Applications of crotonyldiisopinocampheylboranes in synthesis: Total synthesis of restrictinol

Article abstract of DOI:10.1021/jo9815305

The total synthesis of restrictinol, the hydrolysis product of the antifungal natural product restricticin, starting from commercially available methyl (S)-(+)-3-hydroxy-2-methylpropionate is described. Key stages in the strategy involved (i) the use of Brown's allylboration chemistry to construct an acyclic intermediate bearing three of the four stereogenic centers of the natural product, (ii) formation of a C-glycosidic vinyl iodide, and (iii) introduction of the triene side chain via a Suzuki coupling reaction.

Full text of DOI:10.1021/jo9815305

162
J . Org. Chem. 1999, 64, 162-171
Ap p lica tion s of Cr oton yld iisop in oca m p h eylbor a n es in Syn th esis:
Tota l Syn th esis of Restr ictin ol
Anthony G. M. Barrett,* Adrian J . Bennett, Stefan Menzer, Marie L. Smith,
Andrew J . P. White, and David J . Williams
Department of Chemistry, Imperial College of Science Technology and Medicine,
London SW7 2AY, England
Received J uly 30, 1998
The total synthesis of restrictinol, the hydrolysis product of the antifungal natural product
restricticin, starting from commercially available methyl (S)-(+)-3-hydroxy-2-methylpropionate is
described. Key stages in the strategy involved (i) the use of Brown’s allylboration chemistry to
construct an acyclic intermediate bearing three of the four stereogenic centers of the natural product,
(ii) formation of a C-glycosidic vinyl iodide, and (iii) introduction of the triene side chain via a
Suzuki coupling reaction.
In tr od u ction
restrictinol (3) and lanomycinol (4) did not exhibit such
antifungal activity. This family of compounds have been
the subject of considerable interest, and several total
syntheses have been published.7-10 Notably all these
syntheses have introduced the triene side-chain via
carbonyl olefination chemistry (Wittig, Horner-Emmons,
or J ulia reactions) and afforded mixtures of geometric
isomers which were subsequently separated. Herein we
report a synthesis of restrictinol (3) in which the intro-
duction of triene side chain is achieved in geometrically
pure form using a palladium(0)-catalyzed cross coupling
of vinyl iodide 5 and an appropriate “metal” coupling
partner 6 (Scheme 1). We considered that vinyl iodide 5
should be available from lactol 8 by formation of acety-
lenic C-glycoside 7 and subsequent zirconocene dichlo-
ride-catalyzed methylalumination-iodinolysis according
to Negishi.11 Deprotection and oxidative cleavage of olefin
9, with concomitant cyclization, was expected to give
lactol 8. We envisaged that intermediate 9 could be
prepared from aldehyde 10 and borane 11 using Brown’s
allylboration chemistry.12
Restricticin (1) and restrictinol (3) were first isolated
in 1991 by Schwartz and co-workers from the fermenta-
tion broth of Penicillium restrictum.1,2 Restricticin (1) was
found to be unstable due to the lability of the glycine ester
side chain toward base-mediated hydrolysis and the
tendency of the triene functionality to undergo decom-
position. Subsequently, Matsukuma and co-workers re-
ported the isolation of restricticin (1) and restrictinol (3)
from the fermentation broth of Penicillium sp. NR6564.3
In 1992, O’ Sullivan et al. reported the isolation of the
very closely related compounds lanomycin (2) and lano-
mycinol (4) from Pycnidiophora dispersa.4,5 Both restric-
ticin (1) and lanomycin (2) have been shown to exhibit
potent antifungal activity through inhibition of cyto-
chrome P450 lanosterol demethylase and therefore are the
Resu lts a n d Discu ssion
Meth yla lu m in a tion Ap p r oa ch . Aldehyde 12 was
prepared from commercially available methyl (S)-(+)-3-
hydroxy-2-methylpropionate by protection with triethyl-
silyl chloride followed by DIBAL-H reduction.13 Subse-
quent reaction with borane 18 (prepared and used in situ)
according to the procedure of Brown12 afforded, after
first natural products to be isolated that share the same
mode of action as the commercially successful azole
antifungals (e.g. fluconazole).6 Interestingly the desglycyl
(7) J endrzejewski, S.; Ermann, P. Tetrahedron Lett. 1993, 34, 615.
(8) Tsukuda, T.; Umeda, I.; Masubuchi, K.; Shirai, M.; Shimma, N.
Chem. Pharm. Bull. 1993, 41, 1191.
(1) Schwartz, R. E.; Dufresne, C.; Flor, J . E.; Kempf, A. J .; Wilson,
K. E.; Lam, T.; Onishi, J .; Milligan, J .; Fromtling, R. A.; Abruzzo, G.
K.; J enkins, R.; Glazomitsky, K.; Bills, G.; Zitano, L.; Mochales del
Val, S.; Omstead, M. N. J . Antibiot. 1991, 44, 463.
(2) Hensens, O. D.; Wichmann, C. F.; Liesch, J . M.; VanMiddles-
worth, F. L.; Wilson, K. E.; Schwartz, R. E. Tetrahedron 1991, 47, 3915.
(3) Matsukuma, S.; Ohtsuka, T.; Kotaki, H.; Shirai, H.; Sano, T.;
Watanabe, K.; Nakayama, N.; Itezono, Y.; Fujiu, M.; Shimma, N.;
Yokose, K.; Okuda, T. J . Antibiot. 1992, 45, 151.
(4) O’ Sullivan, J .; Phillipson, D. W.; Kirsch, D. R.; Fisher, S. M.;
Lai, M. H.; Trejo, W. H. J . Antibiot. 1992, 45, 306.
(5) Phillipson, D. W.; O’ Sullivan, J .; J ohnson, J . H.; Bolgar, M. S.;
Kahle, A. D. J . Antibiot. 1992, 45, 313.
(9) Kang, S. H.; Kim, C. M. Synlett 1996, 515.
(10) Paterson, I.; Nowak, T. Tetrahedron Lett. 1996, 37, 8243.
Honda, T.; Satoh, A.; Yamada, T.; Hayakawa, T.; Kanai, K. J . Chem.
Soc., Perkin Trans. 1 1998, 397.
(11) Negishi, E.; Choueiry, D. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; J ohn Wiley and Sons:
Chichester, 1995; Vol. 7, p 5192.
(12) Brown, H. C.; J adhav, P. K.; Bhat, K. S. J . Am. Chem. Soc.
1988, 110, 1535.
(13) Barrett, A. G. M.; Edmunds, J . J .; Hendrix, J . A.; Horita, K.;
Parkinson, C. J . J . Chem. Soc., Chem. Commun. 1992, 1238. Barrett,
A. G. M.; Edmunds, J . J .; Hachiya, S. I.; Hendrix, J . A.; Horita, K.;
Malecha, J . W.; Parkinson, C. J .; VanSickle, A. Manuscript in prepara-
tion.
(6) Yuhko, A.; Yamazaki, T.; Kondoh, M.; Sudoh, Y.; Nakayama, N.;
Sekine, Y.; Shimada, H.; Arisawa, M. J . Antibiot. 1992, 45, 160.
10.1021/jo9815305 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/11/1998

Total Synthesis of Restrictinol
Sch em e 1
J . Org. Chem., Vol. 64, No. 1, 1999 163
Sch em e 3
Sch em e 2
Unfortunately, under a variety of different conditions
none of the desired bromide 17 could be isolated. In an
alternative route lactol 15 was oxidized, with Dess-
Martin periodinane,14 to the corresponding lactone 16 so
that we might employ Kishi’s procedure for the stereo-
selective synthesis of C-glycosides (Scheme 2).15
Reaction of lactone 16 with lithium (trimethylsilyl)-
acetylide followed by quenching with methanol resulted
in the formation of hemiketal 19 (81%), with concomitant
(lithium methoxide-mediated) cleavage of the trimethyl-
silyl group (Scheme 3). Interestingly, when the corre-
sponding cerium reagent was used, derived from lithium
(trimethylsilyl)acetylide and cerium(III) chloride, hemi-
ketal 22 was isolated in 100% yield without any cleavage
of the trimethylsilyl group. Reduction of hemiketal 19
with a mixture of triethylsilane and boron trifluoride
diethyl etherate resulted in the formation of the acety-
lenic C-glycosides 20 and 21 in 59% and 20% yields,
respectively. The stereochemistry of these two compounds
was initally assigned by analysis of coupling constants
oxidative workup, the syn homoallylic alcohol 13 (60%)
with greater than 95:5 diastereoselectivity as judged by
analysis of key peaks (2-Me, 3-H, 4-H, 5-H, and 6-H) in
1
in the H NMR spectrum. To confirm our stereochemical
1
the H NMR spectrum (Scheme 2). Subsequent methyl-
assignments, we sought an X-ray crystal structure, and
to that end C-glycoside 20 was converted to its 3,5-
dinitrobenzoate derivative 24 under standard conditions
in 80% yield. Although we were unable to obtain X-ray
quality crystals of 3,5-dinitrobenzoate 24 it proved an
ideal substrate for an NOE experiment, and we were able
to obtain excellent support for our assignments (Figure
1). Subsequently the structure of C-glycoside 21 was
ation of alcohol 13 using sodium hydride and methyl
iodide in DMF proceeded smoothly to afford methyl ether
14 (85%). Conversion of the olefin 13 to lactol 15 was
accomplished by a two-step procedure involving depro-
tection with tetrabutylammonium fluoride and then,
without purification, ozonolysis with a reductive workup
using dimethyl sulfide to afford 15 in 86% overall yield.
Initially we sought to convert lactol 15 into the R-ano-
meric bromide 17 and, subsequently, to convert this into
the corresponding acetylenic C-glycoside 20 (Scheme 3)
by displacement with an appropriate acetylide anion.
(14) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(15) Lewis, D. M.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982,
104, 4976.

164 J . Org. Chem., Vol. 64, No. 1, 1999
Barrett et al.
Sch em e 4
F igu r e 1.
unambiguously confirmed by a single-crystal X-ray analy-
sis (see Supporting Information). Reduction of hemiketal
23 with a mixture of triethylsilane and boron trifluoride
diethyl etherate resulted in formation of the C-glycoside
23 (68%) with none of the other epimer being detected.
Although zirconocene dichloride-catalyzed methyl-
alumination reactions are often tolerant of free hydroxyl
groups, in the first instance, we wished to remove this
additional complication from our system and to that
C-glycoside 20 was converted to the corresponding tri-
ethylsilyl ether 25 by treatment with triethylsilyl tri-
fluoromethanesulfonate and triethylamine to afford 25
(85%). Attempts to convert the acetylenic C-glycoside 25
to vinyl iodide 26 using a mixture of trimethylaluminum
and zirconocene dichloride followed by iodinolysis of the
resultant vinylalane according to Negishi’s procedure11
were unsuccessful, our substrate proving inert to the
reaction conditions. Wipf has recently reported a dra-
matic rate acceleration in zirconocene dichloride-cata-
lyzed methylalumination reactions by the addition of
water to the preformed organometallic reagent.16 On a
single occasion, using this modification we were able to
isolate a trace of our desired vinyl iodide 26. Unfortu-
nately attempts to repeat this result were completely
unsuccessful. All that could be isolated, on occasion, in
trace amounts was another compound tentatively as-
signed as the ring opened hydroxy allene 27. In conse-
quence this approach was abandoned.
