Total synthesis of uvaricin

Article abstract of DOI:10.1021/jo980453a

The first total synthesis of naturally occurring (+)-uvaricin was achieved using three consecutive Sharpless asymmetric dihydroxylation (AD) reactions to place the necessary oxygen functions on a 'naked' carbon skeleton in a regio- and enantioselectively controlled manner. The appropriate bis-THF ring system was constructed using a Williamson type etherification reaction on a functionalized bis-mesylate intermediate.

Full text of DOI:10.1021/jo980453a

J . Org. Chem. 1998, 63, 5863-5868
5863
Tota l Syn th esis of Uva r icin
Ahmad Yazbak,†,‡ Subhash C. Sinha,*,† and Ehud Keinan*,†,‡,§
The Scripps Research Institute, Department of Molecular Biology and the Skaggs Institute for Chemical
Biology, 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 March 10, 1998
The first total synthesis of naturally occurring (+)-uvaricin was achieved using three consecutive
Sharpless asymmetric dihydroxylation (AD) reactions to place the necessary oxygen functions on
a “naked” carbon skeleton in a regio- and enantioselectively controlled manner. The appropriate
bis-THF ring system was constructed using a Williamson type etherification reaction on a
functionalized bis-mesylate intermediate.
In tr od u ction
convergent approach or via the “naked” carbon skeleton
strategy,7,8 thus unequivocally confirming their absolute
configuration.
The diverse bioactivities of the Annonaceous acetoge-
nins as antitumor, immunosuppressive, pesticidal, anti-
protozoal, antifeedant, anthelmintic, and antimicrobial
agents have attracted increasing interest.1 The past few
years have witnessed an explosion of activity in the
isolation (approximately 300 different Annonaceous ac-
etogenins have already been isolated from about 30
plants of the Annonaceae), structural elucidation, and
synthesis of these long chain fatty acid derivatives.2,3 We
have shown that many acetogenins of the mono-THF,4
the bis-THF,5 as well as the newly discovered tris-THF6
subgroups can be efficiently synthesized either by a
Uvaricin, 1, an adjacent bis-THF acetogenin which was
isolated in 1982 from Uvari accuminata, is of special
historical value because it was the first Annonaceous
acetogenin discovered.9 Uvaricin demonstrated antitu-
mor properties in the in vivo PS system (P-388 lympho-
cytic leukemia in mice).10 The synthesis of (15,16,
19,20,23,24)-hexepi-uvaricin by Hoye,11 which was ac-
complished at the time when the absolute configuration
of 1 was still unknown,12 represents the only reported
attempt to synthesize this molecule. That synthetic
work, together with subsequent NMR studies,13 sug-
gested that the absolute configuration of the bis-THF
portion of 1 is 15R,16R,19R,20R,23R,24S. Herein we
report on the first total synthesis of the naturally
occurring isomer, 1.
* Corresponding author. 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) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.;
McLaughlin, J . L. Nat. Prod. Rep. 1996, 13, 275. (b) 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.
(2) 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.
(3) For total synthesis of Annonaceous acetogenins by other groups,
see: (a) ref 11. (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. Biotech. Biochem. 1995, 59, 2355. (i) Hoye, T. R.; Tan, L.
Tetrahedron 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.
(4) Sinha, S. C.; Keinan, E. J . Am. Chem. Soc. 1993, 115, 4891.
(5) (a) Sinha, S. C.; Sinha-Bagchi, A.; Yazbak, A.; Keinan, E.
Tetrahedron Lett. 1995, 36, 9257. (b) Sinha, S. C.; Sinha, A.; Yazbak,
A.; Keinan, E. J . Org. Chem. 1996, 61, 7640.
(7) Keinan, E.; Sinha, A.; Yazbak, A.; Sinha, S. C.; Sinha, S. C. Pure
Appl. Chem. 1997, 69, 423.
(8) (a) Sinha, S. C.; Keinan, E. J . Org. Chem. 1994, 59, 949. (b)
Sinha, S. C.; Keinan, E. J . Org. Chem. 1997, 62, 377. (c) Sinha, S. C.;
Sinha-Bagchi, A.; Keinan, E. J . Org. Chem. 1993, 58, 7789.
(9) J olad, S. D.; Hoffmann, J . J .; Schram, K. H.; Cole, J . R.;
Tempesta, M. S.; Kriek, G. R.; Bates, R. B. J . Org. Chem. 1982, 47,
3151.
(10) Geran, R. I.; Greenberg, N. H.; Macdonald, M. M.; Schumacher,
A. M.; Abbott, B. J . Cancer Chemother. Rep. Part 3, 1972, 3 (2), 100.
(11) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.; Ocain, T. D.;
Zhuang, Z. J . Am. Chem. Soc. 1991, 113, 9369.
(12) J olad, S. D.; Hoffmann, J . J .; Cole, J . R.; Barry III, C. E.; Bates,
R. B.; Linz, G. S.; Konig, W. A. J . Nat. Prod. 1985, 48, 644.
(13) The absolute configuration of a broad variety of acetogenins
has been determined on the basis of NMR data of their Mosher ester
derivatives: Rieser, M. J .; Hui, Y.-H.; Rupprecht, J . K.; Kozlowski, J .
F.; Wood, K. V.; McLaughlin, J . L.; Hanson, P. R.; Zhuang, Z.; Hoye,
T. R. J . Am. Chem. Soc. 1992, 114, 10203.
(6) (a) Sinha, S. C.; Sinha, A.; Sinha, S. C.; Keinan, E. J . Am. Chem.
Soc. 1997, 119, 12014. (b) Sinha, S. C.; Sinha, S. C.; Keinan, E. J . Am.
Chem. Soc. 1998, 120, 4017.
S0022-3263(98)00453-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/01/1998

5864 J . Org. Chem., Vol. 63, No. 17, 1998
Yazbak et al.
Sch em e 1. Syn th esis of 14a
a
Reagents and conditions: (A) i. AD-mix-â, MeSO2NH2, butanol:water (1:1), 0 °C, 16 h. ii. 3 N KOH then 3 N HCl; iii. TsOH (5%),
CH2Cl2, 0.5 h. (B) p-nitrobenzoic Acid, PPh3, DEAD, C6H6, 16 h. (C) i. LAH, Et2O-THF, 0 °C to reflux, 2 h; ii. hexane, acetone, TsOH
(cat.), reflux 16 h. (D) i. PCC, CH2Cl2, 25 °C, 2 h; ii. Vinylmagnesium bromide, -30 °C, 0.5 h. (E) Triethyl orthoacetate, xylene, propionic
acid (cat.). (F) DIBAL-H, toluene, -78 °C, then triethylphosphonoacetate/ NaH, THF, -78 °C to 25 °C, 16 h. (G) DIBAL-H, THF, -78 °C,
1 h. (H) MOMCl, CH2Cl2, diisopropylethylamine, 25 °C, 16 h. (I) AD-mix-R, MeSO2NH2, butanol:water (1:1), 0 °C, 16 h. (J ) MsCl, Et3N,
CH2Cl2, 0 °C, 1 h. (K) AD-mix-â, MeSO2NH2, butanol:water (1:1), 0 °C, 16 h. (L) i. MeOH, TsOH, 16 h; ii. Pyridine, 140 °C, 4 h: 12a
(48%), 12b (13%). (M) BF3‚Et2O, DMS, CH2Cl2, 0 °C, 51% yield from 10b to 12b. (N) TsCl, pyridine, 0 °C, 3.5 h. (O) K2CO3, MeOH, 16 h.
