Enantioselective synthesis of cyclic amides and amines through Mo-catalyzed asymmetric ring-closing metathesis

Article abstract of DOI:10.1021/ja051330s

First, an efficient method for the synthesis of optically enriched N-fused bicyclic structures is reported. Through Mo-catalyzed desymmetrization of readily available achiral polyene substrates, 5,6-, 5,7-, and 5,8-bicyclic amides can be synthesized in up to >98% ee. The effects of catalyst structure, olefin substitution, positioning of Lewis basic functional groups and ring size are examined and discussed in detail. In the second phase of investigations, a catalytic asymmetric method for highly enantioselective (up to 97% ee) synthesis of small- and medium-ring unsaturated cyclic amines is reported; optically enriched products bear a secondary amine or a readily removable Cbz or acetamide unit. Regio- and diastereo-selective functionalizations of olefins within the optically enriched amine products have been carried out. Both catalytic asymmetric methods include transformations that lead to the formation of trisubstituted as well as disubstituted cyclic alkenes. The protocols outlined herein afford various cyclic amines of high optical purity; such products are not easily accessed by alternative protocols and can be used in enantioselective total syntheses of biologically active molecules.

Full text of DOI:10.1021/ja051330s

Published on Web 05/21/2005
Enantioselective Synthesis of Cyclic Amides and Amines
through Mo-Catalyzed Asymmetric Ring-Closing Metathesis
Elizabeth S. Sattely,† G. Alexander Cortez,† David C. Moebius,†
Richard R. Schrock,‡ and Amir H. Hoveyda*,†
Contribution from the Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467, and Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
Received March 2, 2005; E-mail: amir.hoveyda@bc.edu
Abstract: First, an efficient method for the synthesis of optically enriched N-fused bicyclic structures is
reported. Through Mo-catalyzed desymmetrization of readily available achiral polyene substrates, 5,6-,
5,7-, and 5,8-bicyclic amides can be synthesized in up to >98% ee. The effects of catalyst structure, olefin
substitution, positioning of Lewis basic functional groups and ring size are examined and discussed in
detail. In the second phase of investigations, a catalytic asymmetric method for highly enantioselective (up
to 97% ee) synthesis of small- and medium-ring unsaturated cyclic amines is reported; optically enriched
products bear a secondary amine or a readily removable Cbz or acetamide unit. Regio- and diastereo-
selective functionalizations of olefins within the optically enriched amine products have been carried out.
Both catalytic asymmetric methods include transformations that lead to the formation of trisubstituted as
well as disubstituted cyclic alkenes. The protocols outlined herein afford various cyclic amines of high
optical purity; such products are not easily accessed by alternative protocols and can be used in
enantioselective total syntheses of biologically active molecules.
Introduction
One area of investigation is in connection with the develop-
ment of a class of chiral Mo-based alkylidenes (see Chart 1)4
that may be used to prepare optically enriched cyclic amines5
through catalytic asymmetric ring-closing metathesis (ARCM).6,7
As summarized in Scheme 1, we have recently disclosed that
in the presence of chiral Mo complexes, a number of achiral
N-containing trienes can be efficiently desymmetrized to afford
the derived unsaturated amines in up to >98% ee.8 These
investigations established for the first time that enantioselective
olefin metathesis can be used to obtain enantioenriched unsat-
Cyclic and acyclic chiral amines are important building blocks
required for the synthesis of a variety of biologically active
organic molecules. Design and development of catalytic methods
that lead to enantioselective formation of N-containing com-
pounds therefore define an important area of research in organic
synthesis.1 Within this context, several programs in these
laboratories have been focused on the discovery and utility of
various chiral catalysts that promote efficient enantioselective
synthesis of a range of acyclic2 and cyclic amines3 with high
levels of optical purity.
(3) For example, see: Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2003, 125, 4018-4019.
(4) For a review on Mo-catalyzed enantioselective olefin metathesis, see:
Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592-
4633.
† Boston College.
