Synthesis of planar-chiral paracyclophanes via samarium(II)-catalyzed intramolecular pinacol coupling

Article abstract of DOI:10.1021/ol0506258

(Chemical Equation Presented) A series of [n]jparacyclophanediols (n = 8-12) was synthesized by samarium-catalyzed pinacol coupling for their ansa-bridge formation. Enantiomerically pure [n]jparacyclophane esters were derived from the diols in a several steps via chiral resolution (for n = 10) or via crystallization-induced asymmetric transformation (for n = 11) by using amino alcohol auxiliaries and their selective cleavages.

Full text of DOI:10.1021/ol0506258

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2365-2368
Synthesis of Planar-Chiral
Paracyclophanes via
Samarium(II)-Catalyzed Intramolecular
Pinacol Coupling
Tsuyoshi Ueda, Nobuhiro Kanomata,*,† and Hajime Machida
Department of Industrial Chemistry, Meiji UniVersity,
Tama-ku, Kawasaki 214-8571, Japan
kanomata@waseda.jp
Received March 23, 2005
ABSTRACT
A series of [n]paracyclophanediols (n
Enantiomerically pure [n]paracyclophane esters were derived from the diols in a several steps via chiral resolution (for n
crystallization-induced asymmetric transformation (for n 11) by using amino alcohol auxiliaries and their selective cleavages.
)
8
−
12) was synthesized by samarium-catalyzed pinacol coupling for their ansa-bridge formation.
)
10) or via
)
Planar-chiral paracyclophanes are increasingly recognized as
attractive chiral sources for various stereoselective reactions
because of their unique structure and functionality.1-3 We
have previously reported that biomimetic reactions, where
bridged NADH models having a chiral [10]parapyridi-
nophane skeleton reduce pyruvate analogues with high
enantioselectivity, are a successful application of pyridine-
type of cyclophanes to asymmetric induction.4 Although
many synthetic routes are known to [n]paracyclophanes and
their related compounds,5 only limited approaches by in-
tramolecular cyclization of functionalized disubstituted aro-
matics have been reported despite their direct and wide
applicability.6,7 Recently, Sm2+-mediated pinacol coupling
has been proven to be a most versatile and useful C-C bond
formation reaction8,9 and, therefore, seems to be a potent tool
for ansa-bridge construction in cyclophane syntheses. In
(5) Review: Kane, V. V.; De Wolf, W. H.; Bickelhaupt, F. Tetrahedron
1994, 50, 4575-4622.
(6) (a) Cram, D. J.; Daeniker, H. U. J. Am. Chem. Soc. 1954, 76, 2743-
2752. (b) Matsuoka, T.; Sakata, Y.; Misumi, S. Tetrahedron Lett. 1970,
11, 2549-2552. (c) Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi,
S. Bull. Chem. Soc. Jpn. 1972, 45, 1825-1833. (d) Katoono, R.; Kawai,
H.; Fujiwara, K.; Suzuki, T. Tetrahedron Lett. 2004, 45, 8455-8459. For
intermolecular Friedel-Crafts cyclization of monosubstituted benzene: (e)
Huisgen, R. Angew. Chem. 1957, 69, 341-359.
† Present address: Department of Chemistry, Waseda University, Shin-
juku-ku, Tokyo 169-8555, Japan.
(1) Recent reviews: (a) Bra¨se, S.; Dahmen, S.; Ho¨fener, S.; Lauterwasser,
F.; Kreis, M.; Ziegert, R. E. Synlett 2004, 2647-2669. (b) Gibson, S. E.;
Knight, J. D. Org. Biomol. Chem. 2003, 1, 1256-1269.
