Telescoped synthesis of stereodefined pyrrolidines

Article abstract of DOI:10.1021/ol401554y

Telescoped and one-pot olefination/asymmetric functionalization approaches to disubstituted pyrrolidines (dr up to 99:1, up to 99% ee) have been developed using commercially available tetramisole (0.1 to 5 mol %). Using OTMS-quinidine as the Lewis base gi

Full text of DOI:10.1021/ol401554y

ORGANIC
LETTERS
2013
Vol. 15, No. 13
3472–3475
Telescoped Synthesis of Stereodefined
Pyrrolidines
Dorine Belmessieri, David B. Cordes,† Alexandra M. Z. Slawin,† and Andrew D. Smith*
EaStCHEM, School of Chemistry, University of St. Andrews, North Haugh,
St. Andrews KY16 9ST, U.K.
ads10@st-andrews.ac.uk
Received June 4, 2013
ABSTRACT
Telescoped and one-pot olefination/asymmetric functionalization approaches to disubstituted pyrrolidines (dr up to 99:1, up to 99% ee) have been
developed using commercially available tetramisole (0.1 to 5 mol %). Using OTMS-quinidine as the Lewis base gives preferential access to an anti-
configured pyrrolidine in high enantioselectivity.
The pyrrolidine motif is a valuable heterocyclic frame-
work present within a variety of natural products,1 as well
as bioactive and pharmaceutically relevant species.2 This
remarkably versatile scaffold has also been employed
as a chiral auxiliary,3 a chiral ligand,4 and an organo-
catalyst5 for a range of asymmetric transformations. The
wide-reaching applications of this five-membered hetero-
cycle have inspired many novel strategies toward its
asymmetric synthesis,6 with a range of organocatalytic
strategies having been developed.7 It is widely recognized
that a synthetic methodology leading rapidly to structural
complexity from readily available starting materials
through telescoped or one-pot reaction sequences is highly
desirable, with the minimal manual operations involved in
these processes saving time, effort, and cost. Isothioureas,8
initially used as acylation catalysts by Birman and
Okamoto,9 have proven useful organocatalysts for a range
of asymmetric processes.10 Recent work by ourselves and
Romo has utilized isothioureas to promote the catalytic
asymmetric Michael additionÀ and aldolÀlactonization
(NCAL) of a number of enoneÀacids and ketoÀacids,
† These authors contributed crystallographic determination
(1) (a) Lewis, J. R. Nat. Prod. Rep. 2001, 18, 95–128. (b) O’Hagan, D.
Nat. Prod. Rep. 2000, 17, 435–446.
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46, 8748–8758. (b) Fish, P. V.; Andrews, M. D.; Fray, M. J.; Stobie, A.;
Wakenhut, F.; Whitlock, G. A. Bioorg. Med. Chem. Lett. 2009, 19,
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1590. (b) Klatt., M.; Enders, D. Synthesis 1996, 1403–1418. (c) Kim,
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2007, 4627–4640.
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Chem., Int. Ed. 2004, 43, 5138–5175. (c) Seayad, J.; List, B. Org. Biomol.
Chem. 2005, 3, 719–724.
(6) For relevant reviews, see: (a) Moyano, A.; Rios, R. Chem. Rev.
2011, 111, 4703–4832. (b) Pellissier, H. Adv. Synth. Catal. 2012, 354,
237–294. For examples, see: (c) Sakaguchi, H.;Tokuyama, H.; Fukuyama,
T. Org. Lett. 2007, 9, 1635–1638. (d) Kawabata, T.; Majumdar, S.;
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(f) Hirai, Y.; Terada, T.; Yamazaki, T.; Momose, T. J. Chem. Soc.,
Perkin. Trans. 1 1992, 509–516.
€
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~
Beceno, C.; Raabe, G. Adv. Synth. Catal. 2010, 352, 2863–2868. (b)
Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 5652–
5653. (c) Lin, S.; Deiana, L.; Zhao, G.-L.; Sun, J.; Cordova, A. Angew.
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Chem., Int. Ed. 2011, 50, 7624–7630. (d) Jui, N. T.; Garber, J. A. O.;
Finelli, F. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 11400–
11403.
