Gram-scale synthesis of 3,5-methanonipecotic acid, a nonchiral bicyclic β-amino acid

Article abstract of DOI:10.1055/s-0033-1340322

A scalable synthesis was developed of 3,5-methanoni?pecotic acid (3-azabicyclo[3.1.1]heptane-1-carboxylic acid), a rare example of a conformationally constrained nonchiral β-amino acid, potentially useful in peptide engineering and peptidomimetic drug design. A retrosynthetic strategy based on disconnections exclusively within the symmetry planes of the target and the intermediate molecules was found to be useful and might deliver expedite syntheses in other similar cases. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340322

LETTER
▌355
letter
Gram-Scale Synthesis of 3,5-Methanonipecotic Acid, a Nonchiral Bicyclic
β-Amino Acid
3,5-Methanonipecotic Acid
Andriy V. Tymtsunik,a,b Vitaliy A. Bilenko,b Oleksandr O. Grygorenko,*a Igor V. Komarova,b
a
Taras Shevchenko National University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine
Fax +380(44)5732643; E-mail: gregor@univ.kiev.ua
b
Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
Received: 21.09.2013; Accepted after revision: 06.11.2013
O
ψ
Abstract: A scalable synthesis was developed of 3,5-methanoni-
pecotic acid (3-azabicyclo[3.1.1]heptane-1-carboxylic acid), a rare
example of a conformationally constrained nonchiral β-amino acid,
potentially useful in peptide engineering and peptidomimetic drug
design. A retrosynthetic strategy based on disconnections exclu-
sively within the symmetry planes of the target and the intermediate
molecules was found to be useful and might deliver expedite syn-
theses in other similar cases.
φ
N
H
N
H
ω
θ
Figure 1 Torsional angles in a β-peptide, defined according to
Banerjee and Balaram6
Conformational restriction allows the values of the θ-an-
gle or both the θ- and ϕ-angles to be fixed. The latter case
occurs in residues of amino acids containing an endocy-
clic backbone nitrogen atom, for example pyrrolidine-3-
carboxylic acid (1) or nipecotic acid (2) (Figure 2). This
constraint on the θ-angle prevents β-peptides containing
residues of 1 or 2 from adopting any helical conformation.
A sequence consisting of an (R)-nipecotic acid residue
and an (S)-nipecotic residue has been shown to induce a
reverse-turn structure, characterized by a twelve-mem-
bered hydrogen-bonded ring.10 Amino acids 1 and 2 are
also useful in medicinal chemistry; in particular, nipecotic
acid (1) and its derivatives are widely used as inhibitors of
both glial and neuronal uptake of γ-aminobutyric acid.13
Key words: amino acids, bicyclic compounds, heterocycles, con-
formation
The field of β-amino acids and β-peptides has generated
much interest in recent years.1 Such compounds are wide-
spread in nature, because many bacteria, fungi, and plants
incorporate β-amino acids to ensure their survival in com-
petition with other organisms.2 Because β-amino acids de-
rivatives are often characterized by potent biological and
physiological activities, they are potentially useful as lead
structures for the development of new drugs.3 Further-
more, these compounds have been shown to possess con-
siderable stability against a wide range of proteolytic
enzymes.3b
+
H2
N
O
O
The incorporation of β-amino acids in the design of pepti-
domimetics and β-peptides was a pivotal development in
this field, because β-peptides have been shown to adopt
intrinsic secondary structures.4 Interesting parallels and
contrasts in the folding behaviors of α- and β-peptides
have been demonstrated.1,5 As a result, the use of β-amino
acid oligomers might permit testing of basic assumptions
about the forces that are responsible for the molecular
structures of biological macromolecules such as proteins.
O–
O–
O
N
–O
N
N
+
+
H2
+
H2
O–
H2
O
1
2
3
4
+H2N
+H2N
+H2N
O–
O–
O–
O
5
O
6
O
7
β-Amino acids with restricted molecular flexibility are of
particular interest. Conformational restriction has been re-
peatedly used as a tool in model studies on peptides, pro-
teins, and other biologically relevant molecules.7
Conformationally restricted β-amino acids have been suc-
cessfully used to stabilize particular secondary structures
of β-peptides, such as the 14-helix,8 12-helix,9 and 10-he-
lix,10 as well as hairpins and reverse turns.11,12 For a β-pep-
tide to adopt one of these secondary structures, the
constituent residues must adopt the required torsional an-
gles (Figure 1; ϕ, θ, ψ, and ω).
