A study of the effect of zand e-olefinic geometry on the rates of ring closure of 13-membered dienes

Article abstract of DOI:10.1021/ol702868z

An analysis is presented to explain the faster rate of ring formation 5 - 7 as compared to 6 - 8.

Full text of DOI:10.1021/ol702868z

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1055-1057
A Study of the Effect of Z- and
E-Olefinic Geometry on the Rates of
Ring Closure of 13-Membered Dienes
Brian B. Liau, Vijay Gnanadesikan, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford
Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received November 27, 2007
ABSTRACT
An analysis is presented to explain the faster rate of ring formation 5
f 7 as compared to 6 f 8.
Intramolecular cyclizations to form large rings (e.g., of ring
size 12-30 members) have received little attention in recent
years, even though they are poorly understood. Since 5- and
6-membered carbocyclic structures can be formed by cy-
clization reactions more rapidly and efficiently than larger
rings, the activation entropies for the latter are generally
thought to be more negative, and this factor is invoked to
explain lower rates of ring closure. As early as 1935,1
Ruzicka proposed that the probability of cyclizations should
decrease as the distance between the reacting centers on the
open chain increases. A series of kinetic studies by Illuminati,
Mandolini, and their colleagues2 confirmed the numerous
qualitative chemical studies that indicated slow rates of
cyclization for rings in the range from 8 to 11 members.3 In
addition, their work showed only small differences in the
rates of cyclization (for lactone formation) for 12- to 23-
membered rings.4 Studies in this laboratory revealed that rates
for the lactonization of ω-hydroxy-alkanoic esters varied
moderately and irregularly with ring size as follows (ring
size/relative rate): 12/0.20, 13/0.36, 14/1.0 (standard), 15/
1.0, 16/2.5, 17/1.9, 18/1.35, 19/0.55, 20/1.55, 21/0.60. It is
clear that the simple notion that the distance between the
two reacting subunits at the ends of a chain in its maximally
extended form determines rates of ring closure is oversimpli-
fied. There are several reasons why this should be so. As
the number of atoms in the chain increases, the total number
of non-extended, that is partially folded, conformations
increases. Also the number of conformations of the cyclized
structure increases. These two factors would tend to increase
the rate of ring closure.
(3) (a) Galli, C.; Illuminati, G.; Mandolini, L.; Jamborra, P. J. Am. Chem.
Soc. 1977, 99, 2591-2597. (b) Casadei, M. A.; Galli, C.; Mandolini, L. J.
Am. Chem. Soc. 1984, 106, 1051-1056.
(4) Corey, E. J.; Brunelle, D. J.; Stork, P. J. Tetrahedron Lett. 1976, 17,
3405-3408.
(1) Ruzicka, L. Chem. Ind. (London) 1935, 54, 2.
(2) For a review of this work, see: Illuminati, G.; Mandolini, L. Acc.
Chem. Res. 1981, 14, 95-102.
10.1021/ol702868z CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/15/2008

