Synthesis of (±)-gymnomitrol. Mn(OAc)3-initiated free-radical cyclization of alkynyl ketones

Article abstract of DOI:10.1021/jo9622338

Mn(OAc)₃-initiated cyclization of alkynyl ketones in 9-19:1 EtOH/HOAc at 90°C is a useful cyclization procedure in favorable cases. Cyclization of (trimethylsilyl)alkynyl ketone 4e provides 62% of silylalkenes 26 and 27 in the key reaction of a seven-step (16% overall yield) synthesis of gymnomitrol (1) from readily available ketone 23. 9α-Hydroxygymnomitryl acetate (2) and 9-oxogymnomitryl acetate (3) have been prepared from gymnomitrol. Cyclization of propargyl cyclohexanones 39a-c provides bicyclic compounds 40-42 in 40-60% yield.

Full text of DOI:10.1021/jo9622338

1970
J . Org. Chem. 1997, 62, 1970-1975
Syn th esis of (()-Gym n om itr ol. Mn (OAc)3-In itia ted F r ee-Ra d ica l
Cycliza tion of Alk yn yl Keton es
Steven V. O’Neil, Cheri A. Quickley, and Barry B. Snider*
Department of Chemistry, Brandeis University, Waltham, Massachusetts 02254-9110
Received December 2, 1996X
Mn(OAc)3-initiated cyclization of alkynyl ketones in 9-19:1 EtOH/HOAc at 90 °C is a useful
cyclization procedure in favorable cases. Cyclization of (trimethylsilyl)alkynyl ketone 4e provides
62% of silylalkenes 26 and 27 in the key reaction of a seven-step (16% overall yield) synthesis of
gymnomitrol (1) from readily available ketone 23. 9R-Hydroxygymnomitryl acetate (2) and
9-oxogymnomitryl acetate (3) have been prepared from gymnomitrol. Cyclization of propargyl
cyclohexanones 39a -c provides bicyclic compounds 40-42 in 40-60% yield.
Connolly reported the isolation of (+)-gymnomitrol (1)
should convert 3-butenylbicyclooctanone 4c to gym-
nomitrone (6) without the formation of isogymnomitrone
(7). However, the regiochemistry of the radical cycliza-
tion may be a problem since 7-endo-cyclization can occur
in addition to the desired 6-exo-cyclization that leads to
6. For instance, oxidation of 2-(3-butenyl)cyclopentanone
8 with Mn(OAc)3 and Cu(OAc)2 in HOAc at 80 °C leads
to radical 9, which undergoes both 6-exo-cyclization to
give radical 12, which is oxidized by Cu(II) to provide
25% of methylenebicyclo[3.2.1]octane 11, and 7-endo-
cyclization to afford radical 10, which is oxidized by Cu(II)
to give 35% of bicyclo[4.2.1]nonene 13 as a mixture of
double-bond isomers.9 This suggests that oxidative cy-
clization of 4c will give similar mixtures of 6-exo- and
7-endo-cyclization products.
and seven related sesquiterpenoids with the novel per-
hydro-4,8-methanoazulene skeleton from the liverwort
Gymnomitrion obtusum (Lindb) Pears (Hepaticae) in the
early 1970s.1 Asakawa isolated 9R-hydroxygymnomitryl
acetate (2) and 9-oxogymnomitryl acetate (3) from the
liverwort Plagiochila Trabeculata in 1988.2 The unusual
tricyclic gymnomitrane ring system attracted much
interest, culminating in five different syntheses reported
in 1979.3-8 Coates3 and Paquette4 prepared dione 5 by
an aldol reaction of keto aldehyde 4a and oxidation of
the resulting alcohol. Addition of methyllithium to 5 and
dehydration gave a difficultly separable mixture of gym-
nomitrone (6) and isogymnomitrone (7). Welch5 prepared
dione 5 by a Dieckmann cyclization of 4b.
We then considered whether oxidative cyclization of
3-butynylbicyclooctanone 4d would provide 6. Oxidation
of â-keto ester 14 with Mn(OAc)3 in EtOH at 25 °C leads
to the R-keto radical, which cyclizes to give vinyl radical
15.11 The vinyl radical abstracts an R-hydrogen from
ethanol to give 20% of methylenecyclopentanone 16 and
the hydroxyethyl radical, which is oxidized to acetalde-
We recently described Mn(III)-based oxidative cycliza-
tions of unsaturated ketones that proceed in synthetically
useful yield if the ketone enolizes to only one side and
the product ketone does not enolize.9,10 This procedure
(1) Connolly, J . D.; Harding, A. E.; Thornton, I. M. S. J . Chem. Soc.,
Chem. Commun. 1972, 1320; J . Chem. Soc., Perkin Trans. 1 1974,
2587.
(2) Toyota, M.; Nagashima, F.; Asakawa, Y. Phytochemistry 1988,
27, 2161.
(3) Coates, R. M.; Shah, S. K.; Mason, R. W. J . Am. Chem. Soc. 1982,
104, 2198.
(4) Paquette, L. A.; Han Y.-K. J . Am. Chem. Soc. 1981, 103, 1831.
(5) Welch, S. C.; Chayabunjonglerd, S.; Rao, A. S. C. P. J . Org. Chem.
1980, 45, 4086.
(8) For other synthetic studies, see: (a) Uyehara, T.; Osanai, K.;
Sugimoto, M.; Suzuki, I.; Yamamoto, Y. J . Am. Chem. Soc. 1989, 111,
7264. (b) Lago, M. A. Ph.D. Thesis, University of Michigan, 1986, Diss.
Abstr. Int. B 1987, 47, 4135; Koreeda, M., University of Michigan,
unpublished results.
(9) (a) Snider, B. B.; Cole, B. M. J . Org. Chem. 1995, 60, 5376. (b)
Cole, B. M.; Han, L.; Snider, B. B. J . Org. Chem. 1996, 61, 7832.
