Synthesis of the C12-C24 fragment of peloruside A by silyl-tethered diastereomer-discriminating RCM

Article abstract of DOI:10.1016/j.tetlet.2008.09.133

The C12-C24 fragment of peloruside A has been synthesized using, as a key step, a silyl-tethered ring closing metathesis reaction to form the C16-C17 (Z)-alkene. The metathesis reaction discriminates between diastereoisomers of the starting material. A diphenylsilyl bis-ether provides simultaneous protection for the C15 and C24 hydroxyl groups, and is expected to lead to high 1,5-anti selectivity in subsequent aldol reactions of the methyl ketone, allowing for a convergent stereoselective synthesis of peloruside A.

Full text of DOI:10.1016/j.tetlet.2008.09.133

Tetrahedron Letters 49 (2008) 7021–7023
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of the C12–C24 fragment of peloruside A
by silyl-tethered diastereomer-discriminating RCM
*
Emma M. Casey, Paul Teesdale-Spittle, Joanne E. Harvey
School of Chemical and Physical Sciences and School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The C12–C24 fragment of peloruside A has been synthesized using, as a key step, a silyl-tethered ring
closing metathesis reaction to form the C16–C17 (Z)-alkene. The metathesis reaction discriminates
between diastereoisomers of the starting material. A diphenylsilyl bis-ether provides simultaneous pro-
tection for the C15 and C24 hydroxyl groups, and is expected to lead to high 1,5-anti selectivity in sub-
sequent aldol reactions of the methyl ketone, allowing for a convergent stereoselective synthesis of
peloruside A.
Received 21 August 2008
Accepted 22 September 2008
Available online 26 September 2008
Keywords:
Metathesis
Stereoselectivity
Silyl tether
Ó 2008 Elsevier Ltd. All rights reserved.
Natural product synthesis
The isolation of peloruside A from the marine sponge Mycale
hentscheli was reported in 2000 by Northcote et al.1 Miller and
co-workers established peloruside A to be a potent cytotoxic agent
with microtubule stabilizing characteristics similar to those of pac-
litaxel and docetaxel.2 Moreover, peloruside A has a microtubule
binding site different from that of the taxoid drugs, and has lower
susceptibility to the action of drug efflux pumps. When added to
cancer cells in combination with taxoid-site drugs, peloruside A
displays synergy, which enhances the antimitotic action.3 These
features make it exciting as a pre-clinical drug candidate.
Although Northcote and West were able to determine the rela-
tive stereochemistry of peloruside A through extensive NMR stud-
ies, the absolute stereochemistry was not revealed until the first
total synthesis was completed by De Brabander and co-workers.4
Since then, total syntheses have been reported by the research
groups of Taylor5 and Ghosh.6
Our efforts towards the synthesis of peloruside A (1) are based
around a convergent strategy, which invokes an aldol coupling of
two main fragments: a C1–C11 aldehyde 2 and a C12–C24 methyl
ketone 3 (Scheme 1). The synthesis of a protected form of com-
pound 3 using silyl-tethered ring closing metathesis is the subject
of this Letter. Alternative fragments of peloruside A related to 3
have been reported by several groups.7
HO
OH
O
1
OMe
3
15
HO
24
18
O
O
15
24
19
OH
6
3
O
12
HO
20
HO
11
9
OMe
MeO
O
OMe
12
OH
HO
1
1
HO
HO
O
11
O
OMe
OH
2
Scheme 1. Structure and retrosynthetic analysis of peloruside A.
and dichlorodiphenylsilane, to produce diene 5. Ring closing
metathesis (RCM) of this diene is used to access compound 4.
The diphenylsilyl bis-ether of 4 provides simultaneous protection
for the C15 and C24 hydroxyl groups, and is integral to our global
approach to the synthesis of peloruside A. The structure of com-
pound 4 enables three key strategic advantages:
(1) Compound 4 may be generated by silyl-tethered RCM8 of
diene 5, which will produce the C16–C17 alkene with the desired
(Z)-geometry. Silyl-tethered RCM reactions are surrogates for
cross-metathesis processes,8 with the added benefit that they con-
trol the geometry of the alkene produced, especially if the ring
formed is small- to medium-sized.8,9
Our retrosynthesis of a suitably protected form of the C12–C24
ketone 3, viz. compound 4 (Scheme 2), is succinct and establishes a
convergent synthesis that relies on the one-pot coupling of three
components: 2-ethylbut-3-en-1-ol (6), (S)-b-hydroxyketone (S)-7,
(2) Observations of kinetic resolution in silyl-tethered RCM
reactions, in some cases causing diastereoselectivity,9,10 indicate
an opportunity for stereochemical discrimination in the RCM reac-
tion that forms compound 4. This would provide control of the
* Corresponding author. Tel.: +64 4 4635956; fax: +64 4 4635237.
