Investigation of the Diastereoselective Cyclization of Bis-sulfonyl Esters

Article abstract of DOI:10.1021/ol0271436

(Matrix Presented) The diastereoselective cyclization of bissulfonyl esters was investigated by varying both the size and the placement of the substituent on the tether adjoining the reacting centers. Substitution at either the α or β position relative to the ester moiety gave diastereomeric ratios of (1-3):1, while γ substitution dramatically increased the diastereomeric ratios to (6-20):1.

Full text of DOI:10.1021/ol0271436

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4705-4708
Investigation of the Diastereoselective
Cyclization of Bis-sulfonyl Esters
John Colucci,* David Lee, Marie-Claire Wilson, and Ann Chau
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research,
Merck Frosst Canada & Co., P.O. Box 1005, 16711 Trans Canada Highway,
Kirkland, Quebec, Canada H9H 3L1
john_colucci@merck.com
Received October 21, 2002
ABSTRACT
The diastereoselective cyclization of bissulfonyl esters was investigated by varying both the size and the placement of the substituent on the
tether adjoining the reacting centers. Substitution at either the r or â position relative to the ester moiety gave diastereomeric ratios of
(1−3):1, while γ substitution dramatically increased the diastereomeric ratios to (6−20):1.
The formation of cyclohexanones containing several stereo-
centers has been a challenging problem in organic synthesis,
and many elegant solutions have been developed over the
years. A few examples include the Diels-Alder reaction,1
anisole manipulation,2 and intramolecular ene reaction3
followed by oxidation. We would like to introduce a novel
approach to cycloalkanones containing several stereocenters
based on the well-known Claisen condensation of sulfones
with esters. As shown in Scheme 1, Truce4 introduced the
We have been interested in an extension of this reaction
where two “equivalent” sulfones are available to react with
an ester group. As shown in Scheme 2, we envisioned that
Scheme 2
Scheme 1
intramolecular cyclization of sulfonyl esters to produce
cyclopentanones and cyclohexanones, which Grimm5 later
expanded toward the formation of medium-sized rings.
by strategically placing substituents on the tether joining the
two reactive partners, cyclization would preferentially occur
to the cyclohexanone containing both substituents in an
equatorial disposition. Although addition to the ester is an
irreversible process, it is likely that reversible deprotonation
(1) Barluenga, J.; Aznar, F.; Ribas, C.; Valdes, C. J. Org. Chem. 1998,
63, 10052 and references therein.
(2) Schmalz, H. G.; Schellhaas, K. Angew Chem., Int. Ed. Engl. 1996,
35, 2146 and references therein.
(3) Sakane, S.; Maruoka, K.; Yamamoto, H. Tetrahedron 1986, 8, 2203
and references therein.
(4) Truce, W. E.; Knospe, R. H. J. Org. Chem. 1955, 77, 5603.
(5) Grimm, E. L.; Coutu, M. L.; Trimble, L. A. Tetrahedron Lett. 1993,
34, 7017.
10.1021/ol0271436 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/21/2002

