Asymmetric iodocyclization catalyzed by salen-CrIIICl: Its synthetic application to swainsonine

Article abstract of DOI:10.1002/chem.200701199

The previously developed enantioselective iodocyclization of γ-hydroxy-cis-alkenes required 30 mol% of (R,R)-salen-Co^II complex as chiral catalyst and 0.75 equivalent of N-chlorosuccinimide (NCS) as activator to produce 2-substituted tetrahydrofurans with 61 to 90% ee. Due to the considerable loading amount of the Co^II complex, another more effective catalyst was pursued by screening (R,R)-salentransition metal complexes. When 10 mol % of the catalysts were applied with 0.5 equivalent of NCS, a higher level of stereoselectivity was attained with the corresponding Cr^IIICl (84% ee), Mn^IICl (52% ee) and Co^II complexes (66% ee). Refinement of the conditions established a novel catalytic enantioselective iodocyclization protocol using iodine in the presence of 7 mol% of (R,R)-salen-Cr^IIICl complex activated by 0.7 equivalent of NCS in toluene to induce 74 to 93 % ee.

Full text of DOI:10.1002/chem.200701199

FULL PAPER
DOI: 10.1002/chem.200701199
Asymmetric Iodocyclization Catalyzed by Salen–CrIIICl:
Its Synthetic Application to Swainsonine
Hyo Young Kwon,[a] Chul Min Park,[a] Sung Bae Lee,[a] Joo-Hack Youn,[b] and
Sung Ho Kang*[a]
Abstract: The previously developed
enantioselective iodocyclization of g-
hydroxy-cis-alkenes required 30 mol%
of (R,R)-salen–CoII complex as chiral
catalyst and 0.75 equivalent of N-chlor-
osuccinimide (NCS) as activator to
produce 2-substituted tetrahydrofurans
with 61 to 90% ee. Due to the consid-
erable loading amount of the CoII com-
plex, another more effective catalyst
was pursued by screening (R,R)-salen–
transition metal complexes. When
10 mol% of the catalysts were applied
with 0.5 equivalent of NCS, a higher
level of stereoselectivity was attained
with the corresponding CrIIICl (84%
ee), MnIICl (52% ee) and CoII com-
plexes (66% ee). Refinement of the
conditions established a novel catalytic
enantioselective iodocyclization proto-
col using iodine in the presence of
7 mol% of (R,R)-salen–CrIIICl complex
activated by 0.7 equivalent of NCS in
toluene to induce 74 to 93% ee.
Keywords: asymmetric catalysis
·
·
cyclization
·
enantioselectivity
swainsonine
Introduction
TiIV–Binol complexes,[11] and chlorohydroxylation with PdII–
Binap complexes.[12] Most of them have their separate draw-
backs such as stoichiometric use of expensive chiral re-
agents, low enantioselectivity and lack of substrate generali-
ty. We have been engaged in efforts to evolve the catalytic
asymmetric electrophile-promoted cyclization. Planning of
the proposed cyclization study led us to deliberate several
controlling factors such as substrate structures, how to accel-
erate the asymmetric cyclization, how to impose chiral envi-
ronments, electrophilic species and how to suppress the rac-
emic background reaction. In this context, we documented a
highly enantioselective iodoetherification of g-hydroxy-cis-
alkenes using iodine in the presence of salen–CoII complex
and N-chlorosuccinimide (NCS).[13] Since our reported
method requires a relatively considerable amount of the
complex (30 mol%) for high stereoselectivity, we have en-
deavored to exploit more efficient catalysts in terms of their
loading quantities as well as enantioselectivity.
Electrophile-mediated cyclization is one of the most reliable
ways to form heterocycles.[1] The prime concern in the cycli-
zation involves the stereoselectivity which is dictated by the
facial differentiation of olefinic double bonds. The most pre-
ceptive facial differentiation techniques have been invented
in asymmetric epoxidation,[2] dihydroxylation,[3] aminohy-
droxylation[4] and hydrogenation.[5] While the stereochemis-
try issue in electrophile-promoted cyclization has mainly fo-
cused on diastereoselectivity utilizing preexisting stereogenic
centers in substrates,[6] enantioselective versions have
seldom been investigated. The latter examples cover seleno-
cyclization with chiral organoselenyl reagents,[7] mercurio-
cyclization with HgII carboxylates[8] and HgII–bisoxazoline
complexes,[9] iodocyclization with iodonium ion amine com-
plexes[10] and with N-iodosuccinimide in the presence of
[a] H. Y. Kwon, Dr. C. M. Park, Dr. S. B. Lee, Prof. Dr. S. H. Kang
Center for Molecular Design and Synthesis
Department of Chemistry, School of Molecular Science (BK21)
KAIST, Daejeon 305-701 (Korea)
Results and Discussion
Fax : (+82)42-869-2810
E-mail: shkang@kaist.ac.kr
The search for the new catalyst was initiated by scouting a
series of (R,R)-salen–metal complexes in the presence of
NCS in the iodocyclization of the model substrate 9. There-
by, 9 was cyclized using iodine in the presence of 10 mol%
of the catalysts 1–8 activated by 0.5 equivalent of NCS. As
disclosed in Table 1, the experimental data reveal that while
[b] Prof. Dr. J.-H. Youn
Department of Chemical Engineering, Sun Moon University
Asan Si, Chung-Nam 336-840 (Korea)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 1023 – 1028
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1. Iodocyclization of
9
using (R,R)-salen–M complexes 1–8
Table 2. Iodocyclization of 9 using (R,R)-salen–CrIIICl complex 3 with
(10 mol%) with NCS (0.5 equiv).
