Organocatalytic enantioselective synthesis of nitrogen-substituted dihydropyran-2-ones, a key synthetic intermediate of 1β-methylcarbapenems

Article abstract of DOI:10.1021/ol901544q

Organocatalytic enantioselective cycloadditions providing nitrogen-substituted dihydropyran-2-ones were developed in two catalytic systems. The (3R,4R)-product was a versatile intermediate in the synthesis of 1β-methylcarbapenem antibiotics.

Full text of DOI:10.1021/ol901544q

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3934-3937
Organocatalytic Enantioselective
Synthesis of Nitrogen-Substituted
Dihydropyran-2-ones, a Key Synthetic
Intermediate of 1ꢀ-Methylcarbapenems
Shoji Kobayashi,*,† Tatsuhiro Kinoshita,† Hisatoshi Uehara,‡,§ Tomoko Sudo,‡,§
and Ilhyong Ryu†
Department of Chemistry, Graduate School of Science, Osaka Prefecture UniVersity,
Sakai 599-8531, Japan, Mitsubishi Chemical Group Science and Technology Research
Center, Inc., 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-8502, Japan, and API
Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-8502, Japan
koba@c.s.osakafu-u.ac.jp
Received July 7, 2009
ABSTRACT
Organocatalytic enantioselective cycloadditions providing nitrogen-substituted dihydropyran-2-ones were developed in two catalytic systems.
The (3R,4R)-product was a versatile intermediate in the synthesis of 1ꢀ-methylcarbapenem antibiotics.
Enantioselective assembly of contiguous stereogenic centers
remains a great challenge in organic synthesis. The task is
rendered more rigorous when multiple stereocenters are
involved in target molecules such as natural products and
drug candidates. For instance, optically active (3R,4R)-4-
amino-3,6-dimethyl-2-oxo-3,4-dihydro-2H-pyran-5-carboxy-
late (1), a precursor of 1ꢀ-methylazetidinone (2), is a versatile
intermediate in the synthesis of 1ꢀ-methylcarbapenem an-
tibiotics.1 Cycloaddition is a promising approach to this
molecule.2 Turner et al. first reported an inverse-electron-
demand hetero-Diels-Alder reaction between 2-acylami-
nomethylene-3-oxobutanoic acid derivatives (e.g., 4) and a
ketene acetal under thermal conditions to provide substituted
dihydropyranones.2a Although they successfully constructed
dihydropyranone structures, separation of the undesired
diastereomers was unavoidably required. Interestingly, they
found that protection of the carboxylic acid moiety as an
amide was crucial to obtain the 3,4-trans isomer selectively.
No chiral induction, however, was observed when chiral
amide derivatives were subjected to cycloaddition. About
10 years later, Nakai et al. reported the Lewis acid promoted
version of the cycloaddition reaction.2b Despite the high 3,4-
trans diastereoselectivity, less than 26% ee of asymmetric
induction was realized by use of chiral aluminum, titanium,
or borane complexes. We therefore considered that high
enantiocontrol was a critical component for the efficient
preparation of 1. Herein, we wish to report the first
organocatalytic enantioselective synthesis of 1.
† Osaka Prefecture University.
‡ Mitsubishi Chemical Group Science and Technology Research Center.
§ API Corp.
(1) For a review on the synthesis of 1ꢀ-methylcarbapenem antibiotics,
see: Berks, A. H. Tetrahedron 1996, 52, 331–375.
(2) (a) Bayles, R.; Flynn, A. P.; Galt, R. H. B.; Kirby, S.; Turner, R. W.
Tetrahedron Lett. 1988, 48, 6341–6344. (b) Nishiuchi, M.; Honda, K.;
Nakai, T. Chem. Lett. 1996, 321–322.
