Asymmetric kinugasa reaction of cyclic nitrones and nonracemic acetylenes

Article abstract of DOI:10.1021/jo900121x

Kinugasa reactions between chiral acetylenes and five-membered nitrones, achiral and bearing a stereogenic center in both enantiomeric forms, proceed in moderate to good yield with high diastereoselectivity affording mostly one dominant product. The first

Full text of DOI:10.1021/jo900121x

Asymmetric Kinugasa Reaction of Cyclic Nitrones and Nonracemic
Acetylenes
Sebastian Stecko, Adam Mames, Bartlomiej Furman, and Marek Chmielewski*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
chmiel@icho.edu.pl
ReceiVed January 19, 2009
Kinugasa reactions between chiral acetylenes and five-membered nitrones, achiral and bearing a stereogenic
center in both enantiomeric forms, proceed in moderate to good yield with high diastereoselectivity
affording mostly one dominant product. The first step of the reaction is controlled by the configuration
of the nitrone, whereas the protonation of intermediate enolate in the second step depends mainly on the
configuration of the bridgehead carbon atom formed in the first step. In the case of the mismatched pair,
the configuration at the C-6 center of the carbapenam skeleton may also be affected by the configuration
of the stereogenic center in the acetylene portion.
Introduction
imoto,4 represents a direct and simple method of the ꢀ-lactam
ring formation (Scheme 1). While the Kinugasa reaction has
shown a great potential in 2-azetidinone synthesis,5-15 there
are only a few reports detailing the related diastereo-9-11 and
enantioselective protocols.12-15
Very recently, we reported a diastereoselective version of the
Kinugasa reaction involving nonracemic cyclic nitrones, derived
from malic and tartaric acids, and simple achiral acetylenes.11
Such reactions displayed high diastereoselectivity leading to one
dominant product. On the basis of the proposed stereochemical
model of the reaction,11 it has been shown that the stereochem-
ical outcome of the Kinugasa reaction depends on the first step,
The ꢀ-lactam antibiotics represent a powerful tool against
bacterial infections. Owing to their attractive biological activity,
the synthesis and properties of mono- and polycyclic systems
containing the ꢀ-lactam ring have been extensively investigated.1
The history of ꢀ-lactams goes back to 1907 when Staudinger
discovered the imine-ketene cycloaddition.2 Unil then, a
number of methodologies for the construction of a ꢀ-lactam
ring, both in diastereo- and enantioselective fashion, were
developed.3
The copper(I)-mediated reaction between nitrones and ter-
minal acetylenes, discovered in 1972 by Kinugasa and Hash-
(4) (a) Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem. Commun. 1972,
466. (b) Marco-Contelles, J. Angew. Chem., Int. Ed. 2004, 43, 2198. (c) Pal, R.;
Ghosh, S.; Chandra, K.; Basak, A. Synlett 2007, 15, 2321.
(5) Ding, L. K.; Irwin, W. J. J. Chem. Soc., Perkin Trans. 1 1976, 2382.
(6) Basak, A.; Pal, R. Bioorg. Med. Chem. 2005, 15, 2015.
(7) Zhao, L.; Li, Ch.-J. Chem. Asian J. 2006, 1-2, 203.
(8) Basak, A.; Bahattacharya, G.; Bdour, H. M. Tetrahedron 1998, 54, 6529.
(9) Basak, A.; Gosh, S. C.; Bhowmick, T.; Das, A. K.; Bertolasi, V.
Tetrahedron Lett. 2002, 43, 5499.
(10) Zhang, X.; Hsung, R. P.; Li, H.; Zhang, Y.; Johnson, W. L.; Figueroa,
R. Org. Lett. 2008, 10, 3477.
(11) Stecko, S.; Mames, A.; Furman, B.; Chmielewski, M. J. Org. Chem.
2008, 73, 7402.
* To whom correspondence should be addressed. Phone: +48 22 631 87 88.
Fax: +48 22 632 66 81.
(1) (a) ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F., Eds.; Pergamon: New York, 1996; Chapters 1.18-1.20.
(b) Ojima, I.; Delaloge, F. Chem. ReV. Soc. 1997, 26, 377. (c) Ojima, I. Acc.
Chem. Res. 1995, 28, 383. (d) Magriotis, P. A. Angew. Chem., Int. Ed. 2001,
40, 4377. (e) Synthesis of ꢀ-Lactam Antibiotics, Chemistry, Biocatalysis and
Process Integration; Bruggink, A., Ed.; Kluwer: Dordrecht, The Netherlands,
2001. (f) Chemistry and Biology of ꢀ-Lactam Antibiotics; Morin, M.B. M.,
Gorman, M. B., Eds.; Academic Press: New York, 1982. (g) The Organic
Chemistry of ꢀ-Lactams; Georg, G. I., Ed.; Wiley VCH: New York, 1993. (h)
Brandi, A.; Cicchi, S.; Cordero, F. Chem. ReV. 2008, 108, 3988.
(12) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60,
4999.
(2) Staudinger, H. Ann. Chem. 1907, 356, 51.
(3) (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Curr. Med.
Chem. 2004, 11, 1837. (b) Deshmukh, A. R. A. S.; Bhwal, B. M.; Krishnaswamy,
D.; Govande, V. V.; Shinkre, B. A.; Jayanti, A. Curr. Med. Chem. 2004, 11,
1889. (c) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11, 1921. (d)
Alcaide, B.; Almendros, P.; Argoncillo, C. Chem. ReV. 2007, 107, 4437.
(13) (a) Lo, M.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572. (b) Shintani,
R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 4082.
(14) Ye, M.-C.; Zhou, J.; Tang, Y. J. Org. Chem. 2006, 71, 3576.
(15) Coyne, A.; Mu¨ller-Bunz, H.; Guiry, P. J. Tetrahedron: Asymmetry 2007,
18, 199.
