An Evans-Tishchenko-ring-closing metathesis approach to medium-ring lactones

Article abstract of DOI:10.1021/ol062932z

A new approach to the synthesis of medium-ring lactones is reported based on sequential Evans-Tishchenko and ring-closing metathesis (RCM) reactions. High diastereoselectivity (>95:5) is demonstrated in the Evans-Tishchenko reaction of unsaturated aldehyd

Full text of DOI:10.1021/ol062932z

ORGANIC
LETTERS
2007
Vol. 9, No. 4
631-634
An Evans−Tishchenko−Ring-Closing
Metathesis Approach to Medium-Ring
Lactones
Jennifer I. Aird, Alison N. Hulme,* and John W. White
School of Chemistry, The UniVersity of Edinburgh, West Mains Road,
Edinburgh EH9 3JJ, UK
alison.hulme@ed.ac.uk
Received December 4, 2006
ABSTRACT
A new approach to the synthesis of medium-ring lactones is reported based on sequential Evans
−Tishchenko and ring-closing metathesis
(RCM) reactions. High diastereoselectivity (>95:5) is demonstrated in the Evans
-hydroxy ketones, and conditions for the RCM cyclization of the resultant dienes have been optimized to give high yields of medium ring
lactones. The synthetic utility of this sequence is demonstrated through generation of the fully functionalized core of octalactin A.
−Tishchenko reaction of unsaturated aldehydes with unsaturated
â
Medium-ring lactones (8- to 11-membered rings)1 have
attracted considerable interest due to the range of biological
activity exhibited by natural products containing the lactone
functionality. There are a relatively small number of methods
used for closure of the lactone ring, the most popular
traditionally being macrolactonization under high dilution
conditions.2 However, the yields obtained in the synthesis
of medium-ring lactones using this method are rather
unpredictable, and while a few notable examples exist where
high-yielding macrolactonizations of medium rings have been
carried out,3 there is still considerable scope for the develop-
ment of other approaches.4
and benzaldehyde to give the pinacol adduct (PhCHO)2SmI‚
SmI3.5 Evans-Tishchenko cyclization of the medium-ring
lactone in the presence of 30 mol % of this catalyst was
thought to be initiated by hemiacetal formation (TS I)
followed by highly diastereoselective hydride transfer (>95:
5) to form the anti-related hydroxylactone 3. However, this
Scheme 1. Intramolecular Evans-Tishchenko Approach to the
Octalactin A (1) Core5
We have previously reported a novel Evans-Tishchenko
macrolactonization procedure in the synthesis of a model of
the eight-membered lactone, marine polyketide octalactin A
(1).5 In this approach (Scheme 1) a seco-aldehyde precursor
2 was treated with a preformed samarium(III) catalyst
prepared by mixing a THF solution of samarium diiodide
(1) Rousseau, G. Tetrahedron 1995, 51, 2777-2849.
(2) For a comprehensive review of macrolactonizations in the synthesis
of natural products, see: Parenty, A.; Moreau, X.; Campagne, J.-M. Chem.
ReV. 2006, 106, 911-939.
(3) (a) Shiina, I.; Hashizume, M.; Yamai, Y.; Oshiumi, H.; Shimazaki,
T.; Takasuna, Y.; Ibuka, R. Chem. Eur. J. 2005, 11, 6601-6608. (b) Busek,
K. R.; Sato, N.; Jeong, Y. J. Am. Chem. Soc. 1994, 116, 5511-5512.
10.1021/ol062932z CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/27/2007