NCS and additive (0.5 equiv).
Entry
3 (mol%)
Additive
847(312
Yield [%][c]
ee [%]
1
2–
)
25
3
4
–
87 (10)
84
90 (6)
92(5)
90 (5)
88 (9)
87 (9)
89 (6)
7
–
–
–
–
86
86
84
87
84
88
10
15
7
7
7
5
6[d]
7[d]
8[d]
Cs2CO3
K2CO3 or
NaHCO3
K2CO3
Entry
A
Yield [%][c]
ee [%][d,e]
9[d,e]
7
96
83
1
2
3
4
5
6
7
1
2
3
4
5
6
7
8
3
63 (30)
70 (21)
89 (7)
89 (6)
49 (50)
87 (5)
38 (52)
60 (38)
93 (5)
0
[a] [9]=10 mm. [b] Used without drying. [c] Values in parentheses refer
to the recovery of starting material. [d] 0.7 equiv of NCS. [e] [9]=15 mm.
4 (2R,6R)
84 (2R,6R)
52(2 R,6R)
13 (2S,6S)
66 (2R,6R)
9 (2S,6S)
0
concentration had a deleterious effect on the stereoinduc-
tion (entry 9).
The established iodocyclization conditions (entry 8 in
Table 2) were applied to several g-hydroxy-cis-alkenes 11–
19. The results are summarized in Table 3. While most of
8
9[f]
86 (2R,6R)
[a] [9]=10 mm. [b] Distilled from Na before use. [c] Values in parenthe-
ses refer to the recovery of starting material. [d] Determined by HPLC
analysis using DAICEL OD-H. [e] Absolute configurations in parenthe-
ses. [f] PhMe was used without drying.
Table 3. Iodocyclization of 11–19 using (R,R)-salen–CrIIICl complex 3
(7 mol%) with NCS (0.7 equiv) and K2CO3 (0.5 equiv).
the AlIII, TiIV, FeIII, NiII and CuII complexes delivered poor
stereoselectivities (entries 1, 2, 5, 7 and 8), high% ee values
were acquired with the CrIII and CoII complexes (entries 3
and 6), and a moderate value with the MnIII complex
(entry 4). It turned out that (R,R)-salen–CrIIICl complex 3
realized the highest asymmetric induction as well as the
highest chemical conversion (entry 3). In addition, the cycli-
zation was found to proceed a little more rewardingly in wet
toluene than in dry solvent (entry 9). It is worthwhile men-
tioning that the major stereoisomer induced by the catalysts
5 and 7 is enantiomeric to that by the catalysts 2–4 and 6.
With the prospective catalyst 3 in hand, the iodocycliza-
tion conditions were optimized by adjusting the amounts of
3 and NCS, additives, and the concentration. The represen-
tative outcomes are outlined in Table 2. The quantity of the
chiral complex 3 was varied from 0.5 to 20 mol% in the
presence of 0.5 equivalent of NCS. The enantioselectivity in-
creased when amount of the catalyst was augmented (en-
tries 1–3), reaching the maximum level with 7 mol%
(entry 3), and slightly decreased with 15 mol% or more
(entry 5). The optimal NCS amount was calibrated to gain a
marginally increased 87% ee value with 0.7 equivalent con-
sistently (entry 6). Another improvement was endeavored
by addition of K2CO3 or NaHCO3 to result in essentially the
same stereoselectivity with a similar chemical yield, but a
little inferior enantioselectivity was observed with Cs2CO3
(entries 7 and 8). Further improvement was attempted by
concentration variation. However, while the enantioselectiv-
ity was marginally improved in more dilute solution, higher
Entry
Substrate
Product
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
9
9
(R)-10
20
21
22
23
24
25
26
27
89 (6)
43 (56)
94 (2)
94 (3)
93 (2)
92(4)
88 (86)
11
12
13
14
15
16
17
18
19
75 (61)[e,f]
85 (84)[g]
74 (67)[f,h]
88 (82)[f,h]
[h]
89 (85)
89 (73)
[h]
92(2)
90 (3)
90 (8)
90 (2)
87 (71)[h]
93 (90)[i]
91[f,j]
10
28
[a] Used without drying. [b] [substrate]=10 mm. [c] Values in parentheses
refer to the recovery of starting material. [d] Numbers in parentheses
refer to the% ee values in the iodocyclization using 30 mol% of (R,R)-
salen–CoII complex with 0.75 equiv of NCS and [substrate]=8 mm.
[e] Determined by HPLC analysis using DAICEL OD-H. [f] The abso-
lute configuration was not determined. [g] Determined by HPLC analysis
of reductively deiodinated product of 21 using DAICEL OD-H. [h] De-
termined by GC analysis using CHIRALDEX B-DM. [i] Determined by
HPLC analysis of detritylated product of 27 using DAICEL AD-H.
[j] Determined by HPLC analysis using DAICEL AD-H.
the substrates displayed high stereoselectivity (around 90%
ee), somewhat diminished% ee values were observed with
benzyl alkenol 11 and methyl alkenol 13 (entries 2and 4).