(8) For a comprehensive review of the catalytic uses of guanidines,
amidines, and isothioureas, see: Taylor, J. E.; Bull, S. D.; Williams,
J. M. J. Chem. Soc. Rev. 2012, 41, 2109–2121.
(9) (a) Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W. J. Am.
Chem. Soc. 2006, 128, 6536–6537. (b) Kobayashi, M.; Okamoto, S.
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r
10.1021/ol401554y
Published on Web 06/25/2013
2013 American Chemical Society

respectively, via an assumed ammonium enolate inter-
mediate.11 Building upon these precedents, thismanuscript
describes approaches to the catalytic asymmetric syntheses
of stereodefined 2,3- and 3,4-disubstituted pyrrolidines
directly from readily available R- and β-amino acid
derivatives.12
Initial model studies upon an isolated model enone
β-amino acid 1 using pivaloyl chloride as an in situ activat-
ing agent showed that commercially available tetramisole
was the optimal catalyst for this transformation.13 While
lactone 2 could only be isolated in modest yield due to
product instability upon chromatography, conversion into
methyl ester 3 via in situ methanolysis gave reproducibly
higher isolated product yields, giving pyrrolidine 3 with
excellent diastereo- and enantiocontrol (dr 99:1, ee =
99%, Table 1).
approach to pyrrolidines was investigated. Starting from
readily prepared N-sulfonyl-protected N-allyl β-amino
acid 4, consecutive ozonolysis, Wittig olefination, and
asymmetric tetramisole-promoted Michael additionÀ
lactonization, followed by ring-opening with MeOH, gave
pyrrolidine 3. Two solvent changes were required in this
sequence, allowing 3 to be isolated as a single diastereoi-
somer in 52% isolated yield after a single chromatographic
purification (Table 2, entry 1).14 The generality of this
approach was next studied through variation of the enone
substituent and the N-protecting group. Aromatic groups
on the enone bearing either electron-donating or electron-
withdrawing substituents are readily incorporated (entries
2À4), while N-Cbz substitution was also tolerated in this
reaction sequence (entry 5).
Table 2. Synthesis of 3,4-syn-Pyrrolidines via Telescoped Wittig
Olefination/Functionalization Procedure
Table 1. Reaction Optimization
entry
P
product, R1
3, Me
dra
yieldb (%)
eec (%)
tetramisole
(mol %)
lactone 2 yieldb (%), ester 3 yieldb (%),
entry
dra
eec (%)
eec (%)
1
2
3
4
5
Ts
99:1
99:1
99:1
99:1
99:1
52
57
49
64
85
99
96
90
98
96
Ts
6, 4-MeC6H4
7, 4-CF3C6H4
8, 4-MeOC6H4
9, Me
1
2
20
5
99:1
99:1
48, 97
70, 99
67, 99
Ts
À
Ts
a Determined by H NMR spectroscopic analysis of the unpurified
reaction mixture. b Isolated yield of product following chromatography.
c Determined by chiral HPLC analysis.
1
Cbz
a Determined by 1H NMR spectroscopic analysis of the unpurified
reaction product. b Isolated yield of pyrrolidine ester over complete
reaction sequence from the β-amino acid. c Determined by chiral HPLC
analysis. d See Supporting Information for full details.
Following these model studies, the incorporation of this
sequence within a telescoped olefination/functionalization
Further work extended this process to the preparation
of proline derivatives from N-butenyl-R-amino acid 10.15
In this system, the telescoped ozonolysis, Wittig olefina-
tion and asymmetric Michael-addition lactonization/ring-
opening process again proved viable. Using 5 mol % of
tetramisole, a range of alkyl and aryl substituents within
the enone were readily incorporated (Table 3). The corre-
sponding 2,3-syn-proline derivatives were isolated after
a single chromatographic purification in 61À80% yield
as single diastereoisomers and in 91À99% ee (entries 1,
5À10). Notably, this process can be carried out on a
reasonable laboratory scale (3.5 mmol) using 1 mol % of
commercially available tetramisole without compromising
(10) For select examples, see: (a) Birman, V. B.; Guo, L. Org. Lett.
