Synthesis of Boc-protected 4,5-methano-β-proline

Article abstract of DOI:10.1016/j.tetlet.2014.04.038

An efficient method for the preparation of Boc-protected 4,5-methano-β-proline - a novel bicyclic cyclopropane-containing β-amino acid - was developed, starting from readily available itaconic acid. A modified Simmons-Smith reaction was used for the construction of the cyclopropane ring. The method allowed for the synthesis of both cis and trans isomers of the title compound in 49% total yield and can be employed for gram-scale preparations. An approach to the preparation of methyl 5-oxopyrrolidine-3-carboxylate, which is one of the key intermediates in the synthetic scheme, on a multigram scale was also developed.

Full text of DOI:10.1016/j.tetlet.2014.04.038

Accepted Manuscript
Synthesis of Boc-protected 4,5-methano-β-proline
Andriy V. Tymtsunik, Yevhen M. Ivon, Igor V. Komarov, Oleksandr O.
Grygorenko
PII:
S0040-4039(14)00637-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.038
TETL 44500
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 January 2014
29 March 2014
10 April 2014
Please cite this article as: Tymtsunik, A.V., Ivon, Y.M., Komarov, I.V., Grygorenko, O.O., Synthesis of Boc-
protected 4,5-methano-β-proline, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.038
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Graphical Abstract
Synthesis of Boc-protected
4,5-methano-β-proline
Andriy V. Tymtsunik, Yevhen M. Ivon, Igor V. Komarov,
Oleksandr O. Grygorenko∗
HO
rel
HO
rel
OH
O
O
8 steps
O
and
O
49%
N
N
OH
Boc
Boc

1
Tetrahedron Letters
jou rn al h om ep a ge : www .e lse vie r .c om
Synthesis of Boc-protected 4,5-methano-β-proline
Andriy V. Tymtsunik,a,b Yevhen M. Ivon,a,b Igor V. Komarov,a,b Oleksandr O. Grygorenkoa∗
aTaras Shevchenko National University of Kyiv, Volodymyrska Street, 64, Kyiv 01601, Ukraine
bEnamine Ltd., Alexandra Matrosova Street, 23, Kyiv 01103, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient method for the preparation of Boc-protected 4,5-methano-β-proline – a novel
bicyclic cyclopropane-containing β-amino acid – was developed, starting from readily
available itaconic acid. A modified Simmons–Smith reaction was used for the construction of
the cyclopropane ring. The method allowed for the synthesis of both cis and trans isomers of
the title compound in 49% total yield and can be employed for gram-scale preparations. An
approach to the preparation of methyl 5-oxopyrrolidine-3-carboxylate, which is one of the key
intermediates in the synthetic scheme, on a multigram scale was also developed.
Received in revised form
Accepted
Available online
Keywords:
β-Amino acids;
Proline analogues;
Cyclopropane;
2014 Elsevier Ltd. All rights reserved.
Bicyclic compounds;
Simmons–Smith reaction
β-Amino acids are of significant importance among tailor-
made amino acids; their residues are also found in small natural
peptides.1 Peptides constructed from β-amino acids were shown
to adopt a number of intrinsic secondary structures, including
helices, hairpins and reverse turns.2 Notably, many of these
structures were obtained by imposing conformational
restrictions onto the residues of β-amino acids by a number of
methods, which are widely recognized in model studies of
peptides, proteins and other biologically relevant molecules.3
Incorporation of a cyclopropane ring into the amino acid
residues is one such method, which might severely alter the
conformational behavior and electronic properties of the
compounds by minimal structural changes to the parent
scaffolds.4 This can be advantageous in medicinal chemistry in
the search for potential drug candidates, as well as for model
studies of conformational and biological properties in the field
of peptides.
In this paper, we report a scalable synthesis of a novel,
cyclopropane-modified β-proline analogue, 2-azabicyclo-
[3.1.0]hexane-4-carboxylic acid (3) (4,5-methano-β-proline).