Sch em e 5
the reduction of hemiketal 28 as before were unsuccessful
giving complex mixtures of products instead. We sus-
pected either the nucleophilic vinyl silane and/or the
cleavage of the methoxymethyl ether could be complicat-
ing factors in this reaction, and therefore we sought to
test the viability of our approach on a model system. For
this we chose the known gluconolactone derivative 3118
as a starting point (Scheme 5). Lithiation of iodide 30
followed by reaction with lactone 31 afforded hemiketal
32 as a single epimer (64%). Subsequent reduction of 32
with a mixture of boron trifluoride and triethylsilane
afforded the C-glycoside 33 albeit in a modest 49% yield.
Treatment of silane 33 with N-iodosuccinimide gave the
vinyl iodide 35 (95%). The structure and absolute ster-
eochemistry of this compound were unambiguously con-
firmed by a single-crystal X-ray analysis (see Supporting
Information). Although this established the viability of
our approach, the yield of the reduction step was modest
Vin yl Sila n e-Ma sk ed Vin yl Iod id e Ap p r oa ch . We
envisaged that reaction of lactone 16 with the anion
derived from halogen-metal exchange of iodide 30 (as
employed by Nicolaou in the synthesis of rapamycin17
)
should provide hemiketal 28 (Scheme 4). Reduction of
28 as before would lead to vinyl silane 29 which in turn
could be converted to the corresponding vinyl iodide by
treatment with N-iodosuccinimide. Indeed, lithiation of
30 followed by addition of lactone 16 afforded the
hemiketal 28 (77%). Unfortunately, all attempts to effect
(16) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068.
(17) Pisopio, A. D.; Minowa, N.; Chakraborty, T. K.; Koide, K.;
Bertinato, P.; Nicolaou, K. C. J . Chem. Soc., Chem. Commun. 1993,
617.

Total Synthesis of Restrictinol
Sch em e 6
J . Org. Chem., Vol. 64, No. 1, 1999 165
Sch em e 7
Sch em e 8
and, moreover, this transformation had already proved
ineffective with lactone 16. To improve the strategy we
chose to reverse the order of the steps in the sequence
and to reveal the vinyl iodide prior to the reduction step,
thereby carrying out the ionic hydrogenolysis in the
absence of a nucleophilic vinyl silane. Thus, in the model
system, vinyl silane 32 was converted into vinyl iodide
34 (83%) by treatment with N-iodosuccinimide. Much to
our delight, subsequent reduction as before afforded vinyl
iodide 35 in 86% yield as a 85:15 mixture of epimers in
favor of the desired â-C-glycoside.
Following the success of our model studies, hemiketal
28 was allowed to react with N-iodosuccinimide to afford
the (somewhat unstable) iodide 36 (81%) (Scheme 6).
Unfortunately reduction of 36 under standard conditions
at -20 °C afforded the desired iodide 37 (9%) and, as
the major product, epimeric iodide 38 (32%). Reduction
at -40 °C resulted in the formation of iodide 39 as the
major product (42%), again with the undesired glycoside
stereochemistry but with the methoxymethyl group
remaining intact. At this stage, we reasoned that the
methoxymethyl ether might be interfering with the
reduction step, shielding the R-face and leading to the
formation of the undesired epimer. Therefore, hemiketal
28 was allowed to react with camphorsulfonic acid in
methanol, affording alcohol 40 (70%) (Scheme 7) which
was converted into the iodide 41 using N-iodosuccin-
imide-mediated iododesilylation of the corresponding
trimethylsilyl ether (73% overall yield). Reduction of
hemiketal 41 using triethylsilane and boron trifluoride
diethyl etherate afforded the desired iodide 37 (56%)
along with the epimeric iodide 38 (39%). Treatment of
iodide 37 with triethylsilyl trifluoromethanesulfonate and
2,6-lutidine gave the corresponding triethylsilyl ether 26
(96%). Gratifyingly, the 1H NMR of iodide 26 was
identical to one previously obtained from our troublesome
zirconocene dichloride-catalyzed methylalumination ap-
proach.
ether (Scheme 8). We considered that the bulky silyl
group would act as a conformational anchor and prevent
ring flipping of the intermediate pyran oxonium cation
in the reduction step that presumably leads to the
undesired stereochemistry in the product. Also were this
approach to be successful, then our protection strategy
should prove amenable to rationalization with a con-
sumate reduction in the overall number of steps. Protec-
tion of 41 under standard conditions afforded the corre-
sponding silyl ether 42 (97%). Much to our chagrin,
reduction of 42 with 1 equiv of boron trifluoride diethyl
etherate and excess triethylsilane at -40 °C resulted in
the formation of the undesired, epimeric C-glycoside 43
(70%) along with 30% recovered 42 (30%) and not a trace
of the desired epimer 44. In an attempt to force this
reaction to completion, excess boron trifluoride (1.5 equiv)
was employed; however in this case, although no starting
material remained, we noticed significant cleavage of the
tert-butyldimethylsilyl ether.
We postulated that the selectivity in our reduction step,
leading to the formation of our C-glycoside coupling
partner, could be improved by the prior protection of the
free hydroxyl group of 41 as a tert-butyldimethylsilyl
Syn th esis of a Dien yl Cou p lin g P a r tn er . 1-Pentyne
was converted into vinyl iodide 46 (54%) by treatment
with diisobutylaluminum hydride and iodinolysis of the
resultant vinylalane to afford 46 (Scheme 9). Subse-

166 J . Org. Chem., Vol. 64, No. 1, 1999
Barrett et al.
Sch em e 9
Sch em e 10
coupling reaction. The triene coupling methodology is
clearly amenable for the elaboration of analogues.
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless stated otherwise, solvents
and amine bases were dried by distillation under N2 or Ar,
from sodium benzophenone ketyl (THF, Et2O), CaH2 (CH2Cl2,
DMF, MeCN, Et3N, pentane), KOH (2,6-lutidine), and Mg/I2
(MeOH). N-Iododosuccinimide was recrystallized from CCl4/
1,4-dioxane. All other reagents were used as received from
commercial sources. All reactions were performed in oven-dried
(150 °C) glassware under N2 or Ar. Chromatographed and
chromatography refer to column chromatography on BDH 40-
63 µM grade silica gel. Analytical thin-layer chromatography
(TLC) was performed on precoated glass backed plates (Merck
Kieslegel 60 F254) and visualized with ceric molybdate or
potassium permanganate stains and/or ultraviolet light as
appropriate. Bulb to bulb distillation was carried out using a
Kugelrohr distillation apparatus with the collection bulb cooled
with dry ice. The temperatures quoted are oven temperatures
and are approximate.
(2S,3S,4S)-4-(Met h oxym et h oxy)-2-m et h yl-1-(t r iet h yl-
silyloxy)-5-h exen -3-ol (13). To a stirred solution of meth-
oxymethyl allyl ether (2.10 g, ∼90% pure, 18.56 mmol) in THF
(40 mL) at e-85 °C (solution temperature) was dropwise
added sec-BuLi in cyclohexane (1.35 M; 13.2 mL, 17.82 mmol).
After 3 h, the resultant yellow solution was treated with (+)-
B-methoxydiisopinocampheylborane (6.11 g, 19.31 mmol) in
THF (10 mL), maintaining the internal temperature at e-85
°C. The resultant white cloudy solution was stirred at this
temperature for 3 h before adding BF3‚Et2O (2.02 mL, 16.40
mmol). After 15 min, aldehyde 12 (3.0 g, 14.8 mmol) in THF
(20 mL) at -78 °C was added dropwise via cannula (down the
side of the flask), maintaining an internal temperature e-85
°C. The reaction mixture was stirred at this temperature for
18 h before being quenched by the dropwise addition of MeOH
(5 mL). After 15 min, saturated aqueous sodium perborate (75
mL) was added, and the mixture was allowed to warm to room
temperature and stirred for 36 h. The aqueous and organic
phases were separated, and the aqueous phase was extracted
with Et2O (5 × 50 mL). The combined organic extracts were
washed with water (2 × 100 mL) and brine (100 mL), dried
(MgSO4), filtered, and rotary evaporated. The residue was
chromatographed (eluant EtOAc:hexanes 1:9) to afford 13 (2.72
g, 60%) as a colorless oil: TLC Rf ) 0.25 (Et2O:hexanes 1:9);
[R] ) +88.6° (c ) 1.0, CHCl3); IR (film) 3492, 2955, 2878, 1460
cm-1; 1H NMR (CDCl3, 300 MHz) δ 5.90-5.81 (1H, m), 5.30-
5.24 (2H, m), 4.70 (1H, d, J ) 7.0 Hz), 4.55 (1H, d, J ) 7.0
Hz), 4.50-4.10 (1H, dd, J ) 4.5, 7.5 Hz), 3.74 (1H, d, J ) 3.5
Hz), 3.69-3.64 (2H, m), 3.49-3.44 (1H, m), 3.36 (3H, s), 2.02-
1.98 (1H, m), 0.95-0.90 (12H, m), 0.62-0.54 (6H, q, J ) 8.0
Hz); 13C NMR (CDCl3, 75 MHz) δ 135.6, 118.6, 94.0, 78.4, 66.7,
55.7, 36.5, 13.6, 6.7, 4.2; MS (CI+, NH3) m/z 305 (M + H)+.
Anal. Calcd for C15H32O4Si: C, 59.17; H, 10.59. Found: C,
58.88; H, 10.36.
quently, (trimethylsilyl)acetylene (47) was lithiated and
treated sequentially with zinc chloride, vinyl iodide 46,
and tetrakis(triphenylphosphine)palladium(0) to afford
silyl enyne 48 (89%) which was allowed to react with
potassium fluoride in DMF, according to the literature
procedure,19 to afford the volatile enyne 49 which could
not be separated from silane residues and was used
without further purification. Hydroboration of 49 with
catecholborane followed by hydrolysis of the resultant
boronic ester afforded boronic acid 50. Interestingly,
when dried under vacuum, boronic acid 50 underwent
trimerization to give the corresponding cyclic anhydride
(67%). For our purposes we wished to use the free boronic
acid 50, and the anhydride was hydrolyzed with water
and dried on a filter paper.
Syn th esis of Restr ictin ol (3). Kishi has reported a
dramatic rate acceleration in Suzuki couplings if thallium
hydroxide is used as base.20 This base has subsequently
been used in Suzuki couplings in the construction of
sensitive polyene functionality, and we therefore chose
to utilize it in our synthesis of the sensitive triene of
restrictinol (3).21 A mixture of vinyl iodide 26 and boronic
acid 50 was allowed to react with 10% aqueous thallium
hydroxide and tetrakis(triphenylphosphine)palladium(0)
in THF to afford triene 51 (73%) (Scheme 10). Subsequent
deprotection with tetrabutylammonium fluoride afforded
restrictinol (3) which had 1H NMR and 13C NMR identical
to that reported for the natural material.2,22 The optical
rotation [R]26 +64.0 (c 0.25 MeOH), was in close agree-
D
ment to that reported in the literature [R]20D +51 (c 0.20,
MeOH).3
In conclusion we have developed a concise route to
restrictinol (3) from commercially available starting
materials and for the first time introduced the triene side
chain in geometrically pure form via a palladium(0)
(18) Kuzuhara, H.; Fletcher, H. G., J r. J . Org. Chem. 1967, 32, 2531.
