Total Synthesis of Squamotacin

Article abstract of DOI:10.1021/jo990599p

The first total synthesis of (+)-squamotacin, 1, which has shown cytotoxic selectivity for the human prostate tumor cell line, was achieved in 27 steps and 0.83% yield starting with (+)-muricatacin, 4. All asymmetric centers in the bistetrahydrofuran fragment of the molecules were produced by the Sharpless asymmetric dihydroxylation (AD) and the asymmetric epoxidation (AE) reactions.

Full text of DOI:10.1021/jo990599p

J . Org. Chem. 1999, 64, 7067-7073
7067
Tota l Syn th esis of Squ a m ota cin
Santosh C. Sinha,†,‡ Subhash C. Sinha,*,† and Ehud Keinan*,†,‡,§
Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La J olla, California 92037, and Department of Chemistry,
Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel
Received April 6, 1999
The first total synthesis of (+)-squamotacin, 1, which has shown cytotoxic selectivity for the human
prostate tumor cell line, was achieved in 27 steps and 0.83% yield starting with (+)-muricatacin,
4. All asymmetric centers in the bistetrahydrofuran fragment of the molecules were produced by
the Sharpless asymmetric dihydroxylation (AD) and the asymmetric epoxidation (AE) reactions.
In tr od u ction
toward the γ-lactone ring. While in 1 this unit spans
carbons 13-22, in 2 it spans carbons 15-24. We focused
on the total synthesis of 1 not only for confirming the
proposed structure and absolute configuration of this
biologically important compound, but mainly because the
limited amounts of 1 that could be extracted from the
natural source were too small to allow systematic phar-
macological studies.5 Furthermore, we used this op-
portunity to expand the general synthetic strategies for
the construction of chemical libraries of Annonaceous
acetogenins.6-8
We have recently reported on the total synthesis of 2
using a convergent synthetic approach,6b where the
Sharpless asymmetric dihydroxylation (AD)9 reaction
coupled with chirality transfer methods were employed
to introduce all asymmetric centers in the bis-THF
fragment of the target molecule. Here we report on the
A dominant structural feature that appears in more
than 40% of the Annonaceous acetogenins,1 particularly
in those showing the highest cytotoxic, antitumor, anti-
malarial, immunosuppressive, pesticidal, and antifeedant
activities, is a ten-carbon fragment containing two ad-
jacent tetrahydrofuran rings flanked by two hydroxyl
groups. Studies on the primary mode of action have
established that such acetogenins are the most powerful
of the known inhibitors of complex I (NADH-ubiquinone
oxidoreductase) in mammalian and insect mitochondrial
electron transport systems.2 In addition, they are potent
inhibitors of NADH oxidase that is specifically active in
the plasma membranes of the tumor and is inactive in
normal cells.3 These activities decrease ATP production
and thereby lead to apoptosis (programmed cell death).4
Two remarkably potent members of this subgroup are
squamotacin, 1, and bullatacin, 2 (Figure 1).
(6) (a) Sinha, S. C.; Keinan, E. J . Am. Chem. Soc. 1993, 115, 4891.
(b) Sinha, S. C.; Sinha-Bagchi, A.; Yazbak, A.; Keinan, E. Tetrahedron
Lett. 1995, 36, 9257. (c) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J .
Am. Chem. Soc. 1995, 117, 1447. (d) Sinha, S. C.; Sinha, A.; Yazbak,
A.; Keinan, E. J . Org. Chem. 1996, 61, 7640. (e) Sinha, S. C.; Sinha,
A.; Sinha, S. C.; Keinan, E. J . Am. Chem. Soc. 1997, 119, 12014. (f)
Sinha, S. C.; Sinha, S. C.; Keinan, E. J . Am. Chem. Soc. 1998, 120,
4017. (g) Yazbak, A.; Sinha, S. C.; Keinan, E. J . Org. Chem. 1998, 63,
5863. (h) Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha, S. C.; Sinha,
S. C.; Keinan, E. J . Am. Chem. Soc. 1998, 120, 11279. (i) Sinha, A.;
Sinha, S. C.; Sinha, S. C.; Keinan, E. J . Org. Chem. 1999, 64, 2381.
(7) For review articles, see: (a) Figade´re, B. Acc. Chem. Res. 1995,
28, 359. (b) Koert, U. Synthesis 1995, 115. (c) Hoppe, R.; Scharf, H.-D.
Synthesis 1995, 1447. (d) Marshall, J . A.; Hinkle, K. W.; Hagedorn, C.
E. Isr. J . Chem. 1997, 37, 97.
Squamotacin, which was isolated from the bark of
Annona squamosa, showed cytotoxic selectivity for the
human prostate tumor cell line (PC-3), with a potency of
over 108 times that of Adriamycin.5 The structure 1,
which possesses an adjacent erythro-trans-threo-trans-
threo-bis-THF ring system, has been proposed on the
1
basis of H and 13C NMR, MS, and IR spectral data.5
Compound 1 was found to be identical to 2, except that
the ten-carbon unit comprising the adjacent bis-THF
rings with their flanking hydroxyls is shifted two carbons
(8) For total synthesis of Annonaceous acetogenins and analogues
by other groups, see: (a) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.;
Ocain, T. D.; Zhuang, Z. J . Am. Chem. Soc. 1991, 113, 9369. (b) Hoye,
T. R.; Hanson, P. R. Tetrahedron Lett. 1993, 34, 5043. (c) Tam, V. T.;
Chaboche, C.; Figadere, B.; Chappe, B.; Hieu, B. C.; Cave´, A.
Tetrahedron Lett. 1994, 35, 883. (d) Trost, B. M.; Shi, Z. P. J . Am.
Chem. Soc. 1994, 116, 7459. (e) Koert, U. Tetrahedron Lett. 1994, 35,
2517. (f) Yao Z. J .; Wu, Y. L. Tetrahedron lett. 1994, 35, 157. (g)
Makabe, H.; Tanaka, A.; Oritani, T. J . Chem. Soc., Perkin Trans. 1
1994, 1975. (h) Konno, H.; Makabe, H.; Tanaka, A.; Oritani, T. Biosci.
Biotechnol. Biochem. 1995, 59, 2355. (i) Hoye, T. R.; Tan, L. Tetrahe-
dron lett. 1995, 36, 1981. (j) Yao Z. J .; Wu, Y. L. J . Org. Chem. 1995,
60, 1170. (k) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki,
S. J . Org. Chem. 1995, 60, 4419. (l) Hoye, T. R.; Ye, Z. J . Am. Chem.
Soc. 1996, 118, 1801. (m) Konno, H.; Makabe, H.; Tanaka, A.; Oritani,
T. Tetrahedron Lett. 1996, 37, 5393. (n) Konno, H.; Makabe, H.;
Tanaka, A.; Oritani, T. Tetrahedron 1996, 52, 9399. (o) Franck, X.;
Figadere, B.; Cave´, A. Tetrahedron Lett. 1996, 37, 1593. (p) Marshall,
J . A.; Chen, M. J . Org. Chem. 1997, 62, 5996. (q) Marshall, J . A.;
Hinkle, K. W. J . Org. Chem. 1997, 62, 5989. (r) Trost, B. M. Calkins,
T. L.; Bochet, C. G. Angew. Chem., Int. Ed. Engl. 1997, 36, 2632. (s)
Marshall, J . A.; Hinkle, K. W. Tetrahedron Lett. 1998, 39, 1303. (t)
Marshall, J . A.; J iang, H. J . Tetrahedron Lett. 1998, 39, 1493. (u)
Marshall, J . A.; J ian, H. J . Org. Chem. 1999, 64, 971.
* To whom correspondence should be addressed. Phone: (619) 784-
8511. Fax: (619) 784-8732. E-mail: keinan@scripps.edu or subhash@
scripps.edu.
† The Scripps Research Institute.
‡ Technion-Israel Institute of Technology.
§ Incumbent of the Benno Gitter & Ilana Ben-Ami chair of Biotech-
nology, Technion.
