Total synthesis of the enantiomer of the furanocembrane rubifolide

Article abstract of DOI:10.1021/jo970360d

The total synthesis of 57, the enantiomer of the marine furanocembrane rubifolide (3), is described starting from (S)-(-)-perillyl alcohol (5). The successful route proceeded by oxidative cleavage of 5 to ester aldehyde 30 which was protected, reduced, and homologated to the acetylene, 34, the left- hand segment of the synthetic target. Addition to the right-hand aldehyde 39 afforded alcohol 40. The carbonate derivative 41 was converted to the allenylstannane aldehyde 44, which cyclized upon treatment with BF₃·OEt₂. Oxidation with the Dess - Martin periodinane reagent followed by treatment with Et₃N yielded allenone 45. Allenone 45 cyclized to furan 46 in the presence of catalytic AgNO₃ on silica gel. Brief exposure to p-TsOH effected elimination of the OMOM ether, affording the diastereomeric (Z)-vinylfuran carbonates 47 and 49. Saponification of the former led to alcohol 48, which was converted to the final product by sequential treatment with (CF₃- CO)₂O, then Pd(PPh₃)₄ and CO in THF-H₂O and then AgNO₃ on silica gel. The resulting product, 57, was identical to natural rubifolide on the basis of spectral comparison. The optical rotation was equal and opposite in sign to that of the natural material. A second, but unsuccessful approach is also described.

Full text of DOI:10.1021/jo970360d

J . Org. Chem. 1997, 62, 4313-4320
4313
Tota l Syn th esis of th e En a n tiom er of th e F u r a n ocem br a n e
Ru bifolid e
J ames A. Marshall* and Clark A. Sehon
Department of Chemistry , University of Virginia, Charlottesville, Virginia 22901
Received February 25, 1997X
The total synthesis of 57, the enantiomer of the marine furanocembrane rubifolide (3), is described
starting from (S)-(-)-perillyl alcohol (5). The successful route proceeded by oxidative cleavage of
5 to ester aldehyde 30 which was protected, reduced, and homologated to the acetylene 34, the
left-hand segment of the synthetic target. Addition to the right-hand aldehyde 39 afforded alcohol
40. The carbonate derivative 41 was converted to the allenylstannane aldehyde 44, which cyclized
upon treatment with BF3‚OEt2. Oxidation with the Dess-Martin periodinane reagent followed by
treatment with Et3N yielded allenone 45. Allenone 45 cyclized to furan 46 in the presence of
catalytic AgNO3 on silica gel. Brief exposure to p-TsOH effected elimination of the OMOM ether,
affording the diastereomeric (Z)-vinylfuran carbonates 47 and 49. Saponification of the former
led to alcohol 48, which was converted to the final product by sequential treatment with (CF3-
CO)2O, then Pd(PPh3)4 and CO in THF-H2O, and then AgNO3 on silica gel. The resulting product,
57, was identical to natural rubifolide on the basis of spectral comparison. The optical rotation
was equal and opposite in sign to that of the natural material. A second, but unsuccessful approach
is also described.
We recently described a method for the synthesis of
2-vinylfurans through base treatment of 2-hexen-4-yn-
1-ols possessing a leaving group (OR) at the 6-position
(eq 1).1 This reaction was of interest as a possible key
British Columbia. The structure of this natural product
was deduced by Andersen and co-workers, largely through
1H and 13C NMR analysis.4 The relative stereochemistry
was assigned by virtue of the fact that gersemolide (4),
a pseudopterane-related metabolite of known relative
stereochemistry, was isolated from the same species of
soft coral. The relative configuration of gersemolide, in
turn, was established by VanDuyne and Clardy through
X-ray diffraction.4 The absolute configuration was as-
signed arbitrarily.
step in the synthesis of certain furanocembrane natural
products.2 Specifically, we thought that if R1 and R4 were
connected by an appropriate carbon chain, then the
resulting intraannular furan cyclization would afford a
bridged vinylfuran with a (Z)-double bond, as is found
in several furanocembrane natural products or potential
synthetic precursors. In fact, model studies along those
lines were highly promising. Enynol 1, as a mixture of
four racemic diastereomers, afforded the bridged (Z)-
vinylfuran 2 in high yield upon exposure to KO-t-Bu (eq
2).3
In addition to demonstrating the applicability of the
methodology to furanocembranolide construction, we
expected our synthesis to unambiguously establish the
relative and absolute configuration of rubifolide and
taxonomically related natural products. Remarkably, the
absolute configuration of no member of this family is
known.
Our starting material, and the basis for our eventual
assignment of absolute configuration, was (S)-(-)-perillyl
alcohol (5). As the story unfolds, it will be noted that
this choice leads to a structure enantiomeric to that
arbitrarily assigned to rubifolide. However, because the
choice of (R) or (S) was arbitrary, we selected the latter
for economic reasons.5 Hydroxyl-directed epoxidation of
5 followed by periodate cleavage and treatment with
p-TsOH in methanol afforded the ester acetal 6 in 52%
overall yield, without purification of intermediates. Ester
The bridged furan 2 is a skeletal analogue of the
furanocembrane rubifolide (3), a secondary metabolite of
the soft coral, Gersemia rubiformis, a subtidal species
that inhabits the cold temperate waters off the coast of
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
(1) Marshall, J . A.; DuBay, W. J . J . Org. Chem. 1993, 58, 574.
(2) For a review, see: Paquette, L. A. Chemtracts: Org. Chem. 1992,
5, 141. The only other synthesis of a furanocembrane completed to date
is that of racemic acerosolide. Paquette, L. A.; Astles, P. C. J . Org.
Chem. 1993, 58, 165.
(4) Williams, D.; Andersen, R. J .; VanDuyne, G. D.; Clardy, J . J .
Org. Chem. 1987, 52, 332.
(5) Current prices for (R)- and (S)-perillyl alcohol from the 1995-
96 Aldrich Chemical Catalog are $27.60/g and $1.36/g.
(3) Marshall, J . A.; DuBay, W. J . J . Org. Chem. 1994, 59, 1703.
S0022-3263(97)00360-5 CCC: $14.00 © 1997 American Chemical Society

4314 J . Org. Chem., Vol. 62, No. 13, 1997
Marshall and Sehon
6 was reduced to the aldehyde and subjected to Corey-
Fuchs homologation6 to give the acetylene in 70% yield,
again without purification of intermediates. The lithio
acetylide 7 gave the alcohol adduct 9, as an equal mixture
of four diastereomers, upon treatment with aldehyde 8.7
The DPS-protected alcohol 10 was converted to the
aldehyde by acidic hydrolysis of the acetal and then
oxidized to the methyl ester with PDC in methanol. This
ester, without purification, was homologated to keto
phosphonate 11 (eq 3).
logue of alcohol 1.3 However it soon became apparent
that the similarity between 1 and 15 was superficial, as
treatment of the latter with KO-t-Bu led not to the
expected furanocycle 17 but to the DPS-cleaved product
16. We also attempted conversion of 15 to 17 with
AgNO3 on silica gel9 without success. The alcohol 16 was
likewise resistant to furan formation with base or AgNO3,
conditions that successfully converted 1 and various
acyclic analogues to the corresponding furans (eq 5).9
One obvious difference between alcohols 1 and 15 is
the presence of an (E)-double bond in the former which
is replaced by a triple bond in the latter. We surmized
that this difference must, for steric reasons, be the cause
of our failure to close the furan ring in 15. Therefore we
decided to convert alcohol 15 to the less constrained
allenoate 20, a precursor of the butenolide moiety of our
targeted furanocembrane. This was achieved through
Pd-catalyzed carbonylation of the mesylate 18 in the
presence of â-TMS ethanol,10 followed by selective reduc-
tion11 of the enone ester 19. Attempts to effect closure
of the hydroxy ester 20 with AgNO3 were, however, not
successful. Prolonged exposure led only to recovered
starting material. At elevated temperatures, decomposi-
tion of starting material occurred (eq 6).
