Diastereoselective approach to cis-4-methyl/thiol-pipecolic esters based on RCM reaction and conjugate michael addition

Article abstract of DOI:10.1080/00397911.2014.918147

A synthetic route for the access to enantiopure cis-4-methyl/thiol- pipecolic esters is presented. It is based on the ring-closing metathesis reaction to build the β-unsaturated piperidin-2-one derived from (S)-(-)-phenylethylamine, followed by either diastereoselective conjugate addition of methylorganocuprate allowing access to cis-4-methyl pipecolic ester or by tandem diastereoselective hydrosulforization-thionization reaction providing access to cis-4-thiol pipecolic ethyl esters.

Full text of DOI:10.1080/00397911.2014.918147

This article was downloaded by: [University of Winnipeg]
On: 02 September 2014, At: 02:53
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Diastereoselective Approach to cis-4-
Methyl/thiol-pipecolic Esters Based on
RCM Reaction and Conjugate Michael
Addition
Araceli Zárate a , Laura Orea a , Jorge R. Juárez a , Alejandro Castro
b , Angel Mendoza a , Dino Gnecco a & Joel L. Terán a
a Centro de Química del Instituto de Ciencias, Benemérita
Universidad Autónoma de Puebla , Puebla , Mexico
b Departamento de Investigación y Posgrado , Universidad
Politécnica de Tlaxcala , Tepeyanco , Mexico
Accepted author version posted online: 29 May 2014.Published
online: 28 Jul 2014.
To cite this article: Araceli Zárate , Laura Orea , Jorge R. Juárez , Alejandro Castro , Angel Mendoza ,
Dino Gnecco & Joel L. Terán (2014) Diastereoselective Approach to cis-4-Methyl/thiol-pipecolic
Esters Based on RCM Reaction and Conjugate Michael Addition, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:19, 2838-2847,
DOI: 10.1080/00397911.2014.918147
To link to this article: http://dx.doi.org/10.1080/00397911.2014.918147
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or

howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 44: 2838–2847, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.918147
DIASTEREOSELECTIVE APPROACH TO cis-4-METHYL/
THIOL-PIPECOLIC ESTERS BASED ON RCM REACTION
AND CONJUGATE MICHAEL ADDITION
1
Araceli Zarate, Laura Orea, Jorge R. Juarez,
1
1
´
´
Alejandro Castro,2 Angel Mendoza,1 Dino Gnecco,1 and
1
´
Joel L. Teran
1
´
Centro de Quımica del Instituto de Ciencias, Benemerita
Universidad Autonoma de Puebla, Puebla, Mexico
´
´
2
´
Departamento de Investigacion y Posgrado, Universidad
Politecnica de Tlaxcala, Tepeyanco, Mexico
´
GRAPHICAL ABSTRACT
Abstract A synthetic route for the access to enantiopure cis-4-methyl/thiol-pipecolic esters
is presented. It is based on the ring-closing metathesis reaction to build the a,b-unsaturated
piperidin-2-one derived from (S)-(–)-phenylethylamine, followed by either diastereoselec-
tive conjugate addition of methylorganocuprate allowing access to cis-4-methyl pipecolic
ester or by tandem diastereoselective hydrosulforization–thionization reaction providing
access to cis-4-thiol pipecolic ethyl esters.
Keywords Diastereoselective Michael addition; hydrosulforization; pipecolic esters;
ring-closing metathesis
INTRODUCTION
Cyclic a-amino acids are present in many biologically important compounds.[1]
Specifically, 4-substituted pipecolic acids (4-substituted piperidine-2-carboxylic acid)
and their derivatives are key fragments of compounds of pharmacological interest.
Received January 27, 2014.
´
´
´
Address correspondence to Joel Luis Teran Vazquez, Centro de Quımica del Instituto de Ciencias,
Beneme´rita Universidad Auto´noma de Puebla, Edif. 103H, Complejo de Ciencias, C.U., 72570 Puebla,
Pue., Mexico. E-mail: joel.teran@correo.buap.mx
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2838

cis-4-METHYL/THIOL-PIPECOLIC ESTERS
2839
Scheme 1. Compounds containing 4-substituted pipecolic acids.
For example, argatroban, an important anticoagulant, is a small molecule direct
thrombin inhibitor.[2] Sulfur-containing amino acids include pulcherrimine, from
the ovaries of the sea urchin Hemicentrotus pulcherrimus.[3] Consequently,
enantiopure 4-substituted-pipecolic esters, their acids, and their salts are, in general,
important synthetic intermediates (Scheme 1).
