Addition of dithiols to bis-ynones: development of a versatile platform for the synthesis of polyketide natural products.

Article abstract of DOI:10.1021/ol034248f

[reaction: see text] The conjugate addition of dithiols to bis-ynones generates a versatile masked 1,3,5-triketone platform. These functional units are useful intermediates for the synthesis of oxygen-containing heterocycles commonly found in polyketide n

Full text of DOI:10.1021/ol034248f

ORGANIC
LETTERS
2003
Vol. 5, No. 7
1147-1150
Addition of Dithiols to Bis-Ynones:
Development of a Versatile Platform for
the Synthesis of Polyketide Natural
Products
Helen F. Sneddon, Matthew J. Gaunt, and Steven V. Ley*
UniVersity Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW
sVl1000@cam.ac.uk
Received February 12, 2003
ABSTRACT
The conjugate addition of dithiols to bis-ynones generates a versatile masked 1,3,5-triketone platform. These functional units are useful
intermediates for the synthesis of oxygen-containing heterocycles commonly found in polyketide natural products. The tetrahydropyranyl
fragments of the marine macrolides Lyngbouilloside and Callipeltoside A have been synthesized with use of this methodology.
The generation of 1,3-oxygenated functionality in organic
molecules is an important process in modern synthetic
chemistry.1 While there have been many advances in this
area, 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 diastereocontrol.2 Through a number of natural
product programs we have realized the general utility of
â-keto 1,3-dithianes as versatile intermediates for the syn-
thesis of polyketide-type structures. As a result we recently
reported a method for the synthesis of â-keto 1,3-dithianes
through the conjugate addition of dithiols to ynones, ynoates,
and ynals (Scheme 1).3
has not been employed in the synthesis of complex mol-
ecules. However, such a synthetic tactic would provide a
highly versatile platform for the synthesis of structural motifs
that are often found in polyketide natural products.4
Scheme 2. Conjugate Addition of Dithiols to Bis-ynones
In this paper we report the development of a process for
the generation of â,â′-bis-1,3-dithiane ketones by the con-
jugate addition of dithiols to a bis-ynone (Scheme 2). We
Scheme 1. Conjugate Addition of a Dithiol to an Ynone
(1) (a) Schneider, C. Angew. Chem., Int. Ed. 1998, 37, 1375. (b) Norcross,
R. D.; Paterson, I. Chem. ReV. 1995, 95, 2041.
(2) (a) For some recent examples see: Smith, A. B.; Boldi, A. M. J.
Am. Chem. Soc. 1997, 119, 6925. (b) Rychnovsky, S. D.; Khire U. R.;
Yang, G. J. Am. Chem. Soc. 1997, 119, 2058. (c) Evans, D. A.; Fitch, D.
M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033. (d)
Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am.
Chem. Soc. 2001, 123, 9535. (e) Zacuto, M. J.; O’Malley, S. J.; Leighton,
J. L. J. Am. Chem. Soc. 2002, 124, 7890. (f) Burova, S. A.; McDonald, F.
E. J. Am. Chem. Soc. 2002, 124, 8188.
(3) Gaunt, M. J.; Sneddon, H. F.; Hewitt, P. R.; Orsini, P.; Hook, D. F.;
Ley, S. V. Org. Biomol. Chem. 2003, 1, 15.
(4) (a) Schneider, C. Angew. Chem., Int. Ed. 1998, 37, 1375. (b) Norcross,
R. D.; Paterson, I. Chem. ReV. 1995, 95, 2041.
It was envisaged that an orthogonally protected 1,3,5-
triketone could be generated by this strategy through the
conjugate addition of a dithiol to a bis-ynone at â- and â′-
alkyne carbon atoms. To the best of our knowledge the
synthesis and use of orthogonally masked 1,3,5-triketones
10.1021/ol034248f CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/14/2003

