Diastereodivergent synthesis of 4-hydroxy-2,3-methanopipecolic acid derivatives as conformationally constrained homoserine analogues

Article abstract of DOI:10.1002/ejoc.201100962

A short, practical procedure for the diastereodivergent synthesis of cyclopropanated 4-hydroxypipecolic acid derivatives with high optical purity is reported. Key steps are the highly enantioselective lipase-catalyzed kinetic resolution and the stereosele

Full text of DOI:10.1002/ejoc.201100962

FULL PAPER
DOI: 10.1002/ejoc.201100962
Diastereodivergent Synthesis of 4-Hydroxy-2,3-methanopipecolic Acid
Derivatives as Conformationally Constrained Homoserine Analogues
Ernesto G. Occhiato,*[a] Andrea Casini,[a] Antonio Guarna,[a] and Dina Scarpi*[a]
Keywords: Medicinal chemistry / Amino acids / Nonnatural amino acids / Nitrogen heterocycles / Kinetic resolution /
Cyclopropanation
A short, practical procedure for the diastereodivergent syn-
thesis of cyclopropanated 4-hydroxypipecolic acid deriva-
tives with high optical purity is reported. Key steps are the
highly enantioselective lipase-catalyzed kinetic resolution
and the stereoselective cyclopropanation reaction of 4-hy-
droxypyridine derivatives. Under the best conditions for OH-
directed cyclopropanation, Charette’s Zn-carbenoid provided
cis-4-hydroxy-2,3-methanopipecolic acids in the highest
yield (73–86%) and facial selectivity (Ͼ 99:1). The trans
selectivities in Michael-type addition of dimethylsulfoxonium
methylide were 1:4 to 1:7 in DMSO and diastereopure trans
isomers were obtained by chromatography after OH-depro-
tection in 57–73% yield. These compounds are new, confor-
mationally constrained homoserine analogues potentially
useful as conformational probes and for drug discovery in
medicinal chemistry.
est in the enantioselective synthesis of 4-hydroxypipecolic
acids and other 4-hydroxy-substituted piperidine alka-
loids,[1b,1c] we envisioned the possibility of synthesizing all
four stereoisomers of 4-hydroxy-2,3-methanopipecolic acid
1 (Scheme 1) as new, conformationally constrained homo-
serine analogues to be employed as conformational probes
and in the discovery of new drugs.
Introduction
4-Hydroxy-substituted pipecolic acids and their deriva-
tives play an increasingly important role in medicinal chem-
istry as molecular scaffolds and α-amino acid analogues for
the preparation of pharmaceutically active compounds.[1]
They have been incorporated in the structures of the HIV-
protease inhibitor palinavir[2] and antagonists of the cholec-
istokine hormone,[3] and used for the preparation of one
of the most potent and selective N-methyl-d-aspartic acid
(NMDA) receptor antagonists, CGS20281.[4] Moreover,
naturally occurring 4-hydroxypipecolic acid derivatives dis-
play noteworthy biological activities, such as the cyclodepsi-
peptide antibiotic virginiamycin S2,[5] serotonine receptor
antagonist damipipecoline,[6] ovaline,[7] and a sulfate com-
pound possessing NMDA receptor agonistic activity.[8]
As 4-hydroxypipecolic acids can be regarded as con-
strained homoserine analogues,[9] their scope could be wid-
ened by introducing additional conformational restrictions,
which could be crucial for the design of highly selective,
potent peptide analogues in peptide–receptor recogni-
tion.[10] Amino acid analogues containing a cyclopropane
skeleton, including prolines and pipecolic acids (Figure 1),
have attracted much attention as the three-membered ring
introduces severe constraints in the proximal backbone tor-
sion angles, possibly leading to profound changes in the
peptide conformation.[11] On these grounds, given our inter-
Figure 1. Selected examples of methanoprolines and methano-
pipecolic acids.
[a] Dipartimento di Chimica “U. Schiff”, Università di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Fax: +39-055-4573531
E-mail: ernesto.occhiato@unifi.it
dina.scarpi@unifi.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100962.
Scheme 1. Retrosynthetic analysis of methanopipecolic acids.
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Synthesis of 4-Hydroxy-2,3-methanopipecolic Acid Derivatives
both alcohols (R)-2 and (S)-2 were obtained with higher ee
than by a single resolution as previously reported.[1b]
N-Cbz-protected alcohol (Ϯ)-3 was conveniently pre-
pared by the same procedure reported for 2. N-Cbz-pro-
tected δ-valerolactam 5 (Scheme 3) was quantitatively con-
verted into the corresponding enol phosphate 6, which was
subjected to Pd-catalyzed methoxycarbonylation to give 7
in 87% yield over two steps after chromatography. Allylic
oxidation finally afforded (Ϯ)-3 in 57% yield. The kinetic
resolution of this alcohol was carried out in the presence of
various lipases at 30 °C with an excess of either vinyl acetate
or vinyl butyrate (3.5 equiv.) as the acylating reagent. Li-
pases from Aspergillus niger, Candida rugosa, Porcine pan-
creatic, and immobilized CAL-A lipases[13] were tested un-
der various conditions in toluene and tert-butyl methyl
ether (TBME) with vinyl acetate but the reactions were
either very slow or did not take place at all. The best results
were obtained with immobilized lipases CAL-B [E = 97 in
tetrahydrofuran (THF) with vinyl butyrate] and PS “AM-
ANO” IM (E Ͼ 200),[13] the latter providing both (R)-3 and
(S)-3 (see later for the absolute configuration determi-
nation) with ee Ն 99% and in good yields, 38 and 37%,
respectively, (Scheme 3) after two sequential kinetic resolu-
tions in TBME carried out as described above.
Results and Discussion
The starting point for this study was the enantiomerically
enriched (94–96% ee) 4-hydroxytetrahydropyridine deriva-
tive 2 (Scheme 1), whose synthesis we have described either
through the elaboration of the starting material from the
chiral pool[12] or by enzymatic kinetic resolution (EKR) of
N-CO2Me-protected (Ϯ)-2 prepared from the correspond-
ing lactam.[1b] Stereoselective cyclopropanation of the
double bond in both enantiomers of 2 should produce the
four cyclopropanated 4-hydroxypipecolic acids 1. However,
we considered that conformationally restricted amino acids,
in order to be introduced into a peptide sequence, must
have higher enantiomeric excesses than those so far ob-
tained for (R)-2 and (S)-2, and efforts should be made to
obtain such synthetic intermediates in enantiopure forms.
To this end, we first opted for a two-step lipase-catalyzed
kinetic resolution of N-CO2Me-protected (Ϯ)-2. However,
because of the widespread use of the benzyloxycarbonyl
(Cbz) group for N-protection in amino acids, we also de-
cided to study the EKR of N-Cbz derivative (Ϯ)-3 by vari-
ous lipases and to subject the products to stereoselective
cyclopropanation.
Racemic 2 is easily prepared by a three-step procedure
from δ-valerolactam.[1b] A two-step kinetic resolution of
(Ϯ)-2 was realized by stopping the enzyme-catalyzed esteri-
fication of the alcohol, carried out in the presence of PS
“AMANO” IM lipase and vinyl butyrate as an acylating
reagent (Scheme 2)[1b] with 42% conversion. This allowed
us to obtain butyrate (R)-4 with a very high enantiomeric
purity (Ͼ 99.5% ee, determined after hydrolysis) in a suf-
ficient amount to proceed with the synthesis. The residual
(S)-2, obtained in 53% yield after chromatography, was
subjected again to the same EKR conditions, stopping the
reaction after 22 h when the conversion was 17%. After
chromatography, enantiopure (Ͼ 99.5% ee) alcohol (S)-2
was obtained in 35% yield over the two steps. By this pro-
cedure, only a minimal amount of substrate was lost and
Scheme 3. Synthesis and lipase-catalyzed kinetic resolution of
alcohol (Ϯ)-3.
The OH-directed cyclopropanation of γ-hydroxy-α,β-un-
saturated esters has been reported in a handful of cases, i.e.
by samarium/mercury amalgam in conjunction with diiodo-
methane[14–15] and by the Furukawa modification of the
Scheme 2. Lipase-catalyzed kinetic resolution of alcohol (Ϯ)-2.
