Enantioselective synthesis of medium-ring heterocycles, tertiary ethers, and tertiary alcohols by Mo-catalyzed ring-closing metathesis

Article abstract of DOI:10.1021/ja012679s

The Mo-catalyzed asymmetric ring-closing metathesis (ARCM) of various achiral trienes leads to the formation of medium-ring unsaturated heterocycles in high yield and with excellent enantioselectivity. Reactions may be carried out on gram scale and in the

Full text of DOI:10.1021/ja012679s

Published on Web 03/03/2002
Enantioselective Synthesis of Medium-Ring Heterocycles, Tertiary Ethers, and
Tertiary Alcohols by Mo-Catalyzed Ring-Closing Metathesis
Andrew F. Kiely,† Jesper A. Jernelius,† Richard R. Schrock,‡ and Amir H. Hoveyda*,†
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, and
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received December 11, 2001
The advent of chiral Mo-based catalysts, represented by 1-2,
has provided efficient pathways to optically enriched or pure five-
and six-membered ring carbo-1,2a and heterocycles.2,3 In connection
to expanding the generality of catalytic asymmetric ring-closing
metathesis (ARCM), a number of critical issues remain unresolved.
Among these is the need for efficient methods leading to enantio-
selective synthesis of medium rings, formation of which can be
hampered by competitive intermolecular homodimerization. Enan-
tioselective syntheses of seven-membered ring oxygen-containing
unsaturated heterocycles by Mo-catalyzed ARCM are disclosed
herein;4 this protocol thus significantly expands the utility of
catalytic asymmetric metathesis. Tertiary medium-ring siloxanes,
a group of products readily accessible by this method, can be easily
functionalized to deliver tertiary alcohols of high optical puritys
compounds that are often difficult to prepare by any other method.5
Next, we turned our attention to the enantioselective synthesis
of medium-ring heterocycles that bear tertiary ether sites. We
established that treatment of triene 9a with 5 mol % 1a (22 °C, 12
h) leads to the formation of siloxane 10a in 93% ee and 92% yield
after silica gel chromatography (entry 1, Table 1).6 Catalytic ARCM
Table 1. Mo-Catalyzed Asymmetric Synthesis of
Seven-Membered Siloxanes Bearing Tertiary Ether Centers
We began our studies by examining the catalytic ARCM of triene
3 (eq 1); this was based on previous success in using this diallyl
ether core in highly enantioselective syntheses of five-2b,c and six-
membered ring heterocycles.2c,g As illustrated in eq 1, only
homodimeric adduct 4 was formed in the presence of chiral
catalysts, which included complexes 1-2 (5 mol %). To facilitate
ring closure, we turned to all-terminal triene 5 (eq 2); similar
screening studies indicated that substantial amounts of homodimeric
and oligomeric compounds are still generated. To examine the
catalytic ARCM of a substrate with less steric congestion at the
olefinic sites, we synthesized triene 7 (eq 3). Although the
disubstituted olefins of 7 are homoallylic to the siloxy group and
more accessible to the purported terminal Mo-alkylidene (formed
by reaction of the catalyst with the monosubstituted olefin), we
were not optimistic about the stereochemical outcome of this
reaction. This was based on previous studies, indicating that high
stereochemical induction may be attained if the initially formed
metal-alkylidene reacts with an olefin that is directly adjacent to
the pro-stereogenic center.2a Nonetheless, as depicted in eq 3,
catalyst screening revealed that not only is 7 efficiently converted
to 8 (90-95% conv in 12 h, 22 °C) but that the seven-membered
ring heterocycle can also be isolated in 89% ee and 86% yield.6
entry
R
catalyst
conv (%);a yield (%)b
ee (%)c
1
2
3
4
5
6
Ph
a
b
c
d
e
f
1a
1c
1a
1a
1b
2c
>98; 92
>98; 98
>98; 91
>98; 92
>98; 87
>98; 90
93
94
83
90
66
47
p-BrPh
Cy
i-Pr
n-Bu
Me
a Determined by 400 MHz H NMR. b Isolated yields of products after
silica gel chromatography. c Determined by chiral HPLC (Chiralcel OJ, entry
1; Chiralcel OD, entry 2) and chiral GLC (â-DEX, entries 3-5 and CDGTA,
entry 6). See the Supporting Information for details.
