First 1,3-dipolar cycloaddition of azomethine ylides with (E)-ethyl 3-fluoroacrylate: Regio- and stereoselective synthesis of enantiopure fluorinated prolines

Article abstract of DOI:10.1055/s-2006-933127

Enantiopure fluorinated prolines with four chiral centers were obtained from 1,3-dipolar cycloaddition of azomethine ylides and (E)-ethyl 3-fluoroacrylate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-933127

LETTER
543
First 1,3-Dipolar Cycloaddition of Azomethine Ylides with (E)-Ethyl
3-Fluoroacrylate: Regio- and Stereoselective Synthesis of Enantiopure
Fluorinated Prolines
S
ynthesis of
E
nan
i
tiopur
a
Fluorinate
n
d Prolines ca Flavia Bonini, Francesca Boschi, Mauro Comes Franchini,* Mariafrancesca Fochi, Francesco Fini,
Andrea Mazzanti, Alfredo Ricci
Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
E-mail: mauro.comesfranchini@unibo.it
Received 30 November 2005
CO2R*
F
Abstract: Enantiopure fluorinated prolines with four chiral centers
were obtained from 1,3-dipolar cycloaddition of azomethine ylides
and (E)-ethyl 3-fluoroacrylate.
EtO2C
EtO2C
Et3N/AgOAc
1,3-DC
N
*
*
N
*
*
+
CO2R*
R
R
F
1
H
Key words: 1,3-dipolar cycloaddition, fluoroolefins, azomethine
ylides, fluorinated prolines
Scheme 1 1,3-DC of 1 with chiral azomethine ylides
Following our interest for the [3+2] cycloaddition of 1,3-
dipoles with fluorine-containing dipolarophiles8 we report
herein the 1,3-DC of stabilized chiral N-metalated azo-
methine ylides with the F-containing p-deficient alkene
(E)-ethyl 3-fluoroacrylate9 (1) for the synthesis of enan-
tiopure fluorinated prolines (Scheme 1).
Nitrogen-containing heterocycles have attracted wide-
spread attention in the field of synthetic organic chemistry
as well as in medicinal chemistry.1 In particular, the syn-
thesis of pyrrolidines or prolines has received significant
interest due to their known biological activity.2 The 1,3-
dipolar cycloaddition3 (1,3-DC) of azomethine ylides
with p-electronic-deficient olefins has emerged as a pop-
ular way for the obtainment of these heterocycles,4 owing
to its high synthetic efficiency and high regio- and stereo-
selectivity.
According to the Scheme 1 this approach should allow a
general entry to fluorinated pyrrolidines/prolines having
up to four chiral centers giving a satisfactory control of the
regio- and stereochemistry of the final heteroycles. We
decided to use a chiral auxiliary incorporated into the a-
imino esters in order to obtain in situ the chiral enan-
tiopure azomethine ylides.3a
It is also well known that the synthesis of organic mole-
cules containing a stereogenic (sp3-hybridized) carbon
atom bearing fluorine has increased greatly in the last de-
cades, since enantiopure fluorine-containing heterocycles
have shown great potential as drug candidates.5
Thus, a solution of the NHBoc glycine was esterificated
with L-menthol under mild conditions with DCC, DMAP
in CH2Cl2 to give the ester in 86% yield and the removal
of the Boc with TFA gave the free amine 2 in quantitative
yield (Scheme 2).10 We next prepared the a-imino esters
3a,b which were obtained after condensation of 2, with
yields ranging between 86% and 90%, with two aromatic
aldehydes (Scheme 2).11
While there is no doubt that the increasing need of struc-
turally diverse fluorinated enantiopure heterocycles hav-
ing biological relevancy calls for new synthetic strategies,
few general methods to assemble enantiopure fluorinated
heterocycles have been reported so far.5a,b
The different fluorine substitution in hydroxyprolines has
been recently used as probe for stereoelectronic effects in
the Xaa position of collagen.6 Furthermore, it has been
demonstrated that both 3-fluoroprolines and pyrrolidines
can also be used for the production of recombinant bioad-
hesive protein analogues.7a These moieties have been also
claimed as bactericides when incorporated in quinolone
carboxylic acid based structures.7b
Then we examined the conditions required for the cy-
cloaddition of 1 with the azomethine ylides derived from
a-iminoesters 3a,b.4c,d The cycloaddition was carried out
1) L-Menthol, CH2Cl2
DCC, DMAP,
r.t., 24 h, 86%
O
BocNHCH2COOH
H2N
2) TFA, CH2Cl2,
r.t., 35 min
100%
To the best of our knowledge, no methods for the direct
formation of fluorinated enantiopure prolines using 1,3-
DC have been reported in the literature.
