Silenes in organic synthesis: A short synthesis of prelactone B

Article abstract of DOI:10.1039/b608989e

The development of a synthetic methodology for the generation of silacyclohexenes through the cycloaddition of silenes with dienes and their subsequent elaboration to δ-lactones was discussed. It was found that the allyl silane component of the silacycloh

Full text of DOI:10.1039/b608989e

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Silenes in organic synthesis: a short synthesis of prelactone B†
Jonathan D. Sellars and Patrick G. Steel*
Received 26th June 2006, Accepted 7th July 2006
First published as an Advance Article on the web 20th July 2006
DOI: 10.1039/b608989e
A sequence involving dihydroxylation and acid induced frag-
mentation of silene generated silacyclohexenes represents the
key step in a concise synthetic route to b-hydroxy-d-lactones.
accessed through hydroboration of the silacyclochexene with the
regiochemistry directed by the allyl silane unit followed by alcohol
protection, Fleming–Tamao oxidation and oxidative cyclisation
of the resulting diol. Although hydroboration afforded the desired
d-hydroxy silane we were unable to enhance the yield beyond ca.
45% and more importantly the subsequent steps proved inefficient.
Consequently we turned to explore alternative alkene oxidation
protocols. Ultimately dihydroxylation of the olefinic bond under
standard catalytic conditions4 afforded the silacyclic diols 10–12 in
excellent yield. At this stage, simple flash column chromatography
allowed separation of the minor silacycle stereoisomers providing
the desired diols 10a and 10b as single isomers.‡ Stereochemical
assignment of the required C-3 hydroxy unit was confirmed by 1H
NMR NOESY experiment, Fig. 1.
d-Lactones, specifically b-hydroxy-d-lactones, are found as com-
ponents of many bioactive natural products. In addition they also
represent useful building blocks for the synthesis of more complex
structures. The prelactones, 1–4 are a sub-group of this class of
compounds isolated from various polyketide macrolide-producing
microorganisms. First isolated from the bafilomycin-producing
Streptomyces griseus, by Bindseil and Zeeck in 1993,1 prelactone B
(1) represents an early metabolite in the biosynthesis of polyketide
antibiotics. Although a direct product of the polyketide synthase
(PKS) enzyme responsible for the synthesis of the macrolide,
prelactone B is not incorporated into the natural macrolide and it
is believed that it is a shunt product of the biosynthetic pathway.
Reflecting the general interest in this biosynthetic pathway and
the potential of these compounds in other synthetic strategies a
number of synthetic routes have been reported.2
Fig. 1 Selected NOESY correlations for 10 and 14.
With the correct C-3 stereochemistry established, treatment
with BF3·2AcOH complex exploited the directing effect of the
silicon atom to afford, following oxidation under Fleming–Tamao
conditions, the corresponding allylic alcohol 13 without loss of
stereochemical integrity.5 Preliminary attempts to hydroborate the
terminal alkene at this stage were complicated by difficulties in
isolation of the resultant triols. Consequently, selective monopro-
tection of the diol at the allylic position was achieved on treatment
with TBDMSCl as confirmed by 1H NMR NOESY studies, Fig. 1.
Initial attempts at hydroboration of the protected diols 14
with borane–dimethylsulfide complex yielded, after oxidation,
a 1 : 1 mixture of regioisomeric alcohols. However, the use of
dicyclohexylborane directed the hydroboration to the terminal
end of the alkene with only trace amounts of the regioisomeric
product.6 Subsequent TPAP–NMO oxidation generated the lac-
tones. Without purification, silicon deprotection using Et3N·3HF
then afforded prelactone B 1 and the C-5 phenyl analogue 16 in
We have recently described the development of a new synthetic
methodology for the generation of silacyclohexenes through the
=
[4 bu¯ 2] cycloaddition of silenes (compounds containing a Si C
double bond) with dienes and their subsequent elaboration to d-
lactones.3 In this communication we describe how the allyl silane
component of the silacyclohexene can be used to provide a stereo-
controlled synthetic route to b-hydroxy-d-lactones exemplified by
a short synthesis of prelactone B.
The synthesis begins with the silene–diene Diels–Alder reaction
which produces the silacyclohexenes 7–9 in good overall yield,
favouring the product 7 arising from a Z(Si) silene 6 reacting
in an endo Si–Ph orientation (7a : 8a : 9a, 70 : 20 : 10;
7b : 8b : 9b, 80 : 20 : 0), Scheme 1. These are obtained as
an inseparable mixture of isomers with the minor components
reflecting the presence of small amounts of exo addition and trace
amounts of the adducts of the alternative E(Si) silene. Our initial
synthetic plan suggested that the desired hydroxylactones could be
1
excellent overall yield. The H NMR, 13C NMR, IR and mass
spectra of these products were all in excellent agreement with
previously published data.2
In conclusion silene–cycloaddition chemistry enables a concise,
novel and flexible approach to the total synthesis of b-hydroxy-
d-lactones, typified by prelactone B. Current work is focused on
introducing enantioselectivity into this sequence and extending
the methodology to more highly substituted d-lactone natural
products.