1024
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Chem. Eur. J. 2008, 14, 1023 – 1028

Asymmetric Iodocyclization
FULL PAPER
Even though it is difficult to propose a working model of
the asymmetric iodocyclization at present, probably the ster-
ically less demanding small methyl substituent might be at-
tributed to the lower enantioselectivity of 13. In the case of
11, the proximity of the phenyl group to the olefinic double
bond seemed to exert an adverse effect on the stereoselec-
tivity although the reason is unclear. All of the tested sub-
strates produced higher asymmetric induction with the com-
plex 3 than with the complex 6. The enantioselectivity incre-
ments range from 1 to 16%. It is manifest that the CrIII cata-
lyst system is more effective than CoII.
from pyrrolidinone 30, which would be conceivably derived
from intermediate 31 (Scheme 1). Our synthetic strategy for
Scheme 1. Retrosynthetic analysis of swainsonine 29.
Although enough experimental evidence has not been ac-
cumulated to explain the function of our developed catalytic
system in the asymmetric iodocyclization, it is envisioned
that NCS reacts with iodide anion to release ICl slowly,
which is complexed with the catalyst to activate ICl further.
Possibly, the slow generation of ICl is crucial to minimize
the background reaction, and the complex between ICl and
the catalyst exists as a zwitterion-like species such as [I+]-
the target molecule would culminate in preparation of 31
using our developed asymmetric iodocyclization, and the un-
precedented chemoselective oxidation of 31 to the corre-
sponding lactam or lactone depending on the N-protecting
group. The synthesis commenced with the iodocyclization of
the azido alkenol 32 to afford the azido tetrahydrofuran 33
with 90% ee in 86% yield along with 7% of recovered 32
(Scheme 2). The azido group of 33 was reduced with stan-
A
near the right nitrogen due to the left axial hydrogen at the
ring junction (Figure 1). Another conceivable NCS function
Figure 1. A plausible pathway of the iodocyclization.
Scheme 2. Synthesis of swainsonine 29. a) 3, NCS, I2, K2CO3, PhMe,
À788C, 86% (90% ee); b) SnCl2, PhSH, Et3N, MeCN, room tempera-
ture; c) NaOAc, EtOH, reflux; d) Boc2O, NaHCO3, H2O, MeOH, room
temperature, 80% (for steps b–d); e) p-NsCl, NaOH, H2O, EtOH, room
temperature, 64% (for steps b, c and e); f) RuCl3·3H2O, NaIO4, CCl4,
H2O, MeCN, room temperature, 65% for 37, 21% for 38, 65% for 39
(based on 15% of recovered 36); g) TMSI, BF3·OEt2, CH2Cl2, 08C; h)
TBSOTf, 2,6-lutidine, CH2Cl2, 08C; i) NaH, THF, 08C, 88% (for steps g–
i); j) LDA (3 equiv), PhSeBr (1equiv), THF, À788C, then 2,6-di-tert-
butyl-4-methylphenol, À788C, 74% (40/41 3:1); k) LiAlH4, AlCl3, THF,
À788C, 97%; l) NaIO4, NaHCO3, H2O, MeOH, 08C, 91%. NCS=N-
chlorosuccinimide, Boc=tert-butoxycarbonyl, p-Ns=p-nitrobenzenesul-
fonyl, TMS=trimethylsilyl, TBS=tert-butyldimethylsilyl, Tf=trifluoro-
methanesulfonyl, LDA=lithium diisopropylamide.
is oxidation of CrIII to higher oxidation state(s) to enhance
its Lewis acidity, which activates iodine itself to drive the io-
docycization to some extent. The conjecture can explain
why 0.7 equivalents of NCS is enough for the cyclization.
The skewed side-on approach model is suggested as the ra-
tionale of the iodocyclization enantioselectivity.[14] In the
model, the substrate approaches the complex through the
right trough between the cyclohexane and the aryl ring, and
its hydroxypropyl group stays away from the aryl ring due
to the steric congestion from the tert-butyl group in the tran-
sition state of the tetrahydrofuranyl ring formation. The ru-
dimentary scenario favors pathway A over pathway B to
procure the observed enantiomerically enriched tetrahydro-
furans.
nous chloride[16] and the resulting amino iodide was cyclized
under basic conditions. The crude bicyclic tetrahydrofuranyl
pyrrolidine 34 was protected to furnish carbamate 35 and
sulfonamide 36[17] in 80% and 64% overall yield from 33,
respectively. When 35 and 36 were subjected to the similar
oxidation conditions using ruthenium chloride in the pres-
The potential synthetic utility of the developed protocol
led us to pursue asymmetric synthesis of swainsonine 29.[15]
The indolizidine alkaloid was envisioned to be elaborated
Chem. Eur. J. 2008, 14, 1023 – 1028
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1025

S. H. Kang et al.
ence of NaIO4,[18] the former gave 65% of the pyrrolidinone
37 along with 21% of lactone 38, and the latter yielded
65% of lactone 39 based on 15% of recovered 36. Some of
the observed side products seemed to stem from the oxida-
tion of the tertiary carbons. Among the screened protecting
groups including p-toluenesulfonyl, benzyloxycarbonyl, tri-
fluoroacetyl and 2,2,2-trichloroethoxycarbonyl groups, tert-
butoxycarbonyl and p-nitrobenzenesulfonyl groups elicited
the best chemoselectivity.