2006, 8, 4859–4861. (b) Belmessieri, D.; Joannesse, C.; Woods, P. A.;
MacGregor, C.; Jones, C.; Campbell, C. D.; Johnston, C. P.; Duguet,
ꢀ
N.; Concellon, C.; Bragg, R. A.; Smith, A. D. Org. Biomol. Chem. 2011,
9, 559–570. (c) Yang, X.; Birman, V. B. Adv. Synth. Catal. 2009, 351,
2301–2304. (d) Bumbu, V. D.; Birman, V. B. J. Am. Chem. Soc. 2011,
133, 13902–13905. (e) Yang, X.; Birman, V. B. Angew. Chem., Int. Ed.
€
2011, 50, 5533–5555. (f) Dietz, F. R.; Groeger, H. Synthesis 2009, 4208–
ꢀ
4218. (g) Joannesse, C.; Johnston, C. P.; Concellon, C.; Simal, C.; Philp,
D.; Smith, A. D. Angew. Chem., Int. Ed. 2009, 48, 8914–8918. (h) Woods,
P. A.; Morrill, L. C.; Bragg, R. A.; Smith, A. D. Chem.;Eur. J. 2011, 17,
11060. (i) Robinson, E. R. T.; Fallan, C.; Simal, C.; Slawin, A. M. Z.;
Smith, A. D. Chem. Sci. 2013, 4, 2193–2200.
(11) (a) Leverett, C. A.; Purohit, V. C.; Johnson, A. G.; Davis, R. L.;
Tantillo, D. J.; Romo, D. J. Am. Chem. Soc. 2012, 134, 13348–13356.
(b) Leverett, C.; Purohit, V.; Romo, D. Angew. Chem., Int. Ed. 2010, 49,
9479–9483. (c) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin,
A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714–2720.
(d) Simal, C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D. Angew. Chem.,
Int. Ed. 2012, 51, 3653–3657. (e) Morrill, L. C.; Lebl, T.; Slawin,
A. M. Z.; Smith, A. D. Chem. Sci. 2012, 3, 2088–2093.
(14) Isomerization of the N-tosyl enoneÀacid was observed under the
Wittig reaction conditions resulting in decreased yield. See the Support-
ing Information for details.
(12) Starting materials 4, 5, and 10 are easily synthesised in three steps
and on multigram scale from commercially available materials. See the
Supporting Information for full details.
(13) See the Supporting Information for optimization reaction and
catalyst screen.
(15) The relative and absolute configuration within 15 was confirmed
by X-ray crystal structure analysis. CCDC 934644 contains the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Org. Lett., Vol. 15, No. 13, 2013
3473

enantioselectivity or yield (entry 3), although further re-
duction in catalyst loading resulted in reduced isolated
yield (entry 4).
enantioselectivity (dr 99:1, 71 and 65% yield, ee = 98À99%;
Table 5, entries 1 and 2). Derivativaztion of N-Cbz lactone
24 with benzylamine gave 25, with N-deprotection using
Pd(OH)2 giving the parent syn-pyrrolidine 26 in 71%
yield (dr 99:1 and ee = 99%).16,17 Epimerization of
syn-25 (dr 99:1, ee = 99%) was also achieved using
NaOMe/MeOH, giving anti-28 (dr 1:99, ee = 93%) in
70% yield (Table 5).18
Table 3. Synthesis of 2,3-syn-Pyrrolidines via Telescoped Wittig
Olefination/Functionalization Procedure
Table 4. Synthesis of 2,3- and 3,4-syn-Disubstituted Pyrroli-
dines via One-Pot Metathesis Olefination/Functionalization
Procedure
entry
product, R1
11, Me
cat. (mol %) dra yieldb (%) eec (%)
1
5
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
70
60
65
30
61
61
64
76
78
80
93
97
93
92
98
93
91
93
94
99
2d
3e
4f
5
11, Me
5
11, Me
1
11, Me
0.1
5
12, t-Bu
6
13, Ph
5
7
14, 4-MeC6H4
15, 4-CF3C6H4
16, 4-ClC6H4
17, 4-MeOC6H4
5
8
5
9g
10
5
5
amino
product,
R1
yieldb
(%)
eec
entry acid
Nu-H
MeOH
dra
(%)
a Determined by 1H NMR analysis of the unpurified reaction
product. b Isolated yield of pyrrolidine ester from 10. c Determined by
chiral HPLC analysis. d Reaction performed at 0 °C. e Reaction per-
formed from 1 g of 10; see Supporting Information for full details.
f Reaction time 12 h. g The corresponding lactone could also isolated in
93% ee (45% yield).