approach to the octalactin core suffered from a number of
deficiencies: First, competitive epimerization of the R-methyl
group in the enone precursor was observed due to a relatively
slow rate of cyclization. Second, the cyclized material was
isolated in only a low yield, independent of the nature or
mol % of catalyst used, the reaction time, or temperature.
Finally, as an approach to a complex natural product such
as octalactin A, the macrolactonization of a fully function-
alized seco-aldehyde was not readily adaptable to a conver-
gent strategy, making it rather unattractive. For these reasons,
we sought to investigate an alternative approach to the
synthesis of medium-ring lactones, such as that found in
octalactin A.
Scheme 2. Eight-Membered Ring Lactone Synthesis Using an
Evans-Tishchenko-RCM Strategy
Of particular interest were a limited number of recent
reports of the application of ring-closing metathesis (RCM)
to the synthesis of these challenging medium-ring lac-
tones.6,7,8 If the RCM reaction could be used in combination
with the Evans-Tishchenko reaction as a fragment coupling
strategy (rather than as the means of lactonization), we
believed that we would be able to generate a highly
diastereoselective and convergent approach to the synthesis
of medium ring lactones. In order to test this hypothesis, we
first required verification that the Evans-Tishchenko reaction
could be successfully carried out using an unsaturated
aldehyde. We thus set out to develop a very simple model
of the octalactin core (Scheme 2). The required â-hydroxy
ketone substrate was prepared in three steps by sodium
borohydride reduction of 3-oxohex-5-enoate 4,9 conversion
to the Weinreb amide 5 and reaction of the amide with
methyl Grignard.10 Treatment of â-hydroxy ketone 6 with a
preformed samarium benzaldehyde pinacol adduct and pent-
4-enal gave the anti-diol monoester 7 in high yield (85%)
and with high diastereoselectivity (>95:5).11 On this simple
model significant acyl migration was observed to form an
undesired ester side product.12 However, it was found that
immediate protection of the free hydroxyl as the correspond-
ing silyl ether prevented this. Ring closure of the protected
ester 8, using G1 catalyst [PhCHdRuCl2(PCy3)2]13 at room
temperature overnight, gave the unsaturated lactone 9 in
quantitative yield. This simple lactone was found to be
somewhat unstable in the presence of any traces of the
ruthenium catalyst which remained after purification; in later
studies, these problems were negated by removal of ruthe-
nium from the reaction mixture through complexation with
DMSO.14
With these promising results in hand, a new retrosynthesis
of the octalactin core was envisaged (Scheme 3). In this
alternative route, key intermediate 10 was targeted. Success-
ful conversion of 10a (P ) TBS) to octalactin A has been
reported by Busek et al., through directed epoxidation of the
C(10)-C(11) double bond, oxidation of the C(9) alcohol to
the corresponding ketone, and deprotection of the silyl
ether,3b followed by hydrogenation of the oxecene double
bond and oxidative cleavage of the PMB protecting group.6b
We set out to synthesize the related compound 10b (P )
PMB)15 using our combined Evans-Tishchenko-RCM
approach. Retrosynthetic analysis of the metathesis precursor
11 led to the identification of two fragments: the C(1)-
C(5) unsaturated aldehyde 12 and â-hydroxy ketone 13,
which in turn was readily identified as the product of a
Horner-Wadsworth-Emmons (HWE) coupling of â-keto-
phosphonate 14 and C(11)-C(15) aldehyde 15. Synthesis
of the protected â-ketophosphonate 14 was facilitated by the
(4) For alternative approaches to the synthesis of medium ring lactones,
see: (a) O’Sullivan, P. T.; Buhr, W.; Fuhry, M. A. M.; Harrison, J. R.;
Davies, J. E.; Feeder, N.; Marshall, D. R.; Burton, J. W.; Holmes, A. B. J.
Am. Chem. Soc. 2004, 126, 2194-2207. (b) Pilli, R. A.; Victor, M. M.
Tetrahedron Lett. 2002, 43, 2815-2818. (c) Ohi, H.; Inoue, S.; Iwabuchi,
Y.; Irie, H.; Hatakeyama, S. Synlett 1999, 1757-1759. (d) Inoue, S.;
Iwabuchi, Y.; Irie, H.; Hatakeyama, S. Synlett 1998, 735-736. (e) Bermejo,
A.; Tormo, J. R.; Cabedo, N.; Estornell, E.; Figadere, B.; Cortes, D. J.
Med. Chem. 1998, 41, 5158-5166. (f) Tapiolas, D. M.; Roman, M.; Fenical,
W.; Stout, T. J.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 4682-4683.
(5) Hulme, A. N.; Howells, G. E. Tetrahedron Lett. 1997, 38, 8245-
8248.
(6) RCM approaches to the synthesis of 8-membered ring lactones: (a)
Mohapatra, D. K.; Yellol, G. S. ArkiVoc 2003 (ix), 21-33. (b) Buszek, K.
R.; Sato, N.; Jeong, Y. Tetrahedron Lett. 2002, 43, 181-184. (c) Chatterjee,
A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783-3784.
(7) RCM approaches to the synthesis of 9-membered ring lactones: (a)
Takahashi, T.; Watanabe, H.; Kitahara, T. Heterocycles 2002, 58, 99-104.
(b) Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi,
H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81-88.
(8) RCM approaches to the synthesis of 10-membered ring lactones: (a)
Kangani, C. O.; Bru1ckner, A. M.; Curran, D. P. Org. Lett. 2005, 7, 379-
382. (b) Davoli, P.; Spaggiari, A.; Castagnetti, L.; Prati, F. Org. Biomol.
Chem. 2004, 2, 28-47. (c) Anand, R. V.; Baktharaman, S.; Singh, V. K. J.
Org. Chem. 2003, 68, 3356-3359. (d) Gurjar, M. K.; Nagaprasad, R.;
Ramana, C. V. Tetrahedron Lett. 2003, 44, 2873-2875. (e) Diez, E.; Dixon,
D. J.; Ley, S. V.; Polara, A.; Rodriguez, F. Synlett 2003, 1186-1188. (f)
Liu, D.; Kozmin, S. A. Org. Lett. 2002, 4, 3005-3007. (g) Fu¨rstner, A.;
Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J.
Am. Chem. Soc. 2002, 124, 7061-7069.
(11) A preformed Sm(III) catalyst was used to prevent any side reactions
between the unsaturated aldehyde and Sm(II): Edmonds, D. J.; Johnston,
D.; Procter, D. J. Chem. ReV. 2004, 104, 3371-3403.
(12) Mahrwald, R. Curr. Org. Chem. 2003, 7, 1713-1723.
(13) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(14) Ahn, Y. M.; Yang, K.; Georg, G. I. Org. Lett. 2001, 3, 1411-
1413.
(15) It was anticipated that the differential protection of fragments 14
and 15 would allow a facile deprotection of the precursor to â-hydroxy
ketone 13, making 10b a more attractive target.
(9) Bennett, F.; Knight, D. W.; Fenton, G. J. Chem. Soc., Perkin Trans.
1 1991, 133-140.
(10) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
632
Org. Lett., Vol. 9, No. 4, 2007