(1) (a) Rupprecht, J . K.; Hui, Y.-H.; McLaughlin, J . L. J . Nat. Prod.
1990, 53, 237. (b) Fang, X.-P.; Rieser, M. J .; Gu, Z.-M.; Zhao, G.-X.;
McLaughlin, J . L. Phytochem. Anal. 1993, 4, 27. (c) Gu, Z.-M.; Zhao,
G.-X.; Oberlies, N. H.; Zeng, L.; McLaughlin, J . L. In Recent Advances
in Phytochemistry; Arnason, J . T., Mata, R., Romeo, J . T., Eds.; Plenum
Press: New York, 1995; Vol. 29, pp 249-310. (d) Alali, F. Q.; Liu, X.-
X.; McLaughlin, J . L. J . Nat. Prod. 1999, 62, 504.
(2) (a) Ahammadsahib, K. I.; Hollingworth, R. M.; McGovern, P. J .;
Hui, Y.-H.; McLaughlin, J . L. Life Sci. 1993, 53, 1113. (b) Degli Esposti,
M.; Ghelli, A.; Ratta, M.; Cortes, D. Biochem. J . 1994, 301, 161. (c)
Hollingworth, R. M.; Ahammadsahib, K. I.; Gadelhak, G.; McLaughlin,
J . L. Biochem. Soc. Trans. 1994, 22, 230.
(3) Morre´, D. J .; de Cabo, R.; Farley, C.; Oberlies, N. H.; McLaughlin,
J . L. Life Sci. 1995, 56, 343.
(4) Wolvetang, E. J .; J ohnson, K. L.; Krauer, K.; Ralph, S. J .;
Linnane, A. W. FEBS Lett. 1994, 339, 40.
(5) . Hopp, D. C.; Zeng, L.; Gu, Z.-M.; McLaughlin, J . L. J . Nat. Prod.
1996, 59, 97.
(9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
10.1021/jo990599p CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/21/1999

7068 J . Org. Chem., Vol. 64, No. 19, 1999
Sinha et al.
F igu r e 1.
first total synthesis of 1 using a variant of our “naked”
with DIBAL-H. The resultant lactol was subjected to
Wittig-Horner reaction with carbethoxymethyl-triphen-
ylphosphorane to produce the unsaturated ester 10. The
ester was reduced at low temperature with DIBAL-H to
give the allylic alcohol 11. AE reaction with the latter
was carried out in the presence of (+)-diethyl tartrate.
The resultant epoxide intermediate underwent a subse-
quent acid-catalyzed ring-closure reaction to produce the
desired bis-THF fragment 12a . The latter was converted
to epoxide 13 with inversion of the configuration at the
secondary carbinol center using a four-step sequence.
carbon skeleton strategy.10
Resu lts a n d Discu ssion
Our retrosynthetic analysis of 1 (Scheme 1) dissects
the target molecule into two major building blocks: the
bis-THF unit, I, and the butenolide moiety, II. Both
fragments could be easily coupled by Wittig olefination
reaction followed by catalytic hydrogenation. Fragment
I could be prepared from epoxide III which, in turn, could
be obtained from the appropriately polyhydroxylated
skeleton IV via differential activation of the various
hydroxyl groups destined to be either nucleophiles or
leaving groups (as shown by the curved arrows in Scheme
1). This approach suggested that all six asymmetric
centers in the molecule could be introduced via an
appropriate combination of the AD and the asymmetric
epoxidation (AE)11 reactions starting with three disub-
stituted double bonds, as exemplified by V.
Sch em e 1
The synthesis of 1 (Scheme 2) starts with an AD
reaction using trans ethyl heptadec-4-enoate 3 and AD-
mix-R to produce the R-hydroxyfuranone (muricatacin,
4).12 The latter was converted to the acetonide ester 5,
which was reduced to the corresponding primary alcohol
6. PCC oxidation to aldehyde was followed by reaction
with vinylmagnesium bromide. The resultant allylic
alcohol was converted to the unsaturated ester 7 via the
J ohnson-Claisen rearrangement using triethyl orthoac-
etate in xylene. Acidic cleavage of the acetonide in 7 was
followed by conversion of the resultant diol to the trans
epoxide 8. For this transformation we used TMSCl and
triethyl orthoacetate to form an acetoxychloride inter-
mediate, which was converted to 8 under basic condi-
tions.13 A second asymmetric dihdroxylation reaction,
now with AD-mix-â, afforded a diol intermediate, which
underwent a subsequent acid-catalyzed ring-closure reac-
tion to produce the crystalline lactone 9a .
The alcohol function in 9a was protected as a MOM
ether, 9b, and the lactone function was partially reduced
(10) (a) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J . Org. Chem.
1993, 58, 7789. (b) Sinha, S. C.; Keinan, E. J . Org. Chem. 1994, 59,
949. (c) Sinha, S. C.; Keinan, E. J . Org. Chem. 1997, 62, 377. (d)
Keinan, E.; Sinha, A.; Yazbak, A.; Sinha, S. C.; Sinha, S. C. Pure Appl.
Chem. 1997, 69, 423.
(11) (a) J ohnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers Inc.: New York, 1993; p 103.
(b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(12) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.; Sinha-
Bagchi, A.; Keinan, E. Tetrahedron Lett. 1992, 33, 6407.
(13) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515.

Total Synthesis of Squamotacin
J . Org. Chem., Vol. 64, No. 19, 1999 7069
Sch em e 2: Syn th esis of Squ a m ota cin , 1a
a
Conditions: (a) (i) AD-mix-R, MeSO2NH2, tert-butyl alcohol-water, 1:1, 0 °C, 16 h. (ii) KOH (3 N) and then HCl (3 N). (iii) TsOH(cat.),
CH2Cl2, rt, 1 h. (b) DMP, benzene, TsOH(cat.) reflux, 8 h. (c) LAH, Et2O, 0 °C to reflux, 1 h. (d) (i) PCC, Celite, CH2Cl2, 2 h. (ii)
Vinylmagnesium bromide, THF, -20 °C, 0.5 h. (iii) Triethyl orthoacetate, xylene, propionic acid(cat.), 140 °C, 2 h. (e) (i) MeOH, water,
TsOH. (ii) TMSCl, triethyl orthoacetate, 40 °C, 0.5 h. (iii) MeOH, K2CO3, rt, 2 h. (f) (i) AD-mix-â, MeSO2NH2, tert-butyl alcohol-water
(1:1), 0 °C, 16 h. (ii) Acidic Amberlyst, rt, 16 h. (g) MOMCl, diisopropylethylamine, CH2Cl2, 0 °C to room temperature, 16 h. (h) (i) DIBAL-
H, THF, -78 °C, 1.5 h. (ii) Carboethoxymethylene triphenyphosphorane, toluene, 80 °C, 16 h. (i) DIBAL-H, THF, -78 °C, 1 h. (j) TBHP,
(+)-DET, Ti(Oi-Pr)4, CH2Cl2, -20 °C, 16 h. (k) TBDMSCl, diisopropylethylamine, CH2Cl2, 16 h. (l) MsCl, Et3N, CH2Cl2, -30 to 0 °C, 2 h.
(m) TsOH, MeOH, rt, 2 h. (n) MeOH, K2CO3, rt, 2 h. (o) THF, n-BuLi, -78 to -40 °C, BF3‚Et2O, -78 °C, 3 h. (p) (i) Hexane-Et3N (8:2),
Lindlar catalyst, rt, 2 h. (ii) MOMCl, diisopropylethylamine, CH2Cl2, 0 °C to room temperature, 16 h. (q) TBAF, THF, 0 °C, 2 h. (r) I2, Im,
PPh3, 0 °C, 1 h. (s) CH3CN, PPh3, NaHCO3, 40 °C, 48 h. (t) n-BuLi, THF, 0 °C, 0.5 h. (u) (i) RhCl(PPh3)3, benzene-EtOH (1:1), 4 h. (ii)
4% CH3COCl in MeOH and CH2Cl2 (1:1), rt, 16 h.