Formation of the macrocyclic ring was achieved through
removal of the PMB protecting group, oxidation of the
derived alcohol 12, and intramolecular Horner-Emmons
cyclization8 of the acetylenic aldehyde 13 (eq 4).
Reduction of enone 14 with i-Bu2AlH led to the alcohol
15 (as a mixture of eight diastereomers), a close homo-
We did not examine the KO-t-Bu conditions with ester
20 because we felt that the strong base would cause
isomerization of the allenoate to a conjugated dienoate.
However, we thought that the acid 21, as its potassium
salt, might be less prone to isomerize. In fact, base
treatment of acid 21 afforded a single bridged furan acid
but, unfortunately, it was the conjugated trienoate 24
(probable structure). As no intermediates could be
(6) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(7) This aldehyde was prepared as follows:
(9) Marshall, J . A.; Sehon, C. A. J . Org. Chem. 1995, 60, 5966.
(10) Marshall, J . A.; Wolf, M. A. J . Org. Chem. 1996, 61, 3238.
(11) Singaram, B.; Fisher, G. B.; Fuller, J . C.; Harrison, J .; Alvarez,
S. G.; Burkhardt, E. R.; Goralski, C. T. J . Org. Chem. 1994, 59, 6378.
For details see the Supporting Information.
(8) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.
Masamune, S.; Roush, W. R. Tetrahedron Lett. 1984, 2183.

Total Synthesis of Furanocembrane Rubifolide Enantiomer
J . Org. Chem., Vol. 62, No. 13, 1997 4315
isolated, we could not ascertain if isomerization occured
before or after furan closure (eq 7).
the unsuccessful endeavor just described. Thus the
intermediate aldehyde acid 29, prepared as before from
(S)-(-)-perillyl alcohol (5), was esterified with Me3-
SiCHN2 affording the methyl ester 30. Without purifica-
tion, this intermediate was reduced to alcohol 31 and
protected as the TBS ether 32. Reduction with i-Bu2-
AlH and ensuing Swern oxidation afforded aldehyde 33,
which was converted to alkyne 34 with diazo(dieth-
ylphosphono)methane.15 Alkyne 34 incorporates C11-
14/1-3 of rubifolide, and the C1 isopropenyl substituent
(eq 10).
In a final attempt to effect the elusive furan ring
closure, we converted acid 21 to the butenolide 25 with
AgNO3.9 Butenolide 25 would appear to be a close
analogue to the model enynol 1. However, treatment of
25 with KO-t-Bu led to no identifiable products. Here
base-promoted decomposition of the butenolide moiety is
likely responsible for the lack of success (eq 8).
It was now clear that our enynol-furan cyclization
methodology was not sufficiently energetic to overcome
the steric factors associated with the formation of strained
furanocycles such as 17, 22, and 26.12 In considering
other options we turned to a furan synthesis based on
Ag+-catalyzed cyclization of allenones.14 Our previous
experience with this reaction had demonstrated its
applicability to the efficient synthesis of 12- and 14-
membered furanocycles under exceedingly mild condi-
tions. For the case at hand, an intermediate such as 27
would be required (eq 9).
Assemblage of the second substructure, 39, started
from the TBS-protected isopentenyl alcohol 35 (eq 11).
Epoxidation and then addition of the lithio acetylide 36
and protection of the alcohol product 37 with MOMCl
yielded the MOM ether 38. Removal of the TBS group
and oxidation afforded aldehyde 39, incorporating the
remaining ring carbons, C4-10, of rubifolide with the
attached CH3s at C4 and C8 (eq 11).
The approach was especially appealing because we
could employ essentially the same starting materials and
many of the same bond constructions that were used in
Addition of the lithio acetylide derived from 34 (BuLi)
to aldehyde 39 led to alcohol 40 as an equal mixture of
eight diastereomers in 86% yield. The methyl carbonate
41 was prepared (BuLi, ClCO2Me) in 98% yield. Removal
of the PMB protecting group (91% yield) followed by
mesylate formation and addition of the cuprate from Bu3-
SnLi and CuBr‚SMe2 afforded the allenylstannane 42 in
84% overall yield.14 Deprotection (TBAF) gave alcohol
43 (eq 12).
(12) Molecular mechanics calculations on the γ-alkynyl allylic
alcohols 1 and 16 revealed no significant differences in geometry with
regard to the allylic alcohol and its appended enyne substituent.13 Thus
the failure of the latter to cyclize is most likely the result of energy
differences in the transition states. Calculations of these differences
are, at present, beyond our capabilities. The calculated ground state
conformation of the allenic acid 21 differed markedly from that of 1
and 16. Significantly, the allylic OH of the latter two was favorably
disposed to interact with the alkynyl moiety, whereas in 21 that OH
was oriented away from the alkyne.
(13) The program Macromodel 4.5 was employed for these calcula-
tions. Global minimum multiple conformer searching was achieved
with the Monte Carlo subroutine in BATCHMIN through multiple step
interactions (typically 1000) until the minimum energy conformer was
found multiple times (10 or more). For a description of the program,
see: (a) Mohamadi, F.; Richards, N. G.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440. (b) Chang, G.; Guida, W. C.; Still, W.
C. J . Am. Chem. Soc. 1989, 111, 4379.
Alcohol 43 was oxidized, as the magnesium alkoxide,
with ADD affording aldehyde 44 in 85% yield.16 Treat-
ment of allenylstannane aldehyde 44 with BF3‚OEt2 and
subsequent Dess-Martin oxidation of the homopropar-
(15) Gilbert, S. C.; Weerasooriya, U. J . Org. Chem. 1979, 44, 4997.
(16) Narasaka, K.; Morikawa, A.; Saigo, K.; Mukaiyama, T. Bull.
Soc. Chem. J pn. 1977, 50, 2773.
(14) Marshall, J . A.; Wang, X.-j. J . Org. Chem. 1992, 57, 3387.

4316 J . Org. Chem., Vol. 62, No. 13, 1997
Marshall and Sehon
in THF-MeOH did not afford any of the desired ester,
even at elevated temperatures. We therefore decided to
pursue an alternative strategy. For this, we required the
syn-alcohol 48. Accordingly, carbonates 47/49 were
saponified (K2CO3 in MeOH, 96% yield) to a separable
1:1 mixture of epimeric alcohols 48/50. Oxidation of the
mixture, or 50 alone, with MnO2 gave the ketone 51. The
calculated lowest energy conformers of this ketone all
show significant shielding of the “top face” of the carbonyl
by the vinylic CH3 substituent at C8 (Figure 1).13
We therefore surmized that hydride reduction would
proceed with high diastereoselectivity. In accord with
this prediction, reduction of 51 with K-Selectride gave
rise to a single diastereomer, 48, in high yield (eq 14).
The configuration of the carbinyl stereocenter was veri-
fied through 1H NMR analysis of the (R) and (S)-O-
methylmandelate derivatives.21 Additional support was
secured through single-crystal X-ray structure
analysis.22
gylic alcohol and in situ isomerization of the resulting
ketone14 led to allenone 45 as a mixture of eight diaster-
eomers in 74% yield.
