Catalytic enantioselective Dieckmann-type annulation: Synthesis of pyrrolidines with quaternary stereogenic centers

Article abstract of DOI:10.1002/anie.200907067

A new trick for an old dog: A Dieckmanntype cycllzation was used to synthesize the title compounds with up to 96% ee (see scheme; Bn = benzyl). The presence of a β coordinating functionality in the substrate Induces a competition between cycllzation and elimination pathways that Is influenced by the nature of the chiral llgand. A mechanistic rationale Is proposed to account for these observations.

Full text of DOI:10.1002/anie.200907067

Angewandte
Chemie
DOI: 10.1002/anie.200907067
Asymmetric Catalysis
Catalytic Enantioselective Dieckmann-Type Annulation: Synthesis of
Pyrrolidines with Quaternary Stereogenic Centers**
Jonathan D. Hargrave, Joseph C. Allen, Gabriele Kociok-Kꢀhn, Gerwyn Bish, and
Christopher G. Frost*
The stereoselective construction of all-carbon quaternary
stereogenic centers by catalytic methodology is a highly
desirable but challenging goal for synthetic chemists.[1] One
approach that has met with some degree of success is the
catalytic enantioselective conjugate addition of alkyl organ-
ometallic reagents to b,b’-disubstituted alkene acceptors.[2]
The complementary rhodium-catalyzed enantioselective
addition of aryl boronic acids[3] has also been demonstrated
to be effective in establishing quaternary stereogenic centers,
although reports are similarly scarce.[4] Tandem or domino
Scheme 1. Catalytic, enantioselective synthesis of pyrrolidines with
quaternary stereogenic centers.
catalytic reactions have emerged as valuable tools for efficient
organic synthesis, including enantioselective processes.[5] In
this context, Krische and co-workers reported an elegant
desymmetrization approach triggered by an enantioselective
formation for cyclization. To explore the feasibility of this
strategy, we examined the addition of 4-methoxyphenylbor-
onic acid (4a) to substrates 1–3 in the presence of [{RhCl-
(C2H4)2}2] and rac-binap without an added proton source
(Scheme 2).
conjugate addition to reveal
a quaternary stereogenic
center.[6] Herein, we report the development of a catalytic
enantioselective Dieckmann-type annulation to form pyrro-
lidines with quaternary stereogenic centers.
The Dieckmann condensation offers a simple and effec-
tive method for the formation of carbon–carbon bonds in
organic synthesis.[7] Examples of enantioselective Die-
ckmann-type annulations are surprisingly limited to desym-
metrization processes that require two equivalents of a chiral
leaving group.[8] Our approach involves the intramolecular
reaction of a rhodium enolate with an ester to sequentially
install an aryl group and a ketone across an activated alkene
with the concomitant formation a quaternary stereogenic
center (Scheme 1).[9] The principal challenge in the asym-
metric process is that the enantioselectivity is determined at
the acylation step and not, as is common in enantioselective
conjugate addition reactions, at the insertion step. This
reaction is similar in concept to the previously reported
domino catalytic conjugate addition–enantioselective proto-
nation of 1,1’-alkenes.[10] We anticipated that the incorpora-
tion of a hemilabile coordination site within the substrate
would stabilize a reactive intermediate in a suitable con-
In initial experiments, the reactions of 1 and 2 afforded
none of the desired cyclized product. In the absence of a
nitrogen linker, quantitative conversion into the conjugate-
addition product 5a was observed. The incorporation of the
N-Boc functionality led to complete conversion into the a-
benzyl acrylate 6a. Interestingly, under the same conditions,
the N-methyl analogue 3 was converted into the cyclized
[*] Dr. J. D. Hargrave, J. C. Allen, Dr. G. Kociok-Kꢀhn, Dr. C. G. Frost
Department of Chemistry, University of Bath
Claverton Down, Bath, BA2 7AY (UK)
Fax: (+44)1225-386-231
E-mail: c.g.frost@bath.ac.uk
G. Bish
Pfizer Limited
Ramsgate Road, Sandwich, Kent, CT13 9NJ (UK)
[**] This research was supported by the EPSRC. We also thank Dr.