(10) For reviews on Mn(OAc)3 cyclizations, see: (a) Snider, B. B.
Chem. Rev. 1996, 96, 339. (b) Melikyan, G. G. Org. React. 1996, 49,
427.
(6) Kodama, M.; Kurihara, T.; Sasaki, J .; Ito, S. Can. J . Chem. 1979,
57, 3343.
(7) Bu¨chi, G.; Chu, P.-S. Tetrahedron, 1981, 37, 4509.
(11) Snider, B. B.; Merritt, J . E.; Dombroski, M. A.; Buckman, B.
O. J . Org. Chem. 1991, 56, 5544.
S0022-3263(96)02233-5 CCC: $14.00 © 1997 American Chemical Society

Synthesis of (()-Gymnomitrol
J . Org. Chem., Vol. 62, No. 7, 1997 1971
hyde by a second equivalent of Mn(OAc)3. This cycliza-
tion is not regiospecific; the analogous 6-endo-cyclization
leads to 12% of the corresponding cyclohexenone. This
suggests that oxidative cyclization of 4d will also lead to
mixtures of 6 and the cycloheptenone.
Heating alkynylcyclopentanone 18a at 90 °C with 15
equiv of Mn(OAc)3‚2H2O in 9:1 EtOH/HOAc in a reseal-
able tube for 20 h yields 41% of a 1:12 mixture of bicyclic
ketones 19 and 20 resulting from 6-exo- and 7-endo-
cyclization, respectively. As expected, 7-endo-cyclization
is the major product with the terminal alkyne. A large
excess of Mn(OAc)3 is presumably required because of
concomitant oxidation of EtOH to acetaldehyde or HOAc.
A trimethylsilyl group on the acetylene improves the
yield slightly in radical cyclizations and strongly favors
exo-cyclization.12,13 We therefore anticipated that oxida-
tive cyclization of [(trimethylsilyl)butynyl]bicyclooctanone
4e with Mn(OAc)3 would give the vinylsilane correspond-
ing to 6, which could be easily desilylated to give
gymnomitrone (6). However, oxidative free-radical cy-
clizations to alkynes must be carried out in ethanol since
acetic acid does not transfer a hydrogen atom efficiently
to the vinyl radical. Oxidations of ketones by Mn(III)
requires much higher temperatures (80 °C) than that of
â-keto esters (25 °C) because ketones are much less
acidic. We were concerned that EtOH would be oxidized
more rapidly than a ketone by Mn(OAc)3 at the elevated
temperatures needed for enolization of the ketone.
Fortunately, (trimethylsilyl)alkyne 18b undergoes ex-
clusively the desired 6-exo-cyclization under identical
conditions, providing 58% of a 1:1.4 mixture of bicyclic
ketones 21 and 22. As expected,12,13 the TMS group
improves the yield of the cyclization and favors 6-exo-
cyclization. Desilylation of the mixture of vinylsilanes
21 and 22 in HOAc at 100 °C gives 74% of 19. The
stereochemistry of 21 and 22 was assigned on the basis
of the 1H and 13C NMR chemical shift of the allylic proton
and the carbon at the ring fusion. Curran has shown
that a TMS group deshields a cis proton and shields a
cis carbon in similar systems.17 Therefore structure 22
is assigned to the isomer with the methine proton and
carbon at δ 3.18 and 54.3, respectively, and structure 21
is assigned to the isomer with the methine proton and
carbon at δ 2.91 and 60.5, respectively.
There are several possible explanations for the im-
proved yield obtained in the cyclization of (trimethylsilyl)-
alkyne 18b. The silicon may accelerate the radical
cyclization by making the alkyne more electron rich so
that it reacts faster with the electron deficient R-keto
radical. The silicon could also stabilize the intermediate
cyclic vinyl radical18a or facilitate H atom abstraction by
the radical, making termination of the reaction a more
efficient process.18b,c Lastly, the silicon may be stabilizing
the product.
Resu lts a n d Discu ssion
Model studies were conducted with alkynylcyclopen-
tanone 18a , which was prepared in 47% yield by Eschen-
moser fragmentation14 of epoxy ketone 1715 with
TsNHNH2 and HOAc in CH2Cl2. Silylation of the ter-
minal alkyne by treatment of 18a with 2.3 equiv of LDA
and 2.5 equiv of TMSCl and hydrolysis of the silyl enol
ether gives 18b in 95% yield. Mn(III)-induced cyclization
of 18a and 18b was investigated with both Mn(OAc)3 and
10a,16
Mn(pic)3
in a variety of solvents. No cyclic products
are obtained in EtOH at reflux, while cyclization occurs
in low yield in HOAc at 80-100 °C. Fortunately, the
reaction occurs efficiently in EtOH containing 5-30%
HOAc. A greater percentage of HOAc in the solvent
mixture is required with Mn(pic)3 to achieve a reasonable
rate of oxidation. As a consequence, vinylsilanes 21 and
22 partially desilylate during oxidative cyclization with
Mn(pic)3.
Syn th esis of Gym n om itr ol. The successful cycliza-
tion of [(trimethylsilyl)butynyl]cyclopentanone 18b to
vinylsilanes 21 and 22 suggested that oxidative cycliza-
tion of [(trimethylsilyl)butynyl]bicyclooctanone 4e and
desilylation of the product would provide a practical route
to gymnomitrone (6). As part of an unsuccessful route
to gymnomitrol based on the Conia ene reaction, Paquette
prepared 4e in 17% yield by the copper-catalyzed addition
(12) Choi, J .-K.; Hart, D. J .; Tsai, Y. M. Tetrahedron Lett. 1982, 23,
4765.