‡ Massachusetts Institute of Technology.
(1) For reviews regarding enantioselective synthesis of amines, see: (a) Enders,
D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-1946. (b)
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094. (c) Weintraub,
P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953-2989. For representative recent reports, see: (d) Denmark, S. E.;
Stiff, C. M. J. Org. Chem. 2000, 65, 5875-5878. (e) Fujihara, H.; Nagai,
K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055-12056. (f) Dahmen,
S.; Brase, S. J. Am. Chem. Soc. 2002, 124, 5940-5941. (g) Hermanns, N.;
Dahmen, S.; Bolm, C.; Brase, S. Angew. Chem., Int. Ed. 2002, 41, 3692-
3694. (h) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984-995. (i) Boezio, A. A.; Charrette, A. B. J. Am. Chem. Soc. 2003,
125, 1692-1693. (j) Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem.
Soc. 2004, 126, 5686-5687. (l) Keith, J. M.; Jacobsen, E. N. Org. Lett.
2004, 6, 153-155. (l) Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167-
169.
(5) For a review on synthesis of N-containing compounds through catalytic
olefin metathesis, see: (a) Deiters, A.; Martin, S. F. Chem. ReV. 2004,
104, 2199-2238. For a review on catalytic RCM in alkaloid synthesis,
see: (b) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693-3712.
(6) For Mo-catalyzed ARCM, see: (a) Alexander, J. B.; La, D. S.; Cefalo, D.
R.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 4041-
4142. (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)
Weatherhead, G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.; Schrock,
R. R.; Hoveyda, A. H. Tetrahedron Lett. 2000, 41, 9553-9559. (d) 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. (e) Kiely, A. F.; Jernelius,
J. A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 2868-
2869. (f) Teng, X.; Cefalo, D. R.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 10779-10784.
(7) For Ru-catalyzed ARCM, see: (a) Seiders, T. J.; Ward, D. W.; Grubbs, R.
H. Org. Lett. 2001, 3, 3225-3228. (b) VanVeldhuizen, J. J.; Gillingham,
D. G.; Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc.
2003, 125, 12502-12508.
(8) (a) Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J. Am.
Chem. Soc. 2002, 124, 6991-6997. (b) Dolman, S. J.; Schrock, R. R.;
Hoveyda, A. H. Org. Lett. 2003, 5, 4899-4902.
(2) For example, see: (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper,
M. L. J. Am. Chem. Soc. 2001, 123, 984-985. (b) Luchaco-Cullis, C. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192-8193. (c) Akullian,
L. C.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42,
4244-4247. (d) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2004, 126, 3734-3735. (e) Mampreian, D. M.; Hoveyda,
A. H. Org. Lett. 2004, 6, 2829-2832. (f) Wu, J.; Mampreian, D. M.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 4584-4585.
9
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J. AM. CHEM. SOC. 2005, 127, 8526-8533
10.1021/ja051330s CCC: $30.25 © 2005 American Chemical Society

Enantioselective Synthesis through ARCM
A R T I C L E S
Chart 1. Representative Chiral Mo Catalysts for Olefin Metathesis
use of solvent (<2% undesired homodimeric products isolated).
As an example, conversion of 6 (Scheme 1, eq a) can be
performed neat in the presence of 4 mol % of 1c at 22 °C to
afford eight-membered ring amine 7 in 97% ee and >98%
isolated yield.
Despite the abovementioned advances, several critical ques-
tions remained unanswered. One noteworthy issue is whether
chiral Mo-based complexes can be used to initiate olefin
metathesis reactions of amine substrates where the heteroatom
does not bear an aryl substituent. As illustrated in Scheme 1,
so far, our studies have been limited to reactions of various
unsaturated arylamines. The decision to focus the first phase
of our investigations on reactions of sterically hindered aryl-
amines was based on the supposition that interaction of a Lewis
acidic Mo center with a Lewis basic nitrogen could lead to
catalyst deactivation. In addition, since conversion of arylamines
such as 7 and 9 to the derived unprotected dialkylamines (ArNR2
f HNR2) remains an inefficient procedure, development of
synthesis methods that afford optically enriched secondary
amines (HNR2) emerges as a critical objective.
