Cyclopropanation of (E)-Dehydroaspartic Acid Esters with Furan Derivatives: The Synthesis of Highly Functionalized α-2,3-Methanoamino Acid Esters

Article abstract of DOI:10.1055/s-0034-1380812

Highly functionalized α-2,3-methanoamino acid esters were prepared by the cyclopropanation of dehydroaspartic acid esters with 2-methoxyfuran or 2-siloxyfuran derivatives. These reactions proceed smoothly in the absence of any catalysts, bases, additives, or solvents.

Full text of DOI:10.1055/s-0034-1380812

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1710–1714
letter
1710
A. Manabe et al.
Letter
Synlett
Cyclopropanation of (E)-Dehydroaspartic Acid Esters with Furan
Derivatives: The Synthesis of Highly Functionalized α-2,3-Metha-
noamino Acid Esters
O
OR1
Atsushi Manabe
O
MeO2C
R2
Ryotaro Matsumoto
Tetsuro Shinada*
O
R2
N
CO2Me
CO2Et
N
O
CO2R1
O
120 °C
CO2Et
Graduate School of Science, Osaka City University,
Sugimoto, Osaka 558-8585, Japan
shinada@sci.osaka-cu.ac.jp
no catalyst
no solvent
single isomer
8 examples
25–78% yield
R
R
1 = Me, TIPS
2 = alkyl, allyl, Ph
Received: 14.03.2015
Accepted after revision: 21.04.2015
Published online: 18.06.2015
The α-2,3-methanoamino acid (MAA) motif is frequent-
ly encountered as a substructure in biologically active natu-
ral products and drug candidates (Figure 1).1,2 Due to the
potential utility of MAAs in amino acid and peptide chem-
istry, medicinal chemistry, and chemical biology, consider-
able effort has been directed towards their synthesis.1 In
this paper, we report an unprecedented synthetic route to
highly substituted MAA esters 3: the condensation of (E)-
dehydroaspartic acid esters (DAAE) 1 and furans 2, bearing
a methoxy or siloxy group on the carbon atom at the 2-po-
sition (Equation 1). Especially noteworthy is the fact that
catalysts, bases, solvents, or diazo compounds are not re-
quired for these cyclopropanations to proceed.
DOI: 10.1055/s-0034-1380812; Art ID: st-2015-u0181-l
Abstract Highly functionalized α-2,3-methanoamino acid esters were
prepared by the cyclopropanation of dehydroaspartic acid esters with
2-methoxyfuran or 2-siloxyfuran derivatives. These reactions proceed
smoothly in the absence of any catalysts, bases, additives, or solvents.
Key words cyclopropanation, α-2,3-methanoamino acids, furans, de-
hydroaspartic acid ester
HO
N
MeO
O
O
O
O
N
N
S
O
O
H
HN
O
NH
H
OH
O
N
O
N
O
O
O
H
O
O
N
O
NH
O
O
N
O
O
N
O
BMS-605339
BZR-cotoxin II
OH
OH
O
NH
H
H
O
HO
O
HN
O
OMe
H
CO2H
N
O
coronatine
cytotrienin A
O
Figure 1 Examples of biologically active natural products and drug candidates containing MAA moieties
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1710–1714

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A. Manabe et al.
Letter
Synlett
Catalyst- and base-free cyclopropanations have received
much attention, as they are highly attractive with regard to
atom economy and efficiency. Previously reported exam-
ples concern predominantly diazo compounds, for example,
the photolysis of diazo compounds in the presence of ole-
fins, or the 1,3-dipolar addition of diazo compounds to ole-
fins followed by thermolysis of the resulting pyrazolines.3,4
But instead of this diazo-based chemistry, we were inter-
ested in the condensation reactions of electron-deficient
olefins with 2-methoxyfuran, as these should allow access
to cyclopropanes and find applications in the synthesis of
MAA esters (Scheme 1).5 Huisgen et al. have reported the
first synthetic example for such condensation reactions.
