Studies on the total synthesis of disorazole C1. An advanced macrocycle intermediate

Article abstract of DOI:10.1021/jo010249e

Synthesis of protected tetradehydro-(6,6′-S)-(14,14′-S)-(16,16′-R)-disorazole (3), a potential precursor to the natural product disorazole C₁ (1), is described. Key features of this work include (a) an unprecedented sequential 1,5 O → O silyl rearrangement/Horner-Wadsworth-Emmons reaction used to construct 18, (b) a highly convergent Sonogashira reaction between the dienyl iodide 7 and the alkyne 8 to assemble the dienyne monomeric fragment 5, and (c) the selective cyclization of 5 to give either the cyclic monomer 23 or the dimer 3.

Full text of DOI:10.1021/jo010249e

J . Org. Chem. 2001, 66, 6037-6045
6037
Stu d ies on th e Tota l Syn th esis of Disor a zole C1. An Ad va n ced
Ma cr ocycle In ter m ed ia te
M. C. Hillier, A. T. Price, and A. I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
aimeyers@lamar.colostate.edu
Received March 7, 2001
Synthesis of protected tetradehydro-(6,6′-S)-(14,14′-S)-(16,16′-R)-disorazole (3), a potential precursor
to the natural product disorazole C1 (1), is described. Key features of this work include (a) an
unprecedented sequential 1,5 O f O silyl rearrangement/Horner-Wadsworth-Emmons reaction
used to construct 18, (b) a highly convergent Sonogashira reaction between the dienyl iodide 7 and
the alkyne 8 to assemble the dienyne monomeric fragment 5, and (c) the selective cyclization of 5
to give either the cyclic monomer 23 or the dimer 3.
In 1994, J ansen and co-workers reported the crude
structure of disorazole C1 (1), which was isolated from
the fermentation broth of the gliding bacteria Sorangium
cellulosum along with 27 other structurally related
variants.1 It may be clearly seen that 1 is a cyclic dimeric
lactone of the trieneoxazole ester 4. Comprehensive
biological activity data for these compounds was not
presented, but the original isolate was found to have high
cytotoxic and moderate antifungal activity. In light of
these data, and along with our continuing interest in the
construction of oxazole-containing natural products,2 we
contemplated a synthetic route to 1. Unfortunately, only
the general structure of 1 has been reported, and the
relative or absolute stereochemistry of the C6-C6′, C14-
C14′, and C16′-C16 stereocenters was not described. In
addition, the only known sample of disorazole C1 has
since decomposed,3 and as such, no stereochemical in-
formation can be elucidated using degradative tech-
niques. Nevertheless, it became compelling to examine
the synthesis of this molecule in order to identify its
correct structure and possibly gain insight into its
biological mode of action.
nature of the resulting triene system, which prevented
the targeted macrocycle (1) from being properly as-
sembled. In light of these difficulties, a new synthetic
route was devised (Scheme 1) involving the dienyne
monomer 5, wherein one of the olefinic moieties was
replaced by an alkyne linkage. It was envisioned that this
latter intermediate could be reached by a Sonogashira
coupling of the dienyl iodide 7 and the alkyne 8. Double-
esterification of the monomer 5, after hydrolysis of the
methyl ester, could then provide the dimeric “dehydro”-
disorazole C1 (3), which may serve as a precursor to 1,
after silyl ether removal to give 2 and selective reduction
of the alkynyl units. The latter, 2, may also serve as a
more stable derivative of the natural product 1 that could
be further evaluated for biological activity. It is important
to note, however, that the actual stereochemistry of
disorazole C1 was not an initial concern in this study,
but rather the inherent challenges that presented them-
selves in constructing this highly complex molecule. As
such, the primary goal was to obtain the correct gross
molecular structure of 1 and then, by comparison with
authentic spectral and rotation data, attempt to deter-
mine the stereochemical identity of the natural product.
Syn th etic Con sid er a tion s. Initial efforts in this
laboratory focused on the synthesis of 1 from its mono-
meric triene subunit 4 via a highly convergent dilacton-
ization reaction (Scheme 1).4 The triene monomer 4
(P ) SEM), in turn, was prepared via a Stille coupling5
of the stereochemically designated vinyl tin moiety 6 and
the chiral oxazole-containing dienyl iodide 7. However,
during the course of these investigations, it became
evident that this strategy would fail due to the unstable
Dien yl Iod id e 7. Synthesis of the dienyl iodide 7
(Scheme 2) began with the readily available L-malic acid
derivative 9,2a which was coupled with the HCl salt of
L-serine methyl ester6 to provide 10 in 67% yield. Cyclo-
dehydration of 10 to the intermediate oxazoline was
accomplished using diethylaminosulfur triflouride (DAST)7
in CH2Cl2 at -78 °C, followed by oxidation (DBU,
BrCCl3)8 of the resulting oxazoline to furnish the oxazole
11 (79%). The acetonide 11 was hydrolyzed with Dowex-
H+ and furnished diol 12a , which was converted to the
methoxy hydroxy oxazole 12d in 48% overall yield for the
(1) J ansen, R.; Irschik, H.; Reichenbach, H.; Wray, V.; Hˆfle, G.
Liebigs Ann. Chem. 1994, 759-773.
(2) (a) Tavares, F.; Lawson, J . P.; Meyers, A. I. J . Am. Chem. Soc.
1996, 118, 3303-3304. (b) Dvorak, C. A.; Schmitz, W. D.; Poon, D. J .;
Pryde, D. C.; Lawson, J . P.; Amos, R. A.; Meyers, A. I. Angew. Chem.
I. E. E. 2000, 39, 1664-1666.
(6) Racemic serine methyl ester could be used in this reaction as
well, which did not affect the yield of the subsequent cyclodehydration
reaction.
(7) (a) Middleton, W. J . J . Org. Chem. 1975, 40, 574-578. (b)
Lafargue, P.; Geunot, P.; Lellouch, J .-P. Heterocycles 1995, 41, 947-
958.
(8) (a) Williams, D. R.; Brooks, D. A.; Berliner, M. A. J . Am. Chem.
Soc. 1999, 121, 4924-4925. (b) For an alternative method for the
transformation of oxazolines to oxazoles, see: Tavares, F.; Meyers, A.
I. Tetrahedron Lett. 1994, 35, 2481-2484.
(3) J ansen, R. Gesellschaft fu¨r Biotechnologische Forschung mbH,
personal communication, 1998. We further thank Dr. J ansen for kindly
providing the spectral and mass data.
(4) Hillier, M. C.; Park, D. H.; Price, A. T.; Ng, R.; Meyers, A. I.
Tetrahedron Lett. 2000, 41, 2821-2824.
(5) For a general review of the Stille reaction, see: Farina, V.;
Krishnamurthy, V.; Scott, W. J . In Organic Reactions; Paquette, L.
A., Ed.; J ohn Wiley & Sons: New York, 1997; Vol. 50, Chapter 1.
10.1021/jo010249e CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/08/2001

6038 J . Org. Chem., Vol. 66, No. 18, 2001
Hillier et al.
Sch em e 1
Sch em e 2a
a
Reaction conditions: (a) HCl‚L-serineOMe, 1,1′-CDI, THF; (b) DAST, CH2Cl2, -78 °C; (c) DBU, BrCCl3, Ch2Cl2, 0 °C to rt; (d) Dowex-
H+, MeOH; (e) TIPSOTf, 2,6-lutidine, CH2Cl2 (0.05 M), -78 °C; (f) MeI, Ag2O, CH3CN, ∆; (g) TBAF, THF; (h) SO3‚Pyr, DMSO, Et3N,
CH2Cl2; (i) Ph3PdCH2CHO, THF; (j) I-Ph3P+CH2I, NaHMDS, HMPA, -78 °C.
four steps. Construction of the enal 13 was accomplished
in 45% overall yield from 12a via oxidation (SO3‚Pyr,
DMSO, Et3N)9 and reaction of the resultant crude alde-
hyde with triphenylphosphoranylidine acetaldehyde10 in
THF. The enal 13, thus obtained, was then subjected to
a Stork/Zhao modified11 Wittig reaction (I+Ph3PCHI,12
NaHMDS, HMPA, -78 °C) to give the dienyl iodide 7
(76%).
(E)-crotonaldehyde 14 and the tert-butyldimethylsilyl
ketene acetal 1514 to give 16 in 85% yield and 92%
enantiomeric excess (Scheme 3).15 Subsequently, it was
discovered that treatment of the acetal 16 with base
(NaH, THF, 0 °C) resulted in exclusive formation of the
aldehyde 17 (71%) presumably arising from an unusual
1,5 O f O silyl migration16 (shown in brackets) followed
by elimination of ethoxide (Scheme 3). It was subse-
quently found that 17 could be bypassed completely by
addition of NaH to a solution of 16 and triethylphos-
phonoacetate in THF at -78 °C and warming to room
temperature, producing the R,â-unsaturated ester 18 in
Alk yn e 8. The initial step toward construction of the
alkyne 8 involved a modified13 Mukaiyama aldol between
(9) Parikh, J . R.; Doering, W. v. E. J . Am. Chem. Soc. 1967, 89,
5505-5507.
(10) For a general review of this reagent see: McComsey, D. F.;
Maryanoff, B. E. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; J ohn Wiley & Sons: New York, 1995; Vol. 4, pp
2598-2599.
(13) Kiyooka, S,; Kaneko, Y,; Komura, M.; Matsuo, H.; Nakano, M.
J . Org. Chem. 1991, 56, 2276-2278.
(14) Rathke, M. W.; Sullivan, D. F. Synth. Commun. 1973, 3, 67-
72.
(11) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
(12) Seyferth, D.; Heeren, J . K.; Singh, D.; Grim, S. O.; Hughes, W.
B. J . Organometallic Chem. 1966, 5, 267-274.
(15) See the Supporting Information.
(16) For a cursory review of O f O silyl migrations, see: Ru¨cker,
C. Chem. Rev. 1995, 95, 1009-1064.

Total Synthesis of Disorazole C1
J . Org. Chem., Vol. 66, No. 18, 2001 6039
Sch em e 3a
Sch em e 5a
a
Reaction conditions: (a) BH3‚THF, N-Ts-L-valine, CH2Cl2, -78
a
Reaction conditions: (a) PdCl2(PPh3)2, CuI, Et3N, CH3CN, -20
°C; (b) NaH (1 equiv), THF, -78 to 0 °C; (c) (EtO)2P(O)CH2CO2Et,
NaH (2 equiv), THF, -78 °C to rt.
