SmI2-Promoted novel tandem elimination and coupling reactions of aliphatic imides with carbonyl compounds: Application to the synthesis of dl-isoretronecanol

Article abstract of DOI:10.1016/j.tetlet.2005.12.126

Treatment of α-hetero-substituted cyclic imides with carbonyl compounds mediated by samarium(II) diiodide in the presence of HMPA was found to undergo novel tandem elimination and reductive coupling reactions to generate α-hydroxyalkylated imides in good to high yields. Stereochemistry of the coupling products was researched and the result that increasing the steric bulkiness of the N-substituents leads to an increase of threo-selectivity was observed. The mechanistic origins of this stereoselectivity are also briefly documented and the reaction was further applied to the convenient synthesis of a simple pyrrolizidine alkaloid, isoretronecanol.

Full text of DOI:10.1016/j.tetlet.2005.12.126

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1607–1611
SmI2-Promoted novel tandem elimination and coupling reactions
of aliphatic imides with carbonyl compounds: application
to the synthesis of dl-isoretronecanol
Masayuki Kabata, Takamasa Suzuki, Kunihiko Takabe and Hidemi Yoda*
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Received 2 December 2005; revised 15 December 2005; accepted 21 December 2005
Available online 19 January 2006
Abstract—Treatment of a-hetero-substituted cyclic imides with carbonyl compounds mediated by samarium(II) diiodide in the pres-
ence of HMPA was found to undergo novel tandem elimination and reductive coupling reactions to generate a-hydroxyalkylated
imides in good to high yields. Stereochemistry of the coupling products was researched and the result that increasing the steric bulk-
iness of the N-substituents leads to an increase of threo-selectivity was observed. The mechanistic origins of this stereoselectivity are
also briefly documented and the reaction was further applied to the convenient synthesis of a simple pyrrolizidine alkaloid,
isoretronecanol.
Ó 2006 Elsevier Ltd. All rights reserved.
Samarium(II) diiodide1 has been extensively investi-
O
gated as a powerful electron donor able to promote a
wide range of reductions and coupling reactions.2 Its
N R
use in synthesis has been especially advantageous for
ring closure reactions and C–C bond formation such
as hydroxyl-directed addition of carbonyl to C@C dou-
ble bond and stereocontrolled intramolecular pinacol
reactions.2k,3 The reactions of acid chlorides4 and acid
anhydrides5 with this reagent have also been researched.
In addition, intramolecular and intermolecular Barbier-
type reactions with haloalkanes toward the carbonyl
group of ketones6 and imides7 have been reported. In
this connection recent disclosures from this laboratory
have demonstrated the extremely threo-selective prepa-
ration of a-hydroxyalkylated aromatic lactams via the
first pinacolic cross-coupling reaction between phthal-
imides and carbonyl compounds as shown in Scheme
1.8 In addition, a reversibly erythro-selective method
through SmI2-mediated tandem elimination and cou-
pling reactions of hetero-substituted aromatic lactams
with carbonyl compounds was also developed.
R1CHO
SmI2
O
O
O
N R
N R
OH
X = SPh,
SO2Ph,
SePh
X
HO
R
1
R1CHO
SmI2
O
O
N R
OH
N R
OH
R
R
1
1
erythro-isomer
threo-isomer
Scheme 1.
These results demonstrate the mechanistically fascinat-
ing duality of aromatic lactam-employed coupling reac-
tions for stereocontrolled carbon–carbon bond
formation. Significant progress, thus, has been made in
advancing the versatility of samarium(II) compounds,
however, the lack of studies concerning the reactivity
Keywords: SmI2; Reductive coupling; Imide; Pyrrolizidine alkaloid;
Isoretronecanol.
*
Corresponding author. Tel./fax: +81 53 478 1150; e-mail:
tchyoda@ipc.shizuoka.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.126

