Improved protocol for asymmetric, intramolecular heteroatom Michael addition using organocatalysis: Enantioselective syntheses of homoproline, pelletierine, and homopipecolic acid

Article abstract of DOI:10.1021/jo800749t

(Chemical Equation Presented) An improved protocol for the construction of enantioenriched pyrrolidine, indoline, and piperidine rings using an organocatalyzed, intramolecular heteroatom Michael addition is described. Application to the enantioselective synthesis of homoproline, homopipecolic acid, and pelletierine has been accomplished.

Full text of DOI:10.1021/jo800749t

ingly, despite the wealth of research directed toward piperidine-
and pyrrolidine-based alkaloids, we are aware of only limited
examples for the construction of pyrrolidine and pyrrolidine
rings using organocatalysis.5d,e,6,7 Recently, Fustero and co-
workers reported the development of an organocatalyzed
protocol for facilitating enantioselective, intramolecular hetero-
atom Michael additions.8 While this protocol was effective on
a range of substrates with generally high levels of enantiose-
lectivity, it is not without its shortcomings. Specifically, the
reaction temperatures for these transformations are low (typically
starting at -50 °C) and usually require a slow warming of the
reaction over a long period of time (e.g., “warming the resulting
solution from -50°C until -30°C over a period of 48 hours”).8
Additionally, their protocol requires the addition of benzoic acid
for the reaction to proceed at a suitable rate. This additive may
not be advantageous for acid-sensitive substrates. Independently
to this work, our own laboratory had begun developing
conditions for enantioselective, intramolecular heteroatom Michael
additions using organocatalysis which proceeded at more modest
temperatures and did not require the use of any acid additives.
Herein, we disclose an improved protocol for facilitating
enantioselective, intramolecular heteroatom Michael addition
reaction using a diaryl TMS-prolinol catalyst to construct
pyrrolidine, indoline, and piperidine ring systems and its
application to the total synthesis of homoproline, homopipecolic
acid, and pelletierine.
Improved Protocol for Asymmetric,
Intramolecular Heteroatom Michael Addition
Using Organocatalysis: Enantioselective Syntheses
of Homoproline, Pelletierine, and Homopipecolic
Acid
Erik C. Carlson, Lauren K. Rathbone, Hua Yang,
Nathan D. Collett, and Rich G. Carter*
Department of Chemistry, 153 Gilbert Hall, Oregon State
UniVersity, CorVallis, Oregon 97331
rich.carter@oregonstate.edu
ReceiVed April 03, 2008
We first chose to explore the cyclization of the piperidine
precursor 3 (Table 1). This known enal 38 can be readily
prepared by cross-metathesis of the monosubstituted alkene 1
with crotonaldehyde (2) using second generation Grubbs
catalyst. We found that use of alternate catalysts, such first
generation Grubbs catalyst or second-generation Grubbs-Hoveyda
catalyst, gave vastly inferior results. It is also worth noting that
crotonaldehyde gave consistently higher yields than acrolein.
As the product from the cyclization 4 proved unstable on the
chiral HPLC column, we reduced the aldehyde at the end of
each reaction with NaBH4 to provide the alcohol 5. The major
advance in enantioselectivity came when the TMS diphenyl-
prolinol catalyst 7 was used instead of proline (6)sleading to
An improved protocol for the construction of enantioenriched
pyrrolidine, indoline, and piperidine rings using an organo-
catalyzed, intramolecular heteroatom Michael addition is
described. Application to the enantioselective synthesis of
homoproline, homopipecolic acid, and pelletierine has been
accomplished.
Pyrrolidine- and piperidine-based ring systems are ubiquitous
in natural products. Consequently, construction of these het-
erocyclic rings systems in an enantioenriched fashion has been
a subject of considerable synthetic attention. For example, the
elegant work by Beak,1 Hoppe,2 and others3 has showcased the
ability to asymmetrically deprotonate N-protected pyrrolidines
and piperidines. Alternatively, Comins has developed an asym-
metric pyridinium salt reaction using trans-2-(R)-cumylcyclo-
hexanol chloroformate for the synthesis of enantioenriched
piperidines.4 Dipolar cycloadditions5 have also been exploited
for the construction of these heterocyclic ring systems. Interest-
(5) (a) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. ReV. 2006, 106, 4484–
¨
517. (b) Garner, P.; Kaniskan, H. U.; Hu, J.; Youngs, W. J.; Panzner, M. Org.