Anneke Lubben (mass spectrometry) and Dr. John Lowe (NMR) for
valuable assistance.
Scheme 2. Domino catalytic conjugate addition–Dieckmann annula-
tion. Reaction conditions: [{Rh(ethylene)2Cl}2] (2.5 mol%), rac-binap
(5.5 mol%), 4a, KOH, THF, 678C. Boc=tert-butoxycarbonyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907067.
Angew. Chem. Int. Ed. 2010, 49, 1825 –1829
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1825

Communications
product 7a in high yield, with only trace amounts of 6a
observed by 1H NMR spectroscopy of the crude reaction
mixture. These results supported our initial hypothesis and
provided preliminary mechanistic insight into the stereoelec-
tronic influence of the N linker.
Having developed a successful racemic synthesis, we next
explored the asymmetric process with an enantiomerically
pure ligand to access pyrrolidines with quaternary stereogenic
centers (Table 1). Pleasingly, the application of enantiomer-
Table 1: Catalytic enantioselective Dieckmann-type annulation.
Scheme 3. Selected ligands used in the optimization of enantioselec-
tivity.
Entry
Ligand
Conversion [%][a]
7a/6a[b]
e.r.[c]
enantioselectivity of the reaction were consistently good for a
range of boronic acids; however, the more sterically hindered
substrate 8 afforded products with slightly lower enantiose-
lectivity. The catalytic system tolerated a range of substituents
and substitution patterns. Compound 9e proved to be
crystalline, and recrystallization resulted in an enhancement
of enantiomeric purity (e.r. > 99: < 1). The absolute config-
uration of 9e was determined to be S by X-ray crystallography
(Figure 1).[14]
1
2
3
4
5
(R)-binap
>99
>99
62
95:5
100:0
87:13
93:7
90:10
100:0
0:100
95:5
92:8
93:7
92:8
96:4
98:2
67:33
–
8:92
–
–
(R)-xylyl-binap
(R)-tol-binap
(R)-synphos
(R)-difluorphos
(R,R)-Me-duphos
(R,R,R)-dolefin
(S)-binap
89
>99
>99
>99
>99
0
6
7[d]
8
9[e]
10[f]
(S)-binap
(S)-binap
–
>99
0:100
[a] The extent of the conversion of substrate 3 into compounds 7a and
6a was determined by 1H NMR spectroscopy of the crude reaction
mixture. [b] The ratio 7a/6a was determined by 1H NMR spectroscopy of
the crude product after workup. [c] The enantiomeric ratio was
determined by HPLC analysis on a chiral phase (Chiracel OD-H, 2%
iPrOH/hexane, 0.5 mLminÀ1). [d] The product of a second conjugate
addition was isolated. [e] Reactions were carried out at 408C. [f] Reac-
tions were carried out at 1408C.
ically pure binap-type bisphosphine ligands afforded 7a as the
major product with good enantioselectivity (Table 1,
entries 1–5). In terms of enantioselectivity, the most advanta-
geous ligand proved to be (R)-difluorphos (Scheme 3).[11]
Thus, a rhodium complex generated from [{RhCl(C2H4)2}2]
(5 mol% Rh) and (R)-difluorphos (1.1 equiv with respect to
Rh) catalyzed the reaction in THF at 678C to afford the
cyclized product 7a with 96% ee (Table 1, entry 5). The
amount of elimination product 6a observed depended on the
ligand structure and reaction temperature. A striking switch
to the formation of 6a as the major (only) product was
observed when the reaction was carried out at 1408C (Table 1,
entry 10) and with the chiral bicyclo[2.2.2]octadiene (dolefin)
ligand (Table 1, entry 7).[12] In the latter case, the increase in
the rate of b elimination over cyclization could be attributed
to the increased Lewis acidity of the rhodium(I)–diene
complex relative to a rhodium(I)–bisphosphine complex.[13]
We next examined the scope of this transformation with
respect to the boronic acid with both 3 and the N-benzyl
Figure 1. X-ray crystal structure of 9e.