Intraanular furan formation was effected in 84% yield
by exposure of allenone 45 to 10% AgNO3 on silica gel in
hexane.9 This conversion could not be realized with
AgNO3 in acetone under our previously reported condi-
tions.14 Mainly starting material was recovered from
such attempts. The 2,5-furanocycle, 46, underwent
highly selective elimination to a 1:1 mixture of diaster-
eomeric (Z)-vinylfurans 47 and 49 upon exposure to
p-TsOH in CH2Cl2 at moderately high dilution to mini-
mize polymerization. The high stereoselectivity of this
reaction reflects the ∼3 kcal/mol energy difference be-
tween the (Z)- and (E)-isomers, predicted by molecular
mechanics calculation.13 Attempts to effect this elimina-
tion on the propargylic alcohol (46, R ) H) with KO-t-
Bu led to recovered starting material or, under more
forcing conditions, to decomposition.17
We have previously shown that propargylic alcohols,
such as 48, can be converted to butenolides with inversion
of configuration through Pd(0)-catalyzed hydrocarbony-
lation of the mesylate derivative (53 f 54) and AgNO3-
catalyzed cyclization of the intermediate allenic acid (54
f 55), as illustrated in eq 15.10 When this sequence was
applied to the mesylate derivative 52 of alcohol 48, the
expected product 57 (rubifolide) was formed in low yield.
The problem seemed to reside with the lability of the
mesylate under the conditions of its formation and during
isolation. The corresponding trifluoroacetate 56, though
easily hydrolyzed, did not undergo destructive side reac-
tions. Furthermore the carbonylation reaction proceeded
smoothly to the allenic acid. The entire sequence from
We had originally planned to convert the propargylic
carbonates 47/49 to the related allenoic esters by the
Tsuji Pd-catalyzed carbonylation methodology18 and,
after equilibration and ester cleavage, to close the
butenolide ring.19,20 However, treatment of the carbon-
ates under Tsuji’s conditions or with Pd(PPh3)4 and CO
(19) Marshall, J . A.; Bartley, G. S.; Wallace E. M. J . Org. Chem.
1996, 61, 5729.
(20) Molecular mechanics calculations (Macromodel) indicated that
the requisite allenoate diastereomer would be favored by several kcal/
mol.13
(21) Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.;
Balkovec, J . M.; Baldwin, J . J .; Christy, E.; Ponticello, G. S.; Varga, S.
L.; Springer, J . D. J . Org. Chem. 1986, 51, 2370.
(22) This analysis was performed by Dr. Michael Sabat of this
department.
(17) Cf. Marshall, J . A.; Bennett, C. E. J . Org. Chem. 1994, 59, 6110.
(18) Mandai, T.; Tsuji, J .; Tsujiguchi, Y. J . Am. Chem. Soc. 1993,
115, 5865.

Total Synthesis of Furanocembrane Rubifolide Enantiomer
J . Org. Chem., Vol. 62, No. 13, 1997 4317
F igu r e 1. Stereoview Chem 3D structure of the lowest energy conformation of ynone 51, as calculated by Macromodel v4.5
(MM2 force field), illustrating the facial bias at the carbonyl group.
min. The solution was then diluted with water and Et2O, and
the aqueous phase was extracted with Et2O. The organic
extracts were washed with brine and dried over MgSO4, and
the solvent was removed under reduced pressure to give a clear
yellow oil. The oil was diluted with 150 mL of 4:1 benzene-
MeOH, and 29.7 mL (59.4 mmol) of 2.0 M TMSCHN2 in hexane
was slowly added at 0 °C. The solution was stirred at rt for
30 min, and the solvent was removed under reduced pressure
to give a clear bright yellow oil. The oil was diluted with 60
mL of MeOH and cooled to 0 °C, and 1.12 g (29.7 mmol) of
NaBH4 was added to the stirred solution. The solution was
allowed to reach rt and stir for 30 min. The solution was then
diluted with 10% HCl and Et2O. The layers were separated,
and the aqueous phase was extracted with Et2O. The organic
extracts were dried over MgSO4 and concentrated under
reduced pressure.
The residue was diluted with 20.0 mL of DMF, and 6.00 g
(89.0 mmol) of imidazole was added followed by 8.95 g (59.5
mmol) of TBSCl. The solution was stirred for 30 min and then
diluted with water and Et2O. The layers were separated, and
the aqueous phase was extracted with Et2O. The organic
extracts were washed with water and dried over MgSO4, and
the solvent was removed under reduced pressure. Flash
chromatography on silica gel (0-5% EtOAc-hexane) gave 13.2
g (74%) of the ester 32 as a clear light yellow oil: IR (film) υ
3077, 1742, 1438 cm-1; 1H NMR δ 4.78 (m, 1H), 4.69 (m, 1H),
3.65 (s, 3H), 3.54 (m, 2H), 2.23 (m, 3H), 1.84-1.45 (m, 8H),
0.88 (s, 9H), 0.02 (s, 6H); 13C NMR δ 174.2, 145.9, 112.6, 61.2,
51.4, 43.2, 36.2, 32.1, 28.2, 25.9, 18.3, 17.8, -5.3. Anal. Calcd
for C16H32O3Si: C, 63.95; H, 10.73. Found: C, 64.22; H, 10.81.
alcohol to butenolide was best performed without isola-
tion of any intermediate (eq 16).
The 1H and 13C NMR spectra of butenolide 57 were
superimposable with those of rubifolide.4,23 The optical
rotation, however, was equal in magnitude but opposite
in sign to that reported for the natural product. Thus,
we have confirmed the relative and absolute configura-
tion of natural rubifolide as initially, but arbitrarily,
assigned.4 The foregoing synthesis also highlights the
utility of the AgNO3/silica gel method for furan synthesis
from allenones. Finally, the carbonylation of propargylic
trifluoroacetates in aqueous THF and subsequent AgNO3/
silica gel cyclization to prepare chiral butenolides shows
promise as a general method.
Exp er im en ta l Section
(S)-1,2-Ep oxyp er illyl Alcoh ol. To a stirred solution of
20.0 g (0.12 mol) of (S)-(-)-perillyl alcohol and 0.60 g (2 mol
%) of VO(acac)2 in 320 mL of CH2Cl2 at 0 °C was slowly added
33.0 mL (0.18 mol) of ∼5.5 M anhydrous t-BuOOH in decane.
The mixture was allowed to reach rt and stir for 30 min; then
4.40 mL (60.0 mmol) of dimethyl sulfide was added and
stirring was continued for 45 min. The solution was diluted
with saturated NaHCO3 and stirred for 1 h. The layers were
separated, and the solution was extracted with CH2Cl2 . The
organic extracts were dried over MgSO4, and the solvent was
removed under reduced pressure. Flash chromatography on
silica gel (20-30% EtOAc-hexane) gave 20.1 g (99%) of the
epoxy alcohol as a clear light yellow oil: IR (film) υ 3417, 3077,
(S)-6-[(ter t-Bu tyldim eth ylsilyl)oxy]-4-isopr open ylh exan -
1-ol (32.1). To a stirred solution of 12.1 g (40.3 mmol) of ester
32 in 115 mL of THF at -78 °C was added 93.0 mL (93.0
mmol) of 1.0 M DIBAH in hexane. The solution was stirred
for 45 min. To this solution was slowly added 300 mL of Et2O
followed by 500 mL of saturated sodium potassium tartrate
at -78 °C. The reaction solution was slowly warmed to rt and
vigorously stirred overnight. The layers were separated, and
the aqueous phase was extracted with Et2O. The combined
organic extracts were dried over MgSO4, and the solvent was
removed under reduced pressure to afford 10.8 g (98%) of
alcohol 32.1 as a clear oil that was carried on without further
purification: IR (film) υ 3348, 3076, 2857, 1642 cm-1; 1H NMR
δ 4.75 (m, 1H), 4.69 (m, 1H), 3.62 (t, 2H, J ) 6.4 Hz), 3.53 (m,
2H), 2.19 (m, 1H), 1.6 (m, 3H), 1.59-1.33 (m, 6H), 0.88 (s, 9H),
0.03 (s, 6H); 13C NMR δ 147.3, 112.4, 63.6, 61.9, 43.9, 36.9,
31.2, 29.9, 26.5, 18.8, 18.4, -4.8. Anal. Calcd for C15H32O2Si:
C, 66.11; H, 11.84. Found: C, 66.00; H, 11.88.