(P) Pyridine, acetic anhydride, 25 °C, 16 h. (Q) I. (trimethylsilyl)acetylene, THF, n-BuLi, -78 ˚C to -30 °C, 0.5 H, then 13b, BF3‚Et2O (2
equiv), -78 °C to -30 °C, 10 h; ii. TBAF, THF, 0 °C, 0.5 h.
Resu lts a n d Discu ssion
treatment of the resultant aldehyde with vinylmagne-
sium bromide afforded allylic alcohols 6. Treatment of
the latter with triethyl orthoacetate and propionic acid
resulted in the Claisen-J ohnson rearrangement product,
7. Reduction of the ester to the aldehyde using DIBAL-H
in toluene followed by a Wittig-Horner reaction afforded
the (E)-unsaturated ester 8. Reduction of the ester to
the allylic alcohol 9a followed by protection with MOM
chloride produced 9b. Playing a key role in the synthetic
scheme, diene 9b was designed to undergo two consecu-
tive AD reactions to incorporate stereochemical features
necessary for synthesis of 1. Using AD-mix-R, the more
electron-rich double bond was regioselectively dihydroxy-
lated to produce diol 10a . The regioselectivity of this
dihydroxylation was complete, as the only byproduct
observed was the tetrol obtained from overoxidation of
9b. Diol 10a was converted to the bis-mesylate 10b
before undergoing the second AD reaction, now with AD-
mix-â, at the slightly less reactive double bond to give
11. Hydrolysis of the acetonide group followed by heating
under reflux in pyridine produced primarily the desired
bis-THF fragment 12a accompanied by small amounts
of the deprotected alcohol, 12b. Deprotection of 12a was
performed using BF3-Et2O and Me2S in CH2Cl2. Con-
version of the primary alcohol in 12b to the corresponding
tosylate, 12c, set the stage for a ring closure reaction with
K2CO3 in methanol to give epoxide 13a . The epoxide
group served two purposes: (a) protection of the second-
ary alcohol that was destined to be the free alcohol at
C15 in 1, and (b) activation of the primary position
toward the C-C bond formation upon reaction with a
carbon nucleophile. Acetylation using pyridine and acetic
anhydride gave 13b, a key intermediate possessing
correct absolute configurations for synthesis of 1, and is
enantiomeric to the intermediate used by Hoye to prepare
Clearly, the C15-C24 fragment, which contains the
bis-THF structure, represented the main challenge in the
total synthesis of 1. In addition to the requirement of
synthesizing six asymmetric carbinol centers in this
fragment, there was a need to selectively acetylate one
of two nearly identical secondary alcohols at positions 15
and 24. Interestingly, 1 was the only naturally acety-
lated Annonaceous acetogenin reported to date. We
decided to employ here some of the principles of our
“naked” carbon skeleton strategy.7,8 Thus, an unsatur-
ated carbon skeleton of the molecule was first constructed
and then hydroxylated in a regio- and enantioselective
manner using the Sharpless asymmetric dihydroxylation
(AD) reaction.14 All six asymmetric centers of the C15-
C24 fragment were introduced by three AD steps as
shown herein.
The synthesis started with ethyl pentadec-4-enoate, 2,
which was produced in two steps from undecanal (first,
reaction with vinylmagnesium bromide and then, Claisen-
J ohnson rearrangement with triethyl orthoacetate and
propionic acid). An AD reaction using AD-mix-â pro-
duced the threo hydroxy lactone 3 (Scheme 1). As the
two asymmetric centers in 3 were destined to become
positions 23 and 24 in the target molecule, inversion of
the configuration at the latter carbinol center was neces-
sary. Thus, Mitsunobu reaction of 3 with p-nitrobenzoic
acid, triphenylphosphine, and diethyl azodicarboxylate
(DEAD) afforded the erythro lactone ester, 4. LAH
reduction of these functions afforded the corresponding
triol which was protected in the form of the acetonide 5.
Oxidation of the free alcohol using PCC followed by
(14) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.

Total Synthesis of Uvaricin
Sch em e 2. Syn th esis of 21a
J . Org. Chem., Vol. 63, No. 17, 1998 5865
sure. THF and diethyl ether were dried and distilled over
sodium ketyl. AD-mix-R (#39,275-8) and AD-mix-â (#39,276-
6) were purchased from Aldrich.
(tr a n s)-Eth yl P en ta d ec-4-en oa te, 2. Vinylmagnesium
bromide (1 M, 100 mL, 0.1 mol) was added to a solution of
undecanal (15.3 g, 0.09 mol) in THF (150 mL) at 0 °C, and the
mixture was stirred for 0.5 h and then worked up with ether
and saturated aqueous NH4Cl. Removal of solvents followed
by filtration over silica gel (hexanes-ethyl acetate, 4:1) af-
forded tridec-1-en-3-ol (16.7 g, 94%). 1H NMR: δ 5.81 (m, 1H),
5.18 (dq, J ) 18.5, 1.3 Hz, 1H), 5.07 (dq, J ) 10.4, 1.3 Hz,
1H), 4.06 (q, J ) 5.9 Hz, 1H), 1.75 (br s, 1H), 1.60-1.20 (m
and br s, 18H), 0.85 (t, J ) 7.2 Hz, 3H); 13C NMR: δ 141.3,
114.4, 73.3, 37.0, 31.9, 29.5, 29.4, 29.1, 25.3, 22.7, 14.1 ppm;
MS: (C13H26O ) 198) found 181 (MH - H2O)+.
The above-mentioned alcohol (65.12 g, 0.33 mol), triethyl
orthoacetate (106.7 g, 0.67 mol), and propionic acid (0.23 g,
3.1 mmol) were dissolved in xylene (130 mL), and the mixture
was refluxed for 2 h. Solvents were removed under reduced
pressure, and the residue was distilled (kugelrohr, 130 °C/ 0.5
mmHg) to give trans-ethyl pentadec-4-enoate (71.36 g, 81%).
1H NMR: δ 5.39 (m, 2H), 4.08 (q, J ) 7.2 Hz, 2H), 2.29 (m,
4H), 1.93 (q, J ) 6.8 Hz, 2H), 1.25 (m and br s, 16H), 1.23 (t,
J ) 7.0 Hz, 3H), 0.85 (t, J ) 6.8 Hz, 3H); 13C NMR: 173.2,
131.7, 127.8, 60.2, 34.4, 32.4, 31.9, 29.7, 29.5, 29.4, 29.2, 29.1,
27.9, 22.7, 14.2, 14.1 ppm. MS: (C17H32O2 ) 268) found 269
(MH+), 291 (MNa+).
a
Reagents and conditions: (A) i. tert-butyldimethylsilyl chloride
(1.1 equiv), imidazole, DMF, rt, 16 h; ii. tributyltin hydride (1.43
equiv), 1,1-azobis(cyclohexanecarbonitrile) (0.0086 equiv), 130 °C,
2H, then I2, ether. (B) i. Bu4NF, THF, 0 °C, 3 h; ii. TsCl (1.1 equiv),
pyridine, 0 °C to room temperature, 5 h; iii. NaI (5 equiv), acetone,
rt, 3 h. (C) (Me3Si)2NK (1 equiv), (3RS,5S)-5-methyl-3-(phenyl-
sulfenyl)tetrahydrofuran-2-one (1 equiv), THF, 0 ˚C to room
temperature, 2 h.
hexepi-uvaricin.11 Further reaction with lithium (trim-
ethylsilyl)acetylide followed by desilation produces alkyne
14.
