Enantioselective synthesis of unsaturated cyclic tertiary ethers by Mo-catalyzed olefin metathesis

Full text of DOI:10.1021/ja0039177

J. Am. Chem. Soc. 2001, 123, 3139-3140
3139
Chart 1
Enantioselective Synthesis of Unsaturated Cyclic
Tertiary Ethers By Mo-Catalyzed Olefin Metathesis
Dustin R. Cefalo,† Andrew F. Kiely,† Margarita Wuchrer,†
Jennifer Y. Jamieson,‡ Richard R. Schrock,‡ and
Amir H. Hoveyda*,†
Department of Chemistry,
Merkert Chemistry Center
Boston College, Chestnut Hill, Massachusetts 02467
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed NoVember 10, 2000
One popular approach to the synthesis of optically pure
materials involves catalytic metatheses performed on substrates
that have already been accessed in the nonracemic form.1,2 A more
direct approach to enantioselective synthesis takes advantage of
a unique attribute of catalytic metathesis: structural reorganization
of an achiral substrate leading directly to a chiral nonracemic
product.3 Such an objective can now be realized with the advent
of efficient Mo-based chiral complexes represented by 1-4 (Chart
1).4 The results of our studies regarding the catalytic enantiose-
lective synthesis of unsaturated pyrans through Mo-catalyzed
alkene metathesis are reported herein. Readily available starting
materials are used to obtain optically enriched unsaturated cyclic
tertiary ethers that are difficult to access by alternative methods.
Unlike previous cases, highly strained olefins are not required as
substrates.3
Table 1.
To initiate our studies, we subjected cyclopentene 5 (Table 1)
to 5 mol % chiral Mo catalysts shown in Chart 1 (22 °C, C6H6,
12 h). Appreciable conversion was observed in all cases (Table
1), with catalysts 3a and 3b exhibiting the highest levels of
asymmetric induction. Whereas similar enantioselectivity is
obtained at 0 °C, when 5 is treated with 5 mol % 3a at 50 °C (4
h), 6 is generated in 96% ee and 87% isolated yield (see entry 1,
Table 2). Data in Table 2 indicate that a variety of cyclopentenyl
substrates undergo enantioselective Mo-catalyzed rearrangement
to afford the desired pyrans in >90% ee (>70% yield). Several
issues regarding results in Table 2 merit comment: (1) All
transformations were carried out with 5 mol % 3a. Lower catalyst
loadings may however be employed. Treatment of 5 with 2 mol
% 3a (C6H6, 55 °C) leads to the formation of 6 in 92% ee and
90% yield (>98% conv, 24 h).5 (2) All reactions may be
performed at 50 °C with 3a, except for that shown in entry 3.
Dihydropyran 10 is formed in 62% ee (53% conv, 2 h) at 50 °C;
at 80 °C (toluene), >98% conv is achieved and 10 is generated
in 93% ee and 93% yield. (3) In all the transformations in Table
2, <2% dimeric products are detected (1H NMR analysis).
The higher enantioselectivity at elevated temperatures is not
due to equilibration (ring-opening/ring-closing) of the initially
formed and less enantiopure dihydropyrans. Treatment of a sample
of 6 (53% ee) with 5 mol % optically pure 3a (C6H6, 5 mol %
diallyl ether,3 60 °C) leads to the recovery of 6 in 55% ee.
Moreover, a similar equilibration does not lead to diminution of
selectivity: when an optically enriched sample of 8 (91% ee) is
subjected to 5 mol % racemic catalyst (6 h, 50 °C), the unsaturated
pyran is recovered in 91% ee.
a Determined by 1H NMR. b Determined by chiral GLC (CDGTA);
major isomers in entries 1-2 are enantiomers of those in entries 3-5.
clopentenyl substrate i could lead to the preferential formation
of ii or iW, which would then undergo RCM to deliver the desired
pyran. Pathways (a) and (b) are more complex than previously
reported reactions of cyclobutene- and norbornene-containing
substrates,3,6 where Mo-catalyzed rupture of strained alkenes is
irreversible. Here, intermediates ii and iW can readily re-convert
to i; such a possibility renders the identity of the stereochemistry-
determining step more ambiguous. Initial AROM may be enan-
tioselective but the resulting Mo-alkylidene might revert back
to the starting cyclopentene faster than conversion to the corre-
sponding unsaturated pyran. In turn, it may be the minor product
from the AROM process that rapidly undergoes RCM and thus
the majority of products may be generated by such a route. A
third pathway (c) involves reaction through Mo-alkylidene W,
which would subsequently undergo asymmetric ring-closing/ring-
opening metathesis (ARCM/ROM). As in the case where AROM
(3) For a previous report involving structural reorganization of strained
substrates through AROM/RCM, see: Weatherhead, G. S.; Ford, J. G.;
Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 1828-1829.
(4) Complex 1: (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. Complex 2: (c) Alexander, J.
B.; Schrock, R. R.; Davis, W. M.; Hultzsch, K. C.; Hoveyda, A. H.; Houser,
J. H. Organometallics 2000, 19, 3700-3715. Complex 3a: (d) Zhu, S. 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. (e) Weatherhead,
G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.; Schrock, R. R.; Hoveyda,
A. H. Tetrahedron Lett. 2000, 41, 9553-9559. Complex 4: (f) Aeilts, S.;
Cefalo, D. R.; Bonitatbeus, Jr.; P. J.; Houser, J. H.; Hoveyda, A. H.; Schrock,
R. R. Angew. Chem., Int. Ed. 2001, 40, in press.
Several plausible mechanistic scenarios are illustrated in
Scheme 1. Asymmetric ring-opening metathesis (AROM) of cy-
† Boston College.
‡ Massachusetts Institute of Technology.
(1) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043.
(2) For representative examples, see: (a) Johannes, C. W.; Visser, M. S.;
Weatherhead G. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 8340-
8347. (b) Furstner, A.; Thiel, O. R. J. Org. Chem. 2000, 65, 1738-1742. (d)
Limanto, J.; Snapper, M. L. J. Am. Chem. Soc. 2000, 122, 8071-8072.
(5) With 1 mol % 3a, 6 is formed in 91% ee and 79% isolated yield.
(6) La, D. S.; Ford, J. G.; Sattely, E. S.; Bonitatebus, P. J.; Schrock,
R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 11603-11604.
10.1021/ja0039177 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/13/2001