O
2
CO2R*
H
ArCHO, MgSO4
Et3N, r.t., 24 h
N
R* =
2
Ar
3a, Ar = C6H5, 86%
3b, Ar = p-CN-C6H4 90%
SYNLETT 2006, No. 4, pp 0543–0546
0
2.
0
3.
2
0
0
6
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-933127; Art ID: G39005ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthesis of the chiral imines 3a,b

544
B. F. Bonini et al.
LETTER
in dry toluene using 1.5 equivalents of dry AgOAc and
Et3N at –40 °C for 6 hours since at room temperature we
obtained lower yields in the cycloadducts. Analysis of the
crude mixtures using 19F NMR showed for each reaction
only two new signals for the CH–F in a 9:1 ratio thus
indicating the formation of two stereoisomers for each
dipolar cycloaddition. After purification with column
chromatography on silica gel of the two crudes we were
able to obtain (Scheme 3) two diastereoisomeric mixtures
containing the couple of the diastereoisomers 4a,a¢ start-
ing from 3a (75% overall yield) and 5a,a¢ starting from 3b
(82% yield).12
Semi-preparative HPLC allowed the separation of the
enantiopure cycloadducts 4a, 4a¢, 5a and 5a¢. The regio-
chemistry of the adducts was easily demonstrated by the
13C NMR spectra showing that no CH2 signals were
present in the adducts (Figure 1). To investigate the ste-
reochemistry of the adducts, the first step was the assign-
ment of the proton signals by standard 2D-NMR spectra
(gCOSY, gHSQC and gHMBC), and then the determina-
tion of the relative configuration of the four stereogenic
centers (2R*,3S*,4S*,5R*) by means of DPFGSE-NOE
spectra,13 obtained by selective saturation of the H2,H3,H4,
and H5 signals.14
Figure 1 Left: experimentally observed NOE constraints (double
ended arrows) for 4 and 5. Right: calculated structures for 4a, 5a
(upper) and 4a¢, 5a¢ (lower). NOE effects on the (–)-menthol moiety
observed for 4a and 5a are indicated by the arrows (the aryl groups
and the CO2R moieties are omitted for clarity).
far from any pyrrolidine hydrogen, so only negligible
NOE effect should be observed. Indeed, no NOE effects
on the menthol hydrogen were experimentally observed,
and the structure 2R,3S,4S,5R could be satisfactorily
assigned.
Absolute structure could be satisfactorily suggested by the
analysis of the same NOE spectra, looking at the effects
on the signals of the enantiopure (–)-menthol. In the case
of 4a and 5a, selective saturation of H3 shows additional
NOE effects also on two menthol hydrogens, namely the
a-CH–O and on the CH of the isopropyl group. NOE ra-
tios show that the distances H3–HR*CH and H3–H4 are very
similar, and that the distances H3–HR*iPr and H3–H4 are
similar too. By inspecting the MM computed structure,15
only the (–)-menthol-2S,3R,4R,5S structure could match
the experimental NOE data. The same approach used for
4a¢ and 5a¢ suggests that in this case [i.e, the (–)-menthol-
2R,3S,4S,5R structure], all the menthol hydrogens are too
The synthetic scheme was completed by careful hydroly-
sis of the chiral auxiliary under basic conditions. The re-
moval of the L-menthol moiety took place in 48 hours at
room temperature with LiOH in THF–H2O in high yield
for compounds 4a and 4a¢, the subsequent esterification
with SOCl2 in MeOH at room temperature,16 yielded the
diesters 6a and 6a¢ in 50% and 54% yield which proved to
be enantiomers by polarimetric measurements thus con-
firming the attribution of the four stereogenic centers by
NMR in the starting cycloadducts (Scheme 4). The same
results were obtained starting from 5a,a¢, which gave the
two enantiomers 7a and 7a¢ in 50% and 52% yield.