(19) Argenti, L.; Bellina, F.; Carpita, A.; Rossi, E.; Rossi, R. Synth.
Commun. 1994, 24, 2281.
(20) Uenishi, J .; Beau, J .-M.; Armstrong, R. W.; Kishi, Y. J . Am.
Chem. Soc. 1987, 109, 4756.
(21) For a review of the palladium-catalyzed cross-coupling reactions
of organoboron compounds see: Miyaura, N.; Suzuki, A. Chem. Rev.
1995, 95, 2457.
(2S,3S,4S)-3-Met h oxy-4-(m et h oxym et h oxy)-2-m et h yl-
1-(tr ieth ylsilyloxy)-5-h exen e (14). To a stirred mixture of
NaH (987 mg, 60%, 24.68 mmol) and MeI (3.84 mL, 61.70
(22) A 1H NMR spectrum of natural restrictinol 3 was kindly
supplied by O. D. Hensens, Merck Sharpe and Dohme Research
laboratories.
o
mmol) in DMF (80 mL) at -10 C was dropwise added alcohol

Total Synthesis of Restrictinol
J . Org. Chem., Vol. 64, No. 1, 1999 167
13 (3.75 g, 12.34 mmol) in DMF (20 mL). After 1.5 h, the
reaction was quenched with saturated aqueous NH4Cl (10 mL),
diluted with distilled water (150 mL), and extracted with Et2O
(4 × 100 mL). The combined organic extracts were washed
with water (2 × 50 mL) and brine (50 mL), dried (MgSO4),
filtered, and rotary evaporated. The residue was chromato-
graphed (eluant Et2O:hexanes 1:19) to afford 14 (3.34 g, 85%)
as a colorless oil: TLC Rf ) 0.57 (Et2O:hexanes 1:4); [R] )
+51.4° (c ) 1.0, CHCl3); IR (film) 3080, 2955, 2878, 2824, 1642
cm-1; 1H NMR (CDCl3, 270 MHz) δ 5.95-5.82 (1H, m), 5.34-
5.25 (2H, m), 4.71 (1H, d, J ) 7.0 Hz), 4.56 (1H, d, J ) 7.0
Hz), 4.19 (1H, dd, J ) 4.0, 7.5 Hz), 3.65 (2H, d, J ) 5.0 Hz),
3.48 (3H, s), 3.38 (3H, s), 3.08 (1H, dd, J ) 3.5, 7.5 Hz), 2.01-
1.96 (1H, m), 1.02-0.93 (12H, m), 0.61 (6H, q, J ) 8.0 Hz);
13C NMR (CDCl3, 75 MHz) δ 136.1, 118.1, 94.0, 85.6, 77.9, 64.0,
61.2, 55.7, 37.3, 14.2, 6.8, 4.4; MS (CI+, NH3) m/z 319 (M +
H)+, 287 (M - OCH3)+, 257 (M - OCH2OCH3)+. Anal. Calcd
for C16H34O4Si: C, 60.33; H, 10.76. Found: C, 60.05; H, 10.94.
(2R S ,3R ,4S ,5S )-2-H yd r oxy-4-m e t h oxy-3-(m e t h oxy-
m eth oxy)-5-m eth yltetr a h yd r o-2H-p yr a n (15). To a stirred
solution of 14 (3.49 g, 10.97 mmol) in THF (50 mL) was added
Bu4NF in THF (1 M; 12.0 mL 12.0 mmol). After 1 h, the solvent
was evaporated in vacuo and the residue filtered through silica
gel (eluant Et2O). After rotary evaporation, the residue was
suspended in CH2Cl2 (100 mL) and cooled to -78 °C. Ozone-
enriched oxygen was passed through the solution until it
became blue whereupon Me2S (15 mL) was added and the
mixture allowed to warm to room-temperature overnight. After
evaporation in vacuo, the residue was chromatographed (elu-
ant EtOAc:hexanes 2:3) to afford lactol 15 (1.94 g, 86%), a 1:1
mixture of anomers, as a colorless oil: TLC Rf ) 0.22 (EtOAc:
hexanes 2:3); IR (film) 3411, 1727, 1640 cm-1; 1H NMR (CDCl3,
270 MHz) δ 4.94-4.76 (1H, m), 4.75-4.72 (2H, m), 4.08-4.04
(1H single anomer, m), 3.77-3.69 (1H, m), 3.65-3.61 (1H, m),
3.53-3.35 (2H, m), 3.47 (3H single anomer, s), 3.42 (3H single
anomer, s), 3.40 (3H single anomer, s), 3.39 (3H single anomer,
s), 2.27-2.12 (1H, m), 0.92 (3H single anomer, d, J ) 7.0 Hz),
0.89 (3H single anomer, d, J ) 7.0 Hz); MS (CI+, NH3) m/z
224 (M + NH4)+, 206 (M - H2O + NH4)+, 189 (M - OH)+;
HRMS (CI+, NH3) m/z calcd for C9H20N04 (M - H2O + NH4)+
206.1392, found 206.1389.
isomer, m), 3.48 (3H major isomer, s), 3.46 (3H, s), 3.38 (3H
minor isomer, s), 2.59 (1H major isomer, s), 2.57 (1H minor
isomer, s), 2.32-2.23 (1H, m), 1.02 (3H minor isomer, d, J )
7.0 Hz), 0.97 (3H major isomer, d, J ) 7.0 Hz); MS (CI+, NH3)
m/z 248 (M + NH4)+, 230 (M + NH4 - H2O)+, 230 (M - OH)+.
Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.17;
H, 7.59.
(2R S ,3R ,4S ,5S )-2-H yd r oxy-4-m e t h oxy-3-(m e t h oxy-
m eth oxy)-5-m eth yl-2-((tr im eth ylsilyl)eth yn yl)tetr ah ydr o-
2H-p yr a n (22). CeCl3‚7H2O (123 mg, 0.33 mmol) was heated
to 140 °C under vacuum (∼2 mmHg) for 4 h. When cool, THF
(1.0 mL) was added and the resultant suspension stirred
vigorously overnight before being cooled to -78 °C. To a stirred
solution of (trimethylsilyl)acetylene in THF (1.0 mL) at -78
°C was added n-BuLi in hexane (2.3 M; 122 µL, 0.28 mmol).
After 1 h, the resultant anion was transferred via cannula to
the stirred suspension of CeCl3 at -78 °C, and, after a further
2 h, lactone 16 (32 mg, 0.157 mmol) in THF (2 mL) at -78 °C
was added via cannula. The mixture was quenched after 2 h
with saturated aqueous NH4Cl (1 mL) and allowed to warm
to room temperature. The mixture was decanted from the
resultant precipitate (rinsed with Et2O) and the solvent
evaporated in vacuo. The residue was dry loaded onto silica
and chromatographed (EtOAc:hexanes 1:4) to afford hemiketal
22 (48 mg, 100%), a 3:2 mixture of anomers, as a colorless oil:
TLC Rf ) 0.21 (EtOAc:hexanes 1:4); IR (film) 3389, 2963 cm-1
;
1H NMR (CDCl3, 270 MHz) δ 5.71 (1H major isomer, s), 4.92
(1H major isomer, d, J ) 7.0 Hz), 4.87 (2H minor isomer, app
d, J ) 1.0 Hz), 4.74 (1H major isomer, d, J ) 7.0 Hz), 3.96
(1H minor isomer, dd, J ) 3.0, 11.5 Hz), 3.75-3.38 (4H major
isomer and 3H minor isomer, m), 3.49 (3H major isomer, s),
3.46 (3H minor isomer, s), 3.44 (3H major isomer, s), 3.35 (3H
minor isomer, s), 2.37-2.18 (1H, m), 1.02 (3H minor isomer,
d, J ) 7.0 Hz), 0.93 (3H major isomer, d, J ) 7.0 Hz), 0.17
(9H major isomer, s), 0.16 (9H minor isomer, s); MS (CI+, NH3)
m/z 320 (M + NH4)+, 302 (M + NH4 - H2O)+, 285 (M - OH)+.
Anal. Calcd for C14H26O5Si: C, 55.60; H, 8.67. Found: C, 55.72;
H, 8.64.
(2S,3R,4S,5S)-3-H yd r oxy-4-m et h oxy-5-m et h yl-2-((t r i-
m eth ylsilyl)eth yn yl)tetr ah ydr o-2H-pyr an (23). To a stirred
solution of hemiketal 22 (24 mg, 0.079 mmol) and Et3SiH (64
µL, 0.40 mmol) in MeCN(1.5 mL) at -20 °C was added, BF3‚
Et2O (20 µL, 0.16 mmol). After 4 h, saturated aqueous NaHCO3
(200 µL) was added and the mixture allowed to warm to room
temperature. The solvent was evaporated in vacuo and the
residue dry loaded onto silica and chromatographed (eluant
EtOAc:hexanes 1:4) to afford acetylenic C-glycoside 23 (13 mg,
68%): TLC Rf ) 0.18 (EtOAc:hexanes 1:4); [R] ) +43.7° (c )
0.27, CHCl3); IR (film) 3450, 2178 cm-1; 1H NMR (CDCl3, 270
MHz) δ 3.85 (1H, d, J ) 9.0 Hz), 3.82 (1H, dd, J ) 2.0, 12.0
Hz), 3.66 (1H, app td, J ) 2.0, 9.0 Hz), 3.54 (1H, dd, J ) 2.5,
12.0 Hz), 3.40 (3H, s), 3.20 (1H, dd, J ) 5.0, 9.0 Hz), 2.40 (1H,
d, J ) 2.5 Hz), 2.22-2.16 (1H, m), 1.03 (1H, d, J ) 7.0 Hz),
0.19 (9H, s); 13C NMR (CDCl3, 75 MHz) δ 101.8, 91.1, 83.1,
72.2, 71.1, 70.0, 56.3, 31.8, 10.9, -0.17; MS (CI+, NH3) m/z
260 (M + NH4)+, 243 (M + H)+. Anal. Calcd for C12H22O3Si:
C, 59.46; H, 9.15. Found: C, 59.22; H, 8.88.
