Photoactivated Tungsten Hexacarbonyl-Catalyzed Conversion of Alkynols to Glycals

Article abstract of DOI:10.1021/jo034813s

The photoactivated W(CO)₆/DABCO/THF system has been used for the formal endo-cyclization of alkynes to pyran rings. We found that the regioselectivity of ring closure depends on the relative configuration of the 3,5-dihydroxy-1-alkynes, as well

Full text of DOI:10.1021/jo034813s

P h otoa ctiva ted Tu n gsten Hexa ca r bon yl-Ca ta lyzed Con ver sion of
Alk yn ols to Glyca ls
Peter Wipf* and Thomas H. Graham
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
pwipf+@pitt.edu
Received J une 11, 2003
The photoactivated W(CO)6/DABCO/THF system has been used for the formal endo-cyclization of
alkynes to pyran rings. We found that the regioselectivity of ring closure depends on the relative
configuration of the 3,5-dihydroxy-1-alkynes, as well as, more decisively, on the type of O-protective
group. Oxygen substitution at the propargylic carbon slows the rate of alkyne insertion and allows
for dihydrofuran formation through exo-cyclization. In contrast, the use of bulky silyl ethers or
carbon substituents leads to dihydropyrans through endo-cyclization. Substrates bearing leaving
groups such as esters, phenols, or thiophenols at the propargylic site eliminate and thus represent
a limitation to the cycloisomerization methodology. Propargyl vinyl ethers will rearrange to give
dienals instead of glycals. 1,2-Wittig rearrangement products of dihydropyrans are readily prepared
and converted to complex bicyclic building blocks for organic synthesis.
SCHEME 1. Sin gle-Step Syn th esis of
In tr od u ction
Dih yd r ofu r a n s a n d Dih yd r op yr a n s fr om Alk yn ols
The use of transition metals to form cyclic oxacarbenes
was first demonstrated in 1970 by Chisholm and Clark.1
Subsequently, many middle to late transition metals
have been used to form cyclic carbenes.2,3 Prior to 1993,
the cycloisomerization of alkynols to cyclic enol ethers
was accomplished via a two-step procedure: first the
oxacarbene was formed, then the metal was removed
with a base to give the enol ether.4 McDonald and co-
workers introduced a method for the conversion of
alkynols 1 to 2,3-dihydrofurans 2 in one step (Scheme
1).5 In the same report, alkyne diol 3 was cyclized to a
9:1 mixture of dihydrofuran 4 and dihydropyran 5 in 59%
combined yield, suggesting that a one-step synthesis of
dihydropyrans would be possible.
of preformed W(CO)5‚THF complex was used to form
carbenes at room temperature. Further advances in the
tungsten methodology came with the transformation of
the dihydropyranilidene carbenes to dihydropyrans with
triethylamine.7 The two-step, one-pot process also used
a stoichiometric amount of preformed W(CO)5‚THF com-
plex. The resulting mixture was then treated with
triethylamine to induce the release of the metal and
afford the dihydropyran in modest yield. This process was
applied to the iterative synthesis of oligosaccharides.8 The
cycloisomerization methodology was further improved by
the discovery that heating the reaction mixture to 50-
65 °C while constantly irradiating at 350 nm in the
presence of triethylamine and catalytic W(CO)6 (25 mol
%) gave glycal 7 in excellent yield (Scheme 2).9 Control
experiments indicated that constant irradiation was
indeed required. Irradiation is known to decomplex
amines from W(CO)5, thus providing an open coordina-
tion site for the alkyne.10
In 1996, the McDonald group found tungsten to be
superior to molybdenum and chromium for the formation
of dihydropyranilidene carbenes.6 A stoichiometric amount
(1) (a) Chisholm, M. H.; Clark, H. C. J . Chem. Soc., Chem. Commun.
1970, 763. (b) Chisholm, M. H.; Clark, H. C. J . Am. Chem. Soc. 1972,
94, 1532. (c) Chisholm, M. H.; Clark, H. C. Acc. Chem. Res. 1973, 6,
202.
(2) (a) Clark, H. C.; Manzer, L. E. J . Organomet. Chem. 1973, 47,
C17. (b) Oguro, K.; Wada, M.; Okawara, R. J . Organomet. Chem. 1978,
159, 417. (c) Bruce, M. I.; Swincer, A. G.; Thomson, B. J .; Wallis, R. C.
Aust. J . Chem. 1980, 33, 2605. (d) Curtis, P. J .; Davies, S. G. J . Chem.
Soc., Chem. Commun. 1984, 747. (e) Parlier, A.; Rudler, H. J . Chem.
Soc., Chem. Commun. 1986, 514. (f) Do¨tz, K. H.; Sturm, W.; Alt, H. G.
Organometallics 1987, 6, 1424. (g) Hoover, J . F.; Stryker, J . M. J . Am.
Chem. Soc. 1990, 112, 464. (h) O’Connor, J . M.; Pu, L.; Rheingold, A.
L. J . Am. Chem. Soc. 1990, 112, 6232. (i) Le Bozec, H.; Ouzzine, K.;
Dixneuf, P. H. Organometallics 1991, 10, 2768. (j) Werner, H.; Knaup,
W.; Schulz, M. Chem. Ber. 1991, 124, 1121. (k) Stang, P. J .; Huang, Y.
H. J . Organomet. Chem. 1992, 431, 427.
(3) Marten, D. F. J . Chem. Soc., Chem. Commun. 1980, 341.
(4) (a) Casey, C. P.; Anderson, R. L. J . Chem. Soc., Chem. Commun.
1975, 895. (b) Fischer, E. O.; Plabst, D. Chem. Ber. 1974, 107, 3326.
(5) McDonald, F. E.; Connolly, C. D.; Gleason, M. M.; Towne, T. B.;
Treiber, K. D. J . Org. Chem. 1993, 58, 6952.
(7) McDonald, F. E.; Zhu, H. Y. H. Tetrahedron 1997, 53, 11061.
(8) McDonald, F. E.; Zhu, H. Y. H. J . Am. Chem. Soc. 1998, 120,
4246.
(9) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J . Am. Chem. Soc. 2000,
122, 4304.
(6) McDonald, F. E.; Bowman, J . L. Tetrahedron Lett. 1996, 37, 4675.
10.1021/jo034813s CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/16/2003
8798
J . Org. Chem. 2003, 68, 8798-8807

Conversion of Alkynols to Glycals
SCHEME 2. Cycloisom er iza tion of Alk yn ols w ith
Ca ta lytic W(CO)6
SCHEME 3. Tem p er a tu r e Dep en d en ce of
Regioselectivity
F IGURE 1. (A) Dewar-Chatt-Duncanson model for transi-
tion metal-alkyne coordination. (B) Isomerization to the
vinylidene is driven by the repulsive interaction between the
filled d-orbitals of the metal and the π-orbitals of the alkyne
ligand that are orthogonal to the π-orbitals shown in part A.
unique because it possesses a propargylic substituent
that is not a silyl ether.
The participation of the exo-cyclization pathway can
be rationalized by considering the mechanism of vi-
nylidene formation (Scheme 4).14 Initial complexation of
the coordinatively unsaturated metal to alkyne 11 ac-
cording to the Dewar-Chatt-Duncanson model gives the
η2-complex (12a ) that can also be depicted as the met-
allocyclopropene (12b) (Figure 1A).15 Cyclization of 12
could give the exo-cyclization product 13. Alternatively,
12 can form the vinylidene 15 via direct hydride trans-
fer16 or oxidative addition followed by the equivalent of
a 1,3-hydride shift.17 The alkyne-to-vinylidene rearrange-
ment of 12 to 15 is promoted by an unfavorable four-
electron, two-centered interaction between the filled
d-orbitals of the metal and the orthogonal π-orbital of
the alkyne (Figure 1B).18 Cyclization of 15 gives the endo-
cyclization product 17 via the metal-stabilized carbene
16. Competitive cyclization of the vinylidene and the η2-
alkyne has been demonstrated with Fe(II)2d and has been
suggested for W(CO)5‚THF with carbon nucleophiles.19
McDonald and Morokuma recently published a com-
putational study of the cycloisomerization of 4-pentyn-
1-ol.20 The activation barriers for endo- and exo-cycliza-
tion without catalyst were found to be 50-55 kcal/mol.
The computational results suggest that the barrier for
exo-cycloisomerization is not significantly affected by the
presence of catalyst and remains at 47 kcal/mol. In the
presence of catalyst, the endo-cycloisomerization progresses
through a rate-determining barrier of 26.4 kcal/mol that
involves the migration of the hydride to afford the
vinylidene intermediate. The 20.1 kcal/mol difference
between exo- and endo-cycloisomerization pathways sug-
gests the latter will be preferred. The study did not
account for the participation of the amine base in the
SCHEME 4. A Mech a n ism for Alk yn e In ser tion
th a t Exp la in s en d o- a n d exo-Cycliza tion P r od u cts
Later findings demonstrated that using DABCO as the
base gives similar results while allowing the amount of
W(CO)6 to be lowered to 10 mol %.11 Currently, the
standard reaction conditions for the cycloisomerization
of 4-alkyn-1-ols to 3,4-dihydro-2H-pyrans are triethyl-
amine or DABCO in the presence of 5-25 mol % W(CO)6
at 50-65 °C under constant irradiation, using THF as a
solvent.12
The majority of substrates that have been isomerized
to dihydropyrans demonstrate excellent selectivity for a
formal endo-cyclization pathway. There are indications
that the relative configuration of the carbon backbone
can have a minor influence on the ratio of exo- and endo-
cyclization products.9 Experimental data also indicate
that an exo-cyclization pathway to the 2-methylenefuran
competes with the endo-cyclization pathway. The benzyl
ether 8 was reported to give a temperature-dependent
(14) (a) Bruce, M. I. Chem. Rev. 1991, 91, 197. (b) Bruce, M. I.;
Swincer, A. G. Adv. Organomet. Chem. 1983, 22, 59.
(15) (a) Dewar, M. J . S. Bull. Soc. Chim. Fr. 1951, 18, C71. (b) Chatt,
J .; Duncanson, L. A. J . Chem. Soc. 1953, 2939. (c) Weyershausen, B.;
Do¨tz, K. H. Eur. J . Inorg. Chem. 1999, 1057.
(16) Silvestre, J .; Hoffmann, R. Helv. Chem. Acta 1985, 68, 1461.
(17) Wolf, J .; Werner, H.; Serhadli, O.; Ziegler, M. L. Angew. Chem.,
Int. Ed. Engl. 1983, 22, 414.
ratio of endo- (9) and exo- (10) products (Scheme 3).13
A
(18) (a) Connelly, N. G.; Geiger, W. E.; Lagunas, M. C.; Metz, B.;
Rieger, A. L.; Rieger, P. H.; Shaw, M. J . J . Am. Chem. Soc. 1995, 117,
12202. (b) Birdwhistell, K. R.; Burgmayer, S. J . N.; Templeton, J . L.
J . Am. Chem. Soc. 1983, 105, 7789. (c) Templeton, J . L.; Winston, P.
B.; Ward, B. C. J . Am. Chem. Soc. 1981, 103, 7713.
(19) For exo/endo-selectivity with carbon nucleophiles in W(CO)5‚
THF systems, see: (a) Kusama, H.; Yamabe, H.; Iwasawa, N. Org. Lett.
2002, 4, 2596. (b) Iwasawa, N.; Maeyama, K.; Kusama, H. Org. Lett.