1
10
10
10
10
10
10
10
4
11, Me
11, Me
11, Me
18, Me
99:1
99:1
99:1
99:1
99:1
99:1
75
75
73
68
72
80
75
71
80
63
97
97
98
92
97
99
96
98
97
84
2d
3e
4
MeOH
MeOH
i-PrNH2
5
MeO2CCH2NH2 19, Me
6
MeOH
MeOH
MeOH
MeOH
MeOH
20, Et
7f
8
21, 2-furyl 99:1
Cross-metathesis was next investigated as an alternative
to Wittig olefination. Optimization using N-butenyl-R-
amino acid 10 showed that CH2Cl2 could be used as a
solvent for both cross-metathesis and asymmetric cataly-
sis, allowing a one-pot process to be developed. Grubbs II
promoted cross-metathesis, followed by functionaliza-
tion using tetramisole (5 mol %), gave pyrrolidines 11
and 18À21 in 68À80% yield and 92À99% ee as a single
diastereoisomer in each case (Table 4), confirming the
robustness of tetramisole as an organocatalyst in this
protocol. Furthermore, the tetramisole loading could be
reduced to 0.1 mol % without compromising yield or
enantioselectivity (entries 1À3). In addition to methanol,
ring-opening was also performed with either isopropyla-
mine or glycine methyl ester (entries 4 and 5) and extended
to incorporate other aryl and alkyl enones (entries 6 and 7).
This one-pot methodology was also performed in the
β-amino acid series, giving pyrrolidines 3 and 22À23 in
high yield with excellent diastereo- and enantioselectivity
(dr 99:1, ee = 84À97%, entries 8À10).
3, Me
22, Et
99:1
99:1
9
10f
4
4
23, 2-furyl 99:1
a Determined by 1H NMR analysis of the unpurified reaction product.
b Isolated yield of pyrrolidine ester over complete sequence from 10 or 4.
c Determined by chiral HPLC analysis. d 1 mol % of tetramisole used.
e 0.1 mol % of tetramisole used, reaction time 12 h. f Using 10 mol % of
Grubbs II.
We next investigated a complementary and catalyst
selective route into the anti-diastereoisomeric pyrrolidines.
Following Romo’s use of cinchona alkaloid catalysts in
NCAL processes,19 the use of OTMS-quinidine was eval-
uated. Olefination of β-amino acid 5 via ozonolysis and
Wittig reaction, followed by asymmetric functionalization
using OTMS-quinidine, gave preferential access to anti-
lactone 25 (dr syn:anti 33:67). Separation of the diaster-
eoisomers via chromatography gave anti-27 in 60%
(16) ee of syn-26 determined by HPLC analysis of Cbz derivative.
(17) syn-26 was synthesised via ozonolysis/Wittig/functionalization/
ring-opening/deprotection sequence from 5 in 40% overall yield.
(18) Erosion of ee is presumably due to a competitive retro Michael/
Michael process.
(19) (a) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc.
2001, 123, 7945–7946. (b) Oh, S. H.; Cortez, G. S.; Romo, D. J. Org.
Chem. 2005, 70, 2835–2838. (c) Morris, K. A.; Arendt, K. M.; Oh, S. H.;
Romo, D. Org. Lett. 2010, 12, 3764–3767.
