Toward the Total Synthesis of Natural Peloruside A: Stereoselective Synthesis of the Backbone of the Core

Article abstract of DOI:10.1021/ol036058a

(Equation presented) An asymmetric synthesis of the backbone of the core of natural peloruside A is described. Key elements include reiterative application of enantioselective allylation to establish the stereochemistry of the backbone and a double asymme

Full text of DOI:10.1021/ol036058a

ORGANIC
LETTERS
2004
Vol. 6, No. 1
71-74
Toward the Total Synthesis of Natural
Peloruside A: Stereoselective Synthesis
of the Backbone of the Core
Bo Liu and Wei-Shan Zhou*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China
zhws@mail.sioc.ac.cn
Received October 21, 2003
ABSTRACT
An asymmetric synthesis of the backbone of the core of natural peloruside A is described. Key elements include reiterative application of
enantioselective allylation to establish the stereochemistry of the backbone and a double asymmetric aldol reaction to successfully couple
two fragments.
Marine sponges have been extensively investigated as an
important source of biologically active marine natural
products that have proven to be invaluable as agents for
pharmacological manipulation of cellular biochemical path-
ways. Peloruside A (1), together with mycalamide A (2) and
pateamine (3), was isolated from the New Zealand marine
sponge Mycale sp. by Northcote and coworkers.1 Its structure
and relative stereochemistry were determined by extensive
NMR studies, which showed that peloruside A is a poly-
oxygenated 16-membered macrolide with a branched and
Z-configured trisubstituted olefin, containing a densely
functionalized pyranose ring adjacent to a gem-dimethyl
moiety. Although peloruside A bears some structural features
of both mycalamide A (gem-dimethyls and polyhydroxyla-
tion) and pateamine (macrolide ring), it does not appear to
be closely related biochemically.1a
Peloruside A (1) was found to be cytotoxic to P388 murine
leukemia cells at approximately 10 ng/mL (18 nM).1a It
induces biochemical changes consistent with apoptosis in a
(1) (a) West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem.
2000, 65, 445. (b) Hood, K. A.; Ba¨ckstro¨m, B. T.; West, L. M.; Northcote,
P. T.; Berridge, M. V.; Miller, J. H. Anti-Cancer Drug Des. 2001, 16, 155.
number of cultured mamalian cell lines.1b Further studies
(c) Hood, K. A.; West, L. M.; Rouwe´, B.; Northcote, P. T.; Berridge, M.
V.; Wakefield, S. J.; Miller, J. H. Cancer Res. 2002, 62, 3356.
have revealed that it exhibits microtubule-stabilizing activity
10.1021/ol036058a CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/13/2003

