Metathesis approach to the synthesis of polyheterocyclic structures from oxanorbornenes

Article abstract of DOI:10.1021/ol0484106

(Chemical Equation Presented) The synthesis of stereochemically defined tri- and penta-heterocyclic ring systems 9 and 28, respectively, via the metathesis reaction of substituted oxanorbornanes derived from 3 is described.

Full text of DOI:10.1021/ol0484106

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3821-3824
Metathesis Approach to the Synthesis
of Polyheterocyclic Structures from
Oxanorbornenes
Jeffrey D. Winkler,* Sylvie M. Asselin, Stacey Shepard,† and Jing Yuan‡
Department of Chemistry, UniVersity of PennsylVania
Philadelphia, PennsylVania 19104
winkler@sas.upenn.edu
Received August 11, 2004
ABSTRACT
The synthesis of stereochemically defined tri- and penta-heterocyclic ring systems 9 and 28, respectively, via the metathesis reaction of
substituted oxanorbornanes derived from 3 is described.
The ring-opening metathesis polymerization of norbornenes
by Grubbs established the remarkable properties of ruthenium-
Scheme 1. Proposed Construction of Polyheterocyclic Ring
based catalyst systems for the efficient transformation of
strained alkenes.1 Since that time, the synthetic utility of
metathesis ring closure has been demonstrated in the
synthesis of both natural2 and unnatural products.2c,3 We
reasoned that this methodology could be applied to the
construction of polyheterocyclic rings systems 2 via the
metathesis reaction of 1, as outlined in Scheme 1. We
Systems
† Current address: Incyte Pharmaceuticals, Wilmington, DE. Department
of Energy Plant Sciences Graduate Fellow, 1998-2000; 2001-2002 Bristol-
Myers Squibb Graduate Fellowship in Organic Synthesis. University of
Pennsylvania School of Arts and Sciences Dean’s Scholar, 2001.
‡ Current address: Concurrent Pharmaceuticals, Fort Washington, PA.
(1) For reviews of ring-opening metathesis: (a) Grubbs, R. H.; Khosravi,
E. Mater. Sci. Technol. 1999, 20, 65-104. (b) Grubbs, R. H. J. Macromol.
Sci., Pure Appl. Chem. 1994, A31, 1829-33. (c) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413-4450.
(2) For recent reviews on ring-closing metathesis in natural product
synthesis, see: (a) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-
2238. (b) Fu¨rstner, A. Eur. J. Org. Chem. 2004, 5, 943-958. (c) Diver, S.
T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382.
demonstrate herein that this strategy leads to the efficient
synthesis of novel tri- and pentacyclic arrays of heterocyclic
rings.4
We reasoned that the oxanorbornene-derived metathesis
substrate 1 could be prepared in an iterative fashion from
(3) For some recent representative examples, see: (a) Hebach, C.;
Kazmaier, U. J. Chem. Soc., Chem. Commun. 2003, 596-597. (b)
Schafmeister, C. E.; Po, J.; Verdine, G. L. J. Am. Chem. Soc. 2000, 122,
5891-5892. (c) Boger, D. L.; Hong, J. J. Am. Chem. Soc. 2001, 123, 8515-
8519. (d) Belvisi, L.; Colombo, L.; Colombo, M.; Di Giacomo, M.;
Manzoni, L.; Vodopivec, B.; Scolastico, C. Tetrahedron 2001, 57, 6463-
6473. (e) Fu¨rstner, A.; Grela, K.; Mathes, C.; Lehmann, C. W. J. Am. Chem.
Soc. 2000, 122, 11799-11805. (f) Smulik, J. A.; Diver, S. T.; Pan, F.; Liu,
J. O. Org. Lett. 2002, 4, 2051-2054. (g) Roy, R.; Das, S. K.; Dominique,
R.; Trono, M. C.; Hernandez-Mateo, F.; Santoyo-Gonzalez, F. Pure Appl.
Chem. 1999, 71, 565-571.
(4) For the application of ring-opening/ring-closing metathesis to syn-
thesis of polycyclic ring systems, see: (a) Lee, D.; Sello, J. K.; Scheiber,
S. L. Org. Lett. 2000, 2, 709-712. (b) Choi, T.-L.; Grubbs, R. H. Chem.
Commun. 2001, 2648-2649. (c) Zuercher, W. J.; Hashimoto, M.; Grubbs,
R. H. J. Am. Chem. Soc. 1996, 118, 6634-6640. (d) Stragies, R.; Blechert,
S. Synlett 1998, 169-170. (e) Arjona, O.; Csa´ky¨, A. G.; Murcia, M. C.;
10.1021/ol0484106 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/23/2004