(13) Sha, C.-K.; J ean, T.-S.; Wang, D.-C. Tetrahedron Lett. 1990,
31, 3745.
(14) Pattenden, G.; Teague, S. J . J . Chem. Soc., Perkin Trans. 1
1988, 1077.
(15) O'Dell, D. E.; Loper, J . T.; Macdonald, T. L. J . Org. Chem. 1988,
(17) Curran, D. P.; van Elburg, P. A. Tetrahedron Lett. 1989, 30,
2501.
53, 5225.
(18) (a) Wilt, J . W.; Belmonte, F. G.; Zieske, P. A. J . Am. Chem.
Soc. 1983, 105, 5665. (b) Wilt, J . W.; Lusztyk, J .; Peeran, M.; Ingold,
K. U. J . Am. Chem. Soc. 1988, 110, 281. (c) Wilt, J . W. Tetrahedron
1985, 41, 3979.
(16) (a) Snider, B. B.; McCarthy, B. A. J . Org. Chem. 1993, 58, 6217.
(b) Snider, B. B.; Vo, N. H.; Foxman, B. M. J . Org. Chem. 1993, 58,
7228.

1972 J . Org. Chem., Vol. 62, No. 7, 1997
O’Neil et al.
of [(trimethylsilyl)propargyl]magensium bromide to 1,5-
dimethyl-2-methylenebicyclo[3.3.0]octanone followed by
trapping of the enolate with methyl iodide.4 Since this
procedure proceeded in even lower yield in our hands,
we developed an efficient synthesis of 4e.
Alkylation of bicyclooctanone 234 with LHMDS and
1-iodo-2-butyne affords 70% of a 3.6:6.7:1 mixture of the
two stereoisomers of 24 and geminally dialkylated mate-
rial and 24% of recovered 23. Methylation of 24 with
NaH and MeI gives 25 in 42% yield from 23 (56% based
on recovered 23). Methylation occurs from the convex
face of the thermodynamically more stable enolate as
reported by Welch for a similar system.5 Treatment of
25 with KAPA19 isomerizes the internal alkyne to give
terminal alkyne 4d in 71% yield. Silylation of 4d , as
described above for 18a , gives 4e in 92% yield. This four-
step procedure reproducibly converts ketone 23 to (tri-
methylsilyl)alkyne 4e in 37% overall yield.
celerates the cyclization of the 6-heptynyl radical in
addition to directing the regioselectivity of the cyclization
by its steric bulk.
Paquette reported that the thermal Conia ene reaction
of 4d does not give gymnomitrone (6).4 Since that time
Drouin and Conia developed a HgCl2-catalyzed cycliza-
tion of alkynyl silyl enol ethers that proceeds at room
temperature.21 However, this procedure is also not
suitable for the preparation of gymnomitrone (6). Alkyne
4d was converted to alkynyl silyl enol ether 28, which
was treated with 1.2 equiv of HgCl2 and 0.33 equiv of
HMDS in CH2Cl2 for 1 h to afford diketone 29,4 resulting
from hydration of the alkyne, in good yield. The reaction
is very slow (104 h) when excess HMDS (20 equiv) is used
to scavenge water, but still gives bicyclic ketone 29 as
the only product. Apparently, the silyl enol ether cannot
reach the alkyne-mercury complex.
Oxidative cyclization of 4e with 15 equiv of Mn(OAc)3
in 9:1 EtOH/HOAc at 90 °C for 22 h gives 47% (62% based
on recovered 4e) of a 1:1.4 mixture of diastereomeric
vinylsilanes 26 and 27. The methine proton and carbon
absorb at δ 2.63 and 73.7, respectively, in 26, and at δ
2.87 and 67.8, respectively, in 27, establishing the
stereochemistry as discussed above for 21 and 22. De-
silylation of the mixture of 26 and 27 in HOAc at 100 °C
for 5 h affords 80% of gymnomitrone (6), while desilyla-
tion with TFA at room temperature overnight provides
isogymnomitrone (7). Reduction of gymnomitrone (6)
with NaBH4 completes the synthesis, giving gymnomitrol
(1) in 88% yield.
Un su ccessfu l Ap p r oa ch es for th e Cycliza tion of
4c a n d 4d . Oxidative cyclization of terminal alkyne 4d
under the conditions used successfully for the cyclization
of 4e gives mainly oligomeric material and a trace of
gymnomitrone (6) as the only identifiable product. Hy-
drogenation of 4d over 5% Pd/BaSO4 in pyridine20 affords
90% of alkene 4c. Oxidative cyclization of alkene 4c with
3 equiv of Mn(OAc)3 and 1 equiv of Cu(OAc)2 in HOAc at
80 °C for 18 h provides mainly oligomeric material with
<5% of gymnomitrone (6). The low yield of 6 obtained
in the oxidative cyclizations of 4c and 4d is consistent
with the high degree of strain in the gymnomitrane ring
system noted in previous syntheses.3,4 If the R-keto
radical does not cyclize rapidly enough, it will initiate
oligomerization. The TMS group of 4e apparently ac-
Kende has developed Pd(OAc)2-induced cyclizations of
unsaturated silyl enol ethers as a versatile route to
bicyclic enones.22 This cyclization procedure also cannot
be used to prepare gymnomitrone (6). Alkene 4c was
converted to alkenyl silyl enol ether 30, which was
treated with Pd(OAc)2 in CH3CN for 48 h to provide a
mixture with enol acetate 31 being the major identifiable
product. Hydrolysis of the silyl enol ether of 31 in HOAc/
THF/H2O and hydrolysis of the enol acetate with K2CO2
(19) (a) Brown, C. A.; Yamashita, A. J . Am. Chem. Soc. 1975, 97,
891. (b) Brown, C. A. J . Chem. Soc., Chem. Commun. 1975, 222.