E-mail address: joanne.harvey@vuw.ac.nz (J. E. Harvey).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.133

7022
E. M. Casey et al. / Tetrahedron Letters 49 (2008) 7021–7023
catalyzed by (S)-ethylene-1,2-bis(N5-4,5,6,7-tetrahydro-1-inde-
R2
Ph
nyl)zirconium dichloride [(EBTHI)ZrCl2].13b The enantiomer of this
fragment [(S)-6] was used in De Brabander’s synthesis of ent-
peloruside A.4 Meanwhile, (S)-b-hydroxyketone (S)-7 was prepared
by enantioselective boron-mediated aldol reaction of acetone and
methacrolein (Eq. 2, Scheme 3).14
HO
Ph
OH
O Si
18
15
equivalent to
O
O
24
R1
O
R1
R2
12
3
4 R1 = CH2CH3, R2 = CH3
8 R1 = H, R2 = H
Formation of the diene 5 proceeded smoothly, in a one-pot reac-
tion, by treatment of dichlorodiphenylsilane with homoallylic alco-
hol ( )-6 followed, after 48 h, by b-hydroxyketone (S)-7 (Eq. 3,
Scheme 3).15 Due to the use of racemic 6, it was expected that this
reaction would provide two diastereomers. These were indeed evi-
dent in the 13C NMR spectrum by doubling of some peaks, but the
diastereomers were indistinguishable by 1H NMR spectroscopy.
Ring closing metathesis of the diene 5 proved far more chal-
lenging than the equivalent reactions of the des-ethyl variants 8
and 9 previously reported.12 Indeed, alkenes with alkyl groups in
the allylic position are notably sluggish in their engagement in
RCM reactions.16 Attempts were carried out on the mixture of
diene diastereoisomers 5 and, after initial tests with different
metathesis catalysts, Grubbs’ second generation catalyst was se-
lected as the most effective. After exploring an extensive matrix
of time, concentration, catalyst quantity, solvent and temperature,
conditions were found that provided the required dioxasilocine 4
(Scheme 4). These optimized conditions involved the slow addition
(over 24 h) of diene 5 to a dichloromethane solution of 9 mol % cat-
alyst at reflux, followed by heating for a further 24 h.17
9 R1 = H, R2 = CH3
R1
OH
R1
Ph
O
O
Ph
Si
Cl2SiPh2
O
6 R1 = CH2CH3
+
O
OH
R2
5 R1 = CH2CH3, R2 = CH3
R2
(S)-7 R2 = CH3
Scheme 2. Retrosynthetic analysis of the C12–C24 fragment.
relative stereochemistry at C15 and C18, delivering the desired
product (15S,18R)-4.
(3) Compound 4 should deliver the required 1,5-anti-induc-
tion11 during the subsequent aldol reaction with the C1–C11 alde-
hyde 2. Indeed, a preliminary study using simplified analogues of
the C12–C24 fragment of peloruside A, including 8 and 9 (Scheme
2), gave promising results with high 1,5-anti-induction in the sub-
sequent aldol reaction.12 This model study was performed on
dienes lacking the ethyl and/or methyl substituents, and it was
anticipated that inclusion of these substituents would be a simple
extension of the methodology.
Installation of the ethyl group into the homoallylic alcohol was
achieved by treatment of 2,5-dihydrofuran with ethylmagnesium
chloride, using zirconocene dichloride (Eq. 1, Scheme 3).13a This
provided racemic 2-ethylbut-3-en-1-ol [( )-6] in modest yields.