Notably, derivatives of 4,5-methano(-α-)proline (4) – a close
analogue of 3 – were used in the design and synthesis of
saxagliptin (5), an oral anti-diabetic drug approved by the FDA
in 2009,7 as well as captopril analogs.8
Modification of β-amino acid molecules with
a
Our retrosynthetic approach to 3 relied on disconnection of
the cyclopropane ring, which led to the corresponding enamine
derivative 6 (Scheme 1). Many synthetic methods could be
used to implement this approach, but in this work, we relied on
the Simmons–Smith reaction, which was recently applied by
our group for the synthesis of a Boc-protected cyclopropane-
containing proline analogue.9 Compound 6 can be obtained
from methyl 5-oxopyrrolidine-3-carboxylate (7) analogously to
cyclopropane ring has been reported previously in the
literature. In particular, one of the first simple representatives,
1, was described in a patent in 1973.5 Bicyclic cyclopropane-
containing β-amino acids are much rarer. The preparation of a
Boc-protected bicyclic cyclopropane-containing β-amino acid,
3,4-methano-β-proline (2), has also been documented.6
———
∗ Corresponding author. Tel.: +38-044-239-33-15; fax: +38-044-502-48-32; e-mail: gregor@univ.kiev.ua

Tetrahedron Letters
2
4,5-dehydroproline derivative 8, which was prepared from
pyroglutamic acid.8
removed under mild conditions. Reaction of itaconic acid and
10·HCl was performed by heating the starting materials in
pyridine (Scheme 3). Owing to the low aqueous solubility of
11, isolation of the product was very simple and involved
evaporation of the solvent, trituration of the residue with 4 M
HCl and filtration. This gave carboxylic acid 11 (90%), which
was pure enough for the next step.16 Esterification of 11 was
achieved by treatment of its methanolic solution with strong
cationite, which led to the formation of ester 12 in 83% yield.17
Deprotection of the nitrogen atom in 12 by catalytic
hydrogenation using palladium on charcoal as the catalyst
occurred at 20 atm of hydrogen. In order to increase the
conversion rate on large scale, the reaction was carried out at
50 atm to give ester 7 quantitatively.18 For both steps (11 ꢀ 12
and 12 ꢀ 7), isolation of the product included filtration of the
catalyst and evaporation to dryness. It should be noted that up
to 100 g of 7 of more than 95% purity was obtained in a single
run using this reaction sequence without any chromatographic
separations.
Scheme 1. Retrosynthetic analysis of amino acid 3
COOMe
O
NH3
O
50%
O
O
N
H
O
7
NO2
O
CH3NO2
NaOEt
1. H2, Ra-Ni
2. 80 o
O
7
O
O
C
O
O
O
O
9
Compound 7 was transformed into the corresponding Boc
derivative 13 in 99% yield by reaction with Boc2O and
DMAP.19 Selective reduction of the pyrrolidone moiety in 13
was achieved using a stoichiometric amount of DIBAL-H;
under these conditions, cyclic hemiaminal derivative 14 was
obtained. Compound 14 was treated with trifluoroacetic
anhydride in toluene at –80 °C, and the in situ formed
trifluoroacetate was subjected to elimination upon treatment
with N,N-diisopropylethylamine (DIPEA) to give enamine
derivative 15 (91% over 2 steps), which was purified
chromatographically.20
Scheme 2. Selected literature syntheses of 7
Although compound 7 was described in the literature, none
of the methods reported for its synthesis was suitable for large
scale preparation. In our hands, scale-up of the procedure
employing the reaction of dimethyl itaconate and ammonia
(Scheme 2)10 led to the formation of the target product with
insufficient purity and in moderate non-reproducible yields.