They found that the reaction of 2-methoxyfuran (4) with
highly electron-deficient olefin 6a at room temperature af-
forded 5a.5h–k Ito et al. reported that several electron-defi-
cient olefins such as 6b, containing two electron-withdraw-
ing groups (EWG), were able to furnish 5b,5c,e while Kusama
and Iwasawa et al. reported that tungsten carbene complex
O
2
OR
GWE
PHN
PHN
EWG
EWG
2
R = Me, TIPS
CO2R
EWG
1
no additive
no solvent
3
dehydroaspartic
acid ester (DAAE)
highly functionalized MAAs
Equation 1
6c underwent a cyclopropanation reaction at room tem-
perature to generate 5c.5g
Thomas et al. found that chiral tungsten complexes 6d
reacted with 4 to provide optically active cyclopropane
5d.5d Recently, Lewis acid promoted cyclopropanations us-
ing Eu(fod)3, HfCl4, and arylborane 7 were developed. Under
the conditions, 6e, 6f, and 6g were condensed with 4 to give
5e, 5f, and 5g in good to excellent yields, respectively.5a,b,f
We envisioned that DAAE such as 8–10 should also be
potent acceptors for 4, potentially resulting in the direct
R
NC
Ph
F3C
H
CO2Me
CO2Me
NC CF3
NC EWG
H
CO2Me
5c R = Ph, i-Pr
5a (dr = 3:1)
5b (dr = 2:3 to 7:2)
c
a
b
OMe
(OC)6W
d
O
g
f
H
OMe
CO2Me
H
CO2Me
e
4
O
5g
O
O
NC
O
Br
S
5d (dr = 4.5:1)
p-Tol
O
CO2Me
CO2Me
EtO
OEt
H
5f
5e (dr = 3:2)
W(CO)6
R
F3C
CN
Ph
H
MeO
W(CO)6
O
O
NC
CF3
NC
EWG
6a
6b (EWG = CO2Et,
CN, or SO2Ph)
6c (R = Ph, i-Pr)
6d
O
O
B
O
Br
p-Tol
S
CN
OEt
OEt
N
N
O
B
6e
6f
6g
7
Scheme 1 Cyclopropanation reactions using 2-methoxyfuran (4). Reagents and conditions: (a) 6a, CDCl3, r.t.; (b) 6b, CHCl3, r.t., 46–85%; (c) 6c, THF,
r.t., ca. 80%; (d) 6d, toluene, –55 °C, 93%; (e) 6e, Eu(fod)3, MeCN, r.t., 70%; (f) 6f, HfCl4, DCE, r.t., 32%; (g) 6g, 20 mol% of 7, 140 °C, 80%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1710–1714

1712
A. Manabe et al.
Letter
Synlett
formation of MAA esters, and to the best of our knowledge,
this possibility has not yet been examined.
To test our hypothesis, we initially investigated cyclo-
propanation reactions of DAAE 8 and 9, which contain dif-
ferent protecting groups for the amino moiety. However,
treatment of 8 or 9 with an excess of 4 (40 equiv) in toluene
at either room temperature or 120 °C in a sealed tube did
not induce any reaction, and only staring material was re-
covered (Scheme 2). It is feasible to assume that the elec-
tron deficiency of 8 and 9 is insufficient to promote the cy-
clopropanation in these cases. Therefore, the more reactive
phthalimide 10 was employed as a substrate, and indeed,
the cyclopropanation between 10 and 4 in a sealed tube at
120 °C afforded a single diastereoisomer of 11 in 56% yield.
MeO2C
4 (40 equiv)
CbzHN
CO2Me
CO2Et
CbzHN
Figure 2 Molecular structure of 11 with thermal ellipsoids set at 50%
probability (all hydrogen atoms have been omitted for clarity)
CO2Me
sealed tube, neat
120 °C, 21 h
CO2Et
8
Table SI-1 in the Supporting Information). These reactions
represent the first examples of cyclopropanations involving
2-triisopropylsilyloxyfurans.
MeO2C
OHCHN
4 (40 equiv)
OHCHN
CO2Me
CO2Et
CO2Me
CO2Me
No reaction was observed when 12h and 12i bearing a
methyl group at C4 and C5 were employed for the cyclopro-
panation of 10 (Table 1, entries 8 and 9). The poor reactivity
of these furans could be ascribed to the steric influence of
the methyl group, potentially impeding the approach of 10.