Herein, we disclose the results of our investigations illustrat-
ing that Mo-based chiral alkylidenes (Chart 1) can be used to
promote ARCM of unsaturated amines that do not bear an N-aryl
group. We demonstrate that a variety of N-fused bicyclic
structures can be accessed in high optical purity through efficient
Mo-catalyzed ARCM processes. Furthermore, we put forth
catalytic protocols for enantioselective synthesis of a variety
of unsaturated 2-substituted N-containing heterocycles that
contain either unprotected secondary amines or bear an easily
removable amine protecting group (e.g., NCbz). Finally, we
report the first instances of metal-catalyzed ARCM used in the
enantioselective synthesis of cyclic amines that bear a disub-
stituted endocyclic olefin (vs a trisubstituted alkene from
reaction of an acyclic 1,1-disubstituted olefin); representative
examples of regio- and diastereoselective alkene functionaliza-
tion of the optically enriched amine products are provided.
Scheme 1. Mo-Catalyzed ARCM of Unsaturated Arylamines
Results and Discussion
1. Mo-Catalyzed Enantioselective Synthesis of N-Fused
Bicyclic Amides. The first phase of our investigations involved
examination of Mo-catalyzed ARCM reactions that would lead
to the formation of optically enriched N-fused bicyclic struc-
tures,9 represented by conversion of achiral triene i to diene ii
in Scheme 2. The initiative to develop this class of catalytic
asymmetric transformations was inspired by the presence of
these structural units in a number of biologically significant
molecules such as cytotoxic alkaloids cephalezomines B and
F,10 serratinine,11 and stemonamide,12 an alkaloid isolated from
the root of a Chinese medicinal plant (Scheme 2).
a. Synthesis of Substrates. Triene substrates were synthe-
sized as depicted by the representative cases shown in Scheme
(9) For initial key reports on the use of Mo-catalyzed RCM to synthesize
N-containing cyclic structures, see: (a) Fu, G. C.; Grubbs, R. H. J. Am.
Chem. Soc. 1992, 114, 4324-7325. (b) Houri, A. F.; Xu, Z. M.; Cogan,
D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1995, 117, 2943-2944. (c)
Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Patzel, M.; Ramser,
M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251-7264.
(10) Morita, H.; Arisaka, M.; Yoshida, N.; Kobayashi, J. Tetrahedron 2000,
56, 2929-2934.
urated hetero- and carbocyclic amines (cf. Scheme 1), products
that are more difficult to synthesize by alternative approaches.
Another notable feature of the methods summarized in Scheme
1 is the efficiency of catalytic ARCM reactions that deliver
medium ring structures, even under conditions that exclude the
(11) Morita, H.; Arisaka, M.; Yoshida, N.; Kobayashi, J. J. Org. Chem. 2000,
65, 6241-6245.
(12) Ye, Y.; Qin, G.-W.; Xu, R.-S. J. Nat. Prod. 1994, 57, 665-669.
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J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005 8527

A R T I C L E S
Scheme 2
Sattely et al.
Table 1. Initial Catalyst Screening for Mo-Catalyzed ARCM of 19
Mo
conv
(%)a
ee
(%)b
Mo
conv
(%)a
ee
(%)b
entry
complex
entry
complex
1
2
3
4
5
1a
1b
1c
2a
2c
51
43
31
90
44
63
75
77
<10
<10
6
7
8
9
3a
3c
4
53
>98
38
50
33
50
85
5
95
a Conversion to the desired product; measured by analysis of 400 MHz
1H NMR spectrum of the unpurified mixture; homodimers derived from
reaction of terminal olefins observed in several classes. b Determined by
chiral GLC analysis (CDGTA column).