First, the primary alcohol was protected in the form of a
silyl ether, 12b, the secondary alcohol was converted to
the corresponding mesylate, 12c, then the silyl ether was
cleaved by treatment with TsOH in methanol to give the
hydroxymesylate, 13d , and the latter underwent base-
catalyzed ring-closure reaction using K2CO3 in methanol
to produce epoxide 13. Since compound 13 (III in Scheme
1) represents the key intermediate in the entire synthetic
scheme, its successful preparation set the stage for the
completion of the total synthesis of 1.
Elongation of the carbon skeleton of 13 was achieved
by a BF3‚Et2O-catalyzed ring-opening reaction using the
organolithium nucleophile prepared from the terminal
acetylene 14 and n-BuLi. The resultant alkyne 15 was
fully hydrogenated to give 16a , the alcohol was protected
in the form of a MOM-ether, 16b, and the silyl protecting
group was removed to give the corresponding primary
alcohol, 16c. The latter was converted to the primary
iodide, 16d , which, upon reaction with PPh3, produced
the phosphonium salt 16e. Treatment of 16e with n-BuLi
generated the corresponding Wittig reagent, which was
reacted with aldehyde 17 to produce alkene 18. Finally,
catalytic hydrogenation over Wilkinson’s catalyst and
cleavage of all three protecting groups using acidic
methanol afforded 1. The synthetic compound 1 was
1
found to be identical, by H and 13C NMR, and MS, with
the naturally occurring squamotacin.14
In conclusion, the first total synthesis of (+)-squamo-
tacin, 1, was achieved in 27 steps and 0.83% yield
starting with (+)-muricatacin, 4. This synthetic strategy
is complementary to our previously reported approach
to 2 where most of the asymmetric carbinol centers were
produced via chirality transfer methods. Considering the
many possible combinations of AE and AD reactions on
(14) Expectedly, the optical rotation of our synthetic 1, [R]D +11.7°,
was found to be similar to that of naturally occurring 2, [R]D +13.0°
(Hui, Y. H.; Rupprecht, J . K.; Liu, Y. M.; Anderson, J . E.; Smith, D.
L.; Chang, C.-J .; McLaughlin, J . L. J . Nat. Prod. 1989, 52, 463), as
well as the synthetic samples of 2 (+13.2°, ref 6b; +12.8°, ref 8i). The
lower value of optical rotation reported for 1 [+2.59 (c ) 0.0027), ref
5] probably reflects the fact that the sample of the naturally occurring
1 was isolated in very small quantities and was not absolutely pure
(J . L. McLaughlin, personal communication).

7070 J . Org. Chem., Vol. 64, No. 19, 1999
Sinha et al.
13C NMR (125 MHz) δ 107.9, 80.9, 80.8, 62.6, 32.6, 31.8, 29.6,
29.5, 29.4, 29.2, 27.2, 27.1, 26.0, 22.6, 14.0 ppm; MS m/z 329
(MH+).
(tr a n s,8S,9S) Eth yl 8,9-Isop r op ylid en ed ioxyu n eicos-
4,5-en oa te, 7. PCC (18 g, 83.7 mmol) and Celite (18 g) were
added to a solution of 6 (13.0 g, 40.0 mmol) in CH2Cl2 (80 mL).
The mixture was stirred at room temperature for 2 h and then
filtered through silica gel. Removal of the solvent under
reduced pressure afforded the corresponding aldehyde (11.4
g, 84%), which was immediately used in the next step without
further purification.
each of the double bonds in the carbon skeleton, the
synthesis of 1 represents a general methodology that can
be used for the synthesis of many other Annonaceous
acetogenins. Furthermore, the ability to vary the direc-
tionality of the ring-closure reactions by differential
activation of the hydroxyl groups may be used for the
preparation of diverse chemical libraries of acetogenin
stereoisomers. In fact, this strategy is currently being
used in our laboratories for the construction of a complete
library of the bis-THF acetogenin stereoisomers.
Vinylmagnesium bromide (1 M in THF, 40 mL, 40 mmol)
was added to the solution of the above-mentioned aldehyde
(11.4 g, 35 mmol) in ether (100 mL) at -20 °C. The mixture
was stirred at the same temperature for 0.5 h and then worked
up with saturated aqueous NH4Cl and ether. Purification by
column chromatography (silica gel, hexanes-ethyl acetate, 4:1)
afforded the corresponding allylic alcohol (11 g, 88% yield):
1H NMR (500 MHz) δ 5.87 (ddd, J ) 16.5, 10.5, 5.5 Hz, 1H),
5.24 (m, 1H), 5.11 (m, 1H), 4.17 (m, 1H), 3.60 (m, 2H), 1.85-
1.20 (m and br s, 30H), 0.88 (t, J ) 7 Hz, 3H) ppm; MS m/z
355 (MH+).
The above-mentioned allylic alcohol (11 g, 31 mmol), triethyl
orthoacetate (15 mL, 81 mmol), and propionic acid (0.4 mL,
0.56 mmol) were dissolved in xylene (15 mL). The mixture was
refluxed for 2 h, the solvent was removed under reduced
pressure, and the residue was purified by column chromatog-
raphy (silica gel, hexanes-ethyl acetate, 9:1) to give 7 (11.4
g, 86% yield) in the form of a colorless oil: 1H NMR δ 5.45 (m,
2H), 4.11 (q, J ) 7.1 Hz, 2H), 3.56 (m, 2H), 2.32 (m, 4H), 2.18
(m, 1H), 2.05 (m, 1H), 1.56-1.21 (br s, 24H), 1.35 (s, 6H), 1.24
(t, J ) 7.0 Hz, 3H), 0.86 (t, J ) 6.9 Hz, 3H); 13C NMR δ 130.7,
128.6, 107.7, 80.9, 80.3, 60.2, 34.3, 32.9, 32.7, 31.9, 29.7, 29.63,
29.6, 29.5, 29.3, 30.0, 27.9, 27.3, 26.1, 22.6, 14.2, 14.1 ppm;
MS m/z 424 (M+).
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were measured
in CDCl3 at 400 and 100 MHz, respectively. Positive ion mass
spectra, using the fast ion bombardment (FIB) technique, were
obtained on a high-resolution mass spectrometer equipped
with either a cesium or sodium ion gun. Optical rotations were
measured in a 1-dm (1.3 mL) cell using an automatic pola-
rimeter. Column chromatographic separations were performed
on silica gel (Merck, Kieselgel 60, 230-400 mesh, Art. 9385)
under pressure. THF was dried and distilled over sodium ketyl.
AD-mix-R (no. 39,275-8) and AD-mix-â (no. 39,276-6) were
purchased from Aldrich.
(4S,5S)-5-Hyd r oxyh ep ta d eca n e-1,4-olid e, 4. Compound
36e (14.4 g, 48.6 mmol) was added to a cold (0 °C) solution of
AD-mix-R (1.4 g/mmol, 68.0 g) and MeSO2NH2 (4.6 g, 48.4
mmol) in tert-butyl alcohol-water (1:1, 750 mL). The mixture
was stirred at 0 °C for 16 h and then quenched by addition of
sodium metabisulfite (73 g) and extracted with ethyl acetate.
Solvents were removed under reduced pressure, and the
residue was dissolved in methanol (80 mL) and aqueous NaOH
(3 N, 75 mL). After being stirred at 60 °C for 2 h the mixture
was cooled to 0 °C, acidified with 3 N HCl, and extracted with
ethyl acetate. Solvents were removed under reduced pressure,
and the residue was dissolved in CH2Cl2. p-Toluenesulfonic
acid (TsOH, 300 mg) was added, and the mixture was stirred
at room temperature for 1 h. Workup with aqueous NaHCO3
and CH2Cl2 followed by column chromatography (silica gel,
hexanes-ethyl acetate, 1:1) gave lactone 412 (12.8 g, 92% yield),
which was crystallized as white crystals: [R]D +23.5° (c ) 3.3,
CHCl3); 1H NMR δ 4.40 (td, J ) 7.4, 4.7 Hz, 1H), 3.56 (m, 1H),
2.55 (m, 2H), 2.23 (m, 1H), 2.10 (m, 1H), 1.82 (m, 1H), 1.56-
1.24 (m and br s, 22H), 0.86 (t, J ) 6.8 Hz, 3H); 13C NMR δ
82.9, 73.6, 32.9, 31.9, 29.6, 29.5, 29.5, 29.3, 28.7, 25.4, 24.1,
22.6 ppm; MS m/z 307 (MNa+).