10.1021/ol901544q CCC: $40.75
Published on Web 08/07/2009
 2009 American Chemical Society

Recently, a chiral N-heterocyclic carbene (NHC) catalyzed,
enantioselective oxodiene Diels-Alder reaction was reported
by Bode et al.3,4 The reaction efficiently provided a wide
range of 3,4-cis-dihydropyranones with high levels of
diastereo- and enantioselectivity. The high stereoselectivity
was explained by the transition state in which ꢀ-substituted
enones approach the Z-enolates in endo fashion (Figure 1,
required an elaborate preparation method from n-propanal
and N-chlorosuccinimide (NCS).8 After many attempts, we
found that chlorination was successful in CCl4, and the
succinimide formed was easily separated by filtration of
1
the reaction mixture. The H NMR spectrum of the filtrate
showed 98% conversion to 2-chloropropanal with no con-
tamination of succinimide. The racemic 2-chloropropanal
thus obtained was subjected as a CCl4 solution to the
cycloaddition reaction with 4a-f in the presence of 5 mol
% of chiral NHC ligand 3.4,9,10 Remarkably, tetrasubstituted
3,4-dihydropyran-2-ones were obtained in adequate yields
with high enantiomeric excesses. To our surprise, cis-isomers
5a-f predominated over trans-isomers 1a-f in all cases.
The enantiomeric excesses of 5d-f were greater than 97%
ee, reaching >99% ee after a single recrystallization. This
stereochemical outcome was unexpected since endo approach
of the E-oxodiene from the less hindered face of the Z-enolate
should lead to the trans-lactone 1 (cf. Figure 1). This led us
to consider the possibility of olefin isomerization under the
cycloaddition conditions. To this end, the reaction was
stopped prior to completion, and the recovered products were
analyzed by NMR spectroscopy. However, no isomeric
oxodiene was detected, which implied that E-oxodiene was
the actual reactant in the cycloaddition.11,12
Figure 1. Stereochemical models for endo cycloaddition. Bode’s
result (top) and the proposed model for this study (bottom).
In consideration of the above experiments and parallel
studies, the stereochemical mode of cycloaddition was
reconsidered. The R-configuration at C3 is rationalized by a
top). Therefore, we envisioned that endo cycloaddition
between R,ꢀ-disubstituted enones and the Z-enolate would
generate the 3,4-trans stereoisomers 1 predominantly (Figure
1, bottom). In addition, the cycloaddition reaction with an
amino-containing oxodiene was performed to expand this
methodology to complex molecules.
Hence, we prepared various substrates 4a-f in a single
step from the corresponding alkoxymethyleneacetoacetates
(Table 1).5,6 All substrates have a trans configuration with
respect to the ester and amino groups as supported by NMR
data.7 The highly volatile and labile 2-chloropropanal
(3) For a review on N-heterocyclic carbenes as organocatalysts, see:
Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606–5655
.
(4) (a) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
15088–15089. (b) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc.
2006, 128, 8418–8420. (c) He, M.; Beahm, B. J.; Bode, J. W. Org. Lett.
2008, 10, 3817–3820
(5) Crombie, L.; Games, D. E.; James, A. G. J. Chem. Soc., Perkin Trans.
1 1979, 464–471
(6) Leeming, P.; Ray, C. A.; Simpson, S. J.; Wallace, T. W.; Ward,
R. A. Tetrahedron 2003, 59, 341–352
(7) Saito, S.; Uedo, E.; Kato, Y.; Murakami, Y.; Ishikawa, T. Synlett
1996, 1103–1105
.
.
.
.
(8) (a) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2004, 126, 4108–4109. (b) Halland, N.; Braunton, A.; Bachmann, S.;
Marigo, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790–4791.
(c) Recently, R-chloroaldehyde bisulfite salts were identified as potential
alternatives (see ref 4c).
Table 1. Chiral NHC-Catalyzed Asymmetric Cycloaddition
(9) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70,
5725–5728
.
(10) We initially performed the reaction with 0.5 mol % of the catalyst
according to the original procedure. However, no 3,4-dihydropyran-2-ones
were obtained, presumably due to the low reactivity of the amino-containing
oxodienes.
(11) We further explored the influence of olefin geometry on the
stereoselectivity by carrying out the reaction with Z-oxodiene 4g2a where
R-phenethylamide was incorporated as a carboxylic acid protecting group.