Eur. J. Org. Chem. 2011, 6544–6552
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E. G. Occhiato, A. Casini, A. Guarna, D. Scarpi
FULL PAPER
Simmons–Smith reaction.[16] In both cases, the hydroxy ol (TCP, Entry 4). Under these conditions the reaction was
group exerted complete stereocontrol, so we explored the complete in 4 h, providing the cis isomer (1R,5R,6S)-9 in
use of both Sm– and Zn-carbenoids for the cyclopropan- 86% yield.[21] These conditions were thus applied to N-Cbz
ation of enantiopure 2, and the results are reported in protected alcohol (R)-3 to give diastereopure cyclopropan-
Table 1. Disappointingly, the reaction under Molander’s ated (1R,5R,6S)-10 (Entry 5) in good yield (79%), as well
conditions[15] (Entry 1) although reaching complete conver- as its enantiomer (S)-3 to obtain (1S,5S,6R)-10 (73%).
sion after 5 h, provided the target compound in a mixture
For the synthesis of the trans isomers, we needed a bulky
with various unidentified byproducts. Moreover, the stereo- 4-OH protecting group that could direct the cyclopropan-
selectivity was very low, with the unexpected predominance ation onto the opposite face of the double bond. For 4-
of the trans compound (trans/cis ratio of about 1.3:1). Con- OTBS-, OTIPS-, and OtBu-protected derivatives of 2, we
sidering the highly oxophilic nature of samarium and the had already observed good to high facial selectivity in
excellent stereoselectivity reported by Cossy,[14] we can only heterogeneous catalytic hydrogenation and hydroboration
assume that the N-protecting group somehow competes reactions,[1b,1c,12] so we were confident that a similar selec-
with the OH group for the coordination of samarium and tivity could be obtained in cyclopropanation, either by ex-
the delivery of the carbenoid onto the double bond. In sup- ploiting Michael-type reactions of S-ylides or various carb-
port of this hypothesis, the N-Boc-directed cyclopropan- enoids. However, not only did O-protected derivative 11
ation of allylic carbamates with Zn-carbenoids has recently (RЈ = TBS, Scheme 4), prepared as reported,[1b,1c] react very
been described by Davies.[17]
slowly with Charette’s and Wittig–Furukawa’s carbenoids
(53–55% conversion after 20–44 h, Table 2, Entries 1–2) but
the cis isomer still, albeit only slightly, prevailed. This could
be explained by a weak coordination of the Zn-carbenoid
to the oxygen atom in the 4-position. In fact, when com-
pletely changing the reaction mechanism, i.e. using dimeth-
ylsulfoxonium methylide in dimethyl sulfoxide (DMSO) at
25 °C,[11d] steric control by the 4-OR group took place, pro-
viding trans compounds 12, 14, and 16 in an approximately
3.8–7:1 ratio with their cis isomers (Entries 3–5) and in
good yields (77–82%) after chromatography.[21] This ratio
could not be increased under different conditions, even
when carrying out the reaction in N,N-dimethylformamide
(DMF) at –5 °C (Entry 6). The facial selectivity was much
the same (trans/cis ratio = 4.8:1) when we used dimethylsulf-
onium methylide for the trans cyclopropanation in DMF
(Entry 7) at room temperature; however, the isolated yield
was very low (14% after chromatography) under these con-
ditions (and even worse when carrying out the reaction in
DMSO, Entry 8) because of the formation of a large
amount of polar byproducts, which were lost in the work
up or during chromatography. Finally, the Pd-catalyzed cy-
Table 1. OH-directed cyclopropanation of alcohols (R)-2 and (R)-
3.[a]
Entry R-OH Conditions
Conv.[b]
[%]
cis[c]
[%]
trans[c]
[%]
1
2
3
4
5
(R)-2 Sm/HgCl2, CH2I2, THF,
100[d]
43
57
–
–78Ǟ25 °C, 5 h
(R)-2 Et2Zn, CH2I2, CH2Cl2,
–12Ǟ25 °C, 24 h
87
100 (60)[e]
100 (35)[e]
100 (86)[e]
100 (79)[e]
(R)-2 Et2Zn, CH2I2, TFA, CH2Cl2,
–78Ǟ25 °C, 24 h
72
–
(R)-2 Et2Zn, CH2I2, TCP,[f] CH2Cl2,
–40Ǟ25 °C, 4 h
100
100
–
(R)-3 Et2Zn, CH2I2, TCP,[f] CH2Cl2,
–40Ǟ25 °C, 3.5 h
–
[a] Reaction carried out on 0.2–0.9 mmol of substrate. [b] Reaction
monitored by TLC. [c] Relative composition determined by 1H
NMR on the crude reaction mixture. [d] Starting material com-
pletely consumed but several unidentified products in the crude
reaction mixture. [e] Yield after chromatography. [f] TCP = 2,4,6-
trichlorophenol.
We tried the Simmons–Smith reaction under three dif-
ferent sets of conditions (Entries 2–4): (1) with the Wittig–
Furukawa reagent [Zn(CH2I)2],[18] (2) with Charette’s car-
benoid [Cl3C6H2OZnCH2I],[19] and (3) with Shi’s carbenoid
[CF3CO2ZnCH2I].[17,20] In spite of the latter being one the
most reactive carbenoids, the reaction did not reach com-
plete conversion after 24 h (Entry 3), as also observed for
the reaction with the Wittig–Furukawa reagent (Entry 2).
Although in all cases we observed the formation of the ex-
pected cis product only, the best result in terms of cyclopro-
panation rate and yield after chromatography was obtained
with Et2Zn and CH2I2 in the presence of 2,4,6-trichlorophen- Scheme 4. The trans cyclopropanation of OH-protected alcohols.
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Synthesis of 4-Hydroxy-2,3-methanopipecolic Acid Derivatives
clopropanation (Entry 9) carried out in the presence of tri- whose positive optical rotation value is consistent with the
methylsilyldiazomethane (TMSCHN2), as reported for an stereospecificity of the lipase in the kinetic resolution of
electron-poor olefin, failed completely.[22] Despite the fact (Ϯ)-3 {for trans-(1S,5R,6R)-9 obtained from (R)-13 of
that the trans compounds were obtained in mixtures with known absolute configuration the [α]2D5 value is –4.43}.
their cis isomers, these could be easily separated by
chromatography after OH deprotection (Scheme 4), which
Conclusions
provided the enantiopure major trans compounds
(1S,5R,6R)-9 in 69 and 67% yield from (1S,5R,6R)-12 and
(1S,5R,6R)-14, respectively, and (1S,5R,6R)-10 in 73% yield
from (1S,5R,6R)-16. The best conditions were applied to
the synthesis of (1R,5S,6S)-10 from (S)-15.
We have reported a practical, convenient procedure,
which allows the diastereodivergent synthesis of cycloprop-
anated 4-hydroxypipecolic acid derivatives with high op-
tical purity to be realized in very few steps from cheap start-
ing materials. A highly enantioselective lipase-catalyzed ki-
netic resolution plays a key role in the synthesis, whereas
the stereochemical control in the cyclopropanation reaction
is ensured by the 4-OH group itself, either free or protected.
Charette’s Zn-carbenoid for the OH-directed cyclopropan-
ation and Michael-type addition of dimethylsulfoxonium
methylide in DMSO for the synthesis of the trans products
provided the 2,3-methanopipecolic acid derivatives with the
highest yield and facial selectivity. The compounds so ob-
tained are rigidified homoserine analogues, which could
find application in medicinal chemistry as conformational
probes and in drug discovery.
Table 2. Cyclopropanation of alcohol derivatives (R)-11, (R)-13,
and (R)-15.[a]
Entry Substrate Conditions
Conv.[b]
[%]
cis/trans[c]
1
2
3
(R)-11
(R)-11
(R)-11
Et2Zn, CH2I2, CH2Cl2,
–12Ǟ25 °C, 20 h
Et2Zn, CH2I2, TCP, CH2Cl2,
–40Ǟ25 °C, 44 h
TMSOI, NaH, DMSO,
25 °C, 2 h
53
55
1.2:1 (12)
1.3:1 (12)
100 (82)[d] 1:4.7 (12)
4
5
6
(R)-13
(R)-15
(R)-11
1.5 h
2.2 h
100 (77)[d] 1:3.8 (14)
100 (78)[d] 1:7 (16)
93 (13)[d,e] 1:3.1 (12)
TMSOI, NaH, DMF,
–5 °C, 24 h
TMSI, NaH, DMF,
25 °C, 2 h
TMSI, NaH, DMSO,
25 °C, 2 h
TMSCHN2, Pd(OAc)2, benzene,
30 °C, 4 d
7
8
9
(R)-13
(R)-13
(R)-11
82 (14)[d,e] 1:4.8 (14)
Experimental Section
89 (5)[d,e]
0
–
–
General: Chromatographic separations were performed under pres-
sure on silica gel 60 (Merck,70–230 mesh) using flash column tech-
niques; Rf values refer to TLC carried out on 0.25 mm silica gel
plates with the same eluent indicated for column chromatography.
THF was distilled with Na/benzophenone. CH2Cl2 and n-hexane
were distilled from CaH2. Commercial anhydrous DMSO, DMF,
and MeOH were used. 1H NMR (400 and 200 MHz) and 13C
NMR (50.33 and 100.4 MHz) spectra were recorded at 25 °C. Mass
spectra were carried out either by direct inlet on a LCQ FleetTM
Ion Trap LC/MS system (Thermo Fisher Scientific) with an ESI
interface in the positive mode or by EI at 70 eV. HPLC analyses
were carried out with a Dionex Ultimate 3000 instrument. Lipase
PS “AMANO” IM has a reported activity Ն 500 U/g. Compounds
(R)-2, (S)-2, and (R)-4 are known.[1b]
[a] Reaction carried out on 0.5–1 mmol of substrate, monitored
by TLC. [b] Determined by 1H NMR spectroscopy. [c] Relative
1
composition determined by H NMR on the crude reaction mix-
ture. [d] Yield after chromatography. [e] Low yield due to a great
extent of degradation of the starting material.