3094 J. Org. Chem. 2009, 74, 3094–3100
10.1021/jo900121x CCC: $40.75 2009 American Chemical Society
Published on Web 03/26/2009

Asymmetric Kinugasa Reaction of Cyclic Nitrones
SCHEME 1. Postulated Mechanisms of the Kinugasa Reaction12
c
SCHEME 2
1,3-dipolar cycloaddition. The addition is controlled by the
substituent present in the nitrone, whereas the protonation of
intermediate enolate in the second step occurs from the less
shielded side of carbapenam skeleton. Consequently, the major
product displays the relative cis-orientation of protons in the
four-membered ꢀ-lactam ring.11 Good stereoselectivity of these
reactions opens an attractive entry to the carbapenam skeleton
notwithstanding the moderate yield.
Results/Discussion
The interesting preliminary results11 prompted us to further
investigate the Kinugasa reactions involving chiral, optically
pure acetylenes and five-membered ring nitrones, both nonchiral
or with a stereogenic center.
The present paper describes our studies on the asymmetric
induction observed in reactions between acetylenes 1a-e and
the achiral nitrone 2, as well as chiral nitrones in both
enantiomeric forms 3/3-ent and 4/4-ent. The results thus
obtained, together with previously reported studies,11 made
possible to propose the stereochemical pathway of the reaction
in both matched and mismatched variants.
procedure20 whereas the chiral nitrones 3/3ent and 4/4-ent were
prepared from the corresponding L- and D-malic acids, according
to the Brandi methodology.21
As shown in Scheme 2, reactions between nitrone 2 and
acetylenes 1a and 1b proceeded with excellent diastereoselec-
tivity, affording the corresponding carbapenams 5a and 5b in
moderate yield (∼50%). The relative configuration of H-5 and
H-6 protons in both products was proven using 3JH5-H6 coupling
constants and was found to be cis for both of them.22 The
absolute configuration at the newly introduced stereogenic
3
centers in 5a - 5d was assigned using JH6-H1′, by analogy to
compounds 12 and 13a, and is discussed later. The high
diastereoselectivity was observed also for reactions involving
silylated acetylenes 1c and 1d. The detected cis products 5c
and 5d were unstable, however, and decomposed during
isolation and purification steps. Their structure and configuration
were based only on MS and selective NMR data recorded for
crude compounds and the assignment was made by analogy to
5a and 5b. In the case of acetylene 1e, the target carbapenam
5e was even less stable and only traces of product were detected
in the reaction mixture (mass spectrometry analysis) albeit
The acetylene 1a was prepared from D-glyceraldehyde16 by
treatment with the Bestmann-Ohira reagent.17 The acetylenes
1b-d were obtained starting from the commercially available
(S)-3-butyn-2-ol and (R)-1-phenyl-2-propyn-1-ol, using standard
silylation or benzylation protocols.18 The compound 1e was
obtained from Garner’s aldehyde following the procedure
described for the acetylene 1a.19 The nonchiral nitrone 2 was
synthesized from 1,4-dibromobutane following the literature
(20) Cordero, F.; Machetti, F.; De Sarlo, F.; Brandi, A. Gazz. Chim. Ital.
2007, 127, 25.
(21) Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60, 4743. (b) Cicchi,
S.; Hold, I.; Brandi, A. J. Org. Chem. 1993, 58, 5274.
(22) (a) Effenberger, F.; Fischer, P.; Prossel, G.; Kiefer, G. Chem. Ber. 1971,
104, 1987. (b) Effenberger, F.; Fischer, P.; Prossel, G. Chem. Ber. 1971, 104,
2002.
(16) Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6.
(17) (a) Pietruszka, J.; Witt, A. Synthesis 2006, 24, 4266. (b) Mu¨ller, S.;
Liepold, B.; Roth, G. J.; Bestman, H. J. Synlett 1996, 521.
(18) (S)-3-Butyn-2-ol and (R)-1-phenyl-2-propyn-1-ol do not react in the
Kinugasa reaction at all.
(23) The range of 3JH5-H6 coupling constant values for cis-ꢀ-lactams is 5.0-
6.5 Hz, whereas for trans-ꢀ-lactams it amounts to 2-2.5 Hz.
(19) Garner, Ph.; Park, J. M. Org. Synth. 1992, 70, 18.
J. Org. Chem. Vol. 74, No. 8, 2009 3095

Stecko et al.
complete consumption of the acetylene was observed during
the reaction. The low stability of the adducts was probably
caused by the ꢀ-elimination process followed by further
decomposition of the molecule.22
between 3 and 1a leading to 12 proceeded with the remarkably
high yield, exceeding 90%.
Comparison of the NMR spectral data of compounds 12 and
13a allowed, by analogy, to assign the absolute configuration
to all products obtained (5-15). It has been shown previously11
that owing to the influence of the tert-butoxy group, the
dominant product of addition to the nitrone 3 has syn location
of the H-4 and H-5 protons. Bearing in mind coupling constants
within the ꢀ-lactam skeleton (0-2 Hz for anti and 4-6 Hz for
syn); consequently, it is straightforward to assign the absolute
configuration at the C-6 carbon atom, as well. These assignments
were independently supported by the NOEs taken for both
compounds (see the Supporting Information), which for 12 show
a spin-spin interaction between H-4 and H-1′ protons whereas
such interactions were not observed between H-4-H-5 and
H-6-H-1′. For compound 13a, protons H-6 and H-1′ shows
spin-spin interaction, whereas such interactions were not
observed between H-4 proton and H-5, and H-1′. Carbapenam
12 (6S,1′S) is characterized by 3JH6-H1′ ) 10.1 Hz whereas 13a
(6R,1′S) having alternative relation of both protons by 3JH6-H1′
) 2 Hz, similarly 8a shows 3JH6-H1′ ) 4.7 Hz, whereas 9 shows
3JH6-H1′ ) 8.5 Hz. Consequently, on the basis of the large
coupling constants 3JH6-H1′ (10.3, 10.0, 9.4, and 8.0 Hz for 5a,
5b, 5c, and 5d, respectively), we were able to assign theirs
configurations at C-5 and C-6 carbon atoms.