optically pure â-amino acid ester 35 (Scheme 2). Saponifica-
tion of 3 followed by O-allylation provided allyl ester 4,
Scheme 3. Synthesis of 13 via Metathesis Cascade
Scheme 2. Synthesis of 9 via Metathesis Cascade
similar to those employed with 5 led to the formation of 13
in 95% yield. The N-benzyl amide functionality in 12 was
critical to the success of the seven-membered ring formation,
as it led to an increase of the population of the amide rotamer
required for the formation of 13.8
We next examined the extension of this sequence to the
metathesis of dimer 16, in which six-, seven-, and eight-
membered rings would be generated in the formation of 18.
The synthesis of the requisite metathesis substrate is outlined
in Scheme 4. Reaction of the acid chloride 14 derived from
which underwent N-alkylation (allyl bromide, sodium hy-
dride) to generate the metathesis substrate 5. Exposure of 5
to the second-generation Grubbs catalyst 66 in the presence
of ethylene led to the opening of the oxanorbornene to
generate tetraene 7. Bubbling argon through the reaction
mixture to purge the system of ethylene at 25 °C initially
afforded the six-membered tetrahydropyridine ring interme-
diate 8. Warming the resulting solution to reflux for 2 h gave
9, the product of two metathesis cyclization reactions, i.e.,
closure of both the six- and seven-membered rings. The
efficiency of the metathesis cascade proved to be dependent
on the concentration of 5. Reaction of 5 with the Grubbs
catalyst 6 at 3 mM led to the formation of multiple products
and low and variable yields of 9. However, exposure of a
0.5 mM solution of 5 to 6 afforded 9 in 50% yield. The
structure and stereochemistry of 9 was secured by X-ray
crystallographic analysis of the derived secondary amine.7
The lactam analogue of 9, compound 13, was prepared in
a similar manner from 3 as outlined in Scheme 3. N-
Allylation of 3 followed by hydrolysis and condensation of
the resulting carboxylic acid with allylamine gave amide 12.
Reaction of 12 with the Grubbs catalyst under conditions
Scheme 4. Attempted Formation of 18 via Metathesis
Cascade
Plumet, J. Tetrahedron Lett. 2000, 41, 9777-9779. (f) Usher, L. C.; Estrella-
Jimenez, M.; Ghiviriga, I.; Wright, D. L. Angew. Chem., Int. Ed. 2002, 41,
4560-4562. (g) Wrobleski, A.; Sahasrabudhe, K.; Aube´, J. J. Am. Chem.
Soc. 2004, 126, 5475-5481.
(5) Doerksen, R. J.; Chen B.; Yuan, J.; Winkler, J. D.; Klein, M. L.
Chem. Commun. 2003, 2534-2535.
(6) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(7)
acid 11 with amine 159 led to the formation of the metathesis
substrate 16 in 39% yield. However, exposure of 16 to the
(8) Lactam formation using ring-closing metathesis: Vo-Thanh, G.;
Boucard, V.; Sauriat-Dorizon, H.; Guibe´, F. Synlett. 2001, 37-40.
3822
Org. Lett., Vol. 6, No. 21, 2004

