Synthesis of the C(1)-C(12) segment of peloruside A by an α-benzyloxymethyl ketone aldol strategy

Article abstract of DOI:10.1021/ol036393z

The C(1)-C(12) segment of 16-membered antitumor macrolide peloruside A has been prepared by a BF₃·OEt₂-catalyzed Mukaiyama aldol reaction between a glucose-derived C(1)-C(7) aldehyde and a C(8)-C(12) α-benzyloxymethyl ketone. Exclusive 2,3-anti and moderate 3,5-anti/syn facial selectivity (3.5:1) was observed in the aldol reaction. The key C(1)-C(7) aldehyde contains the required stereochemistry at carbons two, three, and five, and has been efficiently prepared on multigram scales from commercial triacetyl D-glucal.

Full text of DOI:10.1021/ol036393z

ORGANIC
LETTERS
2004
Vol. 6, No. 5
663-666
Synthesis of the C(1)−C(12) Segment of
Peloruside A by an r-Benzyloxymethyl
Ketone Aldol Strategy
Darren W. Engers, Martin J. Bassindale, and Brian L. Pagenkopf*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
pagenkopf@mail.utexas.edu
Received December 8, 2003
ABSTRACT
The C(1)−C(12) segment of 16-membered antitumor macrolide peloruside A has been prepared by a BF3‚OEt2-catalyzed Mukaiyama aldol
reaction between a glucose-derived C(1)−C(7) aldehyde and a C(8)−C(12) r-benzyloxymethyl ketone. Exclusive 2,3-anti and moderate 3,5-
anti/syn facial selectivity (3.5:1) was observed in the aldol reaction. The key C(1)−C(7) aldehyde contains the required stereochemistry at
carbons two, three, and five, and has been efficiently prepared on multigram scales from commercial triacetyl D-glucal.
The sponges of the Mycale genus have proven to be a
valuable source for spectacular new antiviral and antitumor
natural products. In 2000, Northcote reported the isolation
of the 16-membered macrolide peloruside A (1, Figure 1)
and is thought to function like Taxol by inducing apoptosis
in the G2-M phase of the cell cycle through microtubule
stabilization.2,3 The promising therapeutic potential of peloru-
side A coupled with severely limited availability from natural
sources (3.0 mg was isolated from 170 g of frozen sponge)
necessitates that additional quantities for biological evaluation
be supplied through synthesis in the laboratory. Recently De
Brabander completed an elegant total synthesis of ent-1, thus
establishing absolute configuration and confirming structural
assignment;4 Several other groups have reported the synthesis
of peloruside fragments.5-9
(2) Hood, K. A.; Backstrom, B. T.; West, L. M.; Northcote, P. T.;
Berridge, M. V.; Miller, J. H. Anti-Cancer Drug Des. 2001, 16, 155-166.
(3) Hood, K. A.; West, L. M.; Rouwe, B.; Northcote, P. T.; Berridge,
M. V.; Wakefield, St. J.; Miller, J. H. Cancer Res. 2002, 62, 3356-3360.
(4) Liao, X.; Wu, Y.; De Brabander, J. K. Angew. Chem., Int. Ed. 2003,
42, 1648-1652.
Figure 1. Peloruside A (1).
from a select subpopulation of deep-sea Mycale sea sponges,
along with known natural products mycalamide A and
pateamine.1 Peloruside A shows potent cytotoxicity at
nanomolar concentrations toward multiple tumor cell lines,
(5) Paterson, I.; Di Francesco, M. E.; Kuhn, T. Org. Lett. 2003, 5, 599-
602.
(6) (a) Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44, 3967-
3969. (b) Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44, 7659-
7661.
(7) Taylor, R. E.; Jin, M. Org. Lett. 2003, 5, 4959-4961.
(8) Gurjar, M. K.; Pedduri, Y.; Ramana, C. V.; Puranik, V. G.; Gonnade,
R. G. Tetrahedron Lett. In press.
(1) West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem. 2000,
65, 445-449.
(9) Liu, B.; Zhou, W.-S. Org. Lett. 2004, 6, 71-74.
10.1021/ol036393z CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/29/2004