As already mentioned, both reactions presented in Scheme 2
afforded the products in moderate yields. It should be underlined
that relatively low yield is a characteristic feature of the
Kinugasa reaction due to a dual character of copper acetylide
which may react either as dipolarophile or as nucleophile.12 For
this reason, the addition of organocopper compound to the imine
can also occur as a side reaction.12 Moreover, additional side
processes such as the Cu(I)-mediated deoxygenation of the
nitrone24 or Glasser coupling25 are also possible. In investigated
cases, the low yield may also be caused by the known low
stability of the nitrone 2.26 Previously, we have reported that
addition of hydrazine increased the reaction yield.11 This works,
however, for phenylacetylene only, while other acetylenes,
particularly those with protected oxygen or nitrogen functions,
do not show such effect.
The outcome of the reactions, in case where both reactants
(acetylene and nitrone) are chiral, can be explained on the basis
of the previous observations. The most important one is that
the first 1,3-dipolar cycloaddition step involving nitrone 3/3-
ent proceeds exclusively anti to the tert-butoxy group. The
reaction of 1c with the nitrone 3 led to two carbapenams 6a
and 6b in a 9:1 ratio, respectively, whereas nitrones’ enantio-
meric form (3-ent) afforded solely the cis isomer 7 (Table 1).
In contrast to the reactions described earlier, the products derived
from 1c, as well as 1d, do not decompose during isolation and
purification steps. The high stereoselectivity was obtained in
the case of pair 3-ent/1b, whereas two products 8a and 8b in a
4:1 ratio were isolated from the postreaction mixture between
nitrone 3 and acetylene 1b. Similarly to pairs 1c/3-ent and 1b/
3-ent, the reaction of 3-ent with 1d yielded product 11,
exclusively. The analogous reaction involving the nitrone 3
afforded a mixture of two ꢀ-lactams 10a and 10b. The
stereochemical outcome of this reaction is similar to the reaction
of 3 with acetylene 1b and 1c (formation of 10a and 10b).
According to these results, all reactions of acetylenes 1b-d with
3-ent represent the matched pairs of reactants, whereas those
involving the nitrone 3 and the same acetylenes are mismatched
pairs.
Finally, reactions involving acetylene 1a and nitrones 4 and
4-ent were performed. The reaction of matched pair (1a/4)
afforded compound 14, whereas in the case of the mismatched
pair (1a/4-ent) two products 15a and 15b were isolated.
Configuration assignments for 14 and 15a,b were made by
analogy to 12 and 13a. The results of this reaction indicate that
in this case, the tert-butoxy group influences also the direction
of asymmetric induction, although the stereogenic center of the
nitrone is moved away from the reaction center. The previously
studied reaction of the nitrone 4 with phenylacetylene led to a
mixture of two cis products in ca. 3:1 ratio.11
Similarly to the reaction involving Garner’s acetylene 1e and
the nitrone 2, which led to decomposition products, the reactions
of the same acetylene 1e with nitrones 3 and 3-ent did not
provide expected adducts either; we were unable to detect any
defined product.
Currently, there is no reasonable explanation for the signifi-
cant enhancement of the yield recorded in the case of reaction
between 1a and 3. We assigned this phenomenon to coordination
of the copper atom at the isoxazoline or/and enolate step by
the oxygen atoms of the 1,3-dioxolane moiety. Such extra
stabilization may accelerate the rate of the Kinugasa reaction
with respect to the other possible side reactions and consequently
causes formation of the desired carbapenam in very high yield
(in 80% after 2 h and over 90% after 24 h).
Due to the inverse absolute configuration at the stereogenic
center next to the triple bond in acetylene 1a (derived from
D-glyceraldehyde) in comparison with 1b-d, the opposite
stereochemical preferences were noticed for the reactions with
nitrones 3 and 3-ent. In the case of the former, a single product
12 was obtained, whereas the latter afforded the mixture of 13a
and 13b in a 92:8 ratio. The overlapping of diagnostic signals
in NMR spectra of the minor product 13b did not allow for the
assignment of configuration at C-5 and C-6 atoms, it was
assigned by analogy to other cases. It should be underlined that
in contrast to other currently investigated cases, the reaction
Very recently, we pointed out that the stereochemical course
of the Kinugasa reaction between nonracemic nitrones 3, 4, and
achiral acetylenes,11 depends on the initial cycloaddition step.
As it is shown in Figure 1, the cycloaddition of the acetylene
from the si side of the nitrone (anti approach with respect to
t-BuO substituent) is more favorable due to steric hindrance of
the nitrones’ re side. The subsequent generation of stereogenic
center at C-6 depends on the configuration at previously created
bridgehead carbon atom (C-5) and proceeds through a proton-
ation of the intermediate enolate (afforded after rearrangement
of the isoxazoline) from its convex or concave side. Experi-
mental observations revealed high preference of convex-side
(24) Singh, S. K.; Reddy, M. S.; Mangle, M.; Ganesh, K. R. Tetrahedron
2007, 63, 126.
(25) Siemsen, O.; Livingstone, R. C.; Diederich, F. Angew. Chem., Int. Ed.
2000, 39, 2632.
(26) (a) Torssell, K. B., Nitrile Oxide, Nitrones and Nitronates in Organic
Chemistry; VCH Publishers, Inc.: New York, 1998. (b) Grigor’ev, I. A. In Nitrile
Oxide, Nitrones and Nitronates in Organic Synthesis: NoVel Strategies in
Synthesis, 2nd ed.; Feuer, H., Ed.; John Wiley & Sons: New York, 2008. (c)
Merino, P. In Science of Synthesis; Padwa, A., Ed.; George Thieme: New York,
2004; Vol. 27, p 511.
3096 J. Org. Chem. Vol. 74, No. 8, 2009

Asymmetric Kinugasa Reaction of Cyclic Nitrones
TABLE 1. Double-Asymmetric Induction in Kinugasa Reaction of Nitrones 3/3-ent and 4/4-ent with Acetylenes 1a-ea
a Standard conditions: acetylene (0.5 mmol), CuI (0.5 mmol), Et3N (2 mmol), and nitrone (1 mmol) in MeCN at rt. b All are isolated yields. c The dr
was determined by using 1H NMR or/and HPLC. d After 2 h. e Configuration of 13b was not assigned due to the overlap of diagnostic signals. f Only
traces of product was detected by mass spectrometry.