Lett. 2006, 8, 3647–50. (c) Hanselmann, R.; Zhou, J.; Ma., P.; Confalone, P. N.
J. Org. Chem. 2003, 68, 8739–41. (d) Ibrahem, I.; Rios, R.; Vesely, J.; Co´rdova,
A. Tetrahedron Lett. 2007, 48, 6252–57. (e) Vicario, J. L.; Reboredo, S.; Bad´ıa,
D.; Carrillo, L. Angew. Chem., Int. Ed. 2007, 46, 5168–70.
(6) Takasu, K.; Maiti, S.; Ihara, M. Heterocycles 2003, 59, 51–55.
(7) Metal-catalyzed: (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc.
1999, 121, 8959–60. (b) Taylor, M. S.; Zalatan, D.; Lerchner, A. M.; Jacobsen,
E. N. J. Am. Chem. Soc. 2005, 127, 1313–17. (c) Gandelman, M.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2005, 44, 2393–97Organocatalyzed: (d) Horstmann,
T. E.; Guerin, D. J,; Miller, S. J. Angew. Chem., Int. Ed. 2000, 39, 3635–38. (e)
Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
9328–29. (f) Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G.-L.; Co´rdova, A. Chem.
Commun. 2007, 849–51. (g) Vesely, J.; Ibrahem, I.; Rios, R.; Zhao, G.-L.; Xu,
Y.; Co´rdova, A. Tetrahedron Lett. 2007, 48, 2193. (h) Dine´r, P.; Nielsen, M.;
Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1983–87. (i) Li,
H.; Wang, J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.; Wang, W. Org. Lett.
2007, 9, 965–68. (j) Wang, J.; Zu, L.; Xie, H.; Wang, W. Synthesis 2007, 2576–
80. (k) Gerasyuto, A. I.; Hsung, R. P.; Sydorenko, N.; Slafer, B. J. Org. Chem.
2007, 70, 4248–56. (l) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis 2007,
2065–92.
(1) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc.
Chem. Res. 1996, 29, 552–60.
(2) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282–316.
(3) (a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206–25. (b) McGrath, M. J.; Bilke, J. L.; O’Brien, P. Chem.
Commun. 2006, 2607–09, and references cited within. (c) Dieter, R. K.; Topping,
C. M.; Kishan, R. C.; Lu, K. J. Am. Chem. Soc. 2001, 123, 5132–5133.
(4) (a) Comins, D. L.; Zhang, Y.-M.; Joseph, S. P. Org. Lett. 1999, 1, 657–
60. (b) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc. 1994,
116, 4719–28.
(8) Fustero, S.; Jime´nez, D.; Moscardo´, J.; Catala´n, S.; del Pozo, C. Org.
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10.1021/jo800749t CCC: $40.75
Published on Web 06/05/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5155–5158 5155

TABLE 1. Optimization of Heteroatom Michael Addition.
SCHEME 2. Synthesis of Additional Cyclization
Precursorsa
% eea
entry
catalyst
conditions
EtOH, rt 48 h
EtOH, rt 48 h
EtOH, rt 48 h
EtOH/CHCl3 (1:1), rt, 48 h
EtOH/DCE (1:1), rt, 48 h
MeOH/DCE (1:1), rt, 24 h
MeOH/DCE (1:1), -25 °C, 3 d
(% yield)
1
2
3
4
5
6
7
6 (20 mol %)
7 (20 mol %)
8 (20 mol %)
8 (20 mol %)
8 (20 mol %)
8 (20 mol %)
8 (20 mol %)
9 (40)
59 (41)
71 (29)
80 (62)
78 (80)
83 (78)
95 (70)
a This enal substrate was formed using “aged” second-generation Grubbs
catalyst which had been left in a container open to the air for a period of
3 d.
a The enantiomeric excess (ee) was determined by chiral HPLC chiral
HPLC (Daicel OD 10 µm, 4.6 mm × 250 mm column) of alcohol.
