Synthesis of β-ketophosphonates from thioester intermediates: A stereocontrolled route to the C29-C35 fragment of the halichondramides

Article abstract of DOI:10.1055/s-1998-1805

An efficient synthesis of β-ketophosphonates from t-butyl thioesters using the lithium anion of either methane- or ethane-phosphonate is described. The elaboration of a range of substrates to intermediates in natural product syntheses via the Horner Wadsworth Emmons reaction is then discussed.

Full text of DOI:10.1055/s-1998-1805

8
28
LETTERS
Synthesis of β-ketophosphonates from Thioester Intermediates: A Stereocontrolled Route to
the C C Fragment of the Halichondramides
2
9- 35
Alison N. Hulme,* Garnet E. Howells, Rachel H. Walker
Department of Chemistry, The University of Edinburgh, King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK
e-mail: Alison.Hulme@ed.ac.uk
Received 13 May 1998
Abstract: An efficient synthesis of β-ketophosphonates from t-butyl
thioesters using the lithium anion of either methane- or ethane-
phosphonate is described. The elaboration of a range of substrates to
intermediates in natural product syntheses via the Horner Wadsworth
Emmons reaction is then discussed.
complex natural products, where it has found use both in fragment
9
10
11
coupling, and macrocyclisation reactions. In a recent paper, Mosset
identified number of distinct routes to the synthesis of β-
a
ketophosphonates. Of particular relevance to this work is the reaction of
α-carbanionic alkylphosphonates with a range of substrates including
1
1,12
9-11,13
aldehydes (followed by oxidation),
carboxylic acid esters,
N-methoxy-N-methylcarboxamides
11,14
carboxylic acid chlorides,
In a recent synthesis of a model for the cytotoxic marine metabolite
(Weinreb amides),1
1,15
and 3-acylthiazolidine-2-thiones.11,10b In this
1
octalactin A 1, we identified a key target 2 (Figure 1). Retrosynthetic
Letter, we report an extension of this strategy to the reaction of α-
carbanionic alkylphosphonates with a range of functionalised thioesters.
analysis of this compound led us to propose a stereocontrolled boron-
mediated anti aldol between t-butyl thiopropionate and
a
1
,7-difunctional aldehyde to set the C -C8 stereochemistry. We were
We found that we could carry out a displacement reaction on t-butyl
thiopropionate using the lithiated anion of dimethyl ethanephosphonate
(Scheme 1), to give the β-ketophosphonate 4 in 76% yield. This was
then coupled to isovaleraldehyde using the mild activated barium
7
then faced with the problem of how to extend the carbon backbone of
the resultant acyclic β-hydroxy thioester to give enone 3, an advanced
precursor to compound 2.
8c
hydroxide HWE conditions of Paterson, to give trisubstituted enone
7
c
5
,
also in excellent yield (85%). When the displacement reaction was
16
carried out using the t-butyldiphenylsilyl protected anti aldol adduct 6,
it was similarly successful, generating β-ketophosphonate 7 as a ~3:1
mixture of diastereomers in 73% yield.17 This could be converted via
the HWE reaction to enone 8 in 71% yield without epimerisation of the
anti stereochemistry derived from the aldol adduct.
Fig. 1
Thioesters have been used as intermediates in a number of important
natural product syntheses. However, their elaboration has largely been
2
2f
2f
limited to the generation of carboxylic acids, esters, lactones,
3
a
3 b
aldehydes, and β-ketoamides. The potential for the use of thioesters
in natural product synthesis has greatly increased recently due to a
number of developments in aldol methodology, where particularly
difficult aspects of stereocontrol have been tackled effectively. Chiral
boron reagents developed by Gennari, and Masamune have been
shown to give high levels of both diastereo- and enantio-control with
thioester substrates, resulting in the formation of anti aldol adducts in
4
5
This displacement reaction was then extended to a series of anti aldol
18
adducts 9, of the type required for the generation of enone 3 (Table 1).
>
95% ds and >95% ee. Similarly, in the development of new chiral
Although these reactions were initially conducted using t-BuLi in the
presence of DMPU (1 eq.) (Method A), we later discovered that
deprotonation by n-BuLi was equally effective, and that the addition of
DMPU was not required (Method B). In general, the best results were
obtained when the solution of the carbanion was added via cannula to a
precooled solution of the thioester. It was also noted that the anion
generated from dimethyl ethanephosphonate was considerably more
sluggish in its reactions than its diethyl counterpart and generally
required either a higher reaction temperature (-42 °C c.f. -78 °C), or
longer reaction times, for the reaction to proceed to completion.
