Asymmetric Aldol-Ring-Closing Metathesis Strategy for the Enantioselective Construction of Six- To Nine-Membered Oxygen Heterocycles

Full text of DOI:10.1021/jo9716688

7548
J . Org. Chem. 1997, 62, 7548-7549
Sch em e 1
Asym m etr ic Ald ol-Rin g-Closin g Meta th esis
Str a tegy for th e En a n tioselective
Con str u ction of Six- to Nin e-Mem ber ed
Oxygen Heter ocycles
Michael T. Crimmins* and Allison L. Choy
Venable and Kenan Laboratories of Chemistry,
The University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
Received September 8, 1997X
The ring closing metathesis reaction has rapidly be-
come an important transformation in organic synthesis.1
Examples of many ring sizes with a variety of functional
appendages2 have been constructed by this powerful
method, largely because of the advent of the functionally
tolerant ruthenium3 and molybdenum4 carbene com-
plexes. Even kinetically and thermodynamically dis-
favored eight-membered rings have been prepared by
ring- closing metathesis. However, virtually all5 suc-
cessful eight-membered ring closures have required the
incorporation of cyclic conformational constraints6 or rigid
acyclic conformational control elements to avoid forma-
tion of dimers or oligomers.7 It is noteworthy that cyclic
constrained dienes underwent more efficient ring- closing
metathesis to form eight-membered rings when the two
olefinic chains were positioned trans on the cyclic con-
straint than when they were cis.7 Grubbs6a has at-
tributed this effect to a greater difference in energy
between the diene and the cyclic olefin in the cis-
substituted substrate. We reasoned that dienes with an
appropriate acyclic conformational bias might allow eight
(or nine)-membered ring formation and avoid the ad-
ditional strain imposed by a fused ring attached to the
newly formed cyclic olefin.
Sch em e 2
We recently reported an asymmetric aldol-ring-closing
metathesis strategy for the enantioselective synthesis of
the carbocyclic fragment of the nucleoside analogue
1592U89.8 In view of the importance of enantioselective
approaches to cyclic ethers of all sizes, particularly eight-
and nine-membered ring metabolites that are abundant
in marine algae,9 an extension of the aldol-metathesis
strategy to oxygen heterocycles seemed in order. We
report here an efficient, general strategy for the asym-
metric synthesis of six- to nine-membered cyclic ethers.10
* To whom correspondence should be address. Phone: (919) 966-
5177. FAX: (919) 962-2388. E-mail: mtc@net.chem.unc.edu.
(1) Grubbs, R. H.; Miller, S. J ., Fu, G. C. Acc. Chem. Res 1995, 28,
446-452.
(2) Selected recent applications: Kim, S. H.; Figueroa, I.; Fuchs, P.
L. Tetrahedron Lett. 1997, 38, 2601-2604. Harrity, J . P. A.; Visser,
M. S.; Gleason, J . D.; Hoveyda, A. H. J . Am. Chem. Soc. 1997, 119,
1488-1489. Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles,
M. R.; Marshall, E. L.; Procopiou, P. A. J . Chem. Soc. Chem. Commun.
1997, 155-156. Huwe, C. M.; Blechert, S. Synthesis 1997, 61-67.
Nicolaou, K. C.; Postema, M. H. D.; Yue, E. W.; Nadin, A. J . Am. Chem.
Soc. 1996, 118, 10335-10336. Yang, Z.; He, Y.; Vourloumis, D.;
Vallberg, H.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1997, 36,
166-168. Meng, D.; Su, D.-S.; Balog, A.; Bertinato, P.; Sorensen, E.
J .; Danishefsky, S. J .; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S.
B. J . Am. Chem. Soc. 1996, 119, 2733-2734.
(3) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
118, 100-110.
(4) (a) Bazan, G. C.; Oskam, J . H.; Cho, H.-N.; Park, L. Y.; Schrock,
R. R. J . Am. Chem. Soc. 1991, 113, 6899-6907 and references therein.
(b) Fukimura, O.; Fu, G. C.; Grubbs, R. H. J . Org. Chem. 1994, 59,
4029-4031.
