Central to Axial Transfer of Chirality in Menthone or Camphor-Derived 2,2′-Biphenols

Article abstract of DOI:10.1021/jo970372z

A study aimed at defining a molecular arrangement where a chiral fragment derived from menthone or camphor transfers its central chirality to a 2,2′-biphenol residue, inducing an axial chirality, is reported. The menthol or isoborneol groups are attached at the two benzylic positions at 3,3′ in order to maximize efficiency in practical applications. A reliable and high-yielding procedure for the synthesis of such C₂-symmetric molecules substituted at the 3,3′-positions has been developed. The procedure entails Mannich condensation with paraformaldehyde and morpholine, protection of the hydroxylic functions, chlorination, metalation, and addition to (-)-menthone and (+)-camphor. The use of samarium diiodide is essential in the latter step for optimum selectivity and efficiency. The tetrols exhibit intramolecular hydrogen bonding between phenolic and alcoholic hydroxy functions within each monomeric unity, so that they retain their rotational freedom. NOEDS and COSY experiments show that the tetrols are present in more than one rotamer. The tetrols react with tetrachlorosilane to afford siloxanes as pure diastereoisomers, showing that the metal is able to induce preferential helicity at the biphenyl residue; i.e., the central chirality of menthol or isoborneol auxiliary is totally transfered to the axial chirality of the biphenyl. The configurations could be determined by NOEDS and heterocorrelated HMQC experiments. Remarkably, while the menthol derivative induces total M helicity, the camphor induces complementary P helicity. These results suggest that these tetrols may be useful as ligands in catalysts for asymmetric synthesis.

Full text of DOI:10.1021/jo970372z

7156
J . Org. Chem. 1997, 62, 7156-7164
Cen tr a l to Axia l Tr a n sfer of Ch ir a lity in Men th on e or
Ca m p h or -Der ived 2,2′-Bip h en ols
Fabrizio Fabris and Ottorino De Lucchi*
Dipartimento di Chimica, Universita` Ca’ Foscari di Venezia, Dorsoduro 2137, I-30123 Venezia, Italy
Vittorio Lucchini
Dipartimento di Scienze Ambientali, Universita` Ca’ Foscari di Venezia, Dorsoduro 2137,
I-30123 Venezia, Italy
Received February 27, 1997X
A study aimed at defining a molecular arrangement where a chiral fragment derived from menthone
or camphor transfers its central chirality to a 2,2′-biphenol residue, inducing an axial chirality, is
reported. The menthol or isoborneol groups are attached at the two benzylic positions at 3,3′ in
order to maximize efficiency in practical applications. A reliable and high-yielding procedure for
the synthesis of such C2-symmetric molecules substituted at the 3,3′-positions has been developed.
The procedure entails Mannich condensation with paraformaldehyde and morpholine, protection
of the hydroxylic functions, chlorination, metalation, and addition to (-)-menthone and (+)-camphor.
The use of samarium diiodide is essential in the latter step for optimum selectivity and efficiency.
The tetrols exhibit intramolecular hydrogen bonding between phenolic and alcoholic hydroxy
functions within each monomeric unity, so that they retain their rotational freedom. NOEDS and
COSY experiments show that the tetrols are present in more than one rotamer. The tetrols react
with tetrachlorosilane to afford siloxanes as pure diastereoisomers, showing that the metal is able
to induce preferential helicity at the biphenyl residue; i.e., the central chirality of menthol or
isoborneol auxiliary is totally transfered to the axial chirality of the biphenyl. The configurations
could be determined by NOEDS and heterocorrelated HMQC experiments. Remarkably, while
the menthol derivative induces total M helicity, the camphor induces complementary P helicity.
These results suggest that these tetrols may be useful as ligands in catalysts for asymmetric
synthesis.
In recent years a number of enantiopure catalysts
same processes where three (as in 1) or two (as in 2)
molecules of ligand are necessary.3 The tetrols have been
planned with a rational design in order to take advantage
of the well-known efficiency of atropoisomer binaphthyl
systems in enantioselective processes4 and, at the same
time, to avoid the separation of diastereoisomers. To
reach this goal, an initial study on the transfer from
consisting of a metal bonded to four hydroxylic functions
has been developed. In most cases they have been
obtained by the reaction of one diol molecule with the
metal prebonded to two alcoholic functions,1 as exempli-
fied in 1, or from two molecules of diols with a suitable
metallic precursor,2 as shown in 2.
(2) For example: Seebach, D.; Behrendt, L.; Felix, D. Angew Chem.,
Int. Ed. Engl. 1991, 30, 1008. Schmidt, B.; Seebach, D. Ibid. 1991,
30, 1321. von dem Bussche-Hu¨nnefeld, J . J .; Seebach, D. Tetrahedron
1992, 48, 5719. Giffels, G.; Dreisbach, C.; Kragl, U.; Weigerding, M.;
Waldmann, H.; Wandrey, C. Ibid. 1995, 34, 2005. Kohra, S.; Ha-
yashida, H.; Tominaga, Y.; Hosomi, A. Tetrahedron Lett. 1988, 29, 89.
Kira, M.; Sato, K.; Sakurai, H. J . Org. Chem. 1987, 52, 948. Corey, E.
J .; Letavic, M. A.; Noe, M. C.; Sarshar, S. Tetrahedron Lett. 1994, 35,
7553.
(3) To the best of our knowledge, the only examples of molecules of
type 3 reported in the literature refer to compound i, able of very high
performances (yields and ee >99%) in asymmetric Diels-Alder reac-
tions with either boron or titanium as the metal promoters (Ishihara,
K.; Yamamoto, H. J . Am. Chem. Soc. 1994, 116, 1561. Maruoka, K.;
Murase, N.; Yamamoto, H. J . Org. Chem. 1993, 58, 2938) and to
compound ii (Corey, E. J .; Cywin, C. L.; Noe, M. C. Tetrahedron Lett.
1994, 35, 69).
In a few cases, these compounds are stable, crystalline
solids and could be isolated, characterized, and even
subjected to X-ray diffractometric analysis in order to
rationalize enantioselective behavior in the catalytic
path. In the present work, we describe a first approach
to the development of a C2-symmetric chiral tetrol of type
3, in principle able to behave as a single ligand in the
* Address correspondence to this author. E-mail: delucchi@unive.it.
X Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) Numerous examples can be found in: Nogradi, M. Stereoselective
Synthesis; VCH: Weinheim, 1986. Ojima, I. Catalytic Asymmetric
Synthesis; VCH: New York, 1993. Noyori, R. Asymmetric Catalyis in
Organic Synthesis; Wiley: New York, 1994. Advanced Asymmetric
Synthesis; Stephenson, G. R., Ed.; Chapman and Hall: London, 1996.
(4) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis
1992, 503.
S0022-3263(97)00372-1 CCC: $14.00 © 1997 American Chemical Society

Chirality Transfer in 2,2′-Biphenols
J . Org. Chem., Vol. 62, No. 21, 1997 7157
central chirality to axial chirality in two molecules was
undertaken and is reported here in detail.
Although this number can vary for different metals and
hybridization geometries, we thought that two carbon
atoms is the optimal choice for the preferential formation
of monomeric species 3 over that of dimeric species 2. It
should also be pointed out that biphenyl systems such
as 6 and 6′ may better adapt their geometry to the
structural requirements of the metal than similar mol-
ecules consisting of binaphthyl systems due to the
limitations imposed on the torsional angle in the latter
aromatic rings. In other words, the atropoisomeric
ligands 6 and 6′ should be able to adopt the dihedral
angle that best fits the size and the nature of the metal.
On the basis of these considerations we decided to
prepare molecules 7 and 8, containing chiral residues
derived from menthone and camphor.
Resu lts a n d Discu ssion
Design of th e Tetr ol. The starting point in this
research is 1,1′-binaphthalene-2,2′-diol (4, BINOL), which
has become a familiar diol in a number of common
transformations4 because of its availability in enantio-
merically pure form,5 its high efficiency, its simple C2-
geometry and clear rationalization of its reactivity. In a
few cases, BINOL has been shown to coordinate around
a central metal atom, giving rise to molecules of type 5
which are highly efficient in enantioselective processes.6
It is also known that substitution at the 3,3′-positions
is beneficial to the efficiency of the catalyst as it increases
steric bulk around the metal complex. For example,
definite improvement of several enantioselective pro-
cesses has been obtained with substitution of R in 4
ranging from methyl to triphenylsilyl.7 Thus, if any
substitution is to be introduced in a binaphthyl skeleton,
it should ideally occupy the 3,3′-positions.