3c (entry 7) provide high conversion to the desired bicyclic
amide, the optical purity of 20 is low and not at a synthetically
useful level (<10% and 33% ee, respectively). Alternatively,
biphenyl-based complexes 1a and 1b (entries 1 and 2, Table 1)
give rise to higher asymmetric induction but at substantially
lower conversion. It is chiral Mo complex 5, bearing an
alkylimido unit (entry 9), that gives rise to the most efficient
(95% conversion) and selective ARCM of 19 to afford 20. Thus,
as illustrated in entry 1 of Table 2, in the presence of 15 mol %
of 5 (to ensure reliably high levels of conversion), 20 may be
obtained in 84% yield and 85% ee after silica gel chromatog-
raphy.
Scheme 3. Synthesis of Substrates for Mo-Catalyzed
Enantioselective Synthesis of N-Fused Bicyclic Structures
c. Scope and Limitations of the Mo-Catalyzed ARCM
Method. On the basis of the positive outcome of our studies
regarding enantioselective synthesis of bicyclic amide 20 (Table
1), we investigated the Mo-catalyzed ARCM of a range of
related substrates. The results of some of these studies are
summarized in entries 2-5 of Table 2 and Scheme 4.
As depicted in entry 2 of Table 2, formation of the
5,8-bicyclic amide 22 is best effected in the presence of 15 mol
% of Mo complex 3c at 22 °C for 48 h; the desired compound
is isolated in 90% ee and 94% yield. Catalytic asymmetric
synthesis of 5,6-bicyclic amide 23 also requires 48 h but
proceeds to >98% conversion with 10 mol % catalyst loading;
in this instance, screening studies point to binaphthol-based Mo
complex 2a as the most effective chiral catalyst, affording 23
in 91% isolated yield and >98% ee.
As may be expected, triene 18a, bearing three terminal
olefins, undergoes ARCM at a faster rate (>98% conversion
with 5 mol % of 2a after 12 h). However, the efficient (92%
isolated yield) and enantioselective (88% ee) formation of 24,
an N-fused bicyclic amide that contains a disubstituted cyclic
alkene, is noteworthy for several reasons.16 In Mo-catalyzed
ARCM reactions depicted in entries 1-3 of Table 2, the catalytic
cycle is likely initiated through reaction with the terminal olefin
to afford a monosubstituted Mo alkylidene, which subsequently
reacts with one of the diastereotopic neighboring 1,1-disubsti-
3. Thus, according to a procedure reported by Bubnov13 and
co-workers, treatment of cyclic amide 12 with triallylborane
13b (R ) Me)14 led to smooth formation of amine 14 in 83%
isolated yield. Subjection of 14 to the appropriate unsaturated
alkyl halide (e.g., allyl bromide) afforded the desired ARCM
substrate. The derived amides 17a,b and 18a,b, shown in
Scheme 3, were prepared by a similar procedure (see the
Supporting Information for details).
b. Screening of Chiral Catalysts. With various triene
substrates in hand, we began the first segment of our investiga-
tion by studying the ability of various chiral Mo-based alkyl-
idenes to promote enantioselective synthesis of N-fused bicycles.
The results of a representative screening study, involving the
asymmetric formation of 5,7-bicyclic amide 20, are summarized
in Table 1. As indicated, subtle variations in the structure of
the chiral catalyst can lead to significant alteration in reaction
efficiency and/or enantioselectivity.15 For example, whereas
binaphthol-based chiral complexes 2a (entry 4, Table 1) and
(15) For a discussion of catalyst generality as a function of substrate structure,
see: Hoveyda, A. H. In Handbook of Combinatorial Chemistry; Nicolaou,
K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH: Weinheim, 2002; pp
991-1016.
(16) For an alternative approach to enantioselective synthesis of this class of
bicyclic amides, see: Groaning, M. D.; Meyers, A. I. Chem. Commun.
2000, 1027-1028.
(13) Bubnov, Y. N.; Pastukhov, F. V.; Yampolsky, I. V.; Ignatenko, A. V. Eur.