For the synthesis of swainsonine 29, 37 was treated with
TMSI[19] in the presence of BF3–etherate to open the tetra-
hydrofuranyl ring (Scheme 2). The resultant hydroxyl iodide
was silylated, the carbamate group of which was concomi-
tantly deprotected, and then cyclized to render the requisite
indolizidinone 30 in 88% overall yield. To install the olefinic
double bond in the pyrrolidinone ring, 30 was phenylseleny-
lated using one equivalent of LDA to give rise to a 1:1 mix-
ture of the a-stereoisomer 40 and the b-stereoisomer 41.
Since later oxidative elimination of the phenylselenylated
derivative from 41 proceeded inefficiently, the phenylseleny-
lation was carried out using three equivalents of LDA and
one equivalent of PhSeBr followed by quenching with 2,6-
di-tert-butyl-4-methylphenol to provide a 3:1 mixture of 40
and 41 in 74% combined yield along with 21% of recovered
30. After separation, 40 was reduced to indolizidine with
alane generated in situ from LiAlH4 and AlCl3,[20] and oxi-
datively eliminated to produce the known indoline 42 in
88% overall yield, which was readily converted to swainso-
nine 29 via stereoselective dihydroxylation.[21]
ene employed in the iodocyclization was used directly from the stock
bottle (Junsei, EP grade) without purification, all other solvents were dis-
tilled from the indicated drying reagents right before use: Et2O and THF
(Na/benzophenone), CH2Cl2 (P2O5), MeCN (CaH2) and DMF (CaH2).
The normal work-up included extraction, drying over Na2SO4 and evapo-
ration of volatile materials in vacuo. Purifications by column chromatog-
raphy were performed using Merck silica gel 60 (230–400 mesh). Addi-
tional intermediates available in the Supporting Information.
Representative procedure for the asymmetric iodocyclization: To a mix-
ture of K2CO3 (66 mg, 0.48 mmol), NCS (90 mg, 0.66 mmol) and (R,R)-
salen–CrIIICl (42mg, 0.066 mmol) were added toluene (114 mL) and al-
cohol 32 (162mg, 0.96 mmol) dissolved in toluene (6 mL) at room tem-
perature. After cooling down the mixture to À788C, iodine (288 mg,
1.14 mmol) was added to it as solid in a portion. The resulting mixture
was stirred at À788C for 20 h and then quenched with 10% aqueous
Na2S2O5 (100 mL). Normal work-up with Et2O (3”30 mL) followed by
column chromatography (Et2O/hexane 1:5) gave azide 33 (243 mg, 86%)
along with the starting alcohol (15 mg, 9%). 33: 1H NMR (400 MHz,
CDCl3): d = 4.07–3.95 (m, 1H), 3.95–3.91 (m, 1H), 3.82–3.80 (m, 1H),
3.71–3.70 (m, 2H), 3.32–3.29 (t, 2H, J=5.6 Hz), 1.95–1.71 (m, 6H), 1.69–
1.57 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d = 82.2, 69.0, 50.6,
40.9, 33.5, 30.8, 29.3, 26.2 ppm; HRMS(EI): m/z: calcd for C8H14IN3O:
295.0182 [M]+, found: 295.0205.
(R)-2-((R)-1-Iodo-3-phenylpropyl)tetrahydrofuran
(10):
1H NMR
(400 MHz, CDCl3): d = 7.29–7.17 (m, 5H), 4.04–4.00 (m, 1H), 3.93 (td,
1H, J=8.2, 6.8 Hz), 3.82 (td, 1H, J=7.8, 5.8 Hz), 3.73 (td, 1H, J=7.2,
4.7 Hz), 3.01–2.95 (m, 1H), 2.74–2.67 (m, 1H), 2.20–2.13 (m, 1H), 2.05–
1.84 (m, 4H), 1.71–1.62ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d =
140.8, 128.6, 128.5, 126.1, 82.4, 69.0, 41.6, 37.9, 35.7, 30.9, 26.2 ppm;
HRMS (EI): m/z: calcd for C13H17IO: 316.0330 [M]+, found: 316.0358.
(R)-2-((R)-1-Iodo-2-phenylethyl)tetrahydrofuran
(20):
1H NMR
(400 MHz, CDCl3): d = 7.31–7.19 (5H, m), 4.32–4.28 (m, 1H), 4.02–3.98
(m, 1H), 3.84–3.80 (m, 1H), 3.55–3.49 (m, 1H), 3.37–3.31 (td, 1H, J=8.5,
6.4 Hz), 3.25–3.19 (td, 1H, J=8.9, 5.3 Hz), 2.04–1.57 ppm (m, 4H);
13C NMR (100 MHz, CDCl3): d = 139.8, 129.1, 128.4, 126.7, 80.4, 69.1,
43.6, 42.7, 31.7, 26.1 ppm; HRMS (EI): m/z: calcd for C12H15IO: 302.0168
[M]+, found: 302.0140.