The butenolide portion of the target molecule was
prepared according to the method described by Hoye
(Scheme 2),11 with slight modifications. Thus, non-8-yn-
1-ol was protected as its tert-butyldimethylsilyl (TBS)
ether, 15. The terminal acetylene was converted into
vinyl iodide 16 via hydrostannation with tributyltin
hydride followed by iodolysis of the resultant vinylstan-
nane.15 The primary alcohol was deprotected and con-
verted to the corresponding tosylate, and the latter was
reacted with iodide to produce diiodide 17. Selective
nucleophilic substitution of the aliphatic iodide by the
enolate of (3RS,5S)-5-methyl-3-(phenylsulfenyl)tetrahy-
drofuran-2-one produced 19.11,15
The final steps of this convergent synthesis were based
on the cross-coupling of key intermediates 14 and 19
(Scheme 3) following the same strategy reported ear-
lier.11,15 Thus, Pd(0)- and CuI-catalyzed cross-coupling
reaction of the terminal acetylene 14 with vinyl iodide
19 afforded the eneyne intermediate, 20, which was
hydrogenated over Wilkinson’s catalyst to give 21. Fi-
nally, oxidation of the thioether to the corresponding
sulfoxide followed by thermal elimination afforded 1.
In conclusion, the first total synthesis of naturally
occurring (+)-uvaricin, 1 has been achieved using (a)
Sharpless AD reactions to incorporate necessary stere-
ochemical features in a regio- and enantioselectively
controlled manner, and (b) a Williamson type etherifi-
cation reaction on an appropriately functionalized bis-
mesylate intermediate for construction of the bis-THF
ring system.
(4R,5R)-5-Hyd r oxyp en ta d eca n -1,4-olid e, 3. Compound
2 (20.26 g, 75.6 mmol) was added to a cold (0 °C) solution of
AD-mix-â (106 g) and MeSO2NH2 (7.16 g, 75.4 mmol) in tert-
butyl alcohol-water (1:1, 750 mL), and the mixture was stirred
at 0 °C for 16 h and then quenched by the addition of sodium
metabisulfite (113 g). The mixture was worked-up with ethyl
acetate and water, solvents were removed under reduced
pressure, and the residue was dissolved in methanol (80 mL).
Aqueous KOH (3 N, 80 mL) was added, and the mixture was
stirred at 60 °C for 2 h and then cooled to 0 °C, acidified with
3 N HCl, and extracted with ethyl acetate. Solvents were
removed under reduced pressure, and the residue was dis-
solved in CH2Cl2. p-Toluenesulfonic acid (TsOH, 0.2 g) was
added, and the mixture was stirred at room temperature for
1 h, worked up with saturated aqueous NaHCO3 and CH2Cl2,
and purified by column chromatography (silica gel, hexanes-
ethyl acetate, 1:1) to give lactone 3 (17.2 g, 89%) in the form
of white crystals. Mp 64-65°; [R]D -25.3 (c ) 2.1, CHCl3); 1H
NMR: 4.40 (td, J ) 7.4, 4.6 Hz, 1H), 3.55 (m, 1H), 2.61 (ddd,
J ) 17.8, 9.9, 5.0 Hz, 1H), 2.53 (dd, J ) 17.8, 9.5 Hz, 1H),
2.28-2.19 (m, 1H), 2.16-2.06 (m, 1H), 1.86 (d, J ) 5.4 Hz,
1H), 1.60-1.20 (m and br s, 18H), 0.86 (t, J ) 6.8 Hz, 3H); 13
C
NMR: 177.3, 83.0, 73.6, 32.9, 31.9, 29.5, 29.3, 28.7, 25.4, 24.1,
22.7, 14.1 ppm; MS: (C15H28O3 ) 256) found 257 (MH+), 279
(MNa+).
(4R,5S)-5-(4-Nitr oben zoyloxy)p en ta d eca n -1,4-olid e, 4.
DEAD (5.71 g, 32.8 mmol) was added to a solution of 3 (7.0 g,
27.3 mmol), PPh3 (8.6 g, 32.8 mmol), and 4-nitrobenzoic acid
(5.48 g, 32.8 mmol) in dry benzene (70 mL), and the mixture
was stirred at room temperature for 16 h and then worked up
by chromatography over a double layer column (neutral active
alumina over silica gel, hexanes-ethyl acetate, 9:1-3:1) to give
the crude nitrobenzoate ester 4 (10.53 g, 95%). 1H NMR: 8.24
(d, J ) 8.8 Hz, 2H), 8.14 (d, J ) 8.8 Hz, 2H), 5.35 (dt, J ) 8.7,
4.4 Hz, 1H), 4.65 (td, J ) 7.4, 4.4 Hz, 1H), 2.54 (m, 2H), 2.34
(m, 1H), 2.20 (m, 1H), 1.73 (m, 2H), 1.40-1.16 (m and br s,
16H), 0.80 (t, J ) 6.8 Hz, 3H); 13C NMR: δ 176.2 164.0, 150.7,
135.1, 130.7, 123.6, 79.9, 75.2, 31.9, 31.8, 29.8, 29.5, 29.4, 29.3,
29.2, 28.0, 25.2, 23.1, 22.6, 14.1 ppm; MS analysis (C22H31NO6
) 405) found 406 (MH+), 428 (MNa+).
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were mea-
sured in CDCl3 at 400 and 100 MHz, respectively. Positive
ion mass spectra, using the fast ion bombardment (FIB)
technique, were obtained on a VG ZAB-VSE double focusing,
high-resolution mass spectrometer equipped with either a
cesium or sodium ion gun. Negative mass spectra were
obtained with Sciex API 100. Optical rotations were measured
in a one decimeter (1.3 mL) cell using an Autopol III automatic
polarimeter. TLC was performed on glass sheets precoated
with silica gel (Merck, Kieselgel 60, F254, Art. 5715). Column
chromatographic separations were performed on silica gel
(Merck, Kieselgel 60, 230-400 mesh, Art. 9385) under pres-
(4R,5S)-(Isop r op ylid en ed ioxy)p en t a d eca n -1-ol,
5.
Lithium aluminum hydride (4.94 g, 0.13 mol) was slowly added
to a solution of 4 (10.53 g, 26.0 mmol) in dry ether (100 mL)
at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then
refluxed for another 2 h, cooled, diluted with ether, and
quenched with water. The mixture was filtered through
Celite, and solvents were removed to afford crude 1,4,5-
trihydroxypentadecane (8.89 g, >100%) which was taken to
(15) Makabe, H.; Tanaka, A.; Oritani, T. J . Chem. Soc., Perkin
Trans. 1 1994, 1975.