°C to rt; (b) 1 N LiOH, THF; (c) DPTC, DMAP, toluene, ∆; (d)
HF‚Pyr, CH3CN.
Sch em e 4a
otal aldehyde was subjected to a Stork/Zhao modified11
Wittig reaction, and the PMB protecting group was
oxidatively removed to afford the vinyl iodide 22 in 67%
yield for the two steps. Treatment of 22 with excess
NaHMDS (2 equiv) resulted in elimination of the iodide
to give the alkyne 822 in high yield (93%).23
Son oga sh ir a Cou p lin g a n d Cycliza tion . With the
requisite subunits 7 and 8 in hand, the Sonogashira
coupling24 was performed providing the dienyne monomer
5 in 87% yield (Scheme 5). The methyl ester of 5 was
hydrolyzed using 1 N LiOH in THF, and the resultant
crude carboxylic acid was treated directly with dipyridyl
thionocarbonate (DPTC)25 and catalytic dimethylamino
pyridine (DMAP) in refluxing toluene to afford, surpris-
ingly, only the protected cyclic monomer 23 (46%).
Furthermore, none of the expected cyclic dimer 3 was
formed.26 Changes in reactant concentration did not
appear to affect the outcome of this transformation.
Deprotection of the silylated alcohols in the cyclic mono-
mer 23 with HF‚pyridine gave a mixture (3:1) of products,
a
Reaction conditions: (a) DIBAL, CH2Cl2, -78 °C; (b) D-(-)-
DIPT, t-BuOOH, Ti(O-i-Pr)4, CH2Cl2, -30 °C; Red-Al, THF, -20
to 0 °C; (d) p-methoxybenzylidene dimethyl acetal, PPTS, CH2Cl2;
(e) DIBAL, CH2Cl2, -78 °C; (f) Dess-Martin periodinane, pyridine,
t-BuOH, CH2Cl2; (g) I-Ph3P+CH2I, NaHMDS, HMPA, THF, -78
°C; (h) DDQ, CH2Cl2, H2O; (i) NaHMDS (2 equiv), THF, -78 °C
to rt.
72% yield. The scope of this one-pot three-step transfor-
mation is currently being examined with other sub-
strates.17
(21) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-
4156. (b) Ireland, R. E.; Liu, L. ibid, 1993, 58, 2899.
(22) This elimination did not work in the absence of the free
hydroxyl:
The R,â-unsaturated ester 18 was next treated with
Dibal in CH2Cl2 at -78 °C furnishing the allylic alcohol,
which was oxidized, via the Sharpless procedure,18 to
provide a diastereomeric mixture (14:1) of epoxy alcohols
in 80% overall yield, with 19 being the major product
(Scheme 4). This mixture, containing 19, was subjected
to selective reduction with Red-Al19 followed by protection
with p-methoxybenzylidine dimethyl acetal and catalytic
PPTS in CH2Cl2 to afford the p-methoxybenzylidine
acetal 20 as a single isomer in 77% yield over the two
steps. The aldehyde 21 was obtained in 81% yield in two
steps via selective ring opening of the acetal 20 using
Dibal,20 followed by oxidation of the primary alcohol with
the Dess-Martin periodinane.21 Subsequently, this piv-
(23) We have examined an alternative route for the synthesis of 8
from the aldehyde 17 via addition of propargylmagnesium bromide.
However, while this reaction is efficient it is not selective, as an
inseparable mixture (1.5:1) of diastereomeric products were formed:
(24) (a) Campbell, I. B. In Organocopper Reagents. A Practical
Approach; Taylor, R. J . K., Ed.; Oxford University Press: Oxford, 1994;
Chapter 10, pp 217-236. (b) Sonogashira, K. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J ., Eds.; Wiley: Weinheim,
1997; Chapter 5, pp 203-229.
(17) Hillier, M. C.; Meyers, A. I. Tetrahedron Lett. 2001, 42, 5145-
5147.
(25) Saitoh, K.; Shiina, I.; Mukaiyama, T. Chem. Lett. 1998, 679-
680.
(18) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5780.
(19) (a) Finan, J . M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719-
2722. (b) Viti, S. Ibid. 1982, 23, 4541-4544.
(20) Schreiber, S.; Wang, Z.; Schulte, G. Tetrahedron Lett. 1988, 29,
4085-4088.
(26) Others have synthesized dimeric natural products via one-step
dimerization of the corresponding monomeric subunits. For example:
(a) Corey, E. J .; Hua, D. H.; Pan, B.-C.; Seitz, S. P. J . Am. Chem. Soc.
1982, 104, 6818-6820. (b) Berger, M.; Mulzer, J . J . Am. Chem. Soc.
1999, 121, 8393-8394.

6040 J . Org. Chem., Vol. 66, No. 18, 2001
Hillier et al.
Sch em e 6a
catalytic DMAP in refluxing toluene, thus giving only the
monoester 26 in 65% yield. Acidic deprotection of 26 with
TFA/H2O (1:1) in THF led to the hydroxyl derivative 27
(65%), whose remaining methyl ester was hydrolyzed (1
N LiOH, THF) and the resultant seco acid cyclized
according to the Yamaguchi protocol28 to give the bislac-
tone 3 in 24% yield.29
With the desired cyclic dimer 3 in hand, removal of
the TBS protecting groups to obtain 2 was next at-
tempted. Unfortunately, as with the cyclic monomer 23,
this transformation led to a complex mixture of trans-
esterified products, which in this instance were not
separable by column chromatography or any other means.
The dimer 3 also seems to be particularly sensitive to
both acidic and basic conditions necessary to remove the
silyl protecting groups, giving rise to significant amounts
of decomposition product. An attempt to reduce the
alkynyl groups of 3 was carried out to obtain the requisite
bis-triene, a protected version of the natural product 1,
but this proved to be unsuccessful.30
Su m m a r y. The synthesis of both monomeric and
dimeric dehydro-disorazole C1 derivatives, 24 and 3,
respectively, has been presented. During these endeavors,
a novel 1,5 O f O silyl migration was discovered, which,
when coupled with Horner-Wadsworth-Emmons condi-
tions, provided for a very efficient synthesis of the R,â-
unsaturated ester intermediate 18. In addition, the
dienyne monomer 5 was found to undergo only intramo-
lecular cyclization to give 24, necessitating a more
stepwise route to the desired dimer 3. Finally, while it
was not possible to successfully desilylate the allylic
alcohols in the dimer 3, or reduce it to the natural product
1, a stereocontrolled synthesis of the correct molecular
framework of disorazole C1 has been achieved.31
a
Reaction conditions: (a) TESTOTf, 2.6-lutidine, CH2Cl2, -78
°C; (b) 1 N LiOH, THF; (c) 5, DPTC, DMAP, toluene, ∆; (d) TFA,
H2O, THF; (e) 1 N LiOH, THF; (f) 2,4,6-trichlorobenzoyl chloride,
DMAP, toluene, rt.
presumably arising from intramolecular transesterifica-
tion. The major product 24 was isolated by recrystalli-
zation (EtOAc/hexanes) in 45% yield. A single X-ray
crystal structure of 24 provided unambiguous confirma-
tion of the structural and stereochemical assignments.15
Interestingly, the fast atom bombardment (FAB) mass
spectrum of 24 showed M + H peaks for both the
monomeric material 24 (M + H ) 386) and the dimer 3
(M + H ) 771).15 However, an electrospray mass spec-
trum of 24 showed only the monomeric material. The
presence of the dimer 3 in the FAB spectrum of 24
invokes an intriguing aspect to this problem. Could it be
that disorazole C1 (1) is not the symmetrical dimer as
reported?27 Could it be a smaller, monomeric macrocycle
like 23, which upon mass spectral analysis dimerizes in
the process to inadvertently suggest the presence of a
dimer? To arrive at a quick, but uncertain, answer to this
intriguing question, the monomer 24 was reduced at its
triple bond to a triene, but the spectrum of this product
did not correspond to the natural disorazole, 1. This
reduced monomer could not be completely characterized;
thus, the experiment was somewhat inconclusive. These
questions will have to await the completion of the
synthesis and further characterization to arrive at a
correct answer.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, all starting
materials were obtained from commercial suppliers and were
used without further purification. Solvents were dried accord-
ing to established procedures by distillation from an appropri-
ate drying agent under an inert atmosphere of argon in
(28) (a) Hikota, M.; Hitoshi, T.; Horita, K.; Yonemitsu, O. Tetrahe-
dron 1990, 46, 4613-4628. (b) Evans, D. A.; Ng, H. P.; Rieger, D. L. J .
Am. Chem. Soc. 1993, 115, 11446-11459. (c) Berger, M.; Mulzer, J . J .
Am. Chem. Soc. 1999, 121, 8393.
(29) A significant amount of the cyclic monomer 23 (67%) was
formed in this reaction, though it was separable from the dimer 3 by
column chromatography. This surprising result is due to the nonselec-
tive hydrolysis of the di-ester 27 under basic conditions. Attempts to
circumvent this problematic transformation were unsuccessful.
(30) While the dimeric dienyne 3 could not be reduced to the triene
found in the natural product 1, the monomer 5 did submit to the
following conditions to give 28, though some isomerization did occur:
Boland, W.; Sieler, C.; Fiegel, M. Helv. Chim. Acta 1987, 70, 1025-
1040:
Alter n a te Dila cton iza tion Str a tegy. In light of the
tendency of the monomer 5 to undergo intramolecular
cyclization, attention was then turned to a more stepwise
route to avoid the lactonization to 23 (Scheme 6). In the
event, the free hydroxyl of 5 was first protected with
TESOTf and 2,6-lutidine in CH2Cl2 at -78 °C to afford
the triethylsilyl (TES) ether 25 (69%). The methyl ester
of 25 was saponified (1 N LiOH, THF) and the free
carboxylic acid coupled to the alcohol 5 using DPTC and
(27) The original isolation team reported (ref 1) a chemical ionization
(CI) mass spectrum for disorazole C1 (1) of M + H ) 775, which had
an intensity of 0.3% when compared to the base peak.
(31) For personal reasons, the senior author will no longer be in
the position to continue this study. Hopefully, other laboratories will
find reasons to pursue disorazole C1 (1) to its conclusion.