J. Org. Chem. 2000, 1503-1505.
(14) Brown, H. C.; Racherla, U. S. J. Org. Chem. 1986, 51, 427-432.
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Enantioselective Synthesis through ARCM
A R T I C L E S
Table 2. Enantioselective Synthesis of Bicyclic Lactams through Mo-Catalyzed ARCMa
a Reactions carried out in C6H6 or toluene at 22 °C. See the Supporting Information for additional experimental details. b Conversion >90% in all cases,
measured by analysis of the 400 MHz 1H NMR spectrum of the unpurified mixture; isolated yields of purified materials are reported. c Determined by chiral
GLC analysis (see Supporting Information for details). d >98% conversion to 26 (30%) and the derived achiral spirocycle 27b (70%).
Scheme 4
tuted olefins. In contrast, with substrates such as 18a, initiation
may occur at any of the three terminal olefins. Such a possibility
can lead to alternative reaction pathways that can lead to low
efficiency and/or enantioselectivity. As an example, achiral
spirocycle 27a (Scheme 4) can lead to the generation of Mo
alkylidene 28a (R ) H), which might undergo asymmetric ring-
closing metathesis/ring-opening metathesis (ARCM/ROM) to
afford 24. The above reaction route finds support in the catalytic
asymmetric conversion of triene 25 to 26 (entry 5, Table 2).
The desired bicyclic amide 26 is cleanly generated in 90% ee
but only constitutes 30% of the product mixture, 70% of which
is achiral spirocycle 27b (R ) Me, Scheme 4). Formation of
1,1-disubstituted Mo alkylidene 28b is likely unfavorable and,
if generated, it would be significantly less reactive than a
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A R T I C L E S
Sattely et al.
terminal alkylidene such as 28a.17 Accordingly, 27b cannot be
readily converted to the bicyclic final product 26. In the context
of such mechanistic complexities, it should be noted that the
enantioselectivity (88% ee) observed for the formation of 24
(R ) H) may arise from at least two different pathways: (1)
through a catalytic ARCM (18af24) that involves Mo-
alkylidene 29 (Scheme 4) as the key intermediate and (2) by a
sequence that proceeds through 18af27af28af24. To what
extent these two routes contribute to the eventual generation of
the desired product is difficult to establish rigorously at the
present time.
Scheme 5. Mo-Catalyzed ARCM of Amines and Isomeric Amides
Several additional points regarding this phase of our studies
merit mention.
(a) As indicated by the data in Tables 1 and 2, the identity
of the optimal Mo-based catalyst can change, depending on the
particular reaction at hand. For example, in studies regarding
catalytic ARCM of triene 21, leading to the formation of 5,8-
bicycle 22, all chiral alkylidenes examined, with the exception
of 3c, give rise to near exclusive formation of homodimers
derived from reactions of the terminal olefin.18 As mentioned
previously, subtle alterations in the structure of a substrate can
lead to significant differences in reactivity and selectivity. As
a result, the availability of a class of chiral catalysts (Chart 1)
offers a notable advantage; the possibility that a highly effective
chiral catalyst may be found for a particular application is more
likely when several catalyst candidates are available.
(b) As illustrated by the representative cases shown in Scheme
5 (30 f 31 and 32 f 33), Mo-catalyzed ARCM of the
corresponding amines is significantly less enantioselective. The
higher catalyst loading required for the reaction of allylic amine
30 (relative to 32) may be due, among other factors, to the
increased proximity of the electron-withdrawing heteroatom,
leading to stabilization and lower activity of the derived Mo
alkylidene.19
plausible that such modes of catalyst sequestration and deactiva-
tion are less likely with substrates such as those shown in Table
2, because of the increased distance between the terminal alkene
and the Lewis basic amide.