Previously, 3-methyl and 5-methyl 2-trimethylsilyloxyfu-
rans were subjected to the cyclopropanation with 5g in the
presence of Lewis acid catalyst 7 to give aromatic cyclopro-
panes via the hetero-Diels–Alder reaction.5g The different
outcomes provide information to propose the reaction
mechanism for the present cyclopropanation to give 11 and
13a–g.
sealed tube, neat
120 °C, 21 h
CO2Et
9
CO2Me
O
O
N
3
1
N
4 (40 equiv)
2
CO2Me
CO2Et
O
sealed tube, neat
120 °C, 21 h, 56%
O
CO2Et
10
(1R*,2S*,3S*)-11
Scheme 2 Cyclopropanation reactions of 2-methoxyfuran with 8–10
1
The H NMR analysis of 11 in CDCl3 revealed the pres-
ence of a cis-α,β-unsaturated ester moiety (J = 11.4 Hz). Sin-
gle crystals of 11 suitable for X-ray crystallography were
obtained from recrystallization in hexane–Et2O. The molec-
ular structure of 11 unambiguously determined the config-
uration of the phthalimide, two carboxylates, and the α,β-
unsaturated ester moieties on the cyclopropane ring as
1R*,2S*,3S* (Figure 2).6
For phthalimides 14 and 15, no cyclopropanation with 4
was observed (Scheme 3), whereas the use of (Z)-DAAE 16
resulted unexpectedly in the formation of a complex mix-
ture. Under the applied conditions, no isomerization from
(Z)-16 to the corresponding E-isomer and from (E)-10 to
the corresponding Z-isomer was observed. These results in-
Subsequently, we directed our attention to the synthesis
of highly substituted MAA esters by using 2-siloxyfurans,7,8
which are easily prepared from 2-furanones by O-silylation.
We found that not only 2-triisopropyloxyfuran (12a), but
also substituted siloxyfurans 12b–g, bearing substituents
on the carbon atom at the 3-position, were able to react
with 10 at 120 °C and afforded the corresponding MAA es-
ters 13a–g in moderate to good yield (25–78%; Table 1, en-
tries 1–7). NOE analysis of 13a–g and a comparison of their
NMR data with those of 11 indicated that the relative ste-
reochemistry of 13a–g and 11 is identical (Figure SI-1 and
4 (40 equiv)
14, 15: no reaction
16: complex mixture
14, 15 or 16
sealed tube, neat
120 °C, 21 h
O
O
O
N
N
CO2Et
N
CO2Me
O
EtO2C
O
EtO2C
O
16
14
15
Scheme 3 Substrate scope
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1710–1714

1713
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Letter
Synlett
Table 1 (continued)
dicate that a cis configuration of the two ester moieties
with respect to each other should be of pivotal importance
to trigger the cyclization reactions.
En- Substrate
try
Product (reaction time)
Yield
(%)
It is noteworthy that these cyclopropanations generate
only one of four possible products stereoselectively. A pro-
posed reaction mechanism, furnishing 11 from 4 and 10 is
outlined in Scheme 4. Huisgen et al. previously proposed a
stepwise reaction mechanism involving a Michael addition
of 4 and 6a, followed by an intramolecular SN2 substitution
to give 5a (Scheme 1).5h–k Ito et al. performed theoretical
calculation studies for the cyclopropanation reaction of 4
and 5b.5c This analysis supported a stepwise polar reaction
mechanism via a twitter ion intermediate. In agreement
with the previous considerations, we propose a stepwise
reaction mechanism for the present cyclopropanation of 4
and 10 (Scheme 4). Addition of 4 to 10 provides intermedi-
ate A, which undergoes an intramolecular cyclization to af-
ford 11. The putative transition model (intermediate B) to
give 17 would be more unstable than that of A due to the
severe A1,3-strain and electronic repulsion between the ke-
tene acetal and the ester moiety (Scheme 4). Although the
details have not been unclear, the putative transition-state
models to give the other cyclopropanes 18 and 19 would be
more unfavorable due to the steric repulsion between the
three substituents placed in all-cis in their product-like
transition states (Scheme SI-1 in the Supporting Informa-
tion).
