Total synthesis of neohedycaryol. Its possible role in the biosynthesis of eudesmane sesquiterpenes

Article abstract of DOI:10.1021/jo962056a

The total synthesis of neohedycaryol (4), the C(9)-C(10) double bond regioisomer of the germacrane sesquiterpene hedycaryol, was accomplished in 10 steps from the known dione 6. A Marshall fragmentation of the intermediate mesylate 14 was used to prepare the trans,trans-cyclodeca-1,6-diene ring present in neohedycaryol. During the synthesis of 14, a pronounced example of through-bond interactions (TBI) was observed. The preferred elongated chair conformation of neohedycaryol was demonstrated spectroscopically and by chemical conversion into α-, β-, and γ-eudesmol. These findings indicate that the occurrence of neohedycaryol as a precursor in the biosynthesis of epi-eudesmanes as proposed in the literature is unlikely. The preference of neohedycaryol for the elongated chair conformation further shows that the compound occupies the meso form. This implies that neohedycaryol may act as a precursor in the biosynthesis of both ent- and usual eudesmanes.

Full text of DOI:10.1021/jo962056a

2344
J . Org. Chem. 1997, 62, 2344-2349
Tota l Syn th esis of Neoh ed yca r yol. Its P ossible Role in th e
Biosyn th esis of Eu d esm a n e Sesqu iter p en es
Adriaan J . Minnaard, Gerrit A. Stork, J oannes B. P. A. Wijnberg,* and Aede de Groot*
Laboratory of Organic Chemistry, Agricultural University,
Dreijenplein 8, 6703 HB Wageningen, The Netherlands
Received November 4, 1996X
The total synthesis of neohedycaryol (4), the C(9)-C(10) double bond regioisomer of the germacrane
sesquiterpene hedycaryol, was accomplished in 10 steps from the known dione 6. A Marshall
fragmentation of the intermediate mesylate 14 was used to prepare the trans,trans-cyclodeca-1,6-
diene ring present in neohedycaryol. During the synthesis of 14, a pronounced example of through-
bond interactions (TBI) was observed. The preferred elongated chair conformation of neohedycaryol
was demonstrated spectroscopically and by chemical conversion into R-, â-, and γ-eudesmol. These
findings indicate that the occurrence of neohedycaryol as a precursor in the biosynthesis of epi-
eudesmanes as proposed in the literature is unlikely. The preference of neohedycaryol for the
elongated chair conformation further shows that the compound occupies the meso form. This implies
that neohedycaryol may act as a precursor in the biosynthesis of both ent- and usual eudesmanes.
Sch em e 1
In tr od u ction
Germacrane sesquiterpenes, structurally characterized
by a trans,trans-cyclodeca-1(10),4-diene unit,1 and their
1,10-monoepoxides are generally considered as direct
precursors of eudesmane sesquiterpenes.2 Strong evi-
dence for the involvement of these monocyclic compounds
in the biogenetic formation of eudesmanes comes from
enzyme- and acid-mediated cyclization reactions. For
instance, incubation of (+)-hedycaryol (1) with a root
suspension of chicory (Cichorium intybus) gave selectively
cryptomeridiol (2),3 while a mixture of R-, â-, and
γ-eudesmol (3a , 3b, and 3c, respectively) was obtained
upon treatment of 1 with acid4 (Scheme 1). The forma-
tion of these eudesmanes can easily be explained by
enzymatic or chemical protonation of the C(1)-C(10)
double bond followed by cyclization (formation of the
C(5)-C(10) bond) and subsequent incorporation of water
(in case of 2) or proton loss (in case of 3a , 3b, and 3c).
Sch em e 2
The stereochemical aspects of these cyclization reac-
1
tions are also important. Although H NMR experiments
clearly show that 1 exists in at least three different
conformations at room temperature,5 cyclization of 1 only
affords the trans-fused eudesmane skeleton with a syn
relationship between the C(10) Me group and the C(7)
side chain. Because the different conformers are inter-
converting at room temperature as depicted in Scheme
2, it is obvious that 1 only cyclizes via the conformer A
in which both vinylic Me groups are on the â-face.6
configuration as present in the structures 2 and 3.7
A
small number of eudesmanes, however, has an aberrant
configuration at C(5) and/or C(10).8 These so-called epi-
eudesmanes have been found in plant species together
with the usual eudesmanes.9
The greater part of the eudesmanes isolated from
higher plants possesses the same relative and absolute
X Abstract published in Advance ACS Abstracts, March 15, 1997.
(1) The numbering system as given in structure 1 will be followed
throughout the text of this paper.
(2) (a) Fischer, N. H. In Recent Advances in Phytochemistry, Vol.
24: Biochemistry of the Mevalonic Acid Pathway to Terpenoids; Towers,
G. H. N., Stafford, H. A., Eds.; Plenum Press: New York, 1990; Chapter
4. (b) Marco, J . A.; Sanz-Cervera, J . F.; Garc´ıa-Lliso, V.; Domingo, L.
R.; Carda, M.; Rodr´ıguez, S.; Lo´pez-Ortiz, F.; Lex, J . Liebigs Ann.
Chem. 1995, 1837 and references cited therein.
(6) This is explained by the Curtin-Hammett principle, see: Eliel,
E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley Interscience: New York, 1994; pp 647-655.
(7) (a) Connolly, J . D.; Hill, R. A. Dictionary of Terpenoids; Chapman
& Hall: London, 1991; Vol. 1, Mono- and Sesquiterpenoids. (b) Pietra,
F. Chem. Soc. Rev. 1995, 24, 65.
(8) The 7-epi-eudesmanes are the antipodes of 5-epi-10-epi-eudes-
manes and, consequently, possess the ent-configuration. For example,
see: van Beek, T. A.; Kleis, R.; Posthumus, M. A.; van Veldhuizen, A.
Phytochemistry 1989, 28, 1909.
(3) Piet, D. P.; Minnaard, A. J .; van der Heyden, K. A.; Franssen,
M. C. R.; Wijnberg, J . B. P. A.; de Groot, A. Tetrahedron 1995, 51,
243.
(4) J ones, R. V. H.; Sutherland, M. D. J . Chem. Soc., Chem.
Commun. 1968, 1229.
(5) (a) Wharton, P. S.; Poon, Y. C.; Kluender, H. C. J . Org. Chem.
1973, 38, 735. (b) Minnaard, A. J . Unpublished.
(9) For some representative examples, see: (a) Prudent, D.; Perineau,
F.; Bessiere, J . M.; Michel, G.; Bravo, R. J . Essent. Oil Res. 1993, 5,
255. (b) Can˜igueral, S.; Vila, R.; Vicario, G.; Tomas, X.; Adzet, T.