(3R,4S,5S)-4-Meth oxy-3-(m eth oxym eth oxy)-5-m eth yltet-
r a h yd r o-2H-p yr a n -2-on e (16). To a stirred solution of lactol
15 (300 mg, 1.46 mmol) in CH2Cl2 (10 mL) at 0 °C was added
Dess-Martin periodinane14 (929 mg, 2.19 mmol). After 1 h,
the mixture was allowed to warm to room temperature and,
after a further 3 h, the mixture was dry loaded onto silica and
chromatographed (eluant EtOAc:hexanes 1:3) to afford 16 (225
mg, 76%) as a colorless oil: TLC Rf ) 0.35 (EtOAc:hexanes
3:7); [R] ) +130.3° (c ) 1.1, CHCl3); IR (film) 2969, 1744 cm-1
;
1H NMR (CDCl3, 270 MHz) δ 4.99-4.97 (1H, d, J ) 6.5 Hz),
4.72-4.70 (1H, d, J ) 6.5 Hz), 4.24-4.09 (3H, m), 3.48-3.42
(1H, m), 3.47 (3H, s), 3.43 (3H, s), 2.46-2.38 (1H, m), 1.04-
1.01 (3H, d, J ) 7.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 169.6,
96.3, 80.4, 72.0, 70.4, 58.5, 56.0, 30.6, 10.9; MS (CI+, NH3) m/z
222 (M + NH4)+, 205 (M + H)+. Anal. Calcd for C9H16O5: C,
52.93; H, 7.90. Found: C, 52.73; H, 7.98.
(2RS,3R,4S,5S)-2-Eth yn yl-2-h ydr oxy-4-m eth oxy-3-(m eth -
oxym eth oxy)-5-m eth yltetr a h yd r o-2H-p yr a n (19). To a
stirred solution of (trimethylsilyl)acetylene (485 µL, 3.43 mmol)
in THF (10 mL) at -78 °C was added n-BuLi in hexane (2.44
M; 1.23 mL, 3.00 mmol). After 1 h, the resultant anion was
transferred, via cannula, to a stirred solution of lactone 16
(584 mg, 2.86 mmol) in THF (15 mL). MeOH (2 mL) was added
after 2 h and the reaction mixture allowed to warm to room-
temperature overnight. After 18 h, saturated aqueous NH4Cl
(3 mL) was added and the solvent evaporated in vacuo. The
residue was dry loaded onto silica gel and chromatographed
(eluant EtOAc:hexanes 1:4) to afford 19 (533 mg, 81%), a 3:1
mixture of anomers, as a colorless oil: TLC Rf ) 0.31 (EtOAc:
hexanes 2:3); IR (film) 3368, 3257, 2969, 2111 cm-1; 1H NMR
(CDCl3, 270 MHz) δ 5.56 (1H major isomer, s), 4.90 (1H major
isomer, d, J ) 7.0 Hz), 4.91-4.84 (2H minor isomer, m), 4.77
(1H major isomer, d, J ) 7.0 Hz), 3.96 (1H minor isomer, dd,
J ) 3.0, 11.5 Hz), 3.81-3.32 (4H major isomer and 3H minor
(2S,3R,4S,5S)-2-Eth yn yl-3-h yd r oxy-4-m eth oxy-5-m eth -
yltetr a h yd r o-2H-p yr a n (20) a n d (2R,3R,4S,5S)-2-Eth yn yl-
3-h ydr oxy-4-m eth oxy-5-m eth yltetr a h ydr o-2H-p yr a n (21).
To a stirred solution of hemiketal 19 (504 mg, 2.19 mmol) and
Et3SiH (1.75 mL, 10.95 mmol) in MeCN (30 mL) at -20 °C
was dropwise added BF3‚Et2O (555 µL, 4.38 mmol). After 2.5
h, the mixture was quenched with saturated aqueous NaHCO3
solution (2 mL), allowed to warm to room temperature, and
filtered. The solvent was evaporated in vacuo and the residue
dry loaded onto silica and chromatographed (eluant EtOAc:
hexanes 7:13) to afford (i) acetylenic C-glycoside 21 (74 mg,
20%) as a crystalline white solid and (ii) acetylenic C-glycoside
20 (219 mg, 59%) as a colorless oil. 21: mp 66-68 °C (hexanes);
TLC Rf ) 0.31 (EtOAc:hexanes 2:3); [R] ) +29.3° (c ) 1.0,
CHCl3); IR (film) 3439, 3281, 2119 cm-1; 1H NMR (CDCl3, 300
MHz) δ 4.58 (1H, d, J ) 2.0 Hz), 3.81-3.72 (2H, m), 3.50-
3.46 (1H, m), 3.43 (3H, s), 3.39-3.36 (1H, m), 2.55 (1H, d, J )
2.0 Hz), 2.36 (1H, bs), 2.26-2.18 (1H, m), 0.91 (3H, d, J ) 7.0

168 J . Org. Chem., Vol. 64, No. 1, 1999
Barrett et al.
Hz); 13C NMR (CDCl3, 75 MHz) δ 79.9, 75.4, 68.2, 67.4, 58.0,
30.0, 11.6; MS (CI+, NH3) m/z 188 (M + NH4)+. Anal. Calcd
for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.38; H, 7.99. 20:
TLC Rf ) 0.20 (EtOAc:hexanes 2:3); [R] ) +78.5° (c ) 1.0,
CHCl3); IR (film) 3433, 3280, 2122 cm-1; 1H NMR (CDCl3, 300
MHz) δ 3.89 (1H, dd, J ) 2.0, 9.0 Hz), 3.85 (1H, dd, J ) 2.0,
12.0 Hz), 3.72 (1H, app td, J ) 1.5, 9.0 Hz), 3.58 (1H, dd, J )
2.5, 12.0 Hz), 3.42 (3H, s), 3.23 (1H, dd, J ) 5.0, 9.0 Hz), 2.61
(1H, d, J ) 2.0 Hz), 2.55 (1H, d, J ) 2.0 Hz), 2.23-2.22 (1H,
m), 1.05 (1H, d, J ) 7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 83.2,
80.6, 74.0, 71.3, 71.1, 69.9, 56.2, 31.6, 10.8; MS (CI+, NH3) m/z
iodide 30 (253 mg, 1.06 mmol) in Et2O (11 mL) at -78 °C was
dropwise added t-BuLi in pentane (2.0 M; 1.06 mL, 2.11 mmol).
After 30 min, lactone 16 (180 mg, 0.88 mmol) in Et2O (8 mL)
at -78 °C was added dropwise via cannula. After a further 1
h, AcOH (80 µL, 1.40 mmol) and then saturated aqueous
NH4Cl (1 mL) were added, and the mixture was allowed to
warm to room temperature. The reaction mixture was diluted
with EtOAc (100 mL) and washed with distilled water (3 ×
30 mL) and brine (30 mL). The organic layer was dried
(MgSO4), filtered, and rotary evaporated. The residue was
chromatographed (eluant EtOAc:hexanes 1:4) to afford 28 (216
mg, 77%), a 3:1 mixture of anomers (with a trace of ring opened
188 (M + NH4)+, 85; HRMS (CI+, NH3) m/z calcd for C9H18
-
NO3 (M + NH4)+ 188.1287, found 188.1284. Crystal data for
21: C9H14O3, M ) 170.2, orthorhombic, P212121 (no. 19), a )
7.408(1), b ) 7.425(2), c ) 17.337(2) Å, V ) 953.6(3) Å3, Z ) 4,
Dc ) 1.186 g cm-3, µ(Cu-KR) ) 7.26 cm-1, F(000) ) 368, T )
293 K; clear blocks, 0.83 × 0.33 × 0.16 mm, Siemens P4/PC
diffractometer, ω-scans, 911 independent reflections. The
structure was solved by direct methods and the non-hydrogen
atoms were refined anisotropically using full matrix least-
squares based on F2 to give R1 ) 0.045, wR2 ) 0.115 for 793
independent observed reflections [|Fo| > 4σ(|Fo|), 2θ e 125°]
and 114 parameters. The absolute structure of 21 was deter-
mined by internal reference.23
isomer), as a colorless oil: IR (film) 3437, 1671, 1623, cm-1
;
1H NMR (CDCl3, 270 MHz) δ 5.98 (1H minor isomer, d, J )
1.0 Hz), 5.91 (1H major isomer, d J ) 1.0 Hz), 5.73 (1H minor
isomer, s), 4.77 (1H major isomer, d, J ) 6.5 Hz), 4.58 (2H
minor isomer, app d, J ) 1.0 Hz), 4.52 (1H major isomer, d, J
) 6.5 Hz), 4.11 (1H major isomer, dd, J ) 2.5, 11.5 Hz), 3.78-
3.38 (4H minor isomer and 3H major isomer, m), 3.56 (3H
minor isomer, s), 3.36 (3H major isomer, s), 3.35 (3H minor
isomer, s), 3.33 (3H major isomer, s), 2.78 (1H major isomer,
s), 2.25-2.20 (1H, m), 1.92 (3H, app s), 1.07 (3H major isomer,
d, J ) 7.0 Hz), 1.03 (3H minor isomer, d, J ) 7.0 Hz), 0.19
(9H, s); MS (CI+, NH3) m/z 336 (M + NH4)+, 301 (M - OH)+,
287 (M - OMe)+. Anal. Calcd for C15H30O5Si: C, 56.57; H, 9.49.
Found: C, 56.64; H, 9.36.
(2S,3R,4S,5S)-2-Eth yn yl-4-m eth oxy-5-m eth yltetr ah ydr o-
2H-p yr a n -2-yl 3,5-Din itr oben zoa te (24). To a stirred mix-
ture of C-glycoside 20 (23 mg, 0.14 mmol), Et3N (38 µL, 0.27
mmol), and DMAP (5 mg, 0.04 mmol) in CH2Cl2 (1 mL) was
added 3,5-dinitrobenzoyl chloride (46 mg, 0.20 mmol). After 1
h, distilled water (0.5 mL) was added and the mixture was
diluted with Et2O (20 mL) and washed with distilled water (3
× 10 mL) and brine (10 mL). The organic layer was dried
(MgSO4), filtered, and rotary evaporated. The residue was
chromatographed (eluant EtOAc:hexanes 1:4) to afford 3,5-
dinitrobenzoate 24 (40 mg, 80%) as a pale yellow solid: mp
140-143 °C (CHCl3/hexanes); TLC Rf ) 0.22 (EtOAc:hexanes
1:4); [R] ) +29.5° (c ) 1.1, CHCl3); IR (film) 3239, 3103, 1740,
1629, 1547, 1461 cm-1; 1H NMR (CDCl3, 300 MHz) δ 9.26 (1H,
t, J ) 2.0 Hz), 9.18 (2H, d, J ) 2.0 Hz), 5.44 (1H, app t, J )
8.0 Hz), 4.33 (1H, dd, J ) 2.0, 8.0 Hz), 3.94 (1H, dd, J ) 4.0,
12.0 Hz), 3.65 (1H, dd, J ) 3.0, 12.0 Hz), 3.54 (1H, dd, J )
4.5, 8.0 Hz), 3.38 (3H, s), 2.46 (1H, d, J ) 2.0 Hz), 2.38-2.35
(1H, m), 1.13 (3H, d, J ) 7.0 Hz); 13C NMR (CDCl3, 75 MHz)
δ 162.0, 149.1, 133.9, 129.9, 123.0, 80.4, 79.1, 75.2, 72.5, 69.8,
68.5, 57.0, 32.3, 11.4; MS (CI+, NH3) m/z 382 (M + NH4)+, 365
(M + H)+. Anal. Calcd for C16H16N2O8: C, 52.75; H, 4.43; N,
7.69. Found: C, 52.89; H, 4.16; N, 7.45.
(E)-2-(1-Hydr oxy-2,3,4,6-tetr a-O-ben zyl-â-D-glu copyr an -
osyl)-1-(tr im eth ylsilyl)p r op -1-en e (32). To a stirred solution
of vinyl iodide 30 (112 mg, 0.47 mmol) in THF (5 mL) at -78
°C was dropwise added t-BuLi (1.5 M; 593 µL, 0.89 mmol).