Scheme 3. Retrosynthetic Analysis of Octalactin A (1)
Scheme 5. Evans-Tishchenko RCM Strategy Using
Unfunctionalized â-Hydroxy Enone 19
unprotected substrate with G2 catalyst [PhCHdRuCl2(PCy3)-
(H2IMes)]19 allowed the isolation of unsaturated lactone 21.
Close examination of the H NMR of the isolated material
use of our recently reported thiol equivalent of the Abiko-
Masamune auxiliary (Scheme 4).16 Dicyclohexylboron triflate
1
revealed a minor side product which was thought to result
from competitive metathesis of the trisubstituted double bond
(9:1 ratio, 21:22). These promising results encouraged us to
pursue this strategy for the synthesis of the fully functional
octalactin precursor 10b.
Scheme 4. Synthesis of Unsaturated â-Ketophosphonate 14
Synthesis of the C(1)-C(5) aldehyde 12 was achieved
using a six-step sequence. Reaction of the (E)-crotylborane
Scheme 6. Synthesis of Aldehyde Fragments 15 and 12
mediated aldol reaction of propionate thioester 16 with
acrolein gave an excellent yield of the desired anti-aldol
adduct 17 in a 93:7 diastereomeric ratio (anti/anti). Silyl
protection followed by facile displacement of the thiol
auxiliary in 18 with the lithium anion of diethyl ethanephos-
phonate gave â-ketophosphonate 14 as a 4:1 ratio of
diastereomers (66% overall yield from acylated auxiliary 16).
Before investigating the use of functionalized aldehyde
fragments 15 and 12, â-ketophosphonate 14 was condensed
with isovaleraldehyde under mild Horner-Wadsworth-
Emmons conditions to furnish a protected enone (Scheme
5).17 This protected enone was then treated with HF in
acetonitrile to reveal â-hydroxy enone 19. Evans-Ti-
shchenko coupling to 5-hexenal gave the monoesterified anti-
diol 20 in excellent yield (93%) and with good diastereo-
selectivity (90:10 anti/syn).18 RCM of this more demanding
synthesized from freshly prepared (-)-Ipc2BOMe with
aldehyde 2320 gave homoallylic alcohol 24 as a single
diastereomer (71% yield, 82% ee). PMB group transfer via
the intermediate MPM acetal was effected through DDQ
oxidation of 24 followed by regioselective DIBAL-H reduc-
(16) Fanjul, S.; Hulme, A. N.; White, J. W. Org. Lett. 2006, 8, 4219-
4222.
(17) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774-776.
(18) Silyl protection of 20 was not required as no significant acyl
migration was observed with this more sterically demanding substrate.
(19) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(20) Zampella, A.; Sepe, V.; D’Orsi, R.; Bifulco, G.; Bassarello, C.;
D’Auria, M. V. Tetrahedron: Asymmetry 2003, 14, 1787-1798.
Org. Lett., Vol. 9, No. 4, 2007
633

