Regiochemical control in intramolecular cyclization of methylene-interrupted epoxydiols

Article abstract of DOI:10.1021/ol016118h

matrix presented Methylene-interrupted epoxydiols have multiple regiochemical routes for cyclization. The 5-exo process is the most prevalent under acidic conditions. However, the regioselectivity can be controlled by the appropriate choice of acid promot

Full text of DOI:10.1021/ol016118h

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2489-2492
Regiochemical Control in Intramolecular
Cyclization of Methylene-Interrupted
Epoxydiols
Radha S. Narayan,† Meenakshi Sivakumar,† Ezzeddine Bouhlel,‡ and
,†
Babak Borhan*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824,
and De´partement de Chimie, Faculte´ des Sciences de Monastir, UniVersite´ du Centre,
Monastir 5000, Tunisia
borhan@cem.msu.edu
Received May 14, 2001
ABSTRACT
Methylene-interrupted epoxydiols have multiple regiochemical routes for cyclization. The 5-exo process is the most prevalent under acidic
conditions. However, the regioselectivity can be controlled by the appropriate choice of acid promoter and pendant groups adjacent to the
epoxide. The 5-exo product is obtained exclusively without the presence of a carbocation-stabilizing pendant group. Alkenyl and thiophenyl
groups adjacent to the epoxide alter the regioselectivity and enable access to the 5-endo tetrahydrofuran and 6-endo tetrahydropyran products.
Regiochemical control in opening of epoxides is paramount
in many synthetic strategies. Coupled with excellent meth-
odologies for establishing desired stereogenic centers for
epoxides,1-3 alcohols,4-7 and diols,8,9 control of intra-
molecular regiochemistry in cyclization of epoxyalcohols can
lead to versatile strategies for stereodefined syntheses. We
are primarily interested in investigating novel metabolites
of arachidonic acid, namely, arachidonic acid tetrahydrofuran
diols (AA-THF-diols, Scheme 1) which possess 3-oxygen-
ated 2,3,5-trisubstituted THF ring as the core structure. These
compounds have exhibited biological activity; however, the
exact stereo- and regioisomer(s) responsible for the activity
remain to be elucidated.10 Quantitative structure/activity
relationship (QSAR) studies of this class of metabolites will
require a straightforward and convenient synthetic strategy
of the various stereo- and regioisomers. This method will
also be useful for the synthesis of other natural products such
† Michigan State University.
‡ Universite´ du Centre.
(1) Jacobson, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
Wiley-VCH: New York, 1993; p 159.
(2) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; Wiley-VCH: New York, 1993; p 101.
(3) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224.
(4) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am.
Chem. Soc. 1988, 110, 1539.
(5) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551.
(6) Masamune, S.; Kim, B.-M.; Petersen, J. S.; Sato, T.; Veenstra, S. J.
J. Am. Chem. Soc. 1985, 107, 4549.
(7) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709.
(9) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; Wiley-VCH: New York, 1993; p 227.
(8) Jacobsen, E. N.; Marko´, I.; Mungall, W. S.; Schro¨der, G.; Sharpless,
K. B. J. Am. Chem. Soc. 1988, 110, 1968.
(10) Moghaddam, M. F.; Motoba, K.; Borhan, B.; Pinot, F.; Hammock,
B. D. Biochim. Biophys. Acta 1996, 1290, 327.
10.1021/ol016118h CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/17/2001

