Development of β-keto 1,3-dithianes as versatile intermediates for organic synthesis

Article abstract of DOI:10.1039/b208982c

β-Keto 1,3-dithianes can be generated by the double conjugate addition of dithiols to propargylic ketones, esters and aldehydes in excellent yields. As masked 1,3-dicarbonyl systems these substrates can be converted to a range of functionalised oxygen-containing heterocycles that can be used in natural product synthesis.

Full text of DOI:10.1039/b208982c

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Development of ꢀ-keto 1,3-dithianes as versatile intermediates for
organic synthesis
Matthew J. Gaunt, Helen F. Sneddon, Peter R. Hewitt, Paolo Orsini, David F. Hook and
Steven V. Ley*
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW.
E-mail: svl1000@cam.ac.uk; Fax: ϩ44 (0) 1223 336442; Tel: ϩ44 (0) 1223 336398
Received 16th September 2002, Accepted 30th October 2002
First published as an Advance Article on the web 3rd December 2002
ꢀ
-Keto 1,3-dithianes can be generated by the double
Table 1 Dithiol additions to propargylic ketones
conjugate addition of dithiols to propargylic ketones,
esters and aldehydes in excellent yields. As masked
Time/ Yield
a
Entry Substrate
1
h
(%) Product
1
,3-dicarbonyl systems these substrates can be converted to
a range of functionalised oxygen-containing heterocycles
that can be used in natural product synthesis.
16
94
The generation of 1,3-oxygenated functionality in organic
molecules is an important process of modern synthetic
chemistry. While there have been many advances in this area,
b
2
4
24
24
18
18
84
88
82
88
48
1
and especially for the assembly of polyketide natural products,
there remains a constant need to develop new methods for
the introduction of 1,3-oxidation patterns with enantio- and
3
4
5
2
diastereocontrol.
We were interested in developing a general functionalised
molecular unit from which we could generate a range of
1
,3-substituted molecules. Here we report our initial studies on
the facile double conjugate addition of dithiols to propargylic
carbonyls to form a β-carbonyl dithiane. This intermediate
provides a versatile platform for the preparation of heterocycles
containing 1,3-oxidation arrangements.
c
6
a
Reagents and conditions: NaOMe (1.3 equiv.), propane-1,3-dithiol
1.1–1.3 equiv.), MeOH–CH Cl (4 : 1, 0.05 M), Ϫ10 ЊC to 0 ЊC.
(
2
2
Scheme 1
b
c
NaOEt, EtOH–CH Cl are used. NBu OH (1.3 equiv.), propane-1,3-
2
2
4
dithiol, THF–MeOH, 0 ЊC.
There are a number of methods available for the gener-
ation of β-keto 1,3-dithianes, although in some cases their
synthesis is complicated and reported applications have there-
propargylic compounds (1a–f ). Pleasingly, the dithiol additions
worked in good to excellent yields, Table 1.† Ketones (entries 1,
3, and 4) and esters (entry 2) with a range of substituents were
3
fore been limited. Potentially, however, orthogonally protected
dicarbonyl intermediates have wide ranging applications. We
conceived that a dithiol would undergo a base mediated double
conjugate addition to a propargylic ketone to generate the
5
good substrates for this process. In general, we found that the
addition of the base to a solution of dithiol and the propargylic
carbonyl at Ϫ10 ЊC and allowing the temperature to rise to 0 ЊC
overnight gave optimal yield of product. Particularly note-
worthy is the formation of dithiane 2e from aldehyde 1e (entry
4
desired β-keto 1,3-dithiane (Scheme 1, 2).
5
). This versatile aldehyde derivative was generated in good
yield. The dithiol addition is amenable to large-scale produc-
tion of dithiane adducts. For example, ethyl propiolate 1b is
converted to dithiane 2b in 84% yield on a 0.1 mole scale.
Dithiane 2f is formed in modest yield from 1f (entry 6). This
6
product is probably formed by dithiol addition to the alkyne
followed by attack of methoxide on the resulting aldehyde and
7
subsequent 1,4-Brook rearrangement.
More complex substrates are also amenable to this reaction.
As part of our natural product synthesis programmes we
required a number of poly-oxygenated 1,3-dicarbonyl com-
pounds. The propargylic ketones were readily prepared by a
two step procedure involving acetylide addition to an aldehyde
and oxidation of the resulting propargylic alcohols. Table 2
shows the addition of dithiols to more complex substrates
(1g–i), highlighting the compatibility of this reaction with a
Scheme 2 Conjugate addition of a dithiol to propargylic ketones.
Initial investigations proceeded on the addition of propane-
,3-dithiol to alkyne 1a to generate desired β-keto dithiane 2a
1
in an excellent yield. The optimal system involved the use of
NaOMe in MeOH with either THF or CH Cl as co-solvent.
2
2
The scope of the reaction was investigated using a range of
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 – 1 6
15