between the sulfonyl groups can occur prior to cyclization.
This should favor products with all substituents equatorially
positioned on the resulting cyclohexanone.6
Scheme 4a
The products could then serve as extremely valuable
synthetic intermediates in organic synthesis since the reactiv-
ity of the two resulting sulfone units are remarkably different.
For example, selective reduction of the â keto sulfone to
the cyclohexanone is a well-known process leaving the
remaining sulfone group to then take part in many chemical
reactions that it is known to undergo.7 One could also
envision alkylating the keto sulfone before its selective
reductive removal, producing a third stereocenter on the
cyclohexanone ring.
We began by investigating cyclohexanone precursors and
arbitrarily chose to synthesize substrates containing a methyl,
isopropyl, and CH2OTBDMS group at all three positions on
the tether. This would deduce whether steric bulk and/or
placement (R, â, or γ), relative to the ester moiety, produces
the greatest influence on selectivity.
A versatile starting material, which allowed us to access
most of the bissulfonyl ester precursors, was the com-
mercially available diol, 1. After conversion of the diol to
the bissulfide8 followed by hydrolysis of the acetal, we
obtained aldehyde 2, which enabled us to rapidly synthesize
most of the cyclization precursors (Scheme 3).
a Key: (a) Ph3PdC(Me)COOEt, CH2Cl2; (b) Oxone, THF/
MeOH/H2O; (c) H2, Pd/C; (d) (EtO)2P(O)CH(iPr)COOEt, NaH,
THF; (e) NaBH4, NiCl2/6H2O, EtOH; (f) Ph3PdCHOOEt, CH2Cl2;
(g) LDA, HMPA, CH2O; (h) TBDMSOTf, NEt3; (i) Na2WO4, H2O2,
MeOH; (j) H2, PtO2, EtOH, 40 psi.
to reduce the olefin but for the isopropyl derivative, 4, we
11
found that the use of NaBH4 and NiCl2 worked best.
Scheme 3a
Introduction of the hydroxy methyl group in 5 was carried
out using a deconjugative aldol reaction12 with formaldehyde
followed by reduction of the olefin at a later stage.
Table 1 shows the results upon cyclization13 followed by
a Key: (a) PBu3, (phenylthio)phthalimide, THF; (b) HCl(aq),
THF.
Table 1. Effect of R-Substitution
The syntheses of the R-substituted precursors are shown
below in Scheme 4, and all utilize aldehyde 2 as their starting
material. All three syntheses involve Horner-Emmons-
Wittig reactions to install the ester moiety and either Oxone9
or hydrogen peroxide10 protocols to oxidize the sulfides to
the corresponding sulfones. Typically hydrogenation sufficed
R
yield (%) (two steps)
dr
Me
iPr
66
85
71
1.5:1
3.0:1
3.0:1
(6) An analogous cyclization was utilized in the synthesis of rhizoxin
that involved an in situ preparation of an alcohol with two equivalent
aldehydes separated by a three-carbon tether. Presumably through a
reversible process, the lactol with all substituents equatorial was formed
exclusively. (a) Keck, G. E.; Park, M.; Krishnamurthy, D. J. Org. Chem.
1993, 58, 3787. (b) Williams, D. R.; Werner, K. M.; Feng, B. Tetrahedron
Lett, 1997, 38, 6825. (c) Burke, S. D.; Hong, J.; Lennox, J. R.; Mongin, A.
P. J. Org. Chem. 1998, 63, 6952.
CH2OTBDMS
Molander14 reduction of the â-keto sulfone. Yields for the
two steps were generally high, and H NMR was used to
determine the diastereomeric ratios. Although it appears that
larger R groups have some positive affect on the diastereo-
1
(11) See, for example: Hanessian, S.; Grillo, A. T. J. Org. Chem. 1998,
63, 1049.
(12) Galatsis, P.; Millan, S. D.; Nechala, P.; Ferguson, G. J. Org. Chem.
1994, 59, 6643.
(13) Typically, all precursors were cooled to -78 °C in THF, and 2.2
equiv of LHMDS was added slowly. The solution was stirred for 1 h before
the reactions were quenched with saturated NH4Cl. Yields for the cycliza-
tions were generally very high, and the cyclized adducts were taken to the
next step without characterization.
(7) Simpkins, N. S. In Sulfones in Organic Synthesis; Baldwin, J. E.,
Magnus, P. D., Eds.; Pergamon Press: Oxford, 1993. Oae, S.; Uchida, S.
In The Chemistry of Sulfones and Sulfoxides; Patai, S., Rappoport, Z.,
Striling, C. J. M., Eds.; Wiley: New York, 1988.
(8) Walker, K. A. M. Tetrahedron Lett. 1977, 51, 4475.
(9) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287.
(10) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140.
(14) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.
4706
Org. Lett., Vol. 4, No. 26, 2002