Biochem. Syst. Ecol. 1994, 22, 307.
S0022-3263(96)02056-7 CCC: $14.00 © 1997 American Chemical Society

Total Synthesis of Neohedycaryol
J . Org. Chem., Vol. 62, No. 8, 1997 2345
Sch em e 3
Several hypotheses have appeared in the literature to
unravel the biosynthesis of epi-eudesmanes. In the most
straightforward explanation, both the epi- and usual
eudesmanes are formed from trans,trans-germacranes.10
From the conformations of 1 depicted in Scheme 2, it can
easily be deduced that cyclization of the conformations
B, C, and D will lead to 5-epi-, 10-epi-, and 5-epi-10-epi-
eudesmanes, respectively. In the literature, two ex-
amples are known in which trans,trans-germacranes
yielded epi-eudesmanes.11,12 In both cases, however, the
trans,trans-cyclodeca-1(10),4-diene ring bears a â sub-
stituent at C(6) as a result of which conformation A will
be less favorable.
A second explanation for the biosynthesis of epi-
eudesmanes assumes the cyclization of double bond
stereoisomers of trans,trans-germacranes.13 It has been
shown that acid-catalyzed cyclizations of cis,trans-
isomers of 1 do give epi-eudesmanes.11,14 A serious
drawback of this hypothesis is the fact that the double
bond stereoisomers of simple trans,trans-germacranes
have not been found in nature.15
Sch em e 4
In a third explanation, the one we will concentrate on,
the cyclization of a double bond regioisomer of trans,-
trans-germacranes has been proposed. It was already
recognized in 1959 by Hendrickson that cyclization of the
C(9)-C(10) double bond regioisomer of hedycaryol, sub-
sequently named neohedycaryol (4), might give an eudes-
mane.16 This suggestion was picked up by McSweeney
et al. who reasoned that cyclization to both epi- and usual
eudesmanes would proceed via different conformations
of 4.17 Experimental information, however, failed to
appear because 4 was not available. Some years later,
a route toward agarofurans based on 4 was postulated.18
Since then, 4 has been mentioned several times in
connection with the biosynthesis of epi-eudesmanes,19
eremophilanes,20 and agarofurans.21
are close to each other and cyclization can occur via stable
tertiary carbocations. In this context, it is important to
note that examination of a three-dimensional model of 4
revealed several interesting stereochemical aspects. The
trans,trans-cyclodeca-4,9-diene system of 4 can be con-
sidered as a cyclohexane ring elongated with two double
bonds (Scheme 3). There are two conformations in which
the double bonds are lying parallel (comparable with the
chair and boat conformation of cyclohexane) and two
conformations in which the double bonds are crossed (the
twist conformations of cyclohexane).24 It also appeared
that in the parallel conformations, 4 has on the average
a symmetry plane, and this means that the compound
occupies a meso form. The two crossed forms are
enantiomers of each other.
Because of our interest in the biogenetic-like cyclization
reactions of germacrane sesquiterpenes3,25 and their
analogues,26 we decided to synthesize neohedycaryol. As
with hedycaryol,3 it was expected that the acid-catalyzed
cyclization of 4 would provide more information about
its possible role in the biosynthesis of eudesmanes.
In our synthetic approach to 4, the known dione 627
was used as the starting material (Scheme 4). A number
of apparently simple reactions was needed to prepare the
mesylate 5 from 6. The key step in this approach, the
conversion of 5 into neohedycaryol, involved a Marshall
fragmentation reaction in which both double bonds are
regio- and stereospecifically formed.28
Although recently two C(5)-C(6) double bond regio-
isomers of hedycaryol have been isolated from higher
plants,22,23 4 has not been found in nature. This does not
imply that 4 does not exist. It may have escaped isolation
due to its supposed instability; the ten-membered ring
should be prone to cyclization because the double bonds
(10) Itokawa, H.; Morita, H.; Watanabe, K.; Mihoshi, S.; Iitaka, Y.
Chem. Pharm. Bull. 1985, 33, 1148.
(11) Kodama, M.; Shimada, K.; Itoˆ, S. Tetrahedron Lett. 1981, 22,
1523.
(12) Appendino, G.; Gariboldi, P. J . Chem. Soc., Perkin Trans. 1
1983, 2017.
(13) An indication for this pathway is the cooccurrence of trans,cis-
farnesol (a precursor of cis,trans-germacranes) and epi-eudesmanes in
Galbanum species, see: Thomas, A. F.; Ozainne, M. Helv. Chim. Acta
1978, 61, 2874.
(14) Kodama, M.; Yokoo, S.; Matsuki, Y.; Itoˆ, S. Tetrahedron Lett.
1979, 1687.
(15) All trans,cis-germacranes (heliangolides) and cis,trans-germac-
ranes (melampolides) possess one or more lactone rings, an exception
being helminthogermacrene, see: Winter, R. E. K.; Dorn, F.; Arigoni,
D. J . Org. Chem. 1980, 45, 4786.
(16) Hendrickson, J . B. Tetrahedron 1959, 7, 82.
(17) MacSweeney, D. F.; Ramage, R.; Sattar, A. Tetrahedron Lett.
1970, 557.
Resu lts a n d Discu ssion
Following the procedure described by Agami et al.,29
the synthesis of 6 started with the addition of ethyl vinyl
(24) Only the interconversion of the conformations by rotation of
the double bonds is considered.
(25) Piet, D. P.; Schrijvers, R.; Franssen, M. C. R.; de Groot, A.
Tetrahedron 1995, 51, 6303.
(18) Bru¨ning, R.; Wagner, H. Phytochemistry 1978, 17, 1821.
(19) (a) Southwell, I. A. Aust. J . Chem. 1978, 31, 2527. (b) Roberts,
J . S. The sesquiterpenes. In Chemistry of Terpenes and terpenoids;
Newman, A. A., Ed.; Academic Press: London, 1972; pp 88-146.
(20) (a) Manitto, P. Biosynthesis of Natural Products; J ohn Wiley
& Sons: New York, 1981; Chapter 5. (b) Teisseire, P. J . Chemistry of
Fragrant Substances; VCH: New York, 1994; pp 216-218.
(21) Southwell, I. A.; Tucker, D. J . Phytochemistry 1993, 33, 857.
(22) Valle, M. G.; Appendino, G.; Nano, G. M.; Picci, V. Phytochem-
istry 1987, 26, 253.