O
O
O
O–
O–
O–
N
N
+
N
+
+
H2
H2
H2
8
9
10
Figure 2 Conformationally constrained amino acids
A promising approach to the design of conformationally
rigid amino acids relies on symmetrization of the parent
cyclic molecules14 (such as 1 or 2) by introducing an ap-
propriate polymethylene bridge to form a rigid bicyclic
structure containing a plane of symmetry. For example,
the application of this concept to a proline molecule af-
SYNLETT 2014, 25, 0355–0358
Advanced online publication: 06.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340322; Art ID: ST-2013-B0898-L
© Georg Thieme Verlag Stuttgart · New York

356
A. V. Tymtsunik et al.
LETTER
fords the amino acids 2,4-methanoproline (3)15 and 2,5-
ethanoproline (4) (Figure 2).16 This approach has also
been used in the design of the pipecolic acid analogues 5–
7.17 Note that all the amino acids 3–7 are nonchiral, which
leads to distinctive conformational behavior of peptides
containing these residues.18 Furthermore, these com-
pounds are promising three-dimensional building blocks,
potential useful in drug discovery.19 In this respect, the
lack of chirality of the compounds can be advantageous
because chiral compounds are more costly to synthesize
and to analyze, and because of the increasing stringency
of regulatory guidelines on submissions for chiral drugs
that have been adopted in many countries.
Scheme 2
diester 13 was elongated by a Horner–Wadsworth–Em-
mons olefination to give triester 15 in 93% yield.24 Cata-
lytic reduction of 15 proceeded smoothly to give the
saturated triester 16 (97%).25
Application of the design concept discussed above to mol-
ecules 1 and 2 generates a family of nonchiral bicyclic β-
amino acids 8–10. Analysis of molecular models showed
that the conformational rigidity of 8–10 restricts large val-
ues of both the ϕ- and θ-torsion angles in molecules of
model peptides; these define antiperiplanar conformations
around the corresponding bonds of the peptide backbone,
a combination rarely encountered in known peptides con-
taining β-amino acid residues.5 Here we report a scalable
and practical synthesis of a first representative of this fam-
ily: 3,5-methanonipecotic acid (9; 3-azabicyclo-
[3.1.1]heptane-1-carboxylic acid).
O
Br
MeO
OMe
MeO
MeO
CH2(COOi-Pr)2
aq HCl
NaH, DMF
53%
THF, 100%
i-PrO2C
CO2i-Pr
i-PrO2C
CO2i-Pr
Br
13
14
O
O
OMe
P
93%
OMe
MeO
NaH, THF
O
CO2Me
CO2Me
NH2
N
H
N2H4⋅xH2O
EtOH, 82%
i-PrO2C
H2, Pd-C
Although several approaches to the synthesis of 3-azabi-
cyclo[3.1.1]heptane derivatives have been reported in the
literature,20 none of these was considered to be amendable
to the synthesis of amino acid 9. Our initial retrosynthetic
analysis of 9 relied on a photochemical intramolecular [2
+ 2] cycloaddition of the corresponding dienes 11
(Scheme 1), in an approach analogous to that reported pre-
viously for the preparation of 2,4-methanoproline deriva-
tives.15a,15b,21 However, neither 11a nor 11b gave any
traces of the expected products; instead, the dienes under-
went polymerization. Therefore we shifted our attention
to sequential construction of the rings in the molecule of
9. Our revised retrosynthetic strategy relied on the discon-
nections of the bicyclic system of 9 (Cs symmetry) exclu-
sively within the symmetry plane, leading to the amine 12
(Scheme 2) and, subsequently, to the ketone 13 (C2v sym-
metry) described previously by our group.22 This strategy
ensures that the key intermediates in the synthesis will
possess planes of symmetry, thereby eliminating any
problems with separating and isolating stereoisomers.
