Sc-catalyzed aldol-yype additions of N-Benzoylcyclopropanecarboxamides via iodide-mediated ring-opening: Stereoselective synthes of □-Lactams

Article abstract of DOI:10.1021/ol800401g

A new catalytic aldol-type addition of cyclopropanecarboximides to aldehydes via iodide-mediated ring-opening is presented. The reaction was found to be catalyzed at 0 °C using either a Sc(OTf)₃/Nal system or Scl₃. Stereoselective formation of αα-disubstituted enolates occurred in situ. γ-Lactams bearing α-carbonyl quaternary stereocenters were obtained in 97-57% yield and dr = 90:10-80:20 after ring closure.

Full text of DOI:10.1021/ol800401g

ORGANIC
LETTERS
+
Sc3 -Catalyzed Aldol-Type Additions of
2008
Vol. 10, No. 8
1661-1664
N-Benzoylcyclopropanecarboxamides via
Iodide-Mediated Ring-Opening:
Stereoselective Synthesis of
γ-Lactams
Sean H. Wiedemann, Hidetoshi Noda, Shinji Harada, Shigeki Matsunaga,* and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo 7-3-1,
Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@mol.f.u-tokyo.ac.jp
Received February 21, 2008
ABSTRACT
A new catalytic aldol-type addition of cyclopropanecarboximides to aldehydes via iodide-mediated ring-opening is presented. The reaction
was found to be catalyzed at 0 C using either a Sc(OTf)3/NaI system or ScI3. Stereoselective formation of -disubstituted enolates occurred
in situ. -Lactams bearing -carbonyl quaternary stereocenters were obtained in 97 57% yield and dr 90:10 80:20 after ring closure.
°
r,r
γ
r
−
)
−
The stereoselective formation of all-carbon quaternary stereo-
centers remains a formidable challenge in the field of organic
synthesis.1 The use of R,R-disubstituted enolates in aldol
reactions is a straightforward approach to provide R-carbonyl
quaternary stereocenters. Given the many modern variants
of the aldol reaction that have been developed,2 however, it
is remarkable that there are few such methods available
wherein R-carbonyl quaternary stereocenters are formed
selectively.3,4 This deficiency can be attributed to the dif-
ficulty inherent in preparing geometrically well-defined R,R-
disubstituted enolates from the corresponding carbonyl com-
pounds under traditional base-mediated conditions. To solve
this problem, nonclassical methods for stereoselective metal
enolate or silyl enolate generation have been devised.5
Alternatively, ketenes6 and silylketene imines7 have been
used as surrogate donors in asymmetric additions to alde-
(3) (a) Yamago, S.; Machii, D.; Nakamura, E. J. Org. Chem. 1991, 56,
2098. (b) Burke, E. D.; Gleason, J. L. Org. Lett. 2004, 6, 405. (c) Kera¨nen,
M. D.; Eilbracht, P. Org. Biomol. Chem. 2004, 2, 1688. (d) Adhikari, S.;
Caille, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7,
2795. (e) Tanaka, S.; Yasuda, M.; Baba, A. Synlett 2007, 1720 and
references therein. See also refs 1 and 2.
(4) For selected recent works in different reactions to construct R-carbonyl
quaternary stereocenters using acyclic tetrasubstituted silyl ketene acetals
or tributyltin enolates, see: (a) Mermerian, A. H.; Fu, G. C. J. Am. Chem.
Soc. 2005, 127, 5604. (b) Doyle, A. G.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2007, 46, 3701.
(5) (a) Haner, R.; Laube, T.; Seebach, D. J. Am. Chem. Soc. 1985, 107,
5396. (b) Kato, M.; Mori, A.; Oshino, H.; Enda, J.; Kobayashi, K.;
Kuwajima, I. J. Am. Chem. Soc. 1984, 106, 1773. (c) Ho, C.-H.; Ohmiya,
H.; Jamison, T. F. Angew. Chem., Int. Ed. 2008, 47, 1893 and references
therein.
(6) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2004, 43, 6358.
(7) Denmark, S. E.; Wilson, T. W.; Burk, M. T.; Heemstra, J. R., Jr. J.
Am. Chem. Soc. 2007, 129, 14864.
(1) (a) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
Germany, 2005. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(2) (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, 2003. (b) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M. Chem. Eur.