(26) (a) Piet, D. P.; Franssen, M. C. R.; de Groot, A. Tetrahedron
1994, 50, 3169. (b) Piet, D. P.; Franssen, M. C. R.; de Groot, A.
Tetrahedron 1996, 52, 11273.
(27) Huffman, J . W.; Hillenbrand, G. F. Tetrahedron 1981, 37,
Supplement No.1, 269.
(28) (a) Marshall J . A. Synthesis 1971, 229. For some recent
examples in germacrane chemistry, see: (b) Minnaard, A. J .; Wijnberg,
J . B. P. A.; de Groot, A. Tetrahedron 1994, 50, 4755, and (c) Zhabinskii,
V. A.; Minnaard, A. J .; Wijnberg, J . B. P. A.; de Groot, A. J . Org. Chem.
1996, 61, 4022.
(23) Gansser, D.; Pollak, F. C.; Berger, R. G. J . Nat. Prod. 1995,
58, 1790.
(29) Agami, C.; Meynier, F.; Puchot, C.; Guilhem, J .; Pascard, C.
Tetrahedron 1984, 40, 1031.

2346 J . Org. Chem., Vol. 62, No. 8, 1997
Minnaard et al.
Sch em e 5
result, no problems were reported for the mesylation of
a homoallylic alcohol similar to 11 but lacking the C(7)
substituent.35 It was therefore assumed that the dif-
ficulties encountered with the mesylation of 11 were due
to the presence of the C(7) 2-propanol group.36 Strong
support for this assumption came from our previous
studies on trans-fused perhydronaphthalene-37 and nor-
bornane-1,4-diol monosulfonate esters.38 It has been
demonstrated that deprotonation of the alcohol function
of these compounds leads to a strongly enhanced leaving
group ability of the sulfonate ester group, almost cer-
tainly as a result of long-range orbital interactions
through the four σ-bonds between the alcoholate anion
(electron donor) and the sulfonate ester bond (electron
acceptor). The extent of these through-bond orbital
interactions (TBI)39 depends on the geometry of the
σ-relay (the intervening σ-framework) and is maximized
for an all-trans arrangement.40 From examination of a
molecular model of 5, it appeared that the σ-relay
between the tertiary hydroxyl group at C(11) and the
mesylate group at C(9) possesses such an all-trans
arrangement. This should mean that deprotonation of
the C(11) hydroxyl group strongly enhances the leaving
group ability of the mesylate group. Because the syn-
thesis of mesylate 5 requires the use of pyridine,41
hydrogen bond formation between pyridine and the C(11)
alcohol function will lead to partial negative charge on
the C(11) oxygen, thereby increasing the leaving group
ability of the mesylate group. Consequently, the mesy-
late group of 5 will be very susceptible to nucleophilic
replacement as the reaction outcome of our initial me-
sylation experiments clearly showed (vide supra).
ketone (EVK) to hydroxycarvone which was easily pre-
pared from (R)-(-)-carvone.27 In our hands, both the
reported enantioselective30 and the acid-catalyzed ring
closure31 of the addition product, a 3:2 mixture of two
triketones, did not yield any workable result. It was then
decided to achieve cyclization with a substoichiometric
amount of pyrrolidine in refluxing benzene. In this way,
racemic 6 was obtained in 38% yield (Scheme 5). Reduc-
tion of the C(9) carbonyl group of 6 with NaBH4 and
protection of the resulting alcohol as its TBDMS ether
gave 7 in good yield. Selective epoxidation of the double
bond in the side chain of 7 was effected with dimethyl-
dioxirane and afforded 8 as a diastereomeric 1:1 mixture.
Reduction of 8 with lithium tri-tert-butoxyalumino-
hydride (LiAl(Ot-Bu)3H) provided 9 also as a diastereo-
meric 1:1 mixture in 87% yield. Since the LiAl(Ot-Bu)3H
reduction of a system comparable to 8 proceeds selectively
from the R-side,32 the orientation of the C(3) hydroxyl
group of 9 is probably â. In order to remove the oxygen
function at C(3), the phosphordiamidate of 9 was reduced
with Li in EtNH2.33 In this way, not only the C(3)-O
bond was reduced but also the epoxide ring was opened
to give almost pure 10 in high yield. Cleavage of the C(9)
Si-O bond with TBAF in hot DMSO afforded the diol
11 in pure form after recrystallization from EtOH.
In order to apply the Marshall fragmentation reaction,
the C(9) hydroxyl group of 11 had to be converted into a
mesylate group, and here we encountered a curious
problem. Despite many attempts, we were not able to
produce the desired mesylate 5. For instance, treatment
of 11 with MsCl in dry pyridine at -10 °C showed the
complete disappearance of the starting material on TLC,
but workup and purification only afforded a small
amount of a compound which contained Cl as deduced
Having thus explained the anomalous behavior of
mesylate 5, the solution was obvious: protection of the
C(11) hydroxyl function as its acetate to prevent hydro-
gen bond formation. In order to confirm this hypothesis,
10 was treated with Ac2O and a catalytic amount of
DMAP in Et3N42 to afford 12 in 82% yield (Scheme 6).
After removal of the TBDMS protecting group, treatment
of the resulting alcohol 13 with MsCl in pyridine now
proceeded without any problems and gave the mesylate
14 in 89% yield. The NMR and mass spectral data of 14
are fully consistent with the assigned structure.
The Marshall fragmentation reaction of mesylate 14
was expected to complete the synthesis of neohedy-
(34) 1H NMR δ 1.04 (s, 3 H), 1.15 (s, 6 H), 1.65 (br s, 3 H), 1.1-2.1
(m, 11 H), 2.55 (ddd, J ) 2.2, 2.2, 12.5 Hz, 1 H), 3.74 (dd, J ) 4.4, 12.2
Hz, 1 H); 13C NMR δ 18.76 (q), 18.84 (t), 19.85 (q), 25.52 (t), 26.87 (q),
27.27 (q), 33.17 (t), 34.37 (t), 37.36 (t), 40.68 (s), 48.98 (d), 72.28 (s),
72.69 (d), 128.58 (s), 133.01 (s); MS m/ z (relative intensity) 258 (M+
+ 2, 3), 256 (M+, 9), 240 (33), 238 (100), 225 (7), 223 (21), 197 (20), 195
(60), 187 (34), 159 (36), 59 (48).
(35) Bundy, G. L. Synthesis of Cyclodecadienes from Decalylborane
Derivatives; Ph.D. Thesis, Northwestern University, Evanston, Illinois,
1968.