1608
M. Kabata et al. / Tetrahedron Letters 47 (2006) 1607–1611
toward simple amides is surprising except in some
special cases.9 Especially no procedure starting with
hetero-substituted aliphatic imides has appeared. This
should be attributed to their low reactivity. Herein, we
report our successful efforts for the development of a
novel SmI2-mediated tandem reaction of sulfur-substi-
tuted imides with carbonyl compounds, leading to the
a-hydroxyalkylated products with threo-selectivity and
its extensive application to the synthesis of a simple
pyrrolizidine alkaloid, isoretronecanol.
ence of a nitrogen atom and two carbonyl groups in
an aliphatic imide affecting the steric- and/or stereoelec-
tronic effects would have a decisive role and indispens-
able for these reactions.
As shown in Table 2, we further found that the use of
aliphatic ketones as well as other aldehydes (entries 1–
6) and sterically more demanded aromatic ketone (entry
7) also underwent fast reactions to afford the corre-
sponding tandem desulfurization–coupling products 3
with moderate to high yields, respectively. Thus, this
strategy will find convenient usage and proved to be a
superior C–C bond formation method with cyclic imides
accompanying the desulfurization reaction.
Initial experiments have been performed on a coupling
reaction promoted by SmI2 between N-benzyl a-, b-,
or c-phenylthio-substituted c-lactams and butanal with
a variety of additives such as HMPA, CuCl2, FeCl3,
6b,10
or NiI2
in expectation of new C–C bond forma-
Since the stereodefined construction of threo- or erythro-
heterocyclic moieties with a hydroxyl-containing side
chain attracts considerable attention due to their pres-
ence in the framework of natural products,14 we next
examined the possibility of stereoselective tandem cou-
pling reactions. As shown in Table 3, it will particularly
be of interest to note that increasing the steric bulkiness
of the N-substituents under these conditions led to an
increase of the threo-selectivity (up to 84:16, indicated
in entries 8 and 9).15 We also found that the threo/ery-
thro ratio of 2 was essentially independent of the leaving
groups together with the reaction temperature17 based
on our supporting experiments.
tion.11 The reactions, however, did not proceed under
any conditions even in the use of excess SmI2. Next,
we examined the same type of reactions employing sim-
ilar sulfur-substituted N-benzylsuccinimide derivative
1a12 prepared from maleimide with butanal, which, in
turn, changed the results and gave the desired tandem
desulfurization and coupling reaction products 2 (Table
1) but in unsatisfactory yield (entry 1) due to the forma-
tion of the aldehyde-self-coupling compounds. The use
of additives, however, had a significant effect on the rate
to give 2 (entries 2–4). After investigation of these reac-
tion conditions, an expected enhancement was finally
observed upon employing HMPA, which could effect
these reactions strongly, leading to the coupling product
2 in 85% isolated yield (entry 5). The same beneficial re-
sult was again obtained in reaction with phenylsulfonyl-
imide (entry 6). Furthermore, we were delighted to find
that this procedure could be also applicable for the pro-
duction of 213 through replacement of the PhS leaving
group to other sulfur-functions together with a change
from the sulfur- to the seleno-substituent (entries 7–9).
Although the reason why such unusual desulfurization
and subsequent coupling reactions were observed only
in the use of imides is not clarified at present, the pres-
In light of the above outcome, we turned our attention
to the short and convenient synthesis of a biologically
active pyrrolizidine alkaloid, isoretronecanol.18 Treat-
ment of the N-MPM imide 1c (R = MPM) with 4-benz-
yloxybutanal in the presence of SmI2 (3 equiv) as
described in Scheme 2 afforded the hydroxyalkylated
threo-imide 10 as a moderate diastereoselective product
(threo/erythro = 56:19, isolated yields, respectively19).
After TBS-protection of threo-10, this was submitted
to reduction with NaBH4 to give the hydroxylactam
11, fortunately with complete chemoselectivity. Accom-
panying formation of the other regioisomer and the
Table 1. Tandem desulfurization and coupling reactions of imides 1aa
Table 2. Tandem desulfurization and coupling reactions of imides 1ba
OH
H
X
SmI2, C3H7CHO
additive, THF
OH
H
O
SPh
O
SmI2, R1COR2
N
R
O
N
Bn
1
O
O
Bn
O
2
1a
R
N
Me
2
HMPA, THF, rt
N
Me
O
O
3
1b
Entry
X
Additives
(equiv)
Temp Time Yield
(°C)
(h)
(%)b
Entry
R1
R2
Time
(h)
Yield
(%)b
1
2
3
4
5
6
7
8
9
PhS
PhS
PhS
PhS
PhS
PhSO2
PhSe
2-PyrS
—
rt
1
3
3
1
1
1
1
1
1
43
48
44
65
85
43
75
79
85
1
2
3
4
5
6
7
8
H
H
H
H
CH3
CH3
n-C3H7
1
1
1
1
3
3
3
3
82
63
66
82
64
68
71
48
NiI2 (0.01)
À20
n-C6H13
(CH3)2CHCH2
C6H5CH2
CH3
CH3CH2
CH3CH2
C6H5
t-BuOH (1.0) À20
t-BuOH (1.0) rt
HMPA (1.0)
HMPA (1.0)
HMPA (1.0)
HMPA (1.0)
rt
rt
rt
rt
rt
CH3CH2
CH3
2-NaphthylS HMPA (1.0)
a All reactions employed 3.0 equiv of SmI2, 2.0 equiv of carbonyl
compounds, and 1.0 equiv of HMPA, respectively.
b Isolated yield.
a All reactions employed 3.0 equiv of SmI2 and 2.0 equiv of butanal,
respectively.
b Isolated yield.

