Total synthesis of scytophycin C. 1. Stereoselective syntheses of the C(1)-C(18) segment and the C(19)-C(31) segment

Article abstract of DOI:10.1021/ol035227o

[Equation presented] Stereoselective total synthesis of scytophycin C, a marine 22-membered macrolide displaying potent activity against a variety of human carcinoma cell lines, has been reported in which the polypropionate structure bearing contiguous as

Full text of DOI:10.1021/ol035227o

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3579-3582
Total Synthesis of Scytophycin C. 1.
Stereoselective Syntheses of the
C(1)−C(18) Segment and the C(19)−C(31)
Segment
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 total synthesis of scytophycin C, a marine 22-membered macrolide displaying potent activity against a variety of human
carcinoma cell lines, has been reported in which the polypropionate structure bearing contiguous asymmetric centers was stereospecifically
constructed by using new acyclic stereocontrol. This paper describes stereoselective syntheses of the C(1)−C(18) segment (Segment A)
including a trans-disubstituted dihydropyran ring and the C(19)−C(31) segment (Segment B) having eight stereogenic centers.
The scytophycins, a novel series of polyoxygenated 22-
membered macrolides isolated from the terrestrial blue-green
alga Scytonema pseudohofmanni,1 have demonstrated potent
cytotoxicity against a variety of human carcinoma cell lines,
as well as broad-spectrum antifungal activity.1b,c,2 Among
them, scytophycin C (1) isolated by Moore et al. in 19861a
has been demonstrated to exhibit significant activity against
solid tumors in vitro.3 The potent biological properties of
scytophycin C, its scarce availability from natural sources,
and its close structural resemblance to the marine natural
product swinholide A have stimulated considerable interest
in its synthesis.4-10 So far, an elegant total synthesis of
scytophycin C has been achieved by Paterson by the
judicious use of stereoselective aldol reactions.4,5 We report
(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, MA, 1994;
pp 1-25.
(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 ProductssChemical 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.
(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.
(7) Roush, W. R.; Dilley, G. J. Tetrahedron Lett. 1999, 40, 4955.
(8) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 3995.
(9) Hunt, K. W.; Grieco, P. A. Org. Lett. 2002, 4, 245.
(10) Yadav, J. S.; Ahmed, M. M. Tetrahedron Lett. 2002, 43, 7147.
10.1021/ol035227o CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/09/2003