5866 J . Org. Chem., Vol. 63, No. 17, 1998
Yazbak et al.
Sch em e 3. Syn th esis of 1a
a
Reagents and conditions: (A) CuI (cat.), Pd(PPh3)4 (cat), Et3N, rt, 22 h. (B) RhCl(PPh3)3 (cat.), H2, MeOH-benzene, 1:1, 24 h. (C) i.
m-CPBA, CH2Cl2, 0 °C, 20 min; ii. toluene, reflux, 1 h.
the next step without further purification. Physical data of a
purified sample: [R]D -3.76 (c ) 1.01, MeOH); 1H NMR: δ
3.76-3.59 (m, 4H), 1.92 (br s, 3H), 1.80-1.60 (m, 3H), 1.60-
stirred at the same temperature for 2 h. In a separate flask,
a mixture of NaH (60% in mineral oil, 0.68 g, 17.0 mmol) in
dry THF (30 mL) was cooled to 0 °C, triethyl phosphonoacetate
(3.81 g, 17.0 mmol) was added dropwise, the mixture was
stirred at 0 °C for 0.5 h, and then the whole mixture was added
dropwise to the first at -78 °C. The combined mixture was
stirred at room temperature for 16 h, water (6 mL) was added,
followed by Celite (6 g), diluted with ether (30 mL), and the
mixture was stirred at 0 °C for 0.5 h. Filtration over Celite
and removal of the solvent followed by column chromatography
(silica gel, hexanes-ethyl acetate, 95:5) yielded 8 (4.67 g, 78%)
in the form of a colorless oil. [R]D ) +1.4 (c ) 1.94, CHCl3);
1H NMR: δ 6.91 (dt, J ) 15.6, 6.7 Hz, 1H), 5.78 (d, J ) 15.6
Hz, 1H), 5.41 (m, 2H), 4.12 (q, J ) 7.2 Hz, 2H), 3.96 (m, 2H),
2.30-1.95 (m, 6H), 1.45-1.18 (m and br s, 20H), 1.37 (s, 3H),
1.30 (s, 3H), 1.25 (t, J ) 6.6 Hz, 3H), 0.83 (t, J ) 7.8 Hz, 3H).
13C NMR: δ 166.6, 148.5, 130.8, 129.0, 121.5, 107.3, 78.0, 77.9,
60.1, 32.1, 31.9, 31.6, 30.9, 29.7, 29.6, 29.5, 29.3, 29.0, 28.6,
26.2, 26.0, 22.6, 14.2, 14.1 ppm; MS: (C26H46O4 ) 422) found
445 (MNa+).
(t r a n s,t r a n s,10R ,11S )-10,11-(Isop r op ylid e n e d ioxy)-
h en eicosa -2,6-d ien -1-ol, 9a . Compound 8 (4.67 g, 11.06
mmol) was dissolved in dry THF (46 mL) and cooled to -78
°C, DIBAL-H (1 M in toluene, 28 mL, 28 mmol) was added,
and the mixture was stirred at -78 °C for 1 h. Water (10 mL)
was added, followed by Celite (10 g), diluted with ether (50
mL), and the mixture was stirred at 0 °C for 0.5 h. Filtration
through Celite and removal of the solvent followed by column
chromatography (silica gel, hexanes-ethyl acetate, 7:3) af-
1.40 (m, 4H), 1.40-1.20 (m, 15H), 0.86 (t, J ) 6.8 Hz, 3H); 13
C
NMR: δ 74.7, 74.3, 63.0, 33.6, 31,9, 30.8, 29.6, 29.3, 29.0, 25.6,
22.7, 14.1 ppm; MS: (C15H32O3 ) 260) found 283 (MNa+).
The above-mentioned triol (8.89 g) was dissolved in a
mixture of acetone (90 mL) and hexane (180 mL) together with
TsOH (0.9 g), and the solution was refluxed for 16 h and then
worked-up with saturated aqueous NaHCO3 and hexane
followed by column chromatography (silica gel, hexanes-ethyl
acetate, 7:3) to give 5 (6.94 g, 89%) in the form of a colorless
oil. [R]D +1.9 (c ) 1.96, MeOH); 1H NMR: δ 4.01 (m, 2H),
3.64 (m, 2H), 2.23 (br s, 1H), 1.69 (m, 2H), 1.52 (m, 4H), 1.41
(s, 3H), 1.31 (s, 3H), 1.24 (m and br s, 16H), 0.84 (t, J ) 6.4
Hz, 3H); 13C NMR: δ 107.5, 78.1, 78.0, 62.7, 31.9, 29.8, 29.7,
29.6, 29.5, 29.3, 28.5, 26.7, 26.2, 25.9, 22.6, 14.1 ppm; MS:
(C18H36O3 ) 300) found 301 (MH+), 323 (MNa+).
(3R S ,6R ,7S )-6,7-(Isop r op ylid e n e d ioxy)h e p t a d e c-1-
en -3-ol, 6. Celite (12.5 g) and PCC (12.5 g, 58 mmol) were
added to a solution of 5 (8.71 g, 29.0 mmol) in CH2Cl2 (90 mL),
and the mixture was stirred at room temperature for 2 h,
monitored by TLC (hexanes-ethyl acetate, 4:1), and then
filtered through silica gel. Removal of the solvent afforded
the corresponding aldehyde (6.46 g, 75%), which was im-
mediately used in the next step without further purification.
Vinylmagnesium bromide (1 M in THF, 26 mL, 26 mmol)
was added to the solution of the above-mentioned aldehyde
(6.46 g, 21.6 mmol) in ether (65 mL) at -30 °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 6 (5.1 g, 72%). 1H NMR (300 MHz): δ 5.84 (ddd, J )
17.2, 10.4, 3.9 Hz, 1H), 5.14 (dq, J ) 17.2, 1,5 Hz, 1H), 5.08
(dq, J ) 10.4, 1.5 Hz, 1H), 4.10 (m, 1H), 4.01 (m, 2H), 2.10 (br
s, 1H), 1.41 (s, 3H), 1.35 (s, 3H), 1.80-1.15 (m and br s, 22H),
0.85 (t, J ) 6.9 Hz, 3H); MS: (C20H38O3 ) 326) found 349
(MNa+).