(2) (a) Dahmen, S.; Bra¨se, S. Org. Lett. 2001, 3, 4119-4122. Dahmen,
S.; Bra¨se, S. J. Am. Chem. Soc. 2002, 124, 5940-5941. Hermanns, N.;
Dahmen, S.; Bolm, C.; Bra¨se, S. Angew. Chem., Int. Ed. 2002, 41, 3692-
3694. (b) Cipiciani, A.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Ruzziconi,
R. J. Org. Chem. 2002, 67, 2665-2670. (c) Li, X.; Chen, W.; Hems, W.;
King, F.; Xiao, J. Org. Lett. 2003, 5, 4559-4561.
(7) For recent papers on RCM for highly functionalized paracyclo-
phanes: (a) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc.
2002, 124, 773-775. (b) Bressy, C.; Piva, O. Synlett 2003, 87-90.
(8) Recent reviews for samarium-mediated reactions: (a) Molander, G.
A. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vol. 1, pp 153-182. (b) Molander, G. A.; Harris,
C. R. Chem. ReV. 1996, 96, 307-338. (c) Molander, G. A. Chem. ReV.
1992, 92, 29-68. (d) Curran, D. P.; Fevig, T. L.; Jasperse, C. P.; Totleben,
M. J. Synlett 1992, 943-961.
(3) (a) Burk, M. J.; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa,
A. Org. Lett. 2000, 2, 4173-4176. (b) Zanotti-Gerosa, A.; Malan, C.;
Herzberg, D. Org. Lett. 2001, 3, 3687-3690.
(4) (a) Kanomata, N.; Nakata, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 1207-1211. (b) Kanomata, N.; Nakata, T. J. Am. Chem. Soc. 2000,
122, 4563-4568.
(9) (a) Nomura, R.; Matsuno, T.; Endo, T. J. Am. Chem. Soc. 1996, 118,
11666-11667. (b) Matsukawa, S.; Hinakubo, Y. Org. Lett. 2003, 5, 1221-
1223.
10.1021/ol0506258 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/17/2005

particular, the high Lewis acidity of Sm3+ generated in such
reactions is known to exhibit heteroatom affinity and,
therefore, seems to be useful for ring closure reactions via
chelated intermediates.10 We further anticipated that catalytic
use of samarium, or its limited concentration, should prefer
intramolecular cyclization to intermolecular oligomerization.
We describe here a novel synthetic method for planar-chiral
paracyclophanes via intramolecular ansa-bridge construction
by SmI2-catalyzed pinacol coupling under mild conditions
and their application to planar-chiral cyclophane synthesis.
Scheme 1 outlines our synthetic route for a representative
Table 1. SmI2-Catalyzed Pinacol Cyclization of 2ca
2c SmI , Mg [excess], TMSCl8 3c
2
HMPA, THF, rt
addition
of 2c
SmI2
[equiv]
HMPA
[equiv]
TMSC
[equiv]
yield
[%]b
entry
1
2
3
4
5
6
7
8
9
24 h
6 h
5.0
5.0
2.0
2.0
1.0
1.0
0.6
0.4
0
0
10
50
50
20
0
10
10
6.0
4.0
20
14
33
54
13
46
59
64
49
0
24 h
24 h
24 h
72 h
72 h
72 h
24 h
4.0
4.0
2.0
2.0
1.2
0.8
4.0
Scheme 1. Synthesis of [10]Paracyclophanediol (3c) via
SmI2-Catalyzed Pinacol Coupling Cyclization
a All the reactions were carried out in the presence of a 50 equiv amount
of magnesium for regenerating Sm2+ b Isolated yields.
.
Sm2+-promoted reactions, to give the desired 3c in 64% yield
as a 1/1 mixture of erythro and threo diols. It is worth
mentioning that the ring-closing metathesis (RCM) of the
corresponding diene derived from 2c furnished undesired
dimer 4 as a less strained product under reversible RCM
conditions.7
Table 1 indicates the results for opimizing the SmI2-
catalyzed pinacol cyclization from 2c to 3c. We found that
the pinacol cyclization was best accomplished in THF at
room temperature in the presence of SmI2, HMPA, TMSCl,
and magnesium in a ratio of 1:2:10:50, respectively. We have
carried out these reactions with various amounts of SmI2
(entries 1-8), and the best result was obtained with 0.6 equiv
of the Sm2+ catalyst for the synthesis of 3c (entry 7).