M. Kabata et al. / Tetrahedron Letters 47 (2006) 1607–1611
Table 3. Stereoselective tandem desulfurization and coupling reactions of imides 1ca
1609
OH
OH
H
H
SPh
SmI2, C3H7CHO
HMPA, THF, rt
O
+
O
O
N
N
R
N
R
O
O
O
R
1c
erythro-2
threo-2
Entry
R (compound)
Time (h)
Yield (%)b
threo/erythroc
1
2
3
4
5
6
7
8
9
H
1
1
1
1
1
2
2
2
2
5
82
87
76
85
59
41
59
67
50:50
65:35
71:29
64:36d
73:27
72:28
73:27
84:16
84:16
Me (1b)
Bn (1a)
MPM
Ph
1-Naphthyl
(m-But)2Ph
CHPh2
(p-But)Ph
a All reactions employed 3.0 equiv of SmI2, 2.0 equiv of butanal, and 1.0 equiv of HMPA, respectively.
b Isolated yield.
c Determined by 1H NMR.
d Isolated ratio.
OH
OH
H
H
SPh
OBn
OBn
a
O
+
O
O
N
N
N
O
O
O
MPM
1c
erythro-10
threo-10
MPM
MPM
OH
OTBS
OTBS
H
H
H
N
OBn
OBn
OBn
c
b
d
threo-10
HO
N
N
H
O
O
O
11
12
13
Boc
MPM
Boc
OH
N
N
H
BocHN
OBn
f
e
g
OBn
15
TBSO
OH
14
dl-isoretronecanol (16)
HO
Scheme 2. Reagents and conditions: (a) BnO(CH2)3CHO, SmI2, HMPA, THF; 56% (threo-10), 19% (erythro-10); (b) 1, TBSCl, imidazole, DMF;
98%; 2, NaBH4, MeOH; quant.; (c) 1, Et3SiH, BF3OEt2, CH2Cl2, À40 °C; 82%; 2, CAN, CH3CN–H2O (9:1); 98%; (d) 1, TBSCl, imidazole, DMF;
90%; 2, (Boc)2O, DMAP, Et3N, CH2Cl2; 99%; (e) 1, NaBH4, MeOH; quant.; 2, Bu4NF, THF; quant.; (f) 1, TBSCl, Et3N, CH2Cl2; 91%; 2, MsCl,
Et3N, CH2Cl2; 3, t-BuOK, THF; 82% (two steps); (g) 1, H2, Pd/C, EtOH; 94%; 2, MsCl, Et3N, CH2Cl2; 3, TFA, CH2Cl2, 0 °C; 70% (two steps).
ring-opened amide alcohol was not observed. Then, 11
was readily effected by BF3OEt2-promoted deoxygen-
ation with Et3SiH followed by removal of the N-
MPM group with cerium ammonium nitrate (CAN),
leading to the N-H lactam 12 in 79% yield (four steps).
For the purpose of the construction of a pyrrolizidine
ring system, reduction of the N-Boc lactam 13 derived
from 12 through protection of the two functional
groups was performed to give the acyclic alcohol 14,
which was, in turn, reacted subsequently under cycliza-
tion conditions after chemoselective TBS-protection of
the primary alcohol to provide the pyrrolidine 15 with
the desired stereochemistry in 66% yield (seven steps
from 12). Finally, 15 thus obtained was submitted to
successive reactions of debenzylation, mesylation, and
TFA-induced Boc-deprotection followed by simulta-
neous cyclization of the resulting pyrrolidine intermedi-
ate to complete the synthesis of dl-isoretronecanol
(16).18
In conclusion, we have developed synthetically useful
tandem SmI2-mediated elimination and reductive cou-
pling reactions between a-hetero-substituted aliphatic
imides and carbonyl compounds with satisfactory
diastereoselectivity.
This procedure found an application in the new syn-
thetic opportunity for biologically important pyrrolizi-
dine and/or indolizidine alkaloids. Current efforts to
expand the scope of the synthetic application to more
complexed natural products such as a recently isolated
amphorogynine family20 are in progress.
Acknowledgments
This work was supported in part by a Grant-in-Aid (No.
15550031) for Scientific Research from the Japan Soci-
ety for the Promotion of Science.