herein the stereoselective total synthesis of scytophycin C
(1) based on new acyclic stereocontrol. The structure of
scytophycin C is characterized by a 22-membered macrolide
containing a dihydropyran ring bearing two trans-substituted
side chains and a unique polypropionate-derived structure
having a terminal N-methyl-N-vinylformamide moiety in
which 15 asymmetric centers are included in total.
introduced at the final stage of the synthesis. At first, we
describe the stereoselective syntheses of both segments A
and B in this paper and then discuss the key coupling reaction
of both segments and macrolactonization culminating in the
total synthesis of scytophycin C (1) in the next paper.
Segment A containing the dihydropyran ring was ef-
ficiently and stereoselectively synthesized according to
Scheme 2, which involves novel acyclic stereocontrol with
Our retrosynthesis of scytophycin C (1) is shown in
Scheme 1. Namely, 1 was divided into the C(1)-C(18)
Scheme 2. Stereoselective Synthesis of Segment Aa
Scheme 1. Synthetic Strategy of Scytophycin C (1)
a Reagents and conditions: (a) allyltrimethylsilane, TMSOTf,
MeCN, 0 °C, 98%; (b) K2CO3, MeOH, rt; (c) TBSCl, imidazole,
DMF, 0 °C to rt, 76% yield for two steps; (d) MsCl, Et3N, Me3N-
HCl, toluene, 0 °C; (e) LiBEt3H, THF, 0 °C to rt; (f) TBAF, THF,
rt, 84% yield for three steps; (g) (PhO)3P+MeI-, DMF, rt, 89%;
(h) propargyl tetrahydropyranyl ether, nBuLi, HMPA, THF, -40
to 60 °C; (i) PPTS, MeOH, 60 °C, 77% yield for two steps; (j)
Red-Al, Et2O, 0 °C to rt, 94%; (k) Ti(OiPr)4, L-(+)-DET, TBHP,
4 Å MS, CH2Cl2, -25 °C; (l) (PhS)2, Bu3P, pyridine, 0 °C, 76%
yield for two steps; (m) Me3Al, CH2Cl2, -30 °C; (n) NaH, MeI,
DMF, 50 °C, 91% yield for two steps; (o) NaIO4, aq MeOH, 0 °C
to rt, 90%; (p) TFAA, 2,6-lutidine, HgCl2, aq MeCN, 0 °C to rt;
(q) MeLi, CeCl3, THF, -78 °C; (r) DMSO, (COCl)2, CH2Cl2, -78
°C, then Et3N, 69% yield for three steps; (s) OsO4, NMO, aq
acetone, rt; (t) NaIO4, aq MeOH, 0 °C to rt, 67% yield for two
steps; (u) 2-methyl-1-trimethylsilyloxy-1,3-butadiene, BF3-Et2O,
Et2O-CH2Cl2, -78 °C, 85% (7R/7â ) 2:7); (v) trimethyl phos-
phonoacetate, nBuLi, THF, 0 °C, 92%; (w) TBSOTf, 2,6-lutidine,
CH2Cl2, -78 °C, 83%.
segment (Segment A) and the C(19)-C(31) segment (Seg-
ment B), and both segments were designed to connect by
an aldol reaction at the C18 and C19 positions under Felkin-
Anh control similarly to the synthesis by Paterson.4,5 Segment
A, including a dihydropyran ring bearing trans-substituted
side chains, would be assembled from commercially available
tri-O-acetyl-D-glucal. On the other hand, segment B contain-
ing eight asymmetric centers was further divided into the
C(19)-C(26) acetylenic segment (Segment B1) and the
C(27)-C(31) aldehyde segment (Segment B2) by discon-
necting the C(26)-C(27) bond. Due to the acid instability
of scytophycin C,1 the acid-labile N-methyl-N-vinyl-
formamide moiety at the terminus was designed to be
double inversion of the configuration as the key step. Thus,
allylation of tri-O-acetyl-D-glucal (2) with allyltrimethylsilane
and TMSOTf11 followed by removal of the acetyl groups
3580
Org. Lett., Vol. 5, No. 20, 2003