and arrests cells in the G2-M phase of the cell cycle, similar
to paclitaxel (Taxol).1c
A concise and stereoselective synthesis of 6 is illustrated
in Scheme 2. A substrate-control stereoselective allylation6
The unusual structure, potent biological activity, and
scarcity of peloruside A make it an attractive target for total
synthesis. Recently, an elegant total synthesis, followed by
comparison of the optical rotation and the biological activity
of the synthetic sample to those of the natural sample,
established the absolute configuration of peloruside A.2
Synthetic studies toward the fragments of it have been
reported by Paterson’s group3 and Ghosh’s group.4 Unfor-
tunately, since its absolute configuration was not clear in
advance, all their synthetic efforts were devoted to the
antipode of peloruside A. Herein, we would like to report
an asymmetric synthesis of the backbone of the core of
natural peloruside A.
Scheme 2 a
Our retrosynthetic plan is outlined in Scheme 1. Peloruside
A (1) can be achieved from a suitable seco acid (4) via
a Reagents and conditions. (a) Ref 6: diallyl zinc, THF, -10 to
20 °C, 85:15 dr, 83%. (b) PhCOOH, Ph3P, DIAD, THF, rt;
separation of diastereoisomers, 67%. (c) Cat. OsO4, NaIO4, THF-
H2O, rt. (d) allylB[(-)-Ipc2], ether, -78 °C, 72% for two steps
(after isolation of the diastereoisomer of 11). (e) MeI, NaH, THF,
rt, 92%. (f) H5IO6, EtOAc, 0 °C. (g) Me3Al, CH2Cl2, 0 °C. (h)
Dess-Martin periodinane, NaHCO3, CH2Cl2, rt, 81% for three
steps. (i) Ethylene glycol, cat. TsOH, PhH, reflux, 97%.
Scheme 1
of 8 in THF afforded 9 as a mixture of diastereoisomers (85:
15 dr) that were separated on silica gel after Mitsunobu
conversion of the free hydroxyl of 9 to give 10. Johnson-
Lemieux oxidation of 10, followed by stereoselective ally-
lation7 of the resultant aldehyde with B-allyldiisopino
campheyl borane in ether, resulted in alcohol 11, whose
1
absolute configuration was confirmed by HNMR analysis
of the corresponding (R)- and (S)-MTPA esters. After
methylation of the free hydroxyl of 11, the resulting
compound 12 then provided a facile entry to ketone 14 by a
three-step sequence, including oxidative cleavage of ac-
etonide,8 chemoselective addition of trimethyl aluminum to
the aldehyde group in the presence of the ester group,9 and
Dess-Martin oxidation of the corresponding alcohol. Protec-
tion of ketone 14 with ethylene glycol in benzene in the
presence of catalytic TsOH under reflux completed the
synthesis of fragment 6.
macrolactonization with simultaneous disconnection at C16-
C17 via Wittig reaction. Retrosynthetic analysis of advanced
intermediate 5 revealed the two subunits 6 and 7 with
disconnections at C10-C11 via an aldol transformation.
Although examples of analogous disconnection were infre-
quently encountered in total synthesis of natural products
structurally similar to peloruside A, we considered it ap-
plicable if suitable protective groups on the subunits were
selected wisely. Both fragment 6 and fragment 7 can be
derived from L-glyceraldelyde acetonide 8, which is readily
accessible.5
Our synthesis of fragment 7 commenced from alcohol 9
(85:15 dr), which acted as a common intermediate with the
synthesis of fragment 6 (Scheme 3). Methyl ether formation,
Johnson-Lemieux oxidation, and asymmetric allylation
provided alcohol 17, whose absolute configuration was
1
confirmed by HNMR spectra of its (R)- and (S)-MTPA
esters. It was notable that asymmetric allylation of aldehyde
(5) (a) Hubschwerlen, C. Synthesis 1986, 962. (b) Hubschwerlen, C.;
Specklin, J.-L.; Higelin, J. Org. Synth. 1993, 72, 1.
(6) Mulzer, J.; Angermann, A.; Mu¨nch, W. Liebigs Ann. Chem. 1986,
825.
(7) (a) Racherla, U. S.; Liao, Y.; Brown, H. C. J. Org. Chem. 1992, 57,
6614. (b) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(8) Li, L.; Wu, Y.; Wu, Y. J. Carbohydr. Chem. 1999, 18, 1067.
(9) Liu, B.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 4933.
(2) Liao, X.; Wu, Y.; De Brabander, J. K. Angew. Chem., Int. Ed. 2003,
42, 1648.
(3) Paterson, I.; Di Francesco, M. E.; Ku¨hn, T. Org. Lett. 2003, 5, 599.
(4) (a) Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44, 3967. (b)
Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44, 7659.
72
Org. Lett., Vol. 6, No. 1, 2004

