Catalytic enantioselective ring-closing metathesis by a chiral biphen- Mo complex [14]

Full text of DOI:10.1021/ja974353i

J. Am. Chem. Soc. 1998, 120, 4041-4042
4041
Scheme 2a
Catalytic Enantioselective Ring-Closing Metathesis
by a Chiral Biphen-Mo Complex
John B. Alexander,† Daniel S. La,‡ Dustin R. Cefalo,‡
Amir H. Hoveyda,*,‡ and Richard R. Schrock*,†
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
Department of Chemistry, Merkert Chemistry Center
Boston College, Chestnut Hill, Massachusetts 02167
ReceiVed December 29, 1997
Mo-based1 and Ru-based2 complexes are regularly used to
catalyze a range of ring-forming or ring-opening processes.3 Mo-
catalyzed reactions that give rise to macrocyclic trisubstituted
olefins,4 and Ru-based catalysts that effect the formation of
disubstituted olefins within large rings,5 have been employed to
fabricate an impressive array of complex molecules. In most
instances, without catalytic ring-closing metathesis (RCM), such
synthesis schemes would have been notably longer and less
convergent, if not impossible. The discovery and development
of a chiral catalyst that effects efficient asymmetric ring-closing
metathesis (ARCM) thus stands as a significant and compelling
research objective.6 Within this context, as outlined in Scheme
1, one possible scenario is where reaction by an optically pure
RCM catalyst gives rise to nonracemic cycloalkenes and acyclic
dienes. Herein, we report a chiral Mo-based complex that can
efficiently catalyze ARCM to effect the kinetic resolution of
dienes with excellent levels of enantioselectivity.
a Key: a. (CH3)2CdCH2 (20 psi), H2SO4, 65 °C, 3 h, quantitative; b.
K2CrO7, H2SO4, H2O, glacial acetic acid, 60 °C, 1h, 50%; c. NaH, 2 h;
POCl3, 1 h; H2O, Et3N, reflux, 5 h; HCl, reflux, 5 h, 95% from 3; d.
(-)-cinchonidine, EtOH, reflux, 1 h; EtOAc, acetone (5:1); HCl, EtOH,
70 °C, 1 h, 90%; Me2SO4, N,N-dimethylacetamide, 10 min, NaHCO3, 8
h, 90%; Red-Al, 2h, 89%; e. KH, THF, 8 h; Mo(CHCMe2Ph)(NAr)-
(triflate)2(dimethoxyethane), THF, 22 °C, 3 h, 64%.
0.4 mol (∼50 g). Subsequent resolution of 2 (via 3)8 affords
(S)-2. Specifically, treatment of 3 with (-)-cinchonidine (in
EtOH), followed by recrystallization, leads to the recovery of
optically pure (-)-cinchonidine salt of 3.9 The methyl ester
derivative of the nonracemic phosphoric acid is generated by
sequential treatment with 6 N HCl and dimethyl sulfate. Optically
pure (>95% enantiomeric excess (ee)) biphen (2) is obtained by
reduction of the resulting phosphoric acid methyl ester with Red-
Al ([R]D ) -53.0 (c ) 0.352, THF)). Chiral complex 1 is
accessed enantiomerically pure by the addition of the dipotassium
salt of (S)-2 to Mo(CHCMe2Ph)(NAr)(triflate)2(dimethoxyethane)
(Ar ) 2,6-(i-Pr)2C6H3); 1 is purified and isolated as a four-
coordinate species through recrystallization from Et2O.10
Scheme 1
1
Analysis of H and 13C NMR spectral data suggest that the
neophilydene ligand in 1 exists primarily as its syn isomer
1
(alkylidene H; δ 10.98 in H NMR and δ 277.1 in 13C NMR;
C6D6). An X-ray crystal structure unambiguously establishes the
stereochemical identity of the transition-metal complex. It is
important to note that, in phenoxide complexes of this type, the
syn isomer typically is in rapid equilibrium with its derived anti
rotamer; both isomers are likely available in the course of the
metathesis reaction. Although it is unclear at the present time
whether the syn or the anti form is responsible for promoting
ARCM, there is evidence that, in the case of Mo(CHCMe2Ph)-
(NAr)[(OCMe(CF3)2)]2, the anti rotamer can be as much as 105
times more reactive than the alternative syn isomer.11
To initiate our studies, we decided to use the chiral biphenol-
containing complex 1 as the catalyst. This preference was based
on the ability of the related chiral Mo systems that contain the
6,6′-dimethyl-3,3′,5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-diol unit
to control the stereochemistry of ring-opening metathesis polym-
erization.7 Synthesis of 1 begins with the commercially available
3,4-dimethylphenol, which after alkylation is subjected to biaryl
coupling conditions to afford 2; this two-step procedure delivers
the desired product in 50% yield when performed on a scale of
As illustrated in entry 1 of Table 1, when unsaturated TES
(triethylsilyl) ether 4a is subjected to 5 mol % 1 (benzene, 22
°C),12 after only 10 min, 43% 5a and 38% of the corresponding
dimeric product is formed (by the reaction of terminal olefins).