2001, 3, 3871. (c) Maeyama, K.; Iwasawa, N. J . Am. Chem. Soc. 1998,
120, 1928.
yield was not reported. Coincidentally, substrate 8 is
(10) Kirtley, S. W. Comprehensive Organometallic Chemistry; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford,
UK, 1982; Vol. 3, p 1079.
(11) McDonald, F. E.; Reddy, K. S. J . Organomet. Chem. 2001, 617-
618, 444.
(12) (a) McDonald, F. E.; Reddy, K. S. Angew. Chem., Int. Ed. 2001,
40, 3653. (b) Cutchins, W. W.; McDonald, F. E. Org. Lett. 2002, 4, 749.
(c) McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979.
(13) McDonald, F. E. Chem. Eur. J . 1999, 5, 3103.
(20) Sheng, Y.; Musaev, D. G.; Reddy, K. S.; McDonald, F. E.;
Morokuma, K. J . Am. Chem. Soc. 2002, 124, 4149.
J . Org. Chem, Vol. 68, No. 23, 2003 8799

Wipf and Graham
SCHEME 5a
SCHEME 6a
a
Reaction conditions: (a) W(CO)6, hν, DABCO, THF, 14 h, 56
a
°C.
Reaction conditions: (1) 19a /19b: (a) allylMgBr, THF (71%);
(b) TBS-Cl, imidazole, DMF (95%) or TES-Cl, imidazole, DMF
(98%); (c) O3, CH2Cl2:MeOH (1:1) then DMS (89%); (d) TMS-
acetylene, n-BuLi, THF (92%); (e) TBAF, THF (92%). (2) 19c/19d :
(a) crotyl bromide, CrCl2, THF (70%); (b) TBS-Cl, imidazole, DMF
(95%); (c) O3, CH2Cl2:MeOH (1:1) then DMS (58%); (d) TMS-
acetylene, n-BuLi, THF (90%); (e) TBAF, THF (63%). (3) 19e/19f:
(a) prenyl bromide, In, DMF (95%); (b) TBS-OTf, 2,6-lutidine,
CH2Cl2; (c) O3, CH2Cl2:MeOH (1:1) then DMS (71%, 2 steps); (d)
TMS-acetylene, n-BuLi, THF; (e) TBAF, THF (92%, 2 steps). (4)
19g/19h : (a) (4S)-4-benzyl-3-propionyl-2-oxazolidinone, n-Bu2B-
OTf, Et3N, CH2Cl2 (82%); (b) Me(MeO)NH2Cl, Me3Al, CH2Cl2; (c)
TBS-OTf, 2,6-lutidine, CH2Cl2 (89%, 2 steps); (d) DiBAL-H, THF
(75%); (e) (i) TMS-acetylene, n-BuLi, THF (88%), (ii) TBAF, THF
(99%).
When 19a was subjected to the photoactivated W(CO)6/
DABCO/THF conditions, NMR analysis (1H/13C/DEPT
135) of the crude reaction indicated that 20a was formed
exclusively. The 3,5-anti diol 19b resulted in the exclusive
formation of the endo-cyclic product 21b in 50% yield
after chromatography on silica gel (Scheme 6).24
To exclude the possibility that the observed selectivity
arose from unforeseen variations in the experimental
conditions, a 1:1 mixture of alkyne-diols 19a and 19b,
W(CO)6, and DABCO in THF was irradiated for 14 h at
56 °C. The 1H NMR spectrum of the crude reaction
mixture indicated the presence of furan 20a and dihy-
dropyran 21b in a ratio of 1.3:1.0. 13C NMR analysis
indicated only 18 signals in addition to DABCO and
tungsten ligand signals.25 Purification by silica gel chro-
matography confirmed the presence of compounds 20a
and 21b.
transition states. The results from our studies (vide infra)
suggest that the regioselectivity of the cyclization is
substrate dependent.
Resu lts a n d Discu ssion
In general, cyclization substrates containing propar-
gylic silyl ethers are considerably more frequently used
than substrates containing propargylic hydroxyl groups.
McDonald and co-workers demonstrated that a related
system with a propargylic benzyl ether gave varying
amounts of exo- and endo-cyclization products (Scheme
3).13 The latter was slightly favored at elevated temper-
atures. The McDonald group also observed that the
relative configuration of substituents on the carbon
backbone can affect the rate and regioselectivity of the
cyclization process.9 To test the dependence of the regi-
oselectivity on the nature of the propargylic oxygen
functional group and the relative configuration of the
carbon backbone, model compounds 19c-h were synthe-
sized (Scheme 5). Regioselective derivatization of the less
sterically hindered hydroxyl group of the 3,5-diols or
derivatization of the 1-trimethylsilyl, 5-O-trialkylsilyl
ether intermediate was accomplished by using standard
synthetic strategies.26 The results of the cyclization
As part of our synthetic approaches toward the poly-
ether marine natural products bistramide A and leucas-
candrolide A,21,22 we considered the tungsten-catalyzed
cycloisomerization of alkynols as a potential methodology
for installing the pyran segments in these target mol-
ecules. Attractive features of the photoactivated W(CO)6/
DABCO/THF system are the relatively mild conditions
and the reportedly high selectivity for the formal endo-
cyclization product. During the course of our studies, we
discovered that the regioselectivity of ring closure de-
pends on the relative configuration of the 3,5-dihydroxy-
1-alkynes. In addition, we were able to extend the
cyclization methodology by incorporating groups that
allow further derivatization of the dihydropyran system.
Our studies also revealed some limitations of the meth-
odology.
Synthesis of our first model system began with the
treatment of isovaleraldehyde with allylmagnesium bro-
mide in THF to afford the homoallylic alcohol in 71%
yield (Scheme 5). Protection of the alcohol as the TBS-
or TES-ether proceeded in excellent yield. Ozonolysis of
the terminal olefin under buffered conditions and treat-
ment of the resulting aldehyde with lithium trimethyl-
silyl acetylide afforded the corresponding propargylic
alcohol in good yields. The diastereomers were separated
prior to silyl deprotection to give the alkynols 19a and
19b.23
(23) Relative configurations for all diols were assigned by using 13
C
NMR analysis of the acetonides (2,2-dimethyl-1,3-dioxanes): (a) Rych-
novsky, S. D.; Skalitzky, D. J . Tetrahedron Lett. 1990, 31, 945. (b)
Evans, D. A.; Rieger, D. L.; Gage, J . R. Tetrahedron Lett. 1990, 31,
7099.
(24) Using a stoichiometric amount of W(CO)6 afforded 21b in lower
yield. Specifically, irradiating a mixture of 19b (50.0 mg, 0.320 mmol,
1.0 equiv), W(CO)6 (112 mg, 0.318 mmol, 1.0 equiv), and DABCO (72.0
mg, 0.638 mmol, 2.0 equiv) in THF (3.0 mL) for 14 h at 55 °C afforded
21b in 40% yield. Irradiating a mixture of 21b (25.0 mg, 0.160 mmol,
1.0 equiv), W(CO)6 (14.0 mg, 0.040 mmol, 0.3 equiv), and DABCO (9.0
mg, 0.080 mmol, 0.5 equiv) in THF (1.6 mL) for 14 h at 55 °C led to
the re-isolation of 21b in 83% yield.
(25) The additional tungsten ligand and DABCO signals in the crude
spectra: 13C (CDCl3, 75 MHz) δ 202.1(C), 199.4 (C), 57.0 (CH2), 48.0
(CH2), 47.2 (CH2).
(21) Wipf, P.; Uto, Y.; Yoshimura, S. Chem. Eur. J . 2002, 8, 1670.
(22) (a) Wipf, P.; Graham, T. H. J . Org. Chem. 2001, 66, 3242. (b)
Wipf, P.; Reeves, J . T. Chem. Commun. 2002, 2066.
(26) See the Supporting Information.
8800 J . Org. Chem., Vol. 68, No. 23, 2003

Conversion of Alkynols to Glycals
TABLE 1. en d o/exo-Selectivity in Cycliza tion s of Alk yn ols
entry
substrate
R1
)
R2
)
R3
)
R4
)
20:21
yield [%]a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
19c
19d
19e
19f
19g
19h
19i
19j
19k
19l
19m
19n
19o
19p
19q
19r
19s
19t
OH
H
OH
H
OH
H
H
H
OH
H
OH
H
OH
OTBDPS
Ot-Bu
OBn
H
OMe
H
OCH2CCTIPS
OTBDPS
OTIPS
H
OCH2CCTIPS
H
Me
H
H
Me
Me
Me
Me
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
1:1
1:0
2:1
1:0
1:2
1:0
1:30
1:4
6:1
0:1
8:1
0:1
8:1
0:1
1:4
49
49
50
44
39
46
15
b
54
67
b
14-46
25
Me
Me
Me
H
H
H
H
H
H
H
H
H
OBn
H
OCH2CCTIPS
H
H
H
H
Me
Me
Me
Me
Me
Me
25
H
49 + (43)c
(53)c
32
OCH2CCTIPS
H
OBn
H
1:0
1:0
(31)c
61
19u
OBn
a
b
Combined yield after purification on SiO2. Decomposed when purification on SiO2 was attempted. c Starting material (%) was
recovered.
could destabilize the π-complex relative to the vinylidene
complex, thus increasing the rate of alkyne insertion
(Table 1, entry 2 vs 14). The regioselectivity could also
be a result of the carbon chain conformation. Methyl
substitution at the C4-position of the carbon backbone
(Table 1, entries 1 and 3 vs 19b) leads to a loss in endo-
selectivity. If cyclization requires a less populated con-
formation, then degradative pathways can compete and
in some cases, starting material is recovered in low yield
(Table 1, entries 16 and 18).
To test our hypothesis that oxygen substitution at the
propargylic carbon allows for chelation with the metal
complex, slowing the rate of alkyne insertion and allow-
ing for exo-cyclization, we turned to the chemistry
developed by Marshall and co-workers that allows for
easy modifications at the propargylic position via mesy-
late displacement.28 The propargylic alcohol 22 was first
converted to the mesylate, which was subjected to InI,
Pd(OAc)2, PPh3, and crotonaldehyde in THF and HMPA
for conversion to the allylic-homopropargylic alcohol
(Scheme 7). Acylation with pivaloyl chloride and desily-
lation with TBAF gave the desired substrate 23 in 47%
yield over 4 steps. The relative configuration of 23 was
assigned based on the precedent established by Marshall
and co-workers. Tungsten-mediated cyclization of this
F IGURE 2. The rate of competing pathways may account for
the regioselectivity of the cyclization process.
reactions are summarized in Table 1. Ratios were derived
from integration of the vinyl proton signals in the 1H
NMR spectra of the crude reaction mixtures after a rapid
filtration through a short plug of silica gel.
These results suggest a strong correlation between the
substituent on the propargylic oxygen atom and the
regioselectivity of the cyclization. Cyclization of the
initially formed π-complex to the furan may compete with
alkyne insertion (Figure 2). Cyclization of the π-complex
is known to compete with alkyne insertion in other metal-
based systems,3 but has not, to our knowledge, been
clearly demonstrated in the photoactivated W(CO)6/
DABCO/THF systems with oxygen nucleophiles.19 Com-
putational results for the cyclization of 4-pentyn-1-ol
suggest that the endo-cyclization is energetically pre-
ferred.20 Our experimental results suggest that the
regioselectivity of the cyclization is substrate dependent.