J. Org. Chem. Vol. 74, No. 8, 2009 3097

Stecko et al.
transposed from C-3 to C-4 (compare Table 1, entries 8 and
10). In this case, however, the anti approach product is also
the major one.
Based on assignments of the configuration at C-5 and C-6
carbon atoms of carbapenams 5a and 5b, as well as other
afforded carbapenams, it can be concluded that the stereochem-
ical outcome of the final protonation step of the intermediate
enolate (Scheme 1) is controlled to the great degree by the
configuration at C-5. Certainly, the influence of the side-chain
stereogenic center cannot be excluded entirely, and its minor
effect can be considered through the Felkin-Ahn model (Figure
2c). Two possible conformations of the side chain in the
intermediate enolate are depicted in Figure 2c. For the lowest
energy conformer A, both convex and concave approaches
should be disfavored, the former one due to steric repulsion of
the large group L (i.e., for 1b, L ) OBn; for 1c, L ) OSiPh2-
t-Bu) and the latter one (Felkin-Ahn approach) due to hindrance
of the fused five-membered ring. In the case of higher energy
conformer B (2 kcal/mol),27 the steric repulsion at the convex
side are minimized, and it can be assumed that a protonation
proceeds from this side (anti-Felkin-Ahn approach), as can be
seen from our experimental results. Such an approach, leading
to 5,6-cis product, predominates, and the formation of 5,6-trans
cabrapenams (minor products) was noticed only in cases of
mismatch pairs (Table 1, entries 3 and 5).
FIGURE 1. Stereochemical outcome of the Kinugasa reaction.
protonation (leading to 5,6-cis products) what can be easily
explained by steric factors.
Inspection of the data collected in Scheme 2 and Table 1
indicates that the stereochemical outcome of Kinugasa reaction
of nonracemic acetylenes 1a-d with nonchiral nitrone 2 is
controlled by the initial cycloaddition step. Parts a and b of
Figure 2 demonstrate this influence of the acetylenes’ chiral
center on the asymmetric induction. Three distinct trajectories
of the approach of the nitrone 2 to acetylide are possible.
Following the observed configuration at the C-5 and C-6 atoms
for compounds 5a-d, as well as for other compounds discussed,
the attack of the nitrone from the bottom side of the acetylene
is preferred to that from the top, due to the lower degree of
steric repulsion between the nitrone and a medium substitutent
(Figure 2a). It can be assumed that the alternative back-side
approach (Figure 2b) is also less favorable. The replacement of
the achiral nitrone 2 by its chiral analogue 3 or 3-ent eliminates
the asymmetric inductive effect of the acetylene stereogenic
center completely, and products of anti approach with respect
to the t-BuO group are observed exclusively. Its influence
decreases slightly when the t-BuO group at the nitrone is
Conclusions
We have shown that the diastereoselective Kinugasa reaction
involving five-membered nitrones, except the unstable nonsub-
stituted nitrone, and simple chiral acetylenes provides an
interesting entry to carbapenams. The reactions displayed high
diastereoselectivity affording mostly one dominant product and
usually proceeded in a moderate yield. In certain cases, however,
FIGURE 2. Stereochemical models of Kinugasa reaction involving nonchiral nitrone 2 and chiral acetylenes.
3098 J. Org. Chem. Vol. 74, No. 8, 2009

Asymmetric Kinugasa Reaction of Cyclic Nitrones
1
-37.9 (c 0.34, CH2Cl2); H NMR (500 MHz, C6D6) δ 8.10-7.20
particularly for the matched pairs, the observed yield was high.
Based on the proposed mechanism, it is possible to explain the
stereochemical pathway of the reaction and to predict the
geometry of synthesized products. The 1,3-dipolar cycloaddition
step is controlled first of all by the configuration of the nitrone.
The geometry of the acetylene controls the configuration only
in the case of reaction with achiral nitrone. The protonation of
intermediate enolate in the second step depends for the most
part on the configuration of the bridgehead carbon atom formed
in the first step. In the case of the mismatched pair, the
configuration at the C-6 atom of the carbapenam skeleton may
also be affected by the geometry of the acetylene portion, and
this influence can be explained by the Felkin-Anh model.
Consequently, the major product exhibits the relative cis
orientation of protons in the four-membered ꢀ-lactam ring.
(10H, m), 4.16 (1H, dq, J 8.4, 6.1 Hz), 3.82 (1H, m), 3.48 (1H,
ddd, J 11.4, 7.8, 5.8 Hz), 3.38 (dd, J 5.8, 4.2 Hz), 3.28 (1H, dd, J
8.4, 5.8 Hz), 2.72 (1H, m), 1.70 (1H, m), 1.51 (1H, m), 1.27 (9H,
s), 1.07 (3H, d, J 6.1 Hz), 0.90 (9H, s); 13C NMR (125 MHz, C6D6,
without Ph carbon atoms) δ 177.4, 73.7, 71.4, 67.3, 61.6, 58.9,
44.2, 38.6, 28.5, 27.3, 23.6, 19.5; IR (film) 1761 cm-1; HR MS
(ESI) calcd for C28H39NO3NaSi [M + Na+] 488.2591, found
488.2590; HPLC hexane/2-propanol 95:5, flow 1 mL/min, tR 4.0
min. Anal. Calcd for C28H39NO3Si: C, 72.21; H, 8.44; N, 3.01.
Found: C, 72.29; H, 8.43; N, 3.00.