Most importantly, cyclic product 5a is obtained in 93% ee (krel
† Massachussetts Institute of Technology.
‡ Boston College.
(1) (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886. (b) Bazan, G.
C.; Schrock, R. R.; Cho, H.-N.; Gibson, V. C. Macromolecules 1991, 24,
4495-4502.
(2) Wu, Z.; Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1995, 117, 5503-5511.
(3) For recent reviews on olefin metathesis in organic synthesis, see: (a)
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-
2056. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388.
(4) Xu, Z.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena,
G. E.; Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 10302-10316 and
references therein.
(5) For example, see: 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. 1997, 119, 2733-2734.
(6) For a recent report on ARCM, see: Fujimura, O.; Grubbs, R. H. J.
Am. Chem. Soc. 1996, 118, 2499-2500. In this study, in all cases, krel e 2.5.
(7) Totland, K. M.; Boyd, T. J.; Lavoie, G. G.; Davis, W. M.; Schrock, R.
R. Macromolecules 1996, 29, 6114-6125.
(8) Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob,
A. C.; Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.; Rheingold, A. L. J.
Am. Chem. Soc. 1996, 118, 3392-3405.
(9) The stereochemical purity of the crystalline phosphoric acid-cinchoni-
dine salt is readily established through 31P NMR analysis of the derived (-)-
cinchonidine salt. Deprotonation of free phosphonic acid with (-)-cinchonidine
affords a mixture of diastereomeric salts with resonances at -0.32 and -0.44
in31P NMR spectrum (5% MeOH:EtOAc; H3PO4 reference).
(10) Complex 1 will be commercially available from Strem Chemicals,
Inc., Newburyport, Massachusetts.
(11) Oskam, J. H.; Schrock, R. R. J. Am. Chem. Soc. 1993, 115, 11831-
11845.
(12) ARCM can be carried out in toluene with similar levels of efficiency
and enantioselection.
S0002-7863(97)04353-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/15/1998

4042 J. Am. Chem. Soc., Vol. 120, No. 16, 1998
Communications to the Editor
Table 1. Kinetic Resolution of Acyclic Dienes Catalyzed by Mo Complex 1a
reaction time (min);
conv (%)
percent
percent
dimerb
unreacted substrate
product
ee (%)c
entry
substrate
product
R
productb
config, ee (%)c
kfast/kslow
1
2
3
4
5
6
7
8
4a
4b
4c
4d
6
8
9
5a
5b
5c
5d
7
5a
10
12
a, R ) TES
b, R ) TBS
c, R ) TBDPS
d, R ) Bn
10; 81
60; 75
120; 83
180; 76
120; 50
5; 59
43
42
43
41
40
55
<5
47
38
33
40
35
10
<5
50
11
R, >99
R, >99
R, 95
R, 91
<5
93
93
92
85
<5
65
58d
56d
52d
22d
R, 97
11e
4e
120; 50
30; 58
11
R, 57
45
1
a Reaction conditions: 5 mol % 1, C6H6, Ar atm, 22 °C. Mass balance >90%. b Conversion determined by analysis of 400 MHz H NMR of
unpurified mixture. c Enantioselectivity determined by GLC analysis (CHIRALDEX-GTA by Alltech) of derived acetates in comparison with authentic
material. d Relative rate calculated based on formation and selectivity of product (see ref 13). e Relative rate determined based on the recovered
starting material.