After 30 min, lactone 31 (200 mg, 0.37 mmol) in THF (4 mL)
at -78 °C was added dropwise via cannula.18 After 1 h, the
mixture was quenched with saturated aqueous NH4Cl (0.5 mL)
and allowed to warm to room temperature. The mixture was
filtered and rotary evaporated and the residue azeotroped with
MeCN, dry loaded onto silica, and chromatographed (eluant
Et2O:hexanes 1:3) to afford hemiketal 32 (156 mg, 64%) as a
crystalline white solid: mp 70-75 °C; TLC Rf ) 0.27 (Et2O:
hexanes 3:7); [R] ) +47.1° (c ) 1.0, CHCl3); IR (film) 3531,
1
3430, 3031, 1620 cm-1; H NMR (CDCl3, 300 MHz) δ 7.20-
7.06 (20H, m), 5.88 (1H, s), 4.72-4.68 (3H, m), 4.54-4.48 (3H,
m), 4.42-4.37 (2H, m), 3.91-3.79 (2H, m), 3.68 (1H, dd, J )
11.0, 4.0 Hz), 3.61-3.52 (2H, m), 3.44 (1H, d, J ) 9.0 Hz), 2.70
(1H, s), 1.79 (3H, s), 0.93 (9H, s); 13C NMR (CDCl3, 75 MHz)
δ 153.1, 139.0, 138.9, 138.7, 138.1, 128.7, 128.6, 128.3, 128.2,
128.1, 128.0, 128.0, 127.8, 127.7, 127.1, 99.0, 83.9, 80.9, 78.5,
76.9, 76.0, 75.5, 75.3, 73.6, 72.5, 69.3, 17.7, 0.0; MS (CI+, NH3)
m/z 670 (M + NH4)+, 635 (M - OH)+. Anal. Calcd for C40H48O6-
Si: C, 73.58; H, 7.41. Found: C, 73.29; H, 7.28.
(2S,3R,4S,5S)-2-Eth yn yl-4-m eth oxy-5-m eth yl-3-(tr ieth yl-
silyloxy)tetr a h yd r o-2H-p yr a n (25). A stirred mixture of
C-glycoside 20 (136 mg, 0.80 mmol) and Et3N (167 µL, 1.20
mmol) in CH2Cl2 (5 mL) was cooled in an ice/salt bath. Et3-
SiO3SCF3 (199 µL, 0.88 mmol) was added dropwise, followed,
after 1 h, by saturated aqueous NaHCO3 (0.5 mL). The mixture
was diluted with Et2O (25 mL) and washed with distilled water
(3 × 10 mL) and brine (5 mL). The organic layer was dried
(MgSO4), filtered, and rotary evaporated. The residue was
chromatographed (eluant EtOAc:hexane 1:19) to afford 25 (192
mg, 85%) as a colorless oil: TLC Rf ) 0.26 (EtOAc:hexanes
1:19); [R] ) +42.5° (c ) 1.1, CHCl3); IR (film) 3312, 3264, 2125
(E)-2-(2,3,4,6-Tetr a-O-ben zyl-â-D-glu copyr an osyl)-1-(tr i-
m eth ylsilyl)p r op -1-en e (33). To a stirred solution of hemi-
ketal 32 (50 mg, 0.08 mmol) and Et3SiH (90 mg, 123 µL, 0.77
mmol) in an MeCN/CH2Cl2 (85:15) solvent mixture (2.5 mL)
at -40 °C was added dropwise BF3‚Et2O (11 µL, 0.08 mmol)
in CH2Cl2 (100 µL). After 15 min, the mixture was quenched
with Et3N (100 µL) and saturated aqueous NaHCO3 (0.5 mL)
and allowed to warm to room temperature. The reaction
mixture was filtered and rotary evaporated and the residue
azeotroped with MeCN, dry loaded on to silica, and chromato-
graphed (eluant EtOAc:hexanes 1:9) to afford silane 33 (24
mg, 49%) as a crystalline white solid: mp 86-89 °C; TLC Rf
) 0.56 (Et2O:hexanes 3:7); [R] ) +29.0° (c ) 1.0, CHCl3); IR
1
cm-1; H NMR (CDCl3, 300 MHz) δ 3.89 (1H, dd, J ) 2.0, 8.0
Hz), 3.79 (1H, dd, J ) 3.5, 11.5 Hz), 3.69 (1H, app t, J ) 8.0
Hz), 3.51 (1H, dd, J ) 2.5, 11.5 Hz), 3.33 (3H, s), 3.09 (1H, dd,
J ) 5.0, 8.0 Hz), 2.43 (1H, d, J ) 2.0 Hz), 2.22-2.21 (1H, m),
1.01-0.95 (12H, m), 0.66 (6H, m). 13C NMR (CDCl3, 75 MHz)
δ 83.7, 81.7, 73.4, 71.8, 70.3, 70.0, 55.9, 31.3, 11.1, 6.9, 5.1;
MS (CI+, NH3) m/z 302 (M + NH4)+, 285 (M + H)+. Anal. Calcd
for C15H28O3Si: C, 63.33; H, 9.92. Found: C, 63.65; H, 9.75.
(2R S ,3R ,4S ,5S )-2-H yd r oxy-4-m e t h oxy-3-(m e t h oxy-
m eth oxy)-5-m eth yl-2-[(E)-1-(tr im eth ylsilyl)pr op-1-en -2-yl]-
tetr a h yd r o-2H-p yr a n (28). To a stirred solution of vinyl
(film) 3064, 3030, 1620 cm-1 1H NMR (CDCl3, 400 MHz) δ
;
7.37-7.19 (20H, m), 5.74 (1H, s), 4.94-4.83 (3H, m), 4.69-
4.56 (5H, m), 3.79-3.63 (5H, m), 3.49-3.45 (2H, m), 1.90 (3H,
s), 0.15 (9H, s); 13C NMR (CDCl3, 100 MHz) δ 150.4, 138.7,
138.5, 138.2, 138.1, 132.5, 129.6, 129.1, 128.4, 128.3, 128.0,
127.9, 127.7, 127.6, 127.6, 127.5, 86.8, 86.6, 80.6, 78.7, 78.3,
77.2, 75.6, 75.0, 74.6, 73.4, 69.1, 17.3, -0.2; MS (CI+, NH3)
m/z 654 (M + NH4)+. Anal. Calcd for C40H48O5Si: C, 75.43; H,
7.60. Found: C, 75.67; H, 7.81.
(E)-2-(1-Hydr oxy-2,3,4,6-tetr a-O-ben zyl-â-D-glu copyr an -
osyl)-1-iod op r op -1-en e (34). Hemiketal 32 (110 mg, 0.17
mmol) and N-iodosuccinimide (191 mg, 0.85 mmol) were mixed
together in THF (5 mL). After 60 h, the reaction had not
(23) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

Total Synthesis of Restrictinol
J . Org. Chem., Vol. 64, No. 1, 1999 169
proceeded to completion, and the volume of solvent was
reduced (5 mL to 1 mL) by purging the flask with a stream of
nitrogen. After a further 24 h, the mixture was diluted with
Et2O (75 mL), washed with saturated aqueous Na2S2O3 (30
mL), distilled water (2 × 30 mL), and brine (30 mL), and rotary
evaporated. The residue was chromatographed (Et2O:hexanes
3:7) to afford 34 (99 mg, 83%) as a colorless oil: TLC Rf )
0.18 (Et2O:hexanes 3:7); [R] ) +6.43° (c ) 0.42, CHCl3); IR
(film) 3522, 3400, 3087, 3063, 3030 cm-1; 1H NMR (CDCl3, 270
MHz) δ 7.41-7.19 (20H, m), 6.82 (1H, d, J ) 1.0 Hz), 4.91
(2H, s), 4.84 (1H, d, J ) 11.0 Hz), 4.70 (1H, d, J ) 10.5 Hz),
4.65-4.59 (2H, m), 4.54-4.48 (2H, m), 4.03-3.90 (2H, m),
3.81-3.64 (3H, m), 3.54 (1H, d, J ) 9.0 Hz), 3.04 (1H, s), 1.84
(3H, d, J ) 1.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 147.2, 138.6,
138.5, 138.2, 137.2, 128.8, 128.5, 128.5, 128.4, 128.4, 128.1,
127.9, 127.7, 127.5, 98.7, 83.8, 83.6, 80.1, 78.1, 77.2, 75.8, 75.3,
75.1, 73.4, 72.2, 68.8, 20.7; MS (FAB+) m/z 689 (M + H -
H2O)+. Anal. Calcd for C37H39O6I: C, 62.89; H, 5.56. Found:
C, 62.61; H, 5.54.
1.0 Hz), 5.79 (1H minor isomer, s), 4.86 (1H major isomer, d,
J ) 7.0 Hz), 4.62 (1H minor isomer, d, J ) 7.0 Hz), 4.53 (1H
minor isomer, d, J ) 7.0 Hz), 4.50 (1H major isomer, d, J )
7.0 Hz), 4.09 (1H major isomer, dd, J ) 2.5, 11.5 Hz), 3.80-
3.71 (2H minor isomer, m), 3.72 (1H major isomer, d, J ) 9.0
Hz), 3.60-3.37 (1H major isomer and 2H minor isomer, m),
3.55 (3H minor isomer, s), 3.52 (1H major isomer, dd, J ) 1.5,
11.5 Hz), 3.35 (3H major isomer, s), 3.34 (3H minor isomer,
s), 3.31 (3H major isomer, s), 2.94 (1H major isomer, d, J )
0.5 Hz), 2.27-2.22 (1H, m), 1.96 (3H, d, J ) 1.0 Hz), 1.06 (3H
major isomer, d, J ) 7.0 Hz), 0.92 (3H minor isomer, d, J )
7.0 Hz); MS (CI+, NH3) m/z 390 (M + NH4)+, 373 (M + H)+,
355 (M - OH)+; HRMS (CI+, NH3) m/z calcd for C12H25NO5I
(M + NH4)+ 390.0778, found 390.0773.
(2R,3R,4S,5S)-2-((E)-1-Iod op r op -1-en -2-yl)-4-m eth oxy-
3-(m eth oxym eth oxy)-5-m eth yltetr a h yd r o-2H-p yr a n (39).