Lewis acids for the catalytic asymmetric Mukaiyama acetate aldol
reaction, many authors have concentrated on the use of thioester
substrates. Thus, new methodology for their synthetic elaboration is
6
particularly important.
The Horner Wadsworth Emmons (HWE) reaction between alkyl
phosphonates and aldehydes is frequently used for the synthesis of di-
and tri-substituted double bonds.7 a,b The development of a number of
mild conditions for the HWE reaction between β-ketophosphonates and
8
aldehydes, makes this reaction particularly suited to the synthesis of

August 1998
SYNLETT
829
From these results it can be seen that a range of protecting groups is
tolerated by these reaction conditions. Where the lithiated anion of
dimethyl methanephosphonate was used to generate β-ketophosphonate
1
0, a di-substituted double bond was generated by the HWE reaction
1
(
Entry 4). The E-geometry of this double bond was confirmed by the H
nmr coupling constant (J = 15.8 Hz). As with aldol adduct 6, the
reactions of dialkyl ethanephosphonate anions with aldol adducts 9 were
found to produce a ~3:1 ratio of diastereomers 10, which were converted
7
c
to a single E-double bond geometry in the HWE reaction.
We have used these conditions in the synthesis of enone 3 (P=P’=TBS,
Entry 6) which has subsequently been used in the construction of key
1
target 2. In order to demonstrate the general applicability of this
protocol we also chose to synthesise β-ketophosphonate 11, which has
been used by Pattenden as the C29-C35 section of the halichondramide
9
d
backbone (12, Scheme 2). Aldehyde 13 was generated through
monoprotection of butane-1,4-diol as its t-butyldimethylsilyl ether,19
followed by oxidation by o-iodoxybenzoic acid. Enolisation of t-butyl
c
thiopropionate with Et N and Hex BBr and reaction with aldehyde 13
3
2
generated the anti aldol adduct in 81% yield as a single diastereomer.
Subsequent methylation of the free hydroxyl was achieved using
Meerwein’s salt in the presence of Proton-Sponge® (Aldrich) to give
protected thioester 14. Phosphonate displacement was carried out using
two equivalents of the anion following the protocol described in Method
1
8
B. A previously unobserved minor impurity, formed by elimination of
1
methanol from β-ketophosphonate 11, was noted in the H nmr of the
crude reaction mixture. However, this impurity was found to be readily
separable by HPLC allowing the isolation of 11 in 64% yield.20 Thus
the synthesis was successfully completed giving (±)-11 in 5 steps with
an overall yield of 38%, which compares extremely favourably with the
earlier synthesis.
Acknowledgements. We thank the EPSRC (GR/95309810 to G.E.H.),
The University of Edinburgh (Vacation Scholarship to R.H.W.), The
Royal Society and GlaxoWellcome for the support of this work.
In conclusion, we have developed an efficient route for the conversion of
functionalised thioesters to β-ketophosphonates and we have
demonstrated the addition of these β-ketophosphonates to aldehydes
under mild Horner Wadsworth Emmons reaction conditions. This
protocol considerably extends the options available for the elaboration
of thioesters in natural product synthesis, as demonstrated by the
synthesis of enone 3 and β-ketophosphonate 11.
References and Notes
1
Hulme, A. N.; Howells, G. E. Tetrahedron Lett. 1997, 38, 8245-
248.
8
2
a) Gennari, C.; Pain, G.; Moresca, D. J. Org. Chem. 1995, 60,
6248-6249; b) Paterson, I.; Hulme, A. N. J. Org. Chem. 1995, 60,
3
288-3300; c) Chamberlin, A. R.; Dezube, M.; Reich, S. H.; Sall,
D. J. J. Am. Chem. Soc. 1989, 111, 6247-6256; d) Masamune, S.;
Lu, L. D.-L.; Jackson, W. P.; Kaiho, T.; Toyoda, T. J. Am. Chem.
Soc. 1982, 104, 5523-5526; e) Kaiho, T.; Masamune, S.; Toyoda,

8
3
30
LETTERS
SYNLETT
T. J. Org. Chem. 1982, 47, 1612-1614; f) Masamune, S.
Aldrichimica Acta 1978, 11, 23-32 and references cited therein.