The method relying on a Michael addition of nitromethane to
dimethyl maleate11 included another step which was
problematic for scale-up, namely, reduction of an aliphatic
nitro group in the Michael adduct 9. Other procedures involved
the use of expensive organocatalysts12 or potentially explosive
reagents such as azides13 or diazoalkanes.14
For the cyclopropanation of 15, we used a slightly modified
Furukawa variation of the Simmons–Smith reaction [Et2Zn
(2.5 mol), ClCH2I (2.55 mol), CH2Cl2, –50 °C to rt,
overnight].21 The reaction showed moderate diastereoselectivity
and led to a ca. 1:3 mixture of the corresponding methyl esters,
which were hydrolyzed with alkali to give a mixture of the
carboxylic acids in 94% yield (over 2 steps). Since neither the
methyl esters nor carboxylic acids could be separated
chromatographically, the latter were transformed into allyl
esters 16a and 16b (in order to simplify the detection of the
Our approach to 7 relied on a transformation used since the
1960s, namely, reaction of itaconic acid or its derivatives with
N-nucleophiles. In order to simplify the isolation and
purification of the intermediate products in the reaction
sequence, we decided to increase their lipophilicity by using
O-benzylhydroxylamine (10) as the nucleophile in the first
step. This reagent is superior to other analogous N-nucleophiles
(e.g., benzylamine15) as the benzyloxy group can be readily
O
O
O
O
O
O
O
O
O
O
py
MeOH
Ph
Ph
O
NH+3Cl
H2 (50 atm)
Pd-C
Ph
HO
+
OH
O
N
90%
strong
cationite
N
HN
OH
O
O
MeOH, 50 o
C
10 . HCl
11
12
7
83%
100%
Boc2O, DMAP
CH3CN
99%
O
(CF3CO)2O
toluene, -80 o
O
HO
O
O
O
O
O
O
+
O
C
1. Et2Zn, ClCH2I, CH2Cl2
DIBAL
BocN
BocN
BocN
then DIPEA, rt
THF
O
2. NaOH, H2O, MeOH
-80 o
C
91% (from 13)
N
Boc
N
Boc
15
3. AllylBr, DIPEA, CH2Cl2
14
13
4. Chromatographic separation
16a (19%)
16b (61%)
COOH
COOH
Pd2(dba)3, PPh3
Pd2(dba)3, PPh3
16b
16a
morpholine
92%
morpholine
87%
N
Boc
N
Boc
17a
17b

3
Scheme 3. Synthesis of Boc-protected 4,5-methano-β-prolines 17a,b (relative configurations are shown)
diastereomers during TLC analysis of the fractions). This
approach was fruitful, and the compounds 16a and 16b were
separated smoothly using column chromatography (19% and
61% yields from 15, respectively).22 In the last step of the
synthesis, deprotection of 16a and 16b with in situ generated
Pd(PPh3)4 gave Boc-protected amino acids 17a and 17b in 87%
and 92% yields, respectively.23, 24
Stammer, C. H. Tetrahedron 1990, 46, 2231–2254 (c) Medda, A.
K.; Lee, H.-S. Synlett 2009, 921–924. (d) Hercouet, A.;
Bessieres, B.; Le Corre, M. Tetrahedron: Asymmetry 1996, 7,
1267–1268. (e) Hanessian, S.; Reinhold, U.; Saulnier, M.;
Claridge, S. Bioorg. Med. Chem. Lett. 1998, 8, 2123–2128. (f)
Mori, M.; Kubo, Y.; Ban, Y. Tetrahedron 1988, 44, 4321–4330.
5. Fosker, G. R.; Harbridge, J. B.; Hubbard, R. German Pat.
DE 2302184, 1973. Chem. Abstr. 1973, 79, 105246.
The relative stereochemistry of the products was established
using NOESY experiments with Boc derivatives 17a and 17b
(Figure 1). Thus, the cis diastereomer was formed
predominantly upon Simmons–Smith cyclopropanation of
alkene 15, which can be rationalized by coordination of the
intermediate zinc species with the ester moiety of 15.
6. Medda, A. K.; Lee, H.-S. Synlett 2009, 921–924.
7. Savage, S. A.; Jones, G. S.; Kolotuchin, S.; Ramrattan, S. A.; Vu,
T.; Waltermire, R. E. Org. Proc. Res. Dev. 2009, 13, 1169–1176.
8. (a) Oliveira, D. F.; Miranda, P. C. M. L.; Correia, C. R. D. J.
Org. Chem. 1999, 64, 6646–6652. (b) Hanessian, S.; Reinhold,
U.; Saulnier, M.; Claridge, S. Bioorg. Med. Chem. Lett. 1998, 8,
2123–2128.