Conclusion
(R)-2-((R)-1-Iodo-4-phenylbutyl)tetrahydrofuran
(21):
1H NMR
(400 MHz, CDCl3): d = 7.29–7.16 (m, 5H), 4.13–4.08 (m, 1H), 3.95 (td,
1H, J=8.2, 6.8 Hz), 3.81 (td, 1H, J=7.8, 5.7 Hz), 3.71 (td, 1H, J=7.1,
4.7 Hz), 2.71–2.56 (m, 2H), 2.05–1.89 (m, 5H), 1.79–1.64 ppm (m, 3H);
13C NMR (100 MHz, CDCl3): d = 141.8, 128.4, 128.3, 125.9, 82.4, 68.9,
42.1, 35.9, 35.0, 31.5, 30.9, 26.2 ppm; HRMS (EI): m/z: calcd for
C14H19IO: 330.0481 [M]+, found: 330.0421.
In conclusion, we have discovered a more efficient iodocyc-
lization of g-hydroxy-cis-alkenes using 7 mol% of salen–
CrIIICl complex rather than the previously reported
30 mol% of salen–CoII complex, in which significantly less
of the catalyst has been loaded and higher enantioselectivity
has been attained. Also, the synthetic value of the devel-
oped iodocylcization has been demonstrated in the synthesis
of an indolizidine alkaloid, swainsonine, in which another
distinctive process is considered as chemoselective oxidation
of 35 and 36.
(R)-2-((R)-1-Iodoethyl)tetrahydrofuran (22): 1H NMR (400 MHz,
CDCl3): d = 4.19–4.12(m, 1H), 3.93 (td, 1H, J=8.1, 6.9 Hz), 3.82(td,
1H, J=7.7, 5.8 Hz), 3.73–3.70 (m, 1H), 2.05–1.91 (m, 3H), 1.86 (d, 3H,
J=7 Hz), 1.65–1.60 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d
=
83.5, 68.9, 31.9, 30.2, 26.3, 24.1 ppm; HRMS (EI): m/z: calcd for
C6H11IO: 225.9855 [M]+, found: 225.9888.
(R)-2-((R)-1-Iodopropyl)tetrahydrofuran (23): 1H NMR (400 MHz,
CDCl3): d = 4.03–3.98 (m, 1H), 3.92(td, 1H, J=8.2, 6.8 Hz), 3.79 (td,
1H, J=7.8, 5.7 Hz), 3.74 (td, 1H, J=7.2, 4.9 Hz), 2.07–1.62 (m, 6H),
1.04 ppm (t, 3H, J=7.3 Hz); 13C NMR (100 MHz, CDCl3): d
= 82.3,
Experimental Section
68.8, 44.7, 30.7, 29.7, 26.2, 14.6 ppm; HRMS (EI): m/z: calcd for
C7H13IO: 240.0011 [M]+, found: 240.0003.
General methods: NMR spectra were obtained on Bruker Avance 400
spectrometer (400 MHz for 1H NMR, 100 MHz for 13C NMR) and mea-
sured in CDCl3. Chemical shifts were recorded in ppm relative to internal
standard CDCl3, and coupling constants were reported in Hz. The high
resolution mass spectra were recorded on VG Autospec Ultima spec-
trometer. The enantioselectivities were determined by HPLC or GC
analysis. HPLC measurements were done on a RAININ model equipped
with SD-200 pump, DVW-100 detector (D-Star Instruments) measured at
254 nm, and chiral column such as DAICEL OD-H and DAICEL AD-H.
Eluting solvent was a mixture of 2-propanol and hexane. GC was mea-
sured on Donam DS-6200 GC with Chiraldex B-DM. All reactions were
carried out in oven-dried glassware under a N2 atmosphere. While tolu-
(R)-2-((R)-1-Iodobutyl)tetrahydrofuran (24): 1H NMR (400 MHz,
CDCl3): d = 4.09–4.06 (m, 1H), 3.92(td, 1H, J=8.2, 6.8 Hz), 3.79 (td,
1H, J=7.8, 5.7 Hz), 3.71 (td, 1H, J=7.2, 4.8 Hz), 2.03–1.79 (m, 4H),
1.71–1.54 (m, 3H), 1.43–1.33 (m, 1H), 0.90 ppm (t, 3H, J=7.2Hz);
13C NMR (100 MHz, CDCl3): d = 82.4, 68.9, 42.2, 38.3, 30.8, 26.2, 23.0,
13.2ppm; HRMS (EI): m/z: calcd for C8H15IO: 254.0168 [M]+, found:
254.0158.
(R)-2-((R)-1-Iodo-2-methylpropyl)tetrahydrofuran
(25):
1H NMR
(400 MHz, CDCl3): d = 4.08–4.04 (m, 1H), 3.90 (td, 1H, J=8.2, 6.9 Hz),
3.79–3.68 (m, 2H), 2.03–1.85 (m, 3H), 1.61–1.52 (m, 1H), 1.30–1.23 (m,
1H), 0.97 ppm (dd, 6H, J=13.7, 6.5 Hz); 13C NMR (100 MHz, CDCl3): d
1026
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Chem. Eur. J. 2008, 14, 1023 – 1028

Asymmetric Iodocyclization
FULL PAPER
= 81.7, 67.9, 54.8, 32.8, 31.6, 26.1, 23.8, 20.9 ppm; HRMS (EI): m/z: calcd
for C8H15IO: 254.0168 [M]+, found: 254.0143.
1H), 1.49 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d = 174.8, 150.2,
82.8, 79.7, 68.7, 60.4, 32.5, 28.3, 28.1, 25.9, 18.7 ppm; HRMS (EI): m/z:
calcd for C13H21NO4: 255.1471 [M]+, found: 255.1454.