More specifically, oxygen substitution at the propargylic
carbon may allow for chelation between the metal and
the propargylic oxygen, slowing the rate of alkyne inser-
tion and allowing for exo-cyclization (Table 1, entries 9
and 11 vs 7 and 8).27 Alternatively, steric compression
(27) An internal alkyne did not give any products of cyclization.
Irradiating a mixture of (6S*,4R*)-2-methylundec-7-yne-4,6-diol (42.7
mg, 0.215 mmol, 1.0 equiv), W(CO)6 (38.0 mg, 0.108 mmol, 0.5 equiv),
and DABCO (24.0 mg, 0.213 mmol, 1.0 equiv) in distilled and degassed
THF (2.1 mL) for 16 h at 55 °C resulted in the recovery of the starting
material (96%). Irradiating a mixture of (6R*,4R*)-2-methylundec-7-
yne-4,6-diol (58.3 mg, 0.294 mmol, 1.0 equiv), W(CO)6 (52.0 mg, 0.148
mmol, 0.5 equiv), and DABCO (33.0 mg, 0.293 mmol, 1.0 equiv) in
distilled and degassed THF (2.1 mL) for 16 h at 55 °C resulted in the
recovery of the starting material (87%). No cyclization product was
evident in the crude 1H NMR spectra for either trial.
(28) (a) Marshall, J . A.; Grant, C. M. J . Org. Chem. 1999, 64, 8214.
(b) Marshall, J . A.; Chobanian, H. R. J . Org. Chem. 2000, 65, 8357. (c)
Marshall, J . A. Chem. Rev. 2000, 100, 3163. (d) Marshall, J . A.;
Chobanian, H. R.; Yanik, M. M. Org. Lett. 2001, 3, 3369.
J . Org. Chem, Vol. 68, No. 23, 2003 8801

Wipf and Graham
SCHEME 7a
TABLE 2. Elim in a tion a s a Sid e Rea ction in
Cycloisom er iza tion Rea ction s
entry substrate
R1
)
R2 ) R3 ) product yield [%]
1
2
3
4
5
19v
19w
19x
19y
19z
OAc
H
O2CCH2COCH3
H
H
Me
28
28
28
11
13
25
a
OAc Me
H
PhS
H
H
H
p-OC6H4CH2OH H
b
a
b
Starting material decomposed. Starting material decom-
posed; 1H NMR analysis of the crude reaction mixture showed
4-hydroxymethylphenol.
a
Reaction conditions: (a) MsCl, Et3N, CH2Cl2 (95%); (b) cro-
tonaldehyde, InI, Pd(OAc)2, PPh3, THF, HMPA; (c) Piv-Cl, DMAP,
Et3N; (d) TBAF, THF (49%, 3 steps); (e) W(CO)6, hν, DABCO, THF
(81%).
SCHEME 9a
SCHEME 8a
a
Reaction conditions: (a) W(CO)6, hν, DABCO, THF, 4 h, 60
°C (65%).
enyne 28 in low yield as the only isolated product (Table
2, entries 1-3). Phenol and thiophenol substitution led
to decomposition and recovery of the phenol (Table 2,
entries 4 and 5). The low yields and decomposition noted
for substrates 19v-z represent a limitation of the pho-
toactivated W(CO)6/DABCO/THF system and may ex-
plain some of the lower yields in Table 1.30 Propargylic
alcohol derivatives have been used for the preparation
of R,â-unsaturated Fischer carbenes, through a â-elimi-
nation of the intermediate Fischer carbene.31 Interest-
ingly, when vinyl ether 29 was subjected to the reaction
conditions, dienal (2E,4E)-30 was formed as the major
isomer in 65% yield (Scheme 9).32 Control experiments33
indicated that photoactivated tungsten hexacarbonyl and
DABCO are required for the rearrangement, suggesting
a vinylidene intermediate.34 The abbreviated reaction
time also indicates that the rearrangement is preferred
over cyclization, thus representing a mild entry into
functionalized dienal systems.
a
Reaction conditions: (a) MsCl, DIEA, CH2Cl2 (95%); (b)
crotonaldehyde, InI, Pd(OAc)2, PPh3, THF, HMPA; (c) Piv-Cl,
DMAP, Et3N; (d) HF‚pyridine, pyridine, THF, then TBAF, THF
(36%, 3 steps); (e) W(CO)6, hν, DABCO, THF (70%).
compound provided dihydropyran 24 in 81% yield. Analo-
gous conditions were used to convert the anti-diol deriva-
tive 25 into dihydropyran 27 (Scheme 8). After 14 h at
40 °C, dihydropyran 27 was formed in 40% yield and
alkynol 26 was recovered in 55% yield. Even when
substrate 26 was subjected to cyclization conditions for
23 h at 40 °C, TLC analysis indicated starting alkynol
remained. Irradiation for an additional 12-h period at 60
°C finally consumed the starting alkynol and gave
dihydropyran 27 in a slightly lower yield (70%) than
diastereomer 24. The products for the competing exo-
We also briefly studied the further functionalization
of the dihydropyran framework 21 through 1,2-Wittig
rearrangements.35 After cycloisomerization of diol 19b,
1
cyclization pathway were not detected in the crude H
NMR in any of these trials, confirming that propargylic
oxygen substituents display a remarkably different re-
activity than carbon-substituted analogues. In addition
to chelation effects, inherent conformational differences
between the different substrates may also be contributing
to determining the dominant reaction pathways.
Our model studies also revealed some limitations of
the cycloisomerization methodology. The photoactivated
W(CO)6/DABCO/THF system proved to be incompatible
with substrates that possess a leaving group at the
propargylic carbon.29 Esters at this site gave the volatile
(30) Cutchins and McDonald recently reported low yields (30%) for
a
substrate bearing
a p-methoxyphenylamine at the propargylic
position. See ref 12b.
(31) (a) Do¨tz, K. H.; Paetsch, D.; Le Bozec, H. J . Organomet. Chem.
1999, 589, 11.
(32) (a) The yield includes approximately 6% of the (2Z,4E)-30
isomer. (b) For W(CO)5‚THF-catalyzed cyclization of aromatic ene-
yne systems see: Maeyama, K.; Iwasawa, N. J . Org. Chem. 1999, 64,
1344.
(33) Irradiating a solution of the propargyl vinyl ether in THF with
W(CO)6 does not give the product. Subsequent addition of DABCO to
this photoactivated reaction mixture at room temperature leads to a
rapid (1 h) formation of the unsaturated aldehyde. DABCO alone or
irradiation with DABCO does not promote the rearrangement.
(34) A chromium(0) pentacarbonyl vinylidene intermediate has been
proposed for the [3.3]-sigmatropic rearrangement of 1-acyloxy-R,â-
unsaturated Fischer carbenes to 3-acyloxy-1-alkynes. So¨derberg, B. C.;
O’Neil, S. N.; Chisnell, A. C.; Liu, J . Tetrahedron 2000, 56, 5037.
(35) Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann. Chem.
1997, 1275.
(29) (a) For applications of propargylic leaving groups in the
synthesis of furan systems using molybdenum hexacarbonyl, see:
McDonald, F. E.; Gleason, M. M. J . Am. Chem. Soc. 1996, 118, 6648.
(b) For similar results involving propargylic leaving groups in ruthenium-
catalyzed isomerizations see: Trost, B. M.; Rhee, Y. H. J . Am. Chem.
Soc. 2002, 124, 2528.
8802 J . Org. Chem., Vol. 68, No. 23, 2003

Conversion of Alkynols to Glycals
SCHEME 10a
momethyldimethylchlorosilane in the presence of imida-
zole in 49% yield. Radical cyclization of the resulting
bromodimethylsilane40 followed by Tamao oxidation41
provided compound 33 in 20% yield.42 The formation of
products 31, 32, and 33 demonstrates the ready access
to complex carbo- and heterobicyclic scaffolds from
alkynols 19 through use of the tungsten cycloisomeriza-
tion methodology.
a
Reaction conditions: (a) W(CO)6, hν, DABCO, THF, 56 °C
(53%); (b) 3-bromo-1-triisopropylsilanylprop-1-yne, n-Bu4NHSO4,
50% NaOH, toluene (94%); (c) n-BuLi, TMEDA, THF, (78%).
Con clu sion s
SCHEME 11a
Our experimental results suggest that in the tungsten-
catalyzed cyloisomerization reaction of alkynols, the ratio
of endo- to exo-products for substrates substituted at the
propargylic position is strongly substituent dependent.
Most likely as a consequence of chelation to the metal
complex, oxygen substitution at the propargylic carbon
slows the rate of alkyne insertion and allows for dihy-
drofuran formation through exo-cyclization. In contrast,
the use of bulky silyl ethers or carbon substituents leads
to dihydropyrans through endo-cyclization. Substrates
bearing leaving groups such as esters, phenols, or thiophe-
nols at the propargylic site represent a limitation to the
cycloisomerization methodology. Such substrates are not
compatible with the experimental conditions, providing
elimination rather than cyclization products. In addition,
we have found that propargyl vinyl ethers will rearrange
to give dienals instead of cyclizing to the corresponding
glycals. While dihydrofurans 20 are difficult to function-
alize further due to their chemical lability, 1,2-Wittig
rearrangement products of dihydropyrans 21 are readily
obtained and converted to interesting bicyclic building
blocks for organic synthesis.
a
Reaction conditions: (a) 4-nitrophenylisocyanate, DBU, CH2Cl2,
rt (88%); (b) TBAF, THF (47%).
SCHEME 12a
a
Reaction conditions: (a) TBAF, THF (70%); (b) bromometh-
yldimethylchlorosilane, imidazole, DMF (49%); (c) Bu3SnH, AIBN,
PhH then KF, KHCO3, H2O2, MeOH/THF (1:1) (20%).
Exp er im en ta l Section
Gen er a l Deta ils. All moisture-sensitive reactions were
performed using syringe-septum techniques under an N2
atmosphere and all glassware was dried in an oven at 140 °C
for more than 4 h prior to use. THF and ethyl ether were
distilled from sodium/benzophenone ketyl. Methylene choride
and toluene were filtered through activated alumina prior to
use. W(CO)6 was purchased from Acros or Strem. DABCO was
sublimed under vacuum.
Gen er a l P r oced u r e for th e Tu n gsten -Ca ta lyzed Cy-
cloisom er iza tion of Alk yn ols. Substrate 19c (59.0 mg, 0.350
mmol, 1.0 equiv) was transferred as a solution in freshly
distilled THF (2.5 mL + 2.5 mL wash) into a flame-dried
reaction flask. The sample was concentrated on the rotary-
evaporator and dried under high vacuum (<1.0 mmHg) for
more than 1 h. Freshly distilled and degassed THF (5.0 mL,
liquid nitrogen freeze-pump-thaw, 3 cycles) was added via
cannula. After the addition of W(CO)6 (61.0 mg, 0.170 mmol,
0.5 equiv) and sublimed DABCO (83.0 mg, 0.740 mmol, 2.1
equiv) under a positive stream of nitrogen, the mixture were
irradiated under nitrogen by a medium-pressure mercury lamp
with a Pyrex filter for 14 h at an oil bath temperature of 56
°C to give a yellow solution. After 14 h, TLC analysis indicated
alkylation36 of the dihydropyran intermediate 21b with
3-bromo-1-triisopropylsilanylprop-1-yne37 and deproto-
nation with n-BuLi and TMEDA in THF gave 31, the
product of a stereoselective 1,2-Wittig rearrangement, in
78% yield (Scheme 10). For an unambiguous assignment
of the relative configuration of this compound, 31 was
exposed to 4-nitrophenylisocyanate in CH2Cl2 and cata-
lytic DBU38 to afford the corresponding 4-nitrophenyl-
isocyanate in 88% yield (Scheme 11). Deprotection with
TBAF in THF gave the oxazolidinone 32 in 47% yield.39
Crystallization from pentane/CH2Cl2 provided crystals
that were suitable for assigning the structure of the 1,2-
Wittig product 31.