In this sense, approaches toward the synthesis of racemic or cis-trans-
4-substituted mixture are known,[4] and several methodologies to the synthesis of
trans-4-substituted pipecolic acids[5] and processes for the synthesis of cis-4-substi-
tuted pipecolic acid have been also disclosed.[6]
In this article, we describe a diastereoselective synthetic route to cis-4-methyl=
thiol pipecolic ethyl esters based on the ring-closing methathesis reaction followed by
either diastereoespecific conjugate addition of methylorganocuprate or by tandem
diastereospecific hydrosulforization=thionization reaction. Interestingly, the presence
of the ester function located at C-6 on the piperidine ring directs the nucleophilic
attack on the Michael addition reaction.
DISCUSSION
The separable diastereomeric mixture of the a,b-unsaturated piperidin-2-ones
7a þ 7b in six steps was prepared. First, (S)-(–)-phenylethylamine was treated with
ethyl 2-bromoacetate, giving the corresponding chiral glycine 2, which was treated
with di-tert-butyl dicarbonate, affording the N-Boc protected glycine 3. Next, the
compound 3 was reacted with lithium diisopropylamide (LDA) and allyl iodide at
ꢀ78 ꢁC providing the unseparable diastereomeric mixture of alkylated adducts
4(aþb),[7] which was reacted with trifluoroacetic acid (TFA) to deliver the
deprotected diastereomeric mixture 5(aþb). These compounds were condensed with
acryloyl chloride affording the unsaturated mixture 6(aþb). Finally, 6(aþb) were
subjected to a ring-closing metathesis reaction giving access to a,b-unsaturated dia-
1
stereomeric mixture of 7a þ 7b in 70:30 dr, determined by H NMR from the crude
reaction mixture (Scheme 2).[8]
The diastereomeric mixture of 7(aþb) was separated, and then 7a and 7b were
crystallized. The absolute configuration at C-6 was determined by X-ray diffraction
analysis as (R) and (S) respectively (Fig. 1).[9]

´
A. ZARATE ET AL.
2840
Scheme 2. Reagents and conditions: (i) ethyl 2-bromoacetate, K2CO3(2 eq), CH3CN, rt, 1.45 h, 90%.
(ii) (Boc)2O (1.5 eq), H2O, rt, 5 h, 98%. (iii) LDA (1.5 eq), THF, ꢀ78 ꢁC, 3 h, then allyl iodide, ꢀ20 ꢁC
8 h. (iv) TFA (5 eq), CH2Cl2, rt, 2 h. (v) Acryloyl chloride, K2CO3 (2 eq), CH2Cl2=H2O 70% after three
steps. (vi) Grubbs’s second-generation (5 mol%), CH2Cl2, rt, 6 h, quantitative.
With the a,b-unsaturated piperidin-2-one in our hands, we started to explore
the conjugate addition of methylcuprate to the a,b-unsaturated lactam 7a. In this
sense, Hanessian[10] reported that the conjugate addition of organocuprates to
N-Boc unsaturated lactams delivers a mixture of cis and trans diastereoisomers.
After testing various reaction conditions, the best result was obtained by the use
of chlorotrimethylsilane (TMSCl), which accelerates copper-mediated conjugate
addition reaction in THF.[11] This procedure afforded the desired 4-methyl
piperidin-2-one 8a as a mayor diastereoisomer (determined direct from the 1H
NMR spectra of the crude reaction mixture), in 80% yield. The analysis of two-
dimensional nuclear Overhauser spectroscopy (2D-NOESY) experiments of lactam
8a indicates that both substituents are cis-oriented for the lactam ring (Scheme 3).
It is worth noting that Antoni et al.[12] reported a highly diastereoselective conjugate
addition of methylorganocuprate to enantiopure N-Boc pipecolic a,b-unsaturated
esters; however, in this case only the trans-4-methyl pipecolic ester was obtained.
Then, compound 7b (minor diastereoisomer) was treated with methylcuprate
following the optimized conditions described. 4-Methyl piperidin-2-one 8b was
obtained in 80% yield. The relative configuration at C-4 as (S) was confirmed from
the X-ray analysis diffraction of compound 8b (Fig. 2).[13]
Next, diastereoisomers 8a and 8b were treated with BH3 SMe2 giving the corre-
sponding piperidines 9a and 9b in 95% yield, which were subject to hydrogenolysis
Figure 1. X-ray ORTEP diagram of compounds 7a and 7b.