(36) Initially, it was thought that just the presence of the homoallylic
double bond frustrated the mesylation of 11, see: Shoppee, C. W.;
Summers, G. H. R. J . Chem. Soc. 1952, 3361.
(37) (a) Orruj, R. V. A.; Wijnberg, J . B. P. A.; J enniskens, L. H. D.;
de Groot, A. J . Org. Chem. 1993, 58, 1199. (b) Orruj, R. V. A.; Wijnberg,
J . B. P. A.; Bouwman, C. T.; de Groot, A. J . Org. Chem. 1994, 59, 374.
(c) Orruj, R. V. A.; Wijnberg, J . B. P. A.; de Groot, A. J . Org. Chem.
1995, 60, 4233.
from its mass spectrum. In its 1H NMR spectrum,34
a
one-proton signal appears as a double doublet at δ 3.74
with couplings of 4.4 and 12.2 Hz, indicating the replace-
ment of the C(9) hydroxyl group by Cl with retention of
configuration. In sharp contrast with this unexpected
(38) Bastiaansen, P. M. F. M.; Wijnberg, J . B. P. A.; de Groot, A. J .
Org. Chem. 1995, 60, 4240.
(39) Paddon-Row, M. N.; J ordan, K. D. In Modern Models of Bonding
and Delocalization; Liebman, J . F., Greenberg, A., Eds.; VCH Publish-
ers: New York, 1988, Chapter 3 and references cited therein.
(40) Paddon-Row, M. N. Acc. Chem. Res. 1982, 15, 245.
(41) Crossland, R. K.; Servis, K. L. J . Org. Chem. 1970, 35, 3195.
(42) Steglich, W.; Ho¨fle, G. Angew. Chem., Int. Ed. Engl. 1969, 8,
981.
(30) Agami, C.; Kadouri-Puchot, C.; Le Guen, V. Tetrahedron:
Asymmetry 1993, 4, 641.
(31) Li, Y.; Chen, X.; Shao, S.; Li, T. Ind. J . Chem. 1993, 32B, 356.
(32) Marshall, J . A.; Ruth, J . A. J . Org. Chem. 1974, 39, 1971.
(33) Ireland, R. E.; Muchmore, D. C.; Hengartner, U. J . Am. Chem.
Soc. 1972, 94, 5098.

Total Synthesis of Neohedycaryol
J . Org. Chem., Vol. 62, No. 8, 1997 2347
Sch em e 6
Con clu d in g Rem a r k s
These findings show that neohedycaryol (4) preferen-
tially exists in the elongated chair conformation at room
temperature. Consequently, its cyclization can only
result in the usual stereochemistry of eudesmanes found
in higher plants as confirmed by the formation of R-, â-,
and γ-eudesmol upon acid treatment. For this reason, 4
is a less likely precursor in the biosynthesis of epi-
eudesmanes and probably also of agarofurans.
The preferred elongated chair conformation further
indicates that 4 occupies the meso form. As a conse-
quence, 4 can only produce racemic eudesmanes under
nonenzymatic circumstances, while pure enantiomers
may be generated enzymatically. If both pathways are
followed in biosynthesis, then enantiomeric mixtures of
eudesmanes with one enantiomer in excess will be
formed. The cooccurrence of both enantiomers of eudes-
manes in the same plant supports this hypothesis.51 It
is therefore tempting to consider the possibility that 4
may be a direct in vivo-formed precursor52 of both ent-
and usual eudesmanes and not, as argued above, of epi-
eudesmanes.
Sch em e 7
caryol.43 However, successive treatment of 14 with
BH3‚Me2S and NaOMe in MeOH gave, instead of ex-
pected 4, the corresponding ethyl ether 15 as the sole
product in moderate yield (36%). Apparently, the C(11)
acetate group was reduced to the corresponding ethyl
ether.44 In order to minimize the reduction of the acetate
group, 14 was treated with BH3‚THF at 0 °C for only a
relatively short time. In this way, after treatment with
NaOMe in MeOH, a complex mixture of 4 and several
unidentified products was obtained. Fortunately, isola-
tion of pure 4 from this mixture was easily effected with
aqueous AgNO3 extraction.45 Although the yield of 4 was
poor (11%),46 all spectral and chromatographic data
including the Kova´ts indices47 could be obtained.
Exp er im en ta l Section 53
Ma ter ia ls. All reagents were purchased from Aldrich or
J anssen except for N,N,N′,N′-tetramethylphosphorodiamidic
chloride (TMPDCl) which was purchased from Fluka. 2-Meth-
yl-5-(1-methylethenyl)-1,3-cyclohexanedione27 and compound
629,54 have been characterized before.
2-Met h yl-5-(1-m et h ylet h en yl)-1,3-cycloh exa n ed ion e.
Epoxycarvone (46 g, 277 mmol) was treated with 1 M aqueous
NaOH at 65 °C for 65 min following a previously described
procedure.27 After workup, the remaining residue was dried
in a vacuum desiccator on P2O5 overnight to give 44 g (96%)
of 2-methyl-5-(1-methylethenyl)-1,3-cyclohexanedione (GC pu-
rity 98%). Its spectroscopic data corresponded with those
reported in the literature.27
cis-(()-3,4,8,8a -Tetr a h yd r o-5,8a -d im eth yl-3-(1-m eth yl-
eth en yl)-1,6-(2H,7H)-n a p h th a len ed ion e (6). A 3:2 mixture
of two epimeric triketones was prepared in 81% yield from
2-methyl-5-(1-methylethenyl)-1,3-cyclohexanedione and EVK
as described.29 To a solution of 17.3 g (69.2 mmol) of this
mixture in 125 mL of benzene was added 0.81 mL (9.8 mmol)
of pyrrolidine. The reaction mixture was heated at reflux and,
after 7 and 18 h, two other 0.81 mL portions of pyrrolidine
were added. The total reflux time amounted to 4 d. The
mixture was allowed to come to rt, poured into water, and
extracted with petroleum ether (bp 40-60 °C). The combined
organic layers were washed successively with 1 M aqueous
HCl, saturated aqueous NaHCO3, and brine. After drying and
evaporation, the remaining residue was flash chromato-
graphed [15% EtOAc in petroleum ether (bp 40-60 °C)] to give
6.1 g (38%) of 6. The spectroscopic data of 6 corresponded with
those reported in the literature.29,54
1
The H NMR spectrum of 4 points to the preference
for one distinct conformation. From its 13C NMR spec-
trum, it follows that 4 possesses a symmetry plane which
means that the crossed conformations (see Scheme 3) can
be excluded. The UV spectrum of 4, in which the
absorption maximum at <200 nm shows strong tailing
toward the red (270 nm), is in line with this conclusion.48
The formation of a 1:2:1 mixture of R-, â-, and γ-eudesmol,
respectively, upon treatment of 4 with TsOH in CH2Cl2
proved that 4 reacts exclusively from the elongated chair
conformation (Scheme 7).49 The NMR data and the
almost quantitative formation of 16 upon irradiation (3.5
h) of 15 in MeCN solution with a low-pressure Hg lamp
indicate that 15 also exists in the elongated chair
conformation.50
(51) Hardt, I. H.; Rieck, A.; Fricke, C.; Ko¨nig, W. A. Flav. Fragr. J .