(4S,5S) Meth yl 4,5-Isopr opyliden edioxyh eptadecan oate,
5. TsOH (120 mg) was added to a solution of 4 (12.8 g, 45
mmol) in a mixture of benzene (50 mL) and dimethoxypropane
(90 mL). The solution was refluxed for 8 h, then cooled to room
temperature, and worked up with saturated aqueous NaHCO3
and ether. Solvents were removed under reduced pressure to
afford crude 5 (15.26 g, 95% yield) which was taken to the next
step without purification: 1H NMR (500 MHz) δ 3.67 (s, 3H),
3.60 (m, 2H), 2.51 (m, 1H), 2.45 (m, 1H), 1.93 (m, 1H), 1.75
(m, 2H), 1.49 (m, 3H), 1.36 (s, 6H), 1.25 (m and br s, 18H),
0.87 (t, J ) 7.0 Hz, 3H); 13C NMR (125 MHz) δ 173.7, 108.0,
80.6, 79.7, 51.5, 32.7, 32.7, 31.8, 30.4, 29.4, 29.4, 29.2, 27.8,
27.2, 27.1, 27.1, 25.9, 22.5, 14.0 ppm; MS m/z 297 (MH+).
(tr a n s,8S,9S) Eth yl 8,9-Oxid ou n eicos-4-en oa te, 8. To a
solution of 7 (7.4 g, 17.5 mmol) in MeOH-H2O (4:1, 30 mL)
was added TsOH (600 mg), the reaction mixture was stirred
at room temperature for 16 h and then worked up with
saturated aqueous NaHCO3 and CH2Cl2. Removal of solvents
under reduced pressure followed by column chromatography
(silica gel, hexane-ethyl acetate, 1:1) afforded (trans,8S,9S)
ethyl 8,9-dihydroxyuneicos-4-enoate (5.5 g, 85% yield): 1H
NMR δ 5.43 (m, 2H), 3.60 (s, 3H), 3.36 (m, 2H), 2.64 (br s,
2H), 2.48-2.24 (m, 4H), 2.16-2.00 (m, 2H), 1.54-1.19 (m and
br s, 24H), 0.83 (t, J ) 7.0 Hz, 3H); 13C NMR δ 173.7, 131.0,
128.6, 74.3, 73.8, 60.4, 57.5, 33.9, 33.5, 33.1, 31.5, 29.7, 29.7,
29.6, 29.4, 29.4, 28.7, 27.8, 25.7, 14.0 ppm; MS m/z 393 (MNa+).
To a solution of the above-mentioned diol and triethyl-
orthoacetate (3.8 mL, 20 mmol) in CH2Cl2 was added chloro-
trimethylsilane (3 mL, 23 mmol) was added dropwise at room
temperature, and the reaction mixture was stirred at 40 °C
for 0.5 h. The volatile materials were removed under reduced
pressure, the residue was redissolved in MeOH (50 mL), K2-
CO3 (2.7 g, 20 mmol) was added, and the mixture was stirred
vigorously at room temperature for 2 h. Workup with water
and CH2Cl2 followed by column chromatography (silica gel,
hexanes-ethyl acetate, 9:1) afforded 8 (3.1 g, 60%) in the form
1
of an oil: [R]D -15.2° (c ) 3.18, CHCl3); H NMR δ 5.42 (m,
2H), 3.62 (s, 3H), 2.61 (m, 2H), 2.35-2.26 (m, 4H), 2.09 (m,
2H), 1.55-1.21 (m and br s, 24H), 0.84 (t, J ) 6.6 Hz, 3H); 13
C
NMR δ 173.5, 130.4, 128.8, 58.9, 58.2, 57.4, 33.9, 32.0, 31.9,
31.8, 29.7, 29.6, 29.6, 29.5, 29.2, 29.1, 29.0, 28.9, 27.8, 26.0,
22.6, 14.0 ppm; MS m/z 375 (MNa+).
(4S,5S)-4,5-Isop r op ylid en ed ioxyh ep t a d eca n -1-ol, 6.
Lithium aluminum hydride (2.6 g, 6.8 mmol) was added slowly
to a solution of 5 (15.26 g, 41.2 mmol) in dry ether (100 mL)
at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then heated
to reflux temperature for another 2 h, cooled to room temper-
ature, diluted with ether, and quenched by careful addition of
water. The inorganic material was removed by filtration
through Celite, solvents were removed under reduced pressure,
and the crude residue was purified by column chromatography
(silica gel, ethyl acetate-hexane, 2:3) to give 6 (13.7 g, 97%
(4R ,5R ,8R ,9S )-5,8-O x id o h e n e ic o s a -9-h y d r o x y -1,4-
olid e, 9a . AD-mix-â (1.4 g/mmol, 13 g, 0.4% OsO4 content) and
MeSO2NH2 (0.88 g, 9.3 mmol) were added to a cold (0 °C)
mixture of 8 (3.1 g, 8.8 mmol) in tert-butyl alcohol-water (1:
1, 180 mL). The mixture was stirred at the same temperature
for 16 h and then worked up by slow addition of sodium
metabisulfite (13.2 g) followed by extraction with ethyl acetate.
Solvent was removed under reduced pressure to produce the
corresponding dihydroxylated product which was taken to the
next step without further purification: 1H NMR δ 4.40 (ddd,
J ) 14.5, 7.3, 4.4 Hz, 1H), 3.64 (m, 1H), 2.72 (m, 2H), 2.63 (m,
1
yield): [R]D -18.4° (c ) 3.09, CHCl3); H NMR (500 MHz) δ
3.67 (m, 2H), 3.60 (m, 2H), 2.34 (br s, 1H), 1.70 (m, 2H), 1.50
(m, 4H), 1.38 (s, 6H), 1.28 (br s, 18H), 0.87 (t, J ) 7 Hz, 3H);

Total Synthesis of Squamotacin
J . Org. Chem., Vol. 64, No. 19, 1999 7071
1H), 2.51 (m and br s, 2H), 2.26 (m, 1H), 2.14 (m, 1H), 1.96
(m, 1H), 1.69 (q, J ) 6.7 Hz, 2H), 1.54-1.28 (m and br s, 23H),
0.86 (t, J ) 7.2 Hz, 3H).
82.6, 81.4, 78.2, 73.3, 63.6, 55.7, 32.8, 31.9, 31.6, 29.6, 29.5,
28.4, 28.2, 26.7, 25.6, 22.6, 14.1 ppm; MS m/z 451 (MNa+).
(2S,3R,6R,7R,10R,11S)-11-(Meth oxym eth oxy)-3,6:7,10-
d ioxid otr icosa -1,2-d iol, 12a . (+)-DET (0.92 g, 4.5 mmol) and
Ti(Oi-Pr)4 (1 g, 3.5 mmol) were added sequentially to a mixture
of the allylic alcohol 11 (1.6 g, 3.74 mmol) and activated
molecular sieves (4 Å, 1.6 g) in dry CH2Cl2. The mixture was
stirred at -20 °C for 0.5 h, TBHP (5-6 M in isooctane, 4 mL)
was added dropwise, and the mixture was stirred at the same
temperature for 16 h. Water (2 mL) and aqueous NaOH (3 N,
4 mL) were added, and the mixture was stirred for 0.5 h.