After the substitution pattern was settled, our research
plan was to introduce a stereopure chiral fragment at
these positions in a biphenyl system. In fact, while with
the use of racemic binaphthol two different diastereo-
isomers were expected (i.e., the stereoisomers composed
by the stereopure fragment and BINOL of M or P
configuration), no such an occurrence can be attained in
the case of the configurationally labile 2,2′-biphenol. We
hoped that the biphenyl residue would have assumed a
preferred conformation by virtue of the chiral substitu-
ents, thus behaving as a binaphthol but avoiding the
separation of stereoisomers and consequent loss of mate-
rial. The two situations where a chiral stereocenter with
central L chirality induces a P or M helicity to the
biphenyl system when linked to a metal atom are
exemplified in 6 and 6′.
We hope that this system may enjoy large applicability
in forming complexes with different metals and exibit
high performance in view of the added chirality derived
from the C2 symmetry,8 the presence of two centrally
chiral fragments, and the induced helicity. These fea-
tures may contribute synergically to the definition of a
highly structured pocket with enhanced chirality capable
of high efficiency in asymmetric synthesis.
Syn th esis. Most methods available for the function-
alization of the 3,3′-positions of BINOL make use of
strongly basic conditions and rather expensive reagents9
or long synthetic procedures.10 Seeking a simpler and
more economic route, we finally applied the Mannich-
type reaction of paraformaldehyde and morpholine to
2,2′-biphenol in dioxane,11 which gives rise to a fair and
reproducible 50% yield of the 3,3′-bismorpholinomethyl
derivative 9 (eq 1).
Protection of the hydroxylic functions was achieved in
the most simple and economic way with dichloromethane
and sodium hydroxide in dimethyl sulfoxide.9 The fol-
lowing replacement of morpholine with chlorine occurred
A final point in the planning of the molecule is the
number of carbons in the side arms at the 3,3′-positions
necessary to ensure the efficient binding to the metal.
(8) Whitesell, J . K. Chem Rev. 1989, 89, 1581.
(5) Fabbri, D.; Delogu, G.; De Lucchi, O. J . Org. Chem. 1995, 60,
6599. De Lucchi, O. Pure Appl. Chem. 1996, 68, 945.
(9) Maruoka, K.; Itoh, T.; Araki, Y.; Shirasaka, T.; Yamamoto, H.
Bull. Chem. Soc. J pn. 1988, 61, 2975. Cox, P. J .; Wang, W.; Snieckus,
V. Tetrahedron Lett. 1992, 17, 2253. Kitajima, H.; Aoki, Y.; Ito, K.;
Katsuki, T. Chem. Lett. 1995, 1113. Stock, H. T.; Kellogg, R. M. J .
Org. Chem. 1996, 61, 3093.
(10) Brunner, H.; Goldbrunner, J . Chem. Ber. 1989, 122, 2005.
(11) Fukazawa, Y.; Kitayama, H.; Yasuhara, K.; Yoshimura, K.;
Usui, S. J . Org. Chem. 1995, 60, 1696.
(6) For example: Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date,
T.; Shibasaki, M. Angew. Chem. Int. Ed. Engl. 1996, 35, 104.
(7) Kelly, T. R.; Whiting, A.; Chandrakumar, N. S. J . Am. Chem.
Soc. 1986, 108, 3510. Maruoka, K.; Hoshino, Y.; Shirasaka, T.;
Yamamoto, H. Tetrahedron Lett. 1988, 29, 3967. Larsen, D. S.; O′Shea,
M.; Brooker, S. J . Chem. Soc., Chem. Commun. 1996, 203.

7158 J . Org. Chem., Vol. 62, No. 21, 1997
Fabris et al.
in almost quantitative yield with phenyl chloroformate
in dichloromethane (eq 2).12,13
However, the same reaction applied to camphor did not
lead to the expected addition product 15, even after
prolonged time or more drastic reaction conditions. The
only product isolated from this reaction was the 1,3-
dioxepine 12, derived from hydrolysis of the organome-
tallic intermediate.
The attachment of the enantiopure ketones (menthone
or camphor) to 11 requires its transformation into an
organometallic reagent. The use of magnesium, even
under special activating techniques as dry stirring,14
gives rise in most cases to oligomeric material derived
from Wurtz-type coupling. The Grignard reagent of 11
was obtained with the use of the complex of magnesium
with anthracene, which is known to minimize Wurtz
reactivity.15 However, the Grignard compound formed
by this route did not react with menthone and gave high
yields of the dimethyl derivative 12 (eq 3) after acidic
workup. This route to 12 might be considered as alter-
native to other methods to obtain 3,3′-dimethyl deriva-
tives of biphenols and might also be applicable to the
binaphthyl series.
A definite improvement was achieved with the use of
freshly prepared samarium diiodide.17,18 With this re-
agent the isobornyl-disubstituted product 15 was ob-
tained in almost quantitative yield. These reaction
conditions also led to nearly quantitative yield of the
menthyl-disubstituted product 14.
Deprotection of the 1,3-dioxepine 14 with boron tri-
fluoride etherate in ethanethiol19 affords 7 in 65% yield
and the ether 16 in 20% yield. The formation of this
product is rationalized as a dehydration of 7 catalyzed
by the Lewis acid, and was the sole product if the reaction
was carried out for a longer time.
Better results were obtained when the Grignard re-
agent of 11 was treated with cerium trichloride16 before
the addition of menthone. In this case the mono- and
disubstituted products 13 and 14 were obtained in 36%
and 48% yield, respectively.
(12) Hobson, J . D.; McCluskey, J . D. J . Chem. Soc. (C) 1967, 2015.
(13) It should be noticed that if the reaction is run with 1 equiv of
Mannich base, the monoadduct iii is obtained in 72% yield.
The stereochemistry of product 16 can be predicted on
the assumption that the intramolecular attack of phenolic
oxygen to the carbocation generated by dehydration of
the menthol hydroxy moiety occurs on the face which is
not hindered by the isopropyl group. This stereochemical
assignment is supported by NOE experiments, which are
in good agreement with the distances obtained in the
structure 16 minimized at PM3 level.20 Figure 1 and
(14) Baker, K. V.; Brown, J . M.; Hughes, N.; Skarnulis, A. J .; Sexton,
A. J . Org. Chem. 1991, 56, 698.
(17) Kagan, H. B.; Namy, J . L.; Girard, P. Tetrahedron (Suppl. 1)
1981, 37, 175.
(18) Namy, J . L.; Girard, P.; Kagan, H. B.; Caro, P. E. Nouv. J . Chim.
1981, 5, 479.
(19) Node, M.; Hori, H.; Fujita, E. J . Chem. Soc., Perkin I 1976, 2237.
(20) Spartan Version 4.0, Wavefunction Inc., 18401 Karman Ave.,
#370, Irvine, CA 92715.
(15) Raston, C. L.; Salem, G. J . Chem. Soc. Chem. Commun. 1984,
1702. Oppolzer, W.; Schneider, P. Tetrahedron Lett. 1984, 25, 3305.
(16) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392. Dimitrov, V.;
Bratovanov, S.; Simova, S.; Kostova, K. Tetrahedron Lett. 1994, 35,
6713.

Chirality Transfer in 2,2′-Biphenols
J . Org. Chem., Vol. 62, No. 21, 1997 7159
ether 19, as tetrol 7 can be obtained directly from the
dichloride 18 under acidic workup.
F igu r e 1. Structure of compound 16, as determined by PM3
computations.
In contrast, the reaction with camphor did not lead to
tetrol 8, suggesting an unfavorable steric interaction of
the trimethylsilyl groups. Therefore, the less hindered
silyl ethers 20 and 21 were prepared. The dimethyl silyl
ether 21 was obtained from 9 in a one pot reaction, as
the intermediate 20 was too unstable to be isolated. The
dichloride 21 reacted with camphor in the presence of
samarium diiodide producing the tetrol 8 in 85% yield.