did not occur under the normal conditions (NaH, PMBCl,
cat. TBAI, rt) but afforded 18 at an elevated temperature in
excellent yield. Compound 18 was advanced to diol 19 by
deprotection of the acetonide catalyzed by TsOH in methyl
alcohol. Since the selective protection of the secondary
hydroxyl as a MOM ether via formation of cyclic orthofor-
mate and then DIBAL-H reduction proved not to be
feasible,11 we turned to protection of the primary hydroxyl
as a TBDPS ether and then protection of the secondary
hydroxyl as a MOM ether 21. Johnson-Lemieux oxidation
and addition of (Z)-alkoxyallylborane,12 generated in situ,
to the corresponding aldehyde at low temperature produced
the desired homoallyl alcohol 23, which was methylated
(NaH, MeI) to provide 24. Following conversion into
aldehyde 26 after deprotection and then oxidation of the
primary hydroxyl of 25, an efficient isopropyl addition was
required to complete the synthesis of fragment 7.
Scheme 3 a
A model study (Scheme 4) revealed that with a Grignard
reagent as a nucleophilic agent, the aldehyde was mainly
Scheme 4
reduced to an alcohol via the transfer of hydride from the
isopropyl Grignard reagent. However, after several trials, we
found out that isopropyllithium13 freshly prepared from
isopropyl chloride and lithium was able to give the desired
product in a satisfactory yield (70%). Thus, isopropylation
of aldehyde 26 with isopropyllithium and Dess-Martin
oxidation of the resultant alcohol 27 produced ketone 7
smoothly.
The planned aldol coupling of fragment 6 and fragment 7
was crucial in our synthetic plan toward the backbone of
the core of peloruside A. To probe the optimal reaction
conditions, we decided to study related model reactions
(Scheme 5) patiently and carefully.
a Reagents and conditions. (a) MeI, KOH, DMSO, rt, 81%. (b)
Cat. OsO4, NaIO4, THF-H2O, rt. (c) allylB[(-)-Ipc2], ether, -78
°C, 75% for two steps (after isolation of the diastereoisomer of
17). (d) PMBCl, cat. TBAI, NaH, THF, reflux, 92%. (e) Cat. TsOH,
MeOH, rt, 96%. (f) HC(OMe)3, CH2Cl2, rt. (g) DIBAL-H, THF,
-78 °C to room temperature, 72% for two steps (after isolation of
the diastereoisomer of 17). (h) TBDPSCl, cat. DMAP, Et3N,
CH2Cl2, rt, quant. (i) MOMCl, iPr2NEt, CH2Cl2, rt, 91% based on
the recovery of starting material. (j) Cat. OsO4, NaIO4, THF-H2O,
rt. (k) 22, sBuLi, THF, -78 °C, 40 min; then (-)-Ipc2BOMe, -78
°C, 1.5 h; then aldehyde, -78 °C, 3.5 h; NaOH, 30% H2O2, ether,
rt, 8 h, 75% from 21. (l) MeI, NaH, THF, rt, 85%. (m) TBAF,
THF, rt, 96%. (n) Dess-Martin periodinane, CH2Cl2, rt. (o)
isopropyllithium, toluene, -78 °C to room temperature. (p) Dess-
Martin periodinane, NaHCO3, CH2Cl2, rt, 62% for three steps based
on the recovery of 25.
It was frustrating that no reaction occurred under standard
conditions of either BF3Et2O-14 or TiCl4 -promoted15 Mu-
(11) Yang, W.-Q.; Kitahara, T. Tetrahedron 2000, 56, 1451.
(12) (a) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc.
1988, 110, 1535. (b) Smith, A. L.; Pitsinos, E. N.; Hwang, C.-K.; Mizuno,
Y.; Saimota, H.; Scarlato, G. R.; Suzuki, T.; Nicolaou, K. C. J. Am. Chem.
Soc. 1993, 115, 7612.
(13) Applequist, D. E.; Peterson, A. H. J. Am. Chem. Soc. 1961, 83,
862.
(14) (a) Yokokawa, F.; Asano, T.; Shioiri, T. Tetrahedron 2001, 57, 6311.
(b) Sulikowski, G. A.; Lee, W.-M.; Jin, B.; Wu, B. Org. Lett. 2000, 2,
1439.
16 using (+)-DIPT modified allylboronate failed,10 while
using enantiopure B-allyl diisopinocampheyl borane deliv-
ered a good result. Protection of alcohol 17 as a PMB ether
(15) (a) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840. (b) Panek, J. S.; Jain, N. F. J. Org. Chem.
2001, 66, 2747.
(10) Ratio of the desired diastereoisomer of alcohol 17 to the undesired
one was determined to be ca. 1:4 on the basis of their isolated yields.
Org. Lett., Vol. 6, No. 1, 2004
73