MeOH, 97%
CO2iPr
i-PrO2C
CO2i-Pr
i-PrO2C
CO2i-Pr
17
16
15
KOH, MeOH
H2O, 88%
NaNO2
aq HCl, Et2O
O
CO2H
1. (COCl)2, CH2Cl2
N3
2. NaN3, H2O–acetone
i-PrO2C
CO2i-Pr
i-PrO2C
CO2i-Pr
20
18
1. heat, toluene
2. heat, i-BuOH
O
NHBoc
1. HCl, EtOAc
OMe
2. NaOMe, MeOH
78%
N
H
O
i-PrO2C
CO2i-Pr
21
19, 44% (from 17)
88% (from 20)
O
Scheme 3
O
O
hν
N
O
Me
Note that the methyl and isopropyl ester functions in 16
differ significantly in their reactivity, a feature necessary
for achieving regioselectivity in subsequent steps of the
synthesis. The reaction of triester 16 with hydrazine hy-
drate gave hydrazide 17 in 82% yield. This was converted
into the acyl azide 18, which was not isolated. Curtius re-
arrangement of 18 and subsequent trapping with tert-bu-
tanol gave carbamate 19. Unfortunately, the yield of 19
(44% from 17) was moderate, which might limit the scal-
N
Me
O
R
R
O
11a, R = Me
11b, R = Ph
Scheme 1
Ketone 13 was obtained in two steps and 53% overall
yield from dibromide 1423 (Scheme 3; for experimental
details, see Supporting Information). The carbon chain in
Synlett 2014, 25, 355–358
© Georg Thieme Verlag Stuttgart · New York

LETTER
3,5-Methanonipecotic Acid
357
Mukhamedzhanov for recording of IR spectra, Dr. Dmitry
Volochnyuk for helpful discussions, and Prof. Andrey A. Tolmachev
for his encouragement and support.
ability of the method. We therefore subjected triester 16 to
selective hydrolysis to give the carboxylic acid 20 in 88%
yield;26 this was transformed into azide 18 via the corre-
sponding acid chloride. Again, 18 was not isolated, but
was converted into carbamate 19 (88% from 20) by using
Supporting Information for this article is available online at
the reaction sequence described above. In this case, carba- http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoprimntgirSatnoIuipfog
r
t
iornat
mate 19 was sufficiently pure to be used in the next step
without further purification.27
References and footnotes
Deprotection of 19 with hydrogen chloride in ethyl acetate
gave amine 12 as its hydrochloride; this was not isolated,
but instead was subjected to the key step of the synthesis,
intramolecular amide formation, which proceeded
smoothly upon action of sodium methoxide in refluxing
methanol. Under these conditions, simultaneous trans-
esterification occurred, and the bicyclic lactam 21 was
isolated in 78% yield.28
(1) Enantioselective Synthesis of β-Amino Acids; Juaristi, E.;
Soloshonok, V. A., Eds.; Wiley-VCH: New York, 2005, 2nd
ed.
(2) von Nussbaum, F.; Spiteller, P. In Highlights in Bioorganic
Chemistry: Methods and Applications; Schmuck, C.;
Wennemers, H., Eds.; Wiley-VCH: Weinheim, 2004, Part 1
Chap. 5.
(3) (a) Ballard, C. E.; Yu, H.; Wang, B. Curr. Med. Chem. 2002,
9, 471. (b) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A.
I.; Aguilar, M.-I. Curr. Med. Chem. 2002, 9, 811.
(4) (a) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
Biodiversity 2004, 1, 1111. (b) Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. Rev. 2001, 101, 3219. (c) DeGrado,
W. F.; Schneider, J. P.; Hamuro, Y. J. Pept. Res. 1999, 54,
206.
(5) (a) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.;
Moore, J. S. Chem. Rev. 2001, 101, 3893. (b) Vasudev, P.
G.; Chatterjee, S.; Shamala, N.; Balaram, P. Chem. Rev.
2011, 111, 657.
(6) Banerjee, A.; Balaram, P. Curr. Sci. 1997, 73, 1067.