(tr a n s,8R,9S)-Eth yl 8,9-(Isopr opyliden edioxy)n on adec-
4-en oa te, 7. A solution of 6 (5.1 g, 15.6 mmol), triethyl
orthoacetate (5.03 g, 31 mmol), and propionic acid (114 mg,
1.5 mmol) in xylene (25 mL) was refluxed for 2 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 7 (5.62 g, 91%) in the form of a colorless
oil. 1H NMR: δ 5.43 (m, 2H), 4.09 (q, J ) 7.1 Hz, 2H), 3.96
(m, 2H), 2.30 (m, 4H), 2.15 (m, 1H), 1.98 (m, 1H), 1.54-1.20
(m and br s, 20H), 1.36 (s, 3H), 1.33 (s, 3H), 1.23 (t, J ) 7.1
Hz, 3H), 0.84 (t, J ) 7.1 Hz, 3H). 13C NMR: δ 173.2, 130.8,
128.6, 107.3, 78.0, 77.3, 60.2, 34.3, 31.9, 29.7, 29.6, 29.5, 29.3,
29.0, 28.6, 27.9, 26.2, 26.0, 22.7, 14.2, 14.1 ppm; MS: (C24H44O4
) 396) found 419 (MNa+).
forded 9a (3.68 g, 88%) in the form of a colorless oil. [R]D
)
+0.7 (c ) 2.2, CHCl3); 1H NMR: δ 5.62 (m, 2H), 5.41 (m, 2H),
4.04 (d, J ) 4.4 Hz, 2H), 3.97 (m, 2H), 2.22-1.95 (m, 6H),
1.69-1.20 (m and br s, 21H), 1.40 (s, 3H), 1.32 (s, 3H), 0.85 (t,
J ) 7.2 Hz, 3H). 13C NMR: δ 132.5, 130.0, 129.3, 107.3, 78.0,
77.3, 63.6, 32.2, 32.1, 31.9, 29.7, 29.6, 29.5, 29.3, 29.0, 28.6,
26.2, 26.1, 26.0, 22.7, 14.1 ppm; MS: (C24H44O3 ) 380) found
381 (MH+), 403 (MNa+).
(tr a n s,tr a n s,10R,11S)-1-(Meth oxym eth oxy)-10,11-(iso-
p r op ylid en ed ioxy)h en eicosa -2,6-d ien e, 9b. Diisopropyl-
ethylamine (3 mL, 17.2 mmol) was added to a solution of 9a
(3.68 g, 9.7 mmol) in dry CH2Cl2 (35 mL) at 0 °C followed by
the addition of chloromethyl methyl ether (1.17 g, 14.52 mmol).
The mixture was stirred overnight at room temperature and
then worked up with water and CH2Cl2. Purification by
column chromatography (silica gel, hexanes-ethyl acetate, 9:1)
afforded 9b (3.96 g, 96%) in the form of a colorless oil. [R]D
)
1
+1.29 (c ) 2.08, CHCl3); H NMR: δ 5.69 (dtd, J ) 15.4, 6.4,
0.8 Hz, 1H), 5.53 (dtd, J ) 15.6, 6.4, 0.6 Hz, 1H), 5.42 (m, 2H),
4.6 (d, J ) 0.8 Hz, 2H), 3.98 (m, 4H), 3.34 (s, 3H), 2.25-1.95
(m, 6H), 1.60-1.15 (m and br s, 20H), 1.40 (s, 3H), 1.31 (s,
3H), 0.82 (t, J ) 6.8 Hz, 3H). 13C NMR: δ 134.4, 130.0, 126.0,
107.3, 95.3, 78.0, 77.3, 67.9, 55.2, 32.3, 32.1, 31.9, 29.7, 29.6,
29.5, 29.3, 29.1, 28.6, 26.2, 26.0, 22.7, 14.1 ppm. MS: (C26H48O4
) 424) found 447 (MNa+).
(tr a n s,tr a n s,10R,11S)-E t h yl 10,11-(Isop r op ylid en ed i-
oxy)h en eicosa -2,6-d ien oa te, 8. DIBAL-H (1 M in toluene,
15.6 mL, 15.6 mmol) was added to a solution of 7 (5.62 g, 14.2
mmol) in dry toluene (56 mL) at -78 °C, and the mixture was
(tr a n s,6S,7S,10R,11S)-1-(Met h oxym et h oxy)-6,7-d ih y-
d r oxy-10,11-(isop r op ylid en ed ioxy)h en eicos-2-en e, 10a .

Total Synthesis of Uvaricin
J . Org. Chem., Vol. 63, No. 17, 1998 5867
Methanesulfonamide (0.27 g) and 9b (1.23 g, 2.9 mmol) were
added to a two-phase mixture of AD-mix-R (4.1 g) in tert-butyl
alcohol-water (1:1, 29 mL). The mixture was stirred at 0 °C
for 16 h and then worked up by slow addition of sodium
metabisulfite (4.5 g) and extraction with ethyl acetate. Puri-
fication by column chromatography (silica gel, hexanes-ethyl
acetate, 3:7) afforded 10a (0.84 g, 63%). [R]D ) -9.22 (c )
1.94, CHCl3); 1H NMR: δ 5.72 (dt, J ) 15.4, 6.2 Hz, 1H), 5.58
(dt, J ) 15.4, 6.2 Hz, 1H), 4.61 (s, 2H), 4.02 (m, 2H), 3.98 (d,
J ) 6.2 Hz, 2H), 3.41 (m, 2H), 3.34 (s, 3H), 2.43 (br s, 2H),
2.23 (m, 1H), 2.14 (m, 1H), 1.75-1.20 (m and br s, 24H), 1.41
(s, 3H), 1.31 (s, 3H), 0.85 (t, J ) 6.8 Hz, 3H). 13C NMR: δ
134.2, 126.5, 107.5, 95.5, 78.1, 74.2, 74.0, 67.9, 55.2, 32.7, 31.9,
30.6, 29.8, 29.7, 29.6, 29.5, 29.3, 28.6, 28.5, 26.3, 26.0, 25.9,
25.8, 22.7, 14.1 ppm. MS: (C26H50O6 ) 458) found 481 (MNa+).
(t r a n s,6S ,7S ,10R ,11S )-1-(Me t h oxym e t h oxy)-6,7-b is-
(m esyloxy)-10,11-(isop r op ylid en ed ioxy)h en eicos-2-en e,
10b. Methanesulfonyl chloride (2.31 g, 20.2 mmol) was added
dropwise to a solution of 10a (2.32 g, 5.1 mmol) in dry CH2Cl2
(24 mL) and triethylamine (5 mL) at -30 °C. The mixture
was warmed to 0 °C, kept at this temperature for an additional
1 h, and then quenched with water and extracted with CH2-
Cl2. Solvent was removed under reduced pressure, and the
residue was purified by column chromatography (silica gel,
hexanes-ethyl acetate, 1:1) to give 10b (3.07 g, 5.0 mmol,
99%). 1H NMR: δ 5.68 (m, 2H), 4.87 (m, 1H), 4.82 (m, 1H),
4.63 (s, 2H), 4.08 (m, 1H), 4.01 (d, J ) 4.4 Hz, 2H), 4.00 (m,
1H), 3.36 (s, 3H), 3.10 (s, 6H), 2.24 (m, 2H), 2.15-1.20 (m and
br s, 24H), 1.42 (s, 3H), 1.32 (s, 3H), 0.87 (t, J ) 6.0 Hz, 3H).
13C NMR: δ 132.0, 127.7, 95.4, 80.7, 80.0, 77.8, 77.4, 67.5, 51.0,
38.6, 31.8, 31.0, 29.6, 29.5, 29.2, 28.4, 27.3, 26.2, 25.7, 25.4,
22.6, 14.1 ppm. MS: (C28H54O10S2 ) 614) found 637 (MNa+).