(20) (a) Smith, A. B.; Guaciaro, M. A.; Schow, S. R.; Wovkulich, P.
M.; Toder, B. H.; Hall, T. W. J . Am. Chem. Soc. 1981, 103, 219. (b)
J ohnson, F.; Paul, K. G.; Favara, D. J . Org. Chem. 1982, 47, 4254.
(21) (a) Drouin, J .; Boanventura, M.-A.; Conia, J .-M. J . Am. Chem.
Soc. 1985, 107, 1726. (b) Boaventura, M.-A.; Drouin, J . Bull. Soc. Chim.
Fr. 1987, 1015.
(22) Kende, A. S.; Roth, B.; Sanfilippo, P. J .; Blacklock, T. J . J . Am.
Chem. Soc. 1982, 104, 5808.

Synthesis of (()-Gymnomitrol
J . Org. Chem., Vol. 62, No. 7, 1997 1973
in MeOH provides diketone 29. Apparently the silyl enol
ether cannot reach the alkene-palladium complex.
Koreeda found that 3-methyl-3-[4-(trimethylsilyl)-3-
butynyl]cyclopentyl (32a ), generated reductively with
Bu3SnH, cyclizes to give 65% of bicyclic vinylsilane 33
resulting from the desired 6-exo-cyclization but that
radical 32b abstracts a hydrogen from Bu3SnH to afford
mainly 34 resulting from reduction.8b The failure of 32b
to cyclize provides further evidence of the ring strain in
the gymnomitrane ring system. Oxidative generation of
the radical from 4e with Mn(III) produces an electrophilic
R-keto radical that adds more rapidly to the electron rich
silylalkyne than does the nucleophilic radical of 32b.
Furthermore, ketone 4e will be regenerated if the R-keto
radical from 4e abstracts a hydrogen atom from EtOH.
Such a process would consume oxidant but not starting
material. For these reasons, the oxidative cyclization of
4e proceeds efficiently, while the reductive cyclization of
32b fails.
Oxid a tive Cycliza tion of 5-Hexyn yl Ra d ica ls. We
examined the Mn(OAc)3-induced cyclizations of 39a -c
and 43a -c to determine the scope of oxidative cyclization
of alkynyl ketones. Alkylation of the sodium salt of the
cycloalkanone carboxylate with the requisite propargyl
halide in THF affords 65-85% of 39 and 43. Reaction
of 39a with 7 equiv of Mn(OAc)3 in 19:1 EtOH/HOAc at
90 °C for 4 d affords 2% of 40a 9 and 38% of 42a .9
Oxidative cyclization of the analogous ethyl 1-allyl-2-
oxocyclohexanecarboxylate9 with Mn(OAc)3 and Cu(OAc)2
affords 4% of 40a , 66% of 42a , and 7% of a double-bond
position isomer of 42a , indicating that both the 5-hexenyl
and 5-hexynyl radicals undergo 6-endo-cyclization 20
times faster than 5-exo-cyclization. Treatment of 39b
with 7 equiv of Mn(OAc)3 in 19:1 EtOH/HOAc at 90 °C
for 4 d affords 13% of 40b, 16% of 41b, and 29% of 42b.
The methine carbon of 41b absorbs at δ 54.3 while the
methine carbon of 40b is shifted upfield to δ 50.6 by the
cis methyl group. A 1:1 mixture of 6-endo- and 5-exo-
cyclization products is obtained with a methyl group on
the triple bond.
Oxidative cyclization of (trimethylsilyl)alkyne 39c with
7 equiv of Mn(OAc)3 in 9:1 EtOH/HOAc at 100 °C for 1 d
provides 21% of 40c, 19% of 41c, and 5% of 42c. The
methine proton and carbon absorb at δ 3.09 and 53.7,
respectively, in 40c and at δ 2.88 and 57.7, respectively,
in 41c, establishing the stereochemistry as discussed
above for 21 and 22.17 An 8:1 mixture of 5-exo- and
6-endo-cyclization products is obtained with a trimeth-
ylsilyl group on the triple bond indicating that a tri-
methylsilyl group is much more effective than a methyl
group at promoting 5-exo-cyclization as noted previously
by Hart.12 Desilylation of 40c and 41c in TFA at 25 °C
affords 80% of 40a .9 Desilylation is slow in HOAc at 100
°C or with p-toluenesulfinic acid in wet acetonitrile at
reflux.31
Syn th esis of 9-Oxogym n om itr yl Aceta te a n d 9r-
Hyd r oxygym n om itr yl Aceta te. With gymnomitrol (1)
in hand we turned our attention to the preparation of
the recently isolated, more highly oxidized gymnomi-
tranes 2 and 3. Acetylation of gymnomitrol in 1:1 Ac2O/
pyridine at 90 °C for 12 h affords gymnomitryl acetate
(35) in 70% yield.1 Allylic oxidation of 35 with SeO2 and
t-BuOOH23 affords 9â-hydroxygymnomitryl acetate (36)
in 81% yield. As expected the alcohol is delivered from
the less hindered â-face. Treatment of 36 with PCC24 in
CH2Cl2 provides a 5:1 mixture of 9-oxogymnomitryl
1
acetate (3), possessing H and 13C NMR data identical
to those reported for the natural compound2 and enal 37.
Use of PDC25 improved the ratio to 15:1. Reduction of 3
to 9R-hydroxygymnomitryl acetate (2) was problematic
due to competing conjugate reduction.26 Treatment of 3
with CeCl3 and NaBH4 in MeOH27 gave a 4.6:2.5:1:1
1
mixture of 2, 38a , 38b, and 38c. Compound 2, with H
and 13C NMR spectral data identical to those reported
for the natural compound,2 was isolated in 47% yield. The
stereochemistry of 38a was established by the similarity
of the 1H NMR spectrum to that of the desacetoxy
compound.28 Hydroxy ketone 38c29 may be formed by
addition of oxygen30 to the least hindered â-face of the
enolate formed by conjugate addition of hydride to 3.