Aqueous solution was filtered through Celite and extracted
with ether. Solvents were removed under reduced pressure,
and the residue was purified by column chromatography (silica
gel, hexanes-ethyl acetate, 1:4) to give 12a (1.24 g, 82% yield,
based on recovered starting material) in the form of a colorless
oil: 1H NMR δ 4.77 (d, J ) 6.6 Hz, 1H), 4.64 (d, J ) 6.6 Hz,
1H), 4.00 (m, 1H), 3.93 (m, 1H), 3.87-3.80 (m, 3H), 3.71-3.64
(m, 2H), 3.58 (m, 1H), 3.37 (s, 3H), 2.39 (b, 2H), 2.02-1.77
(m, 7H), 1.68-1.24 (m and br s, 23H), 0.86 (t, J ) 6.8 Hz, 3H);
13C NMR δ 96.8, 82.1, 82.0, 80.3, 78.5, 72.8, 63.7, 55.7, 31.9,
29.6, 29.6, 28.6, 28.5, 26.8, 25.7, 22.6, 14.1 ppm; MS m/z 467
(MNa+).
Acidic Amberlyst 15 (1 g) was added to a solution of the
above-mentioned diol in CH2Cl2 (25 mL) at 0 °C, the mixture
was stirred at room temperature for 16 h and then filtered,
and the solvents were removed under reduced pressure. The
residue was purified by column chromatography (silica gel,
hexanes-ethyl acetate, 1:1) to give 9a (2 g, 64%) in the form
of white crystals: [R]D -4.1° (c ) 2.94, CHCl3); 1H NMR δ 4.45
(ddd, J ) 7.9, 5.0, 2.4 Hz, 1H), 4.06 (td, J ) 7.6, 2.9 Hz, 1H),
3.86 (td, J ) 7.2, 3.4 Hz, 1H), 3.76 (m, 1H), 2.63 (m, 1H), 2.46
(m, 1H), 2.28-1.65 (m, 6H), 1.37-1.23 (br s, 23H), 0.85 (t, J
) 6.8 Hz, 3H); 13C NMR δ 83.4, 81.4, 81.0, 71.5, 32.5, 31.9,
29.6, 29.5, 29.5, 29.3, 28.2, 28.0, 26.3, 25.9, 24.7, 24.6, 22.6,
14.1 ppm; MS m/z 377 (MNa+).
(4R,5R,8R,9S)-9-(Meth oxym eth oxy)-5,8-oxidoh en eicosa-
1,4-olid e, 9b. Diisopropylethylamine (2.5 mL, 14.4 mmol) and
chloromethylmethyl ether (0.9 mL, 11.6 mmol) were added
sequentially to a solution of 9a (2 g, 5.87 mmol) in dry CH2Cl2
(20 mL) at 0 °C. The mixture was stirred at room temperature
for 16 h and then worked up with water and CH2Cl2. Purifica-
tion by column chromatography (silica gel, hexanes-ethyl
acetate, 8:2) afforded 9b (2 g, 89%) in the form of a colorless
oil: [R]D -24.4° (c ) 2.18, CHCl3); 1H NMR δ 4.72 (d, J ) 6.6
Hz, 1H), 4.62 (d, J ) 6.6 Hz, 1H), 4.43 (ddd, J ) 7.8, 5.3, 2.6
Hz, 1H), 3.98 (m, 2H), 3.63 (m, 1H), 3.30 (s, 3H), 2.62 (m, 1H),
2.43 (m, 1H), 2.24-2.15 (m, 2H), 2.01-1.84 (m, 4H), 1.40-
1.22 (br s, 22H), 0.84 (t, J ) 6.4 Hz, 3H); 13C NMR δ 177.6,
96.6, 95.3, 82.5, 81.2, 80.8, 78.3, 55.6, 31.8, 31.7, 29.6, 29.6,
29.5, 29.5, 29.3, 28.1, 27.9, 26.2,25.5, 24.8, 22.6 ppm; MS m/z
421 (MNa+).
(tr a n s,6R,7R,10R,11S) Eth yl 6-Hyd r oxy-11-(m eth oxy-
m eth oxy)-7,10-oxid otr icosa -2,3-en oa te, 10. DIBAL-H (1 M
in toluene, 7.5 mL, 7.5 mmol) was added to a solution of 9b
(2.0 g, 5 mmol) in dry THF (20 mL) at -78 °C. The mixture
was stirred at -78 °C for 1 h, then diluted with ether (20 mL),
and quenched with saturated aqueous NH4Cl (4 mL). Celite
(4 g) was added, and the mixture was stirred at 0 °C for 0.5 h
and then filtered through Celite, solvents were removed under
reduced pressure, and the residue was purified by column
chromatography (silica gel, hexanes-ethyl acetate, 7:3), af-
fording the corresponding lactol (1.82 g, 90% yield) which was
taken to the next step without purification.
Ethoxycarbonyl methyltriphenylphosphorane (4.0 g, 11.5
mmol) was added to a solution of the above-mentioned lactol
(1.82 g, 4.5 mmol) in dry toluene (25 mL). The mixture was
stirred at 80 °C for 16 h. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography (silica gel, hexanes-ethyl acetate, 9:1) to give
10 (1.8 g, 84% yield): 1H NMR δ 6.96 (dt, J ) 14.0, 6.7 Hz,
1H), 5.84 (dt, J ) 15.6, 1.3 Hz, 1H), 4.75 (d, J ) 4.8 Hz, 1H),
4.64 (d, J ) 4.8 Hz, 1H), 4.16 (q, J ) 7.1 Hz, 2H), 3.95 (m,
1H), 3.78 (m, 1H), 3.66 (m, 1H), 3.37 (s, 3H), 2.46-2.26 (m,
3H), 1.96-1.88 (m, 3H), 1.63-1.22 (m and br s, 25H), 1.27 (t,
J ) 7.1 Hz, 3H), 0.86 (t, J ) 5.6 Hz, 3H); 13C NMR δ 148.6,
121.6, 96.6, 82.5, 81.5, 78.2, 73.0, 60.1, 55.7, 31.9, 31.7,31.6,
29.7, 29.6, 29.3, 28.4, 28.2, 26.7, 25.6, 22.6, 14.2, 14.1 ppm;
MS m/z 493 (MNa+).
(2S,3R,6R,7R,10R,11S)-1-ter t-Bu t yld im et h ylsilyloxy-
11-(m eth oxym eth oxy)-3,6:7,10-bisoxid otr icosa n -2-ol, 12b.
TBDMSCl (506 mg, 3.36 mmol) was added to a solution of 12a
(1.24 g, 2.8 mmol), DMAP (30 mg), and diisopropylethylamine
(3 mL) in dry CH2Cl2 (15 mL). The mixture was stirred at room
temperature for 16 h and then worked up with water and CH2-
Cl2. The organic layer was washed with water and dried over
MgSO4. Solvents were removed under reduced pressure, and
the residue was purified by column chromatography (silica gel,
hexanes-ethyl acetate, 1:1) to give 12b (1.52 g, 96%) in the
1
form of a colorless oil: [R]D -7.6° (c ) 1.95, CHCl3); H NMR
δ 4.73 (d, J ) 6.6 Hz, 1H), 4.64 (d, J ) 6.6 Hz, 1H), 3.98 (td,
J ) 7.5, 3.6 Hz, 1H), 3.91 (m, 1H), 3.86 (m, 2H), 3.71-3.61
(m, 4H), 3.37 (s, 3H), 2.44 (d, J ) 5.4 Hz,1H), 2.02-1.83 (m,
6H), 1.63 (m, 2H), 1.44-1.23 (m and br s, 22H), 0.87 (s, 9H),
0.86 (t, J ) 7.0 Hz, 3H), 0.05 (s, 6H); 13C NMR δ 96.9, 82.1,
82.0, 79.5, 78.6, 73.0, 32.0, 31.9, 29.6, 29.3, 28.6, 28.4, 27.3,
26.0, 25.8, 25.7, 22.6, 14.1, -5.4 ppm; MS m/z 571 (MH+).