1
of 9b (entry 2) proceeds with equal levels of efficiency and
selectivity. Although both 1a and 1c2d,7 perform well in effecting
the ARCM of 9a-b, the more Lewis acidic 1c proves to be a more
effective catalyst and may be preferable in these cases.8 As shown
in entries 3 and 4 of Table 1, aliphatic tertiary ethers 10c and 10d
are obtained in 83% and 90% ee (respectively) and >90% isolated
yields. It is worthy of note that the sense of stereochemical induction
in the formation of 10 is opposite to that seen in the generation of
8 (eq 3); the mechanistic basis for this difference in selectivity is
† Boston College.
‡ Massachusetts Institute of Technology.
9
2868 VOL. 124, NO. 12, 2002 J. AM. CHEM. SOC.
10.1021/ja012679s CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Functionalization of Non-Racemic Siloxane 10a
unclear. When substrates 9e and 9f (entries 5 and 6) bearing
sterically less demanding substituents are used, reactions proceed
to >98% conversion but with diminution in enantioselectivity (66%
and 47% ee, respectively).9
The transformation shown in eq 4 (f12) illustrates that medium-
ring oxepins can also be prepared enantioselectively and in good
isolated yield. However, reactions of the corresponding siloxane 7
are more facile, presumably due to favorable entropic effects
imposed by the SiMe2 group. Formation of 20-30% homodimeric
products in reaction of 11, in contrast to <2% generation of such
products when the corresponding silyl ethers are used, supports
the above hypothesis. As the enantioselective synthesis of dihy-
dropyran 14 indicates (promoted by a binaphtholate-derived
catalyst2c), unsaturated six-membered ring heterocycles may be
prepared by this method as well, allowing access to another class
of chiral unsaturated pyrans by Mo-catalyzed ARCM.2c,g
synthesis13 and are not readily prepared in the nonracemic form by
the more traditional approaches.14
Supporting Information Available: Experimental procedures and
spectral and analytical data for all products (PDF). This material is
available free of charge via the Internet at http//:www.acs.pubs.org.
References
(1) (a) La, D. S.; Ford, J. G.; Sattely, E. S.; Bonitatebus, P. J., Jr.; Schrock,
R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 11603-11604. (b)
La, D. S.; Sattely, E. S.; Ford, J. G.; Schrock, R. R.; Hoveyda, A. H. J.
Am. Chem. Soc. 2001, 123, 7767-7778.
(2) (a) Alexander, J. B.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.; Schrock,
R. R. J. Am. Chem. Soc. 1998, 120, 4041-4042. (b) La, D. S.; Alexander,
J. B.; Cefalo, D. R.; Graf, D. D.; Hoveyda, A. H.; Schrock, R. R. J. Am.
Chem. Soc. 1998, 120, 9720-9721. (c) Zhu, S.; Cefalo, D. R.; La, D. S.;
Jamieson, J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am.
Chem. Soc. 1999, 121, 8251-8259. (d) Weatherhead, G. S.; Houser, J.
H.; Ford, J. G.; Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H.
Tetrahedron Lett. 2000, 41, 9553-9559. (e) Weatherhead, G. S.; Ford, J.
G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 1828-1829. (f) Aeilts, S. L.; Cefalo, D. R.; Bonitatebus, P.
J., Jr.; Houser, J. H.; Hoveyda, A. H.; Schrock, R. R. Angew. Chem. Int.
Ed. 2001, 40, 1452-1456. (g) Cefalo, D. R.; Kiely, A. F.; Wuchrer, M.;
Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 3139-3140. (h) Hultszch, K. C.; Jernelius, J. A.; Hoveyda, A. H.;
Schrock, R. R. Angew. Chem. Int. Ed. 2002, 41, 589-593. (i) For a recent
Ru-catalyzed ARCM, see: Seiders, T. J.; Ward, D. W.; Grubbs, R. H.
Org. Lett. 2001, 3, 3225-3228.
(3) For a brief overview of catalytic enantioselective olefin metathesis, see:
Hoveyda, A. H.; Schrock, R. R. Chem. Eur. J. 2001, 7, 945-950.
(4) For examples involving use of catalytic RCM of medium rings in target-
oriented synthesis, see: (a) Crimmins, M. T.; Tabet, E. A. J. Am. Chem.