we planned to intercept the resulting acetylide anion with a
formylating agent. Standard metalation with n-BuLi followed
by interception with N-formylmorpholine furnished the
desired ynals 2 in good yield. Addition of a second alkyne
anion followed by oxidation formed the bis-ynone 3 as a
simple three-step sequence (for some examples see Table
1).
Table 1. Preparation of Ynones from Dibromoalkenea
To investigate the dithiol additions to bis-ynones, initial
studies were based on the conditions that had been developed
for our earlier work on additions to ynones.3
After brief optimization studies the ideal conditions were
found to require treatment of the bis-ynone 3 with propane-
1,3-dithiol (2.2 equiv) and sodium methoxide (2.2 equiv) in
methanol-dichloromethane (1:1, 0.05 M) at -10 °C. In
some cases it was found that bases such as sodium hydroxide
or tetrabutylammonium hydroxide were required to effect
reaction and that tetrahydrofuran was on occasion preferred
to dichloromethane to aid the overall solubility of the reaction
mixture.
a Reagents and conditions: (a) (i) n-BuLi, THF, -78 to -30 °C, 1 h;
(ii) N-formylmorpholine, rt, 3 h. (b) HCCMgBr, THF, -78°C. (c) Dess-
Martin periodinane, CH2Cl2.
The dithiol addition takes place smoothly on a range of
bis-ynones 3 (Table 2). For example, straightforward alkyl
groups (entry 1), heteroatom substituents (entries 1-3), and
aryl groups (entry 4) are well tolerated and generate the
corresponding bis-dithiane ketones 4 in good yield. Of
particular importance were the successful reactions of
terminal bis-ynones 3d-e. The products 4d-e, which
contain a terminal dithiane moiety, can be further utilized
in C-C bond-forming processes through interception of their
2-lithio derivative with electrophiles.6 On the basis of
experimental observations it is noticeable that the terminal
alkyne unit of the bis-ynone reacts almost instantaneously
to form the 1,3-dithiane moiety. However, when the pro-
pargylic center is more heavily substituted (3e) the addition
also report the use of these masked 1,3,5-triketone units as
key intermediates for the preparation of a range of oxygen-
containing heterocycles that can be used in natural product
synthesis.
This approach would exploit the effective C-C bond-
forming potential of alkynes with the proposed tandem dithiol
functionalization of the bis-ynone to rapidly generate a
versatile trione fragment. Accordingly, initial studies were
aimed at developing a method for the facile assembly of the
required bis-ynones 3 (Table 1). Taking advantage of the
powerful Corey-Fuchs protocol5 for the synthesis of alkynes
Table 2. Dithiol Addition to Bis-ynonesa
a Reagents and conditions: Propane-1,3-dithiol, NaOMe, MeOH-CH2Cl2, -10 °C to rt.
1148
Org. Lett., Vol. 5, No. 7, 2003