(4S,5R,6R,1′S)-4-tert-Butoxy-6-(1′-tert-butyldiphenylsilyloxy)-
ethyl-1-azabicyclo[3.2.0]heptan-7-one (6b): colorless oil; [R]D
-23.8 (c 1.1, CH2Cl2); 1H NMR (500 MHz, C6D6, without protons
of Ph group) δ 4.40 (1H, d, J 12.0 Hz), 4.26 (1H, dd, J 12.0 Hz),
3.67 (1H, dq, J 7.4, 6.2 Hz), 3.56-3.49 (2H, m), 3.43 (1H, ddd, J
14.0, 7.6, 6.5 Hz), 2.75 (1H, dd, J 7.4, 2.3 Hz), 2.79 (1H, ddd, J
14.0, 7.6, 6.5 Hz), 1.73-1.63 (2H, m), 1.23 (3H, d, J 6.2 Hz, Me),
0.99 (9H, s), 0.87 (9H, s); 13C NMR (125 MHz, C6D6, without Ph
carbon atoms) δ 176.1, 74.5, 73.5, 73.4, 70.7, 62.1, 62.1, 44.5, 38.3,
28.5, 28.0, 18.7; IR (film) 1767 cm-1; HR MS (ESI) calcd for
C19H27NO3Na [M + Na+] 488.2591, found 488.2588; HPLC
hexane/2-propanol 95/5, flow 1 mL/min, tR 6.1 min. Anal. Calcd
for C28H39NO3Si: C, 72.21; H, 8.44; N, 3.01. Found: C, 72.18; H,
8.42; N, 3.00.
Experimental Procedures
Reaction of Nitrones with Acetylenes. General Procedure. To
a suspension of CuI (0.5 mmol, 95 mg) in dry, degassed MeCN (3
mL) was added 280 µL (2.0 mmol) of triethylamine. After the
mixture was cooled to 0 °C, a solution of acetylene (0.5 mmol) in
1 mL of MeCN was added, and the obtained mixture was stirred
for 15 min. Then a solution of nitrone (1 mmol) in MeCN (1-2
mL) was added slowly, and the mixture was kept at 0 °C for an
additional 15 min. After that time, the cooling bath was removed,
and the reaction mixture was stirred at room temperature under
nitrogen atmosphere. The progress of the reaction was monitored
by TLC. Subsequently, the solvent was removed under diminished
pressure, and the residue was purified by column chromatography
on silica gel or Florisil. The diastereoisomeric ratio (Table 1) was
(4R,5S,6R,1′S)-4-tert-Butoxy-6-(1′-tert-butyldiphenylsilyloxy)-
ethyl-1-azabicyclo[3.2.0]heptan-7-one (7): colorless oil; [R]D
1
+65.0 (c 2.2, CH2Cl2); H NMR (500 MHz, C6D6) δ 8.10-7.20
(10H, m), 4.93 (1H, m), 4.45 (1H, dq, J 4.1, 6.5 Hz), 3.83 (1H,
ddd, J 11.5, 8.0, 3.2 Hz), 3.76 (1H, dd, J 6.0, 2.5 Hz), 3.13 (1H,
dd, J 6.0, 4.1 Hz), 2.95 (1H, ddd, J 11.5, 9.3, 6.7 Hz), 2.70 (1H,
m), 1.78 (1H, m), 1.28 (9H, s), 1.24 (9H, s), 1.05 (3H, d, J 6.5
Hz); 13C NMR (125 MHz, C6D6) δ 177.6, 73.6, 71.3, 67.4, 64.0,
1
59.6, 45.2, 39.8, 28.9, 27.4, 26.7, 21.9, 19.5; IR (film) 1767 cm-1
;
assigned by HPLC or H NMR.
HR MS (ESI) calcd for C28H39NO3SiNa [M + Na+] 488.2591,
found 488.2575; HPLC hexane/2-propanol 95/5, flow 1 mL/min,
tR 4.3 min. Anal. Calcd for C28H39NO3Si: C, 72.21; H, 8.44; N,
3.01. Found: C, 72.19; H, 8.48; N, 2.99.
(5S,6S,4′S)-6-(2′,2′-Dimethyl-1′,3′-dioxolan-4′-yl)-1-azabicyclo-
[3.2.0]heptan-7-one (5a): colorless oil; [R]D -146.5 (c 0.87,
1
CH2Cl2); H NMR (500 MHz, C6D6) δ 4.12 (1H, dd, J 8.4, 6.0
Hz), 3.97 (1H, ddd, J 10.3, 6.0, 6.0 Hz), 3.87 (1H, dd, J 8.4, 6.0
Hz), 3.33 (1H, m, H-5), 3.13 (1H, dd, J 10.3, 5.2 Hz), 2.35 (1H,
m), 1.50-1.38 (3H, m), 1.34-1.27 (4H, m), 1.23 (3H, s); 13C NMR
(125 MHz, C6D6) δ 176.1, 109.0, 71.6, 68.6, 55.3, 54.7, 45.7, 29.7,
27.1, 25.7, 25.6; IR (film) 1749 cm-1; HR MS (ESI) calcd for
C11H17NO3Na [M + Na+] 234.1101, found 234.1097. Anal. Calcd
for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.50; H,
8.09; N, 6.61.
(4S,5R,6S,1′S)-6-(1′-Benzyloxy)ethyl-4-tert-butoxy-1-azabicyclo-
[3.2.0]heptan-7-one (8a): colorless oil; [R]D +13.3 (c 1.6, CH2Cl2);
1H NMR (500 MHz, C6D6) δ 7.6-7.20 (5H, Ph), 4.41 (1H, d, J
11.8 Hz), 4.23 (1H, d, J 11.8 Hz), 4.10 (1H, m), 3.58 (1H, ddd,
J 11.0, 8.1, 3.7 Hz), 3.53 (1H, dq, J 6.3, 4.7 Hz), 3.47 (1H, dd,
J 6.0, 2.9 Hz), 3.13 (1H, dd, J 6.0, 4.7 Hz), 2.75 (1H, m), 1.92
(1H, m), 1.50 (1H, m), 1.23 (3H, d, J 6.3 Hz), 1.00 (9H, s); 13C
NMR (125 MHz, C6D6) δ 176.9, 71.9, 71.1, 70.7, 63.3, 57.6,
45.0, 39.1, 28.5, 28.0, 18.5; IR (film) 1764 cm-1; HR MS (ESI)
calcd for C19H27NO3Na [M + Na+] 340.1883, found 340.1868;
HPLC hexane/2-propanol 95/5, flow 1 mL/min, tR 8.0 min. Anal.
