Chemistry of Epoxysulfones: Straightforward Synthesis of Versatile Chiral Building Blocks

Article abstract of DOI:10.1021/ol035701q

(Equation presented) Several chiral building blocks have been obtained easily in large quantities from an epoxysulfone (9) that could be obtained in both enantiomeric forms from accessible starting materials.

Full text of DOI:10.1021/ol035701q

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4361-4364
Chemistry of Epoxysulfones:
Straightforward Synthesis of Versatile
Chiral Building Blocks
David D´ıez,* M. Templo Bene´itez, Isidro S. Marcos, N. M. Garrido, P. Basabe,
F. Sanz,‡ Howard B. Broughton,§ and Julio G. Urones
Departamento de Qu´ımica Orga´nica, UniVersidad de Salamanca,
Plaza de los Ca´ıdos 1-5, 37008 Salamanca, Spain
ddm@usal.es
Received September 5, 2003
ABSTRACT
Several chiral building blocks have been obtained easily in large quantities from an epoxysulfone (9) that could be obtained in both enantiomeric
forms from accessible starting materials.
Prostaglandins,1 pentenomycin antibiotics,2 ophiobolins,3 and
the antitumor antibiotic enediynes, such as the Neocarzi-
nostatin Chromophore4 and N1999A2,5 are compounds of
great interest due to their biological activities.6
protected as its TBDMS derivative, described an efficient
route to prostanoid intermediates. Kishi10 presented some
years ago the synthesis of an ophiobolin analogue starting
Most syntheses of these compounds start with 4-hydroxy-
cyclopent-2-en-1-one ((S)- or (R)-1), and in some cases the
transformation into vinyl bromides or vinyl iodides is the
first step. The double alkylation of 4-hydroxycyclopent-2-
en-1-one ((S)- or (R)-1) and its protected forms is one of
the most efficient routes to the E and F series of prostag-
landins.7 Caddick synthesized8 the core of NCS-Chrom
starting from cyclopentenone 2. Levin,9 starting from (S)-1
‡ Servicio de Difraccio´n de Rayos X, Universidad de Salamanca.
§ Lilly S.A., Avda. de la Industria, 30, 28108 Alcobendas, Madrid, Spain.
(1) Collins, P. W.; Djuric, S. W. Chem ReV. 1993, 93, 1553.
(2) Smith, A. B.; Branca, S. J.; Pilla, N. N.; Guaciaro, M. A. J. Org.
Chem. 1982, 47, 1855.
(3) Nozoe, S.; Morisaki, M.; Tsuda, K.; Iitaka, Y.; Takahasi, N.; Tamura,
S.; Ishibashi, K.; Shirasaka, M. J. Am. Chem. Soc. 1965, 87, 4968.
(4) Edo, K.; Mizugaki, M.; Koide, Y.; Seto, H.; Furihata, K.; Otake, N.;
Ishida, N. Tetrahedron Lett. 1985, 26, 331.
(5) Ando, T.; Ishii, M.; Kajiura, T.; Kameyama, T.; Miwa, K.; Sugiura,
Y. Tetrahedron Lett. 1998, 39, 6495.
(6) Lhermite, H.; Grierson, D. S. Contemp. Org. Synth. 1996, 3 (1), 41
(Part 1), and 93 (Part 2).
Figure 1.
10.1021/ol035701q CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/22/2003