Reactions in the absence of HMPA or TMSCl resulted in
low yields (entries 1 and 4). No reaction took place without
SmI2 (entry 9), which rules out the pathway through the
known pinacol coupling by the TMSCl-Mg system in the
presence of HMPA.13
The postulated reaction pathway is shown in Scheme 2.
Single electron transfer from SmI2 reduces a formyl group
of dialdehyde 2c in THF-HMPA to form a samarium(III)
alkoxy radical A, which undergoes the C-C bond formation,
and the subsequent reduction with the second SmI2 gave the
alcoholate B. The alcoholate B was then trapped with TMSCl
to give the corresponding silyl ether and Sm3+. Finally, the
divalent samarium species such as SmI2 or SmClI is
regenerated by electron transfer from magnesium.
[10]paracyclophanediol (3c). The synthesis began with a
double Sonogashira reaction11 of 1,4-diiodobenzene (1) with
4-pentyn-1-ol to give diyne products in a quantitative yield.
Hydrogenation and the following oxidation with PCC
produced dialdehyde 2c in 82% yield (three steps from 1).
The ansa-bridge formation reaction, a key step in this
synthesis, was achieved by Sm2+-mediated pinacol cycliza-
tion of 2c in the presence of HMPA. Endo et al. previously
reported that a novel SmI2-catalyzed pinacol coupling of
some aromatic and phenethyl aldehydes by using magnesium
metal as co-reductant gave the corresponding diols in 23-
81% yields.9a We initially followed Endo’s protocol for the
cyclization of 2c without HMPA, but the yield of [10]-
paracyclophanediol (3c) was poor (see entry 1 in Table 1).
Then we found the cyclization proceeded efficiently in the
presence of HMPA,12 which is often used to activate various
This method was found to be useful for the preparation
of a series of [n]paracyclophanediols 3a-h (n ) 8-12) from
the corresponding dialdehydes 2a-h14 (Table 2). As ex-
pected, yields of 3a-h are dependent on the length of their
oligomethylene bridges (entries 1-5), and the present method
is evidently applicable for synthesis of [n]paracyclophanes
(10) (a) Souppe, J.; Danon, L.; Namy, J. L.; Kagan, H. B. J. Organomet.
Chem. 1983, 250, 227-236. (b) Molander, G. A.; Kenny, C. J. Am. Chem.
Soc. 1989, 111, 8236-8246. (c) Chiara, J. L.; Cabri, W.; Hanessian, S.
Tetrahedron Lett. 1991, 32, 1125-1128. (d) Riber, D.; Hazell, R.;
Skrydstrup, T. J. Org. Chem. 2000, 65, 5382-5390. (e) Hori, N.; Matsukura,
H.; Matsuo, G.; Nakata, T. Tetrahedron 2002, 58, 1853-1864. Hori, N.;
Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 1999, 40, 2811-
2814. Hori, N.; Matsukura, H.; Nakata, T. Org. Lett. 1999, 1, 1099-1101.
(11) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470.
(13) Chan, T. H.; Vinokur, E. Tetrahedron Lett. 1972, 13, 75-78.
(14) The compounds 2b, 2d, and 2h (x * y) were synthesized via
stepwise Sonogashira reactions of 1-bromo-4-iodobenzene with appropriate
alkynols.
(12) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986,
27, 5763-5764.