Oxidative cyclization of 43a , 43b, and 43c with 6-8
equiv of Mn(OAc)3 in 9-19:1 EtOH/HOAc for 1-4 d at
90 °C affords only the 6-exo-cyclization products 44a
(7%),9 44b (10%),9 and 44c (<2%) in very low yield.
Oxidative cyclization of the analogous 1-allyl- and 1-cro-
tyl-2-oxocyclopentanecarboxylates with Mn(OAc)3 and
Cu(OAc)2 affords 6-endo-cyclization products in 83-90%
yield and no 5-exo-cyclization products.9 2-Oxocyclopen-
tyl radicals show a much stronger preference for 6-endo-
cyclization than 2-oxocyclohexyl radicals. The low yields
of 44a -c indicate that 6-endo-cyclization of the 5-hexynyl
radicals obtained from 43 is much less efficient than
(23) Umbreit, M. A.; Sharpless, K. B. J . Am. Chem. Soc. 1977, 99,
5526.
(24) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 2647.
(25) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399.
(26) For a similar reduction problem, see: Bhaskar, K. V.; Chu, W.-
L. A.; Gaskin, P. A.; Mander, L. N.; Murofushi, N.; Pearce, D. W.;
Pharis, R. P.; Takahashi, N.; Yamaguchi, I. Tetrahedron Lett. 1991,
32, 6203.
(27) Luche, J .-L. J . Am. Chem. Soc. 1978, 100, 2226.
(28) Morais, R. M. S. C.; Harrison, L. J .; Becker, H. J . Chem. Res.,
Synop. 1988, 380.
(29) For
a similar natural product, see: Morais, R. M. S. C.;
Harrison, L. J .; Becker, H. Phytochemistry 1991, 30, 1013.
(30) J ones, A. B. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 7, Chapter 2.3.
(31) Bu¨chi, G.; Wu¨est, H. Tetrahedron Lett. 1977, 4305.

1974 J . Org. Chem., Vol. 62, No. 7, 1997
O’Neil et al.
(dq, 1, J ) 17.5, 2.7), 2.73 (dq, 1, J ) 16.5, 2.7), 2.48 (d, 1, J )
18.4), 2.40 (dq, 1, J ) 16.5, 2.7), 2.13 (d, 1, J ) 18.4), 2.12 (dq,
1, J ) 17.5, 2.7), 1.79 (t, 3, J ) 2.7), 1.77 (t, 3, J ) 2.7), 1.80-
1.45 (m, 6), 1.23 (s, 3), 1.16 (s, 3); 13C NMR 79.0, 78.1, 75.8,
74.1, 56.7, 53.1, 51.8, 44.7, 43.9, 39.6, 26.7, 23.5, 22.4, 21.1,
17.7, 3.6, 3.6, carbonyl carbon not observed; IR (CCl4) 2954,
2920, 2874, 1736, 1431, 1384, 1330, 1164 cm-1
.
(1r,3aâ,6aâ)-1-(2-Bu tyn yl)-h exah ydr o-1,3a,6a-tr im eth yl-
2(1H)-p en ta len on e (25). To a suspension of 235 mg (5.8
mmol) of 60% NaH in 30 mL of DME at rt was added 1.0 g of
the above mixture containing 24 in 10 mL of DME over 15
min. The solution was stirred at rt for 3 h and cooled to -10
°C. To the solution was added 0.46 mL (7.4 mmol) of MeI,
and the resulting solution was stirred at rt for 5 h, quenched
with 10 mL of 1.0 M HCl, diluted with 150 mL of Et2O, washed
with H2O and brine, and dried (MgSO4). Removal of the
solvent under reduced pressure followed by flash chromatog-
raphy on silica gel (100:1 hexane/EtOAc) gave 650 mg (42%
from 23, 56% based on recovered 23) of pure 25: 1H NMR 2.35
(d, 1, J ) 19.3), 2.34 (dq, 1, J ) 17.1, 2.6), 2.19 (br d, 1, J )
17.1), 2.18 (d, 1, J ) 19.3), 1.79 (t, 3, J ) 2.6), 1.80-1.59 (m,
6), 1.19 (s, 3), 1.18 (s, 3), 1.14 (s, 3); 13C NMR 222.6, 77.6, 76.2,
53.9, 53.8, 51.6, 45.8, 41.1, 38.6, 25.6, 25.2, 21.4, 20.7, 17.1,
6-endo-cyclization of the analogous 5-hexenyl radicals or
of the 5-hexynyl radicals obtained from 39.
3.5; IR (neat) 2953, 2874, 1734, 1448, 1382, 1190, 1064 cm-1
.