cis-4-METHYL/THIOL-PIPECOLIC ESTERS
2841
Scheme 3. Diastereoselective conjugate addition of methyl cuprate to a,b-unsaturated lactam 7a.
Figure 2. X-ray ORTEP diagram of compound 8b.
in the presence of di-tert-butyl dicarbonate to give the N-Boc-protected piperidines
10a and 10b. The comparison of its optical rotation confirmed that 10a and 10b are
enantiomers and as a correlation compound 8a have the (R) configuration at C-4
(Scheme 4).
We then oriented our attention to the reactivity of 7a (major diastereoisomer)
toward Lawesson’s reagent (LR), taking into account our previous report.[14] When
compound 7a was treated with 0.5 equivalents of LR in boiling toluene, the expected
unsaturated thioamide 11a was obtained in 70% yield. Interestingly, the treatment
of 7a with an equimolar amount of LR gave a mixture of compound 11a and the
unexpected 4-mercapto-substituted thioamide 12a as a single diastereoisomer. The
use of 2 equivalents of LR resulted in exclusive formation of compound 12a in
73% yield. Finally, compound 7b showed the same behavior toward LR (Scheme 5).
Scheme 4. Reagents and conditions: (i) BH3 SMe2, THF, 25 ꢁC, 95%. (ii) H2, (Boc)2O, Pd(OH)2, AcOEt,
25 ꢁC, 90%.

´
A. ZARATE ET AL.
2842
Scheme 5. Reactivity of a,b-unsaturated lactam 7a toward the Lawesson’s reagent.
Compounds 12a and 12b were crystallized and the absolute configuration at
C-4 was determined by x-ray analysis diffraction as (R) for 12a and (S) for 12b,
and the presence of the thiol function was also confirmed (Fig. 3).[15]
To obtain the corresponding pipecolic ethyl ester, compound 12b was
treated with BH3 SMe2, affording the desired reduced compound 13b in 95% yield.
Debenzylation of 13b was performed under Birch conditions to give the desired
piperidine 14b in 43% yield (Scheme 6).
In conclusion, an efficient method for the diastereoselective synthesis of cis-
4-methyl=thiol-pipecolic ethyl esters from (S)-phenylethylamine has been developed.
The stereochemical outcome showed that the conjugate addition occurs from
the same side of the ester function located at C-6 on the piperidine ring. Expansion
of the protocol scope and application of this methodology to the total synthesis are
currently under way in our group.
EXPERIMENTAL
(R)-Ethyl-1,2,3,6-tetrahydro-6-oxo-1-((S)-1-phenylethyl)pyridine-
2-carboxylate, 7a
20
½aꢂD ¼ þ18:45 (c 1.0, CH2Cl2); bp¼ 96–98 ꢁC. IR (film) 2964, 2924, 1738, 1659,
1429, 1018, 809, 707, 536 cmꢀ1; 1H NMR (400MHz, CDCl3) d 1.25 (t, J ¼ 7.2 Hz, 3H),
1.45 (d, J ¼ 7.2 Hz, 3H), 2.50 (AB, J ¼ 1.6, 6.0, 2.3, 2.9, 7.0, 18.1 Hz, 2H), 3.86
Figure 3. X-ray ORTEP diagram of compounds 12a and 12b.

cis-4-METHYL/THIOL-PIPECOLIC ESTERS
2843
Scheme 6. Reagents and conditions: (i) BH3 SMe2, THF, 25 ꢁC, 95%. (ii) Na=NH3, ꢀ78 ꢁC, 43%.
(ddd, J ¼ 1.1, 1.6, 7.0 Hz, 1H), 4.17 (q, J ¼ 7.2 Hz, 2H), 6.04 (m, 2H), 6.35 (m, 1H),
7.28 (m, 5H); 13C NMR (100MHz, CDCl3) d 13.9, 15.1, 28.3, 50.1, 53.0, 61.6,
126.3–141.0, 163.7, 172.0. HRMS (FAB): Calcd. for C16H19NO3: 273.1365. Found:
273.1368.