The efficacy of this method for the synthesis of pyrroli-
dines with quaternary stereogenic centers encouraged us to
examine other substrates. However, our attempts to carry out
an enantioselective Dieckmann-type condensation to afford
piperidines were unsuccessful. The addition of 4-methylphe-
nylboronic acid (4c) to substrate 10 in the presence of
[{RhCl(C2H4)2}2] and rac-binap resulted in the formation of
conjugate-addition product 12; the cyclization product 11 was
not observed (Scheme 4). In this case, the Dieckmann path-
way is disfavored as a result of the increased conformational
flexibility of the substrate, and protonation of the rhodium
enolate prevails.
A mechanism that is consistent with the presented
experimental observations is shown in Scheme 5.[15] The first
step is transmetalation of the aryl boronic acid to the active
rhodium complex I and association of the substrate to afford
II. Subsequent carbometalation of the activated alkene gives
analogue
8 (Table 2). Higher enantioselectivities were
observed with difluorphos (for 3) and synphos (for 8) than
with the other enantiomerically pure ligands. The yield and
1826
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 1825 –1829

Angewandte
Chemie
Table 2: Catalytic enantioselective Dieckmann-type annulation.[a]
R
Ar
Product
Yield [%] e.r.
R
Ar
Product
Yield [%] e.r.
Me 4-MeOC6H4
7a 69
98:2[b]
97:3[b]
94:6[b]
93:7[c]
Bn 4-MeC6H4
Bn 3-Cl-4-OMeC6H3
Bn 4-MeSC6H4
Me 3-thienyl
9c 62
9d 59
9e 52
7 f 40
7g 60
9h 58
93:7[d]
92:8[e]
92:8[d]
94:6[b]
95:5[b]
91:9[e]
Me 2,3-(OCH2O)C6H3
7b 63
7c 58
7d 49
9a 68
9b 54
Me 4-MeC6H4
Me 3-Cl-4-OMeC6H3
Bn 4-MeOC6H4
89:11[d] Me 4-biphenyl
Bn 2,3-(OCH2O)C6H3
90:10[d] Bn 3-MeC6H4
[a] See the Supporting Information for detailed experimental procedures. [b] (R)-Difluorphos was used as the ligand. [c] (S)-Difluorphos was used as
the ligand. [d] (R)-Synphos was used as the ligand. [e] (S)-Synphos was used as the ligand. Bn=benzyl.
an h1-C rhodium species III,[10f] which is anticipated to be in
equilibrium with an oxa-p-allyl species[15] or h1-O rhodium
enolate.[16] The presence of a coordinating functionality in the
substrate at the b position induces competition between
cyclization and elimination pathways. The combination of
an NMe linker and a diphosphine ligand results in cyclization
to afford 7, presumably via the h1-O haptomer. Similarly, the
presence of the NBn linker facilitates cyclization to afford 9.
The treatment of substrate 3 with [{RhCl(C2H4)2}2], KOH,
and rac-binap in the absence of an aryl boronic acid resulted
1
in no change in the H NMR spectrum of 3, which suggests
Scheme 4. Attempted catalytic synthesis of piperidines with quaternary
stereogenic centers. Reaction conditions: [{Rh(C2H4)2Cl}2] (2.5 mol%),
rac-binap (5.5 mol%), 4c, KOH, THF, 808C.
À
that no elimination occurs prior to C C bond formation.
Interestingly, we observed no formation of the elimination
Angew. Chem. Int. Ed. 2010, 49, 1825 –1829
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1827

Communications
tioselective synthesis, and further applications are antici-
pated.
Received: December 15, 2009
Published online: February 4, 2010
Keywords: asymmetric catalysis · conjugate addition ·
.
Dieckmann condensation · domino catalysis · rhodium
[1] For reviews on all-carbon quaternary stereocenters, see: a) E. J.
Corey, A. Guzman-Perez, Angew. Chem. 1998, 110, 402 – 415;
Angew. Chem. Int. Ed. 1998, 37, 388 – 401; b) J. Christoffers, A.
Mann, Angew. Chem. 2001, 113, 4725 – 4732; Angew. Chem. Int.
Ed. 2001, 40, 4591 – 4597; c) I. Denissova, L. Barriault, Tetrahe-
dron 2003, 59, 10105 – 10146; d) C. J. Douglas, L. E. Overman,
Proc. Natl. Acad. Sci. USA 2004, 101, 5363 – 5367; e) E. A.