(1r,3aâ,6aâ)-1-(3-Bu tyn yl)-h exah ydr o-1,3a,6a-tr im eth yl-
2(1H)-p en ta len on e (4d ). To 3.6 g (31.5 mmol) of 35% KH
(rinsed with hexane three times) was added 23 mL of diamino-
propane. The KAPA solution was stirred at rt for 2.5 h, and
550 mg (2.52 mmol) of ketone 25 in 10 mL of diaminopropane
was added dropwise over 15 min. After 30 min of stirring at
rt, the solution was cooled to 0 °C and carefully quenched by
the addition of dilute HCl. The resulting solution was
extracted with Et2O three times, and the combined organic
layers were washed with 1 M HCl, H2O, and brine, dried
(MgSO4), and concentrated under reduced pressure to yield
500 mg of a yellow oil. Flash chromatography of the crude
residue on silica gel (100:1 hexane/EtOAc) yielded 393 mg
(71%) of pure crystalline 4d which was recrystallized from
hexane: mp 70-71 °C (lit.4 mp 70-71 °C); 1H NMR 2.53 (dddd,
1, J ) 16.5, 11.9, 4.8, 2.7), 2.36 (d, 1, J ) 18.8), 2.23 (dddd, 1,
J ) 16.5, 12.0, 5.4, 2.7), 2.20 (d, 1, J ) 18.8), 1.94 (t, 1, J )
2.7), 1.84 (ddd, 1, J ) 14.2, 12.0, 4.9), 1.75-1.49 (m, 7), 1.18
(s, 3), 1.07 (s, 3), 0.97 (s, 3); 13C NMR 222.8, 85.0, 68.1, 54.0,
53.8, 51.9, 45.8, 41.2, 38.4, 34.2, 25.7, 21.4, 19.3, 17.0, 13.8;
IR (CCl4) 3266, 2931, 2877, 2114, 1731, 1470, 1450, 1389, 1245
In conclusion, Mn(OAc)3-initiated cyclization of alkynyl
ketones in 9-19:1 EtOH/HOAc at 90 °C is a useful
cyclization procedure in favorable cases. Cyclization of
(trimethylsilyl)alkynyl ketone 4e provides 62% of silyl-
alkenes 26 and 27 in the key reaction of a seven-step
(16% overall yield) synthesis of gymnomitrol (1) from
readily available ketone 23.
Exp er im en ta l Section
cm-1
.
Gen er a l. All NMR spectra were recorded at 300 MHz in
CDCl3 unless otherwise indicated. Chemical shifts are re-
ported in δ and coupling constants are reported in hertz.
(1r,3a â,6a â)- a n d (1â,3a â,6a â)-1-(2-Bu t yn yl)-h exa h y-
d r o-3a ,6a -d im eth yl-2(1H)-p en ta len on e (24). To a solution
containing 11 mL of 1.0 M LHMDS in 10 mL of THF at -78
°C was added 1.1 g (7.24 mmol) of ketone 234 in 10 mL of THF
dropwise over 15 min. The solution was stirred at -78 °C for
15 min and at 0 °C for 1 h, and 2.0 g (11.1 mmol) of 1-iodo-
2-butyne was added. The solution was slowly warmed to rt
and stirred at rt for 1 h. The reaction was quenched by the
addition of 10 mL of 1.0 M HCl, and the mixture was diluted
with 150 mL of Et2O, washed with H2O and brine, and dried
(MgSO4). Removal of the solvent under reduced pressure
followed by flash chromatography on silica gel (50:1 hexane/
EtOAc) gave 1.03 g of an inseparable 3.6:6.7:1 mixture of the
two stereoisomers of 24 and geminally dialkylated product,
respectively, followed by 268 mg (24%) of recovered 23.
Data for 24: 1H NMR (R-butynyl) 2.61 (ddd, 1, J ) 17.0,
4.7, 2.7), 2.32 (ddd, 1, J ) 8.5, 4.7, 1.3), 2.16 (dd, 1, J ) 19.1,
1.2), 2.07 (d, 1, J ) 19.1), 2.12-1.40 (series of m, 7), 1.76 (t, 3,
J ) 2.7), 1.18 (s, 3), 1.08 (s, 3); (â-butynyl) 2.58 (ddd, 1, J )
17.0, 4.7, 2.7), 2.37 (d, 1, J ) 19.2), 2.28 (dd, 1, J ) 6.6, 4.7),
1.97 (d, 1, J ) 19.2), 2.12-1.40 (series of m, 7), 1.77 (t, 3, J )
2.7), 1.03 (s, 3), 0.91 (s, 3); 13C NMR (R-butynyl) 217.8, 77.7,
77.4, 57.2, 51.9, 50.5, 46.9, 37.6, 34.5, 22.7, 21.2, 20.9, 15.6,
3.5; (â-butynyl) 77.7, 77.1, 55.6, 52.2, 48.9, 46.7, 40.1, 36.5,
22.6, 21.2, 16.4, 14.8, 3.5, carbonyl carbon not observed; IR
(1r,3a â,6a â)-H e xa h yd r o-1,3a ,6a -t r im e t h yl-1-[4-(t r i-
m eth ylsilyl)-3-bu tyn yl]-2(1H)-p en ta len on e (4e). To 1.25
mmol of LDA in 10 mL of THF at -78 °C was added 109 mg
(0.5 mmol) of 4d in 10 mL of THF dropwise over 15 min. The
solution was stirred at rt for 2.5 h, and 0.17 mL (1.34 mmol)
of TMSCl was added. After being stirred for an additional 15
min at rt, the solution was quenched by addition of 5 mL of
H2O and 10 mL of HOAc. The quenched solution was stirred
for 12 h, diluted with Et2O, washed with H2O, saturated
NaHCO3 solution (×3), and brine, dried (MgSO4), and concen-
trated under reduced pressure to yield 150 mg of a clear oil.
Flash chromatography of the crude residue on silica gel (50:1
hexane/EtOAc) gave 134 mg (92%) of pure 4e: 1H NMR 2.53
(ddd, 1, J ) 16.5, 11.6, 4.8), 2.35 (d, 1, J ) 19.0), 2.26 (ddd, 1,
J ) 16.5, 11.7, 4.8), 2.20 (d, 1, J ) 19.0), 1.82 (ddd, J ) 14.1,
11.7, 4.8), 1.75-1.51 (m, 7), 1.17 (s, 3), 1.06 (s, 3), 0.97 (s, 3),
0.14 (s, 9); 13C NMR 222.8, 107.8, 84.2, 54.0, 53.9, 51.8, 45.8,
41.1, 38.4, 34.4, 25.7, 21.4, 19.4, 17.1, 15.2, 0.1 (3 C); IR (neat)
2956, 2875, 2175, 1732, 1248 cm-1
.