9. Tymtsunik, A. V.; Bilenko, V. A.; Ivon, Ye. M.; Grygorenko, O.
O.; Komarov, I. V. Tetrahedron Lett. 2012, 53, 3847–3849.
10. (a) Wu, Y.-B.; Feldkamp, R. F.; Corrigan, J. R. Rhodes, H. J. J.
Org. Chem. 1961, 26, 1524–1528. (b) Felluga, F.; Pitacco, G.;
Prodan, M.; Pricl, S.; Visintin, M.; Valentin, E. Tetrahedron:
Asymmetry 2001, 12, 3241–3250.
11. Zoretic, P. A.; Barcelos, F. Tetrahedron Lett. 1977, 6, 529–532.
12. Lu, H.-H.; Wang, X.-F.; Yao, C.-J.; Zhang, J.-M.; Wu, H.; Xiao,
W.-J. Chem. Commun. 2009, 4251–4253.
H
H
H
H
H
H
Strong NOE
Weak NOE
Boc
N
Boc
N
O
H
H
H
H
H
H
H
HO
HOOC
H
17a
17b
13. Tsuge, O.; Kanemasa, S.; Hatada, A.; Matsuda, K. Bull. Chem.
Soc. Jpn. 1986, 59, 2537–2546.
Figure 1. Correlations in the NOESY spectra of 17a and 17b
14. (a) Arvanitis, E.; Motevalli, M.; Wyatt, P. B. Tetrahedron Lett.
1996, 37, 4277–4280. (b) Yohannes, D.; Akireddy, S. R.; Hauser,
T. A.; Kiser, M. N.; Gurnon, N. J.; Bhatti, B.; Caldwell, W. S.;
Hansen, C. P.; Day, C. S. Org. Lett. 2008, 10, 5353–5356.
15. (a) Gallagher, T.; Durkin, P. M.; Haseler, C. A.; Hirschhaeuser,
C.; Magrone, P.; Derrick, I. J. Org. Chem. 2010, 75, 3766–3774.
(b) Gerus, I. I.; Mironets, R. V.; Shaitanova, E. N.; Kukhar, V. P.
J. Fluorine Chem. 2010, 131, 224–228. (c) Imamura, S.; Ishihara,
Y.; Hattori, T.; Kurasawa, O.; Matsushita, Y.; Sugihara, Y.;
Kanzaki, N.; Iizawa, Y.; Baba, M.; Hashiguchi, S. Chem. Pharm.
Bull. 2004, 52, 63–73. (d) Paytash, P. L.; Sparrow, E.; Gathe, J.
C. J. Am. Chem. Soc. 1950, 72, 1415–1416. (e) Stanetty, P.;
Turner, M.; Mihovilovic, M. D. Molecules 2005, 10, 367–375.
16. Procedure for the preparation of 11: O-benzylhydroxylamine
hydrochloride (10·HCl) (163.4 g, 1.02 mol) was added to a
solution of of itaconic acid (133.2 g, 1.02 mol) in dry pyridine
(900 mL) with stirring, and the resulting mixture was refluxed for
20 h. The solvent was evaporated in vacuo, and the residue
triturated with 4 M aq HCl (1 L) at ambient temperature (external
cooling bath!). The mixture was stirred vigorously for 1 h and
filtered. The precipitate was washed thoroughly with H2O (1 L)
and dried in air for 3 d to give 11 as pale yellow crystals (217.9 g,
90%). Mp 127–128 °C. MS (m/z, CI): 236 (MH+), 91 (C7H7+).
Anal. Calcld. for C12H13NO4 C 61.27, H 5.57, N 5.95. Found C
61.04, H 5.80, N 6.21. 1H NMR (500 MHz, DMSO-d6) δ 12.74
(br s, 1H), 7.52 – 7.19 (m, 5H), 4.90 (s, 2H), 3.62 (t, J = 8.3 Hz,
1H), 3.53 (t, J = 8.2 Hz, 1H), 3.22 – 3.13 (m, 1H), 2.54 – 2.38
(m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 174.1 (C), 169.1 (C),
135.8 (C), 129.6 (CH), 129.0 (CH), 128.8 (CH), 76.1 (CH2), 48.3
(CH2), 33.4 (CH), 30.9 (CH2).