(7) (a) Vagner, J.; Qu, H.; Hruby, V. J. Curr. Opin. Chem. Biol.
2008, 12, 292. (b) Janecka, A.; Kruszynski, R. Curr. Med.
Chem. 2005, 12, 471. (c) Komarov, I. V.; Grygorenko, O.
O.; Turov, A. V.; Khilya, V. P. Russ. Chem. Rev. 2004, 73,
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(e) Soloshonok, V. A. Curr. Org. Chem. 2002, 6, 341.
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Acids 2008, 34, 1. (h) Grygorenko, O. O.; Radchenko, D. S.;
Volochnyuk, D. M.; Tolmachev, A. A.; Komarov, I. V.
Chem. Rev. 2011, 111, 5506.
(8) (a) Appella, D. H.; Barchi, J. J. Jr.; Durell, S. R.; Gellman, S.
H. J. Am. Chem. Soc. 1999, 121, 2309. (b) Raguse, T. L.;
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387, 381.
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Barker, S. F.; Taillefumier, C.; Watterson, M. P.; Fleet, G.
W. J. Tetrahedron Lett. 2001, 42, 4251.
(11) (a) Chung, Y. J.; Huck, B. R.; Christianson, L. A.; Stanger,
H. E.; Krauthäuser, S.; Powell, D. R.; Gellman, S. H. J. Am.
Chem. Soc. 2000, 122, 3995. (b) Chung, Y. J.; Christianson,
L. A.; Stanger, H. E.; Powell, D. R.; Gellman, S. H. J. Am.
Chem. Soc. 1998, 120, 10555.
An attempted selective reduction of the amide moiety in
21 with borane–dimethyl sulfide complex was unsuccess-
ful. The corresponding amino alcohol formed instead, and
was isolated as its protected derivative 22 in 67% yield
(Scheme 4).29 Treatment of alcohol 22 with rutheni-
um(III) chloride–sodium periodate was accompanied by
oxidation of the bicyclic skeleton. We therefore adopted a
two-step procedure, namely, reaction of alcohol 22 with
Dess–Martin periodinane followed by Pinnick oxidation
of an intermediate aldehyde 23. This gave the carboxylic
acid 24 (63% from 22).30 Finally, deprotection of 24 gave
the required amino acid 9, isolated in 85% yield as its hy-
drochloride.31
H
OH
Dess–Martin
O
1. BH3⋅SMe2,
THF
periodinane
O
O
CH2Cl2
2. Boc2O,
Et3N
Me
N
N
N
O
H
Boc
Boc
22
67%
21
23
NaClO2, Na2HPO4
2-methylbut-2-ene
THF–t-BuOH–H2O
63% (from 22)
OH
O
OH
O
HCl
EtOAc
N
Cl–
N
85%
+
H2
Boc
24
9⋅HCl
Scheme 4
(12) Izquieiro, S.; Rúa, F.; Sbai, A.; Parella, T.; Álverez-Lerena,
Á.; Branchadell, V.; Ortuño, R. M. J. Org. Chem. 2005, 70,
7963.
(13) (a) Krogsgaard-Larsen, P.; Frølund, B.; Frydenvang, K.
Curr. Pharm. Des. 2000, 6, 1193. (b) Soudijn, W.; van
Wijngaarden, I. Curr. Med. Chem. 2000, 7, 1063.
(14) Soloshonok, V. A.; Sorochinsky, A. E. Synthesis 2010,
2319.
In conclusion, we have developed an approach to the syn-
thesis of 3,5-methanonipecotic acid, a novel nonchiral bi-
cyclic β-amino acid. The compound was obtained in 17
steps and 10% overall yield from readily available 1,3-di-
bromo-2,2-dimethoxypropane. Note that the final product
was obtained on a gram scale in a single run.
(15) (a) Pirrung, M. C. Tetrahedron Lett. 1980, 21, 4577.
(b) Hughes, P.; Martin, M.; Clardy, J. Tetrahedron Lett.
1980, 21, 4579. (c) Hughes, P.; Clardy, J. J. Org. Chem.