In contrast, cycloaddition did not take place, and 4g was recovered
unchanged. This is probably due to the inherent inertness of the trisubstituted
Z-oxodiene arising from the bulkiness of the amide portion or strong
hydrogen bonding between the amide proton and the carbonyl oxygen,
causing an s-cis conformation which is disfavored for cycloaddition.
ee for [R]D for
e
R′ yielda (%) ratio (1:5)b 5c (%) 5f (deg)
-
entry
4
R
1
2
3
4
5
6
4a Et Ac
4b Et Cbz
4c Et Boc
4d Me Ac
4e Me Cbz
4f Me Boc
40
65
65
62
80
70
1:5
1:5
1:7
1:4
1:12
1:9
N.D.
-97
-74
-86
-95
-89
-79
N.D.
N.D.
97 (>99)
98 (>99)
98 (>99)
(12) The influence of olefin geometry will become more apparent if the
Z-isomers of 4a-f are submitted to cycloaddition. However, in our hands,
those isomers could not be synthesized. We therefore do not exclude the
case that isomerization occurs to generate the Z-isomer, which reacts rapidly
with the catalytically generated enolate, leading to the observed stereo-
chemistry.
a Isolated yield. b Determined by NMR analysis. c N.D.: not determined.
d Determined by chiral-phase HPLC analysis. e The number in parentheses
refers to the ee value after recrystallization from hexane/ethyl acetate. f After
recrystallization.
Org. Lett., Vol. 11, No. 17, 2009
3935

selective addition of oxodiene from the sterically less
congested Si face of the Z-enolate.4 The endo approach
resulting in the trans-isomer 1 was blocked by a severe steric
interaction between the bulky carbamate group (or acetyl-
amino group) of the oxodiene and the triazolium moiety of
the dienophile (cf. Figure 1, bottom). Such an interaction
seems unlikely in the exo transition state where other steric
interactions might increase (Figure S1, Supporting Informa-
tion). We therefore supposed that the concerted transition
states as shown in Figure 1 and S1 (Supporting Information)
did not fully explain the observed stereochemical outcome.
Alternatively, a two-step process consisting of Michael
addition followed by ring closure might be involved in the
present cycloaddition. By taking the steric environment into
consideration, it is likely that Michael addition progresses
through a conformation in which the ꢀ-hydrogen of the enone
turns in the same direction as the bulky triazonium moiety
(Figure 2, A). As a consequence, cis-lactones 5a-f were
presence of a catalytic amount of AcOH (10 mol %) and
R,R-diphenylprolinol trimethylsilyl ether 6a (15 mol %) in
CH3CN-H2O (10:1) at room temperature (Table 2). The
Table 2. Asymmetric Cycloaddition Catalyzed by
Diphenylprolinol Derivatives (6a and 6b)
ee for
ee for
R′ yielda (%) ratio (1:5)b 1c d (%) 5c d (%)
,
,
entry
4
R
1
2
3
4
5
6e
7
4a Et Ac
4b Et Cbz
4c Et Boc
4d Me Ac
4e Me Cbz
4e Me Cbz
4f Me Boc
54
59
38
54
64
54
22
1:1.7
1:1.3
1:1.7
1:1.3
1:1.4
1:1.1
1:1.4
N.D.
N.D.
N.D.
73
90
52
N.D.
N.D.
N.D.
>99
92
32
79
85
a Isolated yield for two steps. b Determined by 1H NMR analysis. c For
ethyl esters, ee values were not determined since two diastereomers were
inseparable. d Determined by chiral-phase HPLC analysis. e 6b was used
instead of 6a as an enamine catalyst.
Figure 2. Stepwise reaction course leading to cis-isomers 5a-f.
generated through the sterically defined Michael adduct B.
Although we cannot fully exclude the concerted pathway, it
is evident that this work provides vital information on the
mechanism of the NHC-catalyzed cyclization reaction.