Finally, to obtain these amino acid analogues in a form
suitable for peptide coupling, we carried out N-deprotection
of both enantiomers of 10 by hydrogenolysis (Scheme 5) at
room temperature with 10% Pd/C, which provided free
amino esters cis-17 and trans-17 both in quantitative
yield.[23]
Two-Step Lipase-Catalyzed Kinetic Resolution of (؎)-2. Dimethyl
(R)-4-(Butyryloxy)-5,6-dihydropyridine-1,2(4H)-dicarboxylate [(+)-
4] and Dimethyl (S)-4-Hydroxy-5,6-dihydropyridine-1,2(4H)-dicarb-
oxylate [(–)-2]: Molecular sieves (4 Å, 153 mg) were added to a
solution of (Ϯ)-2 (253 mg, 1.18 mmol) in THF (1.5 mL) at 30 °C
followed by lipase PS “AMANO” IM (118 mg) under a N2 atmo-
sphere. After 20 min, vinyl butyrate (523 μL, 4.12 mmol) was added
and the reaction was stirred vigorously and monitored by GC. Af-
ter 7 h, the conversion reached 42% and the reaction was stopped
by filtration through a thin layer of Celite. After evaporation, the
crude product was chromatographed (first with EtOAc/n-hexane,
1:2, then EtOAc/n-hexane, 2:1 to collect the alcohol) to give (R)-4
(Rf = 0.60, 122 mg, 38%, 99.5% ee) and (S)-2 (Rf = 0.3, 134 mg,
53%, 69% ee). To a solution of (S)-2 in THF (0.8 mL) at 30 °C
were added molecular sieves (4 Å, 80 mg) followed by lipase PS
“AMANO” IM (62 mg) under a N2 atmosphere. After 20 min, vi-
nyl butyrate (236 μL, 1.86 mmol) was added and the reaction was
left stirring and monitored by GC. After 22 h, the conversion
reached 17% and the reaction was stopped by filtration through a
Scheme 5. Deprotection of N-Cbz methanopipecolic esters.
Of these, trans-(1R,5S,6S)-17 was converted into the cor-
responding N-CO2Me-protected compound (1R,5S,6S)-9 thin layer of celite. After evaporation, the crude product was chro-
Eur. J. Org. Chem. 2011, 6544–6552
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E. G. Occhiato, A. Casini, A. Guarna, D. Scarpi
FULL PAPER
matographed (EtOAc/n-hexane, 1:2) to give (S)-2 (Rf = 0.15,
226 mg, 89%, 99.5% ee).
yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H,
Ph), 6.07 (t, J = 3.9 Hz, 1 H, 3-H), 5.14 (s, 2 H, CH2Ph), 3.67–3.64
(m, 2 H, 6-H), 3.56 (br. s, 3 H, OCH3), 2.27–2.22 (m, 2 H, 4-H),
1.86–1.81 (m, 2 H, 5-H) ppm. 13C NMR (100.4 MHz, CDCl3): δ =
165.1 (s, CO), 154.0 (s, CO), 135.8 (s), 132.4 (s, C-2), 128.5 (d, 2
C), 128.2 (d), 128.1 (d, 2 C), 123.1 (d, C-3), 68.0 (t, CH2Ph), 51.9
(q, OCH3), 43.7 (t, C-6), 22.9 (t, C-4), 22.7 (t, C-5) ppm. MS: m/z
(%) = 276 (2) [M + 1]+, 232 (100). C15H17NO4 (275.30): calcd. C
65.44, H 6.22, N 5.09; found C 65.27, H 6.11, N 5.01.
(R)-4:[1b] [α]2D5 = +215.0 (c = 0.78, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 5.91 (d, J = 4.1 Hz, 1 H, 3-H), 5.31 (pseudo q, J =
3.9 Hz, 1 H, 4-H), 4.10 (dt, J = 13.1, 4.1 Hz, 1 H, 6-H), 3.79 (s, 3
H, OCH3), 3.74 (s, 3 H, OCH3), 3.28 (ddd, J = 13.1, 8.8, 6.2 Hz,
1 H, 6-HЈ), 2.27 (t, J = 7.0 Hz, 2 H, OCH2), 1.94–1.98 (m, 2 H, 5-
H), 1.60–1.68 (m, 2 H, CH2), 0.94 (t, J = 7.3 Hz, 3 H, CH3) ppm.
(S)-2:[1b] [α]2D5 = –139.7 (c = 0.68, CHCl3). 1H NMR (400 MHz,
CDCl3) δ = 5.96 (dd, J = 3.9, 1.0 Hz, 1 H, 3-H), 4.31–4.27 (m, 1
H, 4-H), 4.05 (dt, J = 13.1, 4.1 Hz, 1 H, 6-H), 3.79 (s, 3 H, OCH3),
3.73 (s, 3 H, OCH3), 3.30 (ddd, J = 13.2, 9.2, 5.5 Hz, 1 H, 6-HЈ),
1.96–1.85 (m, 2 H, 5-H) ppm.
1-Benzyl 2-Methyl 4-Hydroxy-5,6-dihydropyridine-1,2(4H)-dicarb-
oxylate (؎)-3: A solution of 7 (663 mg, 2.41 mmol), N-bromosuc-
cinimide (545 mg, 3.06 mmol), and a catalytic amount of azobisiso-
butyronitrile (34 mg, 0.21 mmol) in a 9:1 mixture of anhydrous
CCl4 and CHCl3 (83 mL) was heated to reflux with vigorous stir-
ring for 15 min. After cooling, the reaction mixture was diluted
with CHCl3 (65 mL), washed with water (70 mL), and evaporated
to give the 4-Br derivative as a yellow oil. 1H NMR (200 MHz,
CDCl3): δ = 7.40–7.20 (m, 5 H, Ph), 6.04 (d, J = 4.4 Hz, 1 H, 3-
H), 5.20 (part A of an AB system, J = 12.1 Hz, 1 H, CH2Ph), 5.09
(part B of an AB system, J = 12.1 Hz, 1 H, CH2Ph), 4.88–4.81 (m,
1 H, CHBr), 4.32–4.20 (m, 1 H, 6-H), 3.56 (s, 3 H, OCH3), 3.65–
3.20 (m, 1 H, 3-HЈ), 2.50–2.20 (m, 2 H, 5-H) ppm.
Dimethyl (R)-4-Hydroxy-5,6-dihydropyridine-1,2(4H)-dicarboxylate
[(+)-2]: MeONa (24 mg, 0.43 mmol) was added to a solution of
(+)-4 (116 mg, 0.43 mmol) in dry MeOH (3 mL) at 0 °C and stirred
for 5 h under a N2 atmosphere. Glacial acetic acid (25 μL) was
added, and the solvent evaporated. The residue was diluted with
water (40 mL), extracted into EtOAc (4ϫ40 mL), and dried with
Na2SO4. After filtration and evaporation of the solvent, the crude
product was chromatographed (EtOAc/n-hexane, 2:1, +0.5% Et3N,
Rf = 0.3) to give (R)-2 (89 mg, 96%) as a thick pale yellow oil.
This oil was dissolved in 96% aqueous acetone (68 mL) with six
drops of water, and ZnCl2 (1.362 g, 10 mmol) was added portion-
wise to the resulting solution over 4 h. After 2.5 h, the reaction
mixture was diluted with CHCl3 (60 mL), washed with water
(100 mL), saturated aqueous NaHCO3 (100 mL), and brine
(65 mL), and dried with Na2SO4. After filtration and evaporation
of the solvent, the crude product was chromatographed (EtOAc/n-
hexane, 2:1, Rf = 0.40) to give (Ϯ)-3 (399 mg, 57%) as a thick pale
yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.30 (m, 5 H,
Ph), 5.94 (dd, J = 3.9, 0.6 Hz, 1 H, 3-H), 5.18 (part A of an AB
system, J = 12.1 Hz, 1 H, CH2Ph), 5.09 (part B of an AB system,
J = 12.1 Hz, 1 H, CH2Ph), 4.31–4.27 (m, 1 H, 4-H), 4.08 (dt, J =
13.3, 4.3 Hz, 1 H, 6-H), 3.56 (br. s, 3 H, OCH3), 3.31 (ddd, J =
13.3, 9.4, 4.7 Hz, 1 H, 6-HЈ), 1.94–1.90 (m, 2 H, 5-H) ppm. 13C
NMR (100.4 MHz, CDCl3): δ = 165.0 (s, CO), 153.4 (s, CO), 135.4
(s), 133.6 (s, C-2), 128.5 (d, 2 C), 128.4 (d), 128.3 (d, 2 C), 120.7
(d, C-3), 68.3 (t, CH2Ph), 61.3 (d, C-4), 52.2 (q, OCH3), 40.2 (t, C-
6), 32.2 (t, C-5) ppm. MS: m/z (%) = 291 (1) [M]+, 259 (100).