(S)-6-[(ter t-Bu tyld im eth ylsilyl)oxy]-4-isop r op en ylh ex-
a n a l (33). To a stirred solution of 1.09 mL (12.5 mmol) of
oxalyl chloride in 75 mL of CH2Cl2 was slowly added 1.19 mL
(16.7 mmol) of DMSO. The solution was stirred for 25 min,
2.28 g (8.36 mmol) of the foregoing alcohol was added in 5 mL
of CH2Cl2, and stirring was continued for 25 min, after which
4.66 mL (33.4 mmol) of triethylamine was added and stirring
was continued for 5 min. The mixture was allowed to reach
rt and stirred for 1 h. The mixture was diluted with Et2O and
1
2930, 1646 cm-1; H NMR δ 4.71 (d, 2H, J ) 15.0 Hz), 3.55-
3.65 (m, 2H), 3.29-3.36 (m, 1H), 2.03-2.16 (m, 4H), 1.80-
1.86 (m, 1H), 1.70 (s, 3H), 1.59-1.68 (m, 1H), 1.18-1.47 (m,
2H); 13C NMR δ major diastereomer 148.5, 109.0, 64.4, 60.0,
56.7, 55.7, 36.6, 30.1, 25.7, 23.6; minor diastereomer, partial
148.6, 109.1, 64.5, 60.4, 40.7, 24.5, 20.7, 20.1. Anal. Calcd
for C10H16O2: C, 71.39; H, 9.59. Found: C, 71.13; H, 9.58.
Meth yl (S)-6-[(ter t-Bu tyld im eth ylsilyl)oxy]-4-isop r o-
p en ylh exa n oa te (32). To a stirred solution of 10.0 g (59.4
mmol) of (S)-1,2-epoxyperillyl alcohol in 300 mL of 19:1 THF-
H2O at 0 °C was slowly added 31.0 g (137.0 mmol) of periodic
acid. The mixture was allowed to reach rt and stirred for 30
(23) Copies of the spectra were kindly provided by Professor R. J .
Andersen (University of British Columbia).

4318 J . Org. Chem., Vol. 62, No. 13, 1997
Marshall and Sehon
10% HCl. The organic phase was washed with brine and dried
over MgSO4, and the solvent was removed under reduced
pressure. Flash chromatography on silica gel (20% EtOAc-
hexane) afforded 2.07 g (91%) of aldehyde 33 as a clear yellow
added. After 2 h, the solution was diluted with saturated
NaHCO3 and Et2O and allowed to reach rt. The organic layer
was washed with brine and dried over MgSO4, and the solvent
was removed under reduced pressure. Flash chromatography
on silica gel (10% EtOAc-hexane) afforded 15.2 g (81%) of
alcohol 37 as a clear colorless oil: IR (film) υ 3478, 2233, 1614
oil: IR (film) υ 3075, 2857, 1728 cm-1 1H NMR δ 9.76 (m,
;
1H), 4.80 (m, 1H), 4.70 (m, 1H), 3.68-3.46 (m, 2H), 2.37 (t,
2H, J ) 7.3 Hz), 2.21 (m, 1H), 1.60 (s, 3H), 1.94-1.38 (m, 4H),
0.88 (s, 9H), 0.03 (s, 6H); 13C NMR δ 202.4, 145.8, 112.9, 61.1,
43.1, 41.9, 36.3, 25.9, 25.3, 18.2, 17.8, -5.4. Anal. Calcd for
C15H30O2Si: C, 66.61; H, 11.18. Found: C, 66.44; H, 11.10.
(S)-7-[(ter t-Bu tyld im eth ylsilyl)oxy]-5-isop r op en ylh ex-
1-yn e (34). To a stirred solution of 32.1 mL (32.1 mmol) of
1.0 M KO-t-Bu in 670 mL of THF at -78 °C was added 5.77 g
(29.6 mmol) of N2CHPO(OEt)2 in 15 mL of THF, and stirring
was continued for 15 min. To this solution was slowly added
5.31 g (14.6 mmol) of aldehyde 33 in 10 mL of THF. After 30
min the solution was allowed to reach rt and stir for 1 h. The
solution was diluted with Et2O and brine, the organic layer
was washed with brine and dried over MgSO4, and the solvent
was removed under reduced pressure. Purification by flash
chromatography (1-2.5% EtOAc-hexane) afforded 4.72 g
(90%) of alkyne 34 as a clear colorless oil: IR (film) υ 3314,
cm-1 1H NMR δ 7.08 (ABq, 4H, J ) 8.8 Hz, ∆υ ) 120 Hz),
;
4.54 (ABq, 2H, J ) 11.0 Hz, ∆υ ) 81.0 Hz), 4.18 (q, 1H, J )
6.6 Hz), 1.34 (d, 3H, J ) 1.5 Hz), 0.90 (s, 9H), 0.09 (s, 6H); 13
C
NMR δ 159.6, 130.5, 129.9, 114.1, 82.8, 82.7, 73.0, 70.3, 64.6,
61.1, 55.5, 40.8, 32.9, 77.1, 26.2, 22.8, 18.4, -5.2. Anal. Calcd
for C23H38O4Si: C, 67.94; H, 9.42. Found: C, 67.74; H, 9.48.
1-[(ter t-Bu tyld im eth ylsilyl)oxy]-7-[(4-m eth oxyben zyl)-
oxy]-3-(m eth oxym eth oxy)-3-m eth yl-5-octyn -1-ol (38). To
a stirred solution of 14.9 g (37.0 mmol) of alcohol 37 in 75 mL
of CHCl2 at 0 °C was added 31.9 mL (0.18 mol) of diisopropyl-
ethylamine followed by 11.1 mL (0.15 mol) of MOMCl. The
solution was allowed to reach rt and stir overnight. The
solution was diluted with 10% HCl and CH2Cl2. The organic
layer was washed with brine and dried over MgSO4, and the
solvent was removed under reduced pressure to afford 15.7 g
(95%) of the MOM ether 38 as a clear yellow oil. The crude
material was carried on without further purification: IR (film)
3077, 2860, 2119, 1645 cm-1 1H NMR δ 4.78 (m, 1H), 4.73
;
1
(m, 1H) 3.55 (m, 1H), 3.50 (dt (apparent q), 1H J ) 2.6 Hz),
2.32 (m, 1H), 2.20-1.98 (m, 2H), 1.92 (t, 1H, J ) 2.6 Hz), 1.60
(m, 3H), 1.60-1.53 (m, 4H), 0.88 (s, 9H), 0.03 (s, 6H); 13C NMR
δ 145.8, 112.6, 84.6, 68.1, 61.2, 42.7, 36.1, 32.1, 25.9, 18.3, 17.8,
16.4, -5.3. Anal. Calcd for C16H30OSi: C, 72.11; H, 11.35.