J. 2002, 8, 37.
10.1021/ol800401g CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/18/2008

hydes under Lewis base catalysis. On the other hand, aldol
reactions using an in situ generated R,R-disubstituted metal
enolate to avoid the preformation of an activated donor
compound8 are limited to either donors with specific chelat-
ing functional groups9 or cyclic donors,10 which skirt the
problem of enolate geometry. Notable progress was accomp-
lished by Barbas and co-workers in organocatalytic direct
aldol reactions of acyclic R,R-disubstituted aldehydes;11 how-
ever, there still remains much room for improvement in terms
of donor scope, especially in metal catalysis. Herein, we
report a new Sc3+-catalyzed aldol-type addition of N-
benzoylcyclopropanecarboxamides 1 to aldehydes via iodide-
mediated ring-opening. After ring closure of aldol adducts,
γ-lactams bearing R-carbonyl quaternary stereocenters were
obtained in up to 97% yield and up to 90:10 dr.
opening and then subsequently promote aldol-type addition
with good stereoselectivity (eq 1).
Initially, we screened various cyclopropanecarboxylate-
type donors, Lewis acids, nucleophiles, as well as capping
reagents (Y+ in eq 1) and found that 10 mol % of Sc(OTf)3
promoted the addition of N-benzoylcyclopropanecarbox-
amide 1a (R ) H)16 to benzaldehyde (2a) in the presence of
TMSCl and NaI (Scheme 1). Aldol adduct 3aa was obtained
We set out to develop a new aldol-type reaction for the
construction of R-carbonyl quaternary stereocenters by
exploiting strained cyclopropanecarboxylate-type donors.
Since Carreira’s seminal reports on MgI2-catalyzed Mannich-
type ring expansion of spiro[cyclopropane-1,3′-oxindoles],12
various donors, such as cyclopropyl ketones and methyl-
enecyclopropanecarboxamides,13 have been shown to par-
ticipate in Mannich-type reactions. In contrast, analogous
aldol-type reactions have been observed only with stoichio-
metric use of strong Lewis acids, such as TiCl4, Et2AlI, and
TMSOTf.14 Moreover, R-substituted donors have not been
utilized in those studies to construct R-carbonyl quaternary
stereocenters.14 Until now, catalytic couplings of cyclopro-
panes with aldehydes have been limited to donors bearing
two activating groups, either cyclopropanedicarboxylates or
donor/acceptor cyclopropanes.15 Therefore, the development
of a new catalyst for aldol-type reactions using monoactivated
R-substituted cyclopropanecarboxylate donors is desirable.
We hypothesized that a suitable combination of Lewis acid
catalyst and nucleophile could generate a geometrically well-
defined R,R-disubstituted enolate in situ via nucleophilic ring
Scheme 1. Result of Initial Screening with R-Unsubstituted
Donor 1a
in 75% yield together with cyclized γ-lactams 4aa and 5aa
(total 10% yield) as minor coproducts. Although the required
reaction time was long at 25 °C (120 h), the high diastere-
omeric ratio of 3aa was promising (syn/anti ) 93:7). Based
on this initial result, we studied the reaction using R-sub-
stituted donor 1b (R ) Me) and aldehyde 2a in detail (Table
1). To simplify reaction analyses, crude reaction mixtures
containing aldol adducts and γ-lactams were treated with
Et3N followed by HCl to induce complete cyclization and
desilylation, respectively, giving 5ba. R-Substituted donor
1b showed higher reactivity than 1a; 10 mol % of Sc(OTf)3
promoted the reaction of 1b with aldehyde 2a at 0 °C, giving
5ba in high yield and good diastereoselectivity after 48 h
(Table 1, entry 1, 97% yield, dr ) 89:11). The major
diastereomer of product 5ba was found to be that derived
from a syn-aldol adduct. Neither other rare earth metal
triflates nor Mg(OTf)2 gave satisfactory yields of 5ba (entries
2-5, trace to 8% yield). The heterogeneous mixture of NaI
and TMSCl was superior as an iodide/capping agent com-
(8) Reviews on direct aldol reactions: (a) Alcaide, B.; Almendros, P.
Eur. J. Org. Chem. 2002, 1595. (b) Palomo, C.; Oiarbide, M.; Garc´ıa, J.
