Diastereoselective synthesis of 2,3,6-trisubstituted tetrahydropyran-4-ones via prins cyclizations of enecarbamates: A formal synthesis of (+)-ratjadone A

Article abstract of DOI:10.1021/ja046940r

Enecarbamates are shown to be excellent terminating groups for Prins cyclizations. A noteworthy feature of this methodology is the easy, stereoselective construction of the cyclization precursors by alkylation of metalated (E)-enecarbamates with epoxides.

Full text of DOI:10.1021/ja046940r

Published on Web 09/10/2004
Diastereoselective Synthesis of 2,3,6-Trisubstituted Tetrahydropyran-4-ones
via Prins Cyclizations of Enecarbamates:
A Formal Synthesis of (+)-Ratjadone A
Kimberly N. Cossey and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
Received May 24, 2004; E-mail: rlf@chem.psu.edu
Tetrahydropyrans of varied substitution patterns are embodied
in the structures of numerous natural products. Ratjadone A and
kendomycin are two representative examples that possess more
densely substituted tetrahydropyrans and have in common a
frequently observed 2,3,6-all-cis stereochemical pattern.1 Accord-
ingly, many strategies for the construction of these substructures
have been developed, and by far the most direct approach involves
the cyclization of alkenes with oxocarbenium ions, the Prins
cyclization.2 Despite the fact that a considerable amount of effort
We initially subjected the alcohol 2 to the mild Lewis acid
conditions reported by Dobbs3b for Prins cyclizations of homoallylic
alcohols with aldehydes, namely, InCl3 in methylene chloride
(Scheme 2). We were pleased to discover that alcohol 2 and benz-
aldehyde provided the all-cis tetrahydropyran-4-one 4 in excellent
yield accompanied by comparable amounts of N-BOC-octylamine.
Presumably, this transformation proceeds by cyclization of the di-
equatorial, chairlike conformer of the oxocarbenium ion 3 to provide
an N-acyliminium ion that is then hydrolyzed by the equivalent of
water produced from the formation of the oxocarbenium ion.
Scheme 2
has been directed toward improving the efficiency of the Prins
cyclization, primarily by increasing the nucleophilicity of the alkene
reactant,3 this method has not been extensively applied in natural
product syntheses. Indeed, the majority of the synthetic effort has
been directed toward natural products containing the less complex
2,6-disubstituted tetrahydropyran substructures,4 perhaps due to the
inaccessibility of nonracemic Prins cyclization precursors and/or
inferior cyclization diastereoselectivities for the more complex
substitution patterns.5 We report herein that enecarbamates partici-
pate in highly diastereoselective Prins cyclizations with oxocarbe-
nium ions en route to all-cis-2,3,6-trisubstituted tetrahydropyran-
4-ones and, moreover, show that the cyclization substrates can be
quickly assembled from readily available optically pure epoxides
in the context of a formal total synthesis of (+)-ratjadone A.
The preparation of the enecarbamates such as 2 required for the
Prins cyclization study (Scheme 1) was easily accomplished in a
two-pot reaction sequence. Thus, the enecarbamate 1 was prepared
via acylation of the N-octyl imine derivative of propanal by
modification of a protocol previously reported by Bach.6 Treatment
of enecarbamate 1 with t-BuLi7 followed by the addition of
propylene oxide and BF3‚OEt2 gave the desired reactant for the
Prins cyclization, homoallylic alcohol 2 (single regioisomer, 67%
yield). Similar products were obtained by substitution of the
propylene oxide with styrene oxide, cyclohexene oxide, or ethylene
oxide to furnish the alcohols shown in entries 2 (77%), 5 (53%),
and 6 (53%) of Table 1, respectively.
Additional Lewis acids were also examined and found to afford
the same product but in diminished yields and accompanied by
trace amounts of another diastereomer: BF3‚OEt2 (-78 to 0 °C,
83%); Bi(OTf)3 (-78 °C, 82%); TMSOTf with TMS ether of 2
(-78 to -20 °C, 71%).
The scope and generality of this variant of the Prins cyclization
is presented in Table 1. The preferred Lewis acid, InCl3 (0.5 equiv),
was employed in all of the examples except for entry 7. Entries 1
and 2 demonstrate that saturated aldehydes also participate in this
reaction. Cyclization with an unsaturated aldehyde (entry 4) is also
uneventful and relevant to the ratjadone A application, vide infra.
Substitution patterns other than the 2,3,6-trisubstituted examples
are also accessible, e.g., 2,3,5,6-tetrasubstituted (entry 5), 2,3-
disubstituted (entry 6), and 2,6-disubstituted (entry 7). Finally, a
ketone is also a suitable reaction partner but, in this case, affords
an enecarbamate product in modest yield (entry 8).
We next directed our attention toward the synthesis of ratjadone
A, which has been shown to exhibit cytotoxicities in the picomolar
range on several established cell lines (L929, KB-3.1, KB-V1,
K-562, PC-3)1b,c and functions by inhibiting nuclear export by
blocking CRM1/exportin 1.1c Total syntheses of (+)-ratjadone A
and its enantiomer have been reported by the Kalesse8a,b and
Williams8c groups, respectively.
In both syntheses, the challenging 2,3,6-trisubstituted tetrahy-
dropyran substructure was prepared by initial introduction of the
C(19-21) stereogenic centers followed by 6-exo-ring closure of
an epoxy alcohol. Thus, Kalesse prepared the tetrahydropyran 9
(Scheme 3) in 14 steps from (R)-4-benzyl-2-oxazolidinone, which
was then converted to (+)-ratjadone A in 5 steps via a Heck reaction
with a C(13) vinyl iodide segment. In view of this efficient
endgame, the preparation of tetrahydropyran 9 by the Prins
cyclization of the appropriate enecarbamate became our objective.
Scheme 1
9
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J. AM. CHEM. SOC. 2004, 126, 12216-12217
10.1021/ja046940r CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Prins Cyclizations of Enecarbamates
Scheme 3
(E)-enecarbamates is then transferred with high fidelity to afford
the frequently observed and biologically significant all-cis-2,3,6-
trisubstituted tetrahydropyran substructures of naturally occurring
compounds. This methodology facilitated an exceptionally concise
formal total synthesis of the nuclear export inhibitor (+)-ratjadone
A, and its further development and application is underway.
Acknowledgment. We appreciate the financial support provided
by the National Institutes of Health (GM28553).
Supporting Information Available: Spectroscopic data and ex-
perimental details for the preparation of all new compounds (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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To that end, the known optically pure epoxide 5 was prepared
by a Sharpless asymmetric epoxidation of divinylcarbinol9 followed
by silylation and then subjected to the vinyl anion derivative of
enecarbamate 1 to afford the key homoallylic alcohol 6. Treatment
of enecarbamate 6 with crotonaldehyde in the presence of InCl3
furnished the tetrahydropyranone 7 as a single diastereomer in good
yield (84%). Reduction of pyranone 7 with sodium borohydride
gave exclusively the undesired all-cis alcohol 8b whose Mitsunobu
inversion was problematic due to competing elimination. Accord-
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was found that triisobutylaluminum hydride produced a nearly equal
amount of stereoisomeric alcohols 8a and 8b. The undesired alcohol
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JA046940R
In conclusion, we have shown that enecarbamates are excellent
terminating groups for Prins cyclizations. A noteworthy feature of
this methodology is the easy, stereoselective construction of the
cyclization precursors by alkylation of metalated (E)-enecarbamates
with epoxides. The stereochemistry of the resultant trisubstituted
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12217