Calcd for C19H27NO3: C, 71.89; H, 8.57; N, 4.41. Found: C,
71.92; H, 8.59; N, 4.39.
(5R,6R,1′S)-6-(1′-Benzyloxy)ethyl-1-azabicyclo[3.2.0]heptan-
7-one (5b): colorless oil; [R]D +200.0 (c 0.94, CH2Cl2); 1H NMR
(500 MHz, C6D6) δ 7.40-7.10 (5H, Ph), 4.34 (1H, d, J 11.6 Hz),
4.07 (1H, d, J 11.6 Hz), 3.50 (1H, dq, J 10.0, 6.0 Hz), 3.37-3.29
(2H, m), 3.18 (1H, dd, J 10.0, 5.3 Hz), 2.43 (1H, m), 1.53-1.23
(7H, m); 13C NMR (125 MHz, C6D6, without Ph carbon atoms) δ
177.0, 71.1, 70.2, 56.9, 56.2, 45.2, 29.7, 26.1, 18.2; IR (film) 1761
cm-1; HR MS (ESI) calcd for [M + Na+] C15H19NO2Na 268.1313,
found 268.1310. Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81;
N, 5.71. Found: C, 73.40; H, 7.80; N, 5.69.
(5R,6R,1′S)-6-(1′-tert-Butyldiphenylsilyloxy)ethyl-1-azabicyclo-
[3.2.0]heptan-7-one (5c): 1H NMR (500 MHz, C6D6) selected signals
from spectra of crude product δ 4.04 (1H, dq, J 9.4, 6.1 Hz), 3.18
(1H, dd, J 9.4, 5.1 Hz), 1.34 (3H, d, J 6.1 Hz); IR (film) 1758
cm-1; HR MS (ESI) m/z calcd for [M + Na+] C24H31NO2SiNa
416.2016, found 416.2023.
(4S,5S,6S,1′S)-6-(1′-Benzyloxy)ethyl-4-tert-butoxy-1-azabicyclo-
[3.2.0]heptan-7-one (8b): colorless oil; [R]D -66.5 (c 0.35, CH2Cl2);
1H NMR (500 MHz, C6D6) δ 7.50-7.00 (5H, Ph), 3.67 (1H, dq, J
7.4, 6.2 Hz), 3.53 (1H, m) 3.49 (1H, dd, J 4.2, 2.5 Hz), 3.44 (1H,
ddd, J 14.0, 7.6, 6.5 Hz), 2.75 (1H, dd, J 7.4, 2.5 Hz), 2.70 (1H,
ddd, J 14.0, 7.6, 6.5 Hz), 1.73-1.60 (2H, m), 1.23 (3H, d, J 6.2
Hz), 0.99 (9H, s); 13C NMR (125 MHz, C6D6) δ 176.1, 74.5, 73.5,
73.4, 70.7, 62.1, 62.1, 44.5, 38.3, 28.4, 18.8; IR (film) 1760 cm-1
;
HR MS (ESI) calcd for C19H27NO3Na [M + Na+] 340.1883, found
340.1897; HPLC hexane/i-propanol 95/5, flow 1 mL/min, tR 9.2
min. Anal. Calcd for C19H27NO3: C, 71.89; H, 8.57; N, 4.41. Found:
C, 71.87; H, 8.55; N, 4.45.
(5R,6R,1′S)-6(1′-tert-Butyldiphenylsilyloxy)benzyl-1-azabicyclo-
[3.2.0]heptan-7-one (5d): 1H NMR (500 MHz, C6D6) selected
signals from spectra of crude product δ 5.01 (1H, d, J 8.0 Hz),
3.60 (1H, dd, J 8.0, 5.2 Hz); IR (film) 1760 cm-1; HR MS (ESI)
m/z calcd for [M + Na+] C29H33NO2SiNa 478.2173, found
478.2192.
(4R,5S,6R,1′S)-6-(1′-Benzyloxy)ethyl-4-tert-butoxy-1-azabicyclo-
[3.2.0]heptan-7-one (9): colorless oil; [R]D +124.5 (c 2.5, CH2Cl2);
(27) The conformational analysis was carried out with the MM+ force field,
and the obtained geometries were reoptimized by using DFT calculations at the
B3LYP/6-31+G(d) theory level.
(4S,5R,6S,1′S)-4-tert-Butoxy-6-(1′-tert-butyldiphenylsilyloxy)-
ethyl-1-azabicyclo[3.2.0]heptan-7-one (6a): colorless oil; [R]D
J. Org. Chem. Vol. 74, No. 8, 2009 3099

Stecko et al.
1H NMR (500 MHz, C6D6) δ 7.30-7.00 (5H, Ph), 4.32 (1H, d, J
11.4 Hz), 4.23 (1H, m), 4.08 (1H, d, J 11.4 Hz), 3.67-3.60 (2H,
H-2a), 3.50 (1H, dq, J 8.5, 6.1 Hz), 3.21 (1H, dd, J 8.5, 5.9 Hz),
2.79 (1H, m), 1.69 (1H, m), 1.57 (1H, m), 1.22 (3H, d, J 6.1 Hz),
0.99 (9H, s); 13C NMR (125 MHz, C6D6, without Ph carbon atoms)
δ 178.1, 73.8, 71.7, 71.0, 70.2, 64.3, 58.2, 45.7, 39.5, 28.4, 18.2;
IR (film) 17601 cm-1; HR MS (ESI) calcd for C19H27NO3Na [M
+ Na+] 340.1883, found 340.1882; HPLC hexane/2-propanol 95/
5, flow 1 mL/min, tR 5.5 min. Anal. Calcd for C19H27NO3: C, 71.89;
H, 8.57; N, 4.41. Found: C, 71.87; H, 8.56; N, 4.40.