meric ratio, the influence of an R substituent was never larger
than 3:1 in favor of the diequatorial product.15
The syntheses of the â-substituted precursors are outlined
in Scheme 5, and once again, all utilize aldehyde 2 as their
Table 2. Effect of â-Substitution
Scheme 5a
R
yield (%) (two steps)
dr
Me
iPr
62
83
86
2.0:1
2.0:1
2.0:1
CH2OTBDMS
The syntheses of the γ-substituted precursors are outlined
in Scheme 6, where it is shown that aldehyde 2 could only
Scheme 6a
a Key: (a) Me3Al, CH2Cl2; (b) Swern oxidation; (c) (EtO)2P(O)-
CH2COOEt, NaH; (d) Oxone, THF/MeOH/H2O; (e) H2, PtO2,
EtOH; (f) Ph3PdCHCOOEt; (g) CuI, TMSCl, iPrMgCl, tHF, -35
°C; (h) DIBAL-H, PhMe, -50 °C; (i) CH3C(OEt)3, o-nitrophenol,
160 °C; (j) O3, MeOH/CH2Cl2 then NaBH4; (k) TBDMSCl, DMF,
imidazole.
starting material. We initially envisioned that a cuprate-based
approach would suffice for introduction of the substituents
but in practice, only the isopropyl derivative, 10, could be
reproducibly prepared this way in high yield. The methyl
substituent was introduced by transforming the aldehyde to
a methyl ketone using standard chemistry followed by our
previous employed Wittig reaction-hydrogenation sequence
to complete the synthesis of 9. For the CH2OTBDMS
substrate, 11, we instead found that after reduction of the
Wittig product to an allylic alcohol, a Johnson ortho ester
rearrangement16 effectively introduced an ethylene group beta
to the ester. Subsequent ozonolysis, reduction, and silylation
afforded substrate 11 in good overall yield.
a Key: (a) (EtO)2P(O)CH2SO2Ph, LiCl, DBU, CH3CN; (b)
CH3SO2Ph, BuLi; (c) RuCl3, NaIO4; (d) CH2N2, EtOAc; (d) Oxone,
THF/MeOH/H2O; (e) TMSNEt2, methyl acrylate; (f) DIBAL-H,
PhMe; (g) TIPSOTf, Hunig’s base, CH2Cl2; (h) TBAF, AcOH,
THF; (i) MeOH, NaBH4; (j) TBDMSOTf, NEt3, CH2Cl2; (k)
Na2WO4, MeOH, H2O2.
be used for the CH2OTBDMS precursor, 14. The carbon
skeleton of 14 was constructed using chemistry developed
by Hagiwara,17 which involved a one-pot in situ aldehyde-
enamine conversion of aldehyde 2, followed by Michael
addition to methyl acrylate. The aldehyde was then reduced
and protected to efficiently produce precursor 14. The
synthesis of substrate 12 began with commercially available
2,6-dimethyl-5-hepten-1-al whereupon a Wittig reaction with
Posner’s reagent18 formed the trans unsaturated sulfone in
>90% yield. Introduction of the second sulfone unit was
accomplished via a Michael addition with the anion of
methylphenyl sulfone in an overall yield of 20%.19 The
Table 2 shows the results upon cyclization of the â-sub-
stituted substrates. Once again, the influence of a â-sub-
stituent is not substantial, but it is interesting to note that as
the size of the substituent increases the diastereomeric ratio
is not affected, unlike the trend seen in Table 1.
(15) Stereochemistry was proven by converting to menthone as shown
below and comparison of the 13C NMR of both synthetic and natural
products. Similar sequences were carried out for most of the other products
as well and are described in the Supporting Information.
(16) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T, J.;
Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92,
741-743.
(17) Hagiwara, H.; Komatsubara, H. O.; Okabe, T.; Hoshi, T.; Suzuki,
T.; Ando, M.; Kato, M. J. Chem. Soc., Perkin Trans. 1 2001, 316.
(18) Posner, G. H.; Brunelle, D. J. J. Org. Chem. 1972, 37, 3547.
Org. Lett., Vol. 4, No. 26, 2002
4707

synthesis of 12 was completed by oxidative cleavage20 of
the olefin to the acid and methylation with diazomethane.
The synthesis of precursor 13 began with isovaleraldehyde
and utilized both the Hagiwara chemistry to introduce the
ester group and the Wittig reaction-Michael addition
sequence to introduce the bissulfonyl group.
ratio. We also noted that upon increasing the size of the
substituent on the tether, the ratio increases from 6:1 up to
>20:1. The exact reasons for why γ-substitution gives such
an enhancement are not entirely clear yet although experi-
ments are underway to determine whether the deprotonation
of the “equivalent” sulfone units is a reversible process prior
to cyclization.
Table 3 shows the results upon cyclization of the γ-sub-
We have introduced a novel cyclization protocol of
bissulfone esters that can produce diastereoselectivities as
high as 20:1. The best selectivities result when the substituent
is placed gamma to the ester moiety. Attempts to increase
the diastereomeric ratios regardless of the placement of the
substituents are currently underway and involve varying the
base, solvent and bulk of the ester moiety. Preliminary results
are extremely encouraging, and the full account of these
findings will be disclosed soon.
Table 3. Effect of γ-Substitution
R
yield (%) (two steps)
dr
Acknowledgment. We thank Dr. Erich Grimm for his
invaluable advice during the course of this project.
Me
iPr
53
60
76
6.0:1
>20:1
>20:1
CH2OTBDMS
Supporting Information Available: Experimental and
spectral data (1H NMR, 13C NMR, and HRMS) for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
stituted substrates. Gratifyingly, it is at this position that
substitution produces the greatest effect on the diastereomeric
OL0271436
(19) Although the yield for this transformation is low, it represents the
first case to our knowledge of a Michael addition with phenylmethyl sulfone
to a vinyl sulfone. We are currently trying to improve the yield for this
transformation.
(20) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, B. K. J.
Org. Chem. 1981, 46, 3936.
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