clean conversion was observed to the enal 11. Interestingly, with
newer bottles of Grubbs catalyst, a complex mixture of
compounds was observed in the metathesis reaction. After
considerable experimentation, it was discovered that an “aging”
of the commercial catalyst was required to obtain reproducible
results. The catalyst was removed from the sealed bottle and
allowed to sit on the benchtop (or in a desiccator) exposed to
air for a period of 3 days. This “aging” process has proven
critical to the success of any cross-metathesis where the Cbz
nitrogen is located five atoms away from the internal alkene
carbon (alkenes 10, 15 and 22). We are unsure as to the exact
nature of this “aging” process; however, careful inspection the
aged second-generation Grubbs catalyst 1H NMR spectrum
reveals some subtle changes in the splitting pattern in the
aromatic region. It should be noted that a somewhat related
observation has been recently reported by Blechert.11 Substitu-
tion in the R position (relative to the Cbz nitrogen) was
accomplished by a Curtius rearrangement following known
procedures.12 The ꢀ-substituted enals 24 and 25 were con-
structed from alkylation with the nitrile 19.13
SCHEME 1. Possible Mechanistic Model for Observed
Stereochemical Outcome
a 59% ee (entry 2). Further optimization with Jørgensen’s
trifluoromethyl derivative 89 led to an additional improvement
in enantioselectivity (entry 3). The use of chloroform or 1,2-
dichloroethane (DCE) led to a significant improvement in yield
(entries 5 and 6).10 The optimized conditions required the
reaction to be cooled to -25 °C (typically by placing the flask
unstirred in the freezer until complete by TLC) to yield the
product 5 in 70% yield and excellent enantioselectivity (95%
ee) (entry 7). A possible mechanistic model to address the
stereochemical outcome of the reaction is put forth in Scheme
1.
With a working catalyst system, we next began to explore
the scope of the transformation (Scheme 2). We set out to study
the effects of ring size (five versus six) as well as the effect of
substitution. The first of these two variants to be explored was
substrate 11 for producing the five-membered product 26.
Interestingly, use of the previously discussed second-generation
Grubbs conditions (crotonaldehyde, CH2Cl2, 45 °C) on the five-
membered series gave inconsistent resultssdepending solely on
the bottle of Grubbs catalyst that was used. With older bottles,
With the required precursors in hand, we next studied their
reactivity (Scheme 3). The parent pyrrolidine 26 was constructed
from enal 11 in 67% yield with 90% ee. Substitution on the
carbon backbone yielded some interesting results. In general,
dimethyl substitution in the R position led to a reduced reactivity
(presumably on steric grounds). The R-dimethyl pyrrolidine 27
required extended reaction time to proceed to completion and
(11) Vehlow, K.; Gessler, S.; Blechert, S. Angew. Chem. Int.Ed. 2007, 46,
8082–85.
(9) Marigo, M; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 794–97.
(12) Walborsky, H. M.; Topolski, M.; Hamdouchi, C.; Pankowski, J. J. Org.
Chem. 1992, 57, 6188–91.
29.(13) Toshimitsu, A.; Terao, K.; Uemura, S. J. Org. Chem. 1986, 51, 1724–
(10) One explanation for this observation could be the difference in the
dielectric constants between chloroform (4.8) and 1,2-dichloroethane (10.3).
5156 J. Org. Chem. Vol. 73, No. 13, 2008

SCHEME 3. Exploration of Scope for Organocatalyzed,
Intramolecular Heteroatom Michel Addition
SCHEME 5. Synthesis of Homopipecolic Acid
SCHEME 6. Synthesis of Pelletierine
catalyst provided the enal 33. Not surprisingly, compound 33
proved unstable and had to be immediately submitted to the
cyclization reaction upon its formation. Despite this instability,
the level of enantioselectivity in the cyclization to form indoline
34 was still quite good (92% ee) with a reasonable yield (63%).
With a working methodology developed for synthesizing
pyrrolidine, indoline and piperidine ring systems, we next sought
to demonstrate the utility of this route for the construction of
selected alkaloids and cyclic ꢀ-amino acid derivates. The cyclic
ꢀ-amino acid 3617 was selected as an initial target for application
of this methodology (Scheme 5). Oxidation of the ꢀ-amino
aldehyde 4 to the acid 35 (76%) followed by Cbz deprotection
(99%) yielded the desired material 36. Comparison of observed
optical rotation for synthetic 36 {[R]D ) -23.6 (c ) 0.11,
H2O)}with the literature value {(S)-isomer lit.18 [R]D ) +24
(c ) 0.87, H2O)} allowed us to establish the R absolute
configuration of piperidine 36.
a The enantiomeric excess (ee) was determined by chiral HPLC chiral
HPLC (Daicel OD 10 µm, 4.6 mm × 250 mm column) of alcohol. b This
alcohol contained a minor impurity that could be readily removed after
hydrogenation of the Cbz protecting group (87-90%). c The enantiomeric
excess (ee) was determined by chiral HPLC (Daicel OD 10 µm, 4.6
mm×250 mm column) of (S) Mosher ester.