from (R)-1 and transformed into 3 in the first step; and
Johnson reported an easy synthesis of PGE1 from a TBDMS-
protected (R)-1, which was transformed into 4 in the first
step.11 Compound 1 has been obtained in both enantiomeri-
cally pure forms starting from L- or D-tartaric acid in six
steps in a 22% yield,12 or by a chemoenzymatic access
starting from cyclopentane-1,3-dione to give a 30% yield of
each enantiomer.13 The corresponding vinyl halides were
obtained by treatment of 1 in a bromination-dehydrobro-
mination sequence9 or in a one-step approach by treatment
of 1 with I2/pyridine in CCl4.14
the usual conditions) into cyclopentenone 7 by treatment with
LDA in THF. The transformation gave low yields in both
cases, 10% and 19%, respectively, with the majority of the
starting material being recovered. Compound 7 has been
obtained previously (although in racemic form) by Fuchs23
and used in the synthesis of dl-cephalotaxine,24 and has been
epoxidized by Jackson to give epoxide 8 stereoselectively25
(Scheme 2).
Scheme 2
Figure 2.
The epoxidation of acyclic vinyl sulfones has been widely
studied by Jackson,26 and the reactivity of these species has
been applied in the synthesis of natural products.27 The
stereoselectivity described by Jackson in systems similar to
5 depends on the oxidant used and on the protecting groups.25
Having compound 5 in hand, we decided to study the
epoxidation of this molecule to develop a route to the
â-epoxide of the cyclized compound, which has not been
previously described. When compound 5 was submitted to
epoxidation conditions with t-BuOOLi or t-BuOOK, com-
pounds 9 and 10 were obtained in an excellent yield in a
ratio of 95:5 in both cases. The excellent stereoselectivity
could be understood on the basis of less hindrance in
transition state I than II (see Scheme 3). For a discussion
see ref 25a. To study this further, the combined MCMM/
Lowmode conformational search method in MacroModel28
was used to locate low-energy conformers of 5, using up to
2000 steps, the MMFF force field, TNCG minimization, and
the GB/SA/CHCl3 model for solvation. The lowest energy
conformers found corresponded directly to that required for
transition state I. Geometry optimization of the lowest energy
conformers of 5 of types I and II found in the MacroModel
The versatility of vinyl sulfones in organic chemistry has
been demonstrated by Backwall,15 Fuchs,16 Carretero,17 and
Padwa,18 among others.19 This paper describes a new
contribution to extend the versatility of vinyl sulfone
chemistry, in particular with compound 5, easily obtained
in two steps and in 76% yield from 2,3-O-isopropylidene-
D-erythronolactol.20 The enantiomer is also easily accessible,
starting from L-arabinose.21
Scheme 1
Vinyl sulfones are known to react as Michael acceptors
and to stabilize an anion in the R position.22 Taking this
reactivity into account, we started the transformation of the
vinyl sulfone 5 or its iodide derivative 6 (obtained under
(20) D´ıez, D.; Templo-Bene´itez, M.; Marcos, I. S.; Garrido, N. M.;
Basabe, P.; Urones, J. G. Synlett 2003, 729.
(21) Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem. 1990,
55, 4683 and references therein.
(22) Simpkins, N. S. Sulphones in Organic Synthesis. In Tetrahedron
Organic Series; Pergamon: New York, 1993.
(7) (a) Patterson, J. W.; Fried J. H. J. Org. Chem. 1974, 39, 2506. (b)
Tanaka, T.; Kurozumi, S.; Toru, T.; Kobayashi, M.; Miura, S.; Ishimoto,
S. Tetrahedron Lett. 1975, 1535.
(8) Caddick S.; Khan, S.; Smith, N. J.; Barr, D. M.; Delisser, V. M.
Tetrahedron Lett. 1997, 38, 5035.
(9) Levin J. I. Tetrahedron Lett. 1989, 30, 13.
(23) Nantz, M. H.; Radisson S.; Fuchs, P. L. Synth. Commun. 1987, 17
(1), 55.
(24) Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. Soc. 1990, 112, 9601.
(25) (a) Jackson, R. F. W.; Standen, S. P.; Clegg, W. J. Chem. Soc.,
Perkin Trans. 1 1995, 149.
(26) (a) Ashwell, M.; Jackson, R. F. W. J. Chem. Soc., Perkin Trans. 1
1989, 835. (b) Ashwell, M.; Clegg, W.; Jackson, R. F. W. J. Chem. Soc.,
Perkin Trans. 1 1991, 897. (c) Hewkin, C. T.; Jackson, R. F. W. Tetrahedron
Lett. 1990, 31, 1877. (d) Hewkin, C. T.; Jackson, R. F. W.; Clegg, W. J.
Chem. Soc., Perkin Trans. 1 1991, 3091. (e) Dunn, S. F. C.; Jackson, R. F.
W. J. Chem. Soc., Perkin Trans. 1 1992, 2863. (f) Jackson, R. F. W.;
Standen, S. P.; Glegg, W.; McCamley, A. J. Chem. Soc., Perkin Trans. 1
1995, 141.
(10) Rowley, M.; Kishi, Y. Tetrahedron Lett. 1988, 29, 4909.
(11) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014.
(12) Ogura, K.; Yamashita, M.; Tsuchihashi, G. Tetrahedron Lett. 1976,
10, 759.
(13) Demir, A. S.; Sesenoglu, O. Tetrahedron: Asymmetry 2002, 13, 667.
(14) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.;
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917.
(15) Ba¨ckvall, J.-E.; Juntunen, S. K. J. Org. Chem. 1988, 53, 2398.
(16) Fuchs, P. L.; Hentemann, M. F. Org. Lett. 1999, 1, 1355.
(17) Iradier, F.; Arryas, R. G.; Carretero, J. C. Org. Lett. 2001, 3, 2957.
(18) Padwa, A.; Murphree, S. S.; Ni, Z. J. J. Org. Chem. 1996, 61, 3829.
(19) Ba¨ckvall, J.-E.; Chinchilla, R.; Na´jera, C.; Yus, M. Chem. ReV. 1998,
98, 2291.
(27) Reddy, R.; Jaquith, J. B.; Neelagiri, V. R.; Saleh-Hanna, S.; Durst,
T. Org. Lett. 2002, 4, 695.
(28) MacroModel v 8.1031; Schrodinger, Inc.: Portland, OR.
4362
Org. Lett., Vol. 5, No. 23, 2003