(2S,3R,6R,7R,10R,11S)-1-ter t-Bu tyld im eth ylsilyloxy-2-
m e syloxy-11-(m e t h oxym e t h oxy)-3,6:7,10-b isoxid ot r i-
cosa n e, 12c. Methanesulfonyl chloride (0.41 mL, 3.6 mmol)
was added dropwise to a solution of 12b (1.52 g, 2.7 mmol)
and triethylamine (2 mL) in CH2Cl2 (10 mL), at -30 °C. The
mixture was stirred at -30 to 0 °C for 2 h and worked up with
water and CH2Cl2, and the organic layer was washed with
water and dried over MgSO4. Solvents were removed under
reduced pressure, and the residue was purified by column
chromatography (silica gel, hexanes-ethyl acetate, 4:1) to give
12c (1.7 g, 96%) which was taken to the next step without
further purification: 1H NMR δ 4.74 (d, J ) 4.4 Hz, 1H), 4.63
(d, J ) 4.4 Hz, 1H), 4.62 (m, 1H), 4.15 (ddd, J ) 12.0, 7.2, 5.0
Hz, 1H), 3.92 (m, 1H), 3.85-3.74 (m, 4H), 3.64 (m, 1H), 3.36
(s, 3H), 3.06 (s, 3H), 2.04-1.83 (m, 6H), 1.68-1.61 (m, 2H),
1.41-1.23 (m, 22H), 0.87 (s, 9H), 0.86 (t, J ) 6.5 Hz, 3H), 0.05
(s, 6H); 13C NMR 96.8, 96.7, 84.1, 82.1, 81.8, 81.4, 78.8, 77.6,
63.0, 55.6, 38.2, 31.9, 31.8, 29.6, 29.6, 28.6, 28.2, 26.9, 26.7,
25.8, 25.3, 25.6, 18.2, 14.1, -5.5 ppm; MS m/z 659 (MNa+).
(2S,3R,6R,7R,10R,11S)-2-Mesyloxy-11-(methoxymethoxy)-
3,6:7,10-bisoxid otr icosa n -1-ol, 12d . TsOH (20 mg) was
added to a solution of 12c (1.71 g, 2.68 mmol) in methanol (20
mL), the mixture was stirred at room temperature for 2 h and
worked up with water and CH2Cl2, and the organic layer was
washed with water and dried over MgSO4. Solvents were
removed under reduced pressure, and the residue was purified
by column chromatography (silica gel, hexanes-ethyl acetate,
2:3) to give 12d (1.27 g, 91%): 1H NMR δ 4.73 (d, J ) 6.5 Hz,
1H), 4.67 (m, 1H), 4.61 (d, J ) 6.5 Hz, 1H), 3.93 (m, 1H), 3.90-
3.76 (m, 5H), 3.63 (m, 1H), 3.35 (s, 3H), 3.10 (s, 3H), 2.01-
1.20 (m and br s, 31H), 0.84 (t, J ) 7.0 Hz, 3H); 13C NMR δ
96.7, 84.2, 82.2, 81.9, 81.5, 78.6, 77.9, 62.6, 55.7, 38.3, 31.9,
29.3, 29.0, 28.6, 28.1, 27.7, 26.3, 25.6, 22.6, 14.1 ppm; MS m/z
545 (MNa+).
(tr a n s,6R,7R,10R,11S)-11-(Meth oxym eth oxy)-7,10-oxi-
d otr icosa -2,3-en -1,6-d iol, 11. DIBAL-H (1 M in toluene, 15
mL, 15 mmol) was added to a solution of 10 (1.8 g, 3.8 mmol)
in dry THF (30 mL) at -78 °C. The mixture was stirred at
the same temperature for 1 h, diluted with ether (25 mL), and
quenched with saturated aqueous NH4Cl (7 mL). Celite (7 g)
was added, the mixture was stirred at 0 °C for 0.5 h and
filtered through Celite, solvents were removed under reduced
pressure, and the residue was purified by column chromatog-
raphy (silica gel, hexanes-ethyl acetate, 3:7) to give 11 (1.6
g, 98%) in the form of an oil: 1H NMR δ 5.67 (m, 2H), 4.74 (d,
J ) 6.6 Hz, 1H), 4.63 (d, J ) 6.6 Hz, 1H), 4.05 (m, 2H), 3.94
(m, 1H), 3.75 (m, 1H), 3.67 (m, 1H), 3.38 (m, 1H), 3.37 (s, 3H),
2.34-2.02 (m, 2H), 1.95-1.88 (m, 3H), 1.60-1.22 (m and br s,
27H), 0.86 (t, J ) 6.7 Hz, 3H); 13C NMR δ 132.6, 129.3, 96.6,

7072 J . Org. Chem., Vol. 64, No. 19, 1999
Sinha et al.
(2R,3R,6R,7R,10R,11S)-11-(Met h oxym et h oxy)-1,2:3,6:
7,10-tr isoxid otr icosa n e, 13. K2CO3 (1.3 g, 1 mmol) was
added to a solution of 12d (1.27 g, 2.4 mmol) in methanol (20
mL), the mixture was stirred at room temperature for 1 h and
worked up with water and CH2Cl2, and the organic layer was
washed with water and dried over MgSO4. Solvents were
removed under reduced pressure, and the residue was purified
by column chromatography (silica gel, hexanes-ethyl acetate,
8:2) to give 13 (800 mg, 75%) in the form of a colorless oil:
with water and dried over MgSO4. Solvents were removed
under reduced pressure, and the residue was purified by
column chromatography (silica gel, hexanes-ethyl acetate, 3:2)
to give 16b (1.1 g, 87%) in the form of a colorless oil: 1H NMR
δ 7.65 (dd, J ) 7.9, 1.5 Hz, 4H), 7.38 (m, 6H), 4.80 (d, J ) 6.8
Hz, 1H), 4.78 (d, J ) 6.6 Hz, 1H), 4.64 (d, J ) 6.8, Hz, 2H),
3.98 (m, 2H), 3.87 (m, 2H), 3.68 (m, 1H), 3.63 (t, J ) 6.5 Hz,
2H), 3.46 (m, 1H), 3.37 (s, 3H), 3.35 (s, 3H), 3.35 (m, 1H) 2.04-
1.24 (m and br s, 38H), 1.03 (s, 9H), 0.86 (t, J ) 7.0 Hz, 3H);
13C NMR δ 135.5, 129.4, 127.5, 96.8, 96.7, 81.8, 81.6, 81.4, 81.3,
79.5, 78.7, 63.9, 55.7, 55.6, 32.6, 31.9, 31.5, 30.9, 29.6, 29.3,
28.5, 28.3, 28.1, 26.8, 26.3, 26.0, 26.6, 25.4, 20.6, 14.1 ppm;
HRMS calcd for C47H78O7SiCs 915.4571 (MCs+), found 915.4603.
(6R,7R,10R,11R,14R,15S)-6,15-Bis(m et h oxym et h oxy)-
7,10:11,14-bisoxid oh ep ta cosa n -1-ol, 16c. TBAF (1 M in
THF, 1.4 mL, 1.4 mmol) was added to a solution of 16b (1.1 g,
2.02 mmol) in dry THF (15 mL), at 0 °C. The mixture was
stirred at room temperature for 2 h and worked up with water
and ether, and the organic layer was washed with brine and
dried over MgSO4. Solvents were removed under reduced
pressure, and the residue was purified by column chromatog-
raphy (silica gel, hexanes-ethyl acetate, 1:4) to give 16c (1.05
g, 95% yield) in the form of a colorless oil: [R]D +13.6° (c )
1
[R]D -11.9° (c ) 2.03, CHCl3); H NMR δ 4.75 (d, J ) 6.4 Hz,
1H), 4.59 (d, J ) 6.4 Hz, 1H), 3.94 (m, 1H), 3.91 (m, 2H), 3.84
(m, 1H), 3.66 (m, 1H), 3.35 (s, 3H), 2.93 (m, 1H), 2.68 (m, 2H),
2.06-1.64 (m, 8H), 1.38-1.21 (m and br s, 22H), 0.84 (t, J )
6.0 Hz, 3H); 13C NMR δ 96.8, 82.1, 81.9, 81.5, 78.6, 55.6, 54.1,
44.0, 31.8, 29.7, 29.6, 29.3, 28.7, 28.7, 28.6, 26.1, 25.6, 22.6,
14.1 ppm; MS m/z 449 (MNa+).