2366
Org. Lett., Vol. 7, No. 12, 2005

modynamic aspects of the corresponding chiral cyclophanes,
[10]- and [11]-paracyclophanediols (3c,d) were derived to
diastereomeric mixtures of 7c,d (n ) 10, 11; R ) i-Pr) and
8d (n ) 11; R ) t-Bu), as shown in Scheme 3. Conversion
Scheme 2. Postulated Reaction Pathways of Pinacol
Cyclization Catalyzed by Sm2+
Scheme 3. Transformation of 3c,d to Bridged Benzamides
7c,d and 8d
Table 2. Synthesis of [n]Paracyclophanediols (3a-h) by
SmI2-Catalyzed Pinacol Cyclizationa
Scheme 4. Syntheses of Planar-Chiral
[10]Paracyclophanecarboxylates (R)-(+)- and (S)-(-)-9c
aldehyde
R
product
SmI2
[equiv]
yield
[%]b
entry
2
x
y
3
n
1
2
3
4
5
6
7c
8
2a
2b
2c
2d
2e
2f
H
H
H
H
H
4
4
5
5
6
5
5
4
4
5
5
6
6
5
5
6
0.6
0.6
0.6
0.6
0.6
0.8
2.0
2.0
3a
3b
3c
3d
3e
3f
8
11
47
64
63
57
57
51
18
9
10
11
12
10
10
10
CH2OTBDPS
2g CH2OBn
2h
3g
3h
H
a All the reactions were carried out in the presence of SmI2, HMPA,
TMSCl, and magnesium in 1/2/10/50 ratio unless otherwise specified.
b Isolated yields. c 140 equiv of magnesium was used.
of 3c,d to the parent [10]- and [11]-paracyclophanes (5c17
and 5d15b) was done by Garegg-Samuelsson olefination18,19
followed by hydrogenation. The known carboxylation20 to
6c20a,21 and 6d and the subsequent introducion of (S)-valinol
or (S)-tert-leucinol auxiliary afforded 7c,d and 8d, respec-
tively. Further transformation to enantiomerically pure [10]-
and [11]-paracyclophane esters are summarized in Schemes
4 and 5.
3b-e with middle-size ansa-bridges (n ) 9-12) (entries
2-5). Substituted derivatives 2f,g are also good substrates
(entries 6 and 7), but [4+6]-type pinacol cyclization of 2h
was less effective than [5+5] cyclization for the synthesis
of 3c (entries 3 and 8; see also entry 3 in Table 1).
One most remarkable feature of cyclophanes having an
appropriate length of ansa-bridge is their thermodynamic
flexibility,15 as we have previously reported spontaneous
dynamic stereocontrol of planar-chiral nicotinamides having
[10]parapyridinophane skeletons by crystallization- or ad-
sorption-induced asymmetric transformations (CIAT and
AIAT, respectively).16 For studying the synthetic and ther-
(16) (a) Kanomata, N.; Ochiai, Y. Tetrahedron Lett. 2001, 42, 1045-
1048. (b) Kanomata, N.; Oikawa, J. Tetrahedron Lett. 2003, 44, 3625-
3628.
(17) Otsubo, T.; Misumi, S. Synth. Commun. 1978, 8, 285-289.
(18) (a) Garegg, P. J.; Samuelsson, B. Synthesis 1979, 469-470. (b) Liu,
Z.; Classon, B.; Samuelsson, B. J. Org. Chem. 1990, 55, 4273-4275. (c)
Luzzio, F. A.; Menes, M. E. J. Org. Chem. 1994, 59, 7267-7272.
(19) The Corey-Winter reaction was not so successful in the case of
3c, because the alkene product was obtained only in 36% yield: Corey, E.
J.; Hopkins, B. Tetrahedron Lett. 1982, 23, 1979-1982.
(20) (a) Oi, S.; Miyano, S. Chem. Lett. 1992, 987-990. (b) Cram, D. J.;
Day, A. C. J. Org. Chem. 1966, 31, 1227-1232.
(21) Harada, N.; Soutome, T.; Nehira, T.; Uda, H.; Oi, S.; Okamura,
A.; Miyano, S. J. Am. Chem. Soc. 1993, 115, 7547-7548.
(15) Thermodynamic studies regarding rope-skipping isomerization of
paracyclophanes were reported: (a) Eberhardt, H.; Schlo¨gl, K. Liebigs Ann.