The same reaction sequence gave the menthyl derivative
7 with high efficiency.
Ta ble 1. Dista n ces betw een Atom s Givin g NOE for
Com p ou n d 16 As Op tim ized a t th e P M3 Com p u ta tion a l
Level
selected atoms
distances, Å
H9-H8
3.04
3.03
2.38
2.27
2.94
1.70a
H9-H8′
H8-H5ax
H8′-H3
H8-H7
The tetrols 7 and 8 react with tetrachlorosilane and
triethylamine in chloroform at reflux to produce siloxanes
22 and 23 in high yield.
H8-Me7
a
Distance from the nearest proton of Me7.
Table 1 report the structure of compound 16 as mini-
mized at the PM3 level, the calculated distances, and the
observed NOEs.
In view of the difficulties in the preparation of reason-
able quantities of 7 and 8 via this route and the necessity
of avoiding the utilization of the irritating ethanethiol,
an alternative procedure was sought. It was reasoned
that silyl ethers would be compatible with samarium
diiodide and would be easily cleaved under mild acidic
conditions. In the first trials, the phenolic functions in
9 were protected as trimethylsilyl ethers, producing 17
in almost quantitative yield. The dimorpholino deriva-
tive was transformed into the dichloride 18 as previously
described for the dioxepine 11.21
Str u ctu r a l An a lysis. The configurations of siloxanes
22 and 23 and clear information about the conformational
preferences of tetrols 7 and 8 and of ether 16 were
established by a careful NMR study, and notably by
analysis of the dipolar interactions between relevant
protons, accomplished through NOE differential spec-
troscopy (NOEDS).22,23 The full assignment of the 1H
resonances was accomplished by the combined utilization
of COSY spectroscopy and of heterocorrelated reverse
detection HMQC spectroscopy.24-26 This latter technique
1
allowed the unambigous assignment of H methylenic
and methynic multiplets of the menthol and isoborneol
moieties. In some instances, the multiple-bond HMBC
spectroscopy was utilized.25,27 The HMQC and HMBC
spectroscopies made also possible the assignment of 13C
resonances.
The observed dipolar interactions have been checked
on the structures obtained from geometrical optimization
at the semiempirical PM3 level. For a meaningful
comparison, we assumed that dipolar interactions were
It was noticed that the steric hindrance of the bulky
trimethylsilyl groups in 17 and 18 induces atropoisom-
erism to the biphenyl system, to such an extent that the
two benzylic protons are observed as diastereotopic at
room temperature in the 1H-NMR spectrum. No such
behavior was observed for the related molecules 9, 10,
and 11, suggesting that the dioxepine skeleton is not
sufficient to freeze the conformation of the biphenyl
residue. The dichloride 18 was reacted with samarium
diiodide and menthone, obtaining the menthyl derivative
19 in very high yield. The tetrol 7 can be obtained from
19 quantitatively under mild acidic conditions. From a
practical viewpoint, it is not necessary to isolate the silyl
(22) Neuhaus, D.; Williamson, M. The Nuclear Overhauser Effect
in Structural and Conformational Analysis; VCH Publishers: New
York, 1984.
(23) Kinns, M.; Sanders, J . K. M. J . Magn. Reson. 1984, 56, 518.
(24) Bax, A.; Griggey, R. H.; Hawkins, B. L. J . Magn. Reson. 1983,
55, 301.
(25) Summers, M. F.; Marzilli, L. G.; Bax, A. J . Am. Chem. Soc.
1986, 108, 4285.
(21) Sunggak, K.; Heung, C. Bull. Chem. Soc. J pn. 1985, 58,
3669. Sweeley, C. C.; Bentley, R.; Makita, M.; Wells, W. W. J . Am.
Chem. Soc. 1963, 85, 2497.
(26) Bax, A.; Subramanian, S. J . Magn. Reson. 1986, 67, 565.
(27) Bax, A.; Summers, M. F. J . Am. Chem. Soc. 1986, 108,
2093.

7160 J . Org. Chem., Vol. 62, No. 21, 1997
Fabris et al.
1
F igu r e 3. Notations employed in the descriptions H- and 13C-
NMR spectra of compounds 7, 8, 16, 22, and 23.
proton at 8.8 ppm with the ipso and ortho aromatic
carbons C8a, C9, and C12a (Figure 2a and 3), while the
correlation of the hydroxy proton at 2.7 ppm is with the
methylenic carbon C8 (Figure 2b and 3).
Thus, most H bonding is between the menthol or
isoborneol moiety and the adjacent phenol, so that the
rotation around the biphenyl bond is not affected.
(ii) Similarly to ether 16, but at variance with siloxanes
22 and 23 (vide infra), the irradiation of the ortho
aromatic 1H resonance H9 brings about a NOE enhance-
ment of both resonances of methylenic protons H8 and
H8′. This fact may be attributed either to the preferred
presence of that conformation where the aromatic ring
bisects the angle H8-C8-H8′ or, more probably, to the
presence of fast interconverting conformers. The pres-
ence of H bonding may in principle reduce the number
of conformations to one. The optimization of the geom-
etry of tetrols 7 and 8 with the semiempirical PM3 model
is of no avail, as H bonding is not adequately described
at this computational level. As a matter of fact, the
geometrical optimization of 7 and 8 in the absence of
constraints generates structures with the phenol hydroxy
proton pointing away from the aliphatic hydroxy oxygen.
Also, the optimization of the geometry of tetrols 7 and
8 does not give any hint about their conformational
preference around the biphenyl atropoisomeric bond. The
1
observation of only one set of signals in the H and 13C
spectra of the tetrols can be accounted for by the existence
of only one rotamer, but also by the presence of more fast
interconverting rotamers. Some calculated rotamers of
tetrols 7 and 8 suggested the possibility of NOE dipolar
interactions of some aliphatic protons with the aromatic
proton H11 of the other non-directly-bonded phenyl.
Unfortunatly, no such interactions could be detected even
at low temperature, and thus, no information about the
conformational preference of tetrols 7 and 8 could be
gained.
F igu r e 2. Long-range interactions between low-field hydroxy
protons and aryl carbons in HMBC spectrum of 7. (b) Long-
range interactions between high-field hydroxy protons and
alkyl carbons in HMBC spectrum of 7.
observed for interproton through-space distances shorter
than the threshold of 3.3 Å.
Tetr ols 7 a n d 8. The inspection of the 1H-NMR
spectra and the results of NOEDS experiments reveals
two important features.
(i) When the compounds are examined in carefully
dried CDCl3, the hydroxy protons give rise to two distinct
resonances, at about 8.8 and 2.7 ppm. The frequency of
the low-field resonance suggests that this hydroxy pro-
ton is involved in a good degree of H bonding. On the
basis of the acidity scale of phenols and aliphatic alco-
hols, it may be assumed that the low-field signal at 8.8
ppm is associated with the phenolic proton. This as-
sumption was confirmed by the HMBC analyses of 7
(Figure 2) and 8.
Siloxa n e 22. The bonding of silicon with the four
oxygen atoms “freezes” the conformational freedom of
tetrol 7 around the phenyl-CH2, CH2-menthol, and bi-
1
phenyl bonds. As we observed only one set of H and
13C signals, only one diastereoisomer is obtained, while
the “freezing” can in principle lead to both diastereoiso-
mers (P and M). The geometry of both diastereoisomers
has been computationally optimized at the semiempirical
PM3 level (see Figure 4). The interproton distances
relevant for the comparison with the NOE results are
reported in Table 2. Distances less than the threshold
of 3.3 Å are highlighted by boldface digits.
The HMBC spectrum of 7 shown in Figure 2a displays
clear multiple-bond scalar correlations of the hydroxy
The results of the NOEDS experiment are reported in
Table 2. The discussion of these results requires the

Chirality Transfer in 2,2′-Biphenols
J . Org. Chem., Vol. 62, No. 21, 1997 7161
F igu r e 4. Configurations and conformational preferences of
diastereoisomer P and M of compound 22, as determined by
PM3 computations.
