Magnesium-Ene Cyclization
J. Am. Chem. Soc., Vol. 123, No. 1, 2001 31
and the tendency of the cyclized organolithium to remove
protons from solvent at the temperature required for the
cyclization, the magnesium-ene cyclization was deemed to be
the more useful of these two types of metallo-ene reactions
for demonstrating the value of the allylic oxyanionic group at
the enophilic site. Our initial goal in this endeavor was the
stereoselective synthesis of the bicyclic terpene matatabiether
10.8 Since the all-cis cyclopentanol 2 (eq 3) is a key precursor
MAN)12 in dimethyl ether, according to the new procedure for
preparing and using aromatic radical anions with lithium
counterions in non-THF solvents.13 Transmetalation with MgBr2
in diethyl ether and warming to 23 °C caused cyclization. The
product was again captured with diphenyl diselenide and as
hoped the ratio of selenide 2 to protonated product 3a was now
considerably greater (>10:1). A 64% yield of the selenide 2
was isolated (eq 4).
of 10, the synthesis of the latter would provide a good
demonstration of the directing effect of an allylic oxyanionic
group, which would control the cis relationship of the selenium-
bearing carbon atom and the hydroxyl group in 2. The cis
relationship between that same carbon atom and isopropenyl
group would be a result of the strong preference in the
magnesium-ene reaction to yield kinetic product in which the
magnesium-bearing carbon atom and the unsaturated group are
oriented in a cis fashion.5a
To assess the stereoselectivity of the ring-closure step, the
same reaction was performed but the cyclized organometallic
was quenched with water. The secondary methyl groups of three
diastereomers were now clearly evident in the NMR spectrum
of the crude reaction mixture and it could be determined that
significant stereochemical inhomogeneity had occurred (eq 5).
The first method tried to convert an allyl phenyl thioether to
an allylmagnesium was reductive lithiation9 of the thioether in
the presence of the radical-anion lithium 4,4′-di-tert-butylbi-
phenylide (LDBB)10 in THF and conversion of the resulting
allyllithium11 to a Grignard reagent by transmetalation with
MgBr2. This procedure was applied to 1, after deprotonation
with methyllithium. When the cold bath surrounding the solution
of transmetalated allylmetallic was allowed to warm from -70
°C, the temperature of its generation, to 40 °C, the temperature
at which it was maintained overnight, and the cyclization product
was treated with the electrophilic trapping agent diphenyl
diselenide, the phenylseleninated and protonated cyclization
products (2 and 3a) were formed in a ratio (NMR) of 3:1 (eq
3). The method of assigning the stereochemistry of these
products is outlined below. It was evident that the procedure
was being somewhat compromised mainly by proton transfer
to the cyclized organometallic either from adventitious moisture
or from the THF solvent. Precautions to decrease the formation
of 3a by preventing exposure to moisture, using different
electrophiles (such as D2O) and using excess diphenyl diselenide
with prolonged reaction time, failed, suggesting that proton
abstraction from THF was the most likely source of 3a.
The conjugate base of 1 was next subjected to reductive
lithiation by lithium 1-(dimethylamino)naphthalenide (LD-
Since the lithium-ene cyclization in the absence of the
alcoholate group occurs with only modest cis-stereoselectivity2
reminiscent of that observed in eq 5, while the magnesium-
ene cyclization usually proceeds with high cis-selectivity,5a it
was suspected that the relatively low stereoselectivity was due
to reversibility of the ring closure because of the presence of
lithium ions. The lithium-ene cyclization is reversible even at
room temperature,2 whereas the magnesium-ene cyclization is
reversible only at elevated temperatures.5a This hypothesis was
given more credence when it was shown that reductive lithiation
of 1, without subsequent transmetalation, followed by cyclization
produced more of the trans (methyl and isopropenyl) product
3b than the cis product 3a (eq 6).14 It also seemed possible that
the lithium ions were responsible for the proton transfer to the
cyclized organometallic from THF, a known phenomenon in
the Li-ene cyclization,2 since Grignard reagents are known not
to be particularly basic.
(8) (a) Sakai, T.; Nakajima, K.; Yoshihara, K.; Sakan, T. Tetrahedron
1980, 36, 3115-19 and references therein. (b) Kato, N.; Kamitamari, M.;
Naganuma, S.; Arita, H. Heterocycles 1990, 30, 341-45 and references
therein.
Therefore, the preparation of the allylmagnesium directly from
the allyl thioether was attempted to avoid the presence of lithium
ions. In a pioneering paper, Maercker15 has reported that simple
allyl phenyl sulfides could be converted to allylmagnesiums by
being heated at reflux in THF with magnesium powder which
had been activated by treatment with 1,2-dibromoethane or
iodine. While this procedure failed in our hands, probably due
to the magnesium powder available to us being less reactive
than that used by Maercker (the grade of magnesium was not
specified in the paper),15 reductive magnesiation proceeded
smoothly with our similarly activated magnesium powder when
anthracene16 was used. Because allyl phenyl sulfides are so
(9) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152-61.
(10) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 22, 1924-
30.
(11) Cohen, T.; Guo, B.-S. Tetrahedron 1986, 42, 2803-08. Guo, B.
S.; Doubleday, W.; Cohen, T. J. Am. Chem. Soc. 1987, 109, 4710-11.
(12) Cohen, T.; Matz, J. R. Synth. Commun. 1980, 10, 311-17.
(13) Liu, X.; Kulkarni, V.; Cohen, T. Book of Abstracts; 219th National
Meeting of the American Chemical Society, San Francisco, March 26-30,
2000; ORGN-630.
(14) This is an interesting result since the lithium-ene cyclizations that
we have observed in analogous systems but lacking the hydroxyl function
(see eq 1) yield more cis than trans product.2 A possible explanation is that
the present ring closure is accelerated by the oxyanionic group and occurs
at a lower temperature; we have observed that some cyclization occurs as
low as -20 °C. At this low temperature, the quenching of the reaction that
occurs by intra- and intermolecular proton transfers2 may be slow compared
to that of the des-hydoxyl analogues, which occur at 25 °C. Such slow
quenching may provide time for the equilibration to occur.
(15) Maercker, A.; Jaroschek, H.-J. J. Organomet. Chem. 1976, 116, 21-
37.