with K2CO3 and subsequent protection of the primary alcohol
with TBSCl gave the alcohol 4 in 74% overall yield. The
product was then converted to 5 in three steps: (1)
mesylation by the Tanabe protocol;12 (2) reduction with super
hydride; and (3) removal of the TBS group with TBAF, in
84% yield. Conversion of the resulting alcohol 5 to the iodide
6 and subsequent coupling reaction with alkynyllithium
followed by removal of the THP group with PPTS13 afforded
7, which in turn was reduced with Red-Al to give the (E)-
allylic alcohol 8 in high yield. Upon treatment of 8 under
the asymmetric epoxidation conditions,14 the desired â-epoxy
alcohol was obtained, which was subjected to sulfenylation
with diphenyl disulfide15 to furnish the â-epoxy sulfide 9 in
76% overall yield. The subsequent methylation reaction of
9 with double inversion of the configuration, a crucial step
in the present synthesis, was successfully performed by using
the methodology recently developed by Saigo16 and us.17
Namely, on treatment of 9 with trimethylaluminum, the
methylation occurred stereospecifically via an episulfonium
ion, giving rise to the syn compound 10 as a single product
in 91% yield. After O-methylation of the hydroxyl group in
10, the sulfide was oxidized to the corresponding sulfoxide
11, which was submitted to the Pummerer reaction,18
resulting in the formation of the aldehyde 12. The aldehyde
12 was routinely transformed into the methyl ketone 13 by
methylation followed by oxidation in 69% overall yield from
11.
Scheme 3. Stereoselective Synthesis of Segment B1a
a Reagents and conditions: (a) DMSO, (COCl)2, CH2Cl2, -78
°C, then Et3N; (b) di-o-tolyl ethoxycarbonyl-methyl phosphate,
NaH, THF, -78 °C, 91% yield for two steps; (c) DIBAH, THF, 0
°C; (d) m-CPBA, CH2Cl2, 0 °C, 74% yield for two steps; (e) DMSO,
(COCl)2, CH2Cl2, -78 °C, then Et3N; (f) triethyl phosphono-
acetate, NaH, THF, 0 °C, 89% yield for two steps; (g) (CH3)3Al
(10 equiv), CH2Cl2, -30 °C, then H2O (6 equiv), -30 °C, 2 h,
92%; (h) TESCl, DMAP, imidazole, CH2Cl2, rt; (i) DIBAH, THF,
0 °C, 85% yield for two steps; (j) m-CPBA, CH2Cl2, 0 °C, 97%;
(k) Me2CuLi, ether, -40 to 0 °C; (l) t-BuCOCl, pyridine, CH2Cl2
0 °C to rt; (m) 2,2-dimethoxypropane, CSA, DMF, 94% yield for
three steps; (n) DIBAH, CH2Cl2, -78 °C; (o) DMSO, (COCl)2,
CH2Cl2, -78 °C, then Et3N; (p) Ph3P, CBr4, pyridine, CH2Cl2, 0
°C, 84% yield for three steps.
Regioselective osmylation of the terminal vinyl group in
13 and subsequent oxidation with periodate produced the
aldehyde 14, which was subjected to the Mukaiyama aldol
reaction with 2-methyl-1-trimethylsilyloxy-1,3-butadiene in
the presence of BF3-etherate4 to give a 7:2 mixture of
epimeric alcohols in 85% combined yield. After separation
of the mixture by silica gel chromatography, the major
product was readily converted to segment A (17) by the
Horner-Wadsworth-Emmons reaction with trimethyl phos-
phonoacetate followed by protection of the hydroxyl group
with TBSOTf in high overall yield. 1H and 13C NMR spectra
of the segment A were identical with those of the synthetic
compound elaborated by Paterson et al. by a different
synthetic strategy.5 The overall yield of segment A was 6.5%
for the 23 steps.
reaction with Ando’s reagent19 to afford the (Z)-unsaturated
ester 19 in 91% yield. After reduction of the ester 19 with
DIBAH, the resulting (Z)-allylic alcohol was oxidized with
mCPBA to give the single R-epoxy alcohol 20 in 74% yield,20
which was again subjected to Swern oxidation followed by
the Horner-Wadsworth-Emmons reaction with triethyl
phosphonoacetate to furnish the γ,δ-epoxy unsaturated ester
21 in high yield. A key methylation reaction of 21 was
performed by using our original (CH3)3Al-H2O system21,22
wherein the methylation occurred stereospecifically at the
γ-position with inversion of the configuration, giving rise
to the syn compound 22 as the sole product in 92% yield.
The product was readily converted to the allylic alcohol 23
by protection of the hydroxyl group with TESCl followed
by reduction with DIBAH. Upon treatment of 23 with
mCPBA, the single â-epoxy alcohol 24 was obtained nearly
quantitatively. As we have already reported, epoxidation of
On the other hand, segment B1 containing five contiguous
chiral centers was stereoselectively synthesized according
to Scheme 3.
Namely, (R)-3-benzyloxy-2-methylpropanol (18) was sub-
jected to Swern oxidation followed by the Horner-Emmons
(11) Nakata, T.; Komatsu, T.; Nagasawa, K.; Oishi, T. The 34th
Symposium on the Chemistry of Natural Products, Tokyo, Japan, October,
1992; Symposium paper, p 174.
(12) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y.
Tetrahedron 1999, 55, 2183.
(13) Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977,
42, 3772.
(14) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(15) Nakagawa, I.; Hata, T. J. Chem. Soc., Perkin Trans. 1 1983, 1315.
(16) Liu, C.; Hashimoto, Y.; Kudo, K.; Saigo, K. Bull. Chem. Soc. Jpn.
1996, 69, 2095.
(17) Sasaki, M.; Tanino, K.; Miyashita, M. J. Org. Chem. 2001, 66, 5388.
(18) (a) Pummerer, R. Ber. 1910, 43, 1401. (b) De Lucchi, O.; Miotti,
U.; Modena, G. Org. React. 1991, 40, 157.
(19) (a) Ando, K. J. Org. Chem. 1997, 62, 1934. (b) Ando, K. J. Org.
Chem. 1999, 64, 6815.
(20) (a) Johnson, M. R.; Nakata, T.; Kishi, Y. Tetrahedron Lett. 1979,
4343. (b) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
(21) Miyashita, M.; Hoshino, M.; Yoshikoshi, A. J. Org. Chem. 1991,
56, 6483.
(22) Miyashita, M.; Shiratani, T.; Kawamine, K.; Hatakeyama, S.; Irie,
H. Chem. Commun. 1996, 1027.
Org. Lett., Vol. 5, No. 20, 2003
3581

