Sime3-based homologation-epoxidation-cyclization strategy for ladder THP synthesis

Article abstract of DOI:10.1021/ol0347040

(Matrix presented) A trimethylsilyl (SiMe₃) group is the basis of a strategy that emulates the three fundamental proposed processes in ladder polyether biosynthesis: chain homologation, stereoselective epoxidation (>95% ee or >95:5 dr), and endo-selective, stereospecific (inversion) hydroxyepoxide cyclization (>95:5 endo:exo, >95% dr). A tris-THP was synthesized in 18 total operations from commercial materials using this approach.

Full text of DOI:10.1021/ol0347040

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2339-2342
SiMe3-Based
Homologation−Epoxidation−Cyclization
Strategy for Ladder THP Synthesis
Timothy P. Heffron and Timothy F. Jamison*
Massachusetts Institute of Technology, Department of Chemistry,
Cambridge, Massachusetts 02139
tfj@mit.edu
Received April 28, 2003
ABSTRACT
A trimethylsilyl (SiMe3) group is the basis of a strategy that emulates the three fundamental proposed processes in ladder polyether
biosynthesis: chain homologation, stereoselective epoxidation (>95% ee or >95:5 dr), and endo-selective, stereospecific (inversion)
hydroxyepoxide cyclization (>95:5 endo:exo, >95% dr). A tris-THP was synthesized in 18 total operations from commercial materials using this
approach.
An appealing explanation for the structural and stereo-
chemical similarities among several families of trans-fused
(“ladder”) polyethers is that Nature may have devised a
general solution for assembling these fascinating natural
products. Nakanishi1 proposed that three fundamental opera-
tions might comprise such a strategy: (1) polyene synthesis
via iterative chain homologation, (2) asymmetric epoxidation,
and (3) a series of endo-selective epoxide-opening events.
While this proposal has yet to be verified experimentally,
significant effort has been directed toward mimicking one
or more of these steps.
cades”.3 Many of the iterative methods have been utilized
in synthesis of ladder polyether natural products, but the
cascade approaches have not. We report here that a tri-
methylsilyl (SiMe3) group enables efficient and selective
emulation of all three proposed biogenetic processes (ho-
mologation, epoxidation, cyclization) and is amenable to
rapid, iterative synthesis of a ladder polyether subunit.
We began by evaluating suitable directing groups for these
three transformations (X, Scheme 1). In this approach, chain
homologation (1) with “R” installs all three carbon atoms
of the heterocycle and therefore must contain both a
“masked” nucleophile and electrophile, as it is also the site
of coupling in the next iteration. Epoxidation (2) must be
highly enantioselective in the first iteration and highly
diastereoselective thereafter. We also required that the
removal of X (4) be no more than one step so as not to
unduly lengthen the synthesis simply to incorporate a given
directing group.
The endo-selective epoxide ring-opening component has
been addressed with two contrasting strategies, approaches
typically described as being “iterative”2 or involving “cas-
(1) (a) Nakanishi, K. Toxicon 1985, 23, 473-479. (b) Lee, M. S.; Repeta,
D. J.; Nakanishi, K.; Zagorski, M. G. J. Am. Chem. Soc. 1986, 108, 7855-
7856. (c) Lee, M. S.; Qin, G.-w.; Nakanishi, K.; Zagorski, M. G. J. Am.
Chem. Soc. 1989, 111, 6234-6241. (d) See also: Chou, H.-N.; Shimizu,
Y. J. Am. Chem. Soc. 1987, 109, 2184-2185.
(2) Efforts of dozens of research groups in this area have been the subject
of several recent reviews: (a) Alvarez, E.; Candenas, M.-L.; Pe´rez, R.;
Ravelo, J. L.; Mart´ın, J. D. Chem. ReV. 1995, 95, 1953-1980. (b) Mori, Y.
Chem. Eur. J. 1997, 3, 849-852. (c) Marmsa¨ter, F. P.; West, F. G. Chem.
Eur. J. 2002, 8, 4347-4353. (d) Hirama, M., Rainier, J. D., Eds.
Tetrahedron Symposium-in-Print 90 2002, 58, 1779-2040.
(3) (a) Fujiwara, K.; Hayashi, N.; Tokiwano, T.; Murai, A. Heterocycles
1999, 50, 561-593. (b) Tokiwano, T.; Fujiwara, K.; Murai, A. Synlett 2000,
335-338. (c) McDonald, F. E.; Wang, X.; Do, B.; Hardcastle, K. I. Org.
Lett. 2000, 2, 2917-2919. (d) McDonald, F. E.; Bravo, F.; Wang, X.; Wei,
X.; Toganoh, M.; Rodr´ıguez, J. R.; Do, B.; Neiwert, W. A.; Hardcastle, K.
I. J. Org. Chem. 2002, 67, 2515-2523.
10.1021/ol0347040 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/23/2003

