30

J. Am. Chem. Soc. 2001, 123, 30-34

The Magnesium-Ene Cyclization Stereochemically Directed by an

Allylic Oxyanionic Group and Its Application to a Highly
Stereoselective Synthesis of (()-Matatabiether. Allylmagnesium
Compounds by Reductive Magnesiation of Allyl Phenyl Sulfides1
Dai Cheng, Shirong Zhu, Zhifang Yu, and Theodore Cohen*
Contribution from the Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
ReceiVed August 10, 2000

Abstract: The first example of a magnesium-ene cyclization stereochemically directed by an allylic oxyanionic
group is demonstrated by a highly stereoselective synthesis of the bicyclic terpene matatabiether 10. The synthetic
method is particularly valuable, not only because of the stereochemical control and the utility of the versatile
hydroxyl group introduced into the product, but also because the precursor of the allylmagnesium is an allyl
phenyl sulfide, which is more stable and more easily prepared in a connective fashion than the usual allyl
halide precursor. Since the presence of lithium ions encourages undesirable proton transfer to the cyclized
organometallic and is detrimental to the stereochemical control, the conversion of the allylic thioether to the
allylmagnesium utilizes a lithium-free method involving direct reductive magnesiation in the presence of the
magnesium-anthracene complex.

During our study of the lithium-ene cyclization (eq 1; Met

) Li),2,3 the important finding was made that an oxyanionic

group, allylic to the enophilic alkene, greatly accelerated the
carbanionic cyclization and led to a single diastereomeric
product in which the organolithium function of the cyclized
product was cis to the oxyanionic directing group (eq 2). If these
advantages of allylic oxyanionic groups prove to be general in
intramolecular carbometalations, the latter would obviously
become far more useful because of (1) the facilitating effect of
the oxyanionic group, (2) the high stereoselectivity, and (3) the
very useful alcohol functionality. Although there have been
reports of intermolecular carbolithiations and carbomagnesiations that are facilitated by an allylic oxyanionic group, albeit
with limited efficiency and generality,4 this technique apparently
has not been applied to intramolecular magnesium-ene reac* Address correspondence to this author. E-mail: [email protected].
Phone: 412 624-8220.
(1) Taken in part from the M.S. Thesis of Shirong Zhu, University of
Pittsburgh, 1996.
(2) Cheng, D.; Zhu, S.; Liu, X.; Norton, S. H.; Cohen, T. J. Am. Chem.
Soc. 1999, 121, 10241-42.
(3) Cheng, D.; Knox, R. K.; Cohen, T. J. Am. Chem. Soc. 2000, 122,
412-3.
(4) Reviews: Klumpp, G. W. Recl. TraV. Chim. Pays-Bas 1986, 105,
1-20. Vara Prasad, J. V. N.; Pillai, C. N. Organometallics 1983, 259, 1-30.
Marek, I.; Normant, J.-F. In Metal Catalyzed Cross Coupling Reactions;
Diederich, F., Stang, P., Eds.; Wiley VCH: New York, 1998; pp 269335.