(R)-2-((R)-1-Iodo-3-methylbutyl)tetrahydrofuran
(26):
1H NMR
(400 MHz, CDCl3): d = 4.13–4.06 (m, 1H), 3.94–3.92(m, 1H), 3.82–3.79
(q, 1H, J=5.8 Hz), 3.67–3.66 (m, 1H), 2.02–2.00 (m, 2H), 1.93–1.86 (m,
3H), 1.70–1.65 (m, 1H), 1.33–1.31 (m, 1H), 0.95–0.93 (d, 3H, J=6.5 Hz),
0.84–0.82pppm (d, 3H, J=6.6 Hz); 13C NMR (100 MHz, CDCl3): d =
82.5, 68.9, 45.1, 41.2, 31.1, 28.1, 26.2, 23.1, 20.6 ppm; HRMS (EI): m/z:
calcd for C9H17IO: 268.0324 [M]+, found: 268.0298.
(R)-5-((S)-1-(4-Nitrophenylsulfonyl)pyrrolidin-2-yl)dihydrofuran-2(3H)-
one (39): To 36 (300 mg, 0.93 mmol) dissolved in a mixture of CCl4
(18 mL), MeCN (18 mL) and H2O (27 mL) were added NaIO4 (1.59 g,
7.44 mmol) and RuCl3·3H2O (4 mg, 0.018 mmol). After one day at room
temperature, normal work-up with CH2Cl2 (3”10 mL) followed by chro-
matographic purification (EtOAc/hexane 1:1) provided lactone 39
(207 mg, 65%) along with 15% of the recovered 36 (45 mg). 1H NMR
(400 MHz, CDCl3): d = 8.35 (dd, 2H, J=6.9, 1.8 Hz), 8.00 (dd, 2H, J=
6.9, 1.9 Hz), 4.67–4.65 (m, 1H), 3.85–3.83 (m, 1H), 3.42–3.39 (m, 1H),
3.24–3.21 (m, 1H), 2.58–2.53 (m, 2H), 2.38–2.33 (m, 1H), 2.16–2.14 (m,
1H), 1.91–1.87 (m, 2H), 1.61–1.57 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d = 176.4, 150.2, 143.4, 128.6, 124.5, 81.1, 62.7, 49.2, 28.4, 26.5,
24.9, 24.2 ppm; HRMS (EI): m/z: calcd for C14H16N2O6S: 340.0729 [M]+,
found: 340.0747.
(R)-2-((R)-1-Iodo-4-(trityloxy)butyl)tetrahydrofuran
(27):
1H NMR
(400 MHz, CDCl3): d = 7.45–7.43 (m, 6H), 7.32–7.23 (m, 9H), 4.08–4.03
(m, 1H), 3.95 (td, 1H, J=8.1, 6.8 Hz), 3.82(td, 1H, J=7.8, 5.8 Hz), 3.71
(td, 1H, J=7.1, 4.8 Hz), 3.16–3.06 (m, 2H), 2.08–1.88 (m, 6H), 1.77–
1.63 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d = 144.2, 128.6, 127.7,
126.8, 86.4, 82.3, 68.8, 62.5, 42.4, 33.4, 30.9, 30.2, 26.2 ppm; HRMS (EI):
m/z: calcd for C27H29IO2: 512.1212 [M]+, found: 512.1197.
(R)-2-((R)-5-Azido-1-iodopentyl)tetrahydrofuran
(28):
1H NMR
A
(400 MHz, CDCl3): d = 5.37–5.33 (m, 2H), 3.61–3.58 (t, 2H, J=6.5 Hz),
3.24–3.22 (t, 2H, J=6.9 Hz), 2.10–2.01 (m, 4H), 1.62–1.53 (m, 4H), 1.43–
1.38 pppm (m, 2H); 13C NMR (100 MHz, CDCl3): d = 129.7, 129.6, 62.4,
51.3, 32.5, 28.3, 26.6, 26.5, 23.5 ppm; HRMS (EI): m/z: calcd for
C9H16IN3O: 309.0338 [M]+, found: 309.0372.
(30): TMSI (0.48 mL, 3.38 mmol) and BF3·OEt2 (0.18 mL, 1.69 mmol)
were injected to 37 (505 mg, 1.69 mmol) in CH2Cl2 (4 mL) in an ice bath.
After removal of the bath, the mixture was stirred at room temperature
for 3 h and then quenched with saturated aqueous NH4Cl (5 mL).
Normal work-up with EtOAc (3”5 mL) yielded the crude iodo alcohol.
To the crude alcohol in CH2Cl2 (4 mL) were added TBSCl (509 mg,
3.38 mmol) and 2,6-lutidine (0.39 mL, 3.38 mmol) cooled in an ice bath.