The general strategy for the asymmetric construction
of the required dienes is illustrated in Schemes 1 and 2.
Treatment of 2-propen-1-ol, 3-buten-1-ol, and 4-penten-
1-ol, respectively, with sodium hydride and bromoacetic
acid in THF gave the R-alkoxy acids in nearly quantita-
tive yield. Subsequent exposure of the acids to pivaloyl
chloride and triethyl amine provided the mixed anhy-
drides 1a -c in situ. Acylation of the lithium salt of (S)-
2-benzyloxazolidinone with the mixed anhydrides 1a -c
provided the acyl oxazolidinones 2a -c in greater than
90% yield in all cases. Formation of the dibutylboron
(5) A single example of an N-tosylamide in the formation of an eight-
membered ring from an acyclic diene has been reported. See: Visser,
M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J . F.; Hoveyda, A. H. J . Am.
Chem. Soc. 1996, 118, 4291-4298. Immediately prior to the submission
of our manuscript, a similar approach to the metathetic construction
of medium ring cyclic ethers was reported. Linderman, R. J .; Siedlecki,
J .; O’Neill, S. A.; Sun, H. J . Am. Chem. Soc. 1997, 119, 6919-6920.
(6) (a) Miller, S. J .; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J . Am.
Chem. Soc. 1995, 117, 2108-2109. (b) Martin, S. F.; Chen, H.-J .;
Courtney, A. K.; Liao, Y.; Patzel, M.; Ramser, M. N.; Wagman, A. A.
Tetrahedron 1996, 52, 7251-7264. (c) Furstner, A.; Langeman, K. J .
Org. Chem. 1996, 61, 8746-8749. (d) Clark, J . S.; Kettle, J . G.
Tetrahedron Lett. 1997, 38, 123-126. (e) Clark, J . S.; Kettle, J . G.
Tetrahedron Lett. 1997, 38, 127-130. (f) Delgado, M.; Martin, J . D.
Tetrahedron Lett. 1997, 38, 6299-6300.
(8) Crimmins, M. T.; King, B. W. J . Org. Chem. 1996, 61, 4192-
4193.
(9) Faulkner, D. J . Nat. Prod. Rep. 1996, 13, 75 and earlier reviews
in the same series.
(10) For a review on the synthesis of medium ring cyclic ethers,
see: Moody, C. J .; Davies, M. J . In Studies in Natural Products
Chemistry; Atta-ur-Rahman, A.; Ed.; Elsevier Science Publishers: New
York, 1992; Vol. 10. For more recent examples, see: Berger, D.;
Overman, L. E.; Renhowe, P. J . Am. Chem. Soc. 1997, 119, 2446-
2452. Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J . A.
Synlett 1996, 983-984. Rychnovsky, S. D.; Dahanukar, V. H. J . Org.
Chem. 1996, 61, 7648-7649. Bratz, M.; Bullock, W. H.; Overman, L.
E.; Takemoto, T. J . Am. Chem. Soc. 1995, 117, 5958-5966.
(7) Miller, S. J .; Grubbs, R. H. J . Am. Chem. Soc. 1995, 117, 5855-
5856.
S0022-3263(97)01668-X CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 22, 1997 7549
Ta ble 1
F igu r e 1.
nium carbene (0.003 M CH2Cl2, 40 °C), an excellent yield
(73%) of the ∆-4-oxocene 10 was realized together with
17% of a dimer. An even more impressive result was
obtained upon exposure of diene 7a to ring-closing
metathesis (5-7 mol % catalyst, 0.003 M, CH2Cl2, 40 °C).
Nearly quantitative conversion (94% yield) to the ∆-4-
oxocene 11 was observed in less than 30 min with no
recovered diene and no detectable dimerization. Cyclic
ether 11 contains all the required functionality with the
exception of the C8 alkyl group, needed for the synthesis
of a variety of marine metabolites such as laurencin and
prelaureatin. The contrast in efficiency between the ring-
closing metathesis of diene 7a to ∆-4-oxocene 11 and
diene 4c to oxocene 10 can be rationalized by the relative
energies of the products. The position of the olefin has
a dramatic effect on the relative energy of the oxocene.