Total Synthesis of Disorazole C1
J . Org. Chem., Vol. 66, No. 18, 2001 6041
glassware that had been flame-dried. Chemical shifts are
reported in parts per million (ppm, δ) from an internal
standard of tetramethylsilane (TMS) or deuterated chloroform
(CDCl3). Flash chromatography was performed using Merck
silica gel 60 (230-400 mesh ASTM).
11.0 Hz, 1 H), 2.99-2.95 (m, 2 H); 13C NMR δ 163.8, 161.7,
144.2, 132.9, 69.6, 65.7, 52.3, 32.2; IR (neat) ν 3374, 1738, 1587,
1326, 1112 cm-1. Anal. Calcd for C8H11NO5: C, 47.76; H, 5.51;
N, 6.96. Found: C, 47.67; H, 5.46; N, 6.89. This material
proved to be of sufficient purity to proceed further.
N-(1′-Ca r b om et h oxy-2R-h yd r oxyet h a n yl)-3S,4-d ih y-
d r oxybu ta n a m id e Aceton id e, 10. To a solution of the acid
9 (12 g, 73 mmol)2a in THF (70 mL) at 0 °C was added 1,1′-
carbonyldiimidazole (12 g, 75 mmol), and the mixture was
stirred for 30 min. The cooling bath was removed, HCl‚L-serine
methyl ester was added in one portion, and the reaction
mixture was stirred overnight at room temperature. Solvent
was removed in vacuo, and the crude residue was partitioned
between EtOAc/brine (200:50 mL). The resulting biphasic
mixture was separated, and the aqueous phase was extracted
with EtOAc (4 × 10 mL). The organic extracts were combined,
dried (Na2SO4), concentrated, and purified via column chro-
matography eluting with EtOAc/hexanes (9:1) to provide 13 g
(67%) of 10 as a thick oil, which solidified to a waxy solid upon
standing: [R]D ) +31.0 (c 0.5, CHCl3); 1H NMR δ 6.93 (d, J )
8.0 Hz, 1 H), 4.69-4.42 (m, 2 H), 4.15 (dd, J ) 6.5, 8.5 Hz, 1
H), 3.96 (d, J ) 4.0 Hz, 1 H), 3.78 (s, 3 H), 3.67 (dd, J ) 6.5,
8.5 Hz, 1 H), 2.56 (dd, J ) 3.5, 5.5 Hz, 1 H), 1.46 (s, 3 H), 1.37
(s, 3 H); 13C NMR δ 171.0, 109.5, 72.6, 69.1, 62.9, 54.8, 40.5,
27.0, 25.6 cm-1; IR (neat) ν 3418, 1732, 1730, 1586, 1324. Anal.
Calcd for C11H19NO6: C, 50.57; H, 7.33; N, 5.36. Found: C,
50.58; H, 7.29; N, 5.26.
4-Ca r bom eth oxy-2-(3′S,4′-d ih yd r oxy)-1,3-oxa zolyl Ace-
ton id e, 11. To a solution of 10 (17 g, 63 mmol) from the
preceding experiment in CH2Cl2 (150 mL) was added dieth-
ylaminosulfur trifluoride (DAST) (8.8 mL, 66 mmol), and the
reaction was stirred for 45 min. Solid K2CO3 (18 g, 126 mmol)
was then added, and the reaction was stirred for 1 h and then
warmed to room temperature. The orange slurry was slowly
added (Caution! H2 gas evolution!) to saturated aqueous
NaHCO3 (50 mL), and the resultant biphasic mixture was
separated. The aqueous phase was extracted with CH2Cl2
(2 × 20 mL), and the combined organics were dried (Na2SO4)
and concentrated in vacuo. A small portion of the oxazoline
intermediate was purified for characterization purposes by
4-Ca r bom eth oxy-2-(3′S-h yd r oxy-4′-tr iisop r op ylsiloxy)-
1,3-oxa zole, 12b. To a solution of 12a (12 g, 56 mmol) in CH2-
Cl2 (1.4 L) at -78 °C was added 2,6-lutidine (8.0 mL, 67 mmol)
followed by triisopropylsilyl triflouromethanesulfonate (17 mL,
62 mmol), dropwise over 10 min. The reaction was stirred for
30 min whereupon a solution of brine (500 mL) was added and
the resultant biphasic mixture was separated. The aqueous
phase was extracted with CH2Cl2 (2 × 200 mL), the organic
layers were combined, dried (MgSO4), and concentrated, and
the crude product residue was purified via column chroma-
tography eluting with EtOAc/hexanes (2:5) to provide 16 g
(76%) of 12b as an oil: [R]D ) -13.9 (c ) 0.9, CHCl3); 1H NMR
δ 8.18 (s, 1 H), 4.22-4.18 (m, 1 H), 3.90 (s, 3 H), 3.76 (dd, J )
5.0, 10.0 Hz, 1 H), 3.69 (dd, J ) 5.0, 10.0 Hz, 1 H), 3.05 (m, 2
H), 2.90 (brs, 1 H), 1.05-0.90 (comp, 21 H); 13C NMR δ 163.6,
161.8, 144.1, 133.3, 69.7, 66.5, 52.2, 32.4, 18.0, 12.0; IR (neat)
ν 3444, 2993, 1747, 1587, 1324, 1112 cm-1; mass spectrum
(FAB) m/z 358.2049 (C17H31NO5Si + H requires 358.2050).
4-Ca r bom eth oxy-2-(2′S-m eth oxy-4′-tr iisop r op ylsiloxy)-
1,3-oxa zole, 12c. A solution of 12b (16 g, 45 mmol) in CH3-
CN (90 mL), containing Ag2O (19 g, 81 mmol) and MeI (64
mL), was heated to 60 °C for 12 h. The resulting brown slurry
was diluted with Et2O (200 mL) and filtered through a pad of
Celite. The filtrate was concentrated and the crude residue
purified via column chromatography eluting with EtOAc/
hexanes (1:5) to give 12 g (71%) of 12c as an orange oil:
1
[R]D ) -7.8 (c 0.5, CHCl3); H NMR δ 8.15 (s, 1 H), 3.89 (s, 3
H), 3.85-3.71 (m, 3 H), 3.38 (s, 3 H), 3.15 (dd, J ) 3.8, 15.3
Hz, 1 H), 3.01 (dd, J ) 7.5, 15.3 Hz, 1 H), 1.12-1.00 (m, 21
H); 13C NMR δ 163.9, 161.9, 144.0, 133.5, 79.9, 64.6, 52.2, 31.0,
18.0, 12.5, 12.0; IR (neat) ν 2944, 1748, 1731, 1585, 1324, 1111
cm-1; mass spectrum (FAB) m/z 372.2201 (C18H33NO5Si + H
requires 372.2206).
4-Ca r b om et h oxy-2-(2′S-m et h oxy-4′-h yd r oxy)-1,3-ox-
a zole, 12d . To a solution of 12c (12 g, 32 mmol) in THF (70
mL) at 0 °C was slowly added a solution of 1.0 M TBAF (48
mL, 48 mmol) in THF. After 12 h, solvent was removed in
vacuo and the crude alcohol was purified via column chroma-
tography eluting with EtOAc (9:1) to give 6.2 g (89%) of 12d
as an orange oil: [R]D ) +17.5° (c 1.0, CHCl3); 1H NMR δ 8.14
(s, 1 H), 3.86 (s, 3 H), 3.80-3.50 (m, 3 H), 3.36 (s, 3 H), 3.12
(dd, J ) 6.1, 15.2 Hz, 1 H), 3.05 (ddd, J ) 1.0, 6.5, 15.2 Hz, 1
H), 2.28 (brs, 1 H); 13C NMR δ 162.9, 161.5, 144.0, 133.3, 79.0,
63.0, 57.5, 52.1, 29.6; IR (neat) ν 3418, 1732, 1586, 1324, 1110
cm-1; mass spectrum (FAB) m/z 216.0869 (C9H13NO5 + H
requires 216.0872).
passing through
a small silica gel column eluting with
EtOAc: [R]D ) +121.0 (c 0.9, CHCl3); 1H NMR δ 4.76-4.70
(m, 1 H), 4.50-4.35 (m, 3 H), 4.13 (dd, J ) 6.2, 8.6 Hz, 1 H),
3.78 (s, 3 H), 3.68 (dd, J ) 6.2, 8.6 Hz, 1 H), 2.70 (ddd, J )
1.1, 5.9, 15.4 Hz, 1 H), 2.51 (ddd, J ) 1.1, 7.5, 15.4 Hz, 1 H),
1.40 (s, 3 H), 1.34 (s, 3 H); 13C NMR δ 171.7, 167.6, 109.5,
72.8, 69.6, 69.5, 68.2, 52.8, 32.9, 27.1, 25.7; IR (neat) ν 2986,
1744, 1663, 1212, 1067. The crude oxazoline was taken on
without further purification, dissolved in CH2Cl2 (300 mL), and
then cooled to 0 °C. To this solution was added DBU (19 mL,
126 mmol) followed by BrCCl3 (7 mL, 70 mmol), and the black
reaction mixture was stirred for 12 h without further cooling.