The reaction mixture was stirred at room temperature for 2h, quenched
with saturated aqueous NH4Cl (5 mL) and worked up with EtOAc (3”
4 mL) to supply the crude iodo silyl ether. After addition of NaH
(135 mg, 60% oil dispersion, 3.38 mmol) to the crude silyl ether in an ice
bath, the mixture was stirred in the bath for 30 min and quenched with
saturated aqueous NH4Cl (3 mL). Normal work-up with EtOAc (3”
3 mL) and the subsequent chromatographic purification produced indoli-
(S)-tert-Butyl 2-((R)-tetrahydrofuran-2-yl)pyrrolidine-1-carboxylate (35)
and (S)-1-(4-nitrophenylsulfonyl)-2-((R)-tetrahydrofuran-2-yl)pyrrolidine
(36): To a mixture of SnCl2 (413 mg, 2.18 mmol) and PhSH (0.9 mL,
8.72mmol) in acetonitrile (3 mL) was added Et 3N (0.91 mL, 6.54 mmol)
in an ice bath dropwise. Subsequently, azide 33 (429 mg, 1.45 mmol) was
injected to the resulting solution in the ice bath dropwise over 10 min.
After stirring the mixture at room temperature for 30 min, the volatile
materials were evaporated in vacuo and the residue was dissolved in 2m
aqueous NaOH (5 mL). Normal work-up with CH2Cl2 (3”5 mL) yielded
the crude iodo amine. All the crude amine was heated at reflux with
NaOAc·hydrate (1.37 g) in EtOH (5 mL) for one day. EtOH was evapo-
rated in vacuo and the residue was filtered through celite (500 mg) with
CH2Cl2 (15 mL). Removal of the volatile materials under reduced pres-
sure gave the cyclized product 34. After dissolving the crude pyrrolidine
34 in MeOH (5 mL), Boc2O (381 mg, 1.74 mmol) and saturated aqueous
NaHCO3 (2mL) were added and the resulting solution was stirred at
room temperature for 5 h. The following normal work-up with EtOAc
(3”5 mL) and chromatographic purification (EtOAc/hexane 1:4) afford-
ed the Boc-protected pyrrolidine 35 (280 mg, 80%). 1H NMR (400 MHz,
CDCl3): d = 3.90–3.88 (m, 1H), 3.77–3.72(m, 2H), 3.64–3.62(m, 1H),
3.32–3.30 (m, 1H), 3.25–3.22 (m, 1H), 1.87–1.80 (m, 4H), 1.76–1.53 (m,
4H), 1.37 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d = 154.8, 80.1,
78.9, 68.2, 60.2, 46.6, 28.9, 28.4, 26.3, 25.64, 23.6 ppm; HRMS (EI): m/z:
calcd for C13H23NO3: 241.1678 [M]+, found: 241.1702.
1
zidinone 30 (401 mg, 88% overall yield). H NMR (400 MHz, CDCl3): d =
4.02–3.98 (m, 1H), 3.18–3.14 (m, 2H), 2.53–2.47 (m, 1H), 2.36–2.34
(m, 2H), 2.25–2.23 (m, 1H), 2.02–1.97 (m, 1H), 1.72–1.68 (m, 2H), 1.40–
1.35 (m, 2H), 0.86 (s, 9H), 0.04 ppm (s, 6H); 13C NMR (100 MHz,
CDCl3): d = 173.9, 74.3, 62.9, 39.3, 33.8, 30.2, 25.6, 23.2, 22.9, 17.9, À4.0,
À4.7 ppm; HRMS (EI) calcd for C14H27NO2Si: m/z: 269.1811 [M]+,
found: 269.1817.
(2S,8R,8aS)-8-(tert-Butyldimethylsilyloxy)-2-(phenylselanyl)hexahydroin-
dolizin-3(5H)-one (40): LDA solution was freshly prepared by dropwise
addition of nBuLi (2.5m in THF, 1.79 mL, 4.47 mmol) to diisopropyla-
mine (0.63 mL, 4.47 mmol) in THF (3 mL) at À788C. To the LDA solu-
tion was injected 30 (401 mg, 1.49 mmol) dissolved in THF (2mL) at
À788C. After 1 h, PhSeBr (351 mg, 1.49 mmol) in THF (1 mL) was
added and stirred at that temperature for another one hour. Then, the
mixture was quenched with 2,6-di-tert-butyl-4-methylphenol (1.5 g,
6.8 mmol) and stirred at À788C for 10 min. After addition of saturated
aqueous NH4Cl (10 mL), normal work-up with EtOAc (3”5 mL) fol-
lowed by column chromatography (EtOAc/hexane 1:3) afforded the a-
phenylselenyl indolizidinone 40 (354 mg, 56%) and the b-phenylselenyl
indolizidinone 41 (115 mg, 18%) along with 30 (84 mg, 21%). 1H NMR
(400 MHz, CDCl3): d = 3.97–3.93 (dd, 1H, J=8.5, 4.6 Hz), 3.81–3.78
(dd, 1H, J=6.2, 2.6 Hz), 3.06–3.03 (m, 1H), 2.66–2.60 (m, 1H), 2.36–2.38
(m, 1H), 2.26–2.20 (m, 2H), 1.88–1.82 (m, 1H), 1.66–1.60 (m, 1H), 1.26–
1.20 (m, 1H), 0.83 (s, 9H), 0.00 ppm (s, 6H); 13C NMR (100 MHz,
CDCl3): d = 171.7, 135.9, 129.1, 128.4, 127.6, 73.9, 61.3, 40.6, 39.9, 33.7,
31.3, 25.6, 23.1, 17.8, À4.0, À4.6 ppm; HRMS (EI): m/z: calcd for
C20H31NO2SeSi: 425.1289 [M]+, found: 425.1265.