Found: C, 72.22; H, 11.42.
υ 2237, 1613 cm-1; H NMR δ 7.18 (ABq, 4H, J ) 8.8 Hz, ∆υ
) 120 Hz), 4.76 (ABq, 2H, J ) 7.7 Hz, ∆υ ) 10.6 Hz), 4.5 (ABq,
2H, J ) 11 Hz, ∆υ ) 81 Hz), 4.19 (qt, 1H, J ) 6.6 Hz, J ) 1.8
Hz), 3.80 (s, 3H), 3.77 (t, 2H, J ) 7.0 Hz), 3.39 (s, 3H), 2.54 (d,
2H, J ) 1.8 Hz), 1.94 (m, 2H), 1.42 (d, 3H, J ) 6.6 Hz), 1.37
(s, 3H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR δ 159.1, 130.2,
129.6, 113.7, 91.1, 82.2, 76.8, 69.9, 64.2, 59.0, 55.4, 55.2, 41.6,
30.7, 25.9, 23.9, 22.3, 18.2, -5.3.
3-[(4-Met h oxyben zyl)oxy]-1-b u t yn e (36). To a stirred
suspension of 4.67 g (0.19 mol) of 95% NaH in 350 mL of THF
at 0 °C was added 11.2 mL (0.14 mol) of (()-3-butyn-2-ol. After
30 min, 26.0 mL (0.21 mol) of 4-methoxybenzyl chloride was
added followed by a catalytic amount of Bu4NI. The mixture
was allowed to reach rt and stir for 2 d. The mixture was then
diluted with H2O and Et2O, the organic extracts were dried
over MgSO4, and the solvent was removed under reduced
pressure. Bulb-to-bulb distillation (aspirator pressure) gave
27.0 g (99%) of the alkyne 36 as a clear colorless oil: IR (film)
7-[(4-Meth oxyben zyl)oxy]-3-(m eth oxym eth oxy)-3-m eth -
yl-5-octyn -1-ol (38.1). To 17.7 g (35.0 mmol) of the neat silyl
ether 38 was added 52.2 mL (52.0 mmol) of 1.0 M TBAF in
THF at rt. The solution was stirred for 1 h and then diluted
with H2O and Et2O, and the aqueous layer was extracted with
Et2O. The organic extracts were washed with brine and dried
over MgSO4, and the solvent was removed under reduced
pressure. Flash chromatography on silica gel (20-40% EtOAc-
hexane) provided 10.2 g (87%) of the alcohol as a clear yellow
1
υ 3286, 2106 cm-1; H NMR δ 7.30 (d, 2H, J ) 8.6 Hz), 6.88
1
oil: IR (film) υ 3446, 2233, 1613 cm-1; H NMR δ 7.08 (ABq,
(d, 2H, J ) 8.6 Hz), 4.58 (ABq, 2H, J AB ) 11.4 Hz, ∆υ ) 8.5
Hz), 4.18 (dq, 1H, J ) 2.0 Hz, J ) 6.6 Hz), 3.80 (s, 3H), 2.46
(d, 1H, J ) 2.0 Hz), 1.96 (d, 3H, J ) 6.6 Hz); 13C NMR δ 159.2,
129.8, 129.6, 113.7, 83.7, 72.0, 70.0, 63.7, 55.1, 21.9. Anal.
Calcd for C12H12O2: C, 75.76; H 7.42. Found: C, 75.76; H,
7.48.
4H, J ) 8.8 Hz, ∆υ ) 120 Hz), 4.77 (ABq, 2H, J ) 7.7 Hz, ∆υ
) 10.6 Hz), 4.54 (ABq, 2H, J ) 11 Hz, ∆υ ) 81 Hz), 4.18 (qt,
1H, J ) 6.6 Hz, J ) 1.8 Hz), 3.84 (t, 2H, J ) 5.9 Hz), 3.80 (s,
3H), 3.39 (s, 3H), 2.60 (d, 2H, 1.5 Hz), 1.96 (m, 2H), 1.41 (s,
3H), 1.41 (d, 3H, J ) 6.6 Hz); 13C NMR δ 159.6, 130.5, 130.0,
114.2, 91.5, 83.0, 78.7, 70.4, 64.6, 59.4, 56.0, 55.6, 41.6, 30.8,
23.9, 22.8. Anal. Calcd for C19H28O5: C, 67.83; H, 8.39.
Found: C, 67.59; H, 8.27.
4-[(ter t-Bu t yld im et h ylsilyl)oxy]-2-m et h yl-1,2-ep oxy-
bu ta n e (35.1). To a stirred solution of 11.7 mL (0.12 mol) of
3-methyl-3-buten-1-ol in 25 mL of DMF at rt was added 11.9
g (0.17 mol) of imidazole followed by 17.5 g (0.12 mol) of TBSCl.
The solution was stirred for 30 min and then diluted with H2O
and Et2O. The organic extracts were washed with H2O and
brine and dried over MgSO4, and the solvent was removed
under reduced pressure.
The crude silyl ether 35 was diluted with 580 mL of CH2-
Cl2. To this solution was added 31.0 g (0.21 mol) of NaHPO4
followed by 35.9 g (0.21 mol) of m-CPBA, and the mixture was
stirred for 1 h. The crude reaction mixture was filtered and
diluted with 10% NaOH and CH2Cl2. The organic layer was
washed with 10% NaOH and brine and dried over MgSO4, and
the solvent was removed under reduced pressure. Bulb-to-
bulb distillation (∼1.0 mm at 50-60 °C) gave 19.9 g (79%) of
the epoxide as a clear colorless oil: IR (film) υ 2928, 2855,
1472 cm-1; 1H NMR δ 3.72 (m, 12H), 2.63 (ABq, 2H, J AB ) 4.8
Hz, ∆υ ) 32 Hz), 1.86 (ddd, 1H, J ) 12.9 Hz, J ) 5.9 Hz, J )
5.9 Hz), 1.69 (ddd, 1H, J ) 13.9 Hz, J ) 7.0 Hz, J ) 7.0 Hz),
1.34 (s, 3H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR δ 59.6, 55.4,
54.0, 39.7, 25.8, 21.4, 18.1, -5.4. Anal. Calcd for C11H24O2Si:
C, 61.06; H, 11.18. Found: C, 61.35; H, 11.04.
7-[(4-Meth oxyben zyl)oxy]-3-(m eth oxym eth oxy)-3-m eth -
yl-5-octyn a l (39). To a stirred solution of 1.71 mL (20.0
mmol) of oxalyl chloride in 130 mL of CH2Cl2 at -78 °C was
added 1.89 mL (26.0 mmol) of DMSO, and the solution was
stirred for 20 min. To this solution was added 4.45 g (13.0
mmol) of the foregoing alcohol in 5 mL of CH2Cl2, and stirring
was continued for 25 min. To this solution was added 7.41
mL (53.0 mmol) of Et3N, and the solution was stirred for an
additional 5 min at -78 °C and then allowed to reach rt and
stir for 2 h. The mixture was diluted with 10% HCl and Et2O.
The aqueous layer was extracted with Et2O. The organic
extracts were washed with brine and dried over MgSO4, and
the solvent was removed under reduced pressure to afford 4.40
g (99%) of the aldehyde 39 as a clear yellow oil. The crude
material was carried on without further purification.