C15H17NO5 (291.30): calcd. C 61.85, H 5.88, N 4.81; found C
62.01, H 5.68, N 4.57.
(R)-2:[1b] [α]2D5 = +139.2 (c = 0.71, CHCl3). Spectroscopic data as
reported above for (S)-2.
1-Benzyl 2-Methyl 5,6-Dihydropyridine-1,2(4H)-dicarboxylate (7):
To a solution of potassium bis(trimethylsilyl)amide (20.8 mL of a
0.5 m solution in toluene, 10.4 mmol) in THF (54 mL), at –78 °C
and under nitrogen atmosphere, was added a solution of N-Cbz-
protected δ-valerolactam 5 (1.96 g, 8.39 mmol) in THF (20 mL)
and the resulting mixture was stirred for 1.5 h. A solution of
(PhO)2P(O)Cl (2.15 mL, 10.36 mmol) in THF (16.0 mL) was added
slowly, and the mixture was stirred for 1 h at –78 °C before allowing
the temperature to rise to 0 °C. A 10% NaOH aqueous solution
(165 mL) was added, the mixture extracted into Et2O (3ϫ95 mL),
the combined organic layers washed with 10% NaOH (60 mL), and
dried with anhydrous K2CO3 for 30 min. After filtration and re-
duction of the solvent volume (without heating and leaving a small
volume of solvent), the crude phosphate was chromatographed
(EtOAc/n-hexane, 1:2.5, + 1% Et3N, Rf = 0.25) on a short layer of
silica gel (4.5 cm of silica gel in a column with internal diameter of
3 cm) to give 6 as pale yellow oil (3.875 g, 99%). 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.26 (m, 10 H), 7.25–7.13 (m, 5 H),
5.14 (pseudo q, J = 3.9 Hz, 1 H, 3-H), 5.08 (s, 2 H, CH2Ph), 3.70–
3.61 (m, 2 H, 6-H), 2.24–2.11 (m, 2 H, 4-H), 1.81–1.69, (2 H, 5-H)
ppm. 13C NMR (100.4 MHz, CDCl3): δ = 154.0 (s, CO), 150.4 (s,
2 C), 139.9 (s, C-2), 135.9 (s), 129.7 (d, 4 C), 128.4 (d, 2 C), 128.0
(d), 127.9 (d, 2 C), 125.4 (d, 2 C), 120.0 (d, 4 C), 100.5 (d, C-3),
67.8 (t, CH2Ph), 45.7 (t, C-6), 22.6 (t, C-4), 21.6 (t, C-5) ppm. ESI-
MS: m/z (%) = 953 (100) [2M + 23]+, 488 (10) [M + 23]+, 466 (8)
[M + 1]+.
Lipase-Catalyzed Kinetic Resolution of (؎)-3. 1-Benzyl 2-Methyl
(S)-4-Hydroxy-5,6-dihydropyridine-1,2(4H)-dicarboxylate
[(–)-3]
and 1-Benzyl 2-Methyl (R)-4-(Butyryloxy)-5,6-dihydropyridine-
1,2(4H)-dicarboxylate [(+)-8]: Molecular sieves (4 Å, 323 mg) were
added to a solution of (Ϯ)-3 (728.5 mg, 2.5 mmol) in TBME
(6.2 mL) at 30 °C, followed by lipase PS “AMANO” IM (248 mg)
under a N2 atmosphere. After 20 min, vinyl butyrate (1.11 mL,
8.73 mmol) was added and the reaction was stirred vigorously and
monitored by GC. After 1.9 h, the conversion reached 44% and
the reaction was stopped by filtration through a thin layer of Celite.
After evaporation, the crude product was chromatographed
(EtOAc/n-hexane, 1:2) to give (R)-8 (Rf = 0.54, 352 mg, 39%) and
(S)-3 (Rf = 0.12, 373 mg, 51%, 73% ee). (S)-3 was dissolved again
in TBME (3.3 mL) at 30 °C, and molecular sieves (4 Å, 161 mg)
Compound 6 was immediately dissolved in DMF (20 mL) and to
the resulting solution were added Pd(OAc)2 (189 mg, 0.84 mmol)
and Ph3P (439 mg, 1.67 mmol) under a nitrogen atmosphere. The
solution was stirred 10 min under a CO atmosphere (balloon) be-
fore Et3N (2.3 mL, 16.7 mmol) and MeOH (7.0 mL, 335 mmol) were added followed by lipase PS “AMANO” IM (124 mg) under
were added and stirring was continued at 58 °C for 4 h under static
CO pressure and then left at room temperature overnight. The solu-
tion was diluted with water (150 mL), extracted into Et2O
(5ϫ100 mL), and dried with Na2SO4. After filtration and evapora-
tion of the solvent, the oily residue was chromatographed (EtOAc/
n-hexane, 1:4, Rf = 0.28) to give 7 (2.03 g, 88%) as a thick pale
a N2 atmosphere. After 20 min, vinyl butyrate (546 μL) was added
and the reaction was left to stir and monitored by GC. After 2.4 h,
the conversion reached 16% and the reaction was stopped by fil-
tration through a thin layer of celite. After evaporation, the crude
product was chromatographed to give (S)-3 (269 mg, 37%, 99.8%
ee).
6548
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6544–6552

Synthesis of 4-Hydroxy-2,3-methanopipecolic Acid Derivatives
(S)-3: [α]2D5 = –230.1 (c = 0.50, CHCl3). Spectroscopic data as re-
ported above for (Ϯ)-3.
19.1 (t, C-7) ppm. MS: m/z (%) = 230 (8) [M + 1]+, 197 (100).
C10H15NO5 (229.23): calcd. C 52.40, H 6.60, N 6.11; found C
52.09, H 6.72, N 5.98.
(R)-8: [α]2D5 = +189.9 (c = 0.89, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.28 (m, 5 H, Ph), 5.90 (d, J = 4.3 Hz, 1 H, 3-
H), 5.31 (pseudo q, J = 3.9 Hz, 1 H, 4-H), 5.19 (part A of an AB
system, J = 12.1 Hz, 1 H, CH2Ph), 5.10 (part B of an AB system,
J = 12.1 Hz, 1 H, CH2Ph), 4.17 (dt, J = 13.1, 4.1 Hz, 1 H, 6-H),
3.56 (br. s, 3 H, OCH3), 3.29 (ddd, J = 13.1, 9.4, 5.6 Hz, 1 H, 6-
HЈ), 2.27 (t, J = 7.4 Hz, 2 H, COCH2), 2.00–1.94 (m, 2 H, 5-H),
1.68–1.59 (m, 2 H, CH2CH3), 0.94 (t, J = 7.4 Hz, CH2CH3) ppm.
13C NMR (100.4 MHz, CDCl3): δ = 172.6 (s, CO), 164.6 (s, CO),
153.3 (s, CO), 135.3 (s), 135.2 (s, C-2), 128.5 (d, 2 C), 128.4 (d),
128.3 (d, 2 C), 116.7 (d, C-3), 68.5 (t, CH2Ph), 63.3 (d, C-4), 52.3
(q, OCH3), 40.6 (t, C-6), 36.2 (t, COCH2), 29.3 (t, C-5), 18.4 (t,
CH2CH3), 13.6 (q, CH2CH3) ppm. MS: m/z (%) = 384 (12) [M +
23]+, 296 (100), 162 (18). C19H23NO6 (361.39): calcd. C 63.15, H
6.41, N 3.88; found C 63.03, H 6.44, N 3.65.
2-Benzyl 1-Methyl (1R,5R,6S)-5-Hydroxy-2-azabicyclo[4.1.0]hept-
ane-1,2-dicarboxylate [cis-(+)-10]: Prepared as reported above for
cis-(+)-9 but the reaction was stopped after 3.5 h. Starting from
(R)-3 (262 mg, 0.90 mmol), (1R,5R,6S)-10 (217 mg) was obtained
after chromatography (Et2O, Rf = 0.24) as a colorless oil (79%).