(2R,3R,6S,7S,10R,11S)-1-(Met h oxym et h oxy)-6,7-b is-
(m esyloxy)-10,11-(isop r op ylid en ed ioxy)h en eicosa n e-2,3-
d iol, 11. Compound 10b (3.07 g, 5.0 mmol) was added to a
cold (0 °C) mixture of AD-mix-â (7.0 g) and methanesulfona-
mide (0.475 g, 5 mmol) in tert-butyl alcohol-water (3:2, 50
mL). The mixture was stirred at 0 °C for 16 h and then worked
up by slow addition of sodium metabisulfite (7.5 g) followed
by extraction with ethyl acetate. Solvent was removed, and
the resultant crude 11 (3.4 g) was used in the next reaction
without further purification. 1H NMR: δ 4.85 (m, 2H), 4.63
(s, 2H), 4.04 (m, 1H), 3.98 (m, 1H), 3.69 (m, 1H), 3.62 (m, 3H),
3.37 (s, 3H), 3.11 (s, 3H), 3.10 (s, 3H), 2.07 (m, 2H), 1.84-1.20
(m and br s, 26H), 1.40 (s, 3H), 1.30 (s, 3H), 0.85 (t, J ) 7.0
Hz, 3H). 13C NMR: δ 107.6, 97.0, 80.9, 77.8, 77.4, 72.5, 71.5,
70.5, 55.4, 53.3, 43.2, 38.7, 31.8, 29.5, 29.4, 29.2, 28.4, 28.3,
27.3, 26.7, 26.2, 25.7, 25.4, 22.5, 14.0 ppm. MS: (C28H56O12S2
) 648) found 781 (MCs+).
(2R,3R,6R,7R,10R,11S)-1-(Met h oxym et h oxy)-3,6:7,10-
d ioxyd oh en eicosa n e-2,11-d iol, 12a . TsOH (1.0 g) was
added to a solution of the above-mentioned diol (3.4 g) in
methanol (50 mL), and the mixture was stirred at room
temperature for 16 h and then washed with saturated aqueous
NaHCO3 and extracted with ethyl acetate. Solvent was
removed under reduced pressure, the residue was dissolved
in pyridine (10 mL), and the mixture was heated to 140 °C for
4 h. The solvent was removed again, worked-up with water
and ethyl acetate, and purified over silica gel to give 12a (1.0
g, 48%) and 12b (0.25 g, 13%). Physical data of 12a : 1H
NMR: δ 4.62 (AB quartet, 6.8 Hz, 2H), 3.96 (dt, J ) 8.5, 5.9
Hz, 1H), 3.90 (m, 2H), 3.84 (m, 2H), 3.67-3.50 (m, 3H), 3.33
(s, 3H), 2.75 (br, 1H), 1.96 (m, 4H), 1.91 (m, 2H), 1.77 (m, 2H),
1.56 (br s, 1H), 1.21 (m and br s, 20H), 0.84 (t, J ) 7.1 Hz,
1H). 13C NMR: δ 96.8, 82.8, 82.5, 82.4, 80.2, 73.1, 71.2, 69.5,
55.3, 32.3, 31.9, 29.7, 29.6, 29.5, 29.3, 28.9, 28.8, 28.2, 26.0,
24.4, 22.7, 14.1 ppm. MS: (C23H44O6 ) 416) found 439 (MNa+).
(2R,3R,6R,7R,10R,11S)-1,2,11-Tr ih yd r oxy-3,6:7,10-d i-
oxid oh en eicosa n e, 12b. Compound 12a (1.0 g, 2.4 mmol)
was dissolved in dimethyl sulfide (4 mL) and dry CH2Cl2 (2
mL) and cooled to 0 °C. Boron trifluoride etherate (0.89 mL,
7.2 mmol) was added dropwise, and the mixture was stirred
for additional 5 min then quenched with saturated aqueous
NaHCO3 and extracted with ethyl acetate. Removal of the
solvent and column chromatography (silica gel, hexanes-ethyl
acetate, 3:7) afforded 12b (0.705 g, 79%) in the form of a
colorless oil. [R]D +0.6 (c ) 2.05, CHCl3); 1H NMR: δ 4.01
(dt, J ) 8.3, 5.8 Hz, 1H), 3.95-3.82 (m, 4H), 3.68 (dd, J )
11.5, 3.4 Hz, 1H), 3.60 (dd, J ) 11.5, 5.3 Hz, 1H), 3.53 (td, J
) 5.3, 3.8 Hz, 1H), 2.50 (br s, 3H), 1.93-1.20 (m and br s, 26H),
0.85 (t, J ) 7.2 Hz, 3H); 13C NMR: δ 82.8, 82.7, 82.5, 80.5,
73.6, 71.3, 64.2, 32.3, 31.9, 29.7, 29.6, 29.5, 29.3, 29.0, 28.7,
28.1, 26.1, 24.4, 22.7, 14.1 ppm. MS: (C21H40O5 ) 372) found
395 (MNa+).
(2R,3R,6R,7R,10R,11S)-1-(Tosyloxy)-3,6:7,10-d ioxid o-
h en eicosa n e-2,11-d iol, 12c. Tosyl chloride (0.558 g, 2.93
mmol) was added in small portions to a solution of 12b (0.91
g, 2.44 mmol) in pyridine (5 mL) at 0 °C, and the mixture was
stirred for additional 3.5 h and then worked up with water
and CH2Cl2. Solvent was removed under reduced pressure,
and the residue was purified by column chromatography (silica
gel, ethyl acetate) to give 12c (0.66 g, 51%) and recovered 12b
(0.18 g, 20%). Physical properties of 12c: 1H NMR: δ 7.76
(d, J ) 8.4 Hz, 2H), 7.31 (d, J ) 8.4 Hz, 2H), 4.06-3.98 (m,
2H), 3.94 (dt, J ) 8.5, 5.7 Hz, 1H), 3.92-3.74 (m, 4H), 3.66 (q,
J ) 5.3 Hz, 1H), 2.42 (s, 3H), 2.05-1.16 (m and br s, 26H),
0.84 (t, J ) 7.2 Hz, 3H); 13C NMR: δ 144.9, 132.7, 129.9, 128.0,
127.9, 82.8, 82.5, 79.3, 71.5, 71.2, 71.1, 31.9, 29.7, 29.6, 29.5,
29.3, 28.9, 28.7, 28.1, 26.0, 24.4, 22.7, 21.6, 14.1 ppm. MS:
(C28H46O7S ) 526) found 527 (MH+).
(2R,3R,6R,7R,10R,11S)-11-Hyd r oxy-1,2-ep oxy-3,6:7,10-
d ioxid oh en eicosa n e, 13a . Potassium carbonate (0.345 g, 2.5
mmol) was added to a solution of 12c (0.66 g, 1.25 mmol) in
methanol (10 mL), and the mixture was stirred at room-
temperature overnight, worked up with water and ethyl
acetate, and purified by column chromatography (silica gel,
ethyl acetate) to give 13a (398 mg, 90%). [R]D +4.4 (c ) 1.44,
1
CHCl3); H NMR: δ 3.96 (td, J ) 7.0, 4.4 Hz, 1H), 3.93-3.80
(m, 4H), 2.96 (q, J ) 3.5 Hz, 1H), 2.72 (d, J ) 3.5 Hz, 2H),
2.12-1.20 (m and br s, 26H), 0.84 (t, J ) 7.0 Hz, 3H); 13C
NMR: δ 82.8, 82.6, 82.3, 78.5, 71.2, 54.2, 44.1, 32.4, 31.9, 29.7,
29.6, 29.5, 29.3, 28.8, 28.2, 26.0, 24.5, 22.7, 14.1 ppm. MS:
(C21H38O4 ) 354) found 377 (MNa+); 393 (MK+).