M. Chem. Soc. ReV. 2004, 33, 65.
(9) For selected examples, see: (a) Ito, Y.; Sawamura, M.; Shirakawa,
E.; Hayashizaki, K.; Hayashi, T. Tetrahedron 1988, 44, 5253 and references
therein. (b) Kuwano, R.; Miyazaki, H.; Ito, Y. J. Organomet. Chem. 2000,
603, 18. (c) Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.; Hayashi,
M.; Komiyama, K.; Omura, S.; Smith, A. B., III. J. Am. Chem. Soc. 2000,
122, 2122. For related works of R-carbonyl tert-alcohol construction: (d)
Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.;
Sakamoto, S.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
2169.
(10) (a) Mahrwald, R.; Gu¨ndogan, B. J. Am. Chem. Soc. 1998, 120, 413.
(b) Ogawa, S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M.
Angew. Chem., Int. Ed. 2007, 46, 8666.
(11) Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int. Ed.
2004, 43, 2420 and references therein.
(12) (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira,
E. M. Angew. Chem., Int. Ed. 1999, 38, 3186. (b) Marti, C.; Carreira, E.
M. J. Am. Chem. Soc. 2005, 127, 11505. (c) Lerchner, A.; Carreira, E. M.
Chem. Eur. J. 2006, 12, 8209 and references therein.
(13) (a) Taillier, C.; Lautens, M. Org. Lett. 2007, 9, 591 and references
therein. (b) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4,
3147. (c) Huang, W.-W.; Chin, J.; Karpinski, L.; Gustafson, G.; Baldino,
C. M.; Yu, L.-B. Tetrahedron Lett. 2006, 47, 4911.
(14) (a) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo, H.; Oshima, K.
Tetrahedron 2001, 57, 987. (b) Timmons, C.; Chen, D.-J.; Cannon, J. F.;
Headley, A. D.; Li, G. G. Org. Lett. 2004, 6, 2075. (c) Shi, M.; Yang,
Y.-H.; Xu, B. Tetrahedron 2005, 61, 1893. R-Substituted donors for
constructing R-carbonyl quaternary stereocenters have not been utilized in
these studies.
(15) (a) Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127,
16014. (b) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151. (c)
Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321 and references therein.
For related Sc(OTf)3-catalyzed couplings of cyclopropanedicarboxylates and
donor/acceptor cyclopropanes with nitrones, see: (d) Lebold, T. P.; Carson,
C. A.; Kerr, M. A. Synlett 2006, 364. See also: (e) Jackson, S. K.;
Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008, 130,
4196 and references therein.
(16) Utility of the imide as an achiral template: (a) Myers, J. K.;
Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959. (b) Vanderwal, C. D.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 14724 and references therein.
1662
Org. Lett., Vol. 10, No. 8, 2008

Table 1. Optimization of Reaction Conditions with
R-Substituted Donor 1b
Table 2. Substrate Scope and Limitations of Aldol-Type
Reaction/Cyclization Sequencea
Lewis
acid
TMSCl
(equiv)
iodide source
(equiv)
yield
(%)
cat.
entry (mol %)
yieldb
(%)
entry
dra
R
1
R′
2
5
drc
1
2
3
4
5
6
7
8b
9c
10c
11
Sc(OTf)3
La(OTf)3
Gd(OTf)3
Yb(OTf)3
Mg(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
ScI3
1.6
1.6
1.6
1.6
1.6
1.6
1.6
0
NaI (2.0)
NaI (2.0)
NaI (2.0)
NaI (2.0)
NaI (2.0)
LiI (2.0)
nBu4NI (2.0)
TMSI (1.6)
NaI (2.0)
none
97
5
5
89:11
80:20
80:20
83:17
ND
ND
89:11
ND
1
2d
3
4
5
6
7
8
9
10
5
Me 1b Ph
Me 1b Ph
Me 1b 4-ClC6H4
Me 1b 4-MeC6H4
Me 1b 2-furyl
2a 5ba 97 89:11
2a 5ba 94 87:13
2b 5bb 87 88:12
2c 5bc 57 85:15
2d 5bd 70 83:17
10
10
10
10
10
10
10
10
10
10
8
trace
trace
11
0
42
59
72
Me 1b (E)-PhCHdCH 2e 5be 78 81:19
Me 1b cyclohexyl
Me 1b 1-hexyl
2f 5bf
87 87:13
2g 5bg 87 85:15
0
0
1.6
90:10
88:12
88:12
Me 1b (Z)-1-hex-3-enyl 2h 5bh 90 90:10
Et 1c Ph 2a 5ca 79 80:20
Allyl 1d Ph
H 1a Ph
10
11
12e
ScI3
none
2a 5da 82 83:17
2a 5aa 84 94:6
a Determined by H NMR analysis. b Complex mixtures of byproducts
1
were obtained. c Treatment with HCl was omitted.