Ultimately, it was intended that enantiomerically pure alcohol
(R)-6 could be prepared by ethylmagnesation of 2,5-dihydrofuran
To our delight, the 13C NMR spectrum of dioxasilocine 4 dis-
played only one set of peaks, indicating the presence of only one
diastereoisomer. Additionally, NOE correlations provided unequiv-
ocal evidence for the correct relative stereochemistry as desired for
the side chain of peloruside A. In particular, a significant through-
space interaction was observed between H15 and H18, which is
consistent with (15S,18R)-stereochemistry, as required in the nat-
ural product (Fig. 1). Furthermore, there was no interaction seen
between H15 and either H19 or H20. Thus, it appears that a kinetic
resolution process occurs during this RCM reaction, such that the
required diastereoisomer is fortuitously isolated from the reaction
in approximately 35% overall yield, a very reasonable 70% of the
theoretical yield for this stereoisomer. The remainder of the mate-
rial appeared to be recovered starting diene and a product of cross-
metathesis.
EtMgCl,
(cp)2ZrCl2,
THF, 0 oC to RT
44 h
O
OH
1.
2.
Related resolution processes had been observed previously in
RCM reactions. Indeed, diastereoselectivity has been reported in si-
lyl-tethered RCM reactions forming eight-membered silyl bis-
ethers.9,10 In addition, Roulland and Ermolenko observed partial
( )-6, 45%
1. (+)-(Ipc)2BOTf,
OH
O
iPr2NEt, CH2Cl2, -78 oC,
O
dynamic kinetic resolution in RCM reactions of
a-alkylated ester
2. methacrolein, -20 oC,
16 h
3. pH 7.0 buffer, MeOH,
50% H2O2
diastereomers during their synthesis of the C12–C24 fragment of
peloruside A.7d
(
S
)-7, 60%
The stereoselectivity obtained in this RCM reaction can be jus-
tified by a mechanistic rationale related to that proposed by Evans
for the formation of dioxasilocines by diastereoselective silyl-teth-
ered RCM reaction (Fig. 2).10 The stereochemistry set by C15 and
the preference of the substituent at this position to reside in the
pseudoequatorial position lead to the observed kinetic resolution
of the C18 centre, since diene (15S,18R)-5 reacts via a favoured
Et3N, ( )-6
CH2Cl2
Ph
O
Ph
Cl
Cl
3.
Si
Si
0 oC to RT, 6 h
Reflux 36-48 h
Cl
Ph
Ph
Et3N, (S)-7,
CH2Cl2, RT, 16 h
cp = cyclopentadienyl;
Ipc = isopinocampheyl;
Tf =trifluoromethanesulfonyl
N
N
Mes
Mes
Cl
Ph
(9 mol%)
Ph
Ru
O
O
Ph
Ph
Cl
Ph
O Si
Si
PCy3
O
O
Ph
O
Ph
Si
18
CH2Cl2, reflux, 48 h19
O
15
O
O
20
5
4, 35-53%
Mes = 2,4,6-trimethylphenyl;
Cy = cyclohexyl.
5, 76% over 2 steps
Scheme 3. Synthesis of silyl-tethered diene 5.
Scheme 4. Synthesis of dioxasilocine 4 from diene 5 by silyl-tethered RCM.

E. M. Casey et al. / Tetrahedron Letters 49 (2008) 7021–7023
7023
Supplementary data
18
H
O
Si
O
15
O
O
H
Si
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.133.
H
H
O
O
References and notes
Figure 1. Key NOE correlations used in stereochemical assignment of dioxasilocine
4.
1. West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem. 2000, 65, 445.
2. Hood, K. A.; West, L. M.; Rouwé, B.; Northcote, P. T.; Berridge, M. V.; Wakefield,
S. J.; Miller, J. H. Cancer Res. 2002, 62, 3356.
3. (a) Gaitanos, T. N.; Buey, R. M.; Díaz, J. F.; Northcote, P. T.; Teesdale-Spittle, P.;
Andreu, J. M.; Miller, J. H. Cancer Res. 2004, 64, 5063; (b) Wilmes, A.; Bargh, K.;
Kelly, C.; Northcote, P. T.; Miller, J. H. Mol. Pharm. 2007, 4, 269.
4. Liao, X.; Wu, Y.; De Brabander, J. K. Angew. Chem., Int. Ed. 2003, 42, 1648.
5. Jin, M.; Taylor, R. E. Org. Lett. 2005, 7, 1303.
6. Ghosh, A. K.; Xu, X.; Kim, J.-H.; Xu, C.-X. Org. Lett. 2008, 10, 1001.
7. (a) Paterson, I.; Di Francesco, M. E.; Kühn, T. Org. Lett. 2003, 5, 599; (b) Ghosh, A.