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Table 2 Dithiol addition to complex propargylic ketones
a
Entry
1
Substrate
Time/h
16
Yield (%)
80
Product
2
3
16
16
90
95
a
Reagents and conditions: NaOMe (1.3 equiv.), propane-1,3-dithiol (1.1 equiv.), MeOH–CH Cl (4 : 1, 0.05 M), Ϫ10 to 0 ЊC.
2
2
range of common protecting groups. Moreover, the stereo-
chemical integrity of ketone 1g is conserved in the formation of
in good to excellent yields across a range of substrates. The
potential of these units as versatile platforms for the generation
of 1,3-oxygenated structures is highlighted through the syn-
thesis of spiroketal 3. Functionalised dithianes (2f ) can be
accessed from a silyl substituted propargylic aldehyde (1f ) and
we have also reported a new tandem process that forms highly
functionalised cyclic systems. We are currently exploring the
application of these species in a number of synthesis pro-
grammes and these results will be reported in due course.
2
g implying that this methodology is adaptable to molecules
with base sensitive asymmetric centres.
We also investigated the addition to 1j, a substrate that
contains a second electrophilic site. Dithiol addition proceeded
smoothly and was followed by intramolecular aldol reaction to
form 2j as a 3 : 1 (syn–anti) mixture of diastereomers in 65%
yield. This tandem process generates cyclic systems with high
levels of functionality (Scheme 3).
Acknowledgements
We would like to thank the British Ramsay Memorial Trust
and Magdalene College for Fellowship (to M.J.G.), the EPSRC
(
1
to H.F.S. and D.F.H.), Pharmacia S.p.A., Viale Pasteur,
0-20014 Nerviano (MI) – Italy. (to P.O) and the Novartis
Research Fellowship (to S.V.L).
Scheme 3 Tandem dithiol-intramolecular aldol reaction.
Reagents and conditions: (i) NaOMe (1.3 equiv.), propane-1,3-dithiol
(
1.1 equiv.), MeOH–CH Cl (3 : 1), 0 ЊC to rt, 14 h.
Notes and references
2
2
†
General procedure. NaOMe (1.3 equiv.) was added in one portion to a
The conversion of the propargylic ketone unit to a β-keto
,3-dithiane removes the rigid acetylene unit from the molecule
permitting a range of cyclisation reactions. For example, treat-
stirred solution of propargylic carbonyl compounds and propane-1,3-
dithiol (1.1 equiv.) in MeOH–CH Cl (4 : 1, 0.05 M) at approximately
Ϫ10 ЊC (ice–acetone bath). The reaction mixture was stirred for 14
hours, allowing the temperature to rise to 0 ЊC. On completion
the reaction was quenched by the addition of NH Cl solution
and extracted with Et O. The organic fractions were washed (water
and brine), dried (MgSO ), concentrated under reduced pressure and
purified by flash column chromatography.
1
2
2
ment of 2h with p-TsOH in MeCN–H O for 16 hours facilitated
2
4
removal of the two silicon groups and subsequent cyclisation
afforded spiroketal 3. This sequence of reactions provided a
model compound for the synthesis of the AB spiroketal unit
2
4
8
of spongistatin 1 (Scheme 4). Interestingly, the 1,3-dithiane
1
2
(a) C. Schneider, Angew. Chem., Int. Ed., 1998, 37, 1375; (b)
R. D. Norcross and I. Paterson, Chem. Rev., 1995, 95, 2041.
(a) For some recent examples see: A. B. Smith and A. M. Boldi,
J. Am. Chem. Soc., 1997, 119, 6925; (b) S. D. Rychnovsky, U. R. Khire
and G. Yang, J. Am. Chem. Soc., 1997, 119, 2058; (c) D. A. Evans,
D. M. Fitch, T. E. Smith and V. J. Cee, J. Am. Chem. Soc., 2000, 122,
1
0033; (d ) I. Paterson, G. J. Florence, K. Gerlach, J. P. Scott and
N. Sereinig, J. Am. Chem. Soc., 2001, 123, 9535; (e) M. J. Zacuto,
S. J. O’Malley and J. L. Leighton, J. Am. Chem. Soc., 2002, 124, 7890;
(
8
f ) S. A. Burova and F. E. McDonald, J. Am. Chem. Soc., 2002, 124,
188.
3
4
(a) E. C. Taylor and J. L. LaMattina, Tetrahedron Lett., 1977, 2077;
(
(
b) I. Paterson and L. G. Price, Tetrahedron Lett., 1981, 2829;
c) K. Hatanaka, S. Tanimoto, T. Sugimoto and M. Okano,
Tetrahedron Lett., 1981, 3243.
(a) B. C. Ranu, S. Bhar and R. Chakraborti, J. Org. Chem., 1992,
Scheme 4 Application to the synthesis of spiroketal 3.
5
1
7, 7349; (b) H. Kuroda, I. Tomita and T. Endo, Synth. Commun.,
Reagents and conditions: (i) p-TsOH, MeCN–H O (4 : 1), 30 ЊC.
2
996, 26, 1539. For example of a diol addition to a propargylic
ketone see (c) J. Aiguade, J. L. Hao and C. J. Forsyth, Org. Lett., 2001,
3, 979.
5 All compounds were characterised by H and C NMR, HRMS, I.R.
and optical rotation where applicable.
Although we could isolate the initial dithiol adduct (39% yield) the
reaction proved capricious.
A. Brook, Acc. Chem. Res., 1974, 7, 77.
J. Pietruszka, Angew. Chem., Int. Ed., 1998, 37, 2629.
9 Dr A. J. Hazelwood, Ph. D. Thesis, 2002, University of Cambridge.
unit seems to have a significant effect on the cyclisation of 2h.
Cyclisation of the corresponding dione proved capricious,
9
1
13
however, in the presence of the dithiane unit the cyclisation cleanly
produced the desired spiroketal in excellent yield (95%).
In summary, we have developed an efficient method for the
conjugate addition of dithiols to propargylic ketones, esters
and aldehydes. The resulting β-carbonyl-dithianes are isolated
6
7
8
1
6
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 – 1 6