Department of Chemistry, University of Durham, Science Laboratories,
South Road, Durham, UK DH1 3LE. E-mail: p.g.steel@durham.ac.uk;
Fax: 44 (0)191 384 4737; Tel: bu¯44 (0)191 334 2131
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra for all new compounds. See DOI: 10.1039/b608989e
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Org. Biomol. Chem., 2006, 4, 3223–3224 | 3223
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0.15 mmol) in acetone–water (2.1 ml, 20 : 1) was treated with NMO
(0.04 g, 0.3 mmol) and cooled to 0 ◦C. The solution was then treated
with a catalytic amount of osmium tetroxide (0.002 g, 0.007 mmol)
and reacted for 45 min. The reaction mixture was then treated with aq.
Na2S2O3 and extracted with EtOAc (3 × 5 ml). The combined organic
layers were dried over MgSO4, filtered, concentrated and dried in vacuo.
Flash chromatography (pet. ether–ether [1 : 1], [1 : 2]) afforded the title
compound 10a as a yellow oil (0.06 g, 32%); Rf (pet. ether–ether 1 : 1)
0.3 as a single diastereoisomer; tmax (thin film) 3498–3211, 2950, 2932,
2898, 2864, 1426, 1096, 1022, 992, 832, 731, 697 cm−1; dH (500 MHz;
CDCl3) 7.53–7.51 (2H, m, Ar–H), 7.31–7.30 (3H, m, Ar–H), 4.22–4.19
(1H, m, 5-H), 3.51–3.46 (1H, m, 4-H), 2.29–2.22 (1H, m, 3-H), 2.17–2.10
(1H, m, 2ꢀ-H), 1.39–1.34 (1H, dd, J 14, 9, 6-HH), 1.21–1.15 (1H, m,
6-HH), 1.09–1.07 (1H, dd, J 9, 6, 2-H), 1.05–1.04 (3H, d, J 7, CHCH3),
0.98–0.96 (3H, d, J 7, 3-CH3), 0.92–0.90 (3H, d, J 7, CHCH3), 0.21
(9H, s, Si(CH3)3); dC (126 MHz, CDCl3) 140.2 (ipso-Ar–C), 134.4 (Ar–C),
128.5 (Ar–C), 128.0 (Ar–C), 78.8 (4-C), 70.2 (5-C), 36.8 (2-C), 35.8 (3-C),
29.1 (2ꢀ-C), 23.8 (CHCH3), 19.4 (3-CH3), 16.5 (6-C), −0.4 (Si(CH3)3);
dSi (100 MHz, CDCl3) −17.90, −23.36; m/z (ESbu¯ ) 359 (M bu¯ Nabu¯ );
HRMS (ESbu¯ ) found 359.18339 (C18H32Si2O2Na requires 359.18330).
(3RS,4RS,5RS)-3,5-Dihydroxy-4,6-dimethylheptene (13a). To a solution
of silacyclic diol 10a (0.12 g, 0.3 mmol) in dry dichloromethane (4 ml)
was added trifluoroborane–acetic acid complex (0.09 ml, 0.6 mmol).
The solution was stirred for 15 min at room temperature then mixed
with saturated NaHCO3 solution (5 ml) and extracted with DCM (3 ×
10 ml). The combined organic layers were dried over MgSO4, filtered,
concentrated and dried in vacuo to give a colourless oil which was used
immediately in the following step. To the colourless oil was added KHCO3
(0.1 g, 1.0 mmol) and KF (0.04 g, 0.7 mmol). The mixture was dissolved
in methanol–THF solution (1 : 1, 4 ml) and a 35% w/w solution of
H2O2 in water (0.4 ml, 3.9 mmol) was added. The mixture was heated to
reflux and stirred for 1 h. The mixture was then allowed to cool to room
temperature and saturated Na2S2O3 solution (5 ml) was added together
with EtOAc (10 ml). The aqueous layer was separated and extracted with
EtOAc (3 × 10 ml). The combined organic layers were dried over MgSO4,
filtered, concentrated and dried in vacuo. Flash chromatography (pet.