tions (eq 1; Met ) Mg).5,6 The likely reason is that the

organometallic is usually prepared from an allyl halide that
would form a cyclic ether in the presence of the oxyanionic
group. In addition, in the case of Mg-ene cyclizations,5a the
allyl halide is produced from an allylic alcohol, thus presenting
a regiochemical problem in differentiation between the two
alcohol groups.
We are studying methods for reducing this concept to practice
in the case of carbanionic cyclization of allylmagnesiums and
nonallylic alkyllithiums.7 In both cases, phenyl thioethers, which
because of the great versatility of divalent sulfur are far easier
to assemble than organohalides, are the substrates from which
the organometallic is generated. In this paper, we reveal a
procedure for performing a highly stereoselective magnesiumene cyclization in the presence of an allylic oxyanionic group,
including a general method for generating Li-free allyl- and
benzylmagnesiums from allyl and benzyl phenyl sulfides, and
we apply this procedure to the synthesis of a bridged bicyclic
terpene.
Results and Discussion
In view of what we have learned about the lithium-ene
cyclization,2,3 in particular the thermodynamic unfavorability
(5) (a) Reviews of metallo-ene reactions: Oppolzer, W. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 38-52. Oppolzer, W. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, England, 1991; Vol.
5, pp 29-61. (b) The Zn-ene cyclization has only recently come into
prominence. For recent references see: Nakamura, E.; Kubota, K. J. Org.
Chem. 1997, 62, 792-3. Lorthiois, E.; Marek, I.; Normant, J.-F. J. Org.
Chem. 1998, 63, 2442-50.
(6) Allylic ethers in alkyllithium cyclizations (Bailey, W. F.; Jiang, X.L. J. Org. Chem. 1994, 59, 6528-33) and both allylic ethers and esters in
alkylzinc cyclizations (Meyer, C.; Marek, I.; Courtemanche, G.; Normant,
J. F. Tetrahedron 1994, 50, 11665-92. Lorthiois, E.; Marek, I.; Normant,
J.-F. J. Org. Chem. 1998, 63, 2442-2450) give only modest stereoselectivity
in five-membered-ring formation.
(7) Review: Bailey, W. F.; Ovaska, T. V. In AdVances in Detailed
Reaction Mechanisms; Coxon, J. M., Ed.; JAI Press: Greenwich, CT.; Vol.
3, 1994; pp 251-73.

10.1021/ja0029782 CCC: $20.00 2001 American Chemical Society

Published on Web 12/13/2000

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 seleniumbearing 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
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-butylbiphenylide (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-

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).

(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.
(9) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152-61.
(10) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 22, 192430.
(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.

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 magnesiumene 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.
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
(15) Maercker, A.; Jaroschek, H.-J. J. Organomet. Chem. 1976, 116, 2137.

32 J. Am. Chem. Soc., Vol. 123, No. 1, 2001

Cheng et al.

Scheme 1

Table 1. Reductive Magnesiation of Allyl and Benzyl Phenyl Sulfides (Scheme 1)

sulfide

R1

R2

R3

product

yield, %

4a
4b
4c
4d
4e
PhCH2
PhCH2

H
CH3
CH3
H
H

H
H
CH3
H
H

H
CH3
H
PhCH2
CH2dCH(CH2)3

p-CH3OC6H4CHO
Ph2MeSiCl
Ph2MeSiCl
Ph2MeSiCl
H+
H+
Ph2MeSiCl

5a
5b
5c
6d
a
PhCH3
PhCH2SiPh2Me

92
53
59
76
81
82b
57

a Product not isolated; yield based on GC using an internal standard of chlorobenzene and an authentic sample of 1,7-octadiene. b GC yield with
an internal standard of chlorobenzene.

stable compared to allyl halides, because they can be prepared

by several methods, particularly connective ones, unavailable
for the preparation of allyl halides,11 and because the preparation
of allyl Grignard reagents from allyl halides is plagued by Wurtz
couplings,17 we view the preparation of allylmagnesiums from
allyl phenyl sulfides as a very important synthetic advance not
withstanding the fact that it has never been used for synthetic
purposes since Maerckers paper15 appeared. Perhaps these
advantages have not been generally appreciated. Therefore, we
now diverge from the main course of this paper to describe our
results in this endeavor.
The procedure first used was to mix magnesium powder with
about 10 mol % of 1,2-dibromoethane and 2 mol % of
anthracene in THF, to sonicate for 8-10 h at ambient temperature, and then to add the allyl phenyl sulfide 4 (or benzyl phenyl
sulfide) and heat at 48 C for 16 h. An electrophile E was added
to capture the Grignard-type reagent and the yield of product 5
and/or 6 (or the benzyl analogues) was determined (Scheme
1).
The results for allyl phenyl sulfides and for benzyl phenyl
sulfide are in Table 1. The optimum time and temperature, 16
h and 48 C, were determined for allyl phenyl sulfide 4a. A
lower temperature, 23 C, gave a slightly lower yield (82%) of
product and longer reaction times did not improve the yield.
As in Maerckers report,15 no coupled product could be detected;
this is understandable on the basis that unlike chloride, thiophenoxide is only a nucleofugal group when it is displaced in an
intramolecular nucleophilic substitution to form a threemembered ring.3,18 Where comparisons are possible, the yields
of trapped products in Table 1 are comparable to or far higher
than those obtained from the corresponding allyl chloride using
100 mol % of anthracene.16,19