(3S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-isop r op en yl-14-
[(4-m eth oxyben zyl)oxy]-10-(m eth oxym eth oxy)-10-m eth -
yl-6,12-p en ta d eca d iyn -8-ol (40). To a stirred solution of
3.15 g (12.0 mmol) of alkyne 11 in 100 mL of THF at -78 °C
was added 5.00 mL (13.0 mmol) of 2.5 M BuLi in hexane, and
the solution was stirred for 1 h. To this solution was slowly
added 4.40 g (13.0 mmol) of aldehyde 39 in 15 mL of THF.
The solution was stirred for 10 min at -78 °C and allowed to
reach rt. The solution was diluted with saturated NH4Cl and
Et2O. The aqueous layer was extracted with Et2O, the organic
extracts were dried over MgSO4, and the solvent was removed
under reduced pressure. Flash chromatography on silica gel
1-[(ter t-Bu tyld im eth ylsilyl)oxy]-7-[(4-m eth oxyben zyl)-
oxy]-3-m eth yl-5-octyn -3-ol (37). To a stirred solution of 15.8
g (83.0 mmol) of alkyne 36 in 185 mL of THF at -78 °C was
added 34.0 mL (85.0 mmol) of 2.5 M BuLi in hexane, and the
solution was stirred for 1 h. To this solution was added 10.2
mL (83.0 mmol) of BF3‚OEt2, and stirring was continued for
20 min, after which 10.0 g (42.0 mmol) of epoxide 35.1 was

Total Synthesis of Furanocembrane Rubifolide Enantiomer
J . Org. Chem., Vol. 62, No. 13, 1997 4319
1
(15-25% EtOAc-hexane) afforded 6.17 g (87%) of the prop-
argyl alcohol 40 as a clear orange oil: IR (film) υ 3441, 3071,
1754 cm-1; H NMR δ 5.42 (m, 1H), 4.83-4.61 (m, 4H), 4.54
(m, 1H), 3.78 (s, 3H), 3.52 (m, 2H), 3.36 (s, 1.5H), 3.35 (s, 1.5H),
2.41-1.97 (m, 7H), 1.71-1.19 (m, 32H), 1.00-0.73 (m, 26H),
0.03 (s, 6H).
1
2234, 1614 cm-1; H NMR δ 7.07 (ABq, 4H, J ) 8.8 Hz, ∆υ )
120 Hz), 4.85-4.64 (m, 5H), 4.42 (B of ABq, 0.5H, J ) 11 Hz)
4.40 (B of ABq, 0.5H, J ) 11.4 Hz), 4.18 (m, 1H), 3.80 (s, 3H),
3.51 (m, 2H), 3.39 (apparent d, 3H, J ) 2.2 Hz), 3.25 (m, 1H),
2.74-2.53 (m, 2H), 2.34-1.93 (m, 5H), 1.66-1.32 (m, 14H),
0.88 (s, 9H), 0.02 (s, 6H). Anal. Calcd for C35H56O6Si: C,
69.96; H, 9.39. Found: C, 69.84; H, 9.32.
(3S )-3-Isop r op e n yl-8-(m e t h oxyca r b on yl)-10-(m e t h -
oxym eth oxy)-10-m eth yl-12-(tr i-n -bu tylstan n yl)-12,13-pen -
ta d eca d ien -6-yn -1-ol (43). To a stirred solution of 1.21 g
(1.50 mmol) of allenylstannane 42 in 6 mL of THF was added
0.27 mL (15.0 mmol) of H2O followed by 5.90 mL (5.9 mmol)
of 1.0 M TBAF in THF. The solution was stirred for 8 h at rt.
The solution was diluted with H2O and Et2O, the aqueous layer
was extracted with Et2O, the organic extracts were dried over
MgSO4, and the solvent was removed under reduced pressure.
Flash chromatography on deactivated (5% Et3N-hexane) silica
gel (25% EtOAc-hexane) afforded 0.94 g (91%) of the alcohol
43 as a clear light yellow oil: IR (film) υ 3435, 3075, 2246,
1940, 1753 cm-1; 1H NMR δ 5.40 (m, 1H), 4.85-4.60 (m, 4H),
4.53 (m, 1H), 3.77 (s, 3H), 3.59 (m, 2H), 3.36 (s, 1.5H), 3.34 (s,
1.5H), 2.43-1.95 (m, 7H), 1.69-1.14 (m, 32H), 1.00-0.64 (m,
17H).
(3S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-isop r op en yl-14-
[(4-m eth oxyben zyl)oxy]-8-(m eth oxyca r bon yl)-10-(m eth -
oxym eth oxy)-10-m eth yl-6,12-p en ta d eca d iyn e (41). To a
stirred solution of 6.0 g (10.0 mmol) of alcohol 40 in 10 mL of
THF at -78 °C was added 4.8 mL (12.0 mmol) of 2.5 M BuLi
in hexane. After 1 h, 1.16 mL (15.0 mmol) of methyl chloro-
formate was added dropwise and the solution was allowed to
reach rt and stir overnight. The solution was diluted with
saturated NaHCO3 and Et2O. The aqueous phase was ex-
tracted with Et2O, the organic extracts were dried over MgSO4,
and the solvent was removed under reduced pressure. Flash
chromatography on silica gel (10-40% EtOAc-hexane) af-
forded 6.46 g (98%) of the carbonate 41 as a clear yellow oil:
(3S )-3-Isop r op e n yl-8-(m e t h oxyca r b on yl)-10-(m e t h -
oxym eth oxy)-10-m eth yl-12-(tr i-n -bu tylstan n yl)-12,13-pen -
ta d eca d ien -6-yn a l (44). To a stirred solution of 0.20 mL
(2.14 mmol) of t-BuOH in 10 mL of THF at 0 °C was added
2.10 mL (2.10 mmol) of 1.0 M EtMgBr in THF, and the solution
was stirred for 5 min. To this solution was added 0.88 g (1.30
mmol) of the alcohol 43 in 3 mL of THF. After 10 min, 0.54 g
(2.14 mmol) of 1,1′-(azodicarbonyl)dipiperdine was added and
the mixture was stirred for an additional 30 min. The mixture
was diluted with brine, H2O, and Et2O. The aqueous layer
was extracted with Et2O. The organic extracts were dried over
MgSO4, and the solvent was removed under reduced pressure.
Flash chromatography on deactivated (5% Et3N-hexane) silica
gel (15% EtOAc-hexane) afforded 0.81 g (91%) of the aldehyde
44 as a clear light yellow oil: IR (film) υ 3074, 2714, 2248,
1
IR (film) υ 3072, 2234, 1753, 1612 cm-1; H NMR δ 7.29 (d,
2H, J ) 8.4 Hz), 6.87, (d, 2H, J ) 8.4 Hz), 5.48, (m, 1H), 4.82-
4.65 (m, 5H), 4.42 (B of ABq, 1H, J ) 11.0 Hz), 4.18 (q, 1H, J
) 6.6 Hz), 3.83-3.77 (m, 3H), 3.80 (s, 3H), 3.52 (m, 2H), 3.38
(s, 3H), 2.62-2.43 (m, 2H), 2.35-1.98 (m, 5H), 1.80-1.20 (m,
13H), 0.89 (s, 9H), 0.02 (s, 6H). Anal. Calcd for C37H58O8Si:
C, 67.44; H, 8.87. Found: C, 67.33; H, 8.93.