Peterson, L. E. Overman, Proc. Natl. Acad. Sci. USA 2004, 101,
11943 – 11948; f) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005,
347, 1473 – 1482; g) B. M. Trost, C. Jiang, Synthesis 2006, 369 –
396; h) Quaternary Stereocenters: Challenges and Solutions for
Organic Synthesis (Eds.: J. Christoffers, A. Baro), Wiley-VCH,
Weinheim, 2006.
[2] For selected recent examples, see: a) J. Wu, D. M. Mampreian,
A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127, 4584 – 4585;
b) A. W. Hird, A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127,
14988 – 14989; c) M. dꢀAugustin, L. Palais, A. Alexakis, Angew.
Chem. 2005, 117, 1400 – 1402; Angew. Chem. Int. Ed. 2005, 44,
1376 – 1378; d) E. Fillion, A. Wilsily, J. Am. Chem. Soc. 2006,
128, 2774 – 2775; e) K.-s. Lee, M. K. Brown, A. W. Hird, A. H.
Hoveyda, J. Am. Chem. Soc. 2006, 128, 7182 – 7184; f) D. Martin,
S. Kehrli, M. dꢀAugustin, H. Clavier, M. Mauduit, A. Alexakis, J.
Am. Chem. Soc. 2006, 128, 8416 – 8417; g) Y. Matsumoto, K.-i.
Yamada, K. Tomioka, J. Org. Chem. 2008, 73, 4578 – 4581; h) A.
Wilsily, E. Fillion, Org. Lett. 2008, 10, 2801 – 2804; i) T. L. May,
M. K. Brown, A. H. Hoveyda, Angew. Chem. 2008, 120, 7468 –
7472; Angew. Chem. Int. Ed. 2008, 47, 7358 – 7362.
[3] For reviews, see: a) T. Hayashi, Synlett 2001, 879 – 887; b) T.
Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829 – 2844; c) K.
Fagnou, M. Lautens, Chem. Rev. 2003, 103, 169 – 196; d) S.
Darses, J.-P. Genet, Eur. J. Org. Chem. 2003, 4313 – 4327; e) T.
Hayashi, Bull. Chem. Soc. Jpn. 2004, 77, 13 – 21.
[4] a) P. Mauleꢁn, J. C. Carretero, Chem. Commun. 2005, 4961 –
4963; b) R. Shintani, W.-L. Duan, T. Hayashi, J. Am. Chem.
Soc. 2006, 128, 5628 – 5629; c) R. Shintani, Y. Tsutsumi, M.
Nagaosa, T. Nishimura, T. Hayashi, J. Am. Chem. Soc. 2009, 131,
13588 – 13589.
[5] a) H. C. Guo, J. A. Ma, Angew. Chem. 2006, 118, 362 – 375;
Angew. Chem. Int. Ed. 2006, 45, 354 – 366; b) D. Enders, C.
Grondal, M. R. M. Hꢂttl, Angew. Chem. 2007, 119, 1590 – 1601;
Angew. Chem. Int. Ed. 2007, 46, 1570 – 1581; c) C. J. Chapman,
C. G. Frost, Synthesis 2007, 1 – 21; d) A. M. Walji, D. W. C.
MacMillan, Synlett 2007, 1477 – 1489.
[6] a) D. F. Cauble, J. D. Gipson, M. J. Krische, J. Am. Chem. Soc.
2003, 125, 1110 – 1111; b) B. M. Bocknack, L. C. Wang, M. J.
Krische, Proc. Natl. Acad. Sci. USA 2004, 101, 5421 – 5424.
[7] B. R. Davis, P. J. Garrett, Contemp. Org. Synth. 1991, 2, 806 – 829.
[8] Y. Nagao, Y. Hagiwara, T. Tohjo, Y. Hasegawa, M. Ochiai, M.
Shiro, J. Org. Chem. 1988, 53, 5986 – 5988.