In conclusion, an efficient method for the preparation of the
novel, bicyclic, cyclopropane-containing β-amino acid
derivative, Boc-protected 4,5-methano-β-proline, has been
developed. The synthesis commenced from itaconic acid and
allowed for the preparation of both the cis and trans isomers of
the title compound in 11% and 38% total yields, respectively.
Acknowledgments
The authors thank Mr. Vitaliy Polovinko for NMR
experiments and Prof. Andrey A. Tolmachev for his
encouragement and support.
References and notes
1. Enantioselective Synthesis of β-Amino Acids, 2nd ed. Juaristi, E.;
Soloshonok, V. A., Eds.; Wiley-VCH: New York, 2005.
2. (a) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J.
S. Chem. Rev. 2001, 101, 3893–4011. (b) Vasudev, P. G.;
Chatterjee, S.; Shamala, N.; Balaram, P. Chem. Rev. 2011, 111,
657–687.
3. (a) Vagner, J.; Qu, H.; Hruby, V. Curr. Opin. Chem. Biol. 2008,
12, 292–296. (b) Janecka, A.; Kruszynski, R. Curr. Med. Chem.
2005, 12, 471–481. (c) Komarov, I. V.; Grygorenko, O. O.;
Turov, A. V.; Khilya, V. P. Russ. Chem. Rev. 2004, 73, 785–810.
(d) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180. (e)
Soloshonok, V. A. Curr. Org. Chem. 2002, 6, 341–364. (f)
Cativiela, C.; Ordóñez, M. Tetrahedron: Asymmetry 2009, 20, 1–
63. (g) Trabocchi, A.; Scarpi, D.; Guarna, A. Amino Acids 2008,
34, 1–24. (h) Grygorenko, O. O.; Radchenko, D. S.; Volochnyuk,
D. M.; Tolmachev, A. A.; Komarov, I. V. Chem. Rev. 2011, 111,
5506–5568. (i) Cai, M.; Cai, C.; Mayorov, A. V.; Xiong, C.;
Cabello, C. M.; Soloshonok, V. A.; Swift, J. R.; Trivedi, D.;
Hruby, V. J. J. Pept. Res. 2004, 63, 116−131.
17. Procedure for the preparation of 12: strong cationite (KY-2) (ca.
30 g) was added to a stirred solution of the acid 11 (58.3 g, 0.248
mol) in absolute MeOH (1 L). The mixture was refluxed for 2 d,
filtered through silica and washed thoroughly with MeOH
(0.6 L). The filtrate was evaporated to dryness to give 12 (51.2 g,
83%) as a colourless oil, which crystallized upon standing. Mp
+
42–43 °C. MS (m/z, CI): 250 (MH+), 91 (C7H7 ). Anal. Calcld.
for C13H15NO4 C 62.64, H 6.07, N 5.62. Found C 62.78, H 6.09,
1
N 5.85. H NMR (500 MHz, DMSO-d6) δ 7.49 – 7.35 (m, 5H),
4.91 (s, 2H), 3.68 – 3.56 (m, 1H), 3.65 (s, 3H), 3.54 – 3.48 (m,
1H), 3.32 – 3.24 (m, 1H), 2.57 – 2.39 (m, 2H). 13C NMR (126
MHz, DMSO-d6) δ 173.0, 168.8, 135.8, 129.6, 129.0, 128.8,
76.2, 52.6, 48.2, 33.3, 30.8.
4. (a) Salaun, J. In: Small Ring Compounds in Organic Synthesis VI.