Chem. 1972, 760, 157-170. (b) Hochmuth, D. H.; Ko¨nig, W. A.
Tetrahedron: Asymmetry 1999, 10, 1089-1097.
Org. Lett., Vol. 7, No. 12, 2005
2367

more efficient than that of 7d due to the larger difference in
the melting points between its diastereoisomers. Transes-
terification was also complete within 3 h successfully by
methoxide-carbonate reaction in the presence of 15-crown-5
to give planar-chiral (R)-(+)-9d with up to 99.5% ee. Figure
1 depicts the CD spectra of (R)-(+)-9c,d, whose similarity
Scheme 5. Stereocontrol to Planar-Chiral [11]Paracyclophane
(R)-(+)-9d via CIAT Methods
As for planar-chiral [10]paracyclophanes, Hochmuth and
Ko¨nig reported their GLC-based thermodynamic studies
showed that the decamethylene ansa-bridge is not large
enough to flip over the benzene ring.15b Indeed, planar-chiral
cyclophanes 7c were found to be thermodynamically quite
stable molecules because neither (Rp,S)- nor (Sp,S)-7c
exhibited thermal loss of their planar-chirality in refluxing
xylene for a prolonged reaction time up to 24 h. Enantio-
merically pure and stable carboxylic esters (R)-(+)-9c15a and
(S)-(-)-9c21 were cleanly obtained in high yields by trans-
esterification of the hydroxyethylamide moieties in our
methoxide-carbonate systems.22 The absolute configuration
of (R)-(+)- and (S)-(-)-9c thus obtained was unambiguously
confirmed by further chemical correlation to the known (S)-
(-)-[10]paracyclophane-12-carboxylic acid, namely (S)-
(-)-6c.20a,21
Figure 1. CD spectra of [10]paracyclophane (R)-(+)-9c (broken
line) and [11]paracyclophane (R)-(+)-9d (solid line).
suggests that these two compounds have the same config-
uration for their planar-chirality.
Consequently, we have achieved a facile and convenient
synthetic method for [n]paracyclophanes (n ) 8-12) by
samarium iodide-catalyzed intramolecular pinacol coupling
and its application to planar-chiral cyclophane synthesis in
a preparative scale (see Supporting Information). Although
several synthetic methods of paracyclophaenes with intramo-
lecular ring-closure reactions have been reported, this method
is probably simpler than any other procedure for synthesizing
them. The present method developed here would be widely
applicable for the preparation of various cyclophane systems.
On the other hand, [11]paracyclophanes are recognized
as thermally metastable molecules15b and the compounds
(Rp,S)-7d and (Rp,S)-8d have significantly higher melting
points as compared to their diastereomeric (Sp,S)-isomers (see
Scheme 3), as well as the case for the corresponding planar-
chiral pyridinophanes.16 In each case, CIAT of 7d (70 °C
for 10 days) and 8d (110 °C for 4 h) proceeded well via
rope-skipping isomerization to accumulate (R)-planar chiral-
ity to afford the (Rp,S)-form of 7d (94% de) and 8d (>99%
de) almost quantitatively. Obviously, the CIAT of 8d is much
Acknowledgment. We greatly acknowledge JSPS Grant-
in-Aid for Scientific Research (B) (14350479) and Nagase
Science and Technology Foundation for financial support
of this work.
Supporting Information Available: Full experimental
procedures, characterization data of all new compounds, 1H
and 13C NMR spectra of 2a-h, 3a-h, 4, 5c,d, 6c,d, (Rp,S)-
and (Sp,S)-7c,d, (Rp,S)- and (Sp,S)-8d, and (R)-(+)-9d, and
1H NMR spectra of (R)-(+)- and (S)-(-)- 9c. This material
is available free of charge via the Internet at http://pubs.acs.org.
(22) Kanomata, N.; Maruyama, S.; Tomono, K.; Anada, S. Tetrahedron
Lett. 2003, 44, 3599-3603.
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