Saturated aqueous NH4Cl (200 mL) was then added, and the
biphasic mixture was separated. The aqueous phase was
extracted with CH2Cl2 (3 × 50 mL), the combined organic
extracts were dried (Na2SO4) and concentrated, and the crude
black residue was purified via column chromatography eluting
with EtOAc/hexanes (2:3) to provide 12 g (79%, over two steps)
4-Ca r bom eth oxy-2-[2′S-m eth oxy-3′(E)-p en ten -5′-a l]ox-
a zole, 13. To a solution of the alcohol 12d (2.5 g, 11 mmol) in
CH2Cl2 (12 mL) at 0 °C were added DMSO (11 mL, 160 mmol)
and Et3N (11 mL, 80 mmol), and the mixture was stirred for
10 min. Solid SO3‚Pyr (9.1 g, 57 mmol) was then added in one
portion, and the reaction was stirred for 30 min at 0 °C and
for 1 h at room temperature. Solvent was removed in vacuo,
and the thick residue was filtered through a plug of silica gel
eluting with EtOAc (300 mL). The filtrate was concentrated,
and a small portion of the crude aldehyde was purified for
characterization purposes: [R]D ) -34.0° (c 2.0, CHCl3); 1H
NMR δ 9.79 (d, J ) 1.0 Hz, 1 H), 8.18 (s, 1 H), 4.15 (ddd, J )
5.3, 7.3 Hz, 1 H), 3.91 (s, 3 H), 3.50 (s, 3 H), 3.29 (dd, J ) 5.3,
15.8 Hz, 1 H), 3.15 (dd, J ) 7.8, 15.8 Hz, 1 H); 13C NMR δ
201.2, 161.5, 144.3, 133.5, 82.6, 58.8, 52.2, 29.1; IR (neat) ν
2953, 1731, 1589, 1440, 1324 cm-1. The crude aldehyde was
then dissolved in THF (100 mL), treated with triphenylphos-
phoranylidine acetaldehyde (3.8 g, 13 mmol), and the mixture
was stirred for 2 days at room temperature. Solvent was
concentrated in vacuo and the crude red product residue was
purified via column chromatography eluting with EtOAc/
hexanes (1:1) to furnish 1.2 g (45%, over two steps) of the enal
1
of the oxazole 11 as an oil: [R]D ) -0.7 (c ) 1.0, CHCl3); H
NMR δ 8.18 (s, 1 H), 4.61-4.52 (m, 1 H), 4.15 (dd, J ) 6.0, 8.0
Hz, 1 H), 3.91 (s, 3 H), 3.77 (dd, J ) 6.5, 8.5 Hz, 1 H), 3.16
(dd, J ) 6.5, 15.2 Hz, 1 H), 3.02 (dd, J ) 6.5, 15.2 Hz, 1 H),
1.40 (s, 3 H), 1.34 (s, 3 H); 13C NMR δ 162.2, 161.6, 144.2,
133.4, 109.7, 73.1, 68.8, 52.2, 32.9, 26.9, 25.5; IR (neat) ν 2987,
1747, 1586, 1324, 1111, 1066 cm-1. Anal. Calcd for C11H15
-
NO5: C, 54.77; H, 6.27; N, 5.81. Found: C, 54.86; H, 6.29; N,
5.77.
4-Ca r bom eth oxy-2-(3′S,4-d ih yd r oxy)-1,3-oxa zole, 12a .
The oxazole 11 (14 g, 59 mmol) was dissolved in MeOH (60
mL), treated with Dowex-H+ resin, and stirred for 12 h at room
temperature. The acidic resin was removed by filtration
through a pad of Celite, and the filtrate was concentrated to
provide 12 g (>95%) of 12a as an orange oil: [R]D ) -21.3° (c
0.4, CHCl3); 1H NMR δ 8.13 (s, 1 H), 4.40-4.05 (m, 3 H), 3.84
(s, 3 H), 3.68 (dd, J ) 4.0, 11.0 Hz, 1 H), 3.55 (dd, J ) 6.0,
1
13 as a yellow wax: [R]D ) -14.0 (c 1.0, CHCl3); H NMR δ
9.58 (d, J ) 7.0 Hz, 1 H), 8.18 (s, 1 H), 6.73 (dd, J ) 6.0, 15.8

6042 J . Org. Chem., Vol. 66, No. 18, 2001
Hillier et al.
Hz, 1 H), 6.27 (ddd, J ) 1.3, 7.0, 15.8 Hz, 1 H), 4.50-4.38 (m,
1 H), 3.81 (s, 3 H), 3.39 (s, 3 H), 3.19 (dd, J ) 7.0, 15.1 Hz, 1
H), 3.09 (dd, J ) 6.0, 15.1 Hz, 1 H); 13C NMR δ 193.1, 161.8,
161.6, 153.6, 144.3, 133.6, 133.5, 76.8, 57.8, 52.4, 33.9; IR (neat)
ν 2954, 1738, 1694, 1586, 1324, 1110 cm-1; mass spectrum
(FAB) m/z 240.0874 (C11H13NO5 + H 240.0872).
80.8, 60.3, 42.3, 26.1, 23.6, 22.4, 18.4, 17.9, 14.5, -3.6, -4.7;
IR (neat) ν 2958, 1722, 1651, 1472 cm-1, mass spectrum (FAB)
m/z 326.2228 (C18H34O3Si requires 326.2277), 282 (base).
Ep oxy Alcoh ol, 19. (a ) Allylic Alcoh ol. A solution of 18
(11 g, 29 mmol) in CH2Cl2 (100 mL) at -78 °C was treated
with neat Dibal (10 mL, 59 mmol), and the cooling bath was
removed. After 15 min, the reaction was quenched by addition
of MeOH (5 mL), saturated aqueous Rochelle’s salt (50 mL)
was added, and the biphasic mixture was separated. The
aqueous phase was extracted with CH2Cl2 (2 × 20 mL), the
combined organic layers were dried (Na2SO4) and concen-
trated, and the crude product was purified via column chro-
matography eluting with EtOAc/hexanes (5:95) to afford 8.2 g
(85%) of the intermediate allylic alcohol as a slightly yellow
4-Ca r b om et h oxy-2-[2′S-m et h oxy-5′-iod o-3′-(E,Z)-h ex-
en yl]oxa zole, 7. A slurry of methyltriphenylphosphonium
iodide (0.57 g, 1.1 mmol) in THF (5 mL) at room temperature
was treated, dropwise, with a 1.0 M solution of NaHMDS (1.1
mL, 1.1 mmol) in THF. The resultant red-orange solution was
stirred for 30 min at room temperature, cooled to -78 °C, and
treated with HMPA (0.94 mL, 5.4 mmol) and a solution of 13
(0.26 g, 1.1 mmol) in THF (5 mL). After 3 h at -78 °C, the
mixture was quenched by saturated aqueous NaHCO3 (1 mL)
and diluted with Et2O (20 mL), and the resultant slurry was
filtered through a pad of Celite. The biphasic filtrate was
separated, the organic phase was dried (Na2SO4) and concen-
trated, and the crude product was purified via column chro-
matography eluting with EtOAc/hexanes (1:19) to give 0.3 g
(76%) of the dienyl iodooxazole 7 as an inseparable mixture
(8:1) of E,Z-vinyl iodide isomers: 1H NMR (major isomer) δ
1H NMR 8.14 (s, 1 H), 6.69 (dd, J ) 7.7, 9.9 Hz, 1 H), 6.37 (dd,
J ) 9.9, 15.4 Hz, 1 H), 6.32 (d, J ) 7.7 Hz, 1 H), 5.83 (dd, J )
7.7, 15.4 Hz, 1 H), 4.20 (dt, J ) 5.8, 7.7 Hz, 1 H), 3.87 (s, 3 H),
3.26 (s, 3 H), 3.06 & 3.04 (ABX, J AB ) 14.8 Hz, J AX ) 7.2 Hz,
J BX ) 5.5 Hz, 1 H); 13C NMR (major isomer) δ 162.3, 161.5,
143.9, 137.0, 136.0, 133.3, 84.1, 79.2, 56.8, 52.1, 34.5, 29.7; IR
(neat) 1744, 1585, 1322, 1109 cm-1; mass spectrum (FAB)
m/z ) 364.0047 (C12H14NO3I + H requires 364.0046), 307, 154
(base). This 8:1 mixture of 7 was used as such in the
subsequent Sonogashira coupling step.
1
oil: [R]D ) +1.9 (c 3.8, CH2Cl2); H NMR δ 5.71 (dt, J ) 1.1,
15.8 Hz, 1 H), 5.48 (dt, J ) 6.0, 15.8 Hz, 1 H), 5.42 (dq, J )
6.1, 15.2 Hz, 1 H), 5.27 (ddq, J ) 1.2, 7.6, 15.2 Hz, 1 H), 4,04
(brs, 2 H), 3.60 (d, J ) 7.6 Hz, 1 H), 1.65 (brs, 1 H), 1.61 (dd,
J ) 1.2, 6.1 Hz, 3 H), 0.90 (s, 3 H), 0.89 (s, 3 H), 0.82 (s, 9 H),
-0.05 (s, 3 H), -0.1 (s, 3 H); 13C NMR δ 140.3, 131.5, 127.1,
125.9, 81.1, 64.2, 40.8, 25.9, 24.0, 23.1, 18.2, 17.7, -3.8, -4.9;
IR (neat) ν 3317, 2958, 2929, 2857, 1472, 1382, 1360, 1254
cm-1; mass spectrum (FAB) m/z 285.2089 (C16H32O2Si + H
requires 285.2093) 185 (base).