K.; Kim, J.-H. Tetrahedron Lett. 2003, 44, 7659; (c) Taylor, R. E.; Jin, M. Org. Lett.
2003, 5, 4959; (d) Roulland, E.; Ermolenko, M. S. Org. Lett. 2005, 7, 2225; (e)
Chen, Z.; Zhou, W. Tetrahedron Lett. 2006, 47, 5289.
LnRu
Ph
Ph
O Si
O
H
O
O
O
(15S,18R)-5
Si
H
O
4
Favoured TS
8. (a) Cordier, C.; Morton, D.; Leach, S.; Woodhall, T.; O’Leary-Steele, C.; Warriner,
S.; Nelson, A. Org. Biol. Chem. 2008, 6, 1734. and references therein; (b) Kim, Y.
J.; Lee, D. Org. Lett. 2006, 8, 5219; (c) Denmark, S. E.; Yang, S-M. Org. Lett. 2001,
3, 1749.
9. (a) Boiteau, J.-G.; Van De Weghe, P.; Eustache, J. Tetrahedron Lett. 2001, 42, 239;
(b) Van De Weghe, P.; Aoun, D.; Boiteau, J-G.; Eustache, J. Org. Lett. 2002, 4,
4105.
Ph
LnRu
H
O
Si
Ph
O Si
O
O
O
(15S,18S)-5
H
O
10. Evans, P. A.; Cui, J.; Buffone, G. P. Angew. Chem., Int. Ed 2003, 42, 1734.
11. Paton, R. S.; Goodman, J. M. J. Org. Chem. 2008, 73, 1253.
12. Stocker, B. L.; Teesdale-Spittle, P.; Hoberg, J. O. Eur. J. Org. Chem. 2004, 330.
13. (a) Suzuki, N.; Kondakov, D. Y.; Takahashi, T. J. Am. Chem. Soc. 1993, 155, 8485;
(b) Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am. Chem. Soc. 1993, 115, 6997.
14. Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure, C. K.;
Norcross, R. D. Tetrahedron 1990, 46, 4663.
18-epi-4
Disfavoured TS
Figure 2. Proposed transition states for silyl-tethered ring closing metathesis
reactions of (15S,18R)-5 (favoured) and (15S,18S)-5 (disfavoured).
15. Synthesis of compound 5: To
a solution of dichlorodiphenylsilane (1.2 g,
4.7 mmol) in CH2Cl2 (25 mL) at 0 °C was added Et3N (350 mg, 3.5 mmol)
followed by a solution of alcohol ( )-6 (320 mg, 3.2 mmol) in CH2Cl2 (5 mL).
The reaction mixture was then warmed to 40 °C and stirred for 48 h. After this
time, the reaction mixture was cooled again to 0 °C and Et3N (1.0 g, 10.0 mmol)
was added, followed by b-hydroxyketone (S)-714 (1.0 g, 8.0 mmol) as a solution
in CH2Cl2 (5 mL). The resulting solution was warmed to rt and was stirred
overnight before being quenched with satd aq NaHCO3 (20 mL). The two-phase
mixture was then separated, and the aqueous phase was extracted with CH2Cl2
(3 Â 30 mL). The organic fractions were combined and washed with sat. aq.
brine (2 Â 20 mL) and water (15 mL), then dried (MgSO4), filtered and the
solvent was removed under reduced pressure. Gradient flash chromatography
(20:1–5:1 hexanes/EtOAc) provided diene 5 (980 mg, 76%) as a colourless oil.
1H NMR (500 MHz, CDCl3) d 7.62 (m, 4H), 7.42 (m, 2H), 7.36 (m, 4H), 5.63 (m,
1H), 5.05–5.01 (complex m, 2H), 4.90 (m, 1H), 4.77–4.75 (complex m, 2H), 3.64
(d, J = 6.1 Hz, 2H), 2.78 (dd, J = 14.6, 7.6 Hz, 1H), 2.55 (dd, J = 14.6, 5.1 Hz, 1H),
2.14 (m, 1H), 2.07 (s, 3H), 1.70 (s, 3H), 1.58 (m, 1H), 1.26 (m, 1H), 0.84 (t,
J = 7.6 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 206.6, 145.4, 139.96 and 139.92,
135.08 and 135.06, 132.74 and 132.65, 130.28 and 130.23, 127.75 and 127.68,
115.8, 112.28 and 112.27, 73.3, 66.2, 50.3, 47.89 and 47.88, 30.9, 23.5, 17.39
and 17.38, 11.5. IR (neat) 3100–2850, 1715, 1429, 1357, 1162, 1115, 1060, 997,
906, 740, 717, 699 cmÀ1 HRMS (ESI) calcd for C25H32O3SiNa+ (M+Na)+
431.2013, found 431.2028.