We next applied a modification of this technology to the

production of a simple terminally unsaturated allylmagnesium
compound, 2,7-octadienylmagnesium thiophenoxide; the corresponding Grignard reagent is known to undergo the magnesium-ene cyclization to produce cis-2-(vinylcyclopentyl)methylmagnesium halide.20 The modification involved the use
of 100 mol % of anthracene as used by Bogdanovic16 for the
preparation of allylmagnesium chlorides from the allyl chlorides.
The reductive magnesiation of 4e,2 heating the allylmagnesium
intermediate to execute its cyclization, and capturing the cyclized
organomagnesium with diphenyl disulfide produced the cyclized
phenyl thioether 7 in 87% yield as shown in eq 7.21

These results in hand, we were now in a position to attempt

the reductive magnesiation of 1 in the absence of lithium ions
in the hope of maximizing the all cis stereoselectivity and
minimizing proton transfer of the cyclized organometallic from
solvent. The alcohol was deprotonated with MeMgBr in THF
and the conjugate base was subjected to reductive magnesiation
in the presence of 0.1 equiv of anthracene at 48 C for 24 h.
About 50% of 1 was converted to the allylmagnesium intermediate which cyclized completely. It was eventually found that
higher temperatures and greater amounts of anthracene led to
complete reaction of the starting material as well as complete
cyclization of the allylmagnesium. To assess the stereoselectivity
under these conditions, the cyclized product was trapped by
protonation and the three detectable isomers were quantitated

(16) Anthracene has been used for the production of allyl Grignard
reagents from the corresponding allyl halides: Bogdanovic, B. Acc. Chem.
Res. 1988, 21, 261-67. Bogdanovic, B.; Janke, N.; Kinzelmann, H.-G.
Chem. Ber. 1990, 123, 1507-15.
(17) Benkeser, R. A. Synthesis 1971, 347-58. Nutzel, K. In HoubenWeyl, Methoden der Organischen Chemie; Muller E., Ed.; Georg ThiemeVerlag: Stuttgart, 1973; Vol. 13/2a, p 88.
(18) Cohen, T. Pure Appl. Chem. 1996, 68, 913-18 and citations therein.
(19) We thank Professor Bogdanovic for providing us with chemical
yields from the thesis of N. Janke, Bochum University, 1986. Their yields
were determined by protonation which, as shown for the benzyl case in
Table 1, is expected to give better yields than reaction with other
electrophiles. Their yields from allyl chloride itself ranged from 64 to 97%,
depending on solvent (compare our yield from 4a). In preliminary
experiments, our yield of silylation product (mixture of three isomers) from
crotyl phenyl sulfide was about 60% whereas the yield from crotyl chloride
was reported in the thesis to be 28%. Their yields from benzyl chloride
ranged from 64 to 71%.
(20) Felkin, H.; Hagaman, E.; Umpleby, J. D.; Wenkert, E. Tetrahedron
Lett. 1972, 2285-2288.