Despite the excellent enantioselectivity achieved by em-
ploying the chiral NHC ligand, the undesired diastereose-
lectivity forced us to investigate alternative cycloaddition
methods. Recently, pyrrolidine derivatives such as diaryl-
prolinol ethers have emerged as potentially general organo-
catalysts13 and cycloaddition reactions have been achieved
with good diastereo- and enantioselectivities.14 However,
these organocatalytic cycloadditions are limited to highly
electron-deficient acceptors, and acceptors containing amino
groups are still unknown. Therefore, we examined the
organocatalytic cycloaddition reaction between oxodienes
4a-f and n-propanal to produce dihydropyranones with a
4-amino group.
cycloaddition products 7a-f were obtained as a mixture of
four inseparable diastereomers, which were oxidized as a
mixture by Dess-Martin reagent to afford diastereomeric
lactones (5a-f and 1a-f) in moderate to good yields for
two steps. Notably, in contrast with the results obtained by
NHC-catalyzed cycloaddition, the diastereoselectivity was
rather modest, and the desired 3,4-trans-dihydropyranones
1 were obtained with good enantiomeric excesses. Among
the substrates tested, Cbz-protected methyl ester 4e showed
the best properties and the two diastereomers could be
separated by flash column chromatography (entry 5). While
the diastereoselectivity is still unsatisfactory, this is the first
example of enantioselective assembly of nitrogen-substituted
3,4-trans-dihydropyrones by cycloaddition. Pyrrolidine cata-
lyst 6b, which does not contain a trimethylsilyl ether group,
effected cycloaddition as well, but the enantioselectivity was
considerably decreased (entry 6). Recently, in a related
system Ma and co-workers succeeded in enantioselective
synthesis of tetrasubstituted dihydropyrones lacking the
N-substituent with high trans selectivity.14c Interestingly, they
observed that diastereoselectivity of the product was inde-
pendent of the olefin geometry of the starting oxodienes;
EfZ isomerization occurred first, and the reaction progressed
from the Z-configuration even if the isomerically pure
E-oxodiene was used. In our case, however, EfZ isomer-
izations of oxodienes 4a-f were not observed as evidenced
by the recovery of the unchanged starting materials. It is of
According to the conditions developed by Chen et al.,14d
E-oxodienes 4a-f were treated with n-propanal in the
(13) For reviews on diarylprolinol ethers as organocatalysts, see: (a)
List, B. Chem. Commun. 2006, 819–824. (b) Marigo, M.; Jørgensen, K. A.
Chem. Commun. 2006, 2001–2011. (c) Guillena, G.; Ramo´n, D. J.
Tetrahedron: Asymmetry 2006, 17, 1465–1492. (d) Palomo, C.; Mielgo,
A. Angew. Chem., Int. Ed. 2006, 45, 7876–7880.
(14) For selected examples of enantioselective cycloadditions using
diarylprolinol ether derivatives, see: (a) Juhl, K.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2003, 42, 1498–1501. (b) Samanta, S.; Krause, J.; Mandal,
T.; Zhao, C.-G. Org. Lett. 2007, 9, 2745–2748. (c) Wang, J.; Yu, F.; Zhang,
X.; Ma, D. Org. Lett. 2008, 10, 2561–2564. (d) Han, B.; Li, J.-L.; Ma, C.;
Zhang, S.-J.; Chen, Y.-C. Angew. Chem., Int. Ed. 2008, 47, 9971–9974.
(e) Xie, H.; Zu, L.; Oueis, H. R.; Li, H.; Wang, J.; Wang, W. Org. Lett.
2008, 10, 1923–1926.
3936
Org. Lett., Vol. 11, No. 17, 2009

interest that such a difference in reactivity arises by the
presence or absence of the nitrogen substituent.15
antibiotics (Scheme 1).2,19 Methanolysis of 1e with K2CO3
afforded acyclic ketone 8 as an approximately 1:1 diaster-
It can be rationalized that the configuration at C3 of the
product is controlled by the steric hindrance of the substituent
R to the pyrrolidine nitrogen. This forces the approach of
electrophiles to the Re face of the enamine, thus affording
the product of 3R-configuration.13 The formation of cis-
isomers 5a-f is reasonably explained by a synclinal transi-
tion state, in which there are favorable electrostatic interac-
tions between the enamine nitrogen and the carbonyl group
(Figure 3, top). This arrangement16 widely accounts for the
Scheme 1
.