During our investigations into the stereochemical
assignment of the product from the 1,2-Wittig rearrange-
ment, a radical cascade reaction afforded the interesting
bicyclic structure 33 (Scheme 12). Deprotection of 31 with
TBAF in THF gave the terminal acetylene in 70% yield.
The propargylic alcohol was then derivatized with bro-
(40) (a) Bogen, S.; Gulea, M.; Fensterbank, L.; Malacria, M. J . Org.
Chem. 1999, 64, 4920. (b) J ournet, M.; Malacria, M. J . Org. Chem.
1992, 57, 3085. (c) Go´mez, A. M.; Lo´pez, J . C.; Fraser-Reid, B. J . Org.
Chem. 1995, 60, 3859. (d) Crimmins, M. T.; O’Mahony, R. J . Org. Chem.
1989, 54, 1157.
(41) (a) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organome-
tallics 1983, 2, 1694. (b) Tamao, K.; Ishida, N.; Kumada, M. J . Org.
Chem. 1983, 48, 2120.
(36) (a) Liang, J .; Hoard, D. W.; Van Khau, V.; Martinelli, M. J .;
Moher, E. D.; Moore, R. E.; Tius, M. A. J . Org. Chem. 1999, 64, 1459.
(b) Freedman, H. H.; Dubois, R. A. Tetrahedron Lett. 1975, 16, 3251.
(37) J ones, G. B.; Wright, J . M.; Plourde, G. W., II; Hynd, G.; Huber,
R. S.; Mathews, J . E. J . Am. Chem. Soc. 2000, 122, 1937.
(38) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt,
K. W.; Kranich, R.; Vega, J . A. J . Am. Chem. Soc. 2002, 124, 2233.
(39) For a similar transformation that afforded a 4-methylenetet-
rahydro-1,3-oxazine-2-one, see: Tamaru, Y.; Kimura, M.; Tanaka, S.;
Kure, S.; Yoshida, Z. Bull. Chem. Soc. J pn. 1994, 67, 2838.
(42) The assignment of the relative configuration of this compound
is based on the COSY/NOESY 1H NMR analysis of the bis(3,5-
dinitrobenzoyl) derivative. See the Supporting Information.
J . Org. Chem, Vol. 68, No. 23, 2003 8803

Wipf and Graham
that the starting material had been consumed and the sample
was concentrated. The resulting residue was diluted with ethyl
ether and filtered through a plug of SiO2 (2 cm in a pasteur
pipet, ethyl ether wash). The combined filtrate was concen-
trated and analyzed by 1H and 13C. The product ratios were
determined by integration of the vinyl proton signals in the
1H NMR spectra of the crude reaction mixture and indicated
a product ratio of 20c:21c of 1:1. Purification by chromatog-
raphy on SiO2 (100:1 to 95:5, hexanes/Et3N) gave an insepa-
rable mixture of the title compounds (29.0 mg, 49%) as a
colorless, unstable solid.43 20c: 1H NMR (CD2Cl2) δ 4.17 (s,
1H), 3.96 (t, 1H, J ) 1.6 Hz); 13C NMR (CD2Cl2) δ 83.1, 79.0,
47.7, 43.6, 25.6, 23.9, 22.1, 14.1. 21c: 1H NMR (CD2Cl2) δ 6.36
(d, 1 H, J ) 6.1 Hz), 4.71 (dd, 1H, J ) 6.1, 2.2 Hz); 13C NMR
(CD2Cl2) δ 145.2, 105.7, 78.1, 69.5, 41.8, 41.7, 24.5, 21.6, 24.4,
14.8.
(3R*,5R*)-5-Isob u t yl-2-m et h ylen et et r a h yd r ofu r a n -3-
ol (20a ). According to the general procedure, 19a (49.0 mg,
0.310 mmol, 1.0 equiv), tungsten hexacarbonyl (56.0 mg, 0.160
mmol, 0.5 equiv), and DABCO (70.0 mg, 0.630 mmol, 2.0 equiv)
in freshly distilled and degassed THF (5.0 mL) were irradiated
for 14 h at 56 °C to give a yellow solution that was filtered
through a plug of SiO2 (ethyl ether wash) and the filtrate was
concentrated. Due to the instability of 20a , the crude reaction
mixture was used to acquire spectral data:43 1H NMR δ 4.53-
4.47 (m, 2 H), 4.23 (s, 1 H), 3.99 (s, 1 H), 2.03 (ddd, 1 H, J )
12.9, 5.1, 2.0 Hz), 1.80-1.52 (m, 3 H), 1.31 (ddd, 1 H, J ) 13.4,
7.7, 5.4 Hz), 0.92 (d, 3 H, J ) 6.6 Hz), 0.91 (d, 3 H, J ) 6.7
Hz); 13C NMR δ 166.0, 81.3, 79.6, 71.7, 44.6, 40.9, 25.4, 23.2,
22.6.
(2R*,4S*)-2-Isobu tyl-3,4-d ih yd r o-2H-p yr a n -4-ol (21b).
According to the general procedure, 19b (198.8 mg, 1.272
mmol, 1.0 equiv), tungsten hexacarbonyl (112 mg, 0.318 mmol,
0.25 equiv), and DABCO (143.0 mg, 1.268 mmol, 1.0 equiv) in
freshly distilled and degassed THF (12.0 mL) were irradiated
for 24 h at 50 °C to give a yellow solution. Purification by
chromatography on SiO2 (95:5:1 to 80:20:1, hexanes/ethyl
ether/Et3N) gave 21b (102.2 mg, 51%) as a colorless oil: 1H
NMR δ 6.35 (d, 1 H, J ) 6.0 Hz), 4.72 (dt, 1 H, J ) 6.2, 1.9
Hz), 4.44 (br s, 1 H), 4.03-3.93 (m, 1 H), 2.13 (qt, 1 H, J )
6.7, 1.8 Hz), 1.87-1.72 (m, 1 H), 1.66-1.51 (m, 2 H), 1.27 (ddd,
1 H, J ) 13.3, 8.4, 4.6 Hz), 0.91 (app d, 6 H, J ) 6.6 Hz); 13C
NMR δ 145.5, 105.5, 73.4, 63.4, 44.4, 38.9, 24.4, 23.4, 22.3; IR
(neat) 3346, 3062, 2956, 2923, 2871, 2871, 1643, 1468, 1382,
1369, 1230, 1107, 1037 cm-1; MS (EI) m/z (rel intensity) 156
(M+, 13), 141 ([M - CH3]+, 3), 138 ([M - H2O]+, 3), 123 ([M -
CH3 - H2O]+, 3), 99 (26), 95 (15), 81 (25), 73 (100), 71 (39), 70
(38), 69 (38), 56 (42); HRMS (EI) m/z calcd for C9H16O2
156.1150, found 156.1151.
DABCO (34.0 mg, 0.301 mmol, 2.0 equiv) in freshly distilled
and degassed THF (1.5 mL) were irradiated for 14 h at 55 °C
to give a dark red solution. 1H NMR analysis of the crude
reaction mixture indicated a ratio of 20e:21e of 2:1. Purifica-
tion by chromatography on SiO2 (80:20:1, hexanes/ethyl ether/
Et3N) gave a mixture of 20e and 21e (13.6 mg, 50%) as a
colorless oil.43 20e: 1H NMR δ 4.25 (t, 1 H, J ) 2.0 Hz), 4.21
(dt, 1 H, J ) 9.5, 2.0 Hz), 4.01 (t, 1 H, J ) 2.0 Hz), 3.79 (dd,
1 H, J ) 10.2, 2.2 Hz); 13C NMR δ 164.1, 84.2, 79.9, 79.3, 43.3,
38.2, 13.5. 21e: 1H NMR δ 6.32 (dd, 1 H, J ) 6.0, 1.6 Hz),
4.62 (dd, 1 H, J ) 6.0, 2.0 Hz), 3.97 (dt, 1 H, J ) 8.5, 1.8 Hz),
3.62 (dd, 1 H, J ) 10.8, 2.0 Hz); 13C NMR δ 145.0, 104.3, 80.9,
72.3, 37.3, 35.7, 13.0.
(3R*,5R*)-5-Isobu tyl-4,4-d im eth yl-2-m eth ylen etetr a h y-
d r ofu r a n -3-ol (20f). According to the general procedure, 19f
(21.2 mg, 0.115 mmol, 1.0 equiv), tungsten hexacarbonyl (20.2
mg, 0.057 mmol, 0.5 equiv), and DABCO (26.0 mg, 0.230 mmol,
2.0 equiv) in freshly distilled and degassed THF (1.5 mL) were
irradiated for 14 h at 55 °C to give a dark red solution.
Purification by chromatography on SiO2 (90:10:1, hexanes/
ethyl ether/Et3N) gave 20f (9.4 mg, 44%) as a colorless oil: 1H
NMR δ 4.30 (d, 1 H, J ) 1.5 Hz), 4.12 (d, 1 H, J ) 2.1 Hz),
4.08 (d, 1 H, J ) 1.3 Hz), 3.98 (d, 1 H, J ) 3.7 Hz), 1.89-1.75
(m, 1 H), 1.53 (d, 1 H, J ) 3.8 Hz), 1.44 (ddd, 1 H, J ) 14.1,
10.6, 4.7 Hz), 1.13 (ddd, 1 H, J ) 14.1, 9.2, 2.2 Hz), 1.02 (s, 3
H), 0.96 (d, 3 H, J ) 6.7 Hz), 0.93 (d, 3 H, J ) 6.6 Hz), 0.84 (s,
3 H); 13C NMR δ 165.0, 85.6, 82.7, 80.1, 43.8, 38.2, 25.7, 24.0,
21.9, 19.9, 18.3; IR (neat) 3418, 2957, 2934, 2872, 1939, 1717,
1677, 1468, 1384, 1369, 1082 cm-1; MS (EI) m/z (rel intensity)
184 (M+, 12), 153 ([M - CH3O]+, 7), 125 (5), 121 (10), 111 (30),
98 (16), 85 (30), 69 (100), 57 (42); HRMS (EI) m/z calcd for
C
11H20O2 184.1463, found 184.1465.
(3S*,4S*,5R*)-5-isobu tyl-4-m eth yl-2-m eth ylen etetr a h y-
d r ofu r a n -3-ol (20g) a n d (2R*,3S*,4R*)-2-Isobu tyl-3-m eth -
yl-3,4-d ih yd r o-2H-p yr a n -4-ol (21g). According to the general
procedure, 19g (36.3 mg, 0.213 mmol, 1.0 equiv), W(CO)6 (37.5
mg, 0.107 mmol, 0.5 equiv), and DABCO (48.0 mg, 0.425 mmol,
2.0 equiv) in freshly distilled and degassed THF (2.0 mL) were
irradiated for 12 h at 60 °C. 1H NMR analysis of the crude
reaction mixture indicated a ratio of 20g:21g of 1:2. Purifica-
tion by chromatography on SiO2 (85:15:1, hexanes/ethyl ether/
Et3N) gave a mixture of 20g and 21g (14.1 mg, 39%) as a
colorless, crystalline solid that decomposed upon standing. The
crude reaction mixture was used to acquire spectral data.43
20g: 1H NMR δ 4.69 (d, 1 H, J ) 6.45 Hz), 4.26 (s, 1 H); 13C
NMR δ 164.3, 79.7, 79.6, 74.1, 39.8, 39.5, 25.1, 23.5, 22.4, 6.5.