(1R,5R,6S)-10: [α]2D5 = +31.2 (c = 0.72, CHCl3). 1H NMR
(400 MHz, CDCl3) (2.4:1 mixture of rotamers): δ = 7.36–7.25 (m,
5 H, Ph), 5.26 (d, J = 12.5 Hz, 1 H, CH2Ph, major rotamer), 5.15
(AB system, J = 12.5 Hz, 2 H, CH2Ph, minor rotamer), 5.05 (d, J
= 12.5 Hz, 1 H, CH2Ph, major rotamer), 4.38–4.29 (m, 1 H, 5-H),
4.03 (dt, J = 13.5, 3.7 Hz, 1 H, 3-H, major rotamer), 3.91 (dt, J =
13.5, 3.7 Hz, 1 H, 3-H, minor rotamer), 3.69 (s, 3 H, OCH3, minor
rotamer), 3.51 (s, 3 H, OCH3, major rotamer), 2.83 (td, J = 13.8,
1.8 Hz, 1 H, 3-HЈ, minor rotamer), 2.74 (td, J = 14.2, 2.1 Hz, 1 H,
3-HЈ, major rotamer), 2.12–2.00 (br., 1 H, OH), 2.06–1.90 (m, 2 H,
4-H and 6-H, and 1 H, minor rotamer), 1.87 (dd, J = 9.9, 5.1 Hz,
1 H, 7-H, major rotamer), 1.28–1.16 (m, 1 H, 4-HЈ, major rotamer,
and 1 H, minor rotamer), 1.07 (dd, J = 7.6, 5.1 Hz, 1 H, 7-HЈ,
minor rotamer), 1.08 (dd, J = 7.6, 5.1 Hz, 1 H, 7-HЈ, major rot-
amer) ppm. 13C NMR (100.4 MHz, CDCl3) (mixture of rotamers):
δ = 172.1 and 171.7 (s, CO), 156.2 and 155.7 (s, CO), 136.5 (s, Ph),
128.5 and 128.4 (d, 2 C, Ph), 127.9 and 127.8 (d, Ph), 127.6 (d, 2
C), 67.4 and 67.3 (t, CH2Ph), 64.1 and 63.1 (d, C-5), 52.5 and 52.3
(q, OCH3), 41.9 and 41.4 (s, C-1), 41.2 and 41.0 (t, C-3), 30.7 and
30.3 (d, C-6), 29.0 and 28.7 (t, C-4), 19.7 and 19.1 (t, C-7) ppm.
MS: m/z (%) = 306 (100%) [M + 1]+. C16H19NO5 (305.33): calcd.
C 62.94, H 6.27, N 4.59; found C 62.66, H 6.12, N 4.27.
1-Benzyl 2-Methyl (R)-4-Hydroxy-5,6-dihydropyridine-1,2(4H)-di-
carboxylate [(+)-3]: To a solution of (R)-8 (352 mg, 0.97 mmol) in
dry MeOH (4 mL) cooled in an ice bath was added MeONa
(52.6 mg, 0.97 mmol), and the mixture stirred for 3.5 h at 0 °C un-
der a N2 atmosphere. Glacial acetic acid (57 μL) was added, and
the solvent was evaporated. The residue was diluted with water
(80 mL), extracted into EtOAc (4ϫ80 mL), and dried with
Na2SO4. After filtration and evaporation of the solvent, the crude
product was chromatographed (EtOAc/n-hexane, 1:1, Rf = 0.24) to
give (R)-3 (271 mg, 96%, 98.7% ee) as a colorless oil.
(R)-3: [α]2D5 = +228.7 (c = 0.54, CHCl3). Spectroscopic data as re-
ported above for (Ϯ)-3.
Dimethyl (1R,5R,6S)-5-Hydroxy-2-azabicyclo[4.1.0]heptane-1,2-di-
carboxylate [cis-(+)-9]: To a solution of TCP (248 mg, 1.26 mmol)
in anhydrous CH2Cl2 (12.6 mL) cooled to –40 °C was added Et2Zn
(1.26 mL of a 1 m solution in hexane, 1.26 mmol) under a nitrogen
atmosphere. The mixture was stirred for 15 min before CH2I2
(101 μL, 1.26 mmol) was added dropwise and, after another 15 min
at –40 °C, a solution of alcohol (R)-2 (136 mg, 0.63 mmol) in
CH2Cl2 (0.8 mL) was added dropwise. The ice bath was removed
and reaction mixture was left to stir for 4 h. The suspension was
cooled in an ice bath and a 10% solution of citric acid (5 mL)
was added dropwise with vigorous stirring. The cooling bath was
removed and when the solution became clear the layers were sepa-
rated. The aqueous layer was extracted into CH2Cl2 (6ϫ5 mL),
and the combined organic layers washed with a 10% solution of
Na2CO3 (2ϫ40 mL), and dried with Na2SO4. After chromatog-
raphy (Et2O, Rf = 0.12), (1R,5R,6S)-9 (124 mg, 86%) was obtained
as a colorless oil.
2-Benzyl 1-Methyl (1S,5S,6R)-5-Hydroxy-2-azabicyclo[4.1.0]hept-
ane-1,2-dicarboxylate [cis-(–)-10]: Obtained from (S)-3 as reported
for cis-(+)-10 in 73% yield. [α]2D5 = –31.8 (c = 0.54, CHCl3).
1-Benzyl 2-Methyl (R)-4-(tert-Butyldimethylsilanyloxy)-5,6-dihy-
dropyridine-1,2(4H)-dicarboxylate [(+)-15]: To a stirring solution of
(R)-3 (62 mg, 0.21 mmol) in anhydrous DMF (0.7 mL) were added
imidazole (43 mg, 0.63 mmol) and TBSCl (63 mg, 0.42 mmol), and
the mixture was stirred 2 h at 38 °C under a N2 atmosphere. After
cooling to room temperature, water (5 mL) was added, and the
solution extracted into Et2O (5ϫ4 mL). The combined organic lay-
ers were washed with brine (5 mL) and dried with Na2SO4. After
filtration and evaporation of the solvent, the oily residue was chro-
matographed (EtOAc/n-hexane, 1:5, Rf = 0.45) to give (R)-15
(84 mg, 99%) as a thick colorless oil. [α]2D0 = +126.0 (c = 0.82,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H, Ph),
5.85 (d, J = 3.7 Hz, 1 H, 3-H), 5.18 (part A of an AB system, J =
12.1 Hz, 1 H), 5.09 (part B of an AB system, J = 12.1 Hz, 1 H),
4.24 (pseudo q, J = 3.9 Hz. 1 H, 4-H), 4.02 (dt, J = 12.9, 4.5 Hz,
1 H, 6-H), 3.55 (br. s, 3 H, OCH3), 3.39–3.29 (m, 1 H, 6-HЈ), 1.90–
(1R,5R,6S)-9: [α]2D5
= +51.3 (c =
0.93, CHCl3). 1H NMR
(400 MHz, CDCl3) (1.7:1 mixture of rotamers): δ = 4.35 (dt, J =
10.1, 6.2 Hz, 1 H, 5-H), 4.02 (dt, J = 13.5, 3.9 Hz, 1 H, 3-H, major
rotamer), 3.86 (dt, J = 14.0, 4.3 Hz, 1 H, 3-H, minor rotamer), 3.73
(s, 3 H, OCH3, minor rotamer), 3.71 and 3.70 (s, 3 H + 3 H, OCH3,
both rotamers), 2.81 (td, J = 14.0, 1.8 Hz, 1 H, 3-HЈ, minor rot-
amer), 2.73 (td, J = 13.5, 2.0 Hz, 1 H, 3-HЈ, major rotamer), 2.05–
1.89 (m, 2 H, 4-H and 6-H, and 1 H, minor rotamer), 1.87 (dd, J
= 9.9, 5.3 Hz, 1 H, 7-H, major rotamer), 1.78 (br. s, 1 H, OH),
1.27–1.16 (m, 1 H, 4-HЈ, major rotamer, and 1 H, minor rotamer),
1.09 (dd, J = 7.6, 5.3 Hz, 1 H, 7-HЈ, minor rotamer), 1.06 (dd, J =
1.81 (m, 2 H, 5-H), 0.88 (s, 9 H, TBS), 0.08 (s, 6 H TBS) ppm. 13
C
NMR (100.4 MHz, CDCl3): δ = 165.2 (s, CO), 153.6 (s, CO), 135.6
(s, Ph), 132.5 (s, C-2), 128.5 (d, 2 C, Ph), 128.3 (d, Ph), 128.2 (d, 2
C, Ph), 122.6 (d, C-3), 68.2 (t, CH2Ph), 62.0 (d, C-4), 52.1 (q,
OCH3), 40.4 (t, C-6), 33.1 (t, C-5), 25.8 (q, 3 C, TBS), 18.0 (s,
TBS), –4.59 (q, TBS), –4.74 (q, TBS) ppm. MS: m/z (%) = 405 (62)
[M]+, 361 (100). C21H31NO5Si (405.56): calcd. C 62.19, H 7.70, N
3.45; found C 62.44, H 7.38, N 3.43.
1-Benzyl 2-Methyl (S)-4-(tert-Butyldimethylsilanyloxy)-5,6-dihy-
dropyridine-1,2(4H)-dicarboxylate [(–)-15]: Obtained from (S)-3 as
reported for (R)-15 in 99% yield. [α]2D0 = –127.3 (c = 0.77, CHCl3).