SCHEME 4. Enantioselective Construction of Indoline Ring
Systemsa
Next, we set out to synthesize pelletierine (39)san alkaloid
with a storied history in natural products (Scheme 6). Piperidine
39 was isolated by Tanret in 1878;19 however, debate swirled
in the chemical community for years as to the exact structure
of this natural productsin part due to chemists’ inability to
synthesize it.20 Gilman and Marion finally resolved the issue
through NMR studies 83 years later.21 Further confirmation
came through synthesis by Beyerman and Maat in 1963.22,23
This natural product was synthesized starting from the aldehyde
4. Grignard addition yielded the secondary alcohol 37 as an
inconsequential 3:1 ratio of diastereomers which was oxidized
a Enal 33 was formed using “aged” second-generation Grubbs catalyst
which had been left in a container open to the air for a period of 3 d.
led to a reduced level of enantioselectivity. Formation of the
piperidine analogue 28 was not reliable even under extended
reaction times and increased amounts of catalyst. Conversely,
dimethyl substitution ꢀ to the amino group yielded increased
reactivity with good levels of enantiomeric excess. The increased
reaction rate is likely due to the reduced level of conformational
flexibility for the backbonesin accord with Thorpe and Ingold’s
observations.14
We were also interested in exploring the possibility of
accessing the indoline ring system 34 in an enantioselective
manner (Scheme 4). This precursor 33 was accessed from its
corresponding known o-allyl aniline 31.15 Cbz protection gave
aniline 32.16 Next, Grubbs cross-metathesis using the “aged”
(17) (a) Marshall, W. D.; Nguyen, T. T.; MacLean, D. B.; Spenser, I. D.
Can. J. Chem. 1975, 53, 41–50. (b) Murahashi, S.; Kodera, Y.; Hosomi, T.
Tetrahedron Lett. 1988, 29, 5949–52.
(18) Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R. M.;
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(19) (a) Tanret, C. Compt. Rend. 1878, 86, 1270. (b) Tanret, C. Compt. Rend.
1880, 90, 695.
(20) (a) Menzies, R. C.; Robinson, R. J. Chem. Soc., Trans. 1924, 125, 2163–
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Hirschel, M. I. Recl. TraV. Chim. Pays-Bas 1956, 75, 225–36. (f) Bowman, R. E.;
Evans, D. D. J. Chem. Soc. 1956, 2553–55. (g) Kuwata, S. Bull. Chem. Soc.
Jpn. 1960, 33, 1672–8.
(21) Gilman, R. E.; Marion, L. Bull. Soc. Chim. Fr. 1961, 1993–5.
(22) (a) Beyerman, H. C.; Maat, L. Recl. TraV. Chim. Pays-Bas 1963, 82,
1033–39. (b) Beyerman, H. C.; Maat, L. Recl. TraV. Chim. Pays-Bas 1965, 84,
385–88. (c) Beyerman, H. C.; Maat, L.; van Veen, A.; Zweistra, A. Recl. TraV.
Chim. Pays-Bas 1965, 84, 1367–79.
(14) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735–66.
(15) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem.
Soc. 2006, 128, 3130–31.
(23) (a) Tanret, G. Bull. Soc. Chim. Fr. 1920, 27, 612–24. (b) Wibaut, J. P.;
Beets, M. G. J. Recl. TraV. Chim. Pays-Bas 1940, 59, 653–58. (c) (d) Quick, J.;
Oterson, R. Synthesis 1976, 745–46. (e) Louis, C.; Mill, S.; Mancuso, V.; Hootele,
C. Can. J. Chem. 1994, 72, 1347–50. (f) Takahata, H.; Kubota, M.; Takahashi,
S.; Momose, T. Tetrahedron: Asymmetry 1996, 7, 3047–54.
(16) (a) Danishefsky, S.; Taniyama, E.; Webb, R. R., II Tetrahedron Lett.