F igu r e 5. Configurations and conformational preferences of
diastereoisomers P and M of compound 23, as determined by
PM3 computations.
Ta ble 2. Obser ved NOEs a n d In ter p r oton Dista n ces for
th e Tw o Con for m er s of Com p ou n d 22 As Op tim ized a t
th e P M3 Com p u ta tion a l Level
Ta ble 3. Obser ved NOEs a n d In ter p r oton Dista n ces for
th e Tw o Con for m er s of Com p ou n d 23 As Op tim ized a t
th e P M3 Com p u ta tion a l Level
distances,a
Å
distances,a
Å
selected protons
observed NOE
P
M
selected protons
observed NOE
P
M
H9-H8
x
2.37
3.56
3.10
4.97
2.54
3.72
3.81
2.21
2.63
1.85
2.38
3.45
5.23
2.57
2.91
2.33
2.41
2.24
2.30
3.65
H9-H8
x
2.40
3.58
2.23
4.75
1.79
2.73
2.39
2.48
3.54
4.14
2.38
3.58
3.60
2.85
1.71
2.76
2.87
3.71
3.16
2.62
H9-H8′
H9-H2ax
H9-H7
H9-H8′
x
x
H9-H3endo
H9-H6endo
H8-H3endo
H8-H4endo
H8-H6endo
H8′-H6endo
H8-Me2b
x
x
x
x
H8-H2ax
H8′-H2ax
H8′-H2eq
H8-H6
H8-H7
H8′-H7
x
b
x
c
x
x
H8′-Me2b
x
a
b
Distances shorter than 3.3 Å are in boldface.
Negative
a
b
Distances shorter than 3.3 Å are in boldface. Distance from
nearest proton of Me2. c Negative enhancements due to the
quasi-linear arrangement of Me2-H8′-H8 in M.
enhancements due to the quasi-linear rearrangement of H8-
H8′-H7 in P.
correct assignment of the H8 and H8′ doublets. Upon
saturation of the aromatic H9 resonance only one doublet
is enhanced, suggesting that one methylenic proton
(marked H8) eclipses the aromatic ring, while the other
(H8′) points away. This feature is correctly predicted by
the semiempirical PM3 analysis. The other 1H reso-
nances have been assigned by the COSY and HMQC
spectroscopies.
It should be noted that the observed NOE enhance-
ments correspond to interproton distances shorter than
the threshold in the case of diastereoisomer P. In the
case of diastereoisomer M some observed enhancements
correspond to distances longer than the threshold, while
some shorter distances are not matched. The interaction
between H8 and H7, which leads to negative enhance-
ments, deserves further comment. The negative en-
hancement suggests the interposition between H8 and
H7 of a third proton (H8′) in a quasi-linear H8-H8′-H7
arrangement. This arrangement is found in diastereo-
isomer P, while the isomer M has the H8′-H8-H7
arrangement.
are reported in Table 3. The distance of a given proton
from methyl is that from the nearest methyl proton (the
one most contributing to or most affected by NOE).
As in the previous case, both NOE analysis and
computational results point to methylenic H8 eclipsing
the phenyl ring, while geminal H8′ is oriented away. The
observed NOE enhancements are exactly matched by
distances shorter than the threshold in diastereoisomer
M, while the match is much poorer in diastereoisomer
P. Also, the negative enhancements from the interac-
tions between Me2 and H8 reflects the quasi-linear
arrangement of Me2-H8′-H8 in M, while in P the
arrangement is Me2-H8-H8′.
Again, the lowest computed energy is that of the dia-
stereoisomer M, which is actually observed: M, -233.19
kcal/mol; P, -229.23 kcal/mol.
The specific formation of different atropoisomers, P in
22 and M in 23, makes the two tetrols 7 and 8 potentially
complementary in future practical applications, where
they are planned to be used as ligands in catalysts for
asymmetric synthesis.
The PM3 computed energies of diastereoisomers P
(-297.04 kcal/mol) and M (-273.46 kcal/mol) indicate
that the observed diastereoisomer (P) is also energetically
favored.
Siloxa n e 23. Also in this case only one diastereoiso-
mer is observed, while the computed geometry optimiza-
tions have been performed for both diastereoisomers
(Figure 5). The relevant computed interproton distances
Exp er im en ta l Section
All reactions were performed under nitrogen and carried
out with standard techniques. Manipulations of moisture
sensitive substances were carried out in a glovebox. All
glassware was flame-dried before use. THF was dried over
potassium/benzophenone. Reactions were monitored by TLC
1
or H NMR. Flash chromatography was performed with 230-

7162 J . Org. Chem., Vol. 62, No. 21, 1997
Fabris et al.
400 mesh silica gel Merck 60. Melting points were determined
with a Bu¨chi MP 535 and were uncorrected. 1H-NMR and 13C-
NMR spectra were recorded on a Bruker AC200 using TMS
as internal standard. The NOE spectra have been obtained
in the differential mode (NOEDS)23 on a Varian Unity 400
spectrometer. The lines of the selected multiplet were 0.05 s
cyclically saturated for a total time of 10 s with the proper
attenuation of the decoupling power.23 The heterocorrelated
reverse-mode HMQC25-27 and HMBC26,28 (multiple bond HMQC)
spectra have been acquired on the same spectrometer. In a
typical experiment, a total of 256 t1 measurements were made
in the phase sensitive acquisition mode, with 16 (HMQC) or
32 (HMBC) scans for t1 value. The delay of the BIRD filter is
a ction of 11 w ith Mg‚a n th r a cen e‚3THF , CeCl3, a n d m en -
th on e. To a dispersion of Mg‚anthracene‚3THF (1.7 g, 2.55
mmol) in anhydrous THF (5 mL) was added dropwise a
solution of 11 (325 mg, 1.1 mmol) in anhydrous THF (6 mL).
The resulting solution was added to a previously prepared
slurry of (-)-menthone (0.4 mL, 2.3 mmol), and anhydrous
CeCl3 (490 mg, 2.0 mmol) in dry THF (2 mL) stirred under
nitrogen 1 h at rt. After 12 h, the reaction mixture was filtered
through a glass-wool plug, poured into saturated NH4Cl (100
mL), extracted with Et2O (5 × 50 mL), and dried over Na2SO4.
The combined organic layers were concentrated to ca. 10 mL.
The colorless crystals formed (anthracene) were discarded and
the filtrate was concentrated and purified by flash chroma-
tography (eluant CH2Cl2/hexane 1:1) eluting in the order
monoadduct 13 and bisadduct 14. 13: pale yellow oil, 150 mg
(36% yield), [R]D25 -18.1 (c 2.4, CH2Cl2). 1H NMR (CDCl3, 200
MHz) δ 7.50-7.46 (2 H, m), 7.30-7.11 (4 H, m), 5.72 (1 H, 1/2
AB, J ) 3.9 Hz), 5.67 (1 H, 1/2 AB, J ) 3.9 Hz), 3.93 (2 H, 1/2
AB, J ) 13.4 Hz), 2.61 (2 H, 1/2 AB, J ) 13.4 Hz), 2.49-2.28
(1 H, m), 2.36 (3 H, s), 1.84-0.70 (8 H, serie di m), 1.01 (3 H,
d, J ) 6.9 Hz), 1.00 (3 H, d, J ) 6.9 Hz), 0.77 (3 H, d, J ) 6.5
Hz), (1 H alcohol not observed); 13C NMR (CDCl3, 50 MHz) δ
152.3, 151.5, 132.3, 132.0, 131.9, 130.4, 130.2, 130.0, 127.2,
126.6, 124.6, 124.4, 100.3, 75.0, 50.6, 46.9, 40.4, 35.2, 27.8, 26.1,
23.8, 22.4, 21.0, 18.1, 15.9. IR (film, cm-1) 3567, 2954, 1015,
771. 14: 280 mg (48% yield), mp 186-187 °C (from pentane),
1
matched to the average J CH ) 140 Hz. The fixed delay for
the detection of multiple-bond correlations is tuned to nJ CH
)
5 Hz. IR spectra were collected on a BIO-RAD FTS-40.
Optical rotations were observed on a Perkin-Elmer 638 pola-
rimeter.