(S)-Ethyl-1,2,3,6-tetrahydro-6-oxo-1-((S)-1-phenylethyl)pyridine-
2-carboxylate, 7b
20
½aꢂD ¼ ꢀ55:73 (c 1.0, CH2Cl2); bp ¼ 58–60 ꢁC; IR (film) 2978, 2932, 1744,
1
1665, 1609, 1433, 1190, 1084, 1033, 813, 702 cmꢀ1. H NMR (500 MHz, CDCl3)
d 0.93 (t, J ¼ 7.1 Hz, 3H), 1.55 (d, J ¼ 7.1 Hz, 3H), 2.60 (ddd, J ¼ 1.0, 6.1, 18.1 Hz,
1H), 2.72 (m, 1H), 3.54 (m, 1H), 3.70 (m, 1H), 4.11 (d, J ¼ 7.4 Hz, 1H), 6.03
(dd, J ¼ 3.0, 9.8 Hz, 1H), 6.06 (q, J ¼ 7.1 Hz, 1H), 6.29 (m, 1H), 7.26 (m, 5H); 13C
NMR (125 MHz, CDCl3) d 13.7, 17.3, 28.7, 50.4, 52.6, 61.0, 126.7–138.2, 163.5,
170.9. HRMS (FAB): calcd. for C16H19NO3: 273.1365. Found: 273.1368.
General Procedure for Conjugate Michael Addition of
Organocuprate
Methyl lithium (0.5 M in Et2O, 5 eq) was added to a suspension of CuBr SMe2
(5 eq) in Et2O at ꢀ15 ꢁC. The resulting yellow suspension was stirred for 45 min at
ꢀ15 ꢁC, and then 7a (0.100 g, 0.183 mmol, 1 eq) in 6 mL of Et2O and TMSCl
(0.148 mL, 0.585 mmol, 3.2 equiv) were successively added. The mixture was warmed
to 0 ꢁC and stirred for 18 h. After quenching at 0 ꢁC with saturated NH4Cl, a few
drops of saturated NH4OH were added until the aqueous layer remained colorless.
The organic layer was separated, dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo. The crude residue was purified by column chromatography to afford
the expected product 8a as a white solid in 80% yield.
(2R,4R)-Ethyl-4-methyl-6-oxo-1-((S)-1-phenylethyl)piperidine-2-carboxylate,
20
8a. ½aꢂD ¼ ꢀ15:1 (c 1.0, CH2Cl2). IR (film) 2950, 2938, 1741, 1654, 1434, 1198,
1
1029, 922, 732, 691 cmꢀ1. H NMR (400 MHz, CDCl3) d 0.97 (d, J ¼ 6.4 Hz, 3H),
1.26 (t, J ¼ 7.1 Hz, 3H), 1.45 (d, J ¼ 7.2 Hz, 3H), 1.51 (m, 1H), 1.97 (m, 2H), 2.15
(dd, J ¼ 12, 15.6 Hz, 1H), 2.50 (ddd, J ¼ 1.8, 4.4, 15.6 Hz, 1H), 3.74 (dd, J ¼ 4,
8.7 Hz, 1H), 4.16 (q, J ¼ 7.1 Hz, 2H), 5.98 (q, J ¼ 7.1 Hz, 1H), 7.29 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 14.0, 15.7, 21.7, 26.2, 34.1, 40.4, 50.7, 53.4, 61.4,
127.3–128.4, 133.9, 140.1, 172.2, 173.4. HRMS (FAB): calcd. for C17H23NO3:
289.1678. Found: 289.1680.

´
A. ZARATE ET AL.
2844
(2S,4S)-Ethyl-4-methyl-6-oxo-1-((S)-1-phenylethyl)piperidine-2-
20
carboxylate, 8b. ½aꢂD ¼ ꢀ152 (c 1.0, CH2Cl2); bp ¼ 68–70 ꢁC. IR (film) 2949,
1
2935, 1742, 1651, 1436, 1187, 1029, 733, 701 cmꢀ1; H NMR (400 MHz, CDCl3)
d 0.96 (d, J ¼ 6.6 Hz, 3H), 1.0 (t, J ¼ 7.1 Hz, 3H), 1.48 (m, 1H), 1.54 (d, J ¼ 7.1 Hz,
3H), 1.94 (m, 1H), 2.15 (dd, J ¼ 12.1, 15.8 Hz, 1H), 2.26 (m, 1H), 2.48 (ddd, J ¼ 2.0,
4.5, 15.8 Hz, 1H), 3.60 (m, 2H), 4.08 (dd, J ¼ 5.4, 8.6 Hz, 1H), 5.8 (q, J ¼ 7.1 Hz,
1H), 7.25 (m, 5H); 13C NMR (100 MHz, CDCl3) d 13.7, 16.1, 21.4, 26.3, 34.7,
40.8, 51.7, 54.7, 61.0, 127.5-128.5, 139.2, 171.8, 172.3. HRMS (FAB): Calcd. for
C17H23NO3: 289.1678. Found: 289.1681.