1988, 53, 4793. (d) Rammeloo, T.; Stevens, C. V. Chem.
Acknowledgment
The authors thank Mr. Igor Bilenko for chromatographic purificati-
ons, Mr. Vitaliy Polovinko for 2D NMR experiments, Mr. Timur
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 355–358

358
A. V. Tymtsunik et al.
LETTER
Commun. 2002, 250. (e) Rammeloo, T.; Stevens, C. V.; De
Kimpe, N. J. Org. Chem. 2002, 67, 6509. (f) Varnes, J. G.;
Lehr, G. S.; Moore, G. L.; Hulsizer, J. M.; Albert, J. S.
Tetrahedron Lett. 2010, 51, 3756.
CDCl3): δ = 9.38 (very br s, 1 H), 5.06 (sept, J = 6.1 Hz, 1
H), 5.02 (sept, J = 6.1 Hz, 1 H), 2.67–2.77 (m, 3 H), 2.48 (d,
J = 6.5 Hz, 2 H), 2.22–2.27 (m, 2 H), 1.22 (d, J = 6.1 Hz, 6
H), 1.21 (d, J = 6.1 Hz, 6 H). 13C NMR (125 MHz, CDCl3):
δ = 178.0, 171.28, 171.25, 69.00, 68.96, 49.9, 40.3, 34.3,
25.6, 21.6. MS (CI): m/z = 287 [M + H]+. Anal. Calcd for
C14H22O6: C, 58.73; H 7.74. Found: C, 58.95; H, 7.98.
(27) Diisopropyl 3-{[(tert-Butoxycarbonyl)amino]methyl}-
cyclobutane-1,1-dicarboxylate (19)
(16) (a) Avenoza, A.; Cativiela, C.; Busto, J. H.; Fernández-
Recio, M. A.; Peregrina, J. M.; Rodrígues, F. Tetrahedron
2001, 57, 545. (b) Karaki, F.; Kabasawa, Y.; Yanagimoto,
T.; Umeda, N.; Firman Urano, Y.; Nagano, T.; Otani, Y.;
Ohwada, T. Chem. Eur. J. 2012, 18, 1127.
(17) Radchenko, D. S.; Kopylova, N. A.; Grygorenko, O. O.;
Komarov, I. V. J. Org. Chem. 2009, 74, 5541.
(18) (a) Montelione, G. T.; Hughes, P.; Clardy, J.; Scheraga, H.
A. J. Am. Chem. Soc. 1986, 108, 6765. (b) Avenoza, A.;
Busto, J. H.; Peregrina, J. M.; Rodríguez, F. J. Org. Chem.
2002, 67, 4241.
(19) (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem.
2009, 52, 6752. (b) Kingwell, K. Nat. Rev. Drug Discovery
2009, 8, 931. (c) Feher, M.; Schmidt, J. M. J. Chem. Inf.
Comput. Sci. 2003, 43, 218.
Colorless oil. Rf = 0.26 (hexanes–EtOAc, 5:1). IR (neat):
3365, 1712, 1525 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 5.04 (sept, J = 6.1 Hz, 1 H), 5.01 (sept, J = 6.1 Hz, 1 H),
4.61 (br s, 1 H), 3.18 (d, J = 5.9 Hz, 0.5 H), 3.12 (br s, 1.5
H), 2.45–2.58 (m, 3 H), 2.18–2.23 (m, 2 H), 1.41 (s, 9 H),
1.21 (d, J = 6.1 Hz, 6 H), 1.20 (d, J = 6.1 Hz, 6 H). 13C NMR
(125 MHz, CDCl3): δ = 171.4, 171.1, 156.1, 79.3, 68.93,
68.86, 49.5, 45.2, 32.0, 29.4, 28.5, 21.6. MS (ESI): m/z = 358
[M + H]+. Anal. Calcd for C18H31NO6: C, 60.48; H, 8.74;
N, 3.92. Found: C, 60.70; H, 8.46; N, 4.12.