transition state, where the ethyl group also resides in the pseud-
oequatorial position. Conversely, the diastereoisomeric diene
(15S,18S)-5 must adopt a disfavoured transition state, having steric
interactions between the pseudoaxial ethyl group and one of the
phenyl rings, and thus reacts more slowly.
In one particular RCM experiment, we found the yield of dioxa-
silocine 4 to be 53%. This may have been due to loss of fidelity in
the stereocontrol of the kinetic resolution, with a small quantity
of 18-epi-4 formed through a slow RCM process via the disfavoured
transition state. However, this undesired minor product could not
be detected by either GC or spectroscopic means. An alternative
explanation is that there was a small measure of diastereoselectiv-
ity in the formation of the silyl bis-ether 5, which led to a greater
proportion of (15S,18R)-5 in the diastereomeric mixture of starting
diene. It is anticipated that stereoselective preparation of R-6 for
incorporation into diene 5 will lead to the RCM product in high
yield; yet the resolution process described above has merit as it
proceeds without the requirement for the costly (EBTHI)ZrCl2
catalyst.
In summary, we have completed the synthesis of the C12–C24
fragment of peloruside A in a form suitable for aldol coupling to
the C1–C11 portion. Ring closing metathesis using a silyl-tethered
diene provided target dioxasilocine 4 with the correct stereochem-
istry through kinetic resolution of a diastereoisomeric mixture of
diene 5.
16. (a) Grubbs, R. H. personal communication 2005; (b) Grubbs, R. H. Tetrahedron
2004, 60, 7117.
17. Synthesis of compound 4: To a solution of Grubbs’ second generation catalyst
(25 mg, 0.029 mmol) in refluxing CH2Cl2 (5 mL) was added diene 5 (120 mg,
0.32 mmol) in CH2Cl2 (50 mL) dropwise over 24 h. The refluxing solution was
then stirred for a further 24 h before being cooled to rt, and the solvent was
removed under reduced pressure. The resulting residue was redissolved in
10:1 hexanes/EtOAc and was filtered through a pad of silica gel. Activated
charcoal (50 wt. equiv) was then added, the suspension was stirred for 24 h,
then filtered, and the solvent was removed under reduced pressure. Flash
chromatography (50:1 hexanes/EtOAc) provided the dioxasilocine 4 (56 mg,
53%) as a white solid. 1H NMR (500 MHz, CDCl3) d 7.60 (m, 4H), 7.42–7.34
(complex m, 6H), 5.40 (dd, J = 8.9, 4.6 Hz, 1H), 5.06 (dd, J = 8.9, 0.9 Hz, 1H), 4.09
(dd, J = 10.6, 3.1 Hz, 1H), 3.61 (t, J = 10.5 Hz, 1H), 3.06 (dd, J = 15.3, 9.1 Hz, 1H),
2.75 (m, 1H), 2.61 (dd, J = 15.3, 4.6 Hz, 1H), 2.23 (s, 3H), 1.71 (d, J = 1.3 Hz, 3H),
1.35 (m, 1H), 1.20 (m, 1H), 0.90 (s, 3H). 13C NMR (125 MHz, CDCl3) d 207.5,
138.5, 134.7, 134.5, 134.40, 134.35, 134.31, 134.0, 133.5, 130.00, 129.95, 127.9,
127.8, 127.71, 127.65, 69.9, 67.5, 48.2, 42.5, 31.1, 24.7, 19.1, 12.0. IR (neat)
3070–2870, 1716, 1591, 1429, 1122, 739, 716 cmÀ1. HRMS (ESI) calcd for
C23H29O3Si+ (M+H)+ 381.1881, found 381.1862.
Acknowledgements
Financial support from the Foundation for Research, Science
and Technology, New Zealand is gratefully acknowledged. We sin-
cerely thank Dr. Bridget Stocker for synthesis advice, and Associate
Professor Peter Northcote and Dr. John Ryan for sharing their NMR
expertise.