Electrophile-induced ether transfer: A new approach to polyketide structural units

Article abstract of DOI:10.1021/ol0623318

A strategically novel approach to the formation of syn-1,3-diol mono- and diethers through electrophilic activation of homoallylic alkoxymethyl ethers has been developed. The resulting polyketide-like synthetic fragments are generated in good yield and wi

Full text of DOI:10.1021/ol0623318

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5393-5395
Electrophile-Induced Ether Transfer: A
New Approach to Polyketide Structural
Units
Kai Liu, Richard E. Taylor,* and Rendy Kartika
Department of Chemistry and Biochemistry and the Walther Cancer Research Center,
UniVersity of Notre Dame, 251 Nieuwland Science Hall,
Notre Dame, Indiana 46556-5670
taylor.61@nd.edu
Received September 21, 2006
ABSTRACT
A strategically novel approach to the formation of syn-1,3-diol mono- and diethers through electrophilic activation of homoallylic alkoxymethyl
ethers has been developed. The resulting polyketide-like synthetic fragments are generated in good yield and with excellent stereocontrol. A
chairlike transition state is proposed to account for the high stereoselectivity. Varying the conditions of the reaction workup results in the
efficient generation of mono- and diether containing structural units common to polyketide natural products.
Polyketides represent an important class of natural products
due to their diverse biological activity. Numerous polyketide
natural products contain methyl ether functionality generated
by either methoxymalonyl extender units or a selective
O-methyl transferase associated with the PKS gene cluster.
Peloruside A, a representative example that has received
significant, recent, synthetic interest,1,2 contains three such
methyl ethers. Unfortunately, current synthetic methods for
ether generation lack the selectivity of evolved proteins.
Thus, discrete steps for generating a hydroxyl stereogenic
center and subsequent methylation are typically bracketed
by additional protecting-group manipulation steps.
to polyketides, offers the opportunity to exploit intramo-
lecular delivery. Herein, we report a practical solution to the
methyl ether problem associated with the synthesis of many
polyketide natural products. Moreover, the new chemistry
presented offers additional opportunities for the development
of strategically novel approaches to the synthesis of structural
units common to polyketide natural products.
The general approach is outlined in Scheme 1. A readily
Scheme 1. Electrophile-Induced Ether Transfer: General
Strategy
available homoallylic alcohol, protected as a methoxymethyl
ether (MOM), will be subjected to electrophilic activation
conditions, E+ (e.g., I2, IBr, ICl, NIS, PhSeCl, etc.). On the
basis of related cyclizations of homoallylic carbonates,3 we
expected formation of intermediate oxonium ion 2a, through
a chairlike transition state, leading to halomethyl ether 2b.
A practical solution to this problem would utilize methanol
as a coupling partner, but classic intermolecular iodoetheri-
fications are unlikely to be stereo- and/or regioselective.
However, the repeating pattern of 1,3-oxygenation, common
10.1021/ol0623318 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/12/2006