a Reactions were run using 1.5 equiv of 1, 1.6 equiv of TMSCl, and 2.0
equiv of NaI in CH2Cl2 (0.1 M) at 0 °C for 48 h unless otherwise noted.
b Isolated yield after purification by column chromatography. c Determined
by H NMR analysis. d Reaction time was 72 h. e Reaction was run at 25
1
bination compared to several sets of heterogeneous (entry
6) and homogeneous conditions (entries 7-8). In entries
2-7, cyclopropane ring-opening did proceed, but aldehyde
addition proved problematic, giving γ-lactam 6b17 as a major
product. In entry 9, the reaction proceeded even in the
absence of TMSCl, and 5ba was obtained in similar
diastereoselectivity (90:10) to that of entry 1, albeit in lower
yield. Furthermore, ScI3 alone promoted the reaction with
good diastereoselectivity (entry 10, 59% yield, dr ) 88:12).
The result of entry 10 implies that ScI3 functions not only
as a Lewis acid but also as an iodide source in a manner
analogous to that of MgI2 in related Mannich-type reactions.12
TMSCl slightly improved the reactivity while maintaining
good diastereoselectivity (entry 11, 72% yield, dr ) 88:12).
Optimized reaction conditions in terms of yield (Table 1,
entry 1) were applied to various aldehydes (Table 2). With
nonenolizable aryl, heteroaryl, and alkenyl aldehydes
2a-e, products were obtained in 57-97% yield and
81:19-89:11 dr (entries 1-6).18 Aldehyde 2c bearing an
electron-donating substituent provided a less satisfactory
yield (entry 4). When the loading of Sc(OTf)3 was reduced
to 5 mol %, 5ba was successfully obtained in 94% yield
and 87:13 diastereoselectivity (entry 2). Enolizable alkyl
aldehydes are often poor substrates for typical direct cross-
aldol reactions under basic conditions due to competitive self-
aldol condensation.8,19 It is noteworthy that alkyl aldehydes,
°C for 96 h.
including readily enolizable linear alkyl aldehydes, are applic-
able without problems in the present system. Aldehydes 2f-h
afforded products in high yield and good diastereoselectivity
(entries 7-9, 87-90% yield, dr ) 85:15-90:10). No
products of self-aldol condensations were observed in entries
7-9. The reaction generality with respect to donor substit-
uents was investigated in entries 10-12. Donors 1c (R )
Et), 1d (R ) allyl), and 1a (R ) H) reacted with aldehyde
2a to afford products 5ca (79% yield), 5da (82% yield), and
5aa (84% yield), respectively. Removal of the N-benzoyl
group from 5ba proceeded smoothly by treatment with
NaOH in DME/H2O at 0 °C; NH-lactam 7ba was obtained
in 87% yield (eq 2).
In the present system, syn-aldol adducts 3 were formed
as the major products. On the basis of Oshima and co-
workers’ early work,14a we assume that the observed product
(17) γ-Lactam 6b formed via ring-expansion without aldehyde incor-
(19) For selected exceptional metal-catalyzed direct aldol reactions
wherein enolizable linear alkyl aldehydes afforded good results comparable
to other aldehydes, see: (a) Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner,
K. C.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2005, 127, 7284 and
references therein. (b) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am.
Chem. Soc. 2003, 125, 8706 and references therein. (c) Trost, B. M.; Ito,
H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. (d) Yoshikawa, N.;
Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki,
M. J. Am. Chem. Soc. 2001, 123, 2466. For other examples, see reviews in
ref 2 and references therein.
poration.
(18) The relative stereochemistries of 5bd and 5aa were unambiguously
determined by single crystal X-ray analysis. The relative stereochemistries
of other products are drawn by analogy.