tion.21 Finally, Swern oxidation gave aldehyde 12 (Scheme
6). For the synthesis of C(11)-C(15) aldehyde 15, homo-
allylic alcohol 25 was generated through reaction of (-)-
Ipc2BOMe-derived allylborane with isobutyraldehyde (87%
yield, 84% ee).22 Protection of the secondary alcohol as its
PMB ether (26), and one-pot oxidative cleavage of the double
bond,23 gave aldehyde 15.
In order to investigate the synthesis of key intermediate
10b, HWE coupling of protected â-ketophosphonate 14 with
â-hydroxy aldehyde 15 was carried out (Scheme 7). The
Gratifyingly, under these conditions, ester 28 was isolated
in 96% yield and as a single diastereomer. However, when
this triene was subjected to the same RCM conditions as
used on model substrate 20 [G2 (20 mol %), CH2Cl2, reflux,
24 h], a 1:1 mixture of the desired lactone 10b and
cyclopentene 29 was isolated in good overall yield (74%).24
Use of the G1 catalyst, lower reaction temperatures, micro-
wave conditions, alternative solvents such as toluene, or
conversion of the C(9)-C(11) allylic alcohol to the corre-
sponding epoxy alcohol 3025 or epoxy ketone 31 did not
improve the yield of the desired cyclization, with essentially
no identifiable products of ring closure isolated under any
of these conditions. Finally, in an attempt to reduce any
competitive chelation which might be hindering the desired
cyclization process, a Ti(OiPr)4 cocatalyst was used along
with the G2 catalyst.26 Under these conditions, our target
lactone 10b was isolated as the sole reaction product in 70%
yield.
Scheme 7. Synthesis of Key Intermediate 10b
In conclusion, we have shown that use of the Evans-
Tishchenko reaction is a viable coupling strategy for a range
of unsaturated partners and offers highly regioselective ester
formation while at the same time conveying excellent
diastereoselectivity. The RCM reaction, although it is subject
to subtle steric and electronic influences, is again demon-
strated as an efficient means of effecting medium ring
closure. Overall, a combined Evans-Tishchenko-RCM
approach provides a highly convergent strategy for the
construction of medium rings; the longest linear sequence
for the construction of lactone 10b is merely eight steps.
Acknowledgment. We thank the EPSRC (DTA student-
ships to J.I.A. and J.W.W.) for financial support of this work
and the Royal Society of Edinburgh/Scottish Executive
(Research Support Fellowship to A.N.H.).
Supporting Information Available: Experimental pro-
cedures for the synthesis of compounds 14, 19-21, 12, 15,
and 27-10b. This material is available free of charge via
the Internet at http://pubs.acs.org.
desired â-hydroxy enone 27 was isolated as a single double-
bond isomer after HF deprotection of the silyl ether. Evans-
Tishchenko fragment coupling of 27 was carried out in the
presence of 2 equiv of the functionalized aldehyde 12.
OL062932Z
(21) Kocienski, P. J. Protecting Groups, 3rd ed.; Georg Thieme Verlag:
Stuttgart, 2004.
(24) Presumably introduction of the C(4) allylic methyl group in 28
(which is absent in 20) renders the desired RCM relatively less favorable;
hence, a shift from a 9:1 to 1:1 ratio of products occurs.
(25) The epoxide stereochemistry in 30 and 31 is assumed on the basis
of literature precedent for epoxidation of the related lactones.
(26) Furstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130-
9136.
(22) (a) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401-
404. (b) Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C. Org. Lett.
2005, 7, 223-226.
(23) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org. Chem. 2002,
67, 1982-1992.
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Org. Lett., Vol. 9, No. 4, 2007