General Procedure for Thionation of a,b-Unsaturated
Lactams 7a and 7b
Lawesson’s reagent (1.024 mmol, 2.0 eq) was added to a solution of 7a (0.140 g,
0.512 mmol, 1.0 eq) in 10 mL of dry toluene. The resulting mixture was stirred for 4 h
at reflux temperature and then concentrated under reduced pressure. The residue was
purified by column chromatography using 80:20 petroleum ether=AcOEt as the
eluent to give the compound 12a as a white solid in 60% yield.
(2R,4R)-Ethyl-4-mercapto-1-((S)-1-phenylethyl)-6-thioxopiperidine-2-
20
carboxylate, 12a. ½aꢂD ¼ ꢀ207:4 (c 1.0, CH2Cl2). IR (film) 2976, 2926, 1740,
1
1465, 1311, 1197, 1085, 1023, 801, 700 cmꢀ1. H NMR (500 MHz, CDCl3) d 1.31
(t, J ¼ 7.1 Hz, 3H), 1.54 (d, J ¼ 7.1 Hz, 3H), 1.84 (d, J ¼ 6.5 Hz, 1H), 2.12 (m, 2H),
2.81 (dd, J ¼ 11.6, 15.8 Hz, 1H), 3.15 (m, 1H), 3.64, (dd, J ¼ 5.5, 15.7 Hz, 1H),
3.98 (dd, J ¼ 2.7, 7.4 Hz, 1H), 4.25, (m, 2H), 7.13 (q, J ¼ 7.1 Hz, 1H), 7.34 (m, 5H);
13C NMR (125 MHz, CDCl3) d 14.0, 14.4, 29.4, 36.3, 52.4, 55.3, 57.8, 62.4,
127.0–128.8, 138.4, 170.3, 201.0. HRMS (FAB): calcd. for C16H21NO2S2:
323.1014. Found: 323.1016.
(2S,4S)-Ethyl-4-mercapto-1-((S)-1-phenylethyl)-6-thioxopiperi-
20
dine-2-carboxylate, 12b. ½aꢂD ¼ ꢀ348:9 (c 1.0, CH2Cl2). IR (film) 2975, 2930,
1
1736, 1466, 1313, 1199, 1073, 910, 730, 691 cmꢀ1. H NMR (500 MHz, CDCl3) d
0.98 (t, J ¼ 7.1 Hz, 3H), 1.52 (d, J ¼ 7.0 Hz, 3H), 1.81 (d, J ¼ 6.6 Hz, 1H), 2.15
(ddd, J ¼ 2.3, 5.9, 14.7 Hz, 1H), 2.56 (m, 1H), 2.96 (dd, J ¼ 11.3, 15.6 Hz, 1H),
3.18 (m, 1H), 3.63 (ddd, J ¼ 0.8, 5.6, 15.6 Hz, 1H), 3.73, (m, 2H), 4.2 (dd, J ¼ 2.3,
8.3 Hz, 1H), 7.14 (q, J ¼ 7.1 Hz, 1H) 7.30 (m, 5H); 13C NMR (125 MHz, CDCl3)
d 13.7, 14.4, 29.7, 37.2, 52.3, 55.3, 58.1, 61.7, 128.2-128.9, 136.8, 169.4, 200.7. HRMS
(FAB): Calcd. for C16H21NO2S2: 323.1014. Found: 323.1017.
FUNDING
We are grateful to CONACyT (Project 154104) for financial support, and A. Z.
thanks CONACyT for the postdoctoral scholarship (165517).
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR spectra for this article can be
accessed on the publisher’s website.

cis-4-METHYL/THIOL-PIPECOLIC ESTERS
2845
REFERENCES
1. (a) Yasuda, M.; Ueda, M.; Muramatsu, H.; Mihara, M.; Esaci, N. Enzymatic synthesis of
cyclic amino acids by N-methyl-L-amino acid dehydrogenase from Pseudomonas putida.
Tetrahedron: Asymmetry 2006, 17, 1775–1779; (b) Osipov, S. N.; Dixneuf, P. Ring-closing
metathesis in the synthesis of cyclic a-amino acids. Russ. J. Org. Chem. 2003, 39, 1211–
1220; (c) Pohlman, M.; Kazmaier, U. Efficient stereoselective syntheses of cyclic amino
acids via Michael-induced ring-closing reactions. Org. Lett. 2003, 5, 2631–2633; (d)
Park, K.-H.; Kurt, M. J. Cyclic amino acid derivatives. Tetrahedron 2002, 58,
˜
8629–8659; (e) Bunuel, E.; Jimenez, A.; Diaz-de-Villegas, M. D.; Cativiela, C. A chiral
oxazolone derived from D-glyceraldehyde as an intermediate in the synthesis of enantio-
merically pure cyclic amino acids. Targets Heterocycl. Syst. 2001, 5, 79–111.