Mn (OAc)3-In itia ted Cycliza tion of 4e. A solution con-
taining 45 mg (0.16 mmol) of ketone 4e and 416 mg (1.6 mmol)
of Mn(OAc)3‚2H2O in 3.5 mL of degassed 9:1 EtOH/HOAc was
heated at 90 °C in a resealable tube under N2 for 10 h. An
additional 208 mg (0.78 mmol) of Mn(OAc)3‚2H2O was added,
and heating was continued for another 12 h at 90 °C. Workup
as described for the cyclization of 18a gave 52 mg of crude
material. Flash chromatography of the residue on silica gel
(100:1 hexane/EtOAc) gave 21 mg (47%, 62% based on recov-
ered 4e) of a 1:1.4 mixture of diastereomeric vinylsilanes 26
and 27 followed by 11 mg (24%) of recovered 4e. Early
(neat) 2955, 2871, 1739, 1451, 1381, 1251, 1166 cm-1
.
Data for geminally dialkylated product: mp 154.5-155.5
1
°C (crystallized from crude mixture in MeOH); H NMR 2.81

Synthesis of (()-Gymnomitrol
J . Org. Chem., Vol. 62, No. 7, 1997 1975
fractions contained a ≈9:1 mixture of 27 and 26. Late
fractions contained a ≈9:1 mixture of 26 and 27.
and 30 mg (0.3 mmol) of 90% t-BuOOH in 1 mL of CH2Cl2
was added 3.5 mg (13 µmol) of gymnomitryl acetate (35) in
1 mL of CH2Cl2. The solution was stirred at rt under N2 for 8
h, diluted with 20 mL of ether, washed with 15% NaOH
solution and brine, and dried (MgSO4). Removal of the solvent
under reduced pressure yielded 5 mg of crude material. Flash
chromatography on silica gel (5:1 hexane/EtOAc) gave 3 mg
(81%) of pure 36: 1H NMR 5.13 (dd, 1, J ) 2.3, 1.4), 4.94 (br
s, 1), 4.85 (s, 1), 4.54 (m, 1), 2.55 (s, 1), 2.33 (dd, 1, J ) 13.8,
8.4), 2.08 (s, 3), 1.96-1.72 (m, 4), 1.37 (dd, 1, J ) 13.8, 10.3),
1.25-1.18 (m, 2), 1.16 (s, 3), 1.08 (s, 3), 0.89 (s, 3); 13C NMR
151.9, 109.9, 91.7, 67.6, 60.2, 55.4, 55.3, 48.5, 48.2, 38.7, 37.2,
28.4, 27.1, 23.9, 21.4, 18.7, acetate carbonyl carbon not
observed; IR (CCl4) 3418, 2958, 2870, 1741, 1649, 1465, 1375,
Data for 26: 1H NMR 5.27 (d, 1, J ) 2.5), 2.63 (s, 1), 2.47-
2.30 (m, 2), 2.15-1.33 (series of m, 8), 0.93 (s, 6), 0.82 (s, 3),
0.08 (s, 9); 13C NMR 157.1, 127.6, 73.7, 52.3, 48.9, 47.7, 38.5,
36.7, 35.7, 27.6, 27.0, 24.0, 23.2, 17.7, 0.06 (3 C), carbonyl
carbon not observed; IR (neat) 2955, 2175, 1745, 1605, 1456,
1388, 1248 cm-1
.
Data for 27: 1H NMR 5.32 (dd, 1, J ) 2.4, 0.8), 2.87 (s, 1),
2.73-2.59 (m, 1), 2.19-1.33 (series of m, 9), 0.96 (s, 3), 0.92
(s, 3), 0.83 (s, 3), 0.12 (s, 9); 13C NMR 217.2, 157.7, 127.3, 67.8,
51.9, 49.0, 47.5, 38.1, 36.8, 35.7, 32.2, 26.9, 24.0, 23.2, 17.7,
-1
0.6 (3 C); IR (neat) 2955, 2174, 1743, 1607, 1456, 1249 cm
.
Gym n om itr on e (6). A solution of 15 mg (0.052 mmol) of
a mixture of vinylsilanes 26 and 27 in 2 mL of HOAc was
heated at 100 °C for 5 h. The solution was diluted with 30
mL of ether, washed three times with saturated NaHCO3
solution and once with brine, dried (MgSO4), and concentrated
under reduced pressure to yield 11 mg of crude material.
Flash chromatography of the crude residue on silica gel (100:1
hexane/EtOAc) gave 9 mg (80%) of gymnomitrone (6): 1H NMR
4.77 (br s, 1), 4.76 (br s, 1), 2.64 (s, 1), 2.55 (ddddd, 1, J )
16.3, 12.9, 8.1, 2.7, 2.7), 2.18 (br dd, 1, J ) 16.3, 7.0), 2.09 (br
dd, 1, J ) 12.5, 7.0), 2.01-1.34 (series of m, 7), 0.95 (s, 3),
0.93 (s, 3), 0.83 (s, 3); 13C NMR 148.9, 112.2, 68.9, 52.2, 48.9,
47.3, 38.6, 36.7, 35.7, 28.0, 26.8, 24.0, 23.2, 17.7, carbonyl
carbon was not observed; IR (CCl4) 3077, 2959, 2869, 1745,
1240, 1046 cm-1
.