(b) A flame-dried 100 mL three-neck flask, fitted with a low-
temperature thermometer, was charged with crushed 3 Å
molecular sieves and a solution of (-)-diethyl tartrate (DET,
0.24 g. 1.0 mmol) in CH2Cl2 (15 mL) and then cooled to -20
°C. Ti(O-i-Pr)4 (0.25 mL, 0.84 mmol) and 5.5 M tert-butyl
hydroperoxide (TBHP, 4.0 mL, 22 mmol) were then added, and
the resultant mixture was aged for 30 min before being treated
with a solution of the allylic alcohol from above (2.4 g, 8.4
mmol) from the preceding experiment in CH2Cl2 (10 mL). The
solution was stirred overnight, a solution of FeSO4‚7H2O (5.6
g, 20 mmol) and citric acid (2.1 g, 9 mmol) in H2O (33 mL)
was added, and the biphasic mixture was stirred for 45 min
before being filtered through a plug of Celite. The filtrate was
cooled to 0 °C, treated with 1 N NaOH (5 mL), and stirred at
this temperature for 1 h. The biphasic mixture was separated,
and the aqueous layer was extracted with CH2Cl2 (5 mL). The
combined organic layers were dried (MgSO4) and concentrated,
and the crude product residue was purified via flash chroma-
tography eluting with EtOAc/hexanes (1:5) to provide 2.4 g
(94%) of 19 an inseparable mixture (14:1) of epoxy alcohol
diastereomers; 1H NMR (major diastereomer) δ 5.54-5.34
(comp, 2 H), 3.84 (ddd, J ) 2.5, 6.1, 12.5 Hz, 1 H), 3.71 (d,
J ) 7.5 Hz, 0.93 H), 3.47 (ddd, J ) 5.0, 6.6, 12.5 Hz, 1 H) 2.96
(dt, J ) 2.5, 5.0 Hz, 1 H), 2,88 (d, J ) 2.5 Hz, 1 H), 2.14 (dd,
J ) 6.1, 6.6 Hz, 1 H), 1.64 (d, J ) 5.1 Hz, 3 H), 0.83 (s, 9 H),
TBS Acet a l, 16. To a flame-dried, two-neck flask, fitted
with a low-temperature thermometer, were added N-tosyl-L-
valine (8.3 g, 31 mmol) and CH2Cl2 (76 mL), and the resulting
solution was cooled to 0 °C. A solution of 1.0 M BH3‚THF (28
mL, 28 mmol) was slowly added (Caution! H2 gas evolution),
and the mixture was stirred at 0 °C for 30 min and at room
temperature for 30 min and then cooled to -78 °C. A solution
of crotonaldehyde 14 (2.3 mL, 28 mmol) in CH2Cl2 (21 mL)
was added followed by a solution of tert-butyldimethylsilyl
ketene acetal 1514 (8.3 g, 36 mmol), and the mixture was
stirred for 3 h at - 78 °C before being quenched with pH 7
buffer (100 mL). The resultant biphasic mixture was stirred
at room temperature, and the layers were separated. The
aqueous phase was extracted with CH2Cl2 (2 × 25 mL), the
combined organic layers were dried (Na2SO4) and concen-
trated, and the crude product was purified via flash chroma-
tography eluting with EtOAc/hexanes (2:98) to afford 7.1 g
(85%) of 16 as an oil: [R]D ) +15.6 (c 1.5, CH2Cl2); 1H NMR δ
5.70 (ddq, J ) 9.9, 15.6 Hz, 1 H), 5.45 (ddq, J ) 3.5, 7.6, 15.6
Hz, 1 H), 4.49 (s, 1 H), 4.17-4.10 (m, 1 H), 3.72 (q, J ) 7.2
Hz, 2 H), 3.69 (d, J ) 3.3 Hz, 1 H), 1.70 (d, J ) 7.2 Hz, 3 H),
1.21 (t J ) 7.2 Hz, 3 H), 0.91 (s, 9 H), 0.98 (s, 3 H), 0.85 (s, 3
H), 0.08 (s, 3 H), 0.06 (s, 3 H); 13C NMR δ 130.0, 127.7, 104.8,
76.3, 65.1, 42.9, 25.6, 21.4, 18.8, 18.2, 17.8, 15.2, -3.5, -4.1;
0.81 (s, 6.0 H), 0.73 (s, 6 H), -0.03 (s, 6 H), -0.07 (s, 6 H); 13
C
NMR (diastereomeric mixture) δ 131.2, 127.6, 80.3, 62.3, 60.3,
55.0, 38.7, 25.9, 20.8, 19.0, 18.2, 17.7, -3.7, -5.0; IR (neat) ν
3429, 2957, 2857, 1472, 1386, 1361, 1255 cm-1; mass spectrum
(FAB) m/z 301.2197 (C16H32O3Si + H requires 301.2199), 154
(base).
P MB Aceta l, 20. (a ) Diol. The epoxy alcohol 19 (3.4 g, 11
mmol) was dissolved in THF (20 mL), cooled to -20 °C, and
treated with a 70% solution of Red-Al in toluene (8.2 g, 29
mmol). This mixture was stirred for 12 h at -20 °C and then
at 0 °C for 2 days before being quenched by addition of
saturated aqueous Rochelle’s salt (10 mL). The biphasic
mixture was separated, the aqueous phase was extracted with
CH2Cl2 (3 × 5 mL), and the combined organic layers were dried
(MgSO4), concentrated, and purified via flash chromatography
eluting with EtOAc/hexanes (1:1) to provide 1.7 g (77%) of the
diol as as a single diastereomer: [R]D ) -8.8 (c 8.9, CH2Cl2);
1H NMR δ 5.48 (dq, J ) 5.9, 15.3 Hz, 1 H), 5.36 (ddq, J ) 1.2,
8.1, 15.3 Hz, 1 H), 3.95 (brs, 1 H), 3.87 (d, J ) 8.1 Hz, 1 H),
3.78-3.68 (comp, 3 H), 3.34 (t, J ) 4.9 Hz, 1 H), 1.64 (dd, J )
1.2, 5.9 Hz, 3 H), 1.63-1.56 (m, 2 H), 0.83 (s, 3 H), 0.82 (s, 9
H), 0.64 (s, 3 H), 0.00 (s, 3 H), -0.05 (s, 3 H); 13C NMR δ 131.0,
128.6, 83.2, 79.5, 79.4, 62.5, 41.4, 32.8, 25.9, 21.2, 18.1, 17.7,
15.9, -3.2, -4.7; IR (neat) ν 3377, 2957, 2930, 2883, 2857,
1472, 1254 cm-1; mass spectrum (FAB) m/z 303.2354 (C16H34O3-
Si + H requires 303.2355), 185 (base).
IR (neat) ν 3510, 2980 cm-1
.
r,â-Un sa tu r a ted Ester , 18. A solution of 16 (14 g, 41
mmol) and triethylphosphonoacetate (8 mL, 41 mmol) in THF
(200 mL) at -78 °C was treated with oil-free NaH (2.0 g, 81
mmol), and the cooling bath was removed. After 2 h at room
temperature, the reaction mixture was quenched by addition
of saturated aqueous NaHCO3 (50 mL) and the biphasic
mixture was separated. The aqueous phase was extracted with
CH2Cl2 (2 × 10 mL), the combined organic layers were dried
(Na2SO4), concentrated, and the crude residue was purified
via column chromatography eluting with EtOAc/hexanes (1:
20) to provide 11 g (72%) of 18 as an oil: [R]D ) -4.6 (c 13.9,
1
CH2Cl2); H NMR δ 7.00 (d, J ) 16.0 Hz, 1 H), 5.67 (d, J )
16.0 Hz, 1 H), 5.47 (dq, J ) 6.3, 15.3 Hz, 1 H), 5.27 (ddq, J )
1.4, 7.9, 15.3 Hz, 1 H), 4.13 (q, J ) 7.3 Hz, 2 H), 3.68 (d, J )
7.9 Hz, 1 H), 1.62 (dd, J ) 1.4, 6.3 Hz, 3 H), 1.24 (t, J ) 7.3
Hz, 3 H), 0.95 (s, 3 H), 0.94 (s, 3 H), 0.83 (s, 3 H), -0.04 (s, 3
H), -0.09 (s, 3 H); 13C NMR δ 167.1, 156.6, 131.1, 128.1, 118.8,

Total Synthesis of Disorazole C1
J . Org. Chem., Vol. 66, No. 18, 2001 6043
(b) To a solution of the diol (1.2 g, 3.9 mmol) from the
preceding experiment in CH2Cl2 (30 mL) was added p-
methoxybenzylidine dimethyl acetal (1.2 g, 6.3 mmol) followed
by a catalytic amount of pyridinium p-toluensulfonate (PPTS,
0.1 g, 0.4 mmol), and the mixture was stirred for 12 h. The
reaction was neutralized by addition of saturated aqueous
NaHCO3 (15 mL), the resulting biphasic mixture was sepa-
rated, and the aqueous phase was extracted with CH2Cl2 (2 ×
10 mL). The organic layers were combined, dried (MgSO4),
concentrated, and purified via column chromatography eluting
with EtOAc/hexanes (1:9) to give 1.6 g (>95%) of 20 as a clear
h at -78 °C, the reaction was quenched by the addition of
saturated aqueous NaHCO3 (5 mL), diluted with Et2O (50 mL),
and then filtered through a pad of Celite. The biphasic filtrate
was separated, the organic phase was dried (MgSO4) and
concentrated, and the crude product was purified via column
chromatography eluting with EtOAc/hexanes (1:19) to give 1.4
g (78%) of the protected vinyl iodide as an orange oil: 1H NMR
δ 7.29-7.21 (m, 2 H), 6.90-6.83 (m, 2 H), 6.36 (ddd, J ) 6.3,
7.0, 7.2 Hz, 1 H), 6.21 (ddd, J ) 1.4, 1.7, 7.2, 1 H), 5.55-5.37
(comp, 2 H), 4.51 (d, J ) 11.0 Hz, 1 H), 4.36 (d, J ) 11.0 Hz,
1 H), 3.95 (d, J ) 7.3 Hz, 1 H), 3.80 (s, 3 H), 3.50 (dd, J ) 4.3,
6.9 Hz, 1 H), 2.49 (dddd, J ) 1.7, 4.3, 6.3, 15.6 Hz, 1 H), 2.37
(dddd, J ) 1.4, 6.9, 7.0, 15.6 Hz, 1 H), 1.67 (d, J ) 4.9 Hz, 3
H), 0.95 (s, 3 H), 0.88 (s, 9 H), 0.79 (s, 3 H), 0.03 (s, 3 H), -0.02
(s, 3 H); 13H NMR δ 158.8, 139.8, 131.5, 131.1, 128.8, 127.7,
113.6, 82.6, 81.7, 79.1, 72.8, 55.3, 43.8, 36.2, 26.0, 19.8, 19.3,
18.2, 17.8, -3.3, -4.7; IR (neat) ν 2935, 2929, 2855, 1612, 1514,
1470, 1302 cm-1; mass spectrum (FAB) m/z 545.1800 (C25H40O3-
SiI + H requires 545.1792), 185, 121 (base).
(b) To a solution of the protected vinyl iodide (1.2 g, 2.2
mmol) from the preceding experiment in CH2Cl2/H2O (22:1.2
mL) was added DDQ (0.53 g, 2.4 mmol), and the dark reaction
mixture was stirred at room temperature for 3.5 h. Solvent
was removed in vacuo and the crude product residue was
purified via column chromatography eluting with EtOAc/
hexanes (1:19) to provide 0.81 g (86%) of 22 as a clear oil:
[R]D ) -46.4 (c 2.3, CH2Cl2); 1H NMR δ 6.36 (ddd, J ) 6.4,
6.6, 7.3 Hz, 1 H), 6.23 (ddd, J ) 1.4, 1.4, 7.3 Hz, 1 H), 5.52
(dq, J ) 6.1,15.6 Hz, 1 H), 5.40 (ddq, J ) 1.5, 8.0, 15.6 Hz, 1
H), 3.91 (d, J ) 8.0 Hz, 1 H), 3.61 (dt, J ) 3.2, 10.2 Hz, 1 H),
3.20 (dd, J ) 1.3, 3.2 Hz, 1 H), 2.33 (ddddd, J ) 1.4, 1.4, 6.4,
10.2, 14.8 Hz), 2.17 (dddd, J ) 1.4, 6.6, 10.2, 14.8 Hz, 1 H),
1.67 (dd, J ) 1.5, 6.1 Hz, 1 H), 0.89 (s, 3 H), 0.85 (s, 9 H), 0.75
(s, 3 H), 0.03 (s, 3 H), -0.02 (s, 3 H); 13C NMR δ 139.6, 131.1,
128.6, 83.4, 82.9, 77.2, 41.7, 37.6, 26.0, 21.3, 18.1, 17.8, 16.3,
-3.3, -4.7; IR (neat) ν 3478, 2957, 2930, 2857, 1471, 1255
cm-1; mass spectrum (FAB) m/z 425.1374 (C17H33O2SiI + H
requires 425.1373), 185 (base).