To a stirred mixture of hemiketal 36 (25 mg, 0.07 mmol) and
Et3SiH (55 µL, 0.34 mmol) in a MeCN/CH2Cl2 (85:15) solvent
mixture (2.5 mL) at -40 °C was dropwise added BF3‚Et2O (25
µL, 0.20 mmol). After 1 h, the mixture was quenched with
saturated aqueous NaHCO3 (100 µL) and allowed to warm to
room temperature. The solvent was evaporated in vacuo and
the residue dissolved in EtOAc (50 mL) and washed with
distilled water (2 × 20 mL) and brine (20 mL). The organic
layer was dried (MgSO4), filtered, and rotary evaporated. The
residue was chromatographed (eluant EtOAc:hexanes 3:17
then 1:4) to afford C-glycoside 39 (10 mg, 42%) as a colorless
oil: TLC Rf ) 0.41 (EtOAc:hexanes 3:17); [R] ) -39.5° (c )
0.55, CHCl3); IR (film) 2929, 1626 cm-1; 1H NMR (CDCl3, 400
MHz) δ 6.37-6.36 (1H, m), 4.66 (1H, d, J ) 7.0 Hz), 4.52 (1H,
d, J ) 7.0 Hz), 4.09 (1H, s), 3.76 (1H, dd, J ) 1.0, 3.5 Hz),
3.68 (1H, dd, J ) 5.0, 11.0 Hz), 3.45 (3H, s), 3.42 (1H, app t,
J ) 11.5 Hz), 3.34 (3H, s), 3.26 (1H, t, J ) 3.0 Hz), 2.24-2.17
(E)-2-(2,3,4,6-Tetr a -O-ben zyl-â-D-glu cop yr a n osyl)-1-io-
d op r op -1-en e (35). To a stirred solution of 34 (95 mg, 0.14
mmol) and Et3SiH (109 µL, 0.68 mmol) in a MeCN/CH2Cl2 (85:
15) solvent mixture (5 mL) at -40 °C was added dropwise BF3‚
Et2O (52 µL, 0.41 mmol). After 15 min, the mixture was
quenched with saturated aqueous NaHCO3 (0.5 mL) and
allowed to warm to room temperature. The reaction mixture
was filtered and rotary evaporated and the residue azeotroped
with MeCN, dry loaded on to silica, and chromatographed
(eluant Et2O:hexanes 1:9) to afford C-glycosidic vinyl iodide
35 (83 mg, 86%) as a crystalline white solid (ratio of R:â
epimers: 15:85). Data for â epimer: mp 94-95 °C (hexane);
TLC Rf ) 0.45 (30% Et2O/hexanes); [R] ) -0.59° (c ) 1.0,
CHCl3); IR (film) 3030, 1496 cm-1; 1H NMR (CDCl3, 270 MHz)
δ 7.39-7.16 (20H, m), 6.47 (1H, d, J ) 0.5 Hz), 4.95 (1H, d, J
) 11.0 Hz), 4.89 (1H, d, J ) 11.0 Hz), 4.83 (1H, d, J ) 10.5
Hz), 4.69-4.45 (5H, m), 3.84 (1H, d, J ) 9.5 Hz), 3.73-3.59
(4H, m), 3.49-3.42 (2H, m), 1.83 (3H, d, J ) 1.0 Hz); 13C NMR
(CDCl3, 75 MHz) δ 144.7, 138.6, 138.3, 138.1, 137.7, 128.5,
128.5, 128.4, 128.4, 128.0, 127.8, 127.7, 127.6, 127.6, 86.8, 83.4,
82.5, 79.9, 78.9, 78.2, 75.7, 75.1, 74.9, 73.5, 69.0, 19.9; MS
(FAB+) m/z 691 (M + H)+. Anal. Calcd for C37H39O5I: C, 64.35;
H, 5.69. Found: C, 64.25; H, 5.55. To a stirred solution of vinyl
silane 33 (24 mg, 0.04 mmol) in THF (1 mL) was added
N-iodosuccinimide (55 mg, 0.24 mmol). After 24 h, the mixture
was diluted with Et2O (50 mL), and washed with saturated
aqueous Na2S2O3 (15 mL), distilled water (2 × 15 mL), and
brine (15 mL). The organic layer was dried (MgSO4), filtered,
and rotary evaporated. The residue was chromatographed to
afford vinyl iodide 35 (25 mg, 95%) as a crystalline white solid.
Crystal data for 35: C37H39O5I, M ) 690.6, monoclinic, P21
(no. 4), a ) 13.843(1), b ) 8.903(1), c ) 14.018(1) Å, â )
101.40(1)°, V ) 1693.7(2) Å3, Z ) 2, Dc ) 1.354 g cm-3, µ(Cu-
KR) ) 77.4 cm-1, F(000) ) 708, T ) 293 K; clear fine needles,
0.27 × 0.07 × 0.05 mm, Siemens P4/PC diffractometer,
ω-scans, 3024 independent reflections. The structure was
solved by direct methods, and the non-hydrogen atoms were
refined anisotropically using full matrix least-squares based
on F2 to give R1 ) 0.062, wR2 ) 0.138 for 1789 independent
observed absorption corrected reflections [|Fo| > 4σ(|Fo|), 2θ e
128°] and 341 parameters. The absolute structure of 35 was
(1H, m), 1.84 (3H, d, J ) 0.5 Hz), 0.87 (3H, d, J ) 7.0 Hz); 13
C
NMR (CDCl3, 100 MHz) δ 143.9, 95.9, 79.0, 78.5, 77.5, 70.5,
68.7, 58.9, 56.0, 30.2, 22.0, 12.1; MS (CI+, NH3) m/z 374 (M +
NH4)+, 357 (M + H)+; HRMS (CI+, NH3) m/z calcd for C12H25
NO4I (M + NH4)+ 374.0828, found 374.0815.
-
(2R,3R,4S,5S)-3-Hydr oxy-2,4-dim eth oxy-5-m eth yl-2-((E)-
1-(tr im eth ylsilyl)pr op-1-en -2-yl)-tetr ah ydr o-2H-pyr an (40).
To a stirred solution of 28 (53 mg, 0.17 mmol) in MeOH (3.7
mL) was added (+)-camphorsulfonic acid (38 mg, 0.17 mmol)
at 20 °C. After 12 h, Et3N (50 µL, 0.36 mmol) was added, the
solvent was evaporated in vacuo, and the residue was dry
loaded onto silica and chromatographed (eluant EtOAc:hex-
anes 1:4) to afford 40 (34 mg, 71%) as a colorless oil: TLC Rf
) 0.21 (EtOAc:hexanes 1:4); [R] ) +98.6° (c ) 1.04, CHCl3);
1
IR (film) 3480, 1615 cm-1; H NMR (CDCl3, 270 MHz) δ 5.74
(1H, d, J ) 1.0 Hz), 3.74 (1H, dd, J ) 2.5, 11.5 Hz), 3.55 (1H,
dd, J ) 1.5, 11.5 Hz), 3.52 (1H, dd, J ) 4.5, 9.5 Hz), 3.45 (1H,
dd, J ) 4.5, 9.5 Hz), 3.40 (3H, s), 3.14 (3H, s), 2.21 (1H, m),
2.09 (1H, d, J ) 4.5 Hz), 1.87 (3H, d, J ) 1.0 Hz), 1.04 (3H, d,
J ) 7.0 Hz), 0.14 (9H, s); 13C NMR (CDCl3, 75 MHz) δ 150.1,
127.9, 102.9, 80.7, 71.2, 64.7, 56.8, 49.1, 32.0, 18.3, 10.7, 0.0;
MS (CI+, NH3) m/z 257 (M - OMe)+. Anal. Calcd for C14H28O4-
Si: C, 58.29; H, 9.78. Found: C, 57.94; H, 9.56.
(2R,3R,4S,5S)-3-Hyd r oxy-2-((E)-1-iod op r op -1-en -2-yl)-
2,4-d im et h oxy-5-m et h ylt et r a h yd r o-2H-p yr a n (41). To a
stirred solution of vinyl silane 40 (33 mg, 0.12 mmL) in
Me3SiCN (1 mL) was added DMF (5 drops). After 15 min, the
reaction vessel was purged with a stream of nitrogen for 1 h
to remove volatiles. The residue was dried in vacuo, suspended
in THF (0.5 mL), N-iodosuccinimide (155 mg, 0.69 mmol)
added, and the mixture stirred for 36 h at 25-30 °C (bath
temp). The mixture was diluted with Et2O (50 mL) and washed
with saturated aqueous NaHCO3 (20 mL), saturated aqueous
Na2S2O3 (20 mL), distilled water (20 mL), and brine (10 mL).
The organic layer was dried (MgSO4), filtered, and rotary
evaporated. The residue was dissolved in a solution of K2CO3
(599 mg, 4.33 mmol) in MeOH (1.5 mL) and stirred. After 2 h,
the mixture was diluted with Et2O (50 mL), filtered, and rotary
evaporated. The residue was chromatographed (eluant EtOAc:
hexanes 1:3) to afford vinyl iodide 41 (29 mg, 74%) as a
crystalline white solid: mp 70-72 °C; TLC Rf ) 0.27 (EtOAc:
hexanes 3:7); [R] ) +77.2° (c ) 0.67, CHCl3); IR (film) 3468,
+
determined by a combination of R-factor tests [R1 ) 0.062,
R1 ) 0.089] and by use of the Flack parameter [x+
)
-
-0.01(3)].23
(2RS,3R,4S,5S)-2-Hyd r oxy-2-((E)-1-iod op r op -1-en -2-yl)-
4-m eth oxy-3-(m eth oxym eth oxy)-5-m eth yltetr a h yd r o-2H-
p yr a n (36). To a stirred solution of hemiketal 28 (20 mg, 0.063
mmol) in THF (0.5 mL) was added N-iodosuccinimide (17 mg,
0.075 mmol). After 36 h, the mixture was diluted with EtOAc
(40 mL), washed with saturated aqueous Na2S2O3 (10 mL),
distilled water (2 × 10 mL), and brine (10 mL). The organic
layer was dried (MgSO4), filtered, and rotary evaporated. The
residue was chromatographed (eluant EtOAc:hexanes 1:4) to
afford 36 (19 mg, 81%) as a crystalline solid: mp 73-77 °C;
1
IR (film) 3412, 1620 cm-1; H NMR (CDCl3, 270 MHz) δ 6.80
(1H major isomer, q, J ) 1.0 Hz), 6.76 (1H minor isomer, J )

170 J . Org. Chem., Vol. 64, No. 1, 1999
Barrett et al.
+46.9° (c ) 1.03, CHCl3); IR (film) 2931, 2896, 2856, 1619 cm-1
1610 cm-1; 1H NMR (CDCl3, 270 MHz) δ 6.25 (1H, app q, J )
1.0 Hz), 3.74 (1H, dd, J ) 2.5, 11.5 Hz), 3.54 (1H, dd, J ) 1.5,
11.5 Hz), 3.50 (1H, dd, J ) 4.5, 9.5 Hz), 3.44 (1H, dd, J ) 4.5,
9.5 Hz), 3.37 (3H, s), 3.13 (3H, s), 2.36 (1H, d, J ) 4.5 Hz),
2.23-2.17 (1H, m), 1.94 (3H, d, J ) 1.0 Hz), 1.00 (3H, d, J )
7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 145.6, 102.3, 84.0, 80.5,
72.0, 64.6, 56.5, 49.3, 31.5, 21.6, 10.4; MS (CI+, NH3) m/z 311
(M - OMe)+; HRMS (CI+, NH3) m/z calcd for C10H16O3I (M -
OMe)+ 311.0144, found 311.0133.