21g: 1H NMR δ 6.30 (dd, 1 H, J ) 6.1, 1.3 Hz), 4.63-4.47 (m,
2 H), 4.01-3.94 (m, 1H); 13C NMR δ 145.0, 103.6, 76.5, 66.6,
40.7, 35.9, 24.7, 23.3, 22.4, 5.7.
(3R*,4R*,5R*)-5-Isobu tyl-4-m eth yl-2-m eth ylen etetr ah y-
d r ofu r a n -3-ol (20d ). According to the general procedure, 19d
(41.0 mg, 0.240 mmol, 1.0 equiv), W(CO)6 (42.0 mg, 0.120
mmol, 0.5 equiv), and DABCO (56.0 mg, 0.500 mmol, 2.0 equiv)
in freshly distilled and degassed THF (5.0 mL) were irradiated
for 14 h at 56 °C. Purification by chromatography on SiO2 (80:
20:1, hexanes/ethyl ether/Et3N) gave 20d (20.0 mg, 49%) as a
colorless, unstable solid. Due to the instability of 20d , the
crude reaction mixture was used to acquire spectral data: 1H
NMR δ 4.28 (d, 1 H, J ) 5.2 Hz), 4.20 (s, 1 H), 3.98 (s, 1 H),
4.01-3.94 (m, 1 H), 1.88-1.68 (m, 2 H), 1.45-1.25 (m, 2 H),
0.98 (d, 3 H, J ) 6.8 Hz), 0.90 (d, 3 H, J ) 6.6 Hz), 0.88 (d, 3
H, J ) 6.4 Hz); 13C NMR δ 165.8, 84.3, 81.5, 73.5, 44.0, 43.2,
25.4, 23.7, 22.0, 9.9.
(3R,4S,5R)-5-Isob u t yl-4-m et h yl-2-m et h ylen et et r a h y-
d r ofu r a n -3-ol (20h ). According to the general procedure, 19h
(33.0 mg, 0.194 mmol, 1.0 equiv), tungsten hexacarbonyl (34.1
mg, 0.097 mmol, 0.5 equiv), and DABCO (43.8 mg, 0.388 mmol,
2.0 equiv) in freshly distilled and degassed THF (2.0 mL) were
irradiated for 12 h at 60 °C to give a yellow-orange solution.
Purification by chromatography on SiO2 (80:20:1, hexanes/
ethyl ether/Et3N) gave 20h (15.0 mg, 46%) as a colorless oil:
1
[R]D +48.6 (c 0.84, CH2Cl2, 22 °C); H NMR δ 4.54 (app dt, 1
H, J ) 9.5, 4.9 Hz), 4.31 (s, 1 H), 4.18 (app t, 1 H, J ) 3.0 Hz),
4.08 (d, 1 H, J ) 1.6 Hz), 2.21-2.11 (m, 1 H), 1.83-1.70 (m, 1
H), 1.69 (d, 1 H, J ) 3.6 Hz), 1.51 (ddd, 1 H, J ) 15.0, 9.2, 5.8
Hz), 1.30-1.22 (m, 1 H), 0.95 (d, 3 H, J ) 6.7 Hz), 0.94 (d, 3
H, J ) 6.6 Hz), 0.87 (d, 3 H, J ) 7.2 Hz); 13C NMR δ 164.8,
82.5, 81.2, 78.7, 43.1, 39.1, 25.4, 23.6, 22.4, 11.3; IR (neat) 3383,
2958, 2934, 2872, 1676, 1638, 1467, 1383, 1369, 1023, 984, 814
cm-1; MS (EI) m/z (rel intensity) 170 (M+, 35), 153 ([M - OH]+,
14), 139 ([M - CH3O]+, 10), 128 ([M - C3H6]+, 8), 113 (16),
109 (30), 97 (63), 85 (34), 69 (78), 55 (100); HRMS (EI) m/z
calcd for C10H18O2 170.1307, found 170.1314.
(3S*,5R*)-5-Isobu tyl-4,4-dim eth yl-2-m eth ylen e-tetr ah y-
d r o-fu r a n -3-ol (20e) a n d (2R*,4R*)-2-Isob u t yl-3,3-d i-
m eth yl-3,4-d ih yd r o-2H-p yr a n -4-ol (21e). According to the
general procedure, 19e (27.5 mg, 0.149 mmol, 1.0 equiv),
tungsten hexacarbonyl (26.0 mg, 0.074 mmol, 0.5 equiv), and
(43) 1H and 13C NMR signals for mixtures are tentatively assigned
and based on correlations with spectra of structurally related com-
pounds. For cases where the assignment is ambiguous, only diagnostic
signals are listed.
(2R*,4R*)-2-Isobu tyl-4-(ter t-bu tyld ip h en ylsila n yloxy)-
3,4-d ih yd r o-2H-p yr a n (21i). According to the general pro-
cedure, 19i (55.0 mg, 0.140 mmol, 1.0 equiv), tungsten
8804 J . Org. Chem., Vol. 68, No. 23, 2003

Conversion of Alkynols to Glycals
hexacarbonyl (25.0 mg, 0.070 mmol, 0.5 equiv), and DABCO
(32.0 mg, 0.290 mmol, 2.1 equiv) in freshly distilled and
degassed THF (2.5 mL) were irradiated for 18 h at 56 °C to
(3R*,5R*)-5-Isob u t yl-3-m et h oxy-2-m et h ylen et et r a h y-
d r ofu r a n (20m ) a n d (2R*,4R*)-2-Isobu tyl-4-m eth oxy-3,4-
d ih yd r o-2H-p yr a n (21m ). According to the general proce-
dure, 19m (22.0 mg, 0.128 mmol, 1.0 equiv), tungsten
hexacarbonyl (22.5 mg, 0.064 mmol, 0.5 equiv), and DABCO
(28.7 mg, 0.256 mmol, 2.0 equiv) in freshly distilled and
degassed THF (2.6 mL) were irradiated for 14 h at 56 °C to
1
give a yellow solution. H NMR analysis of the crude reaction
mixture indicated a ratio of endo:exo isomers of 30:1. Purifica-
tion by chromatography on SiO2 (100:0:1 to 98:2:1, hexanes/
ethyl ether/Et3N) gave a mixture of 21i and the exo-cyclization
product (8.0 mg, 15%) as a colorless solid. 21i: 1H NMR δ
7.71-7.65 (m, 4 H), 7.43-7.35 (m, 6 H), 6.39 (d, 1 H, J ) 6.1
Hz), 4.66 (dt, 1 H, J ) 1.8, 6.0 Hz), 4.22-4.10 (m, 2 H), 1.84-
1.74 (m, 2 H), 1.63-1.54 (m, 1 H), 1.42 (ddd, 1 H, J ) 14.0,
11.9, 3.7 Hz), 1.29 (ddd, 1 H, J ) 13.5, 7.7, 5.5 Hz), 1.06 (s, 9
H), 0.97 (d, 3 H, J ) 6.6 Hz), 0.96 (d, 3 H, J ) 6.6 Hz); 13C
NMR δ 146.4, 136.1, 136.0, 134.7, 134.6, 129.8, 127.8, 127.7,
103.6, 69.9, 61.6, 44.4, 38.2, 27.2, 24.6, 23.2, 22.7, 19.3; IR
(neat) 3069, 2958, 2929, 2893, 2858, 1961, 1888, 1821, 1720,
1640, 1469, 1427, 1243, 1108, 1084, 1054, 821, 797, 737, 702
cm-1; MS (EI) m/z (rel intensity) 394 (M+, 15), 337 ([M -
C4H9]+, 52), 253 (82), 199 (100), 161 (16), 105 (16), 81 (31);
HRMS (EI) m/z calcd for C25H34O2Si 394.2328, found 394.2324.
1
give a yellow solution. H NMR analysis of the crude reaction
mixture indicated a ratio of 20m :21m of 8:1. Attempted
purification by chromatography on SiO2 (100:1 to 100:2,
hexanes/Et3N) led to decomposition so spectral data are for
the crude sample.43 20m : 1H NMR δ 4.54-4.47 (m, 1 H), 4.37
(s, 1 H), 4.06 (d, 1 H, J ) 5.2 Hz), 4.00 (s, 1 H), 3.35 (s, 3H),
2.15 (dd, 1 H, J ) 13.1, 4.9 Hz); 13C NMR δ 161.2, 83.7, 80.9,
79.9, 56.1, 44.9, 39.3, 25.6, 23.3, 22.9. 21m : 1H NMR δ 6.52
(d, 1 H, J ) 6.1 Hz), 4.97 (td, 1 H, J ) 6.5, 1.7 Hz), 3.34 (s, 3
H); 13C NMR δ 147.6, 100.2, 70.2, 68.9, 55.3, 44.6, 34.5, 24.6,
23.5, 22.5.
(2R*,4S*)-2-Isob u t yl-4-[3-(t r iisop r op ylsila n yl)p r op -2-
yn oxy]-3,4-d ih yd r o-2H-p yr a n (21n ). According to the gen-
eral procedure, 19n (52.5 mg, 0.150 mmol, 1.0 equiv), tungsten
hexacarbonyl (26.4 mg, 0.075 mmol, 0.5 equiv), and DABCO
(33.9 mg, 0.301 mmol, 2.0 equiv) in freshly distilled and
degassed THF (3.0 mL) were irradiated for 12 h at 40 °C to
give an orange-red solution. Purification by chromatography
on SiO2 (100:0:1 to 95:5:1, hexanes/ethyl ether/Et3N) gave 21n
(24.0 mg, 46%) as a colorless oil: 1H NMR δ 6.38 (d, 1 H, J )
6.2 Hz), 4.80 (app dt, 1 H, J ) 6.3, 1.9 Hz), 4.45-4.40 (m, 1
H), 4.24(s, 2 H), 4.03-3.94 (m, 1 H), 2.16 (app qt, 1 H, J )
6.5, 1.8 Hz), 1.85-1.58 (m, 3 H), 1.29 (ddd, 1 H, J ) 13.3, 8.2,
4.8 Hz), 1.20-1.00 (m, 22 H), 0.91 (app d, 6 H, J ) 6.6 Hz);
13C NMR δ 145.9, 104.0, 102.5, 87.6, 73.2, 69.1, 56.3, 44.3, 34.9,
24.4, 23.3, 22.4, 18.8, 11.4; IR (neat) 3065, 2956, 2893, 2866,
2170, 1644, 1465, 1383, 1366, 1349, 1232, 1075 cm-1; MS (EI)
m/z (rel intensity) 350 (M+, 20), 307 ([M - C3H7]+, 5), 223 (9),
169 (100), 155 (7), 141 (28), 113 (30); HRMS (EI) m/z calcd for
(3R*,5R*)-5-Isobu tyl-3-ter t-bu toxy-2-m eth ylen etetr ah y-
d r ofu r a n (20j) a n d (2R*,4R*)-2-Isobu tyl-4-ter t-bu toxy-3,4-
d ih yd r o-2H-p yr a n (21j). According to the general procedure,
19j (19.0 mg, 0.089 mmol, 1.0 equiv), tungsten hexacarbonyl
(15.7 mg, 0.045 mmol, 0.5 equiv), and DABCO (20.0 mg, 0.178
mmol, 2.0 equiv) in freshly distilled and degassed THF (1.8
mL) were irradiated for 14 h at 56 °C to give a yellow solution.