1
oil: [R]D ) +35.6 (c 4.7, CH2Cl2); H NMR δ 7.41-7.23 (m, 2
H), 6.89-6.83 (m, 2 H), 5.55-5.38 (m, 2 H), 5.36 (s, 1 H), 4.24
(ddd, J ) 1.3, 4.7, 11.0 Hz, 1 H), 3.95 (d, J ) 7.5 Hz, 1 H),
3.88 (dt, J ) 2.6, 11.8 Hz, 1 H), 3.78 (s, 3 H), 3.71 (dd, J ) 2.2,
11.8 Hz, 1 H), 1.86 (ddd, J ) 2.6, 4.7, 12.6 Hz, 1 H), 1.68 (d,
J ) 5 Hz, 3 H), 1.39 (ddd, J ) 1.3, 2.2, 12.6 Hz, 1 H), 0.98 (s,
3 H), 0.87 (s, 9 H), 0.77 (s, 3 H), -0.01 (s, 3 H), -0.04 (s, 3 H);
13C NMR δ 159.5, 131.8, 131.4, 127.4, 127.1, 113.4, 100.8, 81.1,
78.3, 67.3, 55.2, 41.9, 26.0, 25.6, 19.1, 18.2, 18.1, 17.8, -3.4,
-4.9; IR (neat) ν 2958, 2931, 2856, 1616, 1518, 1464, 1391,
1302, 1250, 1170, 1116, 1053, 835, 775 cm-1; mass spectrum
(FAB) m/z 421.2757 (C24H40O4Si + H requires 421.2774), 185
(base).
P MB Ald eh yd e, 21. (a ) P MB Alcoh ol. The acetal 20 (1.6
g, 3.8 mmol) was dissolved in CH2Cl2 (38 mL) and cooled to
-78 °C, whereupon a solution of 1.5 M Dibal in CH2Cl2 (13
mL, 19 mmol) was added, and the solution was stirred for 20
min at -78 °C and for 1 h at 0 °C. The reaction was quenched
by addition of saturated aqueous Rochelle’s salt (15 mL), and
the biphasic mixture was separated. The aqueous phase was
extracted with CH2Cl2 (2 × 10 mL), the combined organic
layers were dried (MgSO4) and concentrated, and the crude
product residue was purified via column chromatography
eluting with EtOAc/hexanes (1:3) to afford 1.5 g (90%) of the
PMB alcohol as a clear oil: [R]D ) -2.6 (c 6.1, CH2Cl2); 1H
NMR δ 7.31-7.23 (m, 2 H), 6.90-6.83 (m, 2 H), 5.54-5.37 (m,
2 H), 4.50 (s, 2 H), 3.86 (d, J ) 7.3 Hz, 1 H), 3.80 (s, 3 H),
3.84-3.65 (m, 1 H), 3.61 (dd, J ) 3.1, 9.5 Hz, 1 H), 2.01 (brs,
1 H), 1.91-1.71 (comp, 2 H), 1.68 (d, J ) 5 Hz, 3 H), 0.99 (s,
3 H), 0.89 (s, 9 H), 0.76 (s, 3 H), 0.01 (s, 3 H), -0.02 (s, 3 H);
13C NMR δ 158.9, 131.4, 130.9, 129.0, 127.9, 113.7, 82.1, 79.0,
74.2, 61.4, 55.2, 43.8, 33.2, 26.0, 19.7, 19.1, 18.2, 17.8, -3.3,
-4.9; IR (neat) ν 3398, 2956, 2931, 2882, 2856, 1614, 1514,
1471, 1249 cm-1; mass spectrum (FAB) m/z 423.2764 (C24H42O4-
Si + H requires 423.2774).
Alk yn e 8. A solution of 22 (0.37 g, 0.87 mmol) in THF (9
mL) at -78 °C was treated with 1.0 M NaHMDS (1.7 mL, 1.7
mmol) in THF, and the cooling bath was removed. After being
stirred at room temperature for 2 h, the reaction was quenched
by the addition of saturated aqueous NaHCO3 (10 mL) and
diluted with Et2O (30 mL), and the layers were separated. The
aqueous phase was extracted with Et2O (2 × 5 mL), the
combined organic layers were dried (MgSO4) and concentrated,
and the crude alkyne was purified via column chromatography
eluting with EtOAc/hecanes (1:9) to give 0.24 g (93%) of 8 as
(b) A solution of the PMB alcohol (1.5 g, 3.4 mmol) from
the preceding experiment in CH2Cl2 (13 mL) was treated with
pyridine (0.6 mL, 6.86 mmol) and Dess-Martin periodinane21
(2.9 g, 6.9 mmol) followed by tert-butyl alcohol (2 drops), and
the resultant slurry was stirred for 1 h at room temperature.
Saturated aqueous NaHCO3 (1 mL) was then added, and the
biphasic mixture was filtered through a plug of Celite washing
with CH2Cl2 (2 × 5 mL). The filtrate was dried (MgSO4) and
concentrated, and the crude residue was purified via flash
chromatography eluting with EtOAc/hexanes (1:9) to give 1.3
1
a clear oil: [R]D ) -10.3 (c 2.0, CH2Cl2); H NMR δ 5.56 (dq,
J ) 5.9, 15.4 Hz, 1 H), 5.40 (ddq, J ) 1.5, 7.8, 15.4 Hz, 1 H),
3.93 (d, J ) 8.0 Hz, 1 H), 3.69 (dd, J ) 3.0, 9.6 Hz, 1 H), 2.94
(brs, 1 H), 2.45 (ddd, J ) 3.0, 3.0, 16.9 Hz, 1 H), 2.28 (ddd,
J ) 2.5, 9.6, 16.9 Hz, 1 H), 2.03 (dd, J ) 2.5, 3.0 Hz, 1 H), 1.70
(dd, J ) 1.5, 5.9 Hz, 1 H), 0.90 (s, 3 H), 0.88 (s, 9 H), 0.75 (s,
3 H), 0.05 (s, 3 H), -0.01 (s, 3 H); 13C NMR δ 131.2, 128.6,
82.9, 81.5, 75.7, 70.1, 42.1, 26.2, 22.9, 20.3, 18.4, 17.5, 0.3, -3.1,
-4.5; IR (neat) ν 3487, 3312, 2957, 2930, 2857, 1472, 1255
cm-1; mass spectrum (FAB) m/z 297.2238 (C17H32O2Si + H
requires 297.2250), 185 (base).
1
g (90%) of 21 as a clear oil: [R]D ) +14.3 (c 1.7, CH2Cl2); H
NMR δ 9.88 (dd, J ) 1.5, 2.8 Hz, 1 H), 7.31-7.25 (m, 2 H),
6.93-6.88 (m, 2 H), 5.58-5.41 (m, 2 H), 4.53 and 4.44 (AB,
J AB ) 11.0 Hz, 1 H), 4.01 (d, J ) 3.6, 7.3 Hz, 1 H), 3.94 (d,
J ) 7.3 Hz, 1 H), 3.84 (s, 3 H), 2.84 (ddd, J ) 1.5, 3.6, 16.7 Hz,
1 H), 2.66 (ddd, J ) 2.8, 7.3, 16.7 Hz, 1 H), 1.74 (d, J ) 5.1
Hz, 3 H), 1.02 (s, 3 H), 0.94 (s, 9 H), 0.83 (s, 3 H), 0.06 (s, 3 H),
0.02 (s, 3 H); 13C NMR δ 202.1, 158.9, 131.1, 130.7, 128.9,
128.1, 113.6, 79.2, 78.1, 72.8, 55.3, 46.0, 43.5, 26.0, 20.0, 19.2,
18.2, 17.8, -3.4, -4.8; IR (neat) ν 2956, 2856, 1726, 1613, 1514,
1471, 1249 cm-1; mass spectrum (FAB) 421.2615 (C24H39O4-
Si + H requires 421.2618).
Dien yn e Oxa zole Mon om er 5. To a solution of the alkyne
8 (230 mg, 0.68 mmol) and dienyl iodide 7 (250 g, 0.68 mmol)
in CH3CN (5 mL) at -20 °C were added PdCl2(PPh3)2 (24 mg,
0.03 mmol), CuI (21 mg, 0.10 mmol), and Et3N (0.47 mL, 3.38
mmol). The reaction was stirred for 20 min at -20 °C and for
2 h at room temperature before being partitioned between
EtOAc (20 mL) and pH 7 buffer (10 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc
(2 × 5 mL). The combined organic layers were dried (Na2SO4),
concentrated, and purified via column chromatography eluting
with EtOAc/hexanes (1:2) to give 340 mg (87%) of 5 as a thick
Vin yl Iod id e, 22. (a ) P MB Vin yl Iod id e. A slurry of
methyltriphenylphosphonium iodide (1.9 g, 3.5 mmol) in THF
(20 mL) at room temperature was treated, dropwise, with a
1.0 M solution of NaHMDS (3.5 mL, 3.5 mmol) in THF. The
resultant red-orange solution was stirred for 30 min, cooled
to -78 °C, and then treated with HMPA (2.7 mL, 15.3 mmol)
and a solution of 21 (1.3 g, 3.1 mmol) in THF (5 mL). After 3
1
syrup: [R]D ) -21.0 (c 0.5, CH2Cl2); H NMR δ 8.16 (s, 1 H),
6.74 (dd, J ) 11.0, 15.4 Hz, 1 H), 6.30 (dd, J ) 10.4, 11.0 Hz,
1 H), 5.69 (dd, J ) 8.8, 15.4 Hz, 1 H), 5.62-5.38 (comp, 3 H),
4.20 (dt, J ) 5.1, 7.8 Hz, 1 H), 3.95 (d, J ) 8.0 Hz, 1 H), 3.90
(s, 3 H), 3.73 (dt, J ) 3.2, 9.4 Hz, 1 H), 3.26 (s, 3 H), 3.12 &

6044 J . Org. Chem., Vol. 66, No. 18, 2001
Hillier et al.