7.6, 5.3 Hz,
1
H, 7-HЈ, major rotamer) ppm. 13C NMR
(100.4 MHz, CDCl3) (mixture of rotamers): δ = 172.2 and 171.7 (s,
CO), 156.9 and 156.3 (s, CO), 64.2 and 64.1 (d, C-5), 53.0 and 52.8
(q, OCH3), 52.5 (q, OCH3), 41.9 and 41.3 (s, C-1), 41.1 and 40.9 Cyclopropanation by Dimethylsulfoxonium Methylide of (R)-11. Di-
(t, C-3), 30.8 and 30.3 (d, C-6), 29.0 and 28.7 (t, C-4), 19.7 and methyl (1S,5R,6R)-5-Hydroxy-2-azabicyclo[4.1.0]heptane-1,2-di-
Eur. J. Org. Chem. 2011, 6544–6552
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6549

E. G. Occhiato, A. Casini, A. Guarna, D. Scarpi
FULL PAPER
carboxylate [trans-(–)-9]: Dry DMSO (0.9 mL) was added to NaH
(60% in weight in mineral oil, 24 mg, 0.6 mmol) previously washed
HЈ, minor rotamer), 0.75 (dd, J = 8.0, 5.3 Hz, 1 H, 7-HЈ, major
rotamer) ppm. 13C NMR (100.4 MHz, CDCl3) (mixture of rota-
with dry n-hexane (2ϫ1.5 mL) under a nitrogen atmosphere. To mers): δ = 172.5 (s, CO), 157.0 (s, CO), 63.2 and 63.1 (d, C-5), 52.9
the resulting suspension was added TMSOI (122 mg, 0.56 mmol)
in three portions and the mixture stirred for 30 min at room tem-
perature. After cooling to 15 °C, a solution of (R)-11 (122 mg,
0.37 mmol) in DMSO (500 μL) was added dropwise. The water
bath was removed and the reaction mixture was left to stir for 2 h.
Water (12 mL) was added, and the mixture extracted into Et2O
(7ϫ9 mL), dried with Na2SO4, filtered, and concentrated.
Chromatography (EtOAc/n-hexane, 1:5, Rf = 0.24) gave 12 (104 mg,
82%) as a 4.7:1 mixture of trans and cis isomers. trans-12: 1H NMR
(400 MHz, CDCl3) (1.8:1 mixture of rotamers): δ = 4.12–4.09 (m,
1 H, 5-H), 3.78 (dt, J = 12.9, 4.2 Hz, 1 H, 3-H, major rotamer),
3.71 (s, 3 H, OCH3, minor rotamer), 3.69 and 3.68 (s, 3 H + 3 H,
OCH3, both rotamers), 3.62 (dt, J = 12.3, 4.1 Hz, 1 H, 3-H, minor
rotamer), 3.23 (ddd, J = 12.3, 10.7, 2.7 Hz, 1 H, 3-HЈ, minor rot-
amer), 3.14 (ddd, J = 12.9, 10.9, 2.9 Hz, 1 H, 3-HЈ, major rotamer),
1.91 (dd, J = 10.3, 5.5 Hz, 1 H, 7-H, minor rotamer), 1.85 (dd, J
= 10.3, 5.3 Hz, 1 H, 7-H, major rotamer), 1.76–1.57 (m, 2 H, 6-H
and 4-H), 1.51–1.39 (m, 1 H, 4-HЈ), 0.88 (s, 9 H, TBS), 0.73 (dd,
J = 7.8, 5.5 Hz, 1 H, 7-HЈ, minor rotamer), 0.70 (dd, J = 8.2,
5.5 Hz, 1 H, 7-HЈ, major rotamer), 0.084 (s, 6 H, TBS) ppm.
and 52.8 (q, OCH3), 52.5 (q, OCH3), 39.0 and 38.6 (s, C-1), 36.5
and 35.9 (t, C-3), 31.1 and 31.0 (d, C-6), 30.9.0 and 30.8 (t, C-4),
20.5 and 20.0 (t, C-7) ppm. MS: m/z (%) = 230 (9) [M + 1]+, 211
(29), 197 (100), 80 (16). C10H15NO5 (229.23): calcd. C 52.40, H
6.60, N 6.11; found C 52.22, H 6.57, N 5.81.
2-Benzyl 1-Methyl (1S,5R,6R)-5-Hydroxy-2-azabicyclo[4.1.0]hept-
ane-1,2-dicarboxylate [trans (–)-10]: The reaction was carried out
as reported above for (R)-11. Starting from (R)-15 (78 mg,
0.19 mmol), chromatography (EtOAc/n-hexane, 1:6, Rf = 0.22) of
the crude reaction mixture gave 16 (62 mg, 78%) as a 7:1 mixture
of trans and cis isomers. trans-16: 1H NMR (400 MHz, CDCl3)
(2.5:1 mixture of rotamers): δ = 7.37–7.26 (m, 5 H, Ph), 5.25 (part
A of an AB system, J = 12.5 Hz, 1 H, major rotamer), 5.20 (part
A of an AB system, J = 12.3 Hz, 1 H, minor rotamer), 5.14 (part
B of an AB system, J = 12.3 Hz, 1 H, minor rotamer), 5.05 (part
B of an AB system, J = 12.5 Hz, 1 H, major rotamer), 4.16–4.10
(m, 1 H, 5-H), 3.81 (dt, J = 12.9, 4.3 Hz, 1 H, 3-H, major rotamer),
3.71 (s, 3 H, OCH3, minor rotamer), 3.53 (s, 3 H, OCH3, major
rotamers), 3.27 (ddd, J = 12.9, 10.5, 2.7 Hz, 1 H, 3-HЈ, minor rot-
amer), 3.17 (ddd, J = 12.9, 10.9, 2.7 Hz, 1 H, 3-HЈ, major rotamer),
1.94 (dd, J = 10.3, 5.7 Hz, 1 H, 7-H, minor rotamer), 1.87 (dd, J
= 10.3, 5.7 Hz, 1 H, 7-H, major rotamer), 1.78–1.58 (m, 2 H, 6-H
and 4-H), 1.52–1.40 (m, 1 H, 4-HЈ), 0.87 (s, 9 H), 0.76 (dd, J = 8.0,
5.7 Hz, 1 H, 7-HЈ, minor rotamer), 0.72 (dd, J = 8.0, 5.7 Hz, 1 H,
7-HЈ, major rotamer), 0.08 (s, 3 H, TBS, major rotamer), 0.07 (s,
3 H, TBS, major rotamer) ppm.
To the mixture of trans- and cis-12 (79 mg, 0.22 mmol) dissolved
in acetonitrile (10 mL) and cooled to 0 °C was added a 3 n solution
of HCl (10 mL) dropwise. The ice bath was removed and the mix-
ture left to stir for 1 h. A saturated solution of NaHCO3 (20 mL)
was slowly added until the mixture reached pH 7, the aqueous layer
extracted into EtOAc (6ϫ20 mL), and the combined organic layers
dried with Na2SO4, filtered, and concentrated. Chromatography
(Et2O, Rf = 0.23) gave (1S,5R,6R)-9 (35 mg, 69%) as a colorless
oil.
The mixture of trans- and cis-16 was deprotected as reported above
for 12, obtaining after chromatography (Et2O/n-hexane, 11:1, Rf =
0.2) trans (–)-10 (29 mg, 73%) as a colorless oil.
(1S,5R,6R)-(–)-10: [α]2D5 = –2.98 (c = 1.01, CHCl3). 1H NMR
(400 MHz, CDCl3) (2.6:1 mixture of rotamers): δ = 7.37–7.26 (m,
5 H, Ph), 5.26 (part A of an AB system, J = 12.5 Hz, 1 H, major
rotamer), 5.19 (part A of an AB system, J = 12.5 Hz, 1 H, minor
rotamer), 5.14 (part B of an AB system, J = 12.5 Hz, 1 H, minor
rotamer), 5.06 (part B of an AB system, J = 12.5 Hz, 1 H, major
rotamer), 4.31–4.25 (m, 1 H, 5-H), 3.89 (dt, J = 13.2, 3.7 Hz, 1 H,
3-H, major rotamer), 3.77 (dt, J = 13.3, 3.7 Hz, 1 H, 3-H, minor
rotamer), 3.71 (s, 3 H, OCH3, minor rotamers), 3.53 (s, 3 H, OCH3,
major rotamers), 3.21 (td, J = 13.3, 2.1 Hz, 1 H, 3-HЈ, minor rot-
amer), 3.11 (td, J = 13.2, 2.57 Hz, 1 H, 3-HЈ, major rotamer), 1.98
(dd, J = 10.5, 5.5 Hz, 1 H, 7-H, minor rotamer), 1.92 (dd, J = 10.5,
5.5 Hz, 1 H, 7-H, major rotamer), 1.85–1.68 (m, 2 H, 6-H and 4-
H), 1.59–1.48 (m, 1 H, 4-HЈ), 0.80 (dd, J = 8.0, 5.5 Hz, 1 H, 7-HЈ,
minor rotamer), 0.76 (dd, J = 8.0, 5.5 Hz, 1 H, 7-HЈ, major rot-
amer) ppm. 13C NMR (100.4 MHz, CDCl3) (mixture of rotamers):
δ = 172.4 and 171.9 (s, CO), 156.2 (s, CO), 136.6 (s, Ph), 128.5 (d,
2 C, Ph), 127.9 (d, Ph), 127.6 (d, 2 C, Ph), 67.4 and 67.2 (t, CH2Ph),
63.1 (d, C-5), 52.5 and 52.3 (q, OCH3), 39.1 and 38.6 (s, C-1), 36.6
and 35.9 (t, C-3), 31.1 and 31.0 (d, C-6), 30.9 and 30.8 (t, C-4),
20.5 and 20.0 (t, C-7) ppm. MS: m/z (%) = 306 (9) [M + 1]+, 262
(100), 244 (6), 198 (9), 170 (9), 154 (8), 91 (2). C16H19NO5 (305.33):
calcd. C 62.94, H 6.27, N 4.59; found C 62.73, H 6.11, N 4.19.