or a hybrid exo/endo process following Warren’s terminol-
ogy.24,25 Herein, we report our initial results in investigating
control elements for regiospecific intramolecular cyclization
of methylene-interrupted epoxydiols. With the appropriate
choice of the pendant functional group (X, Scheme 2) and
reaction conditions, we have been able to access different
reaction pathways to secure regioisomeric THF and THP
rings.
Scheme 1. Proposed Biosynthesis of AA-THF-diols
2-Deoxy-D-ribose was utilized as the entry point to obtain
the common structural motif represented in 1. Epoxydiol
precursors (5a-g) were synthesized using routine transfor-
mations (see Supporting Information for details). Table 1
lists the results obtained upon treatment of 5a-g with various
acidic conditions. Exposure of these compounds to both
protic acid (AcOH:H2O:THF (6:3:1)) and Lewis acid (BF3‚
Et2O) led to selective desilylation of the TMS ether protecting
groups and intramolecular epoxide opening in the same step.
The cyclization products were peracetylated for ease of NMR
characterization, and their structures were established by 2D-
COSY and NOE experiments.
On the basis of the better alignment of the newly forming
and rupturing bonds23 and the electron-withdrawing inductive
effect of the pendant groups (except alkyl group in 5d), we
expected that the 5-exo cyclization (path a, Scheme 2) would
be favored for compounds 5a,b,d,e. As shown in Table 1,
the expected 5-exo product was obtained in each of these
cases as a single diastereomer. Complete stereochemical
inversion was observed at C-2, which is consistent with a
concerted mechanism of epoxide opening. The same regio-
selectivity of epoxide opening was observed with the
diastereomer of 5a (epimeric at both epoxidic carbons), thus
indicating that the stereochemical relationship between the
diol and the epoxide is not of any consequence for this
system.
as the recently discovered nonclassical acetognins, containing
such trisubstituted THF motifs.11-14
A commonly used approach for the synthesis of substituted
cyclic ether units is the intramolecular epoxide opening, first
reported by Kishi.15,16 Most systems studied in this context
have a single hydroxyl group acting as the nucleophile;17-22
however, epoxydiols such as 1 where both hydroxyl groups
can participate in the cyclization event (paths a, b, and c,
Scheme 2) have not been studied. Path a is the typical 5-exo
Scheme 2. Possible Modes of Cyclization (See Ref 25 for
Definitions of Hybrid Nomenclature in Parentheses)
Compound 5c with the olefinic appendage was designed
in order to stabilize a developing positive charge at C-1
during activation and epoxide opening, thus leading to the
5-endo product 7c (path b, Scheme 2). This strategy has been
successfully used by others with monohydroxy epoxy
systems.17,21,22 We examined the possibility of extending the
same idea to our epoxydiol system to selectively generate
2,3,5-trisubstituted THF units. Treatment of 5c with
BF3‚Et2O led to the isolation of 7c after peracetylation via
the 5-endo pathway, thus securing a regiochemically distinct
trisubstituted THF unit. Interestingly, cyclization of 5c with
aqueous acetic acid yielded only THP 8c (Table 1) via the
6-endo route (path c, Scheme 2).
ring opening process. Paths b and c (Scheme 2) can be
labeled as endo processes based on Baldwin nomenclature23
(11) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62,
504.
(12) Capon, R. J.; Barrow, R. A.; Rochfort, S.; Jobling, M.; Skene, C.
Tetrahedron 1998, 54, 2227.
Cyclization of 5c was also triggered with 10% aqueous
HCl in THF (9:1). THP 8c was again obtained as the sole
product in 75% yield, indicating that the strength of the
aqueous acid is not the determining factor in the process.
(13) Kempf, A. J.; Wilson, K. E.; Hensens, O. D.; Monaghan, R. L.;
Zimmerman, S. B.; Dulaney, E. L. J. Antibiot. 1986, 39, 1361.
(14) Robinson, N.; Gibson, T. M.; Chicarelli-Robinson, M. I.; Cameron,
L.; Hylands, P. J.; Wilkinson, D. J. Nat. Prod. 1997, 60, 6.
(15) Nakata, T.; Kishi, Y. Tetrahedron Lett. 1978, 31, 2745.
(16) Nakata, T.; Schmid, G.; Vranesic, M.; Okigawa, M.; Smith-Palmer,
T.; Kishi, Y. J. Am. Chem. Soc. 1978, 100, 2933.
(17) Evans, P. A.; Murthy, V. S. Tetrahedron Lett. 1999, 40, 1235.
(18) Fujiwara, K.; Tokiwano, T.; Murai, A. Tetrahedron Lett. 1995, 36,
8063.
(19) Fujiwara, K.; Mishima, H.; Amano, A.; Tokiwano, T.; Murai, M.
Tetrahedron Lett. 1998, 39, 393.
(20) Mukai, C.; Ikeda, Y.; Sugimoto, Y.; Hanaoka, M. Tetrahedron Lett.
1994, 35, 2179.
(21) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. J.
Am. Chem. Soc. 1989, 111, 5330.
(22) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. J.
Am. Chem. Soc. 1989, 111, 5335.
(23) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(24) McIntyre, S.; Warren, S. Tetrahedron Lett. 1990, 31, 3457.
(25) A hybrid notation of Baldwin’s terminology, used by Warren and
co-workers, and relevant to our work is included in the Supporting
Information.
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Org. Lett., Vol. 3, No. 16, 2001