15 a) Blackwell, C. M.; Davidson, A. H.; Launchbury, S. B.; Lewis,
C. N.; Morrice, E. M.; Reeve, M. M.; Roffey, J. A. R.; Tipping, A.
S.; Todd, R. S. J. Org. Chem. 1992, 57, 1935-1937; b) Dufour, M.-
N.; Jouin, P.; Poncet, J.; Pantaloni, A.; Castro, B. J. Chem. Soc.,
Perkin Trans. I 1986, 1895-1900.
a) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112,
050-7051; b) Ley, S. V.; Smith, S. C.; Woodward, P. R.
Tetrahedron 1992, 48, 1145-1174.
7
1
6
Aldol adduct 6 was prepared in two steps from t-butyl
thiopropionate and hexanal, as shown below:
4
5
6
Gennari, C.; Moresca, D.; Vieth, S.; Vulpetti, A. Angew. Chem.
Int. Ed. Engl. 1993, 32, 1618-1621.
Masamune, S.; Sato, T.; Kim, B.M. Wollmann, T. A. J. Am. Chem.
Soc. 1986, 108, 8279-8281.
a) Review: Mukaiyama, T. Aldrichimica Acta 1996, 29, 59-76;
b) Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117,
2363-2364; c) Review: Bach, T. Angew. Chem. Int. Ed. Engl.
1994, 33, 417-419.
1
7
In this and subsequent reactions, the relative stereochemistry α to
the phosphonate was not determined.
7
8
Reviews: a) Nicolaou, K. C.; Harter, M. W.; Gunzner, J. L.; Nadin,
A. Liebigs Ann. Rec. 1997, 1283-1301; b) Maryanoff, B. E.; Reitz,
A. B. Chem. Rev. 1989, 89, 863-927; c) E-alkene geometry
assigned on the basis of literature precedent.
18 Typical procedure for Method B: to a solution of diethyl
ethanephosphonate (5.84 g, 35.11 mmol) in THF (20 ml) was
added n-BuLi (1.54 M solution in hexanes, 22.80 ml, 35.11 mmol)
dropwise at -78 °C under an atmosphere of argon. After stirring
for 50 min at -78 °C the light yellow solution was transferred via
cannula into a solution of thioester 9 (Entry 6, 4.02 g, 7.98 mmol)
in THF (15 ml) at -78 °C and the resulting solution was stirred for
a further 50 min before carefully pouring onto a saturated aqueous
a) Rubsam, F., Evers, A. M., Michel, C., Giannis, A. Tetrahedron
1997, 53, 1707-1714; b) Bonadies, F.; Cardilli, A.; Lattanzi, A.;
Orelli, L. R.; Scettri, A. Tetrahedron Lett. 1994, 35, 3383-3386;
c) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774-776;
d) Koskinen, A. M. P.; Koskinen, P. M. Synlett 1993, 501-502.
9
For recent examples, see: a) Mulzer, J.; Berger, M. Tetrahedron
Lett. 1998, 39, 803-808; b) Nakada, M.; Kobayashi, S.; Iwasaki,
S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035-1038; c) Boger, D.
L.; Curran, T. T. J. Org. Chem. 1992, 57, 2235-2244; d) Kiefel, M.
J.; Maddock, J.; Pattenden, G. Tetrahedron Lett. 1992, 33, 3227-
solution of NH Cl (150 ml). The mixture was extracted with
4
CH Cl , washed with brine, dried (MgSO ) and the volatiles
2
2
4
removed under reduced pressure. Purification of the crude
material by flash chromatography with hexane/EtOAc (3:2) as
eluent afforded the β-ketophosphonate 10 (Entry 6) as a clear oil
3230; e) Han, Q.; Wiemer, D. F. J. Am. Chem. Soc. 1992, 114,
7692-7697; f) Hoffmann, R. W.; Ditrich, K. Liebigs Ann. Chem.
1990, 23-29.
4
1
1
.23 g (94%).
0 (P=P’=TBS, n=5), 3.3:1 mixture of diastereomers: IR (neat)
712, 1251 cm ; H NMR (200 MHz, CDCl ) 4.26-4.06 (4H, m,
-
1 1
3
10
For recent examples, see: a) Stocksdale, M. G.; Ramurthy, S.;
Miller, M. J. J. Org. Chem. 1998, 63, 1221-1225; b) Astles, P. C.;
Thomas, E. J. J. Chem. Soc., Perkin Trans. I 1997, 845-856;
c) Johnson, C. R.; Zhang, B. R. Abstr. Papers, Am. Chem. Soc.