;
1H NMR (CDCl3, 270 MHz) δ 6.43 (1H, d, J ) 1.0 Hz), 3.69
(1H, dd, J ) 2.5, 11.5 Hz), 3.55 (1H, d, J ) 9.5 Hz), 3.51-3.43
(2H, m), 3.26 (3H, s), 3.14 (3H, s), 2.27-2.19 (1H, m), 1.85 (3H,
d, J ) 1.0 Hz), 1.02 (3H, d, J ) 7.0 Hz), 0.87 (9H, s), 0.03 (3H,
s), -0.01 (3H, s); 13C NMR (CDCl3, 68 MHz) δ 143.5, 104.3,
84.8, 79.9, 71.3, 64.5, 55.5, 49.3, 31.6, 26.2, 21.3, 18.5, 10.6,
-3.9, -4.1; MS (CI+, NH3) m/z 425 (M - OMe)+; HRMS (CI+,
NH3) m/z calcd for C16H30O3SiI (M - OMe)+, 425.1009 found
425.1013.
(2S,3R,4S,5S)-3-Hyd r oxy-2-((E)-1-iod op r op -1-en -2-yl)-
4-m eth oxy-5-m eth yltetr a h yd r o-2H-p yr a n (37) a n d (2R,
3R,4S,5S)-3-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-4-methoxy-
5-m eth yltetr a h yd r o-2H-p yr a n (38). To a stirred solution
of 41 (31 mg, 0.091 mmol) and Et3SiH (74 µL, 0.46 mmol) in
a MeCN/CH2Cl2 (85:15) solvent mixture (2.25 mL) at -40 °C
was added dropwise BF3‚Et2O (29 µL, 0.23 mmol). After 1.75
h saturated aqueous NaHCO3 (300 µL) was added and the
mixture allowed to warm to room temperature, diluted with
Et2O (50 mL), washed with distilled water (3 × 15 mL) and
brine (15 mL), dried (MgSO4), filtered, and rotary evaporated.
The residue was chromatographed (eluant EtOAc:hexanes 1:4
then 3:7) to afford (i) iodide 38 (11 mg, 39%) as a colorless oil
and (ii) iodide 37 (16 mg, 56%) as colorless oil which slowly
crystallized upon standing. 38: TLC Rf ) 0.39 (Et2O:hexanes
(2R,3R,4S,5S)-3-(ter t-Bu t yld im et h ylsilyloxy)-2-((E)-1-
iod op r op -1-en -2-yl)-4-m et h oxy-5-m et h ylt et r a h yd r o-2H-
pyr an (43) an d (2R,3R,4S,5S)-3-Hydr oxy-2-((E)-1-iodopr op-
1-en -2-yl)-4-m eth oxy-5-m eth yltetr a h yd r o-2H-p yr a n (38).
To a stirred solution of 42 (35 mg, 0.077 mmol) and Et3SiH
(45 mg, 61 µL, 0.39 mmol) in a MeCN/CH2Cl2 (85:15) solvent
mixture (2 mL) at -40 °C was added dropwise BF3‚Et2O (15
µL, 0.12 mmol). After 45 min, saturated aqueous NaHCO3 (300
µL) was added. The mixture was allowed to warm to room
temperature, diluted with Et2O (50 mL), washed with distilled
water (2 × 20 mL) and brine (20 mL), dried (MgSO4), filtered,
and rotary evaporated. The residue was chromatographed
(eluant EtOAc:hexanes 3:97 then 1:4) to afford (i) iodide 43
(16 mg, 49%) as a colorless oil which slowly crystallized upon
standing and (ii) iodide 38 (8 mg, 30%) as a colorless oil. 43:
mp 32-36 °C; TLC Rf ) 0.51 (EtOAc:hexanes 1:19); [R] )
1:3); [R] ) -68.1° (c ) 1.0, CHCl3); IR (film) 3461, 1622 cm-1
;
1H NMR (CDCl3, 270 MHz) δ 6.37-6.35 (1H, m), 4.14 (1H, s),
3.82-3.78 (1H, m), 3.63 (1H, dd, J ) 5.0, 11.0 Hz), 3.45 (3H,
s), 3.41 (1H, app t, J ) 11.5 Hz), 3.32 (1H, app t, J ) 3.0 Hz),
2.21-2.09 (1H, m), 1.83 (3H, dd, J ) 0.5, 1.0 Hz), 1.78 (1H, d,
J ) 6.5 Hz), 0.87 (3H, d, J ) 7.0 Hz); 13C NMR (CDCl3, 67.5
MHz) δ 143.9, 80.2, 78.6, 78.0, 69.0, 65.1, 59.1, 29.7, 22.0, 11.9;
MS (CI+, NH3) m/z 330 (M + NH4)+, 313 (M + H)+; HRMS
(CI+, NH3) m/z calcd for C10H21NO3I (M + NH4)+ 330.0566,
found 330.0561. 37: mp 80-86 °C; TLC Rf ) 0.13 (EtOAc:
hexanes 1:3); [R] ) +56.9° (c ) 0.8, CHCl3); IR (film) 3437,
1620 cm-1; 1H NMR (CDCl3, 270 MHz) δ 6.43 (1H, app t, J )
0.5 Hz), 3.81 (1H, dd, J ) 1.5, 12.0 Hz), 3.65-3.54 (3H, m),
3.39 (3H, s, OCH3), 3.31 (1H, ddd, J ) 1.0, 5.0, 7.5 Hz), 2.30
(1H, s), 2.24-2.18 (1H, m), 1.89 (3H, J ) 1.0 Hz), 1.03 (3H, d,
J ) 7.0 Hz); 13C NMR (CDCl3, 67.5 MHz) δ 145.1, 85.0, 84.1,
81.9, 71.1, 68.0, 55.9, 31.5, 19.9, 10.7; MS (CI+, NH3) m/z 330
(M + NH4)+, 211, 185, 153, 115; HRMS (CI+, NH3) m/z calcd
for C10H21NO3I (M + NH4)+ 330.0566, found 330.0570.
-27.4° (c ) 1.0, CHCl3); IR (film) 2955, 2929, 2857, 1627 cm-1
;
1H NMR (CDCl3, 270 MHz) δ 6.22 (1H, app t, J ) 1.0 Hz),
4.10 (1H, s), 3.71 (1H, d, J ) 3.0 Hz), 3.61 (1H, dd, J ) 5.0,
11.0 Hz), 3.44 (3H, s), 3.38 (1H, app t, J ) 11.5 Hz), 3.11 (1H,
app t, J ) 3.0 Hz), 2.26-2.20 (1H, m), 1.80 (3H, s), 0.88 (9H,
s), 0.84 (3H, d, J ) 7.0 Hz), 0.04 (3H, s), 0.00 (3H, s); 13C NMR
(CDCl3, 68 MHz) δ 144.4, 81.8, 79.0, 78.6, 68.6, 66.4, 58.9, 29.5,
25.7, 22.5, 17.9, 12.3, -4.7, -4.9; MS (CI+, NH3) m/z 444 (M
+ NH4)+, 427 (M + H)+; HRMS (CI+, NH3) m/z calcd for
C
16H32O3SiI (M + H)+, 427.1166 found 427.1170.
(E)-1-Iod o-1-p en ten e (46). To 1-pentyne (45) (7.88 mL, 80
mmol) in a sealable tube at 0 °C was added DIBAL-H in
hexane (1 M; 80 mL, 80 mmol). The tube was sealed and
allowed to stand for 30 min at room temperature before being
heated to 55-60 °C for 4 h. When cool, the reaction mixture
was evaporated in vacuo (using a vacuum manifold) and the
residue dissolved in THF (60 mL) at 0 °C. The resultant
solution was cooled to -78 °C and I2 (21.60 g, 85 mmol) in
THF (30 mL) added dropwise. The mixture was allowed to
warm to 0 °C and transferred via cannula to a stirred mixture
of 10% HCl (200 mL) and n-pentane (60 mL). The layers were
separated, and the aqueous phase was extracted with n-
pentane (3 × 50 mL). The combined organic extracts were
washed with saturated aqueous sodium thiosulfate (50 mL),
1 M NaOH (50 mL), distilled water (50 mL), and brine (50
mL), dried (MgSO4), filtered, and rotary evaporated. The
residue was purified by bulb to bulb distillation under reduced
pressure (∼50 °C, 20 mmHg) to afford vinyl iodide 46 (8.41 g,
54%) as a colorless oil: IR (film) 3049, 2959, 2929, 2872, 1606
cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.50 (1H, dt, J ) 7.0, 14.5
Hz), 5.97 (1H, dt, J ) 1.5, 14.5 Hz), 2.03 (2H, app qd, J ) 1.5,
7.5 Hz), 1.42 (2H, app sextet, J ) 7.5 Hz), 0.90 (3H, t, J ) 7.5
Hz); 13C NMR (CDCl3, 75 MHz) δ 146.5, 74.4, 38.0, 21.6, 13.4;
MS (CI+, NH3) m/z 196 (M)+; HRMS (CI+, NH3) m/z calcd for
C5H9I (M)+ 195.9749, found 195.9748 (M + NH4)+.
(E)-1-(Tr im eth ylsilyl)-3-h ep ten -1-yn e (48). To a stirred
solution of (trimethylsilyl)acetylene (47) (3.70 mL, 26.21 mmol)
in THF (12 mL) at -78 °C was dropwise added n-BuLi in
hexane (2.38 M; 11.01 mL, 26.21 mmol). After 1 h, this solution
was added via cannula to a stirred solution of ZnCl2 in THF
(0.5 M; 52.42 mL, 26.21 mmol) at -78 °C and the mixture
allowed to warm to room temperature. After 1 h, a solution of
vinyl iodide 46 (4.67 g, 23.84 mmol) and Pd(PPh3)4 (1.51 g,
1.31 mmol) in THF (20 mL) was added dropwise via cannula.
After approximately 18 h, the mixture was quenched with
saturated aqueous NH4Cl (10 mL), diluted with Et2O (200 mL),
washed with distilled water (2 × 75 mL), saturated aqueous
Na2S2O3 (75 mL), and brine (75 mL), dried (MgSO4), filtered,
and rotary evaporated. The residue was purified by filtration
(2S,3R,4S,5S)-2-((E)-1-Iod op r op -1-en -2-yl)-4-m eth oxy-
5-m eth yl-3-(tr ieth ylsilyloxy)-tetr a h yd r o-2H-p yr a n (26).