(4R,5S,6R,4′S)-4-tert-Butoxy-6-(2′,2′-dimethyl-1′,3′-dioxolan-
4′-yl)-1-azabicyclo[3.2.0]heptan-7-one (13a): colorless oil; [R]D
1
+8.3 (c 1.40, CH2Cl2); H NMR (500 MHz, C6D6) δ 4.52 (1H,
m), 4.08 (1H, dd, J 9.8, 7.8 Hz), 3.96 (1H, ddd, J 9.8, 5.8, 2.0 Hz),
3.64 (1H, dd, J 7.8, 5.8 Hz), 3.54 (1H, ddd, J 14.2, 8.1, 5.3 Hz),
3.44 (1H, dd, J 5.6, 3.9 Hz), 2.84 (1H, dd, J 5.6, 2.0 Hz), 2.76
(1H, m), 2.09 (1H, m), 1.67 (1H, m), 1.49 (3H, s), 1.32 (3H, s),
1.10 (9H, s); 13C NMR (125 MHz, C6D6) δ 175.4, 110.3, 73.6,
72.7, 71.2, 67.8, 62.7, 51.8, 44.6, 38.9. 28.5, 26.9, 26.2; IR (film)
1766 cm-1; HR MS (ESI) calcd for C15H25NO4Na [M + Na+]
306.1676, found 306.1683. Anal. Calcd for C15H25NO4: C, 63.58;
H, 8.89; N, 4.94. Found: C, 63.56; H, 8.90; N, 4.93.
(4S,5R,6S,1′R)-4-tert-Butoxy-6-(1′-tert-butyldiphenylsilyloxy)-
benzyl-1-azabicyclo[3.2.0]heptan-7-one (10a): colorless oil; [R]D
1
(3R,5S,6S,4′S)-4-tert-Butoxy-6-(2′,2′-dimethyl-1′,3′-dioxolan-
-15.7 (c 3.6, CH2Cl2); H NMR (500 MHz, C6D6) δ 8.10-7.20
4′-yl)-1-azabicyclo[3.2.0]heptan-7-one (14): colorless oil; [R]D
(15H, m), 4.73 (1H, d, J 10.4 Hz), 4.07 (1H, dd, J 10.4 Hz, 6.5
Hz), 3.71 (1H, br dd, J 11.6, 7.1 Hz), 3.59 (1H, br d, J 5.4 Hz),
3.39 (1H, d, J 6.5 Hz), 2.75 (1H, ddd, J 11.6, 11.4, 5.3 Hz),
1.34-1.26 (2H, m), 1.24 (9H, s), 1.09 (9H, s); 13C NMR (125 MHz,
C6D6, without Ph carbon atoms) δ 179.4, 73.6, 72.7, 70.4, 63.4,
58.5, 45.9, 38.9, 27.8, 27.3, 19.7. 19.2; IR (film) 1758 cm-1; HR
MS (ESI) calcd for C33H41NO3NaSi [M + Na+] 550.2753, found
550.2751; HPLC hexane/2-propanol 98/2, flow 1 mL/min, tR 5.9
min. Anal. Calcd for C33H41NO3Si: C, 75.10; H, 7.83; N, 2.65.
Found: C, 75.07; H, 7.84; N, 2.63.
1
-123.2 (c 0.6, CH2Cl2); H NMR (500 MHz, C6D6) δ 4.11 (1H,
dd, J 8.2, 6.0 Hz), 4.06 (1H, ddd, J 10.0, 6.0, 5.9 Hz), 3.99 (1H,
m), 3.82 (1H, d, J 8.2, 5.9 Hz), 3.76 (1H, m), 3.65 (1H, d, J 11.8,
5.8 Hz), 3.15 (1H, dd, J 10.0, 5.3 Hz), 2.60 (1H, dd, J 11.8, 3.6
Hz), 1.74-1.69 (2H, m), 1.30 (3H, s), 1.24 (3H, s), 0.91 (9H, s);
13C NMR (125 MHz, C6D6) δ 175.6, 109.1, 75.8, 73.5, 71.9, 68.6,
55.1, 54.4, 53.83, 35.1, 28.1, 27.1, 25.7; IR (film) 1758 cm-1; HR
MS (ESI) calcd for C15H25NO4Na [M + Na+] 306.1676, found
306.1661. Anal. Calcd for C15H25NO4: C, 63.58; H, 8.89; N, 4.94.
Found: C, 63.54; H, 8.86; N, 4.90.
(4S,5R,6R,1′R)-4-tert-Butoxy-6-(1′-tert-butyldiphenylsilyloxy)-
benzyl-1-azabicyclo[3.2.0]heptan-7-one (10b). The sample con-
tained inseparable impurities (purity ∼90% according to HPLC):
(3S,5S,6S,4′S)-4-tert-Butoxy-6-(2′,2′-dimethyl-1′,3′-dioxolan-
4′-yl)-1-azabicyclo[3.2.0]heptan-7-one (15a): colorless oil; [R]D
1
-103.6 (c 0.38, CH2Cl2); H NMR (500 MHz, C6D6) δ 4.61 (1H,
1
colorless oil; H NMR (500 MHz, C6D6, without protons of Ph
ddd, J 10.0, 8.5, 7.7 Hz), 4.22 (1H, dd, J 7.7, 6.1 Hz), 3.99 (1H,
dd, J 8.5, 6.1 Hz), 3.74 (1H, dddd, J 5.6, 4.7, 4.4, 2.8 Hz), 3.52
(1H, dd, J 12.0, 2.8 Hz), 3.45 (1H, dt, J 8.0, 5.3 Hz), 3.32 (1H, dd,
J 10.0, 5.3 Hz), 2.45 (1H, dd, J 12.0, 4.7 Hz), 1.87 (1H, ddd, J
14.1, 5.3, 4.4 Hz), 1.64 (1H, ddd, J 14.1, 8.0, 5.6 Hz), 1.40 (3H,
s), 1.27 (3H, s), 0.91 (9H, s); 13C NMR (125 MHz, C6D6) δ 176.2,
108.7, 75.7, 73.7, 72.2, 68.6, 57.4, 54.7, 54.2, 34.7, 28.1, 27.2, 25.8;
IR (film) 1760 cm-1; HR MS (ESI) calcd for. C15H25NO4Na [M +
Na+] 306.1676, found 306.1677. Anal. Calcd for C15H25NO4: C,
63.58; H, 8.89; N, 4.94. Found: C, 63.55; H, 8.87; N, 4.95.