F
EtOOC
Ph
EtOOC
F
3a, AgOAc, toluene
OR*
Et3N, –40 °C, 6 h, 75%
Ph
OR*
+
N
H
4a'
N
H
4a
O
O
4a:4a' = 9:1
1
F
EtOOC
p-NCC4H6
EtOOC
F
3b, AgOAc, toluene
Et3N, –40 °C, 6 h, 82%
OR*
OR*
p-NCC4H6
+
N
H
5a'
N
H
O
O
5a
5a:5a' = 9:1
Scheme 3 1,3-Dipolar cycloadditions of 1 with 3a,b.
1) LiOH·H2O
TFH–H2O
48 h, r.t.
1) LiOH·H2O
TFH–H2O
48 h, r.t.
MeO2C
F
F
MeO2C
Ar
OMe
O
OMe
4a or 5a
Ar
4a' or 5a'
N
N
2) SOCl2, MeOH
r.t., 24 h
H
2) SOCl2, MeOH
r.t., 24 h
H
O
Ar = Ph 6a'
Ar = 4CN-C6H4 7a'
Ar = Ph 6a
Ar = 4CN-C6H4 7a
Scheme 4 Removal of the chiral auxiliary
Synlett 2006, No. 4, 543–546 © Thieme Stuttgart · New York

LETTER
Synthesis of Enantiopure Fluorinated Prolines
545
(6) Hodges, J. A.; Reines, R. T. J. Am. Chem. Soc. 2003, 125,
9262.
(7) (a) Paolella, D. N.; Gruskin, E. A.; Buechter, D. D. PCT Int.
Appl. WO 2000015789, 2000. (b) Fukui, H.; Shibata, T.;
Nakano, J.; Naita, T.; Senda, N.; Maejima, T.; Watanuki, Y.;
Aryoshi, T. JP 07300471, 1995.
(8) Bernardi, L.; Bonini, B. F.; Comes-Franchini, M.; Fochi, M.;
Folegatti, M.; Grilli, S.; Mazzanti, A.; Ricci, A.
Tetrahedron: Asymmetry 2004, 15, 245.
(9) McElroy, K. T.; Purrington, S.; Bumgardner, C. L.; Burgess,
J. P. J. Fluorine Chem. 1999, 95, 117.
In conclusion, we have developed a mild and general
method for the efficient regio- and stereoselective synthe-
sis of enantiopure pharmacologically important 3F-substi-
tuted prolines. These fluorinated heterocycles could be
used for the creation of new biomaterials for medicinal
applications.6,7
This approach offers an advantage over the direct nucleo-
philic fluorination of hydroxyl groups, which often gives
side products and requires additional steps of protection–
deprotection in the case of polyhydroxylated compounds.
Moreover, this protocol overcomes the problems
associated17 with the difficult handling and toxicity of the
most commonly used nucleophilic fluorinating reagents.
The applications in other target-oriented 1,3-DC with flu-
orinated olefins calls for other studies in our laboratories
and will be reported in due course.