3.01 (ABX, J AB ) 14.7 Hz, J AX ) 7.8 Hz, J BX ) 5.1 Hz, 2 H),
2.96 (d, J ) 3.0 Hz, 1 H), 2.67 (ddd, J ) 2.1, 3.2, 16.9 Hz, 1
H), 2.49 (ddd, J ) 2.2, 9.4, 16.9 Hz, 1 H), 1.70 (dd, J ) 1.3, 6.5
Hz, 3 H), 0.93 (s, 3 H), 0.89 (s, 9 H), 0.79 (s, 3 H), 0.06 (s, 3 H),
-0.01 (s, 3 H); 13C NMR δ 162,8, 161.0, 149.9, 144.1, 137.9,
134.0, 133.4, 131.2, 128.6, 111.5, 95.6, 81.5, 79.6, 79.0, 75.9,
56.9, 52.4, 42.2, 35.1, 26.2, 24.2, 20.4, 18.4 18.0, 17.5, 0.3, -3.1,
eluting with EtOAc/hexanes (1:4) to give 320 mg (69%) of 25
as an oil: [R]D ) -33.6 (c 1.0, CH2Cl2); 1H NMR (400 MHz) δ
8.16 (s, 1 H), 6.75 (dd, J ) 11.0, 15.3 Hz, 1 H), 6.28 (dd, J )
11.0, 11.2 Hz, 1 H), 5.67 (dd, J ) 8.3, 15.3 Hz, 1 H), 5.54 (dq,
J ) 5.9, 15.4 Hz, 1 H), 5.51-5.47 (m, 1 H), 5.40 (ddq, J ) 1.6,
8.2, 15.4 Hz), 4.18 (dt, J ) 5.7, 7.9 Hz, 1 H), 3.91 (s, 3 H), 3.87
(dd, J ) 3.0, 8.1 Hz), 3.26 (s, 3 H), 3.16 & 3.02 (ABX, J AB
)
-4.5; IR (neat) ν 3484, 2955, 2931, 2856, 1748, 1585 cm-1
;
15.0 Hz, J AX ) 7.6 Hz, J BX ) 5.6 Hz, 2 H), 2.72 (ddd, J ) 2.7,
3.0, 16.7 Hz, 1 H), 2.41 (ddd, J ) 2.0, 7.1, 16.7 Hz, 1 H), 1.70
(d, J ) 6.0 Hz, 1 H), 0.97 (t, J ) 8.1 Hz, 9 H), 0.90 (s, 3 H),
0.89 (s, 9 H), 0.75 (s, 3 H), 0.68 (q, J ) 8.1 Hz, 6 H), 0.04 (s, 3
H), -0.02 (s, 3 H); 13C NMR (100 MHz) δ 162.7, 161.8, 144.1,
137.2, 133.6, 133.4, 131.6, 131.3, 127.8, 111.9, 97.6, 79.7, 78.8,
76.1, 56.8, 52.4, 43.8, 35.2, 26.3, 24.6, 19.9, 18.7, 18.5, 18.0,
7.5, 5.9, -3.1, -4.5; IR (neat) ν 2955, 2877, 1751, 1584, 1323
cm-1; mass spectrum (FAB) m/z 646.3942 (C35H59NO6Si2 + H
requires 646.3959), 185 (base).
Bis-P r otected Ester , 26. To a solution of 25 (76 mg, 0.12
mmol) in THF (0.5 mL) was added 1 N LiOH (150 µL), the
reaction was stirred for 2 h at room temperature, and solvent
was concentrated in vacuo. The crude acid was dissolved in
H2O (0.5 mL), acidified by the addition of 1 N HCl (200 µL),
and then extracted with EtOAc (4 × 0.2 mL). The combined
organic layers were dried (Na2SO4) and concentrated, and the
crude product residue was dissolved toluene (1 mL) under an
atmosphere of argon. A solution of the monomer 5 (40 mg, 0.08
mmol) in toluene (1 mL) was then added followed by DPTC
(31 mg, 0.13 mmol) and catalytic DMAP (1.5 mg, 0.012 mmol).
This mixture was heated to reflux for 2 days whereupon
solvent was removed in vacuo and the crude product was
purified via column chromatography eluting with EtOAc/
mass spectrum (FAB) m/z 532.3081 (C29H45NO6Si + H requires
532.3094), 185 (base).
TBS Dien yn e La cton e Mon om er 23. A solution of the
monomer 5 (88 mg, 0.17 mmol) in THF (1.4 mL) was treated
with 1 N LiOH (0.20 mL, 0.20 mmol) and stirred for 7 h, and
solvent was removed in vacuo. The crude product was diluted
with water (2 mL), acidified with 1 N HCl (0.25 mL, 0.25
mmol), and extracted with EtOAc (4 × 1 mL), and the
combined organic layers were dried (Na2SO4) and then con-
centrated. The crude acid was then dissolved in toluene (17
mL) and treated with DPTC (46 mg, 0.20 mmol) and DMAP
(2.0 mg, 0.02 mmol), and the mixture was heated to reflux for
12 h. Solvent was concentrated in vacuo and the crude product
residue purified via column chromatography eluting with
EtOAc/hexanes (1:4) to give 38 mg (46% over two steps) of the
lactone monomer 23 as an oil: [R]D ) +7.9 (c 0.7, CH2Cl2); 1H
NMR δ 8.10 (s, 1 H), 6.70 (dd, J ) 11.0, 16.3 Hz, 1 H), 6.14
(dd, J ) 10.7, 11.0 Hz, 1 H), 5.59 (dq, J ) 6.1, 15.3 Hz, 1 H),
5.51-5.37 (comp, 3 H), 5.24 (dt, J ) 2.2, 10.2 Hz, 1 H), 4.47
(ddd, J ) 5.2, 8.0, 10.8 Hz, 1 H), 3.84 (d, J ) 7.2 Hz, 1 H),
3.39 (s, 3 H), 3.36 (dd, J ) 5.2, 14.5 Hz, 1 H), 2.92 (ddd, J )
2.2, 10.2, 16.4 Hz, 1 H), 2.76 (dt, J ) 3.6, 16.4 Hz, 2.85 (dd,
J ) 10.8, 14.5 Hz, 1 H), 1.72 (d, J ) 5.9 Hz, 3 H), 1.02 (s, 3 H),
0.99 (s, 3 H), 0.92 (s, 9 H), 0.06 (s, 3 H), 0.01 (s, 3 H); 13C NMR
δ 182.3, 170.3, 161.7, 161.5, 144.8, 144.1, 138.2, 134.4, 133.5,
132.8, 130.5, 128.9, 111.3, 93.8, 80.9, 79.6, 57.2, 42.6, 34.4, 26.2,
21.9, 21,2, 19.6, 18.4, 18.0, 0.3, -3.2, -4.7; IR (neat) ν 2955,
2930, 2857, 1721, 1581, 1314 cm-1; mass spectrum (FAB) m/z
500.2823 (C28H41NO5Si + H requires 500.2832), 185 (base).
Hyd r oxyl Dien yn e La cton e Mon om er 24. To a solution
of 23 (13 mg, 0.027 mmol) and THF (0.6 mL) in a Teflon vial
was added HF‚pyridine (50 µL), and the mixture was stirred
for 12 h at room temperature. The solution was partitioned
between saturated aqueous NaHCO3 (1.0 mL) and EtOAc (1
mL), and the layers were separated. The aqueous phase was
extracted with EtOAc (2 × 0.2 mL), the organic layers were
combined, dried (Na2SO4), concentrated, and the crude mate-
rial was dissolved in EtOAc and filtered through a plug of
alumina. The filtrate was concentrated to give 7 mg (66%) of
product that was recrystallized from EtOAc/hexanes to provide
5 mg (45%) of pure 24 as a white solid: mp ) 171-172 °C;
hexanes (1:3) to provide 56 mg (65%) of 26 as an oil: [R]D
)
-37.9 (c 0.5, CH2Cl2); 1H NMR (400 MHz) δ 8.17 (s, 1 H), 8.13
(s, 1 H), 6.78 (dd, J ) 11.0, 15.4 Hz, 1 H), 6.70 (dd, J ) 11.0,
15.5 Hz, 1 H), 6.29 (dd, J ) 10.2, 11.0 Hz, 1 H), 6.22 (dd, J )
11.0, 11.0 Hz, 1 H), 5.70 (dd, J ) 7.8, 15.0 Hz, 1 H), 5.64 (dd,
J ) 8.9, 15.7 Hz, 1 H), 5.56-5.35 (comp, 7 H), 4.22-4.15 (comp,
2 H), 3.92-3.84 (comp, 3 H), 3.90 (s, 3 H), 3.25 (s, 6 H), 3.11
& 3.01 (ABX, J AB ) 14.7 Hz, J AX ) 7.8 Hz, J BX ) 6.8 Hz, 2 H),
3.10 & 3.00 (ABX, J AB ) 14.9 Hz, J AX ) 8.0 Hz, J BX ) 6.0 Hz,
2 H), 2.91 (ddd, J ) 2.3, 3.0, 16.9 Hz, 1 H), 2.76-2.30 (comp,
2 H), 2.40 (ddd, J ) 2.3, 7.8, 17.1 Hz, 1 H), 1.68 (d, J ) 5.4
Hz, 6 H), 0.96 (t, J ) 7.9 Hz, 9 H), 0.93 (s, 3 H), 0.91 (s, 6 H),
0.88 (s, 18 H), 0.74 (s, 3 H), 0.65 (q, J ) 7.9 Hz, 6 H), 0.04 (s,
3 H), 0.03 (s, 3 H), -0.02, (s, 3 H), -0.03 (s, 3 H); 13C NMR
(100 MHz) δ 163.0, 162.8, 161.9, 160.6, 144.2, 143.8, 137.7,
137.3, 133.9, 133.8, 133.7, 133.5, 131.7, 131.4, 131.2, 130.6,
129.0, 127.9, 111.9, 111.4, 97.6, 94.1, 79.5, 79.4, 79.3, 79.0, 78.9.