(2R,3R,6R,7R,10R,11S)-11-Acet oxy-1,2-ep oxy-3,6:7,10-
d ioxid oh en eicosa n e, 13b . Pyridine (1 mL) and acetic
anhydride (0.5 mL) were mixed with 13a (375 mg, 1.06 mmol).
The mixture was stirred at room temperature for 16 h, worked
up with water and ethyl acetate, and purified by column
chromatography (silica gel, hexanes-ethyl acetate, 1:1) to give
13b (291 mg, 69%). 1H NMR: δ 4.88 (m, 1H), 3.96 (m, 1H),
3.95-3.82 (m, 3H), 2.93 (m, 1H), 2.68 (m, 2H), 2.15-1.20 (m
and br s, 26H), 1.90 (s, 3H), 0.87 (t, J ) 7.2 Hz, 3H). MS:
(C23H40O5 ) 396): 397 (MH+), 419 (MNa+).
(4R,5R,8R,9R,12R,13S)-13-Acetoxy-4-h yd r oxy-3,6:7,10-
d ioxid otr icos-1-yn e, 14. A solution of n-BuLi (1.6 M in THF,
0.32 mL, 0.51 mmol) was added to a solution of (trimethylsilyl)-
acetylene (50.6 mg, 0.51 mmol) in THF (1 mL) at -78 °C. The
mixture was warmed to -30 °C, stirred at this temperature
for 0.5 h, and then cooled again to -78 °C. Boron trifluoride
(72.54 mg, 0.51 mmol) was added, the mixture was stirred for
0.5 h, epoxide 13b (98 mg, 0.25 mmol) was added, and the
mixture was stirred between -78 °C and -30 °C for 10 h.
Saturated aqueous ammonium chloride was added, the mix-
ture was extracted with ethyl acetate, and the solvent was
removed under reduced pressure. The residue (102 mg) was
dissolved in THF (2 mL) and cooled to 0 °C, tetrabutylam-
monuim fluoride (1 M solution in THF, 0.25 mL) was added,
and the mixture was stirred for 2 h and then quenched with
saturated aqueous ammonium chloride. Extraction with ethyl
acetate and purification by column chromatography (silica gel,
hexanes-ethyl acetate, 7:3) afforded 14 (41 mg, 39%) and
recovered 13b (33 mg, 35%). [R]D ) -14.6 (c ) 0.84, CHCl3);
1H NMR: δ 4.92 (m, 1H), 3.99 (m, 2H), 3.87 (m, 2H), 3.59 (q,
J ) 5.7 Hz, 1 H,), 2.62 (br s, 1H), 2.41 (m, 2H), 2.03 (s, 3H),
2.05-1.85 (m, 4H), 1.80-1.45 (m, 6H), 1.22 (m and br s, 16H),
0.86 (t, J ) 6.8 Hz, 3H). 13C NMR: δ 82.1, 82.0, 81.3, 80.6,
75.3, 71.9, 70.1, 31.9, 31.0, 29.6, 29.5, 29.3, 28.7, 28.3, 27.5,
25.4, 23.9, 22.7, 21.2, 14.1 ppm. MS: (C25H42O5 ) 422) found
445 (MNa+).

5868 J . Org. Chem., Vol. 63, No. 17, 1998
Yazbak et al.
(E,Z)-8-(ter t-Bu tyld im eth ylsilyloxy)-1-iod on on -1-en e,
16. To a solution of non-8-yn-1-ol11 (2.03 g, 14.5 mmol) in DMF
(30 mL) were added imidazole (2.44 g, 35.9 mmol) and tert-
butyldimethylchlorosilane (2.36 g, 15.6 mmol). The mixture
was stirred at room temperature overnight and worked-up
with ether and water, and the residue was purified by column
chromatography (silica gel, hexanes-ethyl acetate, 7:3) to give
9-(tert-butyldimethylsilyloxy)non-1-yne (3.6 g, 98%). 1H
NMR: δ 3.59 (t, J ) 6.8 Hz, 2H), 2.17 (td, J ) 7.6, 4.8 Hz,
2H), 1.93 (t, J ) 2.8 Hz, 1H), 1.66-0.82 (m, 10H), 0.88 (s, 9H),
0.04 (s, 6H).
chromatography (silica gel, hexanes-EtOAc, 4:1) to give 19
in the form of a 4:1 mixture of two diastereomers (0.361 g,
52%). 1H NMR: δ 7.53 (m, 2H), 7.35 (m, 3H), 6.47 (dt, J )
14.3, 7.2 Hz, 0.8H), 6.14 (m, 0.4H), 5.94 (dt, J ) 14.3, 1.2 Hz,
0.8H), 4.58 (m, 0.2H), 4.47 (m, 0.8H), 2.49 (dd, J ) 14.0, 7.6
Hz, 0.8H), 2.31 (dd, J ) 13.8, 5.4 Hz, 0.2H), 2.11 (m, 0.4H),
2.01 (qd, J ) 7.4, 1.4 Hz, 1.6H), 1.94 (dd, J ) 14.0, 6.8 Hz,
1H), 1.76 (m, 2H), 1.35 (d, J ) 6.2 Hz, 0.6H), 1.62-1.20 (m
and br s, 10H), 1.16 (d, J ) 6.4 Hz, 2.4H); MS: (C20H27IO2S )
458) found 459 (MH+), 481 (MNa+).
3-(P h en ylt h io)-11,12,13,13,14,14-h exa d eh yd r ou va r i-
cin , 20. Copper(I) iodide (3 mg, 0.015 mmol) and Pd(PPh3)4
(4 mg, 0.0034 mmol) were added to a solution of 14 (14 mg,
0.033 mmol) and 19 (30.3 mg, 0.066 mmol) in Et3N (0.5 mL).
The mixture was stirred at room temperature for 22 h, washed
by saturated aqueous ammonium chloride, and extracted with
ether, and the crude product was purified by column chroma-
tography (silica gel, hexanes-ethyl acetate, 1:1) to give 20
(11.2 mg, 45%). 1H NMR: δ 7.49-7.54 (m, 2H), 7.31-7.39
(m, 3H), 6.04 (dt, J ) 15.8, 7.0 Hz, 1H), 5.42 (d, J ) 15.8 Hz,
1H), 4.92 (m, 1H), 4.47 (m, 1H), 3.99 (q, J ) 6.4 Hz, 2H), 3.87
(m, 2H), 3.57 (q, J ) 5.7 Hz, 1H), 2.49 (m, 4H), 2.10-1.85 (m,
6H), 2.03 (s, 3H), 1.75-1.40 (m, 10H), 1.37-1.20 (m, 24H), 1.17
(d, J ) 6.2 Hz, 3H), 0.85 (t, J ) 7.1 Hz, 3H). MS: (C45H68O7S
) 752) found 885 (MCs+).