metathesis cyclization conditions employed for the formation
of 13 from 12 led to none of the desired pentacyclic product
18. Careful examination of the reaction mixture revealed that
trace amounts of 17 were produced, the result of six- and
seven-membered ring formation from 16.
To separately examine the feasibility of the formation of
the eight-membered ring in 18, we examined the metathesis
reaction of 17, the synthesis of which is outlined in Scheme
5. Grubbs metathesis of 199 with ethylene gave, after removal
the branched bicyclic moiety in promoting the trans confor-
mation of the amide shown in trans-17. The absence of
rotameric peaks in the 1H NMR spectrum of 17 is consistent
with the existence of only trans-17 and not cis-17. The failure
to observe eight-membered ring formation can therefore be
attributed to the absence of the cis conformation of the amide
(cis-17) that is required for cyclization. In the case of the
successful reaction of 12 (Scheme 3), the similar steric
environments of the N-benzyl and N-allyl groups leads to
the population of the cis- as well as the trans-amide rotamers
of 12, thereby facilitating the formation of 13.
Scheme 5. Attempted Formation of 18 via Ring-Closing
Metathesis of 17
To remove the stereoelectronic constraints of the amide
linkage in 17, we prepared sulfonamide 27. As outlined in
Scheme 6, reductive amination11 of aldehyde 2512 with the
Scheme 6. Preparation of 28 via Eight-Membered Ring
Closure of Tertiary Amine 27
amine derived from TFA salt 2413 provided 26 in good yield.
Secondary amine 26 (R ) H) was then treated with
p-toluenesulfonyl chloride (TEA, DMAP, 80%) to provide
metathesis substrate 27. We were gratified to find that
exposure of 27 to the Grubbs catalyst led to the formation
of 28 (60-80 °C, 72 h), albeit in a modest yield of 26%.
Having established that the Grubbs metathesis reaction
could be used to form the central eight-membered ring of
28, we returned to the cascade metathesis reaction of 34,
the synthesis of which is outlined in Scheme 7. Reduction
of 10 to alcohol 29, followed by Dess-Martin oxidation,
gave aldehyde 30. The reductive amination of 30 proved to
be very challenging. Addition of sodium triacetoxyboro-
hydride and acetic acid to a solution of the TFA salt of 3114
of the tert-butyl carbamate, the secondary amine 20. Reaction
of allyl amino ester 10 with Grubbs catalyst 6 and ethylene,
followed by hydrolysis of the ester 21, led to the formation
of bicyclic acid 22. The coupling of 22 and the sterically
hindered amine 20 proved to be challenging. After extensive
experimentation, we ultimately found that the metathesis
substrate 17 could be prepared in a modest 18% yield using
Mukaiyama’s reagent 23.10 Reaction of 17 with Grubbs
catalyst 6 gave none of the desired eight-membered ring-
containing product 18 under a variety of reaction conditions.
The presence of the N-benzyl group in 17 was apparently
not sterically demanding enough to overcome the effect of
(11) Abdel-Magid, A.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849-3862.
(12) Compound 25 was synthesized from 21 by reducing the methyl ester
to the alcohol (DIBAL-H, 62%) followed by oxidation to the aldehyde
(Dess-Martin periodinane, 73%).
(9) Compound 15 was synthesized by removal of the tert-butyl carbamate
of compound 19 ((i) TFA, DCM 0 °C; (ii) aq K2CO3, 56%), which in turn
resulted from the benzylation of 4 (BnBr, NaH, DMF, 78%).
(13) Compound 24 was made starting with compound 4 ((a) 30 mol %
6, ethylene, CH2Cl2 [0.5 mM], 25 °C to reflux, 31%; (b) TFA, quantitative
yield).
(10) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163.
Org. Lett., Vol. 6, No. 21, 2004
3823

31 (no TFA or CH3COOH) and aldehyde 30, which led to
the formation of a 1:1.8 mixture of the desired bis-
oxanorbornene 33 and the retro Diels-Alder product 32. The
ratio of the desired product 33 to 32 could be improved to
6:1 by immediate addition of the reducing agent to the
solution of 30 and 31. Separation of 32 and 33 could be
achieved after conversion of the mixture of secondary amines
to 34 and the sulfonamide corresponding to 32.
Scheme 7. Formation of Pentacycle 28 via Metathesis
Cascade Cyclization of 34
After extensive experimentation, it was found that reaction
of 34 with a full equivalent of the Grubbs catalyst over 24
h led to the formation of 28 in 10% yield. The remarkable
metathesis cascade reaction of 34 leads to the formation of
new six-, seven-, and eight-membered rings in a single step.
Further studies on the improvement of this process are
currently underway in our laboratory, and our progress will
be reported in due course.
Acknowledgment. We would like to thank the National
Institutes of Health (CA40250) and GlaxoSmithKline for
their generous support of this program, and the University
of Pennsylvania, the Department of Energy, and Bristol-
Myers Squibb for fellowship support (S.S.).
and aldehyde 30 furnished 32 (44% overall yield from
alcohol 29), the apparent result of retro Diels-Alder reaction
of the desired reductive amination product 33. Separate
exposure of 30 to TFA led to facile retro Diels-Alder
fragmentation, establishing the lability of 30 to these acidic
reaction conditions. We therefore examined the addition of
sodium triacetoxyborohydride to a solution of the free amine
Supporting Information Available: Detailed experi-
mental procedures and spectral data for 3-34 and X-ray data
for the secondary amine derived from carbamate 9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) TFA salt of compound 31 was prepared in quantitative yield from
4 by treatment with TFA in CH2Cl2. Compound 31 was then made by
treating the TFA salt with KHCO3 (aq).
OL0484106
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Org. Lett., Vol. 6, No. 21, 2004