1995, 10, 165.
(43) It was expected that the use of NaOMe in the Marshall
fragmentation reaction would lead to cleavage of the acetate ester bond.
(44) The BH3-reduction of sterically hindered acetate groups to ethyl
ethers has been described before, see: Dias, J . R.; Pettit, G. R. J . Org.
Chem. 1971, 36, 3485.
(45) Southwell, I. A. Phytochemistry 1970, 9, 2243.
(46) The Marshall fragmentation reaction of a mesylate similar to
14 but lacking the C(7) substituent also proceeded in low yield (25%),
see reference 35.
(47) The Kova´ts indices in combination with GC-MS may be very
helpful to detect 4 in complex mixtures of natural origin.
(48) Gleiter, R.; Scha¨fer, W. Acc. Chem. Res. 1990, 23, 369.
(49) (a) White, D. N. J .; Bovill, M. J . Tetrahedron Lett. 1975, 2239.
(b) Neykov, G. D.; Ivanov, P. M.; Orahovats, A. S. J . Mol. Struct. 1987,
153, 147.
(52) A simple double bond isomerization from (+)-hedycaryol (1) to
neohedycaryol (4) can occur with negligible steric complaint.16
(53) For
a general description of the experimental procedures
employed in this research, see: Kesselmans, R. P. W.; Wijnberg, J . B.
P. A.; Minnaard, A. J .; Walinga, R. E.; de Groot, A. J . Org. Chem. 1991,
56, 7237. NMR spectra were recorded at 200 MHz (1H) and 50 MHz
(
13C) in CDCl3, unless otherwise reported. Kova´ts indices were
determined on a gas chromatograph equipped with a J &W DB-1
column (60 m × 0.25 mm i.d., film thickness 0.25 µm) and a Restek
Stabilwax column (60 m × 0.25 mm i.d., film thickness 0.25 µm). Split
ratio 1:100, carrier gas H2, inlet pressure 20 psi, linear velocity 35 cm/
s; temperature program 50 °C (0 min hold) to 238 °C (8 min hold) at
4 °C/min; injector temperature 220 °C; detector temperature 260 °C;
FID detection. Column chromatography was performed using Baker
neutral alumina (activity grade III).
(50) Heathcock, C. H.; Badger, R. A.; Starkey, R. A. J . Org. Chem.
1972, 37, 231.
(54) Lacoume, B.; Zalkow, L. H. Tetrahedron Lett. 1966, 5881.

2348 J . Org. Chem., Vol. 62, No. 8, 1997
Minnaard et al.
(()-(4a r,5r,7r)-4,4a ,5,6,7,8-Hexa h yd r o-1,4a -d im et h yl-
7-(1-m eth yleth en yl)-5-[[(1,1-dim eth yleth yl)dim eth ylsilyl]-
oxy]-2(3H)-n a p h th a len on e (7). After reduction of 6 with
NaBH4 following a previously described procedure,30 the
resulting alcohol (8.82 g, 37.7 mmol) was added to a solution
of 6.42 g (94.4 mmol) of imidazole and 7.08 g (46.9 mmol) of
TBDMSCl in 50 mL of DMF. The mixture was stirred at rt
for two d and then poured into 200 mL of water. After
extraction with petroleum ether (bp 40-60 °C), the combined
organic layers were washed with brine and dried. Flash
chromatography [5% EtOAc in petroleum ether (bp 40-60 °C)]
gave 10.53 g (80%) of 7 as an oil: 1H NMR δ 0.03 (s, 3 H),
0.05 (s, 3 H), 0.88 (s, 9 H), 1.13 (s, 3 H), 1.76 (br s, 6 H), 1.6-
1.8 (m, 3 H), 1.99-2.08 (m, 3 H), 2.36-2.44 (m, 2 H), 2.66 (dd,
J ) 1.6, 9.7 Hz, 1 H), 3.40 (dd, J ) 5.1, 10.7 Hz, 1 H), 4.77 (br
s, 2 H); 13C NMR δ -4.91 (q), -3.91 (q), 11.30 (q), 16.00 (q),
17.00 (s), 20.41 (q), 25.78 (3q), 32.34 (t), 33.55 (t), 33.89 (t),
35.58 (t), 41.55 (d), 41.97 (s), 78.57 (d), 109.71 (t), 130.21 (s),
147.97 (s), 160.11 (s), 199.10 (s); MS m/ z (relative intensity)
291 (M+ - 57, 100), 211 (39), 75 (20), 73 (27); HRMS calcd for
C17H27O2Si (M+ - 57) 291.1780, found 291.1780.
and then 2.4 mL (16.0 mmol) of TMPDCl was added. After
stirring at -78 °C for another 5 min, the reaction mixture was
allowed to come to rt and stirred for an additional 1 h. The
reaction mixture was then slowly added, via syringe, to a
solution of 0.90 g (129 mmol) of Li in 50 mL of EtNH2 at 0 °C.
After stirring at 0 °C for 1 h, 20 mL of saturated aqueous NH4-
Cl was added and EtNH2 was allowed to evaporate by standing
at rt overnight. The remaining layer was extracted with ether,
and the combined organic layers were washed with brine,
dried, and evaporated. Flash chromatography [10% EtOAc in
petroleum ether (bp 40-60 °C)] gave 0.63 g (88%) of 10:55 1H
NMR δ 0.00 (s, 3 H), 0.01 (s, 3 H), 0.88 (s, 9 H), 0.94 (s, 3 H),
1.18 (s, 6 H), 1.60 (br s, 3 H), 1.2-2.0 (m, 11 H), 2.54 (ddd, J
) 2.4, 2.4, 13.4 Hz, 1 H), 3.26 (dd, J ) 4.6, 10.8 Hz, 1 H); 13C
NMR δ -4.83 (q), -3.87 (q), 14.08 (s), 18.02 (2q), 18.86 (t),
19.72 (q), 25.59 (t), 25.87 (3q), 26.79 (q), 32.36 (t), 33.14 (t),
36.72 (t), 41.52 (s), 46.71 (d), 72.26 (s), 79.44 (d), 126.88 (s),
133.51 (s); MS m/ z (relative intensity) 352 (M+, 1), 293 (52),
229 (31), 203 (100), 161 (51), 147 (31), 73 (61), 59 (12); HRMS
calcd for C21H40O2Si (M+) 352.2798, found 352.2795.