MeO2C
PhthN
O
OTIPS
4
5
55
78
CO2TIPS
CO2Et
CO2Et
12d
13d (22 h)
MeO2C
PhthN
O
OTIPS
OTIPS
CO2TIPS
12e
13e (23 h)
O
MeO2C
PhthN
6
7
25
CO2TIPS
CO2Et
12f
13f (20 h)
O
OMe
OTIPS
MeO2C
PhthN
30
CO2TIPS
CO2Et
OMe
13g (19 h)
12g
O
OTIPS
8
9
complex mixture
no reaction
–
–
Table 1 Cyclopropanation Reactions Using Siloxyfurans 12a–i
12h
12i
O
R3
OTIPS
O
OTIPS
R1
CO2TIPS
O
R2
R2
R1
MeO2C
PhthN
N
CO2Me
CO2Et
R3
12a–i (10 equiv)
O
sealed tube, neat
120 °C, time
CO2Et
13a–g
The potential involvement of carbene intermediates is
10
rendered unlikely by the fact that Rh2(OAc)4 and Cu(acac)2
did not exhibit any catalytic effect on the cyclopropanation
between DAAE 8–10 and 4 and resulted only in the forma-
tion of complex product mixtures or the recovery of start-
ing materials.
En- Substrate
try
Product (reaction time)
Yield
(%)
MeO2C
PhthN
O
OTIPS
In summary, we have developed a novel cyclopropana-
tion reaction between N-phthaloyl DAAE (10) and furans
that bear electron-donating 2-methoxy or 2-siloxy groups.
These cyclopropanations provide highly substituted MAA
esters in one step and afford the products as a single stereo-
isomer. A wide variety of 2-siloxyfurans is easily accessible
from commercially available 2-furanones (see the Support-
ing Information), thus providing facile synthetic access to a
broad range of MAA esters. In addition, the reactions pro-
ceed smoothly in the absence of explosive diazo com-
pounds, catalysts, solvents, or any other additives. Further
studies toward development of the atom-economical pro-
1
62
47
50
CO2TIPS
12a
CO2Et
CO2Et
CO2Et
13a (21 h)
MeO2C
PhthN
O
OTIPS
OTIPS
2
CO2TIPS
12b
13b (21 h)
MeO2C
PhthN
O
3
CO2TIPS
12c
13c (27 h)
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A. Manabe et al.
Letter
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References and Notes
PhthN
CO2Me
CO2Et
PhthN =
O
+
(1) (a) Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107, 4493.
(b) Stammer, C. H. Tetrahedron 1990, 46, 2231. (c) Alami, A.;
Calmes, M.; Daunis, J.; Jacquier, R. Bull. Soc. Chim. Fr. 1993, 130,
5. (d) Burgess, K.; Ho, K.-K.; Moye-Sherman, D. Synlett 1994,
575.
OMe
O
N
4
10
O
(2) Scola, P. M.; Wang, A. X.; Good, A. C.; Sun, L.-Q.; Combrink, K. D.;
Campbell, J. A.; Chen, J.; Tu, Y.; Sin, N.; Venables, B. L.; Sit, S.-Y.;
Chen, Y.; Cocuzza, A.; Bilder, D. M.; D’Andrea, S.; Zheng, B.;
Hewawasam, P.; Ding, M.; Thuring, J.; Li, J.; Hernandez, D.; Yu,
F.; Falk, P.; Zhai, G.; Sheaffer, A. K.; Chen, C.; Lee, M. S.; Barry, D.;
Knipe, J. O.; Li, W.; Han, Y.-H.; Jenkins, S.; Gesenberg, C.; Gao, Q.;
Sinz, M. W.; Santone, K. S.; Zvyaga, T.; Rajamani, R.; Klei, H. E.;
Colonno, R. J.; Grasela, D. M.; Hughes, E.; Chien, C.; Adams, S.;
Levesque, P. C.; Li, D.; Zhu, J.; Meanwell, N. A.; McPhee, F. J. Med.
Chem. 2014, 57, 1708.
O
OMe
H
EtO2C
PhthN
NPhth
H
O
MeO
EtO2C
O
O
R1O
R1O
B
A
(3) Gaspar, P. P.; Harrison, J. F.; Herold, J. Carbene Chemistry, 2nd
ed.; Krims, W., Ed.; Academic Press: New York, 1971.
