received July 3, 2003
ABSTRACT
Stereoselective syntheses of the C(1)−C(18) segment (segment A) and the C(19)−C(31) segment (segment B) are described in the preceding
paper. This paper reports the key coupling reaction of both segments, 22-membered lactonization, and the crucial terminal amidation reaction
culminating in the total synthesis of scytophycin C.
Scytophycin C (1),1a isolated from the terrestrial blue-green
alga Scytonema pseudohofmanni,1 has been demonstrated to
exhibit potent activity against a variety of human carcinoma
cell lines including solid tumors.1b,c,2,3
From the significant antitumor activity of scytophycin C
(1) and its scarce availability from natural sources, its supply
by chemical synthesis has emerged as an urgent and
important subject.4-6 In the preceding paper,15 we described
the stereoselective syntheses of the C(1)-C(18) segment
(segment A) including a dihydropyran ring and the C(19)-
C(31) segment (segment B) having eight asymmetric centers
by the use of new acyclic stereocontrol. We report in this
paper the key coupling reaction of both segments, 22-
(1) (a) Ishibashi, M.; Moore, R. E.; Patterson, G. M. L.; Xu, C.; Clardy,
J. J. Org. Chem. 1986, 51, 5300. (b) Moore, R. E.; Patterson, G. M. L.;
Mynderse, J. S.; Barchi, J., Jr.; Norton, T. R.; Furusawa, E.; Furusawa, S.
Pure. Appl. Chem. 1986, 58, 263. (c) Moore, R. E.; Banarjee, S.;
Bornemann, V.; Caplan, F. R.; Chen, J. L.; Corley, D. E.; Larsen, L. K.;
Moore, B. S.; Patterson, G. M. L.; Paul, V. J.; Stewrat, J. B.; Williams, D.
E. Pure. Appl. Chem. 1989, 61, 521.
(2) (a) Moore, R. E. In Marine Natural Products-Chemical and Biological
PerspectiVes; Sheuer, P. J., Ed.; Academic Press: New York, 1981; Vol.
IV, p 1. (b) Carmeli, S.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod.
1990, 53, 1533. (c) Jung, J. H.; Moore, R. E.; Patterson, G. M. L.
Phytochemistry 1991, 30, 3615. (d) Carmeli, S.; Moore, R. E.; Patterson,
G. M. L.; Yoshida, W. Y. Tetrahedron Lett. 1993, 34, 5571.
(3) Valeriote, F. A.; Moore, R. E.; Patterson, G. M. L.; Paul, V. J.; Sheuer,
P. J.; Corbett, T. H. In Anticancer Drug DiscoVery and DeVelopment:
Natural Products and New Molecular Models; Valeriote, F. A., Corbett, T.
H., Baker, L. H., Eds.; Kluwer Academic Publishers: Norwell, 1994; pp
1-25.
(4) Paterson, I.; Watson, C.; Yeung, K.-S.; Wallace, P. A.; Ward, R. A.
J. Org. Chem. 1997, 62, 452.
(5) (a) Paterson, I.; Yeung, K.-S.; Watson, C.; Wallace, P. A.; Ward, R.
A. Tetrahedron 1998, 54, 11935. (b) Paterson, I.; Watson, C.; Yeung, K.-
S.; Ward, R. A.; Wallace, P. A. Tetrahedron 1998, 54, 11955.
(6) (a) Grieco, P. A.; Speake, J. D.; Yeo, S. K.; Miyashita, M.
Tetrahedron Lett. 1998, 39, 1125. (b) Grieco, P. A.; Speake, J. D.
Tetrahedron Lett. 1998, 39, 1275. (c) Roush, W. R.; Dilley, G. J.
Tetrahedron Lett. 1999, 40, 4955. (d) BouzBouz, S.; Cossy, J. Org. Lett.
2001, 3, 3995. (e) Hunt, K. W.; Grieco, P. A. Org. Lett. 2002, 4, 245. (f)
Yadav, J. S.; Ahmed, M. M. Tetrahedron Lett. 2002, 43, 7147.
10.1021/ol0352299 CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/09/2003

Scheme 1. Synthetic Strategy of Scytophycin C (1)
Scheme 2. Key Coupling Reaction of the Segments A and B and 22-Membered Lactonizationa
a Reagents and conditions: (a) LHMDS, TMSCl, Et3N, THF, -78 °C; (b) segment B, BF3‚Et2O, CH2Cl2, -78 °C, 82% in two steps; (c)
catecholborane, THF, -78 to -20 °C, 77%; (d) MeOTf, 2,6-di-tert-butylpyridine, rt, 99%; (e) NaBH4, MeOH, -20 to 0 °C; (f) FeCl3-
silica gel CHCl3, rt, 77% in two steps; (g) Ba(OH)2, MeOH, 40 °C, 93%; (h) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, toluene, rt,
86%; (i) Ti(OiPr)4, CH2Cl2, rt, 96%.
membered macrolactonization, and the crucial construction
of the terminal enamide moiety culminating in the total
synthesis of scytophycin C (1) (Scheme 1).
The key coupling reaction of the segments A and B was
performed by the aldol reaction of the silyl enol ether derived
from segment A and the aldehyde segment B by using
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Org. Lett., Vol. 5, No. 20, 2003