(d) As the example in eq 1 indicates (37 f 38), this class of
(c) Amide substrates, where the carbonyl group is positioned
on the side chain moiety, do not undergo efficient RCM
reactions. As depicted in Scheme 5, even in the presence of
highly reactive achiral 35, <2% conversion is observed in
attempts to induce amide 34 to undergo ring closure. To gain
insight into the aforementioned lack of reactivity, a mixture of
1
achiral complex 35 and triene 34 was monitored by H NMR
Mo-catalyzed ARCM can be used to effect kinetic resolution21
of the corresponding chiral diene substrates with appreciable
enantioselectivity. When the reaction is not carried out under
an atmosphere of ethylene, lower enantioselectivity is observed.
This is likely because formation of the initial Mo alkylidene
occurs at a similar rate for both enantiomers of 37. If ring closure
proceeds prior to the release of the metal alkylidene from the
slower reacting isomer, the efficiency of kinetic resolution
suffers. Ethylene reacts with the Mo alkylidene that undergoes
ring closure at a slower rate (mismatched substrate enantiomer),
thus giving rise to higher optical purity of the recovered starting
material.
spectroscopy. The resulting spectrum contains a triplet (J ) 4.7
Hz) at δ 11.97 ppm, corresponding to the formation of a new
Mo alkylidene. This observation suggests the formation of
chelated alkylidene complex 36, illustrated in Scheme 5; the
purported complex 36 would be expected to exhibit significantly
reduced levels of reactivity toward reaction with a neighboring
olefin. The lower reactivity of 36 is supported by the finding
that the above-mentioned triplet signal persists for several hours,
even when the sample is heated to 60 °C.20 It is therefore
(17) For isolation and characterization of a disubstituted Mo-based alkylidene
complex, see: Schrock, R. R.; DePue, R.; Feldman, J.; Schaverien, C. J.;
Dewan, J. C.; Liu, A. H. J. Am. Chem. Soc. 1988, 110, 1423-1435.
(18) Typically, homodimer formation is detected in all cases. However, in the
more desirable instances, the chiral catalyst converts such compounds to
the ARCM products (homodimers detected if reaction mixture is spectro-
scopically monitored).
(19) For another study where electron-deficient Mo alkylidenes exhibit lower
reactivity than their more electron-rich counterparts, see: La, D. S.; Sattely,
E. S.; Ford, J. G.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 7767-7778.
(20) For instances where similar Mo-based internal chelates have been proposed,
see: (a) Fox, H. H.; Lee, J.-K.; Park, L. Y.; Schrock, R. R. Organometallics
1993, 12, 759-768. (b) ref 9a.
2. Mo-Catalyzed Enantioselective Synthesis of N-Contain-
ing Heterocycles That Do Not Bear a Protecting Group or
Contain One That Is Readily Removable. a. Introduction.
The second phase of our studies focused on Mo-catalyzed
(21) 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.
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Enantioselective Synthesis through ARCM
A R T I C L E S
Table 3. Enantioselective Synthesis of Cyclic Amines through
desymmetrization reactions that deliver heterocyclic amines
where the N atom is either unprotected (R2NH) or bears a
protecting group that can be removed with relative ease (eq 2).
Mo-Catalyzed ARCMa
The ability of achiral Mo complexes to promote olefin metath-
esis reactions of tertiary amines (e.g., 30 f 31, Scheme 5) lends
credence to the possibility that Mo-based complexes can be used
effectively to convert readily accessible achiral substrates to
synthetically versatile N-containing cyclic structures that are
otherwise difficult to synthesize.
b. Scope and Limitations of the Mo-Catalyzed ARCM
Method. The ability of various chiral Mo complexes (Chart 1)
to effect ARCM of acetamide 39 was screened, leading us to
determine that adamantylimido complex 5 (5 mol %) promotes
the formation of 40 in 96% ee and 90% yield after purification
(entry 1, Table 3). This finding, in addition with the studies
outlined above, further indicated that highly enantioselective
Mo-catalyzed ARCM is feasible with substrates that do not bear
an N-aryl unit. We subsequently discovered that when triene
41, bearing the readily removable Cbz group, is subjected to
the same reaction conditions, unsaturated piperidine 42 is
isolated in 95% ee and 98% yield.