(()-(2r,4r,4a r)-1,2,3,4,4a ,5,6,7-Oct a h yd r o-4-h yd r oxy-
r,r,4a ,8-tetr a m eth yl-2-n a p h th a len em eth a n ol (11). To a
stirred solution of 0.62 g (1.76 mmol) of 10 in 10 mL of DMSO
was added 4 mL of TBAF (1 M in THF). The reaction mixture
was placed in an oil bath of 100 °C and stirred for 45 min.
The resulting brown mixture was cooled to rt and poured into
120 mL of water. The mixture was extracted with EtOAc and
the combined organic layers were washed with brine, dried,
and evaporated. Flash chromatography [30% EtOAc in pe-
troleum ether (bp 40-60 °C)] and crystallization from EtOH
gave 0.310 g (74%) of pure 11: mp 147 °C; 1H NMR δ 0.98 (s,
3 H), 1.27 (s, 6 H), 1.62 (br s, 3 H), 1.27-2.0 (m, 12 H), 2.58
(ddd, J ) 2.6, 2.6, 13.8 Hz, 1 H), 3.32 (dd, J ) 4.5, 10.9 Hz, 1
H); 13C NMR δ 17.68 (q), 18.77 (q), 19.81 (t), 25.58 (t), 26.86
(q), 27.28 (q), 31.70 (t), 33.02 (t), 36.20 (t), 40.06 (s), 46.89 (d),
72.38 (s), 79.31 (d), 127.51 (s), 132.93 (s); MS m/ z (relative
intensity) 238 (M+, 100), 223 (47), 195 (50), 187 (33), 159 (40),
147 (33), 145 (30), 105 (39), 59 (34). Anal. Calcd for
C15H26O2: C, 75.58; H, 11.00. Found: C, 75.55; H, 11.21.
(()-(2r,4r,4a r)-[1,2,3,4,4a ,5,6,7-Oct a h yd r o-r,r,4a ,8-
tetr a m eth yl-4-[[(1,1-d im eth yleth yl)d im eth ylsilyl]oxy]-2-
n a p h th a len yl]m eth yl Aceta te (12). To a stirred solution
of 0.324 g (0.93 mmol) of 10 in 3 mL of Et3N was added 0.26
mL (2.80 mmol) of Ac2O followed by 0.010 g (0.08 mmol) of
DMAP at 0 °C. The mixture was allowed to come to rt, stirred
for two d, and then poured into water. After extraction with
EtOAc, the combined organic layers were washed with satu-
rated aqueous NaHCO3 and brine, dried, and evaporated.
Flash chromatography [2% EtOAc in petroleum ether (bp 40-
60 °C)] gave 0.303 g (82%) of 12 as an oil: 1H NMR δ 0.00 (s,
6 H), 0.87 (s, 9 H), 0.92 (s, 3 H), 1.40 (s, 3 H), 1.42 (s, 3 H),
1.58 (br s, 3 H), 1.1-1.7 (m, 7 H), 1.8-2.05 (m, 3 H), 2.02 (s,
3 H), 2.42 (ddd, J ) 2.3, 2.3, 10.5 Hz, 1 H), 3.26 (dd, J ) 4.7,
10.8 Hz, 1 H); 13C NMR δ -4.79 (q), -3.91 (q), 18.06 (q), 18.06
(s, obscured), 18.90 (t), 19.71 (q), 22.43 (q), 23.43 (q), 23.47
(q), 25.50 (t), 25.92 (3q), 32.15 (t), 33.18 (t), 36.67 (t), 40.68
(s), 43.63 (d), 79.18 (d), 84.49 (s), 127.28 (s), 133.10 (s), 170.34
(s); MS m/ z (relative intensity) 334 (M+ - 60, 34), 277 (100),
229 (24), 211 (20), 203 (80), 161 (29), 75 (27), 73 (32); HRMS
calcd for C21H38OSi (M+ - 60) 334.2692, found 334.2689.
(()-(2r,4r,4a r)-[1,2,3,4,4a ,5,6,7-Octa h yd r o-4-h yd r oxy-
r,r,4a,8-tetr am eth yl-2-n aph th alen yl]m eth yl Acetate (13).
To a stirred solution of 0.349 g (0.89 mmol) of 12 in 4 mL of
MeCN was added two drops of 40% aqueous HF every hour
over a period of 6 h. After this time, the reaction mixture was
diluted with EtOAc and washed with saturated aqueous
NaHCO3 and brine. After drying and evaporation, the re-
maining residue was flash chromatographed [30% EtOAc in
petroleum ether (bp 40-60 °C)] to give 0.193 g (78%) of 13 as
an oil: 1H NMR δ 0.98 (s, 3 H), 1.44 (s, 6 H), 1.60 (br s, 3 H),
1.98 (s, 3 H), 1.2-2.1 (m, 11 H), 2.47 (br d, J ) 13.2 Hz, 1 H),
3.33 (dd, J ) 4.3, 11.3 Hz, 1 H); 13C NMR δ 17.67 (q), 18.72
(t), 19.69 (q), 22.44 (q), 23.41 (2q), 25.31 (t), 31.27 (t), 32.96
(()-(4a r,5r,7r)-4,4a ,5,6,7,8-Hexa h yd r o-1,4a -d im et h yl-
5-[[(1,1-d im eth yleth yl)d im eth ylsilyl]oxy]-7-(2-m eth yloxi-
r a n -2-yl)-2(3H)-n a p h th a len on e (8). To a stirred solution
of 10.5 g (30.2 mmol) of 7 in 360 mL of a 1:1 mixture of CH2-
Cl2 and acetone were added 0.755 g (2.86 mmol) of 18-crown-6
and a solution of 11.5 g (137 mmol) of NaHCO3 in 200 mL of
water. The mixture was cooled to 0 °C, and a solution of 20.7
g (33.6 mmol) of Oxone in 100 mL of water was added
dropwise. The reaction mixture was vigorously stirred at 0
°C for 3 h and then treated with an excess of saturated aqueous
Na2S2O3 and saturated aqueous NaHCO3 for 20 min. The
mixture was extracted with CH2Cl2, and the combined organic
layers were washed with water, dried, and evaporated to afford
11.0 g of crude 8, which was used directly for the next step. A
sample (0.125 g, 0.34 mmol) of crude 8 was flash chromato-
graphed [10% EtOAc in petroleum ether (bp 40-60 °C)] to give
0.115 g (93%) of 8 as a 1:1 mixture of diastereomers: 1H NMR
δ 0.01 (s, 3 H), 0.04 (s, 3 H), 0.86 (s, 9 H), 1.10 (s, 3 H), 1.30
(s, 3 H), 1.75 (br s, 3 H), 1.2-2.1 (m, 6 H), 2.35-2.42 (m, 2 H),
2.57-2.72 (m, 3 H), 3.34 (dd, J ) 4.7, 10.7 Hz, 1 H); 13C NMR
δ -4.93 (q), -3.90 (q), 11.32 (q), 15.93 (q), 17.87 (q), 17.97 (s),
18.12 (q), 25.77 (3q), 28.87 (t), 29.33 (t), 32.26 (t), 32.75 (t),
33.49 (t), 33.81 (t), 40.35 (d), 40.57 (d), 42.06 (s), 53.13 (t), 53.32
(t), 58.49 (s), 78.12 (d), 130.40 (s), 130.66 (s), 159.04 (s), 198.86
(s); MS m/ z (relative intensity) 307 (M+ - 57, 46), 249 (98),
227 (35), 215 (40), 204 (44), 86 (52), 75 (94), 73 (100); HRMS
calcd for C17H27O3Si (M+ - 57) 307.1730, found 307.1731.