The pathway of the synthesis of the acetates 13 and 14,
which served as precursors of the products of cyclization,
Z,Z-sulfide 7 and E,E-sulfide 8, is outlined in Scheme 1.
1,7-Octadiyne (9) was transformed in 28% yield to diol 10
by deprotonation and reaction with ethylene oxide. Diol 10
was divergently advanced to both Z,Z-diene 11 and E,E-
diene 12 in good yield by Lindlar reduction and reduction
with LiAlH4, respectively. The Lindlar reduction of 10
formed a 9:1 mixture of desired Z,Z-diene 11 and overre-
duced products. Fortunately, purification of the Z,Z-product
could be effected by chromatography with AgNO3 impreg-
nated silica gel after monotosylation8 of 11.
The 13-membered ring-containing products 7 and 8 were
prepared by treatment of the acetoxy tosylates 13 and 14
with NaOMe in 1:1 THF-MeOH. The stereochemistry of
the olefinic linkages in the Z,Z- and E,E-series was confirmed
1
by H NMR spectroscopy. The yields of 7 and 8 were
Still another factor that should be consequential is the
number of bond rotations required to access the cyclic
transition state from any particular conformation of the
starting compound. That number decreases with an increasing
number of non-rotatable (e.g., endocyclic, double, or triple)
bonds in the path of atoms that separates the reactive terminii.
Thus, it is easy to understand why the macrolactones 1-3
(10-, 13-, and 20-membered rings, respectively) can be
produced rapidly and in high yield by lactonization of the
corresponding hydroxy acids.5 There are numerous other
cases of the facilitation of cyclization reactions by decreasing
the flexibility of the chain undergoing ring closure.6
concentration dependent (especially for the E,E-case) because
of the formation of dimeric bis-sulfide byproduct (15) at
higher concentrations.
The rates of cyclization of the Z,Z- and E,E-sodium
thiolates 5 and 6 were determined at low concentration by
1H NMR. Specifically, the acetates were treated with
NaOCD3 in 1:1 THF-d8-CD3OD under Ar, which caused
rapid cleavage of the S-acetyl bond to form the sodium
thiolate 5 or 6, a reaction that is very fast even at -30 °C
1
(from H NMR studies), and then the rates of cyclization
were followed by observing the development of peaks
characteristic of product (7 or 8) at 30.0 °C, specifically the
methylene protons at C(7) and C(8) of 7 and 8 (Scheme 1).
At concentrations below 0.01 M, the cyclization reactions
were kinetically first order to a good approximation, and the
following values of the first-order rate constant, k1 (30.0 °C),
were extracted from the data: 0.0291 ( 1 × 10-4 min-1 for
the Z,Z-substrate 5, and 0.0038 ( 1 × 10-4 min-1 for the
E,E-substrate 6 at 0.005 M substrate concentration. From
this result, a ratio of relative rates of cyclization of the Z,Z-
sodium thiolate 5 and the E,E-sodium thiolate 6 of ap-
proximately 7.7 follows. Consistent with this difference in
rates of ring closure is the markedly greater tendency for
concentration-dependent formation of the dimeric product
all-E, bis-sulfide 15 which possesses a 26-membered ring.
We believe that the faster rate of 13-membered ring
formation for the Z,Z-sodium thiolate 5 as compared with
the E,E-sodium thiolate 6 is the resultant of at least three
identifiable factors. First, assuming a linear transition state
One starting point for the present study was the finding
that cis-14,15-epoxide of arachidonic acid (4) could be
formed selectively and easily by intramolecular oxygen-
transfer reaction of peroxyarachidonic acid.7 A second
stimulus was the discovery that selective intramolecular
oxygen-transfer reactions of polyunsaturated peroxyacids
containing E-olefinic linkages is considerably less favorable
than the case of the all-Z tetraenoic acid arachidonic acid
(B. Liau, unpublished work). We decided to study this effect
quantitatively by measuring the rates of cyclization by SN2
displacement of the Z,Z-substrate 5 and the E,E-substrate 6
under identical conditions.
for displacement, that is,
S--C-OTs ) 180 °, and an
S-C distance of ca. 2 Å the minimum number of bond
rotations required for generating the cyclic transition state
(5) Corey, E. J.; Nicolaou, K. C.; Melvin, L. S., Jr. J. Am. Chem. Soc.
1975, 97, 653-654.
(6) For a review see Rousseau, G. Tetrahedron. 1955, 51, 2777-2849.
(7) Corey, E. J.; Niwa, H.; Falck, J. J. Am. Chem. Soc. 1979, 101, 1586-
1587.
(8) Bouzide, A.; Sauve´, G. Org. Lett. 2002, 4, 2329-2332.
Org. Lett., Vol. 10, No. 6, 2008
1056

Scheme 1
is estimated to be six for the E,E-sodium thiolate 6 and only
ring closure relative to E-olefinic bonds or saturation. The
same is also likely to be true for cis-1,2-disubstituted 3- to
5-membered rings or 1,2-disubstituted aromatic rings.
three for the Z,Z-sodium thiolate 5. This factor would favor
a faster cyclization of 5 relative to 6, as observed. Second,
there are more conformations within 2 kcal/mol of the global
maximum for cyclization of the Z,Z-substrate 5 (11) than
for the E,E-substrate 6 (7), as determined from MM3
calculations. This factor also is expected to lead to faster
cyclization of 5 relative to 6, since there are more reaction
pathways available for forming the Z,Z-product 7. Finally,
the distance between S- and C-OTs, the reacting termini,
is greater in the most extended conformation for 6 as
compared with 5. We believe that this last factor can play a
modest role in determining the relative rates of closure but
that it is probably not dominant.
Acknowledgment. We thank Dr. Surendra Karavadhi
(Harvard University) for his assistance in making substrates
13 and 14. B. Liau is grateful to Pfizer, Inc. for a Pfizer
(S.U.R.F.) undergraduate research fellowship and to Drs. D.
Behenna, G. Lalic, L. Ku¨rti, and other members of the Corey
Group for their advice and encouragement.
Supporting Information Available: Experimental pro-
cedures and spectral data for reaction products 7-14. This
material is available free of charge via the Internet at
http://pubs.acs.org
In conclusion, the results reported herein strongly point
to the general proposition that the presence of Z-olefinic
linkages on an atom path between two reactive groups favors
OL702868Z
Org. Lett., Vol. 10, No. 6, 2008
1057