2-(2-H yd r oxy-3-(m or p h olin om et h yl)p h en yl)-6-(m or -
p h olin om eth yl)p h en ol (9). Paraformaldehyde (9.9 g, 297.7
mmol) was dissolved in morpholine (30 mL, 344.1 mmol) in a
round-bottomed flask equipped with a reflux condenser (CAU-
TION! strongly exothermic reaction). The resulting syrup
was diluted with dioxane (10 mL), added dropwise to a solution
of 2-(2-hydroxyphenyl)phenol (20.0 g, 107.4 mmol) in dioxane
(20 mL), and stirred 2 h at room temperature (rt) and 4 h at
reflux. The solvent was removed and the residue was dis-
solved in CH2Cl2 (600 mL), washed with 1 M HCl (3 × 50 mL)
and water (3 × 50 mL), dried over Na2SO4, and rotoevaporated.
The crude material was recrystallized from EtOH to obtain
20.6 g (50% yield) of colorless needles: mp 146-148 °C; 1H
NMR (CDCl3, 200 MHz) δ 7.27 (2 H, dd, J ) 7.5 and 1.8 Hz),
7.02 (2 H, dd, J ) 7.5 and 1.8 Hz), 6.88 (2 H, t, J ) 7.5 Hz),
3.78 (4 H, s), 3.71 (8 H, t, J ) 5.8 Hz), 2.59 (8 H, t, J ) 5.8
Hz); 13C NMR (CDCl3, 50 MHz) δ 154.8, 131.0, 128.3, 125.9,
120.8, 118.9, 66.6, 62.0, 52.8. IR (KBr, cm-1) 3443, 2853, 1431,
1118.
22
[R]D -66.8 (c 2.8, CH2Cl2). 1H NMR (CDCl3, 200 MHz) δ
7.50-7.40 (2 H, m), 7.30-7.27 (4 H, m), 5.72 (2 H, s), 3.42 (2
H, 1/2 AB, J ) 13.5 Hz), 2.59 (2 H, 1/2 AB, J ) 13.5 Hz), 2.51-
2.28 (2 H, m), 1.86-0.65 (16 H, serie di m), 1.00 (6 H, d, J )
6.9 Hz), 0.78 (3 H, d, J ) 6.4 Hz) (2 H alcohol not observed);
13C NMR (CDCl3, 50 MHz) δ 151.9, 132.4, 132.2, 130.1, 127.4,
124.5, 100.6, 75.0, 50.6, 46.8, 40.4, 35.2, 27.8, 26.1, 23.8, 22.4,
21.0, 18.1. IR (KBr, cm-1) 3566, 2956, 1384, 1009, 774.
Rea ction of 11 a n d Men th on e w ith Sm I2. A solution of
samarium diiodide 0.1 M in THF (9.0 mL, 0.9 mmol) was
introduced via syringe to a solution of 11 (60 mg, 0.2 mmol)
and (-)-menthone (100 µL, 0.6 mmol) in dry THF (1.0 mL) at
rt under nitrogen. After 30 min the deep blue solution turned
yellow. Aqueous hydrochloric acid (0.1 M, 10 mL) was added,
and the resulting mixture was stirred 15 min at rt. The acidic
solution was extracted with Et2O (3 × 5 mL), washed with
Na2S2O5 (5 mL of a 10% solution) and brine (5 mL), dried
(Na2SO4), and concentrated under vacuum. The crude was
purified by flash chromatography (eluant CH2Cl2/hexanes 1:1)
and recrystallized from CH2Cl2/n-hexane to obtain 95 mg (90%
yield) of colorless crystals, mp 186-187 °C, identical to the
sample obtained as above.
4-((8-(Mor p h olin om eth yl)d iben zo[d ,f][1,3]d ioxep in -4-
yl)m eth yl)m or p h olin e (10). A slurry of 9 (17.0 g, 44.2
mmol), NaOH (4.0 g, 100.0 mmol), CH2Cl2 (50 mL), and DMSO
(250 mL) was refluxed at 100 °C for 45 min. The resulting
solution was poured into water (2 L), extracted with CH2Cl2
(3 × 150 mL), washed with water (4 × 100 mL), dried
(Na2SO4), and rotoevaporated. The resulting oily residue was
recrystallized from EtOH to afford yellow needles: 16.8 g (96%
1
yield); mp 124-126 °C; H NMR (CDCl3, 200 MHz) δ 7.44 (2
H, dd, J ) 7.5 and 1.8 Hz), 7.38 (2 H, dd, J ) 7.5 and 1.8 Hz),
7.24 (2 H, t, J ) 7.5 Hz), 5.85 (2 H, s), 3.73 (8 H, t, J ) 4.5
Hz), 3.60 (4 H, s), 2.52 (8 H, t, J ) 4.5 Hz); 13C NMR (CDCl3,
50 MHz) δ 151.8, 133.1, 130.4, 130.3, 127.6, 124.6, 103.0, 67.2,
57.8, 53.7. IR (KBr, cm-1) 2799, 1113, 1017, 778.
(2S )-2-((8-((2S )-2-H y d r o x y -1,7,7-t r im e t h y lb ic y c lo -
[2.2.1]h ep t -2-yl)m et h yl)d ib en zo[d ,f][1,3]d ioxep in -4-yl)-
m eth yl)-1,7,7-tr im eth ylbicyclo[2.2.1]h ep ta n -2-ol (15). A
solution of samarium diiodide 0.1 M in THF (9.0 mL, 0.9 mmol)
was introduced via syringe to a solution of 11 (60 mg, 0.2
mmol) and (+)-camphor (90 mg, 0.6 mmol) in dry THF (1.0
mL), at rt under nitrogen. The deep blue solution turned
yellow after 1 h. Aqueous hydrochloric acid (0.1 M, 10 mL)
was added and the resulting mixture stirred 15 min at rt. The
solution was extracted with Et2
4,8-Bis(ch lor om eth yl)d iben zo[d ,f][1,3]d ioxep in e (11).
A solution of phenylchloroformate (10.0 mL, 79.7 mmol) in dry
CH2Cl2 (35 mL) was added dropwise under nitrogen to a
solution of 10 (14.0 g, 35.3 mmol) in dry CH2Cl2 (35 mL) at 0
°C. After stirring 2 h at rt, the resulting solution was diluted
in CH2Cl2 (400 mL), washed with 10% Na2CO3 (4 × 100 mL),
dried (Na2SO4), and rotoevaporated. The crude residue was
recrystallized from EtOH to obtain 6.0 g of colorless plates:
mp 104-106 °C. The mother liquor was concentrated and
purified by flash chromatography (eluant hexanes/CH2Cl2 9:1)