(20) For examples, see: (a) Denisenko, A. V.; Mityuk, A. P.;
Grygorenko, O. O.; Volochnyuk, D. M.; Shishkin, O. V.;
Tolmachev, A. A.; Mykhailiuk, P. K. Org. Lett. 2010, 12,
4372. (b) Kim, S. M.; Park, J. H.; Kang, Y. K.; Chung, Y. K.
Angew. Chem. Int. Ed. 2009, 48, 4532. (c) Stanek, J.; Alder,
A.; Bellus, D.; Bhatnagar, A. S.; Haeusler, A.; Schieweck,
K. J. Med. Chem. 1991, 34, 1329. (d) Sheibani, H.;
Bernhardt, P. V.; Wentrup, C. J. Org. Chem. 2005, 70, 5859.
(21) Tkachenko, A. N.; Radchenko, D. S.; Mykhailiuk, P. K.;
Grygorenko, O. O.; Komarov, I. V. Org. Lett. 2009, 11,
5674.
(28) Methyl 2-Oxo-3-azabicyclo[3.1.1]heptane-1-carboxylate
(21)
White crystals; mp 115–116 °C. IR (KBr): 3220 [ν(N–H)],
1741 [ν(C=O)], 1676 cm–1 [ν(C=O)].
1H NMR (500 MHz, DMSO-d6): δ = 7.61 (br s, 1 H), 3.60 (s,
3 H), 3.29 (s, 2 H), 2.53–2.57 (m, 1 H), 2.35–2.42 (m, 2 H),
1.79–1.85 (m, 2 H). 13C NMR (125 MHz, DMSO-d6):
δ = 172.6 (C), 170.9 (C), 51.5 (C), 51.4 (CH3), 44.8 (CH2),
32.7 (CH2), 27.6 (CH). MS (CI): m/z = 170 [M + H]+. Anal.
Calcd for C8H11NO3: C, 56.80; H, 6.55; N, 8.28. Found:
C, 56.53; H, 6.58; N, 8.52.
(22) Radchenko, D. S.; Mykhailiuk, P. K.; Komarov, I. V.;
Bezdudny, A. V. Synlett 2009, 1827.
(29) tert-Butyl 1-(Hydroxymethyl)-3-azabicyclo[3.1.1]-
heptane-3-carboxylate (22)
(23) (a) Kutrov, G. P. Vestn. Kiev. Univ.: Khim. 1990, 31, 37.
(b) Dieckmann, A.; Von Kiedrowski, G.; Beniken, S.;
Doltsinis, N. L.; Lorenz, C. D. Chem. Eur. J. 2011, 17, 468.
(c) Ohmori, Y.; Serizawa, T.; Sugie, K.; Tanaka, K.;
Matsumoto, A. US 20090298894, 2009.
White crystals; mp 97–98 °C. IR (KBr): 3449, 3448, 1666,
1408, 1176 cm–1. 1H NMR (500 MHz, CDCl3): δ = 3.50 (br
s, 2 H), 3.47 (s, 2 H), 3.42 (s, 2 H), 2.45 (br s, 0.5 H), 2.38
(br s, 0.5 H), 1.90 (br s, 2 H), 1.80 (br s, 1 H), 1.47 (s, 9 H),
1.34 (br s, 2 H). 13C NMR (125 MHz, CDCl3): δ = 156.5 (C),
79.4 (C), 67.8 and 67.4 (CH2), 52.2 and 51.8 (CH2), 50.2 and
49.8 (CH2), 42.7 (C), 32.6 and 32.4 (CH2), 28.71 (CH3),
28.67 (CH). MS (CI): m/z = 228 [M + H]+. Anal. Calcd for
C12H21NO3: C, 63.41; H, 9.31; N, 6.16. Found: C, 63.08;
H, 9.14; N, 6.48.
(24) Diisopropyl 3-(2-Methoxy-2-oxoethylidene)cyclobutane-
1,1-dicarboxylate (15)
Colorless oil; Rf = 0.49 (hexanes–EtOAc, 5:1). IR (neat):
1718, 1626, 1625, 1101, 1082 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 5.69 (t, J = 2.0 Hz, 1 H), 5.05 (sept, J = 6.2 Hz,
2 H), 3.67 (s, 3 H), 3.58 (d, J = 2.0 Hz, 2 H), 3.30 (s, 2 H),
1.22 (d, J = 6.2 Hz, 12 H). 13C NMR (125 MHz, CDCl3):
δ = 170.3 (C), 166.3 (C), 157.7 (C), 114.7 (CH), 69.4 (CH),
51.2 (CH3), 49.9 (C), 41.2 (CH2), 39.1 (CH2), 21.6 (CH3).