Scheme 3a
a Reagents and conditions: (a) t-BuOOLi, THF, -78 °C or
t-BuOOK, THF, -78 °C, 95%.
search by using AM1 in MOPAC led to the conformations
shown in color in Scheme 3, with the conformer correspond-
ing to I being 4.7 kcal/mol lower in energy than that
corresponding to II. Thus, the excellent diastereoselectivity
shown may be due to a combination of a preponderance of
the conformer of 5 in which the double bond is gauche to
the C-O bond of the dioxolane, together with greater
exposure of the π face of the double bond to attack by lithium
tert-butylperoxide in these conformers than in the minor
conformer in which the double bond is gauche to the C-H
bond.
The stereochemistry of compound 9 was established by
X-ray crystallography (Figure 3). As would be expected from
the stabilization of anions in the R-position of epoxysul-
fones,29 treatment of 9 with LiHMDS gives an 87% yield of
the cyclized compound 11, which was deprotected under the
usual acid conditions to diol 12 (Scheme 4). To the best of
Figure 3. Single-crystal X-ray structures of 9 and 11. Selected
bond lengths for 9 (Å): O(8)-C(7) 1.393(9), O(8)-C(8) 1.414
(8), C(7)-C(8) 1.429 (7). Selected bond lengths for 11 (Å): O(5)-
C(4) 1.494(13), O(5)-C(5) 1.393 (12), C(4)-C(5) 1.47 (2).
Compound 11 was crystallized from Et2O and the X-ray
data were obtained.
Sulfonyloxiranes show asymmetry of the two C-O bonds,
the bond adjacent to the sulfonyl group being the shorter, as
can be seen for compounds 9 and 11. What is most striking
is the dramatic difference between the bond lengths C(4)-
O(5) and C(5)-O(5) (for crystallographic numbering for 11
see Figure 3) in comparison with compound 8 (O(5)-C(4)
1.449, O(5)-C(5) 1.436 and C(4)-C(5) 1.47525). This could
be due to an interaction between the lone pairs of the epoxide
and of the acetonide for 11.
Scheme 4a
With compound 9 thus available to us in gram quantities,
we decided to study the cyclization reaction and the reactivity
of the cyclic compound. Compounds 11 and 12 seemed to
us to be excellent precursors for the synthesis of cyclopen-
tanones, based upon the reported reactivity of this kind of
compound.30 However, on treatment with various reagents,
only in one case was the expected cyclopentanone obtained
(entry 6 of Table 1). The reactivity of compounds 11 and
12 is described in Table 1.
a Reagents and conditions: (a) LiHMDS, THF, -78 °C, 87%;
(b) TsOH, MeOH, 95%.
our knowledge this is the first time that compound 11 has
been synthesized.
(29) (a) Eisch, J. J.; Galle, J. E. J. Organomet. Chem. 1976, 121, C10.
(b) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996, 118,
8158.
(30) (a) Davis, C. E.; Bailey, J. L.; Lockner, J. W.; Coates, R. M. J.
Org. Chem. 2003, 68, 75. (b) Arjona, O.; Plumet, J. Curr. Org. Chem. 2002,
5, 571.
Org. Lett., Vol. 5, No. 23, 2003
4363