1H NMR analysis of the crude reaction mixture indicated a
ratio of 20j:21j of 1:4. Attempted purification by chromatog-
raphy on SiO2 (100:0:1 to 96:4:1, hexanes/ethyl ether/Et3N) led
to decomposition, so the spectral data are for the crude
1
sample.43 20j: 1H NMR δ 4.30 (s, 1H), 3.97 (s, 1 H). 21j: H
NMR δ 6.46 (d, 1 H, J ) 6.1 Hz), 4.77 (td, 1 H, J ) 6.5, 1.5
Hz); 13C NMR δ 146.5, 103.5, 73.9, 70.1, 59.7, 44.6, 38.3, 28.7,
24.6, 23.5, 22.4.
(3R*,5R*)-3-Ben zyloxy-5-isobu tyl-2-m eth ylen etetr a h y-
d r ofu r a n (20k ) a n d (2R*,4R*)-4-Ben zyloxy-2-isobu tyl-3,4-
d ih yd r o-2H-p yr a n (21k ). According to the general procedure,
19k (26.0 mg, 0.110 mmol, 1.0 equiv), tungsten hexacarbonyl
(19.0 mg, 0.050 mmol, 0.5 equiv), and DABCO (24.6 mg, 0.220
mmol, 2.0 equiv) in freshly distilled and degassed THF (2.2
mL) were irradiated for 14 h at 56 °C to give a yellow solution.
1H NMR analysis of the crude reaction mixture indicated a
ratio of 20k :21k of 6:1. Purification by chromatography on SiO2
(100:1 to 100:2, hexanes/Et3N) gave an inseparable mixture
of the title compounds (14.1 mg, 54%) as a colorless oil.43 20k :
1H NMR δ 4.71, 4.48 (AB, 2 H, J ) 11.8 Hz), 4.41 (t, 1 H, J )
0.8 Hz), 4.27 (d, 1 H, J ) 4.8 Hz), 4.03 (d, 1 H, J ) 1.5 Hz),
2.21 (d, 1 H, J ) 13.1, 4.9 Hz); 13C NMR δ 161.3, 83.9. 21k :
1H NMR δ 6.54 (d, 1 H, J ) 6.1 Hz), 4.99-4.95 (m, 1 H), 4.61,
4.53 (AB, 2 H, J ) 12.1 Hz), 4.08-3.99 (m, 1 H), 3.86-3.83
(m, 1 H); 13C NMR δ 147.7, 100.4.
(2R*,4S*)-4-Ben zyloxy-2-isob u t yl-3,4-d ih yd r o-2H -p y-
r a n (21l). According to the general procedure, 19l (54.0 mg,
0.220 mmol, 1.0 equiv), tungsten hexacarbonyl (38.0 mg, 0.110
mmol, 0.5 equiv), and DABCO (50.0 mg, 0.450 mmol, 2.0 equiv)
in freshly distilled and degassed THF (4.4 mL) were irradiated
for 18 h at 56 °C to give a yellow solution. Purification by
chromatography on SiO2 (2 columns, 99:1, hexanes/Et3N then
hexanes to 96:4, hexanes/ethyl ether) gave 21l (36.2 mg, 67%)
as a colorless oil: 1H NMR δ 7.36-7.26 (m, 5 H), 6.40 (dd, 1
H, J ) 6.3, 1.1 Hz), 4.86 (dt, 1 H, J ) 6.3, 1.9 Hz), 4.57 (s, 2
H), 4.27-4.21 (m, 1 H), 4.04-4.39 (m, 1 H), 2.13 (qt, 1 H, J )
6.6, 1.7 Hz), 1.87-1.60 (m, 3 H), 1.28 (ddd, 1 H, J ) 13.9, 8.8,
3.8 Hz), 0.92 (d, 3 H, J ) 6.7 Hz), 0.92 (d, 3 H, J ) 6.5 Hz);
13C NMR δ 145.8, 138.8, 128.6, 127.8, 127.7, 102.7, 73.2, 70.0,
69.7, 44.5, 35.2, 24.4, 23.4, 22.3; IR (neat) 3089, 3063, 3030,
2956, 2924, 2869, 1644, 1467, 1454, 732, 696 cm-1; MS (EI)
m/z (rel intensity) 246 (M+, 15), 203 ([M - C3H7]+, 8), 155 ([M
- C6H5CH2]+, 17), 140 ([M - C6H5 - CH3]+, 11), 107 (15), 91
(100), 81 (56), 69 (25); HRMS (EI) m/z calcd for C6H22O2
246.1620, found 246.1633.
C
21H38O2Si 350.2641, found 350.2628.
(3R*,5R*)-5-Isobu t yl-3-[3-(t r iisop r op ylsila n yl)p r op -2-
yn oxy]-2-m eth ylen etetr ah ydr ofu r an (20o) an d (2R*,4R*)-
2-Isob u t yl-4-[3-(t r iisop r op ylsila n yl)p r op -2-yn oxy]-3,4-
d ih yd r o-2H-p yr a n (21o). According to the general procedure,
19o (87.0 mg, 0.248 mmol, 1.0 equiv), tungsten hexacarbonyl
(43.6 mg, 0.124 mmol, 0.5 equiv), and DABCO (56.0 mg, 0.496
mmol, 2.0 equiv) in freshly distilled and degassed THF (5.0
mL) were irradiated for 7 h at room temperature to give a
yellow solution. 1H NMR analysis of the crude reaction mixture
indicated a ratio of 20o:21o of 8:1. Purification by chroma-
tography on SiO2 (100:0:1 to 97.5:2.5:1, hexanes/ethyl ether/
Et3N) gave an inseparable mixture of the title compounds (21.5
mg, 25%) as a colorless oil.43 20o: 1H NMR δ 4.59 (d, 1 H, J
) 5.1 Hz), 4.56-4.47 (m, 1 H), 4.39 (s, 1 H), 4.30, 4.29 (AB, 2
H, J ) 16.1 Hz), 4.08 (s, 1 H), 2.21-2.15 (m, 1H); 13C NMR δ
160.3, 103.2, 88.2, 84.2, 80.0, 76.7, 55.8, 44.7, 39.3, 25.5, 23.3,
22.7, 18.8, 11.4. 21o: 1H NMR δ 6.53 (d, 1 H, J ) 6.1 Hz),
4.96 (t, 1 H, J ) 5.0 Hz).
(2R*,3R*,4R*)-4-(ter t-Bu tyldiph en ylsilan yloxy)-2-isobu -
tyl-3-m eth yl-3,4-d ih yd r o-2H-p yr a n (21p ). According to the
general procedure, 19p (100.0 mg, 0.250 mmol, 1.0 equiv),
tungsten hexacarbonyl (26.0 mg, 0.070 mmol, 0.3 equiv), and
DABCO (55.0 mg, 0.490 mmol, 2.0 equiv) in freshly distilled
and degassed THF (3.0 mL) were irradiated for 14 h at 56 °C.
Purification by chromatography on SiO2 (100:0:1 to 95:5:1,
hexanes/CH2Cl2/diethylamine) gave 21p (25.0 mg, 25%) as a
colorless, amorphous solid: 1H NMR (CD2Cl2) δ 7.71-7.68 (m,
4 H), 7.42-7.36 (m, 6 H), 6.24 (d, 1 H, J ) 6.1 Hz), 4.46 (dd,
1 H, J ) 5.9, 5.1 Hz), 4.02 (dd, 1 H, J ) 5.1, 3.7 Hz), 3.97 (app
dt, 1 H, J ) 9.8, 3.2 Hz), 1.93-1.80 (m, 1 H), 1.64-1.54 (m, 1
H), 1.44 (ddd, 1 H, J ) 14.0, 9.9, 4.3 Hz), 1.32 (ddd, 1 H, J )
13.0, 9.7, 3.2 Hz), 1.05 (s, 9 H), 1.00 (d, 3 H, J ) 7.0 Hz), 0.94
(d, 3 H, J ) 6.6 Hz), 0.94 (d, 3 H, J ) 6.7 Hz); 13C NMR (CD2-
Cl2) δ 145.5, 136.7, 136.5, 135.5, 134.8, 130.1, 129.9, 128.1,
127.8, 104.0, 74.5, 66.2, 41.9, 39.2, 27.4, 24.7, 24.2, 21.8, 19.9,
J . Org. Chem, Vol. 68, No. 23, 2003 8805

Wipf and Graham
13.8; IR (neat) 3070, 2957, 2931, 2894, 2857, 1645, 1472, 1427,
1242, 1111, 1085, 1019, 701 cm-1; MS (EI) m/z (rel intensity)
407 ([M - H]+, 22), 393 ([M - CH3]+, 28), 379 ([M - C2H5]+,
12), 365 ([M - C3H7]+, 15), 351 ([M - C4H9]+, 26), 295 (6), 265
(57), 253 (100), 199 (100), 95 (58), 77 (30), 69 (18); HRMS (EI)
m/z calcd for C26H35O2Si (M - H) 407.2406, found 407.2410.
23 (10.9 mg, 0.037 mmol, 1.0 equiv), tungsten hexacarbonyl
(6.0 mg, 0.02 mmol, 0.5 equiv), and DABCO (8.0 mg, 0.07
mmol, 1.9 equiv) in freshly distilled and degassed THF (1.0
mL) were irradiated for 14 h at 55 °C to give a yellow solution.
Purification by chromatography on SiO2 (99:1:1, hexanes/ethyl
ether/Et3N) gave 24 (8.8 mg, 81%) as a colorless oil: 1H NMR
δ 6.38 (dd, 1 H, J ) 6.2, 2.1 Hz), 5.77-5.66 (m, 1 H), 5.37
(ddd, 1 H, J ) 15.3, 7.0, 1.6 Hz), 4.95 (app t, 1 H, J ) 7.2 Hz),
4.57 (app dt, 1 H, J ) 6.2, 1.6 Hz), 3.90-3.82 (m, 1 H), 2.59-
2.50 (m, 1 H), 1.84-1.74 (m, 2 H), 1.70 (app dt, 3 H, J ) 6.5,
0.7 Hz), 1.55 (ddd, 1 H, J ) 14.1, 8.5, 5.7 Hz), 1.33-1.18 (m,
1 H), 1.21 (s, 9 H), 0.91 (d, 6 H, J ) 6.6 Hz); 13C NMR δ 177.9,
145.0, 129.9, 127.7, 100.9, 77.1, 73.5, 45.1, 39.2, 36.3, 32.0, 27.4,
24.4, 23.5, 22.4, 18.1; IR (neat) 3063, 2957, 2925, 2871, 1730,
1645, 1480, 1467, 1159 cm-1; MS (CI) m/z (rel intensity) 193
([M - C5H9O2]+, 12), 177 ([M - C5H9O3]+, 6), 163 ([M -
C6H11O3]+, 6), 135 (6), 129 (14), 89 (23), 73 (100), 61 (37);
HRMS (EI) m/z calcd for C13H20O (M - C5H10O2) 192.1514,
found 192.1516.