to obtain 4.13 g of a pure colorless material for a combined
total yield of 98%. 1H NMR (CDCl3, 200 MHz) δ 7.53 (2 H, d,
J ) 7.6 Hz), 7.43 (2 H, d, J ) 7.6 Hz), 7.27 (2 H, t, J ) 7.6
Hz), 5.90 (2 H, s), 4.73 (4 H, s); 13C NMR (CDCl3, 50 MHz) δ
152.0, 131.7, 130.2, 129.5, 125.0 (two coincident signals), 101.8,
41.3. IR (KBr, cm-1) 2976, 1431, 1009, 686.
Sa m a r iu m Diiod id e (0.1 M Solu tion in THF ). A solution
of 1,2-diiodoethane (2.82 g, 10 mmol) in dry THF (100 mL)
was slowly added to samarium powder (40 mesh) (2.26 g, 15
mmol), with vigorous magnetical stirring, under nitrogen. The
deep blue solution was stirred an additional hour and was
stored under nitrogen.18
(1R,2S,5R)-1-((8-(((1R,2S,5R)-1-Hyd r oxy-2-isop r op yl-5-
m et h ylcycloh exyl)m et h yl)d ib en zo[d ,f][1,3]d ioxep in -4-
yl)m eth yl)-2-isop r op yl-5-m eth ylcycloh exa n -1-ol (14). Re-
O (4 × 5 mL), washed with a
10% solution of Na2S2O5 (5 mL) and brine (5 mL), dried over
Na2SO4, and rotoevaporated. The crude material was purified
by flash chromatography (eluant CH2Cl2/hexanes 1:1) and
recrystallized from CH2Cl2/n-hexane to obtain 85 mg (80%
22
yield) of colorless crystals: mp 149-51 °C; [R]D +105.3 (c
0.7, CH2Cl2). 1H NMR (CDCl3, 200 MHz) δ 7.40 (2 H, dd, J )
7.5 and 2.0 Hz), 7.34 (2 H, dd, J ) 7.5 and 2.0 Hz), 7.24 (2 H,
t, J ) 7.5 Hz), 5.73 (2 H, s), 3.15 (2 H, 1/2 AB, J ) 13.2 Hz),
2.74 (2 H, 1/2 AB, J ) 13.2 Hz), 2.19 (2 H, s), 1.94-1.37 (12
H, m), 1.32-1.10 (2 H, m), 1.06 (6 H, s), 0.90 (6 H, s), 0.88 (6
H, s); 13C NMR (CDCl3, 200 MHz) δ 186.2, 151.4, 132.3, 131.0,
130.4, 127.2, 124.7, 100.2, 80.9, 52.7, 48.8, 44.9, 41.3, 38.0, 30.1,
29.4, 26.8, 21.1, 20.8, 10.0. IR (KBr, cm-1) 3579, 2959, 1207,
1019.
4-(2-((Tr im eth ylsilyl)oxy)-3-(2-((tr im eth ylsilyl)oxy)-3-
(m or p h olin om eth yl)p h en yl)ben zyl)m or p h olin e (17). A
solution of trimethylchlorosilane (0.4 mL, 3.04 mmol) in dry
Et2O was added to a solution of 9 (570 mg, 1.48 mmol),

Chirality Transfer in 2,2′-Biphenols
J . Org. Chem., Vol. 62, No. 21, 1997 7163
triethylamine (0.72 mL, 4.56 mmol), and DBU (2 drops) in dry
Et2O (5 mL) under nitrogen. The resulting slurry was vigor-
ously stirred 6 h, poured into water (20 mL), and extracted
with Et2O (3 × 10 mL). Combined organic layers were dried
over Na2SO4 and rotoevaporated. The residue was recrystal-
lized from n-pentane to obtain 690 mg (93% yield) of colorless
dd, J ) 7.6 and 1.8 Hz), 7.36 (2 H, dd, J ) 7.6 and 1.8 Hz),
7.16 (2 H, t, J ) 7.6 Hz), 4.70 (4 H, s), 0.48 (6 H, s); 13C NMR
(CDCl3, 50 MHz) δ 149.7, 132.2, 130.5, 129.6, 126.3, 123.3,
41.2, -2.1. IR (KBr, cm-1) 3059, 1437, 1260, 931.
(1R,2S,5R)-1-(2-h yd r oxy-3-((2-h yd r oxy-3-((1R,2S,5R)-1-
h yd r oxy-2-isop r op yl-5-m eth ylcycloh exyl)m eth yl)p h en -
yl)ben zyl)-2-isop r op yl-5-m eth ylcycloh exa n -1-ol (7). Via
Dea ceta liza tion of 14. One drop of BF3‚OEt2 was added to
a solution of 14 (130 mg, 0.25 mmol) in EtSH. After stirring
20 min at rt, the solution was poured into saturated NaHCO3
(5 mL) and saturated brine (15 mL) and extracted with CH2Cl2
(4 × 20 mL). The organic extracts were dried over Na2SO4
and rotoevaporated. The residue was purified by flash chro-
matography (CH2Cl2/hexanes 7:3) to obtain two main fractions.
First fraction: 16, colorless oil, 25 mg (20% yield); [R]D25 -48.4
(c 2.2, CH2Cl2). 1H NMR (CDCl3, 400 MHz) δ 7.50 (d, H11,
J 10,11 ) 7.6 Hz), 7.04 (d, H9, J 9,10 ) 7.3 Hz), 6.82 (t, H10), 3.26
1
needles: mp 150-2 °C; H NMR (CDCl3, 200 MHz) δ 7.35 (2
H, dd, J ) 7.4 and 2.1 Hz), 7.09 (2 H, dd, J ) 7.4 and 2.1 Hz),
6.99 (2 H, t, J ) 7.4 Hz), 3.74 (8 H, t, J ) 4.6 Hz), 3.56 (2 H,
1/2 AB, J ) 13.0 Hz), 3.40 (2 H, 1/2 AB, J ) 13.0 Hz), 2.51 (8
H, t, J ) 4.6 Hz), -0.20 (18 H, s); 13C NMR (CDCl3, 50 MHz)
δ 152.9, 132.3, 130.6, 129.9, 128.9, 120.9, 67.0, 58.2, 53.9, 0.3.
IR (KBr, cm-1) 2809, 1112, 917, 842, 766.
2-((Tr im eth ylsilyl)oxy)-1-(2-((tr im eth ylsilyl)oxy)-3-(ch lo-
r om eth yl)p h en yl)-3-(ch lor om eth yl)ben zen e (18). A solu-
tion of phenylchloroformate (0.2 mL, 1.7 mmol) in dry CH2Cl2
(1 mL) was added at 0 °C to a solution of 17 (400 mg, 0.76
mmol) in dry CH2Cl2 (1 mL) under nitrogen. The mixture was
stirred at the same temperature 3 h, diluted with CH2Cl2 (50
mL), washed with water (3 × 10 mL), dried over Na2SO4, and
rotoevaporated. The residue was purified by rapid filtration
through a short silica-gel pad (eluant CH2Cl2/hexanes 1:1) to
obtain 300 mg (92% yield) of colorless needles: mp 85-6 °C;
1H NMR (CDCl3, 200 MHz) δ 7.41 (2 H, dd, J ) 7.4 and 1.8
Hz), 7.18 (2 H, dd, J ) 7.4 and 1.8 Hz), 7.05 (2 H, t, J ) 7.4
Hz), 4.70 (2 H, 1/2 AB, J ) 11.1 Hz), 4.57 (2 H, 1/2 AB, J )
11.1 Hz), -0.14 (18 H, s); 13C NMR (CDCl3, 50 MHz) δ 142.5,
(d, H8, J 8,8′ ) 15.8 Hz), 2.88 (d, H8′), 1.89 (d, H2eq, J 2eq,2ax
)
12.6 Hz), 1.87 (m, H7), 1.80 (dm, H5eq, J 5eq,5ax ) 13.3 Hz), 1.73
(dm, H4eq, J 4eq,4ax ) 12.8 Hz), 1.58 (m, H6), 1.54 (m, H3), 1.35
(t, H2ax, J 2ax,3 ) 12.4 Hz), 1.12 (qd, H5ax, J 4ax,5ax ) J 5ax,6
)
13.1 Hz, J 4eq,5ax
) 3.4 Hz), 0.96 (m, H4ax), 0.92 (d, Me7, J 7,Me7
) 6.7 Hz), 0.91 (d, Me3, J 3,Me3 ) 6.5 Hz), 0.83 (d, Me7′, J 7,Me7′
) 6.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 156.4, 129.2 (C11),
127.5, 123.6 (C9), 119.4, 119.20 (C10), 92.0, 50.7 (C3), 48.5
(C2), 35.0 (C8), 34.8 (C4), 30.2 (C6), 26.9 (C7), 25.5 (C5), 24.4
(Me7), 22.1 (Me3), 19.8 (Me7′). IR (KBr, cm-1
) 2953, 1455,
132.3, 131.9, 130.5, 129.2, 121.7, 41.9, 0.1. IR (KBr, cm-1
2955, 1266, 927, 843, 766.