invalidate the Nakanishi hypothesis. If hydroxyepoxide
cyclizations are involved in the biosynthesis, Coxon’s
experiment simply illustrates the challenge of emulating this
step in the laboratory. Accordingly, significant effort has been
directed toward this problem.
Scheme 1
Many strategies are based on the observations that acid-
catalyzed epoxide ring-opening reactions proceed with inver-
sion of configuration5 and that rate6 and regioselectivity7 are
very sensitive to the electronic nature of the epoxide
substituents.8,9
In this vein, Nicolaou used an alkenyl group to provide
π-stabilization of positive charge at the adjacent epoxide
carbon10 in pioneering studies that formed the basis of
landmark total syntheses of the brevetoxins11,12 and observed
a trend with alkenyl groups (Table 1, entries 3 and 4) that
was reminiscent of Coxon’s experiments. These four results
can be explained by a chair-like transition state (cf. Scheme
1), whereby the steric demand of a larger group in an axial
position disfavors endo cyclization. Similarly, Mori found
that an axial substituent other than H at the equivalent
position prevented analogous epoxysulfone cyclizations.2b,13
A trimethylsilyl (SiMe3) group emerged as an attractive
candidate in other parts of the strategy and because of the
regioselectivity of intermolecular epoxysilane ring-opening
reactions with oxygen-centered nucleophiles.14
The nature of X merits further discussion in the context
of the stereospecific hydroxyepoxide cyclization (3). A single
experiment reported by Coxon in 1973 raised perhaps the
most puzzling question of ladder polyether biosynthesis.4
Treatment of epoxide 1a with boron trifluoride etherate
(Et2O‚BF3) affords an 86:14 mixture of “5-exo” tetrahydro-
furan (THF, 3a) and “6-endo” tetrahydropyran (THP, 2a)
products (Table 1, entry 1).
(5) Except for epoxides with aromatic substituents (e.g., styrene oxides),
whose ring-opening reactions often display different mechanistic profiles.
Reviews: (a) Winstein, S.; Henderson, R. B. Ethylene and Trimethylene
Oxides. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New
York, 1950; Vol. 1. (b) Parker, R. E.; Isaacs, N. S. Chem. ReV. 1959, 59,
737-799. (c) Wohl, R. A. Chimia 1974, 28, 1-5.
(6) Brønsted, J. N.; Kilpatrick, M.; Kilpatrick, M. J. Am. Chem. Soc.
1929, 51, 428-461.
Table 1. Directing Group Effects in Hydroxyepoxide
Cyclizations (Eq 1)
(7) (a) Pritchard, J. G.; Long, F. A. J. Am. Chem. Soc. 1956, 78, 2667-
2670. (b) Addy, J. K.; Parker, R. E. J. Chem. Soc. 1965, 644-649.
(8) Catalytic antibody approach. THP: (a) Janda, K. D.; Shevlin, C. G.;
Lerner, R. A. Science 1993, 259, 490-493. (b) Na, J.; Houk, K. N.; Shevlin,
C. G.; Janda, K. D.; Lerner, R. A. J. Am. Chem. Soc. 1993, 115, 8453-
8454. Oxepane: (c) Janda, K. D.; Shevlin, C. G.; Lerner, R. A. J. Am.
Chem. Soc. 1995, 117, 2659-2660.
(9) Intramolecular (salen)Co(III)-catalyzed kinetic resolution: Wu, M.