1-(ter t-Bu tyld ip h en ylsilyloxy)-bu t-4-yn e, 14. TBDPSCl
(4.5 mL, 17 mmol) was added to a solution of 3-butyn-1-ol (1
g, 14.2 mmol), DMAP (5 mg/mmol, 70 mg), and diisopropyl-
ethylamine (5 mL) in CH2Cl2. The mixture was stirred at room
temperature for 16 h and worked up with water and CH2Cl2,
and the organic layer was washed with water and dried over
MgSO4. Solvents were removed under reduced pressure, and
the residue was purified by column chromatography (silica gel,
hexane) to give 14 (4.1 g, 94%): 1H NMR δ 7.69 (m, 4H), 7.41
(m, 6H), 3.80 (t, J ) 7.1 Hz, 2H), 2.46 (td, J ) 7.0, 2.6 Hz,
2H), 1.95 (dd, J ) 5.4, 2.7 Hz, 1H), 1.07 (s, 9H); 13C NMR δ
135.5, 129.7, 127.6, 81.4, 69.3, 62.3, 26.7, 22.5, 19.2 ppm; MS
m/z 331 (MNa+).
(6R,7R,10R,11R,14R,15S)-1-ter t-Bu tyld ip h en ylsilyloxy-
15-(m eth oxym eth oxy)-7,10:11,14-bisoxid oh ep ta cos-3-yn -
6-ol, 15. n-BuLi (1.6M, 2.37 mL) was added to a solution of
14 (1.2 g, 3.8 mmol) in dry THF (15 mL) at -78 °C and then
allowed to warm to room temperature over 1 h. BF3‚Et2O (0.5
mL, 0.4 mmol) was added dropwise to this solution at -78 °C,
and the mixture was stirred for 0.5 h. A solution of epoxide
13 (800 mg, 1.9 mmol) in dry THF (2 mL) was added dropwise,
the mixture was stirred at the same temperature for 1 h and
then worked up with water and ether, and the organic layer
was washed with brine and dried over MgSO4. Solvents were
removed under reduced pressure, and the residue was purified
by column chromatography (silica gel, hexanes-ethyl acetate,
1:1) to give 15 (1.2 g, 85%) in the form of a colorless oil: 1H
NMR δ 7.65 (dd, J ) 7.8, 1.5 Hz, 4H), 7.38 (m, 6H), 4.77 (d, J
) 6.6 Hz, 1H), 4.64 (d, J ) 6.6 Hz, 1H), 3.98 (m, 2H), 3.84 (m,
2H), 3.73 (t, J ) 7.1 Hz, 2H), 3.71 (m, 1H), 3.49 (m, 1H), 3.37
(s, 3H), 2.41 (m, 2H), 2.34 (m, 2H), 1.95-1.86 (m, 5H), 1.71-
1.60 (m, 3H), 1.42-1.19 (m and br s, 22H), 1.03 (s, 9H), 0.86
(t, J ) 7.0, 3H); 13C NMR δ 135.8, 133.6, 129.6, 127.6, 96.8,
82.0, 82.0, 81.8, 81.3, 78.5, 72.3, 62.4, 55.6, 31.9, 29.7, 29.6,
29.3, 28.7, 28.6, 28.2, 26.7, 26.0, 25.7, 24.1, 22.9, 22.6, 14.1
ppm.
1
3.9, CHCl3); H NMR δ 4.80 (d, J ) 6.8 Hz, 1H), 4.77 (d, J )
6.6 Hz, 1H), 4.65 (d, J ) 6.6 Hz, 1H), 4.63 (d, J ) 6.6 Hz, 1H),
3.97 (m, 2H), 3.86 (m, 2H), 3.66 (m, 1H), 3.61 (m, 2H), 3.47
(m, 1H), 3.37 (s, 6H), 1.95-1.23 (m, 37H), 0.85 (t, J ) 6.4 Hz,
3H); 13C NMR δ 96.7, 81.8, 81.5, 81.3, 79.4, 78.7, 62.7, 55.7,
55.6, 32.6, 31.9, 30.8, 29.3, 28.5, 28.3, 28.0, 26.3, 25.7, 25.6,
25.2, 22.6, 14.1 ppm; HRMS calcd for C31H60O7SiCs 677.3393
(MCs+), found 677.3412.
(6R ,7R ,10R ,11R ,14R ,15S )-1-Iod o-6,15-b is(m e t h oxy-
m eth oxy)-7,10:11,14-bisoxidoh eptacosan e, 16d. Iodine (378
mg, 1.48 mmol) was added to a solution of 16c (672 mg, 1.2
mmol), imidazole (169 mg, 2.46 mmol), and PPh3 (488 mg, 1.85
mmol) in CH2Cl2 (15 mL) at 0 °C. The mixture was stirred for
1 h, saturated aqueous NaHCO3 was added until the solution
became colorless, and then I2 was added until the color of
iodine persisted. The mixture was extracted with CH2Cl2, and
the organic layer was washed with sodium thiosulfate and then
with water and dried over MgSO4. Solvents were removed
under reduced pressure, and the residue was purified by
column chromatography (silica gel, hexanes-ethyl acetate, 9:1)
to give 16d (716 mg, 90%): 1H NMR δ 4.79 (d, J ) 6.7 Hz,
1H), 4.76 (d, J ) 6.7 Hz, 1H), 4.64 (t, J ) 6.7 Hz, 1H), 4.62 (d,
J ) 6.7 Hz, 1H), 3.95 (m, 2H), 3.85 (m, 2H), 3.67 (m, 1H), 3.46
(m, 1H), 3.37 (s, 6H), 3.16 (t, J ) 7.0 Hz, 2H), 1.79-1.20 (m
and br s, 38H), 0.85 (t, J ) 7 Hz, 3H); 13C NMR δ 96.7, 81.8,
81.4, 81.3, 79.4, 78.7, 55.7, 55.6, 33.4, 31.9, 31.9, 30.6, 30.0,
29.7, 29.6, 29.3, 28.5, 28.3, 28.0, 26.3, 25.6, 24.6, 22.6, 14.1,
7.0 ppm; HRMS calcd for C31H59O6ICs 787.2411 (MCs+), found
787.2435.
(6R,7R,10R,11R,14R,15S)-1-ter t-Bu tyld ip h en ylsilyloxy-
15-(m eth oxym eth oxy)-7,10:11,14-bisoxid oh ep ta cosa n -6-
ol, 16a . Lindlar catalyst (124 mg) was added to a solution of
compound 15 (1.2 g, 1.63 mmol) in hexane (10 mL), and the
mixture was stirred under H2 (1 atm) for 2 h. The catalyst
was filtered off, solvents were removed under reduced pres-
sure, and the residue was purified by column chromatography
(silica gel, hexanes-ethyl acetate, 1:1) to give 16a (1.19 g, 99%
yield): 1H NMR δ 7.66 (m, 4H), 7.39 (m, 6H), 4.78 (d, J ) 6.5
Hz, 1H), 4.65 (d, J ) 6.5 Hz, 1H), 4.00 (m, 1H), 3.86 (m, 2H),
3.78 (m, 1H), 3.71 (m, 1H), 3.63 (t, J ) 6.5 Hz, 2H), 3.88-3.6
2(m, 7H), 3.38 (s, 3H), 3.36 (m, 1H), 2.40 (br, 1H), 1.98-1.24
(m and br s, 35H), 1.04 (s, 9H), 0.88 (t, J ) 7.0 Hz, 3H); 13C
NMR δ 135.5, 129.4, 127.6, 96.8, 83.0, 82.0, 81.8, 81.8, 78.6,
73.9, 63.9, 55.6,33.3, 32.5, 31.9, 31.9, 29.7, 29.6, 29.3, 28.8, 28.4,
26.8, 26.6, 25.9, 25.7, 25.4, 22.6, 19.2, 14.1 ppm.