)
1421, 760. Second fraction: 7, 85 mg (65% yield), colorless
crystals from CH2
Cl2/n-hexane, mp 191-193 °C; [R]D20 -229.4
(c 1.2, CH2Cl2). 1H NMR (CDCl3, 400 MHz) δ 8.80 (s, OH12a),
7.25 (dd, H11, J 10,11 ) 7.7 Hz, J 9,11 ) 1.8 Hz), 7.04 (dd, H9,
J 9,10 ) 7.4 Hz), 6.95 (t, H10), 3.69 (d, H8, J 8,8′ ) 14.1 Hz), 2.68
(1R,2S,5R)-1-(2-((Tr im eth ylsilyl)oxy)-3-((2-((tr im eth yl-
silyl)oxy)-3-((1R,2S,5R)-1-h yd r oxy-2-isop r op yl-5-m eth yl-
cycloh exyl)m et h yl)p h en yl)b en zyl)-2-isop r op yl-5-m et h -
ylcycloh exa n -1-ol (19). A 0.1 M solution of samarium
diiodide in THF (36 mL, 3.6 mmol) was introduced via syringe
through a septum to a solution of 18 (310 mg, 0.72 mmol) and
(-)-menthone (370 µL, 2.18 mmol) in dry THF (1.0 mL) at rt
under nitrogen. The deep blue solution turned yellow after 3
h. Aqueous hydrochloric acid (0.1 M, 36 mL) was added, and
the resulting mixture was rapidly extracted with Et2O (3 ×
20 mL). The combined organic layers were washed with a 10%
solution of Na2S2O5 (10 mL) and brine (10 mL), dried over
Na2SO4, and rotoevaporated. The crude reaction mixture was
purified by flash chromatography (eluant CH2Cl2/hexanes 6:4)
and recrystallized from CH2Cl2/n-hexane to obtain 170 mg
(42% yield) of colorless crystals: mp 195-198 °C; [R]D24 -50.2
(c 2.5, CH2Cl2); 1H NMR (CDCl3, 200 MHz) δ 7.13-6.94 (6 H,
series of m), 3.61 (2 H, 1/2 AB, J ) 13.6 Hz), 2.96 (2 H, s),
2.34 (2 H, heptet, J ) 6.8 Hz), 2.54 (2 H, 1/2 AB, J ) 13.6 Hz),
1.85-1.35 (10 H, series of m), 1.16-0.64 (6 H, series of m),
1.02 (6 H, d, J ) 6.8 Hz), 0.98 (6 H, d, J ) 6.8 Hz), 0.74 (6 H,
d, J ) 6.4 Hz), -0.14 (18 H, s); 13C NMR (CDCl3, 200 MHz) δ
152.3, 133.3, 132.5, 131.1, 130.0, 121.7, 75.7, 51.6, 46.8, 42.6,
35.4, 27.6, 25.8, 24.0, 22.4, 21.4, 18.6, 0.1. IR (KBr, cm-1) 3513,
2953, 1256, 845.
4,8-B i s (c h lo r o m e t h y l)-6,6-d i m e t h y ld i b e n z o [d ,f]-
[1,3,2]d ioxa silep in e (21). A solution of dimethyldichlorosi-
lane (0.36 mL, 3.0 mmol) in dry CH2Cl2 (10 mL) was added at
0 °C to a solution of 9 (1.00 g, 2.8 mmol), triethylamine (0.13
mL, 9.0 mmol), and DBU (3 drops) in dry CH2Cl2 (10 mL)
under nitrogen. The reaction mixture was stirred 1 h at 0 °C.
A small sample (ca. 0.5 mL) of the reaction mixture was
rotoevaporated and submitted to 1H NMR, showing quantita-
tive conversion into 20: 1H NMR (CDCl3, 200 MHz) δ 7.42 (2
H, dd, J ) 7.4 and 1.8 Hz), 7.29 (2 H, dd, J ) 7.4 and 1.8 Hz),
7.11 (2 H, t, J ) 7.4 Hz), 3.72 (4 H, t, J ) 4.1 Hz), 3.56 (4 H,
s), 2.51 (4 H, t, J ) 4.1 Hz), 0.39 (6 H, s). A solution of phenyl
chloroformate (0.9 mL, 7.2 mmol) in dry CH2Cl2 (5 mL) was
added at 0 °C and the resulting mixture was stirred at the
same temperature for 3 h, diluted with CH2Cl2 (150 mL),
washed with water (3 × 10 mL), dried over Na2SO4, and
rotoevaporated. The crude reaction mixture was recrystallized
from n-pentane to obtain 120 mg of colorless needles: mp 108-
10 °C. The mother liquors were concentrated and purified by
rapid filtration through a short silica-gel column (eluant
CH2Cl2/hexanes 1:1) to obtain further 490 mg of pure material
(64% overall yield). 1H NMR (CDCl3, 200 MHz) δ 7.47 (2 H,
(s, OH1), 2.41 (m, H7), 2.41 (d, H8′), 1.76 (dm, H4eq, J 4ax,4eq
12.8 Hz), 1.61 (dm, H5eq, J 5ax,5eq ) 13.5 Hz), 1.47 (m, H2eq
and H3), 1.38 (qd, H5ax, J 4ax,5ax ) J 5ax,6 ) 12.9 Hz, J 4eq,5ax
)
)
3.3 Hz), 1.23 (dm, H6), 0.98 and 0.98 (d, Me7 and Me7′, J Me7,7
) J Me7,7′ ) 6.9 Hz), 0.91 (t, H2ax, J 2ax,2eq ) J 2ax,3 ) 13.8 Hz),
0.89 (m, H4ax), 0.80 (d, Me3, J 3,Me3 ) 6.3 Hz); 13C NMR (CDCl3,
100 MHz) δ 151.8 (C12a), 132.2 (C9), 130.4 (C11), 127.5 (C12),
125.8 (C8a), 120.6 (C10), 77.1 (C1), 51.3 (C6), 45.9 (C2), 43.0
(C8), 34.9 (C4), 28.1 (C3), 25.8 (C7), 23.7 (Me7), 22.3 (Me3),
20.9 (C5), 18.1 (Me7′). IR (KBr, cm-1) 3489, 2952, 1446, 1387.
Via Rea ction of 18 w ith Sm I2. A 0.1 M solution of
samarium diiodide in THF (36 mL, 3.6 mmol) was introduced
via syringe through a septum to a solution of 18 (310 mg, 0.72
mmol) and (-)-menthone (370 µL, 2.2 mmol) in dry THF (1.0
mL) at rt under nitrogen. The deep blue solution turned
yellow after 2 h. Aqueous hydrochloric acid (0.1 M, 40 mL)
was added, and the resulting mixture was stirred 15 min. The
solution was extracted with Et2O (3 × 10 mL), and the organic
layers were combined and washed with a 10% solution of
Na2S2O5 (10 mL) and brine (10 mL), dried over Na2SO4, and
concentrated under vacuum. The residue was purified by flash
chromatography (eluant CH2Cl2/hexanes 6:4) and recrystal-
lized from CH2Cl2/n-hexane to obtain 340 mg (90% yield) of
colorless crystals, mp 191-193 °C, identical to the sample
obtained as above.
Via Rea ction of 21 w ith Sm I2. A 0.1 M solution of
samarium diiodide in THF (9.0 mL, 0.9 mmol) was introduced
via syringe through a septum to a solution of 21 (67 mg, 0.2
mmol) and (-)-menthone (100 µL, 0.6 mmol) in dry THF (1.0
mL) at rt under nitrogen. The deep blue solution turned
yellow after 2 h. Aqueous hydrochloric acid (0.1 M, 10 mL)
was added and the resulting mixture was stirred 15 min. The
solution was extracted with Et2O (3 × 5 mL), and the combined
organic layers were washed with a 10% solution of Na2S2O5
(5 mL) and brine (5 mL), dried over Na2SO4, and rotoevapo-
rated. The crude reaction mixture was purified by flash
chromatography (eluant CH2Cl2/hexanes 6:4) and recrystal-
lized from CH2Cl2/n-hexane to obtain 95 mg (90% yield) of
colorless crystals, mp 191-193 °C, identical to the sample
obtained as above.
(1R,2S,4R)-2-(2-h yd r oxy-3-((2-h yd r oxy-3-((1R,2S,4R)-2-
h yd r oxy-1,7,7-tr im eth ylbicyclo[2.2.1]h ep t-2-yl)m eth yl)-
p h en yl)ben zyl)-1,7,7-tr im eth ylbicyclo[2.2.1]h ep ta n -2-ol
(8). A 0.1 M solution of samarium diiodide in THF (50 mL,

7164 J . Org. Chem., Vol. 62, No. 21, 1997
Fabris et al.