Next, we investigated the possibility of catalytic ARCM with
unprotected secondary amine 43 (entry 3, Table 3). Although
appreciable conversion is observed with the more reactive
achiral Mo complex 35 (5 mol %; 75% conversion after 12 h
at 22 °C), with the available chiral alkylidenes there is <2%
reaction. We surmised that such lack of reactivity is likely the
result of internal chelation between the Lewis basic amine and
the Lewis acidic Mo center. To address this reactivity issue, as
illustrated in Scheme 6, we subjected 43 to 1 equiv of
catecholborane at 22 °C (Et2O, 12 h), leading to clean formation
of azaboronate 53. Treatment of 53 (without purification) to
10 mol % of 1a (identified as optimal by examining various
Mo complexes) gives rise to formation of 44 in 87% ee and
50% overall yield (boronate removed by aqueous NaOH
workup; see the Supporting Information for details).22
a Conditions: 5 mol % of catalyst, N2 atm., C6H6, 22 °C, 24 h. See the
Supporting Information for additional experimental details. b Conversion
>98% in all cases, except 75% conversion for entry 3, 70% conversion for
entry 4, and 60% conversion for entry 6; measured by analysis of the 400
MHz 1H NMR spectrum of the unpurified mixture. Isolated yields of purified
materials are reported. c Determined by chiral HPLC or GLC of the derived
acetamides (entries 3 and 5-7) analysis (see Supporting Information for
details). d Reaction via the derived catecholate (see the text).
The Mo-catalyzed ARCM in entry 4 of Table 3, leading to
the formation of an N-substituted quaternary carbon stereogenic
center, affords unsaturated piperidine 46 in 75% ee and 63%
isolated yield. Comparison of catalytic ARCM of 45 with cyclic
amide 18b (see entry 3, Table 2) is noteworthy. These closely
related substrates, in the presence of the same optimal chiral
Mo complex (2a), undergo ring closure with significantly
different levels of asymmetric induction (75% vs >98% ee).
In contrast to amine 43 (entry 3), unprotected amine 47 readily
undergoes catalytic ARCM in the presence of 5 mol % of 1c to
generate the desired product 48 in 71% ee and 95% isolated
yield. As illustrated in entry 6 of Table 3, triene 49 is less
reactive and undergoes Mo-catalyzed ARCM with significantly
lower enantioselectivity (33% ee). The difference in reactivity
between unprotected amine 43 (entry 3) and 47 or 49 (entries
Scheme 6. Synthesis and Mo-Catalyzed ARCM of
Catechol-Protected Amines
(22) For use of borane-protected phosphines in catalytic RCM, see: Slinn, C.
A.; Redgrave, A. J.; Hind, S. L.; Edlin, C.; Nolan, S. P.; Gouvernour, V.
Org. Biomol. Chem. 2003, 1, 3820-3825.
5 and 6) may be because with sterically hindered amines internal
coordination of the Lewis acidic Mo with the Lewis basic
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A R T I C L E S
Sattely et al.
Scheme 7. Deprotection of Optically Enriched Cyclic Amines and Subsequent Functionalization
Scheme 8. Enantioselective Synthesis of Cyclic Amines Bearing
Disubstituted Olefins
appropriate chiral Mo complex (identified by screening) are
transformed to cyclic amines 58 and 61 in 86% ee (70% yield)
and 87% ee (83% yield), respectively. (R)-Coniine is obtained
in 72% yield from optically enriched 61 in two simple reductive
steps.23
Conclusions
We disclose two separate but related methods for enantio-
selective synthesis of N-containing unsaturated heterocycles
through Mo-catalyzed ARCM. In the first segment of our studies
we illustrate how various chiral Mo alkylidenes can be utilized
to access optically enriched (85 to >98% ee) N-fused bicyclic
structures of various sizes (5,6-, 5,7-, and 5,8-bicyclic amides).