Our retrosynthetic strategy for peloruside A is shown in
Scheme 1. After hydrolysis of the 16-membered macrocyclic
bromination conditions (NBS, BaCO3, CCl4, reflux) gave the
known pyranoside 10 in 99% yield.16 Allylation of 10 (Me3-
SiOTf, allyl-SiMe3; MeCN, 95%) afforded exclusively the
expected diastereomer 11.17 It was convenient to stockpile
the material at this stage and prepare the aldehyde only as
needed. Olefin cleavage by ozonolysis proved fickle and at
best a 70% yield of aldehyde was obtained. However,
stepwise dihydroxylation and glycol cleavage (OsO4, NMO;
NaIO4, 96%) consistently delivered aldehyde 12 in excellent
yield. The entire optimized sequence was repeated with 50
g of triacetyl D-glucal 6 and provided approximately ∼31 g
of aldehyde 12 (46% overall). Aldehyde 12 contains atoms
C(1)-C(7) of peloruside A with the correct stereochemistry
at C(2), C(3), and C(5).
Scheme 1
Ketone 15, an equivalent of central piece 4, was prepared
in 69% overall yield by SE2′ addition of an allylic stannane
generated in situ from Barbier-type reaction of 13 with SnCl2‚
2H2O and benzyloxy acetaldehyde 14 (Scheme 3).18
Scheme 3
lactone and C(9) hemi-ketal to afford carboxylic acid 2, we
plan to join fully elaborated left- and right-hand segments 3
and 5 to central unit 4 containing the C(10) geminal dimethyl
group. This synthetic strategy required the development of
an unknown R-hydroxy ketone aldol reaction for C(7)-C(8)
bond construction. While glycolate anti aldols are well
established,10 R-hydroxy ketone aldols are underdeveloped,
particularly with ketones flanked by a quaternary carbon.11-13
The synthesis of 12, an equivalent of the right-hand
aldehyde 5 but with functional groups suitably protected, is
shown in Scheme 2. Reaction of commercial triacetyl
D-glucal 6 with methanol and catalytic Ph3P‚HBr under
conditions described by Mioskowski and Falk et al. gave
the 2-deoxypyranoside 7 in 96% yield.14 Acetate cleavage
and benzylidene acetal formation (Et2NH; PhCH(OMe)2, cat.
TsOH; 60% for both steps) followed by methylation (NaH,
MeI) provided 9 in 90% yield. Selective cleavage of the
primary benzylidene ether under Hanessian-Hullar15 radical
Aldol reactions between ketone 15 and aldehyde 12 were
extensively studied under a variety of conditions to discover
strategies for selectively accessing each of the four possible
diastereomeric products.19 The most effective method identi-
fied for securing the 2,3-anti-3,5-anti diastereomer required
for the peloruside A synthesis is a Mukaiyama aldol reaction
promoted by BF3‚OEt2 (Scheme 4). The optimized aldol
procedure consists of adding 1.1 equiv of BF3‚OEt2 to a -20
°C solution of silyl enol ether 16 and aldehyde 12 in
dichloromethane, allowing the reaction to warm to 0 °C and
maintaining it at this temperature for 2 h. These conditions
provide an 85% isolated yield of the 2,3-anti-3,5-anti (17)
and 2,3-anti-3,5-syn (18) diastereomers in a 3.5 to 1 ratio.
This modest level of selectivity is none the less noteworthy
given the lack of an R stereocenter and the complexity of
the aldehyde. Other Lewis acids that were investigated but
failed to improve stereochemistry include the following:
Scheme 2
664
Org. Lett., Vol. 6, No. 5, 2004