(()-(2r,4a r,5r,7r)-2,3,4,4a ,5,6,7,8-Oct a h yd r o-1,4a -d i-
m et h yl-5-[[(1,1-d im et h ylet h yl)d im et h ylsilyl]oxy]-7-(2-
m eth yloxir a n -2-yl)-2-n a p h th a len ol (9). To a stirred solu-
tion of 8.34 g (32.8 mmol) of Li(t-BuO)3AlH in 100 mL of THF
was added dropwise a solution of 3.27 g (8.98 mmol) of 8 in 60
mL of THF at 0 °C. After being stirred at rt for 1.5 h, the
reaction mixture was quenched with 13.5 g of Na2SO4‚10H2O
followed by the addition of 2 mL of water and excess MgSO4.
The mixture was stirred for an additional 0.5 h and filtered.
The filtrate was evaporated, and the remaining residue was
purified by flash chromatography [15% EtOAc in petroleum
ether (bp 40-60 °C)] to give 2.85 g (87%) of 9 as a 1:1 mixture
1
of diastereomers: H NMR δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.87
(s, 9 H), 0.99 (s, 3 H), 1.28 (br s, 3 H), 1.0-2.4 (m, 12 H), 2.35-
2.62 (m, 3 H), 3.24 (dd, J ) 4.7, 10.7 Hz, 1 H), 3.94 (m, 1 H);
13C NMR δ -4.90 (q), -3.88 (q), 15.55 (q), 18.02 (q), 18.15 (s),
18.29 (q), 25.81 (3q), 26.96 (t), 27.45 (t), 28.39 (t), 31.74 (t),
32.76 (t), 33.25 (t), 41.31 (s), 41.74 (d), 41.91 (d), 53.43 (t), 58.87
(s), 70.90 (d), 76.99 (d), 79.42 (d), 129.88 (s), 129.96 (s), 137.00
(s); MS m/ z (relative intensity) 309 (M+ - 57, 5), 291 (40),
227 (89), 177 (46), 159 (51), 75 (65), 73 (100); HRMS calcd for
C17H29O3Si (M+ - 57) 309.1886, found 309.1884.
(()-(2r,4r,4a r)-1,2,3,4,4a ,5,6,7-Oct a h yd r o-r,r,4a ,8-
tetr a m eth yl-4-[[(1,1-d im eth yleth yl)d im eth ylsilyl]oxy]-2-
n a p h th a len em eth a n ol (10). To a stirred solution of 0.746
g (2.04 mmol) of 9 in a mixture of 16 mL of THF and 4 mL of
TMEDA was added 2.84 mL of BuLi (1.6 M in hexane) at -78
°C. The reaction mixture was stirred at -78 °C for 15 min,
(55) GC analysis revealed the presence of a small amount (<10%)
of another compound, probably a double bond isomer of 10.

Total Synthesis of Neohedycaryol
J . Org. Chem., Vol. 62, No. 8, 1997 2349
(t), 36.12 (t), 40.07 (s), 44.03 (d), 78.96 (d), 84.25 (s), 127.72
(s), 132.46 (s), 170.50 (s); MS m/ z (relative intensity) 220 (M+
- 60, 100), 202 (19), 187 (23), 177 (23), 173 (16), 159 (22), 107
(16), 69 (30), 43 (16); HRMS calcd for C15H24O (M+ - 60)
220.1827, found 220.1829.
combined aqueous layers were washed with 1 mL of tert-butyl
methyl ether and cooled to 0 °C. After addition of 10 mL of
25% aqueous NH3, the mixture was extracted with tert-butyl
methyl ether. The combined organic layers were washed with
brine, dried, and evaporated to give 0.004 g (11%) of 4: UV
(MeCN) λmax < 200 nm, tail to 270 nm; Kova´ts indices: 2341
(()-(2r,4r,4a r)-[1,2,3,4,4a ,5,6,7-Octa h yd r o-r,r,4a ,8-tet-
r a m eth yl-4-[(m eth ylsu lfon yl)oxy]-2-n a p h th a len yl]m eth -
yl Aceta te (14). To a stirred solution of 0.089 g (0.32 mmol)
of 13 in 2 mL of pyridine was added 0.037 mL (0.48 mmol) of
MsCl at 0 °C. The mixture was allowed to come to rt, stirred
for 50 min, and poured into water. After extraction with
petroleum ether (bp 40-60 °C), the combined organic layers
were washed with brine, dried, and evaporated. Removal of
residual pyridine by azeotropic distillation with toluene af-
forded 0.101 g (88%) of almost pure 14: 1H NMR (C6D6) δ 1.09
(s, 3 H), 1.39 (s, 3 H), 1.43 (s, 3 H), 1.54 (br s, 3 H), 1.72 (s, 3
H), 1.2-2.3 (m, 10 H), 2.31 (s, 3 H), 2.44 (br d, J ) 13.2 Hz, 1
H), 4.42 (dd, J ) 4.8, 11.2 Hz, 1 H); 13C NMR (C6D6) δ 18.42
(q), 18.65 (t), 19.48 (q), 21.56 (q), 23.03 (2q), 24.99 (t), 29.91
(t), 32.75 (t), 36.01 (t), 37.67 (q), 39.64 (s), 44.12 (d), 82.76 (s),
88.29 (d), 128 (s, obscured), 131.00 (s), 169.5 (s); MS m/ z
(relative intensity) 298 (M+ - 60, 2), 203 (63), 202 (92), 187
(100), 160 (29), 159 (91), 145 (38), 105 (26), 43 (47); HRMS
calcd for C16H26O3S (M+ - 60) 298.1603, found 298.1603.