de Meijere, A., Ed.; Springer-Verlag: Berlin, 1999, pp. 1–69. (b)

Tetrahedron Letters
4
18. Procedure for the preparation of 7: an autoclave was charged
22. Procedure for the preparation of 16a,b: to a solution of enamide
15 (0.62 g, 2.73 mmol) in absolute CH2Cl2 (15 mL), 15% (0.87
M) ZnEt2 in hexane (7.8 ml, 6.79 mmol) was added in one
portion at –40 °C under an argon atmosphere. After 5 min, the
solution was cooled to –55 °C, and ClCH2I (0.51 ml, 7.00 mmol)
was added in one portion. As a result, the temperature of the
mixture increased to –50 °C. The mixture was stirred for 21 h
with slow warming from –50 °C to 10 °C, then cooled to 0 °C,
and 5% aq NaHCO3 (50 mL) was added. The suspension was
stirred for an additional 10 min and filtered. The slurry was
washed with CH2Cl2 (2×10 mL), the organic layer was separated,
and the aqueous phase extracted with CH2Cl2 (20 mL). The
combined organic extracts were dried over Na2SO4 and
evaporated. The crude product (0.74 g) was dissolved in MeOH
(30 mL), and a solution of NaOH (0.33 g, 8.19 mmol) in H2O
(3 mL) was added. The mixture was stirred at rt for 2 d, after
which the MeOH was evaporated, and the residue was quenched
with H2O (20 mL), washed with Et2O (2×15 mL), acidified with
1 M aq NaHSO4 to pH = 2 and extracted with CHCl3 (3×20 mL).
The combined extracts were dried over Na2SO4 and evaporated to
give a ca. 1:3 mixture of 17a and 17b (0.58 g).
with 12 (51.0 g, 0.205 mol), 10% Pd-C (9.0 g) and MeOH
(400 mL). The mixture was stirred vigorously at 50 atm of
hydrogen at 50 °C for 24 h. The suspension was filtered, and the
slurry of catalyst was washed with MeOH (2×100 mL). The
filtrate was evaporated to dryness in vacuo and the product 7
(29.2 g, 100%) was obtained as colourless oil, which crystallized
upon standing. Mp 55–58 °C (lit.10b 61–62 °C). MS (m/z, CI):
287 (M2H+), 144 (MH+). Anal. Calcd. for C6H9NO3 C 50.35, H
6.34, N 9.79. Found C 50.13, H 6.47, N 10.02. 1H NMR (500
MHz, DMSO-d6) δ 7.67 (s, 1H), 3.64 (s, 3H), 3.46 (t, J = 11.1
Hz, 1H), 3.39 – 3.31 (m, 2H), 2.43 – 2.28 (m, 2H). 13C NMR
(126 MHz, DMSO-d6) δ 175.4, 174.0, 52.4, 44.0, 38.4, 33.4.
19. Procedure for the preparation of 13: lactam 7 (29.2 g, 0.204 mol)
and DMAP (12.5 g, 0.102 mol) were dissolved in MeCN (300
mL). A solution of Boc2O (66.8 g, 0.306 mol) in MeCN (60 mL)
was added to the reaction mixture with stirring over ca. 3 h. The
solution was stirred overnight, and the solvent was evaporated in
vacuo. The residue was carefully acidified with 1 M aq NaHSO4
to pH=2 and extracted with EtOAc (2×300 mL). The combined
extracts were dried over MgSO4 and evaporated in vacuo. Dry
THF (200 mL) was added and the solution evaporated to dryness
to give 13 (49.2 g, 99%) as a brownish-red oil which crystallized
upon standing. Mp 41–42 °C. MS (m/z, CI): 188 (MH+–C4H8).
Anal. Calcd. for C11H17NO5 C 54.31, H 7.04, N 5.76. Found C
The mixture of acids 17 (0.56 g, 2.46 mmol) was dissolved in
CH2Cl2 (40 mL). DIPEA (0.86 mL, 4.93 mmol) and allyl
bromide (0.32 mL, 3.70 mmol) were added to the solution. The
mixture was refluxed for 2 d, cooled to rt, washed with 10% aq
citric acid (30 mL), 5% aq NaHCO3 (20 mL), and H2O (20 mL),
dried over Na2SO4, and evaporated to give a mixture of 16a and
16b (0.64 g). The diastereomers were separated by column
chromatography on silica gel, using hexane – EtOAc (5:1) as
eluent. The trans-isomer 16a was obtained as pale yellow oil
(0.13 g, 19% from 15). Rf = 0.29 [hexane – EtOAc (5:1)]. MS
(m/z, EI) 194 (M+–OC4H9), 167 (M+–CO2–C4H8), 126 (M+–CO2–
1
54.63, H 7.19, N 5.44. H NMR (500 MHz, DMSO-d6) δ 3.88 (t,
J = 9.5 Hz, 1H), 3.82 – 3.73 (m, 1H), 3.67 (s, 3H), 3.38 – 3.28
(m, 1H), 2.76 – 2.61 (m, 2H), 1.46 (s, 9H). 13C NMR (126 MHz,
DMSO-d6) δ 173.2, 171.8, 149.8, 82.3, 52.6, 48.1, 35.6, 34.6,
28.1.