Scheme 5. Mechanistic proposal for the formation of the cyclization
and elimination products.
product 6a when the product 7a was reexposed to the
reaction conditions. The experimental evidence suggests a
competitive catalytic pathway. The a-benzyl acrylate 6 could
arise from the h1-C rhodium species III through a syn b-amido
elimination pathway to afford IV in a process reminiscent of
the elimination step proposed by Darses and co-workers for
the rhodium-catalyzed reaction of unactivated Baylis–Hill-
man adducts with aryl boronic acids.[17] Alternatively, a
hydrolytic elimination pathway via V that involves the
coordination of a proton source to a h1-C rhodium inter-
mediate is postulated.[18] The dominant pathway appears to be
dictated by a ligand-dependent equilibration between rho-
dium enolate species. The enhanced Lewis acidity of the
rhodium(I)–diene complex relative to a rhodium(I)–bisphos-
phine complex would be expected to lead to an increase in the
rate of b elimination by either of the presented pathways.
Further investigations into the mechanism of this reaction and
the striking ligand effects are ongoing in our laboratories.
In conclusion, we have established a new method to form
pyrrolidines with quaternary stereogenic centers through a
catalytic enantioselective Dieckmann-type annulation. The
presence of an amine coordination site within the substrate
was necessary to stabilize a reactive intermediate in a suitable
conformation for cyclization. The asymmetric process is
triggered by the addition of an aryl boronic acid; however,
crucially, the enantioselectivity is determined at the acylation
step and not, as is common in enantioselective conjugate
addition reactions, at the insertion step. This method of
catalytic acylation is of significant potential utility in enan-
[9] J. Le Nꢃtre, D. van Mele, C. G. Frost, Adv. Synth. Catal. 2007,
349, 432 – 440.
[10] a) M. T. Reetz, D. Moulin, A. Gosberg, Org. Lett. 2001, 3, 4083 –
4085; b) C. J. Chapman, K. J. Wadsworth, C. G. Frost, J. Organo-
met. Chem. 2003, 680, 206 – 211; c) R. J. Moss, K. J. Wadsworth,
C. J. Chapman, C. G. Frost, Chem. Commun. 2004, 1984 – 1985;
d) M. P. Sibi, H. Tadamidani, K. Patil, Org. Lett. 2005, 7, 2571 –
1828
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 1825 –1829

Angewandte
Chemie
2573; e) C. G. Frost, S. D. Penrose, K. Lambshead, P. R. Raithby,
J. E. Warren, R. Gleave, Org. Lett. 2007, 9, 2119 – 2122; f) L.
Navarre, R. Martinez, S. Darses, J.-P. Genet, J. Am. Chem. Soc.
2008, 130, 6159 – 6169.
[13] a) A. Kina, Y. Yasuhara, T. Nishimura, H. Iwamura, T. Hayashi,
Chem. Asian J. 2006, 1, 707 – 711; b) S. P. Flanagan, P. J. Guiry, J.
Organomet. Chem. 2006, 691, 2125 – 2154.
[14] See the Supporting Information.
[15] T. Hayashi, M. Takahashi, Y. Takaya, M. Ogasawara, J. Am.
Chem. Soc. 2002, 124, 5052 – 5058.
[16] S. H. Bergens, B. Bosnich, J. Am. Chem. Soc. 1991, 113, 958 – 967.
[17] T. Gendrineau, N. Demoulin, L. Navarre, J.-P. Genet, S. Darses,
Chem. Eur. J. 2009, 15, 4710 – 4715.
[11] S. Jeulin, S. Duprat de Paule, V. Ratovelomanana-Vidal, J.-P.
GenÞt, N. Champion, P. Dellis, Angew. Chem. 2004, 116, 324 –
329; Angew. Chem. Int. Ed. 2004, 43, 320 – 325.
[12] a) C. Fischer, C. Defieber, T. Suzuki, E. M. Carreira, J. Am.
Chem. Soc. 2004, 126, 1628 – 1629; b) C. Defieber, H. Grutz-
macher, E. M. Carreira, Angew. Chem. 2008, 120, 4558 – 4579;
Angew. Chem. Int. Ed. 2008, 47, 4482 – 4502.
[18] The proton source could be boric acid, ethanol, or adventitious
water produced through condensation processes involving the
boronic acid.
Angew. Chem. Int. Ed. 2010, 49, 1825 –1829
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1829