(2R*,4S*)-2-Isobu tyl-3,3-d im eth yl-3,4-d ih yd r o-4-tr iiso-
p r op ylsila n oxy-2H-p yr a n (21q). According to the general
procedure, 19q (28.0 mg, 0.082 mmol), W(CO)6 (15.0 mg, 0.043
mmol, 0.5 equiv), and DABCO (19.0 mg, 0.168 mmol, 2.1 equiv)
in THF (1.0 mL) were irradiated for 12 h at 60 °C to give a
yellow solution. Purification by chromatography on SiO2 (100:
0:1 to 100:2:1, hexanes/ethyl ether/Et3N) gave 19q (11.9 mg,
43%) and a mixture of 20q and 21q (13.8 mg, 49%) as a
colorless oil in a ratio of 20q:21q of 1:4. Characteristic signals
for 20q:43 1H NMR δ 4.26 (d, 1 H, J ) 1.5 Hz), 4.16 (dd, 1 H,
J ) 10.5, 2.2 Hz), 4.07 (s, 1H), 4.02 (d, 1 H, J ) 1.5 Hz).
Purification of the mixture by chromatography on SiO2 (hex-
anes) gave 21q (9.2 mg, 33%) as a colorless oil: 1H NMR δ
6.33 (d, 1 H, J ) 6.0 Hz), 4.81 (app t, 1 H, J ) 5.7 Hz), 3.89
(dd, 1 H, J ) 10.9, 2.0 Hz), 3.62 (d, 1 H, J ) 5.3 Hz), 1.93-
1.79 (m, 1 H), 1.50 (ddd, 1 H, J ) 14.5, 10.9, 3.8 Hz), 1.26-
1.01 (m, 22 H), 0.94 (s, 3 H), 0.90 (d, 3 H, J ) 6.5 Hz), 0.77 (s,
3 H); 13C NMR δ 145.0, 102.9, 75.8, 71.1, 37.6, 37.3, 24.8, 24.3,
22.6, 21.5, 18.9, 18.5, 13.2; IR (neat) 3062, 2959, 2894, 2867,
(2R*,4R*)-2-Isobu tyl-4-[(1R*)-1-p iva loylbu t-2-en -1-yl]-
3,4-d ih yd r o-2H-p yr a n (27). According to the general proce-
dure, 26 (18.0 mg, 0.061 mmol, 1.0 equiv), tungsten hexacar-
bonyl (11.0 mg, 0.031 mmol, 0.5 equiv), and DABCO (14.0 mg,
0.124 mmol, 2.0 equiv) in freshly distilled and degassed THF
(1.5 mL) were irradiated for 23 h at 40 °C, then for 12 h at 60
°C to give a yellow solution. Purification by chromatography
on SiO2 (100:0:1 to 90:10:1, hexanes/ethyl ether/Et3N) gave 27
(12.6 mg, 70%) as a colorless oil: 1H NMR δ 6.38 (dd, 1 H, J
) 6.5, 1.5 Hz), 5.77-5.66 (m, 1 H), 5.36 (dd, 1 H, J ) 15.3, 7.3
Hz), 5.01 (app t, 1 H, J ) 7.6 Hz), 4.65 (dd, 1 H, J ) 6.1, 3.9
Hz), 3.91 (app ddt, 1 H, J ) 10.1, 8.4, 5.3 Hz), 2.38-2.24 (m,
1 H), 1.84-1.71 (m, 2 H), 1.70 (d, 3 H, J ) 6.5 Hz), 1.62-1.49
(m, 2 H), 1.25-1.19 (m, 1 H), 1.20 (s, 9 H), 0.92 (d, 3 H, J )
6.4 Hz), 0.91 (d, 3 H, J ) 6.6 Hz); 13C NMR δ 177.8, 144.6,
130.3, 128.2, 100.4, 78.1, 70.8, 43.8, 39.1, 33.3, 29.9, 27.4, 24.7,
23.3, 22.6, 18.1; IR (neat) 3063, 2957, 2929, 2871, 1730, 1672,
1645, 1480, 1467, 1157 cm-1; MS (EI) m/z (rel intensity) 294
(M+, 0.1), 237 ([M - C4H9]+, 2), 209 (5), 193 ([M - C5H9O2]+,
9), 192 ([M - C5H10O2]+, 14), 139 (33), 121 (8), 57 (100); HRMS
(EI) m/z calcd for C13H20O (M - C5H10O2) 192.1514, found
192.1511.
2722, 1846, 1645, 1466, 1386, 1367, 1241, 1088, 1059 cm-1
;
MS (EI) m/z (rel intensity) 325 ([M - CH3]+, 7), 297 ([M -
C3H7]+, 13), 229 (7), 211 (10), 185 (23), 169 (5), 131 (16), 115
(10), 103 (17), 75 (65), 69 (47), 61 (100); HRMS (EI) m/z calcd
for C17H33O2Si (M - C3H7) 297.2250, found 297.2242.
(3R*,5R*)-2-Isob u t yl-4-[3-(t r iisop r op ylsila n yl)p r op -2-
yn oxy]-3,3-d im eth yl-5-m eth ylen etetr a h yd r ofu r a n (20s).
According to the general procedure, 19s (21.2 mg, 0.056 mmol,
1.0 equiv), W(CO)6 (11.0 mg, 0.031 mmol, 0.5 equiv), and
DABCO (14.0 mg, 0.124 mmol, 2.2 equiv) in freshly distilled
and degassed THF (1.0 mL) were irradiated for 18 h at 55 °C
to afford a dark red solution. Purification by chromatography
on SiO2 (100:1, hexanes/Et3N) gave 20s (6.7 mg, 32%) as a
colorless oil: 1H NMR δ 4.38 (d, 1 H, J ) 1.3 Hz), 4.29 (s, 2
H), 4.10 (dd, 1 H, J ) 10.4, 2.0 Hz), 4.05 (d, 1 H, J ) 1.3 Hz),
3.97 (s, 1 H), 1.87-1.73 (m, 1 H), 1.48-1.38 (m, 2 H), 1.12-
1.04 (m, 21 H), 1.01 (s, 3 H), 0.96 (d, 3 H, J ) 6.7 Hz), 0.92 (d,
3 H, J ) 6.6 Hz), 0.85 (s, 3 H); 13C NMR δ 159.8, 103.6, 88.1,
85.7, 84.7, 84.1, 55.6, 43.8, 37.9, 25.8, 24.0, 22.1, 20.0, 18.8,
18.1, 11.4; IR (neat) 3109, 2958, 2945, 2866, 2171, 1673, 1640,
1466, 1384, 1369, 1354, 1074 cm-1; MS (EI) m/z (rel intensity)
378 (M+, 29), 363([M - CH3]+, 9), 335 ([M - C3H7]+, 67), 249
(9), 223 (19), 153 (100), 111 (34), 69 (50); HRMS (EI) m/z calcd
for C23H42O2Si 378.2954, found 378.2957.
(3R*,5R*)-3-Ben zyloxy-5-isobu tyl-4,4-d im eth yl-2-m eth -
ylen etetr a h yd r ofu r a n (20u ). According to the general pro-
cedure, 19u (46.5 mg, 0.169 mmol, 1.0 equiv), W(CO)6 (30.0
mg, 0.085 mmol, 0.5 equiv), and DABCO (38.0 mg, 0.337 mmol,
2.0 equiv) in freshly distilled and degassed THF (1.0 mL) were
irradiated for 16 h at 55 °C to give a dark red solution.
Purification by chromatography on SiO2 (100:1, hexanes/Et3N)
gave 20u (28.3 mg, 61%) as a yellow oil: 1H NMR δ 7.36-
7.25 (m, 5 H), 4.78, 4.45 (AB, 2 H, J ) 12.3 Hz), 4.43 (s, 1 H),
4.22 (dd, 1 H, J ) 10.4, 1.9 Hz), 4.01 (s, 1 H), 3.61 (s, 1 H),
1.91-1.77 (m, 1 H), 1.46 (ddd, 1 H, J ) 14.4, 10.5, 4.75 Hz),
1.15 (ddd, 1 H, J ) 11.1, 7.2, 1.9 Hz), 1.10 (s, 3 H), 0.98 (d, 3
H, J ) 6.7 Hz), 0.94 (d, 3 H, J ) 6.6 Hz), 0.85 (s, 3 H); 13C
NMR δ 160.6, 138.8, 128.5, 127.7, 127.6, 86.2, 85.7, 84.6, 69.8,
44.2, 38.0, 25.8, 24.0, 22.1, 20.0, 18.2; IR (neat) 3112, 3089,
3065, 3031, 2958, 2928, 2872, 1943, 1807, 1673, 1644, 1467,
1454, 1385, 1365, 1081, 1001, 739, 693 cm-1; MS (EI) m/z (rel
intensity) 274 (M+, 8), 259 ([M - CH3]+, 1), 193 (10), 183 ([M
- C6H5CH2]+, 9), 168 ([M - C6H5CH2 - CH3]+, 8), 153 (78),
91 (100), 73 (24), 69 (37), 61 (30), 59 (24); HRMS (EI) m/z calcd
for C18H26O2 274.1933, found 274.1932.
7-H yd r oxy-2-h yd r oxym e t h yl-9-m e t h yld e ca -2,4-d ie -
n a l (30). To a solution of (3S*,5R*)-7-methyl-3-[3-hydroxy-1-
propenyloxy]-5-(triethylsilanyloxy)-1-(trimethylsilanyl)oct-1-
yne (54.7 mg, 0.137 mmol, 1.0 equiv) in THF (5.0 mL) was
added a solution of TBAF (1.0 M in THF, 0.43 mL, 0.43 mmol,
3.1 equiv). After 2 h at room temperature, the solvent was
removed in vacuo and the residue was partitioned between
ethyl ether and water. The aqueous layer was extracted with
ethyl ether and the combined organic layers were washed with
brine, dried (Na2SO4), filtered, and concentrated to give a
yellow oil. The crude oil was dried under high vacuum (<1.0
mmHg) overnight, diluted with THF (2.5 mL), and added to a
mixture of W(CO)6 (24.0 mg, 0.068 mmol, 0.5 equiv) and
DABCO (31.0 mg, 0.276 mmol, 2.0 equiv). Irradiation for 4 h
at 56 °C followed by concentration and purification by chro-
matography on SiO2 (40:60, hexanes/ethyl acetate) gave
(2E,4E)-30 and (2Z,4E)-30 in a ratio of 15:1 (18.8 mg, 65%, 2
steps) as a yellow oil. (2E,4E)-30: 1H NMR δ 9.45 (s, 1 H),
6.92 (d, 1 H, J ) 11.3 Hz), 6.70 (ddt, 1 H, J ) 14.8, 11.3, 1.2
Hz), 6.41 (app dt,1 H, J ) 14.8, 7.4 Hz), 4.44 (s, 2 H), 3.90-
3.80 (m, 1 H), 2.53 (br s, 1 H), 2.46-2.36 (m, 2 H), 1.80-1.76
(m, 1 H), 1.60 (br s, 1 H), 1.45 (ddd, 1 H, J ) 13.9, 8.9, 5.4
Hz), 1.27 (ddd, 1 H, J ) 13.8, 8.8, 4.2 Hz), 0.94 (d, 3 H, J )
5.1 Hz), 0.92 (d, 3 H, J ) 5.1 Hz); 13C NMR δ 195.7, 150.6,
144.6, 138.1, 127.8, 69.2, 56.0, 46.7, 42.1, 24.8, 23.6, 22.2; IR
(neat) 3377, 3038, 2955, 2925, 2869, 2711, 1672, 1633, 1017
cm-1; MS (EI) m/z (rel intensity) 194 ([M - H2O]+, 52), 176
([M - 2 H2O]+, 7), 133 ([M - 2 H2O - C3H7]+, 6), 126 ([M -
C6H14]+, 41), 108 (100), 107 (52), 80 (66), 79 (95), 69 (52), 57
(21); HRMS (EI) m/z calcd for C12H18O3 (M - H2O) 194.1309,
found 194.1308.