H.; Hansen, K. B.; Jacobsen, E. N. Angew. Chem., Int. Ed. 1997, 38, 22012-
2014.
entry epoxide
R1
R2
promoter
2:3
1a
1a
1b
1c
1d
1e
1f
H
Me
H
CHdCH2
SiMe3
Me
Me
H
Et2O‚BF3 14:86
Et2O‚BF3 e3:97
(10) (a) Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K.; Somers, P. K.
J. Chem. Soc., Chem. Commun. 1985, 1359-1362. (b) Nicolaou, K. C.;
Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989,
111, 5330-5334. (c) See also: Nicolaou, K. C.; Prasad, C. V. C.; Somers,
P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5335-5340.
(11) (a) Brevetoxin B: Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F.
P. J. T.; Tiebes, J.; Sato, M.; Untersteller, E.; Xiao, X.-Y. J. Am. Chem.
Soc. 1995, 117, 1171-1172. (b) Nicolaou, K. C.; Rutjes, F. P. J. T.;
Theodorakis, E. A.; Tiebes, J.; Sato, M.; Untersteller, E.; Xiao, X.-Y. J.
Am. Chem. Soc. 1995, 117, 1173-1174. (c) Brevetoxin A: Nicolaou, K.
C.; Yang, Z.; Shi, G.-Q.; Gunzner, J. L.; Agrios, K. A.; Ga¨rtner, P. Nature
1998, 392, 264-269.
2a
3b
4b
5c
CHdCH2 (+)-CSA
H
Me
SiMe3
>98:2
(+)-CSA
44:56
Et2O‚BF3 >95:5
Et2O‚BF3 see text
6c,d
a See Coxon, ref 4. b See Nicolaou, refs 10a,b. c See Supporting Informa-
tion. d Major product: HO(CH2)4C(O)CH3.
(12) Total or formal synthesis of hemibrevetoxin: (a) Nicolaou, K. C.;
Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X.-Y. J. Am. Chem. Soc. 1992,
114, 7935-7936. (b) Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato,
F.; Xiao, X.-Y.; Hwang, C.-K. J. Am. Chem. Soc. 1993, 115, 3558-3575.
(c) Kadota, I.; Park, J.-Y.; Koumura, N.; Pollaud, G.; Matsukawa, Y.;
Yamamoto, Y. Tetrahedron Lett. 1995, 36, 5777-5780. (d) Morimoto, M.;
Matsukura, H.; Nakata, T. Tetrahedron Lett. 1996, 37, 6365-6368. (e) Mori,
Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1997, 119, 4557-4558.
(f) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Org. Chem. 1998, 63, 6200-
6209. (g) Kadota, I.; Yamamoto, Y. J. Org. Chem. 1998, 63, 6597-6606.
(h) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66, 1380-
1386. (i) Holland, J. M.; Lewis, M.; Nelson, A. J. Org. Chem. 2003, 68,
747-753.
Also noteworthy is that the analogous cyclization with the
diastereomeric epoxide (1b) yields exclusively the exo
cyclization product (3b), demonstrating the sensitivity of such
cyclizations to epoxide substitution pattern (entry 2).
As a central tenet of Nakanishi’s proposal involves a series
of endo-selective epoxide-opening steps, how Nature over-
comes the apparently disfavored mode of cyclization remains
unknown. To be sure, these results do not necessarily
(13) (a) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996,
118, 8158-8159. (b) Mori, Y.; Yaegashi, K.; Furukawa, H. Tetrahedron
Lett. 1999, 40, 7239-7242.
(4) Coxon, J. M.; Hartshorn, M. P.; Swallow, W. H. Aust. J. Chem. 1973,
26, 2521-2526.
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Org. Lett., Vol. 5, No. 13, 2003