Soc. 2000, 122, 5473-5476. (b) Clark, J. S.; Hamelin, O. Angew. Chem.
Int. Ed. 2000, 39, 372-374. (c) Hirama, M.; Oishi, T.; Uehara, H.; Inoue,
M.; Maruyama, M.; Oguri, H.; Satake, M. Science 2001, 294, 1904-
1907. For an example of racemic synthesis of medium-ring siloxanes by
catalytic RCM, see: (d) Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997,
38, 4757-4760.
The present method provides a practical and cost-effective
approach for the synthesis of synthetically versatile tertiary ethers.
Catalytic ARCM of Various trienes may be effected efficiently and
with excellent enantioselectiVity on gram scale, with 1 mol %
catalyst loading (10-20 mg of catalyst for 0.5-1 g of products)
in the absence of solVent (Scheme 1); analytically pure product is
Scheme 1. Cyclic Tertiary Ethers Prepared in Large Scale,
without Solvent
(5) For representative methods for the enantioselective synthesis of tertiary
alcohols through additions to ketones, see: (a) Dosa, P. I.; Fu, G. C. J.
Am. Chem. Soc. 1998, 120, 445-446. (b) Hamashima, Y.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 7412-7413.
(6) The stereochemical identities of 8, 10d, and 10e were established through
comparison with authentic materials obtained by independent synthesis
(see the Supporting Information for details). The remaining stereochemical
assignments are by inference.
(7) Schrock, R. R.; Jamieson, J. Y.; Dolman, S. J.; Miller, S. A.; Bonitatebus,
P. J., Jr.; Hoveyda, A. H. Organometallics 2002, 21, 409-417.
(8) That various catalysts are readily prepared and are available for screening
to idenify an optimal system should be considered an attractive and positive
attribute. It is rare that reactions of different substrates are effected with
equal efficiency and selectivity by a single catalyst entity. See: Hoveyda,
A. H. Chem. Biol. 1998, 5, R187-R191.
(9) Use of the derived diphenylsilyl ethers leads to some enhancement in
asymmetric induction; as an example, the diphenylsiloxane corresponding
to 10f can be obtained in 57% ee and 86% isolated yield (cf. entry 6,
Table 1). Other catalysts or strategies will be required to obtain such
compounds with synthetically useful levels of enantiopurity; these and
related studies are in progress.
obtained by simple distillation. Even in the absence of solvent, no
detectable amounts of homodimeric adducts are formed in the
synthesis of seven-membered ring 10a.
The nonracemic chiral medium-ring siloxanes obtained are
versatile compounds that can be employed to prepare numerous
difficult-to-attain tertiary alcohols. The examples depicted in
Scheme 2 are representative. Treatment of 10a (93% ee) with MeLi
in THF (12 h, 22 °C) results in the formation of tertiary alcohol 15
(93% ee), a compound that cannot be prepared by any enantiose-
lective alkylation5a or kinetic resolution10 protocols and is suitable
for a variety of hydroxyl-directed reactions.11 Subjection of siloxane
10a to m-CPBA leads to the diastereoselective formation of epoxide
16 (>20:1);12 direct treatment of 16 with n-Bu4NF readily delivers
17 in 86% isolated yield (93% ee, >20:1). 1,3-Tertiary diols such
as 17 represent important building blocks in natural product
(10) For recent reviews of metal-catalyzed kinetic resolutions, see: (a) Hoveyda,
A. H.; Didiuk, M. T. Curr. Org. Chem. 1998, 2, 537-574. (b) Cook, G.
R. Curr. Org. Chem. 2000, 4, 869-885. (c) Keith, J. M.; Larrow, J. F.;
Jacobsen, E. N. AdV. Synth. Catal. 2001, 1, 5-26.
(11) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-
1370.
(12) The stereochemical identity of the major diastereomer of 16 was
ascertained through nOe difference experiments. See the Supporting
Information for details.
(13) For an example, see: Semmelhack, M. F.; Shanmugam, P. Tetrahedron
Lett. 2000, 41, 3567-3571.
(14) This research was supported by the NIH (GM-59426).
JA012679S
9
J. AM. CHEM. SOC. VOL. 124, NO. 12, 2002 2869