Org. Lett., Vol. 10, No. 8, 2008
1663

distribution is governed by kinetic control. Syn selectivity
can be rationalized by using stereochemical models based
on closed transition states both for iodide attack and addition
to aldehyde (Figures 1 and 2). Because ScI3 afforded product
tially generating cis-enolate (Figure 1). A proposed catalytic
cycle is shown in Figure 2a. cis-Enolate addition to aldehyde
is believed to proceed via a Zimmerman-Traxler transition
state to minimize 1,3-diaxial interactions, affording syn-
adduct 3. In the absence of TMSCl, the Sc-aldolate 8 should
be protonated by the relatively acidic imide N-H moiety to
regenerate the Sc-catalyst. On the other hand, in the presence
of TMSCl, the resulting Sc-aldolate 8 can be trapped by
silylation, thereby promoting Sc-catalyst regeneration.22
When using 10 mol % of ScI3 instead of Sc(OTf)3/NaI, 5aa
was furnished in g59% yield (Table 1, entries 10 and 11).
These results show that a catalytic amount of iodide source
is sufficient to promote the desired reaction. We suspect that
the catalyst is regenerated, in this case, through in situ ring
closure (Figure 2b). Indeed, γ-lactam 5ba was observed as
a major product by TLC analysis of the reaction mixture in
entry 10, Table 1, before treatment with Et3N.
In summary, we have developed a Sc3+-catalyzed aldol-
type addition of N-benzoylcyclopropanecarboxamides 1 to
various aldehydes, including readily enolizable linear alkyl
aldehydes, via iodide-mediated ring-opening. The reaction
proceeded at 0 °C using either a Sc(OTf)3/NaI system or
ScI3, and γ-lactams bearing R-carbonyl quaternary stereo-
centers were obtained in 97-57% yield and 90:10-80:20
diastereoselectivity after ring closure. Further studies to
improve the reactivity using ScI3 alone, which is preferable
in terms of atom-economy, as well as trials to develop
catalytic enantioselective variants, are ongoing.
Figure 1. Postulated transition-state models for cyclopropane ring
opening.
5ba with similar diastereoselectivity to that obtained with
the use of a Sc(OTf)3/NaI system (Table 1, entry 1 vs entry
11; entry 9 vs entry 10), we believe that Sc3+-bound iodide
may be the active nucleophile involved in cyclopropane ring-
opening. The attack of iodide on the cyclopropane ring can
occur perpendicular to the carbonyl group through either
TS-(A) or TS-(B). Metal-bound iodide would attack the
cyclopropane ring via favorable TS-(A),20 which is closer
to the favorable bisected cis geometry,21 thereby preferen-
Acknowledgment. We thank Prof. S. Kobayashi, Dr. R.
Matsubara, and Mr. H. Morimoto at the University of Tokyo
for X-ray crystallography work. This research was supported
by a Grant-in-Aid for Specially Promoted Research from
MEXT. S.H. and S.H.W. thank JSPS for predoctoral and
postdoctoral fellowships, respectively.
Supporting Information Available: Detailed experi-
mental procedures, spectral data for new compounds, and
X-ray crystallography data in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800401G
(20) We speculate that I- is better alligned for overlap with the σ* orbital
of the cyclopropane C-C bond in TS-(A) than in TS-(B).
(21) In the ground state, donor 1 should stereoelectronically favor the
bisected conformation wherein two C-C σ-bonds of its cyclopropane ring
and the π* orbital of its carbonyl group experience maximal overlap. For
bisected conformations of cyclopropylmethyl ketone, bisected cis geometry
was reported to be more favorable than trans geometry. Tidwell, T. T. In
The Chemistry of Functional Groups: Cyclopropyl Group; Rappoport, Z.,
Ed.; Wiley: New York, 1987; Vol. 1, Chapter 10, pp 565-632. For a related
discussion, see ref 14a.
(22) Although the involvement of a Mukaiyama-type reaction pathway
in the presence of TMSCl cannot be completely ruled out, we believe that
this mechanism is less probable on the basis of certain control experiments
(Table 1). Similar diastereoselectivities were observed even in the absence
of TMSCl, either with Sc(OTf)3/NaI or ScI3 as a catalyst (Table 1, entry 1
vs entry 9; entry 10 vs entry 11). Attempts to isolate a relevant
N-acylsilylketeneaminal failed. Thus, we could not perform definitive control
experiments to clarify the mechanism.
Figure 2. (a) Postulated catalytic cycle of aldol-type addition and
(b) catalyst regeneration in ScI3-catalyzed reaction.
1664
Org. Lett., Vol. 10, No. 8, 2008