P(OCH CH ) ), 4.02-3.95 (0.23H, m, CHOTBS), 3.94-3.84
2
3 2
(
0.77H, m, CHOTBS), 3.63 (2H, t, J = 6.4 Hz, CH OTBS), 3.55-
2
2
.98 (2H, m, CHC(O) and CHP(O)), 1.65-1.20 (13H, m, CH x 5,
2
CH(CH )P(O)), 1.37 (6H, t, J = 7.1 Hz, CH CH x 2), 1.15 (0.7H,
3
2
3
1996, 211, 125 (ORGN); d) Marshall, J. A.; DuBay, W. J. J. Org.
d, J = 7.3 Hz, CH(OTBS)CHCH ), 1.02 (2.3H, d, J = 6.6 Hz,
3
Chem. 1994, 59, 1703-1708; e) Roush, W. R.; Warmus, J. S.;
Works, A. B. Tetrahedron Lett. 1993, 34, 4427-4430.
CH(OTBS)CHCH ), 0.93 (9H, s, C(CH ) ), 0.90 (2.1H, s,
3
3 3
C(CH ) ), 0.89 (6.9H, s, C(CH ) ), 0.08 (6H, s, SiCH ), 0.07
3
3
3 3
3
13
1
1
2
Delamarche, I.; Mosset, P. J. Org. Chem. 1994, 59, 5453-5457,
and references cited therein.
(3.7H, SiCH ), 0.00 (2.3H, SiCH ); C NMR (62.9 MHz,
3 3
CDCl ) major diastereomer 209.1 (d, J = 3.6 Hz), 74.7, 63.07,
3 P-C
2.3 (2C, d, J = 6.7 Hz), 50.7, 48.2 (d, J = 25.5 Hz), 33.4,
2.7, 29.6, 25.9 (3C), 25.8, 25.7 (3C), 22.8, 18.2, 17.8, 16.2 (2C),
2.4, 10.4 (d, 2JP-C = 5.7 Hz), -4.5, -4.8, -5.4 (2C), minor
diastereomer 208.9 (d, J
JP-C = 6.7 Hz), 50.3, 45.0 (d, J
2
2
1
6
3
1
1
a) Pipelier, M.; Ermolenko, M. S.; Zampella, A.; Olesker, A.;
Lukacs, G. Synlett 1996, 24-26; b) Paterson, I.; Yeung, K.-S.;
Tetrahedron Lett. 1993, 34, 5347-5350.
P-C P-C
2
= 4.5 Hz), 73.1, 63.14, 62.3 (2C, d,
P-C
1
3
a) Deziel, R.; Plante, R.; Caron, V.; Grenier, L.; Llinas-Brunet, M.;
Duceppe, J. S.; Malenfant, E.; Moss, N. J. Org. Chem. 1996, 61,
2
1
= 28.6 Hz), 33.4, 32.7, 29.6,
P-C
2
5.9 (3C), 25.8, 25.7 (3C), 24.5, 18.2, 17.9, 16.2 (2C), 12.3, 11.4
2901-2903; b) Neidlen, R.; Feistauer, H. Helv. Chim. Acta 1996,
79, 895-913; c) Konoike, T.; Araki, Y. J. Org. Chem. 1994, 59,
7849-7854; d) Mulzer, J.; List, B. Tetrahedron Lett. 1994, 35,
9021-9024.
2
(
[
d,
J
= 6.9 Hz), -4.7, -4.8, -5.4 (2C); FABMS 581 (24%,
P-C
+
M+H] ), 523 (100), 449 (78), 279 (99).
1
9
0
McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388-3390.
1
4
a) Takemoto, M.; Koshida, A.; Miyazima, K.; Suzuki, K.; Achiwa,
K. Chem. Pharm. Bull. 1991, 39, 1106-1111; b) Kuo, F.; Fuchs, P.
L. Synth. Commun. 1986, 16, 1745-1759; c) Honda, M. Katsuki,
T.; Yamaguchi, M. Tetrahedron Lett. 1984, 35, 3857-3860.
2
We are grateful to Prof. Pattenden for supplying spectral data for
1
1, which was found to be in good agreement with our own data.