The crude pyrrolidine 34 obtained from 33 (429 mg, 1.45 mmol) was
stirred with p-NsCl (384 mg, 1.74 mmol) in a mixture of 1m aqueous
NaOH (3 mL) and Et2O (3 mL) at room temperature for a day. Normal
work-up with EtOAc (3”3 mL) and chromatographic separation
(EtOAc/hexane 1:4) furnished the nosyl-protected pyrrolidine 36
(300 mg, 64%). 1H NMR (400 MHz, CDCl3): d = 8.35–8.32(d, 2H, J=
7.0 Hz), 8.02–7.99 (d, 2H, J=7.9 Hz), 4.01–3.98 (ddd, 1H, J=1.4, 1.0,
5.1 Hz), 3.83–3.78 (m, 2H), 3.74–3.71 (m, 1H), 3.40–3.36 (m, 1H), 3.28–
3.26 (m, 1H), 2.00–1.95 (m, 1H), 1.91–1.86 (m, 4H), 1.75–1.71 (m, 1H),
1.57–1.47 (m, 1H), 1.25–1.19 ppm (m, 1H); 13C NMR (100 MHz, CDCl3):
d
= 149.9, 144.5, 128.6, 124.2, 80.4, 68.6, 63.5, 49.2, 28.8, 26.7, 25.7,
24.4 ppm; HRMS (EI): m/z: calcd for C14H18N2O5S: 326.0936 [M]+,
found: 326.0942.
A
(S)-tert-Butyl 2-oxo-5-((R)-tetrahydrofuran-2-yl)pyrrolidine-1-carboxyl-
ate (37): 35 (280 mg, 1.16 mmol) was dissolved in a mixture of CCl4
(20 mL), MeCN (20 mL) and H2O (30 mL), and NaIO4 (1.98 g,
9.28 mmol) and RuCl3·3H2O (5 mg, 0.023 mmol) were added. After 12 h
at room temperature, normal work-up with CH2Cl2 (3”10 mL) and chro-
matographic separation (EtOAc/hexane 1:1) gave rise to lactam 37
(192mg, 65%) and lactone 38 (62mg, 21%). 1H NMR (400 MHz,
CDCl3): d = 4.17–4.12(m, 2H), 3.80–3.78 (m, 1H), 3.71–3.69 (m, 1H),
2.68–2.62 (m, 1H), 2.37–2.32 (m, 1H), 1.97–1.86 (m, 5H), 1.57–1.53 (m,
(42): Alane was freshly prepared by dropwise addition of LiAlH4 (1.0m
in THF, 3 mL, 3.0 mmol) to AlCl3 (134 mg, 1.0 mmol) in THF (3 mL) at
08C. To 40 (200 mg, 0.47 mmol) dissolved in THF (2 mL) was injected
the alane solution (5.7 mL, 0.94 mmol) dropwise at À788C. The mixture
was stirred for 1 h, and then quenched with H2O (0.11 mL), 15% aque-
ous NaOH (0.11 mL) and H2O (0.33 mL) in sequence at that tempera-
ture. After 5 min, EtOAc (5 mL) and celite (1 g) were added at room
temperature. The resulting mixture was stirred for 2h and filtered
Chem. Eur. J. 2008, 14, 1023 – 1028
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www.chemeurj.org
1027

S. H. Kang et al.
through celite (1 g) with EtOAc (15 mL). Evaporation of the volatile ma-
terials in vacuo followed by chromatographic purification (EtOAc/
hexane 1:10) furnished the corresponding indolizidine (187 mg, 97%).
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To the indolizidine (187 mg, 0.46 mmol) dissolved in a 10:1 mixture of
MeOH and H2O (5.5 mL) were added NaIO4 (197 mg, 0.92mmol) and
NaHCO3 (20 mg, 0.24 mmol) in an ice bath, and the mixture was reacted
in the bath for 30 min. After addition of saturated aqueous NH4Cl
(5 mL), normal work-up with EtOAc (3”5 mL) and the subsequent chro-
matographic separation (EtOAc/hexane 1:1) gave 42 (106 mg, 91%).
1H NMR (400 MHz, CDCl3): d = 6.04–6.03 (brd, 1H, J=5.2Hz), 5.88–
5.85 (dddd, 1H, J=2.0, 2.0, 2.0, 1.8 Hz), 3.64–3.60 (dddd, 1H, J=12.5,
4.2, 1.7, 1.6 Hz), 3.44–3.41 (ddd, 1H, J=10.3, 9.4, 4.3 Hz), 3.24–3.20 (m,
1H), 2. 91–2.88 (brd, 1H, J=10.8 Hz), 2.84 (brs, 1H), 2.40–2.32 (m, 1H),
1.91–1.65 (m, 1H), 1.65–1.60 (m, 2H), 1.26–1.21 (m, 1H), 0.87 (s, 9H),
0.04 (s, 3H), 0.03 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d = 131.6,
128.6, 74.1, 72.0, 57.9, 48.9, 34.4, 25.8, 24.5, 18.1, À4.2, À4.7 ppm; HRMS
(EI): m/z: calcd for C14H27NOSi: 253.1862 [M]+, found: 253.1887.
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Acknowledgement
This work was supported by Korea Research Foundation Grant (KRF-
2005-070-C00073).
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Received: August 1, 2007
Published online: October 30, 2007
1028
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Chem. Eur. J. 2008, 14, 1023 – 1028