(13S)-15-[(ter t-Bu tyld im eth ylsilyl)oxy]-13-isop r op en yl-
8-(m eth oxyca r bon yl)-6-(m eth oxym eth oxy)-6-m eth yl-3,9-
p en ta d eca d iyn -2-ol (41.1). To a stirred solution of 2.61 g
(3.90 mmol) of carbonate 41 in 40 mL of 18:1 CH2Cl2-H2O at
rt was added 1.16 g (5.10 mmol) of DDQ, and the mixture was
stirred for 1 h. The mixture was filtered and diluted with H2O
and CH2Cl2. The aqueous layer was extracted with CH2Cl2,
the organic extracts were dried over MgSO4, and the solvent
was removed under reduced pressure. Flash chromatography
on silica gel (20-30% EtOAc-hexane) gave 1.93 g (91%) of
the propargylic alcohol as a clear light orange oil: IR (film) υ
1935, 1753, 1727 cm-1 1H NMR δ 9.64 (t, 1H, J ) 2.4 Hz),
;
5.40 (m, 1H), 4.85-4.60 (m, 2H), 4.52 (m, 1H), 3.76 (s, 3H),
3.34 (S, 1.5H), 3.33 (s, 1.5H), 2.77 (m, 1H), 2.46-2.01 (m, 8H),
1.73-1.15 (m, 32H), 1.01-0.75 (m, 15H).
(14S )-2,6-D i m e t h y l-14-i s o p r o p e n y l-8-(m e t h o x y -
ca r bon yl)-6-(m eth oxym eth oxy)-2,3-cyclotetr a d eca d ien -
9-yn on e (45). To a stirred solution of 0.77 mL (6.25 mmol)
of BF3‚OEt2 in 210 mL of CH2Cl2 at -78 °C was added 1.45 g
(2.10 mmol) of the allenylstannane aldehyde 44 in 50 mL of
CH2Cl2 over a period of 30 min. The solution was stirred
overnight at -78 °C and then quenched with 5 mL of MeOH
followed by saturated NaHCO3. The solution was allowed to
reach rt, and the aqueous phase was extracted with CH2Cl2.
The organic phase was dried over MgSO4, and the solvent was
removed under reduced pressure to afford the addition product
as a clear dark yellow oil. The oil was diluted with 21 mL of
CH2Cl2, and 1.76 (4.20 mmol) of Dess-Martin24 reagent was
added to the solution. The mixture was stirred for 30 min at
rt, poured into a solution of saturated NaHCO3 containing 7.20
g (29.0 mmol) of Na2S2O3‚5H2O, and stirred until clear. The
aqueous layer was extracted with CH2Cl2, the organic extracts
were dried over MgSO4, and the solvent was removed under
reduced pressure to give a mixture of propargyl and allenyl
ketones as a clear yellow oil. This oil was diluted with 9 mL
of CH2Cl2, and 2.90 mL (21.0 mmol) of Et3N was added. This
mixture was stirred for 6 h, and the solvent was then removed
under reduced pressure. Flash chromatography on deacti-
vated (5% Et3N-hexane) silica gel (15-20% EtOAc-hexane)
gave 0.63 g (74%) of the allenone 45 as a clear yellow oil: IR
1
3453, 3071, 2243, 1755 cm-1; H NMR δ 5.49 (m, 1H), 4.79-
4.65 (m, 4H), 4.50 (m, 1H), 3.78 (s, 3H), 3.52 (m, 2H), 3.37 (s,
3H), 2.62-2.43 (m, 2H), 2.35-1.98 (m, 5H), 1.80-1.20 (m,
13H), 0.88 (s, 9H), 0.02 (s, 6H). Anal. Calcd for C29H50O7Si:
C, 64.65; H, 9.35. Found: C, 64.58; H, 9.39.
(3S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-isop r op en yl-8-
(m eth oxyca r bon yl)-10-(m eth oxym eth oxy)-10-m eth yl-12-
(tr i-n -bu tylsta n n yl)-12,13-p en ta d eca d ien -6-yn e (42). To
a stirred solution of 1.89 g (3.50 mmol) of the foregoing
propargylic alcohol in 35 mL of CH2Cl2 at -78 °C was added
10.0 mL (7.10 mmol) of Et3N followed by 0.41 mL (5.30 mmol)
of methanesulfonyl chloride. After 1 h, the mixture was
diluted with saturated NaHCO3 and Et2O. The aqueous phase
was extracted with Et2O, the organic phase was washed with
saturated NaHCO3, H2O, and brine and dried over MgSO4, and
the solvent was removed under reduced pressure. The crude
material was carried on without further purification.
A two-necked flask was equipped with a stirbar and a side-
arm addition flask containing 1.45 g (7.10 mmol) of CuBr‚
SMe2. The apparatus was evacuated and purged with argon
several times. To this flask, under argon, were added 30 mL
of THF and 1.10 mL (7.80 mmol) of diisopropylamine. To this
solution at 0 °C was added 2.80 mL (7.10 mmol) of 2.5 M BuLi
in hexane, and the solution was stirred for 20 min. To this
solution was added 1.90 mL (7.10 mmol) of Bu3SnH, and
stirring was continued for 30 min. The solution was then
cooled to -78 °C, and the CuBr‚SMe2 was added from the side-
arm flask. After 45 min, the crude mesylate in 5 mL of THF
was added and the mixture was stirred for 30 min. The
mixture was poured into a solution of 9:1 NH4Cl-NH4OH and
stirred until both phases were clear. The aqueous phase was
extracted with CH2Cl2. The organic phase was dried over
MgSO4, and the solvent was removed under reduced pressure.
Flash chromatography on deactivated (5% Et3N-hexane) silica
gel (0-5% EtOAc-hexane) afforded 2.39 g (84%) of the
allenylstannane 42 as a clear yellow oil: IR (film) υ 3071, 1932,
(film) υ 3077, 2238, 1944, 1750, 1674 cm-1; H NMR δ 5.73-
1
5.20 (m, 2H), 4.89-4.64 (m, 4H), 3.80 (m, 3H), 3.39 (m, 3H),
3.28-2.42 (m, 3H), 2.40-1.92 (m, 4H), 1.87-1.07 (m, 13H).
MOM F u r a n 46. To a stirred solution of 0.31 g (0.77 mmol)
of allenone 45 protected from light in 8.0 mL of hexane was
added 0.65 g (0.39 mmol) of 10% AgNO3 on silica gel. After 7
h, the mixture was filtered and the solvent was removed under
reduced pressure. Flash chromatography on deactivated (5%
Et3N-hexane) silica gel (10% EtOAc-hexane) afforded 0.26
(24) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156.

4320 J . Org. Chem., Vol. 62, No. 13, 1997
Marshall and Sehon
g (84%) of furan 46 as a clear light yellow oil: IR (film) υ 3073,
2234, 1751, 1646 cm-1; 1H NMR δ 5.98-5.82 (m, 1H), 5.62 (m,
0.25H), 5.49 (m, 0.25H), 5.25 (m, 0.25H), 5.10 (d, 0.25H, J )
9.5 Hz), 4.92-4.60 (m, 4H), 3.79 (m, 3H), 3.37 (m, 3H), 3.27-
2.36 (m, 4H), 2.33-1.85 (m, 5H), 1.77-0.81 (m, 11H). Anal.
Calcd for C23H32O6: C, 68.29; H, 7.97. Found: C, 68.27; H,
8.03.
(m, 1H), 2.88 (d, 1H, J ) 10.6 Hz), 2.75-2.57 (m, 2H), 2.40-
2.22 (m, 2H), 1.93 (s, 3H), 1.88 (s, 3H), 1.77 (s, 3H), 1.61-1.18
(m, 3H).