Cyclopropanation of (R)-13 by Dimethylsulfoxonium Methylide: The
reaction was carried out as reported above for (R)-11. Starting from
(R)-13 (87 mg, 0.32 mmol), chromatography (EtOAc/n-hexane, 1:4,
Rf = 0.22) of the crude reaction mixture gave 14 (70 mg, 77%) as
a 3.8:1 mixture of trans and cis isomers. trans-14: 1H NMR
(400 MHz, CDCl3) (2.3:1 mixture of rotamers): δ = 3.78–3.65 (s +
m, 7 H, OCH3 and 5-H), 3.28 (ddd, J = 12.5, 8.2, 4.3 Hz, 1 H, 3-
HЈ, minor rotamer), 3.21 (ddd, J = 12.9, 8.6, 4.3 Hz, 3-HЈ, major
rotamer), 1.92 (dd, J = 10.1, 5.5 Hz, 1 H, 7-H, minor rotamer),
1.85 (dd, J = 9.8, 5.1 Hz, 1 H, 7-H, major rotamer), 1.78–1.68 (m,
1 H, 6-H), 1.68–1.60 (m, 1 H, 4-H), 1.58–1.49 (m, 1 H, 4-HЈ), 1.21
(s, 9 H), 0.75 (dd, J = 7.8, 5.1 Hz, 1 H, 7-HЈ, minor rotamer), 0.72
(dd, J = 7.8, 5.1 Hz, 1 H, 7-HЈ, major rotamer) ppm.
To the mixture of trans- and cis-14 (70 mg, 0.25 mmol) dissolved
in acetonitrile (3.2 mL) was added pTsOH·H2O (58 mg, 0.3 mmol)
whilst stirring at room temperature. After 21 h, another portion of
pTsOH·H2O (24 mg) was added and the mixture left to stir for
another 6 h. The mixture was filtered through a short layer of Ce-
lite/NaHCO3 (1:1) and concentrated. Chromatography (Et2O, Rf =
0.23) gave trans-(1S,5R,6R)-9 (38 mg, 67%) as a colorless oil.
(1S,5R,6R)-(–)-9: [α]2D5 = –4.43 (c = 0.47, CHCl3). 1H NMR
(400 MHz, CDCl3) (2:1 mixture of rotamers): δ = 4.28 (br. s, 1 H,
5-H), 3.86 (dt, J = 13.3, 3.9 Hz, 1 H, 3-H, major rotamer), 3.73 (s,
3 H, OCH3, minor rotamer), 3.71 and 3.70 (s, 3 H + 3 H, OCH3,
both rotamers, and 1 H, 3-H, minor rotamer), 3.19 (td, J = 13.6,
2.1 Hz, 1 H, 3-HЈ, minor rotamer), 3.09 (td, J = 13.3, 2.3 Hz, 1 H,
3-HЈ, major rotamer), 1.97 (dd, J = 10.5, 5.5 Hz, 1 H, 7-H, minor
2-Benzyl 1-Methyl (1R,5S,6S)-5-Hydroxy-2-azabicyclo[4.1.0]hept-
ane-1,2-dicarboxylate [trans (+)-10]: Obtained from (S)-15 as re-
ported for trans-(–)-10 in 57% overall yield. [α]2D5 = +3.01 (c = 0.41,
CHCl3).
rotamer), 1.93–1.87 (m, 1 H, 7-H, major rotamer, and 1 H, 6-H, Methyl-(1R,5R,6S)-5-hydroxy-2-azabicyclo[4.1.0]heptane-1-carb-
minor rotamer), 1.87–1.67 (m, 1 H, 6-H, major rotamer, and 1 H,
oxylate [cis (+)-17]: To a solution of (1R,5R,6S)-10 (210 mg,
4-H), 1.58–1.46 (m, 1 H, 4-HЈ), 0.78 (dd, J = 8.0, 5.5 Hz, 1 H, 7-
0.69 mmol) in ethyl acetate (19 mL) under a nitrogen atmosphere
6550
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Synthesis of 4-Hydroxy-2,3-methanopipecolic Acid Derivatives
was added 10% Pd/C (52 mg), and the resulting suspension stirred
under an H2 atmosphere (balloon) at room temperature for 3 h.
After filtration through a Celite layer and evaporation of the sol-
vent, pure amino ester cis-(+)-17 (118 mg) was obtained in quanti-
[1]
[2]
For the most recent syntheses, see: a) N. Purkayastha, D. M.
Shendage, R. Frölich, G. Haufe, J. Org. Chem. 2010, 75, 222;
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56, 4084.
tative yield as a colorless oil. [α]2D5 = +80.9 (c = 0.78, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 4.32–4.25 (m, 1 H, 5-H), 3.72 (s, 3
H, OCH3), 2.84 (dt, J = 12.7, 4.1 Hz, 1 H, 3-H), 2.57 (td, J = 12.7,
2.3 Hz, 1 H, 3-HЈ), 2.10–2.03 (m, 1 H, 4-H), 1.90–1.76 (m, 3 H, 6-
H, OH, and NH), 1.57 (dd, J = 9.8, 4.7 Hz, 1 H, 7-H), 1.24–1.13
(m, 1 H, 4-HЈ), 1.05 (dd, J = 7.4, 4.7 Hz, 1 H, 7-HЈ) ppm. 13C
NMR (100.4 MHz, CDCl3): δ = 174.7 (s, CO), 64.6 (d, C-5), 52.5
(q, OCH3), 42.6 (s, C-1), 41.7 (t, C-3), 31.4 (d, C-6), 28.1 (t, C-4),
21.8 (t, C-7) ppm. MS: m/z (%) = 172 (1%) [M + 1]+, 154 (100),
122 (25), 94 (25). C8H13NO3 (171.19): calcd. C 56.13, H 7.65, N
8.18; found C 56.44, H 7.38, N 7.97.
[3]
[4]
Methyl (1S,5S,6R)-5-Hydroxy-2-azabicyclo[4.1.0]heptane-1-carb-
oxylate [cis-(–)-17]: Obtained from cis-(–)-10 as reported for cis-
(+)-17 in 100% yield. [α]2D5 = –82.1 (c = 0.48, CHCl3).
Methyl (1S,5R,6R)-5-Hydroxy-2-azabicyclo[4.1.0]heptane-1-carb-
oxylate [trans-(–)-17]: The reaction carried out as reported for cis-
(+)-17. Starting from (1S,5R,6R)-10 (29 mg, 0.095 mmol), trans-
(–)-17 (16.3 mg) was obtained in 100% yield as a colorless oil.
[5]
[6]
a) C. Cocito, Microbiol. Rev. 1979, 43, 145; b) H. Vander-
haeghe, G. Janssen, F. Compernolle, Tetrahedron Lett. 1971,
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[α]2D5 = –21.8 (c = 0.76, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
4.37–4.34 (br. s, 1 H, 5-H), 3.71 (s, 3 H, OCH3), 2.95 (td, J = 12.7,
3.1 Hz, 1 H, 3-H), 2.61 (dt, J = 12.7, 3.7 Hz, 1 H, 3-HЈ), 2.14–1.98
(m, 2 H, OH and NH), 1.83 (dd, J = 10.5, 7.8 Hz, 1 H, 7-H), 1.65–
1.50 (m, 3 H, 6-H, 4-H and 4-HЈ), 0.74 (dd, J = 7.8, 4.7 Hz, 1 H,
7-HЈ) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 175.0 (s, CO), 63.5
(d, C-5), 52.5 (q, OCH3), 39.4 (s, C-1), 36.3 (t, C-3), 31.1 (d, C-6),
29.0 (t, C-4), 22.3 (t, C-7) ppm. MS: m/z (%) = 172 (3%)
[M + 1]+, 154 (100). C8H13NO3 (171.19): calcd. C 56.13, H 7.65,
N 8.18; found C 56.38, H 7.44, N 8.01.