(10) A solution of BocNHglycine (3.5 g, 20.2 mmol) in 50 mL of
CH2Cl2 was cooled to 0 °C. N,N-dicyclohexylcarbodiimide
(4.18 g, 20.2 mmol) was added in several portions and a
white precipitate formed quickly. After 10 min, L-menthol
was added (3.78 g, 24.2 mmol) in 60 mL of CH2Cl2 and
DMAP (110 g, 0.9 mmol). The mixture was stirred at r.t. for
24 h. After addition of H2O (15 mL), the organic phase was
extracted with Et2O and dried over MgSO4. The residue was
purified on column chromatography on silica gel (PE–Et2O,
2:1) to afford the L-menthol ester (5.4 g, 86%) as a yellow
oil. [a]D20 –46.5 (c 0.99, MeOH). 1H NMR (400 MHz,
CDCl3): d = 5.06 (s, 1 H), 4.70 (dt, 1 H, J = 12.3, 6.1 Hz),
3.83 (d, 2 H, J = 4.2 Hz), 1.98–1.90 (m, 1 H), 1.85–1.73 (m,
1 H), 1.67–1.59 (m, 2 H), 1.40 (s, 9 H), 1.37–1.29 (m, 1 H),
1.07–0.76 (m, 4 H), 0.85 (d, 3 H, J = 7.3 Hz), 0.84 (d, 3 H,
J = 7.3 Hz), 0.70 (d, 3 H, J = 6.6 Hz). 13C NMR (75.3 MHz,
CDCl3): d = 169.7, 155.4, 79.2, 75.4, 46.8, 42.5, 40.7, 34.0,
31.3, 28.2, 26.1, 23.3, 21.9, 20.6, 16.2. MS (EI): m/e = 313
[M+]. Standard procedures for the removal of the Boc were
followed giving (1R,2S,5S)-2 as a yellow oil. [a]D20 –77.3 (c
0.50, MeOH). 1H NMR (300 MHz, CDCl3): d = 4.60 (dt, 1
H, J = 12.2, 6.1 Hz), 3.32 (s, 2 H), 2.28 (s, 2 H), 1.92–0.60
(18H). 13C NMR (75.3 MHz, CDCl3): d = 173.1, 74.3, 46.6,
43.3, 40.4, 33.8, 30.9, 25.8, 23.0, 21.5, 20.3, 15.9. MS (EI):
m/e = 213 [M+].
(11) For the condensation see ref. 4c and 4d. Starting from
(1R,2S,5S)-2 (860 mg, 4.0 mmol), Na2SO4 (3.2 g, 22.8
mmol) and PhCHO (0.4 mL, 4.0 mmol), 1.03 g (86%) of
(1R,2S,5S)-3a as a yellow oil were obtained. [a]D20 –54.0 (c
0.16, CH2Cl2). 1H NMR (300 MHz, CDCl3): d = 8.17 (s, 1
H), 7.67–7.63 (m, 2 H), 7.32–7.26 (m, 3 H), 4.66 (dt, 1 H,
J = 4.0, 11.3 Hz), 4.26 (s, 2 H), 1.93 (d, 1 H, J = 11.8 Hz),
1.84–1.73 (m, 1 H), 1.61–1.50 (m, 2 H), 1.44–1.24 (m, 2 H),
1.00–0.81 (m, 3 H), 0.77 (d, 6 H, J = 5.5 Hz), 0.64 (d, 3 H,
J = 7.3 Hz). 13C NMR (100.6 MHz, CDCl3): d = 169.4,
164.9, 136.4, 128.7, 128.6, 128.5, 74.6, 62.4, 47.3, 41.2,
34.4, 31.4, 26.6, 23.8, 22.1, 20.8, 16.6. MS (ESI): m/z = 324
[M+ + Na]. Starting from (1R,2S,5S)-2 (1.67 g, 7.8 mmol),
Na2SO4 (6.34 g, 44.6 mmol) and 4-CNC6H4CHO (1.03g, 7.8
mmol), 2.28 g (90%) of (1R,2S,5S)-3b as a yellow oil were
obtained. [a]D20 –42.4 (c 0.50, CH2Cl2). 1H NMR (300 MHz,
CDCl3): d = 8.33 (s, 1 H), 7.89 (d, 2 H, J = 8.6 Hz), 7.72 (d,
2 H, J = 8.6 Hz), 4.87 (dt, 1 H, J = 11.0, 4.3 Hz), 4.43 (s, 2
H), 2.09–0.70 (m, 18 H). 13C NMR (100.6 MHz, C6D6): d =
168.9, 163.1, 139.5, 132.5, 132.2, 129.4, 128.7, 118.4,
114.5, 75.0, 62.2, 47.3, 41.2, 34.3, 31.4, 26.7, 23.8, 22.1,
20.8, 16.6. MS (ESI): m/z = 349 [M+ + Na].