Hydrolysis would then provide a syn-1,3-diol monoether 3.
In contrast to current technology, the stereochemistry would
be generated simultaneous to the ether functionality.4,5
The results of the initial exploration of the ether-transfer
concept using a variety of electrophilic conditions are listed
in Table 1. Methoxymethyl-protected homoallylic alcohol 1
cyclization product, tetrahydrofuran 4. Entry 8 demonstrated
that methoxy transfer could be successfully accomplished
in both high yield and high diastereoselectivity.6
Presumably, related ethers would transfer efficiently as
long as steric or electronic differences compared to the
methyl substrate were insignificant. In fact, the benzyloxy-
methyl substrate 5, readily prepared from commercially
available BOMCl, underwent efficient benzyl ether transfer
(Scheme 2).6b,c This process significantly expands the scope
Table 1. Electrophile-Induced Methoxy Transfer: Initial
Exploration
Scheme 2. Electrophile-Induced Benzyl Transfer:
Competitive Cleavage
conditions;
workup
yield 3
(dr)a
entry
E
yield 4b
1
2
3
PhSeCl, PhCH3, -78 °C PhSe not observed not observed
I(coll)2PF6, CH2Cl2, rt
IBr, PhCH3, -78 °C;
Na2SO3, H2O
ICl, CH2Cl2, -78 °C;
Na2SO3, H2O
ICl, PhCH3, -78 °C;
Na2SO3, H2O
ICl, PhCH3, -78 °C;
NaHSO3, H2O
ICl, PhCH3, -78 °C;
NH4OH
ICl, PhCH3, -78 °C;
DIPA, H2O
I
I
trace
54%
(25:1)
65%
(8:1)
59%
(15:1)
76%
(15:1)
73%
(14:1)
87%
not observed
26%
4
5
6
7
8
I
I
I
I
I
21%
not observed
not observed
not observed
not observed
of the reaction because, in contrast to methyl ethers, benzyl
groups can be easily removed by hydrogenolysis. Thus, the
ether transfer method provides access to orthogonally protect-
ed syn-1,3-diol units. Surprisingly, no products related to tet-
rahydrofuran 4 were observed with the corresponding ben-
zyloxymethyl substrate 5. However, under IBr/CH2Cl2 con-
ditions, competitive benzyl cleavage was observed and acetal
7 was isolated as the major product.7 Activation with ICl in
toluene provided exclusively the ether transfer product 6.
(12:1)
a Diastereomeric ratio was determined by 1H and 13C NMR.6a b The
stereochemistry of 4 was confirmed by independent synthesis from 3 (see
Supporting Information).
The intermediacy of chloromethyl ether 2b was supported
by NMR observation in toluene-d8 (see Supporting Informa-
tion). Thus, we speculated that a methanolic workup would
regenerate the methoxylmethyl group and provide access to
orthogonally protected diethers. Successful demonstration of
this idea as well as the overall scope of the ether transfer
are highlighted in Table 2. Reaction workup with either
MeOTMS or basic methanol solutions provided diethers in
good yield and excellent diastereoselectivity (entries 1 and
2). Moreover, benzyl alcohol workup generated a BOM-ether
and provided 13. Propionate substrates 16 and 18 demon-
strated a strong preference for 1,3-syn products regardless
of the stereochemistry of allylic substitution (entries 5 and
6). For evaluation of the scope of this chemistry, entry 7
was an important test. Appropriate protecting group selection8
was prepared in two steps in racemic form from com-
mercially available materials. Toluene was shown to be the
most suitable solvent. The choice of activation reagent was
also critical in minimizing the formation of an alternative
(1) For the total syntheses of peloruside A, see: (a) Liao, X.; Wu, Y.;
De Brabander, J. K. Angew. Chem., Int. Ed. 2003, 42, 1648-1652. (b) Jin,
M.; Taylor, R. E. Org. Lett. 2005, 7, 1303-1305.
(2) For additional synthetic efforts towards peloruside A, see: (a)
Paterson, I.; Di Francesco, M. E.; Ku¨hn, T. Org. Lett. 2003, 5, 599. (b)
Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2003, 44, 3967. (c) Taylor, R.
E.; Jin, M. Org. Lett. 2003, 5, 4959. (d) Ghosh, A. K.; Kim, J.-H.
Tetrahedron Lett. 2003, 44, 7659. (e) Gurjar, M. K.; Pedduri, Y.; Ramana,
P. C. V.; Puranik, V. G.; Gonnade, R. G. Tetrahedron Lett. 2003, 45, 387.
(f) Liu, B.; Zhou, W.-S. Org. Lett. 2004, 6, 71. (g) Engers, D. W.;
Bassindale, M. J.; Pagenkopf, B. L. Org. Lett. 2004, 6, 663. (h) Roulland,
E.; Ermolenko, M. S. Org. Lett. 2005, 7, 2225. (i) Owen, R. M.; Roush,
W. R. Org. Lett. 2005, 7, 3941. (j) Hoye, T. R.; Ryba, T. D. J. Am. Chem.
Soc. 2005, 127, 8256.
(3) (a) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.;
Jernstedt, K. K. J. Org. Chem. 1982, 47, 4013-4018. (b) Duan, J. J.-W.;
Smith, A. B., III J. Org. Chem. 1993, 58, 3703-3711.
(4) A related delivery of an ether has been applied to the stereocontrolled
synthesis of glycosides: (a) Cumpstey, I.; Chayajarus, K.; Fairbanks, A.
J.; Redgrave, A. J.; Seward, C. M. P. Tetrahedron: Asymmetry 2004, 15,
3207. (b) This chemistry is in a class of reactions defined by temporary
tethers: Gauthier, D. R., Jr.; Zandi, K. S.; Shea, K. J. Tetrahedron 1998,
54, 2289.
(5) For additional examples of acetals participating in electrophilic
cyclization reactions, see: (a) Molas, P.; Matheu, M. I.; Castill´ıon, S.
Tetrahedron Lett. 2004, 45, 3721. (b) Fujioka, H.; Ohba, Y.; Hirose, H.;
Murai, K.; Kita, Y. Angew. Chem., Int. Ed. 2005, 44, 734. (c) Kumar, V.
S.; Aubele, D. L.; Floreancig, P. E. Org. Lett. 2002, 4, 2489.
(6) (a) The syn stereochemistry was determined by NMR spectroscopic
analysis: Hoffman, R. W.; Weidmann, U. Chem. Ber. 1985, 118, 3980.
(b) The syn-1,3-relative stereochemistry was determined by hydrogenolysis
of the benzyl ether and 13C NMR spectroscopic analysis of the corresponding
acetonide. Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945. (c) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099.
(7) Deprotection of benzyl ethers involved in iodoetherification reactions
is well established: Rychnovsky, S. D.; Barlett, P. A. J. Am. Chem. Soc.
1981, 103, 3963.
(8) For a discussion of the lowered basicity of silyl ethers relative to
alkyl ethers, see: Shambayati, S.; Blake, J. F.; Wierschke, S. G.; Jorgensen,
W. L.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 697.
(9) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2002, 65, 1201.
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Org. Lett., Vol. 8, No. 23, 2006