78.8, 77.4, 76.2, 56.8, 56.7, 52.3, 43.8, 42.9, 35.1, 35.0, 26.2,
26.1, 24.5, 21.9, 20.6, 19.8, 19.4, 18.7, 18.4, 18.3, 18.0, 17.9,
7.4, 5.8, -3.3, -3.4, -4.7, -4.8; IR (neat) ν 2955, 2933, 2878,
2856, 1748, 1584 cm-1; mass spectrum (FAB) m/z 1145.6692
(C63H100N2O11Si3 + H requires 1145.6713), 185 (base).
1
[R]D ) +23.0 (c 0.2, CH2Cl2); H NMR (MeOD-d3) δ 8.35 (s, 1
H), 6.56 (dd, J ) 11.0, 16.1 Hz, 1 H), 6.17 (dd, J ) 10.2, 11.0
Hz, 1 H), 5.69 (dq, J ) 6.8, 15.5 Hz, 1 H), 5.57 (ddd, J ) 1.5,
7.3, 15.5 Hz, 1 H), 5.47 (dd, J ) 9.0, 16.0 Hz, 1 H), 5.38 (dd,
J ) 4.4, 10.3 Hz, 1 H), 5.24 (ddd, J ) 1.3, 2.9, 7.4 Hz, 1 H),
4.39 (ddd, J ) 5.1, 8.0, 10.9 Hz, 1 H), 3.87 (d, J ) 7.3 Hz, 1
H), 3.37 (dd, J ) 5.1, 14.8 Hz, 1 H), 3.37 (s, 3 H), 2.95 (ddd,
J ) 2.8, 10.7, 16.8 Hz, 1 H), 2.85 (dd, J ) 11.9, 14.8 Hz, 1 H),
2.76 (ddd, J ) 2.6, 4.6, 16.9 Hz, 1 H), 1.72 (d, J ) 5.7 Hz, 3
H), 0.99 (s, 3 H), 0.95 (s, 3 H); 13C NMR (100 MHz) δ 163.7,
162.9, 146.2, 139.3, 135.4, 134.5, 134.1, 129.7, 112.1, 101.6,
101.4, 94.6, 82.3, 80.2, 78.6, 78.0, 57.4, 42.8, 34.9, 22.1, 20.1,
19.8, 18.2; IR (neat) ν 3440, 2972, 2935, 1718, 1580, 1315, 1167
cm-1; mass spectrum (FAB) m/z 386.1959 (C22H27NO5 + H
requires 386.1967), 154 (base). This sample was subjected to
an X-ray crystallographic procedure.15
Hyd r oxyl Ester 27. To a solution of 26 (40 mg, 0.04 mmol)
in THF (0.4 mL) were added H2O (70 µL) and TFA (70 µL),
and the reaction was stirred for 1 h at room temperature. The
reaction was partitioned between saturated aqueous NaHCO3
(0.2 mL) and EtOAc (1.5 mL), and the layers were separated.
The organic phase was dried (Na2SO4) and concentrated, and
the crude product residue was purified via column chroma-
tography eluting with EtOAc/hexanes (1:2) to afford 34 mg
(65%) of 27 as a slightly orange film: [R]D ) -37.3 (c 0.3, CH2-
Cl2); 1H NMR (400 MHz) δ 8.18 (s, 1 H), 8.14 (s, 1 H), 6.78
(dd, J ) 10.9, 14.9 Hz, 1 H), 6.69 (dd, J ) 11.0, 14.5 Hz, 1 H),
6.31 (dd, J ) 11.0, 11.0 Hz, 1 H), 6.23 (dd, J ) 10.8, 11.0 Hz,
1 H), 5.72 (dd, J ) 8.7, 15.5 Hz, 1 H), 5.65 (dd, J ) 7.5, 14.7
Hz, 1 H), 5.62-5.36 (comp, 7 H), 4.25-4.18 (comp, 2 H), 3.97
(d, J ) 8.8 Hz, 1 H), 3.91 (s, 3 H), 3.85 (d, J ) 7.9 Hz, 1 H),
3.73 (dd, J ) 3.1, 9.5 Hz, 1 H), 3.27 (s, 3 H), 3.26 (s, 3 H), 3.11
& 3.03 (ABX, J AB ) 14.8, J AX ) 7.8 Hz, J BX ) 5.6 Hz, 2 H),
3.10 & 3.01 (ABX, J AB ) 15.5 Hz, J AX ) 8.1 Hz, J BX ) 5.5 Hz,
2 H), 2.93 (ddd, J ) 2.3, 3.0, 17.1 Hz, 1 H), 2.73 (ddd, J ) 7.1,
8.4, 17.1 Hz, 1 H), 2.67 (ddd, J ) 2.3, 3.3, 16.9 Hz, 1 H), 2.51
(ddd, J ) 2.2, 9.1, 16.9 Hz, 1 H), 1.71 (d, J ) 7.7 Hz, 3 H),
1.69 (d, J ) 6.3 Hz, 3 H), 0.97 (s, 3 H), 0.94 (s, 6 H), 0.90 (s, 18
Bis-P r otected Dien yn e Mon om er , 25. To a solution of
the monomer 5 (380 mg, 0.71 mmol) in CH2Cl2 (3 mL) at 0 °C
was added 2,6-lutidine (120 µL, 1.10 mmol) followed by
triethylsilyl trifluoromethanesulfonate (160 µL, 0.71 mmol),
and the reaction was stirred to room temperature over 4.5 h.
Saturated aqueous NaHCO3 (3 mL) was then added,and the
resulting biphasic mixture was separated. The aqueous phase
was extracted with CH2Cl2 (2 × 1 mL), the combined organic
layers were dried (Na2SO4) and concentrated, and the crude
product was residue purified via column chromatography

Total Synthesis of Disorazole C1
J . Org. Chem., Vol. 66, No. 18, 2001 6045
H), 0.80 (s, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H), 0.01 (s, 3 H), -0.01
(s, 3 H); 13C NMR (100 MHz) δ 163.0, 162.8, 162.0, 160.6, 144.2,
143.8, 137.8, 137.7, 134.2, 133.9, 133.8, 133.5, 131.3, 131.0,
130.6, 129.0, 128.7, 111.5, 105.0, 101.7, 95.7, 94.0, 81.5, 81.4,
79.5, 79.3, 79.1, 77.4, 76.2, 75.9, 56.9, 56.8, 52.3, 42.9, 42.2,
35.1, 35.0, 26.2, 26.1, 24.2, 21.9, 20.6, 20.3, 19.4, 19.3, 18.3,
18.0, 17.9, 17.4, -3.2, -3.4, -4.6, -4.8; IR (neat) ν 2955, 2929,
2856, 1744, 1725, 1584 cm-1; mass spectrum (FAB) m/z
1031.5864 (C57H86N2O11Si2 + H requires 1031.5848), 185
(base).
10.8 Hz, 1 H), 2.98-2.90 (comp, 2 H), 2.74 (ddd, J ) 2.2, 9.4,
17.1 Hz, 1 H), 1.68 (d, J ) 5.1 Hz, 3 H), 0.95 (s, 3 H), 0.94 (s,
3 H), 0.90 (s, 9 H), 0.03 (s, 3 H), -0.02 (s, 3 H); 13C NMR (100
MHz) δ 162.9, 160.5, 143.7, 137.8, 134.1, 133.8, 131.4, 130.5,
129.1, 111.5, 94.1, 79.6, 79.0, 78.9, 77.4, 76.1, 56.4, 42.9, 35.0,
26.1, 22.0, 21.2, 19.4, 18.4, 18.0, -3.4, -4.8; IR (neat) ν 2956,
2929, 2856, 1748, 1576, 1252 cm-1; mass spectrum (FAB) m/z
999.5589 (C56H82N2O10Si2+H requires 999.5586), 185 (base);
and 12 mg (67%) of 23.
P r otected Tetr a d eh yd r od isor a zole, 3. To a solution of
27 (36 mg, 0.035 mmol) in THF (0.5 mL) was added 1 N LiOH
(40 µL), and the reaction was stirred for 2 days at room
temperature. Solvent was removed in vacuo, and the crude
hydrolyzed material was dissolved in H2O (0.5 mL) and then
acidified by addition of 1 N HCl (50 µL). This mixture was
extracted with EtOAc (4 × 0.2 mL), and the combined organics
were dried (Na2SO4) and concentrated. The crude carboxylic
acid was then dissolved in toluene (35 mL) under an atmo-
sphere of argon and treated with Et3N (30 µL, 0.22 mmol),
2,4,6-trichlorobenzoyl chloride (33 µL, 0.21 mmol), and DMAP
(6.0 mg, 0.05 mmol). The resultant cloudy solution was stirred
for 2 days at room temperature, CH2Cl2 (30 mL) was added,
and the solution was washed with 0.1 N NaHSO4 (5 mL), dried
(Na2SO4), and concentrated in vacuo. The crude residue was
purified via column chromatography eluting with EtOAc/
Ack n ow led gm en t. Financial support was provided
by the National Institutes of Health, the National
Science Foundation, Merck, SmithKline Beecham, and
the American Cancer Society. M.C.H. gratefully ac-
knowledges the American Cancer Society for a post-
doctoral fellowship (No. PF-99-227-01-CDD). In addi-
tion, we thank Dr. Agnete LaCour for obtaining the
X-ray crystal structure of 24 and Drs. R. Ng and D. H.
Park for the earlier reported synthesis4 of 8 and 16,
respectively.
SupportingInformation Available: Experimentallp;&4q;1data
for the preparation of 17, determination of the enantiomeric
purity of 16 via preparation of a suitable derivative, X-ray
crystal structure data and ORTEP diagram of 24, and copies
of 1H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
hexanes (1:5) to provide 9 mg (24%) of 3 as an oil: [R]D
)
+106.0 (c 0.4, CH2Cl2); 1H NMR (400 MHz) δ 8.21 (s, 1 H),
6.58 (dd, J ) 10.9, 15.4 Hz, 1 H), 6.20 (dd, J ) 10.9, 11.1 Hz,
1 H), 5.60 (dd, J ) 8.2, 15.3 Hz, 1 H), 5.54 (dq, J ) 5.4, 15.4
Hz, 1 H), 5.45-5.37 (comp, 2 H), 4.06 (dt, J ) 4.8, 8.8 Hz, 1
H), 3.82 (d, J ) 8.1 Hz, 1 H), 3.17 (s, 3 H), 3.12 (dd, J ) 5.8,
J O010249E