Scheme 4
Scheme 5
and conversion of the resulting diols to their di-tert-
butylsilylene ethers (Scheme 6).23 Analysis of these diaster-
BF3‚SMe2, Et2AlCl, TiCl4, SnCl4, and MgBr2‚OEt2. Evans
reported good facial selectivities in aldol reactions with
â-heterosubstituted aldehydes under similar nonchelation
control conditions using BF3‚OEt2 as the Lewis acid.20
The synthesis continued with methylation of the C(7)
hydroxyl group of the major 2,3-anti-3,5-anti-aldol product
17, using Meerwein’s salt under conditions described by
Evans (Me3OBF4, proton sponge, 90%) (Scheme 5).21 Vasella
ring cleavage by spontaneous â-elimination of the alkyl zinc
generated in situ by reduction of the alkyl bromide with
zinc-copper couple provided acyclic diol 19.22 At this point
we expected that conditions could be established such that
equilibrium would favor the hemiketal 20 (or the methyl
ketal) over ketone 19, thereby providing a locked cyclic
structure that would greatly facilitate stereochemical assign-
ment by NOE analysis. However, reliably obtaining 20
proved elusive.
Scheme 6
To ascertain the 3,5-anti or syn stereochemistry, both aldol
diastereomers were carried forward by Vasella ring cleavage
(10) (a) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1984, 753-756. (b)
Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem. 1992,
57, 1961-1963. (c) Andrus, M. B.; Soma Sekhar, B. B. V.; Meredith, E.
L.; Dalley, N. K. Org. Lett. 2000, 2, 3035-3037. (d) Crimmins, M. T.;
McDougall, P. J. Org. Lett. 2003, 5, 591-594. (e) Roush, W. R.; Pfeifer,
L. A. Org. Lett. 2000, 2, 859-862.
(11) For proline-catalyzed R-hydroxy ketone aldols, see: List, B.; Lerner,
R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395-2396.
(12) (a) Paterson, I.; Tillyer, R. D. J. Org. Chem. 1993, 58, 4182-1484.
(b) Brimble, M. A.; Nairn, M. R.; Park, J. Org. Lett. 1999, 1, 1459-1462.
(c) Andrus, M. B.; Soma Sekhar, B. B. V.; Meredith, E. L.; Dalley, N. K.
Org. Lett. 2000, 2, 3035-3037.
eomers by NOE spectroscopy clearly showed a strong
enhancement between the quasi-1,3-diaxial methine hydro-
gens in the syn diastereomer 22, and similar NOEs were
absent in 21.24 The 2,3-anti stereochemistry is based on
comparison of coupling constants of the other three diaster-
eomers and literature precedence with tert-butyl ethyl
ketones.13,19,25
(13) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1-200.
(14) (a) Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org. Chem.
1990, 55, 5812-5813. (b) France, C. J.; McFarlane, I. M.; Newton, C. G.;
Pitchen, P.; Webster, M. Tetrahedron Lett. 1993, 34, 1635-1638.
(15) (a) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035-
1044. (b) Hullar, T. L.; Siskin, S. B. J. Org. Chem. 1970, 35, 225-228.
(16) Fisher, M. J.; Myers, C. D.; Joglar, J.; Chen, S.-H.; Danishefsky,
S. J. J. Org. Chem. 1991, 56, 5826-5834.
(17) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976-4978.
With stereochemistry established, we decided to proceed
with the C(10) ketone intact (Scheme 7). The C(5) hydroxyl
(18) Imai, T.; Nishida, S. Synthesis 1993, 395-399.
(19) These results along with additional stereochemical proofs will be
described elsewhere.
(20) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322-4343.
(23) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871-
4874.
(24) Yu, M.; Pagenkopf, B. L. J. Org. Chem. 2002, 67, 4553-4558.
(25) Heathcock, C. H.; Hug, K. T.; Flippin, L. A. Tetrahedron Lett. 1984,
25, 5973-5976.
(21) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. Tetrahedron
Lett. 1994, 35, 7171-7172.
(22) Bernet, B.; Vasella, A. HelV. Chem. Acta 1979, 62, 1990-2016.
Org. Lett., Vol. 6, No. 5, 2004
665

Scheme 7
Figure 2. Peloruside A, with the segment prepared here in red.
regarding protocols for selectively accessing other diaster-
eomeric aldol products from reactions between ketone 15
and aldehyde 12, as well as aldol reactions with related
structures, will be described elsewhere.
in 19 was first protected as its TBS ether (tBu(Me)2SiCl,
imidazole, DMF, 82%). Both alkenes were then cleaved by
ozonolysis (O3, NaHCO3, CH2Cl2; PPh3), and the aldehyde
was immediately oxidized to the carboxylic acid (NaClO2,
NaH2PO4) in the presence of 2-methyl-2-butene as an acid
trap. Esterification (Me3SiCHN2; MeOH, PhH) afforded
methyl ester 24 in 45% isolated yield for the three steps.
In summary, an R-hydroxy ketone anti-anti aldol between
silyl enol ether 16 and aldehyde 12 was developed and
applied to the synthesis of the C(1)-C(12) segment of
peloruside A (Figure 2, in red). A practical and readily
scaleable preparation of aldehyde 12 from commercial
triacetyl D-glucal 6 was executed on a 50-g scale in
approximately 46% overall yield with use of standard
laboratory-sized glassware and equipment. Full details
Acknowledgment. We thank the Texas Advanced Re-
search Program (003658-0455-2001), the DOD Prostate
Cancer Research Program (DAMD17-01-1-0109), the donors
of the Petroleum Research fund, administered by the
American Chemical Society, and the Robert A. Welch
Foundation for partial financial support of this research.
Supporting Information Available: Structural data for
key compounds 12, 17, and 21. This material is available
free of charge via the Internet at http://pubs.acs.org.
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