(21) The cis stereochemistry is assigned to 7 on the basis of two

arguments: (1) The same organomagnesium, with a chloride ligand in place
of the thiophenoxide, has been reported to yield the cis cyclization product.20
(2) The NMR spectrum of 7 is clearly different from that of the isomer
prepared by conjugate addition of the cuprate derived from phenylthiomethyllithium to cyclopentene-1-carboxaldehyde in the presence of Me3SiCl, followed by Wittig olefination; this is thought to be the trans isomer.1
(22) Oppolzer, W.; Jacobsen, E. J. Tetrahedron Lett. 1986, 27, 114144.
(23) Reich, H. J. Acc. Chem. Res. 1979, 12, 22-30.
(24) Inexplicably the alicyclic protons, except for the ether ones, were
omitted from the spectrum reported in ref 8a.
(25) Isoe, S.; Ono, T.; Hyeon, S. B.; Sakan, T. Tetrahedron Lett. 1968,
5319-23. There was no regio- or stereocontrol in this synthesis and the
former was extremely poor in the key cyclization step, when repeated by
a different group; the cyclization led to a 4:1 mixture containing predominantly the wrong isomer.8a
(26) Battioni, J. P.; Capmau, M.-L.; Chodkiewicz, W. Bull. Soc. Chim.
Fr. 1969, 976-80. Ashby, E. C.; Laemmle, J. T. Chem. ReV. 1975, 75,
521-46.

Magnesium-Ene Cyclization

J. Am. Chem. Soc., Vol. 123, No. 1, 2001 33

Scheme 2

by NMR spectroscopy. The results indicate that the absence of

lithium ions did indeed increase the stereoselectivity; the all
cis alcohol 3a constituted 95% of the cyclization products (eq
8).

Scheme 3

To apply this finding to the natural product synthesis, the

procedure was repeated and the cyclized organomagnesium was
trapped with diphenyl diselenide to produce a 78% yield of the
phenyl selenide 2 (eq 9). Only about 3% of protonated product

lithiation product of the des-methyl analogue 11 of 1 by

warming to 23 C overnight yielded the products 12a and 12b
in the ratio of 94:6 (Scheme 3). 12a Consisted of a pair of
diastereomers in slightly unequal amounts. On the other hand,
12b consisted largely of one isomer. Oxidation of the mixture
yielded two ketones 13a and 13b in the same ratio, 94:6. Thus,
the diastereomers of 12a were due to the two possible orientations of the hydroxyl group. Stereochemical equilibration of the
oxidation mixture by means of base essentially reversed the
ratio, thus leading to the conclusion that the cis isomer 13a was
the major one from the oxidation. The addition of methyllithium
to this ketone mixture from the oxidation gave only one
significant product, 3a. It is a safe assumption that the
methyllithium attacks from the side opposite to the substituents
on the ring.26 (2) As indicated in eq 8, 3a can also be generated
by protonation of the magnesium-ene cyclization product of
the allylmagnesium derived from 1. When the intermediate
cyclized organomagnesium compound is phenyl seleninated
instead of being protonated (eq 9), the resulting compound can
be transformed to matatabiether 10 as discussed above; this
transformation requires the stereochemistry shown.
The addition of methyllithium to the equilibrated ketone
mixture yielded an alcohol mixture containing two major
products 3b and 3d, comprising 89% of the alcohol product
(by NMR integration of the ring methyl peaks) and 11% of 3a.
The ring methyl peaks of 3b and 3d overlap but the ratio of 3b
to 3d is approximately 1:2. Since all of the intramolecular
lithium-ene additions to allyl alcohol anions that we have
studied3 give products in which the cyclized organolithium
function is cis to the oxyanionic group (as, for example, in eq
2), it is satisfying that this is the arrangement as well in 3b,
generated in eq 6. The small amount of 3c formed in eq 5 is
assigned the structure shown by a process of elimination; no
such product was clearly detected upon addition of methyllithium to either ketone mixture, an expected result if the
addition to 13a is highly stereospecific.
In conclusion, a method has been devised by which a
magnesium-ene cyclization can be performed on a system
bearing an oxyanionic group allylic to the enophilic alkene. It
is particularly useful that the precursor of the allylmagnesium
intermediate that undergoes the cyclization is an allyl phenyl
sulfide that is far simpler to prepare in a connective fashion
than the traditional allyl halide precursor. It is of considerable
interest that the presence of lithium ions decreases both chemoand stereoselectivity and as a result the allylmagnesium is best