ether–ether [9 : 1], [4 : 1], [3 : 2], [1 : 1], [1 : 2]) gave the title compound
13a as a colourless oil (0.02 g, 64%); Rf ( (pet. ether–ether 1 : 1) 0.3 as a
single diastereoisomer; tmax (thin film) 3525–3134, 2962, 2870, 1459, 1427,
1118, 1081, 974, 919, 844, 697, 639 cm−1; dH (500 MHz; CDCl3) 5.97–5.90
(1H, ddd, J 16, 10, 5, 2-H), 5.31–5.27 (1H, d, J 18, 1-Ha), 5.20–5.18 (1H,
d, J 10, 1-Hb), 4.41 (1H, s, 3-H), 3.40–3.39 (1H, m, 5-H), 3.11 (1H, –OH),
2.53 (1H, –OH) 1.92–1.86 (1H, qd, J 7, 3, 4-H), 1.85–1.79 (1H, m, 6-H),
0.95–0.93 (3H, d, J 8, 6-CH3), 0.93–0.92 (3H, d, J 8, 7-H3), 0.88–0.87
(3H, d, J 7, 4-CH3); dC (126 MHz, CDCl3) 138.9 (2-C), 115.4 (1-C), 79.8
(5-C), 75.1 (3-C), 39.6 (4-C), 30.6 (6-C), 20.0 (6-CH3), 16.0 (7-C), 12.2
(4-CH3); m/z (ESbu¯ ) 181.2 (M bu¯ Nabu¯ ); HRMS (ESbu¯ ) Found 181.11991
(C9H18O2Na requires 181.11990).
i
=
Scheme 1 Reagents and conditions (R = Pr, b R Ph): (i) BuLi, 10 mol%
LiBr, 1,3-pentadiene, THF, −20 ◦C (7a : 8a : 9a [70 : 20 : 10] 40%, 7b :
8b : 9b [80 : 20 : 0] 45%); (ii) OsO4 (cat.), NMO, acetone–H2O (20 : 1),
1 K. U. Bindseil and A. Zeeck, Helv. Chim. Acta, 1993, 76, 150.
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Chakraborty and S. Tapadar, Tetrahedron Lett., 2003, 44, 2541; A. G.
Csaky, M. Mba and J. Plumet, SYNLETT, 2003, 2092; D. Enders and
M. Haas, SYNLETT, 2003, 2182; L. Fournier, A. Gaudel-Siri, P. J.
Kocienski and J. M. Pons, SYNLETT, 2003, 107; P. M. Pihko and A.
Erkkila, Tetrahedron Lett., 2003, 44, 7607; V. K. Aggarwal, I. Bae and
H. Y. Lee, Tetrahedron, 2004, 60, 9725; L. C. Dias, L. J. Steil and V. D.
Vasconcelos, Tetrahedron: Asymmetry, 2004, 15, 147; A. A. Salaskar,
N. V. Mayekar, A. Sharma, S. K. Nayak, A. Chattopadhyaya and S.
Chattopadhyay, Synthesis, 2005, 2777; J. S. Yadav, M. S. Reddy and
A. R. Prasad, Tetrahedron Lett., 2005, 46, 2133.
3 M. B. Berry, R. J. Griffiths, M. J. Sanganee, P. G. Steel and D. K.
Whelligan, Org. Biomol. Chem., 2004, 2, 2381; M. J. Sanganee, P. G.
Steel and D. K. Whelligan, Org. Biomol. Chem., 2004, 2, 2393.
4 V. Van Rheenen, D. Y. Cha and W. M. Hartley, Org. Synth., 1988, Coll.
Vol. VI, 342.
0
◦C to r.t., 30 min (10a 32%, 11/12a 12%; 10b 56%, 11/12b 26%);
(iii) BF3·2AcOH, DCM, r.t., 5 min then KHCO3, KF, H2O2, THF, reflux,
1 h (13a 64%, 13b 72%); (iv) TBSCl, imidazole, DCM, r.t., 1 h (14a 52%,
14b 70%); (v) (C6H11)2BH, THF, 0 ◦C to r.t., 1 h then H2O2, aq. NaOH
(3 M), reflux, 1 h (15a 60%, 15b 70%); (vi) TPAP, NMO, 4A MS, DCM,
r.t., 1 h, then Et3N·3HF, THF, 24 h (1 90%, 16 (R = Ph) 100%).
We thank the EPSRC for financial support of this work
(studentship to JDS); Dr A. M. Kenwright for assistance with
NMR experiments; Dr M. Jones and The EPSRC National Mass
Spectrometry Service, Swansea for mass spectra.
Notes and references
5 G. R. Jones and Y. Landais, Tetrahedron, 1996, 52, 7599.
6 H. C. Brown, A. K. Mandal and S. U. Kulkarni, J. Org. Chem., 1977,
42, 1392.
‡ (1SR,2RS,3SR,4SR,5SR)-4,5-Dihydroxy-3-methyl-1-phenyl-2-prop-2ꢀ-yl-
1-trimethylsilylsilacyclohexane (10a). A solution of silacycles 7–9a (0.05 g,
3224 | Org. Biomol. Chem., 2006, 4, 3223–3224
This journal is
The Royal Society of Chemistry 2006
©