Table 1. Acid-Promoted Cyclization of Methylene-Interrupted Epoxydiols
compound
condition
yield (%)a
productb
5a , X ) CH2OH
A
B
A
B
A
B
A
B
A
B
A
B
C
A
B
C
75
72
17d
20d
82
80
80
78
60
75
65
75
74
70
78
74
6a c
6a c
5b, X ) CHO
5c, X ) CHCH2
5d , X ) CH2CH3
5e, X ) OCH3
5f
9e
9e
7c
8c
6d
6d
6e
6e
7f
6f:7f (70:30)
6f:7f (97:3)
6g:7g (3:97)
6g:7g (80:20)
6g:7g (95:5)
5g
a All reported isolated yields are over the two steps described in conditions A, B, and C. b In each case, the indicated products are the only observed and
isolated products. None of the other possible regioisomers were detectable by TLC, crude GC, or NMR analysis. c Hydroxyl in X is acetylated. d A complex
mixture of products was obtained possibly due to rearrangement and polymerization of aldehyde under acidic conditions. The only isolable product after
acetylation was 9. e Product obtained is due to the 5-exo opening (via 7c) of the epoxide, which underwent intramolecular hemiacetylation. 9 was identified
after peracetylation.
Semiempirical calculations (PM3 force field, Spartan V.
5.1.3) suggest that 8c is slightly more stable than 7c (by about
2 kcal/mol). This prompted us to investigate the possibility
that 7c might have been produced under aqueous acidic
conditions but was then isomerized to yield the more stable
product 8c. However, treatment of 7c with 10% HCl in THF
did not lead to any isomerization product and starting
material was recovered. We also were not able to isomerize
8c into 7c under reaction conditions that led to the isolation
of 7c (BF3‚EtO2). The regioselectivity observed in ring
opening of 5c might be due to differential rates of silyl
deprotection or different transition state energies in the ring
opening for a given substrate under different reaction
conditions in the cases that lead to 8c. We are presently
investigating these possibilities.
We next studied the cyclization reactions of epoxysulfides
5f and 5g, anticipating that under acid conditions these
cyclizations would involve the intermediacy of episulfonium
ions 10 and 11, respectively (Table 1). Warren and co-
workers have extensively studied the selective synthesis
of THF and THP systems with and without 1,2-phenylthio
migrations via episulfonium ion intermediates.26-28 Ep-
oxysulfides are known to undergo rearrangement to form
(26) Fox, D. J.; House, D.; Kerr, F.; Warren, S. J. Chem. Soc., Chem.
Commun. 2000, 1781.
Org. Lett., Vol. 3, No. 16, 2001
2491