Synthesis of All-Trans-Substituted
Tetrahydropyranone
eomeric mixture at C4. The ketone 8 was then treated with
excess Et3SiH and TFA for 4 days to undergo reduction and
spontaneous lactonization.19a In the crude NMR spectrum,
four possible diastereomers were detected in a ratio of 12:
4:3:120 with the all-trans isomer 9 as the major product. After
separation by silica gel chromatography and recrystallization,
the major isomer 9 was isolated as colorless needles in 33%
yield. The absolute configuration of 9 was determined to be
2R,3S,4R,5R by comparison of the specific optical rotation
with the value reported in the literature.19b
Figure 3. Synclinal models leading to cis-isomers 5a-f (top) and
trans-isomers 1a-f (bottom).
prominent syn selectivity of the enamine-catalyzed reac-
tions.13,14,17 However, when the amino substituent is attached
to the ꢀ-position of the enone, such electrostatic interactions
are weakened due to the resonance effect by the amino group.
As a result, the reaction proceeds through either the
conformation which has the carbamate (or acetylamino)
group in the least hindered position (Figure 3, bottom) or,
alternatively, the antiperiplanar transition state,16 where the
amino substituent is away from the pyrrolidine ring to avoid
steric hindrance (Figure S2, Supporting Information). Thus,
comparable amounts of trans-isomers 1a-f were produced
along with cis-isomers 5a-f with good enantioselectivity.18
With optically active trans-δ-lactone 1e in hand, we then
undertook the synthesis of all-trans-substituted tetrahydro-
pyranone 9, a valuable intermediate of 1ꢀ-methylcarbapenem
In conclusion, we have achieved an enantioselective
synthesis of 3,4,5,6-tetrasubstituted 3,4-dihydropyran-2-ones
bearing a nitrogen substituent at C4 by means of organo-
catalytic cycloadditions. Our investigation proved that chiral
triazonium salt 3 gave rise to excellent asymmetric induction
with high 3,4-cis stereoselectivity, while application of
diphenylprolinol silylether 6a resulted in a mixture of cis
and trans isomers with good enantioselectivities. To the best
of our knowledge, this is the first example using the
organocatalytic reaction to construct the four contiguous
asymmetric centers of 1ꢀ-methylcarbapenem skeletons. We
believe that the present investigation will become not only
an important guideline for developing new enantioselective
routes to carbapenems and related biologically active mol-
ecules but also good examples to address their reaction
mechanisms.
(15) Amide-containing Z-oxodiene 4g was again unreactive in the
enamine-catalyzed conditions.
(16) Seebach, D.; Golin´ski, J. HelV. Chim. Acta 1981, 64, 1413–1423.
(17) For selected examples of syn-selective Michael additions with
diarylprolinol ether catalysts, see: (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.;
Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212–4215. (b) Ender, D.; Hu¨ttl,
M. R. M.; Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem., Int. Ed. 2007,
46, 467–469. (c) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew.
Chem., Int. Ed. 2007, 46, 4922–4925. (d) Zhu, S.; Yu, S.; Ma, D. Angew.
Acknowledgment. S.K. and I.R. thank JSPS/MEXT and
Suzuken Memorial Foundation for financial support.
Chem., Int. Ed. 2008, 47, 545–548
.
(18) A concerted mechanism as proposed by Jørgensen et al. for the
addition of aldehyde to enones cannot be ruled out.14a
(19) (a) Bayles, R.; Flynn, A. P.; Galt, R. H. B.; Kirby, S.; Turner, R. W.
Tetrahedron Lett. 1988, 29, 6345–6348. (b) Hatanaka, M. Tetrahedron Lett.
1987, 28, 83–86. (c) Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1988,
53, 2131–2132.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Detailed NMR analysis indicated that two of the products were
not lactones, but acyclic reduction products, namely precursors of lac-
tone.
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