(6R,7R,10R,11R,14R,15S)-1-ter t-Bu tyld ip h en ylsilyloxy-
6,15-b is(m e t h oxym e t h oxy)-7,10:11,14-b isoxid oh e p t a -
cosa n e, 16b. MOMCl (0.32 mL, 4.26 mmol) was added to a
solution of 16a (1.19 g, 1.61 mmol) and diisopropylethylamine
(1.5 mL, 8.5 mmol) in CH2Cl2 (10 mL), at 0 °C. The mixture
was stirred at 0 °C to room temperature for 16 h and worked
up with water and CH2Cl2, and the organic layer was washed
(6R ,7R ,10R ,11R ,14R ,15S )-1-Iod o-6,15-b is(m e t h oxy-
m e t h oxy)-7,10:11,14-b isoxid oh e p t a cosa n -1-ylt r ip h e n -
ylp h osp h on iu m Iod id e, 16e. Triphenylphosphine (860 mg,
3.28 mmol) and NaHCO3 (270 mg, 3.2 mmol) were added to a
solution of 16d (716 mg, 1.09 mmol) in CH3CN (15 mL), and
the mixture was stirred at 40 °C for 48 h. Solvents were
removed under vacuum, the residue was redissolved in CH2-
Cl2, and the inorganic materials were filtered off. Solvents were
removed under reduced pressure, and the residue was tritu-
rated with ether to remove excess triphenylphosphine. Residue
in the flask was dried under reduced pressure to give 16e (871
mg, 87%): 1H NMR δ 7.82-7.69 (m, 9H), 7.24 (m, 6H), 4.77
(d, J ) 6.6 Hz, 1H), 4.75 (d, J ) 6.6 Hz, 1H), 4.62 (d, J ) 6.6
Hz, 1H), 4.61 (d, J ) 6.6 Hz, 1H), 3.94 (m, 2H), 3.82 (m, 2H),
3.73 (m, 2H), 3.66 (m, 1H), 3.40 (m, 1H), 3.36 (s, 3H), 3.30 (s,
3H), 1.90-1.23 (m and br s, 38 H), 0.86 (t, J ) 7.0 Hz, 3H);
MS m/z 789 (M - I)+.
4-ter t-Bu tyld ip h en ylsilyl-13,22-bis(m eth oxym eth yl)-8-
d eh yd r osqu a m ota cin yl Tr iseth er , 18a . n-BuLi (0.24 mL)
was added to a solution of 16e (360 mg, 0.38 mmol) in dry
THF (3 mL) at 0 °C, and the mixture was stirred at the same
temperature for 20 min. A solution of aldehyde 176e (145 mg,
0.33 mmol) in dry THF (1 mL) was added, and the mixture

Total Synthesis of Squamotacin
J . Org. Chem., Vol. 64, No. 19, 1999 7073
was stirred for another 20 min at the same temperature,
quenched with saturated aqueous NH4Cl, diluted with water,
and extracted with ether. The organic layer was washed with
brine and dried over MgSO4. Solvents were removed under
reduced pressure, and the residue was purified by column
chromatography (silica gel, hexanes-ethyl acetate, 3:2) to give
18 (149 mg, 48% yield): 1H NMR δ 7.66-7.61 (m, 4H), 7.43-
7.33 (m, 6H), 6.88 (d, J ) 6.4 Hz, 1H), 5.24 (m, 1H), 5.08 (m,
1H), 4.88 (m, 1H), 4.81 (d, J ) 6.8 Hz, 1H), 4.77 (d, J ) 6.6
Hz, 1 H), 4.64 (d, J ) 6.8 Hz, 1H), 4.63 (d, J ) 6.6 Hz, 1H),
3.97 (m, 3H), 3.87 (m, 2H), 3.67 (m, 1H), 3.46 (m, 1H), 3.36 (s,
6H), 2.43 (m, 2H), 1.97-1.60 (m, 12H), 1.47-1.25 (m and br
s, 30H), 1.30 (d, J ) 6.8 Hz, 3H), 1.02 (s, 9H), 0.85 (t, J ) 7.0
Hz, 3H); 13C NMR δ 151.3, 135.8, 133.9, 130.4, 130.1, 128.8,
127.6, 96.8, 96.7, 81.8, 81.6, 81.4, 81.3, 79.5, 78.7, 77.4, 71.4,
55.7, 55.6, 36.3, 31.9, 31.6, 29.8, 29.6, 29.3, 28.5, 28.3, 28.1,
27.1, 26.9, 26.3, 25.6, 25.3, 22.8, 22.6, 19.3, 18.9, 14.1 ppm;
MS m/z 969 (MNa+).
Squ a m ota cin , 1. Compound 18 (149 mg, 0.158 mmol) was
dissolved in EtOH-benzene (1:1, 6 mL) and purged with argon
for 2 min. Wilkinson’s catalyst (25 mg) was added, and the
mixture was stirred at room temperature under hydrogen (1
atm) for 4 h. Solvents were removed under reduced pressure,
and the residue was filtered through silica gel to give 4-tert-
butyldiphenylsilyl-14,23-bis(methoxymethyl)squamotacinyl
trisether (144 mg, 96%) which was taken to the next step
without further purification: 1H NMR δ 7.65-7.60 (m, 4H),
7.41-7.32 (m, 6H), 6.89 (d, J ) 1.4 Hz, 1H), 4.88 (dq, J ) 6.8,
1.5 Hz, 1H), 4.81 (d, J ) 6.8 Hz, 1H), 4.77 (d, J ) 6.6 Hz, 1H),
4.63 (d, J ) 6.6 Hz, 1H), 3.96 (m, 3H), 3.87 (m, 2H), 3.67 (m,
1H), 3.46 (m, 1H), 3.37 (s, 6H), 2.42 (m, 1H), 1.94-1.21 (m
and br s, 46H), 1.03 (s, 9H), 0.86 (t, J ) 6.8 Hz, 3H); 13C NMR
δ 151.2, 135.8, 135.8, 129.6, 127.5, 96.8, 96.7, 81.8, 81.6, 81.4,
81.3, 79.6, 78.8, 77.4, 71.7, 36.3, 31.9, 31.7, 31.0, 29.8, 29.6,
29.5, 29.4, 29.3, 28.5, 28.3, 28.1, 27.0, 26.3, 25.7, 24.9, 18.9,
14.1 ppm; MS m/z 971 (MNa+).
The above-described compound (144 mg, 0.151 mmol) was
dissolved in CH2Cl2 (2.0 mL). A mixture of CH3COCl-MeOH
(1:24, 2.0 mL) was added, and the mixture was stirred at room
temperature for 16 h. Saturated aqueous NaHCO3 was added
slowly, the mixture was extracted with ethyl acetate, and the
organic layer was washed with brine and dried over MgSO4.
Solvents were removed under reduced pressure, and the
residue was purified by column chromatography (silica gel,
hexanes-ethyl acetate, 1:4) to give 1 (47 mg, 50%): [R]D +11.7°
(c ) 2.20, CHCl3) [lit.5 [R]D +2.59° (c ) 0.0027, CHCl3)]; 1H
NMR δ 7.17 (d, J ) 1.2 Hz, 1H), 5.04 (dq, J ) 6.8, 1.6 Hz,
1H), 3.92 (m, 2H), 3.86 (m, 4H), 3.37 (m, 1H), 2.66 (br s, 1H),
2.53 (m, 1H), 2.41 (m, 1H), 2.35 (br s, 1H), 2.33 (br s, 1H) 2.03-
1.23 (m and br s, 49H), 0.86 (t, J ) 6.8 Hz, 3H); 13C NMR δ
151.8, 83.2, 82.8, 82.5, 82.3, 78.0, 74.07, 71.3, 70.0, 37.4, 33.3,
32.4, 31.9, 29.6, 29.5, 29.5, 29.3, 28.3, 26.0, 25.6, 25.5, 24.4,
22.7, 19.1, 14.1 ppm; MS m/z 645 (MNa+).
Ack n ow led gm en t. We thank the Skaggs Institute
for Chemical Biology, the US-Israel Binational Science
Foundation, the Israel Cancer Research Fund, and
PharMore Biotechnologies Ltd. for financial support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 7, 8, 9a , 9b, 10, 11, 12b, 13, 15, 16b,
16c, 16d , 18, and 1. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O990599P