This oil was diluted with 0.3 mL of THF and cooled to -78
°C. To this stirred solution was added 39.0 mL of 1.0 M
K-Selectride. After 15 min, the solution was diluted with
saturated NaHCO3 and CH2Cl2. The aqueous phase was
extracted with CH2Cl2, and the combined organic extracts were
dried over MgSO4. The solvent was removed under reduced
pressure to afford 9.0 mg (∼99%) of the syn alcohol 48 as a
solid white powder.
syn - a n d a n ti-(Z)-Vin yl F u r a n s 47/49. To a stirred
solution of 80 mg (0.20 mmol) of the MOM ether furan 46 in
4 mL of CH2Cl2 was added a catalytic amount of p-toluene-
sulfonic acid. The reaction mixture was stirred for 13 min and
then quenched with saturated NaHCO3. The aqueous layer
was extracted with CH2Cl2, the organic extracts were dried
over MgSO4, and the solvent was removed under reduced
pressure. Flash chromatography on deactivated (5% Et3N-
hexane) silica gel (5% EtOAc-hexane) gave 50 mg (73%) of
the (Z)-vinyl furans 47/49 as a clear yellow oil: IR (film) υ
(-)-Ru bifolid e (57). To a stirred solution of 43 mg (0.15
mmol) of the syn furyl alcohol 48 and 1.7 mg (1.5 µmol) of Pd-
(PPh3)4 in 3.0 mL of THF under a CO atmosphere was added
37 µL (0.32 mmol) of 2,6-lutidine. The solution was cooled to
0 °C, and 24 µL (0.17 mmol) of trifluoroacetic anhydride was
added. After complete ester formation (10 min), 0.11 mL (6.0
mmol) of H2O was added and the mixture was allowed to reach
rt and stir for 15 min. The solvent was then removed, and
the oil was diluted with 1 mL of hexane and a drop of CH2Cl2
to ensure a homogeneous solution. To this stirred solution,
protected from light, was added 51 mg (30 µmol) of 10% AgNO3
on silica. The mixture was stirred for an additional 3 h and
filtered, and the solvent was removed under reduced pressure.
Flash chromatography on deactivated (5% Et3N-hexane) silica
gel (10% EtOAc-hexane) afforded 23 mg (49%) of (-)-rubi-
folide as a fine white powder: 1H NMR δ 6.90 (bs, 1H), 6.06
(bs, 1H), 5.99 (s, 1H), 4.96 (dm, 1H, J ) 11.7 Hz), 4.90 (m,
1H), 4.88 (bs, 1H), 3.23 (t, 1H, J ) 11.7 Hz), 2.69 (dd, 1H, J )
11.7, 4.4 Hz), 2.60-2.30 (m, 4H), 2.09 (dm, 1H, J ) 14.7 Hz),
1.98 (bs, 3H), 1.92 (bs, 3H), 1.74 (bs, 3H), 1.64 (m, 1H), 1.17
(apparent dt, 1H, J ) 13.6, 3.7 Hz); 13C NMR δ 174.5, 152.1,
149.9, 149.3, 145.4, 132.8, 127.0, 117.4, 117.1, 113.8, 112.9,
78.7, 43.3, 39.5, 31.2, 30.5, 25.7, 20.0, 19.2, 9.5; mp 160 °C;
[R]D -38.3 (c 1.0, CH2Cl2). Anal. Calcd for C20H24O3: C, 76.89;
H, 7.74. Found: C, 76.94; H, 7.82.
1
3071, 2234, 1748, 1646 cm-1; H NMR δ 6.09 (s, 0.5H), 5.99
(s, 0.5H), 5.92 (s, 1H), 5.65 (m, 0.5H), 5.13 (d, 0.5H, J ) 11.0
Hz), 4.92 (m, 0.5H), 4.84 (m, 2.5H), 4.16 (t, 1H, J ) 11.7 Hz),
3.82 (s, 1.5H), 3.80 (s, 1.5H), 3.59-3.39 (m, 0.5H), 3.32 (m,
0.5H), 3.02 (m, 0.5H), 2.82 (dd, 0.5H, J ) 13.6, 7.0 Hz), 2.72-
2.46 (m, 2H), 2.38-1.88 (m, 7H), 1.76 (m, 3H), 1.61-1.00 (m,
3H). Anal. Calcd for C21H26O4: C, 73.66; H, 7.65. Found: C,
73.52, H, 7.71.
syn - a n d a n ti-F u r yl Alcoh ols 48 a n d 50. To a stirred
solution of 35 mg (0.10 mmol) of the carbonates 47/49 in 0.5
mL of MeOH was added a catalytic amount of potassium
carbonate. The mixture was stirred for 2.75 h and then diluted
with water and Et2O. The aqueous layer was extracted with
Et2O, the organic extracts were dried over MgSO4, and the
solvent was removed under reduced pressure. Flash chroma-
tography on deactivated (5% Et3N-hexane) silica gel (15%
EtOAc-hexane) gave 27 mg (96%) of a 1:1 mixture of syn and
anti alcohols 48 and 50 as a solid white powder. Syn isomer:
1H NMR δ 6.10 (s, 1H), 5.91 (s, 1H), 4.83 (m, 2H), 3.36 (dd,
1H, J ) 12.8, 1.8 Hz), 3.04 (m, 1H), 2.73 (dd, 1H, J ) 13.2,
7.33 Hz), 2.69-2.52 (m, 2H), 2.12-2.03 (m, 2H), 1.99 (m, 3H),
1.91 (s, 3H), 1.91 (s, 3H), 1.75 (s, 3H), 1.71-1.39 (m, 1H), 1.31-
1.15 (m, 2H); 13C NMR δ 150.6, 149.0, 147.6, 131.2, 117.2,
116.4, 112.3, 111.1, 85.0, 83.4, 62.1, 43.5, 40.3, 30.0, 29.6, 27.9,
19.9, 16.5, 19.6; mp 114-115 °C; [R]D +274.3 (c 0.37, CH2Cl2).
Anal. Calcd for C19H24O2: C, 80.24; H, 8.51. Found: C, 80.22;
H, 8.56. Anti isomer: 1H NMR δ 5.95 (s, 1H), 5.90 (s, 1H),
4.90 (bs, 1H), 4.84 (m, 1H), 4.31 (d, 1H, J ) 10.3 Hz), 4.02
(dd, 1H, J ) 12.1, 10.6 Hz), 3.34 (m, 1H), 2.77-2.50 (m, 2H),
2.31-1.96 (m, 2H), 1.91 (s, 3H), 1.89 (s, 3H), 1.76 (s, 3H), 1.55
(m, 1H), 1.40 (m, 1H), 1.26 (s, 1H).
Ack n ow led gm en t. Support for this work was pro-
vided by Grant R01-GM29475 from the National Insti-
tutes for General Medical Sciences. We thank Professor
Raymond Andersen for spectra of authentic rubifolide.
We are grateful to Dr. Michael Sabat of this department
for performing the X-ray analysis.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 6-25, 1H NMR spectra for key intermediates,
condensed Macromodel log file for ynone 28 with 3D structures
of the four lowest energy conformers, and an ORTEP diagram
for alcohol 48 (45 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
Syn F u r yl Alcoh ol 48. To a stirred solution of 9.0 mg (32.0
µmol) of the anti isomer 50 in 0.3 mL of CH2Cl was added
84.0 mg (0.96 mmol) of activated MnO2, and the mixture was
stirred overnight at rt. The mixture was filtered, and the
solvent was removed to afford the ynone 51 as a bright yellow
oil: 1H NMR δ 6.03 (s, 1H), 5.98 (s, 1H), 4.90 (m, 3H), 3.24
J O970360D