2. Nisio, M. D.; Middeldorp, S.; Buller, H. R. Direct thrombin inhibitors. N. Engl. J. Med
2005, 353, 1028–1040.
¨
3. Murata, Y.; Sata, N. U. Isolation and structure of pulcherrimine, a novel bitter-tasting
amino acid, from the sea urchin (Hemicentrotus pulcherrimus) ovaries. J. Agric. Food.
Chem. 2000, 48, 5557–5560.
´
4. (a) Beaulieu, P. L.; Lavallee, P.; Abraham, Anderson, P. C.; Boucher, C.; Bousquet, Y.;
Duceppe, J.-S.; Gillard, J.; Gorys, V.; Grand-Maıtre, C.; Grenier, L.; Guindon, Y.; Guse, I.;
ˆ
Plamondon, L.; Soucy, F.; Valois, S.; Wernic, D.; Yoakim, C. Practical, stereoselective
synthesis of palinavir, a potent HIV protease inhibitor. J. Org. Chem. 1997, 62, 3440–
3448; (b) Cossy, J.; Belotti, D. Direct diastereoselective synthesis of (ꢃ)-cis- and (ꢃ)-
trans-4-methylpipecolic acid and derivatives. Tetrahedron Lett. 2001, 42, 2119–2120.
5. (a) Bailey, P. D.; Wilson, R. D.; Brown, G. R. Enantio- and diastereoselective synthesis
of pipecolic acid derivatives using the aza-Diels–Alder reaction of imines with dienes.
J. Chem. Soc., Perkin Trans. 1 1991, 1337–1340; (b) Bailey, P. D.; Brown, G. R.; Korber,
P.; Reed, A.; Wilson, R. D. Asymmetric synthesis of pipecolic acid derivatives using the aza--
Diels–Alder reaction. Tetrahedron: Asymmetry 1991, 2, 1263–1282; (c) Rutjes, F. P. J. T.;
Veerman, J. J. N.; Meester, W. J. N.; Hiemstra, H.; Shcoemaker, H. E. Synthesis of enantio-
pure, functionalized pipecolic acid via amino-acid-derived N-acyliminium ions. Eur. J. Org.
Chem. 1999, 1127–1135; (d) Keenan, T. P.; Yaeger, D.; Holt, D. A. Synthesis of chiral non-
racemic 4-trans-substituted pipecolic acid derivatives. Tetrahedron: Asymmetry 1999, 10,
4331–4341; (e) Agami, C.; Comesse, S.; Kaddouri-Puchot, C. An efficient access to enantio-
merically pure substituted derivatives of pipecolic acid. J. Org. Chem. 2000, 65, 4435; (f)
Agami, C.; Bisaro, F.; Comesse, S.; Guesne, S.; Kadouri-Puchot, C.; Morgentin, R. Asym-
´
metric syntheses of enantiopure 4-substituted pipecolic acid derivatives. Eur. J. Org. Chem.
2001, 2385–2389; (g) Alegret, C.; Santacana, F.; Riera, A. Enantioselective synthesis of trans-
methylpipecolic acid. J. Org. Chem. 2007, 72, 7688–7692.
6. (a) Hays, S. J.; Malone, T. C.; Johnson, G. Synthesis of cis-4-(phosphonooxy)-2-
piperidinecarboxylic acid, an N-methyl-D-aspartate antagonist. J. Org. Chem. 1991,
56, 4084–4086; (b) Golubev, A.; Sewald, N.; Burger, K. An efficient approach to the
family of 4-substituted pipecolic acids: Syntheses of 4-oxo-, cis-4-hydroxy-, and
trans-4-hydroxy-L-pipecolic acids from L-aspactic acid. Tetrahedron Lett. 1995, 36,
2037–2040; (c) Gillard, J.; Abraham, Anderson, P. C.; Beaulieu, P. L.; Bogri, T.;
Bousquet, Y.; Grenier, L.; Guse, I.; Lavallee, P. Preparation of (2S,4R)-4-hydroxypi-
´
pecolic acid and derivatives. J. Org. Chem. 1996, 61, 2226–2231; (d) Hanessian, S.;
Riber, L.; Marin, J. Diastereoselective synthesis of functionally diverse substituted
pipecolic acids. Synlett 2009, 1, 71–74.