Acknowledgment
We acknowledge financial support by the National Project ‘Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazioni’ 2002–
2004.
References and Notes
(1) (a) Tsuge, O.; Kanemasa, S. In Advances in Heterocyclic
Chemistry, Vol. 45; Katritzky, A. R., Ed.; Academic Press:
San Diego, 1989, 232. (b) Janasik, T.; Bergman, J. In
Progress in Heterocyclic Chemistry, Vol. 15; Gribble, G.
W.; Jaule, J. A., Eds.; Pergamon: Amsterdam, 2003, 140.
(2) (a) Pearson, W. H. In Studies in Natural Products Chemistry,
Vol. 1; Atta-Ur-Rahman, Ed.; Elsevier: New York, 1998,
323. (b) Grigg, R. Chem. Soc. Rev. 1987, 16, 89. (c) Lawin,
J. W. In 1,3-Dipolar Cycloaddition Chemistry, Vol. 1;
Padwa, A., Ed.; J. Wiley and Sons: New York, 1984, 653.
(3) (a) Jorgensen, K. A.; Gothelf, K. V. Chem. Rev. 1998, 98,
863. (b) Gothelf, K. V. In Cycloaddition Reaction in
Organic Synthesis; Kobayashi, S.; Jorgensen, K. V., Eds.;
Wiley-VCH: Weinheim, 2001, Chap. 6. (c) Najera, C.;
Sansano, J. M. Angew. Chem. Int. Ed. 2005, 44, 6272.
(4) (a) Synthetic Application of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products;
Padwa, A.; Pearson, W., Eds.; Wiley-VCH: Weinheim,
2002, 169. (b) Kanemasa, S. Synlett 2002, 1371.
(c) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc.
2002, 124, 13400. (d) Chen, C.; Xiaodong, L.; Schreiber, S.
J. Am. Chem. Soc. 2003, 125, 10174. (e) Nyerges, M.;
Bendell, D.; Arony, A.; Hibbs, D. E.; Coles, S. J.;
Hursthouse, M. B. Synlett 2003, 947.
(5) (a) Enantiocontrolled Synthesis of Fluoro-Organic
Compounds. Stereochemical Challenges and Biomedicinal
Targets; Soloshonok, V. A., Ed.; John Wiley and Sons, Inc.:
New York, 1999. (b) AsymmetricFluoroorganic Chemistry;
Ramachandran, P. V., Ed.; ACS Symposium Series:
Washington, DC, 2000. (c) Smart, B. E. Chemistry of
Organic Fluorine Compound: A Critical Review; Hudlicky,
M.; Pavlath, A. E., Eds.; ACS Monograph 187, American
Chemical Society: Washington, DC, 1995, 979. (d) Smart,
B. E. Organofluorine Chemistry: Principles and
(12) According to ref. 4c and 4d. Starting from 1 (212 mg, 1.8
mmol) and 3a (541 mg, 1.8 mmol), 565 mg (75%) of 4a,a¢
were obtained as mixture after column chromatography on
silica with CH2Cl2–EtOAc 200:1. After column
chromatography the two cycloadducts were subjected to
semi-preparative HPLC separation. HPLC (hexane–i-PrOH
gradient starting from 0.5% i-PrOH, to 11 min, then 1.05%
i-PrOH to 25 min, then 2.25% i-PrOH).