To a stirred solution of 37 (17 mg, 0.054 mmol) and 2,6-lutidine
(34 µL, 0.29 mmol) in CH2Cl2 at -20 °C was added dropwise
Et3SiO3SCF3 (21 µL, 0.096 mmol). After 2 h, saturated aqueous
NaHCO3 (0.5 mL) was added and the mixture allowed to warm
to room temperature, diluted with Et2O (50 mL), washed with
distilled water (3 × 20 mL) and brine (20 mL), dried (MgSO4),
and rotary evaporated. The residue was chromatographed
(eluant Et2O:hexanes 1:24) to afford 26 (22 mg, 96%) as
colorless oil: TLC Rf ) 0.34 (EtOAc:hexanes 1:19); [R] ) +23.1°
(c ) 1.0, CHCl3); IR (film) 2954, 1621 cm-1; H NMR (CDCl3,
1
270 MHz) δ 6.31 (1H, d, J ) 1.0 Hz), 3.77 (1H, dd, J ) 1.5,
11.5 H), 3.61-3.49 (3H, m), 3.29 (3H, s), 3.11 (1H, dd, J )
5.5, 8.5 Hz), 2.21-2.17 (1H, m), 1.84 (3H, d, J ) 1.0 Hz), 1.01
(3H, d, J ) 7.0 Hz), 0.92 (9H, t, J ) 8.0 Hz), 0.63-0.49 (6H,
m); 13C NMR (CDCl3, 75 MHz) δ 145.1, 86.5, 84.6, 82.1, 70.9,
69.0, 55.3, 31.6, 19.8, 10.9, 6.9, 5.2; MS (CI+, NH3) m/z 444 (M
+ NH4)+, 427 (M + H)+; HRMS (CI+, NH3) m/z calcd for
C
16H32O3SiI (M + H)+ 427.1166, found 427.1168.
(2R,3R,4S,5S)-3-(ter t-Bu t yld im et h ylsilyloxy)-2-((E)-1-
iod op r op -1-en -2-yl)-2,4-d im eth oxy-5-m eth yltetr a h yd r o-
2H-p yr a n (42). To a stirred solution of 41 (30 mg, 0.09 mmol)
and 2,6-lutidine (92 µL, 0.79 mmol) in CH2Cl2 (1.25 mL) at
-20 °C was added tert-butyldimethylsilyl trifluoromethane-
sulfonate (61 µL, 0.26 mmol). After 2 h, MeOH (0.2 mL) and
saturated aqueous NaHCO3 (0.5 mL) were added. The reaction
mixture was allowed to warm to room temperature, diluted
with Et2O (50 mL), washed with distilled water (3 × 20 mL)
and brine (20 mL), dried (MgSO4), and filtered. Rotary
evaporation and chromatography gave iodide 42 (36 mg, 90%)
as a colorless oil: TLC Rf ) 0.48 (EtOAc:hexanes 1:19); [R] )

Total Synthesis of Restrictinol
J . Org. Chem., Vol. 64, No. 1, 1999 171
through silica gel (eluant pentane) to afford 48 (3.50 g, 89%)
chromatography (eluant Et2O:hexanes 3:97) gave triene 51 (10
mg, 73%) as a colorless oil: TLC Rf ) 0.56 (EtOAc:hexanes
1:10); IR (film) 3023, 2955, 2933, 2876 cm-1; 1H NMR (CDCl3,
500 MHz) δ 6.32 (1H, dd, J ) 11.0, 14.0 Hz), 6.19-6.09 (2H,
m), 6.01 (1H, d, J ) 11.0 Hz), 5.70 (1H, dt, J ) 7.0, 14.5 Hz),
3.71 (1H, dd, J ) 1.5, 11.5 Hz), 3.54-3.50 (2H, m), 3.39 (1H,
d, J ) 9.0 Hz), 3.27 (3H, s), 3.09 (1H, dd, J ) 5.0, 8.5 Hz),
2.20-2.15 (1H, m), 2.19-2.04 (2H, m), 1.74 (3H, d, J ) 1.0
Hz), 1.41 (2H, app sextet, J ) 7.5 Hz), 0.97 (3H, d, J ) 7.0
Hz), 0.90 (3H, t, J ) 7.5 Hz), 0.87 (9H, t, J ) 8.0 Hz), 0.57-
0.43 (6H, m);13C NMR (CDCl3, 125 MHz) δ 135.3, 133.5, 131.2,
129.7, 126.7, 88.1, 85.2, 71.0, 69.4, 55.5, 35.3, 32.1, 30.1, 22.9,
13.9, 12.7, 11.0, 7.0, 5.4; MS (CI+, NH3) m/z 412 (M + NH4)+,
395 (M + H)+; HRMS (CI+, NH3) m/z calcd for C23H43O3Si (M
+ H)+ 395.2981, found 395.2980.
Restr ictin ol (3). To a stirred solution of (triethylsilyl)-
restrictinol (51) (9 mg, 0.023 mmol) in THF (2.5 mL) was added
Bu4NF in THF (1 M; 35 µL, 0.035 mmol). After 2 h, the solvent
was evaporated in vacuo and the residue chromatographed
(eluant EtOAc:hexanes 3:7) to afford restrictinol (3) (6 mg,
94%) as a colorless oil: TLC Rf ) 0.35 (EtOAc:hexanes 3:7);
[R] ) +64.0° (c ) 0.25, MeOH); IR (film) 3455, 2960, 2931,
2873, 1683, 1635 cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.36 (1H,
dd, J ) 11.0, 14.5 Hz), 6.22 (1H, dd, J ) 10.5, 14.5 Hz), 6.12
(1H, ddt, J ) 1.5, 10.5, 14.5 Hz), 6.08 (1H, dd, J ) 1.0, 10.5
Hz), 5.73 (1H, dt, J ) 7.0, 14.5 Hz), 3.76 (1H, dd, J ) 1.5, 11.5
Hz), 3.58 (1H, dd, J ) 2.5, 11.5 Hz), 3.56 (1H, app t, J ) 9.5
Hz), 3.43 (1H, d, J ) 9.5 Hz), 3.36 (3H, s), 3.22 (1H, dd, J )
5.0, 9.0 Hz), 2.22-2.18 (1H, m), 2.11-2.06 (2H, m), 1.78 (3H,
d, J ) 1.0 Hz), 1.42 (2H, app sextet, J ) 7.5 Hz), 1.01 (3H, d,
J ) 7.0 Hz), 0.90 (3H, t, J ) 7.5 Hz);13C NMR (CDCl3, 100
MHz) δ 135.9, 134.6, 134.2, 131.0, 129.5, 126.2, 87.0, 84.6, 71.3,
68.0, 56.1, 35.2, 32.1, 22.8, 13.8, 12.4, 10.9; MS (CI+, NH3) m/z
298 (M + NH4)+, 281 (M + H)+; HRMS (CI+, NH3) m/z calcd
for C17H29O3 (M + H)+ 281.2117, found 281.2102.
as a colorless oil: IR (film) 3021, 2961, 2932, 2179, 2142 cm-1
;
1H NMR (CDCl3, 270 MHz) δ 6.22 (1H, dt, J ) 16.0, 7.0 Hz),
5.50 (1H, dt, J ) 16.0, 1.5 Hz), 2.09 (2H, app dq, J ) 7.0, 1.5
Hz), 1.41 (2H, app sextet, J ) 7.5 Hz), 0.90 (3H, t, J ) 7.5
Hz), 0.18 (9H, s); 13C NMR (CDCl3, 75 MHz) δ 146.1, 109.8,
104.2, 92.4, 35.1, 21.8, 13.6, 0.0; MS (CI+, NH3) m/z 184 (M +
NH4)+; HRMS (CI+, NH3) m/z calcd for C10H22NSi (M + NH4)+
184.1522, found 184.1520; Anal. Calcd for C10H18Si: C, 72.21;
H, 10.91. Found: C, 72.03; H, 10.88.
(E)-3-Hep ten -1-yn e (49). To a stirred solution of 48 (3.47
g, 20.9 mmol) and distilled water (828 µL, 46 mmol) in DMF
(16 mL) was added KF (1.34 g, 23 mmol). After 2 h, the mixture
was diluted with water (30 mL) and extracted with pentane
(3 × 10 mL). The combined organic extracts were washed with
water (10 mL) and brine (10 mL) and dried (MgSO4). The
solvent was evaporated at atmospheric pressure to afford a
mixture of enyne 49 (1.20 g, 61%) and (Me3Si)2O (1.34 g, 79%)
1
as determined by H NMR. 1H NMR (CDCl3, 270 MHz) δ 6.25
(1H, dt, J ) 7.0, 16.0 Hz), 5.46 (1H, m), 2.77 (1H, d, J ) 2.0
Hz), 2.09 (2H, qd, J ) 1.5, 7.0 Hz), 1.43 (2H, app sextet, J )
7.0 Hz), 0.91 (3H, t, J ) 7.0 Hz); 13C NMR (CDCl3, 68 MHz) δ
146.6, 108.7, 75.5, 35.1, 21.8, 13.5, 1.9; MS (EI+) m/z 94 (M)+;
HRMS (EI+) m/z calcd for C7H10 (M)+ 94.0783, found 94.0782.
(E,E)-Hep ta -1,3-d ien yl-1-bor on ic Acid (50). A mixture
of enyne 49 (500 mg, 57% by wt, 3.04 mmol) and catechol-
borane in THF (1 M; 1.26 mL, 1.26 mmol) was heated to 70
°C in a sealed tube. The mixture was allowed to cool and
stirred vigorously with distilled water for 4 h. The resultant
solid was filtered and washed with distilled water to afford
50 as an off-white solid. For quantification purposes, boronic
acid 50 was dried in vacuo to afford the corresponding
anhydride (247 mg, 67%) as a pale brown oil. For subsequent
chemistry and characterization the anhydride was converted
back to the boronic acid 50 by repeating the hydrolysis steps
above: IR (DRIFTS) 3275, 3246, 3203, 3174, 3031, 2954, 1622,
1605, 1560, 1540, 1509 cm-1; 1H NMR (DMSO-d6, 270 MHz) δ
7.58 (2H, bs), 6.84 (1H, dd, J ) 10.5, 17.5 Hz), 6.14-6.05 (1H,
m), 5.87-5.79 (1H, m), 5.37 (1H, d, J ) 17.5 Hz), 2.53-2.51
(2H, m), 1.47-1.31 (2H, m), 0.89 (3H, t, J ) 7.0 Hz); 13C NMR
(DMSO-d6, 68 MHz) δ 147.0, 137.2, 133.1, 125.4, 34.3, 22.0,
13.8; MS (CI+, NH3) m/z 158 (M + NH4)+, 140 (M + H)+; HRMS
(CI+, NH3) m/z calcd for C7H17BNO2 (M + NH4)+ 158.1352,
found 158.1353.
Ack n ow led gm en t. We thank Glaxo Wellcome for
the most generous endowment (to A.G.M.B), the Wolf-
son Foundation for establishing the Wolfson Centre for
Organic Chemistry in Medical Science at Imperial
College, the EPSRC, and Dr. David Gollins for prelimi-
nary studies on the addition of acetylides to lactone 16.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of 15, 20, 26, 36, 39, 41, 37, 38, 42, 43, 50, and
51 and X-ray crystallographic data for 21 and 35 (37 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
(Tr ieth ylsilyl)r estr ictin ol (51). To a stirred solution of
vinyl iodide 26 (15 mg, 0.035 mmol) and boronic acid 50 in
THF (3 mL) were added, dropwise, aqueous ∼10% TlOH (465
µL, ∼0.21 mmol) and, after 2 min, Pd(PPh3)4 (10 mg, 8.7 µmol)
in THF (200 µL). After 2 and 3 h, further portions of Pd(PPh3)4
(5 mg, 4.4 µmol) in THF (100 µL) were added. The mixture
was stirred overnight, diluted with Et2O (∼15 mL), dried
(MgSO4), and filtered through Celite. Rotary evaporation and
J O9815305