Scheme 3. Electrophile-Induced Ether Transfer: Reduction
Table 2. Electrophile-Induced Methoxy Transfer: Reaction
Scope
Quench
class of marine polyketides.9 Similarly, the BOM-protected
substrate 5 provided the orthogonally protected diether
substrate 25, a stereocomplementary fragment to diether 9.
Methods for the asymmetric synthesis of polyketide
structural units have evolved such that even gram-scale
syntheses of complex natural products are obtainable given
the proper rationale.10 We have developed a fundamentally
new tactic capable of significantly simplifying the creation
of functionality common to polyketide natural products by
controlling the generation of a stereogenic center simulta-
neous with ether incorporation. Moreover, the demonstrated
ability to trap the intermediate with a variety of nucleophiles
offers additional opportunities for synthetic creativity. Ap-
plication of these methods to our second-generation synthesis
of peloruside A as well as other natural products is currently
underway in our laboratories and will be reported in due
course.
a TMSOCH3. b CH3OH, iPr2NEt. c BnOH, iPr2NEt. d AcOH, iPr2NEt;
-78 °C f rt.
enabled exclusive ether transfer, and alternative cyclization
events were not observed. These results augur well for
application of this methodology to the synthesis of more
complicated polyketide-like structures.
Acknowledgment. Support provided by the National
Institutes of Health through the National Cancer Institute
(CA85499) and the National Institute of General Medical
Science (GM077683) is gratefully acknowledged.
The in situ generated chloromethyl ether 2b is a versatile
intermediate with the ability to react with a variety of
nucleophiles and provide unique structures applicable to
natural product synthesis. An additional example, comple-
mentary to the ether transfer, is shown in Scheme 3.
Electrophilic activation followed by a reductive workup
provided access to methyl ethers through selective hydride
addition. Coupled with a lithium borohydride quench, the
MOM-protected substrate 1 provided the bismethyl ether 24
in 91% yield.
Supporting Information Available: Full experimental
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0623318
The reaction shown in Scheme 3 is ideally suited for
application to the synthesis of the isotactic polymethoxydiene
(10) Mickel, S. J. Curr. Opin. Drug DeV. 2004, 7, 869. Smith, A. B., III
J. Org. Chem. 1993, 58, 3703-3711.
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