1610
M. Kabata et al. / Tetrahedron Letters 47 (2006) 1607–1611
10. (a) Molander, G. A.; Shakya, S. R. J. Org. Chem. 1994,
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12. We have recently communicated the result that treatment
of unsubstituted simple lactams with aldehydes in the
presence of SmI2 undergoes a novel N–C(hetero)-coupling
reaction instead of the pinacolic-type one to generate N-a-
hydroxyalkylated products, which could be applied to the
synthesis of some biologically active indolizidine natural
products.9e
13. We could not prepare the hydroxyalkylated imide 2 from
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butanal in the presence of base (cf. Lozzi, L.; Ricci, A.;
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15. Relative threo/erythro stereochemistry of 2 obtained was
unambiguously proved after MOM-protection by com-
paring its spectral data with those of the synthesized
compound 9 elaborated through crucial manipulations
from the lactone 4 according to our previous reports16 as
shown below:
O
O
CH OH
Me N
1) Swern oxid.
2
OH
ref. 16
Me NH
2
2
OTBDPS
OTBDPS
OTBDPS
HO
2
O
O
O
HOH C
O
O
2) C H MgBr
5
3
7
6
4
OH
quant.
3) p-TsOH
71%
OMOM
OMOM
OMOM
H
H
1) BnNH
Swern oxid.
PCC
45%
2
BnHN
2) MOMCl
O
O
O
N
Bn
N
Bn
46%
43%
3) Bu NF
8
OH
7
9
4
O
OH
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Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am. Chem.
Soc. 1987, 109, 453; (d) McDonald, C. E.; Galka, A. M.;
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(e) Yoda, H.; Katoh, H.; Ujihara, Y.; Takabe, K.
Tetrahedron Lett. 2001, 42, 2509; (f) Ricci, M.; Blakskjaer,
P.; Skrydstrup, T. J. Am. Chem. Soc. 2000, 122, 12413,
and references cited therein; (g) Blakskær, P.; Gavrila, A.;
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9091; (h) Zheng, X.; Feng, C.-G.; Ye, J.-L.; Huang, P.-Q.
Org. Lett. 2005, 7, 553.
The other compounds were also estimated to have the
same stereochemistry based on the similarity of its spectral
data to those of threo-2 (R = Bn).
16. (a) Yoda, H.; Kimura, K.; Takabe, K. Synlett 2001, 400;
(b) Yoda, H.; Maruyama, K.; Takabe, K. Tetrahedron
Lett. 2003, 44, 1775; (c) Yoda, H.; Suzuki, Y.; Takabe, K.
Heterocycles 2005, 65, 519.
17. The observed stereochemical outcome of these reactions
can be explained by consideration using six-membered
SmI2-chelation model containing nitrogen lone-paired
electrons as described below. In the thermodynamically
stable form in which the larger N-substituent would
occupy the equatorial position, the reaction progressed
through coupling of the radical produced by desulfuriza-
tion with a carbonyl compound. In this case the attack of
the radical present in the chelation model occurred from
the face avoiding the mutual steric repulsion between SmI2
and an aldehyde-alkyl group. In addition, the alkyl
function would also prefer to be equatorial resulting in
an increase of the threo-selectivity. Additional studies on
the precise mechanistic origin of these reactions are in
progress.

M. Kabata et al. / Tetrahedron Letters 47 (2006) 1607–1611
1611
Chem. 2000, 2227; (b) David, O.; Blot, J.; Bellec, C.;
Fargeau-Bellassoued, M.-C.; Haviari, G.; Celerier, J.-P.;
Lhommet, G.; Gramain, J.-C.; Gardette, D. J. Org. Chem.
1999, 64, 3122; (c) Konno, H.; Kishi, M.; Hiroya, K.;
Ogasawara, K. Heterocycles 1998, 49, 33; (d) Knight, D.
W.; Share, A. C.; Gallagher, P. T. J. Chem. Soc., Perkin
Trans. 1 1997, 2089.
O
SmI
N
2
R
H
H
H
O
.
O
R
H
.
H
O
N
R
O
R
19. Whereas the major threo-isomer 10 only was employed for
further synthetic sequence in this communication, minor
erythro-10 could be also taken advantage of the synthesis
of the other stereoisomeric natural alkaloid, trachelanth-
amidine (laburnine).18
O
SmI
2
H
18. For recent examples of the synthesis of isoretronecanol,
´
20. Huong, D. T. T.; Martin, M.-T.; Sevenet, T.; Pa¨ıs, M. J.
see: (a) Bertrand, S.; Hoffmann, N.; Pete, J.-P. Eur. J. Org.
Nat. Prod. 1998, 61, 1444.