Commercial Applications; Banks, R. E.; Smart, B. E.;
Tatlow, J. C., Eds.; Plenum Publishing Corporation: New
York, 1994, 57. (e) Myers, A. G.; Barbay, J. K.; Zhong, B. J.
Am. Chem. Soc. 2001, 123, 7207.
Selected data for 4a,a¢.
Synlett 2006, No. 4, 543–546 © Thieme Stuttgart · New York

546
B. F. Bonini et al.
LETTER
(14) In the case of 5a, on selective saturation of the H3 signal
L-Menthol-(2S,3R,4R,5S)-4a: elution time 9.00 min; yellow
oil; [a]D20 –60.5 (c 0.55, MeOH). 1H NMR (600 MHz,
C6D6): d = 7.22–7.19 (m, 1 H), 7.02–6.95 (m, 4 H), 5.77
(ddd, 1 H, JHF = 53.1 Hz, J = 3.1, 1.6 Hz), 4.99 (dt, 1 H,
J = 11.1, 4.6 Hz), 4.62 (d, 1 H, J = 7.4 Hz), 4.21 (dd, 1 H,
JHF = 28.6 Hz, J = 3.1 Hz), 3.46 (dd, 1 H, J = 10.5, 7.3 Hz),
3.44 (dd, 1 H, J = 10.5, 7.3 Hz), 3.27 (ddd, 1 H, JHF = 20.1
Hz, J = 7.2, 1.6 Hz), 3.11 (s, 1 H), 2.16–2.06 (m, 1 H), 1.47–
1.34 (m, 3 H), 1.21–1.08 (m, 1 H), 0.99–0.60 (m, 3 H), 0.90
(d, 3 H, J = 7.6 Hz), 0.87 (d, 3 H, J = 7.6 Hz), 0.75 (d, 3 H,
J = 7.1 Hz), 0.48 (t, 3 H, J = 7.6 Hz). 13C NMR (150 MHz,
C6D6): d = 169.7 (d, JCF = 9.6 Hz), 169.4 (d, JCF = 14.0 Hz),
137.9, 128.0–127.4, 126.9, 98.3 (d, JCF = 187.6 Hz), 75.5,
68.1 (d, JCF = 24.6 Hz), 64.5, 60.0, 56.1 (d, JCF = 22.2 Hz),
NOE effects were observed only on H2 and H4 (relative
distance from H3: 1.07:1.00), while saturation of H4 showed
NOE effects on H5 and H3 (relative distance from H4:
1.00:1.14). Saturation of H5 revealed strong NOE effects on
H2 and H4 and a very small effect on H3 (relative distance
from H5: 1.00:1.13:ca. 1.8); finally, saturation of H2 revealed
strong NOE effects on H3 and H5 and a not negligible effect
on H4 (relative distance from H2: 1.09:1.00:1.33). These data
imply a trans relationship between H2 and H3, a trans
relationship between H3 and H4, and a cis relationship
between H4 and H5. This concatenation (trans-trans-cis)
corresponds to the 2R*,3S*,4S*,5R* configuration.
Analogous data were obtained for 5a¢, 4a and 4a¢.