[7]
[8]
[9]
For other 4-substituted pipecolic acids as constrained amino
acid analogues, see: a) P. Etayo, R. Badorrey, M. D. Diaz-de-
Villegas, J. A. Galvez, Eur. J. Org. Chem. 2008, 3474 (lysine);
b) M. Del Bosco, A. N. C. Johnstone, G. Bazza, S. Lopatriello,
M. North, Tetrahedron 1995, 51, 8545 (glutamic acid); c) F. M.
Cordero, P. Fantini, A. Brandi, Synlett 2006, 3251 (homoas-
partic and homoglutamic acids); d) L. Isakovic, M. O. Saa-
vedra, D. B. Llewellyn, S. Claridge, L. Zhan, N. Bernstein, A.
Vaisburg, D. Delorme, A. Wahhab, N. Elowe, A. J. Petschner,
J. Rahil, N. Beaulieu, F. Gauthier, A. R. MacLeod, J. M. Be-
sterman, Bioorg. Med. Chem. Lett. 2009, 19, 2742 (homocys-
teine). For the synthesis of constrained analogues of homoser-
ine, see for example: e) K. Undheim, Amino Acids 2008, 34,
357; f) R. Galeazzi, G. Martelli, M. Orena, S. Rinaldi, P. Sabat-
ino, Tetrahedron 2005, 61, 5465; g) S. Krikstolaityté, A. Sackus,
C. Rømmimg, K. Undheim, Tetrahedron: Asymmetry 2001, 12,
393, and references cited therein; h) A. Avenoza, C. Cativiela,
M. A. Fernández-Recio, J. M. Peregrina, Synlett 1995, 891; i)
A. Avenoza, C. Cativiela, M. A. Fernández-Recio, J. M. Pereg-
rina, Tetrahedron: Asymmetry 1996, 7, 721; j) K. Hammer, C.
Rømmimg, K. Undheim, Tetrahedron 1998, 54, 10837.
Reviews: a) S. M. Cowell, Y. S. Lee, J. P. Cain, V. J. Hruby,
Curr. Med. Chem. 2004, 11, 2785; b) S. Hanessian, G. Mc-
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a) S. Hanessian, L. Auzzas, Acc. Chem. Res. 2008, 41, 1241; b)
F. Brackmann, N. Colombo, C. Cabrele, A. de Meijere, Eur. J.
Org. Chem. 2006, 4440; c) Z. Szakonyi, F. Fülöp, D. Tourwé,
N. De Kimpe, J. Org. Chem. 2002, 67, 2192; d) Y. Matsumura,
M. Inoue, Y. Nakamura, I. L. Talib, T. Maki, O. Onomura,
Tetrahedron Lett. 2000, 41, 4619; e) J. Czombos, W. Aelterman,
A. Tkachev, J. C. Martins, D. Tourwé, A. Péter, G. Tóth, F.
Fülöp, N. De Kimpe, J. Org. Chem. 2000, 65, 5469; f) E. Lor-
thiois, I. Marek, J. F. Normant, J. Org. Chem. 1998, 63, 566;
g) J. Ezquerra, A. Escribano, A. Rubio, M. J. Remuiñán, J. J.
Vaquero, Tetrahedron: Asymmetry 1996, 7, 2613; h) A. Her-
couet, B. Bessières, M. Le Corre, L. Toupet, Tetrahedron Lett.
1996, 37, 4529.
Methyl (1R,5S,6S)-5-Hydroxy-2-azabicyclo[4.1.0]heptane-1-carb-
oxylate [trans-(+)-17]: Obtained from trans-(+)-10 as reported for
cis-(+)-17 in 100% yield. [α]2D5 = +22.0 (c = 0.82, CHCl3).
Conversion of trans-(1R,5S,6S)-17 into (1R,5S,6S)-9: To a solution
of trans-(1R,5S,6S)-17 (15 mg, 0.088 mmol) in dry CH2Cl2
(880 μL) cooled to 0 °C were added dropwise Et3N (16 μL,
0.114 mmol) and methyl chloroformate (9 μL, 0.114 mmol). The
resulting mixture was stirred for 20 min before adding further Et3N
(16 μL, 0.114 mmol) and methyl chloroformate (9 μL, 0.114 mmol).
The solution was stirred at 25 °C for 1 h, diluted with CH2Cl2
(3 mL), washed with brine (2.5 mL), and dried with Na2SO4. After
evaporation of the solvent, the crude was dissolved in MeOH
(200 μL) and K2CO3 (1 mg) was added, and the mixture stirred for
1 h. The solution was concentrated and chromatographed (Et2O,
Rf = 0.24) to give trans-(1R,5S,6S)-9 (8 mg, 40%) as a colorless oil.
[α]2D5 = +4.61 (c = 0.41, CHCl3).
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for all new compounds. Chiral
HPLC analyses for 2 and 3. GLC analysis for the resolution of
(Ϯ)-3.
Acknowledgments
Financial support from the University of Florence is acknowl-
edged. Ente Cassa di Risparmio di Firenze is acknowledged for a
grant for a 400 MHz NMR spectrometer. Amano Enzyme Inc. is
acknowledged for generously providing us with a free sample of
lipase PS “AMANO” IM.
[12]
E. G. Occhiato, D. Scarpi, A. Guarna, Eur. J. Org. Chem. 2008,
524.
Eur. J. Org. Chem. 2011, 6544–6552
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6551

E. G. Occhiato, A. Casini, A. Guarna, D. Scarpi
FULL PAPER
[13] Lipases from Candida antarctica CAL-B and CAL-A, and PS
“AMANO” lipase were equilibrated with a saturated aqueous
LiCl (water activity aw = 0.11) for at least 48 h before use.
Asperillus niger lipase, porcine pancreatic lipase and Candida
rugosa lipase were equilibrated with MgCl2·6H2O (aw = 0.38);
a) G. V. Chowdary, S. G. Prapulla, Process Biochem. 2002, 38,
393; b) C. Orrenius, T. Norin, K. Hult, G. Carrea, Tetrahedron:
Asymmetry 1995, 6, 3023; c) S. H. Krishna, M. Persson, U. T.
Bornsheuer, Tetrahedron: Asymmetry 2002, 13, 2693.
[14] J. Cossy, N. Furet, S. BouzBouz, Tetrahedron 1995, 43, 11751.
For a review on substrate-directable chemical reactions includ-
ing cyclopropanation reactions, see: A. H. Hoveyda, D. A. Ev-
ans, G. C. Fu, Chem. Rev. 1993, 93, 1307.
its axial orientation. This is confirmed by a 1D NOESY experi-
ment (mixing time 800 ms), which shows a correlation between
5-H and the axial 3-H proton. In the trans compound, 5-H
resonates at δ = 4.28 ppm as a broad singlet due to its equato-
rial position, as confirmed by the lack of NOE correlation be-
tween 5-H and the protons at C-3. In both isomers, the C-1
methoxycarbonyl group is axially oriented to remove the A(1,3)
strain with the N-protecting group, see: D. L. Comins, S. P.
Joseph, in: Advances in Nitrogen Heterocycles (Eds.: C. J.
Moody), JAI Press, Greenwich, CT, 1996, vol. 2, pp. 251–294.
1
The H NMR spectra of compounds 12, 14, and 16 are quite
complex due to the presence of rotamers for both trans and cis
isomers in solution. However, at least one set of signals allow
for the identification of the two isomers and the determination
of the ratio, i.e. the 3-H axial proton, which is always 0.4–
0.5 ppm more downfield-shifted in the trans isomer. Moreover,
5-H is always a broad singlet due to the lack of trans diaxial
coupling.
[15] G. Molander, L. Harring, J. Org. Chem. 1989, 54, 3525.
[16] J.-C. Poupon, R. Lopez, J. Prunet, J.-P. Ferezou, J. Org. Chem.
2002, 67, 2118.
[17] K. Csatayova, S. G. Davies, J. A. Lee, K. B. Ling, P. M. Rob-
erts, Tetrahedron 2010, 66, 8420.
[18] J. Furukawa, N. Kawabata, J. Nishimura, Tetrahedron 1968, 24,
[22]
A. C. Glass, B. B. Morris, L. N. Zakharov, S.-Y. Liu, Org. Lett.
2008, 10, 4855.
53.
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2000, 112, 4713; Angew. Chem. Int. Ed. 2000, 39, 4539.
[20] Z. Yang, J. C. Lorenz, Y. Shi, Tetrahedron Lett. 1998, 39, 8621.
[21] The relative cis and trans stereochemistry of 9 (and 10) is easily
assigned by the analysis of the coupling constants in the 1H
NMR spectrum and by NOE studies. In the cis compound, 5-
H resonates at δ = 4.35 ppm with J = 10.1 Hz consistent with
[23] To demonstrate the suitability of this procedure to prepare suf-
ficient amounts of compound for medicinal chemistry studies,
we prepared, as an example, ca. 120 mg of cis-(+)-17 in a single
run from racemic 3.
Received: July 1, 2011
Published Online: September 14, 2011
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Eur. J. Org. Chem. 2011, 6544–6552