MS (CI): m/z = 299 [M + H]+. Anal. Calcd for C15H22O6:
C, 60.39; H, 7.43. Found: C, 60.18; H, 7.64.
(30) 3-(tert-Butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-1-
carboxylic Acid (24)
White crystals; mp 172–174 °C. 1H NMR (500 MHz,
CDCl3): δ = 9.38 (br s, 1 H), 3.65 (s, 0.8 H), 3.62 (s, 1.2 H),
3.47 (s, 1.2 H), 3.44 (s, 0.8 H), 2.32–2.41 (m, 3 H), 1.53–1.55
(m, 2 H), 1.42 (s, 9 H). 13C NMR (125 MHz, CDCl3):
δ = 178.5 and 178.1 (C), 156.32 and 156.30 (C), 80.1 and
80.0 (C), 49.9 and 49.6 (CH2), 49.3 and 48.8 (CH2), 44.1 (C),
34.33 and 34.28 (CH2), 28.7 (CH3), 28.6 (CH). MS (ESI):
m/z = 242 [M + H]+. Anal. Calcd for C12H19NO4: C, 59.73;
H, 7.94; N, 5.80. Found: C, 59.48; H, 8.27; N, 5.53.
(31) 3-Azabicyclo[3.1.1]heptane-1-carboxylic Acid
Hydrochloride (9·HCl)
(25) Diisopropyl 3-(2-Methoxy-2-oxoethyl)cyclobutane-1,1-
dicarboxylate (16)
Colorless oil; Rf = 0.46 (hexanes–EtOAc, 5:1). IR (neat):
1720, 1265, 1164, 1097 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.03 (sept, J = 6.2 Hz, 1
H), 4.99 (sept, J = 6.2 Hz, 1 H), 3.61 (s, 3 H), 2.63–2.73 (m,
3 H), 2.42 (d, J = 6.7 Hz, 2 H), 2.18–2.24 (m, 2 H), 1.20 (d,
J = 6.2 Hz, 6 H), 1.18 (d, J = 6.2 Hz, 6 H). 13C NMR (125
MHz, CDCl3): δ = 172.4 (C), 171.24 (C), 171.18 (C), 68.9
(CH), 68.8 (CH), 51.4 (CH3), 49.8 (C), 40.4 (CH2), 34.3
(CH2), 25.9 (CH), 21.6 (CH3). MS (CI): m/z = 301 [M + H]+.
Anal. Calcd for C15H24O6: C, 59.98; H, 8.05. Found:
C, 59.67: H, 7.89.
White crystals; mp >250 °C (dec.). IR (KBr): 3423, 2987
(br), 1724, 1592, 1398 cm–1. 1H NMR (500 MHz, D2O):
δ = 3.69 (s, 2 H), 3.53 (s, 2 H), 2.60–2.68 (m, 2 H), 2.57–
2.61 (m, 1 H), 1.82–1.87 (m, 2 H). 13C NMR (125 MHz,
D2O): δ = 175.7 (C), 47.2 (CH2), 46.7 (CH2), 43.9 (C), 33.3
(CH2), 28.1 (CH). Anal. Calcd for C8H12ClNO4: C, 43.35;
H, 5.46; Cl, 16.00; N, 6.32. Found: C, 43.62; H, 5.09;
Cl, 16.25; N, 6.39.
(26) [3,3-Bis(isopropoxycarbonyl)cyclobutyl]acetic Acid (20)
Colorless solid; mp 80–82 °C; Rf = 0.65 (hexanes–EtOAc,
1:2). IR (KBr): 2987, 1724, 1705 cm–1. 1H NMR (500 MHz,
Synlett 2014, 25, 355–358
© Georg Thieme Verlag Stuttgart · New York