9-Oxogym n om itr yl Aceta te (3). A solution of 1 mg (3.6
µmol) of allylic alcohol 36 and 10 mg (26 µmol) of PDC in
0.5 mL of CH2Cl2 was stirred at rt under N2 for 3 h. The crude
mixture was filtered through a short silica gel plug and
concentrated under reduced pressure to give a quantitative
yield of a 15:1 mixture of enone 3 and enal 37. Enone 3 was
easily obtained pure by flash chromatography on silica gel
(10:1 hexane/EtOAc): 1H NMR 6.07 (d, 1, J ) 1.7), 5.21 (d, 1,
J ) 1.2), 5.04 (s, 1), 2.81 (d, 1, J ) 19.9), 2.73 (s, 3), 2.23 (d, 1,
J ) 19.9), 2.13 (s, 3), 1.85-1.10 (m, 6), 1.20 (s, 3), 1.11 (s, 3),
0.96 (s, 3); 13C NMR 145.2, 123.1, 87.0, 58.2, 55.8, 55.0, 51.5,
48.4, 40.3, 38.8, 28.0, 25.5, 24.2, 21.3, 19.8, carbonyl carbon
not observed. The spectral data are identical to those re-
ported.2
1
1641, 1461, 1388, 1276 cm-1. The H NMR spectral data are
identical to those previously reported.1,3-5
Partial 1H NMR data for 37 were determined from the
mixture: 9.44 (s, 1), 6.56 (m, 1), 4.93 (s, 1), 2.10 (s, 3), 1.20 (s,
3), 1.07 (s, 3), 0.97 (s, 3).
Gym n om itr ol (1). To a solution of 8 mg (0.037 mmol) of
gymnomitrone (6) in 1 mL of MeOH at 0 °C was added 8 mg
of NaBH4. The mixture was stirred at 0 °C for 1 h, and the
reaction was quenched by the addition of 2 drops of 1 M HCl.
The quenched reaction was diluted with ether, washed with 1
M HCl and brine, dried (MgSO4), and concentrated under
reduced pressure to yield 8 mg of crude gymnomitrol. Flash
chromatography of the residue on silica gel (50:1 hexane/
EtOAc) gave 7 mg (88%) of pure gymnomitrol (1): 1H NMR
4.66 (s, 1), 4.65 (s, 1), 3.72 (s, 1), 2.51-2.33 (m, 1), 2.34 (s, 1),
2.14 (dd, 1, J ) 16.8, 8.0), 2.00-1.10 (series of m, 7), 1.40 (ddd,
1, J ) 14.0, 12.2, 8.2), 1.24 (s, 3), 1.09 (s, 3), 0.96 (s, 3); 13C
NMR 151.3, 108.9, 91.8, 62.7, 55.3, 54.3, 47.5, 38.5, 37.2, 37.0,
28.8, 28.3, 27.2, 24.7, 19.8; IR (CCl4) 3625, 3416, 3071, 2933,
9r-Hyd r oxygym n om itr yl Aceta te (2). To a solution of
1.5 mg (5.4 µmol) of enone 3 and 6 mg (16 µmol) of CeCl3‚7H2O
in 0.5 mL of MeOH at 0 °C was added a trace of NaBH4. The
solution was stirred at 0 °C for 5 min, diluted with ether,
washed with 1 M HCl and brine, and dried (MgSO4). Removal
of the solvent under reduced pressure gave 1.4 mg of a mixture
of 2, 38a , 38b, and 38c in a 4.6:2.5:1.0:1.0 ratio, respectively.
Flash chromatography of the crude residue on silica gel (200:1
CH2Cl2/MeOH) gave 0.7 mg (47%) of pure 2: 1H NMR 5.20 (d,
1, J ) 2.4), 5.03 (s, 1), 4.91 (d, 1, J ) 2.4), 4.47 (m, 1), 2.46 (s,
1), 2.08 (s, 3), 1.95 (dd, 1, J ) 14.9, 9.7), 1.86 (m, 1), 1.83 (dd,
1, J ) 14.9, 8.4), 1.5-0.9 (m, 5), 1.15 (s, 3), 1.03 (s, 3), 0.94 (s,
3); 13C NMR 150.5, 111.7, 83.4, 65.1, 58.2, 54.9, 48.6, 42.5, 40.0,
39.4, 28.0, 24.7, 24.6, 21.7, 21.4, acetate carbonyl carbon and
one quaternary carbon were not observed. Spectral data are
identical to those reported except the carbon observed at 83.4
was reported to be 84.3.2
1
2868, 1644, 1464, 1372 cm-1. The H NMR spectral data are
identical to those previously reported.1,3-5
Gym n om itr yl Aceta te (35). A mixture of 9 mg (0.041
mmol) of gymnomitrol (1), 1 mL Ac2O, and 1 mL of pyridine
was heated at 90 °C for 12 h. The crude mixture was diluted
with 30 mL of ether, washed with H2O (×3), CuSO4 solution,
saturated NaHCO3 solution, and brine, and dried (MgSO4).
Removal of the solvent under reduced pressure and purifica-
tion by flash chromatography on silica gel (100:1 hexane/
EtOAc) gave 7.5 mg (70%) of pure 35: 1H NMR 4.77 (s, 1),
4.72 (d, 1, J ) 2.6), 4.71 (d, 1, J ) 2.6), 2.50-2.37 (m, 1), 2.38
(s, 1), 2.19 (dd, 1, J ) 16.9, 8.0), 2.08 (s, 3), 2.00-1.10 (series
of m, 8), 1.15 (s, 3), 1.07 (s, 3), 0.87 (s, 3); 13C NMR 149.5,
110.4, 92.5, 60.3, 55.2, 54.9, 46.8, 38.3, 37.2, 36.8, 28.2, 28.0,
27.2, 24.1, 21.5, 20.0, acetate carbonyl carbon not observed;
Ack n ow led gm en t. We thank the National Insti-
tutes of Health for financial support.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for all other compounds and H and 13C NMR spectra
of new compounds (52 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.
IR (CCl4) 2958, 2869, 1741, 1644, 1464, 1362, 1233 cm-1
.
9â-Hyd r oxygym n om itr yl Aceta te (36). To a solution of
0.1 mg (0.9 µmol) of SeO2, 1 mg (7.2 µmol) of salicylic acid,
J O9622338