(4) (a) Karthik, G.; Rajasekaran, T.; Sridhar, B.; Reddy, B. V. S. Tetra-
hedron Lett. 2014, 55, 7064. (b) Maurya, R. A.; Kapure, J. S.;
Adiyala, P. R.; Srikanth, P. S.; Chamdrasekhar, D.; Kamal, A. RSC
Adv. 2013, 3, 15600.
MeO2C
MeO2C
PhthN
PhthN
CO2Et
CO2Et
CO2Et
11
CO2Et
(5) (a) Kessler, S. N.; Neuburger, M.; Wegner, H. A. J. Am. Chem. Soc.
2012, 134, 17885. (b) Sato, Y.; Kuramochi, K.; Suzuki, T.;
Nakazaki, A.; Kobayashi, S. Tetrahedron Lett. 2011, 52, 626.
(c) Itoh, K.; Kishimoto, S. New J. Chem. 2009, 33, 1127.
(d) Barluenga, J.; Prado, A. D.; Santamaria, J.; Tomas, M. Chem.
Eur. J. 2007, 13, 1326. (e) Itoh, K.; Iwata, S.; Kishimoto, S. Hetero-
cycles 2006, 68, 395. (f) Cruz, D. C.; Yuste, F.; Diaz, E.; Ortiz, B.;
Sanchez-Obregon, R.; Walls, F.; Ruano, J. L. G. ARKIVOC 2005,
(vi), 211. (g) Kusama, H.; Shiozawa, F.; Shido, M.; Iwasawa, N.
Chem. Lett. 2002, 124. (h) Huisgen, R.; Mloston, G. Tetrahedron
Lett. 1994, 35, 4981. (i) Urrutia-Desmaison, G.; Mloston, G.;
Huisgen, R. Tetrahedron Lett. 1994, 35, 4977. (j) Huisgen, R.;
Mloston, G. Bull. Soc. Chim. Belg. 1994, 103, 349. (k) Mloston, G.;
Huisgen, R. J. Heterocycl. Chem. 1994, 31, 1279.
17
MeO2C
PhthN
MeO2C
PhthN
CO2Et
CO2Et
CO2Et
18
CO2Et
19
Scheme 4 Proposed reaction mechanism for the formation of 11 from
4 and 10
(6) Supplementary crystallographic information for 11 is contained
within CCDC 1042557, which can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac. uk/data_request/cif.
(7) For the use of siloxyfurans in Lewis acid catalyzed cyclopro-
panation reactions, see ref. 5a.
cess by reducing the excess amount of furans as well as the
synthesis of chiral MAA using DAAE with a chiral auxiliary
are ongoing in our laboratory.
(8) General Procedure for the Cyclopropanation Reaction (Syn-
thesis of 13a)
Acknowledgment
A mixture of 10 (36.4 mg, 0.120 mmol) and 12a (288 mg, 1.20
mmol) was heated to 120 °C in a sealed tube reactor for 21 h.
After cooling the mixture to r.t., the crude mixture was sub-
jected to silica gel column chromatography to give 13a (40.4
mg, 62%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ = 7.83 (m,
2 H), 7.73 (m, 2 H), 6.29 (dd, J = 11.4, 8.7 Hz, 1 H), 6.08 (d, J =
11.4 Hz, 1 H), 4.30 (t, J = 8.7 Hz, 1 H), 4.09 (q, J = 7.2 Hz, 2 H),
3.69 (s, 3 H), 3.11 (d, J = 8.7 Hz, 1 H), 1.31 (m, 3 H), 1.20 (t, J = 7.2
Hz, 3 H), 1.07 (d, J = 7.2 Hz, 18 H). 13C NMR (75 MHz, CDCl3): δ =
167.4, 167.0, 165.2, 138.5, 134.2, 134.1, 126.2, 123.6, 123.5,
61.5, 53.5, 42.6, 34.0, 32.8, 17.7, 13.9, 11.9. FTIR (neat): 2951,
2871, 1730, 1398, 1273, 1202, 721 cm–1. HRMS–FAB: m/z calcd
for C28H38NO8Si [M + H]+: 544.2367; found: 544.2369.
This study was financially supported by MEXT-Japan (Grant No.
23102009) and JSPS KAKENHI-Japan (Grant No. 23228001 and
25282233).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380812.
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u
p
p
ortiInfogrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1710–1714