(2R*,4S*)-2-Isobu tyl-4-[(1S*)-1-p iva loylbu t-2-en yl]-3,4-
d ih yd r o-2H-p yr a n (24). According to the general procedure,
8806 J . Org. Chem., Vol. 68, No. 23, 2003

Conversion of Alkynols to Glycals
(2R*,4S*)-2-Isobu tyl-3,4-d ih yd r o-4-[(1S*)-3-(tr iisop r o-
p ylsila n yl)-1-h yd r oxyp r op -2-yn -1-yl]-2H-p yr a n (31). To a
solution of 21n (154.5 mg, 0.441 mmol, 1.0 equiv) in THF (4.0
mL) at -78 °C under N2 was added TMEDA (150 µL, 0.994
mmol, 2.3 equiv) followed by n-BuLi (1.2 M in hexanes, 0.85
mL, 0.960 mmol, 2.2 equiv). The resulting black reaction
mixture was stirred for 20 min, quenched with saturated
aqueous NH4Cl (3.0 mL), and warmed to room temperature.
The orange-colored mixture was diluted with water and
extracted with ethyl ether. The combined organic layers were
washed with brine, dried (Na2SO4), filtered, and concentrated
to give an orange oil. Purification by chromatography on SiO2
(95:5:1, hexanes/ethyl ether/Et3N) afforded 31 (120.1 mg, 78%)
as a pale yellow oil: 1H NMR δ 6.46 (dd, 1 H, J ) 6.2, 2.1 Hz),
4.76 (dt, 1 H, J ) 1.8, 6.2 Hz), 4.18 (t, 1 H, J ) 5.5 Hz), 3.94-
3.86 (m, 1 H), 2.65-2.54 (m, 1 H), 1.95-1.74 (m, 3 H), 1.62-
1.51 (m, 2 H), 1.28 (ddd, 1 H, J ) 13.3, 8.1, 5.0 Hz), 1.06 (s, 21
H), 0.92 (d, 3 H, J ) 6.6 Hz), 0.91 (d, 3 H, J ) 6.6 Hz); 13C
NMR δ 146.3, 107.4, 99.9, 86.6, 73.6, 66.1, 45.0, 39.2, 31.7,
24.4, 23.3, 22.5, 18.8, 11.3; IR (neat) 3373, 3061, 2957, 2944,
2866, 2169, 1646, 1464, 1383, 1368, 1240, 1052 cm-1; MS (EI)
m/z (rel intensity) 349 ([M - H]+, 1), 307 ([M - C3H7]+, 8),
207 (7), 203 (11), 139 (100), 121 (9), 83 (41), 75 (33), 69 (19),
59 (25); HRMS (EI) m/z calcd for C18H31O2Si (M - C3H7)
307.2093, found 307.2092.
(5S*)-5-[(2R*,4S*)-2-Isob u t yl-3,4-d ih yd r o-2H-p yr a n -4-
yl]-4-m eth ylen e-3-(4-n itr op h en yl)oxa zolid in -2-on e (32).
To a solution of (2R*,4S*)-2-isobutyl-3,4-dihydro-4-[(1S*)-3-
(triisopropylsilanyl)-1-[(4-nitrophenyl)carbamoyloxy]-prop-2-
yn-1-yl]-2H-pyran (70.1 mg, 0.136 mmol, 1.0 equiv) in THF
(5.0 mL) was added TBAF (1.0 M in THF, 0.15 mL, 0.15 mmol,
1.1 equiv). The reaction mixture instantly turned yellow and
then slowly became dark red over 30 min. Saturated aqueous
NH4Cl was added and the mixture was extracted with CH2-
Cl2. The combined organic layers were dried (Na2SO4), filtered,
and concentrated to give an orange solid. Purification by
chromatography on SiO2 (75:25:0.5 to 60:40:0.5, hexanes/ethyl
ether/Et3N) gave 32 (22.9 mg, 47%) as a pale yellow amorphous
solid that crystallized upon standing. Crystals suitable for
X-ray diffraction were formed by slow evaporation of a pen-
tane/methylene chloride solution: Mp 121.8-122.5 °C (pen-
tane/methylene chloride); 1H NMR δ 8.35 (app dt, 2 H, J )
9.1, 2.1 Hz), 7.60 (app dt, 2 H, J ) 9.1, 2.1 Hz), 6.53 (dd, 1 H,
J ) 6.2, 2.1 Hz), 5.10 (app dt, 1 H, J ) 4.0, 2.0) Hz), 4.56 (dt,
1 H, J ) 6.2, 1.8 Hz), 4.47 (dd, 1 H, J ) 3.2, 2.3 Hz), 4.33 (dd,
1 H, J ) 3.2, 1.8 Hz), 3.96 (dddd, 1 H, J ) 10.6, 8.5, 4.6, 1.6
Hz), 2.96-2.87 (m, 1 H), 1.96 (app ddt, 1 H, J ) 13.0, 6.0, 1.7
Hz), 1.89-1.78 (m, 1 H), 1.75-1.57 (m, 2 H), 1.32 (ddd, 1 H, J
) 13.8, 8.3, 4.6 Hz), 0.94 (d, 6 H, J ) 6.6 Hz); 13C NMR δ 154.6,
147.9, 146.9, 142.4, 139.7, 127.3, 125.2, 96.9, 84.9, 80.3, 73.5,
44.9, 37.5, 30.5, 24.4, 23.4, 22.4; IR (neat) 3112, 3083, 3054,
2956, 2928, 2870, 1777, 1647, 1597, 1525, 1501, 1401, 1341,
854 cm-1; MS (EI) m/z (rel intensity) 358 (M+, 71), 343 ([M -
CH3]+, 5), 329 (11), 328 (50), 315 ([M - C3H7]+, 16), 301 ([M -
C4H9]+, 35), 139 (100); HRMS (EI) m/z calcd for C19H22N2O5
358.1529, found 358.1530.
lution of (2R*,4S*)-2-isobutyl-3,4-dihydro-4-[(1S*)-1-hydroxy-
prop-2-yn-1-yl]-2H-pyran (17.8 mg, 0.092 mmol, 1.0 equiv) and
imidazole (19.0 mg, 0.279 mmol, 3.0 equiv) in DMF (1.0 mL)
at room temperature under N2 was added bromomethylchlo-
rodimethylsilane (20.0 µL, 0.147 mmol, 1.6 equiv). After 10
min, saturated, aqueous NH4Cl and water were added and the
mixture was extracted with ethyl ether. The combined organic
layers were washed with brine, dried (Na2SO4), filtrated, and
concentrated to give an oily residue. Purification by chroma-
tography on SiO2 (100:1 pentane/Et3N) gave a colorless oil (15.6
mg, 49%) that was diluted with benzene (0.5 mL). A solution
of AIBN (3.25 mg, 0.020 mmol, 0.45 equiv) in benzene (0.5 mL)
was added. The reaction mixture was heated to reflux under
N2. Additional AIBN (3.25 mg, 0.020 mmol, 0.45 equiv) and
Bu3SnH (50 µL, 0.19 mmol, 4.1 equiv) in benzene (1.5 mL) were
added portionwise over 6 h. After a total of 8 h, the mixture
was cooled to room temperature and concentrated. To the
resulting residue was added MeOH (1.5 mL), THF (1.5 mL),
KF (30.0 mg, 0.516 mmol, 11.5 equiv), KHCO3 (45.0 mg, 0.450
mmol, 10.0 equiv), and H2O2 (30% in H2O, 1.0 mL, 29 mmol,
650 equiv). The white suspension was heated at reflux for 2
h, stirred at 35 °C overnight (10 h), and filtered through Celite
(ethyl ether wash). The filtrate was concentrated and the
residue was partitioned between ethyl ether and brine. The
aqueous layer was backwashed with ethyl ether. The combined
organic layers were dried (Na2SO4), filtered, and concentrated
to give a colorless solid. Purification by chromatography on
SiO2 (50:50, hexanes/ethyl acetate to ethyl acetate) gave 33
(2.0 mg, 20%) as a colorless, amorphous solid: 1H NMR δ 5.65
(s, 1 H), 4.96 (br s, 1 H), 4.33 (s, 2 H), 4.07 (d, 1 H, J ) 11.7
Hz), 3.65 (dd, 1 H, J ) 12.1, 4.0 Hz), 3.27-3.19 (m, 1 H), 2.69
(app dq, 1 H, J ) 12.0, 6.1 Hz), 2.44 (br s, 1 H), 2.34 (br s, 1
H), 1.98 (br s, 1 H), 1.85-1.71 (m, 1 H), 1.53-1.25 (m, 3 H),
1.17 (ddd, 1 H, J ) 13.2, 8.3, 4.7 Hz), 0.88 (d, 6 H, J ) 6.6
Hz); MS (EI) m/z (rel intensity) 226 (M+, 0.1), 208 ([M - H2O]+,
12), 190 ([M - 2 H2O]+, 33), 179 ([M - C2H5 - H2O]+, 19), 169
([M - C4H9]+, 6), 151 ([M - C4H9 - H2O]+, 9), 133 (9), 121
(16), 104 (100), 91 (53), 61 (52); HRMS (EI) m/z calcd for
C
13H20O2 (M - H2O) 208.1463, found 208.1458.
Ack n ow led gm en t. This work was supported in part
by NIH (GM-55433) and Merck Research Laboratories.
We would like to thank Professor Craig S. Wilcox for
use of a photoreactor, Dr. Steven J . Geib for X-ray
crystallography, and Dr. Fu-Tyan Lin for NMR analy-
ses.
Su p p or tin g In for m a tion Ava ila ble: Syntheses of 19,
21n , 22, 23, 25, 28, (2R*,4S*)-2-isobutyl-3,4-dihydro-4-[(1S*)-
3-(triisopropylsilanyl)-1-[(4-nitrophenyl)carbamoyloxy]prop-2-
yn-1-yl]-2H-pyran, (2R*,4S*)-2-isobutyl-3,4-dihydro-4-[(1S*)-
1-hydroxyprop-2-yn-1-yl]-2H-pyran, and (3R*,5S*,4aS*,7aS*)-
6-(3,5-dinitrobenzoyloxymethyl)-5-(3,5-dinitrobenzoyloxy)-3-
isobutyl-1,3,4,4a,5,7a-hexahydrocyclopenta[c]pyran; 1H and 13
C
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(3R*,5S*,4aS*,7aS*)-6-Hyd r oxym eth yl-3-isobu tyl-1,3,4,-
4a ,5,7a -h exa h yd r o-cyclop en ta [c]p yr a n -5-ol (33). To a so-
J O034813S
J . Org. Chem, Vol. 68, No. 23, 2003 8807