7. For stereoselective alkylation of glycine enolate, see (a) Dellaria, J. F.; Santarsiero, B. D.
Enantioselective synthesis of a-amino acid derivatives via the stereoselective alkylation of a
homochiral glycine enolate synthon. J. Org. Chem. 1989, 54, 3916–3926; (b) Panek, J. S.;

´
A. ZARATE ET AL.
2846
Masse, C. E. An improved synthesis of (4S,5S)-2-phenyl-4-(methoxycarbonyl)-
5-isopropyloxazoline from (S)-phenylglycinol. J. Org. Chem. 1998, 63, 2382–2384;
(c) Yamazaki, T.; Kawashita, S.; Kitazume, T.; Kubota, T. Diastereoselective alkylation
of glycinates by assistance of intramolecular potassium–fluorine interactions. Chem. Eur.
J. 2009, 15, 11461–11464; (d) Rodrı
´
Alvarez-Herna
´
guez-Garnica, C.; Lo
´
ndez, A.; Tapia-Benavides, R.; Garıa-Lo
pez-Ruiz, H.; Rojas-Lima, S.;
pez, M. C. Diastereoselective
´
´
´
alkylation of chiral glycinate derivatives containing the a-phenylethyl group. J. Mex.
Chem. Soc. 2011, 55, 148–153.
8. For the construction of a,b-unsaturated piperidin-2-ones via RCM, see (a) Rudjes, F. P. J.
T.; Schoemaker, H. E. Ruthenium-catalyzed ring closing olefin metathesis of non-natural
a-amino acids. Tetrahedron Lett. 1997, 38, 677–680; Agami, C.; Couty, F.; Rabasso, N.
Synthesis of (–)-b conhydrine and analogues using N-Boc-2-acyl oxazolidine methodology
and ring-closing metathesis. Tetrahedron Lett. 2000, 41, 4113–4116; (b) Hoffmann, T.;
Waibel, R.; Gmeiner, P. A general approach to dehydro-Freidinger lactams: Ex-chiral
pool synthesis and spectroscopic evaluation as potential reverse turn inducers. J. Org.
Chem. 2003, 68, 62–69; (c) Ma, S.; Ni, B. Unexpected dramatic substituent effect for tun-
ing the selectivity in the double ring-closing metathesis reaction of N-containing tetraenes:
An efficient synthesis of bicyclic izidine alkaloids skeletons. Org. Lett. 2002, 4, 639–641;
(d) Gille, S.; Ferry, A.; Billard, T.; Langlois, B. R. Synthesis of a-trifluoromethylated
nitrogen heterocycles. J. Org. Chem. 2003, 68, 8932–8935; (e) Danieli, B.; Lesma, G.;
Passerella, D.; Sacchetti, A.; Silvani, A.; Virdis, A. Total enantioselective synthesis of
(–)-cytisine. Org. Lett. 2004, 6, 493–496; (f) Ma, S.; Ni, B. Double ring-closing metathesis
reaction of nitrogen-containing tetraenes: Efficient construction of bicyclic alkaloid skele-
tons and synthetic application to four stereoisomers of lupinine and their derivatives.
Chem. Eur. J. 2004, 10, 3286–3300; (g) Ma, S.; Ni, B.; Liang, Z. Highly selective synthesis
of bicyclic quinolizidine alkaloids and their analogues via double RCM reaction
of N-alkynyl-N-(1,x)-alkadienyl acrylamides. J. Org. Chem. 2004, 69, 6305–6309;
(h) Krelaus, R.; Westermann, B. Preparation of peptide-like bicyclic lactams via a sequen-
tial Ugi reaction-olefin metathesis approach. Tetrahedron Lett. 2004, 45, 5987–5990;
(i) Wijdeven, M. A.; Botman, P. N. M.; Wijtmans, R.; Schoemaker, H. E.;
Rutjes, F. P. J. T.; Blaaw, R. H. Total synthesis of (þ)-epiquinamide. Org. Lett. 2005,
7, 4005–4007; (j) De Matteis, V.; van Delft, F. L.; Tiebes, J.; Rutjes, F. P. J. T. A
ring-closing metathesis pathway to fluorovinyl-containing nitrogen heterocycles. Eur. J.