3a was detected. Thus, the use of reductive magnesiation not

only led to greater stereoselectivity than reductive lithiation
followed by transmetalation but proton transfer from the solvent
was all but eliminated as well. Furthermore, this procedure is
far easier operationally than reductive lithiation and exchange.
Completion of the synthesis of matatabiether 10 is shown in
Scheme 2. Whereas hydroboration of 2 with borane resulted in
a 1:1 mixture of diastereomers, the use of 9-BBN followed by
oxidative workup gave the desired product in excellent diastereoselectivity; the ratio of product 8 to the other isomer isolated,
presumably the diastereomeric product of the hydroboration,
was 24.5:1. Oppolzer and Jacobsen observed a similar facial
selectivity in a related system.22 There were other unidentified
products in the reaction mixture that were not UV active,
suggesting that partial oxidation, by hydrogen peroxide, and
elimination of the phenyl selenide had occurred.
Conversion of the primary hydroxy group into a tosylate
followed by displacement of the latter by the tertiary oxyanionic
group generated by treatment with sodium hydride resulted in
smooth cyclization to the heterocyclic-bridged structure 9 in
91% yield. Oxidative elimination in 9 turned out to be more
difficult than usual,23 which allowed clean oxidation with
m-CPBA in CH2Cl2 to give the corresponding oxides as a
mixture of 1:1 diastereomers. The selenoxide mixture was
washed with base and sodium thiosulfate, dried, and heated in
pyridine at 85 C for 15 min yielding 89% of racemic
matatabiether 10, the 1H NMR spectrum of which was in
excellent accord with that reported.8a,24 The only other total
synthesis of matatabiether was in connection with its structural
proof and no yields or other details were provided.25
Finally, we provide the evidence for the stereochemistry of
the cyclization products of the lithium-ene and magnesiumene reactions of the allylmetallics derived from 1. The stereochemistry of 3a was assigned on the basis of two lines of
evidence: (1) Cyclization of the transmetalated reductive

34 J. Am. Chem. Soc., Vol. 123, No. 1, 2001

prepared by reductive magnesiation of the allyl sulfide rather
than by the better established reductive lithiation followed by
transmetalation. In this connection, a general method of reductive magnesiation of allyl phenyl sulfides has been devised, a
key aspect of which is the use of the anthracene-magnesium
complex.
The valuable oxyanionic functional group leads to very high
stereoselectivity in the ring closure such that the hydroxyl group
of the cyclized product is cis to the alkylmagnesium group.
There is probably also a rate increase associated with the
introduction of this group since cyclization of allylmetallics
which were generated by reductive lithiation followed by
transmetalation occurred at 23 C, considerably below the usual
temperatures for Mg-ene cyclizations.5 However, in those cases
we cannot be certain that the cyclization is a Mg-ene reaction
because of the presence of lithium ions. Unfortunately, the
reductive magnesiations require high enough temperatures that
the cyclizations occur along with the metalation and we cannot

Cheng et al.
be certain if the hydroxyl group facilitates the ring closure as it
does in the case of the lithium-ene cyclization.
Acknowledgment. This paper is dedicated to Professor Jean
F. Normant, a giant in carbometalation chemistry, on the
occasion of his 65th birthday. We are grateful to the National
Science Foundation, the Petroleum Research fund, administered
by the American Chemical Society, and the Army Research
Office for financial support, Dr. Fu-Tyan Lin for help in NMR
spectroscopy, Dr. Kasi Somayajula for help with the mass
spectra, MDL Information Systems and DuPont-Merck for
generous software and database support, and Prof. Paul Floreancig for useful suggestions.
Supporting Information Available: Experimental procedures and compound characterization (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0029782