five consecutive stereogenic centers was highly stereo-
selectively synthesized, actually without formation of any
stereoisomers. The overall yield of segment B1 was 36%
for the 18 steps.
Scheme 4. Stereoselective Synthesis of Segment Ba
Segment B2 having three contiguous chiral centers was
also constructed by a similar reaction sequence involving
an epoxide-opening reaction of 30 with dimethylcupurate20
and subsequent manipulations (Scheme 4) in 32% overall
yield for the 11 steps. The key coupling reaction of segment
B1, which was generated quantatively from the dibromo-
methylene 28, with segment B2 occurred cleanly and
efficiently at -30 °C, giving rise to the desired adduct 33
in 87% isolated yield. The product was then converted to
segment B by a three-step reaction sequence: (1) hydrogena-
tion of the triple bond, (2) removal of the benzyl group with
LDBB,24 and (3) Swern oxidation. Thus, segment B having
eight stereogenic centers was synthesized in a highly
stereoselective manner. The overall yield of segment B was
21% for the 22 steps based on the longest linear sequence.
Thus, we have established the highly stereoselective
synthesis of segments A and B required for the synthesis of
scytophycin C (1). We will discuss the key coupling reaction
of both segments, subsequent macrolactonization, and the
crucial construction of the terminus N-methyl-N-vinyl-
formamide moiety culminating in the total synthesis of
scytophycin C (1), which will be described a following paper.
a Reagents and conditions: (a) Ti(OiPr)4, L-(+)-DET, TBHP, 4
Å MS, CH2Cl2, -25 °C, 78%; (b) Me2CuLi, ether, -45 °C, 85%;
(c) TBDPSCl, imidazole, DMAP, CH2Cl2, rt; (d) NaH, MeI, TBAI,
THF, 60 °C; (e) AlCl3, m-xylene, CH2Cl2, -40 to -20 °C, 88%
yield for three steps; (f) DMSO, (COCl)2, CH2Cl2, -78 °C, then
Et3N, 85%; (g) 28, nBuLi, THF, -10 to 0 °C, 87%; (h) Pt/Al2O3,
H2, 5 atm, AcOEt, 76%; (i) LDBB, THF, -45 °C, 90%; (j) DMSO,
(COCl)2, CH2Cl2, -78 °C, then Et3N, 97%.
Acknowledgment. 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. We are grateful to the Kaneka
Corporation for providing us with methyl (S)-3-hydroxy-2-
methylpropionate.
such a 5-silyloxyallyl alcohol system with mCPBA exclu-
sively occurs from the opposite side of the bulky TES group,
regardless of the stereochemistry of an adjacent methyl
group.23 On treatment of the epoxy alcohol 24 with dimethyl-
cupurate, the 1,3-diol 25 having five contiguous chiral centers
was obtained quantitatively. Then, 25 was transformed into
the acetonide 26 in two steps: (1) protection of the primary
alcohol as a pivalate and (2) acetonide formation in 94%
overall yield from 24. After removal of the pivaloyl group
in 26 with DIBAH, the resulting primary alcohol was
transformed into dibromoolefin 28 through aldehyde 27 in
84% yield. Thus, the precursor of segment B1 containing
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.
OL035227O
(23) Maruyama, K.; Ueda, M.; Sasaki, S.; Iwata, Y.; Miyazawa, M.;
Miyashita, M. Tetrahedron Lett. 1998, 39, 4517.
(24) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924.
(b) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854.
3582
Org. Lett., Vol. 5, No. 20, 2003