5.0 mmol) was introduced via syringe through a septum to a
solution of 21 (340 mg, 1.0 mmol) and (+)-camphor (455 mg,
3.0 mmol) in dry THF (1.0 mL) at rt under nitrogen. The deep
blue solution turned yellow after 3 h. Aqueous hydrochloric
acid (0.1 M, 15 mL) was added. The resulting mixture was
stirred 15 min, extracted with Et2O (3 × 10 mL), washed with
a 10% solution of Na2S2O5 (5 mL) and brine (5 mL), dried over
Na2SO4, and rotoevaporated. The crude reaction mixture was
purified by flash chromatography (eluant CH2Cl2/hexanes 6:4)
and recrystallized from CH2Cl2/n-hexane to obtain 520 mg
(85% yield) of colorless crystals: mp 166-8 °C; [R]D22 +41.9 (c
0.6, CH2Cl2). 1H NMR (CDCl3, 400 MHz) δ 8.78 (s, OH12a),
7.21 (dd, H11, J 10,11 ) 7.7 Hz, J 9,11 ) 1.7 Hz), 7.17 (dd, H9,
J 9,10 ) 7.5), 6.96 (t, H10), 3.14 (d, H8, J 8,8′ ) 13.9 Hz), 2.93 (s,
OH1), 2.83 (d, H8′), 1.88 (dm, H6exo, J 6endo,6exo ) 13.7 Hz), 1.74
(m, H3, H4 and H6endo), 1.52 (m, H4′), 1.19 (m, H3′), 1.06 (s,
Me7s), 0.88 (s, Me7a), 0.87 (s, Me2); 13C NMR (CDCl3, 100
MHz) δ 152.0 (C12a), 132.1 (C9), 130.5 (C11), 127.3 (C12),
126.6 (C8a), 120.9 (C10), 84.1 (C1), 52.9 (C2), 49.4 (C7), 45.8
(C6), 44.9 (C5), 40.6 (C8), 30.6 (C4), 26.9 (C3), 21.4 (Me7s),
21.1 (Me7a), 10.5 (Me2). IR (KBr, cm-1) 3478, 2955, 1431,
1384.
(1R,1′′R,2′S,3′S,4S,4′′S)-1,1′′,7,7,7′′,7′′-H exa m et h yld i-
sp ir o[bicyclo[2.2.1]h ep ta n e-2,16′-2′,17′,18′,21′-tetr a oxa -1′-
s ila p e n t a c y c lo [8.7.2.21 ,9 .05 ,2 0 .01 4 ,1 9 ]h e n ic o s a -5′,7′,9′-
(20′),10′,12′,14′(19′)-h exa en e-3′,2′′-bicyclo[2.2.1]h ep ta n e]
(23). Freshly distilled tetrachlorosilane (25 µL, 0.22 mmol)
was added to a solution of 8 (100 mg, 0.20 mmol), triethyl-
amine (140 µL, 1.0 mmol), and DBU (2 µL) in dry CHCl3 (4
mL) under nitrogen. The solution was refluxed 3 h, poured
into water (5 mL), and extracted with CH2Cl2 (3 × 5 mL).
The combined extracts were dried over Na2SO4 and rotoevapo-
rated. The residue was purified by flash chromatography
(eluant CH2Cl2/hexanes 1:3) to obtain 80 mg (75% yield) of
23
colorless oil: [R]D -23.7 (c 1.4, CH2Cl2). 1H NMR (CDCl3,
400 MHz) δ 7.39 (dd, H11, J 10,11 ) 7.6 Hz, J 9,10 ) 2.5 Hz), 7.14
(dd, H10, J 10,9 ) J 10,11 ) 7.6 Hz), 7.12 (dd, H9, J 9,10 ) 7.6 Hz,
J 9,11 ) 2.5 Hz), 3.66 (d, H8, J 8,8′ ) 13.3 Hz), 2.46 (d, H8′), 1.73
(m, H4exo, H5 and H6exo), 1.56 (m, H3endo and H3exo), 1.44
(d, H6endo, J 6endo,6exo ) 13.1 Hz), 1.09 (s, Me7s), 1.08 (m,
H4endo), 1.02 (s, Me2), 0.19 (s, Me7a); 13C NMR (CDCl3, 100
MHz) δ 151.4, 131.7, 130.8, 130.2, 126.2 (C11), 123.8, 92.3,
54.4, 49.5, 45.0 (C5), 44.8 (C6), 38.5 (C8), 30.7 (C3), 26.8 (C4),
21.9 (Me7a), 21.4 (Me7s), 10.8 (Me2). IR (film, cm-1) 2949,
2925, 1080.
(1′R,2S,2′′S,3′R,5R,5′′R)-2,2′′-Diisop r op yl-5,5′′-d im et h -
yld isp ir o[cycloh exa n e-1,16′-2′,17′,18′,21′-t et r a oxa -1′-si-
la p e n t a c y c lo [8.7.2.2 1 , 9 .05 , 2 0 .01 4 , 1 9 ]h e n i c o s a -5′,7′,9′-
(20′),10′,12′,14′(19′)-h exa en e-3′,1′′-cycloh exa n e]
(22).
Ack n ow led gm en t. This work was partially sup-
ported by CIBA (Additive Division) Bologna (Italy). We
thank the Regione Veneto, Department for Industry and
Energy, for financial support in purchasing the Varian
Unity 400 spectrometer. Bruker NMR data were ex-
trapolated with the SwaN-MR program,28 available for
download in the word wide web at http://qobrue.usc.es/
jsgroup/swan/home.htm.
Freshly distilled tetrachlorosilane (25 µL, 0.22 mmol) was
added to a solution of 7 (100 mg, 0.20 mmol), triethylamine
(140 µL, 1.0 mmol) and DBU (2 µL) in dry CHCl3 (4 mL) under
nitrogen. The solution was refluxed 3 h, poured into water (5
mL), and extracted with CH2Cl2 (3 × 5 mL). The organic layer
was dried over Na2SO4 and rotoevaporated. The residue was
purified by flash chromatography (eluant CH2Cl2/hexanes 1:3)
23
to obtain 90 mg (85% yield) of a colorless oil: [R]D -27.0 (c
1.9, CH2Cl2). 1H NMR (CDCl3, 400 MHz) δ 7.40 (d, H11, J 10,11
) 7.6 Hz), 7.11 (t, H10, J 9,10 ) 7.5 Hz), 7.03 (d, H9), 4.22 (d,
H8, J 8,8′ ) 13.9 Hz), 2.44 (m, H7), 2.15 (d, H8′), 1.70 (dm, H4eq,
J 4eq,4ax ) 12.6 Hz), 1.58 (m, H3), 1.47 (m, H5ax and H5eq),
1.13 (dm, H6, J 5ax,6 ) 11.8 Hz), 1.03 (m, H2eq), 1.00 (d, Me7,
J 7,Me7 ) 10.0 Hz), 0.98 (d, Me7′, J 7,Me7′ ) 10.0 Hz), 0.79 (qd,
H4ax, J 3ax,4ax ) J 4ax,5ax ) 12.2 Hz, J 4ax,5eq ) 4.0 Hz), 0.70 (d,
Me3, J 3,Me3 ) 6.6 Hz), 0.59 (dd, H2ax, J 2ax,2eq ) 13.8 Hz, J 2ax,3
) 12.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 150.5 (C12a), 131.2
(C12), 130.8 (C8a), 130.1 (C9), 126.0 (C11), 123.6 (C10), 85.0
(C1), 52.3 (C6), 46.2 (C2), 41.3 (C8), 35.2 (C4), 27.6 (C3), 26.4
(C7), 24.0 (Me7′), 22.3 (Me3), 20.8 (C5), 17.7 (Me7). IR (film,
cm-1) 2953, 2927, 1444, 1071.
Su p p or tin g In for m a tion Ava ila ble: 1H- and 13C-NMR
spectra of compounds 7-11, 13-19, 21-23 and HMQC,
HMBC, NOEDS, and NOESY of compounds 7, 8, 16, 22, and
23 (55 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.
J O970372Z
(28) Balacco, G. J . Chem. Inf. Comput. Sci. 1994, 34, 1235.