3-(P h en ylth io)u va r icin , 21. A solution of 20 (10 mg, 0.013
mmol) in benzene-methanol (1:1, 2 mL) was purged with
argon and then hydrogenated (1 atm H2) over chlorotris-
(triphenylphosphine)rhodium (10 mg, 0.01 mmol) for 16 h.
Column chromatography (silica gel, hexanes-ethyl acetate,
1:1) afforded 21 (6 mg, 62%). 1H NMR: δ 7.49-7.55 (m, 2H),
7.31-7.40 (m, 3H), 4.92 (ddd, J ) 9.0, 4.8, 4.2 Hz, 1H), 4.47
(m, 1H), 4.00 (td, J ) 7.5, 5.6 Hz, 1H), 3.86 (m, 2H), 3.80 (td,
J ) 7.6, 6.4 Hz, 1H), 3.36 (m, 1H), 2.50 (dd, J ) 13.9, 7.6 Hz,
2H), 2.04 (s, 3H), 1.95 (m, 4H), 1.80-1.15 (m and br s, 47H),
1.17 (d, J ) 6.3, 3H), 0.85 (t, J ) 7.0 Hz, 3H); MS: (C45H74O7S
) 758) found 781 (MNa+).
Uva r icin , 1. m-CPBA (2 mg) was added to a solution of
the above-described product (6 mg, 0.008 mmol) in CH2Cl2 (2
mL) at 0 °C, and the mixture was stirred at this temperature
for 20 min and then filtered through a silica gel column using
CH2Cl2. Solvent was removed under reduced pressure, and
the residue was refluxed in toluene (1 mL) for 1 h. Solvent
was removed again, and the residue was purified by column
chromatography (silica gel, hexanes-ethyl acetate, 1:1) to give
1 (2 mg, 32%). [R]D +11.6 (c ) 0.09, MeOH), lit.9 11.3 (MeOH);
1H NMR and 13C NMR data were found to be identical to the
reported spectral data.9 HRMS: (C39H68O7Cs ) 781.4019)
found 781.4044 (MCs+).
Tributyltin hydride (6.56 g, 22.6 mmol) was added to a
mixture of the above-mentioned silyl ether (3.6 g, 14.1 mmol)
and 1,1 azobis(cyclohexanecarbonitrile) (30 mg, 0.12 mmol).
The mixture was heated at 130 °C for 2 h and then cooled to
room temperature. Excess tributyltin hydride was removed
by distillation under reduced pressure. The residue was
dissolved in ether (10 mL), iodine (4.0 g, 15.75 mmol) was
slowly added, and the solution was stirred at room tempera-
ture for 2 h. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography (silica
gel, hexanes-EtOAc) to give 16 (3.45 g, 64%). 1H NMR: δ
6.48 (dt, J ) 14.3, 7.2 Hz 0.8H), 6.15 (m, 0.4H), 5.94 (dt, J )
14.3, 1.4 Hz, 0.8H), 3.58 (two t, J ) 6.6 Hz each, 0.4 and 1.6H),
2.10 (qd, J ) 5.7, 2.6 Hz 0.4H), 2.03 (qd, J ) 7.4, 1.4 Hz, 1.6H),
1.52-1.25 (m, 10H), 0.88 (s, 9H), 0.03 (s, 6H). MS: (C15H31
-
IOSi ) 382) found 381 [M - H]-.
(E,Z)-1,9-Diiod on on -1-en e, 17. To an ice-cold solution of
16 (3.45 g, 9.0 mmol) in dry THF (34 mL) was added
tetrabutylammonium fluoride (1 M in THF, 10 mL), and the
mixture was stirred at 0 °C for 3 h and then worked up with
ether and water. The solvent was removed under reduced
pressure, and the residue was purified by column chromatog-
raphy (silica gel, hexanes-EtOAc, 7:3) to give the correspond-
ing alcohol (1.81 g, 75%). MS: 291 (M + Na+). 1H NMR: δ
6.48 (dt, J ) 14.3, 7.2 Hz, 0.8H), 6.15 (m, 0.4H), 5.95 (dt, J )
14.3, 1.2 Hz, 0.8H), 3.17 (t, J ) 7.0 Hz, 0.4H), 3.16 (t, J ) 7.0
Hz, 1.6H), 2.11 (q, J ) 6.7 Hz, 0.4H), 2.02 (q, J ) 7.1 Hz, 1.6H),
1.77 (m, 2H), 1.45-1.22 (m, 8H).
To an ice-cooled solution of the above-described alcohol (1.81
g, 6.76 mmol) in pyridine (30 mL) was added TsCl (1.68 g, 8.8
mmol). The mixture was stirred for 1 h at 0 °C and 3 h at
room temperature and then was diluted with ether, washed
with 1 N HCl, and with water. Solvent was removed under
reduced pressure, and the residue was dissolved in acetone
(20 mL). NaI (2.99 g, 19.9 mmol) was added, and the mixture
was stirred for 3 h, filtered, and concentrated. The residue
was purified by column chromatography (silica gel, hexanes-
EtOAc) to give 17 (2.0 g, 78%). 1H NMR: δ 6.47 (m, 1H), 5.95
(dt, J ) 14.4, 1.2 Hz, 1H), 3.5 (t, J ) 6.8, t Hz, 1H), 3.16 (t, J
) 8.0 Hz, 1H), 2.02 (q, J ) 6.8 Hz, 2H), 1.76 (m, 3H), 1.32 (m,
7H); 13C NMR: δ 146.56, 141.26, 74.54, 45.12, 35.99, 32.55,
30.36, 28.73, 28.68, 28.62, 28.22, 26.75.
(E,Z,3RS,5S)-3-(9-Iod on on -8-en yl)-5-m eth yl-3-(p h en yl-
su lfen yl)-tetr a h yd r ofu r a n -2-on e, 19. Sodium bis(trimeth-
ylsilyl)amide (0.5 M in toluene, 3 mL, 1.5 mmol) was added to
a cold (0 °C) solution of (3RS,5S)-5-methyl-2-(phenylsulfenyl)-
tetrahydrofuran-2-one, 1816 (0.312 g, 1.5 mmol), in THF (7 mL),
and the mixture was stirred at 0 °C for 0.5 h. A solution of
17 (0.567 g, 1.5 mmol) in HMPA (3 mL) was added, and the
mixture was warmed to room temperature and heated under
reflux for 2 h. The mixture was worked up with ether and
saturated aqueous NH4Cl, the solvent was removed under
reduced pressure, and the residue was purified by column
Ack n ow led gm en t. We thank the US-Israel Bina-
tional Science Foundation, the Israel Cancer Research
Fund, PharMore Biotechnologies, and the Skaggs In-
stitute for Chemical Biology for financial support.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of compounds 1, 3, 4, 7, 8, 9a , 10a , 11, 12a , 13a , 14,
19, 20, and 21, 13C NMR spectra of compounds 3, 4, 7, 8, 9a ,
10a , 11, 12a , 13a , 14, and 19 (25 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(16) White, J . D.; Somers, T. C.; Reddy, G. N.; J . Org. Chem. 1992,
57, 4991.
J O980453A