46.9, 40.6, 34.0, 31.1, 26.2, 23.1, 21.8, 20.7, 16.0, 13.2. 19
F
(15) MMFF force field as implemented in Titan 1.0.5,
Wavefunction, Inc. The standard conformational search was
applied to 5a and 5a¢, and the structures within 3 kcal/mol
above the global minima were analyzed for the
NMR (376 MHz, C6D6): d = –173.77 (ddd, JFH = 51.9, 28.9,
21.0 Hz). MS (ESI): m/z = 419 [M+].
L-Menthol-(2R,3S,4S,5R)-4a¢: elution time 9.30 min; yellow
oil; [a]D20 –27.1 (c 0.75, MeOH). 1H NMR (600 MHz,
C6D6): d = 7.23–7.21 (m, 1 H), 7.04–6.95 (m, 4 H), 5.71
(ddd, 1 H, JHF = 52.8 Hz, J = 2.7, 1.6 Hz), 5.02 (dt, 1 H,
J = 10.9, 4.8 Hz), 4.63 (d, 1 H, J = 6.8 Hz), 4.20 (dd, 1 H,
JHF = 28.7 Hz, J = 2.7 Hz), 3.45 (q, 2 H, J = 7.3 Hz), 3.27
(ddd, 1 H, JHF = 20.1 Hz, J = 7.1, 1.5 Hz), 3.08 (s, 1 H),
2.18–2.13 (m, 1 H), 2.06–2.00 (m, 1 H), 1.48–0.58 (m, 7 H),
0.85 (d, 6 H, J = 7.0 Hz), 0.74 (d, 3 H, J = 6.5 Hz), 0.47 (t, 3
H, J = 7.6 Hz). 13C NMR (150 MHz, C6D6): d = 169.9 (d,
JCF = 9.3 Hz), 169.4 (d, JCF = 12.3 Hz), 137.9, 128.0–127.4,
126.8, 98.4 (d, JCF = 186.5 Hz), 75.3, 67.8 (d, JCF = 25.9
Hz), 64.5, 60.0, 56.5 (d, JCF = 24.2 Hz), 47.0, 40.7, 34.1,
31.2, 26.4, 23.4, 21.8, 20.6, 16.4, 13.2. 19F NMR (376 MHz,
C6D6): d = –173.95 (ddd, JFH = 48.9, 28.9, 19.9 Hz). MS
(ESI): m/z = 419 [M+].
determination of the distances between the pyrrolidine
hydrogens and the menthol hydrogens. In Figure 1 are
reported the two global energy minima.
(16) (a) According to: Nyerges, M.; Bendell, D.; Arany, A.;
Hibbs, D. E.; Coles, S. J.; Hursthouse, M. B.; Groundwater,
P. W.; Meth-Cohn, O. Synlett 2003, 947. (b) Selected data
for 7a,a¢. Starting from 5a (130 mg, 0.29 mmol) 44.3 mg
(50%) of (2S,3R,4R,5S)-7a were obtained as a colorless oil;
[a]D20 17.3 (c 0.2, MeOH). 1H NMR (600 MHz, C6D6): d =
7.32–7.28 (m, 2 H), 7.12–7.06 (m, 2 H), 5.71 (dd, 1 H,
J = 52.0, 3.5 Hz), 4.50 (d, 1 H, J = 7.1 Hz), 4.15 (dd, 1 H,
J = 27.9, 3.6 Hz), 3.45 and 3.40 (2 s, 6 H), 3.30 (dd, 1 H,
J = 20.5, 7.0 Hz), 2.90 (s, 1 H, NH). 13C NMR (150 MHz,
C6D6): d = 171.4 (d, J = 9.6 Hz), 170.6 (d, J = 11.5 Hz),
138.8, 128.7, 128.6, 127.1, 127.0, 117.2, 98.8 (d, J = 187.4
Hz), 67.5 (d, J = 26.2 Hz), 65.0, 64.6, 56.3 (d, J = 22.4 Hz),
52.6. 19F NMR (376 MHz, C6D6): d = –174.00 (ddd,
(13) (a) Stonehouse, J.; Adell, P.; Keeler, J.; Shaka, A. J. J. Am.
Chem. Soc. 1994, 116, 6037. (b) Stott, K.; Stonehouse, J.;
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FH = 51.0, 28.0, 20.7 Hz). MS (ESI): m/z = 306 [M+].
Starting from 5a¢ the same procedure gave (2R,3S,4S,5R)-
7a¢ in 52% yield; [a]D –17.8 (c 0.2, MeOH).
(17) (a) Singh, R. P.; Schreeve, J. M. J. Fluorine Chem. 2002,
116, 23. (b) Singh, R. P.; Schreeve, J. M. Synthesis 2002,
2561.
Synlett 2006, No. 4, 543–546 © Thieme Stuttgart · New York