whether the starting material was 11 or 12. Vinyl azide 20
(entries 10 and 11) was obtained from either starting material
in good yield.
Table 1. Reaction of Compounds 9, 11, and 12e
When compound 9 was treated with MgBr2 under the usual
conditions, the THP-sulfone 21 was obtained in good yield.
These kinds of compounds have been used widely by Ley
et al. in natural product synthesis.31
The structure and stereochemistry of all compounds were
determined by extensive NMR studies.
Finally, to explore other kinds of reactivity for compound
11, it was subjected to desulfonylation under the usual
conditions with sodium amalgam,32 giving as sole product
and in high yield the hydroxy sulfone 22, whose stereo-
chemistry was established by NOE experiments (Scheme 5).
Scheme 5
a All reactions were done with 3 equiv of reagent with the exception of
MgBr2, which was done with 2 equiv. Reaction temperature was 60 °C or
reflux except for entry 3, which was done at rt. b Solvent: THF. c Solvent:
Et2O/THF. d Solvent: acetone. e S.M. stands fro starting material.
Analogous compounds have been used as central intermedi-
ates for the synthesis of tricyclo-DNA.33
Thus, this is an excellent procedure for obtaining vinyl
bromides, chlorides, iodides, azides, or halogenated cyclo-
pentenones such as 14, as well as cyclopentanones such as
18 or 22 and THP-sulfones such as 21, in excellent yield.
The method is easy to scale up, and it is worth bearing in
mind that the starting materials could be obtained in both
enantiomerically pure forms. Some of these compounds have
not been described to date and are useful starting materials
for the synthesis of biologically important targets, generating
new ideas for the synthesis of prostaglandin analogues and
other interesting compounds such as the enediynes. Further
studies on the scope and applications of this methodology
are actively under way in these laboratories.
When both compounds were subjected to treatment with
different nucleophiles under the usual conditions, cyclopen-
tenones were obtained. All products in the table can be
rationalized by the well-known nucleophilic attack at the
unhindered position of the epoxide, with concomitant sulfinic
acid loss to initially generate an R-cyclopentanone-acetonide
of general structure 18 (X varied). R- or R′-enolization and
â-elimination from this intermediate secure the products of
Table 1. To test this hypothesis, compound 18 was treated
with acetone-p-TsOH, but instead of the corresponding
acetonide, a 1:1 mixture of compounds 15 and 16 was
obtained. Thus, it is likely that initial formation of the
cyclopentanone is followed by a rapid elimination, un-
expected on the basis of precedent with open-chain
analogues,26b to give the corresponding cyclopentenealcohols.
From Table 1 it is clear that by using MgBr2 (entries 2
and 3) the same products are obtained but in inverse ratio,
depending on whether the starting material was 11 or 12,
while use of LiCl (entries 5 and 6) gave rise to 15 from 11
in excellent yield, or 18 (the only compound that shows no
elimination) from 12. The use of LiI in acetone did not give
any opening, the starting material being recovered (entry 7).
When the solvent was changed to tetrahydrofuran (entries 8
and 9), use of LiI led to the synthesis of compound (R)-1 or
the vinyl iodide 19, both in good yield, depending upon
Acknowledgment. The authors thank the CICYT (BQU
2001-1034), Junta Castilla y Leon for financial support (SA
13-00B), and the Spanish Ministerio de Educacio´n y Cultura
for a doctoral fellowship to M.T.B.
Supporting Information Available: Experimental pro-
cedures and complete characterization for all new com-
pounds, as well as the X-ray crystalographic analysis data
for 9 and 11. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL035701Q
(31) Brown D. S.; Ley, S. V. Org. Synth. 1991, 70, 157.
(32) Carretero, J. C.; Arrayas, R. G. J. Org. Chem. 1998, 63, 2993.
(33) Vonlanthen, D.; Leumann, C. J. Synthesis 2003, 1087.
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