) 58)13 and the unreacted 4a (19%) is isolated in >99% ee (chiral
GLC analysis). Ring closure is slower with reduced catalyst
loadings, but resolution remains effective: with 1 mol % 1, under
otherwise identical conditions, after 4 h, 33% 5a and 33% dimer
are formed. Chiral GLC analysis indicates that the RCM product
5a is generated in 95% ee, whereas 4a is recovered in 70% ee.
Entries 2 and 3 indicate that similarly high levels of enantiose-
lectivity and reaction efficiency are obtained with the bulkier silyl
protective groups (4b and 4c as substrates). When the smaller
benzyloxy group is used (entry 4), catalytic ARCM proceeds
smoothly and resolution efficiency remains high (krel)22).
As the example in entry 5 depicts (6 f 7), when the stereogenic
center is positioned R to the terminal alkene, dimer formation is
diminished, but efficient catalytic kinetic resolution is not
achieved. This finding suggests that formation of Mo-alkylidene
of the substrate terminal olefin is reversible and does not occur
with significant stereodifferentiationsit is the subsequent forma-
tion or the decomposition of the metallabicyclobutane that
determines the identity of the faster reacting enantiomer. With
substrates such as 4a-c, significant diastereotopic face dif-
ferentiation is attained in the cyclic transition state for the addition
of the terminal metal-carbene to the trisubstituted olefin (en route
to metallabicyclobutane).
diene 8 affords 55% of cyclic product 5a and <5% dimeric
product after only 5 min. The recovered starting material is
obtained in 97% ee (krel ) 11). This result, together with the
data in entry 1, indicates that both the starting diene and the
product cycloalkene can be isolated in excellent optical purity
and good yield, depending on whether the trisubstituted (e.g., 4a)
or the 1,1-disubstituted olefin (e.g., 8) is utilized as the starting
material. In light of the data in entry 5, it is feasible that, with
8 as the substrate, resolution efficiency suffers because the chiral
Mo-alkylidene no longer selects the terminal alkene as its initial
site of reaction. That product enantioselection is higher in the
reaction of 4a than in ARCM of 8 is intriguing. It is tenable
that, in the former instance, concomitant dimerization enhances
product enantioselectivity because the slow-reacting enantiomer
concentration is simultaneously diminished through this reaction
pathway. Since the slower substrate enantiomer is consumed at
a higher rate through dimerization as the reaction proceeds,
cyclization of this isomer is expected occur less significantly than
expected. Catalytic RCM of 1,7-diene 9 (entry 7) results only in
the formation of the derived dimer. As before, dimerization is
minimized in the ARCM of the lesser substituted 11. The latter
resolution efficiency represents an improvement to previous
related results on similar substrates6 but is lower than that detected
for 8.16
To minimize dimer formation,14,15 yet attain high asymmetric
induction, we turned our attention to the 1,1-disubstituted alkene
substrate 8. We surmized that cyclization of the less-substituted
olefin would compete more effectively with dimerization to lead
to a more efficient ARCM. As shown in entry 6, reaction with
Studies in connection to the catalytic kinetic resolution of other
classes of chiral substrates, as well as catalytic enantioselective
ring-opening metathesis processes and various Mo-catalyzed
rearrangements,15 are in progress.
(13) The value for krel is calculated by the equation reported by Kagan:
Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330. However,
this calculation is only an approximation of the relative rates of reactions of
enantiomers, as it is based on a first-order equation, where a simultaneous
process that consumes both enantiomers (dimer formation) does not occur.
(14) Under an atmosphere of ethylene, the rate of ring closure is reduced.
Little or no change in the relative amount of dimeric product or enantiose-
lectivity is observed.
(15) For the use of ethylene atmosphere to minimize dimeric products,
see: Harrity, J. P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda, A. H. J. Am.
Chem. Soc. 1997, 119, 1488-1489.
(16) Related resolutions of the derived acetate by a related Mo complex
proceeds with significantly lower levels of efficiency (see ref 6).
Acknowledgment. This research was supported by the NIH (GM-
47480 to A.H.H.) and the NSF (CHE-9632278 to A.H.H. and CHE-
9700736 to R.R.S.). D.S.L. is a Department of Education GAANN Fellow.
Supporting Information Available: Experimental procedures and
spectral and analytical data for all recovered starting materials and reaction
products, in addition to crystallographic details (52 pages, print/PDF).
See any current masthead page for ordering information and Web access
instructions.
JA974353I