20. Procedure for the preparation of 15: DIBAL-H (45 mL, 0.252
mol) was added dropwise to the solution of 13 (49.2 g, 0.202
mol) in absolute THF (600 mL) at –80 °C under an argon
atmosphere. The solution was stirred at –80 °C for 1 h. Saturated
aq NH4Cl (300 mL) was added dropwise with vigorous stirring
while the temperature rose from –80 °C to 10°C (CAUTION! A
violent reaction occurs above 10 °C, such that external cooling is
nessesary in order not to allow the temperature to exceed 25 °C).
The mixture was stirred vigourously for 15 min and filtered
immediately (it should not be left for a long period of time!). The
slurry was washed with THF (3×200 mL). The filtrate was
evaporated in vacuo at a bath temperature below 40 °C. The
resulting oil was quenched with H2O (200 mL) and extracted
with Et2O (2×200 ml). The combined extracts were dried over
MgSO4 and evaporated to give crude 14 (47.3 g) as a yellowish
oil, which was used without further purification. The crude
product should be stored at –20 °C; it is preferrable to use it in
the next step as soon as possible.
+
C4H8–С3H5), 57 (C4H9 ), 41 (С3H5+). Anal. Calcd. for C14H21NO4
C 62.90, H 7.92, N 5.24. Found C 63.06, H 7.69, N 5.21. 1H
NMR (500 MHz, CDCl3) δ 6.00 – 5.85 (m, 1H), 5.34 (d, J = 17.3
Hz, 1H), 5.26 (d, J = 10.6 Hz, 1H), 4.64 (s, 2H), 3.97 (s, 1H),
3.65 – 3.45 (m, 1H), 3.23 – 3.06 (m, 2H), 1.92 – 1.83 (m, 1H),
1.47 (s, 9H), 0.90 – 0.73 (m, 1H), 0.62 (s, 1H). 13C NMR (126
MHz, CDCl3) δ 172.4, 154.5, 131.4, 118.0, 79.4, 65.2, 46.4, 44.2,
43.3, 35.1, 28.0, 18.1, 17.4, 10.0.
The cis-isomer 16b was obtained as a colourless oil which
crystallized upon standing (0.43 g, 61% from 15). Rf = 0.37
[hexane – EtOAc (5:1)]. Mp 52–53 °C. MS (m/z, EI) 194 (M+–
OC4H9), 167 (M+–CO2–C4H8), 126 (M+–CO2–C4H8–С3H5), 57
+
+
(C4H9 ), 41 (С3H5 ). Anal. Calcd. for C14H21NO4 C 62.90, H 7.92,
N 5.24. Found C 62.63, H 8.08, N 5.60. 1H NMR (500 MHz,
CDCl3) δ 5.99 – 5.80 (m, 1H), 5.30 (d, J = 17.2 Hz, 1H), 5.22 (d,
J = 10.3 Hz, 1H), 4.60 (d, J = 5.2 Hz, 2H), 3.89 – 3.63 (m, 1H),
3.60 – 3.41 (m, 1H), 3.35 – 3.26 (m, 1H), 3.26 – 3.16 (m, 1H),
1.89 – 1.77 (m, 1H), 1.44 (s, 9H), 0.82 (s, 1H), 0.67 (s, 1H). 13C
NMR (126 MHz, CDCl3) δ 171.7, 154.4, 131.5, 118.0, 79.4, 65.1,
44.7, 42.6, 42.0, 35.6, 28.0, 18.4, 17.9, 8.5.