(3S,5R,6R,4′S)-4-tert-Butoxy-6-(2′,2′-dimethyl-1′,3′-dioxolan-
4′-yl)-1-azabicyclo[3.2.0]heptan-7-one (15b): colorless oil; [R]D
groups) δ 7.05 (1H, br s), 6.88 (1H, d, J 1.5 Hz), 4.39 (1H, dd, J
3.6, 1.5 Hz), 3.76 (1H, m), 3.62 (1H, ddd, J 11.6, 7.3, 4.9 Hz),
2.90 (1H, m) 1.64-1.52 (2H, m), 1.26 (9H, s), 0.92 (9H, s); IR
(film) 1745 cm-1; HR MS (ESI) calcd for C28H39NO3NaSi [M +
Na+] 488.2591, found 488.2611; HPLC hexane/2-propanol 95/5,
flow 1 mL/min, tR 4.8 min.
(4R,5S,6R,1′R)-4-tert-Butoxy-6-(tert-butyldiphenylsilyloxy)-
benzyl-1-azabicyclo[3.2.0]heptan-7-one (11): colorless oil; [R]D
+344.1 (c 0.25, CH2Cl2); 1H NMR (500 MHz, C6D6) δ 8.00-6.80
(15H, m), 5.37 (1H, d, J 3.3 Hz), 4.98 (1H, m), 3.76 (1H, ddd, J
11.5, 7.9, 3.2 Hz), 3.65 (1H, dd, J 6.1, 2.4 Hz), 3.48 (1H, dd, J
6.1, 3.3 Hz), 2.86 (1H, ddd, J 11.5, 9.2, 6.5 Hz), 2.15 (1H, m),
1.73 (1H, m), 1.19 (9H, s), 1.08 (9H, s); 13C NMR (125 MHz,
C6D6, without Ph carbon atoms) δ 177.6, 74.0, 73.8, 71.5, 64.7,
59.7, 45.3, 39.8, 28.9, 27.4, 19.7; IR (film) 1759 cm-1; HR MS
(ESI) calcd for C33H41NO3NaSi [M + Na+] 550.2748, found
550.2730; HPLC hexane/2-propanol 95/5, flow 1 mL/min, tR 6.3
min. Anal. Calcd for C33H41NO3Si: C, 75.10; H, 7.83; N, 2.65.
Found: C, 75.05; H, 7.80; N, 2.67.
(4S,5R,6S,4′S)-4-tert-Butoxy-6-(2′,2′-dimethyl-1′,3′-dioxolan-
4′-yl)-1-azabicyclo[3.2.0]heptan-7-one (12): colorless oil; [R]D
-77.5 (c 0.78, CH2Cl2); 1H NMR (500 MHz, C6D6) δ 4.15 (1H,
ddd, J 6.3, 2.7, 2.2 Hz), 4.04 (1H, dd, J 8.5, 6.0 Hz), 3.88 (1H,
ddd, J 10.1, 6.0, 5.8 Hz), 3.77 (1H, dd, J 8.5, 6.0 Hz), 3.60
(1H, dd, J 5.7, 2.2 Hz), 3.54 (1H, ddd, J 11.8, 7.5, 3.1 Hz),
3.16 (1H, dd, J 10.1, 5.7 Hz), 2.75 (1H, ddd, J 11.6, 9.84, 6.9
Hz), 1.70-1.58 (2H, m), 1.28 (3H, s), 1.19 (3H, s), 1.11 (9H,
s); 13C NMR (125 MHz, C6D6) δ 176.4, 109.1, 74.0, 71.8, 70.7,
68.7, 63.1, 55.5, 45.6, 39.5, 28.3, 27.0, 25.5; IR (film) 1763
cm-1; HR MS (ESI) calcd for C15H25NO4Na [M + Na+]
306.1676, found 306.1681; HPLC hexane/2-propanol 95/5, flow
1 mL/min, tR 16 min. Anal. Calcd for C15H25NO4: C, 63.58; H,
8.89; N, 4.94. Found: C, 63.56; H, 8.88; N, 4.93.
1
+20.2 (c 1.5, CH2Cl2); H NMR (500 MHz, C6D6) δ 4.30 (1H,
dq, J 7.2, 6.2 Hz), 4.01 (1H, dd, J 9.3, 7.8 Hz), 3.84 (1H, dd, J
11.7, 6.3 Hz), 3.70 (1H, ddd, J 9.3, 5.9, 2.2 Hz), 3.60 (1H, dd,
J 7.8, 5.9 Hz), 3.44 (1H, ddd, J 8.2, 5.8, 4.7 Hz), 2.76 (1H, dd,
J 5.8, 2.2 Hz), 2.61 (1H, dd, J 11.7, 6.2 Hz), 2.23 (1H, ddd, J
14.3, 7.2, 4.7 Hz), 1.58 (1H, ddd, J 14.3, 8.2, 6.2 Hz), 1.51
(3H, s), 1.33 (3H, s), 1.03 (9H, s); 13C NMR (125 MHz, C6D6)
δ 175.9, 110.2, 74.6, 73.4, 72.4, 67.8, 54.1, 53.4, 53.3, 34.4,
28.1, 27.1, 26.3; IR (film) 1759 cm-1; HR MS (ESI) calcd for
C15H25NO4Na [M + Na+] 306.1676, found 306.1680. Anal.
Calcd for C15H25NO4: C, 63.58; H, 8.89; N, 4.94. Found: C,
63.59; H, 8.90; N, 4.92.
Acknowledgment. Financial support for this work was
provided through the Polish Ministry of Science and Higher
Education Grant No. N N204 156036.
Supporting Information Available: 1H and 13C NMR
spectra of 5-15; NOE experiments for 12 and 13a. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO900121X
3100 J. Org. Chem. Vol. 74, No. 8, 2009