Scheme 3. Crucial Terminal Amidation Reaction and Completion of Total Synthesis of Scytophycin Ca
a Reagents and conditions: (a) TPAP, NMO, MS4A, CH2Cl2, rt; (b) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 58% in two steps; (c) TBAF,
AcOH, DMF, rt, 80%; (d) Dess-Martin periodinane, CH2Cl2, rt, 82%; (e) CrCl2, CHI3, THF, 0 °C, 69%; (f) trans-1,2-cyclohexanediamine,
CuI, K3PO4, N-methylformamide, 1,4-dioxane, 60 °C, 85%; (g) HF-pyridine, pyridine, THF, rt, 66%.
conditions similar to those of Paterson5 resulting in the
formation of an almost single aldol 2 in 82% yield (Scheme
2). Then, the aldol 2 was treated with catecholborane to give
the syn-diol exclusively,5 which was treated with methyl
trifluoromethanesulfonate to furnish the dimethyl ether 3
quantitatively. Subsequent reduction of the ketone moiety
at the C27 position with NaBH4 followed by removal of the
acetonide with FeCl3-silica gel produced the triol 4 in 77%
yield. The reduction of the C27 ketone was critical to obtain
the key seco-acid 5, since the following hydrolysis of the
ester with Ba(OH)2 without reducing the C27 ketone moiety
caused elimination of methanol to afford the C28-C29
unsaturated ketone. The stereochemistry of the newly
introduced hydroxyl group at the C27 position was not
determined at this stage.
Paterson,5 on treatment of the 24-congener 7 with titanium
tetraisopropoxide in CH2Cl2, a 3:2 equilibrium mixture of 6
and 7 was formed in 96% yield. By repeating this process
twice, the desired 22-membered macrolide 6 was obtained
in 75% combined yield.
Regioselective oxidation of the hydroxyl group at the C27
position with tetrapropylammonium perruthenate (TPAP) and
subsequent protection of the remaining C23 hydroxyl group
with TESOTf afforded the ketone 8 (Scheme 3). Upon
treatment of 8 with TBAF in AcOH and DMF,8 the terminal
tert-butyldiphenylsilyl protective group was selectively re-
moved giving rise to the lactol 9, which was subjected to
Dess-Martin oxidation9 to provide the crucial keto aldehyde
10 in 82% yield.
The remaining task for the synthesis of scytophycin C (1)
was the introduction of the terminal N-methyl-N-vinyl-
Upon treatment of 4 with Ba(OH)2 in MeOH, the key seco-
acid 5 was obtained in 93% yield. The crucial macrolacton-
ization of the seco-acid 5 was carried out by using the
Yamaguchi conditions7 resulting in the formation of a
mixture of the 22- and 24-membered macrolides, 6 and 7,
in 34% and 52% yields, respectively. As was reported by
(7) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(8) Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.; Shirahama,
H.; Nakata, M. Synlett 2000, 9, 1306.
(9) Dess, P. B.; Martin, J. C. J. Am. Chem. Soc. 1978, 100, 300.
Org. Lett., Vol. 5, No. 20, 2003
3585

formamide moiety. However, its assemblage was found to
be extremely difficult since application of various Wittig-
or Horner-Emmons-type reagents to 10 merely resulted in
elimination of methanol and none of the desired product was
obtained.10 After many attempts, eventually we were able
to overcome these difficulties by a two-step reaction process
involving the Takai reaction leading to vinyl iodide11
followed by Buchwald amidation reaction.12 Namely, treat-
ment of 10 with chromium(II) chloride and iodoform in THF
afforded the desired (E)-vinyl iodide 11 in 69% yield without
elimination of methanol which was then subjected to
Buchwald amidation conditions recently reported12 to give
rise to the long-awaited enamide compound 12 in 85% yield.
Finally, removal of the two silyl protective groups of 12 with
HF-pyridine yielded scytophycin C (1) in 66% isolated
developed assemblage of the N-methylenamide moiety by
the combination of a vinyliodide and the Buchwald amidation
reaction should provide a powerful means for the synthesis
of a variety of natural products having such functional
group(s). Application of these methodologies to natural
product synthesis is underway in our laboratory.
Acknowledgment. We are grateful to Professor Ian
Patterson (University Chemical Laboratory, Cambridge,
U.K.) for his invaluable suggestions and information. We
are also grateful to Professor Masami Ishibashi (Chiba
University) for useful information on purification of scyto-
phycin C. Financial support from the Ministry of Education,
Culture, Sports, Science and Technology, Japan (a Grant-
in-Aid for Scientific Research (A) (No. 12304042) and a
Grant-in-Aid for Scientific Research on Priority Areas (A)
“Exploitation of Multi-Element Cyclic Molecules” (No.
13029003)) is gratefully acknowledged. R.N. thanks JSPS
for a predoctoral fellowship.
1
yield. H and 13C spectral data of the synthetic compound
were identical with those of the synthetic compound elabo-
rated by Paterson.5
Thus, we have achieved the stereoselective total synthesis
of scytophycin C (1) by the use of new types of acyclic
stereocontrol.13,14 The overall yield of 1 was 1.1% for the
36 steps based on the longest segment B sequence. The newly
Supporting Information Available: Experimental details
and characterization data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) For recent synthesis of enamides, see: (a) Shen, R.; Porco, J. A.,
Jr. Org. Lett. 2000, 2, 1333. (b) Paterson, I.; Blakey, S. B.; Cowden, C. J.
Tetrahedron Lett. 2002, 43, 6005, and references therein.
(11) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
OL0352299
(12) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727.
(13) Sasaki, M.; Tanino, K.; Miyashita, M. J. Org. Chem. 2001, 66, 5388.
(14) Miyashita, M.; Hoshino, M.; Yoshikoshi, A. J. Org. Chem. 1991,
56, 6483.
(15) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett. 2003, 5, 3579.
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