tr a n s,tr a n s-r,r,4,8-Tetr a m eth yl-3,8-cyclod eca d ien e-1-
m eth a n ol Eth yl Eth er (15). To a stirred solution of 0.101 g
1
(Stabilwax) and 1689 (DB-1); H NMR (C6D6) δ 1.07 (s, 6 H),
1.64 (br s, 6 H), 0.75-1.75 (m, 4 H), 2.0-2.55 (m, 8 H), 5.14
(br d, J ) 10.8 Hz, 2 H); 13C NMR (C6D6) δ 15.84 (2q), 17.13
(t), 27.16 (2q), 30.27 (2t), 42.20 (2t), 50.39 (d), 74.4 (s), 130.67
(2d), 131.33 (2s); MS m/ z (relative intensity) 222 (M+, 15), 204
(62), 189 (36), 161 (100), 119 (40), 107 (35), 105 (54), 96 (73),
81 (80), 59 (63), 43 (34); HRMS calcd for C15H26O (M+)
222.1984, found 222.1977.
(2r,3a â,3br,6a r,6bâ)-Deca h yd r o-r,r,3b ,6a -t et r a m et h -
ylcyclob u t a [1,2:3,4]d icyclop en t en e-2-m et h a n ol E t h yl
Eth er (16). A solution of 0.008 g (0.03 mmol) of 15 in 4 mL
of MeCN placed in a sealed quartz cuvet was irradiated for
3.5 h using a CAMAG Universal UV-lamp 29230. The reaction
progress was monitored by GC. After completion, the solvent
was evaporated to give 0.007 g (90%) of 16 (GC purity >96%):
1H NMR δ 0.87 (s, 6 H), 1.15 (t, J ) 7.0 Hz, 3 H), 1.17 (s, 6 H),
0.9-2.05 (m, 13 H), 3.38 (q, J ) 7.0 Hz, 2 H); 13C NMR δ 16.24
(q), 18.79 (2q), 23.43 (t), 23.76 (2q), 28.84 (2t), 42.96 (2t), 43.24
(2d), 45.40 (2s), 51.50 (d), 56.00 (t), 75.58 (s); MS m/ z (relative
intensity) 204 (M+ - 46, 31), 189 (13), 161 (20), 96 (36), 87
.
(0.28 mmol) of 16 in 3 mL of THF was added 0.75 mL of BH3 S-
(100), 81 (16), 59 (39), 43 (11); HRMS calcd for C16H27O (M+
15) 235.2062, found 235.2057.
-
(CH3)2 (2 M in THF) at 0 °C. The reaction mixture was stirred
at rt overnight. The resulting white cloudy mixture was cooled
to 0 °C, and 1 mL of MeOH was added dropwise, immediately
followed by 3 mL of NaOMe (2 M in MeOH). The reaction
mixture was allowed to come to rt and stirred overnight. After
addition of water, the mixture was extracted with tert-butyl
methyl ether. The combined organic layers were washed with
brine, dried, and evaporated. Column chromatography (10%
tert-butyl methyl ether in hexane) gave 0.025 g (36%) of 15:
1H NMR (C6D6) δ 1.13 (s, 6 H), 1.16 (t, J ) 6.9 Hz, 3 H), 1.65
(br s, 6 H), 0.9-1.85 (m, 3 H), 2.1-2.56 (m, 8 H), 3.30 (q, J )
6.9 Hz, 2 H), 5.16 (br d, J ) 10.8 Hz, 2 H); 13C NMR (C6D6) δ
15.86 (2q), 16.13 (q), 17.22 (t), 23.17 (2q), 30.13 (2t), 42.21 (2t),
46.97 (d), 55.60 (t), 76.28 (s), 130.90 (2d), 131.32 (2s); MS m/ z
(relative intensity) 250 (M+, 14), 204 (72), 189 (51), 175 (25),
r-, â-, a n d γ-Eu d esm ol (3a , 3b, a n d 3c). To a stirred
solution of 0.001 g (0.005 mmol) of 4 in 1 mL of CH2Cl2 was
added a small crystal of TsOH‚H2O. After stirring at rt for 7
min, the mixture was diluted with CH2Cl2, washed with
saturated aqueous NaHCO3 and brine, and dried. After
evaporation, the remaining residue was analyzed by GC and
GC-MS. The product mixture consisted of R-eudesmol (3a ),
â-eudesmol (3b), and γ-eudesmol (3c) in a ratio of 1:2:1,
respectively.56 Kova´ts indices on Stabilwax and DB-1,
respectively: 3a 2224 and 1643; 3b 2233 and 1638; 3c 2171
and 1620.
Ack n ow led gm en t . We are indebted to Dr. M. A.
Posthumus and Mr. H. J ongejan for the mass spectro-
scopic and microanalytical data, Mr. G. P. Lelyveld for
the chromatographic data, and to Mr. A. van Veldhuizen
for NMR measurements.
161 (75), 96 (62), 87 (100), 59 (70); HRMS calcd for C17H30
O
(M+) 250.2297, found 250.2292.
tr a n s,tr a n s-r,r,4,8-Tetr a m eth yl-3,8-cyclod eca d ien e-1-
m eth a n ol (4). To a stirred solution of 0.062 g (0.17 mmol) of
.
14 in 2 mL of THF was added 0.86 mL of BH3 THF (1 M in
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 4, 7-10, and 12-16 (10 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.
THF) at 0 °C. The mixture was allowed to come to rt and
stirred for 2 h. After cooling to 0 °C, 1 mL of MeOH was added
dropwise and immediately followed by 3 mL of NaOMe (2 M
in MeOH). The mixture was allowed to come to rt and stirred
overnight. After addition of water, the mixture was extracted
with petroleum ether (bp 40-60 °C). The combined organic
layers were washed with brine, dried, and evaporated. The
residue was dissolved in 3 mL of tert-butyl methyl ether and
extracted four times with 2 mL of 20% aqueous AgNO3. The
J O962056A
(56) Reference 8, van Beek et al.