episulfonium ion under acidic conditions.29-31 In light of the
results with 5c, we believed that the use of thiophenyl ether
as the neighboring group should enable us to direct the
regiochemistry of cyclization by both strategies discussed
above, that is by the dual use of functional group participation
as well as the choice of the reagent used to trigger the
functional group participation.
Results of acid-promoted cyclizations of epoxysufide 5f
and 5g are summarized in Table 1. Attack at the less
substituted end of the episulfonium ion was not observed
experimentally. Formation of 7f and 7g involves net retention
of configuration at C-1, thus providing a set of products
complementary to THF systems obtained with 5e; i.e., in
this case net retention at point of attack furnishes the epimer
of the 5-endo cyclization product analogue reported above.
Treatment of 5f with BF3‚Et2O yielded the 5-exo cyclized
product 7f as a single diastereomer. The observed NOEs
confirmed a net retention of configuration at C-1, thus
suggesting the formation of episulfonium ion prior to
cyclization.
Exposure of epoxysulfide 5f to aqueous acetic acid
furnished a mixture of THF products 6f and 7f. However,
when epoxysulfide 5f was treated with 1.5 N HCl, 6f was
isolated as the major product. While 7f is the 5-exo
cyclization product resulting from an episulfonium ion
intermediate, 6f is the 5-exo product resulting from direct
cyclization of the epoxysulfide. Semiempirical calculations
(Spartan 5.1.3, AM1 force field) show 6f to be more stable
than 7f by about 2 kcal/mol. To examine if the product ratio
observed with acetic acid is due to slow equilibration to the
more stable isomer, the reaction was continued for extended
periods. However, the ratio of isomers was not significantly
different even after 24 h. Also, when the product obtained
from the BF3‚Et2O reaction (7f) was submitted to acetic acid
and 1.5 N HCl conditions separately, no equilibration was
observed. These results suggest that in acetic acid the
cyclization probably occurs through two pathways, one
involving an episulfonium ion intermediate and the other by
direct cyclization of the epoxysulfide. On the other hand,
under strong protic acid conditions (HCl), the thio group
could be solvated, thereby disfavoring formation of the
episulfonium ion. Unlike that in the case of epoxy alkene
5c, no THP products were observed. The regioselectivity
observed in the cyclizations of epoxysulfide remains constant
even with a change in the epoxide stereochemistry, as is
evident from the cyclization of 5g (Table 1) using the same
set of conditions to yield 6g and 7g.
In summary, we have demonstrated that regioselectivity
in epoxide opening in case of methylene-interrupted epoxy-
diol system 1 can be controlled with appropriate pendant
groups (X) and the acid promoter. We have obtained five
stereoisomeric 3-oxygenated 2,3,5 trisubstituted THF rings
from a common precursor without the need for orthogonal
protection of the diol functionality. Total synthesis of AA-
THF-diols using this methodology is currently underway.
Acknowledgment. Generous support was provided in part
by Michigan State University Startup funds to B.B., a Harold
Hart Graduate Fellowship for R.S.N., and the Michigan
Economic Development Corporation (GR-183). The authors
wish to thank Professor Rawle Hollingsworth (MSU) for the
generous supply of 2-deoxyribose and Mr. Seung Ho Baek
for help with synthesis of starting material.
(27) House, D.; Kerr, F.; Warren, S. J. Chem. Soc., Chem. Commun.
2000, 1779.
(28) House, D.; Kerr, F.; Warren, S. J. Chem. Soc., Chem. Commun.
2000, 1783.
(29) Gill, M. D.; Pegg, N. A.; Rayner, M. C. J. Chem. Soc., Perkin Trans.
1 1993, 1371.
(30) Gill, M. D.; Pegg, N. A.; Rayner, C. M. Tetrahedron 1996, 52,
3609.
(31) Miyauchi, H.; Nakamura, T.; Ohashi, N. Bull. Chem. Soc. Jpn. 1995,
68, 1731.
Supporting Information Available: Detailed experi-
mental procedures and tabulated spectroscopic data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL016118H
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Org. Lett., Vol. 3, No. 16, 2001