is slower but the reaction still proceeds well to form the
desired bis-dithiane ketone 4e in good yield.
Scheme 3. Synthesis of Bis-ynone 8a
In a previous communication it was shown that â-keto
dithianes decorated with suitable functional groups could be
used to form spiroketals.3 As part of ongoing natural product
programs we were interested in using these substrates to form
functionalized tetrahydropyranyl systems that could be
applied toward the synthesis fragments of polyketide-derived
natural products such as Lyngbouilloside7 and Callipeltoside
A8 (Figure 1).
a Reagents and conditions: (a) Pentan-3-one, TsOH, 53 °C, 16
h. (b) PCC, 4 Å mol sieves, CH2Cl2, rt, 1 h. (c) PPh3, CBr4, CH2Cl2,
0 °C, 5 min. (d) (i) n-BuLi, THF, -78 °C, 1 h; (ii) N-
formylmorpholine, rt, 17 h. (e) HCCMgBr, THF, -78 to -30 °C,
30 min. (f) Dess-Martin periodinane, CH2Cl2, rt, 30 min.
cellent yield to form bis-dithiane ketone 9 (Scheme 4).
Removal of the pentyl ketal with camphorsulfonic acid in
methanol and concomitant cyclization afforded the C1-C8
fragment 10 of Lyngbouilloside as a 4:1 mixture of the enol
ether 10 and the corresponding hemiketal in 70% (82%
brsm.).
Figure 1. Lyngbouilloside and Callipeltoside A.
Scheme 4. Synthesis of the C1-C8 Fragment of
Lyngbouilloside is a marine macrolide isolated from
lyngbya bouilonii and displays a modest cytotoxicity. It
comprises a 14-membered macrolide system, a tetrahydro-
pyranyl hemiketal, a rhamnose pyranoside derivative, and a
diene side chain. The absolute stereochemistry has not been
determined. The C1-C8 unit is ideally suited to demon-
strate the applicability of the dithiol-bis-ynone addition
reaction.
Lyngbouillosidea
Our progress toward the synthesis of the C1-C8 fragment
is shown in Schemes 3 and 4. Triol 5 was protected as its
3-pentylidene ketal and the remaining hydroxyl group
oxidized to the corresponding aldehyde with pyridinium
chlorochromate (PCC). The aldehyde was converted into ynal
7 by using a modified Corey-Fuchs protocol. Formation of
the dibromoalkene 6 followed by acetylide formation and
interception of the resulting anion with N-formylmorpholine
furnished ynal 7 in 70% yield. Addition of ethynylmagne-
sium bromide to ynal 7 formed the bis-ynol and Dess-Martin
oxidation9 generated the bis-ynone 8 in 95% yield over the
two steps.
a Reagents and conditions: (a) Propane-1,3-dithiol, NaOMe,
MeOH-CH2Cl2, -10 °C to rt, 17 h. (b) CSA, HC(OMe)3, MeOH,
45 °C, 5 h.
To further highlight the potential of this method the
synthesis of the C1-C9 fragment of Callipeltoside A was
also envisaged (Schemes 5). Diol 11 was converted to
dibromoalkene 12 in 65% yield over a four-step sequence.
Use of the modified alkynylation protocol (as previously
described) generated ynal 13 in good yield. Finally, treatment
of 13 with ethynylmagnesium bromide followed by mild
oxidation with Dess-Martin periodinane gave the bis-ynone
in good yield.
Using the standard conditions, the double addition of
propane-1,3-dithiol to bis-ynone 8 proceeded in ex-
(5) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(6) For an example of dithiane coupling in natural product synthesis
see: Smith, A. B., III; Adams, C. M.; Lodise Barbosa, S. A.; Degnan, A.
P. J. Am. Chem. Soc. 2003, 125, 350.
(7) Tan, L. T.; Marquez, B. L.; Gerwick, W. H. J. Nat. Prod. 2002, 65,
925.
(8) (a) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis,
C. J. Am. Chem. Soc. 1996, 118, 11085. (b) Zampella, A.; D’Auria, M. V.;
Minale, L.; Debitus, C. Tetrahedron 1997, 53, 3243. (c) Trost, B. M.;
Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124,
10396.
The dithiol addition reaction of the bis-ynone was poor
in the presence of the C7 PMB group; however, when this
group was removed the dithiol addition on 14 (C7-OH)
proceeded smoothly. Interestingly, upon isolation we found
that the bis-dithiane ketone 15 had in fact cyclized to form
the desired tetrahydropyranyl hemiketal 16 in 65% yield. This
pleasing result generates the C1-C9 Callipeltoside A
(9) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4383.
Org. Lett., Vol. 5, No. 7, 2003
1149

The dithiol addition to bis-ynones has enabled the rapid
generation of the C1-C8 fragment of Lyngbouilloside 10 and
the C1-C9 fragment of Callipeltoside A 16 and we are
currently investigating the synthesis of the remainder of these
molecules. This work will be reported in due course.
Scheme 5. Synthesis of the C1-C9 Fragment of Callipeltoside
Aa
In summary, we have developed an efficient method for
the conjugate addition of dithiols to bis-ynones. The resulting
â,â′-bis-1,3-dithiane ketones are isolated in excellent yields
across a range of substrates. The potential of these masked
1,3,5-triketone systems as versatile platforms for the syn-
thesis of polyketide natural products is highlighted through
the synthesis of the tetrahydropyranyl ring systems of
Lyngbouilloside and Callipeltoside A.
Acknowledgment. We thank the EPSRC (to H.F.S.), the
British Ramsay Memorial Trust and Magdalene College for
Fellowship (to M.J.G.), and the Novartis Research Fellowship
(to S.V.L.) for financial support.
a Reagents and conditions: (a) PMPCH(OMe)2, p-TsOH, CHCl3,
rt, 1.5 h. (b) DIBAL-H, CH2Cl2, -10 °C, 2 h. (c) Dess-Martin
periodinane (DMP), CH2Cl2, rt, 2 h. (d) PPh3, CBr4, CH2Cl2, 0 °C,
1 h. (e) (i) n-BuLi, THF, -78 °C, 1 h; (ii) N-formylmorpholine, rt,
3 h. (f) HCCMgBr, THF, -78 to -30 °C, 0.5 h. (g) DMP, CH2Cl2,
rt, 3 h. (h) DDQ, CH2Cl2, pH 7 buffer, rt, 14 h. (i) Propane-1,3-
dithiol, NaOMe, MeOH-CH2Cl2, -10 °C to rt, 17 h.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
fragment 16 directly from bis-ynone 14 making the overall
processes highly efficient.
OL034248F
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Org. Lett., Vol. 5, No. 7, 2003