The ability to N-deprotect the pyrrolidine products and
accessthe alternative anti-diastereoisomericserieswas next
investigated. Olefination of readily available N-Cbz allyl
β-amino acid 5 using both ozonolysis/Wittig and metath-
esis processes, followed by asymmetric cyclization using
tetramisole, afforded N-Cbz lactone 24 in good yields and
3474
Org. Lett., Vol. 15, No. 13, 2013

Table 5. Stereodivergent Approach to 3,4-Disubstituted Pyrrolidinesa
entry olefination
cat.
drb syn:anti product yieldc (%) syn eed (%) syn product yielde (%) anti eed (%) anti
1
2
3
4
O3, Wittig
tetramisole
99:1
syn-24
syn-24
syn-24
syn-24
71
65
33
30
99
Metathesis tetramisole
99:1
98
O3, Wittig
OTMS-quinidine
33:67
33:67
(ent) 50
(ent) 37
anti-27
anti-27
60
66
97
99
Metathesis OTMS-quinidine
a Reaction conditions: (1) see Supporting Information for full details; (2) with tetramisole: Me3CCOCl (1.5 equiv), i-Pr2NEt (1.5 equiv), CH2Cl2, rt,
then, tetramisole (5 mol %), i-Pr2NEt (2.5 equiv), 1 h; with OTMS-quinidine: 29 (1.5 equiv), i-Pr2NEt (2.5 equiv), OTMS-quinidine (20 mol %), CH2Cl2,
1
rt, 2 h. b Determined by H NMR spectroscopic analysis of the unpurified reaction mixture. c Isolated yield of lactone syn-24 pyrrolidine ester over
complete sequence from 5. d Determined by chiral HPLC analysis. e Isolated yield of lactone anti-27 over complete sequence from 5.
yield (dr 1:99, ee = 97%, entry 3) and syn-24 in 33%
yield (ee = 50%). Similarly, olefination via metathesis,
followed by OTMS-quinidine mediated cyclization, gave
accesstotheanti-lactone 27(dr1:99) in66% yield and 99%
ee (Table 5, entry 4).20 In the tetramisole-promoted se-
quence, the syn-preference can be explained by invoking
pretransition state assembly I, in which the enolate oxygen
preferentially liessyn tothe S atom, allowing either anno to
σ*CÀS interaction21 or favorable electrostatic stabilization.
Preferential Michael addition anti- to the stereodirecting
Ph unit on the enolate Re-face generates the syn-product.
When OTMS-quinidine is used, the Michael addition pro-
ceeds preferentially upon the enolate Si-face (through II),
minimizing steric interactions with the ethylene bridge with-
in the quinidine skeleton and giving the anti-diastereoisomer
as the major product in high ee.
N-allyl β-amino acids and N-butenyl R-amino acid deri-
vatives have been developed. This method provides the
corresponding pyrrolidine derivatives with high diastereo-
and enantiocontrol (dr up to 99:1, up to 99% ee) using
commercially available tetramisole. OTMS-quinidine has
been identified as an alternative Lewis base catalyst to
preferentially give a 3,4-anti-pyrrolidine in high enantios-
electivity. The generality of these approaches to hetero-
and carbocycle synthesis, as well as the development of
alternative reaction processes using chiral Lewis bases in
asymmetric catalysis, are underway within our laboratory.
Acknowledgment. We thank the Royal Society for a
University Research Fellowship (A.D.S.) and the EPSRC
National Mass Spectrometry Service Centre (Swansea).
The research leading to these results has received funding
from the European Research Council under the European
Union’s Seventh Framework Programme (FP7/2007-2013)/
ERC grant agreement no. 279850
In conclusion, both telescoped and one-pot olefination/
asymmetric functionalization approaches to 2,3- or
3,4-syn-disubstituted pyrrolidines from readily available
(20) No epimerization was observed upon treatment of syn-lactone
24 under the OTMS-quinidine asymmetric cyclization reaction condi-
tions; see the Supporting Information for full details.
(21) (a) Minkin, V. I.; Minyaev, R. M. Chem. Rev. 2001, 101, 1247–
1266. (b) Brameld, K. A.; Kuhn, B.; Reuter, D. C.; Stahl, M. J. Chem. Inf.
Model 2008, 48, 1–24. (c) Nagao, Y.; Hirata, T.; Goto, S.; Sano, S.; Kakehi,
A. J. Am. Chem. Soc. 1998, 120, 3104–3110. (d) Liu, P.; Yang, X.; Birman,
V. B.; Houk, K. N. Org. Lett. 2012, 14, 3288–3291.
Supporting Information Available. Experimental pro-
cedures plus spectroscopic data for all products are
available. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 13, 2013
3475