Org. Chem. 2006, 1166–1176; (k) Xiao, D.; Wang, C.; Palani, A.; Reichard, G.; Aslanian,
R.; Shih, N.-Y.; Buevich, A. Two complementary, diversity-driven asymmetric syntheses
of a 2,2-disubstituted piperidine NK1 antagonist. Tetrahedron: Asymmetry 2006, 17, 2596–
2598; (l) Lesma, G.; Danieli, B.; Sacchetti, A.; Silvani, A. An efficient enantioselective
approach to cyclic b-amino acid derivatives via olefin metathesis reactions. J. Org. Chem.
˜
2006, 71, 3317–3320; (m) Cardona, W.; Quinones, W.; Robledo, S.; Velez, I. D.; Murga, J.;
´
Garcıa-Fontanet, J.; Carda, M.; Cardona, D.; Echeverri, F. Antiparasite and antimycobac-
´
terial activity of passifloricin analogues. Tetrahedron 2006, 62, 4086–4092; (n) Niida, A.;
Mizumoto, M.; Narumi, T.; Inokuchi, E.; Oishi, S.; Ohno, H.; Otaka, A.; Kitaura, K.; Fujii,
N. Synthesis of (Z)-alkene and (E)-fluoroalkene-containing diketopiperazine mimetics utiliz-
ing organocopper-mediated reduction–akylation and diastereoselectivity examination using
DFT calculations. J. Org. Chem. 2006, 71, 4118–4129.
9. Crystal structure was deposited at the Cambridge Crystallographic Data Centre, deposit
numbers CCDC 943457 for compound 7a and CCDC 943456 for compound 7b.
10. (a) Hanessian, S.; van Otterlo, W. A. L.; Nilsson, I.; Bauer, U. Stereocontrolled synthesis
of a prototype library of enantiopure 2,4-disubstituted 4-aryl-6-piperidinones and
piperidines. Tetrahedron Lett. 2002, 43, 1995–1998; (b) Hanessian, S.; Gauchet, C.;

cis-4-METHYL/THIOL-PIPECOLIC ESTERS
2847
Charron, G.; Marin, J.; Nakache, P. Design and synthesis of diversely substituted
azacyclic inhibitors of endothelin coverting enzyme. J. Org. Chem. 2006, 71, 2760–2770.
11. (a) Corey, E. J.; Boaz, N. W. The reactions of combined organocuprate-chlorotrimethylsi-
lane reagents with conjugate carbonyl compounds. Tetrahedron Lett. 1985, 26, 6019–6022;
(b) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. Me3SiCl accelerated
conjugate addition of stoichiometric organocopper reagents. Tetrahedron Lett. 1986, 27,
4029–4032; (c) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I. Chlorosilane-
accelerated conjugate addition of catalytic and stoichiometric organocopper reagents.
Tetrahedron 1989, 45, 349–362; (d) Deiters, A.; Petterson, M.; Martin, S. F. General strategy
for the syntheses of corynanthe, tacaman, and oxindole alkaloids. J. Org. Chem. 2006,
71, 6547–6561; (e) Oueslati, F.; Perrio, C.; Dupas, G.; Barre, L. Diastereoselective conjugate
´
addition of organocuprates to 3,4-dimethyl-5,6-dihydro-2(1H)-pyridinones: A concise
synthesis of trans-3,4-dimethyl-4-phenylpiperidines. Org. Lett. 2007, 9, 153–156; (f) Guo, F.;
Dhakal, R. C.; Dieter, K. R. Conjugate addition reactions of N-carbamoyl-4-pyridones and
2,3-dihydropyridones with Grignard reagents in the absence of Cu(I) salts. J. Org. Chem.
2013, 78, 8451–8464.
12. Riera, A.; Comely, A.; Ginesta, X. Preparation of trans-(2R)-4-substituted pipecolic acids
and esters. WO PCT Int. Appl. 2011039290=A1 20110407, April 7, 2012.
13. Crystal structure was deposited at the Cambridge Crystallographic Data Centre, deposit
number CCDC 943454.
0
0
´
´
14. Romero, N.; Gnecco, D.; Teran, J.; Juarez, J.; Galindo, A. Reactivity of (1 S)-1-(1 -
phenyl-ethyl)-4-hydroxy-piperidin-2-one with Lawesson’s reagent. J. Sulf. Chem. 2007,
28, 239.
15. Crystal structure was deposited at the Cambridge Crystallographic Data Centre, deposit
numbers CCDC 943458 for compound 12a and CCDC 943455 for compound 12b.