the aldol coupling induced by LDA with 74:26 dr in 60%
yield based on 31% recovery of ketone 7. The orientation
of the newly formed hydroxyl of 5 was determined by -
Scheme 5
1
HNMR analysis of its MTPA esters (modified Mosher’s
method)19 to be the desired R form (Scheme 6).
Scheme 6 a
kaiyama aldol reaction of 29 and 28b, which was easily
i
derived from 28a. In the presence of TiCl4 and Pr2NEt at
-78 °C,16 ketone 28a was prone to decomposition and the
titanium enolate could not be formed to initiate the following
aldol reaction. Similarly, boron-mediated aldol conditions
(Cy2BCl, Et3N, ether, -78 °C)17 turned out to be another
failure, although they are extensively applied in the syntheses
of natural products. The amazing difficulty created by the
lack of reactivity of the aldol coupling, we think, might be
attributed to the structure of isopropyl ketone, which is
resistant to enolation or forms a bulky tetrasubstituted olefin
after enolation, preventing the approach of the aldehyde 29.
Thus, it is not surprising that LiHMDS proved to be another
ineffective agent due to its hindered structure. To our delight,
LDA-induced aldol reaction occurred in THF at -78 °C
giving an acceptable yield.18 It can be argued that a less
hindered base than LDA (such as LiNEt2) should be screened
experimentally. Indeed, we have observed that the R-stereo-
genic center of 28a experienced racemization to a small
extent, which indicates that a less hindered base would give
a lower regioselectivity in the course of enolation and thus
lead to more serious racemization of the adjacent stereogenic
center of ketone 28a. With these results in hand, we effected
a Reagents and conditions. (a) Cat. OsO4, NaIO4, THF-H2O,
rt. (b) 7, LDA, THF, -78 °C; then aldehyde 30, THF, -78 to -40
°C, 74:26 dr, 60%.
In summary, we accomplished the stereoselective synthesis
of the backbone of the core of peloruside A based on a
convergent strategy. A distinguishing feature is the reiterative
application of asymmetric allylation in either a substrate-
control or reagent-control manner to install the syn- and anti-
1, 3-diol functionality stereoselectively. This also allows the
homoallyl alcohol to act as an equivalent of a â-hydroxyl
aldehyde to ensure the stability of intermediates and the
feasibility in the course of diverse protection of hydroxyls.
Another feature can be attributed to the novel double
asymmetric aldol coupling in the last step, which provides a
distinct method for asymmetric synthesis of structural
analogues. Work toward the total synthesis of peloruside A
is in progress in our laboratory and will be reported in due
course.
Supporting Information Available: Spectroscopic data
for compounds 5-7, 10-12, 14, 15, 17-20, and (R)- and
(S)-MTPA esters of 5, along with selected copies of NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Koch, G.; Loisekur, O.; Fuentes, D.; Jantsch, A.; Altmann, K. H.
Org. Lett. 2002, 4. 3811.
(17) Enders, D.; Ince, S. J. Synthesis 2002, 619.
(18) Protective groups of the R-hydroxyl group also proved to be
important since ketone 28c (Scheme 5) could not give an aldol product
with aldehyde 29 even under the LDA conditions.
OL036058A
(19) Chow, S.; Kitching, W. Tetrahedron: Asymmetry 2002, 13, 729.
74
Org. Lett., Vol. 6, No. 1, 2004