3140 J. Am. Chem. Soc., Vol. 123, No. 13, 2001
Communications to the Editor
Table 2. Mo-Catalyzed Enantioselective Rearrangement of
Table 3. Acyclic Trienes to Unsaturated Pyrans by Asymmetric
Cyclopentenes to Unsaturated Pyransa
Mo-Catalyzed Metathesisa
a Conditions: 5 mol % 3a, toluene, 3 h at 50 °C and 2-3 h at 80
°C. b Entries 1-2 at 80 °C; entry 3 at 65 °C. All reactions proceed to
>98% conv. c Determined by 1H NMR analysis. d Determined by chiral
HPLC (Chiralcel OJ column, entry 1) and chiral GLC (CDGTA, entry
2 and â-DEX for entry 3). e Isolated yields.
Scheme 2
a Conditions: 5 mol % 3a, C6H6, 50 °C. b All reactions proceed to
c
>98% conv, except for entry 4 (80% conv). Isolated yields.
Enantioselectivities determined by chiral GLC (â-DEX, entries 4-5
and CDGTA, entries 1, 3) and HPLC analysis (Chiralcel OJ column,
entry 2). d Reaction carried out in toluene at 80 °C.
Scheme 1
well be due to varying involvement of different pathways in
Scheme 1.
In light of the scarcity of asymmetric protocols for the synthesis
of tertiary ethers,7 the present approach offers an efficient method
for the enantioselective preparation of difficult-to-access nonra-
cemic pyrans. The protocols described here should thus find
applications in target-oriented synthesis: unsaturated pyran 8 is
converted to the lactone moiety of the anti-HIV agent tipranavir8
by a six-step sequence (Scheme 2). The stereochemical identity
of 20 (Scheme 2) was compared to an authentic sample; this
analogy establishes the absolute stereochemistry of the product
of the Mo-catalyzed process.9,10
is stereochemistry-determining, the involvement of the cyclic
alkene is critical in establishing stereochemistry in an ARCM
mechanism.
To address these issues, we studied the reactions of the derived
triene substrates (see Table 3). We surmised that if the RCM
processes (ii f iii vs iW f ent-iii) are stereochemistry-determining
(vs the initial ROM or reaction via W), then similar levels of
selectivity should be observed with triene substrates, as intermedi-
ates ii and iW would remain equally accessible. Treatment of
trienes 15, 16, and 17 (Table 3) with the same reaction conditions
described in Table 2 leads to significantly lower enantioselectivity
(35, 30, and 77% ee, respectively). These findings suggest that
AROM or ARCM involving the cyclic cyclopentyl olefin are (at
least) partially responsible for the levels of asymmetric induction
shown in Table 2. Nevertheless, as depicted in Table 3, when
catalytic metatheses are carried out at elevated temperatures (65-
80 °C), 16 and 17 are converted to unsaturated pyrans 10 and 12
with high enantioselectivity. Although formation of 8 from 15
occurs with 74% ee, catalytic metatheses of trienes 16 and 17
deliver 10 and 12 in >99% ee and 92% ee, respectively. The
rationale for dependence of enantioselectivity on temperature may
Supporting Information Available: Experimental procedures and
spectral and analytical data for all recovered starting materials and reaction
products (PDF). This material is available free of charge via the Internet
at http//:www.acs.pubs.org.
JA0039177
(7) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445-446. (b)
Casolari, S.; D’Addario, D.; Tagliavini, E. Org. Lett. 1999, 1, 1061-1063.
(8) Fors, K. S.; Gage, J. R.; Heier, R. F.; Kelly, R. C.; Perrault, W. R.;
Wicnienski, N. J. Org. Chem. 1998, 63, 7348-7356.
(9) The stereochemical outcome, assuming a stereochemistry-determining
ROM step, is consistent with the model in ref 3.
(10) This research was supported by the NIH (GM-59426) and the NSF
(CHE-9905806). Additional assistance was provided by ChiroTech, Schering-
Plough and Natural Sciences and Engineering Research Council of Canada
(J.Y.J.). We are grateful to Dr. V. Farina of Boehringer-Ingelheim for authentic
samples of 20 and tipranavir.