Oxocene 11 was calculated14 to be on the order of 3-4
kcal lower in energy than oxocene 10. This difference in
energy is presumably reflected in the transition states
for formation of the metallocyclobutane intermediates.
Also, the vicinal stereogenic centers in dienes 4c and 7a
provide access to the conformations where the olefinic
chains are gauche, which are required to facilitate ring
closure, by minimizing the difference in energy of the
three staggered conformations about the C3-C4 bond of
4c (C4-C5 bond of 7a ). The dipolar stabilization that
results from the anti disposition of the two oxygens may
contribute substantially to the stabilization of one of the
conformations with the olefinic chains gauche.
Finally, when diene 7b was exposed to ring-closing
metathesis conditions (0.003 M CH2Cl2, 40 °C, 5-7 mol
% catalyst), the nine-membered cyclic ether 12 was
obtained as the major product in 89% yield accompanied
by 10% dimers. Cyclic ether 12 is similar in substitution
to the known metabolite isolaurallene. To our knowl-
edge, this is the first example of the formation of a nine-
membered ring by ring-closing metathesis without a
cyclic conformational constraint.6f
In summary, a general, enantioselective synthesis of
six-, seven-, eight- and nine-membered cyclic ethers has
been achieved through the exploitation of an asymmetric
aldol-ring-closing metathesis strategy. Eight- and nine-
membered cyclic ethers have been prepared without the
need for a rigid cyclic conformational constraint by
incorporation of two stereogenic centers that provide
sufficient acyclic conformation bias to facilitate ring
closure. Application of this strategy to the synthesis of
a variety of pharmacologically and structurally interest-
ing molecules is underway.
a
Reactions were carried out in dichloromethane at 40 °C with
b
5-7 mol % (Cy3P)2Cl2RudCHPh. Yields are for isolated, chro-
matographically purified products.
enolate according to the standard Evans11 protocol and
addition of acrolein gave the syn aldol products 3a -c as
single detectable isomers by 300 MHz NMR. Reductive
removal of the chiral auxilliary (LiBH4, MeOH, THF)
followed by acylation of the resultant diols produced the
required dienes 4a -4c each in five synthetic steps in
good overall yield12 (>99% ee). The homologous dienes
7a ,b were prepared (Scheme 2) from 4-[(tert-butyldi-
phenylsilyl)oxy]butanal. Aldol addition of the boron
enolate of 2a or 2b to 4-[(tert-butyldiphenylsilyl)oxy]-
butanal as described above produced the aldol products
5 with excellent stereoselectivity. Subsequent removal
of the auxilliary and acylation of the resultant diols gave
the diacetates 6. Cleavage of the silyl ether with HF-
pyridine in THF, conversion of the primary alcohol to the
corresponding aryl selenide, and oxidative elimination
under standard conditions13 provided the dienes 7a and
7b.
Ring-closing metathesis reaction of diene 4a (CH2Cl2,
0.1 M, 40 °C) was carried out with 4 mol % of the Grubbs
catalyst {[(C6H11)3P]2Cl2RudCHPh}. The reaction was
complete in 30 min and produced the dihydropyran 8 (see
Table 1) in 90% yield after chromatography. Under
similar conditions, treatment of the diene 4b resulted in
predominant formation of the dimer. Fortunately, when
the concentration was lowered (0.003 M CH2Cl2, 40 °C,
5-7 mol % catalyst), the reaction resulted in exclusive
formation of the oxepene 9 in 95% yield after 2 h. More
interestingly, when diene 4c was exposed to the ruthe-
Ack n ow led gm en t. We thank the NIH and the NSF
for financial support and the Dept of Education for a
GAANN Fellowship for A.L.C.
Su p p or tin g In for m a tion Ava ila ble: Spectral data (1H,
13C NMR, IR) for compounds 4a -c, 7a -c, and 8-12 (12
pages).
(11) Evans, D. A.; Bartroli, J . A.; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127-2129.
(12) Yields are for isolated, chromatographically purified products.
Yields for the aldol reactions are based on recovered acyl oxazolidinone.
(13) Grieco, P. A.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1485-1486.
J O9716688
(14) Molecular mechanics calculations were made using the MM2
force field.