1983, 24, 11–14. (b) Webb, R. R., II; Danishefsky, S Tetrahedron Lett. 1983,
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J. Org. Chem. Vol. 73, No. 13, 2008 5157

SCHEME 7. Synthesis of Homoproline
Experimental Section
General Procedure of Organocatalyzed Heteroatom
Michael Addition with in Situ NaBH4 Reduction. To a solution
of aldehyde (1 equiv) and MeOH (0.2 M) was added a solution of
the catalyst 8 (20 mol %) in DCE (0.04 M in catalyst 8) via syringe
at -25 °C. The reaction was placed in the freezer (-25 °C). After
being judged complete by TLC, the solution was warmed to 0 °C
and NaBH4 (3 equiv) was added. The solution was then allowed to
warm to rt. After 2 h, the reaction was quenched with HCl (2 mL
per mmol of aldehyde, 10% aq), diluted with H2O (50 mL per mmol
aldehyde), and extracted with Et2O (3 × 100 mL per mmol
aldehyde). The combined organic layers were washed with satd aq
NaCl (300 mL per mmol aldehyde), and the dried extract (MgSO4)
was concentrated in vacuo. The crude product was purified by
chromatography over silica gel, eluting with EtOAc/hexanes to give
the alcohol (60-71%).
using Dess-Martin’s periodinane to give ketone 38 in 71% yield
over two steps. Finally, hydrogenation of the Cbz protecting
group revealed (-)-pelletierine (39)24 in 99% yield.
Finally, homoproline (42) has attracted considerable attention
for its use in medicinal chemistry as well as organocatalysis
(Scheme 7).25 Our organocatalyzed heteroatom Michael addi-
tions should provide a rapid synthesis of this compound.
Following a similar sequence as was used for the construction
of homopipecolic acid, sodium chlorite oxidation followed by
Cbz deprotection yielded the target 4218in 54% yield over the
three steps. It should be noted that the oxidation of the aldehyde
40 needed to be conducted immediately after its formation; use
of purified aldehyde 40 led to a considerable erosion in
enantioselectivity.
In conclusion, an improved organocatalyzed, intramolecular
heteroatom Michael addition protocol has been developed for
the asymmetric synthesis of pyrrolidine, indoline and piperidine
derivatives. The scope of this transformation has been explored
on a series of enal precursors. Application to the synthesis of
homopipecolic acid, pelletierine and homoproline has been
demonstrated. Further utilization of this methodology in alkaloid
synthesis will be disclosed in due course.
Alcohol (R)-5. Purified by chromatography over silica gel, eluting
with 10-30% EtOAc/hexanes to give the known alcohol 58 (17.7
mg, 0.067 mmol, 70%) as a pale yellow oil. Enantiomeric excess
was determined by chiral HPLC [4.6 × 250 mm Diacel OD column,
95:5 hexanes/iPrOH, retention times 16.87 (minor) and 18.69 min
1
(major)] to be 95% ee: [R]D +14.2 (c ) 0.8, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.33-7.42 (m, 5H), 5.17 (s, 2H), 4.50-4.60
(m, 1H), 4.05-4.12 (m, 1H), 3.55-3.65 (m, 1H), 3.35-3.50 (m,
1H), 2.79 (t, J ) 12.8 Hz, 1H), 1.98 (t, J ) 13.6 Hz, 1H), 1.52-1.70
(m, 5H), 1.40-1.52 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.8,
136.7, 128.6, 128.1, 127.9, 67.4, 58.7, 47.0, 39.5, 32.6, 29.2, 25.5,
19.1; HRMS (EI+) calcd for C15H21NO3 (M+) 263.1522, found
263.1522.
Acknowledgment. Financial support was provided by the
National Institutes of Health (NIH) (GM63723) and Oregon
State University (OSU). We thank Professor Max Deinzer and
Dr. Jeff Morre´ (OSU) for mass spectra data and Dr. Roger
Hanselmann (Rib-X Pharmaceuticals) for his helpful discussions.
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Asymmetry 1996, 7, 3047–54. (b) Galinovsky, F.; Bianchetti, F.; Vogel, O.
Monatsch. Chem. 1953, 84, 1221.
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Pousset, C.; Callens, R.; Marinetti, A.; Larcheveque, M. Synlett 2004, 2766–70.
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(e) Fu¨lep, G. H.; Hoesl, C. E.; Ho¨fner, G.; Wanner, K. T. Eur. J. Med. Chem.
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Supporting Information Available: Complete experimental
1
procedures are provided, including H and 13C spectra, of all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO800749T
5158 J. Org. Chem. Vol. 73, No. 13, 2008