Compound 14 (47.3 g) was dissolved in absolute toluene and
cooled to –80 °C under an argon atmosphere with vigourous
stirring. (CF3CO)2O (27.7 mL, 0.199 mol) was added dropwise at
that temperature. After 20 min, DIPEA (132 mL, 0.758 mol) was
added at –80 °C and the mixture was allowed to warm to rt
overnight with stirring. The solution was cooled to 0 °C, and H2O
(100 mL) was added. The mixture was acidified carefully with
10% aq citric acid to pH = 6. The toluene layer was separated,
washed with H2O (600 mL), dried over Na2SO4 and evaporated in
vacuo at a bath temperature below 60 °C to give a crude residue
(48.7 g), wich was purified chromatographically on silica using
hexane–EtOAc (8:1) as the eluent to give 15 as a yellowish oil
(41.3 g, 91% over 2 steps). The pure product can be stored at
4 °C for several months. Rf = 0.33 [hexanes – EtOAc (8:1)]. MS
(m/z, EI): 227 (M+), 171 (M+–C4H8), 57 (C4H9+). Anal. Calcd. for
C11H17NO4 C 58.14, H 7.54, N 6.16. Found C 57.83, H 7.50, N
6.37. 1H NMR (500 MHz, CDCl3) δ 6.70 (s, 0.5H), 6.57 (s,
0.5H), 5.06 (s, 0.5H), 5.01 (s, 0.5H), 4.17 – 4.06 (m, 1H), 3.93 –
3.79 (m, 2H), 3.74 (s, 3H), 1.49 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 172.8, 151.7 and 151.0, 131.7, 104.8, 80.7, 80.6, 55.2,
47.7, 47.4, 47.1, 46.6, 28.3.
23. Procedure for the preparation of 17a: a solution of allyl ester 16a
(70 mg, 0.26 mmol) in absolute THF (4 mL) was degassed by
refluxing under an argon flow. Pd2(dba)3 (14 mg, 0.015 mmol)
and PPh3 (8 mg, 0.03 mmol) were added to the solution
sequentially at rt under an argon atmosphere. After 5 min,
morpholine (0.22 ml, 2.6 mmol) was added. The mixture was
stirred at rt for 2 d, then diluted with EtOAc (30 mL) and
extracted with H2O (2×25 mL). The combined aqueous extracts
were washed with EtOAc (15 mL), acidified with 1 M aq
NaHSO4 to pH = 2, and extracted with CHCl3 (2×15 mL). The
combined organic extracts were dried over Na2SO4 and
evaporated to give the product 17a as a yellowish glass (52 mg,
87%). MS (m/z, CI): 226 (M–H+). Anal. Calcd. for C11H17NO4 C
1
58.14, H 7.54, N 6.16. Found C 58.51, H 7.33, N 5.89. H NMR
(400 MHz, CDCl3) δ 10.11 (br s, 1H), 4.05 – 3.87 (m, 1H), 3.65 –
3.39 (m, 1H), 3.19 – 3.00 (m, 2H), 1.91 – 1.79 (m, 1H), 1.44 (s,
9H), 0.89 – 0.66 (m, 1H), 0.60 (s, 1H). 13C NMR (126 MHz,
CDCl3) δ 177.5, 154.8, 79.6, 46.4, 44.3, 43.4, 35.1, 28.0, 18.2,
17.5, 10.1.
21. Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24,
53–58.
24. Acid 17b was prepared from 16b analogously to 17a. The
product was obtained as a colourless viscous oil, which solidified

5
upon standing. Yield 92%. Mp 107–110 °C. MS (m/z, CI): 226
(M–H+). Anal. Calcd. for C11H17NO4 C 58.14, H 7.54, N 6.16.
Found C 58.03, H 7.74, N 6.35. 1H NMR (400 MHz, CDCl3) δ
8.23 (br s, 1H), 3.85 – 3.68 (m, 1H), 3.63 – 3.42 (m, 1H), 3.38 –
3.26 (m, 1H), 3.25 – 3.14 (m, 1H), 1.92 – 1.79 (m, 1H), 1.45 (s,
9H), 0.90 – 0.79 (m, 1H), 0.76 – 0.66 (m, 1H). 13C NMR (126
MHz, CDCl3) δ 176.8, 154.6, 79.8, 44.7, 42.4, 41.7, 35.6, 28.0,
18.5, 17.8, 8.6.