Requisite substrates are readily prepared by reductive bisalkyl-
ation of succinimide, followed by alkylation of the N atom with
an appropriate unsaturated acyclic side chain. In the second
phase of our investigations, we were able to develop Mo-
catalyzed ARCM reactions that deliver unsaturated small- and
medium-ring cyclic amines in 71-97% ee. Importantly, in
several cases the substrate contains an unprotected amine and
in some instances the heteroatom is protected by the readily
removable Cbz unit.
A key feature of the studies described herein is that, unlike
previous reports, catalytic ARCM does not involve N-aryl
substrates. Furthermore, cyclic structures bearing trisubstituted
as well as disubstituted cyclic alkenes can be accessed by both
catalytic asymmetric protocols outlined in this study.24 We
demonstrate that olefins in the optically enriched amine products
can be site and diastereoselectively functionalized. The N-
containing unsaturated heterocycles obtained through the present
approach cannot be easily accessed by alternative protocols and
should prove to be of notable utility in the synthesis of
biologically important molecules.
heteroatom is less favored. Finally, as depicted in entry 7 of
Table 3, catalytic ARCM of unsaturated amine 51 leads to the
formation of the eight-membered ring amine 52 in 94% yield
and with exceptional enantioselectivity (97% ee).
c. Functionalizations and Application of the Catalytic
Asymmetric Method. The Mo-catalyzed asymmetric protocol
allows access to a variety of synthetically useful cyclic amines
in the optically enriched form. For example, as illustrated in
Scheme 7, Cbz-protected 52 (97% ee) may be readily converted
to the derived secondary amine 54 (88% yield). Alternatively,
a highly diastereo- (>98% de) and regioselective (>98%)
oxidation in the presence of 1 equiv of m-CPBA gives rise to
the formation of epoxyamine 55 in 82% yield after silica gel
chromatography. In two straightforward operations, 55 can be
converted to bicyclic amine 56 in 70% overall yield; the
stereochemical identity of 56 was established through X-ray
structure analysis (Scheme 7; see the Supporting Information
for details).
Design of new chiral catalysts for olefin metathesis, develop-
ment of additional catalytic asymmetric olefin metathesis
reactions, related mechanistic studies as well as applications to
target-oriented organic synthesis continue in these laboratories.
(23) Olefin hydrogenation in the presence of Wilkinson’s catalyst is required
before Pd-catalyzed debenzylation, since the latter conditions give rise to
substantial amounts of C-N bond cleavage.
(24) Since the majority of the substrates used in this study are solids or
semisolids, Mo-catalyzed ARCM reactions cannot be carried out easily in
the absence of solvent. In one representative case, the reaction mixture
had to be heated to achieve dissolution of the catalyst sample, leading to
significant lowering of product optical purity (reaction of 18b without
solvent at 80 °C afforded 24 in 75% ee and 62% isolated yield vs 98% ee
and 88% yield at 22 °C in benzene).
The functionalizations illustrated in Scheme 8 demonstrate a
critical aspect of the Mo-catalyzed ARCM protocol: substrates
bearing disubstituted olefins can be effectively utilized to obtain
the desired product with high selectivity. Thus, trifluoro-
acetamide 57 and benzylamine 60, in the presence of an
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8532 J. AM. CHEM. SOC. VOL. 127, NO. 23, 2005

Enantioselective Synthesis through ARCM
A R T I C L E S
Acknowledgment. This research was funded by the NIH
(GM-59426 to A. H. H. and R. R. S.). Additional support was
provided by the American Chemical Society and Wyeth
Research (2003-4 graduate fellowship to E.S.S.) and Pfizer and
NIH (predoctoral fellowships to G.A.C.). We thank Dr. Richard
Staples and Mr. Keith Griswold for obtaining the X-ray structure
of 56.
Supporting Information Available: Experimental procedures
and spectral data for substrates and products (CIF, PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA051330S
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