Nevertheless, its effect on the cyclization was still a
significant concern since no such cyclization of a trisubsti-
tuted epoxysilane or one in which a SiMe3 group would
occupy an axial position in the proposed transition state had
been reported. Schaumann had investigated cyclizations with
SiMe3 in an equivalent equatorial position, but formation
of endo products in these cases could be ascribed to a
significant conformational predisposition such as avoidance
of forming a highly strained trans-5,5 system or the presence
of one or more equatorial “anchoring” groups.15 These
results, along with the trends observed by Coxon, Nicolaou,
and Mori, did not augur well for our plan of placing a large
SiMe3 group in the axial position.
Scheme 2a
The trends we observed with respect to epoxysilane
substitution pattern were therefore quite unexpected (Table
1, entries 5 and 6), as they are exactly opposite those
predicted by the Nicolaou, Mori, and Schaumann studies.
Epoxide 1e (SiMe3 axial) underwent cyclization at 0 °C with
inversion of configuration (>95% dr) and >95% regio-
selectivity (1H NMR), affording exclusiVely the “6-endo”
THP (2e, entry 5). More surprising was that isomeric epoxide
1f (SiMe3 equatorial, entry 6) afforded primarily 1-hydroxy-
5-hexanone14b along with a complex mixture of cyclization
products. Thus, even though it is larger than methyl, an axial
SiMe3 appears to be accommodated more easily in the
transition state.
To our delight, the SiMe3 group also satisfied all other
requirements, enabling efficient emulation of all three
proposed processes in ladder polyether biogenesis (Scheme
2).
After highly selective hydroalumination-iodination,16
direct propargylation (Me3Si-CtC-Me (4), n-BuLi,
TMEDA; CuI) proceeds in high yield and good propargyl/
allenyl selectivity.17 Use of a molar excess of the copper
reagent obviates hydroxyl group protection, and neither
π-bond isomerization nor erosion of geometric purity is
observed in “skipped enynes” 6 and 10. The commercially
available 4 thus embodies the “masked” electrophile/nucleo-
phile in this strategy (Scheme 1).
The method of Shi proved to be superior for the enantio-
selective epoxidation of trisubstituted alkene 6 (>95% ee),18
and Lewis acid-promoted hydroxyepoxide cyclization as
discussed above completed construction of the first THP ring.
Straightforward protiodesilylation (TBAF) cleanly removes
the multipurpose SiMe3 group and proceeds with retention
of configuration. Despite the cis relationship of the Me3Si
and OH groups and the basic character of TBAF solutions,
byproducts corresponding to formal elimination of Me3SiOH
a Reaction conditions: (a) DIBAL; I2. (b) Me3Si-CtC-Me (4),
n-BuLi, TMEDA; CuI, DMAP. (c) Ac2O, DMAP, Et3N. (d) See
ref 17. (e) LiOH, H2O, THF, MeOH. (f) Et2O‚BF3, CH2Cl2. (g)
TBAF, THF. (h) n-BuLi, Me3SiCl. (i) Me2CuCNLi2.
are not observed.19 The very high degree of reagent control
in subsequent epoxidations was a key factor in the assembly
of THP triad 14 by reiteration of these same four procedures.
The Nicolaou, Mori, and SiMe3-based approaches to
iterative ladder polyether synthesis each mirror all three
proposed biogenetic operations. Nicolaou’s strategy uses an
alkenyl group for π-stabilization of positive charge at the
adjacent (R) epoxide carbon in the hydroxyepoxide cycliza-
tion and is part of the carbon framework, whereas Mori uses
the inductive effect of an electron-withdrawing PhSO2 group
to favor epoxide opening at the â carbon. In contrast, a SiMe3
group appears to direct R opening in a different stereoelec-
tronic manner and can occupy an axial position in the course
of the stereospecific and endo-selective cyclization. These
features, in conjunction with the complete stereo- and
regiocontrol in each step, make possible the assembly of THP
triad 14 in 18 total operations, whereas the Nicolaou and
(14) (a) Stork, G.; Colvin, E. J. Am. Chem. Soc. 1971, 93, 2080-2081.
(b) Stork, G.; Jung, M. E. J. Am. Chem. Soc. 1974, 96, 3682-3684. (c)
Robbins, C. M.; Whitham, G. H. J. Chem. Soc., Chem. Commun. 1976,
697-698. (d) Review: Hurdlik, P. F.; Hurdlik, A. M. R,â-Epoxysilanes.
In AdVances in Silicon Chemistry; Larson, G. L., Ed.; JAI Press: Greenwich,
CT, 1993; Vol. 2, pp 1-89.
(15) Aidwidjaja, G.; Flo¨rke, H.; Kirschning, A.; Schaumann, E. Tetra-
hedron Lett. 1995, 36, 8771-8774.
(16) Zweifel, G.; Lewis, W. J. Org. Chem. 1978, 43, 2739-2744.
(17) (a) Commercon, A.; Normant, J.; Villieras, J. J. Organomet. Chem.
1975, 93, 415-421. (b) Heffron, T. P.; Trenkle, J. D.; Jamison, T. F.
Tetrahedron Symposium-in-Print 2003, 59, in press.
(19) (a) Peterson, D. J. J. Org. Chem. 1968, 33, 780-784. (b) Magnus,
P.; Roy, G. J. Chem. Soc., Chem. Commun. 1979, 822-823. (c) Hudrlik,
P. F.; Hudrlik, A. M.; Kulkarni, A. K. J. Am. Chem. Soc. 1982, 104, 6809-
6811.
(18) Warren, J. D.; Shi, Y. J. Org. Chem. 1999, 64, 7675-7677.
Org. Lett., Vol. 5, No. 13, 2003
2341

Mori approaches average 10-13 operations per THP, includ-
ing preparation of necessary building blocks. Our current
studies include synthesis of ladder polyether natural products
based on this strategy.
Chemical Society, Amgen, Boehringer-Ingelheim, Bristol-
Myers Squibb, Merck, Pfizer, and 3M for financial support.
The NSF (CHE-9809061 and DBI-9729592) and NIH
(1S10RR13886-01) provide partial support for the MIT
Department of Chemistry Instrumentation Facility.
Acknowledgment. We thank the James H. Ferry Fund
(MIT) for partial support of this work and Johnson &
Johnson for a research assistantship to T.P.H. We also thank
the National Institute of General Medical Sciences (GM-
063755), the NSF (CAREER CHE-0134704), the donors of
the Petroleum Research Fund, administered by the American
Supporting Information Available: Experimental pro-
cedures and data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0347040
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